PMID- 30425481 TI - pH-sensitive PEGylation of RIPL peptide-conjugated nanostructured lipid carriers: design and in vitro evaluation. AB - Background: RIPL peptide (IPLVVPLRRRRRRRRC)-conjugated nanostructured lipid carriers (RIPL-NLCs) can facilitate selective drug delivery to hepsin (Hpn) expressing cancer cells, but they exhibit low stability in the blood. Generally, biocompatible and nontoxic poly(ethylene glycol) surface modification (PEGylation) can enhance NLC stability, although this may impair drug delivery and NLC clearance. To attain RIPL-NLC steric stabilization without impairing function, pH-sensitive cleavable PEG (cPEG) was grafted onto RIPL-NLCs (cPEG-RIPL NLCs). Methods: Various types of NLC formulations including RIPL-NLCs, PEG-RIPL NLCs, and cPEG-RIPL-NLCs were prepared using the solvent emulsification evaporation method and characterized for particle size, zeta potential (ZP), and cytotoxicity. The steric stabilization effect was evaluated by plasma protein adsorption and phagocytosis inhibition studies. pH-sensitive cleavage was investigated using the dialysis method under different pH conditions. Employing a fluorescent probe (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate [DiI]), in vitro drug delivery capacity of the cPEG-RIPL-NLCs under different pH conditions was also performed on Hpn-expressing SKOV3 cells and 3D tumor spheroids. Results: All prepared NLCs showed homogenous dispersion (<220 nm in size) with a negative ZP (-18 to -22 mV), except for positively charged RIPL NLCs (~10 mV), revealing no significant cytotoxicity in either SKOV3 or RAW 264.7 cell lines. cPEG-RIPL-NLC protein adsorption was 1.75-fold less than that of RIPL NLCs, and PEGylation significantly reduced the macrophage uptake. PEG detachment from the cPEG-RIPL-NLCs was pH-sensitive and time dependent. At 2 hours incubation, cPEG-RIPL-NLCs and PEG-RIPL-NLCs exhibited comparable cellular uptake at pH 7.4, whereas cPEG-RIPL-NLC uptake was increased over 2-fold at pH 6.5. 3D spheroid penetration also demonstrated pH-sensitivity: at pH 7.4, cPEG-RIPL-NLCs could not penetrate deep into the spheroid core region during 2 hours, whereas at pH 6.5, high fluorescence intensity in the core region was observed for both cPEG RIPL-NLC-and RIPL-NLC-treated groups. Conclusion: cPEG-RIPL-NLCs are good candidates for Hpn-selective drug targeting in conjunction with pH-responsive PEG cleavage. PMID- 30425482 TI - From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer. AB - Purpose: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Materials and methods: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. Results: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB 453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. Conclusion: We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies. PMID- 30425483 TI - Magnetic resonance sentinel lymph node imaging and magnetometer-guided intraoperative detection in prostate cancer using superparamagnetic iron oxide nanoparticles. AB - Purpose: Sentinel lymph node (LN) dissection (sLND) using a magnetometer and superpara-magnetic iron oxide nanoparticles (SPION) as a tracer was successfully applied in prostate cancer (PCa). The feasibility of sentinel LN (SLN) visualization on MRI after intraprostatic SPION injection has been reported. In the present study, results of preoperative MRI identification of SLNs and the outcome of subsequent intraoperative magnetometer-guided sLND following intraprostatic SPION injection were studied in intermediate- and high-risk PCa. Patients and methods: A total of 50 intermediate- and high-risk PCa patients (prostate-specific antigen >10 ng/mL and/or Gleason score >=7) scheduled for radical prostatectomy with magnetometer-guided sLND and extended pelvic LND (eLND), were included. Patients underwent MRI before and one day after intraprostatic SPION injection using T1-, T2-, and T2*-weighted sequences. Diagnostic rate per patient was established. Distribution of SLNs per anatomic region was registered. Diagnostic accuracy of sLND was assessed by using eLND as a reference standard. Results: SPION-MRI identified a total of 890 SLNs (median 17.5; IQR 12-22.5). SLNs could be successfully detected using MRI in all patients (diagnostic rate 100%). Anatomic SLN distribution: external iliac 19.2%, common iliac 16.6%, fossa obturatoria 15.8%, internal iliac 13.8%, presacral 12.1%, perirectal 12.0%, periprostatic 3.7%, perivesical 2.3%, and other regions 4.4%. LN metastases were intraoperatively found in 15 of 50 patients (30%). sLND had a 100% diagnostic rate, 85.7% sensitivity, 97.2% specificity, 92.3% positive predictive value, 94.9% negative predictive value, false negative rate 14.3%, and 2.8% additional diagnostic value (LN metastases only outside the eLND template). Conclusion: MR scintigraphy after intraprostatic SPION injection provides a roadmap for intraoperative magnetometer-guided SLN detection and can be useful to characterize a reliable lymphadenectomy template. Draining LN from the prostate can be identified in an unexpectedly high number, especially outside the established eLND template. Further studies are required to analyze discordance between the number of pre- and intraoperatively identified SLNs. PMID- 30425484 TI - Liposomal nanoparticle-based conserved peptide influenza vaccine and monosodium urate crystal adjuvant elicit protective immune response in pigs. AB - Background: Influenza (flu) is a constant threat to humans and animals, and vaccination is one of the most effective ways to mitigate the disease. Due to incomplete protection induced by current flu vaccines, development of novel flu vaccine candidates is warranted to achieve greater efficacy against constantly evolving flu viruses. Methods: In the present study, we used liposome nanoparticle (<200 nm diameter)-based subunit flu vaccine containing ten encapsulated highly conserved B and T cell epitope peptides to induce protective immune response against a zoonotic swine influenza A virus (SwIAV) H1N1 challenge infection in a pig model. Furthermore, we used monosodium urate (MSU) crystals as an adjuvant and co-administered the vaccine formulation as an intranasal mist to flu-free nursery pigs, twice at 3-week intervals. Results: Liposome peptides flu vaccine delivered with MSU adjuvant improved the hemagglutination inhibition antibody titer and mucosal IgA response against the SwIAV challenge and also against two other highly genetically variant IAVs. Liposomal vaccines also enhanced the frequency of peptides and virus-specific T-helper/memory cells and IFN-gamma response. The improved specific cellular and mucosal humoral immune responses in adjuvanted liposomal peptides flu vaccine partially protected pigs from flu-induced fever and pneumonic lesions, and reduced the nasal virus shedding and viral load in the lungs. Conclusion: Overall, our study shows great promise for using liposome and MSU adjuvant- based subunit flu vaccine through the intranasal route, and provides scope for future, pre-clinical investigations in a pig model for developing potent human intranasal subunit flu vaccines. PMID- 30425485 TI - Amino acid composition of nanofibrillar self-assembling peptide hydrogels affects responses of periodontal tissue cells in vitro. AB - Background: The regeneration of tissue defects at the interface between soft and hard tissue, eg, in the periodontium, poses a challenge due to the divergent tissue requirements. A class of biomaterials that may support the regeneration at the soft-to-hard tissue interface are self-assembling peptides (SAPs), as their physicochemical and mechanical properties can be rationally designed to meet tissue requirements. Materials and methods: In this work, we investigated the effect of two single-component and two complementary beta-sheet forming SAP systems on their hydrogel properties such as nanofibrillar architecture, surface charge, and protein adsorption as well as their influence on cell adhesion, morphology, growth, and differentiation. Results: We showed that these four 11 amino acid SAP (P11-SAP) hydrogels possessed physico-chemical characteristics dependent on their amino acid composition that allowed variabilities in nanofibrillar network architecture, surface charge, and protein adsorption (eg, the single-component systems demonstrated an ~30% higher porosity and an almost 2 fold higher protein adsorption compared with the complementary systems). Cytocompatibility studies revealed similar results for cells cultured on the four P11-SAP hydrogels compared with cells on standard cell culture surfaces. The single-component P11-SAP systems showed a 1.7-fold increase in cell adhesion and cellular growth compared with the complementary P11-SAP systems. Moreover, significantly enhanced osteogenic differentiation of human calvarial osteoblasts was detected for the single-component P11-SAP system hydrogels compared with standard cell cultures. Conclusion: Thus, single-component system P11-SAP hydrogels can be assessed as suitable scaffolds for periodontal regeneration therapy, as they provide adjustable, extracellular matrix-mimetic nanofibrillar architecture and favorable cellular interaction with periodontal cells. PMID- 30425486 TI - Immunotoxicity of titanium dioxide nanoparticles via simultaneous induction of apoptosis and multiple toll-like receptors signaling through ROS-dependent SAPK/JNK and p38 MAPK activation. AB - Background: Titanium dioxide nanoparticles (TiO2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO2 NPs with components of innate immune system remains elusive. Aim: This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling. Materials and methods: In this study, chemically synthesized BSA-functionalized TiO2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells. Results: We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Deltapsim) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control. Conclusion: Collectively, this study shows that the molecular nature of TiO2 SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO2 SA20(-) NP-induced immunotoxicity. PMID- 30425487 TI - Loading icariin on titanium surfaces by phase-transited lysozyme priming and layer-by-layer self-assembly of hyaluronic acid/chitosan to improve surface osteogenesis ability. AB - Purpose: Icariin (ICA) is one of the main active constituents of Herba Epimedii for improving osteogenesis. It is necessary to create a simple and efficient method to load ICA onto the surface of titanium (Ti) implant. The purpose of this study was to establish a local ICA delivery system via a layer-by-layer (LbL) self-assembly system on phase-transited lysozyme (PTL)-primed Ti surface. Materials and methods: A PTL nanofilm was first firmly coated on the pristine Ti. Then, the ICA-loaded hyaluronic acid/chitosan (HA/CS) multilayer was applied via the LbL system to form the HA/CS-ICA surface. This established HA/CS-ICA surface was characterized by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and contact angle measurement. The ICA release pattern of the HA/CS-ICA surface was also examined. MC3T3-E1 osteoblast culture test and a rat model were used to evaluate the effects of the HA/CS-ICA surface in vitro and in vivo. Results: SEM, XPS and contact angle measurement demonstrated successful fabrication of the HA/CS-ICA surface. The HA/CS-ICA surfaces with different ICA concentrations revealed a controlled release profile of ICA during a 2-week monitoring span. Osteoblasts grown on the coated substrates displayed higher adhesion, viability, proliferation and ALP activity than those on the polished Ti surface. Furthermore, in vivo histological evaluation revealed much obvious bone formation in the ICA-coated group by histological staining and double fluorescent labeling at 2 weeks after implantation. Conclusion: The present study demonstrated that ICA-immobilized HA/CS multilayer on the PTL-primed Ti surface had a sustained release pattern of ICA which could promote the osteogenesis of osteoblasts in vitro and improve early osseointegration in vivo. This study provides a novel method for creating a sustained ICA delivery system to improve osteoblast response and osseointegration. PMID- 30425488 TI - Decreased Porphyromonas gingivalis adhesion and improved biocompatibility on tetracycline-loaded TiO2 nanotubes: an in vitro study. AB - Background: Titanium dioxide (TiO2) nanotubes are often used as carriers for loading materials such as drugs, proteins, and growth factors. Materials and methods: In this study, we loaded tetracycline onto TiO2 nanotubes to demonstrate its antibacterial properties and biocompatibility. The two-layered anodic TiO2 nanotubes with a honeycomb-like porous structure were fabricated by using a two step anodization, and they were loaded with tetracycline by using a simplified lyophilization method and vacuum drying. Their physical properties, such as chemical compositions, wettability, and surface morphologies of the different samples, were observed and measured by X-ray photoelectron spectroscopy (XPS), contact angle measurement, and scanning electron microscopy (SEM). The in vitro growth behaviors of mouse bone marrow stromal cells (BMSCs) on these substrates were investigated. Results: The TiO2 nanotube (NT) substrates and the tetracycline-loaded TiO2 nanotube (NT-T) substrates revealed a crucial potential for promoting the adhesion, proliferation, and differentiation of BMSCs. Similarly, the NT-T substrates displayed a sudden release of tetracycline in the first 15 minutes of their administration, and the release tended to be stable 90 minutes later. The antibacterial performances of the prepared substrates were assessed with Porphyromonas gingivalis. The result showed that NT and NT-T substrates had antibacterial capacities. Conclusion: Overall, this research provides a promising method with potential for clinical translation by allowing local slow release of antimicrobial compounds by loading them onto constructed nanotubes. PMID- 30425489 TI - The therapeutic effect in gliomas of nanobubbles carrying siRNA combined with ultrasound-targeted destruction. AB - Background: Nanobubbles (NBs) combined with ultrasound-targeted destruction (UTD) have become promising potential carriers for drug or siRNA delivery. Due to their nano-size, NBs could penetrate tumor blood vessels and accumulate in intercellular spaces so that "sonoporation" induced by UTD would act directly on the tumor cells to increase cell membrane permeability. Methods: Based on the successful the fabrication of NBs, we synthesized NBs carrying siRNA (NBs-siRNA) by using a biotin-streptavidin system. We then utilized ultrasound irradiation (UI)-targeted NBs-siRNA to improve siRNA transfection and achieve the inhibition of glioma growth. Results: NBs as carriers combined with UI effectively enhanced siRNA transfection and the effect of silencing targeted genes in vitro. Additionally, a better therapeutic effect was shown in the NBs-siRNA with UI group in vivo compared with that of microbubbles (MBs) with UI or NBs-siRNA without UI. Conclusion: These results indicated that NBs combined with UTD might be an ideal delivery vector for siRNA to achieve the noninvasive treatment of glioma. PMID- 30425490 TI - Oridonin-loaded and GPC1-targeted gold nanoparticles for multimodal imaging and therapy in pancreatic cancer. AB - Purpose: Early diagnosis and therapy are critical to improve the prognosis of patients with pancreatic cancer. However, conventional imaging does not significantly increase the capability to detect early stage disease. In this study, we developed a multifunctional theranostic nanoplatform for accurate diagnosis and effective treatment of pancreatic cancer. Methods: We developed a theranostic nanoparticle (NP) based on gold nanocages (AuNCs) modified with hyaluronic acid (HA) and conjugated with anti-Glypican-1 (anti-GPC1) antibody, oridonin (ORI), gadolinium (Gd), and Cy7 dye. We assessed the characteristics of GPC1-Gd-ORI@HAuNCs-Cy7 NPs (ORI-GPC1-NPs) including morphology, hydrodynamic size, stability, and surface chemicals. We measured the drug loading and release efficiency in vitro. Near-infrared fluorescence (NIRF)/magnetic resonance imaging (MRI) and therapeutic capabilities were tested in vitro and in vivo. Results: ORI GPC1-NPs demonstrated long-time stability and fluorescent/MRI properties. Bio transmission electron microscopy (bio-TEM) imaging showed that ORI-GPC1-NPs were endocytosed into PANC-1 and BXPC-3 (overexpression GPC1) but not in 293 T cells (GPC1- negative). Compared with ORI and ORI-NPs, ORI-GPC1-NPs significantly inhibited the viability and enhanced the apoptosis of pancreatic cancer cells in vitro. Moreover, blood tests suggested that ORI-GPC1-NPs showed negligible toxicity. In vivo studies showed that ORI-GPC1-NPs enabled multimodal imaging and targeted therapy in pancreatic tumor xenografted mice. Conclusion: ORI-GPC1-NP is a promising theranostic platform for the simultaneous diagnosis and effective treatment of pancreatic cancer. PMID- 30425491 TI - Neuronal connectivity in major depressive disorder: a systematic review. AB - Background: The causes of major depressive disorder (MDD), as one of the most common psychiatric disorders, still remain unclear. Neuroimaging has substantially contributed to understanding the putative neuronal mechanisms underlying depressed mood and motivational as well as cognitive impairments in depressed individuals. In particular, analyses addressing changes in interregional connectivity seem to be a promising approach to capture the effects of MDD at a systems level. However, a plethora of different, sometimes contradicting results have been published so far, making general conclusions difficult. Here we provide a systematic overview about connectivity studies published in the field over the last decade considering different methodological as well as clinical issues. Methods: A systematic review was conducted extracting neuronal connectivity results from studies published between 2002 and 2015. The findings were summarized in tables and were graphically visualized. Results: The review supports and summarizes the notion of an altered frontolimbic mood regulation circuitry in MDD patients, but also stresses the heterogeneity of the findings. The brain regions that are most consistently affected across studies are the orbitomedial prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, cerebellum and the basal ganglia. Conclusion: The results on connectivity in MDD are very heterogeneous, partly due to different methods and study designs, but also due to the temporal dynamics of connectivity. While connectivity research is an important step toward a complex systems approach to brain functioning, future research should focus on the dynamics of functional and effective connectivity. PMID- 30425492 TI - Lithium treatment in bipolar adolescents: a follow-up naturalistic study. AB - Background: Although lithium is currently approved for the treatment of bipolar disorders in youth, long term data, are still scant. The aim of this study was to describe the safety and efficacy of lithium in referred bipolar adolescents, who were followed up at the 4th (T1) and 8th (T2) month of treatment. Methods: The design was naturalistic and retrospective, based on a clinical database, including 30 patients (18 males, mean age 14.2+/-2.1 years). Results: Mean blood level of lithium was 0.69+/-0.20 mEq/L at T1 and 0.70+/-0.18 mEq/L at T2. Both Clinical Global Impression-Severity (CGI-S) and Children Global Assessment Scale (C-GAS) scores improved from baseline (CGI-S 5.7+/-0.5, C-GAS 35.1+/-3.7) to T1 (CGI-S 4.2+/-0.70, C-GAS 46.4+/-6.5; P<0.001), without significant differences from T1 to T2. Thyroid-stimulating hormone significantly increased from 2.16+/ 1.8 mU/mL at baseline to 3.9+/-2.7 mU/mL at T2, remaining within the normal range, without changes in T3/T4 levels; two patients needed a thyroid hormone supplementation. Creatinine blood level did not change. No cardiac symptoms and electrocardiogram QTc changes occurred. White blood cell count significantly increased from 6.93+/-1.68 103/mmc at baseline to 7.94+/-1.94 103/mmc at T2, and serum calcium significantly increased from 9.68+/-0.3 mg/dL at baseline to 9.97+/ 0.29 mg/dL at T2, both remaining within the normal range; all the other electrolyte levels were stable and normal during the follow-up. The treatment with lithium was well tolerated, probably due to the relatively low lithium blood levels. Gastrointestinal symptoms (16.7%), sedation (9.7%) and tremor (6.4%) were the most frequently reported side effects. Conclusion: Lithium was effective and safe in adolescent bipolar patients followed-up for eight months. PMID- 30425493 TI - Depression, anxiety, and stress and their association with khat use: a cross sectional study among Jazan University students, Saudi Arabia. AB - Background: Depression, anxiety, and stress levels are considered important indicators for mental health. Khat chewing habit is prevalent among all segments of Jazan population in Saudi Arabia. Few studies have been conducted to evaluate depression, anxiety, and stress among Jazan University students, and information about the correlation between khat use and these disorders is scarce. Thus, this study aims to evaluate the prevalence of depression, anxiety, and stress and their correlation with khat chewing and other risk factors among Jazan University students. Methods: A cross-sectional study was conducted on 642 students from Jazan University. Multistage sampling was used, with probability proportional to size-sampling technique. The Depression, Anxiety, and Stress Scale 21 questionnaire was used to collect the data, which were analyzed using SPSS Version 20.0 software. Results: Moderate depression was prevalent among 53.6% of the sample, anxiety was found among 65.7%, while 34.3% of the students suffered from stress. Female gender was strongly associated with higher mean scores for symptoms of depression, anxiety, and stress, with P-values <0.05 for all. Moreover, anxiety symptoms scores were statistically associated with grade point average and caffeine consumption. Khat use was statistically associated with higher mean scores of anxiety among males and a higher mean score of depression and anxiety among females. Conclusion: The results indicate a high rate of symptoms of depression, anxiety, and stress among Jazan University students. Khat use was associated with anxiety, and a higher rate of symptoms of depression, anxiety, and stress was indicated among female students. Therefore, strategy for the prevention and management of depression, anxiety, and stress is highly recommended to minimize the impact of these serious disorders. PMID- 30425494 TI - Abnormal intrinsic brain activities in stable patients with COPD: a resting-state functional MRI study. AB - Objective: The majority of previous neuroimaging studies have reported both structural and functional changes in COPD, whereas the intrinsic low-frequency oscillations changes and the relationship between the abnormal brain regions and the clinical performances remain unknown. The present study was conducted with the aim of evaluating the intrinsic brain activity in COPD patients using the amplitude of low-frequency fluctuation (ALFF) method. Methods: All participants, including 19 stable patients with COPD and 20 normal controls (NCs) matched in age, sex, and education, underwent resting-state functional MRI scans and performed cognitive function tests and respiratory functions tests. The local spontaneous brain activity was examined using the voxel-wise ALFF. Pearson's correlation analysis was used to investigate the relationships between the brain regions with altered ALFF signal values and the clinical features in COPD patients. Results: Compared with the NCs, COPD patients showed significantly lower cognitive function scores. Also, lower ALFF areas in the cluster of the posterior cingulate cortex (PCC) and precuneus, as well as a higher ALFF area in the brainstem were also found in COPD patients. The mean ALFF values in the PCC, precuneus, and brainstem showed high sensitivity and specificity in operating characteristic curves analysis, which might have the ability to distinguish COPD from NCs. Meanwhile, the mean signal values of the lower ALFF cluster displayed significant positive correlations with FEV1/FVC proportion and significant negative correlation with PaCO2; the higher ALFF cluster showed significant positive correlation with FEV1 proportion in COPD. Conclusion: According to the results of the present study, the COPD patients showed abnormal intrinsic brain activities in the precuneus, PCC, and brainstem, which might provide useful information to better understand the underlying pathophysiology of cognitive impairment. PMID- 30425495 TI - microRNA-451 protects neurons against ischemia/reperfusion injury-induced cell death by targeting CELF2. AB - Objectives: miRNAs are a family of non-coding RNAs that affect cell growth, migration and apoptosis. However, little is known on the behavior of miRNAs in neurons. Hence, this work aimed to investigate the functions and roles of miRNA 451 in neurons induced by ischemia/reperfusion injury. Materials and methods: In this study, we established a 12- or 24-hour oxygen and glucose deprivation/reoxygenation (OGD/R) cell model. miR-451 mimic, si-CUGBP Elav-like family member 2 (siCELF2), oeCELF2 and the corresponding negative controls were transfected into the 24-hour OGD/R cells. The transfection efficiency and the relative expression of miR-451 and CELF2 were measured using quantitative reverse transcription PCR and Western blot analysis. Cell viability, apoptosis, oxidative stress and cleaved-caspase-3 expression were assessed using Cell Counting Kit-8, LDH, SOD, malondialdehyde, ROS assays, flow cytometry and Western blot analysis upon miR-451 overexpression, CELF2 silencing or overexpression of both. Bioinformatics analysis and the dual-luciferase reporter assay were used to examine the relationship between CELF2 and miR-451 in the OGD/R cells. Results: The results showed that miR-451 was downregulated in the OGD/R cells. The overexpression of miR-451 increased cell viability and SOD activity, but decreased apoptosis rate, levels of LDH, MDA, ROS and cleaved caspase-3 expression. CELF2 silencing inhibited apoptosis and oxidative stress. The results suggested that CELF2 was a target of miR-451, and that CELF2 overexpression alleviated the inhibitory effect of miR-451 on apoptosis and oxidative stress of the OGD/R cells. Conclusion: The results demonstrated that miR-451 could protect cells against OGD/R-induced apoptosis and oxidative stress by targeting CELF2. PMID- 30425496 TI - Social adjustment and family function after drug switch from IR-methylphenidate to OROS-methylphenidate in patients with attention-deficit/hyperactivity disorder. AB - Purpose: This prospective, single-arm, open-label, 8-week, multicenter study investigated the effectiveness of switching from immediate-release methylphenidate (IR-MPH) to osmotic controlled-release methylphenidate (OROS-MPH) in patients with attention-deficit/hyperactivity disorder (ADHD). Patients and methods: Overall, 296 patients with ADHD (mean age: 9.5 years) already on IR-MPH treatment were enrolled. Upon enrollment, a flexible dose of OROS-MPH was administered, replacing IR-MPH. Patients were assessed at baseline and weeks 2, 4, and 8 using the Swanson, Nolan, and Pelham version IV scale (SNAP-IV) and the Clinical Global Impression for ADHD symptoms. The Social Adjustment Inventory for Children and Adolescents assessed social functions, and the Chinese Health Questionnaire (CHQ) and Family Adaptation, Partnership, Growth, Affection, and Resolve evaluated parental and family functions. Results: Switching from IR-MPH to OROS-MPH yielded significant improvements in all ADHD symptoms, as rated by parents, teachers (SNAP-IV), and study investigators (Clinical Global Impression). CHQ scores and all Social Adjustment Inventory for Children and Adolescents subscores except spare time scores improved significantly. Patients with poor IR-MPH adherence had greater improvements in teacher-rated SNAP-IV and mothers' mental health (CHQ) after switching. Conclusion: Switching from IR-MPH to OROS-MPH improved patients' behavioral ADHD symptoms and social adjustment, and mental health of patients' mothers. This was most evident in patients who previously exhibited poor IR-MPH adherence. PMID- 30425497 TI - Violence in persons with and without psychosis in the Czech Republic: risk and protective factors. AB - Purpose: To prevent violence among persons with psychosis, further knowledge of the correlates and risk factors is needed. These risk factors may vary by nation. Patients and methods: This study examined factors associated with violent assaults in 158 patients with psychosis and in a matched control sample of 158 adults without psychosis in the Czech Republic. Participants completed interviews and questionnaires to confirm diagnoses, report on aggressive behavior, current and past victimization, and substance use. Additional information was collected from collateral informants and clinical files. Multiple regression analyses were conducted to identify factors that were independently associated with committing an assault in past 6 months. Results: The presence of a psychotic disorder was associated with an increased risk of assaults (OR =3.80; 95% CI 2.060-7.014). Additional risk factors in persons with and without psychosis included recent physical victimization (OR =7.09; 95% CI 3.922-12.819), childhood maltreatment (OR =3.15; 95% CI 1.877-5.271), the level of drug use (OR =1.13; 95% CI 1.063 1.197), and the level of alcohol use (OR =1.04; 95% CI 1.000-1.084). Increasing age (OR =0.96; 95% CI 0.942-0.978) and employment (OR =0.30; 95% CI 0.166-0.540) were protective factors. Except for drug use, which appeared to have greater effect on violence in the group without psychosis, there were no major differences between patients and controls in these risk and protective factors. To our knowledge, this is the first published comparison of assault predictors between schizophrenia patients and matched controls. Conclusion: Recent physical victimization was the strongest predictor of assaults. Our findings are consistent with the emerging empirical evidence pointing to the very important role of victimization in eliciting violent behavior by the victims. Some current prediction instruments may underestimate the risk of violent behavior as they take little account of current victimization. Although psychosis per se elevates the risk of violence, other risk and protective factors for violence in persons with psychosis and comparison group are largely similar. PMID- 30425498 TI - Descending necrotizing mediastinitis in a healthy young adult. AB - A 26-year-old man with right lower mandibular and chest pain, fever, and respiratory distress was urgently transported to our hospital. CT images revealed gas collection and an abscess from the neck to the mediastinum with bilateral pleural effusion. Descending necrotizing mediastinitis (DNM) induced by an odontogenic infection of a right mandibular molar abscess was diagnosed. The cervical and mediastinal areas were drained, extensive debridement was performed, necrotic tissue was excised, and broad-spectrum antibiotics were administered immediately. Prompt diagnosis and intensive care were necessary for managing the DNM, and the patient was discharged with no comorbidities. PMID- 30425499 TI - A low threshold to ECG-gated repeat CTA reduces the risk of false-positive diagnosis of type A dissection in interhospital referrals: a case series study. AB - Background: False-positive diagnosis of acute Stanford type A aortic dissection (AAD) on computed tomography angiography (CTA) is still an issue and may lead to substantial consequences. Given that electrocardiography (ECG)-gated CTA provides greater diagnostic safety, it may be assumed that interhospital referrals with a diagnosis of AAD based on non-ECG-gated pre-referral CTA carry an elevated risk of false-positive diagnosis. Patients and methods: We reviewed a series of patients in whom a diagnosis of AAD based on non-ECG-gated pre-referral CTA was subsequently proven false by ECG-gated CTA. The artifacts that gave rise to the misdiagnosis, as well as the diagnostic pathways followed and the consequences of false-positive diagnosis were investigated. Results: In 5 patients, ECG-gated repeat CTA revealed artifacts in the pre-referral scans that had led to false positive diagnosis and referral for emergent surgery. In the first case, the patient proceeded to surgery. In 4 subsequent cases, ECG-gated CTA was ordered because a false-positive diagnosis was suspected. We found that ECG-gated CTA rather than echocardiography provided sufficient information to rule out AAD in each of these cases. Comparison between pre-referral non-ECG-gated scans and ECG gated repeat CTA demonstrated the wide range of artifacts that may give rise to a diagnosis of AAD. Conclusion: Patient condition permitting, the threshold to ECG gated repeat CTA should be low when doubt arises with regard to a diagnosis of AAD based on non-ECG-gated CTA in interhospital referrals. PMID- 30425500 TI - Endoscopic treatment of biliary complications in left lobe living donor liver transplantation. AB - Purpose: Almost all of the publications regarding the treatment of biliary complications after liver transplantation are related to biliary complications after right lobe living donor liver transplantation (LDLT) and cadaveric liver transplantation (LT). The number of publications regarding endoscopic treatment of biliary complications after left lobe LDLT is negligible. In this study, we aimed to present the results of endoscopic treatments applied in the management of biliary complications developed in left-lobe duct-to-duct LDLT patients. Patients and methods: Between 2008 and 2018, patients with duct-to-duct anastomosis who underwent ERCP due to biliary complication after left lobe LDLT were included in the study. Clinical data included patient demographics, indications for LDLT, duration till the first ERCP after LDLT, number of ERCP procedures, ERCP indications (stricture or leak), and treatment outcomes, including the need for percutaneous and surgical interventions. Results: Among 13 patients who underwent ERCP, 2 (15%) had biliary leakage and 11 (8%) had an anastomotic stricture. Our endoscopic success rate was 100% in patients with biliary stricture. Despite the implementation of ERCP on two patients with leakage, they died due to the biliary complication. Conclusion: Our results suggest that endoscopic treatment methods are successful in the management of biliary stricture complication in patients with left lobe LDLT and duct-to-duct anastomosis. Although our findings show that endoscopic treatments fail when there is a leakage after left lobe LDLT, there is a need for further studies that include more patients to reach a definite conclusion. PMID- 30425501 TI - Erratum: Lower neutrophil-to-lymphocyte ratio predicts high risk of multidrug resistant Pseudomonas aeruginosa infection in patients with hospital-acquired pneumonia [Corrigendum]. AB - [This corrects the article on p. 1863 in vol. 14, PMID: 30323608.]. PMID- 30425502 TI - Benralizumab, an add-on treatment for severe eosinophilic asthma: evaluation of exacerbations, emergency department visits, lung function, and oral corticosteroid use. AB - There are now multiple monoclonal antibodies targeting different inflammatory pathways of severe asthma. Benralizumab is a recently approved monoclonal antibody indicated for the treatment of severe eosinophilic asthma by targeting a subunit of the IL-5 receptor. Treatment with benralizumab results in significant reductions of blood and tissue eosinophils. Early studies report that this therapy has an adequate safety profile, and this was confirmed in later trials. Phase III studies have shown that benralizumab is effective in reducing the rate of exacerbations and improving asthma symptoms and quality of life in patients with severe eosinophilic asthma. Additionally, treatment with benralizumab has resulted in important reductions in the use of chronic oral corticosteroids. In this review, we evaluate the evidence up to date on the efficacy of benralizumab in severe eosinophilic asthma and explore the implications of this therapy in the ever-growing landscape of therapies for severe asthma. PMID- 30425503 TI - Hematocrit and the incidence of stroke: a prospective, population-based cohort study. AB - Background and purpose: Whether higher hematocrit levels could increase the incidence of stroke has always been full of controversy. This study aimed to explore the association between hematocrit and the incidence of stroke in the Chinese population. Subjects and methods: The Kailuan study is a prospective longitudinal cohort study on risk factors and events of chronic diseases. Using a multivariable Cox proportional hazards analysis, we examined the association between baseline hematocrit values and the incidence of stroke in the Kailuan cohort (93,299 participants). Results: A total of 3,624 participants developed stroke during the 9-year follow-up period. In Cox regression models adjusted for demographic information and for clinical variables, there was a significant association between baseline hematocrit levels and the incidence of stroke. The highest hematocrit quartile (quartile 5: men, hematocrit >48.6%; women, hematocrit >43.2%) was associated with a higher incidence of stroke (HR 1.17, 95% CI 1.04-1.31, P for trend =0.0016) compared with the lowest hematocrit quartile (quartile 1: men, hematocrit <41.5%; women, hematocrit <36.6%). In the analysis of ischemic stroke, intracerebral hemorrhage separately, similar association was observed in ischemic stroke, but there were no statistical differences in intracerebral hemorrhage. Conclusion: Higher hematocrit levels are associated with a higher incidence of stroke in the Chinese population. PMID- 30425504 TI - The impact of introducing the early warning scoring system and protocol on clinical outcomes in tertiary referral university hospital. AB - Purpose: The aim of this study was to evaluate the impact of a hospital protocol in response to patient deterioration in general wards, stratified using the national early warning score (NEWS), on primary patient outcomes of in-hospital mortality and percentage of patients transferred to the intensive care unit (ICU). Patients and methods: We conducted a prospective observational cohort study among adult medical patients admitted to a university hospital in Bangkok. A 4-month pre-protocol period (November 2015 to February 2016) was assigned to a control group and a protocol period (March 2016 to June 2016) was allocated to a protocol group. On admission, vital signs (respiratory rate, pulse rate, systolic blood pressure, and temperature), oxygen saturation, presence of oxygen supplementation, and neurological status were used to calculate NEWS. Patients were categorized as low, moderate, or high risk based on the NEWS. During protocol period, when patients' conditions are critical and they are at imminent risk, the NEWS detects the event and triggers a systematic response. The response enables closed monitoring and early treatment by expert physicians to rapidly stabilize and triage the patient to a location where services meet the patient's needs. Primary outcomes were compared between the pre-protocol and protocol groups using historical controls for the intervention, which is the availability of NEWS to staff and an associated escalation pathway. Results: A total of 1,145 patients were included in the analysis: 564 patients in the pre-protocol group and 581 in the protocol group. The mean NEWS of patients at admission was higher in the protocol group than in the pre-protocol group (2.4+/-2.4 vs 1.77+/-2.158; P<0.001). There was no significant difference for in-hospital mortality and percentage of patients transferred to ICU between the groups. Among 95 (8.3%) patients at moderate risk, in-hospital mortality and ICU transfer percentage were lower in the protocol group than in the pre-protocol group (2.9 vs 15.4%; P=0.026; RR 0.188, 95% CI 0.037%-0.968% and 8.7 vs 26.9%; P=0.021; RR 0.322, 95% CI 0.12-0.87, respectively). Conclusion: Implementing the NEWS with the hospital protocol did not change the overall patient's outcomes. PMID- 30425505 TI - Redefined clinical spectra of diabetic foot syndrome. AB - Purpose: The aim of this study was to present the redefined clinical spectra of diabetic foot syndrome (RCS-DFS) and determine whether the RCS-DFS can be used to predict amputations. Patients and methods: This is a retrospective study of type 2 diabetic patients referred with DFS for management at King Abdullah University Hospital (KAUH) between January 2014 and December 2015. Data collection form and diabetic foot (DF) characteristic chart were used to document the following: demographic data, diabetes-related parameters, DF characteristics, surgical interventions and amputations. The predominant clinical presentations of DF problems (ulcer, sepsis or gangrene) were integrated with the clinical criteria for diabetic foot infection (DFI) diagnosis and classification of Infectious Diseases Association of America (IDSA)/International Working Group on Diabetic Foot (IWGDF) to redefine the clinical spectra of DFS. Related risk characteristics and amputation rate at all levels were compared between the three RCS. Results: In this study, there were 95 (47.0%) septic DFS (SDFS) patients, 65 (32.2%) ulcerative DFS (UDFS) patients and 42 (20.8%) gangrenous DFS (GDFS) patients. Poor glycemic control (HbA1c >7.5%), hypertension, history of the same foot problems, duration of symptoms, revascularizations and ischemic severity were significantly different between the three RCS. UDFS had the highest rate of limb salvage without amputations (70.8%). GDFS had the highest rate for final toe amputations (52.4%) and major amputations (23.8%). Final minor amputation rate was around 20% for both SDFS and GDFS. Conclusion: Redefining DFS into ulcerative, septic and gangrenous by integration of the predominant clinical presentation and the clinical criteria for DFI diagnosis and classification of IDSA/IWGDF showed significant differences in amputation rate. Therefore, it can be used clinically to categorize patients with DFS to predict amputations and to help in planning their management. Further prospective studies are suggested to validate these results. PMID- 30425506 TI - Factors influencing male participation in reproductive health: a qualitative study. AB - Introduction: Male involvement in reproductive health is an essential component in promoting maternal and family health. In Nepal, men are not actively engaged in most maternal and child health (MCH) services nor in other reproductive health programs. There is a need to know about the understanding of key professionals in such practices. This study explores gendered perspectives among teachers and health professionals to understand the factors contributing to male involvement in reproductive health. Methods: The data were collected through two focus group discussions (FGDs) and seven key informant interviews (KIIs). FGDs were held among male teachers of selected schools, and KIIs were conducted with health professionals of the health post of Bungamati, Lalitpur. An unstructured interview guide was used to explore their experiences and perceptions. All KIIs and FGDs were recorded, translated and transcribed verbatim. Results: Findings show limited male involvement in reproductive health. Participants reported several hindering and challenging factors such as sociocultural and psychological norms, lack of education, and misinformation and dominance of female as health care providers in many MCH clinics. Perceived motivating factors included positive attitude in men, literacy and awareness, inclusion of reproductive health in school curriculum and certain incentives. Participants also recommended a range of strategies for increasing men's involvement in reproductive health in Nepal. Conclusion: Men's education and attitude, knowledge and awareness, sociocultural factors, psychological factors, health system factors, and policies play important roles in male involvement in reproductive health. Programs on effective implementation of men involvement in reproductive health initiatives should address the barriers and challenges to men's supportive activities. This study also suggests increasing literacy of reproductive health among men that enhances their positivity and motivates them to participate in reproductive health services. PMID- 30425507 TI - Risk assessment during preventive home visits among older people. AB - Background: Preventive home visits (PHV) may contribute to identify risks and needs in older people, and thereby delay the onset of functional decline and illness, otherwise often followed by home care or admission to hospital or nursing homes. There is a need to increase knowledge about which factors are associated with different risk areas among older people, so that the PHV questionnaire focuses on relevant tests and questions to make the PHV more specific and have a clear focus and purpose. Objective: The objective of this study was to examine associations between five kinds of risks: risk of falls, malnutrition, polypharmacy, cognitive impairment, and risk of developing illness and factors related to lifestyle, health, and medical diagnoses among older people living at home. Methods: A cross-sectional study design was applied. PHV were conducted by nurses among 77-year-old people in an urban municipality and among >=75-year-old people in a rural municipality. A questionnaire including tests and a risk assessment score for developing illness was used. Descriptive and inferential statistics including regression models were analyzed. Results: The total sample included 166 persons. Poor perceived health was associated with increased risk of developing illness and risk of fall, malnutrition, and polypharmacy. Lifestyle and health factors such as lack of social support, sleep problems, and feeling depressed were associated with risk of developing illness. Risk of falls, malnutrition, polypharmacy, and cognitive impairment were also associated with increased risk of developing illness. None of the independent factors related to lifestyle, health, or medical diagnosis were associated with risk of cognitive impairment. Conclusion: Poor perceived health was associated with health-related risks in older persons living at home. Preventive health programs need to focus on social and lifestyle factors and self-reported health assessment to identify older people at risk of developing illnesses. PMID- 30425508 TI - Gene expression analyses identify a relationship between stanniocalcin 2 and the malignant behavior of colorectal cancer. AB - Background: Colorectal cancer (CRC) is one of the main causes of cancer-related death worldwide. Stanniocalcin 2 (STC2), a secreted glycoprotein, has been suggested to exert various functions in progression of many cancers. However, the precise biological role in CRC is not fully understood. Therefore, this study based on several public datasets aims at investigating the roles of STC2 in CRC. Methods: We used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to evaluate the STC2 expression and its clinical significance in CRC. Cell migration and invasion by STC2 overexpression and knockdown were assessed using Transwell migration and Matrigel invasion assays. We next performed RNAseq analysis on SW480 cells with or without STC2 overexpression. Differentially expressed genes were selected by using fold-change >5 and P-value <0.05. Results: In this study, we found that STC2 level was significantly higher in CRC than that in adjacent noncancerous tissues from TCGA and GEO. Tumors with high mRNA levels of STC2 were more common in patients with rectal cancer, left-sided CRC, advanced T-stage (T3-T4), positive lymph node involvement and advanced AJCC-stage (III-IV) from TCGA. STC2 displayed the negative correlation with the expressions of epithelial cell markers, while it was positively correlated with the expressions of mesenchymal cell markers, MMPs and the epithelial-mesenchymal transition (EMT) related transcriptional factors. Furthermore, we found that STC2 promoted cell migration and invasion in vitro. And a group of differentially expressed genes, which were modulated by STC2, were identified from RNAseq analyses. Conclusion: Our study demonstrates that STC2 is overexpressed in CRC compared with normal tissues, and promotes CRC cell migration and invasion. Our data suggest that STC2 may be used as a potential biomarker for clinical application and target therapy in future. PMID- 30425509 TI - Prognostic value of NEK2 overexpression in digestive system cancers: a meta analysis and systematic review. AB - Background and objective: Many studies have reported that NEK2 is overexpressed in digestive system cancers (DSCs) and is also correlated with patient survival. We performed a meta-analysis to comprehensively evaluate the prognostic role of NEK2 expression in DSCs. Materials and methods: A comprehensive literature search was performed using PubMed, EMBASE, and Web of Science. Synthesized hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the influence of NEK2 overexpression on the prognosis and clinicopathological features of patients with DSCs. Results: A total of 13 studies involving 1,917 patients was included. Overall, patients with high NEK2 expression had poorer overall survival (HR =1.45; 95% CI: 1.15-1.83; P=0.002) and disease-free survival/recurrence-free survival (HR =2.28; 95% CI: 1.54-3.37; P<0.0001). Furthermore, subgroup analysis also suggested that elevated NEK2 expression was associated with poorer overall survival in patients with hepatocellular carcinoma (HR =1.45; 95% CI: 1.05-2.00; P=0.02) and colorectal cancer (HR =2.03; 95% CI: 1.16-3.54; P=0.01). Additionally, NEK2 overexpression was also associated with pretreatment serum AFP level (OR =1.79; 95% CI: 1.23 2.61; P<0.01) and portal vein thrombosis (OR =2.74; 95% CI: 1.22-6.17; P=0.01) in hepatocellular carcinoma. Conclusion: NEK2 might act as a useful prognostic predictor and a potential therapeutic target in DSCs. However, multicenter homogeneous studies with larger sample sizes are needed to further confirm our findings owing to some limitations in our meta-analysis. PMID- 30425510 TI - Dosimetric comparison of volumetric-modulated arc therapy and intensity-modulated radiation therapy in patients with cervical cancer: a meta-analysis. AB - Background: Intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT) are two of the main treatment techniques for cervical cancer. Whether either technique significantly reduces irradiated volumes of organs at risk (OARs) remains controversial. The aim of this study was to explore which of these treatment paradigms is the superior technique in cervical treatment, taking clinical outcomes and treatment efficiency from published findings into consideration. Materials and methods: PubMed, EMBASE, and Cochrane Library databases were utilized. The average percent irradiated volumes of OAR were extracted from all included studies. Dual arc results were extracted due to their superiority to single arc methods in terms of plan quality. Standard mean deviations and 95% CIs were calculated for delivery time, monitor units, and average percent irradiated volumes of OAR. Assessment of publication bias and sensitivity analyses were performed. All statistical analyses were conducted using R 3.5.0 software. Results: Eight studies were included in this meta analysis. For irradiated volumes of OARs, irradiated volume of rectum receiving 40 Gy (rectum V40) was significantly decreased in VMAT compared with IMRT. However, no significant differences were observed between IMRT and VMAT plans in bladder V40 or small bowel V40/V30. In addition, delivery times and monitor units were significantly lower in the VMAT plan than in the IMRT plan. Conclusion: Compared with IMRT, VMAT is significantly more protective for the rectum, suggesting that it may be an optional therapy technique for patients with cervical cancer. PMID- 30425511 TI - Lentivirus-mediated siRNA knockdown of SPHK1 inhibits proliferation and tumorigenesis of neuroblastoma. AB - Background: The overexpression of sphingosine kinase 1 (SPHK1) is responsible for the progress of many cancers. However, the role of SPHK1 in the development and progression of neuroblastoma (NB) remain largely unknown. Here in this study, we explored whether silencing SPHK1 by lentivirus-mediated siRNA could be employed as a potential therapeutic target for NB. Materials and methods: Lentivirus was adopted to load SPHK1 siRNA. The results were obtained using RT-qPCR, Western blot, cell proliferation assay, transwell cell migration/invasion assays as well as in vivo xenograft tumor models in nude mice. Results: Our results demonstrated that SPHK1 mRNA was upregulated in SH-SY5Y and SK-N-SH cells as well as in human NB tissues. SPHK1 knockdown by siRNA resulted in impaired proliferation, increased apoptosis, as well as impaired migration and invasion of SH-SY5Y and SK N-SH cells. In addition, the in vivo study suggested that SPHK1 knockdown significantly reduced the tumorigenesis of SH-SY5Y xenograft model. Furthermore, intratumorally administered lentivirus-SPHK1 siRNA could significantly inhibit tumor growth in an SH-SY5Y xenograft mice model. Intensive investigations on mechanism revealed that these effects were achieved through the deactivation of STAT3 pathways. Conclusion: These data suggest that SPHK1 inhibition via downregulation of STAT3 pathways by lentivirus-mediated siRNA knockdown can significantly suppress NB progression, which could be a promising target for future gene therapy of NB. PMID- 30425512 TI - Knockdown of lncRNA UCA1 inhibits proliferation and invasion of papillary thyroid carcinoma through regulating miR-204/IGFBP5 axis. AB - Background: Long noncoding RNA (LncRNA) UCA1 has been reported to function as an oncogene in multiple cancers. However, the biological roles and underlying mechanism of UCA1 in papillary thyroid carcinoma (PTC) remain unclear. This study aimed to investigate the underlying function of UCA1 on thyroid cancer progression. Materials and methods: A series of experiments involving Cell Counting Kit-8, wound-healing, and transwell invasion assays were conducted to determine the cellular capabilities of proliferation, migration, and invasion, respectively. Binding sites between UCA1 and miR-204 were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes were determined by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot, respectively. Results: The results revealed that UCA1 was upregulated in PTC tissue and cell lines. UCA1 knockdown significantly suppressed the cell proliferation, migration, and invasion of TPC-1 cells. Bioinformatics analysis and luciferase reporter assay verified the complementary binding within UCA1 and miR-204 at the 3'-UTR. Moreover, miR-204 inhibition reversed the UCA1 knockdown-mediated inhibitory effect on cell proliferation, migration, and invasion. We also found that UCA1 could regulate expression of IGFBP5, a direct target of miR-204 in PTC. Conclusion: Our study demonstrated that UCA1 exerts activity of oncogenes in PTC through regulating miR-204/IGFBP5 axis. PMID- 30425513 TI - The miR-503 cluster is coordinately under-expressed in endometrial endometrioid adenocarcinoma and targets many oncogenes, cell cycle genes, DNA repair genes and chemotherapy response genes. AB - Background: The miR-503 miRNA cluster, located at Xq23.1, is composed of six miRNAs; miR-424, miR-503, miR-542, miR-450a-1, miR-450a-2 and miR-450b. Numerous studies have focused on the relationship of one or two members of the cluster and various human cancers. Here, we suggest that the entire cluster as a single coordinately expressed polycistron transcribed from a single promoter in endometrial endometrioid adenocarcinoma (EEA). Subjects and methods: A tissue panel composed of twenty histologically confirmed endometrial endometrioid adenocarcinomas (EEA) and four benign endometrium was assembled under informed consent. Expression of each member of the miR-503 cluster was determined by quantitative PCR and differences in expression between EEA and benign tissues were assessed via the standard DeltaDeltaCt method. In addition, the role of promoter methylation status in miRNA expression was examined in Ishikawa H cells following exposure to the cytidine analog Decitabine. Results: Expression of each member of the miR-503 cluster is significantly downregulated in EEA in our tumor sample. Both in our tumor sample and in The Cancer Genome Atlas (TCGA) there is evidence of highly correlated expression further supporting the idea that the miR 503 cluster is a polycistron. Looking at each member of the miR-503 cluster we were able to identify 55 unique experimentally validated target genes which include a substantial number of genes involved in carcinogenesis, DNA damage response, cell cycle regulation and chemotherapeutic response. We also found preliminary evidence that regulation of the miR-503 cluster is governed by methylation of the promoter in EEA. Conclusion: The totality of the data presented here strongly suggest that the miR-503 cluster as a whole merits further investigation as an important potential therapeutic target in EEA. PMID- 30425514 TI - TNFalpha promotes glioblastoma A172 cell mitochondrial apoptosis via augmenting mitochondrial fission and repression of MAPK-ERK-YAP signaling pathways. AB - Background and objective: The present study was designed to explore the roles of mitochondrial fission and MAPK-ERK-YAP signaling pathways and to determine their mutual relationship in TNFalpha-mediated glioblastoma mitochondrial apoptosis. Materials and methods: Cellular viability was measured via TUNEL staining, MTT assays, and Western blot. Immunofluorescence was performed to observe mitochondrial fission. YAP overexpression assays were conducted to observe the regulatory mechanisms of MAPK-ERK-YAP signaling pathways in mitochondrial fission and glioblastoma mitochondrial apoptosis. Results: The results in our present study indicated that TNFalpha treatment dose dependently increased the apoptotic rate of glioblastoma cells. Functional studies confirmed that TNFalpha-induced glioblastoma apoptosis was attributable to increased mitochondrial fission. Excessive mitochondrial fission promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, repressed ATP metabolism, elevated ROS synthesis, and downregulated antioxidant factors. In addition, the fragmented mitochondria liberated cyt-c into the cytoplasm/nucleus where it activated a caspase-9-involved mitochondrial apoptosis pathway. Furthermore, our data identified MAPK-ERK-YAP signaling pathways as the primary molecular mechanisms by which TNFalpha modulated mitochondrial fission and glioblastoma apoptosis. Reactivation of MAPK-ERK-YAP signaling pathways via overexpression of YAP neutralized the cytotoxicity of TNFalpha, attenuated mitochondrial fission, and favored glioblastoma cell survival. Conclusion: Overall, our data highlight that TNFalpha-mediated glioblastoma apoptosis stems from increased mitochondrial fission and inactive MAPK-ERK-YAP signaling pathways, which provide potential targets for new therapies against glioblastoma. PMID- 30425515 TI - The elevated glutaminolysis of bladder cancer and T cells in a simulated tumor microenvironment contributes to the up-regulation of PD-L1 expression by interferon-gamma. AB - Background: Metabolic reprogramming occurs in the tumor microenvironment and influences the survival and function of tumor and immune cells. Interferon-gamma (IFN-gamma) produced by T cells up-regulates PD-L1 expression in tumors. However, reports regarding the relationship between nutrient metabolism and the up regulation of PD-L1 expression are lacking. Materials and methods: In this paper, we analyzed the metabolic changes in T cells and bladder cancer cells in a simulated tumor microenvironment to provide evidence regarding their relevance to PD-L1 up-regulation. Results: The glutaminolysis was increased in both activated T cells and glucose-deprived T cells. IFN-gamma production by T cells was decreased in a glucose-free medium and severely decreased when cells were simultaneously deprived of glutamine. Furthermore, the glutaminolysis of the bladder cancer cells under glucose deprivation exhibited a compensatory elevation. The glucose concentration of T cells co-cultured with bladder cancer cells was decreased and T cell proliferation was reduced, but IFN-gamma production and glutaminolysis were increased. However, in bladder cancer cells, the elevation in glutaminolysis under co-culture conditions did not compensate for glucose deprivation because the glucose concentration in the culture medium did not significantly differ between the cultures with and without T cells. Our data also show that inhibiting glutamine metabolism in bladder cancer cells could reduce the elevation in PD-L1 expression induced by IFN-gamma. Conclusion: In a simulated tumor microenvironment, elevated glutaminolysis may play an essential role in IFN-gamma production by T cells, ultimately improving the high PD-L1 expression, and also directly contributing to producing more PD-L1 in bladder cancer cells. PMID- 30425516 TI - Long non-coding RNA ZEB1-AS1 promotes cell invasion and epithelial to mesenchymal transition through inducing ZEB1 expression in cervical cancer. AB - Background: Long non-coding RNAs (lncRNAs) play important roles in cancer initiation and development. The purpose of the present study was to determine the functions and mechanisms of lncRNA ZEB1-AS1 in human cervical cancer (CC). Methods: A total of 106 pairs of CC tissues and adjacent normal epithelial tissues were collected from CC patients who underwent resection. Three human CC cell lines (HeLa, C33A and SiHa) and a normal cervical cell line Crl-2614 and were transfected with human ZEB1-AS1 cDNA, or empty vector as the control. Then, cells were transfected with ZEB1-AS1-specific small interfering RNA (si-ZEB1 AS1), ZEB1-specific siRNA (si-ZEB1) or negative siRNA control (si-NC). The transfection efficiency was confirmed by RT-qPCR analysis. qPCR was applied to determine the qualification of RNA. Cell proliferation was investigated by MTT assay. The apoptosis rate of cells was detected by flow cytometer. Cell invasion was detected by transwell assay. Western blot was applied to determine the expression of proteins. CC xenografts in 12 male BALB/c athymic nude mice were established. And the tumor volumes were measured by vernier caliper. Results: We found that ZEB1-AS1 expression was remarkably increased in human CC tissue samples and cell lines, and its expression levels were closely associated with poor prognosis of CC patients. Moreover, we found that knockdown of ZEB1-AS1 inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of CC cells in vitro and suppressed CC xenograft tumor growth in vivo. Mechanistically, we found that knockdown of ZEB1-AS1 significantly inhibited ZEB1 expression, and knockdown of ZEB1 could rescue the effects of ZEB1 AS1 overexpression in CC cells. Conclusion: In conclusion, our findings indicated that ZEB1-AS1 serves an oncogenic role in CC, which might become a potential prognostic indicator and therapeutic target in CC. PMID- 30425517 TI - Thymosin alpha1 suppresses migration and invasion of PD-L1 high-expressing non small-cell lung cancer cells via inhibition of STAT3-MMP2 signaling. AB - Background: Thymosin alpha1 (Talpha1) is one of the most commonly used immunomodulators for metastatic non-small-cell lung cancer (NSCLC) patients in many countries. Despite the identification of the direct suppression on cancer cell proliferation, little is known about its effect on metastasis and metastasis related signaling such as matrix metalloproteinases (MMPs) and programmed cell death ligand 1 (PD-L1). Materials and methods: NSCLC cells with distinguishing PD L1 expression levels were treated with Talpha1. siRNAs were used to knockdown PD L1. Cell migration and invasion abilities were evaluated by wound-healing and transwell assays. The xenograft model by BALB/c nude mice was constructed to test the inhibitory effect of Talpha1 on metastasis in vivo. The expression levels of metastasis-related signaling pathways and key molecules were assessed by Western blot (WB) and quantitative reverse transcriptase PCR (qRT-PCR). Results: Talpha1 significantly suppressed cell migration and invasion in PD-L1 high-expressing H1299, NL9980, and L9981 cells but not in PD-L1 low-expressing A549 or SPC-A-1 cells. This difference was demonstrated by mouse model in vivo as well. Knocking down of PD-L1 significantly impaired the inhibition of cell migration and invasion caused by Talpha1 treating in PD-L1 high-expressing cells. Besides, Talpha1 inhibited the activation and translocation of STAT3 and the expression of MMP2 in PD-L1 high-expressing NSCLC cells. Moreover, the treatment of STAT3 activator colivelin could partly reverse the Talpha1-induced MMP2 suppression and the migration phenotype. Conclusion: Talpha1 significantly suppresses migration and invasion in PD-L1 high-expressing NSCLC cells compared with PD-L1 low expressing NSCLC cells in vitro and in vivo, through the downregulation of STAT3 MMP2 signaling. These different responses to Talpha1, together with the depiction of Talpha1-induced signaling changes, suggest a potential benefit of Talpha1 for PD-L1-positive NSCLC patients, enlightening the combination of Talpha1 with target therapy or immune checkpoint inhibitors. PMID- 30425518 TI - Radiation therapy's efficacy on tongue cancer: a population-based survival analysis. AB - Objective: To identify survival outcomes for patients with oral tongue cancer and the effects of different prognostic factors on survival. Methods: A study was performed with the Surveillance, Epidemiology, and End Results database to confirm whether survival improved in patients who had received radiation therapy along with surgery compared with others who had received surgery alone. Results: A total of 9,474 patients were included as respondents in the study. Of the group, 2,759 patients had been treated by surgery along with radiotherapy, while 6,714 just had received only surgery. The survival was higher in patients who had been treated by both surgery and radiotherapy. Moreover, old age (P<0.001), being black (P<0.001), distant stage (P<0.001), first malignant primary indicator (P<0.001), being unmarried (P<0.001), and surgery only (P<0.001) were confirmed as significant risk factors associated with low survival rates. Age 50 years and above (hazard ratio: 1.712, 95% CI: 1.550-1.890) was also a significant risk factor. Nevertheless, grade and sex were not independent risk factors. The multivariate model also showed that being black, distant stage, age below 50 years, sex, being unmarried, and surgery were found to be associated with low survival rates (P<0.001). Conclusion: Of the patients with tongue cancer, the group treated by both radiation and surgery had better prognosis than the group that had received surgery only. Also, survival showed no difference in terms of sex among the total tongue cancer population, whereas prognosis was found to differ between two genders in the group that had received both radiation therapy and surgery. Nonetheless, grade was not a risk factor for patients with tongue cancer. PMID- 30425519 TI - Efficacy and safety analysis on dendritic cell-based vaccine-treated high-grade glioma patients: a systematic review and meta-analysis. AB - Background: Dendritic cell (DC)-based vaccine is a promising therapy for high grade gliomas (HGGs); however, its actual effectiveness still remains controversial. This meta-analysis aims to extensively evaluate the efficacy and safety of DC vaccine for HGG patients. Methods: We systematically searched PubMed, the Cochrane Library, EMBASE, Medline, and Web of Science for relevant parallel randomized controlled trials (RCTs) and properly controlled non randomized studies (NRS) published in English. Two investigators reviewed all the texts and extracted information regarding overall survival (OS), progression-free survival (PFS), and adverse events (AEs) from eligible studies. Sensitivity analyses and subgroup analyses were also conducted. Results: Of 353 suitable studies, 13 studies (three RCTs and ten NRS) involving 944 patients were finally included. Compared to the control therapy group (CT group), the DC group showed better OS and PFS without serious AEs. Subgroup analysis showed that trials designed as NRS obtained better results in the DC group in this study; however, no specific subgroup regarding dosages, cycles or injection routes was found to be superior in the DC group compared to the CT group. Conclusion: DC vaccine can significantly improve OS and PFS, with acceptable toxicity, of HGG patients. Nevertheless, further studies are needed to verify this conclusion. PMID- 30425520 TI - Evidence of response to pembrolizumab in a patient with Lynch syndrome-related metastatic colon cancer. AB - Patients with Lynch Syndrome (LS) are at high risk of developing colorectal cancer at an early age. Germline mutations in DNA mismatch repair genes and microsatellite instability are clear signatures of this autosomal dominant disorder. Here, we report the clinical history of a 38-year-old patient with LS related metastatic colon cancer treated in Chile with immunotherapy (pembrolizumab). The patient exhibited a pathogenic deletion in Epithelial cell Adhesion Molecule (EPCAM) and mutS homolog 2 (MSH2) genes, and after diagnosis received 12 cycles of FOLFOX. The tumor mass, however, continued to grow, and a new metastatic mucinous adenocarcinoma of 13 mm appeared at the level of the 11th right dorsal vertebra. To treat these lesions, the patient received immunotherapy scheme with pembrolizumab (200 mg every 21 days). After only four cycles, the patient's symptoms improved and the lesions showed less metabolic activity. After 12 cycles with pembrolizumab, the patient started palliative radiation and systemic second-line treatment with FOLFIRI and Avastin. The immunotherapy scheme with pembrolizumab was capable of delaying the second-line treatment for at least 8 months, becoming a useful therapeutic option for this patient. Thus, our study highlights the importance of implementing immunotherapy treatment programs for LS colorectal cancer patients in South American countries. PMID- 30425521 TI - MCL-1 inhibition in cancer treatment. AB - Myeloid cell leukemia-1 (MCL-1), a member of antiapoptotic BCL-2 family proteins, is a key regulator of mitochondrial homeostasis. Frequent overexpression of MCL-1 in human primary and drug-resistant cancer cells makes it an attractive cancer therapeutic target. Significant progress has been made in the development of small-molecule MCL-1 inhibitors in recent years, and three MCL-1 selective inhibitors have advanced to clinical trials. This review briefly discusses recent advances in the development of small molecules targeting MCL-1 for cancer therapy. PMID- 30425522 TI - Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients. AB - Purpose: ERBB2 exon 20 insertions (20ins) have been identified as oncogenic drivers in lung cancers. Lung cancer patients with 20ins benefit from afatinib. However, response heterogeneity was observed in patients harboring different 20ins subtypes. In this study, we interrogated clinical characteristics in ERBB2 mutated Chinese lung cancer and investigated the clinical outcomes of specific ERBB2 20ins in response to afatinib. Experimental design: In this study, we retrospectively collected genomic profiling data of 7,520 lung cancer patients sequenced using next-generation sequencing in a Clinical Laboratory Improvement Amendments-certified laboratory. We analyzed the clinical and molecular features of patients harboring ERBB2 20ins and evaluated clinical outcomes of 19 patients with clinical records after afatinib treatment. Results: ERBB2 20ins were identified in 2.27% (171/7,520) of this lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. ERBB2 20ins was mutually exclusive with other well-established lung cancer oncogenic driver mutations. The most frequently appearing subtype was Y772_A775dup (69.6%) and several novel insertion subtypes were also identified. The correlations of specific 20ins subtypes and survival were investigated. The presence of a glycine at position 778 in ERBB2 was suggested to be a common feature of drug sensitivity mutations. Patients harboring G778_P780dup (G778) subtype achieved longer median progression-free survival and median overall survival than other 20ins (non-G778) subtypes (median progression-free survival, 10 vs 3.3 months, P=0.32; median overall survival, 19.7 vs 7 months, P=0.16). Moreover, we presented the first clinical case of a lung squamous cell carcinoma patient harboring ERBB2 20ins who achieved partial response to afatinib. Conclusion: This study interrogated the characteristics of ERBB2 20ins in a large cohort from single ethnicity and demonstrated the response heterogeneity to afatinib among different ERBB2 20ins subtypes. Further studies in a larger cohort are needed to investigate the underlying molecular mechanisms and clinical response of different ERBB2 20ins subtypes. PMID- 30425523 TI - Down-regulation of CXCL11 inhibits colorectal cancer cell growth and epithelial mesenchymal transition. AB - Background: The poor prognosis of colorectal cancer (CRC) largely results from local invasion and tumor metastases. Epithelial-mesenchymal transition (EMT) is a key step in the progression of solid tumors and plays a vital role in tumor metastasis. Recent studies demonstrate that C-X-C motif chemokine 11 (CXCL11) is involved in various cancers' progression. However, its biological activity in CRC needs deeper exploration. Methods: The level of CXCL11 in CRC tissues and cell lines was determined using the quantitative real-time PCR (qRT-PCR) assay. The MTT, colony formation, wound healing and Transwell invasion assays were applied to assess the role of CXCL11 in CRC cell growth, migration and invasion, in vitro, respectively. A xenograft model was constructed to analyze the function of CXCL11 in CRC cell growth in vivo. Results: CXCL11 was over-expressed in CRC tissues and cell lines. Repression of CXCL11 significantly inhibited CRC cell migration, invasion and EMT in vitro. In addition, down-regulation of CXCL11 reduced CRC cell growth and metastasis in vivo. Finally, we revealed that repression of CXCL11 inhibited the metastatic ability of CRC cell in a N-cadherin dependent manner. Conclusion: In summary, this study explicates the oncogenic activities of CXCL11 in CRC cell growth and metastasis. PMID- 30425524 TI - Enzalutamide-resistant castration-resistant prostate cancer: challenges and solutions. AB - The new-generation hormonal agent enzalutamide has been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), in both post and predocetaxel setting, due to the significant improvement in overall survival. More recently, enzalutamide also showed impressive results in the treatment of men with nonmetastatic CRPC. Unfortunately, not all patients with CRPC are responsive to enzalutamide, and even in responders, benefits are limited by the development of drug resistance. Adaptive resistance of metastatic prostate cancer to enzalutamide treatment can be due to the activation of both androgen receptor (AR)-dependent pathways (expression of constitutively active AR splice variants, AR point mutations, gene amplification and overexpression) and mechanisms independent of AR signaling pathway (altered steroidogenesis, upregulation of the glucocorticoid receptor, epithelial-mesenchymal transition, neuroendocrine transformation, autophagy and activation of the immune system). In this review, we focus on resistance mechanisms to enzalutamide, exploring how we could overcome them through novel therapeutic options. PMID- 30425525 TI - The efficacy and safety of immune checkpoint inhibitor combination therapy in lung cancer: a systematic review and meta-analysis. AB - The value of immune checkpoint inhibitor (ICI) combination therapy for patients with lung cancer remains unclear. We conducted a meta-analysis using PubMed, Embase, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs) that might provide a reference for clinical practice. The selection criteria were defined according to the population, intervention, comparison, outcome and study design (PICOS) framework. In all, 12 RCTs with 5,989 patients were included in this meta-analysis. Our results showed that ICI combination therapy was significantly associated with the improvement of overall response rate (ORR) (RR =1.44 [95% CI 1.19, 1.74], P=0.0002), progression-free survival (PFS) (HR =0.67 [95% CI 0.59, 0.77], P<0.00001), and OS (HR =0.81 [95% CI 0.70, 0.95], P=0.008) in lung cancer. In subgroup analyses, combination ICI therapy significantly prolonged OS in non-small-cell lung cancer (NSCLC) patients (HR =0.80 [95% CI 0.73, 0.88], P<0.00001) but not in SCLC (HR =0.94 [95% CI 0.82, 1.08], P=0.40) patients. Data suggested that PD-1 inhibitors had higher efficacy and safety profiles than PD-L1 and CTLA-4 inhibitors in combination ICI therapy for lung cancer patients. Furthermore, tolerability analysis revealed higher incidences of grade >=3 AEs, fatigue, and increased transaminases from combination ICI therapy. In conclusion, our meta-analysis indicated that combination ICI therapy should be considered in clinical practice and future study designs for NSCLC patients. However, the current data do not support the large-scale clinical application of combination ICI therapy in SCLC patients. PMID- 30425526 TI - Contribution of dysregulated circRNA_100876 to proliferation and metastasis of esophageal squamous cell carcinoma. AB - Purpose: Accumulating evidence demonstrates that circRNAs regulate diverse cellular processes and cancer progression. However, it remains unclear whether circRNAs play any functional role in esophageal squamous cell carcinoma (ESCC). Materials and methods: The significance of circRNA_100876 in ESCC was analyzed by studying circRNA_100876 expression in ESCC tissues and the association between circRNA_100876 expression and clinicopathologic parameters. The biological effects of circRNA_100876 knockdown by lentivirus-mediated siRNAs on cell proliferation, cell cycle, apoptosis, and migration were investigated in vitro and in vivo. Results: CircRNA_100876 expression was upregulated (P<0.05) and was negatively correlated with survival outcome (P<0.05) in ESCC. Inhibition of proliferation, migration, invasion, and epithelial-mesenchymal transition progression was confirmed after circRNA_100876 depletion. Conclusion: Dysregulation of circRNA_100876 expression leads to poor prognosis in ESCC by accelerating cell proliferation and metastasis. PMID- 30425527 TI - Notch1 serves as a prognostic factor and regulates metastasis via regulating EGFR expression in hypopharyngeal squamous cell carcinoma. AB - Objective: Hypopharyngeal squamous cell carcinoma (HSCC) remains one of the most lethal malignancies in head and neck. Notch1 has been validated to play prominent roles in the occurrence and development of various types of cancer. The aim of this study was to explore the function and underlying mechanism of Notch1 in HSCC. Patients and methods: Seventy-one cancer tissue samples and adjacent noncancerous formalin-fixed paraffin embedded tissue specimens were analyzed by immunohistochemistry. As Notch1 is overexpressed in HSCC, we further questioned whether there was a relationship between Notch1 and the clinicopathological characteristics. After confirming the successful knockdown of Notch1 by siRNA, the migration and invasion after gene knockdown were investigated by Transwell chambers. We then tried to identify YBX1 and EGFR expression using real-time PCR (RT-PCR) and Western blot analyses. To further determine whether the downexpression of EGFR was caused by YBX1 and the overexpression of YBX1 was caused by gene amplification, the expression of EGFR was detected by RT-PCR and Western blot assays. Results: We found that the expression of Notch1 and EGFR in HSCC tissues was upregulated compared with those in the adjacent noncancerous tissues. Further clinicopathological characteristics analysis revealed that the expression of Notch1 was positively correlated with distant metastasis (P=0.003) and tumor differentiation (P=0.031). The high expression of Notch1 is an independent prognostic factor for a poor overall survival in patients with HSCC (P=0.015, chi 2=10.403). Knocking down of Notch1 significantly inhibits the migration and invasion of FaDu cells in vitro. Mechanistic investigation reveals that Notch1 knockdown is found suppressing the expression of EGFR at transcriptional level. Interestingly, we further found that Notch1 knockdown also decreased the expression of YBX1, which is a transcription factor of EGFR. Moreover, the upregulation of YBX1 reverses the suppression of Notch1 on EGFR. Furthermore, forced overexpression of YBX1 induced the invasion of FaDu cells. Conclusion: Taken together, we found a positively cross-linked role of Notch1 signaling in the outcome of HSCC, providing a novel valuable prognostic marker and potential therapeutic target for the treatment of HSCC patients. Notch1 is a core signaling molecule for regulating migration and invasion via interplaying with EGFR in HSCC cells. PMID- 30425529 TI - Research progress on GP73 in malignant tumors. AB - Malignant cancer is one of the most serious diseases that currently endanger human health. As most tumors are diagnosed at an advanced stage, the current treatments show poor therapeutic efficacy, and the patients have poor prognosis. However, a 5-year survival rate higher than 80% could be achieved if tumors are diagnosed at an early stage. Therefore, early diagnosis and treatment play important roles in the prevention and treatment of malignant tumors, and serum tumor markers are important for the early diagnosis of malignant cancers. Recent studies have shown that GP73, a transmembrane protein, has greater diagnostic value in primary liver cancer than in other types of cancers, and research on the regulation of GP73 expression has unveiled broad prospects in anticancer targeted therapy. Thus, GP73, as a new tumor marker, deserves further study. PMID- 30425528 TI - Comprehensive bioinformatics analysis identifies several potential diagnostic markers and potential roles of cyclin family members in lung adenocarcinoma. AB - Purpose: The aim of this study was to identify critical genes in lung cancer progression. Methods: We downloaded and reanalyzed gene expression profiles from different public data-sets using comprehensive bioinformatics analysis. Differentially expressed genes (DEGs) were identified in lung adenocarcinoma tissues compared with adjacent nonmalignant lung tissues. The overlapping DEGs identified from different datasets were used for functional and pathway enrichment analyses and protein-protein interaction (PPI) analysis. Moreover, transcription factors (TFs) and miRNAs that regulated the overlapping DEGs were predicted, followed by a TF-miRNA-target network construction. Furthermore, survival analysis of genes was performed. Several genes were further validated by quantitative real-time PCR (qRT-PCR). Results: A total of 647 overlapping upregulated genes and 979 overlapping downregulated genes were identified. The overlapping upregulated genes and downregulated genes were involved in different functions, such as cell cycle, p53 signaling pathway, immune response, and cell adhesion molecules (CAMs). Several genes belonging to the cyclin family, including CCNB1, CCNB2, and CCNA2, were hubs of the PPI network and TF-miRNA target network. Additionally, genes, including NPAS2, GNG7, CHIA, and SLC2A1, were predicted to be prognosis-related DEGs. Gene expression profiles determined by bioinformatics analysis and qRT-PCR were highly comparable. Conclusion: CCNB1, CCNB2, CCNA2, NPAS2, GNG7, CHIA, and SLC2A1 are promising targets for the clinical diagnosis and therapy of lung adenocarcinoma. PMID- 30425530 TI - Activated pulmonary tuberculosis in a patient with melanoma during PD-1 inhibition: a case report. AB - Background: PD-1 checkpoint inhibitors have shown a robust tumor response in the treatment of various cancers. Pembrolizumab is an anti-PD-1 checkpoint antibody approved for the treatment of unresectable or metastatic melanoma in more than 40 countries. Although autoimmune pneumonitis is considered a common immune-related adverse event of PD-1 inhibitors, only limited studies have assessed the development of opportunistic infections such as pulmonary tuberculosis (TB). Case presentation: A patient with metastatic melanoma whose pulmonary TB was activated after administration of pembrolizumab for melanoma is reported. Anti-TB drugs were administered, followed by pembrolizumab (2 mg/kg, repeated every 28 days), which successfully cured the TB and achieved complete response for melanoma. Conclusion: Activated pulmonary TB was observed during the administration of pembrolizumab. It was safe and effective in the current patient to combine anti TB drugs and PD-1 inhibitors. More importantly, screening pulmonary TB before administration of PD-1 inhibitors is recommended. PMID- 30425531 TI - Regulation of cell proliferation and metastasis by microRNA-593-5p in human gastric cancer. AB - Background: MicroRNA (miRNA) array analysis has reported that the expression of miR-593-5p is associated with lymph node metastasis in gastric cancer (GC); however, the function and mechanism of miR-593-5p in GC have not been described yet. miR-593-5p has also not been elucidated widely in other cancers. Methods: miR-593-5p expression was detected by quantitative RT-PCR (qRT-PCR) in human GC tissues and cell lines. Cell proliferation was investigated using CCK-8 assays, cell cycle was detected by flow cytometric method, and cell migration and invasion abilities were evaluated by wound-healing and transwell assays. miR-593 5p-influenced gene expression profiles were detected by total gene expression chip method in MGC-803 cells, and miR-593-5p candidate target genes were predicted using bioinformatics methods. The candidate target gene and downstream of miR-593-5p were determined by qRT-PCR, Western blot, and dual-luciferase reporter assays. The effects of miR-593-5p on the growth and metastasis of GC were evaluated by tumor xenograft experiment in vivo. Results: miR-593-5p was frequently downregulated in GC patients and GC cell lines. miR-593-5p was significantly correlated with tumor size and distant metastasis in GC patients. miR-593-5p inhibited cell proliferation, migration, and invasion and also arrested cell cycle at the G0/G1 phase in SGC-7901 and MGC-803 cells in vitro. miR-593-5p also suppressed tumor growth and metastasis in vivo. miR-593-5p influenced gene expression profile in MGC-803 cells. MST4 was indirectly targeted by miR-593-5p. miR-593-5p also downregulated FAK, MMP12, and JUN protein expression. Conclusion: Our study suggests that miR-593-5p may function as a tumor suppressor in GC through a mechanism that regulates JUN pathway via indirectly targeting the MST4 gene. PMID- 30425532 TI - ARHGAP30 suppressed lung cancer cell proliferation, migration, and invasion through inhibition of the Wnt/beta-catenin signaling pathway. AB - Objective: Rho GTPase-activating protein 30 (ARHGAP30), a member of the Rho GTPase-activating proteins (Rho GAPs) family, plays an important role in the regulation of cytoskeleton organization and cell adhesion. Materials and methods: mRNA and protein expression was assessed by quantitative real-time PCR and Western blotting, respectively. Cell Counting Kit-8 (CCK-8) and Transwell assays were conducted to detect cell proliferation, migration, and invasion. Results: ARHGAP30 expression was downregulated in specimens and cell lines of lung cancer in comparison to non-cancerous specimens and normal bronchial epithelial cell lines, respectively. Moreover, in vitro experiments demonstrated that ARHGAP30 overexpression impeded the proliferative, migratory, and invasive abilities of lung cancer cells. Moreover, bioinformatics analysis with The Cancer Genome Atlas (TCGA) lung cancer dataset showed a negative association between ARHGAP30 expression and the Wnt signaling pathway. Enforced expression of ARHGAP30 decreased the mRNA and protein levels of beta-catenin, c-Myc, matrix metalloproteinase-2 (MMP-2) and MMP-9. Besides, the beta-catenin inhibitor XAV939 blocked the enhanced cell growth, migration, and invasion caused by ARHGAP30 knockdown. Thus, the Wnt/beta-catenin pathway mediated the functions of ARHGAP30 in lung cancer cells. Conclusion: ARHGAP30 acts as a tumor suppressor in lung cancer by suppressing Wnt/beta-catenin signaling. PMID- 30425533 TI - Distinct features of rabbit and human adipose-derived mesenchymal stem cells: implications for biotechnology and translational research. AB - Introduction: Owing to their similarity with humans, rabbits are useful for multiple applications in biotechnology and translational research from basic to preclinical studies. In this sense, mesenchymal stem cells (MSCs) are known for their therapeutic potential and promising future in regenerative medicine. As many studies have been using rabbit adipose-derived MSCs (ASCs) as a model of human ASCs (hASCs), it is fundamental to compare their characteristics and understand how distinct features could affect the translation to human medicine. Objective: The aim of this study was to comparatively characterize rabbit ASCs (rASCs) and hASCs to further uses in biotechnology and translational studies. Materials and methods: rASCs and hASCs were isolated and characterized by their immunophenotype, differentiation potential, proliferative profile, and nuclear stability in vitro. Results and discussion: Both ASCs presented differentiation potential to osteocytes, chondrocytes, and adipocytes and shared similar immunophenotype expression to CD105+, CD34-, and CD45-, but rabbit cells expressed significantly lower CD73 and CD90 than human cells. In addition, rASCs presented greater clonogenic potential and proliferation rate than hASCs but no difference in nuclear alterations. Conclusion: The distinct features of rASCs and hASCs can positively or negatively affect their use for different applications in biotechnology (such as cell reprogramming) and translational studies (such as cell transplantation, tissue engineering, and pharmacokinetics). Nevertheless, the particularities between rabbit and human MSCs should not prevent rabbit use in preclinical models, but care should be taken to interpret results and properly translate animal findings to medicine. PMID- 30425534 TI - Stem cell therapy in autism: recent insights. AB - Autism spectrum disorders (ASDs) are characterized by core domains: persistent deficits in social communication and interaction; restricted, repetitive patterns of behavior, interests, or activities. ASDs comprise heterogeneous and complex neurodevelopmental pathologies with well-defined inflammatory conditions and immune system dysfunction. Due to neurobiologic changes underlying ASD development, cell-based therapies have been proposed and applied to ASDs. Indeed, stem cells show specific immunologic properties, which make them promising candidates in ASD treatment. This comprehensive up-to-date review focuses on ASD cellular/molecular abnormalities, potentially useful stem cell types, animal models, and current clinical trials on the use of stem cells in treating autism. Limitations are also discussed. PMID- 30425535 TI - Molecular detection of rifampin, isoniazid, and ofloxacin resistance in Iranian isolates of Mycobacterium tuberculosis by high-resolution melting analysis. AB - Background: The emergence of drug resistance among Mycobacterium tuberculosis (MTB) strains is a serious health concern worldwide. The development of rapid molecular diagnostic methods in recent years has a significant impact on the early detection of resistance to major anti-TB drugs in MTB isolates, which helps in employing appropriate treatment regimen and prevents the spread of drug resistant strains. This study was designed to evaluate the efficacy of real-time PCR and high-resolution melting (HRM) curve analysis for the determination of resistance to rifampin (RIF), isoniazid (INH), and ofloxacin (OFX) in MTB isolates and to investigate their resistance-related mutations. Methods: HRM analysis was performed to screen 52 (32 drug-resistant and 20 fully susceptible) MTB clinical isolates for mutations in rpoB, katG, mab-inhA, and gyrA genes. The HRM results were then confirmed by DNA sequencing. Results: In total, 32 phenotypically resistant isolates, comprising 18 RIF-, 16 INH-, and five OFX- resistant strains, were investigated. HRM analysis successfully identified 15 out of 18 mutations in rpoB, 14 out of 16 mutations in katG and mab-inhA, and four out of five mutations in gyrA conferring resistance to RIF, INH, and OFX, respectively. The obtained sensitivity and specificity, respectively, for HRM in comparison with phenotypic susceptibility testing were found to be 83.3% and 100% for RIF, 87.5% and 100% for INH, and 80% and 100% for OFX. In five resistant strains (12.8%), no mutation was detected by using HRM and DNA sequencing. Conclusion: HRM assay is a rapid, accurate, and cost-effective method possessing high sensitivity and specificity for the determination of antibiotic resistance among MTB clinical isolates and screening of their associated mutations. This method can generate results in a shorter period of time than taken by the phenotypic susceptibility testing and also allows for timely treatment and prevention of the emergence of possible MDR strains. PMID- 30425536 TI - The threat of carbapenem-resistant gram-negative bacteria in a Middle East region. AB - Data on the status of carbapenem-resistant microorganisms in the Middle East countries are scarce. The aim of this review was to collect available data regarding resistance to carbapenems in a Middle East region. Available data regarding carbapenem-resistant isolates were considered for evaluation in this review. Biomedical electronic databases were systematically searched to find related articles. The key terms used were "carbapenem-resistant, resistant gram negative bacilli, Enterobacteriaceae, fermenting and non-fermenting gram-negative bacilli, Pseudomonas, Acinetobacter, Klebsiella and Iran". After primary screening, 275 relevant articles were selected to be assessed thoroughly. Resistance rate to carbapenems was reported between 1% and 86% during years 2006 2018. Most of the carbapenem-resistant microorganisms were isolated from burn patients. Modified Hodge test was a commonly used phenotypic test. Only in few studies, genotypic assays were considered. Pattern of antibiotic use can affect emergence of resistant microorganisms. Rational use of drugs, and specifically, antibiotics is a challenging issue in developing countries. Mean number of drugs per prescription in these countries was higher than the World Health Organization standards. Overuse of antibiotics, especially injectable ones, and easy access to antibiotics without prescription is a warning alarm for future antibiotic resistance in developing countries. Establishing antimicrobial stewardship's programs is new in the hospitals. Unfortunately, rules and regulatory issues to restrict antibiotic access in community pharmacies and prescription by general physicians are limited. PMID- 30425537 TI - Ertapenem non-susceptibility and independent predictors of the carbapenemase production among the Enterobacteriaceae isolates causing intra-abdominal infections in the Asia-Pacific region: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART). AB - Objectives: This study investigated the prevalence rates of carbapenemase positivity, antibiotic susceptibility, and independent predictors of carbapenemase producers among the Enterobacteriaceae isolates recovered from patients with intra-abdominal infections (IAI) in the Asia-Pacific region between 2008 and 2014. Materials and methods: Multiplex PCR was used for the detection of specific beta-lactamases, while the broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of antibiotics among the IAI-related Enterobacteriaceae isolates. We studied the abovementioned parameters in 484 ertapenem-non-susceptible (Erta-NS) isolates and explored the independent predictors of carbapenemase-producing Enterobacteriaceae (CPE) isolates. Results: Eighty (16.5%) Erta-NS-IAI Enterobacteriaceae isolates were found to be CPE. Vietnam and the Philippines had the highest CPE prevalence rates. The IAI isolates of Enterobacter species and Klebsiella pneumoniae followed by Escherichia coli were the three major pathogens with 77.4%, 40.9%, and 11.7% Erta NS prevalence rates, respectively. Furthermore, the highest CPE prevalence (35%) was noted among the Erta-NS-K. pneumoniae isolates. The CPE isolates harboring the bla NDM, bla KPC, or blaOXA-48-like alleles had higher imipenem MIC levels than those harboring the bla IMP alleles. Using multivariate logistic regression analysis, we concluded that Erta-NS-IAI isolates with an imipenem non-susceptible phenotype (OR, 56.4), with cefepime MIC >8 ug/mL (OR, 4.4), cultured from the peritoneal space samples (tissue or abscess; OR, 3.3), and harboring the extended spectrum beta-lactamase encoding allele (OR, 11.5) are independent predictors of CPE. Conclusion: Imipenem non-susceptibility, cefepime MIC >8 ug/mL, and the peritoneal space as a culture site are independent clinical predictors of CPE among the Erta-NS-IAI Enterobacteriaceae isolates in the Asia-Pacific region. PMID- 30425538 TI - Efficacy of antifungal drugs in the treatment of vulvovaginal candidiasis: a Bayesian network meta-analysis. AB - Purpose: Antifungal drugs are used frequently in the treatment of vulvovaginal candidiasis (VVC), but have shown controversial results. In this study, we aimed to evaluate the effectiveness of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use. Methods: The published studies on the effectiveness of antifungal drugs in the treatment of VVC (up to April 2018) were retrieved from PubMed, Embase, the Cochrane Library, and Clini-calTrials.gov. We sifted through the literature according to Patients, Interventions, Comparisons and Outcomes principle, extracted data on the basic characteristics of the study, and evaluated the quality of included studies. We used R software for statistical analysis. Results: In total, 41 randomized controlled trials were included in this meta-analysis. The relative risk of VVC associated with ten drugs, including placebo, fluconazole, clotrimazole, miconazole, itraconazole, ketoconazole, econazole, butoconazole, terbinafine, and terconazole, was analyzed. The following drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =6.45, 95% CrI 4.42-9.41), clotrimazole (OR =2.99, 95% CrI 1.61-5.55), miconazole (OR =5.96, 95% CrI 3.17 11.2), itraconazole (OR =2.29, 95% CrI 1.21-4.33), ketoconazole (OR =2.40, 95% CrI 1.55-3.71), butoconazole (OR =1.18, 95% CrI 1.06-1.31), and terconazole (OR =5.60, 95% CrI 2.78-11.3). The value of surface under the cumulative ranking curve of each drug was as follows: placebo (0.5%), fluconazole (91.5%), clotrimazole (61.8%), miconazole (33.8%), itraconazole (50.5%), ketoconazole (42.8%), econazole (46.8%), butoconazole (82.2%), terbinafine (20.9%), and terconazole (65.0%). Conclusion: Antifungal drugs are effective in the treatment of VVC. Fluconazole appeared to be the best drug for the treatment of VVC according to our analysis. PMID- 30425539 TI - Selection inversion: a probable tool against antibiotic resistance. AB - Antibiotic therapy has a dual impact: wanted, in which it immediately inhibits the growth of bacteria and the unwanted, which is responsible for the evolution of antibiotic resistance. The dissociation of therapeutic effectiveness from the possible risk of the antibiotic resistance may be attained by taking the advantage of specific relations between these drugs, and the methods in which mutations associated with resistance against a specific antibiotic may modify these relations or it may increase the sensitivity of the bacterium to the other antibiotics. Although the practical implementation of this notion needs considerable advancement and confirmation that depends upon the improvements in the field of genomics and diagnostics, these interventions propose new paradigms, which may confine or inverse the evolution of antibiotic resistance. PMID- 30425540 TI - Systematic review in South Africa reveals antibiotic resistance genes shared between clinical and environmental settings. AB - A systematic review was conducted to determine the distribution and prevalence of antibiotic-resistant bacteria (ARB), antimicrobial-resistant genes (ARGs), and antimicrobial-resistant gene determinants (ARGDs) in clinical, environmental, and farm settings and to identify key knowledge gaps in a bid to contain their spread. Fifty-three articles were included. The prevalence of a wide range of antimicrobial-resistant bacteria and their genes was reviewed. Based on the studies reviewed in this systematic review, mutation was found to be the main genetic element investigated. All settings shared 39 ARGs and ARGDs. Despite the fact that ARGs found in clinical settings are present in the environment, in reviewed articles only 12 were found to be shared between environmental and clinical settings; the inclusion of farm settings with these two settings increased this figure to 32. Data extracted from this review revealed farm settings to be one of the main contributors of antibiotic resistance in healthcare settings. ARB, ARGs, and ARGDs were found to be ubiquitous in all settings examined. PMID- 30425541 TI - Impact of antiepileptic-drug treatment burden on health-care-resource utilization and costs. AB - Background: Complex titration requirements and dosing of antiepileptic drugs (AEDs) may pose a significant treatment burden for patients with epilepsy. This study evaluated health-care-resource utilization (HCRU) rates and costs by treatment burden, defined as number of daily pills and dosing frequency, among managed-care enrollees with epilepsy who initiated AED monotherapy. Methods: This retrospective longitudinal study examined administrative HC-claim data in patients aged >=18 years with two or more pharmacy claims for an AED and two or more medical claims for epilepsy or afebrile convulsion. The number of daily AED pills was estimated at index as the total number of pills dispensed divided by the days supplied, and categorized as more than zero/one, one/two, two/three, and more than three per day. AED-dosing frequency was measured at index and categorized as one, two, three, or four times daily. Postindex 12-month all-cause and epilepsy-related HCRU and costs were estimated using multivariable Poisson regression models and generalized linear models, respectively. Results: Unadjusted total all-cause and epilepsy-related costs at 12 months postindex averaged US$26,015 per person and US$5,557 per person (2017 values), respectively. Adjusted all-cause and epilepsy-related costs were US$25,918 per person and US$5,602 per person, respectively. A pill burden of more than three a day was associated with a 6.7% increase in total annual HC costs compared with one pill/day. Patients receiving one/two, two/three, and more than three pills per day had 13.3%, 23.9%, and 38.3% higher epilepsy-related costs, respectively, than those receiving one pill per day (P<0.0001). Increase in dosing frequency was associated with greater total HCRU and higher costs, but only patients with twice-daily dosing had significantly higher epilepsy-related costs. Conclusion: Findings from this study suggest that increased treatment burden is associated with greater HCRU and higher overall and epilepsy-related costs. Reducing treatment burden via selection of AED therapy with reduced pill numbers and dosing frequency should be considered to improve health and economic outcomes. PMID- 30425542 TI - Health-related outcomes and economic burden in Japan: focus on inflammatory bowel disease, multiple sclerosis, and depression. PMID- 30425543 TI - Depressive symptoms among elderly diabetic patients in Vietnam. AB - Background and aims: Depression and diabetes are becoming increasingly prevalent within the Vietnamese elderly population. However, the linkage between these health conditions in the Vietnamese elderly has not yet been fully investigated. This study aimed to assess the level of depressive symptoms and associated factors among elderly diabetic patients. Methods: A cross-sectional study was conducted at National Geriatric Hospital in the elder patients aged >=60 years with type 2 diabetes mellitus (T2DM). Depressive symptoms were assessed using the Geriatric Depression Scale, with three categories: normal (0-4 points), mild (5-9 points), and moderate/severe depressive symptoms (>=10 points). We obtained information on the patient's sociodemographic, medical history, glycemic control (fasting plasma glucose and HbA1c), daily activities (activities of daily living [ADLs] and instruments activities of daily living [IADLs] scale), and fall risks (Time Up and Go test). Logistic regression was used to analyze the factors associated with the presence of depressive symptoms. Results: Among 412 patients, 236 (57.3%) had HbA1c level at 7.0% or higher. There were 327 (79.4%) patients having depressive symptoms. The level of HbA1c was significantly different between the depressive symptom group and the non-depressive symptom group (7.74% and 6.61%, P<0.05). The increased likelihood of having depressive symptoms was associated with having risk of falls (OR: 5.50; 95% CI: 1.88-16.11), suffering from 5-10 years of diabetes (OR: 2.74, 95% CI: 1.28-5.85), uncontrolled fasting plasma glucose (OR: 4.06, 95% CI: 1.81-9.12), and an impairment of IADLs (OR: 5.74, 95% CI: 2.24-14.7). Conclusion: This study highlights a high prevalence of depressive symptoms among elderly T2DM patients in Vietnam, suggesting an urgent need for screening depressive symptoms and providing mental health care services to this population promptly, particularly to those suffering from diabetes for a long period of time or co-functional impairments. PMID- 30425544 TI - Influence of gastric bypass surgery on resting energy expenditure, body composition, physical activity, and thyroid hormones in morbidly obese patients. AB - Introduction: One way to lose weight is bariatric surgery. Various studies have shown that after Roux-en-Y gastric bypass (RYGB), resting energy expenditure (REE) decreased may be a result of changes in fat-free mass (FFM) and thyroid stimulating hormone levels. The aim of our study was to assess changes in body composition, REE, and thyroid hormones in patients undergoing RYGB. Methods: A total of 42 patients participated (21 undergoing RYGB and 21 age- and weight matched subjects as controls) in our study. Weight, body-mass index, body composition, resting metabolic rate, physical activity, and thyroid hormones were measured at baseline in cases and 3 months after surgery in case and control groups. Results: At 3 months after surgery, patients lost an average of 21.7+/ 1.4 kg weight, and fat mass, FFM, and REE decreased significantly. REE was higher in cases compared to controls. T4, T3, and thyroid-stimulating hormone at 3 months after RYGB decreased, but the decrease was significant only in T4 compared to controls. FFM was higher and fat mass lower in cases compared to controls. Conclusion: We detected a meaningful difference in REE before and after surgery, but we did not detect any meaningful difference in REE between controls and cases. PMID- 30425545 TI - Astragalus polysaccharides inhibit oxidation in high glucose-challenged or SOD2 silenced H9C2 cells. AB - Introduction: Oxidative stress plays an important role in the development of diabetic cardio-myopathy (DCM). Previously, we reported that Astragalus polysaccharides (APS) improved DCM by inhibition of cardiac oxidative stress. In this study, we evaluated the beneficial effect of APS on high glucose-induced oxidative stress in cardiomyocytes in vitro. Materials and methods: H9C2 cells were cultured in the presence of high concentration of glucose or transfected with siRNASOD2, followed by APS treatment. The cellular mitochondrial ultrastructure was observed using a transmission electron microscope. Cell apoptosis was detected using hairpin oligonucleotide probes and quantified by flow cytometry analysis. Superoxide production was determined by immunohistochemistry using the fluorescent dye dihydroethidium (DHE). Nitrotyrosine and 8-OH-dG antibodies were employed to detect oxidative damage to cytoplasmic proteins and oxidative stress in the nuclei, respectively. Superoxide dismutase (SOD) activity was measured utilizing the SOD Assay Kit, and SOD protein levels were analyzed by Western blotting. Results: APS treatment protected cellular mitochondrial ultrastructure, reduced cell apoptosis (hairpin 1), inhibited cellular superoxide production (DHE), and reduced oxidative damage to cytoplasmic proteins (nitrotyrosine) and oxidative stress in the nuclei (8-OH dG) in high glucose-induced and/or SOD2-silenced H9C2 cells, together with induction of SOD2 enzyme activity and increase of protein levels. Conclusion: Our findings indicated the beneficial effect of APS on high glucose-challenged H9C2 cells, which was associated with inhibition of oxidative stress in vitro. PMID- 30425546 TI - Regularities of free radical processes and involutional changes of face and neck skin in different age groups. AB - Aim: The purpose of this study was to examine the role of free radical oxygen and peroxide- lipid processes along with conducting the study of blood flow level and oxygen saturation of facial tissues in patients of different ages with varying degrees of involutional changes in the skin of the face and neck. Materials and methods: One hundred and fifty-three people (84.3% women and 15.7% men) aged from 26 to 78 years with varying degrees of involutional changes in facial skin were examined. The clinical and laboratory evaluation was carried out dynamically and included various indicators of free radical processes, objective and subjective clinical visualization, and laser Doppler flowmetry (LDF) of the facial skin and transcutaneous oximetry (TcpO2) performed at 10 points on the face. To assess the state of free radical processes, the authors investigated the basal indicator of chemiluminescence intensity (ICb), the intensity of chemiluminescence stimulated (ICs) by zymosan, the activity coefficient (AC) of chemiluminescence, antiperoxide activity of plasma, and malondialdehyde (MDA). Results: With aging, the imbalance of the oxygen constituents of free radical processes grows with the increase in ROS. Proportional to age, the ICs increased 2.1 times on average in people older than 55 years compared to that in people younger than 30 years and ICb decreased by 1.8 times. As a result, the AC increased by 5.6 times. This correlates with involuntary skin changes and with regression of microcirculation and TcpO2. According to LDF, it was established that average total blood flow in people younger than 30 years and people older than 55 years was 8.1 and 6.4 mL/min, respectively The difference between the indicators of TcpO2 in people younger than 30 years and people older than 55 years was 1.6 times (average 56 vs 35 mm Hg). The stability of the indicators of the peroxide-lipid link of oxidative stress in different age groups demonstrated that the activation of ROS formation in mitochondria is not a cause but a consequence of microcirculation and metabolic processes in the face and neck and aging in general. Conclusion: The tissue metabolism and microcirculation parameters naturally regress with aging, which is associated with the increase of ROS. The excess of species leads to the intensification of peroxide processes. This, in turn, is reflected in the aesthetic appearance manifested by aging. PMID- 30425547 TI - Patients with chronic mesenteric ischemia have an altered sublingual microcirculation. AB - Background: Little is known about the microcirculatory alterations in patients with chronic mesenteric ischemia (CMI). We hypothesized that patients with CMI have an impaired microcirculatory function and show an oral microcirculatory response after caloric challenge compared to healthy controls. Methods: All patients and controls received the standard workup for CMI. Sublingual micro circulation was evaluated before (T0) and 20 minutes after (T1) feeding. The total vessel density (TVD; mm/mm2), perfused vessel density (PVD; mm/mm2), proportion of perfused vessels (PPV; %) and microvascular flow index (MFI; AU) were assessed. Results: We included 12 patients (63.2 years [IQR 48.8-70.4 years], 67% males) and 12 controls (32.7 years [IQR 27.7-38.1 years], 42% males). At baseline, patients with CMI had a decreased PPV of the sublingual small vessels (median 84.8% vs 95.7%, P=0.006), PPV of all vessels (PPV median 85.4% vs 95.3%, P=0.007) and microvascular flow index of all vessels (MFIa; median 3.00 vs 2.80, P=0.039) compared to healthy controls. After caloric challenge, PVD increased significantly in both small vessels (perfused vessel density of the small vessels [PVDs]) and all vessels (perfused vessel density of all vessels [PVDa]; PVDs [T0]) median 16.3 [IQR 13.3-22.1] vs [T1] median 19.9 [IQR 14.2 26.2], P=0.008; PVDa [T0] median 19.1 [IQR 16.2-23.6] vs [T1] median 22.2 [IQR 16.5-28.9], P=0.02; proportion of perfused vessels of the small vessels (PPVs; [T0] median 84.8% [IQR 75.3-90.4] vs [T1] median 91.0% [IQR 80.1-93.8], P=0.010). In contrast, no significant changes in microcirculatory parameters were observed after caloric challenge in healthy controls. Conclusion: Patients with CMI have an impaired sublingual microcirculation at baseline and show a significant response in the sublingual microcirculation after caloric challenge, whereas healthy controls have a normal microcirculation at baseline and show no reactive response upon a caloric challenge as seen in CMI patients. Sublingual microcirculation visualization may offer a rapid noninvasive method to identify patients at risk for having CMI. PMID- 30425548 TI - A study of the circulating fibroblast growth factor 21 as a novel noninvasive biomarker of hepatic injury in genotype-4 chronic hepatitis C: Egyptian patients and their response to direct-acting antiviral agents. AB - Background: Fibroblast growth factor (FGF) 21 was reported to be induced by different injurious agents, including chronic hepatitis C (CHC) virus, affecting the liver. The aims of this study were to evaluate the FGF21 levels in CHC patients before and after the treatment with direct-acting antiviral agents (DAAs) in comparison to that in control subjects and to correlate these levels with insulin resistance (IR), lipid profile, and fibrosis stages. Patients and methods: We studied 75 naive CHC patients and 40 age- and gender-matched healthy control subjects. Patients were divided into five groups based on the severity of fibrosis as detected by Fibroscan as follows: F0, n=2; F1, n=13; F2, n=23; F3, n=16; F4, n=21. We estimated the FGF21 levels at the start of the study for all the participants and for the patients only at the end of treatment with simisipivir (SIM) and sofosbuvir (SOF). These levels were compared between the patients and the control subjects and also for the patients before and after the treatment with DAAs. The FGF21 levels were correlated to IR, lipid profile, and stages of liver fibrosis. Results: The FGF21, fasting blood sugar (FBS), fasting insulin, and homeostasis model of IR (HOMA-IR) were significantly higher in CHC patients compared to control (5.04+/-0.75 vs 4.7+/-0.52, 20.15+/-5.13 vs 13.15+/ 4.2, 4.49+/-1.28 vs 2.72+/-0.87, and 123.7+/-52.6 vs 21.8+/-8.8; P<=0.01, P<=0.001, P<=0.001, and P<=0.001, respectively). The posttreatment FGF21 levels were significantly reduced when compared to the pretreatment levels (123.7+/-52.5 vs 60.5+/-32.7, P<=0.001). FGF21 levels showed significant negative correlation with FBS and positive correlation with serum albumin (P<=0.05 and P<=0.003, respectively). The multiple linear regression analysis revealed that serum albumin, high-density lipoprotein cholesterol (HDL-c), and the stage of liver fibrosis were independent risk factors for FGF21. Conclusion: Besides its metabolic modulator role, FGF21 strongly introduced itself as a novel biomarker of hepatic injury in Egyptian, genotype-4, CHC patients. PMID- 30425550 TI - Impact of a multidisciplinary pain management program on patient care utilization and cost of care. AB - Objective: Chronic pain is a highly prevalent and costly condition with few proven treatment options. Since 2014, Geisinger's Department of Pain Medicine has implemented the Multidisciplinary Pain Program (MPP), which consists of a 3-day educational seminar followed by 12 months of comprehensive care. This study examines the impact of MPP on care utilization and cost between 2014 and 2016. Methods: A retrospective health insurance claims data analysis covering a 3-year period between January 2013 and December 2016. Among all patients referred to MPP during the period, a subset of those who were Geisinger Health Plan (GHP) members was identified (113 patients). Those who were GHP members and were referred to MPP after December 2016 served as the contemporaneous comparison group (69 patients). GHP's claims data for the corresponding period were analyzed on a per member-per-month (PMPM) basis. Results: MPP was associated with US$754 PMPM reduction in total cost of care including prescription drug costs (P=0.014) and US$846 reduction in total medical cost excluding prescription drugs (P=0.006). These cost savings were attributable to reductions in utilization of high-end diagnostic imaging (52 per-1,000 members-per month; P=0.015) and acute inpatient admissions (20 per-1,000 members-per month; P=0.086). Conclusion: Patients enrolled in MPP were less likely to use expensive diagnostic imaging and experienced fewer hospitalizations, resulting in total cost of care savings. These findings are consistent with the expectation that MPP improves health outcomes among patients suffering from chronic pain. PMID- 30425549 TI - CYP2D6 genotype can help to predict effectiveness and safety during opioid treatment for chronic low back pain: results from a retrospective study in an Italian cohort. AB - Background: Opioids are widely used for chronic low back pain (CLBP); however, it is still unclear how to predict their effectiveness and safety. Codeine, tramadol and oxycodone are metabolized by CYP/CYP450 2D6 (CYP2D6), a highly polymorphic enzyme linked to allele-specific related differences in metabolic activity. Purpose: CYP2D6 genetic polymorphisms could potentially help to predict the effectiveness and safety of opioid-based drugs in clinical practice, especially in the treatment of CLBP. Patients and methods: A cohort of 224 Italian patients with CLBP treated with codeine or oxycodone was retrospectively evaluated to determine whether adverse reactions and effectiveness were related to CYP2D6 single-nucleotide polymorphisms. CYP2D6 genotyping was performed using the xTAG(r) CYP2D6 Kit v3 (Luminex) to determine CYP2D6 metabolizer phenotype (poor, intermediate, rapid and ultrarapid). Subjects from the cohort were categorized into two groups according to the occurrence of side effects (Case) or benefit (Control) after chronic analgesic treatment. The impact of CYP2D6 polymorphism on treatment outcome was tested at the metabolizer phenotype, diplotype and haplotype levels. Results: CYP2D6 polymorphism was significantly associated with opioid treatment outcome (Omnibus P=0.018, for both global haplotype and diplotype distribution test). CYP2D6*6 and *9 carriers, alleles characterized by a reduced (*9) or absent (*6) enzymatic activity, were significantly (P<0.05) associated with therapeutic failure. CYP2D6 ultrarapid metabolizers (CYP2D6*2N patients) showed an increased risk of side effects, as would be predicted. Despite their low frequency, CYP2D6 *1/*11, *4/*6 and *41/* 2N diplotypes showed significant (P<0.05) associations of efficacy and side effects with chronic opioid treatment. Conclusion: Our results showed that reduced CYP2D6 activity is correlated with lack of therapeutic effect. We found that the pharmacogenetic analysis of CYP2D6 could be helpful in foreseeing the safety and effectiveness of codeine or oxycodone treatment in CLBP. PMID- 30425552 TI - Erratum: Prevalence of central and peripheral neuropathic pain in patients attending pain clinics in Spain: factors related to intensity of pain and quality of life [Corrigendum]. AB - [This corrects the article on p. 1835 in vol. 11, PMID: 30254486.]. PMID- 30425551 TI - Socioeconomic factors, psychological factors, and function in adults with chronic musculoskeletal pain from rural Nepal. AB - Background: Both socioeconomic and psychological factors have been shown to predict patient function in samples of individuals with chronic pain in Western countries. However, little is known about their role as predictors of function in individuals with chronic pain from developing countries. Purpose: The purpose of this study was to examine the associations between measures of socioeconomic factors (income, education) and psychological factors (catastrophizing and resilience) and measures of function in a sample of individuals with chronic pain from rural Nepal. In addition, we sought to evaluate the moderating effects of socioeconomic factors on the associations between the psychological variables and function. Methods: We interviewed 143 adults with chronic musculoskeletal pain from rural areas of Nepal to assess income, education level, pain intensity, catastrophizing, resilience, physical function, and depression. We performed two regression analyses to evaluate the direct and unique effects of the socioeconomic and psychological variables and pain intensity as predictors of patient function, as well as the moderating influence of income, education level, and pain intensity on the associations between the psychological variables and function. Results: Education and income both predicted physical function, but only income predicted depression. In addition, pain catastrophizing, but not resilience, evidenced a direct and significant independent association with depression. Neither catastrophizing nor resilience made independent and significant direct contributions to the prediction of physical function. The association between resilience and physical function was moderated by pain intensity and income, and income (but not education or pain intensity) moderated the associations between both 1) resilience and depression and 2) catastrophizing and depression. Conclusion: The results suggest the possibility that cultural differences may influence the role that psychosocial factors play in chronic pain adjustment. These findings have important implications regarding how psychosocial pain interventions should be adapted by individuals in developing countries. PMID- 30425553 TI - Impact of variation in physical activity after total joint replacement. AB - Purpose: Patients who undergo total knee arthroplasty (TKA) or total hip arthroplasty (THA) often develop postoperative pain. Exercise approaches are recommended postoperatively; however, the impact of excessive variation in physical activity is unclear. The purpose of the present preliminary study was to investigate the impact of excessive variation in physical activity using the accelerometer in the early period after TKA or THA. Patients and methods: Seventy two patients were enrolled in the study. Forty patients underwent initial TKA, and 32 initial THA. Physical activity was measured for 8 days from postoperative day 3 to 10. Patients with substantial correlation between physical activity and postoperative day were classified as the "good-pacing" group. Patients with no correlation between them were classified as the "poor-pacing" group. They were also evaluated using a pain visual analog scale (VAS), pain catastrophizing scale, and hospital anxiety and depression scale. Results: The average age was 68 years, and 59 patients (82%) were women. The average maximum number of steps per day was 2,181. There were 45 patients with good pacing and 27 with poor pacing. The poor-pacing group showed significantly lower maximum number of steps per day, higher postoperative average VAS score, higher postoperative worst VAS score, and longer duration of postoperative hospital stay than the good-pacing group. Conclusion: Patients with excessive variation in physical activity showed severe postoperative pain and prolonged postoperative hospital stay. The postoperative variation in physical activity could be an outcome for improvement in patients after lower-limb arthroplasty. PMID- 30425554 TI - Pregabalin to improve postoperative recovery in bariatric surgery: a parallel, randomized, double-blinded, placebo-controlled study. AB - Purpose: Obesity has been considered as a major public health problem in developed countries for which bariatric surgery has become an important treatment strategy. Postoperative pain, however, is a frequent problem in postoperative management. Pregabalin blocks the development of hyperalgesia and central pain sensitization. The objective of this randomized, placebo-controlled, double blinded trial was to evaluate the effect of a single dose of preoperative pregabalin vs placebo on the quality of postoperative recovery in patients undergoing bariatric surgery. Patients and methods: A total of 70 patients undergoing abdominal gastroplasty were randomly assigned to receive oral pregabalin (75 mg) or an identical placebo 1 hour before surgery. The primary outcome was Quality of Recovery-40 (QoR-40) score at 24 hours. Secondary outcomes included opioid consumption and postoperative pain scores. P<0.05 was considered to indicate statistical significance. Results: In all, 60 of the 70 patients completed the study. The mean (SD) global recovery scores (QoR-40) 24 hours after surgery in the pregabalin and control groups were 183.7 (9) and 182.1 (12), respectively (mean difference=1.6, 95% CI -7.36 to 4.2, P=0.59). There was no significant difference in the total opioid consumption in the 24 hours following surgery between the two groups (pregabalin vs control=0.47*0.2; mean difference=0.26, 95% CI -0.24 to 0.77, P=0.3). There were no significant differences in nausea, vomiting, or time to postanesthesia care unit discharge between the two groups. Conclusion: In patients who underwent bariatric surgery, a single preoperative dose of pregabalin (75 mg) did not improve pain relief, quality of postoperative recovery, or reduction in opioid consumption. Clinical trial registration: http://www.ensaiosclinicos.gov.br (identifier: RBR-2g89x8). PMID- 30425555 TI - Prevalence of fibromyalgia in fourteen Korean tertiary care university hospital pain clinics. AB - Purpose: We aimed to investigate the prevalence of fibromyalgia (FM) in patients who visited outpatient pain clinics in Korea, using the modified 2010 American College of Rheumatology (ACR) criteria and to evaluate comorbid conditions that may be associated with FM. Patients and methods: Outpatients, aged >=18 years, who first visited pain clinics at any of the 14 tertiary care university hospitals, were recruited for this study. Modified 2010 ACR criteria were used to diagnose FM. Participants' demographic information and eleven comorbid measures (sleep disturbance, fatigue, irritable bowel syndrome, amnesia, hypothyroidism, headache, anxiety, depression, rheumatism, low back pain, and history of traffic accident) were also investigated via additional questionnaires. Results: We recruited 1,233 outpatients (754 men and 479 women). Based on the modified 2010 ACR criteria, 13.38% (165/1,233 patients, 95% CI: 11.48-15.28) of patients had FM. As participants with a history of FM were excluded, the prevalence of FM was 11.0% (123/1,118 patients). Patients with FM were more likely to have one or more of the eleven predetermined comorbid conditions. Patients who were female and who had a previous history of FM, sleep disturbance, headache, or a history of traffic accident were more likely to have FM. Conclusion: FM, according to the modified 2010 ACR criteria, appears to be a common disorder among chronic pain patients referred to tertiary care university hospital pain clinics. Therefore, physicians treating pain should consider this prevalence of FM among pain clinic patients. PMID- 30425556 TI - Peripheral sympathetic mechanisms in orofacial pain. AB - Sympathetic nervous system (SNS) is a part of the autonomic nervous system which involuntarily regulates internal body functions. It appears to modulate the processing of nociceptive information. Many orofacial pain conditions involve inflammation of orofacial tissues and/or injury of nerve, some of which might be attributed to SNS. Thus, the aim of this review was to bring together the data available regarding the peripheral sympathetic mechanisms involved in orofacial pain. A clearer understanding of SNS-sensory interactions in orofacial pain may provide a basis for novel therapeutic strategies for conditions that respond poorly to conventional treatments. PMID- 30425557 TI - Predicting factors of outcome in multidisciplinary treatment of chronic neuropathic pain. AB - Purpose: Evidence of the effectiveness of multidisciplinary treatment with a focus on neuropathic pain is still rare. The present study investigated whether multidisciplinary treatment leads to improvement of neuropathic pain in outcome (pain intensity and disability) and psychological (depression, pain acceptance, and catastrophizing) variables at posttreatment and 3-month follow-up. We examined whether and to what extent psychological changes can predict long-term outcome at 3-month follow-up, when other variables are controlled for (baseline characteristics and changes in pain parameters). Patients and methods: Patients suffering from a chronic neuropathic pain condition (n=141) attended an inpatient multidisciplinary program lasting about 15 continuous days with self-report data collected at pretreatment, posttreatment, and 3-month follow-up. Results: Repeated-measures ANOVAs showed a significant improvement of pain intensity, disability, pain acceptance, catastrophizing, and depression at posttreatment. These improvements remained stable over the 3-month follow-up for all variables except for depression. The inclusion of psychological changes in multiple regression analyses greatly increased the variance in outcome, explained by baseline characteristics and changes in pain parameters. Conclusion: The results could help clinicians to determine which variables should be emphasized during inpatient treatment and during the follow-up period, in order to maintain the gains after an inpatient multidisciplinary treatment for neuropathic pain. Perspective: The present study demonstrates the beneficial effects of an inpatient multidisciplinary program for neuropathic pain and further question the resistant nature of neuropathic pain to treatment. The results add evidence to the relevance of cognitive-behavioral models of pain positing an important role for pain-related thoughts and emotions in long-term outcome following multidisciplinary pain treatment. PMID- 30425558 TI - Comparison of different sufentanil-tramadol combinations for pain relief within the first 24 hours after cesarean section: a retrospective study. AB - Introduction: Postcesarean section pain management is important for both the mother and the newborn. This study compared the analgesic effects and incidence of adverse events associated with intravenous patient-controlled analgesia (iv PCA), using different sufentanil-tramadol combinations for postoperative pain control. Methods: Parturients (n=5,794) who had been scheduled for cesarean section under neuraxial anesthesia and had received iv-PCA between September 2013 and March 2017 were retrospectively analyzed. These patients were assigned to three groups, based on different sufentanil-tramadol combinations: ST1 (n=1,347), ST2 (n=2,401), and ST3 (n=2,046). The analgesic efficacy, total drug consumption, and incidence of adverse effects within 24 hours after surgery were compared among the three groups. Results: The ST3 group had lower visual analog scale pain scores at rest and with movement at all time points during the first 24 hours postoperatively than the other two groups (P<0.01, Bonferroni corrected). The sufentanil dosage administered to the ST3 group was lower, and the tramadol dosage was higher than those administered to the other groups within 24 hours after surgery (P<0.01, Bonferroni corrected). Moreover, all parturients scored 2 points on the Ramsay sedation scale. Adverse reactions such as pruritus and respiratory depression were not observed in any group. No significant differences were noted in the incidence of nausea/vomiting, abdominal distension, and dizziness among the three groups (P>0.05). Conclusion: The visual analog scale scores for postoperative pain decreased as the concentrations of sufentanil and tramadol administered in iv-PCA moderately increased over 24 hours after surgery. This analgesic strategy resulted in a significant reduction in the total sufentanil requirement without increasing the incidence of adverse effects. PMID- 30425559 TI - The impact of prophylactic dexamethasone on postoperative sore throat: an updated systematic review and meta-analysis. AB - Background/Aims: An updated systematic review and meta-analysis was conducted to assess the effect of prophylactic dexamethasone for tracheal intubation of general anesthesia on postoperative sore throat (POST). Methods: Comprehensive literature search of databases for randomized controlled trials (RCTs), including Embase, PubMed, and Cochrane Library, which evaluate the effect of prophylactic dexamethasone on POST was conducted. RevMan 5.0 and STATA 12.0 software were used to perform meta-analyses. Results: Fourteen RCTs totaling 1,837 patients were included for analysis. Compared with placebo, a significant reduction in the incidence of POST (OR 0.44, 95% CI 0.33-0.58, P<0.00001), hoarseness (OR 0.42, 95% CI 0.31-0.58, P<0.00001), and postoperative nausea and vomiting (PONV) (OR 0.06, 95% CI 0.03-0.14, P<0.00001) and a comparable incidence of cough (OR 0.59, 95% CI 0.19-1.89, P=0.38) was described in patients receiving dexamethasone, with or without concomitant drugs. Dexamethasone >=0.2 mg/kg had a statistically greater impact on reducing the incidence of POST than dexamethasone 0.1-0.2 mg/kg, while dexamethasone <=0.1 mg/kg did not. Dexamethasone was as effective as other drugs such as ondansetron, magnesium sulfate, ketamine gargle, betamethasone gel, and ketorolac for reducing POST (OR 0.70, 95% CI 0.46-1.07, P=0.10). Dexamethasone plus a different drug was more effective than dexamethasone alone for reducing the incidence of POST at 24 hours (OR 0.40, 95% CI 0.21-0.77, P=0.006). Compared with controls, a statistically higher blood glucose level was the only adverse event during the immediate postoperative period in patients receiving dexamethasone. Conclusions: Intravenous dexamethasone >=0.2 mg/kg within 30 minutes before or after induction of general anesthesia should be recommended as grade 1A evidence with safety and efficacy in reducing the incidence of POST, hoarseness, and PONV in patients without pregnancy, diabetes mellitus, or contraindications for corticosteroids. PMID- 30425560 TI - Effects of transversus abdominis plane blocks after hysterectomy: a meta-analysis of randomized controlled trials. AB - Background: Transversus abdominis plane (TAP) block can provide effective analgesia for abdominal surgery. However, many randomized controlled trials (RCTs) have shown controversial results in hysterectomy. We conducted a meta analysis of RCTs to investigate the effectiveness of TAP block after hysterectomy. Methods: Studies were gathered from PubMed, MEDLINE, EMBASE, Cochrane Library, Web of Science, and ClinicalTrials.gov databases up to March 2018. RCTs involving TAP blocks in women undergoing hysterectomy were selected. The primary outcome of mean 24 hours morphine consumption and other outcomes, such as time to first request for analgesic, rest, and pain scores on movement at different times, and rates of nausea and vomiting, were compared between TAP block and no or sham block groups. Results: A total of 841 participants were included in the 13 selected RCTs. Compared with no or sham blocks, TAP block reduced mean 24-hour morphine consumption in abdominal hysterectomy (AH) (weighted mean difference [WMD] -10.77 mg, P=0.04) but not in laparoscopic hysterectomy (LH)/robotic-assisted hysterectomy (RH) (WMD -1.39 mg, P=0.24). TAP block in AH prolonged analgesic time and reduced nausea and vomiting rates. TAP block also reduced the postoperative pain score at rest and on movement at different times in the AH subgroup, but it did not significantly reduce the postoperative pain score at rest, 6-8, and 24 hours, as well as the pain score on movement at 2, 6-8, and 24 hours in the LH/RH subgroup. Conclusion: TAP block is an effective analgesic for AH. TAP block can reduce postoperative morphine consumption in AH and pain scores at rest and on movement for AH without increasing side effects. However, TAP block has limited analgesic effects for women undergoing LH/RH, as it does not reduce postoperative morphine consumption and pain scores at rest and on movement. PMID- 30425561 TI - Feasibility and reliability of electrical, mechanical and thermal nociceptive testing and assessment of diffuse noxious inhibitory control in dogs. AB - Purpose: Quantitative sensory testing has been used to assess the somatosensory system. This study aimed to evaluate the feasibility and reliability of electrical (ENT), mechanical (MNT) and thermal (TNT) nociceptive testing and the effect of a conditioning stimulus on MNT. Patients and methods: Sixteen healthy client-owned dogs were included in this study. Stimulation was applied bilaterally to the dorsal and plantar aspect of the metacarpus and metatarsus respectively, using transcutaneous electrical stimulator, algometry and a cold nociceptive device in a randomized order until a behavior response was observed or a cut-off reached. Tests were performed twice (60 seconds apart) by two observers. Retesting was performed 5 hours later. The diffuse noxious inhibitory control was tested by comparing MNT pre- and post-conditioning stimuli. Sham testing was performed for ENT and TNT. Statistical analysis included linear model and intra-class correlation coefficient (P<0.05). Results: Feasibility was 99% (ENT), 93.5% (MNT) and 93.6% (TNT). Data for TNT were not analyzed due to inconsistent results. Mean +/- SD were 48+/-22.6 mA (ENT) and 11.9+/-3.5 N (MNT). MNT was higher for thoracic than for pelvic limbs (P=0.002). Conditioning stimulus increased MNT (P=0.049). Inter-observer reliability was 91.4% (ENT) and 60.9% (MNT). False-positive responses were 15% (ENT) and 35.7% (TNT). Conclusion: ENT was feasible, repeatable and superior to MNT and TNT. The assessment of the diffuse noxious inhibitory control with a conditioning stimulus showed promising results in dogs. These tools could be used in naturally-occurring disease to provide insight on their underlying mechanisms and therapeutics. PMID- 30425562 TI - Genetic and psychological factors interact to predict physical impairment phenotypes following exercise-induced shoulder injury. AB - Background: We investigated interactions between genetic and psychological factors in predicting shoulder impairment phenotypes. We hypothesized that pro inflammatory genes would display stronger relationships compared with pain related genes when combined with psychological factors for predicting phenotypic changes. Subjects and methods: Altogether, 190 participants completed a 5-day experimental protocol. An experimental shoulder injury model was used to induce physical impairment, and a priori selected genetic (pain-related, pro inflammatory) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, kinesiophobia) factors were included as predictors of interest. Impairment phenotypes were injury-induced deficits in range of motion (ROM) and strength. After controlling for age, sex, and race, genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each phenotype. Results: Strong statistical evidence was provided for interactions between: 1) IL-1beta (rs1143634) and fear of pain for predicting loss of shoulder flexion and abduction, 2) IL-1beta (rs1143634) and anxiety for predicting loss of flexion, and 3) IL-1beta (rs1143634) and depressive symptoms for predicting loss of internal rotation. In addition, the interaction between OPRM1 (rs1799971) and fear of pain as well as COMT (rs4818) and pain catastrophizing provided strong statistical evidence for predicting strength loss. Conclusion: Pro-inflammatory gene variants contributed more to physical impairment with two single nucleotide polymorphisms (SNPs; IL 1beta [rs1143634] and TNF/LTA [rs2229094]) interacting with psychological factors to predict six shoulder impairment phenotypes. In comparison, two pain-related gene SNPs (OPRM1 [rs1799971] and COMT [rs4818]) interacted with psychological factors to predict four shoulder impairment phenotypes (abduction: 5-day average loss; strength loss: 5-day average, peak, and relative loss). PMID- 30425563 TI - Oral methylnaltrexone is efficacious and well tolerated for the treatment of opioid-induced constipation in patients with chronic noncancer pain receiving concomitant methadone. AB - Purpose: To evaluate the safety and efficacy of oral methylnaltrexone for opioid induced constipation (OIC). Patients and methods: This was a post hoc analysis of patients receiving methadone in a randomized, double-blind, placebo-controlled, Phase 3 trial. The trial included adults with chronic noncancer pain for >=2 months receiving opioid doses >=50 mg/day of oral morphine equivalents for >=14 days and with a history of OIC. Patients were assigned to oral methylnaltrexone (150, 300, or 450 mg) or placebo once daily (QD) for 4 weeks followed by 8 weeks as needed. Percentage of dosing days that resulted in a rescue-free bowel movement (RFBM) within 4 hours of dosing was assessed during QD dosing (primary efficacy endpoint). Other endpoints included percentage of responders (ie, >=3 RFBMs/week, with an increase of >=1 RFBM/week from baseline for >=3 of the 4 weeks) during QD dosing and change in weekly number of RFBMs. Adverse events were assessed. Results: Concomitant methadone was reported in 120 patients (oral methylnaltrexone: 150 mg [n=33], 300 mg [n=30], and 450 mg [n=31]; placebo [n=26]). Oral methylnaltrexone-treated patients had significant increases in mean percentage of dosing days with RFBMs within 4 hours of dosing during weeks 1-4 with 300 mg (33.6%; P<0.01) and 450 mg (38.2%; P<0.001) vs placebo; improvements with 150 mg (20.0%) vs placebo (15.1%) did not reach statistical significance. The percentage of responders was greater vs placebo, but not significant, for the higher doses during the QD period (150 mg [39.4%], 300 mg [60.0%], 450 mg [67.7%], and placebo [38.5%]). Change from baseline in the mean number of weekly RFBMs (weeks 1-4) was significantly greater with oral methylnaltrexone 450 mg vs placebo (least-squares mean difference vs placebo, 1.2; P=0.04); no significant differences were found for 300 or 150 mg. Oral methylnaltrexone was well tolerated at all doses; few patients discontinued treatment. Conclusion: Oral methylnaltrexone, particularly 450 mg, was efficacious and safe for treating OIC in these patients. PMID- 30425564 TI - Functional magnetic resonance imaging: cerebral function alterations in subthreshold and suprathreshold spinal cord stimulation. AB - Background and purpose: Failed back surgery syndrome (FBSS) is a common and devastating chronic neuropathic pain disorder. Conventional spinal cord stimulation (SCS) applies electrical suprathreshold pulses to the spinal cord at a frequency of 40-60 Hz and relieves pain in FBSS patients. During the last decade, two major changes have emerged in the techniques of stimulating the spinal cord: paresthesia-free or subthreshold stimulation and administration of higher frequency or higher amounts of energy to the spinal cord. Despite the positive clinical results, the mechanism of action remains unclear. A functional MRI (fMRI) study was conducted to investigate the brain alterations during subthreshold and suprathreshold stimulation at different frequencies. Methods: Ten subjects with FBSS, treated with externalized SCS, received randomly four different stimulation frequencies (4 Hz, 60 Hz, 500 Hz, and 1 kHz) during four consecutive days. At every frequency, the patient underwent sub- and suprathreshold stimulation. Cerebral activity was monitored and assessed using fMRI. Results: Suprathreshold stimulation is generally accompanied with more activity than sub-threshold SCS. Suprathreshold SCS resulted in increased bilateral activation of the frontal cortex, thalamus, pre- and postcentral gyri, basal ganglia, cingulate gyrus, insula, thalamus, and claustrum. We observed deactivation of the bilateral parahippocampus, amygdala, precuneus, posterior cingulate gyrus, postcentral gyrus, and unilateral superior temporal gyrus. Conclusion: Suprathreshold stimulation resulted in greater activity (both activation and deactivation) of the frontal brain regions; the sensory, limbic, and motor cortices; and the diencephalon in comparison with subthreshold stimulation. Each type of frequency at suprathreshold stimulation was characterized by an individual activation pattern. PMID- 30425565 TI - The effect of physiotherapy and acupuncture on psychocognitive, somatic, quality of life, and disability characteristics in TTH patients. AB - Introduction: Nonpharmacological therapies have been widely used to treat tension type headache (TTH); however, limited evidence exists with regards to their effectiveness. Therefore, the aim of the present study was to examine the combined effect of acupuncture, stretching, and physiotherapy (myofascial release techniques and microwave diathermy) on psychocognitive, somatic, quality of life, and disability characteristics in such patients. Subjects and methods: Patients with TTH (n=44) performed either acupuncture or stretching (control group, n=20) or acupuncture, stretching, and physiotherapy (experimental group, n=24) during a 4-week intervention period including 10 treatment sessions. They were tested for the Greek version of the Short-Form McGill Pain Questionnaire, the Greek version of the Migraine Disability Assessment Questionnaire, the Greek version of the Hospital Anxiety and Depression Scale, Short Form Health Survey 12 9 (SF-12), and Pain Catastrophizing Scale at baseline after the fifth and tenth sessions. Results: All measures were improved throughout the first to tenth session (P<0.05), though no significant differences were observed between the two groups (P>0.05). Conclusion: In summary, a significant beneficial role of acupuncture, stretching, and physiotherapy on cognitive, psychosomatic pain measures, disability index, quality of life, and catastrophizing in patients with TTH was observed. PMID- 30425566 TI - Characterizing classes of fibromyalgia within the continuum of central sensitization syndrome. AB - Background: While fibromyalgia (FM) is characterized by chronic widespread pain and tenderness, its presentation among patients as a continuum of diseases rather than a single disease contributes to the challenges of diagnosis and treatment. The purpose of this analysis was to distinguish and characterize classes of FM within the continuum using data from chronic pain patients. Methods: FM patients were identified from administrative claims data from the ProCare Systems' network of Michigan pain clinics between January 1999 and February 2015. Identification was based on either use of traditional criteria (ie, ICD-9 codes) or a predictive model indicative of patients having FM. Patients were classified based on similarity of comorbidities (symptom severity), region of pain (widespread pain), and type and number of procedures (treatment intensity) using unsupervised learning. Text mining and a review of physician notes were conducted to assist in understanding the FM continuum. Results: A total of 2,529 FM patients with 79,570 observations or clinical visits were evaluated. Four main classes of FM patients were identified: Class 1) regional FM with classic symptoms; Class 2) generalized FM with increasing widespread pain and some additional symptoms; Class 3) FM with advanced and associated conditions, increasing widespread pain, increased sleep disturbance, and chemical sensitivity; and Class 4) FM secondary to other conditions. Conclusion: FM is a disease continuum characterized by progressive and identifiable classifications. Four classes of FM can be differentiated by pain and symptom severity, specific comorbidities, and use of clinical procedures. PMID- 30425567 TI - Tramadol: a valuable treatment for pain in Southeast Asian countries. AB - Background: The supply of controlled drugs is limited in the Far East, despite the prevalence of health disorders that warrant their prescription. Reasons for this include strict regulatory frameworks, limited financial resources, lack of appropriate training amongst the medical profession and fear of addiction in both general practitioners and the wider population. Consequently, the weak opioid tramadol has become the analgesic most frequently used in the region to treat moderate to severe pain. Methods: To obtain a clearer picture of the current role and clinical use of tramadol in Southeast Asia, pain specialists from 7 countries in the region were invited to participate in a survey, using a questionnaire to gather information about their individual use and experience of this analgesic. Results: Fifteen completed questionnaires were returned and the responses analyzed. Tramadol is used to manage acute and chronic pain caused by a wide range of conditions. Almost all the specialists treat moderate cancer pain with tramadol, and every one considers it to be significant or highly significant in the treatment of moderate to severe non-cancer pain. The reasons for choosing tramadol include efficacy, safety and tolerability, ready availability, reasonable cost, multiple formulations and patient compliance. Its safety profile makes tramadol particularly appropriate for use in elderly patients, outpatients, and for long-term treatment. The respondents strongly agreed that tighter regulation of tramadol would reduce its medical availability and adversely affect the quality of pain management. In some countries, there would no longer be any appropriate medication for cancer pain or the long-term treatment of chronic pain. Conclusions: In Southeast Asia, tramadol plays an important part in the pharmacological management of moderate to severe pain, and may be the only available treatment option. If it were to become a controlled substance, the standard of pain management in the region would decline. PMID- 30425568 TI - Impact of tumor dimensions and lymph node density on the survival of patients with hypopharyngeal squamous cell carcinoma. AB - Purpose: To analyze the potential variables affecting the survival of patients undergoing primary surgery for hypopharyngeal squamous cell carcinoma. Patients and methods: Between August 2007 and December 2016, 93 patients with primary hypopharyngeal squamous cell carcinomas undergoing radical surgery at Fudan University Shanghai Cancer Center were reviewed. The clinicopathological features were analyzed retrospectively. The optimal cutoff values were determined based on the receiver operating characteristic curve analysis. Pearson correlation coefficients were used to assess the correlations between variables. The Kaplan Meier and Cox proportional hazard methods were used to evaluate the impact of variables on overall survival (OS), disease-specific survival (DSS), and disease free survival (DFS). Results: Cox multivariate analysis revealed that a depth of invasion (DOI) >= 4.3 mm was correlated with inferior OS (P=0.045), DSS (P=0.046), and DFS (P=0.046). A primary tumor volume (PTV) >=0.36 mL was related to poor OS (P=0.018), DSS (P=0.026), and DFS (P=0.036). A lymph node density (LND) >=0.07 was also associated with worse OS (P=0.014) and DSS (P=0.045). Moreover, additional prognostic value was observed in the combined use of PTV and LND. Conclusion: The DOI, PTV, and LND obtained from the surgical specimens could provide additional valuable information for prognostic stratification and allowed the more appropriate selection of suitable candidates for more aggressive adjuvant therapy. PMID- 30425570 TI - miR-216a-5p inhibits malignant progression in small cell lung cancer: involvement of the Bcl-2 family proteins. AB - Objective: microRNAs are regulatory molecules regarded as important in the pathogenesis of different types of tumors. microRNA-216a (miR-216a-5p) has been identified as a tumor suppressor in multiple malignancies. However, the role of miR-216a-5p in the pathogenesis of small cell lung cancer (SCLC) remains obscure. The objective of this study was to investigate the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis. Materials and methods: All the experimental methods used were as follows: microarray analysis, cell culture, transient, and stable gene transfection; real-time fluorescence PCR; Western blot; flow cytometry for cell cycle analysis; in vitro proliferation assay; in vitro wound healing experiment; in vivo xenograft model in nude mice; and dual luciferase reporter assay. All statistical analyses were carried out using GraphPad Prism 7 software. Statistical significance was analyzed by Student's t-test or one-way ANOVA. P <0.05 (typically compared with the negative control group) was considered as significant and is marked with an asterisk in the figures. Results: In this study, we observed that miR-216a-5p is downregulated in SCLC cell lines compared to that in the normal human bronchial epithelial cell line 16-HBE. In vitro and in vivo experiments demonstrate that upregulation of miR-216a-5p significantly decreased cell growth and migration and its downregulation increased SCLC cell proliferation and migration and influenced the cell cycle. Using bioinformatics analyses, we predicted that the important antiapoptotic gene Bcl-2 is targeted by miR-216a-5p, and we identified a functional miR-216a-5p binding site in the 3' UTR of Bcl-2 using luciferase reporter assay. Furthermore, we determined that suppression of miR-216a-5p modulated the expression of Bcl-2, Bax, and Bad proteins (Bcl-2 family proteins), while Bcl-2 knockdown abrogated the effect of miR-216a-5p downregulation on cell proliferation, cell migration, and the cell cycle. Conclusion: Taken together, these findings suggest that miR-216a-5p regulates SCLC biology via Bcl-2 family proteins. Therefore, our study highlights the role of the miR-216a-5p/Bcl-2 axis in SCLC pathogenesis. PMID- 30425569 TI - Prognostic significance of pretreatment lymphocyte/monocyte ratio in retroperitoneal liposarcoma patients after radical resection. AB - Background: The aim of this study was to evaluate the prognostic value of pretreatment inflammatory biomarkers in retroperitoneal liposarcoma (RPLS) patients after radical resection. Patients and methods: One hundred patients with RPLS who underwent radical resection between September 2004 and October 2010 at Fudan University Shanghai Cancer Center were included in this study. Laboratory tests of peripheral blood were sampled before surgery. The optimal cutoff values of systemic inflammatory markers were defined by receiver-operating curve analyses. Curves of disease-free survival (DFS) and overall survival (OS) were obtained by the Kaplan-Meier method. Cox proportional hazards regression modeling was used to perform univariate and multivariate analyses. Results: The median follow-up time was 53 months. The median DFS and OS were 27 and 86 months, respectively. On the basis of the optimal cutoff value of 3, 24 patients were classified into low lymphocyte/monocyte ratio (LMR) group and 76 patients into high LMR group. In univariate analysis, low LMR group had significantly shorter DFS (P<0.001) and OS (P<0.001) compared to high LMR group. In multivariate analysis, low LMR was demonstrated as an independent negative prognostic factor for both DFS (HR=2.854, 95% CI=1.392-5.851, P=0.004) and OS (HR=3.897, 95% CI=1.681-9.033, P=0.002). Conclusion: Pretreatment LMR is a useful prognostic marker in RPLS patients after radical resection. PMID- 30425571 TI - Identification of chemoresistance-associated miRNAs in breast cancer. AB - Background: Neoadjuvant chemotherapy (NAC) is an effective therapeutic regimen for patients with breast cancer. However, some individuals cannot benefit from NAC because of drug resistance. To date, valid strategies about enhancing sensitivity of breast cancer to NAC are still scarce. miRNAs have been reported to proverbially be involved in the onset and development of malignancies including drug resistance. Methods: GSE73736 was downloaded from the GEO database. Student's t-test was conducted to acquire differentially expressed miRNAs (DE-miRNAs). Potential target genes of DE-miRNAs were predicted by miRTarBase. Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for these target genes were performed by database for annotation, visualization, and integrated discovery. Protein-protein interaction network was constructed by STRING database and visualized through Cytoscape software. The hub target gene-miRNA network was also established by Cytoscape software. Next, the expression of potential functional miRNAs in breast cancer cell lines and tissues was determined. Finally, the roles of miR-3617-3p, miR 3136-3p, and miR-520b in modulating breast cancer chemoresistance were further examined. Results: A total of 123 DE-miRNAs were identified, including 60 upregulated miRNAs and 63 downregulated miRNAs in the chemoresistant breast cancer group when compared with the chemosensitive group. Six hundred and seventeen and 1,146 potential target genes for the top 10 most upregulated and downregulated miRNAs were predicted, respectively. Enrichment analyses revealed that these target genes were enriched in some cancer-associated or chemo resistance-associated pathways, such as MAPK signaling pathway, wnt signaling pathway, and p53 signaling pathway. MAPK1 and PRDM10 were identified as hub genes in the protein-protein interaction network. The top 25 hub genes were potentially regulated by 16 DE-miRNAs, among which miR-3617-3p and miR-3136-3p were commonly upregulated, whereas miR-520b was downregulated in two chemoresistant breast cancer cells compared with chemosensitive cell. By analyzing TCGA data, we found that expression of miR-3136-3p and miR-520b was increased and decreased in breast cancer tissues, respectively. Moreover, functional experiments demonstrated that miR-3136-3p and miR-3617-3p could reduce chemosensitivity of breast cancer, whereas miR-520b could reverse chemoresistance. Conclusion: The present study, based on bioinformatics analysis and experimental validation, brings to light novel mechanisms of breast cancer NAC resistance. PMID- 30425572 TI - The novel mechanism of anticancer effect on gastric cancer through inducing G0/G1 cell cycle arrest and caspase-dependent apoptosis in vitro and in vivo by methionine enkephalin. AB - Background: Gastric cancer (GC) is the second cause of cancer-related deaths. Methionine enkephalin (MENK), an endogenous opioid peptide, has immunological and antitumor activity. Purpose: The aim of this work was to investigate whether MENK could exhibit activity against human GC in vitro and in vivo. Materials and methods: Human GC cells were treated with MENK. Cell viability, colony formation, cell morphology, cell cycle, and apoptosis were assessed. The effects of MENK on gene expression of OGFr, Bax, BCL-2, caspase-3, PARP, Ki67, cyclin D1, c-myc, survivin were quantifed by qRT-PCR. Western blot was used to analyze the effects of MENK on protein expression of OGFr, Bax, BCL-2, caspase-3, PARP. The anti tumor activity of MENK in gastic carcinoma was also investigated with animal experiments. Results: The results indicate that MENK could significantly inhibit the growth of human GC cells SGC7901 and HGC27 in a concentration- and time dependent manner, decrease the number of cell colonies, and arrest cell cycle in the G0/G1 phase by causing a decrease in Ki67, cyclin D1, and c-myc mRNA. Furthermore, MENK could induce tumor cell apoptosis associated with the upregulation of Bax, a corresponding downregulation of BCL-2 and survivin, and activation of caspase-3 and PARP. Moreover, MENK upregulated the expression of opioid receptors (OGFr) in SGC7901 and HGC27 cells. The interaction between MENK and OGFr in SGC7901 and HGC27 cells appears to be essential for the antitumor activity of MENK. Conclusion: We conclude that MENK may be a potential drug for the treatment of GC. PMID- 30425573 TI - Preoperative C-reactive protein/albumin ratio is a significant predictor of survival in bladder cancer patients after radical cystectomy: a retrospective study. AB - Purpose: Earlier studies have indicated the prognostic value of the pretreatment C-reactive protein (CRP)/albumin ratio (CAR) in multiple tumor types. The present study attempts to investigate the predictive role of preoperative CAR in patients with bladder cancer after radical cystectomy (RC), and explores its prognostic index value. Patients and methods: A total of 131 patients with bladder cancer after RC between 2009 and 2015 were analyzed in the present study. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan Meier method and Cox regression analyses. Prediction accuracy was evaluated through the area under the receiver operating characteristic curve (AUC). Results: The median follow-up time for all patients in the present retrospective study was 39.72 months (15.51-53.26 months). The Kaplan-Meier curve analysis indicated that bladder cancer patients with high preoperative CAR (>0.2) were significantly associated with decreased PFS and OS (all, P<0.001). The multivariate analysis confirmed CAR as a common independent prognostic factor for PFS and OS. Furthermore, the effective combination of CAR and pathological T staging constituted a new index (CART), and was observed to be an independent risk factor for OS (CART score =2, HR=0.264; 95% CI: 0.106-0.660, P=0.004; CART score =3, HR =0.371; 95% CI: 0.208-0.661, P=0.001). However, CART did not show any prognostic significance for PFS. Importantly, the AUC values of CAR for OS and PFS were higher than other conventional clinical indices. Conclusion: The present study demonstrated that CAR can be used as a new prognostic indicator of OS and PFS in patients with bladder cancer after RC. Combining the CAR score with pathological T staging as the CART score appears to be a more effective prognostic indicator of poor OS, but not PFS. PMID- 30425574 TI - Health-related quality of life for gemcitabine and nab-paclitaxel plus radiotherapy versus gemcitabine and S-1 plus radiotherapy in patients with metastatic pancreatic cancer. AB - Purpose: To compare the effects of gemcitabine and nab-paclitaxel (GT) plus stereotactic body radiation therapy (SBRT) or gemcitabine and S-1 (GS) plus SBRT on health-related quality of life (HRQOL) of metastatic pancreatic cancer. Methods: Patients with biopsy-proven and radiographically metastatic pancreatic cancer were included. HRQOL was assessed using the Chinese version of Brief Pain Inventory (BPI) and 5-level European quality of life 5-dimensions (EQ-5D-5L). Data were analyzed with Spearman's rank correlation, ordinal regression, and propensity score-matched analysis. Results: A total of 75 and 89 patients received GT and GS, respectively. The median biological effective dose of GT group and GS group was 59.5 Gy (range 48-85.5 Gy) and 64.4 Gy (range 52.48-85.5 Gy) in 5-8 fractions, respectively. More patients in the GS group had improvement in BPI and EQ-5D-5L compared with those in the GT group (n=38 vs n=15, P<0.001; n=42 vs n=20, P<0.001). No differences of BPI scores were found between pre- and post-treatment in each group, while only the post-treatment EQ-5D-5L score was higher than that at baseline in GS the group (P<0.001). Compared with GS group, it was unlikely for patients receiving GT to have better BPI and EQ-5D-5L. After propensity-matched analysis, more patients in GS group had improvement in BPI and EQ-5D-5L (n=24 vs n=12, P=0.002; n=28 vs n=16, P=0.002). Furthermore, patients with GS had a superior overall survival than those with GT (11.1 months [95% CI: 10.6-11.6 months] vs 9.9 months [95% CI: 8.8-11.0 months]; P=0.005). Both incidences of grade 3 hematological (P=0.024) and gastrointestinal (P=0.049) toxicities were higher in the GT group. Conclusion: GS may achieve better HRQOL than GT. Therefore, GS may be an alternative of GT for metastatic pancreatic cancer, especially for Asians. PMID- 30425575 TI - Clofoctol and sorafenib inhibit prostate cancer growth via synergistic induction of endoplasmic reticulum stress and UPR pathways. AB - Background/Purpose: Prostate cancer is a major burden on public health and a major cause of morbidity and mortality among men worldwide. Drug combination therapy is known as a powerful tool for the treatment of cancer. The aim of this study is to evaluate the synergistic inhibitory mechanisms of clofoctol and sorafenib in the treatment of prostate cancer. However, the molecular mechanisms of this phenomenon have not been illuminated clearly. In this study, we investigated the anti-tumor effects of clofoctol in combination with sorafenib in vitro and in vivo. Methods: The activity and mechanism of clofoctol in combination with sorafenib were examined in PC-3cells. mRNA and protein expression of key players in the ER stress pathway were detected with RT-PCR and Western blotting. Cell viability was estimated by CCK-8 assay or Alamar blue assay, and apoptosis and cell cycle were monitored and measured by flow cytometry. PC-3 cells were inoculated subcutaneously in male BALB/c nude mice. The therapeutic regimen was initiated when the tumor began showing signs of growth and treatment continued for 5 weeks. Results: Our data indicate that clofototol and sorafenib induce cell death through synergistic induction of endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR). Combination therapy with clofoctol and sorafenib induced an upregulation of markers of all three ER stress pathways: PERK, IRE1 and ATF6. In addition, combination therapy with clofoctol and sorafenib markedly inhibited the growth of prostate cancer xenograft tumors, compared with clofoctol or sorafenib alone. Conclusion: The combination of clofoctol and sorafenib can serve as a novel clinical treatment regimen, potentially enhancing antitumor efficacy in prostate cancer and decreasing the dose and adverse effects of either clofoctol or sorafenib alone. These results lay the foundation for subsequent research on this novel therapeutic regimen in human prostate cancer. PMID- 30425576 TI - Type-specific high-risk human papillomavirus viral load as a viable triage indicator for high-grade squamous intraepithelial lesion: a nested case- control study. AB - Purpose: Currently, the associations between type-specific high-risk human papillomavirus (HR-HPV) viral loads and cervical lesions are still inconsistent. We aimed to assess the type-specific HR-HPV viral load as a risk triage indicator for development of high-grade squamous intraepithelial lesion or worse (>=HSIL). Patients and methods: A total of 19,446 women who underwent primary screening for cervical cancer using Cervista(r) HR-HPV and cytology assays were enrolled. The viral loads of 1,396 HR-HPV-positive specimens confirmed by Cervista(r) assay were detected by BioPerfectus Multiplex Real-Time PCR assay. The correlation between viral loads and cervical lesions was analyzed. The optimal cutoffs of individual HR-HPV viral loads used to predict >=HSIL were determined from the receiver operating characteristic curve. A logistic regression model was used to analyze the relationship between covariates and the probability of >=HSIL. Results: The viral loads of HPV-16, -31, -33, -52, and -58 were positively correlated with the severity of the cervical lesion, which was significantly elevated in patients with >=HSIL, whereas those of HPV-18, -45, -56, -59, and other types were not. The optimal cutoffs of the log10-transformed viral loads for HPV-16, -31, -33, -52, and -58 in identifying >=HSIL were 4.26, 4.46, 4.48, 4.36, and 4.26 copies per 10,000 cells, respectively. Furthermore, multivariate analysis indicated that type-specific viral loads of HPV-16, -31, -33, -52, and 58 exceeding the cutoffs could be independent risk factors for the incidence of >=HSIL. Conclusion: The BioPerfectus Multiplex Real-Time PCR viral load assay provides viable triage for >=HSIL when using appropriate cutoff levels. PMID- 30425578 TI - CircRNA CDR1as/miR-7 signals promote tumor growth of osteosarcoma with a potential therapeutic and diagnostic value. AB - Background: The circular RNA (circRNA) antisense to the cerebellar degeneration related protein 1 transcript (CDR1as)/micro RNA-7(miR-7) signal axis has been investigated in many diseases via regulation of the target genes of miR-7, which participates in the carcinogenesis and metastasis. However, the clinical role and function of CDR1as/miR-7 pathway in osteosarcoma (OS) remain to be identified. Materials and methods: Noncancerous bone tissues (n=18) and OS tissues (n=38) were used to determine the expressions and roles of CDR1as and miR-7. We knocked down the expression of CDR1as via siRNAs in OS cell lines to analyze its function in vitro and in vivo. Results: CDR1as was upregulated in OS tissues with significant diagnostic value (cutoff value: 1.613). OS patients with high tumor size, Enneking stage, and distant metastasis have high CDR1as levels, but the miR 7 as tumor suppressor negatively correlated with CDR1as. Inhibition of CDR1as in OS cell lines U2OS and MG63 with high CDR1as levels, leading to de-repressed miR 7 levels, impaired cell vitality and increased apoptosis and G1/S arrest in parallel with reduced ability of cell migration, which, however, could be restored by miR-7 inhibitor. Mechanistically, knockdown of CDR1as could restore the availability of miR-7 and inhibit the target genes of miR-7 including EGFR, CCNE1, PI3KCD, and RAF1. Moreover, CDR1as also upregulated N-cadherin and inhibited E-cadherin to promote the epithelial-mesenchymal transition via miR-7 for cell migration. CDR1as inhibition in vivo also induced tumor regression with decreased PCNA levels, and miR-7 inhibitor could reverse these effects via upregulation of EGFR, CCNE1, PI3KCD, and RAF1. The expressions of these genes were confirmed to be higher in CDR1as-high OS samples than in CDR1as-low OS samples. Conclusion: These findings suggested that the CDR1as/miR-7 signal axis could be the molecular target for the treatment of OS. PMID- 30425577 TI - Dosimetric evaluation and systematic review of radiation therapy techniques for early stage node-negative breast cancer treatment. AB - Radiation therapy (RT) is essential in treating women with early stage breast cancer. Early stage node-negative breast cancer (ESNNBC) offers a good prognosis; hence, late effects of breast RT becomes increasingly important. Recent literature suggests a potential for an increase in cardiac and pulmonary events after RT. However, these studies have not taken into account the impact of newer and current RT techniques that are now available. Hence, this review aimed to evaluate the clinical evidence for each technique and determine the optimal radiation technique for ESNNBC treatment. Currently, six RT techniques are consistently used and studied: 1) prone positioning, 2) proton beam RT, 3) intensity-modulated RT, 4) breath-hold, 5) partial breast irradiation, and 6) intraoperative RT. These techniques show dosimetric promise. However, limited data on late cardiac and pulmonary events exist due to challenges in long-term follow-up. Moving forward, future studies are needed to validate the efficacy and clinical outcomes of these current techniques. PMID- 30425579 TI - Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis. AB - Purpose: Metformin is a key pharmaceutical for patients with diabetes mellitus (DM). Metformin also can enhance tumor radiosensitivity in vitro and in vivo. Some retrospective cohort studies have indicated that metformin can improve the efficacy of radiotherapy in patients with cancer and DM. The aim of this systematic review was to evaluate the radiotherapy efficacy of metformin in patients with cancer and DM. Methods: Multiple databases were queried for studies that address the efficacy of metformin in radiotherapy of patients with cancer and DM. Studies were included that involved comparisons of the short-term tumor responses and long-term survival outcomes of these patients who were managed with or without metformin as well as of nondiabetic patients without metformin. The OR and HR with accompanying 95% CI were assessed in a random effects model. The main endpoints were 2-year and 5-year overall survival (2y-OS and 5y-OS, respectively). Results: The database search yielded 17 cohort studies that met the inclusion criteria. The results indicated that the tumor response was higher in patients who also were treated with metformin than in those who were not (OR, 0.48; 95% CI, 0.22-1.07; P=0.07) and nondiabetic (OR, 0.27; 95% CI, 0.07-0.98; P=0.05). Moreover, patients who received metformin had survival benefits compared with patients not treated with metformin (2y-OS: OR, 0.48; 95% CI, 0.29-0.80; P=0.005; 5y-OS: OR, 0.38; 95% CI, 0.25-0.56; P<0.00001). The metformin-related HRs of OS values were not significantly different. Conclusion: Metformin appears to improve the tumor response to radiotherapy in patients with cancer and DM and partly yield survival benefits. Despite the apparent advantages provided by metformin treatment on 2y-OS and 5y-OS, these retrospective data are at risk of bias and should be interpreted with caution. PMID- 30425580 TI - Prognostic role of derived neutrophil-to-lymphocyte ratio in surgical triple negative breast cancer. AB - Introduction: The role of derived neutrophil-to-lymphocyte ratio (dNLR) in predicting the prognosis of patients with triple-negative breast cancer (TNBC) has not been well studied. Here, we attempted to investigate the significance of dNLR in predicting the prognosis of patients with surgical (nonmetastatic) TNBC. Methods: A total of 281 patients diagnosed with surgical TNBC in The First Affiliated Hospital of University of Science and Technology of China from February 2005 to March 2015 were retrospectively included in this study. Kaplan Meier curve analysis was used to assess the disease-free survival (DFS) and overall survival (OS). We used Cox regression model to assess the prognostic significance of pretreatment dNLR and other clinicopathological parameters in TNBC patients. Results: The median DFS in TNBC patients who had low dNLR and high dNLR was 28.9 and 15.1 months (P<0.001), respectively, whereas the median OS in patients who had low dNLR and high dNLR was 71.2 and 42.3 months (P<0.001), respectively. In patients aged <=50 years and with invasive ductal carcinoma, a low dNLR predicted better DFS and OS compared with a high dNLR. Multivariate analysis demonstrated that the increased dNLR was a risk factor of poor DFS (HR=1.90, 95% CI: 1.52-2.46, P=0.007) and OS (HR=2.56, 95% CI: 1.69-3.58, P=0.001). Conclusion: Pretreatment dNLR is an independent factor of prognosis for TNBC patients, which potentially allows clinical doctors to improve outcomes of patients with high dNLR by treating with aggressive therapy, such as high-dose adjuvant chemotherapy and radiotherapy. PMID- 30425581 TI - Microscopic hematuria predicts lower stage in patients with upper tract urothelial carcinoma. AB - Background: The aim of this study was to assess the association between the severity of hema-turia (microscopic or gross) and the tumor stage and grade in a population of histopathologically confirmed upper tract urothelial carcinoma (UTUC) patients. Patients and methods: We conducted a multicenter, observational study of patients who were newly diagnosed with UTUC between January 2011 and December 2016. Demographic information, pathology, and the status of hematuria were retrospectively reviewed. The association between the severity of hematuria and the tumor stage and grade was evaluated using logistic regression. Results: The UTUC patients presented with gross hematuria (GH, 76.7%), microscopic hematuria (MH, 11.1%), and no hematuria (12.2%) at the time of diagnosis. The pathological stages at diagnosis for those with MH were Ta in 5.1%, T1 in 47.5%, and >=T2 in 47.5%. The stages at diagnosis for those with GH were Ta in 1.7%, T1 in 35.5%, and >=T2 in 62.7%. On univariate and multivariate logistic regression analyses, after adjusting for clinical factors such as age, gender, and smoking history, GH was an independent risk factor for muscle-invasive UTUC (>=T2 disease) at diagnosis (OR 1.89, 95% CI 1.073-3.329; P=0.027). High-grade tumor was found in 47.8% of patients with GH and 39.0% of those with MH. The severity of hematuria was not associated with tumor grade. Conclusion: We are the first to report evidence that microscopic hematuria at presentation accurately predicts lower pathological stage in patients with newly diagnosed UTUC. Earlier detection of disease, before the development of GH, may influence the treatment decision and survival. The type of hematuria at the time of diagnosis does not impact the tumor grade. PMID- 30425582 TI - A phenotyping algorithm to identify acute ischemic stroke accurately from a national biobank: the Million Veteran Program. AB - Background: Large databases provide an efficient way to analyze patient data. A challenge with these databases is the inconsistency of ICD codes and a potential for inaccurate ascertainment of cases. The purpose of this study was to develop and validate a reliable protocol to identify cases of acute ischemic stroke (AIS) from a large national database. Methods: Using the national Veterans Affairs electronic health-record system, Center for Medicare and Medicaid Services, and National Death Index data, we developed an algorithm to identify cases of AIS. Using a combination of inpatient and outpatient ICD9 codes, we selected cases of AIS and controls from 1992 to 2014. Diagnoses determined after medical-chart review were considered the gold standard. We used a machine-learning algorithm and a neural network approach to identify AIS from ICD9 codes and electronic health-record information and compared it with a previous rule-based stroke classification algorithm. Results: We reviewed administrative hospital data, ICD9 codes, and medical records of 268 patients in detail. Compared with the gold standard, this AIS algorithm had a sensitivity of 91%, specificity of 95%, and positive predictive value of 88%. A total of 80,508 highly likely cases of AIS were identified using the algorithm in the Veterans Affairs national cardiovascular disease-risk cohort (n=2,114,458). Conclusion: Our algorithm had high specificity for identifying AIS in a nationwide electronic health-record system. This approach may be utilized in other electronic health databases to accurately identify patients with AIS. PMID- 30425583 TI - Comparing causes of death of Hodgkin lymphoma and breast cancer patients between medical records and cause-of-death statistics. AB - Objective: Obtaining accurate data about causes of death may be difficult in patients with a complicated disease history, including cancer survivors. This study compared causes of death derived from medical records (CODMR) with causes of death derived from death certificates (CODDC) as processed by Statistics Netherlands of patients primarily treated for Hodgkin lymphoma (HL) or breast cancer (BC). Methods: Two hospital-based cohorts comprising 1,215 HL patients who died in the period 1980-2013 and 714 BC patients who died in the period 2000-2013 were linked with cause-of-death statistics files. The level of agreement was assessed for common underlying causes of death using Cohen's kappa, and original death certificates were reviewed when CODDC and CODMR showed discrepancies. We examined the influence of using CODDC or CODMR on standardized mortality ratio (SMR) estimates. Results: Agreement for the most common causes of death, including selected malignant neoplasms and circulatory and respiratory diseases, was 81% for HL patients and 97% for BC patients. HL was more often reported as CODDC (CODDC=33.1% vs. CODMR=23.2%), whereas circulatory disease (CODDC=15.6% vs. CODMR=20.9%) or other diseases potentially related to HL treatment were more often reported as CODMR. Compared to SMRs based on CODDC, SMRs based on CODMR complemented with CODDC were lower for HL and higher for circulatory disease. Conclusion: Overall, we observed high levels of agreement between CODMR and CODDC for common causes of death in HL and BC patients. Observed discrepancies between CODMR and CODDC frequently occurred in the presence of late effects of treatment for HL. PMID- 30425584 TI - Does low risk of infections as a marker of effective immunity predict increased risk of subsequent giant cell arteritis or polymyalgia rheumatica? A Danish population-based case-control study. AB - Objective: It has been suggested that a hyper-effective immune system ("hyper immunity") is central to the pathogenesis of giant cell arteritis and polymyalgia rheumatica (GCA/PMR). We examined if a low risk of infections, as a marker of hyper-immunity, can predict increased subsequent risk of GCA/PMR. Patients and methods: We conducted a population-based case-control study including all patients aged >=50 years with incident GCA/PMR diagnosed between 1997 and 2012 in Northern Denmark. For each case, we selected 10 population controls matched on gender, age, place of residence, and time spent in the region. Complete history of hospital-treated infections and community-based anti-infective prescriptions was assessed in population-based registries. We used conditional logistic regression to compute OR of GCA/PMR associated with infections while adjusting for comorbidities, immunosuppressive treatment, and other potential confounders. Results: We included 7,225 GCA/PMR cases and 72,250 controls. When excluding all infections occurring within the last year before GCA/PMR diagnosis, there was no decreased risk for GCA/PMR in people with a history of hospital-treated infection (adjusted OR=1.04, 95% CI: 0.98-1.10) or community anti-infective treatment (adjusted OR=1.07, 95% CI: 0.99-1.16). Within the last year preceding the GCA/PMR index date, patients with hospital-treated infections (adjusted OR=1.59, 95% CI: 1.44-1.75) or community anti-infective treatment (adjusted OR=1.63, 95% CI: 1.48 1.79) had a greatly increased risk of a GCA/PMR diagnosis. Conclusion: These results do not support the hypothesis of "hyper-immunity" leading to GCA/PMR. Instead, incident GCA/PMR is preceded by a slightly increased risk of infection, which may be related to protopathic bias or support theories that infections may be directly involved in the pathogenesis of GCA/PMR. PMID- 30425585 TI - Development and validation of a risk prediction model for severe hypoglycemia in adult patients with type 2 diabetes: a nationwide population-based cohort study. AB - Purpose: There is a scarcity of long-term prediction models for severe hypoglycemia (SH) in subjects with type 2 diabetes mellitus (T2DM). In this study, a model was developed and validated to predict the risk of SH in adult patients with T2DM. Patients and methods: Baseline and follow-up data from patients with T2DM who received health evaluations from January 1, 2009, to December 31, 2010 (n=1,676,885) were analyzed as development (n=1,173,820) and validation (n=503,065) cohorts using the National Health Insurance Database (DB) in Korea. New SH episodes were identified using ICD-10 codes. A Cox proportional hazards regression model and Cox model coefficients were used to derive a risk scoring system, and 14 predictive variables were selected. A risk score nomogram based on the risk prediction model was created to estimate the 1-year risk of SH. Results: In the development cohort, a total of 5,325 (0.45%) patients experienced SH episodes during the follow-up period. After multivariable adjustment, older age, female sex, current smoker, drinking, low body mass index, lack of exercise, previous SH events, insulin or multiple oral hypoglycemic agent use, presence of hypertension or chronic kidney disease, longer duration of diabetes, low or high glucose level, and high Charlson Comorbidity Index score were found to be significant risk factors for the development of SH and were incorporated into the risk model. The concordance indices were 0.871 (95% confidence interval, 0.863 0.881) in development cohort and 0.866 (95% CI, 0.856-0.879) in the validation cohort. The calibration plot showed a nearly 45 degrees line, which indicates that this model predicts well an absolute SH event. Conclusion: This 14-variable prediction model for SH events may be a useful tool to identify high-risk patients and guide prevention of SH in adult patients with T2DM. PMID- 30425586 TI - Bilateral salpingectomy versus bilateral partial salpingectomy during cesarean delivery. AB - Objective: To compare surgical outcomes in patients undergoing bilateral salpingectomy (salpingectomy group) with those who had partial salpingectomy (partial salpingectomy group) during cesarean delivery. Materials and methods: A chart review from July 2015 to November 2016 was performed. We included women who had sterilization during cesarean delivery. We excluded sterilization by occlusive methods. Our primary outcomes were total operative time and a composite score of transfusion rate, internal organ injury, hospital readmission, and endometritis. Secondary outcomes included menstrual abnormalities, pelvic pain, quality of life assessment, and regrets rate. We compared these outcomes between women in the salpingectomy and partial salpingectomy groups. Chi-squared, Fisher's exact, t-test, and Mann-Whitney U were utilized for statistical analysis where appropriate. A P<0.05 was considered significant. Results: We included a total of 160 pregnancies. Of these, 41 were in the salpingectomy and 119 in the partial salpingectomy group. The median total operative time was longer for the salpingectomy group (62 [IQR 54, 71] vs 60 minutes [IQR 46, 72]; P=0.03). The composite of surgical complications (19.5% vs 12.6%; P=0.28) was not significantly different between our study groups. Menstrual irregularities (P>=0.99), quality of life (P>=0.99), dyspareunia (P>=0.99), dysmenorrhea (P=0.36), and regrets (P>=0.99) were not different between groups. Conclusion: Salpingectomy during cesarean delivery increased the median operative time by 2 minutes and may not be associated with an increased risk of surgical complications. We acknowledge the need for larger multi-center trials to corroborate our outcomes. PMID- 30425587 TI - Health perception in menopausal women. AB - Aim: The aim of this study is to find whether the worsening of health perception was related to the menopausal (MNP) state or to its negative consequences on cardiometabolic risk factors (CMRF) and the presence of depression/anxiety. Methods: In this study, 2,562 women, 1,357 (53%) MNP and 1,205 (47%) non-MNP, were analyzed. Blood pressure, heart rate, body mass index, waist circumference, and depression/anxiety screening using the Hospital Depression/Anxiety Scale (HADS) were measured. We collected a blood sample in fasting state for glycemia, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides. Logistic regression models were fitted with a backward method from the potentially confusing variables of the menopause study groups. Results: Age 49.4 (+/-15.9) years; 10.1% belonged to semi-rural population; 87.5% had children. Regarding the educational level, 22.1% had <5 years of education, 31.3% had between 6 and 7 years, 33.4% had between 8 and 12 years, and 13.2% had >12 years of education. The prevalence of CMRF was significantly higher in MNP women, except for smoking. We did not find any differences in the prevalence of depression or anxiety between MNP and non-MNP women. Health was perceived as worse among MNP women (P<0.05) and patients over 45 years of age than patients younger than 45 years. We found a relationship between the negative health perception with metabolic syndrome, depression, and anxiety, having children, smoking, residing in rural area, and low educational level; nevertheless, it is not correlative with MNP status. Conclusion: Perceived health should be viewed as a multifaceted condition related to social circumstances, and various symptoms in women, including menopause symptoms, but not with MNP state itself. PMID- 30425588 TI - Isolated Horner syndrome as a rare initial presentation of nasopharyngeal carcinoma: a case report. AB - Background: Horner syndrome refers to a set of clinical presentations resulting from disruption of sympathetic innervation to the eye and adnexa. Classically, the clinical triad consists of ipsilateral blepharoptosis, pupillary miosis, and facial anhidrosis. Ocular sympathetic denervation may signify life-threatening causes. Timely investigation and accurate diagnosis are essential in patients with oculosympathetic denervation. Case presentation: A 33-year-old Asian man with a heavy smoking habit presented with a 3-week history of left ptosis and no other complaints. His visual acuity was 20/20 bilaterally. An ophthalmic examination was significant for mild ptosis of his left eyelid and anisocoria (smaller left pupil), which was greater in the dark. Both pupils reacted to light briskly without an afferent pupillary defect. Anhidrosis was found on the medial side of the left forehead. A 10% cocaine test was positive. At his first visit, neurologic examination was unremarkable. Comprehensive radiological investigations were scheduled for a left-sided isolated Horner syndrome. Two weeks after his first visit, he experienced a left-sided headache along with ipsilateral Horner syndrome. Neurologic examination revealed hypoesthesia in the left cranial nerve V1-3 territories. Emergent computed tomography angiography was suspected for petrous part of the left internal carotid artery (ICA) dissection. Magnetic resonance imaging demonstrated an enhancing infiltrative lesion with its epicenter at the left sphenoid bone. The lesion encased the left ICA and invaded the left Meckel cave. Rhinoscopy with incisional biopsy revealed squamous cell nasopharyngeal carcinoma. Conclusion: This case involved an unusual initial presentation of nasopharyngeal carcinoma: isolated Horner syndrome with clinical progression to adjacent structures. Infiltration involving the Meckel cave and ICA at the foramen lacerum can present as postganglionic Horner syndrome associated with trigeminal pain and hypoesthesia. These clinical findings may mimic carotid artery dissection on computed tomography angiography. Detailed magnetic resonance imaging with careful attention to the skull base should be performed. PMID- 30425589 TI - Central serous retinopathy and hand-foot-mouth disease: coincidence or causation? AB - Introduction: The clinical and pathological correlation between hand-foot-mouth disease (HFMD) and ocular complications has not yet been established. However, individual case reports indicate a trend that may be the emergence of a new burden of the previous self-limiting virus. This virus is particularly prevalent in childcare centers and poses an infectious disease risk for this workplace. Objectives: The primary objective of this case report is to describe an unusual clinical record of a patient who developed central serous retinopathy while unwell with HFMD. Discussion of management strategies for this workplace, its staff, and visitors is also included. Methods: This was an observational case report that was identified and reported retrospectively. For comparison, a search of the literature to identify similar ocular complications of HFMD was also undertaken. Results from this search, in addition to international data and prevention and management strategies are also provided. Results: A total of 13 individual case reports with ocular associations, including this clinical record, were identified in the literature worldwide. The median age was 33 years, and three patients (23%) were female. No treatment or management guidelines for ocular complications of HFMD have been identified. Conclusion: Severe and potentially life-threatening complications of a seemingly harmless childhood illness are represented sporadically in the literature. The requirement for research and evaluation into this emerging occupational hazard area is necessary for improved prevention, management, and treatment strategies to be developed. PMID- 30425590 TI - Wasp sting of the cornea. AB - Purpose: Many treatments, such as conservative management or penetrating keratoplasty, exist for corneal wasp sting. Here, we report a case of paper wasp sting of the cornea treated by anterior chamber wash immediately following admission, which soon resolved the inflammation. Case: A healthy 9-year-old boy who had been stung by a paper wasp on his left eye 2 days prior to presentation at Dokkyo Medical University Saitama Medical Center was found to have corneal opacity accompanied by ciliary injection. The boy had difficulty opening his left eye due to pain. His left corneal endothelial cell density was 2,789 cells/mm2, which was relatively lesser than that in the right eye. We diagnosed a paper wasp sting of the cornea based on both the patient's clinical findings and sting history. The anterior chamber was promptly irrigated using a balanced salt solution; the inflammation resolved in a few hours, and the patient could open his left eye easily the following day. One day after the operation, the visual acuity improved to 1.2, and only slight corneal opacity remained at the original wasp sting site. Conclusion: The positive outcome of the current case suggested that anterior chamber irrigation leads to rapid resolution of the inflammation. PMID- 30425591 TI - Comments on the authors' reply to the critical appraisal concerning "Wearable cardioverter defibrillators for the prevention of sudden cardiac arrest: a health technology assessment and patient focus group study". PMID- 30425592 TI - The prevalence of overuse injuries in Australian non-elite netballers. AB - Purpose: The aim of this study was to investigate the prevalence of overuse injuries in non-elite netballers and whether these increase over a typical competitive season and to establish if player age, experience, training, and use of bracing are related to overuse injuries. Patients and methods: A prospective study was conducted over a 12-week period, using a recently developed questionnaire. Data were collected on overuse injuries in the knee, ankle, and shoulder areas every week. Results: Thirty-seven players responded to the questionnaire, with an average response rate of 65%. The total prevalence of overuse injuries identified was 52.7%, with ankle problems accounting for 26% (75 cases), knee problems accounting for 21.2% (61 cases), and shoulder problems accounting for 5.5% (16 cases). Ankle injuries increased over the study period, while knee and shoulder problems decreased. Injuries were more common in players over 36 years old or those with less than 5 years of playing experience. Players who used a brace were more likely to have an overuse complaint. Training volume was not associated with increased risk. Conclusion: Overuse injuries are common in netballers, particularly of the knee and ankle. Shoulder overuse complaints are higher than previously reported. Risk factors for injury include older age and less playing experience, and these should be considered when planning injury prevention programs for this sport. PMID- 30425593 TI - Impact of pegloticase on patient outcomes in refractory gout: current perspectives. AB - Gout is currently the most frequent cause of inflammatory arthritis worldwide and is responsible for poor health-related quality of life and loss of work productivity. It is caused by high levels of serum urate, leading to the deposition of monosodium urate crystals in joints and soft tissues. This condition is associated with acute flares and, if untreated or refractory, chronic and potentially destructive arthritis and tophi formation. Pegloticase is a recombinant, pegylated uricase used in the treatment of gout patients who fail conventional urate-lowering therapy. In this review, we discuss the impact of pegloticase on patient outcomes in refractory gout. We analyze different parameters, such as plasma uric acid concentration, frequency of flares, tophi reduction, pain, function, quality of life, and safety. PMID- 30425594 TI - Psychometric evaluation of the Arabic version of the nomophobia questionnaire: confirmatory and exploratory factor analysis - implications from a pilot study in Kuwait among university students. AB - Background: In the past decades, thanks to the widespread use of the new information and communication technologies, nomophobia has emerged as a contemporary psychological disorder. More in detail, it has been defined as the modern fear of feeling disconnected, being out of mobile phone contact, and being unable to access information and/or communicate with others. Few authors have used an Arabic version of the Nomophobia Questionnaire, even though its psychometric properties are not well known and have been poorly investigated from a formal rigorous standpoint. Materials and methods: Our research objective was to develop and validate the Arabic version, administering it to a sample of adolescents and young adults in a country characterized by a high mobile network coverage. A total of 512 subjects (aged 21.62+/-4.33 years, median 20 years), equally distributed between males and females, and based in Kuwait, volunteered to take part in the study. Results: The confirmatory factor analysis did not show a completely satisfactory fitting with the original factor structure. The exploratory factor analysis showed that four factors had 57.24% variance. Overall Cronbach's alpha coefficient was 0.879. However, the coefficient increased from 0.645 to 0.849 with respect to the original factor structure. Scores (and mean scores) were 4.25+/-1.59 (21.23+/-7.95), 2.95+/-1.33 (17.68+/-7.97), 4.48+/-1.78 (8.96+/-3.56), and 4.98+/-1.52 (34.84+/-10.67) for factors I, II, III, and IV, respectively, whereas the overall score (and mean overall score) was 4.14+/-1.13 (82.71+/-22.68). Conclusion: In our sample, no subject (0.0%) was without nomophobia, with 92 (18.0%) and 288 individuals (56.2%) reporting mild and moderate nomophobia levels, respectively. Approximately a quarter of the recruited sample (132 subjects, 25.8%) had severe nomophobia level. PMID- 30425595 TI - Burnout and work satisfaction in general practitioners practicing in rural areas: results from the HaMEdSi study. AB - Background: An increasing number of general practitioners (GPs) are not satisfied with their working conditions and are at risk of developing burnout symptoms. As family medicine is becoming a major subject within the medical curriculum in Germany, practicing GPs need to meet higher demands in the future, ie, treating patients and taking part in the education of medical students. Accordingly, we aimed to determine GPs' work satisfaction and risk of burnout. Materials and methods: A survey was conducted among GPs in the region of Siegen-Wittgenstein. This area is a representative rural region in Germany. The Maslach Burnout Inventory (MBI) was used to assess the risk of burnout, while the Work Satisfaction Questionnaire (WSQ) was applied to assess work satisfaction. Canonical correlations were used to examine the association between work satisfaction and burnout in GPs. Results: A good model fit was demonstrated for both the MBI and the WSQ. The canonical correlation analysis resulted in two statistically significant canonical functions with correlations of 0.64 (P<0.001) and 0.56 (P=0.001). The full model across all functions was significant (chi2 [18]=72.41, P<0.001). Burden and the global item in the WSQ are good predictors of emotional exhaustion, while patient care, personal rewards and professional relations seem to be good predictors of depersonalization/lack of empathy. This supports the approach to burnout as a multidimensional construct which has to be thoroughly diagnosed. Conclusion: Differential interventions tailored to GPs with specific deficits in certain areas should be delivered. GPs with a high score on emotional exhaustion would need a different intervention, as these respondents have different associations with work satisfaction than do GPs with a high score for depersonalization/low empathy. Therefore, the results of this study could contribute to the design of differential interventions aimed at ameliorating symptoms of burnout in GPs. PMID- 30425596 TI - Nesfatin-1 and cortisol: potential novel diagnostic biomarkers in moderate and severe depressive disorder. AB - Background: This study aimed to determine whether plasma nesfatin-1, cortisol, and inflammatory cytokines could be used as novel noninvasive biomarkers for the diagnosis of moderate and severe depressive disorder (MSDD). Materials and methods: A total of 70 patients with MSDD and 70 healthy subjects were assessed. Patients with MSDD were selected from Hefei Fourth People's Hospital, Anhui Mental Health Center, and subjects in the control group were selected from healthy volunteers. Hamilton Depression Rating Scale-17 (HAMD-17) was used to evaluate the two groups. ELISA was used for the measurement of plasma nesfatin-1, cortisol, IL-6, C-reactive protein (CRP), and tumor necrosis factor-alpha (TNF alpha) levels. The diagnostic value of plasma nesfatin-1, cortisol, IL-6, CRP, and TNF-alpha for MSDD was assessed. Results: Compared to healthy controls, the HAMD-17 scores and average nesfatin-1, cortisol, IL-6, and CRP levels in patients with MSDD were significantly increased. Moreover, multivariate linear regression analysis showed that HAMD-17 score was positively associated with plasma nesfatin 1 and cortisol. Furthermore, the results of the receiver operating characteristic (ROC) curve analysis revealed an area under curve (AUC) of 0.985 with 94.3% sensitivity and 97.1% specificity of nesfatin-1, and an AUC of 0.957 with 91.4% sensitivity and 85.7% specificity of cortisol in discriminating patients with MSDD from healthy volunteers. A combined ROC analysis using nesfatin-1 and cortisol revealed an AUC of 0.993 with a sensitivity of 97.1% and a specificity of 98.6% in separating patients with MSDD from healthy volunteers. Conclusion: These results suggest that plasma nesfatin-1 and cortisol might be potential novel biomarkers for the diagnosis of MSDD. PMID- 30425597 TI - The role of gender in association between inhibition capacities and risky decision making. AB - Background: Research on the association between decision making and inhibition abilities has exhibited fundamental controversies. Some authors claim that inhibition abilities are an integral part of the decision-making process, whereas others suggest that the decision-making process does not operate in close association with inhibition abilities. Can gender explain variations in risky decisions via inhibition influences? Purpose: The purpose of the present study was to explore the associations between response inhibition, reflection inhibition, interference inhibition, and decision-making processes in men and women. Methods: To this end, 46 women and 46 men were assessed by the Go/NoGo task, a measure of response inhibition, by the Matching Familiar Figure Test, a measure of reflection inhibition; and by the Stroop task, a measure of interference inhibition. Results: No differences were detected in these measures between groups. The net score of the performance on the last section of the Iowa Gambling Task choices did not correlate with the inhibition measures in the two groups. We did not discover any significant main effects of gender on the association between these measures. Conclusion: These findings do not support the hypothesis that risky decisions are due to impaired inhibitory control. Further studies are needed to identify the cognitive mechanisms involved in the tendency to make risky decisions. PMID- 30425598 TI - Incidences and factors associated with perioperative cardiac arrest in trauma patients receiving anesthesia. AB - Purpose: The aim of this study was to determine the incidences and factors associated with perioperative cardiac arrest in trauma patients who received anesthesia for emergency surgery. Patients and methods: This retrospective cohort study was approved by the medical ethical committee, Faculty of Medicine, Maharaj Nakorn Chiang Mai Hospital, Thailand. Data of 19,683 trauma patients who received anesthesia between January 2007 and December 2016, such as patient characteristics, surgery procedures, anesthesia information, anesthetic drugs, and cardiac arrest outcomes, were analyzed. Data of patients receiving local anesthesia by surgeons or monitoring anesthesia care (MAC) and those with much information missing were excluded. Factors associated with perioperative cardiac arrest were identified using univariate analysis and the multiple regression model. A stepwise algorithm was chosen at a P-value of <0.20 which was selected for multivariate analysis. A P-value of <0.05 was concluded as statistically significant. Results: The perioperative cardiac arrest in trauma patients receiving anesthesia for emergency surgery was 170.04 per 10,000 cases. Factors associated with perioperative cardiac arrest in trauma patients were as follows: age >65 years (risk ratio [RR] =1.41, CI =1.02-1.96, P=0.039), American Society of Anesthesiologist (ASA) physical status 3 or higher (ASA physical status 3-4, RR =4.19, CI =2.09-8.38, P<0.001; ASA physical status 5-6, RR =21.58, CI =10.36 44.94, P<0.001), sites of surgery (intracranial, intrathoracic, upper intra abdominal, and major vascular, each P<0.001), cardiopulmonary comorbidities (RR =1.55, CI =1.10-2.17, P=0.012), hemodynamic instability with shock prior to receiving anesthesia (RR =1.60, CI =1.21-2.11, P<0.001), and having a history of alcoholism (RR =5.27, CI =4.09-6.79, P<0.001). Conclusion: The incidence of perioperative cardiac arrest in trauma patients receiving anesthesia for emergency surgery was very high and correlated with patient's factors, especially old age and cardiopulmonary comorbidities, a history of drinking alcohol, increased ASA physical status, hemodynamic instability with shock prior to surgery, and sites of surgery such as brain, thorax, abdomen, and the major vascular region. Anesthesiologists and surgeons should be aware of a warning system and a well-equipped track to manage the surgical trauma patients. PMID- 30425599 TI - Improving prompt access to malaria diagnostics and treatment in rural remote areas using financial benefit for community health workers in Kilosa district, Tanzania. AB - Purpose: Improving access to malaria treatment in rural remote areas remains a major challenge facing innovative strategies, such as Accredited Drug Dispensing Outlets (ADDOs) and Community Health Workers (CHWs) programs in Tanzania. This study tested the effectiveness of a financial benefit approach to motivate CHWs to improve prompt access to malaria treatment. Patients and methods: We applied a quasi-experimental study design in rural-remote areas in Kilosa district, Tanzania. Febrile children in selected intervention areas were provided access to malaria diagnostic and treatment at a minimal fee to CHWs and compared with non intervention areas. We measured impact using difference in differences (DID) analysis. Results: At baseline, 870 children <5 years of age were recruited and 1,127 in post-intervention. The DID in prompt access to malaria diagnostics and treatment was 28.0% in favor of intervention. A net pre and post decrease (DID=24.1%) in seeking care from public facilities was observed, signifying decrease in workload. Incidentally, knowledge on malaria treatment increased in intervention area (DID 11%-21%). Conclusion: Using the financial benefit approach, CHWs were able to significantly improve prompt access to malaria diagnostics and treatment in rural remote areas. Scaling up of the strategy might speed up the pace toward achieving national target of accurate diagnosis and appropriate treatment by 80% in 2020. PMID- 30425600 TI - Diarrheal status and associated factors in under five years old children in relation to implemented and unimplemented community-led total sanitation and hygiene in Yaya Gulele in 2017. AB - Purpose: The aim of this study was to assess the diarrheal status and associated factors of under five-years old children among implemented and unimplemented community-led total sanitation and hygiene (CLTSH) in Yaya Gulele district, Ethiopia, in 2017. Methods: Community-based comparative cross-sectional study involving 380 households from each implemented and unimplemented CLTSH area was conducted from December 1 to June 30, 2017. Pretested structured questionnaire and a complete observational checklist were used to collect data. Qualitative data were collected via focused group discussions and analyzed manually. Data were checked and entered to Epi-info 3.5.4 and analyzed by SPSS version 20. Bivariate and multivariable logistic regression analyses were computed. Results: In this study, 88% implemented and 66% unimplemented CLTSH had latrine. Of households owning latrine, 85% in implemented and 75% in unimplemented CLTSH utilize latrine properly. In the study area, 12% in implemented and 34% in unimplemented CLTSH area practice open defecation. Two weeks period diarrhea prevalence was 13.4% (95% CI: 10.2-17.3%) in implemented CLTSH and 36.3% (95% CI: 31.7-41.6%) in unimplemented CLTSH. Having two or more children under five years old (adjusted odds ratio [AOR] = 2.33; 95% CI: 1.09-4.96), lack of clean water storage (AOR = 2.36; 95% CI: 1.16-4.80), negative attitude of mothers/caregivers toward diarrhea (AOR = 2.07; 95% CI: 1.06-4.04), presence of feces in the compound (AOR = 1.88; 95% CI: 1.10-3.22), and lack of hand washing facility in the compound (AOR = 2.64; 95% CI: 1.47-4.74) were associated factors of the outcome. Conclusion: Implementation of CLTSH is the applicable tool to reduce diarrhea prevalence. Having two or more children under five years old, unclean water storage, negative attitude of mothers toward diarrhea, existence of feces in the compound, and lack of hand washing facility in the compound were associated factors to the diarrheal status of children under five years old. Health workers and local authorities inspire the community to clean water-storage facilities and the environment, to change mothers' behavior toward diarrhea, as well as construct hand washing facility in the compound. PMID- 30425601 TI - Parental attitudes about acquiring a dental home for preschool children: a new concept in the Arab state of Qatar. AB - Objective: The purpose of the study was to assess parental perceptions and acceptability of a dental home for their preschool children, a new concept in the state of Qatar. Methods: A cross-sectional prospective study was conducted at Hamad Medical Corporation, in the state of Qatar. Parents of infants and children <5 years of age were offered an interview survey. Results: A total of 309 questionnaires were completed (response rate =98%). More than 90% of the participants believed that oral health and dentition affected total-body well being. Only 18% of parents stated that their children had excellent oral health. Interestingly, more than two-thirds of children had not had a routine dentist visit in the 12 months preceding the interview. Reasons for not having such visits included long appointment times (17.4%), the perception that dental care was expensive (15.5%), the notion that deciduous teeth did not need care (9%), the impression that insurance did not cover dental procedures (8%), unawareness of location of dental centers (4%), the child did not want to go (4%), the notion that children are difficult to handle during a dental procedure (3%), a combination of these factors (33.5%), and other factors (5%). When asked what factors would encourage them to enrol a dental home for their children, almost 20% mentioned speedy appointments followed by dentists specialized in pediatrics (14.3%), child-friendly atmosphere (12%), low cost (12%), close to home (5.7%), none (2.7%), others (2%), and all of the above (32.3%). Conclusion: Counseling by primary-care physicians can increase dental home acceptability in the state of Qatar, especially that access to health care is easy in our community. PMID- 30425602 TI - Phylogeny, infrageneric classification and species delimitation in the Malagasy Impatiens (Balsaminaceae). AB - The species-rich genus Impatiens (Balsaminaceae) is represented in Madagascar by no less than 260 species. We conducted molecular phylogenetic analyses of the Malagasy Impatiens based on nuclear and plastid data and 52 accessions (representing 33 species) to: 1) reassess the monophyly of the Malagasy Impatiens; 2) assess the monophyly of the sections Preimpatiens (Humblotianae and Vulgare groups) with spurs and Trimorphopetalum without spurs as delimited by Perrier de la Bathie, as well as that of the subgenera Impatiens and Trimorphopetalum as defined by Fischer and Rahelivololona; 3) infer the current status of some morphologically variable species; and 4) test whether the species of Impatiens from the Marojejy National Park form a monophyletic group. The Malagasy Impatiens are further confirmed to be paraphyletic with respect of the Comorian I.auricoma. The present sectional and subgeneric classifications of the Malagasy Impatiens are partly supported, with strong support for the monophyly of the sect. or subgen. Trimorphopetalum. Section Preimpatiens was not supported as monophyletic and neither the Humblotianae group nor the Vulgare group is monophyletic. Impatienselatostemmoides, I. "hammarbyoides", I.inaperta, I.lyallii and I.manaharensis are either para- or polyphyletic and may represent morpho species. The Impatiens species from the Marojejy National Park do not form a monophyletic group and therefore are suggested to be derived from numerous independent colonisation events from all over Madagascar followed by subsequent diversifications. PMID- 30425603 TI - Hedychiumviridibracteatum X.Hu, a new species from Guangxi Autonomous Region, South China. AB - Hedychiumviridibracteatum X.Hu, a new species from Guangxi Zhuang Autonomous Region, South China, is described and illustrated. Hedychiumviridibracteatum X.Hu is included in the short-anther group of Hedychium and is most similar to HedychiumvillosumWall.var.tenuiflorum Voigt ex Baker, H.villosumWall.var.villosum Wall., and H.chingmeianum N. Odyuo & D. K. Roy. PMID- 30425604 TI - On the identity of a U.S. intercepted Conotrachelus Dejean (Coleoptera: Curculionidae) with avocado (Persea americana). AB - Background: The multimillion-dollar avocado industry is threatened by a number of serious insect pests, including at least seven species of Curculionidae. Of these, three Conotrachelus species are known to develop and feed on avocados: Conotrachelus aguacatae Barber, Conotrachelus perseae Barber and C. serpentinus (Klug); the first two are of economic importance. Recently, a series of unrecognised Conotrachelus was intercepted with avocado and other commodities by the USDA at various southern U.S. ports of entry. The species most closely resembled the U.S. native Conotrachelus posticatus Boheman. Given the threat posed by certain species of Conotrachelus to avocado, the identity and biology of intercepted unknown Conotrachelus species becomes a matter of much concern for regulators due to the potential risk posed by non-native species to local agriculture. This study aims to determine the identity, which in turn may shed light on the biology and native distribution, of possible new non-U.S.-native weevils and provide the tools necessary to distinguish amongst phenotypically similar native species. New information: Amongst the unknown Conotrachelus weevils intercepted with avocados at certain U.S. ports of entry is Conotrachelus lobatus Champion. This poorly known species resembles a commonly collected, phenotypically variable indigenous U.S. species, Conotrachelus posticatus, which, on occasion, is also intercepted with avocado. Conotrachelus lobatus has been collected, since the early 1900s until today, along a narrow corridor in the southwest Mexican states of Michoacan, Jalisco and Nayarit. Specimen label data in natural history collections suggests the presence of this species in large numbers in early July in the avocado growing region of Mexico and, based on notes from former curators, appears to breed in acorns of the Mexican endemic oak species Quercus obtusata. The interception of C. posticatus and C. lobatus wth avocado does not imply strict biological association, however it reveals an important pattern of a non-native species' potential for introduction and its potential vector. Understanding all aspects of an organism's biology will better equip growers, as well as regulators, with effective and well-informed management strategies. Characters are imaged and discussed in order to help distinguish some Conotrachelus species belonging to Conotrachelus group II designated by Schoof (1942). Some characters of particular importance are the shape of the metauncus; shape of the lateral margin of the elytra and presence/absence of costate first and second elytral intervals. This study includes high-resolution images of seven Conotrachelus species, including the known avocado pests C. aguacatae and C. perseae, as well as the first images of C. lobatus, C. scoparius Champion and C. squamifrons Champion. The latter three species are not USA natives and were not included in Schoof's work. This study also confirms the important role played by natural history collections in anchoring the species' name through the study of types, which allows for the linking of biological and distribution data over time. Lectotypes are herein designated for C. lobatus and C. squamifrons. PMID- 30425605 TI - A list of bees from three locations in the Northern Rockies Ecoregion (NRE) of western Montana. AB - Background: Wild bees that were collected in conjunction with a larger study are presented as a checklist of species for the Northern Rockies Ecoregion of Montana, USA. Over the course of four field seasons (2013-2016), 281 species and morphospecies in 32 genera and five families were collected using insect nets, and identified. This paper addresses the distinct lack of studies monitoring bee species in Montana and contributes to a basic understanding of fauna in the northern Rocky Mountains. New information: With this study, the number of known bee species in Montana increases by at least six species, from 366 (Kuhlman and Burrows 2017) to 372. Though literature was not reviewed for all the species on this checklist, published records in Montana revealed no listings for Andrena saccata Viereck; Anthidiellum notatum robertsoni (Cockerell); Ashmeadiella meliloti (Cockerell); Ashmeadiella pronitens (Cockerell); Colletes lutzi lutzi Timberlake; and Dioxys productus (Cresson). PMID- 30425607 TI - Methodology to Evaluate Dripper Sensitivity to Clogging due to Solid Particles: An Assessment. AB - Emitter clogging is a major problem in microirrigation systems, which may result from the isolated or combined effects of physical, chemical, and biological agents. Clogging caused by suspended solid particles is the most common plugging form of emitters. Water quality and emitter geometry are key aspects in clogging processes. Any suitable test procedure to assess the sensitivity of drippers to clogging should take into account the predominant factors that influence clogging and must reproduce the field conditions. This research set out to assess the performance and suitability of a laboratory clogging test procedure in order to validate a methodology and to provide scientific results that may support the standardization of a clogging test method. The evaluated methodology has been used by the IRSTEA laboratory since 1974 (Platform of Research and experiment on Science and Technology for Irrigation - PReSTI, formerly LERMI) and its contents are currently being discussed by the ISO TC23/SC18 committee. The aim is to define a standardized testing protocol to evaluate the sensitivity of emitters to clogging due to solid particles. Replications analyzing the clogging resistance of four models of emitting pipes were carried out in a laboratory. The clogging test procedure enabled an accurate assessment of the combinations of concentration and size of particles that caused clogging in each model of dripper. However, a significant variability in degree of clogging was identified when the results of replications for each model of dripper were compared. Several requirements, concerns, and improvements related to the clogging test protocol were discussed. PMID- 30425606 TI - Nanoparticles applied to cancer immunoregulation. AB - Aim: In recent years, we have seen a considerable increase in the relevance of nanostructures for the safe delivery of therapeutic agents and their capacity as an immunomodulatory tool. Materials and methods: Potential clinical applications related to their unique structural properties have been described in the evolving landscape of immunotherapy. Results: This review briefly summarizes the evidence for the role of nanoparticles in regulating the immune response. Conclusions: Their main features to highlight how to provide an innovative means of biomedical application to oncology research. PMID- 30425608 TI - Molecular Imaging: In Vivo Agents for the Diagnosis and Treatment of Cancer. PMID- 30425609 TI - Contrast-Enhanced Magnetic Resonance Angiography Using a Novel Elastin-Specific Molecular Probe in an Experimental Animal Model. AB - Objectives: The aim of this study was to test the potential of a new elastin specific molecular agent for the performance of contrast-enhanced first-pass and 3D magnetic resonance angiography (MRA), compared to a clinically used extravascular contrast agent (gadobutrol) and based on clinical MR sequences. Materials and Methods: Eight C57BL/6J mice (BL6, male, aged 10 weeks) underwent a contrast-enhanced first-pass and 3D MR angiography (MRA) of the aorta and its main branches. All examinations were on a clinical 3 Tesla MR system (Siemens Healthcare, Erlangen, Germany). The clinical dose of 0.1 mmol/kg was administered in both probes. First, a time-resolved MRA (TWIST) was acquired during the first pass to assess the arrival and washout of the contrast agent bolus. Subsequently, a high-resolution 3D MRA sequence (3D T1 FLASH) was acquired. Signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) were calculated for all sequences. Results: The elastin-specific MR probe and the extravascular imaging agent (gadobutrol) enable high-quality MR angiograms in all animals. During the first-pass, the probes demonstrated a comparable peak enhancement (300.6 +/- 32.9 vs. 288.5 +/- 33.1, p > 0.05). Following the bolus phase, both agents showed a comparable intravascular enhancement (SNR: 106.7 +/- 11 vs. 102.3 +/- 5.3; CNR 64.5 +/- 7.4 vs. 61.1 +/- 7.2, p > 0.05). Both agents resulted in a high image quality with no statistical difference (p > 0.05). Conclusion: The novel elastin specific molecular probe enables the performance of first-pass and late 3D MR angiography with an intravascular contrast enhancement and image quality comparable to a clinically used extravascular contrast agent. PMID- 30425610 TI - Coprophagy in nineteenth-century psychiatry. AB - This paper shows how Austrian psychiatrists of the 1870s developed the first pathological accounts of institutional coprophagia, examining how they related the behaviour to mental illness and dementia. These ideas about coprophagia contrasted dramatically to the long European pharmacological tradition of using excrement for the treatment of a wide range of health conditions. Recent medical scholarship on institutional coprophagia is also reviewed here, with a novel hypothesis proposed about why some patients in long-term care resort to the behaviour in institutions where there is little opportunity for healthy human microbe interactions. PMID- 30425611 TI - Editorial. PMID- 30425612 TI - The gut-brain axis: historical reflections. AB - The gut-brain axis and the microbiome have recently acquired an important position in explaining a wide range of human behaviours and emotions. Researchers have typically presented developments in understandings of the microbiome as radical and new, offering huge potential for better understandings of our bodies and what it means to be human. Without refuting the value of this research, this article insists that, traditionally, doctors and patients acknowledged the complex interactions between their guts and emotions, although using alternative models often based on nerves or psychology. For example, nineteenth-century doctors and patients would have been well acquainted with the idea that their stomachs and minds were somehow connected, and that this interaction could produce positive or negative physical and mental health impacts. To demonstrate this, this article offers a snapshot of medical and public thought on (what we currently call) the gut-brain axis in the nineteenth and twentieth centuries, using Britain as a key case study due to the prevalence of gastric problems in that country. It commences by exploring how nineteenth-century doctors and patients took for granted the intimate relations between gut and mind and used their ideas on this to debate personal health, medical theory and social and political discourse. The article then moves on to argue that various medical sub disciplines emerged (anatomy, physiology, surgery) that threatened to reduce the stomach to a physiologically complex organ but, in doing so, inadvertently began to erase ideas of a gut-mind connection. However, these new models proved unsatisfactory, allowing more holistic ideas of the body-mind relationship to continue to carry currency in twentieth-century psychological and medical thought. In the late century, pharmacological developments once again threatened to minimise the gut-brain axis, before it once again became popular in the early twenty-first century, now debated through a new language of microbiology. PMID- 30425613 TI - LORETA With Cortical Constraint: Choosing an Adequate Surface Laplacian Operator. AB - Low resolution electromagnetic tomography (LORETA) is a well-known method for the solution of the l2-based minimization problem for EEG/MEG source reconstruction. LORETA with a volume-based source space is widely used and much effort has been invested in the theory and the application of the method in an experimental context. However, it is especially interesting to use anatomical prior knowledge and constrain the LORETA's solution to the cortical surface. This strongly reduces the number of unknowns in the inverse approach. Unlike the Laplace operator in the volume case with a rectangular and regular grid, the mesh is triangulated and highly irregular in the surface case. Thus, it is not trivial to choose or construct a Laplace operator (termed Laplace-Beltrami operator when applied to surfaces) that has the desired properties and takes into account the geometry of the mesh. In this paper, the basic methodology behind cortical LORETA is discussed and the method is applied for source reconstruction of simulated data using different Laplace-Beltrami operators in the smoothing term. The results achieved with the different operators are compared with respect to their accuracy using various measures. Conclusions about the choice of an appropriate operator are deduced from the results. PMID- 30425614 TI - Measuring Brain Complexity During Neural Motor Resonance. AB - Background: EEG mu-desynchronization is an index of motor resonance (MR) and is used to study social interaction deficiencies, but finding differences in mu desynchronization does not reveal how nonlinear brain dynamics are affected during MR. The current study explores how nonlinear brain dynamics change during MR. We hypothesized that the complexity of the mu frequency band (8-13 Hz) changes during MR, and that this change would be frequency specific. Additionally, we sought to determine whether complexity at baseline and changes in complexity during action observation would predict MR and changes in network dynamics. Methods: EEG was recorded from healthy participants (n = 45) during rest and during an action observation task. Baseline brain activity was measured followed by participants observing videos of hands squeezing stress balls. We used multiscale entropy (MSE) to quantify the complexity of the mu rhythm during MR. We then performed post-hoc graph theory analysis to explore whether nonlinear dynamics during MR affect brain network topology. Results: We found significant mu-desynchronization during the action observation task and that mu entropy was significantly increased during the task compared to rest, while gamma, beta, theta, and delta bands showed decreased entropy. Moreover, resting-state entropy was significantly predictive of the degree of mu desynchronization. We also observed a decrease in the clustering coefficient in the mu band only and a significant decrease in global alpha efficiency during action observation. MSE during action observation was strongly correlated with alpha network efficiency. Conclusions: The current findings suggest that the desynchronization of the mu wave during MR results in a local increase of mu entropy in sensorimotor areas, potentially reflecting a release from alpha inhibition. This release from inhibition may be mediated by the baseline MSE in the mu band. The dynamical complexity and network analysis of EEG may provide a useful addition for future studies of MR by incorporating measures of nonlinearity. PMID- 30425615 TI - Electroacupuncture Inhibits Visceral Nociception via Somatovisceral Interaction at Subnucleus Reticularis Dorsalis Neurons in the Rat Medulla. AB - Electroacupuncture (EA) is an efficacious treatment for alleviating visceral pain, but the underlining mechanisms are not fully understood. This study investigated the role of medullary subnucleus reticularis dorsalis (SRD) neurons in the effects of EA on visceral pain. We recorded the discharges of SRD neurons extracellularly by glass micropipettes on anesthetized rats. The responses characteristics of SRD neurons to different intensities of EA (0.5, 1, 2, 4, 6, and 8 mA, 0.5 ms, and 2 Hz) on acupoints "Zusanli" (ST 36) and "Shangjuxu" (ST 37) before and during noxious colorectal distension (CRD) were analyzed. Our results indicated that SRD neurons responded to either a noxious EA stimulation ranging from 2 to 8 mA or to noxious CRD at 30 and 60 mmHg by increasing their discharge frequency at an intensity-dependent manner. However, during the stimulation of both CRD and EA, the increasing discharges of SRD neurons induced by CRD were significantly inhibited by 2-8 mA of EA. Furthermore, SRD neurons can encode the strength of EA, where a positive correlation between current intensity and the magnitude of neuronal responses to EA was observed within 2-6 mA. Yet, the responses of SRD neurons to EA stimulation reached a plateau when EA exceeded 6 mA. In addition, 0.5-1 mA of EA had no effect on CRD-induced nociceptive responses of SRD neurons. In conclusion, EA produced an inhibiting effect on visceral nociception in an intensity-dependent manner, which probably is due to the somatovisceral interaction at SRD neurons. PMID- 30425616 TI - Power of Feedback-Induced Beta Oscillations Reflect Omission of Rewards: Evidence From an EEG Gambling Study. AB - The functional role of high beta oscillations (20-35 Hz) during feedback processing has been suggested to reflect unexpected gains. Using a novel gambling task that separates gains and losses across blocks and directly compares reception of monetary rewards to a 'no-reward/punishment' condition with equal probability we aimed to further investigate the role of beta oscillations. When contrasting different feedback conditions across rewards, we found that a late low beta component (12-20 Hz) had increased in power during the omission of rewards relative to the reception of rewards, while no differences were observed during the loss domain. These findings may indicate that late low beta oscillations in the context of feedback processing may respond to omission of gains relative to other potential outcomes. We speculate that late low beta oscillations may operate as a learning mechanism that signals the brain to make future adequate decisions. Overall, our study provides new insights for the role of late low beta oscillations in reward processing. PMID- 30425617 TI - Basal Forebrain Mediates Motivational Recruitment of Attention by Reward Associated Cues. AB - The basal forebrain, composed of distributed nuclei, including substantia innominata (SI), nucleus basalis and nucleus of the diagonal band of Broca plays a crucial neuromodulatory role in the brain. In particular, its projections to the prefrontal cortex have been shown to be important in a wide variety of brain processes and functions, including attention, learning and memory, arousal, and decision-making. In the present study, we asked whether the basal forebrain is involved in recruitment of cognitive effort in response to reward-related cues. This interaction between motivation and cognition is critically impacted in psychiatric conditions such as schizophrenia. Using the Designer Receptor Exclusively Activated by Designer Drug (DREADD) technique combined with our recently developed signaled probability sustained attention task (SPSA), which explicitly assays the interaction between motivation and attention, we sought to determine the role of the basal forebrain in this interaction. Rats were stereotaxically injected in the basal forebrain with either hM4D(Gi) (a virus that expresses receptors which silence neurons in the presence of the drug clozapine-N-oxide; CNO) or a control virus and tested in the SPSA. Behavior of rats during baseline and under saline indicated control by reward probability. In the presence of CNO, differential accuracy of hM4D(Gi) rats on high and low reward-probability trials was abolished. This result occurred despite spared ability of the reward-probability signals to differentially impact choice response latencies and omissions. These results indicate that the basal forebrain is critical for the motivational recruitment of attention in response to reward related cues and are consistent with a role for basal forebrain in encoding and transmitting motivational salience of reward-related cues and readying prefrontal circuits for further attentional processing. PMID- 30425618 TI - TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner. AB - Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene and protein expression, of the neurotrophin brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) of adult TPH2-deficient (TPH2-/-) male and female rats in comparison to wild type (TPH2+/+) counterparts. Interestingly, a development-specific pattern was observed during early postnatal life: whereas the increase in Bdnf expression, mainly driven by the modulation of Bdnf isoform IV was clearly visible after weaning at postnatal day (pnd) 30 in both sexes of TPH2-/- in comparison to TPH2+/+ rats, at early stages (pnd1 and pnd10) Bdnf expression levels did not differ between the genotypes, or even were downregulated in male TPH2-/- animals at pnd10. Moreover, to establish if hyposerotonergia may influence the response to a challenging situation, we exposed adult rats to an acute stress. Although the pattern of corticosterone release was similar between the genotypes, neuronal activation in response to stress, quantified by the expression of the immediate early genes activity regulated cytoskeleton associated protein (Arc) and Fos Proto-Oncogene (cFos), was blunted in both sexes of animals lacking brain serotonin. Interestingly, although upregulation of Bdnf mRNA levels after stress was observed in both genotypes, it was less pronounced in TPH2-/- in comparison to TPH2+/+ rats. In summary, our results demonstrated that serotonin deficiency affects neuroplastic mechanisms following a specific temporal pattern and influences the response to an acute stress. PMID- 30425619 TI - Comparison of in vitro Neuronal Differentiation Capacity Between Mouse Epiblast Stem Cells Derived From Nuclear Transfer and Naturally Fertilized Embryos. AB - Somatic cell nuclear transfer (SCNT) can give rise to fertile adults, but the successful perinatal and postnatal developmental rates are inefficient, including delayed developmental behaviors, and respiratory failure. However, the molecular and cellular mechanisms remain elusive. Mouse epiblast stem cells (mEpiSCs) from E5.5-6.5 epiblasts share defining features with human embryonic stem cells (hESCs), providing a new opportunity to study early mammalian development in vitro. In this study, mEpiSCs were established from naturally fertilized mouse embryos (F-mEpiSCs) and SCNT mouse embryos (NT-mEpiSCs). Also, the in vitro neuronal differentiation capacity of F-mEpiSCs and NT-mEpiSCs was compared. Morphology analysis showed less and smaller neurospheres formation and lower percentage of early neurons generation in NT-mEpiSCs. The immunocytochemical analysis and altered mRNA expression levels of the neuronal markers in differentiated cells further confirmed that neurogenesis was slower in NT-mEpiSCs than in F-mEpiSCs. Moreover, neuronal differentiation capacity was correlated with the basal expression levels of Atox1 and Vinculin but not Brachyury and Otx2, emphasizing that developmental aberrations in neurogenesis were associated with the NT technique but not random variations between clones. This study provided an important in vitro platform using mEpiSCs to study early epigenetic and developmental processes associated with neurogenesis. PMID- 30425620 TI - ALS Yeast Models-Past Success Stories and New Opportunities. AB - In the past two decades, yeast models have delivered profound insights into basic mechanisms of protein misfolding and the dysfunction of key cellular pathways associated with amyotrophic lateral sclerosis (ALS). Expressing ALS-associated proteins, such as superoxide dismutase (SOD1), TAR DNA binding protein 43 (TDP 43) and Fused in sarcoma (FUS), in yeast recapitulates major hallmarks of ALS pathology, including protein aggregation, mislocalization and cellular toxicity. Results from yeast have consistently been recapitulated in other model systems and even specimens from human patients, thus providing evidence for the power and validity of ALS yeast models. Focusing on impaired ribonucleic acid (RNA) metabolism and protein misfolding and their cytotoxic consequences in ALS, we summarize exemplary discoveries that originated from work in yeast. We also propose previously unexplored experimental strategies to modernize ALS yeast models, which will help to decipher the basic pathomechanisms underlying ALS and thus, possibly contribute to finding a cure. PMID- 30425621 TI - Plasma Markers of Neurodegeneration Are Raised in Friedreich's Ataxia. AB - Background: Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA. Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay. Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed. Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (rc = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias. Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation. PMID- 30425623 TI - Maximizing Explanatory Power in Stereological Data Collection: A Protocol for Reliably Integrating Optical Fractionator and Multiple Immunofluorescence Techniques. AB - With the promise of greater reliability and replicability of estimates, stereological techniques have revolutionized data collection in the neurosciences. At the same time, improvements in immunohistochemistry and fluorescence imaging technologies have facilitated easy application of immunofluorescence protocols, allowing for isolation of multiple target proteins in one tissue sample. Combining multiple immunofluorescence labeling with stereological data collection can provide a powerful tool to maximize explanatory power and efficiency, while minimizing tissue use. Multiple cell classes, subtypes of larger populations, or different cell states can be quantified in one case and even in one sampling run. Here, we present a protocol integrating stereological data collection and multiple immunofluorescence using commonly employed widefield epifluorescence filter sets, optimized for blue (DAPI), green (FITC), and far red (CY5) channels. Our stereological protocol has been designed to accommodate the challenges of fluorescence imaging to overcome limitations like fixed filter sets, photobleaching, and uneven immunolabeling. To enhance fluorescence signal for stereological sampling, our immunolabeling protocol utilizes both high temperature antigen retrieval to improve primary antibody binding and secondary antibodies conjugated to optimally stable fluorophores. To illustrate the utility of this approach, we estimated the number of Ctip2 immunoreactive subcerebral projection neurons and NeuN immunoreactive neurons in rat cerebral cortex at postnatal day 10. We used DAPI (blue) to define the neocortex, anti-NeuN (far red) to identify neurons, and co-labeling of anti-Ctip2 (green) and anti-NeuN (far red) to isolate only subcerebral projection neurons. Our protocol resulted in estimates with low sampling error (CE < 0.05) and high intrarater reliability (ICC > 0.98) that fall within the range of published values, attesting to its efficacy. We show our immunofluorescence techniques can be used to reliably identify other cell types, e.g., different glial cell classes, to highlight the broader applications of our approach. The flexibility of the technique, increasingly reduced costs of fluorescence technologies, and savings in experimental time and tissue use make this approach valuable for neuroscientists interested in incorporating stereology to ask precise neurophysiological and neuroanatomical questions. PMID- 30425622 TI - Mechanisms and Role of Dendritic Membrane Trafficking for Long-Term Potentiation. AB - Long-term potentiation (LTP) of excitatory synapses is a major form of plasticity for learning and memory in the central nervous system. While the molecular mechanisms of LTP have been debated for decades, there is consensus that LTP induction activates membrane trafficking pathways within dendrites that are essential for synapse growth and strengthening. Current models suggest that key molecules for synaptic potentiation are sequestered within intracellular organelles, which are mobilized by synaptic activity to fuse with the plasma membrane following LTP induction. While the identity of the factors mobilized to the plasma membrane during LTP remain obscure, the field has narrowly focused on AMPA-type glutamate receptors. Here, we review recent literature and present new experimental data from our lab investigating whether AMPA receptors trafficked from intracellular organelles directly contribute to synaptic strengthening during LTP. We propose a modified model where membrane trafficking delivers distinct factors that are required to maintain synapse growth and AMPA receptor incorporation following LTP. Finally, we pose several fundamental questions that may guide further inquiry into the role of membrane trafficking for synaptic plasticity. PMID- 30425624 TI - Reconstruction of Intratelencephalic Neurons in the Mouse Secondary Motor Cortex Reveals the Diverse Projection Patterns of Single Neurons. AB - The secondary motor cortex (MOs) plays crucial roles in cognitive and executive processes and has reciprocal connections with numerous cortices in rodents. However, descriptions of the neuronal morphologies and projection patterns of the MOs at the level of a single neuron are lacking, severely hindering the comprehensive understanding of the wiring diagram of the MOs. Herein, we used a Cre-dependent adeno-associated virus (AAV) to fluorescently label ~80 pyramidal neurons nearby or in the MOs and acquired an uninterrupted whole-brain 3D dataset at a voxel resolution of 0.2 * 0.2 * 1 MUm with a whole-brain fluorescence imaging system (fMOST). Based on our 3D dataset, we reconstructed the complete morphologies of 36 individual intratelencephalic (IT) neurons nearby or in the MOs and analyzed the projection patterns and projection strengths of these neurons at a single-neuron level based on several parameters, including the projection areas, the total number of branches, the fiber length, and the total number of terminal tips. We obtained a neuron with an axonal length of 318.43 mm, which is by far the longest reported axonal length. Our results show that all individual neurons in the MOs, regardless of whether they are located in layer 2/3 or layer 5, display diverse projection patterns and projection strengths, implying that these neurons might be involved in different brain circuits at different intensities. The results lay a solid foundation for exploring the relationship between neuronal morphologies and behavioral functions of the MOs at the level of a single neuron. PMID- 30425625 TI - Axonal Projections From the Middle Temporal Area in the Common Marmoset. AB - Neural activity in the middle temporal (MT) area is modulated by the direction and speed of motion of visual stimuli. The area is buried in a sulcus in the macaque, but exposed to the cortical surface in the marmoset, making the marmoset an ideal animal model for studying MT function. To better understand the details of the roles of this area in cognition, underlying anatomical connections need to be clarified. Because most anatomical tracing studies in marmosets have used retrograde tracers, the axonal projections remain uncharacterized. In order to examine axonal projections from MT, we utilized adeno-associated viral (AAV) tracers, which work as anterograde tracers by expressing either green or red fluorescent protein in infected neurons. AAV tracers were injected into three sites in MT based on retinotopy maps obtained via in vivo optical intrinsic signal imaging. Brains were sectioned and divided into three series, one for fluorescent image scanning and two for myelin and Nissl substance staining to identify specific brain areas. Overall projection patterns were similar across the injections. MT projected to occipital visual areas V1, V2, V3 (VLP) and V4 (VLA) and surrounding areas in the temporal cortex including MTC (V4T), MST, FST, FSTv (PGa/IPa) and TE3. There were also projections to the dorsal visual pathway, V3A (DA), V6 (DM) and V6A, the intraparietal areas AIP, LIP, MIP, frontal A4ab and the prefrontal cortex, A8aV and A8C. There was a visuotopic relationship with occipital visual areas. In a marmoset in which two tracer injections were made, the projection targets did not overlap in A8aV and AIP, suggesting topographic projections from different parts of MT. Most of these areas are known to send projections back to MT, suggesting that they are reciprocally connected with it. PMID- 30425626 TI - The Absolute Number of Oligodendrocytes in the Adult Mouse Brain. AB - The central nervous system is a highly complex network composed of various cell types, each one with different subpopulations. Each cell type has distinct roles for the functional operation of circuits, and ultimately, for brain physiology in general. Since the absolute number of each cell type is considered a proxy of its functional complexity, one approach to better understand how the brain works is to unravel its absolute cellularity and the quantitative relations between cell populations; in other words, how one population of cells is quantitatively structured, in relation to another. Oligodendrocytes are one of these cell types mainly, they provide electric insulation to axons, optimizing action potential conduction. Their function has recently been revisited and their role extended, one example being their capability of providing trophic support to long axons. To determine the absolute cellularity of oligodendroglia, we have developed a protocol of oligodendrocyte quantification using the isotropic fractionator with a pan-marker for this cell type. We report a detailed assessment of specificity and universality of the oligodendrocyte transcription factor 2 (Olig2), through systematic confocal analyses of the C57BL/6 mouse brain. In addition, we have determined the absolute number (17.4 million) and proportion (about 20%) of this cell type in the brain (and in different brain regions), and tested if this population, at the intraspecific level, scales with the number of neurons in an allometric-based approach. Considering these numbers, oligodendrocytes proved to be the most numerous of glial cells in the mouse brain. PMID- 30425627 TI - Sex and Feeding Status Differently Affect Natural Reward Seeking Behavior in Olfactory Bulbectomized Rats. AB - Substance abuse and depression are common psychiatric disorders with a high rate of comorbidity. Both conditions affect differently men and women and preclinical research has showed many sex differences in drug addiction and depression. The most common approach for modeling depression-addiction comorbidity is the combination of the intravenous drug self-administration and the olfactory bulbectomy (OBX) models in rats. Such a combination has revealed enhanced drug taking and drug-seeking behaviors in OBX rats, but no study has investigated so far potential sex differences in operant responding and motivation for natural reinforcers in OBX rats. This study investigated for the first time operant self administration of palatable food pellets in male and female OBX rats under different feeding status, i.e., ad libitum vs. restricted food, and schedules of reinforcement, i.e., a continuous ratio schedule fixed ratio 1 (FR1) vs. a complex (FR5(x)) second order schedule of reinforcement. In the FR1 experiment, OBX rats of both sexes exhibited lower operant responding and intake of palatable food pellets than sham-operated controls, with food restriction leading to increased operant responding in both OBX and SHAM groups. Female rats showed higher responding than males but this effect was abolished by the OBX lesion. Similarly, in the (FR5(x)) second order schedule of reinforcement both male and female OBX rats showed lower responding and food intake, with SHAM and OBX females showing higher operant responding than corresponding male groups. Overall, our findings showed that: (i) responding for food was lower in OBX than in SHAM rats under both FR1 and (FR5(x)) schedules of reinforcement; (ii) sex and food restriction affect operant responding for palatable food; and (iii) the suppressing effect of OBX lesion on food intake was consistently present in both sexes and represents the most robust factor in the analysis. This may represent anhedonia which is associated with depressive-like phenotype and palatable food self-administration may serve as a robust behavioral index of anhedonia in the OBX model. PMID- 30425629 TI - Developmental Perceptual Impairments: Cases When Tone-Deafness and Prosopagnosia Co-occur. AB - Studies have shown subtle gray and white matter abnormalities in subjects with several developmental disorders including prosopagnosia, tone-deafness, and dyslexia. Correlational evidence suggests that tone-deafness and dyslexia tend to co-occur, suggesting a link between these two developmental disorders. However, it is not known whether tone-deafness can also be associated with other developmental disorders such as impaired face recognition or prosopagnosia. We addressed this question by assessing face perception abilities in a group of tone deaf individuals and matched non-tone-deaf subjects. The Cambridge (CFMT) and the Warrington (WRMT) face memory tests were used to assess face processing in the combined group of 12, out of which six tested in the tone-deaf range. Only tone deaf participants (two out of six) scored in the impaired range on the CFMT, one of whom was also impaired on the WRMT face memory test. Furthermore, the melodic composite score of all participants on the Montreal Battery of Evaluation of Amusia significantly correlated with their face recognition score on the CFMT. Our results suggest that in some cases tone-deafness might co-occur with face recognition impairments. It is implausible that both deficits are linked to a single cognitive dysfunction that spans different perceptual systems in different modalities. They are likely associated with a common pathogenetic mechanism of early development that leads to anomalies affecting the function of different brain systems or the connection between regions. PMID- 30425630 TI - Editorial: Detection and Estimation of Working Memory States and Cognitive Functions Based on Neurophysiological Measures. PMID- 30425628 TI - Expedition Cognition: A Review and Prospective of Subterranean Neuroscience With Spaceflight Applications. AB - Renewed interest in human space exploration has highlighted the gaps in knowledge needed for successful long-duration missions outside low-Earth orbit. Although the technical challenges of such missions are being systematically overcome, many of the unknowns in predicting mission success depend on human behavior and performance, knowledge of which must be either obtained through space research or extrapolated from human experience on Earth. Particularly in human neuroscience, laboratory-based research efforts are not closely connected to real environments such as human space exploration. As caves share several of the physical and psychological challenges of spaceflight, underground expeditions have recently been developed as a spaceflight analog for astronaut training purposes, suggesting that they might also be suitable for studying aspects of behavior and cognition that cannot be fully examined under laboratory conditions. Our objective is to foster a bi-directional exchange between cognitive neuroscientists and expedition experts by (1) describing the cave environment as a worthy space analog for human research, (2) reviewing work conducted on human neuroscience and cognition within caves, (3) exploring the range of topics for which the unique environment may prove valuable as well as obstacles and limitations, (4) outlining technologies and methods appropriate for cave use, and (5) suggesting how researchers might establish contact with potential expedition collaborators. We believe that cave expeditions, as well as other sorts of expeditions, offer unique possibilities for cognitive neuroscience that will complement laboratory work and help to improve human performance and safety in operational environments, both on Earth and in space. PMID- 30425631 TI - Data Driven Classification Using fMRI Network Measures: Application to Schizophrenia. AB - Using classification to identify biomarkers for various brain disorders has become a common practice among the functional MR imaging community. Typical classification pipeline includes taking the time series, extracting features from them, and using them to classify a set of patients and healthy controls. The most informative features are then presented as novel biomarkers. In this paper, we compared the results of single and double cross validation schemes on a cohort of 170 subjects with schizophrenia and healthy control subjects. We used graph theoretic measures as our features, comparing the use of functional and anatomical atlases to define nodes and the effect of prewhitening to remove autocorrelation trends. We found that double cross validation resulted in a 20% decrease in classification performance compared to single cross validation. The anatomical atlas resulted in higher classification results. Prewhitening resulted in a 10% boost in classification performance. Overall, a classification performance of 80% was obtained with a double-cross validation scheme using prewhitened time series and an anatomical brain atlas. However, reproducibility of classification within subjects across scans was surprisingly low and comparable to across subject classification rates, indicating that subject state during the short scan significantly influences the estimated features and classification performance. PMID- 30425632 TI - Molecular Mechanisms of Short-Term Plasticity: Role of Synapsin Phosphorylation in Augmentation and Potentiation of Spontaneous Glutamate Release. AB - We used genetic and pharmacological approaches to identify the signaling pathways involved in augmentation and potentiation, two forms of activity dependent, short term synaptic plasticity that enhance neurotransmitter release. Trains of presynaptic action potentials produced a robust increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs). Following the end of the stimulus, mEPSC frequency followed a bi-exponential decay back to basal levels. The time constants of decay identified these two exponential components as the decay of augmentation and potentiation, respectively. Augmentation increased mEPSC frequency by 9.3-fold, while potentiation increased mEPSC frequency by 2.4 fold. In synapsin triple-knockout (TKO) neurons, augmentation was reduced by 83% and potentiation was reduced by 74%, suggesting that synapsins are key signaling elements in both forms of plasticity. To examine the synapsin isoforms involved, we expressed individual synapsin isoforms in TKO neurons. While synapsin IIIa rescued both augmentation and potentiation, none of the other synapsin isoforms produced statistically significant amounts of rescue. To determine the involvement of protein kinases in these two forms of short-term plasticity, we examined the effects of inhibitors of protein kinases A (PKA) and C (PKC). While inhibition of PKC had little effect, PKA inhibition reduced augmentation by 76% and potentiation by 60%. Further, elevation of intracellular cAMP concentration, by either forskolin or IBMX, greatly increased mEPSC frequency and occluded the amount of augmentation and potentiation evoked by electrical stimulation. Finally, mutating a PKA phosphorylation site to non-phosphorylatable alanine largely abolished the ability of synapsin IIIa to rescue both augmentation and potentiation. Together, these results indicate that PKA activation is required for both augmentation and potentiation of spontaneous neurotransmitter release and that PKA-mediated phosphorylation of synapsin IIIa underlies both forms of presynaptic short-term plasticity. PMID- 30425634 TI - Ketamine Reverses Lateral Habenula Neuronal Dysfunction and Behavioral Immobility in the Forced Swim Test Following Maternal Deprivation in Late Adolescent Rats. AB - Mounting evidence suggests that the long-term effects of adverse early life stressors on vulnerability to drug addiction and mood disorders are related to dysfunction of brain monoaminergic signaling in reward circuits. Recently, there has been a growing interest in the lateral habenula (LHb) as LHb dysfunction is linked to the development of mental health disorders through monoaminergic dysregulation within brain reward/motivational circuits and may represent a critical target for novel anti-depressants, such as ketamine. Here, we show that maternal deprivation (MD), a severe early life stressor, increases LHb intrinsic excitability and LHb bursting activity, and is associated with the development of increased immobility in the forced swim test (FST) in late-adolescent male rats. A single in vivo injection of ketamine is sufficient to exert prolonged antidepressant effects through reversal of this early life stress-induced LHb neuronal dysfunction and the response in the FST. Our assessment of ketamine's long-lasting beneficial effects on reversal of MD-associated changes in LHb neuronal function and behavior highlights the critical role of the LHb in pathophysiology of depression associated with severe early life stress and in response to novel fast-acting antidepressants. PMID- 30425633 TI - Deficient Wnt Signaling and Synaptic Vulnerability in Alzheimer's Disease: Emerging Roles for the LRP6 Receptor. AB - Synapse dysfunction and loss represent critical early events in the pathophysiology of Alzheimer's disease (AD). While extensive research has elucidated the direct synaptotoxic effects of Amyloid-beta (Abeta) oligomers, less is known about how signaling pathways at the synapse are affected by Abeta. A better understanding of the cellular and molecular mechanisms underlying synaptic vulnerability in AD is key to illuminating the determinants of AD susceptibility and will unveil novel therapeutic avenues. Canonical Wnt signaling through the Wnt co-receptor LRP6 has a critical role in maintaining the structural and functional integrity of synaptic connections in the adult brain. Accumulating evidence suggests that deficient Wnt signaling may contribute to AD pathology. In particular, LRP6 deficiency compromises synaptic function and stability, and contributes to Abeta production and plaque formation. Here, we review the role of Wnt signaling for synaptic maintenance in the adult brain and the contribution of aberrant Wnt signaling to synaptic degeneration in AD. We place a focus on emerging evidence implicating the LRP6 receptor as an important modulator of AD risk and pathology. PMID- 30425635 TI - As Time Goes by: A rTMS Study on Age-Related Changes in Sentence Comprehension. AB - It is well established that off-line sentence judgment tasks (oSJTs) typically rely on phonological working memory (WM), beyond specific linguistic processing. Nevertheless, empirical findings suggest that a juvenile level of performance in an oSJT could be associated with the recruitment of age-specific additional supportive neural network in healthy aging. In particular, in one of our previous study, healthy elderlies showed the additional activation of associative visual cortices when compared with young controls. We suggested that age-related hyperactivations, during an auditory sentence judgment task, might represent the neurofunctional correlate of the recruitment of compensatory strategies that are necessary to maintain a juvenile level of performance. To explicitly test this hypothesis we adopted repetitive transcranial magnetic stimulation (rTMS). Twelve healthy elderlies and 12 young participants were engaged in an off-line semantic plausibility judgment task while rTMS was delivered over: (1) the left inferior frontal gyrus (LIFG; i.e., a core region of the WM network); (2) the precuneus; and (3) a Control Site (vertex). Results showed a significant main effect of Stimulation Site and a significant Group-by-Stimulation Site interaction effect. In particular, the rTMS stimulation of the LIFG slowed down reaction times (RTs) both in young and healthy elderly participants, while only healthy elderlies showed an increment of RTs during the stimulation of the precuneus. Taken together our results further support the idea that the maintenance of a juvenile level of performance in graceful aging may be associated with task-specific compensatory processes that would manifest them-selves, from the neurofunctional point of view, by the recruitment of additional neural supportive regions. PMID- 30425637 TI - In Older Patients Treated for Dizziness and Vertigo in Multimodal Rehabilitation Somatic Deficits Prevail While Anxiety Plays a Minor Role Compared to Young and Middle Aged Patients. AB - Objective: Many patients with dizziness and vertigo are of older age. It is still unclear which age-associated factors play a role in the treatment of dizziness and vertigo. Therefore, age-associated characteristics of patients subjected to an interdisciplinary day care approach for chronic vertigo and dizziness were analyzed. Subjects and Methods: 650 patients with chronic dizziness/vertigo subjected to a multimodal vestibular rehabilitation day care program were analyzed. Information concerning age, gender, medical diagnosis, medical consultations, technical diagnostics performed and therapy achieved before attending the clinic were collected. Furthermore, data were gathered using the Vertigo Severity Scale (VSS), Hospital Anxiety and Depression Scale (HADS), Mobility Inventory (MI), as well as the intensity of and the distress due to vertigo/dizziness using visual analog scales. As a follow-up, the VSS, HADS, MI, and the visual analog scales were collected again 6 months after attending the therapy program. Three age groups were compared to each other (<41, 41-65, and >65 years of age). Results: One-third of the patients were older than 65 years. This group had typical diagnoses with mainly organic deficits. In contrast to the dominance of mainly multifactorial, organic deficits the older patients reported less medical consultations, fewer technical diagnostics and even fewer treatments than the younger patients. The elderly scored significantly lower in total VSS, in VSS-V (vestibular-balance subscale), in VSS-A (autonomic-anxiety subscale) and in HADS-anxiety. Psychological diagnoses were clearly associated to the younger patients. 424 patients (65.2%) completed the follow-up questionnaire 6 months after attending the therapy week. The older patients revealed improvements of VSS V and the Avoidance Alone scale of MI as well as decreased distress due to vertigo/dizziness. Conclusion: In the older patients, who took part in our vestibular rehabilitation program, mainly somatic deficits prevail while anxiety plays a minor role compared to young and middle aged patients. Older patients profited from vestibular rehabilitation especially in mobility and vestibular balance. Therefore, vestibular rehabilitation programs for the elderly with a focus on physio- and occupational therapeutic interventions and less cognitive behavioral therapy may be reasonable. PMID- 30425638 TI - The Role of Language Severity and Education in Explaining Performance on Object and Action Naming in Primary Progressive Aphasia. AB - Despite the common assumption that atrophy in a certain brain area would compromise the function that it subserves, this is not always the case, especially in complex clinical syndromes such as primary progressive aphasia (PPA). Clinical and demographic information may contribute to PPA phenotypes and explain the manifested impairments better than atrophy. In the present study, we asked how much variance of the object and action naming impairments observed in PPA may be attributed to atrophy in the language network alone vs. additional clinical and demographic factors including language severity and education. Thirty-nine participants with PPA underwent magnetic resonance imaging (MRI) for volumetric analysis and a complete neuropsychological examination, including standardized tests of object and action naming. We used stepwise regression models to compare atrophy (volumetric model) to clinical/demographic variables (clinical-demographic model) for naming objects and actions. The clinical demographic model was the best-fit model that explained the largest amount of variance in both object and action naming. Brain volume measurements alone explained little variance in both object and action naming. Clinical factors, particularly language severity, and demographic factors, particularly education, need to be considered in conjunction with brain volumes in PPA. The present study emphasizes the complexity of PPA as a syndrome and provides an example of how volumetric, clinical and demographic factors may interact in determining naming performance/deterioration. PMID- 30425636 TI - Exploring Genetic Associations of Alzheimer's Disease Loci With Mild Cognitive Impairment Neurocognitive Endophenotypes. AB - The role of genetic risk markers for Alzheimer's disease (AD) in mediating the neurocognitive endophenotypes (NEs) of subjects with mild cognitive impairment (MCI) has rarely been studied. The aim of the present study was to investigate the relationship between well-known AD-associated single-nucleotide polymorphisms (SNPs) and individual NEs routinely evaluated during diagnosis of MCI, AD, and other dementias. The Fundacio ACE (ACE) dataset, comprising information from 1245 patients with MCI, was analyzed, including the total sample, amnestic MCI (aMCI) (n = 811), and non-amnestic MCI (naMCI) (n = 434). As probable-MCI (Pr-MCI) patients with memory impairment have a higher risk of AD, which could influence the statistical power to detect genetic associations, the MCI phenotype was also stratified into four related conditions: Pr-aMCI (n = 262), Pr-naMCI (n = 76), possible (Pss)-aMCI (n = 549), and Pss-naMCI (n = 358). Validation analyses were performed using data from the German study on Aging, Cognition, and Dementia in primary care patients (AgeCoDe), and the German Dementia Competence Network (DCN). SNP associations with NEs were calculated in PLINK using multivariate linear regression analysis adjusted for age, gender, and education. In the total MCI sample, APOE-epsilon4 was significantly associated with the memory function NEs "delayed recall (DR)" (beta = -0.76, p = 4.1 * 10-10), "learning" (beta = 1.35, p = 2.91 * 10-6), and "recognition memory" (beta = -0.58, p = 9.67 * 10-5); and with "DR" in the aMCI group (beta = -0.36, p = 2.96 * 10-5). These results were confirmed by validation in the AgeCoDe (n = 503) and DCN (n = 583) datasets. APOE-epsilon4 was also significantly associated with the NE "learning" in individuals classified as having Pss-aMCI (beta = -1.37, p = 5.82 * 10-5). Moreover, there was a near study-wide significant association between the HS3ST1 locus (rs6448799) and the "backward digits" working memory NE (beta = 0.52, p = 7.57 * 10-5) among individuals with Pr-aMCI, while the AP2A2 locus (rs10751667) was significantly associated with the language NE "repetition" (beta = -0.19, p = 5.34 * 10-6). Overall, our findings support specific associations of established AD-associated SNPs with MCI NEs. PMID- 30425639 TI - Association Between Folic Acid Supplementation and Retinal Atherosclerosis in Chinese Adults With Hypertension Complicated by Diabetes Mellitus. AB - Background: This cross-section investigation included 2,199 participants with hypertension complicated by diabetes mellitus, a cohort of the China Stroke Primary Prevention Trial in which 20,702 patients with essential hypertension were given enalapril with folic acid or enalapril-only double-blind treatment for 5 years. This study aimed to explore the correlation between folic acid supplementation and retinal atherosclerosis (RA) in adults with hypertension complicated by diabetes mellitus. Methods: The diagnosis of RA was determined by non-mydriatic fundus photography and classified by the Keith-Wagener-Barker system. The statistical correlation of folic acid supplementation with RA prevalence and severity was assessed. Results: Of our cohort, 1,698 (77.6%) participants were diagnosed with RA, and the prevalence in males and females was 78.0 and 75.6%, respectively. Participants in the enalapril group had higher total homocysteine (tHcy) levels than those in enalapril-folic acid group. Compared with the enalapril group in the tHcy > 15 MUmol/L group of females, the odds ratio for the enalapril-folic acid group was 0.28 (95% confidence interval, 0.11-0.67, P = 0.0061). Conclusions: The prevalence of RA was high (77.6%) in our cohort of adults with hypertension complicated by diabetes mellitus. Folic acid supplementation was significantly associated with reduced risk of RA in females with hyperhomocysteinemia. No significant association were seen in males. PMID- 30425640 TI - Non-linear Entropy Analysis in EEG to Predict Treatment Response to Repetitive Transcranial Magnetic Stimulation in Depression. AB - Background: Biomarkers that predict clinical outcomes in depression are essential for increasing the precision of treatments and clinical outcomes. The electroencephalogram (EEG) is a non-invasive neurophysiological test that has promise as a biomarker sensitive to treatment effects. The aim of our study was to investigate a novel non-linear index of resting state EEG activity as a predictor of clinical outcome, and compare its predictive capacity to traditional frequency-based indices. Methods: EEG was recorded from 62 patients with treatment resistant depression (TRD) and 25 healthy comparison (HC) subjects. TRD patients were treated with excitatory repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) for 4 to 6 weeks. EEG signals were first decomposed using the empirical mode decomposition (EMD) method into band-limited intrinsic mode functions (IMFs). Subsequently, Permutation Entropy (PE) was computed from the obtained second IMF to yield an index named PEIMF2. Receiver Operator Characteristic (ROC) curve analysis and ANOVA test were used to evaluate the efficiency of this index (PEIMF2) and were compared to frequency-band based methods. Results: Responders (RP) to rTMS exhibited an increase in the PEIMF2 index compared to non-responders (NR) at F3, FCz and FC3 sites (p < 0.01). The area under the curve (AUC) for ROC analysis was 0.8 for PEIMF2 index for the FC3 electrode. The PEIMF2 index was superior to ordinary frequency band measures. Conclusion: Our data show that the PEIMF2 index, yields superior outcome prediction performance compared to traditional frequency band indices. Our findings warrant further investigation of EEG-based biomarkers in depression; specifically entropy indices applied in band-limited EEG components. Registration in ClinicalTrials.Gov; identifiers NCT02800226 and NCT01887782. PMID- 30425641 TI - Appropriateness of DOAC Prescribing Before and During Hospital Admission and Analysis of Determinants for Inappropriate Prescribing. AB - Background and Objectives: Appropriate dosing of direct oral anticoagulants (DOACs) is required to avoid under- and overdosing that may precipitate strokes or thromboembolic events and bleedings, respectively. Our objective was to analyze the appropriateness of DOAC dosing according to the summaries of product characteristics (SmPC). Furthermore, determinants for inappropriate prescribing were investigated. Methodology: Retrospective cohort study of hospitalized patients aged >=60 years with at least one DOAC intake during hospital stay. Descriptive analyses were used to summarize the characteristics of the study population. Chi-square test was used to evaluate differences between DOACs. Binary logistic regression analysis was performed to assess determinants for inappropriate prescribing. Results: For the 772 included patients, inappropriate dosing occurred in 25.0% of hospitalizations with 23.4, 21.9, and 29.7% for dabigatran, rivaroxaban, and apixaban, respectively (p = 0.084). Underdosing was most prevalent for apixaban (24.5%) compared to dabigatran (14.0%) and rivaroxaban (12.8%), p < 0.001. In 67.1% (apixaban), 26.7% (dabigatran), and 51.2% (rivaroxaban) of underdosed DOAC cases according to the SmPC, the dose would be considered appropriate according to the European Heart Rhytm Association (EHRA) guidelines. Overdosing was observed in 4.5% (apixaban), 4.7% (dabigatran), and 7.7% (rivaroxaban) of patients. For all DOACs, our analysis showed an age >=80 years (p = 0.036), use of apixaban (p = 0.026), DOAC use before hospitalization (p = 0.001), intermediate renal function (p = 0.014), and use of narcotic analgesics (p = 0.019) to be associated with a higher rate of inappropriate prescribing. Undergoing surgery was associated with a lower odds of inappropriate prescribing (p = 0.012). For rivaroxaban, use of medication for hypothyroidism (p = 0.027) and the reduced dose (p < 0.001) were determinants for inappropriate prescribing. Treatment of venous thromboembolism was associated with less errors (p = 0.002). For apixaban, severe renal insufficiency (p < 0.001) and initiation in hospital (p = 0.016) were associated with less and the reduced dose (p < 0.001) with more inappropriate prescribing. No determinants were found in the dabigatran subgroup. Conclusions: Inappropriate DOAC prescribing is frequent with underdosing being the most common drug related problem when using the SmPC as reference. More appropriate prescriptions were found when taking the EHRA guidelines into account. Analysis of determinants of inappropriate prescribing yielded insights in the risk factors associated with inappropriate DOAC prescriptions. PMID- 30425642 TI - Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations. AB - Background: Patients harboring NR5A1 mutations have a wide spectrum of phenotypes. Objective: To investigate the phenotype of patients with NR5A1 gene mutations from a 30 Chinese patient cohort. Methods: We reported the clinical features of children with NR5A1 gene mutations and compared them between two groups of patients with social genders of male (boys group) and female (girls group). Results: Thirty patients with NR5A1 mutations ranging from 2 months to 17 years of age were studied. There were 11 boys and 19 girls who were identified when they visited the hospital. The patients were verified as having testes without a uterus and ovaries by B-mode ultrasound. There was no difference between boys and girls in terms of the Prader stage (p = 0.086), but the position of the testes was higher in girls than in boys (p = 0.013). The patients' average height is -0.43 SDS according to the normal boys' height with SDS (while their average target height was 0.07 SDS). However, there was no such difference between boys and girls (p > 0.05). Although the basal LH and post-hCG testosterone (T) levels were not different (p > 0.05), but the basal FSH level, LH/FSH ratio, and INHB level were decreased in girls (p = 0.002; p = 0.001; p = 0.006). All of the mothers of the patients reported to have normal pregnancies. We found 24 patients (80%) with de novo mutations in the NR5A1 gene; 5 patients had inherited mutations from their mothers, and one inherited from the father. Only the mothers of patients 16 and 18 showed premature ovarian failure at the time of reporting. Among 26 disease associated mutations, 14 novel mutations that have been reported the first time and p.R87C is the most common Among the other 12 had had been reported,the p.R313C is the most common. Conclusion: Patients with 46, XY NR5A1 mutations presented a wide spectrum of external genitalia characteristics and severe Sertoli cell impairment. The p.R87C and p.R313C mutations appeared to be common (10%) in this group, and 14 new mutations were identified, improving our understanding the genotype phenotype correlations. PMID- 30425643 TI - VS-4718 Antagonizes Multidrug Resistance in ABCB1- and ABCG2-Overexpressing Cancer Cells by Inhibiting the Efflux Function of ABC Transporters. AB - Overexpression of ATP-binding cassette (ABC) transporters is one of the most important mechanisms responsible for multi-drug resistance (MDR). VS-4718, a tyrosine kinase inhibitor targeting focal adhesion kinase (FAK) with a potential anticancer effect, is currently evaluated in clinical trials. In this study, we investigated whether VS-4718 could reverse MDR mediated by ABC transporters, including ABCB1, ABCG2, and ABCC1. The results showed that VS-4718 significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR mediated by ABCC1. Treatment of VS-4718 did not alter the protein level and subcellular localization of ABCB1 or ABCG2. Mechanism studies indicated that the reversal effects of VS-4718 were related to attenuation of the efflux activity of ABCB1 and ABCG2 transporters. ATPase analysis indicated that VS-4718 stimulated the ATPase activity of ABCB1 and ABCG2. Docking study showed that VS-4718 interacted with the substrate binding sites of both ABCB1 and ABCG2, suggesting that VS-4718 may affect the activity of ABCB1 and ABCG2 competitively. This study provided a novel insight for MDR cancer treatment. It indicated that combination of VS-4718 with antineoplastic drugs could attenuate MDR mediated by ABCB1 or ABCG2 in ABCB1- or ABCG2-overexpressing cancer cells. PMID- 30425644 TI - Cold Acclimation of Trogoderma granarium Everts Is Tightly Linked to Regulation of Enzyme Activity, Energy Content, and Ion Concentration. AB - In this study, cold hardiness and some physiological characteristics of the Khapra beetle, Trogoderma granarium Everts (Coleoptera: Dermestidae) larvae, were investigated under different thermal regimes, i.e., control, cold-acclimated (CA), fluctuating-acclimated (FA), and rapid cold-hardened (RCH). In all the regimes, the larval survival rate decreased with a decrease in temperature. CA larvae showed the highest cold hardiness following 24 h exposure at -15 and -20 degrees C. Control larvae had the highest glycogen content (34.4 +/- 2.3 MUg/dry weight). In contrast, CA larvae had the lowest glycogen content (23.0 +/- 1.6 MUg/dry weight). Change in trehalose content was reversely proportional to changes in glycogen content. The highest myo-inositol and glucose contents were detected in CA larvae (10.7 +/- 0.4 MUg/dry weight) and control (0.49 +/- 0.03 MUg/dry weight), respectively. In control and treated larvae, [Na+] decreased, though [K+] increased, with increasing exposure time. The shape of the thermal reaction curve of AMP-depended protein kinase and protein phosphatase 2C followed the same norm, which was different from protein phosphatase 1 and protein phosphatase 2A. Protein phosphatase 2A and 2C showed a complete difference in thermal reaction norms. Indeed, thermal fluctuation caused the highest changes in the activity of the enzymes, whereas the RCH showed the lowest changes in the activity of the enzymes. Our results showed a significant enhancement of larval cold tolerance under CA regime, which is related to the high levels of low molecular weight carbohydrates under this regime. Our results showed that among the different thermal regimes tested, the CA larvae had the lowest supercooling point (about -22 degrees C) and the highest cold hardiness following 24 h exposure at -15 and -20 degrees C. PMID- 30425645 TI - Discovery of Causal Paths in Cardiorespiratory Parameters: A Time-Independent Approach in Elite Athletes. AB - Training of elite athletes requires regular physiological and medical monitoring to plan the schedule, intensity and volume of training, and subsequent recovery. In sports medicine, ECG-based analyses are well-established. However, they rarely consider the correspondence of respiratory and cardiac activity. Given such mutual influence, we hypothesize that athlete monitoring might be developed with causal inference and that detailed, time-related techniques should be preceded by a more general, time-independent approach that considers the whole group of participants and parameters describing whole signals. The aim of this study was to discover general causal paths among cardiac and respiratory variables in elite athletes in two body positions (supine and standing), at rest. ECG and impedance pneumography signals were obtained from 100 elite athletes. The mean heart rate, the root-mean-square difference of successive RR intervals (RMSSD), its natural logarithm (lnRMSSD), the mean respiratory rate (RR), the breathing activity coefficients, and the resulting breathing regularity (BR) were estimated. Several causal discovery frameworks were applied, comprising Generalized Correlations (GC), Causal Additive Modeling (CAM), Fast Greedy Equivalence Search (FGES), Greedy Fast Causal Inference (GFCI), and two score-based Bayesian network learning algorithms: Hill-Climbing (HC) and Tabu Search. The discovery of cardiorespiratory paths appears ambiguous. The main, still mild, rules best supported by data are: for supine - tidal volume causes heart activity variation, which causes average heart activity, which causes respiratory timing; and for standing - normalized respiratory activity variation causes average heart activity. The presented approach allows data-driven and time-independent analysis of elite athletes as a particular population, without considering prior knowledge. However, the results seem to be consistent with the medical background. Causality inference is an interesting mathematical approach to the analysis of biological responses, which are complex. One can use it to profile athletes and plan appropriate training. In the next step, we plan to expand the study using time-related causality analyses. PMID- 30425648 TI - Semi-implicit Non-conforming Finite-Element Schemes for Cardiac Electrophysiology: A Framework for Mesh-Coarsening Heart Simulations. AB - The field of computational cardiology has steadily progressed toward reliable and accurate simulations of the heart, showing great potential in clinical applications such as the optimization of cardiac interventions and the study of pro-arrhythmic effects of drugs in humans, among others. However, the computational effort demanded by in-silico studies of the heart remains challenging, highlighting the need of novel numerical methods that can improve the efficiency of simulations while targeting an acceptable accuracy. In this work, we propose a semi-implicit non-conforming finite-element scheme (SINCFES) suitable for cardiac electrophysiology simulations. The accuracy and efficiency of the proposed scheme are assessed by means of numerical simulations of the electrical excitation and propagation in regular and biventricular geometries. We show that the SINCFES allows for coarse-mesh simulations that reduce the computation time when compared to fine-mesh models while delivering wavefront shapes and conduction velocities that are more accurate than those predicted by traditional finite-element formulations based on the same coarse mesh, thus improving the accuracy-efficiency trade-off of cardiac simulations. PMID- 30425647 TI - New Insights Into the Role of Placental Aquaporins and the Pathogenesis of Preeclampsia. AB - Accumulated evidence suggests that an abnormal placentation and an altered expression of a variety of trophoblast transporters are associated to preeclampsia. In this regard, an abnormal expression of AQP3 and AQP9 was reported in these placentas. Recent data suggests that placental AQPs are not only water channel proteins and that may participate in relevant processes required for a normal placental development, such as cell migration and apoptosis. Recently we reported that a normal expression of AQP3 is required for the migration of extravillous trophoblast (EVT) cells. Thus, alterations in this protein might lead to an insufficient transformation of the maternal spiral arteries resulting in fluctuations of oxygen tension, a potent stimulus for oxidative damage and trophoblast apoptosis. In this context, the increase of oxygen and nitrogen reactive species could nitrate AQP9, producing the accumulation of a non-functional protein affecting the survival of the villous trophoblast (VT). This may trigger the exacerbated release of apoptotic VT fragments into maternal circulation producing the systemic endothelial dysfunction underlying the maternal syndrome. Therefore, our hypothesis is that the alteration in the expression of placental AQPs observed at the end of gestation may take place during the trophoblast stem cell differentiation, disturbing both EVT and VT cells development, or during the VT differentiation and turnover. In both situations, VT is affected and at last the maternal vascular system is activated leading to the clinical manifestations of preeclampsia. PMID- 30425646 TI - Preparation for Endurance Competitions at Altitude: Physiological, Psychological, Dietary and Coaching Aspects. A Narrative Review. AB - It was the Summer Olympic Games 1968 held in Mexico City (2,300 m) that required scientists and coaches to cope with the expected decline of performance in endurance athletes and to establish optimal preparation programs for competing at altitude. From that period until now many different recommendations for altitude acclimatization in advance of an altitude competition were proposed, ranging from several hours to several weeks. Those recommendations are mostly based on the separate consideration of the physiology of acclimatization, psychological issues, performance changes, logistical or individual aspects, but there is no review considering all these aspects in their entirety. Therefore, the present work primarily focusses on the period of altitude sojourn prior to the competition at altitude based on physiological and psychological aspects complemented by nutritional and sports practical considerations. PMID- 30425650 TI - Non-invasive Assessment of Systolic and Diastolic Cardiac Function During Rest and Stress Conditions Using an Integrated Image-Modeling Approach. AB - Background: The possibility of non-invasively assessing load-independent parameters characterizing cardiac function is of high clinical value. Typically, these parameters are assessed during resting conditions. However, for diagnostic purposes, the parameter behavior across a physiologically relevant range of heart rate and loads is more relevant than the isolated measurements performed at rest. This study sought to evaluate changes in non-invasive estimations of load independent parameters of left-ventricular contraction and relaxation patterns at rest and during dobutamine stress. Methods: We applied a previously developed approach that combines non-invasive measurements with a physiologically-based, reduced-order model of the cardiovascular system to provide subject-specific estimates of parameters characterizing left ventricular function. In this model, the contractile state of the heart at each time point along the cardiac cycle is modeled using a time-varying elastance curve. Non-invasive data, including four dimensional magnetic resonance imaging (4D Flow MRI) measurements, were acquired in nine subjects without a known heart disease at rest and during dobutamine stress. For each of the study subjects, we constructed two personalized models corresponding to the resting and the stress state. Results: Applying the modeling framework, we identified significant increases in the left ventricular contraction rate constant [from 1.5 +/- 0.3 to 2 +/- 0.5 (p = 0.038)] and relaxation constant [from 37.2 +/- 6.9 to 46.1 +/- 12 (p = 0.028)]. In addition, we found a significant decrease in the elastance diastolic time constant from 0.4 +/- 0.04 s to 0.3 +/- 0.03 s (p = 0.008). Conclusions: The integrated image modeling approach allows the assessment of cardiovascular function given as model based parameters. The agreement between the estimated parameter values and previously reported effects of dobutamine demonstrates the potential of the approach to assess advanced metrics of pathophysiology that are otherwise difficult to obtain non-invasively in clinical practice. PMID- 30425649 TI - Diabetic Cardiomyopathy: Current and Future Therapies. Beyond Glycemic Control. AB - Diabetes mellitus and the associated complications represent a global burden on human health and economics. Cardiovascular diseases are the leading cause of death in diabetic patients, who have a 2-5 times higher risk of developing heart failure than age-matched non-diabetic patients, independent of other comorbidities. Diabetic cardiomyopathy is defined as the presence of abnormal cardiac structure and performance in the absence of other cardiac risk factors, such coronary artery disease, hypertension, and significant valvular disease. Hyperglycemia, hyperinsulinemia, and insulin resistance mediate the pathological remodeling of the heart, characterized by left ventricle concentric hypertrophy and perivascular and interstitial fibrosis leading to diastolic dysfunction. A change in the metabolic status, impaired calcium homeostasis and energy production, increased inflammation and oxidative stress, as well as an accumulation of advanced glycation end products are among the mechanisms implicated in the pathogenesis of diabetic cardiomyopathy. Despite a growing interest in the pathophysiology of diabetic cardiomyopathy, there are no specific guidelines for diagnosing patients or structuring a treatment strategy in clinical practice. Anti-hyperglycemic drugs are crucial in the management of diabetes by effectively reducing microvascular complications, preventing renal failure, retinopathy, and nerve damage. Interestingly, several drugs currently in use can improve cardiac health beyond their ability to control glycemia. GLP-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors have been shown to have a beneficial effect on the cardiovascular system through a direct effect on myocardium, beyond their ability to lower blood glucose levels. In recent years, great improvements have been made toward the possibility of modulating the expression of specific cardiac genes or non-coding RNAs in vivo for therapeutic purpose, opening up the possibility to regulate the expression of key players in the development/progression of diabetic cardiomyopathy. This review summarizes the pathogenesis of diabetic cardiomyopathy, with particular focus on structural and molecular abnormalities occurring during its progression, as well as both current and potential future therapies. PMID- 30425652 TI - Peripheral Nerve Injury Induces Dynamic Changes of Tight Junction Components. AB - Tight junctions seal off physical barriers, regulate fluid and solute flow, and protect the endoneurial microenvironment of the peripheral nervous system. Physical barriers in the peripheral nervous system were disrupted after nerve injury. However, the dynamic changes of tight junction components after peripheral nerve injury have not been fully determined yet. In the current study, by using previously obtained deep sequencing outcomes and bioinformatic tools, we found that tight junction signaling pathway was activated after peripheral nerve injury. The investigation of the temporal expression patterns of components in tight junction signaling pathway suggested that many claudin family members were down-regulated after nerve injury. Moreover, we examined the effects of matrix metalloproteinases 7 and 9 (MMP7 and MMP9) on tight junction genes both in vitro and in vivo and found that MMP7 and MMP9 modulated the expressions of genes coding for claudin 1, claudin 10, and claudin 22. Our study revealed the dynamic changes of tight junction components after peripheral nerve injury and thus might contribute to the understanding of the molecular mechanisms underlying peripheral nerve injury and regeneration. PMID- 30425653 TI - Repurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review. AB - Background: Dementia has a significant impact on quality of life of older individuals. Impaired proteostasis has been implicated as a potential cause of dementia, that can be therapeutically targeted to improve patient outcomes. This review aimed to collate all current evidence of the potential for targeting proteostasis with repurposed drugs as an intervention for age-related dementia and cognitive decline. Methods: PubMed, Web of Science and Embase databases were searched from inception until 4th July 2017 for studies published in English. Interventional studies of repurposed proteostasis-modifying drugs in Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body disease, vascular dementia, and cognitive aging, in either animal models or humans with change in cognition as the outcome were included. The SYRCLE and Cochrane tools were used to assess risk of bias for included studies. Results: Overall 47 trials, 38 animal and 9 human, were isolated for inclusion in this review. Drugs tested in animals and humans included lithium, rapamycin, rifampicin, and tyrosine kinase inhibitors. Drugs tested only in animals included Macrophage and Granulocyte-Macrophage Colony Stimulating Factors, methylene blue, dantrolene, geranylgeranylacetone, minocycline and phenylbutyric acid. Lithium (n = 10 animal, n = 6 human) and rapamycin (n = 12 animal, n = 1 human) were the most studied proteostasis modifying drugs influencing cognition. Nine of ten animal studies of lithium showed a statistically significant benefit in Alzheimer's models. Rapamycin demonstrated a significant benefit in models of vascular dementia, aging, and Alzheimer's, but may not be effective in treating established Alzheimer's pathology. Lithium and nilotinib had positive outcomes in human studies including Alzheimer's and Parkinson's patients respectively, while a human study of rifampicin in Alzheimer's failed to demonstrate benefit. Microdose lithium showed a strongly significant benefit in both animals and humans. While the risk of bias was relatively low in human studies, the risk of bias in animal studies was largely unclear. Conclusion: Overall, the collective findings support the hypothesis that targeting proteostasis for treatment of dementia may be beneficial, and therefore future studies in humans with repurposed proteostasis modifying drugs are warranted. Larger human clinical trials focusing on safety, efficacy, tolerability, and reproducibility are required to translate these therapeutics into clinical practice. PMID- 30425654 TI - Changes in Physiological Parameters, Lipid Metabolism, and Expression of MicroRNAs in Genetically Improved Farmed Tilapia (Oreochromis niloticus) With Fatty Liver Induced by a High-Fat Diet. AB - Tilapia is susceptible to hepatic steatosis when grown in intensive farming systems. The aim of this study was to explore the mechanism of fatty liver induced by a high-fat diet (HFD) in genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Juvenile GIFT were fed with HFD or a normal-fat diet (NFD) for 60 days. Substantial fat deposition in the liver of HFD-fed GIFT on days 20, 40, and 60 was observed using hematoxylin - eosin staining and oil red O staining. The increased fat deposition was consistent with increased triglyceride (TG) and total cholesterol (TC) levels in the liver of HFD-fed GIFT. There were significant differences (P < 0.05) in serum biochemical indexes (TG, TC, low density lipoprotein-cholesterol, and insulin contents, and alanine aminotransferase activity) between GIFT fed a HFD and GIFT fed a NFD on days 20, 40, and 60. Furthermore, 60 days of a HFD significantly changed (P < 0.05) the hepatic fatty acid composition, and led to increased polyunsaturated fatty acid levels and decreased saturated fatty acid and monounsaturated fatty acid levels. Hepatic antioxidant enzyme activities increased by day 20 and then declined, which led to an increase in malondialdehyde contents in the liver of HFD-fed GIFT. Molecular analyses revealed that the microRNAs miR-122, miR-29a, and miR 145-5p were upregulated, whereas miR-34a was downregulated in HFD-fed GIFT. SCD, ELOVL6, and SRD5A2 encode three important enzymes in lipid metabolism, and were identified as potential targets of miRNAs. The transcript levels of hepatic SCD and ELOVL6 were decreased and that of hepatic SRD5A2 was increased in GIFT fed a HFD. Overall, the results of this study revealed a potential link between miRNAs and fatty liver induced by HFD, and suggest that a HFD could lead to excess fat deposition in the GIFT liver, which may disrupt hepatic lipid metabolism and reduce the antioxidant defense capacity. PMID- 30425655 TI - Nuclear Envelope Transmembrane Proteins in Myotonic Dystrophy Type 1. AB - Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with predominant myotonia and muscular dystrophy which is caused by CTG-repeat expansions in the DMPK gene. These repeat expansions are transcribed and the resulting mRNA accumulates RNA-binding proteins involved in splicing, resulting in a general splicing defect. We observed nuclear envelope (NE) alterations in DM1 primary myoblasts. These included invaginations of the NE as well as an altered composition of the nuclear lamina. Specifically, we investigated NE transmembrane proteins (NETs) in DM1 primary myoblasts, staining to determine if their distribution was altered compared to controls and if this could contribute to these structural defects. We also tested the expression of these NETs in muscle and how localization changes in the DM1 primary myoblasts undergoing differentiation in vitro to myotubes. We found no changes in the localization of the tested NETs, but most tended to exhibit reduced expression with increasing DMPK-repeat length. Nonetheless, the DM1 patient expression range was within the expression range of the controls. Additionally, we found a down-regulation of the possible nesprin 1 giant isoform in DM1 primary myoblasts which could contribute to the increased NE invaginations. Thus, nesprin 1 may be an interesting target for further investigation in DM1 disease pathology. PMID- 30425651 TI - Proarrhythmic Remodeling of Calcium Homeostasis in Cardiac Disease; Implications for Diabetes and Obesity. AB - A rapid growth in the incidence of diabetes and obesity has transpired to a major heath issue and economic burden in the postindustrial world, with more than 29 million patients affected in the United States alone. Cardiovascular defects have been established as the leading cause of mortality and morbidity of diabetic patients. Over the last decade, significant progress has been made in delineating mechanisms responsible for the diminished cardiac contractile function and enhanced propensity for malignant cardiac arrhythmias characteristic of diabetic disease. Rhythmic cardiac contractility relies upon the precise interplay between several cellular Ca2+ transport protein complexes including plasmalemmal L-type Ca2+ channels (LTCC), Na+-Ca2+ exchanger (NCX1), Sarco/endoplasmic Reticulum (SR) Ca2+-ATPase (SERCa2a) and ryanodine receptors (RyR2s), the SR Ca2+ release channels. Here we provide an overview of changes in Ca2+ homeostasis in diabetic ventricular myocytes and discuss the therapeutic potential of targeting Ca2+ handling proteins in the prevention of diabetes-associated cardiomyopathy and arrhythmogenesis. PMID- 30425657 TI - Deficiency of Brummer Impaires Lipid Mobilization and JH-Mediated Vitellogenesis in the Brown Planthopper, Nilaparvata lugens. AB - Provisioning of sufficient lipids and vitellogenin to the oocytes is an indispensable process for fecundity of oviparous insects. Acute mobilization of lipid reserves in insects is controlled by the Brummer (Bmm), an orthologous of human adipose triglyceride lipase (ATGL). To investigate the functional roles of brummer-mediated lipolysis in the fecundity of the brown planthopper, Nilaparvata lugens, RNA interference (RNAi) analyses were performed with double-stranded RNA (dsRNA) against NlBmm in adult females. Knockdown of NlBmm expression resulted in obesity and blocked lipid mobilization in the fat body. In addition, NlBmm silencing led to retarded ovarian development with immature eggs and less ovarioles, decreased number of laid eggs, prolonged preoviposition period and egg duration. Furthermore, severe reductions of vitellogenin and its receptor abundance were observed upon NlBmm knockdown. The transcript levels of NlJHE (juvenile hormone esterase) which degrades JH were up-regulated, whereas the expression levels of JH receptors NlMet (Methoprene-tolerant) and NlTai (Taiman) and their downstream transcription factors NlKr-h1 (Kruppel-homolog 1) and NlBr (Broad-Complex) were down-regulated after suppression of NlBmm. JH-deficient females exhibited impaired vitellogenin expression, whereas JH exposure stimulated vitellogenin biosynthesis. Moreover, JH topical application partially rescued the decrease in vitellogenin expression in the NlBmm-deficient females. These results demonstrate that brummer-mediated lipolytic system is essential for lipid mobilization and energy homeostasis during reproduction in N. lugens. In addition to the classical view of brummer as a direct lipase with lipolysis activity, we propose here that brummer-mediated lipolysis works through JH signaling pathway to activate vitellogenesis and oocyte maturation that in turn regulates female fecundity. PMID- 30425658 TI - Acute Sleep Restriction Has Differential Effects on Components of Attention. AB - Inadequate nightly sleep duration can impair daytime functioning, including interfering with attentional and other cognitive processes. Current models posit that attention is a complex function regulated by several separate, but interacting, neural systems responsible for vigilance, orienting, and executive control. However, it is not clear to what extent each of these underlying component processes is affected by sleep loss. The purpose of this study was to evaluate the effects of acute sleep restriction on these attentional components using the Dalhousie Computerized Attention Battery (DalCAB). DalCAB tasks were administered to healthy women (aged 19-25 years) on two consecutive mornings: once after a night with 9 h time in bed (TIB), and once again after either another night with 9 h TIB (control condition, n = 19) or after a night with 3 h TIB (sleep restriction condition, n = 20). Self-ratings of sleepiness and mood were also obtained following each sleep condition. Participants showed increases in self-reported sleepiness and fatigue after the second night only in the sleep restriction group. Sleep restriction primarily affected processing speed on tasks measuring vigilance; however, performance deficits were also observed on some measures of executive function (e.g., go/no-go task, flanker task, working memory). Tasks assessing orienting of attention were largely unaffected. These results indicate that acute sleep restriction has differential effects on distinct components of attention, which should be considered in modeling the impacts of sleep loss on the underlying attentional networks. PMID- 30425659 TI - Longitudinal Associations of Modifiable Lifestyle Factors With Positive Depression-Screen Over 2.5-Years in an International Cohort of People Living With Multiple Sclerosis. AB - Background: Depression is common and has a significant impact on quality of life for many people with multiple sclerosis (MS). A preventive management approach via modification of lifestyle risk factors holds potential benefits. We examined the relationship between modifiable lifestyle factors and depression risk and the change in depression over 2.5 years. Methods: Sample recruited using online platforms. 2,224 (88.9%) at baseline and 1,309 (93.4%) at 2.5 years follow up completed the necessary survey data. Depression risk was measured by the Patient Health Questionnaire-2 (PHQ-2) at baseline and Patient Health Questionniare-9 (PHQ-9) at 2.5-years follow-up. Multivariable regression models assessed the relationships between lifestyle factors and depression risk, adjusted for sex, age, fatigue, disability, antidepressant medication use, and baseline depression score, as appropriate. Results: The prevalence of depression risk at 2.5-years follow-up in this cohort was 14.5% using the PHQ-2 and 21.7% using the PHQ-9. Moderate alcohol intake, being a non-smoker, diet quality, no meat or dairy intake, vitamin D supplementation, omega 3 supplement use, regular exercise, and meditation at baseline were associated with lower frequencies of positive depression-screen 2.5 years later. Moderate alcohol intake was associated with greater likelihood of becoming depression-free and a lower likelihood of becoming depressed at 2.5-years follow-up. Meditating at least once a week was associated with a decreased frequency of losing depression risk, against our expectation. After adjusting for potential confounders, smoking, diet, physical activity, and vitamin D and omega-3 supplementation were not associated with a change in risk for depression. Conclusion: In a large prospective cohort study of people with MS and depression, in line with the emerging treatment paradigm of early intervention, these results suggest a role for some lifestyle factors in depression risk. Further studies should endeavor to explore the impact of positive lifestyle change and improving depression in people living with MS. PMID- 30425660 TI - Reliving, Replaying Lived Experiences Through Auditory Verbal Hallucinations: Implications on Theories and Management. AB - Objective: This study aims to understand the impact of negative life experience (NLE) in auditory hallucinations (AHs) and explain the heterogeneity in phenomenology of auditory verbal hallucinations (AVHs). Method: In depth interviews were conducted with 21 individuals (7 males and 14 females) experiencing AHs and accessing mental health treatment services at a not-for profit organization. Maximum variation purposive sampling technique was used to select the sample to ensure variegation is accounted for and was collected until saturation of themes data was obtained. Results: Various different forms and functions of hallucinations are obtained with an evident pattern that links voices back to the NLE of the individual. Implications for therapeutic methods focusing on distress arising from said NLE is emphasized. Conclusions: The results obtained from this study implicate NLEs as a contributing factor in the development and maintenance of hallucinations. Sociocultural factors act as a catalyst with psychological factors creating distress and contributing to the voice-hearing experience. Treatment strategies must thus focus on content of voices and past experiences of the individual to promote recovery. A model toward conceptualization of the diversity in phenomenology is put forth. PMID- 30425656 TI - The Pathogenesis and Therapies of Striated Muscle Laminopathies. AB - Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far. PMID- 30425661 TI - Pre-treatment Resting-State Functional MR Imaging Predicts the Long-Term Clinical Outcome After Short-Term Paroxtine Treatment in Post-traumatic Stress Disorder. AB - Background: The chronic phase of post-traumatic stress disorder (PTSD) and the limited effectiveness of existing treatments creates the need for the development of potential biomarkers to predict response to antidepressant medication at an early stage. However, findings at present focus on acute therapeutic effect without following-up the long-term clinical outcome of PTSD. So far, studies predicting the long-term clinical outcome of short-term treatment based on both pre-treatment and post-treatment functional MRI in PTSD remains limited. Methods: Twenty-two PTSD patients were scanned using resting-state functional MRI (rs fMRI) before and after 12 weeks of treatment with paroxetine. Twenty patients were followed up using the same psychopathological assessments 2 years after they underwent the second MRI scan. Based on clinical outcome, the follow-up patients were divided into those with remitted PTSD or persistent PTSD. Amplitude of low frequency fluctuations (ALFF) and degree centrality (DC) derived from pre treatment and post-treatment rs-fMRI were used as classification features in a support vector machine (SVM) classifier. Results: Prediction of long-term clinical outcome by combined ALFF and DC features derived from pre-treatment rs fMRI yielded an accuracy rate of 72.5% (p < 0.005). The most informative voxels for outcome prediction were mainly located in the precuneus, superior temporal area, insula, dorsal medial prefrontal cortex, frontal orbital cortex, supplementary motor area, lingual gyrus, and cerebellum. Long-term outcome could not be successfully classified by post-treatment imaging features with accuracy rates <50%. Conclusions: Combined information from ALFF and DC from rs-fMRI data before treatment could predict the long-term clinical outcome of PTSD, which is critical for defining potential biomarkers to customize PTSD treatment and improve the prognosis. PMID- 30425663 TI - Suicide and Youth: Risk Factors. AB - Suicide occurs more often in older than in younger people, but is still one of the leading causes of death in late childhood and adolescence worldwide. This not only results in a direct loss of many young lives, but also has disruptive psychosocial and adverse socio-economic effects. From the perspective of public mental health, suicide among young people is a main issue to address. Therefore we need good insight in the risk factors contributing to suicidal behavior in youth. This mini review gives a short overview of the most important risk factors for late school-age children and adolescents, as established by scientific research in this domain. Key risk factors found were: mental disorders, previous suicide attempts, specific personality characteristics, genetic loading and family processes in combination with triggering psychosocial stressors, exposure to inspiring models and availability of means of committing suicide. Further unraveling and knowledge of the complex interplay of these factors is highly relevant with regard to the development of effective prevention strategy plans for youth suicide. PMID- 30425664 TI - Increased Left Inferior Temporal Gyrus Was Found in Both Low Function Autism and High Function Autism. AB - Previous neuroimaging studies of autism spectrum disorder (ASD) have focused on subjects with IQ > 70 or ASD without considering IQ levels. It remains unclear whether differences in brain anatomy in this population are associated with variations in clinical phenotype. In this study, 19 children with low functioning autism (LFA) and 19 children with high functioning autism (HFA) were compared with 27 healthy controls (HC). We found increased gray matter volume (GMV) in the left inferior temporal gyrus in subjects with both HFA and LFA and increased GMV of left middle temporal gyrus BA21 was found only in the LFA group. A significant negative correlation was found between the left inferior temporal gyrus (LITG) and the score of repetitive behavior in the HFA group. PMID- 30425665 TI - The Evidence of Different Learning Environment Learning Effects on Vocabulary Size and Reading Comprehension. AB - The nature of the effect of learning environments' language setting on second language receptive vocabulary acquisition in both adolescent receptive vocabulary acquisition and reading comprehension performance was explored in a continuous 10 month longitudinal study. The current study divided 170 adolescents into four groups. Their reading comprehension ability and receptive vocabulary size were each measured in two different periods. The results showed that single Chinese instructional learning and single English instructional learning contributed more to students' receptive vocabulary size than bilingual instructional language materials. The results imply that the immersion hypothesis has more positive impact on improving second language receptive vocabulary size acquisition and reading comprehension performance than the depth of processing hypothesis. PMID- 30425662 TI - Multidimensional Connectomics and Treatment-Resistant Schizophrenia: Linking Phenotypic Circuits to Targeted Therapeutics. AB - Schizophrenia is a very complex syndrome that involves widespread brain multi dysconnectivity. Neural circuits within specific brain regions and their links to corresponding regions are abnormal in the illness. Theoretical models of dysconnectivity and the investigation of connectomics and brain network organization have been examined in schizophrenia since the early nineteenth century. In more recent years, advancements have been achieved with the development of neuroimaging tools that have provided further clues to the structural and functional organization of the brain and global neural networks in the illness. Neural circuitry that extends across prefrontal, temporal and parietal areas of the cortex as well as limbic and other subcortical brain regions is disrupted in schizophrenia. As a result, many patients have a poor response to antipsychotic treatment and treatment failure is common. Treatment resistance that is specific to positive, negative, and cognitive domains of the illness may be related to distinct circuit phenotypes unique to treatment refractory disease. Currently, there are no customized neural circuit-specific and targeted therapies that address this neural dysconnectivity. Investigation of targeted therapeutics that addresses particular areas of substantial regional dysconnectivity is an intriguing approach to precision medicine in schizophrenia. This review examines current findings of system and circuit-level brain dysconnectivity in treatment-resistant schizophrenia based on neuroimaging studies. Within a connectome context, on-off circuit connectivity synonymous with excitatory and inhibitory neuronal pathways is discussed. Mechanistic cellular, neurochemical and molecular studies are included with specific emphasis given to cell pathology and synaptic communication in glutamatergic and GABAergic systems. In this review we attempt to deconstruct how augmenting treatments may be applied within a circuit context to improve circuit integration and treatment response. Clinical studies that have used a variety of glutamate receptor and GABA interneuron modulators, nitric oxide-based therapies and a variety of other strategies as augmenting treatments with antipsychotic drugs are included. This review supports the idea that the methodical mapping of system-level networks to both on (excitatory) and off (inhibitory) cellular circuits specific to treatment resistant disease may be a logical and productive approach in directing future research toward the advancement of targeted pharmacotherapeutics in schizophrenia. PMID- 30425667 TI - Commentary: On the Importance of the Speed-Ability Trade-Off When Dealing With Not Reached Items. PMID- 30425666 TI - The N400/FN400 and Lateralized Readiness Potential Neural Correlates of Valence and Origin of Words' Affective Connotations in Ambiguous Task Processing. AB - Recent behavioral studies revealed an interesting phenomenon concerning the influence of affect on the interpretation of ambiguous stimuli. In a paradigm, where the participants' task was to read a word, remember its meaning for a while, and then choose one of two pictorial-alphabet-like graphical signs best representing the word sense, we observed that the decisions involving trials with reflective-originated verbal stimuli were performed significantly longer than decisions concerning other stimuli (i.e., automatic-originated). The origin of an affective reaction is a dimension which allows speaking of an affect as automatic (you feel it in your guts) or reflective (you feel it comes from your mind). The automatic affective reaction represents the immediate and inescapable as opposed to the reflective, i.e., the delayed and controllable affective responses to stimuli. In the current experiment, we investigated the neural correlates of performance in an QR-signs-selection ambiguous task. We found the effects of valence and origin in the N400/FN400 potential by means of a stimuli-locked analysis of the initial part of the task, that is, the remembering of a certain word stimulus in a working memory. The N400/FN400 effects were separated in space on scalp distribution. Reflective originated stimuli elicited more negative FN400 than other conditions, which means that such stimuli indeed are associated with conceptual incongruence or higher affective complexity of meaning, but distinct from purely cognitive concreteness. Moreover, the amplitude of the potential preceding the decision, analyzed in the response-locked way, was shaped by the origin of an affective state but not valence. Trials involving decisions concerning reflective-originated words were characterized by a more negative amplitude than trials involving automatic-originated and control word stimuli. This corresponds to the observed pattern of response latencies, where we found that latencies for reflective stimuli were longer than for automatic originated or control ones. Additionally, this study demonstrates that the proposed new ambiguous paradigm is useful in studies concerning the influence of affect on decisions. PMID- 30425668 TI - Emergence of Skilled Behaviors in Professional, Amateur and Junior Cricket Batsmen During a Representative Training Scenario. AB - The aim of this study was to explore the emergence of skilled behaviors, in the form of actions, cognitions and emotions, between professional state level cricket batters and their lesser skilled counterparts. Twenty-two male cricket batsmen (n = 6 state level; n = 8 amateur grade club level, n = 8 junior state representative level) participated in a game scenario training session against right arm pace bowlers (n = 6 amateur senior club). The batsmen were tasked with scoring as many runs as possible during a simulated limited-overs game. The actions, cognitions, and emotions of each batsmen were recorded in situ with findings showing differences between state level players and those lesser skilled. State level batsmen played more scoring shots and scored more runs, underpinned by superior bat-ball contact and technical efficiency. Furthermore, the state player's cognitive evaluations of their own performance differed from junior batters, with more reported strategies based on an external outcome focus, such as where to score runs, rather than a focus on internal processes, such as making technical changes. State level batsmen also reported lower levels of nervousness compared with junior level batsmen. These results highlight the importance of viewing the emergence of skilled behavior as multi-faceted, rather than simply the acquisition of superior execution and technical proficiency. PMID- 30425669 TI - Relationship Between Attachment Style in Adulthood, Alexithymia, and Dissociation in Alcohol Use Disorder Inpatients. Mediational Model. AB - Background: Attachment theory is a widely used framework for understanding emotion regulation as well as alexithymia, and dissociation and this perspective has also been applied to understand alcohol use disorders. Apart from these theoretical suggestions, there has been scarce empirical research on this subject matter. Therefore, the objective of the present study was to investigate potential associations between attachment style in adulthood, alexithymia, and dissociation in alcohol use disorder inpatients. Methods: The Revised Adult Attachment Scale (RAAS), the Toronto Alexithymia Scale-20 (TAS-20), the Michigan Alcoholism Screening Test (MAST), and the Curious Experiences Survey (CES) were administered to a sample of 97 alcohol use disorder inpatients recruited from drug and alcohol treatment centers in Warsaw, and 104 persons in control groups, Poland. Results: A comparative analysis between the group of alcohol addicts and non-addicts showed statistically significant differences related to: alexithymia, dissociation, and attachment styles. The analysis of models related to the impact of attachment styles on the level of alcohol addiction with regard to a mediatory role of alexithymia and dissociation showed that all models are well fitted to data and statistically significant: intimacy F(3.197) = 34.41; p < 0.001 and explains 34% (R 2 = 0.3438); depend F(3.197) = 36.55; p < 0.001, and explains 36% (R 2 = 0.3576); anxiety F(3.197) = 34.71; p < 0.001, and explains 35% (R 2 = 0.3458) of the variability of alcohol addiction scores. Mediation analysis found that alexithymia and dissociation enhance the fear of intimacy and rejection in a romantic relationship. Conclusion: These findings support the broad attachment theory suggesting that attachment is associated with and predicts alexithymia and dissociation in the sample of substance use disorder inpatients. Alexithymia and dissociation, by inhibiting the processes of emotions' identification and verbalization, cause that language does not serve for the purpose of changing self or others, as the communication is distorted. Absent are common meanings and accurate mutual understanding in a relationship. PMID- 30425670 TI - One Direction? A Tutorial for Circular Data Analysis Using R With Examples in Cognitive Psychology. AB - Circular data is data that is measured on a circle in degrees or radians. It is fundamentally different from linear data due to its periodic nature (0 degrees = 360 degrees ). Circular data arises in a large variety of research fields. Among others in ecology, the medical sciences, personality measurement, educational science, sociology, and political science circular data is collected. The most direct examples of circular data within the social sciences arise in cognitive and experimental psychology. However, despite numerous examples of circular data being collected in different areas of cognitive and experimental psychology, the knowledge of this type of data is not well-spread and literature in which these types of data are analyzed using methods for circular data is relatively scarce. This paper therefore aims to give a tutorial in working with and analyzing circular data to researchers in cognitive psychology and the social sciences in general. It will do so by focusing on data inspection, model fit, estimation and hypothesis testing for two specific models for circular data using packages from the statistical programming language R. PMID- 30425671 TI - Can Nature Walks With Psychological Tasks Improve Mood, Self-Reported Restoration, and Sustained Attention? Results From Two Experimental Field Studies. AB - The evidence for restorative effects of contact with nature is vast. Drawing from two well-known theories in Environmental Psychology, Stress reduction theory and Attention restoration theory, restoration can be seen as a sequential, interactive process that begins with physiological relaxation and results in affective and attention restoration and broader life reflection. This interaction between a person and their environment may be facilitated by actively engaging with the environment but this has been understudied. We examined engagement with the environment by asking participants to complete psychological, restoration theory-driven tasks designed to enhance physiological, affective and attention restoration, while walking on nature trails. We conducted two experimental field studies (conceptual replications) in Finland in a coniferous forest (Study 1; n = 128) and an urban park (Study 2; n = 121). The participants walked at their own pace for 4-6 km with or without psychological tasks. Those in the task conditions completed either theory-based restoration-enhancement tasks or alternative tasks that we expected to be less restorative (Study 1: the same tasks in the reverse order; Study 2: awareness-enhancement tasks). The participants completed self reports on valence, activation, and restoration, and the Sustained Attention to Response Task, before, and after, the walk. We compared the change between measurements using regression models grouped by study conditions, with age, recent stress, difficulties with wayfinding, start time, and navigation method (Study 2 only) as covariates. Valence and self-reported restoration improved after the walk, but there was no additional benefit from the psychological tasks. In both studies, sustained attention consistently improved following different versions of the restoration-enhancement tasks and, to some extent, after a walk without the tasks. Participants who were more stressed experienced greater improvements in valence and self-reported restoration (Study 1) and sustained attention (Study 2). The results support both Stress reduction theory and Attention restoration theory, and imply that some forms of active engagement with the environment can aid sustained attention but not affective restoration. Future research efforts are needed to replicate these findings and to assess any potential long-term or multiplicative effects of engagement-based tasks, or other strategies that could enhance positive engagement with the environment. PMID- 30425672 TI - Impaired Tactile Temporal Discrimination in Patients With Hepatic Encephalopathy. AB - The sensory system constantly receives stimuli from the external world. To discriminate two stimuli correctly as two temporally distinct events, the temporal distance or stimulus onset asynchrony (SOA) between the two stimuli has to exceed a specific threshold. If the SOA between two stimuli is shorter than this specific threshold, the two stimuli will be perceptually fused and perceived as one single stimulus. Patients with hepatic encephalopathy (HE) are known to show manifold perceptual impairments, including slowed visual temporal discrimination abilities as measured by the critical flicker frequency (CFF). Here, we hypothesized that HE patients are also impaired in their tactile temporal discrimination abilities and, thus, require a longer SOA between two tactile stimuli to perceive the stimuli as two temporally distinct events. To test this hypothesis, patients with varying grades of HE and age-matched healthy individuals performed a tactile temporal discrimination task. All participants received two tactile stimuli with varying SOA applied to their left index finger and reported how many distinct stimuli they perceived ("1" vs. "2"). HE patients needed a significantly longer SOA (138.0 +/- 11.3 ms) between two tactile stimuli to perceive the stimuli as two temporally distinct events than healthy controls (78.6 +/- 13.1 ms; p < 0.01). In addition, we found that the temporal discrimination ability in the tactile modality correlated positively with the temporal discrimination ability in the visual domain across all participants (i.e., negative correlation between tactile SOA and visual CFF: r = -0.37, p = 0.033). Our findings provide evidence that temporal tactile perception is substantially impaired in HE patients. In addition, the results suggest that tactile and visual discrimination abilities are affected in HE in parallel. This finding might argue for a common underlying pathophysiological mechanism. We argue that the known global slowing of neuronal oscillations in HE might represent such a common mechanism. PMID- 30425674 TI - Psychodrama's Role in Alleviating Acute Distress: A Case Study of an Open Therapy Group in a Psychiatric Inpatient Ward. AB - Numerous studies point to the acute distress associated with experiencing severe mental illness and psychiatric hospitalization. Another strand of research describes how the unique features of psychodrama group therapy are useful in fostering spontaneity and creativity, and their benefits in treating particularly difficult populations where traditional psychotherapy is limited. This paper provides a framework for understanding the potential of psychodrama group therapy to alleviate the experience of loneliness and distress in psychiatric inpatients. A case study of an open inpatients psychodrama group in a psychiatric hospital in Israel demonstrates the role of therapeutic means such as the doubling technique and group sharing phase in creating and reinforcing empathy, relatedness, and support, which may offer at least partial relief of the distress and loneliness of psychiatric inpatients. The unique contribution of this study is the intimate encounter that it provides to researchers and practitioners with the processes that take place within the setting of inpatients therapy group. PMID- 30425675 TI - Materialism, Body Surveillance, Body Shame, and Body Dissatisfaction: Testing a Mediational Model. AB - The present study aimed to examine the mechanisms underlying the links between materialism and body dissatisfaction. A sample of 583 Chinese undergraduate women completed a questionnaire measuring materialism, body surveillance, body shame, and body dissatisfaction. Correlational analysis showed that materialism, body surveillance, and body shame were significantly positively correlated with body dissatisfaction. The results of path analyses revealed that higher materialism predicted more body dissatisfaction, albeit indirectly, via higher body surveillance and body shame. PMID- 30425673 TI - Cognitive-Motor Interference in Neurodegenerative Disease: A Narrative Review and Implications for Clinical Management. AB - This paper provides a narrative review of cognitive motor interference in neurodegeneration, including brain imaging findings specific to interference effects in neurodegenerative disease, and dual task assessment and intervention in Parkinson's disease (PD), multiple sclerosis (MS), and Huntington's disease (HD). In a healthy central nervous system the ability to process information is limited. Limitations in capacity to select and attend to inputs influence the ability to prepare and perform multiple tasks. As a result, the system balances demands, switching attention to the most task-relevant information as it becomes available. Limitations may become more apparent in persons with neurodegenerative diseases (ND) with system-specific impairments in PD, MS, and HD. These ND affect both cognitive and motor function and are thus particularly susceptible to dual task interference. Issues related to performer and task characteristics and implications of these findings for both the standard assessment of dual task abilities as well as development and evaluation of interventions aimed at improving dual task ability are discussed. In addition, we address the need for optimizing individualized assessment, intervention and evaluation of dual task function by choosing cognitive and motor tasks and measures that are sensitive to and appropriate for the individual's level of function. Finally, we use current evidence to outline a 5-step process of clinical decision making that uses the dual task taxonomy as a framework for assessment and intervention. PMID- 30425676 TI - A Systematic Assessment of Prevalence, Incidence and Regional Distribution of Multiple Sclerosis in Bavaria From 2006 to 2015. AB - Introduction: Worldwide, incidence and prevalence of multiple sclerosis (MS) have increased over the last decades. We present a systematic epidemiological study with recent prevalence and incidence rates of MS in Bavaria. Methods: Incidence and prevalence of MS stratified by gender, age groups and region were analyzed by data records from 2006 to 2015 of more than 10 million people insured by the Bavarian Association of Statutory Health Insurance Physicians. Official statistics of the German Federal Ministry of Health provided the size of the general population. Future prevalence was estimated with a predictive model. Results: From 2006 to 2015 prevalence of MS in Bavaria increased from 171 per 100,000 to 277 per 100,000, while incidence rates remained relatively stable (range 16-18 per 100,000 inhabitants with a female to male ratio between 2.4:1 and 2:1). Incidence and prevalence were higher in urban than urbanized and rural areas. The prevalence is expected to increase to 374 per 100,000 in 2040 with the highest prevalence rates between 50 and 65 years. Conclusion: The prevalence of MS in Bavaria is among the highest worldwide and will further rise over the next two decades. This demonstrates a need to strengthen healthcare provision systems due to the increasing numbers of particularly older patients with MS in the future. PMID- 30425677 TI - A Retrospective Analysis of the Clinical Features of Inpatients With Epilepsy in the Ganzi Tibetan Autonomous Prefecture. AB - Background: There is limited detailed clinical information for patients with epilepsy in Tibet. This study sought to provide data about the clinical features of epilepsy in the Ganzi Tibetan Autonomous Prefecture to improve strategies for epilepsy prevention and management in this region. Methods: We reviewed the clinical record of patients with epilepsy in the Neurology Department, Ganzi Tibetan Autonomous Prefecture People's Hospital and compared the clinical features and compared it with control, from West China Hospital in Chengdu. Results: This retrospective study included 165 patients with epilepsy admitted between January 2015 and February 2018. Majority of patients (97%) in this study had active epilepsy; 28.5% had generalized onset seizures and 68.5% had focal onset seizures. Fifty-four patients had received anti-epileptic drug (AED) treatment prior to hospitalization, however, 38 (70.4%) patients took the medication irregularly. The leading etiology of this cohort was head trauma (20.6%), followed by stroke (10.9%), neurocysticercosis (7.9%), brain hydatidosis (6.7%) and tuberculous infection (5.5%). Compared with in-patients in Chengdu, epilepsy in Ganzi was more frequently caused by infection (OR = 4.216, 95% CI, 2.124-8.367), including neurocysticercosis (OR = 29.301, 95% CI, 1.727-497.167) and brain hydatidosis (OR = 24.637, 95% CI, 1.439-421.670). Conclusions: These data suggest that the control of cerebral infections, especially parasite infection, is essential for the prevention of epilepsy in the Ganzi Tibetan Autonomous Prefecture. Education of local primary doctors and patients about the literacy of epilepsy will enable better management of epilepsy in this population. PMID- 30425678 TI - Errors of Upright Perception in Patients With Vestibular Migraine. AB - Patients with vestibular migraine (VM) often report dizziness with changes in the head or body position. Such symptoms raise the possibility of dysfunction in neural mechanisms underlying spatial orientation in these patients. Here we addressed this issue by investigating the effect of static head tilts on errors of upright perception in a group of 27 VM patients in comparison with a group of 27 healthy controls. Perception of upright was measured in a dark room using a subjective visual vertical (SVV) paradigm at three head tilt positions (upright, +/-20 degrees ). VM patients were also surveyed about the quality of their dizziness and spatial symptoms during daily activities. In the upright head position, SVV errors were within the normal range for VM patients and healthy controls (within 2 degrees from true vertical). During the static head tilts of 20 degrees to the right, VM patients showed larger SVV errors consistent with overestimation of the tilt magnitude (i.e., as if they felt further tilted toward the right side) (VM: -3.21 degrees +/- 0.93 vs. Control: 0.52 degrees +/- 0.70; p = 0.002). During the head tilt to the left, SVV errors in VM patients did not differ significantly from controls (VM: 0.77 degrees +/- 1.05 vs. Control: -0.04 degrees +/- 0.68; p = 0.52). There was no significant difference in SVV precision between the VM patients and healthy controls at any head tilt position. Consistent with the direction of the SVV errors in VM patients, they largely reported spatial symptoms toward the right side. These findings suggest an abnormal sensory integration for spatial orientation in vestibular migraine, related to daily dizziness in these patients. PMID- 30425679 TI - Cognitive Involvement in Balance, Gait and Dual-Tasking in Aging: A Focused Review From a Neuroscience of Aging Perspective. AB - A substantial corpus of evidence suggests that the cognitive involvement in postural control and gait increases with aging. A large portion of such studies were based on dual-task experimental designs, which typically use the simultaneous performance of a motor task (e.g., static or dynamic balancing, walking) and a continuous cognitive task (e.g., mental arithmetic, tone detection). This focused review takes a cognitive neuroscience of aging perspective in interpreting cognitive motor dual-task findings. Specifically, we consider the importance of identifying the neural circuits that are engaged by the cognitive task in relation to those that are engaged during motor task performance. Following the principle of neural overlap, dual-task interference should be greatest when the cognitive and motor tasks engage the same neural circuits. Moreover, the literature on brain aging in general, and models of dedifferentiation and compensation, in particular, suggest that in cognitive motor dual-task performance, the cognitive task engages different neural substrates in young as compared to older adults. Also considered is the concept of multisensory aging, and the degree to which the age-related decline of other systems (e.g., vision, hearing) contribute to cognitive load. Finally, we discuss recent work on focused cognitive training, exercise and multimodal training of older adults and their effects on postural and gait outcomes. In keeping with the principle of neural overlap, the available cognitive training research suggests that targeting processes such as dividing attention and inhibition lead to improved balance and gait in older adults. However, more studies are needed that include functional neuroimaging during actual, upright performance of gait and balance tasks, in order to directly test the principle of neural overlap, and to better optimize the design of intervention studies to improve gait and posture. PMID- 30425681 TI - PACAP Neurons in the Ventromedial Hypothalamic Nucleus Are Glucose Inhibited and Their Selective Activation Induces Hyperglycaemia. AB - Background: Glucose-sensing neurons are located in several parts of the brain, but are concentrated in the ventromedial nucleus of the hypothalamus (VMH). The importance of these VMH neurons in glucose homeostasis is well-established, however, little is known about their individual identity. In the present study, we identified a distinct glucose-sensing population in the VMH and explored its place in the glucose-regulatory network. Methods: Using patch-clamp electrophysiology on Pacap-cre::EYFP cells, we explored the glucose-sensing ability of the pituitary adenylate cyclase-activating peptide (PACAP) neurons both inside and outside the VMH. We also mapped the efferent projections of these neurons using anterograde and retrograde tracing techniques. Finally, to test the functionality of PACAPVMH in vivo, we used DREADD technology and measured systemic responses. Results: We demonstrate that PACAP neurons inside (PACAPVMH), but not outside the VMH are intrinsically glucose inhibited (GI). Anatomical tracing techniques show that PACAPVMH neurons project to several areas that can influence autonomic output. In vivo, chemogenetic stimulation of these neurons inhibits insulin secretion leading to reduced glucose tolerance, implicating their role in systemic glucose regulation. Conclusion: These findings are important as they identify, for the first time, a specific VMH neuronal population involved in glucose homeostasis. Identifying the different glucose sensing populations in the VMH will help piece together the different arms of glucose regulation providing vital information regarding central responses to glucose metabolic disorders including hypoglycaemia. PMID- 30425682 TI - Insulin-Related Lipohypertrophy: Lipogenic Action or Tissue Trauma? AB - Lipohypertrophy has been suggested as an outcome of lipogenic action of insulin and/or injection-related tissue trauma. In a cross-sectional study, we evaluated the predictors of lipohypertrophy in 372 type 1 diabetes patients (mean age 17.1 years) receiving subcutaneous insulin with pen and/or syringes for >=3 months. On examining injection sites with inspection and palpation technique, 62.1% patients demonstrated lipohypertrophy. Univariate analysis showed that gender, BMI, HbA1c, injection device, rotation, injection area, needle length, insulin regimen, and total daily dose of insulin were associated with lipohypertrophy (p < 0.05). Notably, the mean needle reuse was comparable in patients with or without lipohypertrophy (8.1 vs. 7.2, p = 0.534). In multivariate logistic regression, gender, HbA1c, TDD, injection devices, and needle length lost its significance. Further, injections over smaller area (<=8.5 * 5.5 cm) and non-rotation of sites were found to be strongest independent predictor of lipohypertrophy (p < 0.0005 for both) with increased odds of 23.2 (95% CI 9.1-59.2) and 6.3 (95% CI 3.4-11.9) times, respectively. Being underweight was also a significant independent predictor (odds ratio [OR] 13.0 [95% CI 2.2-75.2], p = 0.004). Compared to rapid plus long-acting analogs, regular insulin plus long-acting analogs and conventional premixed insulin users had 3.2 (95% CI 1.5-6.8, p = 0.003) and 4.6 (95% CI 1.4-15.7, p = 0.014) fold higher risk of lipohypertrophy (mean injection frequency 4.01 vs. 4.01 vs. 2.09, respectively). Sub-group analysis showed that lipohypertrophy was 79% less likely in patients with multiple daily injections (>=4) than twice-daily regimen (OR 0.21, p < 0.0005). Moreover, lipohypertrophy was reduced to half with bolus doses of rapid-acting insulin analogs than regular insulin (p = 0.003), even though mean injection frequency was comparable (4.01 vs. 3.93, p = 0.229). This difference was statistically insignificant for basal doses with NPH or long-acting analogs (p = 0.069). Therefore, injection area, rotation, BMI, and insulin regimen are the best predictors of lipohypertrophy and together could correctly identify lipohypertrophy status in 84.4% patients with excellent discrimination capability (AUC = 0.906, p < 0.0005). In conclusion, findings of our study suggest that delivering rapidly absorbed insulin analogs over large injection area along with greater split of total daily doses reduce insulin-induced lipogenesis and outplay tissue trauma added through frequent injections and needle reuse. PMID- 30425680 TI - Forecast or Fall: Prediction's Importance to Postural Control. AB - To interact successfully with an uncertain environment, organisms must be able to respond to both unanticipated and anticipated events. For unanticipated events, organisms have evolved stereotyped motor behaviors mapped to the statistical regularities of the environment, which can be trigged by specific sensory stimuli. These "reflexive" responses are more or less hardwired to prevent falls and represent, maybe, the best available solution to maintaining posture given limited available time and information. With the gift of foresight, however, motor behaviors can be tuned or prepared in advance, improving the ability of the organism to compensate for, and interact with, the changing environment. Indeed, foresight's improvement of our interactive capacity occurs through several means, such as better action selection, processing, and conduction delay compensation and by providing a prediction with which to compare our actual behaviors to, thereby facilitating error identification and learning. Here we review the various roles foresight (prediction) plays in maintaining our postural equilibrium. We start by describing some of the more recent findings related to the prediction of instability. Specifically, we cover recent advancements in the understanding of anticipatory postural behaviors that are used broadly to stabilize volitional movement and compensate for impending postural disturbances. We also describe anticipatory changes in the state, or set, of the nervous system that may facilitate anticipatory behaviors. From changes in central set, we briefly discuss prediction of postural instability online before moving into a discussion of how predictive mechanisms, such as internal models, permit us to tune, perhaps our highest level predictive behaviors, namely the priming associated with motor affordances. Lastly, we explore methods best suited to expose the contribution of prediction to postural equilibrium control across a variety of contexts. PMID- 30425683 TI - Possible Insulinotropic Action of Apolipoprotein A-I Through the ABCA1/Cdc42/cAMP/PKA Pathway in MIN6 Cells. AB - Aims/Introduction: We studied the mechanisms for the possible insulinotropic action of apolipoprotein (Apo) A-I in mouse insulinoma (MIN6) cells. Materials and Methods: The effects of ApoA-I on cAMP production and glucose-stimulated insulin secretion (GSIS), and the dose dependency (ApoA-I at 5, 10, 25, and 50 MUg/ml) were determined using MIN6 cells. The effects of the small-interference ribonucleic acid (siRNA) of ATP-binding cassette transporter A1(ABCA1) and Cell division control protein 42 homolog (Cdc42) on the insulinotropic action of ApoA I was studied, as well as mRNA and protein levels of ABCA1 and Cdc42. Then, the influence of cAMP inhibitor SQ22536, and the cAMP-dependent protein kinase inhibitor Rp-cAMPS on ApoA-I action were studied. Results: Addition of ApoA-I produced cAMP and increased insulin secretion, dose-dependently in high glucose concentration (25 mmmol/l). and ABCA1 protein and Cdc42 mRNA and protein were also enhanced. Specific ABCA1 and Cdc42 siRNA significantly decreased the effects of ApoA-I on insulin secretion compared with negative controls. Manifestations of ABCA1 and Cdc42 mRNA and protein were less than that of the negative control group. Both cAMP inhibiror (SQ22536) and protein kinases inhibitor (Rp-cAMPS) strongly inhibited the effects of ApoA-I on insulin secretion. Conclusions: We demonstrated that ApoA-I enhances glucose-stimulated insulin release in high glucose at least partially through the ABCA1/Cdc42/cAMP/ Protein kinase A (PKA) pathway. PMID- 30425684 TI - Aquatic Bacterial Communities Associated With Land Use and Environmental Factors in Agricultural Landscapes Using a Metabarcoding Approach. AB - This study applied a 16S rRNA gene metabarcoding approach to characterize bacterial community compositional and functional attributes for surface water samples collected within, primarily, agriculturally dominated watersheds in Ontario and Quebec, Canada. Compositional heterogeneity was best explained by stream order, season, and watercourse discharge. Generally, community diversity was higher at agriculturally dominated lower order streams, compared to larger stream order systems such as small to large rivers. However, during times of lower relative water flow and cumulative 2-day rainfall, modestly higher relative diversity was found in the larger watercourses. Bacterial community assemblages were more sensitive to environmental/land use changes in the smaller watercourses, relative to small-to-large river systems, where the proximity of the sampled water column to bacteria reservoirs in the sediments and adjacent terrestrial environment was greater. Stream discharge was the environmental variable most significantly correlated (all positive) with bacterial functional groups, such as C/N cycling and plant pathogens. Comparison of the community structural similarity via network analyses helped to discriminate sources of bacteria in freshwater derived from, for example, wastewater treatment plant effluent and intensity and type of agricultural land uses (e.g., intensive swine production vs. dairy dominated cash/livestock cropping systems). When using metabarcoding approaches, bacterial community composition and coexisting pattern rather than individual taxonomic lineages, were better indicators of environmental/land use conditions (e.g., upstream land use) and bacterial sources in watershed settings. Overall, monitoring changes and differences in aquatic microbial communities at regional and local watershed scales has promise for enhancing environmental footprinting and for better understanding nutrient cycling and ecological function of aquatic systems impacted by a multitude of stressors and land uses. PMID- 30425686 TI - The Simplified Carbapenem Inactivation Method (sCIM) for Simple and Accurate Detection of Carbapenemase-Producing Gram-Negative Bacilli. AB - This study reports the simplified carbapenem inactivation method (sCIM) to detect carbapenemase-producing gram-negative bacilli in a simple and accurate manner. This method is based on the modified carbapenem inactivation method (mCIM) with the improvement of experimental procedures. Instead of incubating the antibiotic disk in the organism culture media, the organism to be tested was smeared directly onto the antibiotic disk in the sCIM. For evaluating the sensitivity and specificity of the method, a total of 196 Enterobacteriaceae, 73 Acinetobacter baumannii, and 158 Pseudomonas aeruginosa isolates were collected. Polymerase chain reaction (PCR) was used to detect the carbapenemase genes. Phenotypic evaluations were performed using both the sCIM and the mCIM. PCR results showed that, of the 196 Enterobacteriaceae strains, 147 expressed the carbapenemase genes blaKPC-2 (58.5%), blaIMP-4 (21.8%), blaIMP-2 (2.0%), blaVIM-1 (6.1%), blaNDM-1 (10.2%), and blaOXA-48 (1.4%). sCIM results had high concordance with PCR results (99.5%) and mCIM results (100%) with the exception of one Klebsiella pneumoniae strain, which had an minimal inhibitory concentration (MIC) for imipenem of 0.25 mg/L. PCR demonstrated that 53 of the 73 A. baumannii isolates expressed the carbapenemase genes blaOXA-23 (98.1%) and blaVIM-2 (1.8%). sCIM and PCR results corresponded but all A. baumannii isolates were carbapenemase negative by the mCIM. PCR demonstrated that 25 of the 158 P. aeruginosa isolates expressed carbapenemase genes blaVIM-1 (52%) , blaVIM-2 (8%) , blaVIM-4 (36%), and blaIMP-4 (4%). sCIM results had high concordance with PCR results (100%) and the mCIM results (99.4%) with the exception of one P. aeruginosa isolate that expressed the blaVIM-4 gene. The sCIM offers specificity and sensitivity comparable to PCR but has the advantage of being more user-friendly. This method is suitable for routine use in most clinical microbiology laboratories for the detection of carbapenemase-producing gram-negative bacilli. PMID- 30425687 TI - Transcriptomics Study on Staphylococcus aureus Biofilm Under Low Concentration of Ampicillin. AB - Staphylococcus aureus is one of the representative foodborne pathogens which forms biofilm. Antibiotics are widely applied in livestock husbandry to maintain animal health and productivity, thus contribute to the dissemination of antimicrobial resistant livestock and human pathogens, and pose a significant public health threat. Effect of antibiotic pressure on S. aureus biofilm formation, as well as the mechanism, remains unclear. In this study, the regulatory mechanism of low concentration of ampicillin on S. aureus biofilm formation was elucidated. The viability and biomass of biofilm with and without 1/4 MIC ampicillin treatment for 8 h were determined by XTT and crystal violet straining assays, respectively. Transcriptomics analysis on ampicillin-induced and non-ampicillin-induced biofilms were performed by RNA-sequencing, differentially expressed genes identification and annotation, GO functional and KEGG pathway enrichment. The viability and biomass of ampicillin-induced biofilm showed dramatical increase compared to the non-ampicillin-induced biofilm. A total of 530 differentially expressed genes (DEGs) with 167 and 363 genes showing up- and down-regulation, respectively, were obtained. Upon GO functional enrichment, 183, 252, and 21 specific GO terms in biological process, molecular function and cellular component were identified, respectively. Eight KEGG pathways including "Microbial metabolism in diverse environments", "S. aureus infection", and "Monobactam biosynthesis" were significantly enriched. In addition, "beta-lactam resistance" pathway was also highly enriched. In ampicillin-induced biofilm, the significant up-regulation of genes encoding multidrug resistance efflux pump AbcA, penicillin binding proteins PBP1, PBP1a/2, and PBP3, and antimicrobial resistance proteins VraF, VraG, Dlt, and Aur indicated the positive response of S. aureus to ampicillin. The up-regulation of genes encoding surface proteins ClfB, IsdA, and SasG and genes (cap5B and cap5C) which promote the adhesion of S. aureus in ampicillin induced biofilm might explain the enhanced biofilm viability and biomass. PMID- 30425688 TI - The EnvZ-OmpR Two-Component Signaling System Is Inactivated in a Mutant Devoid of Osmoregulated Periplasmic Glucans in Dickeya dadantii. AB - Osmoregulated periplasmic glucans (OPGs) are general constituents of alpha-, beta , and gamma-Proteobacteria. This polymer of glucose is required for full virulence of many pathogens including Dickeya dadantii (D. dadantii). The phytopathogenic enterobacterium D. dadantii causes soft-rot disease in a wide range of plants. An OPG-defective mutant is impaired in environment sensing. We previously demonstrated that (i) fluctuation of OPG concentration controlled the activation level of the RcsCDB system, and (ii) RcsCDB along with EnvZ/OmpR controlled the mechanism of OPG succinylation. These previous data lead us to explore whether OPGs are required for other two-component systems. In this study, we demonstrate that inactivation of the EnvZ/OmpR system in an OPG-defective mutant restores full synthesis of pectinase but only partial virulence. Unlike for the RcsCDB system, the EnvZ-OmpR system is not controlled by OPG concentration but requires OPGs for proper activation. PMID- 30425685 TI - Living at the Frontiers of Life: Extremophiles in Chile and Their Potential for Bioremediation. AB - Extremophiles are organisms capable of adjust, survive or thrive in hostile habitats that were previously thought to be adverse or lethal for life. Chile gathers a wide range of extreme environments: salars, geothermal springs, and geysers located at Altiplano and Atacama Desert, salars and cold mountains in Central Chile, and ice fields, cold lakes and fjords, and geothermal sites in Patagonia and Antarctica. The aims of this review are to describe extremophiles that inhabit main extreme biotopes in Chile, and their molecular and physiological capabilities that may be advantageous for bioremediation processes. After briefly describing the main ecological niches of extremophiles along Chilean territory, this review is focused on the microbial diversity and composition of these biotopes microbiomes. Extremophiles have been isolated in diverse zones in Chile that possess extreme conditions such as Altiplano, Atacama Desert, Central Chile, Patagonia, and Antarctica. Interesting extremophiles from Chile with potential biotechnological applications include thermophiles (e.g., Methanofollis tationis from Tatio Geyser), acidophiles (e.g., Acidithiobacillus ferrooxidans, Leptospirillum ferriphilum from Atacama Desert and Central Chile copper ores), halophiles (e.g., Shewanella sp. Asc-3 from Altiplano, Streptomyces sp. HKF-8 from Patagonia), alkaliphiles (Exiguobacterium sp. SH31 from Altiplano), xerotolerant bacteria (S. atacamensis from Atacama Desert), UV- and Gamma-resistant bacteria (Deinococcus peraridilitoris from Atacama Desert) and psychrophiles (e.g., Pseudomonas putida ATH-43 from Antarctica). The molecular and physiological properties of diverse extremophiles from Chile and their application in bioremediation or waste treatments are further discussed. Interestingly, the remarkable adaptative capabilities of extremophiles convert them into an attractive source of catalysts for bioremediation and industrial processes. PMID- 30425689 TI - Molecular and Microbiological Insights on the Enrichment Procedures for the Isolation of Petroleum Degrading Bacteria and Fungi. AB - Autochthonous bioaugmentation, by exploiting the indigenous microorganisms of the contaminated environment to be treated, can represent a successful bioremediation strategy. In this perspective, we have assessed by molecular methods the evolution of bacterial and fungal communities during the selective enrichment on different pollutants of a soil strongly polluted by mixtures of aliphatic and polycyclic hydrocarbons. Three consecutive enrichments were carried out on soil samples from different soil depths (0-1, 1-2, 2-3 m), and analyzed at each step by means of high-throughput sequencing of bacterial and fungal amplicons biomarkers. At the end of the enrichments, bacterial and fungal contaminants degrading strains were isolated and identified in order to (i) compare the composition of enriched communities by culture-dependent and culture-independent molecular methods and to (ii) obtain a collection of hydrocarbon degrading microorganisms potentially exploitable for soil bioremediation. Molecular results highlighted that for both bacteria and fungi the pollutant had a partial shaping effect on the enriched communities, with paraffin creating distinct enriched bacterial community from oil, and polycyclic aromatic hydrocarbons generally overlapping; interestingly neither the soil depth or the enrichment step had significant effects on the composition of the final enriched communities. Molecular analyses well-agreed with culture-dependent analyses in terms of most abundant microbial genera. A total of 95 bacterial and 94 fungal strains were isolated after selective enrichment procedure on different pollutants. On the whole, isolated bacteria where manly ascribed to Pseudomonas genus followed by Sphingobacterium, Bacillus, Stenothrophomonas, Achromobacter, and Serratia. As for fungi, Fusarium was the most abundant genus followed by Trichoderma and Aspergillus. The species comprising more isolates, such as Pseudomonas putida, Achromobacter xylosoxidans and Ochromobactrum anthropi for bacteria, Fusarium oxysporum and Fusarium solani for fungi, were also the dominant OTUs assessed in Illumina. PMID- 30425691 TI - Topical Application of a Vitamin A Derivative and Its Combination With Non ablative Fractional Laser Potentiates Cutaneous Influenza Vaccination. AB - Skin contains a large number of antigen presenting cells, making intradermal (ID) injection one of the most effective ways for vaccine administration. However, although current adjuvants may cause severe local reactions and inflammations in the skin, no adjuvant has been approved for ID vaccination so far. Here, we report that topical application of all-trans retinoic acid (ATRA), a vitamin A derivative produced in the human body, augmented cutaneous influenza vaccination. The adjuvant effects were evaluated in a murine vaccination/challenge model by using A/California/07/2009 pandemic vaccine (09V) or a seasonal influenza vaccine (SIV). ATRA drove a Th2-biased immune response, as demonstrated by profoundly elevated IgG1 titer rather than IgG2 titer. Combining ATRA with a non-ablative fractional laser (NAFL), which represents a new category of vaccine adjuvant utilizing physical stimuli to induce self-immune stimulators, further enhanced the efficacy of influenza vaccines with a more balanced Th1/Th2 immune response. The dual adjuvant strengthened cross-reactive immune responses against both homogenous and heterogeneous influenza viral strains. Analysis of gene expression profile showed that ATRA/NAFL stimulated upregulation of cytosolic nucleic acid sensors and their downstream factors, leading to a synergistic elevation of type I interferon expression. Consistent with this finding, knocking out IRF3 or IRF7, two key downstream regulatory factors in most nucleic acid sensing pathways, resulted in a significant decrease in the adjuvant effect of ATRA/NAFL. Thus, our study demonstrates that the self molecule ATRA could boost cutaneous influenza vaccination either alone or ideally in combination with NAFL. PMID- 30425690 TI - Metagenomics-Based, Strain-Level Analysis of Escherichia coli From a Time-Series of Microbiome Samples From a Crohn's Disease Patient. AB - Dysbiosis of the gut microbiome, including elevated abundance of putative leading bacterial triggers such as E. coli in inflammatory bowel disease (IBD) patients, is of great interest. To date, most E. coli studies in IBD patients are focused on clinical isolates, overlooking their relative abundances and turnover over time. Metagenomics-based studies, on the other hand, are less focused on strain level investigations. Here, using recently developed bioinformatic tools, we analyzed the abundance and properties of specific E. coli strains in a Crohns disease (CD) patient longitudinally, while also considering the composition of the entire community over time. In this report, we conducted a pilot study on metagenomic-based, strain-level analysis of a time-series of E. coli strains in a left-sided CD patient, who exhibited sustained levels of E. coli greater than 100X healthy controls. We: (1) mapped out the composition of the gut microbiome over time, particularly the presence of E. coli strains, and found that the abundance and dominance of specific E. coli strains in the community varied over time; (2) performed strain-level de novo assemblies of seven dominant E. coli strains, and illustrated disparity between these strains in both phylogenetic origin and genomic content; (3) observed that strain ST1 (recovered during peak inflammation) is highly similar to known pathogenic AIEC strains NC101 and LF82 in both virulence factors and metabolic functions, while other strains (ST2-ST7) that were collected during more stable states displayed diverse characteristics; (4) isolated, sequenced, experimentally characterized ST1, and confirmed the accuracy of the de novo assembly; and (5) assessed growth capability of ST1 with a newly reconstructed genome-scale metabolic model of the strain, and showed its potential to use substrates found abundantly in the human gut to outcompete other microbes. In conclusion, inflammation status (assessed by the blood C-reactive protein and stool calprotectin) is likely correlated with the abundance of a subgroup of E. coli strains with specific traits. Therefore, strain-level time series analysis of dominant E. coli strains in a CD patient is highly informative, and motivates a study of a larger cohort of IBD patients. PMID- 30425692 TI - Temperature Controls Crystalline Iron Oxide Utilization by Microbial Communities in Methanic Ferruginous Marine Sediment Incubations. AB - Microorganisms can use crystalline iron minerals for iron reduction linked to organic matter degradation or as conduits for direct interspecies electron transfer (mDIET) to syntrophic partners, e.g., methanogens. The environmental conditions that lead either to reduction or conduit use are so far unknown. We investigated microbial community shifts and interactions with crystalline iron minerals (hematite and magnetite) in methanic ferruginous marine sediment incubations during organic matter (glucose) degradation at varying temperatures. Iron reduction rates increased with decreasing temperature from 30 degrees C to 4 degrees C. Both hematite and magnetite facilitated iron reduction at 4 degrees C, demonstrating that microorganisms in the methanic zone of marine sediments can reduce crystalline iron oxides under psychrophilic conditions. Methanogenesis occurred, however, at higher rates with increasing temperature. At 30 degrees C, both hematite and magnetite accelerated methanogenesis onset and maximum process rates. At lower temperatures (10 degrees C and 4 degrees C), hematite could still facilitate methanogenesis but magnetite served more as an electron acceptor for iron reduction than as a conduit. Different temperatures selected for different key microorganisms: at 30 degrees C, members of genus Orenia, Halobacteroidaceae, at 10 degrees C, Photobacterium and the order Clostridiales, and at 4 degrees C Photobacterium and Psychromonas were enriched. Members of the order Desulfuromonadales harboring known dissimilatory iron reducers were also enriched at all temperatures. Our results show that crystalline iron oxides predominant in some natural environments can facilitate electron transfer between microbial communities at psychrophilic temperatures. Furthermore, temperature has a critical role in determining the pathway of crystalline iron oxide utilization in marine sediment shifting from conduction at 30 degrees C to predominantly iron reduction at lower temperatures. PMID- 30425693 TI - MALDI-TOF MS Applications to the Detection of Antifungal Resistance: State of the Art and Future Perspectives. AB - MALDI-TOF MS technology has made possible revolutionary advances in the diagnosis of infectious diseases. Besides allowing rapid and reliable identification of bacteria and fungi, this technology has been recently applied to the detection of antimicrobial resistance. Several approaches have been proposed and evaluated for application of MALDI-TOF MS to antimicrobial susceptibility testing of bacteria, and some of these have been or might be applied also to yeasts. In this context, the comparison of proteomic profiles of bacteria/yeasts incubated with or without antimicrobial drugs is a very promising method. Another recently proposed MALDI TOF MS-based approach for antifungal susceptibility testing is the application of the semi-quantitative MALDI Biotyper antibiotic susceptibility test rapid assay, which was originally designed for antimicrobial susceptibility testing of bacteria, to yeast isolates. Increasingly effective and accurate MS tools and instruments as well as the possibility to optimize analytical parameter settings for targeted applications have generated an expanding area in the field of clinical microbiology diagnostics, paving the way for the development and/or optimization of rapid methods for antifungal susceptibility testing in the near future. In the present study, the state of the art of MALDI-TOF MS applications to antifungal susceptibility testing is reviewed, and cutting-edge developments are discussed, with a particular focus on methods allowing rapid detection of drug resistance in pathogenic fungi causing systemic mycoses. PMID- 30425694 TI - The Role of ISCR1-Borne POUT Promoters in the Expression of Antibiotic Resistance Genes. AB - The ISCR1 (Insertion sequence Common Region) element is the most widespread member of the ISCR family, and is frequently present within gamma-proteobacteria that occur in clinical settings. ISCR1 is always associated with the 3'Conserved Segment (3'CS) of class 1 integrons. ISCR1 contains outward-oriented promoters POUT, that may contribute to the expression of downstream genes. In ISCR1, there are two POUT promoters named PCR1-1 and PCR1-2. We performed an in silico analysis of all publically available ISCR1 sequences and identified numerous downstream genes that mainly encode antibiotic resistance genes and that are oriented in the same direction as the POUT promoters. Here, we showed that both PCR1-1 and PCR1-2 significantly increase the expression of the downstream genes bla CTX-M-9 and dfrA19. Our data highlight the role of ISCR1 in the expression of antibiotic resistance genes, which may explain why ISCR1 is so frequent in clinical settings. PMID- 30425696 TI - Structural and Functional Characterization of PA14/Flo5-Like Adhesins From Komagataella pastoris. AB - Cell-cell and cell-substrate based adhesion of yeasts are major determinants of their adoption of different life styles. Genome-mining of ascomycetous GPI anchored cell wall proteins with lectin-like PA14 domains identified a unique class of putative adhesins in the clade of methylotrophic Komagataella yeasts, many of which are known to colonize plants and insects involving yet unknown adhesion mechanisms. Here, we report the functional and structural analysis of two of its members: KpFlo1 (=Cea1), that is highly specific for terminal N acetylglucosamine moieties, and KpFlo2, which represents an orphan lectin with intact binding site but unknown specificity. Crystal structures of the Cea1 adhesion domain complexed to N-acetylglucosamine and N,N'-diacetylchitobiose reveal a Ca2+-dependent binding mode that differs from other members of the PA14/Flo5 adhesin family. Heterologous expression of Cea1A in Saccharomyces cerevisiae promotes cellular adhesion to non-reducing ends of non-crystalline chitin. Overall, our data suggest that high-affinity recognition of beta-GlcNAc capped glycans by Cea1 enable Komagataella species to interact with surface cues present in fungi and insects. PMID- 30425695 TI - Puzzling Over the Pneumococcal Pangenome. AB - The Gram positive bacterium Streptococcus pneumoniae (pneumococcus) is a major human pathogen. It is a common colonizer of the human host, and in the nasopharynx, sinus, and middle ear it survives as a biofilm. This mode of growth is optimal for multi-strain colonization and genetic exchange. Over the last decades, the far-reaching use of antibiotics and the widespread implementation of pneumococcal multivalent conjugate vaccines have posed considerable selective pressure on pneumococci. This scenario provides an exceptional opportunity to study the evolution of the pangenome of a clinically important bacterium, and has the potential to serve as a case study for other species. The goal of this review is to highlight key findings in the studies of pneumococcal genomic diversity and plasticity. PMID- 30425697 TI - Interactive Responses of Potato (Solanum tuberosum L.) Plants to Heat Stress and Infection With Potato Virus Y. AB - Potato (Solanum tuberosum) plants are exposed to diverse environmental stresses, which may modulate plant-pathogen interactions, and potentially cause further decreases in crop productivity. To provide new insights into interactive molecular responses to heat stress combined with virus infection in potato, we analyzed expression of genes encoding pathogenesis-related (PR) proteins [markers of salicylic acid (SA)-mediated plant defense] and heat shock proteins (HSPs), in two potato cultivars that differ in tolerance to elevated temperatures and in susceptibility to potato virus Y (PVY). In plants of cv. Chicago (thermosensitive and PVY-susceptible), increased temperature reduced PR gene expression and this correlated with enhancement of PVY infection (virus accumulation and symptom production). In contrast, with cv. Gala (thermotolerant and PVY resistant), which displayed a greater increase in PR gene expression in response to PVY infection, temperature affected neither PR transcript levels nor virus accumulation. HSP genes were induced by elevated temperature in both cultivars but to higher levels in the thermotolerant (Gala) cultivar. PVY infection did not alter expression of HSP genes in the Gala cultivar (possibly because of the low level of virus accumulation) but did induce expression of HSP70 and HSP90 in the susceptible cultivar (Chicago). These findings suggest that responses to heat stress and PVY infection in potato have some common underlying mechanisms, which may be integrated in a specific consolidated network that controls plant sensitivity to multiple stresses in a cultivar-specific manner. We also found that the SA pre treatment subverted the sensitive combined (heat and PVY) stress phenotype in Chicago, implicating SA as a key component of such a regulatory network. PMID- 30425698 TI - Antifungal Activity and Action Mechanism of Ginger Oleoresin Against Pestalotiopsis microspora Isolated From Chinese Olive Fruits. AB - Pestalotiopsis microspora (P. microspora) is one of dominant pathogenic fungi causing rotten disease in harvested Chinese olive (Canarium album Lour.) fruits. The purposes of this study were to evaluate the antifungal activities of ginger oleoresin (GO) against P. microspora and to illuminate the underlying action mechanisms. The in vitro assays indicate that GO exhibited strong antifungal activity against mycelial growth of P. microspore, and with 50%-inhibition concentration (EC 50) and 90%-inhibition concentration (EC 90) at 2.04 MUL GO and 8.87 MUL GO per mL propylene glycol, respectively, while the minimal inhibitory concentration (MIC) and minimal fungicidal concentration were at 10 MUL GO and 30 MUL GO per mL propylene glycol, respectively. Spore germination of P. microspora was inhibited by GO in a dose-dependent manner, and with 100% inhibition rate at the concentration of 8 MUL GO per mL propylene glycol. Compared to the control, the cellular membrane permeability of P. microspora increased due to severe leakage of intercellular electrolytes, soluble proteins, and total sugars with the treatments (EC 50, EC 90) by GO during incubation. In addition, analysis of fatty acid contents and compositions in cellular membrane by GC-MS indicated that GO could significantly promote the degradation or peroxidation of unsaturated fatty acids in P. microspore, resulting in the enhancement of membrane fluidity. Moreover, observations of microstructure further showed the damage to plasma membrane and morphology of P. microspora caused by GO, which resulted in distortion, sunken and shriveled spores and mycelia of the pathogen. Furthermore, in vivo assay confirmed that over 3 MIC GO treatments remarkably suppressed disease development in P. microspore inoculated-Chinese olive fruit. These results demonstrate that owing to its strong antifungal activity, GO can be used as a promising antifungal agent to inhibit the growth of pathogenic fungi in Chinese olives. PMID- 30425699 TI - Efficient Production of the Dicarboxylic Acid Glutarate by Corynebacterium glutamicum via a Novel Synthetic Pathway. AB - The dicarboxylic acid glutarate is an important building-block gaining interest in the chemical and pharmaceutical industry. Here, a synthetic pathway for fermentative production of glutarate by the actinobacterium Corynebacterium glutamicum has been developed. The pathway does not require molecular oxygen and operates via lysine decarboyxylase followed by two transamination and two NAD dependent oxidation reactions. Using a genome-streamlined L-lysine producing strain as basis, metabolic engineering was performed to enable conversion of L lysine to glutarate in a five-step synthetic pathway comprising lysine decarboxylase, putrescine transaminase and gamma-aminobutyraldehyde dehydrogenase from Escherichia coli and GABA/5AVA amino transferase and succinate/glutarate semialdehyde dehydrogenase either from C. glutamicum or from three Pseudomonas species. Loss of carbon via formation of the by-products cadaverine and N acetylcadaverine was avoided by deletion of the respective acetylase and export genes. As the two transamination reactions in the synthetic glutarate biosynthesis pathway yield L-glutamate, biosynthesis of L-glutamate by glutamate dehydrogenase was expected to be obsolete and, indeed, deletion of its gene gdh increased glutarate titers by 10%. Glutarate production by the final strain was tested in bioreactors (n = 2) in order to investigate stability and reliability of the process. The most efficient glutarate production from glucose was achieved by fed-batch fermentation (n = 1) with a volumetric productivity of 0.32 g L-1 h 1, an overall yield of 0.17 g g-1 and a titer of 25 g L-1. PMID- 30425700 TI - Two Populations of Mites (Tyrophagus putrescentiae) Differ in Response to Feeding on Feces-Containing Diets. AB - Background: Tyrophagus putrescentiae is a ubiquitous mite species in soil, stored products and house dust and infests food and causes allergies in people. T. putrescentiae populations harbor different bacterial communities, including intracellular symbionts and gut bacteria. The spread of microorganisms via the fecal pellets of T. putrescentiae is a possibility that has not been studied in detail but may be an important means by which gut bacteria colonize subsequent generations of mites. Feces in soil may be a vector for the spread of microorganisms. Methods: Extracts from used mite culture medium (i.e., residual food, mite feces, and dead mite bodies) were used as a source of feces-inhabiting microorganisms as food for the mites. Two T. putrescentiae populations (L and P) were used for experiments, and they hosted the intracellular bacteria Cardinium and Wolbachia, respectively. The effects of the fecal fraction on respiration in a mite microcosm, mite nutrient contents, population growth and microbiome composition were evaluated. Results: Feces from the P population comprised more than 90% Bartonella-like sequences. Feces from the L population feces hosted Staphylococcus, Virgibacillus, Brevibacterium, Enterobacteriaceae, and Bacillus. The mites from the P population, but not the L population, exhibited increased bacterial respiration in the microcosms in comparison to no-mite controls. Both L and P-feces extracts had an inhibitory effect on the respiration of the microcosms, indicating antagonistic interactions within feces-associated bacteria. The mite microbiomes were resistant to the acquisition of new bacterial species from the feces, but their bacterial profiles were affected. Feeding of P mites on P-feces-enriched diets resulted in an increase in Bartonella abundance from 6 to 20% of the total bacterial sequences and a decrease in Bacillus abundance. The population growth was fivefold accelerated on P-feces extracts in comparison to the control. Conclusion: The mite microbiome, to a certain extent, resists the acquisition of new bacteria when mites are fed on feces of the same species. However, a Bartonella-like bacteria-feces-enriched diet seems to be beneficial for mite populations with symbiotic Bartonella-like bacteria. Coprophagy on the feces of its own population may be a mechanism of bacterial acquisition in T. putrescentiae. PMID- 30425701 TI - Transcriptome and Resistance-Related Genes Analysis of Botrytis cinerea B05.10 Strain to Different Selective Pressures of Cyprodinil and Fenhexamid. AB - The pathogen Botrytis cinerea is a very dangerous pathogen that infects many economically important crops such as grape, strawberry, tomato, and eggplant. Cyprodinil, a pyrimidine amine fungicide, and fenhexamid, an amide fungicide, are new reagents for controlling gray mold with special efficacy. It is necessary to understand the change trends in the toxicological and physiological characteristics of B. cinerea with successive selective pressures of cyprodinil and fenhexamid to elongate the serving life of these fungicides for effective disease control. The toxicities of cyprodinil and fenhexamid at successive concentrations of EC25, EC50 and EC75 on B. cinerea strain BO5.10 were assayed along with mycelial growth-inhibition capacity. The results showed that the EC50 value of the cyprodinil-treated F27 strain increased approximately 18-fold, whereas of which in the fenhexamid-treated F27 strain increased only 3-fold compared with that of the F0 strain. The conductivities and glycerinum contents of the strains resistant to cyprodinil and fenhexamid were obviously enhanced; in contrast, the oxalic acid contents were decreased compared with those in the F0 strain. The transcriptomes of the F27 control (T01), cyprodinil-treated (T02) and fenhexamid- treated (T03) strains were analyzed, and the expression levels of functional genes in the T02 and T03 strains were significantly increased compared with those in the T01 strain; these results were further validated using qRT-PCR. The results indicated that the relative expression of two genes encoding mixed functional oxidases (MFOs) BC1G_16062 and BC1G_16084, two genes encoding transmembrane proteins BC1G_12366 and BC1G_13768, two genes encoding Zinc finger proteins BC1G_13764 and BC1G_10483,one gene encoding citrate synthase enzyme BC1G_09151, one gene encoding gluconolactonase BC1G_15612 in the T02 and T03 strains and one gene encoding lysophospholipids enzyme BC1G_04893 in the T3 strain increased substantially compared with that in the T1 strain (P < 0.01). Functional prediction analysis of upregulated gene expression and structural verification was also performed, and the results showed that BC1G_10483 was a ZnF_C2HC transcriptional regulator interacting with the Sp1 element of these genes to respond to the pressures from cyprodinil and fenhexamid. Our results could contribute to a better understanding of the resistance mechanism of B. cinerea against cyprodinil and fenhexamid. PMID- 30425702 TI - Cytotoxicity and Survival Fitness of Invasive covS Mutant of Group A Streptococcus in Phagocytic Cells. AB - Group A streptococci (GAS) with spontaneous mutations in the CovR/CovS regulatory system are more invasive and related to severe manifestations. GAS can replicate inside phagocytic cells; therefore, phagocytic cells could serve as the niche to select invasive covS mutants. Nonetheless, the encapsulated covS mutant is resistant to phagocytosis. The fate of intracellular covS mutant in phagocytic cells and whether the intracellular covS mutant contributes to invasive infections are unclear. In this study, capsule-deficient (cap-) strains were utilized to study how intracellular bacteria interacted with phagocytic cells. Results from the competitive infection model showed that the cap- covS mutant had better survival fitness than the cap- wild-type strain in the PMA-activated U937 cells. In addition, the cap- covS mutant caused more cell damages than the cap- wild-type strain and encapsulated covS mutant. Furthermore, treatments with infected cells with clindamycin to inhibit the intracellular bacteria growth was more effective to reduce bacterial toxicity than utilized penicillin to kill the extracellular bacteria. These results not only suggest that the covS mutant could be selected from the intracellular niche of phagocytic cells but also indicating that inactivating or killing intracellular GAS may be critical to prevent invasive infection. PMID- 30425703 TI - Construction and Evaluation of a Korean Native Microbial Consortium for the Bioremediation of Diesel Fuel-Contaminated Soil in Korea. AB - A native microbial consortium for the bioremediation of soil contaminated with diesel fuel in Korea was constructed and its biodegradation ability was assessed. Microbial strains isolated from Korean terrestrial environments, with the potential to biodegrade aliphatic hydrocarbons, PAHs, and resins, were investigated and among them, eventually seven microbial strains, Acinetobacter oleivorans DR1, Corynebacterium sp. KSS-2, Pseudomonas sp. AS1, Pseudomonas sp. Neph5, Rhodococcus sp. KOS-1, Micrococcus sp. KSS-8, and Yarrowia sp. KSS-1 were selected for the construction of a microbial consortium based on their biodegradation ability, hydrophobicity, and emulsifying activity. Laboratory- and bulk-scale biodegradation tests showed that in diesel fuel-contaminated soil supplemented with nutrients (nitrogen and phosphorus), the microbial consortium clearly improved the biodegradation of total petroleum hydrocarbons, and all microbial strains constituting the microbial consortium, except for Yarrowia survived and grew well, which suggests that the microbial consortium can be used for the bioremediation of diesel fuel-contaminated soil in Korea. PMID- 30425704 TI - Reduction of Antibiotic Resistant Bacteria During Conventional and Advanced Wastewater Treatment, and the Disseminated Loads Released to the Environment. AB - The occurrence of new chemical and microbiological contaminants in the aquatic environment has become an issue of increasing environmental concern. Thus, wastewater treatment plants (WWTPs) play an important part in the distribution of so-called new emerging pathogens and antibiotic resistances. Therefore, the daily loads released by the WWTP were calculated including a model system for the distribution of these loads within the receiving water body. UV-, as well as ozone-treatment in separate or in combination for wastewater treatment were under investigation aiming at the reduction of these loads. Here, the impact of these treatments on the DNA integrity via antibody staining and PCR efficiencies experiments were included. All three facultative pathogenic bacteria [enterococci (23S rRNA), Pseudomonas aeruginosa (ecfX), and Escherichia coli (yccT)] and seven clinically relevant antibiotic resistance genes (ARGs) (mecA (methicillin resistance gene), ctx-M32 (beta- lactame resistance gene), ermB (erythromycine resistance gene), bla TEM (beta- lactame resistance gene), sul1 (sulfonamide resistance gene), vanA (vancomycin resistance gene), and intI1 (Integrase1 gene) associated with mobile genetic elements were detected in wastewaters. Different reduction efficiencies were analyzed during advanced wastewater treatments. ARGs were still found to be present in the effluents under the parameters of 1.0 g ozone per g dissolved organic carbon (DOC) and 400 J/m2, like ctx-M32, ermB, bla TEM, sul1, and intI1. Especially UV radiation induced thymidine dimerization which was analyzed via antibody mediated detection in the metagenome of the natural wastewater population. These specific DNA alterations were not observed during ozone treatment and combinations of UV/ozone treatment. The dimerization or potential other DNA alterations during UV treatment might be responsible for a decreased PCR efficiency of the 16S rRNA amplicons (176, 490, and 880 bp fragments) from natural metagenomes compared to the untreated sample. This impact on PCR efficiencies was also observed for the combination of ozone and UV treatment. PMID- 30425705 TI - Antimicrobial Activity of NCR Plant Peptides Strongly Depends on the Test Assays. AB - The symbiosis specific NCR247 and NCR335 cationic plant peptides of Medicago truncatula have been shown to exert antimicrobial activity against a wide range of microbes. However, their antimicrobial efficiency is clearly limited by divalent cations. Here, the antibacterial and antifungal activities of NCR247 and NCR335 peptides were compared to those of the well-characterized peptide antibiotics polymyxin B and the aminoglycoside streptomycin on three model microbes, Escherichia coli, Bacillus subtilis and Saccharomyces cerevisiae as representatives of Gram-negative and Gram-positive bacteria as well as eukaryotic fungi. The aim of the study was to assess how the killing efficiency of these peptides depends on various, widely used antimicrobial susceptibility assays. Validated resazurin microdilution assay was used to determine minimal growth inhibitory concentrations in three general test media (MHB, MHBII and low-salt medium LSM). Bactericidal/fungicidal activities were determined by the commonly used drop plate assay. The natural plant peptides showed distinct characteristics, NCR247 had a generally high sensitivity for Ca2+ and Mg2+ in the medium, while NCR335 proved to be a robust and strong antimicrobial agent with comparable efficiency values to polymyxin B. Activity data were confirmed visually, both NCR247 and NCR335 treatments at minimal bactericidal concentrations induced complete disruption of the membranes and provoked cell lysis on all tested microorganisms as observed by scanning electron microscopy. PMID- 30425707 TI - Genetic Signatures of Dairy Lactobacillus casei Group. AB - Lactobacillus casei/Lactobacillus paracasei group of species contains strains adapted to a wide range of environments, from dairy products to intestinal tract of animals and fermented vegetables. Understanding the gene acquisitions and losses that induced such different adaptations, implies a comparison between complete genomes, since evolutionary differences spread on the whole sequence. This study compared 12 complete genomes of L. casei/paracasei dairy-niche isolates and 7 genomes of L. casei/paracasei isolated from other habitats (i.e., corn silage, human intestine, sauerkraut, beef, congee). Phylogenetic tree construction and average nucleotide identity (ANI) metric showed a clustering of the two dairy L. casei strains ATCC393 and LC5, indicating a lower genetic relatedness in comparison to the other strains. Genomic analysis revealed a core of 313 genes shared by dairy and non-dairy Lactic Acid bacteria (LAB), within a pan-genome of 9,462 genes. Functional category analyses highlighted the evolutionary genes decay of dairy isolates, particularly considering carbohydrates and amino acids metabolisms. Specifically, dairy L. casei/paracasei strains lost the ability to metabolize myo-inositol and taurine (i.e., iol and tau gene clusters). However, gene acquisitions by dairy strains were also highlighted, mostly related to defense mechanisms and host-pathogen interactions (i.e., yueB, esaA, and sle1). This study aimed to be a preliminary investigation on dairy and non-dairy marker genes that could be further characterized for probiotics or food applications. PMID- 30425708 TI - Allergen Exposure in Lymphopenic Fas-Deficient Mice Results in Persistent Eosinophilia Due to Defects in Resolution of Inflammation. AB - Asthma is characterized by chronic airway type-2 inflammation and eosinophilia, yet the mechanisms involved in chronic, non-resolving inflammation remain poorly defined. Previously, our group has found that when Rag-deficient mice were reconstituted with Fas-deficient B6 LPR T cells and sensitized and challenged, the mice developed a prolonged type-2-mediated airway inflammation that continued for more than 6 weeks after the last antigen exposure. Surprisingly, no defect in resolution was found when intact B6 LPR mice or T cell specific Fas-conditional knockout mice were sensitized and challenged. We hypothesize that the homeostatic proliferation induced by adoptive transfer of T cells into Rag-deficient mice may be an important mechanism involved in the lack of resolution. To investigate the role of homeostatic proliferation, we induced lymphopenia in the T cell-specific Fas-conditional knockout mice by non-lethal irradiation and sensitized them when T cells began to repopulate. Interestingly, we found that defective Fas signaling on T cells plus antigen exposure during homeostatic proliferation was sufficient to induce prolonged eosinophilic airway inflammation. In conclusion, our data show that the combination of transient lymphopenia, abnormal Fas-signaling, and antigen exposure leads to the development of a prolonged airway eosinophilic inflammatory phase in our mouse model of experimental asthma. PMID- 30425706 TI - The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy. AB - Impaired lung function is common in people with a history of tuberculosis. Host directed therapy added to tuberculosis treatment may reduce lung damage and result in improved lung function. An understanding of the pathogenesis of pulmonary damage in TB is fundamental to successfully predicting which interventions could be beneficial. In this review, we describe the different features of TB immunopathology that lead to impaired lung function, namely cavities, bronchiectasis, and fibrosis. We discuss the immunological processes that cause lung damage, focusing on studies performed in humans, and using chest radiograph abnormalities as a marker for pulmonary damage. We highlight the roles of matrix metalloproteinases, neutrophils, eicosanoids and cytokines, like tumor necrosis factor-alpha and interleukin 1beta, as well as the role of HIV co infection. Finally, we focus on various existing drugs that affect one or more of the immunological mediators of lung damage and could therefore play a role as host-directed therapy. PMID- 30425709 TI - GDF15 Regulates Malat-1 Circular RNA and Inactivates NFkappaB Signaling Leading to Immune Tolerogenic DCs for Preventing Alloimmune Rejection in Heart Transplantation. AB - Recombinant human growth differentiation factor 15 (rhGDF15) affects dendritic cell (DC) maturation. However, whether GDF15 is expressed in DCs and its roles and signaling in DCs remain largely unknown. It is unclear whether GDF15-DCs can induce immune tolerance in heart transplantation (HT). This study aims to understand the impact of endogenous GDF15 on DC's development, function, underlying molecular mechanism including circular RNA (circRNA). This study will also explore GDF15-DC-mediated immune modulation in HT. Bone marrow (BM) derived DCs were cultured and treated to up- or down regulate GDF15 expression. Phenotype and function of DCs were detected. Expression of genes and circRNAs was determined by qRT-PCR. The signaling pathways activated by GDF15 were examined. The impact of GDF15 treated DCs on preventing allograft immune rejection was assessed in a MHC full mismatch mouse HT model. Our results showed that GDF15 was expressed in DCs. Knockout of GDF15 promoted DC maturation, enhanced immune responsive functions, up-regulated malat-1 circular RNA (circ_Malat 1), and activated the nuclear factor kappa B (NFkappaB) pathway. Overexpression of GDF15 in DCs increased immunosuppressive/inhibitory molecules, enhanced DCs to induce T cell exhaustion, and promoted Treg generation through IDO signaling. GDF15 utilized transforming growth factor (TGF) beta receptors I and II, not GFAL. Administration of GDF15 treated DCs prevented allograft rejection and induced immune tolerance in transplantation. In conclusion, GDF15 induces tolerogenic DCs (Tol-DCs) through inhibition of circ_Malat-1 and the NFkappaB signaling pathway and up-regulation of IDO. GDF15-DCs can prevent alloimmune rejection in HT. PMID- 30425711 TI - Heterologous Boost Following Mycobacterium bovis BCG Reduces the Late Persistent, Rather Than the Early Stage of Intranasal Tuberculosis Challenge Infection. AB - Adults are the leading population affected by tuberculosis (TB) epidemic and death. Developing an effective vaccine against adult TB is urgently needed. Mycobacterium bovis Bacillus Calmette-Guerin (BCG) prime-heterologous boost strategy has been explored extensively to protect adults against primary TB infection, but the majority of experimental regimens have not improved the protection primed by the BCG vaccine. The reason attributed to the failure remains unknown. In this study, CTT3H-based vaccines, namely DMT adjuvanted CTT3H subunit or DNA vaccine (pCTT3H-DMT), and recombinant adenovirus rAdCTT3H were constructed. Protective efficacy and immunogenicity of BCG prime-CTT3H based boosters were compared in C57BL/c mice models of primary or late persistent TB infection. Similar protective efficacy against early intranasal infection was provided by different CTT3H-based vaccines alone in vaccinated mice, and their protection was inferior to that of the BCG vaccine. In addition, CTT3H-based heterologous boosters did not enhance the protection conferred by the BCG vaccine against primary infection. However, all of these three boosters provided stronger protection against late persistent TB infection than BCG alone, regardless of vaccine types. Although BCG prime-boosters elicited Th1-biased responses to the antigen CTT3H, the number of CTT3H-sepcific IFN-gamma-expressing TEM (CD62LloCD44hi) and IL-2-expressing TCM (CD62LhiCD44hi) cells in the spleen was not improved before exposure to Mycobacterium tuberculosis infection. In contrast, IFN-gamma+ TEM and IL-2+ TCM cells in spleens, especially in lungs were significantly increased in BCG prime-boosters after exposure vaccination. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against late persistent TB infection by induction of IFN-gamma+ TEM and IL-2+ TCM cells in the lung, which can be used as alternative biomarkers for guiding the clinical practice and future development of TB vaccine for adults. PMID- 30425710 TI - The Role of CD1d and MR1 Restricted T Cells in the Liver. AB - The liver is one of the most important immunological organs that remains tolerogenic in homeostasis yet promotes rapid responses to pathogens in the presence of a systemic infection. The composition of leucocytes in the liver is highly distinct from that of the blood and other lymphoid organs, particularly with respect to enrichment of innate T cells, i.e., invariant NKT cells (iNKT cells) and Mucosal-Associated Invariant T cells (MAIT cells). In recent years, studies have revealed insights into their biology and potential roles in maintaining the immune-environment in the liver. As the primary liver-resident immune cells, they are emerging as significant players in the human immune system and are associated with an increasing number of clinical diseases. As such, innate T cells are promising targets for modifying host defense and inflammation of various liver diseases, including viral, autoimmune, and those of tumor origin. In this review, we emphasize and discuss some of the recent discoveries and advances in the biology of innate T cells, their recruitment and diversity in the liver, and their role in various liver diseases, postulating on their potential application in immunotherapy. PMID- 30425712 TI - Regulatory T Cells Suppress Effector T Cell Proliferation by Limiting Division Destiny. AB - Understanding how the strength of an effector T cell response is regulated is a fundamental problem in immunology with implications for immunity to pathogens, autoimmunity, and immunotherapy. The initial magnitude of the T cell response is determined by the sum of independent signals from antigen, co-stimulation and cytokines. By applying quantitative methods, the contribution of each signal to the number of divisions T cells undergo (division destiny) can be measured, and the resultant exponential increase in response magnitude accurately calculated. CD4+CD25+Foxp3+ regulatory T cells suppress self-reactive T cell responses and limit pathogen-directed immune responses before bystander damage occurs. Using a quantitative modeling framework to measure T cell signal integration and response, we show that Tregs modulate division destiny, rather than directly increasing the rate of death or delaying interdivision times. The quantitative effect of Tregs could be mimicked by modulating the availability of stimulatory co-stimuli and cytokines or through the addition of inhibitory signals. Thus, our analysis illustrates the primary effect of Tregs on the magnitude of effector T cell responses is mediated by modifying division destiny of responding cell populations. PMID- 30425713 TI - How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins. AB - Four inflammatory diseases are strongly associated with Major Histocompatibility Complex class I (MHC-I) molecules: birdshot chorioretinopathy (HLA-A*29:02), ankylosing spondylitis (HLA-B*27), Behcet's disease (HLA-B*51), and psoriasis (HLA-C*06:02). The endoplasmic reticulum aminopeptidases (ERAP) 1 and 2 are also risk factors for these diseases. Since both enzymes are involved in the final processing steps of MHC-I ligands it is reasonable to assume that MHC-I-bound peptides play a significant pathogenetic role. This review will mainly focus on recent studies concerning the effects of ERAP1 and ERAP2 polymorphism and expression on shaping the peptidome of disease-associated MHC-I molecules in live cells. These studies will be discussed in the context of the distinct mechanisms and substrate preferences of both enzymes, their different patterns of genetic association with various diseases, the role of polymorphisms determining changes in enzymatic activity or expression levels, and the distinct peptidomes of disease-associated MHC-I allotypes. ERAP1 and ERAP2 polymorphism and expression induce significant changes in multiple MHC-I-bound peptidomes. These changes are MHC allotype-specific and, without excluding a degree of functional inter dependence between both enzymes, reflect largely separate roles in their processing of MHC-I ligands. The studies reviewed here provide a molecular basis for the distinct patterns of genetic association of ERAP1 and ERAP2 with disease and for the pathogenetic role of peptides. The allotype-dependent alterations induced on distinct peptidomes may explain that the joint association of both enzymes and unrelated MHC-I alleles influence different pathological outcomes. PMID- 30425715 TI - Reactive Oxygen Species as Regulators of MDSC-Mediated Immune Suppression. AB - Reactive oxygen species (ROS) molecules are implicated in signal transduction pathways and thereby control a range of biological activities. Immune cells are constantly confronted with ROS molecules under both physiologic and pathogenic conditions. Myeloid-derived suppressor cells (MDSCs) are immunosuppressive, immature myeloid cells and serve as major regulators of pathogenic and inflammatory immune responses. In addition to their own release of ROS, MDSCs often arise in oxidative-stress prone environments such as in tumors or during inflammation and infection. This evidently close relationship between MDSCs and ROS prompted us to summarize what is currently known about ROS signaling within MDSCs and to elucidate how MDSCs use ROS to modulate other immune cells. ROS not only activate anti-oxidative pathways but also induce transcriptional programs that regulate the fate and function of MDSCs. Furthermore, MDSCs release ROS molecules as part of a major mechanism to suppress T cell responses. Targeting redox-regulation of MDSCs thus presents a promising approach to cancer therapy and the role of redox-signaling in MDSCs in other disease states such as infection, inflammation and autoimmunity would appear to be well worth investigating. PMID- 30425714 TI - Cross-Talk Between Iron and Glucose Metabolism in the Establishment of Disease Tolerance. AB - Infectious diseases are associated with disruption of host homeostasis. This can be triggered directly by pathogens or indirectly by host immune-driven resistance mechanisms. Disease tolerance is a defense strategy against infection that sustains host homeostasis, without exerting a direct negative impact on pathogens. The mechanisms governing disease tolerance encompass host metabolic responses that maintain vital homeostatic parameters within a range compatible with survival. Central to this defense strategy is the host's ability to sense and adapt to variations in nutrients, such as iron and glucose. Here we address how host responses regulating iron and glucose metabolism interact to establish disease tolerance and possibly modulate resistance to infection. PMID- 30425717 TI - Commentary: Arguing for Adaptive Clinical Trials in Sepsis. PMID- 30425716 TI - Precise Delineation and Transcriptional Characterization of Bovine Blood Dendritic-Cell and Monocyte Subsets. AB - A clear-cut delineation of bovine bona fide dendritic cells (DC) from monocytes has proved challenging, given the high phenotypic and functional plasticity of these innate immune cells and the marked phenotypic differences between species. Here, we demonstrate that, based on expression of Flt3, CD172a, CD13, and CD4, a precise identification of bovine blood conventional DC type 1 and 2 (cDC1, cDC2), plasmacytoid DC (pDC), and monocytes is possible with cDC1 being Flt3+CD172adimCD13+CD4-, cDC2 being Flt3+CD172a+CD13-CD4-, pDC being Flt3+CD172adimCD13-CD4+, and monocytes being Flt3-CD172ahighCD13-CD4-. The phenotype of these subsets was characterized in further detail, and a subset specific differential expression of CD2, CD5, CD11b, CD11c, CD14, CD16, CD26, CD62L, CD71, CD163, and CD205 was found. Subset identity was confirmed by transcriptomic analysis and subset-specific transcription of conserved key genes. We also sorted monocyte subsets based on their differential expression of CD14 and CD16. Classical monocytes (CD14+CD16-) clustered clearly apart from the two CD16+ monocyte subsets probably representing intermediate and non-classical monocytes described in human. The transcriptomic data also revealed differential gene transcription for molecules involved in antigen presentation, pathogen sensing, and migration, and therefore gives insights into functional differences between bovine DC and monocyte subsets. The identification of cell-type- and subset-specific gene transcription will assist in the quest for "marker molecules" that-when targeted by flow cytometry-will greatly facilitate research on bovine DC and monocytes. Overall, species comparisons will elucidate basic principles of DC and monocyte biology and will help to translate experimental findings from one species to another. PMID- 30425718 TI - CD3+CD4+LAP+Foxp3-Regulatory Cells of the Colonic Lamina Propria Limit Disease Extension in Ulcerative Colitis. AB - Background and Aims: In ulcerative colitis (UC), inflammation begins in the rectum and can extend proximally throughout the entire colon. The extension of inflammation is an important determinant of disease course, and may be limited by the action of regulatory T cells (Tregs). In this cross-sectional study, we evaluated the relationship between UC extension and the proportions of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3-Tregs in the colonic lamina propria (LP) of 79 UC patients and 29 controls. The role of these cells in UC extension was also investigated in the murine oxazolone-induced colitis model. Methods: Patients: Disease extension was classified according to the Montreal classification. Where possible, endoscopic biopsies of involved and uninvolved tissue were obtained from UC patients. Mouse model: Colitis was induced by intrarectal oxazolone administration. Lamina propria mononuclear cells were isolated from patient biopsies and mouse colon tissue using enzymatic method and the percentage of CD3+CD4+Foxp3+ and CD3+CD4+LAP+Foxp3-cells evaluated by immunofluorescence. Confocal microscopy was applied for the visualization and quantification of CD4+LAP+ cells on tissue histological sections. Results: In UC patients with distal colitis the proportion of LP CD3+CD4+Foxp3+ Tregs was significantly higher in inflamed tissue than uninvolved tissue. As opposite, the proportion of LP CD3+CD4+LAP+ Tregs was significantly higher in uninvolved tissue than involved tissue. Both LP CD3+CD4+Foxp3+ and LP CD3+CD4+LAP+ Tregs proportion in involved tissue was significantly higher than in controls irrespective of the extension of inflammation. In mice with oxazolone-induced distal colitis, treatment with LAP depleting antibody was associated with the development of extensive colitis. Conclusions: Our findings suggest that CD3+CD4+LAP+Foxp3-Tregs limit the extension of inflammatory lesions in UC patients. PMID- 30425719 TI - A Novel Derivative of the Natural Product Danshensu Suppresses Inflammatory Responses to Alleviate Caerulein-Induced Acute Pancreatitis. AB - Acute pancreatitis (AP), a common abdominal inflammatory disorder, is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. Although the mechanism remains to be fully understood, inflammation is the main cause of pancreatic damage in AP. A novel compound [4-(2-acetoxy-3-((R)-3-(benzylthio)-1 methoxy-1-oxopropan-2-ylamino)-3-oxopropyl)-1,2-phenylene diacetate (DSC)], derived from danshensu, exhibits anti-inflammatory and anti-apoptotic properties in vitro. However, its potential beneficial effect in AP has not been demonstrated. This study aimed to investigate the effects and underlying mechanisms of DSC in experimental AP in mice. We found that DSC suppressed inflammatory responses in AP by inhibiting the activation of nuclear factor kappaB (NF-kappaB), signal transducer and activator of transcription 3 (STAT3) and nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome. Furthermore, treatment with DSC modulated the infiltration of neutrophils and the phenotypes of macrophages in mice induced with AP. Interestingly, we found that the expression of nuclear factor-erythroid 2 related factor 2 (Nrf2) and its regulated antioxidant enzyme heme oxygenase-1 (HO-1), which modulate inflammatory activities, was significantly increased in DSC-treated groups. Together, our findings demonstrate that DSC alleviates pancreatic inflammation and damage in AP by inhibiting the activation of NF kappaB, STAT3, and NLRP3 inflammasome and modulating immune cell responses. PMID- 30425720 TI - Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. AB - Adenosine is a potent immunosuppressive purine metabolite contributing to the pathogenesis of solid tumors. Extracellular adenosine signals on tumor infiltrating NK cells to inhibit their proliferation, maturation, and cytotoxic function. Cytokine priming imparts upon NK cells distinct activation statuses, which modulate NK anti-tumor immunity and responses to purinergic metabolism. Here, for the first time, we investigated human NK cell responses to adenosinergic signaling in the context of distinct cytokine priming programs. NK cells were shown to be hyper-responsive to adenosine when primed with IL-12 and IL-15 compared to IL-2, exhibiting enhanced IFN-gamma expression from CD56bright and CD56dim subsets while modulating the expression of activation marker NKG2D. These responses resulted in signaling that was dependent on mTOR. Adenosine induced upregulation of transcriptional signatures for genes involved in immune responses while downregulating cellular metabolism and other protein synthesis functions that correlate to inhibited oxidative phosphorylation and glycolysis. Overall, our findings show that adenosine acts on specific cellular pathways rather than inducing a broad inhibition of NK cell functions. These responses are dependent on cytokine priming signatures and are important in designing therapeutic interventions that can reprogram NK cell immunometabolism for improved immunotherapies of solid tumors. PMID- 30425721 TI - QTL Mapping of Six Spike and Stem Traits in Hybrid Population of Agropyron Gaertn. in Multiple Environments. AB - Most Agropyron Gaertn. species are excellent sources of forage. The derivative lines of wheat-Agropyron cristatum show elite agronomic traits, and some are valuable for wheat breeding. The species of Agropyron Gaertn. was mainly recognized by the spike morphology in traditional taxon. Six traits, including spike length (SL), ear stem length (ESL), the second internodes length (SIL), spikelet number per spike (SNS), floret number per spikelet (FNS), and grain number per spikelet (GNS), are vital to morphology studies and also influences the forage crop yield. To elucidate the genetic basis of spike and stem traits, a quantitative trait locus (QTL) analysis was conducted in a cross-pollinated (CP) hybrid population derived from a cross between two diverse parents, Agropyron mongolicum Keng Z2098 and A. cristatum (L.) Gaertn. Z1842, evaluated across three ecotopes (Langfang, Changli, and Guyuan of Hebei, China) over 3 years (from 2014 to 2016). Construction of a high-density linkage map was based on 1,023 single nucleotide polymorphism (SNP) markers, covering 907.8 cM of the whole Agropyron genome. A total of 306 QTLs with single QTL in different environments explaining 0.07-33.21% of the phenotypic variation were detected for study traits. Seven major-effect QTLs were identified, including one for ESL on chromosome 3, one for SIL on chromosome 5, three for SL (two on chromosome 2 and one on chromosome 4), and two for SNS on chromosomes 3 and 7. Also, seven stable QTLs, including four for ESL, one for SL, one for GNS, and one for FNS, were mainly mapped on chromosomes 2, 3, 4, 5, and 7, respectively, elucidating 0.25-14.98% of the phenotypic variations. On the use of Agropyron CP hybrid population to identify QTL determining spike and stem traits for the first time, these QTLs for six traits would provide a theoretical reference for the molecular marker-assisted selection in the improvement of forage and cereal crop species. PMID- 30425722 TI - Modification of Cassava Root Starch Phosphorylation Enhances Starch Functional Properties. AB - Cassava (Manihot esculenta Crantz) is a root crop used as a foodstuff and as a starch source in industry. Starch functional properties are influenced by many structural features including the relative amounts of the two glucan polymers amylopectin and amylose, the branched structure of amylopectin, starch granule size and the presence of covalent modifications. Starch phosphorylation, where phosphates are linked either to the C3 or C6 carbon atoms of amylopectin glucosyl residues, is a naturally occurring modification known to be important for starch remobilization. The degree of phosphorylation has been altered in several crops using biotechnological approaches to change expression of the starch phosphorylating enzyme GLUCAN WATER DIKINASE (GWD). Interestingly, this frequently alters other structural features of starch beside its phosphate content. Here, we aimed to alter starch phosphorylation in cassava storage roots either by manipulating the expression of the starch phosphorylating or dephosphorylating enzymes. Therefore, we generated transgenic plants in which either the wild-type potato GWD (StGWD) or a redox-insensitive version of it were overexpressed. Further plants were created in which we used RNAi to silence each of the endogenous phosphoglucan phosphatase genes STARCH EXCESS 4 (MeSEX4) and LIKE SEX4 2 (MeLSF), previously discovered by analyzing leaf starch metabolism in the model species Arabidopsis thaliana. Overexpressing the potato GWD gene (StGWD), which specifically phosphorylates the C6 position, increased the total starch-bound phosphate content at both the C6 and the C3 positions. Silencing endogenous LSF2 gene (MeLSF2), which specifically dephosphorylates the C3 position, increased the ratio of C3:C6 phosphorylation, showing that its function is conserved in storage tissues. In both cases, other structural features of starch (amylopectin structure, amylose content and starch granule size) were unaltered. This allowed us to directly relate the physicochemical properties of the starch to its phosphate content or phosphorylation pattern. Starch swelling power and paste clarity were specifically influenced by total phosphate content. However, phosphate position did not significantly influence starch functional properties. In conclusion, biotechnological manipulation of starch phosphorylation can specifically alter certain cassava storage root starch properties, potentially increasing its value in food and non-food industries. PMID- 30425723 TI - Resurrecting the Regulatory Properties of the Ostreococcus tauri ADP-Glucose Pyrophosphorylase Large Subunit. AB - ADP-glucose pyrophosphorylase (ADP-Glc PPase) catalyzes the first committed step for the synthesis of glycogen in cyanobacteria and starch in green algae and plants. The enzyme from cyanobacteria is homotetrameric (alpha4), while that from green algae and plants is heterotetrameric (alpha2beta2). These ADP-Glc PPases are allosterically regulated by 3-phosphoglycerate (3PGA, activator) and inorganic orthophosphate (Pi, inhibitor). Previous studies on the cyanobacterial and plant enzymes showed that 3PGA binds to two highly conserved Lys residues located in the C-terminal domain. We observed that both Lys residues are present in the small (alpha) subunit of the Ostreococcus tauri enzyme; however, one of these Lys residues is replaced by Arg in the large (beta) subunit. In this work, we obtained the K443R and R466K mutants of the O. tauri small and large subunits, respectively, and co-expressed them together or with their corresponding wild type counterparts. Our results show that restoring the Lys residue in the large subunit enhanced 3PGA affinity, whereas introduction of an Arg residue in the small subunit reduced 3PGA affinity of the heterotetramers. Inhibition kinetics also showed that heterotetramers containing the K443R small subunit mutant were less sensitive to Pi inhibition, but only minor changes were observed for those containing the R466K large subunit mutant, suggesting a leading role of the small subunit for Pi inhibition of the heterotetramer. We conclude that, during evolution, the ADP-Glc PPase large subunit from green algae and plants acquired mutations in its regulatory site. The rationale for this could have been to accommodate sensitivity to particular metabolic needs of the cell or tissue. PMID- 30425724 TI - Developing Biostimulants From Agro-Food and Industrial By-Products. AB - In modern agriculture, seeking eco-friendly ways to promote plant growth and enhance crop productivity is of priority. Biostimulants are a group of substances from natural origin that contribute to boosting plant yield and nutrient uptake, while reducing the dependency on chemical fertilizers. Developing biostimulants from by-products paves the path to waste recycling and reduction, generating benefits for growers, food industry, registration and distribution companies, as well as consumers. The criteria to select designated by-products for valorizing as biostimulant are: absence of pesticide residue, low cost of collection and storage, sufficient supply and synergy with other valorization paths. Over the years, projects on national and international levels such as NOSHAN, SUNNIVA, and Bio2Bio have been initiated (i) to explore valorization of by-products for food and agriculture industries; (ii) to investigate mode of action of biostimulants from organic waste streams. Several classes of waste-derived biostimulants or raw organic material with biostimulant components were shown to be effective in agriculture and horticulture, including vermicompost, composted urban waste, sewage sludge, protein hydrolysate, and chitin/chitosan derivatives. As the global market for biostimulants continues to rise, it is expected that more research and development will expand the list of biostimulants from by-products. Global nutrient imbalance also requires biostimulant to be developed for targeted market. Here, we review examples of biostimulants derived from agricultural by products and discuss why agricultural biomass is a particularly valuable source for the development of new agrochemical products. PMID- 30425725 TI - A Holistic Approach to Analyze Systemic Jasmonate Accumulation in Individual Leaves of Arabidopsis Rosettes Upon Wounding. AB - Phytohormones, especially jasmonates, are known to be mediators of the plant responses to wounding and herbivore feeding. Their role in such stress responses has been largely studied locally in treated leaves. However, less is known about the induced systemic distribution of phytohormone signals upon these kinds of stresses. Here, a holistic approach was performed in order to investigate the systemic phytohormone pattern in the rosette of Arabidopsis thaliana after herbivore-related wounding. Levels of different stress-related phytohormones such as jasmonates, abscisic acid, and salicylic acid were analyzed in individual leaves. We demonstrate that the typically used sampling method, where leaves are first cut and immediately frozen, causes false-positive results since cutting already induces systemic jasmonate elevations within less than 1.6 min. Therefore, this approach is not suitable to study systemic phytohormone changes in the whole plant. By developing a new method where leaves are frozen first and subsequently cut, sampling-induced phytohormone elevations could be reduced. Using this new method, we show that jasmonic acid and its active isoleucine conjugate (jasmonoyl-isoleucine) are involved in the fast systemic wound response of Arabidopsis. A systemic induction of the jasmonates' precursor, 12-oxo phytodienoic acid, was not observed throughout our treatments. The systemic phytohormone distribution pattern is strongly linked to the vascular connections between the leaves, providing further evidence that the vascular system is used for long distance-signaling in Arabidopsis. Besides already known vascular connections, we also demonstrate that the systemic distribution of jasmonate signals can be extended to distant leaves, which are systemically but indirectly connected via another vascularly connected leaf. This holistic approach covering almost the whole Arabidopsis rosette introduces a method to overcome false positive results in systemic phytohormone determinations and demonstrates that wounding-induced long-distance signaling includes fast changes in jasmonate levels in systemic, non-treated leaves. PMID- 30425726 TI - Legacy Effects of Climate Extremes in Alpine Grassland. AB - Climate change is particularly apparent in many mountainous regions, with warming rates of more than twice the global average being reported for the European Alps. As a result, the probability of climate extremes has increased and is expected to rise further. In an earlier study, we looked into immediate impacts of experimentally imposed heat waves in alpine grassland, and found that these systems were able to cope with heat as long as enough water was available. However, concomitant drought led to increased stress, and reduced aboveground biomass production and green plant cover. Here, we studied the legacy effects (lag-effects) of the imposed climate extreme to see whether delayed responses occurred and how fast the alpine grassland could rebound from the initial changes. Green cover continued to be suppressed the two following years in communities that had been exposed to the most intense hot drought, while aboveground biomass production had returned to control levels by year 2. The initial lower resistance of the forb fraction in the communities was not compensated by faster recovery later on. This resulted in alpine communities that became (and remained) relatively enriched with graminoids, which resisted the original extreme better. The responses of alpine grassland to heat extremes with or without drought observed in this study resemble those typically found in lowland grassland in the short term. However, alpine grassland exhibited longer legacy effects from an annual perspective, with delayed recovery of aboveground production and persistent changes in community composition. This suggests that once initial resistance thresholds are exceeded, impacts may be longer-lasting in alpine grassland, where recovery is constrained by both the short growing season and difficult seedling establishment. PMID- 30425727 TI - Expression Profiles of Phosphoenolpyruvate Carboxylase and Phosphoenolpyruvate Carboxylase Kinase Genes in Phalaenopsis, Implications for Regulating the Performance of Crassulacean Acid Metabolism. AB - Phalaenopsis is one of the most important potted plants in the ornamental market of the world. Previous reports implied that crassulacean acid metabolism (CAM) orchids at their young seedling stages might perform C3 or weak CAM photosynthetic pathways, but the detailed molecular evidence is still lacking. In this study, we used a key species in white Phalaenopsis breeding line, Phalaenopsis aphrodite subsp. formosana, to study the ontogenetical changes of CAM performance in Phalaenopsis. Based on the investigations of rhythms of day/night CO2 exchange, malate contents and phosphoenolpyruvate carboxylase (PEPC) activities, it is suggested that a progressive shift from C3 to CAM occurred as the protocorms differentiated the first leaf. To understand the role of phosphoenolpyruvate carboxylase kinase (PEPC kinase) in relation to its target PEPC in CAM performance in Phalaenopsis, the expression profiles of the genes encoding PEPC (PPC) and PEPC kinase (PPCK) were measured in different developmental stages. In Phalaenopsis, two PPC isogenes were constitutively expressed over a 24-h cycle similar to the housekeeping genes in all stages, whereas the significant day/night difference in PaPPCK expression corresponds to the day/night fluctuations in PEPC activity and malate level. These results suggest that the PaPPCK gene product is most likely involved in regulation of CAM performance in different developmental stages of Phalaenopsis seedlings. PMID- 30425728 TI - Fibroblast Growth Factor 10 in Pancreas Development and Pancreatic Cancer. AB - The tenacious prevalence of human pancreatic diseases such as diabetes mellitus and adenocarcinoma has prompted huge research interest in better understanding of pancreatic organogenesis. The plethora of signaling pathways involved in pancreas development is activated in a highly coordinated manner to assure unmitigated development and morphogenesis in vertebrates. Therefore, a complex mesenchymal epithelial signaling network has been implicated to play a pivotal role in organogenesis through its interactions with other germ layers, specifically the endoderm. The Fibroblast Growth Factor Receptor FGFR2-IIIb splicing isoform (FGFR2b) and its high affinity ligand Fibroblast Growth Factor 10 (FGF10) are expressed in the epithelium and mesenchyme, respectively, and therefore are well positioned to transmit mesenchymal to epithelial signaling. FGF10 is a typical paracrine FGF and chiefly mediates biological responses by activating FGFR2b with heparin/heparan sulfate (HS) as cofactor. A substantial number of studies using genetically engineered mouse models have demonstrated an essential role of FGF10 in the development of many organs and tissues including the pancreas. During mouse embryonic development, FGF10 signaling is crucial for epithelial cell proliferation, maintenance of progenitor cell fate and branching morphogenesis in the pancreas. FGF10 is also implicated in pancreatic cancer, and that overexpression of FGFR2b is associated with metastatic invasion. A thorough understanding of FGF10 signaling machinery and its crosstalk with other pathways in development and pathological states may provide novel opportunities for pancreatic cancer targeted therapy and regenerative medicine. PMID- 30425729 TI - Exploring the Impact of Single-Nucleotide Polymorphisms on Translation. AB - Over the past 15 years, sequencing of the human genome and The Cancer Genome Atlas (TCGA) project have led to comprehensive lists of single-nucleotide polymorphisms (SNPs) and gene mutations across a large number of human samples. However, our ability to predict the functional impact of SNPs and mutations on gene expression is still in its infancy. Here, we provide key examples to help understand how mutations present in genes can affect translational output. PMID- 30425730 TI - Mediterranean Diet and Particulate Matter Exposure Are Associated With LINE-1 Methylation: Results From a Cross-Sectional Study in Women. AB - Emerging evidence suggests that air pollution increases the risk of cardiovascular disease (CVD) and metabolic disorders, adding to the global burden of disease attributable to lifestyle and behavioral factors. Although long interspersed nucleotide elements 1 (LINE-1) methylation has been associated with these disorders, no studies have simultaneously examined the effects of diet and air pollution exposure on DNA methylation. Herein, we evaluated the association of particulate matter (PM with aerodynamic diameters of less than 10 mm) exposure and adherence to Mediterranean Diet (MD) with LINE-1 methylation. Healthy women (n = 299), aged 15 to 80 years, were enrolled in a cross-sectional study. Dietary data and adherence to MD were assessed by a Food Frequency Questionnaire (FFQ) and Mediterranean Diet Score (MDS). PM10 levels during 1-month before recruitment were recorded by monitoring stations and assigned to each woman based on their residential address and day of recruitment. LINE-1 methylation in blood samples was assessed by pyrosequencing and reported as percentage of 5-methylcytosine (5mC). The Mann-Whitney U test, Spearman's rank correlation test and linear regression models were applied. Our results demonstrated, for the first time, an inverse association between adherence to MD and exposure to PM10 with LINE-1 methylation: while higher monthly PM10 exposure decreases LINE-1 methylation level (beta = -0.121; p = 0.037), the adherence to MD increases it (beta = 0.691; p < 0.001). MDS seemed to interact with PM10 levels (p = 0.002) on LINE-1 methylation, as such we confirmed that the effect of MD decreased with increasing PM10 levels (beta = 0.657; p < 0.001 in the first tertile; beta = 0.573; p < 0.001 in the second tertile; beta = 0.551; p < 0.001 in the third tertile). Thus, we suggest that LINE-1 methylation is a possible mechanism underpinning environment-related health effects, and encourage further research to evaluate whether the adherence to the MD could counteract the negative effect of PM10 exposure. PMID- 30425732 TI - Corrigendum to "Effect of Carboxylic Functional Group Functionalized on Carbon Nanotubes Surface on the Removal of Lead from Water". AB - [This corrects the article DOI: 10.1155/2010/603978.]. PMID- 30425731 TI - Characterization of Duck (Anas platyrhynchos) Short Tandem Repeat Variation by Population-Scale Genome Resequencing. AB - Short tandem repeats (STRs) are usually associated with genetic diseases and gene regulatory functions, and are also important genetic markers for analysis of evolutionary, genetic diversity and forensic. However, for the majority of STRs in the duck genome, their population genetic properties and functional impacts remain poorly defined. Recent advent of next generation sequencing (NGS) has offered an opportunity for profiling large numbers of polymorphic STRs. Here, we reported a population-scale analysis of STR variation using genome resequencing in mallard and Pekin duck. Our analysis provided the first genome-wide duck STR reference including 198,022 STR loci with motif size of 2-6 base pairs. We observed a relatively uneven distribution of STRs in different genomic regions, which indicates that the occurrence of STRs in duck genome is not random, but undergoes a directional selection pressure. Using genome resequencing data of 23 mallard and 26 Pekin ducks, we successfully identified 89,891 polymorphic STR loci. Intensive analysis of this dataset suggested that shorter repeat motif, longer reference tract length, higher purity, and residing outside of a coding region are all associated with an increase in STR variability. STR genotypes were utilized for population genetic analysis, and the results showed that population structure and divergence patterns among population groups can be efficiently captured. In addition, comparison between Pekin duck and mallard identified 3,122 STRs with extremely divergent allele frequency, which overlapped with a set of genes related to nervous system, energy metabolism and behavior. The evolutionary analysis revealed that the genes containing divergent STRs may play important roles in phenotypic changes during duck domestication. The variation analysis of STRs in population scale provides valuable resource for future study of genetic diversity and genome evolution in duck. PMID- 30425733 TI - A Many-Objective Optimization Algorithm Based on Weight Vector Adjustment. AB - In order to improve the convergence and distribution of a many-objective evolutionary algorithm, this paper proposes an improved NSGA-III algorithm based on weight vector adjustment (called NSGA-III-WA). First, an adaptive weight vector adjustment strategy is proposed to decompose the objective space into several subspaces. According to different subspace densities, the weight vector is sparse or densely adjusted to ensure the uniformity of the weight vector distribution on the Pareto front surface. Secondly, the evolutionary model that combines the new differential evolution strategy and genetic evolution strategy is proposed to generate new individuals and enhance the exploration ability of the weight vector in each subspace. The proposed algorithm is tested on the optimization problem of 3-15 objectives on the DTLZ standard test set and WFG test instances, and it is compared with the five algorithms with better effect. In this paper, the Whitney-Wilcoxon rank-sum test is used to test the significance of the algorithm. The experimental results show that NSGA-III-WA has a good effect in terms of convergence and distribution. PMID- 30425734 TI - Information Literacy Assessment with a Modified Hybrid Differential Evolution with Model-Based Reinitialization. AB - Information literacy assessment is extremely important for the evaluation of the information literacy skills of college students. Intelligent optimization technique is an effective strategy to optimize the weight parameters of the information literacy assessment index system (ILAIS). In this paper, a new version of differential evolution algorithm (DE), named hybrid differential evolution with model-based reinitialization (HDEMR), is proposed to accurately fit the weight parameters of ILAIS. The main contributions of this paper are as follows: firstly, an improved contraction criterion which is based on the population entropy in objective space and the maximum distance in decision space is employed to decide when the local search starts. Secondly, a modified model based population reinitialization strategy is designed to enhance the global search ability of HDEMR to handle complex problems. Two types of experiments are designed to assess the performance of HDEMR. In the first type of experiments, HDEMR is tested and compared with seven well-known DE variants on CEC2005 and CEC2014 benchmark functions. In the second type of experiments, HDEMR is compared with the well-known and widely used deterministic algorithm DIRECT on GKLS test classes. The experimental results demonstrate the effectiveness of HDEMR for global numerical optimization and show better performance. Furthermore, HDEMR is applied to optimize the weight parameters of ILAIS at China University of Geosciences (CUG), and satisfactory results are obtained. PMID- 30425736 TI - Synaptic Plasticity Changes: Hallmark for Neurological and Psychiatric Disorders. PMID- 30425735 TI - No Modulatory Effects when Stimulating the Right Inferior Frontal Gyrus with Continuous 6 Hz tACS and tRNS on Response Inhibition: A Behavioral Study. AB - Response inhibition is the cognitive process required to cancel an intended action. During that process, a "go" reaction is intercepted particularly by the right inferior frontal gyrus (rIFG) and presupplementary motor area (pre-SMA). After the commission of inhibition errors, theta activity (4-8 Hz) is related to the adaption processes. In this study, we intend to examine whether the boosting of theta activity by electrical stimulation over rIFG reduces the number of errors and the reaction times in a response inhibition task (Go/NoGo paradigm) during and after stimulation. 23 healthy right-handed adults participated in the study. In three separate sessions, theta tACS at 6 Hz, transcranial random noise (tRNS) as a second stimulation condition, and sham stimulation were applied for 20 minutes. Based on behavioral data, this study could not show any effects of 6 Hz tACS as well as full spectrum tRNS on response inhibition in any of the conditions. Since many findings support the relevance of the rIFG for response inhibition, this could mean that 6 Hz activity is not important for response inhibition in that structure. Reasons for our null findings could also lie in the stimulation parameters, such as the electrode montage or the stimulation frequency, which are discussed in this article in more detail. Sharing negative findings will have (1) positive impact on future research questions and study design and will improve (2) knowledge acquisition of noninvasive transcranial brain stimulation techniques. PMID- 30425737 TI - Only Surgical Treatment to Be Considered for Adhesive Small Bowel Obstruction: A New Paradigm. AB - Background: Adhesive small bowel obstruction (SBO) represents a heavy burden in healthcare systems worldwide and is associated with significant morbidity and mortality. Although conservative treatment alone can lead to SBO resolution in most cases, its optimal duration is still a matter of debate. The aim of this study was to analyze different SBO evolution patterns in order to further determine when to switch to surgical treatment. Study Design: All patients who were admitted for adhesive SBO between 2011 and 2016 were reviewed. Patients who had immediate surgery (IS), a successful medical treatment (SMT), and a failed medical treatment (FMT) were compared in terms of overall morbidity, mortality, and SBO recurrence. Results: Overall 154 patients were identified, including 23 (14.9%) in IS, 27 (17.5%) in FMT, and 104 (67.6%) in SMT groups. In terms of comorbidities, patients were similar in all groups. Overall morbidity rates were highest in IS and FMT groups (30% and 33%, respectively, vs. 4% in the SMT group, p < 0.001) whereas mortality rate was highest in the FMT group (22% vs. 0% and 0% in IS and SMT groups, respectively, p < 0.001). SBO recurrence rate was highest in the SMT group (22% vs. 4% and 7% in IS and FMT groups, respectively, p = 0.042). Conclusion: FMT seems to be associated with similar overall morbidity compared with IS but with increased postoperative mortality. Patient frailty seems to be worsened by prolonged inefficient medical treatment. PMID- 30425739 TI - Biosorption of Cadmium by Filamentous Fungi Isolated from Coastal Water and Sediments. AB - The use of microorganisms in decontaminating the environment encumbered with heavy metal pollutants through biosorption is considered as a good option for bioremediation. This study was conducted to isolate Cadmium (Cd) tolerant fungi from coastal waters and sediments, compare their biosorption capabilities, and identify the isolates with the highest Cd uptake. Water and sediment samples were collected near the effluent sites of industrial belt in Ibo, Lapu-lapu City, Cebu, Philippines. Potato dextrose agar (PDA) plates containing Cd (25, 50, 75, and 100 ppm) were used to isolate Cd tolerant fungi from the samples. The distinct colonies that grew on the highest Cd concentration (100 ppm) were then isolated into pure cultures. The pure cultures of Cd tolerant fungi served as a source of inocula for in vitro biosorption assay using Cd dissolved in potato dextrose broth (PDB) as the substrate. Cd tolerant fungal isolates with the highest Cd uptake were finally identified up to the lowest possible taxon based on their colonial and microscopic characteristics. Most filamentous fungal colonies have grown most at the lower Cd concentrations and least at the higher concentrations. From the characteristics of the fungal growth on the plate with the highest Cd concentration, eight distinct colonies from both sediment and water samples were isolated into pure cultures. Among the eight fungal isolates, only three had significant Cd biosorption efficiency, these were fungal isolate 3 (13.87 %), fungal isolate 6 (11.46 %), and fungal isolate 4 (10.71 %). Two of them (fungal isolates 3 and 4) belong to genus Aspergillus while the other (fungal isolate 6) is a species of Penicillium. The results of this study showed that Cd tolerant fungi with biosorption capacity could be isolated from coastal water and sediments in the vicinity of areas suspected of heavy metal contamination. PMID- 30425740 TI - Corrigendum to "Chronic Glucocorticoid-Rich Milieu and Liver Dysfunction". AB - [This corrects the article DOI: 10.1155/2016/7838290.]. PMID- 30425738 TI - Role of Phytoremediation in Reducing Cadmium Toxicity in Soil and Water. AB - Heavy metals are a noxious form of pollutants present in soil and water. A new plant-based solar energy driven technology, phytoremediation, emerges as eco friendly and cost-effective approach to remove heavy metal from various media with the help of hyperaccumulating plant species. This review paper aims to provide information on phytoremediation and its mechanisms for heavy metal removal especially to focus on Cadmium (Cd) metal and highlights the role of various hyperaccumulating plants for Cd metal remediation in soil and water. It complies various field case studies which play the important role in understanding the Cd removal through various plants. Additionally, it pinpoints several sources and the effects of Cd and other technologies used for Cd remediation. This paper provides the recent development in mechanisms of Cd hyperaccumulation by different plants, in order to motivate further research in this field. PMID- 30425741 TI - Characteristics and Outcomes of 79 Patients with an Insulinoma: A Nationwide Retrospective Study in Finland. AB - Objective: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. Results: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas. PMID- 30425743 TI - Corrigendum to "Expression of Intratumoral IGF-II Is Regulated by the Gene Imprinting Status in Triple Negative Breast Cancer from Vietnamese Patients". AB - [This corrects the article DOI: 10.1155/2015/401851.]. PMID- 30425744 TI - Three-Dimensional Changes of the Auditory Canal in a Three-Year Period during Adolescence Using CBCTs. AB - Purpose: There is a lack of identifying suitable regions in the head that can be used for three-dimensional superimposition techniques. For this reason, with the use of cone-beam computed tomography (CBCT), the ear canals were analyzed to verify changes during a period of three years in the adolescent years. Methods: CBCTs from fifty-six patients (ages: 10 to 20) were used to landmark the anatomy of the ear canals. Each patient was analyzed using two CBCT reconstructions that were taken approximately three years apart. AVIZO(r) software was used to locate 28 landmarks distributed following the ear canal path and foramina (ovale, spinosum, rotundum, etc.) in the cranial base to obtain spatial relationships. Three-dimensional coordinates were obtained from the landmarks, and the average distance between various landmark pairings was calculated. The repeated measure ANCOVA was used to determine statistical significance. Results: In the main data set, the largest mean distance change was found to be 4.37 mm +/- 18.29 mm between the left foramen ovale and the left superior medial ear canal opening. The smallest mean distance change was 0.18 mm +/- 3.25 mm between the right inferior lateral ear canal opening and the right inferior medial ear canal opening. Conclusions: During the adolescent years, the ear canal presents dimensional changes. Even though in different areas throughout the canal, the average distances were minor, still, large standard deviations were present; thus, caution should be taken when trying to use this structure for superimposition of CBCTs. PMID- 30425742 TI - Is Atorvastatin Associated with New Onset Diabetes or Deterioration of Glycemic Control? Systematic Review Using Data from 1.9 Million Patients. AB - Background: Current evidence indicates that statins increase the risk of new onset diabetes mellitus (NOD) and also deteriorate the glycemic control in patients with known diabetes mellitus (DM) after high-dose statin therapy. Aims: The aim of this review was to explore the effect of atorvastatin in causing NOD or deteriorating glycemic control in patients with DM. Methods: Two independent reviewers conducted the literature search, through PubMed database searching for articles published in English until April 2015, and only primary studies were included. Results: Of the 919 articles identified in our original search, 33 met the criteria for this review encompassing 1,951,113 participants. Twenty articles examined dysregulation of DM due to atorvastatin. Half of them showed that there was no significant change in glycemic control in patients treated with atorvastatin. Other studies showed that fasting plasma glucose and HbA1c levels were increased by atorvastatin. Thirteen articles examined if atorvastatin causes NOD. The majority of these articles showed that patients who used atorvastatin had a higher dose-dependent risk of developing NOD. Conclusion: This systematic review suggests that there is an association between atorvastatin treatment and NOD. Moreover, it showed that atorvastatin in high dose causes worsening of the glycemic control in patients with DM. PMID- 30425745 TI - Sinking Skin Flap Syndrome: Phenomenon of Neurological Deterioration after Decompressive Craniectomy. AB - Sinking skin flap syndrome is rare phenomenon that occurs in patients with large craniectomies. Alteration in normal anatomy and pathophysiology can result in wide variety of symptoms including altered mental status, hemodynamic instability, and dysautonomias. Management is largely conservative. We here present a case of a patient with large craniectomy who was admitted to our hospital with pneumonia. Later on, he developed worsening mental status and CT head revealed sinking skin flap with significant midline shift. This is a very rare case of neurological deterioration after craniectomies, commonly known as sinking skin flap syndrome. To our knowledge, only few cases have been reported so far. PMID- 30425746 TI - The Effect of Chronic Inflammation and Oxidative and Endoplasmic Reticulum Stress in the Course of Metabolic Syndrome and Its Therapy. AB - Metabolic syndrome (MetS) is highly associated with a modern lifestyle. The prevalence of MetS has reached epidemic proportion and is still rising. The main cause of MetS and finally type 2 diabetes occurrence is excessive nutrient intake, lack of physical activity, and inflammatory cytokines secretion. These factors lead to redistribution of body fat and oxidative and endoplasmic reticulum (ER) stress occurrence, resulting in insulin resistance, increase adipocyte differentiation, and much elevated levels of proinflammatory cytokines. Cellular therapies, especially mesenchymal stem cell (MSC) transplantation, seem to be promising in the MetS and type 2 diabetes treatments, due to their immunomodulatory effect and multipotent capacity; adipose-derived stem cells (ASCs) play a crucial role in MSC-based cellular therapies. In this review, we focused on etiopathology of MetS, especially on the crosstalk between chronic inflammation, oxidative stress, and ER stress and their effect on MetS-related disease occurrence, as well as future perspectives of cellular therapies. We also provide an overview of therapeutic approaches that target endoplasmic reticulum and oxidative stress. PMID- 30425748 TI - Qi-Deficiency Related Increases in Disease Susceptibility Are Potentially Mediated by the Intestinal Microbiota. AB - Qi-deficiency (QX) is thought to promote the body's susceptibility to disease, but the underlying mechanism through which this occurs is not clear. We surveyed the traditional Chinese medicine constitution (TCMC) of healthy college students to identify those that were PH (balanced TCMC constitution) and QX (unbalanced TCMC constitution). We then used high-throughput sequencing of the 16SrRNA V3-4 region in fecal microbiota samples to identify differences between those obtained from PH and QX individuals. Our results demonstrated that the alpha diversity of QX samples was significantly lower than that of PH samples (p < 0.05) and that beta diversity was remarkably different in QX and PH samples. Four and 122 bacterial taxa were significantly overrepresented in QX and PH groups, respectively. The genera Sphingobium, Clostridium, and Comamonas were enriched in the QX group and had a certain pathogenic role. The QX group also showed a statistically significant lack of probiotics and anti-inflammatory bacteria such as Bifidobacterium and Bdellovibrio. The functional potential of QX bacterial taxa was reduced in fatty acid metabolism and butanoate metabolism. We contend that the imbalanced intestinal microbiota in QX and the following functional changes in metabolism influence immunity and energy metabolism, which could increase susceptibility to disease. PMID- 30425747 TI - The Differential Effects of Leukocyte-Containing and Pure Platelet-Rich Plasma on Nucleus Pulposus-Derived Mesenchymal Stem Cells: Implications for the Clinical Treatment of Intervertebral Disc Degeneration. AB - Background: Platelet-rich plasma (PRP) is a promising strategy for intervertebral disc degeneration. However, the potential harmful effects of leukocytes in PRP on nucleus pulposus-derived mesenchymal stem cells (NPMSCs) have seldom been studied. This study aimed at comparatively evaluating effects of pure platelet rich plasma (P-PRP) and leukocyte-containing platelet-rich plasma (L-PRP) on rabbit NPMSCs in vitro. Methods: NPMSCs isolated from rabbit NP tissues were treated with L-PRP or P-PRP in vitro, and then cell proliferation and expression of stem cell markers, proinflammatory cytokines (TNF-alpha, IL-1beta), production of ECM (extracellular matrix-related protein), and NF-kappaB p65 protein were validated by CCK-8 assay, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and western blot respectively. Results: NPMSCs differentiate into nucleus pulposus-like cells after treatment of PRPs (P PRP and L-PRP), and NPMSCs exhibited maximum proliferation at a 10% PRP dose. L PRP had observably higher concentration of leukocytes, TNF-alpha, and IL-1beta than P-PRP. Furthermore, compared to P-PRP, L-PRP induced the differentiated NPMSCs to upregulate the expression of TNF-alpha and IL-1beta, enhanced activation of the NF-kappaB pathway, increased the expression of MMP-1 and MMP 13, and produced less ECM in differentiated NPMSCs. Conclusions: Both P-PRP and L PRP can induce the proliferation and NP-differentiation of NPMSCs. Compared to L PRP, P-PRP can avoid the activation of the NF-kappaB pathway, thus reducing the inflammatory and catabolic responses. PMID- 30425749 TI - Electroacupuncture: A Feasible Sirt1 Promoter Which Modulates Metainflammation in Diet-Induced Obesity Rats. AB - It is generally accepted that metainflammation, a state of chronic and low-grade inflammation in obesity, plays a great role in metabolic disorder like insulin resistance. To gain further insight into the mechanism of metainflammation and find feasible therapy of obesity, diet-induced obesity (DIO) rats model and Electroacupuncture (EA) treatment were established in this trail. The results indicated that rising Lee's index, hyperlipidemia, insulin resistance, and increasing inflammation factors including NF-kappaB, TNF-alpha, and Macrophages 1 were determined in DIO rats while EA is exhibiting an effective intervention. Furthermore, to clarify this phenomenon and provide new recognition of alternative medicine for the treatment of metainflammation, we found that EA activating Sirt1 and Sirt1-dependent deacetylation of histone (H3K9) was the key of modulation. It should be noted that, while possible, the activating of Sirt1 could lead to deacetylation of NF-kappaB also. In this study, the deacetylation of NF-kappaB depended on higher level of Sirt1 than H3K9, which suggested that the deacetylation via Sirt1 in metainflammation could be specific and programmed. PMID- 30425750 TI - Mutual Information Better Quantifies Brain Network Architecture in Children with Epilepsy. AB - Purpose: Metrics of the brain network architecture derived from resting-state fMRI have been shown to provide physiologically meaningful markers of IQ in children with epilepsy. However, traditional measures of functional connectivity (FC), specifically the Pearson correlation, assume a dominant linear relationship between BOLD time courses; this assumption may not be valid. Mutual information is an alternative measure of FC which has shown promise in the study of complex networks due to its ability to flexibly capture association of diverse forms. We aimed to compare network metrics derived from mutual information-defined FC to those derived from traditional correlation in terms of their capacity to predict patient-level IQ. Materials and Methods: Patients were retrospectively identified with the following: (1) focal epilepsy; (2) resting-state fMRI; and (3) full scale IQ by a neuropsychologist. Brain network nodes were defined by anatomic parcellation. Parcellation was performed at the size threshold of 350 mm2, resulting in networks containing 780 nodes. Whole-brain, weighted graphs were then constructed according to the pairwise connectivity between nodes. In the traditional condition, edges (connections) between each pair of nodes were defined as the absolute value of the Pearson correlation coefficient between their BOLD time courses. In the mutual information condition, edges were defined as the mutual information between time courses. The following metrics were then calculated for each weighted graph: clustering coefficient, modularity, characteristic path length, and global efficiency. A machine learning algorithm was used to predict the IQ of each individual based on their network metrics. Prediction accuracy was assessed as the fractional variation explained for each condition. Results: Twenty-four patients met the inclusion criteria (age: 8-18 years). All brain networks demonstrated expected small-world properties. Network metrics derived from mutual information-defined FC significantly outperformed the use of the Pearson correlation. Specifically, fractional variation explained was 49% (95% CI: 46%, 51%) for the mutual information method; the Pearson correlation demonstrated a variation of 17% (95% CI: 13%, 19%). Conclusion: Mutual information-defined functional connectivity captures physiologically relevant features of the brain network better than correlation. Clinical Relevance: Optimizing the capacity to predict cognitive phenotypes at the patient level is a necessary step toward the clinical utility of network-based biomarkers. PMID- 30425752 TI - Serum Uric Acid as an Independent Risk Factor for the Presence and Severity of Early-Onset Coronary Artery Disease: A Case-Control Study. AB - Serum uric acid (UA) is the final product of purine metabolism in humans. The present study is aimed at identifying the potential association between serum UA and early-onset coronary artery disease (EOCAD). The study population consisted of 1093 EOCAD patients aged <=50 years, and 1117 age- and sex-matched apparently healthy people served as controls. The concentrations of UA were measured by uricase method. The severity of CAD was evaluated by Gensini score. The mean serum level of UA was 5.843 +/- 1.479 mg/dl in EOCAD patients and 5.433 +/- 1.529 mg/dl in controls. Serum UA levels were significantly higher in the EOCAD group than those in the control group (P < 0.001) and was an independent risk factor for EOCAD (OR = 1.100, 95% CI: 1.022-1.185). The early-onset myocardial infarction patients with 3-vessel disease had higher serum UA levels than those with 1- or 2-vessel disease. The serum UA levels of EOCAD patients with acute coronary syndrome were significantly higher than those with chronic coronary artery disease. EOCAD patients with hyperuricemia had higher Gensini scores than those without hyperuricemia. In addition, the serum UA levels were affected by drinking (P < 0.01) and were positively correlated with serum creatinine (r = 0.323) and weight (r = 0.327). Our results show that serum UA was an independent risk factor for EOCAD. The serum UA levels were associated with the presence and severity of EOCAD and suggested that UA may be involved in the progression of EOCAD. PMID- 30425751 TI - Apathy Is Correlated with Widespread Diffusion Tensor Imaging (DTI) Impairment in Amyotrophic Lateral Sclerosis. AB - Apathy is recognized as the most common behavioral change in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), a multisystem neurodegenerative disorder. Particularly, apathy has been reported to be associated with poor ALS prognosis. However, the brain microstructural correlates of this behavioral symptom, reported as the most common in ALS, have not been completely elucidated. Using diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS), here we aimed to quantify the correlation between brain microstructural damage and apathy scores in the early stages of ALS. Twenty-one consecutive ALS patients, in King's clinical stage 1 or 2, and 19 age- and sex-matched healthy controls (HCs) underwent magnetic resonance imaging and neuropsychological examination. Between-group comparisons did not show any significant difference on cognitive and behavioral variables. When compared to HCs, ALS patients exhibited a decreased fractional anisotropy (FA) [p < .05, threshold-free cluster enhancement (TFCE) corrected] in the corpus callosum and in bilateral anterior cingulate cortices. Self-rated Apathy Evaluation Scale (AES) scores and self-rated apathy T-scores of the Frontal Systems Behavior (FrSBe) scale were found inversely correlated to FA measures (p < .05, TFCE corrected) in widespread white matter (WM) areas, including several associative fiber tracts in the frontal, temporal, and parietal lobes. These results point towards an early microstructural degeneration of brain areas biologically involved in cognition and behavior regulation in ALS. Moreover, the significant correlations between apathy and DTI measures in several brain areas may suggest that subtle WM changes may be associated with mild behavioral symptoms in ALS even in the absence of overt cognitive and behavioral impairment. PMID- 30425753 TI - Comment on "Systematic Review and Meta-Analysis of Diagnostic Accuracy of miRNAs in Patients with Pancreatic Cancer". PMID- 30425754 TI - Intrabullous Adhesion Pexia (IBAP) by Percutaneous Pulmonary Bulla Centesis: An Alternative for the Surgical Treatment of Giant Pulmonary Bulla (GPB). AB - Background and Objective: Most patients with giant pulmonary bulla (GPB) are treated by surgery; however, there is a subset for whom surgery is not a viable option, such as those with contraindications, or those unwilling to undergo operation. Therefore, an alternative minimally invasive method is desired for this subpopulation. The aim of this study was to explore an alternative procedure for treating GPB. Methods: This was a prospective, nonrandomized, single-arm, unblinded study evaluating the efficacy and safety of intrabulla adhesion pexia (IBAP) procedure in GPB patients. The study was conducted between December 2004 and April 2017. Results: There were 38 cases in 36 patients (33 males and 3 females) with the target GPB cavities varying in size (range, 10 cm * 7 cm * 5 cm to 15 cm * 8 cm * 30 cm (anteroposterior diameter * medial-lateral diameter * superoinferior diameter)). After IBAP treatment, the closure ratio of GPB in one month was 86.84% (33/38), while the dyspnea index significantly decreased from 4.11 +/- 1.11 to 2.24 +/- 1.15 (P < 0.01). In addition, the mean FEV1 (L) increased from 1.06 +/- 0.73 to 1.57 +/- 1.13 (P < 0.01), while RV (L) decreased from 2.77 +/- 0.54 to 2.36 +/- 0.38 (P < 0.01) and TLC (L) decreased from 6.46 +/ 1.21 to 5.86 +/- 1.08 (P < 0.01). Moreover, PaO2 (mmHg) increased from 52.18 +/- 8.31 to 68.29 +/- 12.34, while the 6 MWD increased by 129.36% from 131.58 +/- 105.24 to 301.79 +/- 197.90 (P < 0.01). Collectively, these data indicated significant improvement in pulmonary function and exercise tolerance after IBAP treatment. Furthermore, no deaths occurred during IBAP treatment, and no cases of aggravated GPB relapse were reported during the 12-month follow-up period. Conclusions: IBAP is a promising strategy for the treatment of GPB. Our findings demonstrated that IBAP had a noteworthy therapeutic effect, desirable safety, and ideal long-term efficacy for GPB. PMID- 30425756 TI - Which Seems to Be Worst? Pain Severity and Quality of Life between Patients with Lateral Hip Pain and Low Back Pain. AB - Purpose: The aim of this study was to compare the pain severity, health-related quality of life (HRQoL), and risk of continue having pain with prognostic risk scores (PRS), between patients referring greater trochanteric pain syndrome (GTPS) and chronic low back pain (CLBP). Methods: A descriptive, cross-sectional design using nonprobability convenience sampling was performed. A total sample of 102 patients were recruited from two primary health-care centers and divided into GTPS (n = 51) and CLBP (n = 51) groups. The primary outcome was pain severity which was assessed with the Spanish version of the Graded Chronic Pain Scale (GCPS). The secondary outcome was the HRQoL which was measured using the Spanish version of EuroQoL Five Dimensions and Five Levels (EQ-5D-5L) as well as the PRS. Results: Significant differences (P<0.05) were found within both groups in the pain severity global score with a medium effect size showing greater values for the CLBP group with regards to the GTPS group. The PRS in both groups did not show statistical differences (P>0.05). Nevertheless, subjects referring CLBP showed greater levels in the PRS than patients with GTPS. Comparing both groups, the HRQoL showed statistical differences (P<0.05) in the "pain/discomfort" domain in the CLBP group with respect to the GTPS group, but not in the other domains. Conclusions: Patients who suffered from CLBP showed greater pain severity and HRQoL discomfort with regard to patients with GTPS. Despite greater scores for CLBP, the PRS did not seem to be different between both conditions. PMID- 30425757 TI - Biovigilance for the Quality and Safety of Medical Products of Human Origin. AB - Progress in science and technology in the health services has led to the development of methods of regenerating and replacing solid organs, tissues and cells, using human body components to create medical products of human origin intended for clinical use. In the activities in which products of human origin are used, however, from the point of donation and harvesting to the subsequent care of the recipient, medical products of human origin are exposed to the risk of specific complications related to the transmission of infectious diseases, and further side-effects. Biovigilance system application is a basic requirement for ensuring the quality and safety of tissues and cells intended for human use. The quality system focuses on error prevention, maintaining a consistent pattern of agreed assays for tissues and cells intended for clinical use. The implementation of quality and safety standards, the development of medical protocols and cooperation protocols between member states, the implementation of Single European Code (SEC), and the development of electronic traceability systems, all aim at vigilance and the surveillance of medical products of human origin from donation to transplantation. PMID- 30425755 TI - The Patient-Reported Outcomes Thermometer-5-Item Scale (5T-PROs): Validation of a New Tool for the Quick Assessment of Overall Health Status in Painful Rheumatic Diseases. AB - Objective: To investigate the construct validity, reliability (internal consistency and retest reliability), and feasibility of the patient-reported outcomes thermometer-5-item scale (5T-PROs), a new tool to measure overall health status in patients with painful chronic rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axialSpA), and fibromyalgia (FM). Methods: Consecutive patients have been involved in this study. The following analyses were performed to establish the validity of the 5T PROs: (1) principal component factor analysis was used to identify the presence of a relatively small number of underlying latent factors than can be used to represent relations among sets of many variables; (2) Cronbach's alpha was calculated as an indicator of internal consistency; and (3) Pearson product moment correlations were conducted to assess the convergent validity. The 5T-PROs was also administered a second time (two weeks after the initial administration) to a subset of sample (n = 426) to allow for calculation of test-retest reliability. We used the intraclass correlation coefficient (ICC) as an estimate of test-retest reliability. Additionally, discriminant validity was tested using analysis of variance (ANOVA) with Bonferroni post hoc multiple comparisons, in different disease conditions. Feasibility was analyzed by the time taken in completing the 5T-PROs and the proportion of patients able to complete the 5 item. Results: 1,199 patients (572 with RA, 251 with axialSpA, 150 with PsA, and 226 with FM) were examined. The mean age was 55.7 (standard deviation: 13.1; range: 20 to 80) years. Factor analysis yielded two factors which accounted for 62.54% of the variance of the 5T-PROs. The first factor "Symptom Summary Score" (35.57% of the variance) revealed a good internal consistency (alpha = 0.88); the internal consistency of the second factor "Psychological Summary Score" (26.97% of the variance) was moderate (alpha = 0.69). The reliability of the whole instrument was good (alpha = 0.82). A very high correlation was obtained between Symptom Summary Score and SF-36 PCS and between pain thermometer intensity and SF 36 bodily pain. For all five items and summary scale scores of the SF-36, there was strong evidence that the mean rank of the scores differs significantly between the groups (Kruskal-Wallis tests, p < 0.001). Discriminant validity, assessed by comparing the 5T-PRO dimensions in patients with different states of disease activity, showed that the 5T-PROs show moderate association with the presence of comorbidities. It was also noted that it was inversely correlated (p=0.01) to years of formal education. Conclusion: The 5T-PROs is easily administered, reliable and a valid instrument for evaluating the extensive multidimensional impact associated with chronic painful rheumatic conditions. PMID- 30425758 TI - The Effects of Geography on Outcomes of Routine Early Versus Selective Late Revascularization Strategy in the Treatment of Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: A Meta-Analysis of Transatlantic Randomized Controlled Trials. AB - Background: The optimal timing of revascularization in unstable angina (UA) or non-ST-segment elevation myocardial infarction (NSTEMI) remains uncertain. We compared routine early revascularization (REV) versus selective late revascularization (SLR) strategies and divergence in the approach of cardiologists in the United States and Europe. Methods: Seventeen randomized controlled trials (RCTs) (15,812 patients) were extracted from PubMed, Cochrane Library, EMBASE and Web of Science databases. The data were pooled using the Der Simonian and Laird random-effect models and expressed as pooled risk ratios (RR) with 95% confidence intervals (95% CIs). Results: Overall, there was no difference in all-cause mortality (RR: 1.01, 95% CI: 0.95 - 1.08, P = 0.7), myocardial infarction (MI) (RR: 0.98, 95% CI: 0.79 - 1.22, P = 0.85) or coronary artery bypass grafting (CABG) (RR: 1.33, 95% CI: 0.92 - 1.91, P = 0.12) between REV and SLR strategy. There were trends of decreased incidence of MI in REV, 13.3% (1,029/7,704) vs. 15.1% (1,108/7,314) in SLR (P = 0.007), and rate of CABG was higher in REV, 4.9% (140/2,831) vs. 3.7% (105/2,819) in SLR (P = 0.031). There were trends of lower all-cause mortality in the combined US/international trials in both REV 8.4% (390/4,624) vs. 22.8% (908/3,975) (P < 0.001) and SLR 8% (359/4,421) vs. 24% (910/3,808) (P < 0.001) compared to the European trials. There were also trends of lower rates of MI in the European trials in the REV group 20% (623/3,080) vs. 25% (712/2,893) in SLR (P = 0.001) and higher rates of CABG in REV 8.3% (96/1,144) vs. 5.7% (67/1,165) in SLR (P = 0.02); however, there were no significant effects in the pooled RR ratios even after subgroup analysis between US/international trials and European trials. Conclusions: Despite having contemporary differences in the management approach towards UA/NSTEMI patients, no significant differences in trends were observed with REV strategy in US/international trials vs. European trials. PMID- 30425760 TI - Clinical Usefulness of the Cardio-Ankle Vascular Index as a Predictor of Primary Cardiovascular Events in Patients With Chronic Kidney Disease. AB - Background: The cardio-ankle vascular index (CAVI) is a physiologic marker reflecting arterial function. There have been no prospective studies investigating the relationship between CAVI and cardiovascular events in patients with chronic kidney disease (CKD). The aim of this prospective study was to assess the clinical usefulness of CAVI as a predictor of primary cardiovascular events in patients with CKD. Methods: The study enrolled 460 outpatients with CKD but no history of cardiovascular disease (152 men and 308 women; mean +/- standard deviation age, 74 +/- 12 years). Patients were assigned to one of three groups: low (L, CAVI < 9; n = 100), medium (M, CAVI 9 - 10; n = 199), or high (H, CAVI > 10; n = 161). The utility of the CAVI as a predictor of primary cardiovascular events was evaluated. Results: During the follow-up period (median 60.1 months), major adverse cardiovascular events (MACE) occurred in 91 cases (L, 8 (8.0%); M, 31 (15.6%); H, 52 (32.3%); P < 0.001, log-rank test). On multivariate Cox regression analysis, the risk for a MACE was significantly higher in group H than in non-group H (hazard ratio, 2.04; 95% confidence interval, 1.31 - 3.02; P < 0.01). A CAVI cut-off of 9.7 yielded the largest area under the curve, 0.701 (95% confidence interval: 0.657 - 0.743, P < 0.001), indicating a sensitivity of 74.0% and a specificity of 59.6% for discriminating between those who did and did not experience a MACE during follow-up. Conclusions: The results of this study showed that a high CAVI is a predictor of primary cardiovascular events in patients with CKD. PMID- 30425759 TI - Present Status and Perspectives on Future Roles of Japanese Clinical Research Coordinators. AB - Background: The new Clinical Trials Act that recently came into effect in Japan emphasizes the reliability of investigator-initiated clinical trials. Although Japanese clinical research coordinators have been mainly engaged in operational roles in industry-initiated clinical trials for drug approval (registration trials), broadening their contribution to cover more types of clinical research may lead to quality improvement of clinical research. To ultimately establish a clinical research infrastructure that meets the needs of the new era of Clinical Trials Act, here we gathered basic information on how clinical research coordinators might make such contributions. Methods: We conducted a survey using self-reporting questionnaires in clinical research-related personnel to examine present status and the perspectives toward broader contribution of clinical research coordinators. The study participants were attendee of group discussion of a clinical research-related meeting in Shikoku area of Japan held in August 2017. Results: Among 88 participants, 69 responded (response rate: 78.4%) and 68 respondents (98.6%) were engaged in support and management of clinical research. The main area of involvement was industry-initiated registration trials (48, 69.7%), and main roles of involvement were cooperators who plays roles under the guidance of investigators (41, 59.5%). When divided by occupation into clinical research coordinators (n = 41) and other clinical research-related personnel (n = 28), approximately half of the respondents in each group replied positively to wanting broader involvement of clinical research coordinators as a clinical research professional. Conclusion: The present study revealed that about half of the clinical research coordinators and other clinical research-related personnel view a broadening of involvement of clinical research coordinators in research activities positively. Accordingly, a structured practical program aimed at encouraging such involvement may help to expand and strengthen their contribution into the future. Whether greater involvement of clinical research coordinators in clinical research will help to ensure the reliability of investigator-initiated clinical research warrants further study. PMID- 30425761 TI - Mycoplasma Pneumoniae Pneumonia: Walking Pneumonia Can Cripple the Susceptible. AB - Background: Mycoplasma pneumoniae pneumonia (MPP), or "walking pneumonia," is an atypical mild disease with varied clinical findings. Specifically, diagnosis is often controversial and understanding of disease presentation is limited. The goal of the study was to evaluate presentation, clinical associations and outcomes of MPP patients admitted to an inner-city hospital. Methods: This was a retrospective analysis of adult patients diagnosed with MPP from January 2010 to January 2017. Primary outcomes were need for intensive care unit (ICU) care, ICU and hospital length of stay (LOS), presence of shock and need for mechanical ventilation (MV). Predictors of mortality were analyzed. Results: Of the 203 patients analyzed, 16 (8%) died. Relative to survivors, non-survivors were older (65 +/- 21 versus 53 +/- 18, P = 0.009) and less frequently had obstructive airway disease (OAD; P = 0.003). Non-survivors also had significantly higher serum levels of lactic dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine, transaminases and troponins. Finally, non-survivors more commonly exhibited shock, need for MV and bilateral lung infiltrates. There were no group differences in patient comorbidities, symptoms, antibiotic use or LOS. Predictors of mortality included age, OAD, low CD4+ T-cell counts in human immunodeficiency virus-infected patients and elevated serum levels of LDH, creatinine, BUN, leukocytes, transaminases and troponins. Conclusion: Despite the availability of appropriate antibiotics, MPP incurs significant mortality and morbidity. Our study indicated that the recommended treatment includes prompt serological diagnosis, aggressive supportive care and presumptive antibiotics, especially in patients with poor prognosis. PMID- 30425762 TI - APACHE II Death Risk and Length of Stay in the ICU Are Associated With Pressure Injury in Critically Ill Patients. AB - Background: The aim of this study was to identify factors associated with pressure injury (PI) occurrence in critically ill patients. This was a retrospective cohort study conducted at a mixed intensive care unit (ICU). Methods: Univariate analysis and logistic regression were used to identify which variables are associated with PI. Results: Twenty-one (15%) of 142 patients developed PI. The median and the range of the variables in the groups without and with PI were as follows: Braden scale risk score, 13 (8 - 20) and 10 (8 - 14) points, respectively; Acute Physiology and Chronic Health Evaluation II (APACHE II) death risk, 39% (2 - 97%) and 75% (26 - 96%), respectively; and length of stay in the ICU, 4 (2 - 36) and 16 (5 - 29) days, respectively. The socio demographic variables included in the logistic regression were age (P = 0.09), Braden scale risk score (P = 0.0003), APACHE II death risk (P < 0.0001), length of stay in the ICU (P < 0.0001) and reason for ICU admission (P = 0.09). Only APACHE II death risk and length of stay in the ICU presented significant differences; the odds ratios were 1.05 and 1.25, respectively, and the 95% confidence intervals were 1.01 - 1.09 and 1.12 - 1.39, respectively. Conclusion: APACHE II death risk and length of stay in the ICU are probably associated with PI occurrence in the study population. PMID- 30425764 TI - Comparison of Comorbid Conditions Between Cancer Survivors and Age-Matched Patients Without Cancer. AB - Background: Cancer survivors suffer from many comorbid conditions even after the cure of their cancers beyond 5 years. We explored the differences in the association of comorbid conditions between the cancer survivors and patients without cancer. Methods: Electronic medical records of 280 adult cancer survivors and 280 age-matched patients without cancer in our suburban internal medicine office were reviewed. Results: Mean age of the cancer survivors was 72.5 +/- 13.1 years, and the age of the patients without cancer was 72.5 +/- 12.8 years. The number of male cancer survivors was significantly higher than the female cancer survivors (52.5% vs. 47.5%, P < 0.001). There were significantly more Caucasians and other races (majority Asians) in the cancer survivor group compared to the patients without cancer group (81.8% vs. 79.3% and 4.6% vs. 0.4%, respectively, P < 0.05); while there were significantly less African Americans and Hispanics in the cancer survivor group compared to the patients without cancer group (10.0% vs. 12.8% and 3.6% vs. 7.5%, respectively, P < 0.05). Hypertension (64.3%), hyperlipidemia (56.1%), osteoarthritis (34.3%), hypothyroidism (21.8%), diabetes mellitus (21.8%) and coronary artery disease (21.8%) were the most common comorbid conditions observed in the cancer survivors. Osteoarthritis was the only comorbid condition that was significantly less frequently associated with the cancer survivors compared to the patients without cancer (42.9%, P < 0.05). The frequencies of all other comorbid conditions were not significantly different between the two groups. The majority of our group of cancer survivors had one or more types of the top six cancers which include prostate cancer (30.7%), melanoma (13.9%), thyroid cancer (11.4%), colon cancer (11.1%), uterine cancer (11.1%) and urinary bladder cancer (11.1%); while only a few had cancer of the cervix (6.1%) or breast cancer (0.3%). Use of aspirin, statin, vitamin D, multivitamins, metformin and fish oil supplement in the cancer survivors was similar to the patients without cancer. Conclusions: Hypertension, hyperlipidemia, osteoarthritis, hypothyroidism, diabetes mellitus and coronary artery disease are the most common associated comorbid conditions in the cancer survivors. Osteoarthritis is less frequently seen in the cancer survivors compared to the patients without cancer. The frequencies of other comorbid conditions are not significantly different between the two groups. PMID- 30425763 TI - Prevalence and Risk Factors of Elevated Liver Enzymes in Japanese Women With Polycystic Ovary Syndrome. AB - Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-aged women. While PCOS is associated with an increased risk of obesity and insulin resistance, little is known regarding the prevalence of and risk factors for nonalcoholic fatty liver disease (NAFLD) among Japanese women with PCOS. We estimated the prevalence of and risk factors for elevated liver enzymes, as the index of NAFLD, in Japanese women with PCOS. Methods: We retrospectively reviewed 102 reproductive-aged women who visited the Department of Gynecology, Kyoto Medical Center in Japan from January 2000 to September 2016. Inclusion criterion was confirmed diagnosis of PCOS using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10) codes. Exclusion criteria were women with a history of liver diseases, missing body mass index (BMI) and serum alanine aminotransferase (ALT) data, and pregnancy. Data regarding age; BMI; and levels of blood glucose, serum lipid, liver enzymes, and sex hormones were obtained from medical records. Elevated liver enzymes was defined as ALT > 19 IU/L. Optimal cutoffs for risk factors for elevated liver enzymes were calculated to determine predictors of elevated liver enzymes using area under the curve (AUC) by receiver-operating characteristics (ROC). Results: The prevalence of elevated liver enzymes was 33.3%. BMI was significantly higher in PCOS patients than in those without elevated liver enzymes (25.3 vs. 20.7 kg/m2, P < 0.05). ROC analyses were performed using BMI and blood glucose and testosterone levels because BMI and blood glucose showed differences between the groups and testosterone is related to fatty liver. AUC of the model including BMI and blood glucose and testosterone levels was 0.861 (sensitivity, 66.7%; specificity, 100%). Conclusions: These findings suggest that elevated liver enzymes are common in women with PCOS. An algorism using BMI and blood glucose and testosterone levels might be useful to determine elevated liver enzymes in women with PCOS. Our finding may be useful for the study of NAFLD among Japanese women with PCOS since several previous studies have indicated elevated liver enzymes to be related to the potential presence of NAFLD. Further examination, including abdominal ultrasonography and/or liver biopsy data, is required to confirm these results. PMID- 30425765 TI - Relationship Between Sarcopenia and Both Physical Activity and Lifestyle in Patients With Chronic Liver Disease. AB - Background: Sarcopenia can affect the prognosis of patients with cirrhosis or hepatocellular carcinoma. Exercise therapy and nutritional therapy are carried out to prevent processing sarcopenia. In addition, changing lifestyle is also important. However, there are only few reports on the physical activities (PAs) and lifestyle of chronic liver disease patients and their association with sarcopenia. The aim of this study is to examine the relationship between sarcopenia in patients with chronic liver disease and both PA and lifestyle. Methods: A total of 214 out-patients with chronic liver disease were enrolled into the present study. All patients were evaluated for with or without sarcopenia based on the sarcopenia diagnostic criteria of the Japan Society of Hepatology. Then, patient's characteristics and laboratory parameters were divided into two groups with or without sarcopenia and compared. In continuous variable with significant difference in univariate analysis, cut-off value was calculated by receiver operating characteristic curve. We determined which factors were associated with sarcopenia in univariate analyses, and variables significant in the univariate analyses were entered in a multivariable logistic regression model. Results: Patients with chronic liver disease had a prevalence of sarcopenia of 12.6% in this study. Sarcopenia patients were older (76.48 +/- 6.69 versus 66.97 +/- 11.19 years old; P < 0.01), had lower body mass index (BMI) (20.84 +/- 2.44 versus 23.76 +/- 3.72 kg/m2; P < 0.01), lower PA (6.6 (2.34 - 19.90) versus 16.5 (6.60 - 41.23) metabolic equivalents (METs)-h/week; P < 0.01) and longer total time sitting and lying on the day (7.43 +/- 4.09 versus 5.68 +/- 3.17 h/day; P = 0.01); retirement status (81.5% versus 48.1%; P < 0.01) and low frequency of driving (40% versus 20%; P = 0.01) were higher in sarcopenia patients than in non-sarcopenia patients. The independent predictive factors of sarcopenia, analyzed with logistic regression, were age (odds ratio (OR): 5.89, 95% confidence interval (CI): 2.15 - 16.20; P < 0.01), BMI (OR: 4.77, 95% CI: 1.87 - 12.10; P < 0.01) and PA (OR: 3.65, 95% CI: 2.15 - 16.20; P < 0.01). Conclusion: Sarcopenia patients' lifestyle characteristics were longer sedentary time and low frequency of driving, high retirement. Independent predictive factors of sarcopenia were elderly, low BMI and low PA. For these patients, intervention in the lifestyle for prevention of sarcopenia may be effective for patients with chronic liver disease. PMID- 30425766 TI - Clinical Impact of Hemorheology on Subclinical Myocardial Injury in Patients with Hypertension. AB - Background: The blood concentration of high-sensitivity cardiac troponin T (hs cTnT) is a useful biomarker for myocardial injury or the pathogenesis of hypertension. Little is known about the relationship between hemorheology and myocardial injury in patients with hypertension. This cross-sectional study aimed to clarify the clinical impact of hemorheology on subclinical myocardial injury assessed with a microchannel array flow analyzer (MC-FAN) and its impact on hs cTnT in patients with hypertension. Methods: A total of 447 outpatients (men: 181; women: 266; mean age: 65 +/- 13 years), with no history of cardiovascular disease, including admission for heart failure, who were undergoing treatment for hypertension, were enrolled. Whole blood passage time (WBPT) as a marker of hemorheology was measured with a MC-FAN, and the relationship between hs-cTnT levels and various clinical parameters, including WBPT, was examined. Results: hs cTnT levels were detected in 400 patients (89.5%). WBPT was significantly higher in patients with detectable hs-cTnT levels than in those with undetectable hs cTnT levels (60.5 +/- 16.8 s versus 50.2 +/- 14.2 s, P < 0.001). In patients with detectable hs-cTnT levels, there was a significant positive correlation between WBPT and hs-cTnT level (r = 0.33; P < 0.001). Multiple regression analysis revealed that WBPT was an independent variable when hs-cTnT was a subordinate factor (beta = 0.15; P < 0.01). Receiver-operating characteristic curve analysis indicated that a cutoff value for WBPT of 55.6 s yielded the largest area under the curve (0.744; P < 0.001) for discriminating high hs-cTnT levels as >= 0.014 ng/mL. Conclusion: The results indicate that WBPT is independently associated with hs-cTnT in hypertensive patients with no history of cardiovascular events, suggesting that impairment of hemorheology in small cardiac vessels causes subclinical myocardial injury. In addition, the study suggests that progression of myocardial injury can be prevented by maintaining WBPT at approximately <= 55 s. PMID- 30425767 TI - Which Nutritional Factors Are Good for HDL? PMID- 30425768 TI - H-magnetic resonance spectroscopy: diagnostic tool in recurrent headache in systemic lupus erythematosus. A case report. AB - We describe serial MR-spectroscopy studies in a patient with systemic lupus erythematosus and headache. We used MR-spectroscopy to monitor disease activity during periods with and without headache. MR-spectroscopy investigates metabolic alterations and was used to explore the pathophysiological mechanism involved in the complications of systemic lupus erythematosus. Our patient underwent serial conventional MRI and MR-spectroscopy at times of controlled and uncontrolled headache, with or without visual aura. MR-spectroscopy showed an increase in the choline/creatine ratio in thalamus and posterior white matter only during periods of uncontrolled headache with visual aura. Conventional MRI scans were normal at all times. MR-spectroscopy should be used in the diagnosis and follow-up of headache in patients with systemic lupus erythematosus. PMID- 30425769 TI - Radiation-induced insufficiency fracture of the femur 18 years after radiation therapy. AB - Advances in oncologic treatment have improved survival rates, allowing late effects of radiotherapy to become more prevalent. Our patient, an 82-year-old woman with a remote history of right thigh basal cell carcinoma treated with resection and radiation therapy 18 years prior, presented with severe right thigh pain and inability to bear weight as she had suffered a femur fracture after a fall from standing. Initial imaging was suspicious for pathologic fracture secondary to malignancy due to imaging findings and because radiation-induced fractures have rarely been reported beyond 44 months from treatment. However, upon further imaging, evidence pointed to radiation-induced osteonecrosis as the mechanism for her insufficiency fracture. This case highlights the permanent deleterious effects of radiation therapy on bone, and the prudence of considering radiation-induced osteonecrosis as a mechanism of injury in low-energy trauma even long after radiation therapy. In addition, the case serves to review the natural history of irradiated bone injury and pertinent imaging findings. PMID- 30425770 TI - Loop formation by an aortic occlusion balloon catheter during resuscitative endovascular balloon occlusion of the aorta (REBOA). AB - A 77-year-old man was transferred to our hospital for endoscopically uncontrollable active bleeding from a duodenal ulcer. Soon after his arrival, he became hemodynamically unstable and resuscitative endovascular balloon occlusion of the aorta was performed using a 7-F aortic occlusion balloon catheter (Rescue Balloon; Tokai Medical Products, Aichi, Japan). He became hemodynamically stable and was transferred to the CT room. CT demonstrated that the distal part of the catheter shaft had made a loop in the aorta and the balloon was located at the level of the upper abdomen. We consider the low-profile occlusion balloon catheter to be less rigid than large ones, and care should be taken to prevent balloon migration and catheter shaft bending. PMID- 30425771 TI - Regression of a solitary osteochondroma of the distal humerus in a toddler following trauma. AB - Osteochondromas are bone exostoses, with the vast majority extending from the metaphyseal region of long bones and are capped by cartilage. A review of the current literature reveals spontaneous regression of osteochondromas is a rarely documented event, with all but two of these recorded events resolving before skeletal maturity and within 6 years of identification. We present a case of trauma-induced resolution of a solitary osteochondroma after less than 3 months in a 15-month-old male, with a review of current literature. PMID- 30425772 TI - Actinomycosis of tongue: Rare presentation mimicking malignancy with literature review and imaging features. AB - Actinomycosis of the tongue is rare. It may be difficult to differentiate this infection clinically and radiologically from other tongue pathology especially neoplasia. We report a substantial tongue lesion which mimicked malignancy at presentation. The patient was treated successfully with 4 weeks of oral antibiotic therapy. It is also important that clinicians are aware of the radiological differential diagnosis of lingual actinomycosis. PMID- 30425773 TI - A case of giant common hepatic artery aneurysm successfully treated by transcatheter arterial embolization with isolation technique via pancreaticoduodenal arcade. AB - Hepatic artery aneurysms are rare and sometimes life-threating. Various treatments for hepatic artery aneurysms, including surgical and endovascular techniques are present. Here, we report the case of a 68-year-old woman who presented with an about 9 cm of common hepatic artery aneurysm detected during a routine medical checkup; she did not exhibit any symptoms. We successfully treated the aneurysm with transcatheter arterial embolization with isolation technique via pancreatic duodenal arcade. PMID- 30425774 TI - Parosteal osteosarcoma with focal fatty metaplasia: A case report. AB - Parosteal osteosarcoma originates on the surface of long bones. The juxtacortical variety is one of the most common ones and accounts for about 5% of all osteosarcomas. We report the case of a 34-year-old female patient with a rare variant of parosteal osteosarcoma. Because of the less aggressive biological behavior, it is important to know it, in order to recognize and differentiate it from benign osseous lesions. PMID- 30425775 TI - Synovial sarcoma of bone: Sarcoma typically of soft tissues presenting as a primary bone tumor. AB - Synovial sarcoma typically presents as periarticular soft tissue mass in adolescent and young adult patients. Very rarely, soft tissue sarcomas may arise primarily within bone posing a significant diagnostic challenge as primary osseous malignancies such as osteosarcoma and metastatic disease are much more common. While tissue sampling with immunohistochemical and genetic testing are required for definitive diagnosis, radiologists and orthopedic oncologists should consider alternate etiologies when typical imaging features of more common bone tumors are not identified. As an example, we present a 33-year-old male referred with a pathologic hip fracture proven to represent primary synovial sarcoma of bone. PMID- 30425776 TI - Severe bilateral knee osteonecrosis in a young man with human immunodeficiency virus. AB - We present a young man with a background Human Immunodeficiency virus (HIV) who presented with bilateral knee pain and reduced mobility. Subsequent imaging of the knees demonstrated florid osteonecrosis (ON), which was managed conservatively. ON is seen more commonly in HIV patients than the general population, however the underlying mechanism for this association is remains unclear. An awareness of this disease is imperative to appropriately identify and manage such patients. PMID- 30425777 TI - Large bowel obstruction caused by urinary retention from benign prostate hyperplasia. AB - Although large bowel obstruction is a common surgical emergency, its occurrence due to bladder distension is rarely reported in the literature. We report a case of large bowel obstruction caused by bladder distention secondary to benign prostate hyperplasia in a 67-year-old man. This case demonstrates a grossly distended urinary bladder compressing the rectosigmoid colon against the sacrum, presenting as a complete large bowel obstruction. Management consisted of transurethral urinary catheter insertion, which resulted in complete resolution of the bowel obstruction with drainage of a large amount of urine. Early recognition of the underlying etiology resulted in the expeditious treatment of large bowel obstruction. PMID- 30425778 TI - Ventriculoperitoneal shunt catheter migration in a patient with breast implants resulting in a peri-implant cerebrospinal fluid pseudocyst. AB - Ventriculoperitoneal (VP) shunts complications are most often divided into 2 broad categories: mechanical failure and infection. We report a case of a migrated VP shunt with subsequent development of a pseudocyst around the patient's breast implant, a rare complication. We review the literature of VP shunt complications, including the increasing number of reported breast-related complications, and discuss proposed mechanisms by which migration may occur. With the increase in patients with breast augmentation procedures, there is potential for an increase in the number of reported cases of VP shunt migration. PMID- 30425779 TI - Probiotics as treatment for food allergies among pediatric patients: a meta analysis. AB - Background: The burden of disease of food allergy is increasing worldwide. The standard of management is allergen avoidance and symptomatic treatment. Probiotics have been proposed to be beneficial for treatment and prevention of food allergy. Objective: To determine the effectiveness of probiotic administration in treating food allergies among pediatric patients. Methods: A systematic search of electronic medical literature databases was conducted. Manual search of the reference lists and search for unpublished articles were also done. All randomized controlled trials available from inception until February 19, 2018 were retrieved. The primary outcome of interest was relief of allergic symptoms, while the secondary outcome of interest was inducement of tolerance. Two independent authors did the search, screening, appraisal, and data abstraction. Data analysis and synthesis were done using RevMan 5.3 software. Subgroup analysis was done based on the probiotic strains and time periods in measuring the outcome. Exclusion sensitivity analysis was also done. Results: Nine trials involving 895 pediatric patients with cow's milk allergy (CMA) were included in the review. The primary outcome of interest, relief of symptoms, was measured using the scoring index for eczema. Pooled results from two studies showed larger reduction in the scoring index among patients given probiotics, but this effect was imprecise (MD -1.30, 95% CI -3.88, 1.28). For the secondary outcome of interest, pooled results from four studies showed benefit of probiotics in inducing tolerance, but again this result is imprecise with significant heterogeneity (RR 0.58, 95% CI 0.34, 1.00). Subgroup analysis per probiotic strain showed benefit of Lactobacillus rhamnosus GG in inducing tolerance based on two studies involving infants with suspected cow's milk allergy (RR = 0.41, 95% CI 0.28 to 0.62). Another subgroup analysis showed a duration-dependent effect associated with probiotic usage, with inducement of tolerance noted after at least 2 years (RR = 0.44, 95% CI 0.29 to 0.67). Conclusion: Analysis of available evidence shows moderate certainty that the use of probiotics can relieve symptoms of children with cow's milk allergy. The reduction in certainty is due to imprecise results. Moreover, there is low certainty that probiotics can induce tolerance among children with cow's milk allergy, due to problems of imprecision and attrition bias. In the subgroup analysis, Lactobacillus rhamnosus GG administration likely results in inducing tolerance among infants with suspected cow's milk allergy. Only studies on CMA were analyzed since no studies were found on probiotics as treatment for other types of food allergy among children. PMID- 30425780 TI - Long-Term Administration of Angiotensin (1-7) to db/db Mice Reduces Oxidative Stress Damage in the Kidneys and Prevents Renal Dysfunction. AB - Aims: The goal of this study was to evaluate the effects of long-term (16 weeks) administration of angiotensin (1-7) [A(1-7)] on kidney function in db/db mice and to identify the protective mechanisms of this therapy. Methods: db/db mice and heterozygous controls were treated with A(1-7) or vehicle daily, subcutaneously for up to 16 weeks. Kidney injury was assessed by measuring blood flow in renal arteries, plasma creatinine levels, and proteinuria. Effects of treatment on oxidative stress were evaluated by histological staining and gene expression. Results: 16 weeks of daily administration of A(1-7) to a mouse model of severe type 2 diabetes (db/db) prevented the progression of kidney damage. Treatment with A(1-7) improved blood flow in the renal arteries, as well as decreased plasma creatinine levels and proteinuria in diabetic mice. Reduction of oxidative stress was identified as one of the mechanisms of the renoprotective action of A(1-7). Treatment prevented formation of nitrotyrosine residues, a marker of oxidative stress damage. A(1-7) also reduced the expression of two enzymes involved in formation of nitrotyrosine, namely, eNOS and NOX-4. A(1-7) regulated the phosphorylation pattern of eNOS to enhance production of NO in diabetic animals, possibly through the Akt pathway. However, these elevated levels of NO did not result in increased nitrosylation, possibly due to reduced NOX-4 levels. Conclusions: Long-term administration of A(1-7) improved kidney function and reduced oxidative stress damage in db/db mice. PMID- 30425781 TI - Pterostilbene 4'-beta-Glucoside Attenuates LPS-Induced Acute Lung Injury via Induction of Heme Oxygenase-1. AB - Heme oxygenase-1 (HO-1) can exert anti-inflammatory and antioxidant effects. Acute lung injury (ALI) is associated with increased inflammation and influx of proinflammatory cells and mediators in the airspaces and lung parenchyma. In this study, we demonstrate that pterostilbene 4'-beta-glucoside (4-PG), the glycosylated form of the antioxidant pterostilbene (PTER), can protect against lipopolysaccharide- (LPS-) or Pseudomonas aeruginosa- (P. aeruginosa-) induced ALI when applied as a pretreatment or therapeutic post-treatment, via the induction of HO-1. To determine whether HO-1 mediates the antioxidant and anti inflammatory effects of 4-PG, we subjected mice genetically deficient in Hmox-1 to LPS-induced ALI and evaluated histological changes, HO-1 expression, and proinflammatory cytokine levels in bronchoalveolar lavage (BAL) fluid. 4-PG exhibited protective effects on LPS- or P. aeruginosa-induced ALI by ameliorating pathological changes in lung tissue and decreasing proinflammatory cytokines. In addition, HO-1 expression was significantly increased by 4-PG in cells and in mouse lung tissues. The glycosylated form of pterostilbene (4-PG) was more effective than PTER in inducing HO-1 expression. Genetic deletion of Hmox-1 abolished the protective effects of 4-PG against LPS-induced inflammatory responses. Furthermore, we found that 4-PG decreased both intracellular ROS levels and mitochondrial (mt) ROS production in a manner dependent on HO-1. Pharmacological application of the HO-1 reaction product carbon monoxide (CO), but not biliverdin or iron, conferred protection in Hmox-1-deficient macrophages. Taken together, these results demonstrate that 4-PG can increase HO-1 expression, which plays a critical role in ameliorating intracellular and mitochondrial ROS production, as well as in downregulating inflammatory responses induced by LPS. Therefore, these findings strongly suggest that HO-1 mediates the antioxidant and anti-inflammatory effects of 4-PG. PMID- 30425782 TI - An Overview on the Anti-inflammatory Potential and Antioxidant Profile of Eugenol. AB - The bioactive compounds found in foods and medicinal plants are attractive molecules for the development of new drugs with action against several diseases, such as those associated with inflammatory processes, which are commonly related to oxidative stress. Many of these compounds have an appreciable inhibitory effect on oxidative stress and inflammatory response, and may contribute in a preventive way to improve the quality of life through the use of a diet rich in these compounds. Eugenol is a natural compound that has several pharmacological activities, action on the redox status, and applications in the food and pharmaceutical industry. Considering the importance of this compound, the present review discusses its anti-inflammatory and antioxidant properties, demonstrating its mechanisms of action and therapeutic potential for the treatment of inflammatory diseases. PMID- 30425783 TI - Rosemary Reduces Heat Stress by Inducing CRYAB and HSP70 Expression in Broiler Chickens. AB - Heat stress negatively affects poultry production and animal health. In response, animals invoke a heat stress response by inducing heat shock proteins (HSPs). Scientists are actively seeking natural products that can enhance the heat shock response. The present study aimed at assessing the effects of a purified rosemary extract comprising antioxidant compounds on the heat shock response and HSP expression profile in broiler chickens. The response of broilers to HS in the presence of purified rosemary extract was assessed using an in vivo myocardial cell model. Pathological lesions of heart tissue were examined microscopically. The levels and activities of enzymes associated with heart damage and oxidative damage were detected. Immunohistochemical staining was performed for HSPs in myocardial cells. The results showed that lactate dehydrogenase (LDH), creatine kinase (CK), and myocardial CK (CKMB) levels were reduced by the purified rosemary extract before and during heat stress. Heat stress alone increased CK and CKMB levels. The levels of oxidative damage-associated enzymes were compared between the rosemary + heat stress and heat stress-alone groups. The results indicated that in terms of these enzymes, the purified rosemary extract induced a more antioxidative state. Pathological examinations showed that heat stress caused myocardial fiber fracture, karyopyknosis, and degeneration. The addition of purified rosemary extract ameliorated these lesions to some degree, preserving more of the basic structure. Heat stress decreased the cellular levels of crystallin alpha B (CRYAB) and HSP70. The addition of the purified rosemary extract significantly increased the levels of CRYAB and HSP70 during heat stress (p < 0.0001). Immunohistochemistry showed that after rosemary treatment, CRYAB and HSP70 showed more intense staining compared with the no heat stress control group. In the rosemary + heat group, after 10 hours of heat stress, the staining intensity of these two proteins remained higher than in the heat stress group. Thus, purified rosemary extract could induce high levels of HSP70 and CRYAB in chicken hearts before and during heat stress. Purified rosemary extract could be used to alleviate heat stress in broiler chickens. PMID- 30425784 TI - Operationalized definition of older adults with high cognitive performance. AB - Recently, there has been an increasing number of studies on exceptional cognitive aging. Herein, we aim to objectively provide the operationalized characterization of older adults with unusually high memory ability. Some authors have defined them as "SuperAgers", individuals aged 80 years or older with memory ability similar or superior to middle-aged subjects. On the other hand, the terminology "high-performing older adults" (HPOA) seems to appropriately conceptualize these individuals without exaggeration. A threshold for age is not a reliable criterion, but may be defined as 75 and 80 years of age for developing and developed countries, respectively. We propose that HPOA may exhibit episodic memory test scores equal to or greater than those of individuals aged 50-60 years, according to the validated tables for the respective country. This group must also have global cognition scores within expected average values for age and education. Executive functioning may play a central role in the exceptional memory performance of this group. Further studies are essential to confirm existing findings and may provide important evidence for cognitive aging theory and the neurobiology of dementia. PMID- 30425785 TI - Sixteen-year predictors of successful aging from a Southern Brazilian cohort The PALA study. AB - : Successful aging (SA) is a current positive aging-related perspective and it is important to determine the variables associated with this concept. Most longitudinal population-based studies on predictors of SA were carried out in developed countries. Objective: This investigation evaluated which baseline characteristics predicted successful aging in 16 years of follow-up in a southern Brazilian cohort - the Porto Alegre Longitudinal Aging study. Methods: At baseline, 345 community-dwelling healthy independent individuals aged 60 or older were assessed for medical and psychiatric conditions, memory, orientation, judgment and problem solving, functioning in the community and at home, and hobbies. SA, according to Rowe and Kahn's definition, was the outcome assessed in the last evaluation at a maximum 16-year follow-up. All baseline variables were evaluated as potential predictors for the outcome SA. Results: Of the 345 individuals evaluated at baseline, 32 (9.3%) participants were classified as successful agers in the follow-up. Younger age (OR=0.926, 95%CI=0.863-0.994), female gender (OR=0.226, 95%CI=0.072-0.711) and higher MMSE (OR=1.220, 95%CI=1.031-1.444) were predictors of SA for the 16-year follow-up in a logistic regression model. Conclusion: In contrast with our previous hypothesis, the impact of the socioeconomic and socio-environmental characteristics was small, as was the baseline classification into successful and normal aging. PMID- 30425786 TI - Validity and reliability of the Brazilian Portuguese version of the Australian National University - Alzheimer's Disease Risk Index (ANU-ADRI). AB - : The ANU-ADRI is a self-report tool that assesses risk for Alzheimer's Disease (AD). Objective: To validate an adapted Portuguese version of this instrument and to carry out the reliability Test-Retest of the ANU-ADRI in Brazil. Methods: In this longitudinal study, the sample was formed (n=100) by two groups (A and B): each comprising 50 patients assisted by GPs (general practitioners) or specialists in dementia. All participants were cognitively healthy upon screening using the MMSE. The ANU-ADRI was applied at baseline (Test) and again within 1 week of the test (Retest). Results: There was a correlation between the mean scores of the ANU-ADRI Test and Retest (r=0.918, P<0.001). Group A had higher ANU ADRI scores than those of group B (P<0.05). There was a moderate negative linear relation between the ANU-ADRI and MMSE scores (r= -0.353, P<0.001). Conclusion: The ANU-ADRI is a valid and reliable instrument to assess whether community dwelling Brazilians are at greater risk for AD. Low levels of education were associated with higher risk scores on the ANU-ADRI. PMID- 30425787 TI - Semantic-cultural validation and internal consistency analysis of the Purpose in Life Scale for brazilian older adults. AB - : Purpose in life is one of the six dimensions of psychological well-being. It refers to the sense that life has meaning and direction, and that goals have been achieved or are attainable. Objective: To perform the semantic-cultural validation and internal consistency analysis of the 10-item Purpose in Life scale of Ryff and Keyes. Methods: Data were drawn from an eight-year follow-up of older adults aged >=80 in the FIBRA Study, conducted in Campinas, Brazil. Results: The mean age of participants (N=187) was 83.81 (+/-3.60), mean number of years of education was 4.38 (+/-3.76), and mean income was 3.49 minimum wages (+/-2.61), comprising 125 (66.8%) females (mean purpose = 3.51 +/-0.68) and 62 (33.2%) males (mean purpose = 3.58+/-0.60). There was no significant difference in the purpose between men and women or between educational levels. For age and income, purpose was higher in the 80- to 84-year-old group (younger age) and with income of 3-5 minimum wages (higher income). Cronbach's alpha for the scale was 0.628, indicating moderate internal consistency. Conclusion: The Purpose in Life scale was translated, adapted for use in Brazil and applied in a sample of old-old adults. Purpose seemed to be influenced by age and income. PMID- 30425788 TI - Decision Making assessed by the Iowa Gambling Task and Major Depressive Disorder A systematic review. AB - : Major Depressive Disorder (MDD) can occur in parallel with cognitive impairment. The search for a neuropsychological profile of depression has been pursued in the last two decades. However, scant research has been done on executive functions and decision-making ability (DM). Objective: To perform a systematic review of the evidence of DM performance evaluated using the Iowa Gambling Task (IGT) in adults with MDD. Methods: A systematic search according to the PRISMA statement was performed on MEDLINE for studies in English using the following keywords: 'depression', 'depressive', 'depressive symptoms' AND 'decision making' OR 'game task'. Results: Five articles that met the inclusion and exclusion criteria were identified. Three reported significant differences between depressed and non-depressed individuals. The results indicated that young adults with MDD exhibited lower performance on all or almost all stages of the IGT. One study that evaluated DM in older adults with MDD showed that depressed non-apathetic participants failed to adopt any advantageous strategy and continued to make risky decisions during the task. Conclusion: Results suggest that performance on the DM task by young and old adults with MDD differed in comparison to non-depressed participants. Given the small number of articles, further studies should be performed. PMID- 30425789 TI - Heterogeneity of math difficulties and its implications for interventions in multiplication skills. AB - : Math learning disability (MLD) is a heterogeneous condition characterized by severe and persistent difficulties in learning math, including difficulties in learning multiplication facts. Objective: In this article, we compared the responses of two MLD children to multiplication facts training. Methods: One of the children was a 9 year-old girl (HV) who presented mild math difficulties associated with lower accuracy of the Approximate Number System (ANS). The other was an 11 year-old boy (GA) who presented severe math difficulties related to impaired phonological processing due to developmental dyslexia. Both children underwent an intervention for multiplication, comprising conceptual instructions and retrieval practice of the times table. Results: HV's accuracy and response speed improved consistently on both training tasks, while GA's accuracy improved on the Simple Calculation Task only. Error analyses indicated that, after training, HV produced fewer errors of the type "close miss", and GA produced less omission but more operand errors. Conclusion: We argue that these differences between their responses to the training tasks were caused by differences in the mechanisms underlying their math difficulties. These results support the notion that individual specificities regarding math disabilities should be taken into account during preparation of training interventions. PMID- 30425790 TI - Pattern of anxiety, insecurity, fear, panic and/or phobia observed by quantitative electroencephalography (QEEG). AB - : Stress is a response in which an individual wants to have more control over a situation. A constant state of stress is called anxiety. Some patients deny symptoms. An instrument can help arrive at a diagnosis. Objective: Using TQ-7 QEEG, this study aimed to evaluate the association of symptoms of anxiety, insecurity, fear, panic and phobia with hot temporals defined as Beta (15-23 Hz) >17% and High-Beta waves (23-38 Hz) >10% at T3 and T4. Methods: Five hundred and forty-three patients of both genders with ages ranging from 16-59 years were evaluated, divided into two groups: Control (without hot temporals: n=274) and Case Group (with hot temporals: n=269). The Chi-square test was used (p-values <=0.05). Results: There was a significant association (p-value <0.001) between the symptoms related to amygdala activation, expressed in the temporals (Beta >17% and High-Beta >10%). (Anxiety, T3=89.6% - T4=88.8%; T3=92.6% - T4=93.3%), (Fear, T3=80.7% - T4=84.4%; T3=82.9% - T4=95.9%), (Insecurity, T3=82.2% - T4=81.4%; T3=69.5% - T4=97.8%), (Panic, T3=52.4 - T4=72.5%; T3=90.3% - T4=74.0%), (Phobia, T3=17.5% - T4=22.7%; T3=19.7% - T4=27.1%), when compared to the respective controls (Beta control, T3=8.4%, 10.2%, 21.2%, 1.1%, 0.4% and T4=11.3%, 4.4%, 23.0%, 2.6%, 1.1%) (High-Beta control, T3=4.0%, 6.9%, 6.2%, 0.4%, 0.0% and T4=17.5%, 6.2%, 3.3%, 4.0%, 0.7%). Conclusion: Anxiety, insecurity, fear, panic and phobia are observed by QEEG when the levels of total Beta >17% and High-Beta waves >10% at T3 and T4. PMID- 30425791 TI - Executive functions assessment in patients with language impairment A systematic review. AB - Acquired language impairments may accompany different conditions. Most recent studies have shown that there is an important relationship between language and cognitive functions, such as executive functions (EF). Therefore, we aimed to investigate which main EF components appear to have the greatest impact in the most prevalent acquired communication disorders in adults, and which neuropsychological tests are being used to evaluate them. In addition, we sought to characterize the relationship between the executive functions and language in these conditions. Working memory (WM) was the most frequently chosen cognitive measure, being evaluated by different span tasks. A relationship between WM and narrative and conversational discourse, writing abilities and grammatical comprehension was found. Other currently used cognitive tests included the Trail Making, Wisconsin, Stroop and Verbal Fluency tests. Language and EF have a complex relationship; hence, a complete assessment should reflect the dynamic processing of cognitive brain functions. PMID- 30425792 TI - Formal language assessment in low-educated healthy subjects. AB - : Although many studies have shown the influence of education on cognition, the impact of low education on the various cognitive functions appears to differ. The hypothesis of the present study is that, with regards to language, the use of parameters derived from populations with 5-8 years of education leads to false positive results. Objective: to determine the influence of low education on the language tasks assessed by the MTL-Brazil Battery. Methods: 30 healthy adults with 2-4 years of education were submitted to the MTL-Br Battery, comprising 22 subtests. The data were submitted to descriptive statistical analysis for each subtest and Z-scores were then calculated based on the parameters of a population with 5-8 years of education. All participants would be considered impaired if the Battery had been applied according to published normative criteria for a population with 5-8 years of education. Results: Separate analysis revealed that published scores for 17 out of the 22 Battery tasks were inappropriate for a population with 2-4 years of education. Conclusion: Education was found to effect performance for each of the language abilities differently. In addition, the study results can be applied to language assessments of individuals with 1-4 years of education using the MTL-Br battery, since this is the only language test for adults available in Brazil, and for which there are no normative data for low educated subjects. PMID- 30425793 TI - Factors associated with depression in patients with Parkinson's disease A multicenter study in Lima, Peru. AB - : The diagnosis and treatment of depression in patients with Parkinson's disease (PD) is inadequate, often contributing to a reduced quality of life, rapid disease progression, higher cognitive impairment, and an increased burden of care for family members of patients with PD. Objective: To determine the factors associated with depression in PD and to examine the frequency of depressive symptoms among patients with PD. Methods: This study was an observational, analytical, multicenter study of a cross-sectional cohort, conducted between July 2016 and May 2017. PD patients were recruited from neurology clinics in Lima, Peru. All statistical analyses were performed using descriptive statistics. Bivariate and multivariate logistic regression analyses were calculated using STATA. Results: Out of 124 patients (average age: 68.7 years; 58% males) included in the study 60.5% (75/124) presented with symptoms of depression; only 20% (25/124) received antidepressants. Factors associated with depression in PD included: unemployment, falls, freezing of gait, involuntary movements micrographia, stooped posture, hyposmia, movement disorders in sleep, rapid disease progression, and the use of MAOIs. Furthermore, statistically significant differences were found in disease duration, UPDRS and MMSE scores, Hoehn and Yahr (HY) stage, and length of time taking L-dopa between PD patients with and without depressive symptoms. Conclusion: Factors associated with depressive symptoms in patients with PD were hyposmia, rapid progression of the disease, the use of L dopa, and use of MAOIs. The frequency of depressive symptoms in patients with PD is high; early diagnosis and prompt treatment are needed to improve their quality of life and the family environment. PMID- 30425794 TI - Profile of caregivers of Parkinson's disease patients and burden measured by Zarit Scale Analysis of potential burden-generating factors and their correlation with disease severity. AB - : Parkinson's disease (PD) promotes burden among patients and caregivers. Objective: To analyze whether disease severity (UPDRS and Karnofsky index), total disease duration, patient cognitive status (MMSE), presence of other diseases, patient age, socioeconomic conditions (ABEP2015), living together with patient, total time caregiving, weekly hours of care and presence of assistance from other caregivers are correlated with, and influence statistically, the degree of caregiver burden measured by the Zarit Burden Interview (ZBI). Methods: After ethics Committee approval, patients and respective caregivers were recruited. Following evaluation with the proper scales, all data were submitted to Pearson's correlation method and multivariate linear regression analysis (ANOVA). Results: A total of 21 patients and respective caregivers were evaluated. 72% (N=15) of caregivers reported burden. One third of caregivers reported a moderate or severe level of burden. A cause-effect relationship could not be established by the statistical method adopted, but disease severity measured by the UPDRS was the sole variable showing statistically significant moderate positive Pearson's correlation with ZBI (r=0.48, for p<0.05). On ANOVA, however, no independent variable had a statistically significant impact on ZBI scores. Conclusion: Despite our conflicting results, optimization of the available treatment, with better control of PD severity, can be considered an important element to effectively achieve the goal of reducing burden among caregivers. PMID- 30425795 TI - Body image satisfaction, sociodemographic, functional and clinical aspects of community-dwelling older adults. AB - : Body image, according to the definition by Ledoux et al.(1) is "the systematic, cognitive, affective, conscious, and unconscious representation that people have concerning their bodies during their biological development and throughout their social relationships". Objective: To determine the prevalence of body image satisfaction (BIS) and its relationship with sociodemographic, functional and clinical aspects in older adults. Methods: A cross-sectional, analytical and prospective study of a random sample of older adults from all health districts of Porto Alegre (30 health units) was conducted. The following aspects were studied: sociodemographic data (sex, age, marital status and education), BIS (Stunkard's scale), functional tests (30 seconds Sit/Stand Test, time to walk 10m, Handgrip Strength - HGS), physical activity (Minnesota Questionnaire) and cognition (Mini Mental State Examination). Results: Most of the 532 participants were dissatisfied with their body image (92.5%), particularly the women (71.7%). After Binary Logistic Regression (6 steps), BIS predictors were: high scores for the Sit/Stand (OR: 1.13; p=0.013), higher HGS (OR: 1.06; p=0.049), shorter time engaged in physical activity (OR: 0.77; p<0.001). Conclusion: The prevalence of BIS was low and most of the variables analyzed bore no relation to BIS. Notwithstanding, a relationship was found with greater HGS, higher Sit/Stand score and less time engaged in physical activity. Given the scarcity of studies on this subject, our study furthers the knowledge on how body image affects this population group. PMID- 30425796 TI - Correlation between cognitive functions and central auditory processing in adolescents with non-cholesteatomatous chronic otitis media. AB - : Auditory deprivation associated with early otitis media with effusion has been considered a risk factor for central auditory processing (CAP), as well as for the development of a number of cognitive functions. Objective: To study the neuropsychological functions of attention, working memory and executive function in adolescents with and without non-cholesteatomatous chronic otitis media (NCCOM) and analyze their interrelationships with the behavioral evaluation of CAP. Methods: Sixty-eight adolescents were recruited, 34 were diagnosed with NCCOM (study group - SG), and 34 had no otological history (control group - CG). The Neupsilin Brief Neuropsychological Assessment Instrument was used. CAP was assessed by: Masking Level Difference, Synthetic Sentence Identification, Random Gap Detection Test, Duration Pattern Sequence Test and Dichotic Digits Test. Results: The results of Neupsilin showed lower scores in the study group when compared to the control group on the following tests: digit sequence repetition, ascending digit ordering, auditory sentence span, and phonemic verbal fluency. An association was found between central auditory processing tests and Neupsilin subtests. Conclusion: The effects of NCCOM on attention, memory and executive function related to central auditory processing disorder in adolescents seem to be enhanced by the severity of the disease. PMID- 30425798 TI - A patient with posterior cortical atrophy due to Alzheimer's disease. PMID- 30425797 TI - Cerebral localization of the mind and higher functions The beginnings. AB - The debates about the mind and its higher functions, and attempts to locate them in the body, have represented a subject of interest of innumerable sages since ancient times. The doubt concerning the part of the body that housed these functions, the heart (cardiocentric doctrine) or the brain (cephalocentric doctrine), drove the search. The Egyptians, millennia ago, held a cardiocentric view. A very long time later, ancient Greek scholars took up the theme anew, but remained undecided between the heart and the brain, a controversy that lasted for centuries. The cephalocentric view prevailed, and a new inquiry ensued about the location of these functions within the brain, the ventricles or the nervous tissue, which also continued for centuries. The latter localization, although initially inaccurate, gained traction. However, it represented only a beginning, as further studies in the centuries that followed revealed more precise definitions and localizations of the higher mental functions. PMID- 30425799 TI - But were you drunk? Intoxication during sexual assault in Norway. AB - Background: Sexual assault often occurs when victims are intoxicated. Rape myth research indicates that intoxicated assaults are sometimes seen as less severe or not as 'real' assaults; however, it is unclear if victims of intoxicated sexual assaults differ from victims of non-intoxicated assaults in terms of health and functioning. Objective: We investigated possible differences in mental health, social support and loneliness between intoxicated and non-intoxicated sexual assault victims. Methods: Participants were 1011 young adults (505 exposed to childhood violence and 506 non-exposed) selected from a community telephone survey (T1), and a follow-up survey 12-18 months later (T2). Analyses include one way ANOVA with Tamhane post hoc tests. Results: There were no significant differences in mental health, social support and loneliness between victims of intoxicated and non-intoxicated sexual assault, although both groups differed significantly from those who did not report sexual assault. Conclusions: These results indicate that intoxicated sexual assaults are no less clinically important than non-intoxicated assaults. PMID- 30425800 TI - Quantitative comparison of ABC membrane protein type I exporter structures in a standardized way. AB - An increasing number of ABC membrane protein structures are determined by cryo electron microscopy and X-ray crystallography, consequently identifying differences between their conformations has become an arising issue. Therefore, we propose to define standardized measures for ABC Type I exporter structure characterization. We set conformational vectors, conftors, which describe the relative orientation of domains and can highlight structural differences. In addition, continuum electrostatics calculations were performed to characterize the energetics of membrane insertion illuminating functionally crucial regions. In summary, the proposed metrics contribute to deeper understanding of ABC membrane proteins' structural features, structure validation, and analysis of movements observed in a molecular dynamics trajectory. Moreover, the concept of standardized metrics can be applied not only to ABC membrane protein structures (http://conftors.hegelab.org). PMID- 30425801 TI - In Vitro and In Silico Insights into sEH Inhibitors with Amide-Scaffold from the Leaves of Capsicum chinense Jacq. AB - Two compounds termed 1 and 2 were isolated from the leaves of Capsicum chinense using column chromatography. Their structures were identified as amide scaffolds by analyzing spectroscopic signals. Compounds 1 and 2 have been confirmed to be competitive soluble epoxide hydrolase (sEH) inhibitors that suppress the catalytic reaction of sEH in a dose-dependent manner in vitro. Molecular docking was used for analyzing two binding clusters of ligand and receptor. The results confirmed that the key amino acids interacting with the ligand were Asp335, Tyr383, and Gln384. On the basis of molecular dynamics, inhibitors 1 and 2 were noted to interact at a distance of 3.5 A from Asp335, Tyr383, Leu408 and Tyr466, and Asp335, Tyr383, and Tyr466, respectively. These results highlight the potential of N-trans-coumaroyltyramine (1) and N-trans-feruloyltyramine (2) as sEH inhibitors. PMID- 30425802 TI - iGHBP: Computational identification of growth hormone binding proteins from sequences using extremely randomised tree. AB - A soluble carrier growth hormone binding protein (GHBP) that can selectively and non-covalently interact with growth hormone, thereby acting as a modulator or inhibitor of growth hormone signalling. Accurate identification of the GHBP from a given protein sequence also provides important clues for understanding cell growth and cellular mechanisms. In the postgenomic era, there has been an abundance of protein sequence data garnered, hence it is crucial to develop an automated computational method which enables fast and accurate identification of putative GHBPs within a vast number of candidate proteins. In this study, we describe a novel machine-learning-based predictor called iGHBP for the identification of GHBP. In order to predict GHBP from a given protein sequence, we trained an extremely randomised tree with an optimal feature set that was obtained from a combination of dipeptide composition and amino acid index values by applying a two-step feature selection protocol. During cross-validation analysis, iGHBP achieved an accuracy of 84.9%, which was ~7% higher than the control extremely randomised tree predictor trained with all features, thus demonstrating the effectiveness of our feature selection protocol. Furthermore, when objectively evaluated on an independent data set, our proposed iGHBP method displayed superior performance compared to the existing method. Additionally, a user-friendly web server that implements the proposed iGHBP has been established and is available at http://thegleelab.org/iGHBP. PMID- 30425803 TI - Budget impact of antimicrobial wound dressings in the treatment of venous leg ulcers in the German outpatient care sector: a budget impact analysis. AB - Background: Hard-to-heal wounds are associated with high treatment costs and, in Germany, are mostly treated in the outpatient care sector. Wound dressings are the main cost-drivers in venous leg ulcer (VLU) care which prescription is budget restricted. Objective: To determine to what extent the choice of antimicrobial dressing affects the spending in outpatient care by investigating the budget impact of the bioburden-reducing dressing Cutimed Sorbact. Methods: The budget impact analysis was performed comparing three different scenarios of the intervention mix of antimicrobial dressings. A Markov model was used to estimate the VLU progression during one year. The budget impact was determined by comparing the dressing and medicine resource use and costs of the three scenarios. Results: This analysis confirms the high treatment costs of VLU care. ScenarioA leads to a decreased resource use of antimicrobial dressings and results in 20.86% lower treatment costs after 12 months. The increased use of Cutimed Sorbact has a positive budget impact. Conclusion: This analysis indicates that the treatment of VLU patients may result in an exceedance of the budget per patient that is available to the treating practitioner. The choice of wound dressing, however, may positively affect the prescribers' budget spending in outpatient care. PMID- 30425804 TI - Patient-reported outcome claims in European and United States orphan drug approvals. AB - Purpose: We aimed to evaluate the rate of usage and the kind of patient-reported outcome (PRO) claims in orphan drug approvals from the European Medicines Agency (EMA) dated between 1/1/2012 and 31/12/2016 and to compare them to those from the US Food and Drug Administration (FDA). Methods: Orphan drug approval documentation was obtained from the EMA website. PRO-related language was extracted from the Summaries of Product Characteristics (SmPCs). Data were compared to a previously published analysis of the FDA approvals from the same time period. Results: Out of 60 approvals that met the inclusion criteria, 12 products approved by the EMA for 13 (21.7%) orphan indications contained PRO language in the Clinical Studies section of the SmPC. Twelve SmPCs contained PRO instruments based on symptoms, five of which also concerned patient functioning. Eight approvals included PRO claims related to quality of life (QoL) most commonly in cancer treatment. Conclusion: The rate of PRO claims was lower for orphan drugs specifically than for all drug approvals by the EMA. However, in accordance with previous findings, the EMA appeared more inclined to grant PRO claims including health-related QoL than the FDA. PMID- 30425805 TI - Does colectomy affect the progression of primary sclerosing cholangitis? A systematic review and meta-analysis. AB - Aim: The aim of this systematic review was to determine if the human colon, through the lower gut-liver axis, drives PSC activity by assessing the progression of the disease in patients with and without colectomy for colonic disease. Background: The gut-liver axis is involved in the pathogenesis of liver disease. Abnormal immune-mediated responses to intestinal microbiome are implicated in primary sclerosing cholangitis (PSC) however the mechanisms remain poorly understood. Currently, no single animal model recapitulates all attributes of PSC in humans and this limits further studies of gut-liver interactions. Methods: A systematic search of PubMed, Medline, and Scopus was performed for articles that contained the terms "colectomy" or "bowel resection" AND "primary sclerosing cholangitis" up to 15th April 2018. Articles were reviewed by 2 reviewers and raw data collated. A Forest plot was used to illustrate the effect of colectomy on subsequent liver transplantation for PSC. Linear regression was used to estimate mortality risk. Results: Colectomy appeared to have no effect on PSC progression, although high-quality studies were lacking. Rates of liver transplantation or transjugular intrahepatic portosystemic shunt for PSC were not affected by colectomy (OR 0.59, 95% CI 0.14 - 2.53, p=0.48). Mortality risk following colectomy in patients with PSC is 2.11% per year (95% CI 0.03% - 4.18%, p=0.032, R2 = 0.722). Conclusion: Current evidence is limited but suggests colectomy does not affect the progression of PSC in patients with colonic disease. Pathogenic micro-organisms or antigens that drive PSC may not be limited to the lower gut. PMID- 30425807 TI - False negative and false positive rates in common bile duct brushing cytology, a single center experience. AB - Aim: In this study we tried to find out the accuracy of biliary tract brushing cytology in our center as the largest referral center in the south of Iran. Background: Common bile duct brushing cytology has been introduced as the method of choice for the diagnosis of pancreaticobiliary malignancies. However, there have been controversial reports about the sensitivity, specificity and overall accuracy of this method in the English literature. Methods: During the study period (2012-2016) there has been 166 cases of common bile duct brushing cytology taken during endoscopic retrograde cholangiopancreatography (ERCP). One case has been excluded because of inadequate number of cells in the cytology smear. All the smears have been stained by routine cytologic stains and screened by cytotechnologists and diagnosed by expert cytopathologist. Final diagnosis by biopsy has been considered as the gold standard. Results: According to the final histologic diagnosis as the gold standard, there were 22 false negative and 7 false positive cases. All of the false positive cases have been suspected cases in the background of primary sclerosing cholangitis. The most common final diagnosis of false negative cytologic diagnoses has been intrahepatic cholangiocarcinoma in which no malignant cell has been identified in the presence of adequate number of normal ductal epithelial cells. Conclusion: Common bile duct brushing cytology is the method of choice for the diagnosis of pancreaticobiliary tract malignancies; however, having high specificity (90%), the sensitivity is low (56%). Cytologic diagnosis of biliary tract malignancies should be made with caution in the patients with primary sclerosing cholangitis. Also it is important to know that high false negative rate is present in common bile duct brushing cytology especially in the cases of intrahepatic cholangiocarcinoma without extension into extrahepatic ducts. PMID- 30425806 TI - Probiotics and their role in gastrointestinal cancers prevention and treatment; an overview. AB - Cancers of the gastrointestinal (GI) track are a serious global health problem. The human GI tract is home to trillions of microorganisms that known as gut microbiota and have established a symbiotic relationship with the host. The human intestinal microbiota plays an important role in the development of the gut immune system, metabolism, nutrition absorption, production of short-chain fatty acids and essential vitamins, resistance to pathogenic microorganisms, and modulates a normal immunological response. Microbiota imbalance has been involved in many disorders including inflammatory bowel disease, obesity, asthma, psychiatric illnesses, and cancers. Oral administration of probiotics seems to play a protective role against cancer development as a kind of functional foods. Moreover, clinical application of probiotics has shown that some probiotic strains can reduce the incidence of post-operative inflammation in cancer patients. In the present narrative review, we carried out update knowledge on probiotic effects and underlying mechanism to GI cancers. Currently, it is accept that most commercial probiotic products are generally safe and can used as a supplement for cancer prevention and treatment. Nevertheless, well-designed, randomized, double blind, placebo-controlled human studies are required to gain the acceptance of the potential probiotics as an alternative therapy for cancer control.. PMID- 30425808 TI - The use of Karnofsky Performance Status (KPS) as a predictor of 3 month post discharge mortality in cirrhotic patients. AB - Aim: Is Karnofsky Performance Status (KPS) a predictor of 3 month post discharge mortality in cirrhotic patients? Background: Cirrhotic patients often experience an abrupt decline in their health, which often leads to frequent hospitalization and can cause morbidity and mortality. Various models are currently used to predict mortality in cirrhotics however these have their limitations. The Karnofsky Performance Status (KPS) being one of the oldest performance status scales, is a health care provider-administered assessment that has been validated to predict mortality across the elderly and in the chronic disease populations. Methods: We used the KPS performance status scale to envisage short-term mortality in cirrhotic and HCC patients who survive to be discharged from hospital. Results: Our study showed that KPS one week post-discharge, child pugh score, hospital stay, international normalized ratio, serum albumin, total bilirubin and serum creatinine showed statistical significance on univariate analysis. On multivariate analysis, KPS was found to be statistical significant predictor of 3-month mortality. Conclusion: Hence KPS can be utilized to identify cirrhotic patients at risk of 3-month post discharge mortality. PMID- 30425809 TI - Emergency stomas; should non-colorectal surgeons be doing it? AB - Aim: The aim of this study was to compare general and stoma specific short term complications in patients having stoma surgery in either an emergency or elective setting during their index hospital stay. It also compares the complications specific to a stoma carried out by surgeons with or without a specialist interest in colorectal surgery. Background: The stoma created in emergency surgery has a high short and long term complication rate. Emergency stomas where the site has not been marked preoperatively by a stoma therapist are more prone to complications. These complications may severely affect a patient's quality of life. Methods: We retrospectively analysed data for all non-urological stomas created over the last three years in our institute. This covered the period from January 2014 to January 2017. The stoma care department kept a full database record of all patients. Besides demography we analysed the type of stoma i.e. colostomy or ileostomy, indications for the stoma, most common operation, length of stay (LOS) and short term complications based on the Clavien-Dindo classification. We also analysed the perioperative stoma related complications within the emergency cohort. Results: A total of 199 patients had new ostomies created during the three-year period. Four patients died during the inpatient stay and were excluded from the analysis. The total number of stomas created in the emergency cohort was 60 and 135 stomas were elective procedures. The male to female ratio was 1:1.01. The average age for the emergency cohort was 6 years older than for the elective cohort. There was a statistically significant difference in length of stay between the two cohorts (T Test P Value =.02). There was a higher number of elective patients discharged in the first week compared to the emergency surgery patients. The rate of grade 3 or 4 complications was higher in the emergency cohort of patients. The rate of grade 3 or 4 complications was also much higher in patients operated by surgeons who did not have a specialist interest in colorectal surgery. The majority of grade 3 complications seen in the emergency surgery cohort and operated on by non-colorectal specialists (NCS) were stoma related, i.e retraction, necrosis and prolapse. Conclusion: Emergency surgery procedures are frequently bowel related. Emergency stoma surgery should not be taken as trivial procedure, non-colorectal surgeons should take advice and assistance from specialist colorectal surgeons for bowel related cases, particularly when a stoma is involved. PMID- 30425810 TI - Effect of red sugar on functional constipation in children compared to figs syrup; a randomized controlled trial study. AB - Aim: The present study is aimed to investigate the effect of red sugar on functional constipation in children compared to figs syrup. Background: Treatment of constipation in childhood improves gastrointestinal function in the future and regular bowel habit. Red sugar is an effective ingredient in the treatment of constipation. Figs syrup is the other common natural substance used to treat constipation in children. Conducted studies on these two substances and similar herbal substances have shown their beneficial effects, but in a conducted study, it is reported that the effect of fig syrup is less than the chemical material. Methods: This Randomized Controlled Trial (RCT) Study was done in 2016. First, by performing an examination and filling out the identifying form of the patient's health status, mothers respond to the designed questionnaire. 30 children with constipation were treated with the usual drug, fig syrup, and 30 other children received red sugar. After a 4-week treatment period, the examination was conducted again and the questionnaire was filled out again. The changes following the intervention were measured and the status before and after treatment were compared as well. The analyses were performed using SPSS 20 (SPSS for Windows, SPSS Inc., Chicago, IL, USA). Results: In this study, there was no significant difference between effects of red sugar and fig syrup in terms of the frequency of fecal excretion, and pain at the time of excretion (p = 0.264). However, the fig syrup was more effective in reducing the anorexia (p < 0.001) and abdominal pain compared with fig syrup (p < 0.001). Also fig syrup was more effective in inducing diarrhea (p = 0.019). Conclusion: In general, treatment by red sugar has been effective in improving the functional characteristics of constipation in children; and did not show any complication and toxic effects. It is easily accessible at affordable prices to resolve childhood constipation. PMID- 30425811 TI - Combination of diclofenac and aggressive hydration for the prevention of post ERCP pancreatitis. AB - Aim: To investigate whether aggressive hydration can increase the efficacy of prophylactic non-steroid anti-inflammatory drugs (NSAIDs) in prevention of post ERCP pancreatitis. Background: NSAIDs are recommended for the prevention of PEP; however, whether aggressive hydration can have additional benefits in this regard is not known. Methods: Patients candidate for ERCP received either pre-procedural rectal diclofenac (100 mg) alone (n = 112) or in combination with aggressive hydration by lactate ringer's (n = 107) as prophylactic method. PEP was defined based on increase in serum levels of pancreatic enzymes (from baseline to 24 hours following the procedure) accompanied with symptoms. Results: PEP was occurred in 3 patients in the diclofenac only group and in 1 patient in the diclofenac + hydration group with no significant difference (2.7% vs. 0.9%, P = 0.622). Serum amylase levels decreased over time in the diclofenac + hydration group but not in the diclofenac only group. Also, serum lipase levels decreased more rapidly over time in the diclofenac + hydration group compared to the diclofenac only group. Conclusion: Combination prophylactic therapy with NSAIDs plus aggressive hydration does not seem to have additional clinically important benefits in preventing PEP. Studies with larger sample of patients are required in this regard. PMID- 30425812 TI - NT-proBNP as a biomarker for hyperdynamic circulation in decompensated cirrhosis. AB - Aim: To assess NT-proBNP as a biomarker for hyperdynamic circulation in decompensated cirrhosis. Background: Hyperdynamic circulation is common in decompensated cirrhosis. The previous studies reveal that N-terminal-proBNP (NT proBNP) is elevated in cirrhosis. Methods: A prospective study involved 47 patients with decompensated cirrhosis. All of them underwent echocardiography with simultaneous measurement of blood pressure and heart rate. Cardiac output and systemic vascular resistance were calculated. The concentration of NT-proBNP in blood was measured with enzyme-linked immunosorbent assay. Results: In patients with decompensated cirrhosis, the concentration of NT-proBNP in blood directly correlated with end-diastolic volume (r=0.482; p<0.001), stroke volume (r= 0.566; p<0.001), cardiac output (r=0.556; p<0.001), volume of the left atrium (r=0.292; p=0.047), and inversely correlated with systemic vascular resistance (r=-0.538; p<0.001). There was no significant correlation between NT-proBNP and ejection fraction (p=0.083). Patients with hyperdynamic circulation have higher concentration of NT-proBNP (152/476 pg/ml vs. 31/133 pg/ml, p<0.001) regardless of the presence of diastolic dysfunction (p=0.222). According to ROC analysis, the best cut-off values for detection of hyperdynamic circulation in decompensated cirrhosis are considered to be 170.0 pg/ml of blood NT-proBNP, showing sensitivity and specificity of 72.0 and 86.4%, respectively. The positive and negative predictive value are 86.4% and 73.1%, AUC = 0.829 (0.709-0.949). Conclusion: NT-proBNP may serve as a non-invasive biomarker for hyperdynamic circulation in decompensated cirrhosis. PMID- 30425813 TI - Designing a novel ELISA method based on CagA, NapA recombinant antigens to increase sensitivity and specificity of Helicobacter pylori whole cell antigen detection. AB - Aim: In this research, we designed a direct Enzyme Linked Immunoassay method to detect Helicobacter pylori antigens in stool specimens. Background: Helicobacter pylori infection as the worldwide problem is related to many gastrointestinal disorders such as gastritis, gastric cancer, non-ulcer disease, peptic ulcer disease and duodenal ulcer. Methods: We produced and purified recombinant CagA and NapA antigens in Escherichia coli and extracted their antibodies from a panel of positive sera specimens. We designed a novel enzyme linked immunoassay direct method in combination with the whole cell for the qualitative and quantitative detection of Helicobacter pylori antigens in human stool. Assay performance was evaluated by histopathology staining and urease activity. Results: The sensitivity and specificity of assay was determined as 91.7 [95% confidence interval: 89.3-95.6%] and 93.1% [95% CI: 91.2-96.4%], respectively. Novel ELISA exhibits enhanced sensitivity and specificity of Helicobacter pylori detection in comparison with another commercially available kit. Conclusion: Combination of the recombinant antigens and whole cell of Helicobacter pylori in immunoassay designing is a new approach about early diagnosis, treatment and fallowing up of the Helicobacter pylori infected patients, especially in peptic cancer cases. PMID- 30425814 TI - Comparative study of gastric cancer and chronic gastritis via network analysis. AB - Aim: In this study the significant differentially expressed genes (DEGs) related to gastric cancer (GC) and chronic gastritis were screened to introduce common and distinctive genes between the two diseases. Background: Diagnosis of gastric cancer as a mortal disease and chronic gastritis the stomach disorder which can be considered as risk factor of GCs required safe and effective molecular biomarkers. Methods: Microarray profiles were downloaded from Gene Expression Omnibus (GEO) and analyzed via GEO2R. The candidate DEGs plus relevant genes from STRING database were interacted by Cytoscape software version 3.6.0 the central nodes were determined and analyzed. Results: JUN, GAPDH, FOS, TP53, PRDM10, VEGFA, and CREB1 as central nodes and TFF1 and ERG1 as the top changed expressed genes were determined as critical nodes related to gastric cancer. GAPDH, PRDM10, TP53, JUN, AKT1, EGFR, MAPK1, EGF, DECR1, and MYC were identified as common remarkable genes between GC and chronic gastritis. Conclusion: Identification of distinctive and common genes between GC and chronic gastritis can be useful in the early stage detection of disease and reducing risk of GCs. PMID- 30425815 TI - Small-scale risk assessment of transmission of parasites from wastewater treatment plant to downstream vegetable farms. AB - Aim: The aim of the present study was to simultaneously investigate parasitic contamination of treated wastewater and downstream vegetable farms that are irrigated with treated sewage, during a year. Background: (Oo) Cysts and eggs of parasites are resistant to most of routine wastewater treatment process. Irrigation of vegetables farms with either treated wastewater or illegally use of raw wastewaters enhances the risk of contamination with enteric pathogens. Methods: The treated wastewater samples were taken after chlorination from a wastewater treatment plant located at the south of Tehran. In addition, 60 vegetable samples (5 samples from each farm) were collected from the selected downstream farms that routinely used treated wastewater for irrigation of crops. Parasitological tests were performed using Ziehl-Neelsen, conventional lugol's iodine staining and direct microscopical examination. Results: Parasites including free living larvae, eggs of Toxoascaris leonina, egg of Toxocara sp. Trichuris sp, Trichostrongylus sp and amoeboid trophozoite were seen in 5/12 (41.7%) of vegetable samples gathered during a year. There was no statistically significant correlation between the season and parasitic contamination of the vegetables (P= 1). Furthermore, parasitic contamination was observed in 7/12 (53.8%) of treated wastewater samples. The correlation between season and parasitic contamination of treated wastewater was evaluated that the results showed a higher contamination of treated wastewater in spring and autumn (P<0.05). Fisher's exact test also showed that there was no significant correlation between parasitic contaminations of vegetable samples and treated wastewater according to seasonal change. Conclusion: The results showed parasites in both treated wastewater plant and downstream crops farms that suggests the public health importance of the quality of water resources that routinely used for irrigation of vegetable farms. PMID- 30425816 TI - A rare presentation of simple renal cyst: gastrointestinal obstruction. AB - Simple renal cysts are one of the most common lesions in elderly. These cysts are usually asymptomatic but when the size of these cysts increase, we would see symptoms such as hypertension, hematuria, flank pain or urinary obstruction. In this study, we explore a case of small bowel obstruction that presented with nausea, repeated vomiting that causes hematemesis, and a submucosal obstructive lesion that was seen in Esophagogastroduodenoscopy (EGD). After endoscopic ultrasound (EUS) evaluation, we detected a large simple renal cyst and approved our diagnosis with CT scan. We planned a medical treatment for this patient that consist consuming small size meals, 5 to 6 times a day, and high calorie liquids in small volumes. We conclude that simple renal cyst can be one of the cause of extrinsic intestinal obstruction and EUS is affective for differentiation of intrinsic submucosal lesion from extrinsic compression. PMID- 30425817 TI - Recent advances in non-alcoholic fatty liver disease. PMID- 30425818 TI - Rank-Two NMF Clustering for Glioblastoma Characterization. AB - This study investigates a novel classification method for 3D multimodal MRI glioblastomas tumor characterization. We formulate our segmentation problem as a linear mixture model (LMM). Thus, we provide a nonnegative matrix M from every MRI slice in every segmentation process' step. This matrix will be used as an input for the first segmentation process to extract the edema region from T2 and FLAIR modalities. After that, in the rest of segmentation processes, we extract the edema region from T1c modality, generate the matrix M, and segment the necrosis, the enhanced tumor, and the nonenhanced tumor regions. In the segmentation process, we apply a rank-two NMF clustering. We have executed our tumor characterization method on BraTS 2015 challenge dataset. Quantitative and qualitative evaluations over the publicly training and testing dataset from the MICCAI 2015 multimodal brain segmentation challenge (BraTS 2015) attested that the proposed algorithm could yield a competitive performance for brain glioblastomas characterization (necrosis, tumor core, and edema) among several competing methods. PMID- 30425819 TI - Blood Pressure Estimation Using Photoplethysmography Only: Comparison between Different Machine Learning Approaches. AB - Introduction: Blood pressure (BP) has been a potential risk factor for cardiovascular diseases. BP measurement is one of the most useful parameters for early diagnosis, prevention, and treatment of cardiovascular diseases. At present, BP measurement mainly relies on cuff-based techniques that cause inconvenience and discomfort to users. Although some of the present prototype cuffless BP measurement techniques are able to reach overall acceptable accuracies, they require an electrocardiogram (ECG) and a photoplethysmograph (PPG) that make them unsuitable for true wearable applications. Therefore, developing a single PPG-based cuffless BP estimation algorithm with enough accuracy would be clinically and practically useful. Methods: The University of Queensland vital sign dataset (online database) was accessed to extract raw PPG signals and its corresponding reference BPs (systolic BP and diastolic BP). The online database consisted of PPG waveforms of 32 cases from whom 8133 (good quality) signal segments (5 s for each) were extracted, preprocessed, and normalised in both width and amplitude. Three most significant pulse features (pulse area, pulse rising time, and width 25%) with their corresponding reference BPs were used to train and test three machine learning algorithms (regression tree, multiple linear regression (MLR), and support vector machine (SVM)). A 10 fold cross-validation was applied to obtain overall BP estimation accuracy, separately for the three machine learning algorithms. Their estimation accuracies were further analysed separately for three clinical BP categories (normotensive, hypertensive, and hypotensive). Finally, they were compared with the ISO standard for noninvasive BP device validation (average difference no greater than 5 mmHg and SD no greater than 8 mmHg). Results: In terms of overall estimation accuracy, the regression tree achieved the best overall accuracy for SBP (mean and SD of difference: -0.1 +/- 6.5 mmHg) and DBP (mean and SD of difference: -0.6 +/- 5.2 mmHg). MLR and SVM achieved the overall mean difference less than 5 mmHg for both SBP and DBP, but their SD of difference was >8 mmHg. Regarding the estimation accuracy in each BP categories, only the regression tree achieved acceptable ISO standard for SBP (-1.1 +/- 5.7 mmHg) and DBP (-0.03 +/- 5.6 mmHg) in the normotensive category. MLR and SVM did not achieve acceptable accuracies in any BP categories. Conclusion: This study developed and compared three machine learning algorithms to estimate BPs using PPG only and revealed that the regression tree algorithm was the best approach with overall acceptable accuracy to ISO standard for BP device validation. Furthermore, this study demonstrated that the regression tree algorithm achieved acceptable measurement accuracy only in the normotensive category, suggesting that future algorithm development for BP estimation should be more specific for different BP categories. PMID- 30425820 TI - Functional and Structural Plasticity of Brain in Elite Karate Athletes. AB - The structural and functional neural differences between the elite karate athletes and control group have been investigated in the concept of this study. 13 elite karate athletes and age-gender matched 13 volunteers who have not performed regular exercises participated in the study. Magnetic resonance imaging was used to acquire the anatomical and functional maps. T1-weighted anatomical images were segmented to form gray and white matter images. Voxel-based morphometry is used to elucidate the differences between the groups. Moreover, resting state functional measurements had been done, and group independent component analysis was implemented in order to exhibit the resting state networks. Then, second-level general linear models were used to compute the statistical maps. It has been revealed that increased GM volume values of inferior/superior temporal, occipital, premotor cortex, and temporal pole superior were present for the elite athletes. Additionally, WM values were found to be increased in caudate nucleus, hypothalamus, and mammilary region for the elite karate players. Similarly, for the elite karate players, the brain regions involved in the movement planning and visual perception are found to have higher connectivity values. The differences in these findings can be thought to be originated from the advances gained through the several years of training which is required to be an elite karate athlete. PMID- 30425821 TI - Evolution Model of Health Food Safety Risk Based on Prospect Theory. AB - In the growing market of health food, certain disturbances occur, such as uneven quality of products, imitation of health food, prohibited drug content in health food, functional efficacy, and actual disagreement. The safety of health food has attracted wide attention from all walks of life. In this study, we constructed a three-party game model of health food safety risk evolution, which includes health food enterprises, health food consumers, and government regulators, based on prospect theory and evolutionary game method. We also consider the attributes of "trust products" of health food, the ability to identify the safety information of health food, the subjective perception of the efficacy of health food, and the certification effect of the regulatory information of the government supervision department. The influence mechanism of these factors, including the cost of searching for health food information, consumers' subjective perception of health food efficiency, and the certification effect of supervision departments, on health food safety risk evolution is described using theoretical deduction and simulation analysis. On this basis, the corresponding conclusions are established, which provide a theoretical basis for further exploration of the strategy of health food market governance. PMID- 30425822 TI - Understanding biogeographical patterns in the western Balkan Peninsula using environmental niche modelling and geostatistics in polymorphic Edraianthus tenuifolius. AB - The Balkan Peninsula represents one of the three southern European glacial refugia where biodiversity persisted throughout the climatically unstable Quaternary. This study considered the 'refugia within refugia' model, which assumes the environmental heterogeneity over time and space in larger refugia. To better understand patterns shaped during the Quaternary climatic oscillations, the present and last glacial maximum (LGM) environmental conditions and current morphological variability of Edraianthus tenuifolius, an endemic plant of the western Balkans with a well-known therphical structure, were considered. Potential present and LGM distributions were studied through environmental niche modelling using 161 data of occurrences and six bioclimatic variables, hindcasting the model to LGM conditions using three different global circulation models. To test the geographical variability of the reproductive region, 41 characters of 667 inflorescences from 35 populations within the distribution range were measured. Geographical patterns, using geostatistics together with univariate and multivariate statistical approaches, were analysed. The environmental niche model suggested the current potential distribution in correspondence to its known occurrences. The hindcast to LGM conditions suggested two separate areas of environmental suitability, one in the present-day northern Adriatic coast of Croatia (Istrian Peninsula, Kvarner) and another on the present day south-eastern Adriatic coast (southern Dalmatia, Montenegro and northern Albania). Morphological variability showed a similar pattern, where southern populations separated from northern populations according to a major split in the central part of its distribution range (central Dalmatia). On other levels, stronger barriers were predicted to separate northern populations from the eastern Istrian Peninsula and the Kvarner area. The results suggested congruent biogeographical patterns to the already known phylogeographical structure. Both environmental niche modelling and the geographical variability of morphological characters suggested spatial partitioning, indicating the potential presence of two separate refugia during the LGM. PMID- 30425823 TI - Effect of Artificial Piglet Suckling Sounds on Behavior and Performance of Piglets and Adrenal Responses of Sows. AB - Operation of the farrowing house is essential to the productivity of a swine farm, requiring not only good management but also knowledge of the behavior of sows and piglets. Stress can negatively affect production in farm animals and could be a factor in production indexes. The objective of this study was to investigate the effect of artificial sucking sounds on the behavior of piglets and fecal glucocorticoid (FGM) concentrations of sows. A total of 30 sows were divided into two groups: a treatment group (15 sows) was exposed to artificial sucking sounds and a control group (15 sows) was not. Both groups received the same management; the two open-house system locations were separated by a distance of about 270 meters. The study had three key objectives: to compare farrowing indexes and to observe the sucking behavior of piglets using CCTV cameras. Fecal samples were collected daily for 21 days from the period after parturition to weaning to assess adrenal activity. The treatment group had a significantly higher average number of times piglets came to a sow's udder, and sows had a shorter onset time for the first piglet to come to the sow's udder than the control group (both P<0.05). The patterns and levels of FGM between the two groups were not different (both P<0.05), but the treatment group had better farrowing indexes than the control group (P>0.05), particularly for litter weight gain and percent preweaning mortality. In addition, the weaning to first service interval of the treatment group was shorter than the control group (P<0.05). This indicates that the artificial suckling sound probably has no adverse effect on adrenal responses of pig; however, it improves production indexes of postparturition sows. PMID- 30425824 TI - Dosing Patterns during Conversion to IPX066, Extended-Release Carbidopa-Levodopa (ER CD-LD), in Parkinson's Disease with Motor Fluctuations. AB - Background: IPX066 is an extended-release (ER) oral formulation of carbidopa levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. Objective: To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Methods: Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The "converted" daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. Results: The average daily LD dose ratio at the end of dose conversion to ER CD LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses >=800 mg and dose frequencies >=6 tended to have higher rates of discontinuation during conversion to ER CD-LD. Conclusions: Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (<=1250 mg) and dose frequencies (<7) of LD, final mean dose ratios were within tight ranges of 2.1 to 2.4 for IR CD-LD (ADVANCE-PD) and 2.4 to 2.8 for CLE (ASCEND-PD) and were generally independent of the LD dosing frequency at study entry. These trials are registered with NCT00974974, NCT01130493. PMID- 30416713 TI - Explicit interaction information from WikiPathways in RDF facilitates drug discovery in the Open PHACTS Discovery Platform. AB - Open PHACTS is a pre-competitive project to answer scientific questions developed recently by the pharmaceutical industry. Having high quality biological interaction information in the Open PHACTS Discovery Platform is needed to answer multiple pathway related questions. To address this, updated WikiPathways data has been added to the platform. This data includes information about biological interactions, such as stimulation and inhibition. The platform's Application Programming Interface (API) was extended with appropriate calls to reference these interactions. These new methods of the Open PHACTS API are available now. PMID- 30425827 TI - Centroid tracking and velocity measurement of white blood cell in video. AB - Automated blood cells tracking system has a vital role as the tracking process reflects the blood cell characteristics and indicates several diseases. Blood cells tracking is challenging due to the non-rigid shapes of the blood cells, and the variability in their videos along with the existence of different moving objects in the blood. To tackle such challenges, we proposed a green star based centroid (GSBC) moving white blood cell (WBC) tracking algorithm to measure its velocity and draw its trajectory. The proposed cell tracking system consists of two stages, namely WBC detection and blob analysis, and fine tuning the tracking process by determine the centroid of the WBC, and mark the centroid for further fine tracking and to exclude the bacteria from the bounding box. Furthermore, the speed and the trajectory of the WBC motion are recorded and plotted. In the experiments, an optical flow technique is compared with the proposed tracking system showing the superiority of the proposed system as the optical flow method failed to track the WBC. The proposed system identified the WBC accurately, while the optical flow identified all other objects lead to its disability to track the WBC. PMID- 30416715 TI - Central sensitization and pain hypersensitivity: Some critical considerations. AB - Since its discovery, central sensitization has gained enormous popularity. It is widely used to explain pain hypersensitivity in a wide range of clinical pain conditions. However, at present there is no general consensus on the definition of central sensitization. Moreover, the use of the term central sensitization in the clinical domain has been criticized. The aim of this paper is to foster the discussion on the definition of central sensitization and its use. PMID- 30425828 TI - Ensemble of subspace discriminant classifiers for schistosomal liver fibrosis staging in mice microscopic images. AB - Schistosomiasis is one of the dangerous parasitic diseases that affect the liver tissues leading to liver fibrosis. Such disease has several levels, which indicate the degree of fibrosis severity. To assess the fibrosis level for diagnosis and treatment, the microscopic images of the liver tissues were examined at their different stages. In the present work, an automated staging method is proposed to classify the statistical extracted features from each fibrosis stage using an ensemble classifier, namely the subspace ensemble using linear discriminant learning scheme. The performance of the subspace/discriminant ensemble classifier was compared to other ensemble combinations, namely the boosted/trees ensemble, bagged/trees ensemble, subspace/KNN ensemble, and the RUSBoosted/trees ensemble. The simulation results established the superiority of the proposed subspace/discriminant ensemble with 90% accuracy compared to the other ensemble classifiers. PMID- 30425829 TI - Evaluation of the diagnostic potential of trans abdominal ultrasonography in detecting intra-abdominal adhesions: A double-blinded cohort study. AB - Background: Intra-abdominal adhesion is one of the most important complications of abdominopelvic surgery. It increases morbidity and mortality for patients. Although laparoscopy is the gold standard of adhesion diagnosis, it can cause visceral damage during the operation. Therefore, surgeons prefer to use non invasive methods for planning the operation. We designed this study to evaluate transabdominal ultrasonography ( TAU) accuracy for diagnosing Intra-abdominal Adhesions. Material & methods: This double-blinded cohort study was conducted on 47 patients with previous laparotomy who undergo another surgery. Spontaneous visceral slide (SVS) and induced visceral slide (IVS) were measured during TAU. Results: The mean age and BMI of 47 patients were 43.21+/-10.3 and 27.545+/-5.76. The majority of the patients were female (76%). Mean SVS and IVS in patients with intra-abdominal adhesion were 8.73+/-1.60 and 44.84+/-11.60. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of TAU in intra-abdominal diagnosis were 83.33%, 51.72%, 51.72%, 83.33%, 63.83%. Conclusions: Although TAU is an appropriate method for detecting the intra-abdominal adhesion, it isn't good enough for diagnosing free adhesion area. We recommended further researches with greater sample size and other non-invasive techniques. PMID- 30425830 TI - Surgical outcome after standard abdominoperineal resection: A 15-year cohort study from a single cancer centre. AB - Background: Abdominoperineal resection (APR) is associated with a poorer oncological outcome than anterior resection. This may be due to higher rates of intra-operative perforation and circumferential resection margin involvement. The aim of this study was to audit our short and long-term results of abdominoperineal resection performed using conventional techniques and to compare this with other published series. Materials and methods: A retrospective review of all patients who had standard APR between January 2000 and December 2016 in a single institution, Cabrini Hospital, Melbourne, Australia. A total of 163 cases performed by nine different colorectal surgeons for primary rectal adenocarcinoma were identified, with their clinicopathological data analysed. Results: Using standard APR, only six patients (3.7%) were found to have a positive circumferential resection margin (CRM). There were two cases of intra-operative perforation (1.2%). Local recurrence rate was 5.6% of patients, with distant recurrence found in 24.9%. Disease-free survival at five years was 73.1%. Five year overall survival was 66.7%, 67.9% of all deaths were cancer-related. Conclusion: Short and long-term outcomes after standard APR in this study were comparable to previous published studies. The CRM rate of 3.7% compares favourably to published positive CRM rates for standard APR which ranged from 6 to 18%. Standard APR remains a viable technique for the treatment of rectal cancer. Patient selection and adequate training remain important factors. PMID- 30425831 TI - A case of NDM-carbapenemase-producing hypervirulent Klebsiella pneumoniae sequence type 23 from the UK. AB - Introduction: Hypervirulent capsular type K1 Klebsiella pneumoniae strains of clonal complex 23 (CC23) are associated with severe community-acquired pyogenic liver abscesses, often complicated by metastatic infections and significant mortality. The majority of hypervirulent strains reported are susceptible to most antibiotics except ampicillin. To the best of our knowledge, this is the first case of New Delhi metallo-beta-lactamase (bla NDM)-producing hypervirulent K. pneumoniae from the UK. Case presentation: We present a case of pyogenic liver abscess in a 63-year-old female of Bangladeshi origin, with a recent diagnosis of pancreatic cancer. The patient was treated with piperacillin/tazobactam and blood cultures grew a fully susceptible Escherichia coli. Despite antimicrobial therapy and drainage of the abscess, the patient continued to deteriorate and died on day seven of admission. The fluid drained from the liver abscess grew a fully susceptible E. coli and a multi-drug-resistant K. pneumoniae. Two weeks prior to admission, a rectal screening swab grew a metallo-beta-lactamase-producing K. pneumoniae. Molecular characterization revealed that both the K. pneumoniae isolates belonged to the hypervirulent K1 cluster of CC23, sequence type 23. The isolate from the rectal screen was positive for the bla NDM metallo-beta lactamase gene. Conclusion: The emergence of carbapenemase-producing hypervirulent K. pneumoniae strains presents a new and significant threat to global public health. Management of these infections will be extremely challenging due to the limited treatment options available and they are likely to be associated with an even greater mortality. PMID- 30425832 TI - A case report of brain abscess caused by Nocardia cyriacigeorgica in a diabetic patient. AB - Introduction: Nocardia are Gram-positive partially acid-fast bacilli capable of inducing a wide range of infections in patients with immunodeficiency, AIDS, cancer, lupus erythematous and diabetes. Nocardia cyriacigeorgica was first isolated in 2001 from a patient with chronic bronchitis. Since then, there have been reports on the clinical significance of this organism in patients with bronchitis, brain abscess and lung diseases. We, herein, report a case of brain abscess in an elderly diabetic patient from Iran. Case presentation: The patient was a 73 year-old woman admitted to hospital due to severe headache and shortness of breath. The patient had lived with diabetes for 20 years and suffered from chronic foot ulcer. She was admitted to hospital with fever, weakness, drowsiness and vomiting. Clinical examination and the head CT scan of the left frontal lobe of the brain revealed a metastatic carcinoma involving skull bone in the tumor that resulted in two surgical operations in the following two years. The brain abscess biopsy revealed an infection with Nocardia cyriacigeorgica confirmed by phenotypic and molecular tests including a PCR-based amplification of a target genetic marker, a 596 bp fragment of 16S rRNA gene, followed by almost full 16S rRNA sequencing. Conclusion: The rare infections, such as brain abscess with Nocardia, are easily neglected or misdiagnosed due to the fastidious nature of the organism and inadequate microbiological experience of laboratories in the hospitals of developing countries. This case shows that hospitals should consider a better laboratory protocol to deal with the clinical cases in which fastidious organisms, and in particular Nocardia, are involved. PMID- 30425833 TI - Characterization of rhinovirus C from a 4-year-old boy with acute onset dilated cardiomyopathy in Jakarta, Indonesia. AB - Introduction: Myocarditis, inflammation of the heart muscle, can be caused by infections, autoimmune disease or exposure to toxins. The major cause of myocarditis in the paediatric population is viral infection, including coxsackievirus B3, adenovirus, herpesvirus, parvovirus, influenza A and B, and hepatitis. Here, we report the detection of rhinovirus C in a boy with a clinical presentation of myocarditis, suggesting a possible causative role of this virus in this case. Case presentation: A previously well 4.5-year-old boy presented with increasing breathlessness for a week prior to admission. He also had upper respiratory tract infection a few days before the event. An echocardiogram revealed severe left ventricle (LV) systolic dysfunction with dilation of the LV. RNA was extracted from serum and two nasal swabs, and tested with conventional PCR at the family level for viruses including enterovirus, dengue, chikungunya, influenza, herpesvirus, paramyxovirus and coronavirus. Further characterization of the enterovirus group was carried out using PCR with primers targeting the VP4/VP2 gene, followed by sequencing. Molecular tests showed the presence of rhinovirus C genetic material in both serum and swab samples. Phylogenetic analysis of the VP4/VP2 region showed 96-97 % similarity with the closest strain isolated in Ulaanbaatar (Mongolia) and Japan in 2012. Conclusion: We report the possible association of rhinovirus C and myocarditis in a child presenting with acute onset of dilated cardiomyopathy. PMID- 30425834 TI - Native valve dual pathogen endocarditis caused by Burkholderia cepacia and Aspergillus flavus - a case report. AB - Introduction: Infective endocarditis (IE) is an important clinical condition with significant morbidity and mortality among the affected population. A single etiological agent is identifiable in more than 90 % of the cases, however, polymicrobial endocarditis (PE) is a rare find, with a poor clinical outcome. Here we report a case of native valve dual pathogen endocarditis caused by Burkholderia cepacia and Aspergillus flavus in an immunocompetent individual. It is among unique occurrences of simultaneous bacterial and fungal etiology in IE. Case presentation: A 30-year-old male was admitted to a cardiology institute with complaints of low grade intermittent fever and progressive shortness of breath for last two months. He was a known case of rheumatic heart disease and had suffered an episode of IE three years ago. On the basis of clinical presentation and the results of radiological investigations, a diagnosis of infective endocarditis was made. Paired blood samples for culture and sensitivity, sampled before the commencement of antimicrobial therapy, yielded growth of Burkholderia cepacia which was highly drug resistant. Sensitivity results-directed therapy consisting of tablet Trimethoprim-Sulfamethoxazole, two double-strength tablets 12 hourly, and Meropenem, 1 g IV every 8 h, was commenced. Despite mild relief of fever intensity, overall clinical condition did not improve and double valve replacement therapy was carried out. Excised valves were sent for microbiological analysis. Burkholderia cepacia was grown on tissue culture with a similar antibiogram to that previously reported from the blood culture of this patient. Direct microscopy of section of valvular tissue with 10 % KOH revealed abundant fungal hyphae. Patient serum galactomannan antigen assay was also positive. Histopathological examination of vegetations also revealed hyphae typical of species of the genus Aspergillus. The patient was successfully treated with meropenem, trimethoprim-sulfamethoxazole and voriconazole. Conclusion: The hallmark of successful treatment in this case was exact identification of pathogens, antibiogram-directed therapy and good liaison between laboratory experts and treating clinicians. PMID- 30425835 TI - Total nephrectomy following Corynebacterium coyleae urinary tract infection. AB - Introduction: Corynebacterium coyleae is a Gram-stain-positive non-lipophilic coryneform rod first described in blood samples and pleural fluid. There is scarce information about the clinical relevance of C. coyleae and none on complicated urinary tract infections has been described so far. Case presentation: A 36-year-old woman with a history of chronic kidney failure, under thrice-weekly haemodialysis since 2014 due to polycystic kidney disease, presented with hypogastric pain, lower left quadrant pain and nausea. Since 1997, the patient had developed several episodes of urinary tract infection. On admission, the patient presented tenderness in the lower abdomen and fist positive lumbar percussion. Urine culture showed significant bacterial growth (>105 c.f.u. ml-1). Slightly glistening colonies of 1 mm in diameter were observed after a 24 h incubation. Gram staining showed coryneform Gram-stain positive rods. The patient was diagnosed as having a complicated urinary tract infection. A bilateral nephrectomy was performed on the fourth day of hospitalization. Two samples of kidney tissue were sent for culture. Direct examination of the material revealed the presence of abundant inflammatory reaction and Gram-positive diphtheroid rods. The organism was identified using MALDI-TOF and conventional biochemical tests; in both isolates further identification was performed by PCR amplification and sequence analysis of the rpoB gene as Corynebacterium coyleae. Conclusions: C. coyleae is an infrequent species among the genus Corynebacterium that should be considered as an emerging pathogen that can be involved in nosocomial infections and complicated urinary tract infections. PMID- 30425836 TI - Salmonella enterica serovar Typhimurium isolated from the urine of a dog undergoing treatment for immune-mediated polyarthritis. AB - Introduction: In people, Salmonella is a common agent of gastroenteritis, but it can also cause extraintestinal disease such as urinary tract infections. In addition, Salmonella is often linked to the post-infection development of reactive arthritis. In canines, cases that document extraintestinal Salmonella infections or diseases similar to reactive arthritis have not been thoroughly described. Case presentation: A case of a 5-year-old German shepherd dog with Salmonella bacteriuria during treatment for immune-mediated polyarthritis (IMPA) is described. The patient first suffered from a 3 month period of diarrhoea and presented for evaluation of a 2 month history of shifting-leg lameness. A diagnosis of IMPA was made based on cytological examination and negative synovial fluid culture. Treatment with immunosuppressive doses of prednisone lead to clinical resolution of lameness, but on a recheck abnormal urine was noted. Salmonella enterica serovar Typhimurium was isolated using standard culture methods. The patient was treated with enrofloxacin to control the bacteriuria. Conclusion: This case report is, to the best of our knowledge, the first to describe Salmonella bacteriuria in a dog and suggests that Salmonella infection may be a potential inciting factor for IMPA. PMID- 30425837 TI - Ehrlichiosis presenting as severe sepsis and meningoencephalitis in an immunocompetent adult. AB - Introduction: Ehrlichia are obligate intracellular pathogens transmitted to vertebrates by ticks. Case presentation: We report the case of a 59-year-old man who presented to the University of Kentucky Albert B. Chandler Medical Center (Lexington, KY, USA) after being found fallen down in the woods. A lumbar puncture revealed what appeared to be bacterial meningitis, yet cerebrospinal fluid cultures, Gram stains and a meningitis/encephalitis panel were inconclusive. However, an Ehrlichia DNA PCR of the blood resulted as being positive for Ehrlichia chaffeensis antibodies. The patient received a 14 day course of doxycycline, and recovered from his multiple organ failure. The aetiology of the ehrlichial meningoencephalitis was likely transmission through a tick-bite, due to the patient's outdoor exposure. Conclusion: While it is rare to see Ehrlichia as a cause of meningitis, this illness can progress to severe multisystem disease with septic shock, meningoencephalitis or acute respiratory distress syndrome (ARDS). Those with compromised immunity are at a higher risk of developing the more severe form of the disease and have higher case fatality rates. PMID- 30425838 TI - Fatal strongyloidiasis after corticosteroid therapy for presumed chronic obstructive pulmonary disease. AB - Introduction: Strongyloidiasis is a neglected tropical disease with global prevalence. Under some cases of immune suppression (especially with corticosteroid administration), the nematode involved disseminates, leading to an amplified, possibly lethal hyper-infection syndrome. Case presentation: A 56-year old Nepalese man presenting with chief complaints of nausea, vomiting, joint pain and abdominal cramps was admitted to Sumeru Hospital. His past history revealed: chronic obstructive pulmonary disease (COPD), systemic hypertension and previously treated pulmonary tuberculosis. The patient had been treated with oral prednisolone (60 mg gl-1) for 8 days due to a presumed exacerbation of his COPD. Sequentially, he developed haemoptysis, chest tightness, frequent wheezing and worsening cough. Bronchoscopy showed severe diffuse alveolar haemorrhage; microbiological examination of broncho-alveolar lavage (BAL) was recommended. Examination of an acid fast bacilli stain preparation of BAL revealed filariform larvae of Strongyloides. Stool specimen examination revealed larvae of Strongyloides. The physical condition of the patient began to deteriorate; a few days after admission, vancomycin-sensitive Enterococcus faecium was isolated from a blood sample. He was treated with ivermectin and albendazole for strongyloides and linezolid plus vancomycin for E. faecium. However, the patient failed to recover from the illness and died. Conclusion: The findings of our study suggest that corticosteroid administration in strongyloidiasis can lead to the development of fatal strongyloides hyper-infection syndrome. Hence our experience suggests the need for early diagnosis of strongyloidiasis to avoid such an outcome. A deterioration of the patient's condition after the initiation of corticosteroid therapy in endemic areas should raise the possibility of strongyloidiasis. PMID- 30425839 TI - Influence of mouth breathing on outcome of scaling and root planing in chronic periodontitis. AB - Introduction: Dryness is known to be associated with inflammatory diseases such as dry eye disease and atopic dermatitis. There is significant water loss from the oral cavity during mouth breathing. This study is conducted to estimate the influence of mouth breathing on the outcome of scaling and root planing (SRP) in chronic periodontitis (CP). Materials and methods: CP patients comprising of 33 mouth breathers (MBs) and 33 nose breathers (NBs) were recruited. Thirty patients in each group completed the study. At baseline, plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL) were measured. SRP was done in both groups. At the 4th, 8th, and 12th week, PI, GI, and BOP were recorded. PD and CAL were also assessed at the 12th week. Results: At the 12th week, there was significantly less improvement in GI at palatal sites of maxillary anterior and maxillary posterior teeth in MB group. Sixty-nine percent of BOP positive sites with PD >4 mm were converted into BOP negative sites with PD <=4 mm in maxillary posterior palatal sites in NB. This success was 38% in MB. Conclusion: Control of periodontal inflammation by SRP in CP patients is affected at palatal sites of mouth breathers. PMID- 30425840 TI - Experience with bruxism in the everyday oral implantology practice in the Netherlands: a qualitative study. AB - Objective: To explore how bruxism is dealt with by accredited oral implantologists within daily clinical practice. Materials and methods: Nine semi structured interviews of oral implantologists practicing in non-academic clinical practices in the Netherlands were performed, and thematic analysis was conducted using a framework-based approach. Results: Oral implant treatments in bruxing patients were a generally well-accepted practice. Complications were often expected, with most being of minor impact. Contradictive attitudes emerged on the topic of bruxism being an etiologic factor for peri-implant bone loss and loss of osseointegration. Views on the ideal treatment plan varied, though the importance of the superstructure's occlusion and articulation features was repeatedly pointed at. Similarly, views on protective splints varied, regarding their necessity and material choice. Bruxism was diagnosed mainly by clinical examination, alongside with patient anamnesis and clinician's intuition. There was little attention for awake bruxism. Discussion: Bruxism was generally not considered a contraindication for implantological treatments by accredited oral implantologists. Views on the interaction between bruxism and bone loss/loss of osseointegration varied, as did views on the ideal treatment plan. Conclusions: There is a need for better understanding of the extent to which, and under which circumstances, sleep and/or awake bruxism can be seen as causal factors for the occurrence of oral implant complications. PMID- 30425841 TI - Modeling site-specific amino-acid preferences deepens phylogenetic estimates of viral sequence divergence. AB - Molecular phylogenetics is often used to estimate the time since the divergence of modern gene sequences. For highly diverged sequences, such phylogenetic techniques sometimes estimate surprisingly recent divergence times. In the case of viruses, independent evidence indicates that the estimates of deep divergence times from molecular phylogenetics are sometimes too recent. This discrepancy is caused in part by inadequate models of purifying selection leading to branch length underestimation. Here we examine the effect on branch-length estimation of using models that incorporate experimental measurements of purifying selection. We find that models informed by experimentally measured site-specific amino-acid preferences estimate longer deep branches on phylogenies of influenza virus hemagglutinin. This lengthening of branches is due to more realistic stationary states of the models, and is mostly independent of the branch-length extension from modeling site-to-site variation in amino-acid substitution rate. The branch length extension from experimentally informed site-specific models is similar to that achieved by other approaches that allow the stationary state to vary across sites. However, the improvements from all of these site-specific but time homogeneous and site independent models are limited by the fact that a protein's amino-acid preferences gradually shift as it evolves. Overall, our work underscores the importance of modeling site-specific amino-acid preferences when estimating deep divergence times-but also shows the inherent limitations of approaches that fail to account for how these preferences shift over time. PMID- 30425842 TI - Gender influence on professional satisfaction and gender issue perception among young oncologists. A survey of the Young Oncologists Working Group of the Italian Association of Medical Oncology (AIOM). AB - Background: The professional gender gap is increasingly recognised in oncology. We explored gender issues perception and gender influence on professional satisfaction/gratification among young Italian oncologists. Methods: Italian oncologists aged <=40 years and members of the Italian Association of Medical Oncology were invited to participate in an online survey addressing workload/burnout, satisfaction in professional abilities and relations, relevant factors for professional gratification, and gender barriers. chi2 test for general association or chi2 test for trend was used to analyse the data. Results: 201 young oncologists participated in the survey: 67% female, 71% aged 30-40 years, 41% still in training and 82% without children. Women and men were equally poorly satisfied by the relations with people occupying superior hierarchical positions. There was heterogeneity between women and men in current (p=0.011) and expected future (p=0.007) satisfaction in professional abilities: women were more satisfied by current empathy and relations with colleagues and were more confident in their future managerial and team leader skills. The most important elements for professional gratification indicated by all participants were, in general, work-life balance (36%) and intellectual stimulation/research (32%); specifically for women, work-life balance (48%) and intellectual stimulation/research (20%); and specifically for men, career (29%) and social prestige/recognition (26%). Heterogeneity within the same gender emerged. For example, the elements indicated by men as the most important were intellectual stimulation/research (39%) and work-life balance (21%) in general, versus social prestige/recognition (24%) and career (24%), respectively, specifically for men (p<0.0001). More women versus men perceived gender issue as an actual problem (60% vs 38%, p=0.03); men underestimated gender barriers to women's career (p=0.011). Conclusions: Satisfaction in professional abilities varied by gender. Work-life balance is important for both women and men. Stereotypes about gender issues may be present. Gender issue is an actual problem for young oncologists, mostly perceived by women. PMID- 30425843 TI - Updated 5-year survival and exploratory T x N subset analyses of ACTS-CC trial: a randomised controlled trial of S-1 versus tegafur-uracil/leucovorin as adjuvant chemotherapy for stage III colon cancer. AB - Objective: Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC), a randomised phase III trial, demonstrated that adjuvant therapy with S-1 for stage III colon cancer was non-inferior in 3-year disease-free survival (DFS) to that of tegafur-uracil plus leucovorin (UFT/LV). We updated DFS and overall survival (OS) and performed T x N subset analysis. Methods: A total of 1518 patients with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days, four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days, five courses). Results: The 5-year DFS rates of the S-1 and UFT/LV group were 70.2 % and 66.9 %, respectively (HR 0.88; 95% CI 0.74 to 1.06; p=0.177), and non-inferiority of DFS was reconfirmed with a median of 63.5-month follow-up. The similarity of OS was also confirmed (HR 0.92; 95% CI 0.72 to 1.17; p=0.488); 5-year OS rates of the S 1 and UFT/LV group were 86.0 % and 84.4 %, respectively. No significant interactions were identified between the major baseline characteristics and DFS of the S-1 and UFT/LV groups, except for histological type; S-1 was more favourable in patients with poorly differentiated adenocarcinoma. Patient outcomes were well separated by TNM-substages (IIIA/IIIB/IIIC). With the patients divided into 20 subsets by T and N factors, the DFS and OS rates of T3 and N1 subset, which accounted for 62 % of stage IIIB patients and 44 % of all studied subjects, were significantly better than those of the other subsets in stage IIIB and similar to those of stage IIIA. Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was reconfirmed to be non-inferior in DFS to those of UFT/LV after long follow-up. No difference in OS was also demonstrated. T3N1 patients might be considered separately from other patients included in stage IIIB because of its favourable outcome. Trial registration number: NCT00660894. PMID- 30425844 TI - Risk factors for the development of brain metastases in patients with HER2 positive breast cancer. AB - Background: Patients with metastatic human epidermal growth factor receptor 2 positive breast cancer (HER2+ BC) frequently experience brain metastases (BM). We aimed to define risk factors for the development of BM in patients with HER2+ BC and to report on their outcome. Methods: This is a retrospective analysis of patients diagnosed with HER2+ BC between January 2000 and December 2014 at Institut Jules Bordet, Belgium. Statistical analyses were conducted with SAS V.9.4 using Kaplan-Meier method and Cox regression analyses. Results: A total of 483 patients were included of whom 108 (22.4%) developed metastases and 52 (10.8%) BM. Among 96 metastatic patients without BM at diagnosis, 40 (41.7%) developed BM in the course of their disease. In multivariate analysis, risk factors for the development of BM were age <=40 years (HR 2.10, 95 % CI 1.02 to 4.36), tumour size >2 cm (HR 4.94, 95% CI 1.69 to 14.47), nodal involvement (HR 3.48, 95% CI 1.47 to 8.25), absence or late start (>=6 months after initial diagnosis) of adjuvant anti-HER2 treatment (HR 3.79, 95% CI 1.52 to 9.43 or HR 2.65, 95% CI 1.03 to 6.82) and the development of lung metastases as first site of relapse (HR 6.97, 95% CI 3.41 to 14.24). Twenty-two patients with HER2+ BC and BM sent to our institute for further treatment were included in the outcome analysis. Asymptomatic patients at the time of BM diagnosis showed a better overall survival than symptomatic patients (HR 0.49, 95% CI 0.25 to 0.94). Conclusion: A considerable number of patients with metastatic HER2+ BC will develop BM. Screening of patients with risk factors for BM might lead to early detection and better outcome. However, randomised controlled trials examining the use of MRI as a screening method for BM in patients with metastatic BC are warranted before such an approach can be recommended. PMID- 30425846 TI - In the literature: October 2018. PMID- 30425845 TI - Precision oncology: separating the wheat from the chaff. AB - Precision oncology based on next-generation sequencing (NGS) test is growing in daily clinical practice. However, the real impact of this strategy in patients' outcome on a large scale remains uncertain. In this review, we summarise existing literature on this topic, limitations for broad NGS implementation, bottlenecks in genomic variant interpretation and the role of molecular tumour boards. PMID- 30425847 TI - ESMO 2018 presidential symposium-IMpassion130: atezolizumab+nab-paclitaxel in triple-negative breast cancer. PMID- 30425848 TI - Correction: Preparing for the incoming wave of biosimilars in oncology. AB - [This corrects the article DOI: 10.1136/esmoopen-2018-000420.]. PMID- 30425850 TI - Introducing the Metastatic Breast Cancer Project: a novel patient-partnered initiative to accelerate understanding of MBC. PMID- 30425849 TI - Efficacy and safety of ramucirumab-containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma. AB - Background: Ramucirumab (RAM), a monoclonal antibody for vascular endothelial growth factor 2 (VEGFR2), has been effective for advanced gastric adenocarcinoma (AC). However, little is known about the efficacy of RAM-containing chemotherapy (RAM-CTx) in gastric neuroendocrine carcinoma (G-NEC). Methods: We retrospectively analysed and compared the clinical outcomes of patients (pts) with G-NEC receiving RAM-CTx, G-NEC receiving CTx without RAM and AC receiving RAM-CTx in our hospital. G-NEC was defined by neuroendocrine carcinoma features, regardless of the proportion, based on histology and neuroendocrine markers (synaptophysin, chromogranin A or CD56). VEGFR2 expression in tumour vessels was evaluated in archival primary G-NEC tissues by immunohistochemistry using the same anti-VEGFR2 primary antibody and scoring scheme (vascular VEGFR2 H-score) as in the REGARD trial. Results: Seventeen G-NEC receiving RAM-CTx, 13 G-NEC receiving CTx without RAM and 173 AC pts receiving RAM-CTx were analysed. The overall response rate (59% vs 8 % vs 28%), progression-free survival (median 7.7 vs 1.8 vs 3.3 months) and overall survival (median 16.1 vs 8.6 vs 9.6 months) were significantly better in pts with G-NEC receiving RAM-CTx than G-NEC receiving CTx without RAM or AC receiving RAM-CTx. No severe or unexpected adverse events occurred. The median vascular VEGFR2 H-score, based on available G NEC tissues from 12 pts receiving RAM-CTx, was 220 (range 150-260), which was markedly higher than that reported on AC tissues from the REGARD trial as historical control (median 35, range 0-240). Conclusions: RAM-CTx showed a promising activity without severe or unexpected safety profile in pts with G-NEC. This may in part be explained by higher vascular VEGFR2 expression in G-NEC tissues. PMID- 30425851 TI - Protective Effects of Epifriedelinol in a Rat Model of Traumatic Brain Injury Assessed with Histological and Hematological Markers. AB - Background: This study evaluated the protective effects of epifriedelinol (EFD) in a rat model of traumatic brain injury (TBI). Methodology: TBI was induced by dropping a weight from a specific height. The animals were separated into control, TBI, and EFD 100 and 200 mg/kg groups. The latter received 100 and 200 mg/kg EFD, respectively, for 2 days beginning 30 min after inducing TBI. The neurological examination score, permeability of the blood-brain barrier (BBB), water content of the brain, cytokine levels, and oxidative stress parameters were measured in the rats. The effects of EFD on glial fibrillary acidic protein (GFAP)-positive cells were evaluated using immunohistochemistry. Result: The EFD treatment significantly decreased the neurological score, permeability of the BBB, and water content of brain compared with the TBI group. The levels of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and oxidative stress were significantly decreased in the EFD-treated groups. The number of GFAP-positive cells was also significantly reduced in the EFD-treated groups. Conclusion: EFD attenuates the secondary injury in TBI rats by reducing the serum cytokine levels and oxidative stress. PMID- 30425852 TI - Efficacy Comparison of Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta Analysis. AB - Purpose: Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy has been widely used for the treatment of neovascularization (NV) secondary to age-related macular degeneration (AMD). This study aimed to compare the efficacy among different subtypes of neovascular age-related macular degeneration (nAMD). Methods: PubMed, Embase, and the Cochrane Library were searched for eligible studies. We performed meta-analysis using Review Manager 5.3 and Stata/SE 12.0. Results: A total of 24 studies met our inclusion criteria and were included in the systematic review. At 3 months, the mean logarithm of the minimum angle of resolution (logMAR) improvements were -0.09, -0.18, and -0.23 for type 1, 2, and 3, respectively, while the mean macular thickness (MT) changes were -104.83, 130.76, and -196.29 MUm. At 12 months, the mean changes in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters were 6.38, 8.12, and 9.37, while the MT decrease was 126.51, 126.52, and 139.85 MUm, respectively. However, statistically significant difference was only found between type 1 and 3 in vision improvement, both in the short term (p=0.0002) and long term (p=0.01). Conclusions: The reactivity to VEGF inhibitors varied among different subtypes of nAMD. The efficacy of intravitreal anti-VEGF therapy in type 3 nAMD was statistically better than type 1 when considering vision improvement at 3 and 12 months. Thus, the lesion subtype is a predictor for the treatment outcome which can help guide prognosis. PMID- 30425853 TI - Characteristics of New Onset Herpes Simplex Keratitis after Keratoplasty. AB - Purpose: To observe clinical characteristics and treatment outcomes of new onset herpes simplex keratitis (HSK) after keratoplasty. Methods: Among 1,443 patients (1,443 eyes) who underwent keratoplasty (excluding cases of primary HSK) in Shandong Eye Hospital, 17 patients suffered postoperative HSK. The clinical manifestations, treatment regimens, and prognoses of the patients were evaluated. Results: The incidence of new onset HSK after keratoplasty was 1.18%. Epithelial HSK occurred in 10 eyes, with dendritic epithelial infiltration in 6 eyes and map like epithelial defects in 4 eyes. Nine eyes had lesions at the junction of the graft and recipient. Stromal necrotic and endothelial HSK occurred in 7 eyes, presenting map-shaped ulcers in the entire corneal graft and recipient (two eyes) or at the graft-recipient junction (five eyes). Confocal microscopy revealed infiltration of a large number of dendritic cells at the junction of the lesion and transparent cornea. All 10 eyes with epithelial lesions and two eyes suffering stromal lesions of <=1/3 corneal thickness healed after systematic and local antiviral treatment. Best-corrected visual acuity and corneal graft transparency were restored. For stromal HSK with an ulcer of >1/3 corneal thickness, amniotic membrane transplantation was performed, and visual acuity and graft transparency decreased significantly. Conclusion: New onset HSK after keratoplasty primarily resulted in epithelial and stromal lesion, involving both the graft and recipient. Effective treatments included antiviral medications and amniotic membrane transplantation. Delayed treatment may lead to aggravated graft opacification. PMID- 30425855 TI - Increased Corneal Toricity after Long-Term Orthokeratology Lens Wear. AB - Purpose: To investigate the change in corneal toricity and associated refractive astigmatism after discontinuation of long-term orthokeratology (ortho-k) lens wear. Methods: This study investigated 136 subjects aged between 6 and 14 (9.1 +/ 1.5) years old at the commencement of ortho-k treatment, who had been undergoing overnight ortho-k treatment for 24 to 72 (37.4 +/- 11.9) months. Corneal refractive power and manifest refraction were measured and compared before ortho k and 1 month after discontinuation of ortho-k lens wear. Changes in corneal curvature were analyzed. Corneal curvature data from a historical longitudinal study were used as control. Results: Compared to pre-ortho-k values, the corneal curvature became significantly flatter in the flatter meridian (-0.22 +/- 0.27 D, P < 0.001) and steeper in the steeper meridian (0.06 +/- 0.34 D, P=0.032) after cessation of ortho-k lens wear, resulting in a significant increase in corneal toricity (0.28 +/- 0.43 D, P < 0.001), which is associated with an increase in refractive astigmatism (0.57 +/- 0.57 D, r=0.465, P < 0.001). The amount of residual corneal flattening in the flatter meridian is significantly affected by the length of ortho-k treatment (t=-2.965, P=0.004) and the baseline age of subject (t=-2.841, P=0.005), but not by the baseline spherical or cylindrical refractive error (both P > 0.05). In the historical control group, there is no significant change in the corneal curvature over two years in children wearing spectacle lenses (both meridians, P > 0.05). Change of corneal toricity was more significant in the ortho-k group than in the spectacle control group (P=0.001). Conclusions: Long-term ortho-k lens wear increases corneal toricity after discontinuation of the treatment, which is associated with an increase in refractive astigmatism. A more pronounced change in corneal toricity was found in subjects who were younger to start ortho-k and have been in a longer period of treatment. This trial is registered with http://www.chictr.org.cn (ChiCTR-TNRC 11001210). PMID- 30425854 TI - Modified Vitrectomy Technique for Phakic Rhegmatogenous Retinal Detachment with Intermediate Break. AB - Purpose: To evaluate the effects of a modification of the traditional 25-gauge pars plana vitrectomy technique in the treatment of uncomplicated macula-on rhegmatogenous retinal detachment (RRD) with intermediate retinal break(s) and marked vitreous traction in the phakic eye. Methods: Prospective, noncomparative, and interventional case series. All consecutive phakic eyes with primary uncomplicated macula-on RRD with intermediate retinal break(s) and marked vitreous traction, with at least 1 year of postoperative follow-up, were enrolled. In all eyes, "localized 25-gauge vitrectomy" under air infusion with localized removal of the vitreous surrounding the retinal break(s), in association with laser photocoagulation and air tamponade, was performed. The primary end point was the rate of primary retinal attachment. Secondary end points were cataract progression and assessed by digital Scheimpflug lens photography (mean change of nuclear density units) and the rate of complications. Results: Thirty-two phakic eyes were included in the final analysis. At 12 months, the primary outcome of anatomical success was achieved in 94% of eyes. The mean nuclear density units did not change significantly at any time point during the follow-up. After localized vitrectomy, one eye developed an epiretinal membrane, and one eye developed cystoid macular edema; no other significant complications were reported. Conclusions: "Localized vitrectomy" has a high anatomical success rate in phakic eyes with primary uncomplicated macula-on RRD with intermediate retinal break(s) and marked vitreous traction, without causing progression of cataract. PMID- 30425856 TI - The Effect of Anterior Capsule Polishing on Capsular Contraction and Lens Stability in Cataract Patients with High Myopia. AB - Purpose: To evaluate the effect of anterior capsule polishing in patients with high myopia after cataract surgery. Setting: The Eye Hospital of Wenzhou Medical University, Zhejiang, China. Design: Prospective study. Methods: High myopic patients with a bilateral cataract who underwent phacoemulsification with 360 degrees anterior capsular polishing in one eye and without polishing in the contralateral eye were recruited. The following parameters were recorded at 1, 3, and 6 months postoperatively, including the area and diameter of the anterior capsule opening (area and D), IOL tilt and decentration, refraction, and postoperative aqueous depth (PAD). Results: Paired samples of 38 eyes of 19 patients were enrolled. The area decreased significantly in both the polished group and unpolished group, whereas the diameter reduced more in the unpolished group. The IOL tilt and decentration at 3-month and 6-month follow-up showed significant differences between two groups. In the unpolished group, the IOL decentration firstly appeared between one-month to three-month visit, while the refraction error, PAD, and IOL tilt were significantly different between the three-month and six-month visits. Conclusion: 360 degrees anterior capsule polishing can effectively reduce the extent of the anterior capsule contraction and increase the stability of IOL. The study was registered at http://www.clinicaltrials.gov, and the clinical trial accession number is NCT 03142269. PMID- 30425857 TI - The First Harmonic of Radial Pulse as an Early Predictor of Silent Coronary Artery Disease and Adverse Cardiac Events in Type 2 Diabetic Patients. AB - Background: It has been reported that harmonics of radial pulse is related to coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). It is still unclear whether or not the first harmonics of the radial pulse spectrum is an early independent predictor of silent coronary artery disease (SCAD) and adverse cardiac events (ACE). Objectives: To measure the risk of SCAD in patients with T2DM and also to survey whether or not an increment of the first harmonic (C1) of the radial pulse increases ACE. Methods: 1968 asymptomatic individuals with T2DM underwent radial pulse wave measurement. First harmonic of the radial pressure wave, C1, was calculated. Next, the new occurrence of ACE and the new symptoms and signs of coronary artery disease were recorded. The follow up period lasted for 14.7 +/- 3.5 months. Results: Out of 1968 asymptomatic individuals with T2DM, ACE was detected in 239 (12%) of them during the follow-up period. The logrank test demonstrated that the cumulative incidence of ACE in patients with C1 above 0.96 was greater than that in those patients with C1 below 0.89 (P < 0.01). By comparing the data of patients with C1 smaller than the first quartile and the patients with C1 greater than the third quartile, the hazard ratios were listed as follows: ACE (hazard ratio, 2.29; 95% CI, 1.55-3.37), heart failure (hazard ratio, 2.22; 95% CI, 1.21-4.09), myocardial infarction (hazard ratio, 2.44; 95% CI, 1.51-3.93), left ventricular dysfunction (Hazard ratio, 2.01; 95% CI, 0.86-4.70), and new symptoms and signs for coronary artery disease (hazard ratio, 2.03; 95% CI, 1.45-2.84). As C1 increased, the risk for composite ACE (P < 0.001 for trend) and for coronary disease (P < 0.001 for trend) also increased. The hazard ratio and trend for cardiovascular-cause mortality were not significant. Conclusions: This study showed that C1 of the radial pulse wave is correlated with cardiovascular events. Survival analysis showed that C1 value is an independent predictor of ACE and SCAD in asymptomatic patients with T2DM. Thus, screening for the first harmonic of the radial pulse may improve the risk stratification of cardiac events and SCAD in asymptomatic patients although they had no history of coronary artery disease or angina-related symptom. PMID- 30425858 TI - Gait Speed Is Not Associated with Vasogenic Shock or Cardiogenic Shock following Cardiac Surgery, but Is Associated with Increased Hospital Length of Stay. AB - Objective: Frailty has been associated with adverse outcomes following cardiac surgery. Gait speed has been validated as a marker of frailty. Slow gait speed has been found to be associated with mortality after cardiac surgery. However, it is unknown why slow gait speed predisposes to cardiac surgical mortality. Design: A retrospective analysis. Participants: Patients undergoing cardiac surgery who had a 5-meter walk test performed preoperatively (n=333 of 1735 total surgical patients) from January 2013 to March 2017. Setting: A tertiary care academic hospital. Measurements and main results: Gait speeds were stratified by tertiles: <0.83 m/s, 0.83-1 m/s, and >1 m/s. There was no difference in the incidence of cardiogenic or vasogenic shock when comparing the gait speed groups. Total hospital length of stay was significantly different among the gait speed groups (p=0.0050). Also, patients in the slowest gait speed tertile had a significant association with need for a postoperative permanent pacemaker (p=0.0298). Conclusion: There was no significant association between gait speed and the incidence of cardiogenic or vasogenic shock after cardiac surgery. Gait speed was associated with increased hospital length of stay and need for a permanent pacemaker after cardiac surgery. PMID- 30425859 TI - Veno-Arterial Extracorporeal Membrane Oxygenation for Septic Cardiomyopathy due to Legionella Pneumonia after Influenza Virus Infection. AB - A 57-year-old man presented to the emergency department with fever and progressive altered level of consciousness of 5 days' duration. Three days before admission, influenza A was diagnosed at a clinic. On admission, his vital signs were unstable. Pneumonia was diagnosed through chest computed tomography, and urinary Legionella antigen test was positive. A diagnosis of septic shock due to Legionella and influenza pneumonia was made, and critical care management was initiated, including mechanical ventilation and vasopressors. However, tachycardia did not improve, left ventricular ejection fraction was 20%, and circulatory insufficiency progressed. Therefore, considering the involvement of septic cardiomyopathy and cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) was initiated for circulation assistance on day 3 since admission. Tachycardia and myocardial dysfunction improved by day 8, and VA ECMO was withdrawn. Subsequently, nutrition management and rehabilitation were performed, and the patient was transferred to a recovery hospital on day 108. VA ECMO may be beneficial when concomitant with circulatory assistance in uncontrollable cases of septic cardiomyopathy using catecholamines and beta blockers. It may be necessary to adopt VA-ECMO at an appropriate time before the patient progresses to cardiopulmonary arrest. PMID- 30425860 TI - Evidence of Direct Toxicological Effects of Scorpion Venom on Central Nervous System in Tunisian Children. AB - Background: Severe scorpion envenomation can lead to severe neurological manifestations, which are an indicator of the severity of the scorpion sting. The direct action of scorpion venom on the central nervous system can explain partly these neurological disorders. Methods and Findings: We report a case of severe scorpion envenomation in 16-month-old boy with no pathological history admitted in ICU for severe scorpion envenomation. The result of cerebral MRI agrees with the hypothesis of direct action of scorpion venom on the central nervous system. Patient had improved; however, he has kept as neurological sequelae language disorders and blindness. The boy was discharged 21 days after ICU admission. Conclusion: Our observation confirms that severe scorpion envenomation can be complicated by severe neurological manifestations. Although one case report is not enough to conclude such important hypothesis regarding the direct effect of scorpion venom on central nervous system (especially that the age of patient is more than one year), our case agrees with this hypothesis. PMID- 30425861 TI - Internal Mammary Artery Injury without Chest Wall Fractures after Cardiopulmonary Resuscitation: A Case Report. AB - High-quality cardiopulmonary resuscitation (CPR) is crucial for survival from cardiac arrest. However, various chest compression-associated injuries have been reported. Internal mammary artery (IMA) injury is one of the rare complications after CPR, and most of cases include rib and sternum fractures. In this report, we describe a rare case of IMA injury without chest wall fractures after CPR. An 85-year-old man with a history of acute myocardial infarction 2 weeks prior visited to our hospital for sustained ventricular tachycardia (VT). After admission, sustained VT requiring CPR occurred several times. Emergency coronary angiogram revealed 90% stenosis at the left anterior descending artery. Hence, emergency percutaneous coronary intervention (PCI) was performed. During the PCI, blood gas analysis showed decreasing serum hemoglobin levels. Contrast computed tomography revealed hemothorax and extravasation at the branch of the right IMA without chest wall fractures. The patient's deteriorating hemodynamic condition precluded thoracotomy or embolization to stop the bleeding. The patient died on the next day of hospitalization. IMA injury can occur after CPR, regardless of chest wall fractures and can be fatal without early diagnosis. For an emergency physician, IMA injury should be considered as a cause of unknown anemia after CPR. PMID- 30425862 TI - Consequences of Misdiagnosed and Mismanaged Hereditary Angioedema Laryngeal Attacks: An Overview of Cases from the Romanian Registry. AB - Emergency department (ED) physicians frequently encounter patients presenting with angioedema. Most of these involve histamine-mediated angioedema; however, less common forms of angioedema (bradykinin-mediated) also occur. It is vital physicians correctly recognize and treat this; particularly since bradykinin mediated angioedema does not respond to antihistamines, corticosteroids or epinephrine and hereditary angioedema (HAE) laryngeal attacks can be fatal. Here we present four case reports illustrating how failures in recognizing, managing, and treating laryngeal edema due to HAE led to asphyxiation and death of the patient. Recognition of the specific type of angioedema is critical for rapid and effective treatment of HAE attacks. Bradykinin-mediated angioedema should be efficiently differentiated from the most common histamine-mediated form. Improved awareness of HAE and the associated risk of life-threatening laryngeal edema among emergency physicians, patients, and relatives and clear ED treatment protocols are warranted. Moreover, appropriate treatments should be readily available to reduce fatalities associated with laryngeal edema. PMID- 30425863 TI - A Case of Complete Remission from Advanced Gastric Adenocarcinoma with Synchronous Liver Metastasis in Response to EOX Chemotherapy. AB - Gastric cancer is a malignant tumor with a high degree of malignancy. Multiple liver metastases from gastric cancer (LMGCs) are common. However, the treatment of LMGCs is very difficult. It is rare to achieve complete remission (CR) and long-term survival after treatment. We present the case of a patient with gastric adenocarcinoma and multiple liver metastases who showed CR for more than 33 months after perioperative EOX (epirubicin, oxaliplatin, and capecitabine) combination chemotherapy with radical distal gastrectomy and resection of liver metastases. The patient is still in follow-up without tumor recurrence. These findings suggest that LMGC does not necessarily mean a poor prognosis; preoperative chemotherapy combined with surgery may be a good treatment option for LMGC in selected patients. Further studies are needed to support this treatment approach. PMID- 30425864 TI - Development of Focal Nodular Hyperplasia after Cyclophosphamide-Based Chemotherapy in a Patient with Breast Cancer. AB - Focal nodular hyperplasia (FNH) is the second most common liver cell-derived benign tumor. It is postulated that chemotherapy-induced hepatic circulatory abnormalities, like sinusoidal obstruction syndrome (SOS), could lead to the development of FNH. Cyclophosphamide was also reported to induce SOS in a synergistic effect with total body irradiation. However, none of cyclophosphamide related FNH had ever been reported before. In this case report, we present a female patient who was treated with neoadjuvant chemotherapy of cyclophosphamide (500mg/m2)-docetaxel (75mg/m2)-pharmorubicin (90mg/m2) regimen every 3 weeks for breast cancer developed FNH after 4 courses of treatment. The patient had no chronic liver disease, no history of smoking, drinking, or medication use. The chronological correlation between the chemotherapy and the appearance of the FNH suggested a cause-effect association. Therefore, this is the first case report about development of FNH after cyclophosphamide-based chemotherapy. Taking into account the frequency of breast cancer, it is instructive to recognize such observation of FNH in the context to make the differential diagnosis with hepatic metastasis. PMID- 30425865 TI - Liver Cholestasis Secondary to Syphilis in an Immunocompetent Patient. AB - Liver involvement is a known feature of secondary syphilis. The prevalence of hepatitis in secondary syphilis ranges broadly from 1 to 50%. We report a case of a 37-year-old man with type 1 diabetes mellitus and sickle cell trait presenting with jaundice and acute liver cholestasis. Abdominal ultrasound revealed mild hepatic fatty infiltration. RPR and Treponema pallidum IgG results were positive with a reflex titer of 1:64. Liver biopsy revealed chronic hepatitis with normal hepatic architecture, Kupffer cell hyperplasia, hepatic cholestasis, and ductal proliferation suggestive of syphilitic hepatitis. PMID- 30425866 TI - Primary Klebsiella pneumoniae Osteomyelitis with Bacteremia and Sepsis in a Patient with Cirrhosis. AB - Osteomyelitis is commonly caused by Staphylococci, Streptococci, Escherichia coli, and anaerobes. There have been cases of rare organisms like Klebsiella pneumoniae (Kp) being initially overlooked as causes of osteomyelitis. We report a case of an elderly cirrhotic adult male transferred for further management of liver failure, who was subsequently diagnosed with Kp osteomyelitis and sepsis. He had a history of blunt leg trauma, and MRI of the leg revealed osteomyelitis, with a negative workup for other sources of infection. Kp osteomyelitis is reported in less than 100 cases, mainly in pediatric and sickle-cell patients. There are no pathognomonic imaging findings. Lesions may be metastatic, with rapid widespread destruction and exuberant periosteal reaction. Kp is a rare, under recognized cause of osteomyelitis in immune-suppressed adults. Given its pathogenicity, early identification is critical. PMID- 30425867 TI - A Challenging Diagnosis of Ascites: A Case Report of Peritoneal Tuberculosis. AB - Approximately 2 billion people, which is about one third of the world's population, are infected with tuberculosis (TB). Around 10% of infected people will develop active TB at one point in their lifetime. We present a rare case of a 68-year-old male who presented to the emergency department with a 2-week progressive dyspnea. In addition, the patient complained of generalized weakness, subjective fevers, and abdominal pain in the right upper quadrant. Ascites was noted on physical exam, and the patient underwent a diagnostic paracentesis with initial workup that was unrevealing for underlying etiology. Abdominal computed tomography was done, which revealed peritoneal carcinomatosis. He underwent omental biopsy which showed necrotizing granulomatous inflammation with rare acid fast bacilli. Repeat biopsy was culture positive for mycobacterium tuberculosis complex. The patient was started on rifampin, isoniazid, pyrazinamide, and ethambutol with improvement of his symptoms days after treatment was started. This case demonstrates how the diagnosis of peritoneal tuberculosis can be elusive. Physicians must be aware of this disease and its behavior in high risk patients, also of the current diagnostic limitations. PMID- 30425868 TI - Complications and Management of a Rare Case of Disseminated Coccidioidomycosis to the Vertebral Spine. AB - Coccidioidomycosis, also known as San Joaquin Valley Fever or Valley Fever, is mostly a pulmonary infection caused by inhalation of spores in an endemic region. Dissemination to bone, joints, meninges, and skin occurs less than one percent of the time. Skeletal involvement accounts for approximately half of the disseminated coccidioidomycosis with the vertebrae as the most common skeletal region. We present a very rare case of disseminated coccidioidomycosis with osteomyelitis and compression fracture of the lumbar vertebral body. This case depicts some of the potential issues that can arise in managing coccidioidomycosis, especially when noncompliance to initial azoles occurs, that can lead to dissemination and complicated bone infections necessitating surgical intervention along with continuous medical therapy. PMID- 30425869 TI - Scleroderma Renal Crisis Debute with Thrombotic Microangiopathy: A Successful Case Treated with Eculizumab. AB - We had the challenged to treat a 40-year-old female with Systemic Scleroderma who was showing unspecific symptoms. During her time at the hospital she rapidly develops renal dysfunction, associated with hypertension. She required renal replacement therapy initiation and we observed a decline in hemoglobin and platelets numbers. We confirm a microangiopathic hemolytic anemia and rule out other immune diseases or thrombotic thrombocytopenic purpura. Systemic Sclerosis is a chronic immune disorder of unknown origin that it is not completely understood. It is believed that environmental factors may contribute and also altered genes may be implicated in the immune system's function. Microangiopathic hemolytic anemia occurs in 43% of patients who develop scleroderma renal crisis and an activation of the complement system through the classical pathway may be involved. Given that context we decided to treat the patients with C5 blocker Eculizumab and obtain an extraordinary positive response. PMID- 30425870 TI - Uterine Prolapse in Pregnancy: Two Cases Report and Literature Review. AB - Uterine prolapse complicating pregnancy is rare. Two cases are presented here: one patient had uterine prolapse at both her second and third pregnancy, and the other developed only once prolapse during pregnancy. This report will analyze etiology, clinical characteristics, complication, and treatment of uterine prolapse in pregnancy. Routine gynecologic examination should be carried out during pregnancy. If uterine prolapse occurred, conservative treatment could be used to prolong the gestational period as far as possible. Vaginal delivery is possible, but caesarean section seems a better alternative when prolapsed uterus cannot resolve during childbirth. PMID- 30425871 TI - Extensive Macular Atrophy with Pseudodrusen Imaged with OCT Angiography. AB - This report describes the first case of extensive macular atrophy with pseudodrusen (EMAP) imaged with optical coherence tomography angiography (OCTA). A 58-year-old Caucasian man presented with decreased central vision in both eyes. Fundus examination showed large areas of macular atrophy centered on the fovea surrounded by diffuse reticular pseudodrusen. Spectral domain OCT (SDOCT) revealed outer retinal and choriocapillaris atrophy. OCTA demonstrated marked absence of choriocapillaris flow. Extensive macular atrophy with pseudodrusen is a rare clinical entity and a new extreme phenotype of macular degenerations that could shed more light on the role of pseudodrusen and choriocapillaris compromise in the pathogenesis of AMD. PMID- 30425872 TI - Lumbar Intraspinal Osteolipoma Presenting as Cauda Equina Syndrome: A Case Report and Review of Literature. AB - Introduction: Osteolipomas are uncommon variants of lipoma. These lesions have been usually reported to arise from the oral cavity, brain, and neck and scarcely from the knee and thigh. Intraspinal osteolipomas are rare. A single case of intraspinal osteolipoma has been reported in the cervical and thoracic spine in the literature. To our knowledge, there is no report of osteolipomas in the lumbar spine. Case Presentation: We report a very rare case of a solitary lumbar intraspinal osteolipoma, presenting as a cauda equina syndrome. The intraspinal osteolipoma was excised en bloc and fusion was performed as it required partial resection of the facet joint within 24 hours of presentation. He has since then improved neurologically, and there has been no recurrence of the lesion so far. The clinical presentation, radiological characteristics, treatment course, and histopathological features of this lesion along with the clinical outcomes and a pertinent literature review were done and have been discussed. Discussion: The heterogeneous signal intensity of the lesion in MRI differentiates it from other dural-based lesions, and this should raise suspicion of an osteolipoma, which warrants a CT. Although intraspinal osteolipomas are benign lesions and generally have good prognosis, they need to be removed en bloc as they may result in rapid neurological deterioration. PMID- 30425873 TI - The Patient-Specific Implant Created with 3D Printing Technology in Treatment of the Irreparable Radial Head in Chronic Persistent Elbow Instability. AB - Successful treatment of the chronic persistent elbow instability is a challenge for orthopedic surgeons. In this form, it is important to recognize and restore the osseous stabilizer in order to obtain the concentric reduction. In the present report, we describe a case of such injury with irreparable radial head treated with patient-specific radial head prosthesis which was created with 3D printing technology. To our knowledge, this is the first report in clinical use of this kind of prosthesis for the radial head fracture. At a 24-month follow-up visit, the patient was satisfied with the functional outcomes. The Mayo Elbow Performance Index (MEPI) increased from 20 points at the preoperative day to 85 points, and the patient-based Disabilities of the Arm, Shoulder, and Hand (DASH) was reduced from 88.33 points to 28.33 points. Due to the favorable result, replacement of the radial head with the patient-specific implant could be a useful treatment for the irreparable radial head in chronic persistent elbow instability. PMID- 30425874 TI - Postoperative Thrombotic Thrombocytopenic Purpura after Total Hip Arthroplasty: A Case Report and Review of the Literature. AB - Thrombotic thrombocytopenic purpura (TTP) is an uncommon and potentially lethal microangiopathy that carries a >90% mortality rate if not treated urgently and appropriately. Postoperative TTP after orthopaedic procedures is particularly rare with only four case reports existing in the literature. We present the case of postoperative TTP in a 57-year-old female who underwent elective total hip arthroplasty. We believe this case adds to the limited literature surrounding the topic. While rare, TTP after orthopaedic procedures poses a real and potentially fatal condition if not managed appropriately. Therefore, it is essential for orthopaedic surgeons to be cognizant of postoperative TTP for timely diagnosis and treatment. PMID- 30425875 TI - Necrotizing Fasciitis of the Breast: Case Report with Literature Review. AB - Necrotizing fasciitis is a life-threatening aggressive soft tissue infection which usually affects the extremities, abdominal wall, or perineum. Breasts are rarely affected, with most cases presenting after trauma or surgical intervention. It may be misdiagnosed as abscess or cellulitis, leading to treatment delays. Here, we report a case of necrotizing fasciitis affecting both breasts in a 60-year-old female. Treatment included core biopsy managed with intravenous antibiotic and surgical debridement followed by a simple mastectomy. Currently, the patient is disease-free with a completely healed wound. PMID- 30425876 TI - Retracted: A Rare Case of Chronic Appendicitis Superimposed on an Incarcerated de Garengeot Hernia Prospectively Identified on Computed Tomography. AB - [This retracts the article DOI: 10.1155/2018/5324320.]. PMID- 30425877 TI - Autoinfarction of Giant Parathyroid Adenoma after Preoperative Withdrawal of Anticoagulants. AB - A 71-year-old man with known history of atrial fibrillation (treated with routine rivaroxaban therapy) was found to have incidental biochemical elevated calcium and parathyroid hormone (PTH) levels. His physical examination demonstrated the presence of a palpable right neck mass. Subsequent imaging studies revealed a large parathyroid mass as well as multiple bone lesions, raising the suspicion of parathyroid carcinoma. The anticoagulant therapy was stopped 5 days prior to his elective surgery. The night before his elective surgery, he presented to the emergency room with profound hypocalcemia. The surgery was postponed and rescheduled after calcium correction. Intraoperative findings and detailed histopathological examination revealed an infarcted 4.0 cm parathyroid adenoma with cystic change. His bony changes were related to brown tumors associated with long-standing hyperparathyroidism. Autoinfarction of a large parathyroid adenoma causing severe hypocalcemia is a rare phenomenon and may be considered in patients with large parathyroid adenomas after withdrawal of anticoagulants. PMID- 30425878 TI - Incarcerated Femoral Hernia Repair with VentralexTM Hernia Patch through Same Skin Incision and Suprainguinal Laparotomy. AB - Purpose: To report our experience with incarcerated femoral hernia procedure, which allows laparotomy through same inguinal skin incision, inspection and resection of compromised bowel, and preperitoneal tension-free transabdominal repair with VentralexTM Hernia Patch. Materials and Methods: The suprainguinal laparotomy was performed via same groin incision without compromising iliopubic tract. The femoral ring was sealed with VentralexTM Hernia Patch pulled through the abdominal cavity and secured outside. Five consecutive patients diagnosed with incarcerated femoral hernias were operated. All of them required laparotomy, either for bowel resection (n = 3) or for inspection of viability (n = 2). Results: All patients tolerated the procedure well. There were no wound or mesh infections, incisional hernias, or recurrences during follow-up. Conclusions: Our easy-to-master operative approach to incarcerated femoral hernia allows easy access to abdominal cavity through same groin incision without compromising iliopubic tract or midline laparotomy. Reduction of incarcerated bowel and its inspection and resection can be safely performed. The femoral ring defect can be effectively obliterated with VentralexTM Hernia Patch. PMID- 30425879 TI - Successful Liver Transplantation Case Report from a Deceased Donor with Sickle Cell Anemia. AB - There is a worldwide problem of waiting time and mortality rate associated with remaining on the waiting list for a liver transplant. However, some situations have been encouraging in terms of determining appropriate recipients and expanding the donor criteria. We herein report a case of useful liver donor with sickle cell anemia for liver transplantation. Here we described a case of liver transplantation from a donor with sickle cell anemia to a recipient with hepatocellular carcinoma who was deemed to be at risk of tumor growth and at risk of being dropped from the waiting list. The literature reveals the importance of using safe donors, and we describe the benefits of using a safe, deceased liver donor with sickle cell anemia who was an adequate option for liver transplantation. PMID- 30425880 TI - Ossifying Renal Tumor of Infancy: Laparoscopic Treatment and Literature Review. AB - We present an unusual case of a rare ossifying renal tumor of infancy. A 6-month old male initially presented with gross hematuria and without any palpable abdominal mass. Renal ultrasound and MRI showed a right lower pole, calcified, endophytic renal mass. Laparoscopic radical nephrectomy was performed without complications. Pathology demonstrated an ossifying renal tumor of infancy. We report this case, in addition to a review of the literature for similar cases, to highlight a rare renal tumor in infancy that can be managed laparoscopically. PMID- 30425881 TI - Recurrent Cholangiocarcinoma in Pregnancy: A Case Report. AB - Hepatobiliary malignancies during pregnancy are extremely rare and portend a poor prognosis. There are only seven published cases of cholangiocarcinoma in an obstetrical patient, all are cases of primary cholangiocarcinoma (1-7). Herein, we describe the first case of recurrent cholangiocarcinoma during pregnancy. The patient did not receive chemotherapy during pregnancy and required prolonged hospitalizations for nutritional and intensive medical support. She delivered preterm, at 30 2/7 weeks gestation, after developing pre-eclampsia with severe features. The infant was healthy, with no malformations, and currently exhibits no neurological or behavioral sequelae at 8months of age. We discuss themanagement considerations inherent to this complex clinical scenario including metastatic disease severity, ethical considerations, and palliative care treatment options. PMID- 30425882 TI - Hemiparasitic plants increase alpine plant richness and evenness but reduce arbuscular mycorrhizal fungal colonization in dominant plant species. AB - Hemiparasitic plants increase plant biodiversity by reducing the abundance of dominant plant species, allowing for the establishment of subordinate species. Hemiparasites reduce host resources by directly removing nutrients from hosts, competing for light and space, and may indirectly reduce host resources by disrupting plant associations with symbiotic root fungi, like arbuscular mycorrhizal fungi and dark-septate endophytes. Here, we explored how a generalist hemiparasite, Castilleja, influences plant richness, evenness, community composition, and mycorrhizal colonization patterns across a ~1,000 m elevational gradient in the North American Rocky Mountains. We hypothesized that the presence of Castilleja would be associated with increased plant richness and evenness, shaping plant community composition, and would reduce mycorrhizal colonization within dominant plant taxa. However, the magnitude of the effects would be contingent upon climate contexts, that is, elevation. Overall, we found that the presence of Castilleja was associated with an 11% increase in plant richness and a 5% increase in plant evenness, regardless of elevation. However, we found that the presence of Castilleja influenced plant composition at only two of the five sites and at the remaining three of five sites, plot pairing was the only predictor that influenced composition. Additionally, we found that the presence of Castilleja reduced mycorrhizal fungal colonization within dominant plant species by ~20%, regardless of elevation. Taken together, our results suggest that hemiparasites regulate plant diversity, evenness, and interactions with mycorrhizal fungi independent of abiotic and biotic contexts occurring at the site, although overall effect on community composition is likely driven by site level factors. PMID- 30425883 TI - Diurnal and seasonal variation of particle and dissolved organic matter release by the coral Acropora tenuis. AB - Release rates of particulate organic carbon and nitrogen (POC and PON) and dissolved organic carbon (DOC) from the scleractinian coral Acropora tenuis were measured during the day and night in summer and winter seasons. Physiological parameters including calcification, photosynthesis and respiration rates were also measured simultaneously. The release rate of both POC and DOC was significantly higher in summer compared to winter and higher during the day compared to the night. The daily release rate of total organic carbon (POC + DOC) was 1,094 and 219 MUmol C cm-2 d-1 for summer and winter, respectively, being 4.9 times higher in summer. The POC:PON ratios of the particulate organic matter released during daytime in both seasons (summer: 12.8 +/- 5.7, winter: 12.0 +/- 4.1) were significantly higher than those during nighttime (summer: 6.1 +/- 2.5, winter: 2.2 +/- 1.8). The DOC:POC ratio was 0.5 +/- 0.03 during summer and 0.32 +/- 0.98 during winter, suggesting higher mucus release in particulate form. Daily net production was estimated to be 199 and 158 MUg C cm-2d-1 for summer and winter, respectively, with the amount of carbon released as mucus accounting for 6.5% and 1.6% of the net carbon fixation, respectively. The study reveals diurnal and seasonal changes in the quantity and quality of mucus released from this coral species. Since coral mucus is used as a food source by reef macro organisms, and can also serve as an energy source for micro-organisms, the observed changes in mucus release rates are expected to influence the seasonal dynamics of organic carbon and nitrogen cycling over coral reefs. PMID- 30425884 TI - Application of a MALDI-TOF analysis platform (ClinProTools) for rapid and preliminary report of MRSA sequence types in Taiwan. AB - Background: The accurate and rapid preliminarily identification of the types of methicillin-resistant Staphylococcus aureus (MRSA) is crucial for infection control. Currently, however, expensive, time-consuming, and labor-intensive methods are used for MRSA typing. By contrast, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a potential tool for preliminary lineage typing. The approach has not been standardized, and its performance has not been analyzed in some regions with geographic barriers (e.g., Taiwan Island). Methods: The mass spectra of 306 MRSA isolates were obtained from multiple reference hospitals in Taiwan. The multilocus sequence types (MLST) of the isolates were determined. The spectra were analyzed for the selection of characteristic peaks by using the ClinProTools software. Furthermore, various machine learning (ML) algorithms were used to generate binary and multiclass models for classifying the major MLST types (ST5, ST59, and ST239) of MRSA. Results: A total of 10 peaks with the highest discriminatory power (m/z range: 2,082-6,594) were identified and evaluated. All the single peaks revealed significant discriminatory power during MLST typing. Moreover, the binary and multiclass ML models achieved sufficient accuracy (82.80-94.40% for binary models and >81.00% for multiclass models) in classifying the major MLST types. Conclusions: A combination of MALDI-TOF MS analysis and ML models is a potentially accurate, objective, and efficient tool for infection control and outbreak investigation. PMID- 30425885 TI - The addition of very light loads into the routine testing of the bench press increases the reliability of the force-velocity relationship. AB - Background: The aim of this study was to examine whether the addition of very light loads for modeling the force-velocity (F-V) relationship during the bench press (BP) exercise can confirm its experimental linearity as well as to increase the reliability and concurrent validity of the F-V relationship parameters (maximum force (F 0), maximum velocity (V 0), F-V slope, and maximum power (P max)). Method: The F-V relationship of 19 healthy men were determined using three different methods: (I) 6-loads free method: six loads performed during the traditional free-weight BP exercise (~ 1-8-29-39-49-59 kg), (II) 4-loads free method: four loads performed during the traditional free-weight BP exercise (~ 29 39-49-59 kg), and (III) 4-loads Smith method: four loads performed during the ballistic bench press throw exercise in a Smith machine (~ 29-39-49-59 kg). Results: The linearity of the F-V relationship was very high and comparable for the three F-V methods (p = 0.204; median Pearson's correlation coefficient (r) = 0.99). The three methods were ranked from the most to the least reliable as follows: 6-loads free (coefficient of variation (CV) range = 3.6-6.7%) > 4-loads Smith (CV range = 4.6-12.4%) > 4-loads free (CV range = 3.8-14.5%). The higher reliability of the 6-loads free method was especially pronounced for F-V slope (CVratio >= 1.85) and V 0 (CVratio >= 1.49) parameters, while the lowest difference in reliability was observed for F 0 (CVratio <= 1.27). The 6-loads free and 4-loads free methods showed a very high concurrent validity respect to the 4-loads Smith method for F 0 and P max (r >= 0.89), a moderate validity for the F-V slope (r = 0.66-0.82), and a low validity for V 0 (r <= 0.37). Discussion: The routine testing of the F-V relationship of upper-body muscles through the BP exercise should include trials with very light loading conditions to enhance the reliability of the F-V relationship. PMID- 30425887 TI - A taxonomically and geographically constrained information base limits non-native reptile and amphibian risk assessment: a systematic review. AB - For many taxa, new records of non-native introductions globally occur at a near exponential rate. We undertook a systematic review of peer-reviewed publications on non-native herpetofauna, to assess the information base available for assessing risks of future invasions, resulting in 836 relevant papers. The taxonomic and geographic scope of the literature was also compared to a published database of all known invasions globally. We found 1,116 species of herpetofauna, 95% of which were present in fewer than 12 studies. Nearly all literature on the invasion ecology of herpetofauna has appeared since 2000, with a strong focus on frogs (58%), particularly cane toads (Rhinella marina) and their impacts in Australia. While fewer papers have been published on turtles and snakes, proportionately more species from both these groups have been studied than for frogs. Within each herpetofaunal group, there are a handful of well-studied species: R. marina, Lithobates catesbeianus, Xenopus laevis, Trachemys scripta, Boiga irregularis and Anolis sagrei. Most research (416 papers; 50%) has addressed impacts, with far fewer studies on aspects like trade (2%). Besides Australia (213 studies), most countries have little location-specific peer reviewed literature on non-native herpetofauna (on average 1.1 papers per established species). Other exceptions were Guam, the UK, China, California and France, but even their publication coverage across established species was not even. New methods for assessing and prioritizing invasive species such as the Environmental Impact Classification for Alien Taxa provide useful frameworks for risk assessment, but require robust species-level studies. Global initiatives, similar to the Global Amphibian Assessment, using the species and taxonomic groups identified here, are needed to derive the level of information across broad geographic ranges required to apply these frameworks. Expansive studies on model species can be used to indicate productive research foci for understudied taxa. PMID- 30425886 TI - Analytical CPG model driven by limb velocity input generates accurate temporal locomotor dynamics. AB - The ability of vertebrates to generate rhythm within their spinal neural networks is essential for walking, running, and other rhythmic behaviors. The central pattern generator (CPG) network responsible for these behaviors is well characterized with experimental and theoretical studies, and it can be formulated as a nonlinear dynamical system. The underlying mechanism responsible for locomotor behavior can be expressed as the process of leaky integration with resetting states generating appropriate phases for changing body velocity. The low-dimensional input to the CPG model generates the bilateral pattern of swing and stance modulation for each limb and is consistent with the desired limb speed as the input command. To test the minimal configuration of required parameters for this model, we reduced the system of equations representing CPG for a single limb and provided the analytical solution with two complementary methods. The analytical and empirical cycle durations were similar (R 2 = 0.99) for the full range of walking speeds. The structure of solution is consistent with the use of limb speed as the input domain for the CPG network. Moreover, the reciprocal interaction between two leaky integration processes representing a CPG for two limbs was sufficient to capture fundamental experimental dynamics associated with the control of heading direction. This analysis provides further support for the embedded velocity or limb speed representation within spinal neural pathways involved in rhythm generation. PMID- 30425889 TI - Wild bees of Grand Staircase-Escalante National Monument: richness, abundance, and spatio-temporal beta-diversity. AB - Interest in bees has grown dramatically in recent years in light of several studies that have reported widespread declines in bees and other pollinators. Investigating declines in wild bees can be difficult, however, due to the lack of faunal surveys that provide baseline data of bee richness and diversity. Protected lands such as national monuments and national parks can provide unique opportunities to learn about and monitor bee populations dynamics in a natural setting because the opportunity for large-scale changes to the landscape are reduced compared to unprotected lands. Here we report on a 4-year study of bees in Grand Staircase-Escalante National Monument (GSENM), found in southern Utah, USA. Using opportunistic collecting and a series of standardized plots, we collected bees throughout the six-month flowering season for four consecutive years. In total, 660 bee species are now known from the area, across 55 genera, and including 49 new species. Two genera not previously known to occur in the state of Utah were discovered, as well as 16 new species records for the state. Bees include ground-nesters, cavity- and twig-nesters, cleptoparasites, narrow specialists, generalists, solitary, and social species. The bee fauna reached peak diversity each spring, but also experienced a second peak in diversity in late summer, following monsoonal rains. The majority of GSENM's bees are highly localized, occurring in only a few locations throughout the monument, and often in low abundance, but consistently across the four years. Only a few species are widespread and super-abundant. Certain flowering plants appear to be inordinately attractive to the bees in GSENM, including several invasive species. GSENM protects one of the richest bee faunas in the west; the large elevational gradient, incredible number of flowering plants, and the mosaic of habitats are all likely contributors to this rich assemblage of bees. PMID- 30425888 TI - PromoterPredict: sequence-based modelling of Escherichia coli sigma70 promoter strength yields logarithmic dependence between promoter strength and sequence. AB - We present PromoterPredict, a dynamic multiple regression approach to predict the strength of Escherichia coli promoters binding the sigma70 factor of RNA polymerase. sigma70 promoters are ubiquitously used in recombinant DNA technology, but characterizing their strength is demanding in terms of both time and money. We parsed a comprehensive database of bacterial promoters for the -35 and -10 hexamer regions of sigma70-binding promoters and used these sequences to construct the respective position weight matrices (PWM). Next we used a well characterized set of promoters to train a multivariate linear regression model and learn the mapping between PWM scores of the -35 and -10 hexamers and the promoter strength. We found that the log of the promoter strength is significantly linearly associated with a weighted sum of the -10 and -35 sequence profile scores. We applied our model to 100 sets of 100 randomly generated promoter sequences to generate a sampling distribution of mean strengths of random promoter sequences and obtained a mean of 6E-4 +/- 1E-7. Our model was further validated by cross-validation and on independent datasets of characterized promoters. PromoterPredict accepts -10 and -35 hexamer sequences and returns the predicted promoter strength. It is capable of dynamic learning from user-supplied data to refine the model construction and yield more robust estimates of promoter strength. PromoterPredict is available as both a web service (https://promoterpredict.com) and standalone tool (https://github.com/PromoterPredict). Our work presents an intuitive generalization applicable to modelling the strength of other promoter classes. PMID- 30425890 TI - Field evaluation of the potential for avian exposure to clothianidin following the planting of clothianidin-treated corn seed. AB - The objective of this study was to quantify consumption of clothianidin-treated corn seed by birds following standard planting practices. Based on post-planting seed counts on 21 fields in southwestern Ontario, Canada, between 29 and 813 seeds/ha (mean of 224 +/- 167 (SD)) were estimated to remain on the soil surface immediately post planting (i.e., less than one seed per 10 m2). This represents between 0.03 and 1.2% of the total sown seeds. The number of seeds missing on each field on the third day after planting as a result of any process (e.g., removal by foraging birds or mammals or burial as a result of heavy rains) ranged from 0 to 136 seeds/ha (0 to 0.0136 seeds/m2). Behavior monitoring of individual birds and 24 h remote video surveillance were deployed to investigate how much of the treated seed remaining on the soil surface was consumed by birds. Spotting scopes were used to monitor the full duration of the field visits of 596 individual birds during morning hours for three consecutive days after planting on the 21 fields. Two birds were observed consuming treated seeds (one seed each) and three birds consumed seeds for which the treatment status could not be visually confirmed. Additionally, constant (24 h) video surveillance for 2-4 days immediately after planting was deployed at 24 areas where multiple treated seeds were found on the soil surface. Across 1,380 h of collected video footage (including both day and night periods), no birds were observed to consume any treated seeds. This study provides field evidence of two factors that determine exposure of birds to clothianidin-treated corn seeds: (1) standard sowing practices in Ontario are effective at burying treated seeds such that the proportion of sown seeds that remain on the soil surface after planting is low, and (2) birds monitored on these fields consumed very few of the clothianidin treated corn seeds remaining on the soil surface after planting. As these results are dependent on planting techniques and seed characteristics, they are not necessarily applicable to other types of clothianidin treated seed. PMID- 30425891 TI - Novel findings on the impact of chytridiomycosis on the cardiac function of anurans: sensitive vs. tolerant species. AB - Background: Understanding of the physiological effects of chytridiomycosis is crucial to worldwide amphibian conservation. Therefore, we analyzed the cardiac function of two anuran species (Xenopus laevis and Physalaemus albonotatus) with different susceptibilities to infection by the causative agent of chytridiomycosis, Batrachochytrium dendrobatidis (hereafter Bd). Methods: We analyzed the in situ heart rate (f H - bpm), relative ventricular mass (RVM -%), and Ca2+ handling in heart of Bd infected animals compared to uninfected controls of both study species. Results: Bd infection resulted in a 78% decrease in contraction force values in P. albonotatus when compared to the less susceptible X. laevis. This negative effect was even more evident (82%) for the cardiac pumping capacity. The time to reach peak tension was 125% longer in P. albonotatus than in X. laevis, and cardiac relaxation was 57% longer. Discussion: These results indicate a delay in the cardiac cycle of P. albonotatus on a beat to-beat basis, which was corroborated by the bradycardia observed in situ. In summary, Bd-sensitive species present impaired cardiac function, which could be a factor in mortality risk. The more pronounced effects of Bd in P. albonotatus may not only result from electrolyte imbalance, as previously reported, but also could be an effect of toxins produced by Bd. For X. laevis, the ability to promote cardiac adjustments seems to be an important homeostatic feature that allows greater tolerance to chytridiomycosis. This study provides new physiological mechanisms underlying the tolerance or susceptibility of amphibian species to chytridiomycosis, which determine their adaptability to survive in the affected environments. PMID- 30425892 TI - Changes in stigma and help-seeking in relation to postpartum depression: non clinical parenting intervention sample. AB - Postpartum depression (PPD) is a prevalent mental illness affecting women, and less commonly, men in the weeks and months after giving birth. Despite the high incidence of PPD in Australia, rates for help-seeking remain low, with stigma and discrimination frequently cited as the most common deterrents to seeking help from a professional source. The present study sought to investigate PPD stigma in a sample of parents and to examine the effects of an intervention on stigma and help-seeking behaviour. A total of 212 parents aged 18-71 years (M = 36.88, 194 females) completed measures of personal and perceived PPD stigma and attitudes towards seeking mental health services and were randomly assigned to one of four groups: an intervention group (video documentary or factsheet related to PPD) or a control group (video documentary or factsheet not related to PPD). Results showed that there were no effects for type of intervention on either personal or perceived PPD stigma scores. No effect was found for help-seeking propensity. Males had higher personal PPD stigma than females and older age was associated with lower personal PPD stigma. Familiarity with PPD was associated with perceived PPD stigma in others but not personal PPD stigma. More work needs to be conducted to develop interventions to reduce PPD stigma in the community. PMID- 30425893 TI - Modelling the dynamics of a large rock landslide in the Dolomites (eastern Italian Alps) using multi-temporal DEMs. AB - Latest advances in topographic data acquisition techniques have greatly enhanced the possibility to analyse landscapes in order to understand the processes that shaped them. High-resolution Digital Elevation Models (DEMs), such as LiDAR derived ones, provide detailed topographic information. In particular, if multi temporal DEMs are available, it is possible to carry out a detailed geomorphic change detection analysis. This analysis may provide information about the dynamics of large landslides and may thus, be useful for landslide risk assessments. However, LiDAR-derived DEMs are mostly available only as post-event surveys. The technique is relatively recent, and local or national authorities only started widespread surveys in the last decade. Therefore, it is of a certain interest to analyse the effectiveness of DEMs derived from technical cartography to produce reliable volumetric estimates related to large landslides. This study evaluates the use of a multi-source DEM of Difference (DoD) analysis for the investigation of a large landslide -Le Laste-, which occurred on November 12, 2014 on Mount Antelao (eastern Italian Alps). The landslide initiated as a 365,000 m3 rockslide close to the summit of the mountain and transformed into a debris avalanche during its runout. The comparison of pre- and post-event DEMs allowed for the identification and quantification of erosion and deposition areas, and for the estimation of landslide volume. A sound back-analysis of the landslide with the 3D numerical model DAN3D was based on this comparison and on seismic records of the event. These seismic records proved to be remarkably useful, as they allowed for the calibration of the simulated landslide velocity. This ensured the reliability of the model notwithstanding the topographic datasets, intrinsic uncertainties. We found that using a pre-event DEM derived from technical cartography tends to slightly overestimate the volume with respect to the use of the more accurate LiDAR-derived DEM. In recent years, the landslide risk around Mt. Antelao has been increasing alongside the ever-growing population and human activities in the area. Sediment accumulations produced by the Le Laste landslide significantly amplified the debris flow hazard by providing new sediment sources. Therefore, it is crucial to delineate the distribution of this material to enable an adequate debris flow hazard assessment. The material properties derived from the back-analysis of the Le Laste landslide can be used to simulate the runout of possible future events, and to generate reliable hazard zone maps, which are necessary for effective risk mitigation. PMID- 30425895 TI - Porewater salinity in a southeastern United States salt marsh: controls and interannual variation. AB - In coastal marsh ecosystems, porewater salinity strongly affects vegetation distribution and productivity. To simulate marsh porewater salinity, an integrated, spatially explicit model was developed, accounting for tidal inundation, evaporation, and precipitation, as well as lateral and vertical exchanges in both surface waters and the subsurface. It was applied to the Duplin River marsh, Sapelo Island, USA, over a 3-year period, which covered both drought and wet conditions. Simulated porewater salinity in the low and high marsh correlated with Duplin River salinity, with evapotranspiration and precipitation leading to substantial variations in porewater salinities across seasons, in particular in the high marsh. The model revealed substantial interannual variability in marsh soil conditions, and-due to its process-based approach linked to external forcings-can be used to explore effects of sea level rise and changes in hydrological forcings on marsh soil conditions. PMID- 30425894 TI - Microbiome differences between river-dwelling and cave-adapted populations of the fish Astyanax mexicanus (De Filippi, 1853). AB - Symbiotic relationships between host and microbiome can play a major role in local adaptation. Previous studies with freshwater organisms have shown that microbiome performs numerous important biochemical functions for the host, playing a key role in metabolism, physiology or health. Experimental studies in fish groups have found an effect of enzymatic activity of gut microbiota on a variety of metabolic processes. The goal of this study was to compare stomach microbiome from cave and surface Astyanax mexicanus, in order to evaluate the potential response of microbiota to contrasting environmental conditions and physiological adaptations of the host. Stomach microbiota was obtained from three different populations: Pachon cave, and two surface rivers (Rascon and Micos rivers). The stomach microbiome was analyzed using the Ion 16S Metagenomic kit considering seven variable regions: V2, V3, V4, V6-7, V8 and V9. A high diversity was observed across samples, including 16 phyla, 120 families and 178 genera. Gammaproteobacteria, Firmicutes, Bacteroidetes and Betaproteobacteria were the most abundant phyla across the samples. Although the relative abundance of the core OTUs at genus level were highly contrasting among populations, we did not recover differences in stomach microbiome between contrasting habitats (cave vs. surface rivers). Rather, we observed a consistent association between beta diversity and dissolved oxygen concentration in water. Therefore, and unexpectedly, the microbiota of A. mexicanus is not linked with the contrasting conditions of the habitat considered here but is related to water parameters. PMID- 30425896 TI - Early identification of recurrence in ovarian cancer: a comparison between the ovarian cancer metastasis index and CA-125 levels. AB - Ovarian cancer (OC) is the second most common gynecologic malignancy. A clinical observational study was performed to investigate whether indicators that assess the risk of metastasis can identify recurrence earlier in OC patients. By successfully recruiting 41 patients with OC who underwent chemotherapy, we compared cancer antigen-125 (CA-125) and the ovarian cancer metastasis index (OCMI), which was previously developed by us in the clinic for this purpose. Our results showed that patients and their families generally took a sensible attitude toward disease progression and were willing to accept a new way to gain knowledge about the disease. Herein, the new way was the possibility of monitoring recurrence by introducing the OCMI into the clinic. Fifteen patients experienced recurrence during chemotherapy, implying treatment failure. For 53% of these patients, an abnormally high OCMI suggested a strong tendency toward metastasis at least one chemotherapy cycle prior to the pathological examination confirming recurrence. In comparison, the early recognition rate of recurrence using CA-125 levels was merely 13%. Furthermore, we found that the mean values of the OCMI no longer declined after the fourth chemotherapy cycle, implying that excessive chemotherapy brings no benefit to OC patients. In conclusion, our findings provide a novel and feasible approach to monitor the effectiveness of chemotherapy in the treatment of OC by assessing the potential risk of metastasis. PMID- 30425897 TI - Along urbanization sprawl, exotic plants distort native bee (Hymenoptera: Apoidea) assemblages in high elevation Andes ecosystem. AB - Native bees contribute a considerable portion of pollination services for endemic as well as introduced plant species. Their decline has been attributed to several human-derived influences including global warming as well as the reduction, alteration, and loss of bees' habitat. With human expansion comes along the introduction of exotic plant species with negative impacts over native ecosystems. Anthropic effects may even have a deeper impact on communities adapted to extreme environments, such as high elevation habitats, where abiotic stressors alone are a natural limitation to biodiversity. Among these effects, the introduction of exotic plants and urbanization may have a greater influence on native communities. In this work, we explored such problems, studying the relationship between the landscape and its effect over richness and abundance of native bees from the subandean belt in the Andes mountain chain. Furthermore, we investigated the effects of exotic plant abundance on this high-altitude bee assemblage. Despite the landscape not showing an effect over bee richness and abundance, exotic plants did have a significant influence over the native bee assemblage. The abundance of exotic plants was associated with a relative increase in the proportion of small and medium bee species. Moreover, Halictidae was the only family that appeared to be favored by an increase in the abundance of exotic plant species. We discuss these results and the urgent need for further research of high-altitude environments due to their vulnerability and high endemicity. PMID- 30425898 TI - Geophysical upheavals and evolutionary diversification of plant species in the Himalaya. AB - The Himalaya is one of the youngest and the loftiest mountain chains of the world; it is also referred to as the water tower of Asia. The Himalayan region harbors nearly 10,000 plant species constituting approximately 2.5% of the global angiosperm diversity of which over 4,000 are endemics. The present-day Himalayan flora consists of an admixture of immigrant taxa and diversified species over the last 40 million years. The interesting questions about the Himalayan flora discussed here are: how did the Himalaya achieve high endemic plant diversity starting with immigrant taxa and what were the main drivers of this diversity? This contribution aims to answer these questions and raise some more. We review and analyze existing information from diverse areas of earth and climate sciences, palaeobiology and phytogeography to evolve a bio-chronological record of plant species divergence and evolution in the Himalaya. From the analysis we infer the effects of major environmental upheavals on plant diversity in the region. The understanding developed in the following discussion is based on the idea that Himalaya experienced at least five phases of major geophysical upheavals, namely: (i) mega-collision between India and Eurasian plates, (ii) tectonic uplift in phases and progressive landform elevation, (iii) onset of southwest (SW) Indian monsoon, (iv) spurring of arid conditions in Central Asia, and (v) cyclic phases of cooling and warming in the Quaternary. The geophysical upheavals that were potentially disrupting for the ecosystem stability had a key role in providing impetus for biological diversification. The upheavals produced new geophysical environments, new ecological niches, imposed physical and physiological isolation barriers, acted as natural selection sieves and led to the formation of new species. This contribution aims to develop a comprehensive understanding of the plant biodiversity profile of the Himalaya in the context of complex, interconnected and dynamic relationship between earth system processes, climate and plant diversity. PMID- 30425899 TI - Migration and transformation of dissolved carbon during accumulated cyanobacteria decomposition in shallow eutrophic lakes: a simulated microcosm study. AB - The decomposition processes of accumulated cyanobacteria can release large amounts of organic carbon and affect the carbon cycling in shallow eutrophic lakes. However, the migration and transformation mechanisms of dissolved carbon (DC) require further study and discussion. In this study, a 73-day laboratory microcosm experiment using suction samplers (Rhizon and syringe) was conducted to understand the migration and transformation of DC during the cyanobacteria decomposition. The decomposition of cyanobacteria biomass caused anoxic and reduction conditions, and changed the acid-base environment in the water column. During the early incubation (days 0-18), a large amount of cyanobacteria-derived particulate organic matter (POM) was decomposed into dissolved organic carbon (DOC) in the overlying water, reaching the highest peak value of 1.82 g L-1 in the treatment added the high cyanobacteria biomass (470 g). After 18 days of incubation, the mineralization of increased DOC to dissolved inorganic carbon (DIC) maintained a high DIC level of overlying water in treatments added cyanobacteria biomass. The treatment added the medium cyanobacteria biomass (235 g) presented the lower DOC/total dissolved carbon ratio than the high cyanobacteria biomass associated with the lower mineralization from DOC to DIC. Due to the concentration differences of DIC at water-sediment interface, the main migration of DIC from pore water to overlying water occurred in the treatment without added cyanobacteria biomass. However, the treatments added the cyanobacteria biomass presented the obvious diffusion of DOC and the low migration of DIC at the water-sediment interface. The diffusive fluxes of DOC at the water-sediment interface increased with the cyanobacteria biomass added, reaching the maximum value of 411.01 mg/(m2.d) in the treatment added the high cyanobacteria biomass. In the overlying water, the group added the sediment and medium cyanobacteria biomass presented a faster degradation of cyanobacteria derived POM to DOC and a higher mineralization level of DOC to DIC than added the medium cyanobacteria biomass without sediment. Therefore, during accumulated cyanobacteria decomposition, the biomass of accumulated cyanobacteria and sediment property can influence the migration and transformation of DC, playing an important role in carbon cycling in shallow eutrophic lakes. PMID- 30425900 TI - Histological analysis of post-eruption tooth wear adaptations, and ontogenetic changes in tooth implantation in the acrodontan squamate Pogona vitticeps. AB - Teeth have been a focus of research in both extinct and extant taxa alike; a significant portion of dental literature is concerned with dental patterning and replacement. Most non-mammalian vertebrates continuously replace their dentition but an anomalous group of squamates has forgone this process in only having one tooth generation; these squamates all have apically implanted teeth, a condition known as acrodonty. Acrodont dentition and various characteristics attributed to it, including a lack of replacement, have often been defined ambiguously. This study explores this type of implantation through histology in the ontogeny of the acrodont agamid Pogona vitticeps. The non-replacing teeth of this squamate provides an opportunity to study wear adaptations, maintenance of occlusion in a non-mammalian system, and most importantly post-eruption changes in the tooth bone interface. In this study the post-eruption changes combined with dental wear likely gives the appearance of acrodont implantation. PMID- 30425901 TI - Risk and protective factors for drug dependence in two Moroccan high-risk male populations. AB - Background: Substance use is linked to biological, environmental, and social factors. This study provides insights on protective and risk factors for drug dependence in two Moroccan, high-risk, male samples. Methods: Data from the "Mental and Somatic Health without borders" (MeSHe) survey were utilized in the present study. The MeSHe survey assesses somatic and mental health parameters by self-report from prison inmates (n = 177) and outpatients from an addiction institution (n = 54). The "Drug dependence" and the "No drug dependence" groups were identified based on the Arabic version of the Drug Use Disorder Identification Test's (DUDIT) validated cutoff for identifying individuals with drug dependence, specifically in Morocco. Results: The majority of participants who had at least high school competence (67.6%), were living in a partnership (53.7%), were a parent (43.1%), and/or had a job (86.8%) belonged to the "No drug dependence" group, while the presence of mental health problems was typical among the "Drug dependence" group (47.4%). A multivariable regression model (chi2 (df = 5, N = 156) = 63.90, p < 0.001) revealed that the presence of depression diagnosis remains a significant risk factor, while a higher level of education, having a child, and being employed are protective factors from drug dependence. Discussion: Findings support the importance of increasing academic competence and treating depression as prevention from the persistence of drug addiction in male high-risk populations. PMID- 30425902 TI - Friction reduction through biologically inspired scale-like laser surface textures. AB - Reducing friction forces is a major challenge in many engineering applications involving moving parts. For the past 50 years, the morphological texturing of surfaces for improving tribological properties has been investigated. Only recently, the application of biologically inspired surface features, like scales found on lizards and snakes, has come to the attention of tribologists. Here, we present results of the lubricated and unlubricated performance of biologically inspired scale-like textures applied with laser light to the surface of bearing steel pins. These were paired in unidirectional sliding against metallic (100Cr6), polymeric (PEEK) and ceramic (Al2O3) counter bodies. Additionally, a possible size effect was investigated by changing the scale diameter between 13 and 150 um under dry sliding contact against sapphire. Our results demonstrate that depending on the contact conditions a biologically inspired surface morphology has the potential to reduce friction forces by more than 80%. However, under certain conditions, especially for slow-moving lubricated steel-on-steel and steel-on-ceramic contacts, these surface morphologies may increase friction as well. Similar to classical laser surface textures, such as round dimples, these biologically inspired morphologies need to be carefully optimized for each tribological system in which they are intended to be applied. There is no standard solution for all sliding conditions. The results presented here demonstrate that such efforts have the potential to yield significant reduction in friction forces and are expected to spark future research in the field of biologically inspired surface morphologies applied to tribological contacts. PMID- 30425903 TI - Exploring the photoleakage current and photoinduced negative bias instability in amorphous InGaZnO thin-film transistors with various active layer thicknesses. AB - The photoleakage current and the negative bias and illumination stress (NBIS) induced instability in amorphous InGaZnO thin-film transistors (a-IGZO TFTs) with various active layer thicknesses (T IGZO) were investigated. The photoleakage current was found to gradually increase in a-IGZO TFTs irrespective of the T IGZO when the photon energy of visible light irradiation exceeded ~2.7 eV. Furthermore, the influence of the T IGZO on NBIS-induced instability in a-IGZO TFTs was explored by the combination of current-voltage measurements in double sweeping V GS mode and capacitance-voltage measurements. The NBIS-induced hysteresis was quantitatively analyzed using a positive gate pulse mode. When the T IGZO was close to the Debye length, the trapped electrons at the etch stopper/IGZO interface, the trapped holes at the IGZO/gate insulator interface, and the generation of donor-like states in an a-IGZO layer were especially prominent during NBIS. PMID- 30425904 TI - Family History as an Important Factor for Stratifying Participants in Genetic Studies of Major Depression. AB - Depression is estimated to affect 350 million people worldwide. The World Mental Health Survey conducted in 17 countries found that, on average, about one in 20 people reported having an episode of depression in the previous year. Although depression has been shown to be moderately heritable by studies conducted in the past, the search for its so-called missing heritability has so far been unsuccessful. The difficulty in identifying common genetic variants predisposing to depression could be due to large sample sizes needed to detect small effects on genetic risk and the heterogeneous nature of major depressive disorder (MDD). The aim of our study was to determine whether there was a connection between a family history of depression in MDD patients and the presence of putative risk variants in the well-studied SLC6A4, COMT and PCLO genes. We analyzed 133 patients with MDD (30.0% with a positive family history for MDD and 70.0% sporadic cases) and compared them to 279 healthy controls. When comparing all the depressed patients to controls, no significant differences in genotype and allele distributions were detected. After stratifying patients according to their family history, the PCLO rs2522833 C allele was shown to be significantly less common in patients with a positive family history (p = 0.001), indicating a possible difference in the genetic structure of MDD between familial and sporadic cases and a less important role of the common genetic risk variants for the development of MDD in familial cases. PMID- 30425905 TI - Detecting EGFR Mutations in Patients with Non-small Cell Lung Cancer. AB - Mutations in the receptor of the epidermal growth factor receptor (EGFR) in non small cell lung cancer (NSCLC) are used as biomarkers for predicting the response of treatment with EGFR tyrosine kinase inhibitors (EGFR TKIs). Non-small cell lung cancer patients usually have activating EGFR mutations that leads to a very good response when they are treated with EGFR TKIs. Our tumor samples were examined for the presence of sensitive mutations in the EGFR gene, resistant mutations or the absence of mutations. To identify the types of the mutation, we used a real-time polymerase chain reaction (RT-PCR) method. Additionally, we evaluated the frequency of EGFR mutations and their association with smoking status, gender and histology. The tumor samples (n = 551) were tested for 29 somatic mutations in the EGFR gene. Sensitive mutations in the EGFR genes were found in 55 NSCLC samples (10.0%). The prevalence of EGFR mutations was much higher for females than for males (27.1 vs. 3.9%, p <0.001). The prevalence of EGFR mutations was greater in subjects who had never smoked than in smokers (15.0 vs. 6.08%, p <0.003). Additionally, the frequency of EGFR mutations was higher in adenocarcinomas than in other histological types (14.9 vs. 5.1%; p <0.001). Our results show that activating mutations on the EGFR gene are more frequent in females than in males, in adenocarcinoma than other histological types and in non smokers than smokers. PMID- 30425906 TI - Analysis of the PPARD Gene Expression Level Changes in Football Players in Response to the Training Cycle. AB - The PPARD gene codes protein that belongs to the peroxisome proliferator activated receptor (PPAR) family engaged in a variety of biological processes, including lipid metabolism in muscle cells. In this study, we assess the relationship between PPARD gene expression lipid metabolism parameters and the variation of the PPARD gene expression before (T1) and after 12 hours of training (T2) sessions in a group of football players. Peripheral blood lymphocytes were obtained from 22 football players (17.5+/-0.7 years, 178+/-0.7 cm, 68.05+/-9.18 kg). The PPARD gene expression, analyzed by quantitative polymerase chain reaction (qPCR), was significantly higher after T2 (p = 0.0006). Moreover, at the end of the training cycle, there was a significant decrease in relative fat tissue (FAT) (%) (p = 0.01) and absolute FAT (kg) (p = 0.01). A negative correlation was observed between absolute FAT (kg) and PPARD gene expression level in T2 (p = 0.03). The levels of cholesterol and triglyceride (TG) fractions were not significantly different (p >0.05) before and after training. No significant relationship between PPARD expression and cholesterol or TG levels was found. We found that physical training affects PPARD expression. Moreover, the negative correlation between PPARD expression and absolute FAT (kg) level may be indicative of the contribution of PPARD in metabolic adaptation to increased lipid uptake that can be used to control the body composition of athletes. PMID- 30425907 TI - Association of E-selectin S128R Polymorphism with Hereditary Breast Carcinoma Susceptibility in Turkish Patients Without BRCA1/2 Germline Mutations. AB - Inherited genetic factors play an important role in breast cancer susceptibility. The BRCA1 and BRCA2 mutations are the most well-known genetic factors associated with increased risk of breast cancer. E-selectin is a cell surface glycoprotein and its serum levels are known to increase in various cancers. The present retrospective study aimed to evaluate whether E-selectin S128R polymorphism (NG_012124.1: g.7161A>C, NM_000450.2: c.445A>C, NP_000441.2: p.Ser149Arg), which is known to have a role in cancer risk, is associated with breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer. The study included 90 patients with breast cancer and 270 healthy controls. All breast cancer patients were screened for BRCA 1/2 mutations and confirmed to be BRCA 1/2 mutation non carriers before inclusion in the study. Genotyping for the E selectin S128R polymorphism was performed using real-time polymerase chain reaction (PCR) analysis. The frequencies of the AA, AC and CC genotypes were 70.0, 25.5 and 4.5%, respectively, in the patient group and 79.25, 19.25 and 1.5%, respectively, in the controls. The frequencies of A and C alleles were 84.8 and 15.2% in the patient group, respectively, and 88.9 and 11.1%, respectively, in the controls. No significant differences were determined in the genotype and allele frequencies of the E-selectin S128R polymorphism between the patient and control groups (p = 0.095). The S128R (A/C) polymorphism was not found to be associated with an increased risk of breast cancer [odds ratio (OR) = 0.69; 95% confidence interval (95% CI): 0.43-1.10; p = 0.1248). There was no association between the S128R polymorphism and breast cancer susceptibility in BRCA 1/2 mutation non carriers with breast cancer in the studied Turkish population. Further studies with larger sample sizes are needed to validate our findings. PMID- 30425908 TI - ADRB2 Gene Polymorphisms and Salbutamol Responsiveness in Serbian Children with Asthma. AB - Inhaled beta2 adrenergic receptor (beta2-AR) agonists are the mainstay of asthma therapy. The beta2-AR protein is encoded by the ADRB2 gene and variants within this gene can have significant consequences for modulating the response to asthma therapy. This cross-sectional study performed at the University Children's Hospital in Belgrade, included 54 children with asthma. The subjects were genotyped for ADRB2 +46A>G (Arg16Gly, rs1042713) and +79C>G (Gln27Glu, rs 1042714) polymorphisms and the association with asthma severity and response to inhaled salbutamol was examined. In Serbian asthmatic children, allele +46A was detected with a frequency of 41.7% and allele +79G was detected with a frequency of 23.1%. Allele +46G was found to be associated with a better response to inhaled salbutamol (p <0.05) and with mild form of asthma (p <0.05). Polymorphism ADRB2 +46A>G may be a determinant of asthma severity and response to salbutamol in children with asthma. We did not find any association of +79C>G polymorphisms with the asthma severity and bronchodilator response to inhaled salbutamol. The results of this study can be potentially useful for personalization of asthma treatment. PMID- 30425909 TI - PPAR?? Gene and Atherosclerosis: Genetic Polymorphisms, Epigenetics and Therapeutic Implications. AB - Atherosclerosis is the leading cause of mortality and morbidity in the developed world. It is characterized by the formation of a plaque in the walls of middle and large arteries leading to macrovascular complications. Several risk factors are included, with diabetes being one of the most important for the onset and development of atherosclerosis. Due to an increase in the prevalence of diabetes in the world, the incidence of diabetic complications (microvascular and macrovascular) is increasing. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a important role in atherosclerotic processes. Peroxisome proliferator activated receptor gamma belongs to the superfamily of nuclear receptors, has a great presence in fat tissue, macrophages, and regulates gene expression and most of the processes that lead to the onset and development of atherosclerosis. In this review, we discuss the basic patho-physiological mechanisms of atherosclerosis in type 2 diabetes mellitus (T2DM). Furthermore, we discuss the impact of PPARgamma polymorphisms, and the epigenetic mechanisms affecting the onset of atherosclerosis, i.e, DNA methylation and demethylation, histone acetylation and deacetylation, and RNA-based mechanisms. Moreover, we add therapeutic possibilities for acting on epigenetic mechanisms in order to prevent the onset and progression of atherosclerosis. PMID- 30425910 TI - Clinical Variability in Two Macedonian Families with Arterial Tortuosity Syndrome. AB - Arterial tortuosity syndrome (ATS) is a rare autosomal recessive disorder caused by mutations in the solute carrier family 2 member 10 (SLC2A10) gene encoding a glucose/ascorbic acid transporter. The clinical features of ATS are mild-to severe tortuosity of the large and medium arteries throughout the body, accompanied by dysmorphisms and joint laxity. Vascular changes in different parts of the body lead to stenosis and/or aneurysms requiring difficult surgical procedures. Here we present two new patients with ATS from two unrelated families. Patient 1 presented at 10 years of age with headache and typical physical appearance, delicate skeleton, large visible pulsation of the carotid arteries in the neck, and joint laxity. On computed tomography (CT) angiography she had severe tortuosity of the aortal branches and cerebral arteries, but no significant tortuosity of the pulmonary arteries. Two cousins of the girl carried the same homozygous c.254T>C, p.(Leu85Pro) mutation in SLC2A10, however, they additionally had a severe involvement of the pulmonary vessels. Patient 2 was a 9 year-old girl diagnosed with severe tortuosity and stenosis of the pulmonary arteries and progressive myocardiopathy. Her physical appearance was very similar to Patient 1, except that she also had growth retardation. After long-term follow up by cardiologists, she underwent cardiac surgery abroad, with an unfavorable outcome. Homozygosity for the c.685C>T, p.(Arg229*) mutation in the SLC2A10 gene was detected. Consanguinity was disclosed within both families. Our findings confirm the intrafamilial phenotype variability of ATS. A novel finding is the severe tortuosity of cerebral arteries causing migraine that has not been described before in a child with ATS. PMID- 30425911 TI - The Mitochondrial tRNAGly T10003C Mutation may not be Associated with Diabetes Mellitus. AB - Mitochondrial DNA (mtDNA) mutations have long been proposed to play important roles in the pathogenesis of diabetes mellitus (DM). A large proportion of these mutations are localized at the mt-tRNA genes. Owing to its high mutation rate, a growing number of mt-tRNA mutations have been reported; however some of them are neutral genetic polymorphisms and will not result in the alteration of the mitochondrial function responsible for DM. In this study, we reassessed a recent reported "pathogenic" mutation, tRNAGly T10003C, in a clinical manifestation of DM. We first performed the conservation assessment of this mutation between different species. Moreover, the bioinformatics analysis was used to predict the secondary structure of mt-tRNAGly in wild type version and the mutant carrying the T10003C mutation. We also screened the presence of the T10003C mutation in 500 unrelated DM patients and 300 healthy controls. We noticed that the T10003C mutation was not very conserved and did not cause the secondary structure change of mt-tRNAGly. Moreover, this mutation was absent in the 500 unrelated DM patients and controls, suggesting that this mutation may be a rare event in the human population. In conclusion, the current study showed no association between the T10003C mutation and DM in humans. PMID- 30425912 TI - UGT1A1 (TA)n Promoter Genotype: Diagnostic and Population Pharmacogenetic Marker in Serbia. AB - The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia. PMID- 30425913 TI - Mutation in Phospholipase C, delta1 (PLCD1) Gene Underlies Hereditary Leukonychia in a Pashtun Family and Review of the Literature. AB - Human hereditary leukonychia is a rare nail disorder characterized by nail plates whitening on all finger and toe nails. Inheritance pattern is both autosomal dominant and recessive. To date, the only gene, phospholipase C, delta1 (PLCD1), on chromosome 3p22.2 has been reported to be involved in hereditary leukonychia. In the present study, a family of Pakhtun ethnicity, carrying leukonychia phenotype was investigated. The family inherited the phenotype in an autosomal dominant fashion. Affected individuals exhibited characteristic features of hereditary leukonychia with involvement of nails on both the hands and feet. Sequence analysis of DNA detected a p.Cys209Arg mutation, reported for the first time in a Pakistani Pashtun family. PMID- 30425914 TI - Problems of Unknown Significance: Counseling in the Era of Next Generation Sequencing. AB - Dear Editor Next generation sequencing (NGS) has changed the way we approach the diagnosis, prognosis and treatment of genetic disorders. It gave us base pair (bp) precision, multi-gene approach that can be executed in a timely and cost effective manner. Despite some minor technical issues in NGS, it comes with great advantages. However, the clinical, and especially, genetic counseling profession will need to rise to the challenge to face some of the new issues, dilemmas and problems this new technology is bringing to the table. Some of the counseling guidelines predate the NGS era and will urgently need to be brought up to par with the technology. PMID- 30425915 TI - Hyperinsulinism-hyperammonemia Syndrome in an Infant with Seizures. AB - Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most common form of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The main clinical characteristics of HI/HA syndrome are repeated episodes of symptomatic hypoglycemia, but not usually severe. Consequently, children with HI/HA syndrome are frequently not recognized in the first months of life. An 8-month-old boy was admitted to a hospital due to hypoglycemia seizures. He also had asymptomatic hyperammonemia with no signs of lethargy or headaches. Genetic testing revealed autosomal dominant syndrome, a mutation in the GLUD1 gene (p.Arg274Cys). The boy started treatment with diazoxide. Subsequent growth and neurological development were normal. Hypoglycemic symptoms in HI/HA syndrome may vary from being non specific to severe. As hypoglycemia could lead to brain injury and impairment of neurological development, timely diagnosis and management are essential. If transient hypoglycemia is ruled out, metabolic disorders must be taken into account. PMID- 30425916 TI - Floating-Harbor Syndrome: Presentation of the First Romanian Patient with a SRCAP Mutation and Review of the Literature. AB - Floating-Harbor syndrome (FHS) is a rare autosomal dominant syndrome characterized by short stature with delayed bone age, retarded speech development, intellectual disability and dysmorphic facial features. Recently, dominant mutations almost exclusively clustered in the final exon of the Snf2 related CREBBP activator protein (SRCAP) gene were identified to cause FHS. Here, we report a boy with short stature, speech delay, mild intellectual disability, dysmorphic features, and with genetically confirmed FHS. To the best of our knowledge, this is the first molecularly confirmed case with this syndrome reported in Romania. An intensive program of cognitive and speech stimulation, as well as yearly neurological, psychological, ophthalmological, otorhinolaryngological, pediatric and endocrinological monitoring for our patient were designed. We propose a checklist of clinical features suggestive of FHS, based on the main clinical features, in order to facilitate the diagnosis and clinical management of this rare condition. PMID- 30425917 TI - Acute Pre-B Lymphoblastic Leukemia and Congenital Anomalies in a Child with a de Novo 22q11.1q11.22 Duplication. AB - Microdeletions and microduplications are recurrent in the q11.2 region of chromosome 22. The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from severe intellectual disability, facial dysmorphism, heart defects, and urogenital abnormalities to very mild symptoms. Both benign and malignant hematological entities are rare. A male patient was diagnosed with mild facial dysmorphia, congenital heart anomalies shortly after birth and acute bowel obstruction due to malrotation of the intestine at the age of 3 years. A whole-genome single nucleotide polymorphism (SNP) array revealed a de novo 6.6 Mb duplication in the 22q11.1q11.22 chromosomal region. A year later, the patient was diagnosed with acute pre-B lymphoblastic leukemia (pre-B ALL). Five genes, CDC45, CLTCL1, DGCR2, GP1BB and SEPT5, in the 22q11.1q11.22 region are potentially responsible for cell cycle division. We hypothesized that dosage imbalance of genes implicated in the rearrangement could have disrupted the balance between cell growth and differentiation and played a role in the initiation of malignancy with a hyperdiploid leukemic clone, whereas over expression of the TBX1 gene might have been responsible for congenital heart defects and mild facial dysmorphia. PMID- 30425918 TI - Evaluating an insurer-based health coaching program: Impact of program engagement on healthcare utilization and weight loss. AB - Insurers and employers are increasingly offering lifestyle and weight-loss coaching programs; however, few evaluations have examined their effectiveness. Our objectives were to determine whether level of program engagement was associated with differences in healthcare utilization and weight pre/post coaching. We conducted a retrospective evaluation of enrollees in an insurer based telephonic health coaching program in Maryland (2013-2014). Our independent variables were program engagement benchmarks (>=3 and >=6 sessions). Our dependent variables included change in outpatient and emergency department (ED) visits (more visits post program, fewer visits post, or no change pre-post) and associated costs (difference pre-post) using claims data. We calculated mean percent weight change from baseline. We used multivariate-adjusted linear and multinomial logistic regression, as appropriate, to examine the association between outcomes and engagement benchmarks. We included 225 enrollees with mean age 50.7 years, 81.3% women, and mean body mass index of 35.0 kg/m2. Most participants focused on weight management (75.6%) and improving general health (57.8%). Few individuals had outpatient or ED visits, and no significant changes in healthcare utilization were associated with program engagement. Among the weight management subgroup (n = 170), mean weight change was -2.1% (SD 5.1). Participants achieved significantly greater weight loss if they met the 6-session engagement benchmark (beta -3.5%, p < 0.01). Weight management is a popular focus for health coaching participants, and these programs can achieve modest weight loss. Programs should consider designing and testing strategies that promote engagement, given that weight-loss success was improved if participants completed at least 6 coaching sessions. PMID- 30425919 TI - Treatment of cerebral mucormycosis with drug therapy alone: A case report. AB - We report on an elderly male patient with headache and right-side weakness. Imaging studies revealed multiple space-occupying lesions in the parietal and occipital cerebral regions. Biopsy revealed broad aseptate ribbon-like structures branching at right angles, suggestive of mucormycosis. Improvement was observed after medical therapy with 20 weeks of liposomal amphotericin B (5 mg/kg/day) combined with posaconazole, followed by posaconazole (400 mg twice a day) alone for 1 month. The patient recovered without neurological deficits; however, multidrug-resistant bacteraemia and hospital-acquired pneumonia occurred, resulting in death. Nevertheless, our report shows that this lethal fungal infection can sometimes show favourable progress with drug therapy alone. PMID- 30425920 TI - Purpuriocillium lilacinum infection in captive loggerhead sea turtle hatchlings. AB - This paper reports a case of Purpureocillium lilacinum infection in seven loggerhead sea turtle (Caretta caretta) hatchlings kept in an aquarium under inadequate condition. The fungus was isolated from skin and pulmonary lesions. Metilene blue and NaCl solutions, Schinus terebinthifolius and eucalyptus essential oils Minimum Inhibitory Concentrations were determined indicating new possibilities for treatment. PMID- 30425921 TI - Ectoparasites are unlikely to be a primary cause of population declines of bent winged bats in south-eastern Australia. AB - While bats carry a diverse range of ectoparasites, little research has been conducted on the effects these organisms may have on bat populations. The southern bent-winged bat (Miniopterus orianae bassanii) is a critically endangered subspecies endemic to south-eastern Australia, whose numbers have declined over the past 50 years for unknown reasons. As part of a larger study to investigate the potential role of disease in these declines, southern bent-winged bats from four locations were captured and examined for the presence of bat flies, mites, ticks and the nematode Riouxgolvania beveridgei (previously associated with skin nodules in bent-winged bats). Results were compared with those obtained from the more common eastern bent-winged bat (Miniopterus orianae oceanensis), sampling animals from three different locations. All four types of parasite were found on both subspecies. There was no correlation between the presence of ectoparasites, body weight or any signs of disease. However, prevalence of tick and R. beveridgei infections were greater in Victorian southern bent-winged bats than South Australian southern bent-winged bats and eastern bent-winged bats, possibly indicative of some type of chronic stress impacting the immune system of this subspecies. PMID- 30425922 TI - Valproic acid as a monotherapy in drug-resistant methyl-CpG-binding protein 2 gene (MECP2) duplication-related epilepsy. AB - Duplication of the methyl-CpG-binding protein 2 gene (MECP2) is a rare condition that results in epilepsy in half of the cases. Although this condition has been well characterized in the literature, there is a lack of research on MECP2 duplication-related epilepsy and its management. We present the case of an eleven year old male with MECP2 duplication and epilepsy, who was resistant to polytherapy. The patient responded well to valproic acid (VPA) initially and upon re-challenge. This case report provides evidence for the use of VPA as an initial monotherapy for treatment of drug-resistant MECP2 duplication-related epilepsy. PMID- 30425923 TI - Flavonifractor (Eubacterium) plautii bloodstream infection following acute cholecystitis. AB - Flavonifractor plautii (formerly Eubacterium plautii) is an anaerobic gram positive rod shaped bacterium belonging to the family of Clostridiales, and a common member of the human gut microbiome. However, it is very rarely isolated from clinical human specimens, so data about its clinical significance are scarce. Here we report of a bloodstream infection due to F. plautii following gangrenous cholecystitis in a 69 year old man. After cholecystectomy and empirical antimicrobial treatment with ceftriaxone and metronidazole the patient recovered. F. plautii was the only bacterium detected in blood culture, suggesting that it might have been causative for cholecystitis. Antimicrobial resistance testing identified decreased susceptibilities against linezolid and penicillin indicating that a targeted therapy might be necessary. F. plautii can be considered a potential pathogen for cholecystitis. PMID- 30425924 TI - Simultaneous occurrence of hypermucoviscous Klebsiella pneumoniae emphysematous prostatic abscess, emphysematous cystitis, and renal abscess. AB - Emphysematous prostatic abscess is a rare clinical entity of uncomplicated urinary tract infections with high mortality rate. Here we report a case of hypermucoviscous Klebsiella pneumoniae causing emphysematous prostatic abscess, emphysematous cystitis, and renal abscess simultaneously in a 75-year-old Japanese male with diabetes mellitus and advanced gastric cancer. The patient was successfully treated with prolonged intravenous antimicrobial agents. PMID- 30425925 TI - Chronic sinusitis-associated antrolith. AB - An antrolith is a calcified mass found in the nasal cavity or sinus, usually maxillary, described in literature as a rare phenomenon. Its presenting symptoms are variable and include symptoms associated with chronic sinusitis. We describe a 66 year old man with chronic sinusitis who presented with facial pain and epistaxis and upon further evaluation was found to have an antrolith of the left maxillary sinus. PMID- 30425926 TI - Benign fibroepithelial polyp of the ureter: A case report. PMID- 30425927 TI - Delayed brain metastasis from renal cell carcinoma. PMID- 30425929 TI - Safety assessment of a standardized cucumber extract (Q-ActinTM): Oral repeat dose toxicity and mutagenicity studies. AB - Cucumus sativus (cucumber) is one of the most widely consumed fruit vegetables worldwide. Recent discovery of iminosugars in commonly consumed fruits and vegetables has promoted the interest in isolating these compounds and understanding the potential benefits to human health. The objective of the present study was to investigate the general toxicity and mutagenic effects of an aqueous extract of cucumber (Q-Actin), standardized to >=1% (1-2%) ido-BR1 iminosugar. Single dose of Q-Actin was well tolerated without mortality at 2000 mg/kg body weight (bw) in Sprague Dawley rats. Oral (gavage) administration of Q Actin up to 1000 mg/kg bw/day was well tolerated followed by repeated administration for a maximum period of 90 days in Sprague-Dawley rats. There were no treatment related changes in clinical observations, ophthalmic examinations, body weights and body weight gains or feed consumption, clinical chemistry and pathological changes compared to control. The mutagenicity as evaluated by Ames assay, in vitro chromosomal aberration test and in vivo micronucleus assay did not reveal any potential of Q-Actin to induce genotoxicity. The results showed that Q-Actin is well tolerated in general toxicity studies and did not induce mutagenicity. The no-observed-adverse-effect level (NOAEL) of the standardized aqueous cucumber extract (Q-Actin) is considered to be >=1000 mg/kg bw/day, followed by repeated administration for90 days. PMID- 30425928 TI - Consolidating probiotic with dandelion, coriander and date palm seeds extracts against mercury neurotoxicity and for maintaining normal testosterone levels in male rats. AB - Objective: Heavy metals are major elements polluting our universe. The inhalation, ingestion or even contacting human body with these elements results in huge health problems. The most common pollutant in our surrounding is mercury. Therefore, the present study aimed to elucidating the protective ability of hot water extracts of dandelion (DA), coriander (CO), date palm seeds (DS), probiotic supernatant (PS) and their combined mixture against mercury-induced neurotoxicity and altered testosterone levels in male rats. Methods: Fifty six male rats were randomly allotted into seven groups (n = 8 rats/group). Group1 (negative control; NC) animals were fed on the basal diet only, group2 (positive controls; PC) animals were fed on the basal diet and given an aqueous solution of mercuric chloride (25 ppm mercuric) in drinking water. Animals of the antioxidant-treated groups (3-7) were fed on the basal diet and given an aqueous solution of mercuric chloride (25 ppm mercuric) in drinking water together with the herbal antioxidant extracts and probiotics (25 ml/rat/day) throughout the experimental period. Where, group3 (Hg/CO) given coriander extract, group4 (Hg/DA) given dandelion extract, group5 (Hg/DS) given date palm seeds extract, group6 (Hg/PS) given probiotic supernatant, and group7 (Hg/Mix) given mixture of equal quantities of probiotic supernatant together with the three herbal extracts. The treatment lasted for 6 weeks, animals were sacrificed and blood samples were collected. Blood testosterone, enzyme activity and histopathological sections were performed. Results: The obtained data exhibited that mercury intoxication revealed increases of lactic dehydrogenase and decreases of glutathione-s transferase and testosterone. Light microscopic investigations of the brain cortex and cerebellum were suggestive of multiple foci of inflammation, cellular infiltration, gliosis and degeneration. Moreover, decreased glial fibrillary acidic protein (GFAP)-immunoreactivity and potential astrocyte toxicity both reflected impaired neuro-protective function of astrocytes necessary for maintaining the brain structure and function. Conclusion: Administration of the herbal extracts and their mixture with probiotics enhance the body defense and contain protective factor against mercury neurotoxicity and for maintaining normal testosterone levels in male rats. Also, treatment restored the normal control levels of biochemical attributes and histological architecture. PMID- 30425930 TI - Soy supplementation: Impact on gene expression in different tissues of ovariectomized rats and evaluation of the rat model to predict (post)menopausal health effect. AB - This toxicogenomic study was conducted to predict (post)menopausal human health effects of commercial soy supplementation using ovariectomized rats as a model. Different target tissues (i.e. breast, uterus and sternum) and non-target tissues (i.e. peripheral blood mononuclear cells (PBMC), adipose and liver) of ovariectomized F344 rats exposed to a commercially available soy supplement for eight weeks, were investigated. Changes in gene expression in these tissues were analysed using whole-genome microarray analysis. No correlation in changes in gene expression were observed among different tissues, indicating tissue specific effects of soy isoflavone supplementation. Out of 87 well-established estrogen responsive genes (ERGs), only 19 were found to be significantly regulated (p < 0.05) in different tissues, particularly in liver, adipose and uterus tissues. Surprisingly, no ERGs were significantly regulated in estrogen sensitive breast and sternum tissues. The changes in gene expression in PBMC and adipose tissue in rats were compared with those in (post)menopausal female volunteers who received the same supplement in a similar oral dose and exposure duration in human intervention studies. No correlation in changes in gene expression between rats and humans was observed. Although receiving a similar dose, in humans the plasma levels expressed as total free aglycones were several folds higher than in the rat. Therefore, the overall results in young ovariectomized female F344 rats indicated that using rat transcriptomic data does not provide a suitable model for human risk or benefit analysis of soy isoflavone supplementation. PMID- 30425931 TI - Syringic acid may attenuate the oral mucosal carcinogenesis via improving cell surface glycoconjugation and modifying cytokeratin expression. AB - Syringic acid (SRA) is an excellent anti-oxidant and anti-cancer property in various in vitro and in vivo studies. In the present study was modifying effect of SRA on 7,12-dimethylbenz(a)anthracene (DMBA) induced cell surface glycoconjugates (GCs) abnormalities in the plasma and buccal mucosa of golden Syrian hamster buccal pouch carcinogenesis (HBPCs). Topical application of DMBA three times a week for 10 weeks on the buccal pouches of the hamsters resulted in well developed squamous cell carcinoma. GCs status was assessed biochemically, histological and immunoexpression pattern of cytokeratin (CK) in the buccal mucosa of the DMBA treated hamsters. Elevated levels of GCs and CK expression were observed in DMBA alone treated hamsters. Oral pre-administration of SRA (50 mg/kg bw) positively modulates the GCs levels and CK expressions to near normal. The present findings suggested that SRA can protect cell surface GCs and CK expression during DMBA induced HBPCs. PMID- 30425932 TI - User-centered, interaction design research approaches to inform the development of health risk behavior intervention technologies. AB - Background: Computers have tremendous potential for helping people change behaviors that put their health at risk. This potential has led to the development of a variety of health behavior intervention technologies (BITs) in recent years. While many of these BITs have been informed by scientific theories on behavior change, poor design can fail to engage intended users. User-centered, interaction design (IxD) research can help BIT developers create tools that are intuitive and enjoyable and that align with intended users' goals. In this manuscript, we describe an IxD research process we used to inform the development of a tablet-optimized web application designed to help heavy drinking gay and bisexual men reduce their risk for HIV when they seek HIV testing. Methods: We conducted focus groups with subject matter experts (SMEs, N = 10) and intended users (N = 25). In the SME group, HIV test counselors were recruited to provide an understanding of the priorities and challenges of post-test counseling. In focus groups with intended users, participants created detailed, personalized models of two "typical" users of the proposed app ("personas") that could be used to guide design decisions. Results: SMEs emphasized the importance of putting patients at ease, and suggested that interventions should prioritize identifying personal risks and provide options for change. Personas created by intended users provided important details about users' attitudinal and emotional contexts, and their possible motivations and goals for using the app. These suggested that users might be most motivated to use the app in order to understand their personal risks, compare their behavior with others like them, help them decide whether they want to change to reduce their risk, and see all their options for doing so. Personas also provided insights about the aesthetic experience that might be most appealing to users. Conclusions: Interaction design research can provide BIT development teams with personal models of likely users to help guide decisions about the allocation of design resources and the overall form and spirit of the software. These insights can help teams build BITs that are more engaging and interesting to intended users. PMID- 30425933 TI - Postpartum nephrotic syndrome related to new onset of systemic lupus erythematosus: A case report. AB - Postpartum nephrotic syndrome in a pregnant woman with rheumatoid arthritis in long-standing remission is rare. Systemic lupus erythematosus can remain undiagnosed, especially in the absence of clinical manifestations. We present the case of a 34-year-old woman (gravida 2, para 1) who underwent a lower-segment cesarean section at 34 weeks and 6 days of gestation because she had developed preeclampsia and nephrotic syndrome. The concomitant presence of significant hypoproteinemia, hypoalbuminemia, uremia, elevated creatinine serum levels, hyperuricemia and hypertriglyceridemia is indicative of impaired renal function and nephrotic syndrome. This woman was diagnosed with systemic lupus erythematosus nephritis. It is imperative for clinicians to investigate the exact pathophysiological causes of nephrotic syndrome with onset in the puerperium and implement the appropriate therapeutic regimens. PMID- 30425934 TI - Assessment health status of ICU medical equipment levels at Neyshabur hospitals using ICNA and ACC indices. AB - This study was conducted to evaluate the health status of medical equipment's in Neyshabur hospital's intensive care units (ICU) before and after daily cleaning in order to compare the efficiency of the observational and microbial methods in evaluating hygienic conditions and cleaning of the environmental surfaces at the hospitals in Neyshabur. The study was performed in a ten-week period, twice a week before and after daily cleaning according to the ICNA observational method and the ACC microbial method were performed on the selected sites. (before and after daily cleaning in order to compare ICNA observational method and the ACC microbial method which performed on the selected sites). Result showed in total, 826 ICNA checklists were completed in this research for the 13 studied spots, 27.12% of the spots were contaminated before cleaning procedures, which dropped to 7.75% after cleaning. Data of the samples using the ACC index revealed that 74.82 were contaminated and 7.75% were clean. Bottle suction with 8.2% and Electroshock with 1% were the most and the least contaminated spots, respectively. As the results proved, the microorganism of Staphylococcus epidermises is the most grown organism in the intensive care unit. This study suggests that visual assessment is not enough to ensure quality of the process and it is necessary to document the level of cleanliness by quantitative methods. Also preparing the integrated instructions and guidelines of cleaning and disinfection and its continuous monitoring with standard methods would be effective in reducing the microbial contamination. PMID- 30425935 TI - Analytic-agent cyber dynamical systems analysis and design method for modeling spatio-temporal factors of malware propagation in wireless sensor networks. AB - Modelers often apply analytical (differential equation-based) epidemic models that mostly characterize the behavior of the network compartments with passage of time. Beyond temporal characterization, agent modeling promises the achievement of relevant spatial (stochastic and heterogeneous) representations. Arising from the combination of the prevalent analytical and agent methods (gleaned from extant literature) is a new method called the Analytic-Agent Cyber Dynamical Systems Analysis and Design Method (A2CDSADM); a modification of the Agent Oriented Analysis and Design (AOAD). Using hypothetical wireless sensor network (WSN) cases, A2CDSADM alleviates the lack of field data/lack of real geographical locations of the occurrence of particular cases by creating an analytical benchmark model for initial validation of the resulting agent model and ensures its easy modifiability and reproducibility. More so, it helps achieve the complementary/generative contribution of agent modeling, diminishes the less tractable nature of representing/analyzing WSN spatial features and provides a formalized method for performing comparative epidemic studies. Also, A2CDSADM covers the additional features for: *Generating the (analytical) equilibriums of WSN.*Performing continuous validation (at several points) in order to ensure model accuracy/suitability for real-world decision making.*Creating a high level conceptual model containing the envisaged WSN features to be represented. PMID- 30425936 TI - Risk of colorectal cancer in patients with diverticular disease. AB - Colorectal cancer constitutes an important burden on the healthcare system. Screening at-risk populations to reduce colorectal cancer-related morbidity and mortality has become part of good clinical practice. However, recommendations regarding subgroups of patients with diverticular disease are subject to controversy. Herein, we review the most recent literature regarding the prevalence of colorectal cancer in patients with diverticular disease, diverticulitis and uncomplicated diverticulitis. The recent literature does not identify diverticular disease as a long-term risk factor for colorectal cancer. However, the risk of colorectal cancer is increased in the short-term period after hospitalization related to diverticular disease. According to a recent systematic review and meta-analysis, the prevalence of colorectal cancer is 1.6% in patients with acute diverticulitis who underwent colonoscopy. The risk of having colorectal cancer after an episode of acute diverticulitis is 44-fold higher than that of an age- and gender-adjusted reference population. Despite lower among patients with uncomplicated episode, the risk of colorectal cancer remains 40-fold higher in that subpopulation than that in the reference population. To conclude, the recent literature describes an increased risk of colorectal cancer among patients with acute diverticulitis compared to the reference population. Colonoscopy is therefore recommended in patients with diverticulitis to exclude colorectal cancer. PMID- 30425937 TI - Lymphocyte subsets predictive value and possible involvement of human papilloma virus infection on breast cancer molecular subtypes. AB - AIM: To detect human papilloma virus (HPV) presence and to characterize cellular immune response in breast cancer patients. METHODS: A total of 74 women were included, of which 48 samples were from patients diagnosed with breast cancer and 26 patients with benign pathology of the breast. Molecular subtype classification was performed based on the immunohistochemical reports of the tumor piece. HPV genome detection and genotyping from fresh breast biopsies was performed using the INNO-LIPA HPV Genotyping Extra test (Innogenetics, Ghent, Belgium). CD3+, CD4+, CD8+ and natural killer (NK)+ cells levels from peripheral blood samples from patients with breast cancer and benign pathology were measured by flow cytometry. RESULTS: Luminal A was the most frequent breast cancer molecular subtype (33.33%). HPV was detected in 25% of the breast cancer patients, and genotype 18 was the most frequent in the studied population. The mean of CD3+, CD4+ and CD8+ subpopulations were decreased in patients with breast cancer, in relation to those with benign pathology, with a statistically significant difference in CD8+ values (P = 0.048). The mean of NK+ cells was increased in the benign pathology group. The average level of CD3+, CD4+, CD8+ and NK+ cells decreased as the disease progressed. HER2+ and Luminal B HER2+ tumors had the lowest counts of cell subsets. HPV breast cancer patients had elevated counts of cellular subsets. CONCLUSION: Determining level changes in cellular subsets in breast cancer patients is a useful tool to evaluate treatment response. PMID- 30425938 TI - Mismatch repair protein expression and intratumoral budding in rectal cancer are associated with an increased pathological complete response to preoperative chemoradiotherapy: A case-control study. AB - AIM: To determine whether the association of rectal adenocarcinoma with a defective-mismatch repair system (dMMR) was associated with a pathological complete response (pCR) to preoperative chemoradiotherapy. METHODS: A case control study was designed with the aim of determining if patients with rectal adenocarcinoma with dMMR had an associated high pCR rate in response to neoadjuvant chemoradiotherapy (nCRT). RESULTS: Seventy-two cases with pCR were compared against 144 controls without pCR. Across 216 cases, the mean age was 56.8 years, 140 (64.8%) were men, and 63 (29.2%) demonstrated the dMMR system. The pCR was associated with G1 tumors, dMMR, the absence of vascular invasion, and low tumor budding in the pretreatment biopsy. In a multivariant analysis, the factors associated with pCR were dMMR (OR: 2.61; 95%CI: 1.355-5.040, P = 0.004) and a low degree of tumor budding (OR: 2.52; 95%CI: 1.366-4.894, P = 0.025). CONCLUSION: We found an independent association between dMMR and a low rate of tumor budding, with a higher rate of pCR, in the basal biopsies of patients with rectal carcinoma subjected to nCRT. PMID- 30425939 TI - Interconversion of two commonly used performance tools: An analysis of 5844 paired assessments in 1501 lung cancer patients. AB - AIM: To establish the Karnofsky performance status (KPS) categories which would facilitate the interconversion of the KPS scale to the Eastern Cooperative Oncology Group (ECOG) performance status (PS) scale. METHODS: This was a retrospective analysis of all patients attending the lung cancer clinic at a tertiary care center over a 5-year period (September 2009 to August 2014). All patients were assessed with both KPS and ECOG PS scales at each visit. Correlation between KPS and ECOG PS was assessed using Spearman's correlation coefficient. KPS categories equivalent to ECOG PS scores were compared using hit rate and weighted kappa (kappaw). RESULTS: A total of 1501 patients were assessed over the study period, providing 5844 paired KPS and ECOG PS assessments. The study cohort had a mean (standard deviation; SD) age of 58.4 (10.8) years, with the majority being current or ex-smokers (76.9%) and males (82.3%). Non-small cell lung cancer was the most common histological type (n = 1196, 79.7%) with the majority having advanced (stage IIIB/IV) disease (83.4%). Mean baseline KPS and ECOG PS scores were 77.6 (SD = 14.4) and 1.5 (SD = 1) respectively. The most frequent KPS score was 80 (29%), and the most frequent ECOG PS score was 1 (43%). The overall correlation between KPS and ECOG PS was good (Spearman r = -0.84, P < 0.0001) but ranged from -0.727 to -0.972 between visits. KPS categories derived from our cohort [10-40 (ECOG 4), 50-60 (ECOG 3), 70 (ECOG 2), 80-90 (ECOG 1), 100 (ECOG 0)] performed better [hit rate 78.1%, kappaw = 0.749 (0.736-0.762) P < 0.0001] than those suggested in the past literature. CONCLUSION: The current study provides the largest set of paired KPS-ECOG assessments to date. We suggest that the KPS categories 10-40, 50-60, 70, 80-90, and 100 are equivalent to ECOG PS categories of 4, 3, 2, 1, and 0 respectively. PMID- 30425941 TI - Giant exophytic renal angiomyolipoma masquerading as a retroperitoneal liposarcoma: A case report and review of literature. AB - A 42-years-old lady, presented with a large retroperitoneal mass which was preoperatively diagnosed as a retroperitoneal liposarcoma following an image guided core biopsy. She underwent a margin-negative resection of the retroperitoneal mass (multi visceral resection - enbloc excision of the retroperitoneal mass with a left nephrectomy and a segmental descending colectomy). The final histopathological examination of the resected specimen confirmed an exophytic renal angiomyolipoma (AML) which was extending into the retroperitoneum. AML is a rare benign tumor arising most commonly from the kidney. It can sometimes present as a diagnostic challenge as it mimics a retroperitoneal liposarcoma or a fat-containing renal cell carcinomas closely. We present this case to share our experience of managing a case of giant exophytic AML which resembled retroperitoneal liposarcoma closely and resulted into an aggressive surgery. PMID- 30425940 TI - Comparison of the eighth version of the American Joint Committee on Cancer manual to the seventh version for colorectal cancer: A retrospective review of our data. AB - AIM: To analyze the survival trends in colorectal cancer (CRC) based on the different classifications recommended by the seventh and eighth editions of the American Joint Committee on Cancer staging system (AJCC-7th and AJCC-8th). METHODS: The database from our institution was queried to identify patients with pathologically confirmed stage 0-IV CRC diagnosed between 2006 and 2012. Data from 2080 cases were collected and 1090 cases were evaluated through standardized inclusion and exclusion criteria. CRC was staged by AJCC-7th and then restaged by AJCC-8th. Five-year disease-free survival (DFS) and overall survival (OS) were compared. SPSS 21.0 software was used for all data. DFS and OS were compared and analyzed by Kaplan-Meier and Log-rank test. RESULTS: Linear regression and automatic linear regression showed lymph node positive functional equations by tumor-node-metastasis staging from AJCC-7th and tumor-node-metastasis staging from AJCC-8th. Neurological invasion, venous infiltration, lymphatic infiltration, and tumor deposition put forward stricter requirements for pathological examination in AJCC-8th compared to AJCC-7th. After re-analyzing our cohort with AJCC-8th, the percentage of stage IVB cases decreased from 2.8% to 0.8%. As a result 2% of the cases were classified under the new IVC staging. DFS and OS was significantly shorter (P = 0.012) in stage IVC patients compared to stage IVB patients. CONCLUSION: The addition of stage IVC in AJCC-8th has shown that peritoneal metastasis has a worse prognosis than distant organ metastasis in our institution's CRC cohort. Additional datasets should be analyzed to confirm these findings. PMID- 30425942 TI - Treatment alliance and adherence in bipolar disorder. AB - The clinician patient relationship lies at the core of psychiatric practice and delivery of mental health care services. The concept of treatment alliance in psychiatry has its origins in psychotherapy, but has also been influenced by several other constructs such as patient-centred care (PCC) and shared decision making (SDM). Similarly, there has been a shift in conceptualization of treatment adherence in psychiatric disorders including bipolar disorder (BD) from illness centred and clinician-centred approaches to patient-centred ones. Moreover, the traditional compliance based models are being replaced by those based on concordance between clinicians and patients. Newer theories of adherence in BD place considerable emphasis on patient related factors and the clinician patient alliance is considered to be one of the principal determinants of treatment adherence in BD. Likewise, current notions of treatment alliance in BD also stress the importance of equal and collaborative relationships, sensitivity to patients' viewpoints, sharing of knowledge, and mutual responsibility and agreement regarding decisions related to treatment. Accumulated evidence from quantitative research, descriptive accounts, qualitative studies and trials of psychosocial interventions indicates that efficacious treatment alliances have a positive influence on adherence in BD. Then again, research on the alliance adherence link in BD lags behind the existing literature on the subject in other medical and psychiatric conditions in terms of the size and quality of the evidence, the consistency of its findings and clarity about underlying processes mediating this link. Nevertheless, the elements of an effective alliance which could have a positive impact on adherence in BD are reasonably clear and include PCC, collaborative relationships, SDM, open communication, trust, support, and stability and continuity of the relationship. Therefore, clinicians involved in the care of BD would do well to follow these principles and improve their interpersonal and communication skills in order to build productive alliances with their patients. This could go a long way in confronting the ubiquitous problem of non-adherence in BD. The role of future research in firmly establishing the alliance-adherence connection and uncovering the processes underlying this association will also be vital in devising effective ways to manage non-adherence in BD. PMID- 30425944 TI - Heterogeneity of Aortic Smooth Muscle Cells: A Determinant for Regional Characteristics of Thoracic Aortic Aneurysms? PMID- 30425943 TI - Women who suffer from schizophrenia: Critical issues. AB - Many brain diseases, including schizophrenia, affect men and women unequally - either more or less frequently, or at different times in the life cycle, or to varied degrees of severity. With updates from recent findings, this paper reviews the work of my research group over the last 40 years and underscores issues that remain critical to the optimal care of women with schizophrenia, issues that overlap with, but are not identical to, the cares and concerns of men with the same diagnosis. Clinicians need to be alert not only to the overarching needs of diagnostic groups, but also to the often unique needs of women and men. PMID- 30425945 TI - Timing of Transjugular Intrahepatic Portosystemic Stent-shunt in Budd-Chiari Syndrome: A UK Hepatologist's Perspective. AB - Budd-Chiari syndrome (BCS) is a rare but fatal disease caused by the obstruction in hepatic venous outflow tract (usually by thrombosis) and is further classified into two subtypes depending on the level of obstruction. Patients with BCS often have a combination of prothrombotic risk factors. Clinical presentation is diverse. Stepwise management strategy has been suggested with excellent 5-year survival rate. It includes anticoagulation, treatment of identified prothrombotic risk factor, percutaneous recanalization, and transjugular intrahepatic portosystemic shunt (TIPS) to reestablish hepatic venous outflow and liver transplantation in unresponsive patients. Owing to the rarity of BCS, there are no randomized controlled trials (RCTs) precisely identifying the timing for TIPS. TIPS should be considered in patients with refractory ascites, variceal bleed, and fulminant liver failure. Liver replacement is indicated in patients with progressive liver failure and in those in whom TIPS is not technically possible. The long-term outcome is usually influenced by the underlying hematologic condition and the development of hepatocellular carcinoma. This review focuses on the timing and the long-term efficacy of TIPS in patients with BCS. PMID- 30425947 TI - Citrate: How to Get Started and What, When, and How to Monitor? AB - In most of the case, regional citrate anticoagulation is using diluted citrate around 1% depending on the types used in clinical practice. Diluted citrate is much more safer when compared to highly concentrated citrate around 4% or even more. In clinical practice, trisodium citrate is used in high concentration (around 30%) as a bactericidal agent with anticoagulant properties for locking deep venous catheters used in hemodialysis (HD; close to 25-30% of citrate). In this review article, buffer and anticoagulant potential of citrate are discussed during renal replacement therapy in critically ill patients with particular focus on the practical approach at the bedside. PMID- 30425946 TI - Advances in Stroke Prevention. AB - There have been recent advances in stroke prevention in nutrition, blood pressure control, antiplatelet therapy, anticoagulation, identification of high-risk asymptomatic carotid stenosis, and percutaneous closure of patent foramen ovale. There is evidence that the Mediterranean diet significantly reduces the risk of stroke and that B vitamins lower homocysteine, thus preventing stroke. The benefit of B vitamins to lower homocysteine was masked by harm from cyanocobalamin among study participants with impaired renal function; we should be using methylcobalamin instead of cyanocobalamin. Blood pressure control can be markedly improved by individualized therapy based on phenotyping by plasma renin and aldosterone. Loss of function mutations of CYP2D19 impair activation of clopidogrel and limits its efficacy; ticagrelor can avoid this problem. New oral anticoagulants that are not significantly more likely than aspirin to cause severe bleeding, and prolonged monitoring for atrial fibrillation (AF), have revolutionized the prevention of cardioembolic stroke. Most patients (~90%) with asymptomatic carotid stenosis are better treated with intensive medical therapy; the few that could benefit from stenting or endarterectomy can be identified by a number of approaches, the best validated of which is transcranial Doppler (TCD) embolus detection. Percutaneous closure of patent foramen ovale has been shown to be efficacious but should only be implemented in selected patients; they can be identified by clinical clues to paradoxical embolism and by TCD estimation of shunt grade. "Treating arteries instead of treating risk factors," and recent findings related to the intestinal microbiome and atherosclerosis point the way to promising advances in future. PMID- 30425949 TI - Aplastic Anemia in China. AB - Aplastic anemia (AA) is a hematologic disease characterized by pancytopenia. Up to now, severe aplastic anemia (SAA) has been recognized by international and domestic scholars as an autoimmune disease with bone marrow (BM) failure mediated by the hyperfunctional T lymphocytes. The incidence of AA is more in China compared with other countries. In the recent years, both the pathogenesis and treatment of AA have made a great progress in our country. Thus, the therapeutic effect of AA was much better than before. Here, we conclude the researches of AA in China. PMID- 30425948 TI - Nanotechnology for Treatment of Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM), a grade IV astrocytoma as defined by the World Health Organization (WHO) criteria, is the most common primary central nervous system tumor in adults. After treatment with the current standard of care consisting of surgical resection, concurrent temozolomide (TMZ), and radiation, the median survival is only 15 months. The limited and less-effective treatment options for these highly aggressive GBMs call for the development of new techniques and the improvement of existing technologies. Nanotechnology has shown promise in treating this disease, and some nanomaterials have demonstrated the ability to cross the blood-brain barrier (BBB) and remain in GBM tissues. Although the retention of nanoparticles (NPs) in GBM tissue is necessary to elicit an antitumor response, the delivery of the NP needs to be enhanced. Current research in nanotechnology is directed at increasing the active targeting of GBM tissue not only for the aid of chemotherapeutic drug delivery but also for imaging studies. This review is aimed at describing advancements in increasing nanotechnology specificity to GBM tissue. PMID- 30425950 TI - Non-invasive Evaluation of Fluid Dynamic of Aortoiliac Atherosclerotic Disease: Impact of Bifurcation Angle and Different Stent Configurations. AB - Objectives: To non-invasively evaluate by computational fluid dynamic (CFD) analysis the physiology and rheology of aortoiliac bifurcation disease at different angles and different stent configurations. Material and methods: For the analysis, we considered a physiologic model of abdominal aorta with an iliac bifurcation set at 30 degrees , 45 degrees and 70 degrees without stenosis. Subsequently, a bilateral ostial common iliac stenosis of 80% was considered for each type of bifurcation. For the stent simulation, we reconstructed Zilver vascular self-expanding (Zilver; Cook, Bloomington, MN) and Palmaz Genesis Peripheral (Cordis, Miami, FL) stents. Results: The physiologic model, across the different angles, static pressure, Reynolds number and stream function, were lower for the 30 degrees bifurcation angle with a gradient from 70 degrees to 30 degrees angles, whereas all the other parameters were inversely higher. After stenting, all the fluid parameters decreased homogenously independent of the stent type, maintaining a gradient in favour of 30 degrees compared to 45 degrees and 70 degrees angles. The absolute greater deviation from physiology was observed for low kissing when self-expandable stents were used across all angles; in particular, the wall shear stress was high at at 45 degrees angle. Conclusion: Bifurcation angle deeply impacts the physiology of aortoiliac bifurcations, which are used to predict the fluid dynamic profile after stenting. CFD, having the potential to be derived both from computed tomography scan or invasive angiography, appears to be an ideal tool to predict fluid dynamic profile before and after stenting in aortoiliac bifurcation. PMID- 30425951 TI - Hepatic Encephalopathy in Patients in Lviv (Ukraine). AB - Background and Objectives: Hepatic encephalopathy (HE) research has long been impeded by the vague definition of this disabling complication of liver failure. This article provides an overview of the etiology and impact of HE on neuromuscular functions as well as its role in the development of infections and anemia. Materials and Methods: This was a descriptive study conducted in 36 patients with HE. Close monitoring of these patients was done by checking on several parameters. Results: The etiological distribution: alcohol (67%), hepatitis C virus (HCV; 17%), HCV and alcohol (8%), hepatitis B virus (HBV; 3%), HBV and alcohol (3%), HBV and HCV (6%), and cryptogenic (3%). The laboratory results indicated an elevation of De Ritis level in 69% of cases and in 92% of total bilirubin values. The Halstead-Reitan (H-R) test score with regards to gender indicated that more than half of the patients had a score of 2, while only few cases received the scores 3 and 4. The frequency of H-R score with regards to Child-Pugh score showed the significant preponderance of Child-Pugh score of 7-9 (B): 58.3% compared to others groups of results, and these results indicated patients' poor prognosis. Conclusion: Findings showed the preponderance of female patients towards developing HE and the poor survival rate of patients older than 65 years. Alcohol and hepatitis C were the main causes associated with the development of HE. The neurological assessment marked the preponderance of Child Pugh grades B and C and also the prevalence in female patients with neuropsychological disabilities through the assessment of H-R test. PMID- 30425952 TI - Cardiogenic Shock after Nifedipine Administration in a Pregnant Patient: A Case Report and Review of the Literature. AB - We present a case of a 21-year-old Caucasian woman at 27 weeks of pregnancy who was admitted to the obstetric department for pre-term labor. She received 10 mg of nifedipine 4 times in 1 h, according to the internal protocol. Shortly after, she brutally deteriorated with pulmonary edema and hypoxemia requiring transfer to the intensive care unit (ICU) for mechanical ventilation. She finally improved and was successfully extubated after undergoing a percutaneous valvuloplasty of the mitral valve. This case illustrates a severe cardiogenic shock after administration of nifedipine for premature labor in a context of unknown rheumatic mitral stenosis. Nifedipine induces a reflex tachycardia that reduces the diastolic period and thereby precipitates pulmonary edema in case of mitral stenosis. This case emphasizes the fact that this drug may be severely harmful and should never be used before a careful physical examination and echocardiography if valvular heart disease is suspected. PMID- 30425953 TI - Rift Valley fever virus: a serological survey in Libyan ruminants. AB - A serological survey was carried out in Libya to investigate the circulation of Rift Valley fever virus (RVFV) among domestic ruminants. A total of 857 serum samples were collected from year 2015 to 2016 in eleven provinces of Libya belonging to five branches of the country. Samples were tested for RVFV antibodies using a competitive Enzyme-Linked Immunosorbent Assay (c-ELISA). Antibodies specific for RVFV were not detected in any of the 857 samples. However, a statistical analysis was carried out to assess the maximum expected number of infected animals and the maximum expected prevalence of RVFV among Libyan ruminants' populations according to the sampled population. The overall maximum expected prevalence was estimated to be 1.8% for cattle and 0.4% for small ruminants. Results seem to exclude the circulation of RVFV, however, a surveillance plan should be implemented in areas at risk of RVFV introduction. PMID- 30425954 TI - First report of camel contagious ecthyma in Nigeria. AB - Camel contagious ecthyma (CCE) is a viral disease of camelids that is caused by a Parapoxvirus (PPV) which is a DNA virus of the viral family: Poxviridae. Diseases affecting camels in Nigeria are scarcely reported. CCE or the laboratory detection of camel PPV (CPPV) has not been reported in Nigeria. This study investigated and described the clinical presentation of CCE and molecular detection of CPPV in Nigeria. Suspected cases of CCE were reported in a farm, live animal market and abattoir, in three different states (Bauchi, Plateau and Zamfara) in Northern Nigeria. Skin scabs, lungs, liver and intestine samples were collected. Polymerase chain reaction (PCR) was carried out using the primers which targets the RPO30 gene fragment of the genus PPV. The clinical signs observed from the suspected cases of CCE were proliferative skin lesions, papules, scabs on the lips and nares. CPPV was detected in 80.0% (4/5) of the samples collected by PCR. CCE was diagnosed based on clinical signs and PCR results. This is the first report of CCE in Nigeria. Further studies should be carried out to genetically characterize the CPPV circulating in Nigeria. PMID- 30425955 TI - One-lung ventilation with use of a double lumen tube in two dogs; when right might be wrong. AB - One-lung ventilation (OLV) is an anaesthetic technique utilised for improved visualisation and access of the surgical field during thoracoscopy. The authors present two cases that underwent OLV with use of a double lumen tube (DLT). The first case was intubated with endoscopic guidance for bronchial port intubation of the right mainstem bronchus. This dog experienced prolonged periods of intraoperative hypoxemia. Upon case review, it was suspected intubation of the mainstem bronchus resulted in occlusion of the right cranial lung lobe. In the second case, the DLT was placed bronchoscopically into the left mainstem bronchus with the aid of computed tomography (CT). Excellent intraoperative oxygenation was achieved. When DLTs are used in dogs, their anatomical differences from humans make them susceptible to additional lung occlusion and pulmonary shunting. Computed tomography is recommended as a fundamental addition to bronchoscopy for correct tube placement. PMID- 30425956 TI - Diagnosis of chronic gastric instability using computed tomography in a Great Dane that progressed to gastric dilatation and volvulus: a literature review and case report. AB - Chronic gastric instability (CGI) is part of the gastric dilatation and volvulus (GDV) complex and contributes to the pathophysiologic mechanism of volvulus. Clinical signs can be attributed to a flaccid and mobile stomach. This manuscript reviews the literature regarding CGI and presents a case where computerized tomography is utilized in combination with abdominal radiography to diagnose CGI in an 8 year old spayed female Great Dane. The patient presented for nonspecific clinical signs including hypersalivation, anorexia, and regurgitation, and was euthanized after failing medical management and developing acute abdominal pain. Necropsy revealed a distended stomach with 180o rotation along its long axis. This case demonstrates that CGI and GDV share a continuum, and cases of CGI may progress to GDV without prophylactic surgical intervention. PMID- 30425957 TI - Devriesea agamarum associated cheilitis in a North African spiny-tailed lizard (Uromastyx acanthinura) in Spain. AB - An 11-year-old, male North African spiny-tailed lizard (Uromastyx acanthinura) was presented with hyperkeratotic cheilitis. Based on clinical examination, histology and microbiological testing, Devriesea agamarum was identified as the causative agent of the dermal disorder. Moreover, an abundant culture of D. agamarum was obtained following sampling of the oral cavity. Cheilitis was present for three years in the spiny-tailed lizard and during the first year of that period the lizard was housed together with an ocellated lizard (Timon lepidus), an Algerian orange-tailed skink (Eumeces algeriensis) and a female U. acanthinura. The latter lizard showed signs of chronic dermatitis and had deceased approximately 2.5 years prior to initial presentation of the male dab lizard because of renal failure. The other cohabiting lizards showed no dermal lesions and D. agamarum could not be demonstrated following dermal, cloacal and oral sampling. Recurrence of the bacterial skin infection was observed following a first antimicrobial treatment. This was considered to result from failure to eliminate the bacterium from the treated dab lizard or re-infection from the environment or asymptomatic carriers. A second treatment, including disinfection of the enclosure with house-hold bleach 0.1%, weekly mechanical debridement of the crusty lesion and treatment with ceftazidime at 20 mg/kg intramuscularly every 72 hours for 57 days resulted in resolution of the skin lesions, elimination of D. agamarum from the oral cavity based on repetitive microbiological sampling and no recurrence of the lesions during a 31 month follow up period. The present case is the first report of devrieseasis in Spain and highlights the importance of a multidirectional diagnostic and therapeutic approach towards controlling devrieseasis in captive lizard collections. Several disease aspects such as persistency are discussed in the light of the contemporary available literature. PMID- 30425958 TI - Clinical and sero-molecular characterization of Escherichia coli with an emphasis on hybrid strain in healthy and diarrheic neonatal calves in Egypt. AB - The present study was carried out to characterize pathogenic E. coli in apparently healthy and diarrheic neonatal calves with special reference to the hybrid E. coli strains and evaluate their clinical and hematobiochemical consequences. One hundred and seventy calves (age 1-30 days) were divided into two groups: apparently healthy (n = 70) and diarrheic (n=100). Animals were subjected to thorough clinical, hematobiochemical and bacteriological examinations. Clinically, diarrheic calves showed various degree of diarrhea with the presence of cardinal signs of dehydration in moderate and severe cases. There was a significant increase (p<0.05) in the hemogram parameters with uremia and hyperkalemia in calves with severe diarrhea. The O-H serotyping of cultural and biochemically positive isolates identified 31 isolates belonging to 12 serotypes including O44:H18, O55:H7, O146:H21, O113:H4, O121:H7, O26:H11, O91:H21, O111:H2, O8, O127: H6, O86 and O128:H2. Molecular characterization of E. coli isolates on three toxin genes: heat-stable enterotoxin (sta), shiga toxin type 1 and 2 (stx1 and stx2) revealed two well-known pathotypes (EPEC O44:H18, O55:H7, O146:H21, O113:H4, O121:H7 and EHEC O26:H11 O91:H21 O111:H2) with high frequency of enterohemorrhagic E. coli (EHEC). Molecular analysis also showed a number of E. coli isolates that carry sta and stx1 or sta and stx2 gene and belonged to O8, and O127:H6, O86 and O128:H2. These isolates were identified as hybrid E. coli strains (ETEC-STEC) and found in both apparently healthy and diarrheic calves. In conclusion, the present study identified high frequency of pathogenic E. coli in both apparently healthy and diarrheic calves. Serological and molecular analysis of E. coli isolates showed that high frequency of EHEC and presence of a new phenotype, STEC-ETEC hybrid, revealing their importance in the etiopathogenesis of diarrhea in calves and reinforcing the role of these animals as a reservoir of potentially pathogenic E. coli for humans. PMID- 30425959 TI - Survey of parasites in domestic pigeons (Columba livia) in Tripoli, Libya. AB - This study was a preliminary survey for identification of parasites (endoparasites and ectoparasites) and their prevalence in domestic pigeons (Columba livia) in Tripoli; Libya. One hundred adult domestic pigeons were purchased from different markets of Tripoli. Blood smears were prepared from each bird and examined using light microscopy with oil immersion lens for the presence of blood parasites. Oropharyngeal swab was taken from each pigeon and were processed through direct smear method and staining with Giemsa to identify Trichomonas gallinae. Each pigeon was examined for ectoparasites. Moreover, intestinal parasites were investigated and all helminths were counted before being fixed in 70% ethyl alcohol for further identification. Out of 100 pigeons examined, 76% (76/100) were infected with Haemoproteus spp. and 55% (55/100) with T. gallinae. The overall prevalence of ecto-parasitic infestation was 89% (82% Columbicloa columbae, 18% Goniodes gallinae, 3% Menopon gallinae and 1% Pseudolynchia canariensis). The overall prevalence of intestinal helminths in examined pigeons were 56% (56/100). Three species of Cestoda (2% Raillietina tetragona, 32% R. echinobothrida and 4% R. cesticillus) and three species of Nematoda (18% Heterakis gallinarum., 22% Ascaridia galli and 4% Capillaria spp.) were identified. Also, this study revealed that the pigeons examined were found infected with mixed parasites. The study highlights that pigeons are hosts of helminths of veterinary importance and may act as an important source of infection for other avian host, which share the common parasitic fauna. PMID- 30425960 TI - Morphological characterization of canine retrobulbar lymphoma. AB - This report characterized seven cases of canine retrobulbar lymphoma that have been diagnosed during 2008 to 2014 by immunophenotyping of CD3 and Pax5. Classification of lymphoma were performed according to the revised WHO guidelines. Four retrobulbar lymphomas were of T-cell origin, while the others were of B-cell. Out of 7 cases, four subtypes were diagnosed in this study; T cell-rich large B-cell lymphoma (3/7), T-cell lymphoblastic lymphoma (2/7), peripheral T-cell lymphoma (1/7), and cutaneous nonepitheliotropic lymphoma (1/7). T-cell-rich large B-cell lymphoma was found to be the most frequent subtype found. PMID- 30425961 TI - Comparative survey on scolicidal effects of selenium and silver nanoparticles on protoscolices of hydatid cyst. AB - Hydatidosis is a zoonotic diseases which affects human and livestock animals. The surgical treatment of hydatid diseases in man is still the most effective approach, but spillage of protoscolices is the risk of surgery. Therefore, it is essential to develop alternative approaches. Injection of protoscolicidal agents into the cysts preoperatively is an alternative method.The aim of the present study was the determination and comparison of lethal effects of silver nanoparticles (Ag-NPs) and selenium nanoparticles (Se-NPs) on protoscolices of hydatid cyst. Livers and lungs of sheep, which was naturally infected by hydatid cyst were collected from Tabriz slaughterhouse and transferred to the parasitology laboratory. Initially, the surface of cysts was disinfected by 70% Alcohol. Then, 25 ml of each cyst fluid were aspirated by sterile syringe and transferred to Erlenmeyer flask. After 30 minutes, the supernatant was discarded and protoscolices were washed with phosphate-buffered saline and tested by 1% eosin to assess their viability. Next, the samples of protoscolices, which were over 90%, were selected and the effect of 50, 125, 250 and 500 (ug/ml) of Se-NPs and Ag-NPs in the exposure times of 10, 20, 30 and 60 min were evaluated. Data were analysed by SAS software and analyzed by Duncan's comparison test. The significant differences were considered to be p<0.0001.The difference between the scolicidal effects of Se-NPs was statistically significant for all examined concentrations and exposure times compared to the control group (p<0.0001). On the other hand, the scolicidal effect of Ag-NPs in 10 and 20 min exposer was not significant in comparison to the control group. Overall scolicidal effect of Se NPs was higher than Ag-NPs and the difference was significant (p<0.0001).The results of the present research indicated that it is possible to use Se-NPs as an effective scolicidal treatment. It is suggested the study of employing this compound in vivo or in combination with other procedures in treating hydatid cyst in further studies. PMID- 30425962 TI - Serum vitamin A and E, copper, zinc and selenium concentrations and their relationship with health outcomes in dromedary hospitalized camels (Camelus dromedarius). AB - The goals of this study were to measure serum vitamin A (retinol) and E (alpha tocopherol) and trace elements concentrations (copper, zinc and selenium) during diseases condition and to determine their association with hematological parameters and immune status of hospitalized camels. A total of 95 dromedary camels [healthy (n=65); hospitalized camels (n=30)] were included in this study. Vitamin A and E concentrations were significantly lower in hospitalized camels than apparently healthy ones (P<0.05). Hospitalized camels had lower concentrations of zinc and selenium compared to healthy camels (P<0.05). Vitamin E, copper, zinc and selenium concentrations were positively correlated with phagocytic activity in hospitalized camels (P<0.05). The likelihood of deficiency of vitamin A and E, zinc and selenium concentrations were significant in female hospitalized camels than males and in young age hospitalized camels < 6 years old compared to old ones (P<0.05). Decreased vitamin A and E and trace elements concentrations were associated with hospitalized camels' phagocytic activity and index. The prevalence of low vitamin A and E, zinc and selenium concentrations were frequent in female hospitalized camels and hospitalized camels of age < 6 years old suggesting severe oxidative stress. PMID- 30425963 TI - Secukinumab in the treatment of psoriasis: patient selection and perspectives. AB - Secukinumab is a human monoclonal antibody targeting IL-17A that has been approved for three indications: moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. In Phase III clinical trials for each of these three indications, secukinumab has proven to be both highly efficacious and well-tolerated. However, several biologic medications are currently approved for the treatment of moderate-to-severe plaque psoriasis, and many demonstrate excellent efficacy and safety. Due to this wide selection, it is often unclear how to choose biologics for specific patients. Important considerations in biologic selection include clinical efficacy, safety, cost, convenience, onset of action, and management of comorbid disease. This article aims to outline the key considerations in patient selection for the treatment of plaque psoriasis with secukinumab. PMID- 30425964 TI - Senolytic Cocktail Dasatinib+Quercetin (D+Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, which develops in the context of fibrosis and cirrhosis caused by chronic inflammation, in turn due to non-alcoholic fatty liver disease (NAFLD), alcohol consumption and/or hepatitis viral infection. An increased number of senescent cells are associated with age-related tissue degeneration during NAFLD-induced HCC, or during chemotherapeutic treatment. Senolytic agents target selectively senescent cells. A combination of the senolytic drugs dasatinib and quercetin (D+Q) reduced hepatic lipid accumulation and alleviated age-associated physical dysfunction in mice. However, whether D+Q can impact the treatment of HCC, at the end-stage of the NAFLD inflammatory spectrum, is unknown. Here, using two well-established HCC cell lines (HepG2, Huh-7), we demonstrate that the maximal cytostatic doses for D and/or Q (1 + 1 MUM) lacked efficacy in removing doxorubicin-induced beta-gal positive senescent cells. Moreover, D+Q did not affect doxorubicin-dependent induction of flattened morphology, activation of p16, expression of SASP associated genes or formation of gammaH2AX foci. We then investigated the antitumor efficacy of doxorubicin, D+Q, or the combination, in xenograft studies conducted with HCC cells inoculated in athymic nude mice. Doxorubicin reduced tumor growth by 30% compared to control mice, while D+Q was ineffective in synergizing with doxorubicin and in clearing doxorubicin-induced HCC senescent cells. Unexpectedly, D+Q alone appeared to have acute pro-tumorigenic effects in control mice. While our data need to be confirmed in animal models that fully recapitulate NAFLD, we demonstrate that these compounds are ineffective, alone or in synergy with senescence-inducing chemotherapy, against experimental HCC. PMID- 30425965 TI - Evaluating Neighborhood Correlates and Geospatial Distribution of Breast, Cervical, and Colorectal Cancer Incidence. AB - Introduction: Though cancer research has traditionally centered on individual level exposures, there is growing interest in the geography of both cancer and its risk factors. This geographic and epidemiological research has consistently shown that cancer outcomes and their known causal exposures exhibit geographic variation that coincide with area-level socioeconomic status and the composition of neighborhoods. A retrospective study was conducted to evaluate geospatial variation for female breast, cervical, and colorectal cancer incidence in Baltimore City. Materials and Methods: Using a Maryland Cancer Registry dataset of incident breast, cervical, and colorectal cancers (N = 4,966) among Baltimore City female residents diagnosed from 2000 to 2010, spatial and epidemiological analyses were conducted through choropleth maps, spatial cluster identification, and local Moran's I. Ordinary least squares regression models identified characteristics associated with the geospatial clusters. Results: Each cancer type exhibited geographic variation across Baltimore City with the neighborhoods showing high incidence differing by cancer type. Specifically, breast cancer had significant low incidence in downtown Baltimore while cervical cancer had high incidence. The neighborhood covariates associated with the geographic variation also differed by cancer type while local Moran's I identified discordant clusters. Discussion: Cancer incidence varied geographically by cancer type within a single city (county). Small area estimates are needed to detect local patterns of disease when developing health and preventative programs. Given the observed variability of community-level characteristics associated with each cancer type incidence, local information is essential for developing place-, social-, and outcome-specific interventions. PMID- 30425966 TI - Transcriptomic Alterations in Lung Adenocarcinoma Unveil New Mechanisms Targeted by the TBX2 Subfamily of Tumor Suppressor Genes. AB - T-box (TBX) transcription factors are evolutionary conserved genes and master transcriptional regulators. In mammals, TBX2 subfamily (TBX2, TBX3, TBX4, and TBX5) genes are expressed in the developing lung bud and tracheae. Our group previously showed that the expression of TBX2 subfamily was significantly high in human normal lungs, but markedly suppressed in lung adenocarcinoma (LUAD). To further elucidate their role in LUAD pathogenesis, we first confirmed abundant expression of protein products of the four members by immunostaining in adult human normal lung tissues. We also found overall suppressed expression of these genes and their corresponding proteins in a panel of human LUAD cell lines. Transient over-expression of each of the genes in human (NCI-H1299), and mouse (MDA-F471) derived lung cancer cells was found to significantly inhibit growth and proliferation as well as induce apoptosis. Genome-wide transcriptomic analyses on NCI-H1299 cells, overexpressing TBX2 gene subfamily, unraveled novel regulatory pathways. These included, among others, inhibition of cell cycle progression but more importantly activation of the histone demethylase pathway. When using a pattern-matching algorithm, we showed that TBX's overexpression mimic molecular signatures from azacitidine treated NCI-H1299 cells which in turn are inversely correlated to expression profiles of both human and murine lung tumors relative to matched normal lung. In conclusion, we showed that the TBX2 subfamily genes play a critical tumor suppressor role in lung cancer pathogenesis through regulating its methylating pattern, making them putative candidates for epigenetic therapy in LUAD. PMID- 30425967 TI - Emerging Molecular Technologies in Genitourinary Tumors. PMID- 30425968 TI - High Sensitive and Non-invasive ctDNAs Sequencing Facilitate Clinical Diagnosis And Clinical Guidance of Non-small Cell Lung Cancer Patient: A Time Course Study. AB - Lung cancer is one of leading causes of cancer death all over the world. Non small cell lung cancer (NSCLC) is the most predominant subtype of lung cancer. Molecular targeting therapy has been shown great success in the treatment of advanced NSCLC. Thus, an easy, sensitive, and specific way of recognizing therapeutic gene targets would help to select effective treatments, to improve physical condition and increase patient survival. In this study, we recruited and followed up a female NSCLC patient, whose plasma ctDNAs (circulating tumor DNAs), blood cell DNAs, psDNAs (pleural effusion supernatant DNAs), and ppDNAs (pleural effusion pellet DNAs), were collected and analyzed over periodic time points by methods of next generation sequencing (NGS), droplet digital PCR (ddPCR), and Amplification Refractory Mutation System (ARMS). In addition, pleural effusion pellets were stained by IHC (immunohistochemistry). The investigation results showed that EGFR L858R mutation was recognized by methods of NGS, ddPCR, and ARMS, while EGFR T790M mutation was only identified by methods of NGS and ddPCR but not ARMS, indicating that ARMS as an auxiliary clinical diagnostic method, is less sensitive and less reliable than NGS and ddPCR. In summary, the non-invasive and sensitive way of collecting ctDNAs for NGS and/or ddPCR screenings offers patients new diagnosis and therapeutic options. PMID- 30425969 TI - Human Antimicrobial Peptide Isolated From Triatoma infestans Haemolymph, Trypanosoma cruzi-Transmitting Vector. AB - The importance of antimicrobial peptides (AMPs) in relation to the survival of invertebrates is well known. The source and the mode of action on the insects' immune system of these molecules have been described from different perspectives. Insects produce their own AMPs as well as obtain these molecules from various sources, for example by absorption through the intestinal tract, as previously described for Boophilus microplus. Blood-sucking barber bug Triatoma infestans attracts social, economic and medical interest owing to its role in the transmission of Chagas disease. Despite new studies, descriptions of AMPs from this insect have remained elusive. Thus, the aims of this work were to characterize the antimicrobial potential of human fibrinopeptide A (FbPA) obtained from the T. infestans haemolymph and identify its natural source. Therefore, FbPA was isolated from the T. infestans haemolymph through liquid chromatography and identified by mass spectrometry. This peptide exhibited antimicrobial activity against Micrococcus luteus. Native FbPA from human blood and the synthetic FbPA also exhibited antimicrobial activity. The synthetic FbPA was conjugated with fluorescein isothiocyanate and offered to the insects. The haemolymph collected after 72 h exhibited fluorescence at the same wavelength as fluorescein isothiocyanate. Our experiments show that beyond intrinsic AMP production, T. infestans is able to co-opt molecules via internalization and may use them as AMPs for protection. PMID- 30425970 TI - Highly Potent 1H-1,2,3-Triazole-Tethered Isatin-Metronidazole Conjugates Against Anaerobic Foodborne, Waterborne, and Sexually-Transmitted Protozoal Parasites. AB - Parasitic infections like amebiasis, trichomoniasis, and giardiasis are major health threats in tropical and subtropical regions of the world. Metronidazole (MTZ) is the current drug of choice for amebiasis, giardiasis, and trichomoniasis but it has several adverse effects and potential resistance is a concern. In order to develop alternative antimicrobials, a library of 1H-1,2,3-triazole tethered metronidazole-isatin conjugates was synthesized using Huisgen's azide alkyne cycloaddition reaction and evaluated for their amebicidal, anti trichomonal, and anti-giardial potential. Most of the synthesized conjugates exhibited activities against Trichomonas vaginalis, Tritrichomonas foetus, Entamoeba histolytica, and Giardia lamblia. While activities against T. vaginalis and T. foetus were comparable to that of the standard drug MTZ, better activities were observed against E. histolytica and G. lamblia. Conjugates 9d and 10a were found to be 2-3-folds more potent than MTZ against E. histolytica and 8-16-folds more potent than MTZ against G. lamblia. Further analysis of these compounds on fungi and bacteria did not show inhibitory activity, demonstrating their specific anti-protozoal properties. PMID- 30425971 TI - Molecular Distance to Health Transcriptional Score and Disease Severity in Children Hospitalized With Community-Acquired Pneumonia. AB - Background: Community-acquired pneumonia (CAP) is a leading cause of hospitalization and mortality in children. Diagnosis remains challenging and there are no reliable tools to objectively risk stratify patients or predict clinical outcomes. Molecular distance to health (MDTH) is a genomic score that measures the global perturbation of the transcriptional profile and may help classify patients by disease severity. We evaluated the value of MDTH to assess disease severity in children hospitalized with CAP. Methods: Children hospitalized with CAP and matched healthy controls were enrolled in a prospective observational study. Blood samples were obtained for transcriptome analyses within 24 h of hospitalization. MDTH scores were calculated to assess disease severity and correlated with laboratory markers, such as white blood cell count, c-reactive protein (CRP), and procalcitonin (PCT), and clinical outcomes, including duration of fever and duration of hospitalization (LOS). Univariate and multivariable logistic regression were applied to assess factors associated with LOS and duration of fever after hospitalization. Results: Among children hospitalized with CAP (n = 152), pyogenic bacteria (PB) were detected in 16 (11%), Mycoplasma pneumoniae was detected in 41 (28%), respiratory viruses (RV) alone were detected in 78 (51%), and no pathogen was detected in 17 (11%) children. Statistical group comparisons identified 6,726 genes differentially expressed in patients with CAP vs. healthy controls (n = 39). Children with confirmed PB had higher MDTH scores than those with RV (p < 0.05) or M. pneumoniae (p < 0.01) detected alone. CRP (r = 0.39, p < 0.0001), PCT (r = 0.39, p < 0.0001), and MDTHs (r = 0.24, p < 0.01) correlated with duration of fever, while only MDTHs correlated with LOS (r = 0.33, p < 0.0001). Unadjusted analyses showed that both higher CRP and MDTHs were associated with longer LOS (OR 1.04 [1 1.07] and 1.12 [1.04-1.20], respectively), however, only MDTH remained significant when adjusting for other covariates (aOR 1.11 [1.01-1.22]). Conclusions: In children hospitalized with CAP MDTH score measured within 24 h of admission was independently associated with longer duration of hospitalization, regardless of the pathogen detected. This suggests that transcriptional biomarkers may represent a promising approach to assess disease severity in children with CAP. PMID- 30425972 TI - Macrophages and Galectin 3 Control Bacterial Burden in Acute and Subacute Murine Leptospirosis That Determines Chronic Kidney Fibrosis. AB - Previous studies have suggested that macrophages may contribute to acute Leptospira dissemination, as well as having a major role in kidney fibrosis. Our aim was to characterize the role of macrophages and galectin 3 (Gal-3) on the survival, clinical course, bacterial burden, interstitial nephritis, and chronic kidney fibrosis in Leptospira interrogans serovar Copenhageni (LIC)-induced experimental murine leptospirosis. C57BL/6J mice depleted of macrophages by liposome-encapsulated clodronate treatment and infected with LIC presented a higher bacterial burden, had reduced subacute nephritis and enhanced chronic kidney fibrosis relative to untreated, infected mice. Moreover, LIC infection in mice whose Gal-3 was disrupted (Lgals3 - /-) had a higher bacterial burden and enhanced subacute nephritis and chronic kidney fibrosis when compared to C57BL/6J wild-type mice. Chronic fibrosis did not correlate with higher transcription levels of TGF-beta1 or IL-13 in the kidneys. Kidney fibrosis was found in chronically infected rats as well as in wild infected rats. On the other hand, human fibroblast cultures exhibited enhanced differentiation to myofibroblasts after treatment with LIC. Our results demonstrate that macrophages and Gal-3 play a critical role in controlling the LIC burden but has a minor role in subsequent fibrosis. Instead, kidney fibrosis was better correlated with bacterial burden. Taken together, our results do not support a role for macrophages to disseminate leptospires during acute infection, nor in chronic kidney fibrosis. PMID- 30425973 TI - Quality of life worsened the most severely in patients immediately after intensity-modulated radiotherapy for prostate cancer. AB - Purpose: The aim of this study was to evaluate the chronological changes in lower urinary tract symptoms (LUTSs), disease-related quality of life (QOL), and health related QOL (HR-QOL) of patients who received intensity-modulated radiotherapy (IMRT). Patients and methods: In 121 patients who had received IMRT and were followed up for >2 years, the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), Expanded Prostate Cancer Index Composite (EPIC), and 8-Item Short-Form Health Survey (SF-8) were used before IMRT, at the halfway point in IMRT, immediately after IMRT, and 1-24 months after the completion of IMRT. Results: The IPSS and OABSS and the urinary and bowel domains of the EPIC indicated that QOL worsened at the halfway point in IMRT, further worsened more severely immediately after IMRT, and then improved. The sexual domain of the EPIC significantly decreased at the halfway point in IMRT, which significantly lowered until 24 months. The scores of physical functioning, role physical, bodily pain, vitality, social functioning, and role emotional domains in the SF-8 significantly decreased and reached their lowest points immediately after IMRT. Conclusion: QOL worsened the most severely in patients immediately after IMRT for prostate cancer. This knowledge can influence treatment recommendations and enable patients to make better informed decisions. PMID- 30425974 TI - Gastric Peroral Endoscopic Myotomy (G-POEM) as a Treatment for Refractory Gastroparesis: Long-Term Outcomes. AB - Background and Aims: Gastric peroral endoscopic myotomy (G-POEM) has been regarded as a novel and minimally invasive therapy for refractory gastroparesis. This study reports the long-term outcomes and possible predictive factors for successful outcomes after G-POEM in an Asian population. Methods: This is a retrospective single-centre study of 16 patients who underwent G-POEM for refractory gastroparesis from August 2016 to October 2017. This study included 11 males and 5 females; in addition, 13 patients had postsurgical gastroparesis, and 3 patients had diabetes. The patients included had severe and refractory gastroparesis, as indicated by a Gastroparesis Cardinal Symptom Index (GCSI) score >=20, and evidence of a delay on gastric emptying scintigraphy (GES). The primary outcome parameter was an assessment of the long-term clinical efficacy of the procedure. The secondary outcome parameter was the detection of possible predictive factors for success and the determination of cut-off values for such predictors. Results: Technical success was achieved in 100% of the patients, with a mean procedure time of 45.25+/-12.96 min. The long-term clinical response was assessed in all patients during a median follow-up of 14.5 months. Clinical success was achieved in 13 (81.25%) patients. There was a significant reduction in the GCSI scores and GES values after the procedure compared to the baseline values, with P values of <0.0001 and 0.012, respectively. Univariate regression analysis showed that the GCSI and GES had significant associations with the future clinical outcomes of the patients, but this finding was not confirmed in multivariate analysis. A GCSI cut-off score of <=30 had a high sensitivity and a negative predictive value (NPV) of 100% for predicting a successful procedure. GES (half emptying time <=221.6 min and 2-hour retention <=78.6%) had a high specificity and a positive predictive value (PPV) of 100%. Conclusions: G-POEM is a safe and effective treatment option with a long-term efficacy of 81.6%. GCSI and GES could serve as good predictive measures. PMID- 30425975 TI - "Fatal Gastrointestinal and Peritoneal Ischemic Disease" of Unknown Cause at Arba Minch Hospital, Southern Ethiopia. AB - Gastrointestinal and peritoneal ischemic disease due to unknown etiology present with intestinal obstruction and/or peritonitis otherwise in healthy patient emerged as fatal disease at Arba Minch General Hospital. This disorder was diagnosed based on intraoperative finding. Clinical presentation and natural history of disease progression were similar. It is estimated that about 6-10 lives are being claimed each year at Arba Minch Hospital with this disease of unidentified cause accounting for the largest figure of surgical department. Here we report case analysis and literature review illustrating clinical presentation, workup, preoperative diagnosis, intraoperative diagnosis, and final outcome of fatal gastrointestinal and peritoneal ischemic disease. PMID- 30425976 TI - Pleiotropic Effects of Heparins: From Clinical Applications to Molecular Mechanisms in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is a major health problem worldwide and most cases are incurable because of late presentation. It is the most common primary neoplasm of the liver and often arises in the context of a chronic liver disease that impairs coagulation. Portal vein thrombosis (PVT) is a common complication of HCC that is associated with a poor prognosis. Heparin derivatives are widely used in the management of venous thromboembolism (VTE). Among them low molecular weight heparin (LMWH) favorably influences the survival in patients with advanced cancer, including HCC. Due to their pleiotropic function, heparins affect tumorigenesis in many ways and may promote or hamper tumorigenic transformation depending on the cancer type and cancer stage along with their structural properties and concentration. Thus, their application as an antithrombotic along with the conventional therapy regime should be carefully planned to develop the best management strategies. In this review, we first will briefly review clinical applications of heparin derivatives in the management of cancer with a particular focus on HCC. We then summarize the state of knowledge whereby heparin can crosstalk with molecules playing a role in hepatocarcinogenesis. Lastly, we highlight new experimental and clinical research conducted with the aim of moving towards personalized therapy in cancer patients at risk of thromboembolism. PMID- 30425977 TI - Regulation of Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF kappabeta) in Inflammatory Bowel Diseases. AB - Inflammatory bowel diseases (IBD), encompassing both Crohn Disease (CD) and ulcerative colitis (UC) are globally prevalent diseases, impacting children of all ages. The hallmark of IBD is a perturbed immune system that leads to continuous inflammation in the gut and challenges optimal treatment. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappabeta), a nuclear transcription factor, plays a major role in gut homeostasis and contributes significantly toward a balanced, homeostatic immune system. Dysregulation in the NF-kappabeta pathway and factors that regulate it lead to a state of uncontrolled inflammation and altered immunity, as typically observed in IBD. Levels of proinflammatory cytokines that are regulated through NF-kappabeta are increased in both CD and UC. Genes known to activate NF-kappabeta, such as, Nucleotide binding oligomerization domain-containing protein 2 (NOD2) and Interleukin 23 (IL 23), are associated with IBD. Factors involved in inhibition of NF-kappabeta, such as A20 and TOLLIP, are also affected in IBD, resulting in failed inflammation suppression/regulation. NOD-2 and A20 have specifically been found to be strongly associated with pediatric IBD. Gut commensals are known to exert anti-inflammatory activities toward NF-kappabeta and can have a potential role in attenuating inflammation that likely occurs due to microbial dysbiosis in IBD. Failure to terminate/downregulate NF-kappabeta signaling results in chronic inflammation in IBD. Well-regulated control of inflammation in children with IBD can help better control the disease and suppress immune responses. Better understanding of factors that control NF-kappabeta can potentially lead toward discovering targeted therapeutic interventions for IBD. Suppression of NF kappabeta can be achieved through many modalities including anti-sense oligonucleotides (ASOs), siRNA (small interfering RNA), factors regulating NF kappabeta, and microbes. This review focuses on the role of NF-kappabeta, especially in pediatric IBD, and potential therapeutic venues for attenuating NF kappabeta-induced inflammation. PMID- 30425978 TI - Structural Evidence for the Substrate Channeling of Rice Allene Oxide Cyclase in Biologically Analogous Nazarov Reaction. AB - Allene oxide cyclase (AOC) is a key enzyme in the jasmonic acid (JA) biosynthetic pathway in plants, during which it catalyzes stereospecific conversion of 12,13(S)-epoxy-9(Z),11,15(Z)-octadecatrienoic acid (12,13-EOT) to cis(+)-12 oxophytodienoic acid. Here, rice allene oxide cyclase (OsAOC) was localized to the chloroplast and its native oligomeric structure was analyzed by gel electrophoresis in the absence and presence of a protein-crosslinking reagent. The results suggest that OsAOC exists in solution as a mixture of monomers, dimers, and higher order multimers. OsAOC preferentially exists as dimer at room temperature, but it undergoes temperature-dependent partial denaturation in the presence of SDS. A heteromeric 2:1 complex of OsAOC and rice allene oxide synthase-1 (OsAOS1) was detected after cross-linking. The yield of cis(+)-12 oxophytodienoic acid reached maximal saturation at a 5:1 molar ratio of OsAOC to OsAOS1, when OsAOC and OsAOS1 reactions were coupled. These results suggest that the OsAOC dimer may facilitate its interaction with OsAOS1, and that the heteromeric 2:1 complex may promote efficient channeling of the unstable allene oxide intermediate during catalysis. In addition, conceptual similarities between the reaction catalyzed by AOC and Nazarov cyclization are discussed. PMID- 30425981 TI - Ruthenium Incorporated Cobalt Phosphide Nanocubes Derived From a Prussian Blue Analog for Enhanced Hydrogen Evolution. AB - Electrochemical water splitting in alkaline media plays an important role in mass production of hydrogen. Ruthenium (Ru), as the cheapest member of platinum-group metals, has attracted much attention, and the incorporation of trace amount of Ru with cobalt phosphide could significantly improve the hydrogen evolution reaction (HER) catalytic activity. In this work, ruthenium-incorporated cobalt phosphide nanocubes are synthesized via a reaction between Co-Co Prussian blue analog (Co PBA) and ruthenium chloride (RuCl3) followed by the phosphidation. The sample with a Ru content of ~2.04 wt.% exhibits the best HER catalytic activity with a low overpotential of 51 and 155 mV, to achieve the current densities of -10 and 100 mA cm-2, respectively, and the Tafel slope of 53.8 mV dec-1, which is comparable to the commercial Pt/C. This study provides a new perspective to the design and construction of high performance electrocatalysts for HER and other catalytic applications in a relatively low price. PMID- 30425979 TI - Does Substrate Positioning Affect the Selectivity and Reactivity in the Hectochlorin Biosynthesis Halogenase? AB - In this work we present the first computational study on the hectochlorin biosynthesis enzyme HctB, which is a unique three-domain halogenase that activates non-amino acid moieties tethered to an acyl-carrier, and as such may have biotechnological relevance beyond other halogenases. We use a combination of small cluster models and full enzyme structures calculated with quantum mechanics/molecular mechanics methods. Our work reveals that the reaction is initiated with a rate-determining hydrogen atom abstraction from substrate by an iron (IV)-oxo species, which creates an iron (III)-hydroxo intermediate. In a subsequent step the reaction can bifurcate to either halogenation or hydroxylation of substrate, but substrate binding and positioning drives the reaction to optimal substrate halogenation. Furthermore, several key residues in the protein have been identified for their involvement in charge-dipole interactions and induced electric field effects. In particular, two charged second coordination sphere amino acid residues (Glu223 and Arg245) appear to influence the charge density on the Cl ligand and push the mechanism toward halogenation. Our studies, therefore, conclude that nonheme iron halogenases have a chemical structure that induces an electric field on the active site that affects the halide and iron charge distributions and enable efficient halogenation. As such, HctB is intricately designed for a substrate halogenation and operates distinctly different from other nonheme iron halogenases. PMID- 30425980 TI - Directed Self-Assembly of Trimeric DNA-Bindingchiral Miniprotein Helicates. AB - We propose that peptides are highly versatile platforms for the precise design of supramolecular metal architectures, and particularly, for the controlled assembly of helicates. In this context, we show that the bacteriophage T4 Fibritin foldon (T4Ff) can been engineered on its N-terminus with metal-chelating 2,2'-bipyridine units that stereoselectively assemble in the presence of Fe(II) into parallel, three-stranded peptide helicates with preferred helical orientation. Modeling studies support the proposed self-assembly and the stability of the final helicate. Furthermore, we show that these designed mini-metalloproteins selectively recognize three-way DNA junctions over double-stranded DNA. PMID- 30425982 TI - Diversity-Oriented Synthesis and Chemoinformatic Analysis of the Molecular Diversity of sp3-Rich Morpholine Peptidomimetics. AB - Diversity-Oriented Synthesis (DOS) consists of generating structurally diverse compounds from a complexity-generating reaction followed by cyclization steps and appendage diversity. DOS has gathered interest to systematically explore the chemical space by generating high-quality small-molecule collections as probes to investigate biological pathways. The generation of heterocycles using amino acid and sugar derivatives as building blocks is a powerful approach to access chemical and geometrical diversity thanks to the high number of stereocenters and the polyfunctionality of such compounds. Our efforts in this field are focused on the generation of diversity-oriented molecules of peptidomimetic nature as a tool addressing protein-protein interactions, taking advantage of amino acid- and sugar-derived polyfunctional building blocks to be applied in couple-pair synthetic approaches. In this paper, the combination of diversity-oriented synthesis and chemoinformatics analysis of chemical space and molecular diversity of heterocyclic peptidomimetics are reported, with particular interest toward carbohydrate- and amino acid-derived morpholine scaffolds with a higher fraction of sp3 carbon atoms. Also, the chemoinformatic analysis of chemical space and molecular diversity of 186 morpholine peptidomimetics is outlined. PMID- 30425983 TI - Marine Bacterial Aromatic Polyketides From Host-Dependent Heterologous Expression and Fungal Mode of Cyclization. AB - The structure diversity of type II polyketide synthases-derived bacterial aromatic polyketides is often enhanced by enzyme controlled or spontaneous cyclizations. Here we report the discovery of bacterial aromatic polyketides generated from 5 different cyclization modes and pathway crosstalk between the host and the heterologous fluostatin biosynthetic gene cluster derived from a marine bacterium. The discovery of new compound SEK43F (2) represents an unusual carbon skeleton resulting from a pathway crosstalk, in which a pyrrole-like moiety derived from the host Streptomyces albus J1074 is fused to an aromatic polyketide SEK43 generated from the heterologous fluostatin type II PKSs. The occurrence of a new congener, fluoquinone (3), highlights a bacterial aromatic polyketide that is exceptionally derived from a characteristic fungal F-mode first-ring cyclization. This study expands our knowledge on the power of bacterial type II PKSs in diversifying aromatic polyketides. PMID- 30425984 TI - SUNSPACE, A Porous Material to Reduce Air Particulate Matter (PM). AB - The World Health Organization reports that every year several million people die prematurely due to air pollution. Poor air quality is a by-product of unsustainable policies in transportation, energy, industry, and waste management in the world's most crowded cities. Particulate matter (PM) is one of the major element of polluted air. PM can be composed by organic and inorganic species. In particular, heavy metals present in PM include, lead (Pb), mercury (Hg), cadmium, (Cd), zinc (Zn), nickel (Ni), arsenic (As), and molybdenum (Mo). Currently, vegetation is the only existing sustainable method to reduce anthropogenic PM concentrations in urban environments. In particular, the PM-retention ability of vegetation depends on the surface properties, related to the plant species, leaf and branch density, and leaf micromorphology. In this work, a new hybrid material called SUNSPACE (SUstaiNable materials Synthesized from by-Products and Alginates for Clean air and better Environment) is proposed for air PM entrapment. Candle burning tests are performed to compare SUNSPACE with Hedera Helix L. leafs with respect to their efficacy of reducing coarse and fine PM. The temporal variation of PM10 and PM2.5 in presence of the trapping materials, shows that Hedera Helix L. surface saturates more rapidly. In addition, the capability of SUNSPACE in ultrafine PM trapping is also demonstrated by using titanium dioxide nanoparticles with 25 nm diameter. Scanning electron microscope (SEM) and Transmission electron microscope (TEM) images of SUNSPACE after entrapment tests highlight the presence of collected nanoparticles until to about 0.04 mm in depth from the sample surface. N2 physisorption measurements allow to demonstrate the possibility to SUNSPACE regeneration by washing. PMID- 30425985 TI - Quartz Crystal Microbalance With Dissipation Monitoring: A Powerful Method to Predict the in vivo Behavior of Bioengineered Surfaces. AB - The Quartz Crystal Microbalance with dissipation monitoring (QCM-D) is a tool to measure mass and viscosity in processes occurring at or near surfaces, or within thin films. QCM-D is able to detect extremely small chemical, mechanical, and electrical changes taking place on the sensor surface and to convert them into electrical signals which can be investigated to study dynamic process. Surface nanotopography and chemical composition are of pivotal importance in biomedical applications since interactions of medical devices with the physiological environment are mediated by surface features. This review is intended to provide readers with an up-to-date summary of QCM-D applications in the study of cell behavior and to discuss the future trends for the use of QCM-D as a high throughput method to study cell/surface interactions overcoming the current challenges in the design of biomedical devices. PMID- 30425986 TI - Constitutive Activation of NF-kappaB Pathway in Hematopoietic Stem Cells Causes Loss of Quiescence and Deregulated Transcription Factor Networks. AB - Identifying physiological roles of specific signaling pathways that regulate hematopoietic stem cell (HSC) functions may lead to new treatment strategies and therapeutic interventions for hematologic disorders. Here, we provide genetic evidence that constitutive activation of NF-kappaB in HSCs results in reduced pool size, repopulation capacities, and quiescence of HSCs. Global transcriptional profiling and bioinformatics studies identified loss of 'stemness' and 'quiescence' signatures in HSCs with deregulated NF-kappaB activation. In particular, gene set enrichment analysis identified upregulation of cyclin dependent kinase- Ccnd1 and down regulation of cyclin dependent kinase inhibitor p57kip2 . Interestingly, constitutive activation of NF-kappaB is sufficient to alter the regulatory circuits of transcription factors (TFs) that are critical to HSC self-renewal and functions. Molecular studies identified Junb, as one of the direct targets of NF-kappaB in hematopoietic cells. In essence, these studies demonstrate that aberrant activation of NF-kappaB signals impairs HSC quiescence and functions and alters the 'TF networks' in HSCs. PMID- 30425988 TI - Comparative Analysis of Podocyte Foot Process Morphology in Three Species by 3D Super-Resolution Microscopy. AB - Since the size selectivity of the filtration barrier and kidney function are highly dependent on podocyte foot process morphology, visualization of foot processes is important. However, the size of foot processes is below the optical resolution of light microscopy. Therefore, electron microcopy has been indispensable to detect changes in foot process morphology so far, but it is a sophisticated and time-consuming technique. Recently, our group has shown that 3D structured illumination microscopy (3D-SIM), a super-resolution microscopy (SRM) technique, can visualize individual foot processes in human biopsies. Moreover, we have developed a software-based approach to directly quantify the structure of podocyte foot processes named Podocyte Exact Morphology Measurement Procedure (PEMP). As shown in patients suffering from minimal change disease (MCD), PEMP allows the quantification of changes of the foot process morphology by measuring the filtration slit density (FSD). Since rodents are frequently used in basic research, we have applied PEMP to quantify foot processes of mice and rats. Comparative analysis of nephrin-stained kidneys from humans, rats, and mice showed significant differences of the FSD. The highest FSD was measured in mice (3.83 +/- 0.37 MUm-1; mean +/- SD) followed by rats (3.36 +/- 0.42 MUm-1) and humans (3.11 +/- 0.26 MUm-1). To demonstrate that PEMP can be used to determine foot process morphology also in affected animals, we measured the FSD in palladin knockout mice on a 129S1 genetic background compared to wild-type littermates. Taken together, we established a method for the quick and exact quantification of podocyte foot process morphology which can be applied to diagnosis and basic research. PMID- 30425987 TI - Adhesive Interactions Delineate the Topography of the Immune Synapse. AB - T cells form adhesive contacts with antigen-presenting cells (APCs) as part of the normal surveillance process that occurs in lymph nodes and other tissues. Most of these adhesive interactions are formed by integrins that interact with ligands expressed on the surface of the APC. The interactive strength of integrins depends on their degree of membrane proximity as well as intracellular signals that dictate the conformation of the integrin. Integrins appear in different conformations that endow them with different affinities for their ligand(s). Integrin conformation and thus adhesive strength between the T cell and the APC is tuned by intracellular signals that are turned on by ligation of the T cell receptor (TCR) and chemokine receptors. During the different stages of the process, integrins, the TCR and chemokine receptors may be interconnected by the actin cytoskeleton underneath the plasma membrane, forming a chemical and physical network that facilitates the spatiotemporal dynamics, positioning, and function of these receptors and supports cell-cell adhesion during T cell activation, allowing it to perform its effector function. PMID- 30425989 TI - Forestalling the Epidemics of Parkinson's Disease Through Plant-Based Remedies. AB - Parkinson's disease (PD) as the second leading neurodegenerative disease, imposes a heavy burden among individuals as well as economies worldwide. The main characteristics of PD is a progressive loss of dopaminergic neurons resulting in the loss of motor function, the occurrence of non-motor symptoms, and cognitive decline. Similar to many other chronic diseases, complementary and alternative therapies (CAT) are very popular for the treatment of this disease. This review evaluates six plants, three each from European and Asian traditional medicinal systems: (1) Atropa belladonna, (2) Hyoscyamus niger, (3) Lepidium meyenii, (4) Aspargus racemosus, (5) Mucuna pruriens L., and (6) Gingko biloba. Atropa belladonna, and Hyoscyamus niger in particular, are better known for their poisonous and narcotic effects than as potentially effective plants for the treatment of neurodegenerative diseases. Ginkgo biloba is one of the most widely cultured plants in Traditional Chinese Medicine with high antioxidant potential which contributes to its neuroprotective/ anti-apoptotic activity. The bioactive compounds, anti-neurodegenerative effects and other neuroprotective effects of all six plants are discussed herein. PMID- 30425991 TI - BLTR1 and CD36 Expressing Microvesicles in Atherosclerotic Patients and Healthy Individuals. AB - Aims: Monocytes/macrophages play a crucial role in the development, progression, and complication of atherosclerosis. In particular, foam cell formation driven by CD36 mediated internalization of oxLDL leads to activation of monocytes and subsequent release of microvesicles (MVs) derived from monocytes (MMVs). Further, pro-inflammatory leukotriene B4 (LTB4) derived from arachidonic acid promotes atherosclerosis through the high-affinity receptor BLTR1. Thus, we aimed to investigate the correlation between different MMV phenotypes (CD14+ MVs) on the one hand, and arachidonic acid and eicosapentaenoic acid contents in different compartments including atherosclerotic plaques, plasma, and granulocytes on the other. Methods and Results: Samples from patients with femoral atherosclerosis and healthy controls were analyzed on an Apogee A60 Micro-PLUS flow cytometer. Platelet-poor plasma was labeled with lactadherin-FITC, anti-CD14-APC, anti-CD36 PE, and anti-BLTR1-AF700. Eicosapentaenoic acid and arachidonic acid content in different compartments in patients were analyzed using gas chromatography. Compared to controls, patients had lower levels of BLTR1+ MVs (p = 0.007), CD14+BLTR1+ MVs (p = 0.007), and CD14+BLTR1+CD36+ MVs (p = 0.001). Further, in patients CD14+ MVs and CD14+CD36+ MVs correlated inversely with arachidonic acid in granulocytes (r = -0.302, p = 0.039 and r = -0.322, p = 0.028, respectively). Moreover, CD14+CD36+ MVs correlated inversely with arachidonic acid in plasma phospholipids in patients (r = -0.315, p = 0.029), and positively with triglyceride in both patients (r = 0.33, p = 0.019) and controls (r = 0.46, p = 0.022). Conclusion: This is the first study of its kind and thus the results are explorative and only indicative. BLTR1+ MVs and CD14+CD36+ MVs has potential as markers of atherosclerosis pathophysiology, but this needs further investigation. PMID- 30425992 TI - Prevalence, Mortality, and Indicators of Health Care Supply-Association Analysis of Cardiovascular Diseases in Germany. AB - Introduction: There are regional differences in the morbidity of major cardiovascular disease between the 16 federal states of Germany. An association between the morbidity and the health care supply has been described in international studies. The aim of the present analysis was to examine the relationship between the prevalence or mortality of major cardiovascular disease and several key indicators of health care supply in Germany. Methods: Life expectancy and the proportion of over 65-year old persons were included as characteristics to depict the general health. Indicators of health care supply were the number of general practitioners, internists, and cardiologists, number of internal medicine and cardiology beds, chest pain units (CPU), cardiac catheterization laboratories (CCL) and stroke units. In the form of an ecological analysis, we compared the cardiovascular disease prevalence and mortality with these indicators and performed a weighted linear regression. Results: Regional variations between the federal states were found in general health and health care supply. The regression analysis yielded significant associations of the prevalence of major cardiovascular disease with the number of internal medicine hospital beds (beta = 10.042, p = 0.045), cardiologists (beta = -0.689, p = 0.031), and the number of residents per chest pain unit (beta = 42,730, p = 0.036). Additionally, the relationship between cardiovascular mortality and also the number of residents per chest pain unit appeared to be significant (beta = 4,962, p = 0.002). For all other indicators, no significant association was observed. Conclusions: We detected regional differences in the general health and health care supply between the 16 German federal states as well as several significant associations between cardiovascular morbidity and health care supply indicators. Especially the decreasing number of cardiologists and rising number of residents per chest pain unit with an increasing prevalence of major cardiovascular disease should lead to a discussion about the structure of the Germany health care system, such as the needs-based planning mechanism of physicians. The results of this study may also aid in future development of other health care systems. PMID- 30425990 TI - It Takes Two: Endothelial-Perivascular Cell Cross-Talk in Vascular Development and Disease. AB - The formation of new blood vessels is a crucial step in the development of any new tissue both during embryogenesis and in vitro models as without sufficient perfusion the tissue will be unable to grow beyond the size where nutrition and oxygenation can be managed by diffusion alone. Endothelial cells are the primary building block of blood vessels and are capable of forming tube like structures independently however they are unable to independently form functional vasculature which is capable of conducting blood flow. This requires support from other structures including supporting perivascular cells and the extracellular matrix. The crosstalk between endothelial cells and perivascular cells is vital in regulating vasculogenesis and angiogenesis and the consequences when this is disrupted can be seen in a variety of congenital and acquired disease states. This review details the mechanisms of vasculogenesis in vivo during embryogenesis and compares this to currently employed in vitro techniques. It also highlights clinical consequences of defects in the endothelial cell-pericyte cross-talk and highlights therapies which are being developed to target this pathway. Improving the understanding of the intricacies of endothelial-pericyte signaling will inform pathophysiology of multiple vascular diseases and allow the development of effective in vitro models to guide drug development and assist with approaches in tissue engineering to develop functional vasculature for regenerative medicine applications. PMID- 30425994 TI - Whole Genome Sequencing of Mycobacterium bovis Isolated From Livestock in the United States, 1989-2018. AB - The United States official bovine tuberculosis (bTB) eradication program has utilized genotyping for Mycobacterium bovis isolates since 2000 and whole genome sequencing was implemented in 2013. The program has been highly successful, yet as bTB prevalence has reached historic lows, a small number of new bTB-affected cattle herds occur annually. Therefore, understanding the epidemiology of bTB transmission is critically important, in order to target limited resources for surveillance and achieve eradication. This evaluation described the diversity and epidemiology of M. bovis isolates identified in the USA livestock. Isolates from animals within the bTB endemic area of Michigan were excluded. Broad diversity was found among 1,248 isolates, collected from affected cattle and farmed cervids herds and fed cattle during 1989-2018. Nearly 70% of isolates from 109 herds/cases during 1999-2018 were European clonal complex 1 and 30% were European clonal complex 2. The sources of infection based on the herd investigation were known for 41% of herds/cases and 59% were not epidemiologically linked to another USA origin herd. Whole genome sequencing results were consistent with the investigation findings and previously unrecognized links between herds and cases were disclosed. For herds/cases with an unknown source of infection, WGS results suggested several possible sources, including undocumented cattle movement, imported cattle and humans. The use of WGS in new cases has reduced the time and costs associated with epidemiological investigations. Within herd SNP diversity was evaluated by examining 18 herds with 10 or more isolates sequenced. Forty percent of isolates had not diverged or accumulated any SNPs, and 86% of the isolates had accumulated 3 or fewer SNPs. The results of WGS does not support a bTB reservoir in USA cattle. The bTB eradication program appears to be highly effective as the majority of herds/cases in the USA are unique strains with limited herd to herd transmission. PMID- 30425993 TI - Review: Roles of Prebiotics in Intestinal Ecosystem of Broilers. AB - In recent years, prebiotics have been considered as potential alternatives to antibiotics. Mechanisms by which prebiotics modulate the ecosystem of the gut include alternation of the intestinal microbiota, improvement of the epithelium, and stimulation of the immune system. It is suggested that the administration of prebiotics not only influences these aspects but also regulates the interaction between the host and the intestinal microbiota comprehensively. In this review, we will discuss how each prebiotic ameliorates the ecosystem by direct or indirect mechanisms. Emphasis will be placed on the effects of prebiotics, including mannan oligosaccharides, beta-glucans, and fructans, on the interaction between the intestinal microbiota, gut integrity, and the immunity of broilers. We will highlight how the prebiotics modulate microbial community and regulate production of cytokines and antibodies, improving gut development and the overall broiler health. Understanding the cross talk between prebiotics and the intestinal ecosystem may provide us with novel insights and strategies for preventing pathogen invasion and improving health and productivity of broilers. However, further studies need to be conducted to identify the appropriate dosages and better resources of prebiotics for refinement of administration, as well as to elucidate the unknown mechanisms of action. PMID- 30425995 TI - Detecting and Predicting Emerging Disease in Poultry With the Implementation of New Technologies and Big Data: A Focus on Avian Influenza Virus. AB - Future demands for food will place agricultural systems under pressure to increase production. Poultry is accepted as a good source of protein and the poultry industry will be forced to intensify production in many countries, leading to greater numbers of farms that house birds at elevated densities. Increasing farmed poultry can facilitate enhanced transmission of infectious pathogens among birds, such as avian influenza virus among others, which have the potential to induce widespread mortality in poultry and cause considerable economic losses. Additionally, the capability of some emerging poultry pathogens to cause zoonotic human infection will be increased as greater numbers of poultry operations could increase human contact with poultry pathogens. In order to combat the increased risk of spread of infectious disease in poultry due to intensified systems of production, rapid detection and diagnosis is paramount. In this review, multiple technologies that can facilitate accurate and rapid detection and diagnosis of poultry diseases are highlighted from the literature, with a focus on technologies developed specifically for avian influenza virus diagnosis. Rapid detection and diagnostic technologies allow for responses to be made sooner when disease is detected, decreasing further bird transmission and associated costs. Additionally, systems of rapid disease detection produce data that can be utilized in decision support systems that can predict when and where disease is likely to emerge in poultry. Other sources of data can be included in predictive models, and in this review two highly relevant sources, internet based data and environmental data, are discussed. Additionally, big data and big data analytics, which will be required in order to integrate voluminous and variable data into predictive models that function in near real-time are also highlighted. Implementing new technologies in the commercial setting will be faced with many challenges, as will designing and operating predictive models for poultry disease emergence. The associated challenges are summarized in this review. Intensified systems of poultry production will require new technologies for detection and diagnosis of infectious disease. This review sets out to summarize them, while providing advantages and limitations of different types of technologies being researched. PMID- 30425996 TI - The Use of Kernel Density Estimation With a Bio-Physical Model Provides a Method to Quantify Connectivity Among Salmon Farms: Spatial Planning and Management With Epidemiological Relevance. AB - Connectivity in an aquatic setting is determined by a combination of hydrodynamic circulation and the biology of the organisms driving linkages. These complex processes can be simulated in coupled biological-physical models. The physical model refers to an underlying circulation model defined by spatially-explicit nodes, often incorporating a particle-tracking model. The particles can then be given biological parameters or behaviors (such as maturity and/or survivability rates, diel vertical migrations, avoidance, or seeking behaviors). The output of the bio-physical models can then be used to quantify connectivity among the nodes emitting and/or receiving the particles. Here we propose a method that makes use of kernel density estimation (KDE) on the output of a particle-tracking model, to quantify the infection or infestation pressure (IP) that each node causes on the surrounding area. Because IP is the product of both exposure time and the concentration of infectious agent particles, using KDE (which also combine elements of time and space), more accurately captures IP. This method is especially useful for those interested in infectious agent networks, a situation where IP is a superior measure of connectivity than the probability of particles from each node reaching other nodes. Here we illustrate the method by modeling the connectivity of salmon farms via sea lice larvae in the Broughton Archipelago, British Columbia, Canada. Analysis revealed evidence of two sub networks of farms connected via a single farm, and evidence that the highest IP from a given emitting farm was often tens of kilometers or more away from that farm. We also classified farms as net emitters, receivers, or balanced, based on their structural role within the network. By better understanding how these salmon farms are connected to each other via their sea lice larvae, we can effectively focus management efforts to minimize the spread of sea lice between farms, advise on future site locations and coordinated treatment efforts, and minimize any impact of farms on juvenile wild salmon. The method has wide applicability for any system where capturing infectious agent networks can provide useful guidance for management or preventative planning decisions. PMID- 30425997 TI - Whole Genome Sequencing for Determining the Source of Mycobacterium bovis Infections in Livestock Herds and Wildlife in New Zealand. AB - The ability to DNA fingerprint Mycobacterium bovis isolates helped to define the role of wildlife in the persistence of bovine tuberculosis in New Zealand. DNA fingerprinting results currently help to guide wildlife control measures and also aid in tracing the source of infections that result from movement of livestock. During the last 5 years we have developed the ability to distinguish New Zealand (NZ) M. bovis isolates by comparing the sequences of whole genome sequenced (WGS) M. bovis samples. WGS provides much higher resolution than our other established typing methods and greatly improves the definition of the regional localization of NZ M. bovis types. Three outbreak investigations are described and results demonstrate how WGS analysis has led to the confirmation of epidemiological sourcing of infection, to better definition of new sources of infection by ruling out other possible sources, and has revealed probable wildlife infection in an area considered to be free of infected wildlife. The routine use of WGS analyses for sourcing new M. bovis infections will be an important component of the strategy employed to eradicate bovine TB from NZ livestock and wildlife. PMID- 30425998 TI - The Effect of Canertinib on Sensitivity of Cytotoxic Drugs in Tamoxifen-Resistant Breast Cancer Cells In Vitro. AB - Aims and Objectives: To investigate and examine the reversal effects of canertinib on the activity of EGFR and tamoxifen resistance in drug-resistant human breast carcinoma cells (MCF-7/TamR). Materials and Methods: The antiproliferative activity of canertinib alone or in combination with a conventional EGFR-targeting chemotherapies cytotoxic drugs differing in the mechanism(s) of action, such as paclitaxel, carboplatin, etoposide, vinorelbine, and daunorubicin as well as resistance mechanisms of EGFR targeting, have been investigated. Results: With an elevated dosage of canertinib, a significant decrease in proliferation and increase in apoptosis was observed. The treatment with higher doses of canertinib resulted in a 2-3-fold increase in apoptosis. In the combined treatment, it had been noticed a significant developed apoptotic cell death rather induced by single agent treatment. A significant downregulation of the antiapoptotic protein bcl-2 was exposed by immunocytochemistry investigation. Sensitivity to paclitaxel was also measured and was found to inversely correlate to bcl-2 status. Conclusion: Proliferation inhibition and apoptosis in MCF-7/TAM-R cells increase with increasing dosage of canertinib. This suggests that canertinib can reverse tamoxifen resistance in breast cancer cells. The antitumor effect of this EGFR-irreversible tyrosine kinase inhibitor provides a rationale for its clinical evaluation in combination with other cytotoxic drugs. PMID- 30425999 TI - Isolation, Characterization, and Quantification of Bacteria from African Sausages Sold in Nairobi County, Kenya. AB - African sausages are local popular delicacies in Kenya. Demand for these sausages has resulted in this delicacy's vendors being on the increase. However, health risk posed to unsuspecting consumers of African sausages sold in informal, unhygienic make shift road-side kiosks in major cities of Kenya is largely unknown. A descriptive study was designed to isolate, characterize and quantify bacteria from African sausages sold in Nairobi County. A total of hundred (100) African sausages (62 roasted and 38 nonroasted) were conveniently collected from three meat eatery points of Westlands, Kangemi slum, and Pangani estates. Five genera of bacteria, namely, Staphylococcus spp. at 50.4%, Bacillus spp. at 19.5%, Streptococcus spp. 9.8%, Proteus spp. 2.4%, and E. coli spp. at 1.6%, were isolated from 80 African sausage samples. The total aerobic bacterial count range was between 1.0-9.9x101 and 1.0-9.9x107 log cfu/g with 37 samples having total aerobic bacterial count of between 1.0-9.9 x104 and 1.0-9.9 x107 log cfu/g. There was no significant difference (p>0.05) in distribution of isolates and total aerobic bacterial count across geographical sites studied among the roasted and nonroasted African sausages. This study has demonstrated presence of bacteria in African sausages which are potentially zoonotic to humans. Comprehensive study is needed to sample more eatery meat points in Nairobi and other areas in order to demonstrate pathogenic attributes of these isolates and establish the respective total aerobic bacterial count. There is also need to establish the sources of bacteria due to high total aerobic bacterial count determined in the current study. PMID- 30426000 TI - Bacterial Extracellular DNA Production Is Associated with Outcome of Prosthetic Joint Infections. AB - In a retrospective study the association of the production of extracellular DNA (eDNA) in biofilms of clinical staphylococcal isolates from 60 patients with prosthetic joint infection (PJI) and the clinical outcome were investigated. Data from a previous study on eDNA production determined in 24-hour biofilms of staphylococcal isolates (Staphylococcus aureus n=30, Staphylococcus epidermidis n=30) was correlated with the patients' clinical outcome after 3 and 12 months. Statistical analysis was performed using either the Spearman's rank correlations test or the t-test. eDNA production of S. epidermidis in 24-hour biofilms correlated with the patients' outcome 'not cured' after 12 months. For S. aureus no such correlation was detected. Thus, eDNA may be a virulence factor of S. epidermidis. Quantification of eDNA production as a surrogate marker for biofilm formation might be a potential predictive marker for the management of PJI. PMID- 30426001 TI - Complementary Role of the Computed Biomodelling through Finite Element Analysis and Computed Tomography for Diagnosis of Transcatheter Heart Valve Thrombosis. AB - Introduction: The TAVR procedure is associated with a substantial risk of thrombosis. Current guidelines recommend catheter-based aortic valve implantation for prohibitive-high-risk patients with severe aortic valve stenosis but acknowledge that the aetiology and mechanism of thrombosis are unclear. Methods: From 2015 to 2018, 607 patients with severe aortic valve stenosis underwent either self-expandable or balloon-expandable catheter-based aortic valve implantation at our institute. A complementary study was designed to support computed tomography as a predictor of complications using an advanced biomodelling process through finite element analysis (FEA). The primary evaluation of study was the thrombosis of the valve at 12 months. Results: At 12 months, 546 patients had normal valvular function. 61 patients had THVT while 6 showed thrombosis and dislodgement with deterioration to NYHA Class IV requiring rehospitalization. The FEA biomodelling revealed a strong link between solid uncrushed calcifications, delayed dislodgement of TAVR and late thrombosis. We observed an interesting phenomenon of fibrosis/calcification originating at the level of the misplaced valve, which was the primary cause of coronary obstruction. Conclusion: The use of cardiac CT and predictive biomodelling should be integrated into routine practice for the selection of TAVR candidates and as a predictor of negative outcomes given the lack of accurate investigations available. This would assist in effective decision-making and diagnosis especially in a high-risk cohort of patients. PMID- 30426002 TI - Effects of Digeda-4 Decoction on the CYP450 Activities in Rats Using a Cocktail Method by HPLC. AB - Digeda-4 decoction is a traditional Mongolian medicine; its effects on cytochrome (CYP) enzymes are still unclear. CYP450 isoenzymes are the main drug metabolic enzymes, and their activities may be induced or inhibited by certain drugs, which lead to drug interactions in clinical use. Effects of Digeda-4 decoction on the activities of CYP450 subtype enzymes CYP1A2, CYP2C9, CYP2E1, CYP2C19, and CYP3A4 in rats were studied by cocktail method, and the pharmacokinetic parameters of five specific probe drugs (theophylline, tolbutamide, chlorzoxazone, omeprazole, and midazolam) were calculated by DAS software; changes of parameters can be used to evaluate the effects of Digeda-4 decoction on enzyme activities. The experimental rats were divided into three groups: control group, Digeda group, and positive group. Rats in Digeda group were given Digeda-4 decoction through continuous gavage for 14 days. After fasting for 12 hours, the mixed probes drug solution was injected into the tail vein; the blood samples were collected through the orbital vein at different time points. The concentrations of probe drugs in rat plasma were measured by HPLC. Compared with the control group, the half-life time (t1/2) of the pharmacokinetic parameters of theophylline, tolbutamide, omeprazole, and midazolam was prolonged, the area under the curve (AUC) increased, and the plasma clearance (CL) decreased in the Digeda group. Continuous gavage administration for 14 days may inhibit the activities of CYP450 subtype enzymes CYP1A2, CYP2C9, CYP2C19, and CYP3A4 of rats. Herb-drug interaction should be noted between Digeda-4 decoction and the drugs metabolized by CYP1A2, CYP2C9, CYP2C19, and CYP3A4. PMID- 30426003 TI - Travel beyond Clinical Uses of Fiber Reinforced Composites (FRCs) in Dentistry: A Review of Past Employments, Present Applications, and Future Perspectives. AB - The reinforcement of resins with short or long fibers has multiple applications in various engineering and biomedical fields. The use of fiber reinforced composites (FRCs) in dentistry has been described in the literature from more than 40 years. In vitro studies evaluated mechanical properties such as flexural strength, fatigue resistance, fracture strength, layer thickness, bacterial adhesion, bonding characteristics with long fibers, woven fibers, and FRC posts. Also, multiple clinical applications such as replacement of missing teeth by resin-bonded adhesive fixed dental prostheses of various kinds, reinforcement elements of dentures or pontics, and direct construction of posts and cores have been investigated. In orthodontics, FRCs have been used also for active and passive orthodontic applications, such as anchorage units, en-masse movement units, and postorthodontic tooth retention. FRCs have been extensively tested in the literature, but today the advances in new technologies involving the introduction of nanofillers or new fibers along with understanding the design principles of FRC devices open new fields of research for these materials both in vitro and in vivo. The present review describes past and present applications of FRCs and introduces some future perspectives on the use of these materials. PMID- 30426004 TI - N-Acetylcysteine for the Treatment of Psychiatric Disorders: A Review of Current Evidence. AB - N-acetylcysteine, a sulphur-containing amino acid for the treatment of paracetamol overdose and chronic obstructive pulmonary disease, is a widely available off-the-shelf oral antioxidant supplement in many countries. With the potential to modulate several neurological pathways, including glutamate dysregulation, oxidative stress, and inflammation that can be beneficial to the brain functions, N-acetylcysteine is being explored as an adjunctive therapy for many psychiatric conditions. This narrative review synthesises and presents the current evidence from systematic reviews, meta-analyses, and latest clinical trials on N-acetylcysteine for addiction and substance abuse, schizophrenia, obsessive-compulsive and related disorders, and mood disorders. Good evidence exists to support the use of N-acetylcysteine as an adjunct treatment to reduce the total and negative symptoms of schizophrenia. N-acetylcysteine also appears to be effective in reducing craving in substance use disorders, especially for the treatment of cocaine and cannabis use among young people, in addition to preventing relapse in already abstinent individuals. Effects of N-acetylcysteine on obsessive-compulsive and related disorders, as well as on mood disorders, remain unclear with mixed reviews, even though promising evidence does exist. Larger and better-designed studies are required to further investigate the clinical effectiveness of N-acetylcysteine in these areas. Oral N-acetylcysteine is safe and well tolerated without any considerable adverse effects. Current evidence supports its use as an adjunctive therapy clinically for psychiatric conditions, administered concomitantly with existing medications, with a recommended dosage between 2000 and 2400 mg/day. PMID- 30426005 TI - Quorum Sensing and Spoilage Potential of Psychrotrophic Enterobacteriaceae Isolated from Milk. AB - The 16S rDNA of six psychrotrophic Enterobacteriaceae isolated from cold raw milk were sequenced and the isolate 039 was identified as Pantoea sp., isolates 059, 068, and 071 were identified as Hafnia alvei, 067 was identified as Enterobacter sp., and 099 was identified as Aeromonas hydrophila. They presented different spoilage potentials in milk with A. hydrophila 099 being the most deteriorative. Only Pantoea sp. 039 was not able to induce the quorum sensing monitor strains of acyl homoserine lactones (AHLs). The halI gene, which encodes the AHL synthase in H. alvei, was identified in the isolates 059, 067, 068, and 071. After initial sequencing characterization and cloning, this gene showed its function by the heterologous synthesis of N-hexanoyl-DL-homoserine lactone and N-3-oxohexanoyl-L homoserine lactone in Escherichia coli. In addition to producing AHLs, A. hydrophila 099 produced AI-2 in higher level than the assay's positive control Vibrio harveyi BB120. Therefore, Enterobacteriaceae strains isolated from cooled raw milk produce a rich array of signaling molecules that may influence bacterial traits in the milk environment. PMID- 30426006 TI - Acupoint Therapy on Diabetes Mellitus and Its Common Chronic Complications: A Review of Its Mechanisms. AB - Acupoint therapy is one of the therapeutic means in Traditional Chinese Medicine (TCM) concerning acupoints and meridians, including manual acupuncture, electroacupuncture, moxibustion, external application, acupoint injection, and catgut embedding. In the treatment of diabetes and its common chronic complications, acupoint therapy has proved to have specific curative effect and notable advantages. Single or combined with western medicine, it has superior efficacy and less side effects than western medicine alone. Studying its mechanism can provide experimental basis for clinical treatment. Relevant researches in the recent 5 years mainly focused on the mechanism of electroacupuncture, point injection, catgut embedding, etc. in the treatment of diabetes and common diabetic complications such as neuropathy, nephropathy, and hepatopathy. The possible theories involve the regulation of nerve conduction, signal pathways, hormone level, protein expression, oxidative stress level, structure restoration, etc. The most studied acupoints are Zusanli (ST36), Shenshu (BL23), Sanyinjiao (SP6), Yishu (EX-B3), and Zhongwan (CV12). However, most of the studies have been based on diabetes model rats rather than clinical trials. Moreover, the mechanism of acupoint therapy treating other chronic complications like diabetic retinopathy and that of other effective methods like pressing ear with beans, auricular points plaster therapy, and external application remain unclear. Therefore, this aspect still awaits further research. PMID- 30426007 TI - The Role of IL-6RA in UHMWPE Promotes Proliferation in Fibro-Like Synovial Cells. AB - UHMWPE granule could induce macrophages and inflammatory responses in interfacial tissues, which eliminated the wear debris of UHMWPE component and further induced dissolution of the surrounding bone, leading aseptic loosening. However, the mechanism of synovial cells, especially fibroblast-like synovial (FLS) cells response to UHMWPE, remains unknown. Herein we choose FLS cells as research object. Vimentin (+) CD68 (-) was identified by flow cytometry and immunofluorescent staining assay, and the cells were identified as FLS cells, which was consistent with the experimental requirements. The inhibitory evaluation showed that UHMWPE could significantly promote the proliferation and inhibit apoptosis of FLS cells in dose- and time-dependent manners and increase the levels of proinflammatory cytokines, including IL-6, IL-1beta, TNF-alpha, PGE2, MMP2, and LOX. UHMWPE also can induce the expression of mIL-6R protein in FLS cells and further investigate the relationship between apoptosis and inflammation. Interestingly enough, when we added the interleukin-6 receptor antagonist (IL-6RA), the expression levels of proapoptosis-related proteins increased; in other words, UHMWPE-induced antiapoptosis diminished by IL-6RA (50 MUg/ml). Taken together, these findings clearly demonstrated that UHMWPE promote growth in FLS cells through upregulating inflammatory factors to produce antiapoptotic effect. PMID- 30426008 TI - A Novel Thermostable GH3 beta-Glucosidase from Talaromyce leycettanus with Broad Substrate Specificity and Significant Soybean Isoflavone Glycosides-Hydrolyzing Capability. AB - A novel beta-glucosidase gene (Bgl3B) of glycoside hydrolase (GH) family 3 was cloned from the thermophilic fungus Talaromyce leycettanus JM12802 and successfully expressed in Pichia pastoris. The deduced Bgl3B contains 860 amino acid residues with a calculated molecular mass of 91.2 kDa. The purified recombinant Bgl3B exhibited maximum activities at pH 4.5 and 65 degrees C and remained stable at temperatures up to 60 degrees C and pH 3.0-9.0, respectively. The enzyme exhibited broad substrate specificities, showing beta-glucosidase, glucanase, cellobiase, xylanase, and isoflavone glycoside hydrolase activities, and its activities were stimulated by short-chain alcohols. The catalytic efficiencies of Bgl3B were 693 and 104/mM/s towards pNPG and cellobiose, respectively. Moreover, Bgl3B was highly effective in converting isoflavone glycosides to aglycones at 37 degrees C within 10 min, with the hydrolysis rates of 95.1%, 76.0%, and 75.3% for daidzin, genistin, and glycitin, respectively. These superior properties make Bgl3B potential for applications in the food, animal feed, and biofuel industries. PMID- 30426009 TI - Effect of the Composition of CAD/CAM Composite Blocks on Mechanical Properties. AB - The aim of this study was to evaluate the effect of the composition of CAD/CAM blocks on their mechanical properties. Nine different CAD/CAM blocks, enamel and dentine, were tested. Sixteen samples of each material were separated for Vickers microhardness test (n=6, 5 readings per specimen), nanohardness test (n=6, 5 readings per specimen), filler weight (n=3), and SEM imaging (n=1). Data were statistically analysed using one-way ANOVA. Vita Mark II ceramic showed significantly higher values of hardness (in both nano- and microscale) and elastic modulus (6.83 GPa, 502 kg/mm2, and 47.7 GPa), respectively, than other materials. CAD/CAM composite blocks showed comparable values of hardness and elastic modulus to those of dentine but lower than those of enamel and ceramics. SEM images highlighted different filler-matrix microstructure of CAD/CAM composite blocks. It was concluded that (1) hardness and elastic moduli are positively correlated with ceramic filler percentage and microstructure and (2) CAD/CAM composite materials have comparable hardness and elastic moduli to tooth structure. PMID- 30426011 TI - Corrigendum to "A Comparison between Piezoelectric Devices and Conventional Rotary Instruments in Bone Harvesting in Patients with Lip and Palate Cleft: A Retrospective Study with Clinical, Radiographical, and Histological Evaluation". AB - [This corrects the article DOI: 10.1155/2018/2059464.]. PMID- 30426010 TI - CSF-S100B Is a Potential Candidate Biomarker for Neuromyelitis Optica Spectrum Disorders. AB - Astrocytic impairment is a pathologic feature of neuromyelitis optica spectrum disorder (NMOSD). S100B and glial fibrillary acidic protein (GFAP) are the two most commonly used astrocytic markers. The aim of this study was to evaluate whether CSF-S100B could serve as a marker of NMOSD. We enrolled 49 NMOSD patients [25 aquaporin-4 antibody (AQP4-Ab)-positive, 8 myelin-oligodendrocyte glycoprotein antibody (MOG-Ab)-positive, and 16 seronegative patients], 12 multiple sclerosis (MS) patients, and 15 other noninflammatory neurological diseases (OND) patients. The CSF levels of S100B and GFAP were measured by ELISA. Both CSF-S100B and GFAP levels significantly discriminated NMOSD from MS [area under curve (AUC) = 0.839 and 0.850, respectively] and OND (AUC = 0.839 and 0.850, respectively). The CSF-S100B levels differentiated AQP4-Ab-positive NMOSD from MOG-Ab-positive NMOSD with higher accuracy than the CSF-GFAP levels (AUC=0.865 and 0.772, respectively). The CSF-S100B levels also significantly discriminated MOG-Ab-positive patients from seronegative patients (AUC = 0.848). Both CSF-S100B and GFAP levels were correlated with the Expanded Disability Status Scale (EDSS) during remission. Only the CSF-S100B levels were correlated with the CSF WBC count and the EDSS during attack. The levels of CSF-S100B seemed to have a longer lasting time than the levels of CSF-GFAP, which may benefit patients who present late. As a result, CSF-S100B might be a potential candidate biomarker for NMOSD in discriminating, evaluating severity, and predicting disability. PMID- 30426013 TI - Assessment of Pain Management, Acceptance of Illness, and Adjustment to Life with Cancer in Patients with Nonmuscle Invasive Bladder Cancer. AB - Purpose: According to the European Association of Urology bladder cancer is the seventh most commonly diagnosed malignancy in the world's male population. Despite its high incidence, papers evaluating psychological state in those patients' group are lacking. The purpose of the study was to evaluate pain management, disease acceptance, and adjustment to cancer in homogenous group of patients diagnosed with nonmuscle-invasive bladder cancer (NMIBC). Methods: Group of 252 male patients who were scheduled for NMIBC treatment were prospectively evaluated. Patients fulfilled Acceptance of Illness Scale (AIS), Mini-Mental Adjustment to Cancer (Mini-MAC) and Coping Strategies (CSQ) questionnaires before treatment introduction. Results: Highest CSQ score was achieved by the coping self-statements subscale (mean=18,37). The catastrophizing subscale score was the lowest (mean=11,24). Place of residence affected results of CSQ statement about pain control. Catastrophizing and coping self-statements strategies were associated with matrimonial status. In the Mini-MAC questionnaire the fighting spirit way of coping had the highest (21,73) and the helplessness-hopelessness subscale had the lowest mean value (13,3). Matrimonial status was strongly associated with anxious preoccupation, fighting spirit, and helplessness - hopelessness way of coping. The mean AIS test score was 28.8. AIS result was influenced by patient's marital status, yet not by education, place of residence, nor any clinical factor. Conclusions: In the examined group, the level of acceptance of the disease reached values that were slightly higher than the average. It indicated a fairly good adaptation to cancer. Among the methods of coping with cancer, the constructive style is definitely dominant with a high intensity of the fighting spirit strategy. The destructive style of cancer coping reached low values with a low intensity of helplessness/hopelessness strategy. From pain coping strategies, self-statements and praying/hoping were the most commonly chosen ways, whereas catastrophizing was the rarest. Many associations between various questioners' results were also observed. PMID- 30426012 TI - Reviewing Interventions against Enterobacteriaceae in Broiler Processing: Using Old Techniques for Meeting the New Challenges of ESBL E. coli? AB - Extended-spectrum beta-lactamase- (ESBL-) producing Enterobacteriaceae are frequently detected in poultry and fresh chicken meat. Due to the high prevalence, an impact on human colonization and the spread of antibiotic resistance into the environment is assumed. ESBL-producing Enterobacteriaceae can be transmitted along the broiler production chain but also their persistence is reported because of insufficient cleaning and disinfection. Processing of broiler chickens leads to a reduction of microbiological counts on the carcasses. However, processing steps like scalding, defeathering, and evisceration are critical concerning fecal contamination and, therefore, cross-contamination with bacterial strains. Respective intervention measures along the slaughter processing line aim at reducing the microbiological load on broiler carcasses as well as preventing cross-contamination. Published data on the impact of possible intervention measures against ESBL-producing Enterobacteriaceae are missing and, therefore, we focused on processing measures concerning Enterobacteriaceae, in particular E. coli or coliform counts, during processing of broiler chickens to identify possible hints for effective strategies to reduce these resistant bacteria. In total, 73 publications were analyzed and data on the quantitative reductions were extracted. Most investigations concentrated on scalding, postdefeathering washes, and improvements in the chilling process and were already published in and before 2008 (n=42, 58%). Therefore, certain measures may be already installed in slaughterhouse facilities today. The effect on eliminating ESBL-producing Enterobacteriaceae is questionable as there are still positive chicken meat samples found. A huge number of studies dealt with different applications of chlorine substances which are not approved in the European Union and the reduction level did not exceed 3 log10 values. None of the measures was able to totally eradicate Enterobacteriaceae from the broiler carcasses indicating the need to develop intervention measures to prevent contamination with ESBL-producing Enterobacteriaceae and, therefore, the exposure of humans and the further release of antibiotic resistances into the environment. PMID- 30426015 TI - Highlighting the Potency of Biosurfactants Produced by Pseudomonas Strains as Anti-Legionella Agents. AB - Legionella pneumophila, the causative agent of Legionnaires' disease, is a waterborne bacterium mainly found in man-made water systems in close association with free-living amoebae and multispecies biofilms. Pseudomonas strains, originating from various environments including freshwater systems or isolated from hospitalized patients, were tested for their antagonistic activity towards L. pneumophila. A high amount of tested strains was thus found to be active. This antibacterial activity was correlated to the presence of tensioactive agents in culture supernatants. As Pseudomonas strains were known to produce biosurfactants, these compounds were specifically extracted and purified from active strains and further characterized using reverse-phase HPLC and mass spectrometry methods. Finally, all biosurfactants tested (lipopeptides and rhamnolipids) were found active and this activity was shown to be higher towards Legionella strains compared to various other bacteria. Therefore, described biosurfactants are potent anti-Legionella agents that could be used in the water treatment industry although tests are needed to evaluate how effective they would be under field conditions. PMID- 30426016 TI - Feasibility of Magnetic Resonance Imaging Monitoring of Postoperative Total Knee Arthroplasty without Metal Artifacts: A Preliminary Study of a Novel Implant Model. AB - Background: Although magnetic resonance imaging (MRI) can provide superior detailed images of tissues without ionizing radiation, the imaging evaluation of total knee arthroplasty (TKA) complications and posttherapy changes can be limited because of abundant artifacts on MRI scans due to metallic implants and endoprosthesis in limb salvage and fracture fixation. This study aimed to develop a novel model of TKA using a polyetheretherketone- (PEEK-) on-highly cross-linked polyethylene (HXLPE) implant and to investigate its feasibility for MRI monitoring of peri-implant bone formation, the healing process, signs of infection, and tumor recurrence after TKA. Methods: Three skeletally mature goats underwent TKA with the PEEK-on-HXLPE implant. Radiographic and MRI examinations were performed at 4 weeks postoperatively. Images were analyzed for the existence of artifact interruption and postoperative changes in the bone and peripheral soft tissue. Results: The results showed that PEEK and HXLPE were invisible, but the metal wires were clearly visualized on X-rays. On MRI scans, PEEK and HXLPE materials showed a low signal intensity, fine metal wires generated no obvious metal artifacts on MRI scans, and the marrow and soft tissue showed a continuous signal intensity without artifact interruption. Conclusions: This preliminary study introduced a novel model using PEEK-on-HXLPE knee implant for in vivo MRI monitoring of the region around the implant without metal artifacts. This novel model may be used to apply MRI to observe bone formation and the healing process around the prosthesis and the signs of infection and tumor recurrence after TKA. This model may be used to improve the diagnostic accuracy of postoperative complications of TKA clinically. PMID- 30426014 TI - Immunomodulatory Effects of Probiotics on Cytokine Profiles. AB - Probiotics confer immunological protection to the host through the regulation, stimulation, and modulation of immune responses. Researchers have shifted their attention to better understand the immunomodulatory effects of probiotics, which have the potential to prevent or alleviate certain pathologies for which proper medical treatment is as yet unavailable. It has been scientifically established that immune cells (T- and B-cells) mediate adaptive immunity and confer immunological protection by developing pathogen-specific memory. However, this review is intended to present the recent studies on immunomodulatory effects of probiotics. In the early section of this review, concepts of probiotics and common probiotic strains are focused on. On a priority basis, the immune system, along with mucosal immunity in the human body, is discussed in this study. It has been summarized that a number of species of Lactobacillus and Bifidobacterium exert vital roles in innate immunity by increasing the cytotoxicity of natural killer cells and phagocytosis of macrophages and mediate adaptive immunity by interacting with enterocytes and dendritic, Th1, Th2, and Treg cells. Finally, immunomodulatory effects of probiotics on proinflammatory and anti-inflammatory cytokine production in different animal models have been extensively reviewed in this paper. Therefore, isolating new probiotic strains and investigating their immunomodulatory effects on cytokine profiles in humans remain a topical issue. PMID- 30426018 TI - The Influence of Pin Deviation on the Fracture Correction and the Fixator Adjustment with Sensitivity and Kinematic Analysis. AB - Fracture correction is important orthopedics operation and can be performed by unilateral external fixator. Due to pin deviations being inevitable during the operation, searching the impacts of pin deviation on the fracture correction and fixator joint adjustment are important. This study puts forward evaluation index with sensitivity analysis for investigating the impact of three orientation deviations and three position deviations on fracture correction. Meanwhile, based on a clinical case from a 28-year-old female, the influence of pin deviation on the adjustment of fixator joints was analyzed by inverse kinematic method. Different pin deviations have different sensitivity; the sensitivity of orientation deviation is relatively larger than position deviation. The existence of pin deviation will result in the change of the adjustment value of fixator joints. In addition, the experiments of seven situations were established to verify the analytical results. This study revealed the sensitivity of different pin deviations which can also be used to predict the adjustment value of fixator joints and the accuracy of fracture correction. This research also helps to reduce operation time and decrease damage to soft tissue by reducing the frequency of inserting pins. PMID- 30426017 TI - Prognostic Value of Frailty for Older Patients with Heart Failure: A Systematic Review and Meta-Analysis of Prospective Studies. AB - Objective: Numerous studies have investigated the prognostic role of frailty in elderly patients with heart failure (HF), but the limited size of the reported studies has resulted in continued uncertainty regarding its prognostic impact. The aim of this study was to integrate the findings of all available studies and estimate the impact of frailty on the prognosis of HF by performing a systematic review and meta-analysis. Methods: PubMed, Embase, Cochrane, and Web of Science databases were searched from inception to November 8th 2017 to identify eligible prospective studies. The Newcastle-Ottawa Scale (NOS) was used to evaluate study quality. The association between frailty and HF outcomes was reviewed. Overall hazard ratios (HRs) for the effects of frailty on all-cause mortality were pooled using a fixed-effect model and publication bias was evaluated using funnel plots. Results: A total of 10 studies involving 3033 elderly patients with HF were included in the systematic review and meta-analysis. All eligible studies indicated that frailty was of prognostic significance for HF patients. The HRs for the effects of frailty on all-cause mortality were 1.70 (95% confidence interval (CI): 1.41-2.04), based on the pooling of six studies that provided related data. However, publication bias was observed among the studies. Conclusions: Frailty has a high prevalence among older patients with HF. Elderly HF patients with frailty have a poorer prognosis than those without frailty. Further studies are now required to implement the use of frailty assessment tools and explore effective interventions for frailty in older HF patients. PMID- 30426019 TI - Associations between Sleep-Disordered Breathing and Metabolic Risk Factors beyond Obesity. AB - Objective: Individuals with multiple metabolic risk factors often experience concomitant sleep-disordered breathing (SDB). We aimed to determine the associations of SDB with individual components of metabolic syndrome independent of obesity. Methods: A cross-sectional study was conducted in 1137 employees aged 30-64 years. Apnea-hypopnea index (AHI) was assessed using a portable monitor for obstructive sleep apnea by admission. Of these, 451 participants took an oral glucose tolerance test to assess homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI). Results: The odds ratio (OR) of the highest category of the AHI (>=15 episodes per hour) compared to the lowest one (<5 episodes per hour) was significantly elevated for hypertension, for hypertriglyceridemia, and for low HDL-cholesterolemia when adjusted for age, sex, and alcohol and smoking status (p < 0.05). After further adjustment for body mass index (BMI) or waist circumference, the associations for hypertension still remained statistically significant (p < 0.05) while those for hypertriglyceridemia and low HDL-cholesterolemia were no longer significant. The association between higher insulin resistance as assessed by HOMA-IR and Matsuda ISI and higher categories of the AHI was also lost after adjustment for BMI. Conclusion: Obesity was a strong confounding factor in the association between SDB and most metabolic risk factors including insulin resistance, except for hypertension. Further longitudinal study is needed to examine the temporal or causal relationships between SDB and metabolic risk factors. This trial is registered with UMIN-CTR UMIN000028067. PMID- 30426020 TI - Corrigendum to "Vitamin D-Binding Protein Clearance Ratio Is Significantly Associated with Glycemic Status and Diabetes Complications in a Predominantly Vitamin D-Deficient Population". AB - [This corrects the article DOI: 10.1155/2018/6239158.]. PMID- 30426021 TI - Insulin Modulates Paracoccidioides brasiliensis-Induced Inflammation by Restoring the Populations of NK Cells, Dendritic Cells, and B Lymphocytes in Lungs. AB - Paracoccidioidomycosis, a key issue for Brazilian health service, can be aggravated in patients with impaired immunological responses, such as diabetic patients. We evaluated the role of insulin in inflammatory parameters in diabetic and nondiabetic mice using a systemic mycosis Paracoccidioides brasiliensis (Pb) model. Diabetic C57BL-6 mice and controls were infected with Pb18 and treated with insulin for 12 days prior to experiments. After 55 days, infected diabetic mice exhibited fewer leukocytes in both peritoneal lavage fluid (PeLF) and bronchoalveolar lavage fluid and reduced secretion of interleukin- (IL-) 6 in lungs. In addition, diabetic mice presented a reduced influx of TCD4+ cells, TCD8+ cells, B lymphocytes, NK cells, and dendritic cells compared to control infected groups. Insulin treatment restored the leukocyte number in PeLF and restored the presence of B lymphocytes, dendritic cells, and NK cells in lungs of diabetic animals. The data suggest that diabetic mice present impaired immunological response to Pb18 infection and insulin modulates inflammation by reducing IL-6 levels in lung and CINC-1 levels in spleen and liver homogenates, restoring leukocyte concentrations in PeLF and also restoring populations of dendritic cells and B lymphocytes in lungs of diabetic mice, permitting the host to better control the infection. PMID- 30426022 TI - Efficacy of Sulphachloropyrazine, Amprolium Hydrochloride, Trimethoprim Sulphamethoxazole, and Diclazuril against Experimental and Natural Rabbit Coccidiosis. AB - There are no anticoccidial drugs labelled for rabbits in Kenya and those available are used as extra labels from poultry. The drugs are used in rabbits with limited knowledge of their efficacy and safety. The aim of this study was to determine the efficacy of sulphachloropyrazine, amprolium hydrochloride, and trimethoprim-sulphamethoxazole relative to diclazuril when used curatively against experimental and natural rabbit coccidiosis. In a controlled laboratory trial, sixty (60) rabbits were randomly allocated to six treatment groups, namely, 1A, 2B, 3C, 4D, 5E, and 6F, each with 10 rabbits. Groups 2B, 3C, 4D, 5E, and 6F were experimentally infected with mixed Eimeria species while group 1A served as uninfected-untreated (negative) control group. Four of the infected groups were treated with sulphachloropyrazine (5E), amprolium hydrochloride (2B), trimethoprim-sulphamethoxazole (6F), and diclazuril (4D) using dosages recommended by manufacturers. Group 3C served as infected-untreated (positive) control. A field efficacy trial in naturally infected rabbits was then undertaken. The results revealed that sulphachloropyrazine and diclazuril were effective against rabbit clinical coccidiosis by significantly reducing oocyst counts from 149.00+/-110.39 x 104 to 3.31+/-0.86 x 104 Eimeria spp. oocysts per gram of feces (opg) and 59.70+/-12.35 x 104 to 0.0+/-0.0 x 104 opg, respectively, in the laboratory trial. Similarly, sulphachloropyrazine and diclazuril recorded reduced oocyst counts in the field trial from 280.33+/-44.67 x 103 to 0.44+/-0.14 x 103 opg and 473.44+/-176.01 x 103 to 0.0+/-0.0 x 103 opg, respectively. Still, sulphachloropyrazine and diclazuril showed superior efficacy by registering lesion scores and fecal scores close to those of uninfected untreated control group. Trimethoprim-sulphamethoxazole recorded a satisfactory efficacy in the field trial by recording reduced oocyst counts from 266.78+/-37.03 x 103 to 0.75+/-0.11 x 103 opg but was not efficacious in the laboratory trial. Amprolium hydrochloride was not efficacious against clinical coccidiosis in both the experimental and field trials. PMID- 30426024 TI - Decrease in Intracellular Perforin Levels and IFN-gamma Production in Human CD8+ T Cell Line following Long-Term Exposure to Asbestos Fibers. AB - Although the tumorigenicity of asbestos, which is thought to cause mesothelioma, has been clarified, its effect on antitumor immunity requires further investigation. We previously reported a decrease in the percentage of perforin+ cells of stimulated CD8+ lymphocytes derived from patients with malignant mesothelioma. Therefore, we examined the effects of long-term exposure to asbestos on CD8+ T cell functions by comparing long-term cultures of the human CD8+ T cell line EBT-8 with and without exposure to chrysotile (CH) asbestos as an in vitro model. Exposure to CH asbestos at 5 MUg/ml or 30 MUg/ml did not result in a decrease in intracellular granzyme B in EBT-8 cells. In contrast, the percentage of perforin+ cells decreased at both doses of CH exposure. CH exposure at 30 MUg/ml did not suppress degranulation following stimulation with antibodies to CD3. Secreted production of IFN-gamma stimulated via CD3 decreased by CH exposure at 30 MUg/ml, although the percentage of IFN-gamma + cells induced by PMA/ionomycin did not decrease. These results indicate that long-term exposure to asbestos can potentially suppress perforin levels and the production of IFN-gamma in human CD8+ T cells. PMID- 30426023 TI - The Biology and Role of Interleukin-32 in Tuberculosis. AB - Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of morbidity and mortality globally, with nearly 10.4 million new cases of incidence and over 1.7 million deaths annually. Drug-resistant M. tuberculosis strains, especially multidrug-resistant or extensively drug-resistant strains, have further intensified the problem associated with tuberculosis control. Host directed therapy is a promising alternative for tuberculosis control. IL-32 is increasingly recognized as an important host molecule against tuberculosis. In this review, we highlight the proinflammatory properties of IL-32 and the mode of action of IL-32 in mycobacterial infections to inspire the development of novel immunity-based countermeasures and host-directed therapies against tuberculosis. PMID- 30426025 TI - A Granulocyte-Specific Protein S100A12 as a Potential Prognostic Factor Affecting Aggressiveness of Therapy in Patients with Juvenile Idiopathic Arthritis. AB - Background: Defining new prognostic biomarkers has become one of the most promising perspectives for the long-term care of patients with juvenile idiopathic arthritis (JIA). The new efficient indicators of disease activity and potential response to treatment are crucial in establishing new therapeutic plans in accordance with the "treat to target" strategy. One of the most studied proteins is called S100A12, which is an alarmin specific for granulocytes, considered as a marker of their activity. Materials and Methods: Study involved 80 patients diagnosed with JIA. Children with systemic subtype were not included in the study. In 53 cases, blood samples were obtained in two time points. Results from the study group were compared to 29 age- and sex-matched healthy individuals. Results: Serum S100A12 levels were higher in JIA than in healthy controls at the study baseline (11.67 +/- 6.59 vs. 6.01 +/- 2.33 ng/ml). There were no significant differences in S100A12 values between assessed subtypes of JIA. The highest concentrations were observed in patients within a disease flare. S100A12 levels were not dependent from using glucocorticosteroids. The studied protein appeared to be an efficient biomarker for JIA patients: 100% specificity as a diagnostic marker (cut-off level: 10.73 ng/ml) and 100% sensitivity as an indicator of exacerbations within a 3-month observation (cut-off level: 5.48 ng/ml). Conclusions: S100A12 may become an important factor influencing decisions on aggressiveness of JIA therapy. Further elaboration on the clinical algorithm is necessary for that protein to be included in everyday practice. PMID- 30426027 TI - Pap1 + confers microtubule damage resistance to mut2a, an extragenic suppressor of the rad26:4A allele in S. pombe. AB - The DNA structure checkpoint protein Rad26ATRIP is also required for an interphase microtubule damage response. This checkpoint delays spindle pole body separation and entry into mitosis following treatment of cells with microtubule poisons. This checkpoint requires cytoplasmic Rad26ATRIP, which is compromised by the rad26:4A allele that inhibits cytoplasmic accumulation of Rad26ATRIP following microtubule damage. The rad26::4a allele also disrupts minichromosome stability and cellular morphology, suggesting that the interphase microtubule damage checkpoint pathway operates in an effort to maintain chromosome stability and proper cell shape. To identify other proteins of the Rad26-dependent interphase microtubule damage response, we used ultra violet (UV) radiation to identify extragenic interaction suppressors of the rad26::4A growth defect on microtubule poisons. One suppressor mutation, which we named mut2a, permitted growth of rad26:4A cells on MBC media and conferred sensitivity to a microtubulin poison upon genetic outcross. In an attempt to clone this interaction suppressor using a genomic library complementation strategy, we instead isolated pap1 + as an extracopy suppressor of the mut2a growth defect. We discuss the mechanism by which pap1 + overexpression may allow growth of mut2a cells in conditions that destabilize microtubules. PMID- 30426026 TI - Myokines as Possible Therapeutic Targets in Cancer Cachexia. AB - Cachexia is an extremely serious syndrome which occurs in most patients with different cancers, and it is characterized by systemic inflammation, a negative protein and energy balance, and involuntary loss of body mass. This syndrome has a dramatic impact on the patient's quality of life, and it is also associated with a low response to chemotherapy leading to a decrease in survival. Despite this, cachexia is still underestimated and often untreated. New research is needed in this area to understand this complex phenomenon and ultimately find treatment methods and therapeutic targets. The skeletal muscle can act as an endocrine organ. Signaling between muscles and other systems is done through myokines, cytokines, and proteins produced and released by myocytes. In this review, we would like to draw attention to some of the most important myokines that could have potential as biomarkers and therapeutic targets: myostatin, irisin, myonectin, decorin, fibroblast growth factor 21, interleukin-6, interleukin-8, and interleukin-15. PMID- 30426029 TI - Association between STAT3 rs1053004 polymorphism and cancer risk: a meta analysis. AB - Several studies examined the relationship between STAT3 rs1053004 polymorphism and the risk of some human cancers, but the findings remains inconclusive. To evaluate the impact of STAT3 rs1053004 on cancer risk, we conducted a meta analysis of all available studies including 4,605 cancer cases and 5,248 controls. Eligible studies were identified by searching PubMed, Web of Science, Scopus, and Google scholar databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in codominant, dominant, recessive, overdominant, and allele models to quantitatively estimate the association. The overall findings showed no significant association between STAT3 rs1053004 polymorphism and cancer risk in codominant, dominant, recessive, overdominant, and allele inheritance model tested. In summary, the findings of this meta analysis indicates no significant association between STAT3 rs1053004 polymorphism and cancer development. Larger and well-designed studies are necessary to estimate this association in detail. PMID- 30426028 TI - Computational prediction of miRNAs in Nipah virus genome reveals possible interaction with human genes involved in encephalitis. AB - Current re-emergence of Nipah virus (NiV) in India caused 11 deaths so far and many patients were kept in quarantine. A thorough study of previous outbreaks occurred in Malaysia, Bangladesh and India represents cases with high rate of fatality due to acute encephalitis. Our work involves genome analysis of NiV for prediction of miRNAs and their targeted genes in human in order to understand encephalitis origin. Ab-intio program-VMir was used for initial screening of genome, obtained nine pre-miRNAs was analyzed by ViralMir to check for any pseudo pre-miRNAs. Eighteen functional mature miRNAs were extracted from pre-miRNAs by using Mature-Bayes tool, which targets 669 genes in human genome as retrieved by miRDB. Gene ontology terms by PANTHER provide important pathways in which target genes were involved like Axon guidance, T cell activation, and nicotinic acetylcholine receptor signaling. Significant outcome was obtained after NCBI Gene and OMIM database mining and literature search for predicted target genes. TLR3, TJP1, NOTCH2, FHL1, and GRIA3 target genes obtained showed their involvement in host defense, blood brain barrier, neurogenesis, mental retardation and encephalitis. To conclude, we predicted significant genes in human that can be inhibited by miRNAs of NiV and results in etiology of encephalitis. PMID- 30426030 TI - IRAP and REMAP based genetic diversity among varieties of Lallemantia iberica. AB - This study describes the genetic relationships among 34 varieties of Lallemantia iberica using inter-retrotransposon amplified polymorphism (IRAP) and retrotransposon-microsatellite amplified polymorphism (REMAP). Samples were collected from Agriculture Research Center of Urmia city (northwest Iran). Ten IRAP and REMAP primers generated 76 scorable electrophoretic bands with 78.94% polymorphism. The pair-wise Jacquard genetic similarity varied from 0.48 to 0.94 for IRAP and REMAP data combined. Average PIC values for IRAP and REMAP markers were 0.38. The retro-elements marker system produced 76 alleles in range of 100- 3000 bp. The cophenetic correlation coefficient between Jaccard's similarity matrix and the plotted dendrogram was 0.66. A dendrogram constructed based on COMPLETE LINKAGE. Cluster analysis of IRAP and REMAP data using the NTSYSpc 2.02 resulted in five clusters. The present study represents high genetic distance at genotype level suggesting that IRAP and REMAP markers are useful for Lallemantia iberica genetic diversity analysis. PMID- 30426031 TI - Cell damaging by irradiating non-thermal plasma to the water: Mathematical modeling of chemical processes. AB - Recently non-thermal plasma (NTP) is applied for many therapeutic applications. By NTP irradiating to the tissues or cell-lines, the water molecules (H2O) would be also activated leading to generate hydrogen peroxide (H2O2). By irradiating plasma to bio-solution, its main output including vacuum UV to UV causes the photolysis of H2O leading to generate hydroxyl (OH) molecules in couple forms with ability to convert to H2O2. Additionally, other plasma's output the oxygen atoms could also penetrate under the liquid's surface and react with H2O to generate H2O2. In NTP applications for killing unwanted-cells of microorganisms (e.g. sterilization) or cancerous tissues, the H2O2 molecule is the main reactive species for cell death via inducing DNA damage in mammalian cells. In this paper we proposed a mathematical model for NTP application describing the formation of hydroxyls in the bio solution and other subsequent reactions leading to DNA damage in vitro. The instant concentrations of the OH and H2O2, the main species for DNA oxidation were obtained and investigated in this simulation. In order to validate the model, the cellular response to NTP stimulation was compared with some experimental findings from viewpoint of DNA damage to show the significant consistency. PMID- 30426032 TI - Assessment of genetic diversity among sunflower genotypes using microsatellite markers. AB - Genetic diversity estimation of plant materials is one of the important pre breeding activities in breeding field crops. Twenty-one microsatellite markers used to assess genetic diversity and relationship of 68 sunflower genotypes (Helianthus annuus L.). All of 21 pairs of SSR (Simple Sequence Repeats) markers produced a total number of 49 polymorphic bands. DNA fragments ranged from 92 to 850 bp. The highest and lowest polymorphic information content (PIC) values were determined as 0.58 and 0.10 for marker Ha806-ar and Ha494-ar. The number of alleles per locus was calculated as 2-6 with the average of 2.86. In this study, CMS (Cytoplasmic Male Sterility) lines showed the highest and Iranian hybrids showed the least polymorphism, respectively. Principal coordinates analysis revealed that Iranian hybrids were well-separated compare to the other groups. The analysis of molecular variance (AMOVA) indicated higher genetic variation within groups (90%) rather than among groups (10%). This study revealed that the SSR markers such as Ha806-ar could be a useful tool for distinguishing sunflowers genotypes. According to the study, there is a significant genetic distance among individuals. Parental lines (R26 and CMS502 lines with lowest similarity coefficient) may be useful for future sunflower crossing and hybrid breeding programs. Generally, high similarity coefficient estimation among investigated sunflower groups revealed that there was a narrow genetic base in investigated materials suggesting broadening its genetic base by introduction of new genes into existing breeding materials. PMID- 30426033 TI - Ischemic Cholangiopathy 11 Years after Liver Transplantation from Asymptomatic Chronic Hepatic Artery Thrombosis. AB - Hepatic artery thrombosis is a concerning complication of orthotopic liver transplantation, and it most often occurs early in the posttransplant period. However, on rare occasions it can occur at a time remote from transplant. We present a case of ischemic cholangiopathy complicated by stricture and anastomotic bile leak from chronic hepatic artery thrombosis that occurred 11 years after the transplant. The initial biliary stenting helped with the resolution of the leak but she was found to have stones, sludge and copious pus at the time of stent exchange. Hepatic arteriography demonstrated complete occlusion of the transplant hepatic artery with periportal collaterals reconstituting intrahepatic hepatic arterial branches. The patient was subsequently referred for repeat liver transplantation. PMID- 30426034 TI - Duodenorenal Fistula after Microwave Ablation Presenting as Melena. AB - A 53-year-old man presented with melena 3 months after microwave ablation of a renal mass. Esophago-gastroduodenoscopy and radiological imaging revealed that a fistulous tract extended from the duodenum to the right kidney. The patient had a hemorrhage that originated from a branch of the renal artery and bled through the fistulous tract into the duodenal lumen. Angiography was used in the successful coiling of the bleeding vessel to control the bleeding. Consideration of a fistulous tract as a source of gastrointestinal bleeding should be included in a clinician's differential diagnosis when dealing with patients who had a recent ablative procedure. PMID- 30426036 TI - Importance of clinical observations. PMID- 30426035 TI - Open-label, add-on trial of cetirizine for neuromyelitis optica. AB - Objective: This pilot study preliminarily examined the efficacy and tolerability of cetirizine as an add-on to standard therapy for neuromyelitis optica (NMO). Methods: Eligible participants met the Wingerchuk 2006 diagnostic criteria or had a single typical episode along with positive NMO immunoglobulin G. After baseline clinical and laboratory assessments, participants began treatment with cetirizine 10 mg orally daily, in addition to their usual disease-modifying therapy for NMO, and continued for 1 year. The primary end point was the annualized relapse rate (ARR) while on the same disease-modifying therapy before starting cetirizine compared with after taking cetirizine. Additional end points included disability (Expanded Disability Status Scale [EDSS]), relapse severity, tolerability, especially with respect to drowsiness measured by the Epworth Sleepiness Scale (ESS), and laboratory parameters. Results: The ARR before cetirizine was 0.4 +/- 0.80 and after cetirizine was 0.1 +/- 0.24 (p = 0.047). There was no statistically significant difference in the EDSS (mean 3.9 +/- 2.18 before the start of the study and 3.2 +/- 2.31 at the conclusion of the study, p = 0.500). The ESS remained fairly consistent throughout the study (mean 6.5 +/- 5.33 at baseline and 6.9 +/- 4.50 at month 12, p = 0.740). Laboratory studies were unrevealing. Conclusions: In this pilot study, cetirizine was well tolerated, and the prespecified primary efficacy end point was satisfied. However, the open label design and the small sample size of this pilot study preclude definitive conclusions. Further research is needed. Classification of evidence: This study provides Class IV evidence that in patients with NMO, the addition of cetirizine to standard therapy is safe, well tolerated, and reduces relapses. PMID- 30426037 TI - Relationships between narcissistic grandiosity, narcissistic vulnerability, regulatory focus, regulatory mode, and life-satisfaction: Data from two surveys. AB - The present data is reported in the article "Regulatory Focus and Regulatory Mode - Keys to Narcissists' (Lack of) Life Satisfaction?" (Hanke et al., in press) [1]. The two data sets represent answers from two German samples. Data were collected via self-report questionnaires using EFS survey from QuestBack Unipark. The surveys included self-questionnaires of narcissistic grandiosity, narcissistic vulnerability, regulatory focus, regulatory mode, self-esteem, life satisfaction, and demographic information. PMID- 30426038 TI - Electrochemical data of Co(II) complexes containing phenanthroline functionalized ligands. AB - The data presented in this paper are related to the research article entitled "Electrochemical properties of a series of Co(II) complexes, containing substituted phenanthrolines" (Ferreira et al., 2018) [1]. This paper presents detailed electrochemical data of eight octahedral Co(II) complexes containing functionalized phenanthrolines-ligands. The data illustrate the shift in the CoIII/II and CoII/I redox couples due to different substituents on the phenanthrolines. Polypyridine Co(II) and Co(III) complexes exhibit properties as potential mediators in dye-sensitized solar cells (DSSCs) (Gajardo and Loeb, 2011; Yu et al., 2011) [2], [3]. The ability of a compound to act as a redox mediator to be used in DSSC, depends on the redox potential of the compound (Gratzel, 2005) [4]. Accurate data of the CoIII/II redox couple is presented here. PMID- 30426039 TI - Data for the synthesis of new 4-aryloxy-N-arylanilines as potent succinate cytochrome c reductase inhibitors. AB - In this data article, we have designed a simple and facile protocol for copper mediated synthesis of new 4-aryloxy-N-arylanilines under mild reaction conditions. The general information and synthetic procedures of all the target compounds were provided, and they were fully characterized by Nuclear Magnetic Resonance (NMR, including 1H NMR and 13C NMR), melting point measurements, and High-Resolution Mass Spectroscopy (HRMS). Furthermore, the inhibitory activities of these compounds against succinate-cytochrome c reductase (SCR) were evaluated, and the methods and procedures of enzyme inhibition experiments were also recorded in this data article. This article is related to "Synthesis of new 4 aryloxy-N-arylanilines and their inhibitory activities against succinate cytochrome c reductase" (Cheng et al., 2018) [1]. PMID- 30426040 TI - Whole-genome sequence data and analysis of type strains 'Pusillimonas nitritireducens' and 'Pusillimonas subterraneus' isolated from nitrate- and radionuclide-contaminated groundwater in Russia. AB - Two strains, 'Pusillimonas nitritireducens' JR1/69-2-13T and 'Pusillimonas subterraneus' JR1/69-3-13T, of aerobic, motile, Gram-negative, non-spore-forming, organotrophic, psychrotolerant bacteria were isolated from a sample of nitrate- and radionuclide-contaminated groundwater in Russia. Here we describe the draft genomes of these strains. The sequenced and annotated genome of the strain JR1/69 2-13T contained 4.3 Mbp with 4108 protein-coding genes. The genome of the strain JR1/69-3-13T contained 4.5 Mbp with 4260 protein-coding genes. Genome analysis of both strains provides an insight into the genomic basis of their resistance to nitrate, heavy metals and metalloids. The draft genome sequences of strains 'Pusillimonas nitritireducens' JR1/69-2-13T and 'Pusillimonas subterraneus' JR1/69-3-13T are available at DDBJ/EMBL/GenBank under the accession nos. https://www.ncbi.nlm.nih.gov/nuccore/PDNV00000000 and https://www.ncbi.nlm.nih.gov/nuccore/PDNW00000000, respectively. PMID- 30426041 TI - The data on the aerobic training with or without calorie restriction and muscular levels of Irisin and muscular FNDC5 concentration in obese male Wistar rats. AB - The present data article aims at investigating the muscular levels of Irisin, FNDC5, and UCP1 in male Wistar rats during the aerobic exercise with or without calorie restriction (CR). Twenty four, 8-week-old male Wistar rats (190+/-16 g) were selected and purchased for the research. After obesity induction by high-fat diet, the animals were randomly divided into three groups: exercise EX (n = 8), EX-CR (n = 8) and CO as control (n = 8). EX exercised 6 sessions per week and EXCR exercise 3 sessions + 3 days caloric restriction per week. The Irisin (Cat.No:CK-E91266 & Intra-Assay: CV<10%), FNDC5 (Cat.No:CK-E91393 & Intra-Assay: CV<10%) levels were assessed by the special Rat ELISA Kit (EASTBIOPHARM, China, under licensed by the United States). Muscular Irisin concentrations in EX group were higher than other groups. In addition, FNDC5 concentrations in EX group was higher than those in other groups. PMID- 30426042 TI - Data on prognostication models comparison for neurological recovery after cardiac arrest using proton chemical shift imaging (1H-CSI). AB - We report in this data article the statistical comparison of three models for neurological prognostication 6 months after cardiac arrest: M1 associated SAPS II and coma Glasgow score at MRI, M2 associated SAPS II, coma Glasgow score, and FLAIR-DWI "deep gray nuclei"score, M3 associated SAPS II, coma Glasgow score, FLAIR-DWI "deep gray nuclei"score, and Lenticular cores NAA/Cr ratio. These data are related to "Value of assessment of multivoxel proton chemical shift imaging to predict long term outcome in patients after out-of-hospital cardiac arrest: A preliminary prospective observational study" (Quintard et al., 2018) [1]. PMID- 30426043 TI - Data set of differentially expressed microRNAs in sanguinarine-treated Caenorhabditis elegans and its F3 progeny. AB - This article presents small RNA sequencing data of Caenorhabditis elegans consist of P0 control worms (untreated), P0 worms treated with a plant alkaloid, sanguinarine, and its F3 offspring. The data were analyzed to identify microRNAs that were differentially expressed in both the sanguinarine-treated P0 and its descendants F3 worms. Targets of the identified miRNAs, gene function annotations and their functional clusters are shown. The data presented here will facilitate comparison with data from other researchers who are working on miRNAs profiling of xenobiotic-treated C. elegans. PMID- 30426044 TI - Geophysical measurement for estimation of groundwater hydraulic properties. AB - In the study, a relationship was establishment between electrical resistivity by using electrical resistivity imaging (ERI) technique with hydraulic conductivity. By using Schlumberger array configuration, 2D electrical resistivity image was produced by using ABEM SAS 4000 with eighty-one (81) electrodes (Loke, 2004) [1]. By using regression equation, hydraulic conductivity was calculated from electrical resistivity and this result was compared with the hydraulic conductivity obtained from pumping tests (Butler, 2005). This data suggested that electrical resistivity survey can be used as preliminary tool to assess any subsurface zone with non- invasive nondestructive for soil, reducing time and cost. PMID- 30426045 TI - Mass spectrometry data of in vitro and in vivo pig digestion of skim milk powder. AB - The data in this article are related to the research article entitled "Physiological comparability of the harmonized INFOGEST in vitro digestion method to in vivo pig digestion" (Egger et al., 2012). In this article, proteins identified in the different sections of pig skim milk powder (SMP) digestion are presented. In addition to the exemplary beta-casein profiles of the paper, the peptide patterns of the other most abundant milk proteins during in vivo digestion in individual pigs are shown as heatmaps and line graphs. These data clearly reveal the digestion resistant protein regions and illustrate the variability between the pigs in the different sampling sections. Moreover, peptide patterns of the same SMP proteins comparing the harmonized in vitro digestion (IVD) with pig in vivo digestion show the physiological relevance of the IVD protocol. Finally, correlation coefficients were calculated to indicate similarities between pig sampling sections and gastric and intestinal IVD endpoints. PMID- 30426046 TI - Data of characterization and related assays of lipid-core nanocapsule formulations and their hydrolysis mechanism. AB - The data presented here are related to the research paper entitled "Chemical stability, mass loss and hydrolysis mechanism of sterile and non-sterile lipid core nanocapsules: the influence of the molar mass of the polymer wall," [1]. Experimental details of the nanoemulsion and nanosphere preparation. Sterilization methodology and their efficacy by microbiological analyses (turbidimetry and fungi and bacteria detection). Characterization data of formulations, LNC 1, LNC 2 and LNC 3, analyzed by laser diffraction and DLS analysis, as well as, characterization data of degradation by SEC, including all statistics analyses. PMID- 30426047 TI - Data on the effect of Angiotensin II and 6-hydroxydopamine on reactive oxygen species production, antioxidant gene expression and viability of different neuronal cell lines. AB - This article describes the effect of the oxidative stress inducers Angiotensin II and 6-hydroxydopamine (6-OHDA) on different cell lines. The levels of expression Angiotensin type 1 and type 2 receptors in different dopaminergic cell lines are shown. The data indicate that treatment with Angiotensin II and 6-OHDA increases the production of reactive oxygen species (ROS) and decreases cell viability. NRF2 is a transcription factor induced by ROS. We provide data that NRF2 overexpression increases cell viability in response to oxidative stress inducers compared to control cells, and that these inducers can, both separately and in combination, enhance the expression of NRF2-regulated genes heme oxygenase 1 (Hmox1), NAD(P)H quinone dehydrogenase 1 (Nqo1) and Kruppel like factor 9 (Klf9). Interpretation of these data and additional information is presented in the research article "Angiotensin II induces oxidative stress and upregulates neuroprotective signaling from the NRF2 and KLF9 pathway in dopaminergic cells" (Parga et al., 2018) [1]. PMID- 30426048 TI - Data on the viscoelastic behavior of neoprene rubber. AB - The present article contains data on the multi-step cyclic stress relaxation tests associated with the viscoelastic behavior of the neoprene rubber. Herein, the present data aims the accurate prediction of the time dependent mechanical behavior of the polymeric materials. The findings of the present data include the demonstration of the Mullin's stress-softening phenomenon, clearly. These data findings may serve as a benchmark to validate the more advanced phenomenological model developments in future as compared to the existing ones. PMID- 30426049 TI - Dataset of the physical conditions of Green Ash (Fraxinus pennsylvanica) in riparian woodlands along the central Platte River. AB - The 2016 discovery of Emerald Ash Borer (Agrilus planipennis; EAB) in Nebraska warranted an assessment of the physical conditions of ash trees (Fraxinus spp.) across the state. Here we present a dataset of current physical conditions and spatial location of 30 Green Ash (Fraxinus pennsylvanica) throughout riparian woodlands along the Platte River in southcentral Nebraska. Ten Green Ash were assessed along transect lines through three riparian woodlands. Physical indicators of EAB infection and morphometric characteristics were recorded at each tree including diameter at breast height (DBH), estimated age, canopy condition rating scale (CCRS), borer holes, woodpecker holes, serpentine gallery, epicormic shoots, basal shoots, and bark splitting to document the health and condition of local Green Ash. We recorded variables of crown class category (CCC), crown ratio, and Green Ash seedling and sapling numbers within 6 m of the measured tree to document current canopy cover and regenerative potential of Green Ash within each woodland. Metric summaries are provided looking at each woodland individually and at the woodlands combined. PMID- 30426050 TI - Data for comparison of computed tomography angiography and dynamic myocardial perfusion to detect significant stenosis by coronary angiography. AB - This article describes data related to a research article titled "Feasibility of dynamic myocardial CT perfusion using single-source 64-row CT", Tomizawa et al. (in press) [1]. Decrease in the myocardial blood flow could be calculated by performing stress dynamic computed tomography perfusion. This article compares the receiver operating characteristics curve of computed tomography angiography and dynamic myocardial perfusion to diagnose significant stenosis by invasive coronary angiography. PMID- 30426051 TI - Data on patient's satisfaction from an emergency department: Developing strategies with the Multicriteria Satisfaction Analysis. AB - This article presents data that examine the patient's satisfaction from the services of an Emergency Department in Greece during the economic crisis. 490 questionnaires have been collected for the assessment of patient satisfaction by taking into account criteria like cleanliness, waiting room, access to the hospital, courtesy, friendliness and professional attitude of the emergency department staff, service processes and waiting times. In order to examine the satisfaction levels of the patients and moreover to design possible strategic actions we use the MUSA method. PMID- 30426052 TI - Data on low-molecular weight proteins of Escherichia coli treated by essential oils components, tetracycline, chlorine and peroxide by MALDI-TOF MS. AB - In this dataset we provide MALDI-TOF MS spectra of Escherichia coli. The data presented in this article are related to the article entitled "Stress response of Escherichia coli to essential oil components - insights on low-molecular-weight proteins from MALDI-TOF" (Bozik et al., 2018) [1]. Essential oils and their components are known for their antibacterial effect. Many studies evaluated the effect of essential oil components (EOCs) on the cell wall, bacterial membranes, and energetic metabolism. But data about low molecular weight proteins (<20 kDa) are limited. Provided data are focused on bacterial response to EOCs; tetracycline, peroxide and chlorine was used as control as common antibiotic and disinfectant agents used against bacteria. These data describe the effect of tested substances to bacterial protein synthesis. PMID- 30426053 TI - The data of genomic and phenotypic profiles of the N-acyl homoserine lactone producing algicidal bacterium Stenotrophomonas rhizophila GA1. AB - Herein, an algicidal strain, Stenotrophomonas rhizophila GA1, was isolated from a marine dinoflagellate and its genome was sequenced using next-generation sequencing technology. The genome size of S. rhizophila GA1 was determined to be 5.92 Mb with a G+C content of 62.39%, comprising eight scaffolds of 67 contigs. A total of 4579 functional proteins were assigned according to COG categories. In silico genome annotation protocols identified multiple putative LuxI-like genes located in the upstream position at contig 4. The thin-layer chromatography analysis showed that three kinds of acyl homoserine lactone (AHL) signals could be produced by S. rhizophila GA1. This work describes an algicidal bacterium capable of generating AHL molecules for its ecological adaptation. The annotated genome sequence of this strain may represent a valuable tool for studying algae bacterium interactions and developing microbial methods to control harmful algae. The genome scaffolds generated are available in the National Center Biotechnology Information (NCBI) BioProject with accession number PRJNA485554. PMID- 30426054 TI - Data on experimental investigation of Methyl Ester Sulphonate and nanopolystyrene for rheology improvement and filtration loss control of water-based drilling fluid. AB - Data presented in this article focused on the application of Methyl Ester Sulphonate (MES) surfactant and nanopolystyrene in water based drilling fluid. Data from rheology study using Bingham and Power law models showed that the synergy of MES and nanopolystyrene improved the formulated drilling fluid. Filtration study under LPLT and HPHT conditions showed that MES and nanopolystyrene drilling fluid reduced filtration loss by 50.7% at LPLT and 61.1% at HPHT conditions. These filtration data were validated by filter cake permeability and scanning electron microscope images. PMID- 30426055 TI - Stop voicing contrast in American English: Data of individual speakers in trochaic and iambic words in different prosodic structural contexts. AB - The data reported in this article contain eleven (6 female and 5 male) individual speaker's speech production patterns for the word-initial voiced and voiceless stops (/p,t/ and /b,d/) in American English. The production patterns are documented in the acoustic parameter: the Integrated Voicing Index (IVI) obtained from Voice Onset Time (VOT) and voicing duration in the stop closure (Voicing-in Closure), in various prosodic contexts: lexically-stressed vs. unstressed; accented (focused) vs. unaccented (unfocused); phrase-initial vs. phrase-medial. The data also contain a CVS file with each speaker's mean values of the IVI, VOT and Voicing-in-Closure for each prosodic condition for the voiced and voiceless stops, along with the information about the speaker gender. For further discussion of the data, please refer to the full length article entitled "Prosodic-structural modulation of stop voicing contrast along the VOT continuum in trochaic and iambic words in American English" (Kim et al., 2018). PMID- 30426056 TI - Dataset on the evaluation of antimicrobial activity and optical properties of green synthesized silver and its allied bimetallic nanoparticles. AB - The pursuit for bioremediation has led to alternative route for the synthesis of nanoparticles and their hybrids. Data in this article display optical properties and progress in the formation of silver and silver/nickel bimetallic nanoparticles using eco-friendly reducing agent (Akinsiku et al. 2018). The as prepared nanoparticles portrayed nanocrystalline nature as revealed in the x-ray powder diffraction (XRPD) data. Data also exposed antimicrobial activity of the synthesized nanoparticles. PMID- 30426057 TI - Data on Spectroscopic, Rheological characterization of neem oil and its isolated fractions. AB - In this article a medicinal oil (neem oil) is fractionated and compared with original oil. The fractions were separated at low temperature using chloroform and methanol. The uniphase mixture of solvents and neem oil at room temperature was transformed to a bi-phasic system at low temperature. The isolated fractions (NOC - isolated using chloroform; NOM - isolated using methanol) were characterized and differentiated by GC, FT-IR and Rheometer. GC and FTIR have well revealed the difference in composition of fatty acids in fractions - NOC; NOM and neem oil (NO). Rheologically all the oils are different in viscosity from parent oil. The NOM fraction of neem oil showed newtonian behavior while NOC shows a non-newtonian behavior. It can be concluded from data that fractions NOC, NOM can be used for targeting drugs using various formulation approaches. PMID- 30426058 TI - Data on acoustic behaviour of coconut fibre-reinforced concrete. AB - The data presented in this research show the results of the experimental study of acoustic behaviour of coconut fibre-reinforced concrete (CFRC). The CFRC was added in percentages of 0.25%, 0.5%, 0.75% and 1% of cement. The acoustic test was conducted to determine the amount of sound that can be absorbed by the fibre. The data showed that the concrete reinforced with coconut fibre had the highest sound absorptive power, of which fibre treated absorbed more sound than other fibres, this is because washing of fibre increase the lignin content which is responsible for the sound absorbing property. The data also showed that the curing time had no effect on the absorbing property of the CFRC. The data presented will be useful in the construction of sound proof reinforced concrete slabs, walls and other elements. PMID- 30426059 TI - Data of adsorption of Basic Blue 41 dye from aqueous solutions by activated carbon prepared from filamentous algae. AB - For this data article the adsorption of Basic Blue 41 (BB 41) dye by activated carbon derived from filamentous algae (AAC) of available in agriculture waste as cheap adsorbents were examined. Activated carbon has been widely used as an adsorbent regard to its massive specific surface area, high porosity, reusability and thermal stability for the removal of pollutants from effluent. These filamentous algae grow widely in irrigation streams, causing decreasing speed of water flow and are not even eaten by livestock so are considered agricultural wastes. They can be used as precursors for activated carbon preparation and as adsorbent for the dye removal. The data of initial dye concentration (50-200 mg//L), pH of dye solution (3-9), adsorbent dosage (0.25-2 g/L), and contact time (5-200 min), were assessed. The structure of AAC was characterized by X-ray diffraction and Fourier transforms infrared spectroscopy. Activated carbon with a 94% removal of dye at concentration of 100 mg/L, pH 9, and adsorbent dose 1 g/L after 90 min. The data of isotherms and Kinetics indicated that the experimental data are fitted to Langmuir and second-pseudo-order models. Under the optimum conditions, maximum adsorption capacity of the AAC in Langmuir model enhanced to amount of 125 mg/g. According to the experimental data, filamentous algae are a suitable raw material for activated carbon production. PMID- 30426060 TI - Plasma lactate measurement as an example of encountered gaps between routine clinical laboratory processes and manufactures' sample-handling instructions. AB - Objectives: Deviation from manufacturers' pre-analytical sample handling recommendations necessitates extensive validation studies. This report uses plasma lactate testing, where a recommended 15 min room temperature sample handling limit cannot be met by the clinical laboratory, as an example for studies to bridge the gap with practice. Design and Methods: Triplicate blood samples were collected from patients (n = 51) with lactate requests by clinicians and from normal volunteers (n = 50). One tube was transported on ice (4 degrees C), the others were maintained at room temperature (23 degrees C). Tubes stored at 4 degrees C were processed at 30 min from collection. Tubes stored at 23 degrees C were processed at 15 and at 30 min from collection. Lactate levels were measured using Roche Diagnostics Cobas 6000(r) analyzer. Results: Lactate levels in normal subjects ranged from 0.6 to 3.1 mmol/L (median 1.1). Patient lactate levels ranged from 0.8 to 26.3 mmol/L (median 2.2). Bias in lactate levels following extended storage of samples from both normal subjects and patients ranged from - 1.3 to2.2 and from - 1.0-1.0 mmol/L when stored for 30 min at 23 degrees C or at 4 degrees C, respectively. The bias between lactate levels at 30 min at 23 degrees C and 4 degrees C was - 1.2 to - 0.5 mmol/L for both populations. Although the bias was not statistically significant for all variables, a clinically significant (>0.2 mmol/L) bias was observed in 28% of normal and 7.0% of patient samples. Conclusion: Extending the pre-analytical time to 30 min at 23 degrees C did not significantly impact clinical utility of lactate measurement in our patient population. PMID- 30426061 TI - Brain metastases in patients with low-grade endometrial carcinoma. AB - Objective: To report characteristics of patients with low-grade endometrioid endometrial carcinoma (EC) who develop brain metastases. Methods: We retrospectively identified all patients treated at our institution for FIGO grades 1/2 EC from 1/2000-12/2016, who developed brain metastases. Electronic medical records were reviewed, data abstracted. Overall survival (OS) was determined from time of brain metastases to death or last follow-up. Appropriate statistical tests were used. Results: Of 3052 patients, 23 (9, grade 1; 14, grade 2) developed brain metastases (incidence = 0.75%). Presentation at initial diagnosis: median age = 61.3 years (range, 41-81); median BMI = 29.8 kg/m2 (range, 20.3-42.6 kg/m2); distribution by stage: I, 15/23 (65%); II, 2/23 (8.7%); III, 3/23 (13.0%); IV, 3 (13.0%). None showed clinical evidence of brain metastases at presentation. Median time to diagnosis of brain metastases = 29.7 months (range, 6-145); median age = 64.6 years (range, 47.5-86.5). Brain metastases were the first, isolated site of recurrence in 2/23 (9%). All presented with neurological symptoms. Six (26%) had solitary brain lesions. Seventeen (74%) received treatment; 6 (28%), supportive care only. Median OS for patients receiving any treatment = 5.8 months (95% CI, 1.6-10.0), versus 2.4 months (95% CI, 1.5-3.3; p = .04) for best supportive care. Conclusion: Brain metastases in low-grade EC is rare, prognosis generally poor. Compared to supportive care only, any treatment results in more favorable outcomes. PMID- 30426062 TI - Pharmacokinetics and clinical response to single agent rucaparib in a dialysis dependent patient with BRCA associated breast and recurrent ovarian cancer. AB - A 56-year old woman with BRCA-associated breast cancer and recurrent ovarian cancer was treated with a poly (ADP-ribose) polymerase enzyme (PARP) inhibitor, rucaparib, in the setting of dialysis-dependence which required dose modification. Rucaparib trough levels were obtained before and after dialysis and a clinically significant disease response was appreciated. PMID- 30426063 TI - Transnational wealth-related health inequality measurement. AB - The study of international differences in wealth-related health inequalities has traditionally consisted of country-by-country comparisons using own-country relative measures of socioeconomic status, which effectively ignores absolute differences in both wealth and health that can differ between and within countries. To address these limitations, we propose an alternative approach: that of constructing a transnational measure of wealth-related health inequality. To illustrate the limitations of the country-by-country approach, we simulate the impact of changes in wealth and health inequalities both between and within countries on cross-country measures of health inequality and find at least five errors that may arise using country-by-country methods. We then empirically demonstrate the transnational approach to wealth-related health inequalities between and within Haiti and the Dominican Republic, the two constituent countries of the island of Hispaniola, using data from their respective Demographic and Health Surveys. Transnational socioeconomic rankings reveal a large and increasing divergence in wealth between the two countries, which would be ignored using the county-by-country approach. We find that wealth-related inequalities in long-term children's health outcomes are larger than inequalities in short-term health outcomes, and decompositions of the influence of place-based variables on these inequalities reveal country of residence to be the most important factor for long-term outcomes, while urban/rural residence and subnational regions are more important for short-term health outcomes. The significance of this novel methodological approach in relation to conventional health inequality research, including hidden dimensions of wealth-related health inequalities, for example the urbanized "middle class" distribution of HIV and a hidden unequal burden of wasting among children uncovered by the transnational approach are discussed, and errors in gauging changes in inequality over time using a country-by-country approach are highlighted. Using the transnational approach can help to measure important trends in wealth-related health inequalities across countries that more commonly used methods traditionally overlook. PMID- 30426064 TI - In vivo coupling of tau pathology and cortical thinning in Alzheimer's disease. AB - Introduction: The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear. Methods: We estimated cortical thickness, tau ([18F]-AV-1451), and amyloid beta (Abeta) status ([11C]-PiB) in 47 subjects who were stratified into Abeta- (14 healthy controls and six mild cognitive impairment-Abeta-) and Abeta+ (14 mild cognitive impairment-Abeta+ and 13 AD) groups. Results: Compared with the Abeta- group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Abeta group. Locally, regional tau was associated with temporoparietal atrophy. Discussion: These findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD. PMID- 30426065 TI - Altered functional connectivity strength in informant-reported subjective cognitive decline: A resting-state functional magnetic resonance imaging study. AB - Introduction: Informant-reported subjective cognitive decline (iSCD) has been associated with a higher risk of conversion to dementia, but the findings of whole brain functional connectivity strength (FCS) changes in iSCD are limited. Methods: The sample comprised 39 participants with iSCD and 39 age- and sex- matched healthy controls. The global absolute (aFCS) and relative functional connectivity strengths were estimated using weighted degree centrality and the z scores of the weighted degree centrality respectively. FreeSurfer was used for measuring cortical thickness. Results: The aFCS was lower in iSCD primarily in left medial superior frontal, left precuneus, left parietal, right cuneus, and bilateral calcarine; while relative functional connectivity strength was higher in posterior cingulate cortex/precuneus compared with healthy controls. No significant differences in cortical thickness were observed. Discussion: There are detectable changes of FCS in iSCD, with the precuneus possibly playing a compensatory role. FCS could therefore have a potential role to serve as one of the earliest neuroimaging markers of neurodegenerative disease. PMID- 30426066 TI - Derivation of cutoffs for the Elecsys(r) amyloid beta (1-42) assay in Alzheimer's disease. AB - Introduction: An Elecsys(r) Amyloid beta (Abeta [1-42]) immunoassay cutoff for classification of patients with Alzheimer's disease was investigated. Methods: Cerebrospinal fluid samples collected from patients with mild-to-moderate Alzheimer's disease were analyzed by Elecsys(r) immunoassays: (1) Abeta (1-42), (2) total tau, and (3) phosphorylated tau. Cutoffs (Abeta [1-42] and ratios with tau) were estimated by method comparison between AlzBio3 (n = 206), mixture modeling (n = 216), and concordance with florbetapir F 18 imaging-based classification (n = 75). Results: A 1065-pg/mL (95% confidence interval: 985 1153) Elecsys(r) Abeta (1-42) cutoff provided 94% overall percentage agreement with AlzBio3. Comparable cutoff estimates (95% confidence interval) were derived from mixture modeling (equally weighted: 1017 [949-1205] pg/mL; prevalence weighted: 1172 [1081-1344] pg/mL) and concordance with florbetapir F 18 imaging (visual read: 1198 [998-1591] pg/mL; automated: 1198 [1051-1638] pg/mL). Discussion: Based on three approaches, a 1100-pg/mL Elecsys(r) Abeta (1-42) cutoff is suitable for clinical trials with similar populations and preanalytical handling. PMID- 30426067 TI - The Cognitive Ageing, Nutrition and Neurogenesis (CANN) trial: Design and progress. AB - Introduction: The Cognitive Ageing, Nutrition and Neurogenesis trial hypothesizes that a combined intervention with long-chain n-3 polyunsaturated fatty acids (n 3) and cocoa flavan-3-ols (FLAV) will mitigate the cognitive decline anticipated to naturally occur over 1 year in older adults. Methods: In a double-blinded, placebo-controlled parallel design, 259 individuals with mild cognitive impairment or subjective memory impairment were randomized to a control or n-3 FLAV group (1.5 g docosahexaenoic acid + eicosapentaenoic acid and 500 mg n-3 FLAV daily) for 12 months. Cognition was measured at 0, 3, and 12 months. The primary end-point is hippocampus-sensitive cognitive function (e.g., number of false-positives on the Picture Recognition Task of the Cognitive Drug Research test battery). Secondary outcomes include additional cognitive measures, brain atrophy and blood flow (assessed by magnetic resonance imaging), vascular function, circulating biomarkers of cardiovascular and cognitive health, gut microflora, red blood cell fatty acid status, and urine flavan-3-ol metabolites. Results: Screening began in 2015, with all baseline visits completed in March 2017. The intervention was finished in March 2018. Discussion: Cognitive Ageing, Nutrition and Neurogenesis aims to identify an effective diet-based intervention to prevent or delay cognitive impairment in cognitively at-risk individuals, which could ultimately contribute to a reduced population burden of dementia. Clinicaltrialsgov: NCT02525198. PMID- 30426068 TI - Comparison of interventional and surgical myocardial revascularization in kidney transplant recipients - A single-centre retrospective analysis. AB - Background: Kidney transplant recipients (KTR) reflect a high-risk population for coronary artery disease (CAD). CAD is the most common cause for morbidity and mortality in this population. However, only few data are available on the favourable revascularization strategy for these patients as they were often excluded from studies and not mentioned in guidelines. Methods: This retrospective single-centre study includes patients with a history of kidney transplantation undergoing myocardial revascularization for multivessel or left main CAD by either percutaneous coronary intervention (PCI, n = 27 patients) or coronary artery bypass grafting (CABG, n = 24 patients) at University Hospital Frankfurt, Germany, between 2005 and 2015. Results: In-hospital mortality was higher in the CABG group (20.8% vs. 14.8% PCI group; p = 0.45). In Kaplan-Meier analysis, one-year-survival showed better outcome in the PCI group (85.2% vs. 75%). After four years, outcome was comparable between both strategies (PCI 66.5% vs. CABG 70.8%; log-rank p = 0.94).Acute kidney injury (AKI), classified by Acute Kidney Injury Network, was observed more frequently after CABG (58.3% vs. 18.5%; p < 0.01). After one year, graft survival was 95.7% in the PCI group and 94.1% in the CABG group. Four year follow-up showed comparable graft survival in both groups (76.8% PCI and 77.0% CABG; p = 0.78). Conclusion: In this retrospective single-centre study of KTR requiring myocardial revascularization, PCI seems to be superior to CABG with regard to in-hospital mortality, acute kidney injury and one-year-survival. To optimise treatment of these high-risk patients, larger scaled studies are urgently warranted. PMID- 30426070 TI - Angioscopic imaging one month after the implantation of a drug-eluting stent following drug-coated balloon treatment. PMID- 30426069 TI - VE/VCO2 slope in lean and overweight women and its relationship to lean leg mass. AB - : Ventilation/carbon dioxide production (VE/VCO2slope) is used clinically to determine cardiorespiratory fitness and morbidity in heart failure (HF). Previously, we demonstrated that lower lean leg mass is associated with high VE/VCO2slope during exercise in HF. In healthy individuals, we evaluated 1) whether VE/VCO2slope differed between lean and overweight women and 2) the relationship between lean leg mass and VE/VCO2slope in overweight sedentary (OWS), overweight trained (OWTR) and lean, trained (LTR) women. Methods: Gas exchange and ventilation were collected during a treadmill peak oxygen uptake test (VO2peak) in 40 women [26 OWS (29 +/- 7 yrs., mean +/- SD), 7 OWTR (33 +/- 5 yrs) and 7 LTR (26 +/- 6 yrs)]. Body composition was measured by dual X-ray absorptiometry. Results: VO2peak was highest in LTR (46.6 +/- 8 ml/kg/min) compared with OWTR (38.1 +/- 4.9 ml/kg/min) and OWS women (25.3 +/- 4.8 ml/kg/min, p < 0.05). Lean leg mass was highest in OWTR and lowest in LTR women (p < 0.05). VE/VCO2slope was similar between groups (p > 0.05). Higher lean leg mass was associated with lower VE/VCO2slope in overweight women (OWS + OWTR: r = 0.55, p < 0.001), contrasting with higher VE/VCO2slope in LTR women (r = 0.86, p < 0.001). Conclusions: These findings suggest VE/VCO2slope may not differentiate between low and high cardiorespiratory fitness in healthy individuals and muscle mass may play a role in determining the VE/VCO2slope, independent of disease. PMID- 30426071 TI - Detection of Common Bile Duct Stones in Mild Acute Biliary Pancreatitis Using Magnetic Resonance Cholangiopancreatography. AB - Background: All patients with mild acute biliary pancreatitis should undergo early cholecystectomy. Whether routine common bile duct (CBD) imaging should be employed before the surgical procedure in these patients is a matter of current controversy. The aim of this study was to investigate the rate of detection of CBD stones using magnetic resonance cholangiopancreatography (MRCP) at different time intervals from admission. Methods: From January 1, 2011, through December 31, 2016, 72 patients with acute biliary pancreatitis underwent MRCP. Fifty-six (n=56) of them with mild biliary pancreatitis met the study criteria. The patients were divided into two groups. Group A did not have stones in the CBD (n=45), and Group B had stones in the CBD (n=11). The time from admission to MRCP was divided into several periods (day 1 through day 180), and the presence of the CBD stones on MRCP was weighted against remoteness from admission. Liver chemistry profiles were compared between the groups on admission and before the MRCP. Results: The cumulative rate of choledocholithiasis was 19.7% (Group B, n=11). Forty-five patients (Group A, n=45, 80.3%) did not have gallstones in the CBD. Eight patients with choledocholithiasis (8/56, 14.2%) were detected during the first 10 days from admission out of 27 patients. In patients who underwent MRCP between days 11 and 20, choledocholithiasis was found in two patients (2/56, 3.5%) and in one patient between days 21 and 30 (1/56, 1.8%). No stones were found in patients who underwent MRCP beyond 30 days from admission. Liver chemistry profiles did not show a significant difference in both groups. CBD dilatation was observed at presentation in 11 patients (n=11/56), 6 in Group A (6/45, 13.3%) and 5 in Group B (5/11, 45.5%) (p=0.016). Conclusions: Routine CBD evaluation should be encouraged after mild acute biliary pancreatitis. Early performance of MRCP gives high yield in selecting the patients for endoscopic retrograde cholangiopancreatography (ERCP) before cholecystectomy. A liver chemistry profile either on admission or before MRCP cannot predict the presence of CBD stones. PMID- 30426072 TI - Oncology Clinicians and the Minnesota Medical Cannabis Program: A Survey on Medical Cannabis Practice Patterns, Barriers to Enrollment, and Educational Needs. AB - Background: Medical cannabis has been available in the State of Minnesota since July 2015 through the Minnesota Medical Cannabis Program (MMCP). Objectives: Our study aimed to delineate oncology providers' views on medical cannabis, identify barriers to patient enrollment, and assess clinicians' interest in a clinical trial of medical cannabis in patients with stage IV cancer. Methods: From June to August 2017, we distributed a 14-question survey to Minnesota oncology physicians, advanced practice nurses, and physician assistants who care for adults and children with cancer. Descriptive analyses for each question were provided for all survey respondents. Results: Of the 529 eligible survey participants, 153 (29%) responded to our survey; 68 respondents were registered with the MMCP. Most identified themselves as a medical oncologist or medical oncology nurse practitioner/physician assistant (n=125, 82%), and most practiced in a community setting (n=102, 67%). Overall, 65% of respondents supported the use of medical cannabis. Perceived cost and inadequate research were the highest barriers to MMCP patient enrollment. The lowest barriers included lack of health group support for allowing certification of patients and risk of social stigma. Of all respondents, 36% lacked confidence in discussing the risks and benefits of medical cannabis, and 85% wanted more education. Conclusions: Although support for cannabis use in the cancer setting is growing, significant barriers remain. This study illustrates a clear need to give clinicians both data and education to guide their discussions about the benefits, risks, and cost considerations of using medical cannabis for cancer-related symptoms. PMID- 30426073 TI - Cannabis Systematics at the Levels of Family, Genus, and Species. AB - New concepts are reviewed in Cannabis systematics, including phylogenetics and nomenclature. The family Cannabaceae now includes Cannabis, Humulus, and eight genera formerly in the Celtidaceae. Grouping Cannabis, Humulus, and Celtis actually goes back 250 years. Print fossil of the extinct genus Dorofeevia (=Humularia) reveals that Cannabis lost a sibling perhaps 20 million years ago (mya). Cannabis print fossils are rare (n=3 worldwide), making it difficult to determine when and where she evolved. A molecular clock analysis with chloroplast DNA (cpDNA) suggests Cannabis and Humulus diverged 27.8 mya. Microfossil (fossil pollen) data point to a center of origin in the northeastern Tibetan Plateau. Fossil pollen indicates that Cannabis dispersed to Europe by 1.8-1.2 mya. Mapping pollen distribution over time suggests that European Cannabis went through repeated genetic bottlenecks, when the population shrank during range contractions. Genetic drift in this population likely initiated allopatric differences between European Cannabis sativa (cannabidiol [CBD]>Delta9 tetrahydrocannabinol [THC]) and Asian Cannabis indica (THC>CBD). DNA barcode analysis supports the separation of these taxa at a subspecies level, and recognizing the formal nomenclature of C. sativa subsp. sativa and C. sativa subsp. indica. Herbarium specimens reveal that field botanists during the 18th 20th centuries applied these names to their collections rather capriciously. This may have skewed taxonomic determinations by Vavilov and Schultes, ultimately giving rise to today's vernacular taxonomy of "Sativa" and "Indica," which totally misaligns with formal C. sativa and C. indica. Ubiquitous interbreeding and hybridization of "Sativa" and "Indica" has rendered their distinctions almost meaningless. PMID- 30426074 TI - Clear Cell Renal Cell Carcinoma with a Ureteral Thrombus. AB - Introduction: Cancers of the kidney, arising from either the renal parenchymal tissue or the renal pelvis, is among the 13 commonest types of malignancy globally, accounting for between 3% and 4% of all newly diagnosed cancers. Renal cell carcinoma (RCC) accounts for 85% of all malignant renal neoplasms. We present a rare case of an RCC directly extending into the renal pelvicalyceal system and with a thrombus within the ureter. Case Presentation: A 39-year-old woman presented with a long-standing history of worsening left flank pain, intermittent visible hematuria, and a fullness in the left flank. Apart from an ill-defined left flank mass with pain on palpation, there was nothing remarkable on clinical examination. Contrast-enhanced abdominal CT scan images showed a large, heterogeneously enhancing soft tissue mass arising from the lower pole of the left kidney. The collecting system and the left proximal ureter were poorly visualized. A tentative diagnosis of RCC, cT3aN0M0 was made. Intraoperatively, we identified a large, left lower pole renal mass, displacing the pedicle superiorly. In addition, we found a bulky, dilated proximal ureter. A decision was made intraoperatively to proceed with radical nephrectomy and ureterectomy. Conclusion: We report a rare case of RCC directly invading from the renal pelvis and down the ureter as a thrombus mass, with no microscopic individual tumor implants in the ureter wall, invasion of the renal vein, or invasion of adjacent organs. To our knowledge, only four such cases have been reported in English literature, and as a result, very few theories explaining renal pelvic invasion and direct growth down the ureter have been postulated. This highlights the significance of adding invasion of the pelvicalyceal system as part of the most recent, updated tumor node metastases classification. In future, consideration needs to be given to include the extension of RCC into the ureter and/or bladder. PMID- 30426075 TI - Hook Wire Placement Facilitates Laparoscopic Excision of Endophytic Renal Tumor in Partial Nephrectomy. AB - Introduction: Endophytic renal tumors that are completely intraparenchymal pose several challenges to surgeons, including in intraoperative tumor identification. Image-guided hook wires, which are now used in surgery, particularly in spinal surgery, thoracoscopic surgery, and breast surgery, allow for the precise localization of tumor sites. The hook wire facilitated the localization of the lesion and avoided cutting into the lesion directly. Case Presentation: A 55-year old woman was referred to our hospital due to an incidentally discovered 16-mm intracortical right renal mass in the anterior medial position. A renal biopsy was performed, which confirmed renal cell carcinoma. A hook wire was placed in the tumor by an interventional radiologist under CT guidance. This was done before performing the partial nephrectomy on the same day. The hook wire was found intraoperatively, and the renal artery was clamped. The renal capsule was resected using scissors under warm ischemia (25 minutes). Histopathology confirmed clear-cell renal carcinoma with negative surgical margins, Classification TNM 2017: pT1a Nx. Conclusion: Use of a hook wire is an alternative method for localizing endophytic lesions in partial nephrectomy. PMID- 30426076 TI - Fibroepithelial Polyp of the Ureter: A Rare Cause of Hydronephrosis. AB - Background: Fibroepithelial polyps of the urothelial system are rare and are considered to be benign tumors. Ultrasonography (USG), contrast-enhanced CT, and contrast-enhanced MRI can be used for detecting fibroepithelial polyps in the urothelial system. These polyps can be treated by performing open exploration and endoscopic or laparoscopic resection. Previous studies have also reported the frequent use of laser treatment for treating fibroepithelial polyps located in the proximal ureter. Case Presentation: A 54-year-old female patient presented to our clinic with right flank pain. Evaluation of the patient by performing USG and CT detected grade-2 hydronephrosis of the right kidney; however, no stone was detected in the urinary system. MRI detected thickening of the wall of the right proximal ureter along with contrast enhancement. These findings suggested the presence of a ureteral polyp. Ureterorenoscopy detected a 7-cm-long ureteral polyp in the proximal ureter, which was resected by performing monopolar cautery. Conclusion: Although fibroepithelial polyps of the urinary tract are rare, they should be considered in the absence of urinary calculi and in the presence of a ureteral obstruction. Furthermore, careful endoscopic resection by performing electrocautery is a safe and useful method for treating ureteral lesions. PMID- 30426078 TI - Late Presentation of a 9 mm Bullet in the Ureteropelvic Junction Causing Acute Renal Failure in a Solitary Functioning Left Kidney. AB - Background: Urinary obstruction as a result of a late complication of a gunshot wound is rarely reported. Bullet shell fragments may migrate from their initial location into an area causing obstruction. In this study, we present a case of a left renal calculus surrounding a 9 mm gun shell in a patient with a solitary functioning left kidney. Case Presentation: A 53-year-old man presented with left hydronephrosis found on an urgent CT scan following complaints of left flank pain and signs of acute renal failure 10 years after suffering a gunshot wound to the abdomen. Urgent cystoscopy and bilateral retrograde pyelograms revealed a left ureteropelvic junction calculus surrounding a 9 mm bullet fragment that was ultimately removed percutaneously. Conclusion: Abdominal gunshot shell fragments may migrate over time causing urinary obstruction. In this case the past medical history of the previous gunshot wounds provided insight into the etiology of the patient's actual clinical presentation. This led to the best endoscopic approach for the effective treatment of this unique case. PMID- 30426077 TI - Does Prostate Median Lobe Really Matter for GreenLight HPS Laser Photovaporization of the Prostate. AB - Background: Benign prostatic hyperplasia (BPH) is a common pathology in elderly patients, inducing lower urinary tract symptoms. The treatment of BPH is first a medical option, then a surgical treatment, either by endoscopy or open surgery. We here report a case of GreenLight HPSTM laser photovaporization (PV) with an impaired maintenance of median lobe postoperatively, unimportant on functional results. Case Presentation: A 68-year-old man presented with lower urinary tract symptoms in the last 2 years, treated first by medicine with good response. On digital rectal examination, the enlarged prostate was homogeneous and regular. International Prostate Symptom Score (IPSS) was 30/35, Incontinence Quality of Life (iQol) 6/6, and International Index of Erectile Function 5 14/25 with regular sexual activity. Transrectal ultrasound (TRUS) reported BPH of 62 g with a median lobe of 6 g protruding into the bladder. At uroflowmetry, maximum urinary flow rate (Qmax) was 8 mL/s for 90 cc void volume and 20 cc postvoid residual. After failure of medical treatment, we offered a surgical treatment option by laser therapy using the 180W XPS GreenLightTM. At 1-month follow-up, functional outcomes were improved with a Qmax of 11 mL/s, postvoiding residual volume 0 cc, IPSS 12/35, and iQol 2/6. At 3-month follow-up, outcomes still improved, although the TRUS reported a prostate volume of 30 g with a persistent median lobe. Conclusion: Impaired maintenance of median lobe after GreenLight laser PV does not seem to affect functional results. This case report opens the way for a new therapeutic strategy for patients according to their prostate anatomy. A randomized clinical trial could be done about surgical treatment for patient BPH according to prostate volume and anatomy. PMID- 30426079 TI - What Is Gender Dysphoria? A Critical Systematic Narrative Review. AB - In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, the American Psychiatric Association has changed the diagnosis of gender identity disorder to gender dysphoria (GD). In this critical narrative review we ask: What is gender dysphoria? We report on some of the inconsistencies in the articles that foreground distress while obfuscating the fact that not all trans and intersex people suffer stress or impaired functioning, and the inappropriate referencing to intersex people in the diagnostic criterion, claims about the GD diagnosis contributing to the depathologization of and reducing stigma surrounding trans people, the conceptualizations of "gender dysphoric" research subjects, and finally we question the etiological approaches using GD as a conceptual framework. We further suggest that there are a number of methodological issues that need to be resolved to be able to claim that the GD diagnosis can be validated. To shed light on these paradoxes and methodological issues in the DSM-5, we report on the content validity of GD by reviewing research articles postdiagnostic inception. These findings will contribute to the debate about the validity of GD as a diagnosis for the 21st century for those people who need to live a different gender to that assigned at birth. PMID- 30426080 TI - Limits of Professional Competency in Nurses Working in NICU. AB - : Our study aimed to find out the views of nurses working in neonatal intensive care units about the limits of professional competencies and to identify situations where the limits are crossed. Methods: The research employed the focus group method. For this research we had three focus groups with nurses working in neonatal intensive care units. The results of the study were analysed using the thematic analysis described in Braun and Clarke. Results and conclusions: Based on our research findings, it can be stated that the limits of professional competence of nursing staff working in neonatal intensive care units are defined and clear, but nurses often perform actions exceeding their competencies. This is usually done on the initiative of the nurses themselves, in cases of the deterioration of the state of the newborn, or when doctors delegate their functions to them. Confidence expressed by doctors leads to conflicting feelings of concern and, at the same time, pride in themselves. PMID- 30426081 TI - High Expression of NLRC5 Is Associated with Prognosis of Gastric Cancer. AB - Objective: To explore the relationships of NLRC5 with clinicopathological characteristics and prognosis of gastric cancer patients. Methods: A total of 97 gastric cancer patients undergoing radical gastrectomy were enrolled. All patients were diagnosed by immunohistochemical staining. The relationship between NLRC5 expression and clinicopatho-logical characteristics of gastric cancer was analyzed via univariate and multivariate Cox regressions. Results: NLRC5 expression was positive in 70 cases (72.2%) and negative in 27 cases (27.8%). No significant differences in age, sex, or tumor size or differentiation were found between the negative and positive groups. NLRC5 expression was related to tumor site, and in the positive group, it was high in the fundus and low in the pylorus (chi2=7.359, P=0.125). NLRC5 expression was significantly related to lymph nodes and tumor node metastasis (TNM) staging (chi2=6.295; chi2=6.268). Multivariate Cox regression indicated positive NLRC5 expression was independently and significantly associated with prognosis of gastric cancer patients (HR=2.92, 95%CI: 1.51-5.63). Conclusions: NLRC5 is closely related to TNM staging and lymph node metastasis of gastric cancer and is an independent risk factor for the prognosis of gastric cancer patients. PMID- 30426082 TI - Is Monitoring Mean Platelet Volume Necessary in Breast Cancer Patients? AB - Background: Mean platelet volume (MPV) is a parameter that increases during thrombotic and cardiovascular events. Tamoxifen (Tmx) and aromatase inhibitors (AIs), which are adjuvant endocrine therapies, may cause serious side effects, such as vascular thrombosis. The present study investigated the changes in MPV values of breast cancer patients receiving long-term adjuvant hormone therapy and the relationship of MPV with adverse effects of hormonotherapy. Methods: Data of 261 patients who had pathologically confirmed estrogen or progesterone receptor positive invasive breast cancer and had received hormonotherapy for at least a 5 year period were retrospectively analyzed. MPV levels were measured at baseline and at the first and fifth year of hormone therapy. Results: All patients were females and their median age was 50 years (range, 27-78 years). The mean MPV value was significantly increased in all patients in the Tmx, AI, and switch groups over time (p<0.001). Conclusion: This is the first study evaluating the relationship between the 5-year adjuvant endocrine therapy and changes in MPV values in breast cancer patients. Monitoring changes in MPV values may be predictive for severe side effects in breast cancer patients receiving hormone therapy. PMID- 30426083 TI - Epidemiological Study of Carbapenem-resistant Klebsiella Pneumoniae. AB - Background: This research is aimed to study the resistance and molecular epidemiological characteristics of carbapenem-resistant Klebsiella pneumoniae (CRKP). Methodology: 38 isolated CRKP strains were collected from clinical specimens. Results: The resistance rates were more than 70.0%. Ampicillin had the highest rates among them (100.0%). 34 strains (89.5%) among the 38 CRKP strains carried bla KPC-2 gene, and 3 strains (7.9%) carried bla IMP-4 gene. 36 strains (94.7%) among the 38 CRKP strains carried bla SHV gene, 29 strains (76.3%) carried bla TEM gene, and 26 strains (68.4%) carried bla CT-M gene. 7 strains (18.4%) among the 38 CRKP strains carried bla DHA-1 gene. 15 strains (39.5%) in 38 CRKP strains lost two fenestra proteins, ompK35 and ompK36, and the rest 23 strains carried ompK36 genes. 38 CRKP strains were divided into five kinds of ST types, with ST11 type as the most (86.8%, 33/38). The rest of the ST types included 2 strains of ST23 (5.3%, 2/38), one strain of ST15, ST1373 and ST1415 (2.6%, 1/38). Conclusions: CRKP resistance is severe, and the mechanism of drug resistance has become increasingly complex. Various ST types and resistance genes are related to CRKP. The clinical prevention and control work is imminent. PMID- 30426084 TI - The CCR5-Delta32 Genetic Polymorphism and HIV-1 Infection Susceptibility: a Meta analysis. AB - The CC chemokine receptor 5 (CCR5) is a chemokine receptor which is widely expressed in several immune cells involved in the inflammatory responses. Previous published studies revealed the relation of the CCR5 gene (CCR5-delta32) with the risk of HIV-1 infection, but the results are debatable and inconclusive. Here by meta-analysis, we have systematically evaluated the relation between the CCR5-delta32 polymorphism and the risk of HIV-1 infection. A comprehensive search in PubMed, EMBASE, CNKI, Cochrane Library, and WanFang database was performed up to April 15, 2018. The pooled odds ratio (ORs) along with its 95% credible interval (95%CI) was used to evaluate the relation between the CCR5-delta32 polymorphism and HIV-1 infection risk. The study included 24 case-control studies involving 4,786 HIV-1 infection patients and 6,283 controls. Compared with the wild-type homozygous genotypes, the results showed that the CCR5-delta32 heterozygotes (OR=1.16, 95%CI=1.02-1.32) had an increased susceptibility to HIV-1 and the delta32 homozygous (OR=0.25, 95%CI=0.09-0.68) had significantly reduced the susceptibility to HIV-1 for healthy controls. Moreover, we have found the delta32 allele carriers (OR=0.71, 95%CI=0.54-0.94) had significantly cut down the HIV-1 infection susceptibility when using exposed uninfected (EU) as controls. We also conducted the stratified analysis by ethnicity, and there significant association was detected in Caucasian in delta32 allele carrier genotype. To summarize, our meta-analysis suggests that the CCR5-delta32 homozygous genotype (delta32/delta32) confer possible protection against HIV-1, especially the exposed uninfected groups. PMID- 30426085 TI - Phenotypic and Molecular Characterisation of Staphylococcus Aureus with Reduced Vancomycin Susceptibility Derivated in Vitro. AB - Vancomycin has been the primary agent used to treat serious Methicillin-resistant Staphylococcus aureus (MRSA) infection for many years. However, the rise of MRSA infection rates and the extensive use of vancomycin have led to the emergence of reduced vancomycin susceptibility. Therefore, four typical Staphylococcus aureus (S. aureus) strains from different clinical specimens were derivated by vancomycin in vitro to better clarify their phenotypic and molecular characteristics. Some experiments, such as stepwise selection of vancomycin resistant strains, pulsed-field gel electrophoresis (PFGE), antimicrobial susceptibility test, population analysis profile-area under the curve (PAP-AUC), molecular typing, transmission electron microscopy, delta-hemolysin expression, autolysis assay, biofilm assay and quantitative real-time polymerase chain reaction (qPCR) for gene expression were carried out to compare the derivated bacteria with their parental strains. Results showed that the observed phenotypes of vancomycin-resistant strains such as hemolysin, autolysis and biofilm significantly reduced, which were associated with vancomycin resistance capability of the selected strain. The changes of phenotype and regulatory genes expression were inversely proportional to the vancomycin minimum inhibitory concentration (MICvan). Most heterogeneous vancomycin intermediate Staphylococcus aureus (hVISA) or VISA strains belonged to spa type t570 and agr group II. In summary, the clinical isolated vancomycin susceptible Staphylococcus aureus (VSSA), hVISA and VISA could be derivated into high vancomycin-resistant VISA in vitro, but it was difficult for them to develop into vancomycin resistant Staphylococcus aureus (VRSA). VISA and hVISA could gradually adapt to the environment with the vancomycin concentration that continuously elevates. PMID- 30426086 TI - Preliminary Results of Highly Injectable Bi-Phasic Bone Substitute (CERAMENT) in the Treatment of Benign Bone Tumors and Tumor-like Lesions. AB - BACKGROUND: CERAMENTTM|BONE VOID FILLER is an injectable and moldable ceramic bone substitute material intended for bone voids. The material consists of hydroxyapatite and calcium sulfate hemihydrate. The aim of this study is to present the first long-term results following open curettage of benign bone tumors and tumor-like lesions and void filling with this novel injectable and synthetic bone graft. METHODS: Thirty three patients were enrolled into the study between June 2013 and October 2014 .Totally, we treated 24 women and 9 men with a median age of 47 years (range: 22-74). All patients suffered from primary musculoskeletal system disorders (enchondroma 63,6%, giant cell tumor 18%, aneurysmal bone cyst 9%, fibrous dysplasia 9%, Gaucher disease 3%). We performed curettage of pathological lesions, then the bone substitute was administered by means of needle to the void. RESULTS: The average follow-up was 13 months (range: 2-13 months, median 10 months). No metastasis or recurrence had been detected. We received significant clinical improvement relating to VAS, MSTS, and oncological results. CONCLUSIONS: The results of our study report that CERAMENT can be successfully used as a bone substitute in patients with various bone diseases, as well as benign bone tumors. CERAMENT can provide an effective and long-term solution for reconstructive procedures following curettage of bone tumors and tumor like lesions. PMID- 30426087 TI - Analysis of Patient Satisfaction with Emergency Medical Services. AB - Background: This study analyses the degree of patient satisfaction regarding the Emergency Medical Services (EMS) by taking into account the waiting time which is considered to be associated with the success of the EMS organizational model. Methodology: Between 1 Jan 2016 and 31 March 2016 a cross-sectional research study among visitors of the EMS clinics in the EMS of the Primary Health Services of Gorenjska was performed. The EUROPEP survey was used for rating the degree of patient satisfaction. Statistical methods were utilized to determine the differences among the studied variables, namely the t test, one way ANOVA, as well as post-hoc multiple comparisons, were used. Results: Nearly all questions associated with the patient survey scored higher than 4.0, indicating patients were generally very satisfied with EMS treatment. Patients were least satisfied with the length of time spent waiting for an examination. The results showed that the waiting time is a statistically significant factor concerning all four dimensions of patient satisfaction: medical staff, clinical facilities, clinical equipment and organization of services (p < 0.05). Conclusions: Research results have confirmed that the effectiveness of the EMS organizational model impacts on the degree of patient satisfaction. The research also revealed a deficiency in the current EMS organizational services at the prehospital level, given that triage frequently failed to be carried out upon a patient's arrival at the EMS clinics. PMID- 30426088 TI - Guillain-Barre Syndrome and Low Back Pain: Two Cases and Literature Review. AB - PURPOSE: To describe the clinical, electrophysiological, and lumbar magnetic resonance imaging (MRI) features of two cases of atypical Guillain-Barre syndrome (GBS). Methods We reported two GBS variant cases with initial and prominent symptoms of low back pain. We analysed their clinical, electrophysiological, and lumbar MRI features. Results Two patients with GBS reported low back pain as the initial and prominent symptom, which was not accompanied by limb weakness. The electrophysiological study showed abnormal F-waves in the common peroneal and tibial nerves, and acute polyradiculoneuropathy in the cauda equina. Examination of the cerebrospinal fluid (CSF) showed albuminocytologic dissociation. Serum was positive for GQ1b-IgM antibodies. Lumbar MRI showed gadolinium enhancement of the nerve roots and cauda equina. A standard regime of intravenous immunoglobulin markedly alleviated the low back pain. Conclusions Low back pain caused by GBS should be differentiated from other diseases. This initial or early prominent symptom may delay the diagnosis of GBS; therefore, it is important to conduct a detailed electrophysiological, CSF, and gadolinium-enhanced lumbar MRI analysis. PMID- 30426089 TI - HELLP Syndrome Complicated By Pulmonary Edema: A Case Report. AB - HELLP syndrome is a combination of symptoms described as hemolysis, elevated liver enzymes and low platelets. HELLP is a common life-threatening complication of pregnancy thought to be a variant or complication of preeclampsia. In this case report, we aimed to present a woman with acute postpartum HELLP syndrome complicated by pulmonary edema after caesarean section following severe preeclampsia. Our experience suggests that early detection of HELLP syndrome and timely management will bring good outcomes. PMID- 30426090 TI - Pharmacokinetics of Vancomycin in Patients with Different Renal Function Levels. AB - There are many determinants of vancomycin clearance, but these have not been analyzed separately in populations with different levels of renal function, which could be why some important factors have been missed. The aim of our study was to compare the pharmacokinetic parameters and factors that may affect vancomycin pharmacokinetics in groups of patients with normal renal function and in those with chronic kidney failure. The study used a population pharmacokinetic modeling approach, based on plasma vancomycin concentrations and other data from 78 patients with chronic kidney failure and 32 patients with normal renal function. The model was developed using NONMEM software and validated by bootstrapping. The final model for patients with impaired kidney function was described by the following equation: CL (L/h) = 0.284 + 0.000596 x DD + 0.00194 x AST, and that for the patients with normal kidney function by: CL (L/h) = 0.0727 + 0.205 x FIB. If our results are confirmed by new studies on two similar populations, these factors could be considered when dosing vancomycin in patients with chronically damaged kidneys, as well as in patients with normal kidneys who frequently require high doses of vancomycin. PMID- 30426091 TI - Recurrent Chronic Subdural Hematoma: Report of 13 Cases. AB - Chronic subdural hematoma is a frequent type of hemorrhage, which terminates with mortality if not diagnosed and treated early. The aim of this clinical study is to evaluate the patients with unilateral and bilateral recurrent chronic subdural hematoma. The study group consisted of 13 cases with unilateral and bilateral recurrent chronic subdural hematomas who underwent aggressive wide craniotomy, duraectomy, inner and outer membranectomy, dural border coagulation, incision through cortical vein trace and hang up of dural edge, between 2009 - 2016. All of our patients were diagnosed by preoperative Magnetic Resonance Imaging. We evaluated the age, gender, complaints and neurologic signs, localization and thickness of the hematoma. We can estimate that wide craniotomy, duraectomy and membranectomy is a good option in preventing recurrent chronic subdural hematoma and complications. PMID- 30426092 TI - High Expression Levels of Fascin-1 Protein in Human Gliomas and its Clinical Relevance. AB - Introduction: The fascin-1 protein is a cytoskeleton-like protein, which can prompt structural changes in cell membranes and affect the integrity of intercellular relations to promote invasion and metastasis of tumor cells. In this study, we researched the expression of fascin-1 in glioma. Material and methods: The fascin-1 protein and mRNA were detected by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR). Then, we analyzed the relationship between the expression of fascin-1 protein and the clinical pathological characteristics of patients with glioma. Finally, the fascin-1 protein expression status and prognosis of glioma patients were investigated. Results: The fascin-1 protein was mainly located in the cytoplasm of cells from glioma. The high expression rate of fascin-1 protein in glioma tissue was higher than that of normal brain tissue. At same time, we found that high fascin-1 protein expression was significantly correlated with World Health Organization (WHO) grading of glioma patients. The results survival analysis suggested high expression of fascin-1 protein in glioma patients with a shorter survival time. Multivariate analysis showed that high expression of fascin-1 protein was an independent predictor of the prognosis of patients with glioma. Conclusions: High expression of the fascin-1 protein indicates poor prognosis for glioma patients. PMID- 29806038 TI - Ethical considerations in Controlled Human Malaria Infection studies in low resource settings: Experiences and perceptions of study participants in a malaria Challenge study in Kenya. AB - Background: The range and amount of volunteer infection studies, known as Controlled Human Infection Model (CHMI) studies, in Low-Middle Income Countries (LMICs) is increasing with rapid technological advancement, world-class laboratory facilities and increasing capacity development initiatives. However, the ethical issues these studies present in LMICs have not been empirically studied. We present findings of a descriptive social science study nested within a malaria volunteer infection study, on-going at the time of writing, at the KEMRI-Wellcome Trust Research Programme (KWTRP) on the Kenyan Coast. Methods: The study included non-participant observations, five group discussions with more than half of the CHMI study participants, two in-depth interviews with study team members, and an exit questionnaire administered to the participants. Results: Participants understood the key elements of the study, including that they would be deliberately infected with malaria parasites and may get malaria as a result, there would be regular blood draws, and they would spend up to 24 days in a residence facility away from their homes. The greatest motivation for participation was the monetary compensation of 20 USD per overnight stay given as a lump-sum at the end of their residency stay. Also appreciated were the health screening tests prior to enrolment and the positive relations with the study team. Concerns raised included the amount and regularity of blood draws experienced, and concerns that this type of research may feed into on-going rumours about research generally. Conclusion: With the increasing range and number of CHMI studies being conducted in LMICs, current ethical guidance are inadequate. This study highlights some of the ethical issues that could emerge in these settings, emphasizing the heavy responsibility placed on research review and regulatory systems, researchers and funders, as well as the importance of carefully tailored community engagement and consent processes. PMID- 30426094 TI - Posterior Gastric Artery Aneurysm. AB - Introduction: Aneurysms of small abdominal vessels are extremely rare; however, even minor aneurysmal accessory arteries can rupture, leading to potentially fatal consequences. The purpose of this paper is to report a case of coil embolisation of an aneurysmal posterior gastric artery. Case presentation: The authors describe the case of a 66 year old female patient with an aneurysm of the posterior gastric artery. Coil embolisation was performed. The six month follow up computed tomography angiogram revealed exclusion of the aneurysm. Discussion: The presented case is exceedingly rare. This type of aneurysm has to be kept in mind as a possible cause of bleeding, despite the limited information regarding their natural history. Conclusion: Owing to the safety and applicability of the endovascular technique, it is nowadays probably the best treatment alternative for this type of aneurysm. PMID- 30426095 TI - An Alternative Technique to Achieve Haemostasis During PEVAR Using Perclose ProGlide. AB - Introduction: Percutaneous endovascular abdominal aortic aneurysm repair (PEVAR) using the Perclose ProGlide suture mediated closure device is currently performed on a global scale. A safe, effective, and cheap technique for achieving haemostasis during PEVAR is described that allows the reversible downsizing of the arteriotomy, without using any other devices. Technique: The procedure consists of pulling the blue thread of the pre-implanted ProGlide, advancing the knot close to the arterial wall by pushing it with the dilator of a small introducer sheath, and maintaining the system under tension by grasping the end of the blue thread with a haemostat until bleeding control is achieved. Discussion: Seventeen PEVAR femoral access downsizing procedures have been performed between February and June 2018 and no complications were observed. The technique could be useful in everyday practice and has now become the author's standard practice. PMID- 30426096 TI - Gendered bio-responsibilities and travelling egg providers from South Africa. AB - 'Unsuspecting young South African women are heading overseas to donate their eggs to infertile couples and earn a free international holiday in the process. But, at what cost?' This was the voice-over during a news show in South Africa in 2016 that described the phenomenon of young white South African women going abroad to 'donate' their eggs. Through the media, medical professionals sought to warn 'naive girls' about 'unscrupulous agencies' taking advantage of them, and in doing so putting them at grave medical risks in 'Third World' clinics. Yet owners of agencies and egg providers themselves countered this imagery; here, the egg provider becomes a far more complex biocitizen who finds an opportunity to combine an act of altruism with an opportunity to earn money and travel. Through interviews with travelling egg providers, doctors and egg agencies, and analysis of public and social media, we analyse these competing discourses critically by situating them within the specific context of egg provision in South Africa. We argue that travelling egg providers' defence of their involvement may challenge some gendered assumptions made by the media and medical staff, but at the same time reaffirm what we call 'gendered bio-responsibilities', or the gendered nature of the emphasis on (individual) responsibilization of biological citizens. By focusing on a relatively understudied aspect of the burgeoning literature on biocitizenship, we argue that the project of biocitizenship assists the expansion and normalization of new biomedical technologies, often without proper emphasis on the disproportionate obligations on the women involved. PMID- 30426098 TI - End-user frustrations and failures in digital technology: exploring the role of Fear of Missing Out, Internet addiction and personality. AB - The present study aimed to explore the potential relationship between individual differences in responses to failures with digital technology. In total, 630 participants (50% male) aged between 18-68 years (M = 41.41, SD = 14.18) completed an online questionnaire. This included a self-report, response to failures in digital technology scale, a measure of Fear of Missing Out, Internet addiction, and the BIG-5 personality traits. Fear of Missing Out, Internet addiction, extraversion, and neuroticism all served as significant positive predictors for maladaptive responses to failures in digital technology. Agreeableness, conscientiousness, and openness acted as significant negative predictors for maladaptive responses to failures in digital technology. The responses to failures in digital technology scale presented good internal reliability, with items loading onto four key factors, these being; 'maladaptive responses', 'adaptive responses', 'external support and venting frustrations', and 'anger and resignation'. The findings are discussed in the context of the end user experience, particularly where individual differences are seen to influence the level of frustration arising from a failure. The findings are also seen as a potential route for reducing the negative impact of failures in digital technology, particularly in the context of organisational productivity and responses to malicious cyberattacks. PMID- 30426097 TI - MAT cross-reactions or vaccine cross-protection: retrospective study of 863 leptospirosis canine cases. AB - : Dogs are naturally exposed to numerous pathogenic serogroups. Leptospirosis vaccines are claimed to afford a clinical protection restricted to the serogroups of which they are composed. Objectives: Dogs exhibiting liver and kidney injury were suspected of having leptospirosis. The purpose of this study was to compare the microscopic agglutination test (MAT) results in naive and vaccinated dogs experiencing leptospirosis outcomes. Only MAT-positive animals were included in the study. Methods: Over five years, 3 512 dogs were suspected of having leptospirosis. For each case, biochemical parameter results were recorded. Leptospirosis involvement was investigated by MAT performed against 6 major serogroups (Icterohaemorrhagiae, Canicola, Australis, Autumnalis, Grippotyphosa and Sejroe). MAT-positive results confirmed leptospirosis cases in 147 naive dogs and in 580 fully vaccinated dogs. Serological titres of agglutinating antibodies were related to the severity of liver and kidney failure. Results: The most prevalent outcome of leptospirosis in unvaccinated dogs was liver failure (57.8%) compared to 51.7% for kidney disease, but the most severe onset (90.8%) was found among the cases of acute kidney injury compared to the severe (42.3%) hepatitis cases. In dogs vaccinated by bivalent Icterohaemorrhagiae and Canicola bacterins, hepatitis decreased from 57.8 to 46.5% and acute kidney injury from 51.7 to 21.6%. The decrease was shown in leptospirosis cases induced by field strains belonging to the six most prevalent serogroups, including the 4 serogroups heterologous to the vaccine. Conclusion: Common vaccination was efficient in decreasing hepatitis and kidney failure induced by field Leptospira spp infection regardless of the MAT-prominent serogroup and limited the disease severity in the remaining cases. PMID- 30426099 TI - Optimization of essential oil extraction from orange peels using steam explosion. AB - In this work, a new extraction process using steam explosion at high temperature and pressure was developed, to drastically shorten the extraction time and improved extraction of the essential oil from citrus peels. In steam explosion process, the material is subjected to the high-pressure saturated steam following by substantially dropping the pressure through an angle valve to a vacuum tank. The optimum essential oil yield by the steam explosion was obtained at the 170 degrees C, 8 bar in 240 seconds duration time. The essential oil extraction of a certain amount of citrus peels by hydro-distillation took nearly eight times longer than explosion extraction process. The obtained citrus oil from hydro distillation processes had 10 to 13 major components more than? the steam explosion, as shown by gas chromatography (GC-MS). The maximum product yield of Limonene, a major favorable component, were 77% and 100% in hydro-distillation and steam explosion processes, respectively. PMID- 30426100 TI - Addicted to cellphones: exploring the psychometric properties between the nomophobia questionnaire and obsessiveness in college students. AB - A potential new clinical disorder is arising due to the addiction to cellphones called nomophobia-or feelings of discomfort or anxiety experienced by individuals when they are unable to use their mobile phones or utilize the conveniences these devices provide. However, before being able to officially classify this disorder as clinically relevant, more research needs to be conducted to determine how nomophobia relates to existing disorders. In a sample of 397 undergraduate students, the present study examined the relationship between the Nomophobia Questionnaire (NMP-Q) and the Obsessiveness Content Scale (OBS) of the Minnesota Multiphasic Personality Inventory-2 (the MMPI-2). Confirmatory factor analysis (CFA) was used to test whether the OBS Content Scale would be related to a one factor NMP-Q solution (Fig. 1) or a four-factor NMP-Q solution (Fig. 2). Convergent and divergent validity were also investigated. The four-factor model was a better fit than the one-factor model as indicated by most fit indices. The findings showed that the OBS latent variable was correlated with all of the four NMP-Q latent variables. Mixed support was found for convergent validity, but high support was found for the divergent validity of the NMP-Q factors. This study contributes to a growing body of literature seeking to better understand the addictive nature of cellphones and takes a new perspective on addiction research and obsessiveness. These findings provide a better understanding between pre existing assessments of personality disorders (e.g., obsessiveness) that are emerging from the overuse of mobile phones or the excessive fear of losing one's cell phone. PMID- 30426101 TI - Students' attitudes towards EFL university writing: A case study at An-Najah National University, Palestine. AB - Writing has always been seen as the most troublesome and challenging area of language learning for all students without exception especially if it is to be done in a foreign language. Most of these students fail to meet the expectations of instructors both communicatively and linguistically. Those students are, in fact of varied backgrounds, different learning methodologies, varied levels of language skills and experience, let alone different insights, attitudes and conceptions about the writing skill. Consequently, it is significant to exhibit what these students think of writing and how they approach it. This study was meant to serve a two-fold purpose. Firstly, it aimed at examining what the Palestinian EFL students' attitudes towards writing in general are; and secondly, whether the Palestinian EFL students feel any difference between expressing ideas while writing in English and Arabic. The participant of this study were (102) EFL students enrolled in four writing courses offered by the English Department in the Faculty of Humanities at An-Najah National University in the Spring Semester 2016/2017. A 28-item questionnaire modified from Daly-Miller Writing Apprehension Questionnaire and an open-ended question to help respondents freely express their attitudes towards writing were used to answer the questions. The study findings showed that students had positive attitudes toward writing, the various writing courses offered by the university, the textbooks and teaching methods used, and their writing skills and strategies. PMID- 30426102 TI - Meningitis B vaccination: knowledge and attitudes of pediatricians and parents in Greece. AB - Bexsero(r), a meningitis B vaccine, was recently included in the National Immunization Programme (NIP) in Greece, with restricted access to high risk groups only. To map the need to expand coverage, this study assessed pediatricians and parents' perceptions and attitudes towards meningitis B, inclusion of Bexsero(r) in the NIP and vaccination uptake. We analyzed data from 201 private practice pediatricians questionnaires and 1003 parents phone interviews. Both (pediatricians 64.7%, parents 88.5%) considered meningitis B a critical challenge. 77.6% of pediatricians would prioritize meningitis B vaccination in the NIP and 90.3% would recommend Bexsero(r) to parents. Of those who would not, 47% feared civil liability challenges and 11.8% hesitated to impose vaccine cost on parents. Only 28.9% of parents had their child vaccinated. Non-reimbursement constituted a major access hurdle. It is critical to expand immunization coverage in Greece through expanded access in the NIP, in line with pediatrician recommendations. PMID- 30426103 TI - Spatial assessment of sugarcane (Saccharurn spp. L.) production to feed the Komenda Sugar Factory, Ghana. AB - Ghana imports about US$ 2 million worth of sugar annually. To address this huge import bill and to take advantage of a growing demand for sugar in the West African sub-region, the Government of Ghana initiated a Sugar Policy. The Government of Ghana, therefore, re-constructed and commissioned the Komenda Sugar Factory in 2016 at a reported cost of US$ 35 million. The Komenda Sugar Factory can process 1,250 tons of sugarcane per day (or 225,000 tons per annum), but was shut down soon after the test run and commissioning. This raised considerable public outcry. Among the numerous reasons that were given, it was widely believed that the factory faced feedstock deficits. This study therefore applied satellite remote sensing and Geographic Information Systems to quantify the potential feedstock supply from current production within the immediate catchment of the factory. Supervised classification was applied to Landsat 8 images, using QGIS, to quantify sugarcane production in the study area and at specified buffer distances from the factory. The results showed that the factory could mobilize only 7% of its feedstock requirement within the industrially recommended radius of 40 miles and 13% within the entire catchment area in the 2016/2017 season. Thus, under current scale of production and production conditions, the Komenda Sugar Factory faces large deficits in feedstock supply. National production data suggests that total national sugarcane production in 2016 would only meet 68% of the factory's requirement if it were operational. The results suggest an urgent need to establish a plantation for the factory and to commit out-growers to production to support and sustain the factory if it is to become operational soon. There is also a need for high-yielding, high-brix, and early maturing varieties, coupled with good agronomic practices, to bridge the quantity and (potentially) quality gaps. PMID- 30426104 TI - Evaluation of methodologies to determine the effect of specific active immunotherapy on VEGF levels in phase I clinical trial patients with advanced solid tumors. AB - Two phase I clinical trials were conducted to evaluate, among other parameters, the humoral response elicited by a vascular endothelial growth factor (VEGF) based therapeutic vaccine in cancer patients with advanced solid tumors. VEGF reduction was studied using an indirect methodology named as "Platelet VEGF". This methodology is based on the estimation of VEGF within platelets by subtracting the plasma VEGF level from the serum level and dividing this by the platelet count, and then this latter expression is additionally corrected by the hematocrit. However, there is broad debate, whether serum or plasma VEGF or platelet-derived VEGF measurements is the most appropriate strategy to study the changes that occur on ligand bioavailability when patients are submitted to a VEGF-based immunotherapy. The current research is a retrospective study evaluating the changes on VEGF levels in serum and plasma as well as platelet derived measurements. Changes in VEGF levels were related with the humoral response seen in cancer patients after an active immunotherapy with a VEGF-based vaccine. The present study indicates that "Platelet VEGF" is the most reliable methodology to investigate the effect of VEGF-based immunotherapies on ligand bioavailability. "Platelet VEGF" was associated with those groups of individuals that exhibited the best specific humoral response and the variation of "Platelet VEGF" showed the strongest negative correlation with VEGF-specific IgG antibody levels. This methodology will be very useful for the investigation of this VEGF based vaccine in phase II clinical trials and could be applied to immunotherapies directed to other growth factors that are actively sequestered by platelets. PMID- 30426106 TI - Microwave-assisted recovery of monomeric sugars from an acidic steam treated wood hydrolysate. AB - Fractionation of components from bio-refinery wastes streams is complicated by the presence of both oligomer and lignin fractions. Microwave-assisted acid hydrolysis was used in this study to convert oligomer sugars in an industrial prehydrolysis liquor (PHL) to monomeric sugars. A total of 19.6 g/L monomeric sugars was obtained at a combined severity factor (CSF) of 3.2. Furthermore, it was found that xylan linked to lignin in a lignin-carbohydrate complex (LCC) could be liberated, resulting in lignin with a relatively low dispersity (3.12) and average molecular weight (1718 g/mol) that has high commercial value in the phenol-formaldehyde resin industry. This study presents for the first time a relatively inexpensive method for recovery of 100% of available sugars in the PHL without apparent loss in monomeric sugar as well as 50% removal of lignin as a valuable by-product. Application of this method can significantly improve the economic sustainability of forest-based biorefineries. PMID- 30426107 TI - Solutions of nonlinear real world problems by a new analytical technique. AB - Here a new analytical scheme is presented to solve nonlinear boundary value problems (BVPs) of higher order occurring in nonlinear phenomena. This method is called second alternative of Optimal Homotopy Asymptotic Method. It converts a complex nonlinear problem into zeroth order and first order problem. A homotopy and auxiliary functions which are consisted of unknown convergence controlling parameters are used in this technique. The unknown parameters are determined by minimizing the residual. Many methods are used to determine these parameters. Here Galerkin's method is used for this purpose. It is applied to solve non linear BVPs of order four, five, six, and seven. The Consequences are compared with other methods e.g., Differential Transform Method (DTM), Adomain Decomposition Method (ADM), Variational Iteration Method (VIM), and Optimal Homotopy Asymptotic Method (OHAM). It gives efficient and accurate first-order approximate solution. The achieved results are compared with the exact solutions as well as with other methods to authenticate the applied technique. This method is very simple and easy but more operative. PMID- 30426105 TI - Regulating gene expression in animals through RNA endonucleolytic cleavage. AB - The expression of any gene must be precisely controlled for appropriate function. This expression can be controlled at various levels. This includes epigenetic regulation through DNA methylation or histone modifications. At the posttranscriptional level, regulation can be via alternative splicing or controlling messenger RNA (mRNA) stability. RNA cleavage is one way to control mRNA stability. For example, microRNA (miRNA)-induced mRNA cleavage has long been recognised in plants. RNA cleavage also appears to be widespread in other kingdoms of life, and it is now clear that mRNA cleavage plays critical functions in animals. Although miRNA-induced mRNA cleavage can occur in animals, it is not a widespread mechanism. Instead, mRNA cleavage can be induced by a range of other mechanisms, including by endogenous short inhibitory RNAs (endo-siRNAs), as well as the Ribonuclease III (RNase III) enzymes Drosha and Dicer. In addition, RNA cleavage induced by endo-siRNAs and PIWI-interacting RNAs (piRNAs) is important for genome defence against transposons. Moreover, several RNase has been identified as important antiviral mediators. In this review, we will discuss these various RNA endonucleolytic cleavage mechanisms utilised by animals to regulate the expression of genes and as a defence against retrotransposons and viral infection. PMID- 30426108 TI - Limited added value of fungal ITS amplicon sequencing in the study of bovine abortion. AB - Bovine mycotic abortion is sporadic and caused by different ubiquitous and opportunistic fungi. Recently, a broad spectrum of bacterial opportunists involved in bovine abortion was revealed by 16S rRNA gene amplicon sequencing. We hypothesized that fungal organisms potentially involved in bovine abortion also might remain undetected by conventional culture. In this retrospective study, we therefore applied fungal internal transcribed spacer 2 (ITS2) region amplicon sequencing to 74 cases of bovine abortion submitted to our diagnostic service. The investigation was complemented by fungal culture and, retrospectively, by data from bacteriological, virological and parasitological analyses and histopathological examination of placentas. Fungal DNA was found in both the placentas and abomasal contents, with 92 fungal genera identified. In 18 cases, >75% of the reads belonged to one specific fungal genus: Candida (n = 7), Malassezia (n = 4), Cryptococcus (n = 3), unidentified Capnodiales (n = 3), Actinomucor (n = 1), Cystofilobasidium (n = 1), Penicillium (n = 1), Verticillum (n = 1) and Zymoseptoria (n = 1) with one case harboring two different genera. By culture, in contrast, fungal agents were detected in only 6 cases. Inflammatory and/or necrotizing lesions were found in 27/40 histologically assessed placentas. However, no lesion-associated fungal structures were detected in HE- and PAS stained specimens. Complementary data revealed the presence of one or more non fungal possible abortifacient: Chlamydiales, Coxiella burnetii, Leptospira spp., Campylobacter fetus subsp. fetus, Streptococcus uberis, Escherichia coli, Streptococcus pluranimalium, Bacillus licheniformis, Campylobacter fetus subsp. fetus, Serratia marcescens, Trueperella pyogenes, Schmallenbergvirus, Neospora caninum. The mycobiota revealed by sequencing did not differ between cases with or without a possible infectious etiology. Our study suggests that amplicon sequencing of the ITS2 region from DNA isolated from bovine abortion does not provide additional information or new insight into mycotic abortion and without complementary analyses may easily lead to a false interpretation of the role of fungal organisms in bovine abortion. PMID- 30426109 TI - A Novel CLCN5 Mutation Associated With Focal Segmental Glomerulosclerosis and Podocyte Injury. AB - Introduction: Tubular dysfunction is characteristic of Dent's disease; however, focal segmental glomerulosclerosis (FSGS) can also be present. Glomerulosclerosis could be secondary to tubular injury, but it remains uncertain whether the CLCN5 gene, which encodes an endosomal chloride and/or hydrogen exchanger, plays a role in podocyte biology. Here, we implicate a role for CLCN5 in podocyte function and pathophysiology. Methods: Whole exome capture and sequencing of the proband and 5 maternally-related family members was conducted to identify X-linked mutations associated with biopsy-proven FSGS. Human podocyte cultures were used to characterize the mutant phenotype on podocyte function. Results: We identified a novel mutation (L521F) in CLCN5 in 2 members of a Hispanic family who presented with a histologic diagnosis of FSGS and low-molecular-weight proteinuria without hypercalciuria. Presence of CLCN5 was confirmed in cultured human podocytes. Podocytes transfected with the wild-type or the mutant (L521F) CLCN5 constructs showed differential localization. CLCN5 knockdown in podocytes resulted in defective transferrin endocytosis and was associated with decreased cell proliferation and increased cell migration, which are hallmarks of podocyte injury. Conclusions: The CLCN5 mutation, which causes Dent's disease, may be associated with FSGS without hyercalcuria and nepthrolithiasis. The present findings supported the hypothesis that CLCN5 participates in protein trafficking in podocytes and plays a critical role in organizing the components of the podocyte slit diaphragm to help maintain normal cell physiology and a functional filtration barrier. In addition to tubular dysfunction, mutations in CLCN5 may also lead to podocyte dysfunction, which results in a histologic picture of FSGS that may be a primary event and not a consequence of tubular damage. PMID- 30426111 TI - Corrigendum to "Ethnic differences in the association between angiotensin converting enzyme gene insertion/deletion polymorphism and peripheral vascular disease: A meta-analysis" [CDTM 3/4 (2017) 230-241]. AB - [This corrects the article DOI: 10.1016/j.cdtm.2017.07.002.]. PMID- 30426110 TI - Measuring Organizational Cultural Competence to Promote Diversity in Academic Healthcare Organizations. AB - Purpose: To evaluate what drives respondent perceptions of health system organizational cultural competence. Methods: We estimated associations between survey respondent (n=3506) demographic characteristics, length of employment, position, and place of work and their reported perceptions of institutional culture. Results: In adjusted analyses, respondents self-identifying as non Hispanic black versus non-Hispanic whites, females versus males, and lesbian/gay/bisexual/transgender/queer versus heterosexuals were significantly less likely to rank the cultural competence of their organization above average. Conclusion: Minorities and women were less likely to rank their organization as culturally competent. Organizational efforts to achieve cultural competency would benefit from measuring this factor to target their efforts. PMID- 30426112 TI - Rational synthesis of hollow cubic CuS@Spiky Au core-shell nanoparticles for enhanced photothermal and SERS effects. AB - Hollow cubic CuS@Spiky Au core-shell nanoparticles (NPs) were rationally synthesized both for guided highly efficient damage to cancer cells by the photothermal effect and for the real-time monitoring of biochemical responses during cellular apoptosis, totally based on label-free SERS intracellular imaging. PMID- 30426113 TI - A pH-responsive stellate mesoporous silica based nanophotosensitizer for in vivo cancer diagnosis and targeted photodynamic therapy. AB - Development of a photosensitizer that can achieve tumor specificity, improve therapeutic efficacy, and reduce side effects remains a challenge for photodynamic therapy (PDT). In this work, a pH-sensitive activatable nanophotosensitizer (SMSN-ZnPc1) has been elaborately designed, which could be readily prepared by using a functionalized zinc(ii) phthalocyanine (ZnPc) to conjugate with stellate mesoporous silica nanoparticles (SMSNs) through an acid sensitive hydrazone bond. Meanwhile, a non-activatable analogue SMSN-ZnPc2 has also been prepared as a negative control. The fluorescence emission and singlet oxygen generation of the photosensitizer are essentially quenched in the intact nanophotosensitizer. However, these properties of SMSN-ZnPc1 can be restored greatly both in acidic solutions and at the cellular level. More importantly, after intravenous administration, SMSN-ZnPc1 can also be selectively activated at the tumor site and exhibit efficient tumor growth inhibition in S180 rat ascitic tumor-bearing KM mice with negligible systemic toxicity. It thus may serve as a promising nanoplatform for cancer diagnosis and targeted PDT. PMID- 30426114 TI - J-Aggregate squaraine nanoparticles with bright NIR-II fluorescence for imaging guided photothermal therapy. AB - We introduce a novel strategy to enhance the fluorescence brightness of organic molecule-based nanoparticles in the second near-infrared window (NIR-II, 1000 1700 nm) by fabricating J-aggregate nanoparticles SQP-NPs(J). Our prepared J aggregate nanoparticles SQP-NPs(J) show an emission maximum near 1100 nm, and the emission intensity is 4.8-fold higher than that of H-aggregate SQP-NPs(H). In addition, SQP-NPs(J) can be used for NIR-II imaging guided photothermal therapy on MCF-7 tumor-bearing mice due to the fact that SQP-NPs(J) have highly effective photothermal properties, which are significant for precise tumor diagnostics and treatments. PMID- 30426115 TI - Correction: ZIF-8@polyoxometalate derived Si-doped ZnWO4@ZnO nanocapsules with open-shaped structures for efficient visible light photocatalysis. AB - Correction for 'ZIF-8@polyoxometalate derived Si-doped ZnWO4@ZnO nanocapsules with open-shaped structures for efficient visible light photocatalysis' by Jingyu Ran et al., Chem. Commun., 2018, DOI: . PMID- 30426116 TI - The influence of electrically conductive and non-conductive nanocomposite scaffolds on the maturation and excitability of engineered cardiac tissues. AB - Utilization of electrically conductive nanomaterials for developing nanocomposite scaffolds has been at the center of attention for engineering functional cardiac tissues. The primary motive in the use of conductive nanomaterials has been to develop biomimetic scaffolds to recapitulate the extracellular matrix (ECM) of the native heart and to promote cardiac tissue maturity, excitability and electrical signal propagation. Alternatively, it is well accepted that the inclusion of nanomaterials also alters the stiffness and nano-scale topography of the scaffolds. However, what is missing in the literature is that to what extent the sole presence of nanomaterials within a scaffold, regardless of their conductivity, influences the maturation and excitability of engineered cardiac tissues. To address this knowledge gap, we developed four different classes of gelatin methacrylate (GelMA) hydrogels, with varied concentrations, embedded electrically conductive gold nanorods (GNRs) and non-conductive silica nanomaterials (SNPs), to assess the influence of matrix stiffness and the presence of nanomaterials on cardiac cell adhesion, protein expression (i.e. maturation), and tissue-level excitability. Our results demonstrated that either embedding nanomaterials (i.e. GNRs and SNPs) or increasing the matrix stiffness significantly promoted cellular retention and the expression of cardiac-specific markers, including sarcomeric alpha-actinin (SAC), cardiac troponin I (cTnI) and connexin43 (Cx43) gap junctions. Notably, excitation voltage thresholds at a high frequency (i.e. 2 Hz and higher), in both coupled and uncoupled gap junctions induced by heptanol, were lower for scaffolds embedded conductive GNRs or non conductive SNPs, independent of matrix stiffness. Overall, our findings demonstrated that the sole presence of nanomaterials within the scaffolding matrix had a more pronounced influence as compared to the scaffold stiffness on the cell-cell coupling, maturation and excitability of engineered cardiac tissues. PMID- 30426118 TI - RRAM-based synapse devices for neuromorphic systems. AB - Hardware artificial neural network (ANN) systems with high density synapse array devices can perform massive parallel computing for pattern recognition with low power consumption. To implement a neuromorphic system with on-chip training capability, we need to develop an ideal synapse device with various device requirements, such as scalability, MLC characteristics, low power operation, data retention, and symmetric/linear conductance changes under potentiation/depression modes. Although various devices have been proposed for synapse applications, they have limitations for application in neuromorphic systems. In this paper, we will cover various RRAM synapse devices, such as filamentary switching RRAM (HfOx, TaOx, Cu-CBRAM) and analog RRAM devices, based on interface resistive switching (Pr0.7Ca0.3MnOx and TiOx) and ferroelectric polarization (HfZrOx). By optimizing potentiation/depression conditions, we could improve the conductance linearity and MLC characteristics of filamentary synapse devices. Interface RRAM has better MLC characteristics with limited retention and conductance linearity. By controlling the reactivity of metal electrodes and the oxygen concentration in oxides, we can modulate the synapse characteristics. Metal-Ferroelectric Insulator-Semiconductor (MFIS) FET devices exhibit good retention characteristics and analog memory characteristics due to polarization. Based on various synapse device characteristics, we have estimated the pattern recognition accuracy of MNIST handwritten digits and CIFAR-10 datasets. We have confirmed that synapse device characteristics directly affect the pattern recognition accuracy of ANNs. In order to simultaneously satisfy all the requirements of synapse devices, it is necessary to develop new technology capable of controlling the movement of oxygen vacancies and metal ions at the atomic scale. Considering the limited synapse characteristics of current 2-terminal RRAM devices, hardware ANNs capable of only off-chip training can be constructed by optimizing the current RRAM devices by limiting the bit number. A 3-terminal synapse device or a device based on a new operation principle should be developed as an alternative for on-chip training applications. PMID- 30426120 TI - Adsorption and diffusion of lithium polysulfides over blue phosphorene for Li-S batteries. AB - Lithium-sulphur (Li-S) batteries suffer from capacity loss due to the dissolution of lithium polysulfides (LiPSs). Although finding cathodes that can trap LiPSs strongly is a possible solution to suppress the "shuttle" effect, fast diffusion of lithium and LiPSs is also pivotal to prevent agglomeration. We report that monolayer blue phosphorene (BP), a recently synthesized two-dimensional material, possesses these characteristics as a cathode in Li-S batteries. Density functional theory calculations showed that while the adsorption energies (Eb) of various LiPSs over pristine BP are reasonably strong (from -0.86 eV to -2.45 eV), defect engineering of the lattice by introducing a single vacancy (SV) increased the binding strength significantly, with Eb in the range of -1.41 eV to -4.34 eV. Ab-initio molecular dynamics simulations carried out at 300 K showed that the single vacancies trap the Li atoms in the LiPSs compared to pristine BP. Projected density of states revealed that the creation of an SV induces metallicity in the cathode. Furthermore, an increase in the adsorption strength did not cause significant structural deformation, implying that the soluble large LiPSs did not decompose, which is essential to suppress capacity fading. The energy barriers for LiPSs' migration over pristine BP are minimal to ensure ultrafast diffusion, with the lowest diffusion energy barriers being 0.23 eV, 0.13 eV and 0.18 eV for Li2S4, Li2S6 and Li2S8, respectively. Furthermore, the energy barrier associated with the catalytic oxidation of Li2S over pristine and defective BP was found to be greater than three times smaller compared to graphene, which suggests that charging processes could be faster by orders of magnitude. Therefore, BP with a suitable combination of defects would be an excellent cathode material in Li-S batteries. PMID- 30426121 TI - Transformation of carbon-supported Pt-Ni octahedral electrocatalysts into cubes: toward stable electrocatalysis. AB - Octahedral Pt-Ni catalyst nanoparticles (NPs) are predicted to exhibit high activity for the oxygen reduction reaction. However, until now this class of catalysts has been limited by its long-term performance, as a result of compositional and morphological instabilities of the NPs. In situ transmission electron microscopy (TEM) is a powerful technique for understanding morphological and compositional evolution under controlled conditions. It is of great importance to study the evolution of the morphology and elemental distribution in bimetallic NPs and their interaction with the support in reducing and oxidizing treatments at the atomic scale for the rational design of catalysts. Here, we use in situ TEM to follow dynamic changes in the NP morphology, faceting and elemental segregation under working conditions in previously unreported Pt-Ni core-shell octahedral structures. We follow changes in the Pt-Ni catalyst from a segregated structure to an alloyed shell configuration and then a more spherical structure as a function of temperature under reducing conditions. Exposure to an oxidizing environment then leads to oxidation of the C support, while the spherical NPs undergo a cycle of transformations into cubic NPs followed by the reaction to spherical NPs. The formation of the cubic NPs results from CO formation during C oxidation, before it is finally oxidized to CO2. Our observations may pave the way towards the design of optimized structure-stability electrocatalysts and highlight the importance of TEM visualization of degradation and transformation pathways in bimetallic Pt-Ni NPs under reducing and oxidizing conditions. PMID- 30426122 TI - The effects of resveratrol supplementation on biomarkers of inflammation and oxidative stress among patients with metabolic syndrome and related disorders: a systematic review and meta-analysis of randomized controlled trials. AB - There are several current trials investigating the effect of resveratrol supplementation on biomarkers of inflammation and oxidative stress among patients with metabolic syndrome (MetS); however, their findings are controversial. This systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted to summarize the existing evidence and collectively determine the effects of resveratrol supplementation on biomarkers of inflammation and oxidative stress among patients with MetS and related disorders. Two authors independently searched electronic databases, including MEDLINE, EMBASE, Cochrane Library, and Web of Science databases, until May 2018 in order to find relevant RCTs. The quality of the selected RCTs was evaluated using the Cochrane Collaboration risk of bias tool. Cochran's Q test and I-square (I2) statistic were used to determine whether heterogeneity exists across included trials. Standardized mean difference (SMD) and 95% CI between two intervention groups were used to determine pooled effect sizes. Out of 317 potential citations selected based on keywords, 24 RCTs met the inclusion criteria and were eligible for the current meta-analysis. The pooled results obtained by using the random effects model showed that resveratrol supplementation significantly decreased C reactive protein (CRP) (SMD = -0.55; 95% CI, -0.84, -0.26; P < 0.001; I2: 84.0) and tumor necrosis factor-alpha (TNF-alpha) (SMD = -0.68; 95% CI, -1.08, -0.28; P = 0.001; I2: 81.3) concentrations among patients with MetS and related disorders. Interleukin 6 (IL-6) (SMD = 0.05; 95% CI, -0.31, 0.41; P = 0.79; I2: 85.0) and superoxide dismutase (SOD) (SMD = 0.21; 95% CI, -3.16, 3.59; P = 0.90; I2: 97.7) concentrations did not significantly change following resveratrol supplementation. Resveratrol supplementation showed a promising lowering effect on some of the inflammatory markers among patients with MetS and related disorders. Additional prospective studies regarding the effect of resveratrol supplementation on biomarkers of inflammation and oxidative stress by using higher doses of resveratrol and longer duration of supplementation are necessary. PMID- 30426126 TI - Manipulation of a floating liquid marble using dielectrophoresis. AB - A liquid marble is a microliter-sized droplet coated with hydrophobic powder. The porous coating prevents the liquid content from being in direct physical contact with its surroundings, making the liquid marble perfectly non-wetting. On the one hand, the non-wetting ability allows the liquid marble to float and move across a liquid surface with little resistance. On the other hand, the porosity enables gas exchange between the liquid marble and its surroundings. These properties allow the liquid marble to serve as a bioreactor platform for important applications such as cell culture. Liquid marbles floating on a free liquid surface prevent evaporation due to the high humidity near the liquid surface. Moving a floating liquid marble allows for stirring and mixing inside the liquid marble. This paper reports a novel technique for manipulating a floating liquid marble using dielectrophoresis. A relatively simple setup can move liquid marbles of various sizes across the water surface at high speeds. We also present an analytical model to model and accurately predict the motion of the floating liquid marble. The technique reported here potentially allows for high-throughput and efficient handling of floating liquid marbles as a digital microfluidics platform. PMID- 30426127 TI - Influence of Ni/Mn distributions on the structure and electrochemical properties of Ni-rich cathode materials. AB - To reveal the influence of element distribution on the structure and electrochemical performances of Ni-rich layered cathode materials, LiNi0.68Co0.13Mn0.19O2 (NCM) with four types of Ni/Mn distributions (homogeneous, core-shell, multi-shell and concentration-gradient structures) is designed and synthesized with a combination of co-precipitation and high-temperature solid state method. Ni/Mn distributions of the as-prepared NCM cathode materials are investigated with focused ion beam (FIB) and energy disperse X-ray spectrum (EDS) line scanning on the cross-section of single particles, which illustrate that NCM materials with the desired Ni/Mn distributions are successfully prepared. For the three spherical heterogeneous NCM materials, the center is the Ni-rich component while the surface is the Mn-rich component. Ni/Mn distributions between the center and surface components are in different forms. Studies imply that the heterogeneous samples exhibit smaller cation disordering, lower charge transfer resistance, higher Li+ diffusion coefficient and higher structural stability than the homogeneous one. Therefore, the heterogeneous samples, especially the multi shell and concentration-gradient ones, display improved cycling and thermal stability compared to the homogeneous one. These results manifest that multi shell and concentration-gradient structures are effective strategies to modify the layered NCM cathode materials for Li-ion batteries. PMID- 30426128 TI - Ag-Cu oxide nanoparticles with high oxidation states: towards new high Tc materials. AB - In Ag-Cu oxides possible to fabricate so far, superconductivity has not been detected, but high conductivity was. In the quest for superconductivity the demand is to create a high and peculiar copper-oxygen coordination. Such coordination makes it non-trivial to determine Cu oxidation states, which may be several and co-existing. Another reason for uncertainty is in oxygen deficiency typical for superconducting crystals. Finally, Cu oxidation is influenced by the other metals in the substance. For chemical fabrication the difficulty is to tune the relative abundances of elements in a fine way. Ag-Cu oxides have been also produced by reactive co-sputtering of Cu and Ag, but the composition with high Cu oxidation states necessary for high conductivity has not been realized. In the present work we have fabricated Ag-Cu-oxide nanoparticles containing Cu and Ag in high oxidation states actual for superconductivity. The fabrication includes reactive sputtering of Ag and Cu metals, their vapour oxidation and aggregation into nanoparticles. The ability to create different and high oxidation states, also co-existing, is demonstrated. The fabrication approach also allows overcoming the poor miscibility of Cu and Ag. The nanoparticle composition and the oxidation states could be determined due to an experimental arrangement in which photoelectron spectroscopy is applied to free nanoparticles in a beam in vacuum, what allows avoiding any contact of the particles to a substrate or atmosphere. The combination of the fabrication and characterization methods has proven to be a powerful approach when fine composition tuning and control are desirable. PMID- 30426129 TI - Potential for city parks to reduce exposure to BTEX in air. AB - Benzene, toluene, ethylbenzene, and xylenes (BTEX) are hazardous air pollutants commonly found in outdoor air. Several studies have explored the potential of vegetation to mitigate BTEX in outdoor air, but they are limited to a northern temperate climate and their results lack consensus. To investigate this subject in a subtropical climate, we deployed passive air samplers for two weeks in parks and outside nearby residences at four locations: three in an urban area and one in a rural area in Alabama, USA. All BTEX concentrations were below health-based guidelines and were comparable to those found in several other studies in populated settings. Concentrations of TEX, but not benzene, were 3-39% lower in parks than at nearby residences, and the differences were significant. Site type (park vs. residential) was a significant predictor of TEX concentrations, while distance to the nearest major road was a significant predictor of BTX concentrations. In and around two of the parks, toluene : benzene ratios fell outside the range expected for vehicular emissions (p < 0.01), suggesting that there were additional, industrial sources of benzene near these two locations. The ratio of m-,p-xylene : ethylbenzene was high at all locations except one residential area, indicating that BTEX were freshly emitted. Concentrations of individual BTEX compounds were highly correlated with each other in most cases, except for locations that may have been impacted by nearby industrial sources of benzene. Results of this study suggest that parks can help reduce exposure to TEX by a modest amount in some situations. PMID- 30426130 TI - Protic additives or impurities promote imine reduction with pinacolborane. AB - We report here that addition of stoichiometric amounts of alcohols or water to mixtures of imines and pinacolborane promote reduction reactions. The reactions of several imines were examined, revealing that alkyl imines were reduced, while aniline derived imines were not effectively reduced. The use of binol as an additive resulted in modest enantioinduction, however other chiral additives that were screened gave negligible enantioinduction. While the reactions described herein are not competitive in conversion with established imine reduction technologies, this work reveals that the presence of protic impurities must be considered as a promoter of side reactions in catalyzed imine hydroborations. Amines also promote imine reduction in certain cases, raising the possibility of a slow autocatalytic reaction. The ability of water or other protic impurities to promote the reduction of imines with pinacolborane represents an important identification of a potential source of background reaction in catalyzed reductions of imines. PMID- 30426131 TI - A mononuclear cobalt complex for water oxidation: new controversies and puzzles. AB - Herein the role of a mononuclear cobalt(iii) complex, [CoIII(DPKOH)2]ClO4 (DPK = di(2-pyridyl)ketone), in the water electrooxidation process is investigated with scanning electron microscopy, energy dispersive spectrometry, X-ray diffraction studies, NMR, chronoamperometry, cyclic voltammetry, extended X-ray absorption fine structure and X-ray absorption near edge structure determination. Our experiments show that, in comparison to the reported literature, other cobalt containing structures on the surface of the FTO electrode could also be the true catalyst for water oxidation. PMID- 30426132 TI - Risk Factors for Penile Intraepithelial Neoplasia: A Population-based Register Study in Sweden, 2000-2012. AB - Studies on risk factors for penile intraepithelial neoplasia have been small in size, have not distinguished penile intraepithelial neoplasia from invasive cancer, and have relied on self-reported information. This study investigated risk factors for penile intraepithelial neoplasia in a cohort of 580 penile intraepithelial neoplasia cases and 3,436 controls using information from 7 Swedish registers. Cases with penile intraepithelial neoplasia had increased odds ratios (ORs) for inflammatory skin diseases (14.7, 95% CI 6.5-33.4) including lichen ruber (12.0, 95% CI 3.0-48.0), indicating lichen ruber to be an important risk factor. Increased ORs were also observed for diseases of the prepuce (4.0, 95% CI 2.2-7.4), immunosuppressive drugs (5.0, 95% CI 2.5-9.8), penile surgical procedures (4.8, 95% CI 2.2-10.8), balanitis (9.2, 95% CI 5.0-16.8), genital warts (9.9, 95% CI 4.3-22.7) and organ transplantation (7.0, 95% CI 2.4-20.8). This study demonstrates important risk factors for penile intraepithelial neoplasia, providing knowledge that can help prevent the development of penile cancer. PMID- 30426133 TI - Effects of mechanical inspiration and expiration exercise on velopharyngeal incompetence in subacute stroke patients. AB - OBJECTIVE: To investigate the therapeutic effects of mechanical inspiration and expiration exercise using mechanical cough assist on velopharyngeal incompetence in patients with subacute stroke. DESIGN: Pilot, randomized controlled study. SETTING: University-based rehabilitation centre. SUBJECTS: Thirty-six patients with subacute stroke diagnosed with velopharyngeal incompetence by videofluoroscopic swallowing study. METHODS: Subjects were randomly assigned to 2 groups. The study group received conventional dysphagia therapy and additional mechanical inspiration and expiration exercise. The control group received conventional dysphagia therapy only. Swallowing function was evaluated according to the American Speech-Language-Hearing association scale, functional dysphagia score, and the penetration aspiration scale, based on the videofluoroscopic swallowing study. Coughing function was measured using peak cough flow. RESULTS: Eighteen patients in each group completed the protocol and were analysed. After treatment, the study group showed significant improvement in functional dysphagia score with regard to nasal penetration degree. Comparing the treatment effect between the 2 groups, nasal penetration degree and peak cough flow showed greater improvement in the study group. CONCLUSION: Mechanical inspiration and expiration exercise had a therapeutic effect on velopharyngeal incompetence in subacute stroke patients with dysphagia. This therapy is easy to provide clinically and could be a useful therapeutic strategy for velo-pharyngeal incompetence with dysphagia in patients with stroke. PMID- 30426134 TI - A Case of Interstitial Lung Disease and Autoimmune Thyroiditis Associated with Ustekinumab. PMID- 30426135 TI - Acrokeratosis Paraneoplastica-like Findings as a Manifestation of Systemic Lupus Erythematosus. PMID- 30426136 TI - System complexities affecting recovery after a minor transport-related injury: The need for a person-centred approach. AB - OBJECTIVE: To understand clients' experiences of the recovery journey through the compensation system and to identify areas and strategies for quality improvement. METHODS: A qualitative study of 23 participants with physical or mental disabilities caused by traffic accidents, which occurred, on average, 4 years ago. Purposive sampling of long-term recovery clients who made a compensation claim after their injuries was applied until data saturation was reached. Data were collected using semi-structured interviews and analysed through conventional thematic analysis. RESULTS: This study demonstrated that recovery is a complex phenomenon that can be impacted by numerous challenges of navigating the compensation system and using its services. Clients perceived the compensation provider as limited in rules around which services they could access. A common perception amongst clients was that the compensation provider did not have the capacity and knowledge to understand health and recovery processes nor did it provide adequate guidelines or instructions that would assist clients with their recovery. Many clients dealt with numerous case managers and felt insufficiently informed on what to expect and do, which led to a lack of trust in rehabilitation management and case managers' decisions. According to clients, financial impacts were neglected and not addressed effectively. Many clients felt abandoned by the system which led to perceived feelings of desertion and negligence. CONCLUSION: Understanding modifiable barriers to recovery in compensation systems presents opportunities to amend current practices and consider a holistic, person-centred care approach. It is apparent that improved recovery management, communication and adequate provision of guidelines are needed to meet clients' needs and facilitate better outcomes. A person-centred care approach is likely to improve quality of life and help clients navigate the compensation system more effectively with assistance from health and compensation professionals, who should be actively involved in their recovery processes. PMID- 30426137 TI - Socioeconomic Status and the Prevalence of Skin and Atopic Diseases in Five European Countries. AB - The aim of this study was to investigate the association between socioeconomic status and the prevalence of self-reported skin and atopic diseases in the general population of 5 European countries. A random sample was drawn from the general population aged 18-74 years, based on electoral precincts. Socioeconomic status was estimated by combining net household income with the highest education of respondents. A total of 7,904 subjects were included in this analysis. The lifetime prevalence of "contact dermatitis" ranged from 13.1% (95% confidence interval (95% CI 11.8-14.4%) in subjects with low socioeconomic status, to 19.1% (95% CI 17.5-20.8%) in those with high socio-economic status. In younger subjects skin cancer was more prevalent in the middle or high socioeconomic status groups compared with the low socioeconomic status group (odds ratio 2.4; 95% CI 1.4 4.3); however, this effect was not found in elderly subjects. The lifetime prevalence for at least 1 atopic disease was 61.2% (95% CI 59.4-63.0%) in the low and 82.8% (95% CI 81.1-84.3%) in the high socioeconomic status group. Individuals with middle or high socioeconomic status reported an overall higher prevalence of skin and atopic diseases compared with those with low socioeconomic status. These findings may reflect differences in reporting, which are likely to result in an underdiagnoses, especially for skin cancer in the younger age groups with low socioeconomic status. PMID- 30426138 TI - Factors associated with persistent post-concussion symptoms following mild traumatic brain injury in adults. AB - OBJECTIVES: Debate regarding factors associated with persistent symptoms following mild traumatic brain injury continues. Nested within a trial aiming to change practice in emergency department management of mild traumatic brain injury, this study investigated the nature of persistent symptoms, work/study outcomes, anxiety and quality of life and factors associated with persistent symptoms following injury, including the impact of receiving information about mild traumatic brain injuries in the emergency department. METHODS: A total of 343 individuals with mild traumatic brain injury completed the Rivermead Post Concussion Symptom Questionnaire, Hospital Anxiety Depression Scale - Anxiety Scale, and Quality of Life - Short Form in average 7 months post-injury. RESULTS: Overall, 18.7% of participants reported 3 or more post-concussional symptoms, most commonly fatigue (17.2%) and forgetfulness (14.6%). Clinically significant anxiety was reported by 12.8%, and was significantly associated with symptom reporting, as were mental and physical quality of life scores. Significant predictors of post-concussional symptoms at follow-up were pre-injury psychological issues, experiencing loss of consciousness, and having no recall of receiving information about brain injury in the emergency department. CONCLUSION: This study confirms that loss of consciousness and pre-injury psychological issues are associated with persistent symptom reporting. Not receiving injury information in the emergency department may also negatively influence symptom reporting. PMID- 30426139 TI - Treatment strategies for ischiofemoral impingement: a systematic review. AB - PURPOSE: There has been relatively little information about the treatment for ischiofemoral impingement (IFI) because of its rarity as well as the uncertainty of diagnosis. The aim of this study was to provide the reader with the available treatment strategies and their related outcomes for IFI based on the best available evidence, whilst highlighting classically accepted ways of treatment as well as relatively new surgical and non-surgical techniques. METHODS: A systematic review of the literature from Medline, Embase, AMED, Cochrane and Google Scholar was undertaken since inception to December 2017 following the PRISMA guidelines. Clinical outcome studies, prospective/retrospective case series and case reports that described the treatment outcome for IFI were included. Animal or cadaveric studies, trial protocols, diagnostic studies without any description of treatments, technical notes without any results, and review articles were excluded. RESULTS: This systematic review found 17 relevant papers. No comparative studies were included in the final records for qualitative assessment, which means all the studies were case series and case reports. Eight studies (47.1%) utilised non-surgical treatment including injection and prolotherapy, followed by endoscopic surgery (5 studies, 29.4%) then open surgery (4 studies, 23.5%). Mean age of the participants was 41 years (11-72 years). The mean follow-up was 8.4 months distributed from 2 weeks to 2.3 years. No complications or adverse effects were found from the systematic review. CONCLUSION: Several treatment strategies have been reported for IFI, and most of them have good short- to medium-term outcomes with a low rate of complications. However, there are no comparative studies to assess the superiority of one technique over another, thus further research with randomised controlled trials is required in this arena. This study explores the wide variety and categories of different treatments used for IFI to guide physicians and shed light on what can be done for this challenging cohort of patients. LEVEL OF EVIDENCE: III. PMID- 30426140 TI - Academic conflict of interest. AB - PURPOSE: We set out to summarize the current challenges in academic conflict of interest. METHODS: This is a narrative review by a multidisciplinary, multinational panel of academic officers including deans of medical/pharmacy schools. RESULTS AND CONCLUSIONS: Disclosing conflict of interest has become the appropriate professional behavior since the 1990s in response to the necessity to fix moral and financial fences around medical activities. The nature of the conflict of interest is academic when either the conflict relates to academic duties and/or the nature of the interest is academic. People usually distinguish between real conflict of interest, when private interest overtly influences one's professional obligations; potential conflict of interest, when there is no obvious direct link between a person interests and current duties without ruling out that expected changes in duties cause a situation of conflict; and apparent conflict of interest, when the risk does not really exist, but serious doubts remain. Areas at risk of academic conflict of interest include peer review process for grant evaluation or journals, scientific communications such as elaborating and disseminating clinical guidelines, lecturing at meeting, advising decision-makers, teaching activities, and mentoring. The management of academic conflict of interest should consider actions in four domains, i.e., education, prevention, measures for enforcement and solving, and communication. Academic conflicts of interest are as frequent as financial conflicts but more difficult to identify and assess, and much less addressed in the literature. Generating more evidence from high-quality research is mandated to improve the management of academic and more generally non-financial conflicts of interest. PMID- 30426141 TI - Total Mercury in Plant Tissue from a Mining Landscape in Western Mexico. AB - Environmental impacts of mining activities are well known, particularly on-site degradation, but long term effects are less known. Mercury content from vegetation samples from a mine dump and surrounding forests was quantified for understanding the fate of this element in the local the environment. The study area, Tlalpujahua, Michoacan, Mexico, has a mining history going back more than 400 years. Including gold and silver extraction by means of mercury amalgamation for 352 years (1554-1906). Mercury was present in all sampled materials. The highest values correspond to wood samples from the mine dump (13.84 +/- 3.88 ppm), while wood samples from adjacent forests had 4.3 +/- 2.4 ppm, almost twice as much as coniferous needles, shrub leaves and corn seeds (2.2 +/- 0.34 ppm). The highest concentration was found for J. deppeana wood (16.05 +/- 2.3 ppm). The capacity of accumulating mercury by Juniperus trees when growing on the mine dumps suggests that this species has a potential to be used for biosequestration purposes. PMID- 30426142 TI - An investigation of the effects of N-acetylcysteine on radiotherapy-induced testicular injury in rats. AB - According to data issued by the International Agency for Research on Cancer in 2012, the estimated number of new cases of all types of cancer worldwide was estimated to exceed 10 million, and 6 million of whom receive radiotherapy. Radiotherapy is the treatment of cancer using ionizing radiation. Our study investigated the effects of x-radiation resulting from radiotherapy (RT) on the testis at the molecular level, and prospectively considered the potential protective characteristics of antioxidants against testicular damage resulting from x-radiation. Forty male Sprague Dawley rats were allocated into five groups, control (group 1), abdominopelvic region 2-Gy-ionizing radiation (group 2), whole body 6-Gy irradiation (group 3), 2 Gy abdominopelvic region irradiation and 300 mg/kg NAC treatment (group 4), and 6-Gy whole-body irradiation and 300 mg/kg NAC treatment (group 5). Disorganization and vacuolization were observed in the epithelial layer in atrophic seminiferous tubules in the only ionizing radiation (IR) groups. In addition, Johnsen's score decreased in the only IR groups, while testis tissue malondialdehyde (MDA) and glutathione (GSH) tissue levels increased. N-Acetylcysteine (NAC) treatment groups Johnsen's score and tissue GSH levels increased than only IR groups. On the other hand, tissue MDA levels decreased in the NAC treatment groups. The findings showed that ionizing radiation caused apoptosis in germinal epithelial cells led to the oxidative stress-mediated testicular injury. On the other hand, NAC may be useful in the prevention of testicular injury-suppressed ROS production. PMID- 30426143 TI - Ratiometric fluorescence probe of MIPs@CdTe QDs for trace malachite green detection in fish. AB - A facile and practical ratiometric fluorescence probe based on two CdTe quantum dots (QDs) coated with molecularly imprinted polymers (MIPs) was prepared for the detection of trace malachite green (MG) in fish. Two CdTe QDs coated with MIPs were fabricated by a one-pot method using MG, (3-aminopropyl) triethoxysilane (APTES) and tetraethyl orthosilicate (TEOS) as template, functional monomer, and cross-linker, respectively. CdTe QDs with lambdaem 530 nm (gQDs) and 630 nm (rQDs) were used as the referential fluorophore and target sensitive fluorophore, respectively. The fluorescence intensity of gQDs remained unchanged in the presence of MG, while the fluorescence of rQDs could be quantitatively quenched by MG based on the strategy of fluorescence resonance energy transfer. The ratiometric fluorescence probe (MIPs@gQDs&rQDs) was characterized by transmission electron microscopy and Fourier transform infrared spectroscopy. The linear range of MG detection was 0.1-32 MUmol L-1 with a detection limit of 8.8 MUg kg-1. The constructed probe has been successfully applied to the detection of MG in fish with the recoveries of 92.3-109.1%, which were validated by the method of HPLC. The result indicated that the probe possessed rapid response, wide linear range, high sensitivity, and relatively high selectivity, and was low-cost and easy in operation in the detection of MG in fish samples. PMID- 30426145 TI - Reply: "Developmental venous anomaly depicted incidentally in fetal MRI and confirmed in post-natal MRI". PMID- 30426144 TI - Delineation of the Genera Haemoproteus and Plasmodium Using RNA-Seq and Multi gene Phylogenetics. AB - Members of the order Haemosporida are protist parasites that infect mammals, reptiles and birds. This group includes the causal agents of malaria, Plasmodium parasites, the genera Leucocytozoon and Fallisia, as well as the species rich genus Haemoproteus with its two subgenera Haemoproteus and Parahaemoproteus. Some species of Haemoproteus cause severe disease in avian hosts, and these parasites display high levels of diversity worldwide. This diversity emphasizes the need for accurate evolutionary information. Most molecular studies of wildlife haemosporidians use a bar coding approach by sequencing a fragment of the mitochondrial cytochrome b gene. This method is efficient at differentiating parasite lineages but insufficient for accurate phylogenetic inferences in highly diverse taxa such as haemosporidians. Recent studies have utilized multiple mitochondrial genes (cyt b, cox1 and cox3), sometimes combined with a few apicoplast and nuclear genes. These studies have been highly successful with one notable exception: the evolutionary relationships of the genus Haemoproteus remain unresolved. Here we describe the transcriptome of Haemoproteus columbae and investigate its phylogenetic position recovered from a multi-gene dataset (600 genes). This genomic approach restricts the taxon sampling to 18 species of apicomplexan parasites. We employed Bayesian inference and maximum likelihood methods of phylogenetic analyses and found H. columbae and a representative from the subgenus Parahaemoproteus to be sister taxa. This result strengthens the hypothesis of genus Haemoproteus being monophyletic; however, resolving this question will require sequences of orthologs from, in particular, representatives of Leucocytozoon species. PMID- 30426146 TI - A back and forth manual aspiration technique using a SOFIA Plus catheter for acute ischemic stroke: technical note. AB - PURPOSE: We describe a new modification of thromboaspiration to facilitate recanalization, referred to as the "back and forth" manual aspiration technique. METHODS: In this technique, the aspiration catheter (SOFIA Plus catheter, MicroVentionInc, Tustin, CA, USA) is positioned adjacent to the occluded segment and then advanced over the thrombus during manual aspiration with a 50-cc syringe. RESULTS: We evaluated this technique in 15 patients who presented to our institution with acute ischemic stroke (AIS). Final mTICI 2b/3 was achieved in 86.6% of the patients with the sole use of this new aspiration technique. No dissection, rupture, or downstream emboli were associated with the procedure. The mean time from puncture to revascularization was 35 min. CONCLUSION: This modified technique with back and forth movements of the SOFIA Plus catheter over the thrombus during aspiration may facilitate thrombectomy in AIS. However, further studies in larger groups are necessary to elucidate its efficacy and to compare with current techniques. PMID- 30426147 TI - Enhanced vestibulo-ocular reflex suppression in dancers during passive high velocity head impulses. AB - The vestibulo-ocular reflex (VOR) is responsible for stabilizing images on the fovea during head movements. However, in some situations, one needs to suppress the VOR to be able to follow a target moving along with the head. Evidence suggests that the visual mechanism underlying VOR suppression can be modulated by experience. Unfortunately, the non-visual mechanism underlying VOR suppression has never been examined in dancers and, consequently, it is still unsure whether dance training can enhance eye-head tracking accuracy. The goal of the present study was to look at the influence of dance training on the VOR suppression during passive head impulses. Twenty-four individuals participated, 12 controls and 12 dancers. VOR and VOR suppression were assessed using a head impulse paradigm as well as a suppression head impulse test paradigm (SHIMP) with video head impulse test, respectively. The results suggest that dancers display a significantly reduced VOR gain during the SHIMP at 60 ms in comparison to controls. Moreover, dancers with more than 10 years of dance training exhibited a significantly reduced VOR gain during the SHIMP at 60 ms. Overall, the results suggest that dance training improves VOR suppression, but also modulates VOR suppression abilities. Although studies are needed to shed light on the possible mechanisms involved in the modulation of the VOR gain, the observed changes in dancers' vestibulo-cerebellum and its role in the modulation of the VOR gain makes the cerebellar-vestibular nuclei pathway a possible model to explain the present results. PMID- 30426148 TI - Mirror-hand selection is influenced by training perspective and model skill level in a motor-learning task. AB - This study examined mirror and non-mirror arm selection processes in an observational learning context. Observer groups watched either a novice (instruction or discovery) or skilled model performing a bimanual task with the right arm leading the left arm. The models were viewed from a third-person perspective. Observers of the skilled model more often selected a mirror-image (left-hand) hand-lead in post-observations tests, while observers of the novice models more often selected a non-mirror image (right hand) hand-lead in post observation tests. This is a novel finding regarding arm selection processes in a learning context, yet it is consistent with imaging data that has revealed specific neural areas linked to the selection of mirror and non-mirror imitation processes for first- and third-person viewing perspectives. The skilled model also supported more accurate and stable performance of the bimanual task in observers compared to the instruction and novice models. It is concluded that a skilled model supports attention focus being directed at pattern analysis, while novice models support attention focus being allocated to strategy identification first, followed by pattern analysis. PMID- 30426149 TI - Radiotherapy of epicondylitis humeri : Analysis of 138 elbows treated with a linear accelerator. AB - BACKGROUND: Epicondylitis humeri is a common disease with a prevalence of 1.7%. One of the treatment options is radiotherapy. Most published cases were treated with the orthovoltage technique or with a telecobalt device. Many radiotherapy institutions are nowadays using linear accelerators for treatment of epicondylitis humeri. There is a discussion whether the treatment results with linear accelerators are comparable to the orthovoltage technique. The aim of this study was to analyze the results of radiotherapy with a linear accelerator for epicondylitis humeri. MATERIAL AND METHODS: The analysis was performed on patients of 2 German radiotherapy institutions and included 138 irradiated elbows. Pain was documented with the numeric rating scale (NRS). Evaluation of the NRS was done before and directly after each radiation therapy course as well as for the follow-up of 24 months. The median age of the patients was 49 years with 48.4% male and 51.6% female. In all, 81.0% were suffering from from epicondylitis humeri radialis while 16.7% were treated because of epicondylitis humeri ulnaris. In 65.4% the dominant arm was treated. RESULTS: A significant response to radiotherapy could be found. For the whole sample the median pain was 7 on the NRS before radiotherapy, 4 after 6 weeks and 0 after 12 and 24 months. The percentage of patients with 0 or 1 on the NRS was 64.6% 12 months after radiotherapy. All subgroups, notably those with epicondylitis humeri radialis and epicondylitis humeri ulnaris had a significant reduction of pain. CONCLUSION: Radiotherapy of epicondylitis humeri with a linear accelerator is an effective treatment without showing side effects. All analyzed subgroups showed a good response to radiotherapy for at least 24 months. PMID- 30426150 TI - Effect of Transcatheter Arterial Microembolization on Phantom Limb Pain Persisting for 17 Years. AB - Phantom limb pain is a frequent consequence of the amputation; currently available treatments are far from satisfactory. The present report describes a case in which transcatheter arterial microembolization had a remarkable curative effect on phantom limb pain persisting for 17 years. The patient began feeling phantom limb sensations and brief intermittent pain following lower limb amputation above the knee in 2001. The frequency, intensity, and duration of the pain increased over time, and it was resistant to conservative treatments. Following transcatheter arterial microembolization in 2018, patient immediately experienced marked improvement. The pain has been infrequent, much less intense, and did not interfere with daily life 6 months posttreatment. Transcatheter arterial microembolization could be an alternative treatment option for phantom limb pain. LEVEL OF EVIDENCE: IV, Case Report. PMID- 30426151 TI - Comparing diagnostic accuracy of 18F-FDG-PET/CT, contrast enhanced CT and combined imaging in patients with suspected vascular graft infections. AB - BACKGROUND: To evaluate the diagnostic accuracy of positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (PET/CT), contrast enhanced CT (CE-CT), and a combined imaging approach (CE-PET/CT) in patients with suspected vascular graft infection (VGI). METHODS: PET/CT and CE-CT were performed prospectively in 23 patients with suspected VGI. Diagnostic accuracy for PET/CT was assessed by using previously suggested cut-off points for maximum standardized uptake values (SUVmax) measured in the vicinity of the graft. Using a new 4-point scale for visual grading, two readers independently assessed the diagnostic accuracy for CE-CT and combined CE-PET/CT. Microbiological culture, obtained after open biopsy or graft explantation, and clinical follow-up of the patients served as the standard of reference. RESULTS: Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of PET/CT for the diagnosis of VGI was 100%, 50%, 100%, 72.2%, and 78.3%, using the most favorable SUVmax cut-off >= 4.9. Respective values for CE-CT were 100%, 50%, 100%, 72.2%, and 78.3% for reader 1, and 92.3%, 80%, 88.9%, 85.7%, and 86.9% for reader 2; while respective values for combined CE-PET/CT were 100%, 70%, 100%, 81.3%, and 86.9% for reader 1, and 100%, 80%, 100%, 86.7%, and 91.3% for reader 2. Additionally, imaging provided a conclusive clinical diagnosis in patients without graft infection (i.e., other sites of infection): five of ten patients with CE-CT, six of ten patients with PET/CT, and seven of ten patients with combined CE-PET/CT. CONCLUSION: The diagnostic accuracy of combined CE-PET/CT in patients with suspected VGI is very high. The combination of the high sensitivity of PET/CT in detecting metabolically active foci in infection, and the high specificity of CE-CT in detecting anatomic alterations, appears to be the reason why combined imaging outperforms stand-alone imaging in diagnosing VGI and may be supportive in future decision-making of difficult cases of suspected VGI. Clinical Trials.gov Identifier: NCT01821664. PMID- 30426153 TI - Microbial beta-mannosidases and their industrial applications. AB - Heteropolymers of mannan are polysaccharide components of the plant cell wall of gymnosperms and some angiosperms, including palm trees (Arecales and Monocot). Degradation of the complex structure of these polysaccharides requires the synergistic action of enzymes that disrupt the internal carbon skeleton of mannan and accessory enzymes that remove side chain substituents. However, complete degradation of these polysaccharides is carried out by an exo-hydrolase termed beta-mannosidase. Microbial beta-mannosidases belong to families 1, 2, and 5 of glycosyl hydrolases, and catalyze the hydrolysis of non-reducing ends of mannose oligomers. Besides, these enzymes are also involved in transglycosylation reactions. Because of their activity at different temperatures and pH values, these enzymes are used in a variety of industrial applications and the pharmaceutical, food, and biofuel industries. PMID- 30426152 TI - Empowering the immune fate of bone marrow mesenchymal stromal cells: gene and protein changes. AB - OBJECTIVE AND DESIGN: Bone marrow mesenchymal stromal cells (BM-MSCs) are referred as a promising immunotherapeutic cell product. New approaches using empowered MSCs should be developed as for the treatment or prevention of different immunological diseases. Such preconditioning by new licensing stimuli will empower the immune fate of BM-MSCs and, therefore, promote a better and more efficient biological. Here, our main goal was to establish the immunological profile of BM-MSCs following inflammatory priming and in particular their capacity to adjust their immune-related proteome and transcriptome. MATERIAL AND METHODS: To run this study, we have used BM-MSC cell cultures, a pro-inflammatory cytokine cocktail priming, flow cytometry analysis, qPCR and ELISA techniques. RESULTS: Different expression levels of several immunological mediators such as COX-1, COX-2, LIF, HGF, Gal-1, HO-1, IL-11, IL-8, IL-6 and TGF-beta were constitutively observed in BM-MSCs. Inflammation priming substantially but differentially modulated the gene and protein expression profiles of these mediators. Thus, expressions of COX-2, LIF, HGF, IL-11, IL-8 and IL-6 were highly increased/induced and those of COX-1, Gal-1, and TGF-beta were reduced. CONCLUSIONS: Collectively, we demonstrated that BM-MSCs are endowed with a specific and modular regulatory machinery which is potentially involved in immunomodulation. Moreover, BM-MSCs are highly sensitive to inflammation and respond to such signal by properly adjusting their gene and protein expression of regulatory factors. Using such preconditioning may empower the immune fate of MSCs and, therefore, enhance their value for cell-based immunotherapy. PMID- 30426154 TI - The co-existence of anammox genera in an expanded granular sludge bed reactor with biomass carriers for nitrogen removal. AB - Anaerobic ammonium oxidation (anammox)-based nitrogen removal saves aeration energy and organic carbon costs, attributed to its anaerobic and autotrophic nature. However, due to the slow growth of anaerobic ammonium oxidation bacteria (AnAOB), drawbacks including long startup time and sensitivity to toxins still hamper the application of anammox-based processes. To cope with the slow growth of AnAOB, various bioreactor configurations have been investigated for the capability of retaining anammox biomass, among which, the expanded granular sludge bed (EGSB) reactor is a promising option. In this study, two laboratory scale EGSB reactors were used to gain insights of microbial population and their response to amending biofilm-carriers, aiming to enhance the biomass retention of AnAOB. The respective ammonium and nitrite removal efficiencies were up to over 90%, and the overall nitrogen removal efficiency (NRE) was stable at over 70%, in the EGSB reactor amended with carriers (CEGSB). Compared to the control EGSB, CEGSB's observed performance was more stable during the 236-day operational period. The abundance of AnAOB reached 22% in the EGSB and 49% in the CEGSB. It was also observed that Ca. Brocadia (14.25%) and Asahi BRW2 (33.19%) coexisted in the CEGSB. The dynamics of major metabolisms and functional genes involved in nitrogen conversion were further observed by FAPROTAX based on the taxonomic data, providing more insights into the functions of the microbial communities. PMID- 30426155 TI - Macrophage-derived CCL18 promotes osteosarcoma proliferation and migration by upregulating the expression of UCA1. AB - Osteosarcoma (OS), which is the most common primary malignant bone tumor, has a high incidence of pulmonary metastasis. CCL18 (C-C motif chemokine ligand 18), which is secreted by tumor-associated macrophages (TAMs), has been found to be increased in various tumors and is associated with tumor metastasis. However, the role of CCL18 in OS remains unclear. Here, we evaluated the effect of CCL18 on the OS cell lines MG63 and 143B and explored its potential mechanisms. We found that CCL18 enhanced the proliferation and migration of OS cells and upregulated UCA1 through transcription factor EP300. Subsequently, we further revealed that the downstream Wnt/beta-catenin signaling pathway participated in this process. In addition, the high expression of CCL18 in both tissue and serum from patients was closely related to pulmonary metastasis and poor survival in OS patients. The tumor xenograft models also showed that CCL18 promoted the metastasis of OS cells. Collectively, our study indicated that macrophage-derived CCL18 promotes OS proliferation and metastasis via the EP300/UCA1/Wnt/beta-catenin pathway and that CCL18 may be used as a prognostic marker and therapeutic target of OS. KEY MESSAGES: CCL18 promotes proliferation and migration of osteosarcoma cells by EP300/ UCA1/ Wnt/beta-catenin pathway. CCL18+ TAMs are significantly correlated with pulmonary metastasis and poor survival in osteosarcoma patients. CCL18 may be used as a prognostic marker and therapeutic target for osteosarcoma. PMID- 30426156 TI - Epidemiological, clinical and genetic characterization of aplastic anemia patients in Pakistan. AB - Aplastic anemia (AA) is the most serious non-malignant blood disorder in Pakistan, ranked second in prevalence, after thalassemia. We investigated various epidemiological, clinical, and genetic factors of AA in a Pakistani cohort of 214 patients reporting at our hospital between June 2014 and December 2015. A control group of 214 healthy subjects was included for comparison of epidemiological and clinical features. Epidemiological data revealed 2.75-fold higher frequency of AA among males. A single peak of disease onset was observed between ages 10 and 29 years followed by a steady decline. AA was strongly associated with lower socioeconomic profile, rural residence, and high rate of consanguineous marriages. Serum granulocyte colony-stimulating factor and thrombopoietin levels were significantly elevated in AA patients, compared to healthy controls (P < 0.0001), while there was no statistical significance in other nine cytokine levels screened. Allele frequencies of DRB1*15 (56.8%) and DQB1*06 (70.3%) were predominantly high in AA patients. Ten mutations were found in TERT and TERC genes, including two novel mutations (Val526Ala and Val777Met) in exons 3 and 7 of TERT gene. Despite specific features of the AA cohort, this study suggests that epidemiologic and etiologic factors as well as host genetic predisposition exclusively or cooperatively trigger AA in Pakistan. PMID- 30426157 TI - Uncommon lymphoplasmacytic lymphoma with IgA paraproteinemia: a challenging clinical diagnosis solved by MYD88 mutation analysis. PMID- 30426158 TI - 6-MOMIPP, a novel brain-penetrant anti-mitotic indolyl-chalcone, inhibits glioblastoma growth and viability. AB - PURPOSE: 3-(6-Methoxy-2-methyl-1H-indol-3-yl)-1-(4-pyridinyl)-2-propene-1-one (6 MOMIPP) is a novel indole-based chalcone that disrupts microtubules. The present study aims to define the mechanism through which 6-MOMIPP induces cell death and to evaluate the efficacy of the compound in penetrating the blood-brain barrier and inhibiting growth of glioblastoma xenografts. METHODS: The effects of 6 MOMIPP were evaluated in cultured U251 glioblastoma cells, using viability, flow cytometry, and tubulin polymerization assays. Scintillation proximity and tubulin crosslinking methods were used to identify the binding site of 6-MOMIPP on tubulin, and western blots were performed to define the signaling pathways that contribute to cell death. LC/MS assays were used to study the pharmacokinetic behavior of 6-MOMIPP in mice. Subcutaneous and intracerebral xenograft models were utilized to assess the effects of 6-MOMIPP on growth of U251 glioblastoma in vivo. RESULTS: The findings indicate that 6-MOMIPP targets the colchicine site on beta-tubulin. At concentrations >= 250 nm, 6-MOMIPP induces mitotic arrest, caspase activation and loss of cell viability. Cells are protected by caspase inhibitors, pointing to an apoptotic mechanism of cell death. Loss of cell viability is preceded by activation of Cdk1(Cdc2) and phosphorylation of Bcl-2 and Bcl-xL. Inhibition of both events with a Cdk1 inhibitor prevents cell death. 6-MOMIPP has broad activity against the viability of multiple glioblastoma, melanoma and lung carcinoma cell lines. Viability of normal cells, including differentiated neurons, is not significantly affected at a drug concentration (1 uM) that reduces viability in most cancer lines. Pharmacokinetic studies in mice show that concentrations of 6-MOMIPP in the brain mirror those in the plasma, indicating that 6-MOMIPP readily penetrates the blood-brain barrier. Studies with mice bearing human U251 glioblastoma xenografts demonstrate that 6-MOMIPP is effective in suppressing growth of subcutaneous and intracerebral tumors without causing general toxicity. CONCLUSIONS: The results indicate that 6-MOMIPP is a novel microtubule disruptor that targets the colchicine binding site on beta tubulin to induce mitotic arrest and cell death. The ability of 6-MOMIPP to penetrate the blood-brain barrier and inhibit growth of glioblastoma xenografts suggests that it warrants further preclinical evaluation as potential small molecule therapeutic that may have advantages in treating primary and metastatic brain tumors. PMID- 30426159 TI - Wolbachia Population in Vectors and Non-vectors: A Sustainable Approach Towards Dengue Control. AB - Wolbachia is gram negative obligate endosymbiont known for reproductive manipulation in the host. It is important to study the presence of natural Wolbachia in mosquitoes which can later help in understanding the effect of transfected strain on indigenous strain. With this view, the present study is undertaken to focus on the prevalence, diversity, infection frequencies, phylogeny and density of indigenous Wolbachia strains in wild mosquito species of Odisha. Our study confirms Wolbachia presence in Ae. albopictus, Cx. quinquefasciatus, Cx. vishnui, Cx. gelidus, Ar. subalbatus, Mn. uniformis, and Mn. indiana. Wolbachia in the above mosquitoes were separated into two supergroups (A and B). Ae. albopictus, the major vector of dengue and chikungungunya had both super-infection and mono-infection. The ovaries of Ae. albopictus were highest in density of Wolbachia as compared to midguts or salivary glands. wAlBA and wAlbB density were variable in mosquitoes of F1 generation for both the sex and at different age. We also found that Wolbachia super-infection in females tends to increase whereas wAlbA density reduced completely as compared to wAlbB in males when they grew old. Giemsa stained squashed ovaries revealed pink pleomorphic Wolbachia cells with different shapes and forms. This study is unique in its kind covering the major aspects of the endosymbiont Wolbachia and focusing on its potential as a biocontrol agent in arboviral outbreaks. Knowledge on potential of the indigenous strain and interactions between Wolbachia and viruses can be utilized further to reduce the global burden of vector borne diseases. PMID- 30426160 TI - A Proposed Etiology for Atrial Tachyarrhythmia in Neonates with Atrial Septal Aneurysms. AB - An atrial septal aneurysm (ASA) is an increasingly recognized entity that involves septal tissue significantly bulging into either atria instead of remaining in a relatively neutral position. ASAs may be described based on the length of the segment of atrial septal tissue involved as well as the distance and direction of excursion into the atria throughout the cardiac cycle. Complications associated with ASA include arrhythmias and thromboembolic events with the latter usually in the context of atrial shunting. While the presence of an ASA has been implicated in the development of atrial tachyarrhythmias, no clear mechanism has been elucidated to-date. In this case, we document one of the previously proposed mechanisms of atrial arrhythmia using echocardiography imaging. PMID- 30426161 TI - How Does Socio-institutional Diversity Affect Collaborative Governance of Social Ecological Systems in Practice? AB - Social and institutional diversity ("diversity" hereafter) are important dimensions in collaborative environmental governance, but lack empirical assessment. In this paper, we examine three aspects of diversity hypothesized in the literature as being important in collaborative forms of environmental governance-the presence of diverse actors, diverse perspectives, and diverse institutions. The presence of these aspects and formative conjectures were empirically considered using a mixed methods approach in four biosphere reserves in Sweden and Canada. We found that the diversity of actors involved and domains of authority varied among cases, that stakeholder perspectives were highly diverse in all cases, and that institutional variety (in terms of strategies, norms, and rules) was evident in all cases, but differed among them. Empirical support from the cases further affirms that diversity contributes to the ability to engage with a broader set of issues and challenges; diversity contributes to novel approaches to solving problems within the governance group; and diversity contributes to the flexibility of the group involved in governance in terms of addressing challenges. One conjecture, that diversity decreases the efficiency of governance in decision-making and responding to issues, was not supported by the data. However, our analysis indicates that there might be a trade-off between diversity and efficiency. The findings highlight differences in the ways in which diversity is conceptualized in the literature and on the ground, emphasizing the pragmatic advantages of actively seeking diversity in terms of competencies and capacities. PMID- 30426162 TI - Expanding Staff Voice in Protected Area Management Effectiveness Assessments within Kenya's Maasai Mara National Reserve. AB - The concept of protected areas (PA) is one of the most widely used policy tools for biodiversity conservation including habitat and wildlife protection. Despite the importance and emphasis placed on protected area management, biodiversity is still in decline and more species are in danger of extinction. Some analyses have indicated that more than 40% of protected areas are poorly managed. To improve management effectiveness, the inclusion of diverse stakeholder information in articulating management strategies has been strongly encouraged; however, stakeholder involvement is often poorly integrated, and an opportunity granted only to select stakeholder groups, with PA staff, especially at lower organizational levels, minimally involved. Further, protected area management effectiveness (PAME) assessments are most frequently used as an aggregated outcome measure of effectiveness but these data should also inform management practice. Thus, for PA managers to obtain a greater understanding of issues impacting their effectiveness, they would benefit from including the voices of staff at all working levels. Therefore, the purpose of this investigation was to survey 135 wardens and rangers at all organizational levels from the two administrative sectors of Maasai Mara National Reserve to determine their perceptions of management effectiveness and to determine if significant differences existed across staff levels and administrative sectors. Significant differences were found to exist across staff levels and administrative authorities supporting the need for expanded staff voice in establishing effective PA management plans. PMID- 30426163 TI - Absorption of blue light by cigarette smoke components is highly toxic for retinal pigmented epithelial cells. AB - Lesion to the retinal pigment epithelium (RPE) is a crucial event in the development of age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries. Tobacco smoking and high-energy visible blue (HEV; 400-500 nm) light exposure are major environmental risk factors for AMD. Individually, they have been shown to cause damage to the RPE. Tobacco smoke contains toxic polycyclic aromatic hydrocarbons (PAH) that can accumulate in RPE and which absorb HEV light. It can thus be postulated that the interaction between both factors in RPE cells can have a synergic toxic effect to the RPE. To test this hypothesis, cultured human RPE cells (ARPE19) were treated with nanomolar concentrations of benzo[a]pyrene (BaP) or indeno[1,2,3-cd]pyrene (IcdP), then exposed to HEV light using an irradiation system that mimics the solar spectrum normally transmitted to the retina through the human ocular media. Using mitochondrial network morphology changes and key features of AMD-related RPE defects such as apoptotic cell death and oxidative stress, we demonstrate that a synergistic phototoxicity is generated when nanomolar concentrations (<= 500 nM) of IcdP interact with sub-lethal amounts of HEV light. Indeed, we found IcdP to be at least 3000 times more toxic for RPE cells when irradiated with HEV light. This synergy translates into disruption of mitochondrial network, ROS enhanced accumulation and apoptosis of RPE cells. Our results underline an important interplay between two environmental risk factors involved in AMD progression and strongly indicate that IcdP, upon interaction with HEV light, may initiate the biological mechanisms underlying the association between cigarette smoking and AMD-related RPE degeneration. PMID- 30426164 TI - Long-term and mechanistic evaluation of drug-induced liver injury in Upcyte human hepatocytes. AB - Drug-induced liver injury (DILI) constitutes one of the most frequent reasons of restricted-use warnings as well as withdrawals of drugs in postmarketing and poses an important concern for the pharmaceutical industry. The current hepatic in vivo and in vitro models for DILI detection have shown clear limitations, mainly for studies of long-term hepatotoxicity. For this reason, we here evaluated the potential of using Upcytes human hepatocytes (UHH) for repeated dose long-term exposure to drugs. The UHH were incubated with 15 toxic and non toxic compounds for up to 21 days using a repeated-dose approach, and, in addition to conventional examination of effects on viability, the mechanisms implicated in cell toxicity were also assessed by means of high-content screening. The UHH maintained the expression and activity levels of drug metabolizing enzymes for up to 21 days of culture and became more sensitive to the toxic compounds after extended exposures, showing inter-donor differences which would reflect variability among the population. The assay also allowed to detect the main mechanisms implicated in the toxicity of each drug as well as identifying special susceptibilities depending on the donor. UHH can be used for a long-term repeated detection of DILI at clinically relevant concentrations and also offers key mechanistic features of drug-induced hepatotoxicity. This system is therefore a promising tool in preclinical testing of human relevance that could help to reduce and/or replace animal testing for drug adverse effects. PMID- 30426165 TI - Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury. AB - The transcription factor NRF2, governed by its repressor KEAP1, protects cells against oxidative stress. There is interest in modelling the NRF2 response to improve the prediction of clinical toxicities such as drug-induced liver injury (DILI). However, very little is known about the makeup of the NRF2 transcriptional network and its response to chemical perturbation in primary human hepatocytes (PHH), which are often used as a translational model for investigating DILI. Here, microarray analysis identified 108 transcripts (including several putative novel NRF2-regulated genes) that were both downregulated by siRNA targeting NRF2 and upregulated by siRNA targeting KEAP1 in PHH. Applying weighted gene co-expression network analysis (WGCNA) to transcriptomic data from the Open TG-GATES toxicogenomics repository (representing PHH exposed to 158 compounds) revealed four co-expressed gene sets or 'modules' enriched for these and other NRF2-associated genes. By classifying the 158 TG-GATES compounds based on published evidence, and employing the four modules as network perturbation metrics, we found that the activation of NRF2 is a very good indicator of the intrinsic biochemical reactivity of a compound (i.e. its propensity to cause direct chemical stress), with relatively high sensitivity, specificity, accuracy and positive/negative predictive values. We also found that NRF2 activation has lower sensitivity for the prediction of clinical DILI risk, although relatively high specificity and positive predictive values indicate that false positive detection rates are likely to be low in this setting. Underpinned by our comprehensive analysis, activation of the NRF2 network is one of several mechanism-based components that can be incorporated into holistic systems toxicology models to improve mechanistic understanding and preclinical prediction of DILI in man. PMID- 30426167 TI - Screening for type 1 diabetes: are we nearly there yet? PMID- 30426166 TI - Afternoon exercise is more efficacious than morning exercise at improving blood glucose levels in individuals with type 2 diabetes: a randomised crossover trial. AB - AIMS/HYPOTHESIS: Exercise is recommended for the treatment and prevention of type 2 diabetes. However, the most effective time of day to achieve beneficial effects on health remains unknown. We aimed to determine whether exercise training at two distinct times of day would have differing effects on 24 h blood glucose levels in men with type 2 diabetes. METHODS: Eleven men with type 2 diabetes underwent a randomised crossover trial. Inclusion criteria were 45-68 years of age and BMI between 23 and 33 kg/m2. Exclusion criteria were insulin treatment and presence of another systemic illness. Researchers were not blinded to the group assignment. The trial involved 2 weeks of either morning or afternoon high intensity interval training (HIIT) (three sessions/week), followed by a 2 week wash-out period and a subsequent period of the opposite training regimen. Continuous glucose monitor (CGM)-based data were obtained. RESULTS: Morning HIIT increased CGM-based glucose concentration (6.9 +/- 0.4 mmol/l; mean +/- SEM for the exercise days during week 1) compared with either the pre-training period (6.4 +/- 0.3 mmol/l) or afternoon HIIT (6.2 +/- 0.3 mmol/l for the exercise days during week 1). Conversely, afternoon HIIT reduced the CGM-based glucose concentration compared with either the pre-training period or morning HIIT. Afternoon HIIT was associated with elevated thyroid-stimulating hormone (TSH; 1.9 +/- 0.2 mU/l) and reduced T4 (15.8 +/- 0.7 pmol/l) concentrations compared with pre-training (1.4 +/- 0.2 mU/l for TSH; 16.8 +/- 0.6 pmol/l for T4). TSH was also elevated after morning HIIT (1.7 +/- 0.2 mU/l), whereas T4 concentrations were unaltered. CONCLUSIONS/INTERPRETATION: Afternoon HIIT was more efficacious than morning HIIT at improving blood glucose in men with type 2 diabetes. Strikingly, morning HIIT had an acute, deleterious effect, increasing blood glucose. However, studies of longer training regimens are warranted to establish the persistence of this adverse effect. Our data highlight the importance of optimising the timing of exercise when prescribing it as treatment for type 2 diabetes. PMID- 30426168 TI - Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2. AB - AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p <= 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Delta plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Delta plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic. PMID- 30426169 TI - Gestational diabetes in young women predicts future risk of serious liver disease. AB - AIMS/HYPOTHESIS: In common with type 2 diabetes, gestational diabetes mellitus (GDM) is associated with a propensity for hepatic fat deposition. We hypothesised that GDM predicts future lifetime risk of serious liver-disease outcomes, such as cirrhosis, liver failure and need for transplantation. METHODS: From population based administrative databases, we identified all women in Ontario, Canada, who had a pregnancy resulting in live birth between April 1994 and March 2002 (N = 698,078). This population was stratified into individuals with (n = 17,932) and without (n = 680,146) GDM, and both groups were further stratified according to subsequent development of type 2 diabetes in the years after delivery. The median follow-up for the development of serious liver disease (defined as hospitalisation for cirrhosis, liver failure or transplantation) was 14.0 years. RESULTS: Women with GDM had a higher risk of serious liver disease than those without GDM (n = 680,146; HR = 1.40, 95% CI 1.01, 1.94). Compared with women who did not have GDM and did not develop diabetes (n = 635,998), those with GDM who subsequently developed type 2 diabetes (n = 8567) had a higher risk of serious liver disease (adjusted HR = 1.56, 95% CI 1.02, 2.39), as did those without GDM who developed type 2 diabetes (n = 44,148; adjusted HR = 2.48, 95% CI 2.10, 2.93), but not those with GDM who did not develop type 2 diabetes (n = 9365; adjusted HR = 1.15, 95% CI 0.69, 1.91). CONCLUSION/INTERPRETATION: GDM is associated with future risk of serious liver disease in young women, the development of which may be dependent upon progression to non-gestational diabetes. PMID- 30426170 TI - The role of coronary artery calcification testing in incident coronary artery disease risk prediction in type 1 diabetes. AB - AIMS/HYPOTHESIS: We sought to assess the role of coronary artery calcification (CAC) and its progression in predicting incident coronary artery disease (CAD) in individuals with type 1 diabetes using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: The present study examined 292 participants who had at least one CAC measure and were free from CAD at baseline; 181 (62%) had repeat CAC assessments 4-8 years later and did not develop CAD between the two CAC measures. The HRs of incident CAD events were estimated using Cox models in categorised or in appropriately transformed CAC scores. C statistics and net reclassification improvement (NRI) were used to assess the added predictive value of CAC for incident CAD. RESULTS: At baseline, the mean age of participants was 39.4 years and the mean diabetes duration was 29.5 years. There were 76 participants who experienced a first incident CAD event over an average follow-up of 10.7 years. At baseline, compared with those without CAC (Agatston score = 0), the adjusted HR (95% CI) in groups of 1-99, 100-399 and >=400 was 3.1 (1.6, 6.1), 4.4 (2.0, 9.5) and 4.8 (1.9, 12.0), respectively. CAC density was inversely associated with incident CAD in those with CAC volume >=100 (HR 0.3 [95% CI 0.1, 0.9]) after adjusting for volume score. Among participants with repeated CAC measures, annual CAC progression was positively associated with incident CAD after controlling for baseline CAC. The HR (95% CI) for above vs below the median annual CAC volume progression was 3.2 (1.2, 8.5). When compared with a model that only included established risk factors, the addition of CAC improved the predictive ability for incident CAD events in the whole group. CONCLUSIONS/INTERPRETATION: CAC is strongly associated with incident CAD events in individuals with type 1 diabetes; its inclusion in CAD risk models may lead to improvement in prediction over established risk factors. PMID- 30426171 TI - A longitudinal comparison of appendicular bone growth and markers of strength through adolescence in a South African cohort using radiogrammetry and pQCT. AB - : To compare growth patterns and strength of weight- and non-weight-bearing bones longitudinally. Irrespective of sex and ethnicity, metacarpal growth was similar to that of the non-weight-bearing radius but differed from that of the weight bearing tibia. Weight- and non-weight-bearing bones have different growth and strength patterns. INTRODUCTION: Functional loading modulates bone size and strength. METHODS: To compare growth patterns and strength of weight- and non weight-bearing bones longitudinally, we performed manual radiogrammetry of the second metacarpal on hand-wrist radiographs and measured peripheral quantitative computed tomography images of the radius (65%) and tibia (38% and 65%), annually on 372 black and 152 white South African participants (ages 12-20 years). We aligned participants by age from peak metacarpal length velocity. We assessed bone width (BW, mm); cortical thickness (CT, mm); medullary width (MW, mm); stress-strain index (SSI, mm3); and muscle cross-sectional area (MCSA, mm2). RESULTS: From 12 to 20 years, the associations between metacarpal measures (BW, CT and SSI) and MCSA at the radius (males R2 = 0.33-0.45; females R2 = 0.12-0.20) were stronger than the tibia (males R2 = 0.01-0.11; females R2 = 0.007-0.04). In all groups, radial BW, CT and MW accrual rates were similar to those of the metacarpal, except in white females who had lower radial CT (0.04 mm/year) and greater radial MW (0.06 mm/year) accrual. In all groups, except for CT in white males, tibial BW and CT accrual rates were greater than at the metacarpal. Tibial MW (0.29-0.35 mm/year) increased significantly relative to metacarpal MW (- 0.07 to 0.06 mm/year) in males only. In all groups, except white females, SSI increased in each bone. CONCLUSION: Irrespective of sex and ethnicity, metacarpal growth was similar to that of the non-weight-bearing radius but differed from that of the weight-bearing tibia. The local and systemic factors influencing site specific differences require further investigation. Graphical abstract ?. PMID- 30426172 TI - Acute Occlusion of the Distal Internal Carotid Artery : Single Center Experience in 46 Consecutive Cases, review of the literature and proposal of a classification. AB - PURPOSE: The acute distal intracranial occlusion of the internal carotid artery (ICA) is a very complex heterogeneous pathology, characterized by various patterns. Aim of this work is to identify the different types and propose a classification. METHODS: Among the patients admitted for stroke in the anterior circulation from august 2014 to October 2017, 46 (25%) presented with intracranial distal carotid artery occlusion. The mean age of the patients was 71 (SD 13.7), 65,2% female. The protocol included general and specific neurological examinations, CT, CT-Angiography with multiphase CTA, followed by Angiography. The occlusion was treated by aspiration device alone or associated with stent retriever. NIHSS at the admission, at discharge and modified ranking Scale (mRS) at four months were examined. RESULTS: The occlusions presented with various patterns. Depending on its site (located at the distal ICA bifurcation or more proximal at the level of the ophthalmic segment of ICA, with or without extent to ICA bifurcation) taking also into account the various involvement of the cerebral vessels and anatomic variations of Circle of Willis, three groups of occlusion types could be identified (T1, T2 and T3). The collateral circulation, and the possibilities of the endovascular revascularization important for the final outcome, were clearly connected with the type of occlusion. NIHSS at admission was 19.1 (Range from 8 to 30, SD 4.4). Good outcome defined as mRS 0-2 at for months was obtained in 17 patients (37%). CONCLUSIONS: The proposed classification reproduces more precisely the complexity and heterogeneity of this pathology, being useful in the diagnosis and treatment of these patients. PMID- 30426173 TI - A major QTL and candidate genes for capsaicinoid biosynthesis in the pericarp of Capsicum chinense revealed using QTL-seq and RNA-seq. AB - KEY MESSAGE: A major QTL and candidate genes controlling capsaicinoid content in the pericarp were identified by QTL-seq and RNA-seq in Capsicum chinense. Capsaicinoid biosynthesis was previously thought to be restricted to the placental tissue; however, the recent discovery of their biosynthesis in the pericarp provides new opportunities to increase the capsaicinoid content in pepper fruits. Currently, the genetic mechanisms regulating capsaicinoid biosynthesis in the pericarp remain unknown. Here, we performed quantitative trait loci (QTL) mapping and RNA sequencing (RNA-seq) to reveal the genes controlling capsaicinoid biosynthesis in the pericarp. A whole-genome sequencing based QTL-seq strategy was employed, identifying a major QTL on chromosome 6. To validate the QTL on chromosome 6, we performed traditional QTL mapping using the same population in QTL-seq with an additional biparental population. A total of 15 QTLs for capsaicinoid content distributed on chromosomes 3, 6, and 11 were newly identified. Among these QTLs, the genetic loci on the lower arm of chromosome 6 were commonly detected in the two mapping populations, corresponding to the location of the major QTL detected using whole-genome sequencing-based QTL seq. Our RNA-seq analysis identified candidate genes within the common QTL that were differentially expressed in the pungent and non-pungent pericarp tissues. Our results are expected to contribute to the elucidation of the regulation of capsaicinoid biosynthesis. We also demonstrated that a combination of QTL mapping and RNA-seq is helpful for refining the candidate genes of a complicated trait of interest. PMID- 30426174 TI - Enhancing grain size in durum wheat using RNAi to knockdown GW2 genes. AB - KEY MESSAGE: Knocking down GW2 enhances grain size by regulating genes encoding the synthesis of cytokinin, gibberellin, starch and cell wall. Raising crop yield is a priority task in the light of the continuing growth of the world's population and the inexorable loss of arable land to urbanization. Here, the RNAi approach was taken to reduce the abundance of Grain Weight 2 (GW2) transcript in the durum wheat cultivar Svevo. The effect of the knockdown was to increase the grains' starch content by 10-40%, their width by 4-13% and their surface area by 3-5%. Transcriptomic profiling, based on a quantitative real-time PCR platform, revealed that the transcript abundance of genes encoding both cytokinin dehydrogenase 1 and the large subunit of ADP-glucose pyrophosphorylase was markedly increased in the transgenic lines, whereas that of the genes encoding cytokinin dehydrogenase 2 and gibberellin 3-oxidase was reduced. A proteomic analysis of the non-storage fraction extracted from mature grains detected that eleven proteins were differentially represented in the transgenic compared to wild-type grain: some of these were involved, or at least potentially involved, in cell wall development, suggesting a role of GW2 in the regulation of cell division in the wheat grain. PMID- 30426175 TI - Identification of a major QTL on chromosome arm 2AL for reducing yellow rust severity from a Chinese wheat landrace with evidence for durable resistance. AB - KEY MESSAGE: A QTL on 2AL for reducing yellow rust severity was identified from a Chinese wheat landrace, being more effective than Yr18, with evidence for durable resistance from field observations. Utilization of wheat resistance is an important strategy to control yellow rust. The Chinese wheat landrace Hong Qimai (HQM) and the advanced breeding line AQ24788-83 (AQ; a progeny of HQM) can significantly reduce disease severity at the adult-plant growth stage. HQM has maintained adult-plant resistance for a prolonged period of time. To study the inheritance of the resistance, 126 recombinant inbred lines (RILs) derived from the cross Thatcher (TC) * HQM and 138 RILs from Luke * AQ were assessed for disease severity in six field trials. A genetic map of TC * HQM was constructed by genotyping these RILs using the 90 K wheat single-nucleotide polymorphism chip. Luke * AQ map was previously constructed for another disease study and also utilized here. Based on these maps and disease data, a quantitative trait locus (QTL) was detected on the chromosome arm 2AL from both TC * HQM and Luke * AQ and designated as QYr.cau-2AL. The resistance allele at QYr.cau-2AL came from HQM and AQ. QYr.cau-2AL was significantly effective across all the test environments and different genetic backgrounds, with its effect magnitude being higher than that of Yr18. QYr.cau-2AL synergistically acted with Yr18 and a QTL for high temperature adult-plant resistance on 2BS, resulting in an elevated resistance from the juvenile plant growth stage onward, although QYr.cau-2AL alone displayed no substantial resistance at juvenile stage. Evidence indicates that QYr.cau-2AL is novel and confers durable resistance, and thus, should have high potential value for practical breeding. PMID- 30426176 TI - Response to letter to the editor concerning "partial extensor mechanism allograft reconstruction for chronic patellar tendon disruption shows superior outcomes in native knees when compared to same technique following total arthroplasty". PMID- 30426177 TI - Distal femoral varus osteotomy: results of the lateral open-wedge technique without bone grafting. AB - BACKGROUND: The lateral opening wedge distal femoral osteotomy (LOWDFO) to reconstruct knee alignment in patients with genu valgum originating in the distal femur has gained importance within the last years. PURPOSE: To analyze clinical and radiographic outcome of patients treated with LOWDFO with respect to bone healing without grafting and patient age. MATERIAL AND METHODS: Twenty-two consecutive patients with genu valgum corrected with 23 LOWDFOs using a Tomofix locking plate were retrospectively analyzed (mean age 23.7 years). Clinical evaluation was based on pre- and post-operative KOOS scores. A pre- and post operative radiographic assessment, including MAD, mLDFA, LLD, bone healing, and patella parameters, was performed. Differences between subgroups (age, bone grafting) were analyzed. RESULTS: The restoration of MAD and mLDFA resulted in significantly improved post-operative KOOS5 scores in younger and older patients (p = 0.001). Bone healing without bone grafting was reliable in all patients. The leg length was significantly increased post-operatively (p = 0.001). The Blackburne-Peel ratio was significantly reduced to more normal values post operatively (p < 0.001). CONCLUSION: LOWDFO without bone grafting is a reliable procedure representing a promising treatment option particularly in young patients with genu valgum. Besides correction of the MAD, a significant leg length increase and additional patella stability can be expected. PMID- 30426178 TI - Failure of lumbar disc surgery: management by fusion or arthroplasty? AB - PURPOSE: To analyze and clarify conflicting aspects of fusion and total disc replacement (TDR) surgery in literature. METHOD: Using keywords, 23 literature reviews, 41 studies accepted by "importance criteria" from the Internet, and 16 articles "published in 2018" were chosen. Altogether 80 studies. RESULTS: General assessment was mentioned as affirmative for TDR in 40 papers, five were negative, 24 without clear decision. Long term results TDR seven affirmative, four nondecisive. Comparison to fusion (general, ALIF, 3600, BAK cage) 18 found as better, nine equal, one nondecisive. Complications TDR 3-50%. Adjacent disc degeneration disease recognized in 14 papers, denied existence in four. Cost benefit effective in three papers comparing to fusions, ALIF, 3600. Nonimbursement from the state mentioned as problem in three papers. Salvage surgery seven papers, rare but extremely problematic. Anterior approach 16 challenging surgery, one 10% minor, one 38.5% transient complications, one 1.8% retrograde ejaculations, one 6.6% vascular injuries, two access surgeon needed. Construct judgment two no importance, 22 wear and durability problems, two inadequate biomechanics and biomaterials, three construct and lateral approach. Impact of TDR upon spine surgery is decreasing, currently is less than 2%. CONCLUSION: It is concluded that problems with anterior surgery, imbursement policy, and potential problems with salvage surgery are major reasons for loosing popularity of TDR surgery. PMID- 30426179 TI - Does the body mass index influence the long-term survival of unicompartmental knee prostheses? A retrospective multi-centre study. AB - PURPOSE: The effect of being obese on the long-term survival of total joint arthroplasty is persistently discussed. Considering only studies with large cohort of patients and meta-analysis, a high body mass index has been correlated with a higher incidence of complication but not univocally with a lower survival rate. In this study, we analyzed, retrospectively, the data of patients that received unicompartmental knee prostheses in order to examine if obesity has an effect on clinical outcomes. METHODS: A retrospective multi-centre study was carried out on 4964 unicompartmental knee replacements between July 2000 and December 2016, the patients involved were 3976, with 988 bilateral cases. The patients were categorized into three groups: non-obese with a body mass index (BMI) < 30 kg/m2, obese with BMI ranged between 30 and 39 kg/m2, and morbidly obese (BMI >= 40 kg/m2). The outcome was measured using the Cox proportional hazards model with end point UKA revision for any reasons. Results were stratified for sex, age, weight, and bi-laterality. RESULTS: The morbidly obese group was significantly younger and required a significantly longer operating time. No statistical significant differences were observed considering the BMI groups in terms of type of insert, type of tibial component, prosthetic condyle, and prosthesis fixation (p > 0.05; chi-square test). CONCLUSIONS: Obese and morbidly obese patients have as much to gain from total knee replacement as non obese patients. PMID- 30426180 TI - Parents' received and expected information about their child's radiation exposure during radiographic examinations. AB - BACKGROUND: Despite regulations, insufficient information is provided to adult patients prior to their radiologic examinations. Information regarding paediatric patients has not been systematically studied. OBJECTIVE: To survey parents' experience and wishes for information in connection with their child's radiographic examination. MATERIALS AND METHODS: We provided a questionnaire to consenting parents of children younger than 12 years old at a university hospital. The questionnaire asked parents about the information obtained from the referrer prior to the radiograph, the chance to discuss with the referrer and their wishes regarding future information. Forty-one parents responded to the survey. Twenty-five children were referred for radiography of extremities, the others for dental, body and skull examinations. RESULTS: Altogether 34/41 (83%, 95% confidence interval [CI] 69-91%) parents said they received adequate information on the purpose of the examination, 8/35 (23%, 95% CI 12-39%) on other options and 3/41 (7%, 95% CI 3-19%) on radiation dose. Ten of 41 parents (24%, 95% CI 12-40%) said they were aware of radiation exposure. The number of previous radiology examinations was not sufficiently discussed. The communication was scored as mean 6.5 (95% CI 5.8-7.1) on a scale from 4 (poor) to 10 (excellent). Thirty-eight of 40 (95%, 95% CI 84-99%) of parents expected information on the purpose, 35/40 (88%, 95% CI 74-95%) on radiation dose and 31/40 (78%, 95% CI 63 88%) on other options. Symbols of radiation and corresponding period of natural background radiation are preferred to convey the dose. A referrer is the preferred source of information. CONCLUSION: Parents did not feel adequately informed prior to their child's radiographic examination. Parents expect more information about the purpose, dose and alternative tests. PMID- 30426182 TI - Chronic low dose of AM404 ameliorates the cognitive impairment and pathological features in hyperglycemic 3xTg-AD mice. AB - RATIONALE: Hyperglycemia accelerates the progression of Alzheimer's disease (AD), and GSK3beta plays a potential link between AD and hyperglycemia. Therefore, a direct or indirect GSK3beta inhibition may have potential to delay the progression of AD. Our previous biochemical assay identified AM404 as a GSK3beta inhibitor at high dose (IC50 = 5.353 MUM); however, other study suggests that AM404 impaired synaptic plasticity of hippocampus at high dose (10 mg/kg; i.p.). Therefore, the dose and duration of treatment are crucial for the effects of AM404. OBJECTIVE: The effects and molecular mechanisms of AM404 at low dose were evaluated from in vitro to in vivo models. METHODS: AM404 (0.1-0.5 MUM) was tested on tau hyperphosphorylated mouse hippocampal primary cultures treated with Wortmannin (WT) and GF109203X (GFX). Hyperglycemic triple transgenic AD (3*Tg-AD) mice at 6 months old were intraperitoneally injected with AM404 (0.25 mg/kg) for 4 weeks. The spatial learning and memory of mice were measured using the Morris water maze. Mouse brain and serum samples were collected for pathological analyses. RESULTS: AM404 (0.5 MUM) exhibited significantly augmented neuroprotection toward tau hyperphosphorylation in primary cultures. The chronic systemic administration of AM404 (0.25 mg/kg) attenuated cognitive deficits in hyperglycemic 3*Tg-AD mice. Moreover, chronic low dose of AM404 significantly attenuated Abeta production, tau protein phosphorylation, and inflammation associated with an increase of pS473Akt and pS9-GSK3beta. Therefore, AM404 at low dose, not only increased neuroprotection, but also ameliorated cognitive deficit, could be partly by regulating the Akt/GSK3beta signaling, which may contribute to downregulation of Abeta, tau hyperphosphorylation, and inflammation in hyperglycemic 3*Tg-AD mice. CONCLUSIONS: These results highlight that chronic administration of AM404 at low dose may be through the Akt/GSK3beta pathway to ameliorate the impairment in hyperglycemic 3*Tg-AD mice. PMID- 30426181 TI - Effects of intra-accumbal or intra-prefrontal cortex microinjections of adenosine 2A receptor ligands on responses to cocaine reward and seeking in rats. AB - RATIONALE AND OBJECTIVES: Many studies indicated that adenosine via its A2A receptors influences the behavioral effects of cocaine by modulating dopamine neurotransmission. The hypothesis was tested that A2A receptors in the nucleus accumbens (NAc) or the prefrontral cortex (PFc) may modulate cocaine reward and/or cocaine seeking behavior in rats. METHODS: The effects of local bilateral microinjections of the selective A2A receptor agonist CGS 21680 or the A2A receptor antagonists KW 6002 and SCH 58261 were investigated on cocaine self administration on reinstatement of cocaine seeking. RESULTS: The intra-NAc shell, but not intra-infralimbic PFc, administration of CGS 21680 significantly reduced the number of active lever presses and the number of cocaine (0.25 mg/kg) infusions. However, tonic activation of A2A receptors located in the NAc or PFc did not play a role in modulating the rewarding actions of cocaine since neither KW 6002 nor SCH 58261 microinjections altered the cocaine (0.5 mg/kg) infusions. The intra-NAc but not intra-PFc microinjections of CGS 21680 dose- dependently attenuated the reinstatement of active lever presses induced by cocaine (10 mg/kg, i.p.) and the drug-associated combined conditioned stimuli using the subthreshold dose of cocaine (2.5 mg/kg, i.p.). On the other hand, the intra-NAc pretreatment with SCH 58261, but not with KW 6002, given alone evoked reinstatement of cocaine seeking behavior. CONCLUSION: The results strongly support the involvement of accumbal shell A2A receptors as a target, the activation of which exerts an inhibitory control over cocaine reward and cocaine seeking. PMID- 30426184 TI - Ameliorative effect of fisetin against lipopolysaccharide and restraint stress induced behavioral deficits via modulation of NF-kappaB and IDO-1. AB - BACKGROUND: Fisetin, a plant active polyphenol, is well known for its antioxidant and free radical scavenging activities. The present study was designed to explore the detailed molecular mechanism underlying its neuroprotective effects. METHODS: The young male mice were either administered a single dose of lipopolysaccharide (0.83 mg/kg) or subjected to restraint stress (6 h per day for 28 days) to induce behavioral deficits in different groups. Fisetin (15 mg/kg) was orally administered for the last 14 days of the study. RESULTS: Lipopolysaccharide (LPS) as well as restraint stress (RS) exposure caused behavioral alterations (anxiety and depressive-like behavior). Gene expression analysis showed upregulation of nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and indoleamine 2,3-dioxygenase (IDO)-1 gene expression along with downregulation of Nrf-2 (nuclear factor erythroid 2-related factor 2), HO-1 (heme oxygenase-1), and ChAT (choline acetyltransferase) gene expression level in RS and RS+LPS groups. Fisetin administration significantly ameliorated behavioral and neurochemical deficits in LPS, RS, and RS+LPS groups. CONCLUSION: These findings clearly indicated that fisetin administration improved behavioral functions and suppressed the NF-kappaB and IDO-1 (indoleamine 2,3-dioxygenase) activation along with their antioxidant effect, suggesting fisetin as an intriguing nutraceutical for the management of inflammation-associated neurological disorders. PMID- 30426186 TI - Indications and Outcomes of a Cross-Linked Porcine Dermal Collagen Mesh (Permacol) for Complex Abdominal Wall Reconstruction: A Multicenter Audit. AB - INTRODUCTION: To reduce the occurrence of complications in the setting of high risk patients with contaminated operative field, a wide range of biologic meshes has been developed. Yet, few series have reported outcomes after abdominal wall repair (AWR) using such meshes. Permacol is an acellular porcine dermal collagen matrix with a cross-linked pattern. This study reports short- and long-term outcomes after AWR for incisional hernia using Permacol. MATERIALS AND METHODS: All consecutive patients undergoing single-stage open AWR using Permacol mesh at eight university hospitals were included. Mortality, complication and hernia recurrence rates were assessed. Independent risk factors for complications and hernia recurrence were identified with logistic regression and Fine and Gray analysis, respectively. RESULTS: Overall, 250 patients underwent single-stage AWR with Permacol. Nearly 80% had a VHWG grade 3 or 4 defect. In-hospital mortality and complication rates were 4.8% (n = 12) and 61.6% (n = 154), respectively. Reintervention for complications was required for 74 patients (29.6%). Mesh explantation rate was 4% (n = 10). Independent risk factors for complications were smoking, defect size and VHWG grade. After a mean follow-up time of 16.8 months (+/- 18.1 months), 63 (25.2%) experienced hernia recurrence. One-, 2- and 3-year RFS were 90%, 74% and 57%, respectively. Previous AWR, mesh location and the need for reintervention were independent predictors of hernia recurrence. DISCUSSION: Single-stage AWR is feasible using Permacol. Mortality and complication rates are high due to patients' comorbidities and the degree of contamination of the operative field. Given the observed recurrence rate, the benefit of biologics remains to be ascertained. PMID- 30426185 TI - Risk Factors for Skin Flap Necrosis in Breast Cancer Patients Treated with Mastectomy Followed by Immediate Breast Reconstruction. AB - BACKGROUND: Skin-sparing mastectomy (SSM) and nipple-sparing mastectomy (NSM) are the standard techniques for achieving a cosmetic outcome, but necrosis of a cutaneous flap including the nipple-areolar complex (NAC) is a serious complication. To analyze the risk factors for skin flap necrosis, we retrospectively evaluated a clinical database of breast cancer patients treated with mastectomy followed by immediate breast reconstruction. METHODS: Four hundred and twelve cases were consecutively recorded between 2006 and 2016. Body weight (BW), body mass index (BMI), distance from NAC to referent tumor, distance from overlying skin to the tumor and weight of breast resection (WBR) as measured in the operating theater were included in the statistical analysis. RESULTS: NSM, SSM and total mastectomy were performed in 123 (30%), 96 (23%) and 193 cases (47%), respectively. A tissue expander was used in 379 cases (92%), a silicone implant in 8 (2%) and autologous breast reconstruction in 25 (6%). Skin flap necrosis was found in 7% of all cases and NAC necrosis in 13% of NSM cases. In a univariate analysis, BW, NSM and WBR were risk factors for skin flap necrosis, and BW, BMI and WBR were risk factors for NAC necrosis. In a multivariate analysis, NSM and WBR remained significant risk factors for skin flap necrosis, and WBR was a significant risk factor for NAC necrosis. CONCLUSIONS: WBR is an important risk factor for skin flap necrosis. Especially, NAC necrosis should be considered for patients with large-volume breasts who undergo NSM and immediate breast reconstruction. PMID- 30426187 TI - Complications After Ostomy Surgery: Emergencies and Obese Patients are at Risk Data from the Berlin OStomy Study (BOSS). AB - BACKGROUND: Complications are common after ostomy surgery. Data from the Berlin OStomy Study were evaluated to determine risk factors for complications. PATIENTS AND METHODS: Patients with a bowel ostomy were questioned using a questionnaire concerning patients' characteristics and history as well as the ostomy and its complications. The questionnaire also contained a nine-fielded abdominal sketch to determine the exact ostomy location. RESULTS: Over 42 months, 2647 patients completed the questionnaire. Obese patients and patients after emergency surgery were more prone to ostomy-related complications. This result was independent of the kind of ostomy (small bowel ostomy or colostomy) and of the abdominal location. The overall ostomy complication rate was 55.6%. CONCLUSION: Significantly more complications were recorded after emergency surgery and in obese patients than after elective surgery and in non-obese patients, respectively. There was no preferential abdominal location for avoiding general ostomy complications. The results emphasized the importance of preoperative ostomy site marking by qualified personnel such as ostomy nurses or surgeons to reduce complication rates by respecting individual abdominal configurations. With an increasing prevalence of obesity, ostomy surgery will become even more challenging in the future. A division of the abdominal wall into nine regions might be helpful and more precise for describing and examining ostomy-related complications in the future. PMID- 30426183 TI - Comparison of local spectral modulation, and temporal correlation, of simultaneously recorded EEG/fMRI signals during ketamine and midazolam sedation. AB - RATIONALE AND OBJECTIVES: The identification of biomarkers of drug action can be supported by non-invasive brain imaging techniques, such as electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), with simultaneous collection plausibly overcoming the limitations of either modality alone. Despite this, few studies have assessed the feasibility and utility of recording simultaneous EEG/fMRI in a drug study. METHODS: We used simultaneous EEG/fMRI to assess the modulation of neural activity by ketamine and midazolam, in a placebo-controlled, single-blind, three-way cross-over design. Specifically, we analysed the sensitivity and direction of the spectral effects of each modality and the temporal correlations between the modulations of power of the common EEG bands and the blood-oxygen-level-dependent (BOLD) signal. RESULTS AND CONCLUSIONS: Demonstrating feasibility, local spectral effects were similar to those found in previous non-simultaneous EEG and fMRI studies. Ketamine administration resulted in a widespread reduction of BOLD fractional amplitude of low frequency fluctuations (fALFF) and a diverse pattern of effects in the different EEG bands. Midazolam increased fALFF in occipital, parietal, and temporal areas, and frontal delta and beta EEG power. While EEG spectra were more sensitive to pharmacological modulations than the fALFF bands, there was no clear spatial relationship between the two modalities. Additionally, ketamine modulated the temporal correlation strengths between the theta EEG band and the BOLD signal, whereas midazolam altered temporal correlations with the alpha and beta bands. Taken together, these results demonstrate the utility of simultaneous recording: each modality provides unique insights, and combinatorial analyses elicit more information than separate recordings. PMID- 30426188 TI - Lung Adenocarcinoma has a Higher Risk of Lymph Node Metastasis than Squamous Cell Carcinoma: A Propensity Score-Matched Analysis. AB - BACKGROUND: Controversy still exists in which subtype of non-small-cell lung cancer [squamous cell carcinoma (SCC) or adenocarcinoma] is more likely to have lymph node (LN) metastasis. The aim of this study is to compare the pattern of LN metastasis in two cohorts of matched patients surgically treated for SCC or adenocarcinoma. METHODS: A retrospective analysis of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy without preoperative treatment for lung SCC or adenocarcinoma was conducted in this study. Data for analysis consisted of age, gender, tumor size, lobe-specific tumor location, tumor location (peripheral or central), and pathologic findings. We conducted the propensity score-matched (PSM) analysis to eliminate potential bias effects of possible confounding factors. RESULTS: From January 2015 to December 2016 in our department, we finally included a total of 387 patients (including 63 patients with SCC and 324 patients with adenocarcinoma) for analysis. For the unmatched cohort, there was no sufficient evidence of significantly different number of positive LNs (P = 0.90) and rate of LN metastasis (P = 0.23) between SCC patients and adenocarcinoma patients. However, potential confounding factors, for example gender, tumor size, tumor location, tumor differentiation, and total number of dissected LNs, were significantly different between patients with SCC and those with adenocarcinoma. In the analysis of matched cohort after PSM analysis, those above confounding factors were comparable between the two groups. However, patients with adenocarcinoma had significantly more mean positive LNs (2.2 and 0.7; P = 0.008) and a higher rate of LN metastasis (53% and 29%; P = 0.016) than those with SCC. CONCLUSIONS: Lung adenocarcinoma had a higher risk of LN metastasis than SCC, suggesting that different therapeutic modalities may be indicated for the two different subtypes of lung cancer. PMID- 30426189 TI - Proteomic Identification of Biomarkers Associated with Eating Control and Bariatric Surgery Outcomes in Patients with Morbid Obesity. AB - BACKGROUND: The current therapeutics of morbid obesity could be significantly improved after the identification of novel biomarkers associated with the food addiction endophenotype of obesity and with bariatric surgery outcomes. METHODS: We applied differential expression proteomics and enzyme-linked immunosorbent confirmatory assays to identify (a) proteins that varied according to loss of control over eating in morbidly obese patients and (b) proteins that varied between normoweight controls and patients before and 1 year after bariatric surgery. RESULTS: Clusterin was the only protein that consistently varied according to eating control in patients. Patients showed increased levels of serum amyloid P protein, apolipoprotein A4, serotransferrin, complement factors B and C3 and haptoglobin with respect to controls; the levels of all these proteins tended to return to control values 1 year after surgery. In contrast, apolipoprotein A1 and transthyretin were initially downregulated in patients and were scarcely changed by surgery. Leucine-rich alpha-2-glycoprotein was markedly increased in patients only after surgery. CONCLUSIONS: Clusterin could be of interest as a putative biomarker for food addiction diagnosis in people with morbid obesity. In addition, postsurgical normalization of the proteins initially dysregulated in obese subjects might help monitor clinical improvements after surgery, while lasting or newly detected alterations (i.e., those affecting transthyretin and leucine-rich alpha-2-glycoprotein) could reflect partial refractoriness and/or contribute to the early prediction of clinical problems. PMID- 30426191 TI - Gestational diabetes mellitus and periodontal diseases: a well-known association. PMID- 30426190 TI - Guidelines for Perioperative Care in Elective Colorectal Surgery: Enhanced Recovery After Surgery (ERAS(r)) Society Recommendations: 2018. AB - BACKGROUND: This is the fourth updated Enhanced Recovery After Surgery (ERAS(r)) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded recommendations for each ERAS item within the ERAS(r) protocol. METHODS: A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: All recommendations on ERAS(r) protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly. CONCLUSIONS: The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS(r) Society in this comprehensive consensus review. PMID- 30426192 TI - Effects of electroacupuncture on reducing labor pain and complications in the labor analgesia process of combined spinal-epidural analgesia with patient controlled epidural analgesia. AB - PURPOSE: To compare the pain scores and rates of complications in the labor analgesia process between the two groups. METHODS: There were 127 participants being recruited in this research, and randomly divided into 2 groups according to the anesthetic technique: CSEA with PCEA with EA group (group 1), CSEA with PCEA group (group 2). Group 1 was first operated CSEA and PCEA, then EA at Hegu (LI4), Neiguan (PC6), Zusanli (ST36) and Sanyinjiao (SP6) by HANS-200A device for 25 min. Group 2 was only treated by CSEA and PCEA. The main outcome was the VAS for labor pain. Meanwhile the complications, use of oxytocin, durations of three stages, delivery mode, cord blood pH and neonatus Apgar score in this study were considered as secondary outcomes. RESULTS: After labor analgesia, the VAS scores of group 1 at the five point-in-times were all lower than that of group 2. The rates of fever and urinary retention of group 1 were lower compared with group 2. Group 1 had less usage of oxytocin and shorter durations of cervical dilation from 3 to 10 cm and third stage than group 2. CONCLUSIONS: EA can help to reduce labor pain in CSEA with PCEA labor analgesia process, and may be able to reduce the complications. PMID- 30426193 TI - [Progressive loss of vision in cone dystrophy. Search for evidence with macular OCT and multifocal ERG]. AB - A 53-year-old patient consulted our practice clinic complaining of progressive visual loss, increased glare sensitivity and color sense disorder. Extensive diagnostic investigation, including multifocal ERG (mfERG) and macular thickness map with the help of optical coherence tomography (OCT), supported the suspected diagnosis of a cone dystrophy. There are, however, no established therapeutic options. A diagnostic confirmation by means of molecular genetics was not successful. PMID- 30426194 TI - Continuation rates of alpha-blockers mono-therapy in adult men, prescribed by urologists or general practitioners: a pharmacy-based study. AB - PURPOSE: alpha-Blockers are commonly used for the treatment of male lower urinary tract symptoms (LUTS). The Dutch GP guideline on male LUTS contains an advice to discontinue treatment after 3-6 months of successful treatment. The guideline for urologists does not support this advice. It is unclear if these differences lead to other patterns of (dis)continuation of alpha-blockers. We aim to study continuation rates of alpha-blockers, prescribed by a urologist or a general practitioner (GP), and to predict discontinuation after 1 year. METHODS: We conducted a retrospective inception cohort study on prescription patterns of alpha-blockers among Dutch men between 2006 and 2014, using the IADB.nl pharmacy prescription database from the University of Groningen. We selected men aged 30 years or older with a first alpha-blocker prescription between 2006 and 2013, and analysed continuation of prescriptions. RESULTS: The database included 12,191 individual patients with at least one alpha-blocker prescriptions from a urologist (44.5%) or a GP (55.5%). The median treatment period for patients who started in the GPs office was 210 days, compared to 150 days for patients with a prescription from a urologist. Of all patients, 60.3% (GP prescriptions) and 66.1% (urologists' prescriptions) had discontinued treatment (Chi-square p < 0.001). Discontinuation rates were age dependent with higher rates in the youngest age groups. CONCLUSION: In this study, the discontinuation rate 1 year after the initiation of treatment was high. Although Dutch GP's and urologist's guidelines differ with respect to a discontinuation advice, we could not find clinically relevant difference in (temporary) discontinuation rates. PMID- 30426195 TI - Local fast-food environment, diet and blood pressure: the moderating role of mastery. AB - PURPOSE: To examine the moderating role of mastery in the association of local fast-food restaurants (FFR) with diet quality and systolic blood pressure (SBP). METHODS: We used cross-sectional data from 1543 adults participating in wave six of the Netherlands Study of Depression and Anxiety (NESDA). Data were collected between 2013 and 2016. Diet quality was defined by adherence with the dietary approaches to stop hypertension (DASH) diet. Individuals reported on their food consumption through a food frequency questionnaire and SBP was measured. Density of FFR in 1600 m, 800 m and 400 m circular buffers around the home postal code was calculated using Geographic Information Systems. We assessed the association between density of FFR, diet and SBP using linear regression analyses, testing for moderation by mastery. RESULTS: Mean age was 52 years and 32.2% of the sample were men. Exposure to FFR ranged from 0 to 35 FFR per km2. Density of FFR was not significantly associated with DASH adherence or SBP. Only one out of the six interaction terms was significant, suggesting that for individuals with lower levels of mastery, higher density of FFR in an 800-m buffer was negatively associated with DASH adherence, while for individuals with higher levels of mastery, this association was positive. CONCLUSIONS: Exposure to FFR was not associated with diet quality and SBP, and we observed little evidence for moderation by level of mastery. This research question should be further explored in a large sample of healthy adults. PMID- 30426196 TI - Cap polyposis in children: case report and literature review. AB - PURPOSE: Cap polyposis is a benign disease of the colon, characterized by inflammatory polyps with a "cap" of inflammatory granulation tissue. Its prevalence is very low, especially in children. METHODS AND RESULTS: A 16-year old girl presented with frequent bowel movements with mucous discharge and bloody stool, leading to the initial suspicion of chronic inflammatory bowel disease. Results of further investigation by endoscopy and histological examination were consistent with a diagnosis of cap polyposis. Treatment with systemic steroids resulted in symptom improvement. CONCLUSION: A review of the literature shows that cap polyposis can occur at any age, including childhood, with a slight predilection for the male gender. Rectal bleeding and rectal polyps are consistent features in all reported cases. Other typical symptoms include constipation, diarrhea, and abdominal pain. Symptoms may be very similar to those of chronic inflammatory bowel disease, the most important differential diagnosis. The cause of cap polyposis is still unclear, and specific therapy has not as yet been established. Conservative therapeutic measures should be preferred, especially in children. PMID- 30426197 TI - Oncological outcome of surgical site infection after colorectal cancer surgery. AB - BACKGROUND: This study evaluated the oncological outcome of surgical site infection (SSI) after colorectal cancer surgery. METHODS: A total of 3675 consecutive patients with colorectal cancer who underwent curative resection from January 2009 to December 2011 were analyzed. The prognostic significance of SSI was evaluated. Risk factors for SSI were also identified using multivariate regression analysis. RESULTS: Overall SSI rate was 9.6%, in which 5.5% was superficial or deep SSI and 4.1% was organ/space SSI. Incidence of SSI varied significantly with tumor location (P < 0.001): 7.1% in colon cancer and 14.0% in rectal cancer. With a median follow-up period of 49.8 months, the 5-year disease free survival rates of patients without and with SSI were 87% and 83%, respectively (P = 0.018). SSI predicted disease-free survival in univariate analysis. However, SSI was not an independent predictor of survival in multivariate analysis. Body mass index, ASA score, preoperative WBC count, rectal tumor, open surgery, operation time, and transfusion during surgery were independent predictors of SSI. CONCLUSION: SSI predicted disease-free survival in colorectal cancer patients following curative surgery. Patient' demographics, tumor characteristics, and perioperative conditions were independently associated with an increased likelihood of SSI. PMID- 30426198 TI - CRISPR/Cas precision: do we need to worry about off-targeting in plants? AB - The CRISPR/Cas technology has recently become the tool of choice for targeted genome modification in plants and beyond. Although CRSIPR/Cas offers a rapid and facile way of introducing changes at genomic loci of interest, its application is associated with off-targeting, i.e. introduction of unintended mutations at off target sites within the genome, which has been reported frequently in the mammalian field. Here we summarise the current knowledge on the precision of CRISPR/Cas in plant systems and provide a summary of state-of the-art strategies for avoiding off-target mutations, as well as unintended on-target changes, in plants. These include using natural (e.g. Cas12a) or engineered (e.g. SpCas9-HF) CRISPR/Cas nucleases characterised by higher precision, as compared to the commonly used wild type SpCas9. In addition, we discuss the usage of CRISPR/Cas nucleases in the form of ribonucleoproteins (RNPs) as an option for reducing off targeting in plants. Finally, we conclude that the most important factor for reducing CRISPR/Cas off-targeting remains careful selection of target sequences, for which we provide an overview of available online software tools and experimental guidance. PMID- 30426199 TI - Standards and guidelines for canine clinical genetic testing laboratories. AB - This publication represents a proposed approach to quality standards and guidelines for canine clinical genetic testing laboratories. Currently, there are no guidelines for laboratories performing clinical testing on dogs. Thus, there is no consensus set of protocols that set the minimal standards of quality among these laboratories, potentially causing variable results between laboratories, inconsistencies in reporting, and the inability to share information that could impact testing among organizations. A minimal standard for quality in testing is needed as breeders use the information from genetic testing to make breeding choices and irreversible decisions regarding spay, neuter or euthanasia. Incorrect results can have significant impact on the health of the dogs being tested and on their subsequent progeny. Because of the potentially serious consequences of an incorrect result or incorrect interpretation, results should be reviewed by and reported by individuals who meet a minimum standard of qualifications. Quality guidelines for canine genetic testing laboratories should include not only the analytical phase, but also the preanalytical and postanalytical phases, as this document attempts to address. PMID- 30426200 TI - A discrete-time dynamical system and an evolution algebra of mosquito population. AB - Recently, continuous-time dynamical systems of mosquito populations have been studied. In this paper, we consider a discrete-time dynamical system, generated by an evolution quadratic operator of a mosquito population, and show that this system has two fixed points, which become saddle points under some conditions on the parameters of the system. We construct an evolution algebra, taking its matrix of structural constants equal to the Jacobian of the quadratic operator at a fixed point. Idempotent and absolute nilpotent elements, simplicity properties, and some limit points of the evolution operator corresponding to the evolution algebra are studied. We give some biological interpretations of our results. PMID- 30426201 TI - The stationary distribution of a sample from the Wright-Fisher diffusion model with general small mutation rates. AB - The stationary distribution of a sample taken from a Wright-Fisher diffusion with general small mutation rates is found using a coalescent approach. The approximation is equivalent to having at most one mutation in the coalescent tree to the first order in the rates. The sample probabilities characterize an approximation for the stationary distribution from the Wright-Fisher diffusion. The approach is different from Burden and Tang (Theor Popul Biol 112:22-32, 2016; Theor Popul Biol 113:23-33, 2017) who use a probability flux argument to obtain the same results from a forward diffusion generator equation. The solution has interest because the solution is not known when rates are not small. An analogous solution is found for the configuration of alleles in a general exchangeable binary coalescent tree. In particular an explicit solution is found for a pure birth process tree when individuals reproduce at rate [Formula: see text]. PMID- 30426202 TI - Host responses and impact on the boxwood blight pathogen, Calonectria pseudonaviculata. AB - MAIN CONCLUSION: Boxwood leaves are more susceptible to Calonectria pseudonaviculata (Cps) and better suited for Cps reproduction than those of pachysandra and sweet box. Passages through a non-boxwood host may alter Cps ability to sporulate. Calonectria pseudonaviculata (Cps) infects boxwood and its two common companion plants-pachysandra and sweet box. This study investigated how boxwood, pachysandra, and sweet box respond to Cps isolates of different host origin. Detached leaves were inoculated with nine isolates, three from each host, and evaluated for colonization, infection rate, lesion size, and production of conidia and microsclerotia. Cps colonized boxwood leaf tissue within 12 h of inoculation, and 60 h ahead of pachysandra and sweet box. Cps also produced significantly larger lesions and more conidia on boxwood than on pachysandra and sweet box. Isolates originating from different host plants did not differ in all the components evaluated except for conidia production. Isolates from boxwood and sweet box produced significantly more conidia than those from pachysandra. Overall, boxwood leaves are more susceptible to the disease and are better suited for Cps reproduction than those of pachysandra and sweet box. Passages through a non-boxwood host may alter Cps ability to sporulate. These results advance the understanding of Cps biology and affirm the importance of taking pachysandra and sweet box into consideration in disease management planning. PMID- 30426203 TI - The metalloprotease ADAMTS4 generates N-truncated Abeta4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease. AB - Brain accumulation and aggregation of amyloid-beta (Abeta) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Abeta peptides (mainly Abeta1-40 and Abeta1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Abeta peptides are truncated at the N-terminus, with Abeta4-x peptides being particularly abundant. Abeta4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Abeta peptide sequence, which facilitates Abeta4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Abeta4-40 but unchanged levels of Abeta1-x peptides. In the 5xFAD mouse model of amyloidosis, Abeta4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4-/- knockout background, Abeta4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Abeta species, but Abeta4-40 peptides were absent in cultures derived from ADAMTS4-/- mice indicating that the enzyme was essential for Abeta4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Abeta4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Abeta peptides. PMID- 30426204 TI - Frailty assessment prior to thoracic surgery for lung or esophageal cancer: a feasibility study. AB - BACKGROUND: Frailty assessment has not been thoroughly assessed in thoracic surgery. Our primary objective was to assess the feasibility of comprehensive frailty testing prior to lung and esophageal surgery for cancer. The secondary objective was to assess the utility of frailty indices in risk assessment prior to thoracic surgery. METHODS: Prospectively recruited patients completed multiple physiotherapy tests (6-min walk, gait speed, hand-grip strength), risk stratification (Charlson Comorbidity Index, Revised Cardiac Risk Index, Modified Frailty Index), and quality of life questionnaires. Lean psoas area was also assessed by a radiologist using positron emission tomography/computed tomography scans. Data was analyzed using Fisher's exact, Mann-Whitney U and independent t tests. RESULTS: The feasibility of comprehensive frailty assessment was assessed over a 4-month period among 40 patients (esophagus n = 20; lung n = 20). Risk stratification questionnaires administered in clinic had 100% completion rates. Physiotherapy testing required a trained physiotherapist and an additional visit to the pre-admission clinic; these tests proved difficult to coordinate and had lower completion rates (63-75%). Although most measures were not significantly associated with occurrence of complications, the Modified Frailty Index approached statistical significance (p = 0.06). CONCLUSIONS: Frailty assessment is feasible in the pre-operative outpatient setting and had a high degree of acceptance among surgeons and patients. Of the risk stratification questionnaires, the Modified Frailty Index may be useful in predicting outcomes as per this feasibility study. Pre-operative frailty assessment can identify vulnerable oncology patients to aid in treatment planning with the goal of optimizing clinical outcomes and resource allocation. PMID- 30426205 TI - Implementation of modern tools in autopsy practice-the way towards contemporary postmortal diagnostics. AB - Medical, legal, and socioeconomic issues have contributed to the decline of autopsy rates. Pathology-related factors, however, with changing clinical duties on the one hand and decreasing interest and lack of substantial technical developments in this field on the other, may have contributed to this condition as well. We present our experience of a restructuring project that culminated in the introduction of a modernized postmortal diagnostic (PMD) unit: Workflows of PMD procedures and space organization were restructured according to LEAN management principles method. Classical autopsy suites were transformed into postmortal operating rooms. A PMD pathologist staff was designated to perform postmortal operative diagnostics (i.e., using laparotomy and thoracotomy approaches) with the intention of gradually replacing classical autopsy procedures. Postmortal minimal invasive diagnostics (PMID) using laparoscopy and thoracoscopy were successfully implemented with the expertise of clinical colleagues. Reorganization of workflow reduced turn-around times for PMD reports from a median of 33 days to 15 days. Short-term analysis revealed that this combined effort leads to a slight increase in the number of adult postmortal examinations 1 year after the introduction of this project. A change of culture in postmortal diagnostics may contribute to a better reputation of postmortal examinations from the perspective of clinicians, the general public, and affected relatives of the deceased. It may also serve to demonstrate that the pathology community is keen not only to preserve but also to further develop this valuable tool for medical quality control and education. PMID- 30426206 TI - How do methane rates vary with soil moisture and compaction, N compound and rate, and dung addition in a tropical soil? AB - Soil moisture and compaction, and source of N and bovine urine can reduce methane (CH4) rates from agricultural soils. However, the magnitude of the effect is unknown in tropical soil under different conditions, as well as the potential of different urine-N concentration, volume, and sources of N in such an effect. This study aimed to investigate the effects of different soil conditions (moist, dry, compacted, moist-dung, moist-dung-compacted), N concentration in urine (2.5, 5.0, 10.0, and 15.0 g N L-1), volume of urine (25, 50, 100, and 200 ml kg-1 dry soil), and source of N (ammonium, nitrate, and urea) on CH4 emissions. A tropical Ferralsol soil from marandu-grass pasture was incubated during 106 days and the CH4 concentration determined by gas chromatography. The CH4 rates varied significantly according to the soil conditions when manipulated the urine-N (p < 0.01) and averaged 0.75, - 0.50, 1.14, 6.23, and 8.17 MUg C-CH4 m-2 h-1for the moist, dry, compacted, moist-dung, and moist-dung-compacted soil, respectively, and, not responded to the level of N (p = 0.73) averaging 2.57 MUg C-CH4 m-2 h-1. When evaluated, the volumes of urine cumulative CH4 averages were - 0.52, - 1.24, - 0.88, 14.48, and 18.56 MUg C-CH4 m-2 h-1 for the moist, dry, compacted, moist dung, and moist-dung-compacted, respectively. Soils were affected by soil treatments (p < 0.001) but not by urine volumes (p = 0.30). The source of N did not influence the CH4 rates (p = 0.1) averaging 0.88, - 1.26, and - 1.19 MUg C CH4 m-2 h-1 respectively, for urea, nitrate, and ammonium. The CH4 fluxes in tropical Ferralsols are controlled by the soil characteristics and dung addition. PMID- 30426207 TI - The association between occupational standing and sedentary leisure time over consecutive workdays among blue-collar workers in manual jobs. AB - PURPOSE: Blue-collar workers spend much leisure time sedentary, which is associated with numerous health impairments. The extensive sedentary leisure time among blue-collar workers could be caused by fatigue from physically demanding work, like stationary standing. Occupational stationary standing is prevalent in many blue-collar jobs and has been shown to induce fatigue. The objective of this study was to investigate the association between occupational standing and sedentary leisure time over several workdays among blue-collar workers. METHODS: This study used data from 925 workers from Danish workplaces within cleaning, transportation, manufacturing, construction, road maintenance, garbage disposal, and health service. Eligible workers wore accelerometers for 2-5 consecutive workdays. A linear regression was used to investigate the association between percent of work time spent standing and leisure time spent sedentary. A multilevel growth model was used to assess the association between standing during work and sedentary leisure time over consecutive workdays. RESULTS: We found no association between percent of work hours spent standing and percent of leisure time spent sedentary (coef. = 0.01, p = 0.84). The results showed an increase in the workers' sedentary leisure time over a week (coef. = 0.70, p < 0.01). However, this increase was not associated with consecutive workdays exposed to occupational standing (coef. = 0.02, p = 0.42). CONCLUSION: In this study, we found no support of a positive association between occupational standing and sedentary leisure time. This lack of association could be attributable to a low variation in sedentary leisure time or the chosen definition and measurement of occupational standing. PMID- 30426208 TI - The Latin American Brain Tumor Board teleconference: results of a web-based survey to evaluate participant experience utilizing this resource. AB - PURPOSE: The Latin American Brain Tumor Board (LATB) is a weekly teleconference connecting pediatric neuro-oncologists from referral centers in high-income countries with pediatric subspecialists from 20 Latin American countries since 2013. This survey explored the participants' experience utilizing this resource. METHODS: A cross-sectional electronic questionnaire was distributed to 159 participants through email and Cure4Kids. RESULTS: Ninety-five respondents (60%) from all the participating countries completed the survey. Sixty-one reported frequent-attendance (>= 1 per month), 23 reported infrequent-attendance (< 1 per month), and 11 never participated. The most frequently reported attendance barriers were the subspecialist's workload (64%), the timing of the teleconference (38%), and Internet connectivity problems (29%). Subspecialist's workload was more frequently reported as a barrier compared with other barriers, in both the frequent- and infrequent-attendance groups (p < 0.05), with the exception of the timing of the meeting in the infrequent-attendance group. More than 80% of attendees found the frequency and duration of the teleconference were sufficient. Utilizing Spanish as the primary language was reported to enhance the recommendations by 93% of the attendees. Moreover, 84% reported that the recommendations (almost) always fit the local circumstances. Furthermore, 99% of attendees found the teleconference provided a continuing medical education opportunity. Finally, 96% of attendees (almost) always found that the provided recommendations helped to improve the outcomes/quality of life of the patients. CONCLUSIONS: The LATB teleconference provided a valuable tool for the management of pediatric brain tumors in Latin America as it provided a feasible and easy to access continued medical education opportunity for the participants. PMID- 30426209 TI - Antagonistic effects of temperature and dissolved organic carbon on fish growth in California mountain lakes. AB - Resources and temperature play major roles in determining biological production in lake ecosystems. Lakes have been warming and 'browning' over recent decades due to climate change and increased loading of terrestrial organic matter. Conflicting hypotheses and evidence have been presented about whether these changes will increase or decrease fish growth within lakes. Most studies have been conducted in low-elevation lakes where terrestrially derived carbon tends to dominate over carbon produced within lakes. Understanding how fish in high elevation mountain lakes will respond to warming and browning is particularly needed as warming effects are magnified for mountain lakes and treeline is advancing to higher elevations. We sampled 21 trout populations in the Sierra Nevada Mountains of California to examine how body condition and individual growth rates, measured by otolith analysis, varied across independent elevational gradients in temperature and dissolved organic carbon (DOC). We found that fish grew faster at warmer temperatures and higher nitrogen (TN), but slower in high DOC lakes. Additionally, fish showed better body condition in lakes with higher TN, higher elevation and when they exhibited a more terrestrial delta13C isotopic signature. The future warming and browning of lakes will likely have antagonistic impacts on fish growth, reducing the predicted independent impact of warming and browning alone. PMID- 30426210 TI - Explicit knowledge of sensory non-redundancy can reduce the strength of multisensory integration. AB - The brain integrates incoming sensory signals to a degree that depends on the signals' redundancy. Redundancy-which is commonly high when signals originate from a common physical object or event-is estimated by the brain from the signals' spatial and/or temporal correspondence. Here we tested whether verbally instructed knowledge of non-redundancy can also be used to reduce the strength of the sensory integration. We used a cursor-control task in which cursor motions in the frontoparallel plane were controlled by hand movements in the horizontal plane, yet with a small and randomly varying visuomotor rotation that created spatial discrepancies between hand and cursor positions. Consistent with previous studies, we found mutual biases in the hand and cursor position judgments, indicating partial sensory integration. The integration was reduced in strength, but not eliminated, after participants were verbally informed about the non redundancy (i.e., the spatial discrepancies) in the hand and cursor positions. Comparisons with model predictions excluded confounding bottom-up effects of the non-redundancy instruction. Our findings thus show that participants have top down control over the degree to which they integrate sensory information. Additionally, we found that the magnitude of this top-down modulatory capability is a reliable individual trait. A comparison between participants with and without video-gaming experience tentatively suggested a relation between top-down modulation of integration strength and attentional control. PMID- 30426211 TI - Comparison of efficacy of shock-wave therapy versus corticosteroids in plantar fasciitis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Corticosteroid (CS) injections have been proven to be effective in ameliorating symptoms of plantar fasciitis. Shock-wave (SW) therapy is another common treatment of plantar fasciitis, and several meta-analyses have documented its advantages when compared to placebo treatment. Despite this, few studies have focused on comparing the use of CS and SW in the treatment of plantar fasciitis. The purpose of this meta-analysis is to assess whether SW is superior to CS in managing plantar fasciitis, both in terms of ameliorating pain as well as improving functionality. METHODS: A systematic search of the literature was conducted to identify relevant articles that were published in Pubmed, Medline, Embase, the Cochrane Library, SpringerLink, Clinical Trials.gov and OVID from the databases' inception to July 2018. All studies comparing the efficacy of SW and CS in terms of pain levels and functionality improvement were included. Data on the two primary outcomes were collected and analyzed using the Review Manager 5.3. RESULTS: Six studies were included in the current meta-analysis. A significant difference in VAS score (MD = - 0.96, Cl - 1.28 to - 0.63, P < 0.00001, I2 = 96%) was noted between the SW group and the CS group. No significant difference was seen in the Mayo CSS or FFI or HFI or 100 Scoring System score at the 3 months follow-up (Chi2 = 0.62, I2 = 0%, P > 0.05). CONCLUSIONS: The clinical relevance of the present study is that both SW and CS were effective and successful in relieving pain and improving self-reported function in the treatment of plantar fasciitis at 3 months. Although inter-group differences were not significant, the VAS score was better improved in the SW group, highlighting that shock-wave therapy may be a better alternative for the management of chronic plantar fasciitis. PMID- 30426212 TI - Decitabine shows potent anti-myeloma activity by depleting monocytic myeloid derived suppressor cells in the myeloma microenvironment. AB - PURPOSE: Multiple myeloma (MM) remains incurable. The MM microenvironment supports MM cells' survival and immune escape. Because myeloid-derived suppressor cells (MDSCs) is important in the MM microenvironment, and demethylating agent decitabine (DAC) can deplete MDSCs in vitro and in vivo, we hypothesized that DAC treatment could inhibit MM by depleting MDSCs in the MM microenvironment. METHODS: In this study, we used the mouse IL6 secreting, myeloma cell line MPC11 as a model. MDSCs were sorted using magnetic beads and cultured. A transwell coculture assay was used to mimic the microenvironment in vitro. And MPC11 bearing mice model was used to observe the efficacy of DAC treatment in vivo. RESULTS: In vitro coculture assay indicated that MPC11 cells showed significantly lower proliferation rate, less IL6 production and more apoptosis when they were cocultured with bone marrow cells without MDSCs (nonMDSCs) or DAC-treated bone marrow cells (DAC BMs) than with MDSCs or PBS-treated bone marrow cells (CTR BM). Supplementation with M-MDSCs rescued the inhibitory effect of DAC BMs, while additional NOHA supplementation further antagonized the rescue effect of M-MDSCs. In MPC11-bearing mice, the combined treatment of DAC with anti-Gr1 antibody showed synergistic effect on inhibiting tumor growth and promoting T cell infiltration in the tumor tissue. M-MDSC reinfusion also antagonized the efficacy of DAC treatment. CONCLUSIONS: DAC treatment can inhibit myeloma cell proliferation and induce enhanced autologous T cell immune response by depleting M-MDSCs in the MM microenvironment. We believe that DAC treatment could improve the prognosis of MM in future. PMID- 30426213 TI - Both Bupivacaine and Levobupivacaine inhibit colon cancer cell growth but not melanoma cells in vitro. AB - BACKGROUND: Retrospective studies indicate that the use of regional anaesthesia causes a reduction in cancer recurrence after oncological surgery, which could be due to anaesthetic's negating effect on immunosuppression related to the surgical stress response. Local anaesthetics may also exert direct suppressive effects on malignant cells, an area where further investigation is urgently needed. METHODS: Human colon cancer cells and human melanoma cells were cultured and then treated with 1 mM bupivacaine or levobupivacaine for up to 24 or 48 h. Their migratory ability was measured by scratch assay, proliferation determined with Ki67 immunofluorescence staining, and apoptosis accessed with annexin V and PI staining on flow cytometry. The effects of bupivacaine and levobupivacaine on cellular signaling and molecular response, specifically, on endoplasmic reticulum stress (ERS), were studied with immunostaining and western blot. RESULTS: In colon cancer cells, treatment with bupivacaine and levobupivacaine significantly inhibited cell migration (**p < 0.01, ***p < 0.001; n = 4) and proliferation (**p < 0.01; n = 4), while increasing the expression of CHOP (***p < 0.001; n = 4) and decreased the expression of Grp78 (*p < 0.05; n = 4). These effects were not mirrored by melanoma cells, such that no significant increase in apoptosis was seen in either melanoma cell lines following treatment. CONCLUSION: These in vitro data suggested that both bupivacaine and levobupivacaine suppress colorectal adenocarcinoma cell proliferation and migration, which are concurrent with increased endoplasmic reticulum stress. Conversely, melanoma cells are more resilient to these two commonly used local anaesthetics. Further in vivo studies or clinical trials are needed. PMID- 30426214 TI - Dietary changes in a diabetes prevention intervention among people with prediabetes: the Diabetes Community Lifestyle Improvement Program trial. AB - AIMS: Diabetes prevention interventions have been less successful in Asian Indians compared to other populations, which may be due in part to dietary differences. The objective of this study was to determine the impact of a diabetes prevention intervention on diet and risk of diabetes in Asian Indians at high risk. METHODS: Data were included from the Diabetes Community Lifestyle Improvement Program (D-CLIP), a randomized control trial to prevent diabetes in overweight/obese Asian Indian adults (20-65 years) with prediabetes. Respondents received standard treatment (control; n = 283) or a 6-month intervention (n = 295) that included education and support to reduce intakes of fat and total calories (kilocalories; kcal). Diet was ascertained using a food frequency questionnaire, and incident diabetes was determined from annual 2-h plasma glucose post-oral glucose tolerance test or biannual fasting plasma glucose. RESULTS: There were 485 (control 240; intervention 245) respondents with complete diet data at baseline. At 6 months, the intervention was associated with decreased intake of total energy (- 185.6 kcal/day; 95% CI - 353.6, - 17.5 kcal/day) and refined cereals (- 7.2 g/1000 kcal; 95% CI - 12.7, - 1.7 g/1000 kcal), and increased intakes of fruits and vegetables (33.4 g/1000 kcal; 95% CI 16.0, 50.8 g/1000 kcal). The intervention group was half (HR 0.49; 95% CI 0.25, 0.94) as likely to develop diabetes at 1 year, and the hazard was significantly attenuated (12.2%; P = 0.015) with adjustment for fruits and vegetable intake. CONCLUSION: The D-CLIP decreased the total energy intake and increased the intakes of fruits and vegetables, and reduced the 1-year incidence of diabetes by half. TRIAL REGISTRATION: Clinicaltrails.gov # NCT01283308. PMID- 30426215 TI - Complete genome analysis of a novel phage GW1 lysing Cronobacter. AB - A newly identified lytic Cronobacter phage, GW1, was isolated from the Pearl River of Guangzhou, China. GW1 had a double-stranded DNA genome of 39,695 nucleotides with an average GC content of 53.18 %. Among the 49 open reading frames (ORFs) identified, genes for rRNA, tRNA, antibiotic resistance, and virulence factors were not found in the phage genome. The morphology, genomic features, and phylogenetic position of GW1 revealed that it represents a new species in the genus T7virus. This novel lytic Cronobacter phage may provide an alternative for phage therapy and biocontrol against Cronobacter. PMID- 30426216 TI - Discovery of a novel Tymoviridae-like virus in mosquitoes from Mexico. AB - A novel Tymoviridae-like virus, designated Ek Balam virus, was isolated from male Culex quinquefasciatus mosquitoes collected in Yucatan, Mexico. The genome was fully sequenced and shown to have no more than 69% nt sequence identity to its closest known relative. Mosquito cells were permissive to Ek Balam virus replication, but mammalian and avian cells were refractory, suggesting that vertebrates are not involved in the maintenance of the virus in nature. PMID- 30426217 TI - Comparison of low-profile plate-screw and Kirschner-wire osteosynthesis outcomes in extra-articular unstable proximal phalangeal fractures. AB - BACKGROUND: We aimed to present the radiological and clinical results of Kirschner-wire (K-wire) fixation and low-profile plate-screw fixation applied to unstable proximal phalangeal fractures without extension to the joint. METHODS: Clinical and radiological data of 22 patients who underwent fixation with open reduction and low-profile 1.5-mm titanium mini plate and unlocked screws and 18 patients who underwent fixation with K-wire due to closed, unstable extra articular proximal phalangeal fractures were retrospectively examined. All evaluation and statistical analyses were based on sixth postoperative month evaluation parameters. Active and passive metacarpophalangeal joint and interphalangeal joint range of motions, total joint range of motion, measurement of grip strength for fractured and healthy hands, visual analog scoring, disabilities of the arm, shoulder, and hand scores, measurement of distance between the pulpa and palmar curve in the operated finger, Belsky score, reoperation, and complications were evaluated. RESULTS: Radiological union was achieved in all patients in a mean duration of 4.2 (3-6) weeks. When the functional results of the patients were evaluated, the mean active metacarpophalangeal joint flexion was 87.3 degrees (75 degrees -90 degrees ), mean proximal interphalangeal joint flexion was 94.3 degrees (65 degrees -100 degrees ), mean distal interphalangeal joint flexion was 77.6 degrees (75 degrees -80 degrees ), and mean total range of motion was 259 degrees (210 degrees -270 degrees ). The grip strength of the fractured hand was 52.7 (40-58) kgW, whereas that of the healthy hand was 54.4 (42-60) kgW. The mean value of visual analog score was 0.8 (0-2), mean score for disabilities of the arm, shoulder, and hand was 7 (2-27), and mean distance between the finger pulpa and finger curve was 3 (0-8) mm. CONCLUSION: Plate-screw osteosynthesis in the extra articular, unstable fractures of the proximal phalanx, which is "small" compared with the body but has a "major function" for the hand and upper extremity, allows for rigid fixation, short immobilization, and early motion in spiral/oblique fragmented fractures. K-wire fixation, an alternative treatment modality, applied to selected fracture patterns with appropriate indications can achieve good excellent results radiologically and functionally. PMID- 30426218 TI - Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome. AB - BACKGROUND: Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. METHODS: We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. RESULTS: Median age at diagnosis was 0.9 months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. CONCLUSIONS: This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses. PMID- 30426219 TI - Long-term outcomes after early treatment with rituximab for Japanese children with cyclosporine- and steroid-resistant nephrotic syndrome. AB - BACKGROUND: Although rituximab (RTX) may be effective treatment in children with nephrotic syndrome who are resistant to cyclosporine A and steroid (CsA-SRNS), long-term outcomes after B cell depleting therapy remain unclear. CASE DIAGNOSIS/TREATMENT: We retrospectively reviewed the clinical courses (median follow-up, 5.1 years) of six CsA-SRNS children (three boys; median age at RTX, 4.2 years) unresponsive to oral cyclosporine combined with >= 2 courses of intravenous methylprednisolone pulses, who received RTX within 6 months after disease onset (median 11 weeks). After initial RTX treatment (median two doses of 375 mg/m2) followed by retreatment with intravenous methylprednisolone pulses and/or high-dose prednisolone, all patients achieved complete remission at a median of 158 days. Although 17 relapses occurred in five patients during follow up, all but one patient became steroid sensitive. Severe neutropenia and hypogammaglobulinemia developed in two and four patients, respectively. However, no life-threatening infections were identified in the cohort. At last visit (median age, 11.3 years), all patients maintained complete remission without renal insufficiency. CONCLUSIONS: Although late-onset adverse events should be considered, particularly for young patients, early RTX treatment may have positive outcomes in children with CsA-SRNS in the long term. PMID- 30426220 TI - Central systolic blood pressure and central pulse pressure predict left ventricular hypertrophy in hypertensive children. AB - BACKGROUND: Central systolic and pulse pressures are stronger predictors of cardiovascular risk and hypertensive organ damage than brachial blood pressure. It is suggested that isolated systolic hypertension typically seen in adolescents is associated with normal central blood pressure and does not lead to organ damage and this phenomenon is called spurious hypertension. METHODS: We assessed the prevalence of spurious hypertension and analyzed utility of pulse wave analysis as determinant of hypertensive organ damage in 294 children (62 girls; 15.0 +/- 2.4 years) diagnosed as primary hypertension. White coat hypertension, ambulatory prehypertension, ambulatory hypertension, and severe ambulatory hypertension were diagnosed in 127, 29, 41, and 97 patients, respectively. RESULTS: Normal central blood pressure was found in 100% in patients with white coat hypertension, 93% in pre-hypertensives, 51.2% in those with ambulatory hypertension, and 27.8% with severe ambulatory hypertension (p = 0.0001). Children with severe ambulatory hypertension had higher central systolic and pulse pressure, pulse wave velocity, and greater prevalence of left ventricular hypertrophy than white coat and prehypertensive children (p < 0.05). Left ventricular mass index and carotid intima-media thickness correlated with central systolic and pulse pressure (p < 0.05 for all). Receiver operating curve area was similar for augmentation pressure (0.5836), 24-h ambulatory systolic blood pressure (0.5841), central systolic blood pressure (0.6090), and central pulse pressure (0.5611) as predictors of left ventricular hypertrophy. CONCLUSIONS: These findings suggest that pulse wave analysis is complementary to ambulatory blood pressure monitoring in assessment of risk of organ damage in hypertensive adolescents. PMID- 30426221 TI - Childhood onset steroid-sensitive nephrotic syndrome continues into adulthood. AB - BACKGROUND: Childhood steroid-sensitive nephrotic syndrome (SSNS) has previously been assumed to be a disease of childhood. This has been challenged by few studies reporting that some patients with childhood SSNS may continue to relapse into adulthood. The aim of this study was to investigate the long-term outcome of childhood SSNS presenting data from an unselected well-defined cohort of Danish patients. METHODS: We conducted a retrospective study of the clinical outcome from a population of patients consecutively admitted to the pediatric departments in the central and northern region of Denmark from 1998 to 2015. Patients were followed until August 2017. Data were collected from the patient's medical records. RESULTS: Long-term outcome was studied in 39 adult patients with childhood onset SSNS. A total of 31% (12/39) had active disease in adulthood. Univariate analysis showed that more severe forms of SSNS (e.g., steroid dependent/frequent relapsing (SD/FR) nephrotic syndrome) in childhood were associated with active disease in adulthood. Comparing adult patients with SD/FR showed a significantly higher number of relapses/patient/year from late childhood and adolescence in the group with active disease vs. non-active disease (1.06 (95%CI: 0.32-1.81) vs. 0.19 (95%CI: 0.06-0.31, p = 0.005). CONCLUSION: In general, one third of all patients with SSNS during childhood continue to have active disease during early adulthood, in particular patients with SD/FR continue to suffer from active disease. The present data illustrates that SSNS is not just a disease of childhood but persists in adulthood in a significant number of patients. PMID- 30426222 TI - Variability in the evalution of pediatric blunt abdominal trauma. AB - PURPOSE: To describe the practice pattern for routine laboratory and imaging assessment of children following blunt abdominal trauma (BAT). METHODS: Children (age < 16 years) presenting to 14 pediatric trauma centers following BAT over a 1 year period were prospectively identified. Injury, demographic, routine laboratory and imaging utilization data were collected. Descriptive, comparative, and correlation analysis was performed. RESULTS: 2188 children with a median age of 8 (4,12) years were included and the median injury severity score was 5 (1,10). There were significant differences in activation status, injury severity, and mechanism across centers; however, there was no correlation of level of activation, injury severity, or severe mechanism with test utilization. Routine laboratory and imaging utilization for hematocrit, hepatic enzymes, pancreatic enzymes, base deficit urine microscopy, chest and pelvis X-ray, and abdominal computed tomography (CT) varied significantly among centers. Only obtaining a hematocrit had a moderate correlation with CT use. There was no correlation between centers that were high or low frequency laboratory utilizers with CT use. CONCLUSIONS: Wide variability exists in the routine initial laboratory and imaging assessment in children following BAT. This represents an opportunity for quality improvement in pediatric trauma. LEVEL OF EVIDENCE: Level II. PMID- 30426223 TI - Long-term outcomes of antegrade continence enema in children with chronic encopresis and incontinence: what is the optimal flush to use? AB - PURPOSE: Severe constipation and encopresis are significant problems in the pediatric population. Medical management succeeds in 50-70%; however, surgical considerations are necessary for the remainder such as the antegrade continence enema (ACE). The purpose of this study is to assess the long-term outcomes following the ACE procedure. METHODS: All patients undergoing an ACE over a 14 year period were included. Data on clinical conditions, treatments, and outcomes were collected. A successful outcome was defined as remaining clean with <= 1 accident per week. Comparative data were analyzed using the Fisher's exact test, Mann-Whitney U test, or Student's t test. RESULTS: There were 42 ACE patients, and overall, 79% had improvement in their bowel regimens. Encopresis rates decreased from 79 to 5% (P < 0.001). Admissions for cleanouts decreased from 52 to 19% (P = 0.003). All cases of Hirschsprung's, functional constipation and spina bifida were successful. Rates of success varied for other diseases such as slow-transit constipation (60%) and cerebral palsy (33%). A majority (85%) required a change in the enema composition for improvement. CONCLUSION: In our study, ACE reduced soiling, constipation, and need for fecal disimpaction. Higher volume saline flushes used once a day was the optimal solution and most preferred option. LEVEL OF EVIDENCE: Level 4 (retrospective case series or cohort). PMID- 30426225 TI - Evaluating the ontogenetic external morphology of an ectoparasitic Torix tukubana (Hirudinida: Glossiphoniidae), with records of its new host amphibian species. AB - Torix is a leech genus containing freshwater proboscidate species, and several members of this taxon are ectoparasites specific to amphibians. Torix tukubana inhabits mountain streams in Japan, and only two frog species are known to be hosts. We collected this leech from two other amphibians, Onychodactylus japonicus (Japanese clawed salamander) and Rana ornativentris (montane brown frog), for the first time. This finding suggests that the host specificity of T. tukubana is low. The immature individuals of T. tukubana were also collected and identified based on DNA data. This is the first juvenile record of this species confirmed by its DNA barcode sequences. Several morphological characters known from large individuals and used as diagnostic characteristics in taxonomic keys were not observed in the juveniles, suggesting that these are ontogenetic traits. PMID- 30426224 TI - A colorimetric aptasensor for the antibiotics oxytetracycline and kanamycin based on the use of magnetic beads and gold nanoparticles. AB - An aptamer based assay is presented for the determination of the antibiotics oxytetracycline (OTC) and kanamycin (KAN). Magnetic beads were applied for separation, and gold nanoparticles (AuNPs) for signal amplification. DNA aptamers against OTC and KAN were firstly designed. After specific recognition events, the aptamer sequences were released from the surface of magnetic beads and the remaining DNA probes captured horseradish peroxidase (HRP) modified AuNPs. Subsequently, 3,3',5,5'-tetramethylbenzidine and o-phenylenediamine are catalytically oxidized by HRP, and the generated colorimetric responses can reflect the concentrations of OTC (at 370 nm) and KAN (at 450 nm), respectively. Experimental results demonstrate that the method is highly sensitive with the detection limit as low as 1 ag mL-1 for OTC and KAN. An extremely wide linear range (over 11 orders of magnitude) is achieved. The high selectivity is attributed to the high affinity between aptamer and the substrate. The results of real sample tests also verify that the method is promising for antibiotics analysis in the applications of food monitoring and clinical diagnosis. Graphical abstract Schematic presentation of a colorimetric assay for antibiotics based on aptamer-modified magnetic beads and horseradish peroxidase modified gold nanoparticles. Colorimetric responses result from the enzymatic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) and o-phenylenediamine (OPD), respectively. PMID- 30426226 TI - Distribution of Alaria spp. mesocercariae in waterfrogs. AB - The distribution of Alaria-spp.-mesocercariae within the host is relevant for the examination via Alaria spp. mesocercariae migration technique (AMT) regarding predilection sites and may indicate an interaction between parasite and host. Naturally Alaria-exposed frogs of Pelophylax species (n = 13) were examined for systemic distribution and localization-specific parasite density of Alaria spp. mesocercariae. The frogs were necropsied and their body was divided into the following localizations: inner organs, head, torso, forelimbs, and hind limbs. The localizations were analyzed individually and in toto using Alaria spp. mesocercariae migration technique. Our results showed neither statistical differences concerning the number of mesocercariae in the different localizations nor in respect of the rate of positive localizations. Therefore, an accumulation in a particular predilection site seems unlikely. Further research on a representative sample is necessary before final conclusions can be drawn. PMID- 30426227 TI - Trichomonas vaginalis triggers the release of THP-1 extracellular traps. AB - Trichomonas vaginalis is responsible for the prevalence of trichomoniasis, which may be one of the most epidemic nonviral sexually transmitted pathogens. Extracellular traps (ET) are a unique form of innate immunity against infection; they bind to and kill microorganisms. However, the effect of T. vaginalis on ET release in the human monocytic cell line THP-1 remains unclear. In the present study, the morphology of ET derived from THP-1 in response to T. vaginalis was observed by scanning electron microscopy (SEM). The results demonstrated ET entangling T. vaginalis. Then, the colocalization of histone (H3) and myeloperoxidase (MPO) with DNA was observed via fluorescence confocal microscopy. Colocalization revealed the classic characteristics of DNA decorated with H3 and MPO. T. vaginalis significantly increased reactive oxygen species (ROS) and THP-1 derived ET. In addition, we measured the levels of lactic dehydrogenase (LDH) and the phosphorylation of the P38 and ERK1/2 MAPK signaling pathways. The results indicated that the formation of ET induced by T. vaginalis was related to phosphorylation of the P38 and ERK1/2 MAPK signaling pathways but not to LDH levels. These data confirmed the phenomenon of THP-1-derived ET being triggered by T. vaginalis in vitro; this process may play a pivotal role in innate immunity during defense against T. vaginalis infection. PMID- 30426228 TI - Complications of using Gore-Tex in medialization laryngoplasty: case series and literature review. AB - PURPOSE: This study was performed to evaluate the incidence and contributing factors of complications associated with medialization laryngoplasty using Gore Tex in patients with unilateral vocal fold paralysis. METHODS: A retrospective chart review was conducted for all patients who underwent medialization laryngoplasty using Gore-Tex at Tohoku University Hospital between January 2014 and April 2018. A search of series and case reports in PubMed was performed to determine the incidence of complications following medialization laryngoplasty using Gore-Tex. RESULTS: Sixty-eight patient charts were reviewed. Two patients (2.9%) had complications (infection and extrusion into the airway) related to the Gore-Tex implant after surgery. In the 555 medialization laryngoplasty cases reported in both our current data and eight additional articles, there were 11 complications related to the Gore-Tex implant (2.0%). The most common event was extrusion into the lumen, which occurred in six cases (1.1%), followed by persistent inflammation with the granulation formation (0.5%). There were 12 cases of Gore-Tex extrusion (one male, six female, and five of unknown gender). The interval to onset ranged from 1 month to 10 years (median, 49 months). CONCLUSIONS: Our findings serve as a reminder that complications can occur with Gore-Tex implants following medialization laryngoplasty in patients with unilateral vocal fold paralysis, even in the long-term. We suggest that the use of excessively large implants in women and occurrence of postoperative hematoma followed by infection are factors that may cause complications. Nevertheless, Gore-Tex has been proven to be a relatively safe and reliable material for medialization laryngoplasty. PMID- 30426229 TI - The role of adjuvant radiotherapy in management of recurrent pleomorphic adenoma of the parotid gland: a systematic review. AB - PURPOSE: Recurrent pleomorphic adenoma poses a significant treatment challenge, considering its propensity for further recurrence and potential for malignant transformation. The role of adjuvant radiotherapy in its management is widely debated. The aim of this study was to determine whether adjuvant radiotherapy is more effective than surgical resection alone in patients with recurrent pleomorphic adenoma of the parotid gland, in terms of further recurrence, malignant transformation and treatment-related complications. METHODS: Using PRISMA guidelines, a systematic review comparing adjuvant radiotherapy with surgery alone in the treatment of recurrent pleomorphic adenoma was conducted. Pubmed, OVID, EBSCO, Embase, The Cochrane Library, SCOPUS and OpenGrey databases from 1988 to 2018 were searched. Quality analysis was carried out using the Newcastle-Ottawa Scale and narrative synthesis used to summarise results. RESULTS: Of 891 records screened, eight studies were included, assessing 366 participants. Two noted a benefit of adjuvant radiotherapy in reducing further recurrence. The remainder did not show significant benefit, although four showed a trend towards lower rates. Only one case of malignant transformation was identified in a patient not irradiated. Similar rates of facial nerve dysfunction were identified between groups. CONCLUSION: The available evidence suggests that adjuvant radiotherapy reduces recurrence rates in patients with recurrent pleomorphic adenoma and certain adverse prognostic factors. While it appears not to have significant adverse effects, given the lack of prospective evidence, we recommend careful use in patients at high risk of further recurrence and further research in the form of well-designed randomised controlled trials. PMID- 30426230 TI - Pharyngocutaneous fistula after total laryngectomy: multivariate analysis of risk factors and a severity-based classification proposal. AB - PURPOSE: The aim of the study is to determine the predisposing factors for pharyngocutaneous fistula (PCF) in patients undergoing total laryngectomy (TL) or extended TL and, secondarily, to propose a new severity-based classification system. METHODS: This is a retrospective study of 400 patients who underwent TL or extended TL. Major fistula was defined as a fistula (1) persisting for >= 4 weeks, (2) requiring surgical treatment, or (3) associated with perioperative mortality. RESULTS: PCF formation occurred in 93 patients (23.3%) and major fistula in 72 (18.0%). Extended surgery with partial or total pharyngectomy, previous treatment with radiotherapy, and postoperative hemoglobin levels < 99 g/L were associated with a significantly higher risk of developing major fistula. CONCLUSIONS: We propose a new PCF classification system according to clinical severity. Predictors of major fistula were the type of surgery, previous radiotherapy, and low (< 99 g/L) postoperative hemoglobin levels. We consider the use of onlay flaps in irradiated patients who require partial pharyngectomy. PMID- 30426232 TI - ? PMID- 30426231 TI - Unraveling KDM4 histone demethylase expression and its association with adverse cytogenetic findings in chronic lymphocytic leukemia. AB - The acquisition of complex karyotypes is related to the progression of chronic lymphocytic leukemia (CLL) and patients with this condition have a poor prognosis. Despite recent advances in the classification of prognosis in CLL patients, understanding of the molecular mechanisms that lead to genomic instability and progression of this disease remains inadequate. Interestingly, dysregulated expression of KDM4 members is involved in the progression of several cancer types and plays a role in the DNA damage response; however, the gene expression profile and the importance of KDM4 members in CLL are still unknown. Here, we assessed the gene expression profile of KDM4A, KDM4B, and KDM4C in 59 CLL samples and investigated whether these histone demethylases have any influence on the prognostic markers of this leukemia. KDM4A gene expression was higher in CLL patients as compared with control samples. In contrast, CLL samples showed decreased levels of the KDM4B transcript in relation to control cases, and no difference was detected in KDM4C expression. Furthermore, patients with positive expression of ZAP-70 had lower expression of KDM4B and KDM4C as compared with ZAP-70-negative patients. More importantly, patients with low expression of these histone demethylases had higher leukemic cell numbers and displayed adverse cytogenetic findings and the acquisition of a complex karyotype. The present data clearly show that the expression of KDM4 members is dysregulated in CLL and impact the prognosis of this leukemia. These findings are useful for a better understanding of the impact of epigenetics on CLL progression. PMID- 30426235 TI - Residual symptoms and disease burden among patients with psoriatic arthritis: is a new disease activity index required? AB - The aim of this study was to investigate residual symptoms or disease burden among patients with psoriatic arthritis (PsA) in remission or low disease activity (LDA) according to different outcome measures. A total of 126 patients with PsA were included and the following variables were assessed: Tender joint count (TJC), swollen joint count (SJC), patient's global assessment, physician's global assessment, pain, extra-articular manifestations, Psoriasis Area and Severity Index, Health Assessment Questionnaire, fatigue, Short Form-36, psoriatic quality of life, Hospital Anxiety and Depression Scale and C-reactive protein (CRP). Disease activity was measured using three different outcome measures including minimal disease activity (MDA), disease activity score for 28 joints (DAS28-CRP) and disease activity in psoriatic arthritis (DAPSA). The number (%) of patients who achieved remission or LDA was 9(14.1), 34(27.0) and 67(53.2) according to MDA, DAPSA and DAS28-CRP criteria, respectively, under usual care. SJC > 1 was seen in 3(8.8%) and 13(19.4%) of patients in remission or LDA as defined by the DAPSA and DAS28-CRP respectively. TJC > 1 was found at least 32.4% of patients with PsA in remission or LDA by any definition. 22.2 49.3% of patients with PsA in remission or LDA still suffered from clinically important fatigue. No patients in MDA had a substantial functional impairment while 2.9-19.4% of patients fulfilling remission or LDA according to the DAPSA and DAS28-CRP experienced functional disability. At least 22.2% of patients with PsA in remission or LDA by any description had higher risk for depression, and at least 11.1% for anxiety. Despite patients with PsA in remission or LDA by various definition, they may continue to experience pain, tender or swollen joints, fatigue, physiologic distress as well as functional impairment suggesting that there is a significant unmet need with regard to definition of remission or LDA in PsA. PMID- 30426234 TI - Persistent eosinophilia in rheumatoid arthritis: a prospective observational study. AB - Eosinophilia is an uncommon manifestation in Rheumatoid arthritis (RA), and there is a paucity of data regarding the relationship of eosinophilia with disease related factors. We prospectively evaluated the clinical and disease-specific characteristics of RA patients with eosinophilia. Consecutive patients with RA with an absolute eosinophil count >= 500/mm3 without an apparent cause for eosinophilia, were investigated for parasitic infestation. Patients with a definite parasitic infestation received targeted therapy, and the rest were treated with albendazole empirically. The RA disease-specific characteristics of the patients with persistent eosinophilia were compared with the patients without eosinophilia. Of the 160 patients with eosinophilia, 30 patients (19%) had allergic diseases, six patients had bronchiectasis, and one patient had hypereosinophilia of undetermined significance. Intestinal helminthiasis was found in 34 patients (21%). Eosinophilia was unexplained in 89 patients (56%) and it resolved after empirical albendazole therapy in about two-thirds (58 patients). Thirty-one patients had persistent eosinophilia. Nonsteroidal anti inflammatory drug and disease-modifying antirheumatic drug modification did not show any effect on eosinophilia. The disease-related characteristics were similar between patients with persistent eosinophilia and those without eosinophilia. Eosinophilia is due to secondary causes in the majority of RA patients, and the most common cause in our setting is an intestinal helminthic infection. Persistent eosinophilia in our cohort of RA did not indicate a more severe disease phenotype. PMID- 30426236 TI - Similarity of autoimmune diseases based on the profile of immune complex antigens. AB - Since immune complexes (IC) are a direct product of immune response through the binding between antigen and antibody, the profile of antigen-associated ICs may depend on each autoimmune disease. In this report, we examined the similarity of four neurological autoimmune diseases, Alzheimer's disease and healthy donors, and seven connective tissue diseases based on the profiling of IC-associated antigens which were previously or recently identified by immune complexome analysis of cerebrospinal fluid (CSF) or serum samples. The similarity between each pair of two diseases was assessed by correlation coefficients as distance matrix with the use of detection frequency (i.e., the percentage of patients who were positive for a certain antigen in each disease) of each IC-associated antigen in a certain disease. Among 15 pairs of five diseases and healthy control examined by the analysis of CSF samples, only 1 pair of neuropsychiatric systemic lupus erythematosus and multiple sclerosis corresponds to the higher correlation value (r = 0.73) than 0.7. On the other hand, among seven connective tissue diseases examined by the analysis of serum samples, 12 of 21 pairs show high correlation value (r > 0.70). Our finding suggested that the profile of IC associated antigens identified by immune complexome analysis of CSF samples can be useful for evaluating the similarity of neurological autoimmune diseases; however, not by that of serum samples. PMID- 30426237 TI - Treatment patterns, unmet need, and impact on patient-reported outcomes of psoriatic arthritis in the United States and Europe. AB - Psoriatic arthritis (PsA) is a chronic, inflammatory disease. The effects of PsA real-world treatment patterns on patient-reported outcomes in the US and 5 European countries (EU5; France, Germany, Italy, Spain, UK) were evaluated. Respondents from the 2016 National Health and Wellness Survey received advanced therapies (e.g., biologic disease-modifying antirheumatic drugs [DMARDs]), other therapies, (e.g., conventional synthetic DMARDs), or no treatment. Assessments included demographics, disease severity (patient-reported), comorbidities (Charlson Comorbidity Index), health status (Short Form-36 Health Survey), depression (Patient Health Questionnaire-9), work productivity (Work Productivity and Activity Index), and treatment adherence (Morisky Medication Adherence Scale 8). Overall, 1037 respondents from the US and 947 respondents from the EU5 were included. Of these, 21.7% US and 7.3% EU5 respondents received advanced therapies; 16.6% and 28.5%, other therapies; and 61.7% and 64.2%, no treatment, respectively. During treatment with advanced or other therapies, 40.8-54.7% US and 57.7-58.9% EU5 respondents self-reported moderate or severe PsA. Respondents receiving advanced therapies had the highest Charlson Comorbidity Index score (US, 1.25; EU5, 1.42); the lowest scores were with no treatment (0.52 and 0.49, respectively). Employment was lowest with other therapies (US, 47.7%; EU5, 41.1%). Overall work impairment was reported by 57.9% US and 62.6% EU5 respondents receiving advanced therapies. Medication adherence was generally low in the US and medium in the EU5 (Morisky Medication Adherence Scale-8: low, US 40.1-46.7%, EU5, 29.0-35.2%; medium, US 29.3-36.1%, EU5 37.8-49.3%; high, US 23.8 24.0%; EU5, 21.7-27.0%). Advanced and other therapies reduced PsA severity; however, > 40% of respondents reported moderate or severe PsA during treatment. Better management and adherence may reduce unmet need and disease burden. Further work is required to improve PsA diagnosis and time to treatment initiation. PMID- 30426238 TI - Comparison of static and mineralogical ARD prediction methods in the Nordic environment. AB - Acid rock drainage (ARD) is a major problem related to the management of mining wastes, especially concerning deposits containing sulphide minerals. Commonly used tests for ARD prediction include acid-base accounting (ABA) tests and the net acid generation (NAG) test. Since drainage quality largely depends on the ratio and quality of acid-producing and neutralising minerals, mineralogical calculations could also be used for ARD prediction. In this study, several Finnish waste rock sites were investigated and the performance of different static ARD test methods was evaluated and compared. At the target mine sites, pyrrhotite was the main mineral contributing to acid production (AP). Silicate minerals were the main contributors to the neutralisation potential (NP) at 60% of the investigated mine sites. Since silicate minerals appear to have a significant role in ARD generation at Finnish mine waste sites, the behaviour of these minerals should be more thoroughly investigated, especially in relation to the acid produced by pyrrhotite oxidation. In general, the NP of silicate minerals appears to be underestimated by laboratory measurements. For example, in the NAG test, the slower-reacting NP-contributing minerals might require a longer time to react than is specified in the currently used method. The results suggest that ARD prediction based on SEM mineralogical calculations is at least as accurate as the commonly used static laboratory methods. PMID- 30426239 TI - Voltammetric determination of the Alzheimer's disease-related ApoE 4 gene from unamplified genomic DNA extracts by ferrocene-capped gold nanoparticles. AB - A sensitive method is described for detection of the apoE 4 gene detection which is important for early diagnosis of Alzheimer's disease. It is based on signal amplification by using ferrocene (Fc) capped gold nanoparticles modified with streptavidin. The immobilized oligonucleotide probe captures complementary apoE 4 gene. This is followed by the specific recognition of the GCGC sequences which are hydrolyzed by the restriction enzyme HhaI. Cleavage only occurs at the complementary apoE 4 duplex, while mismatches prevent enzymatic cleavage. Thus, the apoE 4 sequence can be discriminated against other apoE sequences. Benefitting from amplified signal by Fc-capped nanoparticle/streptavidin and the recognition of HhaI, the detection limit is as low as 0.1 pM of the ApoE 4 gene. Four genomic DNA samples extracted from blood were analyzed for the presence of the apoE 4 gene. The approach presented here will provide viable proof-of principle for an enzyme-assisted electrochemical assay for the apoE 4 gene in genomic DNAs. Graphical abstract Schematic presentation of amplified voltammetric detection of Alzheimer's Disease-related apoE 4 gene from unamplified genomic DNA extracts via ferrocene capped gold nanoparticle/streptavidin. PMID- 30426241 TI - Influence of super-hydrophobic silicone rubber substrate on the growth and differentiation of human lens epithelial cells. AB - Materials with low cell adhesion are advantageous for production of replacement intraocular lens (IOL) to prevent posterior capsular opacification (PCO). We evaluated the feasibility of compression molding for manufacture of silicone rubber with super-hydrophobic surface and low cell infiltrative characteristics compared to ordinary hydrophobic silicone rubber. Silicone specimens with complex surface topology (super-hydrophobic) or smooth surfaces (hydrophobic) were manufactured by vacuum deforming and molding. Contact angle, microscopic surface structure, and transparency were evaluated. Super-hydrophobic and smooth samples were compared for effects on proliferation, adhesion, and morphology of human lens epithelial cells (hLECs). Epithelial-mesenchymal transition (EMT) was examined by immunofluorescence expression of fibronectin (Fn), Alpha-smooth muscle actin (alpha-SMA), and vimentin. The surface contact angle of super hydrophobic silicone was greater than that of smooth silicone (153.8 degrees vs. 116 degrees ). The super-hydrophobic surface exhibited a micron-scale palisade structure under scanning electron microscopy (unit length, width, and height of 80, 25, and 25 MUm, respectively). However, cell number per 50 * microscopic field on super-hydrophobic surfaces was markedly reduced 24 and 72 h post-seeding compared to smooth surfaces (p < 0.01). Cells were cuboidal or spherical after 72h on super-hydrophobic surfaces, and exhibited numerous surface microvilli with fluff-base polarity, while cells on smooth surfaces exhibited morphological characteristics of EMT. Expression levels of the alpha-SMA and vimentin were reduced on super-hydrophobic surfaces compared to smooth surfaces. Super hydrophobic silicon inhibits proliferation, adhesion, and EMT of hLECs, properties that may prevent fibrosis following cataract surgery. PMID- 30426242 TI - Use of water quality index and multivariate statistical techniques for the assessment of spatial variations in water quality of a small river. AB - Rapid urban development has led to a critical negative impact on water bodies flowing in and around urban areas. In the present study, 25 physiochemical and biological parameters have been studied on water samples collected from the entire section of a small river originating and ending within an urban area. This study envisaged to assess the water quality status of river body and explore probable sources of pollution in the river. Weighted arithmetic water quality index (WQI) was employed to evaluate the water quality status of the river. Multivariate statistical techniques namely cluster analysis (CA) and principal component analysis (PCA) were applied to differentiate the sources of variation in water quality and to determine the cause of pollution in the river. WQI values indicated high pollution levels in the studied water body, rendering it unsuitable for any practical purpose. Cluster analysis results showed that the river samples can be divided into four groups. Use of PCA identified four important factors describing the types of pollution in the river, namely (1) mineral and nutrient pollution, (2) heavy metal pollution, (3) organic pollution, and (4) fecal contamination. The deteriorating water quality of the river was demonstrated to originate from wide sources of anthropogenic activities, especially municipal sewage discharge from unplanned housing areas, wastewater discharge from small industrial units, livestock activities, and indiscriminate dumping of solid wastes in the river. Thus, the present study effectively demonstrates the use of WQI and multivariate statistical techniques for gaining simpler and meaningful information about the water quality of a lotic water body as well as to identify of the pollution sources. PMID- 30426240 TI - The role of atrial fibrillation in the short-term outcomes of patients with acute heart failure. AB - AIMS: To investigate whether the presence of atrial fibrillation (AF) is independently associated with adverse short-term outcomes in patients diagnosed with acute heart failure (AHF) in the emergency department (ED). METHODS: We performed a secondary analysis of patients included in the EAHFE registries 4&5. Patients were divided by the presence of sinus rhythm (SR) or AF at ED arrival. The primary outcome was 30-day all-cause mortality. Secondary outcomes included the 30-day post-discharge combined endpoint of ED revisit or hospitalisation due to AHF and all-cause mortality. We recorded 54 independent variables that can affect outcomes. Cox regression was used to investigate adjusted significant associations between AF and outcomes. Analyses were repeated according to whether AF was previously known and whether AF was considered responsible for the AHF episode. RESULTS: We analysed 6045 ED visits (mean age 80.4 years, 55.9% women), 3644 (60.3%) with AF. The cumulative 30-day mortality was 9.4%, and the adverse combined endpoint (ACE) was 25.9% (ED revisit with and without hospitalisation were 16.5 and 8.9% and death occurred in 4.7%). No differences were found in outcomes of AHF patients with SR and AF, and among the latter group, no differences were found depending on whether AF was considered responsible for the AHF episode. Patients with previously known AF had significantly lower 30-day mortality and higher post-discharge ACE rates, although these differences disappeared after adjustment for confounders HR 0.782, 95% CI 0.590-1.037, p = 0.087; and HR 1.131, 95% CI 0.924-1.385, p = 0.234). CONCLUSION: The coexistence of AF does not impact the short-term outcomes of patients diagnosed with AHF in the ED. PMID- 30426243 TI - Multidisciplinary team in head and neck cancer: a management model. AB - Nowadays, the multidisciplinary team (MDT) is an essential component for oncologic disease management. Its benefit is also extensively recognized in head and neck cancer (HNC) community, due to tumor rarity and complex treatment. A well-defined MDT management serves as a stable point to define the better strategy and offers a chance to optimize HNC clinical outcomes and patient's quality of life. We explored both mandatory and additional requirements for establishing a high-quality MDT. Then we proposed an example of HNC MDT organization. The aim is to contribute to the best way to systematize HNC care. PMID- 30426244 TI - Highly Stretchable Micro/Nano Wrinkle Structures for Infrared Stealth Application. AB - We demonstrate a novel infrared stealth structure consisting of SiO2/TiO2 film, which was manufactured as the highly stretchable triangular wrinkle structures. The triangular wrinkle structures have firstly been transferred to the flexible substrate from the surface of Si-substrate, which was manufactured by the MEMS technology. Then, the infrared reflective film have been manufactured to be the triangular wrinkle structures by depositing the materials (noble metal (Ag or Au) or multilayer oxide (SiO2/TiO2)) on the surface of flexible substrate. Due to the lower reflection effect of curved surface, the infrared reflectivity of these structures has been tuned down to 5%. And, compared to the flat surface, the reflection-to-diffuse ratios improved approximately one order of magnitude. These structures can adapt to the environment by changing the reflectivity of triangular wrinkle structures under stretching. Finally, an Au-modified infrared stealth structure has been fabricated as the array structures, which disappeared and then display by stretching the triangular wrinkle structures at room temperature. It features high reflection-to-diffuse ratios, stable repeatability, low-cost, and easy to manufacture. It may open opportunities for infrared camouflage for military security and surveillance field application. PMID- 30426246 TI - Comparison of environmental flow assessment methods with a case study on a runoff river-type hydropower plant using hydrological methods. AB - This paper focuses on the environmental flow assessment (EFA) methods that maintain the river ecosystem and its integrity for hydropower plants (HPP) with their implementations on a run-off river type HPP. EFA is a crucial phenomenon in terms of electricity production and sustaining river integrity simultaneously. The novelty of this study is that it consists both a comparison of widely used preferred EFA methods and a detailed investigation of the river with pre and post dam flow regimes. The research shows that by expanding the content and scope of the methods, their relative reliabilities increase. However, this situation requires much more expert, money, and time. Apart from most of the relevant literature, pre and post-dam situations are investigated with a flow duration curve (FDC). It is concluded that the dramatic difference between the flow characteristics of pre and post-dam situations affects long-term aquatic life. Furthermore, a case study is conducted using the selected hydrological flow assessment methods, Tennant and Tessman methods, and comparisons are made. The calculated flows are compared with monthly average flow values before dam construction, projected environmental flow data, and the current situation. Accordingly, Tennant's "good classification" is proposed to determine the environmental flow (EF) for the considered case study. PMID- 30426247 TI - Impact of high- and low-intensity resistance training on arterial stiffness and blood pressure in adults across the lifespan: a review. AB - Resistance training (RT) is performed for improvements in body composition in young healthy adults and for health benefits in middle-aged and older adults. Traditionally, RT is prescribed at moderate- to high-intensity to promote benefits on skeletal muscle mass and strength in middle-aged and older adults without considering the vascular effects. Recent evidence suggests that muscle strength may be more protective than muscle mass for cardiovascular disease prevention and that muscle strength can be importantly improved with low intensity RT. The main purpose of this review was to examine the effects of RT intensity on arterial stiffness and blood pressure (peripheral and central) in young and older adults. Although small increases in central arterial stiffness (carotid beta and carotid-femoral pulse wave velocity [PWV]) have been reported in young and middle-aged men, this review suggests that low- and high-intensity RT may not affect arterial stiffness whereas low-intensity RT may decrease systemic arterial stiffness (brachial-ankle PWV) in young healthy adults or not affect arterial stiffness in middle-aged and older adults. Independently of the intensity, RT may be effective to reduce blood pressure (peripheral and central) in middle-aged and older adults with at least elevated blood pressure at baseline. Further studies are needed to examine the impact of RT on arterial stiffness, central blood pressure, and wave reflection in middle-aged and older adults. PMID- 30426245 TI - Management of Locally Advanced and Metastatic Esophageal Cancer in the Older Population. AB - PURPOSE OF REVIEW: This review aims to synthesise the current literature on the management of early-stage and metastatic esophageal cancers, focusing on the older population. In particular, we aim to dissect out the elderly-specific data from the relevant trials and to discuss the issues unique to this population. RECENT FINDINGS: While surgery is the curative modality in esophageal malignancies, the CROSS, MAGIC and FLOT trials demonstrate a clear advantage to neoadjuvant therapy (chemotherapy and chemoradiotherapy). These trials, however, included few elderly patients. There is a similar lack of elderly-specific data in the metastatic setting. Esophageal malignancies remain highly lethal with increasing incidence with age. Despite the relative lack of elderly-specific data, the fit older population appear to similarly benefit from multimodal therapy in early-stage and palliative therapy in metastatic disease. PMID- 30426248 TI - Endurance exercise protects skeletal muscle against both doxorubicin-induced and inactivity-induced muscle wasting. AB - Repeated bouts of endurance exercise promotes numerous biochemical adaptations in skeletal muscle fibers resulting in a muscle phenotype that is protected against a variety of homeostatic challenges; these exercise-induced changes in muscle phenotype are often referred to as "exercise preconditioning." Importantly, exercise preconditioning provides protection against several threats to skeletal muscle health including cancer chemotherapy (e.g., doxorubicin) and prolonged muscle inactivity. This review summarizes our current understanding of the mechanisms responsible for exercise-induced protection of skeletal muscle fibers against both doxorubicin-induced muscle wasting and a unique form of inactivity induced muscle atrophy (i.e., ventilator-induced diaphragm atrophy). Specifically, the first section of this article will highlight the potential mechanisms responsible for exercise-induced protection of skeletal muscle fibers against doxorubicin-induced fiber atrophy. The second segment will discuss the biochemical changes that are responsible for endurance exercise-mediated protection of diaphragm muscle against ventilator-induced diaphragm wasting. In each section, we highlight gaps in our knowledge in hopes of stimulating future research in this evolving field of investigation. PMID- 30426249 TI - Probiotics ameliorate renal ischemia-reperfusion injury by modulating the phenotype of macrophages through the IL-10/GSK-3beta/PTEN signaling pathway. AB - After renal ischemic reperfusion injury, a series of pathological changes, such as impaired intestinal barrier function, intestinal flora, and endotoxin translocation, are caused by intestinal ischemia and hypoxia, which then trigger systemic inflammatory responses and affect the condition and prognosis of the patients. In this study, a rat model of ischemia-reperfusion injury was established by examining changes in renal function, intestinal barrier function, inflammatory index, oxidative stress, and macrophage phenotypes to evaluate the effect of probiotic VSL#3 on renal ischemia-reperfusion injury. The results showed that, after VSL#3 intervention, the levels of BUN, Scr, Cys C, PRO, and NGAL were all significantly decreased compared with the I/R group, while the value of Ccr showed a significant increase. In addition, the concentrations of MPO, IL-1beta, TNF-alpha, IL-6, ED-1, and PCNA were all significantly lower than those in the I/R group, while the levels of endotoxin, DOA, and D-lactic acid were significantly decreased. Furthermore, the proteins associated with intestinal barrier functions, such as ZO-1, Occludin, and Claudin-1, were significantly upregulated compared with the I/R group. Overall, the VSL#3 intervention group was able to maintain the required number of beneficial intestinal flora and to inhibit the proliferation of harmful bacteria. At the same time, the VSL#3 intervention could also prevent the decrease in the levels of CAT, GSH-PX, H2O2, and T-SOD, while downregulating the expression of Keap1 and Nrf2. After the intervention with the VSL#3, the expression levels of CD68 and CD86 proteins were significantly decreased, while the expression levels of CD163 and CD206 proteins were significantly higher. Further experiments confirmed that the expression of iNOS protein was significantly decreased after the VSL#3 intervention, and the expression of Arg-1 and Ym1 proteins was significantly increased. The VSL#3 was able to induce high expressions of p-GSK-3beta and p PTEN proteins, while the use of IL-10 antibody impaired the effect of the VSL#3. In summary, this research confirms that probiotics can alleviate renal dysfunction caused by ischemia and reperfusion by protecting the intestinal barrier function and maintaining the functions of intestinal flora. The pathway screening test of this study suggests that IL-10/GSK3beta/PTEN may play an important role in the process of the prototypic VSL#3 inducing M2 transformation of macrophages. PMID- 30426250 TI - Long-term maintenance of hemoglobin levels in hemodialysis patients treated with bi-weekly epoetin beta pegol switched from darbepoetin alfa: a single-center, 12 month observational study in Japan. AB - Recent evidence on maintenance administration of epoetin beta pegol, a continuous erythropoiesis receptor activator (CERA), in dialysis patients shows the clinical benefit of bi-weekly administration (Q2W) in improving hematopoiesis and iron use efficiency. We undertook a single-center observational study of 33 Japanese maintenance dialysis patients, whose anemia had been kept stable through weekly administration (Q1W) of darbepoetin (DA), to evaluate the effectiveness of CERA Q2W switched from DA in maintaining hemoglobin (Hb) levels over a 12-month period. The target Hb level was 10.0-12.0 g/dL. Throughout the 12-month period, the mean Hb was stably maintained at 10.5-10.8 g/dL, 69.7-87.9% of the patients achieving the target Hb level. The mean CERA dose was within the range of 62.9 78.8 ug/2 weeks. The average CERA dose adjustment frequency after switching was low at 0.42-0.67 times/3 months. In both subgroups stratified by the DA dose prior to the switch, Hb levels were kept stable during CERA administration; however, in the low-dose group (10-20 ug/week of DA), the CERA and iron doses decreased over time, whereas in the high-dose group (30-60 ug/week of DA) they remained unchanged. CERA Q2W achieved long-term successful anemia management in Japanese maintenance dialysis patients after switching from DA Q1W. CERA dose was adjusted based on an overall consideration of past changes in Hb levels, erythropoiesis-stimulating agent and iron doses. Subgroup analysis showed the CERA dose in the low-dose group decreased continuously, due possibly to a long term improvement in iron use efficiency. PMID- 30426251 TI - The role of exposure to pesticides in the etiology of Parkinson's disease: a 18F DOPA positron emission tomography study. AB - Susceptibility to Parkinson's disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD. PMID- 30426252 TI - Genetic variations in the ADCK1 gene predict paliperidone palmitate efficacy in Han Chinese patients with schizophrenia. AB - Genome-wide association study results have linked ADCK1 genetic variation with paliperidone efficacy in a European cohort. However, the generalizability of this locus to non-European populations is unknown. Han Chinese schizophrenia patients (n = 159) were treated with paliperidone palmitate and symptom severity was assessed over 3 months. Examination of 13 ADCK1 genetic variants revealed two single nucleotide polymorphisms (rs12590199, rs11159291) and one haplotype (rs2364747-rs12590199) associated with paliperidone palmitate response. Future work into ADCK1's function and its potential interaction with paliperidone is warranted. PMID- 30426253 TI - Incidence of and risk factors for incisional hernia after closure of temporary ileostomy for colorectal malignancy. AB - PURPOSE: Incisional hernia is a major complication after stoma closure and can cause uncomfortable symptoms. In this study, we evaluated the risk factors for hernia formation with the aim of reducing the incidence of incisional hernia. METHODS: A total of 134 oncology patients underwent closure of a temporary loop ileostomy between May 2004 and December 2013. The incidence of incisional hernia was determined by routine follow-up computed tomography scanning every 6 months. The relationships between patients' characteristics, including age, sex, obesity, diabetes mellitus, surgical site infection, chronic obstructive pulmonary disease, hypertension, hypoalbuminemia, smoking, and presence of a midline hernia and the occurrence of incisional hernia were retrospectively evaluated. RESULTS: The median follow-up time was 47 months (range 8-130). Hernias occurred in 23.9% of patients (32/134). The median time to detection of hernias was 8 months (range 2-39). The Chi-squared test revealed significant differences in obesity (P = 0.0003), hypertension (P = 0.0057), and incisional hernia history (P = 0.0000) between patients with and without incisional hernia. Multivariable analysis and univariate analysis revealed that hypertension and the presence of midline incisional hernia were risk factors for incisional hernia. CONCLUSIONS: Hypertension and the presence of a midline incisional hernia were the major risk factors for incisional hernia after loop ileostomy closure. These risk factors can be addressed before planning surgery. PMID- 30426254 TI - Isoperistaltic versus antiperistaltic ileocolic anastomosis. Does it really matter? Results from a randomised clinical trial (ISOVANTI). AB - BACKGROUND: Right hemicolectomy is a very common surgery. Many studies compare different options for laparoscopic ileocolic anastomoses: intra- or extracorporeal; handsewn or stapled; side-to-side or end-to-side. However, there are no studies about the influence that peristalsis could have on this anastomosis. The aim of this study is to compare safety and feasibility of isoperistaltic and antiperistaltic anastomosis in terms of postoperative morbidity and mortality between both groups. The secondary endpoint is to compare long-term functional outcomes (chronic diarrhoea) and quality of life (GIQLI questionnaire) after a 1-year follow-up period. METHODS: A double-blind, randomised, prospective trial in patients undergoing scheduled surgery for right colon cancer with laparoscopic right hemicolectomy and isoperistaltic (ISO) or antiperistaltic (ANTI) ileocolic anastomoses. RESULTS: Hundred and eight patients were included in the study. Patients were randomised either to isoperistaltic or antiperistaltic configuration (54 ISO/ANTI). No significant differences in baseline variables were found. No differences in surgical time (130 [120-150] min ISO vs. 140 [127-160] ANTI, p = 0.481), nor in anastomotic time (19 [17-22] vs. 20 [16-25], p = 0.207) and nor in postoperative complications: 37.0% ISO versus 40.7% ANTI, (p = 0.693) were found. There were no differences in postoperative ileus (p = 0.112) nor in anastomotic leakage (3.7% vs. 5.56%, p = 1.00). Differences in "time to first flatus" and "time to first deposition" were found in favour of the antiperistaltic group (p = 0.004 and p = 0.017). Anastomotic configuration did not influence hospital stay (3 days [2-6] isoperistaltic vs. 3 [2-4] antiperistaltic, p = 0.236). During follow-up, there were no differences between the two groups at 1, 6 and 12 months (p = 0.154, p = 0.498 and p = 0.683), nor in chronic diarrhoea rates in GIQLI scores (24% ISO vs. 31.4% ANTI, p = 0.541). CONCLUSIONS: The isoperistaltic and antiperistaltic ileocolic anastomosis present similar results in terms of performance, safety and functionality. However, further studies must be carried out in order to assess relationship between postoperative ileus and anastomosis configuration. TRIAL REGISTRATION: Randomised Clinical trial (Identifier: NCT02309931). PMID- 30426255 TI - Surgical trainee impact on bariatric surgery safety. AB - BACKGROUND: Roux-en-Y-gastric bypass (RYGB) and sleeve gastrectomy (SG) are commonly performed bariatric procedures that are associated with a significant learning curve. The effect of surgeon experience on perioperative outcomes and safety is established, but the effect of trainee participation remains unclear. The purpose of this study was to assess the impact of trainees on early perioperative safety of bariatric surgery. METHODS: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database for 2015 was used to identify non-revisional laparoscopic and robotic RYGB and SG procedures. Comparisons were made based on assistant level. Multivariable logistic and linear regression methodology was used to compare clinical outcomes. RESULTS: There were 35,354 laparoscopic RYGB, 2896 robotic RYGB, 79,717 laparoscopic SG, and 5449 robotic SG procedures examined. 21,257 (17%) and 11,322 (9%) of all procedures were performed with a resident or fellow, respectively. Fellow presence was independently associated with the development of complications for all procedure types except robotic SG when compared to non-trainee [odds ratio (OR) 1.31, 2.20, 1.28 for laparoscopic RYGB, robotic RYGB, and laparoscopic SG, respectively]. The most common events were urinary tract and superficial surgical site infections. This negative impact of fellow on overall complications was eliminated after accounting for operative duration. In laparoscopic SG, resident participation was associated with higher leak rate (OR 1.61), readmission (OR 1.18), re intervention (OR 1.4), and complication rate (OR 1.32) compared to non-trainee, even after accounting for procedural duration. In robotic SG, there was no impact of trainee on outcomes. CONCLUSIONS: Although fellow training is associated with higher overall complication rate, there is no such impact on major safety benchmarks, including leak rate and re-operation. In contrast, the impact of resident trainees on SG outcomes is substantial. Operative involvement of trainees in bariatric surgery leads to different outcomes based on trainee level and should be judiciously considered during the programmatic design of bariatric educational curricula. PMID- 30426256 TI - Retzius-sparing versus standard robot-assisted radical prostatectomy: a prospective randomized comparison on immediate continence rates. AB - BACKGROUND: Post-prostatectomy urinary incontinence is an adverse event leading to significant distress. Our aim was to evaluate immediate urinary continence (UC) recovery in a single-surgeon prospective randomized comparative study between the traditional robot-assisted laparoscopic radical prostatectomy (TR RALP) and the Retzius-sparing RALP (RS-RALP), for the treatment of the clinically localized prostate cancer (PCa). METHODS: 102 consecutive PCa patients were prospectively randomized to TR-RALP (57) or RS-RALP (45). Postoperative continence was defined as patient-reported absence of leakage or use of 0 pads/day. The immediate continence rate and 95% confidence interval (CI 95%) were calculated for each treatment. Univariable and multivariate logistic regressions were used to assess predictors of immediate continence following RALP. Continence rates from 1 to 6 months were calculated by Kaplan-Meier curves; log-rank test was used for the curve comparison. Two analyses were performed, considering a per protocol (PP) population regarding all randomized patients that received nerve sparing RALP and an Intention-To-Treat (ITT) population regarding all randomized patients that received RALP. RESULTS: In the PP analysis, the rates of immediate continence were 12/40 (30%) (CI 95% 17-47%) for the TR-RALP and 20/39 (51.3%) (CI 95% 35-68%) for the RS-RALP (p = 0.05). In the ITT analysis, the corresponding rates were 12/57 (21%) (CI 95% 11-34%) for the TR-RALP and 23/45 (51%) (CI 95% 36 66%) for the RS-RALP (p = 0.001). Median time to continence was 21 days for the TR-RALP and 1 day for RS-RALP, respectively (p = 0.02). The relative Kaplan-Meier curves regarding continence resulted statistically different when compared with the log rank test (p = 0.02). In the multivariate analysis, lower age and the Retzius-sparing approach were significantly associated to earlier continence recovery. CONCLUSIONS: The Retzius-sparing approach significantly reduces time to continence following RALP. Further studies are required to confirm the reproducibility of our results and investigate the role of the RS-RALP as an additional "protective" factor for postoperative continence in the elderly population. PMID- 30426257 TI - Letter to the Editor concerning "Global tilt: a single parameter incorporating spinal and pelvic sagittal parameters and least affected by patient positioning" by Obeid I et al. [Eur Spine J; (2016) 25: 3644-3649]. PMID- 30426258 TI - Answer to the Letter to the Editor of Changyu Pan et al. concerning "Global tilt: a single parameter incorporating spinal and pelvic sagittal parameters and least affected by patient positioning" by Obeid I et al. (Eur Spine J; [2016] 25:3644 3649). PMID- 30426259 TI - Current status of late and recurrent intraocular lens dislocation: analysis of real-world data in Japan. AB - PURPOSE: To describe relevant patient demographic characteristics and investigate the influence of known risk factors for late intraocular lens (IOL) dislocation. To explore the associations between these risk factors and the incidence of recurrent IOL dislocation. STUDY DESIGN: Retrospective cohort study. METHODS: This study was performed using Nationwide Diagnostic Procedure Combination data in Japan from April 1, 2008 through July 31, 2016. Descriptive statistics for late and recurrent IOL dislocation, incidence rates, and risk factors for recurrent IOL dislocation were analyzed using a Cox proportional hazard model. RESULTS: We identified 678 patients with late IOL dislocation. Most were men (72%, 488/678), and the men were younger than their women counterparts (mean age 65.2 years vs. 74.5 years). The incidence rate of recurrent IOL dislocation was 5.1 per 100 person-years. All 20 cases of recurrent IOL dislocation were observed within the year following surgery. There were no significant associations between potential risk factors and recurrent IOL dislocation (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.55-4.26 for diabetes mellitus; adjusted HR 0.77, 95%CI 0.09-6.40 for atopic dermatitis); no recurrences occurred in patients with pseudoexfoliation syndrome, retinitis pigmentosa, or connective tissue disease. CONCLUSIONS: Late IOL dislocation occurs more frequently in men. We found that recurrent IOL dislocation was rare during long-term follow-up and there were no significant associations between the potential risk factors and recurrent IOL dislocation. Further studies are needed to clarify the sex-related differences involved in IOL dislocation. PMID- 30426260 TI - CRISPR as agent: a metaphor that rhetorically inhibits the prospects for responsible research. AB - In 2015, a group of 18 scientists and bioethicists published an editorial in Science calling for "open discourse on the use of CRISPR-Cas9 technology to manipulate the human genome" and recommending that steps be taken to strongly discourage "any attempts at germline genome modification" in humans with this powerful new technology. Press reports compared the essay to a letter written by Paul Berg and 10 other scientists in 1974, also published in Science, calling for a voluntary deferral of certain types of recombinant DNA experimentation. A rhetorical analysis of the metaphors in these two documents, and in the summary statements that came out of the respective National Academy of Sciences conferences they instigated, shows that while they have a lot in common, they are different in at least one important way. The more recent texts deploy conceptual metaphors that portray the biotechnology in question as an autonomous agent, subtly suggesting an inevitability to its development, in contrast to the earlier texts, which portray the scientists who are using the technology as the primary agents who take action. Rhetorical moves depicting biotechnology as an agent in the 2015 texts hint at contemporary skepticism about whether humans can restrain the forward momentum of science and technology in a global context, thus inhibiting scientists from imagining a consequential role for themselves in shaping the future of responsible research. PMID- 30426261 TI - Correction to: Alison Butler: papers in celebration of her 2018 ACS Alfred Bader Award in Bioorganic or Bioinorganic Chemistry. AB - "In the original online publication, the Foreword was incorrectly attributed. The correct author is Lawrence Que, Jr". PMID- 30426262 TI - Correction to: ASO Author Reflections: Fluorescent-Guided Surgery to Augment Pancreatic Cancer Surgery. AB - In the original version of this article, George A. Poultsides's middle initial was incorrect. PMID- 30426263 TI - ASO Author Reflections: African Americans and Rectal Cancer Surgery. PMID- 30426264 TI - Late Presentation and Missed Opportunities for HIV Diagnosis in Guatemala. AB - Early HIV diagnosis remains a challenge in many regions with delayed diagnosis resulting in increased morbidity and mortality. We conducted a retrospective cohort study of people living with HIV receiving outpatient care at a large tertiary referral center in Guatemala to describe the proportion of late presenters (LP) and missed opportunities for HIV diagnosis. Of 3686 patients, 2990 (81.1%) were LP who were more likely to be male (60.2% vs. 48.0%, p < 0.0001), heterosexual (88.0% vs. 78.0%, p < 0.0001) and rural dwellers (43.7% vs. 33.8%. p < 0.0001). The proportions of patients who presented late or with AIDS at diagnosis decreased over time. Only 665 patients (18.2%) sought care in the 2 years prior to HIV diagnosis. This study, the first of its kind in Central America to focus on late presenters and missed opportunities for HIV diagnosis, demonstrates extremely high rates of LP in Guatemala. Although in recent years rates of LP have improved somewhat, the need for screening outside of traditional healthcare settings is apparent. PMID- 30426265 TI - The influence of enamel sandblasting on the shear bond strength and fractography of the bracket-adhesive-enamel complex tested in vitro by the DIN 13990:2017-04 standard. AB - OBJECTIVES: This study was conducted in order to investigate whether enamel sandblasting as an adjunct or substitute to the acid-etch technique has an effect on the shear bond strength (SBS) and fractography of the bracket-adhesive-enamel complex using the DIN 13990:2017-04 standard. MATERIALS AND METHODS: Upper central incisor brackets (discovery(r), Dentaurum, Germany) were bonded using Transbond XTTM (3M Unitek, Germany) on bovine incisors prepared by four different methods (15 samples each): sandblasting with 27 MUm Al2O3 at 1.2 bar (s), acid etching with 37.4% phosphoric acid (a), sandblasting with 27 MUm Al2O3 at 1.2 bar followed by acid etching (s1a), and sandblasting with 50 MUm Al2O3 at 5.7 bar followed by acid etching (s2a). The SBS and adhesive remnant index (ARI) were measured, followed by one-way analysis of variance and Fisher's exact tests at 5%. RESULTS: The SBS in groups s (5.6 +/- 2.2 MPa), a (17.1 +/- 4.3 MPa), s1a (18.3 +/- 4.3 MPa), and s2a (18.5 +/- 4.6 MPa) indicated that the s group was significantly inferior to all the other groups (p < 0.001). Likewise, the ARI analysis indicated a different performance of the s group (mostly ARI of 0) compared to the other groups (p < 0.001) and a tendency for different ARI between the a and s1a/s2a groups. CONCLUSIONS: In vitro enamel sandblasting could not substitute acid etching and did not offer improved SBS when used before acid etching, regardless of air pressure and powder granulation. Sandblasting without acid etching produced less residual resin on the tooth after debonding. CLINICAL RELEVANCE: The clinical use of adjunct enamel sandblasting prior to etching to enhance SBS has to be questioned. PMID- 30426266 TI - Prevalence of WNT10A gene mutations in non-syndromic oligodontia. AB - OBJECTIVES: Non-syndromic oligodontia is an infrequent clinical condition whose etiology is not yet completely understood being a wide spectrum of gene mutations described in concomitance with this severe form of tooth agenesis. Recently, multiple observations have linked up to 50% of cases with isolated hypodontia to mutations in the WNT10A gene. Here, we hypothesized that mutations in the WNT10A gene could also be present in families affected by non-syndromic oligodontia. MATERIAL AND METHODS: All available patients with non-syndromic oligodontia (n = 20) treated at the Department of Orthodontics, University of Giessen, Germany between 1986 and 2013 as well as their family members were analyzed for mutations in the WNT10A gene. RESULTS: Mutation screening was positive in 50% of the 20 patients. The analysis revealed that the mutations 2:219755011(c.682T>TA)(p.F228I), 2:219754822(c.493G>GA)(p.G165R), 2:219754816(c.487C>CT)(p.R163W), and 2:219747090(c.321C>CA)(p.C107*), the novel missense mutation 2:219757676(c.937G/GT)(p.G313C), and the novel synonym variant 2:219754854(c.525C>CT)(p.H175H) were present. CONCLUSION: Multiple phenotypes are found in individuals presenting mutations in the WNT10A gene. Among them, the stop codon p.C107* as well as the biallelic p.F228I variants correlate with the most severe oligodontia phenotypes. In addition, we diagnosed the monoallelic mutations p.F228I, p.G165R, and p.G313C in healthy relatives with normal dentitions. CLINICAL RELEVANCE: A correct diagnosis of non-syndromic oligodontia is fundamental to discard a possible underlying pathology in which multiple tooth agenesis could be the most evidential clinical sign. Due to the wide spectrum of pathologies that are associated to mutations in the WNT10A gene, an extended genetic analysis of these individuals' relatives is also essential. PMID- 30426267 TI - Exploratory Study of Low Resolution Electromagnetic Tomography (LORETA) Real-Time Z-Score Feedback in the Treatment of Pain in Patients with Head and Neck Cancer. AB - Acute pain from mucositis in patients with head and neck cancer (HNC) undergoing radiation therapy (RT) is common, and may not respond well to narcotics. We used low resolution electromagnetic tomography z-score neurofeedback (LFBz) to investigate whether patients could modify brain wave activity associated with acute pain and whether this would reduce the experience of pain. HNC patients scheduled for RT had baseline pre-pain onset measures (EEG and numeric rating scale) collected before RT and then at pain onset before using analgesics, after each LFBz session and at the end of RT. Up to six sessions of LFBz training were offered over the remaining RT. Up to six 20-min sessions of LFBz were offered over the remaining RT. Data were collected before and after each LFBz session and at the end of RT. Seventeen patients recruited; fourteen were treated and reported decreased pain perception. LFBz allowed patients to modify their brain activity in predesignated areas of the pain matrix toward the direction of their baseline, pre-pain condition (including Brodmann areas (BAs) 3, 4, 5, 13, 24, and 33). LFBz can modify brain regions relevant for pain and these changes were associated with self-reported decreases in pain perception. PMID- 30426268 TI - The post hoc analysis comparing the severity grades of chemoradiotherapy-induced oral mucositis scored between the central and local assessors in a multicenter, randomized controlled trial of rebamipide for head and neck cancer. AB - BACKGROUND: In the treatment of head and neck cancer, severity of chemoradiotherapy-induced oral mucositis has been recognized as one of the key factors affecting the outcomes of the anticancer therapies. Therefore, the development of treatments mitigating oral mucositis would be of clinical significance, although the adequate assessment procedure for efficacy evaluation remains to be established. We conducted this post hoc study to assess the effect of objective evaluation of the severity grade on the outcomes of the clinical trial. METHODS: In the original trial with rebamipide liquids (0, 2, and 4%) for chemoradiotherapy-induced oral mucositis, the investigators in local sites and independent central review separately determined the severity grades in accordance with Common Terminology Criteria of Adverse Events version 3.0 based on the Assessment Sheet scored by the investigators. The discordance in severity grades between the investigators and central review was analyzed on cross table. RESULTS: The analysis revealed the discordance rate over the trial was 34%. While the incidences of severe oral mucositis in the placebo, rebamipide 2%, and 4% groups evaluated by the central review were 39%, 29%, and 25%, respectively, the respective values in the investigator's evaluation were 32%, 39%, and 44%. CONCLUSION: In the clinical trial for the treatment of oral mucositis, it was strongly suggested that objective evaluation with a consistent scale would be required. PMID- 30426269 TI - The final implant position of a commonly used collarless straight tapered stem design (Corail(r)) does not correlate with femoral neck resection height in cement-free total hip arthroplasty: a retrospective computed tomography analysis. AB - BACKGROUND: In total hip arthroplasty, inadequate femoral component positioning can be associated with instability, impingement and component wear and subsequently with patient dissatisfaction. In this study, we investigated the influence of femoral neck resection height on the final three-dimensional position of a collarless straight tapered stem (Corail(r)). We asked two questions-(1) is neck resection height correlated with version, tilt, and varus/valgus alignment of the femoral component, and (2) dependent on the resection height of the femoral neck, which area of the stem comes into contact with the femoral cortical bone? MATERIALS AND METHODS: Three-dimensional computed tomography scans of 40 patients who underwent minimally invasive, cementless total hip arthroplasty were analyzed retrospectively. We analyzed the relationship between femoral neck resection height and three-dimensional alignment of the femoral implant, as well as the contact points of the implant with the femoral cortical bone. This investigation was approved by the local Ethics Commission (No.10-121-0263) and is a secondary analysis of a larger project (DRKS00000739, German Clinical Trials Register May-02-2011). RESULTS: Mean femoral neck resection height was 10.4 mm (+/- 4.8) (range 0-20.1 mm). Mean stem version was 8.7 degrees (+/- 7.4) (range - 2 degrees to 27.9 degrees ). Most patients had a varus alignment of the implant. The mean varus/valgus alignment was 1.5 degrees (+/- 1.8). All 40 patients (100%) had anterior tilt of the implant with a mean tilt of 2.2 degrees (+/- 1.6). Femoral neck resection height did not correlate with stem version, varus/valgus alignment, or tilt. Independent from femoral neck resection height, in most patients the implant had contact with the ventral and ventromedial cortical bone in the upper third (77.5%) and the middle third (52.5%). In the lower third, the majority of the implants had contact with the lateral and dorsolateral cortical bone (92.5%). CONCLUSION: Femoral neck resection height ranging between 0 and 20.1 mm does not correlate with the final position of a collarless straight tapered stem design (Corail(r)). LEVEL OF EVIDENCE: Level 3. PMID- 30426270 TI - Rapid Genomic and Genetic Changes in the First Generation of Autotetraploid Lineages Derived from Distant Hybridization of Carassius auratus Red Var. (?) * Megalobrama amblycephala (?). AB - Autopolyploids are traditionally used to demonstrate multivalent pairing and unstable inheritance. However, the autotetraploid fish (4nRR) (RRRR, 4n = 200) derived from the distant hybridization of Carassius auratus red var. (RCC) (RR, 2n = 100) (?) * Megalobrama amblycephala (BSB) (BB, 2n = 48) (?) exhibits chromosome number (or ploidy) stability over consecutive generations (F1-F10). Comparative analysis based on somatic and gametic chromosomal loci [centromeric, 5S rDNA, and Ag-NORs (silver-stained nucleolar organizer regions)] revealed that a substantial loss of chromosomal loci during genome doubling increases the divergence between homologous chromosomes and that diploid-like chromosome pairing was restored during meiosis in the first generation of 4nRR lineages. In addition, a comparative analysis of genomes and transcriptomes from 4nRR (F1) and its diploid progenitor (RCC) exhibited significant genomic structure and gene expression changes. From these data, we suggest that genomes and genes diverge and that expression patterns change in the first generations following autotetraploidization, which are processes that might contribute to the stable inheritance and successful establishment of autotetraploid lineages. PMID- 30426272 TI - High-pitch versus standard mode CT pulmonary angiography: a comparison of indeterminate studies. AB - PURPOSE: To compare the causes of indeterminate CT pulmonary angiograms using standard mode and high-pitch mode, and determine at what level of the pulmonary arterial tree studies were non-diagnostic. METHODS: IRB approval was obtained. A retrospective review of patients at our institution who underwent a CT pulmonary angiogram, between November 1, 2015 and February 10, 2016 was performed. CT pulmonary angiograms using both high-pitch mode and standard mode were evaluated with positive and indeterminate rates calculated. Causes of indeterminate studies and the level of the pulmonary arterial tree at which the study became non diagnostic were determined by a board certified radiologist by looking at the images of each indeterminate study. The indeterminate rates were compared between high-pitch and standard modes using a generalized estimating equation. RESULTS: Five hundred fifty-nine CT pulmonary angiograms using high-pitch mode were evaluated, while 661 standard mode scans were evaluated. 69/559 (12.3%) scans with high-pitch mode were positive and 84/661 (12.7%) scans with standard mode were positive (not statistically significant, p > 0.05). There was a higher rate of indeterminate scans with standard mode compared to the high-pitch mode (80 [12.1%] standard vs. 25 [4.5%] high-pitch, p value < 0.0001). Findings were indeterminate at the lobar level in 4 (16%), at the segmental level in 11 (44%), and at the subsegmental level in 10 (40%) using high-pitch mode. The most common causes of an indeterminate scan using high-pitch mode were motion in 11 (44%), transient interruption of contrast in 6 (24%), and contrast timing in 5 (20%). Findings were indeterminate at the main pulmonary artery level in 1 (1.3%), at the lobar level in 13 (16.3%), at the segmental level in 28 (35.0%), and at the subsegmental level in 38 (47.5%) using the standard mode. The most common causes of an indeterminate scan using the standard mode were motion in 53 (66.3%), transient interruption of contrast in 19 (23.8%), and contrast timing in 15 (18.8%). CONCLUSIONS: High-pitch mode results in statistically significant fewer indeterminate studies compared with standard mode. Furthermore, there were statistically significant fewer indeterminate studies due to motion artifact with high-pitch mode compared with standard mode. PMID- 30426271 TI - Plasma levels of interleukin-33 and soluble suppression of tumorigenicity 2 in patients with advanced pancreatic ductal adenocarcinoma undergoing systemic chemotherapy. AB - Interleukin-33 (IL-33) and its "decoy" receptor soluble ST2 (sST2) are involved in the development of chronic inflammation and cancer. We explored IL-33 and sST2 as a potential prognostic marker in patients with metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). IL-33 and sST2 plasma levels were assessed in 20 patients with advanced PDAC before start of systemic chemotherapy and were analyzed in relation to clinical outcome. Kaplan Meier and multivariable Cox proportional hazards model analysis revealed a significant association between sST2 plasma levels and survival (HR 2.10, 95% CI 1.33-3.41, p = 0.002) and link high sST2 plasma levels to inferior survival in patients with advanced PDAC undergoing chemotherapy. PMID- 30426273 TI - Characterization and expression of melanin-concentrating hormone (MCH) in common carp (Cyprinus carpio) during fasting and reproductive cycle. AB - Melanin-concentrating hormone (MCH) was initially known as a regulator of teleost skin color and possesses multiple functions in mammals, such as the regulation of energy balance and reproduction. However, the role of MCH in fish remains unclear. In the present study, a 590 bp cDNA fragment of common carp (Cyprinus carpio) MCH gene was cloned. Amino acid sequence similarities with other teleost ranged from 23 to 93%. The mature MCH peptide (DTMRCMVGRVYRPCWEV) located in the C-terminal region of MCH precursor was 100% identical to that of goldfish, zebrafish, chum salmon, and rainbow trout. Tissue expression profiles showed that MCH mRNA was ubiquitously expressed throughout the brain and peripheral tissues and highly expressed in the brain and pituitary. Within the brain, MCH mRNA was expressed preponderantly in the hypothalamus. MCH mRNA expression in the hypothalamus was increased after feeding, decreased after 3, 5, or 7 days fasting, and increased upon refeeding. These results suggested that MCH might have anorexigenic actions in common carp. Meanwhile, MCH gene expression varied based on reproductive cycle, which might be related to the long-term regulation of MCH in energy balance. In conclusion, our novel finding revealed that MCH was involved in the regulation of appetite and energy balance in common carp. PMID- 30426274 TI - Obesity, political responsibility, and the politics of needs. AB - Since overweight and obesity have been framed as one of the main contemporary health challenges in industrialized countries, it has become a matter of public health efforts. While the belief that obese individuals are personally responsible for their body weight prevails in public opinion, evidence-based health science widely acknowledges that obesity is significantly influenced by socio-economic factors and thus that prevention requires structural changes. This constellation bears the chance of politicizing an issue formerly conceived of as private which really is dependent on societal contingencies, such as the particular availability of food. Reflecting on the prevention of obesity from an ethical point of view, therefore, requires an elaborate concept of political responsibility. The core thesis of this paper is that existing approaches within the field of obesity ethics fall short in reasonably grasping the political dimensions at play, due to the prevailing individualistic understanding of responsibility. Drawing upon Iris Marion Young's concept of political responsibility, I propose an alternative approach that emphasizes the structural determinants of obesity. By arguing this way, obesity prevention comes into view as a public endeavor that involves public discourse as well as shared action. Political responsibility then cannot be discharged merely by intrusive governmental action nor by individuals on their own, but should be considered as a task all of us share. As I will sketch in the last part of the paper, this includes contesting discourses on interpretations of need. Thereby, the paper contributes to recognizing obesity as a social instead of an individual problem. PMID- 30426275 TI - Nested exposure case-control sampling: a sampling scheme to analyze rare time dependent exposures. AB - For large cohort studies with rare outcomes, the nested case-control design only requires data collection of small subsets of the individuals at risk. These are typically randomly sampled at the observed event times and a weighted, stratified analysis takes over the role of the full cohort analysis. Motivated by observational studies on the impact of hospital-acquired infection on hospital stay outcome, we are interested in situations, where not necessarily the outcome is rare, but time-dependent exposure such as the occurrence of an adverse event or disease progression is. Using the counting process formulation of general nested case-control designs, we propose three sampling schemes where not all commonly observed outcomes need to be included in the analysis. Rather, inclusion probabilities may be time-dependent and may even depend on the past sampling and exposure history. A bootstrap analysis of a full cohort data set from hospital epidemiology allows us to investigate the practical utility of the proposed sampling schemes in comparison to a full cohort analysis and a too simple application of the nested case-control design, if the outcome is not rare. PMID- 30426276 TI - Is quality of life a suitable measure of patient decision aid effectiveness? Sub analysis of a Cochrane systematic review. AB - PURPOSE: Patient decision-aids (PtDAs) help patients make informed treatment decisions incorporating their values. Health-related quality of life (HRQOL) is sometimes an outcome of PtDA effectiveness trials, but its suitability for this purpose is unclear. We sought to provide insights into this question by critically appraising how randomized controlled trials (RCTs) evaluating PtDA effectiveness measure and report HRQOL. METHODS: We conducted a sub-analysis of RCTs included in the 2017 Cochrane review of PtDAs. Trials assessing HRQOL at baseline and post-PtDA, and comparing PtDA with comparison groups were included. Two reviewers independently extracted data and assessed study quality. Analysis was descriptive. RESULTS: Of 105 RCTs, 11 were eligible for inclusion. Patients randomized to PtDAs did not report better HRQOL than those randomized to usual care. While all 11 RCTs adequately described baseline sample characteristics and reported HRQOL results for study groups, few stated a priori HRQOL expectations or hypotheses (36%); made a link between HRQOL and the decision (18%); provided a rationale or justification for HRQOL assessment (18%); provided reason for choice of HRQOL assessment time-points (9%); or adjusted p-values for multiple HRQOL domains and time-points (0%). DISCUSSION: PtDAs did not conclusively impact HRQOL. If this holds generally, then HRQOL is an uninformative endpoint for PtDA effectiveness trials. When planning trials of PtDAs, investigators considering HRQOL endpoints should consider whether and why their PtDA is likely to affect HRQOL in their context, and if so, which specific aspect(s) of HRQOL and at which time-point(s), and ensure HRQOL is assessed accordingly. PMID- 30426277 TI - Individualized health-related quality of life instrument Measure Yourself Medical Outcome Profile (MYMOP) and its adaptations: a critical appraisal. AB - BACKGROUND: Health-related quality of life (HRQL) is increasingly recognized for its importance in health research. As there is increasing recognition of the inter-individual difference in response to therapeutic interventions, it may be helpful to apply individualized measures of HRQL. The MYMOP is a commonly used example of such measures, although several adaptations have been developed. OBJECTIVE: This review was conducted to identify adaptations of MYMOP, and evaluate the measurement properties of MYMOP and its adaptations. METHODS: Adaptations were identified using MYMOP website and personal communication, supplemented by a SCOPUS search in April 2017. Bibliographies of included studies were hand-searched. COSMIN criteria were used to evaluate the measurement properties. RESULTS: Sixteen studies were included in this review. Adaptations were developed to evaluate individualized therapies in cancer, psychiatry, and acupuncture. The included measures were MYMOP, measure yourself concern and wellbeing, psychological outcome profiles (PSYCHLOPS), and MYMOP-pictorial (MYMOP P). The quality of the measurement properties varied; none of the included measures met all currently recommended quality criteria for measurement properties. CONCLUSION: Current literature provides evidence that MYMOP and its adaptations offer individualized assessment of patient-centered outcomes, and thereby provide a means to understand heterogeneity of treatment effects. However, current recommendations for psychometric testing suggest further validation of these measures would be beneficial. PMID- 30426279 TI - A Cu(II)-anchored unzipped covalent triazine framework with peroxidase-mimicking properties for molecular imprinting-based electrochemiluminescent detection of sulfaquinoxaline. AB - The authors describe a method of electrochemiluminescent quantitation of the antibiotic sulfaquinoxaline (SQX). It relies on the use of a molecularly imprinted polymer and a Cu(II)-anchored unzipped covalent triazine framework (UnZ CCTF) with excellent dispersibility, electrical conductivity, and peroxidaze-like activity. The framework was prepared by unzipping a covalent triazine framework under retention of basic triazine units. It was morphologically and structurally characterized by a range of instrumental techniques. The excellent peroxidase mimicking effect of UnZ-CCTF on the electrochemiluminescence of the luminol/H2O2 system was exploited to design an ultrasensitive SQX assay with a 1.0-20 pM detection range and a detection limit of 0.76 pM (at 3delta/m). The technique was used for SQX quantitation in spiked milk samples, achieving recoveries of 94.0 104.8%. Graphical abstract Scheme of the sulfaquinoxaline molecularly imprinted electrochemiluminescence sensor based on Cu-anchored unzipped covalent triazine frameworks. PMID- 30426280 TI - PPPDE1 promotes hepatocellular carcinoma development by negatively regulate p53 and apoptosis. AB - We have previously identified that PPPDE1 is a deubiquitinase (DUB) belonging to a cysteine isopeptidase family. Here we sought to explore the biological significance of PPPDE1 in hepatocellular carcinoma and its underlying molecular mechanism. In the present study, we found that amplification and overexpression of PPPDE1 were associated with poor prognosis in hepatocellular carcinoma (HCC). We also demonstrated that knocking down of PPPDE1 could significantly block the clonal growth and tumorigenicity of human HCC cells, which revealed a critical role for PPPDE1 in HCC development. Furthermore, we proved that PPPDE1 is a key modulator of p53 protein level and its down stream apoptosis pathway. Taken together, these results suggested that PPPDE1 is a putative HCC driver gene and extensive studies should be conducted in the future to investigate the role of PPPDE1 in HCC and other tumors. PMID- 30426278 TI - Prevention Strategies in Endometrial Carcinoma. AB - PURPOSE OF THE REVIEW: To assess the most recent high-quality evidence for endometrial cancer prevention strategies. RECENT FINDINGS: Obesity is an established risk factor for endometrial cancer. Weight cycling and weight gain in middle age are risk factors for endometrial cancer. Bariatric surgery reduces the risk of endometrial cancer by up to 81% in obese women who attain and maintain a normal weight. Combined oral contraceptives provide durable protection against endometrial cancer for 30 years or more. Ever use of the levonorgestrel intrauterine system (LNG-IUS) and inert intrauterine devices reduce endometrial cancer risk. The first oestrogen-based non-progestin HRT for non-hysterectomised women that contains estradiol and bazedoxifene has an effective protective effect on endometrium. Bisphosphonates reduce endometrial cancer risk. Weight loss and LNG-IUS would seem to be an effective strategy for preventing the development of obesity-driven endometrial cancer in the highest risk women. Future research may identify other safe and effective chemoprevention interventions, such as aspirin, bisphosphonates or metformin. PMID- 30426281 TI - Holistic approach for quantification and identification of pollutant sources of a river basin by analyzing the open drains using an advanced multivariate clustering. AB - Global scarcity of freshwater has been gearing towards an unsustainable river basin management and corresponding services to the humans. It needs a holistic approach, which exclusively focuses on effective river water quality monitoring and quantification and identification of pollutant sources, in order to address the issue of sustainability. These days, rivers are heavily contaminated due to the presence of organic and metallic pollutants released from several anthropogenic sources, such as industrial effluents, domestic sewage, and agricultural runoff. It is astonishing to note that even in many developing countries, most of these contaminants are carried through open drains, which enter river premises without proper treatment. Such practice not only devastates riverine ecosystem but also gives rise to deadly diseases, such as minimata and cancer in humans. Considering these issues, the present study develops a novel approach towards simultaneous identification of major sources of pollution in the rivers, along with critical pollutants and locations using an advanced hierarchical cluster and multivariate statistical analysis. A systematic approach has been developed by agglomerating both R-mode and Q-mode analysis, which develops monoplots, two-dimensional biplots, rotated component matrices, and dendrograms (using "SPSS" and "Analyse It" software) to reveal relationships among various quality parameters to identify the pollutant sources along with clustering of critical sampling sites and pollutants. A case study of the Ganges River Basin of India has been considered to demonstrate the efficacy and usefulness of the model by analyzing 85 open drains. Both organic and metallic pollutants are analyzed simultaneously as well as separately to get a holistic understanding of all the relationships and to broaden the perspective of water characterization. Results provide a comprehensive guidance to the policy makers and water managers to optimize corrective efforts, minimize further damage, and improve the water quality condition to ensure sustainable development of the river basin. PMID- 30426282 TI - An electrochemical aptasensor based on gold@polypyrrole composites for detection of lead ions. AB - This work describes an electrochemical aptasensor for determination of lead ions (Pb2+). Composites prepared from gold nanoparticles and polypyrrole (Au@PPy) with good electrical conductivity were used to modify the surface of a screen printed carbon electrode for amplifying the current signal. Single strand DNA was immobilized on the electrode and binds lead(II) as confirmed by cyclic voltammetry at voltage of -0.2 V~0.6 V. Differential pulse voltammetry, measured at 0.10 V (vs. Ag/AgCl), was used to monitor the interaction between aptamer and lead(II) using hexacyanoferrate as an electrochemical probe. In the presence of Pb2+, the aptamer forms a G-quadruplex, and the peak current is increased. By this method, Pb2+ can be detected in the range of 0.5-10 nM with a low detection limit of 0.36 nM. The aptasensor was successfully applied to the determination of Pb2+ in polluted soil and baby's nail. The method showed outstanding sensitivity and selectivity in detecting Pb2+, therefore is considered to have great potential in developing an environmental monitoring platform. Graphical abstract Schematic illustration of Pb2+ detection procedure and principle using an electrochemical aptasensor. PMID- 30426283 TI - Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts. AB - Recent advances and emerging technologies for metabolic pathway engineering and synthetic biology have transformed the field of natural product discovery, production, and engineering. Despite these advancements, there remain many challenges in understanding how biosynthetic gene clusters are silenced or activated, including changes in the transcription of key biosynthetic and regulatory genes. This knowledge gap is highlighted by the success and failed attempts of manipulating regulatory genes within biosynthetic gene clusters in both native producers and heterologous hosts. These complexities make the choice of native producers versus heterologous hosts, fermentation medium, and supply of precursors crucial factors in achieving the production of the target natural products and engineering designer analogs. Nature continues to serve as inspiration for filling the knowledge gaps and developing new research strategies. By exploiting the evolutionary power of nature, alternative producers, with the desired genetic amenability and higher titers of the target natural products, and new strains, harboring gene clusters that encode evolutionary optimized congeners of the targeted natural product scaffolds, can be discovered. These newly identified strains can serve as an outstanding biotechnology platform for the engineered production of sufficient quantities of the target natural products and their analogs, enabling biosynthetic studies and potential therapeutic applications. These challenges and opportunities are showcased herein using fredericamycin, iso-migrastatin, platencin and platensimycin, the enediynes of C-1027, tiancimycin, and yangpumicin, and the leinamycin family of natural products. PMID- 30426284 TI - Metabolic engineering for improving L-tryptophan production in Escherichia coli. AB - L-Tryptophan is an important aromatic amino acid that is used widely in the food, chemical, and pharmaceutical industries. Compared with the traditional synthetic methods, production of L-tryptophan by microbes is environmentally friendly and has low production costs, and feed stocks are renewable. With the development of metabolic engineering, highly efficient production of L-tryptophan in Escherichia coli has been achieved by eliminating negative regulation factors, improving the intracellular level of precursors, engineering of transport systems and overexpression of rate-limiting enzymes. However, challenges remain for L tryptophan biosynthesis to be cost-competitive. In this review, successful and applicable strategies derived from metabolic engineering for increasing L tryptophan accumulation in E. coli are summarized. In addition, perspectives for further efficient production of L-tryptophan are discussed. PMID- 30426285 TI - The purpose of ward rounds. AB - Ward rounds are a highly important forum for collaborative medical reasoning. Despite being prevalent for over a century, they are under-researched. In particular, no clear and comprehensive statement of the purpose of ward rounds exists in the literature. This letter provides such a statement. Having the purpose of ward rounds clearly described helps to provide a foundation for evaluating the effectiveness of rounds and suggesting ways in which rounds can be improved. PMID- 30426286 TI - Chronic hemodialysis is associated with lower trabecular bone score, independent of bone mineral density: a case-control study. AB - : We measured trabecular bone score (TBS) in 98 patients on permanent hemodialysis (HD) and 98 subjects with similar bone mineral density and normal kidney function. TBS was significantly lower in HD patients, indicating deteriorated bone microarchitecture, independent of bone mass. This might partially explain the increased fracture risk in HD. PURPOSE: In the general population, trabecular bone score (TBS) was shown to predict fracture independent of bone mineral density (BMD). In end-stage renal disease patients on hemodialysis (HD), the value of TBS is beyond that of BMD in currently unclear. Our aim was to assess lumbar spine (LS) TBS in HD patients compared with subjects with normal kidney function matched for age, sex, and LS BMD. METHODS: We assessed TBS and LS and femoral neck (FN) BMD in 98 patient on permanent HD (42.8% males; mean age 57.5 +/- 11.3 years; dialysis vintage 5.5 +/- 3.8 years) and 98 control subjects (glomerular filtration rate > 60 mL/min) using DXA. We simultaneously controlled for sex, age (+/- 3 years), and LS BMD (+/- 0.03 g/cm2). RESULTS: HD patients had significantly lower LS TBS (0.07 [95% CI 0.03 0.1]; p = 0.0004), TBS T-score (0.83 SD [95% CI 0.42-1.24]; p = 0.0001)) and TBS Z-score (0.81 SD [95% CI 0.41-1.20]; p = 0.0001) than matched controls. TBS significantly correlated with LS BMD in both HD patients (r = 0.382; p = 0.001) and controls (r = 0.36; p = 0.002). The two regression lines had similar slopes (0.3 vs. 0.28; p = 0.84) with different intercepts (0.88 vs. 0.98). TBS adjustment significantly increased the 10-year fracture risk from 3.7 to 5.3 for major osteoporotic fracture and from 0.9 to 1.5 for hip fracture. CONCLUSIONS: HD patients have lower TBS than controls matched for LS BMD, indicating altered bone microarchitecture. Also, the magnitude of TBS reduction in HD patients is constant at any LS BMD. Adjustment for TBS partially corrects the absolute 10 year fracture risk. PMID- 30426288 TI - Preventive agents for neurodegenerative diseases from resin of Dracaena cochinchinensis attenuate LPS-induced microglia over-activation. AB - Our previous research revealed resin of Dracaena cochinchinensis as a candidate for therapy of neurodegenerative diseases. In the present study, the material basis of Chinese Dragon's blood and the primary mechanism of the effective components are discussed. Multiple chromatography and spectra analysis were utilized to identify effective constituents. The production of NO was determined using nitrite assay in BV-2 microglial cells stimulated with lipopolysaccharide (LPS). Cell viability was tested using MTT assay. The mRNA level of inducible nitric oxide synthase (iNOS) was investigated by quantitative real-time PCR (qRT PCR), and the production of IL-6 and TNF-alpha in the cell supernatants was tested by ELISA. The bioassay-directed separation of the effective extract of D. cochinchinensis afforded two new compounds, a stilbene-flavane dimer (2) and a quinoid flavonoid (11), in addition to 25 known compounds. The evaluation of their anti-neuroinflammatory activities showed that 5, 9, 12, 13, and 14 could exhibit significant anti-neuroinflammatory effects without cytotoxities at the tested concentration, compared to a positive control, minocycline (21.87 +/- 2.36 uM). A primary mechanistic study revealed that the effective components could inhibit over-activation of microglial through decreasing the expressions of iNOS, proinflammatory cytokines IL-6 and TNF-alpha in LPS- induced BV2 microglial cells. Chalcone 9, homoisoflavane 5 and flavone 12-14 are considered to be responsible for the anti-neuroinflammatory effects of Chinese Dragon's blood. These could inhibit neuroinflammation by reducing the expressions of iNOS, IL-6 and TNF-alpha in over-activated microglial. Furthermore, the SAR is briefly discussed. PMID- 30426287 TI - Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials. AB - Advances in the understanding of cancer immunotherapy and the development of multiple checkpoint inhibitors have dramatically changed the current landscape of cancer treatment. Recent large-scale phase III trials (e.g. PHOCUS, OPTiM) are establishing use of oncolytic viruses as another tool in the cancer therapeutics armamentarium. These viruses do not simply lyse cells to achieve their cancer killing effects, but also cause dramatic changes in the tumor immune microenvironment. This review will highlight the major vector platforms that are currently in development (including adenoviruses, reoviruses, vaccinia viruses, herpesviruses, and coxsackieviruses) and how they are combined with checkpoint inhibitors. These vectors employ a variety of engineered capsid modifications to enhance infectivity, genome deletions or promoter elements to confer selective replication, and encode a variety of transgenes to enhance anti-tumor or immunogenic effects. Pre-clinical and clinical data have shown that oncolytic vectors can induce anti-tumor immunity and markedly increase immune cell infiltration (including cytotoxic CD8+ T cells) into the local tumor microenvironment. This "priming" by the viral infection can change a 'cold' tumor microenvironment into a 'hot' one with the influx of a multitude of immune cells and cytokines. This alteration sets the stage for subsequent checkpoint inhibitor delivery, as they are most effective in an environment with a large lymphocytic infiltrate. There are multiple ongoing clinical trials that are currently combining oncolytic viruses with checkpoint inhibitors (e.g. CAPTIVE, CAPRA, and Masterkey-265), and the initial results are encouraging. It is clear that oncolytic viruses and checkpoint inhibitors will continue to evolve together as a combination therapy for multiple types of cancers. PMID- 30426290 TI - Sheehan syndrome mimicking dementia with Lewy bodies. PMID- 30426291 TI - Chronological renal resistive index increases related to atherosclerotic factors, and effect of renin-angiotensin system inhibitors. AB - BACKGROUND: Renal resistive index (RI) calculated using renal Doppler ultrasonography (RDU) has recently been considered a clinically important indicator of renal outcome, survival, and systemic arteriosclerotic disorders. However, the cause of RI elevation remains unclear. The present study was an effort to first, identify the factors related to RI elevation, and second, understand the effect of renin-angiotensin system inhibitors (RAS-Is) on renal RI elevation. METHODS: We carried out this single-center case-control study among 100 CKD patients, recruited from outpatients who underwent RDU more than twice, at least a year apart. The rate of renal RI change per year (dRIpy) was chosen as the dependent variable: [(last examined renal RI-initial examined renal RI)/(initial examined renal RI * period of observation) * 100 (%/year)]. We examined the association between dRIpy and other clinical and biological data. RESULTS: Among 100 CKD patients, the average serum creatinine and eGFR were 1.76 +/- 0.84 mg/dL and 37.0 +/- 18.2 ml/min/1.73 m2, respectively. The average dRIpy in all patients was 1.8 +/- 1.4%/year. The linear multiple regression demonstrated that dRIpy was positively associated with the presence of diabetes mellitus (DM) and high low-density lipoprotein cholesterol (LDL) levels, and negatively with eGFR and RAS-I use. CONCLUSIONS: This study demonstrated that the elevation of RI was related to DM, eGFR, high LDL, and the use of RAS-Is. In particular, RAS-Is could contribute towards suppressing the elevation of RI in CKD patients and towards preventing the development of renal failure in CKD patients. PMID- 30426293 TI - Instrument errors of an analyzer influence acid-base assessment. PMID- 30426292 TI - Hydrochlorothiazide ameliorates polyuria caused by tolvaptan treatment of polycystic kidney disease in PCK rats. AB - BACKGROUND: Tolvaptan is an effective treatment for polycystic kidney disease (PKD), but also causes unfortunate polyuria. Hydrochlorothiazide (HCTZ) has been shown to reduce urine volume in nephrogenic diabetes insipidus, raising the possibility that HCTZ could also be effective in reducing tolvaptan-induced polyuria. In this study, we examined the combined administration of HCTZ and tolvaptan. METHODS: Male PCK rats were divided into four groups of normal chow (Cont), normal chow plus tolvaptan, gavage HCTZ treatment, and tolvaptan + HCTZ. Biochemical examinations of the plasma and urine were performed as well as histological and molecular (mRNA and protein expression) analyses. RESULTS: Groups treated with tolvaptan had significantly higher 24 h urine excretion, which was significantly reduced in the tolvaptan + HCTZ group after 2 weeks. Cyst size, pERK protein expression, and Cyclin D1 mRNA expression were all significantly reduced in both the tolvaptan and tolvaptan + HCTZ groups, indicating that HCTZ did not affect the beneficial functions of tolvaptan. Notably, aquaporin 2 redistribution from the apical to intracellular domains was observed in tolvaptan-treated rats and was partially reversed in the tolvaptan + HCTZ group. The renal glomerular filtration rate was reduced in the tolvaptan + HCTZ group. Significantly lowered mRNA expression of neuronal nitric oxide synthase, prostaglandin E synthase 2 and renin were also found in the medulla, but not in the cortex. CONCLUSION: HCTZ reduces tolvaptan-induced polyuria without altering its beneficial effects on PKD. This novel therapeutic combination could potentially lead to better PKD treatments and improved quality of life for the affected patients. PMID- 30426294 TI - The role of oxaliplatin in the adjuvant setting of different Lauren's type of gastric adenocarcinoma after D2 gastrectomy: a real-world study. AB - BACKGROUND: To compare the efficacy of oxaliplatin-based and oxaliplatin-free adjuvant chemotherapies in patients with different Lauren type gastric cancers after D2 gastrectomy. METHODS: From our established gastric cancer database, patients with pathological stage II and III gastric cancer who received adjuvant chemotherapy after D2 gastrectomy at Zhongshan Hospital of Fudan University were analyzed. Patients who received different adjuvant chemotherapy regimens were divided into two subgroups: oxaliplatin-based and oxaliplatin-free subgroup. Clinical outcomes were analyzed according to pathological stage and different Lauren types. RESULTS: From Jan 2010 to June 2017, a total of 580 patients met all the eligibility criteria and were enrolled. The median DFS for all the patients was 24.37 months and the median OS was 56.70 months. In patients with intestinal type gastric cancer, the median DFS of the oxaliplatin-based subgroup was significantly longer than that of oxaliplatin-free subgroup (48.73 vs. 18.33 months, P < 0.001). The median OS was not reached in the oxaliplatin-based subgroup and 54.33 months in the oxaliplatin-free subgroup (P = 0.006). In patients with diffuse type gastric cancer, neither DFS nor OS differed significantly between two subgroups. In multivariate analysis, oxaliplatin-based adjuvant chemotherapy was independent positive predictor of DFS (HR 0.40; 95% CI 0.28-0.59; P < 0.001) and OS (HR 0.35; 95% CI 0.20-0.62; P < 0.001) in patients with intestinal type gastric cancer. CONCLUSIONS: The results of our study suggested that oxaliplatin-based adjuvant chemotherapy was more effective in patients with intestinal type gastric cancer after D2 gastrectomy but showed no more survival benefit in patients with diffuse type. PMID- 30426296 TI - Concise Commentary: Caution, Not Cauterization-Management of Post-ESD Colorectal Hemorrhage. PMID- 30426295 TI - Combined detection of serum autoantibodies as diagnostic biomarkers in esophagogastric junction adenocarcinoma. AB - BACKGROUND: We previously found that autoantibodies against a panel of six tumor associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, PRDX6 and Bmi-1) may aid in early detection of esophageal squamous cell carcinoma. Here we aimed to evaluate the diagnostic value of this autoantibody panel in esophagogastric junction adenocarcinoma (EJA) patients. METHODS: Serum autoantibody levels were measured by enzyme-linked immunosorbent assay in a training cohort and a validation cohort. We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy. RESULTS: We recruited 169 normal controls and 122 EJA patients to the training cohort, and 80 normal controls and 70 EJA patients to the validation cohort. Detection of the autoantibody panel demonstrated an area under the curve (AUC) of 0.818, sensitivity 59.0% and specificity 90.5% in training cohort, and AUC 0.815, sensitivity 61.4% and specificity 90.0% in validation cohort in the diagnosis of EJA. Measurement of the autoantibody panel could distinguish early stage EJA patients from normal controls (AUC 0.786 and 0.786, sensitivity 50.0% and 56.0%, and specificity 90.5% and 90.0%, for training and validation cohorts, respectively). Moreover, a restricted panel consisting of autoantibodies against p53, NY-ESO-1 and Bmi-1 exhibited similar diagnostic performance for EJA (AUC 0.814 and 0.823, sensitivity 53.5% and 60.0%, and specificity 90.5% and 93.7%, for training and validation cohorts, respectively) and early stage EJA (AUC 0.744 and 0.773, sensitivity 55.6% and 52.0%, and specificity 90.5% and 93.7%, for training and validation cohorts, respectively). CONCLUSIONS: Autoantibodies against an optimized TAA panel as serum biomarkers appear to help identify the present of early stage EJA. PMID- 30426289 TI - The Italian multiple sclerosis register. AB - The past decade has seen extraordinary increase in worldwide availability of and access to several large multiple sclerosis (MS) databases and registries. MS registries represent powerful tools to provide meaningful information on the burden, natural history, and long-term safety and effectiveness of treatments. Moreover, patients, physicians, industry, and policy makers have an active interest in real-world observational studies based on register data, as they have the potential to answer the questions that are most relevant to daily treatment decision-making. In 2014, the Italian MS Foundation, in collaboration with the Italian MS clinical centers, promoted and funded the creation of the Italian MS Register, a project in continuity with the existing Italian MS Database Network set up from 2001. Main objective of the Italian MS Register is to create an organized multicenter structure to collect data of all MS patients for better defining the disease epidemiology, improving quality of care, and promoting research projects in high-priority areas. The aim of this article is to present the current framework and network of the Italian MS register, including the methodology used to improve the quality of data collection and to facilitate the exchange of data and the collaboration among national and international groups. PMID- 30426298 TI - Survey Study on the Practice Patterns of the Evaluation and Management of Incidental Pancreatic Cysts. AB - BACKGROUND AND AIMS: Various gastrointestinal societies have released guidelines on the evaluation of asymptomatic pancreatic cysts (PCs). These guidelines differ on several aspects, which create a conundrum for clinicians. The aim of this study was to evaluate preferences and practice patterns in the management of incidental PCs in light of these societal recommendations. METHODS: An electronic survey distributed to members of the American Society for Gastrointestinal Endoscopy (ASGE). Main outcomes included practice setting (academic vs. community), preferences for evaluation, management, and surveillance strategies for PCs. RESULTS: A total of 172 subjects completed the study (52% academic-based endoscopists). Eighty-six (50%) and 138 (80%) of the participants responded that they would recommend EUS surveillance of incidental PCs measuring less than 2 cm and 3 cm, respectively. Nearly half of the endosonographers (42.5% community and 44% academic; p = 1.0) would routinely perform FNA on PCs without any high-risk features. More academic-based endoscopists (57% academic vs. 32% community; p = 0.001) would continue incidental PC surveillance indefinitely. CONCLUSIONS: There is significant variability in the approach of incidental PCs among clinicians, with practice patterns often diverging from the various GI societal guideline recommendations. Most survey respondents would routinely recommend EUS-FNA and indefinite surveillance for incidental PCs without high-risk features. The indiscriminate use of EUS-FNA and indefinite surveillance of all incidental PCs is not cost-effective, exposes the patient to unnecessary testing, and can further perpetuate diagnostic uncertainty. Well-designed studies are needed to improve our diagnostic and risk stratification accuracy in order to formulate a consensus on the management of these incidental PCs. PMID- 30426297 TI - Correlation Between Anti-TNF Serum Levels and Endoscopic Inflammation in Inflammatory Bowel Disease Patients. AB - OBJECTIVES: (a) To evaluate the diagnostic accuracy of anti-TNF trough levels to predict mucosal healing in inflammatory bowel disease (IBD); (b) to determine the best cut-off point to predict mucosal healing in IBD patients treated with anti TNF. METHODS: This is a multicenter, prospective study. IBD patients under anti TNF treatment for at least 6 months that had to undergo an endoscopy were included. Mucosal healing was defined as: Simple endoscopic score for Crohn's Disease < 3 for Crohn's disease (CD), Rutgeerts score < i2 for CD in postoperative setting, or Mayo endoscopic score <= 1 for ulcerative colitis (UC). Anti-TNF concentrations were measured using SMART ELISAs at trough. RESULTS: A total of 182 patients were included. Anti-TNF trough levels were significantly higher among patients that had mucosal healing than among those who did not. The area under the curve of infliximab for mucosal healing was 0.63 (best cutoff value 3.4 MUg/mL), and for adalimumab 0.60 (best cutoff value 7.2 MUg/mL). In the multivariate analysis, having anti-TNF drug levels above the cutoff values [odds ratio (OR) 3.1]) and having UC instead of CD (OR 4) were associated with a higher probability of having mucosal healing. Additionally, the need for an escalated dosage (OR 0.2) and current smoking habit (OR 0.2) were also associated with a lower probability of mucosal healing. CONCLUSIONS: There was an association between anti-TNF trough levels and mucosal healing in IBD patients; however, the accuracy of the determination of infliximab and adalimumab concentrations able to predict mucosal healing was suboptimal. PMID- 30426299 TI - Post-implantation shear stress assessment: an emerging tool for differentiation of bioresorbable scaffolds. AB - Optical coherence tomography based computational flow dynamic (CFD) modeling provides detailed information about the local flow behavior in stented/scaffolded vessel segments. Our aim is to investigate the in-vivo effect of strut thickness and strut protrusion on endothelial wall shear stress (ESS) distribution in ArterioSorb Absorbable Drug-Eluting Scaffold (ArterioSorb) and Absorb everolimus eluting Bioresorbable Vascular Scaffold (Absorb) devices that struts with similar morphology (quadratic structure) but different thickness. In three animals, six coronary arteries were treated with ArterioSorb. At different six animals, six coronary arteries were treated with Absorb. Following three-dimensional(3D) reconstruction of the coronary arteries, Newtonian steady flow simulation was performed and the ESS were estimated. Mixed effects models were used to compare ESS distribution in the two devices. There were 4591 struts in the analyzed 477 cross-sections in Absorb (strut thickness = 157 um) and 3105 struts in 429 cross sections in ArterioSorb (strut thickness = 95 um) for the protrusion analysis. In cross-section level analysis, there was significant difference between the scaffolds in the protrusion distances. The protrusion was higher in Absorb (97% of the strut thickness) than in ArterioSorb (88% of the strut thickness). ESS was significantly higher in ArterioSorb (1.52 +/- 0.34 Pa) than in Absorb (0.73 +/- 2.19 Pa) (p = 0.001). Low- and very-low ESS data were seen more often in Absorb than in ArterioSorb. ArterioSorb is associated with a more favorable ESS distribution compared to the Absorb. These differences should be attributed to different strut thickness/strut protrusion that has significant effect on shear stress distribution. PMID- 30426300 TI - Adenosine triphosphate (ATP) and adenosine cause similar vasodilator effect in patients undergoing stress perfusion cardiac magnetic resonance imaging. AB - To evaluate the vasodilator effect of adenosine triphosphate (ATP) compared with adenosine in stress perfusion cardiac magnetic resonance (CMR) examinations. A total of thirty-three patients underwent clinically indicated stress/rest perfusion CMR examination following intravenous injection of a total dose of 0.2 mmol/kg of gadobutrol. Individuals were randomly assigned to ATP (160 mcg/kg/min) or adenosine (140 mcg/kg/min). The vasodilator effect of both drugs was analyzed by comparing differences in heart rate, symptoms during stress, and semiquantitative myocardial and splenic perfusion parameters, including time, time to peak, upslope, myocardial perfusion reserve index, tissue perfusion values, splenic and myocardial signal intensity ratios, and splenic-to-myocardial signal intensity ratios. No significant difference was found in heart rate variation between the stressors (26.1 +/- 19.1 bpm for ATP vs. 21.7 +/- 17.3 bpm for adenosine, p = 0.52). Patients receiving ATP referred less pronounced clinical symptoms. Semiquantitative myocardial perfusion parameters were comparable, and patients in the adenosine and ATP groups showed similar myocardial perfusion reserve index values (2.34 [1.62-2.73] vs 1.63 [1.29-2.10], p = 0.07). Splenic switch off was visually confirmed in all patients and estimated spleen to myocardium ratio was similar (0.92 [0.53-1.09] vs 0.81 [0.53 0.86] with ATP and adenosine, respectively, p = 0.12). Both ATP and adenosine are potent coronary vasodilators that can be safely employed in stress-CMR. Both stressor cause similar hyperemic response. Splenic switch-off can be used to assess stress adequacy in patients undergoing stress-CMR with either adenosine or ATP. PMID- 30426301 TI - Involvement of ERK1/2 activation in the gene expression of senescence-associated secretory factors in human hepatic stellate cells. AB - Senescent hepatic stellate cells (senescent HSCs) are found in patients with liver cirrhosis and have been thought to be involved in the development of hepatocellular carcinoma (HCC) in mice via the senescence-associated secretory proteins. However, in humans, which secretory proteins are involved and what regulate their expression remain unclear. In the current study, we characterized senescence-associated beta-galactosidase-positive senescent human HSCs (hHSCs) induced by repetitive passaging. They exhibited enhanced expression of 14 genes for secretory protein and persistent phosphorylation of ERK1/2 protein but not JNK or p38 MAPK proteins. Enhanced nuclear ERK1/2 phosphorylation was observed in senescent hHSCs. Treatment of the senescent hHSCs with ERK1/2 inhibitor, SCH772984, significantly decreased the levels of angiopoietin like 4 (ANGPTL4), C C motif chemokine ligand 7 (CCL7), Interleukin-8 (IL-8), platelet factor 4 variant 1 (PF4V1), and TNF superfamily member 15 (TNFSF15) mRNA levels in a dose dependent manner. The enhanced phosphorylation of ERK1/2 and expression of ANGPTL4, IL-8 and PF4V1 genes were observed in both of senescent human dermal fibroblasts and X-ray-induced senescent hHSCs. However, transient ERK1/2 activation induced by epidermal growth factor could not mimic the gene profile of the senescent hHSCs. These results revealed involvement of ERK1/2 signaling in the regulation of senescence-associated secretory factors, suggesting that simultaneous induction of ANGPTL4, IL-8, and PF4V1 genes is a marker of hHSC senescence. This study will contribute to understanding roles of senescent hHSCs in liver diseases. PMID- 30426302 TI - Overexpression of CTRP9 attenuates the development of atherosclerosis in apolipoprotein E-deficient mice. AB - This study was aimed to explore the role of C1q/TNF-related protein 9 (CTRP9) on atherosclerotic lesion formation. A recombinant lentiviral vector carrying mouse CTRP9 (Lv-CTRP9) was injected intravenously into apolipoprotein E knockout (ApoE /-) mice given a high-fat diet (HFD). CTRP9 overexpression substantially attenuated atherosclerotic lesion size of mice. The accumulation of macrophages and smooth muscle cells (SMCs) was significantly decreased in atherosclerotic regions with CTRP9 overexpression by immunohistochemical analysis. In addition, CTRP9 downregulated the expressions of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha), two main proinflammatory cytokines in atherosclerosis. Furthermore, the autophagy level remarkably increased which was presented by microtubule-associated protein light chain 3B (LC3B) conversion and sequestosome 1 (SQSTM1/p62) degradation. Further study showed that CTRP9 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased mammalian target of rapamycin (mTOR) phosphorylation in vivo. These observations reveal that CTRP9 exerts a protecting role in early atherosclerotic lesions and its anti-atherosclerotic effect is associated with autophagy induction through AMPK/mTOR signaling pathway. PMID- 30426303 TI - Molecular characterization by PCR-RFLP of indigenous fungal isolates from hypersaline stream water in Romania. AB - This is the first exhaustive report on the fungal community biodiversity in hypersaline water in Romania. A total of 27 fungal strains (19 molds and eight yeast) have been isolated from Lopatari hypersaline water, Buzau County. Based on classical investigation, these strains have been identified as belonging to the genera Aureobasidium, Alternaria, Aspergillus, Penicillium, and Fusarium. The molecular characterization of fungal isolates at species level was performed using PCR-RFLP analysis of the 5.8S-ITS region. PCR products were digested with different combinations of endonucleases. The most frequently isolated species were Aspergillus niger (14.81% of all isolates), A. versicolor, (14.81%) and Penicillium crustosum (14.81%). In addition, ribosomal restriction patterns which exhibited profiles specific to Aureobasidium pullulans were derived, and to discriminate between Aureobasidium isolates, the elongase-encoding gene (ELO) was chosen as a genetic marker followed by digestion with endonuclease HhaI. Five yeast isolates displayed restriction patterns corresponding to Aureobasidium melanogenum (18.52%) and three isolates to Aureobasidium pullulans (11.11%). In addition, the RFLP types of Aureobasidium pullulans varieties with HhaI are clearly distinguished and could be applied to assess the intraspecific variability. PMID- 30426304 TI - Correction to: The Role of Oncolytic Viruses in the Treatment of Melanoma. AB - A correction was made to a sentence in the original article to provide additional clarification in the "Other Oncolytic Viruses" section. PMID- 30426305 TI - A survey-based design of a pricing system for psychotherapy. AB - For admission to statutory health insurance, it is common in Switzerland that health care providers negotiate prices for health care services directly with health insurers. Once they agree upon a price, they must submit the resulting price to the Federal Office of Public Health (FOPH), which can then authorize it. Swiss law requires the prices in health care to be based on empirical data. There has been little research on how to derive such a price for health care from empirical data and which data should be used. Based on a collaboration with psychological psychotherapists in Switzerland, we have designed a pricing system. The empirical basis were two representative surveys: a survey about costs and earnings of psychotherapists, as well as a time-use survey for psychotherapy. This paper shows the methodology followed to establish an empirically based pricing system. The paper may serve as a practical guide for health service providers who want to develop a pricing system. Our approach offers a high degree of freedom because it involves the collection of the data and an explicit modelling phase. At the same time, it might be more resource intensive than other approaches that are based on existing data sources. PMID- 30426306 TI - RotaWire fracturing due to spinning under the maximum rotational speed. PMID- 30426307 TI - Trends in stage at diagnosis for young breast cancer patients in the United States. AB - PURPOSE: Previous studies reported increasing rates of metastatic breast cancer among young US women. However, these studies were based on limited geographic areas and did not account for the sharp decline in unknown-stage disease. In this study, we examined trends in early-onset breast cancer incidence rates by stage at diagnosis in a national dataset, after correcting for temporal changes in unstaged disease. METHODS: Using data from 42 states, covering 82% of the US population, we examined trends in incidence rates by stage at diagnosis and race/ethnicity in women ages 20-39 years. Stage was imputed for non-Hispanic (NH) white and NH black cases with missing information by distributing cases proportionally according to survival statistics. RESULTS: During 2001-2015, incidence rates of early-onset metastatic breast cancer increased sharply among NH white, NH black, Hispanic, and Asian/Pacific Islander (API) women. Increasing trends were also observed for local-stage disease (all racial/ethnic groups) and regional-stage disease (NH white and API). In contrast, rates decreased sharply for unstaged disease among all groups. After imputing stage for cases with missing information, the increasing trends for regional- and distant-stage disease in NH whites and local-stage disease in NH blacks were no longer statistically significant, but the increase in distant-stage disease in NH blacks was unchanged. CONCLUSIONS: After accounting for the sharp decline in unstaged cases, the increase in incidence rates for distant-stage disease became non significant in NH whites but not in NH blacks. Future studies should consider accounting for temporal changes in unstaged disease when examining stage-specific incidence trends. PMID- 30426308 TI - Modeling lifetime greenhouse gas emissions associated with materials for various end-of-life treatments. AB - This research has developed mathematical models for computing lifetime greenhouse gas (GHG) emissions associated with materials. The models include embodied carbon (EC) emissions from the manufacture of materials, and GHG emissions from incineration, or landfill gas (LFG) production from landfill disposal of the material beyond their service lives. The models are applicable to all materials; however, their applications here are demonstrated for the lumber from a residential building with 50- and 100-year service lives, and with incineration, landfill, and deconstruction as end-of-life treatments. This paper introduces a new metric for lifetime GHG emissions associated with materials termed "Global Warming Impact of Materials (GWIM)." The GWIM is subdivided into two portions: (i) productive portion (GWIMp) that includes the materials' emissions until the service life of the facility and (ii) non-productive portion (GWIMnp) which includes the materials' GHG emissions beyond the service life until they are eliminated from the atmosphere. In place of the current, static, EC measurements (kgCO2e or MTCO2e), this model reports the GWIMs in units of kgCO2e-years or MTCO2e-years, which includes the effects of "time of use" of a facility. Using the models, this paper has computed GHG reductions by deconstruction, with material recoveries of 30%, 50%, and 70% at demolition for reuse, recycle, or repurpose. A 70% material recovery, after a 50-year service life of the building, affected a savings of 47% and 52% if the remaining 30% debris was incinerated or landfilled respectively. All of the values computed using models checked out with manual calculations. PMID- 30426309 TI - Exon junction complex (EJC) core genes play multiple developmental roles in Physalis floridana. AB - KEY MESSAGE: Molecular and functional characterization of four gene families of the Physalis exon junction complex (EJC) core improved our understanding of the evolution and function of EJC core genes in plants. The exon junction complex (EJC) plays significant roles in posttranscriptional regulation of genes in eukaryotes. However, its developmental roles in plants are poorly known. We characterized four EJC core genes from Physalis floridana that were named PFMAGO, PFY14, PFeIF4AIII and PFBTZ. They shared a similar phylogenetic topology and were expressed in all examined organs. PFMAGO, PFY14 and PFeIF4AIII were localized in both the nucleus and cytoplasm while PFBTZ was mainly localized in the cytoplasm. No protein homodimerization was observed, but they could form heterodimers excluding the PFY14-PFBTZ heterodimerization. Virus-induced gene silencing (VIGS) of PFMAGO or PFY14 aborted pollen development and resulted in low plant survival due to a leaf-blight-like phenotype in the shoot apex. Carpel functionality was also impaired in the PFY14 knockdowns, whereas pollen maturation was uniquely affected in PFBTZ-VIGS plants. Once PFeIF4AIII was strongly downregulated, plant survival was reduced via a decomposing root collar after flowering and Chinese lantern morphology was distorted. The expression of Physalis orthologous genes in the DYT1-TDF1-AMS-bHLH91 regulatory cascade that is associated with pollen maturation was significantly downregulated in PFMAGO-, PFY14- and PFBTZ-VIGS flowers. Intron-retention in the transcripts of P. floridana dysfunctional tapetum1 (PFDYT1) occurred in these mutated flowers. Additionally, the expression level of WRKY genes in defense-related pathways in the shoot apex of PFMAGO- or PFY14-VIGS plants and in the root collar of PFeIF4AIII-VIGS plants was significantly downregulated. Taken together, the Physalis EJC core genes play multiple roles including a conserved role in male fertility and newly discovered roles in Chinese lantern development, carpel functionality and defense-related processes. These data increase our understanding of the evolution and functions of EJC core genes in plants. PMID- 30426310 TI - Distinctive semantic features in the healthy adult brain. AB - The role of semantic features, which are distinctive (e.g., a zebra's stripes) or shared (e.g. has four legs) for accessing a concept, has been studied in detail in early neurodegenerative disease such as semantic dementia (SD). However, potential neural underpinnings of such processing have not been studied in healthy adults. The current study examines neural activation patterns using fMRI while participants completed a feature verification task, in which they identified shared or distinctive semantic features for a set of natural kinds and man-made artifacts. The results showed that the anterior temporal lobe bilaterally is an important area for processing distinctive features, and that this effect is stronger within natural kinds than man-made artifacts. These findings provide converging evidence from healthy adults that is consistent with SD research, and support a model of semantic memory in which patterns of specificity of semantic information can partially explain differences in neural activation between categories. PMID- 30426311 TI - Leflunomide versus cyclophosphamide in the induction treatment of proliferative lupus nephritis in Chinese patients: a randomized trial. AB - OBJECTIVES: A prospective, multi-center, randomized controlled study was conducted to evaluate the efficacy and safety of a 24-week course low-dose leflunomide combined with prednisone in the induction treatment of proliferative lupus nephritis in Chinese patients. METHOD: Patients (n = 100) with biopsy proved proliferative lupus nephritis were enrolled in this study. They were randomized into two groups and received either leflunomide or cyclophosphamide in conjunction with prednisone for 24 weeks. Leflunomide was given orally with a loading dose of 40 mg/day for 3 days followed by 20 mg/day. Intravenous cyclophosphamide was administered monthly at a dosage of 0.8-1.0 g. The primary efficacy outcome was the frequency of complete remission and partial remission at week 24. The secondary outcomes included changes of urinary protein excretion, serum albumin, complement 3, anti-dsDNA antibody level, and systemic lupus erythematosus disease activity index (SLEDAI) after 24-week therapy. RESULTS: Of 100 patients, 48 received leflunomide combined with prednisone and other 52 received cyclophosphamide with concomitant prednisone. There were no statistically significant differences between groups in complete remission rate and partial remission rate. At week 24, 23% of patients in the leflunomide group and 27% of patients in the cyclophosphamide group achieved complete remission (P = 0.64), while 56% of patients in the leflunomide group and 42% of patients in the cyclophosphamide group achieved partial remission at week 24 (P = 0.16). SLEDAI, serum albumin, complement 3, anti-dsDNA antibody level, and urinary protein excretion improved significantly in both groups. No significant difference was seen in the changes of clinical parameters after therapy between the two groups. There was no significant difference in side effects in both groups. CONCLUSIONS: Compared with cyclophosphamide, low-dose leflunomide in combination with prednisone showed both effectiveness and safety in the induction therapy of proliferative lupus nephritis in Chinese patients. PMID- 30426312 TI - Immunoelectrochemical detection of the human epidermal growth factor receptor 2 (HER2) via gold nanoparticle-based rolling circle amplification. AB - The authors describe an adapted rolling circle amplification (RCA) method for the determination of human epidermal growth factor receptor 2 (HER2). This method (which is termed immunoRCA) combines an immunoreaction with DNA based signal amplification. Gold nanoparticles (AuNPs) were loaded with antibodies against HER2 and DNA, and then fulfill the functions of recognizing HER2 and achieving signal amplification. The DNA serves as a primer to trigger RCA. This results in formation of a long DNA containing hundreds of copies of circular DNA sequence on the electrode surface. Then, molybdate is added which reacts with the phosphate group of the long DNA to generate the redox-active molybdophosphate. This, in turn, results in an increased current and, thus, in strongly increased sensitivity of the immunoassay. A linear response is linear relationship between the change of current intensity and the logarithm of the concentration in the range from 1 to 200 pg.mL-1 of HER2, and the detection limit is 90 fg.mL-1 (at an S/N ratio of 3). The method was applied to the determination of HER2 in breast cancer patients serum samples, and the results correlated well with those obtained by an ELISA. The method was further successfully applied to the determination of HER2 in HER2-expressed mouse breast cancer 4 T1 cells. Conceivably, this strategy may be adapted to other DNA amplification methods and also may be used for the determination of other proteins and biomarkers by using the appropriate antibodies. Graphical abstract Schematic presentation of an adapted rolling circle amplification (RCA) strategy for the electrochemical detection of human epidermal growth factor receptor 2 (HER2), termed "immunoRCA" utilizing gold nanoparticles (AuNPs). Ab stands for antibody, Phi29 is an E.coli DNA polymerase, dNTP represents deoxynucleotides, and SWV stands for square wave voltammetry. PMID- 30426313 TI - Two cases of radiation-associated angiosarcoma of the breast. AB - BACKGROUND: The incidence of radiation-associated angiosarcoma (RAA) of the breast has been increasing, and its prognosis is reportedly poor. It is important to remove tumor tissues completely to prevent recurrence. CASE PRESENTATION: We report two cases of patients with RAA of the breast. Both patients had a nodule in their remaining breast a few years after undergoing breast-conserving surgery and radiation therapy for breast cancer. The nodules were diagnosed as angiosarcoma by skin biopsy and open biopsy, respectively. To determine the extent of lesion spread, mapping biopsy was performed before surgery. Both patients underwent mastectomy, extensive skin resection, and split skin grafting. Pathological findings showed that their tumors could be completely resected. After surgery, chemotherapy was performed. CONCLUSION: In our cases, no local or distant recurrence has been detected in either patient for over 4 years. We identified the range of tumor invasion by preoperative mapping biopsy and completely resected all tumor tissue. PMID- 30426314 TI - Molecular aspects of Rift Valley fever virus and the emergence of reassortants. AB - Rift Valley fever phlebovirus (RVFV) is a mosquito-transmitted pathogen endemic to sub-Saharan Africa and the Arabian Peninsula. RVFV is a threat to both animal and human health and has costly economic consequences mainly related to livestock production and trade. Competent hosts and vectors for RVFV are widespread, existing outside of endemic countries including the USA. Thus, the possibility of RVFV spreading to the USA or other countries worldwide is of significant concern. RVFV (genus Phlebovirus) is comprised of an enveloped virion containing a three segmented, negative-stranded RNA genome that is able to undergo genetic reassortment. Reassortment has the potential to produce viruses that are more pathogenic, easily transmissible, and that have wider vector or host range. This is especially concerning because of the wide use of live attenuated vaccine strains throughout endemic countries. This review focuses on the molecular aspects of RVFV, genetic diversity of RVFV strains, and RVFV reassortment. PMID- 30426315 TI - Molecular identification of Betacoronavirus in bats from Sardinia (Italy): first detection and phylogeny. AB - Bats may be natural reservoirs for a large variety of emerging viruses, including mammalian coronaviruses (CoV). The recent emergence of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in humans, with evidence that these viruses may have their ancestry in bats, highlights the importance of virus surveillance in bat populations. Here, we report the identification and molecular characterization of a bat beta-Coronavirus, detected during a viral survey carried out on different bat species in the island of Sardinia (Italy). Cutaneous, oral swabs, and faecal samples were collected from 46 bats, belonging to 15 different species, and tested for viral presence. Coronavirus RNA was detected in faecal samples from three different species: the greater horseshoe bat (Rhinolophus ferrumequinum), the brown long-eared bat (Plecotus auritus), and the European free-tailed bat (Tadarida teniotis). Phylogenetic analyses based on RNA-dependent RNA polymerase (RdRp) sequences assigned the detected CoV to clade 2b within betacoronaviruses, clustering with SARS-like bat CoVs previously reported. These findings point to the need for continued surveillance of bat CoV circulating in Sardinian bats, and extend the current knowledge on CoV ecology with novel sequences detected in bat species not previously described as beta-Coronavirus hosts. PMID- 30426316 TI - Sensitive and rapid detection of Zika virus by loop-mediated isothermal amplification. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus, which is a pathogen affecting humans in Africa, Asia, and America. It is necessary to detect ZIKV with a rapid and sensitive molecular method to guide timely treatment. In this study, a loop mediated isothermal amplification (LAMP) assay was described, which is an attractive option as a fast, sensitive, and specific method for ZIKV detection using the NS5 protein coding region and the envelope protein (EP) coding region as target sequences. Two different techniques, a calcein/Mn2+ complex chromogenic method and real-time turbidity monitoring, were employed. The specificity and sensitivity of the LAMP assay were determined. The assay's detection limit was 0.5 * 10-9 pmol/ul DNA for NS5 protein coding region and 1.12 * 10-11 pmol/ul DNA for E coding region, respectively, which is a 100-fold increase in sensitivity compared with real-time reverse transcription-polymerase chain reaction (RT-PCR) and conventional PCR. All 12 non-ZIKA respiratory pathogens tested were negative for LAMP detection, indicating the high specificity of the primers for ZIKV. In conclusion, a visual detection LAMP assay was developed, which could be a useful tool for primary quarantine purposes and clinical screening, especially in situations where resources are poor and in point-of-care tests. PMID- 30426317 TI - Comparison of DTI analysis methods for clinical research: influence of pre processing and tract selection methods. AB - BACKGROUND: The primary aim was to compare fractional anisotropy (FA) values derived with different diffusion tensor imaging (DTI) analysis approaches (atlas based, streamline tractography, and combined). A secondary aim was to compare FA values and number of tracts (NT) with the clinical motor outcome quantified by the functional independence measure for children (WeeFIM). METHODS: Thirty-nine DTI datasets of children with acquired brain injury were analysed. Regions of interest for the ipsilesional corticospinal tract were defined and mean FA and NT were calculated. We evaluated FA values with Spearman correlation, the Friedman and Wilcoxon tests, and Bland-Altman analysis. DTI values were compared to WeeFIM values by non-parametric partial correlation and accuracy was assessed by receiver operating characteristics analysis. RESULTS: The FA values from all approaches correlated significantly with each other (p < 0.001). However, the FA values from streamline tractography were significantly higher (mean +/- standard deviation (SD), 0.52 +/- 0.08) than those from the atlas-based (0.42 +/- 0.11) or the combined approach (0.41 +/- 0.11) (p < 0.001 for both). FA and NT values correlated significantly with WeeFIM values (atlas-based FA, partial correlation coefficient (rho) = 0.545, p = 0.001; streamline FA, rho = 0.505, p = 0.002; NT, rho = 0.434, p = 0.008; combined FA, rho = 0.611, p < 0.001). FA of the atlas based approach (sensitivity 90%, specificity 67%, area under the curve 0.82) and the combined approach (87%, 67%, 0.82), provided the highest predictive accuracy for outcome compared to FA (70%, 67%, 0.67) and NT (50%, 100%, 0.79, respectively) of the streamline approach. CONCLUSION: FA values from streamline tractography were higher than those from the atlas-based and combined approach. The atlas-based and combined approach offer the best predictive accuracy for motor outcome, although both atlas-based and streamline tractography approaches provide significant predictors of clinical outcome. PMID- 30426318 TI - Radiomics: the facts and the challenges of image analysis. AB - Radiomics is an emerging translational field of research aiming to extract mineable high-dimensional data from clinical images. The radiomic process can be divided into distinct steps with definable inputs and outputs, such as image acquisition and reconstruction, image segmentation, features extraction and qualification, analysis, and model building. Each step needs careful evaluation for the construction of robust and reliable models to be transferred into clinical practice for the purposes of prognosis, non-invasive disease tracking, and evaluation of disease response to treatment. After the definition of texture parameters (shape features; first-, second-, and higher-order features), we briefly discuss the origin of the term radiomics and the methods for selecting the parameters useful for a radiomic approach, including cluster analysis, principal component analysis, random forest, neural network, linear/logistic regression, and other. Reproducibility and clinical value of parameters should be firstly tested with internal cross-validation and then validated on independent external cohorts. This article summarises the major issues regarding this multi step process, focussing in particular on challenges of the extraction of radiomic features from data sets provided by computed tomography, positron emission tomography, and magnetic resonance imaging. PMID- 30426319 TI - Neuroscientific explanations and the stigma of mental disorder: a meta-analytic study. AB - Genetic and other biological explanations appear to have mixed blessings for the stigma of mental disorder. Meta-analytic evidence shows that these "biogenetic" explanations reduce the blame attached to sufferers, but they also increase aversion, perceptions of dangerousness, and pessimism about recovery. These relationships may arise because biogenetic explanations recruit essentialist intuitions, which have known associations with prejudice and the endorsement of stereotypes. However, the adverse implications of biogenetic explanations as a set may not hold true for the subset of those explanations that invoke neurobiological causes. Neurobiological explanations might have less adverse implications for stigma than genetic explanations, for example, because they are arguably less essentialist. Although this possibility is important for evaluating the social implications of neuroscientific explanations of mental health problems, it has yet to be tested meta-analytically. We present meta-analyses of links between neurobiological explanations and multiple dimensions of stigma in 26 correlational and experimental studies. In correlational studies, neurobiological explanations were marginally associated with greater desire for social distance from people with mental health problems. In experimental studies, these explanations were associated with greater desire for social distance, greater perceived dangerousness, and greater prognostic pessimism. Neurobiological explanations were not linked to reduced blame in either set of studies. By implication, neurobiological explanations have the same adverse links to stigma as other forms of biogenetic explanation. These findings raise troubling implications about the public impact of psychiatric neuroscience research findings. Although such findings are not intrinsically stigmatizing, they may become so when viewed through the lens of neuroessentialism. PMID- 30426320 TI - Uniting the un-united: should established non-unions of femoral shaft fractures initially treated with IM nails be treated by plate augmentation instead of exchange IM nailing? A systematic review. AB - The majority of femoral fractures are surgically treated with intramedullary nails. Non-union rate is low but challenging and costly if it occurs. There have been encouraging results from the use of augmentative plating as a treatment for non-union of femoral fractures. We performed a systematic review of the literature to compare union rates, time to union and complications between exchange nailing and augmentative plating as a primary procedure following a diagnosis of femoral non-union following initial nailing. We found a total of 21 papers, which found the mean union rate of augmentative plating to be 99.8% compared to 74% (P = 2.05-12) found for exchange nailing. Times to union were comparable at 5.9 months for augmentative plating and 6.3 months for exchange nailing (P = 0.68916), and complication rate was 4% for augmentative plating compared to 20% for exchange nailing. From the evidence available, plate augmentation provides a more reliable union rate if used as the first operative intervention on a non-union of a femoral fracture compared to exchange nailing.Level of Evidence IV Systematic review of therapeutic studies. PMID- 30426321 TI - Echinacoside protects against MPTP/MPP+-induced neurotoxicity via regulating autophagy pathway mediated by Sirt1. AB - Parkinson's disease (PD) is a common chronic neurodegenerative disease and greatly affects the quality of PD patients' life. Current symptomatic treatment of PD is limited. There are no effective treatment and drugs that could radically cure PD. Increasing experimental evidence has proven a causal relationship between alpha-synuclein (alpha-synuclein, alpha-syn) and the neuropathology of Parkinson's diseases, although the exact pathophysiological role of alpha synuclein is not fully clarified. Previous studies showed that monomers and polymers of alpha-synuclein were secreted from damaged nerve cells via exocytosis and occupied healthy nerve cells via endocytosis, which afford evidence for the prion-like role of alpha-synuclein. Autophagy is the known mechanism for eukaryotic cells to degrade protein polymers and damaged organelles that proteasome does not cope with. Therefore, promoting the clearance of alpha synuclein by enhancing autophagy in neuronal cells could be a promising treatment in the early stage of PD. SIRT1 is a potent regulator of autophagy, because it deacetylates a mass of important transcription factors such as Forkhead Box subgroup O (FoxO) transcription factors family. SIRT1's action relates to FoxO, because FoxO transcription factors are involved in various molecular pathways underlying neuronal protection and autophagy. Moreover, Sirt1 deacetylates proautophagic proteins such as Atg5, Atg7, and Atg8. Echinacoside (ECH) is the main active ingredient of a widely used Chinese herb cistanche, which has been proven to elicit neuroprotective effects in models of neurodegenerative diseases. In this study, we found that ECH could improve PD-like symptoms in MPTP-lesioned mouse model. We further showed that the underlying mechanism of the action of ECH was associated with enhancing autophagy in neurons via bind to Sirt1 directly and affect FoxO expression. Our study demonstrated ECH as a potential therapeutic agent against PD. PMID- 30426322 TI - Respiratory measurement using infrared thermography and respiratory volume monitor during sedation in patients undergoing endoscopic urologic procedures under spinal anesthesia. AB - We aimed to evaluate changes in respiratory pattern after sedation by simultaneously applying a respiratory volume monitor (ExSpiron1Xi, RVM) and infrared thermography (IRT) to patients undergoing spinal anesthesia during endoscopic urologic surgeries. After spinal anesthesia was performed, the patient was placed in a lithotomy position for surgery. Then, we established the baseline of the RVM, and started monitoring the mouth and nose with the infrared camera. SpO2 was continuously measured throughout these processes. Once the baseline was set, 0.05 mg/kg midazolam was administered for sedation. Apnea was defined as cessation of airflow for >= 10 s with respiratory rate of < 6 breaths/min; hypopnea was defined as a decrease in oxygen hemoglobin of > 4%, compared to baseline. We measured the time at which apnea was detected by IRT, the time at which hypopnea was detected by RVM, and the time at which hypoxia was detected by SpO2. Twenty patients (age: 68.9 +/- 11.2 years, body mass index: 24.2 +/- 2.6 kg/min2) completed the study. Before sedation, the baseline correlation coefficient of respiratory rate detection between RVM and IRT was 0.866. After midazolam administration, apnea was detected in all subjects within the first 5 min by IRT; the median time required to detect apnea was 102.5 [interquartile range (IQR) 25-75%: 80-155] s. Hypopnea was detected in all subjects within the first 5 min by RVM: the median time required to detect hypopnea was 142.5 (IQR 115-185.2) s. The median time required for SpO2 to decrease > 4% from baseline was 160 (IQR 125-205) s. Our results suggest that IRT can be useful for rapid detection of respiratory changes in patients undergoing sedation following spinal anesthesia for endoscopic urologic procedures. PMID- 30426323 TI - Age Moderates Link Between Training Effects and Treatment Response to Attention Bias Modification Treatment for Social Anxiety Disorder. AB - Attention bias modification treatment (ABMT) aims to reduce anxiety symptoms via practice on computerized attention training tasks. Despite evidence of efficacy, clinical effects appear heterogeneous. More research on ABMT mechanisms and moderators of treatment response is needed. Age is one potentially important moderator, as developmental differences in training effects may impact response. We examined developmental links between ABMT training effects and response in social anxiety disorder (SAD). We pooled data from two randomized controlled trials in treatment-seeking youths and adults with SAD (N = 99) that used identical ABMT methods. We first characterized learning effects associated with the eight-session ABMT training protocol. We then tested whether learning magnitude predicted the clinical (change in SAD symptoms) and cognitive (change in attention bias) responses to treatment. Finally, we tested whether age moderated the association between ABMT learning and treatment response. Results indicate that ABMT was associated with an incremental learning curve during the protocol, and that learning improved with age. Age further moderated the association between learning gains during the ABMT protocol and subsequent reduction in self-reported SAD symptoms, such that this association was stronger with age. These effects were not evident in bias scores or clinician ratings. Finally, pre-treatment SAD symptoms and bias scores predicted ABMT learning gains. This study highlights the links among age, learning processes, and clinical response to ABMT. These insights may inform attempts to increase the clinical efficacy of ABMT for anxiety. PMID- 30426324 TI - Impact of funding allocation on physical therapist research productivity and DPT student graduates: an analysis using panel data. AB - Financial support for institutional research is relatively stagnant, and thus institutions are likely to seek tuition revenue to offset the costs of research and teaching. It is likely that this has led to increases in tuition driven activities, and thus has limited research activities of academic physical therapy (PT) programs in particular. However, the relationships between sources of program revenue, the number of graduates from PT programs, and the scholarly production of PT faculty have not been studied. The purpose of this paper is to study the effects of types of funding-including research grants and tuition-on the number of physical therapy graduates from each program and the research productivity of physical therapy faculty. Data from 2008 to 2016 were utilized to perform a fixed-effects panel analysis. Panel models created predictions for the number of graduates and the number of peer-reviewed publications for programs from grant funding, annual tuition, and number of funded faculty members. In any given program, a 1% increase in annual tuition is associated with 24% more graduates per year, but a single percentage point increase in the mix of NIH grant funding over other funding types is associated with 8% fewer graduates, all else equal. For every 1% increase in annual tuition, a program can expect to have 41% fewer publications per year. Those institutions with higher numbers of graduates tended to have higher numbers of publications. Higher annual program tuition appears to be associated with both higher numbers of physical therapy graduates and lower levels of publications. Different funding sources have variable effects on degree production and scholarly productivity. Data are self reported by programs on the Annual Accreditation Report, and cause and effect cannot be established through observational design. PMID- 30426327 TI - Annual Congress of the European Society for Medical Oncology (ESMO): Munich, Germany, 19-23 October 2018. PMID- 30426325 TI - Interaction of the mycotoxin metabolite dihydrocitrinone with serum albumin. AB - Citrinin (CIT) is a nephrotoxic mycotoxin produced by Penicillium, Monascus, and Aspergillus species. CIT appears as a contaminant in cereals, cereal-based products, fruits, nuts, and spices. During the biotransformation of CIT, its major urinary metabolite dihydrocitrinone (DHC) is formed. Albumin interacts with several compounds (including mycotoxins) affecting their tissue distribution and elimination. CIT-albumin interaction is known; however, the complex formation of DHC with albumin has not been reported previously. In this study, we aimed to investigate the interaction of DHC with albumin, employing fluorescence spectroscopy, circular dichroism, and molecular modeling studies. Furthermore, species differences and thermodynamics of the interaction as well as the effects of albumin on the acute in vitro toxicity of DHC and CIT were also tested. Our main observations/conclusions are as follows: (1) Fluorescence signal of DHC is strongly enhanced by albumin. (2) Formation of DHC-albumin complexes is supported by both fluorescence spectroscopic and circular dichroism studies. (3) DHC forms similarly stable complexes with human albumin (K~105 L/mol) as CIT. (4) DHC albumin interaction did not show significant species differences (tested with human, bovine, porcine, and rat albumins). (5) Based on modeling studies and investigations with site markers, DHC occupies the Heme binding site (subdomain IB) on human albumin. (6) The presence of albumin significantly decreased the acute in vitro cytotoxic effects of both DHC and CIT on MDCK cell line. PMID- 30426328 TI - Comparison of Three Real-Time PCR Assays for the Detection of PIK3CA Somatic Mutations in Formalin-Fixed Paraffin Embedded Tissues of Patients with Breast Carcinomas. AB - Breast cancer is the leading cause of cancer-related death in women worldwide. Mutations of the PIK3CA gene are found in approximately 25% of breast carcinomas and are reported as activators of the PI3K/AKT/mTOR pathway. This study aims to compare three assays for the somatic mutation detection of PIK3CA gene in FFPE tissues of patients with breast cancer. We compared Cobas(r) PIK3CA Mutation Test (Roche Diagnostics, Meylan, France), PCR amplification-refractory mutation system Scorpions(r) (ARMS) and High-Resolution Melting PCR assay (HRM) for the detection of PIK3CA mutations. Discrepant samples were assessed using Next Generation Sequencing (NGS). 46 FFPE breast carcinomas samples of patients treated for breast cancer have been assessed for PIK3CA mutations using the three PCR assays. Among the 46 samples, 17 (37.8%), 13 (28.36%) and 19 (41.3%) had a PIK3CA mutation, with Cobas(r), ARMS and HRM assays respectively. Three different mutations of PIK3CA have been detected for one sample. Calculated kappa were 0.95[0.86;1] between Cobas(r) and HRM, 0.75[0.55;0.95] between Cobas(r) and ARMS and 0.72[0.51;0.92] between HRM and ARMS. Five samples were found with discrepant results. Our study shows that the Cobas(r) assay is suitable for PIK3CA mutation assessment in patients with breast cancer. HRM assay is also suitable for PIK3CA mutation assessment but requires a mutation characterization with a specific assay. PMID- 30426329 TI - Evolving use and indications for implantable cardioverter defibrillators. PMID- 30426330 TI - The insect, Galleria mellonella, is a compatible model for evaluating the toxicology of okadaic acid. AB - The polyether toxin, okadaic acid, causes diarrhetic shellfish poisoning in humans. Despite extensive research into its cellular targets using rodent models, we know little about its putative effect(s) on innate immunity. We inoculated larvae of the greater wax moth, Galleria mellonella, with physiologically relevant doses of okadaic acid by direct injection into the haemocoel (body cavity) and/or gavage (force-feeding). We monitored larval survival and employed a range of cellular and biochemical assays to assess the potential harmful effects of okadaic acid. Okadaic acid at concentrations >= 75 ng/larva (>= 242 MUg/kg) led to significant reductions in larval survival (> 65%) and circulating haemocyte (blood cell) numbers (> 50%) within 24 h post-inoculation. In the haemolymph, okadaic acid reduced haemocyte viability and increased phenoloxidase activities. In the midgut, okadaic acid induced oxidative damage as determined by increases in superoxide dismutase activity and levels of malondialdehyde (i.e. lipid peroxidation). Our observations of insect larvae correspond broadly to data published using rodent models of shellfish-poisoning toxidrome, including complementary LD50 values: 206-242 MUg/kg in mice, ~ 239 MUg/kg in G. mellonella. These data support the use of this insect as a surrogate model for the investigation of marine toxins, which offers distinct ethical and financial incentives. PMID- 30426331 TI - A global priority list of the TOp TEn resistant Microorganisms (TOTEM) study at intensive care: a prioritization exercise based on multi-criteria decision analysis. AB - The World Health Organization (WHO) proposed a global priority pathogen list (PPL) of multidrug-resistant (MDR) bacteria. Our current objective was to provide global expert ranking of the most serious MDR bacteria present at intensive care units (ICU) that have become a threat in clinical practice. A proposal addressing a PPL for ICU, arising from the WHO Global PPL, was developed. Based on the supporting data, the pathogens were grouped in three priority tiers: critical, high, and medium. A multi-criteria decision analysis (MCDA) was used to identify the priority tiers. After MCDA, mortality, treatability, and cost of therapy were of highest concern (scores of 19/20, 19/20, and 15/20, respectively) while dealing with PPL, followed by healthcare burden and resistance prevalence. Carbapenem-resistant (CR) Acinetobacter baumannii, carbapenemase-expressing Klebsiella pneumoniae (KPC), and MDR Pseudomonas aeruginosa were identified as critical organisms. High-risk organisms were represented by CR Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae. Finally, ESBL Serratia marcescens, vancomycin-resistant Enterococci, and TMP-SMX-resistant Stenotrophomonas maltophilia were identified as medium priority. We conclude that education, investigation, funding, and development of new antimicrobials for ICU organisms should focus on carbapenem-resistant Gram-negative organisms. PMID- 30426332 TI - Evaluation of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for identifying Burkholderia pseudomallei and Burkholderia thailandensis isolates. AB - Since Burkholderia thailandensis is included in the reference spectra of the VITEK MS libraries rather than Burkholderia pseudomallei, B. pseudomallei cannot be correctly identified in the current version of VITEK MS. This study was undertaken to evaluate the utility of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with the VITEK MS plus system in the detection of B. pseudomallei and B. thailandensis isolates. For each species, we increased the reference spectra, and then, a SuperSpectrum was created based on the selection of 39 specific masses. In a second step, we validated the SuperSpectra with 106 isolates identified by 16S rRNA gene sequencing. The results showed that there was 100% agreement between the validation strains analyzed by MALDI-TOF MS and those evaluated using 16S rRNA gene sequencing analysis methods. Therefore, MALDI-TOF MS is a promising, rapid, and economical method to monitor the outbreaks and spread of B. pseudomallei and B. thailandensis isolates. PMID- 30426333 TI - A Critical Review of Nebivolol and its Fixed-Dose Combinations in the Treatment of Hypertension. AB - beta-Adrenergic receptor blockers (beta-blockers) are well-known useful and cost effective drugs for managing hypertensive patients with coronary heart disease, stroke, and heart failure. However, it is often difficult to use beta-blockers for patients with asthma or chronic obstructive pulmonary disease (COPD). Moreover, most beta-blockers negatively influence glucose or lipid metabolism. Nebivolol is a third-generation lipophilic beta-1 receptor-selective blocker with nitric oxide-mediated vasodilatory effects, metabolically neutral and usually well tolerated by patients with asthma or COPD. Nebivolol has significant effects of reduction in central blood pressure and improvements in endothelial dysfunction and arterial stiffness. To summarize the merits and demerits of nebivolol in different clinical situations, we conducted a review using the word 'nebivolol' on Pubmed and Embase, limiting the search to hypertension, clinical trials, and meta-analyses. This review summarizes the clinical studies on nebivolol itself and on the combination of nebivolol with other antihypertensive drugs, such as hydrochlorothiazide, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and amlodipine. Most studies showed the safety and well-tolerated profile of nebivolol and the combination of nebivolol with other antihypertensive drugs, which suggests that new fixed combinations of nebivolol with other antihypertensive drugs would be useful for patients who are unable to tolerate traditional beta-blockers. PMID- 30426335 TI - Different effects of spatial and temporal attention on the integration and segregation of stimuli in time. AB - Having expectations about when and where relevant stimuli will appear engenders endogenous temporal and spatial orienting and can provide vital benefits to visual processing. Although more is known about how each of these forms of orienting affects spatial processing, comparatively little is understood about their influences on the temporal integration and segregation of rapid sequential stimuli. A critical question is whether the influence of spatial cueing on temporal processing involves independent spatial and temporal orienting effects or a synergistic spatiotemporal impact. Here we delineated between the temporal and spatial orienting engendered by endogenous cues by using a paradigm with identical visual stimulation when the goal was to integrate or segregate the stimuli, in separate blocks of trials. We found strong effects of spatial orienting on both integration and segregation performance. In contrast, temporal orienting engendered only an invalid cueing cost, and for integration trials only. This clear differentiation between spatial and temporal cueing effects provides constraints to inform arbitration between theories of how attention biases the visual processing stream and influences the organization of visual perception in time. PMID- 30426334 TI - Effects of nitrogen and phosphorus imbalance on photosynthetic traits of poplar Oxford clone under ozone pollution. AB - Ozone (O3) pollution and the availability of nitrogen (N) and phosphorus (P) in the soil both affect plant photosynthesis and chlorophyll (Chl) content, but the interaction of O3 and nutrition is unclear. We postulated that the nutritional condition changes plant photosynthetic responses to O3. An O3-sensitive poplar clone (Oxford) was subject to two N levels (N0, 0 kg N ha- 1; N80, 80 kg N ha- 1), two P levels (P0, 0 kg P ha- 1; P80, 80 kg P ha- 1) and three levels of O3 exposure (ambient concentration, AA; 1.5 * AA; 2.0 * AA) over a growing season in an O3 free air controlled exposure (FACE) facility. The daily change of leaf gas exchange and dark respiration (Rd) were investigated at mid-summer (August). Chl a fluorescence was measured three times in July, August and September. At the end of the growing season, Chl content was measured. It was found that Chl content, the maximum quantum yield (Fv/Fm), Chl a fluorescence performance index (PI) and gas exchange were negatively affected by elevated O3. Phosphorus may mitigate the O3-induced reduction of the ratio of photosynthesis to stomatal conductance, while it exacerbated the O3-induced loss of Fv/Fm. Nitrogen alleviated negative effects of O3 on Fv/Fm and PI in July. Ozone-induced loss of net photosynthetic rate was mitigated by N in medium O3 exposure (1.5 * AA). However, such a mitigation effect was not observed in the higher O3 level (2.0 * AA). Nitrogen addition exacerbated O3-induced increase of Rd suggesting an increased respiratory carbon loss in the presence of O3 and N. This may result in a further reduction of the net carbon gain for poplars exposed to O3. PMID- 30426336 TI - MiR-20a Plays a Key Regulatory Role in the Repair of Spinal Cord Dorsal Column Lesion via PDZ-RhoGEF/RhoA/GAP43 Axis in Rat. AB - Spinal cord injury (SCI) causes sensory dysfunctions such as paresthesia, dysesthesia, and chronic neuropathic pain. MiR-20a facilitates the axonal outgrowth of the cortical neurons. However, the role of miR-20a in the axonal outgrowth of primary sensory neurons and spinal cord dorsal column lesion (SDCL) is yet unknown. Therefore, the role of miR-20a post-SDCL was investigated in rat. The NF-200 immunofluorescence staining was applied to observe whether axonal outgrowth of dorsal root ganglion (DRG) neurons could be altered by miR-20a or PDZ-RhoGEF modulation in vitro. The expression of miR-20a was quantized with RT PCR. Western blotting analyzed the expression of PDZ-RhoGEF/RhoA/GAP43 axis after miR-20a or PDZ-RhoGEF was modulated. The spinal cord sensory conduction function was assessed by somatosensory-evoked potentials and tape removal test. The results demonstrated that the expression of miR-20a decreased in a time-dependent manner post-SDCL. The regulation of miR-20a modulated the axonal growth and the expression of PDZ-RhoGEF/RhoA/GAP43 axis in vitro. The in vivo regulation of miR 20a altered the expression of miR-20a-PDZ-RhoGEF/RhoA/GAP43 axis and promoted the recovery of ascending sensory function post-SDCL. The results indicated that miR 20a/PDZ-RhoGEF/RhoA/GAP43 axis is associated with the pathophysiological process of SDCL. Thus, targeting the miR-20a/PDZ-RhoGEF /RhoA/GAP43 axis served as a novel strategy in promoting the sensory function recovery post-SCI. PMID- 30426337 TI - Effect of x-rays and gamma radiations on the bone mechanical properties: literature review. AB - The bone auto grafting, isografting, allografting and xenografting are used for defective bone replacement or treatment in almost all living species. The X-ray and Gamma (electromagnetic radiation) sterilization performed on the donor bone graft to prevent toxicity or migration of virus/bacterial infections from donors to reciver. Conversely, X-ray and Gamma radiation deteriorates the bone mechanical properties and bone become more susceptible to fracture. Fracture toughness as well as other mechanical properties of bone change with these radiations. In this literature review the effect of the X-rays and Gamma radiation on bone mechanical properties are discussed. All relevant literature was reviewed. After reviewing the literature only the research relating to the effect of X-rays and Gamma radiations on bone mechanical properties are included. Literature studies showed significant effect of the X-rays and Gamma radiations on the mechanical properties of the bones. In some studies the differences exists on the doses of radiations which were discussed in this study. The high energetic electromagnetic radiation (X-rays and Gamma radiations) changed/modify the collagen network of the bone, which reduced the mechanical properties of bone; however these changes depend on the radiation dose. PMID- 30426338 TI - Death by hanging: a retrospective case-control investigation of the intervertebral disc vacuum phenomenon on PMCT. AB - During hanging gravitational forces affect the spine. Intervertebral vacuum phenomenon (VP) implies that gas accumulations in the discs are caused by degeneration of the spine and trauma. It was hypothesized that VP detected on postmortem computed tomography (PMCT) has a higher incidence in hanging deaths, which can be correlated to age, degenerative spinal changes and type of hanging (complete-incomplete). Secondly, it was investigated whether the presence of Simon's bleedings is related to hanging type and VP on PMCT. A retrospective hanging case-control study of 72 cases was conducted. PMCT data were evaluated by two observers for the presence of VP and its localization within the thoracic and lumbar discs, and for any degenerative changes of the spine. Autopsy protocols were assessed for the presence of Simon's bleedings during autopsy. VP did not statistically differ among hanging and control cases but it was statistically correlated to complete hanging, increasing age and degenerative spinal changes. Centrally located VP within the discs was correlated to hanging, especially complete hanging, and younger ages, contrary to control cases that showed gas at the disc periphery. Simon's bleedings were correlated with complete hanging and centrally located VP. Centrally located VP within the discs increases the probability for complete hanging, while increasing age and degenerative changes reduce this probability. Intervertebral VP is multifactorial radiological entity. The presence of centrally located VP can indicate that hanging could be considered as an alternative mechanism of death and that great forces and loads may have affected the spine perimortem, especially with decreasing age and when Simon's bleedings are present. PMID- 30426339 TI - Risk factors associated with occurrence of anthelmintic resistance in sheep of resource-poor farmers in Limpopo province, South Africa. AB - Anthelmintic treatment is the most common way of controlling nematode infections in ruminants even though several countries have reported anthelmintic resistance (AR), resulting in limitation for sustainable small ruminant production. The aim of the present study was to evaluate the knowledge of resource-poor sheep farmers in Limpopo province of South Africa on the use of anthelmintics. A questionnaire regarding helminthosis control practices was administered to small ruminant farmers in five districts of Limpopo province namely Capricorn, Sekhukhune, Waterberg, Vhembe, and Mopani. A total of 77 resource-poor farmers were interviewed between June and August of 2017 using a structured questionnaire with a combination of qualitative and quantitative open-ended questions. The interviewed farmers were divided into three groups based on their farming experience (< 5; 6-10, and ? 10 years of farming experience). Limited farming experience was shown as one of the risks, as farmers that owned sheep for less than 10 years could not identify the symptoms of gastrointestinal parasites infection and did not know how nematodes are transmitted to animals. However, no significant difference (p < 0.05) was found to exist between the three groups of farmers in terms of clinical signs identification and correct application of anthelmintics. About 43% of the respondents were unaware of gastrointestinal nematodes (GI) that infect sheep, could not identify the clinical symptoms of gastrointestinal nematodes infection, and only 34% knew how animals become infected. Although 67.5% of farmers mentioned that they never dose their sheep, 32.5% use anthelmintics at varying times in a year. None of the farmers weighed their sheep before dosing them instead visual appraisal of individual weight was the most common means of estimating the anthelmintic dose. The above information is an indication of risks associated with possible occurrence of anthelmintic resistance in the study areas. There is therefore, a need to give training to resource-poor farmers of small stock on proper application of anthelmintic treatment and to educate them on how to prevent development of AR. Future studies on AR should also be conducted in the province in flocks with high-treatment frequencies to establish the occurrence of AR using both in vivo and in vitro methods. The most common risk factor associated with the occurrence of AR in all the five districts of Limpopo province was found to be the use of anthelmintics without weighing the animals to determine the correct dosage. PMID- 30426340 TI - Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus. AB - Metformin (MET), an antidiabetic agent, also has antioxidative effects in metabolic-related hypertension. This study was designed to determine whether MET has anti-hypertensive effects in salt-sensitive hypertensive rats by inhibiting oxidative stress in the hypothalamic paraventricular nucleus (PVN). Salt sensitive rats received a high-salt (HS) diet to induce hypertension, or a normal salt (NS) diet as control. At the same time, they received intracerebroventricular (ICV) infusion of MET or vehicle for 6 weeks. We found that HS rats had higher oxidative stress levels and mean arterial pressure (MAP) than NS rats. ICV infusion of MET attenuated MAP and reduced plasma norepinephrine levels in HS rats. It also decreased reactive oxygen species and the expression of subunits of NAD(P)H oxidase, improved the superoxide dismutase activity, reduced components of the renin-angiotensin system, and altered neurotransmitters in the PVN. Our findings suggest that central MET administration lowers MAP in salt-sensitive hypertension via attenuating oxidative stress, inhibiting the renin-angiotensin system, and restoring the balance between excitatory and inhibitory neurotransmitters in the PVN. PMID- 30426341 TI - Ke Hsin Kuo: A distinguished scientist and great mentor. PMID- 30426342 TI - Is Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium Justifiable for Gastrointestinal Quality of Life? AB - BACKGROUND: Globally, enteric-coated mycophenolate sodium (EC-MPS) is replacing mycophenolate mofetil (MMF) in maintenance immunosuppressant regimens. The predominant reason for conversion is the purported improvement in gastrointestinal (GI) quality of life. This paper considers the level of bias associated with studies comparing EC-MPS and MMF for GI-related improvement and provides insight into whether conversion is supported by evidence. METHODS: Using a pre-determined protocol, a literature search was conducted. Full-text review, data extraction and risk of bias analysis was conducted by two independent authors using the Cochrane domain-based evaluation of risk of bias. The review was reported according to the preferred reporting items for systematic reviews and meta-analyses. RESULTS: Twenty-nine studies were included in risk of bias analysis. Of these, only three were deemed a low risk of bias. Across these three studies, there were no statistically significant differences in the proportion of GI-related adverse events nor was there a significant difference in the GI related quality of life between EC-MPS- and MMF-treated patients in these data. CONCLUSION: There was a high risk of bias across the 29 studies investigating conversion from MMF to EC-MPS for potential improvement in GI-related quality of life. The consolidated results of the three studies with low risk of bias suggest no evidence to convert patients stabilised on MMF. If a patient experiences GI related adverse events whilst taking MMF, other methods should be explored before conversion to EC-MPS. PMID- 30426344 TI - When Suicide Happens in the Medical Community. AB - When suicide happens close to doctors, students, and faculty, to our families, friends, colleagues, students, residents, fellows and patients, it challenges us as individuals and as members of institutions that seek to provide safety and support. The US suicide rate has increased and suicide remains difficult to predict or to prevent despite its association with depression and addiction. It is less common in medical students and residents than in the general, age-matched population but generates troubling, complex aftershocks for us. Individuals react according to their history and style, through stages, psychological defenses, and difficult affects. Grief, shock, anger, denial, and guilt are prevalent. People responding to a close suicide seek information, asking "why", "what if" and "if only", despite the speculative nature of attempting to understand what happened and why. Nearby suicide may be more challenging for us in the medical profession because the helplessness it evokes undermines our sense of omniscience and omnipotence. Thus, we engage in retrospection and a search for preventive interventions that may or may not be evidence based, salutary, or healing. PMID- 30426345 TI - Fat-Free Adipose Tissue Mass: Impact on Peak Oxygen Uptake (VO2peak) in Adolescents with and without Obesity. AB - Fat-free body mass (FFM) is a surrogate for skeletal muscle mass and is often used for the normalization of several physiological variables (e.g., oxygen uptake). However, FFM includes non-skeletal muscle components such as the fat free component of adipose tissue fat cells. As the amount of adipose tissue mass increases, the FFM will also increase and be included in the measurement of FFM. Therefore, FFM may not be an appropriate indicator of muscle mass when targeting individuals with a large amount of body fat. This review aimed (1) to examine the fat-free adipose tissue (FFAT) in adolescents with and without obesity and (2) to investigate the impact of FFAT on peak oxygen uptake (VO2peak) by comparing VO2peak expressed relative to FFM and FFM minus FFAT between adolescents with and without obesity. Calculated FFAT was threefold higher in adolescents with obesity compared to those without obesity (mean +/- SD; 6.94 +/- 1.40 vs. 2.22 +/- 0.58 kg). The VO2peak expressed relative to FFM-FFAT was similar between the two groups (56.5 +/- 6.7 vs. 57.4 +/- 8.9 ml min-1 kg-1 FFM-FFAT, respectively). On the other hand, VO2peak expressed relative to FFM was approximately 8% different between groups. When normalizing VO2peak by FFM, eliminating the FFAT component from FFM may be needed, especially when comparing groups with different body fat mass. PMID- 30426346 TI - Overlap of the Pitt-Hopkins and Lennox-Gastaut syndromes. PMID- 30426347 TI - Sleep Problems and Their Correlates in Children with Autism Spectrum Disorder: An Indian Study. AB - Sleep problems were studied in both typically developing (TD) children and those with autism spectrum disorder (ASD) using the Sleep Disturbance Scale for Children. Factors associated with these problems were also studied in children with ASD. Seventy-three children with ASD and their age and sex matched TD controls in age group of 3-12 years were enrolled in the study. Higher sleep problems were found in children with ASD than TD children. Most common sleep problem reported in children with ASD was Sleep Wake Transition Disorders, followed by Disorder of Initiation and Maintenance; while in TD controls, it was Sleep Breathing Disorders. Apart from severity of Autism; hyperactivity, sensory issues and poor motor skills were significantly associated with sleep problems, which may be important targets for intervention in children with sleep problems. PMID- 30426348 TI - Susceptibility to Abetao and TBOA of LTD and Extrasynaptic NMDAR-Dependent Tonic Current in the Aged Rat Hippocampus. AB - Aging, as the major risk factor of Alzheimer's disease (AD), may increase susceptibility to neurodegenerative diseases through many gradual molecular and biochemical changes. Extracellular glutamate homeostasis and extrasynaptic glutamate N-methyl-D-aspartate receptors (NMDAR) are among early synaptic targets of oligomeric amyloid beta (Abetao), one of the AD related synaptotoxic protein species. In this study, we asked for the effects of Abetao on long-term depression (LTD), a form of synaptic plasticity dependent on extrasynaptic NMDAR activation, and on a tonic current (TC) resulting from the activation of extrasynaptic NMDAR by ambient glutamate in hippocampal slices from young (3-6 month-old) and aged (24-28-month-old) Sprague-Dawley rats. Abetao significantly enhanced the magnitude of LTD and the amplitude of TC in aged slices compared to young ones. TBOA, a glutamate transporter inhibitor, also significantly increased LTD magnitude and TC amplitude in slices from aged rats, suggesting either an age related weakness of the glutamate clearance system and/or a facilitated extrasynaptic NMDAR activation. From our present data, we hypothesize that senescence-related impairment of the extrasynaptic environment may be a vector of vulnerability of the aged hippocampus to neurodegenerative promotors such as Abetao. PMID- 30426350 TI - Bariatric or Metabolic Surgery? PMID- 30426351 TI - Health-Related Quality of Life 5 Years After Roux-en-Y Gastric Bypass in Young (18-25 Years) Versus Older (>= 26 Years) Adults: a Scandinavian Obesity Surgery Registry Study. AB - BACKGROUND: To compare changes in health-related quality of life (HRQoL) in young (18-25 years) versus older (>= 26 years) adults up to 5 years after Roux-en-Y gastric bypass (RYGB). METHODS: Data on Short Form-36 (SF-36) and obesity-related problems scale (OP) at baseline and 1, 2, and 5 years after RYGB were extracted from the Scandinavian Obesity Surgery Registry. Within-group changes and the effect of age group on 5-year changes in SF-36 and OP were analyzed. Effects sizes (ESs) were calculated. RESULTS: A total of 2542 young and 12,425 older adults were included at baseline, and 138 young (20.7% of those eligible) and 1021 older (31.8%) adults were followed-up 5 years post-RYGB. At this time, average to large improvements (ES >= 0.5) were observed in physical functioning, physical component score and OP in young adults, and in physical functioning, role physical, general health, physical component score, and OP in older adults (all, p <= 0.001). Both age groups displayed negligible to weak (ES < 0.5) or no improvements in mental HRQoL (all, p < 0.55). Older adults displayed greater 5 year improvements than their young counterparts in role physical, general health, vitality, social functioning, physical component score, and obesity-related problems scale (all, p < 0.05). CONCLUSIONS: Both young and older adults displayed improvements in OP and physical HRQoL 5 years post-RYGB compared to baseline, while mental HRQoL did not improve to the same extent. Greater HRQoL improvements could be expected in older patients why future research on HRQoL post-RYGB should stratify data on age groups. PMID- 30426349 TI - Psoralidin Stimulates Expression of Immediate-Early Genes and Synapse Development in Primary Cortical Neurons. AB - Upon synaptic stimulation and glutamate release, glutamate receptors are activated to regulate several downstream effectors and signaling pathways resulting in synaptic modification. One downstream intracellular effect, in particular, is the expression of immediate-early genes (IEGs), which have been proposed to be important in synaptic plasticity because of their rapid expression following synaptic activation and key role in memory formation. In this study, we screened a natural compound library in order to find a compound that could induce the expression of IEGs in primary cortical neurons and discovered that psoralidin, a natural compound isolated from the seeds of Psoralea corylifolia, stimulated synaptic modulation. Psoralidin activated mitogen-activated protein kinase (MAPK) signaling, which in turn induced the expression of neuronal IEGs, particularly Arc, Egr-1, and c-fos. N-methyl-D-aspartate (NMDA) receptors activation and extracellular calcium influx were implicated in the psoralidin induced intracellular changes. In glutamate dose-response curve, psoralidin shifted glutamate EC50 to lower values without enhancing maximum activity. Interestingly, psoralidin increased the density, area, and intensity of excitatory synapses in primary hippocampal neurons, which were mediated by NMDA receptor activation and MAPK signaling. These results suggest that psoralidin triggers synaptic remodeling through activating NMDA receptor and subsequent MAPK signaling cascades and therefore could possibly serve as an NMDA receptor modulator. PMID- 30426352 TI - Robotic-assisted ileocolic resection for Crohn's disease: outcomes from an early national experience. AB - Crohn's disease is an incurable inflammatory disorder that can affect the entire gastrointestinal tract. While medical management is considered first-line treatment, approximately 70-90% of patients with Crohn's disease will require at least one surgical intervention during the course of their lifetimes. Traditionally, abdominal surgery for Crohn's disease has been performed via an open approach with an increasing adoption of minimally invasive techniques. The aim of this study was to evaluate and compare postoperative outcomes from an initial national experience with robotic-assisted ileocolic resection for Crohn's disease. Patients who underwent elective ileocolic resection for Crohn's disease by robotic-assisted or open approaches from 2011 to Q3 2015 were identified using ICD-9 codes from the Premier Healthcare Database. Propensity-score matching (1:1) was performed using age, gender, race, Charlson index score, and year of surgery to form comparable cohorts in order to compare the robotic-assisted and open groups. 3641 patients underwent elective ileocolic resection for Crohn's disease during the study period (1910 [52.5%] open and 109 [3%] robotic-assisted). Post matched comparison of cohorts (n = 108 per cohort) showed that robotic-assisted cases were longer by a mean of 60 min (p < 0.0001), had shorter length of hospital stay by a median of 2 days (p < 0.001) and a lower 30-day complication rate (24% vs. 38%; p = 0.039). This national database assessment of patients undergoing elective ileocolic resection for Crohn's disease demonstrated that a robotic-assisted approach was associated with longer operative times, shorter length of hospital stay and lower 30-day complication rates compared to open approach. PMID- 30426353 TI - Early experience with the Senhance(r)-laparoscopic/robotic platform in the US. AB - The introduction of new robotic platforms will grow considerably in the near future as several manufacturers are in the developing stages of different innovative systems. One of the newest systems, the Senhance(r) platform (TransEnterix Surgical Inc., Morrisville, NC, USA) has been utilized in a variety of cases in Europe but only recently approved for limited clinical use in the United States. Here, we present our initial experience with this state-of-the-art system in patients requiring a variety of procedures. PMID- 30426354 TI - MRI criteria of subtypes of adenomas and epithelial cysts of the pituitary gland. AB - This study aimed to assess the clinical applicability of MRI criteria for differentiation of pituitary adenomas and cystic pituitary lesions. One hundred ninety-eight consecutive patients with surgical resection of a pituitary adenoma/cystic pituitary lesion were retrospectively analyzed, blinded to clinical data and histopathological diagnosis. Different morphologic criteria were assessed: signal intensity in T2/T1w images, pattern of contrast enhancement, size, super-/infrasellar extension, and invasion of the cavernous sinus. For validation of the criteria, a second independent patient cohort (n = 102) was analyzed for diagnostic accuracy of the criteria. We identified differences between subtypes of pituitary adenomas regarding morphological MRI criteria. Especially, ACTH-producing adenomas and GH-producing adenomas showed partially specific imaging features. Application of our criteria on the second patient cohort (n = 102) did however not significantly improve diagnostic accuracy. Only differentiation between cystic pituitary lesions and adenomas was facilitated using these criteria, but did not reach statistical significance in this cohort (P = 0.352). MRI criteria might facilitate differentiation between pituitary adenomas and cystic pituitary lesions, but not between subtypes of pituitary adenomas. These subtypes show partially specific MR imaging features, however, due to a high variability knowledge of clinical symptoms and laboratory findings remain essential for the correct diagnosis. PMID- 30426355 TI - Prophylactic enlargement of the thecal sac volume by spinal expansion duroplasty in patients with unresectable malignant intramedullary tumors and metastases prior to radiotherapy. AB - Unresectable malignant intramedullary tumors and metastases usually require radiotherapy which intensifies spinal cord edema and might result in neurological decline. Spinal expansion duroplasty before radiotherapy enlarges the intrathecal volume and might thus prevent neurological deficits. The study aims to evaluate the clinical course of patients undergoing expansion duroplasty. This retrospective analysis (2007-2016) included all patients with unresectable intramedullary tumors who underwent spinal expansion duroplasty. To assess the degree of preoperative cord enlargement, we calculated the "diameter ratio": diameter of the spinal cord below and above the tumor / diameter of the tumor * 2. The presence of perimedullary cerebrospinal fluid (CSF) at the affected levels was analyzed on the preoperative magnetic resonance imaging (MRI). We recorded the occurrence of neurological deficits, wound breakdown, and CSF fistula. We screened 985 patients, 11 of which were included. Eight patients had an intramedullary metastasis, three patients a spinal malignant glioma. A diameter ratio <= 0.8 representing a significant preoperative intramedullary enlargement was seen in 10 cases (90.9%). Postoperative imaging was available in 9 patients, demonstrating successful decompression in 8 of the 9 patients (88.9%). The postoperative course was uneventful in 9 patients (81.8%). Mean overall survival was 13.4 (SD 16.2) months. Spinal expansion duroplasty prior to radiotherapy is a previously undescribed concept. Despite neoadjuvant radiation, no wound breakdown or CSF fistula occurred. In unresectable intramedullary tumors and metastases, spinal expansion duroplasty seems to be a safe procedure with the potential to prevent neurological decline due to radiation-induced cord swelling. PMID- 30426356 TI - Visualization of the pulp chamber roof and residual dentin thickness by spectral domain optical coherence tomography in vitro. AB - The aim of this study was to evaluate the ability of spectral-domain optical coherence tomography (SD-OCT) to display the roof of the pulp chamber and to estimate the residual dentin thickness (RDT) of the pulp complex. The roots of 20 extracted human molars were embedded in epoxy resin, and crowns were longitudinally sectioned in the mesial-distal direction, exposing the pulp chamber. The coronal part of the crown was removed up to an RDT to the pulp chamber roof of 2 mm. Samples were imaged by SD-OCT from coronal view and by light microscopy (LM) in the sagittal plane. Using a microtome, dentin was subsequently removed in four levels from the occlusal aspect in steps of 250 MUm. At each level, RDT was documented and measured by both methods. The data were compared (Spearman's rho correlation coefficient, Wilcoxon signed-rank test). Using OCT, the roof of the pulp chamber was first displayed at a maximum RDT of 1.94 mm. The minimal RDT that could be imaged by OCT was 0.06 mm. Values from both methods were strongly correlated (r, 0.83-0.95; pi <= 0.05) and differed significantly for large RDTs (dentin levels 1, 2; pi < 0.05) but not for small RDTs (levels 3, 4; pi >= 0.226). The roof of the dental pulp chamber could be already visualized by SD-OCT with a RDT of 1.94 mm. Therefore, the method could be a useful diagnostic tool during the preparation of deep dentin cavities and might help to preserve the integrity of the pulp chamber. PMID- 30426357 TI - Therapeutic switching of sulpiride, an anti-psychotic and prokinetic drug, to an anti-colitic drug using colon-specific drug delivery. AB - To test whether sulpiride (SP), an anti-psychotic and prokinetic drug, shows beneficial effects on experimental murine colitis, a colon-targeted prodrug of SP, 5-(aminoethanoylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2 methoxybenzamide (glycylsulpiride (GSP)), was synthesized and its colonic delivery and therapeutic activity against 2,4-dinitrobenzenesulfonic acid (DNBS) induced rat colitis were assessed. Synthesis of GSP was verified by infrared and proton nuclear magnetic resonance spectroscopy. GSP was converted to SP when incubated with the cecal contents but not when incubated with the small intestinal contents. The percent conversion was about 50.5% at 6 h and 67.7% at 10 h. Colonic delivery of GSP was examined by comparison with sulfasalazine (SSZ), a colon-specific prodrug of 5-aminosalicylic acid currently used for the treatment of inflammatory bowel disease. The two prodrugs accumulated similar concentrations of the corresponding parent drugs in the cecum at 2, 4, and 6 h after oral gavage. Although oral gavage of GSP released millimolar level of SP in the large intestine, SP was hardly detected in the blood. GSP improved colonic damage score and reduced myeloperoxidase activity up to 80.5% in the inflamed colon in a dose-dependent manner. Moreover, GSP was able to reduce the levels of inflammatory mediators in the inflamed colon. Overall, the anti-colitic effectiveness of GSP and SSZ was similar. In conclusion, colonic delivery of SP ameliorates DNBS-induced colitis in rats with no significant systemic absorption of SP. Thus, colon-targeted SP may be therapeutically switched to an anti-colitic drug. PMID- 30426358 TI - Correction to: The Therapy of Congenital Myasthenic Syndromes. AB - The third paragraph in the left column of page 256 of the article pertaining to the treatment of congenital choline acetyl transferase (ChAT) deficiency states that "Because apneic attacks occur suddenly in infants and children, the parents should be provided with an inflatable rescue bag." PMID- 30426359 TI - Dynamin 2 (DNM2) as Cause of, and Modifier for, Human Neuromuscular Disease. AB - Dynamin 2 (DNM2) belongs to a family of large GTPases that are well known for mediating membrane fission by oligomerizing at the neck of membrane invaginations. Autosomal dominant mutations in the ubiquitously expressed DNM2 cause 2 discrete neuromuscular diseases: autosomal dominant centronuclear myopathy (ADCNM) and dominant intermediate Charcot-Marie-Tooth neuropathy (CMT). CNM and CMT mutations may affect DNM2 in distinct manners: CNM mutations may cause protein hyperactivity with elevated GTPase and fission activities, while CMT mutations could impair DNM2 lipid binding and activity. DNM2 is also a modifier of the X-linked and autosomal recessive forms of CNM, as DNM2 protein levels are upregulated in animal models and patient muscle samples. Strikingly, reducing DNM2 has been shown to revert muscle phenotypes in preclinical models of CNM. As DNM2 emerges as the key player in CNM pathogenesis, the role(s) of DNM2 in skeletal muscle remains unclear. This review aims to provide insights into potential pathomechanisms related to DNM2-CNM mutations, and discuss exciting outcomes of current and future therapeutic approaches targeting DNM2 hyperactivity. PMID- 30426360 TI - Distinguishing Core from Peripheral Psychiatric Symptoms: Addictive and Problematic Internet Gaming in North America, Europe, and China. AB - We explore the problem of distinguishing the relatively constant versus culturally variable dimensions of mental suffering and disorder in the context of a cross-cultural study of Internet gaming-related distress. We extend the conceptual contrast of "core" and "peripheral" symptoms drawn from game studies and use a framework that synthesizes cultural and neurobiological understandings of emotional distress. In our framework, "core" symptoms are relatively constant across cultures and therefore presumed to be more closely tied to a neurobiological base. By contrast, we treat as "peripheral" symptoms those that are more culturally variable, and thus less directly tied to the neurobiology of addiction. We develop and illustrate this approach with a factor analysis of cross-cultural survey data, resting on previous ethnographic work, through which we compare online gaming distress experienced in North America (n = 2025), Europe (n = 1198), and China (n = 841). We identify the same four-factor structure across the three regions, with Addiction always the first and most important factor, though with variability in regional factors' exact item composition. The study aims to advance an integrative biocultural approach to distinguishing universal as opposed to culturally contingent dimensions of human suffering, and to help resolve debates about whether problem gaming represents a form of addiction. PMID- 30426361 TI - Clinical Application of Pharmacokinetics: Basis for Rational Dose Selection in a Critically Ill Patient on Renal Replacement Therapy. AB - BACKGROUND: Individualizing drug dosing regimens in critically ill patients on renal replacement therapy is a challenge to clinicians as guidelines are often imprecise and specific-validated pharmacokinetic software is unavailable. OBJECTIVE: A case of a septic patient on hemodialysis is presented, where a quick solution for antibiotic dose adjustment based on the application of pharmacokinetic principles was found. METHODS: The dose adjustment was made in two steps-the first step was to calculate total antibiotic clearance (using the formula: total drug clearance = dialysate flow rate * fraction of unbound drug in plasma + extrarenal clearance), and the second step was to calculate maintenance dose based on target plasma concentrations in steady-state (using the formula: maintenance dose = target plasma concentration * total drug clearance * dose interval). RESULTS: After the doses of antibiotics were adjusted, the patient's condition gradually improved, with a drop in body temperature to normal values, a decrease in plasma levels of inflammatory parameters, and the emergence of spontaneous diuresis. The plasma concentration of vancomycin was within the recommended therapeutic range. CONCLUSIONS: Specific pharmacokinetic software and measuring plasma concentrations of the drugs should be used for calculation of total drug clearance and dose adjustment whenever possible. However, if unavailable, basic pharmacokinetic formulas and principles could be successfully used instead to adjust the dose in critically ill patients on hemodialysis. PMID- 30426362 TI - Automated detection of vulnerable plaque in intravascular ultrasound images. AB - Acute coronary syndrome (ACS) is a syndrome caused by a decrease in blood flow in the coronary arteries. The ACS is usually related to coronary thrombosis and is primarily caused by plaque rupture followed by plaque erosion and calcified nodule. Thin-cap fibroatheroma (TCFA) is known to be the most similar lesion morphologically to a plaque rupture. In this paper, we propose methods to classify TCFA using various machine learning classifiers including feed-forward neural network (FNN), K-nearest neighbor (KNN), random forest (RF), and convolutional neural network (CNN) to figure out a classifier that shows optimal TCFA classification accuracy. In addition, we suggest pixel range-based feature extraction method to extract the ratio of pixels in the different region of interests to reflect the physician's TCFA discrimination criteria. Our feature extraction method examines the pixel distribution of the intravascular ultrasound (IVUS) image at a given ROI, which allows us to extract general characteristics of the IVUS image while simultaneously reflecting the different properties of the vessel's substances such as necrotic core and calcified nodule depending on the brightness of the pixel. A total of 12,325 IVUS images were labeled with corresponding optical coherence tomography (OCT) images to train and evaluate the classifiers. We achieved 0.859, 0.848, 0.844, and 0.911 area under the ROC curve (AUC) in the order of using FNN, KNN, RF, and CNN classifiers. As a result, the CNN classifier performed best and the top 10 features of the feature-based classifiers (FNN, KNN, RF) were found to be similar to the physician's TCFA diagnostic criteria. Graphical Abstract AUC result of proposed classifiers. PMID- 30426363 TI - An ultra-fast non-conventional waste management protocol to recycle of industrial fly ash into zeolite X. AB - An ultra-fast non-conventional waste management protocol was being designed and applied to recycle and reuse industrial coal fly ash (CFA) waste to generate highly pure nanozeolite X. Both microwave heating-assisted hydrothermal treatment method and ultrasonic waves-assisted hydrothermal method have been successfully used for the fast valorization of power plant CFA waste, and the results were compared with conversional valorization method for CFA conversion to zeolite. While conventional methods like hydrothermal treatment using sodium hydroxide took up to 4 days in valorization of the solid CFA waste into a useful zeolitic X material; the non-conventional methods using microwave irradiation of frequency 2.45 GHz and ultrasound irradiation of frequency 20 kHz took 90 min and 20 min respectively to fast-valorize the solid waste into highly pure zeolite material with high cation-exchanged capacity. The unconventional techniques, therefore, can be used in the large-scale valorization of solid waste recycling and reuse to yield highly pure zeolite. PMID- 30426364 TI - Removal of Pb(II) from aqueous solutions by adsorption on magnetic bentonite. AB - Bentonite is a porous clay material that shows good performance for adsorbing heavy metals and other pollutants for wastewater remediation. In our previous study, magnetic bentonite (M-B) was prepared to solve the separation problem and improve the operability. In this study, we investigated the influence of various parameters on the Pb(II) adsorption of M-B, and it showed effective performance. About 98.9% adsorption removal rate was achieved within 90 min at adsorbent dose of 10 g/L for initial Pb(II) concentration of 200 mg/L at 40 degrees C and pH 5. The adsorption kinetic fit well by the pseudo-second-order model, and also followed the intra-particle diffusion model up to 90 min. Moreover, adsorption data were successfully reproduced by the Langmuir isotherm; the maximum adsorption capacity was calculated as 80.40 mg/g. The mechanism of interaction between Pb(II) ions and M-B was ionic exchange, surface complexation, and electro static interactions. Thermodynamics study indicated that the reaction of Pb(II) adsorption on M-B was endothermic and spontaneous; increasing the temperature promoted adsorption. This study was expected to provide a reference and theoretical basis for the treatment of Pb-containing wastewater using bentonite materials. PMID- 30426365 TI - Determination of histological, immunohistochemical and biochemical effects of acute and chronic grayanotoxin III administration in different doses in rats. AB - Grayanotoxin (GTX)-III is a Na-channel neurotoxin. Grayanotoxins can be found in the nectar, pollen, and other plant parts of the Rhododendron genus plants from the Ericaceae family. It is widely believed that honey produced from these plants, which are concentrated in the Black Sea region, is traditionally characterized as enhancing sexual performance. It is thought that the effective factor is dose for this compound, which has both beneficial and toxic effects reported. Therefore, it is aimed to evaluate the histological, immunohistochemical, and biochemical effects of acute and chronic impact of GTX III in different doses on testes tissue in this study. For this purpose, 100 Sprague-Dawley male rats were divided into 5 separate groups for acute and chronic research. While dose groups were (control, 0.1, 0.2, 0.4, ve 0.8 MUg/kg/bw) for experimental groups, a single dose (i.p.) was administered for acute impact whereas the same doses were administered daily for 3 weeks to assess chronic effect. At the end of the experiment, Johnsen testicular biopsy scoring was performed on testicular tissue samples, seminiferous tubule diameters were measured, and apoptotic cells were evaluated by TUNEL method. Testosterone, LH, and FSH levels were measured by ELISA method in serum and tissue specimens. It was found that Johnsen score of acute doses was significantly lower than the control group, and the diameter of the seminiferous tubules decreased significantly in acute and chronic dose-administered groups compared to the control. Hemorrhage, epithelial shedding, irregularity in seminiferous epithelium, and vacuolization were observed in acute and chronic dose administered groups, and increase in apoptotic cells was determined. Hormone levels varied depending on the dose. In conclusion, it was found that dose dependent acute and chronic effects of GTX-III are different, and this factor should be taken into account in studies to be carried out due to the adverse effects of high doses. PMID- 30426366 TI - Pollutant source analysis and tempo-spatial analysis of pollutant discharge intensity in a transboundary river basin. AB - From the perspective of river basin refined management and pollution control of water bodies, a transboundary river basin and its regional pollutant sources are identified and the typical status of discharging processes of different pollutant sources are screened. Then organic connection which can comprehensively reflect and dynamically characterize the discharge of transboundary water pollutants is constructed. In addition, the integrated prediction (IP) model of the transboundary river basin and its regional water pollutants discharge is established. Finally, the dynamic simulation of typical status characteristics of the transboundary river basin and its regional pollutant sources discharge as well as the tempo-spatial changing pattern of pollutant discharge intensity is conducted in this paper. This paper selected the Songhua River basin as an example where planting, industry, household (urban living and rural living), and livestock and poultry are the main pollutant sources. The dynamic simulation of water pollution discharge in Songhua River basin during the 13th Five-year Plan and its tempo-spatial changing trend analysis are conducted by employing the established IP model of transboundary river basin water pollution discharge. The results show that during the 13th Five-year Plan, through comprehensive management and control of pollutant sources in Songhua River basin, the discharge amounts of different pollutant sources (planting, industry, household, livestock, and poultry) present an overall decreasing trend and the main pollutants discharge intensity decreases significantly year by year. It is demonstrated that pollution discharge in Songhua River basin is controlled effectively. PMID- 30426367 TI - Polychlorinated biphenyls (PCBs) in commonly consumed seafood from the coastal area of Bangladesh: occurrence, distribution, and human health implications. AB - Dietary intake is the most important route of polychlorinated biphenyls (PCBs) exposure and seafood is the major dietary component for the coastal populations. It is, therefore, an urgent need to assess the levels of PCBs in seafood. A comprehensive congener-specific evaluation of PCBs was carried out for the first time in Bangladesh. All 209 congeners of PCBs in 48 seafood samples (5 finfish and 2 shellfish species) collected in winter and summer of 2015 were measured by GC-MS/MS. Regardless of season and site, the ?PCBs (ng/g wet weight) in finfish and shellfish were in the range of 6.4-86.2 and 3.8-37.7, respectively. The results were comparable to or higher than those observed in other studies worldwide, particularly from Spain, China, Korea, Thailand, and Hong Kong. No significant seasonal variation was observed in the levels of ?PCBs in the examined seafood (p > 0.05); however, interspecies differences were significant (p < 0.05). Nonetheless, spatial distribution revealed seafood collected from the areas with recent urbanization and industrialization (Chittagong, Cox's Bazar, and Sundarbans) were more contaminated with PCBs than the area unaffected by industries (Meghna Estuary). Moderately chlorinated (4-6 Cl) homologs dominated the PCB profiles. The congener profile and homolog composition revealed that the source origin of PCBs in the Bangladeshi seafood was related to mixtures of technical PCBs formulations. The dietary exposure assessment revealed that the coastal residents are sufficiently exposed to the dietary PCBs through seafood consumption which may cause severe health risk including dioxin-like toxic effects. PMID- 30426368 TI - No evidence of the role of early chemical exposure in the development of beta cell autoimmunity. AB - Exposure to environmental chemicals can modulate the developing immune system, but its role in the pathogenesis of type 1 diabetes is largely unexplored. Our objective was to study the levels of circulating concentrations of environmental pollutants during the first years of life and their associations with the later risk of diabetes-predictive autoantibodies. From two birth-cohort studies including newborn infants with HLA-conferred susceptibility to type 1 diabetes (FINDIA and DIABIMMUNE), we identified case children with at least one biochemical diabetes-associated autoantibody (n = 30-40) and from one to four autoantibody-negative controls per each case child matched for age, gender, diabetes-related HLA-risk, delivery hospital, and, in FINDIA, also dietary intervention group. Plasma levels of 13 persistent organic pollutants and 14 per- and polyfluorinated substances were analyzed in cord blood and plasma samples taken at the age of 12 and 48 months. Both breastfeeding and the geographical living environment showed association with circulating concentrations of some of the chemicals. Breastfeeding-adjusted conditional logistic regression model showed association between decreased plasma HBC concentration at 12-month-old children and the appearance of diabetes-associated autoantibodies (HR, 0.989; 95% Cl, 0.978-1.000; P = 0.048). No association was found between the plasma chemical levels and the development of clinical type 1 diabetes. Our results do not support the view that exposure to the studied environmental chemicals during fetal life or early childhood is a significant risk factor for later development of beta-cell autoimmunity and type 1 diabetes. PMID- 30426369 TI - The suitability of growing mulberry (Morus alba L.) on soils consisting of urban sludge composted with garden waste: a new method for urban sludge disposal. AB - Efficient disposal of urban sewage sludge, material that typically contains high concentrations of heavy metals, has become a significant concern worldwide. The empirical purpose of the current study is to investigate physical and chemical parameters of composted sludge and garden waste at different ratios. Results reveal that nutrient content has significantly increased after the application of composts as compared to the controlled sample. Composting garden waste with sewage sludge at a 1:1 ratio promoted plant growth and gradually showed superiority in the later period. The maximum plant height, total biomass, and crown width of mulberry trees increased by 12.1, 33.5, and 45.7%, respectively, compared with the control treatment. The bound to organic matter of Hg, Cr, and Pb in the sewage sludge increased after composting with garden waste, and the mulberry exhibited a high ability to accumulate Ni and Cd from the soil. Conclusively, compared to using the two soil mediums separately, composting garden waste and sewage sludge together is beneficial for soil improvement and vegetation growth. PMID- 30426370 TI - Assessment of the content, occurrence, and leachability of arsenic, lead, and thallium in wastes from coal cleaning processes. AB - The aim of the study was to evaluate the content, occurrence, and leachability of arsenic (As), lead (Pb), and thallium (Tl) in wastes from coal cleaning processes with respect to the safe management of this waste. The study focused on wastes resulting from the wet gravitation and flotation processes employed for the purposes of coking coal cleaning in four coal mines situated in the Upper Silesian Coal Basin (Poland). The scope of the study included (i) determination of the content of these elements in the investigated wastes using atomic absorption spectrometry, (ii) evaluation of their mode of occurrence using electron microprobe analysis, and (iii) preliminary assessment of their leachability in deionized water. The content of the analyzed elements in the examined samples of coal waste was twice as high as the average content of these elements in the Earth's crust. The contents of As and Pb, however, did not exceed their permissible contents in inert waste in accordance with Polish legal regulations based on EU directives. The limit on the content of Tl is not specified by these regulations, but its amount in the examined samples was similar to that occurring in the soils. Moreover, leaching tests have shown that these elements are hardly eluted from the analyzed material. Their content in the water leachates was generally lower than the detection limit of the analytical method, complying with the standards for good and very good water quality. Low leachability of these elements most probably results from their mode of occurrence in the investigated wastes. The chemical analysis using an electron microprobe and the analysis of the correlation between these elements, e.g., total and pyritic sulfur, have shown that Pb, As, and Tl are mainly found in sulfide minerals which are characterized by negligible solubility. In conclusion, the investigated hard coal processing waste does not constitute a threat to the environment and can be commercially used or safely neutralized, e.g., by landfilling. PMID- 30426371 TI - Inflammatory and oxidative stress biomarkers at protein and molecular levels in workers occupationally exposed to crystalline silica. AB - Workers chronically exposed to respirable crystalline silica (CS) are susceptible to adverse health effects like silicosis and lung cancer. This study aimed to investigate potential early peripheral biomarkers of inflammation and oxidative stress in miners. The subjects enrolled in this study were occupationally unexposed workers (OUW, n = 29) and workers exposed to crystalline silica (WECS), composed by miners, which were divided into two subgroups: workers without silicosis (WECS I, n = 39) and workers diagnosed with silicosis, retired from work (WECS II, n = 42). The following biomarkers were evaluated: gene expression of L-selectin, CXCL2, CXCL8 (IL-8), HO-1, and p53; malondialdehyde (MDA) plasma levels and non-protein thiol levels in erythrocytes. Additionally, protein expression of L-selectin was evaluated to confirm our previous findings. The results demonstrated that gene expression of L-selectin was decreased in the WECS I group when compared to the OUW group (p < 0.05). Regarding gene expression of CXCL2, CXCL8 (IL-8), HO-1, and p53, significant fold change decreases were observed in workers exposed to CS in relation to unexposed workers (p < 0.05). The results of L-selectin protein expression in lymphocyte surface corroborated with our previous findings; thus, significant downregulation in the WECS groups was observed compared to OUW group (p < 0.05). The MDA was negatively associated with the gene expression of CXCL-2, CXCL8 (IL-8), and p53 (p < 0.05). The participants with silicosis (WECS II) presented significant increased non-protein thiol levels in relation to other groups (p < 0.05). Taken together, our findings may contribute to help the knowledge about the complex mechanisms involved in the silicosis pathogenesis and in the risk of lung cancer development in workers chronically exposed to respirable CS. PMID- 30426372 TI - Evaluation of efficacy of the essential oil from Ostericum viridiflorum (Turcz.) Kitagawa in control of stored product insects. AB - The natural and ecologically safe control of stored product insects has gained considerable attention in modern society. In this study of further searching for botanical pesticides from wild-growing plant, the contact toxicity and repellency towards Tribolium castaneum and Liposcelis bostrychophila were assessed for the essential oil (EO) from Ostericum viridiflorum. The EO was distilled from aboveground parts of O. viridiflorum and checked by gas chromatography-mass spectrometry. Twenty-two compounds were identified and the main components were beta-caryophyllene (24.3%), alpha-humulene (21.0%), apiol (10.2%), and carotol (2.5%). For bioactivity tests, results indicated that the EO and its two main compounds (beta-caryophyllene and alpha-humulene) all showed potent contact toxicity towards L. bostrychophila with LD50 values of 44.52 MUg/cm2, 74.11 MUg/cm2, and 118.56 MUg/cm2, respectively. The EO and the two main compounds also exhibited comparable repellency towards T. castaneum and L. bostrychophila. The results evidenced the EO of O. viridiflorum aboveground parts and its major compounds could be considered for the development of eco-friendly botanical insecticides and repellents in controlling stored product insects. PMID- 30426373 TI - Cyhalothrin biodegradation in Cunninghamella elegans. AB - The insecticide lambda-cyhalothrin was incubated with planktonic and biofilm cultures of the fungus Cunninghamella elegans. 19F nuclear magnetic resonance spectroscopy demonstrated that the compound was initially biosorbed to the biomass and more slowly degraded by the fungus. Furthermore, the presence of trifluoromethyl-containing metabolites was observed. Analysis of culture extracts by gas chromatography-mass spectrometry (GC-MS) identified non-fluorinated metabolites that suggested the likely catabolic pathway. The hydroxylated metabolites were probably generated from the action of cytochromes P450 (CYPs), as the presence of CYP inhibitors resulted in the absence of biodegradation. Planktonic cells were measurably faster at degrading the pesticide compared with biofilm. PMID- 30426374 TI - The relative role of spatial and environmental processes on seasonal variations of phytoplankton beta diversity along different anthropogenic disturbances of subtropical rivers in China. AB - The phytoplankton community structure is potentially influenced by both environmental and spatial processes. In addition, the relative importance of these two processes to phytoplankton assemblage will be affected by hydrological connectivity. However, the impacts of anthropogenic activities on phytoplankton beta diversity and the relative importance of these two processes to phytoplankton are still poorly understood, especially in water conservation areas. Here, we examined the relative importance of local and regional environmental control and spatial structuring of phytoplankton communities in five rivers with different degrees of disturbance during wet and dry seasons. We found that community structure and local environmental conditions varied greatly in seasons and rivers. The reference river (with minimum disturbance) had the highest homogeneity of environmental conditions and phytoplankton assemblage, while the excessive disturbance rivers (sand mining activities) had the greatest environmental heterogeneity and species dissimilarity between sites. Variation partitioning analysis showed that the phytoplankton community variation was mainly explained by the spatial variables in the wet season (summer and autumn) and winter, while the local environmental variables explained the largest variation of phytoplankton community in the dry season (spring). However, broad scale variables were selected by redundancy analysis in both dry and wet seasons, which indicates that long-distance scales always have low river connectivity, regardless of whether the river is overflowing or drying up. Local environmental processes explained the most variation in phytoplankton community within all of the rivers, suggesting that deterministic processes usually work on relatively small spatial scales. However, this effect would be weakened by anthropogenic activities, especially sand mining activities. We inferred that sand mining activities increased the environmental heterogeneity and species dissimilarity between sites by causing watercourse habitat patches and obstructing river connectivity. On the other hand, as the excessive disturbance, sand mining activities significantly reduced the species richness and abundance of phytoplankton. PMID- 30426375 TI - In situ genotoxicity assessment in freshwater zooplankton and sediments from different dams, ponds, and temporary rivers in Tunisia. AB - Tunisia water resources are limited. The country currently has 29 large dams, more than 1000 hill lakes, and 220 small dams which are essential for economic and social development given their contribution to irrigation, drinking water consumption, flooding protection, production of electrical energy, groundwater recharge, and industrial uses. Given the scarcity of these resources, it is crucial to be able to ensure the quality of freshwater environments, particularly those intended for human consumption. In this study, we meant to assess the health status of various freshwater ecosystems in different regions of Tunisia (north and center west) in order to detect genotoxic components in sediments and their potential effect on zooplankton (cladocerans). Sediment and cladoceran species were collected from dams, ponds, and temporary rivers in Tunisia. For each collection site, micronucleus (MN) assay was performed, in triplicates, using a pool of ten specimens of the same cladoceran species. MN occurrence in cladocerans varied from one site to another and MN frequencies varied between 0.67 and 220/00, suggesting the presence of genotoxic substances in certain sites. Sediment genotoxicity and mutagenicity were assessed using the SOS Chromotest and the Ames test. Sediment results showed that genotoxicity varies from one site to another displaying a quantitative and a qualitative variation of pollutant among the sites. These results suggest an urgent need for continuous monitoring of freshwater environments in Tunisia, particularly those intended for drinking water. PMID- 30426377 TI - Multi-criteria decision approach for evaluation, ranking, and selection of remediation options: case of polluted groundwater, Kuwait. AB - Freshwater groundwater resources at north Kuwait were contaminated by infiltrated oil as well as sea water that was used to fight the oil-well fires during the liberation of Kuwait in 1991. This paper investigates the feasibility of five remediation options to restore the polluted aquifers. These options include: (i) pump and treat of contaminated groundwater; (ii) cleaning the aquifer formation; (iii) construction of additional desalination plant; (iv) constructing additional storage tanks, and (v) development of artificial aquifer recharge schemes. The basis for this assessment study is to supply minimum basic drinking water to Kuwait City at a total rate of 50,000 m3/day in an emergency for up to one year based on essential basic need of 32 liters per capita per day. To compare these options, a decision matrix to select suitable remediation options using Multiple Criteria Decision Analysis (MCDA) approach is developed. The cost was given a relative weight of 20 whereas other criteria are given weight of 10. Based on these MCDA scores, it was found that option 3, namely, establishing an additional water desalination plant, is the most feasible option followed by option 5, artificial recharge of aquifers. PMID- 30426376 TI - Effective degradation of Orange G and Rhodamine B by alkali-activated hydrogen peroxide: roles of HO2- and O2.. AB - Advanced oxidation processes offer effective solutions in treating wastewater from various industries. The process of alkali-activated hydrogen peroxide (H2O2) was superior for the treatment of alkaline dye wastewater because no additional reagents were required except H2O2. However, an important and interesting phenomenon had been observed that the primary reactive species were found different for degrading organic pollutants with the process of alkali-activated H2O2. Azo dye of Orange G (OG) and triphenylmethane dye of Rhodamine B (RhB) were chosen as the target organic pollutants. The influences of various parameters on OG and RhB degradation by alkali-activated H2O2 were evaluated. Furthermore, different scavengers, including ascorbic acid, methanol, t-butanol, isopropyl alcohol, furfuryl alcohol, and nitro blue tetrazolium, have been tested to identify the active species involved in dye degradation, and it was found that O2.- was mainly responsible for degrading OG, while HO2- anion was the primary oxidant for degrading RhB. PMID- 30426378 TI - Natural disasters, climate change, and their impact on inclusive wealth in G20 countries. AB - This paper uses the 1990-2010 natural disaster and carbon emission data of G20 countries to examine the impact of natural disasters and climate change on the natural capital component of inclusive wealth. Our study shows that climate change and GDP have no positive impacts on the growth of natural capital. By contrast, trade openness and natural disaster frequency contribute to the accumulation of natural capital in G20 countries. There is an inverted U-shaped relationship between the growth of natural capital and the magnitude of natural disaster. Natural capital growth is not affected very much by small disasters. By contrast, large disasters tend to make the growth of natural capital fall sharply. PMID- 30426379 TI - Composition, mixing state, and size distribution of single submicron particles during pollution episodes in a coastal city in southeast China. AB - Size-resolved particle composition, size distribution, and mixing state were characterized at the single-particle level during two air pollution episodes during 12-25 January, 2016 in a coastal city in southeast China. The two pollution episodes occurred under distinct meteorological conditions (i.e., different wind speeds, relative humidity, and backward trajectories); thus, they were assigned to stagnation and transport episodes, respectively. Single-particle data, obtained from single-particle aerosol mass spectrometry (SPAMS), showed that carbonaceous particles were the predominant particles during the whole study period, accounting for more than 60% of the total particles. However, the number fractions of carbonaceous particles and nitrate-containing particles significantly increased in the stagnation episode, while the number fractions of sulfate- and ammonium-containing particles both increased in the transport episode compared to the levels over the whole study period. The potassium-rich (K rich) particle class was more abundant and more strongly mixed with sulfate in the transport episode, which indicates the impact of biomass burning emissions and the subsequent aging process by acquiring sulfate during transport. The particle classes (e.g., carbonaceous and K-rich classes) had a broader size distribution during the pollution episodes than during the clean episode. The diameters of the size distribution peak for all particle classes (except for dust class) were observed to be larger in the transport episode than in the stagnation episode. This suggests that the particles underwent an extensive aging process through the addition of sulfate and ammonium during transport, leading to the growth of particles. PMID- 30426380 TI - Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience. AB - Whole-exome sequencing (WES) is an ideal method for the diagnosis of autosomal recessive diseases. The aim of this study was to evaluate the diagnostic power of WES in patients with autosomal recessive inheritance and to determine the relationship between genotype and phenotype. Retrospective screenings of 24 patients analysed with WES were performed and clinical and genetic data were evaluated. Any pathogenic mutation that could explain the suspected disease in 4 patients was not identified. A homozygous pathogenic mutation was detected in 18 patients. 2 patients had heterozygous mutations. According to this study results, WES is a successful technique to be used at the stage of diagnosis in patients who are accompanied by various degrees of intellectual disability matching the inheritance of the autosomal recessive. PMID- 30426381 TI - Substrate and inhibitor selectivity, and biological activity of an epoxide hydrolase from Trichoderma reesei. AB - Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases. PMID- 30426383 TI - Nucleolar PTEN in human colorectal adenomas. PMID- 30426382 TI - Molecular genetic diagnosis of Wilson disease by ARMS-PCR in a Pakistani family. AB - Wilson disease is a rare autosomal recessive disorder caused by mutations in the ATP7B gene causing hepatic and neurological damage due to copper accumulation. Early diagnosis and treatment could lead to improved survival of patients. Patients are best treated at pre-symptomatic stages but early diagnosis of Wilson disease is challenging owing to complex diagnosis. Evidence based genetic counseling requires characterization of underlying mutations in Wilson disease families. The aim was to characterize the causative mutation(s) in a Pakistani Wilson disease family by custom developed ARMS-PCR assay. A proband (19 years old boy) having Wilson disease with evidence of K-F ring, severe neurological and psychiatric manifestations and clinical findings supported by biochemical abnormalities was followed. Following screening for 12 putative mutations in ATP7B, we identified a homozygous mutation (p.Cys271*, c.813C > A) in proband by T-ARMS-PCR assay and validated by Sanger DNA sequencing. Furthermore, on screening of his family members, a younger sister (aged 9 years) was found to have the same homozygous mutation even though she was clinically asymptomatic except for a light K-F ring. Parents were heterozygous for this mutation and an elder brother was homozygous normal. Molecular diagnosis by PCR based assays (M ARMS-PCR and T-ARMS-PCR) is cost effective, reliable, and efficient for preliminary screening of mutations in the ATP7B gene in developing countries like Pakistan, which can be successfully applied to Wilson disease families for genetic testing and follow-up evidence based genetic counseling. PMID- 30426384 TI - Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis. AB - Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naive RA patients compared to controls (14.582 +/- 1.766 ng/ml vs. 7.37 +/- 1.450 ng/ml; p <= 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naive RA patients compared to healthy controls (12.322 +/- 2.91 vs. 16.998 +/- 4.298 ng/ml; p <= 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis. PMID- 30426385 TI - Cytotoxic and cell cycle arrest induction of pentacyclic triterpenoides separated from Lantana camara leaves against MCF-7 cell line in vitro. AB - Lantana camara is an important medicinal plant that contains many active compounds, including pentacyclic triterpenoids, with numerous biological activities. The present study was conducted to evaluate the anti-oxidant, anti tumour, and cell cycle arrest properties of chemical compounds extracted from L. camara leaves. Four compounds were identified after subjecting the plant methanolic extract to LC-MS/MS analysis: lantadene A, lantadene B, icterogenin, and lantadene C. Potential antioxidant activity was examined using 2, 2-diphenyl 1-picrylhydrazyl and compared with vitamin C as a control. Lantadene A and B were confirmed to possess the highest scavenging activity, while icterogenin and lantadene C exhibited a lesser antioxidant effect. All extracted compounds exerted a dose-dependent reduction in MCF-7 cell viability; however, lantadene B showed the highest anti-cancer activity, with an IC50 of 112.2 MUg mL-1, and was therefore used in subsequent experiments. The results also confirmed the significant release of caspase 9 in a dose-dependent pattern following treatment of MCF-7 cells with a range of lantadene B concentrations. Lantadene B was found to induce MCF-7 cell cycle arrest in G1, blocking the G1/S transition with a maximum significant (p <= 0.01) cell count of 80.35% at 25 ug mL-1. No significant changes were observed in S phase, but a decrease in the MCF-7 population was exhibited in G2/M phase. PMID- 30426386 TI - Correction to: Development of a simultaneous LC-MS/MS method to predict in vivo drug-drug interaction in mice. AB - The author would like to change conflict of interest statement of the online published article. PMID- 30426387 TI - Targets of monoclonal antibodies for immunological diseases. AB - Immunological disorders such as allergy, autoimmune diseases, auto-inflammatory syndromes and immunological deficiency syndromes are difficult to treat with chemical drugs. Recently, many monoclonal antibodies targeting various molecules including interleukin, tumor necrosis factor-alpha, cluster of differentiation, integrins, complement C5 and B lymphocyte stimulator are clinically available and give a hope to patients suffering from these intractable diseases. Here, we selected twenty-seven monoclonal antibodies approved by US FDA since 1997 and they are classified according to their target molecules. Although these biomedicines possessed some restrictions such as high cost and susceptible to infectious disease, these drawbacks can be overcome through cost-cutting innovations including biosimilars and careful monitoring. New targets are emerging rapidly and more effective biomedicines with acceptable side effects are in the pipeline for next decade. PMID- 30426388 TI - Use of hyperbaric oxygen therapy in pediatric neuro-oncology: a single institutional experience. AB - INTRODUCTION: Hyperbaric oxygen therapy (HBOT) has been utilized as adjunctive treatment of CNS tumors and for radiation necrosis (RN) with reported success. The safety and efficacy in pediatric patients is less understood. METHODS: Seven patients (ages 10-23 years, six females) were treated with HBOT (3-60 sessions) for either RN (n = 5) or tumor-associated edema (n = 2). Tumor diagnosis included low-grade glioma (n = 4, two with neurofibromatosis type 1), meningioma (n = 1), medulloblastoma (n = 1) and secondary high grade glioma (n = 1). Prior therapies included: surgery (n = 4), chemotherapy (n = 4) and radiation (N = 5: four focal, one craniospinal). Three underwent biopsy: one confirming RN, one high-grade glioma, and one low-grade glioma. Patients were assessed for clinical and radiographic changes post HBOT. RESULTS: Median time to clinical and radiographic presentation was 8.5 months (range 6 months-11 years) in those who had prior radiation. Clinical improvement after HBOT (median: 40 sessions) was observed in four of seven patients. Symptoms were stable in two and worsened in one patient. Radiographic improvement was seen in four patients; three had radiographic disease progression. In the subgroup treated for presumed and biopsy-confirmed RN (n = 5), four of five (80%) had clinical and radiographic improvement. There were no long-term adverse events due to HBOT. CONCLUSIONS: HBOT is safe and well tolerated in pediatric and young adult patients with CNS tumors. Clinical and radiographic improvements were observed in over half of patients. Clinical trials are needed to establish safety and efficacy of HBOT as adjunct therapy in pediatric CNS tumors. PMID- 30426389 TI - Effect of Exercise and Abeta Protein Infusion on Long-Term Memory-Related Signaling Molecules in Hippocampal Areas. AB - Alzheimer's disease (AD) results from over-production and aggregation of beta amyloid (Abeta) oligopeptides in the brain. The benefits of regular physical exercise are now recognized in a variety of disorders including AD. In order to understand the effect of exercise at the molecular level, we studied the impact of exercise on long-term memory-related signaling molecules in an AD rat model. The rat model of AD (AD rat) was produced by 14-day osmotic pump infusion of i.c.v. 250 pmol/day Abeta1-42. The effects of 4 weeks of regular rodent treadmill exercise on the protein levels of CREB, CaMKVI, and MAPK-ERK1/2 in this model were determined by immunoblot analysis in the CA1 and dentate gyrus (DG) areas of the hippocampus, which is among the first brain structures impacted by AD. Abeta infusion caused marked reductions in the basal protein levels of CaMKVI and phosphorylated CREB without significantly affecting total CREB levels in both CA1 and DG areas. As predicted, our exercise regimen totally prevented these effects in the brains of exercised AD rats. Surprisingly, however, neither Abeta infusion nor exercise had any significant effect on the levels of phosphorylated or total ERK in the CA1 and DG areas. Additionally, exercise did not increase any of these molecules in healthy normal rats, which indicated a protective effect of exercise. These findings suggest that CaMKIV is likely a major kinase for phosphorylation of CREB. Therefore, regular exercise is highly effective in preventing the effects of AD even at the molecular level in both areas of the hippocampus. Considering the well-known resistance of the DG area to insults relative to area CA1, the present findings revealed similar molecular vulnerability of the two areas to AD pathology. PMID- 30426390 TI - News from the European Association for Cancer Education: a Long-standing Partner of AACE. PMID- 30426391 TI - Polynucleotide transport through lipid membrane in the presence of starburst cyclodextrin-based poly(ethylene glycol)s. AB - Symmetrical cyclodextrin-based 14-arm star polymers with poly(ethylene glycol) PEG branches were synthesized and characterized. Interactions of the star polymers with lipid bilayers were studied by the "black lipid membrane" technique in order to demonstrate the formation of monomolecular artificial channels. The conditions for the insertion are mainly based on dimensions and amphiphilic properties of the star polymers, in particular the molar mass of the water soluble polymer branches. Translocation of single-strand DNA (ssDNA) through those synthetic nanopores was investigated, and the close dimension between the cross-section of ssDNA and the cyclodextrin cavity led to an energy barrier that slowed down the translocation process. PMID- 30426392 TI - Detection of Human Enteric Viruses in French Polynesian Wastewaters, Environmental Waters and Giant Clams. AB - Lack of wastewater treatment efficiency causes receiving seawaters and bivalve molluscan shellfish to become contaminated, which can lead to public health issues. Six wastewater samples, five seawater samples and three batches of giant clams from Tahiti (French Polynesia) were investigated for the presence of enteric viruses, but also if present, for the diversity, infectivity and integrity of human adenoviruses (HAdV). Enteroviruses (EV), sapoviruses (SaV) and human polyomaviruses (HPyV) were detected in all wastewater samples. In decreasing frequency, noroviruses (NoV) GII and HAdV, rotaviruses (RoV), astroviruses (AsV), NoV GI and finally hepatitis E viruses (HEV) were also observed. Nine types of infectious HAdV were identified. HPyV and EV were found in 80% of seawater samples, NoV GII in 60%, HAdV and SaV in 40% and AsV and RoV in 20%. NoV GI and HEV were not detected in seawater. Intact and infectious HAdV 41 were detected in one of the two seawater samples that gave a positive qPCR result. Hepatitis A viruses were never detected in any water types. Analysis of transcriptomic data from giant clams revealed homologues of fucosyltransferases (FUT genes) involved in ligand biosynthesis that strongly bind to certain NoV strains, supporting the giant clams ability to bioaccumulate NoV. This was confirmed by the presence of NoV GII in one of the three batches of giant clams placed in a contaminated marine area. Overall, all sample types were positive for at least one type of virus, some of which were infectious and therefore likely to cause public health concerns. PMID- 30426393 TI - Low Molecular Weight Sulfated Chitosan: Neuroprotective Effect on Rotenone Induced In Vitro Parkinson's Disease. AB - The present investigation was an attempt to study the effect of low molecular weight sulfated chitosan (LMWSC) on in vitro rotenone model of Parkinson's disease (PD) by evaluating cell viability, oxidative stress, mitochondrial membrane potential, DNA fragmentation, and apoptosis. Incubation of SH-SY5Y cells with 100 nm rotenone resulted in neuronal cell death, redox imbalanced mitochondrial dysfunction, DNA fragmentation, condensation, and apoptotic cellular morphology. Rotenone exposure enhanced the expression of preapoptotic (cytochrome C (cyto c), caspase-3, -8, -9, and Bax) and down-regulated the expression of anti-apoptotic (Bcl-2) markers. Reduction of the intracellular reactive oxygen species (ROS) levels ensued due to pretreatment of LMWSC along with consequent normalization of antioxidant enzymes, mitigation of rotenone induced mitochondrial dysfunction and apoptosis. Our current findings suggested that LMWSC exhibit the pronounced neuroprotective effects, which could be due to its antioxidant, mitochondrial protection, and anti-apoptotic properties. We thus conclude that LMWSC could be developed as a novel therapeutic molecule for the benefit of reducing the consequences of PD. However, further extensive preclinical and clinical studies are warranted. PMID- 30426394 TI - Mini-Incision Open Appendectomy with Incision Skin Tissue Retractor vs. Laparoscopic Appendectomy: A Retrospective Study of the Management of Child Acute Appendicitis. AB - INTRODUCTION: This study aims to compare the clinical effects of an incision skin tissue retractor for mini-incision open appendectomy and laparoscopic surgery for pediatric appendicitis. METHODS: From January 2014 to July 2017, a total of 248 patients were included in the present study. Laparoscopic appendectomy was performed for 108 cases (LA group), and mini-incision open appendectomy with an incision skin tissue retractor was performed for 140 cases (MOA-ISTR group). Then, medical history, age, gender, operative duration, amount of bleeding during the operation, the determination of whether or not the appendix was perforated during the operation, hospitalization days, total cost of hospitalization, and complications after the operation (incision infection or intestinal obstruction) were compared. The SPSS 20.0 software package was used for the statistical analysis. RESULTS: There were no statistically significant differences in history, age, gender, perioperative perforation of the appendix, postoperative hospital stay and postoperative complications (incisional infection or intestinal obstruction, P > 0.05). However, the values for duration of surgery, intraoperative blood loss and total hospitalization expense were smaller, when compared with the LA group (P < 0.05). CONCLUSION: Mini-incision open appendectomy with an incision skin tissue retractor has similar efficacy and incision appearance when compared with laparoscopic appendectomy. Furthermore, this approach leads to shorter operation time, less intraoperative blood loss and less hospitalization time, and is more convenient, especially for perforated appendicitis. Moreover, it can be widely used for pediatric appendicitis, and is more suitable for doctors who are not skilled in basic hospitals and laparoscopy. PMID- 30426395 TI - Post-treatment fibrotic modifications overwhelm pretreatment liver fibrosis in predicting HCC in CHC patients with curative antivirals. AB - BACKGROUND/AIMS: Liver fibrosis determined hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C patients with sustained virological response (SVR). We aimed to determine whether post-treatment fibrotic modification overwhelmed pretreatment fibrotic status in terms of long-term HCC prediction. METHODS: 265 SVR patients with paired biopsies before and after antiviral therapy were enrolled for analysis of the association of fibrotic changes with HCC. RESULTS: Eighteen (6.8%) of the 265 patients developed HCC over 1931 person years. Cox regression analysis without post-treatment fibrosis as a covariant revealed that factors predicted HCC included age (hazard ratio [HR]/confidence intervals [CI] 1.07/1.01-1.13, p = 0.01), male gender (HR/CI 4.57/1.45-14.36, p = 0.009), diabetes (HR/CI 3.60/1.32-9.85, p = 0.01) and pretreatment advanced fibrosis (HR/CI 2.73/1.05-7.07, p = 0.039). Advanced fibrosis in post-treatment status replaced pretreatment fibrosis as the most critical determinant of HCC when it was included for analysis (HR/CI 3.53/1.34-9.30, p = 0.01). The incidences of HCC among patients with fibrotic modification from F0-2 to F0-2, F34 to F0-2, F0-2 to F34 and F34 to F34 were 0.41%, 0.84%, 1.68%, and 3.05%, respectively (p = 0.004). Compared to patients whose fibrotic stage remained at F0-2 before and after treatment, the HCC risk decreased and did not differ among those whose fibrotic stage improved from F34 to F0-2. However, HCC risk increased significantly and gradually in patients whose fibrotic stages changed from F0-2 to F34 (HR/CI 4.13/1.11-15.36, p = 0.035) and whose fibrotic stages remained at F34 before and after treatment (HR/CI 7.47/2.37-23.55, p = 0.001) (trend p = 0.003). CONCLUSIONS: Post-treatment fibrotic modifications overwhelmed pretreatment fibrotic statuses in predicting HCC. PMID- 30426397 TI - Cardiovascular disease in the literature: A selection of recent original research papers. PMID- 30426396 TI - Risks of hepatocellular carcinoma and cirrhosis-associated complications in patients with rheumatoid arthritis: a 10-year population-based cohort study in Taiwan. AB - BACKGROUND/PURPOSE: Although rheumatoid arthritis (RA) has been linked to several important malignancies, data for the risks of hepatocellular carcinoma (HCC) in patients with RA are scarce. We aimed to examine the risk of HCC and cirrhosis associated complications and the use of biologics in a national representative RA sample in Taiwan. METHODS: All study subjects aged >= 18 years in the Taiwan National Health Insurance program between January 1, 2000, and December 31, 2009 were enrolled. We matched RA and non-RA subjects by propensity scores in a 1:1 ratio. Our primary outcome was a diagnosis of HCC and cirrhosis-associated complications during a 10-year follow-up period. The risk of outcomes was represented as a hazard ratio (HR) calculated in Cox proportional hazard regression models. RESULTS: 24,245 RA and 24,245 non-RA subjects were included in the primary outcome analysis. Mean overall person-years (PY) of follow-up were 116,608 PY for the RA cohort, and 234,280 PY for the non-RA cohort. The overall incidence of HCC and cirrhosis-associated complications was lower in the RA cohort than in the non-RA cohort (0.66% vs. 1.41% HCC events and 1.45% vs. 1.95% cirrhosis-associated complications events during 10-year follow-up). The HRs adjusted for age, sex, the frequency of medical visits, and CCI were 0.57 (0.46 0.71) for HCC and 0.67 (0.59-0.76) for HCC and cirrhosis-associated complications. Although immunomodulatory agents may alter the risk of malignancy, use of biologics did not increase HCC risk in RA patients. CONCLUSIONS: RA is associated with a reduced risk of developing HCC and cirrhosis-associated complications. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02880306. PMID- 30426398 TI - Assessment of four different cardiac softwares for evaluation of LVEF with CZT SPECT vs CMR in 48 patients with recent STEMI. AB - PURPOSE: To compare, vs CMR, four softwares: quantitative gated SPECT (QGS), myometrix (MX), corridor 4DM (4DM), and Emory toolbox (ECTb) to evaluate left ventricular ejection fraction (LVEF), end-systolic (ESV), and end-diastolic volumes (EDVs) by gated MPI CZT-SPECT. METHODS: 48 patients underwent MPI CZT SPECT and CMR 6 weeks after STEMI, LV parameters were measured with four softwares at MPI CZT-SPECT vs CMR. We evaluated (i) concordance and correlation between MPI CZT-SPECT and CMR, (ii) concordance MPI CZT-SPECT/CMR for the categorical evaluation of the left ventricular dysfunction, and (iii) impacts of perfusion defects > 3 segments on concordance. RESULTS: LVEF: LCC QGS/CMR = 0.81 [+ 2.2% (+/- 18%)], LCC MX/CMR = 0.83 [+ 1% (+/- 17.5%)], LCC 4DM/CMR = 0.73 [+ 3.9% (+/- 21%)], LCC ECTb/CMR = 0.69 [+ 6.6% (+/- 21.1%)]. ESV: LCC QGS/CMR = 0.90 [- 8 mL (+/- 40 mL)], LCC MX/CMR = 0.90 [- 9 mL (+/- 36 mL)], LCC 4DM/CMR = 0.89 [+ 4 mL (+/- 45 mL)], LCC ECTb/CMR = 0.87 [- 3 mL (+/- 45 mL)]. EDV: LCC QGS/CMR = 0.70 [- 16 mL (+/- 67 mL)], LCC MX/CMR = 0.68 [- 21 mL (+/- 63 mL], LCC 4DM/CMR = 0.72 [+ 9 mL (+/- 73 mL)], LCC ECTb/CMR = 0.69 [+ 10 mL (+/- 70 mL)]. CONCLUSION: QGS and MX were the two best-performing softwares to evaluate LVEF after recent STEMI. PMID- 30426399 TI - Robotic surgical rehearsal on patient-specific 3D-printed skull models for stereoelectroencephalography (SEEG). AB - PURPOSE: Medically refractory epilepsy patients commonly require surgical alternatives for diagnosis and treatment. Stereoelectroencephalography (SEEG) is a useful diagnostic procedure in seizure focus elucidation. Modern techniques involve the use of robotics and neuronavigation for SEEG. A steep learning curve combined with multiple complex technologies employed during the case makes this procedure a perfect candidate for surgical rehearsal. This paper tests the feasibility of the use of patient-specific 3D-printed model for surgical rehearsal of robotic SEEG. METHODS: A 3D-printed model was created using the patient's cranial computed tomography and computed tomography angiography radiological imaging. A rehearsal in an operating room (OR) prior to the actual procedure date was used for surgical planning of SEEG electrodes, education of the residents and fellows as well as training of the support staff. Attention was paid to assure precise recreation of the surgical procedure. RESULTS: The patient specific 3D-printed model tolerated each step of the procedure from facial registration, to drilling, bolt insertion and lead placement. Accuracy of the designed trajectory to the electrode final position was visually confirmed at the end of procedure. Important modification to the plan of eventual surgery improved the efficiency of the real operation. CONCLUSION: For surgical planning, education and training purposes in robotic SEEG, 3D-printed models may be utilized as a realistic anatomy tool. Potential applications of this technique include trajectory feasibility evaluation, patient positioning optimization, increasing OR efficiency, as well as neurosurgical education and patient counseling. PMID- 30426400 TI - Automatic bone segmentation in whole-body CT images. AB - PURPOSE: Many diagnostic or treatment planning applications critically depend on the successful localization of bony structures in CT images. Manual or semiautomatic bone segmentation is tedious, however, and often not practical in clinical routine. In this paper, we present a reliable and fully automatic bone segmentation in whole-body CT scans of patients suffering from multiple myeloma. METHODS: We address this problem by using convolutional neural networks with an architecture inspired by the U-Net [17]. In this publication, we compared three training procedures: (1) training from 2D axial slices, (2) a pseudo-3D approach including axial, sagittal and coronal slices and (3) an approach where the network is pre-trained in an unsupervised manner. RESULTS: We evaluated the method on an in-house dataset of 18 whole-body CT scans consisting of 6800 axial slices, achieving a dice score of 0.95 and an intersection over union (IOU) of 0.91. Furthermore, we evaluated our method on the dataset used by Perez-Carrasco et al. (Comput Methods Progr Biomed 156:85-95, 2018). The data and the ground truth have been made publicly available. The proposed method outperformed the other methods, obtaining a dice score of 0.92 and an IOU of 0.85. CONCLUSION: These promising results could facilitate the evaluation of bone density and the localization of focal lesions in the future, with a potential impact on both disease staging and treatment planning. PMID- 30426401 TI - The Human Microbiota and Asthma. AB - Over the last few decades, advances in our understanding of microbial ecology have allowed us to appreciate the important role of microbial communities in maintaining human health. While much of this research has focused on gut microbes, microbial communities in other body sites and from the environment are increasingly recognized in human disease. Here, we discuss recent advances in our understanding of host-microbiota interactions in the development and manifestation of asthma focusing on three distinct microbial compartments. First, environmental microbes originating from house dust, pets, and farm animals have been linked to asthma pathogenesis, which is often connected to their production of bioactive molecules such as lipopolysaccharide. Second, respiratory microbial communities, including newly appreciated populations of microbes in the lung have been associated with allergic airway inflammation. Current evidence suggests that the presence of particular microbes, especially Streptococcus, Haemophilus, and Morexella species within the airway may shape local immune responses and alter the severity and manifestations of airway inflammation. Third, the gut microbiota has been implicated in both experimental models and clinical studies in predisposing to asthma. There appears to be a "critical window" of colonization that occurs during early infancy in which gut microbial communities shape immune maturation and confer susceptibility to allergic airway inflammation. The mechanisms by which gut microbial communities influence lung immune responses and physiology, the "gut-lung axis," are still being defined but include the altered differentiation of immune cell populations important in asthma and the local production of metabolites that affect distal sites. Together, these findings suggest an intimate association of microbial communities with host immune development and the development of allergic airway inflammation. Improved understanding of these relationships raises the possibility of microbiota directed therapies to improve or prevent asthma. PMID- 30426402 TI - How It All Began: A Personal History of Gel Electrophoresis. AB - Arne Tiselius' moving boundary electrophoresis method was still in general use in 1951 when this personal history begins, although zonal electrophoresis with a variety of supporting media (e.g., filter paper or starch grains) was beginning to replace it. This chapter is an account of 10 years of experiments carried out by the author during which molecular sieving gel electrophoresis was developed and common genetic variants of two proteins, haptoglobin and transferrin, were discovered in normal individuals. Most of the figures are images of pages from the author's laboratory notebooks, which are still available, so that some of the excitement of the time and the humorous moments are perhaps apparent. Alkaline gels, acidic gels with and without denaturants, vertical gels, two-dimensional gels and gels with differences in starch concentration are presented. The subtle details that can be discerned in these various gels played an indispensable role in determining the nature of the change in the haptoglobin gene (Hp) that leads to the polymeric series characteristic of Hp 2/Hp 2 homozygotes. Where possible the names of scientific friends who made this saga of gel electrophoresis so memorable and enjoyable are gratefully included. PMID- 30426403 TI - Introduction to Protein Electrophoresis. AB - This chapter briefly discusses the developments in electrophoresis of proteins from Tiselius' moving-boundary electrophoresis to the modern-day two-dimensional polyacrylamide gel electrophoresis. It also touches upon the staining methods used to visualize total proteins post electrophoresis. PMID- 30426404 TI - Measuring Protein Concentration with Absorbance, Lowry, Bradford Coomassie Blue, or the Smith Bicinchoninic Acid Assay Before Electrophoresis. AB - Measuring the concentration of proteins is an essential part of enzyme analysis or serves to monitor protein yields and losses during protein isolation procedures. Decisions on the usefulness of any protein isolation procedure depend on knowing the concentration of proteins before and after a procedure. Protein concentration in solution is generally measured with spectrophotometry in the UV range or in the presence of dyes or copper interacting with the protein. This review describes absorbance at 280 nm, the Lowry, Bradford (Coomassie Blue), and Smith (bicinchoninic acid) assays for measuring protein and includes suggestions for optimizing each method. PMID- 30426405 TI - Concentrating Proteins by Salt, Polyethylene Glycol, Solvent, SDS Precipitation, Three-Phase Partitioning, Dialysis, Centrifugation, Ultrafiltration, Lyophilization, Affinity Chromatography, Immunoprecipitation or Increased Temperature for Protein Isolation, Drug Interaction, and Proteomic and Peptidomic Evaluation. AB - In protein isolation, drug interaction studies, and proteomic or peptidomic procedures, protein solutions are often concentrated to remove solvents and undesirable molecules, to separate protein fractions, or to increase protein concentrations. Proteins can be concentrated by precipitation from solution with ammonium sulfate, polyethylene glycol, organic solvents, trichloroacetic acid, potassium chloride/sodium dodecyl sulfate thermal denaturation, and three-phase partitioning. Solvents can be removed by passage through a semipermeable barrier where protein solutions are forced against the barrier in a centrifuge tube or with increased pressure, concentrating proteins in the remaining solution. The semipermeable barrier can be surrounded by a hygroscopic reagent to draw the solvent across the membrane. Proteins can be concentrated by freeze-drying (lyophilization). Unique ligand interactions with proteins can be used to select for proteins by affinity purification or immunoprecipitation. All these methods to concentrate proteins are discussed. PMID- 30426406 TI - Lysis Buffer Choices Are Key Considerations to Ensure Effective Sample Solubilization for Protein Electrophoresis. AB - The efficient extraction of proteins of interest from cells and tissues can be challenging. Here we demonstrate the differences in extraction of the focal adhesion protein Kindlin-2 and the transcriptional repressor Snail from choriocarcinoma cells using NP-40 and RIPA lysis buffer. We also show the use of a more denaturing urea/thiourea lysis buffer for solubilization, by comparing its effectiveness with the often utilized RIPA lysis buffer for solubilization of heat shock proteins (HSP) B1 and B5 and the cytoplasmic adapter protein integrin linked kinase (ILK) from smooth muscle. Overall, the results demonstrate the importance of optimizing lysis buffers for specific protein solubilization prior to finalizing the experimental workflow. PMID- 30426407 TI - The Cydex Blue Assay: A One-Step Protein Assay for Samples Prior to SDS Electrophoresis. AB - Determination of protein concentrations prior to (sodium dodecyl sulfate) SDS electrophoresis is made difficult by the simultaneous presence of SDS and reducers in the buffers used for protein extraction. Reducers interfere with the copper-based assays, while SDS interferes with the dye-binding assays. The combined use of cyclodextrins with a commercial Bradford reagent concentrate, described in this chapter, allows to determine protein concentrations in a Laemmli-type buffer, containing both SDS and reducers, in a single step (without any precipitation) with a simple spectrophotometric assay. The use of various cyclodextrins brings compatibility not only with SDS but also with other nonionic and ionic detergents such as sodium deoxycholate or detergents of the Triton type. PMID- 30426408 TI - Cellulose Acetate Electrophoresis of Hemoglobin. AB - The electrophoresis on cellulose acetate membrane is most widely used because of its simplicity, and is without the use of any sophisticated instrument other than electrophoresis apparatus and the cellulose acetate strip. Here we describe a modified version of cellulose acetate membrane electrophoresis for hemoglobin separation from blood sample. Sharp, clear bands without tailing effects can be obtained with this method. The method and apparatus described here would be appropriate to separate protein fractions under 1 h at voltages up to 60 V/cm measured between the electrodes. PMID- 30426409 TI - Native Polyacrylamide Gels. AB - Proteins can easily be separated by polyacrylamide gel electrophoresis (PAGE) in the presence of a detergent and under (heat-) denaturing and (non- or) reducing conditions. The most commonly used detergent is sodium dodecyl sulfate (SDS). The major function of SDS is to shield the respective charge of the proteins present in the mixture to be analyzed and to provide all proteins with a negative charge. As a consequence, the proteins will be separated according to their molecular weight. Electrophoresis of proteins can also be performed in the absence of SDS. Using such "native" conditions, the charge of each of the proteins, which will depend on the primary amino acid sequence of the protein (isoelectric point) and the pH during electrophoresis, will mainly influence the mobility of the respective protein during electrophoresis. Here we describe a starting protocol for "native" PAGE. PMID- 30426410 TI - Isoelectric Focusing on Non-Denaturing Flatbed Gels. AB - Isoelectric focusing (IEF) serves as a very useful procedure for cell protein separation and characterization. We have used this method to study antibody clonotype changes. Here we discuss the use of a sensitive native flatbed isoelectric focusing method to analyze specific antibody clonotype changes in a patient with systemic lupus erythematosus, who developed autoantibodies to the Ro 60 autoantigen under observation. Patient sera samples collected over several years were used for analysis using flatbed IEF. Following electrofocusing, the gel is analyzed by affinity immunoblotting utilizing Ro 60-coated nitrocellulose membrane to determine oligoclonality of the anti-Ro 60 containing sera. PMID- 30426411 TI - Determination of Protein Molecular Weights on SDS-PAGE. AB - An apparent molecular weight (MW) of a protein can be determined from the migration distance of a protein complexed with a strong cationic detergent sodium dodecyl sulfate (SDS) separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This method was established around 1969 and has been utilized substantially even today because of its simplicity. During the following half a century, although it has been reported that many proteins show some deviation in MW when determined on SDS-PAGE especially when their peptide chains are posttranslationally modified, this versatile method is still being used very often in current biochemical works. In this protocol, a simple method to estimate MW by running SDS-PAGE of standard proteins is explained by an example in which proteins extracted from mouse retina were analyzed by two-dimensional isoelectric focusing (2-D IEF) SDS-PAGE followed by protein identification by peptide mass fingerprinting. PMID- 30426412 TI - Two-Dimensional Gel Electrophoresis by Glass Tube-Based IEF and SDS-PAGE. AB - The genome information combined with data derived from modern mass spectrometry enables us to determine the identity of a protein once it is isolated from a complex mixture. Two-dimensional gel electrophoresis established more than four decades ago serves as a powerful protocol to isolate many proteins at once for such protein analysis. In the first two decades, the original procedure to use a glass tube-based IEF had been commonly used. Since an IEF in glass tubes is rather difficult to maneuver, a new method to use an IEF on a thin agarose slab backed by a plastic film (IPG Dry Strip) had been invented and is now widely used. In this chapter, we describe a protocol that uses a glass tube-based IEF because the capacity of protein loading and resolving power of this type of classic two-dimensional gel is still indispensable for many applications, not only for protein identification but also for protocols that are benefited by larger amounts of materials, i.e., analysis of posttranslational modification of proteins such as phosphorylation, methylation, glycosylation, and others. PMID- 30426413 TI - Cationic Electrophoresis. AB - Denaturing, discontinuous electrophoresis in the presence of SDS has become a standard method for the protein scientist. However, there are situations where this method produces suboptimal results. In these cases electrophoresis in the presence of positively charged detergents like cetyltrimethylammonium bromide (CTAB) may work considerably better. Methods for electrophoresis and staining of such gels are presented. PMID- 30426414 TI - Two-Dimensional Gel Electrophoresis with Immobilized pH Gradients. AB - Isoelectric focusing (IEF) is a technique in protein research that has been used since 1975 to separate proteins based on their isoelectric point. When combined with sodium dodecyl sulfate polyacrylamide gel electrophoresis, this procedure allows for high-resolution separation of cellular proteins for analytical purposes. Laboratories perform IEF by (a) using carrier ampholytes that migrate through a gel to create the pH gradient or (b) using immobilized pH gradients (IPG) that contain ampholytes bound covalently to a gel. Here we describe an IEF system that uses immobilized pH gradient (IPG) strips that undergo the desired current and voltage setting to separate proteins based on its charge in the first dimension followed by SDS PAGE to generate a two-dimensional map of serum proteins. PMID- 30426415 TI - SARCOSYL-PAGE: Optimized Protocols for the Separation and Immunological Detection of PEGylated Proteins. AB - PEGylation of recombinant proteins and synthetic peptides aims to generate biopharmaceuticals with altered physical properties. The modification may lead to a prolonged serum half-life caused by decreased receptor-mediated endocytosis and/or delay in renal clearance caused by the increased hydrodynamic volume of the pharmaceutical. MIRCERA, a PEGylated recombinant erythropoietin (rhEPO) used in the treatment of anemia due to chronic kidney disease, has also been abused by athletes as performance-enhancing drug. While it can be detected by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting, the sensitivity of the test is significantly lower compared to other epoetins. By replacing SDS with sarcosyl in the sample and running buffers, the interaction between SDS and the PEG group of the protein no longer reduces the affinity of the monoclonal anti-EPO antibody (clone AE7A5) to the protein chain. Contrary to SDS, sarcosyl only binds to the amino acid chain of the PEGylated protein and thus leads to a sharper electrophoretic band and enhanced antibody binding. While the method was originally developed for anti-doping purposes, it may also be useful for the electrophoretic separation and immunological detection of other PEGylated proteins. Protocols for urine and serum are presented. They are also applicable for the general detection of EPO-based erythropoiesis-stimulating agents (ESA) in these matrices. PMID- 30426416 TI - Tricine-SDS-PAGE. AB - Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (tricine-SDS PAGE) is an efficient way of separating low molecular mass proteins. However, the standard system is quite complicated and specifically may not be useful when the separated proteins are to be recovered from the gel for quantitative analysis. Here, we describe a simplified system whereby these smaller proteins can be resolved in comparatively low percentage gels which have high compatibility with modern detectors such as UV and inductively coupled plasma-mass spectrometry (ICP MS). PMID- 30426417 TI - Analysis of Protein Glycation Using Phenylboronate Acrylamide Gel Electrophoresis. AB - Carbohydrate modification of proteins adds complexity and diversity to the proteome. However, undesired carbohydrate modifications also occur in the form of glycation, which have been implicated in diseases such as diabetes, Alzheimer's disease, autoimmune diseases, and cancer. The analysis of glycated proteins is challenging due to their complexity and variability. Numerous analytical techniques have been developed that require expensive specialized equipment and complex data analysis. In this chapter, we describe two easy-to-use electrophoresis-based methods that will enable researchers to detect, identify, and analyze these posttranslational modifications. This new cost-effective methodology will aid the detection of unwanted glycation products in processed foods and may lead to new diagnostics and therapeutics for age-related chronic diseases. PMID- 30426418 TI - Immunofixation Electrophoresis for Identification of Proteins and Specific Antibodies. AB - Immunofixation electrophoresis (IFE) is a technique for the identification of proteins within complex mixtures after separation by either conventional zone electrophoresis or isoelectric focusing. Most commonly antigens (which are often immunoglobulins) are separated by electrophoresis followed by precipitation with specific antibodies in situ. However, immunoglobulins with specific reactivity can be also precipitated with the proper antigens after electrophoresis in reverse or reversed IFE. Because of its great versatility, potentially high sensitivity, ease to perform and customize, and relatively low cost with no requirement for expensive instrumentation, manual IFE remains a valuable tool for both clinical diagnostic testing and research. Any low-viscosity body fluid specimen or, possibly, culture fluid could be tested with IFE if proper antibodies (or antigens in reverse[d] IFE) are available. After pretreatment with chaotropic and/or reducing agents, even high-viscosity specimens might be amenable to testing with IFE. PMID- 30426419 TI - Electrophoretic Separation of Very Large Molecular Weight Proteins in SDS Agarose. AB - Very large proteins (subunit sizes, >200 kDa) are difficult to electrophoretically separate on polyacrylamide gels. A SDS vertical agarose gel system has been developed that has vastly improved resolving power for very large proteins. Proteins with molecular masses between 200 and 4000 kDa can be clearly separated. Inclusion of a reducing agent in the upper reservoir buffer and use of a large pore-sized agarose have been found to be key technical procedures for obtaining optimum protein migration and resolution. PMID- 30426420 TI - Increase in Local Protein Concentration by Field-Inversion Gel Electrophoresis. AB - Proteins that migrate through cross-linked polyacrylamide gels (PAGs) under the influence of a constant electric field experience negative factors, such as diffusion and nonspecific trapping in the gel matrix. These negative factors reduce protein concentrations within a defined gel volume with increasing migration distance and, therefore, decrease protein recovery efficiency. Here, we describe the enhancement of protein separation efficiency for up to twofold in conventional one-dimensional PAG electrophoresis (1D PAGE), two-dimensional (2D) PAGE, and native PAGE by implementing pulses of inverted electric field during gel electrophoresis. PMID- 30426421 TI - Two-Dimensional Difference Gel Electrophoresis. AB - Two-dimensional difference gel electrophoresis (2D DIGE) is a modified form of 2D electrophoresis (2D E) that allows one to compare two or three protein samples simultaneously on the same gel. The proteins in each sample are covalently tagged with different color fluorescent dyes that are designed to have no effect on the relative migration of proteins during electrophoresis. Proteins that are common to the samples appear as "spots" with a fixed ratio of fluorescent signals, whereas proteins that differ between the samples have different fluorescence ratios. With conventional imaging systems, DIGE is capable of reliably detecting as little as 0.2 fmol of protein, and protein differences down to +/- 15%, over a ~10,000-fold protein concentration range. DIGE combined with digital image analysis therefore greatly improves the statistical assessment of proteome variation. Here we describe a protocol for conducting DIGE experiments, which takes 2-3 days to complete. We have further improved upon 2D DIGE by introducing in-gel equilibration to improve protein retention during transfer between the first and second dimensions of electrophoresis and by developing a fluorescent gel imaging system with a millionfold dynamic range. PMID- 30426422 TI - Immunoelectrophoresis: A Method with Many Faces. AB - Immunoelectrophoresis (IEP) was the first practical method that combined electrophoresis and immunoprecipitation for identifying and characterizing proteins within complex mixtures. Over the years, IEP has been extended to include a variety of techniques and, as a general name, has been applied to virtually any technique that involves electrophoresis and antigen-antibody precipitin reaction for proteins. Because of the diversity in technical details of different IEP versions, the method described here deals only with classic IEP. Although it requires some manual expertise, IEP is versatile, relatively easy to customize, and economical with no need for expensive instrumentation. Further, it can discern identity, partial identity, and nonidentity of the proteins. Any low viscosity body fluid specimen or, possibly, culture fluid and tissue extract could be tested with IEP if proper antibodies are available. With these attributes, classic IEP remains a valuable tool for clinical diagnostic testing, purity checking of biochemical and pharmaceutical products, and research. PMID- 30426423 TI - Tris-Acetate Polyacrylamide Gradient Gels for the Simultaneous Electrophoretic Analysis of Proteins of Very High and Low Molecular Mass. AB - Polyacrylamide gel electrophoresis (PAGE) is one of the most powerful tools used for protein analysis. We describe the use of Tris-acetate buffer and 3-15% polyacrylamide gradient gels to simultaneously separate proteins in the mass range of 10-500 kDa. We show that this system is highly sensitive, it has good resolution and high reproducibility, and it can be used for general applications of PAGE such as Coomassie Brilliant Blue staining and immunoblotting. Moreover, we describe how to generate mini Tris-acetate polyacrylamide gels to use them in miniprotein electrophoresis systems. These economical gels are easy to generate and to manipulate and allow a rapid analysis of proteins. All these features make the Tris-acetate-PAGE system a very helpful tool for protein analysis. PMID- 30426424 TI - Diagonal Electrophoresis for the Detection of Proteins Involved in Disulfide Bonds. AB - The formation and reduction of disulfide bonds through thiol-disulfide exchange is an important cellular mechanism for the regulation of protein activity and plays a crucial role in redox signaling. Thiol-disulfide exchange on key regulatory cysteine residues offers an efficient and reversible mechanism for regulatory control in response to alterations in the intracellular redox environment. Cysteines are one of the most rarely used amino acids in proteins, but when conserved in proteins, they usually play critical roles in protein structure, function, or regulation. Diagonal electrophoresis is a relatively simple technique to analyze the formation of protein disulfides by sequential nonreducing/reducing electrophoresis. Proteins that do not form disulfides migrate identically in both dimensions and form a diagonal after the second dimension; proteins that contained intra-chain disulfides lie above the diagonal, while proteins involved in inter-disulfides fall below the diagonal. This technique allows for the detection and subsequent identification of proteins with inter-disulfides and has been applied in combination with mass spectrometry to identify proteins involved in redox signaling cascades. PMID- 30426425 TI - Identification of Proteins on Archived 2D Gels. AB - Separation technology of proteins from a complex mixture by two-dimensional gel (2D gel) was invented more than 40 years ago. With a good laboratory practice, the 2D gels are likely to be dried and stored at ambient temperature as archived record. Up until the beginning of this century, it had been difficult to identify the protein spots isolated on 2D gels. However, the advent of mass spectrometry based proteomics protocols combined with genome information enabled us to determine the identity of a protein separated on 2D gels archived decades ago. The protocol will assist researchers to decipher molecular mechanisms involved in the system by identifying and quantifying the protein of interest from archived 2D gels. PMID- 30426426 TI - Two-Dimensional Gel Electrophoresis: Vertical Isoelectric Focusing. AB - Two-dimensional gel electrophoresis is one of the most powerful tools for separating proteins based on their size and charge. Two-dimensional gel electrophoresis (2-DE) is very useful to separate two proteins with identical molecular weights but different charges, which cannot be achieved with just sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Here, a simpler and easier version of 2-DE is presented which is also faster than all the currently available techniques. In this modified version of 2-DE, isoelectric focusing is carried out in the first dimension using a vertical sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) apparatus. Following the first-dimensional IEF, each individual lane is excised from the IEF gel and after a 90 degrees rotation, is inserted into a second-dimensional SDS-PAGE, which can be stained with Coomassie Brilliant Blue for protein analysis or immunoblotted for further analysis. This version of IEF can be run in less than 2 h compared to the overnight run required by O'Farrell's method. Difficult tube gel casting and gel extrusion as well as tube gel distortion are eliminated in our method. This method is simpler, faster, and inexpensive. Both dimensions can be done on the same SDS-PAGE apparatus, and up to ten samples can be run simultaneously using one gel. PMID- 30426427 TI - A Foodomics Approach: CE-MS for Comparative Metabolomics of Colon Cancer Cells Treated with Dietary Polyphenols. AB - The potential of capillary electrophoresis-mass spectrometry (CE-MS) for metabolomics is demonstrated through the analysis of metabolites from human HT29 colon cancer cells treated and non-treated with dietary polyphenols. Prior to CE MS analysis, four different metabolite purification strategies are investigated. Namely, the results obtained after methanol deproteinization, ultrafiltration, and two solid-phase extraction methods using C18 and polymer-based cartridges are described. These generic methods can have broad applications to analyze metabolites in a large variety of matrices and fields, including the new Foodomics area. PMID- 30426428 TI - Characterization of New Cyclic D,L-alpha-Alternate Amino Acid Peptides by Capillary Electrophoresis Coupled to Electrospray Ionization Mass Spectrometry. AB - The self-assembly of peptide nanotubes (PNTs) depends on the structure and chemistry of cyclic peptide (CP) monomers, impacting on their properties, which makes the choice of their monomers and their characterization a high challenge. For this purpose, we developed for the first time a capillary electrophoresis coupled to electrospray ionization mass spectrometry (CE-ESI-MS) methodology and characterized a set of eight original CP sequences of 8, 10, and 12 D,L-alpha alternate amino acids with a controlled internal diameter (from 7 to 13 A) and various properties (diameter, global surface charge, hydrophobicity). This new CE ESI-MS methodology allows verifying the structure, the purity, as well as the stability (when stored during several months) of interesting potential precursors for PNTs that could be employed as nanoplatforms in diagnostics or pseudo sieving tools for separation purposes. PMID- 30426429 TI - "Microchip Electrophoresis," with Respect to "Profiling of Abeta Peptides in the Cerebrospinal Fluid of Patients with Alzheimer's Disease". AB - Aggregation of beta-amyloid peptides especially Abeta1-42 in amyloid plaques is one of the major neuropathological events in Alzheimer's disease. This event is normally accompanied by a relative reduction of the concentration of Abeta1-42 in the cerebrospinal fluid (CSF) of patient developing the signs of Alzheimer's disease. Here, we describe methods for isolation and for microchip gel electrophoresis of Abeta peptides in polydimethylsiloxane (PDMS) microfluidic chip. The method was applied to compare the relative concentration of Abeta1-42 with other Abeta peptides, for example, Abeta 1-40 in CSF. In order to increase the sensitivity of detection, Abeta peptides in the CSF samples were first captured and concentrated using magnetic beads coated with specific anti-Abeta antibodies. PMID- 30426430 TI - Measuring Low-Picomolar Apparent Binding Affinities by Minigel Electrophoretic Mobility Shift. AB - Measuring protein/DNA interactions that have apparent binding affinity constants in the low-picomolar range presents a unique experimental challenge. To probe the sequence specificity of telomere binding proteins, our laboratory has developed an electrophoretic mobility shift assay protocol that allows for the routine measurement of K D,app values in the 1-20 pM range. Here, we describe the protocol and highlight the particular considerations that should be made to successfully and reproducibly measure high-affinity interactions between proteins and single-stranded DNA. PMID- 30426431 TI - Identification of Proteins Interacting with Single Nucleotide Polymorphisms (SNPs) by DNA Pull-Down Assay. AB - Single nucleotide polymorphisms (SNPs) are the most abundantly found common form of DNA variation in the human genome. Many genetic association studies have proved that some of these SNPs are involved in regulating several cellular/physiological processes ranging from gene regulation to disease development. Analysis of the protein complex that binds to these SNPs is a crucial step in studying the mechanisms by which gene expressions are regulated in cis- or trans-acting manner. Commonly used techniques to determine DNA-protein interaction, such as electrophoretic mobility shift assay (EMSA), have limited value for simultaneously analyzing a large number of proteins in the complex. Furthermore, this assay is tedious and time-consuming and often requires radiolabeled probe as well as extensive optimization. Here, we describe a pull down assay before performing the EMSA, which helps in the detection of differentially-bound protein(s) in an allele-specific manner. The assay is easy to perform and does not require radiolabeling of DNA probes. Biotinylated DNA probe bound to streptavidin beads can be complexed with protein(s) from cell nuclear lysate, nonspecific proteins were washed out, and only protein(s) having high affinity to SNP-specific DNA were detected on SDS-PAGE and identified by mass spectrometry. PMID- 30426432 TI - Horizontal Agarose Gel Mobility Shift Assay for Protein-RNA Complexes. AB - Recent advances in agarose gel electrophoresis protocols established conditions for the high-resolution separation of DNA and RNA using higher voltages combined with short run times. We subsequently developed a protocol for using these conditions to measure the binding affinity of a protein for an RNA ligand on an agarose gel. This native gel mobility shift assay is highly accessible, using common molecular biology reagents found in most laboratories. Here, we describe the protocol for carrying out native agarose gel electrophoresis to characterize the binding affinity of a protein for an RNA ligand. The electrophoresis time is less than 10 min, which minimizes the dissociation of protein and ligand. We have used the p19 siRNA binding protein and its cognate dsRNA ligand to demonstrate strategies for identifying optimal conditions to measure apparent binding constants using this agarose gel shift system. PMID- 30426433 TI - Applications of Immobilized Metal Affinity Electrophoresis. AB - Immobilized metal affinity electrophoresis (IMAEP) is a technique in which metal ions are integrated in a localized polyacrylamide gel section and which possess an insignificant electrophoretic migration. IMAEP has been implemented into both native and sodium dodecyl sulfate (SDS) one-dimensional (1-D) and two-dimensional (2-D) polyacrylamide gel electrophoresis (PAGE) systems. The gel piece containing metal ions is overlaid on top of an individual well in 1-D IMAEP, and gel strip is overlaid on top of the two-second dimensional polyacrylamide gel in 2-D IMAEP, respectively. This method is used to capture/enrich metal ion binding proteins. Due to the preferential binding between iron (III), manganese (II), or aluminum (III) ions and the phosphate group, these metal ions are used to capture/enrich phosphoproteins from a mixture of proteins. Data shows that SDS not only does not interfere with the extraction of phosphoproteins but also help unmasking phosphate groups by unfolding the phosphoproteins to facilitate metal ion phosphate binding while supplying the protein with negative charges. In addition, IMAEP together with avidin functional affinity electrophoresis (AFAEP) and antibody affinity electrophoresis (AAEP) have been used to demonstrate the separation of proteins by their functionalities. AFAEP is used here to capture biotinylated proteins using avidin and AAEP is used here to capture protein G using IgG. PMID- 30426434 TI - Isoelectric Focusing in Agarose Gel for Detection of Oligoclonal Bands in Cerebrospinal and Other Biological Fluids. AB - Isoelectric focusing (IEF) coupled with immunodetection (immunofixation or immunoblotting) has become the leading technique for the detection and study of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) and also is increasingly used in other body fluids such as the tear and serum. Limited commercial availability of precast agarose IEF gels for research and a need for customization prompted reporting a detailed general protocol for the preparation and casting of agarose IEF gel along with sample, control, and isoelectric point marker preparation and carrying out the focusing itself for CSF OCBs. However, the method is readily adaptable to the use of other body fluid specimens and, possibly, research specimens such as culture fluids as well. PMID- 30426435 TI - A Combined Free-Flow Electrophoresis and DIGE Approach to Compare Proteins in Complex Biological Samples. AB - Free-flow electrophoresis has been applied in numerous studies as a protein separation technique due to its multiple advantages such as fast and efficient sample recovery, high resolving power, high reproducibility and wide applicability to protein classes. As a stand-alone platform, however, its utility in comparative proteomic analysis is limited as protein samples must be run sequentially rather than simultaneously which introduces inherent variability when attempting to perform quantitative analysis. Here we describe an approach combining fluorescent CyDye technology (DIGE) with free-flow electrophoresis to simultaneously separate and identify differentially expressed proteins in a model cell system. PMID- 30426436 TI - SDS-PAGE for 35S Immunoprecipitation and Immunoprecipitation Western Blotting. AB - This report discusses recent methods of sample preparation and gel electrophoresis for 35S immunoprecipitation (IP) and IP western blotting. In both methods, IP is used to obtain purified proteins, and sodium dodecyl sulfate polyacrylamide gel electrophoresis is used to separate the proteins on a gel. In 35S IP, the proteins are radiolabeled and visualized on film by fluorography; in IP blotting, proteins are transferred onto nitrocellulose paper, and antibodies are used to detect specific proteins. A similar IP and SDS-PAGE method can be used for both procedures, but IP blotting has the potential advantages of improvement in sensitivity for low-abundance proteins and enhanced specificity for identification of proteins from a mixture. Some of the technical adaptations discussed here to facilitate IP blotting and avoid loss of beads or purified proteins may also be useful for 35S IP. PMID- 30426437 TI - A Multichannel Gel Electrophoresis and Continuous Fraction Collection Apparatus for High-Throughput Protein Separation and Characterization. AB - We developed a multichannel gel electrophoresis system that continuously collects fractions as protein bands migrate to the bottom of gel columns. The device uses several short linear gel columns, each of a different percent acrylamide, to achieve a separation power similar to that of a long gradient gel. A "counter free-flow" elution technique allows continuous and simultaneous fraction collection from multiple channels at low cost. Using the system with SDS-PAGE, 300 MUg samples of protein can be separated and eluted into 48-96 fractions over a mass range of 10-150 kDa in 2.5 h. Each eluted protein can be recovered at 50% efficiency or higher in ~500 MUL. The system can also be used for native gel electrophoresis, but protein aggregation limits the loading capacity to about 50 MUg per channel and reduces resolution. This system has the potential to be coupled with mass spectrometry to achieve high-throughput protein identification. PMID- 30426438 TI - Cell Surface Protein Biotinylation for SDS-PAGE Analysis. AB - Proteins expressed at the cell surface play important roles in physiology and represent valuable targets for new therapeutic agents. Indeed, the so-called druggable proteome consists, for about two thirds, of proteins that are either integral to or associated with the cell membrane. In spite of its importance, however, a complete characterization of the cell surface proteome has remained elusive because of the difficulty to efficiently purify these proteins from other contaminants. Methods exploiting the strong interaction between biotin and streptavidin have paved the way for the most significant advances in this field. The present chapter focuses on techniques for cell surface biotinylation with commercially available reagents and capture by avidin affinity chromatography and release of the biotinylated surface proteins for downstream analysis by electrophoretic methods. PMID- 30426439 TI - Isolation of Proteins from Polyacrylamide Gels. AB - Minute amounts of proteins are required for immunization of mice for the development of antibodies including monoclonal antibodies. Here we describe a rapid procedure for the isolation of proteins from polyacrylamide gels after sodium dodecyl sulfate polyacrylamide gel electrophoresis in sufficient amounts for immunization of animals. PMID- 30426440 TI - Continuous Elution SDS-PAGE with a Modified Standard Gel Apparatus to Separate and Isolate an Array of Proteins from Complex Mixtures. AB - Sodium dodecyl sulfate polyacrylamide gel electrophoresis is a powerful tool to separate proteins according to their relative sizes. The technique provides information about both the size of a number of proteins and potentially the comparative amounts of each protein. To confirm the identity of proteins, proteins can be eluted from the gel and transferred electrophoretically to nitrocellulose for antibody-based detection. During electrophoresis, if the current is not stopped, proteins continue to pass down the gel and elute from the bottom of the gel. The standard electrophoresis gel apparatus can be employed with the addition of some tubing and alterations to the separating gel to collect proteins separated by size as they elute from the base of the gel as described in this chapter. Complex protein mixtures can be separated into multiple fractions containing single proteins in a few hours. Small amounts (<500 MUg of protein) of protein sample can be fractionated. PMID- 30426441 TI - Protein Extraction from Gels: A Brief Review. AB - Protein gel electrophoresis is an important procedure carried out in protein studies. Elution and recovery of proteins separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) are often necessary for further downstream analyses. The process involves localizing the protein of interest on the gel following SDS-PAGE, eluting the protein from the gel, removing SDS from the eluted sample, and finally renaturing the protein (e.g., enzymes) for subsequent analyses. Investigators have extracted proteins from gels by a variety of techniques. These include dissolution of the gel matrix, passive diffusion, and electrophoretic elution. Proteins eluted from gels have been used successfully in a variety of downstream applications, including protein chemistry, proteolytic cleavage, determination of amino acid composition, polypeptide identification by trypsin digestion and matrix-assisted laser desorption ionization-time of flight mass spectroscopy, as antigens for antibody production, identifying a polypeptide corresponding to an enzyme activity, and other purposes. Protein yields ranging from nanogram levels to 100 MUg have been obtained. Here, we review some of the methods that have been used to elute proteins from gels. PMID- 30426442 TI - Gel Absorption-Based Sample Preparation Method for Shotgun Analysis of Membrane Proteome. AB - Membrane proteins solubilized in a starting buffer containing high concentration of SDS are directly entrapped and immobilized into gel matrix when the membrane protein solution is absorbed by the vacuum-dried polyacrylamide gel. After the detergent and other salts are removed by washing, the proteins are subjected to in-gel digestion, and the tryptic peptides are extracted and analyzed by CapLC MS/MS. The newly developed method not only avoids protein loss and the adverse protein modifications during gel-embedment but also improves the subsequent in gel digestion and the recovery of tryptic peptides, particularly hydrophobic peptides. Thus, this method facilitates the identification of membrane proteins, especially integral membrane proteins. PMID- 30426443 TI - Ultrarapid Sodium Dodecyl Sulfate Polyacrylamide Mini-Gel Electrophoresis. AB - We describe here an ultrafast method for electrophoresing proteins on SDS-PAGE. Previously we reported a method to complete SDS-PAGE and immunoblotting in an hour, including electrophoresing proteins at 70 degrees C in 10 min. Here we show that we can electrophorese molecular weight standards and bovine serum albumin on a 4-20% gradient gel in well under 10 min using heated (44 degrees C) Laemmli running buffer and high voltage. PMID- 30426444 TI - A Brief Review of Other Notable Electrophoretic Methods. AB - Electrophoretic methodologies for qualitative and preparative purposes are commonly used in biological research and have been well established as an integral analytical tool for a long time in most research laboratories. Listed here are some of the more specialized innovations that have been developed in recent times for special purposes of study. These include micropreparative isoelectric focusing in liquid suspension, accelerated protease digestion by SDS PAGE, two-dimensional SDS-PAGE for membrane protein resolution, carbon nanotube modified page for resolution of complement C3, electrophoretic resolution of ultra-acidic proteomes in acidic media, and two-dimensional immunoelectrophoresis of pre-beta/alpha lipoprotein A-I in agarose. All these methods are briefly reviewed in this chapter. PMID- 30426445 TI - Single-Cell High-Resolution Detection and Quantification of Protein Isoforms Differing by a Single Charge Unit. AB - Isoelectric focusing (IEF) is an electrophoretic technique that enables the separation of proteins based on their isoelectric points. Until recently, this valuable method was not feasible for single-cell applications, which are necessary to interrogate heterogeneous cell populations. Herein we highlight a recently published method enabling the analysis of single-cell proteomics, which utilizes microfluidics coupled with IEF, photocapture, and immunoprobing of the protein in the same micro-gel, which can be stripped and reprobed multiple times. PMID- 30426446 TI - Artifacts and Common Errors in Protein Gel Electrophoresis. AB - In spite of taking precautions, some common mistakes creep into well-planned gel electrophoresis experiments. This occurs commonly in relation to calculating the cross-linking factor of a gel, polymerization temperature and time for a polyacrylamide gel, inducing aggregates in samples for electrophoresis, titrating the running buffer in electrophoresis, proper sample preparation, amount of protein to be loaded on a gel, sample buffer-to-protein ratios, incompletely removing phosphate-buffered saline from cells prior to cell lysis, and over focusing of IPG strip in two-dimensional gel electrophoresis. In addition, subtle artifacts can have significant deleterious effects on carefully planned and executed experiments. Proteases that act at room temperature upon proteins in the sample buffer prior to heating, cleavage of the Asp-Pro bond upon prolonged heating of proteins at high temperatures, contamination of sample or sample buffer with keratin, leaching of chemicals from disposable plastic ware, and contamination of urea with ammonium cyanate are some of the common reasons for artifacts in gel electrophoresis. Taking proper heed to all these factors can greatly help generate good experimental results. PMID- 30426447 TI - Genome sequencing of Aureobasidium pullulans P25 and overexpression of a glucose oxidase gene for hyper-production of Ca2+-gluconic acid. AB - Gluconic acid (GA) has many applications such as in the food and pharmaceutical industry. Aureobasidium pullulans P25 strain is able to produce high levels of Ca2+-GA. The genome length, GC content and the gene number of this yeast were found to be 30.97 Mb, 50.28% and 10,922, respectively. The pathways for gluconic acid biosynthesis were annotated. Glucose oxidase (Gox) sequences from different strains of A. pullulans were highly similar but were distinct from those of other fungi. The glucose oxidase had two FAD binding sites and a signal sequence. Deletion of the GOX gene resulted in a strain that showed no Gox activity and that was unable to produce Ca2+-GA. Overexpression of the GOX gene in strain P25 generated strain GA-6 that produced 200.2 +/- 2.3 Ca2+-GA g/l and 2480 U/mg of Gox activity. The productivity of Ca2+-GA was 2.78 g/l/h and the yield was 1.1 g/g. PMID- 30426448 TI - Confirmatory factor analysis of the parental feeding style questionnaire with a preschool sample. AB - PURPOSE: Despite being widely used, there has not yet been a confirmatory factor analysis (CFA) on the English version of the Parental Feeding Style Questionnaire (PFSQ). Preschool is a critical time to assess parental feeding styles, and the PFSQ is one of the few measures that can be used with young children. As such, the current study conducted the first CFA on the PFSQ in an English-speaking sample in the United States to establish preliminary evidence of its factor structure. METHODS: Parents of preschoolers aged 3-5 years (N = 297; M = 33.47 years; 85.2% mothers) presenting to a pediatric dentistry office in the Midwest of the United States were recruited to participate in this cross-sectional study. Parents completed the PFSQ in the waiting room of the dental office. Robust maximum likelihood factor analyses were conducted on the PFSQ. RESULTS: The original four-factor model was not confirmed, but rather, results provided preliminary support for a five-factor solution: Control over Eating, Instrumental Feeding, Emotional Feeding, Encouragement of Variety, and Prompting of Eating, CFI = 0.91, SRMR = 0.06, RMSEA = 0.05. CONCLUSIONS: The PFSQ is a widely used measure for assessing parental feeding styles in young children. However, the CFA indicated that the originally proposed four-factor structure did not fit well. Certain modifications to the measure were necessary to improve model fit. A five factor model fit better, and six items were removed, reducing the original 27 item scale to 21 items. LEVEL OF EVIDENCE: Level V, cross-sectional descriptive study. PMID- 30426449 TI - Assessment and Comparison of the Four Most Extensively Validated Prognostic Scales for Intracerebral Hemorrhage: Systematic Review with Meta-analysis. AB - BACKGROUND/OBJECTIVE: Intracerebral hemorrhage (ICH) is a devastating disorder, responsible for 10% of all strokes. Several prognostic scores have been developed for this population to predict mortality and functional outcome. The aim of this study was to determine the four most frequently validated and most widely used scores, assess their discrimination for both outcomes by means of a systematic review with meta-analysis, and compare them using meta-regression. METHODS: PubMed, ISI Web of Knowledge, Scopus, and CENTRAL were searched for studies validating the ICH score, ICH-GS, modified ICH, and the FUNC score in ICH patients. C-statistic was chosen as the measure of discrimination. For each score and outcome, C-statistics were aggregated at four different time points using random effect models, and heterogeneity was evaluated using the I2 statistic. Score comparison was undertaken by pooling all C-statistics at different time points using robust variance estimation (RVE) and performing meta-regression, with the score used as the independent variable. RESULTS: Fifty-three studies were found validating the original ICH score, 14 studies were found validating the ICH-GS, eight studies were found validating the FUNC score, and five studies were found validating the modified ICH score. Most studies attempted outcome prediction at 3 months or earlier. Pooled C-statistics ranged from 0.76 for FUNC functional outcome prediction at discharge to 0.85 for ICH-GS mortality prediction at 3 months, but heterogeneity was high across studies. RVE showed the ICH score retained the highest discrimination for mortality (c = 0.84), whereas the modified ICH score retained the highest discrimination for functional outcome (c = 0.80), but these differences were not statistically significant. CONCLUSIONS: The ICH score is the most extensively validated score in ICH patients and, in the absence of superior prediction by other scores, should preferably be used. Further studies are needed to validate prognostic scores at longer follow-ups and assess the reasons for heterogeneity in discrimination. PMID- 30426450 TI - Peristeen Transanal Irrigation System to Manage Bowel Dysfunction: A NICE Medical Technology Guidance. AB - The Peristeen transanal irrigation system is intended to allow people with bowel dysfunction to flush out the lower part of the bowel as part of their bowel management strategy. Peristeen was the subject of an evaluation by the National Institute for Health and Care Excellence, through its Medical Technologies Evaluation Programme, for the management of bowel dysfunction. The company, Coloplast, submitted a case for adoption of the technology, claiming that the technology improves the severity of chronic constipation or faecal incontinence and improves quality of life for people with bowel dysfunction. Other claimed benefits included reduced frequency of UTIs, stoma surgery and hospitalisation rates, as well as reduced costs. The submission was critiqued by Cedar. The clinical evidence assessed included one randomised controlled trial, and 12 observational studies for adults and 11 studies for children. Although there are limitations in the evidence, the assessed studies show some improvement in outcomes for patients who choose to continue using Peristeen. The committee heard from patient experts that Peristeen had improved their lives and allowed them increased independence. The submitted economic evidence had numerous flaws, however following Cedar's changes to the model, and additional sensitivity analysis, the use of Peristeen was judged unlikely to be cost incurring compared with standard bowel care. The Peristeen transanal irrigation system received a positive recommendation in Medical Technologies Guidance 36. PMID- 30426451 TI - [Is healthcare consumption in the country of origin among Moroccan and Turkish migrants of older age (55+) associated with less use of care in the Netherlands?] AB - A substantial part of all Dutch people of Turkish and Moroccan origin use healthcare in the country of origin when travelling to their country of origin for a shorter or longer period of time (21% and 10%, respectively). If using care in the country of origin leads to avoidance of care in the Netherlands, this could threaten the continuity of care. We linked data of the HELIUS study to health insurance data. We examined the relationship between healthcare utilisation in the country of origin and the Netherlands, in the period of 2010 2015, adjusting for health status as an indicator of need. Contrary to our expectations, Dutch people of Turkish or Moroccan origin using healthcare consumption in the country of origin utilise more care in the Netherlands than individuals that do not utilize healthcare in the country of origin. Thus, our results do not provide any indication for avoidance of healthcare in the Netherlands among this group of older migrants in the Netherlands. PMID- 30426452 TI - LRRC8A potentiates temozolomide sensitivity in glioma cells via activating mitochondria-dependent apoptotic pathway. AB - Chloride (Cl-), a primary anion in the extracellular fluid, plays an important role in a variety of physiological and pathological processes, such as cell apoptosis and proliferation. However, the information about Cl- in cancer cell apoptosis and chemoresistance is poorly understood. In the present study, we found that temozolomide (TMZ) treatment led to a decrease in intracellular concentration of Cl- ([Cl-]i) in both U87 and TMZ-resistant U87/R glioma cells. The decrease in [Cl-]i was more noticeable in U87 cells than in U87/R cells. Moreover, the expression of LRRC8A was reduced in U87/R cells compared with U87 cells. LRRC8A downregulation inhibited TMZ, induced the decrease in [Cl-]i and abolished the difference of [Cl-]i between U87 cells and U87/R cells. Knockdown of LRRC8A using small interfering RNA attenuated TMZ-induced U87 cell growth inhibition and apoptosis, while overexpression of LRRC8A by adenoviral infection enhanced the effect of TMZ on U87 and U87/R cell viability and apoptosis. Furthermore, LRRC8A downregulation inhibited TMZ-induced mitochondria-dependent apoptosis, including elevated Bcl-2 expression, reduced Bax expression, cytochrome c release, and caspase nine and caspase three activation. On the contrary, upregulation of LRRC8A augmented the activation of mitochondria dependent apoptotic pathway in U87 and U87/R cells. In conclusion, this study demonstrates that LRRC8A potentiates TMZ-induced glioma cell apoptosis via promoting mitochondria-dependent apoptosis, suggesting that LRRC8A can be represented as a novel target for drug resistance treatment in glioma cells. PMID- 30426453 TI - The Need to Implement and Evaluate Telehealth Competency Frameworks to Ensure Quality Care across Behavioral Health Professions. PMID- 30426454 TI - Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting the MAPK and NF-kappaB pathways in B and T cells. AB - The angiotensin II type 1 receptor (AT1R) antagonist losartan has been confirmed to have a moderate anti-inflammatory effect in vitro and in vivo. However, how it affects immune cells in Rheumatoid Arthritis (RA) is still unknown. We found that in human synovial tissues, AT1R is significantly expressed on T cells and B cells. Treatment with losartan (15 mg/kg) alone and in combination with a low dose of methotrexate (MTX 0.25 mg/kg/3 days) significantly suppressed the progression of CIA. Secondary paw swelling, joint destruction and the presence of pro-inflammatory cytokines (TNF-alpha and IFN-gamma) in the serum were alleviated after treatment. The therapeutic effects of losartan were based on reduced T-cell and B-cell activation, specifically by decreased cell vitality and pro inflammatory cytokine production. In addition, losartan combined with a low dose of MTX achieved a similar therapeutic effect, while protecting liver and kidney from MTX damage. Mechanistically, losartan inhibits the production of pro inflammatory mediators, reduces the phosphorylation of p38, ERK, and p65, p50 nuclear transposition in T cells and B cells. Phosphorylation of JNK is not affected by losartan in the CIA rat model. losartan can be used as an effective RA treatment, which exhibits anti-arthritic effects potentially through down regulating the phosphorylation of p38, ERK and signaling through NF-kappaB. While achieving similar anti-rheumatic effects, a combination therapy of losartan with a low dose of MTX, can protect from liver and renal damage caused by giving a high dose of MTX. PMID- 30426455 TI - Ultra-stable super-resolution fluorescence cryo-microscopy for correlative light and electron cryo-microscopy. AB - Remarkable progress in correlative light and electron cryo-microscopy (cryo-CLEM) has been made in the past decade. A crucial component for cryo-CLEM is a dedicated cryo-fluorescence microscope (cryo-FM). Here, we describe an ultra stable superresolution cryo-FM that exhibits excellent thermal and mechanical stability. The temperature fluctuations in 10 h are less than 0.06 K, and the mechanical drift over 5 h is less than 200 nm in three dimensions. We have demonstrated the super-resolution imaging capability of this system (average single molecule localization accuracy of ~13.0 nm). The results suggest that our system is particularly suitable for long-term observations, such as single molecule localization microscopy (SMLM) and cryogenic super-resolution correlative light and electron microscopy (csCLEM). PMID- 30426456 TI - Genetic diversity and population structure analysis in Perilla crop and their weedy types from northern and southern areas of China based on simple sequence repeat (SSRs). AB - INTRODUCTION: Identification of genetic variation is an essential ability for the long-term success of breeding programs and maximizes the use of germplasm resources. In East Asia, China has a long history of the cultivation of Perilla crop, but there has been little research on the genetic diversity and genetic relationships among accessions of Perilla crop and their weedy types. OBJECTIVES: To better understand the genetic variations of the cultivated and weedy types of Perilla crop in China, the 91 accessions were evaluated for genetic diversity by 21 simple sequence repeat (SSR) markers. METHODS: SSR amplifications were conducted in a total volume of 20 uL, consisting of 20 ng genomic DNA, 1X PCR buffer, 0.5 uM forward and reverse primers, 0.2 mM dNTPs, and 1 U Taq polymerase. Power Marker version 3.25 was applied to obtain the information on the number of alleles, allele frequency, major allele frequency, gene diversity (GD), and polymorphic information content (PIC). The similarity matrix was used to construct an unweighted pair group method with arithmetic mean dendrogram by the application of SAHN-Clustering from NTSYS-pc.V.2.1. RESULTS: A total of 147 alleles were identified with an average of 7 alleles per locus. The average values of PIC and GD were 0.577 and 0.537, respectively. The genetic diversity level of accessions from Northern China was lower than accessions from Southern China. The genetic diversity level and PIC values for accessions of var. crispa were the highest. For accessions of cultivated var. frutescens, genetic diversity in Southern China was higher than that in Northern China. CONCLUSION: Most cultivated Perilla accessions were clearly separated from weedy Perilla accessions, but there was no clear geographic structure between cultivated Perilla crop and weedy types based on their regional distribution. This study demonstrated the utility of SSR analysis for performing genetic and population analysis of cultivated and weedy types of Perilla accessions in China. PMID- 30426457 TI - Comparison between auto-trilevel and bilevel positive airway pressure ventilation for treatment of patients with concurrent obesity hypoventilation syndrome and obstructive sleep apnea syndrome. AB - PURPOSE: Our study aims to compare the difference in clinical efficacy between auto-trilevel positive airway pressure (auto-trilevel PAP) ventilator and conventional fixed bilevel positive airway pressure (BiPAP) ventilator for obesity hypoventilation syndrome (OHS) patients with coexisting moderate or severe obstructive sleep apnea hypopnea syndrome (OSAHS). METHODS: Twenty-three OHS patients with moderate or severe OSAHS enrolled between January 2015 and September 2017 underwent ventilation by three different modes of positive airway pressure (PAP) for 8 h per night. A single variable mode was applied at the first night followed by two nights when no PAP therapy was carried out as a washout period between each mode. The inspiratory positive airway pressure (IPAP) decided by PaCO2 was consistently used for modes 1, 2, and 3. In mode 1, the expiratory positive airway pressure (EPAP) issued by BiPAP was decided by the minimal PAP levels for cessation of snoring. However, in mode 2, the EPAP was fixed at 3 cmH2O higher than this value. With the use of auto-trilevel PAP in mode 3, the EPAP was set to initially match that of mode 1 but the end of EPAP (EEPAP) was automatically regulated to be elevated according to upper airway patency condition. We also compared the following parameters including apnea hypopnea index (AHI), minimal SpO2 (miniSpO2), arousal index, and sleep efficiency during sleep; PaCO2 in the morning and Epword sleepiness score (ESS) at daytime were measured prior to and during PAP treatment as well as between three selected PAP modes. RESULTS: Compared with the parameters before ventilation therapies, all three variable modes of ventilation were associated with a higher nocturnal miniSpO2 and sleep efficiency (all P < 0.01). Among the three variable modes, mode 3 resulted in not only the lowest arousal index and daytime ESS but also the highest sleep efficiency. Compared to mode 1, mode 2 demonstrated a significantly reduced AHI and an elevated miniSpO2 and morning PaCO2 (all P < 0.05), while mode 3 was associated with a decreased AHI, an increased miniSpO2 (all P < 0.05), and no statistical change of PaCO2 following the end of PAP treatment (P > 0.05). Comparison between mode 2 and mode 3 revealed that mode 3 had a significantly lower PaCO2 (P < 0.05), but displayed no remarkable changes of AHI and miniSpO2 (all P > 0.05). CONCLUSION: Compared to fixed BiPAP ventilation, auto-trilevel PAP ventilation could more effectively correct hypercapnia, achieve lower index of nocturnal apnea and hypopnea, more improved sleep quality, and lower daytime sleepiness score. Auto-trilevel PAP ventilation is therefore more efficacious than conventional BiPAP ventilation in non-invasive ventilation therapy for OHS patients with concurrent moderate or severe OSAHS. PMID- 30426458 TI - Epic failure: Lessons learned from interprofessional faculty development. AB - Interprofessional education (IPE) is now recognized as an important initiative to prepare the next generation of health providers. Although IPE has been embraced by many institutions, faculty development still remains an issue. In this manuscript, the authors share their story of one attempt to educate a variety of health science faculty on IPE in what was perceived as an approachable venue. The story of its epic failure and lessons learned will be shared to help others avoid similar pitfalls. PMID- 30426459 TI - Ribonucleoproteins Mediated Efficient In Vivo Gene Editing in Skin Stem Cells. AB - The clustered regularly interspaced, short palindromic repeats (CRISPR)-Cas9 system functions like an adaptive immune system in a variety of microbes and has recently been engineered as a powerful tool for manipulating genomic sequences in a huge variety of cell types. In mammals, CRISPR/Cas9 has the potential to bring curative therapies to patients with genetic diseases, although it remained unknown whether suitable in vivo methods for its use are feasible. It is now appreciated that the efficient delivery of these genome-editing tools into most tissue types, including skin, remains a major challenge. Here, we describe a detailed protocol for performing in vivo gene editing of genomic sequences in mouse skin stem cells using Cas9/sgRNAs ribonucleoproteins in combination with electrotransfer technology. We here present all of the required methods needed for the protocol, including molecular cloning, in vitro sgRNA expression and sgRNA purification, Cas9 protein purification, and in vivo delivery of cas9 ribonucleoproteins. This protocol provides a novel in vivo gene editing strategy using ribonucleoproteins for skin stem cells and can potentially be used as curative treatment for genetic diseases in skin and other somatic tissues. PMID- 30426461 TI - Acknowledgment to Referees. PMID- 30426460 TI - The protective microRNA-199a-5p-mediated unfolded protein response in hypoxic cardiomyocytes is regulated by STAT3 pathway. AB - The protective effects of downregulated miR-199a-5p on ischemic and hypoxic cardiomyocytes were well recognized, but the underlying mechanism of inhibited miR-199a-5p is not yet clear. The present study explored the relationship between enhanced signal transducer and activator of transcription 3 (STAT3) signaling and lowered production of miR-199a-5p in hypoxic cardiomyocytes. This study firstly found the correlation between elevated interleukin (IL)-6 and IL-11, as well as subsequent STAT3 signaling activation and the downregulation of miR-199a-5p in hypoxic myocardial samples from children with congenital heart disease. Then, using model of hypoxic mice and the intervention of phosphorylated STAT3 (pSTAT3), it was observed that pSTAT3 affected the expression of miR-199a-5p and modulated the expression of its target genes, including endoplasmic reticulum stress (ERS)-related activating transcription factor 6 (ATF6) and 78 kDa glucose regulated protein (GRP78). Further observation revealed that the pSTAT3 signal in cardiac tissue could affect the expression of pri-miR-199a-2, a precursor of miR 199a-5p. And the chromatin immunoprecipitation (ChIP) assay also confirmed that pSTAT3 could bind to the promoter region of miR-199a-2 gene, which is more significant under hypoxic conditions. In conclusion, the activation of STAT3 signaling in cardiomyocytes during chronic hypoxia leads to downregulation of miR 199a-5p, which promotes the expression of many downstream target genes. This is an important pathway in the adaptive protection mechanism of myocardium during hypoxia. PMID- 30426462 TI - Autologous Chondrocyte Implantation with Chondrosphere for Treating Articular Cartilage Defects in the Knee: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - Chondrosphere (Spherox) is a form of autologous chondrocyte implantation (ACI). It is licensed for repair of symptomatic articular cartilage defects of the femoral condyle and the patella of the knee with defect sizes up to 10 cm2 in adults. In a single technology appraisal (STA) [TA508] undertaken by the National Institute of Health and Care Excellence (NICE), Warwick Evidence was the Evidence Review Group (ERG) invited to independently review the evidence submitted by the manufacturer, Co.Don. The clinical effectiveness data came from their COWISI randomised controlled trial (RCT), which compared Chondrosphere with microfracture (MF). The timing of this appraisal was unfortunate given that MF was no longer the most relevant comparator because NICE had contemporaneously published guidance approving ACI in place of MF. Moreover, the COWISI RCT enrolled mostly patients with small defect sizes. Evidence of clinical effectiveness for Chondrosphere used in people with larger defect size came from another RCT, which compared three doses of Chondrosphere and that by design could not provide evidence comparing Chondrosphere to any other forms of ACI. To estimate the relative clinical performance of Chondrosphere versus other ACI, Co.Don conducted an indirect treatment comparison by network meta-analyses (NMA). The NMA was flawed in that the distribution of population characteristics that are effect modifiers greatly differed across the treatment comparisons of the network. The ERG questioned both the appropriateness of the NMA and the validity of the resulting estimates. Co.Don estimated the cost-effectiveness of Chondrosphere using a lifetime Markov model with all patients receiving the first repair during the first cycle of the model then moving into one of three health states: success, no further repair (NFR), or a second repair, if necessary. Subsequent to the first cycle, those who were a success either remained a success or moved to second repair. All those in NFR remained in NFR. The cost effectiveness of Chondrosphere compared to other ACI forms relied on the clinical effectiveness estimates of success and failure rates obtained from the company's indirect comparisons, the validity of which the ERG questioned. The company revised cost-effectiveness estimates for Chondrosphere versus MF and for Chondrosphere versus matrix-applied characterised autologous cultured chondrocyte implant (MACI) were L4360 and around L18,000 per quality-adjusted life year gained, respectively. NICE recommended ACI using Chondrosphere for treating symptomatic articular cartilage defects of the femoral condyle and patella of the knee in adults only if certain requirements were met. PMID- 30426463 TI - Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. AB - The National Institute for Health and Care Excellence (NICE) invited Teva, the company manufacturing arsenic trioxide (ATO; tradename Trisenox(r)), to submit evidence for the clinical and cost effectiveness of ATO for untreated and relapsed or refractory acute promyelocytic leukaemia (APL). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group (ERG). This paper presents a summary of the company submission (CS), the ERG's critical review of the clinical and cost effectiveness evidence in the CS, key methodological considerations and the development of the NICE guidance by the Appraisal Committee (AC). The CS presented three randomized controlled trials (RCTs). Two of these were trials in newly diagnosed APL (APL0406 and AML17) and the third trial was in patients with relapsed APL. Results from APL0406 showed that more people having AATO [ATO plus all-trans retinoic acid (ATRA)] were alive at 50 months compared with people having AIDA (ATRA in combination with idarubicin) (99% vs. 93%; p = 0.007). There was also a statistically significant lower cumulative incidence of relapse with AATO compared with AIDA at 50 months (2% vs. 14%; p = 0.001). At 4 years, results from AML17 showed a significant difference in event-free survival (91% vs. 70%; p = 0.002) favouring AATO but not in overall survival (93% vs. 89%; p = 0.250). The only trial presented for relapsed/refractory patients compared AATO with ATO, which was not a relevant comparison according to the NICE scope. The AC concluded that AATO was effective for untreated APL while for relapsed or refractory APL the effectiveness of ATO was considered uncertain and the long-term safety remains unexplored. In the CS base-case, AATO was less expensive (L31,088 saved) and more effective (2.546 quality-adjusted life-years (QALYs) gained) than AIDA and thus the dominating strategy for newly diagnosed low- to intermediate-risk APL. However, the ERG's critical assessment highlighted a number of concerns, including deviations from the NICE reference case and a lack of detailed description and justification of parameters and assumptions related to (the extrapolation of) treatment effectiveness. However, it was reassuring that AATO for untreated APL remained dominant in the ERG base-case, and that the worst-case scenario produced by the ERG resulted in an incremental cost-effectiveness ratio (ICER) of L21,622. The AC concluded that although there was uncertainty in the model, it could recommend ATO for both untreated and relapsed or refractory APL. PMID- 30426464 TI - The Effect of Encapsulation on The Stability of Probiotic Bacteria in Ice Cream and Simulated Gastrointestinal Conditions. AB - The objective of this work was to explore the effect of two encapsulating polysaccharides (sodium alginate and carrageenan) on the viability of probiotic bacteria (L. acidophilus) in ice cream and under simulated gastrointestinal (GIT) conditions. For the purpose, probiotic cells were encapsulated in sodium alginate and carrageenan by an encapsulator using standard operating conditions. Ice cream was manufactured by adding free and microencapsulated probiotics. The survival of free and encapsulated probiotics was monitored over a period of 120 days at - 20 degrees C. Furthermore, the survival of free and encapsulated probiotic bacteria under the simulated GIT conditions was investigated. The results of the study showed that encapsulation significantly (p < 0.05) improved the cell survival of probiotics in ice cream compared to free cells (non-encapsulated). The viable cell count of probiotic bacteria in the free-state in ice cream was 9.97 log cfu/ml at 0 day that decreased to 6.12 log cfu/ml after 120 days. However, encapsulation improved the viability of the probiotics in the prepared ice cream and GIT. The cell count of probiotics encapsulated with sodium alginate and carrageenan was 9.91 log cfu/ml and 9.89 log cfu/ml respectively at 0 day that decreased to 8.74 log cfu/ml and 8.39 log cfu/ml respectively after 120 days. Similarly, during simulated gastrointestinal assay, the survival rate of encapsulated probiotic bacteria in simulated gastric solution and intestinal solutions was higher than that of free cells. In the case of encapsulated bacteria, only three log while for free cells seven log reduction was recorded. Sodium alginate microcapsules exhibited better release profile than carrageenan. Conclusively, the incorporation of encapsulated probiotics had a significant effect on quality parameters and sensorial characteristics of ice cream. PMID- 30426465 TI - Feasibility and safety of exclusive echocardiography-guided intravenous temporary pacemaker implantation. AB - BACKGROUND: The standard approach for urgent trans-venous temporary cardiac pacemaker (TVTP) implantation is fluoroscopy guidance. The delay in activation of the fluoroscopy-room and the transfer of unstable patients may be life threatening. Echocardiography-guided TP implantation may increase the safety of the patients by obviating the need for in-hospital transfer. We examined the feasibility and safety of echocardiography-guided vs. fluoroscopy-guided TVTP implantation. METHODS: From January 2015 to September 2017 data for consecutive patients who needed emergent TVTP implantation were retrospectively reviewed. Ultrasound-guided TVTP protocol that was introduced in our center in January 2015 involved ultrasound guidance for both central venous access and pacing lead positioning. Access sites included femoral, subclavian, or jugular veins. Electrodes were placed in the right ventricular apex by means of echocardiographic monitoring in intensive care unit or by fluoroscopic guidance. Endpoints were achievement of successful ventricular pacing and procedural complications. RESULTS: Sixty-six patients (17 echocardiography-guided and 49 fluoroscopy-guided) were included. There were no differences in pacing threshold between the echocardiography-guided group and the fluoroscopy-guided group (0.75 +/- 0.58 mA vs. 0.57 +/- 0.35 mA, p = 0.24). The access site for implantation was femoral vein in 27% for the fluoroscopy-guided vs. none for the echocardiography guided approach (p = 0.015). One hematoma and one related infection occurred in the fluoroscopy-guided group. The need for electrode repositioning was observed in 1 patient in each group. There were no procedural-related deaths in either group. CONCLUSIONS: Echocardiography-guided temporary cardiac pacing is a feasible and safe alternative to fluoroscopy-guided approach and significantly lowers the need for in-hospital transfer. PMID- 30426466 TI - Touching the Sky: Coccinellids (Coleoptera: Coccinellidae) at High Altitudes in South America. AB - Records of extreme altitudes where several coccinellid species from South America inhabit the Andes of Argentina, Bolivia, Chile, Colombia, Ecuador, and Peru are provided. After an intensive review of several entomological collections and literature, records for 35 species with at least one location over 3500-m elevation were obtained, including the genera Cycloneda (ten species), Eriopis (15 species and one subspecies), Harmonia (one species), Hippodamia (two species), Mimoscymnus (two species), Psyllobora (one species), and Stenadalia (four species). In total, 184 location records are listed, of which 119 were from between 3000 and 4000 m, 57 between 4000 and 4900 m and eight above 4900 m, with the highest altitude record at 5250 m for Eriopis minima Hofmann. All records above 4000 m were obtained in the Puna biogeographic province within the Paramo Punena biogeographic subregion. These records are the highest altitudes observed for the American continent and by far surpass others known for coccinellids worldwide. Several species of coccinellids living in sympatry at these high altitudes were verified, and in some cases, in situ development was inferred by the presence of immature stages. These findings are important to foresee the future effects of global warming that will affect especially the biological communities of extreme altitudes. PMID- 30426467 TI - Assessment of morphological changes and steroid receptors in the uteri of postmenopausal women. AB - INTRODUCTION: The morphology of the endometrium constantly changes in the reproductive period, depending on the levels of ovarian steroid hormones, and undergoes atrophic changes during menopause as a result of their insufficiency. The purpose of this study was to analyze morphological and morphometric changes in the mucous and muscle layers of the uterine wall in postmenopausal women, and to assess localization and number of cells showing the expression of steroid hormone receptors, namely estrogen receptor alpha (ER-alpha), progesterone receptor (PR), and androgen receptor (AR) in glandular epithelial cells and smooth muscle cells in particular groups of women. MATERIAL AND METHODS: The study material consisted of uterine specimens sectioned across the full thickness of the uterine wall, and embedded in 164 paraffin blocks. The specimens came from women without menopausal hormone therapy (MHT) operated due to reproductive organ prolapse or uterine myomas. The material was divided into four groups depending on the time interval from menopause to surgery: group I - from 1 to 5 years after menopause, group II - from 6 to 10 years after menopause, group III - more than 11 years after menopause, and group IV - women over 70 years of age. The sections were stained by standard HE, Masson's trichrome, and immunohistochemical methods (ERalpha, PR, AR). Quantitative assessment of the results was based on computer image analysis. RESULTS: Analysis of morphological changes in the endometrium and myometrium revealed the presence of increasing regressive changes, such as various types of atrophy, fibrosis, and calcification, augmented over time from the last menstruation. Furthermore, endometrial polyps, foci of endometriosis, and leiomyomas were observed. Based on the results of morphometric measurements, a constant decrease in the endometrial and myometrial thickness was noticed in the studied groups (I-IV). Significant differences between the groups were observed in the number of ER-alpha positive cells in the myometrium, but not in the endometrial glandular epithelium. Statistically significant differences in the number of AR positive cells were detected in the endometrial epithelium and in the uterine muscle. The analysis the number of PR positive cells demonstrated differences between the groups in the endometrial stroma and the myometrium. CONCLUSION: The uterus of postmenopausal woman undergo major morphological changes (mainly atrophic lesions in the endometrium and myometrium), leading to a decline in their morphometric parameters over time from the last menstruation. Localization and number of cells showing the expression of steroid receptors: ER alpha, PR, and AR in the uterus of postmenopausal women, depending on the time interval from the last menstruation. PMID- 30426468 TI - Acute promyelocytic leukaemia with increased basophils. PMID- 30426469 TI - Phylogenomic incongruence, hypothesis testing, and taxonomic sampling: The monophyly of characiform fishes. AB - Phylogenomic studies using genome-wide datasets are quickly becoming the state of the art for systematics and comparative studies, but in many cases, they result in strongly supported incongruent results. The extent to which this conflict is real depends on different sources of error potentially affecting big datasets (assembly, stochastic, and systematic error). Here, we apply a recently developed methodology (GGI or gene genealogy interrogation) and data curation to new and published datasets with more than 1000 exons, 500 ultraconserved element (UCE) loci, and transcriptomic sequences that support incongruent hypotheses. The contentious non-monophyly of the order Characiformes proposed by two studies is shown to be a spurious outcome induced by sample contamination in the transcriptomic dataset and an ambiguous result due to poor taxonomic sampling in the UCE dataset. By exploring the effects of number of taxa and loci used for analysis, we show that the power of GGI to discriminate among competing hypotheses is diminished by limited taxonomic sampling, but not equally sensitive to gene sampling. Taken together, our results reinforce the notion that merely increasing the number of genetic loci for a few representative taxa is not a robust strategy to advance phylogenetic knowledge of recalcitrant groups. We leverage the expanded exon capture dataset generated here for Characiformes (206 species in 23 out of 24 families) to produce a comprehensive phylogeny and a revised classification of the order. PMID- 30426473 TI - Connecting the dots between metformin and high-grade glioma. PMID- 30426471 TI - Circulating dendritic cells deficiencies as a new biomarker in classical Hodgkin lymphoma. AB - No robust biomarkers have been yet validated to identify the recurrence of disease in classical Hodgkin Lymphoma (cHL) patients upon induction treatment. The relevance of the inflammatory microenvironment in cHL prompted us to investigate the key immunomodulator myeloid dendritic cells type-1 (mDC1), type-2 (mDC2) and plasmacytoid dendritic cells (pDC). Blood DC levels were assessed in 52 newly diagnosed patients through multiparametric flow-cytometry. All but two patients received ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine). The median counts of all DC subsets were lower in cHL patients than in healthy controls (P < 0.001). Median mDC counts were inferior for the advanced vs early stage patients for both mDC1s and mDC2s (P = 0.008; P = 0.0007 respectively). Also, median mDC2 counts were reduced in case of bulky (P = 0.0004) and extra-nodal (P = 0.046) disease. Patients with B symptoms had lower levels for mDC1s (P = 0.046), mDC2s (P = 0.009) and pDCs (P = 0.040). All the DC subtypes increased at the end of treatment in 26 patients (P < 0.001): 4.6-fold for mDC1, 2.4-fold for mDC2, 4.5-fold for pDC and aligned DCs subsets with the reference frequencies and the interquartile ranges of the controls. In conclusion, DCs may contribute to the disturbed immunological interplay typical of cHL, prompting a further evaluation of their value as a potential new biomarker. PMID- 30426470 TI - Corpus callosum low-frequency stimulation suppresses seizures in an acute rat model of focal cortical seizures. AB - OBJECTIVE: Low-frequency fiber-tract stimulation has been shown to be effective in treating mesial temporal lobe epilepsies through activation of the hippocampal commissure in rodents and human patients. The corpus callosum is a major pathway connecting the two hemispheres of the brain; however, few experiments have documented corpus callosum stimulation. The objective is to determine the efficacy of corpus callosum stimulation at low frequencies to suppress cortical seizures. METHODS: 4-Aminopyridine was injected in the primary motor cortex of 24 rats under anesthesia. Recording electrodes were placed in the contralateral motor cortex and hippocampus. Three pairs of stimulating electrodes were inserted into the corpus callosum along its longitudinal axis. Local field potentials were recorded 1 hour before, during, and after stimulation to determine the effect of stimulation on seizure duration. Stimulation was delivered from each pair of electrodes independently in separate experiments. Furthermore, electrical stimulation was applied to the region of the corpus callosum with the highest degree of innervation of the seizure focus to compare the efficacy of different stimulation frequencies (1-30 Hz) on seizure suppression. RESULTS: Corpus callosum stimulation was effective at suppressing seizures at 10 Hz by 76% (P < 0.05, n = 5) and at 20 Hz by 95% (P < 0.0001, n = 14). Stimulation at frequencies of 1 and 30 Hz did not have a significant effect on reducing the total time spent seizing (P > 0.9999, n = 5). Furthermore, stimulation was only effective at suppressing seizures when the pair of electrodes was placed within the section of corpus callosum containing fibers innervating the seizure focus. Secondarily generalized seizures in the hippocampus were eliminated when seizures in the cortical focus were suppressed. SIGNIFICANCE: Low-frequency fiber-tract stimulation of the corpus callosum suppresses both cortical and cortically induced hippocampal seizures in an acute model of focal cortical seizures. The stimulation paradigm is selective, as it is only effective when targeted to specific regions of the corpus callosum that project maximally to cortical regions generating the seizure activity. Selective placement of stimulation electrodes along the corpus callosum could be used as a patient-specific treatment for cortical epilepsies. PMID- 30426472 TI - A guideline for the management of specific situations in polycythaemia vera and secondary erythrocytosis: A British Society for Haematology Guideline. PMID- 30426474 TI - Pre-hospital thrombolysis of ischemic stroke in the emergency service system-A case report from the Treat-NASPP trial. PMID- 30426476 TI - The EU Court of Justice extends the GMO Directive to gene-edited organisms. PMID- 30426475 TI - Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk. AB - miRNAs play a central role in the complex signaling network of cancer cells with the tumor microenvironment. Little is known on the origin of circulating miRNAs and their relationship with the tumor microenvironment in lung cancer. Here, we focused on the cellular source and relative contribution of different cell types to circulating miRNAs composing our risk classifier of lung cancer using in vitro/in vivo models and clinical samples. A cell-type specific expression pattern and topography of several miRNAs such as mir-145 in fibroblasts, mir-126 in endothelial cells, mir-133a in skeletal muscle cells was observed in normal and lung cancer tissues. Granulocytes and platelets are the major contributors of miRNAs release in blood. miRNAs modulation observed in plasma of lung cancer subjects was consistent with de-regulation of the same miRNAs observed during immunosuppressive conversion of immune cells. In particular, activated neutrophils showed a miRNA profile mirroring that observed in plasma of lung cancer subjects. Interestingly mir-320a secreted by neutrophils of high-risk heavy-smokers promoted an M2-like protumorigenic phenotype through downregulation of STAT4 when shuttled into macrophages. These findings suggest a multifactorial and non-epithelial cell-autonomous origin of circulating miRNAs associated with risk of lung cancer and that circulating miRNAs may act in paracrine signaling with causative role in lung carcinogenesis and immunosuppression. This article is protected by copyright. All rights reserved. PMID- 30426477 TI - The repertoire of seizure onset patterns in human focal epilepsies: Determinants and prognostic values. AB - OBJECTIVE: In this study, we seek to analyze the determinants of the intracranial electroencephalography seizure onset pattern (SOP) and the impact of the SOP in predicting postsurgical seizure outcome. METHODS: To this end, we analyzed 820 seizures from 252 consecutive patients explored by stereo-electroencephalography (total of 2148 electrodes), including various forms of focal refractory epilepsies. We used a reproducible method combining visual and time-frequency analyses. RESULTS: We described eight SOPs: low-voltage fast activity (LVFA), preictal spiking followed by LVFA, burst of polyspikes followed by LVFA, slow wave/DC shift followed by LVFA, sharp theta/alpha waves, beta sharp waves, rhythmic spikes/spike-waves, and delta-brush. LVFA occurred in 79% of patients. The seizure onset pattern was significantly associated with (1) underlying etiology (burst of polyspikes followed by LVFA with the presence of a focal cortical dysplasia, LVFA with malformation of cortical development, postvascular and undetermined epilepsies), (2) spatial organization of the epileptogenic zone (EZ; burst of polyspikes followed by LVFA with focal organization, slow wave/DC shift followed by LVFA with network organization), and (3) postsurgical seizure outcome (better outcome when LVFA present). SIGNIFICANCE: This study demonstrates that the main determinants of the SOP are the underlying etiology and the spatial organization of the EZ. Concerning the postsurgical seizure outcome, the main determinant factor is the spatial organization of the EZ, but the SOP plays also a role, conferring better prognosis when LVFA is present. PMID- 30426478 TI - Basic Considerations for the Use of Monoclonal Antibodies in Migraine. AB - BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States. PMID- 30426479 TI - Pre-hospital emergency anaesthesia in awake hypotensive trauma patients: Beneficial or detrimental? PMID- 30426480 TI - Hepatitis E virus infection after haploidentical haematopoietic stem cell transplantation: incidence and clinical course. AB - Hepatitis E virus (HEV) is increasingly found to cause hepatitis in allogeneic haematopoietic stem cell transplantation (HSCT) patients. However, little is known about HEV infection in patients receiving haploidentical HSCT (haplo-HSCT). Here, we retrospectively evaluate the incidence and clinical course of HEV infection in haplo-HSCT patients. From January 2014 to July 2017, 177 patients with unexplained elevated transaminases after receiving haplo-HSCT at Peking University Institute of Haematology were screened for HEV using HEV serology. HEV RNA was assessed in blood samples when HEV-IgG and/or IgM antibodies were positive. Acute HEV infection was identified in 7 patients (3.9%), 1 of whom had developed a chronic HEV infection. The median time from haplo-HSCT to HEV infection was 17.5 (range, 6-55) months. HEV infection was confirmed by the presentation of anti-HEV IgM + anti-HEV IgG (rising) (n = 5) or HEV-RNA + anti HEV IgM + anti-HEV IgG (n = 2). None of the patients died of HEV infection directly: 2 patients with HEV infection died showing signs of ongoing hepatitis, and 5 patients cleared HEV with a median duration of HEV infection of 1.5 (range, 1.0-5.7) months. In conclusion, HEV infection is a rare but serious complication after haplo-HSCT. We recommend screening of HEV in haplo-HSCT. PMID- 30426481 TI - Incidence of Persistent Headache at 18 Months Following Accidental Dural Puncture in the Obstetric Population: A Prospective Service Evaluation in 45 Patients. AB - OBJECTIVE: The aim of the prospective longitudinal service evaluation was to reveal the incidence of persistent headache at 18 months following accidental dural puncture with a 16-gauge Tuohy needle. This followed an observation that a subset of female patients was presenting to the local pain medicine clinic with persistent headache following an accidental dural puncture. BACKGROUND: Two thirds of patients with an accidental dural puncture develop post dural puncture headache that is believed to be a self-limiting condition. There is emerging evidence from retrospective studies that post dural puncture headache can result in persistent headache. METHODS: Prospective longitudinal service evaluation in obstetric patients who suffered an accidental dural puncture headache. Patients provided written consent for telephone follow-up at 6, 12, and 18 months. Patients reporting persistent headache were reviewed at a pain medicine clinic for further investigations and management. RESULTS: Over an 18-month period, 45 patients suffered accidental dural puncture. Five patients declined consent. One patient was lost to follow-up. Of the 39 patients who completed follow-up, 12 patients (30%) reported persistent headache at 18 months. Six patients reported new onset headache while 6 patients reported worsening of pre-existing headache. CONCLUSION: Post dural puncture headache from an accidental dural puncture can no longer be considered a self-limiting condition. Current evidence probably mandates the addition of persistent headache as one of the potential complications of an epidural insertion during informed consent process. PMID- 30426482 TI - The epidemiology of drug-resistant epilepsy: A systematic review and meta analysis. AB - OBJECTIVE: The definition of drug-resistant epilepsy (DRE) affects case identification and treatment, and impacts prevalence or incidence estimates and health burden estimation in epidemiology. The objective of this systematic review is to evaluate the consistency between definitions of DRE in the literature and the official definition in the International League Against Epilepsy (ILAE) guidelines, and to estimate the incidence, prevalence, and risk factors for DRE. METHODS: MEDLINE and EMBASE were searched for observational studies of DRE published between January 1980 and July 2015. The definitions of DRE in these studies were compared with the definition in the ILAE guidelines. Random-effect model meta-analyses were used to generate pooled estimates of prevalence or incidence and pooled odds ratios of the association with risk factors. RESULTS: Thirty-five studies met inclusion criteria, including 13 080 epilepsy patients and 3941 patients with DRE. The definition of DRE varied widely across studies, with only 12% meeting the requirements of the ILAE definition. The pooled prevalence proportion of DRE among epilepsy patients was 0.30 (95% confidence interval [CI] 0.19-0.42), and the pooled incidence proportion was 0.15 (95% CI 0.11-0.19). Age at onset, symptomatic epilepsy, abnormal neuroimaging findings, abnormal electroencephalography results, history of mental retardation, neuropsychiatric disorders, febrile seizure, and status epilepticus increased risk for DRE. SIGNIFICANCE: There are limited high-quality data available on DRE. Lack of consistency in definitions limits the ability to obtain robust estimates on the burden of DRE. More data based on the ILAE definition from well-designed epidemiologic studies are needed to generate accurate and reliable results. PMID- 30426483 TI - High long-term mortality after incident status epilepticus in adults: Results from a population-based study. AB - OBJECTIVE: To determine annual incidence, etiology, severity, and short- and long term mortality of first-time, nonanoxic status epilepticus (SE) in adults in a population-based retrospective cohort study. METHODS: We systematically identified all episodes of SE in the year 2014 on the island of Funen. Patients with SE due to anoxia, patients with recurrent SE, and patients <18 years old were excluded. Nonconvulsive SE in coma was diagnosed according to the Salzburg criteria. Etiology, semiology, modified Rankin Scale (mRS) at discharge, survival, and the Status Epilepticus Severity Score were retrospectively determined from patients' records. Patients with first-time nonanoxic SE diagnosed during 2008-2013 from our database (n = 88) were used to confirm the results. RESULTS: The incidence of first-time, nonanoxic SE in 2014 was 10.7/100 000 persons at risk (n = 41). Median Status Epilepticus Severity Score was 3; in hospital mortality was 24.4%. After median follow-up of 39.2 months, 53.7% of the patients had died (age- and gender-adjusted mortality rate of 5.2/100 000). Mortality stabilized 2 years after diagnosis. Analysis of the cohort from 2008 2013 confirmed stabilization of survival after 2-3 years and the high mortality 2 years after discharge. When correcting for acute symptomatic causes, the in hospital mortality was 16.7% and 46.7% at follow-up (crude mortality rate of nonhypoxic and nonacute symptomatic SE = 3.5/100 000). An exploratory multivariate analysis of pooled patients with SE from 2008 to 2014 revealed mRS >= 2 at discharge as a prognostic factor for long-term mortality. SIGNIFICANCE: In this cohort, the overall mortality of first-time nonhypoxic SE was >50%. Mortality of SE after discharge was substantially higher than in-house mortality and stabilized after 2 years. The degree of disability as indicated by mRS at discharge was associated with long-term mortality after discharge. PMID- 30426484 TI - Looking back and moving forward: Evaluating and advancing translation from animal models to human studies of early life stress and DNA methylation. AB - Advances in epigenetic methodologies have deepened theoretical explanations of mechanisms linking early life stress (ELS) and disease outcomes and suggest promising targets for intervention. To date, however, human studies have not capitalized on the richness of diverse animal models to derive and systematically evaluate specific and testable hypotheses. To promote cross-species dialog and scientific advance, here we provide a classification scheme to systematically evaluate the match between characteristics of human and animal studies of ELS and DNA methylation. Three preclinical models were selected that are highly cited, and that differ in the nature and severity of the ELS manipulation as well as in the affected epigenetic loci (the licking and grooming, maternal separation, and caregiver maltreatment models). We evaluated the degree to which human studies matched these preclinical models with respect to the timing of ELS and of DNA methylation assessment, as well as the type of ELS, whether sex differences were explicitly examined, the tissue sampled, and the targeted loci. Results revealed <50% match (range of 8-83%) between preclinical models and human work on these variables. Immediate and longer-term suggestions to improve translational specificity are offered, with the goal of accelerating scientific advance. PMID- 30426485 TI - LL202 ameliorates colitis against oxidative stress of macrophage by activation of the Nrf2/HO-1 pathway. AB - LL202, a newly synthesized flavonoid derivative, has been confirmed to inhibit the mitogen-activated protein kinase pathway and activation protein-1 activation in monocytes; however, the anti-inflammatory mechanism has not been clearly studied. Uncontrolled overproduction of reactive oxygen species (ROS) has involved in oxidative damage of inflammatory bowel disease. In this study, we investigated that LL202 reduced lipopolysaccharide (LPS)-induced ROS production and malondialdehyde levels and increased superoxide dismutase, glutathione, and total antioxidant capacity in RAW264.7 cells. Mechanically, LL202 could upregulate heme oxygenase-1 (HO-1) via promoting nuclear translocation of nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) to regulate LPS-induced oxidative stress in macrophages. In vivo, we validated the role of LL202 in dextran sulfate sodium- and TNBS-induced colitis models, respectively. The results showed that LL202 decreased the proinflammatory cytokine expression and regulated colonic oxidative stress by activating the Nrf2/HO-1 pathway. In conclusion, our study showed that LL202 exerts an anti-inflammatory effect by enhancing the antioxidant capacity of the Nrf2/HO-1 pathway to macrophages. PMID- 30426486 TI - A review of the molecular pathways mediating the improvement in diabetes mellitus following caloric restriction. AB - Lifestyle modification is the cornerstone of diabetes prevention and treatment. Weight loss through caloric restriction (CR) is effective in improving glycemic control, though it is difficult for patients to follow in practice, and remains critical to achieve optimal glucose homeostasis. In this review, we look at what is known about the molecular pathways involved in CR-induced insulin sensitivity and improved insulin resistance. PMID- 30426487 TI - Coffee and pancreatic cancer risk among never-smokers in the UK prospective Million Women Study. AB - Reported associations between coffee consumption and an increased risk of pancreatic cancer could be due to residual confounding by smoking and/or biased recall of coffee consumption in retrospective studies. Studying associations prospectively in never smokers should minimise these problems, but thus far such studies have included relatively small numbers of cases. In this study, 309,797 never-smoking women self-reported typical daily coffee consumption at a mean age of 59.5 years (SD 5.0 years) and were followed up for a median of 13.7 years (IQR: 12.2-14.9) through record linkage to national health cancer and death registries. During this period, 962 incident cases of pancreatic cancers were registered. Cox regression was used to calculate adjusted relative risks [RRs] of incident pancreatic cancer with 95% confidence intervals [CIs] in relation to coffee consumption at baseline. After adjustment for potential confounding factors, including body mass index and alcohol consumption, RRs of pancreatic cancer in never-smokers who reported usually consuming 1-2, 3-4, and >=5 cups of coffee daily, compared to non-drinkers of coffee, were 1.02 (CI 0.83-1.26), 0.96 (0.76-1.22), and 0.87 (0.64-1.18), respectively (trend p=0.2). A meta-analysis of results from this cohort and 3 smaller prospective studies found little or no statistically significant association between coffee consumption and pancreatic cancer risk in never smokers (summary RR=1.00, CI 0.86-1.17 for >=2 versus zero cups of coffee per day). This article is protected by copyright. All rights reserved. PMID- 30426488 TI - Quantitative analysis of the core 2D arrangement and distribution of enamel rods in cross-sections of mandibular mouse incisors. AB - Considerable descriptive information about the overall organization of mouse mandibular incisor enamel is available but almost nothing is known about the quantitative characteristics of enamel rod arrangement and distribution in these teeth. This has important implications concerning cell movement during the secretory stage because each ameloblast makes one enamel rod. Knowing how many enamel rods are cut open in a cross-section of the enamel layer could provide insights into understanding the dynamics of how groups of ameloblasts form the enamel layer. In this study, cross-sections of fully mineralized enamel were cut on 24 mandibular mouse incisors, polished and etched, and imaged by scanning electron microscopy in backscatter mode. Montaged maps of the entire enamel layer were made at high magnification and the enamel rod profiles in each map were color-coded based upon rod category. Quantitative analyses of each color layer in the maps were then performed using standard routines available in imagej. The data indicated that that there were on average 7233 +/- 575 enamel rod profiles per cross-section in mandibular incisors of 7-week-old mice, with 70% located in the inner enamel layer, 27% located in the outer enamel layer, and 3% positioned near the mesial and lateral cementoenamel junctions. All enamel rod profiles showed progressive increases in tilt angles, some very large in magnitude, from the lateral to mesial sides of the enamel layer, whereas only minor variations in tilt angle were found relative to enamel thickness at given locations across the enamel layer. The decussation angle between alternating rows of rod profiles within the inner enamel layer was fairly constant from the lateral to central labial sides of the enamel layer, but it increased dramatically in the mesial region of the enamel layer. The packing density of all rod profiles decreased from lateral to central labial regions of the enamel layer and then in progressing mesially, decreased slightly (inner enamel, mesial tilt), increased slightly (outer enamel layer) or almost doubled in magnitude (inner enamel, lateral tilt). It was concluded that these variations in rod tilt angle and packing densities are adaptations that allow the tooth to maintain a sharp incisal edge and shovel-shape as renewing segments formed by around 7200 ameloblasts are brought onto the occluding surface of the tooth by continuous renewal. PMID- 30426489 TI - Recent advances in breast cancer research impacting clinical diagnostic practice. AB - During the last decade, the genomics revolution has driven critical advances in molecular oncology and pathology, and a deeper appreciation of heterogeneity that is beginning to reshape our thinking around diagnostic classification. Recent developments have seen existing classification systems modified and improved where possible, gene-based diagnostics implemented and tumour-immune interactions modulated. We present a detailed discussion of this progress, including the advances in understanding of breast tumour classification, for example mixed ductal-lobular tumours and the spectrum of triple-negative breast cancer. The latest information on clinical trials and implementation of gene-based diagnostics, including MammaPrint and Oncotype Dx and others, is synthesized, and emerging targeted therapies as well as the burgeoning immuno-oncology field, and their relevance in breast cancer, are discussed. PMID- 30426490 TI - UCP2-dependent improvement of mitochondrial dynamics protects against acute kidney injury. AB - Acute kidney injury (AKI) is a public health concern with high morbidity and mortality rates in hospitalized patients and because survivors have increased risk of progression to chronic kidney disease. Mitochondrial damage is the critical driver of AKI-associated dysfunction and loss of tubular epithelial cells; however, the pathways that mediate these events are poorly defined. Here, in murine ischemia/reperfusion-induced (I/R-induced) AKI, we determined that mitochondrial damage is associated with the level of renal uncoupling protein 2 (UCP2). In hypoxia-damaged proximal tubular cells (PTCs), a disruption of mitochondrial dynamics demonstrated by mitochondrial fragmentation and disturbance between fusion and fission was clearly indicated. Ucp2-deficient mice (knockout mice) with I/R injury experienced more severe AKI and mitochondrial fragmentation than wild-type (WT) mice. Moreover, genetic or pharmacologic treatment increased UCP2 expression, improved renal function, reduced tubular injury and limited mitochondrial fission. In cultured proximal tubular epithelial cells, hypoxia-induced mitochondrial fission was exacerbated in cells with UCP2 deletion, while an increase of UCP2 ameliorated the hypoxia-induced disturbance of the balance between mitochondrial fusion and fission. Furthermore, results following modulation of UCP2 suggested it has a role in preserving mitochondrial integrity by preventing loss of membrane potential and reducing subsequent mitophagy. Taken together, our results indicate that UCP2 is protective against AKI and suggest that enhancing UCP2 to improve mitochondrial dynamics has potential as a strategy for improving outcomes of renal injury. This article is protected by copyright. All rights reserved. PMID- 30426491 TI - Pre-eclampsia onset and SPARC: A possible involvement in placenta development. AB - Pre-eclampsia (PE) is a multisystem disorder commonly diagnosed in the latter half of pregnancy and it is a leading cause of intrauterine fetal growth retardation (IUGR). The aim of this study was to investigate the localization and the role of SPARC, secreted protein acidic, and rich in cysteine, in PE and PE IUGR placentas in comparison with normal placentas. SPARC was mainly expressed in the villous and extravillous cytotrophoblastic cells in first trimester, whereas in PE, PE-IUGR and at term placentas, SPARC immunostaining was visible in both cytotrophoblastic cells and syncytiotrophoblast. SPARC expression significantly decreased in normal placenta from first to third trimester and a further significant reduction was demonstrated in PE and PE-IUGR. The latter downregulation of SPARC depends on hypoxic condition as shown by in vitro models. In conclusion, SPARC can play a pivotal role in PE and PE-IUGR onset and it should be considered as a key molecule for future investigations in such pathologies. PMID- 30426492 TI - A genetic variant in LINGO2 contributes to the risk of gestational diabetes mellitus in a Chinese population. AB - Genome-wide association studies (GWASs) showed that three single nucleotide polymorphisms (SNPs; rs10968576, rs1412239, and rs824248) in the leucine-rich repeat and Ig domain containing 2 (LINGO2) were associated with obesity or type 2 diabetes (T2D). We aimed to determine the influence of the LINGO2 variants on the gestational diabetes mellitus (GDM) risk. Thus, we performed a case-control study including 964 GDM cases and 1,021 controls to test the associations between the three LINGO2 variants (rs10968576, rs1412239, and rs824248) and susceptibility to GDM. Logistic regression analyses showed no significant association between LINGO2 variations (rs10968576 and rs1412239) and GDM susceptibility, but we observed that LINGO2 rs824248 A > T was significantly associated with an increased risk of GDM using the dominant model (TT/AT vs. AA: adjusted odds ratio [OR] = 1.26, 95% confidence interval [CI] = 1.05-1.51; p = 0.012) and the additive model (TT vs. AT vs. AA: adjusted OR = 1.16, 95% CI = 1.03-1.31; p = 0.016). In the additive model, a stronger risk effect of rs824248 was observed among obese women (prepregnancy body mass index [BMI] > 22 kg/m2 , adjusted OR = 1.34, 95% CI = 1.12-1.59) compared with that in lean women (prepregnancy BMI <= 22 kg/m2 , adjusted OR = 1.02 , 95% CI = 0.86-1.21; p = 0.029 for heterogeneity test). Further interactive analyses also detected a significant multiplicative interaction between rs824248 and prepregnancy BMI for the risk of GDM (p = 0.041). These findings indicate that LINGO2 rs824248 may serve as a susceptibility marker for GDM in Chinese females. PMID- 30426493 TI - Bands of Fontana are caused exclusively by the sinusoidal path of axons in peripheral nerves and predict axon path; evidence from rodent nerves and physical models. AB - The precise cause of the bands of Fontana, striations on peripheral nerves visible to the naked eye, has been the subject of debate for hundreds of years. Some researchers have described them as reflecting the sinuous course of nerve fibres passing through nerves, and others have proposed that endoneurial collagen and sheaths surrounding nerves play a role in their appearance. We hypothesised that the bands are caused exclusively by reflection of light from the surfaces of nerve fibres travelling in phase in sinusoidal waveforms through peripheral nerves. We aligned images of obliquely illuminated nerves with confocal images of axons in those nerves, and the numbers and positions of the bands precisely matched the axonal waves. We also developed three-dimensional models of nerves with representations of the sinusoidal path of axons at their surface. We observed patterns resembling the bands of Fontana when these models were obliquely illuminated. This provides evidence that the bands of Fontana can be caused by light reflected sinusoidal path of axons alone. We subsequently describe a mechanism of band production based on our observations of both nerves and models. We report that smaller diameter nerves such as phrenic nerves and distal branches of sciatic nerves have shorter band intervals than larger nerves, such as proximal trunks of sciatic nerves, and that shorter band intervals correlate with longer axons per unit length of nerve, which suggests a greater tolerance to stretch. Inspection of banding patterns on peripheral nerves may permit prediction of axon length within nerves, and assist in the interpretation of nerve conduction data, especially in diseases where axon path has become altered. PMID- 30426494 TI - TGFbeta mediates collagen production in human CRSsNP nasal mucosa-derived fibroblasts through Smad2/3-dependent pathway and CTGF induction and secretion. AB - Chronic rhinosinusitis without nasal polyp (CRSsNP) is characterized by tissue remodeling and fibrosis. Transforming growth factor-beta (TGF-beta) is considered a master switch in the induction of the profibrotic program which can induce fibroblasts to synthesize and contract extracellular matrix (ECM) proteins. A previous study has shown TGF-beta1 signaling and collagen overproduction in the CRSsNP, but the responsible cells and mechanism of action remain unclear. Therefore, this study was aimed to investigate the relationship between TGF-beta1 stimulation and collagen expression and to explore the role of connective tissue growth factor (CTGF) during the remodeling process using human CRSsNP nasal mucosa tissues and mucosa-derived fibroblasts as main materials. We found that TGF-beta1 and its isoforms could promote collagen protein expression. Concomitantly, TGF-beta1 caused CTGF expression and secretion. An addition of exogenous CTGF to fibroblasts also caused collagen expression. In accordance with these observations, TGF-beta1, CTGF, and collagen were highly expressed in the subepithelial stroma region of CRSsNP nasal mucosa, as determined by immunohistochemistry. The TGF-beta1-mediated collagen expression could be blocked by actinomycin D and SIS3, suggesting that the induction was through transcriptional regulation and Smad2/3-dependent pathway. Finally, we demonstrated that CTGF small interfering RNA knockdown led to a substantial decrease in TGF-beta1-mediated collagen expression. Collectively, our results provide first and further evidence that TGF-beta1 mediates collagen expression production through a canonical Smad2/3-dependent pathway and CTGF induction and secretion in human nasal fibroblasts. Moreover, TGF-beta1, CTGF, and collagen are highly expressed in human CRSsNP nasal mucosa specimens, suggesting their roles in tissue remodeling during CRSsNP progression. PMID- 30426495 TI - The urea transporter DUR3 contributes to rice production under nitrogen-deficient and field conditions. AB - Nitrogen is one of the most important elements for plant growth, and urea is one of the most frequently used nitrogen fertilizers worldwide. Besides the exogenously supplied urea from the soil, urea is endogenously synthesized during secondary nitrogen metabolism. Here, we investigated the contribution of a urea transporter, DUR3, to rice production using a reverse genetic approach combined with localization studies. Tos17 insertion lines for DUR3 showed a 50% yield reduction in hydroponic culture, and a 26.2% yield reduction in a paddy field, because of decreased grain filling. Because shoot biomass production and shoot total N was not reduced, insertion lines were disordered not only in nitrogen acquisition but also in nitrogen allocation. During seed development, DUR3 insertion lines accumulated nitrogen in leaves and could not sufficiently develop their panicles, although shoot and root dry weights were not significantly different from the wild-type. The urea concentration in old leaf harvested from DUR3 insertion lines was lower than that in wild-type. DUR3 promoter-dependent GUS activity was localized in vascular tissue and the midribs of old leaves. These results indicate that DUR3 contributes to nitrogen translocation and rice yield under nitrogen-deficient and field conditions. This article is protected by copyright. All rights reserved. PMID- 30426496 TI - Epidemiology and outcomes of acute kidney injury in hospitalized cancer patients in China. AB - Acute kidney injury (AKI) is a common complication in cancer patients, but the data are lacking in Asian countries. We aimed to assed the epidemiology, correlated risk factors and outcomes of AKI in cancer patients from China. We conducted a nationwide cohort study of cancer patients who were admitted to 25 general and children hospitals across China from January 1, 2013 to December 31, 2015. We obtained patient-level data from the electronic hospitalization information system and laboratory databases of all inpatients who had at least two serum creatinine tests within any 7-day window during their first 30 days of hospitalization. AKI was defined and staged according to Kidney Disease Improving Global Outcomes criteria. Incidence rate and risk factor profiles for AKI were examined. Outcomes of interest included in-hospital mortality, length of stay and daily costs. A total of 136,756 adult cancer patients were assessed in our study. The overall incidence of AKI was 7.5%, of which 1.6% were community acquired and 5.9% hospital acquired. The top three cancer types with high incidence of AKI were bladder cancer, leukemia, and lymphoma. Risk factors for community-acquired and hospital-acquired AKI were similar, including age, increased baseline serum creatinine, shock and urinary tract obstruction. In-hospital death occurred in 12.0 % with AKI versus 0.9% cancer patients without AKI. After adjustment for confounders, the severe AKI was associated with higher risk of in-hospital death, prolonged length of stay and higher daily costs. Clinicians should increase their awareness of AKI in hospitalized cancer patients. This article is protected by copyright. All rights reserved. PMID- 30426497 TI - Reply to Lu: Connecting the dots between metformin and high-grade glioma. PMID- 30426498 TI - Preoperative monocyte-to-lymphocyte ratio predicts recurrence in gastrointestinal stromal tumors. AB - BACKGROUND AND OBJECTIVES: Several inflammation markers were found to have a prognostic value in cancer. We investigated the significance of preoperative white cell ratios in determining gastrointestinal stromal tumors (GISTs) outcome. METHODS: Clinicopathological features of patients who underwent surgery for GIST were reviewed. The following peripheral blood inflammation markers were calculated: neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), platelet-lymphocyte ratio (PLR), neutrophil-white blood cell ratio (NWR), lymphocyte-white cell ratio (LWR), monocyte-white cell ratio (MWR), and platelet white cell ratio (PWR). RESULTS: We analyzed 127 patients. Three- and five-year disease-free survival (DFS) were 89.7% and 86.9%, respectively. The univariate analysis selected tumor diameter (P = 0.003), gastric location ( P = 0.024), cell type ( P = 0.024), mitosis ( P < 0.001), MLR ( P = 0.014), NLR ( P = 0.016), and PLR ( P = 0.001) as the factors associated to DFS. The independent prognostic factors for DFS were mitosis ( P = 0.001), NLR ( P = 0.015), MLR ( P = 0.015), and PLR ( P = 0.031), with MLR showing the highest statistical significance and hazard ratio (HR) value. MLR, NLR, and PLR were the only prognostic factors in the subgroup of patients with moderate to high Miettinen's risk class. A high value of MLR was associated with reduced DFS. CONCLUSION: MLR, NLR, and PLR are independent prognostic factors for DFS in GISTs. We first demonstrated the role of MLR as a predictor of recurrence in GIST. Its inclusion into clinical management may improve the recurrence estimation. PMID- 30426499 TI - The cotton endocycle-involved protein SPO11-3 functions in salt stress via integrating leaf stomatal response, ROS scavenging and root growth. AB - The SPORULATION 11 (SPO11) proteins are among eukaryotic the topoisomerase VIA (Topo VIA) homologues involved in modulating various important biological processes, such as growth, development and stress response via endoreduplication in plants, but the underlying mechanism response to stress remains largely unknown under salt treatment. Here, we attempted to characterize a homolog of TOP VIA in upland cotton (Gossypium hirsutum L.), designated as GhSPO11-3. The silencing of GhSPO11-3 in cotton plants resulted in a dwarf phenotype with a failure of cell endoreduplication and a phase shift in the ploidy levels. The GhSPO11-3-silenced plants also showed substantial changes including accumulated malondialdehyde (MDA), significantly reduced chlorophyll and proline contents, and decreased antioxidative enzyme activity after salt treatment. In addition, transgenic Arabidopsis lines overexpressing GhSPO11-3 accelerated both leaf and root growth with cell expansion and endopolyploidy. Both leaf stomatal density and aperture were markedly decreased, and the transgenic Arabidopsis lines were more tolerant with expression of stress-responsive genes under salinity stress. Furthermore, consistent with the reduced reactive oxygen species (ROS), the expression of ROS scavenging-related genes was largely reinforced, and antioxidant enzyme activities were accordingly significantly enhanced in transgenic Arabidopsis lines under salt stress. In general, these results indicated that GhSPO11-3 likely respond to salt stress by positively regulating root growth, stomatal response, ROS production and the expression of stress related genes to cope with adverse conditions in plants. This article is protected by copyright. All rights reserved. PMID- 30426500 TI - Defining differences in patient characteristics between spasmodic dysphonia and laryngeal tremor. AB - OBJECTIVE: To compare presenting characteristics of patients with adductor spasmodic dysphonia (ADSD), ADSD with laryngeal tremor (ADSD + LT), and laryngeal tremor without ADSD (LT). DESIGN: Cross-sectional analysis. METHODS: Patients treated for laryngeal movement disorders (1990-2016) were included. Analysis of variance and chi square tests measured differences in patient characteristics across the three disease groups. Using ADSD as the referent, multivariable logistic regression models were used to determine whether potential risk factors including patient demographics, family history, presence of potential inciting events prior to disease onset, and coprevalent movement disorders were associated with ADSD + LT or LT. RESULTS: In all, 652 patients with ADSD (n = 377), ADSD + LT (n = 98), and LT (n = 177) were included. ADSD patients were significantly younger than those with ADSD + LT and LT (52.5 +/- 13.4, 63.9 +/- 11.3, and 69.3 +/- 10.5 years, respectively; P < 0.001). Coprevalent movement disorders were more common in ADSD + LT (38.7%) and LT (57.1%) groups than in the ADSD group (11.5%; P < 0.001). Compared to ADSD, patients with ADSD + LT and LT were more likely to develop an additional movement disorder during follow-up. In multivariable analyses, increasing age, female gender, and having a movement disorder at presentation were associated with significantly greater odds of having ADSD + LT or LT when compared to ADSD. CONCLUSION: ADSD + LT patients demonstrate intermediate gender composition and age distributions between those with ADSD and LT. These findings suggest that ADSD + LT may be a distinct phenotype in the spectrum of laryngeal movement disorders. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30426501 TI - A Review on Conventional and Biotechnological Approaches in White Pepper Production. AB - White pepper is the dried seeds obtained from pepper berries (Piper nigrum L.) after the removal of the pericarp. It has been widely used as seasoning and condiments in food preparation. Globally, white pepper fetches a higher price compared to black pepper due to its lighter colour, preferable milder flavour and pungency. Increasing global demand of the spice outpaced the supply as the conventional production method used is laborious, lengthy and also less hygienic. The most common conventional method is water retting but can also include pit soil, chemical, boiling, steaming and mechanical methods. The introduction of biotechnology approach has gain a lot of interests, as it is a more rapid, convenient and hygienic method of producing white pepper. This technique involves the application of microorganisms and/or enzymes. This review highlights both conventional and latest biotechnological processes of white pepper production. This article is protected by copyright. All rights reserved. PMID- 30426502 TI - Assessment of herd effects among women and heterosexual men following girls-only HPV16/18 vaccination in the Netherlands: a repeated cross-sectional study. AB - Data on the impact of human papillomavirus (HPV) vaccination on the population HPV prevalence are largely obtained from women. We assessed the impact of the girls-only HPV16/18 vaccination program in the Netherlands that started in 2009, on trends in HPV prevalence among women and heterosexual men, using data from the PASSYON study. In this cross-sectional study, the HPV prevalence among 16- to 24 year-old visitors to sexually transmitted infection clinics was assessed in 2009, 2011, 2013, and 2015. We compared the genital postvaccination HPV prevalence with the prevaccination prevalence (2009) using Poisson GEE models. In total, we included 4996 women and 1901 heterosexual men. The percentage of women who reported to be vaccinated increased from 2.3% in 2009 to 37% in 2015. Among all women, the HPV16/18 prevalence decreased from 23% prevaccination to 15% in 2015 (adjusted prevalence ratio [aPR] 0.62, ptrend <0.01). Among heterosexual men, the HPV16/18 prevalence decreased from 17% prevaccination to 11% in 2015 (aPR 0.52, ptrend <0.01). Of the heterosexual men with a steady partner, HPV16/18 prevalence was lower among those whose steady partner had been vaccine-eligible in the national immunization program (aPR 0.13). Among unvaccinated women, the HPV16/18 prevalence in 2015 was not different from prevaccination. The decreasing HPV16/18 prevalence among heterosexual men and the reduced HPV16/18 prevalence among heterosexual men with a vaccine-eligible steady partner strongly suggests herd protection from girls-only vaccination. Absence of notable herd effects among unvaccinated women 6 years postvaccination may be due to the moderate vaccine uptake among girls in the Netherlands. This article is protected by copyright. All rights reserved. PMID- 30426504 TI - Taylor's power law captures the effects of environmental variability on community structure: An example from fishes in the North Sea. AB - 1.Taylor's power law (TPL) describes the relationship between the mean and variance in abundance of populations, with the power law exponent considered a measure of aggregation. However the usefulness of TPL exponents as an ecological metric has been questioned, largely due to its apparent ubiquity in various complex systems. 2.The aim of this study was to test whether TPL exponents vary systematically with potential drivers of animal aggregation in time and space, and therefore capture useful ecological information of the system of interest. 3.We derived community TPL exponents from a long term, standardised and spatially dense data series of abundance and body size data for a strongly size-structured fish community in the North Sea. We then compared TPL exponents between regions of contrasting environmental characteristics. 4.We find that, in general, TPL exponents vary more than expected under random conditions in the North Sea for size-based populations compared to communities considered by species. Further, size-based temporal TPL exponents are systematically higher (implying more temporally-aggregated distributions) along hydrographic boundaries. Time-series of size-based spatial TPL exponents also differ between hydrographically distinct basins. 5.These findings support the notion that TPL exponents contain ecological information, capturing community spatio-temporal dynamics as influenced by external drivers. This article is protected by copyright. All rights reserved. PMID- 30426503 TI - Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer. AB - Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid. We used quantitative proteomics (SILAC-MS), to compare protein expression in a bone-homed variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that Dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by Western blotting. BM1 cells also had enhanced invasive ability compared with parental cells which could be reduced by DOCK4-shRNA. In a training Tissue Microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p=0.004) but not oestrogen receptor status (p=0.19) or lymph node involvement (p=0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n=689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronic acid) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p=0.034). No corresponding association was found in patients who received zoledronic acid (HR 0.812, 95%CI 0.176-3.76, p=0.790), suggesting that treatment with zoledronic acid may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk. This article is protected by copyright. All rights reserved. PMID- 30426505 TI - Doxorubicin-induced cardiotoxicity involves IFNgamma-mediated metabolic reprogramming in cardiomyocytes. AB - Immune responses contribute to a large extent to heart diseases. However, it is still not clear how the key inflammatory mediator Interferon-gamma (IFNgamma) plays a role in doxorubicin (DOX)-induced cardiomyopathy. We report here that DOX induced heart dysfunction involves IFNgamma signaling in mice. The IFNgamma receptor was found to be highly expressed on cardiomyocytes, and its downstream signaling was activated in heart tissues upon DOX treatment. In vitro, IFNgamma strongly aggravated the injury of cardiomyocytes exposed to DOX. Although not affecting DOX-induced cell death, IFNgamma disrupted mitochondrial respiration and fatty acid oxidation in DOX-exposed cardiomyocytes. IFNgamma extended the suppression of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) axis by DOX to a p38-dependent branch. Activation of AMPK or inhibition of p38 inhibited the enhancing effect of IFNgamma on the DOX-induced cardiotoxicity and prolonged the survival time in DOX treated mice. Taken together, our results indicate that reprogramming of cardiac metabolism by IFNgamma represents a previously unidentified key step for DOX-induced cardiomyopathy. This unavoidable impact of IFNgamma on cardiomyocyte metabolism during chemotherapy redirects our attention to the balance between beneficial immunosurveillance of cancer cells and unwanted toxic side-effects. PMID- 30426506 TI - Effect of skimmed milk and vegetable powders on shelf stability of millet-based composite flour. AB - BACKGROUND: Millet porridge is a major complementary food used in Uganda but it is limited in protein and micronutrients like zinc and beta-carotene. Addition of milk and vegetable powders are known to greatly improve the nutrient content of millet flour. However, there was limited information on the shelf stability of the resultant composite flour. This study aimed at assessing the effect of milk and vegetable powders on the shelf stability of millet based composite flour. RESULTS: There was a general increase in the moisture content (MC), peroxide value (PV), free fatty acids (FFA), Thiobaturic Acid (TBA) and total plate count (TPC) of both composite and millet flours over the 8 weeks storage period. However, higher MC, PV, FFA, TBA and TPC values were recorded in the composite flour compared to millet flour (control) at each sampling interval. Sensory evaluation results revealed that panelists preferred porridges prepared from millet only compared to those from composite flour. The degree of liking of porridges from both composite and millet flours generally decreased over the storage period. However, both porridges were deemed as acceptable by the end of the storage period. The TPC also remained below 105 cfu/g which is the maximum limit recommended by the National Bureau of Standards (UNBS). CONCLUSION: The study findings indicated that addition of milk and vegetables powders negatively affected the stability of the composite flour. We recommend further studies to stabilize the product during storage. This article is protected by copyright. All rights reserved. PMID- 30426507 TI - A plasma metabolite panel as biomarkers for early primary breast cancer detection. AB - In recent years, metabolites have attracted substantial attention as promising novel biomarkers of various diseases. However, breast cancer plasma metabolite studies are still in their infancy. Here, we investigated the potential of metabolites to serve as minimally invasive, early detection markers of primary breast cancer. We profiled metabolites extracted from the plasma of primary breast cancer patients and healthy controls using tandem mass spectrometry (UHPLC MS/MS and FIA-MS/MS). Two metabolites were found to be upregulated, while 16 metabolites were downregulated in primary breast cancer patients compared with healthy controls in both the training and validation cohorts. A panel of seven metabolites was selected by LASSO regression analysis. This panel could differentiate primary breast cancer patients from healthy controls, with an AUC of 0.87 (95% CI: 0.81 ~ 0.92) in the training cohort and an AUC of 0.80 (95% CI: 0.71 ~ 0.87) in the validation cohort. These significantly differentiated metabolites are mainly involved in the amino acid metabolism and breast cancer cell growth pathways. In conclusion, using a metabolomics approach, we identified metabolites that have potential value for development of a multimarker blood based test to complement and improve early breast cancer detection. The panel identified herein might be part of a prescreening tool, especially for younger women or for closely observing women with certain risks, to facilitate decision making regarding which individuals should undergo further diagnostic tests. In the future, the combination of metabolites and other blood-based molecular marker sets, such as DNA methylation, microRNA, and cell-free DNA mutation markers, will be an attractive option. This article is protected by copyright. All rights reserved. PMID- 30426508 TI - The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: high frequency of FANCM pathogenic variants. AB - NGS-based multiple gene panel resequencing in combination with a high resolution CGH-array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and ten other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients. This article is protected by copyright. All rights reserved. PMID- 30426509 TI - Serum Copper and Zinc levels at Diagnosis and Hepatocellular Carcinoma Survival in the Guangdong Liver Cancer Cohort. AB - Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR=1.87, 95% CI: 1.22-2.86; P<0.01 for trend) and OS (Q4 vs. Q1: HR=2.06, 95% CI: 1.36-3.11; P<0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR=1.31, 95% CI: 0.89-1.92; P=0.04 for trend) and OS (Q4 vs. Q1: HR=1.43, 95% CI: 0.99-2.08; P=0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival. This article is protected by copyright. All rights reserved. PMID- 30426510 TI - Fc-binding proteins enhance autoantibody-induced BP180 depletion in pemphigoid. AB - Immunoglobulins consist of two antigen-binding regions (Fab) and one constant region (Fc). Protein A and protein G are bacterial proteins used for the purification of IgG by virtue of their high affinities for Fc fragment. Rheumatoid factors are autoantibodies against IgG Fc fragments, which are present in the body under physiological conditions. Little is known about the influence of Fc-binding proteins on the pathogenicity of antibody-induced autoimmune diseases. Pemphigoid diseases are a group of autoimmune sub-epidermal blistering disorders that includes bullous pemphigoid and mucous membrane pemphigoid. IgGs targeting the non-collagenous NC16A domain of the 180-kDa bullous pemphigoid antigen (BP180) are known to induce skin fragility in mice and the depletion of BP180 in keratinocytes. In this study, monoclonal antibody (mAb) against NC16A in combination with Fc-binding proteins was found to enhance BP180 depletion. Although mAb against the C-terminus of BP180 does not show pathogenicity in vivo or in vitro, mAb treatment with Fc-binding proteins clearly induced skin fragility in mice and BP180 depletion in keratinocytes. Anti-BP180 mAbs and Fc binding proteins were colocalized in the cytoplasm and at the basement membrane zone. Cell adhesion strengths were decreased in parallel with BP180 amounts. Clinically, bullous pemphigoid patients had higher rheumatoid factor titers than controls. Anti-BP180 mAb in combination with high titer rheumatoid factor serum was found to enhance BP180 depletion. Furthermore, saliva from mucous membrane pemphigoid patients contained larger quantities of bacteria and Fc-binding proteins than controls. Our results suggest that Fc-binding proteins (rheumatoid factor or protein G) may enhance the pathogenicity of autoantibodies in pemphigoid diseases. PMID- 30426511 TI - Mice with epidermal filaggrin deficiency show increased immune reactivity to nickel. AB - BACKGROUND: Nickel allergy and dermatitis have been associated with filaggrin gene mutations in epidemiological studies, but the mechanisms mediating these associations are unknown. OBJECTIVES: To investigate whether filaggrin-deficient flaky tail (ft/ft) mice show increased immune reactivity to nickel and elucidate the mechanisms mediating this. METHODS: The immune responses to nickel, 2,4 dinitrofluorobenzene (DNFB), cinnamal and p-phenylenediamine were assessed in ft/ft and wild-type (WT) mice. The amounts of nickel in the skin of ft/ft and WT mice were determined 20 hours after nickel exposure. The effect of blocking either the interleukin (IL)-17A pathway or the IL-1 pathway on the response to nickel in ft/ft mice was evaluated. RESULTS: Increased responsiveness to nickel, DNFB and cinnamal was observed in ft/ft mice as compared with controls. A reduced amount of nickel was found in the skin of ft/ft mice as compared with WT mice, suggesting increased nickel absorption by the skin of ft/ft mice. Blocking either the IL-17A pathway or the IL-1 pathway reduced nickel responsiveness in ft/ft mice. CONCLUSIONS: These findings suggest that the increased nickel responsiveness associated with epidermal filaggrin deficiency is mediated by a combination of increased nickel penetration and the steady-state inflammation found in the skin of filaggrin-deficient mice. PMID- 30426512 TI - Food colorant Sunset Yellow (E110) intervenes developmental profile of zebrafish (Danio rerio). AB - In this study, we tested the teratogenic/embryotoxic potentials of food colorant, Sunset Yellow (E110) using zebrafish embryos as a model. Laboratory-raised developing embryos of Danio rerio were exposed to graded concentrations (00, 0.1, 1.0, 2.0, 3.0, 4.0, 5.0, 10, 20, 30, 40, 50 and 100 mm) of E110 from gastrulation stage (~6 hours post-fertilization [hpf]) up until hatching. The developmental trajectory of each embryo and post-hatched larva was traced from 24 to 168 hpf. The no observed effect concentration (NOEC), median effective concentration (EC50 ), median lethal concentration (LC50 ) and teratogenic index were determined. In the 0.1 mm E110-exposed embryos, the development proceeded as in controls (NOEC), while, exposure of embryos to 1-5 mm of E110 led to a decrease in body size, dry body mass of resultant larvae along with appearance of morphological deformities such as, microphthalmia, pericardial edema, yolk sac edema and spinal curvature. Larvae of 10-50 mm E110-exposed embryos exhibited increased cellular apoptosis in the cardiac region with significantly declined heartbeats and elevated mortality rates, in addition to the above-mentioned abnormalities. In the 100 mm exposure group, all embryos succumbed to death within 24 hpf. The NOEC and LC50 recorded were at 0.1 and 42.57 mm respectively. EC50 (96 hpf) recorded for pericardial edema and yolk sac edema was 19.41 and 39.84 mm with teratogenic index quotient 2.1 and 1.06 respectively The study provides direct evidence for the developmental toxicity/teratogenic potential of E110. PMID- 30426513 TI - Arabidopsis HSP70-16 is required for flower opening under normal or mild heat stress temperatures. AB - Sepals play important roles in protecting inner floral organs from various stresses and in guaranteeing timely flower opening. However, the exact role of sepals coordinating interior and exterior signals remains elusive. In this study, we functionally characterized a heat shock protein gene, Arabidopsis HSP70-16, in flower opening and mild heat stress response, using combined genetics with anatomic, physiological, chemical, and molecular analyses. We show that HSP70-16 is required for flower opening and mild heat response. Mutation of HSP70-16 led to significant reduction in seed setting rate under 22 degrees C, which was more severe at 27 degrees C. Mutation of HSP70-16 also caused postgenital fusion at overlapping tips of two lateral sepals, leading to failed flower opening, abnormal floral organ formation, and impaired fertilization and seed setting. Chemical and anatomic analyses confirmed specific chemical and morphological changes of cuticle property in mutant lateral sepals, and qRT-PCR data indicated that expression levels of different sets of cuticle regulatory and biosynthetic genes were altered in mutants grown at both 22 degrees C and 27 degrees C temperatures. This study provides a link between thermal and developmental perception signals, and expands the understanding of the roles of sepal in plant development and heat response. PMID- 30426514 TI - Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice. AB - Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (137 Cs). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity. PMID- 30426515 TI - Orexin supplementation in narcolepsy treatment: A review. AB - Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy. PMID- 30426516 TI - Methylchloroisothiazolinone and/or methylisothiazolinone in cosmetic products-A market survey. AB - BACKGROUND: There was a global 'epidemic' of methylchloroisothiazolinone (MCI) and/or methylisothiazolinone (MI) contact allergy from 2009 to 2015. In response, the Thai Ministry of Public Health regulated the use of MCI/MI in cosmetics. OBJECTIVE: To survey the presence of MCI/MI and MI alone, as labelled on cosmetics sold on the Thai market, before and after the ministerial directive. METHODS: The presence of MCI and/or MI in leave-on and rinse-off cosmetics sold on the market, based on the labelling of ingredients in 3445 products, was analysed. RESULTS: Before the implementation date, most leave-on products contained MCI/MI. After the regulations came into force, the only leave-on cosmetic subcategories that complied with the law were facial skin-care, sunscreen and make-up products. MCI/MI and MI alone were found on the labels of both leave-on and rinse-off products, the presence of each varying between product subcategories. CONCLUSIONS: Despite the ministerial regulations restricting their use, MCI and/or MI are still found in cosmetics sold on the Thai market. Dermatologists should be aware of this situation, and counsel patients to avoid products containing MCI and/or MI. PMID- 30426517 TI - Interactions between recreational cannabis use and cognitive function: lessons from functional magnetic resonance imaging. AB - Cannabis use is becoming increasingly popular as a growing number of states pass legislation to legalize cannabis and cannabis-derived products for recreational and/or medical purposes. Given the widespread use of cannabis, it is critical to understand the neural consequences related to cannabis use. In this review, we focus on evidence from functional magnetic resonance imaging studies that document acute and residual alterations in brain function during tasks spanning a variety of cognitive domains: executive function, attention and working memory, memory, motor skills, error monitoring, and reward and affective processing. Although it is clear that cannabis affects brain function, the findings are somewhat inconsistent; variables that potentially affect study outcomes are outlined, including a discussion of the impact of chronological age and age of cannabis onset as well as length of abstinence at the time of assessment, which are important considerations when measuring cannabis use patterns. Inherent differences between recreational/adult cannabis use versus use for medical purposes are also discussed, given their importance to public policy decisions. PMID- 30426518 TI - The Role of Real-Time Elastography in the Differential Diagnosis of Salivary Gland Tumors. AB - OBJECTIVES: The aim of the study was to scrutinize the value of qualitative elastography in the diagnosis of salivary gland masses. METHODS: Sixty patients were enrolled in this prospective study. Patients aged between 1 and 91 years (mean age, 48.8 +/- 20.48) with a salivary gland mass were studied with real-time elastography. All patients were examined by 1 examiner, blinded to all relevant data. On elastography, masses were scored into 4 types according to their stiffness compared to normal tissue. Scores of 3 and 4 were accepted as signs of malignancy. Sensitivity, specificity, and positive and negative predictive value were calculated for elastography in verifying malignancy. RESULTS: Forty-two percent of the masses were located in the parotid, and the rest in submandibular gland. The diameter of the lesions varied between 12 and 60 mm (mean, 24.36 +/- 11.98 mm). Forty-four masses were benign (73%), and among them the majority were inflammatory lesions (31 of 60; 51.7%). There were 16 malignant lesions (27%). On elastography, not only all malignant lesions but 15 benign lesions were scored as 3 to 4. All masses scored as 1 to 2 were benign. Sensitivity was 100%; specificity, 66%; positive predictive value, 52%; and negative predictive value, 100%. When only Score 4 lesions were accepted as malignant, these values became 75%, 77%, 55%, and 90%, respectively. CONCLUSIONS: Elastography alone cannot be used to discriminate malignant from benign in the evaluation of salivary gland lesions. However, with its high negative predictive value, it may be used as an adjunct tool to increase the diagnostic value of ultrasonography. PMID- 30426519 TI - SNP panel development for genetic management of wild and domesticated white bass (Morone chrysops). AB - White bass (Morone chrysops), striped bass and their interspecific hybrid are important game fishes, whereas the hybrid striped bass is an important aquaculture species in the US. Numerous state, federal and private hatcheries, therefore, rear these species for stocking purposes as well as for food fish. Although striped bass populations (both wild and domesticated) have been extensively evaluated, relatively little effort has been directed toward the study and improvement of white bass. In this study, we developed SNP resources to examine the genetic relationships among a long-term domesticated white bass line and five potential founder stocks for selective breeding collected from drainages in Arkansas, Texas and Alabama. Using genotyping-by-sequencing, we generated 13 872 genome-wide SNP loci across the six populations. Stringent filtering of SNP calling parameters identified 426 informative SNP loci. Population genetic and structure analyses using these loci revealed only moderate genetic differentiation between populations (global Fst = 0.083) and indicated two major genetic clusters. A final 57-SNP assay was successfully designed and validated using the MassARRAY system. The developed SNP panel assigned 96 additional genotyped individuals to their population of origin with 100% accuracy. The SNP resources developed in this study should facilitate ongoing efforts in selective breeding and conservation of white bass. PMID- 30426520 TI - Shear Wave Elastography of the Lumbar Multifidus Muscle in Patients With Unilateral Lumbar Disk Herniation. AB - OBJECTIVES: To assess lumbar multifidus muscle stiffness in patients with unilateral lumbar disk herniation (LDH) causing nerve root compression using shear wave elastography (SWE). METHODS: Thirty-three patients with unilateral subarticular LDH (L3-L4, L4-L5, and L5-S1) causing nerve root compression, diagnosed by magnetic resonance imaging, were enrolled in the study. Exclusion criteria were bilateral or multilevel LDH confirmed on magnetic resonance imaging, bilateral leg symptoms, and patients with a history of any spinal operation, malignancy, trauma, infection, spondylolisthesis, severe lateral recess stenosis, spinal canal stenosis, and substantial comorbidities. Two observers separately evaluated the multifidus muscle using SWE. Shear wave elastographic examinations of the muscle were performed slightly below the herniation using the spinous process of the vertebra as a landmark. The stiffness of the muscle between affected and normal sides was compared. Moreover, the correlation between the stiffness and duration of the symptoms and the correlation between the stiffness and severity of the nerve compression were also calculated. RESULTS: The mean stiffness values of the multifidus muscle on the affected side (mean +/- SD: observer 1, 14.08 +/- 3.57 kPa; observer 2, 13.70 +/- 4.05 kPa) were significantly lower compared to the contralateral side (observer 1, 18.81 +/- 3.95 kPa; observer 2, 18.28 +/- 4.12 kPa; P < .001). The muscle stiffness had a moderate negative correlation with the duration of the symptoms and the severity of the nerve compression (observer 1, r = -0.535; observer 2, r = -0.458; P < .001). CONCLUSIONS: The multifidus muscle on the ipsilateral side of the LDH showed reduced stiffness values, and stiffness values were negatively correlated with the disease duration and severity of the nerve compression. Further studies might reveal the potential role of SWE of the multifidus muscle in determining clinical outcomes and assessing effectiveness treatment in patients with LDH. PMID- 30426521 TI - Atlantic salmon (Salmo salar L.) genetics in the 21st century: taking leaps forward in aquaculture and biological understanding. AB - Atlantic salmon (Salmo salar L.) is among the most iconic and economically important fish species and was the first member of Salmonidae to have a high quality reference genome assembly published. Advances in genomics have become increasingly central to the genetic improvement of farmed Atlantic salmon as well as conservation of wild salmon stocks. The salmon genome has also been pivotal in shaping our understanding of the evolutionary and functional consequences arising from an ancestral whole-genome duplication event characterising all Salmonidae members. Here, we provide a review of the current status of Atlantic salmon genetics and genomics, focussed on progress made from genome-wide research aimed at improving aquaculture production and enhancing understanding of salmonid ecology, physiology and evolution. We present our views on the future direction of salmon genomics, including the role of emerging technologies (e.g. genome editing) in elucidating genetic features that underpin functional variation in traits of commercial and evolutionary importance. PMID- 30426522 TI - Red/blue light ratio strongly affects steady-state photosynthesis, but hardly affects photosynthetic induction in tomato (Solanum lycopersicum). AB - Plants are often subjected to rapidly alternating light intensity and quality. While both short- and long-term changes in red and blue light affect leaf photosynthesis, their impact on dynamic photosynthesis is not well documented. It was tested how dynamic and steady-state photosynthetic traits were affected by red/blue ratios, either during growth or during measurements, in tomato leaves. Four red/blue ratios were used: monochromatic red (R100 ), monochromatic blue (B100 ), a red/blue light ratio of 9:1 (R90 B10 ) and a red/blue light ratio of 7:3 (R70 B30 ). R100 grown leaves showed decreased photosynthetic capacity (maximum rates of light-saturated photosynthesis, carboxylation, electron transport and triose phosphate use), leaf thickness and nitrogen concentrations. Acclimation to various red/blue ratios had limited effects on photosynthetic induction in dark-adapted leaves. B100 -grown leaves had a approximately 15% larger initial NPQ transient than the other treatments, which may be beneficial for photoprotection under fluctuating light. B100 -grown leaves also showed faster stomatal closure when exposed to low light intensity, which likely resulted from smaller stomata and higher stomatal density. When measured under different red/blue ratios, stomatal opening rate and photosynthetic induction rate were hardly accelerated by increased fractions of blue light in both growth chamber-grown leaves and greenhouse-grown leaves. However, steady-state photosynthesis rate 30 min after photosynthetic induction was strongly reduced in leaves exposed to B100 during the measurement. We conclude that varying red/blue light ratios during growth and measurement strongly affects steady-state photosynthesis, but has limited effects on photosynthetic induction rate. PMID- 30426523 TI - Immediate hypersensitivity to p-phenylenediamine. PMID- 30426524 TI - Pattern of cerebral blood flow and the interrelationship of vascular parameters of transcranial Doppler imaging in children with sickle cell disease. AB - PURPOSE: We assessed the pattern of cerebral blood flow and the relationship between the different transcranial Doppler imaging (TCDI) vascular parameters in children with sickle cell disease (SCD). METHODS: Forty-three SCD pediatric patients with a stable condition (21 HbSS, 19 HbSbeta0 Thal, and 3 HbSD), aged 10.1 +/- 3.9 years were studied. A control group of 26 with age and sex-matched, were included for comparison. TCDI scanning was carried out using a phased array transducer of 1-3 MHz through the trans-temporal window. Peak systolic velocity (PSV), end diastolic velocity (EDV), time-averaged mean of the maximum velocity (TAMxV), pulsatility index (PI), and resistive index (RI) were in the anterior circle of Willis vessels and posterior cerebral artery. RESULTS: The highest mean +/- SD values for the middle cerebral artery PSV, EDV, TAMxV, PI, and RI were 130.30 + 26.5, 145.0 +/- 21.9; 58.60 + 13.70, 67.90 +/- 13.3; 84.90 + 14.50, 94.80 +/- 17.9; 0.95 + 0.20, 0.80 +/- 0.20; 0.58 + 0.09, 0.50 +/- 0.10 in the control and SCD groups, respectively. Independent t-test showed significant difference (P < .05) for all vascular parameters in all vessels in each side between both groups. There was a positive significant correlation between TAMxV, PSV, and EDV (P = .001, r = .96), and a negative significant correlation between TAMxV and PI in the SCD group (P = .001, r = -.46) but not in the control group (P > .05, r = -.62). CONCLUSIONS: There was a direct relationship between TAMxV and PSV and EDV, and an inverse relationship between TAMxV and PI in a group of SCD patients with normal TCDI values. PMID- 30426525 TI - Evaluating the effect of electronic monitoring and feedback on hand cream use in healthcare workers: Healthy Hands Project. AB - BACKGROUND: Healthcare workers (HCWs) are at high risk of developing hand dermatitis (HD). Current guidelines on HD prevention recommend the use of emollients; however, in practice, adherence is poor. OBJECTIVE: To assess whether the provision of creams, electronic monitoring and feedback on cream consumption can improve skin care in HCWs. METHODS: A cluster randomized controlled trial was conducted on 19 academic hospital wards, including 501 HCWs, for 12 months. The intervention wards (n = 9; 285 HCWs) were provided with hand cream dispensers equipped with an electronic system to monitor use, which was regularly communicated to the HCWs by the use of posters. The process outcomes were self reported cream consumption in both groups, and electronically measured consumption per ward in the intervention group (IG) vs the control group (CG). RESULTS: Self-reported cream use at follow-up was significantly higher in the IG than in the CG, before (odds ratio [OR] 2.27; 95%CI: 1.29-3.97; P = 0.004) and during (OR 3.30; 95%CI: 1.80-6.06, P < 0.001) the shift, whereas at baseline there was no difference between the groups. In the IG, electronically measured cream use was, on average, 0.4 events per shift per HCW. CONCLUSION: The intervention improved hand cream use, and may therefore be considered as a practical strategy to promote skin care in HCWs. Notwithstanding this, the application frequency remained lower than recommended in the present study and current guidelines. PMID- 30426526 TI - Enantioselective LC-ESI-MS/MS determination of dropropizine enantiomers in rat plasma and application to a pharmacokinetic study. AB - We developed and validated a simple, sensitive, selective and reliable LC-MS/MS ESI method for direct quantitation of dropropizine enantiomers namely levodropropizine (LDP) and dextrodropropizine (DDP) in rat plasma without a need of derivatization as per regulatory guideline. Dropropizine enantiomers and carbamazepine (internal standard; IS) were extracted from 50 MUL rat plasma using ethyl acetate. LDP and DDP resolved with good baseline separation (Rs = 4.45) on a Chiralpak IG-3 column. The mobile phase consisted of methanol with 0.05% diethylamine pumped at a flow rate of 0.5 mL/min. Detection and quantitation was done by MRM mode following the transitions: m/z 237 -> 160 and 237 -> 194 for dropropizine enantiomers and the IS, respectively in the positive ionization mode. Propose method provided accurate and reproducible results over the linearity range of 3.23-2022 ng/mL for each enantiomer. The intra- and inter-day precisions were in the range of 3.38-13.6 and 5.11-13.8; 4.19-11.8 and 8.89 10.1for LDP and DDP, respectively. Both LDP and DDP were found to be stable under different stability conditions. The method was successfully used in a stereoselective pharmacokinetic study of dropropizine enantiomers in rats post oral administration of racemate dropropizine at 100 mg/Kg. The pharmacokinetic results indicate that the disposition of dropropizine enantiomers is not stereoselective and chiral inversion does not occur in rats. PMID- 30426527 TI - Selective ablation of atrial ganglionated plexus attenuates vasovagal reflex in a canine model. AB - BACKGROUND: Atrial ganglionated plexus (GP) ablation was proved to have therapeutic effects on vasovagal syncope. The study aimed to investigate whether selective ablation of only right anterior GP (ARGP) and right inferior GP (IRGP) was effective in a canine model of vasovagal syncope. METHODS: Seventeen mongrel dogs were divided into control (N = 10) and ablation group (N = 7). Bilateral thoracotomy was performed at the fourth intercostal space and ARGP and IRGP were ablated in the ablation group. A bolus of veratridine (15 ug/kg) was injected into the left atrium to induce vasovagal reflex. Surface electrocardiogram and blood pressure (BP) were continuously monitored. Heart rate (HR) variability was calculated to represent cardiac autonomic tone. RESULTS: Veratridine injection induced vasovagal reflex in all dogs. HR decreased from 149 +/- 17 to 89 +/- 33 beats/min (P < 0.001) in the control group, while in the ablation group HR decreased from 141 +/- 35 to 125 +/- 34 beats/min (P = 0.032). The postveratridine HR in the ablation group was significantly higher than that in the control group (P = 0.045). A significantly less intense HR decrease was observed in the ablation group compared with control (-17 +/- 16 vs -61 +/- 34 beats/min, P = 0.006). Significant BP decreases were induced in both the groups (all P < 0.01), while no evident differences in postveratridine BP and the extent of BP decreases were found between the groups. HR variability revealed significant decrease in cardiac vagal tone after ablation [high-frequency power, 0.50 (0.17-1.05) vs 6.28 (0.68-8.99) ms2 , P = 0.005]. CONCLUSIONS: Selective ablation of ARGP + IRGP weakened cardiac parasympathetic control and significantly attenuated the cardioinhibitory response in an animal model of vasovagal reflex. This ablation strategy might be effective for vasovagal syncope with evident cardioinhibitory response. PMID- 30426528 TI - Selective ablation of atrial ganglionated plexus as a therapeutic option for vasovagal syncope. PMID- 30426530 TI - Oxidative stress in cervical cancer pathogenesis and resistance to therapy. AB - Cervical cancer (CC) is one of the most common cancers among females, and it is most notable in developing countries. The exact etiology of CC is poorly understood; but, smoking, oral contraceptives, immunosuppression, and infection with human papillomavirus (HPV) may increase the risk of CC. There is also an association between CC and oxidative stress. Oxidative stress is caused by a disturbed oxidant-antioxidant balance in favor of the former, leading to an excessive generation of free radicals, particularly reactive oxygen species (ROS), and subsequently to biological damages. Thus, redox enzymatic and nonenzymatic regulators are required to maintain the redox homeostasis. Dysregulated antioxidants system and the pathogenic role of oxidative stress in CC have been investigated in several clinical and preclinical studies. In this study, we reviewed studies that have addressed the cross-talk between oxidative stress and CC pathogenesis and resistance to therapy. PMID- 30426529 TI - A simplified radiosynthesis of [18 F]MK-6240 for tau PET imaging. AB - [18 F]MK-6240 (6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine) is a highly selective PET radiotracer for the in vivo imaging of neurofibrillary tangles (NFTs). [18 F]MK-6240 was synthesized in one step from its bis-Boc protected precursor N-[(tert-butoxy)carbonyl]-N-(6-nitro-3-[1H-pyrrolo[2,3 c]pyridin-1-yl]isoquinolin-5-yl) carbamate in DMSO using [18 F] fluoride with TEA HCO3 with step-wise heating up to 150 degrees C, resulting in an isolated radiochemical yield of 9.8% +/- 1.8% (n = 3) calculated from the end of bombardment (5.2% +/- 1.0% calculated from the end of synthesis). This new synthetic approach eliminates the acidic deprotection of the bis-Boc 18 F-labeled intermediate, which reduces the number of operations necessary for the synthesis as well as losses which occur during deprotection and neutralization of the crude product mixture prior to the HPLC purification. The synthesis was performed automatically with a single-use cassette on an IBA Synthera+ synthesis module. This synthesis method affords the radioligand with a reliable radiochemical yield, high radiochemical purity, and a high molar activity. [18 F]MK-6240 synthesized with this method has been regularly (n > 60) used in our ongoing human and animal PET imaging studies. PMID- 30426531 TI - Investigating the role of CRIPTO-1 (TDGF-1) in glioblastoma multiforme U87 cell line. AB - Cripto-1 has been implicated in a number of human cancers. Although there is high potential for a role of Cripto-1 in glioblastoma multiforme (GBM) pathogenesis and progression, few studies have tried to define its role in GBM. These studies were limited in that Cripto-1 expression was not studied in detail in relation to markers of cancer initiation and progression. Therefore, these correlative studies allowed limited interpretation of Criptos-1's effect on the various aspects of GBM development using the U87 GBM cell line. In this study, we sought to delineate the role of Cripto-1 in facilitating pathogenesis, stemness, proliferation, invasion, migration and angiogenesis in GBM. Our findings show that upon overexpressing Cripto-1 in U87 GBM cells, the stemness markers Nanog, Oct4, Sox2, and CD44 increased expression. Similarly, an increase in Ki67 was observed demonstrating Cripto-1's potential to induce cellular proliferation. Likewise, we report a novel finding that increased expression of the markers of migration and invasion, Vimentin and Twist, correlated with upregulation of Cripto-1. Moreover, Cripto-1 exposure led to VEGFR-2 overexpression along with higher tube formation under conditions promoting endothelial growth. Taken together our results support a role for Cripto-1 in the initiation, development, progression, and maintenance of GBM pathogenesis. The data presented here are also consistent with a role for Cripto-1 in the re-growth and invasive growth in GBM. This highlights its potential use as a predictive and diagnostic marker in GBM as well as a therapeutic target. PMID- 30426532 TI - FOXD2-AS1 correlates with the malignant status and regulates cell proliferation, migration, and invasion in cutaneous melanoma. AB - Long noncoding RNA (lncRNA) FOXD2 adjacent opposite strand RNA 1 (FOXD2-AS1) has been shown to be dysregulated in several types of human cancer. However, the role of FOXD2-AS1 in cutaneous melanoma was still unclear. In our study, FOXD2-AS1 expression has been found to be upregulated in cutaneous melanoma tissue specimens and cell lines compared with that in normal tissue specimens and normal human epidermal melanocyte, respectively. Furthermore, high expression of FOXD2 AS1 was obviously correlated with deep Breslow thickness, present ulceration, high Clark level and distant metastasis in cutaneous melanoma patients. However, there were no statistical associations between FOXD2-AS1 expression and cutaneous melanoma patients' disease-free survival and overall survival. The results of loss-of-function study showed that inhibition of FOXD2-AS1 suppresses cutaneous melanoma cell proliferation, migration and invasion through regulating phospho Akt expression. In conclusion, FOXD2-AS1 is associated with clinical progression in cutaneous melanoma patients, and functions as oncogenic lncRNA in cutaneous melanoma cells. PMID- 30426533 TI - NOTCH1 regulates the proliferation and migration of bladder cancer cells by cooperating with long non-coding RNA HCG18 and microRNA-34c-5p. AB - In recent years, the NOTCH signaling pathway has been gradually studied in human malignancies. Inactivation of the NOTCH signaling pathway was uncovered to be correlated with the carcinogenesis of bladder cancer (BCa). Nevertheless, the specific molecular mechanism of NOTCH1 (one of the core factors of the NOTCH signaling pathway) is not well elucidated in BCa. This study focused on the mechanism by which NOTCH1 affects the biological behaviors of BCa cells. According to the experimental results of quantitative real-time polymerase chain reaction, NOTCH1 was dysregulated in BCa tissues and cell lines. The prognostic value of NOTCH1 for the patients with BCa was determined using the Kaplan-Meier method. Mechanism investigations revealed that NOTCH1 is a target of miR-34c-5p in BCa. Furthermore, microarray analysis was used to find the dysregulated long noncoding RNAs (lncRNA), which can bind with miR-34c-5p. Mechanism experiments further demonstrated the rationality of the HCG18-miR-34c-5p-NOTCH1 pathway. Functional assays were then applied to validate the inhibitory influences of NOTCH1 on the proliferation and migration of BCa cells. Furthermore, the inhibitory effects of NOTCH1 could be affected by miR-34c-5p or lncRNA HCG18. All findings in this study revealed that NOTCH1 suppresses the BCa progression by cooperating with lncRNA HCG18 and miR-34c-5p. PMID- 30426534 TI - Phosphoinositide-specific phospholipase C in normal human liver and in alcohol abuse. AB - The phosphoinositide (PI) signal transduction pathway participates in liver metabolism. Abnormal activity or expression of PI-specific phospholipase C (PLC) enzymes has been described in different liver diseases. We resume the role of the PI metabolism in liver and PLC abnormalities in different liver diseases. Moreover, we present the results of PLC analyses in a normal human liver and an alcohol-damaged liver. PLC enzymes and the expression of the corresponding genes in liver biopsies from individuals deceased for complications of the alcoholic liver disease (ALD) at different stages compared with normal controls (deceased individuals with histologically normal livers without alcohol addiction anamnesis) were analyzed by using immunohistochemistry and molecular biology techniques. The expression panel of PLCs was described in normal and alcohol abuse liver. Our observations suggest that the regulation of PLC expression might be due to posttranscriptional events and that alcohol affects the epigenetic control of PLC expression belonging to PI signaling. We also describe the alternate expression of PLCB1 and PLCH1 genes in liver. Our results corroborate literature data suggesting that PLC enzymes are differently expressed in normal versus pathological liver, playing a role in the histopathogenesis of liver tissue damage. The expression and/or localization of selected PLC isoforms is especially affected in alcohol-related liver tissue histopathology. Our present observations confirm that the modulation of protein synthesis plays a role in the regulation of PLC enzymes. We also suggest that this modulation might act at the transcription level. Further studies are required to investigate related epigenetic mechanisms. PMID- 30426535 TI - Radiolabeling, quality control, biodistribution, and imaging studies of 177 Lu ibandronate. AB - The purposes of this study were as follows: (1) to radiolabel ibandronic acid (IBA, a third-generation bisphosphonate) with 177 Lu, investigating optimal labeling conditions, and (2) to analyze biodistribution and imaging properties of intravenous 177 Lu-ibandronate (177 Lu-IBA) administered in animals. 177 Lu labeled methylene diphosphonate (177 Lu-MDP) served as a comparator agent. Differing proportions of IBA solution and 177 LuCl3 solution were combined to determine an optimal ratio for radiolabeling purposes, varying pH, temperature, and time to establish ideal reactivity conditions. Radiochemical purity of the labeled compounds was then assessed by paper chromatography. In vitro and in vivo stabilities were also measured at specific time intervals. In Kunming mice, biodistributions of 177 Lu-IBA and 177 Lu-MDP and respective agent activities in various organs were monitored by gamma counter, and we performed single photon computed tomography/computed tomography (SPECT/CT) imaging of 177 Lu-IBA in normal New Zealand White rabbits. Radiolabeling yields for 177 Lu-IBA proved to be >97% within 30 minutes at 90 degrees C, and its radiochemical purity ensured stability in vitro and in vivo. Furthermore, we found that 177 Lu-IBA is readily soluble in water, showing higher skeletal uptake than 177 Lu-MDP but lower uptake by liver and spleen. The image quality of 177 Lu-IBA was so clear that even after 6 days, analysis was still feasible. PMID- 30426536 TI - Enhanced Point-of-Care Ultrasound Applications by Integrating Automated Feature Learning Systems Using Deep Learning. AB - Recent applications of artificial intelligence (AI) and deep learning (DL) in health care include enhanced diagnostic imaging modalities to support clinical decisions and improve patients' outcomes. Focused on using automated DL-based systems to improve point-of-care ultrasound (POCUS), we look at DL-based automation as a key field in expanding and improving POCUS applications in various clinical settings. A promising additional value would be the ability to automate training model selections for teaching POCUS to medical trainees and novice sonologists. The diversity of POCUS applications and ultrasound equipment, each requiring specialized AI models and domain expertise, limits the use of DL as a generic solution. In this article, we highlight the most advanced potential applications of AI in POCUS tailored to high-yield models in automated image interpretations, with the premise of improving the accuracy and efficacy of POCUS scans. PMID- 30426538 TI - A note on a naive regression-based test on the validity of an instrumental variable. PMID- 30426539 TI - microRNA-383 regulates cell viability and apoptosis by mediating Wnt/beta-catenin signaling pathway in non-small cell lung cancer. AB - The aim of this study was to investigate the roles of microRNA-383 (miRNA-383) in progression of non-small cell lung cancer (NSCLC) and the potential mechanism. The expressions of miR-383 and Wnt1 protein were detected in lung cancer tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. After the transfection of miR-383 mimics, si-Wnt1 or miR 383+Wnt1, the viability and apoptosis of NSCLC cells were detected by cell counting kit-8 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, respectively. The interaction between miR-383 and Wnt1 was investigated by luciferase activity and Western blot analysis. Cells stably transfected with miR-383 mimics were inoculated into the right axillary of nude mice by subcutaneous injection. The tumor volume and weight were measured, and the expressions of miR-383, Wnt1, beta-catenin, and cyclin D1 were detected by qRT PCR and Western blot analysis. The expression of miR-383 was significantly decreased, and the level of Wnt1 was significantly increased (P < 0.05) in lung cancer tissues and cells. Upregulation of miR-383 or inhibition of Wnt1 expression inhibited the cell viability and induce apoptosis in NSCLC cells. Moreover, Wnt1 was the target gene of miR-383, and its overexpression weakened the regulatory effect of miR-383 on cell viability and apoptosis in NSCLC cells. Besides, the addition of miR-383 decreased the tumor volume and size and inhibited the expressions of Wnt1, beta-catenin, and cyclin D1 at the protein level in nude mice. Collectively, miR-383 induced apoptosis and inhibited cell viability as well as tumorigenic capacity in nude mice via regulating the Wnt/beta-catenin signaling pathway. PMID- 30426537 TI - Programmed cell death protein 4 deficiency suppresses foam cell formation by activating autophagy in advanced glycation end-product low-density lipoprotein induced macrophages. AB - BACKGROUND: Advanced glycation end-product is a modified form of low-density lipoprotein (AGE-LDL) and accelerates atherosclerosis through undefined mechanisms. Programmed cell death protein 4 (PDCD4), a transcriptional regulator, plays an important role in the regulation of autophagy. The aim of the present study was to investigate the role of PDCD4 involved in AGE-LDL-induced foam cell formation. METHODS: The characterization of AGE-LDL was measured by the thiobarbituric assay and agarose gel electrophoresis in vitro. RAW264.7, THP-1 cell line and primary peritoneal macrophages of mice were transfected with shPDCD4 plasmid AGE-LDL-induced foam cell formation was stained by Oil Red, and the levels of autophagy and apoptosis were determined by Western blot analysis. Autophagosome was observed with immunofluorescence microscopy. Mitochondrial membrane potential and autophagic flux were assessed by flow cytometry. RESULTS: AGE modification resulted in significant reduction of absorbance shown by thiobarbituric assay and augmentation of electrophoresis mobility. Further studies suggest that macrophages exposed AGE-LDL triggered autophagy in the early stage of foam cell formation. PDCD4 deficiency enhanced lipoautophagy but inhibited apoptosis and mitochondria dysfunction. Previous studies have been reported that autophagy is an adaptive response might prevent lesional macrophage apoptosis. In our study, we found PDCD4 deficiency attenuated apoptosis and AGE LDL-induced foam cell formation relied on increased autophagy. CONCLUSION: Our data revealed that PDCD4 deficiency can facilitate autophagy and benefit for AGE LDL-induced foam cell formation. PMID- 30426540 TI - circRNAs (hsa_circ_00156, hsa_circ _000224, and hsa_circ _000520) are novel potential biomarkers in hepatocellular carcinoma. AB - Circular RNAs (circRNAs) are a newly validated type of noncoding RNAs recently found to be deregulated in several human cancers. More accurate and specific noninvasive biomarkers are strongly needed for better diagnosis and prognosis of hepatocellular carcinoma (HCC). We performed a bioinformatics analysis to retrieve a novel panel of circRNAs potentially relevant to HCC. We examined their expression in the sera of 68 patients with HCC, 60 patients with chronic hepatitis C, and 36 healthy controls using quantitative polymerase chain reaction. We examined the performance characteristics of the selected circRNA biomarker panel in comparison with alpha-fetoprotein (AFP). In addition, we performed a survival analysis to correlate between their expression levels and patient survival. The circRNAs hsa_circ _00224 and hsa_circ _00520 showed a strong biomarker potential with relatively high sensitivities and specificities compared with AFP. The combined panel including the three circRNAs showed superior performance characteristics relative to those of AFP. The median follow up period was 26 months. hsa_circ_00520 expression has been shown to be associated with relapse-free survival (P < 0.005). circRNAs hsa_circ_00156, hsa_circ_000224, and hsa_circ_000520 are novel potential biomarkers of high sensitivity and specificity, which could potentially be used in the diagnosis of HCC. PMID- 30426541 TI - Noninvasive in vivo Assessment of the Re-endothelialization Process Using Ultrasound Biomicroscopy in the Rat Carotid Artery Balloon Injury Model. AB - OBJECTIVES: Ultrasound biomicroscopy (UBM), or ultra high-frequency ultrasound, is a technique used to assess the anatomy of small research animals. In this study, UBM was used to assess differences in intimal hyperplasia thickness as a surrogate measurement of the re-endothelialization process after carotid artery balloon injury in rats. METHODS: Ultrasound biomicroscopic data from 3 different experiments and rat strains (Sprague Dawley, Wistar, and diabetic Goto-Kakizaki) were analyzed. All animals were subjected to carotid artery balloon injury and examined with UBM (30-70 MHz) 2 and 4 weeks after injury. Re-endothelialization on UBM was defined as the length from the carotid bifurcation to the most distal visible edge of the intimal hyperplasia. En face staining with Evans blue dye was performed at euthanasia 4 weeks after injury, followed by tissue harvesting for histochemical and immunohistochemical evaluations. RESULTS: A significant correlation (Spearman r = 0.63; P < .0001) was identified when comparing all measurements of re-endothelialization obtained from UBM and en face staining. The findings revealed a similar pattern for all rat strains: Sprague Dawley (Spearman r = 0.70; P < .0001), Wistar (Spearman r = 0.36; P < .081), and Goto-Kakizaki (Spearman r = 0.70; P < .05). A Bland-Altman test showed agreement between en face staining and UBM. Immunohistochemical staining confirmed the presence of the endothelium in the areas detected as re-endothelialized by the UBM assessment. CONCLUSIONS: Ultrasound biomicroscopy can be used for repeated in vivo assessment of re-endothelialization after carotid artery balloon injury in rats. PMID- 30426542 TI - Chemerin/ChemR23 axis triggers an inflammatory response in keratinocytes through ROS-sirt1-NF-kappaB signaling. AB - Psoriasis is a chronic disease which carries the emotional and social burden, promotes joint disability and raises comorbidity possibility in patients. Obesity is closely correlated with the occurrence of psoriasis and adipokines produced by adipose tissues were found to be critical culprits. Chemerin is one of them and its expression was increased in patients with psoriatic arthritis. In our hypothesis, chemerin might act on keratinocytes and promote an inflammatory response, which plays an essential role in psoriatic epidermis. To validate our hypothesis, HaCaT cells and primary human keratinocytes were treated with chemerin (5, 10, and 20 ng/mL for 24 hours). Enzyme-linked immunosorbent assay (ELISA) was used to determine the secretion of inflammatory factors. Nuclear factor-kappaB (NF-kappaB) activation and p65 acetylation were evaluated by Western blot analysis. The expression and activity of sirtuin 1 (sirt1), a deacetylase act on p65, were also analyzed. The results showed that chemerin prompted inflammatory factors secretion, NF-kappaB activation and p65 acetylation through chemerin receptor 23 receptor. Chemerin constrained the expression and deacetylase activity of sirt1 through augment of reactive oxygen species (ROS) production. Additionally, chemerin exacerbated psoriasiform dermatitis in imiquimod-treated mice model. In conclusion, chemerin can seduce inflammatory response and promote NF-kappaB activation through inhibition of sirt1 activity by ROS production. PMID- 30426543 TI - Cepharanthine suppresses osteoclast formation by modulating the nuclear factor kappaB and nuclear factor of activated T-cell signaling pathways. AB - The increased activation of osteoclasts is the major manifestation of several lytic bone diseases, including osteoporosis, rheumatoid arthritis, aseptic loosening of orthopedic implants, Paget disease and malignant bone diseases. One important bone-protective therapy in these diseases focuses on the inhibition of osteoclast differentiation and resorptive function. Given that the deleterious side-effects of currently available drugs, it is beneficial to search for effective and safe medications from natural compounds. Cepharanthine (CEP) is a compound extracted from Stephania japonica and has been found to have antioxidant and anti-inflammatory effects. In this study, we found that CEP inhibited receptor activator of nuclear factor-kappaB (NF-kappaB) ligand (RANKL)-induced osteoclast formation and bone-resorbing activities using osteoclastogenesis and bone resorption assay. By polymerase chain reaction, we also found that CEP inhibited the expression of osteoclast-differentiation marker genes including Ctsk, Calcr, Atp6v0d2, Mmp9 and Nfatc1. Mechanistic analyses including Western blot and luciferase reporter assay revealed that CEP inhibited RANKL-induced activation of NF-kappaB and nuclear factor of activated T-cell, which are essential for the formation of osteoclast. Collectively, these data suggested that CEP can potentially be used as an alternative therapy for preventing or treating osteolytic diseases. PMID- 30426544 TI - When I say... moral distress as a teaching point. PMID- 30426545 TI - Perspectives of parents and nurses on the content validity of the Family Empowerment Scale for parents of children with a chronic condition: a mixed methods study. AB - BACKGROUND: Insight into parental empowerment is important to understanding the impact of healthcare policy and to supporting and strengthening parents in the care of their child. The Family Empowerment Scale (FES) is a valid 24-item instrument that measures parental empowerment. It was originally developed for parents of children with emotional disabilities. It has been translated from English into Dutch. Before using the translated FES in another context, the aim of this study was to assess the content validity of the Dutch FES in the context of children with a chronic condition in a children's hospital, according to parents and nurses. METHOD: This content validity study has a convergent, mixed methods design. The content validity index was used to examine the relevance, according to 22 parents and 12 nurses quantitatively, on a scale and item level. The qualitative part assessed the comprehensiveness and comprehension of the FES through cognitive interviewing with eight parents and four nurses. The results of both analyses were converged to determine content validity. RESULTS: The scale content validity index was 0.88; three items scored < 0.78 on the item level. For 10 (of 24) items, issues were noticed about the tone and clarity of wording. Participants considered the FES to be not only an instrument of research but also an instrument that could be used to give insight into the personal degree of parental empowerment. CONCLUSION: The content validity of the Dutch FES for parents of children with a chronic condition can be considered sufficient. Resolving some minor translation issues in some of the items is advised. The FES can be used in further research to examine the value of the FES in healthcare services, aiming to support the needs of parents and to increase their empowerment. PMID- 30426546 TI - Characterization of Breast Microcalcifications Using a New Ultrasound Image Processing Technique. AB - OBJECTIVES: To evaluate a new commercial image-processing technique (MicroPure; Toshiba America Medical Systems, Tustin, CA) for detection and characterization of breast microcalcifications in patients undergoing stereotactic or ultrasound guided biopsies using mammography as the reference standard. METHODS: One hundred female patients, with a total of 104 lesions, scheduled for an image-guided biopsy of an area with breast microcalcifications (identified on a prior mammogram) underwent MicroPure examinations of the breast using an Aplio XG scanner (Toshiba America Medical Systems) with a broad-bandwidth linear array. MicroPure combines nonlinear imaging and speckle suppression to mark suspected calcifications as white spots in a blue overlay image. Four independent and blinded readers (2 radiologists and 2 physicists) analyzed 208 digital clips consisting of dual grayscale ultrasound and MicroPure imaging, counting the number of microcalcifications seen with MicroPure. The observers also assessed the level of suspicion on a qualitative, visual analog, 6-point scale from 0 (no findings) over 1 (benign) to 5 (malignant). RESULTS: The mean number of microcalcifications +/- SD seen was 6.3 +/- 3.5, whereas mammography saw 28.9 +/- 24.6 (P = .66). When the MicroPure level of suspicion scores were compared with pathologic results using a receiver operating characteristic curve analysis, the areas under the curve ranged from 0.54 to 0.59. Nonetheless, malignant cases were seen to have significantly more microcalcifications than benign cases (mean number of microcalcifications, 6.9 +/- 5.1 versus 5.3 +/- 3.7; P = .02). CONCLUSIONS: MicroPure can be used to identify areas with breast microcalcifications but cannot effectively characterize such areas. Instead, MicroPure may represent a new imaging method for guiding a biopsy to areas of microcalcifications. PMID- 30426547 TI - MKL1/miR34a/FOXP3 axis regulates cell proliferation in gastric cancer. AB - Megakaryoblastic leukemia 1 (MKL1) was closely related to the pathogenesis of various human malignant cancers. MiR34a was reported to be closely related to cancer cell proliferation. Forkhead box protein 3 (FOXP3) was a transcription factor that played a different role in different cancer types. CDK6 was involved in cell cycle progression and was upregulated in several types of cancers. The present study investigated the effects of MKL1/miR34a/FOXP3 axis on cell proliferation in MGC803 gastric cancer cells. Our results demonstrated that overexpression of MKL1 promoted proliferation of MGC80-3 cells, MKL1 directly binding to the promoter of CDK6 to increase its expression. Knockdown of FOXP3 promoted proliferation of MGC80-3 cells and MKL1 inhibited the expression of FOXP3 via miR-34a. The finding can contribute to elucidating the regulatory mechanism involved in the cell cycle progression of gastric cancer cells and may aid in screening potential gene targets for the biological therapy of gastric cancer. PMID- 30426548 TI - Knockdown GREM1 suppresses cell growth, angiogenesis, and epithelial-mesenchymal transition in colon cancer. AB - Gremlin 1 (GREM1), as a bone morphogenetic protein (BMP) antagonist and vascular endothelial growth factor receptor-2 (VEGFR2) novel agonist, has been confirmed as overexpressed in colorectal cancer (CRC) tissues but its role in carcinogenesis remains unclear. Here we reported that the GREM1 expression in mesenchymal-like colon cancer cells (SW620 and SW480) was significantly higher than that of epithelial-like colon cancer cells (Caco-2, HTC116, and HT29) and normal colon cell. Simultaneously, we analyzed two series of CRC transcriptomes from Gene Expression Omnibus (GEO) databases and found the great majority of primary CRC tissues expressed high level of GREM1 messenger RNA (mRNA) compared with adjacent normal tissues, and that the GREM1 mRNA expression is correlated with low histological grade development and stage 2 to 3 metastatic recurrence in CRC based on a data analysis of 104 different stage CRC tissue from the GEO databases. Functional studies showed that GREM1 silencing by short hairpin RNA (shRNA) significantly inhibited CRC cells proliferation, migration, the formation of vascular endothelial growth factor (VEGF)-induced capillary structure of human umbilical vein endothelial cells (HUVECs), and epithelial-mesenchymal transition in colon cancer cells by repressing phosphorylation levels of BMP downstream signal Smad1, vascular endothelial growth factor (VEGF) downstream signal matrix metallopeptidase 2 (MMP2), and metastasis-related factor C-X-C motif chemokine ligand 12 (CXCL12) expression. In addition, shGREM1 combined with VEGF inhibitor BAW2881 displayed more effective antiangiogenesis to inhibit the tube formation of HUVEC. Hence, these experiments demonstrated that GREM1 is involved in CRC development and procession and provide a new idea for CRC diagnosis, resistance therapy, and prognosis. PMID- 30426549 TI - The role of tumor suppressor of resveratrol and prednisolone by downregulation of YKL-40 expression in CCRF-CEM cell line. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is characterized by excessive accumulation of lymphoblast and progenitors. Leukemia is the most common cancer in children and ALL is the most common subtype. Many studies have shown that the YKL-40 gene is one of the most widely expressed genes in tumors, including leukemia, but not in healthy blood cells. Clinical studies have shown that serum YKL-40 levels have a positive correlation with tumor expansion, in addition to being a prognostic agent independent of a short relapse-free interval, as well as a brief overall survival in patients with various cancers. The previous study shows that YKL-40 is closely related to the degree of pathology or degree of human leukemia pathology and plays an important role in cell proliferation. Hence, the YKL-40 can be an attractive target in designing anticancer therapies. METHODS: CCRF-CEM cells were treated with resveratrol and prednisolone. For analysis of YKL-40 expression changes under medication, real-time polymerase chain reaction (PCR) and Western blot techniques were used at resonating intervals of 24 and 48 hours. RESULTS: The effect of 15, 50, and 100 MUM resveratrol and 700 MUM of prednisolone on CCRF-CEM cells reduced YKL-40. The YKL 40 gene was quantitatively measured using RT-PCR. The Western blot method was used to evaluate changes in the expression of YKL-40 protein. CONCLUSION: In this study, we first evaluated YKL-40 expression and resveratrol and prednisolone effect on YKL-40 in ALL. This finding supports the idea of targeting YKL-40 as a new drug treatment of ALL and extends the use of resveratrol in antileukemia research. PMID- 30426550 TI - A rare complication of acute myocardial infarction: Intra-myocardial dissecting hematoma. AB - A rare and unusual form of myocardial rupture that can complicate acute myocardial infarction is intra-myocardial dissecting hematoma (IDH). Reports in the literature describing this entity are limited to case reports or series. The diagnosis prior to the advent of noninvasive imaging was at autopsy. We present a case of IDH occurring after acute anterior wall myocardial infarction that terminated fatally preceded by a hemodynamically unstable incessant ventricular tachycardia. PMID- 30426551 TI - Efferocytosis capacities of blood monocyte-derived macrophages in Systemic sclerosis. AB - A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of auto-immunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte-derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 + 3.0; n=21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 + 3.0; n=31; P < 0.001). In comparison with HD, SSc MDM exhibited a down-regulated expression of SR-B1, SR-A1 and Integrin beta5. In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of Integrin beta5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder. This article is protected by copyright. All rights reserved. PMID- 30426552 TI - Gene therapy by lentivirus-mediated RNA interference targeting extracellular regulated kinase alleviates neuropathic pain in vivo. AB - BACKGROUNDS: Neuropathic pain is an abnormal pain, which is related to the activation of extracellular-regulated kinase (ERK) signaling. This study was to investigate the effects of ERK knockdown via lentivirus-mediated RNA interference on allodynia in rats with chronic compression of the dorsal root ganglia (DRG) and to uncover the potential mechanisms. METHODS: The model of chronic compression of the dorsal root ganglia (CCD) was established in rats by surgery. Gene silence was induced by injecting rats with lentivirus expressing ERK short hairpin RNA (shRNA). Behavioral test was performed by calculating paw withdrawal mechanical threshold (PWMT) and thermal paw withdrawal latency (TPWL). RESULTS: We firstly generated lentivirus expressing ERK shRNA to downregulate ERK gene expression both in vitro and in vivo by using Western blot analysis and quantitative reverse transcription polymerase chain reaction. In CCD, ERK mRNA, and protein levels in DRG neurons were dramatically increased, accompanied with decreased PWMT and TPWL. Lentivirus-mediated RNA interference decreased ERK gene expression in DRG neurons and normalized the PWMT and TPWL in CCD rats, but not in rats infected with lentivirus expressing negative control shRNA. Further, calcium responses of DRG neurons to the hypotonic solution and 4alpha-phorbol 12,13-didecanoate were enhanced in CCD rats, which were suppressed by lentivirus mediated ERK gene silence. Finally, the levels of transient receptor potential vanilloid 4 gene expressions in DRG neurons and L4 to L5 spinal cord isolated from CCD rats were dramatically upregulated, which were reversed by lentivirus mediated ERK gene knockdown. CONCLUSION: Lentivirus-mediated RNA interference (RNAi) silencing targeting ERK might reverse CCD-induced neuropathic pain in rats through transient receptor potential vanilloid 4. PMID- 30426553 TI - Carbohydrate restriction for glycaemic control in Type 2 diabetes: a systematic review and meta-analysis. AB - AIM: To conduct a systematic review and meta-analysis to evaluate the effect of carbohydrate restriction on glycaemic control in Type 2 diabetes. METHODS: We searched Medline, EMBASE and CINAHL for the period between 1976 and April 2018. We included randomized controlled trials comparing carbohydrate restriction with a control diet which aimed to maintain or increase carbohydrate intake, and that reported HbA1c as an outcome and reported the amount of carbohydrate consumed during or at the end of the study, with outcomes reported at >=3 months. RESULTS: We identified 1402 randomized controlled trials, 25 of which met the inclusion criteria, incorporating 2132 participants for the main outcome. Definitions of low carbohydrate varied among the studies. The pooled effect estimate from meta analysis was a weighted mean difference of -0.09% [95% CI -0.27, 0.08 (P = 0.30); I2 72% (P <0.001)], suggesting no effect on HbA1c of restricting the quantity of carbohydrate. A subgroup analysis of diets containing 50-130 g carbohydrate resulted in a pooled effect estimate of -0.49% [95% CI -0.75, -0.23 (P <0.001); I2 0% (P = 0.56)], suggesting a clinically and statistically significant effect on HbA1c in favour of low-carbohydrate diets in studies of <=6 months' duration. CONCLUSIONS: There was no overall pooled effect on HbA1c in favour of restricting carbohydrate; however, restriction of carbohydrate to 50-130 g per day had beneficial effects on HbA1c in trials up to 6 months. Future randomized controlled trials should be of >12 months' duration, assess pre-study carbohydrate intake, use recognized definitions of low-carbohydrate diets and examine reasons for non-concordance in greater detail. This article is protected by copyright. All rights reserved. PMID- 30426555 TI - Localized constrictive pericarditis due to an intrapericardial myxoma. PMID- 30426554 TI - Disentangling the effects of high permittivity materials on signal optimization and sample noise reduction via ideal current patterns. AB - PURPOSE: To investigate how high-permittivity materials (HPMs) can improve SNR when placed between MR detectors and the imaged body. METHODS: We used a simulation framework based on dyadic Green's functions to calculate the electromagnetic field inside a uniform dielectric sphere at 7 Tesla, with and without a surrounding layer of HPM. SNR-optimizing (ideal) current patterns were expressed as the sum of signal-optimizing (signal-only) current patterns and dark mode current patterns that minimize sample noise while contributing nothing to signal. We investigated how HPM affects the shape and amplitude of these current patterns, sample noise, and array SNR. RESULTS: Ideal and signal-only current patterns were identical for a central voxel. HPMs introduced a phase shift into these patterns, compensating for signal propagation delay in the HPMs. For an intermediate location within the sphere, dark mode current patterns were present and illustrated the mechanisms by which HPMs can reduce sample noise. High amplitude signal-only current patterns were observed for HPM configurations that shield the electromagnetic field from the sample. For coil arrays, these configurations corresponded to poor SNR in deep regions but resulted in large SNR gains near the surface due to enhanced fields in the vicinity of the HPM. For very high relative permittivity values, HPM thicknesses corresponding to even multiples of lambda/4 resulted in coil SNR gains throughout the sample. CONCLUSION: HPMs affect both signal sensitivity and sample noise. Lower amplitude signal-only optimal currents corresponded to higher array SNR performance and could guide the design of coils integrated with HPM. PMID- 30426556 TI - Prohedonic properties of gamma-hydroxybutyrate are associated with changes in limbic resting-state functional connectivity. AB - OBJECTIVE: Gamma-hydroxybutyrate (GHB) is an endogenous GHB-/GABA-B receptor agonist and a narcolepsy treatment. However, GHB is also abused for its prohedonic effects. On a neuronal level, it was shown that GHB increases regional cerebral blood flow in limbic areas such as the right anterior insula (rAI) and the anterior cingulate cortex (ACC). We aimed to further explore the association between the subjective and neuronal signatures of GHB. METHOD: We assessed subjective effects and resting-state functional connectivity (rsFC) of an rAI- and an ACC-seed in 19 healthy male subjects after GHB (35 mg/kg p.o.) using a placebo-controlled, double-blind, randomized, cross-over functional magnet resonance imaging design. RESULTS: GHB increased subjective ratings for euphoria (p < 0.001) and sexual arousal (p < 0.01). Moreover, GHB increased rAI-rsFC to the right thalamus and the superior frontal gyrus and decreased ACC-rsFC to the bilateral paracentral lobule (all p < 0.05, cluster corrected). Moreover, GHB induced euphoria was associated with rAI-rsFC to the superior frontal gyrus (p < 0.05, uncorrected). CONCLUSIONS: GHB induces prohedonic effects such as euphoria and sexual arousal and in parallel modulates limbic rsFC with areas linked to regulation of mood, cognitive control, and sexual experience. These results further elucidate the drug's effects in neuropsychiatric disorders and as drug of abuse. PMID- 30426557 TI - Health care purchasing in Kenya: Experiences of health care providers with capitation and fee-for-service provider payment mechanisms. AB - BACKGROUND: Provider payment mechanisms (PPMs) play a critical role in universal health coverage due to the incentives they create for health care providers to deliver needed services, quality, and efficiency. We set out to explore public, private, and faith-based providers' experiences with capitation and fee-for service in Kenya and identified attributes of PPMs that providers considered important. METHODS: We conducted a qualitative study in two counties in Kenya. Data were collected using semistructured interviews with 29 management team members in six health providers accredited by the National Hospital Insurance Fund (NHIF). RESULTS: Capitation and fee-for-service payments from the NHIF and private insurers were reported as good revenue sources as they contributed to providers' overall income. The expected fee-for-service payment amounts from NHIF and private insurers were predictable while capitation funds from NHIF were not because providers did not have information on the number of enrolees in their capitation pool. Moreover, capitation payment rates were perceived as inadequate. Capitation and fee-for-service payments from NHIF and private insurers were disbursed late. Finally, public providers had lost their autonomy to access and utilise capitation and fee-for-service payments from the NHIF. CONCLUSION: Through their experiences, health care providers revealed characteristics of PPMs that they considered important. PMID- 30426558 TI - Simultaneous NODDI and GFA parameter map generation from subsampled q-space imaging using deep learning. AB - PURPOSE: To develop a robust multidimensional deep-learning based method to simultaneously generate accurate neurite orientation dispersion and density imaging (NODDI) and generalized fractional anisotropy (GFA) parameter maps from undersampled q-space datasets for use in stroke imaging. METHODS: Traditional diffusion spectrum imaging (DSI) capable of producing accurate NODDI and GFA parameter maps requires hundreds of q-space samples which renders the scan time clinically untenable. A convolutional neural network (CNN) was trained to generated NODDI and GFA parameter maps simultaneously from 10* undersampled q space data. A total of 48 DSI scans from 15 stroke patients and 14 normal subjects were acquired for training, validating, and testing this method. The proposed network was compared to previously proposed voxel-wise machine learning based approaches for q-space imaging. Network-generated images were used to predict stroke functional outcome measures. RESULTS: The proposed network achieves significant performance advantages compared to previously proposed machine learning approaches, showing significant improvements across image quality metrics. Generating these parameter maps using CNNs also comes with the computational benefits of only needing to generate and train a single network instead of multiple networks for each parameter type. Post-stroke outcome prediction metrics do not appreciably change when using images generated from this proposed technique. Over three test participants, the predicted stroke functional outcome scores were within 1-6% of the clinical evaluations. CONCLUSIONS: Estimates of NODDI and GFA parameters estimated simultaneously with a deep learning network from highly undersampled q-space data were improved compared to other state-of-the-art methods providing a 10-fold reduction scan time compared to conventional methods. PMID- 30426559 TI - Circulating tumor cells detected using fluid-assisted separation technique in esophageal squamous cell carcinoma. AB - BACKGROUND AND AIM: Esophageal squamous cell carcinoma (ESCC) is one of the aggressive gastrointestinal tract cancers. Detection of circulating tumor cells (CTCs) in peripheral blood from patients with various malignancies has been reported to have diagnostic, prognostic, and therapeutic implications. We aimed to evaluate CTCs in patients with ESCC and assess the clinical significance of CTCs in the early diagnosis of ESCC. METHODS: Peripheral blood samples for CTCs analyses were prospectively obtained from 73 patients with ESCC prior to treatment between March 2015 and June 2018. CTCs were detected using a centrifugal microfluidic system with a new fluid-assisted separation technique. Blood samples from 31 healthy volunteers were used as controls. RESULTS: After creating a receiver operating characteristic curve to determine the optimal CTC threshold to differentiate patients with ESCC from healthy controls, sensitivity and specificity were most optimized at a CTC threshold of two per 7.5 mL of blood. Among 66 subjects with >= 2 CTCs per 7.5 mL of blood, 63 (95.5%) had ESCC. Among 38 subjects with < 2 CTCs per 7.5 mL of blood, 28 (73.7%) were healthy controls. When using this threshold, the sensitivity and specificity for differentiating patients with ESCC from healthy controls were 86.3% and 90.3%, respectively. CTC count was associated with tumor-node-metastasis stage, especially lymph node metastasis, but there was no correlation with any other relevant clinicopathologic variable. CONCLUSIONS: Our results suggest that CTCs detected using fluid-assisted separation technique could be helpful for early diagnosis of ESCC. Further large-scale prospective studies are warranted to validate our findings. PMID- 30426560 TI - A novel messenger RNA and long noncoding RNA signature associated with the progression of nonmuscle invasive bladder cancer. AB - AIM: To explore the molecular mechanism of nonmuscle invasive bladder cancer (NMIBC), matched normal, and cancer tissues of 10 NMIBC were examined for RNA sequencing. METHODS: We profiled the messenger RNA (mRNA) and long noncoding RNA (lncRNA) expression of patients with NMIBC. Differentially expressed mRNAs and lncRNAs were screened between cancer and normal tissues and validated by quantitative polymerase chain reaction (qPCR), and lncRNA-mRNA-miRNA interaction network was constructed. RESULTS: A total of 91 upregulated and 190 downregulated genes and 34 upregulated and 58 downregulated lncRNAs were screened from the sequencing result. The differentially expressed mRNAs were enriched in focal adhesion, rap1 signaling pathway, Hippo signaling pathway, PI3K-Akt signaling pathway, extracellular matrix (ECM)-receptor interaction, Ras signaling pathway, and mitogen-activated protein kinases signaling pathway, of which some pathways were involved in the cancer development. In the RNA sequencing, KIT and laminin subunitgamma gamma3 (LAMC3) were significantly downregulated in the NMIBC group compared with the normal group. The results of quantitative reverse transcription PCR showed that the expression of LAMC3 and KIT were significantly decreased in the NMIBC group compared with the normal group. The lncRNA-mRNA-miRNA interaction network was constructed by Cytoscape software to further investigate the interaction correlations. The results implied that KIT and LAMC3 might regulate the lncRNAs (such as ENST00000445707, ENST00000501122, ENST00000505254, ENST00000528986, ENST00000557661, ENST00000602964, ENST00000614517, ENST00000620864, and ENST00000623414) by the miRNAs (such as hsa-let-7f-2-3p, hsa miR-125a-3p, hsa-miR-134-3p, hsa-miR-191-5p, hsa-miR-210-5p, hsa-miR-30a-5p, hsa miR-30d-5p, hsa-miR-30e-5p, hsa-miR-92a-2-5p, and hsa-miR-95-3p), and finally played a role in the development of NMIBC cancer. CONCLUSION: Altogether, our study preliminarily indicated that KIT and LAMC3 might play a crucial role in the development of NMIBC cancer via a complex mRNA-lncRNA-miRNA regulatory network. PMID- 30426561 TI - Proteomics as a tool for tapping potential of entomopathogens as microbial insecticides. AB - Biopesticides are collective pest control harnessing the knowledge of the target pest and its natural enemies that minimize the risks of synthetic pesticides. A subset of biopesticides; bioinsecticides, are specifically used in controlling insect pests. Entomopathogens (EPMs) are micro-organisms sought after as subject for bioinsecticide development. However, lack of understanding of EPM mechanism of toxicity and pathogenicity slowed the progress of bioinsecticide development. Proteomics is a useful tool in elucidating the interaction of entomopathogenic fungi, entomopathogenic bacteria, and entomopathogenic virus with their target host. Collectively, proteomics shed light onto insect host response to EPM infection, mechanism of action of EPM's toxic proteins and secondary metabolites besides characterizing secreted and membrane-bound proteins of EPM that more precisely describe relevant proteins for host recognition and mediating pathogenesis. However, proteomics requires optimized protein extraction methods to maximize the number of proteins for analysis and availability of organism's genome for a more precise protein identification. PMID- 30426562 TI - MicroRNA-141 binds to the nerve growth factor receptor associated protein 1 gene and restores the erectile function of diabetic rats through down-regulating the nerve growth factor/neurotrophin receptor p75 (NGF/p75NTR) signaling. AB - BACKGROUND: Erectile dysfunction (ED) is one of the major complications in diabetes mellitus (DM). We have previously reported that the nerve growth factor (NGF)/tyrosine kinase receptor (TrkA) signaling is actively involved in DM induced ED (DMED). Here, we investigate the effect of micro-RNA-141 (miR-141) on the NGF/p75 neurotrophin receptor (p75NTR) signaling and erectile function of diabetic rats. METHODS: Sprague-Dawlay (SD) rats were used to establish a DMED model. The dual-luciferase reporter gene assay was first performed to identify the nerve growth factor receptor-associated protein 1 (NGFRAP1) gene as the target gene of miR-141. The regulatory mechanisms underlying miR-141 governing NGFRAP1 in vivo were then validated by modulating the expressions of miR-141 and knocking down NGFRAP1. RESULTS: The expressions of miR-141 were decreased while the expressions of NGFRAP1, NGF, and p75NTR were increased in DMED. miR-141 and downregulation of NGFRAP1, respectively, increased the density of corpus cavernosum smooth muscle and the ratio of intracavernosal pressure (ICP)/mean arterial blood pressure (MAP) and promoted the expression of alpha-actin and desmin as well. miR-141 also upregulated the expressions of NGFRAP1 in DMED, and knockdown of NGFRAP1 inhibited the productions of NGF and p75NTR. Furthermore, miR-141 suppressed the NGF/p75NTR signaling via binding to NGFRAP1. CONCLUSIONS: NGF/p75NTR signaling actively participates in the pathogenesis of DMED. miR-141 binds to NGFRAP1 and restores the erectile function of diabetic rats via downregulation of NGF/p75NTR signaling. PMID- 30426563 TI - Phase-contrast single-point imaging with synchronized encoding: a more reliable technique for in vitro flow quantification. AB - PURPOSE: The purpose of this study is to provide a standard method for flow velocity measurements with phase-contrast (PC) MRI. This method can be used for in vitro studies that place high demands on measurement accuracy. Clinically relevant PC MRI techniques can be validated using this method before being applied in vivo. METHODS: Many motion-related errors in PC MRI, particularly flow misregistration, depend on the timing of the encoding gradients in the pulse sequence. By synchronizing all encoding gradients and shortening the overall encoding interval, these errors can be significantly reduced. Based on this concept, a single-point PC MRI method is proposed. RESULTS: Flow experiments were conducted in vitro. No considerable errors were found in the velocity data of the proposed method. For comparison, a conventional PC MRI technique showed up to 100% local velocity deviation and up to 35% flow rate deviation in the same experiments. CONCLUSIONS: With the proposed method, the overall measurement accuracy is significantly increased compared to conventional PC MRI techniques. Due to long acquisition times and high specific absorption rates, this method can only be applied in vitro. PMID- 30426564 TI - Tumor-suppressive microRNA-10a inhibits cell proliferation and metastasis by targeting Tiam1 in esophageal squamous cell carcinoma. AB - Aberrant microRNAs (miRNAs) expressions could contribute to the progression of numerous cancers, including esophageal squamous cell carcinoma, while miR-10a participates in multiple biological processes on cancers. However, the molecular mechanism of miR-10a in esophageal squamous cell carcinoma (ESCC) has not been investigated. Herein, miR-10a was significantly reduced in ESCC clinical tissues and ESCC cell lines (EC109 and TE-3). In addition, immunohistochemistry indicated that the expressions of alpha-SMA, Ki-67, and PCNA in tumor tissues were higher than that of controls. In vitro, overexpression of miR-10a dramatically suppressed cell proliferation and enhanced cell apoptosis, while the decrease of miR-10a expressed the opposite outcome. Specially, overexpression of miR-10a caused a G0/G1 peak accumulation. Moreover, miR-10a also negatively regulated ESCC cell migration and invasion. Furthermore, targetscan bioinformatics predictions and the dual-luciferase assay confirmed that Tiam1 was a direct target gene of miR-10a. The statistical analysis showed Tiam1 was negatively in correlation with miR-10a in ESCC patient samples. And silencing Tiam1 could lead to a decline on cell growth, invasion, and migration in ESCC cell lines, while it could enhance cell apoptosis and cause a G0/G1 peak accumulation. In vivo, it revealed that miR-10a notably decreased the tumor growth and metastasis in xenograft model and pulmonary metastasis model. And it showed a lower expressions of Tiam1 in the miR-10a mimics group by immunohistochemistry. Taken together the results, they indicated that miR-10a might function as a novel tumor suppressor in vitro and in vivo via targeting Tiam1, suggesting miR-10a to be a candidate biomarker for the ESCC therapy. PMID- 30426565 TI - TRF4, the novel TBP-related protein of Drosophila melanogaster, is concentrated at the endoplasmic reticulum and copurifies with proteins participating in the processes associated with endoplasmic reticulum. AB - Understanding the functions of TBP-related factors is essential for studying chromatin assembly and transcription regulation in higher eukaryotes. The novel TBP-related protein-coding gene, trf4, was described in Drosophila melanogaster. trf4 is found only in Drosophila and has likely originated in Drosophila common ancestor. TRF4 protein has a distant homology with TBP and TRF2 in the region of TBP-like domain and is evolutionarily conserved among distinct Drosophila species, which indicates its functional significance. TRF4 is widely expressed in D. melanogaster with high levels of its expression being observed in testes. Interestingly enough, TRF4 has become a cytoplasmic protein having lost nuclear localization signal sequence. TRF4 is concentrated at the endoplasmic reticulum (ER) and copurifies with the proteins participating in the ER-associated processes. We suggest that trf4 gene is an example of homolog neofunctionalization by protein subcellular relocalization pathway, where the subcellular relocalization of gene product of duplicated gene leads to the new functions in ER-associated processes. PMID- 30426566 TI - Associations of dietary macronutrient and fibre intake with glycaemia in individuals with Type 1 diabetes. AB - AIMS: To study the association between dietary intake and glycaemia in Type 1 diabetes. METHODS: Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution. RESULTS: In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (beta = -0.428, 95% CI -0.624 to -0.231; P<0.001). In these same analyses, carbohydrate (beta = 0.011, 95% CI 0.002 to 0.020; P=0.014), alcohol (beta = 0.013, 95% CI 0.003 to 0.023; P=0.009) and monounsaturated fatty acid intakes (beta=0.012, 95% CI 0.001 to 0.023; P=0.029) were associated with higher variability in blood glucose measurements. In the macronutrient substitution analyses, substituting proteins for either carbohydrates (beta = -0.026, 95% CI -0.040 to -0.013; P<0.001), fats (beta = 0.018, 95% CI -0.033 to -0.004; P=0.014), or alcohol (beta = -0.026, 95% CI 0.045 to -0.006; P=0.010), or fats for carbohydrates (beta=-0.009, 95% CI -0.017 to -0.001; P=0.030), were all associated with lower variability in the measured blood glucose values. After adjusting for fibre intake, no significant results were observed in analyses of mean self-monitored blood glucose. CONCLUSIONS: This observational, cross-sectional study indicates that dietary fibre is associated with lower mean blood glucose concentrations in people with Type 1 diabetes. Glycaemic excursions were reduced when protein was substituted for other macronutrients and when fat replaced carbohydrate, after adjusting for fibre intake. PMID- 30426567 TI - Impact of good and poor mobilizers on hematopoietic progenitor cell collection efficiency and product quality. AB - BACKGROUND: Mobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known. METHODS: We evaluated the impact of granulocyte-colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM). RESULTS: Overall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 * 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004). CONCLUSION: Products collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg. PMID- 30426568 TI - Simultaneous estimation of PD, T1 , T2 , T2 * , and ?B0 using magnetic resonance fingerprinting with background gradient compensation. AB - PURPOSE: This study aims to estimate PD, T1 , T2 , T2 * , and METHODS: MRF based on fast imaging with steady-state precession (FISP) and multi-echo spoiled gradient (SPGR) schemes are alternatively used, which encode T2 and T2 * , respectively. Simulations are performed to determine the appropriate ratio of the FISP and SPGR sections with respect to the T2 and T2 * accuracy. Additionally, background field inhomogeneity (Gz ) compensation using z-shim gradients are incorporated into the SPGR section and the dictionary. The background field compensation is tested in the phantom experiment under well-shimmed and poor shimmed conditions. An in vivo experiment is performed and the estimated parameters are compared before and after Gz compensation. RESULTS: The T1 , T2 , and T2 * values from the phantom results are in good agreement with the reference methods under well-shimmed condition. The underestimated T2 and T2 * values under poor-shimmed condition are recovered by Gz compensation and the parameters are also in good agreement with the reference methods. In the human brain, T2 and T2 * values are restored by Gz compensation in regions where the magnetic field is particularly inhomogeneous, such as near the sinus and ear canals. CONCLUSIONS: The proposed FISP and SPGR combined MRF provides a simultaneous estimation of PD, T1 , T2 , T2 * , and PMID- 30426569 TI - Long noncoding RNA uc.4 inhibits cell differentiation in heart development by altering DNA methylation. AB - In previous studies, we have demonstrated that long noncoding RNA uc.4 may influence the cell differentiation through the TGF-beta signaling pathway, suppressed the heart development of zebrafish and resulting cardiac malformation. DNA methylation plays a significant role in the heart development and disordered of DNA methylation may cause disruption of control of gene promoter. In this study, methylated DNA immunoprecipitation was performed to identify the different expression levels of methylation regions. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were also performed to identify the possible biological process and pathway that uc.4 may join, associated with Rap1 signaling pathway, gonadotropin-releasing hormone signaling pathway, and Calcium signaling pathway. We found that the distribution of differentially methylated regions peaks was mainly located in intergenic and intron regions. Altogether, our result showed that differentially methylated genes are significantly expressed in uc.4 overexpression cells, providing valuable data for further exploration of the role of uc.4 in heart development. PMID- 30426570 TI - Systematic analysis of multigene predictors in gastric cancer exploiting gene expression signature. AB - Gastric cancer (GC) is the second most common cause of cancer death worldwide but could be more curable if diagnosed at an earlier stage. At present, the capability to predict the efficaciousness of molecular diagnosis for GC for each patient remains elusive. The purpose of this study was to identify tumor biomarkers through systems analysis of multigene predictors exploiting the available data resource. In this study, we investigated the top 10% overexpressed genes in GC from five data sets of the Oncomine platform, with 265 GC samples versus 174 normal gastric mucosa samples. Sixteen candidate genes were identified as predictors of GC, of which 14 genes were verified through the comparison of expression levels in specimens from normal (chronic gastritis, 21 samples) and GC groups (38 samples). In addition, unique molecular portraits of diffuse adenocarcinoma (DA), intestinal adenocarcinoma (IA), and mixed adenocarcinoma (MA) were studied through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, where DA showed higher extracellular matrix alteration while IA and MA showed higher cell-cycle alteration than other types. We also found that the elevated expressions of genes during GC progression were independent of gene mutations, and high core-binding factor subunit beta expression is correlated with a high overall survival rate in GC patients. Our research may provide an efficient clinical diagnosis of GC at an early stage with high accuracy and thus help improve the overall survival rate through early therapeutic interventions. PMID- 30426571 TI - The serotonin transporter and the activity regulated cytoskeleton-associated protein genes in antidepressant response and resistance: 5-HTTLPR and other variants. PMID- 30426572 TI - Function-Oriented: The Construction of Lanthanide MOF Luminescent Sensors Containing Dual Function Urea Hydrogen Bond Sites for Picric Acid. AB - Two novel lanthanide metal-organic framework (Ln-MOF) luminescent sensors for the detection of picric acid have been successfully assembled. Follow the function oriented research strategy, urea hydrogen bond functional sites were introduced into the MOF framework. The structural analyses indicate that the two MOFs have the same exact structure, both of which are 2D layers with diamond-shaped holes, which are accumulated into 3D framework by the interaction of urea and carboxylate hydrogen bonds. Interestingly, only half of the urea units is involved in support MOF framework in the form of N-H...O hydrogen bonding interactions, while the other half is located in the pore canal, thus reserving empty recognition sites. There are abundant N-H urea bonds in the inner walls of three types of interpenetration 1D channels. Luminescence studies revealed that the two Ln-MOFs exhibited high sensitivity, good selectivity and fast luminescence quenching response towards picric acid. Especially, the two Ln-MOFs can be simply and quickly regenerated, which exhibited excellent recyclability. We successfully use of function-oriented research strategy to achieve multiple functions with a ligand to construct lanthanide MOF luminescent sensors for the detection of picric acid, providing an idea for the development of clear purpose MOF luminescent sensors. PMID- 30426573 TI - A scoping review of empirical evidence on the impacts of the DRG introduction in Germany and Switzerland. AB - CONTEXT: Germany and Switzerland have introduced diagnosis-related groups (DRGs) for hospital reimbursement. This scoping review aims to evaluate if empirical evidence exists on the effect of the DRG introduction. METHODS: Medline via PubMed, Embase (Elsevier), CINAHL, PsychINFO, and Psyndex were systematically screened for studies from 2003 onwards using keywords-DRG, prospective payment system, and lump sum-in English, German, and French. Abstracts were screened for alignment with our inclusion criteria and classified as editorial/commentary, review, or empirical study. The full-text extraction included data on country, study design, collected data, study population, specialty, comparison group, and outcome measures. RESULTS: Our literature search yielded 1944 references, of which 1405 references were included in the abstract screening after removal of duplicates. 135 articles were relevant to DRG, including 94 editorials/comments/reviews and 41 empirical articles from 36 different samples. The most frequently used outcome parameters were length of stay (12), reimbursement/cost (9), and case numbers (9). CONCLUSIONS: Only a minority of identified articles (30.4%; 41 of 135) presented empirical data. This indicates that discussion on the topic is not totally evidence-based. The only common trend was a decrease in length of stay. PMID- 30426574 TI - Doppler changes in the umbilical artery and ductus venosus during fetoscopic prenatal surgical repair of myelomeningocele. AB - OBJECTIVE: Cardiac dysfunction has been described in 60% of fetuses undergoing open myelomeningocele (MMC) repair. Routine Doppler evaluation of the umbilical artery (UA) and ductus venosus (DV) is challenging during fetal surgery. This study describes Doppler changes in the UA and DV in a cohort of fetuses during MMC repair. METHODS: Fetuses who underwent fetoscopic repair of MMC at a single institution between 2014 and 2017 were included in this study (n=35). Ultrasound images taken intraoperatively were analyzed to describe the changes in Doppler parameters of the UA and DV during fetal MMC repair. The timing of Doppler changes was matched with the phase of the surgery to determine whether a pattern to their appearance could be ascertained. RESULTS: Fetoscopic (n=35) fetal MMC repairs were included. Of the 35 fetoscopic MMC repairs, Doppler data of the UA was obtained in 12 cases, and Doppler data of the DV was obtained in 13 cases. In the 12 fetoscopic repairs for which there was UA data, 9 (75%) showed transient absence of end-diastolic flow (EDF), with 5 (41.7%) of them progressing to reversal of EDF. In the 13 fetoscopic cases for which there was DV data, 9 had elevated pulsatility index; however, none of them had absent or reversed blood flow during the atrial contractions. In the 9 fetoscopic cases with absent EDF in the UA, this abnormality first appeared during the fetoscopic repair in 5 cases (55.6%), after uterus exteriorization but before CO2 insufflation in 2 cases (22.2%), after uterus replacement but before skin closure in 1 case (11.1%), and after CO2 insufflation but before the start of the MMC repair in 1 case (11.1%). The Doppler abnormalities in four fetuses with reversed EDF and in three with absent EDF resolved during surgery. Follow-up scan one day after surgery demonstrated resolution of UA and DV Doppler abnormalities in all fetuses. CONCLUSION: Transient Doppler abnormalities of the umbilical artery without significant changes in the ductus venosus can be seen during fetal MMC repair. The clinical significance of these Doppler findings remains unclear due to their transient and intermittent nature. This article is protected by copyright. All rights reserved. PMID- 30426575 TI - How repeatable is the assessment of external anal sphincter trauma by exo-anal 4D ultrasound? AB - OBJECTIVE: Three/Four dimensional translabial ultrasound (TLUS) is gaining popularity for assessment of anal sphincter trauma, although repeatability data is lacking. This study aimed to determine TLUS repeatability for external anal sphincter trauma and compare the performance of a novice with that of an experienced investigator. METHODS: This is a retrospective study analysing archived ultrasound datasets of 103 patients. Each was assessed twice between 2012 and 2016 at an average interval of 260 (1-1100) days. All volumes were obtained using Voluson 730 expert or E8 systems. Post-processing of volumes was performed independently by two authors, one with over one year's experience and another with no prior experience, blinded against all other data including results obtained at the other time point. Intra- and interobserver agreement were determined using Cohen's kappa and Intra-class correlation coefficients. RESULTS: During the study period, 105 women had two TLUS assessments of the anal sphincter. Two had missing volumes, leaving 103 datasets. The novice investigator produced average repeatability for significant trauma and single slice defect (kappa 0.3 and 0.22) despite relatively high agreement (84.5% and 79.3%), whereas the experienced investigator demonstrated good to very good repeatability (kappa 0.91 and 0.78) between the two assessments which equates to 98.9% and 94.7% agreement. CONCLUSION: The repeatability of TLUS measurements for external anal sphincter trauma seem to be very good when imaging is undertaken with state of the art equipment and the analysis is performed by an experienced observer in comparison to analysis being performed by a novice investigator. This article is protected by copyright. All rights reserved. PMID- 30426576 TI - Left ventricular mechanics in the late second trimester of healthy pregnancy. AB - INTRODUCTION: Healthy pregnancy causes significant changes in maternal hemodynamics that lead to structural and functional adaptation of a woman's heart. Reductions in ejection fraction have been reported in healthy pregnancy; however, this measure of cardiac contractile function is over simplistic and insensitive to the underpinning hemodynamic load. Indices of systolic myocardial deformation, such as left ventricular strain and twist ('LV mechanics') may therefore provide a more accurate assessment of cardiac function during gestation. As such, the aim of this study was to evaluate LV mechanics in the second trimester of healthy pregnancy and secondly, to determine the influence of underpinning hemodynamics (heart rate (HR), preload and afterload) on LV mechanics during gestation. METHODS: We conducted a cross-sectional study of non pregnant (n=18), primiparous pregnant (22-26 weeks gestation; n=14) and postpartum (12-16 weeks after delivery; n=13) women. All pregnant and postpartum women had uncomplicated, singleton gestations. Cardiac structure and function were assessed using echocardiography. LV mechanics, specifically longitudinal strain, circumferential strain and twist/untwist, were measured using speckle tracking echocardiography. Differences between groups were identified using ANCOVA, with age, HR, end-diastolic volume (EDV) and systolic blood pressure (SBP) as covariates. Relationships between LV mechanics and hemodynamics were examined using Pearson's correlation. RESULTS: Pregnant women had significantly greater resting longitudinal and basal circumferential strain compared to non pregnant women (-22+/-2 vs. -17+/-3%, P=0.002 and -23+/-4 vs. -16+/-2%, P=0.001, respectively) but not apical circumferential strain or LV twist. No statistically significant relationships between LV mechanics and HR, EDV or SBP were observed within groups. CONCLUSION: Compared to the non-pregnant state, pregnant women in the second trimester of healthy pregnancy have significantly greater resting systolic function, as assessed by LV longitudinal and circumferential strain. Contrary to previous work, these data show that healthy pregnant women should not exhibit reductions in resting systolic function between 22-26 weeks. The enhanced myocardial contractile function does not appear to be related to hemodynamic load and could be the result of other physiological adaptations during gestation. This article is protected by copyright. All rights reserved. PMID- 30426577 TI - Adherence to the Mediterranean diet was positively associated with micronutrient adequacy and negatively associated with dietary energy density among adolescents. AB - BACKGROUND: The possible associations between adherence to the Mediterranean diet and micronutrient and energy intakes are unknown among Israeli adolescents. METHODS: A cross-sectional, nationally representative, school-based study was conducted in Israeli adolescents. Schoolchildren (n = 5005), aged 11-18 years, who completed a food frequency questionnaire and had complete data to compose a 14-item modified KIDMED score were included. RESULTS: The nutrient intakes for all the micronutrients showed a significant monotonic increase in the poor, average and good KIDMED groups (all P < 0.001). The same monotonic increasing was also shown in nutrient densities for most micronutrients (for calcium, magnesium, potassium, copper, vitamin A, vitamin E, vitamin C, thiamin, riboflavin, vitamin B6 , folate in both genders, additionally for phosphorus in girls) (all P < 0.05). A positive association was shown between the percentages of students with adequate intakes (AIs) or recommended dietary allowances (RDAs) in micronutrients and modified KIDMED scores. The positive association also existed between the number of micronutrients with AIs or RDAs and modified KIDMED scores (r = 0.495 and 0.501, P < 0.001) for boys and girls, respectively. By contrast, dietary energy density (calibrated by 1000 kcal) was negatively linearly associated with modified KIDMED scores, and a significant monotonic decrease in energy density was shown among the poor, average and good KIDMED groups (all P < 0.001). CONCLUSIONS: The modified KIDMED score was positively associated with better micronutrient profile and negatively associated with dietary energy density in Israeli adolescents, indicating that the KIDMED index is a useful tool for combating the malnutrition of micronutrient deficiency and overweight/obesity. PMID- 30426578 TI - Prediction of adverse perinatal outcomes by the cerebroplacental ratio in women undergoing induction of labour. AB - OBJECTIVE: To investigate the performance of screening for adverse perinatal outcome by the cerebroplacental ratio (CPR) measured within 24 hours of induction of labor. METHODS: This was a prospective observational study in 1,902 singleton pregnancies undergoing induction of labor at >= 37 weeks' gestation. Doppler ultrasound was used to measure the pulsatility index (PI) in the umbilical artery (UA) and fetal middle cerebral artery (MCA) before induction of labor. The measured UA PI and MCA PI and their ratio were converted to multiples of the median (MoM) after adjustment for gestational age. Univariate and multivariate logistic regression analysis was used to determine whether CPR improved the prediction of adverse perinatal outcome that was provided by maternal characteristics, medical history and obstetric factors. The detection rate (DR) and false-positive rate (FPR) of screening by CPR were estimated for cesarean section for presumed fetal distress and neonatal adverse outcome, which included umbilical arterial or venous cord blood pH <=7 and <=7.1, respectively, 5-minute Apgar score <7, admission to the neonatal intensive care unit (NICU) for >24 hours, or hypoxic ischemic encephalopathy. RESULTS: A combination of maternal and pregnancy characteristics, including age, weight, racial origin, previous obstetric history, preeclampsia, gestational age at delivery and amniotic fluid volume, identified 39% of pregnancies requiring cesarean section for fetal distress at FPR of 10%; addition of CPR did not improve the performance of screening. In screening for adverse neonatal outcome by a combination of parity and CPR the DR was 17% at FPR of 10%. CONCLUSION: Low CPR, measured within 24 hours of induction of labor, is associated with increased risk of cesarean section for fetal distress and adverse neonatal outcome, but the performance of CPR for such surrogates of adverse perinatal outcome is poor. This article is protected by copyright. All rights reserved. PMID- 30426579 TI - Mesoporous PtCu Alloy Nanoparticles with Tunable Compositions and Particles Sizes Using Diblock Copolymer Micelle Templates. AB - A simple, scalable route for the generation of mesoporous Rh particles by chemical reduction on self-assembled block-copolymer micelle templates was reported recently (Nat. Commun. 2017, 8, 15581). Here, this concept is extended to generate mesoporous PtCu alloy nanoparticles through the same approach. The PtCu alloy particles possess high-surface-area nanoporous architectures and good chemical stability for applications in catalysis. Both the composition and diameter of the bimetallic PtCu nanoparticles can be controlled by adjusting the amount of precursor in the reaction, which affects the electrochemical properties of the material. The combination of the mesoporous structure with the synergistic bimetallic electronic effects of PtCu gives rise to enhanced activity for the catalytic oxidation of methanol compared with commercial Pt black. PMID- 30426580 TI - Mercury(II) binding to metallothionein in Mytilus edulis revealed by high energy resolution XANES spectroscopy. AB - Of all divalent metals, mercury (Hg(II)) has the highest affinity for metallothioneins. Hg(II) is considered to be enclosed in the alpha and beta domains as tetrahedral alpha-type Hg4Cys11-12 and beta-type Hg3Cys9 clusters similarly to Cd(II) and Zn(II). However, neither the four-fold coordination of Hg nor the existence of Hg-Hg atomic pairs have ever been demonstrated, and the Hg(II) partitioning among the two protein domains is unknown. Using high energy resolution XANES spectroscopy, MP2 geometry optimization, and biochemical analysis, we provide evidence for the coexistence of two-coordinate Hg-thiolate complex and four-coordinate Hg-thiolate cluster with a metacinnabar-type (beta HgS) structure in the alpha domain of separate metallothionein molecules from blue mussel under in vivo exposure. The findings suggest that the CXXC claw setting of thiolate donors, which only exists in the alpha domain, acts as a nucleation center for the polynuclear complex and that the five CXC motifs from this domain serve as the cluster-forming motifs. Oligomerization is driven by metallophilic Hg-Hg interactions. Our results provide clues as to why Hg has higher affinity for the alpha than the beta domain. More generally, they provide a foundation for understanding how metallothioneins mediate mercury detoxification in the cell under in vivo conditions. PMID- 30426581 TI - Comparison of vaccination coverage of four childhood vaccines in New Zealand and New York State. AB - AIM: To ensure that children are vaccinated, different national governments use diverse strategies. We compared childhood vaccination coverage rates between New York State (NYS) and New Zealand (NZ) as the vaccination strategies are different. METHODS: We used vaccination records from the NYS Immunisation Information System and the National Immunisation Register of NZ to measure (i) vaccination coverage by school entry and by age six; (ii) coverage of different socio-demographic groups; and (iii) trend in vaccination coverage between 2011 and 2015. RESULTS: We analysed the records of 583 767 NYS children and 269 800 NZ children 7 years of age. NZ children were 3.3-21.5% more likely than NYS children to receive each of the vaccines. Compared to NYS, NZ children were 39.6% more likely to be up-to-date by the start of school and 28.1% more likely to be up-to date by age 6 years. Both NYS and NZ had statistically significant increases in the proportion of children who were up to date on each vaccine and all vaccines by the start of school and by 6 years of age (P < 0.001). CONCLUSIONS: We identified under-vaccinated groups and examined the point in the vaccine series where children were most vulnerable to being under-vaccinated. This information is useful in targeting future investigations and interventions aimed at mitigating disparities in vaccine coverage. This comparison of regions with different vaccination programmes and policies is important when considering whether the particular vaccination coverage strategies of one region could be adapted and applied for the benefit of another. PMID- 30426582 TI - Bias in heritability estimates from genomic restricted maximum likelihood methods under different genotyping strategies. AB - We investigated the effects of different strategies for genotyping populations on variance components and heritabilities estimated with an animal model under restricted maximum likelihood (REML), genomic REML (GREML), and single-step GREML (ssGREML). A population with 10 generations was simulated. Animals from the last one, two or three generations were genotyped with 45,116 SNP evenly distributed on 27 chromosomes. Animals to be genotyped were chosen randomly or based on EBV. Each scenario was replicated five times. A single trait was simulated with three heritability levels (low, moderate, high). Phenotypes were simulated for only females to mimic dairy sheep and also for both sexes to mimic meat sheep. Variance component estimates from genomic data and phenotypes for one or two generations were more biased than from three generations. Estimates in the scenario without selection were the most accurate across heritability levels and methods. When selection was present in the simulations, the best option was to use genotypes of randomly selected animals. For selective genotyping, heritabilities from GREML were more biased compared to those estimated by ssGREML, because ssGREML was less affected by selective or limited genotyping. PMID- 30426583 TI - IMPULSE: A scalable algorithm for design of minimum specific absorption rate parallel transmit RF pulses. AB - PURPOSE: Managing local specific absorption rate (SAR) in parallel transmission requires ensuring that the peak SAR over a large number of voxels (> THEORY AND METHODS: IMPULSE optimizes parallel transmit pulses for small-tip-angle slice selective excitation to minimize a single cost function incorporating multiple quantities (local SAR, global SAR, and per-channel power) averaged over the entire multislice scan subject to a strict constraint on excitation accuracy. Pulses for an 8-channel 7T head coil were designed with IMPULSE and compared with pulses designed using generic optimization algorithms and VOPs to assess the computation time and SAR performance benefits. RESULTS: IMPULSE achieves lower SAR and shorter computation time compared with a VOP approach. Compared with the generic sequential quadratic programming algorithm, computation time is reduced by a factor of 5-6 by using IMPULSE. Using as many as 6 million local SAR terms, up to 120 slices can be designed jointly with IMPULSE within 45 s. CONCLUSIONS: IMPULSE can handle significantly larger number of SAR matrices and slices than conventional optimization algorithms, enabling the use of uncompressed or partially compressed SAR matrices to design pulses for a multislice scan in a practical time frame. PMID- 30426584 TI - Reward motivation normalises temporal attention after sleep deprivation. AB - Preparation of attention facilitates speeded responding at time points with a high probability of target occurrence. Conversely, time points with low target probability are disadvantaged due to lower readiness. When targets are uniformly distributed in time, this effect results in higher readiness after longer preparation times (foreperiods). During sleep deprivation, this temporal bias is amplified, resulting in greater performance decrement when stimuli occur at unfavourable times. In this study, we examined whether reward motivation could modulate this increased temporal bias in response speed. Participants (n = 24) performed the psychomotor vigilance task under four reward conditions (0, 1, 5 or 15c per fast response), both after normal sleep (rested wakefulness) and sleep deprivation. To assess temporal preparation (foreperiod-effect), trials were binned based on the lead time prior to target presentation (short foreperiod: 1-6 s; long foreperiod: 6-10 s). As previously observed, the foreperiod-effect (slower reaction time for short foreperiod trials) increased after sleep deprivation. However, this state effect was attenuated with reward, reaching a response speed comparable to that observed in the unrewarded, well-rested condition. The current findings, therefore, suggest that reward improves overall response performance and normalises temporal attention in sleep-deprived individuals. PMID- 30426585 TI - Phosphorus-Containing Block Copolymers from the Sequential Living Anionic Copolymerization of a Phosphaalkene with Methyl Methacrylate. AB - Although living polymerization methods are widely applicable to organic monomers, their application to inorganic monomers is rare. For the first time, we show that the living poly(methylenephosphine) (PMPn - ) anion can function as a macroinitiator for olefins. Specifically, the phosphaalkene, MesP=CPh2 (PA), and methyl methacrylate (MMA) can be sequentially copolymerized using the BnLi-TMEDA initiator system in toluene. A series of PMPn -b-PMMAm copolymers with narrow dispersities are accessible (D=1.05-1.10). Analysis of the block copolymers provided evidence for -P-CPh2 -CH2 -CMe(CO2 Me)- switching groups. Importantly, this indicates that the -P-CPh2 - anion directly initiates the anionic polymerization of MMA and stands in stark contrast to the isomerization mechanism followed for the homopolymerization of PA. For the first time, the glass transition of a PMPn homopolymer has been measured (Tg =45.1 degrees C, n=20). The PMPn -b-PMMAm copolymers do not phase separate and show a single Tg which increases with higher PMMA content. PMID- 30426586 TI - Composition analysis of carotenoids and phenolic compounds and antioxidant activity from hibiscus calyces (Hibiscus sabdariffa L.) by HPLC-DAD-MS/MS. AB - INTRODUCTION: The hibiscus flower has received increasing interest because it contains high levels of bioactive compounds with remarkable functional properties. To the best of our knowledge, for the first time a detailed description of the carotenoid composition of hibiscus calyces is reported. OBJECTIVES: Identification and quantification of carotenoids, phenolic compounds and antioxidant activity from hibiscus calyces. MATERIAL AND METHODS: The composition of the carotenoids and phenolic compounds from hibiscus calyces was determined by high-performance liquid chromatography coupled to a diode array detector and tandem mass spectrometry (HPLC-DAD-MS/MS). Antioxidant activity was assessed using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging and hydroxyl radicals scavenging assays. RESULTS: Twenty-one carotenoids were found and from these compounds 15 were identified or tentatively identified. The major carotenoids were all-trans-lutein (316.43 +/- 19.92 MUg/100 g) and all-trans-beta-carotene (147.76 +/- 5.59 MUg/100 g). Twenty phenolic compounds were found, from which 14 compounds were identified or tentatively identified. The major phenolic compounds were delphinidin 3-sambubioside (218.17 +/- 12.69 mg/100 g) and 3-caffeoylquinic acid (79.22 +/- 7.01 mg/100 g), representing almost 60% (w/w) of the total phenolic compounds from hibiscus calyces. The hibiscus presented low vitamin A activity, measure as retinol activity equivalent (13.52 MUg/100 g). The scavenging activity of ABTS and hydroxyl radicals were 7.8 MUmol Trolox equivalent/g and 81%, respectively. CONCLUSION: In this study we have shown that the hibiscus calyces can be considered as a food rich in lutein, chlorogenic acids and anthocyanins (delphinidin 3-sambubioside). PMID- 30426587 TI - Learning curve for the ultrasonographic diagnosis of deep endometriosis using a structured off-line training program. AB - OBJECTIVE: The aim of the present study was to assess the learning curves of trainees during a structured off-line/hands-on training program on the diagnosis of deep infiltrating endometriosis (DIE). METHODS: A two-week training program was conducted. One day was devoted to theoretical issues and guided off-line analysis of 10 volumes of three-dimensional (3D) ultrasound. During the following days, five sessions of real-time sonographic examinations were performed in a DIE referral center Ultrasound unit. In between sessions, the trainees analyzed four off-line sets, containing twenty-five 3D volumes each. At the end of each set, misinterpreted volumes were assessed with the trainer. One trainer and 4 trainees (all post-graduated Ob/Gyn with at least 5 years of experience in ultrasonography in Obstetrics and Gynecology but with no experience in DIE sonographic examinations) participated in the study. Presence or absence of DIE at surgery was considered as gold standard for the trainees. Trainee's results were evaluated by learning curve cumulative summation (LC-CUSUM) and the deviations of the level of trainees' performance at the control stage by CUSUM (standard CUSUM) for different locations of DIE. RESULTS: The trainees reached competence on average after 17 evaluations (range 21-14) for bladder locations, after 39 evaluations (range 60-30) for rectosigmoid locations, after 25 evaluations (range 34-14) for forniceal locations, after 44 evaluations (range 66-25) for utero sacral locations (USL), after 21 evaluations (range 43-14) for rectovaginal septum (RVS) locations respectively, and kept the process under control with error levels of less than 4.5% until the end of the test. The overall accuracy for each trainee at the different locations ranged from 0.91 to 0.96 for bladder DIE, from 0.80 to 0.94 for recto-sigmoid DIE, from 0.90 to 0.94% for forniceal DIE, from 0.79 to 0.82 for utero-sacral ligaments DIE and from 0.89 to 0.97 for recto-vaginal septum DIE. CONCLUSIONS: The suggested two-weeks learning program based on a mix of off-line and live sessions is feasible and suggests a good performance in training for the diagnosis of DIE. This article is protected by copyright. All rights reserved. PMID- 30426588 TI - Deep eutectic solvent as a green solvent for enhanced extraction of narirutin, naringin, hesperidin and neohesperidin from Aurantii Fructus. AB - INTRODUCTION: In the present study, a green and efficient extraction method using deep eutectic solvents as extraction solvent was developed for extracting the four major active compounds narirutin, naringin, hesperidin and neohesperidin from Aurantii Fructus. METHODOLOGY: A series of tunable deep eutectic solvents were prepared and investigated by mixing choline chloride or betaine to different hydrogen-bond donors, and betaine/ethanediol was found to be the most suitable extraction solvent. To achieve the best extraction yield, the primary factors affecting the extraction efficiency, such as hydrogen-bond acceptor/hydrogen-bond donor ratio, water content in deep eutectic solvents, extraction temperature, solid/liquid ratio and extraction time, were investigated. RESULTS: The optimal extraction conditions were 40% of water in betaine/ethanediol (1:4) at 60 degrees C for heated extraction of 30 min and solid/liquid ratio 1:100 g/mL. Under the optimum extraction condition, the extraction yields of narirutin, naringin, hesperidin, and neohesperidin were 8.39 +/- 0.61, 83.98 +/- 1.92, 3.03 +/- 0.35 and 35.94 +/- 0.63 mg/g, respectively, which were much higher than those of methanol as extraction solvent (5.5 +/- 0.48, 64.23 +/- 1.51, 2.16 +/- 0.15 and 30.14 +/- 0.62 mg/g). CONCLUSION: The present results showed that deep eutectic solvents could be promising green and efficient solvents for extraction of the bioactive ingredients from traditional Chinese medicine. PMID- 30426589 TI - Metabolomic study of bioactive compounds in strawberries preserved under controlled atmosphere based on GC-MS and DI-ESI-QqQ-TOF-MS. AB - INTRODUCTION: The storage of the vegetables products in a controlled atmosphere (CA) with low O2 and high CO2 concentrations, reduces respiration rates and delays the ripening process, and in some cases, improves their quality and organoleptic properties. OBJECTIVE: To obtain deep insight into strawberry fruit metabolic changes caused by these CA treatments. METHODOLOGY: Freshly harvested strawberries were preserved under different atmospheres enriched with 10%, 20% and 30% of CO2 , for 2 days at 0 degrees C, containing in all the cases 5% of O2 and were subjected to a metabolomic analysis based on gas chromatography-mass spectrometry (GC-MS) and direct-infusion with electrospray ionisation source equipped with triple quadrupole coupled to time of flight mass spectrometry (DI ESI-QqQ-TOF-MS). Partial least square discriminant analysis (PLS-DA) was employed to compare the control and treated samples for the identification of altered metabolites. RESULTS: Several metabolites related to CA treatment could be identified by databases and literature, which are mainly sugars, organic acids and phenolic compounds (bioactive compounds). CONCLUSIONS: Good correlation coefficients were obtained between discriminant metabolites and fruit quality parameters. These results suggest that treated strawberries under CA could be considered as bioactive healthy compounds, suggesting that treated strawberries under CA could be used as raw material for the preparation and formulation of food supplements and nutraceutical products. PMID- 30426590 TI - Glucagon infusion alters the hyperpolarized 13 C-urea renal hemodynamic signature. AB - Renal urea handling is central to the urine concentrating mechanism, and as such the ability to image urea transport in the kidney is an important potential imaging biomarker for renal functional assessment. Glucagon levels associated with changes in dietary protein intake have been shown to influence renal urea handling; however, the exact mechanism has still to be fully understood. Here we investigate renal function and osmolite distribution using [13 C,15 N] urea dynamics and 23 Na distribution before and 60 min after glucagon infusion in six female rats. Glucagon infusion increased the renal [13 C,15 N] urea mean transit time by 14%, while no change was seen in the sodium distribution, glomerular filtration rate or oxygen consumption. This change is related to the well-known effect of increased urea excretion associated with glucagon infusion, independent of renal functional effects. This study demonstrates for the first time that hyperpolarized 13 C-urea enables monitoring of renal urinary excretion effects in vivo. PMID- 30426591 TI - Annual report of the committee on gynecologic oncology, the Japan Society of Obstetrics and Gynecology: Annual patients report for 2015 and annual treatment report for 2010. AB - AIM: To provide information including the trend of gynecological malignancies in Japan, we hereby present the Annual Patient Report for 2015 and the Annual Treatment Report for 2010 on the outcomes of patients who started treatment in 2010. METHODS: The Japan Society of Obstetrics and Gynecology maintains an annual tumor registry where information on gynecological malignancies from various participating institutions is gathered. The data of patients whose treatment was initiated in 2015 were analyzed retrospectively. Survival of the patients who started treatment in 2010 was analyzed by using the Kaplan-Meier, log-rank and Wilcoxson tests. RESULTS: Treatment was initiated in 2015 for 7527 patients with cervical cancer, 10 119 with endometrial cancer, 6424 with ovarian cancer and 2181 with ovarian borderline tumors. This clinicopathological information was summarized as the Patient Annual Report. Prognoses were analyzed across 4309 patients with cervical cancer, 5054 with endometrial cancer and 3423 with ovarian cancer, whose treatment was initiated in 2010. The 5-year survival rates of the patients with cervical cancer were 92.1%, 74.2%, 52.0%, and 29.8% for stages I, II, III, and IV, respectively. The 5-year survival rates for the patients with endometrial cancer were 94.3%, 88.8%, 74.0% and 26.6% for stages I, II, III and IV, respectively. The 5-year survival rates for the patients with ovarian cancer (surface epithelial-stromal tumors) were 88.5%, 80.1%, 46.3% and 36.2% for stages I, II, III and IV, respectively. CONCLUSION: The annual tumor report is an important survey that provides knowledge on gynecological malignancy trends in Japan. PMID- 30426592 TI - Predictors and outcomes of nurse professional autonomy: A cross-sectional study. AB - AIMS: This paper is a report examining the level of professional autonomy as well as its predictors and outcomes among practicing nurses in the Philippines. METHODS: This study adopted a descriptive, cross-sectional research design. One hundred sixty-six (n = 166) nurses participated in the study or a response rate of 83% during the months of January 2017 to May 2017. Seven self-reported scales were used for this study: the Nurse Autonomy Scale, Job Stress Scale, Burnout Measure Scale, Job Satisfaction Index, Organizational Commitment Questionnaire, Turnover Intention Inventory Scale, and the Six Dimension Scale of Nursing Performance. Inferential and descriptive statistics were used to analyse the collected data. RESULTS: Nurses demonstrated moderate levels of professional autonomy with education and hospital bed capacity as strong predictors. Regression analysis showed positive effects of professional autonomy on nurses' job outcomes such as organizational commitment, job satisfaction, and work performance. CONCLUSION: Consistent to international studies, nurses in the Philippines demonstrated moderate levels of professional autonomy. Nurses who had higher levels of autonomy tended to be high performing, satisfied, and committed in their jobs. Organizational efforts are critically important to foster autonomy in practicing nurses through adequate support, education, training, and developed policies. PMID- 30426594 TI - Editorial comments on this issue of the Journal. PMID- 30426593 TI - Pyruvate secreted from patient-derived cancer-associated fibroblasts supports survival of primary lymphoma cells. AB - Cancer-associated fibroblasts (CAF) are a key component in the tumor microenvironment and play functional roles in tumor metastasis and resistance to chemotherapies. We have previously reported that CAF isolated from lymphoma samples increase anaerobic glycolysis and decrease intracellular production of reactive oxygen species, promoting the survival of tumor cells. Herein, we analyzed the mechanisms underlying this support of tumor-cell survival by CAF. As direct contact between lymphoma cells and CAF was not indispensable to survival support, we identified that the humoral factor pyruvate was significantly secreted by CAF. Moreover, survival of lymphoma cells was promoted by the presence of pyruvate, and this promotion was canceled by inhibition of monocarboxylate transporters. Metabolome analysis of lymphoma cells in coculture with CAF demonstrated that intermediates in the citric acid cycle were significantly increased, indicating that tumor cells produced energy by aerobic metabolism. These findings indicate that energy production in lymphoma cells is regulated in coordination not only with anaerobic glycolysis, but also with aerobic metabolism termed the reverse-Warburg effect, involving the secretion of pyruvate from CAF resulting in increased use of the citric acid cycle in lymphoma cells. PMID- 30426595 TI - Length of stay by uncomplicated diabetes bariatric surgery patients: A laparoscopic adjustable banding versus laparoscopic sleeve gastrectomy. AB - RATIONALE, AIMS, AND OBJECTIVE: Bariatric surgery is an effective procedure for morbidly obese patients when all else fails. The purpose of this study was to compare the hospital length of stay (LOS) for two surgical procedures, laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG). METHODS: This study was a retrospective cross-sectional analysis of the Nationwide Inpatient Sample (NIS) from 2009 to 2014. Patients who received bariatric surgery as indicated by International Classification of Diseases, Ninth Revision (ICD-9) procedure codes were selected (N = 4001). Cases were limited to uncomplicated diabetic patients. Differences in the odds of long vs short (2< and >=2) stay for a patient receiving LSG were compared with LAGB while adjusting for hospital volume, hospital size, patient age, gender, ethnicity, season, and year using logistic regression analysis. RESULTS: The odds for LSG (odds ratio [OR] = 0.100, 0.066-0.150, P < 0.001) patients for long LOS are lower when compared with LAGB. In the stratified logistic regression model, both male (OR = 0.157, 0.074-0.333, P < 0.001) and female (OR = 0.077, 0.046 0.127, P < 0.001) had reduced odds of extended LOS for LSG. Discharged patients in the year 2012 (OR = 0.660, 0.536-0.813, P < 0.001) had decreased odds of having a longer LOS when compared with the year 2014. Both government, nonfederal (OR = 0.452, 0.251-0.816, P = 0.008), and private investor-owned (OR = 0.421, 0.244-0.726, P < 0.001) patients had similar odds for long duration of stay when compared with government or private. Urban non-teaching (OR = 1.954, 1.653-2.310, P < 0.001) patients had higher odds for long LOS in comparison with urban teaching. New England patients' (OR = 0.365, 0.232-0.576, P < 0.001) odds for extended LOS were lower when compared with pacific. Both patients who received care in low (OR = 1.330, 1.109-1.595, P = 0.002) and medium (OR = 1.639, 1.130 2.377, P = 0.009) volume hospital had increased odds for long duration of stay. Female patients in the stratified logistic regression model with high (OR = 1.330, 1.109-1.595, P < 0.002) volume had elevated odds of extended LOS when compared with very low volume hospital. CONCLUSION: Among the uncomplicated diabetic patients, LSG provides a substantially low odds of extended LOS after adjusting for covariates when compared with LAGB. The finding of the relative reduction in LOS for LSG suggests opportunities for improvement both for cost reduction for third party insurance payers and greater efficacy and outcomes for patients. PMID- 30426596 TI - Substance use screening and brief intervention: Evaluation of patient and implementation differences between primary care and emergency department settings. AB - RATIONALE, AIMS, AND OBJECTIVES: There are well-documented barriers that have limited widespread, sustained adoption of screening and brief intervention for risky substance use in health care settings. In order to better inform implementation efforts, this study evaluates whether patient characteristics, screening results, and implementation success indicators differed between two clinical setting types: primary care and emergency. METHODS: Patients presenting to an emergency or primary care setting were screened for risky substance use (n = 41 567). Patients with a positive screen were further assessed for psychosocial, health, and substance use problems (n = 1604). Differences in patient characteristics between primary care and emergency settings were examined using chi-square and t tests. Multilevel logistic regression was used to examine whether setting type predicted screening results. Site-level indicators of implementation success were calculated (percentage prescreens completed, percentage full screens completed, and percentage refused services) for all patient visits (n = 78 656). RESULTS: As compared with primary care patients, emergency patients had more severe substance use patterns and screening scores, were more likely to use a variety of illicit drugs, and reported more psychosocial issues. In logistic regression models, setting type did not predict whether patients screened positive; however, it did predict screening into a higher vs lower risk category such that emergency patients were more likely to be in a higher risk category. Emergency settings had lower indicators of implementation success (eg, 14% lower prescreen completion rate) as compared with primary care settings on some implementation measures. CONCLUSIONS: This evaluation found important differences in patient characteristics and screening and implementation results between primary care and emergency settings. Health care organizations and administrators implementing screening and brief intervention should attend to setting differences that could affect implementation and clinical care. PMID- 30426597 TI - Audit of the diagnosis of rectal evacuation disorders in chronic constipation. AB - BACKGROUND: Balloon expulsion test (BET) and high-resolution anorectal manometry (HRM) are used in diagnosis of rectal evacuation disorders (REDs); their performance characteristics are suboptimal. METHODS: We audited records of 449 consecutive patients with chronic constipation (CC). We documented anal sphincter tone and contraction, puborectalis tenderness, and perineal descent on digital rectal exam (DRE); maximum resting and squeeze pressures, and rectoanal pressure gradient on HRM; weight or time to balloon expulsion; colonic transit, and area of rectal area on radiograph (RASF). We based the diagnosis of RED on >=2 abnormalities on both DRE and HRM, excluding results of BET, as the performance of BET is being investigated. Results of RED vs non-RED and results obtained using tbBET vs wbBET groups were compared. We used multivariate logistic regressions to identify predictors of RED using different diagnostic modalities. KEY RESULTS: Among 449 individuals, 276 were included (74 RED and 202 non-RED). Predominant exclusions were for no HRM (n = 79) or use of low resolution anorectal manometry (n = 77). Logistic regression models for abnormal tbBET showed time >60 seconds, RASF and age-predicted RED. For tbBET, the current cutoff of 60 seconds had sensitivity of 39.0% and specificity 93.0% to diagnose RED; on the other hand, applying the cutoff at 22 seconds, the sensitivity was 77.8% and specificity 69.8%. CONCLUSIONS & INFERENCES: The clinical diagnosis of RED in patients with CC is achieved with combination of DRE, HRM and an optimized, time-based BET. Prospective studies are necessary to confirm the proposed 22 second cutoff for tbBET. PMID- 30426599 TI - CCL2 Induces Resistance to the Antiproliferative Effect of Cabazitaxel in Prostate Cancer Cells. AB - Understanding the mechanism of chemoresistance and disease progression in patients with prostate cancer is important for developing novel treatment strategies. In particular, developing resistance to cabazitaxel is a major challenge in patients with docetaxel- and castration-resistant prostate cancer (CRPC) because cabazitaxel is often administered as a last resort. However, the mechanism by which cabazitaxel resistance develops is still unclear. C-C motif chemokine ligands (CCLs) were shown to contribute to castration resistance of prostate cancer cells via an autocrine mechanism. Therefore, we focused on CCLs as key factors of chemoresistance in prostate cancer cells. We previously established a cabazitaxel-resistant cell line, DU145-TxR/CxR, from a previously established paclitaxel-resistant cell line, DU145-TxR. cDNA microarray analysis revealed that the expression of CCL2 was upregulated in both DU145-TxR and DU145 TxR/CxR cells compared with DU145 cells. The secreted CCL2 protein level in DU145 TxR and DU145-TxR/CxR cells was also higher than in parental DU145 cells. The stimulation of DU145 cells with CCL2 increased the proliferation rate under treatments with cabazitaxel, and a CCR2 (a specific receptor of CCL2) antagonist suppressed the proliferation of DU145-TxR and DU145-TxR/CxR cells under treatments of cabazitaxel. The CCL2-CCR2 axis decreased apoptosis through the inhibition of caspase-3 and poly(ADP-ribose) polymerase (PARP). CCL2 is apparently a key contributor to cabazitaxel resistance in prostate cancer cells. Inhibition of the CCL2-CCR2 axis may be a potential therapeutic strategy against chemoresistant CRPC in combination with cabazitaxel. This article is protected by copyright. All rights reserved. PMID- 30426600 TI - Energetic Switch of the Proline Effect in Collision-Induced Dissociation of Singly and Doubly Protonated Peptide Ala-Ala-Arg-Pro-Ala-Ala. AB - Suppression of the selective cleavage at N-terminal of proline is observed in the peptide cleavage by proteolytic enzyme trypsin and in the fragment ion mass spectra of peptides containing Arg-Pro sequence. An insight into the fragmentation mechanism of the influence of arginine residue on the proline effect can help in prediction of mass spectra and in protein structure analysis. In this work, collision-induced dissociation spectra of singly and doubly charged peptide AARPAA were studied by ESI MS/MS and theoretical calculation methods. The proline effect was evaluated by comparing the experimental ratio of fragments originated from cleavage of different amide bonds. The results revealed that the backbone amide bond cleavage was selected by the energy barrier height of the fragmentation pathway although the strong proton affinity of the Arg side chain affected the stereo structure of the peptide and the dissociation mechanism. The thermodynamic stability of the fragment ions played a secondary role in the abundance ratio of fragments generated via different pathways. Fragmentation studies of protonated peptide AACitPAA supported the energy dependent hypothesis. The results provide an explanation to the long term arguments between the steric conflict and the proton mobility mechanisms of proline effect. PMID- 30426598 TI - Developing definitions for invasive fungal diseases in critically ill adult patients in intensive care units.Protocol of the FUNgal infections Definitions in ICU patients (FUNDICU) project. AB - BACKGROUND: The reliability of diagnostic criteria for invasive fungal diseases (IFD) developed for severely immunocompromised patients is questionable in critically-ill adult patients in intensive care units (ICU). OBJECTIVES: To develop a standard set of definitions for IFD in critically-ill adult patients in ICU. METHODS: Based on a systematic literature review, a list of potential definitions to be applied to ICU patients will be developed by the ESCMID Study Group for Infections in Critically Ill Patients (ESGCIP) and the ESCMID Fungal Infection Study Group (EFISG) chairpersons. The proposed definitions will be evaluated by a panel of 30 experts using the RAND/UCLA appropriateness methods. The panel will rank each of the proposed definitions on a 1-9 scale trough a dedicated questionnaire, in two rounds: one remote and one face-to-face. Based on their median rank and the level of agreement across panel members, selected definitions will be organized in a main consensus document and in an executive summary. The executive summary will be made available online for public comments. CONCLUSIONS: The present consensus project will seek to provide standard definitions for IFD in these patients, with the ultimate aims of improving their clinical outcome and facilitating the comparison and generalizability of research findings. This article is protected by copyright. All rights reserved. PMID- 30426601 TI - Respiratory muscle weakness increases dead-space ventilation ratio aggravating ventilation-perfusion mismatch during exercise in patients with chronic heart failure. AB - BACKGROUND AND OBJECTIVE: Respiratory muscle weakness causes fatigue in these muscles during exercise and thereby increases dead-space ventilation ratio with decreased tidal volume. However, it remains unclear whether respiratory muscle weakness aggravates ventilation-perfusion mismatch through the increased dead space ventilation ratio. In ventilation-perfusion mismatch during exercise, minute ventilation versus carbon dioxide production (VE/VCO2 ) slope > 34 is an indicator of poor prognosis in patients with chronic heart failure (CHF). We examined the relationship of respiratory muscle weakness with dead-space ventilation ratio and ventilation-perfusion mismatch during exercise and clarified whether respiratory muscle weakness was a clinical predictor of VE/VCO2 slope > 34 in patients with CHF. METHODS: Maximal inspiratory pressure (PImax ) was measured as respiratory muscle strength 2 months after hospital discharge in 256 compensated patients with CHF. During cardiopulmonary exercise test, we assessed minute dead-space ventilation versus VE (VD/VE ratio) as dead-space ventilation ratio and VE/VCO2 slope as ventilation-perfusion mismatch. Patients were divided into low, moderate and high PImax groups based on the PImax tertile. We investigated determinants of VE/VCO2 slope > 34 among these groups. RESULTS: The low PImax group showed significantly higher VD/VE ratios at 50% of peak workload and at peak workload and higher VE/VCO2 slope than the other two groups (P < 0.001, respectively). PImax was a significant independent determinant of VE/VCO2 slope > 34 (odds ratio (OR): 0.67, 95% CI: 0.54-0.82) with area under the receiver operating characteristic curve of 0.812 (95% CI: 0.750-0.874). CONCLUSION: Respiratory muscle weakness was associated with an increased dead space ventilation ratio aggravating ventilation-perfusion mismatch during exercise in patients with CHF. PMID- 30426602 TI - Short-term outcomes of robotic-assisted versus conventional laparoscopic radical hysterectomy for early-stage cervical cancer: A single-center study. AB - AIM: Our hospital adopted laparoscopic surgery for early-stage cervical cancer in August 1998, with robot-assisted surgery implemented in October 2013. This study aimed to compare short-term outcomes for conventional laparoscopic radical hysterectomy (LRH) and robot-assisted radical hysterectomy (RARH) and assess the technical feasibility of RARH for early-stage cervical cancer. METHODS: We retrospectively compared operative time, blood loss, number of resected lymph nodes, length of postoperative hospital stay, rate of positive vaginal margin and perioperative complications between two groups of 121 patients (LRH group, n = 57; RARH group, n = 64) with stage IA2 to IIB, among 164 patients who underwent endoscopic radical hysterectomy for early-stage cervical cancer performed between January 2010 and December 2017 by an expert surgeon, excluding cases of para aortic lymphadenectomy. RESULTS: No differences in patient background, in terms of age and body mass index, were identified. For the LRH/RARH groups (mean +/- standard deviation), results obtained were as follows: operative time, 211 +/- 38/280 +/- 59 min (P < 0.01); blood loss, 219 +/- 114/370 +/- 231 mL (P < 0.01); number of resected lymph nodes, 38.5 +/- 15.9/50.2 +/- 18.2 (P < 0.01); length of postoperative hospital stay, 11.6 +/- 3.3/11.3 +/- 4.8 days (P = 0.67); and perioperative complications with Clavien-Dindo classification of grade III or higher, 1.8/7.8% (P = 0.13). CONCLUSION: The operative time was significantly longer and blood loss greater in the RARH than LRH group. A greater number of lymph nodes were removed in the RARH group. However, these differences seem to be within a clinically acceptable range, showing that RARH is as feasible and safe as LRH in terms of short-term outcomes. PMID- 30426603 TI - Measuring word retrieval in narrative discourse: core lexicon in aphasia. AB - BACKGROUND: Discourse analysis procedures are time consuming and impractical in a clinical setting. Critical to clinicians are simple and informative discourse measures that require minimal time and labour to complete. Many studies, however, have overlooked difficulties that clinicians face. We recently developed core lexicon lists for nouns, verbs, adjectives and adverbs for two narrative discourse tasks with healthy control groups. Core lexicon lists consist of important lexical items required to produce coherently meaningful discourse in response to discourse tasks. Measuring core lexicon is useful for quantifying word retrieval impairments at the discourse level in clinical populations. AIMS: To apply an age-based core lexicon list for nouns, verbs, adjectives and adverbs for the wordless picture books Good Dog Carl (1985) and Picnic (1984) and to determine how well the lists measured linguistic impairments in persons with aphasia (PWA). MATERIALS & METHODS: Lemma forms were extracted from 470 control participants who were divided into seven age groups. Twenty-five core lexicons were identified for four word classes (nouns, verbs, adjectives and adverbs) among the seven age groups. The nouns, verbs, adjectives and adverbs for each PWA (N = 11) were then compared with the core lexicon for their respective age group. Per cent agreement was computed by comparing the number of total items within each list to the number of items that PWA produced. A Spearman's correlation coefficient was computed between the WAB-R AQ and the per cent agreement for each word type for PWA. OUTCOMES & RESULTS: The percentage of agreement for each word type among the age cohorts ranged between 56% and 96%. Of the four word types, core verbs significantly correlated with the WAB AQs for both discourse tasks. A post-hoc analysis found significant differences between fluent and non-fluent aphasia for core verbs. CONCLUSIONS & IMPLICATIONS: Core lexicon analysis appears to be a practical way to capture impairments in word retrieval at the discourse level. Core verbs may be a better indicator to understand holistic language performances for PWA. Use of the core lexicon checklist can serve as an option to reconcile ecological validity with clinical usability. PMID- 30426604 TI - The dimensionality of suicidal ideation and its clinical implications. AB - OBJECTIVES: No consensus has been reached regarding the theoretical dimensions underlying the Scale for Suicide Ideation (SSI) and Beck's Scale for Suicide Ideation (BSI), widely used in research and clinical practice. This undermines the understanding and management of suicidal behavior. METHODS: The factor structure of the SSI and the BSI was investigated in 201 patients visiting the emergency department of the Geneva University Hospital, Switzerland, for suicidal ideation or a suicide attempt. RESULTS: Exploratory factor analyses (EFAs) identified a unique theoretical dimension. Item removal based on analyses of communalities improved the explained part of variance in both scales. A joint factor analysis provided results very similar to those yielded by initial EFAs. CONCLUSIONS: The single factor underlying the SSI and the BSI was composed of items encompassing a construct of suicide desire. Nonretained items corresponded to other elements of suicidal behavior (e.g., plans and preparations regarding the upcoming suicide attempt). These scales could not discriminate between suicide ideators and suicide attempters. PMID- 30426605 TI - Lewis Acid-Mediated One-Electron Reduction of Nitrous Oxide. AB - The one-electron reduction of nitrous oxide (N2 O) was achieved using strong Lewis acids E(C6 F5 )3 (E=B or Al) in combination with metallocenes. In the case of B(C6 F5 )3 , electron transfer to N2 O required a powerful reducing agent such as Cp*2 Co (Cp*=pentamethylcyclopentadienyl). In the presence of Al(C6 F5 )3 , on the other hand, the reactions could be performed with weaker reducing agents such as Cp*2 Fe or Cp2 Fe (Cp=cyclopentadienyl). The Lewis acid-mediated electron transfer from the metallocene to N2 O resulted in cleavage of the N-O bond, generating N2 and the oxyl radical anion [OE(C6 F5 )3 ]?- . The latter is highly reactive and engages in C-H activation reactions. It was possible to trap the radical by addition of the Gomberg dimer, which acts as a source of the trityl radical. PMID- 30426606 TI - Reconceptualizing developmental language disorder as a spectrum disorder: issues and evidence. AB - BACKGROUND: There is considerable variability in the presentation of developmental language disorder (DLD). Disagreement amongst professionals about how to characterize and interpret the variability complicates both the research on understanding the nature of DLD and the best clinical framework for diagnosing and treating children with DLD. We describe and statistically examine three primary possible models for characterizing the variability in presentation in DLD: predictable subtypes; individual differences; and continuum/spectrum. AIMS: To test these three models of DLD in a population-based sample using two distinct types of cluster analyses. METHODS & PROCEDURES: This study included children with DLD (n = 505) from the US Epidemiological Study of Language Impairment database. All available language and cognitive measures were included. Two cluster methods were used: Ward's method and K-means. Optimal cluster sizes were selected using Bayesian information criteria (BIC). Bootstrapping and permutation methods were used to evaluate randomness of clustering. OUTCOMES & RESULTS: Both clustering analyses yielded more than 10 clusters, and the clusters did not have spatial distinction: many of these clusters were not clinically interpretable. However, tests of random clustering revealed that the cluster solutions obtained did not arise from random aggregation. CONCLUSIONS & IMPLICATIONS: Non-random clustering coupled with a large number of non-interpretable subtypes provides empirical support for the continuum/spectrum and individual differences models. Although there was substantial support for the continuum/spectrum model and weaker support for the individual differences model, additional research testing these models should be completed. Based on these results, clinicians working with children with DLD should focus on creating treatment plans that address the severity of functioning rather than seeking to identify and treat distinct subtypes. Additional consideration should be given to reconceptualizing DLD as a spectrum condition. PMID- 30426607 TI - Nurses' perceptions of intensive care unit palliative care at end of life. AB - BACKGROUND: Significant barriers can block the provision of palliative care at the end of life in the intensive care unit (ICU). However, the relationship between perceptions of ICU quality palliative care and barriers to palliative care at the end of life is not well documented. AIMS AND OBJECTIVES: To describe ICU nurses' perceptions of quality palliative end-of-life care, barrier intensity and frequency to palliative care and their association with one another. DESIGN: This was a descriptive, correlational, cross-sectional design. METHODS: A convenience sample of 126 ICU nurses from two hospitals in Israel was recruited for the study. Participants completed three pencil-and-paper questionnaires (a personal characteristics questionnaire, the Quality of Palliative Care in the ICU and a revised Survey of Oncology Nurses' Perceptions of End-of-Life Care). Respondents were recruited during staff meetings or while on duty in the ICU. Ethical approval was obtained for the study from participating hospitals. RESULTS: The item mean score of the quality of palliative end-of-life care was 7.5/10 (SD = 1.23). The item mean barrier intensity and frequency scores were 3.05/5 (SD = 0.76) and 3.30/5 (SD = 0.61), respectively. A correlation of r = 0.46, p < 0.001 was found between barrier frequency and intensity and r = -0.19, p = 0.04 between barrier frequency and quality palliative end-of-life care. CONCLUSIONS: ICU nurses perceived the quality of palliative care at the end of life as moderate despite reports of moderate barrier levels. The frequency of barriers was weakly associated with quality palliative end-of-life care. However, barrier intensity did not correlate with quality palliative end-of-life care at a statistically significant level. Further research that investigates other factors associated with quality ICU palliative care is recommended. RELEVANCE TO CLINICAL PRACTICE: Barriers to palliative care are still common in the ICU. Increased training and education are recommended to decrease barriers and improve the quality of ICU palliative care. PMID- 30426608 TI - Ultrahigh resolution activation mapping of a left atrial macroreentrant tachycardia using a Marshall bundle epicardial connection. PMID- 30426609 TI - High-resolution impedance manometry parameters in the evaluation of esophageal function of non-obstructive dysphagia patients. AB - BACKGROUND: High-resolution impedance manometry (HRIM) allows evaluation of esophageal bolus retention, flow, and pressurization. We explored novel HRIM measures and assessed their temporal relationship to dysphagia symptoms for boluses of different volume and consistency in non-obstructive dysphagia (NOD) patients. METHODS: Thirty-three NOD patients (n = 19 minor or no disorder of peristalsis ("Normal") and n = 14 esophagogastric junction outflow obstruction ("EGJOO")) were evaluated with HRIM. Patients were administered 5 and 10 mL liquid, semisolid, and 2 and 4 cm solid boluses and indicated bolus perception during individual swallows using a 5-point Likert scale. HRIM was analyzed to assess Chicago Classification and pressure flow metrics, esophageal impedance integral (EII) ratio, and bolus flow time (BFT). KEY RESULTS: Overall, bolus perception increased with increasing bolus consistency (P < 0.001), but did not differ significantly between EGJOO and Normal patients. EGJOO patients had higher IRP4, higher levels of bolus residual (ie, EII ratio and IR), and restricted esophageal emptying. The results for linking semisolid bolus perception to semisolid-derived measures revealed more biomechanically plausible and consistent patterns when compared to those derived for liquid boluses. In Normal patients, perception of boluses of heavier viscosity was related to higher bolus flow resistance during transport, whilst in EGJOO, perception was related to restriction of esophageal emptying. CONCLUSION & INFERENCES: These novel pressure impedance measures may aid in the evaluation of NOD patients by revealing abnormal motor patterns, which may explain symptom generation. Future studies are needed to evaluate which of these measures are worthy of calculation and to establish protocol settings that allow for their meaningful interpretation. PMID- 30426610 TI - The traditional care culture and the Western nursing culture in Cameroon. AB - AIM: This study explored the relationship between the traditional care culture and the Western nursing culture. BACKGROUND: Cameroonians are highly dependent on seeking medical aid from traditional healers and medicines, despite the emergence of contemporary health practices that are provided by Western nursing care. METHODS: This study was conducted based on Bourdieu's praxeological approach using observational and descriptional research, and interviews. RESULTS: While the traditional care culture and the Western nursing culture practices coexist, there are also conflicts and challenges. The people of Cameroon prefer the availability of both health care forms because they are provided with options in terms of the care they are offered and can afford. CONCLUSION: Traditional care culture practices can be combined with the contemporary practices of Western nursing care. Both health care forms have advantages, and when integrated, they can contribute to providing more effective health care practices that can improve health care services in Cameroon. PMID- 30426611 TI - PD-L1 expression enhancement by infiltrating macrophage-derived TNF-alpha leads to poor pancreatic cancer prognosis. AB - Immunotherapy using anti-PD-1/PD-L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD-L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD-L1 expression in PDAC cells. Among the various cytokines tested, tumor-necrosis factor (TNF)-alpha up-regulated PD-L1 expression in PDAC cells through NF-kappaB signaling. The induction of PD-L1 expression was also caused by co-culture with activated macrophages, and the up-regulation was inhibited by neutralization with anti-TNF-alpha antibody after co-culture with activated macrophages. PD-L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD-L1 expression was significantly associated with poor prognosis in 235 PDAC patients, and especially in patients harboring high CD8-positive T cells infiltration. These findings indicate that tumor-infiltrating macrophage-derived TNF-alpha could be a potential therapeutic target for PDAC. This article is protected by copyright. All rights reserved. PMID- 30426612 TI - Everyday protective buffering predicts intimacy and fear of cancer recurrence in couples coping with early-stage breast cancer. AB - OBJECTIVE: Patient and spouse/partner mutual self-disclosure is central for maintaining intimacy and cognitive processing when transitioning to life after cancer. Protective buffering inhibits self-disclosure and is defined as efforts to protect one's partner from upset and burden by hiding or denying cancer related concerns. Intimacy and fear of cancer recurrence (FCR) are important determinants of individual and couple adaptation following cancer. Links between protective buffering and intimacy have not been examined in the context of daily life, and links with FCR have not been studied. We hypothesized that protective buffering is associated with decreased intimacy and increased FCR at a daily, within-person level. METHODS: Sixty-nine early-stage breast cancer (BC) survivors and their spouses completed electronic diaries for 21 consecutive days at the end of adjuvant treatment. Patients and spouses reported on daily protective buffering, intimacy, and FCR. Dyadic multilevel path modeling was used to estimate within-person effects. Patient and spouse protective buffering on one's own as well as one's partner's same-day intimacy and FCR were examined, controlling for previous levels of intimacy and FCR. RESULTS: Protective buffering was associated with decreased intimacy and increased FCR for the individual reporting buffering that same day. Patient and spouse protective buffering was also linked to decreased intimacy for her/his partner that same day. Moreover, patient protective buffering predicted increased spouse FCR that same day. CONCLUSIONS: Findings supported a daily, within-person link between buffering, intimacy, and FCR, suggesting open disclosure of cancer-related concerns may be a relevant target for interventions for adaptation to BC. PMID- 30426613 TI - A multicenter cross-sectional study of episiotomy practice in Romania. AB - RATIONALE, AIMS, AND OBJECTIVES: The aim of this study was to focus attention on episiotomy practice in Romanian maternity units in order to identify factors associated with the very high rate of the procedure in Romania and to consider strategies to reduce it. METHODS: In this clustered cross-sectional study, a total of 11 863 patients were recorded in eight Romanian maternity units to assess the prevalence of episiotomy. A random effects Poisson model was used to estimate the prevalence rate in univariate and multivariate models. RESULTS: Among the 11 863 patients included for analysis, 8475 (71.4%) had an episiotomy. The prevalence of episiotomy was 92.7% for the first vaginal birth, 73.2% for the second vaginal birth, and 35% for the third vaginal birth. The overall rate of suturing was higher than the episiotomy rate for all patients (total rate 79.2%). The likelihood of exiting the maternity ward with an intact perineum after the first vaginal birth was less than 5% at the first vaginal birth. CONCLUSIONS: In conclusion, routine episiotomy is the norm in Romanian maternity units, with episiotomy rates among the highest in Europe. Episiotomy use is mainly driven by local professional norms, experiences, previous training, and practitioners' decisions rather than evidence, guidelines, or variations in patient needs at the time of vaginal birth. PMID- 30426614 TI - T cell receptor beta-chain repertoire analysis of tumor infiltrating lymphocytes in pancreatic cancer. AB - Pancreatic cancer is lethal due to lack of perceptible symptoms and effective treatment methods. Immunotherapy may provide promising therapeutic choices for malignant tumors like pancreatic cancer. Tumor infiltrating lymphocytes (TILs) in tumor mesenchyme could recognize peptide antigens presented on the surface of tumor cells. This study aimed to test the relationship between the TCR beta repertoire of the tumor and peripheral blood, and also to investigate the intra tumor spatial heterogeneity of the TCR beta repertoire in pancreatic cancer. To the best of our knowledge, this is the first study to evaluate the clonal composition of TCR beta repertoire in TILs across the spatial extent of pancreatic cancer. In this study, we studied five patients who were diagnosed with primary pancreatic cancer. Ultra-deep sequencing was used to assess the rearrangement of the TCR beta-chain (TCR beta) gene. HE staining and immunohistochemistry of CD3, CD4, CD8 and HLA class I were used to show histopathology and immune conditions macroscopically. TILs repertoire showed that different regions of the same tumor showed a greater number of repertoire overlaps between each other than between peripheral blood, which suggested that T cell clones in pancreatic cancer might be quite different from those in peripheral blood. Whereas, intra-tumoral TCR beta repertoires were spatially homogeneous between different regions of a single tumor tissue. Based on these results, we speculated that the cellular adaptive immune response in pancreatic cancer was found to be spatially homogeneous, and this may pave way for immunotherapy for the treatment of pancreatic cancer patients. This article is protected by copyright. All rights reserved. PMID- 30426615 TI - Y-box binding protein-1 promotes tumorigenesis and progression via the EGFR/AKT pathway in spinal chordoma. AB - Chordomas are rare bone tumors with a poor prognosis and no approved targeted therapy. Y-box binding protein-1 (YBX1) promotes tumor growth, invasion and drug resistance. However, the role of YBX1 in chordoma is unclear. In this study, we examined the expression of YBX1 using immunohistochemistry and found that YBX1 was significantly upregulated in thirty-two chordoma tissues compared to distant normal tissues. Additionally, YBX1 upregulation was associated with surrounding tissue invasion, recurrence and poor prognosis. Biological function studies demonstrated that YBX1 promoted cell proliferation, invasion, accelerated G1/S phase transition and inhibited apoptosis. Further investigations found that YBX1 enhanced epidermal growth factor receptor (EGFR) transcription by directly binding to its promoter in chordoma cells. YBX1 regulated protein expression of p EGFR, p-AKT and its downstream target genes that influenced cell apoptosis, cell cycle transition and cell invasion. YBX1 activated the EGFR/AKT pathway in chordoma and YBX1-induced elevated expression of key molecules in the EGFR/AKT pathway were downregulated by EGFR and AKT pathway inhibitors. These in vitro results were further confirmed by in vivo data. These data showed that YBX1 promoted tumorigenesis and progression in spinal chordoma via the EGFR/AKT pathway. YBX1 might serve as a prognostic and predictive biomarker, as well as a rational therapeutic target, for chordoma. This article is protected by copyright. All rights reserved. PMID- 30426616 TI - Mechanisms of the anterograde trafficking of GPCRs: Regulation of AT1R transport by interacting proteins and motifs. AB - Anterograde cell surface transport of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum (ER) through the Golgi apparatus represents a crucial checkpoint to control the amount of the receptors at the functional destination and the strength of receptor activation-elicited cellular responses. However, as compared with extensively studied internalization and recycling processes, the molecular mechanisms of cell surface trafficking of GPCRs are relatively less defined. Here, we will review the current advances in understanding the ER-Golgi-cell surface transport of GPCRs and use angiotensin II type 1 receptor as a representative GPCR to discuss emerging roles of receptor interacting proteins and specific motifs embedded within the receptors in controlling the forward traffic of GPCRs along the biosynthetic pathway. PMID- 30426617 TI - What defines a clinically meaningful outcome in the treatment of substance use disorders: 'Getting your life back'. PMID- 30426618 TI - Phosphatidylinositol 4-phosphate on Rab7-positive autophagosomes revealed by the freeze-fracture replica labeling. AB - Phosphatidylinositol 4-phophate (PtdIns(4)P) is an essential signaling molecule in the Golgi body, endosomal system, and plasma membrane and functions in the regulation of membrane trafficking, cytoskeletal organization, lipid metabolism and signal transduction pathways, all mediated by direct interaction with PtdIns(4)P-binding proteins. PtdIns(4)P was recently reported to have functional roles in autophagosome biogenesis. LC3 and GABARAP subfamilies and a small GTP binding protein, Rab7, are localized on autophagosomal membranes and participate at each stage of autophagosome formation and maturation. To better understand autophagosome biogenesis, it is essential to determine the localization of PtdIns(4)P and to examine its relationship with LC3 and GABARAP subfamilies and Rab7. To analyze PtdIns(4)P distribution, we used an electron microscopy technique that labels PtdIns(4)P on the freeze-fracture replica of intracellular biological membranes, which minimizes the possibility of artificial perturbation because molecules in the membrane are physically immobilized in situ. Using this technique, we found that PtdIns(4)P is localized on the cytoplasmic, but not the luminal (exoplasmic), leaflet of the inner and outer membranes of autophagosomes. Double labeling revealed that PtdIns(4)P mostly colocalizes with Rab7, but not with LC3B, GABARAP, GABARAPL1 and GABARAPL2. Rab7 plays essential roles in autophagosome maturation and in autophagosome-lysosome fusion events. We suggest that PtdIns(4)P is localized to the cytoplasmic leaflet of the autophagosome at later stages, which may illuminate the importance of PtdIns(4)P at the later stages of autophagosome formation. PMID- 30426619 TI - Eating and drinking with an inflated tracheostomy cuff: a systematic review of the aspiration risk. AB - BACKGROUND: Speech and language therapists (SLT) lack consensus with regard to assessing the swallow function of a patient with a cuff-inflated tracheostomy. In the UK, one-third would not accept such a referral due to perceived negative effects on swallow safety. Patients may be spending longer hospitalized and fed enterally as a result. AIMS: To establish the evidence base for aspiration risk in the adult population when eating/drinking with a cuff-inflated tracheostomy. METHODS & PROCEDURES: Systematic searches of seven key electronic databases, grey literature and reference lists of full-text articles were conducted until January 2017. Two researchers independently identified eligible studies according to inclusion criteria (studies written in English, reporting aspiration rates in adult humans with inflated cuff tracheostomies). Methodological quality was assessed using the Downs and Black checklist. Owing to the heterogeneity of included studies in their design, population and measured outcomes, a narrative synthesis was employed. OUTCOMES & RESULTS: In total, 454 titles, 168 abstracts and 37 full papers were retrieved with 10 studies included in the final review. Methodological flaws and risk of bias were identified in all studies. Meta analysis was not feasible. Narrative synthesis found no study identified a statistically significantly higher incidence of aspiration in cuff-inflated patients. CONCLUSIONS & IMPLICATIONS: Evidence regarding aspiration risk is inconclusive. These results imply SLT services need to review policy to consider accepting referrals on a case-by-case basis, regardless of cuff status. Further research, though challenging to conduct, would inform best-practice and policy/guideline development, allowing a consistent clinical approach. PMID- 30426620 TI - Effect of intrauterine device insertion on Candida species in cervicovaginal specimen identified by polymerase chain reaction technic: A longitudinal study on Iranian women. AB - AIM: To assess the effects of copper T-380-A intrauterine device (IUD) insertion on Candida species in cervicovaginal specimen by a molecular method, polymerase chain reaction. METHODS: This is a longitudinal prospective study performed on 95 women attending Health Centers of Tehran, Iran in 2012, who selected copper T-380 A IUD for contraception and had no history of local or systemic antibiotics or antifungals use during the previous 2 weeks. Cervicovaginal specimens were twice collected and cultured on Sabouraud dextrose agar and CHROMagar Candida, before and 3 months after IUD insertion. Finally, a molecular method, PCR-RFLP was performed for identification of Candida species. P-values <0.05 were considered significant. RESULTS: The mean age of participants was 28 +/- 7.44 years. Positive Candida cultures were significantly increased 3 months after IUD insertion (25.3% vs 11.6%, P = 0.007). The most common identified species before and after IUD insertion, were Albicans, Glabrata and then both 'Albicans & Glabrata', respectively. The prevalence of Albicans and Glabrata decreased, while both 'Albicans & Glabrata' increased insignificantly. CONCLUSION: There was more than about fourfold increase in positive Candida cultures after IUD insertion. As the prevalence of simultaneous infection with both 'Albicans & Glabrata' species which are resistant to usual treatment, increased, it seems necessary to provide more intensive follow-up care for IUD users. PMID- 30426621 TI - Development of verb inflections among Bangla-speaking children with language disorder. AB - BACKGROUND: Children with language disorder across languages have problems with verb morphology. The nature of these problems varies according to the typology of the language. The language analyzed in this paper is the Standard Bangla spoken in Dhaka, Bangladesh, by more than 200 million people. It is an underexplored language with agglutinative features in its verb inflections. Some information on the acquisition of the language by typically developing children is available, but to date we have no information on the nature of ALD. As in many places in the developing world, the circumstances for research into language disorder are challenging, as there is no well-ordered infrastructure for the identification of these children and approaches to intervention are not evidence based. This study represents the first attempt to characterize the nature of morphosyntactic limitations in standard Bangla-speaking children with language disorder. AIMS: To describe the performance of a group of children with language disorder on elicitation procedures for three Bangla verb inflections of increasing structural complexity-present simple, present progressive and past progressive-and to compare their abilities on these forms with those of a group of typically developing Bangla-speaking children. METHODS & PROCEDURES: Nine children with language disorder (mean age = 88.11 months) were recruited from a special school in Dhaka. Eight of the children also had a differentiating or co-occurring condition. They responded to three tasks: a semi-structured conversation to elicit present simple, and two picture-based tasks to elicit present progressive and past progressive. Their performance was compared with data available from a large group of younger typically developing children. OUTCOMES AND RESULTS: Group data indicated a comparable trajectory of performance by the children with language disorder with the typically developing children (present simple > present progressive > past progressive), but with significantly lower mean scores. Standard deviations suggested considerable individual variation and individual profiles were constructed for each child, revealing varying patterns of ability, some of which did not accord with the typical developmental trajectory and/or substitution patterns. CONCLUSIONS & IMPLICATIONS: This study identified verb morphology deficits in Bangla-speaking children with language disorder who had asociated conditions. Variation in performance among the children suggests that individual profiles will be most effective in guiding intervention. PMID- 30426622 TI - Textual cohesion in oral narrative and procedural discourse: the effects of ageing and cognitive skills. AB - BACKGROUND: Knowledge of the discourse performance of non-brain-damaged individuals is critical not only for its differentiation from disordered expression but also for more accurate models of ageing and communication. The effect of ageing and cognitive skills on the cohesive adequacy of discourse has, until now, presented a confusing and ambiguous picture. AIMS: To examine comprehensively the effects of both age and cognitive skills on the discourse cohesion of 32 non-brain-damaged males divided into four age groups. METHODS & PROCEDURES: A large body of narrative and procedural samples (394 samples) was elicited from the participants. Their cognitive skills were determined using three tests, whilst their discourse cohesion was analyzed and correlated with the cognitive test results. OUTCOMES & RESULTS: This extensive investigation of ageing effects on discourse cohesion and their relationship to cognitive behaviour did not provide neat generalizable results. It showed that ageing significantly increases the number of cohesive errors and reduces the quantity of referential ties in picture-sequence narratives. The changes with age were limited to two aspects of cohesion and not linear across age groups. The participants' cognitive skills declined with age. Correlations between some cognitive tests and certain cohesive changes suggest co-occurring deficits rather than a causal explanation of cohesive decline with age. CONCLUSIONS & IMPLICATIONS: With ageing there are increased cohesive errors and decreased referential ties, co-occurring with declining cognitive skills. This study yields important guidance for future research, suggesting that picture-sequence narrative is the most effective tool for clinical evaluation of discourse, but also that findings from one discourse sample may be misleading. PMID- 30426623 TI - Rab-mediated trafficking in the secondary cells of Drosophila male accessory glands and its role in fecundity. AB - The male seminal fluid contains factors that affect female post-mating behavior and physiology. In Drosophila, most of these factors are secreted by the two epithelial cell types that make up the male accessory gland: the main and secondary cells. Although secondary cells represent only ~4% of the cells of the accessory gland, their contribution to the male seminal fluid is essential for sustaining the female post-mating response. To better understand the function of the secondary cells, we investigated their molecular organization, particularly with respect to the intracellular membrane transport machinery. We determined that large vacuole-like structures found in the secondary cells are trafficking hubs labeled by Rab6, 7, 11 and 19. Furthermore, these organelles require Rab6 for their formation and many are essential in the process of creating the long term post-mating behavior of females. In order to better serve the intracellular membrane and protein trafficking communities, we have created a searchable, online, open-access imaging resource to display our complete findings regarding Rab localization in the accessory gland. This article is protected by copyright. All rights reserved. PMID- 30426624 TI - Nutritional quality and reformulation of a selection of children's packaged foods available in Australian supermarkets: Has the Health Star Rating had an impact? AB - AIM: To examine whether the nutritional quality of children's packaged food products available in Australian supermarkets improved between 2013 and 2016, and whether any change could be detected in product reformulation since the introduction of the Health Star Rating (HSR) labelling scheme. METHODS: Packaged food products marketed towards children were purchased from three Australian supermarkets in July 2013 (for a previous study) and July 2016. Nutritional quality was assessed using the Food Standards Australian New Zealand Nutrient Profiling Scoring Criterion. Comparisons were made between the nutrient composition and formulation of products (a) available in 2013 and 2016; and (b) with and without HSR graphics. RESULTS: Of the 252 children's packaged products analysed, 53.6% were classified as 'less healthy'. HSR-labelled products had a significantly higher proportion classified as 'healthy' than those without the HSR (chi2 = 26.5; P < 0.0001; 73.8% and 59.0%, respectively). Overall, 28.5% displayed the HSR; the majority (81.5%) having a rating of >=3.0 stars. Cereal based products had the greatest uptake of the scheme, with HSR-labelled products having significantly lower mean energy and saturated fat content (P < 0.01) and higher mean protein and fibre content (P < 0.001) than non-HSR products. Reformulation of products that were available in 2013 had occurred in 100% of HSR labelled products in comparison to 61.3% of non-HSR labelled products. CONCLUSIONS: Despite the introduction of the HSR, more than half of children's packaged foods sampled are 'less healthy'. However, early indications suggest that the HSR may stimulate healthier product reformulation. PMID- 30426625 TI - Triple-Shelled Manganese-Cobalt Oxide Hollow Dodecahedra with Highly Enhanced Performance for Rechargeable Alkaline Batteries. AB - Precisely carving of multi-shelled manganese-cobalt oxide hollow dodecahedra (Co/Mn-HD) with shell number up to three is achieved by a controlled calcination of the Mn-doped zeolitic imidazolate framework ZIF-67 precursor (Co/Mn-ZIF). The unique multi-shelled and polycrystalline structure not only provides a very large electrochemically active surface area (EASA), but also enhances the structural stability of the material. The residual C and N in the final structures might aid stability and increase their conductivity. When used in alkaline rechargeable battery, the triple-shelled Co/Mn-HD exhibits high electrochemical performance, reversible capacity (331.94 mAh g-1 at 1 Ag-1 ), rate performance (88 % of the capacity can be retained with a 20-fold increase in current density), and cycling stability (96 % retention over 2000 cycles). PMID- 30426626 TI - The effect of glycemic control on cardiovascular disease in individuals with type 2 diabetes with pre-existing cardiovascular disease - a systematic review and meta-analysis. AB - Controversy exists with respect to the role of intensive glucose control in people with type 2 diabetes and pre-existing cardiovascular disease (CVD). Thus, the aim of this systematic-review and meta-analysis was to determine in the subset of people with type 2 diabetes and pre-existing CVD, the CV effect of intensive glucose control versus standard of care. We searched Medline, the Cochrane library, EMBASE and the NIH Trial registration database for randomized controlled trials that evaluated the effect of intensive glucose control versus standard glucose control in people with type 2 diabetes on incident CVD. Data were extracted using a structured form. When data were not available in the publications, authors were contacted. Eight trials involving 8339 participants were included. Among adults with type 2 diabetes and pre-existing CVD, there was no difference in the risk for CV events in those allocated to intensive glucose control versus standard of care arm (RR 0.98, 95%CI 0.87-1.09). In conclusion, in people with diabetes and pre-existing CVD, intensive glucose control vs. standard care had a neutral effect on incident CV events. This article is protected by copyright. All rights reserved. PMID- 30426627 TI - Development of text messages targeting healthy eating for children in the context of parenting partnerships. AB - AIM: There has been an increase in the use of text messaging to deliver and support health interventions. The aim was to develop a bank of text messages targeting healthy eating for children in the context of parenting partnerships that could be used in a family intervention. METHODS: Text messages were developed using the Theoretical Domains Framework and Behaviour Change Wheel COM B model by study investigators using a three-phase approach: (i) initial development of a message bank; (ii) messages were reviewed and evaluated by experts and parents on their clarity, usefulness, and relevance using a 5-point Likert scale and open text spaces for additional feedback and (iii) refinement of messages content and finalised the message bank. RESULTS: Messages were reviewed for 'clarity', 'usefulness' and 'relevance' by 20 parents and 28 health experts, who were predominantly female (92%), parents of primary school age children (33%), of low to middle socioeconomic status (78%), with a mean age of 39 years (SD +/- 9.87). From an initial set of 97 messages developed, 48 messages were retained through consultation. Messages were designed to complement the intervention, while engaging both parents. CONCLUSIONS: The three-phase development created a set of text messages acceptable to experts and parents that aim to support improvement in child eating behaviours. The process provides a template and practical guide for researchers and health providers looking to apply a systematic approach to text messages development. Future research should investigate acceptability and impact of these messages as a component of family based nutrition intervention. PMID- 30426628 TI - Recent Trends in Cyclic Vomiting Syndrome - Associated Hospitalizations with Liberalization of Cannabis Use in the State of Colorado. AB - BACKGROUND: Currently 29 states in the United States along with the District of Columbia have legalized cannabis in some forms. There is a paucity of data on the impact of legalization of cannabis use on hospitalizations due to cyclic vomiting syndrome (CVS). AIM: To study the trends in CVS-related hospitalizations and cannabis use in CVS in relation to legalization of recreational cannabis use in Colorado. METHODS: All hospital admissions in Colorado between 2010 -2014 with the diagnosis of CVS were identified using the Colorado State Inpatient Database (SID). Five-year trends in CVS-related hospitalizations along with the cannabis use were analyzed. Multivariate logistic regression analysis was performed to determine predictors of cannabis use in CVS. RESULTS: There was a significant increase in CVS- related hospitalizations by 46% from 806 in 2010 to 1,180 in 2014 when CVS was included as all-listed diagnoses (P<0.001). The overall prevalence of cannabis use in CVS (13% with CVS as primary diagnosis and 17% with CVS as all-listed diagnoses) was much higher than non-CVS related hospitalizations (1.7%) (P<0.001 for both comparisons). Cannabis use increased dramatically in both CVS and non-CVS related hospitalizations following legalization of cannabis for recreational use in 2012. CONCLUSION: Our study shows a significant increase in CVS-related hospitalizations concomitant with an increase in cannabis use with its liberalization in Colorado. Future studies on the relationship between cannabis use and hyperemesis are warranted, especially with its ongoing legalization in the US. This article is protected by copyright. All rights reserved. PMID- 30426629 TI - Halogen Bonding Directed Supramolecular Quadruple and Double Helices from Hydrogen-Bonded Arylamide Foldamers. AB - Halogen bonding has been used to glue together hydrogen-bonded short arylamide foldamers to achieve new supramolecular double and quadruple helices in the solid state. Three compounds, which bear a pyridine at one end and either a CF2 I or fluorinated iodobenzene group at the other end, engage in head-to-tail N???I halogen bonds to form one-component supramolecular P and M helices, which stack to afford supramolecular double-stranded helices. One of the double helices can dimerize to form a G-quadruplex-like supramolecular quadruple helix. Another symmetric compound, which bears a pyridine at each end, binds to ICF2 CF2 I through N???I halogen bonds to form two-component supramolecular P and M helices, with one turn consisting of four (2+2) molecules. Half of the pyridine-bearing molecules in two P helices and two M helices stack alternatingly to form another supramolecular quadruple helix. Another half of the pyridine-bearing molecules in such quadruple helices stack alternatingly with counterparts from neighboring quadruple helices, leading to unique quadruple helical arrays in two-dimensional space. PMID- 30426630 TI - Spiritual reminiscence therapy for older people with loneliness, anxiety and depression living in a residential aged care facility, Malaysia: A qualitative approach. AB - OBJECTIVE: To explore how older people with loneliness, anxiety and depression experience a spiritual reminiscence therapy (SRT) program and to explore its acceptability within the Malaysian population. METHODS: Unstructured observations and a focus-group discussion were carried out with 18 participants involved in a six-week SRT program in a residential care facility in Kuala Lumpur. RESULTS: Analysis revealed four themes: (i) Enthusiastic participation; (ii) Connections across boundaries; (iii) Expressing and reflecting; and (iv) Successful use of triggers. CONCLUSIONS: The findings suggest that the process of reminiscence, on which the program was based, was enjoyable for the participants and created opportunities to form connections with other members of the group. The use of relevant triggers in the SRT program that related to Malaysian cultures, ethnicities and religions was helpful to engage the participants and was acceptable across the different religions and ethnicities. PMID- 30426631 TI - Service providers' and health professionals' views and suggestions for the Australian National Meal Guidelines for the Commonwealth Home Support Program. AB - AIM: To summarise the views and suggestions of service providers and health professionals on issues related to the development of National Meal Guidelines. METHODS: A national online survey of meal service providers and health professionals in Australia was conducted. Potential participants were identified from previously conducted workshop consultations. Snowball sampling was used whereby participants were encouraged to share the survey link with relevant colleagues. De-identified data were collated and closed responses calculated based on the proportion of participants answering each question. Open-ended responses were systematically examined to identify common themes within the data. RESULTS: The 289 participants were mostly female (83%) and service providers (47%). Most participants described their services to be home-delivery (57%), sourcing meals from external providers (47%), were providing menu choice (59%), and were able to cater for special diets (95%). Participants felt that National Meal Guidelines would be beneficial in improving meal service provision and promoting consistency between organisations but were concerned that they may be impractical and costly. They also identified priority areas for inclusion in the guidelines including nutrition recommendations for customers, dietary modifications for special needs, menu variety/structure and considerations about meal types. Nourishing mid-meal snacks, food fortification and screening and monitoring of malnutrition are future considerations for service activities. CONCLUSIONS: Future research should examine the uptake and satisfaction of service providers and health professionals with the National Meal Guidelines. PMID- 30426632 TI - The Royal Australian and New Zealand College of Ophthalmologists, 50th Annual Scientific Congress, Adelaide Convention Centre, Adelaide, 17 - 21 November 2018. PMID- 30426633 TI - Wednesday 21 November. PMID- 30426634 TI - Invited Speakers. PMID- 30426635 TI - Tuesday 20 November. PMID- 30426636 TI - Scientific Program. PMID- 30426637 TI - Monday 19 November. PMID- 30426639 TI - Sunday 18 November. PMID- 30426640 TI - The Royal Australian and New Zealand College of Ophthalmologists 50th Annual Scientific Congress17-21 November 2018 Adelaide Convention Centre, Adelaide. PMID- 30426638 TI - Past Lecturers and Briefs For the Named Lectures: RANZCO Annual Scientific Congress. PMID- 30426641 TI - Functional Polymeric Materials Based on Main Group Elements. AB - The past decade has witnessed tremendous advances in the synthesis of polymers that contain elements from the Main Groups beyond those found in typical organic polymers. Unique properties that arise from dramatic differences in bonding and molecular geometry, electronic structure, and chemical reactivity, are exploited in diverse application fields. In here we highlight recent advances in inorganic backbone polymers, discuss how Lewis acid/base functionalization of polymers results in unprecedented reactivity, and survey conjugated hybrids with unique electronic structures for sensor and device applications. PMID- 30426642 TI - Use of the Internet as a source for reproductive health information seeking among adolescent girls in secondary schools in Enugu, Nigeria. AB - BACKGROUND: Adolescent female students should be provided opportunities to access reproductive health information to navigate this period of development successfully. Examining the use of the Internet for accessing reproductive health information by this group will provide useful information on their information needs and seeking behaviour. OBJECTIVE: The aim of this study was to investigate the use of the Internet for reproductive health information among adolescent female students in secondary schools in Enugu, Nigeria. METHOD: This descriptive study was conducted on adolescent female students in six secondary schools in Enugu urban. Data were collected using a self-administered questionnaire. A total of 120 adolescent female students participated in the study. FINDINGS: The adolescent female students use the Internet to seek for information on general see education (n = 120, 100%), sexual hygiene (n = 71, 59%), abstinence from premarital sex (n = 68, 57%), avoidance of sexual abuse (n = 67, 56%). Their preference for the Internet include its privacy (n = 115, 96%) and wealth of information (n = 111, 92%). CONCLUSIONS: Adolescent female students use the Internet to meet their reproductive health information needs. Access to the Internet should be enhanced for this group. PMID- 30426643 TI - Contribution of cell wall peroxidase- and NADPH oxidase -derived reactive oxygen species to Alternaria brassicicola-induced oxidative burst in Arabidopsis. AB - Cell wall peroxidases and plasma membrane-localized NADPH oxidases are considered as main sources of an apoplastic oxidative burst in plants attacked by microbial pathogens. In spite of this established doctrine, approaches attempting a comparative, side-by-side analysis on the functions of extracellular ROS generated by the two enzymatic sources are scarce. We previously reported about the roles of Arabidopsis NADPH oxidase RBOHD in plants challenged by the necrotrophic fungus Alternaria brassicicola (Pogany et al., 2009). Here we present results on the activity of apoplastic class III peroxidases PRX33 (At3g49110) and PRX34 (At3g49120) investigated in the same Arabidopsis-Alternaria pathosystem. ROS generated by Arabidopsis PRX33 and PRX34 peroxidases increase necrotic symptoms and colonization success of A. brassicicola. In addition, knocking down PRX33 and PRX34 transcript levels leads to a reduced number of host cells showing extracellular burst of ROS after inoculation with A. brassicicola. Our results also reveal an age-dependent transcript distribution of ROS-producing peroxidase and NADPH oxidase enzymes and some potential new components of the RBOHD, PRX33 and PRX34 signaling networks. This article is protected by copyright. All rights reserved. PMID- 30426644 TI - Biomimetic Bottlebrush Polymer Coatings for Fabrication of Ultralow Fouling Surfaces. AB - Demand for long-lasting antifouling surfaces has steered the development of accessible, novel, biocompatible and environmentally friendly materials. Inspired by lubricin (LUB), a component of mammalian synovial fluid with excellent antifouling properties, three block polymers offering stability, efficacy, and ease of use were designed. The bottlebrush-structured polymers adsorbed strongly on silica surfaces in less than 10 minutes by a simple drop casting or online exposure method and were extremely stable in high-salinity solutions and across a wide pH range. Antifouling properties against proteins and bacteria were evaluated with different techniques and ultralow fouling properties demonstrated. With serum albumin and lysozyme adsorption <0.2 ng cm-2 , the polymers were 50 and 25 times more effective than LUB and known ultralow fouling coatings. The antifouling properties were also tested under MPa compression pressures by direct force measurements using surface forces apparatus. The findings suggest that these polymers are among the most robust and efficient antifouling agents currently known. PMID- 30426645 TI - Psychotherapeutic skills training for nurses on an acute aged mental health unit: A mixed-method design. AB - This study examines the need for, and outcomes of, a psychotherapeutic skills training programme, within an acute psychogeriatric unit. Nursing staff were surveyed to explore their training needs in psychotherapeutic skills with inpatients diagnosed with depressive, anxiety, or neurocognitive disorders. Staff were then invited to participate in a focus group (n = 6) to identify content of such training, possible barriers, and an implementation strategy. Next, to ascertain the feasibility and acceptability of such training, materials and schedules were developed and piloted with a small group of nurses (n = 8), before being administered to nurses across the unit (n = 23). Impacts of training on the confidence and competence of nurses to use such skills were investigated. Of nurses surveyed (n = 20), 80% wanted to use psychotherapeutic skills in routine practice, but only 35% had received training in such skills in the last 5 years. Focus group results identified that nurses wanted training in skills related to engaging patients, responding to resistance from patients, problem solving, reminiscence, relaxation, and cognitive behaviour therapy. Nurses who underwent the pilot training reported increases in confidence and competence in using such skills. These findings were replicated in the unit-wide training programme and were found to be durable across a 3-month follow-up period. This study highlighted the training needs of nurses working in an inpatient psychogeriatric setting, approaches to implementing new skills, and benefits of training for nurses' levels of confidence and competence in using psychotherapeutic skills. PMID- 30426646 TI - A Branched Diterpene Cascade: The Mechanism of Spinodiene Synthase from Saccharopolyspora spinosa. AB - A diterpene synthase from Saccharopolyspora spinosa was found to convert geranylgeranyl diphosphate into the new natural products spinodiene A and B, accompanied by 2,7,18-dolabellatriene. The structures and the formation mechanism of the enzyme products were investigated by extensive isotopic labelling experiments, which revealed an unusual branched isomerisation mechanism towards the neutral intermediate 2,7,18-dolabellatriene. A Diels-Alder reaction was used to convert the main diterpene product with its rare conjugated diene moiety into formal sesterterpene alcohols. PMID- 30426647 TI - Improved efficacy of antibody cancer immunotherapeutics through local and sustained delivery. AB - Antibodies are a growing class of cancer immunotherapeutics that facilitate immune cell mediated killing of tumors. However, the efficacy and safety of immunotherapeutics are limited by transport barriers and poor tumor uptake, which leads to high systemic concentrations and potentially fatal side effects. To increase tumor antibody immunotherapeutic concentrations while decreasing systemic concentrations, local delivery vehicles for sustained antibody release are being developed. The focus of this review is to define material properties required for implantable controlled antibody delivery and highlight controlled release strategies applicable for antibody immunotherapeutics. PMID- 30426648 TI - Epithelial Invasion by Salmonella Typhi using STIV-Met Interaction. AB - Typhoid is a life-threatening febrile illness, which affects ~24.2 million people worldwide and is caused by the intracellular bacteria, Salmonella Typhi (S. Typhi). Intestinal epithelial invasion by S. Typhi is essential for the establishment of successful infection and is traditionally believed to depend on Salmonella Pathogenicity Island (SPI1) encoded Type 3 Secretion System (T3SS-1). We had previously reported that bacterial outer membrane protein T2942/STIV functions as a standalone invasin and contributes to pathogenesis of S. Typhi by promoting epithelial invasion independent of T3SS-1 (Cell Microbiol, 2015). Here, we show that STIV, using its 20-amino acid extracellular loop, interacts with receptor tyrosine kinase, Met, of host intestinal epithelial cells. This interaction leads to Met phosphorylation and activation of a downstream signaling cascade, involving Src, PI3-K/Akt and Rac1, which culminates into localized actin polymerization and bacterial engulfment by the cell. Inhibition of Met tyrosine kinase activity severely limited intestinal invasion and systemic infection by S. Typhi in vivo, highlighting the importance of this invasion pathway in disease progression. This is the first report elucidating the mechanism of T3SS-1 independent epithelial invasion of S. Typhi and this crucial host-pathogen interaction may be targeted therapeutically to restrict pathogenesis. PMID- 30426649 TI - Intrinsic Flame-retardant Organic Electrolyte for Safe Lithium-Sulfur Batteries. AB - Safety concern poses a significant challenge for the large-scale employment of lithium-sulfur batteries. Extreme flammable conventional electrolyte and dendritic lithium deposition cause severe safety issues. Herein, we report an intrinsic flame-retardant (IFR) electrolyte consisting of 1.1 M lithium bis(fluorosulfonyl)imide in a solvent mixture of flame-retardant triethyl phosphate and high flash point solvent 1,1,2,2-tetrafluoroethyl 2,2,3,3 tetrafluoropropyl (1:3, v/v) for safe lithium-sulfur (Li-S) batteries. This electrolyte exhibits favorable flame-retardant property and high reversibility of lithium metal anode (Coulombic efficiency >99%). Importantly, this IFR electrolyte enables stable lithium plating/stripping behavior with micro-sized and dense-packing lithium deposition at high temperatures. When coupled with sulfurized pyrolyzed poly(acrylonitrile) cathode (sulfur content: 52.6 wt%), Li-S batteries deliver high composite capacity (840.1 mAh g-1) and high sulfur utilization of 95.6%. More advantages of this system are its enhanced energy conversion efficiency and energy density under high temperature operation. PMID- 30426650 TI - Efficacy of a self-administered treatment using a smart tablet to improve functional vocabulary in post-stroke aphasia: a case-series study. AB - BACKGROUND: Aphasia is an acquired language disorder that occurs secondary to brain injury, such as stroke. It causes communication difficulties that have a significant impact on quality of life and social relationships. Although the efficacy of speech-language therapy has been clearly demonstrated in this population, long-term services are currently limited due to logistical and financial constraints. In this context, the potential contribution of technology, such as smart tablets, is worth exploring, especially to improve vocabulary that is relevant in daily life. AIMS: The main aim was to investigate the efficacy of a self-administered treatment using a smart tablet to improve naming of functional words in post-stroke anomia. METHODS & PROCEDURES: Four adults with post-stroke aphasia took part in the study. An ABA design with multiple baselines was used to compare naming performances for four equivalent lists: (1) trained with functional words chosen with the participant; (2) trained with words randomly chosen from a picture database; (3) exposed but not trained; and (4) not exposed (control). OUTCOMES & RESULTS: For all participants, the treatment self administered at home (four times/week for 4 weeks) resulted in a significant improvement for both sets of trained words that was maintained 2 months after the end of treatment. Moreover, in two participants, evidence of generalization to conversation was found. CONCLUSIONS & IMPLICATIONS: This study confirms the efficacy of using smart tablets to improve naming in post-stroke aphasia. Although more studies are needed, the use of new technologies is unquestionably a promising approach to improve communication skills in people with aphasia, especially by targeting vocabulary that is relevant to them in their daily lives. PMID- 30426651 TI - 'Looking after the Survivors': The Health of a Cohort of Long term HIV Patients 25 Years on. AB - BACKGROUND: Patients with Human Immunodeficiency Virus (HIV) infection have higher rates of cardiovascular disease, metabolic disorders and malignancy than their uninfected peers. AIM: To survey the health of a South Australian cohort of long term HIV patients, who had been diagnosed with HIV prior to the availability of combination antiretroviral therapy (cART). METHODS: Data from 88 patients was collected retrospectively across four domains: demographics, HIV history, antiretroviral medication and medical co-morbidity. RESULTS: There were high rates of cardiovascular risk factors, in particular active smoking, dyslipidaemia and diabetes mellitus, which translated into a high rate of ischaemic heart disease and cerebrovascular accidents. A large proportion of the patients suffered depression and cognitive impairment. Approximately one fifth of the cohort had been diagnosed with a malignancy, with anal cancer being the most prevalent. Many patients had experienced permanent toxicity from antiretroviral therapy. CONCLUSIONS: This study showed high rates of 'non-HIV morbidity' in a group of long term HIV patients in South Australia. Clinicians should aggressively modify cardiovascular risk factors, ensure appropriate immunisations, monitor mental health and consider targeted malignancy screening in these patients. A robust clinical infrastructure and multidisciplinary team is required to facilitate the complex care needs of long term HIV patients. This article is protected by copyright. All rights reserved. PMID- 30426652 TI - Serum urate levels and therapy in adults treated with long-term dialysis: a retrospective cross-sectional study. AB - BACKGROUND: To estimate the point prevalence of gout, gout treatment, and achievement of target serum urate (SU) among adults treated with long-term dialysis. METHODS: Three secular cohorts of adults receiving dialysis for at least 90 days on 1st February 2017, 1st January 2016 and 1st January 2015 were identified. Medical records were reviewed for SU concentrations. Results were compared between haemodialysis (HD) and peritoneal dialysis (PD), and participants prescribed and not prescribed urate-lowering therapy. The percentage reduction in SU 24 and 48 hours post-haemodialysis was estimated based on data from a previous study. SU concentrations were then used to estimate the percentage time the SU was <0.36mmol/l using linear interpolation. RESULTS: Of 216 dialysis patients, 61 (point prevalence 28.2%, 95%CI 22.35-34.8%) had a diagnosis of gout. The mean (SD) age among those with gout was 61years (14.4), 46 (75.4%) were men and 18 (31.1%) identified as Maori or Pacific Island. Forty-two (68.9%) were prescribed allopurinol (mean (SD) dose 116.0+/-66.9mg/day). 46% had a pre-dialysis SU <=0.36mmol/l on less than 25% of occasions and 23% were below target on 76-100% of occasions. SU was below target 41% of time, with no statistically significant difference in those on HD or PD (p=0.39), and those prescribed or not prescribed allopurinol (p=0.55). CONCLUSIONS: Gout is experienced by approximately one in four adults treated with dialysis and two thirds are prescribed allopurinol. A minority have SU at a target sufficient to prevent gout despite allopurinol and haemodialysis. A treat to target SU should be considered in those with SU above target. This article is protected by copyright. All rights reserved. PMID- 30426654 TI - Written consent should not be obtained at the time of emergency caesarean section: FOR: Written consent for emergency caesarean section is not legally required, may delay delivery, and can cause distress. PMID- 30426653 TI - Use of Monitoring Data to Improve Implementation of a Home Fortification Program in Bihar, India. AB - This paper describes the use of program-monitoring data to track program performance and inform activities. Monitoring data were collected as part of an effectiveness trial of multiple micronutrient powders (MNPs) for children 6-18 months in Bihar, India. Communities (n=70; reaching over 10,000 children) were randomized to receive either counselling on infant and young child feeding or both counselling and MNPs. Government frontline health workers (FLWs), implemented and monitored program activities with support from CARE, India and university partners. Monitoring data were collected over the duration of the entire program to assess program impact pathways using various checklists, which captured information about: (i) attendance and training of FLWs at health sub centre meetings, (ii) distribution of MNPs, (iii) receipt and use of MNPs at the household level, and (iv) midline mixed methods survey. At the beginning of the program, 72% of households reported receiving and 53% reported currently consuming MNPs. These numbers fell to 40% and 43% at midline, respectively. The main barrier to use by household was a lack of MNPs, due in part to infrequent FLW distribution. However, FLWs rarely reported MNP shortages at Aanganwadi Centres. Side effects also emerged as a barrier and were addressed through revised recommendations for MNP use. Qualitative data indicated high community acceptance of MNPs and a good understanding of the program by FLWs. The use of real-time program data allowed for recognition of key program issues and decision making to enhance program implementation. PMID- 30426655 TI - Written consent should not be obtained at the time of emergency caesarean section: AGAINST: Written consent should be obtained. PMID- 30426657 TI - Consent and consequences in obstetrics and gynaecology. PMID- 30426656 TI - Ectopic pregnancy: 130 years of medical diagnostic challenges. PMID- 30426659 TI - Plastic operations or the transvaginal mesh. Are we going full circle? PMID- 30426660 TI - A mourning walk. PMID- 30426661 TI - Identification of functionally primitive and immunophenotypically distinct subpopulations in secondary acute myeloid leukemia by mass cytometry. AB - BACKGROUND: Background: Mass cytometry (CyTOF) is a powerful tool for analyzing cellular networks at the single cell level. Due to the high-dimensional nature of this approach, analysis algorithms have been developed to visualize and interpret mass cytometry data. In this study, we applied these approaches to a cohort of patients with secondary acute myeloid leukemia (sAML). METHODS: We utilized mass cytometry to interrogate localization and intensity of thrombopoietin-mediated intracellular signaling in sAML. Extracellular and intracellular phenotypes were dissected using SPADE, viSNE, and PhenoGraph. RESULTS: Healthy controls exhibited highly localized signaling responses largely restricted to the hematopoietic stem/progenitor cell (HSPC) compartment. In contrast, sAML samples contained subpopulations outside the HSPC compartment exhibiting thrombopoietin (TPO) sensitivity comparable to or greater than immunophenotypically defined HSPCs. We employed unsupervised clustering by PhenoGraph to elucidate distinct subpopulations within these heterogeneous samples. One metacluster composed almost exclusively of Lin- CD61+ CD34- CD38- CD45low cells was identified. This subpopulation was not readily identified by established manual gating approaches, and generally exhibited greater STAT phosphorylation in response to TPO stimulation than did Lin- CD61- CD34+ CD38- cells. Lin- CD61+ CD34- CD38- CD45low cells were identified in three additional sAML patients analyzed independently using a manual gating approach based upon PhenoGraph results. Each patient exhibited a similar TPO hypersensitivity to the PhenoGraph metacluster. CONCLUSIONS: The identification of this cellular subpopulation highlights the limitations of manual gating in sAML. Our study demonstrates the potential for mass cytometry to elucidate rare subpopulations in highly heterogeneous tumors by utilizing unsupervised high dimensional analysis. (c) 2018 International Clinical Cytometry Society. PMID- 30426662 TI - Inhibiting the urokinase-type plasminogen activator receptor system recovers STZ induced diabetic nephropathy. AB - The urokinase-type plasminogen activator (uPA) receptor (uPAR) participates to the mechanisms causing renal damage in response to hyperglycaemia. The main function of uPAR in podocytes (as well as soluble uPAR -(s)uPAR- from circulation) is to regulate podocyte function through alphavbeta3 integrin/Rac-1. We addressed the question of whether blocking the uPAR pathway with the small peptide UPARANT, which inhibits uPAR binding to the formyl peptide receptors (FPRs) can improve kidney lesions in a rat model of streptozotocin (STZ)-induced diabetes. The concentration of systemically administered UPARANT was measured in the plasma, in kidney and liver extracts and UPARANT effects on dysregulated uPAR pathway, alphavbeta3 integrin/Rac-1 activity, renal fibrosis and kidney morphology were determined. UPARANT was found to revert STZ-induced up-regulation of uPA levels and activity, while uPAR on podocytes and (s)uPAR were unaffected. In glomeruli, UPARANT inhibited FPR2 expression suggesting that the drug may act downstream uPAR, and recovered the increased activity of the alphavbeta3 integrin/Rac-1 pathway indicating a major role of uPAR in regulating podocyte function. At the functional level, UPARANT was shown to ameliorate: (a) the standard renal parameters, (b) the vascular permeability, (c) the renal inflammation, (d) the renal fibrosis including dysregulated plasminogen-plasmin system, extracellular matrix accumulation and glomerular fibrotic areas and (e) morphological alterations of the glomerulus including diseased filtration barrier. These results provide the first demonstration that blocking the uPAR pathway can improve diabetic kidney lesion in the STZ model, thus suggesting the uPA/uPAR system as a promising target for the development of novel uPAR-targeting approaches. PMID- 30426663 TI - Social adjustment of adolescent cancer patients transitioning off active treatment: A short-term prospective mixed methods study. AB - BACKGROUND: Psychosocial follow-up in survivorship is a standard of care in pediatric oncology; however, little is known about patients' psychosocial functioning during the transition off active treatment, a unique time in the cancer journey. This study examined the social adjustment of adolescent cancer patients during this transition period, which has been understudied to date. PROCEDURE: Participants were 21 patients (ages 12-18 years; age M = 14.71 years; 62% female, 81% White) with various cancer diagnoses. Patients and their parents completed the Social Competence subscale of the Youth Self-Report (YSR) and Child Behavior Checklist (CBCL), respectively, PedsQL Social Functioning subscale, and a semistructured interview 1-2 months prior to ending treatment (time 1) and 3-7 months after ending treatment (time 2). RESULTS: YSR and CBCL social competence scores were within the normal range at both time points. PedsQL social functioning scores were more consistent with norms for pediatric cancer samples at time 1 and norms for healthy children at time 2, with self-reported scores significantly improving from time 1 to time 2. A subset of patients had elevated social concerns at time 1, a number that decreased by time 2. Interviews revealed both positive and negative themes related to peer relationships and support, quantity of friends, and socialization. CONCLUSIONS: Most adolescent cancer patients are socially well adjusted as they transition off treatment, although a subset have elevated concerns. Interviews provide insight into complex social experiences not captured on questionnaires. Patients may benefit from screening and support during this unique time. PMID- 30426664 TI - Calibration strategies for use of the nanoDot OSLD in CT applications. AB - Aluminum oxide based optically stimulated luminescent dosimeters (OSLD) have been recognized as a useful dosimeter for measuring CT dose, particularly for patient dose measurements. Despite the increasing use of this dosimeter, appropriate dosimeter calibration techniques have not been established in the literature; while the manufacturer offers a calibration procedure, it is known to have relatively large uncertainties. The purpose of this work was to evaluate two clinical approaches for calibrating these dosimeters for CT applications, and to determine the uncertainty associated with measurements using these techniques. Three unique calibration procedures were used to calculate dose for a range of CT conditions using a commercially available OSLD and reader. The three calibration procedures included calibration (a) using the vendor-provided method, (b) relative to a 120 kVp CT spectrum in air, and (c) relative to a megavoltage beam (implemented with 60 Co). The dose measured using each of these approaches was compared to dose measured using a calibrated farmer-type ion chamber. Finally, the uncertainty in the dose measured using each approach was determined. For the CT and megavoltage calibration methods, the dose measured using the OSLD nanoDot was within 5% of the dose measured using an ion chamber for a wide range of different CT scan parameters (80-140 kVp, and with measurements at a range of positions). When calibrated using the vendor-recommended protocol, the OSLD measured doses were on average 15.5% lower than ion chamber doses. Two clinical calibration techniques have been evaluated and are presented in this work as alternatives to the vendor-provided calibration approach. These techniques provide high precision for OSLD-based measurements in a CT environment. PMID- 30426666 TI - Abstracts of the 27th Malaysian Urological Conference, MUC 2018, Malaysia, 22-24 November 2018. PMID- 30426665 TI - Real-world efficacy and toxicity of combined nivolumab and ipilimumab in patients with metastatic melanoma. AB - BACKGROUND: There is limited real-world data on the efficacy and safety of combination programmed cell death protein-1 (PD-1) inhibitor, nivolumab and the cytotoxic T-lymphocyte antigen (CTLA-4) inhibitor ipilimumab. METHOD: We retrospectively identified patients (pts) with metastatic melanoma treated with three-weekly nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) for four cycles followed by nivolumab monotherapy (3 mg/kg) fortnightly. Patient demographics and treatment parameters were collected and outcomes determined. RESULTS: A total of 45 pts received combination treatment with a median follow up of 8.7 months (range 0.33-25.9 months). A total of 67% were male, and BRAF V600 mutations detected in 38%. At treatment commencement, 14 (31%) pts had brain metastases, 51% had an elevated LDH and 18 (40%) were treatment-naive. Almost a third (30%) required corticosteroids for symptom control or management of prior toxicities. Nineteen (42%) patients had prior anti-PD-1 therapy. The disease control rate (DCR) was 54% and objective response rate (ORR) was 29%. Of pts treated with prior immune checkpoint inhibitors, the DCR and ORR were 50% and 33%, respectively. Intracranial responses were observed in 18% (n = 2). The median progression-free survival (PFS) was 5.8 months (95% Confidence interval (CI), 2.9-14.1 months). PFS was higher in treatment naive patients compared to those who had prior immunotherapy (6.2 months vs 4.9 months, P = 0.59). The median OS was 17.4 months (95% CI, 7.1-NR). pts requiring corticosteroids had a shorter PFS (4.9 months vs 6.8 months) and OS (7.1 months vs NR, P = 0.01).Treatment-related adverse events of any grade were experienced by 88% of pts, with 54% having grade 3-4 adverse events. Treatment discontinuation due to adverse events occurred in 44% of pts. CONCLUSION: In this study, responses to combination immunotherapy were lower than reported. Patients treated with prior immunotherapy had similar responses as treatment-naive pts. The toxicity profile seen in this study is similar to those reported in clinical trials. PMID- 30426667 TI - Using the Patient-Reported Outcomes Measurement Information System (PROMIS) to measure symptom burden reported by patients with brain tumors. AB - BACKGROUND: Children with brain tumors can experience symptom burden throughout their disease continuum. The aim of the study was to evaluate symptom burden reported by children with brain tumors and factors that potentially were associated with their symptoms. METHODS: Data from 199 children with brain tumors aged 7-22 (mean age = 14 years; 52% males; 76% white) were analyzed. Symptom burden was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) via computerized adaptive testing (CAT)-anxiety, depression, fatigue, mobility, upper extremity function, peer relationship, and cognition. Patients and parents completed Symptom Distress Scales (SDS). Test statistics and ANOVA were used to evaluate relationships between PROMIS measures and potentially influential variables. RESULTS: Significant results (P < 0.01) showing impact of symptom burden included: PROMIS measures correlated with SDSs reported by patients and parents on all comparisons. Fatigue, mobility, and upper extremity function were associated with Karnofsky functional performance status, number of treatment modalities (0-3), and time since last treatment (<=1 year, >1 year). Fatigue and cognition were associated with educational program (regular classroom without an individualized education plan vs those that had an individualized education plan); mobility and upper extremity function were associated with time since last radiation. Mobility, upper extremity function, and anxiety were associated with time since last chemotherapy. CONCLUSIONS: Significant associations were found between PROMIS and SDS as well as clinical and demographic characteristics. Brief-yet-precise PROMIS CATs can be used to systematically assess symptom burden experienced by children with brain tumors. PMID- 30426669 TI - A complete workflow for utilizing Monte Carlo toolkits in clinical cases for a double-scattering proton therapy system. AB - The methods described in this paper allow end users to utilize Monte Carlo (MC) toolkits for patient-specific dose simulation and perform analysis and plan comparisons for double-scattering proton therapy systems. The authors aim to fill two aspects of this process previously not explicitly published. The first one addresses the modeling of field-specific components in simulation space. Patient specific compensator and aperture models are exported from treatment planning system and converted to STL format using a combination of software tools including Matlab and Autodesk's Netfabb. They are then loaded into the MC geometry for simulation purpose. The second details a method for easily visualizing and comparing simulated doses with the dose calculated from the treatment planning system. This system is established by utilizing the open source software 3D Slicer. The methodology was demonstrated with a two-field proton treatment plan on the IROC lung phantom. Profiles and two-dimensional (2D) dose planes through the target isocenter were analyzed using our in-house software tools. This present workflow and set of codes can be easily adapted by other groups for their clinical practice. PMID- 30426668 TI - Associations between antenatal depression and neonatal outcomes in Malawi. AB - Studies from several low- and middle-income countries have shown that antenatal depression may be a risk factor for poor neonatal outcomes. However, those studies conducted in sub-Saharan Africa have not consistently demonstrated this association. We set out to investigate whether antenatal depression is associated with shorter duration of pregnancy and reduced newborn size in rural Malawi. Pregnant women recruited from four antenatal clinics to the International Lipid Based Nutrient Supplements Project-DYAD-Malawi (iLiNS-DYAD-M) randomised controlled trial of nutrient supplementation were screened for antenatal depression in the second or third trimester using a locally validated version of the Self Reporting Questionnaire (SRQ). Outcomes were duration of pregnancy, birthweight, newborn length for age z-score (LAZ), head circumference z-score, and mid-upper arm circumference (MUAC). Other potential confounding factors and predictors of birth outcome were measured and adjusted for in the analysis. 1,391 women were enrolled to the trial. 1,006/1,391 (72.3%) of these women completed an SRQ and gave birth to a singleton infant whose weight was measured within 2 weeks of birth. 143/1,006 (14.2%) scored SRQ >= 8, indicating likely depression. Antenatal depression was not associated with birth weight, duration of pregnancy, newborn LAZ, or head-circumference Z-score. There was an inverse association with newborn MUAC (adjusted mean difference - 0.2 cm (95% CI -0.4 to 0, p = 0.021) the significance of which is unclear. The study was conducted within a randomised controlled trial of nutritional supplementation and there was a high proportion of missing data in some enrolment sites; this may have affected the validity of our findings. PMID- 30426670 TI - From Evidence to National Scale: An Implementation Framework for Micronutrient Powders in Rwanda. AB - Micronutrient powders (MNP) are an efficacious intervention in terms of reducing anaemia among young children, yet challenges remain regarding implementation at scale. Research that can guide effective implementation of nutrition interventions and facilitate integration into existing healthcare platforms is needed. This paper seeks to advance the implementation science knowledge-base by presenting our multi-phased strategy and findings for scaling-up MNP in Rwanda. The multi-phased implementation strategy, spanning a five-year period (2011 2016), included: 1) A feasibility study involving formative research; 2) a 30-day trial of improved practices (n=60 households); 3) a 12-month pilot that included an effectiveness study (n=1066 caregiver/child pairs); and 4) a staggered approach to national scale-up. At the end of Phase Four, the program had been implemented in 19 of Rwanda's 30 districts with the scale-up in the final 11 districts completed in the following year. The caregivers of over 270,000 eligible children 6-23 months of age received a box of 30 MNP sachets in the final 3-month assessment period, representing a coverage rate of 87%. Initial problems with the supply chain and distribution, and on-going challenges to monitoring and reporting have been the largest obstacles. Continued success will be dependent on adequate resources for capacity development, refresher training, and responsive monitoring. Rwanda is one of the first countries to successfully scale-up home fortification sub-nationally with MNP. Lessons learned have implications for other countries. PMID- 30426672 TI - Shame and the psychosis continuum: A systematic review of the literature. AB - OBJECTIVES: Shame is increasingly implicated in the development and maintenance of several psychological problems including psychosis. The aim of the current paper was to review the research literature concerning the relationship between shame and the psychosis continuum, examining the nature and direction of this relationship. METHOD: Systematic searches of databases PsycINFO, Medline, Scopus, and Web of Science (from the earliest available database date until November 2016) were undertaken to identify papers that examined the relationship between shame and psychosis or psychotic experiences. RESULTS: A total of 20 eligible papers were identified. Risk of bias assessment identified methodological shortcomings across the research in relation to small, unrepresentative samples and failure to control for confounding variables. Narrative synthesis suggested positive associations between shame and paranoia (n = 10, r = .29-.62), shame and psychosis (n = 1, r = .40), and shame and affiliation with voices (n = 1, beta = .26), and suggested that shame was greater in those with psychosis compared to controls (n = 4, d = 0.76-1.16). CONCLUSIONS: Overall, several studies provide partial support for the theory that shame is an important factor in relation to psychotic experiences in both clinical and non-clinical populations, particularly paranoia. However, the predominance of cross-sectional designs prevents any conclusions being drawn concerning the temporal nature of associations. Additional research is necessary to further delineate the role of shame in relation to specific psychotic experiences such as voice-hearing. Longitudinal research is particularly needed to help establish the directionality and temporal aspects of effects. PRACTITIONER POINTS: Research indicates moderate-to-strong positive associations between shame and psychotic experiences in the existing literature. The results provide preliminary evidence that shame may play a role in relation to psychosis and, more specifically, paranoia. Findings should be interpreted with caution due to many disparities across the studies reviewed and methodological shortcomings (e.g., small sample sizes). It is not currently possible to determine causality or direction of effect due to the cross-sectional design of all existing studies. PMID- 30426671 TI - Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET >= 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH HD2002 trial. AB - PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values >= 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value >= 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS <= 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS <= 4) and to 56% (23%; 85%) when the qPET threshold was >= 2.0 (vDS 5). The negative predictive values remained stable at >=92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET >= 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given. PMID- 30426673 TI - Can bioelectrical impedance analysis using a home-use device properly estimate sarcopenia in community-dwelling older adults? PMID- 30426674 TI - Demand for home medical care will continue to increase in the next decades: An analysis from the Yokohama Original Medical Database (YoMDB). PMID- 30426675 TI - Hydroxyurea for Primary Stroke Prevention: The time draweth nigh. PMID- 30426676 TI - Burden and determinants of under nutrition among young pregnant women in Ethiopia: A multivariable hierarchical regression analysis. AB - Undernutrition is a major public health concern due to its association with the mortality and disease burden of women and children. This study aimed at identifying the extent and determinants of undernutrition among young pregnant women in Ethiopia. A multivariable regression analysis was fitted to identify determinants of undernutrition and anemia in a sample of 1,393 pregnant women. Risk ratios with 95% confidence interval were estimated. All the analyses were performed using STATA version 14 and adjusted for clustering. The study revealed that 38% of the women were undernourished and 22% were anemic. Improved maternal education (RR=0.94, 95% CI: 0.89, 0.98), higher wealth status (RR=0.72, 95% CI: 0.47, 0.95), higher minimum dietary diversity for women (MDDW) (RR=0.87, 95% CI: 0.77, 0.98), increased maternal height (RR=0.96, 95% CI: 0.94, 0.98) and protected water source (RR=0.93, 95% CI: 0.86, 0.96) have decreased the risk of undernutrition while using unimproved toilet (RR=1.31, 95% CI: 1.06, 1.63) and depression (RR=1.33, 95% CI: 1.14, 1.55) increased the risk of anemia. Animal source food (ASF) consumption decreased both the risk of undernutrition (RR=0.85, 95% CI: 0.77, 0.94) and anemia (RR=0.91, 95% CI: 0.85, 0.95). The burden of undernutrition is still high. While improved socio-economic status and dietary practices decreased the risk of undernutrition, poor health and environmental conditions were still significant risk factors. These findings suggest the need to target this set of important determinants to significantly decrease the burden of undernutrition among young pregnant women. PMID- 30426677 TI - Progress on the Photocatalytic Reduction Removal of Chromium Contamination. AB - Rapid industrialization leads to increased wastewater discharge encompassing hexavalent chromium (Cr(VI)), which leads to serious environmental problems of toxicity and potential carcinogenicity. Removal of these species is normally carried out by ion-exchange, precipitation, membrane filtration, sorption, photocatalytic reduction, etc. This review mainly focuses on the photocatalytic and photoelectrocatalytic (PEC) reduction of Cr (VI), because of their advantages over other methods such as reduced risk of secondary pollution by non-reduced Cr (VI), no sludge formation, no need for a large amount of chemical reagents, clean and easy installation. The main factors influencing the photocatalytic reduction efficiency of Cr (VI) such as catalyst activity, solution pH, Cr adsorption on the catalyst and additives, are briefly discussed. Finally, a special emphasis is provided to the photoelectrocatalytic (PEC) reduction of Cr (VI). PMID- 30426678 TI - Age-related deterioration of motor function in male and female 5xFAD mice from 3 16 months of age. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age related cognitive and sensori-motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age related changes in motor ability of male and female 5xFAD mice from 3-16 months of age, using a battery of behavioural tests. At 9-10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open-field and impaired performance on the rotarod compared to wild-type controls. At 12-13 months, 5xFAD mice showed reduced locomotor activity on the open-field, and impaired balance on the balance beam. At 15-16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 x SJL hybrid background, a subset of mice may be homozygous recessive for the Dysfim mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysfim on motor function, suggesting that Dysfim contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment. This article is protected by copyright. All rights reserved. PMID- 30426679 TI - The potential "additive" thromboembolic risk of radiotherapy. PMID- 30426680 TI - Photo-driven Transformation from Superhelix to Nanokebab and Chiral Structure Conveyed Circularly Polarized Luminescence. AB - While chiral nanostructures are interesting, it remains a big challenge to control the hierarchical chirality transfer from molecule to the higher order structures and their switching. Here, photo-sensitive cinnamic acid conjugated glutamides (L/D-CG) were designed to demonstrate the photo-controlled hierarchical chirality transfer and switching in self-assembly system. The cinnamic acid derivative self-assembled into superhelix in methanol, which could be switched into nanokebab upon UV irradiation. These two nanostructures showed opposite helicity. The chiral nanostructures could further convey their chirality to achiral fluorescent molecules and emit circularly polarized luminescence (CPL). Remarkably, the CPL followed the helicity of the chiral nanostructure rather than inherent molecular chirality. It was revealed that photo-driven dimerization of the cinnamic moiety lead to a significant change in molecular packing and subsequent switching of the helicity of the formed nanostructures. These findings provide a profound understanding on the relationship between the inherent molecular chirality and chiral nanostructures and would help to develop new functional CPL materials. PMID- 30426681 TI - Mitochondrial complex III Qi -site inhibitor resistance mutations found in laboratory selected mutants and field isolates. AB - BACKGROUND: Complex III inhibitors targeting the Qi -site have been known for decades; some are used or are being developed as anti-microbial compounds. Target site resistance mutations have been reported in laboratory-selected mutants and in field isolates. Here we present a brief over-view of mutations found in laboratory selected resistant mutants. We also provide a study of mutations observed in field isolates of Plasmopara viticola, in particular the ametoctradin resistance substitution, S34L that we analyzed in the yeast model. RESULTS: The survey of laboratory mutants showed that resistance could be caused by a large number of substitutions in the Qi -site. Four residues seemed key in term of resistance, N31, G37, L198 and K228. Using yeast, we analyzed the effect of the ametoctradin resistance substitution S34L reported in field isolates of P.viticola. We showed that S34L caused a high level of resistance combined with a loss of complex III activity and growth competence. CONCLUSION: The use of single site QiIs is expected to result in the selection of resistant mutants. However if the substitution is associated with a fitness penalty, as it could be the case with S34L, resistance development might not be an insuperable obstacle but careful monitoring is required. This article is protected by copyright. All rights reserved. PMID- 30426682 TI - Longitudinal refractive changes in adults: evidence from population-based studies. PMID- 30426683 TI - The needle, or the knife? PMID- 30426684 TI - Continuing Professional Development. PMID- 30426685 TI - Promoting non-verbal skills in medical students. PMID- 30426687 TI - The storyteller. PMID- 30426686 TI - Assessing teamwork in medical students. PMID- 30426689 TI - Empathic leadership: where to... performance review? PMID- 30426688 TI - Medical students working with interpreters. PMID- 30426690 TI - Embracing error: an undergraduate's perspective. PMID- 30426691 TI - Self-regulated learning in professional students. PMID- 30426692 TI - Polygonati sibiricum polysaccharide potentially attenuate diabetic retinal injury in a diabetic rat model. AB - AIMS/INTRODUCTION: To investigate the protective effect of polygonati sibiricum polysaccharide (PSP) on the retina in diabetic rats. MATERIALS AND METHODS: A total of 120 SD rats were randomly divided into blank control (BC), model control meaning diabetic mellitus (DM), and DM with PSP intervention of high (H), medium (M) and low (L) doses groups. The difference of retinal vascularization between groups was evaluated by fluorescein isothiocyanate-dextran (FITC-dextran) perfusion. Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End labeling (TUNEL) staining was used to assess apoptosis in the retinal ganglion cells (RGCs); reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting were utilized to evaluate the expression of Bax, Bcl-2, EGF, p38, TGF beta, and VEGF at mRNA and protein level. RESULTS: FITC-dextran perfusion showed retinal vascular anomaly in DM rats but vascular tortuosity and leakage were relatively alleviated after PSP intervention. TUNEL staining demonstrated numerous TUNEL-positive retinal cells in group DM, which then were reduced by PSP treatment. RT-PCR showed that PSP intervention decreased Bax, EGF, p38, VEGF and TGF-beta mRNA expression but increased Bcl-2 mRNA expression. Western blot indicated that PSP intervention up-regulated the expression of Bcl-2 and down regulated the expression of Bax, EGF, p38, VEGF and TGF-beta proteins. CONCLUSIONS: PSP exhibits a protective effect against diabetes-induced retinal injury in a dose-dependent manner. The mechanism of action deserves further study and exploration. This article is protected by copyright. All rights reserved. PMID- 30426693 TI - A nationwide population-based study of social demographic factors, associated diseases and mortality of keratoconus patients in Denmark from 1977 to 2015. AB - PURPOSE: To study sociodemographic factors, associated diseases and survival of Danish keratoconus patients. METHODS: All patients diagnosed with keratoconus 1977-2015 (n = 2679) were matched to 10 persons who had not been diagnosed with keratoconus (n = 26 790). Conditional logistic regression assessed whether sociodemographic factors and specific systemic diseases were associated with the odds of keratoconus. Mortality was assessed with time-to-event analysis. RESULTS: After adjustment, non-Europeans had more than threefold higher odds of keratoconus compared to Europeans (OR, 3.34; 96% CI 2.94-3.80). Single persons had 27% higher odds (OR, 1.27; 95% CI 1.13-1.43), and divorced persons had 18% lower odds (OR 0.82; 95% CI 0.68-0.97) of keratoconus compared with persons in a relationship. Persons living in cities with <500 and 500-4999 inhabitants had 40% (OR, 0.60; 95% CI 0.51-0.71) and 30% (OR, 0.70; 95% CI 0.61-0.81) lower odds of keratoconus, respectively, compared with those living in the capital (>1 000 000 inhabitants). Persons receiving government substitution had 68% higher odds of keratoconus (OR, 1.68; 95% CI 1.30-2.17) compared to self-employed. Keratoconus patients had more than twofold higher odds of asthma (OR, 2.21; 95% CI 1.91 2.55), more than threefold higher odds of allergic rhinitis (OR, 3.44; 95% CI 2.75-4.30), more than sevenfold higher odds of atopic dermatitis (OR, 7.97; 95% CI, 6.21-10.21) and 69% higher odds of depression (OR, 1.69; 95% CI 1.18-2.43). Mortality rates were similar among keratoconus patients and controls (HR, 1.02; 95% CI 0.90-1.16). CONCLUSION: Danish keratoconus patients differ from controls on several sociodemographic factors and have higher risk of allergic rhinitis, asthma, atopic dermatitis and depression. They do not have excess mortality compared to controls. PMID- 30426694 TI - Effects of a Community-Based Diabetes Prevention Program for Latino Youth with Obesity: A Randomized Controlled Trial. AB - OBJECTIVE: This study examined the short- and long-term effects of a community based lifestyle intervention among Latino youth with obesity. METHODS: Latino adolescents (14-16 years old) were randomized to a 3-month lifestyle intervention (n = 67) or comparison control (n = 69) and followed for 12 months. The intervention included weekly nutrition and health classes delivered to groups of families and exercise sessions (3 days/week) delivered to groups of adolescents. Comparison youth received laboratory results and general health information. Primary outcomes included insulin sensitivity and weight-specific quality of life (QoL) with secondary outcomes of BMI percentile (BMI%), waist circumference, and percent body fat. RESULTS: At 3 months, youth in the intervention group exhibited significant increases in insulin sensitivity (P < 0.05) and weight-specific QoL (P < 0.001), as well as reductions in BMI%, waist circumference, and percent body fat compared with controls. Increases in weight-specific QoL and reductions in BMI% and percent body fat remained significant at 12 months (P < 0.001), while changes in insulin sensitivity did not. In a subsample of youth with prediabetes at baseline, insulin sensitivity (P = 0.01), weight-specific QoL (P < 0.001), and BMI% (P < 0.001) significantly improved at 3 months. CONCLUSIONS: Lifestyle intervention can improve cardiometabolic and psychosocial health in a vulnerable population of Latino adolescents at high risk for developing type 2 diabetes. PMID- 30426696 TI - Recent Advances in the Metal-Catalyzed Activation of Amide Bonds. AB - The amide functional group is commonly found in peptides, proteins, pharmaceutical compounds, natural products, and polymers. The synthesis of amides is typically performed by using classical approaches that involve the reaction between a carboxylic acid and an amine in the presence of an activator. Amides are thought to be an inert functional group, because they are unsusceptible to nucleophile attack, owing to their low electrophilicity. The reason for this resistance is clear: the resonance stability of the amide bond. However, transition metal catalysis can circumvent this stability by selectively rupturing the N-C bond of the amide, thereby facilitating further cross-coupling or other reactions. In this Focus Review, we discuss the recent advances in this area and present a summary of methods that have been developed for activating the amide N C bond by using precious and non-precious metals. PMID- 30426695 TI - Food Insecurity is Associated with Maladaptive Eating Behaviors and Objectively Measured Overeating. AB - OBJECTIVE: The association between food insecurity and obesity may be partially explained by overeating in response to unpredictable food availability cycles. The aim of this study was to measure objective food intake in food-insecure individuals. METHODS: Eighty-two volunteers (53 m; BMI 29 +/- 7; 38 +/- 12 years) were admitted to our inpatient Clinical Research Unit and completed the Food Security Short Form, Three-Factor Eating Questionnaire, Gormally Binge Eating Scale, and body composition assessment (dual-energy x-ray absorptiometry). After 5 days of a weight-maintaining diet, participants self-selected food from an ad libitum vending machine paradigm for 3 days. Mean daily intake (kilocalories), macronutrient intake, and percentage of weight-maintaining energy needs (%WMEN) were calculated. RESULTS: Based on Food Security Short Form cutoffs, food insecure participants (n = 46; 56%) had higher body weight (P = 0.04), fat-free mass (P = 0.05), disinhibition (P = 0.008), hunger (P = 0.02), and binge-eating scores (P = 0.02) but not cognitive restraint (P = 0.37) compared with food secure individuals. They overate more kilocalories (P = 0.001), %WMEN (P = 0.003), fat (P = 0.003), and carbohydrates (P = 0.004) during the vending machine paradigm, continued to increase their hourly rate of kilocalories (group * time; beta = 37.7 cumulative kcal/h; P < 0.0001), and ate more total kilocalories across the 72 hours (beta = 47.09 kcal/h; P = 0.003). CONCLUSIONS: Food insecurity may amplify susceptibility to weight gain via overeating during times of unlimited food access. PMID- 30426697 TI - Patterns and predictors of end-of-life care in older patients with pancreatic cancer. AB - BACKGROUND: Little is known about end-of-life care among patients with pancreatic adenocarcinoma (PDAC). We used the Surveillance, Epidemiology, and End Results Medicare linked database to analyze patterns of hospice use and end-of-life treatment in patients with PDAC. METHODS: We included patients diagnosed with PDAC between 2000-2011 and who had died by December 31, 2012. We assessed patterns of hospice use, chemotherapy receipt, and intensive care unit (ICU) admissions at end-of-life. We used multivariable logistic regression to investigate predictors of end-of-life care. RESULTS: In our cohort of 16 309 patients, 70.5% enrolled in hospice, of which 29.1% enrolled in the last 7 days of life. Use of hospice increased over time, from 61.6% in 2000 to 77.5% in 2012 (P-value for trend <0.0001). Among the entire cohort, 6.4% received chemotherapy within the last 14 days of life and 13.1% were admitted to the ICU within the last 30 days of life. Late ICU admissions increased over time, while chemotherapy receipt at the end-of-life decreased. Patients who were older, female, with higher SES, or from the South or Midwest were more likely to enroll in hospice. Those who were younger or male were more likely to receive chemotherapy or have an ICU admission at the end-of-life. CONCLUSION: Although hospice enrollment has increased among patients with PDAC, late enrollment still occurs in a substantial proportion of patients. While chemotherapy at the end-of-life has decreased slightly, ICU admissions at the end-of-life have continued to increase. Further research is needed to determine effective ways of enhancing end-of-life care for patients with PDAC. PMID- 30426698 TI - Aqueous Solution Processing of Combustible Precursor Compounds into Amorphous Indium Gallium Zinc Oxide (IGZO) Semiconductors for Thin Film Transistor Applications. AB - Combustion synthesis of semiconducting amorphous indium gallium zinc oxide IGZO (In:Ga:Zn, 7:1:1.5) thin films was carried out using urea nitrate precursor compounds of indium(III), gallium(III) and zinc(II). This approach provides further understanding towards the oxide formation process under a moderate temperature regime by employment of well-defined coordination compounds. All precursor compounds were fully characterized by spectroscopic techniques as well as by single crystal structure analysis. Their intrinsic thermal decomposition was studied by a combination of differential scanning calorimetry (DSC) and thermogravimetry coupled with mass spectrometry and infrared spectroscopy (TG MS/IR). For all precursors a multistep decomposition involving a complex redox reaction pathway under in situ formation of nitrogen containing molecular species was observed. Controlled thermal conversion of a mixture of the indium, gallium and zinc urea nitrate complexes into ternary amorphous IGZO films could thus be achieved. Thin film transistors (TFTs) were fabricated from a defined compositional mixture of the molecular precursors. The TFT devices exhibited decent charge carrier mobilities of 0.4 and 3.1 cm2 /(Vs) after annealing of the deposited films at temperatures as low as 250 and 350 degrees C, respectively. This approach represents a significant step further towards a low temperature solution processing of semiconducting thin films. PMID- 30426699 TI - MoImd4 mediates crosstalk between MoPdeH-cAMP signaling and purine metabolism to govern growth and pathogenicity in Magnaporthe oryzae. AB - The high-affinity cyclic adenosine monophosphate (cAMP) phosphodiesterase MoPdeH is important not only for cAMP signaling and pathogenicity, but also for cell wall integrity (CWI) maintenance in the rice blast fungus Magnaporthe oryzae. To explore the underlying mechanism, we identified MoImd4 as an inosine-5' monophosphate dehydrogenase (IMPDH) homolog that interacts with MoPdeH. Targeted deletion of MoIMD4 resulted in reduced de novo purine biosynthesis and growth, as well as attenuated pathogenicity, which were suppressed by exogenous xanthosine monophosphate (XMP). Treatment with mycophenolic acid (MPA) that specifically inhibits MoImd4 activity resulted in reduced growth and virulence attenuation. Intriguingly, further analysis showed that MoImd4 promotes the MoPdeH phosphodiesterase activity thereby decreasing intracellular cAMP levels, and MoPdeH also promotes the IMP dehydrogenase activity of MoImd4. Our studies revealed the presence of a novel crosstalk between cAMP regulation and purine biosynthesis in M. oryzae and indicated that such a link is also important in pathogenesis of M. oryzae. This article is protected by copyright. All rights reserved. PMID- 30426700 TI - Effects of Indoor Thermal Environment on Human Food Intake, Productivity, and Comfort: Pilot, Randomized, Crossover Trial. AB - OBJECTIVE: It was hypothesized that exposure to mild temperatures above the human thermoneutral zone would decrease caloric intake in a sedentary office environment. METHODS: Women (n = 25) were randomized in a crossover design to perform seated office work for 7 hours in a thermoneutral condition (control, 19 degrees C-20 degrees C) and a condition above the thermoneutral zone (warm, 26 degrees C-27 degrees C). Food intake was estimated by weight and bomb calorimetry, peripheral temperature by thermal imaging, and thermal comfort and productivity by questionnaires. Mixed effects models were used to examine the effects of thermal condition on caloric intake. RESULTS: Participants ate, on average, 357 kcal less in the warm condition, adjusting for BMI and peripheral temperature (P = 0.0219). According to the survey results at midday (after 3.5 hours of exposure), 96% of the participants in the warm condition reported being comfortable (n = 24) compared with 32% in the control condition (n = 8). More participants reported being as productive or more productive than usual in the warm condition (n = 22, 88%) than in the control condition (n = 12, 48%). CONCLUSIONS: This line of research is worthy of further exploration. Untightening climate control toward warmer conditions during summer to increase comfort and productivity while decreasing caloric intake may prove both effective and comfortable. PMID- 30426702 TI - Masthead: Macromol. Biosci. 11/2018. PMID- 30426701 TI - Retrospective analysis for valproate screening targets with LC-ESI-HRMS: An omics based approach. AB - Liquid chromatography coupled high-resolution mass spectrometry (LC-HRMS) is an important analytical tool in the systematic toxicological analysis performed in forensic toxicology. However, some important compounds, such as the antiepileptic drug valproate (valproic acid; VPA), cannot be directly detected with positive electrospray ionization (ESI+ ) due to poor ionization. Here we demonstrate an omics-based retrospective analysis for the identification of indirect screening targets for VPA in whole blood with LC-ESI+ -HRMS. Analysis was performed utilizing data acquired across four years from LC-ESI+ -HRMS, with VPA results from a quantitative LC-MS/MS method. The combined data with VPA results were split into an exploration set (n = 68; 28% positive) and a test set (n = 37; 32% positive). Eight indirect targets for VPA were identified in the exploration set. The evaluation of these targets was confirmed with retrospective target analysis of the test set. Using a combination of two out of the eight indirect targets, we attained a sensitivity of 92% (n = 12; VPA concentration range: 4.4-29.7 mg/kg) and 100% specificity (n = 25) for VPA with LC-ESI+ -HRMS. VPA screening targets were identified with retrospective data analysis and could be appended to the existing screening procedure. A sensitive and specific screening with LC-ESI+ HRMS was achieved with targets corresponding to the sodium adducts of C7 H14 O3 and C8 H14 O3 . Three chromatographic resolved isomer peaks were observed for the latter, and the consistently highest intensity peak was tentatively identified as 3-hydroxy-4-en-VPA. PMID- 30426703 TI - Three Generations of Cobalt Porphyrins as Catalysts in the Oxidation of Cycloalkanes. AB - Three generations of cobalt porphyrins were synthesized, physicochemically characterized by FTIR and UV/Vis spectroscopy as well as cyclic voltammetry and applied as catalysts in the oxidation of cycloalkanes with atmospheric molecular oxygen under mild conditions. All examined catalysts were active in the tested reaction, and their catalytic activity varied with the nature and number of substituents on the porphyrin ring. Introduction of electron-withdrawing or electron-donating substituents at the porphyrin rings increases the activity of metalloporphyrin complexes. It was found, for the first time, that generation II cobalt porphyrins show higher activity in cycloalkane oxidation than cobalt porphyrins of generation III. The lower catalytic activity of generation III cobalt porphyrins can be attributed to the saddle-shaped deformation of the porphyrin macrocycle. DFT modeling of Co porphyrins and their interactions with molecular oxygen provided explanations for the observed effects. On the basis of prior reports and the obtained results, a reaction mechanism is proposed and discussed. PMID- 30426704 TI - Consistency and Balancing in Everyday Health Behaviour: An Ecological Momentary Assessment Approach. AB - BACKGROUND: Little is known about the sequential interplay of different health behaviours. Health behaviours may be connected in four different ways: a healthy behaviour may lead to a subsequent healthy or unhealthy behaviour (positive consistency and licensing, respectively), or an unhealthy behaviour may lead to a subsequent unhealthy or healthy behaviour (negative consistency and cleansing, respectively). In this study, these four possible types of sequential health behaviours were examined jointly in people's daily life. METHODS: The study used ecological momentary assessment. Participants (N = 235; 55% female; age 18-45) were randomly signalled five times daily on their smart phones for seven consecutive days. They reported both healthy and unhealthy behaviours that occurred within the past hour. Participants were also asked if the (healthy or unhealthy) behaviour was related to any previous healthy or unhealthy behaviour. In addition, they completed measures of life satisfaction, general health status, and compensatory health beliefs. RESULTS: Positive consistency predicted satisfaction with life, whereas negative consistency and cleansing negatively predicted general health status. Compensatory health beliefs were not related to actual cleansing or licensing behaviour. CONCLUSIONS: Fostering positive consistency and discouraging cleansing behaviour should play a pivotal role in health promotion programmes. PMID- 30426705 TI - Nursing Diagnoses in People with Digestive Stoma and their Association with Sociodemographic and Clinical Factors. AB - PURPOSE: To determine nursing diagnoses in people with a digestive stoma and their relationship with sociodemographic and clinical variables. METHOD: A cross sectional descriptive study of 102 subjects in the General Surgery Unit of a first-level hospital (Granada, Spain) was conducted. Data were collected on the presence of nursing diagnoses, sociodemographic and clinical variables. RESULTS: NANDA-I: "Deficient knowledge (00126)" and "Readiness for enhanced health management (00162)" were present in the entire sample studied. The period of care (postoperative vs. follow-up) was the most common significant variable among diagnoses. CONCLUSIONS: This work contributes to the determination of NANDA-I diagnoses in people with digestive stomas. IMPLICATIONS FOR NURSING PRACTICE: The results provide a guide to help nursing professionals develop individual care plans. PMID- 30426707 TI - Ectopic pregnancy rate in Iranian midwifery clients and infertile patients treated by assisted reproductive technologies. AB - OBJECTIVE: There are some studies on the prevalence of ectopic pregnancy (EP) in a different population of Iranian women. This study aimed to estimate the ectopic pregnancy prevalence in obstetrical clients and infertile patients treated by assisted reproductive technologies in Iran. METHODS: International and national databases including PubMed, Web of Science, Ovid, Scopus, ScienceDirect, Magiran, Iran doc, and Iran Medex were searched up to January 2016. Also, conference databases were searched. All studies in which, the ectopic pregnancy prevalence in Iranian obstetrical clients and infertile patients treated by assisted reproductive technologies were reported, included and reviewed. Data of studies were extracted into a standard data sheet. Meta-analysis was conducted by a random-effects model with 95% confidence interval. RESULTS: Eight studies were included, involving overall 571 826 women of whom 1446 had an ectopic pregnancy. The overall prevalence of ectopic pregnancy in obstetrical units of the hospitals and assisted reproductive technologies patients was 2.9 (95% CI: 2.1, 3.7) and 53 (95% CI: 20.4, 85.6) per 1000 clients, respectively. CONCLUSION: There is limited evidence on the ectopic pregnancy prevalence in Iranian obstetrical clients and assisted reproductive technologies patients. Furthermore, a significant heterogeneity existed between the results. So, more population-based studies on national data are needed for the exact estimation of the ectopic pregnancy prevalence in Iran. PMID- 30426708 TI - Use of Aggregation-Induced Emission for Selective Detection of Phase Transformation during Evaporative Crystallization of Hexaphenylsilole. AB - Crystallization of organic molecules is quite complicated because the crystallization process is governed by weak intermolecular interactions. By exploiting aggregation-induced emission (AIE), we attempted to realize the selective detection of phase transformation during the evaporative crystallization of hexaphenylsilole (HPS), which shows different fluorescent colors in the amorphous and crystalline phases. No fluorescence emission was observed in the HPS solution immediately after dropping on the glass substrate due to the non-radiative deactivation induced by intramolecular rotational or vibrational motion, suggesting that HPS exists as a monomer in solution. As time elapsed after dropping, green emission first appeared, which changed to blue after solvent evaporation, because of phase transformation from the amorphous state to the crystalline state. This phenomenon supports not only the two-step nucleation model involving an intermediate such as a liquid-like cluster prior to nucleation but also the real-time detection of Ostwald's rule of stages during evaporative crystallization. PMID- 30426709 TI - Development of an ultra-high performance liquid chromatography-tandem mass spectrometry method for the determination of anabolic steroids currently available on the black market in the Czech Republic and Slovakia. AB - Over the past decade, the use of anabolic androgenic steroids (AAS) by recreational bodybuilders and regular gym members has been increasing exponentially. However, there is a lack of knowledge on AAS products sold in the Czech Republic and Slovakia. The aim of this study was to assess the quantity of active substances in AAS products obtained from AAS users in the Czech Republic and Slovakia. In addition, the study also examines the current trends in counterfeit AAS products used by recreational bodybuilders and regular gym members. For this purpose, the authors developed and validated a universal ultra high performance liquid chromatography with tandem mass spectrometry method to determine the most popular doping substances in different pharmaceutical formulations (oil-based injectables, tablets, and capsules). This method was successfully utilized for the analysis of 358 AAS products. Our results showed that 58.9% AAS products analyzed contained the declared active substances at the declared concentrations, 15.9% contained no active substance, 16.8% were under concentrated, 4.5% contained active substances different from those declared on the label, and 3.6% products were over-concentrated. Alarmingly, the results demonstrated that over 40% of the AAS analyzed failed to meet label claims and therefore may pose serious health risks to consumers. This study also highlighted that the availability of AAS should be more rigorously restricted and their quality closely monitored in order to protect AAS users. In conclusion, the authors have developed a precise, accurate, sensitive, selective, and robust method for the routine screening of products containing anabolic androgenic steroids. PMID- 30426706 TI - Blood collection in unstressed, conscious, and freely moving mice through implantation of catheters in the jugular vein: a new simplified protocol. AB - The mouse has become the most common mammalian animal model used in biomedical research. However, laboratory techniques used previously in rats and other larger animals to sample blood had to be adapted in mice due to their lower mouse plasma volume. Sampling is further confounded by the variability in plasma hormone and metabolite concentrations that can occur from the stress or the anesthesia that accompanies the collection. In this article, we describe in detail a protocol we developed for blood sampling in conscious, unrestrained mice. Our protocol implements the use of chronic indwelling catheters in the right external jugular vein, allowing the mice to recover fully in their home cages, untethered until the time of blood sampling. This protocol employs catheters that remain patent for days and does not require the purchase of expensive equipment. We validated this protocol by measuring the time course of plasma norepinephrine (NE) concentration during and after the relief of acute immobilization stress in wild type (WT) and pendrin knockout (KO) mice and compared these results with our previously published values. We found that following relief from immobilization stress, it takes longer for plasma NE concentration to return to basal levels in the pendrin KO than in the wild type mice. These results highlight the potential utility of this protocol and the potential role of pendrin in the neuroendocrine response to acute stress. PMID- 30426710 TI - Melanocortin-3 Receptors Expressed on Agouti-Related Peptide Neurons Inhibit Feeding Behavior in Female Mice. AB - OBJECTIVE: Activation of hypothalamic agouti-related peptide expressing (AgRP)+ve neurons during energy deficit is a negative valence signal, rapidly activating food-seeking behaviors. This study examined the roles of melanocortin-3 receptors (MC3Rs) coexpressed in a subpopulation of AgRP+ve neurons. METHODS: AgRP-MC3R mice expressing MC3Rs selectively in AgRP+ve neurons were generated by crossing AgRP-IRES-Cre mice with LoxTBMc3r mice containing a "loxP-STOP-loxP" sequence in the 5' untranslated region. Body weight, body composition, and feeding behavior were assessed during ad libitum and time-restricted feeding conditions. RESULTS: In females, food intake of AgRP-IRES-Cre+ve (n = 7) or AgRP-IRES-Cre-ve (n = 9) mice was not significantly different; these mice were therefore pooled to form the "control" group. Female AgRP-MC3R mice exhibited lower food intake (25.4 +/- 2.4 kJ/12 h; n = 6) compared with controls (35.3 +/- 1.8 kJ/12 h; n = 16) and LoxTBMc3r mice (32.1 +/- 2.1 kJ/12 h; n = 9) in the active phase during the dark period. Food intake during the rest phase (lights on) when mice consume less food (9-10 kJ) was normal between genotypes. Body weight and composition of AgRP-MC3R and LoxTBMc3r mice were similar, suggesting compensatory mechanisms for reduced calorie intake. Remarkably, AgRP-MC3R mice continued to consume less food during refeeding after fasting and time-restricted feeding. CONCLUSIONS: MC3Rs expressed on AgRP+ve neurons appear to exert a strong inhibitory signal on hypothalamic networks governing feeding behavior. PMID- 30426711 TI - Colorimetric detection of gallic acid based on the enhanced oxidase-like activity of floral-like magnetic Fe3 O4 @MnO2. AB - In this study, a colorimetric method was developed for rapid and sensitive determination of gallic acid (GA) by using floral-like magnetic Fe3 O4 @MnO2 composite material with enhanced oxidase-like activity. Fe3 O4 @MnO2 composite material is able to oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to a blue product (oxTMB) with apparent color change and absorbance at 652 nm. GA can reduce the oxTMB yielding a fading blue color. Based on these results, a technique is proposed to detect GA quantitatively and qualitatively with UV-vis spectroscopy and bare eyes. A low detection limit of 0.105 MUM and a detection range of 0.01 to 15 MUM were obtained with UV-vis spectroscopy. This methodology possesses high potential for application in determination of GA. PMID- 30426712 TI - A Monolithic Fluid Structure Interaction Framework Applied to Red Blood Cells. AB - A parallel fully-coupled (monolithic) fluid-structure interaction (FSI) algorithm has been applied to the deformation of red blood cells (RBCs) in capillaries, where cell deformability has significant effects on blood rheology. In the present FSI algorithm, fluid domain is discretized using the side-centered unstructured finite volume method based on Arbitrary Lagrangian-Eulerian (ALE) formulation, meanwhile solid domain is discretized with the classical Galerkin finite element formulation for the Saint Venant-Kirchhoff material in a Lagrangian frame. In addition, the compatible kinematic boundary condition is enforced at the fluid-solid interface in order to conserve the mass of cytoplasmic fluid within the red cell at machine precision. In order to solve the resulting large-scale algebraic linear systems in a fully coupled manner, a new matrix factorization is introduced similar to that of the projection method and the parallel algebraic multigrid solver Boomer AMG is used for the scaled discrete Laplacian provided by the HYPRE library which we access through the PETSc library. Three important physical parameters for the blood ow are simulated and analyzed: (i) the effect of capillary diameter, (ii) the effect of red cell membrane thickness and (iii) the effect of red cell spacing (hematocrit). The numerical calculations initially indicate a shape deformation in which biconcave discoid shape changes to a parachute-like shape. Furthermore, the parachute-like cell shape in small capillaries undergoes a cupcake shaped buckling instability, which has not been observed in the literature. The instability forms thin rib like features and the red cell deformation is not axisymmetric but three dimensional. PMID- 30426713 TI - Complete intracorporeal defect closure using unidirectional barbed suture in laparoscopic incisional hernia repair: Preliminary experience with short-term follow-up. AB - INTRODUCTION: Surgical techniques to close defects in laparoscopic incisional hernia repair vary across the literature. We herein demonstrate our original and standardized surgical technique for laparoscopic incisional hernia repair with complete intracorporeal defect closure using barbed suture. MATERIALS AND SURGICAL TECHNIQUE: Complete intracorporeal defect closures were indicated for defects less than or equal to 6 cm in transverse diameter. We performed a defect closure with a running suture using barbed suture in a caudal to cranial direction, with tissue bites and inter-suture spacing of 1 cm each. The hernial sac was incorporated into the suturing to reduce possible dead space. After the procedure, intraperitoneal onlay mesh was placed. Seven patients underwent this procedure. The median total operative time was 188 min, and the median time specifically for defect closure was 25 min. There was no seroma, mesh bulge, persisting pain, or hernia recurrence at follow-up. DISCUSSION: Our proposed technique is simple and can be safely performed with good short-term outcomes. PMID- 30426714 TI - Intravenous fosaprepitant for the prevention of chemotherapy-induced vomiting in children: A double-blind, placebo-controlled, phase III randomized trial. AB - BACKGROUND: Fosaprepitant is a neurokinin-1 receptor antagonist, approved for the prevention of chemotherapy-induced nausea and vomiting. The data on the use of fosaprepitant in children are limited and therefore we conducted a phase III randomized controlled trial. PROCEDURE: Children aged 1-12 years scheduled to receive moderately or highly emetogenic chemotherapy were randomly assigned to arm-A (fosaprepitant) or arm-B (placebo). Children recruited to arm-A received intravenous ondansetron plus dexamethasone followed by fosaprepitant infusion. Children recruited to arm-B received the same drugs as those given to children in arm-A, except that fosaprepitant was substituted with a placebo. Ondansetron and dexamethasone were continued for 48 hours after completion of chemotherapy. The primary end point of the study was to determine the proportion of patients who achieved a complete response (CR), defined as no vomiting, no retching, and no use of rescue medication, during the 24-120 hours (delayed phase) after administration of the last dose of chemotherapy. Secondary end points were the proportion of patients who achieved a CR during the acute phase (0-24 hours) and overall after administration of the last dose of chemotherapy. RESULTS: One hundred-sixty-three patients were analyzed (81 in the fosaprepitant arm and 82 in the placebo arm). CR rates were significantly higher in the fosaprepitant arm compared to those in the placebo arm during the acute phase (86% vs 60%, P < 0.001), delayed phase (79% vs 51%, P < 0.001), and overall phase (70% vs 41%, P < 0.001). Three (4%) patients in the fosaprepitant arm and sixteen (20%) in the placebo arm required rescue anti-emetics (P = 0.0017). CONCLUSION: Addition of fosaprepitant to ondansetron and dexamethasone improved chemotherapy-induced vomiting control in children treated with moderately or highly emetogenic chemotherapy. PMID- 30426715 TI - Backward sensitivity analysis and reduced-order covariance estimation in non invasive parameter identification for cerebral arteries. AB - Using a previously developed inversion platform for functional cerebral medical imaging with ensemble Kalman filters, this work analyses the sensitivity of the results with respect to different parameters entering the physical model and inversion procedure, such as the inlet flow rate from the heart, the choice of the boundary conditions and the non-symmetry in the network terminations. It also proposes an alternative low complexity construction for the covariance matrix of the hemodynamic parameters of a network of arteries including the circle of Willis. The platform takes as input patient specific blood flow rates extracted from Magnetic Resonance Angiography and Magnetic Resonance Imaging (dicom files) and is applied to several available patients data. The paper presents full analysis of the results for one of these patients, including a sensitivity study with respect to the proximal and distal boundary conditions. The results notably show that the uncertainties on the inlet flow rate led to uncertainties of the same order of magnitude in the estimated parameters (blood pressure and elastic parameters) and that 3-lumped parameters boundary conditions are necessary for a correct retrieval of the target signals. PMID- 30426717 TI - Perils and Promises of Therapeutic Approaches for the Stem Cell Disease Fibrous Dysplasia. PMID- 30426718 TI - Maternal vitamin D and E intakes in pregnancy and asthma to age 15 years: A cohort study. AB - This study investigated whether the previously reported associations in this birth cohort between maternal vitamin D and E intakes during pregnancy and childhood wheeze/asthma outcomes at age 5 and 10 years are still evident at age 15 years. In a prospective study of 1924 children recruited in utero, maternal vitamin D and E intakes during pregnancy were assessed by food frequency questionnaire and the children completed raespiratory questionnaire at age 15 years. Treatment for asthma at age 15 was also ascertained using healthcare data. Maternal vitamin D and E intakes were also related to combined childhood asthma data collected at 1, 2, 5, 10, and 15 years of age. Symptom data were available for 747 (39%) 15-year olds and healthcare data for 1689 (88%). There were no associations between maternal vitamin D and E intakes and childhood wheeze and asthma at age 15. Analysis of combined data collected between 1 and 15 years of age demonstrated that higher maternal vitamin D and E intakes during pregnancy were associated with a reduced likelihood of being diagnosed with asthma in the first 15 years: hazard ratio (95%CI) per quartile increase in vitamin intake of 0.87 (0.78,0.98) and 0.88 (0.78,0.98), respectively. Lower maternal vitamin D and E intakes during pregnancy are associated with increased risk of children wheezing and being diagnosed with asthma in the first 10 years but not after puberty, suggesting that post-natal exposures predominate in the etiology of incident asthma as children transition through puberty into adulthood. PMID- 30426716 TI - Red blood cell volume is not decreased in ESA-naive anemic chronic kidney disease patients. AB - Anemia is defined according to decreased blood hemoglobin concentration ([Hb]), which is considered a marker of low total red blood cell volume (RBCV). Alterations of plasma volume (PV) may also modify [Hb] without concomitant changes in RBCV. Since anemia and fluid retention are frequent complications of chronic kidney disease (CKD), we hypothesized that anemia during CKD may in part be related to expanded PV without a simultaneous decrease in RBCV. We quantified hemoglobin mass, RBCV, PV, and total blood volume (BV) using an automated carbon monoxide device in 40 consecutive stage 3-5 CKD patients not on dialysis and in seven healthy male controls of the same age range. These were compared within and to predicted volumes according to Nadler's formula. Arterial stiffness and NT proBNP were measured. RBCV was similar to predicted values range in anemic CKD patients 2073 (1818-2704) versus, 2061 (1725-2473) mL, P > 0.05. In contrast, PV was largely increased in anemic CKD patients (3881 (3212-4352) vs. 2916 (2851 3201)), P = 0.01. Of 26 anemic patients, only six had a >20% decrease in RBCV as the cause for their anemia, whereas 14 had a >20% increase of PV as a cause for their anemia. NT-pro BNP correlated with eGFR but neither with PV nor BV, whereas arterial stiffness was not correlated to blood volumes. Anemia in CKD as diagnosed by low [Hb] is not necessarily associated to low RBCV but may reflect increased PV. This finding has implications for the treatment of CKD patients and may refrain from normalizing [Hb] levels in all CKD patients. PMID- 30426719 TI - Reducing Palivizumab Dose Requirements Through Rational Dose Regimen Design. AB - Palivizumab for respiratory syncytial virus (RSV) immunoprophylaxis in premature infants poses a significant economic challenge. Although standard dosing of palivizumab results in unnecessary drug accumulation without additional clinical benefit, some clinicians have moved outside of evidence-based practice by implementing untested dose modifications, potentially jeopardizing efficacy. Using an industry-developed population pharmacokinetic model, this study evaluated the previously published alternate dosing regimens and developed a revised regimen that minimizes palivizumab dose requirements while maintaining established therapeutic concentrations. All published dose modifications resulted in unacceptably high proportions of infants not attaining minimum protective concentrations, compromising efficacy. Through intelligent dose regimen design, a clinically practical palivizumab regimen was devised that reduces drug use by 25%, while enabling a greater proportion of infants attaining early season target concentrations, particularly those at greatest risk of the consequences of RSV infection. This novel regimen has the potential to substantially change clinical practice and increase drug availability. PMID- 30426720 TI - Multiregional radiomics profiling from multiparametric MRI: Identifying an imaging predictor of IDH1 mutation status in glioblastoma. AB - PURPOSE: Isocitrate dehydrogenase 1 (IDH1) has been proven as a prognostic and predictive marker in glioblastoma (GBM) patients. The purpose was to preoperatively predict IDH mutation status in GBM using multiregional radiomics features from multiparametric magnetic resonance imaging (MRI). METHODS: In this retrospective multicenter study, 225 patients were included. A total of 1614 multiregional features were extracted from enhancement area, non-enhancement area, necrosis, edema, tumor core, and whole tumor in multiparametric MRI. Three multiregional radiomics models were built from tumor core, whole tumor, and all regions using an all-relevant feature selection and a random forest classification for predicting IDH1. Four single-region models and a model combining all-region features with clinical factors (age, sex, and Karnofsky performance status) were also built. All models were built from a training cohort (118 patients) and tested on an independent validation cohort (107 patients). RESULTS: Among the four single-region radiomics models, the edema model achieved the best accuracy of 96% and the best F1-score of 0.75 while the non-enhancement model achieved the best area under the receiver operating characteristic curve (AUC) of 0.88 in the validation cohort. The overall performance of the tumor-core model (accuracy 0.96, AUC 0.86 and F1-score 0.75) and the whole-tumor model (accuracy 0.96, AUC 0.88 and F1-score 0.75) was slightly better than the single regional models. The 8-feature all-region radiomics model achieved an improved overall performance of an accuracy 96%, an AUC 0.90, and an F1-score 0.78. Among all models, the model combining all-region imaging features with age achieved the best performance of an accuracy 97%, an AUC 0.96, and an F1-score 0.84. CONCLUSIONS: The radiomics model built with multiregional features from multiparametric MRI has the potential to preoperatively detect the IDH1 mutation status in GBM patients. The multiregional model built with all-region features performed better than the single-region models, while combining age with all region features achieved the best performance. PMID- 30426721 TI - Coverage for Obesity Prevention and Treatment Services: Analysis of Medicaid and State Employee Health Insurance Programs. AB - OBJECTIVE: This study examined changes in coverage for adult obesity treatment services in Medicaid and state employee health insurance programs between 2009 and 2017. METHODS: Administrative materials from Medicaid and state employee health insurance programs in all 50 states and the District of Columbia were reviewed for indications of coverage and payment policies specific to evidence based treatment modalities for adults (>= 21 years of age) with obesity, including nutritional counseling, pharmacotherapy, and bariatric surgery. RESULTS: From 2009 to 2017, the proportion of state employee programs indicating coverage increased by 75% for nutritional counseling (from 24 to 42 states), 64% for pharmacotherapy (from 14 to 23 states), and 23% for bariatric surgery (from 35 to 43 states). The proportion of Medicaid programs indicating coverage increased by 133% for nutritional counseling (from 9 to 21 states) and 9% for bariatric surgery (from 45 to 49 states), with no net increase for pharmacotherapy (16 states in both plan years). CONCLUSIONS: Coverage for adult obesity care improved substantially in Medicaid and state employee insurance programs since 2009. However, recommended treatment modalities are still not covered in many states. Where coverage has expanded, educating providers and beneficiaries on the availability and proper use of evidence-based obesity treatments may improve health outcomes. PMID- 30426722 TI - "Work-to-Work" exercise slows pulmonary oxygen uptake kinetics, decreases critical power, and increases W' during supine cycling. AB - We have previously demonstrated that the phase II time constant of pulmonary oxygen uptake kinetics ( tauvo2 ) is an independent determinant of critical power (CP) when O2 availability is not limiting, that is, during upright cycle exercise in young, healthy individuals. Whether this causative relationship remains when O2 availability is impaired remains unknown. During supine exercise, which causes an O2 availability limitation during the exercise transition, we therefore determined the impact of a raised baseline work rate on tauvo2 and CP. CP, tauvo2 , and muscle oxygenation status (the latter via near-infrared spectroscopy) were determined via four severe-intensity constant-power exercise tests completed in two conditions: (1) with exercise initiated from an unloaded cycling baseline (U >S), and (2) with exercise initiated from a moderate-intensity baseline work rate of 90% of the gas exchange threshold (M->S). In M->S, critical power was lower (U >S = 146 +/- 39 W vs. M->S = 132 +/- 33 W, P = 0.023) and tauvo2 was greater (U >S = 45 +/- 16 sec, vs. M->S = 69 +/- 129 sec, P = 0.001) when compared to U->S. There was no difference in tissue oxyhemoglobin concentration ([HbO2 + MbO2 ]) at baseline or during exercise. The concomitant increase in tauvo2 and reduction in CP during M->S compared to U->S shows for the first time that tauvo2 is an independent determinant of CP in conditions where O2 availability is limiting. PMID- 30426724 TI - Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma. AB - Asthma is a chronic inflammatory disease characterized by airway inflammation and remodeling, which can lead to progressive decline of lung function. Although mesenchymal stromal cells (MSCs) have shown beneficial immunomodulatory properties in preclinical models of allergic asthma, effects on airway remodeling have been limited. Mounting evidence suggests that prior exposure of MSCs to specific inflammatory stimuli or environments can enhance their immunomodulatory properties. Therefore, we investigated whether stimulating MSCs with bronchoalveolar lavage fluid (BALF) or serum from asthmatic mice could potentiate their therapeutic properties in experimental asthma. In a house dust mite (HDM) extract asthma model in mice, unstimulated, asthmatic BALF-stimulated, or asthmatic serum-stimulated MSCs were administered intratracheally 24 hours after the final HDM challenge. Lung mechanics and histology; BALF protein, cellularity, and biomarker levels; and lymph-node and bone marrow cellularity were assessed. Compared with unstimulated or BALF-stimulated MSCs, serum-stimulated MSCs further reduced BALF levels of interleukin (IL)-4, IL-13, and eotaxin, total and differential cellularity in BALF, bone marrow and lymph nodes, and collagen fiber content, while increasing BALF IL-10 levels and improving lung function. Serum stimulation led to higher MSC apoptosis, expression of various mediators (transforming growth factor-beta, interferon-gamma, IL-10, tumor necrosis factor alpha-stimulated gene 6 protein, indoleamine 2,3-dioxygenase-1, and IL-1 receptor antagonist), and polarization of macrophages to M2 phenotype. In conclusion, asthmatic serum may be a novel strategy to potentiate therapeutic effects of MSCs in experimental asthma, leading to further reductions in both inflammation and remodeling than can be achieved with unstimulated MSCs. Stem Cells Translational Medicine 2018. PMID- 30426723 TI - LPS-stimulated NF-kappaB p65 dynamic response marks the initiation of TNF expression and transition to IL-10 expression in RAW 264.7 macrophages. AB - During injury and infection, inflammation is a response by macrophages to effect healing and repair. The kinetics of the responses of proinflammatory TNFalpha, anti-inflammatory IL-10, and inflammatory master regulator NF-kappaB elicited by lipopolysaccharide (LPS) may be critical determinants of the inflammatory response by macrophages; however, there is a lack of homogeneous kinetic data in this pathway. To address this gap, we used the RAW 264.7 macrophage cell line to define intracellular signaling kinetics and cytokine expression in cells treated with LPS for 15 min to 72 h. The abundance of IkappaBalpha was maximally reduced 45-min following LPS treatment, but expression increased at 10-h, reaching a maximum at 16 h. NF-kappaB phosphorylation was significantly increased 45-min following LPS treatment, maximal at 2-h, and decreased to basal levels by 6-h. Nuclear NF-kappaB expression was elevated 30-min following LPS treatment, maximal by 45-min, and returned to basal levels by 24-h. Binding of nuclear NF-kappaB to consensus oligonucleotide sequences followed a similar pattern to that observed for p-NF-kappaB, but lasted slightly longer. Following LPS treatment, TNFalpha mRNA expression began at 1-h, was maximal at 6-h, and decreased starting at 10-h. TNFalpha protein secretion in conditioned growth medium began at 4-h and was maximal by 16-h. IL-10 mRNA expression was induced by LPS at 10-h, and was maximal at 16-h. IL-10 protein secretion was induced at 16-h and was maximal at 24-h. Our data reveal the temporal kinetics of pro- and anti-inflammatory signaling events that may be important therapeutic targets for inflammatory diseases. PMID- 30426725 TI - Morita therapy for the treatment of emetophobia: A case report. AB - Until recently, the treatments for emetophobia (the fear of vomiting) have not been well studied. In Japan, Morita therapy is a known, excellent treatment option for emetophobia, but to our knowledge, there is currently no case report of Morita therapy for the treatment of emetophobia in English. Here, we present a case of emetophobia that was treated with Morita therapy and discuss its effectiveness and characteristics. PMID- 30426726 TI - HDAC8, A Potential Therapeutic Target, Regulates Proliferation and Differentiation of Bone Marrow Stromal Cells in Fibrous Dysplasia. AB - Fibrous dysplasia (FD) is a disease of postnatal skeletal stem cells caused by activating mutations of guanine nucleotide-binding protein alpha-stimulating activity polypeptide (GNAS). FD is characterized by high proliferation and osteogenesis disorder of bone marrow stromal cells (BMSCs), resulting in bone pain, deformities, and fractures. The cAMP-CREB pathway, which is activated by GNAS mutations, is known to be closely associated with the occurrence of FD. However, so far there is no available targeted therapeutic strategy for FD, as a critical issue that remains largely unknown is how this pathway is involved in FD. Our previous study revealed that histone deacetylase 8 (HDAC8) inhibited the osteogenic differentiation of BMSCs via epigenetic regulation. Here, compared with normal BMSCs, FD BMSCs exhibited significantly high proliferation and weak osteogenic capacity in response to HDAC8 upregulation and tumor protein 53 (TP53) downregulation. Moreover, inhibition of cAMP reduced HDAC8 expression, increased TP53 expression and resulted in the improvement of FD phenotype. Importantly, HDAC8 inhibition prevented cAMP-induced cell phenotype and promoted osteogenesis in nude mice that were implanted with FD BMSCs. Mechanistically, HDAC8 was identified as a transcriptional target gene of CREB1 and its transcription was directly activated by CREB1 in FD BMSCs. In summary, our study reveals that HDAC8 associates with FD phenotype and demonstrates the mechanisms regulated by cAMP CREB1-HDAC8 pathway. These results provide insights into the molecular regulation of FD pathogenesis, and offer novel clues that small molecule inhibitors targeting HDAC8 are promising clinical treatment for FD. Stem Cells Translational Medicine 2018. PMID- 30426728 TI - The Nursing Diagnosis of "Death Anxiety": Content Validation by Experts. AB - PURPOSE: To validate the content of the NANDA-I diagnosis "death anxiety" (00147). METHODS: Descriptive study using the Fehring model with 202 Spanish nurses who were expert in end-of-life care to explore the adequacy of the components of the NANDA-I diagnosis "death anxiety" (00147) in the Spanish edition. FINDINGS: None of the diagnosis definitions were considered as representative. Furthermore, 5 of the 56 defining characteristics and 5 of the 26 related factors were validated as major. CONCLUSIONS: In general, the components of the diagnosis "death anxiety" (00147) in the Spanish edition are not representative according to experts. IMPLICATIONS FOR NURSING PRACTICE: The results support the need to either exclude the diagnosis from the taxonomy or adjust its content. PMID- 30426727 TI - The influence of knowledge of performance endpoint on pacing strategies, perception of effort, and neural activity during 30-km cycling time trials. AB - It is understood that withholding information during exercise can alter performance during self-paced exercise, though less is known about neural activity during such exercise. The aim of this study was to compare the effects of withholding versus providing distance feedback on perception, muscular activation, and cerebral activity during cycling time trials (TT). Nine well trained male cyclists randomly completed 2 x 30-km TT, with provision of performance information and distance feedback (known; KTT), and without performance information and remaining distance (unknown; UTT). Prefrontal cortex (PFC) hemoglobin concentration, electroencephalogy (EEG) responses of the parietal lobe (PL) and motor cortex (MC), and surface electromyogram (EMG) of the right thigh were monitored throughout the TTs, in addition to heart rate (HR), rating of perceived exertion (RPE), and power output (PO). Time to completion was shorter for the KTT compared to UTT (51.04 +/- 3.26 vs. 49.25 +/- 3.57 min, P = 0.01). There were no differences evident for RPE between conditions (P > 0.50). However, during the final 2 km, the KTT presented higher PO (P <= 0.05), HR (P = 0.03) and MC, and PL EEG activity (d = 0.51-0.71) in addition to increased tissue hemoglobin index (nTHI) and oxygen extraction (HHb) (d = 0.55-0.65) compared to the UTT. In conclusion, when withholding information pertaining to remaining distance, performance was reduced due to the application of a conservative pacing strategy. In addition, the increase in HHb across the PFC was strongly correlated with PO (r = 0.790; P < 0.001) suggesting knowledge about remaining distance may increase activation across the PFC. Further, it appears that changes within the PFC may play a role in the regulation of cycling performance. PMID- 30426729 TI - Patterns of dyspnoea onset in patients with acute heart failure: clinical and prognostic implications. AB - AIMS: Despite attempts to improve the management of patients with acute heart failure (HF), virtually all therapeutic agents investigated in large clinical trials failed to show any consistent reduction in mortality and morbidity. Complexity of the clinical syndrome of acute HF seems to be likely an underlying explanation. Traditionally, clinical trials studied mixed patient populations with acute HF, and only recently, better clinical characterization of patients has been proposed. Dyspnoea is the most common presenting symptom related to hospital admission for acute HF. Whether in patients with acute HF, the pattern of symptoms onset preceding hospital admission is associated with clinical characteristics, and the outcomes have not yet been established. METHODS AND RESULTS: We investigated 137 patients (mean age: 65 +/- 13 years; 80% men) hospitalized due to acute HF with dyspnoea as major reported symptom, who were divided according to the time of its onset into those with acute (n = 98) vs. subacute (n = 39) onset (i.e. within 7 days vs. >7 days preceding hospital admission, respectively). On admission, the former group presented higher blood pressure (138 +/- 33 vs. 121 +/- 32 mmHg), more often moderate-severe pulmonary congestion (33 vs. 8%), and lower bilirubin level [1.07 (0.72-1.60) vs. 1.27 (0.87-2.06); P < 0.05 in all comparisons]. There were no other differences in baseline clinical characteristics and laboratory indices. Higher percentage of patients with an acute dyspnoea onset reported marked/moderate dyspnoea relief after 6 (18% vs. 7%), 24 (59% vs. 24%), and 48 h (80% vs. 46% assessed as an improvement of at least 5 points in self-reported 10-point Likert scale; P < 0.05 in all time points). In patients with an acute onset of dyspnoea after 48 h, a decrease of N-terminal pro BNP was more frequently observed (83% vs. 65%), and the levels of endothelin-1 were more reduced [-1.1 (-2.9-0.03) vs 0.4 (-2.2-1.4); all P < 0.05]. Patients with acute onset experienced less in-hospital HF worsening (13% vs. 40%, P = 0.001), and 1 year cardiovascular mortality was significantly lower (20% vs. 41%, P = 0.01). On the multivariable analysis, subacute pattern of dyspnoea was independent predictor of 12 month cardiovascular mortality in patients with acute HF after adjusting for other prognostic factors: systolic blood pressure, urea, and HF de novo [hazard ratio (95% confidence interval): 2.32 (1.13-4.75), P = 0.02]. CONCLUSIONS: In patients with acute HF, the pattern of symptoms onset is associated with baseline differences in clinical characteristics, biomarker profile, response to standard treatment, and the long term outcomes. This is relevant information for planning future clinical trials. PMID- 30426730 TI - Contact, high-resolution spatial diffuse reflectance imaging system for skin condition diagnosis. AB - Spatially resolved diffuse reflectance spectroscopy (srDRS) is a well-established technique for noninvasive, in vivo characterization of tissue optical properties toward diagnostic applications. srDRS has a potential for depth-resolved analysis of tissue, which is desired in various clinical situations. However, current fiber-based and photodiode-based systems have difficulties achieving this goal due to challenges in sampling the reflectance with a high enough resolution. We introduce a compact, low-cost architecture for srDRS based on the use of a multipixel imaging sensor and light-emitting diodes to achieve lensless diffuse reflectance imaging in contact with the tissue with high spatial resolution. For proof-of-concept, a prototype device, involving a commercially available complementary metal-oxide semiconductor coupled with a fiber-optic plate, was fabricated. Diffuse reflectance profiles were acquired at 645 nm at source-to detector separations ranging from 480 MUm to 4 mm with a resolution of 16.7 MUm. Absorption coefficients (MUa) and reduced scattering coefficients (MUs') of homogeneous tissue-mimicking phantoms were measured with 4.2 +/- 3.5 % and 7.0 +/- 4.6 % error, respectively. The results obtained confirm the potential of our approach for quantitative characterization of tissue optical properties in contact imaging modality. This study is a first step toward the development of low-cost, wearable devices for skin condition diagnosis in vivo. PMID- 30426731 TI - Improving the identification of patients with delirium using the 4AT assessment. AB - Delirium is a common neuropsychiatric disorder that all those working with older people will have encountered at some stage. Delirium is often poorly identified in hospital settings and therefore not optimally managed. After data collection on the acute medical unit in an acute hospital trust in the UK it was evident that patients with signs of delirium were not being formally assessed and therefore not appropriately managed in many cases. A quality improvement project introduced the 4AT delirium assessment tool to try to ensure that patients with delirium were being identified. The project team carried out several plan-do studyact cycles to bring about our changes, which included a 4AT assessment sticker for nursing staff to complete and teaching for all healthcare staff. Through involvement of all members of the multidisciplinary team and ongoing feedback and changes we were able to increase assessment of delirium from 0% to 64%. There is ongoing work to be done to continue to improve delirium management, but by initially improving the assessment and identification of delirium we will make a difference to these patients' outcomes. PMID- 30426732 TI - Postoperative pain (POP) after vitreo-retinal surgery is influenced by duration of surgery and anaesthesia conduction; opioids are not necessary for its management. AB - BACKGROUND: The control of postoperative pain (POP) is a key component of perioperative care. POP after vitreo-retinal surgery (VRS) has been under investigated, and its incidence remains elusive. METHODS: In order to assess POP after VRS, the associated risk factors and efficacy of the analgesic protocol in use at our institution, we made a 1-year retrospective study on patients undergoing VRS. Patients aged >18 years, ASA status I-III undergoing VRS entered the study. POP was evaluated by measuring a Numerical Rating Scale (NRS), and analgesic consumption. RESULTS: 782 patients entered the study. Patients received locoregional (LRA) or general anaesthesia (GA) with supplemental block. 22% of patients needed analgesics (acetaminophen in 97% of cases), mostly between 2-6 hours after surgery. The univariate analysis showed a positive association between POP and duration of surgery (p<0.0001) and glaucoma (p=0.04), and a negative association with age (p=0.008), analgesic administration at the end of surgery (p=0.005) and the intra-operative administration of remifentanil for surgery under LRA (p= 0.02); sedation to execute the block for LRA did not reduce POP. Patients treated with GA with supplemental block had less pain compared to those treated with LRA with/without remifentanil (p=0.03, p=0.002 respectively). The multivariate analysis confirmed a positive correlation between POP and duration of surgery (p= 0.0007) and a negative correlation with the intra operative remifentanil administration during LRA (p=0.04), and with GA with supplemental block (p=0.01). CONCLUSIONS: The incidence of POP after VRS is low but not absent, especially for long procedures, it does not require postoperative opioids and can be modified by anesthesiologic choices. PMID- 30426733 TI - Overexpression of kynurenic acid and 3-hydroxyanthranilic acid after rat traumatic brain injury. AB - Using an immunohistochemical technique, we have studied the distribution of kynuneric acid (KYNA) and 3-hydroxyanthranilic acid (3-HAA) in a rat brain injury model (trauma). The study was carried out inducing a cerebral ablation of the frontal motor cortex. Two mouse monoclonal specific antibodies previously developed by our group directed against KYNA and 3-HAA were used. In control animals (sham-operated), the expression of both KYNA and 3-HAA was not observed. In animals in which the ablation was performed, the highest number of immunoreactive cells containing KYNA or 3-HAA was observed in the region surrounding the lesion and the number of these cells decreased moving away from the lesion. KYNA and 3-HAA were also observed in the white matter (ipsilateral side) located close to the injured region and in some cells placed in the white matter of the contralateral side. The distribution of KYNA and 3-HAA perfectly matched with the peripheral injured regions. The results found were identical independently of the perfusion date of animals (17, 30 or 54 days after brain injury). For the first time, the presence of KYNA and 3-HAA has been described in a rat trauma model. Moreover, by using a double immunocytochemistry protocol, it has been demonstrated that both metabolites were located in astrocytes. The findings observed suggest that, in cerebral trauma, KYNA and 3-HAA are involved in tissue damage and that these compounds could act, respectively, as a neuroprotector and a neurotoxic. This means that, in trauma, a counterbalance occurs and that a regulation of the indoleamine 2,3 dioxygenase (IDO) pathway could be required after a brain injury in order to decrease the deleterious effects of ending metabolites (the neurotoxic picolinic acid). Moreover, the localization of KYNA and 3-HAA in the contralateral side of the lesion suggests that the IDO pathway is also involved in the sprouting and pathfinding that follows a traumatic brain injury. PMID- 30426734 TI - One-Step Synthesis of Statically Amphiphilic/Dynamically Amphiphobic Fluoride Free Transparent Coatings. AB - Although amphiphobic materials have attracted tremendous attention recently owing to their many important applications, there remain some critical challenges such as complex or expensive fabrications, poor long-term stability, nontransparency, etc. Herein, we develop a novel kind of amphiphobic materials-statically amphiphilic but dynamically amphiphobic fluoride-free transparent coating-through one-step reaction. The obtained transparent coating can be readily applied to different kinds of substrates including flat surfaces, curved surfaces, or inner walls of some tubes and bottles, and demonstrate excellent repellency against various high/low-surface-tension liquids and outstanding stability against external damages. PMID- 30426735 TI - Exfoliation Behavior of van der Waals Strings: Case Study of Bi2S3. AB - The family of crystals constituting covalently bound strings, held together by van der Waals forces, can be exfoliated into smaller entities, similar to crystals made of van der Waals sheets. Depending on the anisotropy of such crystals, as well as the spacing between their strings in each direction, van der Waals sheets or ribbons can be obtained after the exfoliation process. In this work, we demonstrate that ultrathin nanoribbons of bismuth sulfide (Bi2S3) can be synthesized via a high-power sonication process. The thickness and width of these ribbons are governed by the van der Waals spacings around the strings within the parent crystal. The lengths of the nanoribbons are initially limited by the dimensions of the starting bulk particles. Interestingly, these nanoribbons change stoichiometry and composition and are elongated when the duration of agitation increases because of Ostwald ripening. An application of the exfoliated van der Waals strings is presented for optical biosensing using photoluminescence of Bi2S3 nanoribbons, reaching detection limits of less than 10 nM L-1 in response to bovine serum albumin. The concept of exfoliating van der Waals strings could be extended to a large class of crystals for creating bodies ranging from sheets to strings, with optoelectronic properties different from that of their bulk counterparts. PMID- 30426736 TI - Electrical Conductivity Modeling of Graphene-based Conductor Materials. AB - Graphene-based conductors such as films and fibers aim to transfer graphene's extraordinary properties to the macroscopic scale. They show great potential for large-scale applications, but there is a lack of theoretical models to describe their electrical characteristics. We present a network simulation method to model the electrical conductivity of graphene-based conductors. The method considers all of the relevant microscopic parameters such as graphene flake conductivity, interlayer conductivity, packing density, and flake size. To provide a mathematical framework, we derive an analytical expression, which reproduces the essential features of the network model. We also find good agreement with experimental data. Our results offer production guidelines and enable the systematic optimization of high-performance graphene-based conductor materials. A generalization of the model to any conductor based on two-dimensional materials is straightforward. PMID- 30426737 TI - Dual Functionalization of Nanoparticles for Generating Corona-Free and Non Cytotoxic Silica Nanoparticles. AB - Protein coronas form on the surfaces of nanomaterials in biological fluids. This layer of proteins affects the properties of nanomaterials, altering their behavior and masking engineered functionality. The use of non-fouling moieties reduces or prevents corona formation, however these ligands typically complicate functionalization. We present here a surface modification strategy for silica nanoparticles using specific molar ratios of zwitterionic and amine moieties. Through proper balance of ligands, we were able to generate particles that featured reactive 'handles', while retaining non-fouling properties, high hemocompatibility and low cytotoxicity. PMID- 30426738 TI - Effects of Charcoal on Carbonyl Delivery from Commercial, Research, and Make-Your Own Cigarettes. AB - Previous literature has shown that adding charcoal to cigarette filters can have varying effects on the delivery of toxic carbonyls depending on filter design, amount of charcoal, and puffing profiles. However, these studies have relied on either comparisons between commercially available charcoal and noncharcoal filtered cigarettes or experimental modification of filters to insert a charcoal plug into existing cellulose acetate filters. Make-your-own (MYO) cigarettes can help obviate many of the potential pitfalls of previous studies; thus, we conducted studies using commercial charcoal cigarettes and MYO cigarettes to determine the effects of charcoal on carbonyl delivery. To do this, we analyzed carbonyls in mainstream smoke by HPLC-UV after derivatization with 2,4 dinitrophenylhydrazine (DNPH). Charcoal was added in-line after the cigarettes or through the use of MYO charcoal cigarette tubes. MYO cigarettes had carbonyl deliveries similar to that of 3R4F research cigarette, regardless of tobacco type. The greatest effect on carbonyl delivery was observed with 200 mg of charcoal, significantly reducing all carbonyls under both methods tested. However, "on-tow" design charcoal filters, available on many commercially available charcoal brands, appeared to have a minimal effect on carbonyl delivery under intense smoking methods. Overall, we found that charcoal, when added in sufficient quantity (200 mg) as a plug, can substantially reduce carbonyl delivery for both MYO and conventional cigarettes. As carbonyls are related to negative health outcomes, such reductions may be associated with reductions in carbonyl-related harm in smokers. PMID- 30426739 TI - Multiplexed Label-Free Fractionation of Peripheral Blood Mononuclear Cells for Identification of Monocyte-Platelet Aggregates. AB - Monocytes and platelets play key roles in atherosclerosis and thrombosis, and circulating monocyte-platelet aggregates (MPA) in blood have been widely proposed as surrogate biomarkers for cardiovascular risk stratification and monitoring antiplatelet therapies. However, conventional MPA characterization is based on whole-blood fixation and flow cytometry analysis which adversely affect cell viability and detection accuracy due to significant leukocyte and platelet contaminations. Herein, we introduce a rapid and label-free microfluidic approach for complete size-based fractionation of peripheral blood mononuclear cells (PBMCs) into monocytes, lymphocytes, and platelets. The developed biochip enables gentle sorting of intact MPA in the enriched monocytes with efficient depletion of lymphocytes and platelets for accurate MPA quantification. We first compared the developed microfluidic technology (dean flow fractionation, DFF) with standard magnetic negative isolation (MACS) and observed that DFF-sorted monocytes had similar viability, purity, and key immune functions (phagocytosis, macrophage differentiation) as MACS-sorted monocytes. As proof of concept for diabetes testing, we isolated and characterized monocytes/MPA from a cohort of healthy ( n = 5) and type 2 diabetes mellitus (T2DM) subjects ( n = 8) in PBMCs and DFF-sorted monocytes. High-speed imaging, immunofluorescence, and flow cytometry analysis clearly indicated higher levels of MPA in T2DM patients ( P < 0.05) with enhanced MPA detection sensitivity in DFF-sorted monocytes ( P < 0.05). Taken together, the developed DFF technology greatly facilitates high throughput (~130 MUL min-1) label-free isolation of monocyte/MPA from PBMCs and can be further developed into a clinical tool for point-of-care cardiovascular risk stratification in metabolic disorders including T2DM. PMID- 30426740 TI - Thiocyanate Containing Two-Dimensional Cesium Lead Iodide Perovskite, Cs2PbI2(SCN)2: Characterization, Photovoltaic Application, and Degradation Mechanism. AB - We explored thiocyanate (SCN)-based two-dimensional (2D) organometal lead halide perovskite families toward photovoltaic applications. Using an SCN axial ligand and various cation species, we examined AA'PbI2(SCN)2-type 2D perovskite by replacing the cation species (AA') between methylammonium (MA), formamidinium (FA), and cesium. Among various cation compositions, only all-inorganic cesium based SCN perovskite, Cs2PbI2(SCN)2, film showed high thermal stability compared to known 2D perovskites. Perovskite solar cells (PSCs) using the Cs2PbI2(SCN)2 absorber yielded approximately 2% conversion efficiency on the mesoscopic device. Relatively low efficiency is attributed, in addition to optical properties (large band gap (2.05 eV) and exciton absorption), to the orientation of perovskite layer parallel to the layered structure, preventing carrier extraction from the light-absorber perovskite. In device stability, the Cs-based 2D perovskite was stable against oxygen (oxidation), whereas it was found to be unstable against humidity. X-ray diffraction and X-ray photoelectron spectroscopy measurements showed that, unlike long alkylammonium-based 2D perovskite families such as BA2PbI4 (BA = butylammonium), the Cs-based 2D perovskite can undergo hydrolysis due to the hydrophilic Cs cations. PMID- 30426741 TI - Engineered Slippery Surface to Mitigate Gypsum Scaling in Membrane Distillation for Treatment of Hypersaline Industrial Wastewaters. AB - Membrane distillation (MD) is an emerging thermal desalination process, which can potentially treat high salinity industrial wastewaters, such as shale gas produced water and power plant blowdown. The performance of MD systems is hampered by inorganic scaling, particularly when treating hypersaline industrial wastewaters with high-scaling potential. In this study, we developed a scaling resistant MD membrane with an engineered "slippery" surface for desalination of high-salinity industrial wastewaters at high water recovery. A polyvinylidene fluoride (PVDF) membrane was grafted with silica nanoparticles, followed by coating with fluoroalkylsilane to lower the membrane surface energy. Contact angle measurements revealed the "slippery" nature of the modified PVDF membrane. We evaluated the desalination performance of the surface-engineered PVDF membrane in direct contact membrane distillation using a synthetic wastewater with high gypsum scaling potential as well as a brine from a power plant blowdown. Results show that gypsum scaling is substantially delayed on the developed slippery surface. Compared to the pristine PVDF membrane, the modified PVDF membranes exhibited a stable MD performance with reduced scaling potential, demonstrating its potential to achieve high water recovery in treatment of high-salinity industrial wastewaters. We conclude with a discussion of the mechanism for gypsum scaling inhibition by the engineered slippery surface. PMID- 30426742 TI - Gate-Free Hydrogel-Graphene Transistors As Underwater Microphones. AB - A perfect impedance match from water-rich hydrogels to an oceanic background makes hydrogel microphones ideal for long-distance, underwater acoustic reception with zero reflection. A novel hydrogel-graphene transistor is thus designed to work under a gate-free mode, in which a sheet of graphene directly converts mechanical vibrations from a microstructured hydrogel into electrical current. This work shows that the quantum capacitance of graphene plays an important role in determining the shift of Fermi level in graphene, and subsequently the amplitude of the current signal. Once employed underwater, this device provides a response to sound waves with high stability, low noise, and high sensitivity in a much-needed low frequency domain. PMID- 30426743 TI - A Single-Molecule Homogeneous Immunoassay by Counting Spatially "Overlapping" Two Color Quantum Dots with Wide-Field Fluorescence Microscopy. AB - We developed a single-molecule homogeneous immunoassay by counting spatially "overlapping" two-color quantum dots (QD) under a wide-field fluorescence microscope. QD 655 with red fluorescence and QD 565 with green fluorescence were modified with capture and detection antibodies, respectively. A capture antibody modified QD 655 and a detection antibody-modified QD 565 were conjugated by a corresponding antigen molecule to form a "sandwich" immunocomplex. The conjugated QD 655 could not be distinguished from the conjugated QD 565 by fluorescent microscopy because the distance between them was smaller than the resolution of an optical microscope (approximately 200 nm). The immunocomplex color became yellow because of the spatial "overlap" of the red and green fluorescence. The number of the yellow spots was equal to the number of immunocomplex molecules, while the concentration of the antigen was related to the ratio of the yellow dots to the red dots. The successful quantification of two model proteins in the human plasma, namely, alpha-fetoprotein and carcinoembryonic antigen, demonstrated the accuracy and reliability of our approach. PMID- 30426744 TI - Impedance-Based Microfluidic Assay for Automated Antischistosomal Drug Screening. AB - Schistosomiasis is a neglected tropical disease, caused by parasitic worms, which affects almost 200 million people worldwide. For over 40 years, chemotherapeutic treatment has relied on the administration of praziquantel, an efficacious drug against schistosomiasis. However, concerns about developing drug resistance require the discovery of novel drug compounds. Currently, the drug-screening process is mostly based on the visual evaluation of drug effects on worm larvae in vitro by a trained operator. This manual process is extremely labor-intensive, has limited throughput, and may be affected by subjectivity of the operator evaluation. In this paper, we introduce a microfluidic platform with integrated electrodes for the automated detection of worm larvae viability using an impedance-based approach. The microfluidic analysis unit consists of two sets of electrodes and a channel of variable geometry to enable counting and size detection of single parasite larvae and the collective evaluation of the motility of the larvae as an unbiased estimator for their viability. The current platform also allows for multiplexing of the analysis units resulting in increased throughput. We used our platform to record size and motility variations of Schistosoma mansoni larvae exposed to different concentrations of mefloquine, a drug with established in vitro antischistosomal properties. The developed platform demonstrates the potential of integrated microfluidic platforms for high throughput antischistosomal drug screening. PMID- 30426745 TI - Counting Single Redox Molecules in a Nanoscale Electrochemical Cell. AB - We report the use of a Pt bipolar electrochemical nanocell and fluorescence to detect single redox molecules. A Pt nanocell is formed by depositing a Pt particle at a nanopipet orifice which separates the inside pipet volume from the bulk solution. Highly fluorescent resorufin molecules are generated on the inner Pt surface and optically detected and counted due to unique properties of the nanocell. First, the pipet is horizontally positioned on a microscope allowing one to examine a 6-MUm distance from the electrode/solution interface. Second, the resazurin/resorufin molecules are confined inside a 100 nm pipet resulting in a very high signal/background ratio in fluorescence detection. Third, the small pipet size confines the motion of the redox molecules increasing the probability of transient molecular adsorption on the quartz walls. This, along with the longer diffusion distance increases the chance of fluorescence detection. The ability to count single redox molecules allows us to estimate the detection efficiency. This study shows the unique power of fluorescence-based electrochemical detection in studying single redox events. Future use of this method may enable one to study single redox events of conventional nonfluorogenic redox reactions on the outer surface of the bipolar nanoelectrode, such as oxidation of H2 catalyzed by a metal cluster electrocatalyst or a single enzyme. PMID- 30426746 TI - Electrical-Charge-Mediated Cancer Cell Targeting via Protein Corona-Decorated Superparamagnetic Nanoparticles in a Simulated Physiological Environment. AB - A critical issue in nanomedicine is on the understanding of nano-bio interface behaviors, particularly when the nanoparticles are inevitably decorated by protein coronas in the physiological fluids. In this study, the effects of particle surface corona on cancer cell targeting were investigated in simulated physiological fluids. Cell targeting was achieved by two strategies: (1) using conventional epithelial cell adhesion molecule antibody-functionalized Fe3O4 nanoparticles and (2) rendering the same but naked magnetic nanoparticles electrically positively charged, enabling them to electrostatically bind onto the negatively charged cancer cells. The cell-particle electrostatic binding was found to be much stronger with faster reaction kinetics than the immunological interactions even at 4 nC. Both types of nanoparticles were decorated with various protein coronas by administration in a simulated physiological system. Well-decorated by protein coronas, the electrically charged particles retained strong electrostatic interactions with cancer cells, even upon reversal of the particle zeta potential from positive to negative. This behavior was explained by a nonuniform corona modulation of the particle surface charge distributions, exposing locally positively charged regions, capable of strong electrostatic cell binding and magnetic capturing in a physiological environment. This fundamental discovery paves new way for sensitive detection of circulating tumor cells in whole blood in clinical settings. PMID- 30426747 TI - Ultrasensitive Fluorescence Monitoring and in Vivo Live Imaging of Circulating Tumor Cell-Derived miRNAs Using Molecular Beacon System. AB - Circulating tumor cells (CTCs) have considerable clinical significance in cancer progression and prognosis. In this context, CTC-derived microRNAs (miRs) in blood and tissues have been proposed as the novel noninvasive biomarkers for monitoring tumor progression, especially at the early stages. To monitor circulating miRs, a tool should have high sensitivity, be a simple procedure, and allow detection in very small volumes. Thus, we designed a sensing tool for sensitive monitoring of blood or tissue miRs using a fluorophore-quencher probe-based molecular beacon (MB). This MB-based tool displayed an ultrasensitive limit of detection (LOD) level of 6.7 * 10-17 M and 8.7 * 10-17 for metastasis-derived miR-21a and miR 221, respectively. It also can discriminate miR-21a/221 from both guide strand miRs and its precursor forms (pre-miR). Furthermore, the tool discriminated between blood and tissue-related miR-21a/221-expression and detected metastasis and epithelial-mesenchymal transition and also describe a noninvasive miR fluorescence imaging of CTCs in a mouse model, showing the potential for clinical diagnosis and prognosis. PMID- 30426748 TI - Flexible SIS/HKUST-1 Mixed Matrix Composites as Protective Barriers against Chemical Warfare Agent Simulants. AB - We fabricated and demonstrated, for the first time, metal-organic framework (MOF), polymer mixed-matrix composites (MMCs) as effective, low burden barriers against chemical warfare agent (CWA) simulants. We incorporated the MOF HKUST-1 into elastomeric triblock copolymers of polystyrene- block-polyisoprene- block polystyrene (SIS) for use as semipermeable barrier against the CWA simulant 2 chloroethyl ethyl sulfide (CEES). MMCs containing up to 50 wt % HKUST-1 were cast and evaluated for CEES permeation, moisture vapor transport rate (MVTR), and mechanical properties, such as elastic modulus and percent elongation. Increasing the MOF content resulted in longer protection against CEES with breakthrough times ranging from immediate breakthrough for the baseline SIS to over 4000 min for the best-performing MMC. MVTRs of high-MOF-content MMCs were approximately 5 10 times higher than either SIS or typical laboratory gloves made from nitrile and latex. The elastic moduli increased with increased MOF content corresponding to a reduction in percent elongation. The triblock copolymer also was found to protect the MOF crystal structure after exposure to CEES and liquid water, which may lead to longer usage time and shelf life. The ability to resist degradation due to moisture shows the potential utility of these composites when exposed to rain, sweat, or other moisture-rich environments. Finally, the MOF-containing composites functioned as robust colorimetric indicators of CEES exposure. Thus, these MMC materials present a potential route toward next-generation personal protective equipment with a combination of detoxification, sensing, environmental stability, and thermal/user-comfort properties not present in current materials solutions. PMID- 30426749 TI - Synthesis, Molecular Engineering, and Photophysical Properties of Fluorescent Thieno[3,2- b]pyridine-5(4 H)-ones. AB - We describe a synthetic approach for a set of fluorescent thieno[3,2- b]pyridine 5(4 H)-one derivatives and their photophysical properties. These fluorophores are prepared by a series of reactions employing the Suzuki-Miyaura cross-coupling reaction and a regioselective aza-[3 + 3] cycloaddition of 3-aminothiophenes with alpha,beta-unsaturated carboxylic acids. Our findings revealed that the photophysical properties are chemically tunable by an appropriate choice of functional group on the thieno[3,2- b]pyridine-5(4 H)-one scaffold. PMID- 30426750 TI - Synthesis of Cryptophane-B: Crystal Structure and Study of Its Complex with Xenon. AB - Whereas the synthesis of the anti-cryptophane-A (1) derivative has been known for nearly 40 years, the preparation of its diastereomer (cryptophane-B according to Collet's nomenclature) has never been reported. Thus, the synthesis of the cryptophane-B derivative represents a real challenge for chemists interested in the preparation of these hollow molecules. Herein, we describe a synthetic route that allows us to prepare cryptophane-B (2), albeit in a low yield. The X-ray crystallographic structure of this compound is described, and it reveals the presence of an ethanol molecule inside the cavity of the host. Finally, the ability of cryptophane-B to bind xenon in 1,1,2,2-tetrachloroethane- d2 is also studied via hyperpolarized 129Xe NMR. PMID- 30426751 TI - Resveratrol Ameliorates Intestinal Barrier Defects and Inflammation in Colitic Mice and Intestinal Cells. AB - This study is aimed to investigate the ameliorative effect of resveratrol in a dextran sodium sulfate (DSS)-induced colitis mouse model and intestinal Caco-2 cells, focusing on neutrophil infiltration and tight junction (TJ) barriers. DSS administration caused body weight loss (day8, control 104 +/- 1, DSS 72 +/- 2%, p < 0.05), shortening of colon length (control 5.1 +/- 0.1, DSS 3.8 +/- 0.1 cm, p < 0.05), pro-inflammatory cytokines increase-including interleukin (IL)-1beta (control 1.0 +/- 0.2, DSS 58.5 +/- 29.6 arbitrary unit (AU), p < 0.05), IL-6 (control 1.0 +/- 0.3, DSS 312 +/- 82 AU, p < 0.05), and chemokine motif ligand 2 (CXCL-2, a murine IL-8 homologue, control 1.0 +/- 0.4, DSS 696 +/- 262 AU, p < 0.05), decreased TJ proteins (e.g., occludin, control 1.0 +/- 0.05, DSS 0.11 +/- 0.03 AU, p < 0.05), and neutrophil infiltration (control 1.2 +/- 0.2, DSS 25.9 +/ 1.1 cells, p < 0.05). Supplemental resveratrol (0.1% (w/w) in the diet) partially or totally reversed these symptoms (body weight change 100 +/- 1, colon length 4.6 +/- 0.1; IL-1beta 5.9 +/- 1.8, IL-6 10 +/- 3, CXCL-2 14 +/- 7, occludin 0.76 +/- 0.06, neutrophil infiltration 9.3 +/- 0.7, p < 0.05). Pretreatment of intestinal Caco-2 cells with resveratrol suppressed the TNF-alpha induced production of IL-8 (control 1.00 +/- 0.04, TNFalpha 3.40 +/- 0.16, TNFalpha+Res 1.81 +/- 0.28 AU, p < 0.05) and phosphorylation of the inflammatory signaling molecules including NF-kappaB, extracellular signal-regulated kinase and stress c-Jun N-terminal protein kinase. Collectively, the reduction of TJ barrier defect and IL-8 in intestinal cells, leading to reduced neutrophil infiltration into colonic tissues, appears to be one of the central mechanisms for the resveratrol-mediated effect. PMID- 30426752 TI - Additive-Free Three-Component Synthesis of Spiro-isoxazolidine-oxindoles Employing Trifluorodiazoethane. AB - An efficient three-component protocol for the synthesis of trifluoromethylated spiro-isoxazolidine-oxindoles has been developed. This approach employs the 1,3 dipolar cycloaddition of trifluoromethyl nitrone, generated in situ from trifluorodiazoethane and nitrosoarene, with phenacylideneoxindoles. A range of phenacyclideneoxindoles and nitrosoarenes can be subjected to this reaction to generate the spiro-isoxazolidine-oxindole derivatives. The reductive ring-opening reaction of isoxazolidines carried out to demonstrate the synthetic potential of our strategy resulted in an interesting rearrangement to yield pyrroloquinoline derivatives. PMID- 30426753 TI - Intramolecular Vinylation of Aryl Rings by Vinyl Cations. AB - A Lewis acid mediated intramolecular electrophilic vinylation of aryl rings by vinyl cations is reported. This reaction takes advantage of beta-hydroxy-alpha diazo ketones as vinyl cation precursors and provides good yields of tricyclic 1 indenones that contain a seven-membered ring. Extending the alkane chain that tethers the vinyl cation to the aromatic ring leads to 2-napthol and 2-indenone products. PMID- 30426754 TI - Cross-cultural differences in recovery from schizophrenia: What to compare? PMID- 30426755 TI - Intramural haematoma of the ascending aorta - not so malignant after all? PMID- 30426756 TI - Factors that facilitate and constrain the utilization of a Kaupapa Maori therapeutic approach with Mahi-a-Atua. AB - OBJECTIVES:: To further progress Kaupapa Maori ( Maori focused) approaches within mental health services this study explored the experiences of Maori clinicians from a dedicated Maori mental health service in New Zealand, with a focus on a specific Kaupapa Maori therapeutic approach, Mahi-a-Atua. METHODS:: A qualitative approach was used to ascertain factors that facilitate and obstruct the utilization of Mahi-a-Atua. In a focus group hui ( Maori meeting process), eight Maori clinicians discussed their experiences. RESULTS:: Facilitation of Mahi-a Atua by Maori clinicians occurred through interconnectedness of a number of factors including cultural identity, relationships, wairuatanga (spirituality), kaitiakitanga (guardianship), validation of the model and the ability to co-work and engage in meaningful wananga (learning) around the intervention. The extent to which clinicians used the model depended on their own perceived knowledge and confidence and how best able to integrate both cultural and clinical knowledge. Other constraining factors pertained to inadequate prior training, limited workforce development training and lack of adequate resourcing for specialized services. CONCLUSIONS:: This research highlights the need for Maori focused specialized training that utilizes co-working within sessions and ongoing wananga. PMID- 30426757 TI - Is ultrasonography sufficient for evaluation of mental foramen? AB - METHODS:: The measurements were established on 60 MFs of 30 patients (16 males, 14 females) with a mean age of 30.70 +/- 9,23 years. The vertical and the horizontal diameters, distance to the alveolar crest of the MF was measured by both CBCT and USG. Results obtained with CBCT and USG were statistically compared. And also the blood flow of the MF determined by Doppler USG. RESULTS:: All of the MFs could be detected by CBCT and USG. The vertical and the horizontal diameter measurements were compatible with each other by CBCT and USG. However, the distance to the alveolar crest was lower in USG than CBCT (p < 0.0001). The blood flow could be detected in all patients by Doppler USG that was weak in 8 MFs and strong in 52 MFs. Also there was no statistically significant association between the blood flow and age or gender. Furthermore, the blood flow was related with the horizontal diameter of the MF; however, it was not related with the vertical diameter and the distance to the alveolar crest. CONCLUSIONS:: USG is quite effective in showing the shape, size, and the location of the MF easily and rapidly. However, it is not as accurate as CBCT in measuring the distance from the MF to alveolar crest. And also it allows to examine the flow rate of mental artery with its Doppler modes. PMID- 30426758 TI - Response to the letter regarding: Description of Doppler waveforms to detect lower extremity peripheral artery disease. AB - Doppler waveforms analysis is a interesting to diagnose peripheral artery disease as suggested by the international recommendations. However as mentioned in the present letter, there is a lack of consensus about the terminology that should be used. PMID- 30426760 TI - Description of Doppler waveforms to detect lower extremity peripheral artery disease. AB - Doppler waveforms analysis is a interesting to diagnose peripheral artery disease as suggested by the international recommendations. However as mentioned in the present letter, there is a lack of consensus about the terminology that should be used. PMID- 30426759 TI - Sustainable Cleft Care Through Education: The First Simulation-Based Comprehensive Workshop in the Middle East and North Africa Region. AB - OBJECTIVE:: To describe the conduct of the first multidisciplinary simulation based workshop in the Middle East/North Africa region and evaluate participant satisfaction. DESIGN:: Cross-sectional survey-based evaluation. SETTING:: Educational comprehensive multidisciplinary simulation-based cleft care workshop. PARTICIPANTS:: Total of 93 workshop participants from over 20 countries. INTERVENTIONS:: Three-day educational comprehensive multidisciplinary simulation based cleft care workshop. MAIN OUTCOME MEASURES:: Number of workshop participants, number of participants stratified by specialty, satisfaction with workshop, number of workshop staff, and number of workshop staff stratified by specialty. RESULTS:: The workshop included 93 participants from over 20 countries. The response rate was 47.3%, and participants reported high satisfaction with all aspects of the workshop. All participants reported they would recommend it to colleagues (100.0%) and participate again (100.0%). No significant difference was detected based on participant specialty or years of experience. The majority were unaware of other cleft practitioners in their countries (68.2%). CONCLUSION:: Multidisciplinary simulation-based cleft care workshops are well received by cleft practitioners in developing countries, serve as a platform for intellectual exchange, and are only possible through strong collaborations. Advocates of international cleft surgery education should translate these successes from the regional to the global arena in order to contribute to sustainable cleft care through education. PMID- 30426761 TI - ANNALS EXPRESS: Analytical performances of PENIA and PETIA urinary cystatin C determination allow tubular injury investigation. AB - BACKGROUND: The study was designed to evaluate the analytical performances of two ERM-DA471/IFCC traceable cystatin C (CysC) reagents available on the market for urinary CysC (u-CysC) quantification. In addition, clinical relevance was assessed by measuring u-CysC in healthy controls and in patients with tubular dysfunction. METHODS: CysC in urine was measured by a particle enhanced nephelometric immunoassay (PENIA) using Siemens reagents and by a particle enhanced turbidimetric immunoassay (PENIA) using DiaSys reagents. Imprecision, linearity, limit of detection and limit of quantification were evaluated according to CLSI recommendations. The two methods were tested on 150 urinary samples from 50 healthy subjects, 50 HIV patients with tubular dysfunction and 50 patients who developed acute kidney acute injury. RESULTS: Within-laboratory coefficients of variations were below 4%. The lower limit of quantification of the assay was found at 0.043 and 0.046 mg/L for DiaSys and Siemens respectively. The following Passing-Bablok regression equations were obtained: DiaSys = 0.99 Siemens + 0.00. Using Bland-Altman analysis, the mean bias was -0.004 mg/L on the analytical range between 0.02 and 1 mg/L. Median u-CysC in 50 HIV patients with tubular dysfunction and in 50 patients with AKI was higher than in control subjects. CONCLUSIONS: Both Siemens and DiaSys reagents demonstrated reliable and reproducible performances allowing easy determination of u-CysC on automated platforms in clinical practice with potential interest for detection of tubular dysfunction. Key words: Urinary cystatin C; PENIA; PETIA; Tubular dysfunction. PMID- 30426762 TI - Assessment of image quality and exposure parameters of an intraoral portable X rays device. AB - OBJECTIVE:: To evaluate the exposure parameters, radiation protection, absorbed dose and radiographic image quality of the DIOX(r) intraoral portable radiography device. METHODS:: The exposure parameters were measured using the Xi UNFORS detector. Operator exposure to secondary radiation was measured using the 1800cc ionization chamber coupled to the electrometer. The absorbed dose (D) in the patient was calculated using TLD-100H positioned in the Alderson RANDO anthropomorphic simulator. The quality of the radiographic digital image was assessed by comparing radiographic images obtained from two convencional devices (CS 2200- Carestream Health(r); Heliodent plus- Sirona Dental Systems GMbH(r)) with the radiological simulator of the upper molar region (RMI) (Radiation Measurements Instruments), using three acquisition sensors: Kodak RVG 5000(r) and Kodak PSP(r), Eastman Kodak Company, Rochester, NY; EVO Micro Image(r), Brazil. RESULTS:: The DIOX intraoral portable radiographic device demonstrated reliability in relation to the performance of the standard evaluated parameters, except for the diameter of the radiation field (5.8 mm) less or greater. No evidence of device head radiation was detected. The Pb lead protection of the apparatus attenuates the secondary radiation, thus protecting the operator. However, it was observed that the region of the operator's gonads was the most exposed during the measurements. In the Alderson RANDO anthropomorphic simulator, the highest value of D was in the region corresponding to the submandibular and lingual glands of the left side (0.568mGy). The image quality of the DIOX portable radiographic apparatus presented quality standards equivalent to those produced by the two conventional radiographic devices. CONCLUSION:: The DIOX intraoral portable radiography device demonstrated reliability in relation to the quality control and radioprotection criteria, according to international standards. Results obtained demonstrated the safe use of the DIOX intraoral portable radiography device and indicated the need for debate and change in international sanitary oversight standards regarding the use of portable XR devices in dentistry. PMID- 30426763 TI - Clinical correlates of sluggish cognitive tempo in adolescents with autism spectrum disorder. AB - Adolescents with autism spectrum disorder frequently experience social communication difficulties, executive functioning deficits, and anxiety and depressive symptoms, which are similar to the symptoms and correlates of sluggish cognitive tempo. Although sluggish cognitive tempo is related to, but distinct from, the inattentive and hyperactive-impulsive symptoms of attention deficit/hyperactivity disorder that commonly co-occur with autism spectrum disorder, few studies have examined sluggish cognitive tempo in autism spectrum disorder. We examined whether sluggish cognitive tempo and attention deficit/hyperactivity disorder were differentially associated with autism symptomatology, daily life executive functioning, and internalizing and externalizing symptoms in 51 adolescents (ages 13-18 years) with autism spectrum disorder without intellectual disability. Regression analyses controlling for age and IQ showed that sluggish cognitive tempo symptoms, but not attention deficit/hyperactivity disorder symptoms, were associated with increased autism symptomatology and internalizing symptoms. Attention-deficit/hyperactivity disorder symptoms, but not sluggish cognitive tempo symptoms, were associated with increased externalizing behaviors and behavior regulation deficits. Both sluggish cognitive tempo and attention-deficit/hyperactivity disorder were independently associated with increased metacognitive deficits. This study provides preliminary evidence that sluggish cognitive tempo symptoms are elevated in autism spectrum disorder and associated with key clinical correlates, with implications for the assessment and treatment in adolescents with autism spectrum disorder. PMID- 30426764 TI - Developing a risk-based composite neurologic outcome for a trial of hydroxyurea in young children with sickle cell disease. AB - BACKGROUND: Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial. METHODS: In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome. RESULTS: In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well. CONCLUSION: This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study. PMID- 30426765 TI - Differential diagnostic value of diffusion-weighted and dynamic contrast-enhanced MR imaging in non-cystic lesions in floor of the mouth. AB - METHODS:: A total of 82 patients were included in this study. The apparent diffusion coefficient (ADC) values and time-signal intensity curves (TICs) were measured. Clinical characteristics, ADC value, and TIC pattern were compared between benign and malignant FOM lesions. Receiver operating characteristic curve and logistic regression analyses were performed to evaluate respective and combined value of ADC value and TIC pattern for differential diagnosis. The retrospective study was approved by our institutional review board, and the need for informed consent was waived. RESULTS:: The area under the curve ADC value and TIC pattern were 0.71 and 0.73, respectively. The combined use of ADC value and TIC pattern increased the area under the curve value to 0.81 [95% confidence interval (CI), (0.66-0.97)]. ADC < 1.23 * 10-3 mm2 s-1 (odds ratio, 45.8; 95% CI, 2.8-737.9) and both the plateau and washout TIC patterns (OR, 6.8; 95% CI, 1.8 24.8) were significantly associated with malignancy of FOM lesions. CONCLUSIONS:: Our results suggest that both diffusion-weighted imaging and DCE-MRI could contribute to the differential diagnosis of non-cystic FOM lesions, especially when used in combination. PMID- 30426766 TI - Opportunities and barriers to effective operation and maintenance of public toilets in informal settlements: perspectives from toilet operators in Kampala. AB - Although classified by the Joint Monitoring Programme (JMP) as unimproved sanitation facilities, public toilets still play a critical role in eliminating open defecation in informal settlements. We explored perspectives of toilet operators on opportunities and barriers to operation and maintenance (O&M) of public toilets in informal settlements. A cross-sectional study design was used. Up to 20 in-depth interviews were used to obtain data on the experiences of public toilet operators. Thematic content analysis was used. Ressults show that opportunities for improving O&M include; operation of public toilets is a source of livelihood; operators are knowledgeable on occupational risks, and the community is involvedin sanitation activities. Barriers to effective O&M include; high operation costs, failure to break even and a lack of investments in occupational health Therefore, there is need to recognise the significance of public toilets as a viable alternative to open defecation in areas where ownership of private sanitation facilities is difficult. Failure to observe the health and safety of toilet operators may further compromise O&M. PMID- 30426767 TI - Surgical timing and presence of a vitreoretinal fellow on postoperative adverse events following pars plana vitrectomy. AB - INTRODUCTION:: To evaluate the adverse event rate following pars plana vitrectomy as a function of surgical start time and the presence of a vitreoretinal fellow. METHODS:: Single-institution retrospective cohort study of patients undergoing pars plana vitrectomy from 1 January 2016 to 31 December 2016 at Stanford University School of Medicine (Palo Alto, CA, USA). Records were reviewed for surgical start time, the presence of vitreoretinal fellow, and postoperative adverse events defined as any finding deviating from the expected postoperative course requiring observation or intervention. RESULTS:: A total of 310 pars plana vitrectomies were performed. There was no statistical difference in the rate of any adverse event when comparing cases starting after 16:01 (9/13, 69.2%) and after 12:01 (42/99, 42.4%) to a morning start time (69/198, 34.9%, adjusted p = 0.083). There was a statistically significant increase in the risk of postoperative vitreous hemorrhage with afternoon and evening cases as compared to morning cases (adjusted p = 0.021). In addition, there was no difference in any adverse event with a fellow present (93/244, 38.1%) compared to without (27/66, 40.9%, adjusted p = 0.163). There was a higher risk of postoperative hypotony when a fellow was involved (6.6% vs 0%, p = 0.028), though this difference disappeared after adjusting for confounders (adjusted p = 0.252). There was no difference in the length of surgery with and without a fellow (49 vs 54 min, respectively; p = 0.990). DISCUSSION:: Afternoon start time and the presence of a fellow were not independent risk factors for postoperative adverse events. PMID- 30426768 TI - DNA hydroxymethylation changes in response to spinal cord damage in a multiple sclerosis mouse model. AB - AIM: Roles of DNA 5-hydroxymethylcytosine (5hmC) in myelin repair were investigated in an experimental autoimmune encephalomyelitis (EAE) mouse model via its regulation on brain-derived neurotrophic factor (BDNF). METHODS: DNA 5hmC level and its limiting enzymes were detected in EAE mice. RESULTS: Global 5hmC modification, Tet1 and Tet2 significantly decreased in the spinal cord tissues of EAE mice. BDNF protein and mRNA decreased and were highly associated with BDNF 5hmC. Vitamin C, a Tet co-factor, increased global DNA 5hmC and reduced the neurological deficits at least by increasing BDNF 5hmC modification and protein levels. CONCLUSION: Tet protein-mediated 5hmC modifications represent a critical target involved in EAE-induced myelin damage. Targeting epigenetic modification may be a therapeutic strategy for multiple sclerosis. PMID- 30426770 TI - Strength training in congenital heart disease: A way to boost respiratory function? PMID- 30426769 TI - Prevalence and significance of T-wave inversion in Arab and Black paediatric athletes: Should anterior T-wave inversion interpretation be governed by biological or chronological age? AB - BACKGROUND: International electrocardiographic (ECG) recommendations regard anterior T-wave inversion (ATWI) in athletes under 16 years to be normal. DESIGN: The aim of this study was to identify the prevalence, distribution and determinants of TWI by ethnicity, chronological and biological age within paediatric athletes. A second aim was to establish the diagnostic accuracy of international ECG recommendations against refinement within athletes who present with ECG variants isolated to ATWI (V1-V4) using receiver operator curve analysis. Clinical context was calculated using Bayesian analysis. METHODS: Four hundred and eighteen Arab and 314 black male athletes (11-18 years) were evaluated by ECG, echocardiogram and biological age (by radiological X-ray) assessment. RESULTS: A total of 116 (15.8%) athletes presented with ATWI (V1-V4), of which 96 (82.8%) were observed in the absence of other ECG findings considered to be abnormal as per international recommendations for ECG interpretation in athletes; 91 (12.4%) athletes presented with ATWI confined to V1-V3, with prevalence predicted by black ethnicity (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.3-3.5) and biological age under 16 years (OR 2.0, 95% CI 1.2 3.3). Of the 96 with ATWI (V1-V4) observed in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes, diagnostic accuracy was 'fail' (OR 0.47, 95% CI 0.00 1.00) for international recommendations and 'excellent' (OR 0.97, 95% CI 0.92 1.00) when governed by biological age under 16 years, providing a positive and negative likelihood ratio of 15.8 (95% CI 1.8-28.1) and 0.0 (95% CI 0.0-0.8), respectively. CONCLUSION: Interpretation of ECG variants isolated with ATWI (V1 V4) using international recommendations (chronological age <16 years) warrants caution, but governance by biological age yielded an 'excellent' diagnostic accuracy. In the clinical context, the 'chance' of detecting cardiac pathology within a paediatric male athlete presenting with ATWI in the absence of other ECG findings considered to be abnormal, as per international recommendations for ECG interpretation in athletes (positive likelihood ratio 15.8), was 14.4%, whereas a negative ECG (negative likelihood ratio 0.0) was 0%. PMID- 30426771 TI - Cardiovascular disease in nonagenarians: Prevalence and utilization of preventive therapies. AB - AIMS: Nonagenarians are a fast growing segment of industrialized countries' populations. Despite a greater risk of cardiovascular disease, there are limited data about their use of preventive therapies and factors guiding decisions regarding their prescription. The aim of this study was to evaluate the prevalence of cardiovascular diseases and the patterns of use of cardiovascular treatments in subjects >=90 years old. METHODS: Population-based, cross-sectional study, in all nonagenarians residing in the Community of Madrid (Spain). Data were obtained from their electronic clinical records in primary care. RESULTS: Data were available from 59,423 subjects (mean age 93.3 years, 74.2% female, 13.5% with dementia). Prevalence of cardiovascular disease was 24.1% (10.9% with coronary artery disease (CAD), 13.1% with cerebrovascular disease (CVD) and 2.7% with peripheral artery disease(PAD)). In primary prevention, the use of statins and antiplatelet agents was 21.9% and 26.7%, respectively. Of subjects with vascular disease 27.7% were receiving a combined preventive strategy (use of antithrombotics, plus statins, plus blood pressure below 140/90 mmHg). Factors favourably associated with a combined preventive strategy were: female sex (odds ratio (OR) 1.29; 95% confidence interval (CI): 1.11-1.49), being independent versus totally dependent (OR 1.94; 95% CI: 1.43-2.65), diabetes (OR 1.42; 95% CI: 1.20-1.68), and negatively, age (OR 0.87; 95% CI: 0.85-0.90), CVD versus CAD (OR 0.41; 95% CI: 0.35-0.47), PAD versus CAD (OR 0.23; 95% CI: 0.18-0.30), dementia (OR 0.61; 95% CI: 0.49-0.76) and nursing home residency (OR 0.73; 95% CI: 0.57 0.93). CONCLUSION: Nonagenarians have a great burden of cardiovascular diseases and receive a great number of preventive therapies, even in primary prevention, despite their unproven efficacy at these ages. PMID- 30426772 TI - Attainment of lipid goals and long-term mortality after coronary-artery bypass surgery. AB - INTRODUCTION: There is paucity of data regarding lipid goal attainment after coronary-artery bypass graft surgery (CABG) and its impact on adverse outcomes. We aimed to investigate the attainment of lipid goals and the association between plasma lipid levels achieved after CABG and mortality. METHODS: Retrospective analysis of 1230 patients undergoing CABG. Mortality was examined in relation to most-recent lipid levels attained, categorized by clinically-relevant thresholds, and according to the improvement from pre-operative levels. RESULTS: Low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL was attained by 44% of the patients. After multivariable adjustment, the hazard ratio for long-term mortality was 1.33 (95% confidence interval, 1.05-1.67) and 1.97 (1.55-2.50) for patients attaining LDL-C 70-100 mg/dL and >100 mg/dL, respectively, compared with LDL-C < 70 mg/dL. The hazard ratio was 1.42 (1.07-1.88) and 1.73 (1.33-2.23) for patients attaining high-density lipoprotein cholesterol (HDL-C) 40-50 mg/dL and <40 mg/dL, respectively, compared with HDL-C > 50 mg/dL; and 1.11 (0.85-1.45) and 4.28 (1.89 9.68) for patients with triglycerides 200-500 mg/dL and >500 mg/dL compared with triglycerides <200 mg/dL. A progressive stepwise association was seen between the cumulative status of the lipid measures achieved and long-term mortality, with the lowest risk observed in those with optimal level of all lipid measures ( p < 0.0001). Improvement in any of the lipid measures from pre-operative to latest documented levels was associated with reduced mortality. CONCLUSIONS: Lack of attainment of optimal levels of routine lipid measures after CABG was common and associated both independently and additively with long-term mortality, emphasizing the importance of addressing plasma lipid profile as both a risk marker and a treatment target after CABG. PMID- 30426773 TI - Recurrent PAX 6 mutation in a Chinese family with congenital aniridia, progressive cataracts and mental retardation. AB - BACKGROUND:: One prominent pathological feature of congenital aniridia is hypoplasia of the iris, often accompanied by other eye abnormalities. The objective of this study is to identify gene mutations responsible for autosomal dominance in a Chinese family with congenital aniridia, progressive cataracts and mental retardation. METHODS:: A total of 11 family members, including 6 affected and 5 unaffected individuals were recruited. Whole exome sequencing was performed on the proband and Sanger sequencing was applied to identify the causal mutation in the other family members and control samples. RESULTS:: A heterozygous mutation, c. 112delC (p. Arg38fs) in PAX 6, was identified in the family that was associated with congenital aniridia, progressive cataracts and mental retardation. The mutation was exclusively observed in all affected individuals but not in unaffected family members or unrelated healthy controls without aniridia recruited from Beijing Tongren Hospital. Bioinformatics analysis indicated that the mutation c. 112delC (p. Arg38fs) in PAX 6 affected sugar phosphate backbone construction, leading to half reduction of the full-length protein. Other symptoms such as lens opacity, keratitis, lens dislocation, ciliary body hypoplasia, foveal hypoplasia and mental development retardation were also observed in this family. CONCLUSION:: These results provided a new insight into the effects of PAX 6 as a mutational hotspot, with a symptom complex that includes congenital aniridia, progressive cataracts and mental retardation. These findings suggested the cognitive treatment of PAX 6-mutated individuals could be considered earlier clinically, combined with medication or surgery of congenital aniridia and progressive cataracts. PMID- 30426774 TI - The 24-h clinical microbiology service is essential for patient management. PMID- 30426775 TI - Testing interventions to improve response to a National Health Service Staff Survey. AB - The National Health Service Staff Survey is an annual, England-wide survey of staff employed by National Health Service organisations. It is administered using online and paper questionnaires. Response rates have fallen over time, while the proportion of staff receiving the online version - which historically has a lower response rate - has increased. Three interventions to increase online response were tested using an experimental design: more reminders; change of signatory to the invitation to participate and concise messaging in the invitation. Thirteen thousand staff members in five National Health Service trusts received the online survey. Results were analysed using contingency tables and logistic regression to determine the effect of interventions independently and in combination. More reminders improved response by six percentage points (odds ratio 1.33, 95% CI 1.23-1.43) and concise messaging by two percentage points (odds ratio 1.08, 95% CI 1.00-1.17). Change of signatory had no statistically significant effect and neither did any combination of the interventions. Given that costs for the successful interventions were minimal, more reminders in combination with concise messaging are recommended as a strategy to improve online response to the survey. PMID- 30426776 TI - 'Adolescents are reckless': Representations at stake in the construction of the relationship of trust in paediatric diabetology. AB - A total of 10 focus groups were held with adolescents living with diabetes, their parents and health professionals in order to explore their needs in therapeutic education. The analysis showed that the relationship of trust was a central concern for a number of participants. Several adults were divided between a feeling of confidence inspired by the need to empower adolescents to cope with the chronic condition and a sense of distrust inspired by the idea of carelessness and irresponsibility thought to characterize adolescence. Adolescents, for their part, seemed relatively clear-sighted about how they can be perceived, and blamed adults for not trusting them. These findings emphasize the importance of considering the representations at stake in the dynamics of the therapeutic relationship in order to better understand the construction of the relational climate. PMID- 30426777 TI - Timing of Open Reduction and Internal Fixation of Ankle Fractures. AB - BACKGROUND: Unstable ankle fractures are treated with open reduction internal fixation (ORIF) to prevent posttraumatic arthritis. Typically, ORIF is performed as an ambulatory surgery several days to a few weeks after injury. It is unclear what effect this delay may have on functional outcome. This study aimed to assess the effect of timing of ankle ORIF on wound complications and functional outcome. METHODS: A retrospective review of 121 patients who underwent ankle ORIF was performed. A total of 58 patients had a follow-up of at least 24 months. Time between injury and surgery greater than 14 days was defined as "delayed." Demographic variables, injury characteristics, length of surgery, and postoperative stay were documented. Comparison of demographic variables, wound complications, and functional outcome determined by Foot and Ankle Outcome Score (FAOS) was performed. RESULTS: 118 patients were included. The duration between injury and surgery was 6 days in the "early" group and 19 days in the "delayed" group. There were no significant differences in demographic variables, injury characteristics, and length of surgery between the groups. Wound complications in the early and delayed groups were 5% and 11.8%, although this difference was not statistically significant. Among 58 patients who had a follow-up of at least 24 months, the median follow-up time was 38 (range, 24-76) months. Each subscale of FAOS demonstrated no significant difference. CONCLUSION: Ankle ORIF more than 14 days after injury did not significantly increase the rate of wound complication, nor did it impair ultimate functional outcome in this group. LEVELS OF EVIDENCE: Level III. PMID- 30426778 TI - Comprehensive analysis of miRNA-mRNA-lncRNA networks in severe asthma. AB - AIM: This study aimed to explore the molecular mechanism of severe asthma. MATERIALS & METHODS: The shared and divergent differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in asthma and severe asthma were identified by RNA-sequencing. Severe asthma-specific and shared DEmiRNA DEmRNA-DElncRNA interaction networks were performed. RESULTS: Compared with normal control, 1328 DEmRNAs, 608 DElncRNAs and 63 DEmiRNAs were identified in severe asthma. Compared with asthma, 95 DEmRNAs, 143 DElncRNAs and 96 DEmiRNAs were identified in severe asthma. MiR-133a-3p-EFHD2/CNN2-AC144831.1 interactions and miR-3613-3p-CD44/BCL11B-LINC00158/CTA-217C2.1/AC010976.2/RP11-641A6.2 interactions were speculated to involve with the development of severe asthma. The results of GSE69683 validation were generally consistent with our RNA sequencing results. CONCLUSION: This study provides clues for understanding the mechanism of severe asthma. PMID- 30426779 TI - Maternal Acrylamide Intake during Pregnancy and Sex Hormone Levels in Maternal and Umbilical Cord Blood and Birth Size of Offspring. AB - Exposure to acrylamide during pregnancy may disturb pregnancy hormones and the growth of the fetus. The present study aimed to examine the association of maternal acrylamide intake with maternal and cord sex hormone levels during pregnancy and at birth and birth size of offspring. The study subjects were 204 pregnant Japanese women and their newborn girls. Intake of acrylamide was assessed based on 5-day diet records at approximately the 29th week of pregnancy. The concentrations of estradiol, estriol, and testosterone were measured in maternal serum at the 29th weeks of pregnancy and at delivery and umbilical cord blood at delivery. Birth weight, length, and head circumference were measured at the delivery. After controlling for covariates, higher intake of acrylamide was significantly positively associated with higher level of umbilical cord estradiol at the delivery (p for trend = .01), but not with any hormone levels measured in maternal blood. A positive association between acrylamide intake and head circumference was of borderline significance (p for trend = .06). Overall, there were no consistent associations between maternal acrylamide intake and sex hormone levels during pregnancy. However, as this is the first study to examine these associations, additional studies are needed. PMID- 30426780 TI - Real-world treatment patterns and outcomes of patients with stage IV squamous cell carcinoma of the head and neck. AB - AIM: To understand the treatment patterns and outcomes for stage IV squamous cell carcinoma of the head and neck, patients receiving second-line or later drug therapy. MATERIALS & METHODS: Real-world data were collected from 1152 patients in the USA, France, Germany and the UK through a retrospective chart analysis and patient-reported outcomes were collected using validated questionnaires in a subgroup of patients. RESULTS: Forty-four percent of patients had stage IVA/B disease. A total of 77, 19 and 3% of patients had received 2, 3 and 4 plus lines of active drug treatment. Platinum- and cetuximab-based regimens were common at early treatment lines. Time to progression was short (5.2 months post first line), survival rates low and patient-reported health status poor. CONCLUSION: Novel therapies that could improve clinical and patient-reported outcomes would address a significant unmet need. PMID- 30426781 TI - NHS Activism: The Limits and Potentialities of a New Solidarity. AB - Using Thompson's conceptualization of the moral economy, I describe how NHS activists in the UK utilize moral arguments to form alliances between different occupational groups, in a political battle against health care privatization, reflecting how a consciousness is being built upon solidarity and shared interests. In this context, professional duties of health care professionals are linked to the interests of all citizens. I explore how the deployment of professional ethics elides a moral hierarchy that may hinder the movement's egalitarian potential. PMID- 30426782 TI - Building blocks of resiliency: a transactional framework to guide research, service design, and practice in pediatric rehabilitation. AB - PURPOSE: Children's resiliency is seen as important in pediatric rehabilitation, but is seldom the focus of research or intervention. This article presents a resiliency framework to inform pediatric rehabilitation research, service design, and practice. METHODS: The development of the framework was guided by a transactional, life course perspective, and a review of self-constructs in the resiliency literature. RESULTS: The framework comprises health-related adversities, self-capacities, self-regulatory processes, and adaptive benefits. Four adaptive self-capacities are highlighted (activity self-efficacy, capacity to marshal resources and supports to achieve goals, capacity to adapt to changing life situations, and capacity to envision a positive future). These self capacities are linked to common adversities experienced by children with disabilities, namely activity limitations, functioning and participation restrictions, transition issues, and anticipated future life challenges. The self capacities are also associated with empowered, optimistic, adaptive, and hopeful mindsets, which influence accommodative and assimilative self-regulatory strategies affecting children's adaptive benefits. CONCLUSIONS: The framework can inform resiliency-related research exploring self-capacities and resiliency processes. The framework points to what is modifiable through intervention targeting the person-in-context, namely self-capacities, mindsets, and situated experiences. Implications for service design and delivery include providing opportunities and interacting with clients in ways that support the development of these self-capacities. Implications for rehabilitation Fostering resiliency means preparing children with disabilities to negotiate and navigate the adversities and challenges they will encounter over their lives. Important resiliency-related self-capacities include activity self-efficacy, capacity to marshal resources and supports to achieve goals, capacity to adapt to changing life situations, and capacity to envision a positive future. The resiliency framework suggests the importance of enhancing children's views of themselves as empowered, optimistic, adaptive, and hopeful. Practice will be enriched by acknowledging that a range of health concerns are relevant to practice, including issues of impairment, functioning, participation, and adaptation. PMID- 30426783 TI - Informing the Adaptation and Implementation of a Lifestyle Modification Program in Hispanics: A Qualitative Study Among Low-Income Hispanic Adults. AB - Low-income Hispanics are a hard to reach population that face unique challenges in achieving behavior change. Understanding such challenges can inform the adaptation of lifestyle behavioral interventions and increase participant engagement. This descriptive qualitative study aimed to (1) inform lifestyle modification programs focused on improving the physical activity and healthy eating of low-income Hispanic adults and (2) explore potential gender differences necessary for consideration. Five gender-specific focus groups were conducted with Hispanic adults from a free community clinic ( n = 45, 64% women, 53.1 +/- 10.1 years). Sessions were audio-recorded, transcribed, and coded using a general inductive approach. The qualitative software program Dedoose was used to perform a content analysis. Emergent themes included topics of interest, methods of increasing engagement in healthy behaviors, and the delivery of lifestyle modification programs. Men expressed greater interest in physical activity, while women desired to learn about healthy eating. Men described the importance of physician communication, while women focused on the role of social support as facilitators for participating in such programs. Both genders described education as key to behavior change and viewed text messaging as a valuable complement. Results from this study can inform the adaptation of lifestyle modification programs and increase the engagement of low-income Hispanic populations. PMID- 30426784 TI - The quantitative profiling of blood mSEPT9 determines the detection performance on colorectal tumors. AB - AIM: To investigate the quantitative relationship between the positive detection rate (PDR) in colorectal tumor detection and the mSEPT9 level. MATERIALS & METHODS: The level of blood mSEPT9 in various colorectal diseases was quantified by the Epi proColon 2.0 assay. DeltaDeltaCt values were calculated representing the mSEPT9 level. A total of 1347 subjects were recruited in this quantitative study. RESULTS: PDR or sensitivity was positively correlated with the progression of colorectal tumors and the mSEPT9 level in an exponential relationship. The mSEPT9 level of CRC exhibited a distinct pattern of distribution. Strong correlation was found between mSEPT9 level and PDR or sensitivity in various tumor differentiation, pathological types or metastasis. CONCLUSION: The quantitative profiling of blood mSEPT9 determines the detection performance on colorectal tumors. PMID- 30426785 TI - Differences in Maternal Risk Factors Among Undocumented Latinas in Nebraska by Country of Origin. AB - OBJECTIVE:: This study compared maternal risk factors by country of origin for 4,188 Mexican and Guatemalan unauthorized immigrants. METHOD:: Data were drawn from 2007 to 2011 public birth certificate records of unauthorized immigrant mothers residing in Nebraska at the time of delivery. The study sample included 4,188 women ages 18 years or older and originating from either Mexico or Guatemala. Risk factors, including age risk, preexisting health risks, pregnancy health risks, and prior pregnancy risks, were examined by country of origin. Stata 11.0 was used to compute descriptive statistics and conduct chi2 test for binary variables and Student t test for continuous variables. RESULTS:: Analyses found that Mexican and Guatemalan participants have distinct maternal risk factors. Mexican participants were older and at greater risk of obesity and excessive weight gain during pregnancy, while Guatemalan participants were more likely to receive inadequate prenatal care. CONCLUSION:: Findings suggest that both Mexican and Guatemalan immigrants encounter maternal risk factors that could threaten not only their own health but that of their infants as well. Health and social service providers can tailor education and outreach efforts that are specific to Latina subgroups by origin. Furthermore, targeted strategies to delivering prenatal care to unauthorized immigrants are essential for the well being of mothers and newborns. PMID- 30426786 TI - Letter to the Editor reply: economic model of the FilmArray Meningitis Encephalitis panel in children. PMID- 30426787 TI - Assessment of the 8th edition of TNM staging system for gastric cancer: the results from the SEER and a single-institution database. AB - AIM: To investigate whether the 8th edition of Tumor, Node, Metastasis (TNM) staging could properly evaluate the prognosis of gastric cancer patients. METHODS: The prognostic performance between the 7th and 8th edition of TNM staging was compared and clinicopathologic features were analyzed. RESULTS: The stage shifts in the 8th edition staging resulted in the increased numbers of stage IIIA patients and decreased numbers of stage IIB, stage IIIB and stage IIIC patients. Compared with the previous edition, the 8th edition of TNM staging provided a better prognostic stratification for stage III patients. However, whether it is reasonable to incorporate T4aN2, T4aN3a and T4bN3b into stage IIIA, stage IIIB and stage IIIC respectively, which still need further validation. CONCLUSION: Despite the obvious superiority, several deficiencies may still exist in the new edition staging. To better provide prognostic information and therapeutic guidance for gastric cancer patients, the TNM staging system should be further improved in the future. PMID- 30426788 TI - Respiratory syncytial virus vaccine: where are we now and what comes next? AB - INTRODUCTION: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants and elderly and to date, there is no safe or effective vaccine against RSV. Areas Covered: This review provides a roadmap to RSV vaccine development. It is a journey spanning over more than half a century from the initial disappointment with inactivated formalin vaccine to the current advancements in vaccine technology. We highlight the important aspects of RSV structural biology and protective immune response. We include discussion of newer fusion glycoprotein immune targets and current vaccine candidates. We used Pub Med and Medline resources for literature search. Expert opinion: A resurgence of information on the burden related to RSV infection coupled with the newer understanding of the molecular mechanism of RSV infection has reignited a tremendous activity in RSV vaccine discovery. The vaccine pipeline is diverse and target populations are varied, thus making the goal of a safe and effective RSV vaccine in the future within reach. PMID- 30426789 TI - Methyl isocyanate inhalation induces tissue factor-dependent activation of coagulation in rats. AB - Methyl isocyanate (MIC) is a highly toxic industrial chemical causing acute lethality after inhalation. The objective of this study was to determine whether alterations in hemostasis also occur in the immediate hours after exposure. Male rats were exposed to MIC (125-500 ppm) by nose-only vapor inhalation for 30 min. Arterial O2 saturation was monitored prior to exposure, and hourly thereafter. Rats were euthanized at 1, 2, 4, and 8 hr and plasma analyzed for recalcification clotting time, tissue factor (TF) activity, and protein levels. Hypoxemia, as assessed by pulse oximetry, was an early feature of MIC inhalation. In contrast to sham or low (125 ppm) concentrations, 250 and 500 ppm MIC caused significant declines in blood oxygen saturation (% SpO2) at 1 hr, which remained at deficit during the postexposure period. Commensurate with hypoxemia, plasma clotting time was significantly accelerated 1 hr after MIC inhalation (sham treatment: 955 +/- 62.8 s; 125 ppm MIC: 790 +/- 62 s; 250 ppm: 676 +/- 28.0 s; 500 ppm: 581 +/- 175 s). This procoagulant effect was transient, with no difference observed between sham and all MIC groups by 8 hr. Similarly, elevated TF activity and protein were detected in plasma 1 hr after MIC inhalation, each of which showed a progressive decline back to control levels at later timepoints. This study demonstrates that MIC inhalation resulted in hypoxemia and transient hypercoagulability of blood. Accelerated clotting occurred rapidly and was likely due to intravascular TF, which initiates the extrinsic coagulation pathway. PMID- 30426790 TI - Effect of endosulfan and bisphenol A on the expression of SUMO and UBC9. AB - This study was designed to investigate possible interference of Xenobiotics with SUMOylation in eukaryotic cells. To begin with, we docked 71 chemical structures from PubChem with human SUMO1 and UBC9 protein structures using Auto Dock 4.2 and Hex 6.3 and selected five compounds for binding studies in Surface Plasmon Resonance (SPR) with human SUMO1. In SPR studies, only endosulfan showed binding to SUMO1 (Kd1.313 * 10-4 M). Further, we treated HePG2 and differentiated 3T3-L1 cells with endosulfan/bisphenol A/perfluorooctanoic acid (PFOA) to test induction of oxidative stress and SUMO isoform/UBC9 expression. Treatment with these compounds resulted in higher levels of nitric oxide (NO), NOS2A mRNA, and reactive oxygen species (ROS) associated with decreased NADPH levels. Additionally, treatment with these chemicals resulted in elevated mRNA levels of IL-6 and IL-1beta in 3T3-L1 cells. In HePG2 cells, endosulfan treatment resulted in elevated mRNA levels of SUMO1, 3 and UBC9, whereas, treatment with bisphenol A resulted in increased mRNA of SUMO2, 3 and UBC9. Treatment with PFOA resulted in elevated mRNA levels of SUMO2. Apart from influencing the gene expression, endosulfan caused decrease in SUMO1-Sumoylation of few proteins. We propose that one reason for the severe health consequences of exposure to endosulfan/bisphenol could be due to induction of oxidative stress and modulation in SUMO and UBC9 gene expression. PMID- 30426791 TI - Changes in periacetabular bone mineral density five years after resurfacing hip arthroplasty versus conventional total hip arthroplasty. AB - INTRODUCTION:: We studied whether acetabular bone mineral density (BMD) is better preserved after resurfacing hip arthroplasty (RHA) versus small diameter metal-on metal total hip arthroplasty (THA). METHODS:: This randomised controlled trial included 82 patients. BMD was measured in 5 periprosthetic regions of interest (ROI) with dual-energy absorptiometry (DEXA) preoperatively, at 3 and 6 months, 1, 2, 3 and 5 years postoperative. 34 RHA and 26 THA had a complete 5 years follow-up. 1 RHA and 1 THA were revised due to pseudotumour formation, 2 THA were revised because of recurrent dislocations and 1 RHA for avascular necrosis. RESULTS:: Overall an initial decrease in BMD was observed for both implants, stabilising after 2 years. 5 years after RHA a BMD change of +1% in upper cranial, -4% ( p < 0.01) in cranial, -8% ( p < 0.01) in craniomedial, -7% ( p < 0.01) in medial and +4% in caudal ROI compared to baseline values was seen. 5 years after THA a BMD change of -3% ( p = 0.01), -13% ( p < 0.01), -21% ( p < 0.01), -11% ( p < 0.01) and -2% for each respective ROI. The observed BMD decrease in different regions was structurally favouring the RHA-cup, with significantly higher levels in the cranial and craniomedial ROI. CONCLUSION:: Acetabular BMD is better preserved behind a rigid press-fit convex cup in RHA compared to a titanium threaded cup in conventional THA in the cranial and craniomedial ROI. Despite of a theoretical higher stress-shielding behind the stiff acetabular component in RHA, compared to the more elastic threaded titanium THA-cup, bone depletion behind the RHA component does not seem to be of major concern. REGISTRATION:: EudraCT (2006-005610-12). PMID- 30426792 TI - Gastroprotective effects of oleuropein and thymol on indomethacin-induced gastric ulcer in Sprague-Dawley rats. AB - Ethnopharmacological studies demonstrated that thymol (Thym) and oleuropein (Ole) have therapeutic potential for gastric ulcers. The molecular mechanism underlying the gastroprotective effects of these compounds have not been elucidated yet especially for their individual and combination use at high dose. Therefore, this study was conducted to explore their gastroprotective mechanisms on indomethacin (Indo)-induced gastric ulcer model. Ole (50,100, 250, and 500 mg/kg) and Thym (50,100, 200, and 500 mg/kg) were orally administered to the rats 10 min before the induction of ulcer with Indo. The combination of 500 mg/kg doses of Ole and Thym were applied. The gastric mucosa was evaluated histopathologically. Moreover, TAC/TOS, tumor necrosis factor-alpha (TNF-alpha), prostaglandin E2 (PGE2), endothelial nitric oxide synthase (eNOS), and caspase-3 levels were assessed by ELISA and the caspase-3 and TNF-alpha expressions were quantified by qRT-PCR. Indo-induced histopathological changes while Ole and Thym pretreatment prevented these effects. Unlike the 500 mg/kg dose of Ole treatment, the 500 mg/kg dose of Thym administration enhanced these damages. The decreased TAC, PGE2 levels and increased TOS, eNOS, TNF-alpha, caspase-3 levels were obtained in Indo group. However, these changes were reversed by Ole and Thym groups except the 500 mg/kg dose of Thym and the combination treatment groups. Similar trends were observed in the caspase-3 and TNF-alpha expression levels. These results demonstrated that enhanced inflammation, oxidant/antioxidant imbalance, and apoptotic activities were occurred in Indo, 500 mg/kg dose of Thym and the combination treatment groups while not in the other groups. The findings demonstrated the gastroprotective ability of Ole and low doses of Thym in gastric ulcer models. PMID- 30426793 TI - New frontiers in antimicrobial leadership: an interview with Joan Butterton. AB - The Editor of Future Microbiology speaks to Joan R Butterton, M.D., Associate Vice President and Section Head for Antibacterials and CMV for the Infectious Disease therapeutic area at Merck & Co. Joan joined Merck in 2005 in the Department of Clinical Pharmacology where she served as co-chair of the HIV and HCV Early Development Teams and as Clinical Pharmacology Infectious Disease Lead. In these roles, she supported numerous programs within the HCV, HIV, antibacterial and CMV portfolio. Prior to joining Merck, Butterton served on the Faculty of the Infectious Disease Division at the Massachusetts General Hospital, conducting basic bench research in bacterial pathogenesis. She received her B.S (biology) from Yale University, an M. Phil. (history and philosophy of science) from Cambridge University, an M.D. from Harvard Medical School, and a Diploma in Tropical Medicine and Hygiene from the University of London. She completed her residency in internal medicine and a clinical/research fellowship in Infectious Diseases at the Massachusetts General Hospital (MGH) in Boston. PMID- 30426794 TI - Apalutamide and its use in the treatment of prostate cancer. AB - High-risk nonmetastatic castration-resistant prostate cancer is a lethal disease that previously lacked clear treatment options. Progression to bone metastases is associated with significant morbidity and high cost. Apalutamide, an androgen receptor inhibitor, has substantial clinical response in nonmetastatic castration resistant prostate cancer. Apalutamide + androgen deprivation therapy is well tolerated and improves metastasis-free survival, progression-free survival and time to symptomatic progression, and is associated with a favorable trend of improved overall survival. Future research is needed to elucidate mechanisms of resistance to treatment with androgen signaling inhibitors. PMID- 30426795 TI - Power-frequency magnetic fields at 50 Hz do not affect fertility and development in rats and mice. AB - In the present study, the effects of power-frequency magnetic fields (PF-MF) on fertility and development were investigated in rats and mice. Adult Sprague Dawley rats and C57BL/6J mice were divided into four groups: a sham exposure group and 30-uT, 100-uT and 500-uT PF-MF exposure groups. The rats were exposed for 24 weeks, and the exposure time for mice ranged from 18 d to 12 weeks, dependent on the different investigated end points. The rats and mice were exposed for 20 h/d. Plasma hormone levels in rats and mice were analyzed. Furthermore, pregnancy rates and implanted embryos were recorded in pregnant mice. Finally, the neonatal growth of mice was evaluated. The results showed that none of the three intensities affected the body weight and paired ovary weight in female rats. Meanwhile, none of the three intensities affected the body weight, weights of paired testes, weights of paired epididymis and sperm count in male rats. Similarly, no significant differences were found in plasma sex hormone levels between the different PF-MF exposure groups and the sham exposure group. In addition, the pregnancy rates and implanted embryos were not significantly different between the four groups. Moreover, PF-MF exposures had no effects on either the number of fetuses in pregnant mice or the growth and development of neonatal mice. PMID- 30426796 TI - Is synergy the key to treating high-density infections? PMID- 30426797 TI - Clinical Features and Efficacy of Lens Surgery in Patients with Lens Subluxation Misdiagnosed as Primary Angle-Closure Glaucoma. AB - PURPOSE: To investigate the clinical features and efficacy of lens surgery in patients with lens subluxation misdiagnosed as primary angle-closure glaucoma. METHODS: 2054 inpatients with primary angle-closure glaucoma were consecutively recruited. Eighty-five of the patients were rediagnosed as lens subluxation following ultrasound biomicroscopy after hospitalization. Lens surgeries were performed in all patients, and 35 had a follow-up of at least 12 months. Risk factors of postoperative intraocular pressure control were identified with multivariate logistic regression analysis. RESULTS: Eighty-five inpatients (4.1%, 85/2054) with lens subluxation were misdiagnosed as primary angle-closure glaucoma, of which 71.8% (2.97% of all cases, 61 out of 2054 subjects) had ocular blunt trauma and 18.8% (0.78% of all cases, 16 out of 2054 subjects) had spontaneous dislocation. Lens surgery significantly decreased the intraocular pressure and improved best-corrected visual acuity, meanwhile increased the anterior chamber depth (all P < 0.001). Postoperatively, the intraocular pressure was controlled with antiglaucomatous eye drops administration in 17 eyes, in which greater range of preoperative angle closure and zonular dialysis, and longer operation time delay were detected. Risk factors for poor postoperative IOP control were more quadrants of angle closure (P = 0.038) and operation time delay (P = 0.045). CONCLUSION: Lens subluxation was the major cause of the misdiagnosed cases as primary angle-closure glaucoma. Misdiagnosed patients could benefit from the lens surgery, while more angle-closure quadrants and operation time delay indicated worse postoperative intraocular pressure control. PMID- 30426798 TI - Effects of infrared radiation combined with heating on grape seeds and oil quality. AB - The objective of this work was to determine the effects of infrared radiation combined with heating on grape seeds and oil quality. Experimental results showed that high moisture removal was achieved through infrared radiation heating. After infrared radiation heating for 108 s, the inactivation rates of total aerobic bacterial and total mold-yeast counts of the grape seeds were 1.97 +/- 0.12 and 0.62 +/- 0.09 log CFU/g, respectively. The maximum microbial reduction was achieved after infrared radiation heating of the grape seeds to 135 C and subsequent holding at 75 C for 60 min. The crude oil yield of samples subjected to these conditions was 10.39%, which was significantly higher ( p < 0.05) than that of the control sample, and their final moisture content was 7.20%. Additionally, increases in the free fatty acid content and peroxide value of the oil were achieved. The iodine value of the oil decreased. In conclusion, surface pasteurization with a high oil yield could be achieved by the combination of infrared radiation heating and the holding process. Consequently, infrared radiation treatment is suggested to be a promising method for the surface pasteurization of grape seeds. PMID- 30426799 TI - Effect of low frequency ultrasound thawing method on the quality characteristics of Peru squid ( Dosidicus gigas). AB - The effects of different thawing methods (air thawing, water soak thawing, refrigeration thawing, low frequency ultrasound thawing at 160, 240, 320 and 400 W) on thawing time, thawing loss, cooking loss, water-holding capacity and texture of frozen squid were investigated. The results showed that thawing loss and thawing time were reduced significantly ( p < 0.05) by ultrasound thawing compared with the water soak thawing and air thawing, but the cooking loss had no significant difference ( p > 0.05). Results of the ultrasound thawing especially at 160 and 240 W on microstructure showed less destructive effect on muscle. The microstructure of the muscle was destroyed significantly after air thawing and water soak thawing compared with the ultrasound thawing, which showed that more fibre structure was broken and the gap between the muscle fibres was increased significantly. Low-field NMR results showed that the ability of immobile water shifting to free water after ultrasound thawing was lower than air thawing and water soak thawing, which was consistent with the results of thawing loss and cooking loss. Ultrasound thawing might be chosen as an alternative method to enhance the quality during thawing process. PMID- 30426800 TI - High flow nasal cannula in the emergency department: indications, safety and effectiveness. AB - INTRODUCTION: Heated humidified high flow nasal cannula therapy (HHHFNCT) is emerging as a popular non-invasive mode of respiratory support in adults and children. In recent years, its use has extended beyond the intensive care unit to other clinical areas. This review aims to explore the mechanism of action, indications, safety, and effectiveness of HHHFNCT use in the Emergency Department (ED). Areas covered: The mechanism of action of HHHFNCT, as well as its use in adult and pediatric ED will be discussed in this review. Expert commentary: While there exists increasing enthusiasm in the use of HHHFNCT in the ED, constant monitoring of the patients and an experienced assessment of their response to treatment are critical and may require additional manpower deployment, which may be challenging, in the busy ED environment. Our experience with the use of HHHFNCT in children is still growing. Continual research in this area remains crucial in helping us better understand the patient types and conditions managed in ED that would most benefit from this device. PMID- 30426801 TI - A scoping review of metamodeling applications and opportunities for advanced health economic analyses. AB - INTRODUCTION: Metamodels, also known as meta-models, surrogate models, or emulators, are used in several fields of research to negate runtime issues with analyzing computational demanding simulation models. This study introduces metamodeling and presents results of a review on metamodeling applications in health economics. Areas covered: A scoping review was performed to identify studies that applied metamodeling methods in a health economic context. After search and selection, 13 publications were found to employ metamodeling methods in health economics. Metamodels were used to perform value of information analysis (n = 5, 38%), deterministic sensitivity analysis (n = 4, 31%), model calibration (n = 1, 8%), probabilistic sensitivity analysis (n = 1), or optimization (n = 1, 8%). One study was found to extrapolate a simulation model to other countries (n = 1, 8%). Applied metamodeling techniques varied considerably between studies, with linear regression being most frequently applied (n = 7, 54%). Expert commentary: Although it has great potential to enable computational demanding analyses of health economic models, metamodeling in health economics is still in its infancy, as illustrated by the limited number of applications and the relatively simple metamodeling methods applied. Comprehensive guidance specific to health economics is needed to provide modelers with the information and tools needed to utilize the full potential of metamodels. PMID- 30426802 TI - Novel drugs for the treatment of chronic pruritus. AB - INTRODUCTION: Chronic pruritus (CP) is a multidimensional condition severely affecting the quality of life of those affected. Although a multitude of topical and systemic agents are recommended for CP of different origins, the condition often remains refractory to treatment. However, a deeper understanding of the pathophysiology of CP is leading to the development of novel antipruritic drugs. Areas covered: This paper reviews antipruritic therapies in development by gathering data from recently published articles and clinical trials databases. Interleukin-31 antibodies and other biologics, neurokinin-1 receptor antagonists, opioid-receptor agonists/antagonists, TrkA-antagonists, and ileal bile acid transporter inhibitors are discussed. Expert opinion: Clinical trials have rendered promising data on the antipruritic efficacy and safety of novel drugs, but further studies are necessary to enhance our understanding of the different conditions associated with CP. High-quality clinical trial data is necessary for these agents to be approved for the treatment. Basic research should be intensified to identify pathways relevant for CP and to further the development of new specific antipruritic drugs. PMID- 30426803 TI - Endoplasmic reticulum stress contributes to the pathogenesis of stress urinary incontinence in postmenopausal women. AB - OBJECTIVE: To investigate the relationship between endoplasmic reticulum stress (ERS) and the pathogenesis of stress urinary incontinence (SUI) in postmenopausal women. METHODS: Anterior vaginal wall tissue was collected from postmenopausal women with SUI and control subjects. Western blotting was performed for glucose regulated protein (GRP78), inositol-requiring enzyme 1(IRE1), protein kinase-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), C/EBP-homologous protein (CHOP), and B-cell lymphoma 2 (Bcl-2). Additionally, mRNA expression levels of PERK, activating transcription factor 4 (ATF4), and CHOP were examined by real-time polymerase chain reaction. RESULTS: GRP78 protein and mRNA expression levels were significantly lower in women with SUI, compared with control subjects. PERK and p-PERK expression levels were higher in women with SUI than in control subjects. However, no differences in IRE1 or ATF6 expression levels were observed in either group. Notably, higher CHOP and lower Bcl-2 protein expression levels were detected in women with SUI, compared with control subjects. Furthermore, PERK, ATF4, and CHOP mRNA expression levels were significantly higher in women with SUI than in control subjects. CONCLUSIONS: Alterations of ERS markers in SUI suggest that ERS may be involved in the development of SUI in postmenopausal women. PMID- 30426804 TI - Prognostic Utility of Tumor-Infiltrating Lymphocytes in Noncolorectal Gastrointestinal Malignancies. AB - BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and mismatch repair gene mutation (MMR) status are emerging biomarkers in immunotherapy. MMR status and TILs have significant clinical implications with regard to treatment with checkpoint inhibitors. We designed a study to determine the frequency and prognostic utility of TILs and MMR in advanced unresectable noncolorectal gastrointestinal (NCGI) malignancies. METHODS: This is a retrospective cohort study of patients who were diagnosed with advanced noncolorectal gastrointestinal tumors. Biopsy specimens were tested for MMR status by immunohistochemistry along with evaluation of TILs. Kaplan-Meier analysis was performed to determine the impact of TILS and MMR on survival. RESULTS: We analyzed 146 patients; the mean age at diagnosis was 66.4 +/- 11.2 years. 65.8% patients were male, and 62.3% patients had stage 4 disease. All cases had proficient MMR status. The percentage of patients with TILs >5 was 50.7%. There was no statistically significant difference in median overall survival (OS) by TILs when stratified by stage of tumor. When stratified by type of tumor, median OS by TILs level was significantly different for hepatocellular cancers (?5 TILs, 86 days versus >5 TILs 312 days, P = .031). CONCLUSIONS: Our study suggests that MMR-deficient tumors are quite rare in advanced NCGI malignancies. More than 5 TILs per high power field, evaluated simply on a routine hematoxylin and eosin-stained glass slide confer a better prognosis to most noncolorectal gastrointestinal malignancies, especially hepatocellular carcinoma. This has immense clinical utility with regard to eligibility for immunotherapy. PMID- 30426806 TI - Chronic Spontaneous Urticaria or Autoinflammatory Disease? The Therapeutic Effect of Omalizumab in a Pediatric Patient. AB - Chronic spontaneous urticaria is a clinical condition characterized by spontaneous or inducible recurrent wheals. This condition may significantly affect quality of life of patients and of their families. Aetiology is not identified in 25-85% of cases that are indicated as "idiopathic", because all diagnostic tests are negative. Autoimmune processes may be present in 30-50% of patients, although a definite etiological diagnosis is seldom possible. Some patients, in fact, have autoantibodies against the high-affinity IgE receptor FcepsilonR1 or IgE. These patients show an increased incidence of anti-thyroid autoantibodies and represent 30-50% of the patients designated as having chronic spontaneous urticaria. FCAS must be distinguished from acquired cold urticaria, which is characterized by a rash occurring within a few minutes after cold exposure, and is often described as "allergy to cold". Cold urticaria is rare in childhood and is not linked to inflammatory markers. The treatment is based on antihistamines. However, in non-responders a second line treatment with omalizumab can show efficacy. We describe the clinical case of a 9-year-olf female with recurrent monthly episodes of fever, arthralgia, abdominal pain, and urticaria-angioedema who did not respond to steroids associated with antihistamines, however showed the complete resolution of the disease with omalizumab. PMID- 30426805 TI - Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors. AB - INTRODUCTION: Hypoxic tumors overexpress two carbonic anhydrases (CA, EC 4.2.1.1), CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, and dissemination of the tumor). The biochemical rationale behind these processes is orchestrated by the transcription factor hypoxia inducible factor 1 (HIF-1). Areas covered: CA IX and XII have been validated as antitumor/antimetastatic drug targets and may be used for imaging hypoxic tumors. Many CA inhibitors (CAIs) belonging to the sulfonamide, coumarin and sulfocoumarin classes selectively inhibit these two isoforms. CA IX/XII inhibitors inhibit the growth of primary tumors and the formation of metastases and deplete the cancer stem cell population, alone or in combination with other agents. These are three beneficial antitumor mechanisms that make them unique among anticancer drugs available. Expert opinion: Indisulam entered clinical trials as an antitumor sulfonamide; it progressed to Phase II trials but was terminated in 2016. However, SLC-0111, a sulfonamide CA IX/XII inhibitor 1, recently completed a successful Phase I clinical trial for the treatment of advanced, metastatic solid tumors. This compound is now in Phase Ib/II clinical trials and is being assessed as a monotherapy or in combination with other agents such as gemcitabine. CA IX/XII inhibitors are synergistic with other anticancer agents (cisplatin, proton pump inhibitors, doxorubicin, temozolamide) and are a versatile, emerging class of antitumor drugs. PMID- 30426807 TI - Psychopathy and Suicidal Thoughts and Behaviors Revisited: Results From a Statewide Population of Institutionalized Youth. AB - Suicide is the leading cause of death for incarcerated youth, and up to half of all juveniles in confinement experience suicidal ideation in addition to other psychopathology, including psychopathic personality features. Unfortunately, limited research has investigated the psychopathy-suicidality link among juvenile delinquents and using newer psychopathy measures. Based upon a statewide population of incarcerated juvenile offenders, we found that psychopathy was a significant risk factor for suicidal ideation and lifetime suicide attempts, but the latter relationship was attenuated by lifetime depression diagnosis. In addition, certain affective psychopathic features such as Stress Immunity conferred protection against suicidality, whereas behavioral and lifestyle components including Carefree Nonplanfulness, Blame Externalization, and Rebellious Nonconformity were positively linked to suicidal thoughts among the youth offenders. As these risk factors are routinely screened for in juvenile justice settings, this study's findings have considerable implications to applied practice and prevention among juvenile justice involved youth. PMID- 30426808 TI - Obstetric venous thromboembolism: a systematic review of dalteparin and pregnancy. AB - A systematic review of studies published between 1 January 1985 and 31 August 2017 was performed to analyse the efficacy of the low-molecular-weight heparin, dalteparin, in venous thromboembolism (VTE) treatment and prophylaxis during pregnancy, and to evaluate dosing practices, anticoagulant monitoring and adverse events. A therapeutic dosing throughout pregnancy or followed by reduced doses effectively prevented VTE recurrence. Anti-factor Xa activity was the most commonly used method of dose monitoring. The risk of bleeding with dalteparin was generally minor. Major bleeding was observed when a high dose of dalteparin was employed during (or close to) delivery, or postpartum. Other adverse events were minor. Disparity exists in VTE treatment and thromboprophylaxis, with wide variety in the dosing regimens, treatment strategies and monitoring practices employed. Large randomised controlled trials are warranted but due to ethical reasons, and the rarity of VTE-associated obstetric complications, case-control, registry and large observational studies present more likely options. PMID- 30426809 TI - Pyocyanin induces NK92 cell apoptosis via mitochondrial damage and elevated intracellular Ca2. AB - Pseudomonas aeruginosa-derived pigment pyocyanin (PCN) has been proved to induce cell apoptosis mediated by the generation of reactive oxygen species (ROS), which has been studied mainly in epithelial cells and neutrophils. However, we previously found that the PCN-producing strain PA14 induces cell apoptosis in human NK cell line NK92 more effectively than in PCN-deficient strain PA14-phZ1/2 via a yet undetermined mechanism. In the current study, we found that PCN-induced NK92 cell apoptosis occurs through mitochondrial damage despite inhibiting intracellular ROS generation. Intracellular Ca2+ ([Ca2+]i) and Bcl-2 family proteins act as important "priming signals" for apoptosis. PCN treatment increased [Ca2+]i in NK92 cells more than twofold after 2 h stimulation, whereas the Ca2+-chelating agent ethylene glycol tetra-acetic acid (EGTA) inhibited apoptosis. PCN triggered the activation of Bim, Bid, Bik, Bak, and phospho-Bad in NK92 cells in a concentration-dependent manner, but these pro-apoptotic Bcl-2 family proteins were not inhibited by EGTA. In this study, we describe the function of PCN in NK92 cells and identify mitochondrial damage as the mechanism underlying the apoptosis. [Ca2+]i and pro-apoptotic Bcl-2 family proteins are novel targets for PCN-induced apoptosis. Clarification of the cytotoxic diversity of PCN provides a new therapeutic target for defense from P. aeruginosa-induced immune cell damage. PMID- 30426810 TI - Survey of acne-related post-inflammatory hyperpigmentation in the Middle East. AB - AIM: Acne vulgaris is a common inflammatory skin disease in the Middle East, similar to other regions of the world. In the Middle East, there are a relatively large proportion of patients with darker pigmentation (Fitzgerald skin types III VI) who are prone to developing post-inflammatory hyperpigmentation (PIH) as a sequela of acne. Data are sparse on the frequency and characteristics of PIH throughout the world. What information is available indicates that pigmentation problems can be very bothersome for patients and are often quite long-lasting. Thus, it is important for clinicians to be aware of the scope of the problem of acne-associated PIH as well as potential treatment options. METHODS: Prospective non-interventional study of acne patients consulting dermatologists (n = 262) in the Middle East. RESULTS: PIH was present in 87.2% of subjects. The majority of subjects (52.6%) reported that PIH had been present for one year or longer. Of note, 69.0% of subjects reported excoriating their acne lesions, suggesting that this may be a key modifiable risk factor for clinicians to stress during patient education efforts. CONCLUSIONS: PIH was bothersome for patients, with half of subjects indicating that PIH was more bothersome than acne. In addition to our study results, we present here a brief overview of PIH and its treatment. PMID- 30426811 TI - Ophthalmic manifestations in patients with Leigh syndrome, French Canadian type. AB - BACKGROUND: Leigh syndrome, French Canadian type is a rare neurodegenerative disease. To our knowledge, there have been no studies based on ocular findings published for this disease. The purpose of this study is to describe ophthalmic findings in these patients. PATIENTS: Six patients genetically identified as having the syndrome were included in this study. METHODS: Four patients had an ophthalmic examination with an ophthalmologist including evaluation of visual acuity, extraocular motility and lid position, orthoptic workup, evaluation of stereopsis, refraction, evaluation of pupils, color vision, slit-lamp biomicroscopy, measurement of intraocular pressure, and fundoscopy. Two patients had a chart review. RESULTS: Visual acuity ranged from 0.00 logmar to 1.55 logmar. Extraocular motility abnormalities and ptosis were noted in half of the patients. Strabismus was present in the entire cohort, and stereopsis was absent in half of these patients. Amblyopia was noted in 83% of individuals and suppression in 33%. Only one patient had nystagmus. Refraction varied throughout patients. It included severe hyperopia, myopia, astigmatism, and significant anisometropia. Pupils, anterior segment, fundus, and color vision were normal in all patients. Intraocular pressure was slightly elevated in one patient. CONCLUSION: Patients with Leigh syndrome, French Canadian type display a variety of ophthalmic findings, and screening at a young age is recommended. PMID- 30426812 TI - Log-transformed B-type natriuretic peptide as a prognostic predictor in patients undergoing cardiovascular surgery. AB - OBJECTIVE: This study was performed to explore the association between circulating B-type natriuretic peptide (BNP) and other mortality-related factors in patients undergoing cardiovascular surgery. METHODS: In this observational study, multilevel linear regression analysis and multilevel survival analysis were performed to measure the log-transformed BNP (lnBNP) value at four time points in 197 patients with 788 repeated data measurements. Effects of the interaction between the time points and the two intervention groups (cardiac surgery and vascular surgery) were also investigated. Six models were evaluated to identify the best fit for the data. Stata/MP(r) version 14.2 (Stata Corp., College Station, TX, USA) was used to analyze the two-level variance component model fitting. RESULTS: There were significant differences in the fixed-effect parameters of lnBNP, such as the time point, age, body mass index, emergency operation, prognostic nutritional index, and estimated glomerular filtration rate. According to the multilevel survival analysis for all-cause death and vascular death, lnBNP significantly differed and was a common prognostic marker. CONCLUSION: As lnBNP increased by 1 point, all-cause death increased 2.07 times and vascular death increased 3.10 times. lnBNP is an important prognostic predictor and quantitative biochemical marker in patients undergoing cardiovascular surgery. PMID- 30426813 TI - An Exploration of Breastfeeding Practices by Bhutanese Women. AB - BACKGROUND:: Researchers have shown beneficial influences of exclusive breastfeeding for women and infants. Therefore, the World Health Organization recommends exclusively breastfeeding infants for the first 6 months following birth. In Bhutan, researchers have found, through survey research, variable exclusive breastfeeding rates at 6 months. They have not, however, explored the experiences and views of participants in relation to breastfeeding. RESEARCH AIM:: The aim was to explore first-time mothers' views, intentions, and experiences related to exclusive breastfeeding. METHODS:: A qualitative, prospective, longitudinal, descriptive study was undertaken using semistructured, audio-recorded interviews at two points of time with first-time mothers prenatally during late third trimester ( n = 24) and at 6 weeks after birth ( n = 22). The framework approach to analysis was used to identify themes. RESULTS:: Two themes (breastfeeding, but uncertainty about achieving exclusive breastfeeding and acceptance that breastfeeding is painful) were identified from interviews at term. Five themes were identified from interviews at 6 weeks after birth (lack of timely breastfeeding information and support from health professionals, misconceptions about exclusive breastfeeding, being unprepared for the reality of breastfeeding, limited control or choice over feeding, and adoption of cultural and traditional practices). CONCLUSION:: The participants breastfed but did not practice exclusive breastfeeding due to a lack of timely breastfeeding information and inadequate breastfeeding support. While family elders supported breastfeeding, they also promoted the adoption of certain traditional and cultural practices, which affected exclusive breastfeeding. PMID- 30426814 TI - Limbic encephalitis with relapsing polychondritis: persistent white matter lesions and brain atrophy. AB - Relapsing polychondritis (RP) is a rare autoimmune disorder affecting cartilage. Limbic encephalitis is a rare central nervous system manifestation of RP. This current case report describes a 66-year-old Chinese male patient who complained of developing myoclonus in the left leg, ataxia and speech difficulties 3 weeks prior to hospital admission. The patient presented with cognitive impairment, sleep disorder and extrapyramidal symptoms. The patient was diagnosed with RP that affected auricular cartilage, which also manifested as limbic encephalitis. Magnetic resonance imaging showed bilateral temporal lobe lesions involving the hippocampi and basal ganglia. Signal abnormalities in the white matter persisted during the 15-month follow-up period after treatment with corticosteroids and intravenous immunoglobulin. Over the same period, the bilateral hippocampi showed significant atrophy. PMID- 30426815 TI - Identification of the Novel Tooth-Specific Transcription Factor AmeloD. AB - Basic-helix-loop-helix (bHLH) transcription factors play an important role in various organs' development; however, a tooth-specific bHLH factor has not been reported. In this study, we identified a novel tooth-specific bHLH transcription factor, which we named AmeloD, by screening a tooth germ complementary DNA (cDNA) library using a yeast 2-hybrid system. AmeloD was mapped onto the mouse chromosome 1q32. Phylogenetic analysis showed that AmeloD belongs to the achaete scute complex-like ( ASCL) gene family and is a homologue of ASCL5. AmeloD was uniquely expressed in the inner enamel epithelium (IEE), but its expression was suppressed after IEE cell differentiation into ameloblasts. Furthermore, AmeloD expression showed an inverse expression pattern with the epithelial cell-specific cell-cell adhesion molecule E-cadherin in the dental epithelium. Overexpression of AmeloD in dental epithelial cell line CLDE cells resulted in E-cadherin suppression. We found that AmeloD bound to E-box cis-regulatory elements in the proximal promoter region of the E-cadherin gene. These results reveal that AmeloD functions as a suppressor of E-cadherin transcription in IEE cells. Our study demonstrated that AmeloD is a novel tooth-specific bHLH transcription factor that may regulate tooth development through the suppression of E-cadherin in IEE cells. PMID- 30426816 TI - The Children's Oncology Group: Organizational Structure, Membership, and Institutional Characteristics. AB - BACKGROUND: The Children's Oncology Group (COG) is the only organization within the National Cancer Institute's National Clinical Trials Network dedicated exclusively to pediatric cancer research. The purpose of this article is to provide an overview of COG's organizational structure, to characterize its institutional and individual membership, and to summarize enrollments onto COG clinical trials. METHOD: Data from 2013 to 2015 were compiled from sources internal (Network Operations, Statistics and Data Center, Chair's Office) and external (American Hospital Association, American Nurses Credentialing Center) to COG, to present a comprehensive overview of COG's structure, individual and institutional membership, and group operations. RESULTS: In 2016, COG comprised 8,785 individuals from 223 member institutions, across seven countries. An average of 9,661 new patients were registered with COG per year over the most recent (2013-2015) 3-year period. Over the same 3-year time frame, there were an average of 16,836 enrollments onto therapeutic (i.e., treatment) and nontherapeutic (e.g., epidemiology, survivorship, biology) trials per year. CONCLUSIONS: COG institutions have diverse characteristics related to size, geographical location, and infrastructure. Individual membership also reflects diversity with representation from over 28 disciplines and groups. The diversity of COG institutions and individual members allows for unique perspectives and contributions to science unified under a common goal to enroll children/adolescents onto clinical trials. COG's collaborative, multidisciplinary approach to science functions to support the development of research that seeks to continually improve outcomes for children and adolescents with cancer. PMID- 30426817 TI - Imidacloprid induced alterations in oxidative stress, biochemical, genotoxic, and immunotoxic biomarkers in non-mammalian model organism Galleria mellonella L. (Lepidoptera: Pyralidae). AB - Imidacloprid (IMI), a neonicotinoid insecticide, is widely used to control pests in agriculture. We investigated the changes in antioxidant enzyme activities, lipid peroxidation levels, biochemical effects, genotoxic effect, and immunotoxic effect of sublethal doses (0.25, 0.50, 0.75, and 1.00 ug) of IMI at different time periods (24, 48, 72, and 96 h) on a model organism, Galleria mellonella L. The results indicated that there were dose-dependent increases in both antioxidant enzyme activities (SOD and CAT) and MDA levels. Protein content was not affected by IMI at 24th and 48th, whereas it was decreased by the highest dose of IMI (1.00 ug) at 72nd and 96th h. Lipid and carbohydrate contents were reduced with increasing doses of IMI. Micronucleus frequency significantly increased in all IMI doses. All IMI doses caused a significant decrease in THC at 24th, 48th, and 72nd h. Our results can help to illustrate the effects of IMI in target organisms and indirectly may aid to discover potential risk of it on nontarget organisms. Future studies, at molecular levels, will be helpful in understanding the mechanism of action of IMI on these biomarkers. PMID- 30426818 TI - Single Leg Squat Delicacies - The Position of the Non-Stance Limb is an Important Consideration. AB - CONTEXT:: The single leg squat task is often used as a rehabilitative exercise or as a screening tool for the functional movement of the lower limb. OBJECTIVE:: To establish the effect of three different positions of the non-stance leg on three dimensional kinematics, muscle activity and centre of mass (CoM) displacement during a single leg squat. DESIGN:: Within-subjects, repeated-measures design. SETTING:: Movement analysis laboratory. PARTICIPANTS:: Ten participants, aged 28.2+/-4.42 years performed three squats to 60 degrees of knee flexion with the non-stance A) hip at 90 degrees flexion and knee at 90 degrees flexion; B) hip at 30 degrees flexion with the knee fully extended; or C) hip in neutral / 0 degrees and the knee flexed to 90 degrees . MAIN OUTCOME MEASURES:: Trunk, hip, knee and ankle joint angles, and CoM displacement were recorded with inertial sensors while muscle activity was captured through wireless electromyography. RESULTS:: Most trunk flexion (21.38 degrees +/-18.43 degrees ) occurred with the non-stance hip in 90 degrees and most flexion of the stance hip (23.10 degrees +/-6.60 degrees ) occurred with the non-stance hip in 0 degrees . Biceps femoris activity in the 90 degrees squat was 40% more than in the 0 degrees squat, while rectus femoris activity in the 0 degrees squat was 29% more than in the 90 degrees squat. CONCLUSION:: The position of the non-stance limb should be standardised when the single leg squat is used for assessment and be adapted to the aim when used in rehabilitation. PMID- 30426819 TI - Male Sexual Victimization: Examining Variation in the Probability of Weapon Use and Victim Injury. AB - The sexual victimization of adult males remains an understudied subject within criminology. Prior research has generally been restricted to descriptive analysis of small clinical samples and inmate populations. Using general strain theory (GST), this study examines the simultaneous influence of community- and incident level factors on the likelihood of weapon use and victim injury in cases of adult male sexual victimization. This study applies hierarchical generalized linear modeling (HGLM) to 2,155 cases of sexual victimization of adult males nested within 113 U.S. cities. Community-level data are procured from the 2011-2015 American Community Survey (ACS) 5-year summary file and incident-level data are taken from cases of sexual violence contained in the 2011-2015 National Incident Based Reporting System (NIBRS). Findings demonstrate moderate support for GST as a framework through which to examine male sexual victimization, as community levels of disadvantage/violence and ethnic heterogeneity, as well as offender gender, race, intoxication, and weapon use each exhibit statistically significant relations with crime severity. This study finds that community and situational context are each important in predicting weapon use and victim injury, demonstrating the need to further explore male sexual victimization from a multilevel perspective. PMID- 30426820 TI - Investigation of Body Awareness Level and Performance Emotional Status of Athletes in Different Branches. AB - CONTEXT:: The level of body awareness, performance emotional status and demographic characteristics in different sports branches are subjects to be investigated. It is important to examine the concepts of performance emotional state and body awareness to better understand the body-mind relationship in different sports branches. OBJECTIVE:: The aim of this study was to investigate the level of body awareness and performance emotional status (PES) of athletes. DESIGN:: In this cross-sectional study, independent variables are groups (4 sports branches) and dependent variables are body awareness and performance emotional status. PARTICIPANTS:: The study was conducted on 188 licensed athletes (85 footballers, 36 basketball players, 34 handball players and 33 swimmers). The mean age of participants was 14.64+/-1.89 years, height was 172.44+/-11.03cm and body weight was 62.35+/-13.12 kg. SETTINGS:: Four sports clubs and 2 high schools were the intervention facilities. INTERVENTION:: Body Awareness Questionnaire (BAQ) and Continuous Optimal Performance Emotional Status Scale-2(COPESS-2) were used for data collection. Sociodemographic information was recorded. MAIN OUTCOME MEASURES:: One-way ANOVA was used for analysis of normal distribution data in four different groups, and the Kruskal Wallis test was used for the analysis of data that did not show normal distribution. RESULTS:: There was no difference in body awareness among the branches (p=0.171). The performance emotional state (PES) of the footballers was better than that of other athletes (p=0.01). The correlation between body awareness and PES was medium (r=0.47, p<0.01) and the corelations between body awareness and age, licensed year and number of weekly training sessions were weak (r=0.22, p<0.01; r=0.19, p<0.01; r=0.15, p=0.03). CONCLUSIONS:: The body awareness of athletes may not differ among the sports branches, but PES is related to many factors such as mood, age, license years and number of training sessions. In rehabilitation and training, body awareness and PES should be evaluated together. PMID- 30426821 TI - Risk factors for complications after volar plate fixation of distal radial fractures. AB - This study assessed risk factors for complications after volar plate fixation of distal radial fractures. An assessment of electronic patient records from 2008 to 2016 identified 867 patients with a total of 881 distal radial fractures who underwent volar plating in our hospital. A total of 132 complications after volar plate fixation of distal radial fractures were observed (complication rate 15%). Surgery performed by a low-volume surgeon and patient age less than 40 years were the most important risk factors for plate-related complications. In logistic regression analysis, operation performed by a low-volume surgeon and patient age less than 40 years were independent predictors of plate-related complications. Patient age less than 40 years and low-volume surgeon were also found to be independent risk factors for plate-related secondary operations. Surgical delay had no effect on the complication rate. Level of evidence: IV. PMID- 30426822 TI - Prognostic effect of pain sensitization in patients with de Quervain's tenovaginosis receiving corticosteroid injection. AB - We investigated the influence of pain sensitization on the prognosis of de Quervain's tenovaginosis after a local corticosteroid injection. One hundred and fifteen patients with de Quervain's tenovaginosis who were treated with corticosteroid injection were recruited. We initially measured pain sensitization by assessing the patients' pressure pain thresholds in the mid-dorsal forearm and by administering a Pain Sensitivity Questionnaire. The pain score using a visual analogue scale, the result of Eichhoff's test, and the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire were assessed at baseline and at 6 and 24 weeks after the injection. The DASH scores at 6 weeks correlated slightly with higher Pain Sensitization Questionnaire scores, and the DASH scores at 24 weeks correlated moderately with higher Pain Sensitization Questionnaire scores and lower pressure pain thresholds. Lower pressure pain thresholds, higher Pain Sensitization Questionnaire scores, and heavy manual work were independently associated with a higher likelihood of persistent symptoms and signs after a local corticosteroid injection for de Quervain's tenovaginosis. Level of evidence: III. PMID- 30426823 TI - Target-specific toxicity knowledgebase (TsTKb): a novel toolkit for in silico predictive toxicology. AB - As the number of man-made chemicals increases at an unprecedented pace, efforts of quickly screening and accurately evaluating their potential adverse biological effects have been hampered by prohibitively high costs of in vivo/vitro toxicity testing. While it is unrealistic and unnecessary to test every uncharacterized chemical, it remains a major challenge to develop alternative in silico tools with high reliability and precision in toxicity prediction. To address this urgent need, we have developed a novel mode-of-action-guided, molecular modeling based, and machine learning-enabled modeling approach for in silico chemical toxicity prediction. Here we introduce the core element of this approach, Target specific Toxicity Knowledgebase (TsTKb), which consists of two main components: Chemical Mode of Action (ChemMoA) database and a suite of prediction model libraries. PMID- 30426824 TI - Chest tightness is relieved with the use of asthma drugs except bronchodilators. AB - OBJECTIVE: Many patients with a chief complaint of chest tightness are examined in medical facilities, and a lack of diagnosis is not uncommon. We have reported that these patients often include those with chest tightness relieved with bronchodilator use (CTRB) and those with chest tightness relieved with the use of asthma drugs except bronchodilators (CTRAEB). The purpose of this study was to demonstrate the clinical characteristics of the patients with CTRAEB and compare them with data from patients with CTRB. METHODS: Patients with CTRB (n = 13) and CTRAEB (n = 7) underwent a bronchodilator test, assessments of airway responsiveness to methacholine, bronchial biopsy, and bronchial lavage under fiberoptic bronchoscopy before receiving treatment. In all, 10 healthy subjects, 11 bronchial biopsy control patients, and 10 asthmatic patients were recruited for comparison. RESULTS: Inhalation of a short-acting beta2-agonist (SABA) increased the forced expiratory volume in one second (FEV1) by 5.1% +/- 4.0% in patients with CTRB and by 1.3% +/- 3.5% in patients with CTRAEB, and the difference was statistically significant (p = 0.0449). The bronchial biopsy specimens from the patients with CTRB and CTRAEB exhibited significant increases in T cells (p < .05) compared with those of the control subjects. The bronchial responsiveness to methacholine was increased in only a minor portion of patients with CTRB and CTRAEB. CONCLUSIONS: We hypothesized that the clinical condition of patients with CTRAEB involves chest tightness arising from inflammation alone, and this chest tightness is mostly associated with airway T cells, without constriction of the airways. There is little to distinguish CTRAEB from CTRB aside from the response to bronchodilator treatment. This clinical trial is registered at www.umin.ac.jp (UMIN13994, 13998, and 16741). PMID- 30426825 TI - Global Health Security: Protecting the United States in an Interconnected World. PMID- 30426826 TI - Immobilization of cadmium and lead by Lactobacillus rhamnosus GR-1 mitigates apical-to-basolateral heavy metal translocation in a Caco-2 model of the intestinal epithelium. AB - Heavy metals are highly toxic elements that contaminate the global food supply and affect human and wildlife health. Purification technologies are often too expensive or not practically applicable for large-scale implementation, especially in impoverished nations where heavy metal contamination is widespread. Lactobacillus rhamnosus GR-1 (LGR-1) was shown in previous work to reduce heavy metal bioaccumulation in a Tanzanian cohort of women and children through indeterminant mechanisms. Here, it was hypothesized that LGR-1 could sequester the heavy metals lead (Pb) and cadmium (Cd), thereby reducing their absorption across intestinal epithelium. LGR-1 and other lactobacilli significantly reduced the amount of Pb and Cd in solution at all concentrations tested (0.5 mg/L - 50 mg/L) and exhibited sustained binding profiles over a 48-hour period. Relative binding efficiency of LGR-1 decreased as Pb concentration increased, with an absolute minimum binding threshold apparent at concentrations of 2 mg/L and above. Electron microscopy revealed that Pb formed irregular cell-surface clusters on LGR-1, while Cd appeared to form intracellular polymeric clusters. Additionally, LGR-1 was able to significantly reduce apical-to-basolateral translocation of Pb and Cd in a Caco-2 model of the intestinal epithelium. These findings demonstrate the absorbent properties of LGR-1 can immobilize Pb and Cd, effectively reducing their translocation across the intestinal epithelium in vitro. Oral administration of heavy metal-binding Lactobacillus spp. (many of which are known human symbionts and strains of established probiotics) may offer a simple and effective means to reduce the amount of heavy metals absorbed from foods in contaminated regions of the world. PMID- 30426828 TI - Joint Hypermobility as a Predictor of Mechanical Loading in Dancers. AB - CONTEXT:: Dance requires the performance of complex movements that may exceed normal anatomical range however in hypermobile individuals this may have implications for injury and performance. OBJECTIVES:: The aim of the study was to investigate the efficacy of the Beighton score (BS) in predicting mechanical loading in dancers in hypermobile and non-hypermobile dancers with consideration of accelerometer placement and lumbar flexion hypermobility. DESIGN:: Cohort study, clinical measurement. SETTING:: University. PARTICIPANTS:: Thirty-four dancers had their joint hypermobility assessed by the BS. Participants completed the Dance Aerobic Fitness Test (DAFT) with a Global positioning device incorporating a triaxial accelerometer located at the cervico-thoracic junction (C7) and one at the mid belly of the gastrocnemius. MAIN OUTCOME MEASURES:: Accelerometry data was used to calculate PlayerLoad total, PlayerLoad medial lateral, PlayerLoad anterior-posterior and Player Load vertical. Physiological response was measured via heart rate and fatigue response by rate of perceived exertion. RESULTS:: The total BS was a poor predictor of all mechanical loading directions with PlayerLoad anterior posterior C7 (r = .15) and PlayerLoad total lower limb (r = .20) the highest values. Multiple linear regression was a better predictor with values of C7 (r = .43) and lower limb (r = 0.37). No significant difference existed between hypermobile and non-hypermobile subjects for mechanical loading values for all stages of the DAFT and for heart rate and fatigue responses. CONCLUSIONS:: The BS is not a good predictor of mechanical loading which is similar in hypermobile and non-hypermobile dancers for all levels of the DAFT. Mechanical loading and fatigue responses are similar between hypermobile and non-hypermobile dancers. PMID- 30426827 TI - Vemurafenib-induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemia cutis. AB - Neutrophilic panniculitis is an infrequent but characteristic adverse event under therapy with BRAF inhibitors (BRAFi). Since the approval of vemurafenib for treatment of metastatic melanoma in 2011, only two cases of neutrophilic panniculitis in malignancies other than melanoma have been published. Histiocytoid infiltrates of immature neutrophils resembling histiocytes or myelocytes have been reported in Sweet's syndrome and rarely in other neutrophilic dermatoses. We describe a novel variant of neutrophilic panniculitis with histiocytoid myeloid cells in an early lesion from a patient treated with vemurafenib in combination with an anti-EGFR (epidermal growth factor receptor) agent for metastatic colon carcinoma, three weeks after initiation of therapy. Recognizing this variant of panniculitis associated to BRAFi can avoid misinterpretation of the atypical subcutaneous infiltrate as myeloid leukaemia cutis. PMID- 30426829 TI - "Thou Shalt Not Die in This Place": An Ethnomethodological Approach to an Ecuadorian Hospice Through Symbolic Interactionism. AB - Ecuador, located in South America, has a population of 16 million people. According to the National Institution of Statistics in Ecuador, every year 8 out of a 1000 individuals die due to various causes. Palliative care and hospice are relatively new concepts for the Ecuadorian society. In Ecuador people usually die at home, in hospitals, or in nursing homes. In 2012, the first Ecuadorian hospice was created. According to symbolic interactionism theory, research needs to study participants' world in order to understand the dynamic nature of human behavior. Symbolic interactionism proposes that human beings cannot be understood without the context of their interactions. Through an ethnomethodological approach, the following research aims to understand the way that individuals understand and describe death while in the local hospice in Ecuador. Results emerge from the introspection of real stories, field notes, participant observation, and informal conversations at the hospice. Based on a thematic analysis, the following study presents major themes that emphasize the dynamic process of creating meaning of death. PMID- 30426830 TI - Elevated Blood Lead Levels in Infants and Children in Haiti, 2015. AB - OBJECTIVE:: Few studies have reported blood lead levels (BLLs) in Haitian children, despite the known presence of lead from environmental factors such as soil, water, leaded paint and gasoline, improperly discarded batteries, and earthquakes. We sought to determine the prevalence of elevated blood lead levels (EBLLs) among healthy Haitian children. METHODS:: We enrolled children aged 9 months to 6 years from 3 geographic areas in Haiti (coastal, urban, and mountain) from March 1 through June 30, 2015. We obtained anthropometric measurements, household income, potential sources of lead exposure, and fingerstick BLLs from 273 children at 6 churches in Haiti. We considered a BLL >=5 MUg/dL to be elevated. RESULTS:: Of 273 children enrolled in the study, 95 were from the coastal area, 78 from the urban area, and 100 from the mountain area. The median BLL was 5.8 MUg/dL, with higher levels in the mountain area than in the other areas ( P < .001). BLLs were elevated in 180 (65.9%) children. The prevalence of EBLL was significantly higher in the mountain area (82 of 100, 82.0%; P < .001) than in the urban area (42 of 78, 53.8%) and the coastal area (56 of 95, 58.9%; P < .001). Twenty-eight (10.3%) children had EBLLs >=10 MUg/dL and 3 (1.1%) children had EBLLs >=20 MUg/dL. Exposure to improperly discarded batteries ( P = .006) and living in the mountain area ( P < .001) were significant risk factors for EBLLs. CONCLUSIONS:: More than half of Haitian children in our study had EBLLs. Public health interventions are warranted to protect children in Haiti against lead poisoning. PMID- 30426831 TI - IR-A/IGF-1R-mediated signals promote epithelial-mesenchymal transition of endometrial carcinoma cells by activating PI3K/AKT and ERK pathways. AB - BACKGROUND: Obesity is a risk factor for endometrial cancer (EC). However, it is not known how insulin receptor isoform A (IR-A) and insulin-like growth factor 1 receptor (IGF-1R), cognate receptors for insulin and IGFs, respectively, regulate malignant behaviors of EC. In this study, we examined the biological effects of IR-A/IGF-1R, explored the downstream signaling cascades, and assessed the therapeutic potential of targeting IR-A/IGF-1R in vivo. METHODS: The expression levels of IR-A and IGF-1R were examined by qRT-PCR and Western blotting. Upon down-regulating IR-A and/or IGF-1R by sh-IR-A and/or sh-IGF-1R, respectively, cell migration, invasion, apoptosis, and epithelial-mesenchymal transition (EMT) were examined by wound healing, transwell invasion, flow cytometry, and Western blotting, respectively. Furthermore, the effect of sh-IR-A and/or sh-IGF-1R on phosphatidylinositide 3-kinases (PI3K)/AKT and ERK pathways was measured by Western blotting. Lastly, we monitored xenograft growth and EMT in vivo. RESULTS: Both IR-A and IGF-1R were significantly up-regulated in EC cells. Knockdown of IR A or IGF-1R alone was sufficient to reduce migration and invasion, enhance apoptosis, and inhibit EMT of EC cells, and the most significant alterations were observed in cells co-transfected with sh-IR-A+ sh-IGF-1R. These phenotypes were associated with inactivating PI3K/AKT and ERK signaling by sh-IR-A and/or sh-IGF 1R. Consistent with in vitro findings, sh-IR-A or sh-IGF-1R significantly inhibited xenograft growth and EMT in vivo. CONCLUSION: IR-A and IGF-1R-mediated signals, by activating PI3K/AKT and ERK pathways, can induce multiple malignant phenotypes of EC cells. Therefore, targeting IR-A or IGF-1R may provide therapeutic benefits for EC. PMID- 30426832 TI - Validity of an on-Field Readaptation Program Following a Hamstring Injury in Professional Soccer. AB - CONTEXT:: Despite the presence of various injury prevention programs, the rate of hamstring injuries and re-injuries is increasing, warranting the need for a soccer-specific rehabilitation program. OBJECTIVE:: To develop and validate a new, functional on-field program for the rehabilitation and readaptation after a hamstring strain injury through a panel of experts; and determine its usefulness through the application of this program in professional soccer players. DESIGN:: A thirteen-item program was developed which was validated by a panel of experts and later applied to professional soccer players. SETTING:: Soccer training ground. PARTICIPANTS:: Fifteen strength and conditioning, and rehabilitation fitness coaches with a professional experience of 15.40+/-1.57 years in elite clubs and national teams in Europe validated the program. The program was later applied to nineteen professional soccer players of the Spanish First Division (La Liga). INTERVENTIONS:: Once a player sustained a clinically diagnosed injury, the player would first be subject to mobilization and strengthening exercises in the gym after undergoing treatment by percutaneous needle electrolysis. The player would then complete an on-field readaptation program consisting of thirteen drills arranged in a progressive manner in terms of complexity. The drills integrated various aspects of repeated sprint abilities, retraining and re education of biomechanical patterns, and neuromuscular control of the core and lower limbs. MAIN OUTCOME MEASURES:: Aiken's V for each item of the program and number of days taken by the players to return-to-play. RESULTS:: The experts evaluated all items of the program very highly, as seen from Aiken's V values between 0.78 and 0.98 (0.63-0.99) for all drills; while the return to play was in 22.42+/-2.32 days. CONCLUSION:: This program has the potential to help a player suffering from a hamstring strain injury to adapt to real-match conditions in the readaptation phase through the application of sports-specific drills that were very similar to the different injury mechanisms. PMID- 30426833 TI - The influence of motivational priority on younger and older adults' positive gaze preferences. AB - The present study investigated whether manipulating emotional goal priority within a series of divided attention tasks influenced the presence or absence of age-related positive gaze preferences. Across two experiments, participants viewed image pairs while performing an auditory version of a 3-back n-back task. In Experiment 1, four conditions were presented: full attention viewing, emotion regulation priority, n-back task priority, and equal priority. The same conditions were included for Experiment 2, with the addition of a "no priority" divided attention condition and full attention n-back condition. Both age groups demonstrated greater positive relative to negative preferences when emotion regulation goals were prioritized, in spite of the challenge presented by a secondary task in divided attention. The present findings are discussed in terms of how positive emotional processing preferences may emerge despite cognitive control constraints in old age. Implications for the role of explicit motivations for older adults' positivity preferences are discussed. PMID- 30426834 TI - Interstitial pneumonitis associated with trastuzumab emtansine. AB - Trastuzumab emtansine is an antibody-drug conjugate that is effective in human epidermal growth factor receptor-2 expressing advanced breast cancer. Trastuzumab emtansine is generally well tolerated and grade 3-4 toxicities are rare. Pulmonary complications were rarely reported. Here we present a patient presenting with dyspnea after trastuzumab emtansine therapy and treated with a diagnosis of interstitial pneumonitis. PMID- 30426835 TI - Male Sexual Jealousy: Lost Paternity Opportunities? AB - Numerous studies have shown that men experience relatively greater levels of jealousy in response to the sexual aspects of an infidelity (relative to women), whereas women experience relatively greater levels of jealousy in response to the emotional aspects of an infidelity (relative to men). The traditional explanation for this relationship suggests that men experience this greater level of jealousy due to threats of a loss of paternal certainty. In this article, we present three studies that demonstrate that men's differentially greater jealousy occurs in response to situations that threaten paternity opportunities. These results suggest that a loss of perceived paternity opportunities is the ultimate origin of men's increased jealousy in response to sexual infidelity. PMID- 30426836 TI - Personality and Postpartum Sexual Functioning in Israeli Women: The Mediating Role of Body Image. AB - In this study, we aimed to measure the association between the postpartum personality and sexual functioning. This association was examined in light of the possible mediation effect of body image measures, that is, body satisfaction and body exposure during sexual activity. This cross-sectional study employed a web based questionnaire for women who had given birth in the previous year ( N = 382). Key outcome measures included sexual functioning after birth, body image satisfaction, neuroticism, and extraversion personality dimensions. Among the key findings, increased anxiety regarding body exposure during sexual activity and lower body satisfaction were associated with lower postpartum sexual functioning. Higher neuroticism, but not extraversion, was associated with lower postpartum sexual functioning; however, this association was mediated by the body image measures. Given this mediation by body image variables, it may be beneficial to address body image issues when treating women with postpartum sexual difficulties. PMID- 30426837 TI - Influence of Future Possible Selves on Outcome Expectancies, Intended Behavior, and Academic Performance. AB - The purpose of this study was to investigate whether contact with future possible selves impacts individuals' outcome expectancies, intended behaviors, and long term outcomes with regard to academic performance. Specifically, we investigated whether having college students attempt to connect with an academically successful or unsuccessful future possible self through a message composition activity would impact their perceived likelihood of getting a good grade point average, intended academic engagement (i.e., intentions to attend class, study, etc.), and academic performance as measured by grade point average over two subsequent semesters. The study was novel in that we considered the role of temporal position-that is, the current self contacting a future possible self or a future possible self contacting the current self. Results found that students who composed a message from an academically unsuccessful future possible self to their current self had lower outcome expectancies-that is, they believed that they had less chance of obtaining a good grade point average-and lower intended academic engagement than a control group that composed a message to a friend; however, the groups did not vary in academic performance. It is possible that contact with a future possible self that was academically unsuccessful introduced a form of learned helplessness in those participants. PMID- 30426838 TI - Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel induced peripheral neuropathy in breast cancer survivors. AB - BACKGROUND: Paclitaxel is one of the most commonly used drugs to treat breast cancer. Its major dose-limiting toxicity is paclitaxel-induced peripheral neuropathy (PIPN). PIPN persists into survivorship and has a negative impact on patient's mood, functional status, and quality of life. No interventions are available to treat PIPN. A critical barrier to the development of efficacious interventions is the lack of understanding of the mechanisms that underlie PIPN. Mitochondrial dysfunction has been evaluated in preclinical studies as a hypothesized mechanism for PIPN, but clinical data to support this hypothesis are limited. The purpose of this pilot study was to evaluate for differential gene expression and perturbed pathways between breast cancer survivors with and without PIPN. METHODS: Gene expression in peripheral blood was assayed using RNA seq. Differentially expressed genes (DEG) and pathways associated with mitochondrial dysfunction were identified between survivors who received paclitaxel and did (n = 25) and did not (n = 25) develop PIPN. RESULTS: Breast cancer survivors with PIPN were significantly older; more likely to be unemployed; reported lower alcohol use; had a higher body mass index and poorer functional status; and had a higher number of lower extremity sites with loss of light touch, cold, and pain sensations and higher vibration thresholds. No between-group differences were found in the cumulative dose of paclitaxel received or in the percentage of patients who had a dose reduction or delay due to PIPN. Five DEGs and nine perturbed pathways were associated with mitochondrial dysfunction related to oxidative stress, iron homeostasis, mitochondrial fission, apoptosis, and autophagy. CONCLUSIONS: This study is the first to provide molecular evidence that a number of mitochondrial dysfunction mechanisms identified in preclinical models of various types of neuropathic pain including chemotherapy-induced peripheral neuropathy are found in breast cancer survivors with persistent PIPN and suggest genes for validation and as potential therapeutic targets. PMID- 30426839 TI - ? AB - Diagnosis of Carpal Tunnel Syndrome: Value of Ultrasound Compared to Nerve Conduction Studies Abstract. Carpal tunnel syndrome is the most common compression syndrome of the peripheral nerves. The patient's history with nocturnal brachialgia, daytime brachialgia, nocturnal paraesthesia and daytime paraesthesia (part of the 6-item CTS symptom scale) and a specific clinical exam take part while making a diagnosis. Additional diagnostics include electrophysiological testings. A high-resolution ultrasound examination for the evaluation of the morphology of the median nerve has gained importance in diagnosis of a carpal tunnel syndrome, whilst an electrophysiological exam allows a functional evaluation. Cardinal finding in ultrasound is an absolute or relative enlargement of the cross-section of the nerve at the edge proximal to the flexor retinaculum. Despite multiple studies that demonstrated ultrasound as a fist-line diagnostic tool, there is no consensus on optimal sonographic criteria for the definition of a compressed median nerve. Our aim was to demonstrate the use of ultrasound and electrophysiological exams for diagnostics of carpal tunnel syndrome in our own patient population and compared to the literature. PMID- 30426840 TI - Velocity- and power-load relationships in the half, parallel and full back squat. AB - This study aimed to compare the load-velocity and load-power relationships of three common variations of the squat exercise. 52 strength-trained males performed a progressive loading test up to the one-repetition maximum (1RM) in the full (F-SQ), parallel (P-SQ) and half (H-SQ) squat, conducted in random order on separate days. Bar velocity and vertical force were measured by means of a linear velocity transducer time-synchronized with a force platform. The relative load that maximized power output (Pmax) was analyzed using three outcome measures: mean concentric (MP), mean propulsive (MPP) and peak power (PP), while also including or excluding body mass in force calculations. 1RM was significantly different between exercises. Load-velocity and load-power relationships were significantly different between the F-SQ, P-SQ and H-SQ variations. Close relationships (R2 = 0.92-0.96) between load (%1RM) and bar velocity were found and they were specific for each squat variation, with faster velocities the greater the squat depth. Unlike the F-SQ and P-SQ, no sticking region was observed for the H-SQ when lifting high loads. The Pmax corresponded to a broad load range and was greatly influenced by how force output is calculated (including or excluding body mass) as well as the exact outcome variable used (MP, MPP, PP). PMID- 30426841 TI - VE-cadherin and ACE co-expression marks highly proliferative hematopoietic stem cells in human embryonic liver. AB - Despite advances to engineer transplantable hematopoietic stem and progenitor cells (HSPCs) for research and therapy, an in depth characterization of the developing human hematopoietic system is still lacking. The human embryonic liver is at the crossroad of several hematopoietic sites and harbors a complex hematopoietic hierarchy including the first, actively dividing HSPCs that will further seed the definitive hematopoietic organs. However few are known about the phenotypic and functional HSPC organization operating at these stages of development. Here, by using a combination of four endothelial and hematopoietic surface markers i.e. the endothelial-specific marker VE-cadherin, the pan leukocyte antigen CD45, the hemato-endothelial marker CD34 and the Angiotensin Converting Enzyme (ACE, CD143), we identified distinct HSCP subsets, among them, a population co-expressing the four markers that uniquely harbored an outstanding proliferation potential both ex vivo and in vivo. Moreover, we traced back this population to the yolk sac and AGM sites of hematopoietic emergence. Taken together, our data will help to identify human HSPC self-renewal and amplification mechanisms for future cell therapies. PMID- 30426842 TI - Sudden Events Change Old Visual Objects Into New Ones: A Possible Role for Phasic Activation of Locus Coeruleus. AB - We report a novel visual phenomenon called the rejuvenation effect. It causes an "old" object that has been on view for some time to acquire the properties of a suddenly appearing new object. In each experiment, a square outline was displayed continuously on one side of fixation. The target (an asterisk) was presented either inside the square or on the opposite side of fixation. On half of the trials, a transient visual or auditory event preceded the target. In Experiment 1a ( N = 139), response times were faster when the target appeared inside the square, but only when it was preceded by a transient event, consistent with the network-reset theory of locus coeruleus-norepinephrine (LC-NE) phasic activation. Three further experiments confirmed the predictions of network-reset theory, including the absence of rejuvenation in participants with atypical LC-NE functioning (individuals with symptoms of autism spectrum disorder). These findings provide new perspectives on what causes a visual object to be perceived as new. PMID- 30426843 TI - RNA Therapeutics for Tissue Engineering. AB - RNA has several theoretical advantages as a therapeutic agent, but exploiting RNA in this fashion has faced several major hurdles. RNA is unstable and difficult to deliver across hydrophobic cell membranes. Moreover, extraneous RNAs activate innate immune nucleic acid sensors which make them toxic and inflammatory. PMID- 30426844 TI - Digital Storytelling With Heroin Users in Vancouver. AB - As the opioid crisis escalates across North America, photographers are highlighting the gravity of the situation. However, many of their images of people who use drugs are problematic and stigmatizing. This study looks at how digital storytelling (DST) was used in order to assist long-term heroin users taking part in North America's first heroin-assisted treatment program in Vancouver, BC, in amplifying and sharing their personal experiences. DST is a participatory and collaborative process designed to help people share narrative accounts of life events. A total of 10 participants took part in a 3-day DST workshop and eight individuals completed 2 to 3-minute digital stories. Participants demonstrated increased agency in terms of how they represented themselves. Their digital stories disrupt hegemonic representations of heroin users and can help educate the public and decision makers about compassionate and science-based treatments for chronic addiction. Theory, methodology, practical applications, and ethics are discussed. PMID- 30426845 TI - Relationship Between Parenting Styles and Adolescents' Self-Esteem. AB - Poor self-esteem among adolescents poses a great challenge, which parenting styles can influence. This study examined gender differences in perceived parenting styles and self-esteem of adolescents and examined the relationship between perceived parenting styles and adolescents' self-esteem among in-school adolescents in Ibadan, Oyo State, Nigeria. This study utilized a multistage sampling technique. Responses were elicited from 504 consenting pupils using the parental authority questionnaire and a self-esteem questionnaire adjusted to the Rosenberg scale. Self-esteem was scored on a (12-30) scale; scores >= 26 indicate high self-esteem, and scores <= 25 indicate low self-esteem. The mean age and self-esteem score were 14.9+/-1.5 years and 24.0+/-3.3. About one third of respondents reported parenting styles as authoritative or flexible (fathers: 36.3%, mothers: 38.9%). Pearson correlation coefficient test showed a positive significant relationship between flexible parenting style and adolescent self esteem for fathers ( r = 0.141, p = .001) and mothers ( r = 0.137, p = .001). Research findings reveal significant association between perceived parenting styles and adolescents' self-esteem. PMID- 30426846 TI - Characterization and Therapeutic Uses of Exosomes: A New Potential Tool in Orthopedics. AB - In recent years, regenerative medicine has directed its interests onto the use of stem cells to heal human tissue. One specific class of cells that has been employed in this field of research is mesenchymal stem cells. Due to difficulties with the usage of whole stem cells, researchers have turned to an alternative, the secretome of these mesenchymal stem cells. In recent years, research has explored numerous aspects of the mesenchymal stem cell secretome, especially the most promising aspect, exosomes. This review explores a variety of interest in exosomes including the classification and molecular composition, mechanisms for isolation, and the various biological functions. As more is discovered about these exosomes different diagnostic and therapeutic uses in the medical field have also been explored. A new field attempting to exploit these exosomes in clinical practice is orthopedics. While a significant deal of research has been carried out, even more is being discovered to allow utilization of these vesicles in clinical practice. PMID- 30426847 TI - Splinter haemorrhages, splenic infarcts, and pulmonary embolism in granulomatosis with polyangiitis. PMID- 30426849 TI - Cardiopulmonary-induced deformations of the thoracic aorta following thoracic endovascular aortic repair. AB - OBJECTIVES: Thoracic endovascular aortic repair has become a preferred treatment strategy for thoracic aortic aneurysms and dissections. Yet, it is not well understood if the performance of endografts is affected by physiologic strain due to cyclic aortic motion during cardiac pulsation and respiration. We aim to quantify cardiac- and respiratory-induced changes of the postthoracic endovascular aortic repair thoracic aorta and endograft geometries. METHODS: Fifteen thoracic endovascular aortic repair patients (66 +/- 10 years) underwent cardiac-resolved computed tomography angiographies during inspiratory/expiratory breath holds. The computed tomography angiography images were utilized to build models of the aorta, and lumen centerlines and cross-sections were extracted. Arclength and curvature were computed from the lumen centerline. Effective diameter was computed from cross-sections of the thoracic aorta. Deformation was computed from the mid-diastole to end-systole (cardiac deformation) and expiration to inspiration (respiratory deformation). RESULTS: Cardiac pulsation induced significant changes in arclength, mean curvature, maximum curvature change, and effective diameter of the ascending aorta, as well as effective diameter of the stented aortic segment. Respiration, however, induced significant change in mean curvature and effective diameter of the ascending aorta only. Cardiac-induced arclength change of the ascending aorta was significantly greater than respiratory-induced arclength change. CONCLUSIONS: Deformations are present across the thoracic aorta due to cardiopulmonary influences after thoracic endovascular aortic repair. The geometric deformations are greatest in the ascending aorta and decline at the stented thoracic aorta. Additional investigation is warranted to correlate aortic deformation to endograft performance. PMID- 30426848 TI - Humerus fracture and combined venous injury increases limb loss in axillary or subclavian artery injury. AB - OBJECTIVE: Axillosubclavian vessel injury is rare, with most cases occurring after penetrating trauma. A prior database (2002-2006) analysis demonstrated an overall limb loss rate of 2.9%, with no difference between isolated arterial axillosubclavian vessel injury and combined artery/vein axillosubclavian vessel injury. Given increases in advanced vascular surgical techniques, as well as improved multidisciplinary care and expeditious diagnosis with computed tomography angiography, we hypothesized the national rate of limb loss in patients with arterial axillosubclavian vessel injury has decreased. In addition, we attempted to identify current predictors for limb loss in arterial axillosubclavian vessel injury. Finally, we hypothesized that combined artery/vein axillosubclavian vessel injury, as well as associated brachial plexus injury will have a higher risk for limb-loss and mortality compared to isolated arterial axillosubclavian vessel injury. METHODS: A retrospective analysis of the National Trauma Data Bank was performed between 2007 and 2015. All patients >= 18 years of age with arterial axillosubclavian vessel injury were included. The primary outcome was limb loss. After a univariable logistic regression model identified significant covariates, we performed a multivariable logistic regression for analysis. RESULTS: Of the total 5,494,609 trauma admissions, 3807 patients had arterial axillosubclavian vessel injury (<0.1%). Of these, 3137 (82.4%) had isolated arterial axillosubclavian vessel injury and 670 (17.6%) had combined artery/vein axillosubclavian vessel injury. The overall limb loss rate was 2.4% (from 2.9% in 2006, p = 0.47). After adjusting for covariates, independent risk factors for limb loss included a combined artery/vein axillosubclavian vessel injury (odds ratio = 3.54, confidence interval = 2.06 6.11, p < 0.001), blunt mechanism (odds ratio = 7.81, confidence interval = 4.21 14.48, p < 0.001), open repair (odds ratio = 2.37, confidence interval = 1.47 3.82, p < 0.001), and open proximal humerus fracture (odds ratio = 8.50, confidence interval = 4.97-14.54, p < 0.001). An associated brachial plexus injury was not associated with limb loss ( p = 0.37). Combined artery/vein axillosubclavian vessel injury was associated with higher risk for mortality compared to isolated arterial axillosubclavian vessel injury (odds ratio = 2.17, confidence interval = 1.73-2.71, p < 0.001). CONCLUSIONS: The national rate of limb loss in trauma patients with arterial axillosubclavian vessel injury has not changed in the past decade. A combined artery/vein axillosubclavian vessel injury is an independent risk factor for limb loss, as well as open repair. However, the strongest risk factor is an open proximal humerus fracture. An associated brachial plexus injury is not associated with increased risk of limb loss. Patients with combined artery/vein axillosubclavian vessel injury have a twofold increased risk of death compared to patients with isolated arterial axillosubclavian vessel injury. PMID- 30426850 TI - Fathers' experiences during the first postnatal week at home after early discharge of mother and baby from the maternity unit: A meta-synthesis. AB - AIM: The aim of this study was to explore and describe fathers' experiences during the first postnatal week after early discharge of mother and baby from the maternity unit. METHODS: A meta-synthesis. INCLUSION CRITERIA: peer-reviewed qualitative single studies of fathers' experiences during the first week after early discharge (defined as less than 72 hours postpartum) from hospital after the birth of a healthy singleton baby born between weeks 37 and 40. Databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Medline, Maternity and Infant Care, Joanna Briggs, SweMed+ and PsycInfo were searched in May 2015 and May 2018. Of the 940 titles scanned for eligibility, three articles met the inclusion criteria. The consolidated criteria for reporting qualitative research checklist was used. FINDINGS: All included studies were conducted in Sweden during the period 2002-2012. The total sample of participants in the meta synthesis comprised 35 fathers. Analysis of the included studies generated two themes: building confidence and coping with responsibility. CONCLUSIONS: The fathers' experiences were affected by the emotional support of midwives, which boosted their confidence. This seems to be a premise for taking and coping with responsibility during the first days at home. Good cooperation between hospitals and municipalities is vital, and midwives must be available and present in order to ensure continuity in maternity care. PMID- 30426851 TI - The effect of laminin-111 hydrogels on muscle regeneration in a murine model of injury. AB - Volumetric muscle loss (VML) is characterized by a critical loss of muscle tissue that is accompanied by severe functional impairment and often long-term disability. Clinical therapies currently employed in the treatment of VML are ineffective at regenerating lost muscle and restoring function. In this study, we used a novel hydrogel composed of fibrinogen and laminin-111, to promote regeneration and recovery of VML traumatized muscle. Our previous study showed that these hydrogels exhibit fibrous structure and Young's modulus of ~2kPa while supporting C2C12 myoblast proliferation, myogenic marker expression, and pro regenerative growth factor secretion in vitro. In a murine model of VML injury, the implantation of these hydrogels showed significant improvements in muscle weights and heightened infiltration of satellite, endothelial, hematopoietic, and immune cells at two weeks post-injury compared to the untreated muscles. At four weeks post-injury, the hydrogel treated muscle showed increased myogenic activity, acetylcholine receptor clustering, and induction of the anti inflammatory M2-like macrophage phenotype. However, improvements in muscle weights and force production were not observed at four weeks. An adjunct therapy such as physical rehabilitation or co-delivery of stem cells may be required for the effective treatment of VML. Overall, these results will inform and guide the development of a successful tissue engineering strategy for the regeneration of skeletal muscle following trauma. PMID- 30426852 TI - Using GIS to detect cluster and spatial disparity in maternal health indicators: a need for social health interventions. AB - Maternal mortality remains a serious global health concern. Although global efforts have produced some encouraging results in some World Health Organization's health regions, disparities persist within many countries. Additionally, in many developing countries, inadequate documentation of various health events including maternal mortality and morbidity, make it difficult to determine the true extent of the problem. Maternal health indicators are therefore proxies used in estimating health status in developing countries. Using geospatial and geovisualization techniques, this study examines district level disparities in two maternal health indicators in Ghana antenatal care (ANC) visits and skilled birth attendance (SBA). The results reveal districts with complete lack of access to higher health care professionals and others with underutilization of antenatal services. The findings provide important input for targeting location-specific public health and maternal health interventions. PMID- 30426853 TI - Treating the troponin: adverse consequences of over-treatment of elevated troponin in non-coronary presentations. AB - BACKGROUND AND AIMS: Anti-platelet and anti-thrombotic therapy are well established treatments in acute coronary syndromes. Highly sensitive assays have diminished the positive predictive value of troponin in acute coronary syndromes and increased the importance of the clinical assessment in interpreting positive results. This cohort study sought to investigate over-treatment of non-coronary troponin rises and associated adverse outcomes. METHODS AND RESULTS: We reviewed 223 consecutive patients presenting to Queen Elizabeth University Hospital, Glasgow, with suspected acute coronary syndromes over a six-week period. Of these, 27 (12%) met our 'inappropriate therapy' criteria. This group had a low ischaemic risk (HEART score: 4.2 +/- 1.4) (GRACE score: 117 +/- 30.8) but an intermediate-high bleeding risk (CRUSADE score: 34 +/- 14.5). Approximately half of the patients (14/27, 52%) reported chest pain, with only 4/27 (15%) having ischaemic ECG changes. There were three intracranial haemorrhages, each after the patient had received a single dose of aspirin, ticagrelor and fondaparinux. CONCLUSION: The combination of injudicious high-sensitivity troponin testing with potent anti-platelet and anti-thrombotic therapy was associated with possible over-treatment of patients and associated harm. Emphasis on interpretation of troponin in the context of clinical presentation and improved awareness of type 2 myocardial infarction are essential to limit iatrogenic pharmacological harm. PMID- 30426854 TI - The speedboat vertebral fracture: a hazard of holiday watersports. AB - PURPOSE: The purpose of this study was to describe and characterise spinal fractures sustained by watercraft occupants due to splashdown of light watercraft when riding over uneven water surfaces. METHODS: A retrospective review of all patients presenting with these injuries to St Luke's and Mater Dei state hospitals in Malta over a 10-year period was undertaken to determine patient demographics, the nature of spinal injuries sustained and the incidence of any associated extra-spinal injuries. RESULTS: Twenty-one patients (mean age 41.2 years) suffered 25 fractures. Injuries were seasonal, occurring exclusively between the months of May and October. One patient was local whilst 20 were from other countries. All fractures were Magerl type A fractures and occurred around the thoracolumbar junction. The L1 vertebra was most commonly affected (12 patients). Four patients sustained two vertebral fractures. There were no extra spinal injuries. CONCLUSIONS: Watercraft splashdown can transmit significant forces to occupants, resulting in Magerl type A vertebral fractures around the thoracolumbar junction. These injuries occur under compression. They are highly consistent in their morphology and localisation and should be excluded in individuals complaining of back pain after watercraft use. Almost all patients were from outside Malta and injuries were seasonal, providing opportunities for targeted injury prevention campaigns. PMID- 30426855 TI - Sicyos angulatus ameliorates acute liver injury by inhibiting oxidative stress via upregulation of anti-oxidant enzymes. AB - OBJECTIVE: We aimed to investigate the effect of Sicyos angulatus (SA) ethanolic extracts as antioxidants and potential treatments for liver disease. METHODS: To establish a mouse model of liver injury, C57BL/6 male mice were injected via the caudal vein with a single dose of concanavalin A (Con A, 15 mg kg-1). SA extracts were administered once by oral gavage 30 min before Con A injection. RESULTS: In vitro studies showed that SA decreased tert-butyl hydroperoxide (t-BHP)-induced reactive oxygen species (ROS) production. SA administration reduced plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, as well as hepatic ROS levels, in a dose-dependent manner. Moreover, SA increased the activities of the hepatic antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in a dose-dependent manner. Furthermore, SA treatment reduced pro-apoptotic protein levels. Con A-mediated cytosolic release of Smac/DIABLO and apoptosis-inducing factor (AIF), which are markers of necrosis, were dramatically decreased in HepG2 cells treated with SA. CONCLUSION: SA ameliorated liver injury and might be a good strategy for the treatment of liver injury. PMID- 30426856 TI - Towards the use of multidimensional performance indicators in football small sided games: the effects of pitch orientation. AB - This study aimed to compare youth football players' performance during two small sided games with different pitch orientation: i) 40x30m and ii) 30x40m formats. Twenty under-15 players (age = 14.1 +/- 0.5 years) participated in nine GK+4vs4+GK situations in each format, with the duration of six minutes each. Positional data were collected using individual GPS units, and computed for tactical and physical performance indicators. The SSG were video recorded, using notational analysis for collecting technical indicators. A novel method that incorporates time dependent notational information with spatiotemporal data was used to compute multidimensional parameters. Standardised effect sizes and non clinical magnitude-based inferences were used to compare formats. Results showed that players covered more distance at higher intensities, presented more passes and dribbles and were more synchronised in the longitudinal axis while playing in the 40x30m pitch. In the 30x40m pitch, results showed a lower distance between team centroids, higher number of shots, more lateral passes and a wider team positioning. Multidimensional indicators, as players position and distance to the closest defender while shooting, revealed a more constant distance between attacker and defender in the 40x30m pitch. These results highlight the importance of integrating information from different indicators for a contextually valid information. PMID- 30426857 TI - The intrinsic prognostic value of the ankle-brachial index is independent from its mode of calculation. AB - The object of this study was to compare the prognostic value of different methods of ankle-brachial index (ABI) calculation. From April 1998 to September 2008, we calculated the ABI in 1223 patients before coronary artery bypass grafting. The ABI was calculated according to five different calculation modes of the numerator. The patients were classified into three groups: clinical peripheral artery disease (PAD), subclinical PAD if no clinical history but abnormal ABI (< 0.90 or > 1.40), and no PAD. The primary outcome was total mortality. During a follow-up of 7.6 years (0.1-15.9), 406 patients (33%) died. The prevalence of the subclinical PAD varied from 22% to 29% according to the different modes of ABI calculation. Areas under the ROC curve to predict mortality according to different calculation modes varied from 0.608 +/- 0.020 to 0.625 +/- 0.020 without significant differences. The optimal ABI threshold to predict mortality varied for every method, ranging from 0.87 to 0.95. In multivariate models, ABI was significantly and independently associated with total mortality (hazard ratio (HR) = 1.46, 95% CI: 1.15-1.85, p = 0.002); however, this association was not significantly different between the various methods (HRs varying from 1.46 to 1.67). The use of the optimal ABI threshold for each calculation mode (rather than standard 0.90) allowed a slight improvement of the model. In conclusion, the ABI prognostic value to predict mortality is independent from its method of calculation. The use of different optimal thresholds for each method enables a comparable prognosis value. PMID- 30426858 TI - Inhibition of mRNA processing activity from ginger-, clove- and cinnamon-extract, and by two ginger constituents, 6-gingerol and 6-shogaol. AB - Inhibition of mRNA processing, including splicing in the nucleus, is a potential anti-cancer candidate. To obtain mRNA processing inhibitors, we have screened for active constituents from spices. Ginger, clove, and cinnamon showed an inhibitory effect on mRNA processing in the nucleus. Two components in ginger, 6-gingerol and 6-shogaol, exhibited the inhibition of mRNA processing. PMID- 30426861 TI - Freeze-dried chitosan-platelet-rich plasma implants improve supraspinatus tendon attachment in a transosseous rotator cuff repair model in the rabbit. AB - Rotator cuff tears result in shoulder pain, stiffness, weakness and loss of motion. After surgical repair, high failure rates have been reported based on objective imaging and it is recognized that current surgical treatments need improvement. The aim of the study was to assess whether implants composed of freeze-dried chitosan (CS) solubilized in autologous platelet-rich plasma (PRP) can improve rotator cuff repair in a rabbit model. Complete tears were created bilaterally in the supraspinatus tendon of New Zealand White rabbits ( n = 4 in a pilot feasibility study followed by n = 13 in a larger efficacy study), which were repaired using transosseous suturing. On the treated side, CS-PRP implants were injected into the transosseous tunnels and the tendon itself, and healing was assessed histologically at time points ranging from one day to two months post-surgery. CS-PRP implants were resident within transosseous tunnels and adhered to tendon surfaces at one day post-surgery and induced recruitment of polymorphonuclear cells from 1 to 14 days. CS-PRP implants improved attachment of the supraspinatus tendon to the humeral head through increased bone remodelling at the greater tuberosity and also inhibited heterotopic ossification of the supraspinatus tendon at two months. In addition, the implants did not induce any detectable deleterious effects. This preliminary study provides the first evidence that CS-PRP implants could be effective in improving rotator cuff tendon attachment in a small animal model. PMID- 30426860 TI - Long-term exposure to crotonaldehyde causes heart and kidney dysfunction through induction of inflammatory and oxidative damage in male Wistar rats. AB - Crotonaldehyde is a ubiquitous hazardous pollutant, present in cigarette smoke and automobile exhaust and is endogenously generated by lipid peroxidation. Most of the current studies focus on its lung toxicity. However, there have been few investigations on the cardiac and renal toxicity caused by crotonaldehyde exposure. We hypothesized that oral intake of crotonaldehyde can cause inflammatory and oxidative/nitrosative damage to the heart and kidneys. Therefore, we treated male rats with crotonaldehyde by gavage at 0, 2.5, 4.5, and 8.5 mg/kg/day for 120 days and evaluated the alterations in histological and serological parameters, oxidative state, and inflammation responses to explore the roles of crotonaldehyde-induced oxidative/nitrosative stress and inflammation in the heart and kidney dysfunction and to explore the relationship between heart and kidney dysfunction. We found that body weight increment, as well as heart and kidney coefficients decreased with an increasing crotonaldehyde dosage. Histological examinations indicated that crotonaldehyde exposure led to focal myocardial necrosis, cardiac fibrosis, renal tubular epithelial cell edema, and renal lymphocyte infiltration. We also assessed the impact of crotonaldehyde treatment on oxidative/nitrosative stress markers, antioxidant enzymes, inflammatory biomarkers, heart/kidney functional markers, and angiotensin II aldosterone-brain natriuretic peptide (AngII-ALD-BNP) levels. Overall, we found that proinflammatory cytokine and malondialdehyde levels increased in a dose dependent manner. Furthermore, crotonaldehyde treatment (4.5 and 8.5 mg/kg) significantly prevented the upregulation of antioxidant enzyme activity, thereby increasing oxidative/nitrosative stress (P < 0.05). Moreover, we found that the levels of AngII and ALD increased, whereas the levels of BNP decreased, consistent with heart and kidney dysfunction. Collectively, these results suggest that long-term, low-dose crotonaldehyde exposure leads to an imbalance in AngII ALD-BNP levels, which mediates cardiac hemodynamic changes causing internal oxidative/nitrosative stress and inflammatory reactions, leading to renal and cardiac dysfunction in male rats. PMID- 30426862 TI - Histological and structural evaluation of growth hormone and PLGA incorporation in macroporous scaffold of alpha-tricalcium phosphate cement. AB - An in vivo study was conducted to evaluate the effects of the incorporation of fibers of poly(lactic acid-co-glycolic acid, PLGA) and poly(isoprene) blend and recombinant human growth hormone (rhGH) in a macroporous scaffold of alpha tricalcium phosphate cement (alpha-TCP) samples inserted into calvarial defects (8 mm in diameter) of 48 Wistar rats. The samples of alpha-TCP + PLGA/poly(isoprene) blend fibers were also submitted to a mechanical test of flexural strength. The animals of the different experimental groups [1] alpha-TCP (n = 6); [2] alpha-TCP + PLGA/poly(isoprene) blend fibers (n = 6); [3] alpha-TCP + rhGH, (n = 6) and [4] alpha-TCP + PLGA/poly(isoprene) blend fibers + rhGH, (n = 6) (the numbers within square brackets identify the experimental groups), after two weeks (subdivision "a") and four weeks (subdivision "b"), were euthanized and the implants removed for histological analysis. There was no statistical difference (p > 0.05) between the samples with and without fibers in the mechanical test. Light microscopy revealed good integration of the material in the host tissue, represented by tissue penetration into the macropores and adequate angiogenesis. In the two-week period, the groups [3a] and [4a] were significantly superior (p < 0.05) to the other groups with regard to angiogenesis and bone neoformation. In the four-week period, the group [3b] was significantly superior (p < 0.05) to the other groups with regard to bone neoformation. We conclude that the macroporous alpha-TCP scaffold used in this study has low mechanical resistance, is biocompatible and has significantly improved the osteoconductive capacity when rhGH is incorporated into its structure. PMID- 30426863 TI - Evaluation of the bioactivity about anti-sca-1/basic fibroblast growth factor urinary bladder matrix scaffold for pelvic reconstruction. AB - : Introduction and hypothesis: Pelvic support structure injury is the major cause of pelvic organ prolapse. At present, polypropylene-based filler material has been suggested as a common method to treat pelvic organ prolapse. However, it cannot functionally rehabilitate the pelvic support structure. In addition to its poor long-term efficiency, the urinary bladder matrix was the most suitable biological scaffold material for pelvic floor repair. Here, we hypothesize that anti-sca-1 monoclonal antibody and basic fibroblast growth factor were cross linked to urinary bladder matrix to construct a two-factor bioscaffold for pelvic reconstruction. METHODS: Through a bispecific cross-linking reagent, sulfosuccinimidyl 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (sulfo-smcc) immobilized anti-sca-1 and basic fibroblast growth factor to urinary bladder matrix. Then scanning electron microscope and plate reader were used to detect whether the anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold was built successfully. After that, the capacity of enriching sca-1 positive cells was measured both in vitro and in vivo. In addition, we evaluated the differentiation capacity and biocompatibility of the scaffold. Finally, western blotting was used to detect the level of fibulin-5 protein. RESULTS: The scanning electron microscope and plate reader revealed that the double-factor biological scaffold was built successfully. The scaffold could significantly enrich a large number of sca-1 positive cells both in vitro and in vivo, and obviously accelerate cells and differentiate functional tissue with good biocompatibility. Moreover, the western blotting showed that the scaffold could improve the expression of fibulin-5 protein. CONCLUSION: The anti-sca-1/basic fibroblast growth factor-urinary bladder matrix scaffold revealed good biological properties and might serve as an ideal scaffold for pelvic reconstruction. PMID- 30426865 TI - Introduction to the Special Issue: Learning to Listen from Sounds to Words. AB - The eight articles in this special issue 'Learning to listen from sounds to words' were presented at the conference Sound to Word in Bilingual and Second Language Speech Perception held at the University of Iowa in spring 2016. The selected contributions focus on how second language speech perception interacts with orthography, how phonology interacts with speech perception and how listeners use the cues in the input to segment and create the word forms for lexical processing. This collection of papers expands the field of speech perception and production by granting a central role to the lexicon and exploring how listeners and speakers activate representations, from sounds to words. PMID- 30426864 TI - 3D printing mesoporous bioactive glass/sodium alginate/gelatin sustained release scaffolds for bone repair. AB - Drug delivery and release are a major challenge fabricating bone tissue engineering. In this study, we fabricated new sustained release hydrogel scaffolds composited of mesoporous bioactive glass, sodium alginate and gelatin by a three-dimensional printing technique. Naringin and calcitonin gene-related peptide were used as drugs to prepare drug-loaded scaffolds by direct printing or surface absorption. The physicochemical properties of the scaffolds and the drug release profiles of the two drug-loading models were investigated. We also examined the biocompatibility of the scaffolds, as well as the effect of the released medium on the proliferation and osteogenic differentiation of human osteoblast-like MG-63 cell. The results showed that the scaffolds had a high porosity (approximately 80%) with an interconnected cubic pore structure, rough surface morphology, bioactivity and strong biocompatibility. Furthermore, the naringin or calcitonin gene-related peptide co-printed into the scaffold displayed a steady sustained release behaviour for up to 21 days without an initial burst release, while both naringin and calcitonin gene-related peptide absorbed onto the surface of the scaffold were completely released within two days. MG-63 cells cultured with the extraction containing released drugs displayed promoted cell proliferation and the expression of osteogenesis-related genes more effectively compared with the drug-free extractions. Therefore, these results demonstrate that the developed mesoporous bioactive glass/sodium alginate/gelatin sustained release scaffolds provide a potential application for bone tissue engineering. PMID- 30426866 TI - Multiple object tracking and pupillometry reveal deficits in both selective and intensive attention in unilateral spatial neglect. AB - INTRODUCTION: Unilateral spatial neglect is typically associated with a spatial attention deficit, as neglect patients fail to respond to objects in their contralesional hemispace. However, growing evidence suggests that also nonspatial attention impairments (e.g., arousal) play a role and influences the recovery from this syndrome. METHOD: Nonspatial and spatial attentional functions were assessed in 13 right-hemisphere stroke patients with neglect, 13 right-hemisphere stroke patients without neglect, and 26 healthy control participants, by investigating pupillary responses and performance on a multiple object tracking task (MOT)-that is, a dynamic task of divided attention where cognitive load can be manipulated precisely. The task was alternately presented in the left and right hemispace to assess spatial attention functioning. RESULTS: Results revealed smaller pupillary dilations in both patient groups than in controls, suggesting reduced attentional resources or arousal, and while patients without neglect and controls revealed significant effects of cognitive load on their pupillary responses, neglect patients did not. Both MOT and visual search (VS) tasks revealed spatial symptoms of neglect, while MOT performance measures additionally indicated reduced cognitive functioning in the ipsilateral hemispace. Moreover, the MOT task revealed severely reduced divided attention in neglect patients, as they only managed to track one target in the contralesional hemispace and occasionally two targets at the time in the ipsilesional hemispace. CONCLUSION: Our results suggest that a stroke may lead to reduced attentional resources. Furthermore, as neglect patients showed no indications in their pupillary responses that they were able to regulate the allocation of resources in accordance with the varying task demands, it appears they additionally had impaired mechanisms for adjusting arousal levels. Our findings suggest that neglect involves nonspatial as well as spatial attention impairments, as also ipsilesional performance was reduced in this group. PMID- 30426867 TI - Motor Lateralization May Be Influenced by Long-Term Piano Playing Practice. AB - Motor lateralization is viewed as anatomical or functional asymmetry of the two sides of the body. Functional motor asymmetry can be influenced by musical practice. This study explored whether piano playing experience modulates motor asymmetry and leads to an altered pattern of hand selection, reflecting an altered handedness. We asked two groups of right-handed participants-piano players and non-piano players-to reach targets in their frontal space with both arms, and we tested the motor performance of each arm on this task and then on an arm preference test. As musical practice can decrease motor asymmetry between arms, we hypothesized that participants with piano playing experience would display less interlimb asymmetry and that this, in turn, would change their arm preference pattern, compared with participants without piano playing experience. We found support for both hypotheses, and we conclude that arm selection (preference) is not biologically fixed, but, rather, can be modulated through long-term piano playing. PMID- 30426868 TI - Attention, Impulsiveness, and Gender in Academic Achievement Among Typically Developing Children. AB - Although several studies have examined the relationships among attention, impulse control, gender, and academic achievement, most have focused on clinical samples and have considered only one or two academic subjects. This study investigated these relationships among typically developing children using general achievement measures (academic scores and grades). Our participants were 270 typically developing primary school students (142 boys and 128 girls) of different nationalities living in Malaysia, recruited with purposive sampling with a mean age of 9.75 years. We found that both attention and impulse control significantly predicted academic achievement. Girls had a higher level of attention and impulse control than boys, but gender was not a significant moderator between either attention or impulse control and academic achievement. We discuss the implications of these findings and the need for further research. PMID- 30426869 TI - Public Health Rising to the Challenge: The Bloomberg American Health Initiative. PMID- 30426870 TI - Bringing Evidence to Bear on Public Health in the United States. PMID- 30426871 TI - A Public Health Strategy for the Opioid Crisis. AB - Drug overdose is now the leading cause of injury death in the United States. Most overdose fatalities involve opioids, which include prescription medication, heroin, and illicit fentanyl. Current data reveal that the overdose crisis affects all demographic groups and that overdose rates are now rising most rapidly among African Americans. We provide a public health perspective that can be used to mobilize a comprehensive local, state, and national response to the opioid crisis. We argue that framing the crisis from a public health perspective requires considering the interaction of multiple determinants, including structural factors (eg, poverty and racism), the inadequate management of pain, and poor access to addiction treatment and harm-reduction services (eg, syringe services). We propose a novel ecological framework for harmful opioid use that provides multiple recommendations to improve public health and clinical practice, including improved data collection to guide resource allocation, steps to increase safer prescribing, stigma-reduction campaigns, increased spending on harm reduction and treatment, criminal justice policy reform, and regulatory changes related to controlled substances. Focusing on these opportunities provides the greatest chance of making a measured and sustained impact on overdose and related harms. PMID- 30426872 TI - Grappling With Complex Food Systems to Reduce Obesity: A US Public Health Challenge. AB - Despite 2 decades of effort by the public health community to combat obesity, obesity rates in the United States continue to rise. This lack of progress raises fundamental questions about the adequacy of our current approaches. Although the causes of population-wide obesity are multifactorial, attention to food systems as potential drivers of obesity has been prominent. However, the relationships between broader food systems and obesity are not always well understood. Our efforts to address obesity can be advanced and improved by the use of systems approaches that consider outcomes of the interconnected global food system, including undernutrition, climate change, the environmental sustainability of agriculture, and other social and economic concerns. By implementing innovative local and state programs, taking new approaches to overcome political obstacles to effect policy, and reconceptualizing research needs, we can improve obesity prevention efforts that target the food systems, maximize positive outcomes, and minimize adverse consequences. We recommend strengthening innovative local policies and programs, particularly those that involve community members in identifying problems and potential solutions and that embrace a broad set of goals beyond making eating patterns healthier. We also recommend undertaking interdisciplinary research projects that go beyond testing targeted interventions in specific populations and aim to build an understanding of the broader social, political, and economic context. PMID- 30426873 TI - Opportunity Youth: Insights and Opportunities for a Public Health Approach to Reengage Disconnected Teenagers and Young Adults. AB - Approximately 1 in 9 teenagers and young adults aged 16-24 in the United States is currently disconnected from school and employment. These disconnected young people (ie, opportunity youth) are not only at high risk for long-term emotional, behavioral, and health problems, but they also represent a loss of human capital, with high social and economic costs. In this article, we offer a public health perspective on opportunity youth by describing their distribution in the population and consequences of their disconnection; proposing a conceptual model of the issue based on epidemiological principles, life course development concepts, and ecological theory; and recommending multisector strategies for preventing disconnection of young people and reengaging opportunity youth. A public health approach to the problem of opportunity youth would involve developing and investing in youth monitoring data systems that can be coordinated across multiple sectors, consolidating both the delivery and funding of services for opportunity youth, developing policies and programs that encourage engagement of young people, and fostering systematic approaches to the testing and scaling up of preventive and reengagement interventions. PMID- 30426875 TI - Building Healthy Community Environments: A Public Health Approach. AB - Environmental quality has a profound effect on health and the burden of disease. In the United States, the environment-related burden of disease is increasingly dominated by chronic diseases. At the local level, public health practitioners realize that many policy decisions affecting environmental quality and health transcend the authorities of traditional health department programs. Healthy decisions about the built environment, including housing, transportation, and energy, require broad collaborative efforts. Environmental health professionals have an opportunity to address the shift in public health burden toward chronic diseases and play an important role in the design of healthy communities by bringing data and tools to decision makers. This article provides a guide for community leaders to consider the public health effects of decisions about the built environment. We present a conceptual framework that represents a shift from compartmentalized solutions toward an inclusive systems approach that encourages partnership across disciplines and sectors. We discuss practical tools to assist with environmental decision making, such as Health Impact Assessments, environmental public health tracking, and cumulative risk assessment. We also identify priorities in research, practice, and education to advance the role of public health in decision making to improve health, such as the Health Impact Assessment, as a core competency for environmental health practitioners. We encourage cross-disciplinary communication, research, and education that bring the fields of planning, transportation, and energy in closer collaboration with public health to jointly advance the systems approach to today's environmental challenges. PMID- 30426874 TI - Progress on Major Public Health Challenges: The Importance of Equity. PMID- 30426876 TI - The Importance of Policy Change for Addressing Public Health Problems. PMID- 30426877 TI - The Bloomberg American Health Initiative. PMID- 30426879 TI - Ischemia of the glans 24 hours after circumcision: A case report and therapeutic solution. AB - INTRODUCTION:: Circumcision is a common surgical procedure, typically performed under local anesthesia and somehow also as outpatient clinic. Although complications are rare and most frequently related to the procedure itself, ischemia of the glans may occur as a major complication and can be related to local ischemia following dorsal penile nerve block. CASE DESCRIPTION:: We describe the case of a 33-year-old patient who underwent circumcision at our institution and, 24 h after the procedure, developed an acute ischemia of the glans; a re-intervention was performed in emergency setting to ensure a large, not-tightened circular suture under the glans, and low-molecular-weight heparin and antiplatelet therapy was introduced to achieve anti-coagulative/antiaggregant effects. After 48 h, the skin returned to its normal color and in 7 days the penile glans achieved complete remission of the ischemic aspect. A 6-month follow up confirmed regular outcomes with normal erectile functions. CONCLUSION:: The treatment we proposed to treat acute post-circumcision ischemia of the glans is a simple and effective one, with a perfect aesthetic and functional outcome observed within 4 weeks and confirmed at 6-month follow-up. PMID- 30426880 TI - Risk factors for urethral stricture and/or bladder neck contracture after monopolar transurethral resection of the prostate for benign prostatic hyperplasia. AB - OBJECTIVE:: To identify risk factors for urethral stricture and/or bladder neck contracture after transurethral resection of benign prostatic hyperplasia. MATERIALS AND METHODS:: We performed a retrospective analysis of 402 patients, which underwent a monopolar transurethral resection of the prostate in the urology clinic of Sechenov First Moscow State Medical University for prostatic hyperplasia during the period 2011-2014. Urethral stricture and (or) bladder neck contracture in the postoperative period were diagnosed in 61 (15.27%) patients; 34 patients (8.6%) had urethral stricture, 20 (4.97%) bladder neck contracture, and 7 (1.7%) had a combination of urethral stricture and bladder neck contracture. In 341 of cases (84.73%), no late postoperative complications were observed. A total of 106 of the 341 patients met the inclusion criteria, hence, containing all the information necessary for analysis such as the volume of the prostate, the duration of the surgery, the size of the endoscope, data on concomitant diseases, analysis prostatic secretion, and so on. Thus, two groups were formed. Group 1 (106 patients) is the control group in which urethral strictures and/or bladder neck contractures did not occur in the long-term postoperative period and group 2 (61 patients), in which was observed the formation of these complications. To calculate the statistical significance of the differences for categorical data, Fisher criterion was used. For quantitative variables, in the case of normal data distribution, an unpaired t-test or one-way analysis of variance was used; for data having a distribution different from normal, a Mann-Whitney rank test was used. RESULTS:: Regression analysis established the significance of the influence of four factors on the development of scar-sclerotic changes of urethra and bladder neck: the tool diameter 27 Fr ( p < 0.0001), presence of prostatitis in past medical history ( p < 0.0001), prostate volume ( p = 0.003), and redraining of the bladder ( p = 0.0162). CONCLUSION:: The relationship between the diameter of the instrument, presence of chronic prostatitis in anamnesis, increased volume of the prostate, and repeated drainage of the bladder using the urethral catheter with the risk of developing scar-sclerotic changes in the urethra and/or bladder neck are statistically reliable and confirmed as a result of regression analysis. PMID- 30426878 TI - An Integrated Public Health Approach to Interpersonal Violence and Suicide Prevention and Response. AB - Violence is a leading source of morbidity and mortality in the United States. In this article, we suggest a public health framework for preventing community violence, intimate partner violence and sexual violence, and suicide as key forms of interpersonal and self-directed violence. These types of violence often co occur and share common risk and protective factors. The gender, racial/ethnic, and age-related disparities in violence risk can be understood through an intersectionality framework that considers the multiple simultaneous identities of people at risk. Important opportunities for cross-cutting interventions exist, and intervention strategies should be examined for potential effectiveness on multiple forms of violence through rigorous evaluation. Existing evidence-based approaches should be taken to scale for maximum impact. By seeking to influence the policy and normative context of violence as much as individual behavior, public health can work with the education system, criminal justice system, and other sectors to address the public health burden of interpersonal violence and suicide. PMID- 30426881 TI - Unusual metastatic localization to the kidney of basaloid squamous cell carcinoma of the oropharynx. AB - CASE PRESENTATION:: A 55-year-old man with a history of basaloid squamous cell carcinoma of the oropharynx with laterocervical lymph node metastases 6 years before (and treated with chemoradiation) presented with flank pain and hematuria. Computed tomography scan found a renal lesion, with radiological features more suspicious for primitive renal neoplasia. Histopathological and immunohistochemical examination after surgical excision revealed a basaloid squamous cell carcinoma involving renal parenchyma. CONCLUSION:: Basaloid squamous cell carcinoma is a rare tumor but with a high percentage of distant metastasis, and it is mandatory, also for a general pathologist, to know this disease. Moreover, in a patient with renal metastases, any type of cancer should be taken into account, and this case is emblematic of why the previous medical history is crucial for differential diagnosis. PMID- 30426882 TI - Persistent Mullerian duct syndrome: Report of two cases with phenotypical immunohistochemical profiling. AB - INTRODUCTION:: Persistent Mullerian duct syndrome is a rare disorder of male organ development characterized by internal male pseudohermaphroditism. Persistent Mullerian duct syndrome is usually an incidental finding in patients presenting cryptorchidism, inguinal hernia, or a previous story of undescended testes. CASE DESCRIPTION:: We report on two cases of persistent Mullerian duct syndrome: an adult fertile male with uterus and ectopic prostate occurring as pelvic mass and a 75-year-old organ donor with uterus and two fallopian tubes, discovered in course of organ recruitment. We performed routine histological analysis and immunohistochemical profiling of the different tissue components. Examined tissues were all benign, and the living patient is well after surgery. CONCLUSION:: In order to prevent further complications such as infertility and potential malignant change, surgeons and surgical pathologists must be aware of this condition and should consider excision of the Mullerian remnant where possible. PMID- 30426883 TI - Onabotulinumtoxin-A improves health status and urinary symptoms in subjects with refractory overactive bladder: Real-life experience. AB - OBJECTIVE:: Onabotulinumtoxin-A has been approved for wet overactive bladder refractory to anticholinergics in randomised controlled trials; however, data from real-life practice are scarce. This study was designed to assess the efficacy of intravesical onabotulinumtoxin-A injections, focusing on health status, urinary symptoms and subjective satisfaction. METHODS:: Data from consecutive patients with overactive bladder-refractory to anticholinergics treated with onabotulinumtoxin-A were prospectively collected and analysed. Standard doses (100-150 U) were used, followed by repeat sessions when clinical benefits diminished. Efficacy and safety of repeat onabotulinumtoxin-A administrations were assessed at 12-week post-injection. Clinical parameters evaluated were: change in the magnitude and frequency of incontinence, urgency and nocturia episodes, change in the number of pads used and procedural complications. Quality of life was evaluated using the 36-Item Short-Form Health Survey, Overactive Bladder Screener and Treatment Benefit Scale questionnaires. RESULTS:: Consecutive overactive bladder-refractory to anticholinergics patients ( n = 22) (median duration of oral therapy: 10 months) were enrolled. No intraoperative complications occurred, but two urinary retention cases were recorded. Forty-five percent of patients (10/22) were re-treated (median duration of perceived benefits: 18 months, range: 8-55 months). The number of urinary incontinence, frequency and nocturia episodes, and pads used went from 3.6, 11.3, 2.7 and 2.4 preoperatively to 1.0, 5.8, 0.7 and 0.7 postoperatively ( p < 0.005). Quality of life (36-Item Short-Form Health Survey) was significantly improved and symptom scores (Overactive Bladder Screener) were reduced, from 34.5 to 17.1 at week 12 ( p < 0.05). Eighty-seven percent of patients indicated improvement/great improvement in their condition (Treatment Benefit Scale). CONCLUSION:: Intradetrusor injections of onabotulinumtoxin-A in patients with overactive bladder-refractory to anticholinergics significantly improved health status and urinary symptoms, with high subjective satisfaction. PMID- 30426884 TI - What Modern Sports Competitions Can Tell Us About Human Nature. AB - To fully understand human behavior, it seems inevitable to approach it from an evolutionary perspective. However, much of human behavior has been overwritten by culture and society, thus allowing little insight into how it might have evolved amid natural and sexual selection. Here, I argue that sports competitions, although a cultural phenomenon in themselves, strip away many of the cultural layers and reveal more primary, rudimentary aspects of human behavior. Fortunately, because they are ubiquitous, meticulously recorded, and often quantified in great detail, sports competitions provide a plethora of usable data. In this article I provide an evolutionary account of the cross-cultural existence and popularity of sports by reviewing evidence of four functional hypotheses that regard the omnipresence of sports as a by-product of fitness related adaptations (skill acquisition and development, status seeking, courtship display, and coalition formation). Then I outline how the growing body of sports data and documentation can be exploited for increasing our understanding of human nature (e.g., on conflict and cooperation, lateral preferences, territoriality, and nonverbal communication). The article concludes by giving guidelines for future cross-disciplinary research to advance the understanding of how evolution has shaped human behavior. PMID- 30426885 TI - The Development and Reliability of Four Clinical Neurocognitive Single-leg Hop Tests: Implications for Return to Activity Decision Making. AB - CONTEXT:: Functional tests are limited primarily by measuring only physical performance. However, athletes often multitask, and deal with complex visual spatial processing while being engaged in physical activity. OBJECTIVE:: Present the development and reliability of four new neurocognitive single-leg hop tests that provide more ecological validity to test sport activity demands than previous functional return to sport testing. DESIGN:: Cross-sectional. SETTING:: Gymnasium. PARTICIPANTS:: Twenty-two healthy participants (9 Male, 13 Female, 20.9+/-2.5 years, 171.2+/-11.7 cm, 70.3+/-11.0 kg) were recruited. INTERVENTIONS:: Maximum distance (physical performance) and reaction time (cognitive performance) were measured for three of the neurocognitive hop tests all testing a different aspect of neurocognition (single-leg central-reaction hop - reaction time to one central stimulus, single-leg peripheral-reaction crossover hop - reaction time between two peripheral stimuli, and single-leg memory triple hop - reaction to memorized stimulus with distractor stimuli). Fastest time (physical performance) and reaction time (cognitive performance) was measured for the fourth neurocognitive hop test (single-leg pursuit 6m hop - requiring visual field tracking (pursuit) and spatial navigation). MAIN OUTCOME MEASURES:: Intraclass correlation coefficients (ICCs) were calculated to assess reliability of the four new hop tests. Additionally, Bland-Altman plots and one-sample t tests were conducted for each single-leg neurocognitive hop to evaluate any systematic changes. RESULTS:: ICCs based on day one and day two scores ranged from 0.87-0.98 for both legs for physical and cognitive performance. The Bland Altman plots and one-sample t-tests (p>0.05) indicated that all four single-leg neurocognitive hop tests did not change systematically. CONCLUSION:: These data provide evidence that a neurocognitive component can be added to the traditional single-leg hop tests to provide a more ecologically valid test that incorporates the integration of physical and cognitive function for return to sport. The test retest reliability of the four new neurocognitive hop tests is highly reliable and does not change systematically. PMID- 30426886 TI - Incidence of neonatal hyperthyroidism among newborns of Graves' disease patients treated with radioiodine therapy. AB - BACKGROUND: The serum TSH receptor antibody (TRAb) titers of Graves' disease (GD) patients is known to increase after radioiodine (RAI) therapy and remain high for years. The incidence of neonatal hyperthyroidism (NH) among the newborns born to mothers with GD who conceived after RAI therapy have not been reported in the past. Objective; To investigate the incidence of NH among the newborns born to mothers who conceived within 2 years after RAI therapy, and to identify predictors of NH. Patients; The cases of 145 GD patients who conceived within 2 years after RAI therapy were retrospectively reviewed, and information regarding their newborns was collected. Results; Fifty-four of the 145 pregnant women (37%) were treated with anti-thyroid drugs (ATD) or potassium iodide (KI) for maternal hyperthyroidism during the first trimester. There were 8 newborns with NH, and its incidence was 5.5%. Seven of the eight mothers whose newborns had NH were treated with ATD or KI during their pregnancy. The incidence of NH among the newborns born to mothers who conceived within 6 to 12 months after RAI therapy was 8.8%, 5.5% within 12 to18 months and 3.6% within 18 to 24 months. Multivariate analysis revealed the TRAb value in the third trimester to be the only risk factor for NH. The cut-off TRAb value in the third trimester for predicting NH was 9.7 IU/L (reference values <2.0 IU/L). Conclusion; The incidence of NH among the newborns born to mothers who conceived within 2 years after RAI therapy was 5.5%. The fetuses of pregnant GD patients whose TRAb value is high in the third trimester should be carefully followed up by an obstetrician during pregnancy, and the newborns should be carefully followed up by a pediatrician after birth. PMID- 30426887 TI - Cytological diagnoses associated with non-invasive follicular thyroid neoplasms with papillary-like nuclear features, (NIFTP) according to the Bethesda System for Reporting Thyroid Cytopathology: a systematic review and meta-analysis. AB - BACKGROUND: The recent introduction of non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) in the WHO classification of thyroid tumors has significantly modified the risk of malignancy of cytological diagnoses. In fact, while this tumor was previously classified as a carcinoma (the encapsulated, non-invasive form follicular variant of papillary thyroid carcinoma), it is now considered a neoplasm with low malignant potential. Given that the NIFTP cytological features are not specific and overlap with other pathologic entities, there is no specific cytological diagnostic category for NIFTP. To obtain more robust information about the cytological findings associated with NIFTP, we systematically reviewed published articles and carried out a meta-analysis of the data. RESEARCH DESIGN AND METHODS: The review was conducted according to Prisma guidelines. A comprehensive literature search of the PubMed/MEDLINE and Scopus databases was conducted using a combination of terms "non-invasive", "encapsulated", "follicular variant", "NIFTP" and "thyroid cancer". The search was updated until June 2018, and references of the retrieved articles were also screened. Only original articles reporting the classification of histologically proven NIFTPs with cytological findings according to the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) were eligible for inclusion. RESULTS: The literature search revealed 117 articles, of which 15 were included in the study. All studies were retrospective. A total number of 915 NIFTP cases were retrieved. The incidence of cases cytologically classified according to TBSRTC was as follows: non-diagnostic 3%, benign 10%, atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) 30%, follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN) 21%, suspicious for malignancy 24%, and malignant 8%. Mild heterogeneity between the studies was found. Publication bias was absent. CONCLUSIONS: This meta-analysis shows that the cytological diagnoses associated with NIFTP by fine needle aspiration cytology includes a wide spectrum of findings. The majority of cases are cytologically indeterminate and the remainders may be read as non diagnostic, benign or malignant. In order to develop an accurate presurgical diagnosis of these cases, further cytological and/or molecular characteristics need to be identified. PMID- 30426888 TI - Arterial stiffness and total cerebral small vessel disease score in community dwelling older adults: Results from the Atahualpa Project. AB - Information on the association between arterial stiffness and cerebral small vessel disease (cSVD) is limited and confined to white and Asian populations. More regional information is needed to confirm this association in different ethnic groups. Using the Atahualpa Project cohort, we aimed to assess whether the aortic pulse wave velocity (PWV) is associated with the total cSVD score, as well as with each of the neuroimaging signatures of cSVD, in a population of Amerindians living in rural Ecuador. Atahualpa residents aged ? 60 years were offered a brain magnetic resonance imaging scan (MRI) and aortic PWV determination. An ordinal logistic regression model, adjusted for demographics and cardiovascular risk factors, was constructed to predict the total cSVD score by levels of aortic PWV. The association between the neuroimaging signatures of cSVD and the aortic PWV was assessed by adjusted logistic regression models. Of 437 candidates, 303 (69%) underwent a brain MRI and aortic PWV determinations. The total cSVD score was 0 points in 65% of individuals, 1 point in 18%, 2 points in 11%, and 3-4 points in 6%. The mean aortic PWV was 10.4 +/- 1.8 m/s, which increased from 9.8 +/- 1.2 to 12.3 +/- 1.8 m/s in individuals with a cSVD score of 0 and 3-4, respectively ( p < 0.001). An ordinal logistic regression model showed significant association between the PWV and the cSVD score. A change of one unit of the aortic PWV increased the odds of having a higher total cSVD score by 1.73 (95% CI: 1.28-2.35; p < 0.001). In addition, individual neuroimaging signatures of cSVD, with the exception of lacunar infarcts, were associated with the aortic PWV. This study shows a significant association between the aortic PWV and total cSVD score and most of its individual components in older Amerindians. PMID- 30426889 TI - Assessing geographical inequity in availability of hospital services under the state-funded universal health insurance scheme in Chhattisgarh state, India, using a composite vulnerability index. AB - BACKGROUND: Countries are increasingly adopting health insurance schemes for achieving Universal Health Coverage. India's state-funded health insurance scheme covers hospital care provided by 'empanelled' private and public hospitals. OBJECTIVE: This paper assesses geographical equity in availability of hospital services under the universal health insurance scheme in Chhattisgarh state. METHODS: The study makes use of district data from the insurance scheme and government surveys. Selected socio-economic indicators are combined to form a composite vulnerability index, which is used to rank and group the state's 27 districts into tertiles, named as highest, middle and lowest vulnerability districts (HVDs, MVDs, LVDs). Indicators of hospital service availability under the scheme - insurance coverage, number of empanelled private/public hospitals, numbers and amounts of claims - are compared across districts and tertiles. Two measures of inequality, difference and ratio, are used to compare availability between tertiles. RESULTS: The study finds that there is a geographical pattern to vulnerability in Chhattisgarh state. Vulnerability increases with distance from the state's centre towards the periphery. The highest vulnerability districts have the highest insurance coverage, but the lowest availability of empanelled hospitals (3.4 hospitals per 100,000 enrolled in HVDs, vs 8.2/100,000 enrolled in LVDs). While public sector hospitals are distributed equally, the distribution of private hospitals across tertiles is highly unequal, with higher availability in LVDs. The number of claims (per 100,000 enrolled) in the HVDs is 3.5-times less than that in the LVDs. The claim amounts show a similar pattern. CONCLUSIONS: Although insurance coverage is higher in the more vulnerable districts, availability of hospital services is inversely proportional to vulnerability and, therefore, the need for these services. Equitable enrolment in health insurance schemes does not automatically translate into equitable access to healthcare, which is also dependent on availability and specific dynamics of service provision under the scheme. PMID- 30426890 TI - Nanotechnology as an emerging pathway for cancer therapy and diagnosis. AB - Background- The increasing rate of cancer in younger generation is an issue of concern in 21st century. It is highly concerned to know that the available methods of cancer therapy like, radiotherapy and chemotherapy have several side effects causing infertility and neuronal diseases. Radiotherapy is one of the main modalities for the treatment of cancer as we don't have any other reliable treatment methods till date. Now-a-days, nanotechnology have been introduced for cancer detection and diagnosis. Therefore, cancer nanotechnology is an interdisciplinary area of research in science, engineering, and medicine with broad applications in molecular imaging, molecular diagnosis, and targeted therapy. Nanotechnology have potential to solve one of the most challenging problems in medicine, and to eliminate cancer without harming normal body tissue. Nanotechnology has enabled the manipulation of the biological and physicochemical properties of nanomaterials to facilitate more efficient drug targeting and delivery. Objective-This review highlights the use of nanotechnology in cancer therapy and different types of nanoparticles for examples lipid nanoparticle, polymer-based nanoparticle, carbon-based nanoparticles, engineered nanoparticles used in cancer detection and diagnosis. Study also distinguish between classical treatment methods (Radio & chemotherapy) and nanotherapy with futuristic approach. Method- As a part of method, different types of nanoparticles were opted based on their size and compatibility used in cancer detection and diagnosis. This article mainly opted advance nanotherapy methods, based on most recent studies. Result and conclusion- Nanotechnology provides new molecular contrasts agents and materials to enable earlier and more accurate initial diagnosis, as well as continual monitoring of patient while cancer treatment. This review concludes that nanotechnology as nanodrugs, nano carrier, nanoparticles in combination with radiological methods have a better future in cancer treatment. In this paper, several diagrammatic pathways presented the opted studies and proposed conclusion. PMID- 30426892 TI - Current Approaches to Diagnostics and Therapies of Chronic Diseases: Focus on Molecular and Cell Biology. PMID- 30426891 TI - Current Scenario in Structure and Ligand-Based Drug Design on Anti-Colon Cancer Drugs. AB - Colorectal cancer is the third most commonly detected cancer and the fourth foremost cause of cancer deaths in the world. Recent molecular modeling approaches, driven by rapidly improving computational platforms, have led to many success stories for the use of computer-assisted drug design in the discovery of the structure and ligand-based drugs. This study highlights aspects of the anticancer drug design. The structure and ligand-based drug design are discussed to investigate the molecular and quantum mechanics in anti-cancer drugs. Recent advances in anticancer agent identification driven by structural and molecular insights are presented. As a result, the recent advances in the field and the current scenario in drug designing of cancer drugs are discussed. This review provides information on how cancer drugs were formulated and identified using computational power by the drug discovery society. PMID- 30426893 TI - What is New in Food Allergy? PMID- 30426894 TI - Coronary Microcirculation and Ischemic Heart Disease, Today. PMID- 30426895 TI - Synthesis of novel alpha-amidino carboxylic acids and their use as H-Bond Catalysts in Strecker reaction. AB - AIM AND OBJECTIVE: A wide variety of synthesized amidine derivatives are bioactive compounds. They show a vast range of medical properties. Therefore, a simple route for synthesis of novel class of amidine derivatives called amidino carboxylic acids and their use as catalysts in Strecker reaction has been reported in the current work. The stability, local charge density and hydrogen bond parameters were calculated for eight derivatives with different substituents. MATERIALS AND METHODS: In order to synthesis these amidino carboxylic acids, we initially prepared Knovenogel condensation products via the reaction of isatin derivatives with malonitrile. When the reaction was performed in water, the resulting nitrile groups of malonitrile derivatives was hydrolyzed with HOAC/ H2SO4 to generate the desired amide groups. The amide groups in resulting compound converted to amine groups with two Hoffman rearrangements in the presence of NaOH/Br2. Further neutralization led to the final zwitterionic alpha-amidino carboxylic acids. In the next step, the catalytic activity of these compounds as H-bond donor catalyst was investigated in Strecker reaction. RESULTS: The overall yields of the derivatives with substituent on the aromatic ring of starting isatins are higher than that for the overall yields of nitrogen substituted isatins. The reaction of 5-nitro isatin with the next reagent gives lower yield in aryl-substituted products. An increase of catalytic activity is observed by rising the electron-withdrawing power of the aromatic ring substituents., The presence of nitro group in the structure of catalyst caused a large increase of catalytic activity in Strecker reaction. DFT calculations at B3LYP/6-31++g(d,p) and Lanl2dz level of theory showed that these compounds act as single H-bond catalysts and higher yields were obtained for complexes with stronger hydrogen bond. CONCLUSION: A simple and efficient method for synthesis of alpha-amidino carboxylic acids was developed in this research. These compounds have been used as a single H-bond donor catalyst in the Strecker reaction. DFT calculations were carried out to confirm the experimental results. The obtained data from computations are in good agreement with experimental results. PMID- 30426896 TI - Clinical Efficacy of Combination Intravenous and Intraperitoneal Chemotherapy in the Treatment of Gastric Cancer with Peritoneal Carcinomatosis. AB - OBJECTIVE: To identify the clinical and adverse effects of intravenous chemotherapy combined with intraperitoneal chemotherapy in the treatment of gastric cancer with abdominal peritoneal carcinomatosis. METHODS: Retrospective analysis was performed on 49 gastric cancer patients with abdominal peritoneal carcinomatosis. Patients were divided into two groups: patients subjected to intravenous chemotherapy (n = 27) were defined as the Control group and patients subjected to combined intravenous and intraperitoneal chemotherapy (n = 22) were defined as the Combination Therapy group. Then the objective efficacy, survival, and adverse effects of two groups were evaluated. RESULTS: The clinical characteristics of two groups were equally distributed. Compared with the Control group, the objective response rate (ORR) and disease control rate (DCR) of the Combination Therapy group were significantly higher (all P<0.05). The median survival time (MST) of the Control group was (6.57 +/- 0.75) months, which was significantly shorter than in the Combination Therapy group (15.03 +/- 2.31) months (P < 0.05). In addition, the 12-, 18-, 24-, 30-, 36-, and 60-month survival rates of the Control group were all significantly lower than those of the Combination Therapy group. Furthermore, the incidence of adverse reactions in the two groups was not statistically significant; neither of the treatments resulted in severe complications. CONCLUSION: Compared with intravenous chemotherapy alone, the combined intravenous and intraperitoneal chemotherapy was more effective in improving quality of life and extending survival time in patients with abdominal peritoneal carcinomatosis from gastric cancer. In addition, the combination treatment is tolerable and therefore worth further clinical study. PMID- 30426898 TI - Creatinine Deiminase: Characterization, Using in Enzymatic Creatinine Assay, and Production of the Enzyme. AB - The goal of the review is description of the main characteristics of creatinine deiminase (CDI), an important bioanalytical tool for creatinine (Crn) assay. Crn is an essential metabolite for diagnostics of kidney disfunction and some other diseases, a biomarker to control the hemodialysis procedure, as well as an important analyte for sport medicine (estimation of general physiological status of athletes). We have described the important sources for CDI isolation, cloning of the corresponding gene, the construction of microbial recombinant strains, overproducing CDI, and characteristics of the enzyme from different microorganisms. There are reviewing also the new bioanalytical methods for quantitative determination of Crn, including enzymatic ones based on using CDI. PMID- 30426897 TI - Insights into the microbial L-asparaginases: from production to practical applications. AB - L-asparaginase is a valuable protein therapeutic drug utilized for the treatment of leukemia and lymphomas. Administration of asparaginase leads to asparagine starvation causing inhibition of protein synthesis, growth, and proliferation of tumor cells. Besides its clinical significance, the enzyme also finds application in the food sector for mitigation of a cancer-causing agent acrylamide. The numerous applications ensue huge market demands and create a continued interest in the production of cost-effective, more specific, less immunogenic and stable formulations which can cater both the clinical and food processing requirements. The current review article approaches the process parameters of submerged and solid-state fermentation strategies for the microbial production of the L asparaginase from diverse sources, genetic engineering approaches used for the production of L-asparaginase enzyme and major applications in clinical and food sectors. The review also addresses the immunological issues associated with the L asparaginase usage and the immobilization strategies, drug delivery systems employed to circumvent the toxicity complications are also discussed. The future prospects for microbial L-asparaginase production are discussed at the end of the review article. PMID- 30426899 TI - Cannabis Associated "High" Cardiovascular Morbidity and Mortality: Marijuana Smoke Like Tobacco Smoke? A deja vu / deja vecu story? AB - BACKGROUND: Cannabis use has increased over the past several years as some countries have legalized its use for treatment of certain medical conditions and/or for recreational use. Thus, concerns have risen about potential adverse health effects. Increasing number of reports have associated cannabis use with serious cardiovascular (CV) complications. Furthermore, there appears to be a likeness in the harmful health effects, especially on the CV and respiratory systems, of cannabis smoking to those of tobacco smoking. OBJECTIVE: to review the CV effects of cannabis use and compare them with those of tobacco use. METHODS: Articles were reviewed that were published in the English literature reporting on cannabis and cannabinoid pharmacology and their effects on the CV system and their attendant consequences. Emphasis was also placed on articles reporting on cannabis use in adolescents, exposure to secondhand smoke, its effect on exercise and finally its inter-relationship and similarities with tobacco use. RESULTS: With growing cannabis use, increasing number of reports have emerged associating marijuana use with serious and life-threatening CV complications, including acute coronary syndromes, potentially lethal cardiac arrhythmias and ischemic strokes. There are certain similarities of the deleterious CV and respiratory effects of cannabis smoking with those of tobacco smoking. Despite the difference in the active ingredients (tetrahydrocannabinol vs nicotine), each substance produces a plethora of chemicals when smoked and these are largely identical; furthermore, due to different modes of smoking, cannabis chemicals are retained in the body for a longer time. Of course, concomitant tobacco and cannabis smoking is a perplexing factor in isolating damages specifically pertaining to cannabis use, while the health risk is additive. Although the mechanisms producing CV harm may be somewhat different between these two substances, the outcome appears similar, or even worse, as the effects may emerge at a younger age. CONCLUSION: There is an increasing concern that, apart from the mental health problem with cannabis smoking, societies may be facing another wave of a deja vu / deja vecu phenomenon similar to the tobacco smoking story. PMID- 30426900 TI - Comparative Activity of Adenosine Deaminase Acting on RNA (ADARs) Isoforms for Correction of Genetic Code in Gene Therapy. AB - Members of the adenosine deaminase acting on RNA (ADAR) family of enzymes consist of double-stranded RNA-binding domains (dsRBDs) and a deaminase domain (DD) that converts adenosine (A) into inosine (I), which acts as guanosine (G) during translation. Using the MS2 system, we engineered the DD of ADAR1 to direct it to a specific target. The aim of this work was to compare the deaminase activities of ADAR1-DD and various isoforms of ADAR2-DD. We measured the binding affinity of the artificial enzyme system on a BiacoreTM X100. ADARs usually target dsRNA, so we designed a guide RNA complementary to the target RNA, and then fused the guide sequence to the MS2 stem-loop. A mutated amber (TAG) stop codon at 58 amino acid (TGG) of EGFP was targeted. After transfection of these three factors into HEK 293 cells, we observed fluorescence signals of various intensities. ADAR2-long without the Alu-cassette yielded a much higher fluorescence signal than ADAR2 long with the Alu-cassette. With another isoform, ADAR2-short, which is 81 bp shorter at the C-terminus, the fluorescence signal was undetectable. A single amino acid substitution of ADAR2-long-DD (E488Q) rendered the enzyme more active than the wild type. The results of fluorescence microscopy suggested that ADAR1 DD is more active than ADAR2-long-DD. Western blots and sequencing confirmed that ADAR1-DD was more active than any other DD. This study provides information that should facilitate the rational use of ADAR variants for genetic restoration and treatment of genetic diseases. PMID- 30426901 TI - Preparation, characterization, and in vitro pH-sensitivity evaluation of superparamagnetic iron oxide nanoparticle-misonidazole pH-sensitive liposomes. AB - BACKGROUND: The use of misonidazole (MISO), the first and a potential hypoxic tumor cell radiosensitizer, has been limited by peripheral neurotoxicity, thus discouraging phase III clinical trials. OBJECTIVE: To develop a targeted drug delivery and tracing system with pH-sensitive liposomes (SpHLs) and superparamagnetic iron oxide nanoparticles (SPIONs) to counter MISO-related adverse effects and to enable tracing under magnetic resonance. METHODS: SPION MISO-SpHLs were prepared by a reverse evaporation and freeze-thawing method. HPLC and phenanthroline spectrophotometry were established for MISO and Fe determination. The characterization and in vitro pH-sensitivity of SPION-MISO SpHLs were evaluated. RESULTS: The maximal entrapment efficiencies of MISO and SPIONs in SPION-MISO-SpHLs were 30.2% and 23.7%, respectively. The cumulative release rates of MISO and SPIONs were respectively 2.49 and 2.47 times higher in pH 5.5 than in pH 7.4 buffer. The mean particle size of SPION-MISO-SpHLs was 950 nm. The zeta potential was -58.9 mV in pH 7.4 buffer and 36.3 mV in pH 5.5 buffer. SEM imaging showed that SPION-MISO-SpHLs had similar spherical morphologies. SPIONs were packed in the center of liposomes and were well dispersed in a TEM graph. Magnetization curve showed that SPION-MISO-SpHLs retained superparamagnetic properties. SPION-MISO-SpHLs were compared with MISO+SPION+blank liposome in hypoxia and control groups of A549 cells. MISO and SPION concentrations in culture medium showed significant differences between the same concentration groups (P <0.0001) and at different times (P <0.0001). CONCLUSION: SPION-MISO-SpHLs possess pH-dependent release ability and superparamagnetism, and thus provides a system for targeted delivery and tracing under magnetic resonance. PMID- 30426902 TI - Insulin therapy in pregnancy hypertensive diseases and its effect on the offspring and mother later in life. AB - Pregnancy hypertensive disorders such as preeclampsia (PE) are strongly correlated with insulin resistance, a condition in which the metabolic handling of D-glucose is deficient. In addition, the impact of preeclampsia is enhanced by other insulin resistant disorders, including polycystic ovary syndrome and obesity. For this reason, there is a clear association among maternal insulin resistance, polycystic ovary syndrome, obesity and the development of PE. However, whether PE is a consequence or the cause of these disorders is still unclear. Insulin therapy is usually recommended to pregnant women with diabetes mellitus when dietary and lifestyle measures have failed. The advantage of insulin therapy for gestational diabetes mellitus (GDM) patients with hypertension is still controversial; surprisingly, there are no studies in which insulin therapy has been used in patients with hypertension in pregnancy without or with an established GDM. This review is focused on the use of insulin therapy in hypertensive disorders in the pregnancy and its effect on offspring and mother later in life. PubMed and relevant medical databases have been screened for literature covering research in the field especially in the last 5-10 years. PMID- 30426903 TI - Can Combined Therapy Benefit Immune Checkpoint Blockade Response in Hepatocellular Carcinoma? AB - BACKGROUND: Hepatocellular Carcinoma (HCC) is one of the most common cancers with high mortality rate. The effects of most therapies are limited. The immune checkpoint blockade (ICB) improves the prognosis in multiple malignancies. The application of immune checkpoint blockade to hepatocellular carcinoma patients has recently started. Early phase clinical trials have shown some benefits to cancer patients. METHODS/RESULTS: This review focuses on the immune system of liver and clinical trials of immune checkpoint blockage therapies. In particular, we analyze the mechanisms by which immune checkpoint blockade therapies can be used for treatment of hepatocellular carcinoma patients, then examine the factors in cancer resistance to the therapies and finally suggest possible combination therapies for treatment of hepatocellular carcinoma patients. CONCLUSION: ICB is a promising therapy for advanced HCC patients. Combined therapy exhibits a great potential to enhance ICB response in these patients. The better understanding of the factors influencing the sensitivity of ICB and more clinical trials will consolidate the efficiency and minimize the adverse effects of ICB. PMID- 30426904 TI - Design, Synthesis and Evaluation of Novel 3/4-((Substituted benzamidophenoxy)methyl)-N-hydroxybenzamides / propenamides as Histone Deacetylase Inhibitors and Antitumor Agents. AB - BACKGROUND: Histone Deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as givinostat (ITF2357) and belinostat (PXD-101). AIMS: This study aims at developing novel HDAC inhibitors bearing N-hydroxybenzamides and N hydroxypropenamides scaffolds with potential cytotoxicity against different cancer cell lines. METHOD: Two new series of N-hydroxybenzamides and N hydroxypropenamides analogues (4a-j, 6a-j) designed based on the structural features of nexturastat A, AR-42, and PXD-101, were synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines (SW620 (colorectal adenocarcinoma), PC3 (prostate adenocarcinoma), and NCI H23 (adenocarcinoma, non-small cell lung cancer). Molecular simulations were finally carried out to gain more insight into the structure-activity relationships. RESULTS: It was found that the N-hydroxypropenamides (6a-e) displayed very good HDAC inhibitory potency and cytotoxicity. Various compounds, e.g. 6a-e, especially compound 6e, were up to 5-fold more potent than suberanilohydroxamic acid (SAHA) in term of cytotoxicity. These compounds also comparably inhibited HDACs with IC50 values in sub-micromolar range. Docking experiments showed that these compounds bound to HDAC2 at the enzyme active binding site with the same binding mode of SAHA, but with higher binding affinities. PMID- 30426905 TI - New Drug Discovery from Medicinal Plants and Phytoconstituents for Depressive Disorders. AB - Depression, a risk factor for several serious diseases, is a highly prevalent and life-threatening psychiatric disorder. It can affect the individual's position in life and reduce the living standards. The research on the use of medicinal plants in treating this disease has increased enormously because of the possible low rehabilitation rate and side effects of available synthetic drugs, such as sexual dysfunction, nausea, fatigue, insomnia, hypersomnia, and weight gain. Therefore, this review aimed to draw attention to the antidepressant effects of culinary herbs and traditional medicinal plants and their active components, thereby promoting their use in the development of more potent antidepressants with improved side effect profile. PMID- 30426906 TI - Generation and characterization of a functional Nanobody against inflammatory chemokine CXCL10, as a novel strategy for treatment of multiple sclerosis. AB - Chemokines and their receptors play a pivotal role in the pathogenesis of various autoimmune diseases such as multiple sclerosis, infectious diseases, and also in cancer metastasis via attraction of the pathogenic immune cells into the inflammation sites. Inflammatory chemokine CXCL10 as a T helper (Th)1-chemokine directs chemotaxis of many cell subsets especially Th1 into the central nevous system (CNS) via its receptor CXCR3 and it has been put forward as a potential therapeutic target in treatment of multiple sclerosis. Nanobodies are the smallest intact antigen binding fragments derived from heavy chain-only antibodies occurring in camelids with unique biochemical and biophysical features which render them superior to conventional antibodies or antibody fragments. Here we describe the generation, selection, and characterization of CXCL10-specific Nanobodies from camel immunized with CXCL10. The obtained Nanobodies displayed high affinity toward CXCL10 about 10-11-10-8 M. Then a Nanobody with the highest affinity named 3Nb12 was selected and investigated as a migration inhibitor of CXCR3+ cells. Chemotaxis assay results showed that 3Nb12 blocked CXCL10-CXCR3 binding and potently inhibited chemotaxis of CXCR3-transfected HEK293T cells. The Nanobody 3Nb12 might be a promising specific and powerful blocking agent of CXCL10 function, which can be used for diagnostic, therapeutic and research purposes in MS. PMID- 30426907 TI - Xuesaitong may protect against ischemic stroke by modulating microglial phenotypes and inhibiting neuronal cell apoptosis via the STAT3 signaling pathway. AB - BACKGROUND: Xuesaitong mainly comprises Panax notoginseng saponins and has shown promise in an acute ischemic stroke model; however, its effect on long-term recovery following stroke, and the related mechanisms, are unknown. The objective of this study was to investigate the long-term protective effects of xuesaitong against ischemic stroke and its effect on microglial polarization. Experimental cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 45 min, and C57BL/6 mice were immediately injected with xuesaitong or vehicle through the caudal vein at the onset of cerebral reperfusion consecutively for 14 days. The animals were randomly divided into three groups: a sham-operated group, vehicle-treated group and xuesaitong-treated group at a dose of 15MUg/g. Subsequently, 2,3,5-triphenyltetrazolium chloride staining was used to assess infarct volume, and adhesive removal tests and balance beam tests were used to evaluate neurological deficits at days 1, 3, 7 and 14 following ischemia. Reverse transcriptase polymerase chain reaction and immunofluorescence staining for M1 markers (CD16, iNOS) and M2 markers (CD206, arginase-1) were performed to characterize phenotypic changes in microglia. TUNEL staining was conducted to detect neuronal cell apoptosis, and western blots were used to determine the activation of signal transducer and activator of transcription 3 (STAT3). RESULTS: Our results reveal that xuesaitong treatment, compared with vehicle treatment, significantly reduced cerebral infarct volume 1 and 3 days after MCAO and resulted in significant improvements in long-term neurological outcomes. Furthermore, xuesaitong treatment, compared with vehicle treatment, significantly reduced M1 markers and elevated M2 markers 7 and 14 days after MCAO at both the mRNA and protein level in ipsilateral brain tissue. This finding was also accompanied by a reduction in neuronal cell apoptosis and p-STAT3 transcription factor levels in the xuesaitong-treated group compared with the vehicle-treated group. CONCLUSIONS: We demonstrated that xuesaitong has long-term neuroprotective effects against ischemic stroke, possibly by promoting the polarization of microglia to an M2 phenotype and by inhibiting neuronal cell death via down regulation of the STAT3 signaling pathway, providing new evidence that xuesaitong might be a promising therapeutic strategy for ischemic stroke. PMID- 30426908 TI - A prospective study of transmission of Multidrug-Resistant Organisms (MDROs) between environmental sites and hospitalized patients-the TransFER study. AB - OBJECTIVE: Hospital environmental surfaces are frequently contaminated by microorganisms. However, the causal mechanism of bacterial contamination of the environment as a source of transmission is still debated. This prospective study was performed to characterize the nature of multidrug-resistant organism (MDRO) transmission between the environment and patients using standard microbiological and molecular techniques. SETTING: Prospective cohort study at 2 academic medical centers. DESIGN: A prospective multicenter study to characterize the nature of bacterial transfer events between patients and environmental surfaces in rooms that previously housed patients with 1 of 4 'marker' MDROs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Clostridium difficile, and MDR Acinetobacter baumannii. Environmental and patient microbiological samples were obtained on admission into a freshly disinfected inpatient room. Repeat samples from room surfaces and patients were taken on days 3 and 7 and each week the patient stayed in the same room. The bacterial identity, antibiotic susceptibility, and molecular sequences were compared between organisms found in the environment samples and patient sources. RESULTS: We enrolled 80 patient-room admissions; 9 of these patients (11.3%) were asymptomatically colonized with MDROs at study entry. Hospital room surfaces were contaminated with MDROs despite terminal disinfection in 44 cases (55%). Microbiological Bacterial Transfer events either to the patient, the environment, or both occurred in 12 patient encounters (18.5%) from the microbiologically evaluable cohort. CONCLUSIONS: Microbiological Bacterial Transfer events between patients and the environment were observed in 18.5% of patient encounters and occurred early in the admission. This study suggests that research on prevention methods beyond the standard practice of room disinfection at the end of a patient's stay is needed to better prevent acquisition of MDROs through the environment. PMID- 30426909 TI - Head Growth and Intelligence from Birth to Adulthood in Very Preterm and Term Born Individuals. AB - OBJECTIVES: The aim of this study was to investigate the effects of infant and toddler head growth on intelligence scores from early childhood to adulthood in very preterm (<32 weeks gestational age; VP) and/or very low birth weight (<1500 g; VLBW) and term born individuals. METHODS: 203 VP/VLBW and 198 term comparisons were studied from birth to adulthood as part of the prospective geographically defined Bavarian Longitudinal Study (BLS). Head circumference was assessed at birth; 5, 20 months; and 4 years of age. Intelligence was assessed with standardized tests in childhood (6 and 8 years: K-ABC) and at 26 years (Wechsler Adult Intelligence Scale, WAIS). Structural equation modeling (SEM) was used to model the effect of head growth on IQ. RESULTS: On average, VP/VLBW had lower head circumference at birth (27.61 cm vs. 35.11 cm, mean difference 7.49, 95% confidence interval [7.09-7.90]) and lower adult intelligence scores (88.98 vs. 102.54, mean difference 13.56 [10.59-16.53]) than term born comparison individuals. Head circumference at birth (e.g., total effect beta=.48; p<.001 for adult IQ) and head growth in childhood predicted intelligence development from age 6 to 26 years in both VP/VLBW and term born individuals (70% of variance in adult IQ explained by full model). Effects of gestation and birth weight on intelligence were fully mediated by head circumference and growth. CONCLUSIONS: This longitudinal investigation from birth to adulthood indicates head growth as a proxy of brain development and intelligence. Repeated early head circumference assessment adds valuable information when screening for long-term neurocognitive risk. (JINS, 2018, 00, 1-9). PMID- 30426910 TI - Investigating multilevel pathways of developmental consequences of maltreatment. AB - The impact of maltreatment spreads across many developmental domains and extends across the entire life span. Identifying unidirectional or bidirectional drivers of developmental cascades of the effects of maltreatment experiences is critical to efficiently employing interventions to promote resilient development in maltreated children. This 1-year longitudinal study utilized a multiple-levels approach, investigating "bottom-up" and "top-down" cascades using structural equation modeling between cortisol regulation, externalizing behavior, and peer aggression. Neither a bottom-up model driven by cortisol regulation nor a top down model driven by peer aggression fit the data well. Instead, lower rates of externalizing behavior at Year 1 most strongly predicted improvements at all levels of analysis (reduced cortisol, externalizing behavior, and peer aggression) at Year 2. These results provide initial indication of a mechanism through which interventions for maltreated children may be most effective and result in the most substantial positive changes across developmental domains. PMID- 30426911 TI - Is the Montreal Cognitive Assessment (MoCA) screening superior to the Mini-Mental State Examination (MMSE) in the detection of mild cognitive impairment (MCI) and Alzheimer's Disease (AD) in the elderly? AB - : ABSTRACTObjective:To compare the accuracy of Mini-Mental State Examination (MMSE) and of the Montreal Cognitive Assessment (MoCA) in tracking mild cognitive impairment (MCI) and Alzheimer's Disease (AD). METHOD: A Systematic review of the PubMed, Bireme, Science Direct, Cochrane Library, and PsycInfo databases was conducted. Using inclusion and exclusion criteria and staring with 1,629 articles, 34 articles were selected. The quality of the selected research was evaluated through the Quality Assessment of Diagnostic Accuracy Studies 2 tool (QUADAS-2). RESULT: More than 80% of the articles showed MoCA to be superior to MMSE in discriminating between individuals with mild cognitive impairment and no cognitive impairment. The area under the curve varied from 0.71 to 0.99 for MoCA, and 0.43 to 0.94 for MMSE, when evaluating the ability to discriminate MCI in the cognitively healthy elderly individuals, and 0.87 to 0.99 and 0.67 to 0.99, respectively, when evaluating the detection of AD. The AUC mean value for MoCA was significantly larger compared to the MMSE in discriminating MCI from control [0.883 (CI 95% 0.855-0.912) vs MMSE 0.780 (CI 95% 0.740-0.820) p < 0.001]. CONCLUSION: The screening tool MoCA is superior to MMSE in the identification of MCI, and both tests were found to be accurate in the detection of AD. PMID- 30426912 TI - Quantitative Aspects of PLAD Sidewall Doping Characterization by SIMS and APT. AB - Application of atom probe tomography (APT) and 1.5D secondary ion mass spectrometry (SIMS) as complimentary techniques to study fin sidewall doping by plasma implantation (PLAD) is the focus of this paper. Unlike planar transistors, characterization of 3D devices both by SIMS and APT requires sample preparation via trench backfill with alpha-Si, or other material, via chemical vapor deposition or atomic layer deposition process due to high aspect ratio of test structures. Certain artifacts with adverse impacts on quantitative results encountered in this study are discussed. PMID- 30426913 TI - Bereavement risk assessment of family caregivers of patients with cancer: Japanese version of the Bereavement Risk Assessment Tool. AB - OBJECTIVES: The Bereavement Risk Assessment Tool (BRAT) seems to be useful in identifying those who are likely to suffer from the more severe consequences of bereavement. To date, however, only a few studies have examined bereavement risk using the BRAT. This study investigated bereavement risk in family caregivers of patients with cancer using the Japanese version of the Bereavement Risk Assessment Tool (BRAT-J). We also investigated the relationship of bereavement risk with psychological distress and resilience among caregivers to determine the validity of the BRAT-J. METHODS: We conducted family psychoeducation in the palliative care unit of Tohoku University Hospital with participants who were recruited in this study. Among the participants, 50 family caregivers provided their written informed consent and were included in this study. Participants were assessed using the BRAT-J and completed the Japanese version of the Kessler Psychological Distress Scale (K6) and the Tachikawa Resilience Scale (TRS). RESULTS: According to the BRAT-J, five individuals (10%) were in the high category of bereavement risk (level 4 or 5). We also found that family caregivers of patients experienced many different pressures, such as facing the unknown; their own work; and insufficient financial, practical, or physical resources. These issues are associated with various mental problems. Additionally, the level of bereavement risk was significantly correlated with K6 scores (rho = 0.30, p = 0.032), and the TRS score (rho = -0.44, p = 0.001). These correlations confirmed previous findings and that the BRAT-J can be an efficient screening tool for the bereavement risk of family caregivers of patients with cancer.Significance of resultsIt appears that the BRAT-J is useful in predicting the likelihood of difficulties or complications in bereavement for family caregivers and could help to provide support with these issues when needed. PMID- 30426914 TI - Improving the diagnosis and prediction of progression in mild cognitive impairment. AB - Mild cognitive impairment (MCI) is a clinical condition conceptualized as a stage between normal cognition and dementia. To diagnose it requires subjective cognitive impairment, evidence of cognitive impairment on cognitive testing but no abnormality in a person's functioning and no evidence of dementia (American Psychiatric Association, 2013). There has been growing interest in the condition over the past two decades or so because people with MCI are much more likely than people with no cognitive impairment to progress to dementia (Roberts et al., 2013). However, a significant percentage of people with MCI will not progress to dementia and some will revert to having normal cognition. Rates of progression and reversion to normal cognition vary widely in different studies (Manly et al., 2008). People with MCI experience worry about their symptoms and this is partly alleviated by receiving a diagnosis of MCI and being reassured they do not have dementia (Gomersall et al., 2017). The benefits of diagnosis also include gaining a greater understanding of their symptoms and accessing clinical support but a significant amount of uncertainty remains with regards to the risk of progression and recipients of the diagnosis remain frustrated at the lack of treatments for MCI (Gomersall et al., 2017). There has been much interest in improving the prediction of progression to dementia from MCI but to date, the best predictors of progression remain structured clinical and functional assessments, with some additional benefit from measures of cortical volume/thickness from brain imaging (Korolev et al., 2016). As yet, however, there are no interventions that can prevent (Kane et al., 2017) or treat (Cooper et al., 2013) MCI so it seems set to remain an important clinical entity for the foreseeable future. PMID- 30426915 TI - The concept of mild cognitive impairment: a victim of its ubiquity. AB - Mild cognitive impairment (MCI) is a term used to describe individuals with cognitive impairment that is not severe enough to affect daily functioning (e.g. Petersen, 2004; Winblad et al., 2004). Although MCI has been used to describe cognitive abnormality due to any number of causes that can be progressive, stable, or reversible, it is most often considered to be a transition phase between normal cognition and dementia. PMID- 30426916 TI - Mild cognitive impairment: some steps forward. AB - There is no doubt that the term mild cognitive impairment (MCI) has become popular in the last decades (Flicker et al., 1991; Petersen et al., 1997). A superficial quantification of the publications that include said term in the title in the Web of Science yields 9,334 citations, including 6,553 articles, 667 reviews, 187 editorials, 37 books, and 249 patents. PMID- 30426917 TI - Loneliness interacts with family relationship in relation to cognitive function in Chinese older adults. AB - : ABSTRACTObjectives:Loneliness and social networks have been extensively studied in relation to cognitive impairments, but how they interact with each other in relation to cognition is still unclear. This study aimed at exploring the interaction of loneliness and various types of social networks in relation to cognition in older adults. DESIGN: a cross-sectional study. SETTING: face-to-face interview. PARTICIPANTS: 497 older adults with normal global cognition were interviewed. MEASUREMENTS: Loneliness was assessed with Chinese 6-item De Jong Gierverg's Loneliness Scale. Confiding network was defined as people who could share inner feelings with, whereas non-confiding network was computed by subtracting the confiding network from the total network size. Cognitive performance was expressed as a global composite z-score of Cantonese version of mini mental state examination (CMMSE), Categorical verbal fluency test (CVFT) and delayed recall. Linear regression was used to test the main effects of loneliness and the size of various networks, and their interaction on cognitive performance with the adjustment of sociodemographic, physical and psychological confounders. RESULTS: Significant interaction was found between loneliness and non-confiding network on cognitive performance (B = .002, beta = .092, t = 2.099, p = .036). Further analysis showed a significant interaction between loneliness and the number of family members in non-confiding network on cognition (B = .021, beta = .119, t = 2.775, p = .006). CONCLUSIONS: Results suggested that a non-confiding relationship with family members might put lonely older adults at risk of cognitive impairment. Our study might have implications on designing psychosocial intervention for those who are vulnerable to loneliness as an early prevention of neurocognitive impairments. PMID- 30426918 TI - A clinically-translatable machine learning algorithm for the prediction of Alzheimer's disease conversion: further evidence of its accuracy via a transfer learning approach. AB - : ABSTRACTBackground:In a previous study, we developed a highly performant and clinically-translatable machine learning algorithm for a prediction of three-year conversion to Alzheimer's disease (AD) in subjects with Mild Cognitive Impairment (MCI) and Pre-mild Cognitive Impairment. Further tests are necessary to demonstrate its accuracy when applied to subjects not used in the original training process. In this study, we aimed to provide preliminary evidence of this via a transfer learning approach. METHODS: We initially employed the same baseline information (i.e. clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy) and the same machine learning technique (support vector machine with radial-basis function kernel) used in our previous study to retrain the algorithm to discriminate between participants with AD (n = 75) and normal cognition (n = 197). Then, the algorithm was applied to perform the original task of predicting the three-year conversion to AD in the sample of 61 MCI subjects that we used in the previous study. RESULTS: Even after the retraining, the algorithm demonstrated a significant predictive performance in the MCI sample (AUC = 0.821, 95% CI bootstrap = 0.705-0.912, best balanced accuracy = 0.779, sensitivity = 0.852, specificity = 0.706). CONCLUSIONS: These results provide a first indirect evidence that our original algorithm can also perform relevant generalized predictions when applied to new MCI individuals. This motivates future efforts to bring the algorithm to sufficient levels of optimization and trustworthiness that will allow its application in both clinical and research settings. PMID- 30426919 TI - Evaluating PCR-Based Detection of Salmonella Typhi and Paratyphi A in the Environment as an Enteric Fever Surveillance Tool. AB - With prequalification of a typhoid conjugate vaccine by the World Health Organization, countries are deciding whether and at what geographic scale to provide the vaccine. Optimal local data to clarify typhoid risk are expensive and often unavailable. To determine whether quantitative real-time PCR can be used as a tool to detect typhoidal Salmonella DNA in the environment and approximate the burden of enteric fever, we tested water samples from urban Dhaka, where enteric fever burden is high, and rural Mirzapur, where enteric fever burden is low and sporadic. Sixty-six percent (38/59) of the water sources of Dhaka were contaminated with typhoidal Salmonella DNA, in contrast to none of 33 samples of Mirzapur. If these results can be replicated in larger scale in Bangladesh and other enteric fever endemic areas, drinking water testing could become a low-cost approach to determine the presence of typhoidal Salmonella in the environment that can, in turn, guide informed-design of blood culture-based surveillance and thus assist policy decisions on investing to control typhoid. PMID- 30426920 TI - Zika Virus in Israeli Travelers: Emergence of Asia as a Major Source of Infection. AB - Zika virus (ZIKV) had emerged as a global arboviral concern since late 2015. In this study, we describe the results of ZIKV testing in returning Israeli travelers from Zika-endemic countries. We conducted a nation-wide prospective observational study, including all ZIKV tests during January 2016-June 2017. Zika virus infection was defined as confirmed, if diagnosed by PCR or serology confirmed by neutralization, and as possible if diagnosed by serology alone. During the study period, 1,188 travelers were tested: 66.7%, 30.5%, 1.6%, and 1.2% had returned from the Americas, Asia, Africa, and Oceania, respectively. Thirty persons were diagnosed with ZIKV. Most travelers tested were women of reproductive age; the gender ratio among infected travelers however was 1.0. During 2016, 19/20 (95%) ZIKV cases were acquired in the Americas; in 2017, however, 6/10 (60%) cases were acquired in Asia. Of 248 symptomatic travelers, 28 (11.3%) were diagnosed with ZIKV infection, whereas only 2/940 (0.2%) of asymptomatic travelers were diagnosed with ZIKV infection Odds ratio = 59.7 (95% confidence interval: 14.1-252.5, P < 0.0001). Our findings suggest that although women are more likely to be referred for ZIKV testing, gender does not affect the likelihood of ZIKV infection and that asymptomatic ZIKV infection appears to be rare in travelers. Furthermore, it appears that in 2017, Southeast Asia emerges as the leading source of travel-related ZIKV infection. PMID- 30426921 TI - Integrating Case Detection of Visceral Leishmaniasis and Other Febrile Illness with Vector Control in the Post-Elimination Phase in Nepal. AB - Nepal has completed the attack phase of visceral leishmaniasis (VL) elimination and now needs active case detection (ACD) and vector control methods that are suitable to the consolidation and maintenance phases. We evaluated different ACD approaches and vector control methods in Saptari district. We assessed 1) mobile teams deployed in villages with VL cases in 2015 to conduct combined camps for fever and skin lesions to detect VL/PKDL (post-kala-azar dermal leishmaniasis) and other infections; 2) an incentive approach by trained female community health volunteers (FCHVs) in villages with no VL cases in 2015. Both were followed by house-to-house visits. For vector control, four villages were randomly allocated to insecticide impregnation of bednets, insecticide wall painting, indoor residual spraying (IRS), and control. Sandfly density (by CDC light traps) and mortality (World Health Organization cone bioassay) were assessed in randomly selected households. One VL, three tuberculosis, one leprosy, and one malaria cases were identified among 395 febrile cases attending the camps. Post-camp house-to-house screening involving 7,211 households identified 679 chronic fever and 461 skin lesion cases but no additional VL/PKDL. No VL/PKDL case was found by FCHVs. The point prevalence of chronic fever in camp and FCHV villages was 242 and 2 per 10,000 populations, respectively. Indoor residual spraying and bednet impregnation were effective for 1 month versus 12 months with insecticidal wall paint. Twelve-month sandfly mortality was 23%, 26%, and 80%, respectively, on IRS, bednet impregnation, and insecticide wall painting. In Nepal, fever camps and insecticidal wall paint prove to be alternative, sustainable strategies in the VL post-elimination program. PMID- 30426922 TI - Case Report: Percutaneous Treatment of Multiple Echinococcal Cysts Presenting as Abdominal Palpable Mass. AB - We report the case of an adolescent Moroccan girl with abdominal pain and palpable mass in the upper right side of the abdomen. In the emergency department, an abdominal ultrasound showed hepatomegaly and eight active liver cysts, compatible with cystic echinococcosis. Serology for Echinococcus granulosus confirmed the diagnosis. Other sites of localization were excluded. Treatment involved albendazole combined with puncture, aspiration, injection, re aspiration, performed only for the most medial cysts. Periodical follow-up with abdominal ultrasound and with abdominal magnetic resonance imaging showed a progressive involution of all cysts. The treatment with albendazole was stopped after, overall, 6 months, and monthly ultrasound scan were planned as follow-up. In case of hepatic cysts, E. granulosus should be excluded, especially in children from endemic countries. A multidisciplinary approach with pediatric infectious disease specialists, radiologists, and surgeons is fundamental for disease management. PMID- 30426923 TI - Triatoma costalimai Naturally Infected by Trypanosoma cruzi: A Public Health Concern. AB - The rupestrian Triatoma costalimai species has been found infected by Trypanosoma cruzi in wild, peridomicile, and intradomicile environments in the municipality of Aurora do Tocantins, Tocantins, Brazil. Proximity between rock outcrops increases the risk of vector transmission of Chagas disease via this species. This work describes a focus of colonization by T. costalimai specimens infected by T. cruzi in rock outcrops located in an urban area in this municipality. Parasitological examination of feces from the collected specimens, axenic cultivation of T. cruzi-positive samples, and genetic characterization of the isolates were performed. Nymph and adult specimens were collected with a high infection prevalence (64.5%) for T. cruzi TCI. Participation of the T. costalimai species in the wild cycle of T. cruzi in rock outcrops located in an urban area demonstrates the need for entomological surveillance and control of vector transmission of Chagas disease in the municipality of Aurora do Tocantins, Tocantins. PMID- 30426924 TI - Artemisinin Resistance Outside of Southeast Asia. AB - Artemisinin Resistance Outside of Southeast Asia. PMID- 30426925 TI - Closing the circle. AB - In Chlamydomonas the different stages of the Calvin-Benson cycle take place in separate locations within the chloroplast. PMID- 30426927 TI - gamma-Tubulin small complex formation is essential for early zebrafish embryogenesis. AB - The centrosomal protein gamma-tubulin is part of the cytoplasmic gamma-tubulin small (gamma-TuSCs) and large complexes (gamma-TuRCs). Both, molecular and cellular evidence indicate that gamma-tubulin plays a central role in microtubule nucleation and mitotic spindle formation. However, the molecular mechanisms of complex formation and subsequent biological roles in animal development remain unclear. Here, we used gamma-tubulin gene knockdown in the zebrafish early embryo model to gain insights into its activity and cellular contribution during vertebrate embryogenesis. gamma-Tubulin loss-of-function impaired gamma-TuSC formation, impacting the microtubule nucleation rate in vitro. Moreover, decreased gamma-tubulin synthesis caused dramatic defects in nuclear dynamics and cell cycle progression, leading to developmental arrest at the mid-gastrula stage. At the subcellular level, microtubule organization and function were altered, affecting chromosome segregation and triggering cell proliferation arrest and apoptosis. Our results suggest that de novo translated gamma-tubulin participates in gamma-TuSC formation required for early animal development. Importantly, formation of this complex is essential for both centrosome assembly and function, and cell proliferation. Thus, gamma-TuSC integrity appears to be critical for cell cycle progression, and concomitantly, for coordinating the many distinct activities carried out by the early embryo. Our findings identify a novel role for gamma-TuSC in the regulation of early vertebrate embryogenesis, providing molecular and biochemical starting points for future in depth studies of gamma-tubulin functionality and its specific role in development. PMID- 30426928 TI - [Schizotypy Personality Questionnaire Brief Revisited (SPQ-BR) Hungarian adaptation and interpretation of factors]. AB - INTRODUCTION: The purpose of the Schizotypy Personality Questionnaire - Brief Revised (SPQ-BR) is to help the diagnosis of schizotypial personality disorders within the framework of the DSM-5 and identification of people with an increased vulnerability towards schizophrenia related symptoms. The aim of our current study is twofold; validation of the SPQ-BR's Hungarian adaptation and investigating it's latent structure. METHODS: The sample consisted of 1702 Hungarian university students and university graduated persons. Exploratory factor analytic procedures were performed, cross-validating their results by the use if confirmatory factor analysis. RESULTS: The results suggested that the Hungarian SPQ-BR is best represented by a model of the hierarchical structure, reflected by seven first order factors, and two higher order dimensions of positive and negative symptoms. On lower order factors males were shown significantly greater constricted affects, and proneness to eccentric behaviors and unusual perceptions, while females were characterized by higher magical thinking, next to stronger social anxieties. Gender differences in the Ideas of references - Suspicion and odd speech scales were found to be non-significant. Concerning it''s validity with other scales we found that magical thinking and unusual perceptions from the positive symptoms significantly positively correlated with the magical ideation (MI), anxiousness (ASI), and self-concept clarity (SCCS) scales, next to a negative correlation between unusual perceptions and the self-esteem (RSES) scale. Among the negative symptoms the No close friends-Constricted affect and the Ideas of references - Suspicion subscales showed significant negative linear associations with the ASI, SCCS scales. CONCLUSION: The Hungarian version of the SPQ-BR showed adequate psychometrical properties, it was found to be reliable. PMID- 30426926 TI - Decoding hierarchical control of sequential behavior in oscillatory EEG activity. AB - Despite strong theoretical reasons for assuming that abstract representations organize complex action sequences in terms of subplans (chunks) and sequential positions, we lack methods to directly track such content-independent, hierarchical representations in humans. We applied time-resolved, multivariate decoding analysis to the pattern of rhythmic EEG activity that was registered while participants planned and executed individual elements from pre-learned, structured sequences. Across three experiments, the theta and alpha-band activity coded basic elements and abstract control representations, in particular, the ordinal position of basic elements, but also the identity and position of chunks. Further, a robust representation of higher level, chunk identity information was only found in individuals with above-median working memory capacity, potentially providing a neural-level explanation for working-memory differences in sequential performance. Our results suggest that by decoding oscillatory activity we can track how the cognitive system traverses through the states of a hierarchical control structure. PMID- 30426929 TI - [Dissonance in addictology - The missed encounter between Laszlo Levendel and Thomas Szasz]. AB - The starting point for this paper is a consideration of Jozsef Gerevich's seminal study of binarisms and dissonance in the field of drug treatment policies. Gerevich suggests the possibility of a synthesis of conflicting and divergent approaches. The present study focuses on some historical aspects of this polarisation or dichotomy, as it was exemplified in the contrasting life-works of two scholars of addictionology: Laszlo Levendel and Thomas Szasz. Levendel was one of the most important founding fathers of Hungarian drug treatment system, whilst the Hungarian descended Szasz is perhaps the most famous critic and opponent of addictionology. Born at the same time and growing up in the same city, they shared a generational experience of exclusion. Both initially focused on other medical specialties before developing their careers in the field of addiction. Their approach and methods were contradictory and became polarised. On the one hand Levendel practised an eclectic and inclusive "bricolage" approach to alcohol treatment policy, whilst on the other Szasz was committed to a critical and polemical perspective of "destructive creation". After the democratic transformation of Hungary, the two were about to meet, but Levendel's sudden death prevented this from happening. The lesson we should perhaps take from this fact is that "opportunity is fleeting" and should be taken whenever it occurs. PMID- 30426930 TI - [Medically Unexplained Symptoms]. AB - The term "medically unexplained symptoms" (MUS) refers to the manifestation of multiple somatic complaints not explained satisfactorily by organic changes, where the origin of the symptoms is not psychoactive drug use or simulation. Even though the beginnings of the investigations of this topic are dated back to the mid-18th century, still no adequate conceptual consensus has been reached. In the treatment of MUS we face the challenges of the need for multidisciplinarity and the issue of not putting enough emphasis in the medical training on the evaluation of the possible psychological background of somatic symptoms and on the teaching of communication skills. This study outlines the main characteristics of MUS, the related epidemiological results and - together with the effect of MUS on the healthcare system and economy - highlights the attitudes of patients and medical doctors. We make practical and theoretical points, which may contribute to the efficient treatment of MUS. PMID- 30426931 TI - [Patient Journey in Schizophrenia - Lessons of a Hungarian Survey]. AB - The disorder-related experiences of schizophrenic patients are an important basis for personalized treatment. This illness experience is now described with the concept of patient journey. The patient journey shows how the symptoms and treatment interfere with the patient's personal existence and how they affect the optimal functionality. The purpose of our research was to map the patient journey in Hungary, among patients with schizophrenia, in particular how they represent their illness, what kind of met and unmet needs they have in relation to living with the disorder or their treatment. 155 patients living with schizophrenia participated in the study. The survey was conducted through self-completed questionnaires covering the following topics: first encounter with the disorder, life with the disorder, treatment expectations, experiences, support and needs. The first encounter of the patients with the disease was predominantly traumatizing, and the refusal of the diagnosis was characteristic. The inappropriate information on the disorder and the treatment might have been also responsible for this negative perception. Nevertheless, patients were expecting the information primarily from the treatment staff. The decisive majority expects from treatment the possibility of a normal life, the maintenance of stability, and according to every second patient well-being is also a basic requirement. Three-quarters of the patients think that effective medication and treatment staff are the greatest help in relation to the disorder. A significant proportion of the patients formulated the need for psychic and family support, and the need for social relations. Patients with schizophrenia have significant difficulties with financial problems, medication side effects, and stigma. Our results confirm that the subjective perception of patient journey of patients with schizophrenia is significantly determined by the met and unmet needs. The results also emphasize the importance of adequate information transfer and the therapeutic relationship. PMID- 30426932 TI - [Accessibility to Electroconvulsive Therapy in Hungary]. AB - INTRODUCTION: In spite of its efficacy, use of electroconvulsive therapy (ECT) has been declined in Hungary over the past decade. This survey explores the circumstances that have obstructed the accessibility to ECT in Hungary. METHODS: This study was part of a comprehensive survey on the use of ECT in which two semi structured questionnaires with 25 and 6 questions were sent out to all psychiatric departments in Hungary. The second questionnaire was targeted those departments that did not perform ECT in 2014. Questions were asked about the reasons for not using ECT and the available treatment strategies for patients who needed ECT. RESULTS: Thirty-one of the 58 Hungarian psychiatric departments did not offer ECT in 2014. Twelve chiefs of service asserted that no patient needed ECT in that year. Due to unavailability of ECT, patients were transferred to other departments for ECT in further 12 departments. Finally, in 7 departments, patients who would have needed ECT were treated with pharmacotherapy instead of transferring them to ECT centers. As for the reasons for the lack of access to ECT, 17 departments had no ECT machine, 12 departments did not have access to anesthesiologists, 6 departments had no budget for ECT, and in 5 departments staff with expertise to deliver ECT was not available. CONCLUSION: The rate of ECT use in Hungarian psychiatric departments decreased by 20 percent between 2002 and 2014. The most important reasons for this decline were lack of the modern ECT devices or financial sources to buy a modern ECT machine. Further reasons for not using ECT were the availability of anesthesiologists or the lack of finances to employ them. The lack of experience in administering ECT was another reason for not utilizing ECT. These difficulties could be solved with the centralization of ECT provision to a few centres in the country together with defining the pathways for patients to reach these centres. PMID- 30426933 TI - [Experiences with the validation of the Hungarian version of Personality Inventory for DSM-5 Brief Form: predicting personality disorders based on self report inventory]. AB - INTRODUCTION: The recent Diagnostic and Statistical Manual of Mental Disorders (DSM-5) provided a dimensional model of personality disorders grounded on the empirical validated concept of maladaptive personality traits. Accordingly, based on this model, the Personality Inventory for DSM-5 Brief Form (PID-5-BF) enables the identification of maladaptive personality traits in 5 dimensions: Negative Affect, Detachment, Antagonism, Disinhibition and Psychoticism. Former studies showed, that this self-report measure can reliably predict the likelihood of the development of personality disorders. AIM: We aimed to develop the Hungarian version of the PID-5-BF and to verify its construct-, concurrent-, predictive-, and discriminative validity. METHOD: Based on the results of former studies regarding PID-5-BF, we asked 379 participants to fill out several selfreport measures. Besides PID-5-BF, the Bipolar Rating Scale for the Big Five Personality, the Unconventionality subscale from the Openness scale of the HEXACO model and the Interpersonal Problems-Personality Disorders-25 were also administered. RESULTS: According to the original 5 factor version, the fit of our model was acceptable (CFI = 0,868; RMSEA = 0,061 [90% CI = 0,055 - 0,068]; Cronbach-alpha = 0,61-0,79). In our view, the results vindicate the reliability and validity of the Hungarian PID-5-BF. CONCLUSIONS: According to former studies along with our recent findings, the PID-5-BF can be seen as an effective and reliable self-report scale for clinical studies and at the same time, it may be useful for the psychiatric diagnostic process, mainly in the case of personality disorders. With more clinical data and knowledge, this inventory could be useful for psychiatrists and clinical psychologists in planning of clinical treatment. PMID- 30426934 TI - [Reflections on Attila Nemeth's "Three neuralgicpoints of psychiatric services: suicide prevention, treatment of dementia and the care of homeless psychiatric patients" article]. AB - No abstract available. PMID- 30426936 TI - [Short comment to "Entirely and For Nothing"]. AB - No abstract available. PMID- 30426935 TI - [Competence - Congruent - Co-operation (Comment to article of Attila Nemeth)]. AB - No abstract available. PMID- 30426937 TI - [Incest and the Double - Grete and Georg Trakl]. AB - No abstract available. PMID- 30426938 TI - History of liver transplantation in Poland. AB - Experimental research on liver transplantation was introduced in Poland by Waldemar Olszewski with his team. It was in 1972. Not until 15 years later, in 1987, did Stanislaw Zielinski in Szczecin and Marian Pardela in Katowice make an attempt of transplanting liver in humans. In 1989, the attempt was made by Jacek Pawlak and Marek Krawczyk in Warsaw. The first successful liver transplantation in Poland was performed by Piotr Kalicinski at the Children's Memorial Health Institute, Warsaw. Also, in early 1990s the attempts were made by Jerzy Polanski in Warsaw and Piotr Szyber in Wroclaw. In the next years, liver transplantations were connected with three centers in Szczecin and were associated with the following persons: Roman Kostryka, Maciej Wojcicki and Samir Zeaira. In Warsaw, 1994, Jacek Pawlak, Bogdan Michalowicz and Krzysztof Zieniewicz performed another successful liver transplantation. The program started to develop rapidly and is still up and running. In 2000, Wojciech Rowinski and Marek Pacholczyk created another liver transplant center in Warsaw, while in 2005 Lech Cierpka and Robert Krol did the same in Katowice. In the following years, liver transplantation was initiated by Maciej Slupski in Bydgoszcz (2017) and Zbigniew Sledzinski in Gdansk (2018). In the developing liver transplant centers, an exceptional contribution was made by Pawel Nyckowski, Jacek Pawlak, Krzysztof Zieniewicz, Waldemar Patkowski, Tadeusz Wroblewski, Rafal Paluszkiewicz, Marek Pacholczyk, Andrzej Chmura, Maciej Kosieradzki and Marek Krawczyk - all employees of the Medical University of Warsaw. In Wroclaw, Dariusz Patrzalek and Pawel Chudoba were very active in the field of liver transplantations. In 1996, the Organizing Coordinating Center for Transplantation POLTRANSPLANT was brought to life. It was directed by Janusz Walaszewski, then by Roman Danielewicz and Artur Kaminski. In 1999, Piotr Kalicinski and Marek Krawczyk started the program for liver fragment harvesting and transplantation from living donors. Until the end of 2016, 4186 liver transplantations including 314 liver transplants from living donors were performed in Poland. Currently, the active centers are three centers from Warsaw, namely Pediatric Surgery and Transplantation Surgery, Children's Memorial Health Institute; Department of General, Transplant and Liver Surgery, Medical University of Warsaw; Department of General and Transplant Surgery, Medical University of Warsaw. Other active centers include Department of General and Transplant Surgery, Provincial Hospital in Szczecin, Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Department of Vascular, General and Transplant Surgery in Wroclaw. Liver transplant programs have also been initiated at the Department of Liver and General Surgery, Bydgoszcz, and Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk. PMID- 30426939 TI - Recommendations for the standards of equipping of the Bariatric and Metabolic Surgery Center. AB - INTRODUCTION: The prevalence of obesity in Poland and worldwide is constantly rising. High effectiveness of bariatric surgery has been proven in literature. It is recommended that bariatric procedures should be done by highly qualified surgeons with the appropriate, up-to-date medical equipment. AIM: The purpose of the study is to establish Polish recommendations and standards for the use of medical equipment for bariatric surgery centers. MATERIALS AND METHODS: The review of the present recommendations of the worldwide organizations and societies (including EAES, IFSO, SAGES) and guidelines was made. On the basis of current literature and authors's clinical experience we proposed standardized protocol for bariatric surgical equipment. CONCLUSIONS: Relevant equipping of bariatric surgery centers and implementation of standardized perioperative and surgery protocols will result in significant improvements in bariatric treatment. This will ensure patients safety, a shorter length of hospital stay and considerably reduce the risk of morbidity. Moreover, it will contribute to the efficacy of the bariatric and metabolic surgery procedures, in accordance with the highest globally accepted standards. PMID- 30426940 TI - Colonoscopy for colorectal cancer screening - is it effective in the hands of a general surgery resident? AB - INTRODUCTION: Colonoscopy is considered to be a gold standard for colorectal cancer (CRC) screening. Endoscopy training is an essential component of general surgery training program. Patients should receive care at the highest level possible, nevertheless residents need to gain experience. The aim of our study was to evaluate the effectiveness of colonoscopy performed by general surgery residents by comparing quality indicators between surgical trainees and consultants MATERIALS AND METHODS: The analysis included 6384 patients aged 40-65 who underwent screening colonoscopy between October 2014 and February 2018. The patients were divided into two groups: group I - patients examined by residents, group II - patients examined by board certified general surgeons. Quality indicators such as cecal intubation rate, adenoma detection rate and patient tolerance scale were compared between the two groups. RESULTS: Group I comprised 2268 (35.53%) and group II 4116 (64.47%) patients. The overall cecal intubation rate (CIR) was 95.99%, equal for the both groups (p=0.994). There was no statistically significant difference in adenoma detection rate: 29.30% in residents group and 27.66% among consultants (p=0.203). Patient tolerance for exam was very good (4-point scale) in consultants group in 78.98% of cases and in 75.18% cases among residents (p<0.001). CONCLUSION: . Within a proper learning environment general surgery residents are able to perform high quality and effective screening colonoscopy. However, residents need to continue the progress in their technique to improve patient tolerance in order to reach the proficiency of the consultant. PMID- 30426941 TI - Pancreatic cysts or pancreatic cystic neoplasms? An analysis of 145 cases. AB - Introduction Frequency of detection of pancreatic cystic lesions increased recent years. The majorities are pseudocysts, the remaining cysts are mainly neoplasms. Proven risk of malignancy affects intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). Material and methods 145 patients operated on at the Department of General and Transplant Surgery in Barlicki Hospital in Lodz, Poland, in 2007-2016 due to pancreatic cystic lesion. The type of surgery, histopathological diagnosis and basic demographic data were analyzed. Results Nonneoplastic cyst (mainly pseudocysts) was found in 66.9% of patients, neoplasms were detected in 33.1%. The mean age was significantly higher in patients with neoplasms than without neoplasm (57.06 years vs. 50.88 years, p = 0.009). Neoplastic cyst occurred more frequently in women (68.75% of women, 31.25% of men, p = 0.001), Nonneoplastic cyst was found significantly more often in men (64.95% of men, 35.05% of women, p = 0.001). Malignant tumor was found in 14.58% of neoplasms cases. Pancreatic resections in neoplastic cysts were performed in 77,08%. In patients with nonneoplastic cysts drainage operations were performed most frequently (80.41%). Conclusions Neoplastic cysts are more common in women. The average age in the group of patients with neoplasms is higher than in the group with nonneoplastic cysts. In women with pancreatic cystic lesion without history for pancreatitis, the probability of neoplasms diagnosis is high. Discussion Pancreatic cystic tumors are treated radically due to the lack of sufficiently sensitive and specific pre-operative examinations. The natural history of mucinous neoplasms (IPMN and MCN) ranges from dysplasia to cancer. There are no guidelines that could be in satisfactory way used in follow up patients with pancreatic cysts. PMID- 30426942 TI - Carcinoembryonic antigen and matrix metalloproteinase 2 serum and peritoneal washes concentration in staging and prognosis in colorectal cancer patients. AB - PURPOSE: The aim of the study was to determine of carcinoembryonal antigen and matrix metalloproteinase 2 peritoneal washes and serum concentration in patients suffering from colorectal cancer concerning tumor staging and 5-year survival rate in these patients. METHODS: 80 patients who underwent curative surgery for colorectal cancer were included into the study. Preoperative serum and intraoperative peritoneal washes CEA and MMP-2 concentrations were measured. RESULTS: Concerning tumor penetration CEA-s and CEA-p concentration was higher in subsequent stages from T2 to T4. Both CEA-s and CEA-p concentration was lower in T2 comparing to T3 and T4. Significant difference of CEA-s and CEA-p was noted between T2 and T4 stages. MMP2-s concentration was higher in T3 comparing to T2, the highest MMP2-p concentration was in T4, with no statistical significance. Concerning nodular status significant difference of CEA-s was noted between N0 and N1. For CEA-p significance was found between N0 and N2 as between N1 and N2. MMP2-s concentration was the highest in N1, MMP2-p concentration was the highest in T4, with no statistical significance. 5-year survival rate for all patients was 63,53%. There were significant differences in CEA-s and CEA-p concentration between patients with negative and positive 5-year survival. CONCLUSION: Intraoperative peritoneal washes concentration of CEA may potentially serve as an important factor for more precise colorectal cancer staging. CEA-p and CEA-s concentration correlates with survival rate in patients suffering from colorectal cancer and can be useful as an additional prognostic factor. Usefulness of MMP2 measurement still requires further studies. PMID- 30426943 TI - Vacuum-assisted closure (VAC) for postoperative secondary peritonitis: Effect on bacterial load as well as local and systemic cytokine response (initial results). AB - BACKGROUND: It is still a matter of debate what the best management of peritonitis is following eliminating the source of infection. This particularly concerns the amplitude of local and systemic inflammatory response as well as bacterial clearence at the infectious site. AIM: To investigate the effects of vacuum-assisted closure (VAC) vs. relaparotomy on demand (ROD) onto the i) severity and course of disease, ii) surgical outcome, iii) intraperitoneal bacterial load as well as iv) local and systemic inflammatory and immune response in postoperative secondary peritonitis. METHODS: Over a defined time period, all consecutive patients of the reporting surgical department with a secondary peritonitis (assessed by Mannheim's Peritonitis Index [MPI] and APPACHE II score) were enrolled in this systematic unicenter clinical prospective observational pilot study reflecting daily surgical practice and as a contribution to internal quality assurance. Patients were subclassified into VAC or ROD group according to surgeon's individual decision at the time point of primary surgical intervention with the intent to sanitize the source of infection. Early postoperative result was assessed by 30-d and in-hospital mortality. Bacterial load was characterized by microbiological culture of intraperitoneal fluid collection obtained on postoperative days (POD) 0 (primary surgical intervention), 1, 4, 7, 10, 13 and following description of the microbial spectrum including semiquantitative assessment of bacterial load. Local and systemic inflammatory and immune response was determined by ELISA-based analysis of CrP, PCT and the representative cytokines such as TNF-alpha, IL-1beta, IL-6, IL-8, and IL-10 of serum and peritoneal fluid samples. RESULTS: Over a 26-months investigation period, 18 patients (sex ratio, male:female=9:9) were eligible for study criteria: n=8 were enrolled in the VAC (m:f=4:4) and n=10 in the ROD group (m:f=5:5). With regard to early postoperative results represented by mortality, there is no significant difference between both patients groups. Despite the relatively low number of cases enrolled in this study, a trend for more severe findings associated with the VAC group could be detected based on MPI score. There was also a trend of higher APACHE II scores in the VAC group from the 7th POD on and, in addition, patients of this group had a longer hospital stay. For patients with persisting infection, there were no relevant differences comparing VAC therapy and ROD. Cytokines released, in particular, at the beginning of the inflammation cascade with proinflammatory characteristics, showed higher values within the peritoneal fluid whereas CrP and PCT were found to be higher within the serum samples. Summary & Conclusion: Comparing data of various local and systemic inflammatory and immune parameters, there were only a few correlations. This may indicate a compartimentation of the inflammatory process within the abdominal cavity. Based on the observed inter-individual variation of this pilot study data, the clinically applicable benefit appears questionable. In this context, a reliable effect of VAC therapy onto reduction of bacterial burden within the abdominal cavity could not clearly be detected. PMID- 30426944 TI - Prognostic value of using neutrophil-lymphocyte ratio in patients with burn injury for the diagnosis of sepsis and bacteraemia. AB - OBJECTIVE: At present time, despite the progress made in the treatment of burn injuries, mortality rate among seriously ill patients remains high. The main causes of fatal cases with the extensive deep burns are generalized infectious complications, the major of which is sepsis. According to the authors, from 25 to 85% of deceased in later periods of burn injuries die from sepsis. The frequency and severity of infectious complications in patients with burn injuries requires an accurate diagnosis of infection that will determine the tactics of therapeutic and surgical treatment of such patients (Di Lonardo A. et al., 1993). However, the clinical diagnosis of wound infection in patients with burn injuries is quite difficult. MATERIALS AND METHODS: Clinical material makes 188 patients with burn injuries. The average age of patients ranged from 20 to 59 years. Men ? 98 (52.1%), women ? 90 (47.9%). The survey has been conducted from April 2014 to July 2016. RESULTS: In our opinion, the strength of the NLR (neutrophil lymphocyte ratio) is the possibility of implementing this parameter simply by using already available biomarkers (neutrophil count and lymphocyte count). Therefore, this ratio is easy to integrate in clinical practice and cost effective. CONCLUSION: The application of NLR for the diagnosis of sepsis in patients with burn injuries is the option of choice, since its determination requires only the overall blood test. PMID- 30426945 TI - Splenic tuberculosis: a comprehensive review of literature. AB - Tuberculosis(TB) is one of the most common infections affecting the population in the developing countries. With the rising human immunodeficiency(HIV) infection its incidence is on a rise even in the developed countries. Pulmonary TB is the commonest form of infection, However, multiple extrapulmonary sites have also been reported. The spleen is thought to be a rare organ involved in this infection. Various presentations of the splenic TB have been reported in the literature. The definitive diagnosis of this is essentially formulated on the post-splenectomy specimen. A consensus statement based on the available case reports is lacking. The authors are providing an insight into this form of extrapulmonary TB after reviewing the available literature. PMID- 30426946 TI - The influence of selected bariatric surgeries on glycolipid balance. AB - : The aim of this study was to compare the efficacy of two laparoscopic bariatric procedures, i.e. Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (LSG) in terms of body mass reduction and improvement in carbohydrate and lipid metabolism. MATERIAL AND METHODS: The study group consisted of patients subjected to RYGB (Group I) and LSG (Group II) procedures. Body mass and fasting concentrations of glucose, insulin, glycated haemoglobin, total cholesterol, HDL, LDL and triglycerides were evaluated on the day preceding the surgery and 1, 3 and 6 months thereafter. BMI, HOMA-IR and HOMA-B were calculated as well. RESULTS: The reduction of BMI, glucose, insulin, glycated haemoglobin, triglycerides levels as well as the HOMA-IR, and HOMA-B indices and increase of HDL were observed in both groups 6 months after the surgery. No reduction of both total cholesterol and LDL concentrations was obtained in both groups. The differences of the studied parameters in both groups were not statistically significant. CONCLUSIONS: RYGB and LSG are equally effective in terms of body mass reduction, improvement of carbohydrates and lipid metabolism assessed 6 months after the surgery. PMID- 30426947 TI - Can urea breath test (UBT) replace rapid urea test (RUT)? AB - BACKGROUND: Helicobacter pylori (Hp) is classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen. Its influence on the carcinogenesis of gastric cancer has been confirmed in many researches. The conclusion is obvious- early detection and eradication of Hp can prevent the development of the disease. METHODS: The objective of the study was to analyse the clinical and practical value of Carbon-13 urea breath test (UBT) in patients hospitalized due to pain complaints in the upper abdomen and dyspeptic symptoms. Fifty patients were enrolled in the study. Each patient underwent urea breath test according to the instruction included by the producer. Thereafter, each patient included in the study group was performed endoscopy of the upper gastrointestinal tract with the biopsy of the mucosa to determine the urease activity with rapid urease test (RUT). RESULTS: In the study group, 14 patients (28%) achieved a positive urease test result which was confirmed in RUT. Four (8%) patients, despite a positive breath test, did not have a positive result in urease activity from gastric mucosa. In 2 cases (4%) despite negative result of UBT there was urease actitvity confirmed in gastroscopic sections. The remaining 30 patients (60%) had a negative result in both studies. CONCLUSIONS: The limited availability of the gold standard for diagnostics of upper gastrointestinal tract diseases (gastroscopy) is the basis for the search for new methods for the detection of Helicobacter pylori infection. The urea breath test is a method of high sensitivity and specificity. The positive result of urea breath test may be the basis for the inclusion of eradication therapy. PMID- 30426949 TI - Traversing the Road not Taken. PMID- 30426950 TI - Defining the Best Interest of a Child: Who Comes First - The Child or the Fetus? AB - In 2017, a 10-year-old girl, who was allegedly raped and impregnated, was denied an abortion on the basis of the Medical Termination of Pregnancy Act 1971. This perspective re-examines this issue while prioritizing the best interest of the child. We recommend that boards should be constituted at district-level hospitals, headed by senior pediatricians, and supported by obstetricians, psychologists, neonatologists, medical social workers, and others to decide the course of action - in particular, the outcome, irrespective of the weeks of pregnancy. If not compatible with the child's life, earlier termination of pregnancy should be considered ensuring the availability of state-of-the-art care to the newborn and the young mother. PMID- 30426948 TI - Surgery in patients with congenital factor VII deficiency - a single center study. AB - INTRODUCTION: Congenital factor VII deficiency is a rare hemorrhagic disorder inherited in an autosomal recessive pattern. Surgical treatment with insufficient diathesis correction is burdened with high risk of bleeding complications. The aim of the study was evaluation of the surgical outcome in patients with congenital factor VII deficiency and assessment of the efficacy and safety of recombinant activated factor VII (rFVIIa) used for perioperative hemostatic coverage in our two schemas of substitutive therapy. MATERIAL AND METHODS: In the years 2002-2017 a total of 22 patients with congenital factor VII deficiency were subjected to surgery. Substitution therapy relied on rFVIIa used in two schemas. One involved 15 patients with factor VII activity of<10% of normal value who were injected rFVIIa at a dose of 30 MUg/kg b.w. every12 hours on surgery day, 15 MUg/kg b.w. every 12 hours on the first postoperative day and 15 MUg/kg b.w. every 24 hours on the following days. The second schema involved 7 patients with factor VII activity of 10-25% of normal value who were given rFVIIa at a dose of 15 MUg/kg b.w. every 12 hours on surgery day and the first postoperative day; then the same dose was administered every 24 hours on consecutive days. The treatment continued for 4-10 days. RESULTS: In the 22 patients a total of 26 surgeries were performed; 17 surgeries in 15 patients with factor VII<10% of normal and 9 in 7 patients with factor VII deficiency of 10-25% of normal. The surgeries included: 9 cholecystectomies (8 laparoscopic,1 open), 7 thyroidectomy procedures, 2 exploratory laparotomies, 1 left hemicolectomy, 1 total proctocolectomy, 3 inguinal hernia repairs and 3 excisions of varicose veins. One patient with factor VII activity of 9% required an additional dose of rFVIIa in the intraoperative period due to diathesis bleeding. Intraoperative hemostasis was normal for all other patients; no postoperative hemorrhagic complications were reported. In patients with FVII activity<10% average daily dose of rFVIIa was 31.3(range 20-56) MUg/kg b.w., total daily dose 186(136-303) ug/kg b.w., total dose of rFVIIa-15.2(12-112) mg. In patients with FVII activity 10-25% the doses were 21.2(15-31), 117(46-271) ug/kg b.w. and 9.1(6-17) mg respectively. CONCLUSIONS: Surgery in patients with congenital factor VII deficiency can be safely and efficiently performed with rFVIIa as substitutive treatment securing perioperative hemostasis. PMID- 30426951 TI - Promising Advances in Budd-Chiari Syndrome in Children. PMID- 30426952 TI - Postnatal Maturation of Amplitude Integrated Electroencephalography (aEEG) in Preterm Small for Gestational Age Neonates. AB - OBJECTIVE: The primary objective was to evaluate the postnatal maturation pattern on aEEG during first two weeks of life in clinically stable and neurologically normal preterm small for gestational age (PSGA) and gestation matched (1 week) preterm appropriate for gestational age (PAGA) neonates born between 300/7 and 346/7 weeks of gestation. METHODS: Serial aEEG tracings were recorded on 3rd, 7th and 14th day of life. The primary outcome was total aEEG maturation score. Three blinded assessors assigned the scores. RESULTS: We analyzed a total of 117 aEEG recordings in 40 (19 PSGA and 21 PAGA) neonates. The baseline characteristics were comparable except for birthweight [1186 (263) vs 1666(230) g]. There was no difference in the mean (SD) total scores on day 3 (9.0 (1.8) vs. 9.5 (1.1), P=0.32) and day 14 of life, but was lower in PSGA infants on day 7 (8.6 (2.4) vs. 10.1 (1.1), P=0.02). On multivariate analysis, maturation of PSGA neonates was found to be significantly delayed at any point of life from day 3 to day 14 (mean difference, -0.8, 95% CI: -1.6 to -0.02, P=0.04). CONCLUSIONS: Lower aEEG maturation score on day 7 possibly indicates delayed maturation in PSGA neonates in the first week of life. PMID- 30426953 TI - Pediatric Budd-Chiari Syndrome: A Case Series. AB - OBJECTIVE: To study the diagnostic methods and treatment outcomes in children with Budd- Chiari syndrome. METHODS: Case records of 25 patients with Budd-Chiari syndrome were evaluated retrospectively. These patients were investigated with imaging techniques and underwent balloon angioplasty or surgical management. RESULTS: 21 patients underwent balloon angioplasty, of which 17 had good medium- to long-term results, while only one out of four patients who underwent a portocaval shunt survived. CONCLUSIONS: The balloon angioplasty has satisfactory outcome in the treatment of acute Budd-Chiari syndrome. In failed cases, the surgical therapy may be attempted, but the outcomes do not appear rewarding. PMID- 30426954 TI - Non-vaccine Pneumococcal Serotypes Among Children with Invasive Pneumococcal Disease. AB - OBJECTIVE: To report the percentage of non-vaccine pneumococcal serotypes and their antibiotic susceptibility pattern in children with invasive peumococcal disease. METHODS: Invasive pneumococcal isolates of children <5 years during January 2007 to December 2016 were serotyped by a co-agglutination reaction and sequential multiplex polymerase chain reaction. RESULTS: Among the total 170 S. pneumoniae invasive isolates, 54 (31.8%) and 44 (25.9%) were the serotypes, which are not included in current 10-valent or 13-valent vaccines, respectively. Very low resistance was observed against penicillin (4.5%) and all isolates were susceptible to cefotaxime. CONCLUSIONS: One-fourth to one-third of the S. pneumoniae serotypes in under-five children with invasive pneumococcal disease are not covered by existing pneumococcal vaccines in India. PMID- 30426955 TI - Clinical Characteristics and Associated Congenital Lesions with Tracheomalacia in Infants. AB - OBJECTIVE: To describe clinical presentation, bronchoscopy findings and associated anomalies in cases of congenital tracheomalacia in infants (age <1y). METHODS: Hospital record review of 88 infants (mean age 8 mo, 57 males) diagnosed as having tracheomalacia by flexible bronchoscopy between 2012 and 2015. RESULTS: The predominant features were wheeze (57.9%), stridor (42.1%), cough (38.6%), pneumonia (29.5%) and collapse (12.5%). On bronchoscopy, malacia was observed in lower half of trachea in 51 (57.9%) infants. Synchronized airway lesions observed were laryngomalacia (30.7%) and bronchomalacia (3.4%). 15 (17%) infants had associated congenital heart disease and 21 (23.8%) required care in intensive care unit. CONCLUSION: Wheeze,stridor and cough are the main symptoms in tracheomalacia. Laryngomalacia and congenital heart diseases are the most common other anomalies associated in these infants. PMID- 30426957 TI - Bacterial Meningitis: Bugs' Story. PMID- 30426956 TI - Electroencephalography in Pediatric Epilepsy. AB - Surface electroencephalography (EEG) is a useful electrophysiological investigation for evaluating a paroxysmal event in children. It measures the electro potential difference between two points on the scalp. It is a non invasive tool that analyzes neuronal maturation and abnormal cortical excitability. EEG helps in differentiating epileptic from non-epileptic clinical event and focal seizures from generalized seizure. This review is to discuss the rational use of interictal scalp EEG in diagnosis of epilepsy and different types of epilepsy syndromes in children. It further highlights its role in febrile seizure, first unprovoked seizure, status epilepticus and unexplained coma. PMID- 30426958 TI - Paradoxical Vocal Cord Motion in a Pair of Twin Preterm Infants. AB - BACKGROUND: Intractable obstructive apneas requiring multiple intubations are rare in newborns. CASE CHARACTERISTICS: We report a pair of twins born at 29 weeks gestation who had severe obstructive apneas due to Paradoxical Vocal Cord Motion (PVCM). OUTCOME: The symptoms resolved promptly with ipratropium nebulization. Follow-up at 12 months of age revealed normal development. MESSAGE: PVCM should be considered in the differential diagnosis of intractable obstructive apneas in very low birth weight preterm infants. PMID- 30426959 TI - Laser Treatment of a Tracheal Inflammatory Myofibroblastic Tumor. AB - BACKGROUND: Inflammatory myofibroblastic tumors of the trachea are rare childhood quasi-neoplastic lesions. Case characteristics: 7-year-old boy with recurrent episodes of cough, breathing difficulty and wheeze, initially treated as asthma. INTERVENTION: CT chest and flexible bronchoscopy revealed a mass lesion of the trachea, which was excised by diode laser through the ventilating bronchoscope. Histopathology confirmed it as the inflammatory myofibroblastic tumor. Message: Use of laser ensured complete endotracheal excision of the tumor. PMID- 30426960 TI - Milky Mesentery: Acute Abdomen with Chylous Ascites. AB - BACKGROUND: Clinical presentations of intestinal lymphangiectasia include pitting edema, chylous ascites, pleural effusion, diarrhea, malabsorption and intestinal obstruction. CASE CHARACTERISTICS: An 8-year-old male child presented to the emergency department with clinical features of peritonitis, raising suspicion of appendicular or small bowel perforation. INTERVENTION/OUTCOME: Diagnosis of chylous ascites with primary intestinal lymphangiectasia made on laparotomy. MESSAGE: Acute peritonitis may be a presentation of primary intestinal lymphangiectasia and chylous ascites. PMID- 30426961 TI - Autism Spectrum Disorders and Celiac Disease: Is there an Association? AB - We included 150 children aged 2-12 years with Autism Spectrum Disorders and normal serum total IgA levels, and screened them for celiac disease using anti tissue transglutaminase IgA levels. All the children were screen negative, suggesting lack of positive association between Autism Spectrum Disorders and Celiac disease. PMID- 30426962 TI - Continuous Temperature Monitoring Using Bluetooth- enabled Thermometer in Neonates. AB - We aimed to compare continuous temperature-monitoring using Bluetooth-enabled thermometer (BET) and intermittent monitoring by digital thermometer (DT) in neonates. Continuous monitoring using BET identified 377 episodes of hypo/hyperthermias in 90 baby-days; 316 (83.8%) episodes were confirmed by DT and 61 (16.2%) were false alarms. Five episodes were missed by BET. The agreement between digital thermometer and BET was good. Continuous temperature monitoring helps in early identification of hypo/hyperthermia in neonates. PMID- 30426963 TI - The Tongue Tie: Untied. PMID- 30426964 TI - To Ride or Not to Ride? PMID- 30426965 TI - Status of Nurses in India. PMID- 30426966 TI - Urbach-Wiethe Disease. PMID- 30426967 TI - Detrended fluctuation analysis of the oximetry signal to assist in paediatric sleep apnoea-hypopnoea syndrome diagnosis. AB - OBJECTIVE: To evaluate whether detrended fluctuation analysis (DFA) provides information that improves the diagnostic ability of the oximetry signal in the diagnosis of paediatric sleep apnoea-hypopnoea syndrome (SAHS). APPROACH: A database composed of 981 blood oxygen saturation (SpO2) recordings in children was used to extract DFA-derived features in order to quantify the scaling behaviour and the fluctuations of the SpO2 signal. The 3% oxygen desaturation index (ODI3) was also computed for each subject. Fast correlation-based filter (FCBF) was then applied to select an optimum subset of relevant and non-redundant features. This subset fed a multi-layer perceptron (MLP) neural network to estimate the apnoea-hypopnoea index (AHI). MAIN RESULTS: ODI3 and four features from the DFA reached significant differences associated with the severity of SAHS. An optimum subset composed of the slope in the first scaling region of the DFA profile and the ODI3 was selected using FCBF applied to the training set (60% of samples). The MLP model trained with this feature subset showed good agreement with the actual AHI, reaching an intra-class correlation coefficient of 0.891 in the test set (40% of samples). Furthermore, the estimated AHI showed high diagnostic ability, reaching an accuracy of 82.7%, 81.9%, and 91.1% using three common AHI cut-offs of 1, 5, and 10 events per hour (e h-1), respectively. These results outperformed the overall performance of ODI3. SIGNIFICANCE: DFA may serve as a reliable tool to improve the diagnostic performance of oximetry recordings in the evaluation of paediatric patients with symptoms suggestive of SAHS. PMID- 30426968 TI - Correction of respiratory and cardiac motion in cardiac PET/MR using MR-based motion modeling. AB - Cardiac positron emission tomography (PET) imaging suffers from image blurring due to the constant motion of the heart that can impact interpretation. Hybrid PET/magnetic resonance (MR) has the potential to use radiation-free MR imaging to correct for the effects of cardio-respiratory motion in the PET data, improving qualitative and quantitative PET imaging in the heart. The purpose of this study was (i) to implement a MR image-based motion-corrected PET/MR method and (ii) to perform a proof-of-concept study of quantitative myocardial PET data in patients. The proposed method takes reconstructions of respiratory and cardiac gated PET data and applies spatial transformations to a single reference frame before averaging to form a single motion-corrected PET (MC-PET) image. Motion vector fields (MVFs) describing the transformations were derived from affine or non rigid registration of respiratory and cardiac gated MR data. Eight patients with suspected cardiac sarcoidosis underwent cardiac PET/MR imaging after injection of 5 MBq kg-1 of 18F-fluorodeoxyglucose (18F-FDG). Myocardial regions affected by motion were identified by expert readers within which target-to-background ratios (TBR) and contrast-to-noise ratios (CNR) were measured on non-MC-non-gated, MC PET, and double respiratory and cardiac gated PET images. Paired t-tests were used to determine statistical differences in quantitative uptake-measures between the different types of PET images. MC-PET images showed less blurring compared to non-MC-non-gated PET and tracer activity qualitatively aligned better with the underlying myocardial anatomy when fused with MR. TBR and CNR were significantly greater for MC-PET (2.8 +/- 0.9; 21 +/- 22) compared to non-MC-non-gated PET (2.4 +/- 0.9, p = 0.0001; 15 +/- 13, p = 0.02), while TBR was lower and CNR greater compared to double-gated PET (3.2 +/- 0.9, p = 0.04; 6 +/- 3, p = 0.004). This study demonstrated in a patient cohort that motion-corrected (MC) cardiac PET/MR is feasible using a retrospective MR image-based method and that improvement in TBR and CNR are achievable. MC PET/MR holds promise for improving interpretation and quantification in cardiac PET imaging. PMID- 30426969 TI - Concentration dependent morphology and composition of n-alcohol modified cetyltrimethylammonium bromide micelles. AB - Cetyltrimethylammonium bromide (CTAB) is one of the most commonly used surfactants in nanoparticle synthesis and stabilization. Usually, CTAB is used in high concentrations besides co-surfactants leading to well defined products but the complex mesoscopic CTAB structures stay mostly unknown. N-alcohols for instance are widely used co-surfactants which modify the properties of native CTAB dispersions. In this paper we report about a detailed structure analysis of n-alcohol modified CTAB micelles. In particular, n-pentanol and n-hexanol exhibit a significantly different influence on the size, shape and composition of CTAB micelles. Using a combination of small-angle x-ray spectroscopy (SAXS) and neutron scattering spectroscopy (SANS), we applied a method for a complete structural characterization of such micelles. The incorporation of n-pentanol into CTAB micelles generally does not influence the morphology but enhances the number of micelles due to the volume of the added alcohol. N-hexanol, however, leads to an elongation of the micelles as a function of its concentration. It was found by extended contrast variation measurements that this difference is caused by a different distribution of the alcohols between the micellar core and shell. N-pentanol molecules are generally located at the core-shell interface of the CTAB micelles with not only the head group but also two additional methylene bridging groups located in the micellar shell. This leads to an increase of its effective head group volume. In comparison, in n-hexanol modified micelles the whole alkyl chain is located within the micellar core. The detailed structure for n-alcohol modified CTAB micelles is described herein for the first time. The knowledge of the structural details found is indispensable for an in-depth understanding of CTAB-n-alcohol-water interfaces in general which is relevant for the synthesis of many functional nanostructures like mesoporous silica and gold or silver nanoparticles. PMID- 30426970 TI - Therapeutic Evaluation of Radiotherapy with Contrast-Enhanced Ultrasound in Non Resectable Hepatocellular Carcinoma Patients with Portal Vein Tumor Thrombosis. AB - BACKGROUND Therapeutic evaluation of 3-dimensional conformal radiotherapy (3DCRT) is rarely reported for non-resectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). The aim of this study was to determine the value of contrast-enhanced ultrasound (CEUS) in evaluating the therapeutic response of HCC with PVTT treated with 3DCRT. MATERIAL AND METHODS PVTT reduction rate in the study was determined after 3DCRT using time intensity curve (TIC) analysis software before and after radiotherapy. Seventy-nine HCC patients with PVTT treated with 3DCRT were studied. HCC and PVTT were performed by CEUS, before and after 3DCRT, over time. The parameters of blood flow, including arrival time (AT), time to peak (TTP), peak intensity (PI), washout time (WT), and area under the curve (AUC), were quantified and evaluated on still images by CEUS. RESULTS After 3DCRT, typing and staging of PVTT in 38 patients was decreased, the reduction rate was 48.1%. HCC was effective in 45 patients, the effective rate was 57%; No differences were found between the PVTT reduction rate and the HCC effective rate (chi2=2.96, P>0.05). In the effective group, the PI and AUC of HCCs and PVTTs after 3DCRT were significantly lower than before 3DCRT, while the other parameters of TIC were not significantly different before and after 3DCRT. CONCLUSIONS CEUS might be a useful monitoring option for the evaluation of HCC with PVTT treated with 3DCRT. CEUS might be useful as an important choice for monitoring and evaluation HCC with PVTT after 3DCRT. TIC parameters might provide quantitative data for efficacy evaluation, which helps to modify treatment strategies timely and accurately. PMID- 30426971 TI - [The patient's voice: outlines for future development]. PMID- 30426972 TI - Prognostic Nutritional Index: an easy nutritional screening for patients with head and neck cancer? PMID- 30426974 TI - Review: a comprehensive summary of a decade development of the recombinase polymerase amplification. AB - Nucleic acid amplification has permeated every field in the life sciences since the introduction of the classic polymerase chain reaction (PCR) method in 1983. Yet, despite its fundamental reach, PCR has been constrained within the walls of a laboratory, due to its requirement for a sophisticated thermocycling machine, limiting external application in low-resource settings. New isothermal amplification strategies are seeking to break through traditional laboratory boundaries by providing nucleic acid replication at constant temperatures. Of these methods, recombinase polymerase amplification (RPA) is one of the fastest developing, experiencing rapid uptake and market, even though it was introduced comparatively late. Critically, RPA's technology potentiates highly accessible and sensitive nucleic acid amplification outside of laboratory, and even self testing. Here we provide a comprehensive review of the equipment-free simplicity of RPA over its first decade of development. Our review includes key knowledge of RPA technology, such as its reaction components, mechanism, sensitivities and specificities, and distinctive detection methods. The review also provides know how for developing RPA assays, and information about commercially available RPA reaction kits and accessories. We summarise critical RPA experimental tips and issues available through data mining the published literature, to assist researchers in mastering the RPA reaction. We also outline influential hotspots of RPA development, and conclude with outlooks for future development and implications for eclipsing PCR and further revolutionising the life sciences. PMID- 30426973 TI - Prognostic Nutritional Index as an independent prognostic factor in locoregionally advanced squamous cell head and neck cancer. AB - Background: Locally advanced head and neck squamous cell carcinoma (LAHNSCC) is a heterogeneous disease in which better predictive and prognostic factors are needed. Apart from TNM stage, both systemic inflammation and poor nutritional status have a negative impact on survival. Methods: We retrospectively analysed two independent cohorts of a total of 145 patients with LAHNSCC treated with induction chemotherapy followed by concurrent chemoradiotherapy at two different academic institutions. Full clinical data, including the Prognostic Nutritional Index (PNI), neutrophil to lymphocyte ratio and derived neutrophil to lymphocyte ratio, were analysed in a training cohort of 50 patients. Receiver operating characteristic curve analysis was used to establish optimal cut-off. Univariate and multivariate analyses of prognostic factors for overall survival (OS) were performed. Independent predictors of OS identified in multivariate analysis were confirmed in a validation cohort of 95 patients. Results: In the univariate analysis, low PNI (PNI<45) (p=0.001), large primary tumour (T4) (p=0.044) and advanced lymph node disease (N2b-N3) (p=0.025) were significantly associated with poorer OS in the validation cohort. The independent prognostic factors in the multivariate analysis for OS identified in the training cohort were dRNL (p=0.030) and PNI (p=0.042). In the validation cohort, only the PNI remained as independent prognostic factor (p=0.007). Conclusions: PNI is a readily available, independent prognostic biomarker for OS in LAHNSCC. Adding PNI to tumour staging could improve individual risk stratification of patients with LAHNSCC in future clinical trials. PMID- 30426975 TI - "Turn-on" Pb2+ sensing and rapid detection of biothiols in aqueous medium and real samples. AB - Detection of lead has continued to be of immense interest in the present industrial as well as environmental diaspora. To this end, we report a prudent Schiff base which enables the sensitive detection of Pb2+ ions in mixed aqueous medium. The probe is afforded by simple synthetic and purification processes. Further, the probe employs simple mechanistic detection of Pb2+ and also successively detects a host of biothiols. The sensor is also used to detect Pb2+ ions in real water samples and consecutive detection of a variety of biothiols, including functionalized thiouracils, in onion and garlic extract. The fact that the Pb2+-L ensemble is 'non-selective' towards any particular thiol substituted analyte in real samples could as well prove to be an interesting contribution for chemical and biological detoxification processes. PMID- 30426976 TI - Chitosan-gold nanocomposite and its functionalized paper strips for reversible visual sensing and removal of trace Hg2+ in practice. AB - To eliminate mercury contamination in aqueous environment, chitosan-gold nanocomposite and its functionalized paper strips were designed and developed for visual sensing and removal of trace Hg2+. By simply immersing a common filter paper into the resultant composite dispersion, gold nanochromophores could be well dispersed with minor aggregation by virtue of the dual supporting roles of the chitosan and the filter paper. Under optimized conditions, the colour of both the chitosan-gold nanocomposite and its functionalized paper strips could change from dark red to yellow upon addition of Hg2+, with a detection limit of 3.2 * 10 9 mol L-1 and 5.0 * 10-8 mol L-1, respectively. Importantly, the chitosan-gold nanocomposite was non-toxic and could be utilized repeatedly for sensing trace Hg2+ in both environmental aqueous solutions and some fruit or vegetable juice samples, with satisfactory results. Furthermore, using the resulting functionalized filter-paper, more than 93.5% Hg2+ in aqueous solution with an initial concentration as high as 1.0 * 10-5 mol L-1 could be enriched and separated by a simple filtration process. The proposed operating mechanism is based on the reversible gold amalgam formation between the gold nanoparticles and Hg2+. This study will be the first report for paper-based sensing to visually detect, enrich and remove Hg2+ with minimal secondary pollution. PMID- 30426977 TI - Reaction of porphyrin-based surface-anchored metal-organic frameworks caused by prolonged illumination. AB - Crystalline surface-anchored metal-organic framework (SURMOF) thin films made from porphyrin-based organic linkers have recently been used in both photon upconversion and photovoltaic applications. While these studies showed promising results, the question of photostability in this organic-inorganic hybrid material has to be investigated before applications can be considered. Here, we combine steady-state photoluminescence, transient absorption, and time-resolved electron paramagnetic resonance spectroscopy to examine the effects of prolonged illumination on a palladium-porphyrin based SURMOF thin film. We find that phototreatment leads to a change in the material's photoresponse caused by the creation of stable products of photodecomposition - likely chlorin - inside the SURMOF structure. When the mobile triplet excitons encounter such a defect site, a short-lived (80 ns) cation-anion radical pair can be formed by electron transfer, wherein the charges are localized at a porphyrin and the photoproduct site, respectively. PMID- 30426978 TI - A hybridization-triggered DNAzyme cascade assay for enzyme-free amplified fluorescence detection of nucleic acids. AB - An enzyme-free and ultrasensitive fluorescence assay for the detection of nucleic acids was successfully established by a hybridization-triggered DNAzyme cascade (HTDC). This simple and cost-effective sensor has good sensitivity, selectivity and the capability for detection of target DNA from complex fluids. PMID- 30426979 TI - Topographical alterations render bacterial biofilms susceptible to chemical and mechanical stress. AB - For the inactivation or removal of bacterial biofilms via chemical or physical processes, it is crucial to sufficiently wet the biofilm surface. However, many bacterial biofilms efficiently resist wetting by water, oil or even organic solvents. Here, we demonstrate how exposing the surface of mature biofilm colonies to concentrated ethanol, saline or glucose solutions results in topographical changes that enable their wettability. With this approach, even omniphobic biofilm colonies become wettable towards aqueous solutions and oils. As a result of this reduced liquid repellency, the biofilms become susceptible to erosion by water which allows for their removal from the substrate they have been grown on. Moreover, bacteria within pre-treated biofilms can now be inactivated with antibiotic solutions. Thus, the biofilm treatment strategy presented here presents a new stepping stone for fighting biofilms in either industrial or medical settings. PMID- 30426980 TI - Photostability of oxazoline RNA-precursors in UV-rich prebiotic environments. AB - Pentose aminooxazolines and oxazolidinone thiones are considered as the key precursors which could have enabled the formation of RNA nucleotides under the conditions of early Earth. UV-irradiation experiments and quantum-chemical calculations demonstrate that these compounds are remarkably photostable and could accumulate over long periods of time in UV-rich prebiotic environments to undergo stereoisomeric purification. PMID- 30426981 TI - Exploring the efficacy and cellular uptake of sorafenib in colon cancer cells by Raman micro-spectroscopy. AB - In recent years, many subcellular proteins have emerged as promising therapeutic targets in oncology. One crucial target is the epidermal growth factor receptor. Inhibition of this receptor has significantly improved the survival rate of patients for many cancers. However, oncogenic mutations such as B-RAFV600E have rendered tumours resistant to this therapeutic approach. Therefore, this mutation has emerged as a potential target for cancer therapy. Sorafenib is developed to overcome the B-RAFV600E mutation and restore the response of the mutated tumour to therapy. Here, we explore the efficacy and distribution of sorafenib at a cellular level using colon cancer cell lines with B-RAFV600E or K-RASG12V mutations. The Raman results detected significant sorafenib-induced spectral differences in both cell lines. In addition, the western blot and real-time cell analysis in vitro assays revealed that the ERK phosphorylation and the cellular proliferation of cells are inhibited, respectively, in the sorafenib-treated cells. Thus, the observed Raman spectral changes illustrate the potent effect of sorafenib on cells despite the presence of the B-RAFV600E or K-RASG12V mutations. These results are in agreement with the clinical studies, where patients with the B-RAFV600E mutation respond to sorafenib. Furthermore, the Raman spectral imaging results have shown the uptake and the distribution of sorafenib in colon cancer cells with the B-RAFV600E mutation through its label-free marker bands in the fingerprint region. The present results of sorafenib efficacy and distribution in cells demonstrate the potential of Raman micro-spectroscopy as the in vitro assay for the assessment of drugs, which is important in drug discovery. PMID- 30426982 TI - Trimeric coiled coils expand the range of strength, toughness and dynamics of coiled coil motifs under shear. AB - Coiled coils are widespread protein motifs in nature, and promising building blocks for bio-inspired nanomaterials and nanoscale force sensors. Detailed structural insight into their mechanical response is required to understand their role in tissues and to design building blocks for applications. We use all-atom molecular dynamics simulations to elucidate the mechanical response of two types of coiled coils under shear: dimers and trimers. The amino acid sequences of both systems are similar, thus enabling universal (vs. system-specific) features to be identified. The trimer is mechanically more stable - it is both stronger and tougher - than the dimer, withstanding higher forces (127 pN vs. 49 pN at v = 10 3 nm ns-1) and dissipating up to five times more energy before rupture. The deformation mechanism of the trimer at all pull speeds is dominated by progressive helix unfolding. In contrast, at the lowest pull speeds, dimers deform by unfolding/refolding-assisted sliding. The additional helix in the trimer thus both determines the stability of the structure and affects the deformation mechanism, preventing helix sliding. The mechanical response of the coiled coils is not only sensitive to the oligomerization state but also to helix stability: preventing helix unfolding doubles the mechanical strength of the trimer, but decreases its toughness to half. Our results show that coiled coil trimers expand the range of coiled coil responses to an applied shear force. Altering the stability of individual helices against deformation emerges as one possible route towards fine-tuning this response, enabling the use of these motifs as nanomechanical building blocks. PMID- 30426983 TI - Advances in mass spectrometry based single-cell metabolomics. AB - Metabolomics has grown into a prominent field contributing to the molecular understanding of complex biological processes in both health and disease. Furthermore, single-cells are known to display metabolic differences between seemingly homogeneous populations of cells. Single-cell metabolomics attempts to analyze many cellular metabolites from single cells to understand phenotypic heterogeneity, which is a significant challenge due to the low analyte abundances and limited sample volumes. Label-free metabolite detection can be achieved with mass spectrometry, which is capable of simultaneously analyzing hundreds of metabolites. Herein, we review the recent advances in mass spectrometry based single-cell metabolomics, highlighting the current state-of-the-art within the last three years, and identify the challenges to move the field forward. PMID- 30426984 TI - Mechanochromic luminescent covalent organic frameworks for highly selective hydroxyl radical detection. AB - The mechanochromic luminescence phenomenon was first reported in the low-cost mechanochemical (MC) synthesis process of a covalent organic framework (COF-TpMA (MC)) prepared using triformylphloroglucinol (Tp) and melamine (MA) as precursors, which shows excellent performance as a hydroxyl radical (OH) detector in living systems. This work not only shows a new kind of mechanochromic luminescent material but also exhibits a close relationship between the pi-pi stacking and luminescence properties of COF materials. PMID- 30426985 TI - Two dimensional boron nanosheets: synthesis, properties and applications. AB - Two dimensional boron nanosheets have been proposed theoretically for a decade, but were not experimentally synthesized until very recently. Research into their fundamental properties and device applications has since seen exponential growth. In this perspective, we review recent research progress related to 2D boron sheets, touching upon the topics of fabrication, properties, and applications, as well as discussing challenges and future research directions. We highlight the intrinsic electronic and mechanical properties of boron sheets, resulting from their diverse structures. Their facile fabrication and novel properties have inspired the design and demonstration of new nanodevices; however, further progress relies on resolving technical obstructions, like non-scalable fabrication techniques. We also briefly describe some feasible schemes that can address the associated challenges. It is expected that this fascinating material will offer tremendous opportunities for research and development in the foreseeable future. PMID- 30426986 TI - Significant structural relaxations of excited [n]cycloparaphenylene dications (n = 5-9). AB - Hoop-shaped macrocycles such as cycloparaphenylenes ([n]CPPs, where n denotes the number of phenylene rings) have attracted considerable attention in recent years because of their interesting properties arising from the highly strained aromatic structure and radially oriented p-orbitals. While the radical cation and dication states of [n]CPPs have been characterized, there is no information available about their excited states, which are expected to exhibit enhanced redox properties. In this study, we investigated the S1 state of [n]CPP2+ by transient absorption measurements in the visible and near-IR regions. The energy of the transient absorption peak exhibited a linear relationship with the reciprocal of the repeating unit, which indicated that the distribution of the excited state expanded with the size of the ring. In addition, smaller CPP2+s showed longer excited state lifetimes. Theoretical calculations suggested that there was a substantial structural relaxation of the smaller CPP2+s accompanying the changes in the charge distribution. Therefore, it was concluded that the smaller Franck Condon factor resulting from the considerable structural change and larger S1 energy were responsible for the longer S1 state lifetime of smaller CPP2+s. PMID- 30426987 TI - Use of an NIR-light-responsive CO nanodonor to improve the EPR effect in photothermal cancer treatment. AB - The carbon monoxide (CO)-carrying palladium nanosheet (PdNS-CO) was exploited as a photothermally triggered donor of CO. Irradiating material containing PdNS-CO with 808 nm-wavelength light caused a rapid heating of the material, triggering a release of CO. The enhanced permeability and retention (EPR) effect was found to be improved by such released CO and resulted in an increase in the accumulation of PdNS-CO at tumors and hence promoted its use in photothermal therapy (PTT) using a low laser power density. PMID- 30426988 TI - Improved visible-light absorbance of monolayer MoS2 on AlN substrate and its angle-dependent electronic structures. AB - In this paper, we performed density functional theory (DFT) calculations to investigate the geometric structures, electronic structures and visible-light absorbance of MoS2/AlN heterostructure based on van der Waals interaction. The calculated formation energy indicated that the designed MoS2/AlN heterostructure could be experimentally prepared. The Mo-N stacked MoS2/AlN heterostructure exhibited more considerable optical absorption in visible-light region than MoS2 and AlN monolayers. More interestingly, the band gaps were sensitive to strain, which led to an obvious shift of optical absorption spectra along the direction of the infrared region. The two most energetically favorable twisted MoS2/AlN heterostructures (Mo-N and Mo-HAl) had similar band structures, which were different from the non-twisted MoS2/AlN heterostructure. With different rotation angles, their band structures all exhibited an indirect band gap and almost had the same values of indirect band gaps, indicating that the indirect band gaps had no clear dependence on rotation angles. PMID- 30426989 TI - The effect of N-methylation on the conformational landscape of alanine: the case of N-methyl-l-alanine. AB - The non-proteinogenic amino acid N-methyl-l-alanine has been brought into the gas phase using laser ablation techniques and studied by high resolution chirped pulse and molecular-beam Fourier transform microwave spectroscopies coupled to supersonic expansion. Four conformers showing the three types of hydrogen bond interactions I (NHO[double bond, length as m-dash]C), II (OHN) and III (N-HO-H) have been unambiguously identified, based on the comparison of the experimental rotational and 14N nuclear quadrupole constants with the calculated ab initio values. The observation of a type III conformer evidences the role of methyl groups in both sides to impose the steric hindrance, precluding the relaxation from type III to type I conformers and explains the responsibility for the unique conformational landscape observed in the case of NMA. PMID- 30426990 TI - How efficient is Li+ ion transport in solvate ionic liquids under anion-blocking conditions in a battery? AB - An experimental analysis based on very-low-frequency (VLF) impedance spectra and the Onsager reciprocal relations is combined with advanced analysis of dynamic correlations in atomistic molecular simulations in order to investigate Li+ transport in solvate ionic liquids (SILs). SILs comprised of an equimolar mixture of a lithium salt with glyme molecules are considered as a promising class of highly concentrated electrolytes for future Li-ion batteries. Both simulations and experiments on a prototypical Li-bis(trifluoromethanesulfonyl)imide (TFSI) salt/tetraglyme mixture show that while the ionic conductivity and the Li+ transport number are quite high, the Li+ transference number under 'anion blocking conditions' is extremely low, making these electrolytes rather inefficient for battery applications. The contribution of cation-anion correlation to the total ionic conductivity has been extracted from both studies, revealing a highly positive contribution due to strongly anti-correlated cation anion motions. Such cation-anion anti-correlations have also been found in standard ionic liquids and are a consequence of the constraint of momentum conservation. The molecular origin of low Li+ transference number and the influence of anti-correlated motions on Li+ transport efficiency have been investigated as a function of solvent composition. We demonstrate that Li+ transference number can be increased either by reducing the residence time between Li+ and solvent molecules or by adding excessive solvent molecules that are not complexing with Li+. PMID- 30426991 TI - Cyanine platelet single crystals: growth, crystal structure and optical spectra. AB - Crystalline organic semiconducting materials are much in demand for multiple electronic and optoelectronic device applications. Here, solution grown ultrathin rhombic crystals of a trimethine carbocyanine anionic dye are used to establish relationships between structural and optical properties. The dye crystallized in the monoclinic space group P21/c featuring alternating layers of molecules in two different herringbone type patterns, with perchlorate counterions located mostly within one of the two layers. Micro transmittance spectroscopy revealed a broadened spectrum compared to those obtained in solution and in an amorphous thin film. Using polarized light, transmission spectroscopy revealed strong low energy and weak high-energy bands polarized along the crystallographic b- and c axis, respectively. Using the extended dipole approximation, significant exciton couplings are predicted between neighboring molecules in the crystal, of the order of the intrinsic monomer reorganization energies associated with nuclear relaxation after excitation, depicting a complex spectral scenario. The exciton coupling pattern explains the relative energies of the b- and c-polarized components but the observed intensities are opposite to expectations based on chromophore alignment within the crystal. PMID- 30426992 TI - Unraveling the highest oxidation states of actinides in solid-state compounds with a particular focus on plutonium. AB - The nature and extent of the highest oxidation state (HOS) in solid-state actinide compounds are still unexplored compared with those of small molecules, and there is burgeoning interest in studying the actinide-ligand bonding nature in the condensed state. A comprehensive understanding of the electronic structure and unraveling the possibility of a HOS are of paramount importance in solid state actinide chemistry. Here, we report the physical OS of the early to middle actinides (Th -> Cm) in solid-state compounds via a more rigorous quantum mechanical definition of OS under the DFT+U theoretical frameworks for the first time. This work implies that the highest physical OS of the Pu solid ion is PuV in PuO2F and PuOF4, which can be achieved via tuning the ligand, thus improving our knowledge of oxidation states and chemical bonding in high OS solid-state compounds. We highlight the importance of ligand design in terms of the actinide HOS, employing a highly electronegative ligand and showing the capacity to form multiple bonds. PMID- 30426993 TI - A linear trinuclear ferrous single molecule magnet. AB - A linear trinuclear ferrous complex [FeII3(pymp)4(MeOH)2][BPh4]2.2MeOH (1) (Hpymp = 2-[(pyridine-2-ylimine)-methyl]phenol) was isolated and characterized both structurally and magnetically. A magnetic study revealed the ferromagnetic coupling (J = +3.54 cm-1) within the [FeII3] units and uniaxial magnetic anisotropy (D = -1.21 cm-1) of the molecule. Slow relaxation of the magnetization at below 5 K and an effective energy barrier of 26.0(2) cm-1 under a 1200 Oe applied dc field were evidenced. Moreover, clear magnetic hysteresis loops were observed at below 2.5 K, which further corroborated the single-molecule magnet behavior of 1. PMID- 30426994 TI - Theoretical evaluation of thermal decomposition of dichlorosilane for plasma enhanced atomic layer deposition of silicon nitride: the important role of surface hydrogen. AB - Silicon nitride (SiN) thin films have been widely employed for various applications including microelectronics, but their deposition presents a challenge especially when highly conformal layers are necessary on nanoscale features with high aspect ratios. Plasma-enhanced atomic layer deposition (PEALD) has been demonstrated to be a promising technique for controlled growth of SiN thin films at relatively low temperatures (<400 degrees C), in which thermal decomposition of Si-containing precursors on a N-rich surface is a critical step. Based on periodic density functional theory calculations, we present potential underlying mechanisms leading to facile thermal decomposition of dichlorosilane (DCS, SiH2Cl2) on the N-rich beta-Si3N4(0001) surface. Our study highlights the importance of high hydrogen content on the N-rich surface, rendering primary and secondary amine groups. When the N-rich beta-Si3N4(0001) surface is fully hydrogenated, the molecular adsorption of DCS is predicted to be exothermic by 0.6 eV. In this case, DCS decomposition appears to be initiated by nucleophilic attack by an amine lone-pair on the electrophilic Si, leading to the formation of a DCS-amine adduct intermediate followed by release of a Cl- anion and a proton. The predicted activation barrier for the DCS decomposition reaction is only 0.3 eV or less, depending on its adsorption configuration. We also discuss the formation and desorption of HCl, the subsequent formation and nature of Si-N bonds, and the interaction between adsorbed DCS molecules. While clearly demonstrating the advantageous features of DCS as a Si precursor, this work suggests that the thermal decomposition of Si precursors, and in turn the ALD kinetics and resulting film quality, can be strongly influenced by surface functional groups, in addition to product accumulation and precursor coverage. PMID- 30426995 TI - Two Ce3+ centers induced broadband emission in Y3Si6N11:Ce3+ yellow phosphor. AB - The Y3Si6N11:Ce3+ yellow phosphor shows a well-known ~150 nm broad emission band, exhibiting a potential application in UV or blue based white LEDs. We report the observation of two Ce3+ emitting centers, the superposition of which forms the broad emission band. One center has a green emission band peaked at 539 nm (Ce1) with the first excitation band at 420 nm. The other has a red emission band peaked at 600 nm (Ce2) with the first excitation band at 485 nm. The two Ce3+ centers are assigned to the substitution for two Y sites in Y3Si6N11. It was found that the Ce2 emission intensity is continuously enhanced relative to that of Ce1 with an increasing Ce3+ concentration, thus leading to a redshift of the broadband. Meanwhile, a more notable fluorescence lifetime shortening of Ce1 compared to Ce2 with an increasing Ce3+ concentration was observed. These results suggest the occurrence of energy transfer from Ce1 to Ce2. The temperature dependent luminescence intensity of Y3Si6N11:Ce3+ was also studied in the range of 93 to 473 K. PMID- 30426996 TI - Ultralight supercapacitors utilizing waste cotton pads for wearable energy storage. AB - Successful popularization of wearable energy storage devices lies in the exploitation of scalable fabrication technologies that are based on economically viable materials. Herein, we reveal that discarded cotton pads can be used as a cost-efficient substrate for the in situ polymerization of pyrrole and exhibited good mechanical flexibility, lightness, and high conductivity. To extend the applications of the resulting PPy-coated cotton pads (PCPs) to the supercapacitor field, a layer of MnO2 nanosheets was further decorated on the surface of PCPs (PCPs@MnO2) by a simple electrochemical deposition technique. The PPy coating not only improves the electrical conductivity of the cotton pads, but also increases the contact between the active materials and the cotton fibers. Amazingly, ultrathin (~ 0.8 mm) flexible solid-state asymmetric supercapacitors (ASCs) using PCPs@MnO2 as the positive electrode and active carbon coated on PCPs (PCPs@AC) as the negative electrode display a high areal capacitance of 1.21 F cm-2 at 1 mA cm 2, and a high energy density of 6.8 mW h cm-3 at a power density of 11.2 mW cm-3, which can also be tailored and folded into various shapes with only slight capacitance fading. These findings demonstrate that the prepared advanced ultralight, flexible and renewable cotton pads hold great promise for practical application in wearable energy storage systems with high cost effectiveness and scalability. PMID- 30426997 TI - The value of enzymes in solar fuels research - efficient electrocatalysts through evolution. AB - The reasons for using enzymes as tools for solar fuels research are discussed. Many oxidoreductases, including components of membrane-bound electron-transfer chains in living organisms, are extremely active when directly attached to an electrode, at which they display their inherent catalytic activity as electrical current. Electrocatalytic voltammograms, which show the rate of electron flow at steady-state, provide direct information on enzyme efficiency with regard to optimising use of available energy, a factor that would have driven early evolution. Oxidoreductases have evolved to minimise energy wastage ('overpotential requirement') across electron-transport chains where rate and power must be maximised for a given change in Gibbs energy, in order to perform work such as proton pumping. At the elementary level (uncoupled from work output), redox catalysis by many enzymes operates close to the thermodynamically reversible limit. Examples include efficient and selective electrocatalytic reduction of CO2 to CO or formate - reactions that are very challenging at the chemistry level, yet appear almost reversible when catalysed by enzymes. Experiments also reveal the fleeting existence of reversible four-electron O2 reduction and water oxidation by 'blue' Cu oxidases, another reaction of great importance in realising a future based on renewable energy. Being aware that such enzymes have evolved to approach perfection, chemists are interested to know the minimal active site structure they would need to synthesise in order to mimic their performance. PMID- 30426998 TI - Recent applications of C-H functionalization in complex natural product synthesis. AB - In this review, recent examples featuring C-H functionalization in the synthesis of complex natural products are discussed. A focus is given to the way in which C H functionalization can influence the logical process of retrosynthesis, and the review is organized by the type and method of C-H functionalization. PMID- 30426999 TI - Disorder induced polymorphic transitions in the high hydrogen density compound Sr(BH4)2(NH3BH3)2. AB - The new compound Sr(BH4)2(NH3BH3)2 has been synthesized and characterized with in situ powder X-ray diffraction and fast (28 or 60 kHz) magic angle spinning 1H, 11B and 15N NMR and structurally optimized with density functional theory calculations. This investigation reveals complex structural rearrangements for this compound as a function of temperature. A room temperature orthorhombic polymorph, alpha-Sr(BH4)2(NH3BH3)2, with the space group symmetry Pbca, has been determined with a layered structure of alternating ammonia borane and Sr(BH4)2, partially stabilized by dihydrogen bonding. Surprisingly the crystal symmetry is lowered upon heating, as evidenced both by in situ synchrotron powder X-ray diffraction and 11B MAS NMR data, resulting in an intermediate polymorph, beta' Sr(BH4)2(NH3BH3)2, present from ~65 to 115 degrees C. beta-Sr(BH4)2(NH3BH3)2, a sub structure of the beta'-polymorph showing higher symmetry with the space group symmetry Aba2, forms upon further heating. Ab initio molecular dynamics simulations show that the ammonia borane molecule can dynamically alternate between a bidentate and a tridentate coordination to Sr at finite temperature. The dynamic properties of the ammonia borane molecule in the solid state are suggested to cause the observed structural complexity. Based on simultaneous thermogravimetric analysis, differential scanning calorimetry and mass spectrometry, the decomposition of the compound was investigated showing a stabilization of ammonia borane in the structure relative to other metal borohydride ammonia boranes and neat ammonia borane. PMID- 30427000 TI - Interplay between H-bonding and interpenetration in an aqueous copper(ii) aminoalcohol-pyromellitic acid system: self-assembly synthesis, structural features and catalysis. AB - Two new copper(ii) coordination compounds, [Cu(H1.5mdea)2]2(H2pma) (1a) and [{Cu2(MU-Hmdea)2}2(MU4-pma)]n.2nH2O (1b), were self-assembled at different temperatures from the same multicomponent reaction system, comprising copper(ii) nitrate, N-methyldiethanolamine (H2mdea), pyromellitic acid (H4pma), and potassium hydroxide. Products 1a and 1b were isolated as microcrystalline solids and fully characterized and their structures were established by single-crystal X ray diffraction. Compound 1a features the bis-aminoalcohol(ate) monocopper(ii) units and H2pma2- anions that are multiply interconnected by strong H-bonds into a firm 2D H-bonded layer. Compound 1b reveals the bis-aminoalcoholate dicopper(ii) motifs that are interlinked by the MU4-pma4- spacers into a 3D + 3D interpenetrated metal-organic framework. From a topological perspective, both networks of 1a and 1b are uninodal and driven by similar 4-connected H2pma2- or pma4- nodes, but result in distinct sql and dia topologies, respectively. Compound 1a was applied as an efficient catalyst for two model cycloalkane functionalization reactions: (1) oxidation by H2O2 to form cyclic alcohols and ketones and (2) hydrocarboxylation by CO/H2O and S2O82- to form cycloalkanecarboxylic acids. The substrate scope, effects of various reaction parameters, selectivity and mechanistic features were also investigated. PMID- 30427001 TI - Pathways for creation and annihilation of nanoscale biomembrane domains reveal alpha and beta-toxin nanopore formation processes. AB - Raft-like functional domains with putative sizes of 20-200 nm and which are evolving dynamically are believed to be the most crucial regions in cellular membranes which determine cell signaling and various functions of cells. While the actual sizes of these domains are believed to vary from cell to cell no direct determination of their sizes and their evolution when cells interact with external agents like toxins and relevant biomolecules exists. Here, we report the first direct determination of the size of these nanoscale regions in model raft forming biomembranes using the method of super-resolution stimulated emission depletion nanoscopy coupled with fluorescence correlation spectroscopy (STED FCS). We also show that the various pathways for creation and destruction of such nanoscale membrane regions due to interaction with prototypical alpha and beta nanopore-forming toxins, can reveal the nature of the respective pore formation processes. The methodology, in turn, establishes a new nano-biotechnological protocol which could be very useful in preventing their cytotoxic effects in particular but also enable microscopic understanding of biomolecule-cell membrane interactions in general. PMID- 30427002 TI - The use of a semi-flexible bipyrimidyl ligand for the construction of azide-based coordination polymers: structural diversities and magnetic properties. AB - Using a semi-flexible quadritopic N-donor ligand, 5,5'-bipyrimidine (bpym), four new azide-based coordination polymers, {[Co2(bpym)(N3)4].MeCN}n (1), [Co(bpym)(N3)2]n (2), [Mn(bpym)(N3)2]n (3) and {[Ni3(bpym)3(N3)6].2H2O}n (4) were synthesized and structurally characterized. With bpym aciting as a planar MU4 bridging ligand, the resulting compound, 1, comprised a net-to-net 3D framework composed of two grid-like 44-subnets, Co(EE-N3)2-based and Co2(bpym)-based sheets, with a (4,6)-connected (42.64)(48.66.8)2 topology. Compound 2 adopted a 3D pillared-layer framework with a pts topology based on six-connected Co(ii) centers and four-connected twisted MU4-bpym ligands, while compound 3 adopted a 3D pillared-layer structure with a bcu topology based on Co(EE-N3)2-based 44 layers and two-connected twisted MU2-bpym pillars. In contrast, compound 4 had a 2D layered structure composed of 1D Ni(ii) chains with alternating double EE-N3 and double EO-N3 bridges in an EE-EE-EO sequence and two-connected bpym linkers. The magnetic properties of 1-4 were investigated. The findings indicate that 1 showed weak ferromagnetism due to spin-canted antiferromagnetism and long-range magnetic ordering with a critical temperature, TC = 12.6 K. In contrast, compound 2 exhibited weak ferromagnetism due to spin-canted antiferromagnetism and antiferromagnetic ordering. In compound 3, antiferromagnetic interactions dominated between the Mn(ii) centers through the EE-N3 bridges. In compound 4, the antiferromagnetic and ferromagnetic interactions were transmitted through double EE-N3 and double EO-N3 bridges, respectively, resulting in an AF-AF-F topological ferrimagnetic Ni(ii) chain. Furthermore, field-induced magnetic phase transitions of metamagnetism for 2 and 4 were also observed below TN = 3.6 K and 8.2 K, respectively. PMID- 30427003 TI - Eu3+/Tb3+ functionalized Bi-based metal-organic frameworks toward tunable white light emission and fluorescence sensing applications. AB - The rational design strategy to construct lanthanide ion functionalized metal organic frameworks (MOFs) has attracted tremendous attention as they are promising candidates for developing novel luminescence materials and optical sensors owing to their intense, long-lived and tunable luminescence performances. In this work, a series of Eu3+/Tb3+ singly doped or codoped bismuth-based MOFs were prepared under in situ facile solvothermal conditions using BiOBr nanoplates as bismuth resources. A red-green-blue-based trichromatic white-light emission can be finely achieved by modulating the doping ratio of Eu3+/Tb3+ in the blue emitting Bi-MOF host material and such photoluminescence tuning can also be realized by controlling the excitation wavelength. In addition, the Eu3+/Tb3+ singly incorporated Bi-MOF can serve as a multifunctional fluorescent probe for sensing Fe3+ and Cr2O72- ions in aqueous solution, as well as small organic pollutants of acetone molecules, and their sensing mechanisms have also been analyzed. These lanthanide ion functionalized Bi-MOF materials exhibit great potential in exploring white-light emitting devices and construction of supersensitive multifunctional sensors. PMID- 30427004 TI - The relationship between lipid phytochemicals, obesity and its related chronic diseases. AB - The prevalence of obesity has received global attention in recent years, and lipid consumption has been considered as one of the direct reasons for obesity and related diseases. However, increasing evidence has indicated that edible vegetable oils could exert non-negligible physiological benefits in the daily diet, including suppression of appetite, lowering of blood lipids, prevention of adipocyte synthesis, and reduction of inflammatory response. Bioactive phytochemicals in lipids and oils, such as tocopherol, phenolic compounds, and phytosterol, play an important role in these effects according to in vitro and in vivo studies. For these reasons, the present review focusses on minor bioactive components in oil and their anti-obesity effects, aiming to provide a systematic overview of the relationships between these minor components and obesity and related diseases. PMID- 30427005 TI - Synthesis, characterization and mass-spectrometric analysis of [LSn(IV)F4-x]x+ salts [L = tris ((1-ethyl-benzoimidazol-2-yl)methyl)amine, x = 1-4]. AB - A series of complexes with the formulae [(BIMEt3)SnF4-x][OTf]x with x = 1-4 has been synthesized by successive fluoride abstraction from SnF4 with TMSOTf in the presence of the tetradentate nitrogen donor BIMEt3 (tris ((1-ethyl-benzoimidazol 2-yl)methyl)amine). Single crystal X-ray diffraction and heteronuclear NMR spectroscopic analysis provided insight into these new main group cations. Electrospray ionization mass spectrometric analysis on solutions containing the different salts allowed for successful detection of the cations [(BIMEt3)SnF]3+, [(BIMEt3)SnF2]2+ and [(BIMEt3)SnF3]+. PMID- 30427006 TI - Solvation energies of the proton in methanol revisited and temperature effects. AB - We report in this work the absolute solvation enthalpies and the absolute solvation free energies of the proton in methanol at temperatures ranging from 20 to 340 K and an extrapolation to a desired temperature. To achieve this, we thoroughly investigated the structures of neutral methanol clusters (MeOH)n=2-10 and those of the protonated methanol decamer H+(MeOH)n=10 at the M06-2X/6 31++g(d,p) level of theory. As a result, we noted that up to the octamer, the population of the neutral methanol clusters is constituted by cyclic isomers. For nonamers and decamers, both cyclic and branched cyclic isomers contribute to the population of the clusters. Moreover, folded or distorted cyclic isomers are the most favored at low temperatures, while higher temperatures favored the flat cyclic isomers for n = 7-9. For the methanol decamer, a branched cyclic isomer is found to be the most favored at low temperatures. Elsewhere, the infrared spectra of all the investigated structures are provided and compared against experiment. The binding energy of neutral methanol is calculated at the X/6-31++g(d,p) levels of theory, where X represents the DFT functionals M062X, APFD, MN15, omegaB97XD and M08HX. It is observed that these functionals provide results in good agreement with the experimental vaporization enthalpy. However, the APFD functional shows the best performance followed by the other functionals in the order of M062X, MN15 and omegaB97XD. Furthermore, the calculated solvation energies of the proton in methanol at these various levels of theory and at MP2/6 31++g(d,p) show that the omegaB97XD functional shows the best performance in evaluating the solvation enthalpy and the solvation free energy of the proton in methanol and the calculated values are respectively -1140.5 kJ mol-1 and -1100.7 kJ mol-1 at room temperature. Elsewhere, we noted that the absolute solvation enthalpy of the proton in methanol is less affected by a change in temperature. However, the absolute solvation free energy of the proton in methanol remains constant only at temperatures lower than 180 K. For higher temperatures, the absolute solvation free energy of the proton in methanol increases as a linear function of the temperature and can be approximated by DeltaGm(H+,T) = 0.200T - 1161.4. PMID- 30427012 TI - Self-supported bimetallic Ni-Co compound electrodes for urea- and neutralization energy-assisted electrolytic hydrogen production. AB - Hydrogen represents one of the most promising renewable energy sources for next generation energy systems, however, its large scale production is high cost and high energy. A proof-of-concept alkaline-acid electrolyzer is reported here that can significantly reduce the amount of electrical energy consumed in electrolytic hydrogen production, implemented by the development of self-supported bimetallic Ni-Co compound electrodes used as the anode and cathode, respectively, where a urea oxidation reaction (UOR) occurs at the alkaline Ni0.67Co0.33(OH)2 nanosheet anode, coupled to the hydrogen evolution reaction (HER) at the acidic Ni0.67Co0.33S2 cathode. The asymmetric-electrolyte electrolyzer can efficiently harvest two kinds of energies, i.e. electrochemical neutralization energy (ENE) and electrochemical urea oxidation energy, to assist electrolytic hydrogen production using waste urea, acid, and base. The as-designed electrolyzer can deliver a current density of 10 mA cm-2 for electrolytic H2 generation with a rather low applied voltage of 0.54 V, with the potential to use up waste urea, acid and base. PMID- 30427014 TI - Ultrafine and highly dispersed platinum nanoparticles confined in a triazinyl containing porous organic polymer for catalytic applications. AB - The fabrication of stable porous organic polymers (POPs) with heteroatoms that can firmly anchor noble metal nanoparticles (NPs) is a challenging and significant task for heterogeneous catalysis. In the current work, we used piperazine and cyanuric chloride as precursors and successfully fabricated a PC POP material. Then, through the impregnation method and subsequently the reduction method, ultrafine Pt NPs were confined in the PC-POP with a high dispersion. The Pt NP active sites are accessible due to the uniform mesopores of the PC-POP that facilitate diffusion and mass transfer. The organic cages and nitrogen atoms in the PC-POP frameworks can make the Pt NPs stably anchored in the PC-POP during the catalytic process. The obtained Pt@PC-POP nanocatalyst showed excellent catalytic activity and good recyclability in the selective hydrogenation of halogenated nitrobenzenes and catalytic hydrolysis of ammonia borane as compared with many other reported noble metal catalysts. PMID- 30427015 TI - Switchable synchronisation of pirouetting motions in a redox-active [3]rotaxane. AB - In this study, the crown/ammonium [3]rotaxane R2 is reported which allows a switchable synchronisation of wheel pirouetting motions. The rotaxane is composed of a dumbbell-shaped axle molecule with two mechanically interlocked macrocycles which are decorated with a redox-active tetrathiafulvalene (TTF) unit. Electrochemical, spectroscopic, and electron paramagnetic resonance experiments reveal that rotaxane R2 can be reversibly switched between four stable oxidation states (R2, R2+, R22(+), and R24+). The oxidations enable non-covalent, cofacial interactions between the TTF units in each state-including a stabilised mixed valence (TTF2)+ and a radical-cation (TTF+)2 dimer interaction-which dictate a syn (R2, R2+, and R22(+)) or anti (R24+) ground state co-conformation of the wheels in the rotaxane. Furthermore, the strength of these wheel-wheel interactions varies with the oxidation state, and thus electrochemical switching allows a controllable synchronisation of the wheels' pirouetting motions. DFT calculations explore the potential energy surface of the counter-rotation of the two interacting wheels in all oxidation states. The controlled coupling of pirouetting motions in rotaxanes can lead to novel molecular gearing systems which transmit rotational motion by switchable non-covalent interactions. PMID- 30427016 TI - Solvothermal synthesis of cesium lead halide perovskite nanowires with ultra-high aspect ratios for high-performance photodetectors. AB - One-dimensional (1D) inorganic perovskite nanowires (NWs) have attracted promising attention for application in the fields of photodetection, lasers and lighting due to their outstanding optoelectronic properties. However the direct synthesis of highly pure all-inorganic perovskite NWs with well-defined morphologies and compositions still remains challenging. Here we report the controllable synthesis of brightly emitting cesium lead halide CsPbX3 (X = Cl, Br) NWs and their assembly into high-performance photodetector nanodevices. High quality CsPbX3 NWs have been directly synthesized via a solvothermal method without using post-synthetic anion-exchange reactions. The NWs are single crystalline, with uniform diameters of ~10 nm and lengths of up to tens of microns, showing ultra-high aspect ratios. Both CsPbCl3 and CsPbBr3 NWs show excellent photoluminescence (PL) characteristics with narrow emission spectra and high PL quantum yields (PLQYs). The photodetectors constructed on the CsPbX3 NWs and interdigital electrodes (with interdigitation widths up to 100 MUm) exhibit promising photoelectric properties, achieving high switching ratios (5.8 * 103 for CsPbCl3 NW devices and 1.1 * 103 for CsPbBr3 NW devices) and fast response time. The present solvothermal approach is controllable, convenient, and is easily realized for quantifiable preparation, and can further promote the application of the all-inorganic perovskite NWs in the optoelectronic field. PMID- 30427017 TI - Improved stability of CsPbBr3 perovskite quantum dots achieved by suppressing interligand proton transfer and applying a polystyrene coating. AB - All-inorganic lead halide perovskite quantum dots (PQDs) have shown great promise for optoelectronic applications due to their unique optical and electrical properties. However, their poor stability against moisture, UV light or thermal attacks greatly hinders their practical applications. One of the reasons for this instability is the proton transfer between oleic acid (OA) and oleylamine (OLA), which induces serious ligand loss. The idea of this work is to prevent the interligand proton transfer by replacing OLA with cetyl trimethylammonium bromide (CTAB) that cannot be protonated. The synthesized CsPbBr3 PQDs in solution show high photoluminescence quantum yields up to 71% and also exhibit higher stability against acetone than the counterparts synthesized using oleylammonium bromide (OLABr). Subsequently, CsPbBr3 PQDs with a peak wavelength of 515 nm (g-CsPbBr3) synthesized using CTAB are further composited with a polymer of carboxyl functionalized polystyrene (cPS). The composite shows enhanced thermal and moisture stability. It is demonstrated that this green-emitting composite can produce high color gamut (130%) white light-emitting diodes when combined with the K2SiF6:Mn4+ phosphor and a blue InGaN chip, enabling its use in display backlights. PMID- 30427018 TI - Nano-SQUIDs with controllable weak links created via current-induced atom migration. AB - As the most sensitive magnetic field sensor, the superconducting quantum interference device (SQUID) became an essential component in many applications due to its unmatched performance. Through recently achieved miniaturization, using state-of-the-art fabrication methods, this fascinating device extended its functionality and became an important tool in nanomaterial characterization. Here, we present an accessible and yet powerful technique of targeted atom displacement in order to reduce the size of the weak links of a DC nano-SQUID beyond the limits of conventional lithography. The controllability of our protocol allows us to characterize in situ the full superconducting response after each electromigration step. From this in-depth analysis, we reveal an asymmetric evolution of the weak links at cryogenic temperatures. A comparison with time resolved scanning electron microscopy images of the atom migration process at room temperature confirms the peculiar asymmetric evolution of the parallel constrictions. Moreover, we observe that when electromigration has sufficiently reduced the junction's cross section, superconducting phase coherence is attained in the dissipative state, where magnetic flux readout from voltage becomes possible. PMID- 30427021 TI - Near-field digital holography: a tool for plasmon phase imaging. AB - The knowledge of the phase distribution of the near electromagnetic field has become very important for many applications. However, its experimental observation is still technologically a very demanding task. In this work, we propose a novel method for the measurement of the phase distribution of the near electric field based on the principles of phase-shifting digital holography. In contrast to previous methods the holographic interference occurs already in the near field and the phase distribution can be determined purely from the scanning near-field optical microscopy measurements without the need for additional far field interferometric methods. This opens a way towards on-chip phase imaging. We demonstrate the capabilities of the proposed method by reconstruction of the phase difference between interfering surface plasmon waves and by imaging the phase of a single surface plasmon wave. We also demonstrate a selectivity of the method towards individual components of the field. PMID- 30427022 TI - Chelation-assisted assembly of multidentate colloidal nanoparticles into metal organic nanoparticles. AB - We propose a chelation-assisted assembly of multidentate CNs into metal-organic nanoparticles (MONs). Multidentate CNs functionalized with coordination sites participate equally as organic linkers in MON construction, which is driven by chelation between metal ions and coordination sites. MONs assembled from Au nanoparticles display particle number- and size-dependent optical properties. In addition, the resulting CN-assembled MONs give evidence that assembly was dictated by the multidentate surface ligand rather than the size, shape or material of CNs. With this chelation-assisted strategy, it is possible to control the number of assembled CNs and build the connections between them. PMID- 30427023 TI - Siderophore profiling of co-habitating soil bacteria by ultra-high resolution mass spectrometry. AB - The chemical structure of organic molecules profoundly impacts their interactions with metal ions and mineral phases in soils. Understanding the sources and cycling of metal-chelating compounds is therefore essential for predicting the bioavailability and transport of metals throughout terrestrial environments. Here we investigate the molecular speciation of organic molecules that solubilize trace metals in calcareous soils from Eastern Washington. Ultra-high performance Fourier transform ion cyclotron resonance mass spectrometry at 21 Tesla enabled fast and confident detection and identification of metal chelators that are produced by microbes that inhabit these soils based on screening for features that match diagnostic metal isotope patterns. We compared two approaches, one based on direct infusion using the incorporation of a rare isotope to validate true iron-binding features, and another based on separation with liquid chromatography and detection of isotopologues with coherent elution profiles. While the isotopic exchange method requires significantly shorter analysis time, nearly twice as many features were observed with liquid chromatography mass spectrometry (LCMS), mostly due to the reduction in ion suppression where major features limit the sensitivity of minor features. In addition, LCMS enabled the collection of higher quality fragmentation spectra and facilitated feature identification. Siderophores belonging to four major classes were identified, including ferrioxamines, pseudobactins, enterobactins, and arthrobactins. Each of these siderophores likely derives from a unique member of the microbial community, and each possesses different chemical characteristics and uptake pathways, likely contributing to fierce competition for iron within these soils. Our results provide insight into the metabolic pathways by which microbes that co inhabit calcareous soils compete for this essential micronutrient. PMID- 30427024 TI - A theory of waveguide design for plasmonic nanolasers. AB - We propose a theory for the waveguide design and analysis for plasmonic nanolasers by reformulating the fundamental waveguide requirements. This theory does not rely on further optimizing previously used structures, but examines each possible design without prejudice. Our exploration of one-dimensional (i.e., layered) plasmonic nanowaveguide geometries and the subsequent extension to 2D structures not only provides a deep understanding of the characteristics of currently used designs, but also leads to superior structures with the potential to address long-standing challenges in plasmonic nanolasers. In addition, we discover analogies between the reformulated fundamental requirements for the waveguide for nanolasers and nanoscale four-wave mixing (FWM) devices. Therefore, after a slight modification, our theory can also be applied to the waveguide design for plasmonic FWM devices. PMID- 30427025 TI - Electrostatic interaction of particles trapped at fluid interfaces: effects of geometry and wetting properties. AB - The electrostatic interaction between pairs of spherical or macroscopically long, parallel cylindrical colloids trapped at fluid interfaces is studied theoretically for the case of small inter-particle separations. Starting from the effective interaction between two planar walls and by using the Derjaguin approximation, we address the issue of how the electrostatic interaction between such particles is influenced by their curvatures and by the wetting contact angle at their surfaces. Regarding the influence of curvature, our findings suggest that the discrepancies between linear and nonlinear Poisson-Boltzmann theory, which have been noticed before for planar walls, also occur for spheres and macroscopically long, parallel cylinders, though their magnitude depends on the wetting contact angle. Concerning the influence of the wetting contact angle theta simple relations are obtained for equally sized particles which indicate that the inter-particle force varies significantly with theta only within an interval around 90 degrees . This interval depends on the Debye length of the fluids and on the size of the particles but not on their shape. For unequally sized particles, a more complicated relation is obtained for the variation of the inter-particle force with the wetting contact angle. PMID- 30427026 TI - Self-immobilized Pd nanowires as an excellent platform for a continuous flow reactor: efficiency, stability and regeneration. AB - Despite extensive use of Pd nanocrystals as catalysts, the realization of a Pd based continuous flow reactor remains a challenge. Difficulties arise due to ill defined anchoring of the nanocrystals on a substrate and reactivity of the substrate under different reaction conditions. We demonstrate the first metal (Pd) nanowire-based catalytic flow reactor that can be used across different filtration platforms, wherein, reactants flow through a porous network of nanowires (10-1000 nm pore sizes) and the product can be collected as filtrate. Controlling the growth parameters and obtaining high aspect ratio of the nanowires (diameter = ~13 nm and length > 8000 nm) is necessary for successful fabrication of this flow reactor. The reactor performance is similar to a conventional reactor, but without requiring energy-expensive mechanical stirring. Synchrotron-based EXAFS studies were used to examine the catalyst microstructure and Operando FT-IR spectroscopic studies were used to devise a regenerative strategy. We show that after prolonged use, the catalyst performance can be regenerated up to 99% by a simple wash-off process without disturbing the catalyst bed. Thus, collection, regeneration and redispersion processes of the catalyst in conventional industrial reactors can be avoided. Another important advantage is avoiding specific catalyst-anchoring substrates, which are not only expensive, but also non-universal in nature. PMID- 30427027 TI - Controlled p-type substitutional doping in large-area monolayer WSe2 crystals grown by chemical vapor deposition. AB - Tungsten diselenide (WSe2) is a particularly interesting 2D material due to its p type conductivity. Here we report a systematic single-step process to optimize crystal size by variation of multiple growth parameters resulting in hexagonal single crystals up to 165 MUm wide. We then show that these large single crystals can be controllably in situ doped with the acceptor Niobium (Nb). First principles calculations suggest that substitutional Nb doping of W would yield p doping with no gap trap states. When used as the active layer of a field effect transistor (FET), doped crystals exhibit conventional p-type behavior, rather than the ambipolar behaviour seen in undoped WSe2 FETs. Nb-doped WSe2 FETs yield a maximum field effect mobility of 116 cm2 V-1 s-1, slightly higher than its undoped counterpart, with an on/off ratio of 106. Doping reduces the contact resistance of WSe2, reaching a minimum value of 0.55 kOmegaMUm in WSe2 FETs. The areal density of holes in Nb-doped WSe2 is approximately double that of undoped WSe2, indicating that Nb doping is working as an effective acceptor. Doping concentration can be controlled over several orders of magnitudes, allowing it to be used to control: FET threshold voltage, FET off-state leakage, and contact resistance. PMID- 30427028 TI - One-scan fluorescence emission difference nanoscopy developed with excitation orthogonalized upconversion nanoparticles. AB - We experimentally realized one-scan fluorescence emission difference nanoscopy (FED) by simultaneously imaging two different color emissions of NaYF4:Er3+@NaYF4@NaYF4:Yb3+/Tm3+ upconversion nanoparticles. Under the irradiation of two synchronized laser beams, a solid 940 nm beam and a hollow 808 nm beam, green emission of Er3+ and blue emission of Tm3+ can be orthogonally generated and collected. After simple subtraction, a resulting super-resolution image featuring 54 nm resolution was obtained. This strategy of excitation orthogonality would greatly improve the imaging speed and the applicability of FED nanoscopy. PMID- 30427029 TI - New stable isomorphous Ag34 and Ag33Au nanoclusters with an open shell electronic structure. AB - A novel atom-precise 3-electron homosilver nanocluster (Ag34) has been assembled for the first time by the oxidation of a thiol. When adding AuPPh3Cl in the reaction, we obtained an alloyed Ag33Au nanocluster, which shares a similar framework as that of Ag34, in which a doping Au atom replaced a core silver atom. Notably, both Ag34 and alloyed Ag33Au demonstrated exceptional stability in solution and solid state over 3 months, which is difficult to explain by using the superatom model. Such Ag34 and Ag33Au complexes complement the nanoclusters with an open shell electronic structure and unveil a new approach to synthesize monodisperse nanoclusters under mild conditions. PMID- 30427030 TI - Responsive peptide-based supramolecular hydrogels constructed by self-immolative chemistry. AB - Peptide-based supramolecular hydrogels that are stimuli-responsive under aqueous conditions have many potential biological applications, including drug delivery and sensing. Herein, we reported a series of responsive peptide-based supramolecular hydrogels that respond to glutathione (GSH), nitric oxide (NO) and hydrogen sulfide (H2S), which are biologically important signaling molecules. The responsive hydrogelators were designed by "self-immolative" chemistry and constructed by using self-immolative groups to modify short peptides. The self immolative capping group could be removed in the presence of a corresponding trigger, thus causing gel-sol phase transitions. The potential of our responsive hydrogels for drug release was also demonstrated in this study. Our study offered several candidates of responsive hydrogels for sensing and drug delivery. PMID- 30427031 TI - Chiral selenide-catalyzed enantioselective synthesis of trifluoromethylthiolated 2,5-disubstituted oxazolines. AB - Chiral selenide-catalyzed enantioselective trifluoromethylthiolation of 1,1 disubstituted alkenes is disclosed. By this method, a variety of chiral trifluoromethylthiolated 2,5-disubstituted oxazolines were obtained in good yields with high enantioselectivities. This work not only provides a new pathway for the synthesis of chiral oxazolines, but also expands the library of chiral trifluoromethylthiolated molecules. PMID- 30427032 TI - Impregnation of paper with cellulose nanocrystal reinforced polyvinyl alcohol: synergistic effect of infrared drying and CNC content on crystallinity. AB - Paper was impregnated with neat polyvinyl alcohol (PVOH) or cellulose nanocrystal (CNC) reinforced PVOH, and dried by infrared radiation. Complex phenomena involved during paper impregnation and drying have been rarely investigated in the scientific literature, although these steps are crucial for the properties of the ensuing paper. The drying kinetics was studied and it showed that CNC tends to reduce the skin effect classically observed during fast PVOH drying. Furthermore, the nanoparticles induced faster water removal at the end of the drying step, which can be explained by an increase of the absorbed heat flux density. In addition, PVOH crystallization mechanisms have been studied through classical equations (Avrami, and Arrhenius) and a model (the Hoffman-Weeks method) and it was proved that both the drying conditions and the presence of CNC act on the crystallization of the polymer. PMID- 30427033 TI - Drop mobility on superhydrophobic microstructured surfaces with wettability contrasts. AB - Manipulation of drop motion has attracted considerable attention recently as it is pertinent to industrial/biological applications such as microfluidics. Wettability gradients/contrasts applied to microtextured, superhydrophobic surfaces are probable candidates for engineering drop motion by virtue of their wettability controllability and low contact angle hysteresis. In the present work, we present a systematic study of drop mobility induced via wettability contrasts. A millimetre-sized water drop, placed on the boundary between two surfaces with distinct, uniform arrays of pillars, immediately moved toward the surface more densely populated with asperities, which was relatively more hydrophilic. The velocity of the motion was found to increase proportionally with the difference in pillar densities on each surface, in circumstances where the rear side surface had sufficiently small contact angle hysteresis. To elucidate the underlying mechanism of drop motion, we implemented a surface energy analysis for each motion event. Motion was initiated by the excess surface free energy due to drop deformation and directed in favour of energy minimisation. Lastly, we propose a theory to predict the direction of the drop which at the same time acts as the criterion for the motion to ensue. PMID- 30427034 TI - Rattle-type porous Sn/C composite fibers with uniformly distributed nanovoids containing metallic Sn nanoparticles for high-performance anode materials in lithium-ion batteries. AB - Rattle-type porous Sn/carbon (Sn/C) composite fibers with uniformly distributed nanovoids containing metallic Sn nanoparticles in void space surrounded by C walls (denoted as RT-Sn@C porous fiber) were prepared by electrospinning and subsequent facile heat-treatment. Highly concentrated polystyrene nanobeads used as a sacrificial template played a key role in the synthesis of the unique structured RT-Sn@C porous fiber. The RT-Sn@C porous fiber exhibited excellent long-term cycling and rate performances. The discharge capacity of the RT-Sn@C porous fiber at the 1000th cycle was 675 mA h g-1 at a high current density of 3.0 A g-1. The RT-Sn@C porous fiber had final discharge capacities of 991, 924, 890, 848, 784, 717, 679, and 614 mA h g-1 at current densities of 0.1, 0.2, 0.3, 0.5, 1.0, 2.0, 3.0, 5.0, and 10.0 A g-1, respectively. The numerous void spaces, surrounding a Sn nanoparticle as the rattle-type particle, and the surrounding C could efficiently accommodate the volume changes of the Sn nanoparticles, improve the electrical conductivity, and enable efficient penetration of the liquid electrolyte into the structure. PMID- 30427035 TI - Lipid vesicle-loaded meso-substituted chlorins of high in vitro antimicrobial photodynamic activity. AB - Photodynamic inactivation potential against bacteria of four chlorin derivatives with phenyl or fluorophenyl substituents was evaluated. The quantum yield values of singlet oxygen formation were in the range of 0.16-0.86. Compounds were characterized by high quantum yields of fluorescence (0.15-0.44) and moderate photostability in DMF solutions. Irradiation of chlorins in DMSO resulted in their phototransformation and then photodecomposition. Photodynamic inactivation of bacteria was performed after the compounds had been loaded into lipid vesicles. The following log reductions of growth values were obtained: Enterococcus faecalis >5.44; Staphylococcus aureus 2.74-5.34; Escherichia coli 0.01-2.14. No activity of meso-substituted chlorins was noticed against Pseudomonas aeruginosa and fungi Candida albicans and Trichophyton mentagrophytes. PMID- 30427036 TI - On-demand concentration of an analyte on laser-printed polytetrafluoroethylene. AB - Controllable targeted deposition of an analyte dissolved in a liquid drop evaporating on a superhydrophobic surface has recently emerged as a promising concentrator approach with various applications ranging from ultrasensitive bioidentification to DNA molecule sorting. Here, we demonstrate that surface textures with non-uniform wettability fabricated using direct easy-to-implement femtosecond-pulse filament-assisted ablation of polytetrafluoroethylene substrates can be used to concentrate and deposit an analyte at a designated location out of a water droplet. The proposed surface textures contain a central superhydrophilic trap surrounded by superhydrophobic periodically arranged pillars with a hierarchical roughness. By optimizing the arrangement and geometry of the central trap and the surrounding superhydrophobic textures, the analyte dissolved in a 5 MUL water drop was fixed onto a 90 * 90 MUm2 target. The proposed textures provide a concentration factor of 103, an order of magnitude higher than those for the previously reported surface textures. This promising ultrasensitive versatile platform allows the detection of fingerprints of the deposited analyte via surface-enhanced spectroscopy techniques (Raman scattering or photoluminescence) at an estimated detection threshold better than 10-15 mol L 1. PMID- 30427037 TI - Photocatalytic inactivation of bioaerosols in a fixed-bed reactor with TiO2 coated glass rings. AB - The photocatalytic inactivation of Bacillus subtilis spores in air was evaluated employing a fixed-bed reactor with TiO2-coated glass rings, under artificial UV-A radiation. Calculations of the radiation effectively absorbed inside the reactor were carried out by Monte Carlo simulations. The photocatalytic inactivation was assessed by analyzing the viability of the microorganisms retained by the coated glass rings inside the reactor at different irradiation periods. The initial concentration of the spores was reduced by almost 55% at the end of the experiment (12 h). Complementary assays were carried out employing Bacillus subtilis vegetative cells, obtaining a reduction of more than 96% under the same conditions. Two efficiency parameters were computed to assess the reactor performance: the photonic efficiency and the quantum efficiency of inactivation. Results of the efficiency parameters allow an objective comparison of the reactor performance under different experimental conditions and configurations. PMID- 30427038 TI - Non-Mie optical resonances in anisotropic biomineral nanoparticles. AB - The optical properties of nanoparticles have attracted continuous attention owing to their high fundamental and applied importance across many disciplines. A recently emerged field of all-dielectric nanophotonics employs optically induced electric and magnetic Mie resonances in dielectric nanoparticles with a high refractive index. This property allows obtaining additional valuable degrees of freedom to control the optical responses of nanophotonic structures. Here we propose a conceptually distinct approach towards reaching optical resonances in dielectric nanoparticles. We show that, lacking conventional Mie resonances, low index nanoparticles can exhibit a novel anisotropy-induced family of non-Mie eigenmodes. Specifically, we investigate light interactions with calcite and vaterite nanospheres and compare them with the Mie scattering by a fused silica sphere. Having close permittivities and the same dimensions, these particles exhibit significantly different scattering behavior owing to their internal structure. While a fused silica sphere does not demonstrate any spectral features, the uniaxial structure of the permittivity tensor for calcite and the non-diagonal permittivity tensor for vaterite result in a set of distinguishable peaks in scattering spectra. Multipole decomposition and eigenmode analysis reveal that these peaks are associated with a new family of electric and magnetic resonances. We identify magnetic dipole modes of ordinary, extraordinary and hybrid polarization as well as complex electric dipole resonances, featuring a significant toroidal electric dipole moment. As both vaterite and calcite are biominerals, naturally synthesized and exploited by a variety of living organisms, our results provide an indispensable toolbox for understanding and elucidating the mechanisms behind the optical functionalities of true biological systems. PMID- 30427039 TI - Nanoscale LuFeO3: shape dependent ortho/hexa-phase constitution and nanogenerator application. AB - In multiferroic LuFeO3 the hexagonal (-h) phase is an intermediate metastable phase encountered during the amorphous to orthorhombic (-o) transformation and is ferroelectric in nature. Thus far it has only been stabilized in a substrate supported few layered ultrathin film form. Herein we show that the surface induced strain field intrinsically present in nano-systems can self-stabilize this phase and the hexagonal to orthorhombic phase constitution ratio depends on the shape of the nanomaterial. Thus, nanoparticles (nanofibres) strain-stabilize the o : h ratio of about 75 : 25 (23 : 77). The inclusion of nano-LuFeO3 into PDMS renders impressive nanogenerator performance, consistent with the ferroelectric phase content. PMID- 30427040 TI - Carbon quantum dots derived by direct carbonization of carbonaceous microcrystals in mesophase pitch. AB - Aggregation of the central aromatic ring system of asphaltene molecules due to pi pi interaction can lead to the formation of carbon quantum dots (CQDs). However, to date, such a roadmap has not been demonstrated. Here, we present a simple approach to the synthesis of CQDs by direct carbonization of dispersed carbonaceous microcrystals in mesophase pitch. The size of the as-prepared CQDs is modulated by adjusting the nucleation temperature for mesophase formation. Due to the oxygen-free character, the CQDs exhibit excitation-independent fluorescent behavior with a quantum yield up to 87%. The CQDs were successfully applied to fluorescent detection of Fe3+ ions with good specificity and sensitivity. Our results not only provide a scalable production of CQDs at low cost, but also give valuable clues to understand the solidification of asphaltene at nanoscale. PMID- 30427041 TI - Cobalt layered double hydroxides derived CoP/Co2P hybrids for electrocatalytic overall water splitting. AB - Cobalt layered double hydroxides (Co-LDHs) obtained by an imidazole-assisted route were used as precursors to prepare dual-functional electrocatalysts CoP/Co2P. CoP/Co2P showed an enhanced electrocatalytic performance for HER and OER. The reason was attributed to porous sheets providing more catalytic sites and multi-components improving conductivity and substrate adsorption capability. PMID- 30427042 TI - Exactly matched pore size for the intercalation of electrolyte ions determined using the tunable swelling of graphite oxide in supercapacitor electrodes. AB - The intercalation of solvent molecules and ions into sub-nanometer-sized pores is one of the most disputed subjects in the electrochemical energy storage applications of porous materials. Here, we demonstrate that the temperature- and concentration-dependent swelling of graphite oxide (GO) can be used to determine the smallest pore size required for the intercalation of electrolyte ions into hydrophilic pores. The structure of Brodie graphite oxide (BGO) in acetonitrile can be temperature-switched between the ambient one-layer solvate with an interlayer distance of ~8.9 A and the two-layer solvate (~12.5 A) at low temperature, thus providing slit pores of approximately 2.5 and 6 A. Using in situ synchrotron radiation X-ray diffraction (XRD) and the temperature dependence of capacitance in supercapacitor devices, we found that solvated tetraethylammonium tetrafluoroborate (TEA-BF4) ions do not penetrate into both the 2.5 and 6 A slit pores formed by BGO interlayers. However, increasing the electrolyte concentration results in the formation of a new phase at low temperature. This phase shows a distinct interlayer distance of ~15-16.6 A, which corresponds to the insertion of partly desolvated TEA-BF4 ions. Therefore, the remarkable ability of the GO structure to adopt variable interlayer distances allows for the determination of pore sizes that are optimal for solvated TEA-BF4 ions (about 9-10 A). The intercalation of TEA-BF4 ions into the BGO structure is also detected as an anomaly in the temperature dependence of supercapacitor performance. The BGO structure remains to be expanded, even after the removal of acetonitrile, adopting an interlayer distance of ~10 A. PMID- 30427043 TI - Generalized Langevin dynamics: construction and numerical integration of non Markovian particle-based models. AB - We propose a generalized Langevin dynamics (GLD) technique to construct non Markovian particle-based coarse-grained models from fine-grained reference simulations and to efficiently integrate them. The proposed GLD model has the form of a discretized generalized Langevin equation with distance-dependent two particle contributions to the self- and pair-memory kernels. The memory kernels are iteratively reconstructed from the dynamical correlation functions of an underlying fine-grained system. We develop a simulation algorithm for this class of non-Markovian models that scales linearly with the number of coarse-grained particles. Our GLD method is suitable for coarse-grained studies of systems with incomplete time scale separation, as is often encountered, e.g., in soft matter systems. We apply the method to a suspension of nanocolloids with frequency dependent hydrodynamic interactions. We show that the results from GLD simulations perfectly reproduce the dynamics of the underlying fine-grained system. The effective speedup of these simulations amounts to a factor of about 104. Additionally, the transferability of the coarse-grained model with respect to changes of the nanocolloid density is investigated. The results indicate that the model is transferable to systems with nanocolloid densities that differ by up to one order of magnitude from the density of the reference system. PMID- 30427044 TI - Nazarov cyclisations initiated by DDQ-oxidised pentadienyl ether: a mechanistic investigation from the DFT perspective. AB - The Nazarov cyclisation is an important and reliable reaction for the synthesis of cyclopentenones. Density functional theory (DFT) has been utilised to study the mechanism of Nazarov cyclisations initiated by oxidation of pentadienyl ethers by a benzoquinone derivative (DDQ), as recently reported by West et al. (Angew. Chem., Int. Ed., 2017, 56, 6335). We determined that the reaction is most likely initiated by a hydride transfer from the pentadienyl ether to an oxygen of DDQ through a concerted pathway and not a single electron transfer mechanism. This oxidation by hydride abstraction leads to the formation of a pentadienyl cation from which the 4pi electrocyclisation occurs, giving an alkoxycyclopentenyl cation. The ensuing cation is subsequently deprotonated by the reduced DDQ to afford an enol ether product. Consistent with experimental results, the hydride transfer is calculated to be the rate determining step and it can be accelerated by using electron donating substituents on the pentadienyl ether substrate. Indeed, the electron donating substituents increase the HOMO energy of the ether, making it more reactive toward oxidation. It is predicted that an unsubstituted benzoquinone, due to having a higher lying LUMO, shows much less reactivity than DDQ. Interestingly, we found an excellent correlation between the hydride transfer activation energy and the gap between the ether HOMO and the benzoquinone LUMO. From this correlation, we propose a predictive formula for reactivity of different types of substrates in the corresponding reaction. PMID- 30427048 TI - Per- and polyfluoroalkyl substances and fluorine mass balance in cosmetic products from the Swedish market: implications for environmental emissions and human exposure. AB - Per- and polyfluoroalkyl substances (PFASs) are a diverse class of >4700 chemicals used in commercial products and industrial processes. Concerns surrounding PFASs are principally due to their widespread occurrence in humans and the environment and links to adverse health effects. One of the lesser known uses for PFASs is in cosmetic products (CPs) which come into contact with the skin (e.g. hair products, powders, sunblocks, etc.). In the present work, thirty one CPs from five product categories (cream, foundation, pencil, powder and shaving foam) were analyzed for 39 PFASs by liquid chromatography-tandem mass spectrometry, as well as extractable organic fluorine (EOF) and total fluorine (TF) by combustion ion chromatography (CIC). This multi-platform approach enabled determination of the fraction of fluorine accounted for by known PFASs (i.e. fluorine mass balance). Foundations and powders contained 25 different PFASs with the most frequently detected being perfluorinated carboxylic acids (perfluoroheptanoic acid and perfluorohexanoic acid) and polyfluoroalkyl phosphate esters (PAPs). Sigma14PAP concentrations up to 470 MUg g-1 were measured in products listing mixtures of PAPs as an ingredient. For all samples, Sigma39PFAS concentrations only explained a small fraction of the EOF and TF, pointing to the presence of unknown organic and/or inorganic fluorinated substances, including polymers. While creams, pencil and shaving foams did not contain measurable concentrations of any of the 39 PFASs targeted here, CIC revealed high to moderate TF content. Overall, these data highlight the need for further investigations into the occurrence of PFASs in CPs and their importance with regards to human and environmental exposure. PMID- 30427049 TI - Synthesis of fluoroalkylated alkynes via visible-light photocatalysis. AB - Fluoroalkylated alkynes, which are versatile building blocks for the synthesis of various biologically active organofluorine compounds, were synthesized from easily available alkynyl halides and fluoroalkyl halides by visible-light photocatalysis. Addition of fluoroalkyl radicals to alkynes and subsequent dehalogenation selectively yielded fluoroalkylated alkynes. PMID- 30427050 TI - Regioselectivity of aryl radical attack onto isocyanates and isothiocyanates. AB - The combination of multistage mass spectrometry experiments employing the distonic radical approach together with DFT calculations are used to examine addition of the N-methyl-pyridinium-4-yl radical cation (gamma-NMP) to iso(thio)cyanates in the gas-phase. The type of products formed depend on the nature of the iso(thio)cyanate: (1) hydrogen atom abstraction occurs for alkyl isocyanates; (2) aryl isocyanates undergo radical-ipso substitution; (3) radical attack occurs at the C[double bond, length as m-dash]C bond of allyl isocyanate; (4) radical attack occurs at the C[double bond, length as m-dash]S bond of isothiocyanates to generate S adducts of gamma-NMP and isonitriles. DFT calculations provide insight into the reactivity differences of these heterocumulenes towards the electrophilic C-centered gamma-distonic radical cations. Translation of these gas phase results to the solution phase were hampered by dominating radical recombination reactions which appear to be favoured over the radical-iso(thio)cyanate reactions. PMID- 30427053 TI - Femoral Cortical Button Malposition Rates in Anterior Cruciate Ligament Reconstruction: A Retrospective Review. AB - The purpose of this study was to determine the rate of malposition of the femoral cortical button during anterior cruciate ligament reconstruction and to present a classification system of femoral cortical button positioning that is both accurate and reproducible. A total of 361 patients undergoing primary anterior cruciate ligament reconstruction during a 5-year period were identified, and postoperative button position was graded as follows: reduced and congruent (entirety of button <2 mm from cortex); reduced and incongruent (part of button <2 mm from cortex, part of button >2 mm from cortex); displaced (entirety of button >2 mm from cortex); intraosseous (all or part of button remains within bone); or ungradable. Radiographs were evaluated by 2 orthopedic surgeons at 2 time points to define interrater and intrarater reliability. A total of 312 buttons (86.43%) were reduced and congruent, 18 (4.99%) were reduced and incongruent, 10 (2.77%) were displaced, 13 (3.60%) were intraosseous, and 8 (2.21%) were ungradable based on the available postoperative imaging. There was outstanding interrater reliability, with an overall kappa value of 0.84. Intrarater reliability for raters 1 and 2 was 0.77 and 0.83, respectively, representing excellent intrarater reliability for both observers. Cortical button placement during femoral fixation in anterior cruciate ligament reconstruction is variable. This study presents a classification system for grading femoral cortical button placement that is accurate and reproducible. An organized grading scheme may be useful for future studies of the effect of cortical button malposition on stability and durability of fixation. [Orthopedics. 201x; xx(x):xx xx.]. PMID- 30427054 TI - A Prospective Randomized Study Comparing the Effectiveness of Midlateral and Posterior Subacromial Steroid Injections. AB - The authors sought to compare the accuracy and effectiveness of the mid-lateral and posterior routes of subacromial injection. They conducted a prospective randomized study involving 50 shoulders scheduled to receive subacromial injection via the midlateral or posterior route. After injection, a blinded musculoskeletal radiologist interpreted the radiographs. Age, sex, body mass index, side of shoulder involved, circumference of the proximal humerus, and acromial type were assessed. The accuracy rates of the injections, modified University of California Los Angeles shoulder scores, and visual analog scale pain scores were compared. The accuracy rate of the midlateral route was significantly higher than that of the posterior route (92% vs 68%; P<.034). Although there were significantly improved modified University of California Los Angeles shoulder and visual analog scale pain scores in both groups after injection, differences in functional outcomes were not statistically significant (P>.05). Univariate analysis showed no correlation between accuracy and age, sex, body mass index, or circumference of the proximal humerus. However, injection route had some influence on accuracy, with a crude odds ratio of 5.41 (95% confidence interval, 1.017-28.791; P=.048) for the midlateral route. Midlateral was the preferred route for subacromial injection. [Orthopedics. 201x; xx(x):xx xx.]. PMID- 30427055 TI - Subscapularis-Sparing Total Shoulder Arthroplasty: A Prospective, Double-Blinded, Randomized Clinical Trial. AB - Although total shoulder arthroplasty (TSA) is generally associated with good to excellent outcomes in most patients, the integrity and function of the subscapularis tendon (SSC) is of paramount importance because SSC rupture after TSA can lead to inferior outcomes. Therefore, the efficacy of a SSC-sparing TSA procedure was evaluated through a prospective, double-blinded, randomized study. Patients with end-stage osteoarthritis of the shoulder were randomized into 2 groups. Group 1 patients were treated with TSA in which the prosthesis was inserted entirely through the rotator interval without violating the SSC tendon (SPARING). Group 2 patients were treated with TSA using the SSC tenotomy approach (STANDARD). Both the patients and the evaluators remained blinded to the surgical approach throughout the study. Outcome data collected included the visual analog scale score for pain and the American Shoulder and Elbow Surgeons outcome score. Complete 2-year outcome data were collected from 32 SPARING and 38 STANDARD patients at a mean follow-up of 31.1 and 33.4 months, respectively. The American Shoulder and Elbow Surgeons and visual analog scale scores improved significantly for both groups. Differences between groups did not reach statistical significance. Complication profiles were similar for the 2 groups, with 3 patients in the SPARING group and 2 patients in the STANDARD group requiring revision surgery during the study. At short-term follow-up, the outcome of TSA using the SSC-sparing surgical approach was similar to the outcome of TSA using the standard approach. Studies with longer follow-up are required to document the potential benefits of this surgical technique. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30427056 TI - Early Subspecialization in Orthopedic Surgery Training. AB - Recent studies have shown that applicants to the American Board of Orthopaedic Surgery Part II examination are performing fewer procedures outside of their chosen subspecialty. In this study, the authors assessed whether trainees are beginning their subspecialization during residency. The authors reviewed the chosen fellowships and case logs of 231 residents graduating from 5 academic orthopedic residency training programs from 2002 to 2017. The number of cases logged by residents who chose a specialty was then compared with the number of cases logged by residents who chose other specialties. Residents who chose spine surgery (108.4+/-50.7 vs 74.4+/-60.2, P<.01), hand surgery (242.2+/-92.9 vs 194.3+/-78.2, P<.01), and sports medicine (278.5+/-105.8 vs 229.0+/-93.9, P<.01) performed significantly more procedures in their chosen fields than their colleagues. In contrast, for total joint arthroplasty (P=.18) and foot and ankle surgery (P=.46), there was no significant difference in the number of cases between residents who chose the sub-specialty and those who did not. Residents pursuing careers in spine surgery, hand surgery, and sports medicine obtained additional operative exposure to their chosen field during residency. Formalizing this early experience with specialization tracks during the chief year may be considered. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30427057 TI - Age Alone Does Not Predict Complications, Length of Stay, and Cost for Patients Older Than 90 Years With Hip Fractures. AB - The purpose of this study was to analyze the perioperative complication rate and inpatient hospitalization costs associated with hip fractures in patients older than 90 years compared with patients younger than 90 years. Patients 60 years and older with hip fractures treated operatively at 1 academic medical center between October 2014 and September 2016 were analyzed. Patient demographics, comorbidities, length of stay, procedure performed, and inpatient complications were analyzed. Total cost of admission was obtained from the hospital finance department. Outcomes were compared between patients older than 90 years and patients younger than 90 years. A total of 500 patients with hip fractures were included in this study. There were 109 (21.8%) patients 90 years and older and 391 (78.2%) patients 60 to 89 years. There was no difference in fracture pattern, operation performed, Charlson Comorbidity Index, or length of stay between the 2 groups. The mean length of stay for patients 90 years and older with hip fractures was 7.8+/-4.3 days vs 7.6+/-4.2 days for the younger cohort (P=.552). There was no observed difference in perioperative complications. Finally, there was no difference in the total mean cost of admission. Patients 90 years and older are at no greater risk for perioperative complications based on age alone. They are also no more likely to require longer or more costly hospitalizations than patients younger than 90 years. [Orthopedics. 201x; xx(x):xx-xx.]. PMID- 30427058 TI - Rehabilitation in chronic spatial neglect strengthens resting-state connectivity. AB - OBJECTIVES: Rehabilitation of patients with chronic visuospatial neglect is underexplored, and little is known about neural mechanisms that can be exploited to promote recovery. In this study, we present data on resting-state functional connectivity within the dorsal attention network (DAN) in chronic neglect patients as they underwent training in a virtual reality (VR) environment that improved left-side awareness. METHODS: The study included 13 patients with visuospatial neglect persisting more than six months after a right-sided stroke. The patients underwent resting-state functional magnetic resonance imaging (fMRI). Scans were collected at baseline and after five weeks of intense training. We specifically examined resting-state functional connectivity within the DAN. In addition, using spatial concordance correlation, we compared changes in the spatial topology of the DAN with that of other networks. RESULTS: We found a longitudinal increase in interhemispheric functional connectivity between the right frontal eye field and the left intraparietal sulcus following training (before: 0.33 +/- 0.17 [mean +/- SD]; after: 0.45 +/- 0.13; P = 0.004). The spatial concordance analyses indicated that training influenced the DAN connectivity more than any of the other networks. CONCLUSION: Intense VR training that improved left-sided awareness in chronic stroke patients also increased sporadic interhemispheric functional connectivity within the DAN. Specifically, a region responsible for saccadic eye movement to the left became more integrated with the left posterior parietal cortex. These results highlight a mechanism that should be exploited in the training of patients with chronic visuospatial neglect. PMID- 30427059 TI - Identifying the optimal regional predictor of right ventricular global function: a high-resolution three-dimensional cardiac magnetic resonance study. AB - Right ventricular (RV) function has prognostic value in acute, chronic and peri operative disease, although the complex RV contractile pattern makes rapid assessment difficult. Several two-dimensional (2D) regional measures estimate RV function, however the optimal measure is not known. High-resolution three dimensional (3D) cardiac magnetic resonance cine imaging was acquired in 300 healthy volunteers and a computational model of RV motion created. Points where regional function was significantly associated with global function were identified and a 2D, optimised single-point marker (SPM-O) of global function developed. This marker was prospectively compared with tricuspid annular plane systolic excursion (TAPSE), septum-freewall displacement (SFD) and their fractional change (TAPSE-F, SFD-F) in a test cohort of 300 patients in the prediction of RV ejection fraction. RV ejection fraction was significantly associated with systolic function in a contiguous 7.3 cm2 patch of the basal RV freewall combining transverse (38%), longitudinal (35%) and circumferential (27%) contraction and coinciding with the four-chamber view. In the test cohort, all single-point surrogates correlated with RV ejection fraction (p < 0.010), but correlation (R) was higher for SPM-O (R = 0.44, p < 0.001) than TAPSE (R = 0.24, p < 0.001) and SFD (R = 0.22, p < 0.001), and non-significantly higher than TAPSE F (R = 0.40, p < 0.001) and SFD-F (R = 0.43, p < 0.001). SPM-O explained more of the observed variance in RV ejection fraction (19%) and predicted it more accurately than any other 2D marker (median error 2.8 ml vs 3.6 ml, p < 0.001). We conclude that systolic motion of the basal RV freewall predicts global function more accurately than other 2D estimators. However, no markers summarise 3D contractile patterns, limiting their predictive accuracy. PMID- 30427060 TI - Elevated circulating levels of monocyte activation markers among tuberculosis patients with diabetes co-morbidity. AB - Alteration in the frequency of monocyte subsets is a hallmark of tuberculosis diabetes comorbidity (TB-DM). To study this association, we examined the plasma levels of sCD14, sCD163, C-reactive protein (CRP) and soluble tissue factor (sTF) in individuals with either TB-DM, TB, diabetes mellitus (DM) or healthy controls (HC). Circulating levels of sCD14, sCD163 and sTF were significantly increased in TB-DM and DM compared to TB and HC, however CRP was significantly increased in TB DM and TB compared to DM and HC. During longitudinal follow up, sCD14, CRP and sTF levels remained significantly increased in TB-DM compared to TB from baseline (pre-treatment), during treatment (2nd Month) and at the completion (6th month) of anti-TB treatment (ATT), while sCD163 was significantly higher in TB-DM compared to TB only at baseline. Moreover, the levels of sCD14 and sCD163 were significantly higher in TB-DM individuals with bilateral and cavitary disease and exhibited a significant positive relationship with bacterial burden. sCD14, sCD163 and CRP levels exhibited positive relationship with HbA1c levels. Within the TB-DM group, those with known diabetes before incident TB (KDM) exhibited significantly higher levels of sCD14 and sCD163 compared to newly diagnosed DM individuals with TB (NDM). Finally, KDM individuals on metformin treatment exhibited significantly lower levels of sCD14, sCD163 and CRP compared to those on non-metformin containing regimens. Our data demonstrate that systemic monocyte activation markers levels reflect baseline disease severity and extent in TB-DM, differentiate KDM from NDM and are modulated by ATT and metformin therapy. This article is protected by copyright. All rights reserved. PMID- 30427061 TI - Anterior thalamic deep brain stimulation in refractory epilepsy: a randomized, double-blinded study. AB - OBJECTIVES: The safety and effect on seizure frequency of anterior thalamic nucleus deep brain stimulation (ANT-DBS) were studied in this prospective, randomized, double-blinded study. Patients were followed for 12 months. The first 6 months were blinded with regard to active stimulation or not. After 6 months, all patients received active stimulation. MATERIAL AND METHODS: Bilateral ANT electrodes were implanted into 18 patients suffering from focal, pharmacoresistant epilepsy. Antiepileptic treatment was kept unchanged from three months prior to operation. The Liverpool seizure severity scale (LSSS) was used to measure the burden of epilepsy. RESULTS: There was no significant difference between the 2 groups at the end of the blinded period at 6 months. However, when considering all patients and comparing 6 months of stimulation with baseline, there was a significant, 22% reduction in the frequency of all seizures (p=0.009). Four patients had >= 50% reduction in total seizure frequency and 5 patients >= 50% reduction in focal seizures after 6 months of stimulation. No increased effect over time was shown. LSSS at 6 months compared to baseline showed no significant difference between the 2 groups, but a small, significant reduction in LSSS was found when all patients had received stimulation for 6 months. CONCLUSIONS: Our study supports results from earlier studies concerning DBS as a safe treatment option, with effects even in patients with severe, refractory epilepsy. However, our results are not as encouraging as those reported from many other, mainly unblinded, and open studies. This article is protected by copyright. All rights reserved. PMID- 30427062 TI - Short-chain fatty acids and gut microbiota in multiple sclerosis. AB - BACKGROUND: Multiple Sclerosis (MS) is a chronic immune-mediated neurological disease of the central nervous system with a complex and still not fully understood aetiology. In recent years, the gut microbiota and fermentative metabolites like short-chain fatty acids (SCFAs) have received increased attention in relation to the development and disease course of MS. This systematic review highlights and summarizes the existing literature within this field. METHODS: A systematic search in PubMed was conducted on 12 October 2017, to find published original studies on SCFAs and their impact on MS and the animal model of MS experimental autoimmune encephalomyelitis (EAE). Furthermore, all studies analysing the gut microbiota in MS patients were included. A total of 14 studies were eligible for this review. RESULTS: Short-chain fatty acids have been shown to ameliorate the disease course in EAE, but no studies specifically addressing the role of SCFAs in human MS patients were identified. However, some investigations have shown that the microbiota of MS patients is characterized by a reduction in SCFA-producing bacteria. CONCLUSIONS: Studies of EAE in mice suggest that SCFAs may play a role in the development and progression of EAE, but so far this has not been confirmed in humans. An aberrant gut microbiota in MS patients has been reported to be differentially abundant compared with healthy controls, although with little consistency in the bacterial taxa. Further investigations are required to elucidate the involvement of the gut microbiota and its metabolites, including potential beneficial effects of SCFAs, in the development and course of MS. PMID- 30427063 TI - GATOR1 variants in Chinese people with sporadic drug-resistant focal epilepsy. AB - OBJECTIVES: GATOR1 (Gap Activity TOward Rags 1) is composed of three different subunits, DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator-like 2), and NPRL3 (nitrogen permease regulator-like 3), and variants in these three genes have mostly been reported in familial focal epilepsy. However, very few studies have been carried out on sporadic drug-resistant focal epilepsy patients. In this study, we aimed to identify the frequency of variants in DEPDC5, NPRL2 and NPRL3 in patients with sporadic drug-resistant focal epilepsy. MATERIALS & METHODS: One hundred and ninety-three Chinese people with sporadic drug-resistant focal epilepsy were enrolled in the study. Targeted sequencing of DEPDC5, NPRL2 and NPRL3 was applied at an average coverage depth of 2500x. RESULTS: In the 193 patients with sporadic focal epilepsy included in this study, the median age was 24.6 years with a median age at onset of 13.99 years, and 130 of these patients had identifiable structural lesions. One possibly pathogenic missense variant of DEPDC5, c.2984G>A, p.Arg995His, was found in one patient (0.52%) with hippocampal sclerosis, and one variant of unknown significance, DEPDC5 c.20A>G, p.Tyr7Cys, was found in two patients with hippocampal sclerosis (1.04%). CONCLUSIONS: Our findings suggested that DEPDC5 might be of more importance than NPRL2 or NPRL3 in Chinese epilepsy patients with sporadic drug-resistant focal epilepsy. Future research should focus on the mechanism by which the mechanistic target of rapamycin (mTOR) is involved in epileptogenesis in sporadic epilepsy. This article is protected by copyright. All rights reserved. PMID- 30427064 TI - Ecological lifestyles and the scaling of shark gill surface area. AB - Fish gill surface area varies across species and with respect to ecological lifestyles. The majority of previous studies only qualitatively describe gill surface area in relation to ecology and focus primarily on teleosts. Here, we quantitatively examined the relationship of gill surface area with respect to specific ecological lifestyle traits in elasmobranchs, which offer an independent evaluation of observed patterns in teleosts. As gill surface area increases ontogenetically with body mass, examination of how gill surface area varies with ecological lifestyle traits must be assessed in the context of its allometry (scaling). Thus, we examined how the relationship of gill surface area and body mass across 11 shark species from the literature and one species for which we made measurements, the Gray Smoothhound Mustelus californicus, varied with three ecological lifestyle traits: activity level, habitat, and maximum body size. Relative gill surface area (gill surface area at a specified body mass; here we used 5,000g, termed the 'standardized intercept') ranged from 4,724.98 to 35,694.39 cm2 (mean and standard error: 17,796.65 +/- 2,948.61 cm2 ) and varied across species and the ecological lifestyle traits examined. Specifically, larger bodied, active, oceanic species had greater relative gill surface area than smaller-bodied, less active, coastal species. In contrast, the rate at which gill surface area scaled with body mass (slope) was generally consistent across species (0.85 +/- 0.02) and did not differ statistically with activity level, habitat, or maximum body size. Our results suggest that ecology may influence relative gill surface area, rather than the rate at which gill surface area scales with body mass. Future comparisons of gill surface area and ecological lifestyle traits using the quantitative techniques applied in this study can provide further insight into patterns dictating the relationship between gill surface area, metabolism, and ecological lifestyle traits. PMID- 30427065 TI - Assessment of haemoglobin measurement by several methods - blood gas analyser, capillary and venous HemoCue(r) , non-invasive spectrophotometry and laboratory assay - in term and preterm infants. AB - A laboratory haematology analyser is the gold standard for measuring haemoglobin concentration but has disadvantages, especially in neonates. This study compared alternative blood-sparing and non-invasive methods of haemoglobin concentration measurement with the gold standard. Haemoglobin concentrations were measured using a laboratory haematology analyser (reference method), blood gas analyser, HemoCue(r) using venous and capillary blood samples and a newly developed non invasive sensor for neonates < 3 kg. A total of 63 measurements were performed. Body weight (2190 (1820-2520 [967-4450]) g) and haemoglobin concentration (12.3 (10.6-15.2 [8.2-20.5]) g.dl-1 ) varied widely. Bias/limits of agreement between the alternative methods and reference method were -0.1/-1.2 to 1.0 g.dl-1 (blood gas analyser), -0.4/-1.8 to 1.1 g.dl-1 (HemoCue, venous blood), 0.7/-1.9 to 3.2 g.dl-1 (HemoCue, capillary blood) and -1.2/-4.3 to 2 g.dl-1 (non-invasive haemoglobin measurement). Perfusion index, body weight and fetal haemoglobin concentration did not affect the accuracy of the alternative measurement methods, and these were successfully applied in term and preterm infants. However, the accuracies of non-invasive haemoglobin measurement and HemoCue of capillary blood especially lacked sufficient agreement with that of the reference method to recommend these methods for clinical decision making. PMID- 30427066 TI - The gut microbiota of hand, foot and mouth disease patients demonstrates down regulated butyrate-producing bacteria and up-regulated inflammation-inducing bacteria. AB - AIM: This study explored the gut microbiota of children with hand, foot and mouth disease (HFMD). METHODS: We enrolled 15 cases with HFMD admitted to the West China Second Hospital, Sichuan University, China, from July to September 2016 at a median age of three years. The controls were 15 healthy children of a similar age who underwent routine health examinations at the hospital during the same period. Gut microbiota was analysed using high throughput 16S ribosomal deoxyribonucleic acid sequencing. RESULTS: The gut microbiota in the HFMD patients was distinct from the controls. Compared with the controls, the composition of gut microbiota in the HFMD cases represented a reduction of two butyrate-producing bacteria, Ruminococcus (0.73 +/-1.28 versus 7.78 +/-20.01, p=0.026) and Roseburia (0.67 +/-1.69 versus 1.61 +/-3.27,p=0.024) and an up regulation of Escherichia (5.26 +/-10.50 versus 1.59 +/-5.90,p<0.01) and Enterococcus (4.12 +/-12.49 versus 0.12 +/-0.41, p=0.015). CONCLUSION: The dysbiosis of gut microbiota of the HFMD cases included a reduction of butyrate producing bacteria and an up-regulation of inflammation-inducing bacteria. These may have impaired the intestinal biological mucosal barrier and host immune functions, promoting the invasion of the enterovirus. This article is protected by copyright. All rights reserved. PMID- 30427067 TI - New insights into the origin of mast cells. PMID- 30427068 TI - The impact of blood pressure variability and pulse pressure on graft survival and mortality after kidney transplantation. AB - BACKGROUND: Blood pressure variability and pulse pressure are strong and independent predictors of cardiovascular morbidity and mortality in the general population. So far, there are no data on the impact of blood pressure variability on mortality and graft survival after renal transplantation. METHODS: We performed a retrospective analysis of 877 patients who underwent kidney transplantation between 1997 and 2011 in two transplant centers in Germany (Berlin and Bochum) with a follow-up of 12-266 months. Visit-to-visit blood pressure variability over the first 12 months after transplantation (3 visits) and during the first 120 months after transplantation (7 visits) was calculated as the coefficient of variation (CV = standard deviation (SD)/mean blood pressure). Patient and graft survival was defined as composite endpoint. RESULTS: Cumulative survival was significantly higher for those patients with lower systolic blood pressure and pulse pressure within both the first 12 months and the 120 months posttransplant. After adjustment of data for gender, age, body mass index, and coronary artery disease, the cumulative incidence of the combined endpoint did not significantly differ between patients with lower vs higher CV (12 months CV hazard ratio (HR) (95% CI) = 0.90 (0.66-1.23), P = 0.51; 120 months CV HR (95% CI) = 0.92 (0.67-1.26), P = 0.60). A lower systolic blood pressure remained highly predictive for better survival in adjusted analyses. CONCLUSION: Visit-to-visit blood pressure variability is not associated with mortality or graft loss after kidney transplantation in this retrospective analysis. In analogy to the general population, however, there is an inverse relationship of survival and pulse pressure as a marker of arterial stiffness. PMID- 30427069 TI - Innate and adaptive stimulation of murine diverse NKT cells result in distinct cellular responses. AB - Natural killer T (NKT) cells recognize glycolipids presented on CD1d. They share features of adaptive T lymphocytes and innate NK cells, and mediate immunoregulatory functions via rapid production of cytokines. Invariant (iNKT) and diverse (dNKT) NKT cell subsets are defined by their TCR. The immunological role of dNKT cells, that do not express the invariant TCRalpha-chain used by iNKT cells, is less well explored than that of iNKT cells. Here, we investigated signals driving Toll-like receptor (TLR) ligand activation of TCR-transgenic murine dNKT cells. IFN-gamma production by dNKT cells required dendritic cells (DC), cell-to-cell contact and presence of TLR ligands. TLR-stimulated DC activated dNKT cells to secrete IFN-gamma in a CD1d-, CD80/86- and type I IFN independent manner. In contrast, a requirement for IL-12p40, and a TLR ligand selective dependence on IL-18 or IL-15 was observed. TLR ligand/DC stimulation provoked early secretion of pro-inflammatory cytokines by both CD62L+ and CD62L- dNKT cells. However, proliferation was limited. In contrast, TCR/co-receptor mediated activation resulted in proliferation and delayed production of a broader cytokine spectrum preferentially in CD62L- dNKT cells. Thus, innate (TLR ligand/DC) and adaptive (TCR/co-receptor) stimulation of dNKT cells resulted in distinct cellular responses that may contribute differently to the formation of immune memory. PMID- 30427070 TI - Indoor Thermal Stratification and Its Statistical Distribution. AB - Thermal stratification is established when warmer air rises and cooler air descends under thermal buoyancy. It occurs in indoor environment situations including large warehouse-type buildings, buoyancy-driven ventilated spaces with displacement, under-floor ventilation, and/or natural ventilation, and enclosure fires with hot smoke layer on top of cold air layer. This paper reports a recent study that thermal stratification of indoor environment follows the statistical Beta distribution so the vertical temperature distribution is the Cumulative Distribution Function of the Beta distribution defined by two shape parameters, Alpha (alpha) and Beta (beta), despite ventilation types, heat source and other details. It is then possible to estimate a complete vertical temperature profile under thermal stratification by four temperature points (i.e. 4-point Beta distribution), or as few as two points (i.e. 2-point Beta distribution) with a slight loss of accuracy. The study was confirmed by the field measurement data of five warehouse-type buildings, and eleven thermal stratification studies from the literature. A few applications were demonstrated including quantitative characterization of thermal stratification; estimation of mean and spatial temperature uniformities and other key parameters. The dimensionless nature of the methodology may also be potentially applied to other indoor stratification phenomena. This article is protected by copyright. All rights reserved. PMID- 30427071 TI - Increasing pre-transplant confidence and safety for use of questionable donor lungs with ex-situ assessment and reconditioning. AB - Since its successful kick-off in the early eighties, lung transplantation has evolved as a live-saving treatment for selected patients with end-stage lung disease [1]. As for all types of solid organ transplantation, the practice of lung transplantation is limited by the number of available donors and their percentage of good quality pulmonary grafts [2]. Strict donor criteria as set by experts in the early days of lung transplantation were not derived from high quality scientific studies [3]. This article is protected by copyright. All rights reserved. PMID- 30427072 TI - Evaluation of drug susceptibility test for Efinaconazole compared with conventional antifungal agents. AB - BACKGROUND: Superficial fungal infections are one of the most common and burdensome skin problems affecting quality of life in patients. Various conventional antifungal agents have been used to treat fungal infections; however, various problems have been reported including drug interaction, drug resistance and low effectiveness. Efinaconazole is a novel antifungal agent, which has proven to be particularly effective against onychomycosis compared with conventional antifungal agents. However, the antifungal efficacy of Efinaconazole for specific strains has not been analysed. OBJECTIVE: We conducted an In-vitro study to measure the antifungal activity of Efinaconazole against strains of T. rubrum, T. mentagrophytes and C. albicans compared with widely-used antifungal drugs. METHODS: We obtained strains of T. rubrum, T. mentagrophytes and C. albicans isolated from patients with onychomycosis and tinea pedis. The minimal inhibitory concentration (MIC) for various strains of fungal species was evaluated for the antifungal susceptibility test. RESULTS: Efinaconazole showed a low MIC against almost strains of dermatophytes and C. albicans and also presented low resistance, indicating high potency of efinaconazole for treatment of superficial fungal infections. CONCLUSION: Efinaconazole could be a comparable alternative to replace existing conventional agents. This article is protected by copyright. All rights reserved. PMID- 30427073 TI - Ms1 RNA increases the amount of RNA polymerase in Mycobacterium smegmatis. AB - Ms1 is a sRNA recently found in mycobacteria and several other actinobacterial species. Ms1 interacts with the RNA polymerase (RNAP) core devoid of sigma factors, which differs from 6S RNA that binds to RNAP holoenzymes containing the primary sigma factor. Here we show that Ms1 is the most abundant non-rRNA transcript in stationary phase in Mycobacterium smegmatis. The accumulation of Ms1 stems from its high-level synthesis combined with decreased degradation. We identify the Ms1 promoter, PM s1 , and cis-acting elements important for its activity. Furthermore, we demonstrate that PNPase (an RNase) contributes to the differential accumulation of Ms1 during growth. Then, by comparing the transcriptomes of wt and DeltaMs1 strains from stationary phase, we reveal that Ms1 affects the intracellular level of RNAP. The absence of Ms1 results in decreased levels of the mRNAs encoding beta and beta' subunits of RNAP, which is also reflected at the protein level. Thus, the DeltaMs1 strain has a smaller pool of RNAPs available when the transcriptional demand increases. This contributes to the inability of the DeltaMs1 strain to rapidly react to environmental changes during outgrowth from stationary phase. This article is protected by copyright. All rights reserved. PMID- 30427074 TI - Outcome-dependent geographic and individual variations in the access to renal transplantation in incident dialysed patients: a French nationwide cohort study. AB - This study investigated geographical variations of access to renal transplantation using three outcomes (access to the transplant waiting list, access to renal transplantation after waitlisting and access to renal transplantation after dialysis start). Associations of patient-related and regional variables with the studied outcomes were assessed using a Cox shared frailty model and a Fine and Gray model. At the study endpoint (December 31, 2015), 26.3% of all 18-90-year-old patients who started dialysis in the 22 mainland and four overseas French regions in 2012 (n = 9312) were waitlisted and 15.1% received a kidney transplant. The geographical disparities of access to renal transplantation varied according to the studied outcome. Patients from the Ile-de-France region had the highest probability of being waitlisted, but were less likely to receive a kidney transplant. Two regional factors were associated with the access to the waiting list and to renal transplantation from dialysis start: the incidence of preemptive kidney transplantation and of ESRD. The use of different outcomes to evaluate access to kidney transplantation could help healthcare policy-makers to select the most appropriate interventions for each region in order to reduce treatment disparities. PMID- 30427075 TI - Different health effects of indoor- and outdoor-originated PM2.5 on cardiopulmonary function in COPD patients and healthy elderly adults. AB - Numerous research has explored the associations of outdoor or indoor fine particulate matter (PM2.5 ) and health effects; however, few studies compared the effects of indoor PM2.5 originated from outdoor (PM2.5,os ) and indoor sources (PM2.5,is ). To assess the associations of PM2.5,os and PM2.5,is with cardiopulmonary function in patients with chronic obstructive pulmonary disease (COPD) and healthy elderly adults, blood pressure (BP) and pulmonary function were repeatedly examined in 43 COPD patients and their 32 healthy spouses in Beijing, China. Iron was used as tracer element to separate PM2.5,os and PM2.5,is . Mixed-effects models were applied to assess the associations of PM2.5,os or PM2.5,is and health effects after controlling for potential confounders. There was a reduction in forced expiratory volume in first second (FEV1 ) in COPD patients associated with PM2.5,is during the heating season. PM2.5,os was positively associated with diastolic BP (DBP) in healthy elderly adults during the heating season. There was a reduction in peak expiratory flow (PEF) in healthy elderly adults associated with PM2.5,os during the non-heating season. Exposure to indoor- and outdoor-originated PM2.5 had different health effects on cardiopulmonary function in different populations. The results provide supporting evidence for improving indoor air quality to promote public health among susceptible population. PMID- 30427076 TI - Prevention of esophageal stricture after endoscopic resection. AB - Stricture formation after esophageal endoscopic resection has a negative impact on patients' quality of life because it causes dysphagia and requires multiple endoscopic dilations. Various methods by which to prevent stricture have recently been developed and reported. Among these methods, local steroid injection is the most commonly used and is currently considered the standard method for noncircumferential resection. However, local steroid injection has a limited effect on circumferential resection. Thus, oral steroid administration is used for such cases because it may have a stronger effect than local injection. Steroid treatment, both by local injection and oral administration, is effective and low-cost; however, it may cause fragility of the esophageal wall, resulting in adverse events such as perforation during balloon dilatation. Many innovative approaches have been developed, such as tissue-shielding methods with polyglycolic acid, tissue engineering approaches with autologous oral mucosal epithelial cell sheet transplantation, and stent insertion. These methods may be promising, but they are limited by a scarcity of data. Further investigations are needed to confirm the efficacy of these methods. This article is protected by copyright. All rights reserved. PMID- 30427077 TI - The protective effects of Delta9 -tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia. AB - OBJECTIVES: A large amount of fructose is metabolized in the liver and causes hepatic functional damage. Delta9 -tetrahydrocannabinol (THC) is known as a therapeutic agent for clinical and experimental applications. The study aims to investigate the effects of THC treatment on inflammation, lipid profiles and oxidative stress in rat liver with hyperinsulinemia. METHODS: Sprague-Dawley rats were divided into groups: control, fructose (10% fructose in drinking water for 12 weeks), THC (1.5 mg/kg/day for the last 4 weeks, intraperitoneally) and fructose+THC groups. Biochemical parameters were measured spectrophotometrically. ELISA method was used for insulin measurement. Apoptosis and inflammation markers were detected by the streptavidin-biotin peroxidase method. KEY FINDINGS: The consumptions of food and fluid are inversely proportional to fructose and non fructose groups. Insulin levels were the highest in fructose group. The reduced glutathione-S-transferase level significantly increased in fructose + THC group compared with fructose group. Total cholesterol level in the fructose + THC group was higher than the fructose group. Caspase-3 and NF-kappabeta immunopositive cell numbers increased in fructose + THC rats compared with fructose group. The number of IL-6 immunopositive cell decreased in fructose + THC group compared with fructose group. CONCLUSIONS: According to the result, long-term and low-dose THC administration may reduce hyperinsulinemia and inflammation in rats to some extent. PMID- 30427078 TI - The cap-snatching reaction of yeast L-A double-stranded RNA virus is reversible and the catalytic sites on both Gag and the Gag domain of Gag-Pol are active. AB - The yeast L-A double-stranded RNA virus synthesizes capped transcripts by a unique cap-snatching mechanism in which the m7 Gp moiety of host mRNA (donor) is transferred to the diphosphorylated 5' end of the viral transcript (acceptor). This reaction is activated by viral transcription. Here, we show that cap snatching can be reversible. Because only m7 Gp is transferred during the reaction, the resulting decapped donor, as expected, retained diphosphates at the 5' end. We also found that the 5' terminal nucleotide of the acceptor needs to be G but not A. Interestingly, the A-initiated molecule when equipped with a cap structure (m7 GpppA...) could work as cap donor. Because the majority of host mRNAs in yeast have A after the cap structures at the 5' ends, this finding implies that cap-snatching in vivo is virtually a one-way reaction, in favor of furnishing the viral transcript with a cap. The cap-snatching sites are located on the coat protein Gag and also the Gag domain of Gag-Pol. Here, we demonstrate that both sites are functional, indicating that activation of cap snatching by transcription is not transmitted through the peptide bonding between the Gag and Pol domains of Gag-Pol. PMID- 30427079 TI - Weekend effect on early allograft outcome after kidney transplantation- a multi centre cohort study. AB - Weekend surgery may be associated with a higher risk of early complications, but the effect of the timing of kidney transplant surgery on early allograft outcome remains uncertain. The aim of this study is to evaluate whether the association between weekend transplant surgery and allograft failure was modified by prevalent vascular disease. Using data from the Australia and New Zealand Dialysis and Transplant registry, we examined the association between weekend status and 90-day and 1-year allograft failure in deceased donor transplant recipients between 1994-2012. Two-way interaction between vascular disease and weekend status was examined. Of 6622 recipients, 1868 (28.2%) received transplants during weekends. Compared with weekday transplants, weekend transplants were associated with an adjusted hazard ratio (HR) for 90-day and 1 year allograft failure of 0.99 (0.78-1.25; P = 0.917) and 0.93 (0.76-1.13, P = 0.468), respectively. There was a significant interaction between prevalent vascular disease and weekend status for 90-day allograft failure (Pinteraction = 0.008) but not at 1-year, such that patients with vascular disease were more likely to experience 90-day allograft failure if transplanted on weekend (versus weekdays), particularly failures secondary to vascular complications. Timing of transplantation does not impact on allograft outcome, although those with vascular disease may benefit from more intensive post-transplant follow-up for potential vascular complications. PMID- 30427080 TI - The European Young Chemist Award 2018. AB - Young traditions: The 2018 European Young Chemist Award competition was held in Liverpool during the 7th EuCheMS Chemistry Congress continuing the tradition of showcasing and recognizing the excellent research being carried out by young scientists working in the chemical sciences. PMID- 30427081 TI - De novo genome assembly of the stress tolerant forest species Casuarina equisetifolia provides insight into secondary growth. AB - Casuarina equisetifolia (C. equisetifolia), a conifer-like angiosperm with resistance to typhoon and stress tolerance, is mainly cultivated in the coastal areas of Australasia. C. equisetifolia, making it a valuable model to study secondary growth associated genes and stress-tolerance traits. However, the genome sequence is unavailable and thus wood-associated growth rate and stress resistance at the molecular level is largely unexplored. We therefore constructed a high-quality draft genome sequence of C. equisetifolia by a combination of Illumina second-generation sequencing reads and Pacific Biosciences single molecule real time (SMRT) long reads to advance the investigation of this species. Here, we report the genome assembly, which contains approximately 300 megabases (Mb) and scaffold size of N50 is 1.06 Mb. Additionally, gene annotation, assisted by a combination of prediction and RNA-seq data, generated 29,827 annotated protein-coding genes and 1,983 non-coding genes, respectively. Furthermore, we found that the total number of repetitive sequences account for one third of the genome assembly. Here we also construct the genome-wide map of DNA modification, such as two novel forms N6 -Adenine (6mA) and N4-methylcytosine (4mC) at the level of single-nucleotide resolution using single-molecule real time (SMRT) sequencing. Interestingly, we found that 17% of 6mA modification genes and 15% of 4mA modification genes also included alternative splicing events. Finally, we investigated cellulose, hemicellulose, and lignin-related genes, which associated with secondary growth and contained different DNA modification. The high-quality genome sequence and annotation of C. equisetifolia of this study provide valuable resources to strengthen our understanding of the diverse traits of trees. This article is protected by copyright. All rights reserved. PMID- 30427082 TI - Approaches to integrating genetic data into ecological networks. AB - As molecular tools for assessing trophic interactions become common, research is increasingly focused on the construction of interaction networks. Here we demonstrate three key methods for incorporating DNA data into network ecology and discuss analytical considerations using a model consisting of plants, insects, bats and their parasites from the Costa Rican dry forest. The simplest method involves the use of Sanger sequencing to acquire long sequences to validate or refine field identifications, for example of bats and their parasites, where one specimen yields one sequence and one identification. This method can be fully quantified and resolved and these data resemble traditional ecological networks. For more complex taxonomic identifications, we target multiple DNA loci e.g. from a seed or fruit pulp sample in faeces. These networks are also well resolved but gene targets vary in resolution and quantification is difficult. Finally for mixed templates such as faecal contents of insectivorous bats we use DNA metabarcoding targeting two sequence lengths (157bp, 407bp) of one gene region and a MOTU, BLAST and BIN association approach to resolve nodes. This network type is complex to generate and analyse and we discuss the implications of this type of resolution on network analysis. Using these data we construct the first molecular-based network of networks containing 3304 interactions between 762 nodes of 8 trophic functions and involving parasitic, mutualistic, and predatory interactions. We provide a comparison of the relative strengths and weaknesses of these data types in network ecology. This article is protected by copyright. All rights reserved. PMID- 30427083 TI - Seeds in motion: genetic assignment and hydrodynamic models demonstrate concordant patterns of seagrass dispersal. AB - Movement is fundamental to the ecology and evolutionary dynamics within species. Understanding movement through seed dispersal in the marine environment can be difficult due to the high spatial and temporal variability of ocean currents. We employed a mutually enriching approach of population genetic assignment procedures and dispersal predictions from a hydrodynamic model to overcome this difficulty and quantify the movement of dispersing floating fruit of the temperate seagrass Posidonia australis Hook.f. across coastal waters in southwestern Australia. Dispersing fruit cohorts were collected from the water surface over two consecutive years and seeds were genotyped using microsatellite DNA markers. Likelihood-based genetic assignment tests were used to infer the meadow of origin for seed cohorts and individuals. A three-dimensional hydrodynamic model was coupled with a particle transport model to simulate the movement of fruit at the water surface. Floating fruit cohorts were mainly assigned genetically to the nearest meadow, but significant genetic differentiation between cohort and most-likely meadow of origin suggested a mixed origin. This was confirmed by genetic assignment of individual seeds from the same cohort to multiple meadows. The hydrodynamic model predicted 60% of fruit dispersed within 20 km, but that fruit were physically capable of dispersing beyond the study region. Concordance between these two independent measures of dispersal provide insight into the role of physical transport for long distance dispersal (LDD) of fruit and the consequences for spatial genetic structuring of seagrass meadows. This article is protected by copyright. All rights reserved. PMID- 30427084 TI - Mycorrhizal divergence and selection against immigrant seeds in forest and dune populations of the partially mycoheterotrophic Pyrola rotundifolia. AB - Plant populations occupying different habitats may diverge from each other over time and gradually accumulate genetic and morphological differences, ultimately resulting in ecotype or even species formation. In plant species that critically rely on mycorrhizal fungi, differences in mycorrhizal communities can contribute to ecological isolation by reducing or even inhibiting germination of immigrant seeds. In this study, we investigated whether the mycorrhizal communities available in the soil and associating with the roots of seedlings and adult plants of the partially mycoheterotrophic Pyrola rotundifolia differed between populations growing in sand dunes and forests. In addition, reciprocal germination experiments were performed to test whether native seeds showed higher germination than immigrant seeds. Our results showed that the mycorrhizal communities differed significantly between forest and dune populations, and that within populations seedlings and adults also associated with different mycorrhizal communities. In both forest and dune populations, mycorrhizal communities were dominated by members of the Thelephoraceae, but dune populations showed a higher incidence of members of the Inocybaceae, whereas forest populations showed a high abundance of members of the Russulaceae. Reciprocal germination experiments showed that native seeds showed a higher germination success than immigrant seeds and this effect was most pronounced in dune populations. Overall, these results demonstrate that plants of P. rotundifolia growing in dune and forest habitats associate with different mycorrhizal communities and that reduced germination of non-native seeds may contribute to reproductive isolation. We conclude that selection against immigrants may constitute an important reproductive barrier at early stages of the speciation process. This article is protected by copyright. All rights reserved. PMID- 30427085 TI - Genetic diversity mirrors trophic ecology in coral reef fish feeding guilds. AB - Genetic diversity is essential for species persistence because it provides the raw material for evolution. For marine organisms, short pelagic larval duration (PLD) and small population size are characteristics generally assumed to associate with low genetic diversity. The ecological diversity of organisms may also affect genetic diversity, with an expected corollary that more restricted habitat and dietary requirements could lead to a reduced genetic diversity because of pronounced genetic structuring. Here, we tested whether groups of species with narrower trophic niches displayed lower genetic diversity than those with broader niches. In order to test those predictions, we used different trophic guilds (i.e. groups of species having similar trophic habits) of coral reef damselfishes in Moorea (French Polynesia) for which we determined their genetic diversity using Restriction site-associated DNA sequencing (RADseq) and their trophic ecology with stomach contents and stable isotope data. We found that pelagic feeders, i.e. the guild picking zooplankton in the water column, exhibited the lowest genetic diversity despite having the longest PLD and the largest population size. This guild had also the lowest variation in habitat characteristics and dietary composition compared to benthic feeders (i.e. those mainly grazing on algae) and the intermediate group (i.e. those feeding on zooplankton, filamentous algae and small benthic invertebrates). Our findings highlight the association between trophic ecology and genetic diversity that should be more commonly investigated in population genetics. This article is protected by copyright. All rights reserved. PMID- 30427086 TI - The toxin from a ParDE toxin-antitoxin system found in Pseudomonas aeruginosa offers protection to cells challenged with anti-gyrase antibiotics. AB - Toxin-antitoxin systems are mediators of diverse activities in bacterial physiology. For the ParE-type toxins, their reported role of gyrase inhibition utilized during plasmid-segregation killing indicates they are toxic. However, their location throughout chromosomes leads to questions about function, including potential non-toxic outcomes. The current study has characterized a ParDE system from the opportunistic human pathogen Pseudomonas aeruginosa (Pa). We identified a protective function for this ParE toxin, PaParE, against effects of quinolone and other antibiotics. However, higher concentrations of PaParE are themselves toxic to cells, indicating the phenotypic outcome can vary based on its concentration. Our assays confirmed PaParE inhibition of gyrase-mediated supercoiling of DNA with an IC50 value in the low micromolar range, a species specificity that resulted in more efficacious inhibition of Escherichia coli derived gyrase versus Pa gyrase, and overexpression in the absence of antitoxin yielded an expected filamentous morphology with multi-foci nucleic acid material. Additional data revealed that the PaParE toxin is monomeric and interacts with dimeric PaParD antitoxin with a KD in the lower picomolar range, yielding a heterotetramer. This work provides novel insights into chromosome-encoded ParE function, whereby its expression can impart partial protection to cultures from selected antibiotics. PMID- 30427087 TI - Arabidopsis E2Fc is required for the DNA damage response under UV-B radiation epistatically over the microRNA396 and independently of E2Fe. AB - UV-B radiation inhibits plant growth, and this inhibition is, to a certain extent, regulated by miR396-mediated repression of Growth Regulating transcription Factors (GRFs). Moreover, E2Fe transcription factor also modulates Arabidopsis leaf growth. Here, we provide evidence that, at UV-B intensities that induce DNA damage, E2Fc participates in the inhibition of cell proliferation. We demonstrate that E2Fc deficient plants show a lower inhibition of leaf size under UV-B conditions that damage DNA, decreased cell death after exposure and altered SOG1 and ATR expression. Interestingly, the previously reported participation of E2Fe in UV-B responses, which is a transcriptional target of E2Fc, is independent and different of that described for E2Fc. On the other hand, we here demonstrate that E2Fc has an epistatic role over the miR396 pathway under UV-B conditions. Finally, we show that inhibition of cell proliferation by UV-B is independent of the regulation of class II TCP transcription factors. Together, our results demonstrate that E2Fc is required for miR396 activity on cell proliferation under UV-B, and that its role is independent of E2Fe, probably modulating DNA damage responses through the regulation of SOG1 and ATR transcript levels. This article is protected by copyright. All rights reserved. PMID- 30427088 TI - The role of parasite dispersal in shaping a host-parasite system at multiple evolutionary scales. AB - Parasite dispersal can shape host-parasite interactions at both deep and shallow timescales. One approach to understanding the effects of dispersal is to study parasite lineages that differ in dispersal capability but are from the same group of hosts. We compared phylogenetic and population genetic patterns of wing and body lice from ground-doves. Wing lice are more capable of dispersal than body lice. We sequenced full genomes of individual lice for multiple representatives of several wing and body louse species. From these data, we assembled genes for phylogenetic analysis and called SNPs for population genetic analysis. At the phylogenetic level, body lice showed more codivergence with their hosts than did wing lice. However, both wing and body lice exhibited some phylogenetic congruence with their hosts. Within species, body lice showed more population genetic structure than wing lice, although both types of lice showed some structure according to biogeography. Body lice also had significantly lower heterozygosity than wing lice, suggesting more inbreeding. Our results demonstrate that dispersal can shape a host-parasite system across evolutionary time, but also that other factors (e.g., host association and biogeography) can have varying degrees of influence on different groups of parasites and at different timescales. This article is protected by copyright. All rights reserved. PMID- 30427089 TI - Elevational patterns and hierarchical determinants of biodiversity across microbial taxonomic scales. AB - Microbial biogeography is gaining increasing attention due to recent molecular methodological advance. However, the diversity patterns and their environmental determinants across taxonomic scales are still poorly studied. By sampling along an extensive elevational gradient in subarctic ponds of Finland and Norway, we examined the diversity patterns of aquatic bacteria and fungi from whole community to individual taxa across taxonomic coverage and taxonomic resolutions. We further quantified cross-phylum congruence in multiple biodiversity metrics and evaluated the relative importance of climate, catchment and local pond variables as the hierarchical drivers of biodiversity across taxonomic scales. Bacterial community showed significantly decreasing elevational patterns in species richness and evenness, and U-shaped patterns in local contribution to beta diversity (LCBD). Conversely, no significant species richness and evenness patterns were found for fungal community. Elevational patterns in species richness and LCBD, but not in evenness, were congruent across bacterial phyla. When narrowing down the taxonomic scope towards higher resolutions, bacterial diversity showed weaker and more complex elevational patterns. Taxonomic downscaling also indicated a notable change in the relative importance of biodiversity determinants with stronger local environmental filtering, but decreased importance of climatic variables. This suggested that niche conservatism of temperature preference was phylogenetically deeper than that of water chemistry variables. Our results provide novel perspectives for microbial biogeography and highlight the importance of taxonomic scale dependency and hierarchical drivers when modelling biodiversity and species distribution responses to future climatic scenarios. This article is protected by copyright. All rights reserved. PMID- 30427090 TI - Potential use of ivabradine for treatment of atrial fibrillation. PMID- 30427091 TI - Health-related quality of life in paediatric haemophilia B patients treated with rIX-FP. AB - INTRODUCTION: Frequent infusions and bleeds can impact on the health-related quality of life (HRQoL) of paediatric haemophilia B patients. rIX-FP (IDELVION(r) ) is a fusion protein linking recombinant factor IX with recombinant albumin, and is associated with low bleeding rates with a weekly regimen, which could improve HRQoL. AIMS: To measure the effect of rIX-FP prophylaxis on the HRQoL of paediatric patients and treatment satisfaction in their caregivers using the Haemo-QoL and Hemo-SATP questionnaires, respectively. METHODS: At baseline and end-of-study (EOS), patients 4-11 years old participating in the PROLONG-9FP program answered the Haemo-QoL questionnaire and gave information on their socio demographic data and physical activity. Caregivers completed the Hemo-SatP . Minimal important differences (MID) (|Cohen's d| > 0.5) between baseline and EOS and the number of responders (patients with meaningful subject-level improvements over time) at EOS were calculated. RESULTS: Twenty patients (age group I: 4-7 years old [n = 12]; age group II: 8-12 years old [n = 8]) completed the Haemo-QoL questionnaire at baseline. MIDs were found in age group I representing improvement for "physical health" (d = -0.547) domain; 60% of patients were responders for "physical health." In age group II, MIDs were seen in most domains; 71.4% patients were responders in "total score." In caregivers, improvements were seen for most domains of the Hemo-SatP with a small effect size. Fewer patients missed school when treated with rIX-FP and 94.1% patients maintained their physical activity level. CONCLUSION: Prophylaxis with rIX-FP led to substantial improvements in HRQoL in paediatric patients and treatment satisfaction in caregivers. PMID- 30427092 TI - Variations of electrocardiographic parameters during hospitalization predict long term outcomes in patients with non-ST-segment elevation myocardial infarction. AB - BACKGROUND: Electrocardiogram is an essential modality for diagnosis and early risk stratification for patients with acute coronary syndrome (ACS), but its long term prognostic value has not been well studied. This study tried to investigate the long-term prognostic value of variations of ECG parameters at admission and discharge in patients with non-ST-segment elevation myocardial infarction (NSTEMI). METHODS: A total of 170 NSTEMI patients were recruited consecutively from 2013 to 2014 in West China Hospital of Sichuan University. All subjects' ECGs at admission and discharge were reviewed. Follow-up was performed, and the survival difference between groups was analyzed. RESULTS: Comparing with at admission, NSTEMI patients at discharge with a wider P wave (19.4% vs. 8.1%, p = 0.047), with new-onset PtfV1 positive (31.2% vs. 8.1%, 11.5%, 13.3%, p = 0.147) and with a greater number of leads showing ST depression (21.9% vs. 10.3%, p = 0.037) were prone to MACEs during long-term follow-up. The independent risk factors for the primary endpoints determined using a multivariate cox regression were new-onset PtfV1 positive during hospitalization (HR = 4.705, 95% CI = 1.457 15.197, p = 0.010) and prolonged QRS duration at discharge comparing to admission (HR = 2.536, 95% CI = 1.057-6.083, p = 0.030), besides diabetes mellitus, stage 3 hypertension, and multiple vessel lesions. CONCLUSION: Discharge ECG with new onset PtfV1 positive and prolonged QRS duration were independent risk factors for recurrence of MACEs in NTEMI patients. The differences of ECG parameters between at admission and discharge, including P-wave duration, number of leads with ST segment depression, carried long-term prognostic information for NSTEMI patients. PMID- 30427094 TI - The coronary sinus: Novel arrhythmogenic aspects. PMID- 30427093 TI - Randomized, double-blind, placebo-controlled phase II trial of nanocurcumin in prostate cancer patients undergoing radiotherapy. AB - Clinical potential of curcumin in radiotherapy (RT) setting is outstanding and of high interest. The main purpose of this randomized controlled trial (RCT) was to assess the beneficial role of nanocurcumin to prevent and/or mitigate radiation induced proctitis in prostate cancer patients undergoing RT. In this parallel group study, 64 eligible patients with prostate cancer were randomized to receive either oral nanocurcumin (120 mg/day) or placebo 3 days before and during the RT course. Acute toxicities including proctitis and cystitis were assessed weekly during the treatment and once thereafter using CTCAE v.4.03 grading criteria. Baseline-adjusted hematologic nadirs were also analyzed and compared between the two groups. The patients undergoing definitive RT were followed to evaluate the tumor response. Nanocurcumin was well tolerated. Radiation-induced proctitis was noted in 18/31 (58.1%) of the placebo-treated patients versus 15/33 (45.5%) of nanocurcumin-treated patients (p = 0.313). No significant difference was also found between the two groups with regard to radiation-induced cystitis, duration of radiation toxicities, hematologic nadirs, and tumor response. In conclusion, this RCT was underpowered to indicate the efficacy of nanocurcumin in this clinical setting but could provide a considerable new translational insight to bridge the gap between the laboratory and clinical practice. PMID- 30427095 TI - Sports participation and physical activity in patients with von Willebrand disease. AB - INTRODUCTION: Patients with bleeding disorders may experience limitations in sports participation and physical activity. Several studies on sports participation have been performed in haemophilia patients, but studies in patients with von Willebrand disease (VWD) are lacking. AIM: We assessed the sports participation and physical activity of a large cohort of VWD patients. METHODS: Patients were included from the "WiN study." All patients completed a questionnaire on sports participation, physical activity, quality of life and bleeding symptoms (Tosetto bleeding score). RESULTS: From the 798 included patients, 474 had type 1, 301 type 2 and 23 type 3 VWD. The mean age was 39 +/- 20 (standard deviation) years. Five hundred and fifty-two patients (69.3%) participated in various types of sports. Type 3 VWD patients more often did not participate in sports due to fear of bleeding and physical impairment, respectively, OR = 13.24 (95% CI: 2.45-71.53) and OR = 5.90 (95% CI: 1.77-19.72). Patients who did not participate in sports due to physical impairment had a higher bleeding score item for joint bleeds 1.0 (+/-1.6) vs 0.5 (+/- 1.1) (P = 0.036). Patients with type 3 VWD and patients with a higher bleeding score frequently had severe limitations during daily activities, respectively, OR = 9.84 (95% CI: 2.83-34.24) and OR = 1.08 (95% CI: 1.04-1.12). CONCLUSION: The majority of VWD patients participated in sports. Patients with type 3 VWD, a history of joint bleeds and a more severe bleeding phenotype frequently experienced limitations in sports participation and physical activities during daily life. PMID- 30427096 TI - Holobiont suture zones: Parasite evidence across the European house mouse hybrid zone. AB - Parasite hybrid zones resulting from host secondary contact have never been described in nature although parasite hybridization is well known and secondary contact should affect them similarly to free-living organisms. When host populations are isolated, diverge, and re-contact, intimate parasites (host specific, direct life cycle) carried during isolation will also meet and so may form parasite hybrid zones. If so, we hypothesize these should be narrower than the host's hybrid zone as shorter parasite generation time allows potentially higher divergence. We investigate multilocus genetics of two parasites across the European house mouse hybrid zone. We find each host taxon harbours its own parasite taxa. These also hybridize: parasite hybrid zones are significantly narrower than the host's. Here we show a host hybrid zone is a suture zone for a subset of its parasite community and highlight the potential of such systems as windows on the evolutionary processes of host-parasite interactions and recombinant pathogen emergence. This article is protected by copyright. All rights reserved. PMID- 30427097 TI - Accuracy of Three Digitization Methods for the Dental Arch with Various Tooth Preparation Designs: An In Vitro Study. AB - PURPOSE: To evaluate the accuracy of three digitization methods for the maxillary dental arch. MATERIALS AND METHODS: A maxillary typodont with various tooth preparation designs was used as the reference model. The scanned data were classified into direct scanning (DS), cast scanning (CS), and impression scanning (IS) groups according to the techniques applied for digitization (n = 10/group). An intraoral scanner was used for the DS group. Impressions obtained with polyether impression material were scanned with a tabletop scanner for the IS group. For the CS group, the definitive casts fabricated from the obtained impressions were scanned with the same tabletop scanner. The accuracy (trueness and precision) of the produced virtual dental casts was evaluated with specialized software. The full-arch and individual abutment deviations were measured with regard to root mean square error (RMSE) values. Data were analyzed with statistical software with an RESULTS: The RMSE values for both trueness and precision were lowest in the IS group, followed by the CS and DS groups, with statistically significant differences among the groups (p < 0.05). The trueness of individual abutments was significantly higher in the IS group than in the DS group. In addition, the trueness of individual abutments was affected by the location of the abutments in the DS group, whereas it did not differ between individual abutments in the CS and IS groups. CONCLUSIONS: These findings suggest that the IS method is an accurate digitization technique for the creation of a virtual dental cast. PMID- 30427099 TI - Previews. PMID- 30427098 TI - The early repolarization pattern: Echocardiographic characteristics in elite athletes. AB - BACKGROUND: The electrocardiographic early repolarization (ER) pattern is associated with idiopathic ventricular fibrillation and increased long-term cardiovascular mortality. Whether structural cardiac aberrations influence the phenotype is unclear. Since ER is particularly common in athletes, we evaluated its prevalence and investigated predisposing echocardiographic characteristics and cardiopulmonary exercise capacity in a cohort of elite athletes. METHODS: A total of 623 elite athletes (age 21 +/- 5 years) were examined during annual preparticipation screening from 2006 until 2012 including electrocardiography, echocardiography, and exercise testing. ECGs were analyzed with focus on ER. All athletes participated in a clinical follow-up. RESULTS: The prevalence of ER was 17% (108/623). ER-positive athletes were predominantly male (71%, 77/108), showed a lower heart rate (57.1 +/- 9.3 bpm versus 60.0 +/- 11.2 bpm; p = 0.015) and a higher lean body mass compared to ER-negative participants (88.1% +/- 5.6% versus 86.5% +/- 6.3%; p = 0.015). Echocardiographic measurements and cardiopulmonary exercise capacity in male and female athletes with and without ER largely showed similar results. Only the notching ER subtype (n = 15) was associated with an increased left atrial diameter (OR 7.01, 95%CI 1.65-29.83; p = 0.008), a higher left ventricular mass (OR 1.02, 95%CI 1.00-1.03; p = 0.038) and larger relative heart volume (OR 1.01, 95%CI 1.00-1.01; p = 0.01). During a follow-up of 7.4 +/- 1.5 years, no severe cardiovascular event occurred in the study sample. CONCLUSIONS: In elite athletes presence of ER is not associated with distinct alterations in echocardiography and cardiopulmonary exercise. Athletes presenting with ER are rather male, lean with a low heart rate. PMID- 30427100 TI - Measurement of joint health in persons with haemophilia: A systematic review of the measurement properties of haemophilia-specific instruments. AB - INTRODUCTION: Accurate assessment of joint health in persons with haemophilia is crucial. Several haemophilia-specific measurement tools are available, but an overview of the measurement properties is lacking. AIM: To provide an overview of the measurement properties of haemophilia-specific measurement tools to assess clinical joint health. METHODS: MEDLINE and EMBASE were searched for reports on reliability, validity or responsiveness of the World Federation of Haemophilia Orthopedic Joint Score (WFH), Colorado Physical Examination Score (CPE), joint examination score by Petrini (PJS) and Hemophilia Joint Health Score (HJHS). Methodological quality of the studies was assessed using an adapted COSMIN checklist. RESULTS: The search yielded 2905 unique hits, and 98 papers were included. The methodological quality of the included studies was limited. The HJHS was studied most extensively, which yielded limited evidence for good internal consistency and structural validity, moderate evidence for hypothesis testing in adults and conflicting evidence for hypothesis testing in children. Reliability, measurement error and responsiveness were rated unknown due to low COSMIN scores. For the CPE and PJS, we found limited to moderate evidence for good responsiveness and conflicting evidence for hypothesis testing. CONCLUSION: Only patchy evidence is available on the quality of measurement properties of all haemophilia-specific joint health scores. Although significant gaps in the evidence for all instruments remain, measurement properties of the HJHS were most extensively studied and show no drawbacks for use in clinical practice. This review forms the basis for further research aimed at the assessment of measurement properties of measurement tools to assess joint health. PMID- 30427101 TI - Does haemophilia slow down the development of liver fibrosis? PMID- 30427102 TI - Fungal adaptation to plant defenses through convergent assembly of metabolic modules. AB - The ongoing diversification of plant defense compounds exerts dynamic selection pressures on the microorganisms that colonize plant tissues. Evolutionary processes that generate resistance towards these compounds increase microbial fitness by giving access to plant resources and increasing pathogen virulence. These processes entail sequence-based mechanisms that result in adaptive gene functions, and combinatorial mechanisms that result in novel syntheses of existing gene functions. However, the priority and interactions among these processes in adaptive resistance remains poorly understood. Using a combination of molecular genetic and computational approaches, we investigated the contributions of sequence-based and combinatorial processes to the evolution of fungal metabolic gene clusters encoding stilbene cleavage oxygenases (SCOs), which catalyze the degradation of biphenolic plant defense compounds known as stilbenes into monophenolic molecules. We present phylogenetic evidence of convergent assembly among three distinct types of SCO gene clusters containing alternate combinations of phenolic catabolism. Multiple evolutionary transitions between different cluster types suggest recurrent selection for distinct gene assemblages. By comparison, we found that the substrate specificities of heterologously expressed SCO enzymes encoded in different clusters types were all limited to stilbenes and related molecules with a 4'-OH group, and differed modestly in substrate range and activity under the experimental conditions. Together, this work suggests a primary role for genome structural rearrangement, and the importance of enzyme modularity, in promoting fungal metabolic adaptation to plant defense chemistry. This article is protected by copyright. All rights reserved. PMID- 30427103 TI - Putatively adaptive genetic variation in the giant California sea cucumber (Parastichopus californicus) as revealed by environmental association analysis of RADseq data. AB - Understanding the spatial scale of local adaptation and the factors associated with adaptive diversity are important objectives for ecology and evolutionary biology, and have significant implications for effective conservation and management of wild populations and natural resources. In this study, we used an environmental association analysis (EAA) to identify important bioclimatic variables correlated with putatively adaptive genetic variation in a benthic marine invertebrate - the giant California sea cucumber (Parastichopus californicus) - spanning coastal British Columbia and southeastern Alaska. We used a redundancy analysis (RDA) with 3,699 SNPs obtained using RAD sequencing to detect candidate markers associated with 11 bioclimatic variables, including sea bottom and surface conditions, across two spatial scales (entire study area and within sub-regions). At the broadest scale, RDA revealed 59 candidate SNPs, 86% of which were associated with mean bottom temperature. Similar patterns were identified when population structure was accounted for. Additive polygenic scores, which provide a measure of the cumulative signal across all candidate SNPs, were strongly correlated with mean bottom temperature, consistent with spatially varying selection across a thermal gradient. At a finer scale, 23 candidate SNPs were detected, primarily associated with surface salinity (26%) and bottom current velocity (17%). Our findings suggest that environmental variables may play a role as drivers of spatially varying selection for P. californicus. These results provide context for future studies to evaluate the genetic basis of local adaptation in P. californicus and help inform the relevant scales and environmental variables for in situ field studies of putative adaptive variation in marine invertebrates. This article is protected by copyright. All rights reserved. PMID- 30427104 TI - Histopathological characterization of the neuroglial tissue in ovarian teratoma associated with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. AB - Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare but occasionally fatal limbic encephalitis that may be accompanied by ovarian teratoma. Since the neuroglial tissue within the teratoma may be involved in the pathogenesis of this encephalitis, we attempted morphological and immunohistochemical characterization of the neuroglial tissue in four cases of ovarian teratoma associated with anti NMDA receptor encephalitis and 12 control cases, i.e., six consecutive cases of immature teratoma and six cases of mature teratoma with an abundant neuronal component, focusing mainly on NMDA receptor-expressing neurons. NMDA receptor expressing neurons, being observed in all of the cases analyzed, were significantly densely aggregated (P = 0.030, Wilcoxon test) and relatively smaller in size in the encephalitis-associated cases than in the control cases, and the Ki-67 labeling index of neuroglial cells with these neurons was significantly higher in the encephalitis-associated cases (P = 0.004, Wilcoxon test). In the cases with encephalitis, aggregation of B-cells within or around the neuroglial tissue was also observed. Our present findings may be useful for more accurate diagnosis of anti-NMDA receptor encephalitis and contribute to a better understanding of the pathogenesis. PMID- 30427105 TI - Metabolic factors affecting hepatocellular carcinoma in steatohepatitis. AB - BACKGROUND & AIMS: With the rising prevalence of alcoholism, obesity and metabolic syndrome, steatohepatitis will become the leading cause of end-stage liver disease and hepatocellular carcinoma in the United States by 2025. Patients with non-alcoholic steatohepatitis and alcoholic liver disease have similar clinical and histopathological presentations, whether these similarities persist in non-alcoholic steatohepatitis and alcoholic liver disease patients with hepatocellular carcinoma remains unknown. METHODS: A retrospective analysis of the clinical features of adult patients from a large transplant center who underwent liver transplantation for steatohepatitis due to non-alcoholic steatohepatitis and alcoholic causes (alcoholic liver disease) between 1/1/02 and 1/1/12 was performed. Clinical features, explant histopathology, and clinical outcomes were compared. RESULTS: Hepatocellular carcinoma was present in 80 of 317 patients, who underwent liver transplantation for steatohepatitis with equivalent distribution in non-alcoholic steatohepatitis and alcoholic liver disease patients (24% vs 26%; P = 0.8). On multivariate analysis, significant predictors of hepatocellular carcinoma included age, ethnicity (Hispanic), and diabetes, but not BMI, hypertension or smoking. A lower risk of hepatocellular carcinoma was associated with a clinical history of hyperlipidemia. Clinical parameters were similar between patients with alcoholic liver disease - hepatocellular carcinoma and non-alcoholic steatohepatitis-hepatocellular carcinoma, except sex and presence of metabolic syndrome. non-alcoholic steatohepatitis-hepatocellular carcinoma livers retained histopathological features of non-alcoholic steatohepatitis such as ballooning and Mallory bodies, while alcoholic liver disease-hepatocellular carcinoma livers did not. There were no significant differences in hepatocellular carcinoma recurrence rates or post transplant overall survival. CONCLUSIONS: We report the largest single-center study evaluating clinical, histopathological and outcome measures of patients undergoing liver transplantation for steatohepatitis. Older patients, diabetics, and Hispanics may warrant more frequent cancer screening due to increased risk of hepatocellular carcinoma. PMID- 30427106 TI - Functional traits but not environmental gradients explain seed weight in Mongolian plant species. AB - Seed weight varies by several orders of magnitude among vascular plant species. However, the importance of potential drivers like environmental conditions and plant functional traits were rarely assessed for a larger taxonomic sample. We collected seeds of 148 species from 237 sites spread across Mongolia and compared their weight among the major zonal vegetation types, taxonomic groups and a set of functional traits (growth form, dispersal mode, fruit type, storage organs and palatability). Seed weight strongly varied among all functional traits and taxonomic groups, but no differences among vegetation zones were detected. These results suggest a low impact of environmental conditions on the evolution of seed weight contrasting the strong phylogenetic signal. This article is protected by copyright. All rights reserved. PMID- 30427107 TI - Helical Multi-Coordination Anion-Binding Catalysts Enable Highly Enantioselective Dearomatization of Pyrylium Derivatives. AB - A general and highly enantioselective synthesis of oxygen heterocycles from readily available in situ generated pyrylium derivatives has been realized by embracing a multi-coordination triazole-based anion-binding catalysis approach. The high activity of the helical tetrakistriazole catalysts (TetraTri), with distinct confined anion-binding pockets, allows remarkably low catalytic loadings (down to 0.05 mol%), while providing a simple access to chiral chromanones and dihydropyrones in high enantioselectivities (up to 98:2 e.r.). Moreover, experimental and theoretical studies provide new insights into the H-donor ability and key binding interactions of the TetraTri catalysts and its host:guest complexes, suggesting the formation of a 1:3 species. PMID- 30427109 TI - Processing and targeting of Cathepsin L (TbCatL) to the Lysosome in Trypanosoma brucei. AB - Cathepsin L (TbCatL) is an essential lysosomal thiol protease in African trypanosomes. TbCatL is synthesized as two precursor forms (P/X) that are activated to mature form (M) with the removal of the prodomain upon arrival in the lysosome. We examine TbCatL trafficking in a novel system: truncated TbCatL reporter without the C-terminal domain (CTD) (TbCatL?) ectopically expressed in an RNAi cell-line targeting the CTD/3'UTR of endogenous mRNA. TbCatL? is synthesized as P'/X'/M' species, localizes to the lysosome, and rescues the lethal TbCatL RNAi phenotype. Inactive TbCatLDelta:C150A is only processed to M' in the presence of endogenous TbCatL indicating trans-auto-catalysis activation. X' is formed with active ER-retained TbCatLDelta:MDDL, but not with TbCatLDelta:C150A, indicating stochastic generation in the ER by cis-auto cleavage within the prodomain of newly synthesized P'. Modeling the TbCatL prodomain on the human CatL structure suggests three solvent accessible features that could contain post-Golgi targeting signals: the N-terminus, the Helix 1 Turn 1 junction, and a separate turn (T3). We demonstrate that the critical motif for lysosomal targeting is an asparagine-proline dipeptide in T3 that is strictly conserved in all Kinetoplastida. These findings show novel insights on the maturation of TbCatL, which is a critical virulence factor in mammalian infection. PMID- 30427108 TI - Host membrane glycosphingolipids and lipid microdomains facilitate Histoplasma capsulatum internalisation by macrophages. AB - Recognition and internalisation of intracellular pathogens by host cells is a multifactorial process, involving both stable and transient interactions. The plasticity of the host cell plasma membrane is fundamental in this infectious process. Here, the participation of macrophage lipid microdomains during adhesion and internalisation of the fungal pathogen Histoplasma capsulatum (Hc) was investigated. An increase in membrane lateral organisation, which is a characteristic of lipid microdomains, was observed during the first steps of Hc macrophage interaction. Cholesterol enrichment in macrophage membranes around Hc contact regions and reduced levels of Hc-macrophage association after cholesterol removal also suggested the participation of lipid microdomains during Hc macrophage interaction. Using optical tweezers to study cell-to-cell interactions, we showed that cholesterol depletion increased the time required for Hc adhesion. Additionally, fungal internalisation was significantly reduced under these conditions. Moreover, macrophages treated with the ceramide glucosyltransferase inhibitor (P4r) and macrophages with altered ganglioside synthesis (from B4galnt1-/- mice) showed a deficient ability to interact with Hc. Coincubation of oligo-GM1 and treatment with Cholera toxin Subunit B, which recognises the ganglioside GM1, also reduced Hc association. Although purified GM1 did not alter Hc binding, treatment with P4 significantly increased the time required for Hc binding to macrophages. The content of CD18 was displaced from lipid microdomains in B4galnt1-/- macrophages. In addition, macrophages with reduced CD18 expression (CD18low ) were associated with Hc at levels similar to wild-type cells. Finally, CD11b and CD18 colocalised with GM1 during Hc macrophage interaction. Our results indicate that lipid rafts and particularly complex gangliosides that reside in lipid rafts stabilise Hc-macrophage adhesion and mediate efficient internalisation during histoplasmosis. PMID- 30427110 TI - A feared combination: Hypertension and chronic kidney disease. PMID- 30427111 TI - Secondary mania as a possible presentation of a C9orf72 hexanucleotide repeat expansion. AB - C9Orf72 hexanucelotide repeat expansions have been associated with ALS and FTD. Although various psychiatric symptoms have been described in patients with C9Orf72 hexanucleotide repeat expansions, the full clinical spectrum has not yet been elucidated. There is increasing evidence that inflammation plays a role in the disease progression of ALS and FTD (1) and immune dysfunction is strongly associated with bipolar disorder. We present a case in which we hypothesize that inflammation may trigger a secondary mania as an expression of latent FTD/ALS in an older male C9orf72 hexanucleotide repeat expansion carrier. We also review the literature on psychiatric disease in association with FTD and C9orf72 hexanucleotide repeat expansions. This article is protected by copyright. All rights reserved. PMID- 30427113 TI - Automated Glycan Assembly of Plant Oligosaccharides and Their Application in Cell Wall Biology. AB - The plant cell wall provides the richest available resource of fermentable carbohydrates and bio-based materials. The main component of plant cell walls is cellulose, the most abundant biomolecule on earth. Besides cellulose, which is constructed from relatively simple beta-1,4-glucan chains, plant cell walls also contain the structurally more complex heteropolysaccharides hemicellulose and pectin, as well as lignin and cell wall proteins. A detailed understanding of the molecular structures, functions, and biosyntheses of cell wall components is required to further promote their industrial use. Plant cell wall research is to a large part hampered by a lack of available well-defined oligosaccharide samples representing the structural features of cell wall glycans. One technique to access these oligosaccharides is automated glycan assembly, a technique in which monosaccharide building blocks are, similarly to automated peptide and oligonucleotide chemistry, successively added to a linker-functionalized resin in a fully automated manner. This concept article covers recent research from our laboratory on the automated glycan assembly of different classes of cell wall glycans that were used as molecular tools for cell wall biology. More than 60 synthetic oligosaccharides were prepared and printed as microarrays for screening monoclonal antibodies that recognize plant cell wall polysaccharides. The synthesized oligosaccharides have also been used to investigate glycosyltransferases and glycosyl hydrolases, which are involved in synthesis and degradation of plant cell walls, as well as for the analysis of cell wall remodeling enzymes. PMID- 30427112 TI - A Noble-Metal-Free Metal-Organic Framework (MOF) Catalyst for the Highly Efficient Conversion of CO2 with Propargylic Alcohols. AB - Cyclization of propargylic alcohols with CO2 is an important reaction in industry, and noble-metal catalysts are often employed to ensure the high product yields under environmentally friendly conditions. Herein a porous noble-metal free framework 1 with large 1D channels of 1.66 nm diameter was synthesized for this reaction. Compound 1 exhibits excellent acid/base stability, and is even stable in corrosive triethylamine for one month. Catalytic studies indicate that 1 is an effective catalyst for the cyclization of propargylic alcohols and CO2 without any solvents under mild conditions, and the turnover number (TON) can reach to a record value of 14 400. Furthermore, this MOF catalyst also has rarely seen catalytic activity when the biological macromolecule ethisterone was used as a substrate. Mechanistic studies reveal that the synergistic catalytic effect between CuI and InIII plays a key role in the conversion of CO2 . PMID- 30427114 TI - Seed Enhancing Treatments: Comparative Analysis of Germination Characteristics of 23 Key Herbaceous Species used in European Restoration Programs. AB - The response of seeds from 23 wild plant species to a range of seed enhancing treatments was studied. We tested the hypothesis that sensitivity of the 23 species to these compounds is related to their ecological niche. The three ecological niches we considered were open land, open-pioneer and woodland, each with distinct characteristics. Hence, the germination of a species is likely adapted to different light conditions and other environmental signals related to the niche. As representatives of environmental signals, the effects of smoke related compounds (karrikinolide, KAR1 ), nitrate and plant growth regulator (gibberellic acid, GA3 ) on germination were studied. Seeds were exposed to these three additives in the imbibition medium; all described as germination cues. We also investigated the effect of different light regimes and additives on germination parameters, which included final germination, germination rate and uniformity of germination. Seeds were placed to germinate under three light conditions: constant red light, constant darkness and 12h white light photoperiod. The results showed that no single treatment increased the germination of all the tested species, rather a wide variation of responsiveness of the different species to the three compounds was found. Additionally, no interaction was found between responsiveness to compounds and ecological niche. However, species in the same ecological niche and dormancy class showed a similar responsiveness to light. Species that share a similar environment have similar light requirements for germination, while differences exist among species in their responsiveness to other germination cues. This article is protected by copyright. All rights reserved. PMID- 30427115 TI - Pressure drop in liquid chromatography. AB - Measurement of pressure drop is routinely performed during chromatographic runs. In many cases this information is only used for regulation of mobile phase flow rate to keep pressure drop below defined limit. However, pressure drop can provide additional important information about performance of chromatographic process. In this review different parameters affecting pressure drop such as compressibility of chromatographic media, nature of applied sample and mobile phase flow regime are discussed. Detailed analysis correlating organization of particle based chromatographic media and pressure drop is presented together with its extension to convective media such as membranes and monoliths but also novel 3D printed media. Finally, estimation of layer thickness formed by adsorbed molecules based on a pressure drop data is presented and its applicability is discussed. PMID- 30427116 TI - The circadian blood pressure variability: There is a signal in the noise. PMID- 30427117 TI - Design, synthesis and biological evaluation of imidazo[1,2-a]pyridine analogues or derivatives as anti-helmintic drug. AB - The Albendazole was used as the lead compound, which was modified by structural transformation and with alkyl groups. A total of 18 compounds (4a-4r) were designed and synthesized. The in vitro experiment results showed that compounds 4e, 4f, 4k, 4l, 4q and 4r had good inhibitory effect on egg and imago of roundworm. IC50 of compound 4l to anti-egg of roundworm was 0.65 +/- 0.01 MUmol/L and to anti-imago of roundworm was 1.04 +/- 0.01 MUmol/L. At the same time, it showed that compound 4l had the best effect in vivo, and the rate of anti helmintic could reach more than 99%. The results of acute toxicity tests indicated that these compounds were with LD50 > 2100 mg/kg by oral administration, so they were low toxicity compounds. In a word, compound 4l was most likely to be a new anti-helmintic drug through screening in vitro and in vivo. PMID- 30427118 TI - Study on the metabolites of betulinic acid in vivo and in vitro by ultra high performance liquid chromatography with time-of-flight mass spectrometry. AB - Betulinic acid is a triterpenoid organic acid with remarkable antitumor properties and is naturally present in many fruits, condiments and traditional Chinese medicines. Currently, a strategy was developed for the identification of metabolites following the in vivo and in vitro biotransformation of Betulinic acid with rat intestinal bacteria utilizing ultra high performance liquid chromatography with time-of-flight mass spectrometry with polymeric solid-phase extraction. As a result, 46 metabolites were structurally characterized. The results demonstrated that Betulinic acid is universally metabolized in vivo and in vitro, and Betulinic acid could undergo general metabolic reactions, including oxidation, methylation, desaturation, loss of O and loss of CH2 . Additionally, the main metabolic pathways in vivo and in vitro were determined by calculating the relative content of each metabolite. This is the first study of Betulinic acid metabolism in vivo, whose results provide novel and useful data for better understanding of the safety and efficacy of Betulinic acid. PMID- 30427119 TI - Matrix-induced Linear Stark Effect of Single Dibenzoterrylene Molecules in 2,3 Dibromonaphthalene Crystal. AB - Absorption and fluorescence from single molecules can be tuned by applying an external electric field - a phenomenon known as the Stark effect. A linear Stark effect is associated to a lack of centrosymmetry of the guest in the host matrix. Centrosymmetric guests can display a linear Stark effect in disordered matrices, but the response of individual guest molecules is often relatively weak and non uniform, with a broad distribution of the Stark coefficients. Here we introduce a novel single-molecule host-guest system, dibenzoterrylene (DBT) in 2,3 dibromonaphthalene (DBN) crystal. Fluorescent DBT molecules show excellent spectral stability with a large linear Stark effect, of the order of 1.5 GHz/kVcm 1 , corresponding to an electric dipole moment change of around 2 D. Remarkably, when the electric field is aligned with the a crystal axis, nearly all DBT molecules show either positive or negative Stark shifts with similar absolute values. These results are consistent with quantum chemistry calculations. Those indicate that DBT substitutes three DBN molecules along the a-axis, giving rise to eight equivalent embedding sites, related by the three glide planes of the orthorhombic crystal. The static dipole moment of DBT molecules is created by host-induced breaking of the inversion symmetry. This new host-guest system is promising for applications that require a high sensitivity of fluorescent emitters to electric fields, for example to probe weak electric fields. PMID- 30427120 TI - Redox-mediator-enhanced Electrochemical Capacitors: Recent Advances and Future Perspectives. AB - Supercapacitors deliver exceptional power density, long cycling stability, and instinctive safety, but suffer from a low energy density. Many methods to enhance the energy density are based on exploring electrode materials with well-developed structures and designing asymmetric systems with a wide voltage window. The energy density is substantially enhanced at the compromise of power density for the sluggish kinetics of pseudocapacitive materials. The emerging redox-active electrolytes can contribute additional pseudocapacitance from the reactions of redox mediators at the interface, which have attracted increasing attentions of researchers. The redox-mediator-enhanced supercapacitors deliver a high energy density with retaining high power density. This minireview highlights the recently prominent progresses of single-, dual- and ambipolar-redox-mediator enhanced supercapacitors, their facing challenges, and approaches to suppress self-discharge and develop high-concentration redox-active electrolyte for performance promotion. PMID- 30427121 TI - Counter-current chromatography melamine-modified column and its separation mechanism. AB - In this work, to further verify and develop the novel counter-current chromatography modified column separate mode, a melamine modified counter-current chromatography column was prepared. Meanwhile, the modified counter-current chromatography column was used to separate stevioside and rebaudioside A with the same partition coefficient in chosen solvent system to evaluate its separation efficiency. The results show that because of the presence of intermolecular forces between melamine and model compounds, better separation could be achieved on the modified column while it's almost impossible to be separated on the unmodified column. So the results of this research further show that column modified method is a possible approach to further increase the separation ability of counter-current chromatography. Take advantage of large sample handing capacity of counter-current chromatography, the mothed may have great potential to be an efficient method of separation and preparation enantiomer compounds. PMID- 30427122 TI - Using natural deep eutectic solvents for the extraction of metabolites in Byrsonima intermedia leaves. AB - Natural deep eutectic solvents have been used as an alternative to organic solvents for the extraction of plants metabolites, allowing for the extraction of compounds of different polarities, while being inexpensive, non-toxic, and easy to prepare. This work presents the comparison of the chromatographic profiles by high-performance liquid chromatography with diode-array detection obtained from Byrsonima intermedia (Malpighiaceae) using five choline chloride-based natural deep eutectic solvents, in addition to the most used traditional extraction solvents, methanol/water 7:3 and ethanol/water 7:3 v/v. A reference extract was used to tentatively identify compounds by high-performance liquid chromatography with tandem mass spectrometry. The water content appeared to be important for the extraction efficiency and the mixture choline chloride/glycerol was shown to be the best candidate for efficiently extracting this matrix when compared with the traditional extraction media in addition to being far greener as shown by the environmental analysis tool. Seven phenolic compounds (digalloyl quinic acid, proanthocyanidin dimer, galloylproanthocyanidin dimer, quercetin-O-hexoside, galloyl quercetin hexoside, quercetin-O-pentoside, and galloyl quercetin pentoside) were tentatively identified in all extracts. Moreover, the influence of these solvents on the antioxidant activity of the extracts was studied and the results for choline chloride/glycerol extracts were very similar to that of the traditional extraction solvents. PMID- 30427123 TI - Live cell imaging of Plasmodiophora brassicae-host plant interactions based on a two-step axenic culture system. AB - Plasmodiophora brassicae, a parasitic protist, induces club-shaped tumor-like growth of host Brassicas roots and hypocotyls after infection. Due to its soil borne nature and intracellular, biotrophic parasitism the infection biology and early pathogenesis remains in doubt. In this study, we have established a new protocol, based on a two-step axenic culture of P. brassicae with its host tissues, for easy and in planta observation of cellular interactions between P. brassicae and host plants: first, coculture of P. brassicae with infected canola root tissues, on growth-medium plates, enables the propagation of P. brassicae that serves as pure inoculum for pathogenicity assays, and second, the pure inoculum is subsequently used for pathogenicity tests on both canola and Arabidopsis seedlings grown on medium plates in Petri dishes. During the first axenic culture, we established a staining protocol by which the pathogen was fluorescently labeled with Nile red and calcofluor white, thus allowing in planta observation of pathogen development. In the pathogenicity assays, our results showed that axenic cultures of P. brassicae, in calli, remains fully virulent and completes its life cycle in both canola and Arabidopsis roots grown in Petri dishes. Combining visualization of fluorescent probe-labeled P. brassicae structures with fluorescent protein tagging of Arabidopsis cellular components, further revealed dynamic responses of host cells at the early stages of P. brassicae infection. Thus, established protocols for in planta detection of P. brassicae structures and the live cell imaging of P. brassicae-Arabidopsis interactions provide a novel strategy for improving our detailed knowledge of P. brassicae infection in host tissues. PMID- 30427124 TI - Antihypertensive therapy prescribing patterns and correlates of blood pressure control among hypertensive patients with chronic kidney disease. AB - We used electronic health records (EHRs) data from 5658 ambulatory chronic kidney disease (CKD) patients with hypertension and prescribed antihypertensive therapy to examine antihypertensive drug prescribing patterns, blood pressure (BP) control, and risk factors for resistant hypertension (RHTN) in a real-world setting. Two-thirds of CKD patients and three-fourths of those with proteinuria were prescribed guideline-recommended renoprotective agents including an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB); however, one-third were not prescribed an ACEI or ARB. CKD patients, particularly those with stages 1-2 CKD, who were prescribed regimens including beta-blocker (BB) + diuretic or ACEI/ARB + BB + diuretic were more likely to have controlled BP (<140/90 mm Hg) compared to those prescribed other combinations. Risk factors for RHTN included African American race and major comorbidities. Clinicians may use these findings to tailor antihypertensive therapy to the needs of each patient, including providing CKD stage-specific treatment, and better identify CKD patients at risk of RHTN. PMID- 30427125 TI - Relationships between residual blood pressure variability and cognitive function in the general population of the PAMELA study. AB - The present study was aimed at assessing the relationships between absolute and individual residual blood pressure (BP) variability and cognitive function in a general population. This cross-sectional study evaluated cognitive function using minimental state evaluation (MMSE) in 471 subjects enrolled in the PAMELA study. MMSE was calculated 10 years after initial enrollment of the subjects in the PAMELA study. Measurements included office, home, and 24-hour ambulatory BP monitoring. BP variability was obtained by calculating: (a) 24-hour standard deviation (SD) for systolic and diastolic BP and (b) individual residual BP variability. Mean age (+/-SD) of the subjects enrolled was 63 +/- 5.7 years at the initial evaluation, with a 10-year increase when MMSE was performed. There was no significant difference in BP or heart rate values measured at office, home, or during 24-h BP monitoring between subjects with MMSE < 24 and those with >=24. BP variability measured by SBP and DBP SD was also similar between these two groups. However, individual residual BP variability was significantly greater in subjects with lower MMSE and this difference became more pronounced when the study population was divided in three groups according to MMSE score (10-20, 21 23, 24-30). Individual residual SBP and DBP variability gradually decreased with the increase in MMSE score. Our data show that a sensitive parameter for the development of cognitive impairment is not BP or absolute BP variability but rather its short-term erratic component, which has been previously shown to be an important prognostic marker for organ damage, cardiovascular, and all-cause mortality. PMID- 30427126 TI - Porcine reproductive and respiratory syndrome virus NADC30-like strain accelerates Streptococcus suis serotype 2 infection in vivo and in vitro. AB - Porcine reproductive and respiratory syndrome (PRRS), an economically significant pandemic disease, commonly results in increased impact of bacterial infections, including those by Streptococcus suis (S. suis). In recent years, PRRS virus (PRRSV) NADC30-like strain has emerged in different regions of China, and co infected with S. suis and PRRSV has also gradually increased in clinical performance. However, the mechanisms involved in host innate responses towards S. suis and their implications of co-infection with NADC30-like strain remain unknown. Therefore, the pathogenicity of NADC30-like strain and S. suis serotype 2 (SS2) co-infection in vivo and in vitro was investigated in this study. The results showed that NADC30-like increased the invasion and proliferation of SS2 in blood and tissues, resulting in more severe pneumonia, myocarditis and peritonitisas well as higher mortality rate in pigs. In vitro, NADC30-like strain increased the invasion and survival of SS2 in porcine alveolar macrophages (PAM) cells, causing more drastic expression of inflammatory cytokines and activation of NF-KB signaling. These results pave the way for understanding the interaction of S. suis with the swine immune system and their modulation in a viral co infection. This article is protected by copyright. All rights reserved. PMID- 30427127 TI - Recent advances in mixed-mode chromatographic stationary phases: Special issue on "Separation Innovations" in the Journal of Separation Science (JSS) dedicated to Prof. Frantisek Svec on the occasion of his 75th birthday. AB - The mixed-mode phases have become very popular in the last decade and the number of new mixed/multi-mode sorbents is growing fast. Unlike single-mode stationary phases perfectly suited for the separation of the analytes possessing similar physicochemical properties, for instance reversed-phase chromatography for hydrophobic solutes, mixed-mode sorbents providing multimodal interactions can render a better separation selectivity for complex mixtures of solutes differing significantly in their physicochemical characteristics. The most frequent modern mixed-mode stationary phases are di/tri-mode sorbents embracing the following interactions, hydrophobic, electrostatic (coulombic) and hydrophilic. According to their structures, it is possible to distinguish silica-based, polymer-based, hybrid, and monolithic mixed-mode stationary phases. Herewith, newly synthesized mixed-mode sorbents developed within the last two and half years are categorized, discussed, and summarized. The main attention is devoted to the description of the synthetic routes and characterization methods applied for the new stationary phases. This article is protected by copyright. All rights reserved. PMID- 30427128 TI - Ultrasonographic assessment of articular cartilage of the femoral condyle in patients with an increased Q-angle. AB - INTRODUCTION: The patella is a sesamoid for the quadriceps, which increases its power during knee extension and thus transfers considerable forces. The etiology of patellofemoral pain is multifactorial. In the absence of injury, the commonly accepted hypothesis is associated with increased compression of articulating surfaces. AIM: The aim of the study was to perform an ultrasound evaluation of the thickness of articular cartilage covering the medial and lateral femoral condyle in patients with an increased Q-angle. MATERIALS AND METHODS: The study included 26 women aged between 35 and 45 years. A total of 13 patients with Q >15 degrees were included in the study group, and 13 patients with Q <=15 degrees were included in the control group. A goniometer was used for Q-angle measurement. The thickness of articular cartilage covering the medial and lateral femoral condyle of the femoral bone was measured using a HONDA HS-2200 ultrasound with a linear HLS-584M transducer. The Shapiro-Wilk test was used for the assessment of data distribution normality; the distribution was normal. The differences in the measured parameters were assessed with the ANOVA test for independent samples. The Bonferroni test was used for a multiple comparison. RESULTS: The statistical analysis showed statistically significantly reduced thickness of articular cartilage on the lateral femoral condyle ( p = 0.00) in the Q >15 degrees group. No statistically significant differences were demonstrated for the thickness of articular cartilage on the medial femoral condyle ( p = 0.47). CONCLUSIONS: The thickness of the articular cartilage on the lateral femoral condyle is lower than that of the medial femoral condyle in women aged between 35 and 45 years with the Q-angle >15 degrees . PMID- 30427129 TI - Incidence of intrauterine abnormalities in Pakistani women with unexplained infertility diagnosed via saline infusion sonography. AB - To determine the frequency of intrauterine abnormalities in women with unexplained infertility using saline infusion sonography. This was a retrospective cohort study conducted at Aziz medical centre, Karachi, Pakistan between January and December 2015. The study population comprised of women with unexplained infertility who underwent saline infusion sonography as a part of their diagnostic workup. The frequency of uterine abnormalities in these women was determined and the relationship between these pathologies and patient age and body mass index was assessed. Of the 769 women included, 202 (26.3%) had uterine abnormalities. Endometrial polyp (118 cases, 15.3%) was the most common abnormality, followed by submucous fibroids (54, 7%), intrauterine adhesions (20, 2.6%), and septae (10, 5%). Intrauterine pathologies were more common in women with primary infertility (71.8% versus 28.2%, p = 0.002). Uterine abnormalities were most common in the age group 30-34 years ( n = 80, 39.6%) and in overweight patients ( n = 95, 47%). The distribution of abnormalities differed significantly in various age groups ( p = 0.009) and among women with different BMI ( p = 0.029). A significant number of women with unexplained infertility present with unsuspected uterine abnormalities; therefore an assessment of the uterine cavity should be performed in all cases. PMID- 30427130 TI - Comparison of lung ultrasound and chest X-ray findings in children with bronchiolitis. AB - Respiratory syncytial virus is the main pathogen responsible for bronchiolitis. Usually, there is no indication to perform diagnostic imaging or run laboratory tests in patients with bronchiolitis since the diagnosis is based on the clinical presentation. Chest radiogram can be useful in severe cases. So far, lung ultrasound has not been considered as an alternative in guidelines for imaging diagnosis of bronchiolitis. The aim of the study was to compare lung ultrasound and chest X-ray findings in children with bronchiolitis. In our study we retrospectively compared diagnostic imaging findings in children with confirmed respiratory syncytial virus infection. The study included 23 children aged 2 weeks to 24 months and 3 children older than 24 months. Chest X-ray showed lesions in only 4 cases, whereas ultrasound abnormalities were found in 21 patients. Pathologies revealed by chest X-ray were the same for all 4 cases and consisted of an enlarged hilus and peribronchial cuffing. Sonographic lesions included inflammatory consolidations larger than 10 mm in 11 patients, small consolidations (<10 mm diameter) in 8 patients, interstitial syndromes in 6 patients, and alveolar-interstitial syndromes in 11 patients. A small amount of pleural effusion was detected in 3 patients. Considering safety, short time of examination, high sensitivity in finding pleural effusion, small consolidations and signs of interstitial infiltrations, transthoracic lung ultrasound may be useful in the diagnosis of bronchiolitis. PMID- 30427131 TI - Ultrasound findings in extragenital endometriosis. AB - We present a report on ultrasound findings in extragenital endometriosis and a literature review accompanied by illustrations. Intestinal endometriosis should be considered in female patients of reproductive age who present with constipation, gastrointestinal bleeding, nausea, vomiting, cramp-like abdominal pain, diarrhoea and pelvic pain. Although definitive preoperative diagnosis of endometriosis is difficult, clinical suspicion and appropriate imaging might prevent extensive surgical procedures with higher morbidity. Contrast-enhanced ultrasound is an efficient non-invasive imaging method without any radiation exposure that supports the early diagnosis of intestinal endometriosis and may help assess the vascularization of endometriotic lesions within the distinct layers of the intestinal wall. PMID- 30427132 TI - TRUS-guided drainage of the ectopic ureter entering the prostatic urethra and TRUS-guided transurethral neo-orifice formation using holmium laser. AB - A fifty-nine year-old male was hospitalized for exacerbation of chronic pancreatitis. As a gigantic cyst of the pancreatic tail was identified, it was fused with the jejunal loop. Due to persistent fever and severe symptoms in the storage and voiding phases, the patient was referred to a urologist. Because transrectal ultrasound examination revealed a fluid collection resembling the left seminal vesicle filled with purulent material, a transrectal puncture procedure was performed. The analysis of computed tomography scans led to the diagnosis of duplicated collecting system of the left kidney with the enormous ureter of the upper moiety that entered the prostate gland. In order to permanently decompress the hydronephrosed upper moiety of the left kidney, the patient was deemed eligible for endoscopic treatment. A transurethral incision through the bladder wall and the adjacent segment of the ectopic ureter was made with holmium laser under transrectal ultrasonography guidance, thus creating a neo-orifice of this ureter. PMID- 30427134 TI - Charcot foot in a diabetic patient - clinical and imaging considerations. PMID- 30427133 TI - Spontaneous resolution of unifocal Langerhans cell histiocytosis of the skull: potential role of ultrasound in detection and imaging follow-up. AB - Langerhans cell histiocytosis is a tumor-like condition characterized by idiopathic proliferation of Langerhans cells. The disease may involve the skeleton as well as other organs systems. Bone involvement may be solitary or multifocal. Unifocal osseous Langerhans cell histiocytosis may involve virtually any bone, with the calvarium being most frequently involved. Plain radiography, computed tomography and magnetic resonance imaging are the most used techniques for detection and characterization of the lesion. The use of ultrasound is less known, although it may be a valuable technique in detection and follow-up of superficially located lesions such as calvarial lesions. This case report describes an 8-year-old girl, in whom the lesion was initially detected by ultrasound. Furthermore, ultrasound was used to evaluate spontaneous resolution of the lesion. The knowledge of ultrasound characteristics may be important to avoid unnecessary radiation and gadolinium administration, particularly in a pediatric population. PMID- 30427135 TI - APPLICATION OF GRAFTSKINTO ACCELERATE HEALING OF ULCERSIN DIABETIC FOOT SYNDROME. AB - Diabetic foot syndrome (DFS) is one of the severe and morefrequent complications of diabetes. It is characterized by occurrenceof chronic purulent necrotic processes (trophic ulcers) onthe foot with damage of skin, soft tissues and osteoarticular systemdue to pathological changes in the peripheral nervous system(diabetic neuropathy) and vascular system (diabetic angiopathy).This study aimed to evaluate the possibility of accelerating ofwound healing in DFS by using the dermal equivalent (graftskin)and determine the safety of the method, factors and indicationsfor its application. The research included 60 patients with DFSwho were cured at the period from 2013 to 2016 in departmentsof purulent surgery of Hospital of war veterans and Municipalhospital No 14 of Saint-Petersburg. The patients were dividedinto 2 groups by random sampling of two comparable groups inage and sex. The patients of main group were treated by standardmethod and using application of dermal equivalent (DE) on thearea of trophic ulcers. The patients of control group had onlystandard treatment. The DE showed a high efficacy in the maingroup of patients. The application of DE in complex treatment ofpatients with DFS stimulated processes of healing and acceleratedthe rate of epithelization. The application of DE was themost effective in patients with neuropathic form of DFS. PMID- 30427136 TI - ANALYSIS OF COMPLICATIONSIN ELIMINATION OF THE COLOSTOMYAFTER HARTMANN SURGERY. AB - An analysis of early postoperative complications was madein reconstructive surgery on the colon in case of the end colostomyin patients with left-half colon cancer complicated byintestinal obstruction. This work investigated the prognosticfactors, which could influence on incidence of complications.The research included results of reconstructive operations in 192patients. The early postoperative complications were noted in 18(9,4%) patients. The univariant analysis of risk factors showed,that the presence COPD increased the possibility of complicationincidence in 1,7 times (p=0,044). The incidence of purulentcomplications on previous stage of treatment increased complicationsin 4,3 times (p=0,011) and the third degree of adhesionsprocess intensity compared with the first degree - in 9,7 times(p=0,001). The multivariant analysis demonstrated a correlationof the complication risks in reconstructive operations with presenceof complications on the previous stage of treatment. Thiscorrelation was 4,3 (CI 1,7-23,3; p=0,021) and it consisted of 7,5 (CI 1,3-15,6; p=0,001) in case of presence of the third degreeof adhesion process. PMID- 30427137 TI - EXPERIENCE OF 424 ROBOT-ASSISTEDOPERATIONS IN ST-PETERSBURG:RADICAL PROSTATECTOMY,PARTIAL AND RADICAL NEPHRECTOMY. AB - The article presents the results of 257 robot-assisted radicalprostatectomies, 135 partial nephrectomies and 32 radicalnephrectomies at the period from 2010 to 2016. The operationswere performed on robotic complex da Vinci S. The mean operativetime was 170+/-50 min, 158,4+/-72,2 min and 143,3+/-67,3 min,the mean blood loss was 130+/-35 ml, 213,0+/-102,2 ml and141,4+/-49,0 ml for robotic radical prostatectomy, partial and radicalnephrectomy, respectively. The mean time of warm ischemiaconsisted of 13,1+/-2,7 min. Five-year cancer-specific survival ratewas 100%, 100% and 98%. The overall survival rate was 97,5%,87% and 92% for robotic radical prostatectomy, partial and radicalnephrectomy, respectively. PMID- 30427138 TI - EXPERIENCE OF APPLICATION OF VOLUMEFORMING AGENT "DAM+" IN TREATMENTOF ANAL INCONTINENCE ASSOCIATED WITHINCOMPETENCE AND TRAUMA OF ANALSPHINCTER. AB - The attempts of introduction of volume forming agent insubmucous layer started at the beginning of 1990th. The aim ofthese innovations was to rise of basal pressure. This researchhas been performing since 2007. It included experimental andclinical phases with participation of 41 patients with anal incompetenceaged 3 26 years old. The agent "DAM+" was introducedin submucous layer of anal sanal in four points. The basal pressurewas risen in 2-3 times after implantation and it was at theaverage more 65% of age standards. The application of volumeforming agent "DAM+" is effective method of correction of analincontinence. It'll require the re-introduction procedure in longtermperiod. PMID- 30427139 TI - PHARMACOECONOMIC ANALYSISOF EFFICACY OF DIFFERENT MODESOF ANTIBIOTIC PROPHYLAXISIN CHOLECYSTECTOMY. AB - Pharmacoeconomic assessment of efficacy of differentmodes of antibiotic prophylaxis was made in 27 patients withdiagnosis of acute calculous cholecystitis using method of"cost-efficacy". Patients have taken ampicillin/sulbactam intravenouslyin the dose of 1,5 g or cephazolin intravenously inthe dose 2,0 g. Medicine should be taken in 30 min. before theoperation. The most expensive was antibiotic prophylaxis bycephazolin. The coefficient of "cost-efficacy" was 774,2 rubleson 1 unit of efficacy in case of cephazolin and it was 506,1 rubleson 1 unit of efficacy in other group with antibiotic prophylaxis byampicillin/sulbactam. The authors noted the economical and clinicaladvantage of antibiotic prophylaxis by ampicillin /sulbactam. PMID- 30427140 TI - INFLUENCE OF PERMANENT PACINGOF THE ATRIA FROM UPPER ANTERIORAREA OF INTERCARDIAC SEPTA (AREAOF BAKHMAN'S FASCICLES) ON THEPART OF AMOTIVATIONAL VENTRICLESTIMULATION. AB - This research includes 74 patients with syndrome of thesinus node asthenia. The application of permanent bilocularpacing was indicated for these patients. An atrial electrode waslocated in the right atrial auricle in 37 patients and it was in thearea of Bakhman's fascicles in other 37 patients. All the patientshad a stimulated atrio-ventricular delay on 250 ms, but sensingdelay was shorter on 20 ms. Given data were analyzed afteroperation in the periods of 6 and 12 months. Cumulative percentof ventricular stimulation was significantly less in the group withelectrode in the area of Bakhman's fascicles (6%) as comparedwith the group where electrode installed in the right atrial auricle(41%) after 6 months. There were 4% in comparison with 43%after 12 months. The localization of atrial electrode in the areaof Bakhman's fascicles led to reduction of cumulative percent ofventricular stimulation on 35% after 6 months and on 39% after12 months. Permanent pacing in the area of Bakhman's fasciclescould be an effective mode to decrease the part of amotivationalstimulation of the right ventricle. PMID- 30427141 TI - COMPARATIVE ASSESSMENTOF THORACOSCOPY AND DESTRUCTIONOF PULMONARY BULLAS COMBINEDWITH PLEURODESIS AND PLEURECTOMY. AB - The article presents the results of thoracoscopic surgeriesin case of bullous emphysema of the lung in 88 patients. Thepatients have been divided into 2 groups according to the methodof treatment: 1) destruction of pulmonary bullas and pleurodesisusing diathermic electrocoagulation (42 people); 2) destructionof pulmonary bullas and subtotal pleurectomy (47 people). Theoperative periods weren't statistically differentiated in patient'sgroups. The volume of hemorrhage and exudation period fromthe pleural cavity were significantly higher in patient's group,where patients underwent pleurectomy. However, lung spreadingterms and ending of air leakage, periods of drains removal fromthe pleural cavity, hospital stay and rate of pneumothorax recurrencewere considerably smaller in the group without applicationof pleurodesis. PMID- 30427142 TI - ENDOSCOPIC METHODS OF DIAGNOSTICS ANDTREATMENT OF PAPILLOSTENOSIS. AB - Differential diagnostics of papillospasm and papillostenosisshould be based on the complex of clinical and instrumentalresearches with the priority to endoscopic technologies. Conservativetherapy should be considered as optimal option oftreatment for the patients with papillospasm. Preference of endoscopicoperations have to be in case of revealed papillostenosis ofdifferent degree. Similar differentiated diagnostics and treatmentmanagement justified in 90% of cases and led to improvement ofpatient's conditions and their recovery. PMID- 30427144 TI - CYTOREDUCTIVE OPERATIONSIN TREATMENT OF THE PATIENTS OF ELDERLYAND SENILE AGE WITH DISSEMINATED FORMSOF COLORECTAL CANCER. AB - Late diagnostics of colon cancer along with high specificweight of the patients of elder age groups indicated the urgencyof study of application of cytoreductive surgery in elderly andsenile patients of with colorectal cancer. A comparative assessmentof the results of cytoreductive operations (primary tumorresection) was made in two groups of patients with disseminatedcolon cancer (younger and older than 60 years old). It was stated,that the performance of palliative resection allowed them toobtain of encouraging remote results, provide more higher survivalrates than in patients of young and mean age groups. Themore frequent development of complications after cytoreductiveoperations was associated with decompensation of accompanyingpathology in patients of elder age groups. These data confirmedthe need of their adequate correction in preoperative period. Theapplication of cytoreductive surgery significantly improved thequality of life of the patients of elder age groups with disseminatedforms of colon cancer. PMID- 30427143 TI - LAPAROSCOPIC ADJUSTABLE GASTRICBANDING. ILLUSIONS AND REALITY. AB - This work analyzed the results of surgical treatment of 380patients who underwent the laparoscopic adjustable gastric banding(LAGB) at the period from 2004 to 2015. The patients wereinitially divided into 2 groups with metabolic syndrome (MS)and without MS according to the sex, age (up to 40 years old orolder). As the result of performed analysis, there was stated thatLAGB operation wasn't effective and couldn't be recommendedfor an application on the patients with MS. The patients haveto follow necessary advice for life. Otherwise, the probabilityof complication development and recurrent operation would bereally high and because of this, the more effective surgical treatmentshould be initially used. LAGB operation didn't influenceon pathogenetic mechanisms of main components of MS andcouldn't be regarded as effective. This LAGB operation is reasonableto apply in women without MS of young age group withinitial body mass index lower than 43 kg/m2. These women haveto be able strictly follow doctor's advice for life. PMID- 30427145 TI - [Evolution of treatment of syphilis through history]. AB - In this article, we present a historical revision of syphilis treatment since the end of the XV century up until the current days. For centuries, it was understood that syphilis had been brought to Spain by Columbus after coming back from America. It became an epidemic soon after. Later on, it was spread all over Europe. The chronologic and geographic origin of this illness have been debated in recent years, however, there has been no agreement about it as yet. Mercury was the main used therapy for four and a half centuries, until the discovery of penicillin in 1943. This discovery changed the therapeutic approach to syphilis since then. Other remedies were used during this period. Guaiacum was one of them, but it was dismissed in the mid-sixteenth century. Iodides were also used, especially in the tertiary symptoms of the disease. The discovery of arsphenamine (Salvarsan) at the beginning of the XX century, used by itself at its onset and associated to mercury or bismuth later on, was a significant therapeutic contribution. Bismuth was in itself a great therapeutic asset. It displaced the use of mercury in an important way until 1943, when the appearance of penicillin became the treatment of choice. PMID- 30427146 TI - EPIDEMIOLOGIC AND DEMOGRAPHICFEATURES OF INTRACRANIALOTO- AND RHINOSINUSOGENICPYOINFLAMMATORY COMPLICATIONSIN RUSSIAN FEDERATION. AB - An analysis of demographic and epidemiologic situationwas made in cases of otogenic and rhinosinusogenic intracranialcomplications on the area of 32 regions of Russian Federation atthe period from 2009 to 2014. The state of ENT-service of examinedsubject is characterized by reduction of provision of duringENT-beds and lower level of hospitalization of population overindicated period. There was revealed a reliable correlated dependenceof the main medical statistical indices from the intracranialcomplications with climatic and demographic factors, the rate ofmorbidity and activities of ENT-service in the area of this region. PMID- 30427147 TI - ABDOMINAL HEMORRHAGE IN CASEOF CATATRAUMA. AB - The results of diagnostic and treatment were analyzed in 111victims with abdominal multitrauma at the period from 2010 to2013. Abdominal traumas were diagnosed on the basis of instrumentalinvestigations and laparascopic data. Combined injurieswere often observed in 3-5 areas. The abdominal hemorrhageswere in 66 patients as a result of injury of the parenchymatousorgans. Diagnostic value of clinical symptoms wasn't more than45,9% in abdominal catatrauma, though in case of plan radiographyit was from 41,2% to 66,4% and in case of ultrasoundstudy - 91,6%. The laparotomy was performed for 28 patients.The laparoscopy was applied in 66 cases. However, there wererevealed the cases of continuing bleeding in 31 patients andbecause of these complications, the operations were convertedto laparotomy in 27 cases. Different variants of laparoscopiccoagulation were performed on 4 patients. The rate of lethalityconsisted of 27%. The authors proposed an algorithm of treatmentof the patients with closed abdominal injury on the basis ofscore assessment of hemoperitoneum (according to USS), whichallowed significant rise of treatment efficacy, decrease the rate ofpostoperative complications and lethality. PMID- 30427148 TI - COOPERATIVE MANAGEMENTOF NEUROSURGEON ANDOTOLARYNGOLOGIST IN TREATMENTOF CHILDREN WITH OTORHINOGENICSUPPURATIVE-INFAMMATORY BRAINDISEASES. AB - This work analyzed 47 cases of oto- and rhinosinusogenicsuppurative meningoencephalitis, abscesses and empyemas ofthe brain in children at the age from 3 months to 17 years old.The article presents the treatment strategy, results and the volumeof diagnostic measures. On the basis of this research, the authorscame to conclusion, that care of the children with otogenic andrhinosinusogenic suppurative diseases of the brain required aninterdisciplinary approach and effective cooperation of a neurosurgeon,otolaryngologist, pediatrician, resuscitation specialist,infectionist and a clinical pharmacologist. PMID- 30427149 TI - CHANGES IN BURNING WOUNDIN APLLICATION OF MAGNETO-PLASMATICTHERAPY. AB - The article analyzed treatments results of 76 patients withdeep burns. It was stated that magneto-plasma therapy facilitatedto the change from an inflammatory type of burn cytograms toregenerative type. These changes were expressed in reducingof neutrophil quantity in wound on the fifth day, decreasing ofdegenerative changed leukocytes on the tenth day, increasing ofphagocytic activity of neutrophils in all terms, growing of macrophagereaction by the fifth day and multiplication of fibroblastquantity in wound on the tenth day. The neutrophil and macrophagequantities were increased in the wound after necrectomydue to influence of magneto-plasmatic therapy on the third day.There was synthesized interleukin-8. The quantity of cells producingIL-8 was reduced on the tenth day. PMID- 30427150 TI - BASIC PRINCIPLES OF MODELLINDOF FACIAL COMPOSITE TISSUE ALLOGRAFTS. AB - The article presents the results of anatomical studies aimedto develop modelling of facial allografts taking into account the peculiarities of blood supply. The allografts should meet bothaesthetic and functional needs of the recipient for further use inclinical practice. There were selected 3 facial composite tissueallografts out of 50 modifications, which are more suitable forrequired parameters. On basis of these data, there was successfullyperformed the facial composite tissue allograft transplantationon the patient. PMID- 30427151 TI - FEATURES OF REHABILITATIONOF THE PATIENTS AFTER NONINFECTIOUSCOMPLICATIONS OF TOTAL HIPARTHROPLASTY. AB - The authors analyzed noninfectious complications (dislocationof endoprosthesis head, periprosthesis fractures) in8 patients out of 40 with hip arthroplasty. There were estimatedclinical, biomechanical results and quality of life of the patients.An application of the external fixator-orthezes should be recommendedin order to prevent complications of hip replacement.The wearing of brace is considered to be reasonable after revisioninterventions. PMID- 30427152 TI - PREDICTORS OF FATAL OUTCOMEIN PATIENTS WITH HEMORRHAGIC SHOCKIN GASTROINTESTINAL BLEEDING. AB - This work aimed to reveal the statistically reliable clinicaland laboratory markers, which are associated with fatal outcomesin patients with hemorrhagic shock of the III degree on the stageof hospital treatment. It was stated that decrease of body temperature(till 35,9 degrees C), pH of venous blood (till 7,19) and content ofionized calcium (till 0,32 mmole/l) in venous blood and increaseof lactate content (up to 4,1 mmole/l) in venous blood and rise ofactivated partial thromboplastin time (up to 59 sec) are connectedwith fatal outcomes. PMID- 30427153 TI - PERORAL ENDOSCOPIC MYOTOMYIN ESOPHAGEAL ACHALASIA:INTRAOPERATIVE COMPLICATIONSAND METHODS OF THEIR CORRECTION. AB - The authors analyzed complications in peroral endoscopicmyotomy in case of esophageal achalasia in 27 patients. Therewere noted hypercapnia, carboxyperitoneum, hemorrhage, perforationof mucous coat of esophagus. These complications weresuppressed during endoscopic manipulations. PMID- 30427154 TI - COMPLICATIONS OF TERMINAL COLOSTOMYIN PATIENTS WITH TUMOROUS LARGEINTESTINE ILEUS AND THEIR SURGICALMANAGEMENT. AB - The article analyzed the structure, incidence rate and resultsof surgical treatment of paracolostomal complications in 69 patients out of 134 (aged from 23 to 77 years old). The patientswere divided into 2 groups according to the variant of terminalcolostomy. The single-barrel colostomy was formed by classical(intraperitoneal) method using "proboscis" design in 58 patients(43,3%) of the first group. Various complications were developedin the area of colostomy in 42 (72,4%) patients. The single-barrelflat colostomy was applied at the skin level using the methodmodified by the authors in 76 (56,7%) patients of the secondgroup. The authors designed the method of controlled intra- andpostoperative decompression and lavage of the colon by a newmodel of aspiration-irrigation device in order to unload thecolon through colostomy. There were noted complications in thearea of colostomy in 27 (35,5%) cases. The developed rationalmethod of terminal colostomy formation, upgrading the ways ofintra- and postoperative decompression and lavage of the colonfacilitated to decrease of the rate of postcolostomy complicationsmore than two times (from 72,4 to 35,5%). The author's methodled to optimization of immediate and long-term results of surgicaltreatment. PMID- 30427155 TI - METHOD OF OPERATIVE TREATMENTOF POSTNECROTIC CYSTS OF THE PANCREAS. AB - An analysis of treatment results was made in 26 patientswith postnecrotic cysts of different degree of maturity. Thelaparotomy with trans-gastral cystogastrostomy on the externaldrainage were performed on 11 patients. A new modifiedoperation underwent 15 patients. This operation was transgastriccystogastrostomy on the external drainage from mini-access,which was developed in 2011. The laparotomy of 4-5 cm wasmade in pseudocyst projection of the pancreas using a standard setof tools "mini-assistant". Postoperative period have passed withoutcomplications in all the patients. The drainage was removedon 30-40 days of postoperative period. The terms of hospital stayreduced from (14,4+/-0,9) bed/ days to (10,8+/-0,5) bed/days due toapplication of proposed method of treatment. PMID- 30427156 TI - METHOD OF FORMING OF RESERVOIRPANCREATOANASTOMOSIS INPANCREATODUODENAL RESECTION. AB - The method based on formation of ileal reservoir with followinginvagination of pancreas stump inside it. A presence ofthe ileal reservoir with regulated vertical incision of the intestineexcepted the possibility of compression of the pancreas stumpby the intestine wall in glands invagination to the lumen. Themethod could be used in the existence of main risk factors: softtissues of the gland and the diameter less than 3 mm. This meanswas applied in 19 patients. There was noted inconsistence of pancreatoanastomosisin 3 (15,8%) patients. One female patient died(5,3%). The reason of death wasn't associated with features ofanastomosis forming. The results obtained indicated about goodpreventive properties of the proposed pancreatoanastomosis inrelation to complication development in case of unfavorableconditions for anastomosis formation. PMID- 30427157 TI - OUR EXPERIENCE OF OPTIMIZATIONAND LEGITIMIZATION OF HEART TEAM WORK(MEDICAL CONSULTATIONFOR DETERMINATION OF TREATMENTMANAGEMENT IN PATIENTSWITH ISCHEMIC HEART DISEASE). AB - The article raises the problem of optimization and legitimizationof work of the Heart Team. It also described thebackground and international experience, provided an overviewof the recent international guidelines in relation to managementof revasculization in patients with stable coronary artery disease.The article presents an experience of the I. P. Pavlov First Saint-Petersburg State Medical University. PMID- 30427158 TI - DIAGNOSTICS AND TREATMENTOF PERFORATED PYLORODUODENUM ULCERSIN WOMEN. AB - The results of treatment of 75 women with perforated ulcershave been studied. There were prevailed women of middle andelderly age groups among patients who underwent surgery. Awound closure of perforated opening and abdominal sanationwere performed by laparoscopic means in 30,7% of patients andusing midline laparotomy in 29,3% cases. There were carriedout the laparoscopic sanation of the abdominal cavity and thewound closure of perforated ulcer from mini-access using theset of mini-assistant in 10,7% patients. Radical operations wereapplied in 16% cases. The early postoperative complicationstook place in 8,1% of the patients, the rate of lethality was 4,0%.The long-term results were evaluated and considered as good in55,5% women, satisfactory - in 30,1% and unsatisfactory - in14,2% cases. PMID- 30427160 TI - Combined anti-and retrograde restoration of continuity of the common hepatic duct after multisystem injury. PMID- 30427159 TI - LONG-TERM RESULTS OF SURGICALTREATMENT OF DIVERTICULAR DISEASEOF COLON. AB - The work evaluated the long-term treatment results of 103patients with complicated diverticular disease, who underwentthe elective surgery in the volume of left hemicolectomy. Thefirst group included 53 patients with recurrent diverticula. Thesecond group consisted of 50 patients, who underwent theoperation on diverticula of sigmoid colon with formation ofsigmostoma on the first stage. The number of patients with functionalgastro-intestinal and psyco-emotional disorders was moresignificant in the first group compared with the second groupand it was associated with presence of these disorders beforethe operation. There was noted the reliable decrease of qualityof life rates according to questionnaire scales MOS-SF 36 in thefirst group. The average indices of scales had some matching tothe rates of health people in the patients of the second group.The authors came to conclusion, that indications for electivesurgery should be determined very carefully in case of recurrentdiverticula. PMID- 30427161 TI - Role of chemoembolization of the renal artery in surgical treatment of cancer of the kidney Parenchyma, Complicated By tumors thrombosis of the postcava. PMID- 30427162 TI - Surgical treatment of decompensated Hirschsprung's disease in adults with coexistent gastric cancer. PMID- 30427163 TI - History of treatment of esophageal atresia. PMID- 30427164 TI - Diabetic ketoacidosis following PEG-asparaginase therapy AB - We report a case of a 21-year-old African American female with history of pre diabetes, and a diagnosis of a rareleukemia, blastic-plasmacytoid dendritic neoplasm (BPDCN), who developed diabetic ketoacidosis (DKA) after the thirddose of PEG-asparaginase infusion. She was successfully treated with insulin. Asparaginase is a vital part of treatmentprotocols for acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic drugs. Asparaginasetherapy has been reported to cause hyperglycemia especially when used in conjunction with glucocorticoids for thetreatment of ALL in the pediatric population. Multiple mechanisms for hyperglycemia have been hypothesized whichinclude decreased insulin secretion, impaired insulin receptor function and excess glucagon formation. Hyperglycemia isusually self-limiting but can deteriorate to diabetic ketoacidosis. DKA is a rare adverse effect with asparaginase therapywith an incidence rate of about 0.8%.Learning points:** DKA is a rare finding following asparaginase therapy.** Hyperglycemia is most commonly seen with asparaginase treatment when used along with glucocorticoid.** Frequent blood glucose monitoring and prompt initiation of insulin treatment with hyperglycemia can preventsevere complications.** Patients and physician education on this complication can reduce morbidity due to DKA. PMID- 30427165 TI - An unusual presentation of post gastric bypass hypoglycemia with both postprandial and fasting hypoglycemia AB - There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH). Histopathologic findings fromsuch patients who underwent partial/total pancreatomy, however, can vary widely from minimal changes to classicnesidioblastosis, making the pathologic diagnosis challenging. PGBH typically presents as postprandial hypoglycemia, asopposed to insulinoma, which presents as fasting hypoglycemia. Herein, we describe an unusual case of a patient withPGBH who initially presented with postprandial hypoglycemia three years after surgery, but later developed fastinghyperinsulinemic hypoglycemia as the disease progressed. Our hypothesis for this phenomenon is that this disease isprogressive, and later in its course, the insulin release becomes dissociated from food stimulation and is increased atbaseline. Future studies are needed to investigate the prevalence as well as etiology of this progression from postprandialto fasting hypoglycemia.Learning points:** There has been an increasing awareness of post gastric bypass hypoglycemia (PGBH).** Histopathologically, PGBH can vary from minimal changes to nesidioblastosis.** Although uncommon, patients with PGBH after Roux-en-Y gastric bypass may present with both postprandial andfasting hyperinsulinemic hypoglycemia as disease progresses.** Our hypothesis for this phenomenon is that the insulin release becomes dissociated from food stimulation and isincreased at baseline with disease progression. PMID- 30427166 TI - Precise Modulation of Molecular Building Blocks from Tweezers to Rectangles for Recognition and Stimuli-Responsive Processes. AB - Alkynylplatinum(II) terpyridine complexes have been increasingly explored since the previous decades, mainly arising from their intriguing photophysical properties and aggregation affinities associated with their extensive Pt(II)...Pt(II) and pi-pi stacking interactions. Through molecular engineering, one can modulate their fundamental properties and assembly behavior by introduction of various functional groups and structural features. They can therefore serve as ideal candidates to construct metal complex-based molecular architectures to provide an alternative to organic compounds. The metal-based framework can be simultaneously built from predetermined building blocks, giving rise to their well-defined, unique, and discrete natures for molecular recognition. The individual constituents can contribute to molecular architectures with their integrated properties, allowing the manipulation of the various noncovalent intermolecular forces and interactions for selective guest capture. In this Account, our recent progress in the development of these metallomolecular frameworks based on the alkynylplatinum(II) terpyridine system and their recognition properties toward different guest molecules will be presented. Phosphorescent molecular tweezers have been constructed from the alkynylplatinum(II) terpyridine moiety to demonstrate host-guest interactions with cationic, charge-neutral and anionic platinum(II), palladium(II), gold(I), and gold(III) complexes and their binding affinities were found to be perturbed by different metal...metal, pi-pi and electrostatic interactions. The host-guest assembly process has also resulted in dramatic color changes, together with the turning on of near-IR (NIR) emissions as a result of extensive Pt(II)...Pt(II) interactions. Further work has also been performed to demonstrate that the tweezers can selectively recognize pi-surfaces of different planar pi-conjugated organic guests. The framework of molecular tweezers has been extended to a double decker tweezers structure, or a triple-decker structure, which can bind two equivalents of square-planar platinum(II) guests cooperatively to induce a significant color change in solution, representing rare examples of discrete Magnus' green-like salts. By the approaches of structural modifications, we have further modulated the host architecture from molecular tweezers to molecular rectangles. The rectangles have been found to show selective encapsulation of different transition metal complex guests based on the size and steric environment of the host cavity. The molecular rectangles also exhibit reversible host-guest association, in which guest capture and ejection processes can be manipulated by the pH environment, illustrating a potential approach for precise and smart delivery of therapeutic reagents to the slightly more acidic cancer cells. PMID- 30427167 TI - Visible-Light Driven Photoelectrochemical Platform Based on the Cyclometalated Iridium(III) Complex with Coumarin 6 for Detection of MicroRNA. AB - In this study, a novel iridium(III) complex-based photoactive species, [(C6)2Ir(dppz)]+PF6-, was synthesized with coumarin 6 (C6) as a cyclometalated ligand and dipyrido[3,2-a:2',3'-c]phenazine (dppz) as an ancillary ligand. The photophysical and electrochemical properties of the complex have been investigated. It exhibits intense visible-light absorption with a molar extinction coefficient up to 9.8 * 104 M-1 cm-1 at 485 nm. The photoelectrochemical (PEC) properties of [(C6)2Ir(dppz)]+PF6- were also investigated by spin-coating on the ITO electrode. By illumination with 490 nm light, cathodic photocurrent up to 260 nA/cm2 was observed at 0 V bias potential with dissolved O2 as an electron acceptor. On the other hand, an anodic photocurrent was generated in the presence of triethanolamine (TEOA) as a sacrificial electron donor. The probable mechanisms for photocurrent generation were deduced by UV-vis absorption spectrum and cyclic voltammetry data. Adopting [(C6)2Ir(dppz)]+PF6- as photoactive intercalator, a visible-light driven PEC detection platform was successfully fabricated for microRNA detection based on an enzyme-free hybridization chain reaction as an amplification strategy. Expected, the PEC platform for microRNA-122b detection showed excellent linear response with a limit of detection down to 0.23 fM (3sigma), comparable or superior to those of the reported analogous approaches. Encouragingly, this study would provide a new approach to exploit efficient photoactive species for PEC bioanalysis. PMID- 30427169 TI - Standing Mesochannels: Mesoporous PdCu Films with Vertically Aligned Mesochannels from Nonionic Micellar Solutions. AB - Mesoporous bimetallic palladium (Pd) alloy films with mesochannels perpendicularly aligned to the substrate are expected to show superior electrocatalytic activity and stability. The perpendicular mesochannels allow small molecules to efficiently access the active sites located not only at the surface but also within the film because of low diffusion resistance. When compared to pure Pd films, alloying with a secondary metal such as copper (Cu) is cost-effective and promotes resistance against adventitious poisoning through intermediate reactions known to impair the electrocatalytic performance. Here, we report the synthesis of mesoporous PdCu films by electrochemical deposition in nonionic micellar solutions. The mesoporous structures are vertically aligned on the substrate, and the final content of Pd and Cu can be adjusted by tuning the initial precursor molar ratio in the electrolyte solution. PMID- 30427170 TI - Convenient and Universal Fabrication Method for Antibody-Enzyme Complexes as Sensing Elements Using the SpyCatcher/SpyTag System. AB - Antibody-enzyme complexes (AECs) are ideal sensing elements, especially when oxidoreductases are used as the enzymes in the complex, with the potential to carry out rapid electrochemical measurements. However, conventional methods for the fabrication of AECs, including direct fusion and chemical conjugation, are associated with issues regarding the generation of insoluble aggregates and production of homogeneous AECs. Here, we developed a convenient and universal method for the fabrication of homogeneous AECs using the SpyCatcher/SpyTag system. We used an anti-epidermal growth factor receptor (EGFR) variable domain of a heavy chain antibody (VHH) and a glucose dehydrogenase (GDH) derived from Aspergillus flavus ( AfGDH) as the model antibody and enzyme, respectively. Both SpyTag-fused VHH and SpyCatcher-fused AfGDH were successfully prepared using an Escherichia coli expression system, whereas anti-EGFR AECs were produced by simply mixing the two fusion proteins. A bivalent AEC, AfGDH with two VHH at both terminals, was also prepared and exhibited an increased affinity. A soluble EGFR was successfully detected in a dose-dependent manner using immobilized anti-EGFR immunoglobulin G (IgG) and bivalent AEC. We also confirmed the universality of this AEC fabricating method by applying it to another VHH. This method results in the convenient and universal preparation of sensing elements with the potential for electrochemical measurement. PMID- 30427168 TI - A Difference in Internal Exposure Makes Newly Weaned Mice More Susceptible to the Hepatotoxicity of Retrorsine Than Adult Mice. AB - Pyrrolizidine alkaloids (PAs) are known hepatotoxins. Children have been reported to be particularly susceptible to PA-induced hepatotoxicity. To improve our understanding of the mechanisms of the age-dependent difference in susceptibility to PA hepatotoxicity, a comparative study of hepatotoxicities of retrorsine (RTS), a representative PA, was performed in newly weaned (3-4 weeks of age) and adult mice (8-12 weeks of age). Intraperitoneal administration of RTS at a dose of 50 mg/kg induced limited increases in serum ALT and AST activities in adult mice, while the same dosage of RTS caused intensified increases in serum ALT and AST activities in newly weaned mice. Toxicokinetic and metabolic activation studies in vitro and in vivo were performed to examine the factors responsible for the observed difference in toxicity susceptibility in mice of both ages. The values of AUC0-4h in plasma and liver of newly weaned mice are higher (all by 1.4 fold) than those in adult mice given the same dosage of RTS. As expected, more plasma pyrrolic ester-glutathione (GSH) conjugates (1.3-fold more) and pyrrolic ester-derived hepatic protein adduction (1.3-fold more) were found in newly weaned mice. Administration of RTS induced dramatic decreases in hepatic GSH levels (as little as 55% remained) of newly weaned mice, while the same dose of RTS did not reveal such GSH depletion in adult mice. The Vmax/ Km (CLint) for RTS metabolic activation in newly weaned mouse liver microsomes was found to be similar to that of adult mice. In conclusion, more internal exposure of RTS made newly weaned mice more susceptible to PA-induced hepatotoxicity. PMID- 30427171 TI - Multifunctional La0.67Sr0.33MnO3 (LSMO) Thin Films Integrated on Mica Substrates toward Flexible Spintronics and Electronics. AB - Integrating oxide thin films on flexible substrates is a critical step toward future applications of multifunctional oxides for flexible electronics and spintronic devices. As a demonstration, multifunctional La0.67Sr0.33MnO3 (LSMO) thin films have been deposited on flexible mica substrates. The crystallinity and microstructure of the films have been characterized to show the good epitaxial quality of the films. The LSMO thin films on mica present excellent ferromagnetic and magnetoresistance properties (such as saturation magnetization Ms of 125-400 emu/cm3 at 10 K and a high MR value of ~45% at 5 K under 1 T for the 50 mTorr deposited sample), which is even better than the ones on conventional rigid single-crystal oxide substrates. More interestingly, no deterioration of the properties is observed under mechanically bending condition, which demonstrates the good mechanical stretchability and property stability of the LSMO thin films on mica. The demonstration of functional oxides integrated on flexible mica substrates paves a route toward future flexible spintronics and electronics. PMID- 30427172 TI - Chemical Vapor-Deposited Vanadium Pentoxide Nanosheets with Highly Stable and Low Switching Voltages for Effective Selector Devices. AB - Recently, attempts to overcome the physical limits of memory devices have led to the development of promising materials and architectures for next-generation memory technology. The selector device is one of the essential ingredients of high-density stacked memory systems. However, complicated constituent deposition conditions and thermal degradation are problematic, even with effective selector device materials. Herein, we demonstrate the highly stable and low-threshold voltages of vanadium pentoxide (V2O5) nanosheets synthesized by facile chemical vapor deposition, which have not been previously reported on the threshold switching (TS) properties. The electrons occupying trap sites in poly-crystalline V2O5 nanosheet contribute to the perfectly symmetric TS feature at the bias polarity and low-threshold voltages in V2O5, confirmed by high-resolution transmission electron microscopy measurements. Furthermore, we find an additional PdO interlayer in V2O5 nanodevices connected with a Pd/Au electrode after thermal annealing treatment. The PdO interlayer decreases the threshold voltages, and the Ion/ Ioff ratio increases because of the increased trap density of V2O5. These studies provide insights into V2O5 switching characteristics, which can support low power consumption in nonvolatile memory devices. PMID- 30427173 TI - Defect Engineering in Single-Layer MoS2 Using Heavy Ion Irradiation. AB - Transition metal dichalcogenides (TMDs) have attracted much attention due to their promising optical, electronic, magnetic, and catalytic properties. Engineering the defects in TMDs represents an effective way to achieve novel functionalities and superior performance of TMDs devices. However, it remains a significant challenge to create defects in TMDs in a controllable manner or to correlate the nature of defects with their functionalities. In this work, taking single-layer MoS2 as a model system, defects with controlled densities are generated by 500 keV Au irradiation with different ion fluences, and the generated defects are mostly S vacancies. We further show that the defects introduced by ion irradiation can significantly affect the properties of the single-layer MoS2, leading to considerable changes in its photoluminescence characteristics and electrocatalytic behavior. As the defect density increases, the characteristic photoluminescence peak of MoS2 first blueshifts and then redshifts, which is likely due to the electron transfer from MoS2 to the adsorbed O2 at the defect sites. The generation of the defects can also strongly improve the hydrogen evolution reaction activity of MoS2, attributed to the modified adsorption of atomic hydrogen at the defects. PMID- 30427174 TI - Fluorescent Tracking of the Endoplasmic Reticulum in Live Pathogenic Fungal Cells. AB - In fungal cells, the endoplasmic reticulum (ER) harbors several of the enzymes involved in the biosynthesis of ergosterol, an essential membrane component, making this organelle the site of action of antifungal azole drugs, used as a first-line treatment for fungal infections. This highlights the need for specific fluorescent labeling of this organelle in cells of pathogenic fungi. Here we report on the development and evaluation of a collection of fluorescent ER trackers in a panel of Candida, considered the most frequently encountered pathogen in fungal infections. These trackers enabled imaging of the ER in live fungal cells. Organelle specificity was associated with the expression of the target enzyme of antifungal azoles that resides in the ER; specific ER labeling was not observed in mutant cells lacking this enzyme. Labeling of live Candida cells with a combination of a mitotracker and one of the novel fungal ER trackers revealed sites of contact between the ER and mitochondria. These fungal ER trackers therefore offer unique molecular tools for the study of the ER and its interactions with other organelles in live cells of pathogenic fungi. PMID- 30427176 TI - Quantification of Lipid Corona Formation on Colloidal Nanoparticles from Lipid Vesicles. AB - Formation of a protein corona around nanoparticles when immersed into biological fluids is well-known; less studied is the formation of lipid coronas around nanoparticles. In many cases, the identity of a nanoparticle-acquired corona determines nanoparticle fate within a biological system and its interactions with cells and organisms. This work systematically explores the impact of nanoparticle surface chemistry and lipid character on the formation of lipid coronas for 3 different nanoparticle surface chemistries (2 cationic, 1 anionic) on 14 nm gold nanoparticles exposed to a series of lipid vesicles of 4 different compositions. Qualitative (plasmon band shifting, zeta-potential analysis, dynamic light scattering on the part of the nanoparticles) and quantitative (lipid liquid chromatography/mass spectrometry) methods are developed with a "pull-down" scheme to assess the degree of lipid corona formation in these systems. In general, cationic nanoparticles extract 60-95% of the lipids available in vesicles under the described experimental conditions, while anionic nanoparticles extract almost none. While electrostatics apparently dominate the lipid-nanoparticle interactions, primary amine polymer surfaces extract more lipids than quaternary ammonium surfaces. Free cationic species can act as lipid-binding competitors in solution. PMID- 30427175 TI - Gabapentin Can Suppress Cell Proliferation Independent of the Cytosolic Branched Chain Amino Acid Transferase 1 (BCAT1). AB - The metabolism of branched-chain amino acids (BCAA) has recently been implicated in the growth of several cancer cell types. Gabapentin, a synthetic amino acid, is commonly used in high concentrations in this context to inhibit the cytosolic branched-chain amino acid transferase (BCAT1) enzyme. Here, we report that 10 mM gabapentin reduces the growth of HCT116 cells, which have an active branched chain amino acid transferase but express very low levels of BCAT1, and presumably rely on the mitochondrial BCAT2 enzyme. Gabapentin did not affect transamination of BCAA to branched-chain keto acids (BCKA) in HCT116 cells, nor the reverse formation of BCAA from BCKA, indicating that the branched-chain amino acid transaminase is not inhibited. Moreover, the growth-inhibitory effect of gabapentin could not be rescued by supplementation with BCKA, and this was not due to the lack of uptake of BCKA, indicating that other effects of gabapentin are important. An untargeted LC-MS analysis of gabapentin-treated cells revealed a marked depletion of branched-chain carnitines. These results demonstrate that gabapentin at high concentrations can inhibit cell proliferation without affecting BCAT1 and may affect mitochondrial BCKA catabolism. PMID- 30427178 TI - Chromium/Nickel-Doped Silicon Oxide Thin-Film Electrode: Mechanism and Application to Microscale Light-Emitting Diodes. AB - Light extraction of microscale light-emitting diodes (MULEDs) is fundamentally limited by p-type metal electrodes for current injection due to the small pixel size of the LEDs. We propose Cr/Ni-doped silicon oxide (CN-SiOX) films as p-type contact electrodes for blue MULEDs to increase the light-output power under the same emitting areas. The conductivity of CN-SiOX electrode originates from the diffusion of top Cr/Ni atoms via electric-field-induced doping treatments, which allows for effective hole injection into the active layer. Consequently, we achieved a 62% improvement in the current density and a 47% increase in the light output power compared to ITO-based MULEDs. PMID- 30427177 TI - CsPbBr3 Nanocrystal/MO2 (M = Si, Ti, Sn) Composites: Insight into Charge-Carrier Dynamics and Photoelectrochemical Applications. AB - Though coating CsPbBr3 nanocrystal (NC) with an outer layer has been regarded as an effective strategy to address its instability issues, deep investigations into the electronic interaction between CsPbBr3 NC and coating layer have yet to be conducted. In this study, the dynamics of hot carrier and charge carrier of CsPbBr3 nanocrystal with various MO2 (M = Si, Ti, Sn) coating layers have been comprehensively studied. Combined transient optical characterizations (time resolved photoluminescence and ultrafast transient absorption) and photoelectrochemical measurements reveal that coating with insulating SiO2 accelerates the hot carrier relaxation and enhances the radiative recombination by passivating surface traps, whereas efficient charge-carrier separation and extraction are observed after coating with SnO2 and TiO2. The electron injection from CsPbBr3 NC to SnO2 (1.14 * 108 s-1) is 2-fold faster than to TiO2 (5.4 * 107 s-1) owing to the lower conduction band edge and the higher electron mobility of SnO2. Particularly, the first time fabricated CsPbBr3 NC/SnO2 composite exhibits superior stability against UV light and moisture, as well as the best photocurrent response in this study. This work has implied that rational design of the coating layer for perovskite NC can not only improve the stability but also tailor the electronic and optoelectronic properties for various applications. PMID- 30427179 TI - Enhanced Polymer Crystallinity in Mixed-Matrix Membranes Induced by Metal-Organic Framework Nanosheets for Efficient CO2 Capture. AB - The design and fabrication of novel mixed-matrix membranes (MMMs) with simultaneously enhanced gas permeability and selectivity are highly sought for the industrial deployment of membrane technology for large-scale CO2 capture and storage. Conventional isotropic bulky particle fillers often exhibit limited interfacial compatibility that eventually leads to significant selectivity loss in MMMs. Here, we report the incorporation of chemically stable metal-organic framework (MOF) nanosheets into a highly permeable polymer matrix to prepare defect-free MMMs. MOF nanosheets are homogeneously dispersed within the polymer matrix, owing to their high aspect ratios that improve the polymer-filler integration. The strong hydrogen bonding and pi-pi interactions between the two components not only enhance the interfacial compatibility but also favor the efficient polymer chain packing along the surface of MOF nanosheets, leading to enhanced polymer crystallinity as well as size-sieving capability of the membranes. The as-prepared MMMs demonstrate high CO2-selective separation performance, good antipressure, and antiaging abilities, thus offering new opportunities in developing advanced membranes for industrial gas separation applications. PMID- 30427180 TI - Phosphine-Ligated Gold Clusters with Core+ exo Geometries: Unique Properties and Interactions at the Ligand-Cluster Interface. AB - Over recent years, research on the structures and properties of ligand-protected gold cluster molecules has gained significant interest. The crystal structure information accumulated to date has revealed the structural preference to adopt closed polyhedral geometries, but the use of multidentate ligands sometimes leads to the formation of exceptional structures. This Account describes results of our studies on diphosphine-coordinated [core+ exo]-type gold clusters featuring extra gold atoms outside the polyhedral cores, highlighting (1) their distinct optical properties due to the unique electronic structures generated by the exo gold atoms and (2) electronic/attractive ligand-cluster interactions that cause definite perturbation effects on the cluster properties. Subnanometer gold clusters with [core+ exo]-type geometries (nuclearity = 6, 7, 8, and 11) commonly displayed single absorption bands in the visible region, which are distinct in patterns from those of conventional polyhedral-only homologues. Theoretical studies demonstrated that the exo gold atoms are critically involved in the generation of unique electronic structures characterized by the HOMO-LUMO transitions with dominant oscillator strengths, leading to the appearance of the isolated absorption bands. On the basis of the frontier orbital distributions, the HOMO and LUMO were shown to be localized around the polyhedral cores and exo gold atoms, respectively. Therefore, the HOMO-LUMO transitions responsible for the visible absorptions occur in the core -> exo direction. The HOMO-LUMO gap energies showed no clear trends with respect to the nuclearity (size), indicating that the individual geometric features of the inorganic framework primarily govern the clusters' electronic structures and properties. Systematic studies using octagold clusters bearing various anionic coligands revealed that electronic or attractive interactions between the gold framework and ligand functionalities, such as pi-electron systems and heteroatoms, cause substantial perturbations of the wavelength of the visible absorption band due to the HOMO LUMO transitions. Especially, significant red shifts were observed as a result of the electronic coupling with specific pi-resonance contributors. It was also found that the orientation of aromatic rings around the inorganic framework is a factor that affects the cluster photoluminescence. These findings demonstrate the utility of the ligand moieties surrounding the gold frameworks for fine-tuning of the optical properties. During these studies, unusual but definite attractive interactions between the gold framework and C-H groups of the diphosphine ligand were found in the hexagold clusters. On the basis of careful crystallographic and NMR analyses, these interactions were deemed as a certain kind of M...H hydrogen bonds, which critically affect the maintenance of the cluster framework. Such unique interaction activities are likely due to the valence electrons in the gold framework, which serve as the hydrogen-bond acceptor for the unfunctionalized C-H groups. Overall, these observations imply the uniqueness of the ligand-cluster interface associated with the partially oxidized gold entities, which may expand the scope of ligand-protected clusters toward various applications. PMID- 30427181 TI - Hydride Doping of Chemically Modified Gold-Based Superatoms. AB - Atomically size-selected gold (Au) clusters protected by organic ligands or stabilized by polymers provide an ideal platform to test fundamental concepts and size-specific phenomena, such as the superatomic concept and metal-to-nonmetal transition. Recent studies revealed that these stabilized Au clusters take atomlike quantized electronic structures and can be viewed as chemically modified Au superatoms. An analogy between Au and hydrogen (H) atoms is an interesting proposal made for bare Au clusters: a Au atom at a low-coordination site of a Au cluster can be replaced with a H atom while retaining the structural motif and electronic structure. However, this proposal has not been experimentally proved in chemically modified Au superatoms while a recent theoretical study predicted the formation of [HAu25(SR)18]0 (RS = thiolate). This Account summarizes our recent studies on the interaction of hydride(s) with two types of chemically modified Au-based superatoms: (1) the Au cores of [Au9(PPh3)8]3+ and [PdAu8(PPh3)8]2+ formally described as (Au9)3+ and (PdAu8)2+, respectively, and (2) Au34 cluster stabilized by poly( N-vinyl-2-pyrrolidone) (PVP). The (Au9)3+ and (PdAu8)2+ cores correspond to oblate-shaped superatoms with six electrons and a coordinatively unsaturated site at the center, whereas the Au34 cluster in PVP is viewed as a nearly spherical superatom having a closed electronic structure with 34 electrons and multiple uncoordinated sites on the surface. Through this study, we aimed to deepen our understanding on the role of a hydride in the formation processes of Au superatoms, the effect of adsorbed hydride(s) on the electronic structure of Au superatoms, and the activity of adsorbed hydrogen species for hydrogenation catalysis. Mass spectrometry and nuclear magnetic resonance spectroscopy demonstrated that a single hydride (H-) was selectively doped to (Au9)3+ and (PdAu8)2+ upon reactions with BH4- to form (HAu9)2+ and (HPdAu8)+, respectively. Density functional theory (DFT) calculations showed that (HAu9)2+ and (HPdAu8)+ were more spherical than the original superatoms and had a closed electronic structure with eight electrons. The hydride-doped (HAu9)2+ was selectively converted to the well-known (Au11)3+ by electrophilic addition of two Au(I) units whereas (HPdAu8)+ was converted to a new hydride-doped (HPdAu10)3+. A two-step mechanism was proposed for hydride-mediated growth of Au-based superatoms: closure of the electronic structures by adsorption of a hydride, followed by the addition of two Au(I) units. The selective formation of Au34 superatoms in PVP is also explained by assuming that hydride-doped Au clusters with 34 electrons were involved as key intermediates. The Au34 superatom exhibited the localized surface plasmon resonance (LSPR) band by reacting with BH4- due to the electron donation by multiply adsorbed hydrides. The LSPR band disappeared by exposing hydride-doped Au34 to dissolved O2, but reappeared by reaction with BH4-. Catalysis for hydrogenation of C?C bonds was generated by doping a single Pd or Rh atom to Au34. The results reported here demonstrate that the hydride doped to chemically modified Au superatoms mimics Au- in terms of electron count. The hydride-mediated growth processes observed will contribute to the development of an atomically precise, bottom-up method of synthesizing new artificial elements in a periodic table for nanoscale materials. The interaction of hydride(s) with Au superatoms will find application in hydrogenation catalysis and hydrogen sensing. PMID- 30427182 TI - Rational Control of Size and Photoluminescence of WS2 Quantum Dots for White LEDs. AB - Transition metal dichalcogenides like tungsten disulfide (WS2) are luminescent but still bear low quantum yields and hardly meet the requirement of practical applications. Here, we developed a hot injection method to prepare highly luminescent WS2 quantum dots with tunable particle size in a noncoordinating solvent, some are even smaller than its Bohr-radius. The as-synthesized WS2 quantum dots exhibit a narrow size distribution and a high photoluminescence quantum yield of 32%, the highest record compared to the known reports. WS2 quantum dot layer was employed to fabricate white light-emitting diodes with a maximum brightness of 507 cd/m2, adjustable color temperatures from 4100 to 10000 K, and excellent color rendering index of 91. These results confirm the promising optoelectronic applications of WS2 quantum dots. PMID- 30427183 TI - Laser Photolysis Kinetic Study of OH Radical Reactions with Methyl Tert-Butyl Ether and Trimethyl Orthoformate under Conditions Relevant to Low Temperature Combustion; Measurements of Rate Coefficients and OH Recycling. AB - Methyl tertiary butyl ether (MTBE) and trimethyl orthoformate (TMOF) are potential biofuel ethers, and could replace conventional fossil fuels, or act as additives to aid combustion. Laser flash photolysis with laser-induced fluorescence detection of the OH radical has been used to measure the rate coefficients of the OH reaction with these ethers, from 298 K to approximately 740 K. The temperature dependence of the rate coefficients is parameterised as: "k" _"OH+MTBE" ("298-680 K" )" = 9.8 * " ?"10" ?^"-13" ("T" /"298" )^"2.7" "* exp" ["2500" /"RT" ] ?"cm" ?^"3" " " ?"molecule" ?^"-1" "s" ^"-1" "k" _"OH+TMOF" ("298-744 K" )" = 8.0 * " ?"10" ?^"-13" [("T" /"298" )^"2.6" "+" ("T" /"298" )^" 8.1" ]"* exp" ["2650" /"RT" ] ?"cm" ?^"3" " " ?"molecule" ?^"-1" "s" ^"-1" The room temperature (298 K) bimolecular rate coefficients were measured as kOH+MTBE = (2.81 +/- 0.32) * 10-12 cm3 molecule-1 s-1 and kOH+TMOF = (4.65 +/- 0.50) * 10 12 cm3 molecule-1 s-1 where the errors represent statistical uncertainties at the 2sigma level in combination with an estimated 10% systematic error. Regeneration of OH radicals was observed for both reactions at higher temperatures in the presence of O2 via biexponential OH decays, which were observed above 489 K, and 568 K, for TMOF and MTBE respectively. The OH yield from MTBE/O2 between 620 and 700 K, was invariant with the concentration of oxygen (1015 - 1018 molecule cm-3) at (36 +/- 5) %. Mechanisms for OH regeneration from MTBE are briefly discussed and compared with those in the literature and from dimethyl and diethyl ether. The lower OH yield from MTBE, compared to these other ethers, is most likely due to competition with an HO2 formation channel. PMID- 30427184 TI - Legacy Lead Stored in Catchments Is the Dominant Source for Lakes in the U.K.: Evidence from Atmospherically Derived 210Pb. AB - There has been a considerable reduction in anthropogenic lead (Pb) emission in the atmosphere in recent decades. However, the reduction in Pb inputs in many lakes does not match this as the Pb stored in catchment upper soil layers, derived from previous deposition, has become an important source although it is difficult to assess quantitatively. This work uses atmospherically deposited 210Pb as a tracer to track Pb movement, and so for the first time, we were able to calculate the relative Pb inputs from direct atmospheric deposition and catchment sources to lakes in the U.K. directly. Within individual lake sites, ratios of 210Pb/Pb in the catchment terrestrial mosses were normally an order of magnitude higher than those in the catchment surface soils, trapped lake sediments, and the surface sediments in the lake bottom. Results suggest that the Pb isotope signatures in the mosses are close to or dominated by atmospheric depositions, and it is reasonable to use the ratios of 210Pb/Pb in terrestrial mosses collected from the lake sites with a high annual rainfall over 2000 mm to represent those in atmospheric depositions. It reveals that after the reduction in Pb emissions, catchment Pb inputs now typically account for more than 95% of the total Pb entering the lakes. PMID- 30427185 TI - PAN@ZIF-67-Derived "Gypsophila"-Like CNFs@Co-CoO Composite as a Cathode for Li-O2 Batteries. AB - CNFs@Co-CoO (CNFs = carbon nanofibers) composite showing "gypsophila"-like morphology was designed and prepared for the first time with in situ grown PAN@ZIF-67 (PAN = polyacrylonitrile) as the precursor. Benefiting from its unique morphology, hierarchically porous structure, and high-activity Co-CoO catalyst centers, the composite shows a better electrochemical performance than pure CNFs as a cathode for Li-O2 batteries. PMID- 30427186 TI - Transition-Metal-Free Synthesis of C3-Arylated Benzofurans from Benzothiophenes and Phenols. AB - We report a transition-metal-free synthesis of benzofurans from benzothiophenes and phenols that exploits the unique reactivity of sulfoxides. Through a sequence involving an interrupted Pummerer reaction and [3,3] sigmatropic rearrangement, phenols can be combined with readily accessible yet synthetically unexplored benzothiophene S-oxides to provide C3-arylated benzofuran products. The products from this approach can undergo subsequent functionalization to gain access to a range of important benzofuran derivatives. PMID- 30427187 TI - Two Lanthanide Borate Chlorides LnB4O6(OH)2Cl (Ln = La, Ce) with Wide Ultraviolet Transmission Windows and Large Second-Harmonic Generation Responses. AB - Two borate chlorides LaB4O6(OH)2Cl and CeB4O6(OH)2Cl have been synthesized and characterized. Both of them exhibit structure similar to that of notable KBe2BO3F2 and feature two-dimensional [B4O6(OH)2]infinity layers constructed by [B4O8(OH)]2 fundamental building blocks. Thermal analyses, infrared spectroscopy, UV-vis-NIR spectra, and second harmonic generation measurement were performed to investigate their physical properties. The results show that both of them have high decomposition temperatures and large second-harmonic generation responses (2.3 and 2.1 * KH2PO4, respectively), and LaB4O6(OH)2Cl possesses a deep-UV cutoff edge below 180 nm and large band gap. Moreover, the first-principle calculations were carried out to clarify the role of the electronic structure in determining the associated optical properties of LaB4O6(OH)2Cl. These results demonstrate that LaB4O6(OH)2Cl can be considered as a candidate for ultraviolet nonlinear optical material. PMID- 30427188 TI - Labeling Single Domain Antibody Fragments with Fluorine-18 Using 2,3,5,6 Tetrafluorophenyl 6-[18F]Fluoronicotinate Resulting in High Tumor-to-Kidney Ratios. AB - ImmunoPET agents are being investigated to assess the status of epidermal growth factor receptor 2 (HER2) in breast cancer patients with the goal of selecting those likely to benefit from HER2-targeted therapies and monitoring their progress after these treatments. We have been exploring the use of single domain antibody fragments (sdAbs) labeled with 18F using residualizing prosthetic agents for this purpose. In this study, we have labeled two sdAbs that bind to different domains on the HER2 receptor, 2Rs15d and 5F7, using 2,3,5,6-tetrafluorophenyl 6 [18F]fluoronicotinate ([18F]TFPFN) and evaluated their HER2 targeting properties in vitro and in vivo. The overall decay-corrected radiochemical yield for the synthesis of [18F]TFPFN-2Rs15d and [18F]TFPFN-5F7 was 5.7 +/- 3.6 and 4.0 +/- 2.0%, respectively. The radiochemical purity of labeled sdAbs was >95%, immunoreactive fractions were about 60%, and affinity was in the low nanomolar range. Intracellularly trapped activity from [18F]TFPFN-2Rs15d and [18F]TFPFN-5F7 in HER2-expressing SKOV-3 ovarian and BT474M1 breast carcinoma cells were similar to the sdAbs labeled using the previously validated radioiodination residualizing prosthetic agents N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB) and N-succinimidyl 3-guanidinomethyl-5-[125I]iodobenzoate ( iso [125I]SGMIB). Intracellular activity was about 2-fold higher for radiolabeled 5F7 compared with 2Rs15d for both 18F and 125I. While tumor uptake of both [18F]TFPFN 2Rs15d and [18F]TFPFN-5F7 was comparable to those for the coadministered 125I labeled sdAb, renal uptake of the 18F-labeled sdAbs was substantially lower. In microPET images, the tumor was clearly delineated in SKOV-3 and BT474 xenograft bearing athymic mice with low levels of background activity in normal tissues, except the bladder. These results indicate that the [18F]TFPFN prosthetic group could be a valuable reagent for developing sdAb-based immunoPET imaging agents. PMID- 30427189 TI - Functional Characterization of a Novel Lipopolysaccharide-Binding Antimicrobial and Anti-Inflammatory Peptide in Vitro and in Vivo. AB - Antimicrobial peptides (AMPs) are key components of host immune defense of vertebrates against microbial invasions. Here, we report a new AMP (esculentin 1GN) characterized from the skin of the frog Hylarana guentheri. Esculentin-1GN (GLFSKKGGKGGKSWIKGVFKGIKGIGKEVGGDVIRTGIEIAACKIKGEC) with high amphipathic alpha helical structure in membrane-mimetic environments has the microbial-killing activity by destruction of the cell membrane. Moreover, esculentin-1GN inhibits LPS-induced expression of proinflammatory nitric oxide, interleukin-1beta, interleukin-6, and tumor necrosis factor while it enhances expression of interleukin-10. Furthermore, esculentin-1GN can bind to d-(+)-galacturonic acid and LPS. Meanwhile, esculentin-1GN suppresses the activation of inflammatory response pathway induced by LPS. In addition, esculentin-1GN significantly reduces acute inflammation in carrageenan-induced mice paw. Taken together, the novel LPS-binding esculentin-1GN with antimicrobial and anti-inflammatory activities will be an excellent temple for designing new antibiotic formulations. PMID- 30427190 TI - Suzuki-Miyaura Micellar One-Pot Synthesis of Symmetrical and Unsymmetrical 4,7 Diaryl-5,6-difluoro-2,1,3-benzothiadiazole Luminescent Derivatives in Water and under Air. AB - The Suzuki-Miyaura cross-coupling reaction of 4,7-dibromo-5,6-difluoro-2,1,3 benzothiadiazole with different arylboronic acids can be efficiently carried out in water and under air by means of micellar coupling. The careful tuning of reaction conditions enables preparation of symmetrically and unsymmetrically substituted derivatives. The moderate to good yields obtained, along with the wide variety of available substitution patterns, makes this sustainable methodology very useful for the preparation of building blocks for luminescent optoelectronic materials. PMID- 30427191 TI - Repeated measurements of paraben exposure during pregnancy in relation to fetal and early-childhood growth. AB - Parabens are potential endocrine disruptors with short half-lives in the human body. To date, few epidemiological studies regarding repeated paraben measurements during pregnancy associated with fetal and childhood growth have been conducted. Within a Chinese prenatal cohort, 850 mother-infant pairs from whom a complete set of maternal urine samples were acquired during three trimesters were included, and the levels of five parabens were measured. We assessed the associations of both average and trimester-specific urinary paraben levels with weight and height z-scores at birth, 6 months, 1, and 2 years of age. In all infants, each doubling increase in average ethyl paraben (EtP) was associated with -2.82% (95% CI: -5.11%, -0.53%) decrease in weight z-score at birth, whereas no significant age-specific associations were identified. After stratifying by sex, we further observed age-specific association of average EtP with -3.96% (95% CI: -7.03%, -0.89%) and -3.38% (95% CI: 6.72%, -0.03%) reduction in weight z-scores at 1 and 2 years in males, respectively. Third-trimester EtP was negatively associated with weight z-scores at birth, 1 and 2 years in males. Our results suggested negative associations between prenatal paraben exposure and fetal and childhood growth, and the third trimester may be the window of susceptibility. PMID- 30427192 TI - Luminescence and Cationic-Size-Driven Site Selection of Eu3+ and Ce3+ Ions in Ca8Mg(SiO4)4Cl2. AB - In this work, the morphology, composition, crystal, and electronic structure of Ca8Mg(SiO4)4Cl2 (CMSOC) prepared by a high-temperature solid-state reaction technique are characterized first. To investigate the site occupancies of Eu3+ and Ce3+ in CMSOC, the emission spectra under well-chosen wavelength excitations and the corresponding excitation spectra by monitoring of the specific wavelength emissions are measured in detail for singly doped samples with different concentrations. Two kinds of Eu3+ or Ce3+ luminescence spectra are found. On the basis of the chemical environments of two Ca2+ sites and dielectric chemical bond theory, the sites of these two kinds of Eu3+ and Ce3+ luminescence spectra are respectively assigned. Because energy transfer between the two types of luminescent centers, concentration-dependent emission-wavelength shifting, and luminescence concentration quenching are negligible, the emission spectra of Eu3+ and Ce3+ give us a hint of their occupation preferences on two Ca2+ sites. The results indicate that, with an increase of the doping concentration, the Eu3+ ions with smaller cationic size show an occupation preference on the smaller Ca2+(1) sites, but the Ce3+ ions with larger cationic size are inclined to enter the larger Ca2+(2) sites. These opposite occupation preferences of Eu3+ and Ce3+ in CMSOC are thought to be the cationic-size-driven site selection. PMID- 30427193 TI - Polar-Nonpolar Interfaces of Inverse Bicontinuous Cubic Phases in Phytantriol/Water System are Parallel to Triply Periodic Minimal Surfaces. AB - We investigated two distinct lyotropic liquid crystal inverse bicontinuous cubic phases of phytantriol/water mixtures by small-angle X-ray crystallography of the single-crystal regions. Reconstructed electron density maps revealed hydrophilic head and hydrophobic tail regions of the phytantriol bilayer membranes and water regions. The bilayer membranes are shown to be located on the D and gyroid triply periodic minimal surfaces. To investigate the structures of the polar-nonpolar interfaces, we optimized two models: a parallel surface model and a constant mean curvature surface model. The parallel surface model agreed well with the X-ray data, and the R factors, which show the degree of agreement between those structural models and the data, were less than 0.04. In stark contrast, the constant mean curvature surface model deviated significantly from the data, and the R factors were around 0.15. We therefore conclude that the polar-nonpolar interface of the inverse bicontinuous cubic phase of the phytantriol/water system is close to a parallel surface to a triply periodic minimal surface. PMID- 30427194 TI - Living Metathesis and Metallotropy Polymerization Gives Conjugated Polyenynes from Multialkynes: How to Design Sequence-Specific Cascades for Polymers. AB - On the basis of a combined experimental and computational study, a novel method for preparing fully conjugated polyenynes via cascade metathesis and metallotropy (M&M) polymerization of various multialkynes is developed. DFT calculations elucidate the detailed mechanism of the metallotropic 1,3-shift, which is a key process of M&M polymerization. An alpha,beta-(C,C,C)-agostic interaction stabilizing the metallacyclobutadiene transition state is found to be critically important for the successful polymerization with excellent specificity. The polymerization efficiency displayed by the tetrayne monomer is controlled by the steric demands of its substituents, and more complex hexayne monomers can be successfully polymerized to give access to highly conjugated polyenynes via a series of intramolecular metathesis and metallotropic shift cascade reactions. Furthermore, living polymerization led to the synthesis of block copolymers consisting of fully conjugated polyenyne backbones. The implementation of pentayne monomers provides polyenynes with successive C-C triple bonds via consecutive metallotropic 1,3-shift. In short, the design of multialkynes enables the preparation of diverse conjugated polyenyne motifs via selective M&M cascade reactions. PMID- 30427195 TI - Solvent Quality Controls Macromolecular Structural Dynamics of a Dendrimeric Hydrogenase Model. AB - We report a spectroscopic investigation of the ultrafast dynamics of a second generation poly(aryl ether) dendritic hydrogenase model using two-dimensional infrared (2D-IR) spectroscopy to probe the metal carbonyl vibrations of the dendrimer and a reference small molecule, [Fe(u-S)(CO)3]2. We find that the structural dynamics of the dendrimer are reflected in a slow phase of the spectral diffusion which is absent from [Fe(u-S)(CO)3]2, and we relate the slow phase to the quality of the solvent for poly(aryl ether) dendrimers. We observe a solvent dependent modulation of the initial phase of vibrational relaxation of the carbonyl groups which we attribute to an inhibition of solvent-assistance in the IVR process for the dendrimer. There is also a clear solvent dependence of the vibrational frequencies of both the dendrimer and [Fe(u-S)(CO)3]2. Our data represents the first 2D-IR study of a dendritic complex, and provides insight into the solvent-dependence of molecular conformation in solution and the ultrafast dynamics of moderately-sized, conformationally mobile compounds. PMID- 30427196 TI - beta2-Type Amyloidlike Fibrils of Poly-l-glutamic Acid Convert into Long, Highly Ordered Helices upon Dissolution in Dimethyl Sulfoxide. AB - Replacing water with dimethyl sulfoxide (DMSO) completely reshapes the free energy landscapes of solvated proteins. In DMSO, a powerful hydrogen-bond (HB) acceptor, formation of HBs between backbone NH groups and solvent is favored over HBs involving protein's carbonyl groups. This entails a profound structural disruption of globular proteins and proteinaceous aggregates (e.g., amyloid fibrils) upon transfer to DMSO. Here, we investigate an unusual DMSO-induced conformational transition of beta2-amyloid fibrils from poly-l-glutamic acid (PLGA). The infrared spectra of beta2-PLGA dissolved in DMSO lack the typical features associated with disordered conformation that are observed when amyloid fibrils from other proteins are dispersed in DMSO. Instead, the frequency and unusual narrowness of the amide I band imply the presence of highly ordered helical structures, which is supported by complementary methods, including vibrational circular dichroism and Raman optical activity. We argue that the conformation most consistent with the spectroscopic data is that of a PLGA chain essentially lacking nonhelical segments such as bends that would provide DMSO acceptors with direct access to the backbone. A structural study of DMSO dissolved beta2-PLGA by synchrotron small-angle X-ray scattering reveals the presence of long uninterrupted helices lending direct support to this hypothesis. Our study highlights the dramatic effects that solvation may have on conformational transitions of large polypeptide assemblies. PMID- 30427198 TI - From 1,4-Disaccharide to 1,3-Glycosyl Carbasugar: Synthesis of a Bespoke Inhibitor of Family GH99 Endo-alpha-mannosidase. AB - Understanding the enzyme reaction mechanism can lead to the design of enzyme inhibitors. A Claisen rearrangement was used to allow conversion of an alpha-1,4 disaccharide into an alpha-1,3-linked glycosyl carbasugar to target the endo alpha-mannosidase from the GH99 glycosidase family, which, unusually, is believed to act through a 1,2-anhydrosugar "epoxide" intermediate. Using NMR and X-ray crystallography, it is shown that glucosyl carbasugar alpha-aziridines can act as reasonably potent endo-alpha-mannosidase inhibitors, likely by virtue of their shape mimicry and the interactions of the aziridine nitrogen with the conserved catalytic acid/base of the enzyme active site. PMID- 30427199 TI - Total Synthesis of (+)-Aplykurodinone-1. PMID- 30427197 TI - Crystal Structure and Magnetic Properties of Uranium Hydride UH2 Stabilized as a Thin Film. AB - A new type of uranium binary hydride, UH2, with the CaF2 crystal structure, was synthesized in a thin-film form using reactive sputter deposition at low temperatures. The material has a grain size of 50-100 nm. The lattice parameter a = (535.98 +/- 0.14 pm) is close to that in known Np (534.3 pm) and Pu (535.9 pm) iso-types. UH2 is a metallic ferromagnet with the Curie temperature TC ~ 120 K. A very wide hysteresis loop indicates strong magnetocrystalline anisotropy. X-ray photoelectron spectroscopy reveals similarities with electronic structure of UH3, which is also ferromagnet with higher TC = 165 K. PMID- 30427200 TI - A Late-Stage Synthetic Approach to Lanthionine-Containing Peptides via S Alkylation on Cyclic Sulfamidates Promoted by Molecular Sieves. AB - A one-pot, high-yield procedure for synthesizing lanthionine-containing peptides was developed. It relies on the S-alkylation of cysteine-containing peptides with chiral cyclic sulfamidates. The key feature of this approach is the use of mild reaction conditions (only activated molecular sieves are employed as the catalyst), leading to good chemoselectivity and excellent stereochemical control. The potential of the new methodology has been investigated by synthesizing the thioether ring of a natural lantibiotic, Haloduracin beta. PMID- 30427201 TI - Generation and Cross-Coupling of Organozinc Reagents in Flow. AB - A versatile flow synthesis method for in situ formation of organozinc reagents and subsequent cross-coupling with aryl halides and activated carboxylic acids is reported. Formation of organozinc reagents is achieved by pumping organic halides, in the presence of ZnCl2 and LiCl, through an activated Mg-packed column under flow conditions. This method provides efficient in situ formation of aryl, primary, secondary, and tertiary alkyl organozinc reagents, which are subsequently telescoped downstream to a Negishi or decarboxylative Negishi cross coupling reaction. The described method offers access to a variety of C-C bond formations with organozinc reagents that are otherwise commercially unavailable or difficult to prepare under traditional batch reaction conditions. PMID- 30427202 TI - Synthesis of Diverse Boron-Handled N-Heterocycles via Radical Borylative Cyclization of N-Allylcyanamides. AB - A synthetic method based on radical borylation/cyclization cascades of N allylcyanamides was developed to construct diverse boron-substituted N heterocycles. In the reaction process, the N-heterocyclic carbene-boryl radical underwent a chemo- and regioselective addition to the alkene moiety, followed by cyclization with the N-cyano group. The resulting amide-iminyl radical intermediates underwent further reactions to afford various boron-tethered N heterocyclic molecules. Further transformations to access synthetically useful building blocks were also demonstrated. PMID- 30427203 TI - Differential Effects of Content-Oriented Versus User-Oriented Social Media on Risk Perceptions and Behavioral Intentions. AB - Social media have become increasingly important in risk and crisis situations. However, little is known about which types of social media have greater influence on risk perceptions and behaviors. This study pursues two goals related to this question. The first is to explicate the cognitive mechanism underlying the process through which exposure to risk information on social media shapes people's behavioral intentions. The second is to determine whether exposures to risk information on two different types of social media-content-oriented social media focusing on shared interests versus user-oriented social media focusing on social relationships-have different effects on people's risk perceptions and behavioral intentions. Analyzing survey data from 688 adults from the general population of South Korea in the context of carcinogenic hazards, we found that self-reported content-oriented social media exposure (to risk information) was significantly related to both personal-level and societal-level risk perceptions. In addition, content-oriented social media exposure was associated with behavioral intentions indirectly through risk perceptions. However, user-oriented social media exposure had no impact on risk perceptions and behavioral intentions, either directly or indirectly through risk perceptions. PMID- 30427204 TI - Forkhead Box O3 promotes cell proliferation and inhibits myotube differentiation in chicken myoblast cells. AB - 1. In the poultry industry, growth performance is important due to its effects on economic value. Much effort has been put forth to achieve introgression of specific genes and DNA markers related to muscle proliferation and differentiation in selective breeding approaches. 2. This study investigated the biological functions of the gene Forkhead Box O3 (Foxo3) during myogenic differentiation in chicken myoblast cells. Foxo3 was downregulated in primary chicken myoblast (pCM) cells by the piggyBac transposon-mediated miRNA knockdown (KD) system. 3. The pCM cells that were stably integrated into the Foxo3 KD expression vector showed significant downregulation of Foxo3 protein and mRNA levels. Expression levels of Pax7 and target genes such as CCAAT/enhancer binding protein beta (CEBPB) and serum response element (SRE) decreased in Foxo3 KD pCM cells. In addition, in the undifferentiated myoblast stage, there were no significant differences in cell morphology; however, proliferation rate in Foxo3 KD pCM cells was significantly lower during days 4 and 5 of in vitro culture. By contrast, when myotube differentiation was induced, Foxo3 KD pCM cells exhibited rapid initiation of myotube formation, higher expression of myogenin and desmin as myogenic indicators, and a further differentiated phenotype than observed in regular pCM (rpCM) cells. 4. These results demonstrated that Foxo3 promotes cell proliferation and inhibits myotube differentiation in chicken myoblast cells. Therefore, the regulation of Foxo3 could be applied to improve muscle differentiation in commercial poultry. PMID- 30427205 TI - "Silence! The body is speaking" - a correlational study of personality, perfectionism, and self-compassion as risk and protective factors for psychosomatic symptoms distress. AB - The current study examined the role of personality traits on psychosomatic distress (PD) and tested the hypothesis that the association between perfectionism and PD would be moderated by self-compassion. One hundred and seventy-three community volunteers, of whom 24.9% were men, mean age 31.52 +/- 13.29, reported online on the DS14, a measure of Type D personality, on the TCI 140, a measure of temperament and character, on the Frost multidimensional perfectionism scale, on the short form of the self-compassion scale and on the SOMS-7 for psychosomatic symptoms. We defined psychosomatic distress as the product of the symptom count and severity rating score of the SOMS-7. The hierarchical linear regression model that included all the personality variables as well as the interaction term between self-compassion and perfectionism accounted for 25% of the variance in PD. The interaction between perfectionism and self-compassion entered into the model in the last block was highly protective. High self-compassion moderated the effect of perfectionism on PD. Our finding correspond with the notion that personality can enhance PD but can also mitigate it. Protective personality traits, such as self-compassion, might be good targets for psychological intervention. PMID- 30427206 TI - Activity profile in elite Polish soccer players. AB - The aim of the present study was to determine and characterize the activity of male Polish Premier League soccer players during elite-level matches, depending on playing position, activity intensity range, and match period. The study sample comprised 1178 players. Amisco Pro(r) was used to track the match activity players. Statistical analysis of the total distance covered by players revealed that the greatest distance was covered by central midfielders (11894 +/- 765 m) and external midfielders (11751 +/- 686 m). In terms of velocity, the greatest distance was covered by players in the V1 range (0 <= V1 < 11 km . h-1, standing, walking), (7028 +/- 294 m). The difference between the match periods was statistically non-significant, amounting to only 0.5%. As such they could prove useful for present and future comparisons between positions and represent the scientific basis for developing position-specific conditioning/training regimes for both clubs and individuals. PMID- 30427207 TI - LRF acts as an activator and repressor of the human beta-like globin gene transcription in a developmental stage dependent manner. AB - LRF, a hematopoietic transcription factor, has been suggested to repress fetal gamma-globin genes in the human adult stage beta-globin locus. Here, to study the role of LRF in the fetal stage beta-globin locus we knocked out its expression in erythroid K562 cells, in which the gamma-globin genes are mainly transcribed. The gamma-globin transcription was reduced in LRF KO cells, and transcription factor binding to the beta-globin locus control region hypersensitive sites (LCR HSs) and active histone organization in the LCR HSs were disrupted by the depletion of LRF. In contrast, LRF loss in the adult stage beta-globin locus did not affect active chromatin structure in the LCR HSs and induced the fetal gamma-globin transcription. These results indicate that LRF may act as an activator and repressor of the human beta-like globin gene transcription in a developmental stage dependent manner. PMID- 30427208 TI - beta-secretase 1 inhibitory activity and AMP-activated protein kinase activation of Callyspongia samarensis extracts. AB - The methanolic extract of Callyspongia samarensis (MCS) significantly inhibited beta-secretase 1 (IC50 99.82 ug/mL) in a dose-dependent manner and demonstrated a noncompetitive type of inhibition. Furthermore, it exhibited the highest AMPK activation (EC50 14.47 MUg/mL) as compared with the standard, Aspirin (EC50 >100 MUg/mL). HPLC/ESI-MS analysis of MCS extract revealed 15 peaks, in which nine peaks demonstrated similar fragmentation pattern with the known compounds in literature and in database library: 5-aminopentanoic acid (1), 4-aminobutanoic acid (3), Luotonin A (4), (E)-3-(1H-imidazol-5-yl) prop-2-enoic acid (8), Galactosphingosine (10), D-sphingosine (11), 5,7,4'-trihydroxy-3',5' dimethoxyflavone (12), hydroxydihydrovolide (13), and 3,5-dibromo-4 methoxyphenylpyruvic acid (14); and 6 peaks are not identified (2, 5-7, 9, and 15). Acute oral toxicity test of MCS extract revealed that it is nontoxic, with an LD50 of >2000 mg/kg. Assessment of BBB permeability of MCS extract showed that compound 15 was able to cross the BBB making it a suitable candidate for developing CNS drugs. PMID- 30427209 TI - New Classification of Research Misconduct from the Viewpoint of Truth, Trust, and Risk. AB - Fabrication, Falsification and Plagiarism (FFP) and Questionable Research Practice (QRP) have been used worldwide in the classification of research misconduct. However, FFP comprises two distinct categories of misconduct: FF is extreme research misconduct that betrays truth, while P undermines trust of science community. Irreproducibility and inadequate practice of research also betray trust. Research misconduct has the potential to cause serious risk of safety in daily life. The proposed classification system is outlined as follows: Class I misconduct: Betrayal of the truth: (1) Fabrication and (2) Falsification. Class II misconduct: Betrayal of trust: (1) Plagiarism of text ; Irreproducibility; and (3) Inadequate research practice. Class III misconduct: Risk to safety of health and industrial products: (1) Risk to safety of health and (2) Risk to safety of industrial products. The proposed classification reflects deeper values of truth, trust, and risk more directly than the previous classification and elucidates issues about nature and significance of misconduct. PMID- 30427210 TI - A targeted neuropsychological examination of children with a history of sport related concussion. AB - : Experimental research suggests that sport-related concussion can lead to persistent alterations in children's neurophysiology and cognition. However, the search for neuropsychological tests with a similar ability to detect long-term deficits continues. PRIMARY OBJECTIVE: The current study assessed whether a target battery of neuropsychological measures of higher cognition and academic achievement would detect lingering deficits in children 2 years after injury. RESEARCH DESIGN: Cross-sectional. METHODS AND PROCEDURE: A total of 32 pre adolescent children (16 concussion history, 16 control) completed a targeted battery of neuropsychological and academic tests. MAIN OUTCOMES AND RESULTS: Children with a history of concussion exhibited selective deficits during the Raven's Coloured Progressive Matrices, Comprehensive Trail-Making Test, and the mathematics sub-section of the WRAT-3. Deficit magnitude was significantly related to age at injury, but not time since injury. CONCLUSIONS: The current results suggest that neuropsychological measures of higher cognition and academic achievement may be sensitive to lingering deficits, and that children injured earlier in life may exhibit worse neuropsychological and academic performance. PMID- 30427211 TI - Gambling, motor cautiousness, and choice impulsivity: An experimental study. AB - BACKGROUND: Impulsivity is currently more commonly regarded as multifaceted, comprising both motor and cognitive subdomains. However, it is less clear how distinct these subdomains are, and the extent to which they interact and draw upon the same psychological resources. METHODS: The present experiment comprised 70 regular (non-problem) gamblers, and investigated the potential to induce impulsivity transfer effects within an electronic gambling context. Original and existing harm-minimization approaches were tested for their efficacy in inducing motor cautiousness during an electronic slot machine simulation. Participants were exposed to a forced discriminatory motor choice procedure, or pop-up responsible gambling messages that either contained emotive or non-emotive responsible gambling content. The subsequent impact these interventions had on delay discounting and reflection impulsivity was also measured using the 27-item Monetary Choice Questionnaire and Information Sampling Task, respectively. RESULTS: Findings demonstrated that only original harm-minimization approaches, which force the gambler to engage in discriminatory motor choice procedures during gambling, were successful in inducing motor cautiousness. However, both the discriminatory choice procedure and emotive message harm-minimization approaches were successful in facilitating cognitive choice, even though the emotive message intervention was unsuccessful in facilitating motor response inhibition, suggesting both an indirect motor cautiousness route, and a more direct route to improved cognitive choice during gambling. CONCLUSION: This study demonstrated that decision-making during gambling can be improved by making simple structural changes to slot machine platforms, by encouraging active engagement in motor processes, which result in a transfer of cautiousness to wider cognitive domains. PMID- 30427212 TI - The dark side of internet: Preliminary evidence for the associations of dark personality traits with specific online activities and problematic internet use. AB - BACKGROUND AND AIMS: Research has shown that personality traits play an important role in problematic internet use (PIU). However, the relationship between dark personality traits (i.e., Machiavellianism, psychopathy, narcissism, sadism, and spitefulness) and PIU has yet to be investigated. Consequently, the objectives of this study were to investigate the relationships of dark traits with specific online activities (i.e., social media, gaming, gambling, shopping, and sex) and PIU. METHODS: A total of 772 university students completed a self-report survey, including the Dark Triad Dirty Dozen Scale, Short Sadistic Impulse Scale, Spitefulness Scale, and an adapted version of the Bergen Facebook Addiction Scale. RESULTS: Hierarchical regression analysis and a multiple mediation model indicated that being male was positively associated with higher online gaming, online sex, and online gambling, and negatively associated with social media and online shopping. Narcissism was related to higher social media use; Machiavellianism was related to higher online gaming, online sex, and online gambling; sadism was related to online sex; and spitefulness was associated with online sex, online gambling, and online shopping. Finally, Machiavellianism and spitefulness were directly and indirectly associated with PIU via online gambling, online gaming, and online shopping, and narcissism was indirectly associated with PIU through social media use. DISCUSSION: Findings of this preliminary study show that individuals high in dark personality traits may be more vulnerable in developing problematic online use and that further research is warranted to examine the associations of dark personality traits with specific types of problematic online activities. PMID- 30427213 TI - Treatment efficacy of a specialized psychotherapy program for Internet Gaming Disorder. AB - BACKGROUND AND AIMS: Internet Gaming Disorder (IGD) has become health concern around the world, and specialized health services for the treatment of IGD are emerging. Despite the increase in such services, few studies have examined the efficacy of psychological treatments for IGD. The primary aim of this study was to assess the efficacy of a specialized psychotherapy program for adolescents with IGD [i.e., the "Programa Individualizado Psicoterapeutico para la Adiccion a las Tecnologias de la Informacion y la Comunicacion" (PIPATIC) program]. METHODS: The sample comprised 31 adolescents (aged 12-18 years) from two public mental health centers who were assigned to either the (a) PIPATIC intervention experimental group or (b) standard cognitive-behavioral therapy (CBT) control group. The interventions were assessed at pre-, middle-, and post-treatment phases, as well as a 3-month assessment was carried out after completing the interventions. RESULTS: No significant differences between either group in the pre-treatment phase were found. Relating to the different interventions examined, significant differences were found at pre-test and post-test on the following variables: comorbid disorders, intrapersonal and interpersonal abilities, family relationships, and therapists' measures. Both groups experienced a significant reduction of IGD symptoms, although the PIPATIC group experienced higher significant improvements in the remainder of the variables examined. DISCUSSION AND CONCLUSIONS: The findings suggest that PIPATIC program is effective in the treatment of IGD and its comorbid disorders/symptoms, alongside the improvement of intra- and interpersonal abilities and family relationships. However, it should also be noted that standard CBT was also effective in the treatment of IGD. Changing the focus of treatment and applying an integrative focus (including the addiction, the comorbid symptoms, intra- and interpersonal abilities, and family psychotherapy) appear to be more effective in facilitating adolescent behavior change than CBT focusing only on the IGD itself. PMID- 30427214 TI - Gambling disorder, increased mortality, suicidality, and associated comorbidity: A longitudinal nationwide register study. AB - BACKGROUND AND AIMS: Gambling disorder (GD) appears to be an independent risk factor for suicide, and all-cause mortality has been sparsely studied in patients with GD. This study aims to explore mortality and suicide rates in individuals with GD compared to the general population as well as explore risk factors associated with all-cause mortality and suicide mortality. METHODS: This is a nationwide register study on 2,099 individuals with a GD diagnosis in the Swedish inpatient and/or outpatient specialist health care system between the years of 2005-2016. Comorbid diagnoses from treatment episodes included in national registers were categorized into diagnostic groups according to the 10th revision of International Classification of Diseases, and prevalence rates (any occurrence during 2005-2016) were calculated for each diagnostic group. Multivariate Cox regression analyses on risk factors for death and suicide were performed, controlling for age, gender, and major categories of comorbidity. Standardized mortality ratios (SMRs) were calculated for men and women with regard to overall mortality and suicide compared to the general Swedish population. RESULTS: The population consisted of 1,625 men and 474 women ranging from 18 to 83 years of age at first GD diagnosis (mean: 36.5 years). Sixty-seven individuals passed away, among whom 21 deaths were due to suicide. SMR calculations showed a 1.8 fold increase in mortality for individuals 20-74 years old with GD compared to the general population, and a 15-fold increase in suicide mortality. All-cause mortality was predicted by higher age and any treatment episode for cardiovascular disease, whereas suicide death was predicted by depression. DISCUSSION AND CONCLUSIONS: Mortality and suicide rates are significantly elevated among individuals with GD. Although common mental health comorbidities did not predict overall mortality, depression predicted suicide death. Findings call for attention to long-term risk of death in GD patients and interventions against comorbid health problems. PMID- 30427215 TI - Breaking the habit. AB - Internet gaming disorder has been widely recognized as a new health issue. At present, we are experiencing a rapid growth of knowledge on different aspects of this disorder, such as, for instance, prevalence rates, underlying neurobiological mechanisms, and treatment strategies. In contrast, preventing individuals from developing Internet gaming disorder is a matter that has not yet progressed sufficiently. Although we can basically refer to measures and techniques known to be effective in preventing other addictive behaviors, the special demands of preventing Internet gaming disorder remain largely obscured or disregarded. The policy actions identified in the review by Kiraly et al. (2018) demonstrate that first preventive approaches have been initiated but, on the other hand, it also points out that empirical research on their feasibility and effectiveness needs improvement. PMID- 30427216 TI - DNA methylation/hydroxymethylation regulate gene expression and alternative splicing during terminal granulopoiesis. AB - AIM: To determine whether epigenetic modifications of DNA regulate gene expression and alternative splicing during terminal granulopoiesis. MATERIALS & METHODS: Using whole genome bisulfite sequencing, reduced representation hydroxymethylation profiling and mRNA sequencing, we compare changes in DNA methylation, DNA hydroxymethylation, gene expression and alternative splicing in mouse promyelocytes and granulocytes. RESULTS & CONCLUSION: We show reduced DNA methylation at the promoters and enhancers of key granulopoiesis genes, indicating a regulatory role in the activation of lineage-specific genes during differentiation. Notably, increased DNA hydroxymethylation in exons is associated with preferential inclusion of specific exons in granulocytes. Overall, DNA methylation and hydroxymethylation changes at particular genomic loci may play specific roles in gene regulation or alternative splicing during terminal granulopoiesis. Data deposition: Whole genome bisulfite sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE85517); mRNA sequencing of mouse promyelocytes and granulocytes: Gene Expression Omnibus (GSE48307); reduced representation 5-hydroxymethylation profiling of mouse promyelocytes and granulocytes: Bioproject (PRJNA495696). PMID- 30427218 TI - Functional and therapeutic potential of mitochondrial SIRT3 deacetylase in disease conditions. PMID- 30427217 TI - Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors. AB - A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 +/- 1.25 nM) and MDA-MB-436 cancer cell (11.62 +/- 2.15 MUM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 +/- 0.91 MUM) which was stronger than neostigmine (12.01 +/- 0.45 MUM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP 1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease. PMID- 30427219 TI - Role of PKC and AMPK in hypertonicity-stimulated water reabsorption in rat inner medullary collecting ducts. AB - Hypertonicity increases water permeability, independently of vasopressin, in the inner medullary collecting duct (IMCD) by increasing aquaporin-2 (AQP2) membrane accumulation. We investigated whether protein kinase C (PKC) and adenosine monophosphate kinase (AMPK) are involved in hypertonicity-regulated water permeability. Increasing perfusate osmolality from 150-290 mosM and bath osmolality from 290-430 mosM significantly stimulated osmotic water permeability. The PKC inhibitors, chelerythrine (10 uM) and rottlerin (50 uM) significantly reversed the increase in osmotic water permeability stimulated by hypertonicity in perfused rat terminal IMCDs. Chelerythrine significantly increased phosphorylation of AQP2 at S261 but not at S256. Previous studies show that AMPK is stimulated by osmotic stress. We tested AMPK phosphorylation under hypertonic conditions. Hypertonicity significantly increased AMPK phosphorylation in inner medullary (IM) tissues. Blockade of AMPK with Compound C decreased hypertonicity stimulated water permeability, but did not alter phosphorylation of AQP2 at S256 and S261. AICAR, an AMPK stimulator, caused a transient increase in osmotic water permeability and increased phosphorylation of AQP2 at S256. When IM tissue was treated with the PKC activator PDBu, the AMPK activator metformin, or both, AQP2 phosphorylation at S261 was decreased with PDBu or metformin alone, but there was no additive effect on phosphorylation with PDBu and metformin together. In conclusion, hypertonicity regulates water reabsorption by activating PKC. Hypertonicity-stimulated water reabsorption by PKC may be related to the decrease in endocytosis of AQP2. AMPK activation promotes water reabsorption, but the mechanism remains to be determined. PKC and AMPK do not appear to act synergistically to regulate water reabsorption. PMID- 30427220 TI - Characterization of renal NaCl and oxalate transport in Slc26a6-/- mice. AB - The apical membrane chloride-oxalate exchanger SLC26A6 has been demonstrated to play a role in proximal tubule NaCl transport based on studies in microperfused tubules. The present study is directed at characterizing the role of SLC26A6 in NaCl homeostasis in vivo under physiological conditions. Free-flow micropuncture studies revealed that volume and chloride absorption were similar in surface proximal tubules of wild-type and Slc26a6-/- mice. Moreover, the increments in urine flow rate and sodium excretion following thiazide and furosemide infusion were identical in wild-type and Slc26a6-/- mice, indicating no difference in NaCl delivery out of the proximal tubule. The absence of an effect of deletion of SLC26A6 on NaCl homeostasis was further supported by the absence of lower blood pressure in Slc26a6-/- compared to wild-type mice on normal or low salt diets. Moreover, raising plasma and urine oxalate by feeding mice a diet enriched in soluble oxalate did not affect mean blood pressure. In contrast to the lack of effect of SLC26A6 deletion on NaCl homeostasis, fractional excretion of oxalate was reduced from 1.6 in wild-type mice to 0.7 in Slc26a6-/- mice. We conclude that although SLC26A6 is dispensable for renal NaCl homeostasis, it is required for net renal secretion of oxalate. PMID- 30427221 TI - Human Serum Albumin Redox State is Associated with Decreased Renal Function in a Community-Dwelling Population. AB - The redox state of human serum albumin (HSA) has attracted interest as a possible biomarker for oxidative stress (OS) in humans. Although previous studies on this topic have taken only clinical settings into consideration, evidence of its efficacy in nonclinical settings remains to be established. The present study aimed to examine and validate the relationship between HSA redox state and renal function in a rural Japanese population. We analyzed two independent datasets from health check-up programs conducted in 2013 and 2016: one for discovery (n = 267) and the other for replication (n = 367). The fraction of human mercaptalbumin (HMA) to total HSA [f(HMA)] was determined using our revised method of high-performance liquid chromatography with post-column bromocresol green. The estimated glomerular filtration rate (eGFR) was calculated based on each individual's serum creatinine value, sex, and age. Adjustment for potential confounders revealed positive associations of f(HMA) with eGFR in the discovery and replication analyses ( p < 0.001 and p = 0.03, respectively). Multivariate logistic regression analyses demonstrated significant inverse associations between renal dysfunction (defined as eGFR < 60 mL/min/1.73 m2) and f(HMA) by a factor of 0.50 and 0.65 (confidence intervals of 0.26-0.91 and 0.37-1.00), respectively, with a unit of 10% f(HMA). Our results indicate that HSA redox state is consistently associated with renal dysfunction in both clinical and nonclinical settings. PMID- 30427222 TI - SGLT2 inhibition and renal urate excretion: the role of luminal glucose, GLUT9 and URAT1. AB - Inhibitors of the sodium-glucose cotransporter SGLT2 enhance urinary glucose and urate excretion and lower plasma urate levels. The mechanisms remain unclear, but a role for enhanced glucose in the tubular fluid has been proposed, which may interact with tubular urate transporters like GLUT9 or URAT1. Studies were performed in non-diabetic mice using the SGLT2 inhibitor canagliflozin and gene targeted mice lacking the urate transporter GLUT9 in the tubule or mice with whole body knockout of SGLT2, SGLT1, or URAT1. Renal urate handling was assessed by analyzing urate in spontaneous plasma and urine samples and normalization to creatinine concentrations or renal clearance studies with assessment of GFR by FITC-sinistrin. The experiments confirmed the contribution of URAT1 and GLUT9 to renal urate reabsorption, showing a greater contribution of the latter and additive effects. Both genetic and pharmacologic inhibition of SGLT2 enhanced fractional renal urate excretion (FE-urate), indicating that a direct effect of the SGLT2 inhibitor on urate transporters is not absolutely necessary. Consistent with a proposed role of increased luminal glucose delivery, absence of SGLT1, which by itself had no effect on FE-urate, enhanced both the glycosuric and uricosuric effect of the SGLT2 inhibitor. The SGLT2 inhibitor enhanced renal mRNA expression of GLUT9 in WT mice, but tubular GLUT9 seemed dispensable for the increase in FE-urate in response to canagliflozin. First evidence is presented that URAT1 is required for the acute uricosuric effect of the SGLT2 inhibitor in mice. PMID- 30427223 TI - The power of proteasome inhibition in multiple myeloma. AB - INTRODUCTION: Proteasome inhibitors (PIs) are therapeutic backbones of multiple myeloma treatment, with PI-based therapies being standards of care throughout the treatment algorithm. Proteasome inhibition affects multiple critical signaling pathways in myeloma cells and interacts synergistically with mechanisms of action of other conventional and novel agents, resulting in substantial anti-myeloma activity and at least additive effects. Areas covered: This review summarizes the biologic effects of proteasome inhibition in myeloma and provides an overview of the importance of proteasome inhibition to the current treatment algorithm. It reviews key clinical data on three PIs, specifically bortezomib, carfilzomib, and ixazomib; assesses ongoing phase 3 trials with these agents; and looks ahead to the increasingly broad role of both approved PIs and PIs under investigation in the frontline and relapsed settings. Expert commentary: Progress to date with PIs in multiple myeloma has been impressive, but there remain unmet needs and challenges, as well as increasing opportunities to optimize the use of these agents. Understanding discrepancies between PIs in terms of efficacy and safety profile is a key goal of ongoing research, along with proteomics-based efforts to identify potential biomarkers of sensitivity and resistance, thereby enabling increasingly personalized treatment approaches in the future. PMID- 30427225 TI - Considerations for the Scientific Support Process and Applications to Case Studies. AB - Case studies are vehicle to bridge the gap between science and practice because they provide opportunities to blend observations and interventions that have taken place in real-world environments with scientific rigour. The purpose of this invited commentary is to present considerations for those providing applied sport science support to athletes with the intention of broadcasting this information to the scientific community. We present a four phased approach (1: Athlete overview; 2: Needs analysis; 3: Intervention planning; 4: Results, evaluation and conclusion) for scientific support to assist practitioners in the development and implementation of scientific support. These considerations are presented in the form of 'performance questions' designed to guide and critically evaluate the scientific support process and aid the transfer of this knowledge via case studies. PMID- 30427224 TI - HPLC-UV assay for the evaluation of inhibitors of plasma amine oxidase using crude bovine plasma. AB - Recently, we have described a method for evaluation of plasma amine oxidase (PAO) inhibitors, which monitors the formation of 6-(5-phenyl-2H-tetrazol-2-yl)hexanal from the corresponding amine substrate by HPLC with UV-detection using purified bovine PAO. We now investigated, whether crude bovine plasma can be used as enzyme source in this assay instead of the purified enzyme. With the aid of specific inhibitors, it was ensured that there was no detectable activity of other important amine oxidases in the plasma, namely monoamine oxidase (MAO) A and B and diamine oxidase (DAO). For a series of omega-(5-phenyl-2H-tetrazol-2 yl)alkan-1-amine substrates similar conversion rates were measured for both the purified PAO and crude plasma. The inhibition values determined for the PAO inhibitor 2-(4-phenylphenyl)acetohydrazide (16) under different conditions also corresponded. Additionally, inhibition data of the known PAO inhibitor 2-amino-N (3-phenylbenzyl)acetamide (17) and a newly synthesised meta-substituted derivative of 16 were determined, which together reflect the two-step inhibition mechanism of these covalent inhibitors. PMID- 30427226 TI - Physiologic, Metabolic and Nutritional Attributes of Collegiate Synchronized Swimmers. AB - PURPOSE:: The purpose of this study was to identify physiological characteristics and dietary habits of collegiate synchronized swimmers. METHODS:: Twenty-one female participants (mean +/- SD, age: 20.4 +/- 1.6 years; height: 168.0 +/- 4.9 cm; weight: 64.4 +/- 8.7 kg) performed resting metabolic rate (RMR) test. Body composition was determined using skinfolds (4-site and 7-site) and dual-energy X ray absorptiometry (DEXA). Dietary intake was assessed using four-day dietary records. RESULTS:: RMR was 110.9 +/- 10.5 kJ/kg normalized to body weight and calculated relative daily caloric intake was 121.4 +/- 42.3 kJ/kg. Estimated energy availability ranged from 109.1 +/- 52.1 to 126.7 +/- 52.6 kJ/kg FFM/day and was correlated (p = 0.045) to RMR. Percent body fat using DEXA (28.7 +/- 4.8 % fat) was higher than both 4-site (25.7 +/- 4.8 % fat, p = 0.001) and 7-site (25.3 +/- 4.7 % fat, p = 0.001) skinfold values. No significant correlations were reported between bone mineral density, body composition and dietary intake data. CONCLUSIONS:: Synchronized swimmers have similar body composition and training habits as other competitive aquatic athletes. Dietary intake data revealed low energy availability and lower than recommended macronutrient levels. PMID- 30427227 TI - Effects of Drop-Height on Jump Performance in Male and Female Elite Adolescent Handball Players. AB - PURPOSE:: The purpose of the present study was to examine the effects of drop height on drop jump (DJ) performance and on associations between DJ and horizontal jump/sprint performances in ad-olescent athletes. METHODS:: Male (n=119, 2.5+/-0.6 yrs post-peak height velocity [PHV]) and fe-male (n=120, 2.5+/ 0.5 yrs post-PHV) adolescent handball players (national level) performed DJs in randomized order using 3 drop-heights (20, 35, and 50-cm). DJ performance (jump height, re-active strength index [RSI]) was analyzed using the Optojump Next system. Additionally, corre-lations were computed between DJ height and RSI with standing long jump (SLJ) and 20-m linear sprint performances. RESULTS:: Statistical analyses revealed medium-sized main effects of drop-height for DJ height and RSI (p<.001, 0.63<=d<=0.71). Post-hoc tests indicated larger DJ heights from 20 to 35, and 35 to 50-cm (p<=.031, 0.33<=d<=0.71) and better RSI from 20 to 35-cm drop-height (p<.001, d=0.77). No significant difference was found for RSI between 35 and 50-cm drop-height. Irrespective of drop-height, associations of DJ height and RSI were small with 5-m split time (-.27<=r<=.05), medium with 10-m split time (-.44<=r<=.14), and medium-to-large with 20-m sprint time and SLJ distance (-.57<=r<=.22). CONCLUSIONS:: The present findings indicate that, irre-spective of sex, 35-cm drop-heights are best suited to induce rapid and powerful DJ performance (i.e., RSI) during reactive strength training in elite adolescent handball players. Moreover, train-ing-related gains in DJ performance may at least partly translate to gains in horizontal jump and longer sprint distances (i.e., >=20-m) and/or vice versa in male and female elite adolescent athletes, irrespective of drop-height. PMID- 30427228 TI - A Novel Method of Assessment for Monitoring Neuromuscular Fatigue Within Australian Rules Football Players. AB - PURPOSE:: To compare the sensitivity of a submaximal run test (SRT) with a countermovement jump (CMJ) test to provide an alternate method of measuring neuromuscular fatigue (NMF) in high performance sport. METHODS:: 23 professional and semi-professional Australian rules football (ARF) players, performed a SRT and CMJ test, pre-match, 48- and 96-hours post-match. Variables from accelerometers recorded during the SRT were; player load 1D up (PL1Dup) (vertical vector); player load 1D side (PL1Dside) (medio-lateral vector); and player load 1D forward (PL1Dfwd) (anterio-posterior vector). Meaningful difference was examined through magnitude-based inferences (effect-size; ES), with reliability assessed as typical error of measurements expressed as coefficient of variance (CV). RESULTS:: A small decrease in CMJH; ES -0.43 +/- 0.39 (likely) was observed 48 hours post-match before returning to baseline 96 hours post-match. This was accompanied by corresponding moderate decreases in the SRT variables; PL1Dup; ES 0.60 +/- 0.51 (likely) and PL1Dside; ES -0.74 +/- 0.57 (likely) 48 hours post match before also returning to pre-match baseline. CONCLUSION:: The results suggest that in the presence of NMF, players utilise an alternative running profile to produce the same external output (i.e. time). This supports changes in accelerometer variables during a SRT can be used as an alternate method of measuring NMF in high performance ARF and provides a flexible option for monitoring changes within the recovery phase post-match. PMID- 30427229 TI - Force-Velocity-Power Profiling During Weighted Vest Sprinting in Soccer. AB - PURPOSE:: To describe the load-velocity relationship and the effects of increasing loads on spatio-temporal and derived kinetics variables of sprinting using weighted vest (WV) in soccer players and determining the load that maximized power output. METHODS:: Twenty-three soccer players (age: 20.8+/-1.5 years) performed ten maximal 30-m sprints wearing a WV, with five different loads (0, 10, 20, 30 and 40% body mass (BM). Sprint velocity and time were collected using a radar device and wireless photocells. Mechanical outputs were computed using a recently developed valid and reliable field method that estimates the step-averaged ground reaction forces (GRF) during over ground sprint acceleration from anthropometric and spatio-temporal data. Raw velocity-time data were fitted by an exponential function and used to calculate the net horizontal GRF and horizontal power output. Individual linear force-velocity relationships were then extrapolated to calculate the theoretical maximum horizontal force (F0) and velocity, and the ratio of force application (RF: proportion of the total force production that is directed forward at sprint start). RESULTS:: Magnitude-based inferences showed an almost certain decrease on F0 (effect size [ES]=0.78-3.35), maximum power output (ES=0.78-3.81), and maximum ratio of force (ES=0.82-3.87) as the load increased. The greatest changes occurred with loads heavier than 20% BM, especially in RF. Additionally, the maximum power was achieved under unloaded condition. CONCLUSIONS:: Increasing load on WV sprinting affects the spatio temporal and kinetic variables. The greatest change in RF happened with loads heavier than 20% BM. Thus, we recommend the use of loads <=20% BM for WV sprinting. PMID- 30427230 TI - Comparison of Critical Speed and D' Derived From 2 or 3 Maximal Tests. AB - PURPOSE:: The hyperbolic distance-time relationship can be used to profile running performance and establish critical speed (CS) and D'. Typically, to establish these parameters multiple (3+) performance trials are required, which can be highly fatiguing and limit the usability of such protocols in a single training session. This study aimed to compare CS and D' calculated from a two trial (2-point model) and a three-trial (3-point model) method. METHODS:: 14 male distance runners completed three fixed-distance (3600, 2400, 1200 m) time trials on a 400 m outdoor running track, separated by a 30-minute recovery. Participants completed the protocol nine times across a twelve-month period, with approximately 42-days between each test. CS and D' were calculated using all three distances (3-point model) and also using the 3600 and 1200 m distances only (2-point model). RESULTS:: Mean (+/-SD) CS for both 3-point and 2-point models was 4.94 +/- 0.32 m.s-1, whilst D' was 123.3 +/- 57.70 m and 127.4 +/- 57.34 m for 3-point and 2-point models, respectively. Overall bias for both CS and D' between 3-point and 2-point model was classed as trivial. CONCLUSIONS:: A 2-point time-trial model can be used to calculate CS and D' as proficiently as a 3-point model, making it a less fatiguing, inexpensive and applicable method for coaches, practitioners and athletes to monitor running performance in one training session. PMID- 30427231 TI - The effect autophagy-enhancing peptide in moisturizer on atopic dermatitis: A randomized controlled trial. AB - BACKGROUND: Pentasodium tetracarboxymethyl palmitoyl dipeptide-12 (PTPD-12), a newly-synthesized peptide, enhances the autophagy activity, ultimately managing inflammation. OBJECTIVE: To determine the effect of a new moisturizer containing PTPD-12 as the treatment of mild-to-moderate atopic dermatitis (AD). METHODS: In this double-blind, randomized, placebo-controlled trial, 43 patients with mild-to moderate AD were randomly assigned to either the PTPD-12 or control groups. Evaluations were performed at baseline, week 2, and week 4, including SCORing Atopic Dermatitis (SCORAD) index score, corneometry, trans-epidermal water loss (TEWL), visual analogue scale (VAS) for pruritus, 7-point investigator's global assessment (IGA), and collection of adverse events. RESULTS: The PTPD-12 group showed significant improvement with respect to SCORAD score, skin hydration, TEWL, and pruritus at weeks 2 and 4 when compared with baseline. Although the control group showed significant improvement regarding the SCORAD score and skin hydration, no significant change in TEWL or pruritus was demonstrated throughout the study. The mean changes in the SCORAD index score, skin hydration, TEWL, pruritus, and number of patients with improvement in IGA were not statistically different between the two groups. CONCLUSION: The moisturizer with autophagy stimulating property provides a good therapeutic option to mild-to-moderate atopic dermatitis by contributing to skin barrier restoration and control of inflammation. PMID- 30427232 TI - Ingesting a Bitter Solution: The Sweet Touch to Increasing Short-Term Cycling Performance. AB - PURPOSE:: We investigated the potential benefit of ingesting 2 mM of quinine (bitter tastant) on 3000 m cycling time-trial (TT) performance. METHODS:: Nine well-trained male cyclists (maximal aerobic power 386 +/- 38 W; mean +/- SD) performed a maximal incremental cycling ergometer test, three 3000 m familiarization TT and four 3000 m intervention TT (~4 min) on consecutive days. The four interventions were: 1) 25 ml of Placebo, 2) a 25 ml Sweet solution, and 3) and 4) repeat 25 ml of 2 mM quinine solutions (Bitter1 and Bitter2), 30 seconds prior to each trial. Participants self-selected their gears and were only aware of distance covered. RESULTS:: Overall mean power output for the full 3000 m was similar for all four conditions: Placebo, 348 +/- 45 W (mean +/- SD); Sweet, 355 +/- 47 W; Bitter1, 354 +/- 47 W; and Bitter2, 355 +/- 48 W. However, quinine administration in Bitter1 and Bitter2 increased power output during the first km by 15 +/- 11 W and 21 +/- 10 W (mean+/- 90% confidence limits) respectively over Placebo, followed by a decay of 34 +/- 32 W during Bitter1 and Bitter2 during the 2nd km. Bitter2 also induced a 11 +/- 13 W increase during the 1st km compared with the Sweet condition. CONCLUSIONS:: Ingesting 2 mM of quinine can improve cycling performance during the first 1/3 of a 3000 m TT and could be used for sporting events lasting ~80 s in order to potentially improve overall performance. PMID- 30427233 TI - Case Study: Assessment of Energy Expenditure of a Professional Goalkeeper From the English Premier League Using the Doubly Labeled Water Method. AB - PURPOSE:: To better understand the energy and carbohydrate (CHO) requirements of a professional goalkeeper (GK) in elite soccer, we quantified physical loading, energy expenditure (EE) and energy intake (EI) during a two game per week in season micro-cycle. METHODS:: Daily training and match loads were assessed in a professional GK |(age, 26 years; height, 191 cm; body mass, 86.1 kg) from the English Premier League using global positioning systems (GPS) and ProZone(r), respectively. Assessments of EE (using the doubly labelled water method) and EI (using food diaries supported by the remote food photographic method and 24-h recalls) were also completed. RESULTS:: Physical loading was greater on match days (MD) versus training days (TD) as inferred from total distance (4574 +/- 432 vs 1959 +/- 500 m), average speed (48 +/- 5 v 40 +/- 4 m/min) and distance completed when jogging (993 +/- 194 v 645 +/- 81 m) and running (138 +/- 16 v 21 +/- 20 m). Average daily energy and macronutrient intake appear reflective of a self-selected "low CHO" diet (Energy: 3160 +/- 381 kcal, CHO: 2.6 +/- 0.6; Protein: 2.4 +/- 0.4; Fat: 1.9 +/- 0.3 g.kg-1 body mass). Mean daily EE was 2894 kcal. CONCLUSIONS:: The average daily EE of this professional GK was approximately 600 kcal.d-1 lower than that previously reported in outfield players from the same team. Such data suggest the nutritional requirements of a GK should be carefully considered depending on the required daily and weekly loading patterns. PMID- 30427234 TI - Repeated Menthol Spray Application Enhances Exercise Capacity in the Heat. AB - PURPOSE:: Exercise performance is impaired in the heat and a contributing factor to this decrement is thermal discomfort. Menthol-spraying of skin is one means of alleviating thermal discomfort but has yet to be shown to be ergogenic using single spray applications. We examined whether repeated menthol-spraying could relieve thermal discomfort, reduce perception of exertion and improve exercise performance in hot (35oC), dry (22% RH) conditions; we hypothesised it would. METHOD:: Eight trained cyclists completed two separate conditions of fixed intensity (FI) cycling (50% PMax) for 45-minutes before a test to exhaustion (TTE; 70% PMax) with 100 mL of menthol-spray (0.20% menthol) or control-spray applied to the torso after 20 and 40-minutes. Perceptual (thermal sensation (TS), thermal comfort (TC), RPE) performance (TTE duration), thermal variables (skin temperature (Tskin), rectal temperature (Trec), cardiac frequency (fc)) and sweating were measured. Data were compared using ANOVA to 0.05 alpha level. RESULTS:: Menthol-spray improved TS ('cold' sensation cf 'warm/hot' after first spraying; p=.008) but only descriptively altered TC ('comfortable' cf 'uncomfortable'; p=.173). Sweat production (994 (380) mL cf 1180 (380); p=.020) mL and rate (827 (327)mL.hr-1 cf 941 (319)mL.hr-1; p=.048) lowered. TTE performance improved (4.6 (1.74) cf 2.4 (1.55) minutes (p=.004). Menthol-spray effects diminished despite repeated applications indicating increased contribution of visceral thermoreceptors to thermal perception. CONCLUSION:: Repeated menthol-spray improves exercise capacity but alters thermoregulation potentially conflicting behavioural and thermoregulatory drivers; care should be taken with its use. Carrying and deploying menthol-spray would impose a logistical burden which needs consideration against performance benefit. PMID- 30427235 TI - Caffeine Supplementation: Ergogenic in Both High and Low Caffeine Responders. AB - PURPOSE:: Inconsistent results among studies examining the effects of caffeine on exercise performance are potentially due to inter-individual variability in biological responses to caffeine ingestion. The aims, therefore, of the present study were to identify high and low caffeine responders and compare the influence of caffeine on exercise performance and biological responses between groups during a simulated soccer-game protocol on treadmill. METHODS:: Well-trained soccer-players were distinguished as high (n = 11) and low (n = 9) caffeine responders based on resting blood pressure, plasma glycerol, non-esterified fatty acid and epinephrine responses to caffeine. Participants underwent two simulated soccer-game protocols on treadmill after caffeine (6 mg?kg-1) or placebo ingestion. Exercise performance and several biological responses were evaluated. RESULTS:: Exercise performance was not different between the high (H) and low (L) responders to caffeine (P > 0.05). However, time-to-fatigue (H, caffeine: 797+/ 201 s vs placebo: 487+/-258 s; L, caffeine: 625+/-357 s vs placebo 447+/-198 s) and countermovement jumps (H, caffeine: 42.1+/-5.5 cm vs placebo: 40.5+/-5.7 cm; L, caffeine: 41.0+/-3.8 cm vs placebo: 38.8+/-4.6 cm) improved with caffeine relative to placebo (P < 0.001). Rating of perceived exertion was lower (P < 0.001) in H (13.4+/-2.3) compared to L (14.3+/-2.4) with caffeine ingestion. CONCLUSIONS:: Caffeine improved aerobic endurance and neuromuscular performance in well-trained soccer-players regardless of their responsiveness to caffeine at rest. Since no changes in substrate utilization were found with caffeine supplementation, performance improvements could be attributed to positive effects on the central nervous system and/or neuromuscular function, although the precise mechanism remains unclear. PMID- 30427236 TI - Individual Factors Affecting Rugby Sevens Match Performance. AB - PURPOSE:: To examine the collective independent influence of a range of individual characteristics on physical and technical match performance during international rugby sevens matches. METHODS:: Data was collected from 20 international rugby sevens players from one team across one season. Activity profiles were measured using wearable microtechnology devices, and technical performance measures were collected from match video analysis. Subjective wellbeing measures were collected using a wellbeing questionnaire completed in the morning of main training days, and groin squeeze assessments at 0 degrees and 60 degrees knee flexion were also conducted using a sphygmomanometer. Assessments of aerobic fitness were completed periodically across the season, including time to complete a two-kilometre run, and final velocity during the 30:15 intermittent fitness test (VIFT). A principal components analysis was conducted to reduce the dimensionality of the physical and technical variables into single factor values. Linear mixed models were then constructed to examine the collective influence of a range of individual contextual variables on physical and technical performance factors. RESULTS:: Increased muscle soreness, stress, and VIFT were associated with trivial to small increases in physical and technical performance values; whilst trivial to small decreases were associated with higher perceived recovery, bodyweight, and groin squeeze (0 degrees knee flexion). CONCLUSIONS:: A range of wellbeing metrics are required to account for a significant portion of the variance in physical and technical performance. These factors may be manipulated by coaches or practitioners to achieve favourable physiological readiness which may lead to improved match performance. PMID- 30427237 TI - A 12-Year Cohort Study of Doc-Stoppage Professional Mixed Martial Arts. AB - PURPOSES: This research sought to determine actions during bouts which generate serious enough injury to stop the bout, verifying the injury incidence, types, and prevalence of doctor stoppages (doc-stoppage), and identify potential risk factors by analyzing technical-tactical profiles for injury in sanctioned mixed martial arts (MMA) bouts taking place over a 12-year period. METHODS: The research analyzed 440 paired MMA matches separated by doc-stoppage (n=220) and no doc-stoppage (n=220) from 2002-2014. Technical-knockouts for doc-stoppage were diagnosed and managed by attending ringside doctors and the time-motion variables were categorized into total combat time separated by low- or high-intensity activity per round, stand-up or groundwork actions, p<=0.05. RESULTS: The main cause of injuries in doc-stoppage situations were due to facial injuries (>90%), with 87.1% occurring after striking actions during the second round. Lacerations were the leading type of injury, which occurred with 80% frequency. The results showed differences between doc-stoppage and no doc-stoppage for standing combat with low-intensity actions (130.6+/-8.5s vs. 83.3+/-6.9s for first round; 115.7+/ 10.5s vs. 100.1+/-9.6s for second round and 121.5+/-19.5s vs. 106.3+/-11.7s for third round) and total strike attempts (34.5, 23.0-51.8 vs. 25.0, 12.0-40.8); in standing combat, head strike attempts (21, 10-33 vs. 11, 4-21) and body strikes (2.5, 1.0-5.8 vs. 1.0-2); and in groundwork combat, head strikes landed (0.0-3.0 vs. 0.0-5.0). CONCLUSIONS: Our research showed higher values of strike attempts with two main orientations, namely the head (on the ground and in stand-up actions) and body (in stand-up actions), and may provide important information regarding the technical knockout (TKO) and when it can be called by officials supervising MMA bouts. PMID- 30427239 TI - 5-aminolevulinic acid photodynamic therapy for condyloma acuminatum of urethral meatus. AB - Condyloma acuminatum are the most common sexually transmitted diseases worldwide, and they are closely associated with human papillomavirus (HPV) infections. Urethral meatus warts are uncommon. And many treatments are limited by a difficult approach, recurrences, and potential complications. In our study, 21 patients diagnosed with urethral condyloma acuminatum were included. After 4h treatment of 5-aminolevulinic acid (ALA), patients received photodynamic therapy (PDT). Each patient received HPV test before every PDT cycle. The frequency of PDT was dependent on viral load changes. As a result, all patients achieved complete clinical remission after the last session of ALA-PDT. There were significant differences in HPV viral loads between pretherapy and after one or three rounds of PDT treatment. So we concluded that ALA-PDT is a safe and effective method for treatment of condyloma acuminatum in urethra meatus. Dynamic monitoring of HPV viral loads can more objectively demonstrate the effectiveness and guide the treatment of PDT. PMID- 30427238 TI - Circulation, Cell-free DNA for Monitoring Player Load in Professional Football. AB - PURPOSE:: Player monitoring in elite sports settings is becoming increasingly important. Beside questionnaire based methods, biomarkers, such as circulating, cell-free DNA (cfDNA) are sug-gested for load monitoring. cfDNA concentrations were shown to increase dependent on total distance covered in football and was associated with overtraining in weightlifters. Thus, the objective of this study was to examine whether cfDNA is feasible as a monitoring tool in elite football players. METHODS:: We collected capillary blood samples from 22 male elite football players over 4 months of a regular season. Sampling was conducted the day before, one day after or several days after regular season games and/or training. In addition, each player filled in a Visual-Analogue-Scale questionnaire (VAS) including the items "general perceived exer-tion", "muscular fatigue" and "mental fatigue". Performance during training and games was tracked by the Catapult system (training) and with the OPTA system (games), respectively. RESULTS:: cfDNA values were significantly elevated in players the day after regular season games (1.4-fold; p=0.0004) in line with the scores of the VAS. Both parameters showed sig-nificantly higher values during midweek game weeks. While cfDNA concentrations correlated with training data, the VAS was correlated with the tracking of the season games. However, cfDNA and VAS did not correlate with each other. CONCLUSIONS:: Here we show that cfDNA concentrations at rest and VAS scores are influenced by previous load in professional football players. Future studies will reveal whether cfDNA might serve as a practically applicable marker for player load in football players. PMID- 30427240 TI - Training Load and Baseline Characteristics Associated With New Injury/Pain Within an Endurance Sporting Population: A Prospective Study. AB - PURPOSE:: To determine the association between training load (TL) factors, baseline characteristics and new injury and/or pain (IP) risk within an endurance sporting population (ESP). METHODS:: Ninety-five endurance sporting participants from running, triathlon, swimming, cycling and rowing disciplines. Participants initially completed a questionnaire capturing baseline characteristics. TL and IP data was submitted weekly over a 52-week study period. Cumulative TL factors, Acute:Chronic Workload Ratios (ACWR) and Exponentially Weighted Moving Averages (EWMA) were calculated. A shared frailty model was used to explore time to new IP and association to TL factors and baseline characteristics. RESULTS:: 92.6% of the ESP completed all 52 weeks of TL and IP data. The following factors were associated with the lowest risk of a new IP episode; (a) a low to moderate 7-day lag EWMA (0.8-1.3: HR=1.21, 95% CI 1.01-1.44, p=0.04) (b) a low to moderate 7-day lag weekly training load (WL) (1200-1700AU: HR=1.38, 95% CI=1.15-1.65, p<0.001) (c) a moderate to high 14-day lag 4-weekly cumulative training load (CL) (5200 8000AU: HR=0.33, 95% CI=0.21-0.50, p<0.001) and (d) a low number of previous IP episodes in the preceding 12 months (1 previous IP episode: HR=1.11, 95% CI=1.04 1.17, p=0.04). CONCLUSIONS:: To minimise new IP risk an ESP should avoid high spikes in acute TL whilst maintaining moderate to high chronic TLs. A history of previous IP should be considered when prescribing TLs. The demonstration of a lag between a TL factor and its impact on new IP risk may have important implications for future ESP TL analysis. PMID- 30427241 TI - Understanding the Impact of Trunk and Arm Impairment on Wheelchair Rugby Performance During Competition. AB - PURPOSE:: To determine the effect of trunk and arm impairment on physical and technical performance during wheelchair rugby (WR) competition. METHODS:: Thirty one highly trained WR players grouped according to their trunk (no trunk [NT]; some trunk [T] function) and arm impairment (poor [PAF]; moderate [MAF]; good [GAF] arm function) participated in 5 WR matches. Player's physical (wheelchair mobility) and technical (ball handling) activities were analysed using an indoor tracking system and video analysis respectively. RESULTS:: Trunk impairment explained some of the variance in physical (10.6-23.5%) and technical (16.2 33.0%) performance. T covered more distance, had more possession, scored more goals, received and made more passes, yet spent less time at low speeds and performed fewer inbounds than NT (<= 0.05). Arm impairment explained some of the variance in all physical (16.7-47.0%) and the majority of technical (13.1-53.3%) performance measures. MAF and GAF covered more distance, reached higher peak speeds, spent more time in higher speed zones, scored more goals, had more possession, received and made more passes, with a higher percentage of one-handed and long passes than PAF. GAF also received more passes and made a higher percentage of one-handed passes and defensive blocks than MAF (P <= 0.05). CONCLUSIONS:: Arm impairment impacts a greater number of physical and technical measures of performance specific to WR than trunk impairment during competition. Having active finger function (GAF) yielded no further improvements in physical performance but positively influenced a small number of technical skills. PMID- 30427242 TI - The Influence of Hamstring Muscle Peak Torque and Rate Of Torque Development for Sprinting Performance in Football Players: A Cross-Sectional Study. AB - PURPOSE:: This cross-sectional study aimed to investigate the association between hamstring muscle peak torque and rapid force capacity (rate of torque development: RTD) versus sprint performance in elite youth football players. METHODS:: Thirty elite academy youth football players (16.75 +/- 1.1 years, 176.9 +/- 6.7 cm, 67.1 +/- 6.9 kg) were included. Isometric peak torque (Nm/kg) and early (0-100 ms) and late (0-200 ms) phase RTD (RTD100, RTD200) (Nm/s/kg) of the hamstring muscles were obtained as independent predictor variables. Sprint performance was assessed during a 30-m sprint trial. Mechanical sprint variables (maximal horizontal force production (FH0) (N/kg); maximal theoretical velocity (V0) (m/s); maximal horizontal power output (Pmax) (W/kg)) and sprint split times (0-5 m; 0-15 m; 0-30 m; 15-30 m) (s) were derived as dependent variables. Subsequently, linear regression analysis was conducted for each pair of dependent and independent variables. RESULTS:: Positive associations were observed between hamstring RTD100 and FH0 (r2=0.241, p=0.006) and Pmax (r2=0.227, p=0.008). Furthermore, negative associations were observed between hamstring RTD100 and 0-5 m (r2=0.206, p=0.012), 0-15 m (r2=0.217, p=0.009) and 0-30 m sprint time (r2=0.169, p=0.024). No other associations were observed. CONCLUSION:: The present data indicate that early-phase (0-100 ms) rapid force capacity of the hamstring muscles plays an important role for the acceleration capacity in elite youth football players. In contrast, no associations were observed between hamstring muscle function and maximal sprint velocity. This indicates that strength training focusing on improving early-phase hamstring rate of force development may contribute to enhance sprint acceleration performance in this athlete population. PMID- 30427243 TI - Impaired Heat Adaptation From Combined Heat Training and Live High-Train Low Hypoxia. AB - PURPOSE:: To determine whether combining training in heat with 'Live High, Train Low' hypoxia (LHTL) further improves thermoregulatory and cardiovascular responses to a heat tolerance test compared to independent heat training. METHODS:: Twenty-five trained runners (VO2peak = 64.1 +/-8.0 ml.min.kg-1) completed three-weeks training in one of three conditions: 1) Heat training combined with LHTL (H+H; FiO2 =14.4% (3000 m), 13 h.day-1; train at <600 m, 33 degrees C, 55% RH); 2) heat training (HOT; live and train <600 m, 33 degrees C, 55% RH); 3) temperate training (CONT; live and train <600 m, 13 degrees C, 55% RH). Heat adaptations were determined from a 45 min heat response test (33 degrees C, 55% RH, 65% vVO2peak) at baseline, immediately, one and three weeks' post exposure (Baseline, Post, 1wkP and 3wkP, respectively). Core temperature, heart rate, sweat rate and sodium concentration, plasma volume, and perceptual responses were analysed using magnitude based inferences. RESULTS:: Submaximal heart rate (ES= -0.60(-0.89; -0.32)) and core temperature [ES= -0.55(-0.99; 0.10)] were reduced in HOT until 1wkP. Sweat rate [ES= 0.36(0.12; 0.59)] and sweat sodium concentration [ES= -0.82(-1.48; -0.16)] were respectively increased and decreased until 3wkP in HOT. Submaximal heart rate [ES= -0.38 (-0.85; 0.08)] was likely reduced in H+H at 3wkP, whilst CONT had unclear physiological changes. Perceived exertion and thermal sensation were reduced across all groups. CONCLUSIONS:: Despite greater physiological stress from combined heat training and LHTL, thermoregulatory adaptations are limited in comparison to independent heat training. The combined stimuli provides no additional physiological benefit during exercise in hot environments. PMID- 30427244 TI - Reducing Aerodynamic Drag by Adopting a Novel Road Cycling Sprint Position. AB - PURPOSE:: To assess the influence of a seated, standing, and forward standing cycling sprint position on aerodynamic drag CdA and the reproducibility of a field test of CdA calculated in these different positions. METHODS:: Eleven recreational male road cyclists rode 250 m in two directions at around 25, 32, and 40 km.h-1 and in each of the three positions, resulting in a total of 18 efforts per participant. Riding velocity, power output, wind direction and velocity, road gradient, temperature, relative humidity, and barometric pressure were measured and used to calculate CdA use regression analysis. RESULTS:: A main effect of position showed that the average CdA of the two days was lower for the forward standing position (0.295 +/- 0.059), compared with both the seated (0.363 +/- 0.071; p = 0.018) and standing positions (0.372 +/- 0.077; p = 0.037). Seated and standing positions did not differ from each other. While no significant difference was observed in CdA between the two test days, a poor between day reliability was observed. CONCLUSION:: A novel forward standing cycling sprint position resulted in a 23 and 26% reduction in CdA compared with a seated and standing position. This decrease in CdA could potentially result in an important increase in cycling sprint velocity of 3.9-4.9 km.h-1, although these results should be interpreted with caution since poor reliability of CdA was observed between days. PMID- 30427245 TI - Physical Load in Soccer: Strengths and Limitations of Three Different Methods. AB - PURPOSE:: This study investigates the strengths and limitations of different indicators to measure physical load. Furthermore, indicators were evaluated for discrimination between performance levels and playing positions. METHODS:: Ninety positional match files from 70 elite players and 91 match files from 69 sub-elite players were collected during 14 official under-18 matches using a local position measurement system. Indicators are calculated from either speed, absolute acceleration (acc-abs), or percentage acceleration (acc-%). The acc-% describes the level of acceleration depending on the maximal voluntary acceleration (amax) for each initial running speed. Effect sizes (ES) were used to determine discriminative ability. RESULTS:: The number of high accelerations largely depended on the method (absolute threshold > 3 m?s-2 and > 4 m?s-2: 120 and 59 efforts; high percentage threshold (> 75% amax): 84 efforts). Only a small number of highly accelerated efforts reached speeds considered as high-speed running (> 19.8 km.h-1: 32.6%). More high acc-% exist from initial running speed > 2 m?s-1 (23.0) compared to acc-abs (> 3 m?s-2: 14.4; > 4 m?s-2: 5.9). Elite players achieve higher values in most performance indicators, with ES being highest for the number of high acc-% (ES 0.91) and high acc-abs (> 3 m?s-2: ES 0.86; > 4 m?s 2: ES 0.87) as well as for covered distance in jogging (ES 0.94). CONCLUSIONS:: Estimated physical load, discriminative ability of physical indicators, and positional requirements largely depend on the applied method. A combination of speed-based and acc-% methods is recommended to get a comprehensive view. PMID- 30427246 TI - No Effect of Beetroot Juice Supplementation on 100-m and 200-m Swimming Performance in Moderately-Trained Swimmers. AB - PURPOSE:: Dietary nitrate supplementation has been reported to improve performance in kayaking and rowing exercise which mandate significant recruitment of the upper body musculature. Since the effect of dietary nitrate supplementation on swimming performance is unclear, the purpose of this study was to assess the effect of dietary nitrate supplementation on 100-m and 200-m swimming freestyle time-trial (TT) performance. METHODS:: In a double blind, randomized crossover design, ten moderately-trained swimmers underwent two separate 3-day supplementation periods, with a daily dose of either 140 mL nitrate-rich (BRJ; ~800 mg/d nitrate) or nitrate-depleted (PLA) BRJ. Following blood sampling on day 3, the swimmers performed both 200-m and 100-m freestyle swimming TTs, with 30 min recovery between trials. RESULTS:: Plasma nitrite concentrations was greater after BRJ relative to PLA consumption (432 +/- 203 nmol/L, 111 +/- 56 nmol/L, respectively, p = 0.001). Systolic BP was lowered after BRJ compared to PLA supplementation (114 +/- 10, 120 +/- 10 mmHg, respectively p = 0.001), but time to complete the 200-m (BRJ: 152.6 +/- 14.1 s, PLA: 152.5 +/- 14.1 s) and 100-m (BRJ: 69.5 +/- 7.2 s, PLA: 69.4 +/- 7.4 s) freestyle swimming TTs were not different between BRJ and PLA (p > 0.05). CONCLUSION:: While 3 days of BRJ supplementation increased plasma nitrite concentration and lowered blood pressure, it did not improve 100-m and 200-m swimming TT performance. These results do not support an ergogenic effect of nitrate supplementation in moderately-trained swimmers, at least for 100-m and 200-m freestyle swimming performance. PMID- 30427247 TI - SNP Panel Population Genetics Approach Based in 1000genomes and Elite Soccer Players. AB - PURPOSE:: Soccer is one of the most popular sport worldwide, a physical activity of great physiological demand and complexity. Currently, numerous trials involving physiological responses such as hypertrophy, energy expenditure, vasodilation, cardiac output, VO2max, and recovery supported the possibility of genomic predictors affecting performance. In a complementary way to association studies with SNPs, the objective was evaluate if the use of population genetics data from human genomics databases can provide information for a better understanding of relationship between heritability and sports performance. METHODS:: The study included 25 healthy male professional soccer players (25.5 +/ 4.3 years; 177.4 +/- 6.4 cm; 76.4kg +/- 6.4 kg; body fat 10.5 +/- 4.3 %) from Brazilian first division soccer club. Anthropometric measurements, field and isokinetic tests were performed to evaluate performance and physiologic parameters of subjects. Moreover, 10 genetic polymorphisms previously related to performance were genotyped. The genotypes of the same polymorphisms were obtained of 2504 individuals from the populations deposited in the 1000genomes database. A PCA and matrix genetic distances approach (Fst) were evaluated. RESULTS:: As expected the admixture Brazilian population have numerous genetic similarity with the European and American population from genomic database. Although the African component is absolutely recognized in genomes from Brazilian population, using the specific performance-related SNPs, surprisingly African population was one of the most genetically distant of the players (p<0.00001). CONCLUSIONS:: Our early results suggest a selective pressure on genes of elite soccer players, possibly related simultaneously to physical performance, environmental, cognitive and socio-cultural aspects. PMID- 30427248 TI - Peripheral Muscle Function During Repeated Changes of Direction in Basketball. AB - PURPOSE:: To examine differences between adult male basketball players of different competitive levels (study 1) and changes over a basketball season (study 2) of knee extensor peripheral muscle function during a multi-stage changes of direction exercise (MCODE). METHODS:: In study 1, 111 players from 4 different divisions completed the MCODE during the regular season. In study 2, the MCODE was performed before (T1) and after (T2) the preparation period and during the competitive season (T3) by 32 players from division I, II and III. The MCODE comprised 4 levels of increasing intensity for each player. The peak twitch torque (PT) of knee extensors was measured after each level. PTmax (the highest value of PT) and fatigue were calculated. RESULTS:: In study 1, we found possibly small differences (ES+/-90%CI: -0.24+/-0.39) in fatigue between division I and II. Division I was characterized by likely (ES: 0.30 to 0.65) and very likely-to almost certain (ES: 0.74 to 1.41) better PTmax and fatigue levels compared to division III and VI, respectively. In study 2, fatigue was very likely reduced (ES: -0.91 to -0.51) among all divisions from T1 to T2, while PTmax was likely-to very likely reduced (ES: -0.51 to -0.39) in division II and III. CONCLUSIONS:: Professional basketball players are characterized by a better peripheral muscle function during a MCODE. Most of the seasonal changes in peripheral muscle function occurred after the preparation period. These findings inform practitioners on the development of training programs to enhance the ability to sustain repeated changes of direction efforts. PMID- 30427249 TI - The Within-Subject Correlation Between Salivary IgA and Measures of Training Load in Elite Football Players. AB - PURPOSE: To quantify the association between salivary secretory immunoglobulin A (sIgA) and training load in elite football players. METHODS: Data were obtained in four consecutive days during the preparation camp for the Rio 2016 Olympic Games. Saliva samples of 18 elite male football players were collected prior to breakfast. The session rating of perceived exertion (s-RPE) and external training load metrics from GPS were recorded. Within-subject correlation coefficients between training load and sIgA concentration, and magnitude of relationships were calculated. RESULTS: sIgA presented moderate to large negative correlations with s-RPE (r=-0.39), total distance covered (r=-0.55), accelerations (r=-0.52) and decelerations (r=-0.48). Trivial to small associations were detected between sIgA and distance covered per minute (r=0.01), high-speed distance (r=-0.23) and number of sprints (r=-0.18). sIgA displayed a likely moderate decrease from day 1 to day 2 (d=-0.7) but increased on day 3 (d=0.6). The training load variables had moderate to very large rises from day 1 to day 2 (d=0.7 to 3.2), but lowered from day 2 to day 3 (d=-5.0 to -0.4), except for distance per minute (d=0.8) and sprints (unclear). On day 3, all training load variables had small to large increments compared with day 1 (d=0.4 to1.5), with exception of accelerations (d= 0.8) and decelerations (unclear). CONCLUSIONS: In elite football sIgA might be more responsive to training volume rather than intensity. External load such as GPS-derived variables presented stronger association with sIgA compared with s RPE. Salivary IgA can be used as an additional objective tool in monitoring football players. PMID- 30427250 TI - IL-6 inhibitor for the treatment of rheumatoid arthritis: A comprehensive review. AB - Tocilizumab (TCZ) is an interleukin-6 (IL-6) inhibitor used for the treatment of rheumatoid arthritis (RA). It was developed in 2008, and its effectiveness is supported by evidence from all over the world based on its first decade of use. Although the overall efficacy and safety profiles of TCZ are similar to those of tumor necrosis factor (TNF) inhibitors, TCZ displays certain differences. The most notable advantage of TCZ is its usefulness as a monotherapy. Additionally, TCZ is favorable in the improvement of systemic inflammatory symptoms such as anemia and fatigue. The low immunogenicity of TCZ contributes favorably to long term drug retention. Due to frequent relapse after TCZ cessation, TCZ use should be tapered beyond remission. During TCZ therapy, C-reactive protein (CRP) is unable to recognize disease activity and the severity of infection. The most common adverse events (AEs) are infection and abnormalities in laboratory findings including dyslipidemia, neutropenia, thrombocytopenia, and abnormality of liver enzymes. TCZ obscures the symptoms of infection. Therefore, stealth infections without obvious CRP elevation can sometimes cause severe damage to patients. Lower intestinal perforation is an uncommon but serious AE in TCZ therapy. Further clinical investigations will continue to refine the IL-6 inhibitory strategy. PMID- 30427251 TI - Joint-Level Analyses of the Back Squat With and Without Intra-Set Rest. AB - PURPOSE:: To provide a joint level analysis of traditional (TS) and cluster (CS) set structure during the back squat exercise. METHODS:: Eight men (24+/-3 y; 177.3+/-7.9 cm; 82.7+/-11.0 kg; 11.9+/-3.5 %bodyfat; 150.3+/-23.0 kg one repetition maximum [1RM]) performed the back squat exercise (80%1RM) using TS (4 x 6, 2 min inter-set rest) and CS (4 x [2 x 3], 30-sec intra-set rest, 90-sec inter-set rest), randomly. Lower limb kinematics were collected by motion capture as well as kinetic data via bilateral force platforms. RESULTS:: CS attenuated the loss in mean power (TS, -21.6+/-3.9%; CS, -12.4+/-7.5%; p = 0.042), though no differences in gross movement pattern (sagittal plane joint angles) within and between conditions were observed (p>=0.05). However, joint power produced at the hip increased from REP 1 through REP 6 during TS, while a decrease was noted at the knee. A similar pattern was observed in the CS condition, but limited to the hip. Joint power produced at the hip increased from REP 1 through REP 3, but returned to REP 1 values before a similar increase through REP 6, resulting in differences between conditions (REP 4, p = 0.018; REP 5, p = 0.022). CONCLUSIONS:: Sagittal plane joint angles did not change in either condition, though CS elicited greater power. Differing joint power contributions (hip and knee) suggest potential central mechanism that may contribute to enhanced power output during CS and warrant further study. Practitioners should consider incorporating CS into training to promote greater power adaptations and mitigate fatigue. PMID- 30427252 TI - Platelet rich plasma compared to dry needling in the treatment of non-insertional Achilles tendinopathy. AB - OBJECTIVES: The efficacy of platelet rich plasma in the treatment of Achilles tendinopathy is controversial. Despite positive results observed in open studies, randomized controlled trials failed to show difference against saline or rehabilitation. Aims of this retrospective observational study were to compare the efficacy of platelet-rich plasma and dry needling and to assess possible differences age and sex-related. METHODS: Groups of 46 and 38 patients with non insertional Achilles tendinopathy were treated with platelet-rich plasma and dry needling (once a week for 3 weeks), respectively. At baseline, 3 and 6 months, pain and function scores and the percentage of satisfactory outcomes were evaluated. Sub-group analyses were performed according to age and sex. RESULTS: At 3 and 6 months no differences in terms of pain and function between groups were observed, but the percentage of subjects reporting satisfactory results, at 6 months, was higher in platelet rich plasma group. Better results were observed in younger subjects, with a greater reduction of pain, improvement of function, and accordingly of the percentage of positive outcomes. A trend toward better results was also observed in males. CONCLUSION: Beneficial effects of platelet rich plasma and dry needling in non-insertional Achilles tendinopathy have been observed only in some subjects, but not in others; platelet rich plasma shows a slight superiority against dry needling, mainly in younger persons; finally, a gender difference in the therapeutic response can be hypothesized. PMID- 30427253 TI - Challenges and opportunities in building critical health literacy. AB - BACKGROUND:: Critical health literacy is the least explored domain of health literacy and is addressed by few projects seeking to build health literacy. Lack of research means there is little evidence upon which to design effective interventions. Yet critical health literacy offers potential for individuals and communities to make important contributions to their own and society's health. This paper reports on an evaluation of a community project designed to develop critical health literacy. METHOD:: The evaluation explored, (a) processes used to build critical health literacy and (b) the impact on the critical health literacy of participants. A mixed methods approach was used combining a pre-and post intervention assessment of 14 of the 24 participants using the All Aspects of Health Literacy Scale, with participant focus groups and facilitator interviews. RESULTS:: Strategies used to build critical health literacy included informal and participatory learning, supported and independent assessment of the problem, appraising information, familiarisation of health systems and services, and social support. Common to these was learning within the context of participants' lives. Fewer strategies encouraged empowerment and political action. The evaluation showed slight improvements in some critical health literacy competencies: the ability to critically appraise health information and apply it to the context of their own lives and being able to critically question health professionals based on an individual's own research. However, there was no change in participants' ability to understand the determinants of health or involvement in activities for social and political change. CONCLUSION:: Informal, participatory community projects can successfully build many characteristics of critical health literacy. However, the political action element of critical health literacy remains the least well understood and faces particular challenges in its implementation. PMID- 30427254 TI - The role of thioredoxin reductase in gold nanoparticle radiosensitization effects. AB - AIM: To identify new mechanisms responsible for the radiosensitization effect of gold nanoparticles (GNPs). MATERIALS & METHODS: A549 lung carcinoma cells were incubated with 10-nm GNPs during 6 or 24 h before to be exposed to 25 keV/MUm protons or 225 kV x-rays. RESULTS: GNP incubation led to a time-dependent mitochondria membrane depolarization, oxidative stress and to x-ray and proton radiosensitization. Moreover, a marked inhibition of thioredoxin reductase was observed. Irradiation of cells invalidated for thioredoxin reductase evidenced a radiosensitization effect, suggesting that this enzyme is a potential GNP target. CONCLUSION: We suggest that GNPs play a radiosensitizer role by weakening detoxification systems. Altogether, these results open up promising novel strategies for the development of nanotechnologies associated to radiotherapy. PMID- 30427256 TI - The pull of soccer and the push of Xhosa boys in an HIV and drug abuse intervention in the Western Cape, South Africa. AB - There is growing interest in engaging men and boys in health and development programmes targeting the intersection of HIV risk, substance abuse, and violence. Understanding the conceptualisations of masculinities or masculine identities that shape both behaviours and opportunities for intervention is central to advancing the global agenda to engage men in health and development interventions. This paper examines an intervention using soccer and job training to engage and deliver activities for HIV prevention, substance abuse, and gender based violence in a South African township. A literature review provides theoretical, historical and social context for the intersection of gender, masculinity, soccer, violence, and sexual relationships. Qualitative data from in depth interviews and focus groups is analysed using theoretical and contextual frames to elucidate the negotiation of shifting, contradictory, and conflicting masculine roles. Results highlight how changing risky, normative behaviours among young men is a negotiated process entailing men's relationships with women and with other men. PMID- 30427257 TI - When do we need clinical endpoint adjudication in clinical trials? AB - Clinical endpoint adjudication (CEA) is a standardized process for assessment of safety and efficacy of pharmacologic or device therapies in clinical trials. CEA plays a key role in many large clinical trials with the aim of achieving consistency and accuracy of the study results, by applying independent and blinded evaluation of suspected clinical events reported by investigators. However, due to high costs there are different opinions regarding the use of central adjudication versus more simplified strategies or site-based assessments and whether the final results differ significantly. There is a lack of scientific evaluation of different adjudication strategies, and more knowledge is needed on the optimal adjudication process and how to achieve the best cost-effectiveness. New methodologies using national registry data and artificial intelligence may challenge the traditional adjudication strategy and could potentially reduce cost considerably with a similar result. Further research and evidence in this field of clinical trials methodology are essential. PMID- 30427258 TI - Health literacy as a determinant, mediator and/or moderator of health: empirical models using the European Health Literacy Survey dataset. AB - BACKGROUND/RESEARCH QUESTION:: In the health literacy (HL) discourse there is debate about the ways by which HL is impacting health. Three different, logically non-exclusive hypotheses are proposed: (a) HL as a specific, direct, social determinant of health; (b) HL as a mediator between other determinants and health; and (c) HL as a moderator of the effect of other determinants on health. Only few examples of empirically testing the mediator or moderator hypothesis exist. The data of the European Health Literacy Survey allow testing of the three hypotheses comparatively in parallel for functional and comprehensive HL. METHODS:: Data collection was based on multistage random samples of about 1000 European Union citizens aged 15 or older with Computer Assisted Personal Interviewing or Paper Assisted Personal Interviewing methodology in 2011 in eight Member States of the EU. Demographic and socio-economic indicators, a comprehensive (European Health Literacy Survey Q47) and a functional (Newest Vital Sign Test) health literacy measure and one self-assessed health variable were surveyed. Correlation analysis, multiple regression analysis and path analysis were performed. RESULTS:: Comprehensive HL (and to a much lesser degree functional HL) is a relevant predictor for self-assessed health. Also, comprehensive HL is only to a limited degree mediating the effects of other determinants on self-assessed health and only for age does HL partly moderate the effect on health. Explained variance and strength of effects vary considerably by national context. CONCLUSIONS/IMPLICATIONS:: Comprehensive HL is a critical, direct determinant of health. Therefore comprehensive HL has a considerable potential for health promotion to improve population health and tackle the health gap. But comprehensive HL measurement should be standardised in every country to allow for designing adequate measures for the specific situation of the country and also for benchmarking. For better understanding of the causal structure of the impact of HL on health, longitudinal studies will be needed. PMID- 30427259 TI - Discovery of a novel DNA polymerase inhibitor and characterization of its antiproliferative properties. AB - Chromosomal duplication is targeted by various chemotherapeutic agents for the treatment of cancer. However, there is no specific inhibitor of DNA polymerases that is viable for cancer management. Through structure-based in silico screening of the ZINC database, we identified a specific inhibitor of DNA polymerase delta. The discovered inhibitor, Zelpolib, is projected to bind to the active site of Pol delta when it is actively engaged in DNA replication through interactions with DNA template and primer. Zelpolib shows robust inhibition of Pol delta activity in reconstituted DNA replication assays. Under cellular conditions, Zelpolib is taken up readily by cancer cells and inhibits DNA replication in assays to assess global DNA synthesis or single-molecule bases by DNA fiber fluorography. In addition, we show that Zelpolib displays superior antiproliferative properties to methotrexate, 5-flourouracil, and cisplatin in triple-negative breast cancer cell line, pancreatic cancer cell line and platinum resistant pancreatic cancer cell line. Pol delta is not only involved in DNA replication, it is also a key component in many DNA repair pathways. Pol delta is the key enzyme responsible for D-loop extension during homologous recombination. Indeed, Zelpolib shows robust inhibition of homologous recombination repair of DNA double-strand breaks and induces "BRCAness" in HR-proficient cancer cells and enhances their sensitivity to PARP inhibitors. PMID- 30427260 TI - Indigenous microalgae biomass cultivation in continuous reactor with anaerobic effluent: effect of dilution rate on productivity, nutrient removal and bioindicators. AB - Effluents from municipal wastewater treatment have been long recognized as suitable media for the cultivation of microalgae biomass. However, few studies report data concerning biomass productivity in continuous reactors using unsterilized wastewater effluents. This study focuses on indigenous microalgae strains that grow with native bacteria and are applicable for biomass production and tertiary wastewater treatment in continuous growth mode. Initially, five Chlorophyta strains were isolated and grown in batch mode to single out a potential inoculum for the experiments in continuous growth mode. The isolate Chlorella sp. L06 was selected and evaluated based on five dilution rates from 0.1 to 0.5 day-1 on continuous growth reactor using unsterilized secondary effluent as culture medium. Maximal volumetric biomass productivity of 283 mg L-1 day-1 was achieved at 0.3 day-1 without CO2 addition or air bubbling. Carbohydrates were the major fraction of the dried biomass, followed by proteins and then lipids. The highest removal rates of total nitrogen and phosphorus from the liquid phase were 13.0 and 1.4 mg L-1 day-1, respectively, and were obtained at 0.4 day-1. The maximal decay rate for E. coli (2.9 day-1) was achieved both at 0.3 and 0.4 day-1. Conclusively, Chlorella sp. L06 cultivation in unsterilized secondary effluent can be adjusted depending on the objective: for biomass production, a dilution rate of approximately 0.3 day-1 is recommended; and for tertiary treatment a rate of 0.4 day-1 is suggested. PMID- 30427261 TI - Clinical commentary on "Warts and all: Fingolimod and unusual HPV associated lesions". PMID- 30427262 TI - Pathophysiology of large vessel vasculitis and utility of interleukin-6 inhibition therapy. AB - Takayasu arteritis (TAK) and giant cell arteritis (GCA) affect mainly large- and medium-sized arteries. In refractory cases, vascular remodeling progresses and leads to serious outcomes. Studies have demonstrated that cytokines such as interleukin (IL)-6 play crucial roles in the pathophysiology of TAK and GCA. Recently, randomized controlled trials on IL-6 inhibition therapy using tocilizumab (TCZ) were performed, and significant effects were exhibited. The purposes of conventional treatments have been to improve symptoms and decrease the levels of inflammatory markers. Arterial changes have been considered as damages. However, after TCZ came into practical use, establishment of treat to target is desired to prevent vascular remodeling. In contrast, a combination therapy of glucocorticoids (GCs) and TCZ notably increases the risk of infections. When TCZ is used, careful attention must be paid to possible infections, and dose of GC should be tapered as much as possible. Future tasks are to establish indication and dosage of TCZ, indication for discontinuation of TCZ due to remission, efficacy of TCZ monotherapy, and protocols of TCZ for pediatric cases. PMID- 30427263 TI - Validation of a wireless shoe insole for ground reaction force measurement. AB - Ground reaction force measurements are a fundamental element of kinetic analyses of locomotion, yet they are traditionally constrained to laboratory settings or stationary frames. This study assessed the validity and reliability of a new wireless in-shoe system (Novel Loadsol/Pedoped) for field-based ground reaction force measurement in hopping, walking, and running. Twenty participants bilaterally hopped on a force plate and walked (5 km/hr) and ran (10 km/hr) on an instrumented treadmill on two separate days while wearing the insoles. GRFs were recorded simultaneously on each respective system. Peak GRF in hopping and peak GRF, contact time (CT), and impulse (IMP) in walking and running were compared on a per-hop and step-by-step basis. In hopping, the insoles demonstrated excellent agreement with the force plate (ICC: 0.96). In walking and running, the insoles demonstrated good-to-excellent agreement with the treadmill across all measures (ICCs: 0.88-0.96) and were reliable across sessions (ICCs within 0.00-0.03). A separate verification study with ten participants was conducted to assess a correction algorithm for further agreement improvement but demonstrated little meaningful change in systemic agreements. These results indicated that the Novel Loadsol system is a valid and reliable tool for wireless ground reaction force measurement in hopping, walking, and running. PMID- 30427264 TI - Effects of age on attention level: changes in performance between the ages of 12 and 90. AB - The purpose of the present study was to assess the changes in attention level among individuals between the ages of 12 and 90 years. A cross-sectional design was used, with each participant tested once by means of the Mathematics Continuous Performance Test (MATH-CPT). Participants were 496 males and females who were divided into eight age-groups, with each group spanning a period of ten years. Attention level was assessed through comparison with nine variables assessing attention. As people aged, significant reductions in the quality of performance emerged on the five main measures of the MATH-CPT: Two of the four sustained attention variables showed an improvement with age. The peak attention level was in the 30 to a 40-age range, after that, there was a constant decline in the level of attention. The study offers encouraging results with respect to the effect of aging on cognitive functioning and specifically sustained attention. PMID- 30427265 TI - Restricting short-wavelength light in the evening to improve sleep in recreational athletes - A pilot study. AB - Sleep is crucial for recovery and skill acquisition in athletes. Paradoxically, athletes often encounter difficulties initiating and maintaining sleep, while having sufficient sleep opportunity. Blue (short-wavelength) light as emitted by electronic screens is considered a potential sleep thief, as it suppresses habitual melatonin secretion. The current study sought to investigate whether blocking short-wavelength light in the evening can improve sleep onset latency and potentially other sleep parameters among recreational athletes. The study had a within-subject crossover design. Fifteen recreational athletes, aged between 18 and 32 years (12 females, 3 males), were randomly assigned to start the intervention period with either the light restriction condition (LR; amber-lens glasses), or the no-light restriction condition (nLR; transparent glasses). Sleep hygiene practices, actigraphy and diary-based sleep estimates were monitored during four consecutive nights within each condition. Sleep hygiene practices did not significantly differ between conditions. Results indicate that blocking short wavelength light in the evening, as compared to habitual light exposure, significantly shortened subjective sleep onset latency (Delta = 7 min), improved sleep quality (Delta = 0.6; scale 1-10), and increased alertness the following morning. Actigraphy-based sleep estimates showed no significant differences between conditions. Blocking short-wavelength light in the evening by means of amber-lens glasses is a cost-efficient and promising means to improve subjective sleep estimates among recreational athletes in their habitual home environment. The relatively small effects of the current study may be strengthened by additionally increasing morning- and daytime light exposure and, potentially, by reducing the alerting effects of media use before bedtime. PMID- 30427266 TI - Warts and all: Fingolimod and unusual HPV-associated lesions. AB - BACKGROUND:: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster. METHODS:: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy. RESULTS:: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod. CONCLUSION:: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended. PMID- 30427267 TI - Deep learning algorithms to identify documentation of serious illness conversations during intensive care unit admissions. AB - BACKGROUND:: Timely documentation of care preferences is an endorsed quality indicator for seriously ill patients admitted to intensive care units. Clinicians document their conversations about these preferences as unstructured free text in clinical notes from electronic health records. AIM:: To apply deep learning algorithms for automated identification of serious illness conversations documented in physician notes during intensive care unit admissions. DESIGN:: Using a retrospective dataset of physician notes, clinicians annotated all text documenting patient care preferences (goals of care or code status limitations), communication with family, and full code status. Clinician-coded text was used to train algorithms to identify documentation and to validate algorithms. The validated algorithms were deployed to assess the percentage of intensive care unit admissions of patients aged ?75 that had care preferences documented within the first 48 h. SETTING/PARTICIPANTS:: Patients admitted to one of five intensive care units. RESULTS:: Algorithm performance was calculated by comparing machine identified documentation to clinician-coded documentation. For detecting care preference documentation at the note level, the algorithm had F1-score of 0.92 (95% confidence interval, 0.89 to 0.95), sensitivity of 93.5% (95% confidence interval, 90.0% to 98.0%), and specificity of 91.0% (95% confidence interval, 86.4% to 95.3%). Applied to 1350 admissions of patients aged ?75, we found that 64.7% of patient intensive care unit admissions had care preferences documented within the first 48 h. CONCLUSION:: Deep learning algorithms identified patient care preference documentation with sensitivity and specificity approaching that of clinicians and computed in a tiny fraction of time. Future research should determine the generalizability of these methods in multiple healthcare systems. PMID- 30427268 TI - Simultaneous determination of nine acaricides and two metabolites in comb honey by LC/MS/MS. AB - We developed a method for the simultaneous determination of acaricides in comb honey using LC/MS/MS. Because methods for honey analysis had not previously been applied to comb honey, we modified three techniques for sample preparation and LC/MS/MS conditions. First, we used a modified QuEChERS method that changed the extraction solution from ethyl acetate to acetonitrile. Second, we replaced the InertSep(r) MA-1 (30 mg, 1 ml) clean-up cartridge with an Oasis(r) HLB (60 mg, 3 ml). Third, we changed the ionisation mode from ESI to atmospheric pressure chemical ionisation (APCI). With these modifications, sample matrices had no effect on the identification and quantification of analytes, using an external solvent calibration curve. We verified this new method with nine acaricides and two metabolites on comb honey and honey samples from three different honey origins. The trueness ranged from 74.0 to 99.4%. The relative standard deviation of repeatability (RSDr) ranged from 0.8 to 14.8% and that of within-laboratory reproducibility (RSDWR) ranged from 1.3 to 14.8%. All criteria met Japanese validation guidelines. The LOQ was 1.0 MUg kg-1 for all analytes. We applied this method to 10 comb honey and 31 honey samples commercially available in Tokyo. From the results of the analysis of 41 samples, we observed that amitraz remained as N-(2,4-dimethylphenyl)-N-methylformamidine (DMPF) in 9 comb honey and 23 honey samples and that their residual concentrations were less than 20 MUg kg-1. Using this new method, we improved recovery and precision, which enabled precise quantitative determination. Furthermore, the residual amitraz value in honey determined by both this new and the previous method were in good agreement. PMID- 30427269 TI - Validation of an opto-electronic instrument for the measurement of weighted countermovement jump execution velocity. AB - The purpose of this study was to analyse the reliability and validity of an opto electronic sensor system (Velowin) compared to a linear velocity transducer (T Force System) considered as the gold standard. Mean velocity (MV) and peak velocity (PV) generated in the Smith machine bar placed on the shoulders in counter-movement jump exercise (CMJ) were analysed. The study was conducted with a sample of 21 men with experience in resistance training. Five measurements were analysed for CMJ exercise in concentric phase using a progressive loading increase. Three jumps were made per load with a 3-4 min recovery between loads. The analysis of the variance confirmed that there were no significant differences (p > 0.05) in the execution velocity between Velowin and T-Force with each of the loads. The reliability analysis showed, with each of the loads, high values of the intraclass correlation coefficient (ICC = 0.95-0.99) and a 'substantial' Lin's concordance coefficient in MV (CCC >=0.96) and between 'substantial' (CCC = 0.98) and 'almost perfect' (CCC = 0.99) in PV. These results confirm the reliability and validity of the Velowin device is reliable for measuring the execution velocity in loaded CMJ exercise. PMID- 30427270 TI - Method development and validation for low-level propineb and propylenethiourea analysis in baby food, infant formula and related matrices using liquid chromatography-tandem mass spectrometry. AB - Two simple, selective and rugged liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were developed and validated for determination of propineb and propylenethiourea (PTU) in infant formula, fruit-based and cereal-based baby food and raw materials used in production of infant formula, including carbohydrates, protein isolates, vegetable oils and emulsifiers. The sample preparation procedure for propineb analysis was based on streamlined derivatisation to form and stabilise the target analyte (propylenebisdithiocarbamate-dimethyl), followed by extraction using a modified QuEChERS procedure with a dispersive solid phase extraction (d-SPE). The PTU determination employed an aqueous extraction with optimised protein precipitation and single-step SPE clean-up. To achieve maximum sensitivity, electrospray ionisation and atmospheric-pressure chemical ionisation were employed for LC-MS/MS analysis of propineb and PTU, respectively. Validation of the developed methods was performed in accordance with Document SANTE/11813/2017. Mean recoveries were in the range of 86-120% for propineb and PTU, respectively, with interday and intraday repeatabilities below 13%. A limit of quantification (LOQ) of 0.003 mg kg-1 was validated for most of the evaluated analyte/sample matrix combinations with the exception of PTU in soy protein isolate and soybean oil, for which an LOQ of 0.01 mg kg-1 was obtained. This is the first report that provides validated methods for monitoring propineb and PTU in infant formula and baby foods at concentrations compliant with the maximum residue levels established in the EU legislation. PMID- 30427271 TI - Editorial. PMID- 30427272 TI - Pharmacokinetics of low-dose and high-dose buprenorphine in cats after rectal administration of different formulations. AB - OBJECTIVES: A prospective experimental study was performed in nine young healthy cats to investigate a pharmacokinetic profile and the clinical relevance of rectally administered buprenorphine. Rectal pH value was measured in all nine cats. METHODS: Blood was collected 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after the rectal administration of a suppository and a gel at doses between 0.02 mg/kg and 0.1 mg/kg buprenorphine to determine the plasma concentration of buprenorphine. Rectal pH was measured with the help of pH paper. RESULTS: Upon pharmacokinetic non-compartment analysis of high-dose buprenorphine (0.1 mg/kg), average maximal plasma concentration was found to be 1.13 ng/ml, time to maximal plasma concentration was 45 mins and area under the plasma concentration-time curve was 94.19 ng*min/ml, representing low but potential bioavailability. Mean residual time was 152.2 mins and the half-life was 92.6 mins. A wide range of plasma concentrations within the cohort was measured and two of the cats had to be excluded from statistical analysis owing to incomplete uptake. Vital parameters of all cats were considered to be normal but three of the cats showed mydriasis up to 8 h after application. After the administration of a low-dose suppository or a rectal gel (0.02 mg/kg) within pilot studies, no buprenorphine was detected in cat plasma. Rectal pH in all cats was between 7.7 and 8. CONCLUSION AND RELEVANCE: The rectal application of buprenorphine at a dose of 0.1 mg/kg revealed a potential but weak uptake in cats. Regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia in cats. Pharmacological investigations of formulation and galenics in order to improve the rectal bioavailability of buprenorphine remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed. PMID- 30427274 TI - Comparison of metabolomics and platelet aggregometry between Plavix and generic clopidogrel in cats: a pilot study. AB - OBJECTIVES: This pilot study sought to assess the metabolism of Plavix (Bristol Myers Squibb/Sanofi) and generic clopidogrel in cats, using a novel assay for the measurement of clopidogrel, clopidogrel carboxylic acid (CCA) and clopidogrel active metabolite (CAM-D). METHODS: This was a prospective, randomized, double blind study. Four healthy, skeletally mature cats were enrolled into the study. There were two treatment phases during which cats received either Plavix or generic clopidogrel at a dosage of 18.75 mg PO q24h for 7 days with a 2 week washout between phases. During each phase, plasma concentrations of parent drug and active and inactive metabolites were measured along with impedance platelet aggregometry in response to adenosine diphosphate (ADP). RESULTS: The ratio of CAM-D between generic clopidogrel and Plavix was 0.83 (equivalence reference 1.00, 90% confidence interval 0.80-1.25). Inhibition of ADP-induced platelet aggregation was variable, with two cats classified as non-responders in both treatment phases. The concentrations of CAM-D were not predictive of aggregometry based responsiveness to either formulation of clopidogrel. CONCLUSIONS AND RELEVANCE: This is the first study comparing Plavix and generic clopidogrel in cats. Administration of the generic formulation resulted in comparable plasma concentrations of clopidogrel active metabolite when compared with Plavix. PMID- 30427273 TI - Use of maropitant for the control of pruritus in non-flea, non-food-induced feline hypersensitivity dermatitis: an open-label uncontrolled pilot study. AB - OBJECTIVES: Non-flea, non-food-induced hypersensitivity dermatitis (NFNFIHD) is a common inflammatory and pruritic skin disease in cats. When avoidance and conventional systemic immunosuppressive treatments fail to control the clinical signs, there are limited treatment options. The aim of this study was to evaluate the efficacy and tolerability of maropitant in feline NFNFIHD. METHODS: In an open-label uncontrolled study, cats with proven non-seasonal NFNFIHD were treated with maropitant 2 mg/kg PO q24h daily for 4 weeks. Clinical lesions were evaluated with the Scoring Feline Allergic Dermatitis (SCORFAD) system and pruritus was evaluated with a 10 cm visual analogue scale (VAS) before and at the end of the study. Owners assessed global efficacy and tolerability with a 4-point scale at the end of the study. Adverse events and body weight changes were recorded. RESULTS: Twelve cats were treated with a mean initial maropitant dose of 2.22 mg/kg PO q24h. The treatment decreased both SCORFAD and pruritus VAS (pVAS) scores in all cats except one, in which only pruritus was reduced. The efficacy and the tolerability of the treatment were judged as excellent or good by 83.3% of owners. Treatment did not cause any side effects other than, in few cases, short-time, self-limiting sialorrhoea. CONCLUSIONS AND CLINICAL RELEVANCE: Maropitant seems to be an effective, well-tolerated therapeutic option to control pruritus in cats. Caution is needed in interpreting the results as the pVAS score system has not yet been validated in cats and the trial was uncontrolled. A further controlled study is required to confirm our findings. PMID- 30427275 TI - Homocysteine Modification in Protein Structure/Function and Human Disease. AB - Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B12, and one carbon metabolism, is associated with poor health, including heart and brain diseases. Earlier studies show that patients with severe hyperhomocysteinemia, first identified in the 1960s, exhibit neurological and cardiovascular abnormalities and premature death due to vascular complications. Although homocysteine is considered to be a nonprotein amino acid, studies over the past 2 decades have led to discoveries of protein-related homocysteine metabolism and mechanisms by which homocysteine can become a component of proteins. Homocysteine-containing proteins lose their biological function and acquire cytotoxic, proinflammatory, proatherothrombotic, and proneuropathic properties, which can account for the various disease phenotypes associated with hyperhomocysteinemia. This review describes mechanisms by which hyperhomocysteinemia affects cellular proteostasis, provides a comprehensive account of the biological chemistry of homocysteine-containing proteins, and discusses pathophysiological consequences and clinical implications of their formation. PMID- 30427276 TI - Building and Regenerating the Lung Cell by Cell. AB - The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding the cellular and molecular mechanisms controlling its morphogenesis provides the framework for understanding the pathogenesis of acute and chronic lung diseases. Recent single-cell RNA sequencing data and high-resolution imaging identify the remarkable heterogeneity of pulmonary cell types and provides cell selective gene expression underlying lung development. We will address fundamental issues related to the diversity of pulmonary cells, to the formation and function of the mammalian lung, and will review recent advances regarding the cellular and molecular pathways involved in lung organogenesis. What cells form the lung in the early embryo? How are cell proliferation, migration, and differentiation regulated during lung morphogenesis? How do cells interact during lung formation and repair? How do signaling and transcriptional programs determine cell-cell interactions necessary for lung morphogenesis and function? PMID- 30427277 TI - Sarcopenia: Aging-Related Loss of Muscle Mass and Function. AB - Sarcopenia is a loss of muscle mass and function in the elderly that reduces mobility, diminishes quality of life, and can lead to fall-related injuries, which require costly hospitalization and extended rehabilitation. This review focuses on the aging-related structural changes and mechanisms at cellular and subcellular levels underlying changes in the individual motor unit: specifically, the perikaryon of the alpha-motoneuron, its neuromuscular junction(s), and the muscle fibers that it innervates. Loss of muscle mass with aging, which is largely due to the progressive loss of motoneurons, is associated with reduced muscle fiber number and size. Muscle function progressively declines because motoneuron loss is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons. At the intracellular level, key factors are qualitative changes in posttranslational modifications of muscle proteins and the loss of coordinated control between contractile, mitochondrial, and sarcoplasmic reticulum protein expression. Quantitative and qualitative changes in skeletal muscle during the process of aging also have been implicated in the pathogenesis of acquired and hereditary neuromuscular disorders. In experimental models, specific intervention strategies have shown encouraging results on limiting deterioration of motor unit structure and function under conditions of impaired innervation. Translated to the clinic, if these or similar interventions, by saving muscle and improving mobility, could help alleviate sarcopenia in the elderly, there would be both great humanitarian benefits and large cost savings for health care systems. PMID- 30427278 TI - Intolerance of uncertainty in parents of childhood cancer survivors: A clinical profile analysis. AB - PURPOSE: This research aimed to investigate the psychological adjustment related to the risk factor of intolerance of uncertainty in parents of childhood cancer survivors. DESIGN: Participants were mothers (N = 45) and fathers (N = 16) of a childhood cancer survivor (from 4 until 6 years of cancer remission). Parents completed measures of intolerance of uncertainty and its associated factors (positive beliefs about worry, cognitive avoidance, rumination, and problem solving), measures of psychological distress (anxiety, depression somatization, and worries), and performed two Stroop tasks. FINDINGS: A substantial subgroup of parents reported clinical levels of psychological distress and 64% reported a significant level of intolerance of uncertainty. Parents presented a high profile for intolerance of uncertainty (generalized anxiety disorder [GAD] profile) were those who had a high level of distress associated with ineffective psychological adjustment. CONCLUSION: The data are supportive of brief intervention to reduce intolerance of uncertainty. Sensitizing health care professionals to the identification of intolerance of uncertainty and its associated factors is essential for efficient intervention strategies. PMID- 30427279 TI - Trends in Passenger Exposure to Carbon Monoxide Inside a Vehicle on an Arterial Highway of the San Francisco Peninsula over 30 Years: A Longitudinal Study. AB - This paper describes a long-term trend study of passenger exposure to carbon monoxide (CO) inside a vehicle travelling on an arterial highway in Northern California. CO exposure was measured during four field surveys on State Route #82 (El Camino Real) on the San Francisco Peninsula in 1980-1981, 1991-1992, 2001 2002, and 2010-2011. Each field survey took at least 12 months. Fifty trips from each survey-for a total of 200 trips-were matched by date, day of the week, and starting time of the day to facilitate comparisons over three decades. The mean net CO concentration of each trip was obtained by subtracting the background CO level from the average CO concentration for the entire trip. The mean net CO concentration (0.5 ppm) for 2010-2011 was only 5.2% of that (9.7 ppm) for 1980 1981. For the 50 trips, the average travel time for the 1980-1981 period (39.6 min) was only 8.3% higher than during the 2010-2011 period (36.3 min). The estimated round-trip distance on the highway was held constant at 11.8 miles. The reduction in the mean net CO concentration was attributed to more stringent CO emission standards on new vehicles sold in California since 1980. The state's cold-temperature CO standard implemented in 1996 appeared to reduce high CO concentrations that were observed during the late fall and winter of 1980-1981. In addition, the observed standard deviation in concentration fell from 3.1 ppm in 1980-1981 to 0.2 ppm in 2010-2011, and the range of the 50 mean net CO concentrations narrowed from 14.9 ppm in 1980-1981 to 1.1 ppm in 2010-2011; but the relative variability, as indicated by the geometric standard deviation, remained the same. These results have important scientific implications for regulatory policies designed to control air pollution from motor vehicles. PMID- 30427280 TI - Extracurricular School-Based Social Change Communication Program Associated with Reduced HIV Infection Among Young Women in South Africa. AB - BACKGROUND: Young women in South Africa are at high risk for HIV, particularly after they leave school. There are few studies examining the long-term impact of school-based public health interventions aimed at protecting young women from HIV. We undertook a long-term evaluation of an extracurricular, school-based HIV prevention program, that leveraged off a mass media television series in South Africa. METHODS: We recruited 403 women aged 18-28 years. One hundred and seventy were members of Soul Buddyz Clubs (SBCs) between 2004 and 2008 and 233 were matched controls from the same communities as the ex-Buddyz. Face-to-face interviews were conducted and HIV testing undertaken. Analysis was restricted to 320 women who had ever had sex (136 ex-Buddyz and 184 controls). Multivariate analysis in Stata v14 was conducted. FINDINGS: 16.4% of women tested HIV positive. Ex-Buddyz were more likely to be HIV negative than controls (AOR 2.92, 95% CI 1.26-6.77, p = 0.013). Ex-Buddyz were more likely to have only had one sexual partner in the past year (AOR 2.14, 95% CI 1.17-3.89, p = 0.013) and 1.7 times more likely to have used a condom at first sex (95% CI 0.99-2.92, p = 0.053). INTERPRETATION: Participation in an SBC is associated with a decrease in young women's HIV risk and suggests an impact on some key risky sexual behaviors. School-based prevention programs that leverage off of other media platforms demonstrate a positive outcome on health status. PMID- 30427281 TI - Collection of airborne ultrafine cellulose nanocrystals by impinger with an efficiency mimicking deposition in the human respiratory system. AB - As cellulose nanocrystals (CNCs) are increasing in production, establishing safe workplace practices in industry will be paramount to their continued use and growth. Particles other than CNCs with similar high aspect ratios have exhibited toxicity on inhalation. Safeguards are needed to monitor concentrations of CNCs in air in industrial and laboratory settings to protect workers. However, because of their size, morphology, and chemical makeup, CNCs are difficult to characterize and differentiate from other dust and cellulose products. This work is focused on developing an effective method of characterizing the concentration of airborne ultrafine CNCs that may deposit in the respiratory tract. CNCs were tagged with rhodamine b (RhB-CNCs) for improved visualization and characterized using UV-vis spectroscopy (UV-vis), transmission electron microscopy (TEM), and dynamic light scattering (DLS), then aerosolized and collected via a novel method using plastic impingers. Concentration of RhB-CNCs was measured using UV-vis and scanning mobility particle sizer (SMPS). The plastic impinger with 3D-printed nozzle collected airborne CNCs at an efficiency that improves upon commercially available impingers for relevant particle sizes. PMID- 30427282 TI - Federalism, two-level games and the politics of abortion rights implementation in subnational Argentina. AB - The implementation of the 2012 Argentinean Supreme Court landmark ruling, which declared abortion legal in all cases of rape and established standards of implementation of lawful abortions at all levels of government, shows an uneven pattern of compliance by subnational governments throughout the country. Based on a case-study of the implementation of the Court's decision in the province of Salta, this article advances an explanation of mechanisms that can affect the definition and enforcement of abortion rights at the local level, in a federation. Drawing on Putnam's concept of two-level games, it argues that, at critical junctures, local authorities and especially strong governors with presidential aspirations, may have electoral incentives at the national level to comply at least partially with national laws and judicial decisions which are contrary to their own ideological preferences and their local political allegiances. The study suggests that analyses of political opportunities for local reproductive rights activists in federal regimes should include the potential two-level games of local authorities, such as politicians with presidential aspirations, and judges who intend to pursue a career in national or international institutions. Through this analysis, the article intends to contribute to our understanding of the political determinants of subnational compliance with national abortion laws and court decisions in federal systems, and more generally, political factors and dynamics that shape inequities in the protection of women's rights under federalism. PMID- 30427283 TI - Carbonyl compounds in different stages of vinification and exposure risk assessment through Merlot wine consumption. AB - The objective of this research was to estimate for the first time the transformations that the free form of some target carbonyl compounds may undergo during winemaking and assess the exposure risk to these compounds through the consumption of the Merlot commercial wines under study. Acrolein and furfural were found in grapes and the respective wines, although levels were observed to decline throughout the winemaking process. Formaldehyde was found in all stages of wine production in levels lower than the limit of quantification of the method and ethyl carbamate was not found in samples. Acetaldehyde seems to be a precursor of acetoin and 2,3-butanediol, since the levels of this aldehyde decreased along winemaking and the formation of the ester and alcohol was verified. Furfural levels decreased, while the occurrence of furan-containing compounds increased during winemaking. The formation of acetaldehyde during alcoholic fermentation and the potential environmental contamination of grapes with acrolein and furfural are considered as the critical points related to the presence of toxic carbonyl compounds in the wine. Acrolein was found in the samples under study in sufficient quantities to present risk to human health, while other potentially toxic carbonyl compounds did not result in risk. This study indicated for the first time the presence of acrolein in grapes suggesting that environmental pollution can play an important role in the levels of this aldehyde detected in wines. Reduction of the emission of this aldehyde to the environment may be achieved by replacing wood burning by another heat source in fireplaces or wood stones, and abandoning the practice of burning garbage and vegetation. PMID- 30427284 TI - Firefighter hood contamination: Efficiency of laundering to remove PAHs and FRs. AB - Firefighters are occupationally exposed to products of combustion containing polycyclic aromatic hydrocarbons (PAHs) and flame retardants (FRs), potentially contributing to their increased risk for certain cancers. Personal protective equipment (PPE), including firefighter hoods, helps to reduce firefighters' exposure to toxic substances during fire responses by providing a layer of material on which contaminants deposit prior to reaching the firefighters skin. However, over time hoods that retain some contamination may actually contribute to firefighters' systemic dose. We investigated the effectiveness of laundering to reduce or remove contamination on the hoods, specifically PAHs and three classes of FRs: polybrominated diphenyl ethers (PBDEs), non-PBDE flame retardants (NPBFRs), and organophosphate flame retardants (OPFRs). Participants in the study were grouped into crews of 12 firefighters who worked in pairs by job assignment while responding to controlled fires in a single family residential structure. For each pair of firefighters, one hood was laundered after every scenario and one was not. Bulk samples of the routinely laundered and unlaundered hoods from five pairs of firefighters were collected and analyzed. Residual levels of OPFRs, NPBFRs, and PAHs were lower in the routinely laundered hoods, with total levels of each class of chemicals being 56-81% lower, on average, than the unlaundered hoods. PBDEs, on average, were 43% higher in the laundered hoods, most likely from cross contamination. After this initial testing, four of the five unlaundered exposed hoods were subsequently laundered with other heavily exposed (unlaundered) and unexposed (new) hoods. Post-laundering evaluation of these hoods revealed increased levels of PBDEs, NPBFRs, and OPFRs in both previously exposed and unexposed hoods, indicating cross contamination. For PAHs, there was little evidence of cross contamination and the exposed hoods were significantly less contaminated after laundering (76% reduction; p = 0.011). Further research is needed to understand how residual contamination on hoods could contribute to firefighters' systemic exposures. PMID- 30427285 TI - Recent spatial gradients and time trends in Dhaka, Bangladesh air pollution and their human health implications. AB - Dhaka, the capital of Bangladesh, is among the most polluted cities in the world. This research evaluates seasonal patterns, day-of-week patterns, spatial gradients, and trends in PM2.5 (< 2.5um in aerodynamic diameter), PM10 (< 10um in aerodynamic diameter), and gaseous pollutants concentrations (SO2, NO2, CO, and O3) monitored in Dhaka from 2013 to 2017. It expands on past work by considering multiple monitoring sites and air pollutants. Except for ozone, the average concentrations of these pollutants showed strong seasonal variation, with maximum during winter and minimum during monsoon, with the pollution concentration of PM2.5 and PM10 being roughly 5-6 fold higher during winter vs. monsoon. Our comparisons of the pollutant concentrations with Bangladesh-NAAQS and US-NAAQS limits analysis indicate particulate matter (PM2.5 & PM10) as the air pollutants of greatest concern, as they frequently exceeded the Bangladesh-NAAQS and US NAAQS, especially during non-monsoon time. In contrast, gaseous pollutants reported far fewer exceedances throughout the study period. During the study period, the highest number of exceedances of NAAQS limits in Dhaka city (Darus Salam site) found for PM2.5 (72% of total study days), followed by PM10 (40% of total study days), O3 (1.7% of total study days), SO2 (0.38% of total study days), and CO (0.25% of total study days). The trend analyses results showed statistically significant positive slopes over time for SO2 [5.6 ppb yr-1, 95% Confidence Interval (CI): 0.7, 10.5] and CO [0.32 ppm yr-1, 95% CI: 0.01, 0.56] which suggest increase in brick kilns operation and high sulfur diesel use. Though the statistically non-significant annual decreasing slopes for PM2.5 [-4.6 ug/m3 yr-1, 95% CI: -12.7, 3.6] & PM10 [-2.7 ug/m3 yr-1, 95% CI: -7.9, 2.5] were observed during this study period, the PM2.5 concentration is still too high (~82.0 ug/m3) and can cause severe impact on human health. Implications This study revealed key insights into air quality challenges across Dhaka, Bangladesh, indicating particulate matter (PM) as Dhaka's most serious air pollutant threat to human health. The results of these analyses indicate that there is a need for immediate further investigations, and action based on those investigations, including the conduct local epidemiological PM exposure-human health effects studies for this city, in order to determine the most public health effective interventions. PMID- 30427286 TI - Characterization of CO and NO2 exposures of ice skating rink maintenance workers. AB - Air quality is a common concern among indoor ice rink facilities due to the use of gasoline/propane ice resurfacing equipment. Although previous studies have investigated spectator, guest, and skater exposures, a review of the literature revealed little published research regarding ice maintenance employees' exposures. Ice maintenance includes edging and resurfacing. The resurfacer is commonly referred to as a Zamboni(r). Edging is almost always followed by resurfacing, but resurfacing frequently happens independently of edging. The purpose of this study was to characterize ice rink maintenance employees' exposures to CO and NO2. Employees from four ice rinks in Salt Lake County, Utah were sampled using direct reading instruments during routine ice maintenance activities. Maintenance was divided into four activities: 1) Edging only, 2) Resurfacing after edging (not including edging), 3) Edging and resurfacing (Activities 1 and 2 combined), and 4) Resurfacing only (independent of edging). Activities 1, 2 and 3 were sampled twenty-four (n = 24) times. Activity 4 was sampled eight times. Sampling results were graphed and summarized using descriptive statistics. The highest measured CO concentration was 202 ppm, which occurred during edging. Average CO concentrations for all activities ranged from 0 ppm to 60.4 ppm. Minimal CO exposure was observed when resurfacing occurred without edging, which implies that elevated CO exposure measured while using the resurfacer may be residual CO from prior edging activities. NO2 concentrations were negligible for all rinks and all activities. Results confirmed that gasoline edgers significantly contribute to indoor CO levels, with peak levels exceeding some recommended exposure levels. Indoor ice rink facilities should monitor employees' CO exposures and implement procedures to limit exposures. This may be achieved by limiting the number of laps taken with the edger or replacing gasoline powered edgers with electric edgers. PMID- 30427287 TI - Dr. Marc B. Schenker named Journal of Agromedicine "Leader in the Field" 2019. PMID- 30427288 TI - Community Gun Violence as a Social Determinant of Elementary School Achievement. AB - The association of indirect exposure to firearm-related violence and standardized test scores among third grade elementary school children were analyzed using geospatial mapping of police department data for all gunshots in Syracuse, NY (n = 2, 127) and state standardized test scores from 2009-2015. Confirmed gunshots were geocoded and mapped across the city and neighborhood school catchment areas. Third grade standardized New York State test scores for English Language Arts (ELA) and math were coded as dichotomous variables of proficient and below proficient scores. State standardized test scores for ELA and math were found to be 50% lower in the elementary schools located within higher concentration gunshot areas, than in elementary schools in lower gunshot areas. Higher levels of gun violence within school catchment areas were significantly associated with higher rates of ELA and math failure (p <= .05). These findings suggest that community violence may be an important, though under recognized, social determinant of poor school performance. PMID- 30427289 TI - A controlled trial using a factorial design reported in 1946. PMID- 30427290 TI - The appeal of belonging to a profession of letter writers. PMID- 30427291 TI - Euthanasia and assisted dying: what is the current position and what are the key arguments informing the debate? AB - Assisted dying is a highly controversial moral issue incorporating both physician assisted dying (PAD) and voluntary active euthanasia. End-of-life practices are debated in many countries, with assisted dying receiving different consideration across various jurisdictions. In this paper, we provide an analytic framework of the current position and the main arguments related to the rights and moral principles concerning assisted dying. Assisted dying proponents focus on the respect of autonomy, self-determination and forestalling suffering. On the other hand, concerns are raised regarding the interpretation of the constitutional right to life and balancing this with the premise of assisted dying, alongside the impacts of assisted dying on the doctor-patient relationship, which is fundamentally based on trust, mutual respect and the premise of 'first do no harm'. Our review is underpinning the interpretation of constitutional rights and the Hippocratic Oath with the premise of assisted dying, alongside the impacts of assisted dying on the doctor-patient relationship. Most clinicians remain untrained in such decision making, with fears against crossing key ethical divides. Due to the increasing number of cases of assisted dying and lack of consensus, our review enables the integration of ethical and legal aspects and facilitates decision making. PMID- 30427294 TI - Paramedics: what can we expect. PMID- 30427296 TI - "The Action Level"(r). PMID- 30427297 TI - From the Editor: Progress on JOEH procedural changes. PMID- 30427298 TI - Quantitative evaluation of carbon nanomaterial releases during electric heating wire cutting and sawing machine cutting of expanded polystyrene-based composites using thermal carbon analysis. AB - Field measurements were conducted at a facility where expanded polystyrene-based carbon nanomaterial composites, namely, carbon nanotube and carbon black composites, were cut with an electric heating wire cutter or a circular sawing machine. The aerosol particles released during the cutting of the composites were measured using real-time aerosol monitoring, gravimetric analysis, thermal carbon analysis, and scanning electron microscopic observations. This study had two major goals: (1) to quantitatively evaluate the concentrations of airborne carbon nanomaterials during the cutting of their composites; (2) to evaluate the capability of thermal carbon analysis to quantify airborne carbon nanomaterials in the presence of expanded polystyrene-derived particles. The results of thermal carbon analysis showed that the concentrations of elemental carbon (an indicator of carbon nanomaterials) for all the respirable dust samples in both cutting processes were less than the limit of detection (~2 MUg/m3), which is nearly equivalent to or lower than the occupational exposure limits for carbon nanotubes (1 to 50 MUg/m3). For total dust, which includes particles larger than respirable size, although the elemental carbon concentrations during heating wire cutting were low (<3 MUg/m3), those during sawing machine cutting were up to 58 MUg/m3. In scanning electron microscopic observations, micron-sized particles composed of or including carbon nanotubes were detected only in aerosol particles collected during the sawing machine cutting. Therefore, heating wire cutting is considered preferable. This study demonstrated that thermal carbon analysis can quantify airborne carbon nanomaterials in the presence of expanded polystyrene-derived particles. PMID- 30427299 TI - Levels and distribution of PBDEs and PFASs in pork from different European countries. AB - Meat and meat products are included in a great number of human diets. However, the great consumption of meat needs to be controlled for the presence of traces of contaminants. The European Commission has not stated maximum limits for some environmental pollutants such as the perfluoroalkyl substances (PFASs) and polybrominated diphenyl ether (PBDE); the European Food Safety Authority (EFSA) Scientific Panel has recommended that more occurrence data for PFASs in food should be collected to improve the accuracy of future exposure calculations. Therefore, the distribution of PFASs and PBDEs trace contaminants from eight EU Member States were investigated through liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and Gas Chromatography-Mass Spectrometry (GC-MS/MS). No PFASs were detected, except perfluorooctanoic acid, in only one Austrian sample at the concentration of 0.531 ng g-1. PBDEs were detected in 3 out of 77 samples: one from Germany showed the presence of all congeners analysed in the concentration range 0.53-0.77 ng g-1, the others, from Netherland and Italy, respectively contained PBDE 153 (0.53 ng g-1) and PBDE 100 (0.62 ng g-1). The results show that the analysed samples do not pose a risk for human beings in regard to PFASs and PBDEs. Further studies are needed to keep monitoring their presence in foodstuff, as it has been suggested by European Commission. PMID- 30427300 TI - Evaluation of salinomycin isolated from Streptomyces albus JSY-2 against the ciliate, Ichthyophthirius multifiliis. AB - The present study was undertaken to investigate the antiparasitic activity of extracellular products of Streptomyces albus. Bioactivity-guided isolation of chloroform extracts affording a compound showing potent activity. The structure of the compound was elucidated as salinomycin (SAL) by EI-MS, 1H NMR and 13C NMR. In vitro test showed that SAL has potent anti-parasitic efficacy against theronts of Ichthyophthirius multifiliis with 10 min, 1, 2, 3 and 4 h (effective concentration) EC50 (95% confidence intervals) of 2.12 (2.22-2.02), 1.93 (1.98 1.88), 1.42 (1.47-1.37), 1.35 (1.41-1.31) and 1.11 (1.21-1.01) mg L-1. In vitro antiparasitic assays revealed that SAL could be 100% effective against I. multifiliis encysted tomonts at a concentration of 8.0 mg L-1. In vivo test demonstrated that the number of I. multifiliis trophonts on Erythroculter ilishaeformis treated with SAL was markedly lower than that of control group at 10 days after exposed to theronts (P < 0.05). In the control group, 80% mortality was observed owing to heavy I. multifiliis infection at 10 days. On the other hand, only 30.0% mortality was recorded in the group treated with 8.0 mg L-1 SAL. The median lethal dose (LD50) of SAL for E. ilishaeformis was 32.9 mg L-1. PMID- 30427301 TI - Streptomyces reniochalinae sp. nov. and Streptomyces diacarni sp. nov., from marine sponges. AB - Two marine actinomycete strains, LHW50302T and LHW51701T, were isolated from marine sponges collected in Sansha, Hainan Province, China. The morphological, chemotaxonomic and phylogenetic characteristics were consistent with their classification in the genus Streptomyces. The strains formed hooked and looped chains of arthrospores with smooth surfaces. The cell-wall hydrolysates of the strains contained ll-diaminopimelic acid as the diagnostic diamino acid. MK-9(H8) was the predominant menaquinone. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylinositol. Major fatty acids of the strains were iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The 16S rRNA gene sequences indicated that the strains clustered together with Streptomyces albus CGMCC 4.1640T and Streptomyces qinglanensis CGMCC 4.6825T. Multilocus sequence analysis (MLSA) confirmed their relationship. Genome relatedness in forms of average nucleotide identity, digital DNA-DNA hybridization value and MLSA evolutionary distance between each of the strains and its closest relatives showed that they belonged to distinct species. On the basis of these results, strains LHW50302T and LHW51701T belong to two novel species in the genus Streptomyces, for which the names Streptomyces reniochalinae sp. nov. (type strain LHW50302T=CCTCC AA 2018013T=DSM 106194T) and Streptomyces diacarni sp. nov. (type strain LHW51701T=CCTCC AA 2018017T=DSM 106126T) are proposed, respectively. PMID- 30427302 TI - Vanrija jinghongensis sp. nov., an asexual basidiomycetous yeast from rotting wood. AB - Three strains of a novel basidiomycetous yeast were isolated from the Xishuangbanna Tropical Rainforest, Yunnan Province, PR China. Sequence analysis of the D1/D2 domains of the large subunit (LSU) rRNA gene and the internal transcribed spacer (ITS) regions indicated that the novel species represents a member of the genus Vanrija. It differed from the most closely related known species, Vanrija albida CBS 2839T, by 1.5 % sequence divergence (seven substitutions and two gaps out of 597 bp) in the D1/D2 domains and by 7.4 % sequence divergence (17 substitutions and 20 gaps over 495 bp) in the ITS regions, respectively. The three strains of the novel species reproduced asexually, and no mating could be found. In contrast to V. albida, the novel yeast species was able to assimilate d-glucosamine, inulin, erythritol and galactitol and unable to assimilate raffinose. The name Vanrija jinghongensis sp. nov. is proposed to accommodate these strains, with NYNU 17910T (=CICC 33269=CBS 15229) as the type strain. PMID- 30427303 TI - Pseudomonas syringae: enterprising epiphyte and stealthy parasite. AB - The lifecycle and pathogenicity mechanisms of Pseudomonas syringae. Transmission: P. syringae can be disseminated by rainsplash, aerosols and airborne plant particles (1), insect vectors (2) or as a seed-borne pathogen (3). If carried into the atmosphere (4), ice-nucleating P. syringae strains can contribute to ice nucleation in clouds and be disseminated in snow or rainfall (5). P. syringae can also be disseminated through terrestrial water systems (6, 8) and through plant debris in soil (7, 8). Symptoms: P. syringae infections are commonly characterized by chlorosis and necrosis of leaves, stem tips, buds and flowers (top); by necrotic lesions and delayed ripening or altered development of fruit (middle); and by cankers and galls of woody tissues (bottom). Mechanism: P. syringae enters plant tissues through wounds and natural openings such as stomata. Some strains of P. syringae can increase frost damage to plant tissues through ice nucleation promoted by proteins such as InaZ. Pathogen-associated molecular patterns (PAMPs) produced by P. syringae, such as flagellin, are recognized by plant pattern recognition receptors (PRRs), triggering the induction of plant immune responses. P. syringae counters plant immune responses through the production of toxins, and the secretion of effector proteins via a type III secretion system (T3SS). Effector proteins and toxins disable or subvert plant immune responses and alter plant metabolism and physiology to promote P. syringae infection. Effectors can also be directly or indirectly recognized by plant immune receptors, notably nucleotide-binding domain and leucine-rich repeat region (NLR)-containing proteins, thereby triggering plant immune responses. Picture: Nattapong Sanguankiattichai.Pseudomonas syringae is best known as a plant pathogenic bacterium that causes diseases in a multitude of hosts, and it has been used as a model organism to understand the biology of plant disease. Pathogenic and non-pathogenic isolates of P. syringae are also commonly found living as epiphytes and in the wider environment, including water sources such as rivers and precipitation. Ice-nucleating strains of P. syringae are associated with frost damage to crops. The genomes of numerous strains of P. syringae have been sequenced and molecular genetic studies have elucidated many aspects of this pathogen's interaction with its host plants. PMID- 30427305 TI - Impact of HHV-6A and HHV-6B lytic infection on autophagy and endoplasmic reticulum stress. AB - Herpesviruses are known to manipulate autophagy to optimize their replication, counteract immune response and probably to promote tumourigenesis. This study explored, for the first time, the impact of human herpesvirus (HHV)-6 lytic infection on autophagy and demonstrated that HHV-6A and B (viruses sharing more than 80 % homology) differently affected this cellular process. Indeed, while HHV 6A (GS) infection of HSB2 cells promoted autophagy, HHV-6B (Z29) or the virus isolated from the serum of roseola infantum-affected patient-inhibited autophagy in Molt-3 cells or in PBMCs, respectively. Interestingly, the different behaviour of HHV-6A and B on the autophagic process was accompanied by different effects on endoplasmic reticulum stress, unfolded protein response and cell survival that was more strongly reduced by HHV-6B infection. We hypothesize that the ability to inhibit autophagy displayed by HHV-6B could be due to the fact that it contains gene homologues of those encoding for TRS1; the protein responsible for the block of autophagy by human cytomegalovirus. Understanding how HHV-6A/B infection regulates autophagy could be of particular interest, as it has been recently shown that this virus may be involved in Alzheimer's disease in which a dysregulation of autophagy may also play a role. PMID- 30427304 TI - Staphylococcus caeli sp. nov., isolated from air sampling in an industrial rabbit holding. AB - Strain 82T, a Gram-stain-positive, coagulase-negative staphylococcus was isolated from an air sample obtained from an industrial rabbit holding in Italy. It is phylogenetically closely related to the coagulase-negative species Staphylococcus saprophyticus, Staphylococcus xylosus and Staphylococcus edaphicus. However, it could be distinguished from these species by sequence differences between the 16S rRNA, hsp60, rpoB, dnaJ and gap genes. At the whole genome level, the isolate had an average nucleotide identity of <95 % and an inferred DNA-DNA hybridization of <70 % when compared to these species. Based on the genotypic results, it is proposed that this isolate is a novel species, with the name Staphylococcus caeli sp. nov. The type strain is 82BT (=NCTC 14063T=CCUG 71912T). PMID- 30427306 TI - Lactobacillus vini: mechanistic response to stress by medium acidification. AB - This work describes the response of Lactobacillusvini, a bacterium found as a contaminant in winemaking and fuel ethanol fermentation processes, to acid stress caused by inorganic or weak organic acids. First, we observed for the first time that bacterial cells become resistant to lysis by lysozyme when submitted to acidic stress. Then, the predicted intracellular acidification can be reversed by the presence of arginine, histidine and glutamine. However, these molecules were not able to reverse the effect of resistance to lysis, indicating the independence of these mechanisms. In general, a reduction in the expression of the main genes involved in the synthesis and deposition of material in the cell wall was observed, whereas the genes involved in the reabsorption of this structure showed increased expression. These data suggested that L. vini responds to the acidification of the medium through early entry into the stationary phase, firing two signals for cell wall remodelling and maintenance of intracellular pHin a coordinated way, most probably by alkalization and the proton extrusion process. If this picture is conserved among lactobacilli, it may not only have an impact on research associated with fermentation processes, but also on that associated with probiotic improvement. PMID- 30427307 TI - A whole lifespan mouse multi-tissue DNA methylation clock. AB - Age predictors based on DNA methylation levels at a small set of CpG sites, DNAm clocks, have been developed for humans and extended to several other species. Three currently available versions of mouse DNAm clocks were either created for individual tissues or tuned towards young ages. Here, we constructed a robust multi-tissue age predictor based on 435 CpG sites, which covers the entire mouse lifespan and remains unbiased with respect to any particular age group. It can successfully detect the effects of certain lifespan-modulating interventions on DNAm age as well as the rejuvenation effect related to the transition from fibroblasts to iPSCs. We have carried out comparative analyses of available mouse DNAm clocks, which revealed their broad applicability, but also certain limitations to the use of tissue-specific and multi-tissue age predictors. Together, these tools should help address diverse questions in aging research. PMID- 30427312 TI - CORR Insights(r): What Is the Adverse Event Profile After Prophylactic Treatment of Femoral Shaft or Distal Femur Metastases? PMID- 30427310 TI - The relationship between chest pain and level of perioperative anxiety in patients with lung cancer. AB - INTRODUCTION: Chest pain is one of the symptoms of lung cancer.Chest pain disrupts patient's functioning in somatic and psychic area. PURPOSE: Whether the existence of chest pain affects the level of perioperative anxiety in lung cancer patients. Is there a relationship between everyday functioning due to the chest pain and the level of perioperative anxiety? Is there a relation between anxiety associated with pain and gender? What is the cause of anxiety in this group of the patiens? METHODOLOGY: The study was conducted among 150 patients with lung cancer before the scheduled surgery. Data was collected with the use of questionnaire assessment of perioperative anxiety level in patients with lung cancer. RESULTS: The chest pain before the surgery was confirmed by 63 (42%) patients, in case of 87 (58%) patients it was not identified. Chest pain was in case of 48% women and 36% men. 50 (33,3%) research participants who experienced chest pain and 35 patients (23,3%) without this symptom declared experiencing perioperative anxiety. In patients with lung cancer, the correlation: between chest pain and perioperative anxiety was (Z = -4.67; p< .001); between the difficult daily functioning of pain and perioperative anxiety was (Z = -4.72; p< .001); between gender and perioperative anxiety associated with pain was (Z = 3.24; p = 001).Patients afraid of: pain (37,3%), breathing problems (24,0%), physical disability (16,0%), eating problems (12,0%) sleep disorders (9,3%), nothing (1,3%). CONCLUSIONS: Patients with chest pain exhibited significantly higher of perioperative anxiety levels than non-symptomatic patients, as well as higher anxiety levels due to deteriorated daily functioning caused by the disorder. Women had a higher level of anxiety associated with pain than men before the surgery. Patients with lung cancer were most afraid of pain in the perioperative period. PMID- 30427308 TI - Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation and loss. AB - Organ renewal is governed by the dynamics of cell division, differentiation and loss. To study these dynamics in real time, we present a platform for extended live imaging of the adult Drosophila midgut, a premier genetic model for stem cell-based organs. A window cut into a living animal allows the midgut to be imaged while intact and physiologically functioning. This approach prolongs imaging sessions to 12-16 hr and yields movies that document cell and tissue dynamics at vivid spatiotemporal resolution. By applying a pipeline for movie processing and analysis, we uncover new and intriguing cell behaviors: that mitotic stem cells dynamically re-orient, that daughter cells use slow kinetics of Notch activation to reach a fate-specifying threshold, and that enterocytes extrude via ratcheted constriction of a junctional ring. By enabling real-time study of midgut phenomena that were previously inaccessible, our platform opens a new realm for dynamic understanding of adult organ renewal. PMID- 30427313 TI - CORR Insights(r): Statistical Methods Dictate the Estimated Impact of Body Mass Index on Major and Minor Complications After Total Joint Arthroplasty. PMID- 30427309 TI - High-resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types. AB - Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology. PMID- 30427314 TI - Wear Particle-induced Priming of the NLRP3 Inflammasome Depends on Adherent Pathogen-associated Molecular Patterns and Their Cognate Toll-like Receptors: An In Vitro Study. AB - BACKGROUND: Orthopaedic wear particles activate the NLRP3 inflammasome to produce active interleukin 1beta (IL1beta). However, the NLRP3 inflammasome must be primed before it can be activated, and it is unknown whether wear particles induce priming. Toll-like receptors (TLRs) are thought to mediate particle bioactivity. It remains controversial whether pathogen-associated molecular patterns (PAMPs) and/or alarmins are responsible for TLR activation by wear particles. QUESTIONS/PURPOSES: (1) Does priming of the NLRP3 inflammasome by wear particles depend on adherent PAMPs? (2) Does priming of the NLRP3 inflammasome by wear particles depend on TLRs and TIRAP/Mal? (3) Does priming of the NLRP3 inflammasome by wear particles depend on cognate TLRs? (4) Does activation of the NLRP3 inflammasome by wear particles depend on adherent PAMPs? METHODS: Immortalized murine macrophages were stimulated by as-received titanium particles with adherent bacterial debris, endotoxin-free titanium particles, or titanium particles with adherent ultrapure lipopolysaccharide. To study priming, NLRP3 and IL1beta mRNA and IL1beta protein levels were assessed in wild-type, TLR4, TLR2, and TIRAP/Mal macrophages. To study activation, IL1beta protein secretion was assessed in wild-type macrophages preprimed with ultrapure lipopolysaccharide. RESULTS: Compared with titanium particles with adherent bacterial debris, endotoxin-free titanium particles induced 86% less NLRP3 mRNA (0.05 +/- 0.03 versus 0.35 +/- 0.01 NLRP3/GAPDH, p < 0.001) and 91% less IL1beta mRNA (0.02 +/- 0.01 versus 0.22 +/- 0.03 IL1beta/GAPDH, p < 0.001). ProIL1beta protein level was robustly increased in wild-type macrophages stimulated by particles with adherent PAMPs but was not detectably produced in macrophages stimulated by endotoxin-free particles. Adherence of ultrapure lipopolysaccharide to endotoxin-free particles reconstituted stimulation of NLRP3 and IL1beta mRNA. Particles with adherent bacterial debris induced 79% less NLRP3 mRNA (0.09 +/- 0.004 versus 0.43 +/- 0.13 NLRP3/GAPDH, p < 0.001) and 40% less IL1beta mRNA (0.09 +/- 0.04 versus 0.15 +/- 0.03 IL1beta/GAPDH, p = 0.005) in TLR4 macrophages than in wild-type. Similarly, those particles induced 49% less NLRP3 mRNA (0.22 +/- 0.10 versus 0.43 +/- 0.13 NLRP3/GAPDH, p = 0.004) and 47% less IL1beta mRNA (0.08 +/- 0.02 versus 0.15 +/- 0.03 IL1beta/GAPDH, p = 0.012) in TIRAP/Mal macrophages than in wild-type. Particles with adherent ultrapure lipopolysaccharide induced 96% less NLRP3 mRNA (0.012 +/- 0.001 versus 0.27 +/- 0.05 NLRP3/GAPDH, p = 0.003) and 91% less IL1beta mRNA (0.03 +/- 0.01 versus 0.34 +/- 0.07 IL1beta/GAPDH, p < 0.001) expression in TLR4 macrophages than in wild-type. In contrast, those particles did not induce less NLRP3 and IL1beta mRNA in TLR2 macrophages. IL1beta protein secretion was equivalently induced by particles with adherent bacterial debris or by endotoxin-free particles in a time-dependent manner in wild-type macrophages. For example, particles with adherent bacterial debris induced 99% +/- 2% of maximal IL1beta secretion after 12 hours, whereas endotoxin-free particles induced 92% +/- 11% (p > 0.5). CONCLUSIONS: This cell culture study showed that adherent PAMPs are required for priming of the NLRP3 inflammasome by wear particles and this process is dependent on their cognate TLRs and TIRAP/Mal. In contrast, activation of the NLRP3 inflammasome by titanium particles is not dependent on adherent PAMPs. Animal and implant retrieval studies are needed to determine whether wear particles have similar effects on the NLRP3 inflammasome in vivo. CLINICAL RELEVANCE: Our findings, together with recent findings that aseptic loosening associates with polymorphisms in the TIRAP/Mal locus, support that adherent PAMPs may contribute to aseptic loosening in patients undergoing arthroplasty. PMID- 30427315 TI - Erratum to: Can a Conical Implant Successfully Address Complex Anatomy in Primary THA? Radiographs and Hip Scores at Early Followup. PMID- 30427316 TI - Letter to the Editor: Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases. PMID- 30427317 TI - Reply to the Letter to the Editor: Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases. PMID- 30427318 TI - Letter to the Editor: Editorial: The Nazi Musculoskeletal Experiments-Why Publish an Article About Them in 2018? PMID- 30427320 TI - Reply to the Letter to the Editor: Nazi Medicine-Part 2: The Downfall of a Profession and Pernkopf's Anatomy Atlas. PMID- 30427319 TI - Letter to the Editor: Nazi Medicine-Part 2: The Downfall of a Profession and Pernkopf's Anatomy Atlas. PMID- 30427321 TI - Letter to the Editor: Editorial: The Nazi Musculoskeletal Experiments-Why Publish an Article About Them in 2018? PMID- 30427324 TI - Molecular characterization of central cytoplasmic loop in Aspergillus nidulans AstA transporter. AB - AstA (alternative sulfate transporter) belongs to a large, but poorly characterized, Dal5 family of allantoate permeases of the Major Facilitator Superfamily. The astA gene has been cloned from an IAM 2006 Japanese strain of Aspergillus nidulans by complementation of a sulfate permease-deficient mutant. In this study we show that conserved lysine residues in Central Cytoplasmic Loop (CCL) of the AstA protein may participate in anion selectivity, and control kinetic properties of the AstA transporter. A three-dimensional model containing four clustered lysine residues was created, showing a novel substrate-interacting structure in Major Facilitator Superfamily transporters. The assimilation constant (Ktau) of wild type AstA protein is 85 MUM, while Vmax/mg of DW of AstA is twice that of the main sulfate transporter SB per mg of dry weight (DW) of mycelium (1.53 vs. 0.85 nmol/min, respectively). Amino acid substitutions in CCL did not abolish sulfate uptake, but affected its kinetic parameters. Mutants affected in the lysine residues forming the postulated sulfate-interacting pocket in AstA were able to grow and uptake sulfate, indicating that CCL is not crucial for sulfate transportation. However, these mutants exhibited altered values of Ktau and Vmax, suggesting that CCL is involved in control of the transporter activity. PMID- 30427323 TI - A Novel Perfusion System for Damage Control of Hyperkalemia in Swine. AB - INTRODUCTION: The standard of care for refractory hyperkalemia is renal replacement therapy (RRT). However, traditional RRT requires specialized equipment, trained personnel, and large amounts of dialysate. It is therefore poorly suited for austere environments. We hypothesized that a simplified hemoperfusion system could control serum potassium concentration in a swine model of acute hyperkalemia. METHODS: Ten pigs were anesthetized and instrumented. A dialysis catheter was inserted. After bilateral nephrectomy, animals received intravenous potassium chloride and were randomized to the control or treatment group. In both groups, blood was pumped through an extracorporeal circuit (EC) with an in-line hemodialyzer. In the treatment arm, ultrafiltrate from the hemodialyzer was diverted through cartridges containing novel potassium binding beads and returned to the EC. Blood samples were obtained every 30 min for 6 h. RESULTS: Serum potassium concentration was significantly lower in the treatment than in the control group over time (P = 0.02). There was no difference in serum total calcium concentration for group or time (P = 0.13 and 0.44, respectively) or platelet count between groups or over time (P = 0.28 and 1, respectively). No significant EC thrombosis occurred. Two of five animals in the control group and none in the treatment group developed arrhythmias. All animals survived until end of experiment. CONCLUSIONS: A simplified hemoperfusion system removed potassium in a porcine model. In austere settings, this system could be used to temporize patients with hyperkalemia until evacuation to a facility with traditional RRT. PMID- 30427325 TI - Bioinspired reinforcement of cyclosiloxane hybrid polymer. AB - Structural analysis showed that cyclosiloxane hybrid polymer (CHP) is a collection of nano-sized nacre-like structures in random orientations. Inspired by the reinforcement of nacre-like materials, basal-functionalized graphene (GO AA) was inserted between CHP layers, acting as 'double-sided tape' to improve the mechanical properties. The resulting GO-AA/CHP nanocomposites showed a 156% improvement in toughness with only a 0.08 wt% loading of GO-AA, and a 25% improvement in thermal conductivity with a 0.10 wt% loading of GO-AA. The proposed 'double-sided tape' effect was also used to explain the highly efficient enhancement in thermal conductivity. This research promotes the application of CHP in harsher environments, demonstrates its prospects in thermal management areas, and contributes to nature-inspired materials design. PMID- 30427326 TI - Exploiting the chemical differences between Ag and Au colloids allows dramatically improved SERS detection of "non-adsorbing" molecules. AB - In colloidal SERS only analytes that can spontaneously adsorb onto nanoparticles are detected. Therefore, considerable effort has been placed on modifying the surface properties of colloidal particles, particularly Ag particles, to promote the absorption of "difficult" analytes which do not spontaneously adsorb to as prepared nanoparticles. In contrast, much less attention has been paid to the role which the identity of the underlying metal plays in the absorption since it is widely believed that the chemical properties of Ag and Au are very similar. This leads to the assumption that molecules which do not adsorb to Ag, such as hydrocarbons, will also not adsorb to aggregated Au colloids for SERS measurements. Here, we challenge this common perception by showing that SERS detection of "difficult" aromatic targets such as naphthalene, trinitrotoluene and 3,4-methylenedioxymethamphetamine which cannot be achieved even at >10-3 M concentrations with bare aggregated Ag colloids is possible at >=10-8 M with unmodified aggregated Au colloids. For naphthalene and 3,4 methylenedioxymethamphetamine the detection limit obtained in this work with bare citrate-capped Au particles exceeds the previous best limit of detection obtained with surface-modified nanoparticles by an order of magnitude. PMID- 30427327 TI - On-surface nickel porphyrin mimics the reactive center of an enzyme cofactor. AB - Metal-containing enzyme cofactors achieve their unusual reactivity by stabilizing uncommon metal oxidation states with structurally complex ligands. In particular, the specific cofactor promoting both methanogenesis and anaerobic methane oxidation is a porphyrinoid chelated to a nickel(i) atom via a multi-step biosynthetic path, where nickel reduction is achieved through extensive molecular hydrogenation. Here, we demonstrate an alternative route to porphyrin reduction by charge transfer from a selected copper substrate to commercially available 5,10,15,20-tetraphenyl-porphyrin nickel(ii). X-ray absorption measurements at the Ni L3-edge unequivocally show that NiTPP species adsorbed on Cu(100) are stabilized in the highly reactive Ni(i) oxidation state by electron transfer to the molecular orbitals. Our approach highlights how some fundamental properties of synthetically inaccessible biological cofactors may be reproduced by hybridization of simple metalloporphyrins with metal surfaces, with implications towards novel approaches to heterogenous catalysis. PMID- 30427328 TI - Covalent affixation of histidine-tagged proteins tethered onto Ni nitrilotriacetic acid sensors for enhanced surface plasmon resonance detection of small molecule drugs and kinetic studies of antibody/antigen interactions. AB - The Ni2+-histidine (His) chelation yields a more uniform and predicable orientation of immobilized protein molecules than an amine-coupling reaction in surface plasmon resonance (SPR) analyses. However, the gradual dissociation of His-tagged proteins leads to a long and sloped baseline, which adversely affects kinetic studies. Furthermore, as shown in this work for the first time, the strong binding affinity between the histidine-rich Fc domain of immunoglobulin type antibodies and Ni-nitrilotriacetic acid (NTA) interferes with the kinetic studies of these antibodies and their His-tagged antigens. By performing an amine coupling reaction immediately after the Ni2+-His chelation, essentially all of the Ni2+-tethered protein molecules can be covalently linked to the carboxyl groups on the underlying carboxymethylated dextran surface. The sequential injections of pH 8.6 phosphate-buffered saline provided additional time to ensure a higher amine coupling efficiency and reverted NHS esters on the protein molecules to carboxyl groups. The application of our method to antibody/antigen interactions is demonstrated with the kinetic analysis of His-tagged t-DARPP protein/anti-t-DARPP interactions. In a separate experiment, the highly efficient immobilization method resulted in a higher immobilization density of His-tagged human carbonic anhydrase (HCA) II, affording accurate kinetic measurements for the binding of 4-carboxybenzenesulfonamide. In addition, the higher HCA II density enhanced the SPR sensitivity, allowing 4-carboxybenzenesulfonamide to be determined with a remarkable detection limit (14 nM). PMID- 30427329 TI - An immunofiltration strip method based on the photothermal effect of gold nanoparticles for the detection of Escherichia coli O157:H7. AB - An immunofiltration strip is a promising rapid and powerful tool for the routine monitoring of foodborne pathogenic bacteria. However, the strip assay is generally less sensitive than other immunological techniques. A novel immunofiltration strip method based on the photothermal effect of gold nanoparticles (GNPs) was developed for the sensitive, rapid, simple handheld and low-cost detection of Escherichia coli O157:H7. The photothermal effect of GNPs was used to achieve the amplification of signals to improve the sensitivity of the strip method. The thermal contrasts caused by the photothermal effect were proportional to the bacteria concentrations and yield an almost logarithmic relation. Under optimal conditions, the detection limit was 1.95 * 104 CFU mL-1, and the sensitivity was improved about ten times compared to that of the conventional visual strip method. In brief, the photothermal based immunofiltration strip could be used for the rapid and sensitive detection of other pathogens as a great potential food quality control technique. PMID- 30427330 TI - Insights into the kinetics of thermally induced crystallization of amorphous calcium phosphate. AB - Transformations between amorphous and crystalline apatite mechanistically govern some of the most essential processes in bone metabolism, including biomineralization and bone remodeling. Fundamental understanding of this phase transition can help us gain control over the formation and dissolution of boney tissues in vivo and utilize that knowledge for various therapeutic ends. Crystallization of hydroxyapatite (HAp) and two tricalcium phosphate (TCP) polymorphs from the metastable precursor, amorphous calcium phosphate (ACP) was here studied kinetically and mechanistically using thermal analyses, X-ray diffraction and Fourier-transform infrared spectroscopy. Crystallization was detected in the differential thermal analysis as the exothermic peak at 639.5 degrees C at the slowest heating regimen of 5 degrees C min-1, while a combination of different kinetics models, including Augis-Bennett, Borchardt Daniels, Johnson-Mehl-Avrami, Kissinger, Ozawa and Piloyan, yielded activation energies in the 435-450 kJ mol-1 range. Dehydrated ACP required a significant energy input to transform to HAp, thus indirectly proving the key role that structural water plays in this process in a biological setting. The phase transformation at high temperatures involved preformed nuclei and was solely due to their 3D growth, contrasting the edge-controlled nucleation derived earlier as the mechanism of growth in the solution. Crystallization was in both cases accompanied by the formation of needle-shape crystals of HAp through aggregation of ultrafine spherical units of ACP. Relationship between crystallinity and the heating rate was detected only for the initially amorphous structure, indicating a more intense and coherent lattice ordering process in annealed ACP than in HAp. Despite that, crystallization disobeyed the rule of inverse proportionality between the thermal energy required for the relaxation of defects and the level of strain, as the recovery rate of the initially poorly crystalline HAp was higher than that of ACP. PMID- 30427331 TI - Adsorption and oxidation of propane and cyclopropane on IrO2(110). AB - We investigated the adsorption and oxidation of n-propane and cyclopropane (C3H8 and c-C3H6) on the IrO2(110) surface using temperature programmed reaction spectroscopy (TPRS) and density functional theory (DFT) calculations. We find that the activation of both C3H8 and c-C3H6 is facile on IrO2(110) at low temperature, and that the dissociated alkanes oxidize during TPRS to produce CO, CO2 and H2O above ~400 K. Propane conversion to propylene is negligible during TPRS for the conditions studied. Our results show that the maximum yield of alkane that oxidizes during TPRS is higher for c-C3H6 compared with C3H8 (~0.30 vs. 0.18 monolayer) and that pre-hydrogenation of the surface suppresses c-C3H6 oxidation to a lesser extent than C3H8. Consistent with the experimental results, DFT predicts that C3H8 and c-C3H6 form sigma-complexes on IrO2(110) and that C-H bond activation of the complexes as well as subsequent dehydrogenation are highly facile via H-transfer to Obr atoms (bridging O-atoms). Our calculations predict that propane conversion to gaseous propylene is kinetically disfavored on IrO2(110) because HObr recombination makes Obr atoms available to promote further dehydrogenation at lower temperatures than those needed for the adsorbed C3H6 intermediate to desorb as propylene. We also present evidence that that the ability for c-C3H6 to activate via ring-opening is responsible for cyclopropane attaining higher reaction yields during TPRS and exhibiting a weaker sensitivity to surface pre-hydrogenation compared with n-propane. PMID- 30427332 TI - Characterization of mixed-ligand shells on gold nanoparticles by transition metal and supramolecular surface probes. AB - We report herein two methods to characterize the surface of mixed-ligand shell gold nanoparticles, which was explored with gold nanoparticles containing varying molar ratios of 3-mercaptopropionic acid (MPA) and 3-mercapto-1-propanesulfonate (MPS) or 11-mercaptoundecanoic acid (MUA) and triethylene glycol mono-11 mercaptoundecyl ether (TEG) in their ligand shell. Incubation of gold nanoparticles with a solution containing the transition metal cation Ni2+ allows the extraction of Ni2+ depending on the number of negatively charged surface groups and the reaction of surface carboxylic acid groups with an aminomethyladamantane derivative allows the extraction of the supramolecular host molecule cucurbit[7]uril (CB7) depending on the number of reactive surface groups. In both the methods, the remaining surface probes in the supernatant could be conveniently quantified in a homogeneous solution after a simple centrifugation step. An excellent linear correlation between the amount of Ni2+ extracted and the ligand density of MPA and MPS in MPA/MPS gold nanoparticles or MUA in MUA/TEG gold nanoparticles afforded a simple and reliable assay method to determine the number of negatively charged surface groups. The supramolecular CB7 assay enabled the determination of the accessible ligand density of reactive surface carboxylic acid groups and revealed a striking difference in the number of surface groups that can be reacted with MPA/MPS gold nanoparticles or MUA/TEG gold nanoparticles, which suggests a simple method to probe the surface structure of mixed monolayer gold nanoparticles. PMID- 30427333 TI - A fluorescence nanoscopy marker for corticotropin-releasing hormone type 1 receptor: computer design, synthesis, signaling effects, super-resolved fluorescence imaging, and in situ affinity constant in cells. AB - Class B G protein-coupled receptors (GPCRs) are involved in a variety of human pathophysiological states. These groups of membrane receptors are less studied than class A GPCRs due to the lack of structural information, delayed small molecule drug discovery, and scarce fluorescence detection tools available. The class B corticotropin-releasing hormone type 1 receptor (CRHR1) is a key player in the stress response whose dysregulation is critically involved in stress related disorders: psychiatric conditions (i.e. depression, anxiety, and addictions), neuroendocrinological alterations, and neurodegenerative diseases. Here, we present a strategy to label GPCRs with a small fluorescent antagonist that permits the observation of the receptor in live cells through stochastic optical reconstruction microscopy (STORM) with 23 nm resolution. The marker, an aza-BODIPY derivative, was designed based on computational docking studies, then synthesized, and finally tested in biological cells. Experiments on hippocampal neurons demonstrate antagonist effects in similar concentrations as the well established antagonist CP-376395. A quantitative analysis of two color STORM images enabled the determination of the binding affinity of the new marker in the cellular environment. PMID- 30427334 TI - A simple colorimetric sensor for the detection of moisture in organic solvents and building materials: applications in rewritable paper and fingerprint imaging. AB - A simple off-the-shelf dye molecule, 1,4-dihydroxy-9,10-anthraquinone or quinizarin (1), has been investigated for the effective detection of moisture in organic solvents and building materials. Anion-induced deprotonation of 1 to 1.F followed by re-protonation with water is the working principle of the sensor system. Changes in colour, UV-Vis spectra and emission intensity indicate the moisture detection of 1.F in various organic solvents. The probe 1.F is more effective at the detection of water in acetonitrile and THF with a LOD of 0.0011 and 0.0026 wt%. Probe 1.F is reversible, reusable, highly selective, and sensitive and has a fast response time both in solution phase and in test papers. Probe 1.F is also applied for the detection of unknown moisture content in raw building materials such as cement, fly ash, foundry sand, and limestone. 1.F incorporated cellulose-based papers are applicable for inkless writing and stamping in the read-erase manner. Furthermore, these papers are also suitable for fingerprint imaging and sweat pore mapping by the simple colour change method. PMID- 30427335 TI - Excited interatomic potential energy surfaces of Rb + He that correlate with Rb terms 52S through 72S. AB - The excited state interatomic potential energy surfaces for Rb + He are computed at the spin-orbit multi-reference configuration interaction level of theory using all-electron basis sets of triple and quadruple-zeta quality that have been contracted for Douglas-Kroll-Hess (DKH) Hamiltonian and includes core-valence correlation. Davidson-Silver corrections (MRCI+Q) are employed to ameliorate size consistency error. An extrapolation of CASSCF energies is performed using the procedure of Karton and Martin whereas extrapolation of correlation energy is performed using an expression involving the inverse powers of (lmax + 1/2), the highest angular momentum value present in the basis set. The spin-orbit energies in the limit of complete basis set are obtained by replacing the energy eigenvalues in the spin-orbit matrix by the relativistic-corrected MRCI+Q energies extrapolated to the complete basis set limit. MRCI diabatic potential energy surfaces for a few selected 2Sigma states are calculated to study the general topology and avoided crossings and repulsive form of the 6s 2Sigma+ state. Important features of the potential energy surfaces are discussed with implications for alkali laser spectroscopy. PMID- 30427336 TI - A fluorescence assay for the detection of hydrogen peroxide and hydroxyl radicals generated by metallonucleases. AB - Metal complexes can initiate DNA cleavage by the formation of reactive oxygen species (ROS). A conventional assay to probe for ROS is to add quenchers in a gel electrophoresis experiment. As we show here, such an assay is neither selective nor reliable. Instead, we suggest the use of simple fluorogens, as tested here with several metallonucleases for the detection of H2O2 and HO. PMID- 30427337 TI - Copper(ii) serves as an efficient additive for metal-directed self-assembly of over 20 thiacyclophanes. AB - Cu2+ salts are presented as an alternative to previously reported pnictogen additives in the self-assembly of 23 different thiacyclophanes. This process allows for further tuning of library equilibrium mixtures: for instance, by altering additive types and concentrations, trimeric macrocycles are amplified. These trimeric disulfides can then be covalently trapped to form 2 novel thioethers, highlighting the facile route to access these new naphthalene-bridged cyclophanes. PMID- 30427338 TI - Enhanced cathode performance of a rGO-V2O5 nanocomposite catalyst for microbial fuel cell applications. AB - A reduced graphene oxide-V2O5 nanocomposite was synthesized by a low temperature surfactant free hydrothermal method and its MFC performance was assessed. The structural properties of the synthesized nanocomposite were studied by X-ray diffraction. Field emission scanning electron microscopy of the nanocomposite revealed a wrinkled paper-like structure of rGO and a nanobelt-like structure of V2O5. This study estimated the viability of the graphene-based nanocomposite rGO V2O5 as a novel cathode catalyst in single chamber air-cathode MFCs. A series of MFCs with different catalyst loadings were produced. The electrochemical behavior of the MFCs was calculated by cyclic voltammetry. The MFCs with the rGO-V2O5 nanocomposite cathode exhibited superior maximum power densities (83%) to those with the pure V2O5 cathodes. The rGO-V2O5 with a double-loaded nanocomposite catalyst achieved an enhanced power density of 1668 +/- 11 mW m-2 and an OCP of 698 +/- 4 mV, which was 83% of that estimated for the Pt/C 2004 +/- 15 mW m-2 nanocomposite cathode. The significant increase in power density suggests that the reduced graphene oxide-V2O5 nanocomposite is a promising material for MFC applications. The CV result showed good agreement with the MFC result. The prepared rGO-V2O5 nanocomposite cathode, particularly with a double loading catalyst, is promising as a sustainable low-cost green material for stable power generation and long-term operation of MFCs. PMID- 30427339 TI - Photoelectron spectroscopy of solvated dicarboxylate and alkali metal ion clusters, M+[O2C(CH2)2CO2]2- [H2O]n (M = Na, K; n = 1-6). AB - We present results of combined experimental photoelectron spectroscopy and theoretical modeling studies of solvated dicarboxylate species (-O2C(CH2)2CO2-) in complex with Na+ and K+ metal cations. These ternary clusters serve as simple models for the investigation of aqueous ion/solute specific effects that play an important role in biological systems. The experimental characterization of these systems was performed in the presence of up to six solvating waters. In both Na+ and K+ cases, we observe the presence of one major broad band that gradually shifts to higher electron binding energy (EBE) with an increasing number of waters. In the Na+ case further detailed analysis of experimental spectra was performed using ab initio calculations. In particular, we have identified the structures of the lowest energy clusters whose EBE values match well the major band in the experimental spectra. Our results show that evolution of an aqueous solvation shell emphasizes the coordination of the negatively charged carboxylate groups accompanied by simultaneous interaction with metal cations. Calculations also indicate that in the solvation range investigated experimentally (up to 6 waters), Na+ retains direct contact with the dicarboxylate species, i.e. a contact ion-pair (CIP) complex. Preliminary modeling studies show evidence of an alternative solvent separated ion-pair complex once the solvation range approaches 8 waters, however its energy still remains above that of (~7-8 kcal/ mol-1) the CIP complex. At a higher number of waters (n = 3 for Na+ and n = 5 for K+), the experimental spectra also show the development of a weak low energy band. Its origin cannot be precisely identified. Our calculations in the Na+ case point out the existence of a quaternary complex consisting of Na+, H2O, OH- and a singly protonated dicarboxylate anion (HO2C(CH)2CO2-). Such a complex appears to be stabilized in the solvation range corresponding to the appearance of the low EBE band and does match its peak, even though the energy of such a complex is fairly high compared to the ternary structure. PMID- 30427340 TI - Phonon mode contributions to thermal conductivity of pristine and defective beta Ga2O3. AB - beta-Ga2O3 is emerging as a promising semiconductor for high-power high-frequency electronics. The low thermal conductivity of pristine beta-Ga2O3 and the presence of defects, which can further suppress the thermal conductivity, will result in critical challenges for the performance and reliability of beta-Ga2O3-based devices. We use first-principles density functional theory (DFT) along with the Boltzmann transport equation (BTE) to predict the phonon transport properties of pristine and defective beta-Ga2O3. Our predictions of anisotropic thermal conductivity are in good agreement with the experimental results. We find that the low-frequency optical phonon modes make a significant contribution to the thermal conductivity compared to the acoustic modes, especially in the [010] direction because of the non-negligible group velocities of the low-frequency optical branches. To better understand the influence of defects on the phonon transport mechanism, we investigate the thermal conductivity of beta-Ga2O3 with 1 2% oxygen or gallium vacancies considering the defect-induced phonon scatterings. We observe that the Ga vacancies lead to a larger suppression in the thermal conductivity than in those with O vacancies. Furthermore, we find that the vacancies have more influence on the optical modes than on acoustic modes, which suppress the contribution of optical modes to the thermal conductivity. The results from this work will help us understand the mechanism of phonon transport considering the influence of defects and provide insights for the future design of beta-Ga2O3-based electronic devices. PMID- 30427341 TI - Interaction between nanoparticles and charged phospholipid membranes. AB - Charged lipids in cell membranes and subcellular organelles are arranged in the form of a bilayer with the hydrocarbon tails sequestered away from the water and the polar head groups exposed to the aqueous environment. Most of them bear net negative charges leading to the negatively charged cell membranes. Charged lipid lipid and lipid-protein interactions are generally dynamic and heavily depend on their local molecular concentrations. To examine the electrostatic properties of charged lipid layers in contact with an electrolyte solution, we incorporate the single chain mean field theory with Poisson-Boltzmann theory to explore the equilibrium structure of charged phospholipid membranes. Using the three bead coarse-grained model we reproduced the essential equilibrium properties of the charged phospholipid bilayer. We also investigate the influence of the mobile ions on the thickness of the layer, the area per lipid (APL), and the electrostatic potential of the membrane. Then we investigate the attraction repulsion property of two charged nanoparticles which are stuck on the charged lipid molecules surrounded with mobile ions. After that we simulated the interaction between the Pleckstrin homology domain (PH domain) of Akt and the cytoplasmic membrane. Taking into account the electrostatic interaction, we observe the structure changes of the membrane at different concentrations of mobile ions in its equilibrium state. Also we discuss the influence of mobile ions on the size of the pore opened in the membrane by the charged protein. Such an observation may shed light on the activation of oncogenic Akt (or protein kinase B) around the membrane at the molecular level. PMID- 30427342 TI - Ru-Loaded mesoporous WO3 microflowers for dual applications: enhanced H2S sensing and sunlight-driven photocatalysis. AB - We report a facile synthesis of Ru-loaded WO3 marigold structures through a hydrothermal route and their bidirectional applications as enhanced H2S gas sensors and efficient sunlight-driven photocatalysts. The developed hierarchical marigold structures provide effective gas diffusion channels via a well-aligned mesoporous framework, resulting in remarkable enhancement in the sensing response to H2S. The temperature and gas concentration dependence on the sensing properties reveals that Ru loading not only improves the sensing response, but also lowers the operating temperature of the sensor from 275 to 200 degrees C. The 0.5 wt% Ru-loaded WO3 shows selective response towards H2S, which is 45 times higher (142) than that of pristine WO3 (3.16) sensor, whereas the 0.25 wt% Ru loaded WO3 exhibits the highest photocatalytic activity, as shown by the degradation of rhodamine B (RhB) under natural sunlight. The gas sensing and photocatalytic properties are explained through the role of Ru and the structural and morphological properties of the developed material. PMID- 30427343 TI - Effect of dark states on the fluorescence of carbon nanodots. AB - The nonlinear fluorescence properties of colloidal carbon dot solutions in glycerol were investigated at T = 298 K and 77 K. It was first found that the fluorescence intensity depended sublinearly on optical excitation intensity even at moderate excitation levels. With increasing excitation, the fluorescence signal shows a trend toward saturation, the latter being most pronounced at liquid nitrogen temperature. The relation between the fluorescence intensity and the excitation density was shown to be well approximated by the hyperbola equation. The behavior of the fluorescence intensity was theoretically described by a 3-level model that involves the singlet fluorescent state S1 and optically "dark" triplet state T1 of a carbon dot. The triplet states are almost inactive optically and manifest themselves in a very weak phosphorescence of the carbon dots that is several orders weaker than the fluorescence of the dots. The lifetimes of the triplet state were measured to be 0.75 ms at room temperature and 0.25 s at T = 77 K. Within the model used, the intersystem crossing (S1 -> T1) lifetime in the carbon dots was estimated to be tauIST ~ 10-5 s at T = 77 K and tauIST ~ 10-6 s at T = 298 K. PMID- 30427344 TI - Structure stabilization effect of configuration entropy in cubic WN. AB - The microscopic structure of cubic WN has been studied combining scanning transmission electron microscopy and first-principles calculations. Because of the contribution of configurational entropy, NaCl-type WN with disordered vacancies becomes more stable at high temperatures than NbO-type WN. Moreover, electron beam irradiation can induce an order-disorder transition in cubic WN. It is suggested that the ordered NbO-type WN can be obtained after annealing below the transition temperature. The results shed light on the stability of materials synthesized at high pressures and high temperatures. PMID- 30427345 TI - Hydroboration of carbon dioxide with catechol- and pinacolborane using an Ir-CNP* pincer complex. Water influence on the catalytic activity. AB - Iridium complexes based on deprotonated lutidine-derived CNP* pincers 2a/2b selectively catalyzed the hydroboration of CO2 under mild conditions (1-2 bar CO2, 30 degrees C) to methoxyborane using HBcat (TOF up to 56 h-1) and to the formate level with HBpin (TOF up to 1245 h-1). Interestingly, an intriguing, positive water effect on the reaction rates has been observed. NMR spectroscopy and ESI-MS analysis of the hydroboration reactions have shown the formation of ligand-protonated [Ir(CNP)(CO)(BR2)H][B(R2)2] (R2 = catecholate, pinacolate) derivatives under catalytic conditions. Control experiments, however, have demonstrated that these derivatives are not catalytically competent species in the hydroboration of CO2. PMID- 30427346 TI - Redox-state dependent activation of silanes and ammonia with reverse polarity (PCcarbeneP)Ni complexes: electrophilic vs. nucleophilic carbenes. AB - A rigidified PCalkylP ligand allowed for the synthesis and characterization of cationic and radical PCCarbeneP nickel complexes in which the carbene anchor of the pincer framework is electrophilic rather than nucleophilic. Alpha-hydride abstraction from a (PCalkylP)nickel halide complex readily leads to the cationic carbene complex, which furnishes the radical carbene complex by one electron reduction. The reactivity of these reverse polarity carbene complexes towards small molecules (H2, CO, CO2, R3SiH, NH3) reveals different modes of activation when compared to previously reported nucleophilic nickel carbene complexes, and a clear dependence on the redox state of the complex. For H2, CO and CO2, no reaction is observed, but silanes react via hydride transfer and formation of solvated silylium ions. Ammonia is activated in a novel way, wherein it coordinates the carbene carbon and is deprotonated to form a robust C-N bond. This is not only a rare example of ammonia activation by a first row transition metal but also evidence of the intermediacy of group 10 carbenes in direct C-N bond forming reactions. PMID- 30427347 TI - The lanthanide complexes of 2,2'-bipyridyl-6,6'-dicarboxylic dimethylanilides: the influence of a secondary coordination sphere on the stability, structure, luminescence and f-element extraction. AB - Four of the six possible isomeric 2,2'-bipyridyl-6,6'-dicarboxylic dimethylanilides were studied from the point of view of the impact of a secondary coordination sphere on the formation of complexes with lanthanides in solution, as well as the crystal structure and photophysical properties of the complexes. All ligands form complexes with a 1 : 1 metal-to-ligand ratio with an lg beta1 in the range of 6.0-8.8, and strong correlations between secondary coordination sphere modulation and stability of the complexes within the lanthanide series. Although substitution at the o-position of the aromatic ring leads to significant elongation of M-OL bonds in a crystal, this significantly affects the stability of the complexes. The luminescence of the complexes is the most effective for europium complexes. From luminescence measurements of gadolinium complexes, the triplet energy levels of ligands were located as follows: o-methylated ligands show 10% higher levels than other isomers. Also, o-methylation of the phenyl ring increases the lifetime value while m-methylation reduces this value. PMID- 30427348 TI - The catalytic behaviour in aqueous-phase hydrogenation over a renewable Ni catalyst derived from a perovskite-type oxide. AB - Water is inevitably associated with the production of bio-derived platform molecules, but most supported metallic catalysts have poor water compatibility. Although there have been a great number of investigations regarding the hydrogenation of bio-derived unsaturated compounds in the organic phase, the reactions that proceed in water are still quite challenging. Herein, we report the synthesis of a supported nickel catalyst (Ni-LN650) by the reduction of the perovskite-type oxide LaNiO3 precursor at 650 degrees C. The derived catalyst affords attractive activity in the hydrogenation of furfural by using water as the reaction medium, in which furfural is completely converted into tetrahydrofurfuryl alcohol with the highest productivity of 289.7 mmol gNi-1 h-1 at 120 degrees C and 1 MPa of H2 within 5 h of reaction. The Ni-LN650 catalyst also exhibits good stability and renewability in a cycle test, stemming from the self-regeneration peculiarity of the perovskite-type oxide precursor. Moreover, the catalyst can also demonstrate high activity in the aqueous-phase hydrogenation of various aldehydes, alkenes and carboxylic acids in a series of experiments. Due to the merits of usability in water, the renewability and wide application scope, the Ni-LN650 catalyst can be treated as a promising candidate for the catalytic conversion of bio-derived platform molecules into high value added fuels and chemicals. PMID- 30427349 TI - Ultrastable g-C3N4 assemblies with high quantum yield and reversible photoluminescence. AB - Ultrastable g-C3N4 assemblies consisting of amorphous/crystalline nanosheets with high quantum yields up to 78% were prepared for the first time. A reversible photoluminescence was observed from green to blue when the pH was adjusted. Conversely, this phenomenon was not observed for amorphous or crystalline samples. These assemblies exhibit high stability in PL devices. PMID- 30427350 TI - Synthesis of quinolinyl-based pincer copper(ii) complexes: an efficient catalyst system for Kumada coupling of alkyl chlorides and bromides with alkyl Grignard reagents. AB - Quinolinamide-based pincer copper(ii) complexes, kappaN,kappaN,kappaN-{C9H6N-(MU N)-C(O)CH2NEt2}CuX [(QNNNEt2)CuX (X = Cl, 2; X = Br, 3; X = OAc, 4)], were synthesized by the reaction of ligand (QNNNEt2)-H (1) with CuX2 (X = Cl, Br or OAc) in the presence of Et3N. The reaction of (QNNNEt2)-H with CuX (X = Cl, Br or OAc) also afforded the Cu(ii) complexes 2, 3 and 4, respectively, instead of the expected Cu(i) pincer complexes. The formation of Cu(ii) complexes from Cu(i) precursors most likely occurred via the disproportionation reaction of Cu(i) into Cu(0) and Cu(ii). A cationic complex [(QNNNEt2)Cu(CH3CN)]OTf (5) was synthesized by the treatment of neutral complex 2 with AgOTf. On the other hand, the reaction of (QNNNEt2)-H (1) with [Cu(MeCN)4]ClO4 produced cationic Cu(i) complex, [(QNN(H)NEt2)Cu(CH3CN)]ClO4 (6), in good yield. All complexes 2-5 were characterized by elemental analysis and HRMS measurements. Furthermore, the molecular structures of 2, 3 and 4 were elucidated by X-ray crystallography. Complex 4 crystallizes in a dimeric and catemeric pattern. The cationic complex 5 was found to be an efficient catalyst for the Kumada coupling reaction of diverse nonactivated alkyl chlorides and bromides with alkyl magnesium chloride under mild reaction conditions. PMID- 30427354 TI - A pilot study of metabolites of organophosphorus flame retardants in paired maternal urine and amniotic fluid samples: potential exposure risks of tributyl phosphate to pregnant women. AB - Organophosphorus flame retardants (OPs) are of wide concern due to their presence in human urine and their considerable endocrine disruption and neuro-development toxicity. It has been confirmed that electronic waste (e-waste) dismantling activities have contributed to human exposure to OPs. However, assessments of OP exposure and the health risks for pregnant women and fetuses living in areas associated with e-waste dismantling have been impeded by a lack of data. In this study, six OP metabolites (mOPs) were measured in paired maternal urine and amniotic fluid samples collected from an e-waste dismantling area in Guangdong Province, China. All mOPs were detectable in maternal urine, whereas two were found in amniotic fluid. Dibutyl phosphate (DBP) was the predominant mOP in both maternal urine (geometric mean (GM): 2.9 ng ml-1) and amniotic fluid (1.3 ng ml 1); and diphenyl phosphate (DPHP) was the secondary one found (0.94 ng ml-1 in maternal urine, 0.12 ng ml-1 in amniotic fluid). The GM urinary concentrations of DBP and DPHP were two and seven times higher than those in amniotic fluid, respectively. The estimated daily intakes (EDIs) of triphenyl phosphate (TPHP) and tributyl phosphate (TnBP) by pregnant women were calculated from their daily urine excretion rate as fractions of OP metabolized to the corresponding metabolite (FUE). Our results showed high exposure levels to TPHP (median: 273 or 613 ng per kg bw per day) and TnBP (404 ng per kg bw per day) for pregnant women living in the e-waste associated area. Most importantly, 13% of mothers had EDITnBP levels that exceeded the reference dose (RfD: 2400 ng per kg bw per day), suggesting potential health risks from TnBP exposure for pregnant women living in areas associated with e-waste dismantling. This study, as a pilot study, presents the first measurements of mOPs in human amniotic fluid. PMID- 30427356 TI - Preliminary characterization and antioxidant and hypoglycemic activities in vivo of polysaccharides from Huidouba. AB - Here, the antioxidant and hypoglycemic activities of polysaccharides from Huidouba were preliminarily characterized. Two novel polysaccharides, HDBP-1 and HDBP-2 (127.33 kDa and 9.703 kDa, respectively), were purified by ultrafiltration using a Sephadex G-200 column and then characterized by high-performance gel permeation chromatography (HPGPC), high-performance liquid chromatography (HPLC), infrared spectroscopy (FT-IR), GC-MS, NMR and the Congo red test. HDBPs (crude Huidouba polysaccharide (CHDBP), HDBP-1 and HDBP-2) exhibited significant antioxidant and alpha-glucosidase inhibitory activities in vitro. In addition, in vivo hypoglycemia experiments in mice revealed that CHDBP, HDBP-1 and HDBP-2 demonstrated active roles in reversing diabetic symptoms. These polysaccharides decreased the serum triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels and significantly improved oral glucose tolerance (OGT), indicating that HDBPs suppressed obesity and alleviated insulin resistance. Moreover, HDBP-2 with lower molecular weight performed better in antioxidant capacity, alpha-glucosidase-inhibiting activity and hypoglycemic activity. These results suggest that HDBPs have the potential to be functional foods with hypoglycemic properties. PMID- 30427358 TI - A radial microfluidic platform for higher throughput chemotaxis studies with individual gradient control. AB - Chemotaxis plays a fundamental role in immune defense and cancer metastasis. Microfluidic devices are increasingly applied to studying chemotaxis, owing to their advantages of reduced reagent consumption, ability to control chemical gradients, tracking of individual cells, and quantification of chemotaxis. Many existing microfluidic chemotaxis devices suffer from limited throughput and complex operation. Here, we describe a microfluidic device with a radial channel design which allows for simultaneous chemotaxis tests of different cell types and different gradient conditions. This radial microfluidic device was capable of stand-alone stable gradient generation using passive pumping and pressure balancing strategies. The device was validated by testing the migration of fast migrating human neutrophils and two slower-migrating human breast cancer cell lines, MDA-MB-231 and MCF-7 cells. Furthermore, this radial microfluidic device was useful in studying the influence of the nuclear chromatin binding protein high mobility group A2 (HMGA2) on the migration of the human triple negative breast cancer cell line MDA-MB-231. PMID- 30427359 TI - Protein denaturation caused by heat inactivation detrimentally affects biomolecular corona formation and cellular uptake. AB - Adsorption of blood proteins to the surface of nanocarriers is known to be the critical factor influencing cellular interactions and eventually determining the successful application of nanocarriers as drug carriers in vivo. There is an increasing number of reports summarizing large data sets of all identified corona proteins. However, to date our knowledge about the multiple mechanisms mediating interactions between proteins and nanocarriers is still limited. In this study, we investigate the influence of protein structure on the adsorption process and focus on the effect of heat inactivation of serum and plasma, which is a common cell culture procedure used to inactivate the complement system. As in general routine lab procedure, heat inactivation was performed at 56 degrees C for 30 min in order to denature heat labile proteins. When nanocarriers were exposed to native versus heat inactivated serum, we saw that the cellular uptake by macrophages was significantly affected. These results were then correlated with an altered corona composition that depended on the treatment of the protein source. In summary, we were able to prove that the protein structure is one of the key parameters determining protein corona formation. PMID- 30427360 TI - Atomic-scale imaging of the ferrimagnetic/diamagnetic interface in Au-Fe3O4 nanodimers and correlated exchange-bias origin. AB - Exchange-biased magnetic heterostructures have become one of the research frontiers due to their significance in enriching the fundamental knowledge in nanomagnetics and promising diverse applications in the information industry. However, the physical origin of their exchange bias effect is still controversial. A key reason for this is the lack of unequivocal observations of interface growth. In this work, we fill this gap by experimentally imaging the ferrimagnetic/diamagnetic interfaces of Au-Fe3O4 nanodimers at the atomic level. A different physical mechanism from the reported mechanisms is found based on the atomic-resolution observation of their interfacial structure and electronic states, which reveals that the antiferromagnetic and ferromagnetic interactions of the formed weak/strong ferrimagnetic bilayer are responsible for the intrinsic exchange-bias origin in Au-Fe3O4 nanodimers. The theoretical quantitative analysis of the exchange bias shift based on the observed interfacial occupation model agrees well with the experimental value for the exchange bias effect, strongly verifying the proposed exchange-bias mechanism. PMID- 30427361 TI - Oxygen vacancy modulation of two-dimensional gamma-Ga2O3 nanosheets as efficient catalysts for photocatalytic hydrogen evolution. AB - Controlling the creation of oxygen vacancies can effectively regulate the optical and electronic properties of metal oxide nanomaterials. Over the past several decades, numerous metal oxides with oxygen vacancies have been developed. However, an investigation about oxygen vacancies leading to the formation of nanosheets with different thicknesses has not been available up to now. Here, we report the oxygen vacancy modulated formation of gamma-Ga2O3 nanosheets and demonstrate that the thickness of the nanosheets is not the decisive factor in the photocatalytic hydrogen evolution reaction of ultrathin 2D nanosheets. Detailed structural characterization indicated that gamma-Ga2O3 prepared at 160 degrees C (gamma-160) with a morphology of ultrathin nanosheets possesses the highest oxygen vacancy concentration and an optimal thickness of the nanosheets. The enhanced photocatalytic performance could be determined from the synergistic effects between the ultrathin 2D structure and the O-vacancies confined in the ultrathin nanosheets. This work provides an efficient strategy to regulate the formation of nanosheets at the atomic scale and enrich the study on the effect of oxygen vacancies in the photocatalytic water splitting reaction. PMID- 30427363 TI - Dy-DOTA integrated mesoporous silica nanoparticles as promising ultrahigh field magnetic resonance imaging contrast agents. AB - Integrating Dy-DOTA motifs into mesoporous silica nanoparticle scaffolds generates remarkable ultrahigh field T2 relaxivities for a well-defined and tailorable contrast agent, attributed to enhanced Curie outer-sphere contributions as supported by simulation. PMID- 30427364 TI - Properties of hydrated TiO2 and SiO2 nanoclusters: dependence on size, temperature and water vapour pressure. AB - Nanoscale titania (TiO2) and silica (SiO2) are massively produced technologically important nanomaterials used in a wide range of technological applications where nano-titania is the active component (e.g. water splitting, pollution remediation, self-cleaning coatings). Generally, these applications entail contact with water and a degree of hydration of these nano-oxides. Although the hydration of nano-silica has been fairly well studied, the corresponding level of microscopic understanding for nano-titania is severely lacking. Here, using accurate electronic structure calculations we perform a detailed and comprehensive study of the hydration of titania nanoclusters. Firstly, using global optimisation, we establish the most energetically stable structures of a set of (TiO2)M(H2O)N nanoclusters with sizes ranging through M = 4-16 and with N/M ratios of <= 1.0. Using this extensive dataset we investigate how the structures, energy gaps, and thermodynamic stabilities of these species depend on size, temperature and water vapour pressure. To provide a broader chemical context for our study we also provide this full set of data for the respective set of (SiO2)M(H2O)N nanoclusters which we use to compare and contrast their properties with those of nano-titania. Our broad systematic study thus provides a comparative and foundational reference study for a thorough understanding of how hydration affects the structure, energetics and properties of both nano-SiO2 and nano-TiO2. PMID- 30427366 TI - Electrochemical cobalt-catalyzed C-H or N-H oxidation: a facile route to synthesis of substituted oxindoles. AB - Two comparable protocols for the electrochemical cobalt-catalyzed C-H/N-H oxidation have been exploited for the synthesis of substituted oxindoles via radical pathways. The electrochemical cobalt-catalyzed system was demonstrated to be efficient and eco-friendly and avoided the use of stoichiometric oxidants to afford the arylation or alkylation products in good yields at room temperature. PMID- 30427367 TI - Four novel sesquiterpenoids with their anti-Alzheimer's disease activity from Nardostachys chinensis. AB - Nardochinins A-D (1-4), four novel sesquiterpenoids, along with four known ones were isolated from the underground parts of Nardostachys chinensis Batal in ethanol. Their structures were determined by extensive spectroscopic methods and single-crystal X-ray diffraction. Nardochinin A (1) possessed a norsesquiterpene skeleton with an unusual 3/6/5/5 tetracyclic ring system, which had not appeared in natural products. Nardochinins B (2) and C (3) were the first time found naturally occurring sesquiterpenoids with a 4,5-seco-nardosinane skeleton. Besides, compound 3 represented an unprecedented 4,5-seco-nardosinane type norsesquiterpenoid with losing an isopropenyl at C-6 compared with 2 in the structural framework. Nardochinin D (4) was a novel, highly oxygenated valerenane type sesquiterpenoid possessing a rare 3,12-epoxy group and an unusual 9,11-epoxy group. The anti-Alzheimer's disease (AD) activities of 1-4 were also evaluated using the Caenorhabditis elegans AD pathological model, and nardochinin B (2) had the highest anti-AD activity. PMID- 30427368 TI - I2-Triggered N-O cleavage of ketoxime acetates for the synthesis of 3-(4 pyridyl)indoles. AB - A facile and complementary [3 + 2 + 1] annulation of aryl ketoxime acetates and 3 formylindoles to give pyridine derivatives is reported. The condensation reaction demonstrated that I2 was capable of triggering N-O bond cleavage of ketoxime acetates to generate iminyl radicals via a single electron transfer pathway. This direct and operationally simple protocol provides a fundamental platform to synthesize 3-(4-pyridyl)indoles with high functional group compatibility and high regioselectivity. PMID- 30427369 TI - Correction: Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction. AB - Correction for 'Rationalising the effects of ionic liquids on a nucleophilic aromatic substitution reaction' by Rebecca R. Hawker et al., Org. Biomol. Chem., 2017, 15, 6433-6440. PMID- 30427370 TI - Molecular rotors report on changes in live cell plasma membrane microviscosity upon interaction with beta-amyloid aggregates. AB - Amyloid deposits of aggregated beta-amyloid Abeta(1-42) peptides are a pathological hallmark of Alzheimer's disease. Abeta(1-42) aggregates are known to induce biophysical alterations in cells, including disruption of plasma membranes. We investigated the microviscosity of plasma membranes upon interaction with oligomeric and fibrillar forms of Abeta(1-42). Viscosity-sensing fluorophores termed molecular rotors were utilised to directly measure the microviscosities of giant plasma membrane vesicles (GPMVs) and plasma membranes of live SH-SY5Y and HeLa cells. The fluorescence lifetimes of membrane-inserting BODIPY-based molecular rotors revealed a decrease in bilayer microviscosity upon incubation with Abeta(1-42) oligomers, while fibrillar Abeta(1-42) did not significantly affect the microviscosity of the bilayer. In addition, we demonstrate that the neuroprotective peptide H3 counteracts the microviscosity change induced by Abeta(1-42) oligomers, suggesting the utility of H3 as a neuroprotective therapeutic agent in neurodegenerative disorders and indicating that ligand-induced membrane stabilisation may be a possible mechanism of neuroprotection during neurodegenerative disorders such as Alzheimer's disease. PMID- 30427374 TI - Patchy colloidal particles at the fluid-fluid interface. AB - Colloidal particles have significantly different characteristics when they are at interfaces from when they are in the bulk. In this study, we applied Monte Carlo simulations to investigate the stability and dynamics of smooth patchy particles and rough patchy particles near or at the fluid-fluid interface. By adjusting the surface area ratio of the two faces of a smooth Janus particle, we show how its stability, in terms of free energy, in either side of the interface can be tuned relative to the smooth homogeneous particle. We demonstrate how roughness can affect the stability and the orientation of a colloidal particle. Moreover, position-dependent diffusion constants in directions parallel and perpendicular to the interface are calculated for the colloidal particles as a function of distance from the interface. We report drastic slowdowns in the perpendicular diffusivity (and less severe slowdowns for the parallel diffusivity) for all the colloidal particles when they approach the fluid-fluid interface. While such a slowdown is well-known for the fluid-solid interface in the literature in terms of frictional force in hydrodynamics, why this happens for the fluid-fluid interface has not been adequately discussed. We provide evidence for the decrease in terms of discrepancy in the fluid density that leads to depletion forces. PMID- 30427375 TI - Two-time correlations for probing the aging dynamics of glassy colloids. AB - We present results for the aging dynamics of a dense 2D colloidal system obtained with molecular dynamics simulations. To this end, systems are quenched to densities far above the glass transition with relaxation time scales that used to be prohibitive for such a comprehensive study. We performed extensive simulations to gather detailed statistics about rare rearrangement events. With a simple criterion for identifying irreversible events based on Voronoi tessellations, we find that the rate of those events decelerates hyperbolically. We track the probability density function for particle displacements, the van-Hove function, with sufficient statistics as to reveal its two-time dependence that is indicative of aging. Those displacements, measured from a waiting time tw after the quench up to times t, exhibit a data collapse as a function of t/tw. These findings can be explained comprehensively as manifestations of record dynamics, i.e., a relaxation dynamic driven by record-breaking fluctuations. We show that an on-lattice model of a colloid that was built on record dynamics indeed reproduces the experimental results in great detail. PMID- 30427377 TI - Failure mechanisms of coiling fibers with sacrificial bonds made by instability assisted fused deposition modeling. AB - Instability-assisted 3D printing is a method for producing microstructured fibers with sacrificial bonds and hidden lengths that mimic nature's toughening mechanisms found in spider silk. This hierarchical structure increases the effective toughness of poly(lactic acid) (PLA) fibers by 240-340% in some specimens. Nevertheless, many specimens show worse toughness as low as 25% of that of the benchmark straight fiber due to the incomplete release of hidden lengths caused by premature failures. Here, we report the mechanical tests and simulations of microstructured fibers with coiling loops that identify the material plastic deformation as being crucial to fully release the hidden lengths. Without sufficient material yielding, high local tensile stress results from the bending-torsion-tension coupled deformation of the coiling loop and induces crack initiation at the fiber backbone during the loop unfolding process. On the other hand, the influence of bond-breaking defects is found to be negligible here. Moreover, for a number of broken bonds beyond a critical value, the accumulated elastic energy along the released loops induces a high strain rate (~1500 mm mm-1 s-1) in a quasi-static tensile test, which fractures the fiber backbone within 0.1 ms after the breaking of a new bond. We also show a size effect in fused deposition modeling (FDM) extruded PLA fibers, which results in a higher effective toughness (~5 times the performance of the straight fiber benchmark) in small coiling fibers (dia. = 0.37 mm), due to the better ductility in bending and torsion compared to large fibers (dia. = 1.20 mm). The failure mechanisms of single microstructured fibers presented here lay the groundwork for further optimizations of fiber arrays in the next generation of high energy absorption composites for impact protection and safety-critical applications. PMID- 30427378 TI - Clinical protocol for Hearing Health Services for the care of adults and elderly. AB - PURPOSE: To develop a clinical protocol for patient care in the selection, verification, and validation process of hearing aids; to verify the viability of the protocol during its use by specialists in the field; to establish the graphical representation of the protocol by means of a flowchart with algorithms. METHODS: We conducted a literature review to collect the procedures required for developing clinical protocols in healthcare services and the main procedures at each step along the process of fitting hearing aids. Subsequently, we developed the protocol, which was evaluated by eight audiologists in terms of its content and ease of use. We considered the issues raised by the professionals and then drew up a final document, as well as a flowchart with process algorithms. RESULTS: A protocol after having conducted an extensive survey of the literature was developed; all audiologists reported that the use of the instrument was of great value in their clinical practice; finally, we created the flowchart with algorithms after having developed the protocol and, by extension, we also created the Standard Operational Procedure for the selection, verification and validation process of hearing aids. CONCLUSION: The clinical protocol for the care of patients in the selection, verification and validation process of hearing aids was developed and validated by means of its use by professionals. The information and data we collected allowed a graphical representation of the protocol and its steps as a flowchart with algorithms. PMID- 30427379 TI - Instrumentalized evaluation for diagnosis of developmental disorders in childhood: a new Brazilian reality. AB - PURPOSE: To present the Griffiths Mental Development Scale (GMDS), as well as its cross-cultural adaptation to Brazil. METHODS: GMDS is a diagnostic tool for assessing child development. The result of its application allows verifying if development is typical or if there are alterations in a certain specific area (gross motor, personal-social, language, fine-adaptive motor and execution) or global development. After contact with the authors, permission to use GMDS was obtained and in compliance with ethical aspects, the Portuguese version of the instrument was adapted to Brazilian Portuguese with maintenance of semantic, idiomatic, experimental and conceptual equivalences. The adaptation was carried out by two speech therapists, experienced in evaluating infants, who were submitted to training course prior to the application of the instrument. The adapted final version was applied to 21 infants with typical development. RESULTS: Thirty-nine items were adapted without any exclusion. All items were possible to be applied, suitable for the target age group, with no response in any item. CONCLUSION: GMDS has been trans-culturally adapted in several countries and widely used for performing diagnosis in the age group essential for stimulation with brain plasticity in full development. The cross-cultural adaptation of GMDS for Brazil was carried out, transforming the Brazilian scenario in relation to child care. After normalization and verification of psychometric measures, it was possible, in addition to early diagnosis, to improve the quality of care for this population; carry out cross-cultural studies and publish the results in international journals regarding the feasibility of GMDS being accepted and used worldwide. PMID- 30427380 TI - Toxicity bioassay and sub-lethal effects of diazinon on blood profile and histology of liver, gills and kidney of catfish, Clarias gariepinus. AB - The catfish, Clarias gariepinus, was exposed to different acute concentrations (5 10 mg/l) of diazinon and the Lc50 value was recorded as high as 7.3 mg/l for 96 hours. The fishes exposed to three sub-lethal levels of diazinon (0.73, 1.095 and 1.46 mg/l) for 30 days showed that the pesticide induces changes in different blood parameters. Number of red blood cells (RBC), haemoglobin level and haematocrit values were elevated whereas white blood cells (WBC) count was reduced. Various blood indices like mean corpuscular volume (MCV), mean corpuscular haemoglobine (MCH) and mean corpuscular haemoglobine concentration (MCHC) vary insignificantly in the fish treated with diazinon. Glucose level and activity level of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was increased in Clarias gariepinus exposed to diazinon. Protein level in plasma of fish treated with pesticide was changed but the change was insignificant. Histological changes in the liver, gills and kidney of fishes exposed to diazinon were apparent when compared to control. Hepatocytes necrosis and bleeding were more distinct in the fishes exposed to pesticide. Glomerulus hypertrophy and bleeding in kidneys; and fusion and degeneration of secondary lamellae and epithelial hyperplasia in gills were also observed in the exposed fish. PMID- 30427381 TI - Accidentally catching of the catfish Lophiosilurus alexandri (Steindachner, 1876) larvae in aquariums with different colors. AB - The aim of this study was to evaluate the effect of different colors in development and survival of catfish Lophiosilurus alexandri larvae, as well as over the visual ability of the handler. Larvae were placed in 5 L-aquariums at a density of 7 larvae L-1 , and aquariums had different colors, and were: green and blue (light colors); brown and black (dark colors). The final development; survival, total and standard length, weight and biomass of the larvae were similar in all colored aquaria. The highest mortality occurred during the first days after hatching, declining over the period, when it is observed the larval development, indicating that care should be necessary in the first few days. During cleaning handling, the accidental catch of larvae was higher in black aquariums. In the first days of life, due to the fragility of the larvae, it is possible to verify that between the second and third day occur the greatest mortalities. The number of accidentally captured larvae was lower than the mortality, suggesting that the high mortality in early larval life is not influenced by the handler management. The catfish L. alexandri larvae should be cultivated in aquariums that allow a good contrast between the larvae and the background, to avoid accidental capture of larvae by the handler. It is suggested to avoid the use of dark and black aquariums. PMID- 30427382 TI - Determination of acute toxicity of ammonium in juvenile Patagonian blenny (Eleginops maclovinus). AB - Deionized ammonium (NH3) acute toxicity (LC50-96h) in Patagonian blenny juveniles (Eleginops maclovinus) was assessed. Concentrations of deionized ammonium in salt water were prepared by using 24.09 +/- 2.1 g ammonium chloride (NH4Cl). Fish were exposed in triplicates to different ammonium concentrations: 0.05; 0.094; 0.175; 0.325 and 0.605 mg NH3 L-1. Additionally, a control group was included. Experimental fish were kept at a photoperiod of 16:8h. Average temperatures were 16.24 +/- 1.40 degrees C. Oxygen concentration was 7.16 +/- 0.40 mg L -1. Water pH was 7.89 +/- 0.2. LC50-96 h, was estimated by using Probit statistical method (95% intervals) using EPA software (1993). Juveniles of E. maclovinus showed a LC50-96h of 0.413mg NH3 L-1 value, different from most marine species. This study presents the first record of ammonium toxicity in marine species of Chile. PMID- 30427383 TI - Ecotoxicological risk assessment due to the presence of bisphenol A and caffeine in surface waters in the Sinos River Basin - Rio Grande do Sul - Brazil. AB - Bisphenol A (BPA) is an emerging contaminant, regularly detected in aquatic ecosystems, considered as an endocrine disrupting compound (EDC). Caffeine is another chemical related to human activity, often found in surface waters. The objective of this study was to evaluate the ecotoxicological risk due to BPA and caffeine in water samples from the Sinos River basin, Rio Grande do Sul, Brazil. Water samples were collected at three sites monthly from May 9 th, 2016 to April 11th, 2017 (n = 36). BPA concentrations in water samples collected were in the range of not detected to 517 ng L-1 and caffeine concentrations in the range of 41.7 to 28,439.6 ng L-1. The concentration of BPA in the analyzed samples had a moderate correlation with caffeine (rs = 0.402). High ecotoxicological risk for BPA was characterized in 77.77% of samples, with 11.11% presenting medium and 11.1% presenting low risk. For caffeine 13.9%, 50% and 36.11% of the samples presented high, medium and low risk, respectively. Caffeine concentrations in water can be used as predictors of BPA concentrations above 10 ng L-1, the lower concentration of ecotoxicological risk, with specificity of 66.7% and sensitivity of 70.4%. The assessment of aquatic risks has shown that both investigated compounds pose risks to organisms in the studied surface waters, mouth of the Pampa stream, mouth of the Luiz Rau stream and catchment point for public supply in Lomba Grande. PMID- 30427384 TI - Fruit availability at the individual and local levels influences fruit removal in Cecropia pachystachya. PMID- 30427386 TI - How psychiatrists think about religious and spiritual beliefs in clinical practice: findings from a university hospital in Sao Paulo, Brazil. AB - OBJECTIVE: To examine the relationship between psychiatrists' religious/spiritual beliefs and their attitudes regarding religion and spirituality in clinical practice. METHODS: A cross-sectional survey of religion/spirituality (R/S) in clinical practice was conducted with 121 psychiatrists from the largest academic hospital complex in Brazil. RESULTS: When asked about their R/S beliefs, participants were more likely to consider themselves as spiritual rather than religious. A total of 64.2% considered their religious beliefs to influence their clinical practice and 50% reported that they frequently enquired about their patients' R/S. The most common barriers to approaching patients' religiosity were: lack of time (27.4%), fear of exceeding the role of the doctor (25%), and lack of training (19.1%). Those who were less religious or spiritual were also less likely to find difficulties in addressing a patient's R/S. CONCLUSION: Differences in psychiatrists' religious and spiritual beliefs are associated with different attitudes concerning their approach to R/S. The results suggest that medical practice may lead to a religious conflict among devout psychiatrists, making them question their faith. Training might be of importance for handling R/S in clinical practice and for raising awareness about potential evaluative biases in the assessment of patients' religiosity. PMID- 30427385 TI - Cost-effectiveness analysis of the treatment of mild and moderate Alzheimer's disease in Brazil. AB - OBJECTIVE: To perform a cost-effectiveness analysis of donepezil and rivastigmine therapy for mild and moderate Alzheimer's disease (AD) from the perspective of the Brazilian Unified Health System. METHOD: A hypothetical cohort of 1,000 individuals of both sexes, aged >65 years, and diagnosed with AD was simulated using a Markov model. The time horizon was 10 years, with 1-year cycles. A deterministic and probabilistic sensitivity analysis was performed. RESULTS: For mild AD, the study showed an increase in quality-adjusted life years (QALYs) of 0.61 QALY/21,907.38 Brazilian reais (BRL) for patients treated with donepezil and 0.58 QALY/BRL 24,683.33 for patients treated with rivastigmine. In the moderate AD group, QALY increases of 0.05/BRL 27,414.96 were observed for patients treated with donepezil and 0.06/BRL 34,222.96 for patients treated with rivastigmine. CONCLUSIONS: The findings of this study contradict the standard of care for mild and moderate AD in Brazil, which is based on rivastigmine. A pharmacological treatment option based on current Brazilian clinical practice guidelines for AD suggests that rivastigmine is less cost-effective (0.39 QALY/BRL 32,685.77) than donepezil. Probabilistic analysis indicates that donepezil is the most cost effective treatment for mild and moderate AD. PMID- 30427387 TI - Twelve-month utilization rates and adequacy of treatment for mental health and substance use disorders in Argentina. AB - OBJECTIVE: To estimate the 12-month prevalence of mental health services utilization (overall and by type of service sector), the adequacy of treatment provided, and sociodemographic correlates in the Argentinean Study of Mental Health Epidemiology (ASMHE). METHODS: The ASMHE is a multistage probability household sample representative of adults in urban areas of Argentina. The World Health Organization World Mental Health Composite International Diagnostic Interview (WMH-CIDI) was used to evaluate psychiatric diagnosis and service utilization. RESULTS: Among those with a disorder, 27.6% received any treatment in the prior 12 months. Of these, 78.3% received minimally adequate treatment using a broad definition and only 43.6% using a stringent definition. For individuals with a disorder, more services were provided by mental health professionals (17.7%) than by general medical professionals (11.5%) or non healthcare sectors (2.6%). Younger individuals with low education and income were less likely to receive treatment; those never married and those with an anxiety or mood disorder were more likely to receive treatment. Among those in treatment, treatment was least adequate among younger individuals with low education and low income. CONCLUSIONS: Policies to increase access to services for mental health disorders in Argentina are needed, as is training for primary care practitioners in the early detection and treatment of psychiatric disorders. PMID- 30427388 TI - Acute effects of ayahuasca in a juvenile non-human primate model of depression. AB - OBJECTIVE: The incidence rate of major depression in adolescents reaches approximately 14%. This disorder is usually recurrent, without remission of symptoms even after pharmacological treatment, and persists throughout adult life. Since the effects of antidepressants take approximately 2 weeks to begin, new pharmacological therapies are under continuous exploration. Recent evidence suggests that psychedelics could produce rapid antidepressant effects. In this study, we evaluated the potential antidepressant effects of ayahuasca in a juvenile non-human primate model of depression. METHODS: While living with their families, juvenile marmosets (8 males; 7 females) were observed on alternate days for four weeks during a baseline phase. This was followed by 8 weeks of an induced depressive state protocol, the social isolated context (IC), in which the animals were monitored in the first and last weeks. Subsequently, five males and four females were randomly selected for treatment, first with a single administration of saline vehicle (1.67 mL/300 g of body weight, via gavage), followed by a single dose of ayahuasca (1.67 mL/300 g of body weight, via gavage). Both phases lasted 1 week and the animals were monitored daily. A third week of sampling was called the tardive-pharmacological effects phase. In all phases the marmosets were assessed for behavior, fecal cortisol levels, and body weight. RESULTS: After IC, the animals presented typical hypocortisolemia, but cortisol recovered to baseline levels 24 h after an acute dose of ayahuasca; this recovery was not observed in vehicle-treated animals. Additionally, in males, ayahuasca, but not the vehicle, reduced scratching, a stereotypic behavior, and increased feeding. Ayahuasca treatment also improved body weight to baseline levels in both sexes. The ayahuasca-induced behavioral response had long-term effects (14 days). Thus, in this translational juvenile animal model of depression, ayahuasca presented beneficial effects. CONCLUSIONS: These results can contribute to the validation of ayahuasca as an antidepressant drug and encourage new studies on psychedelic drugs as a tool for treating mood disorders, including for adolescents with early-onset depression. PMID- 30427389 TI - Spatial Distribution of Euschistus heros (Hemiptera: Pentatomidae) in Cotton (Gossypium hirsutum Linnaeus). AB - Recently, the Neotropical brown stink bug, Euschistus heros (Pentatomidae: Hemiptera), has been detected in cotton in the Brazilian Cerrado. Several reliable surveys have been conducted on the spatial distribution of stink bugs in soybean; however, few studies have examined the behavior of this insect in cotton in Brazil. Thus, this study examined the spatial distribution of E. heros in cotton using aggregation indices based on the variance-to-mean ratio, Morisita index, exponent k, Poisson and negative binomial distributions. Inverse Distance Weighting interpolation maps were also used to represent insect density. The study was conducted in a 1.1 hectare experimental cotton field in which 64 equally-sized plots were sampled on a weekly basis. Our findings revealed that stink bugs presented an aggregate distribution in 2 sampling weeks based on aggregation indices, and this pattern was best described by a negative binomial distribution. Maps showing the density of pests can be an important tool for sampling pests in crops and control measures in early stages of infestation, when there is an edge effect on the distribution of E. heros, can be an efficient strategy in cotton. PMID- 30427390 TI - Assessment of the yield loss imparted by Orobanche aegyptiaca in tomato in Pakistan. AB - Broomrapes (Orobanche sp.) are root holoparasitic plants causing severe damage to various families of horticultural crops. A Preliminary survey was carried in tomato fields infested with orobanche in Potohar plateau of Pakistan. Results indicated that each planting bed comprising10-12 tomato plants contained 7-8 parasitic weeds. Overall survey indicated the 65-70% plants suffered partial or complete yield loss. Further, it was estimated that the number of weeds inhabiting plant-1 was ranged from 2-4. Yield loss was estimated at 57.17 tons/ha while in terms of financial loss, it was 2579.87 $/ha. Hence total estimated loss on the total surveyed area of 16 hectares was 41395.85 $. The high potential of tomato cultivation in Pakistan reinforces the urgent protection measures to resolve this emerging issue. PMID- 30427391 TI - One-eye-set sugarcane susceptibility to weed interference. AB - The new technology of sugarcane planting, known as one-eye-set seedlings, offer a high standard of plant health and vegetative vigor. However, there are no reports in the literature that evaluate the weed competition with one-eye-set sugarcane seedlings, and the periods in which weed communities need to be controlled in this system. Two interference experiments were conducted in field conditions. The first experiment determined the periods of weed interference of an infesting community predominated by Ipomoea hederifolia and Merremia aegyptia in sugarcane. In the second experiment, these same species competed with plants of the same sugarcane cultivar. Productivity and qualitative aspects of production were evaluated. The critical period of interference prevention in one-eye-set sugarcane system was 103 days, with weed community interference starting at 35 days and lasting until 138 days after planting. Weed coexistence during the entire sugarcane cycle reduced productivity by 60% and affected qualitative characteristics such as the total reducing sugars. Both species affected the vegetative development of the crop, mainly the tillering. I. hederifolia plants developed ahead of the M. aegyptia plants but in late evaluations the interference caused by M. aegyptia (77%) was greater (P<0.01) than that caused by I. hederifolia (72%). PMID- 30427392 TI - Athelia (Sclerotium) rolfsii in Allium sativum: potential biocontrol agents and their effects on plant metabolites. AB - Garlic (Allium sativum L.) plays an important role in popular culture due to its dietary and medicinal uses. It is also used to produce a wide range of pharmacologically interesting molecules. Several pathogens affect garlic plants, especially Athelia (Sclerotium) rolfsii, a fungus that is widespread and causes large economic losses. It causes direct damage to crops and leads to plant stress, which induces secondary metabolite production in plants. The use of microorganisms as biocontrol agents may induce the production of beneficial metabolites in plants that will protect it and promote resistance to pathogen attack. In addition to suppressing disease, biological control agents may have elicitor effects that could induce an increase in the production of useful bioactive secondary metabolites in plants, some of which may be of pharmacological interest. Therefore, the search for new biological control agents should also consider their potential as elicitor agents. This paper presents an analysis of the biological control of Athelia (Sclerotium) rolfsii by antagonistic microrganisms, the potential of yeasts and bacteria of the genus Bacillus for the biocontrol of phytopathogens, microrganisms influence in nutritional and bioactive compounds content of interest to the pharmaceutical industry. PMID- 30427393 TI - Molecular marker assisted selection for increasing inbreeding in S1 populations of cassava. AB - The objective of the present work was to use MAS in self-pollinated cassava populations for obtaining individuals with high inbreeding (f) aimed at rapid development of partial inbred lines. Three progenies (F0222, F1378 and F1662) were self-pollinated, generating a total of 233 S1 individuals. The progenies and the S1 individuals were evaluated in the seedlings and clonal evaluation trials (CETs). In the CET, plants were evaluated for the following traits: plant height (PH), root dry matter content (DMC), above ground yield (AGY), root (RY) and starch yield (SY). Twenty-seven microsatellites and five minisatellites were used to determine the level of inbreeding of the S1 individuals. Inbreeding (f) values varied from 0.15 to 0.89 within progenies, whereas most of the S1 individuals presented f values above 0.50. In average, 25% of the S1 individuals were selected, which resulted in a 38% inbreeding increase in the cassava progenies. In contrast, phenotypic selection showed no differences in inbreeding increase. Furthermore, there was no correlation between the level of inbreeding and agronomic traits. MAS was efficient for the identification and selection of cassava S1 individuals, with higher inbreeding values contributing to the decrease in the breeding cycles necessary to obtain new cassava inbred lines. PMID- 30427394 TI - Neuroscience: unveiling the brain of Saimiri collinsi (Squirrel Monkey). AB - Behavioral intelligence among non-human primates is a somewhat puzzling area to study, since it is closely linked to the morphology of the central nervous system. However, this morphology is still unknown to science in the case of Saimiri collinsi. As a means of assisting future studies on the social behavior of this species, we analyzed the brains of six adult females from the National Primate Center / Para, which were sent to the Animal Morphological Research Laboratory at the Federal Rural University of Amazonia after death by natural causes. The animals were fixed in formaldehyde solution (10%) and dissected. The brains were covered externally by the dura mater, with long cerebral hemispheres, although there was a complete absence of gyri. The internal structures which form a part of the telencephalon, diencephalon, midbrain, hindbrain and myelencephalon were identified, with the exception of the mammillary bodies. This condition, when linked to the lissencephaly found in these individuals raises questions about the real learning abilities of this species. PMID- 30427396 TI - Epidemiology of HIV and AIDS in the state of Rio Grande do Sul, Brazil, 1980 2015. AB - OBJECTIVE: to describe the HIV/AIDS epidemic in the state of Rio Grande do Sul and the metropolitan region of Porto Alegre (MRPA), Brazil, in the period 1980 2015. METHODS: this was a descriptive study using data from Ministry of Health information systems. RESULTS: 83.313 AIDS cases were recorded in the state; during the periods 1980-1990, 1991-2000 and 2001-2015, the detection rates in the state were 1.1, 17.2 and 40.3/100,000 inhab., respectively, and in the MRPA the detection rates were 2.4, 33.6 and 66.9/100,000 inhabitants, while mortality rates were 0.5, 8.5 and 12.6/100,000 inhab. in the state, and 1.3, 17.3 and 21.7/100,000 inhab. in the MRPA; in 2001-2015, the detection rate of HIV+ pregnant women per 1.000 live births in the state was 8.1 and 13.7 in the MRPA, while injecting drug users in the state (8.2%) and in the MRPA (8.9%) also stood out. CONCLUSION: the epidemic is generalized in the MRPA and with greater magnitude in relation to the state. PMID- 30427395 TI - Multivariate analysis relating milk production, milk composition, and seasons of the year. AB - Our objective was to quantify the relationship between seasons of the year, milk production, and milk composition of a dairy farm based on data for 48 consecutive months, using multivariate statistical analyses. The dataset contained information on productive indexes and milk composition from the bulk tank milk, which was measured from milk samples, collected monthly and used to determine the total dry extract and defatted dry extract, lactose, fat, protein, somatic cell count, and total bacterial count. Seasons of the year and milk production/hectare were also considered. Factor, cluster, and discriminant analysis were used to study the relationships between the above-mentioned variables. A positive relationship was noted between season and total dry extract, defatted dry extract, milk fat, and protein, with higher values being observed in winter and spring. Similarly, a positive relationship was noted between season and milk production/hectare, lactose content, with an increase in milk production and lactose content in winter and spring, which was negatively related to the somatic cell count and total bacterial count. Milk production and composition varied mainly with seasons. Multivariate analyses facilitated a better understanding of the relationship between milk production and composition on this dairy farm. PMID- 30427397 TI - Operational difficulties in the use of insecticidal dog collars for the control of visceral leishmaniasis, municipality of Montes Claros, MG, Brazil, 2012. AB - OBJECTIVE: to describe operational difficulties in the implementation of deltamethrin-impregnated dog collars for the control of visceral leishmaniasis. METHODS: this was a community intervention trial in the municipality of Montes Claros, MG, Brazil, comparing (i) control area - dogs without dog collars - and (ii) intervention area - use of 4% deltamethrin-impregnated collars; an initial serological survey was performed, followed by three further cycles (at 12, 18 and 24 months). RESULTS: out of 4,388 dogs initially seronegative wearing collars, 36.9% were not found in the second cycle, 27.0% of them were lost owing to disappearance/given away/sale, and 22.6% because no one was at home; 56.1% of collars were lost in one year; while among dogs that stayed longer in the study, collar loss was lower. CONCLUSION: high frequencies of collar loss and no one being at home at the time of the visit are operational difficulties for the implementation of a national control program based on the strategy evaluated. PMID- 30427398 TI - Sexual practices and health care of women who have sex with women: 2013-2014. AB - OBJECTIVE: to describe sexual practices and health care of women who have sex with women (WSW). METHODS: this was a cross-sectional study with data obtained by means of an electronic questionnaire answered by WSW from the five regions of the country (2013-2014). RESULTS: among 582 WSW, oral sex (95.2%) and digital penetration of the vagina (97.3%) were predominant, with rare use of barrier methods (6.7% and 5.8%, respectively); in the last five years, women who had sex exclusively with women, compared to those who had sex with women and men, were less likely to use barrier methods with women (28.3% versus 41.1%; p=0.041), less likely to have an annual check-up with a gynecologist (38.9% vs. 70.8%; p=0.033), less likely to receive guidance about sexually transmitted infections (STI) (44.0% vs. 59.1%; p=0.034) and about sexual doubts (50.0% vs. 63.0%; p=0.044). CONCLUSION: infrequent use of barrier methods may be a vulnerability factor for STI; it highlights the importance of guidelines for adequate health care for WSW. PMID- 30427399 TI - Evaluation of Primary Health Care performance in Florianopolis, Santa Catarina, Brazil, 2012: a cross-sectional population-based study. AB - OBJECTIVE: to evaluate the performance of Primary Health Care (PHC) in Florianopolis, SC, Brazil. METHODS: this was a cross-sectional population-based study with adults living in the catchment areas of the Health Centers (HC) located in the Northern Health District of Florianopolis in 2012; the Primary Care Assessment Tool (PCATool-Brazil) was applied do assess the presence and extent of PHC characteristics. RESULTS: of the 598 interviewees, 68,4% reported that they considered PHC centers to be their usual source of care; while the usage subdimension of the First Contact Access characteristic was the best evaluated (8.4; 95%CI 8.2;8.6), the service delivery subdimension of the First Contact Access/subdimension accessibility was the worst evaluated (3.5; 95%CI 3.3; 3.6); four (36.6%) of the eleven PHC centers evaluated had a high overall and essential PHC score, although their overall mean score was low (6.4; 95%CI 6.2;6.5). CONCLUSION: considering the PHC model evaluated by PCATool-Brazil, PHC services need to be improved, especially with regard to their process and structure components. PMID- 30427400 TI - Hearing Screening in children with Congenital Zika Virus Syndrome in Fortaleza, Ceara, Brazil, 2016. AB - OBJECTIVE: to describe the results of hearing screening performed in children with Congenital Zika Virus Syndrome (CZS) in Fortaleza, Ceara, Brazil. METHODS: this was a descriptive cross-sectional study involving children with CZS receiving health care in Fortaleza, 2016; the hearing screening tests performed were immittance audiometry, transient otoacoustic emissions (TOAE), acoustic reflexes, and cochleopalpebral reflex (CPR). RESULTS: The study included 45 children with an average age of 10 months. 44 of them underwent tympanometric screening, with 16 of these having the right ear within the normal range and 22 having the left ear within the normal range. Among the 43 children evaluated by TOAE, 30 "passed" in both ears, nine "refered" in both ears and four "refered" just in ear; 13/43 "refered" and needed to repeat screening. 43 children evaluated by CPR, 37 showed responses. CONCLUSION: most of the children evaluated had completed cochlear function and middle ear results refer in compatible with their age range. PMID- 30427401 TI - Sanitation utilities and fluoridation of water supply systems: an ecological study in Brazilian municipalities, 2008-2010. AB - OBJECTIVE: to describe the characteristics of Brazilian sanitation utilities and municipalities according to the water supply system fluoridation situation. METHODS: this was an ecological study using data from the National Survey of Basic Sanitation 2008, the Demographic Census 2010 and the Atlas of Human Development 2010. RESULTS: of the 5,565 Brazilian municipalities, 60% had a fluoridation service; there was variation in fluoridation provision depending on the characteristics of the service providers and the municipality; the greater the coverage of water supply and sewerage and the higher the level of human development, the greater the provision of fluoridation (p<0.001); fluoridation provision was higher in municipalities where the sanitation utilities were mixed capital companies (75%) and lower when the companies were private (27%) and also when the service was provided only by the municipal government (40%). CONCLUSION: there was an important dependence relationship between the characteristics of the companies and the provision of water fluoridation in Brazilian municipalities. PMID- 30427402 TI - High detection rate of new cases of multibacillary leprosy in Mato Grosso do Sul, Brazil: an observational study from 2001-2015. AB - Leprosy remains a public health problem in Brazil, and the Mato Grosso do Sul State (MS) had the seventh highest rate of detection of new cases in the country in 2015 (26.59 per 100,000 inhabitants) which was classified as very high. This work aimed to determine the epidemiological characteristics of leprosy in MS. Descriptive statistics were performed with data from the Information System on Diseases of Compulsory Declaration (SINAN) between 2001 and 2015, with all patients included in the system serving as the sample. Clinical forms of multibacillary (MB) leprosy predominated in MS during the study period, with a clear positive trend from 2009 to 2015 and a peak in the detection rate of new cases (NCDR) in 2014 corresponding to 40.39 per 100,000 population (p<0.001). The most affected groups were men (56.7%) aged 20-59 years (70.52%), an economically active population. We observed that Northern MS had the highest overall NCDR in the State. In cities bordering other countries, NCDRs were significantly lower than in those of other analyzed cities. There was no dependency ratio correlating NCDRs in cities with higher or lower indexes with basic care coverage (p=0.799) and human development index (p=0.887). In conclusion, the large number of patients with MB leprosy indicates that the diagnosis of leprosy is delayed in MS, perhaps due to difficulties related to diagnostic methods. This situation contributes to the continuing prevalence of leprosy in MS. PMID- 30427403 TI - Inflammatory cytokines in leprosy reactions and periodontal diseases. AB - The inflammatory cytokines involved in the immune response to chronic periodontal disease (CPD) in the context of leprosy reactions (LR) were analyzed in 57 new cases of multibacillary leprosy (MBL). They were stratified by the presence of CPD and LR. Messenger RNA (mRNA) expression of inflammatory mediators was determined by qRT-PCR using skin biopsy and by ELISA using serum samples, maintaining 5% of significance level in ANOVA and correlation analyses. Twenty three (40.4%) patients presented the first LR, whereas 22 (45.0%) patients presented CPD. IL-4 and IL-6 serum levels were significantly lower in patients with CPD and LR than in patients without CPD but with LR; IFN-gamma serum levels were higher in patients with CPD and LR than in patients with no CPD and no LR; IL-4 serum levels were negatively correlated with TNF-alpha gene expression, while IL-6 serum levels were positively correlated with IFN-gamma gene expression, in the skin of subjects with CPD and LR. The presence of DPC in individuals with LR immunoregulated IL-6, IFN-gamma, and IL-4 concentrations. The presence of DPC decreased serum levels of IL-6 and IL-4 in reactional individuals. CPD concomitant to LR resulted in increased IFN-gamma serum levels. PMID- 30427404 TI - Low occurrence of Hepatitis A virus in water samples from an urban area of Southern Brazil. AB - Hepatitis A virus (HAV), a member of Picornaviridae family, is the main causative agent of acute viral hepatitis in the world, mainly in developing countries. HAV may be present in contaminated water and food and its presence is often associated to a lesser extent with socioeconomic factors and environmental quality. The main goals in the present study were to standardize a cell culture combined to a polymerase chain reaction protocol for the detection and quantification of viral viability and analyze whether the virus could be found in water samples collected in four urban streams of Sinos River watershed. Virus recovery was assayed from known virus concentrations measured in experimentally contaminated raw and ultrapure water (MilliQ(r)). Recovery rates ranged from 270% in raw water to 15,000% in ultrapure water. In a second step, a qPCR coupled to a previous passage in cells, demonstrated more analytical sensitivity when compared to samples assayed without a previous passage in cell cultures. HAV genome was detected in only 1 of 84 samples analyzed, pointing to a very low occurrence of HAV in water samples in the studied region. These findings are remarkable, since no more than 5% of the domestic sewage in this area is treated pointing to a low occurrence of HAV in the population living nearby during the study period. PMID- 30427406 TI - Treatment of mucosal leishmaniasis with amphotericin B lipid complex (ABLC). PMID- 30427405 TI - Hand, foot and mouth disease and herpangina caused by enterovirus A71 infections: a review of enterovirus A71 molecular epidemiology, pathogenesis, and current vaccine development. AB - Enterovirus A71 (EV-A71) infections are one of the main etiological agents of hand, foot and mouth disease (HFMD) and herpangina worldwide. EV-A71 infection is a life-threatening communicable disease and there is an urgent global need for the development of vaccines for its prevention and control. The morbidity rate of EV-A71 infection differs between countries. The pathogen's genetic lineages are undergoing rapid evolutionary changes. An association between the occurrence of EV-A71 infection and the circulation of different genetic strains of EV-A71 virus has been identified around the world. In this review, we present and discuss the molecular epidemiology and pathogenesis of the human disease caused by EV-A71 infection, as well as current prospects for the development of an EV-A71 vaccine. PMID- 30427407 TI - [Concepts and ideas concerning universal health care: results of the intergovernmental arrangement in Greater Metropolitan Buenos Aires, Argentina, from 2003 to 2011]. AB - In the context of a federal and highly fragmented institutional framework like that Argentina, the article analyzes the concepts and ideas on which government actors organize their health policy instruments at three different levels of government. Based on this focus, the article investigates the convergences, divergences, and tensions permeating the exercising of the right to health. The analysis is organized in three dimensions of universal care that became challenges for the national policy during the period in question: ease of access to services, insured coverage, and a guaranteed set of explicit benefits for the entire population. Concerning these challenges, the actors deconstruct and reconstruct the meaning of the policies for universal health care, based on the issues on their agendas, the ideas existing prior to the programs (and based on which the changes are conceived), and the political logic by which their decisions are made. This perspective seeks to transcend the programs' underlying technical ideas in order to capture the political dimension of their implementation, seen as a complex social construction, which also faces structural problems that are part of the agenda at each level of government in relation to health services provision. PMID- 30427408 TI - Cross-cultural adaptation of the Four Habits Coding Scheme (4HCS) for teaching and assessing patient-centered communication skills in Brazil. AB - Brazilian educational guidelines reinforce patient-centered care communication skills as an important competence for medical students. The Four Habits Coding Scheme (4HCS) is an instrument used for teaching and assessing clinicians' communication skills in a person-centered care approach. We aimed to translate and culturally adapt the 4HCS into Brazilian Portuguese. The translation process was accomplished in seven stages: initial translation, reconciliation, back translation, review by the author, independent review, consensus version through Delphi technique, review by a language coordinator, and pretest. During pretest, three independent observers assessed four medical consultations, which were performed by medical students and residents, that had been recorded in a real healthcare scenario. Reviewers had difficulty in reaching consensus on expressions referring to understanding the person as a whole, such as "Engage in small talk", "Expansion of concerns", "Elicit full agenda", "Use patient's frame of reference", and "Explore plan acceptability". They also had difficulty in reaching consensus on the translation of the word "clinician", which was first translated as "physician". Historical and cultural issues in the physician patient relationship may have influenced this result. The Brazilian 4HCS is a culturally, conceptually, semantically and operationally sound instrument. It may represent an important advance for strengthening the person-centered care model in Brazil. PMID- 30427409 TI - Zika: an ongoing threat to women and infants. AB - Recent data from the municipality of Rio de Janeiro, Brazil, shows a sharp drop in the number of reported occurrences of Zika during the summer of 2016/2017, compared to the previous summer. There is still a much higher incidence among women than men, almost certainly due to sexual transmission. An unexpected feature of the new data is that there are proportionally far more cases affecting children under 15 months than older age classes. By comparing incidence rates in 2016/2017 and 2015/2016, we were able to deduce the proportion of reported cases affecting men and women, and verify that gender disparity is still present. Women and children are still risk groups for Zika infection, even during non-epidemic seasons. PMID- 30427410 TI - [Deaths that save lives: the complexities of medical care for patients with suspected brain death]. AB - The objective of this study was to understand how physicians at the largest emergency department in a large Brazilian city orient care for critical patients with suspected brain death and who are potential organ donors. This ethnographic study was conducted in an emergency care hospital, a reference in traumatology in Latin America, located in downtown Belo Horizonte, Minas Gerais State. The institution took pioneering steps in Brazil with a specific sector where patients with suspected brain death are referred. The fieldwork was performed over the course of nine months, based on targeted observations and interviews with 43 on duty staff physicians (25 men and 18 women), from 28 and 69 years of age. Data analysis followed the "signs, meanings, and actions" model. The ethnography revealed the process of medical care for patients with suspected brain death, including: intensive care, adherence to protocol, and communicating the patient's status to the family. In the latter case, the dialogue reveals the controversies in the concept of brain death, the sociocultural context, and the emergency care context. It became clear that this process of medical care extrapolates merely normative issues, entering into a complex web of elements, especially the professional's role as mediator of a myriad of interwoven elements and tensions. Between confirmation of the brain death and communicating the situation to the family, ambivalent perceptions emerge, both for the physicians and the family members. The study evidenced how the tenuous definition of what constitutes life and death touches on all of the medical act, with direct implications on care for patients/potential donors and their families. PMID- 30427411 TI - ["We live on the tightrope": the experience of health professionals working with HIV/AIDS in a remote area of Northeast Brazil]. AB - This ethnographic study aimed to understand the experience of health professionals working in a Specialized Service for HIV/AIDS Care in a remote area of Northeast Brazil. Data collection used participant observation and a semi structured interview with seven professionals in the health care team. The thematic coding technique yielded three categories: "I didn't even know what it was": aspects of becoming a specialist in HIV/AIDS; "They're all out there, kind of hidden": strategies for dealing with the (in)visibility of serological status; and "We live on the tightrope": experiences in the work process. The study's most relevant aspect was the service's institutional invisibility as a result of the current configuration of the AIDS structure in Brazil. The results revealed several difficulties that are typical of services located in remote areas, especially the health professionals' lack of experience, aggravated by the lack of continuing education, unmet infrastructure needs, the position of HIV/AIDS care on the local political agenda, and the physician-centered organization of the work process. The study also highlighted the interlocutors' agency in the production of strategies to deal with these difficulties. The study further emphasized the local dimension as a social marker of difference that modeled the interlocutors' experiences, where the health policy's guidelines and principles are performed by health professionals, administrators, and users, comprising diverse material forms. PMID- 30427412 TI - World Cup 2018: private water and sewage companies score high in Brazil. PMID- 30427413 TI - [Factors associated with the involuntary pilgrimage for childbirth care in Sao Luis (Maranhao State) and Ribeirao Preto (Sao Paulo State), Brazil: a contribution from the BRISA cohort]. AB - The objectives of this study were to estimate the involuntary pilgrimage by women in labor in search of childbirth care and to identify factors associated with this endeavor in two Brazilian cities. This was a cross-sectional study nested in the BRISA birth cohort, whose sample consisted of 10,475 women admitted to the selected maternity hospitals for delivery in Sao Luis (Maranhao State) and Ribeirao Preto (Sao Paulo State). Interviews were held with questionnaires that contained sociodemographic and obstetric variables. Hierarchical modeling was used, and relative risk was calculated with Poisson regression. Involuntary pilgrimage during labor was more frequent in Sao Luis (35.8%) than in Ribeirao Preto (5.8%). In Sao Luis, factors associated with pilgrimage were: first pregnancy (RR = 1.19; 95%CI: 1.08-1.31) and schooling less than 12 complete years. However, age 35 years or older (RR = 0.65; 95%CI: 0.54-0.84) was associated with less pilgrimage. In Ribeirao Preto, such trekking for obstetric care was more frequent in women with high-risk pregnancies (RR = 2.45; 95%CI: 1.81-3.32) and those with gestational age less than 37 weeks (RR = 1.93; 95%CI: 1.50-2.50). Meanwhile, delivery with gestational age equal to or greater than 42 weeks was associated with less pilgrimage (RR = 0.57; 95%CI: 0.33-0.98). In both cities, poor women had to trek more in search of childbirth care and had no guarantee of care, even for those who had received prenatal care. The study revealed the lack of guarantee of universal and equitable access and highlighted the unequal access to childbirth care between Brazil's major geographic regions. PMID- 30427414 TI - [Liver transplants and organ allocation in Brazil: from Rawls to utilitarianism]. AB - The process of liver donations and transplants in Brazil reveals major inequalities between regions and states of the country, ranging from uptake of the organs to their transplantation. In 2006, the MELD score (Model for End-stage Liver Disease), inspired by the U.S. model and based on the principle of need, was introduced in Brazil for liver transplant allocation. However, Brazil's inequalities have partially undermined the initiative's success. Other countries have already benefited from growing discussion on the benefits of models that seek to harmonize utilitarianism and need. The current article reviews the relevant literature with a special focus on the Brazilian reality. PMID- 30427415 TI - [Dancing with numbers: measuring experiences with among multiply marginalized groups]. AB - The aim of this study was to analyze the Explicit Discrimination Scale (EDS), in order to determine its capacity to reflect intersectional experiences with discrimination among groups subjected to class, race, and gender oppression. The study was based on data from a study conducted in a representative sample of students (n = 1,023) at Federal University of Santa Catarina, Brazil, regularly enrolled during the first semester of 2012. The statistical analysis included estimation of the relative frequencies of each of the 18 items in the EDS, as well as the main reasons, stratified by sex/gender, color/race, and socioeconomic status. Negative binomial regression models allowed assessing whether sex/gender, race/color, and socioeconomic status are predictors of the discrimination score, even after adjusting for covariates that potentially affect the target associations. The results of the analysis of each of the instrument's 18 items suggest that the EDS allows measurement of discrimination in among multiply marginalized groups, since it draws out the experiences with discrimination in minority subgroups, such as low-income black women. Still, this tendency was not observed in the instrument's global score, suggesting that it does not allow positioning the respondent along a spectrum of discrimination that includes less and more intense expressions of the phenomenon. Future studies are needed to deal with this observed limitation and which thus lend greater visibility to the experiences of discrimination in groups exposed to multiple marginalization. PMID- 30427416 TI - [Trends in reporting of sexual violence in Brazil from 2009 to 2013]. AB - The objective was to analyze the trends in reporting of sexual violence in Brazil from 2009 to 2013, with special emphasis on rape. An observational times series study was conducted, analyzing data from 2009 to 2013 coming from a secondary database of the Brazilian National Information System for Notificable Diseases (SINAN). The independent variable was the number of reports of sexual violence from 2009 to 2013, which was compared to several sociodemographic, violence related, and health-related variables. The data were analyzed with a Prais Winsten generalized linear regression model, determining the variations as stable, upward, or downward by analysis of the coefficient of determination (Pearson's R2) and level of significance set at p < 0.05. The reports of sexual violence showed greater positive variation in the 10-19-year age bracket (364%), indigenous individuals (520%), in the South of Brazil (414%), females (331%), and individuals with low schooling (343%). More than 70% of the reports were rapes, while one-third were repeat offenses, with a downward trend in reports of sexual violence accompanied by beating. The aggressors' characteristics remained stable. The site of violence changed, with fewer cases occurring on public byways. Finally, the reporting rate for rape increased by 590%, with a similar trend in rapes in the household and an increase in case resolutions. The study reveals the sociodemographic profile of cases of sexual violence reported in Brazil and an increase in reported rapes, especially inside the household. There was also an increase in case resolution. PMID- 30427417 TI - Scientific authorship in CSP. PMID- 30427418 TI - Commentary on Zika: An Ongoing Threat to Women and Infants. PMID- 30427419 TI - Reply to commentary on Zika: An Ongoing Threat to Women and Infants. PMID- 30427420 TI - [Dimensional structure of the Brazilian version of the Functional Activities Questionnaire (FAQ-BR)]. AB - This study aimed to assess the dimensional structure and internal consistency of the Brazilian version of the Functional Activities Questionnaire (FAQ-BR) for measurement of functional capacity in the elderly, based on the informant's report. This was a cross-sectional study with 525 non-institutionalized elderly informants, in which confirmatory factor analyses (CFA) and exploratory/confirmatory factor analyses (E/CFA) modeled according to CFA principles were used to identify the most parsimonious model and that with the best fit. The internal consistency of the FAQ-BR was assessed by composite reliability, and correlations between its dimensions were examined to investigate discriminant factor validity. CFA did not corroborate the unidimensional structure as originally proposed. Next, E/CFA fit a bidimensional structure that was reassessed by CFA, displaying a model without cross loads as the most parsimonious and with adequate fit indices. The internal consistency of FAQ-BR was considered satisfactory, and the correlation between its dimensions was acceptable. These findings are important, since they demonstrate the scale's capacity to capture the elderly's functional capacity construct in a different sociocultural context from that in which it was originally developed. The FAQ-BR can thus be considered an appropriate bidimensional instrument for measuring the elderly's functional capacity based on the informant's report, and its use in studies with similar populations is recommended. PMID- 30427421 TI - Being a woman: gestation and giving birth: meanings in transition and challenges for the health sector. PMID- 30427422 TI - Sexual and reproductive health: team competences in Primary Health Care services. AB - Sexual and reproductive health rights were developed recently as a result from the movements held for Human Rights and citizenship. Delimitations of this subject have not been explored in Brazil yet, even though the importance of developing skills related to this subject is recognized. This paper aims to construct a Sexual and Reproductive health transversal skills framework based on specialists' point of view. A mix methods descriptive exploratory research with the use of the Delphi Technique was developed with 41 specialists in sexual and reproductive health and rights. Three rounds of data gathering were carried out. Of the 36 skills resulting from the qualitative analysis, 32 achieved a general consent and were classified in four domains: ethics and professional principles; leadership and management; community work, health and education, counseling and evaluation; and health care. Results corroborate skills content recommended by the international literature. These skills, which are transversal, may support the development of actions and practices of the health professionals concerning sexual and reproductive health care. PMID- 30427423 TI - Sexism against women among primary healthcare workers. AB - The objective of this study was to research the existence of sexism against women among primary healthcare (PHC) workers and to identify associated factors. This was a cross-sectional study in which 163 PHC professionals of both sexes participated, all of whom were aged over 18 and had completed their primary or secondary education. The Gender Stereotyping and Ambivalent Sexism Inventory questionnaires were used. The average scores were more than 50% of the maximum score: Gender Stereotyping - 53.8%, hostile sexism - 58.2%, benevolent sexism - 64.1%. The average scores stratified by sociodemographic variables were higher. Significant differences in the hostile sexism score were found for sex (men scored higher than women), religion (higher scores for evangelical Christians) and among those who drank alcohol. For benevolent sexism, differences were found for schooling (greater scores for those who had only completed their primary education), religion (higher scores for evangelical Christians and Catholics) and area of work (greater for those working in general services). The stratification of the Gender Stereotyping scores did not point to significant differences. Sexist prejudice was found to exist for hostile sexism, benevolent sexism and gender stereotyping. This finding could have a negative influence on the service user relationship, leading to greater inequities in health as a result of gender inequality. PMID- 30427424 TI - [The vulnerability of Afro-Brazilian women in perinatal care in the Unified Health System: analysis of the Active Ombudsman survey]. AB - With principles of respect to the protection and implementation of human rights, cultural, ethnic and racial diversity and also the promotion of equity, the Stork Network ensures the right to reproductive planning and continued provision of care in maternal and child health. This study sought to evaluate the Active Ombudsman Survey of the Stork Network conducted with women who had their births assisted by the Unified Health System (SUS) in 2012, in order to analyze ethnic/racial differences in prenatal and childbirth care. This descriptive study used the secondary database from the survey conducted by the SUS Ombudsman. The universe of this investigation was constituted by 253,647 women, and 50.8% self declared themselves as brown, 35.4% white, 10.6% black 2.1% yellow, 0.6% Indians and for 0.5% race/color was not informed. Women of black/brown race appear to be worse off in socioeconomic characteristics, prenatal and childbirth care, in all variables studied, except concerning aggression and supplementary payment. Knowledge about inequalities and vulnerability of this group may serve to alert society and the government, and as a guideline for the development of policies and actions to reduce health inequalities. PMID- 30427425 TI - [New childbirth practices and the challenges for the humanization of health care in southern and southeastern Brazil]. AB - The humanization of care in childbirth and the choice of performing cesarean or vaginal delivery have long been discussed in Brazil and worldwide. The complexities of the factors surrounding this issue range from the quality of obstetric care through to the significance of childbirth for women. A new proposal for humanization of delivery was introduced by the Brazilian Ministry of Health, the objectives of which were to make changes to the current system of delivery practices regarding, access, care, quality and resolution, in order to make it a more human and less technical experience. The Sofia Feldman Hospital, in Belo Horizonte - MG, is a benchmark in the adoption of best practices in care during childbirth, according to the Brazilian National Health Agency. However, for the humanization to become a national reality, there are still many challenges to be overcome within the public health system and the private partnerships. The most important problems are related with the current education system that continues to prepare health professionals to act in an interventional way, focused on the physician figure. This study aims to provide an overview about the different humanized care practices focused on pregnancy and childbirth, conducted in southern and southeastern Brazil. PMID- 30427426 TI - [The cultural representation of "natural childbirth": the outlook on the pregnant body in the mid-twentieth century]. AB - The scope of this study is to discuss teaching strategies directed towards women to institutionalize the representation of normal birth based on the work "Natural Childbirth: A Guide for Future Parents", published in 1955. The research begins with a historical and cultural analysis of the 1955, 1957, 1960 and 1964 editions of this book. It is aided by materials published, in the same period, which share the same meanings and representations concerning issues surrounding childbirth in the Brazilian context. It is a period marked by retrospectives and the emergence of methods for preparing women for the childbirth process. The results of our analysis, in the light of Roger Chartier's theoretical framework, especially applying the notion of representation of Michel Foucault, indicate that the apparatuses used in the work's registers sought to propose a disciplinary model for childbirth: institutionalization, medical insertion and industrialization of normal childbirth in the Brazilian context of the mid-twentieth century. PMID- 30427428 TI - [Factors associated with the lack of breastfeeding upon discharge from hospital in a public maternity facility in Maceio, Alagoas, Brazil]. AB - This article sets out to evaluate the prevalence and associated factors with the lack of breastfeeding upon discharge from hospital in a public maternity facility in Maceio, Alagoas, Brazil. It involved a cross-sectional study performed with women who had recently given birth at the moment of discharge from the maternity ward of a university hospital in the capital. Prevalence ratios (PR) and confidence intervals of 95% (CI95%) were calculated by Poisson regression with the use of a hierarchical model. Approximately 20% of mothers did not breastfeed. Smoking during pregnancy [PR = 5.20; (CI95% =1.75 to 15.33), p = 0.003]; complications during pregnancy [PR =3.50; (CI95% =1.04 to 11.77), p = 0.042] and insufficient information about breastfeeding during prenatal care [PR = 5.44; (CI95% 1.78 to 16.67); p = 0.003] were the major negative factors associated with the lack of breastfeeding. Breastfeeding in the maternity ward was lower than ideal. Guidelines on smoking prevention and encouragement of breastfeeding must be highlighted during prenatal care, especially for women with complications during pregnancy. PMID- 30427427 TI - Burden of Mild Mental Retardation attributed to prenatal methylmercury exposure in Amazon: local and regional estimates. AB - The gold rush in the Amazon Region caused an increase of mercury (Hg) levels in the environment, and, consequently, raised human exposure. Once released into aquatic systems, Hg could generate methylmercury (MeHg), an extremely toxic compound, which is accumulated through trophic chains. Several studies have provided evidences of the brain sensitivity to MeHg, as well as, of the fetus vulnerability during pregnancy. The main objective of this study was to estimate the Mild Mental Retardation (MMR) in Amazonian populations, caused by prenatal exposure to MeHg, using the methodology proposed by Poulin (2008), which quantifies the environmental burden of disease. The estimates of the MMR burden, attributed to prenatal MeHg exposure, were based on the calculation of Disability Adjusted Life Years (DALY), which were obtained from MMR incidence rate in the studied populations. At the local level, the MMR incidence rate calculations were based on primary data of MeHg exposure of riverine women at childbearing age. The MMR incidence rate was equal to 5.96/1,000 infants, which would result in 2.0 IQ points loss in 34.31% of the newborns. The estimated DALY/1,000 infants was equal to 71.2, while the DALY was 576. For the regional estimates, different exposure scenarios were created. The calculated DALY varied from 3,256 to 65,952 per year. PMID- 30427429 TI - Non-performance of Pap smears among pregnant women in the Extreme South of Brazil: prevalence and associated factors. AB - Cervical cancer is the third most common cause of cancer among women worldwide, and Pap smears are the best screening strategy for its detection. This study evaluated the prevalence and the associated factors of the non-performance of Pap smears among pregnant women above the age of 25 during prenatal care in the municipality of Rio Grande, Brazil, in 2013. The multivariate analysis was performed by Poisson regression evaluated by prevalence ratio (PR). Of the 1,474 pregnant women included in the study, 21.6% (95% CI, 19.5%-23.7%) had not been screened. The adjusted analysis evidenced a PR for the non-performance among puerperae with 0-4 years schooling of 2.14 (95% CI, 1.35-3.38) compared to those with 12 years or more. Reporting previous abortion and alcohol use during pregnancy showed a PR of 1.38 (1.10-1.73) and 1.39 (1.04-1.84) of not doing so compared to the other, respectively. Finally, performing 1-5 prenatal visits evidenced a PR of 1.35 (1.03-1.77) compared to the others. A high proportion of pregnant women non-performing Pap smears and non-compliance with the basic recommendation by the Brazilian Ministry of Health has been found. Health professionals should reinforce the need for this test and active search for pregnant women in the community with the profile described herein. PMID- 30427430 TI - [Healthcare and gestational factors associated with anemia in nursing mothers attended in a human milk bank]. AB - Anemia is a public health problem that affects about 30% of Brazilian women, which may cause deleterious effects on the health and quality of life of mother and child. This article seeks to evaluate the healthcare and gestational factors associated with anemia among mothers receiving care at a human milk bank (HMB) of reference. It is a cross-sectional study with secondary data about sociodemographic and pregnancy information on 12283 nursing mothers from 2009 to 2012. The Kolmogorov-Smirnov and chi-square or Fisher's exact tests were applied. The prevalence ratios (PR) and their 95% confidence intervals were estimated by Poisson regression with robust variance. Anemia was identified in 29.2% of the sample and the prevalence was higher among mothers who did not have prenatal appointments (PR = 3.84; 95% CI 3.26 to 4.54); those who made 3 or less antenatal visits (PR = 1.92; 95% CI 1.21 to 3.06) and those who have had multiple pregnancies (OR = 2.29, 95% CI 1.25 to 4.19). The results showed a higher prevalence of anemia among women who did not have the appropriate prenatal care and who have had multiple pregnancies, highlighting the importance of healthcare as a factor in the prevention of anemia and other complications during pregnancy. PMID- 30427432 TI - Common mental disorder among incarcerated women: a study on prevalence and associated factors. AB - Mental disorders are present in four of the ten main causes of incapacity across the world. This article aims to analyze the prevalence of Common Mental Disorders (CMD) in incarcerated women and associated factors. A cross-sectional study was conducted with a population of 1,013 women incarcerated in a female prison. The prevalence of CMD was assessed by the SRQ-20. The hierarchical logistic regression was the method of analysis used to search for independent associations between sociodemographic, lifestyle, morbidity and violence variables with CMD and strength of association. The prevalence of CMD was 66.7%. The following variables were independently and positively associated with CMD: lack of income, hypertension, tranquilizers, physical inactivity, smoking, scabies/pediculosis, psychological violence in the year before being arrested, and having witnessed psychological violence in the family in childhood/adolescence. Interdisciplinary activities among health, justice and education institutions can contribute to a qualified assessment of women before admission into the prison system. This can enable an approach that does not exacerbate or trigger the onset of CMD, contributing to the improvement in living conditions and for better health and recovery strategies. PMID- 30427431 TI - [Factors associated with general obesity and the percentage of body fat of women during the menopause in the city of Sao Paulo, Brazil]. AB - To verify the association between obesity and demographic, clinical and lifestyle variables in climacteric women, a cross-sectional study was conducted in outpatient clinics, with 469 women aged 40 to 65 years in the city of Sao Paulo, Brazil. The dependent variables were: obesity according to body mass index (BMI) and obesity according to percentage of body fat (% BF). The main explanatory variable was: climacteric phase (pre or postmenopausal); and control variables were: age; years of formal study; parity; menopausal hormone therapy (MHT) use; physical activity practice and smoking habit. Multiple regression analysis was performed using the Stata 9.2 software. According to the BMI, obesity was positively associated with parity (RR = 1.62, 95% CI = 1.11-2.37) and, negatively, with years of formal study (RP = 0.71, CI 95% = 0.55-0.91) and with physical activity practice (PR = 0.45, 95% CI = 0.33-0.61). According to the % BF, obesity was positively associated with parity (PR = 1.60, 95% CI = 1.03-2.49) and negatively with physical activity practice (PR = 0.43; 95% CI = 0.29-0.63). While being active physically was protective, multiparity was a risk factor for developing obesity for women in this study. PMID- 30427433 TI - Gender asymmetry and symmetry in Brazilian intimate partner violence research. AB - This study aims to analyze intimate partner violence from the gender symmetry and asymmetry concepts. Seventy-nine papers were selected for analysis, and most were published in the 2006-2014 period (78.5%). The fields of journals that addressed the subject were psychology (32.9%) followed by public health (27.9%) and nursing (27.6%). Of the researchers, 46.8% work with the feminist theoretical line discourse, whose gender approach is asymmetrical. They mostly produce qualitative research with a sample consisting of women only (81.1%), and 78.3% collected data from violence victims' support services. When looking at the characteristics of the studies conducted by researchers from the theoretical line of family sociologists who advocate gender symmetry (25.3%), qualitative and quantitative approaches were used in similar proportions. Bidirectional violence was identified in 80% of this research. We noted a strong leadership of the feminist theoretical line, which was identified in the discourses of the researchers. We stress the relevance of the discussion of the data with different theoretical frameworks, since analysis in isolation, regardless of the field, runs the risk of being biased and thus weaken the results. PMID- 30427434 TI - Influence of maternal confidence on exclusive breastfeeding until six months of age: a systematic review. AB - Breastfeeding is a practice directly related to the health of the mother and especially the baby. Despite being a natural process, many mothers report difficulties with breastfeeding. This study aimed to seek scientific evidence on the issue: "Can a mother with more confidence in breastfeeding exclusively breastfeed her baby for 06 months?". We conducted a systematic review with a search in five electronic databases, and included four cohort studies for evaluation. We conducted a qualitative analysis of the results, considering the methodological differences and lack of data, and were unable to perform meta analysis. Confidence in breastfeeding was evaluated by using the Breastfeeding Self-Efficacy Scale. The studies analyzed showed statistically significant association between the practice of breastfeed and confidence in breastfeeding. The application of a scale to evaluate trust and identify mothers at risk for early weaning appeared to be a reliable measurement tool, capable of facilitating action planning by health professionals. The evidence showed association between mothers with higher levels of confidence in breastfeeding and exclusive breastfeeding for 6 months, but these results could not be generalized because of the heterogeneity of the population. PMID- 30427435 TI - [Body image of healthy adolescent women and its association with physical activity: a systematic review]. AB - The aim of this study was to evaluate the related scientific production on body image in healthy female adolescents and its association with physical activity. A systematic review of national and international journals was conducted using the major electronic databases. The following inclusion criteria selection were used: sample of female adolescents, with different results; papers in English, Spanish and Portuguese; papers published from 2005 to 2015. Eighteen studies were included and carefully analyzed. The most published paper concentrations were found in Europe (61.2 %). Several studies (95%) used questionnaires as a research instrument to assess physical activity and 55% studies used scales to analyze the body image. No increase was found in the production of literature involving body image study and physical active behavior in healthy female adolescents. In conclusion, the main findings of this review relate to the lack of parameters for the measurement of physical activity and body image analysis. Thus, although it is a current thematic area in the literature, it is possible to consider that the diversity of methodological design between studies makes it difficult to compare the data, making it imperative to standardize instruments and definitions. PMID- 30427436 TI - The National Reproductive Health Programme in Cape Verde: scope, limits and challenges. AB - Cape Verde is an archipelago on the African coast, with 538,535 inhabitants living on nine islands. Since it gained independence in 1975, the country has experienced rapid economic and social growth, with significant gains in education as well as a reduction in maternal and infant mortality deaths. In 2001, following the guidelines of the International Conference on Population and Development (ICPD, Cairo, 1994), the National Reproductive Health Program (PNSR) was launched aiming to provide sexual and reproductive health (SRH) services to adolescents, young people and adult men, in partnership with the education sector and youth centers. However, the continuance of unplanned pregnancies, illegal abortions and HIV infections has indicated that there are gaps in the program's implementation. Studies conducted in the country point to socio-cultural aspects as well as aspects covering organizations and the services on offer, as some of the reasons for the identified problems. This paper aims to reflect on the scope and limits of the PNSR in Cape Verde with consideration being given to the challenges of implementing health policies that affect cultural practices related to gender and sexuality. Consideration is also given to the specifics of Cape Verde's demographics, economic and cultural aspects as well as the importance of the SRH services to its development. PMID- 30427437 TI - [Factors associated with concentrations of hemoglobin in preschoolers]. AB - This study sought to identify the association between the concentration of hemoglobin and socio-environmental, maternal, biological-nutritional and health condition characteristics in preschool children; as well as the serum concentrations of zinc and retinol. It involved a cross-sectional study with 335 individuals, a representative sample of children enrolled in child day care centers in the city of Campina Grande, Paraiba. In the 294 children studied, the adjusted model showed lower concentrations of hemoglobin when the house was not made of bricks; there was no sewerage system; no public garbage collection; no treatment of drinking water; maternal difficulties for reading, writing and making calculations; age between 9 - 24 months; weight/age < - 2 score Z and health problems in the last 15 days, as well as in cases of lower serum concentrations of zinc and retinol. The multicausality of lower hemoglobin levels included socio-environmental conditions and child-maternal characteristics that reinforce the importance of measures that prioritize the younger children of mothers with lower education levels and prejudiced in weight, health and nutritional status of other important micronutrients for growth. PMID- 30427438 TI - [Aspects related to the use of antiretrovirals in high complexity patients in the state of Rio de Janeiro]. AB - Treatment of AIDS involves the use of the cocktail of drugs that make up the antiretroviral therapy. Its logistic control is monitored by a computerized national system of dispensation, the Logistic Control System of Medication (SICLOM). This study aimed to investigate, by means of SICLOM data, the use of antiretroviral therapy in patients treated at two University Hospitals in the state of Rio de Janeiro. A cross-sectional study was conducted with sociodemographic and dispensation data collected from SICLOM. The evaluation of drug ownership was done by calculating the Proportion of Days Covered (PDC). Five hundred and thirty-eight patients of both genders with active registration in SICLOM and over 18 years of age were included. The ART most used in both hospitals was lamivudine, considering the total of 58 different schemes identified. The mean of possession of groups was 88% (+/- 0,16). The factor associated with possession of drugs was the ART scheme, with PDC of 91% (p<0,001) for rescue schemes. This study confirmed that SICLOM was a reliable source to establish the profile of the population assisted. PMID- 30427439 TI - Association between socioeconomic factors, behavioral, general health and oral mucosa status in elderly. AB - This study aimed to investigate the association between socioeconomic and behavioral factors, general health, oral health, and plaque accumulation and oral mucosa condition outcomes in the elderly. This is a cross-sectional study conducted from 2004 to 2005 with 785 elderly dwellers of the city of Carlos Barbosa (RS), Brasil. We used questionnaires to collect socioeconomic, behavior and health status data. The physical examination of the oral structures comprised the Mucosal-Plaque Index proposed by Henriksen (MPS). A higher prevalence of moderate/severe plaque accumulation was observed in the elderly group, in less educated male elderly. The use of full upper dentures and income under one minimum wage were protective factors for moderate/severe plaque accumulation. Only the variables of the first block of the conceptual structure, male gender (OR = 2.13; 95% CI 1.26-3.61) and lower education (OR = 1.37; 95% CI 1.06-1.78) remained associated with an unacceptable MPS score. The findings suggest that, as per MPS, less educated male elderly are more likely to have poor oral health. PMID- 30427440 TI - Use of Facebook, perceived stress and alcohol consumption among university students. AB - Analysis of the effect between the use of Facebook, perceived stress and alcohol consumption among young people. A descriptive, correlative and cross-sectional study was carried out. The sample of 1110 young university students from Nuevo Leon, Mexico, was selected by probability sample. Personal Data and Prevalence of Alcohol Consumption Inventory, Alcohol Use Disorders Identification Test (AUDIT), Facebook Use Identification Test, Perceived Stress Scale were used. The Research Ethics Committee approved it. We observed 6.4% of young people have mentioned that the use of Facebook affected the alcohol consumption. Seeing adds with alcohol on Facebook was related to alcohol consumption (rs = 0,204, p < 0,05). At the time Facebook was used, it was related to the perceived stress (rs = 0,189, p < 0,05). Finally, it was observed that there is a significant impact between the hours and days of use of Facebook, the stress perceived by young people, the age and gender regarding the harmful alcohol consumption among university students (R2 = 30,9%, p = 0,003). Therefore, it is crucial and necessary to consider social networks an important variable to be included in future interventions regarding mental health. PMID- 30427441 TI - Application of the DPSEEA Model to Healthcare Waste Management. AB - The use of health indicators is indispensable for understanding the complex relationship between the environmental and health fields. For the proposition of environmental health indicators, the Brazilian Ministry of Health (MH) recommends using a model proposed by the World Health Organization. This model is composed of the following elements: Driving Force, Pressure, State, Exposure, Effect, and Action; it is called the DPSEEA model. The objective of this study is to propose the application of this model in healthcare waste (HCW) management. This study was performed by documentary research using two data sources: a) technical reports on research on HCW from the last 15 years (outpatient, dental, hospital, veterinary, university, and primary care unit) at the University of Caxias do Sul, Brazil; and b) the MH manual entitled "Environmental Health: Basic Guide for the Construction of Indicators". The results show that the model is relevant because it makes it possible to analyse a particular context, proposing indicators and defining specific actions for the case of this study, to monitor and improve methods of managing HCW. The results also show that the proposed model is an important analytical tool for both medical waste management and planning actions that will minimize risks, particularly chemical and biological, resulting in environmental health and protection. PMID- 30427442 TI - Relationship between the perception of dental care and Oral Health conditions in hypertensive and diabetic patients. AB - The aim of this study was to evaluate the relationship between the perception of dental care services and oral health conditions in a hypertensive and diabetic population subscribed to the Family Health Strategy in the city of Alfenas, Minas Gerais, Brazil. This was a domiciliary, descriptive-analytical study with random and stratified sample, consisting of 186 individuals. The following indexes were applied: Decayed, Missing and Filled Teeth (DMFT); Filled and Sound Teeth (FS-T); Dental Care Index (DCI); Evaluation of the use and need of dentures; Oral health for primary care assessment questionnaire (OHPCA). A predominance of women (67.74%), hypertensive non-diabetic people (58.60%) and elderly people (52.69%), with an average age of 64.26 (+/- 12.22) years, was observed. We noticed a total DMFT of 27.00 (+/- 6.24); FS-T = 8.94 (+/- 10.28); DCI = 19.42 (+/- 26.80); 39.78% of partial dentures usage, 56.45% of total prosthesis usage with necessity of 36.02% of partial dentures and 28.49% of total prosthesis. In the OHPCA questionnaire, positive assessments of services were prevalent. Oral Health proved to be best among those individuals who reported good relationship with their dentists and worse among those individuals who considered as good the equipment used in the services. The critical aspects were: access, speed and professional-patient communication. PMID- 30427443 TI - [A protocol for evaluating the probability of the recreational use of rivers and its application in risk analysis]. AB - Contaminated waters constitute health risks not only due to direct consumption, but also in recreational use. Risk analysis strategies aim to reduce the instances of contaminations and must include the population's perceptions and willingness to assume risks. A rapid and simple method was developed to evaluate the probability of use of recreational waters. Interviews were conducted in municipalities with different ecological conditions, in order to define the factors used by people to decide to use, or otherwise, river waters. After analyzing the results, the "Indice de Probabilidade de Uso Recreativo de Aguas (I PURA)" was elaborated and tested. The index was then employed at 26 river locations representing five of the nine hydrographic regions of Rio de Janeiro state. The frequency of use, water contamination and a Habitat Assessment Visual Index (IAH) was also measured. The I-PURA was correlated with the frequency of use. Furthermore, the I-PURA was not correlated with IAH, showing that user perceptions are different from purely ecological aspects. This tool offers useful information for risk assessment and environmental management. Sites with a high probability of use, or observed use, that are highly contaminated should be prioritized for interventions. PMID- 30427444 TI - Homelessness and incarceration among psychiatric patients in Brazil. AB - Psychiatric patients are at increased risk of adverse life events, such as being incarcerated and homelessness in their life course. Using data from a cross sectional multicenter study of 2,475 patients selected from 26 mental health services in Brazil, we examined the association of sociodemographic, clinical, behavioral, and adverse life characteristics with history of homelessness, incarceration or their co-occurrence during lifetime. Odds ratios were obtained by multinomial logistic regression models. The prevalence of homelessness, incarceration and co-occurrence of these two conditions were 8.6%, 16.4%, and 9.4%, respectively. Lower income, living in unstable condition, intellectual disability, and cigarette smoking were associated with homelessness. Being male, lower schooling, sex under effect of alcohol or drugs, and multiple sex partners were associated with incarceration. Psychiatric hospitalizations, substance use, and history of sexually transmitted diseases, and sexual, physical, or verbal violence were associated with co-occurrence of both conditions. Our findings suggest that incarceration and homelessness are very prevalent and correlated in psychiatric patients in Brazil. Many of the associated factors are potentially modifiable, and may act synergistically requiring integrated care. PMID- 30427445 TI - [Medicinal plants and herbal medicines in Primary Health Care: the perception of the professionals]. AB - The Ministry of Health through the National Policy on Integrative and Complementary Practices (PNPIC) encourages the offer of Acupuncture, Homeopathy, Herbal Medicine, Hydrotherapy and Anthroposophical Medicine in the Unified Health System (SUS). This study evaluated the profile for the prescription/suggestion and credibility of herbal medicine usage as complementary therapy among the 157 professionals from the 66 Family Health Strategy (FHS) teams in Blumenau city. Data collection was conducted between the years of 2014 and 2015 through a semi structured questionnaire applied to a sample comprised of 42 (26.8%) physicians, 40 (25.5%) nurses, 66 (42%) nursing technicians, 5 (3.2%) dentists and 4 (2.5%) oral health technicians. Bivariate associations were assessed using the Chi Square test or Fisher's exact test for variables. Despite 65.6% of respondents being aware of the existence of the PNPIC, the presence of herbal medicines on the National List of Medicines was unknown by 85.4%. The majority (96.2%) of the professionals believe in the therapeutic effects of medicinal plants but do not prescribe this medicine. However, 98.7% agreed with the initiative to offer this complementary and integrative practice through SUS after training in the area. PMID- 30427446 TI - Prevalence and factors associated with cognitive impairments in the elderly of charity asylums: a descriptive study. AB - The current transversal and descriptive study evaluates the prevalence and factors associated with cognitive liabilities in a sample of 98 elderly people residents of philanthropic institutions. The sociodemographic and clinical data were retrieved from the patients' clinical charts. The cognition was assessed by the Mental State Mini-Exam, while the maintenance of independence regarding basic activities (such as bathing, putting on clothes, and others) was evaluated using the Katz Index. The Short Physical Performance Battery exam assessed their physical performance. Non-parametric tests were employed for the statistical analysis. Cognitive impairment was registered in 27.6% of the elderlies and was not associated with sociodemographic variables, independence in basic activities, and physical performance. We verified a high prevalence of endocrine diseases, mental disorders, and psychiatric treatment in the elderlies with cognitive impairments. The percentage of elderly with cognitive alterations is similar to those found in the literature. We identified no significant risk factors associated with cognition among the evaluated variables. PMID- 30427447 TI - Risk and protective factors for suicide attempt in emerging adulthood. AB - The aim of this study was to investigate the risk and protective factors for suicide attempt in emerging adulthood. 189 individuals (18 to 30 years old) participated in the study: 63 had already attempted suicide, 63 had a history of suicidal ideation, and 63 have never had suicidal ideation. They all completed an online research protocol about suicidal attempt and ideation, anxiety, self esteem, self-efficacy, developmental stressors; social expression, and friendship. Those participants with no history of suicidal attempt showed higher scores of self-efficacy (M = 35.35, SD = 6.44), self-esteem (M = 41.33, SD = 7.02), and family relationships (M = 59.63, SD = 10.01). The suicidal ideation group showed higher scores of social anxiety (M = 26.03, SD = 10.25). Protective factors were essential to prevent the risk of suicide and help in solving problems in emerging adulthood. PMID- 30427448 TI - Collective portfolio: assessment of teaching and learning in health undergraduate courses. AB - The potential of the reflective collective portfolio as a method of teaching, learning and assessment needs to be emphasized. The objectives is to assess and validate the quality of the collective portfolio as a method of teaching, learning and assessment in the training of health professional. Portfolio quality was analyzed using an inventory of analysis that was adapted and tested for this study. In total, 70 portfolios were analyzed. The Kappa test was used to analyze reproducibility, confirming the level of agreement between the appraisers. Descriptive analysis and the t-test were performed to compare results from the years the portfolios were produced. The constructs (layout and organization, comprehensive, reflective, critical and creative thought) exhibited Cronbach alpha values above 0.7, confirming the high reliability of the tool. The weighted Kappa test revealed an elevated and significant agreement (+90%) between the appraisers. Notably, certain items and constructs exhibited significant differences over the years. All of the constructs were assessed better from 2011 onwards, when the assessment and self-assessment tool was implemented. The success of the portfolio depends on strategies that provide students with greater clarity and forms of developing the method. PMID- 30427449 TI - Comparative study between formal and informal caregivers of older adults. AB - OBJECTIVE: This study was aimed to compare the health conditions and burden of formal and informal caregivers of older adults. Cross-sectional and comparative study with a quantitative approach. The data were collected in 2014 in Sao Carlos/SP, using the Zarit Burden Interview and the SRQ 20 (Self Reported Questionnaire). RESULTS: The sample included 15 formal and 35 informal caregivers. Among the formal caregivers, women were predominant (86.7%), with a mean age of 36.7, mean of 13.7 years of education, mean workload of 7.5 hours per day, 26.7% were diagnosed with emotional distress and they the majority mentioned feeling "a little overloaded" (40%). Concerning the informal caregivers, women were predominant (85.7%), 42.9% were the children of the older adult, with a mean age of 55.2 years, mean of 7.1 years of education, length of time as caregiver of 6.5 years, mean of 19.8 hours per day taking care of the older adult, 17 (48.6%) presented mild overload and 16 (45.7%) presented emotional distress. CONCLUSIONS: The results revealed important differences and attention is needed to planning interventions to improve health and work conditions of these people. PMID- 30427450 TI - Brazilian Mental Health Services Assessment: user satisfaction and associated factors. AB - Patient satisfaction is an important criterion for assessing the quality of Brazilian mental health services at Psychosocial Care Centers (CAPS - from the Portuguese 'Centro de Atencao Psicossocial'). The aim of this study was to evaluate the satisfaction of users at the main CAPS in a region of Minas Gerais state, Brazil, as well as associated factors. This was a cross-sectional study with 11 CAPS. Patients were interviewed using the Patient Satisfaction with Mental Health Services Scale (SATIS-BR) and a semi-structured questionnaire containing sociodemographic and clinical variables. The users were satisfied with the CAPS, particularly in terms of staff competence and the welcome received and care provided. The physical facilities and comfort at the centers obtained the lowest satisfaction scores on the scale. Almost half of the users were unfamiliar with basic aspects of their drug therapy, such as the name of medicines, and one third reported inappropriate use of medications. Users of midsize CAPS and those providing treatment for alcohol and drug addiction were more satisfied than patients at mental health or 24-hour CAPS. Although this study identified a need for improvement in physical facilities, mechanisms of participation and patient empowerment, the users were satisfied with the CAPS care model. PMID- 30427451 TI - The association between muscle strength and sociodemographic and lifestyle factors in adults and the younger segment of the older population in a city in the south of Brazil. AB - Adequate muscular strength is required to perform daily activitiesand is considered a marker of overall health. The aim of this study was to identify sociodemographic and lifestyle factors associated with handgrip strength (HGS) in adults and the younger segment of the older population. A cross sectional,population-based study was conducted with 705 individuals aged between 25 and 65 years in the city of Florianopolis, capital of the State of Santa Catarina, Brazil.HGS was assessed usinga manual hand dynamometer. Interviews were conducted with the participants to collect sociodemographic and lifestyle data.Multiple linear regressionwas performed to identify the predictors of HGS. The findings revealed that women and individuals from older age groups showed lower HGS, while being active during leisure time was associated with higher HGS.Interventions aimed at maintaining HGS levels in individuals should pay special consideration toaging and individuals who are physically inactive or insufficiently active during leisure time. PMID- 30427452 TI - Trends and multiple causes of death due to chronic renal failure in a municipality in the Brazilian Amazon. AB - This study examined the mortality trend due to chronic renal failure (CRF) and verified the underlying and associated causes for this trend in the capital of the state of Acre in the Brazilian Amazon. This ecological study used data provided by DATASUS related to mortality due to CRF, which occurred between 1986 and 2012 for male and female residents of the city of Rio Branco, Acre, Brazil. The estimated annual percentage chance (EAPC) was calculated by using Poisson log linear regression and utilizing the Joinpoint program. The results showed that the adjusted mortality rates due to CRF, with correction, ranged from 15.4 per 100,000 inhabitants in 1986 to 4.0 per 100,000 inhabitants in 2012. The EAPC was 3.5% from 1986- 2012. Deaths by CRF presented associated causes such as respiratory diseases, pneumonia and pulmonary edema, septicemias and poorly defined signs and symptoms. When CRF was analyzed as an associated cause of death, the main primary causes of death were hypertensive diseases and diabetes. Thus, there was a decrease in mortality due to CRF as an underlying cause during the period studied; however, preventive and heath care measures should be maintained. PMID- 30427453 TI - Prevalence of concomitant hypertension and diabetes in Brazilian older adults: individual and contextual inequalities. AB - The simultaneous occurrence of specific diseases in older adults is explored little in the literature. The aim of this study was to estimate the prevalence of concomitant hypertension and diabetes in Brazilian older adults and determine associated contextual and individual factors. A population-based cross-sectional study was conducted with 10,991 older adults (>= 60 years of age) interviewed during the 2012 Vigitel Survey. Statistical analysis involved multi-level Poisson regression. Mean age was 69.4. The prevalence of the concomitant occurrence of hypertension and diabetes was 16.2%, with differences found among the capital cities. Higher prevalence rates were found in cities located in the southern, southeastern and central-western regions of the country as well as among black and brown older adults, those with up to eight years of schooling, non-smokers, ex-smokers and those with excess weight. The effect of geographic region was demonstrated by the 23.5% increase in the prevalence of the concomitant diseases after adjusting for individual variables. The present findings enabled gauging the effect of context (region of residence) on the prevalence of the main diseases related to an increased mortality rate in the older population. PMID- 30427454 TI - [Reproducibility of a questionnaire on physical activity among school students from 9 to 15 years of age]. AB - The objective of this study was to analyze the "test-retest" reproducibility of a questionnaire on physical activity among 1189 school students of both genders, from 9 to 15 years age in public schools in Curitiba/PR. The reproducibility of the questionnaire was determined by the repeated measures procedure called "test retest", with an interval of one week between applications. For data analysis the Intraclass Correlation Coefficient (ICC), the percentage of correlation, the Kappa index, adjusted Kappa (Kappa PABAK) and Bland-Altman scatter diagram were used. Statistical analyses were performed using SPSS 21.0 adopting a 5% significance level. All ICC were higher than 0.80. The correlation between the application replicas of the questionnaire was moderate, Kappa ranging from 0.51 to 0.61. There was a correlation between the questionnaire applications, the average difference between the first and second being equal to 106.49 min/wk (IC95%: 79.05-133.92) with limits of correlation ranging from 1070.97 (+2SD) to 857.99 (-2SD) min/week. In conclusion, the survey analyzed in this study showed satisfactory levels of reproducibility, having the possibility of being used to measure physical activity in both children and adolescents. PMID- 30427455 TI - External control of fluoridation in public water supply systems in the state of Goias, Brazil. AB - The addition of fluoride to the public water supply is a method used for reducing tooth decay. In this sense, the control of fluoridation is important for maintaining its efficiency and, at the same time, for avoiding the risk of fluorosis as a result of the consumption of water with excess of fluoride. The objective of this study was to evaluate the adequacy of fluoride levels in the water distributed to populations of the state of Goias, Brazil. Towards this aim, 5,039 water samples collected between 2011 and 2013 in 225 municipalities of the state of Goias were analyzed for fluoride level. The results were assessed with regard to season, type of water source and geographic location. Fluoride levels were found to vary between complete absence and 2.5 mg F/L, with 28.2% of the samples being between 0.6 and 0.8 mg F/L, and 39.1% between 0.55 and 0.84 mg F/L. The rainy season produced a greater number of atypical results and higher values than the dry period. The systems supplied by groundwater sources were shown to have a limited control of fluoride concentration compared to systems supplied by surface water sources. Lower concentrations of fluoride were found in samples collected in the North and East Mesoregions of Goias, with less than 7.5% being between 0.6 and 0.8 mg F/L, which systems are mainly supplied by groundwater sources with fluoride addition . PMID- 30427456 TI - Epidemiological pattern of malocclusion in Brazilian preschoolers. AB - This study aimed to evaluate the prevalence and distribution profile of malocclusion in Brazilian preschoolers and its association with macro-region, housing, gender, and self-reported race. In total, 6,855 children aged five years participating in the National Oral Health Survey (called SB Brasil 2010) were analyzed. Malocclusion was diagnosed according to the Foster and Hamilton index. We conducted descriptive, bivariate and multiple regression analyses (PR/CI95%). We identified that 63.2% of children had at least one of the occlusal problems evaluated: canines' key (22.9%), overjet (32.9%), overbite (34.6%), and posterior crossbite (18.7%) and, thus, were considered with malocclusion. Higher probability of the presence of malocclusion was identified among the residents of the Midwest (1.08/95%CI 1.01-1.15), Northeast (1.21/95%CI 1.14-1.28), Southeast (1.27/95%CI 1.20-1.34) and South (1.34/95%CI 1.26-1.42) regions when compared to residents in the North. It was also higher among female children (1.06/95% CI 1.02-1.09). No associations were identified concerning race and location of the municipality (capital/no capital). A high prevalence of malocclusion was identified in Brazilian preschoolers, and it was associated with gender and the macro-region. These findings may contribute to expanded public policies and greater access to treatment for this population. PMID- 30427457 TI - [Occupational stress and associated factors among civil servants of a federal university in the south of Brazil]. AB - The aim of the study was to verify the prevalence of stress and associated factors in technical-administrative employees of a federal university of the south of Brazil. The sample was comprised of 371 civil servants. Sociodemographic, behavioral and occupational variables were collected. The occupational stress was measured by the Job Stress Scale (JSS). Data analysis was performed using descriptive and inferential statistics, through bivariate and multivariate analysis. Most subjects were female (57.4%) and the average age and education of the sample were, respectively, 45.1 years and 18 years of study. The workplace infrastructure was classified as inadequate by 42% of subjects. Of the civil servants, 22.7% were classified as being in high stress positions and 28% in passive work routines. In the adjusted analysis, occupational stress was associated with a lower level of education, poor workplace infrastructure and less social support. Individuals with adequate structure had odds of 2.79 and 2.30, respectively, of being in low stress and passive job positions. These aspects should be the focus of interventions by university managers to reduce the level of stress and risk of illness. PMID- 30427458 TI - [The association between normative and subjective oral health conditions and dissatisfaction with dental services among adult Brazilians]. AB - The prevalence of dissatisfaction with dental services and its association with normative and subjective oral health conditions among adult Brazilians was evaluated. This cross-sectional study used data from the last Brazilian National Oral Health Survey (SBBrasil), conducted in 2010. It was considered a representative sample of the adult Brazilian population. Data were analyzed by descriptive, univariate and multiple statistics (OR / 95% CI), with correction by the design effect. Among the 4539 adults included in the study, 614 (13.4%) reported dissatisfaction with dental services. Dissatisfaction was higher among adults who had any decayed teeth (1.61 / 1.06; 2.44), adults who were dissatisfied with their teeth and mouth (2.36 / 1.39; 4.02) and adults who had reported toothache in the previous six months (1.99 / 1.29, 3.07). The conclusion drawn was that the prevalence of dissatisfaction with dental services among Brazilian adults was low and associated to normative and subjective oral health conditions. PMID- 30427459 TI - [Phosphorus delivered to surface waters resulting from the use of powder detergents: environmental and public health aspects]. AB - This article addresses the social and environmental aspects related to the presence of phosphorus in surface water bodies, assessing the impacts caused by the utilization of powder detergents on the quality and availability of water resources, with particular respect to the occurrence of eutrophication. Based on data concerning the composition and consumption of the products currently sold in Brazil, the evolution of this phenomenon leading to the current situation is reported. Indications are that Brazilian detergents have a low phosphorus content, thus it is possible to infer that these products offer a small risk of impacting the trophic levels of surface waters. There is, however, a need to adjust the content of legislation to market practices, as well as improve public policies related to environmental education. By means of an intensive process of communication and education, awareness about the issue can be raised, keeping this major source of phosphorus in the environment under control and contributing to the increase in the availability of water, through the prevention of eutrophication processes. PMID- 30427460 TI - Pesticide exposure among students and their families in Nova Friburgo, Rio de Janeiro. AB - Farming is a risky occupation, especially family farming in developing country. The occupational hazards commonly used in such activity could affect all family members, including children and adolescents. This study describes the pattern of pesticide exposure among students and their families from a farming region located in Nova Friburgo, State of Rio de Janeiro, Brazil. Sociodemographic characteristics, habits, working practices and the degree of exposure to pesticides were assessed by a questionnaire. Our study population consisted of students and family members of both sexes, aged between 6 and 85 years old (N = 352) being 167 women and 185 men. There was a predominance of participants between 10-19 years (71.3%), singles (77.5%), and most had not completed primary education (54.5%). In terms of occupation, 45.5% reported to be farmers and 39.6% were students. The variables mostly associated with pesticide exposure were sex (p < 0.001), educational level (p < 0.001), and being a farmer (p < 0.001). Our results showed that children and teenagers seemed to have the same degree of exposure to pesticides as the adults. Our findings also suggest that sex, occupation and educational level, despite teachers were included, are directly associated with degree of exposure. PMID- 30427462 TI - Comparative study of quality of life of elderly nursing home residents and those attneding a day Center. AB - The aim of this study was to compare the QOL of the elderly living in nursing homes and those who attend the Day Center (Centro Dia) at the the Asilo Vila Vicentina in the city of Bauru/SP. The sample consisted of 48 subjects, 21 men, 5 from the Day Center and 16 nursing home residents, and 27 women, 16 from the Day Center and 11 nursing homes residents, who answered the following questionnaires: socio-demographic characteristics, WHOQOL-Old, and WHOQOL-Bref. The responses were submitted to descriptive and inferential statistics to compare the QOL scores of the nursing home residents with the elderly who attend the Day Center using the Mann Whitney test. The results showed better QOL scores for the elderly who attend the Day Center, in which women stood out. Among the institutionalized elderly, women presented the worst QOL values, particularly in the Physical and Psychological domains. The domains with the lowest scores were Environment (42.6 +/- 10.7 for women in nursing homes and 44.4 +/- 9.7 for men at the Day Center) and Intimacy (13.1 +/- 17.3 for women in nursing homes and 9.4 +/- 22.7 for men in nursing homes). The domains with the highest scores were Social Affairs (74.0 +/- 13.6 for women at the Day Center and 68.3 +/- 10.9 for men at the Day Center) and Death/Dying (83.6 +/- 22.0 for women at the Day Center and 80.0 +/- 32.6 for men at the Day Center). PMID- 30427461 TI - Reported diabetes mellitus: incidence and determinants in cohort of community dwelling elderly people in Sao Paulo City, Brazil: SABE study, health, wellness and aging. AB - To verify the association between the incidence of DM and predictors, in a cohort of elderly people. Elderly people (>= 60 y) were analyzed, of both genders, participants of the SABE Survey, carried out in the city of Sao Paulo, Brazil, in 2000 (n = 2,143) and 2006 (n = 1,115). The study variables were: DM; demographic (gender, age group, education level, companionship in the residence), nutritional status (risk for obesity, body obesity, and high abdominal fat), clinical (number of reported diseases), and lifestyle (alcohol consumption, smoking, intake of meat and fruit and vegetables). Multiple logistic regression (p < 0.05) was used to verify the association between variables of this study, with the statistical software Stata/SE 10.1. In 2006, 914 subjects, survivors of 2000, were analyzed and 72 were identified as new cases of DM (7.7/1.000 person-years). It was found that body obesity (OR = 1.67, CI = 1.00 to 2.81) and high abdominal fat (OR = 2.32, CI = 1.47 to 3.67) were predictors of the incidence of DM in the elderly (p < 0.000). It was concluded that body obesity and abdominal fat are the variables which contribute to the development of DM in the elderly. PMID- 30427463 TI - [Analysis of the digital preference for age in the pharmacovigilance system in Brazil, 2008-2013]. AB - The scope of this article is to analyze the digital preference for the "age" variable in the database of cases of adverse drug events reported between 2008 and 2013 in the pharmacovigilance system in Brazil. The database was analyzed in three stages: 1) Initial exploration; 2) standardization of variables; and 3) duplicate records management. The digital preference for the "age" variable according to sex and grouped regions of the country, was determined using the Whipple and Myers methods and also measured by the adhesion test based on statistical chi2 at 5% significance level. The female population was predominant (60.3%), with a female/male ratio of 1.5:1 and a female majority in 8 of the 12 age groups. Throughout the period under analysis, no preference for a terminal digit was observed in the "age" variable. The ages that were registered in the database appear not to reveal any imprecision and, therefore, this information cannot be interpreted as unreliable. These results point to a good performance in collecting data and information related to the "age" variable of the Brazil's pharmacovigilance system. PMID- 30427464 TI - Psychometric Validation of the Short Form of the Smoking Consequences Questionnaire (S-SCQ) for Brazil. AB - Smoking accounts for 24% of deaths in the general population and is also the factor that explains the biggest amount of years of life lost. It is important to understand the expectations regarding smoking behavior. The present study aimed to validate the Short Form of the Smoking Consequences Questionnaire (S-SCQ) for a Brazilian version. The Researchers did the process of semantic adaptation to language and national context. The S-SCQ was applied in a sample of 129 people. The next step was to perform psychometric analyses for the set of 21 items. Exploratory Factor Analysis, with pairwise treatment for missing cases, was used to achieve construct validity. To carry out Factor Analysis, the method of Principal Component Analysis (PCA) was used initially. Afterwards, Principal Axis Factoring (PAF) using Varimax rotation with Kaiser normalization was applied. The reliability of the total scale (21 items) showed a Cronbach alpha index of 0.851 and a 0.870 Lambda2 of Gutmann. Quite satisfactory rates were also observed in the subscales. Similarly, the item-overall correlation values also confirmed the scale's good reliability indices. PMID- 30427466 TI - Brazilian social protection and demands of children and adolescent cancer treatment. AB - This article discusses the issue of social protection against the demands presented in the treatment of children and adolescents in Brazil. It aims to problematize the advances and limits of the Brazilian social protection system in face of the social demands arising from the treatment of children and adolescents that go beyond the specific limits of health care. It is a qualitative study that was structured based on the analysis of official documents, Laws, Decrees, Ordinances and Policies and the literature destined to children and adolescents in cancer treatment whose incapacitating consequences produce social demands that impact, above all, family life. The paper presents social policies as a fundamental resource for treatment, considering the demand for income and displacement, in order to enable an effective health care. However, the reflections indicate that there is now a retraction of social policies by the State that was expressed in the focus and transfer of responsibilities of the State to other sectors of civil society. PMID- 30427465 TI - Concerns about dental aesthetics are associated with oral health related quality of life in Southern Brazilian adults. AB - It aims to evaluate the association between dental appearance and Oral Health Related Quality of Life. Fifteen primary care services with dental services were selected in Porto Alegre, Brazil. Individuals were interviewed from a random sampling of households in the catchment area of the health centres. The outcome was having an OHIP14 score > 0 (any impact). The main exposures included self reported tooth colour and position, perception of oral health and concern with dental aesthetics. Data were analysed with stepwise logistic regression. Of 1943 individuals contacted, 433 used public dental services in the last year. Seventy three percent had some impact on quality of life, 35.2% and 47.5% reported stained and crowded teeth, respectively. Also, 22.2% had already tried bleaching their teeth. Individuals concerned with colour were 2.56 times (95% CI: 1.34 4.89) more likely to report any impact after adjusting for number of teeth, smoking and education. Concerns about tooth position, reporting stained or crowded teeth, age, sex and income were not significant (p > 0.30). There is a direct and independent association between concerns with tooth colour and quality of life. The effect of tooth colour on quality of life may be mediated by individuals' perceptions of aesthetics. PMID- 30427467 TI - Risk factors for the ill-defined causes of death in the Brazilian states: a multilevel analysis. AB - This study describes the spatial-temporal changes of the proportion of ill defined causes of death in Brazil (1998-2012) and investigates which demographic and socioeconomic factors affect this proportion. We collected information of the proportion of ill-defined causes of death by age (15-59 years), sex, period, locality, and socioeconomic data. We used a multilevel Poisson model to investigate which factors affect the risk of ill-defined causes of death. Unlike states located in the South and Midwest, we detected clusters with high proportional levels of these deaths in states in the North and Northeast regions. A greater proportion occurred in 1998-2002 (0.09), in the North and Northeast (0.14 and 0.12, respectively), in older age groups (0.09), and in places with poor socioeconomic conditions. The adjusted analysis showed differences in proportion according to the region, age, period, schooling, social inequality, and income. The results indicate that the lower the age group and the better the socioeconomic situation, the lower the risk to register the cause of death as ill defined. Although over the past years, the quality of Brazil's mortality data has gradually increased, investments towards improving mortality registries cannot be discontinued. PMID- 30427468 TI - [The risk of death by suicide in the Colombian population 2000-2013]. AB - The scope of this article is to analyze the risk of death by suicide in Colombia based on the covariables of sex, age group, year, region and/or department from 2000 to 2013. The databases of deaths by suicide and population projections of DANE were used. A longitudinal and analytical study was conducted. From 2000 to 2013, annual trends of deaths by suicide by means of modeling of covariables were established and risk estimates were collected. The Poisson regression model (PRM) was used. IRR was used according to the MRP with a level of significance of (P <0.05). Colombians between the years 2000-2013, male, 15 to 34 years old, from the Central and Eastern regions and from the Departments of Vaupes, Huila and Quindio were those with the highest risk of death by suicide. The suicide rate decreased slightly as the years went by. The highest risk of suicide occurred among men of productive age, older adults, and in underdeveloped regions. Colombia requires a mental health policy that implements strategies for primary care, health promotion and disease prevention, aimed at promoting the quality of life, detection of suicidal ideation, treatment and rehabilitation of these people from a comprehensive rights and care approach. PMID- 30427469 TI - Use of triggers tools to search for adverse drug reactions in the elderly admitted to emergency departments. AB - Adverse drug reactions (ADRs) can cause illness, disability or death, especially in the elderly. An active search for suspected ADRs was carried out using triggers, which motivated the search of elderly people under care in adult emergency departments (ED). It was a cross-sectional and retrospective study that used an adaptation of the Institute of Health Care Improvement triggers. A total of 287 medical records were analyzed and 38 triggers were found, identifying 7 suspected ADRs. One was found without the use of triggers. Thus, in total, 8 ADRs (2.79%) were found, of which 6 were considered serious. There was a higher prevalence of ADRs in females (62.5%) and in those over 80 years of age (50%). The medications most implicated were those for alimentary tract and metabolism and cardiovascular system. Of the triggers tested, some are essential for use at EDs, such as those that indicate problems with anticoagulants, hypoglycemic agents and antihypertensives. Triggers have proved useful for an active search for suspected ADRs at EDs, including severe ones, identifying problems occurring outside hospital settings and signaling medications that pose an increased risk to the elderly . PMID- 30427471 TI - ? AB - [This corrects the article doi: 10.1590/1413-81232018237.07182016]. PMID- 30427470 TI - [Factors associated with the self-rated health of elderly frequenters of low budget community restaurants in Belo Horizonte]. AB - The scope of this paper was to evaluate the self-rated health among elderly frequenters of low-budget community restaurants (RP) in Belo Horizonte (BH) and the factors associated with this outcome. It involved a cross-sectional study in all RP and BH cafeteria. The self-rated health was classified as bad and very bad; average; good and very good. Sociodemographic and economic variables were considered to be possible associated factors, as well as those related to physical health and social resources. In the univariate analysis, the Chi-square test and Mann-Whitney tests were used. In the multivariate analysis a model of ordinal logistic regression was created. The sample consisted of 279 elderly people, the majority (68.5%) being male. Most of the elderly (57.5%) considered their health as being good or very good. Factors associated with better health perception in the multivariate analysis (p-value < 0.05) were satisfaction with relationships with friends, not having diabetes or any other cardiovascular disease and finally, the low frequency and lack of problems that hinder the elderly from doing the things they need or want to do. Such studies contribute to the understanding of the health perception of elderly people associated with several factors that can influence healthy aging. PMID- 30427472 TI - Surface morphology and mechanical properties of conventional and self-adhesive resin cements after aqueous aging. AB - : The stable long-term performance of resin cement under oral environmental conditions is a crucial factor to obtain a satisfactory success of the allceramic dental restoration. OBJECTIVE: This study aimed at evaluating and comparing the surface morphology and mechanical property of conventional and self-adhesive resin cement after aqueous aging. MATERIALS AND METHODS: Disc-shaped specimens of 3 conventional (C1: Multilink N, C2: Duolink, C3: Nexus 3) and 3 self-adhesive (S1: Multilink Speed, S2: Biscem, S3: Maxcem) types of resin cements were subjected to irradiation. After 24 h, the Knoop microhardness of each resin cement was evaluated. The specimens were immersed separately in distilled water and maintained at 37 degrees C. A total of 5 specimens of each resin cement were collected at the following time intervals of immersion: 1, 6, 12 and 18 months. The samples were used to evaluate the Knoop parameters of microhardness, sorption and solubility. The surface morphology of the specimens after 18 months of immersion was observed by scanning electron microscopy. The sorption and solubility data were analyzed by two-way ANOVA. The Knoop microhardness was tested by the ANOVA repeated measures (P<0.05). RESULTS: The sorption and solubility parameters of C1 and S1 exhibited significant fluctuations during the aqueous aging. The hardness of the S1 and S2 specimens decreased significantly after an 18-month water immersion. The S1, S2 and S3 specimens indicated higher filler exposure and stripping and apparent pores and cracks compared to specimens C1, C2 and C3, respectively. CONCLUSION: The surface of selfadhesive resin cements is more susceptible to aqueous damage than that of the conventional resin cements. PMID- 30427473 TI - Stanozolol promotes osteogenic gene expression and apposition of bone mineral in vitro. AB - : Stanozolol (ST) is a synthetic androgen with high anabolic potential. Although it is known that androgens play a positive role in bone metabolism, ST action on bone cells has not been sufficiently tested to support its clinical use for bone augmentation procedures. OBJECTIVE: This study aimed to assess the effects of ST on osteogenic activity and gene expression in SaOS-2 cells. MATERIAL AND METHODS: SaOS-2 deposition of mineralizing matrix in response to increasing doses of ST (0 1000 nM) was evaluated through Alizarin Red S and Calcein Green staining techniques at 6, 12 and 24 days. Gene expression of runt-related transcription factor 2 (RUNX2), vitamin D receptor (VDR), osteopontin (SPP1) and osteonectin (ON) was analyzed by RT-PCR. RESULTS: ST significantly influenced SaOS-2 osteogenic activity: stainings showed the presence of rounded calcified nodules, which increased both in number and in size over time and depending on ST dose. RT PCR highlighted ST modulation of genes related to osteogenic differentiation. CONCLUSIONS: This study provided encouraging results, showing ST promoted the osteogenic commitment of SaOS-2 cells. Further studies are required to validate these data in primary osteoblasts and to investigate ST molecular pathway of action. PMID- 30427475 TI - Effects of cyclosporin, nifedipine and phenytoin on gingival myofibroblast transdifferentiation in monkeys. AB - OBJECTIVE: Myofibroblasts have been associated with the development of several pathologic fibrotic conditions. This longitudinal study aims to assess the proliferative and antiapoptotic effects of cyclosporin, nifedipine and phenytoin on gingival connective tissue cells of nonhuman primate, as well as to analyze a possible role of myofibroblasts in gingival overgrowth. MATERIALS AND METHODS: Gingival samples from the right superior canine area were obtained from 12 male monkeys ( Sapajus spp ) to comprise the control group. After one week, the animals were randomly assigned to three groups, which received daily oral doses of cyclosporin, nifedipine or phenytoin for 120 days. Gingival samples were collected from the left superior canine area of two animals of each group at 52 and 120 days. Histological sections were stained with hematoxylin and eosin, and immunoreacted against alpha-SMA, Ki- 67 and bcl-2. RESULTS: alpha-SMA immunoreaction was negative in the control and experimental groups. Similarly, no difference between groups concerning immunostaining against Ki-67 and bcl-2 was observed in connective tissue cells. CONCLUSION: Based on this methodology, it may be concluded that gingival overgrowths induced by cyclosporin, nifedipine and phenytoin are not associated with neither myofibroblast transdifferentiation, proliferation nor apoptosis of gingival connective cells in monkeys. PMID- 30427476 TI - The link between ankylosing spondylitis and oral health conditions: two nested case-control studies using data of the UK Biobank. AB - : Ankylosing Spondylitis (AS) is an inflammatory rheumatic disease that affects the axial skeleton and the sacroiliac joints. Recent studies investigated the link between AS and oral diseases, particularly periodontitis. Others suggested that periodontitis may have a role in the pathogenesis of rheumatic diseases. OBJECTIVE: The aim of this study is to investigate the association between AS and oral conditions. MATERIAL AND METHODS: This research was conducted using the UK Biobank Resource under Application Number 26307. The UK Biobank recruited around 500000 participants throughout Great Britain. Clinical records were available for 2734 participants. Two case-control studies were conducted based on whether AS was self-reported or clinically diagnosed. Oral conditions were identified using self-reported reports of oral ulcers, painful gums, bleeding gums, loose teeth, toothache, and dentures. The association between AS and oral conditions was assessed using logistic regression adjusted for age, gender, educational level, smoking status, alcohol consumption, and body mass index. RESULTS: A total of 1307 cases and 491503 control participants were eligible for the self-reported AS study. The mean age was 58 years for the cases [7.5 standard deviation (SD)] and 57 years for the control groups (8.1 SD). Also, 37.1% of the cases and 54.2% of the control participants were females. Among the oral conditions, only oral ulcers were strongly associated with AS [1.57 adjusted odds ratio (OR); 95% confidence interval (CI) 1.31 to 1.88]. For the study of clinically diagnosed AS, 153 cases and 490351 control participants were identified. The mean age for both cases and control groups was 57 years; 7.6 SD for the cases and 8.1 for the control group. Females corresponded to 26.1% of the cases, and 54.2% of the control participants. Clinically diagnosed AS was associated with self-reported oral ulcers (2.17 adjusted OR; 95% CI 1.33 to 3.53). CONCLUSION: Self-reported and clinically diagnosed AS populations have increased risk of reporting oral ulcers. Further investigations are required to assess the link between a specific type of oral condition and AS. PMID- 30427474 TI - Correlation of salivary immunoglobulin A with Body Mass Index and fat percentage in overweight/obese children. AB - : Obesity is considered a risk factor for periodontal health due to the low- grade inflammation promoted by the increased adipose tissue. OBJECTIVE: This study aimed to determine correlations and associations between gingival inflammation (Simplified Oral Hygiene Index, and Gingival Index), salivary immunoglobulin A (s-IgA), and salivary parameters (salivary flow and osmolality) in normal-weight and overweight/obese children. MATERIAL AND METHODS: Ninety-one children, aged 6 to 12 years old (8.6+/-1.9 years), were divided into two groups according to their body mass index (BMI), circumferences, skinfold measurements and body fat percentage: normal- weight group (NWG; n =50) and overweight/obese group (OG; n =41). A calibrated examiner performed the clinical examination using the Simplified Oral Hygiene Index, Gingival Index, and salivary collection. Data analysis included descriptive statistics and association tests ( p <0.05). RESULTS: OG presented statistically higher s-IgA values compared with NWG, especially among the obese children ( p <0.05). Significant positive correlations between s-IgA and salivary osmolality in OG ( p <0.05), and between s-IgA and BMI values ( p <0.05) and body fat percentage ( p <0.05) were observed among all the children. Effect size varied from moderate for s-IgA values ( d =0.57) to large for BMI ( d =2.60). CONCLUSION: Gingival inflammation and salivary parameters were similar for NWG and OG; however, s-IgA presented higher values in OG, with correlations between BMI and body fat percentage. PMID- 30427478 TI - Isolated middle colic artery injury after blunt abdominal trauma. PMID- 30427479 TI - Helium-oxygen mixture: clinical applicability in an intensive care unit. AB - OBJECTIVE: To evaluate if distress respiratory decreases after using helium oxygen mixture in pediatric patients diagnosed with bronchospasm. METHODS: This is a retrospective, non-randomized study that included patients diagnosed with bronchospasm, who received a helium-oxygen mixture at three time points (30, 60, and 120 minutes) according to the organization protocol singular, and were admitted to the intensive care unit, from January 2012 to December 2013. This protocol includes patients with bronchospasm who sustained a modified Wood score of moderate to severe, even after one hour of conventional treatment. RESULTS: Twenty children were included in the study. The mean score of severity of the disease at the initial moment was 5.6 (SD:2.0), and at moment 120 minutes, it was 3.4 (SD: 2.0). The severity score showed a significant improvement as of 30 minutes (p<0.001). CONCLUSION: The use of helium-oxygen mixture proved to be effective in diminishing the respiratory distress score for children with airway obstructions; it should be considered a supplementary therapeutic option, together with drug therapy, in specific clinical situations. PMID- 30427477 TI - Effects of in-office bleaching agent combined with different desensitizing agents on enamel. AB - OBJECTIVE: To analyze color change, microhardness and chemical composition of enamel bleached with in-office bleaching agent with different desensitizing application protocols. MATERIALS AND METHODS: One hundred and seventeen polished anterior human enamel surfaces were obtained and randomly divided into nine groups (n = 13). After recording initial color, microhardness and chemical composition, the bleaching treatments were performed as G1: Signal Professional White Now POWDER&LIQUID FAST 38% Hydrogen peroxide(S); G2: S+Flor Opal/0.5% fluoride ion(F); G3: S+GC Tooth Mousse/Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) paste(TM); G4: S+UltraEZ/3% potassium nitrate&0.11% fluoride(U); G5: S+Signal Professional SENSITIVE PHASE 1/30% Nano-Hydroxyapatite (n-HAP) suspension(SP); G6: S-F mixture; G7: S-TM mixture; G8: S-U mixture; G9: S SP mixture. Color, microhardness and chemical composition measurements were repeated after 1 and 14 days. The percentage of microhardness loss (PML) was calculated 1 and 14 days after bleaching. Data were analyzed with ANOVA, Welch ANOVA, Tukey and Dunnett T3 tests (p<0.05). RESULTS: Color change was observed in all groups. The highest DeltaE was observed at G7 after 1 day, and DeltaE at G8 was the highest after 14 days (p<0.05). A decrease in microhardness was observed in all groups except G6 and G7 after 1 day. The microhardness of all groups increased after 14 days in comparison with 1 day after bleaching (p>0.05). PML was observed in all groups except G6 and G7 after bleaching and none of the groups showed PML after 14 days. No significant changes were observed after bleaching at Ca and P levels and Ca/P ratios at 1 or 14 days after bleaching (p>0.05). F mass increased only in G2 and G6, 1 day after bleaching (p<0.05). CONCLUSIONS: The use of desensitizing agents containing fluoride, CPP-ACP, potassium nitrate or n-HAP after in-office bleaching or mixed in bleaching agent did not inhibit the bleaching effect. However, they all recovered microhardness of enamel 14 days after in-office bleaching. PMID- 30427480 TI - Efficiency in the operational process: reduction of incorrect entries and guarantee of compliance in the rendering of accounts. AB - OBJECTIVE: To verify the impact of the Lean Six Sigma methodology in reducing incorrect entries of non-appropriated revenues and expenses. METHODS: Process for the review and application of the Lean Six Sigma methodology between December 2015 and September 2016, in a high-complexity general hospital in the city of Sao Paulo (SP). RESULTS: A total of 3,756,814 (100%) entries were audited between December 2015 and September 2016. The Sigma level evolved over the course of the process and increased from 3.44 Sigma in December 2015 to 5.92 Sigma in September 2016. Entries classified as non-appropriated revenues and expenses were brought down to 0% at the end of the study. CONCLUSION: The use of the Lean Six Sigma methodology was efficient in reducing incorrect entries, calculating costs, ensuring compliance in rendering of accounts and accurately determining cost outcome ratios. PMID- 30427481 TI - Medications used in pediatric cystic fibrosis population. AB - OBJECTIVE: To describe the drug utilization profile used by pediatric cystic fibrosis patients. METHODS: A transversal study comprising the analysis of records and interviews with caregivers of pediatric patient in a reference center of Southern Brazil. We collected information about patients' clinical condition, medication used and household therapy. RESULTS: Out of 78 patients participating in the study, prevailing characteristics were: female, self-declared white color, mutation F508del and countryside resident. Forty-three patients had health monitoring exclusively in the hospital's outpatient division. We analyzed 509 prescribed medication (6.5 medication/patient). The caregiver acknowledged the correct indication in 83% of cases. Patients with pulmonary complications and diseases and/or comorbities related to the cystic fibrosis had an increased quantity of prescribed medication. Vitamins, pancreatic enzymes, hypertonic saline solution, dornase alpha, acid ursodesoxicolic and inhalation antibiotics were most commonly prescribed. Out of the sum of medication, 265 (52.1%) were registered in the Relacao Nacional de Medicamentos Essenciais , 26.7% were registered in the basic component and 25.4% were registered in the specialized component of pharmaceutical assistance. Seventy-four interviewees informed difficulty in the acquisition of at least one prescribed medication. Most of the reports acknowledge the State Health Department as the place to find and receive medication for cystic fibrosis. CONCLUSION: This study allowed reaching a deeper understanding about therapy, caring needed with patients with cystic fibrosis, highlighting to implement strategies that might contribute to enhance life quality and to execute the patients' therapy plan. PMID- 30427483 TI - Influence of grandmothers on exclusive breastfeeding: cross-sectional study. AB - OBJECTIVE: To evaluate the influence of grandmothers of infants on exclusive breastfeeding, from their perspective. METHODS: A descriptive cross-sectional study was carried out with 91 women from a hospital in the inland state of Sao Paulo. By means of a questionnaire, the following data were collected: sociodemographic data of the grandmother, mother and child; duration of exclusive breastfeeding of daughter or daughter-in-law; information on kinship of participant and grandchild; kind of help provided by grandmother; and knowledge about breastfeeding. RESULTS: The prevalence of infants on exclusive breastfeeding at two months was 35.17%; a total of 67.3% of grandmothers considered it important to give food to babies before six months of life, and 54% considered relevant breastfeeding at regular intervals. Moreover, 40% believed in weak milk and were not aware of signs of sufficient breast milk. Of the grandmothers interviewed, 69% had already offered tea and water to their grandchildren. In the univariate analysis, the maternal grandmother was more involved and close to the pair mother and child. CONCLUSION: The presence of grandmothers influences in exclusive breastfeeding. PMID- 30427482 TI - Low birth weight and its associated factors. AB - OBJECTIVE: To calculate the frequency and evaluate the factors associated with low birth weight. METHODS: A retrospective study, with data from pregnant women who participated in the Programa de Atencao as Gestantes do Programa Einstein na Comunidade de Paraisopolis, between 2011 and 2014, and who returned for the postpartum evaluation of their newborns. Variables related to the pregnant woman, pregnancy, and newborn were evaluated. The outcome variable was low birth weight, defined as <2.5kg. The associations between the independent variables and low birth weight were assessed by chi2 and Mann-Whitney tests. Logistic regression models analyzed the combined effects of the independent variables on low birth weight. RESULTS: Data of 794 pregnant women and their newborns (52.1% males) were analyzed. The age of pregnant women varied from 13 to 44 years (median of 24 years), and the majority reported being married or living in cohabitation (74.7%), and having between 9 to 11 years of schooling (53.4%). The proportion of low birth weight was 7.6% (newborn mean weight of 3.2kg) and, in multivariate analysis, presence of twinning, age group of the pregnant women (showing protection for low birth weight between ages >=18 years and <35 years), and cesarean section were associated with low birth weight. CONCLUSION: The proportion of low birth weight was 7.6% and twining, age of the pregnant woman, and cesarean delivery were associated with the occurrence of low birth weight. PMID- 30427485 TI - Nurse work environment: comparison between private and public hospitals. AB - OBJECTIVE: To compare the characteristics of the work environment that enable the professional practice of nurses in private and public organizations. METHODS: A quantitative, exploratory, cross-section study, carried out in four health organizations - one public and three private, with 188 registered nurses. Participants answered the Brazilian version of the Nursing Work Index - Revised, which aims to evaluate the presence of characteristics that favor the development of nursing activities through 15 items distributed into three subscales: autonomy, control over the practice setting and relationships with physicians. The measurement scale used is Likert, and lower scores represent better evaluation of the environment, i.e. , more favorable characteristics are present to assist the development of nursing activities. RESULTS: The means of the responses of participants of private hospitals were smaller in all subscales of the instrument, as compared to those from public hospitals. CONCLUSION: The environment of private hospitals showed more favorable characteristics to the professional practice of registered nurses than the public hospital environment. PMID- 30427484 TI - Comparative study of transepidermal water loss in patients with and without hyperhidrosis by closed-chamber measurer in an air-conditioned environment. AB - OBJECTIVE: To evaluate the difference in transepidermal water loss in patients diagnosed with hyperhidrosis and healthy subjects, in an air-conditioned environment. METHODS: Twenty patients diagnosed with hyperhidrosis and 20 healthy subjects were subjected to quantitative assessment using a closed-chamber device, in six previously established sites. RESULTS: The measurements showed different transepidermal water loss values for healthy subjects and patients with hyperhidrosis, especially in the hands and feet. In the Control Group, the median for the hands was 46.4g/m2/hour (p25: 36.0; p75: 57.6), while in the Hyperhidrosis Group, the median was 123.5g/m2/hour (p25: 54.3; p75: 161.2) - p<0.001. For the feet, the Control Group had a median of 41.5g/m2/hour (p25: 31.3; p75: 63.5) and the Hyperhidrosis Group, 61.2g/m2/hour (p25: 32.3; p75: 117) - p<0.02. Measurements of the axillas also showed differences. In the Control Group, the median was 14.8g/m2/hour (p25: 11.8; p75: 19.0) and, in the Hyperhidrosis Group, 83.5g/m2/hour (p25: 29.5; p75: 161.7) - p<0.001. CONCLUSION: Measuring transepidermal water loss is sufficient for diagnosis and follow-up of patients with hyperhidrosis. PMID- 30427486 TI - Suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups. AB - OBJECTIVE: To analyze suitability of new drugs registered in Brazil from 2003 to 2013 for pediatric age groups. METHODS: A descriptive study of drugs with pediatric indication included in a retrospective cohort of new drugs registered in Brazil. The evaluation of drug suitability for the pediatric age group was performed using the following criteria: suitability of dosage form and capacity to deliver the recommended dose. The drugs were considered adequate for the pediatric age groups when they met both criteria. The statistical analysis included calculation of frequencies and proportions. RESULTS: Suitability due to the drug capacity to deliver the recommended dose was greater than 80% across all age groups. Regarding suitability of the dosage form, we identified that the older the age group, the greater suitability for pediatric use. Concerning the drugs presented in solid dosage form, we showed that half were classified as inadequate for one or more pediatric age groups to whom they were indicated. The adequacy of drugs to the pediatric age group was 64.3% for preschool children, 66.7% for full-term newborns, 66.7% for premature newborns, and over 70% for other age groups. CONCLUSION: Drugs for children aged under 6 years were less often adequate, considering the dosage form and capacity to provide the recommended dose. The availability and proportional suitability of medicines for pediatric use are greater for older age groups, according to age groups the drug is registered for. PMID- 30427487 TI - Indications, clinical outcomes and complications of 1,949 flexible bronchoscopies. AB - OBJECTIVE: To describe indications, clinical outcomes and complications of flexible bronchoscopy. METHODS: A descriptive observational study of bronchoscopies performed at the endoscopy service of Hospital Israelita Albert Einstein . Demographic (age, gender and origin) and medical (indications and results of endoscopy and diagnostic tests, such as biopsy collection, lavage, cytology and culture) data were analyzed. Electronic medical records with incomplete data or reporting interventional procedures were excluded. RESULTS: Over a three-year period (2013 to 2016), a total of 1,949 bronchoscopies were performed by respiratory endoscopy team and anesthesia specialists of the hospital. The mean age of patients was 57.7+/-21.9 years (range of 3 days to 99 years), with prevalence of males (56.4%). The procedures were mostly (86.3%) elective and 30.7% were carried out in the intensive care unit. Major indications for bronchoscopy were infection or secretion (42.4%), followed by suspected neoplasm (10.8%). Endoscopic changes were reported in 91.9% of cases, with more than one change described in approximately 6.9% of patients. Positive results were obtained via direct testing or culture in 36.3% and 53.9% of 1,399 bronchoalveolar lavages, respectively. The overall diagnostic yield (bronchoalveolar lavage and biopsy) was 72.6%. Mild adverse event rate was 7.2%. The rate of severe adverse events requiring additional intervention was 0.5% (pneumothorax, 0.4%; severe bleeding with patient death, 0.1%). CONCLUSION: Lower airway endoscopy is critical for respiratory disease assessment, diagnosis and treatment. Flexible bronchoscopy is associated with good diagnostic yield and minimal inherent risk. PMID- 30427489 TI - Changes to transform. PMID- 30427490 TI - Jaws can be referred to as narrow or hypoplastic, but the term "atresia" is inaccurate! AB - In order to lead to insights and discussion on proper use of Orthodontics and Pathology-related terminology, particularly in cases of smaller-than-usual maxilla and mandible - that is, anomalous ones -, this study compared the conceptual meaning of the term "atresia." It is considered improper when referring to maxilla and mandible with deficient growth compared to development that is satisfactory enough to reach normal size. To identify smaller maxilla and mandible, the most proper and accurate term is hypoplastic maxilla or mandible. This is because "atresia" stands for an anomaly related to lumen blockage in hollow organs, which is not the case for neither maxilla nor mandible. Hypoplastic maxilla or mandible can be properly and specifically referred to as micrognathia. PMID- 30427488 TI - Late secondary urological reconstruction of separated ischiopagus twins with exstrophic bladder and urinary incontinence. AB - We report a case of secondary urinary reconstruction of previously separated conjoined twins with exstrophic bladder and urinary incontinence. Patients were male and aged 13-year-old. Twin one had a history of failed enterocystoplasty that extruded and was visible like an exstrophic neobladder. He underwent a procedure to close bladder neck and reconfigure abdominal wall. After the procedure the patient developed a fistula that was treated, but it persisted and, for this reason, a catheterizable pouch was constructed and native bladder was discarded. Twin two required the immediately construction of catheterizable pouch using the Macedo's technique. Currently, both patients are continent at 4 hour intervals. The mean follow-up was 8 months. Modern continent urinary diversion techniques offer new perspectives and hope for such complex population. PMID- 30427491 TI - An interview with Giorgio Fiorelli. PMID- 30427492 TI - Expression of cytokines in gingival crevicular fluid associated with tooth movement induced by aligners: a pilot study. AB - INTRODUCTION: The search for more aesthetic and comfortable orthodontic devices has led to an increase in the use of clear aligners. OBJECTIVE: To increase knowledge on biological mechanisms of orthodontic tooth movement using Invisalign aligners. METHODS: This study included 11 patients with a mean age of 23.6 +/- 4.8 years. Cases planning included alignment and leveling of lower incisors using Invisalign aligners. Gingival crevicular fluid samples were collected from the lower incisors on the day of delivery of aligner number 1 (T0) and after 1 (T24h), 7 (T7d), and 21 (T21d) days. During the observation period of the study, the patients used only the aligner number 1. Levels of nine cytokines were quantified using Luminex's multi-analysis technology. Non-parametric tests were used for comparisons between cytokine expression levels over time. RESULTS: Cytokine expression levels remained constant after 21 days of orthodontic activation, except those of MIP-1beta, which presented a statistical difference between T24h and T21d with a decrease in the concentration levels. IL-8, GM-CSF, IL-1beta, MIP-1beta, and TNF-alpha showed the highest concentrations over time. CONCLUSIONS: The different behavior in the levels of the investigated cytokines indicates a role of these biomarkers in the tissue remodeling induced by Invisalign. PMID- 30427493 TI - Evaluation of the attractiveness of different gingival zeniths in smile esthetics. AB - OBJECTIVE: To evaluate the smile attractiveness of different gingival zeniths by general dentists, orthodontists and laypersons and the esthetic perception in the symmetric and asymmetric changes in gingival zeniths. METHODS: Posed photographs of five patients were taken and digitally manipulated in Keynote software, in the gingival zenith region, in increments of 0.5 to 1mm in maxillary central and lateral incisors, symmetrically and asymmetrically, in nine different ways for each patient. The photos were then uploaded to a website, where evaluators (general dentists, orthodontists and laypersons) could observe and vote according to their esthetic perception, scoring from 1 to 10, 1 being the least attractive and 10 the more attractive. Kruskal-Wallis and Mann-Whitney tests were used for comparison. RESULTS: Asymmetric gingival zeniths were less attractive than symmetrical gingival zeniths; gingival zenith differences greater than 1mm were perceptible in the smile attractiveness, both by laypersons, general dentists and orthodontists. When comparing maxillary central incisors with maxillary lateral incisors, the aesthetic change performed in the central incisors are more perceptible than those performed in lateral incisors, both symmetrical and asymmetrical. In a general way, orthodontists and general dentists are more critical in the evaluation and perception of gingival zenith changes, with the laypersons perceiving this change only from 1mm of maxillary right central incisor asymmetrical change. CONCLUSIONS: Asymmetric gingival zeniths are less attractive than symmetrical ones. Gingival zenith differences greater than 1mm are perceptible in the smile attractiveness. Orthodontists and general dentists are more critical in evaluating smile esthetics. PMID- 30427494 TI - Effect of mangosteen peel extract as an antioxidant agent on the shear bond strength of orthodontic brackets bonded to bleached teeth. AB - INTRODUCTION: The number of patients who seek orthodontic treatment that may have a history of tooth bleaching is increasing over the time. Bleaching may influence the decrease of the bond strength of orthodontic brackets. OBJECTIVE: To determine and prove the effect of mangosteen peel (MP) extract to reverse the reduced shear bond strength (SBS) of orthodontic brackets after bleaching. METHODS: A total of 150 maxillary first premolar teeth were randomly divided into 6 experimental groups as follow (n=25): negative-control (N: no bleaching), positive-control (P: bleaching + no treatment), and the treatment groups (bleaching + 10% sodium ascorbate (SA), 10% (MP-10), 20% (MP-20) and 40% (MP-40) MP extract gel). After treatment, the brackets were bonded with the resin modified glass ionomer cement, SBS testing was performed using universal testing machine, and the adhesive remnant index (ARI) was examined using stereoscopic microscope after debonding. The SBS data were analyzed by analysis of variance (Anova) and the Tukey test. For the ARI, the Kruskal-Wallis test was performed. RESULT: There was significant SBS difference (p< 0.001) between various groups. The group without bleaching showed significantly higher SBS (8.19 +/- 2.26 MPa) compared to others, while SBS in the group treated with 40% MP gel was significantly higher (7.93 +/- 1.92 MPa) than other groups treated with antioxidants. The failure of orthodontic brackets bonded after bleaching and treatment using MP extract occurred at the enamel-adhesive interface. CONCLUSION: The application of MP extract as an antioxidant after bleaching was effective in reversing the reduced shear bond strength of orthodontic brackets after bleaching. PMID- 30427495 TI - Perception of attractiveness of missing maxillary lateral incisors replaced by canines. AB - OBJECTIVE: The aim of this study was to evaluate the degree of perception of attractiveness of the smile among dentists, dental students, and lay persons in cases of agenesis of the maxillary lateral incisors replaced by canines for space closure. METHODS: A smiling front view extraoral photograph of a 20-year-old woman was digitally altered simulating agenesis and its treatment, by means of: repositioning, reshaping or bleaching the canine, and gingival contour. A questionnaire was distributed to individuals of the three groups (n= 150), with a view to evaluating their degree of esthetic perception. An attractiveness scale was also used, with '0' representing unattractive and '10', very attractive. RESULTS: In the comparative evaluation among all the photographs, the original image obtained the highest level of acceptance. Photograph 'i' (agenesis of both lateral incisors treated with reposition and reshaping of the canines) was ranked as the least attractive by the dentists, whereas the student and lay persons ranked photograph 'f' (agenesis of both lateral incisors treated with reposition of the canines, gingival contour, bleaching and reshaping) as the worst. CONCLUSION: The methods of treatment most accepted among the dentists and students were those that involved changes in the gingival contour, whereas among lay persons, they were those that involved only reshaping. PMID- 30427497 TI - Do premolar extractions necessarily result in a flat face? No, when properly indicated. AB - The esthetic benefits are among the main goals of orthodontic treatment; therefore, tooth extractions have been avoided as a protocol for orthodontic treatment because they may impair the facial profile. The present article discusses aspects as the magnitude and response of soft tissue profile due to changes in incisor positioning, and the effect of different sequences of premolar extraction. One case report illustrates the subject, with favorable and stable esthetic and occlusal outcomes five years after orthodontic treatment with extraction of second premolars. PMID- 30427496 TI - Diagnostic validity of different cephalometric analyses for assessment of the sagittal skeletal pattern. AB - INTRODUCTION: Numerous cephalometric analyses have been proposed to diagnose the sagittal discrepancy of the craniofacial structures. OBJECTIVE: This study aimed at evaluating the reliability and validity of different skeletal analyses for the identification of sagittal skeletal pattern. METHODS: A total of 146 subjects (males = 77; females = 69; mean age = 23.6 +/- 4.6 years) were included. The ANB angle, Wits appraisal, Beta angle, AB plane angle, Downs angle of convexity and W angle were used to assess the anteroposterior skeletal pattern on lateral cephalograms. The sample was classified into Class I, II and III groups as determined by the diagnostic results of majority of the parameters. The validity and reliability of the aforementioned analyses were determined using Kappa statistics, sensitivity and positive predictive value (PPV). RESULTS: A substantial agreement was present between ANB angle and the diagnosis made by the final group (k = 0.802). In the Class I group, Downs angle of convexity showed the highest sensitivity (0.968), whereas ANB showed the highest PPV (0.910). In the Class II group, ANB angle showed the highest sensitivity (0.928) and PPV (0.951). In the Class III group, the ANB angle, the Wits appraisal and the Beta angle showed the highest sensitivity (0.902), whereas the Downs angle of convexity and the ANB angle showed the highest PPV (1.00). CONCLUSION: The ANB angle was found to be the most valid and reliable indicator in all sagittal groups. Downs angle of convexity, Wits appraisal and Beta angle may be used as valid indicators to assess the Class III sagittal pattern. PMID- 30427498 TI - Mini-implant selection protocol applied to MARPE. AB - INTRODUCTION: Rapid maxillary expansion (RME) is the therapy of choice to correct skeletal transverse dimension in children and adolescents, associating orthopedic and dental effects. In an attempt to prevent the undesirable dentoalveolar effects and optimize the potential of skeletal expansion in individuals in advanced stages of skeletal maturation, the miniscrew-assisted rapid palatal expander (MARPE) was proposed by Lee et al. in 2010. OBJECTIVE: This paper presents a systematized protocol for selection of miniscrews indicated for MARPE, by the evaluation of cone-beam computed tomographies (CBCT). Variables related with the bone and soft tissue thicknesses at the palatal regions of interest, as well as in relation to the fixation rings of miniscrews of the palatal expander are analyzed and discussed to provide better performance in the clinical practice. PMID- 30427501 TI - Erratum. AB - [This corrects the article doi: 10.1590/0004-282X20180062]. PMID- 30427499 TI - Correlation between tooth size-arch length discrepancy and interradicular distances measured on CBCT and panoramic radiograph: an evaluation for miniscrew insertion. AB - INTRODUCTION: The selection of appropriate sites for miniscrew insertion is critical for clinical success. OBJECTIVES: The aim of the present study was to evaluate how interradicular spaces measured on panoramic radiograph compare with Cone-Beam Computed Tomography (CBCT), and how crowding can influence the presence of available space for miniscrew insertion, in order to define a new "safe zones" map. METHODS: A total of 80 pre-treatment panoramic radiographs and 80 CBCT scans with corresponding digital models were selected from the archives of the department of Dentistry, Aarhus University. Crowding was measured on digital models, while interradicular spaces mesial to the second molars were measured on panoramic radiographs and CBCTs. For panoramic radiographs, a magnification factor was calculated using tooth widths measured on digital models. Statistical analyses were performed to investigate the correlation between the amount of crowding and the available interradicular space. Visual maps showing the amount of interradicular spaces measured were drawn. RESULTS: The most convenient interradicular spaces are those between the second molar and the first premolar in the mandible, and between the central incisors in the maxilla. However, some spaces were revealed to be influenced by crowding. CONCLUSIONS: Calibration of panoramic radiographs is of utmost importance. Generally, panoramic radiographs underestimate the available space. Preliminary assessment of miniscrew insertion feasibility and the related selection of required radiographs can be facilitated using the new "safe zone" maps presented in this article. PMID- 30427502 TI - Pharmacogenetics in multiple sclerosis: the long and winding road ahead of us. PMID- 30427500 TI - Periodontal health knowledge and awareness among subjects with fixed orthodontic appliance. AB - OBJECTIVE: To report on periodontal health knowledge and awareness among orthodontic patients and to investigate the effect of age, attitude and duration of orthodontic treatment on periodontal health awareness among orthodontic patients. METHODS: A total of 297 orthodontics patient (90 males, 207 females) with mean age of 17.7 +/- 5.0 years (older then 18 years = 119, 18 years or younger = 178) were included in this study. Subjects were currently wearing upper and lower fixed orthodontic appliances for an mean period of 12.55 +/- 10.86 months (less than or equal to 18 months = 231, more than 18 months = 66). Data was collected through a self-administered questionnaire (demographic characteristics, subjects' awareness toward their periodontal health, periodontal knowledge among orthodontic patient and patients' attitude toward orthodontic treatment regarding periodontal health) and clinical periodontal examination. RESULTS: Periodontal knowledge was poor among orthodontic patients in relation to dental plaque. Only 24 subjects (8%) correctly answered knowledge-related questions. Adult orthodontic patients reported negative attitude toward fixed orthodontic treatment in respect to periodontal health (p<0.001). Duration of orthodontic treatment negatively affected subjects' attitude toward fixed orthodontic treatment (p<0.01). The majority of subjects were in the high level of awareness group (64%). Orthodontic patients' awareness toward their periodontal health during fixed orthodontic treatment was affected by attitude scores (p=0.005), number of teeth with gingival recession (p=0.041), Gingival Index (p=0.000), duration of treatment (p=0.047) and age (p=0.008). CONCLUSIONS: Periodontal health knowledge among orthodontic patients was poor. Orthodontic patients' awareness of their periodontal health was moderate and was affected by age, attitude and duration of orthodontic treatment. PMID- 30427504 TI - Effects of virtual reality therapy on upper limb function after stroke and the role of neuroimaging as a predictor of a better response. AB - OBJECTIVE: Virtual reality therapy (VRT) is an interactive intervention that induces neuroplasticity. The aim was to evaluate the effects of VRT associated with conventional rehabilitation for an upper limb after stroke, and the neuroimaging predictors of a better response to VRT. METHODS: Patients with stroke were selected, and clinical neurological, upper limb function, and quality of life were evaluated. Statistical analysis was performed using a linear model comparing pre- and post-VRT. Lesions were segmented in the post-stroke computed tomography. A voxel-based lesion-symptom mapping approach was used to investigate the relationship between the lesion and upper limb function. RESULTS: Eighteen patients were studied (55.5 +/- 13.9 years of age). Quality of life, functional independence, and dexterity of the upper limb showed improvement after VRT (p < 0.001). Neuroimaging analysis showed negative correlations between the internal capsule lesion and functional recovery. CONCLUSION: VRT showed benefits for patients with stroke, but when there was an internal capsule lesion, a worse response was observed. PMID- 30427503 TI - Stroke recurrence in the different subtypes of ischemic stroke. The importance of the intracranial disease. AB - : The aim of the study was to analyze the long-term recurrence rate in patients with a first-ever ischemic stroke secondary to intracranial large artery atherosclerosis (LAA) in a Brazilian population. METHODS: All stroke patients admitted to the hospital between October 2012 and September 2015 were evaluated. The stroke mechanism subtypes were classified as cardioembolism, LAA, small vessel occlusion, other determined etiologies, and stroke of undetermined etiology. RESULTS: The 359 first-ever ischemic stroke patients were followed up for a mean time of 21.6 +/- 15.1 months. The LAA intracranial (38.9%) and extracranial (24.6%) stroke patients presented with a higher stroke recurrence. Intracranial LAA [HR, 10.2 (3.6-29.1); p < 0.001] and extracranial LAA [HR, 5.05 (1.79-14.2); p = 0.002] were the only conditions to show positive correlation with the recurrence rate, after adjusting for risk factors, thrombolysis, and National Institutes of Health Stroke Scale score at admission. CONCLUSION: Intracranial LAA presents a higher incidence of recurrence of ischemic stroke when compared with other etiologies in a Southern Brazilian population. PMID- 30427505 TI - Botulinum toxin A (BT-A) versus low-level laser therapy (LLLT) in chronic migraine treatment: a comparison. AB - OBJECTIVE: The aim of this work was to evaluate patients with chronic migraine treated with botulinum toxin A (BT-A) and compare this with low level laser therapy (LLLT), referencing: pain days, pain intensity, intake of drugs/self medication, anxiety and sleep disorders. METHODS: Patients were randomized into two groups: BT-A group (n = 18) and LLLT group (n = 18). Each patient kept three pain diaries: one before (baseline) (30 days), one during treatment (30 days) and one after the post-treatment phase (30 days). Repeated ANOVA plus the Bonferroni post-test, Student's t test, and factorial analysis were applied, and p < 0.05 was accepted as significant. RESULTS: Our data showed that both treatments were able to reduce headache days, acute medication intake and decrease the intensity of pain. Anxiety was reduced in the BT-A group, while sleep disturbance was reduced in the LLLT group. CONCLUSION: Our data showed that both treatments can be used to treat chronic migraine, without notable differences between them. PMID- 30427506 TI - Medication-overuse headache. Retrospective comparison of preventive treatments. AB - OBJECTIVE: Medication-overuse headache is commonly seen in tertiary centers. Limited evidence is available regarding treatment. We compared the use of one or two drugs, three drugs, or four pharmacological agents for the prevention of headache. METHODS: This was a retrospective analysis of 149 consecutive patients. Sudden withdrawal and pharmacological prevention with one or more drugs were carried out. Adherence and the decrease of headache frequency of more than 50% were compared after four months between the one or two, three, and four drug groups. RESULTS: There was no difference in adherence (p > 0.6). Headache frequency reduction was shown in 23 (54.8%, one or two drugs), 33 (70%, three drugs) and 11 (55%, four drugs); p = 0.13 and p = 0.98, not significant. There was a tendency towards significance between the one or two drug takers versus the three drug and four drug takers together (p = 0.09). CONCLUSIONS: The use of more drugs was not better at improving headache. However, there is the possibility that acting simultaneously on different sites may promote broader modulation and better outcome. PMID- 30427507 TI - Cross-cultural adaptation and validation of the International Cooperative Ataxia Rating Scale (ICARS) to Brazilian Portuguese. AB - OBJECTIVE: The clinical assessment of patients with ataxias requires reliable scales. We aimed to translate, adapt and validate the International Cooperative Ataxia Rating Scale (ICARS) into Brazilian Portuguese. METHODS: The steps of this study were forward translation, translation synthesis, backward translation, expert committee meeting, preliminary pilot testing and final assessment. Thirty patients were enrolled in the preliminary pilot testing and 61 patients were evaluated for construct validity, internal consistency, intra- and inter-rater reliability and external consistency. RESULTS: This study showed good validity of the construct and high internal consistency for the full scale, except for the oculomotor domain (Cronbach's alpha = 0.316, intraclass correlation coefficients intra- = 82.4% and inter- = 79.2%). A high correlation with the Scale for the Assessment and Rating of Ataxia was observed. We found good intra-rater agreement and relative inter-rater disagreement, except in the posture and gait domain. CONCLUSION: The present ICARS version is adapted for the Brazilian culture and can be used to assess our ataxic patients. PMID- 30427509 TI - Development of the Brazilian Portuguese version of the "Grading scale for idiopathic normal pressure hydrocephalus": cross-cultural adaptation, reliability and validity. AB - OBJECTIVE: The current study translated to Portuguese and validated the normal pressure hydrocephalus (NPH) scale originally developed in English as the Grading Scale for Idiopathic Normal Pressure Hydrocephalus. METHODS: Following Guillemin's validation protocol, the last version of the Portuguese NPH scale was applied to 121 consecutive patients with a diagnosis of normal pressure hydrocephalus (73 men and 48 women) from the Group of Cerebral Hydrodynamics from July 2010 to March 2012. RESULTS: The mean age was 71.09 years old, ranging from 35 to 92 years. The rate of agreement and reproducibility was high, as confirmed by Cohen's Kappa coefficient, with excellent intraobserver correlation for the NPH scale items individually evaluated: gait (0.80), dementia (0.90) and incontinence (0.87). CONCLUSIONS: The Portuguese version of the Grading Scale for Idiopathic Normal Pressure Hydrocephalus was successfully translated and validated for use in Brazilian patients. PMID- 30427508 TI - Factors associated with cognitive performance in elderly caregivers. AB - OBJECTIVE: To explore the socioeconomic, demographic and psychosocial factors associated with cognitive performance in elderly caregivers from Brazil. METHODS: We evaluated 351 Brazilian elderly caregivers attending primary healthcare services regarding sociodemographic and care variables. Addenbrooke's Cognitive Examination-Revised (ACE-R) domains of orientation/attention, memory, verbal fluency, language and visuospatial were used as dependent variables in the Tobit model. RESULTS: Literacy and family income were positively associated with all ACE-R domains. Age, gender, time of care (days/week) were negatively associated with some cognitive domains. Moreover, receiving emotional help and the level of hope were positively associated with specific domains. DISCUSSION: The results may be useful for planning interventions aimed at elderly caregivers in order to prevent deficits in the different cognitive domains. PMID- 30427510 TI - Multiple sclerosis: disease modifying therapy and the human leukocyte antigen. AB - OBJECTIVE: To investigate the potential relationship between the human leukocyte antigen (HLA) type (class I and II) and the response to several disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS). METHODS: We analyzed clinical data of 87 patients with MS at the beginning and end of each type of DMT including the disease duration, Expanded Disability Status Scale and Multiple Sclerosis Severity Score (MSSS). Genotyping of HLA-DRB1, HLA-DPB1, HLA-DQB1, HLA A, HLA-B and HLA-C alleles were identified using high-resolution techniques. Statistical correlation between the HLA type and response to DMTs was done using the initial and final MSSS. RESULTS: Statistical relationships (p < 0.05) were found for only 15 of 245 alleles tested. There was a reduction in the MSSS for patients treated with corticosteroids (DRB1*15:01, DPB1*04:01, DQB1*02:01 and DQB1*03:01), azathioprine (DRB1*03:01, DPB1*04:01, DQB1*03:02, DQB1*06:02, HLA C*07:02), interferon beta-1a 22 mcg (DRB1*11:04, DQB1*03:01 and DQB1*03:02), interferon beta-1a 30 mcg (DPB1*02:01, HLA-C*05:01) and interferon beta-1b (DQB1*02:01). CONCLUSION: These findings suggest a few relationships between the HLA and response to DMTs in the disability for some types of HLA class I and II alleles in a specific subset of MS patients. PMID- 30427511 TI - Complex proteinopathies and neurodegeneration: insights from the study of transmissible spongiform encephalopathies. AB - Protein misfolding diseases are usually associated with deposits of single "key" proteins that somehow drive the pathology; beta-amyloid and hyperphosphorylated tau accumulate in Alzheimer's disease, alpha-synuclein in Parkinson's disease, or abnormal prion protein (PrPTSE) in transmissible spongiform encephalopathies (TSEs or prion diseases). However, in some diseases more than two proteins accumulate in the same brain. These diseases might be considered "complex" proteinopathies. We have studied models of TSEs (to explore deposits of PrPTSE and of "secondary proteins") infecting different strains and doses of TSE agent, factors that control incubation period, duration of illness and histopathology. Model TSEs allowed us to investigate whether different features of histopathology are independent of PrPTSE or appear as a secondary result of PrPTSE. Better understanding the complex proteinopathies may help to explain the wide spectrum of degenerative diseases and why some overlap clinically and histopathologically. These studies might also improve diagnosis and eventually even suggest new treatments for human neurodegenerative diseases. PMID- 30427512 TI - Joao Carlos Teixeira Brandao, the first Brazilian professor of Psychiatry. AB - OBJECTIVE: To describe the highlights in the personal, professional, and political life of the first Brazilian Professor of Psychiatry. METHODS: The article draws on a wide range of documents: newspaper articles, documents of Brazilian medical institutions, scientific articles, theses, and books. RESULTS: Joao Carlos Teixeira Brandao was a distinguished 19th-century Brazilian psychiatrist and leader of the institutionalization and consolidation of the field of Psychiatry in Brazil. He contributed to the recognition of the professional jurisdiction of the "alienist", a specialized professional, qualified in clinical practice, diagnosis, and the definition of the boundaries between sanity and madness, based on scientific criteria, in the late 19th and early 20th centuries. CONCLUSION: This article highlights the key moments in the professional and political career of Professor Joao Carlos Teixeira Brandao, from his graduation from the Rio de Janeiro School of Medicine in 1877 to his death in 1921, when he was still active in national politics. PMID- 30427513 TI - Babinski's hand sign: many have tried.... AB - Recognizing the semiologic importance of the second, and most famous, sign described by Joseph Babinski - the extension of the hallux after stimulation of the plantar region in order to differentiate organic from pithiatic paralysis- several authors have tried to find a comparable signal in the hand. After 122 years, no one has succeeded. PMID- 30427514 TI - Posterior reversible encephalopathy syndrome during treatment with tocilizumab in juvenile idiopathic arthritis. PMID- 30427515 TI - Pediatric spinal perimedullary arteriovenous fistula. PMID- 30427516 TI - Diffuse axonal injury: diffusion tensor imaging and cognitive outcome. PMID- 30427517 TI - Reply. PMID- 30427518 TI - Occurrence of Dioctophyme renale larvae (Goeze, 1782) (Nematoda: Enoplida) in a new host from southern Brazil. AB - Dioctophymatosis is caused by the giant kidney worm Dioctophyme renale which occurs in dogs, cats, and wild mammals. In Brazil, the disease has been diagnosed in dogs from several states around the country. In the present study, the occurrence of D. renale larvae in snakes from southern of Brazil is reported. Three specimens of Philodryas patagoniensis (Serpentes: Dipsadidae) (common names in Brazil: "parelheira", "papa-pinto") roadkill in the county of Capao do Leao, State of Rio Grande do Sul, southern Brazil, were necropsied. Two third-stage larvae of D. renale were found in the coelomic cavity of P. patagoniensis. This study reveals a new host for D. renale larvae in the southern region of the State of Rio Grande do Sul, Brazil. This particular geographic area of the country has stood out as several cases of D. renale infection have been reported in a number of vertebrates from this region including domestic dogs and cats and wild animals such as carnivores, fish, and freshwater turtles. PMID- 30427519 TI - Eimeria spp. (Apicomplexa: Eimeriidae) of marsupials (Mammalia: Didelphimorphia) in southern Bahia, Brazil. AB - The occurrence of Eimeria Schneider, 1875 in mammals of the order Didelphimorphia indicates the infection-predisposition of these animals, which in turn is mainly determined for their eating habits. The objective of this work was to evaluate the parasitism of Eimeria spp. in marsupials of the Atlantic Forest of the southern region of Bahia. Fecal samples were collected from marsupials captured in the regions of Ilheus, Una, Belmonte and Mascote, with traps of the Sherman model (23 * 8 * 9 cm), Tomahawk (50 * 17 * 17 cm) and pitfall and analyzed by Sheather's modified centrifugal-flotation method. Oocysts were identified by microscopical evaluation of their morphology and morphometry. Didelphis aurita Wied-Neuwied, 1826, Gracilinanus agilis Burmeister, 1854, Monodelphis americana Muller, 1776, Marmosa demerarae O. Thomas, 1905 and Marmosa murina Linnaeus, 1758 were parasitized by Eimeria philanderi Lainson & Shaw, 1989 and Eimeria gambai Carini, 1938. Mixed parasitism for these two coccidia was observed in two of the 56 marsupials sampled. In conclusion, this work registers new hosts for E. philanderi and E. gambai, as well as the state of Bahia as a new distribution site for these coccidia. PMID- 30427520 TI - Prevalence and associated factors with Neospora caninum infection in female water buffaloes (Bubalus bubalis) from Pernambuco, Brazil. AB - Neosporosis is one of the major parasitic diseases that causes reproductive problems, making it a limitation for optimal efficiency in livestock. The aim of the present study was to conduct a seroepidemiological survey for bubaline neosporosis and to analyse associated factors associated with N. caninum infection in female water buffaloes in the State of Pernambuco, northeast Brazil. The prevalence of N. caninum infection in the bubaline herds examined was 35.4% (122/345; 95% CI: 30.4%-40.7%), at least 1 Neospora-positive animal was found in each farm. Associated factors for N. caninum infection identified in this study were exclusive pasture feeding (OR: 5.91, p <0.001) and purchase of animals of free fair and from reputable sellers (OR: 1.85; p =0.045). In this survey, we document the occurrence of neosporosis in female water buffaloes. Associated factors should be controlled in order to reduce the risk of N. caninum infection in these herds. PMID- 30427521 TI - Rhinonyssidae (Acari) in the house sparrows, Passer domesticus (Linnaeus, 1758) (Passeriformes: Passeridae), from southern Brazil. AB - We report the occurrence and infection parameters of two species of nasal mites in Passer domesticus (Linnaeus, 1758) (house sparrow). Nasal passages, trachea, lungs, and air sacs of 100 house sparrows captured in an urban area at the city of Pelotas, State of Rio Grande do Sul, southern Brazil, were examined with a stereomicroscope. The mite, Sternostoma tracheacolum Lawrence, 1948 was present in the trachea and/or lungs (or both) of 13 birds (13%) at a mean intensity of 6.7 mites/infected host. Ptilonyssus hirsti (Castro & Pereira, 1947) was found in the nasal cavity of 1 sparrow (1%); coinfection was not observed in this bird. There was no significant difference in the prevalence and mean intensity of infection of S. tracheacolum between male and female birds. To our knowledge, this is the first study reporting the occurrence of S. tracheacolum in P. domesticus in Brazil and the presence of P. hirsti in P. domesticus from Rio Grande do Sul, Brazil. This is the first survey to provide the infection parameters of each of these mites in house sparrows. PMID- 30427522 TI - Helminth metacommunity structure of wild rodents in a preserved area of the Atlantic Forest, Southeast Brazil. AB - The helminth fauna and metacommunity structure of eight sympatric sigmodontine rodents were investigated at the Serra dos Orgaos National Park, an Atlantic Forest reserve located in the State of Rio de Janeiro, southeast Brazil. Rodents of the species Abrawayaomys ruschii, Akodon montensis, Blarinomys breviceps , Delomys dorsalis, Oligoryzomys flavescens, Oligoryzomys nigripes, Oxymycterus quaestor and Thaptomys nigrita were found infected with helminths. Akodon montensis presented the highest total helminth species richness, with six different species of helminths. The nematode Stilestrongylus lanfrediae was the most abundant and prevalent helminth species observed. The host-parasite network analysis showed little interactions among host species. Akodon montensis seems to act as a keystone-species in the rodent community. This species shared the nematodes Stilestrongylus aculeata with A. ruschii and Protospirura numidica criceticola with T. nigrita, and the cestode Rodentolepis akodontis with D. dorsalis. The congeners host species O. flavescens and O. nigripes shared the nematodes Guerrerostrongylus zetta and S. lanfrediae. The rodents B. breviceps and O. quaestor did not share any helminths with other hosts. The helminth metacommunity showed a random pattern on both infracommunity and component community levels, indicating different responses by each helminth species to the environmental gradient. PMID- 30427523 TI - Detection of a putative novel genotype of Ehrlichia sp. from opossums (Didelphis aurita) from Brazil. AB - Erlichiosis affects humans and animals worldwide. Its distribution and prevalence depends on the presence of tick vectors and hosts in one geographic area. The aim of the present study was to investigate the occurrence of Ehrlichia spp. and Anaplasma spp. in opossums (Didelphis sp.) from the State of Rio de Janeiro, southeast Brazil. Blood samples from 37 animals were tested for these two pathogens using molecular methods. One animal (2.7%) was positive for Ehrlichia sp. by 16S rRNA-based nested PCR. In a phylogenetic analysis based on the 16S rRNA gene using the maximum likelihood method and the GTRGAMMA+I evolutionary model, we detected a novel Ehrlichia sp. genotype closely related to genotypes of E. canis previously reported in dogs from Brazil. To the authors' knowledge, this is the first molecular detection of Ehrlichia sp. in opossums from this State in the southeastern region of the country. PMID- 30427524 TI - A cysteine protease from the latex of Ficus benjamina has in vitro anthelmintic activity against Haemonchus contortus. AB - Haemonchus contortus is a gastrointestinal nematode that is responsible for high mortality rates in ruminant herds. The resistance of nematodes to synthetic anthelmintics is widespread and requires a continuous search for new bioactive molecules, such as proteins. The objective of this study was to evaluate the anthelmintic potential of a protease purified from the latex of Ficus benjamina against H. contortus . Fresh latex was collected from plants via small incisions in the green stems, the rubber was removed by centrifugation, and the latex protein extract (LPE) was obtained. After LPE fractionation with ammonium sulfate and chromatography of the fraction containing the highest proteolytic activity on CM-cellulose, a cysteine protease (FbP) was purified. FbP has a molecular mass of approximately 23.97 kDa, and its proteolytic activity was stable between pH 6.0 and pH 10 and over a broad temperature range, with optimum activity at 60 degrees C. FbP inhibited both the development and exsheathment of H. contortus larvae, with 50% effective concentrations of 0.26 and 0.79 mg/mL, respectively. We conclude that this cysteine protease from F. benjamina latex with anthelmintic activity against H. contortus could be a promising alternative for the development of products for use in parasite control programmes. PMID- 30427525 TI - Nematode resistance to five anthelmintic classes in naturally infected sheep herds in Northeastern Brazil. AB - This study aimed to evaluate the occurrence of nematode resistance to anthelmintics on sheep herds from the semi-arid region of Paraiba, Northeastern Brazil. Fecal Egg Count Reduction Test (FECRT) was carried out on 20 properties. In each herd, 30 animals were divided into five groups containing six animals each: group I, treated with albendazole 10%, 4 mg/kg; group II, ivermectin 0.08%, 0.2 mg/kg; group III, closantel 10%, 10 mg/kg; group IV, levamisole hydrochloride 5%, 5 mg/kg; and group V, monepantel 2.5%, 2.5 mg/kg. All treatments were administered orally as a single dose. Fecal samples were collected on days zero and 10 after treatment, to perform FECRT and coprocultures. Multiresistance was observed in all the properties; 95% had high resistance to albendazole, 85% to ivermectin, 80% to closantel, 40% to levamisole, and 45% to monepantel. On property 15, where monepantel was ineffective, a second FECRT for this anthelmintic was carried out 4 months after the first, resulting in 75% efficacy. Immediately after the FECRT result, two ewes were euthanized and necropsied, and Haemonchus contortus, Trichostrongylus axei, Trichostrongylus colubriformis, Oesophagostomum columbianum, and Trichuris ovis were recovered. It was concluded that the resistance of sheep gastrointestinal nematodes to antthelmintic, including monepantel, is high. PMID- 30427526 TI - Cucullanus marajoara n. sp. (Nematoda: Cucullanidae), a parasite of Colomesus psittacus (Osteichthyes: Tetraodontiformes) in the Marajo, Brazil. AB - Cucullanus marajoara n. sp. (Cucullanidae) is reported to parasitize Colomesus psittacus (Tetraodontiformes), which is a fish species from the Marajo Archipelago, state of Para, estuarine region of the Brazilian Amazon. The new species differs from similar species by the presence of a protruding upper lip on the cloacal opening, the distribution of the cloacal papillae: five pre-cloacal papillae pairs and 5 are ventral and located posteriorly to the pre-cloacal sucker and an unpaired papilla is located on the upper cloacal lip and five post cloacal pairs, and a pair of lateral phasmids located between papillae pairs. Additionally, Cucullanus marajoara n. sp. is compared to other species of this genus described in Brazil, particularly Cucullanus ageneiosus and Cucullanus oswaldocruzi, which both occur in the same zoogeographic region of this study but parasitize fish of a different order (Siluriformes). Cucullanus dodsworthi and Cucullanus brevicaudatus are the only described species parasitizing fish of the order Tetradontiformes in Brazil, and the new species differs from these species by the distribution of the cloacal papillae and the host habitat. The description of Cucullanus marajoara n. sp. adds data to the biodiversity of described parasites that parasitize Tetradontiformes of the estuarine ichthyofauna in the Brazilian Amazon. PMID- 30427527 TI - Changes in hematological and biochemical parameters of tambaqui (Colossoma macropomum ) parasitized by metazoan species. AB - The aim of this study was to evaluate the impacts of metazoan parasites on hematological and biochemical parameters and relative condition factor of tambaqui (Colossoma macropomum ) farmed in northern Brazil. A total of 32 juvenile fish were captured from a commercial fish farm located in the municipality of Rio Preto da Eva, Amazonas state, Brazil. Parasite prevalence was 100% for Anacanthorus spathulatus, Mymarothecium boegeri and Notozothecium janauachensis, 100% for Neoechinorhynchus buttnerae and 53.13% for Dolops geayi. The greatest mean parasite intensity was found in acantocephalans followed by monogeneans and branchiuran crustaceans. A negative correlation was observed between abundance of N. buttnerae and hematocrit percentage, hemoglobin concentration, total thrombocyte count and glucose and between abundance of the monogenean and glucose concentration. Parasitic infections caused damage in tambaqui in terms of the observed hematological parameters that were characterized by hypochromic anemia and thrombocytopenia, which are important parameters to be used in parasitic diagnosis. This study is the first record of the occurrence of Dolops geayi in farmed tambaqui in the Amazon. PMID- 30427528 TI - Theileria sp. in water buffaloes from Maranhao State, northeastern Brazil. AB - Anaplasma marginale and piroplasm species are widespread among Brazilian cattle herds. Both of these tick-borne pathogens hamper livestock production and cause a significant economic impact. Although buffaloes have demonstrated a high level of adaptability, data on tick-borne pathogens are scarcely reported in Brazil. Thus, the aim of this study was to screen water buffaloes from the state of Maranhao for piroplasm and A. marginale occurrence using PCR assays. All samples were negative for A. marginale. One of the 287 (0.35%) water buffaloes tested was positive for Theileria sp. Sequencing of the 18S rDNA fragment (356 bp) showed that the Theileria sp. identified was closely related to the T. buffeli /orientalis group. Future studies on the clinical signs of infection and the main vector in this country are needed. PMID- 30427529 TI - Nematode capilaridae in the tongue of Cerdocyon thous of free life in Brazil. AB - Studies of helminths in road-killed wild animals are still uncommon but may provide promising results since they can identify the parasites in juvenile and adult hosts and meet the recommendations of current discussions on bioethics that prioritize alternative methods for the use of animals. This study evaluated three Cerdocyon thous individuals that were donated after dying from being run over. Two of them had small nematode adults in the epithelial and connective tissues of the tongue. The diagnosis was based on the presence of eggs, observed in histological sections, and morphological characteristics of the nematodes in the tongue. Morphologically, this nematode has a body with transverse grooves, simple mouth opening and no lips, esophagus and stichosome with stichocytes and bacillary bands along the body, which is characteristic morphology of the family Capilariidae and genus Capillaria . The presence of this nematode in the tongue of C. thous is an extremely important fact that contributes to what is known about the biodiversity of zoonotic parasites in wild canid populations. However, an explanation for these findings remains unclear because, until now, this has not been observed in the biological cycle of the species. PMID- 30427530 TI - Long-term effects of combined percutaneous atrial septal defect occlusion and pulmonary valvuloplasty in children below 2.5 years old. PMID- 30427531 TI - Ex Vivo Culture of Cells Derived From Circulating Tumour Cell Xenograft to support Small Cell Lung Cancer Research and Experimental Therapeutics. AB - BACKGROUND AND PURPOSE: Small cell lung cancer (SCLC) is an aggressive disease with median survival of < 2 years. Tumour biopsies for research are scarce, especially from extensive-stage patients, with repeat sampling at disease progression rarely performed. We overcame this limitation for relevant preclinical models by developing SCLC circulating tumour cell derived explants (CDX) which mimic the donor tumour pathology and chemotherapy response. To facilitate compound screening and identification of clinically relevant biomarkers, we developed short term ex vivo cultures of CDX tumour cells. EXPERIMENTAL APPROACH: CDX tumours were disaggregated and the derived human tumour cells were cultured for a maximum of 5 weeks. Phenotypic, transcriptomic and pharmacological characterization of these cells was performed KEY RESULTS: CDX cultures maintained a neuroendocrine phenotype and most changes in protein coding gene expression observed in up to 4 week of cultures were reversible when the cells were re-implanted in vivo. Moreover, CDX cultures exhibited similar sensitivity to chemotherapy than the corresponding CDX tumour in vivo and were able to predict in vivo responses to therapeutic candidates. CONCLUSION AND IMPLICATIONS: Short term cultures of CDX provide a tractable platform to screen new treatments, identify predictive and pharmacodynamic biomarkers and interrogate mechanisms of resistance to better understand progression of this recalcitrant tumour. PMID- 30427532 TI - Annual Report to the Nation on the Status of Cancer, Part II: Recent changes in prostate cancer trends and disease characteristics. PMID- 30427534 TI - Ethical considerations about emergent surgical hospitalizations in patients with advanced cancer. PMID- 30427533 TI - A phase 2 trial of abiraterone acetate without glucocorticoids for men with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Abiraterone acetate suppresses adrenal androgens and glucocorticoids through the inhibition of CYP17; however, given the risk of mineralocorticoid excess, it is administered with glucocorticoids. Herein, the authors performed a phase 2, single-arm study that was designed to assess the safety of abiraterone acetate without steroids in patients with castration-resistant prostate cancer. METHODS: Eligible patients had castration-resistant prostate cancer with controlled blood pressure and normal potassium. Patients initially received abiraterone acetate at a dose of 1000 mg daily alone. Those with persistent or severe mineralocorticoid toxicity received treatment with prednisone initiated at a dose of 5 mg twice daily. Therapy was continued until radiographic progression, toxicity, or withdrawal. The primary objective of the current study was to determine the percentage of men requiring prednisone to manage mineralocorticoid toxicity. Toxicity was graded according to Common Terminology Criteria for Adverse Events, version 4.0. RESULTS: A total of 58 patients received at least 1 dose of abiraterone acetate; the majority had metastases (53 patients; 91.4%). Sixteen patients (27.6%) received prior chemotherapy, 6 patients (10.3%) received prior enzalutamide, and 4 patients (7%) received prior ketoconazole. Grade 3 to 4 adverse events of interest included hypertension (9 patients; 15.5%) and hypokalemia (4 patients; 7%). There was no grade >=3 edema. Seven patients (12%) initiated prednisone therapy for mineralocorticoid toxicity, 3 patients for hypertension (5%), and 4 patients for hypokalemia (7%). Two patients initiated prednisone therapy for fatigue (3%). Forty patients (68%) experienced a decline in prostate-specific antigen of >=50% with the use of abiraterone acetate alone. Patients with lower baseline levels of androstenedione (P = .04), androsterone (P = .01), dehydroepiandrosterone (P = .03), and 17-hydroxyprogesterone (P = .03) were found to be more likely to develop mineralocorticoid toxicity. CONCLUSIONS: Treatment with abiraterone acetate without steroids is feasible, although clinically significant adverse events can occur in a minority of patients. The use of abiraterone acetate without prednisone should be balanced with the potential for toxicity and requires close monitoring. PMID- 30427535 TI - Does race predict the development of metastases in men who receive androgen deprivation therapy for a biochemical recurrence after radical prostatectomy? AB - BACKGROUND: In this study among men who underwent radical prostatectomy (RP), African American men (AAM) were 28% more likely to develop recurrent disease compared with Caucasian men (CM). However, among those who had nonmetastatic, castration-resistant prostate cancer (CRPC), race did not predict metastases or overall survival. Whether race predicts metastases among men who receive androgen deprivation therapy (ADT) after a biochemical recurrence (BCR) (ie, before CRPC but after BCR) is untested. METHODS: The authors identified 595 AAM and CM who received ADT for a BCR that developed after RP between 1988 and 2015 in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database. Univariable and multivariable Cox models were used to test the association between race and the time from ADT to metastases. Secondary outcomes included the time to CRPC, all cause mortality, and prostate cancer-specific mortality. RESULTS: During a median follow-up of 66 months after ADT, 62 of 354 CM (18%) and 38 of 241 AAM (16%) developed metastases. AAM were younger at the time they received ADT (63 vs 67 years; P < .001), had received ADT in a more recent year (2008 vs 2006; P < .001), had higher prostate-specific antigen levels at RP (11.1 vs 9.2 ng/mL; P < .001), lower pathologic Gleason scores (P = .004), and less extracapsular extension (38% vs 48%; P = .022). On multivariable analysis, there was no association between race and metastases (hazard radio, 1.20; P = .45) or any of the other secondary outcomes (all P > .5). CONCLUSIONS: Among veterans who received ADT post-BCR after RP, race was not a predictor of metastases or other adverse outcomes. The current findings suggest that research efforts to understand racial differences in prostate cancer biology should focus on early stages of the disease (ie, closer to the time of diagnosis). PMID- 30427536 TI - Reply to Annual Report to the Nation on the Status of Cancer, Part II: Recent changes in prostate cancer trends and disease characteristics. PMID- 30427537 TI - Prevalence and risk factors for RBC alloantibodies in blood donors in the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III). AB - BACKGROUND: Little information exists on red blood cell (RBC) alloimmunization in healthy US blood donors, despite the potential significance for donors themselves, blood recipients, and the blood center. STUDY DESIGN AND METHODS: Donor/donation data were sourced from the Recipient Epidemiology and Donor Evaluation Study-III, which contains information from four US blood centers during 2012 through 2016. Multivariable logistic regression was used to assess prevalence of positive antibody screen by donor demographics, blood type, parity, and transfusion history. RESULTS: More than 2 million units were collected from 632,378 donors, with 0.51% of donations antibody screen positive and 0.77% of donors having at least one positive antibody screen. The most common antibody specificities were D (26.4%), E (23.8%), and K (21.6%). Regression analysis indicated that increasing age, female sex, D-negative status, and history of transfusion and pregnancy were positively associated with a positive antibody screen. Prior transfusion history was most strongly associated with a positive antibody screen, with donors reporting a prior transfusion having a higher adjusted odds ratio (3.9) of having a positive antibody screen compared to donors reporting prior pregnancy (adjusted odds ratio, 2.0). Though transfusion was a more potent immune stimulus for RBC alloantibody formation than pregnancy, the sheer number of previously pregnant donors contributed to pregnancy being a risk factor for the majority of clinically significant RBC alloantibodies detected in females. CONCLUSION: These findings on prevalence of and risk factors for RBC antibodies may have implications for future medical care of donors and for operations at blood centers. PMID- 30427538 TI - STAT6 inhibitory peptide reduces dendritic cell migration to the lymph nodes to control Th2 adaptive immunity in the mouse lung. AB - Type 2 immunity in the lung is promoted through the release of innate cytokines, including TSLP, from lung structural cells. These cytokines drive Type 2 immunity in part through upregulation of OX40L on dendritic cells (DCs). DCs expressing OX40L are potent inducers of Th2 differentiation. We have shown previously that STAT6 inhibitory peptide (STAT6-IP), a cell penetrating peptide designed to inhibit the STAT6 transcription factor, reduces the induction of Th2 adaptive immunity in murine models of respiratory syncytial virus infection. Here we show that intranasal administration of STAT6-IP at the time of antigen priming with ovalbumin (OVA), in conjunction with the Nod2 agonist, MDP, reduced frequencies of CD11b+ lung DCs expressing OX40L. Consistent with these reductions, fewer activated DCs were localized to the lung draining lymph nodes in STAT6-IP-treated mice. Upon OVA challenge four weeks later, mice treated with STAT6-IP at the time of OVA/MDP priming did not develop airway hyperresponsiveness (AHR) and had reduced influx of eosinophils into the airways, mucus production, and serum OVA specific IgE levels. Our findings provide evidence that the long-lasting inhibitory effects of STAT6-IP are due in part to inhibition of DC responses that drive maladaptive Th2 adaptive immunity and allergic airways disease. This article is protected by copyright. All rights reserved. PMID- 30427539 TI - Regional differences in gallbladder cancer pathogenesis: Insights from a multi institutional comparison of tumor mutations. AB - BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials. PMID- 30427540 TI - Evaluation of the National Healthcare Safety Network Hemovigilance Module for transfusion-related adverse reactions in the United States. AB - INTRODUCTION: The National Healthcare Safety Network (NHSN) Hemovigilance Module (HM) collects data on the frequency, severity, and imputability of transfusion associated adverse events. These events contribute to significant morbidity and mortality among transfusion patients. We report results from the first systematic assessment of eight attributes of the HM. MATERIALS AND METHODS: Standard methods were used to assess the HM. Evaluation data included training materials, system modification history, and facility survey information. A concordance analysis was performed using data from the Baystate Medical Center's (Boston, MA) electronic transfusion reporting system. RESULTS: In 2016, system representativeness remained low, with 6% (277 of 4690) of acute care facilities across 43 jurisdictions enrolled in the HM. In 2016, 48% (2147 of 4453) and 89% (3969 of 4,453) of adverse reactions were reported within 30 and 90 days of the reaction date, respectively, compared to 21% (109 of 511) and 56% (284 of 511) in 2010, demonstrating improved reporting timeliness. Data quality from most reactions was adequate, with 10% (45 of 442) misclassified transfusion-associated circulatory overload reactions, and no incomplete transfusion-transmitted infection data reported from 2010 to 2013. When compared to the Baystate system to assess concordance, 43% (24 of 56) of NHSN-reported febrile reactions were captured in both systems (unweighted kappa value, 0.47; confidence interval, 0.33-0.61). CONCLUSION: Since the 2010 HM pilot, improvements have led to enhanced simplicity, timeliness, and strengthened data quality. The HM serves an important and unique role despite incomplete adoption nationwide. Facility efforts to track and prevent transfusion-associated adverse events through systems like the NHSN HM are a key step toward improving transfusion safety in the United States. PMID- 30427541 TI - Silver Nanorings: New generation of Transparent Conductive Films. AB - Low-cost and high yield silver nanorings with uniform ring diameter of 15+/-5 um and thickness of 120+/-20 nm were synthesized via a simple solvothermal method. As we know, it is the first time that solvothermal method is used to prepare silver nanorings. Herein, by using ammonium salts as an additive salts in the present of pressure inside the reactor, the repeatability and yield of nanorings extremely increased. The prepared silver nanorings easily dispersed in ethanol and coated by spray method on PET substrate to make flexible transparent conductive film (TCF). The film based on nanorings was shown better opto electrical properties (higher transparency with lower haze) in comparison with nanowires with higher aspect ratio and lower thickness, at the same sheet resistance (Rs). These results introduce silver nanorings as an outstanding candidate for optoelectronics applications. PMID- 30427542 TI - Evaluation of a new West Nile virus nucleic acid test for screening of blood donations. AB - BACKGROUND: West Nile virus (WNV) is transmitted to humans through mosquito bites and can be further transmitted to humans through transfusion or transplantation. Because most infected individuals are asymptomatic, blood donor screening is important in areas where WNV is endemic. These studies evaluated the performance of a new test for detection of WNV RNA in blood donations. STUDY DESIGN AND METHODS: Analytical performance evaluation included sensitivity, specificity, inclusivity, and correlation. A clinical specificity study was conducted at four blood donor testing laboratories in parallel with the cobas TaqScreen WNV Test (Roche Molecular Systems, Inc.). RESULTS: The 95% and 50% limit of detection for cobas WNV was 12.9 copies/mL (95% confidence interval [CI], 10.8-16.3) and 2.1 copies/mL (95% CI, 1.9-2.4) for WNV lineage 1, respectively, and 6.2 copies/mL (95% CI, 4.8-8.9) and 1.1 copies/mL (95% CI, 0.8-1.3) for WNV lineage 2, respectively. Clinical specificity was 100% in 10,823 donor samples tested individually (95% CI, 99.966%-100%) and 63,243 tested in pools of 6 (95% CI, 99.994%-100%). Samples of other members of the Japanese encephalitis virus serocomplex, including St Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, Usutu, and Kunjin viruses were detected by cobas WNV. CONCLUSION: The cobas WNV test for use on the cobas 6800/8800 System, a fully automated test system, demonstrated high sensitivity and specificity and is suitable for the detection of WNV in blood donors. PMID- 30427543 TI - Combined effect of titanium dioxide nanoparticles and glucose on the cardiovascular system in young rats after oral administration. AB - Titanium dioxide nanoparticles (TiO2 NPs) have already been used as food additive in various products and are usually consumed with a considerable amount of sugar. Oral consumption of TiO2 NPs poses concerning health risks; however, research on the combined effect of ingested TiO2 NPs and glucose is limited. We examined young Sprague-Dawley rats administrated TiO2 NPs orally at doses of 0, 2, 10 and 50 mg/kg body weight per day with and without 1.8 g/kg body weight glucose for 30 and 90 days. Heart rate, systolic and diastolic blood pressure, blood biochemical parameters and histopathology of cardiac tissues was assessed to quantify cardiovascular damage. The results showed that oral exposure to TiO2 NPs and high doses of glucose both could induce cardiovascular injuries. The toxic effects were dose-, time- and gender-dependent. The interaction effects between oral exposed TiO2 NPs and glucose existed and revealed to be antagonism in most of the biological parameters. However, toxic effects of the high-dose glucose seemed to be more severe than TiO2 NPs and the interaction of TiO2 NPs with glucose. These results suggest that it may be more important to control the sugar intake than TiO2 NPs for protecting the health of TiO2 NP consumers. PMID- 30427544 TI - Poor Vitamin K Status Is Associated With Low Bone Mineral Density and Increased Fracture Risk in End-Stage Renal Disease. AB - Chronic kidney disease and osteoporosis are major public health problems associated with an aging population. Vitamin K insufficiency is prevalent among patients with end-stage renal disease (ESRD). Preliminary data indicate that poor vitamin K status may compromise bone health and that increased inflammation may be in the causal pathway. We performed an ancillary analysis of data collected in the frame of prospective observational cohort studies exploring various aspects of bone health in de novo renal transplant recipients to investigate the association between vitamin K status, inflammation, bone mineral density, and incident clinical fractures. Parameters of mineral metabolism (including biointact PTH and FGF23, sclerostin, calcidiol, calcitriol) and inflammation (CRP and IL-6), osteoprotegerin, bone turnover markers (P1NP, BsAP, and TRAP5B), and dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were assessed on blood samples collected immediately prior to kidney transplantation in 468 patients. Areal bone mineral density (aBMD) was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry within 14 days posttransplant. Poor vitamin K status, defined by dp-ucMGP >500 nmol/L, was highly prevalent (90%). High dp-ucMGP levels independently associated with elevated inflammatory markers and low aBMD. No associations were observed between vitamin K status and bone turnover markers. During a median follow-up of 5.1 years, 33 patients sustained a fragility fracture. In Cox-proportional hazards analysis, a dp-ucMGP above median associated with incident fractures, independent of classical determinants, including age, gender, history of fracture, and aBMD (HR 2.21; 95% CI, 1.00 to 4.91; p < 0.05). In conclusion, poor vitamin K status associates with inflammation and low aBMD in patients with ESRD and confers an increased risk of incident fractures in de novo renal transplant recipients. (c) 2018 American Society for Bone and Mineral Research. PMID- 30427545 TI - Glial GLP1R: A novel neuroprotector? PMID- 30427546 TI - Challenges in accurately assessing prenatal alcohol exposure in a study of Fetal Alcohol Spectrum Disorder in a youth detention center. AB - BACKGROUND: Prenatal alcohol exposure (PAE) can result in permanent disability, including physical, neurodevelopmental and cognitive impairments, known as Fetal Alcohol Spectrum Disorder (FASD). Individuals with FASD are more likely to engage with the law, including being placed in detention, than individuals without FASD. Young people who were sentenced to detention participated in a FASD prevalence study in Western Australia (WA). The diagnosis of FASD requires a multidisciplinary assessment and confirmation of maternal alcohol consumption during pregnancy. Obtaining accurate assessment of prenatal alcohol exposure (PAE) for young people participating in the study was challenging. METHOD: An interview with the birth mother or other responsible adult for young people sentenced to detention in WA was conducted as part of the FASD assessment. The Alcohol Use Disorders Identification Test, consumption subset (AUDIT-C), other relevant questions and documentary evidence were used to assess PAE. PAE was categorized according to the Australian Guide to the Diagnosis of FASD: no PAE reported, confirmed or confirmed high-risk, or unknown. RESULTS: Among the 101 participants, information on PAE was unable to be obtained for 13 (13%) young people. Of the remaining 88 participants with information of PAE, 41 reported no PAE and 47 had confirmed PAE. CONCLUSION: Accurately assessing prenatal alcohol consumption is challenging in any setting but it is exceptionally challenging when assessed 13-17 years retrospectively as part of a FASD assessment for a young person sentenced to detention. Recording and recoding detailed qualitative responses was required to provide an accurate assessment of PAE using the AUDIT C. Standardized recording of PAE in antenatal and birth records would facilitate later assessments for FASD and provide opportunities for advice and support for women who continue to drink during pregnancy. This article is protected by copyright. All rights reserved. PMID- 30427547 TI - Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high risk myelodysplastic syndrome. AB - OBJECTIVE: Short telomere length is a known risk factor for developing clonal hematopoietic stem cell disorders, probably due to chromosomal instability. We tested the hypotheses that bone marrow mononuclear cell telomere length change from diagnosis through chemotherapy-induced remission and relapse, and that long telomere length is associated with low risk of relapse and all-cause mortality in patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome. METHODS: We measured telomere length in bone marrow mononuclear cells from 233 patients at diagnosis, 112 patients at chemotherapy-induced remission and 58 patients at relapse of disease. RESULTS: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length was similar at diagnosis and relapse, but increased after chemotherapy induced remission. Furthermore, bone marrow mononuclear cell telomere length was longer in patients with higher age at diagnosis. There was no association between telomere length at diagnosis, remission or relapse and all-cause mortality, nor did we find any association between telomere length at diagnosis or remission and risk of relapse. CONCLUSION: In patients with acute myeloid leukaemia or high risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length increased from diagnosis to remission. Furthermore, telomere length paradoxically was longer at higher age at diagnosis, even after adjusting for known risk factors of disease severity. Finally, we did not detect any prognostic information in telomere length. This article is protected by copyright. All rights reserved. PMID- 30427549 TI - Use of a Lithotripter to Salvage a Bile duct stone and Kinking Retrieval Basket In the Distal Common Bile Duct. AB - A 65-year-old man was transferred from a secondary hospital after a bile duct stone and a retrieval basket became impacted in the common bile duct (CBD) during an endoscopic retrograde cholangiopancreatography (ERCP). Prior to transfer, lithotripsy after exchanging the basket sheath for a metal sheath was tried but failed because of the fracture of a wire near the patient's mouth. After transfer to our facility, we attempted an ERCP prior to considering surgery. This article is protected by copyright. All rights reserved. PMID- 30427548 TI - Spontaneous astrocytic Ca2+ activity abounds in electrically suppressed ischemic penumbra of aged mice. AB - Experimental focal cortical ischemic lesions consist of an ischemic core and a potentially salvageable peri-ischemic region, the ischemic penumbra. The activity of neurons and astrocytes is assumed to be suppressed in the penumbra because the electrical function is interrupted, but this is incompletely elucidated. Most experimental stroke studies used young adult animals, whereas stroke is prevalent in the elderly population. Using two-photon imaging in vivo, we here demonstrate extensive but electrically silent, spontaneous Ca2+ activity in neurons and astrocytes in the ischemic penumbra of 18- to 24-month-old mice 2-4 hr after middle cerebral artery occlusion. In comparison, stroke reduced spontaneous Ca2+ activity in neurons and astrocytes in adult mice (3-4 months of age). In aged mice, stroke increased astrocytic spontaneous Ca2+ activity considerably while neuronal spontaneous Ca2+ activity was unchanged. Blockade of action potentials and of purinergic receptors strongly reduced spontaneous Ca2+ activity in both neurons and astrocytes in the penumbra of old stroke mice. This indicates that stroke had a direct influence on mechanisms in presynaptic terminals and on purinergic signaling. Thus, highly dynamic variations in spontaneous Ca2+ activity characterize the electrically compromised penumbra, with remarkable differences between adult and old mice. The data are consistent with the notion that aged neurons and astrocytes take on a different phenotype than young mice. The increased activity of the aged astrocyte phenotype may be harmful to neurons. We suggest that the abundant spontaneous Ca2+ activity in astrocytes in the ischemic penumbra of old mice may be a novel target for neuroprotection strategies. A video abstract of this article can be found at https://youtu.be/AKlwKFsz1qE. PMID- 30427550 TI - Population Pharmacokinetics of Adjunctive Lacosamide in Pediatric Patients With Epilepsy. AB - A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose. PMID- 30427551 TI - The acceleration of CAR-T therapy in non-Hodgkin lymphoma. AB - Recent advances in diffuse large B-cell lymphomas have included both identification of high-risk subtypes characterized by multiply relapsed and/or refractory disease as well as novel treatment in the form of cellular therapy. Chimeric antigen receptor (CAR)-T cell therapy is a recently developed approach to address the poor outcomes in this patient population. The CAR-T cell construct has evolved although several iterations as it transitioned from the lab to the clinic. Three major studies have evaluated the efficacy of CD19-directed CAR-T cell therapy in aggressive B-cell non-Hodgkin lymphoma; each demonstrating durable complete remissions in heavily pretreated patients. The cost of this remarkable therapy, however, includes cytokine release syndrome and neurotoxicity shortly after administration as well as delayed infectious complications due to B cell aplasia. Future investigations are focused on the optimizing both safety and efficacy of CAR-T cell therapy. PMID- 30427552 TI - Earlier onset of motor complications in Parkinson's patients with comorbid diabetes mellitus. PMID- 30427553 TI - FLAD1, encoding FAD synthase, is mutated in a patient with myopathy, scoliosis and cataracts. PMID- 30427554 TI - Homozygous splicing mutation in NUP133 causes Galloway-Mowat syndrome. AB - OBJECTIVE: Galloway-Mowat syndrome (GAMOS) is a neural and renal disorder, characterized by microcephaly, brain anomalies, and early-onset nephrotic syndrome. Biallelic mutations in WDR73 and the four subunit genes of the KEOPS complex are reported to cause GAMOS. Furthermore, an identical homozygous NUP107 (nucleoporin 107 kDa) mutation was identified in four GAMOS-like families, although biallelic NUP107 mutations were originally identified in steroid resistant nephrotic syndrome. NUP107 and NUP133 (nucleoporin 133 kDa) are interacting subunits of the nuclear pore complex in the nuclear envelope during interphase, and these proteins are also involved in centrosome positioning and spindle assembly during mitosis. METHODS: Linkage analysis and whole exome sequencing were performed in a previously reported GAMOS family with brain atrophy and steroid-resistant nephrotic syndrome. RESULTS: We identified a homozygous NUP133 mutation, c.3335-11T>A, which results in the insertion of 9 bp of intronic sequence between exons 25 and 26 in the mutant transcript. NUP133 and NUP107 interaction was impaired by the NUP133 mutation based on an immunoprecipitation assay. Importantly, focal cortical dysplasia type IIa was recognized in the brain of an autopsied patient and focal segmental glomerulosclerosis was confirmed in the kidneys of the three examined patients. A nup133-knockdown zebrafish model exhibited microcephaly, fewer neuronal cells, underdeveloped glomeruli, and fusion of the foot processes of the podocytes, which mimicked human GAMOS features. nup133 morphants could be rescued by human wildtype NUP133 mRNA but not by mutant mRNA. INTERPRETATION: These data indicate that the biallelic NUP133 loss-of-function mutation causes GAMOS. This article is protected by copyright. All rights reserved. PMID- 30427555 TI - Investigation of stress and nursing support in mothers of preterm infants in neonatal intensive care units. AB - BACKGROUND: The birth and hospitalisation of a premature infant in a neonatal intensive care unit (NICU) are stressful experiences for the mother and the family. The support of neonatal nurses is necessary to control and reduce the stress of mothers. And nurse-parent support may play a role in effective stress management and make a positive contribution to the health of mothers. AIM: To determine the correlation of stress and nurse-parent support levels with mothers' age and educational status, number of children, gestational week of the infant and the hospitalisation period of the infant among mothers of premature infants hospitalised in the NICU. METHODS: This descriptive and cross-sectional study was conducted in the NICUs of two medical faculties. The study was conducted between March and June 2017 with the participation of 106 mothers with hospitalised premature infants. The data of the study were collected using a 'mother information form', Parental Stressor Scale: Neonatal Intensive Care Unit and Nurse-Parent Support Tool. Number, percentage, mean, standard deviation, t-test, analysis of variance test, Pearson's correlation and multiple regression analysis were used to analyse the data. RESULTS: It was determined that the stress levels were high in mothers regarding their PSS: NICU parental role subscale. The stress levels of mothers with infants connected to mechanical ventilation and fed parenterally were high (p < 0.05). The nurse support levels of mothers with middle- and low-income status were high. Multiple regression analysis, mechanical ventilation was determined to be effective in the use of the PSS:NICU total score (p < 0.05). CONCLUSIONS: As a result, it was determined that mechanical ventilation and parenteral nutrition of the infant increased the stress level of mothers. Furthermore, in the study, the Nurse-Parent Support score of the mothers with middle- and low-income status was higher. PMID- 30427556 TI - Dual institution validation of an ageism scale for dental students. AB - PURPOSE/AIM: Ageism negatively affects health care. This paper presents an extended validation of a novel scale assessing ageism among dental students. METHOD AND MATERIALS: A previously pilot-tested 27-question scale applied to a larger sample (n = 315) from two U.S. dental schools with Principal Component Analysis used to assess internal structure of the measure. Questions whose deletion increased the overall alpha loading on >1 factor or those unexpectedly grouped in another factor were thoroughly examined. RESULTS: The scale resulted in five statements (grouped in two factors), which explained 63% of the overall variance with a substantially higher reliability value than other solutions (0.76). Two factors highly correlated were grouped together in a single scale. The five statements are "Elderly people do not take good care of their teeth" (0.62), "Elderly patients do not usually comply with dental advice" (0.93), "The Elderly patient does not live long enough to make it worthwhile to invest time and effort in complex dental treatment" (0.81), "The elderly patient does not live long enough to make it worthwhile to invest money in expensive dental treatment" (0.95), and "Dental treatment of elderly patients is too time consuming" (0.57). CONCLUSIONS: Five items achieved high reliability toward the validity of this scale. PMID- 30427558 TI - Selective inhibitors of a human prolyl hydroxylase (OGFOD1) involved in ribosomal decoding. AB - Human prolyl hydroxylases are involved in the modification of transcription factors, procollagen, and ribosomal proteins, and are current medicinal chemistry targets. To date, there are few reports on inhibitors selective for the different types of prolyl hydroxylases. Here we report a structurally informed template based strategy for the development of inhibitors selective for the human ribosomal prolyl hydroxylase OGFOD1. These inhibitors did not target the other human oxygenases tested, including the structurally-similar hypoxia-inducible transcription factor prolyl hydroxylase, PHD2. PMID- 30427557 TI - Mandibular Implant-Retained Overdentures: Potential Accelerator of Bone Loss in the Anterior Maxilla? AB - PURPOSE: To compare the residual ridge resorption (RRR) of the anterior maxillary bone beneath complete dentures when opposed by mandibular complete dentures (CD) and implant-retained overdentures (IRO). MATERIALS AND METHODS: 18 patients were rehabilitated with maxillary CD opposing mandibular IRO, and 4 patients were prescribed with conventional CD. Cone beam computed tomography (CBCT) scans of the maxilla were acquired before and 1 year post-treatment and converted into 3D models using Mimics research software. RRR was quantified by measuring the changes in bone volume following superimpositioning and sectioning of these models at the anterior maxillary region. Subsequently, the sectioned 3D models of the anterior maxilla were exported to 3-Matic software to reveal the predominant region and depth of RRR. RESULTS: The mean reduction in bone volume of the anterior maxilla in the CD group was 2.60% (SD = 1.71%, range = -4.89 % to 0.92%, median = -2.30%), while the mean reduction in the IRO group was almost three times higher at 7.25% (SD = 3.16%, range = -13.25 to -1.50, median = 7.15%). The predominant areas of RRR were on the buccal and occlusal ridge of the anterior maxilla. CONCLUSION: Within the limits of this study, it may be concluded that an IRO caused significantly higher RRR of the anterior maxilla than a CD. PMID- 30427559 TI - Should they stay or should they go? Nitric oxide and the clash of regulators governing Vibrio fischeri biofilm formation. AB - A key regulatory decision for many bacteria is the switch between biofilm formation and motile dispersal, and this dynamic is well illustrated in the light organ symbiosis between the bioluminescent bacterium Vibrio fischeri and the Hawaiian bobtail squid. Biofilm formation mediated by the syp gene cluster helps V. fischeri transition from a dispersed planktonic lifestyle to a robust aggregate on the surface of the nascent symbiotic organ. However, the bacteria must then swim to pores and down into the deeper crypt tissues that they ultimately colonize. A number of positive and negative regulators control syp expression and biofilm formation, but until recently the environmental inputs controlling this clash between opposing regulatory mechanisms have been unclear. Thompson et al. have now shown that Syp-mediated biofilms can be repressed by a well known host-derived molecule: nitric oxide. This regulation is accomplished by the NO sensor HnoX exerting control over the biofilm regulator HahK. The discoveries reported here by Thompson et al. cast new light on a critical early stage of symbiotic initiation in the V. fischeri-squid model symbiosis, and more broadly it adds to a growing understanding of the role(s) that NO and HnoX play in biofilm regulation by many bacteria. This article is protected by copyright. All rights reserved. PMID- 30427560 TI - Targeting hippocampal adult neurogenesis using transcription factors to reduce Alzheimer's disease-associated memory impairments. AB - Hippocampal adult neurogenesis results in the persisting formation of new neurons that contribute to hippocampal-dependent learning and memory. This has led to the hypothesis that memory impairments associated with neurodegenerative diseases such as Alzheimer's disease may involve abnormal neurogenesis. Supporting this idea, evidence for decreased adult neurogenesis has been reported in the brain of Alzheimer's disease patients and in several mouse models of the disease. Thus, the development of strategies designed to stimulate the production of new neurons in the diseased brain has raised growing interest. In this review, we discuss putative strategies and present recent studies showing that it is now possible to instruct hippocampal endogenous neural progenitors to adopt an exclusive neuronal fate. We further report how such strategies lead to the rescue of cognitive functions in mouse models of Alzheimer's disease. Altogether, these findings provide the proof-of-concept that neurogenesis can be stimulated in the adult brain in vivo, and consequently overcomes pathological memory deficits. PMID- 30427561 TI - Firing properties of ventral medullary respiratory neurons in sino-aortic denervated rats. AB - NEW FINDINGS: What is the central question of this study? After sino-aortic denervation (SAD) rats present normal levels of mean arterial pressure (MAP), high MAP variability and changes in breathing. However, mechanisms involved in SAD-induced respiratory changes and their impact on the modulation of sympathetic activity remain unclear. Herein, we characterized the firing frequency of medullary respiratory neurons after SAD. What is the main finding and its importance? SAD-induced prolonged inspiration was associated with a reduced interburst frequency of Pre-I/I and an increased long-term variability of Late-I neurons, but no changes were observed in the Ramp-I and Post-I neurons. This imbalance in the respiratory network may contribute to the modulation of sympathetic activity after SAD. ABSTRACT: In previous studies we documented that after sino-aortic denervation (SAD) in rats there are significant changes in the breathing pattern, but no significant changes in sympathetic activity and mean arterial pressure (MAP) compared with Sham-operated rats. However, the neural mechanisms involved in the respiratory changes after SAD and the extent to which they may contribute to the observed normal sympathetic activity and MAP remain unclear. Here, we hypothesized that after SAD, rats present with changes in the firing frequency of the ventral medullary inspiratory and post-inspiratory neurons. To test this hypothesis, male Wistar rats underwent SAD or Sham surgery and 3 days later were surgically prepared for an in situ preparation. The duration of inspiration significantly increased in SAD rats. During inspiration, the total firing frequency of Ramp-I, Pre-I / I, and Late-I neurons was not different between groups. During post-inspiration, the total firing frequency of Post-I neurons was also not different between groups. Furthermore, the data demonstrate a reduced interburst frequency of Pre-I/I and an increased long-term variability of Late-I neurons in SAD compared with Sham rats. These findings indicate that the SAD-induced prolonged inspiration was not accompanied by alterations in the total firing frequency of the ventral medullary respiratory neurons, but it was associated with changes in the long-term variability of Late I neurons. We suggest that the timing imbalance in the respiratory network in SAD rats may contribute to the modulation of presympathetic neurons after removal of baroreceptor afferents. This article is protected by copyright. All rights reserved. PMID- 30427562 TI - Cyaarside (CAs-) and 1,3-Diarsaallendiide (AsCAs2-) Ligands Coordinated to Uranium and Generated via Activation of the Arsaethynolate Ligand (OCAs-). AB - Reaction of the trivalent uranium complex [((Ad,MeArO)3N)-U(DME)] with one molar equivalent [Na(OCAs)(dioxane)3], in the presence of 2.2.2-crypt, yields [Na(2.2.2 crypt)]-[{((Ad,MeArO)3N)-UIV(THF)}-(MU-O)-{((Ad,MeArO)3N)-UIV(CAs)}] (1), which is the arsenic containing analogue of the previously reported, MU-oxo-bridged di uranium cyaphide complex. The structural characterization of complex 1 reveals the first example of a coordinated eta1-cyaarside ligand (CAs-). The terminal CAs anionic ligand formation is promoted by the highly reducing, oxo-philic uranium(III) precursor [((Ad,MeArO)3N)-U(DME)] and proceeds through reductive C-O bond cleavage of the bound arsaethynolate anion, OCAs-. If two equivalents of OCAs- are allowed to react with the uranium(III) precursor, the binuclear, u-oxo bridged diuran-ium(IV/IV) complex [Na(2.2.2-crypt)]2-[{((Ad,MeArO)3N)-UIV}2-(MU O)(MU-AsCAs)] (2), comprising the hitherto unknown MU:eta1,eta1-coordinated (AsCAs)2- ligand, is isolated. The mechanistic pathway en route to the metalla arsa-allene complex forma-tion likely is the decarbonylation of a dimeric inter mediate formed in the reaction of 1 with OCAs-. An alternative path-way to complex 2 is the conver-sion of complex 1 to 2 by addition of one further equivalent of OCAs-. The mechanistic proposals are corroborated by DFT calculations. PMID- 30427563 TI - Evidence of predisposing epimutation in retinoblastoma. AB - Retinoblastoma (RB), which represents the most common childhood eye cancer, is caused by biallelic inactivation of RB1 gene. Promoter hypermethylation is quite frequent in RB tissues but conclusive evidence of soma-wide predisposing epimutations is currently scant. Here, 50 patients who tested negative for RB1 germline sequence alterations were screened for aberrant promoter methylation using methylation-specific MLPA. The assay, performed on blood, identified a sporadic patient with methylation of CpG106, absent in parents' DNA. Bisulfite pyrosequencing accurately quantified CpG methylation in blood DNA (mean ~49%) and also confirmed the aberration in DNA isolated from oral mucosa although at lower levels (mean ~34%). Using a tag-SNP, methylation was demonstrated to affect the maternal allele. Real-time qPCR demonstrated RB1 transcriptional silencing. In conclusion, we documented that promoter methylation can act as the first "hit" in Knudson's model. This mosaic epimutation mimics the effect of an inactivating mutation and phenocopies RB onset. PMID- 30427564 TI - Effects of glial glutamate transporter activator in formalin-induced pain behavior in mice. AB - BACKGROUND: Nociceptive pain remains a prevalent clinical problem and often poorly responsive to the currently available analgesics. Previous studies have shown that astroglial glutamate transporter-1 (GLT-1) in the hippocampus and anterior cingulate cortex (ACC) is critically involved in pain processing and modulation. However, the role of astroglial GLT-1 in nociceptive pain involving the hippocampus and ACC remains unknown. We investigated the role of 3-[[(2 Methylphenyl) methyl]thio]-6-(2-pyridinyl)-pyridazine (LDN-212320), a GLT-1 activator, in nociceptive pain model and hippocampal-dependent behavioral tasks in mice. METHODS: We evaluated the effects of LDN-212320 in formalin-induced nociceptive pain model. In addition, formalin-induced impaired hippocampal dependent behaviors were measured using Y-maze and object-recognition test. Furthermore, GLT-1 expression and extracellular signal-regulated kinase phosphorylation (pERK1/2) were measured in the hippocampus and ACC using Western blot analysis and immunohistochemistry. RESULTS: The LDN-212320 (10 or 20 mg/kg, i.p) significantly attenuated formalin-evoked nociceptive behavior. The anti nociceptive effects of LDN-212320 were reversed by systemic administration of DHK (10 mg/kg, i.p), a GLT-1 antagonist. Moreover, LDN-212320 (10 or 20 mg/kg, i.p) significantly reversed formalin-induced impaired hippocampal-dependent behavior. In addition, LDN-212320 (10 or 20 mg/kg, i.p) increased GLT-1 expressions in the hippocampus and ACC. On the other hand, LDN-212320 (20 mg/kg, i.p) significantly reduced formalin induced-ERK phosphorylation, a marker of nociception, in the hippocampus and ACC. CONCLUSION: These results suggest that the GLT-1 activator LDN-212320 prevents nociceptive pain by upregulating astroglial GLT-1 expression in the hippocampus and ACC. Therefore, GLT-1 activator could be a novel drug candidate for nociceptive pain. This article is protected by copyright. All rights reserved. PMID- 30427566 TI - Selective Array-based Sensing of Anabolic Steroids in Aqueous Solution by Host:Guest Reporter Complexes. AB - Arrayed complexes of a water-soluble deep cavitand and two fluorescent indicators show selective sensing of anabolic-androgenic steroids in aqueous environments. By combining the host:guest complexes with small amounts of heavy metal ions, discrimination between steroids that vary in structure by only a single pi bond is possible. The sensing occurs via a triggered aggregation mechanism, which can be mediated by both the presence of metal ions and the steroids. The use of both "turn-on" and "turn-off" fluorophores is essential for good discrimination. As low as 10 uM steroid can be detected, and the discrimination is selective in steroid samples spiked into human urine. PMID- 30427565 TI - Experimentally Calibrated Analysis of the Electronic Structure of CuO+ : Implications for Reactivity. AB - The CuO+ core is a central motif of reactive intermediates in copper-catalysed oxidations occurring in nature. The high reactivity of CuO+ stems from a weak bonding between the atoms, which cannot be described by a simple classical model. To obtain the correct picture, we have investigated the acetonitrile-ligated CuO+ ion using neon-tagging photodissociation spectroscopy at 5 K. The spectra feature complex vibronic absorption progressions in NIR and visible regions. Employing Franck-Condon analyses, we derived low-lying triplet potential energy surfaces that were further correlated with multireference calculations. This provided insight into the ground and low-lying excited electronic states of the CuO+ unit and elucidated how these states are perturbed by the change in ligation. Thus, we show that the bare CuO+ ion has prevailingly a copper(I)-biradical oxygen character. Increasing the number of ligands coordinated to copper changes the CuO+ character towards the copper(II)-oxyl radical structure. PMID- 30427567 TI - Prevalence of FVIII inhibitors in severe haemophilia A patients: Effect of treatment and genetic factors in an Indian population. AB - INTRODUCTION: Factor replacement therapy in treatment of haemophilia A is complicated by the production of neutralising antibodies known as inhibitors. The formation of inhibitors is multifactorial being associated with both genetic and environmental factors. AIM: To document the prevalence of inhibitors in severe haemophilia in the community where most patients receive only infrequent episodic replacement therapy and evaluate the factors which could be contributing to it. METHODS: Community based camps were conducted in different parts of the country. Patients were assessed through a structured questionnaire and blood samples were obtained for laboratory evaluation of inhibitors and defined immunological parameters. RESULTS: Inhibitors were present in 87/447 (19.5%) of the evaluated patients. High-titre inhibitor (>5 Bethesda Units [BU]) was identified in 31 (35.6%) patients. HLA DRB1-13-positive cases (RR = 2.04; 95% CI 1.06-3.911; P = 0.033) had an increased risk of inhibitor formation which was retained in the high-titre subset. A decreased risk of inhibitor formation was noted with heterozygous IL4-590 C/T allele (RR = 0.22; 95% CI 0.108-0.442: P = 0.000). There were no significant correlations between any of the evaluated environmental factors and the development of inhibitors in this study. CONCLUSION: The overall prevalence of inhibitors in patients with severe haemophilia A is similar to that reported among patients receiving regular replacement therapy. The data from this study, limited by its retrospective and cross-sectional study design, would suggest that genetic rather than environmental are more likely to impact the development of inhibitors. PMID- 30427568 TI - Bioinspired Radical Stetter Reaction: Radical Umpolung Enabled by Ion-Pair Photocatalysis. AB - A bioinspired, intermolecular radical Stetter reaction of alpha-keto acids and aldehydes is disclosed that is contingent on a formal "radical-Umpolung" concept. Enabled by secondary amine activation, electrostatic recognition ensures that the alpha-ketocarboxylic acids, which function as latent acyl radicals, are proximal to the in-situ generated iminium salts. This photoactive contact ion-pair is an electron-donor-acceptor (EDA) complex, which undergoes facile single electron transfer (SET) and rapid decarboxylation prior to radical-radical recombination. Importantly, decarbonylation is mitigated via this strategy. The initial computational validation on which the process is predicated matches closely with experiment. Synergising organo- and photo-catalysis activation principles finally expands the mechanistic and synthetic scope of the classic Stetter reaction to include alpha,beta-unsaturated aldehydes as acceptors. PMID- 30427569 TI - Phosphorus-Mediated MoS2 Nanowires as a High-Performance Electrode Material for Quasi-Solid-State Sodium-Ion Intercalation Supercapacitors. AB - Molybdenum disulfide (MoS2 ) is a promising electrode material for electrochemical energy storage owing to its high theoretical specific capacity and fascinating 2D layered structure. However, its sluggish kinetics for ionic diffusion and charge transfer limits its practical applications. Here, a promising strategy is reported for enhancing the Na+ -ion charge storage kinetics of MoS2 for supercapacitors. In this strategy, electrical conductivity is enhanced and the diffusion barrier of Na+ ion is lowered by a facile phosphorus doping treatment. Density functional theory results reveal that the lowest energy barrier of dilute Na-vacancy diffusion on P-doped MoS2 (0.11 eV) is considerably lower than that on pure MoS2 (0.19 eV), thereby signifying a prominent rate performance at high Na intercalation stages upon P-doping. Moreover, the Na vacancy diffusion coefficient of the P-doped MoS2 at room temperatures can be enhanced substantially by approximately two orders of magnitude (10-6 -10-4 cm2 s 1 ) compared with pure MoS2 . Finally, the quasi-solid-state asymmetrical supercapacitor assembled with P-doped MoS2 and MnO2 , as the positive and negative electrode materials, respectively, exhibits an ultrahigh energy density of 67.4 W h kg-1 at 850 W kg-1 and excellent cycling stability with 93.4% capacitance retention after 5000 cycles at 8 A g-1 . PMID- 30427570 TI - Accurate Determination of Human CPR Conformational Equilibrium by smFRET using Dual Orthogonal Non-Canonical Amino Acid Labeling. AB - Conjugation of fluorescent dyes to proteins - a prerequisite for the study of conformational dynamics by single molecule Forster resonance energy transfer (smFRET) - can lead to substantial changes of the dye's photophysical properties, ultimately biasing the determination of inter-dye distances. In particular, cyanine dyes and their derivatives, the most used dyes in smFRET experiments, exhibit such behavior. To overcome this, we developed a general strategy to site specifically equip proteins with FRET pairs by chemo-selective reactions using two distinct non-canonical amino acids simultaneously incorporated through genetic code expansion in Escherichia coli. Applied to human NADPH-cytochrome P450 reductase (CPR), the importance of homogenously labeled samples for accurate determination of FRET efficiencies was demonstrated and the effect of NADP+ on the ionic strength dependent modulation of the conformational equilibrium of CPR was unveiled. Given its generality and accuracy, the presented methodology establishes a new benchmark to decipher complex molecular dynamics on single molecules. PMID- 30427571 TI - Making the SF5 Group More Accessible: A Gas Reagent-free Approach to Aryl Tetrafluoro-lambda6-sulfanyl Chlorides. AB - Modern pentafluorosulfanyl (SF5) chemistry has an Achilles heel: synthetic accessibility. Herein, we present the first approach to aryl-SF4Cl compounds (key intermediates in state-of-the-art aryl-SF5 synthesis) that overcomes the reliance on hazardous fluorinating reagents and/or gas reagents (e.g. Cl2) by employing easy-to-handle trichloroisocyanuric acid, potassium fluoride, and catalytic acid. These simple, mild conditions allow direct access to aryl-SF4Cl intermediates that have not been or cannot be demonstrated using previous methods. Furthermore, the same approach provides access to aryl-SF3 and aryl-SeF3 compounds, which extend the applications of this chemistry beyond arene SF5-functionalization, and demonstrate its ability to address a more general oxidative polyfluorination problem. PMID- 30427572 TI - Acoustic Actuation of Integrin-Bound Microbubbles for Mechanical Phenotyping during Differentiation and Morphogenesis of Human Embryonic Stem Cells. AB - Early human embryogenesis is a dynamic developmental process, involving continuous and concomitant changes in gene expression, structural reorganization, and cellular mechanics. However, the lack of investigation methods has limited the understanding of how cellular mechanical properties change during early human embryogenesis. In this study, ultrasound actuation of functionalized microbubbles targeted to integrin (acoustic tweezing cytometry, ATC) is employed for in situ measurement of cell stiffness during human embryonic stem cell (hESC) differentiation and morphogenesis. Cell stiffness, which is regulated by cytoskeleton structure, remains unchanged in undifferentiated hESCs, but significantly increases during neural differentiation. Further, using the recently established in vitro 3D embryogenesis models, ATC measurements reveal that cells continue to stiffen while maintaining pluripotency during epiblast cyst formation. In contrast, during amniotic cyst formation, cells first become stiffer during luminal cavity formation, but softens significantly when cells differentiate to form amniotic cysts. These results suggest that cell stiffness changes not only due to 3D spatial organization, but also with cell fate change. ATC therefore provides a versatile platform for in situ measurement of cellular mechanical property, and cell stiffness may be used as a mechanical biomarker for cell lineage diversification and cell fate specification during embryogenesis. PMID- 30427573 TI - Strategy and Effects of Polyproline Peptide Stapling by Copper(I)-catalyzed Alkyne-azide Cycloaddition Reaction. AB - Polyproline is a unique type of peptide that exhibits a stable, robust and well defined helical structure in an aqueous environment. These features have allowed polyproline to be employed as a nano-sized scaffold for applications in chemical biology and related fields. To understand its structural properties and to expand the applications, this secondary structure was tested systematically by stapling the peptide at different locations with various staple lengths. With the efficient Copper(I)-catalyzed Alkyne-azide Cycloaddition (CuAAC) reaction, we successfully prepared stapled polyproline and investigated the impact of this peptide macrocyclization through circular dichroism analysis. While the stapling seems to have no significant effect on polyproline helix II (PPII) conformation in water, the location and the length of the staple affect the transformation of conformation in n-propanol. These results provide valuable information for future research using peptide stapling to manipulate polyproline conformation for various applications. PMID- 30427574 TI - Body Mass Index as a Determinant of Systemic Exposure to Gallotannin Metabolites during 6-Week Consumption of Mango (Mangifera indica L.) and Modulation of Intestinal Microbiota in Lean and Obese Individuals. AB - SCOPE: This human clinical pilot trial investigated pharmacokinetics of gallotannin-metabolites and modulation of intestinal microbiota in healthy lean and obese individuals after 6 weeks of daily mango consumption. METHODS AND RESULTS: Participants are divided into three groups: Lean Mango (LM: n = 12; BMI = 22.9 kg m-2 ), Obese Mango (OM: n = 9; BMI = 34.6 kg m-2 ), and Lean Control (LC: n = 11; BMI = 22.1 kg m-2 ). LM and OM consumed 400 g of mango per day for 6 weeks. LC consumed mango only on Days 0 and 42. After 6 weeks, LM experienced increased systemic exposure (AUC0-8h ) to gallotannin-metabolites, 1.4-fold (p = 0.043). The greatest increase is 4-O-methyl-gallic acid, 3.3-fold (p = 0.0026). Cumulative urinary excretion of gallotannin-metabolites significantly increased in LM and OM, but not LC. For OM, qPCR data show increased levels of tannase producing Lactococcus lactis and decreased levels of Clostridium leptum and Bacteroides thetaiotaomicron, bacteria associated with obesity. LM experienced an increased trend of fecal levels of butyric (1.3-fold; p = 0.09) and valeric acids (1.5-fold; p = 0.056). Plasma endotoxins showed a decreased trend in LM and OM. CONCLUSION: Continuous mango intake significantly increased systemic exposure to gallotannin- metabolites and induced an increased trend for fecal short-chain fatty acids in lean but not obese individuals. This pharmacokinetic discrepancy may result in BMI-associated reduced gallotannin-derived health benefits. PMID- 30427575 TI - Optical Sensor for Real-Time pH Monitoring in Human Tissue. AB - This article reports on a fiber-based ratiometric optical pH sensor for use in real-time and continuous in vivo pH monitoring in human tissue. Stable hybrid sol gel-based pH sensing material is deposited on a highly flexible plastic optical fiber tip and integrated with excitation and detection electronics. The sensor is extensively tested in a laboratory environment before it is applied in vivo in a human model. The pH sensor performance in the laboratory environment outperforms the state-of-the-art reported in the current literature. It exhibits the highest sensitivity in the physiological pH range, resolution of 0.0013 pH units, excellent sensor to sensor reproducibility, long-term stability, short response time of <2 min, and drift of 0.003 pH units per 22 h. The sensor also exhibits promising performance in in vitro whole blood samples. In addition, human evaluations conducted under this project demonstrate successful short-term deployment of this sensor in vivo. PMID- 30427576 TI - Unfolding B?O?B Bonds for an Enhanced ORR Performance in ABO3 -Type Perovskites. AB - Identifying the relationship between catalytic performance and material structure is crucial to establish the design principle for highly active catalysts. Deficiency in B?O bond covalency induced by lattice distortion severely restricts the oxygen reduction reaction (ORR) performance for ABO3 -type perovskite oxides. Herein, a rearrangement of hybridization mode for B?O bond is used to tune the overlap of the electron cloud between B 3d and O 2p through A-stie doping with larger radius ions. The B?O bond covalency is strengthened with a B?O?B bond angle recovered from intrinsic structural distortion. As a result, the adsorption and the reduction process for O2 on the oxide surface can be promoted via shifting the O-2p band center toward the Fermi Level. Simultaneously, the spin electrons in the Mn 3d orbit become more parallel. It will lead to a high electrical conductivity by the enhanced double exchange process and thereof mitigate the ORR efficiency loss. Further density functional theory calculation reveals that a flat [BO2 ] plane will make contribution to the charge transfer process from lattice oxygen to adsorbed oxygen (mediated with B ions). Through such exploration of the effect of crystal structure on the electronic state of perovskite oxides, a novel insight into design of highly active ORR catalysts is offered. PMID- 30427577 TI - Control of Shell Morphology in p-n Heterostructured Water-Processable Semiconductor Colloids: Toward Extremely Efficient Charge Separation. AB - This article describes p-n heterostructured water-borne semiconductor naonoparticles (NPs) with unique surface structures via control of shell morphology. The shell particles, comprising PC60-[6,6]-phenyl-C61-butyric acid methyl ester (PC61 BM) composite, having n-type semiconductor characteristics, notably influence the charge carrier behavior in the core-shell NPs. A one- or two-phase methodology based on a PC60 surfactant-water phase and PC61 BM n-type semiconductor-organic phase provides highly specific control over the shell structure of the NPs, which promote their superior charge separation ability when combined with poly-3-hexyl-thiophene (P3HT). Moreover, the resulting water-borne NP exhibits shell morphology-dependent carrier quenching and stability, which is characterized via luminescence studies paired with structural analysis. Corresponding to the results, outstanding performances of photovoltaic cells with over 5% efficiency are achieved. The results suggest that the surrounding shell environments, such as the shell structure, and its electronic charge density, are crucial in determining the overall activity of the core-shell p-n heterostructured NPs. Thus, this work provides a new protocol in the current fields of water-based organic semiconductor colloids. PMID- 30427578 TI - Highly Compact Artificial Memristive Neuron with Low Energy Consumption. AB - Neuromorphic systems aim to implement large-scale artificial neural network on hardware to ultimately realize human-level intelligence. The recent development of nonsilicon nanodevices has opened the huge potential of full memristive neural networks (FMNN), consisting of memristive neurons and synapses, for neuromorphic applications. Unlike the widely reported memristive synapses, the development of artificial neurons on memristive devices has less progress. Sophisticated neural dynamics is the major obstacle behind the lagging. Here a rich dynamics-driven artificial neuron is demonstrated, which successfully emulates partial essential neural features of neural processing, including leaky integration, automatic threshold-driven fire, and self-recovery, in a unified manner. The realization of bioplausible artificial neurons on a single device with ultralow power consumption paves the way for constructing energy-efficient large-scale FMNN and may boost the development of neuromorphic systems with high density, low power, and fast speed. PMID- 30427579 TI - PRMT1-dependent Labeling and Isolation of Histone H4 Through N-Mustard Analogs of S-Adenosyl-L-methionine. AB - Histones, the fundamental building blocks of nucleosomes, undergo post translational modifications and play a major role in the regulation of transcriptional processes. While the significance of these modifications, including methylation, is widely recognized, little is known about the mechanisms that link such events. To improve our understanding of how protein methylation is intricately linked, we have developed novel N-mustard analogs of S-adenosyl-L methionine (SAM) functionalized with azides and alkynes to serve as probes of biological methylation. Here, we demonstrate their ability to serve as effective cofactor mimics of SAM and to be enzymatically transferred by protein arginine methyltransferase 1 (PRMT1) to histone H4 with high site-selectively for its' target arginine 3 on the histone tail. Further incorporation of biotin through copper-catalyzed click chemistry permitted visualization and isolation of the analog-modified histone H4 from a complex mixture. This work validates the future utility of N-mustard analogs as probes of protein methylation events beyond PRMT1. PMID- 30427580 TI - VyCAP's puncher technology for single cell identification, isolation, and analysis. AB - Here we present the Puncher technology for the isolation of single cells. This technology combines a silicon chip with microwells, fluorescence imaging, and a punching method to isolate and transfer the single cells to standard reaction tubes. The technology is compatible with commercially available downstream workflows and instrumentation. Here we focus on the isolation of CTC but the Puncher technology can be applied to isolate single cells from liquid biopsies and more general from cell suspensions. It is especially suited for cell suspensions that contain: Cells of interest at a frequency of 1 per 10,000 or less A low total number of cells ranging from 1 to 100,000, that are present in a volume of 0.01 to 50 mL. The frequency of appearance of CTC in blood is in the order of the 1 per 106 leukocytes. To be able to isolate the single CTC with the Puncher technology, enrichment of the CTC by a 3 logs reduction of the leukocytes is required. Here we describe the use of Rosettesep and Parsortix as examples of pre-enrichment methods that are compatible with the Puncher technology and further downstream applications. (c) 2018 International Society for Advancement of Cytometry. PMID- 30427581 TI - Effects of astaxanthin on sensory-motor function in a compression model of spinal cord injury: Involvement of ERK and AKT signaling pathway. AB - BACKGROUND: Spinal cord injury (SCI) causes continuous neurological deficits and major sensory-motor impairments. There is no effective treatment to enhance sensory-motor function following SCI. Thus, it is crucial to develop novel therapeutics for this particular patient population. Astaxanthin (AST) is a strong anti-oxidant, anti-inflammatory, and anti-apoptotic agent. In the present study, it was tested in a severe compression SCI model with emphasis on sensory motor outcomes, signaling pathway, along with other complications. METHODS: A severe SCI was induced by compression of the rat thoracic spinal cord with an aneurysm clip and treatment with AST or the vehicle were done, 30 min after injury. Behavioral tests including open field, von Frey, hot plate, and BBB were performed weekly to 28 days post-injury. Rats were assigned to measure blood glucose, weight, and auricle temperature. Western blot and histological analysis also were done at the same time points. RESULTS: AST decreased mechanical and thermal pain and also improved motor function performance, reduced blood glucose and auricle temperature increases, and attenuated weight loss in SCI rats. Western blot analysis showed decreased activation of ERK1/2 and increased activation of AKT following AST treatment. The histology results revealed that AST considerably preserved myelinated white matter and the number of motor neurons following SCI. CONCLUSION: Taken together, the beneficial effects of AST to improve sensory-motor outcomes, attenuate pathological tissue damage, and modulate ERK and Akt signaling pathways following SCI, suggest it as a strong therapeutic agent toward clinical applications. This article is protected by copyright. All rights reserved. PMID- 30427583 TI - Re: Evaluating the incidence of pathological complete response in current international rectal cancer practice: the barriers to widespread safe deferral of surgery. PMID- 30427582 TI - The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study. AB - INTRODUCTION: Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. AIM: Describe health-related outcomes in PwHA with inhibitors in HAVEN 1. METHODS: PwHA with inhibitors aged >=12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5 Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. RESULTS: At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ-VAS (-9.7 [-17.6, 1.82]; P = 0.017); and IUS (-0.16 [-0.25, -0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. CONCLUSIONS: In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes. PMID- 30427584 TI - Evaluation of Drug-Drug Interactions of Rucaparib and CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp Substrates in Patients With an Advanced Solid Tumor. AB - This phase 1 study (CO-338-044; NCT02740712), conducted in patients with an advanced solid tumor, evaluated the effect of the poly(ADP-ribose) polymerase inhibitor rucaparib on the pharmacokinetics of caffeine 200 mg, warfarin 10 mg, omeprazole 40 mg, and midazolam 2 mg (cytochrome P450 [CYP] 1A2, CYP2C9, CYP2C19, and CYP3A substrates; dosed as a cocktail) and digoxin 0.25 mg (P-glycoprotein substrate; dosed separately) without rucaparib and following oral rucaparib 600 mg twice daily (BID). Geometric mean (GM) ratios (90% CI) of AUC from time zero to last quantifiable measurement with and without rucaparib were: caffeine, 2.26 (1.93-2.65); S-warfarin, 1.49 (1.40-1.58); omeprazole, 1.55 (1.32-1.83); midazolam, 1.39 (1.14-1.68); and digoxin, 1.20 (1.12-1.29). There was limited effect on peak concentration of the substrates (GM ratios, 0.99-1.13). At steady state, rucaparib 600 mg BID moderately inhibited CYP1A2, weakly inhibited CYP2C9, CYP2C19, and CYP3A, and marginally increased digoxin exposure. This article is protected by copyright. All rights reserved. PMID- 30427585 TI - Evaluation of the Short-, Mid-, and Long-term Effects of Tofacitinib on Lymphocytes in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts, and a potential association with increased infection rates, have been reported in patients with RA treated with JAK inhibitors. We evaluated the short-, mid-, and long-term effects of tofacitinib on lymphocytes and infection rates in patients with RA. METHODS: In this post-hoc analysis, absolute lymphocyte counts (ALCs) were obtained from Phase (P)3 (12-24 months) and P1/2/3/long-term extension (LTE) ('All RA' population; <=117 months) studies of tofacitinib; lymphocyte subset counts (LSCs) were from P2 studies (1.5-6 months' exposure), an ORAL Sequel vaccine sub-study (~22 months), and an ORAL Sequel lymphocyte sub-study (~50 months) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC with infections was analyzed in the 'All RA' population. The value of monitoring ALC alone was assessed by examining ALC/LSC correlations. RESULTS: Tofacitinib treatment resulted in an initial increase in ALC versus pre-treatment baseline, which gradually declined to steady state by around 48 months. CD4+ and CD8+ T-cell counts decreased over long-term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALC <500 cells/mm3 had increased risk of serious infections (SIs). There was no strong association between CD4+ T-cell, CD8+ T-cell, B cell, and NK cell counts and SI incidence rates. ALC and CD4+ or CD8+ T-cell counts correlated well (R=0.65-0.86). CONCLUSION: ALC monitoring alone appears to be adequate to assess infection risk in tofacitinib-treated patients with RA This article is protected by copyright. All rights reserved. PMID- 30427586 TI - The Fine Art of Destruction: A Guide to In-Depth Glycoproteomic Analyses - Exploiting the Diagnostic Potential of Fragment Ions. AB - The unambiguous mass spectrometric identification and characterization of glycopeptides is crucial to elucidate the micro- and macroheterogeneity of glycoproteins. Here, we propose combining lower and stepped collisional energy fragmentation for the in-depth and site-specific analysis of N- and O glycopeptides. Using a set of four representative and biopharmaceutically relevant glycoproteins (IgG, fibrinogen, lactotransferrin, and ribonuclease B), we highlight the benefits and limitations of the developed workflow and provide a state-of-the-art blueprint for conducting high-quality in-depth N- and O glycoproteomic analyses. Further, we describe a modified and improved version of cotton HILIC-based solid phase extraction for glycopeptide enrichment. For the unambiguous identification of N-glycopeptides we propose the use of a conserved fragmentation signature [Mpeptide +H+0,2 X GlcNAc]+ , that has rarely been employed in glycoproteomic analyses up to now. We show for the first time that this fragmentation signature can consistently be found across all N glycopeptides, but not on O-glycopeptides. Moreover, we have systematically and comprehensively evaluated the use of the relative abundance of oxonium ions to retrieve glycan structure information, e.g. differentiation of hybrid- and high mannose-type N-glycans or differentiation between antenna GlcNAc and bisecting GlcNAc. Our findings may increase confidence and comprehensiveness in manual and software-assisted glycoproteomics. This article is protected by copyright. All rights reserved. PMID- 30427587 TI - Can interfaces at bracket-wire and between teeth in multi-teeth finite element model be simplified? AB - OBJECTIVE: Finite element (FE) method's correctness depends heavily on modeling method. This study aimed at determining whether the interfaces at bracket-wire and between teeth can be simplified for multi-teeth FE analysis. METHOD: A three dimensional FE model of a mandible was created from cone-beam computed tomography scan. Due to symmetry, only a half of the mandible was modeled, which consisted of five teeth (1st premolar extraction and only 1st molar), brackets and archwire, periodontal ligament (PDL), cortical bone and cancellous bone. All the bone, teeth, PDL were considered to be isotropic and linear. The En-masse retraction case was simulated. A detailed model, which has contact elements between the bracket and archwire and between teeth, was developed to allow relative motion at the interfaces. A model with simplified interfacial conditions, which does not allow the relative motion, was also created. The stresses and displacements as results of the treatment on these two models were calculated and compared. RESULTS: The stress and displacement distributions from the detailed model were more close to reality based on the expected displacement pattern of the clinical case than from the simplified model. The maximum stresses from the two methods were also different. The highest stress from the detailed model is twice as high as from the simplified model. CONCLUSIONS: The detailed model provides much more reasonable results than the simplified model. Thus, the simplified model should not be used to replace the detailed model if the stress magnitude and highest stress location are the expected outcomes. PMID- 30427588 TI - Effect of Food on the Pharmacokinetics of Ertugliflozin and Its Fixed-Dose Combinations Ertugliflozin/Sitagliptin and Ertugliflozin/Metformin. AB - Ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, is approved in the United States and European Union for the treatment of type 2 diabetes in adults, both as monotherapy and as part of fixed-dose combination (FDC) therapies with either sitagliptin or immediate-release metformin. The effect of a standard, high fat breakfast on the pharmacokinetics of the highest strengths of ertugliflozin monotherapy (15 mg), ertugliflozin/sitagliptin FDC (15-/100-mg), and ertugliflozin/metformin FDC (7.5-/1000-mg) tablets was evaluated. In 3 separate open-label, 2-period, 2-sequence, single-dose, crossover studies, 14 healthy subjects per study were randomized to receive either ertugliflozin monotherapy or FDC tablets comprising ertugliflozin and sitagliptin or ertugliflozin and metformin under fasted and fed (or vice versa) conditions. Food did not meaningfully affect the pharmacokinetics of ertugliflozin, sitagliptin, or metformin. For FDCs, the effect of food was consistent with that described for individual components. All treatments were well tolerated. Ertugliflozin and ertugliflozin/sitagliptin FDC tablets can be administered without regard to meals. As metformin is administered with meals because of its gastrointestinal side effects, the ertugliflozin/metformin FDC should also be administered with meals. PMID- 30427589 TI - Lichen Planus Pigmentosus and Frontal Fibrosing Alopecia Mimicking Discoid Lupus Erythematosus. AB - A 77-year old Caucasian woman presented with a 10-year history of discoid, scaly, pigmented, telangiectatic and atrophic patches on the upper cheeks (Figure 1), and gradually progressive alopecia of the frontal scalp (Figure 2). A biopsy of the cheek demonstrated interface dermatitis, epidermal hyperkeratosis and atrophy, dyskeratotic keratinocytes, and a superficial perivascular lymphohistiocytic infiltrate with pigment incontinence. She had a low-titer ANA (1:80, nucleolar), negative SS-A and SS-B, and unremarkable blood counts/chemistry. This article is protected by copyright. All rights reserved. PMID- 30427590 TI - Midwifery-Related Research (2018/086). PMID- 30427592 TI - Preventing Iron Deficency Anemia During Pregnancy. PMID- 30427593 TI - Burkholderia mallei: The dynamics of networks and disease transmission. AB - Glanders is a highly infectious zoonotic disease caused by Burkholderia mallei. The transmission of B. mallei occurs mainly by direct contact, and horses are the natural reservoir. Therefore, the identification of infection sources within horse populations and animal movements is critical to enhance disease control. Here, we analysed the dynamics of horse movements from 2014 to 2016 using network analysis in order to understand the flow of animals in two hierarchical levels, municipalities and farms. The municipality-level network was used to investigate both community clustering and the balance between the municipality's trades and the farm-level network associations between B. mallei outbreaks and the network centrality measurements, analysed by spatio-temporal generalized additive model (GAM). Causal paths were established for the dispersion of B. mallei outbreaks through the network. Our approach captured and established a direct relationship between movement of infected equines and predicted B. mallei outbreaks. The GAM model revealed that the parameters in degree and closeness centrality out were positively associated with B. mallei. In addition, we also detected 10 communities with high commerce among municipalities. The role of each municipality within the network was detailed, and significant changes in the structures of the network were detected over the course of 3 years. The results suggested the necessity to focus on structural changes of the networks over time to better control glanders disease. The identification of farms with a putative risk of B. mallei infection using the horse movement network provided a direct opportunity for disease control through active surveillance, thus minimizing economic losses and risks for human cases of B. mallei. PMID- 30427594 TI - Pharmacokinetics of Single and Repeat Doses of Fluticasone Furoate/Umeclidinium/Vilanterol in Healthy Chinese Adults. AB - The pharmacokinetics (PK) and safety of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) after single and repeat dosing in healthy Chinese adults were assessed. In this open-label study (NCT02837380), subjects received once-daily FF/UMEC/VI 100/62.5/25 MUg on day 1 and repeat doses on days 2-7. PK parameters (days 1 and 7) included maximum observed concentration (Cmax ) and area under the plasma concentration-time curve (AUC) from time zero (predose) to last time of quantifiable concentration (AUC0-t ). Terminal phase half-life (t1/2 ) on day 1 was estimated. The primary objective was to assess systemic exposure of FF 100 MUg, UMEC 62.5 MUg, and VI 25 MUg following single inhaler triple therapy on days 1 and 7. On day 1, geometric mean t1/2 of UMEC and VI was 0.36 and 0.52 hours, respectively; t1/2 of FF was not representative because of nonquantifiable concentration data. On days 1 and 7, geometric mean Cmax of FF was 10.46 and 27.32 pg/mL, respectively; Cmax of UMEC was 144.14 and 241.35 pg/mL, respectively; and Cmax of VI was 120.42 and 196.78 pg/mL, respectively. AUC0-t of FF was 1.77 and 276.96 pg.h/mL, respectively; AUC0-t of UMEC was 28.44 and 117.19 pg.h/mL, respectively; and AUC0-t of VI, 42.46 and 101.12 pg.h/mL, respectively. The PK of FF/UMEC/VI was as expected for the individual-component PK previously reported in healthy Chinese adults. No new safety signals were observed. PMID- 30427595 TI - Urban particulate matter induced decomposition of S-nitrosoglutathione relevant to aberrant nitric oxide biological signaling. AB - Exposure to airborne particulate matter (PM) is associated with hazardous effects on human health. Soluble constituents of PM may be released in biological fluids and disturb the precisely tuned nitric oxide signaling processes. The influence of aqueous extracts from two types of airborne urban particulate matter (SRM 1448a, a commercially available sample, and KR PM2.5, a sample collected 'in house' in Krakow, Poland) on the stability of S-nitrosoglutathione (GSNO) was investigated. The particle interfaces had no direct effect on the studied reaction, but extracts obtained from both samples facilitated NO release from GSNO. The effectiveness of NO release was significantly affected by glutathione (GSH) and ascorbic acid (AscA). Examination of the combined influence of Cu2+, Fe3+ and reductants on GSNO stability, revealed copper to be the main GSNO decomposing species. Computational models of nitrosothiols interacting with metal oxide substrates and solvated metal ions, support these claims. The study stresses the importance of the interplay between metal ions and biological reductants in S-nitrosothiols decomposition. PMID- 30427596 TI - ? PMID- 30427597 TI - [When home become breathtaking]. AB - We spend most of our time indoor and mainly at home. Thermal insulation has greatly improved in the last decades, thus leading to deficiency in ventilation and poor indoor air quality. Many studies suggest that there is a link between respiratory diseases and various indoor air pollutants such as moulds, allergens, volatile organic compounds, combustible smoke, house dust mite, radon or asbestos. This article reviews the most common pathogenic pollutants at home as well as their sources and related respiratory diseases. Preventive measures are further presented for every category of contaminant. PMID- 30427598 TI - [Pulmonary rehabilitation in respiratory disorders other than COPD : an individualized approach]. AB - Pulmonary rehabilitation is a multimodal intervention which includes an individualized physical training program, patient education, nutritional assessment and counseling, and recommendations for behavioral changes (smoking cessation, physical activity, nutrition...). This approach, validated and widely accepted by international expert societies in COPD, has been explored and evaluated in other chronic respiratory disorders. This overview analyses the impact of pulmonary rehabilitation in interstitial lung diseases, pulmonary hypertension, lung cancer (pre and post surgery), and morbid obesity. The recent medical literature encourages clinicians to consider the possibility of pulmonary rehabilitation in most chronic pulmonary disorders. PMID- 30427599 TI - [Noninvasive ventilation for chronic hypercapnic respiratory failure]. AB - Chronic hypercapnic respiratory failure is essentially a ventilatory failure. Noninvasive ventilation (NIV ) reduces the work of breathing, improves pulmonary compliance and alveolar ventilation, corrects gas exchange disorders and improves dyspnoea. However, treatment efficacy depends on the underlying pathology, on correct timing and on patient compliance. In this context, the principal role of the primary care physician is to search for, at every visit of at risk patients, signs and symptoms of ventilatory failure and to refer the patient to a respiratory care specialist. He also plays a role in the follow up of patients under noninvasive ventilation for the detection of clinical parameters suggesting NIV failure. PMID- 30427600 TI - [COPD and cognitive impairment]. AB - Patients with chronic respiratory failure, especially COPD, suffer from a multi systemic disease with organic, behavioral and social consequences that impact largely beyond the respiratory system. Cognitive impairment is associated with decreased quality of life and increased mortality in the general population, but remains underestimated and poorly studied in chronic respiratory diseases despite their increased prevalence. However, there is growing interest in research on the association between cognitive impairment and chronic respiratory diseases. Different risk factors, some modifiable, could contribute to the early development of cognitive disorders in this population. Patients with cognitive impairment need appropriate care to promote adherence to the therapeutic project. Respiratory rehabilitation, as a multimodal intervention, seems to have a positive effect on cognitive functions. PMID- 30427601 TI - [Systemic biomarkers in respiratory tract infections]. AB - Respiratory tract infections represent a major cause of morbidity and mortality despite the progress made in their diagnosis and treatment. Since the clinical presentation of a viral or bacterial infection is often similar, the identification of a biomarker that could guide the clinician whether or not to introduce an antibiotic therapy is crucial. C-reactive protein and procalcitonin are the most commonly used biomarkers as a diagnostic tool for respiratory tract infections. New biomarkers show promising results for assessing the severity of infection and identifying patients at risk for complications. However, the use of biomarkers has limitations and the diagnosis of a bacterial infection should not be based solely on the measurement of a biomarker. PMID- 30427602 TI - [Transbronchial cryobiopsies : a minimally invasive tool for the diagnosis of interstitial lung disease]. AB - The diagnosis of interstitial lung disease (ILD) is challenging and relies on a multidisciplinary discussion involving clinical, radiological and sometimes histological features. Bronchoscopic lung cryobiopsies have emerged as a new minimally invasive method of lung sampling and an alternative to surgical lung biopsies. A good diagnostic performance and excellent safety profile make it an interesting and worthful procedure which could decrease the number of patients without proper diagnosis and treatment. There is a need for further studies to standardize the technique in expert centers and to establish its role in the diagnostic work-up of ILD. PMID- 30427603 TI - ? PMID- 30427604 TI - ? PMID- 30427605 TI - ? PMID- 30427606 TI - ? PMID- 30427607 TI - ? PMID- 30427608 TI - ? PMID- 30427609 TI - ? PMID- 30427610 TI - ? PMID- 30427611 TI - ? PMID- 30427612 TI - ? PMID- 30427613 TI - ? PMID- 30427614 TI - ? PMID- 30427615 TI - ? PMID- 30427617 TI - ? PMID- 30427616 TI - ? PMID- 30427641 TI - CRITERIA OF SURGICAL RISK IN PATIENTSWITH DIFFUSE LUNG EMPHYSEMAWITH LARGE AND GIANT BULLAS. AB - The article presents an assessment of postoperative period inpatients with diffuse lung emphysema with large and giant bullason the basis of surgical risk criteria, which were developed forthe patients with diffuse emphysema without bullas. Retrospectivestudy determined the group of patients who had high rate ofsurgical complications after bullectomy. The patients (46) weredivided into 2 groups and it depended on the initial condition ofthe patients. There was stated, that the main criterion of surgicalrisk was a decrease of the level of OFL lower than 20% of theproper level in patients with large and giant bullas. PMID- 30427643 TI - STUDY OF DINAMICS OF PYOINFLAMMATORY PROCESS IN SOFT TISSUE OF PATIENTS WITH ACUTE ANAEROBIC PARAPROCTITIS (EXPERIMENTAL-CLINICAL RESEARCH). PMID- 30427642 TI - DIAGNOSTICS AND TREATMENT OF OBSTRUCTIVE JAUNDICE AT CHRONIC OPISTHORCHIASIS. AB - A comparative analysis of possibilities of visual methods of diagnostics was made in order to reveal the causes of obstructive jaundice in chronic opisthorchiasis. There was estimated the possibility of topical diagnostics of rate and character of the bile passages block while conducting MR-imaging cholangiography. Types of architectonics of the bile passages were specified in chronic opisthorchiasis. A differentiated algorithm of treatment was developed and applied in relation to the obtained data. PMID- 30427644 TI - Severity of peanut allergy and the unmet gaps in care: a call to action. AB - Peanut allergy is one of the most common food allergies in children, with a prevalence that has been increasing over the past several decades. The allergy is a type I, immunoglobulin E (IgE)-mediated reaction that commonly presents in childhood and can be associated with an anaphylactic response. There are many theories that attempt to explain the increasing prevalence, including dietary changes, improvements in hygiene, and intentional allergen avoidance. Diagnosis is made through a combination of a thorough patient history, peanut-specific serum-specific IgE levels, peanut skin-prick test, and, if necessary, an oral food challenge. Guidelines based on the landmark 2015 Learning Early About Peanut Allergy trial suggest that peanuts should be introduced into the diet as early as 4 to 6 months of age in infants who are at highest risk of developing peanut allergy. It is important for providers to recognize risk factors for the development of peanut allergy, identify associated clinical symptoms, and provide an accurate diagnosis of patients to effectively manage them and their families and prevent future reactions. PMID- 30427645 TI - Management of peanut allergy: a focus on novel immunotherapies. AB - The management of peanut allergy involves strict avoidance, prompt recognition of allergic reactions, and rapid initiation of epinephrine and other supportive therapy for anaphylaxis. Avoidance presents several challenges and burdens to quality of life and daily activities. Currently, no treatment options are available for peanut allergy apart from epinephrine, which is the treatment of choice for severe allergic reactions. In recognition of the need for improved treatment options among patients with peanut allergy, several novel immunotherapies are undergoing clinical development, and clinicians must be knowledgeable about the safety and efficacy of these agents. This educational activity will provide an overview of current practices in peanut allergy management and novel immunotherapies with potential to improve outcomes among children and adults with peanut allergy. PMID- 30427646 TI - The economic impact of peanut allergies. AB - The prevalence of peanut allergies, the most common food allergy in children, has tripled in the past 2 decades. Today, up to 2.5% of the pediatric population has been diagnosed with a peanut allergy. Peanut allergies result in significant medical, out-of-pocket, and opportunity costs to payers, parents, and employers. They are also a leading cause of food allergy-related deaths in children. Although there is evidence that peanut oral immunotherapy may be effective in reducing the severity of the allergy, such approaches require a long intervention with no standardized protocol available. The introduction of biologic compounds to treat peanut allergies has the potential to revolutionize how these patient cases are managed. Their anticipated high cost, however, raises several issues for payers as to how to integrate these new therapies into formularies and treatment continuums. PMID- 30427647 TI - Endocrine Conditions in Older Adults: Foreword. PMID- 30427648 TI - Endocrine Conditions in Older Adults: Osteoporosis. AB - Osteoporosis management has undergone several paradigm shifts over the past 20 years because of emerging technologies and new treatments and decision support tools to guide risk assessment. Practice guidelines in the United States and abroad differ widely on recommendations for screening, prevention, and management. Screening has evolved, with improvements in bone mineral density testing, vertebral fracture assessment, trabecular bone scores, and decision support tools. All of these have improved the identification of patients at high risk of fractures. Prevention of osteoporosis should begin early in life, with adequate dietary calcium and vitamin D intake and exercise in childhood. At older ages, patients should undergo continuous reevaluation to minimize secondary risk factors (eg, comorbid conditions, drugs). Recommended management of osteoporosis includes exercise, bisphosphonates, denosumab, and parathyroid hormone analogs. Choice of optimal management depends on efficacy, potential adverse effects, patient and societal costs, and patient characteristics (eg, severity of disease, underlying etiologies, management preferences). The ideal duration of pharmacotherapy remains unclear. There is potential continued benefit with long term management but increased risk of some adverse effects. These include atypical fractures and osteonecrosis of the jaw with bisphosphonates and denosumab, and osteosarcoma with parathyroid hormone analogs. PMID- 30427649 TI - Endocrine Conditions in Older Adults: Menopause. AB - Menopause is the cessation of menstruation due to loss of ovarian function and is diagnosed retrospectively after 12 consecutive months of amenorrhea. The average age of onset in the United States is 51 years but symptoms can be present for many years before and after. Vasomotor and genitourinary symptoms are the most common. Hormone replacement therapy (HRT) is the most effective management. Given the possible risks of cardiovascular disease and breast cancer, recommendations for HRT after the Women's Health Initiative study are to limit HRT to the lowest dose and shortest duration to relieve symptoms. Based on more recent data, women younger than 60 years and less than 10 years from menopause onset appear to be at lower risk of these factors when initiating HRT. Dosing, type of HRT, administration route, and duration of use are individualized. Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, gabapentin, and clonidine are alternative nonhormonal options with high-quality evidence supporting their use for symptom relief. However, these management options are less effective than HRT. Local vaginal therapy is effective and recommended for management of isolated vulvovaginal symptoms. Decisions to discontinue HRT should be based on symptoms and risk factors, not age. PMID- 30427650 TI - Endocrine Conditions in Older Adults: Adrenal Tumors. AB - Incidentally discovered adrenal masses, referred to as adrenal incidentalomas, are fairly common given the routine use of imaging as part of clinical care in a variety of settings. Adrenal incidentalomas most frequently are benign and hormonally inactive tumors. However, approximately 11% to 15% are hormonally active, which can lead to diagnosis of clinically relevant conditions that affect morbidity and mortality. Thus, all adrenal incidentalomas should be tested for production of hormones at initial diagnosis. A 1-mg dexamethasone suppression test is the initial screening test. Patients then should be referred for appropriate treatment. Among the adrenal mass subtypes, pheochromocytomas are associated with the highest risk of mortality. Every effort should be made to exclude the presence of these tumors. Patients with hypertension and adrenal incidentalomas should be evaluated for aldosterone excess with an aldosterone to renin ratio. Primary malignancy represents a low percentage of adrenal incidentalomas. A minority of adrenal malignancies are primary adrenocortical tumors, which are associated with a poor prognosis and for which management often is palliative. PMID- 30427651 TI - Endocrine Conditions in Older Adults: Anti-Aging Therapies. AB - Interest in slowing or reversing the process of aging continues to grow and has encouraged the growth of an entire anti-aging industry. However, there is a dearth of data based on randomized trials in humans to support proposed therapies to address the various complex processes involved in aging. Hormonal therapies, in particular, have little data to support safe use and are associated with some degree of risk. Experimental data in animal models suggest possible molecular targets but their use in clinical medicine is far in the future. Observational data guide the current recommendations to maintain a healthy lifestyle, including consumption of a healthful diet and achieving adequate sleep, toward the goal of slowing the aging process. Patients may ask their physicians to offer opinions about treatments they hope will increase their health span. To counsel patients effectively, it is important for physicians to understand the basic principles of anti-aging science. Maintenance of supportive, nonjudgmental therapeutic relationships with patients is critical to avoid harmful and costly treatments while trying to present reliable evidence for available anti-aging therapies. PMID- 30427652 TI - Triggered Reversible Reconfiguration of G-Quadruplex-Bridged "Domino"-Type Origami Dimers: Application of the Systems for Programmed Catalysis. AB - The reversible and switchable reconfiguration of the two-origami-dimer mixture AB plus CD into the dimer mixture DA plus BC and back using the triggered formation of K+-ion-stabilized G-quadruplexes and subsequent treatment with 18-crown-6 ether is presented. The reconfiguration processes are followed by atomic force microscopy imaging of the dimer structures that include tiles marked with 0, 1, 2, and 3 4* hairpin labels. By the functionalization of AB and CD dimers with the Mg2+-ion-dependent DNAzyme subunits, the AB plus CD mixture leads to the cleavage of the fluorophore- and quencher-modified substrate of the DNAzyme and to the activation of the fluorescence of the fluorophore (fluorescein)-modified fragment product. The K+-ion-induced isomerization of the mixture of AB plus CD into the mixture DA plus BC separates the Mg2+-ion-dependent DNAzyme subunits and concomitantly reconfigures the K+-ion-stabilized G-quadruplex associated with the two dimers. After the binding of hemin to the G-quadruplexes, the hemin/G quadruplex DNAzyme is generated, leading to the catalyzed oxidation of Amplex Red by H2O2 to yield the fluorescent resorufin product. By the cyclic treatment of the AB plus CD mixture with K+ ions to yield the DA plus BC mixture and the subsequent recovery of the AB plus CD mixture by subjecting the DA plus BC mixture to 18-crown-6-ether, the fluorescence output signals of the system are switched on and off between the fluorescence of fluorescein and resorufin, respectively. PMID- 30427653 TI - Mechanically Assembled, Three-Dimensional Hierarchical Structures of Cellular Graphene with Programmed Geometries and Outstanding Electromechanical Properties. AB - Three-dimensional (3D) cellular graphene structures have wide applications in energy storage, catalysis, polymer composites, electromagnetic shielding, and many others. However, the current strategies to form cellular graphene are only able to realize limited structure control and are hard to achieve the construction of 3D hierarchical architectures with complex, programmed configurations, limiting the design capabilities to satisfy various next generation device applications. In addition, cellular graphene usually exhibits limited electromechanical properties, and its electrical and electrochemical performances are dramatically affected by mechanical deformations, constraining its applications in emerging wearable electronics and energy devices. Herein, we report a simple, general, and effective route to 3D hierarchical architectures of cellular graphene with desired geometries through the use of a mechanically guided, 3D assembly approach to overcome the aforementioned two challenges. Demonstrations include more than 10 3D hierarchical architectures with diverse configurations, ranging from mixed tables and tents, to double-floor helices, to kirigami/origami-inspired structures, and to fully separated multilayer architectures. The LED arrays interconnected with 3D helical coils and 3D interdigital supercapacitors fabricated with solid-state electrolytes provide prototypic examples of wearable devices that exhibit outstanding electromechanical properties and can maintain stable performances with little change in the electrical and electrochemical responses under extreme deformations, in both the static and cyclic loading conditions. PMID- 30427654 TI - Effect of Silica Supports on Plasmonic Heating of Molecular Adsorbates as Measured by Ultrafast Surface-Enhanced Raman Thermometry. AB - Plasmonic materials show great potential for selective photocatalysis under relatively mild reaction conditions. However, the catalytic activity of these plasmonic catalysts can also depend upon the support material that stabilizes the catalysts, where the composition of the catalytic support may change the overall photocatalytic efficiency and yield. It is unknown how changes in the support material may change the plasmon-driven photocatalysis, which may be initiated by plasmon-derived hot carriers, localized heating, or enhanced electromagnetic fields. Herein, we probe the effects of catalytic supports on heating in plasmon driven catalysis by examining various gold nanoparticle oxide systems. We use ultrafast surface-enhanced Raman thermometry to measure the effective temperature, equivalent to the vibrational kinetic energy, of reporter molecules located between plasmonic gold nanostructures and local environments ranging from ligands to mesoporous silica shells to silica shells. Upon photoexcitation, the transient effective temperature, equivalent to the energy deposited into a vibrational mode, of adsorbed molecules on the silica-coated samples increases, and the energy quickly dissipates within 3 ps. However, the baseline effective temperature that arises from the surface-enhanced Raman spectroscopy probing process depends upon the encapsulant, where the energy deposition differs by 200 300 K between the ligand-coated (citrate or CTAB) and the silica-coated samples. Adsorbates surrounded by a silica shell experience significantly higher effective temperatures than the adsorbates surrounded by ligands or solvent, likely because of the differing effective heat capacities of these media. Taken together, this work shows that a silica support impacts the localized heating of molecular adsorbates on the gold surface and may play a role in enhanced plasmonic photocatalysis because of increased thermal contributions. PMID- 30427655 TI - Metal-Organic Frameworks-Derived Carbon Nanoparticles for Photoacoustic Imaging Guided Photothermal/Photodynamic Combined Therapy. AB - Combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has become a promising cancer treatment in recent years. However, their applications are limited by complex synthetic protocols and low efficacy. Hence, optimizing experimental approach and improving the efficiency of phototherapy is the current research focus. In this work, various pyrolysis temperatures and sizes of zeolitic imidazolate framework-8 (ZIF-8) derived carbon nanoparticles (ZCNs) are obtained by a simple direct pyrolysis of the ZIF-8 nanoparticles. Meanwhile, the ZCNs can be used as photothermal agents and photosensitizers to produce heat and reactive oxygen species simultaneously upon near-infrared laser irradiation. Moreover, it is observed that the phototherapy effects and photoacoustic (PA) signal of ZCNs could be enhanced with the increase in the nanoparticle size. Subsequently, guided by PA imaging, the therapeutic effect of ZCNs is investigated on a small animal model, where tumors are entirely eliminated with minimal side effect, demonstrating the high efficacy of the larger size of ZCNs through combination of PTT and PDT. Therefore, it is expected that the ZCN is a simple and highly effective phototherapeutic platform for oncotherapy, and the concept of size-dependent enhanced behavior of phototherapy and PA imaging will be very useful in the development of nanomaterials for cancer therapy. PMID- 30427657 TI - Dual Imaging-Guided Oxidative-Photothermal Combination Anticancer Therapeutics. AB - Heme oxygenase-1 (HO-1) is a stress-response protein with potent cytoprotective and antioxidant activity, and its expression in cancer cells is enhanced in response to chemotherapy and radiotherapy. HO-1 is known to serve as a shield to protect cancer cells from anticancer therapy and attenuate apoptotic signals. It can be therefore reasoned that inhibition of HO-1 reduces the antioxidant level, making cancer cells more sensitive to photothermal heating. In this work, we developed dual imaging-guided oxidative-photothermal combination nanotherapeutics (OPCN) consisting of amphiphilic polymers conjugated with zinc protoporphyrin as a HO-1 inhibitor and fluorescent IR820 as a photothermal agent. A combination of OPCN and near-infrared (NIR) laser irradiation markedly increased the temperature and exerted significant toxicity through induction of apoptosis. In a mouse model of xenografts, tumors were identified by the strong fluorescence and photoacoustic signals. OPCN combined with NIR laser irradiation resulted in effective and complete thermal ablation of tumors without discernable side effects and tumor recurrence. We believe that OPCN hold tremendous translational potential for dual imaging-guided oxidative-photothermal combination anticancer therapy. PMID- 30427656 TI - SAR Studies Leading to the Identification of a Novel Series of Metallo-beta lactamase Inhibitors for the Treatment of Carbapenem-Resistant Enterobacteriaceae Infections That Display Efficacy in an Animal Infection Model. AB - The clinical effectiveness of carbapenem antibiotics such as meropenem is becoming increasingly compromised by the spread of both metallo-beta-lactamase (MBL) and serine-beta-lactamase (SBL) enzymes on mobile genetic elements, stimulating research to find new beta-lactamase inhibitors to be used in conjunction with carbapenems and other beta-lactam antibiotics. Herein, we describe our initial exploration of a novel chemical series of metallo-beta lactamase inhibitors, from concept to efficacy, in a survival model using an advanced tool compound (ANT431) in conjunction with meropenem. PMID- 30427659 TI - Avidin-Biotin Cross-Linked Microgel Multilayers as Carriers for Antimicrobial Peptides. AB - Herein, we report on the formation of cross-linked antimicrobial peptide-loaded microgel multilayers. Poly(ethyl acrylate- co-methacrylic acid) microgels were synthesized and functionalized with biotin to enable the formation of microgel multilayers cross-linked with avidin. Microgel functionalization and avidin cross linking were verified with infrared spectroscopy, dynamic light scattering, and z potential measurements, while multilayer formation (up to four layers) was studied with null ellipsometry and quartz crystal microbalance with dissipation (QCM-D). Incorporation of the antimicrobial peptide KYE28 (KYEITTIHNLFRKLTHRLFRRNFGYTLR) into the microgel multilayers was achieved either in one shot after multilayer formation or through addition after each microgel layer deposition. The latter was found to strongly promote peptide incorporation. Further, antimicrobial properties of the peptide-loaded microgel multilayers against Escherichia coli were investigated and compared to those of a peptide loaded microgel monolayer. Results showed a more pronounced suppression in bacterial viability in suspension for the microgel multilayers. Correspondingly, LIVE/DEAD staining showed promoted disruption of adhered bacteria for the KYE28 loaded multilayers. Taken together, cross-linked microgel multilayers thus show promise as high load surface coatings for antimicrobial peptides. PMID- 30427658 TI - Two-Dimensional Unilamellar Cation-Deficient Metal Oxide Nanosheet Superlattices for High-Rate Sodium Ion Energy Storage. AB - Cation-deficient two-dimensional (2D) materials, especially atomically thin nanosheets, are highly promising electrode materials for electrochemical energy storage that undergo metal ion insertion reactions, yet they have rarely been achieved thus far. Here, we report a Ti-deficient 2D unilamellar lepidocrocite type titanium oxide (Ti0.87O2) nanosheet superlattice for sodium storage. The superlattice composed of alternately restacked defective Ti0.87O2 and nitrogen doped graphene monolayers exhibits an outstanding capacity of ~490 mA h g-1 at 0.1 A g-1, an ultralong cycle life of more than 10000 cycles with ~0.00058% capacity decay per cycle, and especially superior low-temperature performance (100 mA h g-1 at 12.8 A g-1 and -5 degrees C), presenting the best reported performance to date. A reversible Na+ ion intercalation mechanism without phase and structural change is verified by first-principles calculations and kinetics analysis. These results herald a promising strategy to utilize defective 2D materials for advanced energy storage applications. PMID- 30427660 TI - Erythrocyte-Inspired Discoidal Polymeric Nanoconstructs Carrying Tissue Plasminogen Activator for the Enhanced Lysis of Blood Clots. AB - Tissue plasminogen activator (tPA) is the sole approved therapeutic molecule for the treatment of acute ischemic stroke. Yet, only a small percentage of patients could benefit from this life-saving treatment because of medical contraindications and severe side effects, including brain hemorrhage, associated with delayed administration. Here, a nano therapeutic agent is realized by directly associating the clinical formulation of tPA to the porous structure of soft discoidal polymeric nanoconstructs (tPA-DPNs). The porous matrix of DPNs protects tPA from rapid degradation, allowing tPA-DPNs to preserve over 70% of the tPA original activity after 3 h of exposure to serum proteins. Under dynamic conditions, tPA-DPNs dissolve clots more efficiently than free tPA, as demonstrated in a microfluidic chip where clots are formed mimicking in vivo conditions. At 60 min post-treatment initiation, the clot area reduces by half (57 +/- 8%) with tPA-DPNs, whereas a similar result (56 +/- 21%) is obtained only after 90 min for free tPA. In murine mesentery venules, the intravenous administration of 2.5 mg/kg of tPA-DPNs resolves almost 90% of the blood clots, whereas a similar dose of free tPA successfully recanalizes only about 40% of the treated vessels. At about 1/10 of the clinical dose (1.0 mg/kg), tPA-DPNs still effectively dissolve 70% of the clots, whereas free tPA works efficiently only on 16% of the vessels. In vivo, discoidal tPA-DPNs outperform the lytic activity of 200 nm spherical tPA-coated nanoconstructs in terms of both percentage of successful recanalization events and clot area reduction. The conjugation of tPA with preserved lytic activity, the deformability and blood circulating time of DPNs together with the faster blood clot dissolution would make tPA-DPNs a promising nanotool for enhancing both potency and safety of thrombolytic therapies. PMID- 30427661 TI - Anionic Surfactant-Triggered Steiner Geometrical Poly(vinylidene fluoride) Nanofiber/Nanonet Air Filter for Efficient Particulate Matter Removal. AB - The emergence of Steiner minimal tree is of fundamental importance, and designing such geometric structure and developing its application have practical effect in material engineering and biomedicine. We used a cutting-edge nanotechnology, electrospinning/netting, to generate a Steiner geometrical poly(vinylidene fluoride) (PVDF) nanofiber/nanonet filter for removing airborne particulate matter (PM). Manipulation of surface morphologies by precise control of charged situation enabled the creation of two-dimensional nanonets with Steiner geometry. A significant crystalline phase transition of PVDF from alpha-phase to beta-phase was triggered by the dipole orientation and the intermolecular interactions derived from the electrostatic potential analysis. Particularly, the synergy of electrical interaction (ion-dipole and dipole-dipole) and hydrophobic interaction facilitated the formation of Steiner geometric structure during the evolution process of nanonets. The resultant PVDF nanofiber/nanonet air filter exhibited high filtration efficiency of 99.985% and low pressure drop of 66.7 Pa under the airflow velocity of 32 L/min for PM0.26 removal by the safest physical sieving mechanism. Furthermore, such filter possessed robust structure integrity for reusability, comparable optical transmittance, superior thermal stability, and prominent purification capacity for smoke PM2.5. The successful construction of such fascinating Steiner geometrical PVDF nanonets will provide new insights into the design and exploitation of novel filter media for air cleaning and haze treatment. PMID- 30427662 TI - Neuro-Regenerative Choline-Functionalized Injectable Graphene Oxide Hydrogel Repairs Focal Brain Injury. AB - Brain damage is associated with spatial imbalance of cholinergic system, which makes severe impact in recovery of damaged neurons of brain. Therefore, maintenance of cholinergic system is extremely important. Here, we fabricated an injectable hydrogel with acetylcholine-functionalized graphene oxide and poly(acrylic acid). Results revealed that this hydrogel is non-cytotoxic, promotes neurite outgrowth, stabilizes microtubule networks, and enhances the expression of some key neural markers in rat cortical primary neurons. Further, this hydrogel exhibits significant potential in neuro-regeneration and also promotes fast recovery of the sham injured mice brain. Moreover, we found significant enhancement of reactive astrocytes in the hippocampal dentate gyrus region of the sham injured brain, indicating its excellent potential in neural repair of the damaged brain. Finally, above results clearly indicate that this neuro-regenerative hydrogel is highly capable of maintaining the cholinergic balance through local release of acetylcholine in the injured brain, which is crucial for brain repair. PMID- 30427663 TI - van der Waals Graphene Kirigami Heterostructure for Strain-Controlled Thermal Transparency. AB - Programming thermal transport across interfaces by engineering strain is of critical importance for exploring mechanical controllable and thermal manageable devices with multifunctionalities. Here, we report a van der Waals heterostructure that is composed of bilayer graphene kirigami with diverse layer cut patterns and assembly organizations and show that the thermal flow intensity across the van der Waals interfaces, named as thermal transparency, could be continuously regulated by applying an external in-plane tensile strain. The density of atomic interactions across the interfaces and the distribution of delocalized phonon modes in each graphene kirigami are elucidated to understand the underlying thermal transport mechanism and are also incorporated into a theoretical model for quantitative predictions of thermal conductance under mechanical strain. A proof-of-conceptual van der Waals graphene kirigami heterostructure by design is proposed and validated through extensive full-scale atomistic simulations on the feasibility and reliability of regulating the transparency ratio of thermal transport by mechanical strain, demonstrating its potential applications in thermal and electronic devices. PMID- 30427664 TI - Nanostructured Bromide-Derived Ag Film: An Efficient Electrocatalyst for N2 Reduction to NH3 under Ambient Conditions. AB - Electrochemical reduction has been regarded as a sustainable strategy to tackle energy-intensive operations by the Haber-Bosch process achieving catalytic conversion of N2 to NH3 under mild conditions. However, the challenge of N2 electroconversion emphasizes the requirement of efficient electrocatalysts. In this paper, we report the development of porous bromide-derived Ag film (BD Ag/AF) as an efficient electrocatalyst for N2 reduction reaction. During electrochemical test, Br- anions are released and adsorbed onto the surfaces of the electrode, suppressing hydrogen evolution reaction. Such BD-Ag/AF shows a high Faradaic efficiency of 7.36% at -0.6 V vs reversible hydrogen electrode in 0.1 M Na2SO4, which is higher than that (0.38%) of porous Ag film without Br- anions. Moreover, it exhibits excellent long-term electrochemical durability. PMID- 30427665 TI - Abundance of Chlorinated Solvent and 1,4-Dioxane Degrading Microorganisms at Five Chlorinated Solvent Contaminated Sites Determined via Shotgun Sequencing. AB - Shotgun sequencing was used for the quantification of taxonomic and functional biomarkers associated with chlorinated solvent bioremediation in 20 groundwater samples (five sites), following bioaugmentation with SDC-9. The analysis determined the abundance of (1) genera associated with chlorinated solvent degradation, (2) reductive dehalogenase (RDases) genes, (3) genes associated with 1,4-dioxane removal, (4) genes associated with aerobic chlorinated solvent degradation, and (5) D. mccartyi genes associated with hydrogen and corrinoid metabolism. The taxonomic analysis revealed numerous genera previously linked to chlorinated solvent degradation, including Dehalococcoides, Desulfitobacterium, and Dehalogenimonas. The functional gene analysis indicated vcrA and tceA from D. mccartyi were the RDases with the highest relative abundance. Reads aligning with both aerobic and anaerobic biomarkers were observed across all sites. Aerobic solvent degradation genes, etnC or etnE, were detected in at least one sample from each site, as were pmoA and mmoX. The most abundant 1,4-dioxane biomarker detected was Methylosinus trichosporium OB3b mmoX. Reads aligning to thmA or Pseudonocardia were not found. The work illustrates the importance of shotgun sequencing to provide a more complete picture of the functional abilities of microbial communities. The approach is advantageous over current methods because an unlimited number of functional genes can be quantified. PMID- 30427666 TI - Optical control of metal ion probes in cells and zebrafish using highly selective DNAzymes conjugated to upconversion nanoparticles. AB - Spatial and temporal distributions of metal ions in vitro and in vivo are crucial in our understanding of the roles of metal ions in biological systems, and yet there is a very limited number of methods to probe metal ions with high space and time resolution, especially in vivo. To overcome this limitation, we report a Zn2+-specific near infrared (NIR) DNAzyme nanoprobe for real-time metal ion tracking with spatiotemporal control in early embryos and larvae of zebrafish. By conjugating photocaged DNAzymes onto lanthanide-doped upconversion nanoparticles (UCNPs), we have achieved upconversion of a deep tissue penetrating NIR 980 nm light into 365 nm emission. The UV photon then photo-decages a substrate strand containing a nitrobenzyl group at the 2'-OH of adenosine ribonucleotide, allowing enzymatic cleavage by a complementary DNA strand containing a Zn2+-selective DNAzyme. The product containing a visible FAM fluorophore that is initially quenched by BHQ1 and Dabcyl quenchers, is re-leased after cleavage. The DNAzyme UCNP probe enables Zn2+ sensing by exciting in the NIR biological imaging window in both living cells and zebrafish embryos, and detecting in the visible region. This report introduces a platform that can be used to un-derstand the Zn2+ distribution with spatiotemporal control, thereby giving insights into the dynamical Zn2+ ion distribution in intracellular and in vivo models. PMID- 30427668 TI - Correction to Direct Comparison of Amino Acid and Salt Interactions with Double Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations. PMID- 30427667 TI - Facile CO2 Cycloaddition to Epoxides by Using a Tetracarbonyl Metal Selenotungstate Derivate [{Mn(CO)3}4(Se2W11O43)]8. AB - A novel polyoxometalate cluster, i.e., Na1.5H4.5[(CH3)4N]2{[Mn(CO)3]4(Se2W11O43)}.9H2O (1), has been successfully synthesized under moderately acidic conditions. Compound 1 contains four electron donating {Mn(CO)3}+ organometallic entities, which are grafted over an unprecedented heteropolytungstate electron-acceptor group. Compound 1 was further structurally characterized by various physicochemical techniques like elemental analyses, inductively coupled plasma (ICP) analyses, IR and UV-vis spectroscopy, electrochemistry, and single-crystal X-ray diffraction, and so on. The polyoxoanion of 1 comprises a novel {Se2W11} fragment, which is obtained from molecular assembly of rare {SeW3} and {SeW8} species. Evaluation of the data from solution-state IR spectrum showed excellent agreement with the solid state IR spectrum, indicating the intact clusters in the CH3CN/Na2SO4 solvent. Also, negative electrospray ionization mass spectrometry (ESI-MS) was an alternative tool to verify the stability of 1 in the mixed solvent. Additionally, the resulting hybrid can act as a catalyst for cyclic carbonate formation from the reactants epoxides and CO2 under modest reaction conditions in conjunction with a 1-ethyl-1-methylpyrrolidinium bromide (2). The good activity can be substantiated due to the cooperative influence of polyoxoanion and Br- ions. Complex 1 can also be easily recycled and reused three times without obvious decrease of catalytic activity. PMID- 30427669 TI - Correction to Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment. PMID- 30427670 TI - Correction to Large-Scale Analysis of 48 DNA and 48 RNA Tetranucleotides Studied by 1 MUs Explicit-Solvent Molecular Dynamics Simulations. PMID- 30427671 TI - Atmospheric Decomposition of Trifluoromethanol Catalyzed by Formic Acid. AB - Quantum chemistry calculations are used to investigate the energetics and kinetics of CF3OH decomposition catalyzed by a single formic acid (FA) molecule acting alone and in conjunction with a single water (H2O) molecule to form the products carbonyl fluoride (CF2O) and hydrofluoric acid (HF). While the uncatalyzed reaction has a barrier of ~44.7 kcal/mol, the presence of a FA molecule reduces the barrier to 6.4 kcal/mol, while the presence of both a FA and H2O molecule acting in unison decreases the barrier to -1.6 kcal/mol measured relative to the separated reactants. For comparison, we have also examined the decomposition of CF3OH catalyzed by HO2 and HO2 + H2O, which have been suggested in the literature to be an important atmospheric catalyst for CF3OH decomposition. In addition, we have also examined the loss of CF3OH via its bimolecular reaction with OH radicals. The rate constants for these various reactions were calculated using canonical variational transition state theory coupled with small curvature tunneling corrections over the temperature range between 200 and 300 K. Our results show that the rates for the CF3OH + FA and CF3OH + FA + H2O reactions are ~104 times faster compared, respectively, to the corresponding reactions involving CF3OH + HO2 and CF3OH + HO2 + H2O at 300 K. Further, we find that, although the CF3OH + FA reaction has a higher barrier compared to CF3OH + FA + H2O, measured relative to the separated reagents, its effective first order rate for CF3OH decomposition is significantly faster for temperatures above 240 K compared to that of CF3OH + FA + H2O. This trend arises from the higher unimolecular reaction barrier for the reactant complex associated with the CF3OH + H2O + FA reaction compared to that for CF3OH + FA, as well as the lower concentration of reactant dimer complexes for CF3OH + H2O + FA compared to the concentration of the monomer FA reactant in the CF3OH + FA reaction. Finally, our calculations show that the rate for CF3OH decomposition catalyzed by FA is ~104 times faster relative to the loss of CF3OH via its bimolecular reaction with OH radicals over the 200-300 K temperature range. Thus, the present study suggests that, among the various known loss mechanisms, a unimolecular reaction catalyzed by FA is likely the dominant gas phase decomposition pathway for CF3OH in the troposphere. PMID- 30427672 TI - Fourier Transform Microwave Spectra of the Nitrogen Molecule-Ethylene Sulfide and Nitrogen Molecule-Dimethyl Sulfide Complexes. AB - We recorded the rotational spectra of N2-ethylene sulfide (ES) and N2-dimethyl sulfide (DMS) including the 15N2 and 15N14N isotopomers in the frequency range of 5-25 GHz by using a Fourier transform microwave spectrometer. The b-type transitions for the ortho and para states of 14N2-ES and 15N2-ES and c-type transitions of 14N2-DMS and 15N2-DMS were observed. The 15N14N-ES and 15N14N-DMS species were found to exist in two isomeric forms: inner (14N15N-ES and 14N15N DMS) and outer (15N14N-ES and 15N14N-DMS). Neither the -ES nor -DMS complexes showed weak accompanying spectra, which had been observed for N2-ethylene oxide (EO). This is because the potential barriers to internal rotation of ES and DMS are higher than that of EO. The spectra were analyzed by an A-reduced asymmetric top rotational program with less than 4 kHz standard deviation, except for the 15N14N-DMS and 14N15N-DMS complexes. Rotational, centrifugal distortion, and nuclear electric quadrupole coupling constants were determined by the spectral analysis. The V3 potential barrier to internal rotation of the two equivalent methyl groups of DMS in the ortho and para states of the 15N2-DMS complex was determined to be about 740 cm-1. We performed ab initio calculations in order to complement the information on the intracomplex motions obtained from the experimental spectra. PMID- 30427673 TI - Stress Evolution during Ge Nanoparticles Growth in a SiO2 Matrix. AB - Superstructures are explored that were obtained by multilayer magnetron deposition at room temperature of 20 SiO2 and SiO2:Ge bilayers, each 2 * 4 nm thick, and subsequently annealed in inert N2 atmosphere at different temperatures in the range of 500-750 degrees C. The structural and optical changes induced by annealing and the formation and growth of Ge nanoparticles (nps) from early clusters to their full growth and final dissolution were studied by the simultaneous grazing-incidence small- and wide-angle X-ray scattering, transmission electron microscopy, and (time-resolved) photoluminescence (PL). It is shown that in as-deposited multilayers aggregation of small clusters already occurred, and the clusters were reasonably well intercorrelated in the lateral plane. During annealing at Ta = 550 degrees C or higher temperatures, Ge nps start to form and remain partly amorphous at lower Ta but crystallize completely at about 600 degrees C. At even higher temperatures, the Ge nps dissolve and Ge diffuses out almost completely, leaving voids in the SiO2 matrix. Visible PL from the samples was detected and attributed to defects in the nps/matrix interface layers rather than to the nps itself because PL persisted even after Ge nps dissolution. PMID- 30427674 TI - Multilevel Approach for Direct VSCF/VCI MULTIMODE Calculations with Applications to Large "Zundel" Cations. AB - We test existing efficient schemes for the "direct-dynamics" approach in building a potential energy surface (PES) in the code MULTIMODE. These are (1) the n-mode representation (nMR) approach to the PES, (2) the exploitation of the normal mode's symmetry to reduce the computational effort in constructing the PES, (3) the use of sparse grids for fitting the n-mode potentials, and (4) different levels of ab initio theory for these potentials. These schemes are applied to a four-dimensional calculation for the proton-bound methanol dimer (CH3OH)2H+. In addition to the major reduction in complexity obtained by considering only four modes, the combination of these schemes leads to a significant reduction in the computational effort without any major loss of accuracy. VSCF/VCI test calculations are presented for (CH3OH)2H+. PMID- 30427675 TI - NHC-Catalyzed Formal [2+2] Annulations of Allenoates for the Synthesis of Substituted Oxetanes. AB - An N-heterocyclic carbene (NHC)-catalyzed reaction of gamma-substituted allenoates for the synthesis of substituted oxetanes has been developed. The method provides an approach to access substituted oxetanes in a single step and is the first example of an NHC-catalyzed formal [2+2]-annulation employing gamma substituted allenoates with trifluoromethyl ketones. Mechanistic and modeling studies provide a rationale for the divergence in reactivity observed compared to the analogous reaction using unsubstituted allenoates and inform a hypothesis to explain the observed diastereoselectivity under different reaction conditions. PMID- 30427676 TI - An Adaptable Platform for Directed Evolution in Human Cells. AB - The discovery and optimization of biomolecules that reliably function in metazoan cells is imperative for both the study of basic biology and the treatment of disease. We describe the development, characterization, and proof-of-concept application of a platform for directed evolution of diverse biomolecules of interest (BOIs) directly in human cells. The platform relies on a custom-designed adenovirus variant lacking multiple genes, including the essential DNA polymerase and protease genes, features that allow us to evolve BOIs encoded by genes as large as 7 kb while attaining the mutation rates and enforcing the selection pressure required for successful directed evolution. High mutagenesis rates are continuously attained by trans-complementation of a newly engineered, highly error-prone form of the adenoviral polymerase. Selection pressure that couples desired BOI functions to adenoviral propagation is achieved by linking the functionality of the encoded BOI to the production of adenoviral protease activity by the human cell. The dynamic range for directed evolution can be enhanced to several orders of magnitude via application of a small molecule-based adenoviral protease inhibitor to modulate selection pressure during directed evolution experiments. This platform makes it possible, in principle, to evolve any biomolecule activity that can be coupled to adenoviral protease expression or activation by simply serially passaging adenoviral populations carrying the BOI. As proof-of-concept, we use the platform to evolve, directly in the human cell environment, several transcription factor variants that maintain high levels of function while gaining resistance to a small molecule inhibitor. We anticipate that this platform will substantially expand the repertoire of biomolecules that can be reliably and robustly engineered for both research and therapeutic applications in metazoan systems. PMID- 30427677 TI - Chemical Photocatalysis with Rhodamine 6G: Investigation of Photoreduction by Simultaneous Fluorescence Correlation Spectroscopy and Fluorescence Lifetime Measurements. AB - Recent research has demonstrated that consecutive excitation of the radical anion state of commercially available dye molecules-generated by a photoinduced electron-transfer process-yields sufficient energy to stimulate challenging chemical reactions in photocatalysis. For this reason, an efficient transfer of dye molecules into their radical anion states upon photoexcitation is highly desirable, as is a long radical lifetime. However, the formation of these reactive states is strongly dependent on the redox agent, the local environment, for example, the solvents and additives, as well as on the properties of the excited states of the dye molecule. Finding the best conditions for radical formation is crucial, but, owing to the complexity of the underlying photochemical process, this is usually only achieved by an iterative exploratory approach. Here, we demonstrate that the formation and lifetime of the rhodamine 6G (Rh6G) radical anion can be followed in detail by single-molecule fluorescence correlation spectroscopy combined with simultaneous fluorescence lifetime measurements. We elucidate the role of the first excited singlet and triplet states of the dye molecule in the formation of the radical at different concentrations of the reducing agent, ascorbic acid (AscA); for different solvents, water and dimethyl sulfoxide; and for different reducing agents, AscA and N, N-diisopropylethylamine; as well as for varying pH values. The results provide a guideline toward generating an increased yield of radical anions of the dye under photoexcitation. As an example, we find that the lifetime of the radical anion state of Rh6G can be increased by over an order of magnitude from 7 to 110 MUs in an aerated solution. PMID- 30427678 TI - Interplay between Aromaticity and Radicaloid Character in Nitrogen-Doped Oligoacenes Revealed by High-Level Multireference Methods. AB - Aromaticity is a multivariable concept in organic chemistry that plays a central role for understanding the structure, stability, and reactivity of polycyclic aromatic hydrocarbons (PAHs). Several types of PAHs are characterized as singlet biradicaloid species and their chemical stability is intimately linked to the degree of aromatic character. In this study, theoretically designed routes to tune the biradical character (and thereby its chemical stability) of nitrogen substituted octacenes have been investigated on the basis of the high-level multireference averaged quadratic coupled-cluster MR-AQCC method necessary for the appropriate description of polyradicaloid systems. The influence of nitrogen centers on the aromaticity of octacene is probed through structural (HOMA) and electron localization (ELF) indices by comparing the N- against NH-doping cases. These analyses reveal that the aromaticity and biradical character of octacene is only slightly affected by replacing one pair of CH groups with N atoms, i.e., by N-doping. However, a significant aromatic stabilization can be obtained when NH doping is applied at the inner octacene rings; this is also accompanied by an overall decrease of the open-shell character, as evidenced by the gradual quenching of the unpaired electrons and increase in the singlet-triplet splittings when the NH doping groups are moved toward the center of the octacene molecule. Our findings aid in the rational design of new PAH compounds with balanced biradicaloid character and chemical stability which is important, e.g., for practical applications in organic solar cells based on the singlet-fission mechanism. PMID- 30427679 TI - Qubit Coupled Cluster Method: A Systematic Approach to Quantum Chemistry on a Quantum Computer. AB - A unitary coupled cluster (UCC) form for the wave function in the variational quantum eigensolver has been suggested as a systematic way to go beyond the mean field approximation and include electron correlation in solving quantum chemistry problems on a quantum computer. Although being exact in the limit of including all possible coupled cluster excitations, practically, the accuracy of this approach depends on the number and type of terms are included in the wave function parametrization. Another difficulty of UCC is a growth of the number of simultaneously entangled qubits even at the fixed Fermionic excitation rank. Not all quantum computing architectures can cope with this growth. To address both problems, we introduce a qubit coupled cluster (QCC) method that starts directly in the qubit space and uses energy response estimates for ranking the importance of individual entanglers for the variational energy minimization. Also, we provide an exact factorization of a unitary rotation of more than two qubits to a product of two-qubit unitary rotations. Thus, the QCC method with the factorization technique can be limited to only two-qubit entanglement gates and allows for very efficient use of quantum resources in terms of the number of coupled cluster operators. The method performance is illustrated by calculating ground-state potential energy curves of H2 and LiH molecules with chemical accuracy, <=1 kcal/mol, and a symmetric water dissociation curve. PMID- 30427680 TI - Enhancing Antiproliferative Activity and Selectivity of a FLT-3 Inhibitor by Proteolysis Targeting Chimera Conversion. AB - The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT 3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention. PMID- 30427681 TI - Hemilabile Proton Relays and Redox Activity Lead to {FeNO} x and Significant Rate Enhancements in NO2- Reduction. AB - Incorporation of the triad of redox activity, hemilability, and proton responsivity into a single ligand scaffold is reported. Due to this triad, the complexes Fe(PyrrPDI)(CO)2 (3) and Fe(MorPDI)(CO)2 (4) display 40-fold enhancements in the initial rate of NO2- reduction, with respect to Fe(MeOPDI)(CO)2 (7). Utilizing the proper sterics and p Ka of the pendant base(s) to introduce hemilability into our ligand scaffolds, we report unusual {FeNO} x mononitrosyl iron complexes (MNICs) as intermediates in the NO2- reduction reaction. The {FeNO} x species behave spectroscopically and computationally similar to {FeNO}7, an unusual intermediate-spin Fe(III) coupled to triplet NO- and a singly reduced PDI ligand. These {FeNO} x MNICs facilitate enhancements in the initial rate. PMID- 30427682 TI - Monolithic Axial and Radial Metal-Semiconductor Nanowire Heterostructures. AB - The electrical and optical properties of low-dimensional nanostructures depend critically on size and geometry and may differ distinctly from those of their bulk counterparts. In particular, ultrathin semiconducting layers as well as nanowires have already proven the feasibility to realize and study quantum size effects enabling novel ultrascaled devices. Further, plasmonic metal nanostructures attracted recently a lot of attention because of appealing near field-mediated enhancement effects. Thus, combining metal and semiconducting constituents in quasi one-dimensional heterostructures will pave the way for ultrascaled systems and high-performance devices with exceptional electrical, optical, and plasmonic functionality. This Letter reports on the sophisticated fabrication and structural properties of axial and radial Al-Ge and Al-Si nanowire heterostructures, synthesized by a thermally induced exchange reaction of single-crystalline Ge-Si core-shell nanowires and Al pads. This enables a self aligned metallic contact formation to Ge segments beyond lithographic limitations as well as ultrathin semiconducting layers wrapped around monocrystalline Al core nanowires. High-resolution transmission electron microscopy, energy dispersive X ray spectroscopy, and MU-Raman measurements proved the composition and perfect crystallinity of these metal-semiconductor nanowire heterostructures. This exemplary selective replacement of Ge by Al represents a general approach for the elaboration of radial and axial metal-semiconductor heterostructures in various Ge-semiconductor heterostructures. PMID- 30427683 TI - Wettability of Amphoteric Surfaces: The Effect of pH and Ionic Strength on Surface Ionization and Wetting. AB - We present a novel theory to predict the contact angle of water on amphoteric surfaces, as a function of pH and ionic strength. To validate our theory, experiments were performed on two commonly used amphoteric materials, alumina (Al2O3) and titania (TiO2). We find good agreement at all pH values, and at different salt concentrations. With increasing salt concentration, the theory predicts the contact angle-pH curve to get steeper, while keeping the same contact angle at pH = PZC (point of zero charge), in agreement with data. Our model is based on the amphoteric 1-p K model and includes the electrostatic free energy of an aqueous system as well as the surface energy of a droplet in contact with the surface. In addition, we show how our theory suggests the possibility of a novel responsive membrane design, based on amphoteric groups. At pH ~ PZC, this membrane resists flow of water but at slightly more acidic or basic conditions the wettability of the membrane pores may change sufficiently to allow passage of water and solutes. Moreover, these membranes could act as active sensors that only allow solutions of high ionic strength to flow through in wastewater treatment. PMID- 30427684 TI - Selected and Enhanced Single Whispering-Gallery Mode Emission from a Mesostructured Nanomembrane Microcavity. AB - Quantum sciences are revolutionizing computing and communication technologies, in which single-photon emitters are the key components for creating strong quantum entanglement. Color centers in diamonds in coupled-cavity systems are considered great candidates for the efficient generation of quantum carriers over other solid-state emitters. Owing to the multi-mode nature of high quality factor ( Q) diamond cavities, however, it is a grand challenge to the achievement of single photon emission with high rate and indistinguishability. To this end, a single mode high- Q diamond cavity is highly desired. Here, we report a diamond mesostructured nanomembrane microcavity of a discrete rotational symmetry that selectively produces the desired single-mode emission in a broad spectrum. The strategic rolling up of a flexible diamond nanomembrane with aligned holes effectively defines the designed symmetry while maintaining the high- Q resonance through the whispering-gallery mode supported in the central hollow microcavity. The demonstrated diamond mesostructured microcavity features a distinct and enhanced single-mode emission, a step toward efficient quantum sources with designed positions or bands for quantum information technology. PMID- 30427685 TI - Concurrent Zinc-Blende and Wurtzite Film Formation by Selection of Confined Growth Planes. AB - Recent research on nanowires (NWs) demonstrated the ability of III-V semiconductors to adopt a different crystallographic phase when they are grown as nanostructures, giving rise to a novel class of materials with unique properties. Controlling the crystal structure however remains difficult and the geometrical constraints of NWs cause integration challenges for advanced devices. Here, we report for the first time on the phase-controlled growth of micron-sized planar InP films by selecting confined growth planes during template-assisted selective epitaxy. We demonstrate this by varying the orientation of predefined templates, which results in concurrent formation of zinc-blende (ZB) and wurtzite (WZ) material exhibiting phase purities of 100% and 97%, respectively. Optical characterization revealed a 70 meV higher band gap and a 2.5* lower lifetime for WZ InP in comparison to its natural ZB phase. Further, a model for the transition of the crystal structure is presented based on the observed growth facets and the bonding configuration of InP surfaces. PMID- 30427686 TI - Copper-Catalyzed Regioselective and Diastereoselective Synthesis of Borylated 1 Benzo[ b]azepines. AB - A practical regioselective and diastereoselective synthesis of functionalized 1 benzo[ b]azepines by copper-catalyzed intramolecular cyclization has been developed. The reaction involves borylcupration of a mixture of ( E/ Z)-1,3 dienes, followed by capture of the generated ( Z)-allylcopper species with an imine to produce 7-membered N-heterocycles as single diastereomers. The reaction is applicable to various ( E/ Z)-dienyl arenes with an imine moiety at the ortho position, including aryl, alkyl, and heterocyclic aldimines, and ketimines, affording borylated 2,3- cis-substituted 1-benzo[ b]azepines in good yields. PMID- 30427687 TI - Visible-Light-Induced C-O Bond Formation for the Construction of Five- and Six Membered Cyclic Ethers and Lactones. AB - Visible-light-induced intramolecular C-O bond formation was developed using 2,4,6 triphenylpyrylium tetrafluoroborate (TPT), which allows the regiocontrolled construction of cyclic ethers and lactones. The reaction is likely to proceed through the single-electron oxidation of the phenyl group, followed by the formation of a benzylic radical, thus preventing a competing 1,5-hydrogen abstraction pathway. Detailed mechanistic studies suggest that molecular oxygen is used to trap the radical intermediate to form benzyl alcohol, which undergoes cyclization. This new approach serves as a powerful platform by providing efficient access to valuable five- and six-membered cyclic ethers and lactones with a unified protocol. PMID- 30427688 TI - Ultraflexible Nanowire Array for Label- and Distortion-Free Cellular Force Tracking. AB - Living cells interact with their immediate environment by exerting mechanical forces, which regulate important cell functions. Elucidation of such force patterns yields deep insights into the physics of life. Here we present a top down nanostructured, ultraflexible nanowire array biosensor capable of probing cell-induced forces. Its universal building block, an inverted conical semiconductor nanowire, greatly enhances both the functionality and the sensitivity of the device. In contrast to existing cellular force sensing architectures, microscopy is performed on the nanowire heads while cells deflecting the nanowires are confined within the array. This separation between the optical path and the cells under investigation excludes optical distortions caused by cell-induced refraction, which can give rise to feigned displacements on the 100 nm scale. The undistorted nanowire displacements are converted into cellular forces via the nanowire spring constant. The resulting distortion-free cellular force transducer realizes a high-resolution and label-free biosenor based on optical microscopy. Its performance is demonstrated in a proof-of principle experiment with living Dictyostelium discoideum cells migrating through the nanowire array. Cell-induced forces are probed with a resolution of 50 piconewton, while the most flexible nanowires promise to enter the 100 femtonewton realm. PMID- 30427690 TI - Lorentz Nanoplasmonics for Nonlinear Generation. AB - While past works have suggested that the Lorentz magnetic contribution to second harmonic generation from metal nanostructures is negligible as compared to other terms, here we demonstrate a dominant Lorentz contribution from T-shaped apertures in a gold film. The apertures are designed to have overlapping magnetic and electric near-field intensities at the plasmonic resonance. This gives 65% greater nonlinear generation from the Lorentz term than the sum of the other two terms. We demonstrate this effect experimentally by milling of nanoapertures of different size and orientation in a metal film and measuring their second harmonic generation. Good agreement is seen between the experiments and comprehensive calculations. In the development of highly efficient nonlinear metasurfaces, careful optimization of the Lorentz contribution should be considered in addition to all other contributions. Following the approach of this work, the Lorentz contribution may also be optimized for THz generation. PMID- 30427689 TI - Favorable Core/Shell Interface within Co2P/Pt Nanorods for Oxygen Reduction Electrocatalysis. AB - Nanostructures with nonprecious metal cores and Pt ultrathin shells are recognized as promising catalysts for oxygen reduction reaction (ORR) to enhance Pt efficiency through core/shell interfacial strain and ligand effects. However, core/shell interaction within a real catalyst is complex and due to the presence of various interfaces in all three dimensions is often oversimply interpreted. Using Co2P/Pt core/shell structure as a model catalyst, we demonstrate, through density functional theory (DFT) calculations that forming Co2P(001)/Pt(111) interface can greatly improve Pt energetics for ORR, while Co2P(010)/Pt(111) is highly detrimental to ORR catalysis. We develop a seed-mediated approach to core/shell Co2P/Pt nanorods (NRs) within which Co2P(001)/Pt(111) interface is selectively expressed over the side facets and the undesired Co2P(010)/Pt(111) interface is minimized. The resultant Co2P/Pt NRs are highly efficient in catalyzing ORR in acid, superior to benchmark CoPt alloy and Pt nanoparticle catalyst. As the first example of one-dimensional (1D) core/shell nanostructure with an ultrathin Pt shell and a nonprecious element core, this strategy could be generalized to develop ultralow-loading precious-metal catalysts with favorable core/shell interactions for ORR and beyond. PMID- 30427691 TI - Synthesis of the Non-Reducing Hexasaccharide Fragment of Saccharomicin B. AB - A synthesis of the nonreducing end hexasaccharide of saccharomicin B, alpha-l-Eva (1->4)-alpha-l-Eva-(1->4)-alpha-l-Dig-(1->4)-alpha-l-Eva-(1->4)-alpha-l-Dig-(1 >4)-beta-d-Fuc, has been developed. Selective glycosylations of l-digitoxose (l Dig) using AgPF6/TTBP-mediated thioether activation and l-4-e pi-vancosamine (l Eva) using Tf2O/DTBMP-mediated sulfoxide activation produced the hexasaccharide as a single diastereomer in very good yield. This hexasaccharide is properly functionalized to serve as a glycosyl donor for the total synthesis of saccharomicin B. PMID- 30427692 TI - FeCl3 as an Ion-Pairing Lewis Acid Catalyst. Formation of Highly Lewis Acidic FeCl2+ and Thermodynamically Stable FeCl4- To Catalyze the Aza-Diels-Alder Reaction with High Turnover Frequency. AB - The aza-Diels-Alder reaction of nonactivated dienes and imines was realized through the action of the ion-paired Lewis acid catalyst [FeCl2]+[FeCl4]- generated by the in situ disproportionation of FeCl3. The uniquely high reactivity of [FeCl2]+[FeCl4]- was attributed to both the highly Lewis acidic FeCl2+ and thermodynamically stable FeCl4- acting as an ion-paired catalyst. Synchrotron-based X-ray absorption fine structure measurements provided fundamental insights into the disproportionation and structure of the resulting ion-paired iron complex. A theoretical study was performed to analyze the catalytic reaction and better understand the "ion-pairing effect" which transforms simple FeCl3 into a high turnover frequency Lewis acid catalyst in the aza-Diels-Alder reaction of nonactivated dienes and imines. PMID- 30427693 TI - Tissue-Level Mechanosensitivity: Predicting and Controlling the Orientation of 3D Vascular Networks. AB - Understanding the mechanosensitivity of tissues is a fundamentally important problem having far-reaching implications for tissue engineering. Here we study vascular networks formed by a coculture of fibroblasts and endothelial cells embedded in three-dimensional biomaterials experiencing external, physiologically relevant forces. We show that cyclic stretching of the biomaterial orients the newly formed network perpendicular to the stretching direction, independent of the geometric aspect ratio of the biomaterial's sample. A two-dimensional theory explains this observation in terms of the network's stored elastic energy if the cell-embedded biomaterial features a vanishing effective Poisson's ratio, which we directly verify. We further show that under a static stretch, vascular networks orient parallel to the stretching direction due to force-induced anisotropy of the biomaterial polymer network. Finally, static stretching followed by cyclic stretching reveals a competition between the two mechanosensitive mechanisms. These results demonstrate tissue-level mechanosensitivity and constitute an important step toward developing enhanced tissue repair capabilities using well-oriented vascular networks. PMID- 30427694 TI - Complementary iTRAQ Proteomic and Transcriptomic Analyses of Leaves in Tea Plant ( Camellia sinensis L.) with Different Maturity and Regulatory Network of Flavonoid Biosynthesis. AB - The quality of tea is highly related with the maturity of the fresh tea leaves at harvest. The present study investigated the proteomic and transcriptomic profiles of tea leaves with different maturity, using iTRAQ and RNA-seq technologies. A total of 4455 proteins and 27 930 unigenes were identified, with functional enrichment analyses of GO categorization and KEGG annotation. The compositions of flavonoids (catechins and flavonols) in tea leaves were determined. The total content of flavonoids decreased with leaf maturity, in accordance with the protein regulation patterns of shikimate, phenylpropanoid, and flavonoid pathways. The abundance of ANR had a positive correlation with epi-catechin content, while LAR abundance was positively related with catechin content ( P < 0.05). The biosynthetic network of flavonoid biosynthesis was discussed in combination with photosynthesis, primary metabolism, and transcription factors. Bud had the lowest activities of photosynthesis and carbon fixation but the highest flavonoid biosynthesis ability in opposite to mature leaf. SUS-INV switch might be an important joint for carbon flow shifting into the follow-up biochemical syntheses. This work provided a comprehensive overview on the functional protein profile changes of tea leaves at different growing stages and also proposed a research direction regarding the correlations between primary metabolism and flavonoid biosynthesis. PMID- 30427695 TI - From Tunable DNA/Polymer Self-Assembly to Tailorable and Morphologically Pure Core-Shell Nanofibers. AB - In reported experimental studies, DNA/polymer self-assemblies are usually kinetically trapped, leading to the encapsulation and irregular collapse of DNA chains within the resultant assemblies. In striking contrast, eukaryotic cells use tetrasome-to-nucleosome pathways to escape possible kinetic trapping for the formation of well-defined 10 nm chromatin fibers. Here, we report a novel pathway for DNA and amphiphilic diblock copolymer self-assembly inspired by the tetrasome pathway with highly controllable kinetics. The polymer is an A- b-B diblock copolymer with a hydrophilic and noninteractive block A and a hydrophobic and interactive block B. Below the critical water content for the micellization, B blocks wrap the backbone of a DNA chain by weak electrostatic interactions to form a linear DNA/polymer complex. With a gradual increase in the water content, the diblock copolymer unimers in the bulk solution tend to aggregate on the linear DNA/polymer complex, which induces the originally wrapped DNA chain, to change its conformation to wrap around the polymer aggregate, guiding and tailoring the self-assembly. Highly controllable kinetics is achieved via the reduced DNA/polymer electrostatic interactions and the high dynamics of the polymer chains in the system. DNA/polymer self-assembly leads to tailorable and morphologically pure core-shell nanofibers. Compared to the DNA/micelle self assembly pathway described in our previous study, the present self-assembly pathway exhibits advantages for the fabrication of flexible nanofibers with lengths in micrometers and the potential for unique applications in preparing not only 2D networks at extremely low percolation thresholds but also chemiresistors with large on/off current ratios. PMID- 30427696 TI - The Effect of T'ai Chi and Qigong Training on Patients with Obstructive Sleep Apnea: A Randomized Controlled Study. AB - OBJECTIVES: This study aims to investigate the effects of t'ai chi and qigong (TCQ) training on severity of obstructive sleep apnea (OSA). DESIGN: A prospective, 12-week, single-center, double-blinded, randomized controlled trial. SETTING: Sleep Disorders Center of Medical Faculty in Istanbul, Turkey. SUBJECTS: Fifty adult patients with mild and moderate OSA. INTERVENTIONS: Patients were randomly allocated into either an intervention group or a control group. The intervention group (n = 25) received TCQ training under physiotherapist supervision for 1 h, three times per week, for 12 weeks and a home exercise program was provided for another 2 days. The control group (n = 25) received only a home exercise program for 12 weeks, 5 days per week. OUTCOME MEASURES: All patients were assessed before and after the exercise program. Objective parameters of sleep were measured by polysomnography, while subjective parameters of sleep were assessed using the Epworth Sleepiness Scale (ESS) and the 3-factor Pittsburgh Sleep Quality Index (PSQI). Pulmonary functions were assessed with a pulmonary function test; health-related quality of life was evaluated through the Short Form-36. RESULTS: In the intervention group, there was a statistically significant decrease in the apnea-hypopnea index (AHI) (p = 0.001) and percentage and duration of stage N2 sleep (p = 0.041 and p = 0.037, respectively), while there was a statistically significant increase in percentage and duration of stage N3 sleep when compared with the controls (p = 0.048 and p = 0.043, respectively). There was a statistically significant decrease in the ESS, PSQI sleep efficiency, and total scores (p = 0.001, p = 0.003, and p = 0.003, respectively). CONCLUSIONS: Our study results suggest that TCQ training may reduce AHI and daytime sleepiness, while improving subjective sleep quality, in patients with mild and moderate OSA. PMID- 30427697 TI - Autism Spectrum Disorders: Potential Neuro-Psychopharmacotherapeutic Plant-Based Drugs. AB - Over the years, scientific researches have validated the healing benefits of many psychopharmacotherapeutic plant-based drugs to ameliorate psychiatric disorders. In contrast, the use of chemical procedures to isolate and purify specific compounds from plants that have been used to treat autism spectrum disorders (ASDs) and its clinical features may contribute to improve the quality of life of many patients. Also, herbal pharmacological treatments could improve the core symptoms of autism with fewer side effects. This review will focus on the uses and actions of phytopharmaceuticals in the behavioral conditions of ASDs. A large number of natural compound-based plant drugs have been tested in murine models of autism and in clinical trials with remarkable success in reversing the core and associated behaviors with autism such as flavonoids, cannabinoids, curcuminoids, piperine, resveratrol, and bacosides. This plant-based drug alternative is safer given that many psychiatric disorders and neurodegenerative pathologies do not often respond well to currently prescribed medications or have significant side effects. However, it is noteworthy to consider the need for large clinical trials to determine safety and efficacy. Many results are based on case reports or small size samples, and often the studies are open label. Standardization of procedures (i.e., purity and concentrations) and quality controls are strictly required to ensure the absence of side effects. PMID- 30427698 TI - Sodium Loading, Treadmill Walking and the Acute Redistribution of Bone Mineral Content on Dual Energy X-ray Absorptiometry Scans. AB - PURPOSE: To assess relationships between plasma sodium concentration ([Na+]) and bone mineral content (BMC) after an acute sodium load plus treadmill walking and quantify the amount of sodium the dual energy x-ray absorptiometry (DXA) scan could detect. METHODS: The primary study was a single-blind randomized control crossover trial under two Conditions: ingestion of six flour tablets (P: placebo trial) or six 1g-NaCl tablets (S: salt intervention trial). Tablets were ingested after baseline blood and urine collection followed immediately by the DXA scan. After 60 minutes of rest, a 45-minute treadmill walk was conducted. Immediately post-exercise, blood and urine collected and the DXA scan repeated. Main outcomes included changes (?: post minus pre) in plasma [Na+] and BMC. Additionally, six 1g-NaCl tablets were superimposed over a DXA spine phantom for separate quantification of sodium as BMC. RESULTS: 14 subjects completed the primary study. Two-way repeated-measures ANOVA tests revealed significant Interaction (F=13.06;p=0.0007), Condition (F=21.88;p<0.001) and Time (F=6.51;p=0.014) effects in plasma [Na+]. Significant Condition (F=6.46;p=0.014) effect also noted in urine [Na+]. Total body BMC? negatively correlated with plasma [Na+]? (r= 0.43;p=0.02) and urine [Na+]? (r=-0.47;p=0.01). Total body BMC? in the S trial ( 5.5+/-27g) closely approximated the amount of NaCl ingested and subsequently absorbed into the bloodstream. The DXA scan quantified 67% of NaCl tablets as BMC, in spine phantom analyses. CONCLUSIONS: Total body BMC? negatively related to plasma and urine [Na+]? after treadmill walking. Reductions in total body BMC closely approximated the amount of NaCl ingested (~6g). The DXA scan quantified NaCl as BMC. PMID- 30427699 TI - miR-196a Promotes Proliferation and Inhibits Apoptosis of Immature Porcine Sertoli Cells. AB - Our previous study showed that the expression of miR-196a was significantly higher in immature porcine testes than in mature porcine testes. However, the role of miR-196a in immature Sertoli cells remains unclear. In this study, miR 196a mimics, miR-196a inhibitor, and microRNA-small hairpin negative control (miRNA-ShNC) were transfected into immature Sertoli cells, respectively. Subsequently, the cell cycle and apoptosis rate of the immature Sertoli cells were measured by flow cytometry, and the viability of the Sertoli cells was measured by the MTS assay. Furthermore, the candidate target genes of miR-196a were analyzed by bioinformatics, and the target genes were validated by dual luciferase reporter assays, then the expression of target genes was detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot assays. The results showed that miR-196a promotes the proliferation and inhibits the apoptosis of immature Sertoli cells. miR-196a directly binds the 3' untranslated region (3' UTR) of RCC2 and ABCB9. The expression of miR-196a was shown to be negatively correlated with the messenger RNA and protein levels of the RCC2 and ABCB9 genes. The study demonstrates that miR-196a regulates immature Sertoli cell proliferation and apoptosis and inhibits the expression of RCC2 and ABCB9. PMID- 30427700 TI - Concurrent Validity of an Automated Footprint Detection Algorithm to Measure Plantar Contact Area during Walking. AB - BACKGROUND: Monitoring footprints during walking can lead a better identification of foot structure and abnormalities. Current techniques for footprint measurements are either static or dynamic, with low resolution. This work presents an approach to monitor the plantar contact area when walking, using high speed videography. METHODS: Footprint images were collected by asking the participants to walk across a custom-built acrylic walkway, with a high resolution digital camera placed directly underneath the walkway. This study proposes an automated footprint identification algorithm (Automatic Identification Algorithm) to measure the footprint throughout the stance phase of walking. This algorithm used the coloration of the plantar tissue that was in contact with the acrylic walkway to distinguish the plantar contact area from other regions of the foot that were not in contact. RESULTS: The Intraclass Correlation Coefficient (ICC) demonstrated strong agreement between the proposed automated approach and 'gold standard' manual method (ICC = 0.939). Strong agreement between the two methods also was found for each phase of stance (ICC= >0.78). CONCLUSIONS: The proposed automated footprint detection technique identified the plantar contact area during walking with strong agreement to a manual 'gold standard' method. This is the first study to demonstrate the concurrent validity of an automatic identification algorithm to measure the plantar contact area during walking. PMID- 30427701 TI - Patellar Tendon-Lateral Trochlear Ridge Distance: A Novel Measurement of Patellofemoral Instability. AB - BACKGROUND:: Abnormalities in the trochlea-patella-tibia relationship have been shown to be risk factors for recurrent patellofemoral instability, although no current measurements quantify patellar containment in the trochlea. Standard measurements, such as tibial tubercle-trochlear groove (TT-TG) distance, do not account for the containment of the patella by the trochlea. Our goal was to develop a measurement to assess how well the trochlea contained the extensor mechanism. HYPOTHESIS:: A novel measurement describing the amount of the patellar tendon lateral to the lateral trochlear ridge (PT-LTR) would be a reliable measurement and significantly greater among patients with patellofemoral instability. STUDY DESIGN:: Cohort study (diagnosis); Level of evidence, 2. METHODS:: The authors analyzed radiology records from 2005 to 2014 for patients aged 5 to 18 years with and without patellofemoral dislocations who had knee magnetic resonance imaging (MRI). Two blinded reviewers evaluated 215 MRI studies. Standard and novel morphology measurements were calculated for each knee and compared in a case-control design. Interobserver reliability of each measure was assessed by the intraclass correlation coefficient. Predictability for patellofemoral dislocation was calculated with 2-tailed independent-samples Student t tests. Discriminative capacity was calculated with receiver operating characteristic analyses and area under the curve (AUC). An optimal measurement cutoff with resultant sensitivity and specificity was calculated. RESULTS:: Standard measurements of TT-TG distance, tangential axial width of the patella (TAWP), and tangential axial trochlear width (TATW) had excellent agreement between raters; lateral femoral condyle length had good agreement; and the novel measurement-width of the tendon beyond the lateral femoral condyle (PT-LTR)-also had excellent agreement. These underwent predictability and discriminative capacity analyses. TT-TG, TAWP, TATW, and PT-LTR were significant predictors of patellofemoral instability. In receiver operating characteristic analysis, TAWP had an AUC of 0.65, below the 0.8 threshold. TATW had an AUC of 0.814 and, when <32.5 mm, was 76% sensitive and 77% specific for dislocations. TT-TG demonstrated an AUC of 0.806. TT-TG >=13.5 mm was 76% sensitive and 76% specific for dislocations. PT-LTR demonstrated an AUC of 0.876 and, when >=5.55 mm, was 73% sensitive and 89% specific for patellofemoral dislocation. CONCLUSION:: PT-LTR is reliable, predictable, and discriminative for patellofemoral dislocations. This measurement had sensitivity similar to that of TT-TG but with higher specificity. PMID- 30427702 TI - Overreaction in Football Wagers. AB - Football scores are an imperfect measure of a team's ability, and consequently exaggerate differences in abilities. Those teams that perform the best and the worst are not really so far from average in their ability; thus their future performances regress to the mean. Betting data indicate that gamblers do not fully account for this regression. PMID- 30427703 TI - From the Editor-in-Chief's Desk. PMID- 30427704 TI - Consumer Antimicrobials on Gut Microbiota and Gut Health. AB - Triclosan (TCS) is a high-volume chemical used as an antimicrobial ingredient in over 2000 consumer products such as toothpastes, cosmetics, and toys. Due to its widespread use, it causes ubiquitous contamination in the environment and is frequently detected in the human body, raising concerns about its impact on environmental pollution and human health. Our recent study showed that short-time exposure to low-dose TCS causes colonic inflammation, increases severity of colitis, and exacerbates colitis-associated colon tumorigenesis in mice, through gut microbiota- and Toll-like receptor 4 (TLR4)-dependent mechanisms. In addition, we demonstrate that beyond TCS, other antimicrobial chemicals used in consumer products also exaggerate colitis and colon cancer in mice. Together, these results highlight the importance to further evaluate these consumer antimicrobials on gut health, to develop potential further regulatory policies. PMID- 30427705 TI - Female C57BL/6J Mice Lacking the Circadian Clock Protein PER1 are Protected from Non-Dipping Hypertension. AB - The circadian clock is integral to the maintenance of daily rhythms of many physiological outputs including blood pressure. Our lab has previously demonstrated the importance of the clock protein PER1 in blood pressure regulation in male mice. Briefly, a high salt diet (4% NaCl, HS) plus injection with the long-acting mineralocorticoid deoxycorticosterone pivalate (DOCP) resulted in non-dipping hypertension (<10% difference between night and day blood pressure (BP) in Per1 Knockout (KO) mice but not in wild-type (WT) mice. To date, there have been no studies that have examined the effect of a core circadian gene KO on BP rhythms in female mice. The goal of the present study was to determine if female Per1 KO mice develop non-dipping hypertension in response to HS/DOCP treatment. For the first time we demonstrate that loss of the circadian clock protein PER1 in female mice does not significantly change MAP nor the BP rhythm relative to female C57BL/6 WT control mice. Both WT and Per1 KO female mice experienced a significant increase in MAP in response to HS/DOCP. Importantly however, both genotypes maintained a >10% dip in BP on HS/DOCP. This effect is distinct from the non-dipping hypertension seen in male Per1 KO mice, demonstrating that female sex appears to be protective against PER1- mediated non dipping hypertension in response to HS/DOCP. Together these data suggest that PER1 acts in a sex-dependent manner in the regulation of cardiovascular rhythms. PMID- 30427706 TI - Viral Hepatitis and a Hospital Infrastructure in Ruins in Cameroon. AB - Ethnographic material dealing with the contemporary viral hepatitis B and C epidemics in Cameroon provide a window onto the acute constraints and shortcomings of hospital care for patients, families, and health care workers. Although viral hepatitis has long been an invisible epidemic in international and global public health regimes, in Cameroon, it is diagnosed, made visible, and felt as a financially daunting and feared disease. Building on Ann Stoler's framework of imperial ruins, I consider hepatitis as an iatrogenic disease, emerging from scarce and unsound hospital infrastructures, such as blood transfusion techniques, as well as colonial public health vaccination practices. Such hospital technologies continue to produce anxieties, risk and excessive health expenses and hence cast their shadows on the future. PMID- 30427707 TI - Glutathione: subcellular distribution and membrane transport. AB - Glutathione (gamma-glutamylcysteinylglycine) is a small tripeptide found at millimolar concentrations in nearly all eukaryotes as well as many prokaryotic cells. Glutathione synthesis is restricted to the cytosol in animals and fungi and to the cytosol and plastids in plants. Nonetheless, glutathione is found in virtually all subcellular compartments. This implies that transporters must exist, which facilitate glutathione transport into and out of the various subcellular compartments. Glutathione may also be exported and imported across the plasma membrane in many cells. However, in most cases, the molecular identity of these transporters remains unclear. Whilst glutathione transport is essential for the supply and replenishment of subcellular glutathione pools, recent evidence supports a more active role for glutathione transport in the regulation of subcellular glutathione redox homeostasis. However, our knowledge of glutathione redox homeostasis at the level of specific subcellular compartments remains remarkably limited and the role of glutathione transport remains largely unclear. In this review we discuss how new tools and techniques have begun to yield insights into subcellular glutathione distribution and glutathione redox homeostasis. In particular, we discuss the known and putative glutathione transporters and examine their contribution to the regulation of subcellular glutathione redox homeostasis. PMID- 30427708 TI - Scopulariopsis brevicaulis Rhinosinal Infection in a Dog. AB - A 1 yr old castrated male American Staffordshire terrier mix was treated for Scopulariopsis brevicaulis that was discovered during an evaluation of chronic rhinosinusitis. A sinusotomy was performed, with intraoperative infusion of amikacin-impregnated gel and systemic administration of postoperative amikacin. Antibiotic therapy was initially chosen because of historic culture of Mycoplasma. Fungal culture of the frontal sinus identified S. brevicaulis by combined phenotypic characterization and DNA sequencing after morphologic analysis failed to identify the organism. Systemic terbinafine therapy was instituted after fungal culture results were available. The patient recovered well and has had no clinical relapse of disease 3 yr after treatment. This is the first reported case of a fungal rhinosinusitis caused by S. brevicaulis in a dog. Reports of Scopulariopsis infections in humans indicate that treatment of S. brevicaulis infection is hampered by multidrug resistance; prognosis may be poor in people with invasive infections and is currently unknown in dogs. Multimodal therapy, including concurrent surgical and systemic intervention, may be necessary to optimize treatment success. PMID- 30427709 TI - Presumptive Glucocorticoid-Induced Refractory Hypocalcemia in a Dog with Idiopathic Immune-Mediated Hypoparathyroidism, Thrombocytopenia, and Hemolytic Anemia. AB - Clinically relevant hypocalcemia is a well-documented complication of glucocorticoid administration in people with hypoparathyroidism. The current report describes the phenomenon in a dog. A 7 yr old neutered male Pomeranian was diagnosed with immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, and primary hypoparathyroidism. This dog required long-term parenteral calcium gluconate to prevent clinical hypocalcemia despite appropriate doses of oral calcitriol and calcium carbonate. This is the first description of clinically significant presumptive glucocorticoid induced hypocalcemia in a dog with primary hypoparathyroidism. PMID- 30427710 TI - Short-Term Administration of Single-Agent Toceranib in Six Cases of Inoperable Massive Canine Hepatocellular Carcinoma. AB - Six dogs with massive hepatocellular carcinoma that was not amenable to surgery were treated by oral administration of single-agent toceranib at a dose of 2.0 3.0 mg/kg every other day for a minimum of 60 days. Partial response was achieved in three dogs, stable disease was achieved in one dog, and progressive disease occurred in two dogs, according to the canine Response Evaluation Criteria in Solid Tumors v1.0. Observed adverse events were mild to moderate in severity and reported in accordance with the Veterinary Cooperative Oncology Group's common terminology criteria for adverse events v1.1. Activities of alanine aminotransferase and alkaline phosphatase decreased in the cases that were sensitive to treatment with toceranib, whereas the activities remained high in resistant cases. Additionally, the level of phospho-vascular endothelial growth factor receptor 2 was found to be increased in a resistant case. Single-agent toceranib might prove to be an effective treatment for canine hepatocellular carcinoma pending further validation. PMID- 30427711 TI - Immune-Mediated Neutropenia in a Miniature Poodle. AB - A 10 yr old spayed female toy poodle was presented to a tertiary referral center for a 10 day history of waxing and waning lethargy, vomiting, diarrhea, and anorexia. An immune-mediated neutropenia (IMN) was suspected to be the underlying cause of her clinical signs. A bone marrow aspirate was obtained from the chostochondral junction of the 11th and 12th ribs on the right side and provided a definitive diagnosis of IMN. A positive response to therapy and repeat blood work further confirmed the diagnosis. Obtaining bone marrow aspirates from the chostochondral junction is a safe, cheap, and reliable method of diagnosing IMN and can be performed in the private practice setting with light sedation and minimal need for specialized equipment. PMID- 30427712 TI - Vaccination and Associated Adverse Events in Dogs Previously Treated for Primary Immune-Mediated Hemolytic Anemia. AB - This study described the rate of vaccine reactions in a population of dogs receiving vaccines after diagnosis of primary immune-mediated hemolytic anemia (IMHA). A secondary objective was to describe the time elapsed between vaccination and initial diagnosis of IMHA. A medical record search identified cases meeting criteria for primary IMHA. Owners and referring veterinarians were surveyed regarding vaccination of the dog following diagnosis. Referring veterinarians were surveyed regarding vaccination prior to diagnosis of IMHA. A completed survey was returned in 44 cases. Twenty-two dogs received vaccinations after diagnosis, and 22 dogs did not. The median time elapsed between vaccination and initial diagnosis was 280 days. No dog was vaccinated within 30 days of diagnosis. Two of the following possible reactions were noted out of 22 dogs vaccinated: vomiting and urticarial eruption in a dog administered a rabies and canine distemper vaccine, and recurrent anemia in a dog administered a rabies vaccine. The rate of vaccine reactions was higher than previously reported, although the time period evaluated was longer than in previous studies. The relationship between initial vaccination and development of IMHA, and between vaccination and vaccine reaction, in this population is uncertain and may reflect coincidence or differences in susceptibility. PMID- 30427713 TI - Relative Oral Bioavailability of Two Amoxicillin-Clavulanic Acid Formulations in Healthy Dogs: A Pilot Study. AB - The use of human generic amoxicillin-clavulanic acid formulations in veterinary medicine is currently lacking supportive evidence. This pilot study was conducted to determine preliminary pharmacokinetic parameters and relative oral bioavailability of a human generic and veterinary proprietary 4:1 amoxicillin clavulanic acid formulation in healthy dogs to evaluate whether drug exposure was similar and to determine if further comparative investigation is warranted. Each dog received a single oral dose of each formulation containing 500:125 mg of amoxicillin-clavulanic acid at two separate instances with a 2 wk washout period between product administration. Following drug administration, blood was collected at fixed times over 24 hr to measure plasma amoxicillin and clavulanic acid concentrations using liquid chromatography-mass spectrometry. There were no statistically significant differences between pharmacokinetic parameters of either formulation. Clavulanic acid showed greater between-dog variation in drug exposure between formulations compared with amoxicillin and was also observed to be more variable within the veterinary proprietary formulation. The average relative oral bioavailability was 98.2% (23.6% coefficient of variation) for amoxicillin and 152.6% (64.3% coefficient of variation) for clavulanic acid between formulations. This pilot investigation supports the need for further bioequivalence studies regarding these formulations before commenting on product interchangeability. PMID- 30427714 TI - Long-Term Survival and Glycemic Control with Toceranib Phosphate and Prednisone for a Metastatic Canine Insulinoma. AB - Canine insulinoma is a highly metastatic neoplasm that is associated with a guarded to poor prognosis in dogs with distant metastases. A median survival of 6 mo has been reported for dogs with metastatic insulinoma. The dog in this report, diagnosed with stage III pancreatic insulinoma, had long-term glycemic control with survival of over 24 mo while receiving prednisone and toceranib phosphate after partial pancreatectomy. Toceranib phosphate has been shown to be an efficacious therapy for canine mast cell tumors with increasing evidence that it may be beneficial in the medical management of neuroendocrine tumors. PMID- 30427715 TI - Caudal Mediastinal Fish Hook Foreign Body with Pulmonary Artery Penetration in Two Dogs. AB - A 1.5 yr old spayed female mixed-breed dog and a 3 yr old spayed female Labrador retriever were evaluated for suspected esophageal fishhook foreign bodies. Radiographs yielded fishhook foreign bodies present caudal to the cardiac silhouette. Endoscopic retrieval for suspected caudal esophageal foreign body was attempted and aborted due to inadequate visualization of the entire fishhooks within the lumen of the esophagus. At surgery, the fishhooks were seen within the caudal mediastinum, and were engaging the left caudal pulmonary artery. Manual fishhook extraction was performed successfully with minimal hemorrhage. Fishhook foreign bodies caudal to the cardiac silhouette may have vascular involvement. Clinicians should exercise caution when attempting endoscopic retrieval of fishhooks in this location. PMID- 30427716 TI - Clinicopathological Correlation and Prevalence of Increased Copper in Canine Hepatic Cytology. AB - Special staining and grading of canine liver cytology samples aids in detection of increased copper content. The prevalence of copper in routine diagnostic liver cytology samples, clinical findings associated with high cytologic copper (cCu) grade, and the correlation between cCu grade and histologic findings, including histologic copper (hCu) grade, are unknown. This data may be helpful in ascertaining when to determine a cCu grade and when interpreting cCu grade. Clinical data and available archived hepatic histologic and cytologic samples from 198 dogs were collected, evaluated, rhodanine stained, and graded for copper. Prevalence of increased cCu >5 in a randomly collected group of 163 individuals, and the correlation between cCu and clinical data (n = 198), hCu grade (n = 37), or findings on hematoxylin and eosin-stained hepatic sections (n = 32) were evaluated. The observed prevalence was 1.23%. Dogs with elevated alanine transaminase >180 IU/L or aspartate transaminase >90 IU/L and patients who subsequently had hepatic copper quantification were statistically more likely to have pathologic levels of copper detected by cytology. There was significant and modest correlation between cCu and hCu, interface hepatitis, portal inflammation, and fibrosis. Evidence of hepatocellular leakage may be indications for determination of cCu. PMID- 30427717 TI - Evaluation of Transdermal Administration of Phenobarbital in Healthy Cats. AB - The purpose was to determine the safety and achievable serum concentrations of transdermally administered phenobarbital in healthy cats. The hypothesis was that transdermal phenobarbital would achieve therapeutic serum concentrations (15-45 ug/mL) with minimal short-term adverse effects. Enrolled cats had normal physical and neurologic exams and unremarkable bloodwork. Transdermal phenobarbital in a pluronic lecithin organogel-based vehicle was administered at a dosage of 3.0-3.1 mg/kg per ear pinna (total of 6.0-6.2 mg/kg) every 12 hr for 14 days. Serum phenobarbital concentrations were measured 3-6 hr after dosing at seven different times over 15 days. The mean and median serum concentration of phenobarbital at study completion were 5.57 and 4.08 ug/mL, respectively. Mean peak concentration and mean time to peak concentration were 5.94 ug/mL and 13.3 days, respectively. Mild adverse effects were observed. Potency was analyzed in three replicates of the transdermal phenobarbital gel administered; potencies ranged from 62.98 to 82.02%. Transdermal application of phenobarbital in healthy cats achieves a detectable, but subtherapeutic, serum concentration and appears safe in the short term. The use of therapeutic drug monitoring is recommended when this formulation of phenobarbital is used to ensure therapeutic serum concentrations are achieved. PMID- 30427718 TI - Retrospective Study on the Effects of Long-Term Use of Methylprednisolone Acetate on the Blood Work of 25 Cats. AB - Twenty-five cats at a private animal sanctuary received multiple nonimmunosuppressive doses of parenteral methylprednisolone acetate for at least 3 yr. Complete blood count, chemistry, and T4 results from these cats were examined to look for statistically significant changes. Results found significant changes in triglycerides, amylase, and monocytes. However, these changes remained within the reference interval. All other values showed no significant changes. These results suggest that after 3 yr of chronic parenteral administration of nonimmunosuppressive doses of methylprednisolone acetate, the complete blood count, chemistry, and T4 values in 25 cats were not significantly affected and did not result in abnormal laboratory values. PMID- 30427719 TI - Persistent Leptospiruria in Five Dogs Despite Antimicrobial Treatment (2000 2017). AB - In dogs with leptospirosis, doxycycline therapy is recommended as the preferred therapy for its ability to eliminate the organism from all tissues, including the renal tubules. Elimination of organisms from the renal tubules terminates leptospiruria and prevents transmission of the organism. This report describes the discovery of persistent leptospiruria in the face of therapy with doxycycline in four dogs and enrofloxacin in one dog. Leptospiruria was confirmed by polymerase chain reaction testing for pathogenic leptospires in all five dogs. In two dogs, leptospiruria resolved after a change in therapy to enrofloxacin. In three dogs, doxycycline and/or enrofloxacin were ineffective at eliminating leptospiruria, which then resolved after therapy with clarithromycin. Pet owners could be at risk as persistent leptospiruria poses a potential zoonotic risk. The potential reasons for persistent leptospiruria as demonstrated by polymerase chain reaction testing are discussed. PMID- 30427720 TI - Genetic ablation or pharmacological inhibition of Kv1.1 potassium channel subunits impairs atrial repolarization in mice. AB - Voltage-gated Kv1.1 potassium channel alpha-subunits, encoded by the Kcna1 gene, have traditionally been regarded as neural-specific with no expression or function in the heart. However, recent data revealed Kv1.1 subunits are expressed in atria where they may have an overlooked role in controlling repolarization and arrhythmia susceptibility independent of the nervous system. To explore this concept in more detail and to identify functional and molecular effects of Kv1.1 channel impairment in the heart, atrial cardiomyocyte patch-clamp electrophysiology and gene expression analyses were performed using Kcna1 knockout ( Kcna1-/-) mice. Specifically, we hypothesized that Kv1.1 subunits contribute to outward repolarizing K+ currents in mouse atria and that their absence prolongs cardiac action potentials. In voltage-clamp experiments, dendrotoxin-K (DTX-K), a Kv1.1-specific inhibitor, significantly reduced peak outward K+ currents in wildtype (WT) atrial cells but not Kcna1-/- cells, demonstrating an important contribution by Kv1.1-containing channels to mouse atrial repolarizing currents. In current-clamp recordings, Kcna1-/- atrial myocytes exhibited significant action potential prolongation which was exacerbated in right atria, effects that were partially recapitulated in WT cells by application of DTX-K. Quantitative RT-PCR measurements showed mRNA expression remodeling in Kcna1-/- atria for several ion channel genes that contribute to the atrial action potential including the Kcna5, Kcnh2, and Kcnj2 potassium channel genes and the Scn5a sodium channel gene. This study demonstrates a previously undescribed heart-intrinsic role for Kv1.1 subunits in mediating atrial repolarization, thereby adding a new member to the already diverse collection of known K+ channels in the heart. PMID- 30427721 TI - Piezo1 mediates angiogenesis through activation of MT1-MMP signaling. AB - Angiogenesis is initiated in response to a variety of external cues, including mechanical and biochemical stimuli; however, the underlying signaling mechanisms remain unclear. Here we investigated the pro-angiogenic role of the endothelial mechanosensor Piezo1. Genetic deletion and pharmacological inhibition of Piezo1 reduced endothelial sprouting and lumen formation induced by wall shear stress and proangiogenic mediator sphingosine-1-phosphate while Piezo1 activation by a selective Piezo1 activator Yoda1 enhanced sprouting angiogenesis. Similarly to wall shear stress, sphingosine-1-phosphate functioned by activating the Ca2+ gating function of Piezo1, which in turn signaled the activation of the matrix metalloproteinase-2 and membrane expression of type 1-matrix metalloproteinase during sprouting angiogenesis. Studies in mice in which Piezo1 was conditionally deleted in endothelial cells demonstrated the requisite role of sphingosine-1 phosphate-dependent activation of Piezo1 in mediating angiogenesis in vivo. These results taken together suggest that both mechanical and biochemical stimuli trigger Piezo1-mediated Ca2+ influx and thereby activate matrix metalloproteinase 2 and type 1-matrix metalloproteinase, and synergistically facilitate sprouting angiogenesis. PMID- 30427722 TI - Revising the PLAC8 Gene Family: From a Central Role in Differentiation, Proliferation, and Apoptosis in Mammals to a Multifunctional Role in Plants. AB - PLAC8 is a cysteine-rich protein described as a central mediator of tumor evolution in mammals, being a promising candidate for diagnostic and therapeutic targeting. The PLAC8 gene also acts in the contact hypersensitivity response and serves a role in psoriatic skin. In plants, PLAC8 motif-containing proteins are involved in determination of organ size, growth, response to infection, Ca2+ influx, Cd resistance, and zinc detoxification. In general, the PLAC8 motif containing proteins present the conserved CCXXXXCPC or CLXXXXCPC region. However, there is no devised nomenclature for the PLAC8 motif-containing proteins. Here, through the analysis of 445 sequences, we show that PLAC8 motif-containing proteins compose a unique gene family, and we propose a unified nomenclature. This is the first report indicating the existence of different groups of PLAC8 proteins, which we have called types I, II, and III. The type I genes are found in mammals, fungi, plants, and algae, while the types II and III are exclusive to plants. Our study describes for the first time the PLAC8 type III proteins. Whether these sequences maintain their known functional role or possess distinct functions of types I and II genes, remains unclear. PMID- 30427723 TI - Multidisciplinary Management of Adolescent Early-Onset, Treatment-Resistant Schizophrenia Complicated by Avoidant/Restrictive Food Intake Disorder and Catatonia in Acute Exacerbations. PMID- 30427724 TI - A framework to guide the optimal development and use of real-world evidence for drug coverage and formulary decisions. AB - AIM: To provide a framework for optimizing the development and use of real-world evidence (RWE) in drug coverage decisions. Materials & methods: The Institute for Clinical and Economic Review convened a Policy Summit with representatives from 23 payer and life science companies that compose the Institute for Clinical and Economic Review membership. RESULTS: Summit participants helped refine a new conceptual framework that emphasizes the central role of contextual considerations and the evidentiary argument that the RWE is intended to support in designing the process for the development and interpretation of RWE. CONCLUSION: This framework may provide a structured way for pharmaceutical manufacturers and payers to develop a shared understanding of the best way to develop RWE that will ultimately be useful in informing coverage and formulary decisions. PMID- 30427725 TI - Meta-analytic insights into factors influencing the repeatability of hormone levels in agricultural, ecological, and medical fields. AB - Interest in individual variation in hormone concentrations is rapidly increasing, particularly with regards to the evolutionary and practical implications. A key aspect of studying individual variation in any labile trait is estimating the degree of within- versus among-individual variation, but at present we do not have a broad consensus on the extent to which hormone levels are repeatable and what factors might influence repeatability. To address this knowledge gap, we conducted a comprehensive meta-analysis of hormone levels that included 1132 estimates of repeatability from 368 studies across three fields of study: agriculture, ecology, and medicine. We assessed the influence of sex, age class, sample type, hormone family, type of hormone measure, assay type, number of subjects, number of samples per subject, and sampling interval on repeatability estimates. Overall mean repeatability was 0.58, but estimates differed substantially among study disciplines, being lowest in ecology (0.34), moderate in agriculture (0.52), and relatively high in medicine (0.68). In addition, repeatability decreased slightly as sampling interval increased, and also tended to be higher for peak hormone levels than baseline levels. Overall, hormone levels are moderately repeatable, suggesting that they can potentially be useful indicators of individual variation. However, estimates of repeatability are quite variable among fields, so caution should be used when relying on single samples to assess individual variation. PMID- 30427726 TI - Functional Annotation of Animal Genomes (FAANG): Current Achievements and Roadmap. AB - Functional annotation of genomes is a prerequisite for contemporary basic and applied genomic research, yet farmed animal genomics are deficient in such annotation. To address this, the FAANG (Functional Annotation of Animal Genomes) Consortium is producing genome-wide data sets on RNA expression, DNA methylation, and chromatin modification, as well as chromatin accessibility and interactions. In addition to informing our understanding of genome function, including comparative approaches to elucidate constrained sequence or epigenetic elements, these annotation maps will improve the precision and sensitivity of genomic selection for animal improvement. A scientific community-driven effort has already created a coordinated data collection and analysis enterprise crucial for the success of this global effort. Although it is early in this continuing process, functional data have already been produced and application to genetic improvement reported. The functional annotation delivered by the FAANG initiative will add value and utility to the greatly improved genome sequences being established for domesticated animal species. Expected final online publication date for the Annual Review of Animal Biosciences Volume 7 is February 15, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30427727 TI - Control of Listeria monocytogenes in Caramel Apples by Use of Sticks Pretreated with Potassium Sorbate. AB - A multistate listeriosis outbreak associated with caramel apples from 2014 to 2015 prompted research on the survival of Listeria monocytogenes in fresh apples and caramel apples. Research indicated that stem end-inoculated caramel apples with stick insertion allowed for the survival and growth of L. monocytogenes at both refrigeration and ambient temperatures. This study aimed to assess the effectiveness of chemical preservatives as pretreatments for the wooden stick component to reduce L. monocytogenes loads in stem end-inoculated caramel apples during storage. Wooden sticks were pretreated with 1, 3, or 5% ascorbic acid (vitamin C), Nisaplin (2.5% nisin), potassium sorbate, and sodium benzoate and then inoculated with L. monocytogenes at 7 log CFU per stick. After storage at 25 degrees C, the pathogen was reduced most effectively by the ascorbic acid pretreatments. At all three ascorbic acid concentrations tested, L. monocytogenes levels were reduced below the level of enumeration (2.5 log CFU per apple) at 24 h and were no longer detectable by enrichment after 72 h. Ascorbic acid (5, 10, and 20%) and potassium sorbate (10, 20, 30, and 40%) were further tested as wooden stick pretreatments for pathogen reduction on stem end-inoculated caramel apples stored at 5 and 25 degrees C. The 40% potassium sorbate solution at 25 degrees C was the most effective pretreatment condition in caramel apples and demonstrated a 3.1-log CFU per apple overall decrease in L. monocytogenes population levels after 216 h. Pretreatment of the wooden stick component of a caramel apple with potassium sorbate may be a viable preventive measure to reduce postprocess L. monocytogenes population levels and hence reduce consumer risk associated with caramel apple consumption. PMID- 30427728 TI - Erratum. PMID- 30427729 TI - Purification and Characterization of Plantaricin ZJ316, a Novel Bacteriocin against Listeria monocytogenes from Lactobacillus plantarum ZJ316. AB - Bacteriocins are known to be natural preservatives, which are becoming increasingly necessary in many types of food to control the proliferation of pathogenic bacteria. In this study, a novel bacteriocin produced by Lactobacillus plantarum ZJ316, called plantaricin ZJ316, was purified by ammonium sulfate precipitation, gel chromatography, and high-performance liquid chromatography. By mass spectrometry, the molecular mass of plantaricin ZJ316 was determined to be 2,366.06 Da. No homologous sequences were found in databases based on comparisons with the N-terminal amino acid sequencing. The bacteriocin was heat resistant and stable after incubation at pH 2.0 to 10.0. It was sensitive to alpha chymotrypsin, trypsin, and proteinase K. Plantaricin ZJ316 had a broad inhibitory activity against gram-negative and gram-positive bacteria, especially Listeria monocytogenes. Our results suggested that this bacteriocin has the potential to inhibit pathogenic bacteria in food products. PMID- 30427730 TI - Re: "CXCR5+ CD8+ T Cells Indirectly Offer B Cell Help and Are Inversely Correlated with Viral Load in Chronic Hepatitis B Infection" by Jiang et al. (DNA Cell Biol 2017;36, 321-327.). PMID- 30427731 TI - Longitudinal Trends in Real-World Outcomes Following Initiation of Ivacaftor: A Cohort Study from the Cystic Fibrosis Registry of Ireland. AB - RATIONALE: Patient registries have the potential to collect and analyse high quality post-authorisation data on new medicines. OBJECTIVES: We used cystic fibrosis (CF) registry data to assess outcomes following the initiation of ivacaftor, a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator approved for the treatment of CF with a defective gating CFTR mutation. METHODS: Longitudinal trends were examined using mixed effects regression analysis in 80 ivacaftor-treated CF patients aged 6-56 years registered with the CF Registry of Ireland with >=36 month's pre- and post commencement data. The effects of ivacaftor treatment on percentage-predicted forced expiratory volume in 1s (ppFEV1), body mass index (BMI), hospitalisation for pulmonary exacerbation, oral and IV antibiotic usage were assessed. RESULTS: In the 36 months after ivacaftor initiation, ppFEV1 improved by 2.26% per annum [95% CI (0.23 to 4.29), p=0.03] for patients aged <12 years, remained unchanged for 12-<18 years olds [95% CI (-1.87 to 2.88), p=0.67] and declined in adults by 1.74% per annum [95% CI (-3.08 to -0.39), p=0.01]. BMI in adults increased 0.28 kg m-2 per annum [95% CI (0.03 to 0.52), p=0.027] and there was no significant decline in BMI z score in children, [95% CI (-0.01 to 0.13), p=0.08]. In the year after ivacaftor initiation, IV antibiotic treatment reduced by 46% [95% CI ( 62.5% to -23.3%), p<0.01], oral antibiotic treatment by 49% [95% CI (-61.1% to 32.1%), p<0.01], and there was no significant reduction in hospitalisation [95% CI (-59.2% to 9.7%), p=0.11]. CONCLUSIONS: In this study of real-world CF registry data, clinical outcomes improved and healthcare resource utilization reduced after commencing ivacaftor. . PMID- 30427732 TI - Temperature as a Causative Factor in Diabetic Foot Ulceration: A Call to Revisit Ulcer Pathomechanics. AB - BACKGROUND: Diabetic foot ulcers are a major burden to patients and to the healthcare systems of many countries. To prevent and/or treat ulcers more effectively, predictive biomarkers are needed. We examined temperature as a biomarker and as a causative factor in ulcer development. METHODS: 37 individuals with diabetes were enrolled in this observational case-control study: nine with diabetic neuropathy and ulcer history (DFU), 14 with diabetic neuropathy (DN), and 14 non-neuropathic participants (DC). Resting barefoot plantar temperatures were recorded using an infrared thermal camera. Mean temperature in each region was determined based on 4 anatomical regions; hallux, medial forefoot, central forefoot, and lateral forefoot and separate linear models with specified contrasts between DFU, DN, and DC groups were set to reveal mean differences for each foot region, while controlling for group characteristics. RESULTS: Mean temperature readings in each foot region was higher than 30.0 degrees C in the DFU and DN compared to the DC group with all temperatures below 30.0 degrees C. Mean differences were greatest between the DFU and the DC group, with mean differences ranging from 3.2 degrees C in the medial forefoot to 4.9 degrees C in the hallux. CONCLUSIONS: Increased plantar temperatures in individuals with a history of ulcers may include acute temperature increases from plantar stresses, chronic inflammation from prolonged stresses, and impairment in temperature regulation from autonomic neuropathy. Diabetic foot temperatures, particularly in those with previous ulcers, may easily reach hazard thresholds indicated by prior pressure ulcer studies. The results necessitate further exploration of temperature in diabetic foot and how it may contribute to ulceration. PMID- 30427733 TI - Plague Masks: The Visual Emergence of Anti-Epidemic Personal Protection Equipment. AB - Often described as "masks" face-worn devices are employed as personal protection equipment by health workers and the general public and considered to be an indispensable technology against epidemics. Simultaneously, they are potent symbols of existential risk. Could these material and visual aspects be more than simply indexically connected? In this article, I examine these apparatuses through a historical anthropological approach of their invention during the 1910 11 Manchurian plague outbreak. Arguing that they should be taken seriously as masks, I demonstrate that their emergence was rooted in their configuration as transformative agents of medical reason. PMID- 30427734 TI - A Comparison of GLI12 with NHANES III Spirometry Reference Values: The Implications in Defining Obstruction. AB - RATIONALE: Obstructive lung disease is diagnosed by a decreased ratio of forced expiratory volume in the first second (FEV1) to forced vital capacity (FVC); however, there is no universally accepted lower limit of normal (LLN) for the FEV1/FVC ratio. Current established reference values use the NHANES III database. In 2012, the Global Lung Initiative (GLI) introduced GLI12: a compilation reference set that uses standard deviation values to define normal spirometry. OBJECTIVES: To evaluate the changes in classification of obstructive spirometry with use of GLI12 compared to NHANES III in a heterogenous, multiracial population. METHODS: We evaluated the spirometric studies conducted in our pulmonary function laboratory between January 2005 and December 2015. NHANES III reference equations were calculated to predict LLN for FEV1, FVC, and FEV1/FVC. GLI12 values were established using ERS published computer software. FEV1 severity was graded using 2005 ATS Guidelines for NHANES III and using z-scoring based criteria for GLI12. Asymmetric partition analysis evaluated agreement between the reference sets. RESULTS: 11,888 studies were evaluated. Obstruction was diagnosed in 2,857 studies using NHANES III versus 2,489 using GLI12. Agreement regarding the presence or absence of obstruction occurred in 2,483 of studies with obstruction and 9,025 studies without obstruction (agreement 96.8%, kappa 0.91). Of the studies with obstruction, 1,595 had agreement in severity grading. Overall, agreement regarding obstruction and severity grading occurred in 10,620 studies, representing 89.3% of all studies. 380 studies (3.2%) had discordance regarding presence or absence of obstruction, 34.0% (844 of the 2,483 obstructed studies) had one-degree of change in FEV1 disease severity scoring, with 44 cases (1.8%) had changes of two categories FEV1 severity scores. No studies had greater than two degrees of change. Asymmetric partition analysis suggested the highest clinically significant changes were seen in older individuals, particularly African-American males older than 65. CONCLUSION: Our evaluation suggests there is moderate overall agreement between NHANES III and GLI12. We found a 3.2% change in classification of obstruction when transitioning from NHANES III to GLI12. When incorporating a z-based FEV1 and GLI12 reference set, 10.7% of the spirometric studies had a change in their categorization. The disagreement between the two data sets was most pronounced in elderly subjects. Although we cannot endorse one reference set over the other, we highlight the potential implications from adopting the GLI12 reference sets and suggest caution when interpreting spirometry in the elderly. PMID- 30427735 TI - Racial Differences in Escitalopram/Citalopram-Related Weight Gain in Children and Adolescents: A Natural Language Processing-Based Electronic Medical Record Study. PMID- 30427737 TI - Synthesis and biological activity of new derivatives with the preserved carane system. AB - Terpenoid derivatives, which contain a preserved carane system in their structure, exhibit a broad spectrum of biological activities. Among them, we can distinguish insecticides, structures with pharmacological application etc. In the presented paper, the substrate - (-)-cis-caran-trans-4-ol was transformed using the reactions of typical organic synthesis to obtain novel derivatives. Most importantly, bromolactone ((-)-(1R,4R,6S)-2'-(bromomethyl)-4,7,7 trimethylspiro[bicyclo[4.1.0]heptan-3,3'-furan]-5'(4'H)-one) with the preserved carane system was synthesized. This bromolactone was tested for antifeedant activity against the lesser mealworm, Alphitobius diaperinus Panzer, and peach potato aphid (Myzus persicae). In addition, its moderate antibacterial activity was observed against the Bacillus subtilis strain (with Minimal Inhibitory Concentration of 200 ug/mL). PMID- 30427736 TI - Current Controversies in Chronic Obstructive Pulmonary Disease: A Report from the GOLD Scientific Committee. PMID- 30427738 TI - Assessment of seroprevalence against poliovirus among Italian adolescents and adults. AB - In 2002, the WHO European Region was declared polio-free. Nonetheless global eradication has not yet been completed and the reintroduction from at risk areas is still possible. This seroprevalence study evaluated samples collected from each Italian region in the 12-50 years old age range to assess protection against Poliovirus (PV) 1, 2 and 3 among subjects immunised with different vaccination schedules. 1073 samples (50.5% females) were examined. WHO standardized microneutralization assay was used. Seroprotection rates were 92.9%, 96.2% and 83.4%, for PV1, PV2 and PV3, respectively. Geometric Mean Titres (GMTs) were higher for PV2 (52.8) and PV1 (41.1) than for PV3 (21.0). Increasing the age, a decreasing trend in seropositivity was observed, in particular for PV3. The 2017 2019 Italian National Immunisation Plan emphasises, as primary objective, the maintenance of the polio-free status and strongly validates the 2 + 1 schedule in the first year of life with IPV vaccine associated with the administration of booster doses at 6 years and during the adolescence. Surveillance system and high population immunity are crucial to ensure the maintenance of polio-free status. PMID- 30427739 TI - Alcohol and tobacco use in men: the role of alexithymia and externally oriented thinking style. AB - BACKGROUND: A high prevalence of alexithymia has been consistently reported in alcohol- and drug-dependent populations. However, less is known about the role of alexithymia, and its individual dimensions on substance use in healthier populations. OBJECTIVES: To examine how different alexithymia dimensions associate with substance use, while controlling for confounding factors. METHODS: In the FinnBrain Birth Cohort Study, we analyzed a sample of 994 men. We assessed alexithymia levels (difficulty identifying feelings, difficulty describing feelings and externally oriented thinking (EOT) style), self-reported quantity and frequency of alcohol use in two different time points during and after their partners' pregnancy, as well as cigarette smoking status. Age, education level, and anxiety scores were used as control variables. RESULTS: Men scoring high on EOT style drank more alcohol per occasion, compared to low scorers (Cohen's d = 0.43, p < 0.001 during pregnancy, and Cohen's d = 0.3, p = 0.012 after pregnancy). Individuals in the high EOT quartile were also more likely to be daily smokers (8.7% vs. 17.3%, p = 0.023), and engage in binge drinking (23.7% vs. 43.6%, p = 0.001). CONCLUSIONS: The association of alexithymia and substance use may be specifically explained by EOT, a trait characterized by low levels of introspection and pragmatic thinking. It is important for future studies to distinguish between individual alexithymia dimensions and their specific roles in shaping mental health. PMID- 30427740 TI - A new protostane-type triterpenoid from Alisma plantago-aquatica subsp. orientale (Sam.) Sam. AB - A new protostane-type triterpenoid bearing an oxetane ring in the side-chain, named alisol W (1), has been obtained from the dried rhizome of Alisma plantago aquatica subsp. orientale. The structure and absolute configuration of compound 1 was determined from extensive spectroscopic analysis. In addition, the vasorelaxant activity and the inhibition on 11beta-HSD1 of compound 1 were also evaluated, however, it didn't show remarkable effects. PMID- 30427741 TI - Immunogenicity and safety of an investigational tetravalent recombinant subunit vaccine for dengue: results of a Phase I randomized clinical trial in flavivirus Naive adults. AB - There is an unmet medical need for vaccines to prevent dengue. V180 is an investigational recombinant subunit vaccine that consists of truncated dengue envelope proteins (DEN-80E) for all 4 serotypes. Three dosage levels of the tetravalent DEN-80E antigens were assessed in a randomized, placebo-controlled, Phase I dose-escalation, first-in-human proof-of-principle trial in healthy, flavivirus-naive adults in Australia (NCT01477580). The 9 V180 formulations that were assessed included either ISCOMATRIXTM adjuvant (2 dosage levels), aluminum hydroxide adjuvant, or were unadjuvanted, and were compared to phosphate-buffered saline placebo. Volunteers received 3 injections of assigned product on a 0, 1, 2 month schedule, and were followed for safety through 1 year after the last injection. Antibody levels were assessed at 6 time-points: enrollment, 28 days after each injection, and 6 and 12 months Postdose 3 (PD3). Of the 98 randomized participants, 90 (92%) received all 3 injections; 83 (85%) completed 1-year follow-up. Immunogenicity was measured by a qualified Focus Reduction Neutralization Test with a 50% neutralization cutoff (FRNT50). All 6 V180 formulations with ISCOMATRIXTM adjuvant showed robust immunogenicity, while the 1 aluminum-adjuvanted and 2 unadjuvanted formulations were poorly immunogenic. Geometric mean antibody titers generally declined at 6 months and 1 year PD3. All 9 V180 formulations were generally well tolerated. Formulations with ISCOMATRIXTM adjuvant were associated with more adverse events than aluminum-adjuvanted or unadjuvanted formulations. PMID- 30427742 TI - Challenges Associated with Anticipatory Medications in Rural and Remote Settings. AB - BACKGROUND: Anticipatory medications (AM) have been widely used in various settings across many countries in people approaching end of life. Access to palliative care in rural and remote areas of Australia is lacking as are other medical services when compared with the metropolitan setting. Our aim is to identify challenges with the administration and access to AM in rural and remote communities with outcomes to guide improved delivery of care. METHODS: An online survey administered using Qualtrics, a secure survey platform was distributed to a total of 18 managers from 18 rural and remote organizations across the South East of Victoria in Australia. The survey was distributed to a total of 108 nurses working in these organizations. RESULTS: A total of 29 nurses completed the survey (response rate 28%). Most of the nurses were working in a mixed practice providing community palliative and district nursing. A significant number of nurses (n = 9, 31%) were working in remote settings and the remainder were located in regional areas. Almost a third of all nurses surveyed did not have specific guidance regarding the use of AM for their patients. Opioids (55%) were by far the most commonly used AM followed by antiemetics (45%). The most common decisions taken by nurses to administer AM were cited as patient deterioration or in their terminal phase with a fluctuating level of anxiety, and patients agitation. Access to AM and lack of staff education were major challenges in rural and remote areas. CONCLUSIONS: Provision of timely AM has the potential to improve the quality of life of patients and their caregivers. Key barriers to access AM can be overcome with community-level planning and nurses' education. Advanced nurses' roles have the opportunity to provide specialized care where access to specialist physicians is challenging. PMID- 30427743 TI - Functional and Anatomical Relationships Between the Medial Precentral Cortex, Dorsal Striatum, and Head Direction Cell Circuitry. II: Neuroanatomical Studies. AB - An animal's directional heading within its environment is encoded by the activity of head direction (HD) cells. In rodents, these neurons are found primarily within the limbic system in the interconnected structures that form the limbic HD circuit. We previously described two HD cell populations located outside of this circuit in the medial precentral cortex (PrCM) and dorsal striatum (DS); these extralimbic areas receive their HD signals from the limbic system, but do not provide critical input or feedback to limbic HD cells (Mehlman et al. 2018). Here, we complement our previous lesion and recording experiments with a series of neuroanatomical tracing studies in rats designed to examine patterns of connectivity between the PrCM, DS, limbic HD circuit, and related spatial processing circuitry. Retrograde tracing revealed that the DS receives direct input from numerous structures known to contain HD cells and/or other spatially tuned cell types. Importantly, these projections preferentially target and converge within the most medial portion of the DS - the same area in which we previously recorded HD cells. The PrCM receives direct input from a subset of these spatial processing structures. Anterograde tracing identified indirect pathways that could permit the PrCM and DS to convey self-motion information to the limbic HD circuit. These tracing studies reveal the anatomical basis for the functional relationships observed in our lesion and recording experiments. Collectively, these findings expand our understanding of how spatial processing circuitry functionally and anatomically extends beyond the limbic system into the PrCM and DS. PMID- 30427744 TI - Associations Between IL-10 Polymorphisms and Susceptibility to Melanoma, Basal Cell Carcinoma, and Squamous Cell Carcinoma: A Meta-Analysis. AB - BACKGROUND: According to relevant reports, interleukin-10 (IL-10), as a multifunctional anti-inflammatory cytokine, has a critical influence in cancer development. A meta-analysis was carried out regarding the relationships among the -592 A/C, -1082 G/A, and -819 T/C polymorphisms as well as the susceptibility to skin squamous cell carcinoma (sSCC), melanoma, and basal cell carcinoma (BCC). MATERIALS AND METHODS: A meta-analysis was carried out on the inter-relationships among the -592 A/C, IL-10-1082 G/A, and -819 T/C polymorphisms as well as the susceptibility to sSCC, melanoma, and BCC. RESULTS: In this analysis, a total of 11 researches, involving 2149 controls and 2128 cases, were included. No association was found between skin cancer risk and the -592A/C or IL-10-1082G/A polymorphisms in any of the analyses. However, a moderately decreased skin cancer risk was found in the -819 TC versus CC model (odds ratio [OR] = 0.81 and 95% confidence interval [CI] = 0.67-0.99, p = 0.04). From the subgroup analysis, a decreased risk was found between the studies of nonmelanoma skin cancers and IL 10-819T/C in the dominant model (OR = 0.60, 95% CI = 0.43-0.85, p = 0.004 for TT+TC vs. CC). Egger's and Begg's tests demonstrated that there was no significant publication bias. CONCLUSION: This meta-analysis showed that the 592A/C and 1082G/A IL-10 polymorphisms might not be risk factors for melanoma or for BCC and sSCC patients, but we obtained a correlation between skin cancer risk and the IL-10 -819T/C polymorphism. PMID- 30427745 TI - Phenotypic and functional profile of IFN-alpha-differentiated dendritic cells (IFN-DCs) from HIV-infected individuals. AB - Dendritic cell (DC)-based immunotherapy is a promising strategy for the treatment of HIV-infected individuals. Different from the conventional protocol for DC differentiation based on the cytokine IL-4 (IL4-DCs), several studies have suggested obtaining DCs by culturing monocytes with type I IFN (IFN-alpha) to yield IFN-DCs, as performed in cancer therapy. To evaluate the phenotypic and functional characteristics, monocytes from HIV-infected subjects were differentiated into IFN-DCs or IL4-DCs, pulsed with chemically inactivated HIV and stimulated with pro-inflammatory cytokines. A comparative analysis between both types of monocyte-derived DCs (MoDCs) showed that immature IFN-DCs were phenotypically distinct from immature IL4-DCs at the baseline of differentiation, presenting a pre-activated profile. From the functional profile, we determined that IFN-DCs were capable of producing the cytokine IL-12 p70 and of inducing the production of IFN-gamma by CD4 + T lymphocytes but not by TCD8+ lymphocytes. Our results suggest that IFN-DCs derived from HIV-infected individuals are able to recognize and present viral antigens to induce TCD4+ cellular immunity to HIV. PMID- 30427746 TI - Spatial and Temporal Variability of Upper Extremity Edema Measures After Breast Cancer Surgery. AB - BACKGROUND: Tissue dielectric constant (TDC), as an index of local tissue water, and girth measurements are quantitative methods to measure and characterize lymphedema. OBJECTIVE: To describe the spatial and temporal variability in arm girth and TDC values in women surgically treated for breast cancer and to describe the relationship between these measures. METHODS AND RESULTS: This was a prospective longitudinal study that observed 36 women for 78 weeks after breast cancer surgery with lymph node removal. Arm circumferences and TDC values, as indices of local tissue water, were measured on both arms at multiple sites at postsurgery weeks 2, 4, 12, and 78 in women undergoing surgical breast cancer treatment with one or more axillary lymph nodes removed. TDC and girth values remained relatively uniform from visit-to-visit for both at-risk and contralateral control arms with no overall statistically significant difference in values (p > 0.05). There was a strong inverse correlation between arm girth and the TDC value in both the at-risk and control arms (p < 0.001). Overall, there was no statistically significant difference in TDC interarm ratios among visits or anatomical sites. TDC values for at-risk and control arms tended to significantly decrease with increasing distance from the wrist (p < 0.001). CONCLUSION: TDC arm values and girth measures remained relatively uniform in women after breast cancer surgery. The fact that TDC values are higher distally than proximally provides new information from which TDC measurements may be interpreted and also provides a better understanding of arm spatial variability in relation to girth measures. PMID- 30427747 TI - Bilateral Vision Loss with p-ANCA Associated Lymphocytic Vasculitis. AB - PURPOSE: To describe a case of p-ANCA associated vasculitis in a patient with bilateral vision loss with no systemic symptoms or signsMethods: A descriptive review of a caseResults: We report a case of bilateral sequential vision loss in a 73-year-old woman who had no constitutional symptoms except headache and was found to have positive p-ANCA and lymphocytic infiltration on bilateral temporal artery biopsy. Despite the early administration of systemic corticosteroids, the visual outcome was unfavorable. CONCLUSION: It is important to consider ANCA associated vasculitides when temporal artery biopsy does not support GCA. PMID- 30427748 TI - Characterization of Quinolone-Resistant Determinants in Tribe Proteeae Isolated from Pet Turtles with High Prevalence of qnrD and Novel gyrB Mutations. AB - Development of antibiotic resistance in bacteria has challenged significantly in both veterinary and human medicine. In this study, we analyzed the potential risk of pet turtles harboring tribe Proteeae as a source of quinolone-resistant determinants, including plasmid-mediated quinolone resistance (PMQR) genes and target gene alterations in the quinolone resistance-determining region (QRDR). Antimicrobial susceptibility of 54 Proteeae isolates against ciprofloxacin, ofloxacin, levofloxacin, and nalidixic acid was examined. The PMQR genes and QRDR alterations were identified using conventional PCR assays and sequencing. Four isolates were resistant to all quinolones tested in this study. Nine isolates showed resistance to nalidixic acid and showed either intermediate resistance or susceptibility to other tested quinolones. All isolates resistant to one or more tested quinolones harbored mutations in gyrB and some also had gyrA and parC mutations. Of 54, 12 Proteeae isolates displayed the novel E466D, N440T, Q411S, and F417L mutations in gyrB. Among the PMQR genes, 41 (76%) isolates harbored the qnrD gene with the highest prevalence, whereas aac(6')Ib-cr, qnrS, qnrA, and qnrB genes were detected in 28 (52%), 9 (17.0%), 7 (13.0%), and 1 (1.9%) study isolates, respectively. The QRDR analysis of selected mutants revealed that increasing quinolone selective pressure led to a predominance of gyrA mutants. All results indicate that a healthy pet turtle can play as a potential reservoir for quinolone-resistant Proteeae, which it might cause public health risk on pet owners. PMID- 30427749 TI - Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine compared to 13-valent pneumococcal conjugate vaccine in adults >=65 years of age previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. AB - BACKGROUND: Pneumococcal disease remains a public health priority in adults. Previous studies have suggested that administration of pneumococcal polysaccharide vaccine or pneumococcal conjugate vaccine within three years following receipt of PPV23 was associated with increased reactogenicity and reduced antibody titers in comparison to longer intervals. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) was evaluated in adults >= 65 years of age with prior history of PPV23 vaccination (V114-007; NCT02573181). METHODS: A total of 250 adults who received PPV23 at least 1 year prior to study entry received a single dose of either PCV15 or PCV13 (125/arm) and were followed for safety for 14 days postvaccination. Serotype-specific Immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 30 days postvaccination. RESULTS: Safety profiles were comparable between PCV15 and PCV13 recipients. Following vaccination, serotype-specific antibody responses for the 13 shared serotypes were generally comparable between recipients of PCV15 and PCV13 for IgG GMCs, OPA GMTs, and geometric mean fold rises (GMFRs) and percentages of subjects with >= 4-fold-rise from baseline for both IgG and OPA. Recipients of PCV15 had numerically higher antibody responses than PCV13 for two serotypes unique to PCV15 (22F, 33F). CONCLUSION: PCV15 was generally well tolerated and induced high levels of IgG and OPA antibodies to all 15 serotypes included in the vaccine when given as a single dose to adults >= 65 years of age previously vaccinated with PPV23. PMID- 30427750 TI - Acute aerobic exercise improves memory across intensity and fitness levels. AB - The present study was designed to examine the impact of exercise intensity and aerobic fitness on free recall, judgments of learning (JOLs), and metacognitive accuracy. In Experiment 1, 30 college students engaged in either (1) no exercise, (2) light exercise (55% of predicted maximal heart rate), or (3) moderate exercise (75% of predicted maximal heart rate) on three different days. In Experiment 2, 29 high-fit students (VO2 max >= 70th percentile) and 28 low-fit students (VO2 max <= 50th percentile) completed sedentary and light exercise conditions. In both experiments, free recall scores significantly increased in the exercise conditions compared with the sedentary condition, but JOL magnitude and metacognitive accuracy were largely unaffected. These results demonstrate that exercise can improve recall at both light and high intensities, and that the benefit can be obtained by individuals regardless of their fitness level. PMID- 30427751 TI - The J-domain co-chaperone Rsp1 interacts with Mto1 to organize non-centrosomal microtubule assembly. AB - Microtubule biogenesis initiates at various intracellular sites, including the centrosome, the Golgi apparatus, the nuclear envelope, and pre-existing microtubules. Similarly, in the fission yeast Schizosaccharomyces pombe, interphase microtubules are nucleated at the spindle pole body (SPB), the nuclear envelope, and pre-existing microtubules, depending on Mto1 activity. Despite the essential role of Mto1 in promoting microtubule nucleation, it has remained elusive as how distribution of Mto1 in different sites is regulated. Here we show that the J-domain co-chaperone Rsp1 interacts with Mto1 and specifies the localization of Mto1 to non-SPB nucleation sites. The absence of Rsp1 abolishes the localization of Mto1 to non-SPB nucleation sites, with concomitant enrichment of Mto1 to the SPB and the nuclear envelope. In contrast, Rsp1 overexpression impairs the localization of Mto1 to all microtubule organization sites. These findings delineate a previously uncharacterized mechanism in which Rsp1-Mto1 interaction orchestrates non-SPB microtubule formation. PMID- 30427752 TI - Ethanol content in traditionally fermented ayurvedic formulations: Compromised Good Manufacturing Practice regulations - compromised health. AB - BACKGROUND: A large part of the population of India prefers the traditional medicine (ayurvedic formulations) for primary health care. However, the effective quality control of herbal medicine is still a big challenge. Numerous reports indicate noncompliance with Compromised Good Manufacturing Practice (GMP) guidelines by the manufacturers which may lead to adverse drug reactions or toxic effects. Asava and arishta are the classical herbal dosage forms wherein fermentation occurs during production leading to the generation of ethanol. The presence of ethanol in these preparations may lead to their misuse. The self generated ethanol is responsible for extraction of active constituents and acts as a self-preservative. As the procedure for preparation for asava and arishta is same, the ethanol content is also expected to be the same irrespective of the manufacturer. OBJECTIVE: The objective of the present study was to assess and compare the ethanol content of some traditionally fermented ayurvedic formulations available in the market. METHOD: In this study, 20 formulations from 3 different manufacturers available as over-the-counter products were obtained and their ethanol contents were determined using gas chromatograph with flame ionization detector. RESULTS: Statistically significant differences were noted in the ethanol content of various ayurvedic formulations. A simple, less time consuming, economic, and validated gas chromatographic method for estimation of ethanol in fermented ayurvedic formulations was also developed successfully in present study. CONCLUSION: The data generated during study reflected poor compliance of GMP guidelines by the manufacturers and hence the quality is being grossly compromised posing a safety hazard. PMID- 30427753 TI - Gallic acid as main product in the water extractives of Quercus frainetto ten. AB - The autoclave extraction of Hungarian oak (Quercus frainetto Ten.) wood gave 5.3% extractives. The chloroform soluble fraction obtained from the extracts of Q. frainetto allows to identify sesamin. The insoluble fraction contains mainly ribose and mannose. Water extraction in autoclave of thermo-treated Q. frainetto wood gave a lower amount of extractives (3.31%). The main product of the insoluble fraction was, on the basis of its mass spectrum, the monoacetyl derivative of gallic acid. PMID- 30427754 TI - Pleurotus ferulae polysaccharides improve the antitumor efficacy of therapeutic human papillomavirus dendritic cell-based vaccine. AB - We previously found that Pleurotus ferulae polysaccharides (PFPS) improved the maturation and function of dendritic cells (DCs). In this study, we investigated the effects of PFPS on the antitumor efficacy of therapeutic human papillomavirus (HPV) DC-based vaccine. PFPS stimulated DCs pulsed with HPV E6/E7 peptides were used to treat tumor mice on day 5 & 12 (HPV + PFPS-DCs early) and day 12 & 19 (HPV + PFPS-DCs late) after TC-1 cell injection. Compared to control group, both HPV + PFPS-DCs early and HPV + PFPS-DCs late strategies significantly inhibited tumor growth, which was significantly correlated with the increased activation status of both CD4+ and CD8+ T cells, the decreased frequencies of myeloid derived suppressor cells, and the induction of HPV-specific CD8+ T cell responses. The survival of tumor mice was also greatly improved by HPV + PFPS-DCs early. Moreover, HPV + PFPS-DCs early completely inhibited the growth of second challenged TC-1 cells in tumor free mice. The results showed that PFPS improved the antitumor efficacy of therapeutic HPV DC-based vaccine, suggesting that PFPS might be a potential adjuvant for DC-based vaccines. This study provides a potential strategy for developing the therapeutic DC-based vaccine against cervical cancer. PMID- 30427755 TI - Parental perceptions of human papillomavirus vaccination in central China: the moderating role of socioeconomic factors. AB - BACKGROUND: The huge gap in adolescent human papillomavirus (HPV) uptake between China (< 2%) and developed countries (> 60%) indicates the necessity of comprehensive examination on the modifiable factors for parents' decision-making. The present study investigated parental perceptions of HPV vaccination for children in China from a socio-economic perspective. METHODS: Parents of 9-to-14 year-old adolescents who understood the HPV vaccination (n = 925) completed our questionnaire survey in Fall 2017. Based on the structural equation modeling, we examined the relationship among knowledge, awareness, and intentions of 20 items by 7-point Likert scale, the moderating effects also were tested among 5 socioeconomic variables. RESULTS: Parents of female students have more positive intention about the HPV vaccination than male students' parents (3.74 vs 2.80, p < 0.001). Parents of 12-14-years old students have higher average scores in knowledge (p = 0.006) and intention (p < 0.001) than that of 9-11-years old students' parents. The average score of mothers on knowledge (p = 0.018) and awareness (p < 0.001) was lower than that of fathers. The elder parents (>= 50 years) performed significantly better on knowledge (p < 0.001) and awareness (p < 0.001) than the other two subgroups. Annual household income is an important factor in determining the knowledge (p = 0.0017), awareness (p < 0.001), and intention (p < 0.001). Knowledge and awareness were considered as the positive determinant of intention, and awareness was partial mediator. Child gender (P = 0.046), child age (P = 0.004), parent gender (P = 0.043) and parental age (P = 0.021) were significant moderators. CONCLUSION: To improve the acceptability of HPV vaccination among Chinese adolescents, policymakers should develop positive strategies for their parents. PMID- 30427756 TI - The clinical use of IDH1 and IDH2 mutations in gliomas. AB - INTRODUCTION: Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 have been reported in a limited number of tumors. In gliomas, IDH mutations are primarily detected in WHO grade II-III tumors and represent a major biomarker with diagnostic, prognostic, and predictive implications. The recent development of IDH inhibitors and vaccines suggests that the IDH mutation is also an appealing target for therapy. Areas covered: This review focuses on the role of IDH mutations in diffuse gliomas. Besides discussing their role in gliomagenesis, we will emphasize the role of IDH mutations in clinical practice as a diagnostic, prognostic and predictive biomarker, and as a potential therapeutic target. Noninvasive detection of the IDH mutation by means of liquid biopsy and MR spectroscopy will also be discussed. Expert commentary: While IDH mutation is a consolidated diagnostic and prognostic biomarker in clinical practice, its role in oncogenesis is far from being elucidated, and there are several pending issues. The routine use of noninvasive techniques for detection and monitoring of the IDH status remains challenging. Although the IDH mutation is a very early alteration in gliomagenesis, it may then be omitted during tumor progression. This observation has important implications when designing targeted clinical trials. PMID- 30427757 TI - The roles of a flagellar HSP40 ensuring rhythmic beating. AB - HSP40s are regarded as co-chaperones perpetually shuttling client polypeptides to HSP70s for refolding. However, many HSP40s central for disparate processes diverge from this paradigm. To elucidate the noncanonical mechanisms, we investigated the HSP40 in the radial spoke (RS) complex in flagella. Disruption of the gene by the MRC1 transposon in Chlamydomonas resulted in jerky flagella. Traditional electron microscopy, cryo-electron tomography and sub-tomogram analysis revealed RSs of various altered morphologies which, unexpectedly, differed in the two RS species. This indicates that HSP40 locks the RS into a functionally rigid conformation, facilitating its interactions with the adjacent central pair apparatus for transducing locally varied mechanical feedback which permits rhythmic beating. Missing HSP40, like missing RSs, could be restored in a tip-to-base direction when HSP40 mutants fused with a HSP40 donor cell. However, without concomitant de novo RS assembly, the repair was exceedingly slow, suggesting HSP40/RS-coupled intraflagellar trafficking and assembly. Biochemical analysis and modeling uncovered spoke HSP40's co-chaperone traits. Taken together, we propose that HSP40 accompanies its client RS precursor when traveling to the flagellar tip. Upon arrival, both refold concertedly to assemble into the mature configuration. HSP40's roles in chaperoning and structural maintenance shed new light on its versatility and flagellar biology. PMID- 30427758 TI - Agmatine Preferentially Antagonizes GluN2B-Containing N-Methyl-D-Aspartate Receptors in Spinal Cord. AB - The role of the N-Methyl-D-Aspartate receptor (NMDAr) as a contributor to maladaptive neuroplasticity underlying the maintenance of chronic pain is well established. Agmatine, an NMDA receptor antagonist, has been shown to reverse tactile hypersensitivity in rodent models of neuropathic pain while lacking the side effects characteristic of global NMDAr antagonism including sedation and motor impairment, indicating a likely subunit-specificity of agmatine's NMDAr inhibition. The present study assessed whether agmatine inhibits subunit-specific NMDAr-mediated current in the dorsal horn of mouse spinal cord slices. We isolated NMDAr-mediated excitatory postsynaptic currents (EPSCs) in small lamina II dorsal horn neurons evoked by optogenetic stimulation of Nav1.8-containing nociceptive afferents. We determined that agmatine abbreviated the amplitude, duration and decay constant of NMDAr-mediated EPSCs similar to the application of the GluN2B antagonist ifenprodil. In addition, we developed a site-specific knockdown of the GluN2B subunit of the NMDAr. We assessed whether agmatine and ifenprodil were able to inhibit NMDAr-mediated current in the spinal cord dorsal horn of mice lacking the GluN2B subunit of the NMDAr by analysis of electrically evoked EPSCs. In control mouse spinal cord, agmatine and ifenprodil both inhibited amplitude and accelerated the decay kinetics. However, agmatine and ifenprodil failed to attenuate the decay kinetics of NMDAr-mediated EPSCs in the GluN2B-knockdown mouse spinal cord. The present study indicates that agmatine preferentially antagonizes GluN2B-containing NMDArs in mouse dorsal horn neurons. PMID- 30427759 TI - ADP-ribosylation factor-like 4A interacts with Robo1 to promote cell migration by regulating Cdc42 activation. AB - Cell migration is a highly regulated event that is initiated by cell membrane protrusion and actin reorganization. Robo1, a single-pass transmembrane receptor, is crucial for neuronal guidance and cell migration. ADP-ribosylation factor (Arf)-like 4A (Arl4A), an Arf small GTPase, functions in cell morphology, cell migration, and actin cytoskeleton remodeling; however, the molecular mechanisms of Arl4A in cell migration are unclear. Here, we report that the binding of Arl4A to Robo1 modulates cell migration by promoting Cdc42 activation. We found that Arl4A interacts with Robo1 in a GTP-dependent manner and that the Robo1 amino acid residues 1394-1398 are required for this interaction. The Arl4A-Robo1 interaction is essential for Arl4A-induced cell migration and Cdc42 activation but not for the plasma membrane localization of Robo1. In addition, we show that the binding of Arl4A to Robo1 decreases the association of Robo1 with the Cdc42 GAP srGAP1. Furthermore, Slit2/Robo1 binding downregulates the Arl4A-Robo1 interaction in vivo, thus attenuating Cdc42-mediated cell migration. Therefore, our study reveals a novel mechanism by which Arl4A participates in Slit2/Robo1 signaling to modulate cell motility by regulating Cdc42 activity. PMID- 30427760 TI - Phosphatidylinositol 3,5-Bisphosphate Regulates the Transition between trans SNARE Complex Formation and Vacuole Membrane Fusion. AB - Phosphoinositides (PIs) regulate myriad cellular functions including membrane fusion, as exemplified by the yeast vacuole, which uses various PIs at different stages of fusion. In light of this, the effect of phosphatidylinositol 3,5 bisphosphate [PI(3,5)P2] on vacuole fusion remains unknown. PI(3,5)P2 is made by the PI3P 5-kinase Fab1 and has been characterized as a regulator of vacuole fission during hyperosmotic shock where it interacts with the TRP Ca2+ channel Yvc1. Here we demonstrate that exogenously added dioctanoyl (C8) PI(3,5)P2 abolishes homotypic vacuole fusion. This effect was not linked to Yvc1, as fusion was equally affected using yvc1Delta vacuoles. Thus, the effects of C8-PI(3,5)P2 on fusion versus fission operate through distinct mechanisms. Further testing showed that C8-PI(3,5)P2 inhibited vacuole fusion after trans-SNARE pairing. Although SNARE complex formation was unaffected we found that C8-PI(3,5)P2 blocked outer leaflet lipid mixing. Overproduction of endogenous PI(3,5)P2 by the fab1T2250A hyperactive kinase mutant also inhibited at the lipid mixing stage, bolstering the model in which PI(3,5)P2 inhibits fusion when present at elevated levels. Taken together, this work identifies a novel function for PI(3,5)P2 as a regulator of vacuolar fusion. Moreover, it suggests that this lipid acts as a molecular switch between fission and fusion. PMID- 30427761 TI - Utilization of Three-Dimensional Photography (VECTRA) for the Evaluation of Lower Limb Lymphedema in Patients Following Lymphovenous Anastomosis. AB - PURPOSES: Conventionally, lower limb circumference is measured using a measuring tape; however, a measuring tape may not provide sufficient precision to measure the magnitude of the lymphedema. We report the use of three-dimensional photography (VECTRA(r)) for the evaluation of lymphedema in patients after lymphovenous anastomosis (LVA). METHODS: We calculated the percent error in measuring lower limb circumference with a measuring tape. We performed VECTRA before and after LVA and measured the change in volume. Because of the limitation of photographic range, the measurement of the entire lower limb was difficult using this approach. We were limited to thigh measurements. RESULTS: The ratio of error was calculated using the largest and smallest mean measurements. The largest measurement errors, 4.3%-5.8%, were observed for the measurement of thigh circumferences, whereas the smallest measurement errors, 2.3%-2.9%, were observed in the foot and lower leg areas. The change in volume postoperatively measured using VECTRA decreased by an average of 35.1 cc. CONCLUSIONS: The evaluation with a measuring tape for the foot and lower leg region was useful because a lesser content of soft tissue was not influenced to the error by power. Contrarily, VECTRA was useful for measuring the thigh region because of the higher quantity of soft tissue, and the combination of both reduced the error. PMID- 30427762 TI - FIRING PROPERTIES OF MUSCLE SPINDLES SUPPLYING THE INTRINSIC FOOT MUSCLES OF HUMANS IN UNLOADED AND FREE-STANDING CONDITIONS. AB - We recently developed an approach to record from muscle spindles in the intrinsic muscles of the foot in free-standing humans by inserting a tungsten microelectrode into the posterior tibial nerve behind the medial malleolus of the ankle. Here, we characterize the behaviour of muscle spindles in the small muscles of the foot in (i) seated subjects with the leg horizontal and foot naturally plantarflexed and (ii) in standing subjects. In the first study recordings were made from 26 muscle spindle afferents located within flexor digiti minimi brevis (n=4), abductor digiti minimi (n=3), quadratus plantae (n=3), plantar interossei (n=4), flexor digitorum brevis (n=3), dorsal interossei (n=2) and lumbricals (n=2), with one each supplying abductor hallucis, adductor hallucis and flexor hallucis brevis. The identity of another two muscle afferents was unknown. The majority of the units were silent at rest; only 7 (27%) being spontaneously active. Because of the anatomic constraints of the foot, some spindles supplying muscles acting on the toes responded to movements of one or more digits. In the second study 12 muscle spindle afferents were examined during standing. The ongoing discharge of 8 spindle afferents covaried with changes in the centre of pressure during postural sway. We conclude that the majority of spindle endings in the small muscles of the foot are silent at rest, which may allow them to encode changes in conformation of the foot when it is loaded during standing. Moreover, these muscle spindle afferents can provide useful proprioceptive information during standing and postural sway. PMID- 30427763 TI - First Report of Whole-Genome Sequence of Colistin-Resistant Klebsiella quasipneumoniae subsp. similipneumoniae Producing KPC-9 in India. AB - AIM: Klebsiella pneumoniae carbapenemase (KPC) is a class A carbapenemase endemic in the United States, China, South America, and Europe but is rarely reported from India. A single report of KPC-9 from K. pneumoniae in Israel has been published. K. pneumoniae has been classified into three phylogenetic groups: group 1 consists of K. pneumoniae and its subspecies, group 2 consists of Klebsiella quasipneumoniae and its subspecies, and group 3 consists of Klebsiella variicola. This is the first report of whole-genome sequencing of colistin resistant K. quasipneumoniae subsp. similipneumoniae harboring blaKPC-9 gene. RESULTS: The isolate was obtained from the culture of a respiratory catheter tip from a 41-year-old woman with traumatic brain injury. Whole-genome sequencing showed the presence of blaOKP-B-3 gene and hence it was identified as K. quasipneumoniae subsp. similipneumoniae. The isolate was resistant to all antimicrobials except tigecycline. Colistin resistance was chromosomally mediated; mcr-1 to mcr-5 genes and their variants were not identified. The isolate belonged to the novel clonal type ST2957. CONCLUSION: The isolation of KPC-9 from India, a nonendemic region, and in an isolate of K. quasipneumoniae highlights the importance of accurate identification of Klebsiella species and determination of mechanism of resistance. The novel sequence type obtained indicates evolution of the organism and acquisition of plasmid-mediated resistance. The occurrence of KPC in India is a potential public health threat. PMID- 30427764 TI - A rapid visuomotor response on the human upper limb is selectively influenced by implicit motor learning. AB - How do humans learn to adapt their motor actions to achieve task success? Recent behavioral and patient studies have challenged the classic notion that motor learning arises solely from the errors produced during a task, suggesting instead that explicit cognitive strategies can act in concert with the implicit, error based, motor learning component. Here, we show that the earliest wave of directionally-tuned neuromuscular activity that begins within ~100 ms of peripheral visual stimulus onset is selectively influenced by the implicit component of motor learning. In contrast, the voluntary neuromuscular activity associated with reach initiation, which evolves ~100 to 200 ms later is influenced by both the implicit and explicit components of motor learning. The selective influence of the implicit, but not explicit, component of motor learning on the directional tuning of the earliest cascade of neuromuscular activity supports the notion that these components of motor learning can differentially influence descending motor pathways. PMID- 30427765 TI - A review and consideration on the kinematics of reach-to-grasp movements in macaque monkeys. AB - The bases for understanding the neuronal mechanisms that underlie the control of reach-to-grasp movements among nonhuman primates, particularly macaques, has been widely studied. However, only a few kinematic descriptions of their prehensile actions are available. A thorough understanding of macaques' prehensile movements is manifestly critical, in light of their role in biomedical research as valuable models for studying neuromotor disorders and brain mechanisms, as well as for developing brain-machine interfaces to facilitate arm control. This article aims to review the current state of knowledge on the kinematics of grasping movements that macaques perform in naturalistic, semi-naturalistic, and laboratory settings, to answer the following questions: Are kinematic signatures affected by the context within which the movement is performed? In what ways is kinematics of humans' and macaques' prehensile actions similar/dissimilar? Our analysis reflects the challenges involved in making comparisons across settings and species due to the heterogeneous picture in terms of the number of subjects, stimuli, conditions, and hands used. The kinematics of free-ranging macaques are characterized by distinctive features that are exhibited neither by macaques in laboratory setting nor human subjects. The temporal incidence of key kinematic landmarks diverges significantly between species, indicating disparities in the overall organization of movement. Given such complexities, we attempt a synthesis of extant body of evidence, intending to generate some significant implications for directions that future research might take, to recognize the remaining gaps and pursue the insights and resolutions to generate an interpretation of movement kinematics that accounts for all settings and subjects. PMID- 30427766 TI - Global impact of varicella vaccination programs. AB - Although varicella is usually a mild and self-limited disease, complications can occur. In 1998, the World Health Organization recommended varicella vaccination for countries where the disease has a significant public health burden. Nonetheless, concerns about a shift in the disease to older groups, an increase in herpes zoster in the elderly and cost-effectiveness led many countries to postpone universal varicella vaccine introduction. In this review, we summarize the accumulating evidence, available mostly from high and middle-income countries supporting a high impact of universal vaccination in reductions of the incidence of the disease and hospitalizations and its cost-effectiveness. We have also observed the effect of herd immunity and noted that there is no definitive and consistent association between vaccination and the increase in herpes zoster incidence in the elderly. PMID- 30427767 TI - Functional and Anatomical Relationships Between the Medial Precentral Cortex, Dorsal Striatum, and Head Direction Cell Circuitry. I: Recording Studies. AB - Head direction (HD) cells fire as a function of the animal's directional heading and provide the animal with a sense of direction. In rodents, these neurons are located primarily within the limbic system, but small populations of HD cells are found in two extralimbic areas: the medial precentral cortex (PrCM) and dorsal striatum (DS). HD cell activity in these structures could be driven by output from the limbic HD circuit or generated intrinsically. We examined these possibilities by recording the activity of PrCM and DS neurons in control rats and rats with anterodorsal thalamic nucleus (ADN) lesions, a manipulation that disrupts the limbic HD signal. HD cells in the PrCM and DS of control animals displayed characteristics similar to those of limbic HD cells, and these extralimbic HD signals were eliminated in animals with complete ADN lesions, suggesting that the PrCM and DS HD signals are conveyed from the limbic HD circuit. Angular head velocity cells recorded in the PrCM and DS were unaffected by ADN lesions. Next, we determined if the PrCM and DS convey necessary self motion signals to the limbic HD circuit. Limbic HD cell activity recorded in the ADN remained intact following combined lesions of the PrCM and DS. Collectively, these experiments reveal a unidirectional functional relationship between the limbic HD circuit and the PrCM and DS; the limbic system generates the HD signal and transmits it to the PrCM and DS, but these extralimbic areas do not provide critical input or feedback to limbic HD cells. PMID- 30427768 TI - Electrospun PLGA membrane incorporated with andrographolide-loaded mesoporous silica nanoparticles for sustained antibacterial wound dressing. AB - AIM: To assess the wound-healing ability of poly(lactic-co-glycolic acid) (PLGA) nanofibrous wound dressing incorporated with andrographolide (Andro)-loaded mesoporous silica nanoparticles (MSNs). MATERIALS & METHODS: PLGA/Andro-MSNs nanofibrous membrane wound dressings were produced by electrospinning. The effects of MSNs on the hydrophilicity, degradation and mechanical strength of membranes were evaluated. The cumulative release of Andro in vitro was obtained. Cell culture and in vivo tests on infectious models were carried out. RESULTS: The PLGA/Andro-MSNs membrane showed a sustained release of Andro. The incorporation of MSNs into PLGA improved the hydrophilicity of the nanofibrous membranes. Cell culture and in vivo tests showed that PLGA/Andro-MSNs membrane can promote epidermal cell adhesion and reduce inflammation process. CONCLUSION: PLGA/Andro-MSNs nanofibrous membrane exhibited an efficient wound-healing ability. PMID- 30427769 TI - Intra-Arrest Induction of Hypothermia via Large-Volume Ice-Cold Saline for Sudden Cardiac Arrest: The New York City Project Hypothermia Experience. AB - Therapeutic hypothermia, the standard for post-resuscitation care of out-of hospital sudden cardiac arrest (SCA), is an area that the most recent resuscitation guidelines note "has not been studied adequately." We conducted a two-phase study examining the role of intra-arrest hypothermia for out-of hospital SCA, first standardizing the resuscitation and transport of patients to resuscitation centers where post-resuscitation hypothermia was required and then initiating hypothermia during out-of-hospital resuscitation efforts. The primary end points were return of spontaneous circulation (ROSC), sustained ROSC, survival to hospital admission, and survival to discharge. Comparing the cohort of standard hospital-initiated hypothermia (Phase I) with the prehospital initiated hypothermia via large-volume ice-cold saline (LVICS) infusion (Phase II), no difference was noted for any end point: ROSC (56.4% vs. 53.4%, p = 0.51; 95% confidence interval [CI]: -5.7 to 11.4), sustained ROSC (46.9% vs. 42.8%, p = 0.38; 95% CI: -4.7 to 12.4), hospital admission (44.7% vs. 37.7%, p = 0.13; 95% CI: -1.9 to 15.4), hospital discharge among those surviving to admission (40.0% vs. 28.0%, p = 0.08; 95% CI: -1.5 to 27.8), or neurological outcome among those surviving to discharge (76.0% vs. 71.4%, p = 0.73; 95% CI: -26.9 to 38.7). Patients presenting in ventricular fibrillation were more likely to survive to hospital discharge in both phases, although a trend toward worsened early outcomes (ROSC, sustained ROSC, and survival to admission) with intra-arrest hypothermia was noted in this subgroup. Multivariable regression analyses failed to demonstrate any survival benefit associated with the intra-arrest initiation of hypothermia via LVICS. Our study, the largest study of intra-arrest initiation of hypothermia published to date, failed to demonstrate any effect on survival for out-of-hospital SCA patients, confirming findings of previously published smaller studies. We therefore do not recommend the use of intra-arrest cooling via LVICS infusion as part of routine out-of-hospital SCA resuscitative efforts. PMID- 30427770 TI - Neuropsychological Risk Factors to Consider When Assessing for Sexually Abusive Youth. AB - Present literature exploring neuropsychological characteristics of sexually abusive youth is lacking, especially with regard to females and youth with low intellectual functioning. Moreover, although areas of neuropsychological functioning have been researched in this population, findings are vastly inconsistent and contradictory. Such gaps in the literature create obvious barriers in the ability to adequately assess risk, particularly pertaining to neuropsychological factors that could inform effective treatment, case management, and supervision options. The purpose of this article is to explore neuropsychological and cognitive deficits that may manifest in youth who have and who have not experienced instances of abuse, for those who have and who have not been convicted of a sex offense, and to provide information for treatment providers, case managers, and supervisors regarding when to consider referring for additional testing. PMID- 30427771 TI - Clinical Practice Guidelines in Complicated Intra-Abdominal Infection 2018: An Indonesian Perspective. AB - BACKGROUND: The occurrence of complicated intra-abdominal infections (cIAI) remains high despite system improvement in accordance with Joint Commission International because of heterogeneity of management. However, published clinical practice guidelines (CPGs) were not feasible to be implemented because these guidelines were not specific to Indonesian characteristics. Thus, a national CPG should be developed to minimize heterogeneity in the management of cIAI in Indonesia. METHODS: We developed a CPG on cIAI through the adaptation of published CPGs. The process proceeded in steps recommended by ADAPTE. Published CPGs were critically appraised using Appraisal of Guidelines for Research and Evaluation (AGREE) II critical appraisal tools. For a specific updated CPG, the analysis was performed using Checklist for the Reporting of Updated Guidelines (CheckUp). Appropriate statements and recommendations in selected CPGs were adapted into our CPG with consideration of Indonesian characteristics. The recommendations were established by the hierarchy of evidence on Grading of Recommendations Assessment, Development and Evaluation (GRADE). The approval of the recommendation draft was performed using the Delphi method. RESULTS: Sixty eight full-text guidelines were downloaded from several sites. Thirty-three CPGs were related to intra-abdominal infection and 18 others were specific on CPG on intra-abdominal infection and cIAI. On review of these 18 CPGs, 13 were strongly recommended, three were recommended, and two were not recommended. On review updated CPGs, five updated CPGs were found, all with the same score. Two of the strongly recommended updated CPGs had been published in 2016 and 2017, i.e. recommendations by the World Society of Emergency Surgery 2016 consensus conference and revised CPG of the Surgical Site Infection Society. There were a total of 84 statements and recommendations developed and approved by the task force through using the Delphi method. CONCLUSIONS: This guideline summarizes the definition, classification, pathophysiology, etiology, risk factors, assessments, and management of cIAI. Evidence-based recommendations have been developed with consideration of Indonesian-specific characteristics. PMID- 30427772 TI - Clinical Q & A: Translating Therapeutic Temperature Management from Theory to Practice. PMID- 30427773 TI - Predicting Colonoscopy Screening Behavior and Future Screening Intentions for African Americans Older than 50 Years. AB - African Americans experience a disproportionate burden of morbidity and mortality from colorectal cancer, which may be due to low adherence to screening recommendations. Previous studies have found relationships between decision making factors and screening behavior, but few have looked at both cognitive and affective factors or within a specifically African American sample. To better understand determinants that drive screening behavior, this study examines affective, cognitive, and social variables as predictors of colonoscopy in an age eligible African American population. Participants completed surveys assessing affective associations with colonoscopy, perceived benefits and barriers, self efficacy, knowledge, fear of colonoscopy, perceived risk, and colorectal cancer worry and fear. Regression analysis was used to model decision-making constructs as predictors of screening behavior/intentions. Affective, cognitive, and health care experience variables predicted colonoscopy completion and intentions. Provider-level factors and previous cancer screenings predicted prior screening only, but not intentions. Affective and cognitive components of perceived risk were associated with decreased likelihood of colonoscopy behavior, but increased likelihood of colonoscopy intentions. These findings suggest that colonoscopy decision making involves a complex array of both cognitive and affective determinants. This work extends our knowledge of colorectal cancer screening decision making by evaluating the effects of these multiple determinants on screening behavior in an African American sample. Future work exploring the interplay of affect and cognitions as influences on colonoscopy decision making and how health care experiences may moderate this effect is needed to develop effective intervention approaches and reduce screening disparities. PMID- 30427774 TI - Surgical technique for biological fixation of closed segmental tibial fractures by the Less Invasive Stabilization System (LISS). AB - INTRODUCTION: This prospective case series study aimed to assess the value of the Less Invasive Stabilization System (LISS) to treat closed Segmental Tibial Fractures (STFs) using a proposed surgical technique. MATERIALS AND METHODS: Between August 2010 and January 2014, 21 consecutive recently (within 1 week) closed STFs that matched the inclusion criteria were enrolled. Patients were treated with the 13-hole LISS plate. All patients were followed up every 2 weeks for the first 2 months, then every month for the rest of the first 6 months and then every 6 months thereafter. Patients were assessed radiologically during the follow-up appointments and clinically at the final visit by the Lower Extremity Functional Scale (LEFS) to evaluate the result. RESULTS: The mean time to union of the proximal fracture was 15.72 +/- 2.78 (range: 12-20) weeks and for the distal fracture was 20 +/- 2.22 (range: 16-24) weeks, excluding delayed union in three patients. All patients except the three showed radiological observable callus in a mean duration of 4.95 (range: 3-7) weeks. The mean final follow-up LEFS was 72.4 (range: 60-80). CONCLUSION: The mean time to union of the proximal fracture was shorter than the distal fracture. The use of LISS to treat closed STFs using the proposed surgical technique has proved to give favorable results. Further studies using the described technique are needed to justify the achieved results. LEVEL OF EVIDENCE: IV (Prospective case series). PMID- 30427776 TI - Central adrenal insufficiency: open issues regarding diagnosis and glucocorticoid treatment. AB - Background Central adrenal insufficiency (CAI) is characterized by impaired adrenocorticotropin (ACTH) secretion because of a disease or injury to the hypothalamus or the pituitary, leading to a reduced cortisol production. CAI suspicion arises more frequently in patients with pituitary tumors, cranial irradiation/surgery/injury/infections, as well as after exogenous glucocorticoid withdrawal. Nevertheless, a late diagnosis is not uncommon because CAI may present with nonspecific signs or symptoms, as fatigue or hyponatremia. Content The PubMed database was searched (years 1980-2018), using "central adrenal insufficiency" and "ACTH deficiency" as keywords. Subsequently, reference sections of the retrieved articles were searched. Summary Dynamic tests are needed when morning basal cortisol levels are not sufficient to exclude or to confirm CAI. Short Synacthen Test (SST) is the most used, and Endocrine Society's guidelines recommend a cortisol peak >500 nmol/L to exclude CAI. Despite thresholds, understanding the pretest probability of ACTH deficiency (the clinical background of the patient) is essential because the diagnostic accuracy of SST in case of a negative result is suboptimal. Glucocorticoid replacement therapy, able to replicate cortisol circadian rhythm, is required in patients with CAI; fludrocortisone treatment is not necessary. Short-acting glucocorticoid drugs (hydrocortisone or cortisone acetate) are the most used; lower doses than previously used are nowadays recommended to reduce cortisol-related comorbidities. Promising results have been obtained with modified-release hydrocortisone, especially regarding glucose metabolism in patients with primary adrenal insufficiency. Outlook An accurate clinical diagnosis and a careful individualized therapy are mandatory in patients with CAI. PMID- 30427775 TI - Shear-induced damped oscillations in an epithelium depend on actomyosin contraction and E-cadherin cell adhesion. AB - Shear forces between cells occur during global changes in multicellular organization during morphogenesis and tissue growth, yet how cells sense shear forces and propagate a response across a tissue is unknown. We found that applying exogenous shear at the midline of an epithelium induced a local, short term deformation near the shear plane, and a long-term collective oscillatory movement across the epithelium that spread from the shear-plane and gradually dampened. Inhibiting actomyosin contraction or E-cadherin trans-cell adhesion blocked oscillations, whereas stabilizing actin filaments prolonged oscillations. Combining these data with a model of epithelium mechanics supports a mechanism involving the generation of a shear-induced mechanical event at the shear plane which is then relayed across the epithelium by actomyosin contraction linked through E-cadherin. This causes an imbalance of forces in the epithelium, which is gradually dissipated through oscillatory cell movements and actin filament turnover to restore the force balance across the epithelium. PMID- 30427777 TI - Effect of an activated charcoal product (DOAC StopTM) intended for extracting DOACs on various other APTT-prolonging anticoagulants. AB - Background The aim of the study was to investigate the specificity of an activated charcoal-based product (DOAC StopTM) initially intended for the specific extraction of direct oral anticoagulants (DOACs) from test plasmas on a range of other anticoagulants. Methods Test plasmas were prepared by adding various anticoagulants to pooled normal plasma at concentrations prolonging an activated partial thromboplastin time (APTT) test by a factor of 1.5-3. These plasmas were treated with DOAC StopTM for 5 and 20 min. Then APTTs were repeated and residual anticoagulant concentrations estimated from dose-response curves. Results The activated charcoal (AC)-based product was found to extract DOACs efficiently. It also bound the intravenous anticoagulants argatroban and lepirudin, but it had no effect on heparin, enoxaparin or danaparoid in plasma. Among other APTT-inhibiting agents that might be present in test plasmas from patients, it extracted protamine, aprotinin and polymyxin. It had no effect on annexin V, thrombomodulin, a typical lupus anticoagulant, a factor VIII antibody, activated protein C or its activator, but it did bind some cationic inhibitors of the APTT with molecular weight below approximately 30 kDa. Conclusions The AC based product extracted DOACs efficiently with no effect on heparin-type anticoagulants. It did bind argatroban and hirudin-type anticoagulants, which might occur in plasmas from some inpatients, and APTT results obtained after its use should be interpreted after due consideration of patient medications. PMID- 30427778 TI - Learning from tragedy: the Julia Berg story. AB - This is a case report involving diagnostic errors that resulted in the death of a 15-year-old girl, and commentaries on the case from her parents and involved providers. Julia Berg presented with fatigue, fevers, sore throat and right sided flank pain. Based on a computed tomography (CT) scan that identified an abnormal appearing gall bladder, and markedly elevated bilirubin and "liver function tests", she was hospitalized and ultimately underwent surgery for suspected cholecystitis and/or cholangitis. Julia died of unexplained post-operative complications. Her autopsy, and additional testing, suggested that the correct diagnosis was Epstein-Barr virus infection with acalculous cholecystitis. The correct diagnosis might have been considered had more attention been paid to her presenting symptoms, and a striking degree of lymphocytosis that was repeatedly demonstrated. The case illustrates how cognitive "biases" can contribute to harm from diagnostic error. The case has profoundly impacted the involved healthcare organization, and Julia's parents have become leaders in helping advance awareness and education about diagnostic error and its prevention. PMID- 30427779 TI - Effects of different exercise loads on the thyroid hormone levels and serum lipid profile in swimmers. AB - Background The aim of this study was to investigate the effects of different exercise loads (short, medium and long swimming distances) on the thyroid hormone (THs) levels and serum lipid profiles of male professional swimmers. Materials and methods The participants in this study were 20 healthy male professional swimmers aged 18-22 years, who all competed at an elite level. The THs levels [thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4)] and serum lipid profile were also obtained. Results It was determined that the TSH and T4 values increased after exercise (p < 0.05). When compared to the pretest values, the increase in the TSH and T4 values following the L400 tests was statistically significant (p < 0.001 and p < 0.05). It was also determined that the changes in the cholesterol, high-density lipoprotein (HDL) and total glucose (TG) values were significant after exercise (p < 0.001). There was no significant difference between the groups in terms of the low-density lipoprotein (LDL) values (p = 0.07). According to the results, the cholesterol counts for the M200 and L400 groups were lower than the pretest counts (p < 0.001). When compared to the pretest values, the decrease in the HDL counts for the M200 and L400 groups was higher than the pretest HDL counts (p < 0.001 and p < 0.05, respectively). Further, the triglycerides counts for the M200 and L400 groups were higher than the pretest counts (p < 0.001). Conclusions Different exercise loads can have a positive impact on the physical health of swimmers via their lipid profiles and THs. Additionally, swimming exercise could be considered an efficient protective strategy against metabolic disorders, as it serves to balance the serum lipid levels. PMID- 30427780 TI - Direct and indirect effects of psychopharmacological treatment on the cardiovascular system. AB - Background Severe mental disorders, i.e. psychotic disorders, unipolar and bipolar disorders are associated with increased morbidity and mortality from cardiovascular and metabolic disorders. The underlying cause of this association is complex and comprises disorder specific alterations such as dysfunctions of immunological and hormonal systems, body-composition changes and health associated behaviors (smoking, sedentary lifestyle, alcohol intake and treatment compliance). Furthermore, some psychopharmacological drugs may exert unwanted side effects that impact the cardiovascular system. Methods This paper reviews studies concerning commonly used antidepressant and antipsychotics drugs with a particular focus on direct and indirect cardiovascular side effects. Results Newer antidepressant drugs have a favorable cardiovascular safety profile compared to tricyclic antidepressants. However, QTc prolongation, increased blood pressure and potentially higher risks of bleeding have been observed in some newer antidepressants. Some second generation (atypical) antipsychotics have raised concern because of indirect cardiovascular, metabolic side effects such as weight gain and disturbances in lipid and glucose metabolism. Conclusions Psychiatrists need to be aware of potential direct and indirect cardiovascular side effects and to include them in the risk/benefit assessment when choosing a specific individualized treatment. PMID- 30427781 TI - Acetylcholinesterase activity and bone biochemical markers in premature and full term neonates. AB - Background Almost 30% of the premature infants have low body weight and bone mineral density due to prematurity. There is no consensus of screening premature neonates for metabolic bone disease; therefore, it is important to investigate the use of bone biochemical parameters. Latest studies involved the activity of acetylcholinesterase as a mediator in bone remodeling. It is hypothesized that there is a possible correlation of bone biochemical biomarkers and acetylcholinesterase (AChE) activity in premature infants. Methods We studied 50 neonates (26 preterm with gestational age <32 weeks, 24 full-term). Clinical data (sex, gestational week) and anthropometric parameters (body weight) were recorded. We directly measured the bone biochemical markers in serum such as alkaline phosphatase (ALP), calcium (Ca), phosphorus (P), magnesium (Mg) and parathyroid hormone (PTH). In addition, we measured the AChE activity. Results ALP and parathyroid hormone levels were higher, but Ca, P and AChE were lower in premature neonates group compared with full-term ones. There is a significant positive correlation of gestational age with body weight, Ca and AChE. A significant negative correlation was observed for ALP and PTH with gestational age. Conclusions We found a gestational age-related increase of AChE activity. There were significant relationships between AChE activity with P and PTH. PMID- 30427782 TI - Investigation of a novel pyrolusite particle electrode effects in the chlorine containing wastewater. AB - Research on three-dimensional electrode system mainly focuses on the material of plate electrode and catalytic activity, and minimal attention is provided to particle electrode. Pyrolusite was prepared as a novel particle electrode with high active chlorine (ACl) yield. The particle electrode was characterised by scanning electrode microscopy (SEM), X-ray diffraction (XRD), X-ray fluorescence (XRF) and electrochemical properties. Results show that the intended pyrolusite particle electrode was prepared successfully. These pyrolusite particle electrodes were applied to degrade sulphonated phenolic resin in chlorine containing wastewater and displayed an excellent catalytic activity. A total of 68.76 mg/L ACl was produced, and the CODCr removal rate was 49.55%. These results indicated that pyrolusite particle electrode is much more effective than the reference material, that is, granular activated carbon. Furthermore, the product of electrolytic process was characterised by gas chromatography-mass spectrometry (GC-MS) and ultraviolet visible spectrometry (UV-vis). The enhanced mechanism was proposed that the high degradation efficiency could be ascribed to the increase of ACl. PMID- 30427783 TI - Assessing the negative impact of an aquaculture farm on effluent water quality in Itacuruba, Pernambuco, Brazilian semiarid region. AB - This study was conducted at a fish farm in Itacuruba, located in the Brazilian semiarid region. Its objective was to quantify the impacts of aquaculture on water quality by comparing effluent and inlet water, particularly in relation to CONAMA Resolution 430 (2011) limits. Regarding the effluent, electrical conductivity, total phosphorus (TP) and total nitrogen presented values above the limits, other parameters complied with the mentioned legislation. During the dry period, the effluent's TP values were 447% higher than the inlet water and 473% above the Resolution limit. During the wet period, TP concentration in the inlet water increased 1,000% while the effluent exceeded legislation limits by 1,175%. Based on these results, treatment of effluent from fish farms in accordance with legislation prior to its release into the receiving water body is recommended, thereby minimizing eutrophication risk for the local population, guaranteeing food security, reducing impacts to public health and aquatic biota and favoring the sustainability of the enterprise. Due to limited water resources, it is especially necessary to adopt better management practices that minimize the negative impacts of aquaculture activities. PMID- 30427784 TI - Gliding arc plasma pre-treatment of kaolin in spatial post-discharge mode for removal of Reactive Red 2 dye from aqueous solution. AB - This study investigates the ability of spatial post-discharge mode functionalized kaolin to remove textile dye Reactive Red 2 from aqueous solution compared to that of the raw kaolinite. To fulfill the aim, the removal conditions, including plasma exposure time, processed mode (direct and post-discharge), pH of the aqueous dye solution, initial dye concentration and adsorbent dosage, were investigated. The changes that occur on clay surfaces before and after gliding arc plasma treatment were followed by Fourier transform infrared spectroscopy, scanning electron microscopy and nitrogen physisorption. The point of zero charge and the changes of the textural properties after gliding arc plasma treatment were also examined. The experimental data were analyzed using pseudo-first-order, pseudo-second-order and empirical Elovich models. The diffusion phenomenon was also studied. The results obtained indicate that spatial post-discharge pre treatment of kaolin deeply influences the functional groups of some of its minerals as well as the morphology and texture of its particles. Consequently, at room temperature (~30 degrees C), the maximum adsorption capacities of natural raw kaolin clay were tripled after treatment with gliding arc plasma in spatial post-discharge mode and were almost doubled after the direct treatment mode. PMID- 30427785 TI - Elimination of typical polycyclic musks in a full-scale membrane bioreactor combined with anaerobic-anoxic-oxic process in municipal wastewater treatment plant. AB - The objective of this study was to investigate the removal of 11 synthetic polycyclic musks in a municipal wastewater treatment plant located in Jilin, China, by using a membrane bioreactor combined with anaerobic-anoxic-oxic process. The analysis of synthetic polycyclic musks was conducted with gas chromatography/mass spectrometry after solid-phase extraction. The removal efficiency of 11 synthetic polycyclic musks ranged from 65.9% (3 methylcyclopentadecanone) to 84.6% (Galoxolide) in the influent. Along the treatment process, it was observed that the anaerobic tank could remove the synthetic polycyclic musks effectively whereas the role of the membrane was to the musks, which could be ascribed to the relatively strong hydrophobic property of the musks. The sludge-water distribution coefficients (Kd values) as indicator of adsorption propensity for the sludge from anaerobic, anoxic, oxic and membrane tanks were measured. The high value of Kd, above 5.0 litres per gram of suspended solids, showed most of the musks could be removed by sludge through the adsorption process; thus the removal rate from the water phase caused by adsorption in the wastewater treatment plant can be predicted. PMID- 30427786 TI - The characteristics of heat-driven ammonium adsorption in aerobic granular sludge. AB - Adsorption is an important step during the migration of ammonium from the aqueous phase to biomass in biological nitrogen removal processes. A deeper understanding of the adsorption mechanisms is encouraged in constructing nitrogen conversion models. In this study, the ammonium adsorption in aerobic granular sludge was investigated at different conditions. Analysis of kinetic data indicated that ammonium adsorption was a fast process and followed pseudo-second-order kinetics (adsorption rate constant k2 was between 0.031 and 0.065 g/(mg . min)). The maximum adsorption capacity and half saturation constant KL in the Langmuir isotherm model were 4.95 mgNH4+-N/g total suspended solids and 0.0126 L/mg, respectively. Effects of environmental conditions such as temperature, pH and competitive cations were also estimated. The optimum pH was 7 and the effects of competitive cations were in the order Ca2+ > Mg2+ > K+ > Na+. Values of thermodynamic parameters (DeltaHO = -14.697 kJ/mol, DeltaSO = -6.65 J/(mol . K)) indicated that the adsorption process was spontaneous and exothermic. Desorption tests showed that the process was reversible and low temperature had a negative effect on ammonium desorption. These findings could be useful for completing the mathematical model of the nitrogen removal process in bioreactors. PMID- 30427787 TI - Effects of inorganic anions on the photolysis of triclosan under UV irradiation. AB - Triclosan is a widely used antimicrobial agent and may pose health risks to many aquatic organisms. Photodegradation is an important transformation pathway for triclosan, but studies on the effects of inorganic anions on photodegradation of triclosan are limited. In the present study, the single and combined effects of NO3-, Cl- and HCO3- on the photolysis of triclosan in aqueous solutions under UV irradiation was evaluated. The results showed that photodegradation of triclosan was inhibited by NO3- and promoted by HCO3-, while no significant effect was observed with Cl-. When Cl- was added to NO3-, no effect was observed, but the addition of Cl- hindered the promotion effect of HCO3-. The coexistence of NO3-, Cl- and HCO3- inhibited the photolysis of triclosan. These results showed the complex effects of inorganic anions in the photolysis of triclosan and provide useful information for an accurate ecological risk assessment of triclosan in natural waters. It will also help to develop appropriate treatment ways of triclosan. PMID- 30427788 TI - Electroflotation of oily wastewater using stainless steel sponge electrodes. AB - In this study, emulsified oil removals have been studied electrochemically by using stainless steel sponge electrode beds. A first-order electroflotation model was developed and the model estimation were consistent with the experimental results. It was found out that the mean electroflotation rate constant was mainly a function of the voltage applied to the electrode beds. In addition, the properties of intermediate materials (electrical conductivity) placed between the anode and cathode electrode beds strongly affected removal yields. For the initial concentration of 57,150 mg/L, the chemical oxygen demand (COD) removal was obtained as 85% under the conditions of voltage gradient 15 V. The experiments were also performed by varying the electrode bed lengths. Even though higher oil yields were obtained at 27 cm bed length, similar oil yields were also obtained at 18 cm bed length, especially after 60 min, with less energy consumption. Therefore, the optimum electrode bed length was concluded to be 18 cm. PMID- 30427789 TI - Nitric acid-anionic surfactant modified activated carbon to enhance cadmium(II) removal from wastewater: preparation conditions and physicochemical properties. AB - The authors used a nitric acid (HNO3)-sodium dodecyl benzene sulfonate (SDBS) method to modify a lignite-based activated carbon. These modified carbons were appraised for their removal of Cd(II) from aqueous solutions. Response surface methodology was employed to optimize the preparation factors including nitric acid concentration CN, temperature T and SDBS concentration CS. Statistical analysis indicated that the interaction of CN and CS incurred the most effect on the maximum cadmium adsorption capacity (Qm). The optimal Qm appeared at CN = 3.29 mol/L, T = 76 degrees C and CS=30,700 mg/L. The optimal protocol achieved 44.21 mg/g Qm for Cd(II) which was about 7 times larger than for this pristine lignite activated carbon (LAC) (6.78 mg/g). The physical-chemical properties of the modified activated carbons following each synthesis step were characterized relative to their surface area, oxygen functionality, and external surface charge. It was confirmed that the developed surface area, functional groups and negative charges were mainly responsible for the higher adsorption capacity for the LAC that have been more favorably tailored by this HNO3-SDBS protocol. PMID- 30427790 TI - Automated monitoring system for events detection in sewer network by distribution temperature sensing data measurement. AB - This study is related to distribution temperature sensing (DTS) in sewers for tracing illicit or unintended inflows to foul sewers. A DTS measurement is performed with a fiber optic cable that is installed at the invert of a sewer pipe in combination with a standalone laser/computer instrument. This set-up generates in-sewer temperature measurements with high resolutions in time (every minute) and space (every metre) along the cable over long periods of time (weeks on end). The prolonged monitoring period in combination with the high level of detail in the dataset allows the study of anomalies (i.e., unexpected temperatures and/or temperature variations at certain locations), even if these only occur very infrequently. The objective of this paper is to develop an automated tool to analyze the large data masses and identify anomalies caused by illicit or unintended inflows. In this study, an algorithm for detecting the temperature changes that are caused by both wastewater discharge and inflow of stormwater are developed. A comparison of the results of the automated procedure to the results of a manual assessment of the datasets (Elmehaven, Denmark) shows that the automated procedure performs very well. PMID- 30427791 TI - Water remediation contaminated with MTBE using a catalytic oxidation process in batch reactor: influence of the cerium loading on the activity and CO2 selectivity. AB - Destruction of methyl tert-butyl ether (MTBE) in liquid phase and in a batch reactor was studied using ruthenium catalysts over alumina support, modified with different cerium loadings. Ce loading increment causes an increase in the particle size from 1.26 nm to 2.3 nm, enhancing the MTBE oxidation (at 150 degrees C), and the selectivity toward CO2. The high catalytic activity of Ru/ACe10 is attributed to the species Ce4+-O2--M that could favor the oxygen transfer between the catalyst surface and the adsorbed species by a redox mechanism. Thus, CeOx plays an important role in both enhancing the affinity between MTBE and catalyst during MTBE adsorption and promoting the catalytic activity for MTBE oxidation. PMID- 30427792 TI - Isolation and characterization of organic matter-degrading bacteria from coking wastewater treatment plant. AB - As a step toward bioaugmentation of coking wastewater treatment 45 bacteria strains were isolated from the activated sludge of a coking wastewater treatment plant (WWTP). Three strains identified as Bacillus cereus, Pseudomonas synxantha, and Pseudomonas pseudoaligenes exhibited high dehydrogenase activity which indicates a strong ability to degrade organic matter. Subsequently all three strains showed high naphthalene degradation abilities. Naphthalene is a refractory compound often found in coking wastewater. For B. cereus and P. synxantha the maximum naphthalene removal rates were 60.4% and 79.8%, respectively, at an initial naphthalene concentration of 80 mg/L, temperature of 30 degrees C, pH of 7, a bacteria concentration of 15% (V/V), and shaking speed of 160 r/min. For P. pseudoaligenes, the maximum naphthalene removal rate was 77.4% under similar conditions but at 35 degrees C. PMID- 30427793 TI - Biosorption of zinc from aqueous solution by cyanobacterium Fischerella ambigua ISC67: optimization, kinetic, isotherm and thermodynamic studies. AB - In this present study, biosorption of Zn(II) from aqueous solution by cyanobacterium Fischerella ambigua was investigated in batch experiments. The effects of pH, bacterial dosage, initial Zn(II) concentration, contact time and temperature were studied. Removal process was influenced significantly by the variation of pH, biosorbent concentration, initial Zn(II) ion concentration, temperature and contact time. Optimum biosorption conditions were found to be initial pH of 5, bacterial dosage of 0.2 g/l and initial Zn(II) ion concentration of 175 mg/l at room temperature and contact time of 90 min. The maximum uptake capacity of F. ambigua for Zn(II) ions was found to be 98.03 mg/g at optimum conditions. The correlation coefficient for the second-order kinetic model was 0.995. The Freundlich isotherm model showed better fit to the equilibrium of the system, compared with the Langmuir model. Fourier transform infrared analysis of bacterial biomass revealed the presence of carboxyl, hydroxyl, sulfite and amino groups, which are likely responsible for the biosorption of Zn(II). The negative values of Gibbs free energy, DeltaG degrees , confirm the spontaneous nature of the biosorption process. Finally, F. ambigua adsorption capacity was compared with other biosorbents. Results showed that F. ambigua was an efficient biosorbent in the removal of Zn(II) ions from an aqueous solution. PMID- 30427794 TI - Study on the metabolites of DH-e, a Halomonas marine bacterium, against three toxic dinoflagellate species. AB - Algicidal bacteria play an important role in mitigating harmful algal blooms (HABs). In the study, five bacterial strains were isolated from the East China Sea. One strain of algicidal bacterium, named DH-e, was found to selectively inhibit the motor ability of Prorocentrum donghaiense, Alexandrium tamarense (ATDH-47) and Karenia mikimotoi Hansen. Both 16S rDNA sequence analysis and morphological characteristics revealed that the algicidal DH-e bacterium belonged to Halomonas. Furthermore, results showed that the metabolites in the DH-e cell free filtrate could kill algae directly, and the minimum inhibitory concentrations (MICs) of the bacterial metabolites on the cells of the three dinoflagellate species ranged from 35.0-70.0 MUg/mL. Following short-term inhibitory tests, the dinoflagellates in mixed crude extract solution (0.7 mg/mL) ceased movement after 5 min. The algicidal mechanism of the metabolites was investigated through enzyme activities, including that of catalase (CAT), alkaline phosphatase (AKP), acetone peroxide (T-ATP) synthetase and nitrite reductase (NR). Results indicated that metabolites did not disrupt the energy or nutrient routes of the algae (P > 0.05), but did initiate an increase in free radicals in the algal cells, which might explain the subsequent death of sensitive algae. Thus, the metabolites of the DH-e bacterium showed promising potential for controlling HABs. PMID- 30427795 TI - Enhancing sludge dewatering and heavy metal removal by bioleaching with Na2S2O3 as substrates. AB - Bioleaching has been demonstrated to be an effective technology for the removal of heavy metals and sludge dewaterability. Since bacteria gain nutrients by diffusion of soluble compounds, the insolubility of elemental sulfur may slow the growth of bacteria. Thus, it is very important to find an energy substance quickly become available to Acidithiobacillus thiooxidans. This paper studies the improvement of sludge dewaterability and heavy metal removal with sodium thiosulfate as the source of energy for Acidithiobacillus thiooxidans. Through orthogonal experiments with specific resistance to filtration (SRF) as the target index, four factors (FeSO4 dosage, Na2S2O3 dosage, sludge reflux ratio and sludge moisture content) were identified to be the important influencing parameters. The optimal conditions were: FeSO4 dosage, 8 g/L; Na2S2O3 dosage, 1.5 g/L; sludge reflux ratio, 30%; sludge moisture content, 97%. Results indicated that the SRF of the sludge decreased from 9.89 * 1012 to 1.03 * 1011 m/kg. The removal efficiencies of heavy metals Cu, Zn, Pb and Cr could reach 83%, 78%, 31% and 38% within 3 days, respectively. These results confirm the potential of sodium thiosulfate as an alternative energy substance in bioleaching to improve sludge dewaterability as well as removal of metals. PMID- 30427796 TI - Nutrient recycling from the effluent of a decentralized anaerobic membrane bioreactor (AnMBR) treating fresh domestic wastewater by cultivation of the microalgae Acutodesmus obliquus. AB - This study investigates the feasibility of microalgae cultivation with the effluent (permeate) of a decentralized anaerobic membrane bioreactor (AnMBR) treating high strength domestic wastewater. Two experiments, consisting of three and two successive batch experiments with incubation times varying between 5 and 9 days, were conducted. Nutrient removal and growth of the microalgae species Acutodesmus obliquus were studied for the following culture media: (A) permeate, (B) permeate enriched with iron (Fe), magnesium (Mg), manganese (Mn), sulfur (S) and the chelating agent EDTA, (C) commercial fertilizer as control culture. Initial nutrient concentrations in the culture media ranged from 9.3 to 16.6 mg.L 1 total phosphorus (TP) and from 85.1 to 126.2 mg.L-1 total nitrogen (TN). TP reached an average removal of 97%, 98% and 99% in (A), (B) and (C) respectively. An average TN removal of 94% and 96% was achieved in (B) and (C). Starting from the third batch of the first experiment and the second batch of the second experiment, the culture with permeate (A) showed a decrease in TN removal. Further batch experiments showed the need to add iron to ensure an optimal TN removal from the permeate. PMID- 30427797 TI - Novel biofilm reactor for denitrification of municipal wastewater. AB - A pilot-scale CFIC(r) (continuous flow intermittent cleaning) reactor was run in anoxic conditions to study denitrification of wastewater. The CFIC process has already proven its capabilities for biological oxygen demand removal with a small footprint, less energy consumption and low cost. The present study focused on the applicability for denitrification. Both pre-denitrification (pre-DN) and post denitrification (post-DN) were tested. A mixture of primary treated wastewater and nitrified wastewater was used for pre-DN and nitrified wastewater with ethanol as a carbon source was used for post-DN. The pre-DN process was carbon limited and removal rates of only 0.16 to 0.74 g NOx-N/m2-d were obtained. With post-DN and an external carbon source, 0.68 to 2.2 g NO3-Neq/m2-d removal rates were obtained. The carrier bed functioned as a good filter for both the larger particles coming with influent water and the bio-solids produced in the reactor. Total suspended solids removal in the reactor varied from 20% to 78% (average 45%) during post-DN testing period and 9% to 70% (average 29%) for pre-DN. The results showed that the forward flow washing improves both the DN function and filtration ability of the reactor. PMID- 30427798 TI - Anomalocardia brasiliana shellfish shells as a novel and ecofriendly adsorbent of Nylosan Brilliant Blue acid dye. AB - Malacoculture waste (Anomalocardia brasiliana) shellfish shells (ABSS) were evaluated as adsorbents of Nylosan Brilliant Blue (NBB) acid dye. The ABSS were thermally activated at 1,000 degrees C for 10 h and then characterized by Fourier-transform infrared spectroscopy, analysis of specific surface area (BET), X-ray diffraction (XRD), and scanning electron microscopy. Point of zero charge (PZC) analysis of ABSS verified pHPZC 13.0. The study of kinetics showed that the pseudo-second-order model fit the experimental data best and the system reached equilibrium within 5 min. Adsorption isotherms followed the Langmuir-Freundlich isotherm and ABSS reached an outstanding maximum adsorption capacity of 405 mg.g 1 under the following optimum conditions: pH 12.4, 303 K, 450 rpm, 2.0 g of adsorbent, and 150 MUm average particle size. These conditions were obtained after a previous statistical analysis of the variables. Enthalpy and Gibbs energy obtained in the thermodynamics experiments were -23.79 kJ.mol-1 and -4.07 kJ.mol 1, respectively. These parameters confirm that the process is exothermic, spontaneous, and indicative of the physical nature of the adsorption. The adsorption of NBB onto ABSS tended to be more favorable at a lower temperature. Low value of enthalpy suggested that weak binding forces, such as electrostatic interactions, govern the sorption mechanism. ABSS high availability in the environment, its low toxicity and high efficiency make it a promising ecofriendly adsorbent of textile dyes. PMID- 30427799 TI - Mitigating peak pressure of storm geysering by orifice plates installed at the top of vent pipes. AB - Large air pockets can be trapped in storm sewer systems during intense rain events. Uncontrolled release of these air pockets may cause geysering and pressure surges, resulting in flooding, pipe failures and safety issues. Thus, there is a great need to develop methods to retrofit existing sewer systems and to provide guidance on system design. A large-scale physical model was established to evaluate air-control orifice plates in reducing geysering intensity by utilizing air cushion effects over the process of air escape. Experimental results indicate that the magnitude of pressure fluctuations can be reduced significantly with partially open vent pipes. The maximum pressure head can be reduced by approximately two-thirds, and the magnitude of relative pressure oscillation decreased by about 95% when the diameter ratio of the air control orifice to the vent pipe is below 25%. Air-water mixture jets can be avoided in such cases. The effect of using multiple vent pipes with orifice plates was also evaluated and found to be effective. Thus, air-control vent pipes can be applied to alleviate geysering and related pressure transients. PMID- 30427800 TI - Primary sedimentation as a sustainability measure for newly built municipal wastewater treatment plants: too expensive? AB - A study was performed based on the design of a new wastewater treatment plant (WWTP) to be built in Weesp, The Netherlands (about 46,000 Population Equivalents (PE)). The conventional activated sludge plant was considered among the alternatives, with and without primary sedimentation. This pre-treatment technique is considered a sustainability measure as it improves the energy balance of the WWTP. However, at the same time, the question arose about the cost effectiveness of this measure. The scope of the study was to assess whether other sustainability measures (like solar panels) can realise the same level of sustainability with lower costs. The outcome of the study indeed shows that, for a new WWTP, it is considerably cheaper to avoid primary sedimentation and focus on other measures like solar panels instead. This appeared not only to be the case for the scale of WWTP Weesp, but also for WWTPs with capacities higher than 500,000 PE. For existing WWTPs with primary sedimentation, the choice can be different as customisation is necessary. PMID- 30427801 TI - Efficient capture of phosphate from aqueous solution using acid activated akadama clay and mechanisms analysis. AB - In this study, akadama clay, a kind of volcano ash, was activated with sulfuric acid and then evaluated for the adsorption of phosphate from aqueous solution via batch experiments. The effects of adsorbent dose, initial pH and coexisting anions on phosphate removal by natural akadama clay and acid-activated akadama clay were investigated. Based on the pH effect, the modified adsorbent could efficiently capture phosphate over a wider pH range of 3.00-6.00 than natural akadama clay. Competitive anions showed negative effects on the phosphate adsorption, especially citrate and carbonate. The adsorption process followed the pseudo-second-order kinetic equation and the intra-particle diffusion. Langmuir isotherm model was found to fit the data better than Freundlich model, and the maximum adsorption capacities of phosphate onto the natural akadama clay and acid activated akadama clay were 5.88 and 9.19 mg/g, respectively. Furthermore, thermodynamic studies confirmed that the adsorption of acid-activated akadama clay was a spontaneous process. The mechanisms of phosphate adsorption on the clay could be ascribed to electrostatic attraction and ligand exchange. These results suggest that after modification, acid-activated akadama clay could be used as a promising adsorbent for phosphate removal from wastewater in real application and then further used as fertilizers. PMID- 30427802 TI - Sodium hydroxide modified rice husk for enhanced removal of copper ions. AB - Although rice husk (RH) is a readily available, natural, heavy metal adsorbent, adsorption capacity in its natural form is insufficient for certain heavy metal ions. In this context, the study is based on enhancement of the adsorption capacity of RH for Cu(II). NaOH modified rice husk (SRH) shows higher extent of removal for Cu(II) ions than that of heated rice husk (HRH) and HNO3 modified rice husk (NRH). The extent of removal of SRH is increased with the concentration of NaOH, and the optimum NaOH concentration is 0.2 mol dm-3, used to modify rice husk for further studies. The surface area of SRH is 215 m2 g-1, which is twice as much as that of HRH according to previous studies. The sorption of Cu(II) on SRH obeys the Langmuir adsorption model, leading to the maximum adsorption capacity of 1.19 * 104 mg kg-1. Kinetics studies show that the interaction of Cu(II) with SRH obeys pseudo second order kinetics. The X-ray fluorescence spectroscopy confirms the adsorption of Cu(II) on SRH, while desorption studies confirm that Cu(II) adsorbed on SRH does not leach it back to water under normal conditions. PMID- 30427803 TI - Corrigendum: Water Science and Technology 77 (4), 871-879: Separate As(V) from solution by mesoporous Y-Al binary oxide: batch experiments, Hang Liu, Caiyun Han, Liu Yang, Dekun Liu and Yongming Luo. PMID- 30427804 TI - Predicting Suicide. PMID- 30427805 TI - Visual Attention Affects the Amplitude of the Transcranial Magnetic Stimulation associated Motor-evoked Potential: A Preliminary Study With Clinical Utility. AB - BACKGROUND: The transcranial magnetic stimulation (TMS)-elicited motor-evoked potential (MEP) is a valuable measure for clinical evaluations of various neurological disorders and is used to determine resting motor threshold for repetitive TMS dosing. Although MEP amplitude is primarily associated with motor system function, there is evidence that nonmotor factors may also influence amplitude. This experiment tested the hypotheses that manipulation of 2 factors (visual attention, cognitive regulation) in human participants would significantly affect MEP amplitude. METHODS: Blocks of MEPs were recorded from the dominant right hand as participants (N=20) were instructed to shift their visual attention (toward and away from the hand) and cognitively regulate the MEPs (rest, attenuate MEP amplitude, potentiate MEP amplitude) using their thoughts (6 blocks, 20 pulses/block, randomized, 110% resting motor threshold). RESULTS: MEP amplitude was significantly affected by the direction of visual attention; looking away from the hand led to higher amplitudes (P=0.003). The relationship with cognitive regulation was nonsignificant. CONCLUSIONS: The significant effect of visual attention on MEP suggests that this should be a standardized parameter in clinical and research studies. These data underscore the importance of rigorous reporting of methods and use of standardized practices for MEP acquisition and TMS dosing to ensure consistent clinical measurement and treatment. PMID- 30427806 TI - Scientific Evidence for the Evaluation of Neurological Soft Signs as Atypical Neurodevelopment Markers in Childhood Neuropsychiatric Disorders. AB - Motor dysfunction is commonly present in children with neurodevelopmental disorders. Developmental changes in voluntary control of motor skills include improvements in speed and motor coordination as well as reduced frequency of neurological soft signs (NSS) that are commonly observed in typically developing younger children. NSS are motor and sensory conditions that cannot be linked to specific cerebral lesions. The persistence of NSS into later childhood and adolescence is linked with an increased risk of psychiatric disorders. This finding gives support to the neurodevelopmental model of NSS in which minor neurological impairments may be viewed as potential signs of deviant brain development and might represent trait markers of vulnerability for neurodevelopmental disorders. Given that NSS are easily detectable, it is important that clinicians increase their knowledge of the clinical presentation and research implications of the relationship between NSS and childhood neurodevelopmental disorders. To the best of our knowledge, this is the first review article to give an updated overview of the current knowledge of NSS in the most common neuropsychiatric disorders of childhood/adolescence, such as attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, bipolar disorder, and first episode of psychosis. The article also presents key points for future research studies on this topic. PMID- 30427807 TI - The Developmental Profile Inventory: Constructing a Clinically Useful Self-Report for Levels of Psychodynamic Personality Functioning. AB - OBJECTIVE: The Developmental Profile Inventory (DPI) was constructed to assess psychodynamic personality functioning by self-report. METHOD: On the basis of the frame of reference of the Development Profile interview method, a self-report was developed covering 3 domains, self, interpersonal functioning, and problem solving strategies, which represent 6 maladaptive and 3 adaptive developmental levels of psychodynamic functioning. The DPI was administered to patients with personality disorders who were receiving psychotherapy (N=179) and to normal controls (N=228). RESULTS: The internal reliabilities of the subscales were in general in the fair to good range in the patient sample, (alpha=0.67 to 0.88, omegah=0.52 to 0.87) and adequate to good in the healthy controls (alpha=0.71 to 0.91, omegah=0.71 to 0.90). Mean item-rest correlations were adequate (0.30 to 0.50). Test-retest reliability was good (intraclass correlation=0.73 to 0.91). The hypothesized factorial structure of the DPI with 9 subscales organized in 3 clusters was partly confirmed by confirmatory factor analysis chi/df=2.37, root mean square error of approximation=0.060, root mean residual square=0.078, and comparative fit index=0.630, with each factor showing over 80% standardized loadings >0.30, and at least 75% loadings >0.40. The DPI discriminated patients and healthy controls in a meaningful way. Correlations among the DPI and other self-report measures of global personality pathology and psychological complaints showed satisfactory convergent and discriminant validity. CONCLUSIONS: The DPI is a promising self-report measure for assessing both adaptive and maladaptive patterns of psychodynamic personality functioning. The appropriate initial psychometric properties justify proceeding with more formal tests of construct validity and predictive performance in broader mental health settings. PMID- 30427808 TI - Religious Activity, Psychotic Features, and Suicidality in 688 Acute Psychiatric Inpatients. AB - BACKGROUND: Religiosity has been linked to mental health outcomes for decades. This study examined the potential relationship between religiosity and demographic and clinical variables in a sample of psychiatric inpatients. METHODS: In total, 688 adults admitted to an acute psychiatric facility with a primary mood or psychotic disorder completed the Duke University Religion Index (DUREL). The DUREL measures religious activity in 3 domains: organizational religious activity (ORA), nonorganizational religious activity (NORA), and intrinsic (or subjective) religiosity (IR). We categorized scores into high and low religiosity. Bivariate analyses with chi and independent sample t tests were used to examine the association between the DUREL subscales and demographic, clinical, and outcome measures. A generalized linear model was used to identify predictors of suicidality, psychosis, and 30-day rehospitalization. RESULTS: Elevated religious activity was common in the inpatient sample, with 58% categorized as high IR, 43% as high NORA, and 36% as high ORA. For all 3 DUREL subscales, high religiosity scores were associated with significantly more psychosis (P<0.05) and significantly less suicidal ideation (P<0.001). High ORA (P=0.001) and high IR (P=0.01) were associated with significantly fewer suicide attempts. High ORA scores were also associated with an increased length of stay (P<0.05) and more frequent 30-day readmission rates (P=0.01). In the generalized linear model, predictors of lower levels of suicidality were high ORA, high IR, and a diagnosis of schizophrenia, schizoaffective disorder, or other psychotic disorder, whereas a diagnosis of depressive disorder was associated with greater suicidality. Predictors of psychosis were high IR and Hispanic ethnicity, whereas a diagnosis of depressive disorder was associated with lower rates of psychosis. Female inpatients were more likely than male inpatients to score high on the ORA (P<0.05), NORA (P<0.05), and IR (P<0.0001) subscales. In addition, a significant relationship was detected between age and high IR scores (P<0.005), with increasing age associated with higher IR scores. CONCLUSIONS: Although preliminary, these results suggest that a brief measure of religiosity may provide important information concerning clinical features and acute outcomes in patients hospitalized with serious mental illness. PMID- 30427809 TI - Drug-drug Interactions in Psychiatric Practice, Part 1: Reasons, Importance, and Strategies to Avoid and Recognize Them. AB - This column begins a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. As explained in this column, this topic is important for multiple reasons. First, a large percentage of the population is receiving psychiatric medications. Second, these patients are likely to be on multiple medications which means that they are at risk for an adverse DDI. Third, DDIs may occur but not be recognized even though they have significant health care consequences for the patient. Fourth, these consequences can range from a catastrophic outcome to more everyday clinical problems involving a myriad of presentations as enumerated in this column. Also discussed in this column is the fact that all drugs, including psychiatric medications, interact on the basis of their pharmacodynamics and pharmacokinetics rather than their therapeutic use. Therefore, psychiatric medications may interact with medications prescribed for nonpsychiatric reasons as well as with other psychiatric medications. Tables are included that explain reasons for multiple medication use and principles to follow to minimize the risk of adverse DDIs. PMID- 30427810 TI - Rural Assertive Community Treatment and Telepsychiatry. AB - Assertive community treatment (ACT) is an evidence-based treatment for patients with severe and persistent mental illness. ACT has been shown to reduce inpatient hospitalization and is increasingly being used as a mainstay of evidence-based psychiatric practice for these clinical populations. The increasing implementation of evidence-based practices has led to the expansion of ACT in rural areas. Variability in the adaptation of ACT in rural areas has included accommodation by teams to multiple barriers. One way to increase psychiatric professional efficiency in rural areas is with telepsychiatry and possibly with rural ACT, but with unknown effects on fidelity and outcomes. Telepsychiatry has been considered a means of expanding the reach of and access to ACT. Concerns about the use of telepsychiatry by ACT teams include the psychiatrist's ability to develop a relationship with patients and staff and difficulties observing the patient's entire living environment via telemedicine. The Piedmont Community Services Board (CSB) Program for Assertive Community Treatment (PACT) serves patients in southwestern Virginia in collaboration with the Virginia Tech Carilion School of Medicine. The Piedmont CSB PACT uses telemedicine to expand the treating psychiatrist's reach and contact with PACT patients, increasing the efficiency of the psychiatrist's PACT time. Telemedicine is used for crisis intervention and augmentation of regular ongoing visits. The goals of this project were to measure patient, staff, and psychiatrist comfort and satisfaction with the use of telepsychiatry in ACT in addition to monitoring routine outcome measures. PMID- 30427811 TI - Whether Called Acute Suicidal Affective Disturbance or Suicide Crisis Syndrome, a Suicide-specific Diagnosis Would Enhance Clinical Care, Increase Patient Safety, and Mitigate Clinician Liability. AB - Separate research groups have independently argued the need for a suicide specific diagnosis within the psychiatric diagnostic nomenclature. Although a suicide-specific diagnosis could possibly enhance clinical care and improve patient safety, some clinicians have expressed concerns regarding the legal risk of utilizing a suicide-specific diagnosis. In this column, the first of a 2-part series exploring the potential risks and benefits of a suicide-specific diagnosis, the authors draw from their decades of experience in clinical work, legal consulting, as well as the litigation of suicide and wrongful death lawsuits and contend that the bona fide use of a suicide-specific diagnosis would mitigate legal liability to clinicians. PMID- 30427812 TI - Is Ketamine the Future Clozapine for Depression? A Case Series and Literature Review on Maintenance Ketamine in Treatment-resistant Depression With Suicidal Behavior. AB - Ketamine has shown effectiveness as a rapid-acting antidepressant with antisuicidal effects in terms of reduction of suicidal ideation in the short term. However, the evidence for long-term maintenance ketamine therapy for treatment-resistant depression (TRD) and suicidal behavior is limited. This case series (N=13) highlights the role of adjunctive serial maintenance ketamine infusions in restoring functionality in treatment-resistant unipolar and bipolar (mixed) depression with significant suicide risk and multiple comorbidities, including alcohol dependence. Two cases of TRD achieved functional remission with long-term maintenance ketamine treatment. The first case illustrates the potential synergistic interaction between ketamine and lamotrigine to achieve a sustained antidepressant response in the patient for 7 months. The second case may possibly be the longest reported case of maintenance ketamine therapy, with treatment continuing for 5 years to date. Ketamine treatment showed acute effectiveness in another 7 cases, especially in terms of reduction of suicidal ideation, albeit without significant long-term antidepressant effect. Factors that may contribute to lack of effectiveness of serial ketamine include inadequate mood stabilization in TRD in bipolar spectrum diagnoses, concomitant benzodiazepine use, complex comorbidities, and adverse effects such as significant hypertension and severe dissociation. Future systematic controlled studies are warranted to establish the efficacy and safety profile of long-term ketamine as maintenance therapy for TRD with suicidal behavior. PMID- 30427813 TI - Treatment of Comorbid Adult Attention-deficit/Hyperactivity Disorder and Generalized Anxiety Disorder: 2 Case Reports. AB - Attention-deficit/hyperactivity disorder (ADHD) is often comorbid with anxiety disorders such as generalized anxiety disorder, but the best approach to treat this comorbidity in adults has yet to be determined, as current evidence on which disorder should be treated first is poor and conflicting. In this report, we present 1 case in which we treated adult ADHD first and 1 case in which we treated generalized anxiety disorder before prescribing any medication for ADHD. More studies are required on this topic, but our results suggest that treating anxiety disorders until a clear reduction of anxiety symptoms is observed, or at least taking a combined treatment approach, is more appropriate than treating adult ADHD alone and waiting for a reduction in anxiety symptoms as a secondary effect. PMID- 30427814 TI - Trauma Does Not Predict Patients' Experiences With Constant Observation. AB - OBJECTIVE: Little is known about which patient factors are associated with a positive or negative experience of constant observation (CO) in a general hospital or emergency department. We hypothesized that posttraumatic stress disorder (PTSD) would predict a more negative experience with CO. METHODS: A survey regarding the positive and negative aspects of being observed by a staff member was administered to 83 patients who were admitted to an inpatient psychiatric unit after experiencing CO; 55 of these patients had a history of trauma and 13 were diagnosed with PTSD. A total score reflecting the overall positive or negative experience of CO was calculated for each survey response. The survey also included 4 follow-up questions regarding the importance of individual observer characteristics (eg, sex), which were scored individually along a Likert scale. RESULTS: Neither PTSD, trauma history, nor any other participant characteristic was associated with either a positive or negative overall experience with CO. Female participants were more likely than males to consider the sex and age of their staff observers to be important. CONCLUSIONS: Neither PTSD nor trauma history predicts a negative or positive experience with CO. A predictive model regarding which patients are likely to experience CO positively or negatively remains to be established. PMID- 30427815 TI - Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis: Retraction. PMID- 30427816 TI - Attachment. PMID- 30427817 TI - PTSD Symptom Severity, but Not Trauma Type, Predicts Mental Health Help-seeking in the Military. AB - OBJECTIVE: Although veterans with posttraumatic stress disorder (PTSD) have been reported to have high rates of inadequate treatment, to our knowledge this is the first study to evaluate associations between each individual PTSD symptom and treatment-seeking, and the first PTSD help-seeking study to evaluate variables across all-rather than specific-types of trauma. METHODS: This case-control study surveyed a consecutive sample of active duty military outpatients with trauma histories (N=211), comparing those attending voluntary mental health services (help-seeking cases, n=128) or mandatory dental services required for all active duty personnel (general military population controls, n=83). We used logistic regression to estimate associations between help-seeking and demographics, PTSD symptoms, trauma type, suicide attempts, substance use problems, and chronic pain, with each variable adjusted for sex, age, and race. RESULTS: Significant associations were found between help-seeking and PTSD diagnosis (adjusted odds ratio=4.15, P<0.001) and between help-seeking and severities of PTSD symptoms (total, clusters, all individual symptoms except recklessness; each adjusted odds ratio>1, P<0.05). CONCLUSIONS: In this clinical sample, a clear positive relationship was found between help-seeking and PTSD symptom severity, but not with trauma type, suicide attempts, substance use problems, or pain, after adjusting for multiple testing. Possible explanations and implications of these findings are discussed. PMID- 30427818 TI - Thiamine Prescribing and Wernicke's Encephalopathy Risk Factors in Patients With Alcohol Use Disorders at a Psychiatric Hospital. AB - BACKGROUND: Alcohol use disorder (AUD) is the leading cause of thiamine deficiency and can lead to Wernicke's encephalopathy (WE). WE has a higher prevalence of development in patients with AUD, and current recommendations emphasize parenteral administration of thiamine. Our objective was to characterize thiamine utilization in patients with AUD who were prescribed thiamine and evaluate if those who received oral thiamine had risk factors for the development of WE. METHODS: This retrospective chart review enrolled adults admitted to a psychiatric hospital from October 2014 through September 2015 diagnosed with AUD as per the International Classification of Diseases, Ninth Edition (ICD-9). The cohort was divided on the basis of route of thiamine administration (nonparenteral vs. parenteral) and was then screened retrospectively for risk factors for WE. Descriptive data and measures of central tendency were utilized to assess the objectives. RESULTS: The majority of patients were white male individuals, with a mean age of 48 years. Of the 226 patients, 201 (89%) were prescribed oral thiamine. Of the first 100 patients who received oral thiamine, 36% had risk factors for WE, with the most common risk factor being malnutrition. A chi analysis revealed that WE risk factors did not influence route of thiamine administration (chi=2.148, df=1, P=0.143). No patients were diagnosed with WE during their admission; however, 8 patients received parenteral thiamine at a treatment dose indicated for WE. CONCLUSIONS: Parenteral thiamine is underutilized in patients with AUD and risk factors for WE. Education is needed to enhance thiamine prescribing and evaluation of risk factors for WE in this population. A thiamine prescribing protocol has been developed for further thiamine optimization. PMID- 30427819 TI - Diagnosis and Use of Psychotherapy Among Children and Adolescents Prescribed Antipsychotics. AB - OBJECTIVE: To examine the diagnoses, demographics, and prevalence of psychotherapy use among children and adolescents prescribed antipsychotics by psychiatric providers in a community setting. METHODS: Medical records from 1127 children aged 0 to 17 years who were prescribed antipsychotics in 2014-2015 at Pine Rest Christian Mental Health Services (PRCMHS) outpatient network were analyzed. Antipsychotics, diagnosis codes, demographics, and number of psychotherapy sessions during this time frame were analyzed using chi and logistic regression analyses. RESULTS: During this year, 50.8% of the patients attended psychotherapy, and 35.6% attended 5 or more sessions of psychotherapy. The most prevalent primary diagnosis was bipolar disorder (37.1%), followed by attention-deficit/hyperactivity disorder (19.7%). Females being treated with antipsychotics were significantly more likely to attend psychotherapy than their male peers (55.7% vs. 47.9%, P=0.01). In the fully adjusted models, patients with diagnoses of bipolar disorder or disorders first diagnosed in infancy, childhood, or adolescence were less than half as likely to attend psychotherapy as patients with depressive disorders, with adjusted odds ratios of 0.41 and 0.42, respectively. CONCLUSIONS: Approximately half of the child and adolescent patients prescribed antipsychotics in this community sample did not attend psychotherapy, and 39% of the patients did not have a diagnosis of bipolar disorder, psychotic disorder, or autistic disorder. PMID- 30427820 TI - A New Therapeutic Group To Help Women With Borderline Personality Disorder and Their Infants. AB - OBJECTIVES: Few treatments have been described to treat the population of women with borderline personality structure who present in a dysregulated state with their infants. Therefore, a new treatment program was developed for this target group. METHODS: A total of 45 women, who were identified clinically as meeting full or partial diagnostic criteria for borderline personality disorder (BPD) and having an infant younger than 3 years of age, were offered entry with their infant(s) into specialized dialectical behavior therapy groups, adapted to focus on parenting and the mother-infant relationship. Outcomes measured included maternal mood and anxiety, BPD functioning, parenting sense of competence, parental reflective functioning, and caregiver-infant interaction (CARE Index). Infants received high-quality child care while mothers attended each group, with dyadic reunions a further therapeutic focus each week. RESULTS: A total of 29 women who met clinical or self-report measures for BPD and were offered group therapy began the program, 21 (72%) of whom completed the 24-week group program, with complete premeasures and postmeasures available for 20 dyads. Of the 20 women, 15 met full diagnostic criteria for BPD and 5 met partial criteria. Significant improvements were noted in maternal mood, with positive changes on 2 subscales of the Parental Reflective Function Questionnaire (prementalizing and increased curiosity in mental states); significant reductions in anxiety and BPD symptomatology were also observed. Only a medium effect size was found for parenting sense of competence, and in smaller numbers of participants as this scale was introduced later. It should particularly be noted that 15 dyads showed substantial change on the CARE Index, indicating improvement in dyadic relationships. CONCLUSIONS: This innovative adaptation of mother-infant dialectical behavior therapy showed promising improvements in maternal BPD symptoms and caregiver-infant relationships. Given that the feasibility and safety of this method have been demonstrated, a more methodologically rigorous trial with further refinements appears warranted to help this troubled cohort of patients. PMID- 30427821 TI - Drug-Drug Interactions (DDIs) in Psychiatric Practice, Part 2: Strategies to Minimize Adverse Outcomes From Unintended DDIs. AB - This column is the second in a series exploring drug-drug interactions (DDIs) with a special emphasis on psychiatric medications. The first column in this series discussed why patients being treated with psychiatric medications are at increased risk for taking multiple medications and thus experiencing DDIs and how to recognize such DDIs, and strategies for avoiding them. This second column in the series discusses strategies for minimizing adverse outcomes from such unintended DDIs. Given the huge and rapidly increasing number of available prescription and over-the-counter medications as well as nutritional supplements, the author recommends that all prescribers develop a personal formulary of ~30 drugs that they use in everyday practice and with which they are intimately familiar. It is recommended that their knowledge of these drugs include both their generic and brand names (to avoid confusion leading to prescription of the wrong drugs), routinely used doses, pharmacokinetics including half-lives, pharmacodynamics including mechanism(s) of action and binding profile for specific receptors, adverse effect profiles, potential DDIs, and the evolving research literature on these agents. The author stresses the value of establishing a therapeutic alliance involving the patient and the people around him or her (eg, prescribers, family members, pharmacists, nurse practitioners, home health professionals, friends when appropriate) to promote the patient's understanding of and adherence to treatment. It is also important to establish a therapeutic goal with a specific time expectation (eg, reduction in depressive symptoms within 4 wk), after which the prescriber should discuss adherence with the patient and significant others, consider a dose adjustment, or discontinue the drug after an adequate therapeutic trial or the development of an adverse effect that outweighs any benefit the drug may be having. The author outlines major principles for avoiding adverse DDIs and includes a table of online resources that provide information concerning different types of DDIs. The column ends with a discussion of limitations of currently available drug alert software programs and information on how and where to report adverse drug reactions. PMID- 30427822 TI - Emerging Psychotherapies for Psychosis. AB - Recent developments in the research and clinical literatures have highlighted the importance of focusing on higher-order cognitive processes in the treatment of psychotic disorders. A particular emphasis has been placed on how impairments in self-monitoring and the ability to form mental representations of others uniquely manifest in psychosis. At the same time, the recovery movement has influenced clinical innovations by emphasizing the importance of subjective domains of recovery that privilege the individual's phenomenological experience. In this column, we outline 2 emerging approaches to the treatment of psychosis, Metacognitive Reflection and Insight Therapy and Mentalization-based Therapy for Psychosis, highlighting the ways that each approach targets higher-order cognitive processes as a focused point of intervention, while maintaining a collaborative treatment approach that values the patient's agency. PMID- 30427823 TI - The Potential Perils of a Suicide-specific Diagnosis. AB - The clinical and scientific challenges inherent in treating and investigating suicide warrant novel approaches to this public health issue of paramount importance. The implementation of suicide-specific diagnoses has been proposed as one possible way to address this problem and was described in the first column of this special 2-part series. This second column explores potential unintended consequences related to such proposed diagnoses and alternative solutions that might afford greater benefits. The idea of suicide-specific diagnoses represents a novel approach, and one worthy of further discussion and consideration; the debate featured in this series represents a joint effort to advance the dialogue about suicide and to promote innovation. PMID- 30427824 TI - Paranoid Syndrome as the First Sign of Central Neurocytoma: A Case Report. AB - Central neurocytoma (CN), first described in 1982 by Hassoun and colleagues, is a rare tumor accounting for 0.25% to 0.5% of all tumors of the central nervous system. The tumor is a neoplasm of neuroepithelial origin, with intermediate malignancy (WHO grade II), detectable with both computed tomography and magnetic resonance imaging. Complete excision of the tumor gives favorable long-term results, with infrequent recurrences and/or metastases. Only 3 previous cases in which CN presented with co-occurring psychotic symptoms were found in the PubMed database. This report presents the case of a 27-year-old patient with paranoid syndrome without neurological symptoms, in whom magnetic resonance imaging confirmed a large intracranial tumor located predominantly in the right lateral ventricle and third ventricle reaching down to the hypothalamus. Resection of the tumor (histopathologically a CN) resulted in complete remission of the psychotic symptoms. This case supports the need for neuroimaging in all patients with first episode psychosis because of the possibility of neurologically silent brain tumors. Quick diagnosis in such cases is crucial for the selection of treatment methods and prognosis. PMID- 30427825 TI - Complex PTSD in ICD-11: A Case Report on a New Diagnosis. AB - The World Health Organization (WHO) has included complex post-traumatic stress disorder (C-PTSD) in the final draft of the 11th edition of the International Statistical Classification of Diseases and Related Health Problems (ICD-11), which was published in June, 2018 and is scheduled to be submitted to WHO's World Health Assembly for official endorsement in 2019. Mental health providers will want to be informed about this diagnosis in order to provide effective treatment. Complex PTSD, or developmental PTSD as it is also called, refers to the constellation of symptoms that may result from prolonged, chronic exposure to traumatic experiences, especially in childhood, as opposed to PTSD which is more typically associated with a discrete traumatic incident or set of traumatic events. Although it has been a controversial diagnosis and is not included in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM 5), lines of evidence support its distinct profile and utility. In this case study, we elucidate and discuss some aspects of the diagnosis and its treatment. PMID- 30427826 TI - High Expression of KIF22/Kinesin-Like DNA Binding Protein (Kid) as a Poor Prognostic Factor in Prostate Cancer Patients. AB - BACKGROUND Kid (kinesin-like DNA binding protein), a member of microtubule dependent molecular motor proteins, also known as KIF22, is reported to be associated with carcinogenesis and cancer progression in different types of malignant tumor, but the biologic behavior and clinical outcome of KIF22 in prostate cancer (PCa) has not been well studied. This study aimed to analyze the association between KIF22 and clinical outcome in PCa patients. MATERIAL AND METHODS The expression of KIF22 in tumor specimens compared with paired paracancerous tissue from 114 patients undergoing radical prostatectomy was detected by immunohistochemistry; results were verified using The Cancer Genome Atlas (TCGA) database. Subsequently, the relationship between KIF22 expression and clinical prognosis of PCa patients was then statistically analyzed. RESULTS Both immunohistochemistry and database analysis showed that KIF22 was obviously overexpressed in PCa tissues compared with paracancerous tissue. The overexpression of KIF22 at the protein level was significantly related to higher clinical stage (P=0.025), Gleason score (P=0.002), seminal vesicle invasion (P=0.007), and lymph node metastasis (P=0.009). Furthermore, with the overexpression of KIF22 mRNA level in PCa patients, the oncological prognosis of PCa patients was much poorer. CONCLUSIONS High-level expression of KIF22 was related to both tumor progression and adverse clinical outcome. For this reason, KIF22 may become a potential prognostic factor for PCa. PMID- 30427827 TI - Conditional mutagenesis by oligonucleotide-mediated integration of loxP sites in zebrafish. AB - Many eukaryotic genes play essential roles in multiple biological processes in several different tissues. Conditional mutants are needed to analyze genes with such pleiotropic functions. In vertebrates, conditional gene inactivation has only been feasible in the mouse, leaving other model systems to rely on surrogate experimental approaches such as overexpression of dominant negative proteins and antisense-based tools. Here, we have developed a simple and straightforward method to integrate loxP sequences at specific sites in the zebrafish genome using the CRISPR/Cas9 technology and oligonucleotide templates for homology directed repair. We engineered conditional (floxed) mutants of tbx20 and fleer, and demonstrate excision of exons flanked by loxP sites using tamoxifen-inducible CreERT2 recombinase. To demonstrate broad applicability of our method, we also integrated loxP sites into two additional genes, aldh1a2 and tcf21. The ease of this approach will further expand the use of zebrafish to study various aspects of vertebrate biology, especially post-embryonic processes such as regeneration. PMID- 30427828 TI - Intramembrane ionic protein-lipid interaction regulates integrin structure and function. AB - Protein transmembrane domains (TMDs) are generally hydrophobic, but our bioinformatics analysis shows that many TMDs contain basic residues at terminal regions. Physiological functions of these membrane-snorkeling basic residues are largely unclear. Here, we show that a membrane-snorkeling Lys residue in integrin alphaLbeta2 (also known as lymphocyte function-associated antigen 1 [LFA-1]) regulates transmembrane heterodimer formation and integrin adhesion through ionic interplay with acidic phospholipids and calcium ions (Ca2+) in T cells. The amino group of the conserved Lys ionically interacts with the phosphate group of acidic phospholipids to stabilize alphaLbeta2 transmembrane association, thus keeping the integrin at low-affinity conformation. Intracellular Ca2+ uses its charge to directly disrupt this ionic interaction, leading to the transmembrane separation and the subsequent extracellular domain extension to increase adhesion activity. This Ca2+-mediated regulation is independent on the canonical Ca2+ signaling or integrin inside-out signaling. Our work therefore showcases the importance of intramembrane ionic protein-lipid interaction and provides a new mechanism of integrin activation. PMID- 30427830 TI - On-going transmission of human onchocerciasis in the Massangam health district in the West Region of Cameroon: Better understanding transmission dynamics to inform changes in programmatic interventions. AB - BACKGROUND: Massangam health district (HD), in the West Region of Cameroon, has received ivermectin mass drug administration (MDA) for 20 years, however there is evidence of continued high transmission of Onchocerca volvulus. In order to better understand the transmission dynamics in the HD and inform intervention strategies there is a need to delineate the boundaries of the suspected area of high transmission within the wider transmission zone. METHODOLOGY/PRINCIPAL FINDINGS: Parasitological and entomological surveys were conducted to map out the breeding sites of Simulium damnosum and evaluate the prevalence of onchocerciasis in neighbouring communities, including Makouopsap sentinel community. Potential rapids were prospected for identification of S. damnosum larvae and black flies collected to determine infectivity rates. Adults were assessed for the presence of O. volvulus microfilariae through a skin snip biopsy and examined for the presence of nodules. Anti Ov-16 antibodies were tested for in children. Four perennial breeding sites were identified on the Rivers Mbam and Nja. Large number of flies were collected along the River Mbam, especially in the rainy season, with up to 955 flies per day, suggesting this river is a perennial source of black flies. A total of 0.8% of parous flies were infective across the study area. Parasitological studies provided evidence of high rates of infection in the sentinel community and three neighbouring communities, with 37.1% of adults microfilariae positive in Makouopsap. High Ov-16 seropositivity in children also provided evidence of recent on-going transmission. In comparison, communities sampled further away from the sentinel community and neighbouring breeding sites were much closer to reaching onchocerciasis elimination targets. CONCLUSIONS/SIGNIFICANCE: This study provides evidence of a particular geographic area of high transmission in an approximate 12 km range around the sentinel community of Makouopsap and the neighbouring breeding sites on the River Nja. To eliminate onchocerciasis by 2025, there is a need to explore alternative intervention strategies in this area of high transmission. PMID- 30427829 TI - First-in-human randomized controlled trial of an oral, replicating adenovirus 26 vector vaccine for HIV-1. AB - BACKGROUND: Live, attenuated viral vectors that express HIV-1 antigens are being investigated as an approach to generating durable immune responses against HIV-1 in humans. We recently developed a replication-competent, highly attenuated Ad26 vector that expresses mosaic HIV-1 Env (rcAd26.MOS1.HIV-Env, "rcAd26"). Here we present the results of a first-in-human, placebo-controlled clinical trial to test the safety, immunogenicity and mucosal shedding of rcAd26 given orally. METHODS: Healthy adults were randomly assigned to receive a single oral dose of vaccine or placebo at 5:1 ratio in a dosage escalation of 10^8 to 10^11 rcAd26 VP (nominal doses) at University of Rochester Medical Center, Rochester, NY, USA. Participants were isolated and monitored for reactogenicity for 10 days post vaccination, and adverse events were recorded up to day 112. Rectal and oropharyngeal secretions were evaluated for shedding of the vaccine. Humoral and cellular immune responses were measured. Household contacts were monitored for secondary vaccine transmission. RESULTS: We enrolled 22 participants and 11 household contacts between February 7 and June 24, 2015. 18 participants received one dose of HIV-1 vaccine and 4 participants received placebo. The vaccine caused only mild to moderate adverse events. No vaccine-related SAEs were observed. No infectious rcAd26 viral particles were detected in rectal or oropharyngeal secretions from any participant. Env-specific ELISA and ELISPOT responses were undetectable. No household contacts developed vaccine-induced HIV-1 seropositivity or vaccine-associated illness. CONCLUSIONS: The highly attenuated rcAd26.MOS1.HIV-Env vaccine was well tolerated up to 10^11 VP in healthy, HIV-1 uninfected adults, though the single dose was poorly immunogenic suggesting the replicative capacity of the vector was too attenuated. There was no evidence of shedding of infectious virus or secondary vaccine transmission following the isolation period. These data suggest the use of less attenuated viral vectors in future studies of live, oral HIV-1 vaccines. TRIAL REGISTRATION: ClinicalTrials.gov NCT02366013. PMID- 30427831 TI - Identifying riparian climate corridors to inform climate adaptation planning. AB - Riparian habitats have been frequently identified as priority areas for conservation under climate change because they span climatic gradients and have cool, moist microclimates relative to surrounding areas. They are therefore expected to act as dispersal corridors for climate-induced species range shifts and to provide microclimatic refugia from warming. Despite recognition of these values, rigorous methods to identify which riparian areas are most likely to facilitate range shifts and provide refugia are currently lacking. We completed a novel analysis across the Pacific Northwest, USA, that identifies potential riparian corridors featuring characteristics expected to enhance their ability to facilitate range shifts and provide refugia. These features include large temperature gradients, high canopy cover, large relative width, low exposure to solar radiation, and low levels of human modification. These variables were used to calculate a riparian climate-corridor index using a multi-scale approach that incorporates results ranging in scale from local watersheds to the entire Pacific Northwest. Resulting index values for potential riparian corridors in the Pacific Northwest were highest within mountainous areas and lowest within relatively flat, lowland regions. We also calculated index values within ecoregions, to better identify high-value riparian climate corridors within the relatively flat, degraded areas where they may most contribute to climate adaptation. We found that high-value riparian climate-corridors are least protected in flat, lowland areas, suggesting that such corridors should be high priorities for future conservation effort. Our analysis provides critical information on valuable riparian climate-corridors to guide climate adaptation efforts (and riparian management and restoration efforts) in the Pacific Northwest, while offering a novel approach that may be applied to similar efforts in other geographies. PMID- 30427832 TI - Synthetic STARR-seq reveals how DNA shape and sequence modulate transcriptional output and noise. AB - The binding of transcription factors to short recognition sequences plays a pivotal role in controlling the expression of genes. The sequence and shape characteristics of binding sites influence DNA binding specificity and have also been implicated in modulating the activity of transcription factors downstream of binding. To quantitatively assess the transcriptional activity of tens of thousands of designed synthetic sites in parallel, we developed a synthetic version of STARR-seq (synSTARR-seq). We used the approach to systematically analyze how variations in the recognition sequence of the glucocorticoid receptor (GR) affect transcriptional regulation. Our approach resulted in the identification of a novel highly active functional GR binding sequence and revealed that sequence variation both within and flanking GR's core binding site can modulate GR activity without apparent changes in DNA binding affinity. Notably, we found that the sequence composition of variants with similar activity profiles was highly diverse. In contrast, groups of variants with similar activity profiles showed specific DNA shape characteristics indicating that DNA shape may be a better predictor of activity than DNA sequence. Finally, using single cell experiments with individual enhancer variants, we obtained clues indicating that the architecture of the response element can independently tune expression mean and cell-to cell variability in gene expression (noise). Together, our studies establish synSTARR as a powerful method to systematically study how DNA sequence and shape modulate transcriptional output and noise. PMID- 30427833 TI - Continuing evidence of Chagas disease along the Texas-Mexico border. AB - BACKGROUND: Chagas disease is a chronic parasitic infection that progresses to dilated cardiomyopathy in 30% of human cases. Public health efforts target diagnosing asymptomatic cases, as therapeutic efficacy diminishes as irreversible tissue damage progresses. Physician diagnosis of Chagas disease cases in the United States is low, partially due to lack of awareness of the potential burden in the United States. METHODOLOGY/PRINCIPAL FINDINGS: The current study tested a patient cohort of 1,196 Starr County, Texas residents using the Hemagen Chagas ELISA Kit as a preliminary screening assay. Samples testing positive using the Hemagen test were subjected to additional confirmatory tests. Two patients (0.17%) without previous Chagas disease diagnosis were identified; both had evidence of acquiring disease in the United States or along the Texas-Mexico border. CONCLUSIONS/SIGNIFICANCE: The Texas-Mexico border is a foci of Chagas disease human cases, with a local disease burden potentially twice the national estimate of Hispanic populations. It is imperative that physicians consider persons with residential histories along the Texas-Mexico border for Chagas disease testing. PMID- 30427834 TI - The effect of early life conditions on song traits in male dippers (Cinclus cinclus). AB - Song complexity and singing frequency in male birds are shaped by female choice; they signal male quality because song is costly to develop and produce. The timing of song learning and the development of the brain structures involved occur during a period when chicks are exposed to a number of potential stressors. The quality and quantity of song produced by adults may therefore reflect the level of stress experienced during early life, a theory known as the 'developmental stress hypothesis'. We tested this hypothesis using song recordings and life-history data from an individually marked, long-term study population of wild dippers (Cinclus cinclus). The extent to which early life conditions predict adult song traits was investigated using natal brood size as a measure of sibling competition; the rate of provisioning by parents as a proxy for nutritional stress; and residuals of the linear regression between body mass and tarsus length as a measure of nestling condition. The syllable diversity in the songs of adult males was positively correlated with their body condition as nestlings, but there was no significant correlation with either provisioning rate or brood size. Provisioning rate did, however, predict song rate; males in relatively poor condition as nestlings or those raised in smaller broods which were fed more frequently by their parents sang at a higher rate in adulthood. These results support the developmental stress hypothesis and provide some of the first evidence from a wild bird of how the conditions experienced during early life impact adult song. Song traits may therefore provide females with information regarding both the current condition and developmental history of males. PMID- 30427835 TI - Emergence of online communities: Empirical evidence and theory. AB - Online communities, which have become an integral part of the day-to-day life of people and organizations, exhibit much diversity in both size and activity level; some communities grow to a massive scale and thrive, whereas others remain small, and even wither. In spite of the important role of these proliferating communities, there is limited empirical evidence that identifies the dominant factors underlying their dynamics. Using data collected from seven large online platforms, we observe a relationship between online community size and its activity which generally repeats itself across platforms: First, in most platforms, three distinct activity regimes exist-one of low-activity and two of high-activity. Further, we find a sharp activity phase transition at a critical community size that marks the shift between the first and the second regime in six out of the seven online platforms. Essentially, we argue that it is around this critical size that sustainable interactive communities emerge. The third activity regime occurs above a higher characteristic size in which community activity reaches and remains at a constant and higher level. We find that there is variance in the steepness of the slope of the second regime, that leads to the third regime of saturation, but that the third regime is exhibited in six of the seven online platforms. We propose that the sharp activity phase transition and the regime structure stem from the branching property of online interactions. PMID- 30427837 TI - Removal of adult subconjunctival Loa loa amongst urban dwellers in Nigeria. AB - Loiasis is a neglected tropical disease caused by infection with the filarial parasite Loa loa. It is a disease considered by many to be benign. Several reports of trans border importation of the Loa loa worm amongst immigrants and visitors from endemic regions of the world exist. In most cases an adult subconjunctival worm is removed from the patient. An interventional case series is reported and examines the practice of removal of subconjunctival adult Loa loa worms amongst urban dwellers in Nigeria. Four cases of ocular loiasis seen amongst urban dwellers in Nigeria exemplify the different presentations and removal methods of the subconjunctival adult worm. There were 2 males and 2 females aged 35years, 23years, 25years and 30years respectively. Each patient gave a history of having been raised in a rural community in childhood years, during which they were exposed to streams and muddy farm land; and then migrated to the urban community in later years. They all present with the finding of a subconjunctival adult worm, which was successfully removed and identified to be Loa loa. There are more urban dwellers in Nigeria who present with symptoms of foreign body sensation that may be related to the manifestation of a subconjunctival worm and are not recognized. This is because the emphasis on this disease has erstwhile been on the rural, village dwellers and not on urban dwellers. Eye care practitioners working in urban centers need to be aware of the possibility of this presentation, and be ready to remove any subconjunctival worm when it presents. PMID- 30427836 TI - The kinetics of gut microbial community composition in patients with irritable bowel syndrome following fecal microbiota transplantation. AB - BACKGROUND: Gut microbiota alterations are important in irritable bowel syndrome (IBS). The aim was to investigate the effect of fecal microbiota transplantation (FMT) on gut microbiota and the symptoms in patients with IBS. MATERIAL AND METHODS: The study included 13 IBS patients according to Rome III criteria and 13 healthy donors. Freshly donated feces were administered to the descending part of the duodenum via a gastroscope. Feces were collected from donors and patients before FMT, and from the patients at 1, 3 and 12 weeks and donors and patients at 20/28 weeks after FMT. Microbiota analysis was performed using GA-map Dysbiosis test (Genetic Analysis AS, Oslo, Norway). The patients completed the following questionnaires before and at the aforementioned weeks after FMT: IBS Symptom Questionnaire (IBS-SQ), IBS-Symptom Severity Scoring system (IBS-SSS), Short Form of Nepean Dyspepsia Index (SF-NDI), Bristol stool form scale, the Eysenck Personality Questionnaire-Neuroticism and Hospital Anxiety and Depression. RESULTS: Donors and IBS patients had significantly different bacterial strain signals before FMT (Ruminococcus gnavus, Actinobacteria and Bifidobacteria) that became non-significant after 3 weeks following FMT. The changes in gut microbiota were similar between donors and patients at 20/28 weeks after FMT. Thus, patients' microbiota profiles became more-or-less similar to donors. The scores of all the questionnaires were significantly improved at all time points following FMT. No reported adverse effects. CONCLUSIONS: FMT was associated with a change in gut microbiota and improvement in IBS symptoms and quality of life lasting for up to 28 weeks. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03333291. PMID- 30427838 TI - Diffusion spectrum imaging in white matter microstructure in subjects with type 2 diabetes. AB - This study aimed to investigate the feasibility and clinical applicability of Diffusion Spectrum Imaging (DSI) for quantitative detection of white matter microstructural integrity. Twenty-seven patients with type 2 diabetes mellitus (T2DM; aged 60.6+/-7.6 years) and 21 healthy controls (HC; aged 56.1+/-7.8 years) underwent high-resolution T1-weighted imaging and DSI scanning. Cognitive function scores were obtained using such instruments as the Montreal Cognitive Assessment (MoCA). The fasting blood glucose, glycated hemoglobin, and total cholesterol (CHO) of T2DM were measured. The bilateral uncinate fasciculus and superior cingulum bundle were reconstructed by DSI tractography. Statistical analysis was performed using SPSS 21.0 software and P<0.05 was considered significant. Generalized fractional anisotropy (GFA) values were significantly decreased in the left uncinate fasciculus (t = -2.915, p = 0.005) and right superior cingulum bundle (t = -2.604, p = 0.012) in T2DM patients compared with the healthy controls (p<0.05). The MoCA (t = -3.339, p = 0.002) and CDT (t = 3.039, p = 0.004) scores of T2DM were significantly lower than those of healthy controls. Meanwhile, the GFA value of the right superior cingulum bundle was negatively associated with VFT score (r = -0.475, p = 0.012), and that of the right superior cingulum bundle was negatively associated with blood CHO level (r = -0.458, p = 0.016). DSI tractography is capable of evaluating the microstructural integrity of the white matter bundle in T2DM and is related to clinical cognitive scores and related biochemical indices; therefore, it can help to predict early white matter abnormalities in T2DM. PMID- 30427839 TI - Automated high-throughput light-sheet fluorescence microscopy of larval zebrafish. AB - Light sheet fluorescence microscopy enables fast, minimally phototoxic, three dimensional imaging of live specimens, but is currently limited by low throughput and tedious sample preparation. Here, we describe an automated high-throughput light sheet fluorescence microscope in which specimens are positioned by and imaged within a fluidic system integrated with the sheet excitation and detection optics. We demonstrate the ability of the instrument to rapidly examine live specimens with minimal manual intervention by imaging fluorescent neutrophils over a nearly 0.3 mm3 volume in dozens of larval zebrafish. In addition to revealing considerable inter-individual variability in neutrophil number, known previously from labor-intensive methods, three-dimensional imaging allows assessment of the correlation between the bulk measure of total cellular fluorescence and the spatially resolved measure of actual neutrophil number per animal. We suggest that our simple experimental design should considerably expand the scope and impact of light sheet imaging in the life sciences. PMID- 30427840 TI - Comparison of techniques to control the aggressive environmental invasive species Galenia pubescens in a degraded grassland reserve, Victoria, Australia. AB - Across many southern regions of Australia, native grasslands have become seriously threatened by human activity, with only a fraction of the original areas remaining undisturbed. In particular, the introduction and establishment of exotic invasive weeds has caused significant degradation to the ecosystems in these areas by contributing to a decrease in native plant density and diversity, and this has ultimately led to major changes to the ecosystem structure and function. One such example is Galenia pubescens. Our objective of this study was to assess the effectiveness of four different attempts to control G. pubescens: herbicide control with glyphosate; organic herbicide control with pine oil; the application of mulch; and the addition of seeds of native species to the seedbank. Results shows that any one single control strategy is insufficient to control G. pubescens, and, in addition, it has shown that regeneration of native vegetation is limited unless direct seeding is applied. There was a strong indication that a combined strategy employing more than two of the aforementioned techniques is likely to be the most effective approach, at least in the short term. Underscoring the complexity of this task, our analysis on foliage cover of G. pubescens shows that the interaction of pine oil and glyphosate treatments appeared to be very effective after six months, but were not so effective after 18 months. By contrast, seeding with native seeds was not particularly effective at six months, but its longer-term contribution appears to be effective at 18 months. Further, our results obtained from the seedbank abundance study indicate that time alone was not a significant factor in restoration of the grasslands (p = 0.165); however there were interactions with time, shown by time*glyphosate (p = 0.008) and time*seeding (p = 0.016). Both interactions indicated that the applications of glyphosate and seeding were more beneficial after 18 months compared to six months. However, full regeneration of invaded native grasslands may not be possible unless further restoration programs are re-implemented after the first cycle of G. pubescens' treatments have been completed. PMID- 30427842 TI - Design and compatibility analysis of a solar panel integrated UHF antenna for nanosatellite space mission. AB - A compact UHF antenna has been presented in this paper for nanosatellite space mission. A square ground plane with slotted rectangular radiating element have been used. Coaxial probe feeding is used to excite. The rectangular slot of the radiating patch is responsible for resonating at lower UHF bands. One of the square faces of the nanosatellite structure works as the ground plane for the slotted radiating element. The fabricated prototype of the proposed antenna has achieved an impedance bandwidth (S11< -10dB) of 7.0 MHz (398 MHz- 405 MHz) with small size of 97 mm* 90 mm radiating element. The overall ground plane size is 100 mm * 100 mm * 0.5 mm. The proposed antenna has achieved a gain of 1.18 dB with total efficiency of 62.5%. The proposed antenna addresses two design challenges of nanosatellite antenna, (a) assurance of the placement of solar panel beneath the radiating element; (b) providing about 50% open space for solar irradiance to pass onto the solar panel, enabling the solar panel to achieve up to 93.95% of power under of normal conditions. PMID- 30427841 TI - Antagonizing the corticotropin releasing hormone receptor 1 with antalarmin reduces the progression of endometriosis. AB - Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding effective, non-hormonal and long-term treatments for endometriosis still remains one of the most significant challenges in the field. Corticotropin releasing hormone (CRH) is one of the main signaling peptides within the hypothalamic pituitary adrenal (HPA) axis released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of two types of CRH receptors: CRHR1 and CRHR2. Our aim was to determine if blocking CRHR1 with antalarmin will reduce endometriosis progression. In experiment 1 we induced endometriosis in female rats by suturing uterine horn tissue next to the intestinal mesentery and allowed to progress for 7 days. We determined that after 7 days, there was a significant increase in CRHR1 within endometriotic vesicles as compared to normal uterus. In Experiment 2, we induced endometriosis and administered either antalarmin (20 mg/kg, i.p.) or vehicle during the first 7 days after surgery. A separate group of sham surgery rats served as non-endometriosis controls. Endometriosis was allowed to progress until 60 days after surgery, at which time rats were tested for anxiety behaviors. At the time of sacrifice, endometriotic vesicles, uterus and blood were collected. Treatment with antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 mRNA within endometriotic vesicles but not of glucocorticoid receptor. Endometriosis did not change anxiety behaviors in the open field and zero-maze tests and prior antalarmin administration did not modify this. Our data provides the first in-vivo demonstration for use of CRHR1 antagonist for the treatment of endometriosis opening the possibility for further exploring CRH signaling as a treatment target for this debilitating disease. PMID- 30427843 TI - Gastroesophageal reflux disease in an area with low Helicobacter pylori infection prevalence. AB - The association between gastroesophageal reflux disease (GERD) prevalence and its risk factors in an area with low Helicobacter pylori prevalence is important to clarify. We analyzed the prevalence of GERD and risk factors in an area of Indonesia with low prevalence of H. pylori infection. We recruited 104 dyspeptic patients who underwent endoscopy in Surabaya. Patients were diagnosed with GERD based on the Los Angeles classification. We evaluated gastric biopsy specimens and measured serum pepsinogen levels. Interleukin polymorphisms were evaluated by polymerase chain reaction-restriction fragment length polymorphism. Of 104 patients, 56 (53.8%) were endoscopically found to have GERD, with most categorized as grade A; 48 (46.2%) were classified as non-GERD. Higher economic status, smoking, and a history of proton-pump inhibitor use significantly increased the risk of GERD. GERD Questionnaire scores showed a positive correlation with GERD (P < 0.001). An association was found between antral atrophic gastritis and GERD (P = 0.030), and patients with GERD more frequently had severe antral atrophy than nonerosive reflux disease (P = 0.018). We found an association between pepsinogen I/II levels and GERD (P = 0.047), but with low accuracy. IL-1beta -511 TT and CT were predominant among the IL-1beta -511 genotypes, and IL-8-251 AT and TT were predominant among the IL-8-251 genotypes. In conclusion, we found a high prevalence of GERD in an area with low prevalence of H. pylori infection, which could be associated with acid reflux. Smoking, history of proton-pump inhibitor use, and higher economic group significantly increased the risk of GERD. PMID- 30427844 TI - Aseptic loosening after total hip arthroplasty and the risk of cardiovascular disease: A nested case-control study. AB - BACKGROUND: Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation compared with controls. Our hypothesis is that this increased risk after total hip arthroplasty (THA) is mediated by development of periprosthetic osteolysis leading to aseptic loosening of the implant. METHODS: We conducted a nation-wide, nested, case-control study consisting of patients receiving a cemented THA due to osteoarthritis between the years 1992 and 2005. Our study population included a total of 14,430 subjects identified in the Swedish hip arthroplasty register and linked to the Swedish National Patient Register. The case group consisted of patients (n = 2,886) who underwent reoperation of the treated hip due to osteolysis or aseptic loosening at any time within five years after the index surgery. Each case was matched with four controls (n = 11,544) who had not undergone reoperation. The main outcomes were cardiovascular events i.e. myocardial infarction, heart failure and cerebral infarction according to ICD-codes and time to the first cardiovascular event during the exposure period. Outcomes were subgrouped into cardiac and cerebral events. We used regression models to calculate the incidence rates and adjusted our results for confounders. FINDINGS: Overall, 5.1% of patients had cardiac events, with slightly more overall cardiovascular events occurring in the control group (8.1% vs. 6.7%, odds ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0). After adjusting for confounders, the case group had an increased relative risk of 1.3 (95% confidence interval (CI) 1.1 to 1.3) for total number of cardiovascular events. Similar effect sizes were observed for time to first event. INTERPRETATION: Patients with osteoarthritis who received THA and subsequently underwent a revision operation due to loosening had a higher relative risk of developing cardiovascular events than controls. Thus there is an association which could be explained by a common inflammatory disease pathway that requires further experimental research. PMID- 30427845 TI - What are the financial barriers to medical care among the poor, the sick and the disabled in the Special Administrative Region of China? AB - Although Hong Kong is one of the richest cities in the world and has some of the best health outcomes such as long life expectancy, little is known about the people who are unable to access healthcare due to lack of financial means. Cross sectional data from a sample of 2,233 participants aged 18 or above was collected from the first wave of the "Trends and Implications of Poverty and Social Disadvantages in Hong Kong" survey. Socio-demographic factors, lifestyle factors, and physical and mental health conditions associated with people who were unable to seek medical services due to lack of financial means in the past year were examined using forward stepwise logistic regression analyses. Of the 2,233 participants surveyed, 8.4% did not seek medical care due to lack of financial means during the past year. They were more likely to be income-poor. With respect to physical and mental health, despite having less likelihood to have multimorbidity, they tended to have higher levels of both anxiety and stress, poorer physical and mental health-related quality of life, and suffer from more severe disability and pain symptoms affecting their daily activities, when compared to the rest of the Hong Kong population. People who were denied of medical care due to financial barriers are generally sicker than people in the general Hong Kong population, implying that those with greater healthcare needs may have financial difficulties in receiving timely and appropriate medical care. Our findings suggest that inequity in healthcare utilization remains a critical issue in Hong Kong. PMID- 30427846 TI - Tolerating tigers: Gaining local and spiritual perspectives on human-tiger interactions in Sumatra through rural community interviews. AB - Religious beliefs and spiritual connections to biodiversity have the potential to reduce animosity towards wildlife that might otherwise present a real or perceived threat to local people. Understanding this social dynamic can therefore be important for formulating locally-appropriate species-specific conservation strategies. Using semi-structured interviews which incorporated human-tiger conflict scenarios, we investigated how beliefs towards tigers varied between ethnic groups living around a large protected area that is home to the largest tiger population in Sumatra. We gathered this information to determine the degree to which cultural tolerance may contribute to the survival of the tiger in the Kerinci Seblat landscape, Indonesia. From 154 interviewees, 133 respondents came from three main ethnic groups, Minangkabau, Kerincinese and Melayu. The majority (73.5%) of Minangkabau interviewees cited that their ethnic group had customary laws regarding tigers, as did 52% of Melayu and 44% of Kerincinese. Irrespective of ethnicity, most participants did not perceive there to be a connection between Islam and tigers. All participants acknowledged the existence of zoological tigers and two groups (Minangkabau and Kerincinese) held a strong common belief that different types of spirit tigers also existed. From presenting different human-tiger conflict scenarios, with varying levels of severity towards livestock or human life, an unprovoked tiger attack in the village elicited the most calls for the tiger to be killed. Yet, if a village or family member was killed by a tiger whilst hunting in the forest then most respondents across all ethnic groups said to do nothing. The frequency of this response increased if a tiger killed someone in the village who had committed adultery, reflecting beliefs associated with the role of the tiger as an enforcer of moral rule. Our study highlights the importance of consulting with local communities who live in close proximity to large and potentially dangerous carnivores when developing conflict mitigation strategies, which hitherto has not been the case in Sumatra. PMID- 30427848 TI - Equality over intentionality: The normative social preferences of neutral third parties. AB - This paper studies whether intentionality is more prevalent than fairness in social preferences. We do this by introducing a new three-player game in which the choices of neutral third-party arbiters are isolated from any monetary or strategic concerns. This allows us to study the normative preferences of subjects, and to compare the relative weight they give to intentions and inequality. The results show that arbiters are mainly concerned with inequality, while other's (selfish) intentions seem to play a minor role in their preferences. This result is robust to a series of experimental designs, suggesting that the role of intentions in social preferences might be smaller than implied by the previous literature. PMID- 30427847 TI - Genome-wide identification and functional prediction of tobacco lncRNAs responsive to root-knot nematode stress. AB - Root-knot nematodes (RKNs, Meloidogyne spp.) are destructive plant parasites with a wide host range. They severely reduce crop quality and yield worldwide. Tobacco is a versatile model plant organism for studying RKNs-host interactions and a key plant material for molecular research. Long noncoding RNAs (lncRNAs) play critical roles in post transcriptional and transcriptional regulation in a wide range of biological pathways, especially plant development and stress response. In the present study, we obtained 5,206 high-confidence lncRNAs based on RNA sequencing data. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the target genes of these lncRNAs are mainly involved in plant biotic and abiotic stresses, plant hormone signal transduction, induced systemic resistance, plant-type hypersensitive response, plant-type cell wall organization or biogenesis. The 565 differentially expressed lncRNAs found to be involved in nematode stress response were validated by quantitative PCR using 15 randomly-selected lncRNA genes. Our study provides insights into the molecular mechanisms of RKNs-plant interactions that might help preventing nematode damages to crops. PMID- 30427850 TI - Hygienic behaviour selection via freeze-killed honey bee brood not associated with chalkbrood resistance in eastern Australia. AB - Hygienic behaviour is a social immune response in honey bees shown to help provide resistance to honey bee pests and diseases. A survey of hygienic behaviour and brood diseases was conducted on 649 colonies in eastern Australia to initiate a selective breeding program targeting disease resistance and provide a level of resistance to Varroa (Varroa destructor Anderson and Trueman and V. jacobsoni Oudemans) mites should they become established in Australia. The test population showed a remarkably high baseline level of hygienic behaviour with 17% of colonies meeting or exceeding breeding selection thresholds. Colonies belonging to a breeding program were 5.8 times more likely to be highly hygienic and colonies headed by queens raised from hygienic queen mothers were 2.2 times more likely. Nectar availability (nectar yielding flowering plants within honey bee forage range) influenced hygienic behaviour expression but was not a significant predictor of level of hygienic behaviour. Surprisingly, hygienic behaviour was not a significant predictor of the presence of infection of the honey bee brood disease chalkbrood (Ascosphaera apis) and was not influential in predicting severity of chalkbrood infection in surveyed honey bee colonies. This study, along with reports from commercial beekeepers that chalkbrood infection is on the rise, warrants a deeper exploration of the host-pathogen relationship between Apis mellifera and Ascosphaera apis in Australia. PMID- 30427849 TI - Microscopic picture of water-ethylene glycol interaction near a model DNA by computer simulation: Concentration dependence, structure, and localized thermodynamics. AB - It is known that crowded molecular environment affects the structure, thermodynamics, and dynamics of macromolecules. Most of the previous works on molecular crowding have majorly focused on the behavior of the macromolecule with less emphasis on the behavior of the crowder and water molecules. In the current study, we have precisely focused on the behavior of the crowder, (ethylene glycol (EG)), salt ions, and water in the presence of a DNA with the increase of the EG concentration. We have probed the behavior of water and crowder using molecular dynamics (MD) simulation and by calculating localized thermodynamic properties. Our results show an interesting competition between EG and water molecules to make hydrogen bonds (H-bond) with DNA. Although the total number of H-bonds involving DNA with both EG and water remains essentially same irrespective of the increase in EG concentration, there is a proportional change in the H-bonding pattern between water-water, EG-EG, and EG-water near DNA and in bulk. At low concentrations of EG, the displacement of water molecules near DNA is relatively easy. However, the displacement of water becomes more difficult as the concentration of EG increases. The density of Na+ (Cl-) near DNA increases (decreases) as the concentration of EG is increased. The density of Cl- near Na+ increases with the increase in EG concentration. It was also found that the average free energy per water in the first solvation shell increases with the increase in EG concentration. Putting all these together, a microscopic picture of EG, water, salt interaction in the presence of DNA, as a function of EG concentration, has emerged. PMID- 30427851 TI - Factors in healthcare violence in care of pregnancy termination cases: A case study. AB - BACKGROUND: Workplace violence is a widely-reported phenomenon among healthcare providers and negatively affects quality of care and treatment. This study aims to understand the potential factors related to HCV through the experiences of women who have undergone a pregnancy termination due to fetal anomaly. METHODS: Qualitative interview was used to collect data in this case study. Forty-one pregnant women who decided to terminate their pregnancy due to fetal anomaly were recruited from four Chinese hospital facilities, including three general hospitals and one specialty hospital in Changsha, Hunan, China. In-depth interviews were conducted from May to September 2017. Content analysis was used to analyze the data. RESULTS: Several potential factors related to violence in healthcare facilities were identified, including preventive factors, which possibly relieve healthcare violence; and negative experiences, which potentially related to healthcare violence. Preventive factors include healthcare providers gaining patient trust with detailed observation, expressing patient-centered care through discreet behavior, and showing patience and professionalism. Factors related to violence include busy work schedules, hurried visits, mechanized process, patients' scant medical knowledge and mental distress. CONCLUSIONS: This study highlights potential factors related to healthcare violence. The results will be submitted to the Chinese government's policy making department in order to improve the healthcare system. We also suggest several important strategies to prevent HCV in a healthcare setting, both in China and globally. PMID- 30427852 TI - The gill-associated microbiome is the main source of wood plant polysaccharide hydrolases and secondary metabolite gene clusters in the mangrove shipworm Neoteredo reynei. AB - Teredinidae are a family of highly adapted wood-feeding and wood-boring bivalves, commonly known as shipworms, whose evolution is linked to the acquisition of cellulolytic gammaproteobacterial symbionts harbored in bacteriocytes within the gills. In the present work we applied metagenomics to characterize microbiomes of the gills and digestive tract of Neoteredo reynei, a mangrove-adapted shipworm species found over a large range of the Brazilian coast. Comparative metagenomics grouped the gill symbiont community of different N. reynei specimens, indicating closely related bacterial types are shared. Similarly, the intestine and digestive gland communities were related, yet were more diverse than and showed no overlap with the gill community. Annotation of assembled metagenomic contigs revealed that the gill symbiotic community of N. reynei encodes a plethora of plant cell wall polysaccharides degrading glycoside hydrolase encoding genes, and Biosynthetic Gene Clusters (BGCs). In contrast, the digestive tract microbiomes seem to play little role in wood digestion and secondary metabolites biosynthesis. Metagenome binning recovered the nearly complete genome sequences of two symbiotic Teredinibacter strains from the gills, a representative of Teredinibacter turnerae "clade I" strain, and a yet to be cultivated Teredinibacter sp. type. These Teredinibacter genomes, as well as un-binned gill derived gammaproteobacteria contigs, also include an endo-beta-1,4 xylanase/acetylxylan esterase multi-catalytic carbohydrate-active enzyme, and a trans-acyltransferase polyketide synthase (trans-AT PKS) gene cluster with the gene cassette for generating beta-branching on complex polyketides. Finally, we use multivariate analyses to show that the secondary metabolome from the genomes of Teredinibacter representatives, including genomes binned from N. reynei gills' metagenomes presented herein, stands out within the Cellvibrionaceae family by size, and enrichments for polyketide, nonribosomal peptide and hybrid BGCs. Results presented here add to the growing characterization of shipworm symbiotic microbiomes and indicate that the N. reynei gill gammaproteobacterial community is a prolific source of biotechnologically relevant enzymes for wood-digestion and bioactive compounds production. PMID- 30427854 TI - Effects of lowering inspiratory oxygen fraction during microvascular decompression on postoperative gas exchange: A pre-post study. AB - BACKGROUND: Despite many previous studies, the optimal oxygen fraction during general anesthesia remains controversial. This study aimed to evaluate the effects of lowering intraoperative fraction of inspired oxygen on postoperative gas exchange in patients undergoing microvascular decompression (MVD). METHODS: We conducted a pre-post study to compare postoperative gas exchange with different intraoperative oxygen fractions. From April 2010 to June 2017, 1456 consecutive patients who underwent MVD were enrolled. Starting in January 2014, routine oxygen fraction was lowered from 1.0 to 0.3 during anesthetic induction/awakening and from 0.5 to 0.3 during anesthetic maintenance. Postoperative gas exchange, presented as the minimum value of PaO2/FIO2 ratio within 48 hours, were compared along with adverse events. RESULTS: Among 1456 patients, 623 (42.8%) patients were stratified into group H (high FIO2) and 833 (57.2%) patients into group L (low FIO2). Intraoperative positive end-expiratory pressure was used in 126 (15.1%) patients in group H and 90 (14.4%) patients in group L (p = 0.77).The minimum value of PaO2/ FIO2 ratio within 48 hours after surgery was significantly greater in the group L (226.13 vs. 323.12; p < 0.001) without increasing any adverse events. CONCLUSION: In patients undergoing MVD, lowering routine FIO2 and avoiding 100% O2 improved postoperative gas exchange. PMID- 30427853 TI - Reducing Wallacean shortfalls for the coralsnakes of the Micrurus lemniscatus species complex: Present and future distributions under a changing climate. AB - South American coralsnakes are characterized by inconspicuous and poorly known species, which are potentially very sensitive to climate change. Here, we assess the impact of future climate change on the distributions of the Micrurus lemniscatus species complex after addressing the Wallacean shortfalls and refining the knowledge about their current geographic distributions. We also evaluate the efficiency of the current reserve network to protect the species in the present and future. We applied ecological niche model tools through a carefully examined set of occurrence records to generate potential present distributions and to project these distributions into future scenarios of climate change. Specific thresholds based on occurrence records along with expert opinions were used to delineate the geographic distribution of each species. A hierarchical ANOVA was applied to evaluate the uncertainties in species distributions across niche modeling methods and climate models and nested into the time factor (present and future). Multiple regression models were used to infer the relative importance of the climatic variables to determine the species' suitability. A gap analysis was performed to address the representativeness of species distributions into protected areas. Predicted geographic distributions were compatible with the known distributions and the expert opinions, except for M. l. carvalhoi. New areas for field research were identified. Variation in precipitation was the most important factor defining the habitat suitability for all species, except for M. diutius. All taxa (except M. l. lemniscatus) will shrink their distributions in the future; less than 50% of the present suitable areas are protected in reserve networks, and less than 40% of these areas will be held in reserves in the future. We found strong evidence that coralsnakes may be highly sensitive to the ongoing changes and must be protected. PMID- 30427855 TI - Uncertainty and depressive symptoms as mediators of quality of life in patients with heart failure. AB - Uncertainty in illness is regarded as a source of stress in many chronic diseases and is negatively related to health-related quality of life (HRQoL). However, studies on the relationship between uncertainty and HRQoL in patients with heart failure are limited. This study used Mishel's theory of uncertainty in illness to investigate the mediating role of uncertainty in illness and depressive symptoms between symptom distress and HRQoL in patients with heart failure. This study used a cross-sectional correlation design. Participants were recruited by convenience sampling from outpatient services and medical wards of cardiology departments of a medical center in northern Taiwan. Data were collected for uncertainty, depressive symptoms, symptoms distress of heart failure, and HRQoL using self-report questionnaires. Demographics and clinical characteristics were analyzed with descriptive statistics. The mutual effects of disease characteristics, symptom distress, uncertainty in illness, depressive symptoms and HRQoL, as well as the overall model fitness, were analyzed by with structural equation modeling. We collected 147 qualified questionnaires. The mean score for the Mishel Uncertainty in Illness Scale for patients with heart failure was 73.5 (SD = 18.55); 65.3% of participants had a score of ?13 on the Beck Depressive Inventory-II, indicating mild depression. Uncertainty, depressive symptoms, and HRQoL were directly related to symptom distress. Symptom distress and depressive symptoms were both mediators between uncertainty and depressive symptoms. Depressive symptoms also mediated emotional support and HRQoL. Uncertainty and depressive symptoms were important factors in the pathway between symptom distress and HRQoL for heart failure patients. We suggest providing heart failure patients with tailored interventions for effective self-management of symptoms based on Mishel's theory of uncertainty in illness, which could help control disease symptoms, alleviate uncertainty and depression as well as improve HRQoL. PMID- 30427856 TI - How different are parents and educators? A comparative study of interactive differences between parents and educators in a collaborative adult-child activity. AB - Involving children in collaborative tasks supports their cognitive, motor and social development. This study, performed in Portugal, aims to describe and compare early childhood educators and parents regarding their collaborative and interactive behavior when working with children. For that purpose, 55 educators (of both genders) with a child from their class and 45 parents (of both genders) with their children, participated in an everyday-like quasi-experimental situation for 20 minutes. The participants were invited to build an object of their choice, using a range of available materials and tools. The children included 47 boys and 48 girls, between 3 and 5 year-old. In comparison with the parents, the educators encouraged the children more to explore and find their own solutions. Conversely, the parents helped their children by offering demonstrations and directions. When the educators and the parents were grouped by gender ("men" versus "women"), different opportunities were offered to boys and girls by male and female adults. Our study suggests that educators and parents serve as diverse, but complementary educational role models and provide different learning opportunities. PMID- 30427858 TI - Physical, social, and psychological characteristics of community-dwelling elderly Japanese dog and cat owners. AB - OBJECTIVES: Previous studies examined the physical characteristics of older dog owners. However, associations of health-related factors with dog/cat ownership have not been comprehensively evaluated. This cross-sectional study examined physical function, physical activity, social function, and psychological function of a population of community-dwelling older Japanese dog and cat owners after controlling for important confounders. METHODS: The analysis included data from 11,233 community-dwelling adults aged 65 years or older (51.5% women; 52.3% aged 75-84), in Ota City, Tokyo, Japan. Pet ownership experience and pet species owned were determined by self-reported questionnaire, and current, past, and never dog/cat ownership was analyzed. RESULTS: Analysis of variables related to physical function and physical activity showed that motor fitness scale and walking activity were significantly associated with experience of dog ownership, after adjustment for important sociodemographic and health characteristics. Analysis of social function showed that interaction with neighbors, social isolation, and trust in neighbors were significantly associated with experience of dog ownership and cat ownership. CONCLUSIONS: As compared with respondents with no history of pet ownership, motor fitness and walking activity are greater for dog owners and social function is higher for dog and cat owners. Caring for a dog or cat might be an effective health promotion strategy to increase physical activity and facilitate social participation among older adults. PMID- 30427857 TI - Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. AB - Previously, we showed that SAMM50, a mitochondrial outer membrane protein, is N myristoylated, and this lipid modification is required for the proper targeting of SAMM50 to mitochondria. In this study, we characterized protein N myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25, three of which are components of the mitochondrial intermembrane space bridging (MIB) complex, which plays a critical role in the structure and function of mitochondria. In vitro and in vivo metabolic labeling experiments revealed that all four of these proteins were N-myristoylated. Analysis of intracellular localization of wild-type and non-myristoylated G2A mutants of these proteins by immunofluorescence microscopic analysis and subcellular fractionation analysis indicated that protein N-myristoylation plays a critical role in mitochondrial targeting and membrane binding of two MIB components, SAMM50 and MIC19, but not those of TOMM40 and MIC25. Immunoprecipitation experiments using specific antibodies revealed that MIC19, but not MIC25, was a major N-myristoylated binding partner of SAMM50. Immunoprecipitation experiments using a stable transformant of MIC19 confirmed that protein N-myristoylation of MIC19 is required for the interaction between MIC19 and SAMM50, as reported previously. Thus, protein N-myristoylation occurring on two mitochondrial MIB components, SAMM50 and MIC19, plays a critical role in the mitochondrial targeting and protein-protein interaction between these two MIB components. PMID- 30427860 TI - Sow communication with piglets while being active is a good predictor of maternal skills, piglet survival and litter quality in three different breeds of domestic pigs (Sus scrofa domesticus). AB - Maternal care behaviour is crucial for offspring quality and survival in pigs. Defining care is therefore essential for ensuring the welfare of pigs and sustainability of pig production. The aim of the present study was to investigate the relationship between sow nest building, communication with piglets (sniffing, nudging, grunting) during resting and activity, and piglet survival in three different sow breeds: a maternal line selected for high weaned pig production (Landrace), a paternal line selected for meat traits (Duroc), and a crossbred line (Landrace and Yorkshire). We predicted that a higher frequency of nest building and sow communication would have a positive impact on piglet survival. Secondly, we predicted that a high level of maternal care outside the time of nursing (nest building and communication) would increase the quality of the litter (weight at weaning). We also predicted that nest building activity and sow communication would be more pronounced in maternal sow lines selected for maternal traits than in a non-selected, paternal line, and that primiparous sows would perform more nest building behaviour and communicate more than multiparous sows due to high investment in their first litter. Finally, an impaired condition around farrowing (i.e. low body condition score and presence of shoulder lesions) was predicted to be negatively correlated to care behaviours. Data was collected on 38 sows with 511 born piglets. Sows with their litters, were loose-housed in individual farrowing pens until weaning. Nest building activity can be partly considered as maternal care behaviour as it prepares the sows for motherhood and is associated with a lower proportion of stillborn piglets (P < 0.001), starved piglets (P = 0.004), and overlaid piglets (P = 0.034). As predicted, sows that communicated more while being active had lower postnatal piglet mortality (starvation (P < 0.001), less overlying (P < 0.001), overlying with (P < 0.001), and without the milk in the stomach (P < 0.001) and fewer that died of other causes (P < 0.001), higher piglet survival (P < 0.001) and litter weight (P < 0.001) at weaning irrespective of the breed. A higher level of communication while active was associated with more pronounced shoulder lesions in sows (P = 0.010), suggesting a positive association between good maternal care and prevalence of shoulder lesions. We also found that resting sows that communicated more with piglets outside the time of nursing, had higher postnatal piglet mortality (P < 0.001) due to starvation (P < 0.001), overlying (P < 0.001), overlying with (P < 0.001), or without milk (P < 0.001). Communication during resting was more pronounced with increasing litter size at birth (P < 0.001), especially for thin sows (P < 0.001). Communication during resting was more pronounced in the non-selected Duroc line (P < 0.001). Our results suggest that sow communication while being active is a good predictor of good maternal care, piglet survival and litter quality in three different breeds of domestic pigs. PMID- 30427859 TI - Differences in sperm protein abundance and carbonylation level in bull ejaculates of low and high quality. AB - In breeding and insemination centres, significant variation in bull ejaculate quality is often observed between individuals and also within the same individual. Low-quality semen does not qualify for cryopreservation and is rejected, generating economic loss. The mechanisms underlying the formation of low-quality ejaculates are poorly understood; therefore, the aim of the present study was to investigate the proteomic differences and oxidative modifications (measured as changes in protein carbonylation level) of bull ejaculates of low and high quality. Flow cytometry and computer-assisted sperm analysis were used to assess differences in viability, reactive oxygen species (ROS) level, and sperm motility. To analyse changes in protein abundance, two-dimensional difference gel electrophoresis (2D-DIGE) was performed. Western blotting in conjunction with two-dimensional electrophoresis (2D-oxyblot) was used to quantitate carbonylated sperm proteins. Proteins were identified using matrix assisted laser desorption/ionisation time-of-flight/time-of-flight spectrometry. High quality ejaculates were characterised by higher sperm motility, viability, concentration, and a lower number of ROS-positive cells (ROS+). We found significant differences in the protein profile between high- and low-quality ejaculates, and identified 14 protein spots corresponding to 10 proteins with differences in abundance. The identified sperm proteins were mainly associated with energetic metabolism, capacitation, fertilisation, motility, and cellular detoxification. High-quality ejaculates were characterised by a high abundance of extracellular sperm surface proteins, likely due to more efficient secretion from accessory sex glands and/or epididymis, and a low abundance of intracellular proteins. Our results show that sperm proteins in low-quality ejaculates are characterised by a high carbonylation level. Moreover, we identified, for the first time, 14 protein spots corresponding to 12 proteins with differences in carbonylation level between low- and high-quality ejaculates. The carbonylated proteins were localised mainly in mitochondria or their immediate surroundings. Oxidative damage to proteins in low-quality semen may be associated with phosphorylation/dephosphorylation disturbances, mitochondrial dysfunction, and motility apparatus disorders. Our results contribute to research regarding the mechanism by which low- and high-quality ejaculates are formed and to the identification of sperm proteins that are particularly sensitive to oxidative damage. PMID- 30427862 TI - Uncoupling protein-1 deficiency promotes brown adipose tissue inflammation and ER stress. AB - Inflammation and endoplasmic reticulum (ER) stress are hallmarks of metabolic syndrome. While these metabolic derangements have been well-investigated in white adipose tissue, their existence and etiology in brown adipose tissue (BAT) are poorly understood. Here, we aimed to investigate ER homeostasis and the inflammatory status and of BAT lacking uncoupling protein-1 (UCP1), a protein required for BAT thermogenesis. H&E staining illustrated lipid accumulation and crown-like structures surrounding adipocytes in BAT of UCP1-/- mice housed at room temperature compared to control mice. Further, immunohistological evaluation of F4/80 and gene expression studies demonstrated BAT macrophage infiltration and robust elevation of pro-inflammatory markers in UCP1-/- BAT. ER stress was also present in BAT of UCP1-/- mice, as evidenced by elevated gene expression and post translational modifications of unfolded protein response components. After four weeks of thermoneutral housing, UCP1-/- mice did not exhibit elevated BAT inflammation and ER stress gene expression compared to WT mice, but depot expansion persisted. Collectively, we demonstrate that the effects of UCP1 deficiency in BAT are not restricted to mitochondrial uncoupling. We conclude that brown adipose tissue of UCP1-/- mice exhibits pro-inflammatory immune cell infiltration and perturbations in ER homeostasis and that this phenotype is driven by cold exposure rather than lipid accumulation. PMID- 30427861 TI - Probing the ecological and evolutionary history of a thermophilic cyanobacterial population via statistical properties of its microdiversity. AB - Despite extensive DNA sequencing data derived from natural microbial communities, it remains a major challenge to identify the key evolutionary and ecological forces that shape microbial populations. We have focused on the extensive microdiversity of the cyanobacterium Synechococcus sp., which is a dominant member of the dense phototrophic biofilms in the hot springs of Yellowstone National Park. From deep amplicon sequencing of many loci and statistical analyses of these data, we showed previously that the population has undergone an unexpectedly high degree of homologous recombination, unlinking synonymous SNP pair correlations even on intragenic length scales. Here, we analyze the genic amino acid diversity, which provides new evidence of selection and insights into the evolutionary history of the population. Surprisingly, some features of the data, including the spectrum of distances between genic-alleles, appear consistent with primarily asexual neutral drift. Yet the non-synonymous site frequency spectrum has too large an excess of low-frequency polymorphisms to result from negative selection on deleterious mutations given the distribution of coalescent times that we infer. And our previous analyses showed that the population is not asexual. Taken together, these apparently contradictory data suggest that selection, epistasis, and hitchhiking all play essential roles in generating and stabilizing the diversity. We discuss these as well as potential roles of ecological niches at genomic and genic levels. From quantitative properties of the diversity and comparative genomic data, we infer aspects of the history and inter-spring dispersal of the meta-population since it was established in the Yellowstone Caldera. Our investigations illustrate the need for combining multiple types of sequencing data and quantitative statistical analyses to develop an understanding of microdiversity in natural microbial populations. PMID- 30427864 TI - Publications as predictors of racial and ethnic differences in NIH research awards. AB - This research expands efforts to understand differences in NIH funding associated with the self-identified race and ethnicity of applicants. We collected data from 2,397 NIH Biographical Sketches submitted between FY 2003 and 2006 as part of new NIH R01 Type 1 applications to obtain detailed information on the applicants' training and scholarly activities, including publications. Using these data, we examined the association between an NIH R01 applicant's race or ethnicity and the probability of receiving an R01 award. The applicant's publication history as reported in the NIH biographical sketch and the associated bibliometrics narrowed the black/white funding gap for new and experienced investigators in explanatory models. We found that black applicants reported fewer papers on their Biosketches, had fewer citations, and those that were reported appeared in journals with lower impact factors. Incorporating these measures in our models explained a substantial portion of the black/white funding gap. Although these predictors influence the funding gap, they do not fully address race/ethnicity differences in receiving a priority score. PMID- 30427863 TI - Generation of white-eyed Daphnia magna mutants lacking scarlet function. AB - The crustacean Daphnia magna is an important model in multi-disciplinary scientific fields such as genetics, evolutionary developmental biology, toxicology, and ecology. Recently, the draft genome sequence and transcriptome data became publicly available for this species. Genetic transformation has also been achieved via the introduction of plasmid DNA into the genome. The identification of a screenable marker gene and generation of mutant strains are essential to further advance D. magna functional genomics. Because crustaceans are closely related to insects, we hypothesized that, similar to Drosophila genetic studies, eye color-related genes can function as marker genes in Daphnia. We searched orthologs of Drosophila eye pigment transporters White, Scarlet, and Brown in the genome of D. magna. Amino acid sequence alignment and phylogenetic analysis suggested that D. magna has six white and one scarlet orthologs, but lacks the brown ortholog. Due to the multiplicity of white orthologs, we analyzed the function of the scarlet ortholog, DapmaSt, using RNA interference. DapmaSt RNAi embryos showed disappearance of black pigments both in the compound eye and in the ocellus, suggesting that DapmaSt is necessary for black pigmentation in Daphnia eyes. To disrupt DapmaSt using the Crispr/Cas9 system, we co-injected DapmaSt-targeting gRNAs with Cas9 mRNAs into eggs and established white-eyed DapmaSt mutant lines that lack eye pigments throughout their lifespan. Our results suggest that DapmaSt can be used as a transformation marker in D. magna and the DapmaSt mutants would be an important resource for genetic transformation of this species in the future. PMID- 30427865 TI - Gravitational stress during parabolic flights reduces the number of circulating innate and adaptive leukocyte subsets in human blood. AB - Gravitational stress occurs during space flights or certain physical activities including extreme sports, where the change in experienced gravitational acceleration can reach large magnitudes. These changes include reduction and increase in the physical forces experienced by the body and may potentially induce pathogenic alterations of physiological processes. The immune system is known to regulate most functions in the human organism and previous studies suggest an impairment of the immune function under gravitational stress. However, systematic studies aiming to investigate the effect of gravitational stress on cellular immune response in humans are lacking. Since parabolic flights are considered as feasible model to investigate a short-term impact of gravitational changes, we evaluated the influence of gravitational stress on the immune system by analyzing leukocyte numbers before and after parabolic flight maneuvers in human blood. To correct for circadian effects, samples were taken at the corresponding time points on ground the day before the flight. The parabolic flight maneuvers led to changes in numbers of different leukocyte subsets. Naive and memory T and B cell subsets decreased under gravitational stress and lower numbers of basophils and eosinophils were observed. Only circulating neutrophils increased during the parabolic flight. The observed changes could not be attributed to stress-induced cortisol effects, since cortisol levels were not affected. Our data demonstrate that the gravitational stress by parabolic flights can affect all parts of the human immune system. Consequently, it is possible that gravitational stress can have clinically relevant impacts on the control of immune responses. PMID- 30427867 TI - Host shift induces changes in mate choice of the seed predator Acanthoscelides obtectus via altered chemical signalling. AB - The mechanisms of host shift in phytophagous insects are poorly understood. Among the many proposed processes involved, sexual selection via semiochemicals has recently been suggested. This hypothesizes that sexual communication using pheromones is modified as a result of development on a new host, and such plant induced phenotypic divergence in mate recognition cues can lead to reproductive isolation between host lines. We tested this hypothesis on Acanthoscelides obtectus, an oligophagous bruchid of Phaseolus vulgaris beans worldwide, which also develops in acceptable non-hosts, such as chickpea (Cicer arietinum L.). Male sex pheromone blends of the bean, chickpea and chickpea/bean host lines during artificially induced host shifts showed different composition. Bean-reared females did not distinguish between blends, whereas chickpea and chickpea/bean females preferred the chickpea male pheromone. However, electrophysiological (EAG) responses to male odour of antennae of the three female host lines were similar, all preferring bean-reared males. Egg-laying choice tests revealed a uniform preference for bean seeds across female host lines, even after multiple generations, whereas larvae did not distinguish between bean and chickpea seeds. We conclude that the development of divergent chemical signalling systems during host shifts does not facilitate the evolution of host races in A. obtectus, because oviposition preferences remain unaffected. PMID- 30427866 TI - Does sex education before college protect students from sexual assault in college? AB - PURPOSE: College-bound young people experience sexual assault, both before and after they enter college. This study examines historical risk factors (experiences and exposures that occurred prior to college) for penetrative sexual assault (PSA) victimization since entering college. METHODS: A cross-sectional study, including an online population-based quantitiative survey with undergraduate students was conducted in spring 2016. Bivariate analyses and multivariable regressions examined risk and protective factors associated with ever experiencing PSA since entering college. Concurrently-collected in-depth ethnographic interviews with 151 students were reviewed for information related to factors identified in the survey. RESULTS: In bivariate analyses, multiple historical factors were significantly associated with PSA in college including adverse childhood experiences and having experienced unwanted sexual contact before college (for women) and initiation of alcohol, marijuana, and sexual behaviors before age 18. Significant independent risk factors for college PSA included female gender, experiencing unwanted sexual contact before college, first oral sex before age 18, and "hooking up" (e.g., causual sex or sex outside a committed partnership) in high school. Receipt of school-based sex education promoting refusal skills before age 18 was an independent protective factor; abstinence-only instruction was not. In the ethnographic interviews, students reported variable experiences with sex education before college; many reported it was awkward and poorly delivered. CONCLUSIONS: Multiple experiences and exposures prior to college influenced the risk of penetrative sexual assault in college. Pre-college comprehensive sexuality education, including skills-based training in refusing unwanted sex, may be an effective strategy for preventing sexual assault in college. Sexual assault prevention needs to begin earlier; successful prevention before college should complement prevention efforts once students enter college. PMID- 30427869 TI - The informative value of museum collections for ecology and conservation: A comparison with target sampling in the Brazilian Atlantic forest. AB - Since two decades the richness and potential of natural history collections (NHC) were rediscovered and emphasized, promoting a revolution in the access on data of species occurrence, and fostering the development of several disciplines. Nevertheless, due to their inherent erratic nature, NHC data are plagued by several biases. Understanding these biases is a major issue, particularly because ecological niche models (ENMs) are based on the assumption that data are not biased. Based on it, a recent body of research have focused on searching adequate methods for dealing with biased data and proposed the use of filters in geographical and environmental space. Although the strength of filtering in environmental space has been shown with virtual species, nothing has yet been tested with a real dataset including field validation. In order to contribute to this task, we explore this issue by comparing a dataset from NHC to a recent targeted sampling of the cockroach genus Monastria Saussure, 1864 in the Brazilian Atlantic forest. We showed that, despite strong similarities, the area modeled with NHC data was much smaller. These differences were due to strong climate biases, which increased model's specificity and reduced sensitivity. By applying two forms of rarefaction in the environmental space, we showed that deleting points at random in the most biased climate class is a powerful way for increasing model's sensitivity, so making predictions more suitable to the reality. PMID- 30427868 TI - Association of progesterone production with serum anti-Mullerian hormone levels in assisted reproductive technology cycles with corifollitropin alfa. AB - The use of corifollitropin alfa (CA) in assisted reproductive technology (ART) cycles is dependent on the antral follicle count and body weight of patients. The present study investigated the safety and efficacy of using 100MUg of CA in predicted excessive responders based on serum anti-Mullerian hormone (AMH) level. The results of 381 ART cycles stimulated by CA versus daily recombinant follicle stimulation hormone (rFSH) in patients with low (<1.0 ng/mL; n = 38 vs. n = 90), moderate (1.0-3.36 ng/mL; n = 38 vs. n = 95), and high (> 3.36 ng/mL; n = 48 vs. n = 72) serum AMH levels, were analyzed. Pregnancy and live birth rates did not significantly differ between CA and daily rFSH groups. In the patients with high AMH levels, serum progesterone (P4) levels on the day of human chorionic gonadotropin (hCG) injection were significantly lower in the CA group than in the rFSH group (0.93 +/- 0.55 vs. 1.16 +/- 0.64 ng/mL). Furthermore, serum P4 levels on the day of hCG injection were negatively correlated with baseline AMH levels in the CA group, but not in the rFSH group, in the patients with high AMH levels. In conclusion, the use of 100 MUg of CA in patients with high AMH levels is safe and effective and is associated with a lower P4 level on the day of hCG injection compared with the use of daily rFSH. PMID- 30427870 TI - Factors in hybridization of local medical systems: Simultaneous use of medicinal plants and modern medicine in Northeast Brazil. AB - The presence of mainstream medicine in local medical systems inserts a set of external treatments and concepts that generate adjustments in the local conceptions of health and disease. What points in the system are most receptive to change? Who are the residents most likely to adopt these external treatments to deal with diseases? To answer these questions, this work used a study model consisting of the simultaneous use of medicinal plants and modern medicine, testing whether diseases that require greater treatment efforts are the main targets of adherence to modern medicine and if socioeconomic characteristics of residents can cause intracultural variation in relation to simultaneous use. To obtain socioeconomic data on the knowledge of medicinal plants and simultaneous use of these resources with modern medicine, semistructured interviews were conducted in a rural community that has easy access to modern medicine. Participatory workshops were held to access the local perceptions about the frequency of occurrence and severity of illnesses. A multilevel logistic regression model was applied for data analysis. We found that chronic, severe and frequently occurring diseases in the community tended to show greater simultaneous use locally. Among the socioeconomic factors, we determined that high educational levels positively influenced the combined use of plants and modern medicine. The need to ensure the cure of frequent, severe and chronic diseases is a factor that leads residents to seek a greater number of possible treatments, stimulating the combined use of plants and modern medicine. Residents with higher educational levels were more likely to use a combination of treatments than those with lower educational levels, demonstrating that more participation in formal education may facilitate the combined use of medicinal plants and modern medicine. PMID- 30427871 TI - Deuterium isotope effects in drug pharmacokinetics II: Substrate-dependence of the reaction mechanism influences outcome for cytochrome P450 cleared drugs. AB - Two chemotypes were examined in vitro with CYPs 3A4 and 2C19 by molecular docking, metabolic profiles, and intrinsic clearance deuterium isotope effects with specifically deuterated form to assess the potential for enhancement of pharmacokinetic parameters. The results show the complexity of deuteration as an approach for pharmacokinetic enhancement when CYP enzymes are involved in metabolic clearance. With CYP3A4 the rate limiting step was chemotype-dependent. With one chemotype no intrinsic clearance deuterium isotope effect was observed with any deuterated form, whereas with the other chemotype the rate limiting step was isotopically sensitive, and the magnitude of the intrinsic clearance isotope effect was dependent on the position(s) and extent of deuteration. Molecular docking and metabolic profiles aided in identifying sites for deuteration and predicted the possibility for metabolic switching. However, the potential for an isotope effect on the intrinsic clearance cannot be predicted and must be established by examining select deuterated versions of the chemotypes. The results show how in a deuteration strategy molecular docking, in-vitro metabolic profiles, and intrinsic clearance assessments with select deuterated versions of new chemical entities can be applied to determine the potential for pharmacokinetic enhancement in a discovery setting. They also help explain the substantial failures reported in the literature of deuterated versions of drugs to elicit a systemic enhancement on pharmacokinetic parameters. PMID- 30427872 TI - Think then act or act then think? AB - We introduce a new agent-based model of opinion dynamics in which binary opinions of each agent can be measured and described regarding both pre- and post influence at both of two levels, public and private, vis-a-vis the influence source. The model combines ideas introduced within the q-voter model with noise, proposed by physicists, with the descriptive, four-dimensional model of social response, formulated by social psychologists. We investigate two versions of the same model that differ only by the updating order: an opinion on the public level is updated before an opinion on the private level or vice versa. We show how the results on the macroscopic scale depend on this order. The main finding of this paper is that both models produce the same outcome if one looks only at such a macroscopic variable as the total number of the individuals with positive opinions. However, if also the level of internal harmony (viz., dissonance) is measured, then significant, qualitative differences are seen between these two versions of the model. All results were obtained simultaneously within Monte Carlo simulations and analytical calculations. We discuss the importance of our studies and findings from three points of view: the theory of phase transitions, agent-based modeling of social systems, and social psychology. PMID- 30427873 TI - Guiding practitioners through end of life care for people with dementia: The use of heuristics. AB - BACKGROUND: End of life care (EOLC) for people with dementia can present a multitude of challenges and difficult decisions for practitioners. These challenges may include assessment and management of difficulties with eating and swallowing, responding to agitation, treating pain, and managing recurrent infections. Practitioners sometimes lack both confidence in making end of life decisions and guidance. This study developed an alternative to lengthy guidelines, in the form of heuristics which were tested in clinical settings. The aim of this study was to test the usability and acceptability of a set of heuristics which could be used by practitioners providing EOLC for people with dementia in a variety of clinical and care settings. METHODS: A three phase co design process was adopted: 1) Synthesis of evidence and outputs from interviews and focus groups with family carers and practitioners, by a co-design group, to develop heuristics; 2) Testing of the heuristics in five clinical or care settings for six months; 3) Evaluation of the heuristics at three and six months using qualitative individual and group interviews. RESULTS: Four heuristics were developed covering: eating and swallowing difficulties, agitation and restlessness, reviewing treatment and interventions at the end of life, and providing routine care. The five sites reported that the heuristics were simple and easy to use, comprehensive, and made implicit, tacit knowledge explicit. Four themes emerged from the qualitative evaluation: authority and permission; synthesis of best practice; providing a structure and breaking down complexity; and reassurance and instilling confidence. CONCLUSION: Use of heuristics is a novel approach to end of life decision making in dementia which can be useful to both experienced and junior members of staff making decisions. Heuristics are a practical tool which could overcome a lack of care pathways and direct guidance in end of life care for people with dementia. PMID- 30427874 TI - Impact of implementation intentions on physical activity practice in adults: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVE: The aim of this study was to verify the efficacy of using theory-based strategies on implementation intentions in promoting physical activity (PA) among adults. METHODS: This review was conducted in accordance with the PRISMA recommendations. The search was carried out in seven electronic databases (LILACS, PubMed, SciELO, Cochrane, Web of Science) and two searches of the "grey literature" were performed (Openthesis and OpenGrey). Randomized clinical trials (RCT), published up to September 2016, were considered eligible for this study. Two reviewers independently and systematically evaluated the eligibility criteria, and performed data extraction. A meta-analysis was performed for the purpose of comparing the effect between the intervention and control groups. The effect sizes were grouped in two subgroups with the purpose of more accurately verifying the effect caused by reinforcing the implementation intentions strategy, and using the inverse variance statistical method with random effects models to estimate the main effect of the implementation intention strategy on the PA behavior. Heterogeneity among the studies was evaluated by using I-square statistics, and the Jadad scale to evaluate the quality of included papers. RESULTS: The search resulted in 12,147 records, of which 13 RCTs were considered eligible for this review. Sample age ranged from 18 to 76 years, and participants had conditions such as medullary lesion, coronary disease, obesity, diabetes mellitus, sedentarism or occupational stress. When the summary of the effect was analyzed in the meta-analysis, the result found in the subgroup with reinforcement of the implementation intentions strategy was 0.25 (IC 95% = 0.05 0.45) in favor of the intervention group. This demonstrated that application of the implementation intentions strategy was capable of increasing PA practice in the participants of these studies, in comparison with others that did not use this reinforcement. CONCLUSION: The findings of this review indicated that application of the theory of implementation intentions promoted PA behavior among the adults who received reinforcement of this strategy. The systematic review protocol was registered in the PROSPERO database under the number CRD42018090482. PMID- 30427875 TI - Identification of factors affecting rice yield gap in southwest China: An experimental study. AB - Knowledge about the relative importance of influencing-factors on rice yield gap is crucial to rice production, especially in southwestern China where topography is extremely complicated. In the current study, the data of rice yield from a total of 76 experiments were collected in 2008 and 2009 in Chongqing, southwest China. For each location, two treatments with fertilizer and without fertilizer were carried out, each treatment was performed with three replications, and yield gap was calculated using fertilized yield minus unfertilized yield. Seventeen influencing-factors including variety, fertilization, climate, terrain, and soil properties were obtained at each location. Regression tree (RT) model were employed to investigate relative important of influencing-factors to rice yield gap variability. The result of Pearson correlation analysis suggested yield gap of rice was positively correlated with sunshine hours, phosphorous and potassium fertilizers, while negatively correlated with soil available nitrogen content. The results of RT showed that the selected influencing-factors explained about 74.1% of rice yield gap variation. Meanwhile, the result also indicated variety followed by others had more influence on rice yield gap variation. Our findings analyzed by regression model at a regional scale suggested that more precise fertilization recommendation should be formulated based on comprehensive factors (e.g., soil, climate, terrain, variety), which reasonably guided farmer and government for rice production. PMID- 30427876 TI - First record of the Miocene hominoid Sivapithecus from Kutch, Gujarat state, western India. AB - Hominoid remains from Miocene deposits in India and Pakistan have played a pivotal role in understanding the evolution of great apes and humans since they were first described in the 19th Century. We describe here a hominoid maxillary fragment preserving the canine and cheek teeth collected in 2011 from the Kutch (= Kachchh) basin in the Kutch district, Gujarat state, western India. A basal Late Miocene age is proposed based on the associated faunal assemblage that includes Hipparion and other age-diagnostic mammalian taxa. Miocene Hominoidea are known previously from several areas of the Siwalik Group in the outer western Himalayas of India, Pakistan, and Nepal. This is the first record of a hominoid from the Neogene of the Kutch Basin and represents a significant southern range extension of Miocene hominoids in the Indian peninsula. The specimen is assigned to the Genus Sivapithecus, species unspecified. PMID- 30427877 TI - High burden of neural tube defects in Tigray, Northern Ethiopia: Hospital-based study. AB - INTRODUCTION: Neural tube defects are the major causes of fetal loss and considerable disabilities in infants. Currently, there is no significant research on the incidence of Neural tube defects in the Tigray region of Ethiopia. OBJECTIVE: To determine the incidence and clinical pattern of the Neural Tube Defects. METHODS: A hospital-based cross-sectional study was conducted from October 2016 to June 2017. All pregnancy outcomes were examined for any externally visible birth defects and neurological integrity by trained midwives under the supervision of senior obstetrics and gynecology and a neurosurgeon. Data were collected using a survey tool to collect maternal and newborn demographic data and a checklist developed to capture newborns with Neural Tube Defects. Data were analyzed using SPSS version 20. The prevalence of NTDs was calculated per 10,000 births. RESULT: Out of the 14,903 births during the study period, a total of 195 infants were born afflicted with Neural Tube Defects. The burden of infants with anencephaly and spina bifida was 66.4 and 64.4 per 10, 000 births, respectively. The overall incidence rate of NTDs in this study was 131 per 10, 000 births of which 23% were liveborn and 77% were stillborn. The highest burden of Neural Tube Defects was observed in Adigrat Hospital from Eastern Zone of Tigray (174 per 10,000 births) and Lemlem Karl Hospital from Southern Zone of Tigray (304 per 10,000 births) compared to Kahsay Abera Hospital from Western Zone (72.8 per 10,000 births) and Sihul Hospital from North Western Zone of Tigray (69.8 per 10,000 births). CONCLUSION AND RECOMMENDATION: Assuming that the non folic acid preventable rate should be 5 per 10,000 births, our prevalence rate is 131 per 10,000 births, and then we have a rate or an epidemic that is 26 times what it should be. This just emphasizes the urgency to implement effective programs to get all women of reproductive age to have adequate folic acid to prevent all of folic acid-preventable spina bifida and anencephaly, which would prevent 96% (125/130) of spina bifida and anencephaly in the Tigray Provence. PMID- 30427879 TI - Development and validation of quality of life instruments for chronic diseases Chronic gastritis version 2 (QLICD-CG V2.0). AB - Quality of life is an important outcome indicator to evaluate whether treatment is successful or not. Chronic gastritis leads to ongoing deterioration of subjectively perceived quality of life. There are several generic measures, but they are not developed particularly to assess chronic gastritis problems. The Quality of Life Instruments for Chronic Diseases-Chronic Gastritis (QLICD-CG V2.0) questionnaire is a 39-item, multi-dimensional, self-report instrument to assess chronic gastritis patients' perception of their health related quality of life in four domains. The instrument was developed in China. The current study aimed to evaluate the psychometric properties of the QLICD-CG V2.0. 194 patients with chronic gastritis were enrolled from 4 hospitals in China. The QLICD-CG V2.0 was administered to patients by trained research assistants. In addition, their demographic characteristics were also recorded. The psychometric testing included construct validity, convergent validity, discriminant validity, test-retest, and responsiveness. The results showed good internal consistency and acceptable floor and ceiling effects (Cronbach's alpha range from 0.80 to 0.93). CFA showed that the instrument structure has a reasonable fitness (RMSEA = 0.063, 95%CI = [0.057 0.079], CFI = 0.93, GFI = 0.95, SRMR = 0.028). The convergent validity was considered appropriate, with 38 of the 39 items correlated stronger with their assigned scale than a competing scale, except for GPS1. Known groups comparisons showed that the QLICD-CG V2.0 discriminated well between subgroups on the basis of gender, marriage status, and economy status, thus providing evidence of discriminative validity. Convergent validity testing revealed that the QLICD-CG V2.0 domain scores correlated significantly with SF-36 dimension scores, which ranged from 0.21 to 0.58. Test-retest coefficients were satisfactory. A majority of intraclass correlation coefficients were above 0.70, except the psychological domain (0.60) and the items of social support/security (0.61). Responsiveness was tested on 157 patients. Significant differences were found on all QLICD-CG V2.0 domains, between baseline responses and after a treatment, except for the items of appetite and sleep. Robust sensitivity to change was observed. The QLICD-CG V2.0 appears to be a valid and reliable instrument to measure QOL in chronic gastritis patients. Scores were reproducible. PMID- 30427880 TI - Development and validation of warning system of ventricular tachyarrhythmia in patients with heart failure with heart rate variability data. AB - Implantable-cardioverter defibrillators (ICD) detect and terminate life threatening ventricular tachyarrhythmia with electric shocks after they occur. This puts patients at risk if they are driving or in a situation where they can fall. ICD's shocks are also very painful and affect a patient's quality of life. It would be ideal if ICDs can accurately predict the occurrence of ventricular tachyarrhythmia and then issue a warning or provide preventive therapy. Our study explores the use of ICD data to automatically predict ventricular arrhythmia using heart rate variability (HRV). A 5 minute and a 10 second warning system are both developed and compared. The participants for this study consist of 788 patients who were enrolled in the ICD arm of the Sudden Cardiac Death-Heart Failure Trial (SCD-HeFT). Two groups of patient rhythms, regular heart rhythms and pre-ventricular-tachyarrhythmic rhythms, are analyzed and different HRV features are extracted. Machine learning algorithms, including random forests (RF) and support vector machines (SVM), are trained on these features to classify the two groups of rhythms in a subset of the data comprising the training set. These algorithms are then used to classify rhythms in a separate test set. This performance is quantified by the area under the curve (AUC) of the ROC curve. Both RF and SVM methods achieve a mean AUC of 0.81 for 5-minute prediction and mean AUC of 0.87-0.88 for 10-second prediction; an AUC over 0.8 typically warrants further clinical investigation. Our work shows that moderate classification accuracy can be achieved to predict ventricular tachyarrhythmia with machine learning algorithms using HRV features from ICD data. These results provide a realistic view of the practical challenges facing implementation of machine learning algorithms to predict ventricular tachyarrhythmia using HRV data, motivating continued research on improved algorithms and additional features with higher predictive power. PMID- 30427878 TI - An open-source k-mer based machine learning tool for fast and accurate subtyping of HIV-1 genomes. AB - For many disease-causing virus species, global diversity is clustered into a taxonomy of subtypes with clinical significance. In particular, the classification of infections among the subtypes of human immunodeficiency virus type 1 (HIV-1) is a routine component of clinical management, and there are now many classification algorithms available for this purpose. Although several of these algorithms are similar in accuracy and speed, the majority are proprietary and require laboratories to transmit HIV-1 sequence data over the network to remote servers. This potentially exposes sensitive patient data to unauthorized access, and makes it impossible to determine how classifications are made and to maintain the data provenance of clinical bioinformatic workflows. We propose an open-source supervised and alignment-free subtyping method (Kameris) that operates on k-mer frequencies in HIV-1 sequences. We performed a detailed study of the accuracy and performance of subtype classification in comparison to four state-of-the-art programs. Based on our testing data set of manually curated real world HIV-1 sequences (n = 2, 784), Kameris obtained an overall accuracy of 97%, which matches or exceeds all other tested software, with a processing rate of over 1,500 sequences per second. Furthermore, our fully standalone general purpose software provides key advantages in terms of data security and privacy, transparency and reproducibility. Finally, we show that our method is readily adaptable to subtype classification of other viruses including dengue, influenza A, and hepatitis B and C virus. PMID- 30427881 TI - The music that helps people sleep and the reasons they believe it works: A mixed methods analysis of online survey reports. AB - Sleep loss is a widespread problem with serious physical and economic consequences. Music can impact upon physical, psychological and emotional states, which may explain anecdotal reports of its success as an everyday sleep aid. However, there is a lack of systematic data on how widely it is used, why people opt for music as a sleep aid, or what music works; hence the underlying drivers to music-sleep effects remain unclear. We investigated music as a sleep aid within the general public via a mixed methods data online survey (n = 651) that scored musicality, sleep habits, and open text responses on what music helps sleep and why. In total, 62% of respondents stated that they used music to help them sleep. They reported fourteen musical genres comprising 545 artists. Linear modelling found stress, age, and music use as significant predictors of sleep quality (PSQI) scores. Regression tree modelling revealed that younger people with higher musical engagement were significantly more likely to use music to aid sleep. Thematic analysis of the open text responses generated four themes that described why people believe music helps sleep: music offers unique properties that stimulate sleep (Provide), music is part of a normal sleep routine (Habit), music induces a physical or mental state conducive to sleep (State), and music blocks an internal or external stimulus that would otherwise disrupt sleep (Distract). This survey provides new evidence into the relationship between music and sleep in a population that ranged widely in age, musicality, sleep habits and stress levels. In particular, the results highlight the varied pathways of effect between music and sleep. Diversity was observed both in music choices, which reflected idiosyncratic preferences rather than any consistent musical structure, and in the reasons why music supports good sleep, which went far beyond simple physical/mental relaxation. PMID- 30427882 TI - Socio-demographic determinants of low birth weight: Evidence from the Kassena Nankana districts of the Upper East Region of Ghana. AB - OBJECTIVE: To examine the social, economic and demographic factors that determine low birth weight in the two Kassena Nankana districts of the Upper East region of Ghana. METHODS: Cross-sectional data was collected from January 2009 to December 2011 using the Navrongo Health and Demographic Surveillance System which monitors routine health and demographic outcomes in the study area. Data on foetal characteristics such as birth weight, and sex and maternal age, parity, maternal education, marital status, ethnicity, religious affiliation and socio-economic characteristics were collected and described. Tests of means, proportions and Chi squares are employed in bivariate analysis, and adjusted logistic regression models fitted to control for potential confounding variables. All tests were two sided and test of significance was set at p-value of < 0.05. RESULTS: There were 8,263 live births (44.9% females) with an overall average birth weight of 2.85 kg (2.9 kg for males and 2.8 kg for females). The average maternal age was 28 years, median parity 2, maternal literacy rate was about 70% and 83% of mothers were married. The prevalence of low birth weight was 13.8% 95%CI [13.10, 14.6] and more in female babies than in males (15.5% vs 12.2%; p<0.0001). Determinants of low birth-weight after controlling for confounding factors were sex of neonate (OR = 1.32, 95%CI [1.14,1.52]; p<0.0001), maternal age (p = 0.004), and mothers who are not married (OR = 1.44 [1.19, 1.74]; p<0.0001). CONCLUSION: Female neonates in this population were likely to present with low birth weight and maternal factors such as younger age, lower socio-economic status and single parenthood were major determinants of low birth weight. Effective and adequate antenatal care should therefore target women with these risk factors. PMID- 30427883 TI - Callitetrarhynchus gracilis (Rudolphi, 1819) Pintner, 1931 (Cestoda: Trypanorhyncha) parasitizing the musculature of Sardinella brasiliensis (Steindachner, 1879) (Actinopterygii) off the coast of the state of Rio de Janeiro, Brazil. AB - Cestodes of the order Trypanorhyncha can frequently be found infecting the muscles of several marine fish species, and lead to a repugnant aspect of the fish and rejection by consumers. The Brazilian sardinella, Sardinella brasiliensis, occurs from the Gulf of Mexico and the Caribbean to northern Uruguay. In southeastern Brazil, fishing for the species is very intensive since it generates significant revenue as one of the most commonly consumed fish and an important element of the canned fish industry. The aims of the present study were to identify and report the occurrence of tiny cestodes (3 mm-6.6 mm) in the musculature of Brazilian sardinella that were purchased in the Sao Pedro fish market in the municipality of Niteroi, state of Rio de Janeiro, Brazil. From October 2013 to November 2016, 75 specimens of S. brasiliensis were investigated. The trypanorhynch cestodes encountered were identified as plerocerci of Callitetrarhynchus gracilis using morphological, morphometric and molecular data. Parasitic indices were calculated, and the cestodes infection of the musculature of Brazilian sardinella had the following values: prevalence, 40%; mean intensity, 3.47; mean abundance, 1.39; and range of infection, 1-18, specimens. The presence of this trypanorhynch cestode in the musculature of Brazilian sardinella is an important indicator of fish hygiene. PMID- 30427884 TI - Platelet-to-lymphocyte ratio as a predictive factor of complete pathologic response to neoadjuvant chemotherapy in breast cancer. AB - Response to neoadjuvant chemotherapy in breast cancer patients is of prognostic value in determining short- and mid-term outcomes. Inflammatory biomarkers, such as platelet-to-lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR), have been proposed as predictive factors of response to neoadjuvant chemotherapy. Currently, there are no studies in Colombian patients reporting the role of inflammatory biomarkers as response predictors in patients receiving neoadjuvant chemotherapy. Therefore, in this study we performed a cross-sectional study and analyzed the association between inflammatory biomarkers and pCR (pathological complete response) in patients diagnosed with breast cancer-of different molecular subtypes- and treated with neoadjuvant chemotherapy. A total of 288 patients were included in the study, with a median age of 51 years old. Disease was locally advanced in 83% of the participants, and 77.7% had compromised lymph nodes. In our cohort, the most frequent tumor molecular subtype was luminal B/Her2- (27.8%) followed by triple negative [TN] (21.5%), luminal B/Her2+ (19.8%), Her2-enriched (16%) and luminal A (13.5%). PLR was not associated with age, menopausal status, baseline tumor size, histologic grade, axillary lymph node involvement, disease stage, estrogen receptor status, or Ki67; however, complete pathological response was significantly higher in the low PLR group (PLR<150) compared with the high PLR group (35.1% Vs. 22.2%, p = 0.03). In addition, Her2-enriched tumors achieved the highest pCR rates (65%), followed by TN (34%) tumors. Our results suggest that breast cancer patients with low platelet-to-lymphocyte ratio (PLR <150), treated with neoadjuvant chemotherapy achieve higher complete pathological response, independently of primary tumor molecular subtype. PMID- 30427885 TI - Optimization of fermentation conditions through response surface methodology for enhanced antibacterial metabolite production by Streptomyces sp. 1-14 from cassava rhizosphere. AB - Streptomyces species 1-14 isolated from cassava rhizosphere soil were evaluated for their antibacterial efficacy against Fusarium oxysporum f.sp. cubense race 4 (FOC4). Of the 63 strains tested, thirteen exhibited potent antibacterial properties and were further screened against eight fungal pathogens. The strain that showed maximum inhibition against all of the test pathogens was identified by 16S rDNA sequencing as Streptomyces sp. 1-14, was selected for further studies. Through the propagation of Streptomyces sp. 1-14 in soil under simulated conditions, we found that FOC4 did not significantly influence the multiplication and survival of Streptomyces sp. 1-14, while indigenous microorganisms in the soil did significantly influence Streptomyces sp. 1-14 populations. To achieve maximum metabolite production, the growth of Streptomyces 1-14 was optimized through response surface methodology employing Plackett-Burman design, path of steepest ascent determinations and Box-Behnken design. The final optimized fermentation conditions (g/L) included: glucose, 38.877; CaCl2*2H2O, 0.161; temperature, 29.97 degrees C; and inoculation amount, 8.93%. This optimization resulted in an antibacterial activity of 56.13% against FOC4, which was 12.33% higher than that before optimization (43.80%). The results obtained using response surface methodology to optimize the fermentation medium had a significant effect on the production of bioactive metabolites by Streptomyces sp. 1-14. Moreover, during fermentation and storage, pH, light, storage temperature, etc., must be closely monitored to reduce the formation of fermentation products with reduced antibacterial activity. This method is useful for further investigations of the production of anti-FOC4 substances, and could be used to develop bio-control agents to suppress or control banana fusarium wilt. PMID- 30427886 TI - Depressive symptoms and suicidal behaviours in adolescent non-daily smokers compared to daily smokers and never-smokers in Korea: National cross-sectional study. AB - INTRODUCTION: We aimed to investigate the association of non-daily smoking with depressive symptoms and suicidal behaviours among adolescents by analysing data from the 2016 Korean Youth Risk Behavior Web-based Survey (KYRBWS), a national school-based survey. METHODS: We analysed data from a nationally representative sample of Korean adolescents aged 12-18 years (n = 65,528). We investigated the risks of depressive symptoms, suicide ideation, plan and attempt in adolescent non-daily smokers using multiple logistic regression analyses after adjusting for confounding factors. Taking into account the trajectory of smoking patterns in adolescents, we assessed all analyses with stratification by early (aged 12-15) and late (aged 16-18) adolescents. RESULTS: Among early adolescents, non-daily smokers were more likely to have depressive symptoms, suicide ideation and plan compared with never smokers and even more likely to have depressive symptoms compared with daily smokers. Among late adolescents, non-daily smokers had higher risks of depressive symptoms, suicide ideation, plan and attempt than never smokers, whereas the risk for suicide attempts was lower than daily smokers. CONCLUSIONS: Our findings suggest that non-daily smoking in adolescents was associated with risks for depressive symptoms and suicidal behaviours, and the association was more prominent in early adolescents. Careful attention on the mental health of adolescent non-daily smokers is needed because this is an increasing and easily overlooked group. PMID- 30427887 TI - The use of procalcitonin in the determination of severity of sepsis, patient outcomes and infection characteristics. AB - OBJECTIVE: The primary objective of this study was to determine the correlation between procalcitonin values and illness severity by evaluating the degree of end organ dysfunction using the Sequential Organ Failure Assessment score, length of stay and the severity of sepsis (sepsis alone vs. septic shock), The hypothesis that procalcitonin values would be higher in sicker patients was formulated before data collection began. Secondary outcomes studied in relation to procalcitonin levels included infection characteristics such as the site of infection, microbial agent and dialysis dependent CKD. DESIGN: Unblinded retrospective cohort study. September 2014-December 2016. SETTING: 364 patients with a diagnosis of sepsis or severe sepsis who were admitted to the general medical ward and ICU at Methodist Medical Center and Proctor Hospital in Peoria, Illinois, USA. RESULTS: This study demonstrates the following: Weak positive correlation between procalcitonin and SOFA score. Negligible correlation with length of stay. Higher values in patients who died than in patients who survived to discharge (p = 0.058). Sensitivity and specificity of procalcitonin for septic shock was 63 and 65% respectively. Sites typically infected by gram negative bacteria have higher procalcitonin values than sites infected by gram positive bacteria (p = 0.03). Higher procalcitonin in bacteremia than non-bacteremic infections (p = 0.004). Higher procalcitonin in dialysis-dependent CKD patients (p = 0.020). CONCLUSIONS: Procalcitonin has a higher specificity for bacterial infections than other acute phase reactants. Although initial procalcitonin value may be helpful in the determination of illness severity, it is not always a reliable prognostic indicator and carries little significance as a standalone value. Procalcitonin values may be influenced by preexisting comorbid conditions such as chronic kidney disease, which are associated with higher procalcitonin values at baseline. Procalcitonin can provide invaluable information when viewed as one piece of a clinical puzzle, and is most powerful when the interpreting physician is aware of how values are influenced by the different clinical scenarios presented in this article. PMID- 30427889 TI - The effect of demand-side financial incentives for increasing linkage into HIV treatment and voluntary medical male circumcision: A systematic review and meta analysis of randomised controlled trials in low- and middle-income countries. AB - INTRODUCTION: Linkage to HIV treatment is a vital step in the cascade of HIV services and is critical to slowing down HIV transmission in countries with high HIV prevalence. Equally, linkage to voluntary medical male circumcision (VMMC) has been shown to decrease HIV transmission by 60% and increasing numbers of men receiving VMMC has a substantial impact on HIV incidence. However, only 48% of newly diagnosed HIV positive people link to HIV treatment let alone access HIV prevention methods such as VMMC globally. METHODS: A systematic review investigating the effect of demand-side financial incentives (DSFIs) on linkage into HIV treatment or VMMC for studies conducted in low- and middle-income countries. We searched the title, abstract and keywords in eight bibliographic databases: MEDLINE, EMBASE, Web of Science, Econlit, Cochrane, SCOPUS, IAS Conference database of abstracts, and CROI Conference database of abstracts. Searches were done in December 2016 with no time restriction. We fitted random effects (RE) models and used forest plots to display risk ratios (RR) and 95% CIs separately for the linkage to VMMC outcome. The RE model was also used to assess heterogeneity for the linkage to HIV treatment outcome. RESULTS: Of the 1205 citations identified from searches, 48 full text articles were reviewed culminating in nine articles in the final analysis. Five trials investigated the effect of DSFIs on linkage to HIV treatment while four trials investigated linkage to VMMC. Financial incentives improved linkage to HIV treatment in three of the five trials that investigated this outcome. Significant improvements were observed among postpartum women RR 1.26 (95% CI: 1.08; 1.48), among people who inject drugs RR 1.42 (95% CI: 1.09; 1.96), and among people testing at the clinic RR 1.10 (95% CI: 1.07; 1.14). One of the two trials that did not find significant improvement in linkage to ART was among people testing HIV positive in clinics RR 0.96 (95% CI: 0.81; 1.16) while the other was among new HIV positive individuals identified through a community testing study RR 0.82 (95% CI: 0.56; 1.22). We estimate an average 4-fold increase in the uptake of circumcision among HIV negative uncircumcised men from our fitted RE model with overall RR 4.00 (95% CI: 2.17; 7.37). There was negligible heterogeneity in the estimates from the different studies with I-squared = 0.0%; p = 0.923. CONCLUSIONS: Overall, DSFIs appeared to improve linkage for both HIV treatment and VMMC with greater effect for VMMC. Demand-side financial incentives could improve linkage to HIV treatment or VMMC in low- and middle-income countries although uptake by policy makers remains a challenge. PMID- 30427888 TI - Tucum-do-cerrado (Bactris setosa Mart.) modulates oxidative stress, inflammation, and apoptosis-related proteins in rats treated with azoxymethane. AB - Oxidative and inflammatory responses play an important role in the development and prevention of cancer, with both responses being modulated by phytochemical compounds. This study investigated the chemopreventive effect of tucum-do-cerrado fruit in rats treated with azoxymethane. Wistar rats were treated for 12 weeks with: a control diet (CT); a control diet + AOM (CT/DR); a control diet + 15% tucum-do-cerrado (TU); or a control diet + 15% tucum-do-cerrado + AOM (TU/DR). The association of tucum-do-cerrado and AOM (TU/DR) increased glutathione-S transferase activity, decreased MDA levels, increased levels of COX2, TNFalpha and BAX, and decreased Bcl2/Bax ratio, compared to the CT/DR group. Carbonyl levels, IL-1beta and IL-6 mRNA levels, and aberrant crypt foci showed no difference between the treatments. In conclusion, tucum-do-cerrado reduced lipid oxidative damage, induced a pro-inflammatory effect, and promoted a pro-apoptotic "environment" in rats treated with AOM; however no changes in aberrant crypts were observed. PMID- 30427890 TI - UAS imagery reveals new survey opportunities for counting hippos. AB - INTRODUCTION: The common hippopotamus Hippopotamus amphibius L. is a vulnerable species that requires efficient methods to monitor its populations for conservation purposes. Rapid evolution of civil drones provides new opportunities but survey protocols still need development. This study aims to determine the optimal flight parameters for accurate population estimates. A second objective is to evaluate the effects of three environmental factors: wind speed, sun reflection and cloud cover. METHOD: We estimated the population of two main hippo schools (Dungu and Wilibadi II) located in Garamba National Park in Democratic republic of Congo. Eight observers reviewed 252 photos taken over the Dungu school, representing a total of 2016 experimental units. A detection rate and a level of certainty were associated with each experimental unit, and five parameters were related to each count: flight height, three environmental parameters (sun reflection on water surface, cloud cover, and wind speed), and observers' experience. RESULTS: Flight height reduced the observers' confidence in their detection ability, rather than the detection itself. For accurate counts of large groups an average height of 150 m was shown to be a good compromise between animal detection without zooming in and the area covered in one frame. Wind speed had little influence on the counts, but it affected the performance of the UAS. Sun reflection reduced the detection rate of hippos and increased level of certainty, while cloud cover reduced detection rates slightly. Therefore, we recommend flying when the sun is still low on the horizon and when there is little cloud, or when cloud cover is light and even. This last point reinforces our recommendation for flights early in the day. The counts also showed large differences between groups of inexperienced and experienced observers. Experienced observers achieved better detection rates and were generally more confident in their detection. Experienced observers detected 86.5% of the hippos on average (confidence interval = +/-0.76%). When applied to data from the second site, the detection was 84.3% (confidence interval = +/-1.84%). Two correction factors were then calculated, as the inverse of the detection rate, based on the estimated number of hippos present during one flight (Factor 1) or in the general population respectively (Factor 2). Factor 2 especially was consistent with previous studies using traditional aerial counts (1.22 vs 1.25). Factor 2 was found to be appropriate for use by experienced observers. These results confirm the use of correction factor 2 for hippo surveys, regardless of the study site, as it accounts for hippo behavior. Optimum counting and cost efficiency were achieved with two trained observers counting 7 pictures. CONCLUSION: This study is a promising approach for routine surveys of the hippopotamus which is a species usually ignored in wildlife counts. Drone technology is expected to improve rapidly; therefore UAS could become a very useful and affordable survey tool for other species requiring specific monitoring. PMID- 30427891 TI - Modelling heterogeneity in host susceptibility to tuberculosis and its effect on public health interventions. AB - A tuberculosis (TB) model that accounts for heterogeneity in host susceptibility to tuberculosis is proposed, with the aim of investigating the implications this may have for the effectiveness of public health interventions. The model examines the possibility that recovered individuals treated from active TB and individuals treated with preventive therapy acquire different levels of immunity. This contrasts with recent studies that assume the two cohorts acquire the same level of immunity, and therefore both groups are reinfected at the same rate. The analysis presented here examines the impact of this assumption when designing intervention strategies. Comparison of reinfection rates between cohorts treated with preventive therapy and recovered individuals who were previously treated for active TB provides important epidemiological insights. It is found that the reinfection rate of the cohort treated with preventive therapy is the one that plays the key role in qualitative changes in TB dynamics. By contrast, the reinfection rate of recovered individuals (previously treated from active TB) plays a minor role. Moreover, the study shows that preventive treatment of individuals during early latency is always beneficial regardless of the level of susceptibility to reinfection. Further, if patients have greater immunity following treatment for late latent infection, then treatment is again beneficial. However, if susceptibility increases following treatment for late latent infection, the effect of treatment depends on the epidemiological setting. That is: (i) in (very) low burden settings, the effect on reactivation predominates and the burden declines with treatment; (ii) in moderate to high burden settings the effect of reinfection predominates and burden increases with treatment. The effect is most dominant between the two reinfection thresholds, RT2 and RT1, respectively associated with individuals being treated with preventive therapy and individuals with untreated late latent TB infection. PMID- 30427892 TI - Development and validation of an algorithm to predict the treatment modality of burn wounds using thermographic scans: Prospective cohort study. AB - BACKGROUND: The clinical evaluation of a burn wound alone may not be adequate to predict the severity of the injury nor to guide clinical decision making. Infrared thermography provides information about soft tissue viability and has previously been used to assess burn depth. The objective of this study was to determine if temperature differences in burns assessed by infrared thermography could be used predict the treatment modality of either healing by re epithelization, requiring skin grafts, or requiring amputations, and to validate the clinical predication algorithm in an independent cohort. METHODS AND FINDINGS: Temperature difference (DeltaT) between injured and healthy skin were recorded within the first three days after injury in previously healthy burn patients. After discharge, the treatment modality was categorized as re epithelization, skin graft or amputation. Potential confounding factors were assessed through multiple linear regression models, and a prediction algorithm based on the DeltaT was developed using a predictive model using a recursive partitioning Random Forest machine learning algorithm. Finally, the prediction accuracy of the algorithm was compared in the development cohort and an independent validation cohort. Significant differences were found in the DeltaT between treatment modality groups. The developed algorithm correctly predicts into which treatment category the patient will fall with 85.35% accuracy. Agreement between predicted and actual treatment for both cohorts was weighted kappa 90%. CONCLUSION: Infrared thermograms obtained at first contact with a wounded patient can be used to accurately predict the definitive treatment modality for burn patients. This method can be used to rationalize treatment and streamline early wound closure. PMID- 30427893 TI - Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells. AB - Endothelial dysfunction is a hallmark of a wide range of cardiovascular diseases and is often linked to oxidative stress and inflammation. Our earlier study reported the formation of a functional heterodimer between bradykinin receptor 2 (B2R) and dopamine receptor 2 (D2R) that may modulate cell responses, dependent on intracellular signaling. Here, for the first time, we showed a cooperative effect of these receptors on the modulation of processes involved in oxidative stress, inflammation, and apoptosis in endothelial cells. Sumanirole, a specific D2R agonist, was shown to diminish the excessive production of reactive oxygen species induced by bradykinin, a proinflammatory B2R-activating peptide. This effect was accompanied by modified activities of antioxidant enzymes and increased phosphorylation of endothelial nitric oxide synthase, leading to enhance NO production. In turn, endothelial cell co-stimulation with B2R and D2R agonists inhibited the release of interleukin-6 and endothelin-1 and modulated the expression of apoptosis markers, such as Bcl-2, Bcl-xL, Bax, and caspase 3/7 activity. All these observations argue that the D2R agonist counteracts the pro oxidative, pro-inflammatory, and pro-apoptotic effects induced through B2R, finally markedly improving endothelial functions. PMID- 30427894 TI - Motivation to participate in high-intensity functional exercise compared with a social activity in older people with dementia in nursing homes. AB - BACKGROUND: Motivation to participate in exercise among people with dementia has not been well studied. The symptoms of dementia, including apathy, may lead to low motivation to participate in exercise. The aim of this study was to evaluate the motivation of older people with dementia to participate in a high-intensity exercise program compared with motivation of those participating in a social group activity. METHODS: The Umea Dementia and Exercise Study (UMDEX) was a cluster-randomized controlled intervention trial including 186 people (mean age; 85, 75% female) with dementia in nursing homes. Participants were randomized to participate in the High-Intensity Functional Exercise (HIFE) Program (n = 93) or a seated social group activity (n = 93). The activities were conducted in groups of 3-8 participants for 45 minutes, five times per two-week period, for 4 months (40 sessions in total). Participants' motivation to go to and during activity sessions were assessed by the activity leaders and nursing homes staff using a five-point Likert scale. Data were analyzed using cumulative link mixed models. RESULTS: Motivation was high or very high during 61.0% of attended sessions in the exercise group and 62.6% in the social activity group. No overall significant difference between groups was observed, but motivation increased over time in the exercise group and decreased in the social activity group (p < 0.05). Motivation during the sessions was significantly higher than motivation to go to the sessions, especially in the exercise group [OR 2.39 (95% CI 2.38-2.40) and 1.50 (95% CI 1.32-1.70), respectively]. CONCLUSIONS: Among older people with dementia in nursing homes, motivation to participate in a high-intensity functional exercise program seems to be high, comparable to motivation to participate in a social activity, and increase over time. Since motivation during activity sessions was higher than motivation to go to sessions the promotion of strategies to encourage people with dementia to join exercise groups is of great importance. PMID- 30427895 TI - Investment preference promotes cooperation in spatial public goods game. AB - It is usually assumed that each cooperator contributes equally to different public pools in spatial public goods game. However, it is more reasonable to invest differently according to individual investment preference. In this paper, an extended public goods game, in which cooperators contribute to the groups according to the investment preference, is developed. The investment preference of a cooperator is characterized by the fraction of the cooperator from his/her own memory about a group and the intensity of investment preference is represented by a tunable parameter alpha. The well-mixed population and the structured population are analyzed under this mechanism. It is shown that the investment preference can give rise to coordination. Moreover, the extensive numerical simulation results show that with the increasing of investment preference density or memory length, the proportion of cooperation can increase monotonously. This is because the investment preference could help cooperators resist the invasion from defectors. Compared with the basic version, the new mechanism is able to promote cooperation effectively. Our research may provide a valuable insight for further exploring the nature of cooperation in the real world. PMID- 30427897 TI - Moral and Affective Film Set (MAAFS): A normed moral video database. AB - Moral psychology has relied nearly exclusively on text stimuli in the development and testing of theories. However, text stimuli lack the rich variety of morally relevant social and contextual cues available in everyday interactions. A consequence of this pervasive ecological invalidity may be that moral psychological theories are mischaracterized by an overreliance on cue impoverished moral stimuli. We address this limitation by developing a cue-rich Moral and Affective Film Set (MAAFS). We crowd-sourced videos of moral behaviours, using previously validated text stimuli and definitions of moral foundations as a guide for content. Crowd-sourced clips were rated by 322 American and 253 Australian participants on a range of moral and affective dimensions, including wrongness, moral foundation relevance, punishment, arousal, discrete emotion-relevance, clarity, previous exposure, and how weird/uncommon the moral acts were. The final stimulus set contained sixty nine moral videos. Ratings confirmed that the videos are reliably rated as morally wrong and feature a variety of moral concerns. The validation process revealed features that make the MAAFS useful for future research: (1) the MAAFS includes a range of videos that depict everyday transgressions, (2) certain videos evoke negative emotions at an intensity comparable to mood induction films, (3) the videos are largely novel: participants had never seen more than 90% of the videos. We anticipate the MAAFS will be a particularly valuable tool for researchers in moral psychology who seek to study morality in scenarios that approximate real-life. However, the MAAFS may be valuable for other fields of psychology, for example, affective scientists may use these videos as a mood induction procedure. The complete stimulus set, links to videos, and normative statistics can be accessed at osf.io/8w3en. PMID- 30427896 TI - Force production parameters as behavioural measures for anger expression and control: The Method of Stamp Strike Shout. AB - This study presents first test results of a new performance-based, psychomotor method to measure anger expression and control, based on voice expression and physical force production in directional movement of arms and legs, called the Method of Stamp Strike Shout (MSSS). Recorded are the standardized impact of stamping on a force plate, hitting a punching bag, and the amplitude of shouting in a microphone at various force levels. The premise is, that these body behaviours stand for the 'urge to act or shout' that belongs to anger-related emotions. The MSSS is meant to be applied in addition to potentially biased self report questionnaires and has been designed for diagnostic as well as therapeutic purposes in clinical practice. First, this paper focusses on the instrumentation, internal structure and reliability of the MSSS. An explorative study in a student sample (n = 104) shows correlation patterns between increasing and decreasing levels of force production within each subtest (Stamp, Strike and Shout) and between the three subtests. We found excellent internal consistency of the three subtests and high test-retest reliability. The parameters of increasing and decreasing force levels form the slopes of what we call a force pyramid. To adjust for the clustering within persons, aggregated outcomes were calculated: sum scores per subtest as an indication of total force produced, two linear contrast scores to indicate the rate of increase / decrease, and two quadratic contrast scores as measures of the curvature of the slopes. On all subtests, all aggregated scores showed differences between men and women, also when controlled for weight. To test the validity of the MSSS, the second part of the paper examines the relationship between force parameters and anger coping style, measured by the Self-Expression and Control Scale (SECS). The results suggest that the Shout subtest was the most sensitive indicator for anger coping style, showing negative correlations with Anger In, for women as well as men. For women, higher amplitude was also associated with higher Anger Out and lower amplitude with higher Anger Control. The Stamp subtest showed weak positive correlations with the Anger In subscales, whereas no correlations were found on the Strike subtest. Further, a more robust comparison was made between two groups of participants who reported to have an internalizing versus an externalizing anger coping style. Results indicated that internalizing women as well as men used less force than externalizing participants on all three subtests, especially on the Shout subtest. This was confirmed by lower mean sum scores on the Shout subtest for internalizing women compared with externalizing women. No differences in linear contrast scores were shown between internalizing and externalizing participants. The quadratic contrast scores suggested differences of the curvation of the slopes between women with more or less anger control when stamping, and men with more or less anger control when striking. As this is an explorative study, findings should be interpreted with caution. PMID- 30427899 TI - A pyramid-like model for heartbeat classification from ECG recordings. AB - Heartbeat classification is an important step in the early-stage detection of cardiac arrhythmia, which has been identified as a type of cardiovascular diseases (CVDs) affecting millions of people around the world. The current progress on heartbeat classification from ECG recordings is facing a challenge to achieve high classification sensitivity on disease heartbeats with a satisfied overall accuracy. Most of the work take individual heartbeats as independent data samples in processing. Furthermore, the use of a static feature set for classification of all types of heartbeats often causes distractions when identifying supraventricular (S) ectopic beats. In this work, a pyramid-like model is proposed to improve the performance of heartbeat classification. The model distinguishes the classification of normal and S beats and takes advantage of the neighbor-related information to assist identification of S bests. The proposed model was evaluated on the benchmark MIT-BIH-AR database and the St. Petersburg Institute of Cardiological Technics(INCART) database for generalization performance measurement. The results reported prove that the proposed pyramid-like model exhibits higher performance than the state-of-the-art rivals in the identification of disease heartbeats as well as maintains a reasonable overall classification accuracy. PMID- 30427898 TI - Protein Disulfide Isomerase (PDI1-1) differential expression and modification in Mexican malting barley cultivars. AB - Barley malting quality depends on seed characteristics achieved during grain development and germination. One important parameter is protein accumulation in the mature seed, which may vary between cultivars. Here we conducted a protein pattern analysis in the range of pI 4-7 of mature grains from five Mexican barley cultivars, commonly used for malt and beer production. Reproducibly distinct protein spots, separated by 2D SDS PAGE, were identified by mass spectrometry and considered as potential markers for cultivars with distinct seed protein accumulation. The expression patterns of glutamate decarboxylase (GAD) and protein disulfide isomerase (PDI1-1) were followed at transcript level during grain development for three independent growth cycles to establish whether differences between cultivars were reproducible. Quantitative determination of PDI1-1 protein levels by ELISA confirmed a reproducibly, distinctive accumulation and post-translational modifications between cultivars, which were independent of plant growth regimes. According to its impact on differential storage protein accumulation, we propose the PDI1-1 protein as potential biomarker for Mexican malting barley cultivars. PMID- 30427900 TI - Repeatability and predictive value of lactate threshold concepts in endurance sports. AB - INTRODUCTION: Blood lactate concentration rises exponentially during graded exercise when muscles produce more lactate than the body can remove, and the blood lactate-related thresholds are parameters based on this curve used to evaluate performance level and help athletes optimize training. Many different concepts of describing such a threshold have been published. This study aims to compare concepts for their repeatability and predictive properties of endurance performance. METHODS: Forty-eight well-trained male cyclists aged 18-50 performed 5 maximal graded exercise tests each separated by two weeks. Blood lactate related thresholds were calculated using eight different representative concepts. Repeatability of each concept was assessed using Cronbach's alpha and intra subject CV and predictive value with 45 minute time trial tests and a road race to the top of Mont Ventoux was evaluated using Pearson correlations. RESULTS: Repeatability of all concepts was good to excellent (Cronbach's alpha of 0.89 0.96), intra-subject CVs were low with 3.4-8.1%. Predictive value for performance in the time trial tests and road race showed significant correlations ranging from 0.65-0.94 and 0.53-0.76, respectively. CONCLUSION: All evaluated concepts performed adequate, but there were differences between concepts. One concept had both the highest repeatability and the highest predictability of cycling performance, and is therefore recommended to be used: the Dmax modified method. As an easier to apply alternative, the lactate threshold with a fixed value of 4 mmol/L could be used as it performed almost as well. TRIAL REGISTRATION: Dutch Trial Registry NTR5643. PMID- 30427901 TI - Shared decision making embedded in the undergraduate medical curriculum: A scoping review. AB - OBJECTIVE: Shared decision making (SDM) training is shown to be effective and is increasingly embedded in continuing medical education. There is little evidence, however, about undergraduate medical education for SDM. The aim of this scoping review was to identify existing SDM training embedded in the undergraduate medical curriculum and analyze their impact. METHODS: The authors systematically searched the extant literature for peer reviewed articles, hand searched key journals and reference lists of key articles, and contacted relevant stakeholders as part of a key informant analysis. RESULTS: Included in the qualitative synthesis were 12 studies evaluating 11 SDM courses in medical education across six countries. Most courses integrated SDM training in clinical clerkship and varied in length from one to seven hours. The majority of studies assessed course impact on students' skills in SDM. Most studies suggested that students' skills and confidence in SDM significantly increased post-training, but three studies reported no significant improvement in SDM. Ten courses continue to be taught routinely. CONCLUSION: Overall, studies suggested a positive impact on medical students' skills, confidence, and attitudes regarding SDM. Embedding SDM training in undergraduate medical education may be a practical and effective solution for current barriers to the widespread adoption of SDM. PMID- 30427903 TI - Open-source sensor for measuring oxygen partial pressures below 100 microbars. AB - The ability to measure partial pressures of oxygen below 100 microbars and nanomolar dissolved oxygen concentrations in in situ laboratory systems benefits many fields including microbiology, geobiology, oceanography, chemistry, and materials science. Here, we present an easily constructible open-source design for a networked luminescence lifetime measurement system for in situ measurements in arbitrary laboratory containers. The system is well suited for measuring oxygen partial pressures in the 0-100 MUbar range, with the maximum potentially usable upper range limit at around 10 mbar, depending on experimental conditions. The sensor has a limited drift and its detectability limit for oxygen is at 0.02 MUbar for short timescale measurements. Each sensor can connect to a Wi-Fi network and send the logged data either over the Internet or to a local server, enabling a large number of parallel unattended experiments. Designs are also provided for attaching the sensor to various commercially available containers used in laboratories. The design files are released under an open source license, which enables other laboratories to build, customize, and use these sensors. PMID- 30427902 TI - ADHD symptoms and learning behaviors in children with ASD without intellectual disability. A mediation analysis of executive functions. AB - In spite of its importance for education, the relationship between learning behaviors (LB), attention deficit hyperactivity disorder symptoms (ADHD) and executive functioning (EF) in children with autism spectrum disorder (ASD) has hardly been explored. The first objective of the present study was to compare children with ASD without intellectual disability and children with typical development (TD) on ADHD symptoms and learning behaviors: Motivation/competence, attitude toward learning, persistence on the task, and strategy/flexibility. The second objective was to analyze the mediator role of behavioral regulation and metacognition components of EF between ADHD symptoms and learning behaviors in children with ASD. Participants were 89 children between 7 and 11 years old, 52 with ASD and 37 with TD, matched on age and intelligence. Their teachers filled out questionnaires assessing executive functioning as well as learning behaviors. Parents and teachers reported on inattention and hyperactivity/impulsivity behaviors. Compared to children with TD, children with ASD presented significantly more ADHD symptoms and poorer learning behaviors. In addition, there were significant mediation effects of the behavioral regulation index (BRI) and metacognition index (MI) of EF, indicating that both are part of the route through which ADHD symptoms impact to learning behaviors of children with ASD. PMID- 30427904 TI - Use of live yeast and mannan-oligosaccharides in grain-based diets for cattle: Ruminal parameters, nutrient digestibility, and inflammatory response. AB - The objective of this study was to evaluate the effects of diet supplementation with live yeast (Saccharomyces cerevisiae) and mannan-oligosaccharides (MOS) on ruminal parameters, nutrient digestibility, and the inflammatory response in cattle fed grain-based diets. Three Holstein steers (body weight of 497+/-3 kg) with ruminal and duodenal cannulas were assigned to a 3 * 3 Latin square design. The animals were kept in individual pens and fed a diet containing 5% sugarcane bagasse and 95% concentrate (906.5 g/kg ground corn). Diet treatments were Control (without additive), Yeast (1.5 g/kg DM live yeast Saccharomyces cerevisiae, NCYC 996) and MOS (1.5 g/kg DM MOS, beta-glucans and mannan). Dry matter intake, ruminal, intestinal, and total digestibility of nutrients were not affected by the treatments. The ruminal concentration of isobutyric acid increased in animals fed on diets supplemented with Yeast and MOS, whereas isovaleric acid increased with Yeast and decreased with MOS supplementation. Dietary supplementation with Yeast and MOS increased pH and decreased ammonia concentration in the rumen. Lipopolysaccharide (LPS) concentrations in the rumen and duodenal fluid were not influenced by the additives. However, both Yeast and MOS decreased the plasma levels of LPS and serum amyloid A (SAA). In conclusion, when high-concentrate diets fed to beef cattle are supplemented with either Yeast or MOS, ruminal pH is increased, LPS translocation into the blood stream is decreased, and blood SAA concentration is decreased. These factors reduce the inflammation caused by consumption of grain-based diets, and either supplement could be used to improve the rumen environment in beef cattle susceptible to ruminal subacute acidosis. PMID- 30427905 TI - Contrasting phylogeographic patterns and demographic history in closely related species of Daphnia longispina group (Crustacea: Cladocera) with focus on North Eastern Eurasia. AB - Species with large geographic distributions present a challenge for phylogeographic studies due to the logistic difficulties of obtaining adequate samples. Daphnia O.F. Muller (Anomopoda: Daphniidae) is a model genus for evolutionary biology and ecology, but many regions such as the remote areas of Siberia, remain poorly studied. Here we examined genetic polymorphism in the ribosomal 12S and the protein-coding ND2 mitochondrial genes of three closely related taxa of the Daphnia (Daphnia) longispina complex, namely D. galeata Sars, D. longispina O.F. Muller and D. dentifera Forbes. We estimated the phylogenetic relationships among these taxa based on a concatenated alignment of these two genes. Using sequences from the present study and those available in GenBank, we investigated the geographic distributions of the mitochondrial haplotypes of these species and proposed an evolutionary scenario for each taxon. Network structures, haplotype distribution patterns, and FST values indicated significant differences in the evolutionary history of the examined species. Our analysis of D. galeata populations confirmed its recent and fast expansion, without a previous phase of a strong population disconnection. In contrast, the high haplotype diversity in D. dentifera and D. longispina could be explained by the survival of different phylogroups in several glacial refugia located in different geographic regions. For all studied species, maximum haplotype diversity was recorded in the remote regions of Siberia-lakes of the Yenisei River and Transbaikalia. Our study is an important step in our understanding of the evolutionary history of the Daphnia longispina group and provides further evidence of the biogeographic significance of Siberia for freshwater taxa. PMID- 30427906 TI - Music for pain relief during bed bathing of mechanically ventilated patients: A pilot study. AB - BACKGROUND: Pain is a universal issue and is of particular concern in mechanically ventilated patients, as they require intensive nursing care and multiple invasive procedures, while being unable to communicate verbally. The aim of this study was to assess the effect of music on pain experienced by mechanically ventilated patients during morning bed bathing. METHODS: Of the 60 mechanically ventilated patients enrolled in this single-center pilot study between March 2013 and October 2015, the first 30 received no music and the next 30 the music intervention, during the morning bed bath. The Behavioral Pain Scale (BPS) score was determined during and at the end of the bath then 30, 60, and 120 minutes after the bath. BPS score changes over time were assessed and the proportions of bath times spent with a BPS score >=5 and with the maximal BPS score were determined. RESULTS: At baseline, no patient had pain (defined as a BPS score <5) and the median BPS score was 3 [IQR, 3;3] in both groups (P = 0.43). After bed bath initiation, 88% of patients experienced pain. The maximum BPS value during the bath was lower in the music group (5 [5;6.7] vs. 7 [5;7]). Proportions of total bath time spent with BPS>=5 and with the maximum BPS were significantly lower in the music group than in the control group (2.0 [0.3;4.0] vs. 10 [4.3;18.0]; P < .0001 and 1.5 [0;3.0] vs. 3.5 [2.0;6.0]; P = .005; respectively). Two hours after the end of the bath, the BPS values had returned to baseline in both groups. CONCLUSION: In our population, music significantly decreased pain intensity and duration during the morning bed bath in mechanically ventilated patients. These results warrant further assessment in a large multicenter randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT02883959. PMID- 30427907 TI - hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction. AB - Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance. PMID- 30427908 TI - Patient clusters based on HbA1c trajectories: A step toward individualized medicine in type 2 diabetes. AB - AIMS: To identify clinically meaningful clusters of patients with similar glycated hemoglobin (HbA1c) trajectories among patients with type 2 diabetes. METHODS: A retrospective cohort study using unsupervised machine learning clustering methodologies to determine clusters of patients with similar longitudinal HbA1c trajectories. Stability of these clusters was assessed and supervised random forest analysis verified the clusters' reproducibility. Clinical relevance of the clusters was assessed through multivariable analysis, comparing differences in risk for a composite outcome (macrovascular and microvascular outcomes, hypoglycemic events, and all-cause mortality) at HbA1c thresholds for each cluster. RESULTS: Among 60,423 patients, three clusters of HbA1c trajectories were generated: stable (n = 45,679), descending (n = 6,084), and ascending (n = 8,660) trends, which were reproduced with 99.8% accuracy using a random forest model. In the clinical relevance assessment, HbA1c levels demonstrated a J-shape association with the risk for outcomes. HbA1c level thresholds for minimizing outcomes' risk differed by cluster: 6.0-6.4% for the stable cluster, <8.0% for the descending cluster, and <9.0 for the ascending cluster. CONCLUSIONS: By applying unsupervised machine learning to longitudinal HbA1c trajectories, we have identified clusters of patients who have distinct risk for diabetes-related complications. These clusters can be the basis for developing individualized models to personalize glycemic targets. PMID- 30427909 TI - Non-alcoholic fatty liver disease in underweight patients with inflammatory bowel disease: A case-control study. AB - Non-alcoholic fatty liver disease (NAFLD) was shown to also occur in lean and underweight patients. So far, the prevalence of NAFLD in underweight individuals with and without inflammatory bowel disease (IBD) is insufficiently enlightened. In this cross-sectional age, gender and disease-matched case-control study, underweight patients (BMI<18.5 kg/m2) with inflammatory bowel disease (IBD), who underwent abdominal MRI at 1.5 T/3 T with fat-saturated fast-spin-echo imaging from 10/2005-07/2018 were analysed (control-to-case-ratio 1:1, n = 130). All patients were additionally investigated for duration, history of surgery, medical treatment, laboratory values, liver and spleen diameters. On MRI, liver fat was quantified by two observers based on the relative signal loss on T2-weighted fast spin-echo MR images with fat saturation compared to images without fat saturation. The prevalence of NAFLD/liver steatosis, defined as a measured intrahepatic fat content of at least 5%, was significantly higher in underweight IBD patients than in normal weight patients (87.6% versus 21.5%, p<0.001). Compared to the cases, the liver fat content of the controls was reduced by -0.19 units on average (-19%; 95%Cl: -0.20; -0.14). Similar results were obtained for the subgroup of non-IBD individuals (n = 12; -0.25 units on average (-25%); 95%Cl: -0.35; -0.14). Patients with extremely low body weight (BMI <17.5 kg/m2) showed the highest liver fat content (+0.15 units on average (+15%) compared to underweight patients with a BMI of 17.5-18.5 kg/m2 (p<0.05)). Furthermore, underweight patients showed slightly increased liver enzymes and liver diameters. There were no indications of significant differences in disease duration, type of medications or surgery between cases and controls and also, there were no significant differences between observers or field strengths (p>0.05). The prevalence of liver steatosis was higher among underweight IBD and non-IBD patients compared to normal weight controls. Also, underweight patients showed slightly increased liver enzymes and liver diameters, hinting at initial metabolic disturbances. PMID- 30427910 TI - Overexpression of BcHsfA1 transcription factor from Brassica campestris improved heat tolerance of transgenic tobacco. AB - Heat shock proteins (HSPs) are a type of conserved molecular chaperone. They exist extensively in plants and greatly contribute to their survival under heat stress. The transcriptional regulation factor heat shock factor (HSF) is thought to regulate the expression of Hsps. In this study, a novel gene designated BcHsfA1 was cloned and characterized from Brassica campestris. Bioinformatic analysis implied that BcHsfA1 belongs to the HsfA gene family and is most closely related to HsfA1 from other plants. Constitutive overexpression of BcHsfA1 significantly improved heat tolerance of tobacco seedlings by affecting physiological and biochemical processes. Moreover, the chlorophyll content of transgenic tobacco plants was significantly increased compared with wild type after heat stress, as were the activities of the important enzymatic antioxidants superoxide dismutase and peroxidase. BcHsfA1 overexpression also resulted in decreased malondialdehyde content and comparative electrical conductivity and increased soluble sugar content in transgenic tobacco plants than wild-type plants exposed to heat stress. Furthermore, we identified 11 candidate heat response genes that were significantly up-regulated in the transgenic lines exposed to heat stress. Together, these results suggested that BcHsfA1 is effective in improving heat tolerance of tobacco seedlings, which may be useful in the development of new heat-resisitant B. campestris strains by genetic engineering. PMID- 30427911 TI - An in vitro correlation of metastatic capacity and dual mechanostimulation. AB - Cells are under the influence of multiple forms of mechanical stimulation in vivo. For example, a cell is subjected to mechanical forces from tissue stiffness, shear and tensile stress and transient applied strain. Significant progress has been made in understanding the cellular mechanotransduction mechanisms in response to a single mechanical parameter. However, our knowledge of how a cell responds to multiple mechanical inputs is currently limited. In this study, we have tested the cellular response to the simultaneous application of two mechanical inputs: substrate compliance and transient tugging. Our results suggest that cells within a multicellular spheroid will restrict their response to a single mechanical input at a time and when provided with two mechanical inputs simultaneously, one will dominate. In normal and non-metastatic mammary epithelial cells, we found that they respond to applied stimulation and will override substrate compliance cues in favor of the applied mechanical stimulus. Surprisingly, however, metastatic mammary epithelial cells remain non-responsive to both mechanical cues. Our results suggest that, within our assay system, metastatic progression may involve the down-regulation of multiple mechanotransduction pathways. PMID- 30427912 TI - Midwest pharmacists' familiarity, experience, and willingness to provide pre exposure prophylaxis (PrEP) for HIV. AB - INTRODUCTION: Pharmacist provision of pre-exposure prophylaxis (PrEP) through collaborative practice agreements with physicians could expand access to people at risk for HIV. We characterized pharmacists' familiarity with and willingness to provide PrEP services in Nebraska and Iowa. METHODS: An invitation to complete an 18-question survey was emailed to 1,140 pharmacists in Nebraska and Iowa in June and July of 2016. Descriptive analyses and Pearson chi-square tests were used to determine to what extent demographics, familiarity and experience were associated with respondent willingness to provide PrEP. Wilcoxon rank-sum tests compared ages and years of experience between groups of respondents. RESULTS: One hundred forty pharmacists (12.3%) responded. Less than half were familiar with the use of PrEP (42%) or the CDC guidelines for its use (25%). Respondents who were older (p = .015) and in practice longer (p = .005) were less likely to be familiar with PrEP. Overall, 54% indicated they were fairly or very likely to provide PrEP services as part of a collaborative practice agreement and after additional training. While familiarity with PrEP use or guidelines did not affect respondents' willingness to provide PrEP, respondents were more likely to provide PrEP with prior experience counseling HIV-infected patients on antiretroviral therapy (OR 2.43; p = 0.023) or PrEP (OR 4.67; p = 0.013), and with prior HIV related continuing education (OR 2.77; p = 0.032). CONCLUSIONS: Pharmacist respondents in Nebraska and Iowa had limited familiarity and experience with PrEP, but most indicated willingness to provide PrEP through collaborative practice agreements after additional training. Provision of PrEP-focused continuing education may lead to increased willingness to participate in PrEP programs. PMID- 30427913 TI - Optimal intensive care outcome prediction over time using machine learning. AB - BACKGROUND: Prognostication is an essential tool for risk adjustment and decision making in the intensive care unit (ICU). Research into prognostication in ICU has so far been limited to data from admission or the first 24 hours. Most ICU admissions last longer than this, decisions are made throughout an admission, and some admissions are explicitly intended as time-limited prognostic trials. Despite this, temporal changes in prognostic ability during ICU admission has received little attention to date. Current predictive models, in the form of prognostic clinical tools, are typically derived from linear models and do not explicitly handle incremental information from trends. Machine learning (ML) allows predictive models to be developed which use non-linear predictors and complex interactions between variables, thus allowing incorporation of trends in measured variables over time; this has made it possible to investigate prognosis throughout an admission. METHODS AND FINDINGS: This study uses ML to assess the predictability of ICU mortality as a function of time. Logistic regression against physiological data alone outperformed APACHE-II and demonstrated several important interactions including between lactate & noradrenaline dose, between lactate & MAP, and between age & MAP consistent with the current sepsis definitions. ML models consistently outperformed logistic regression with Deep Learning giving the best results. Predictive power was maximal on the second day and was further improved by incorporating trend data. Using a limited range of physiological and demographic variables, the best machine learning model on the first day showed an area under the receiver-operator characteristic curve (AUC) of 0.883 (sigma = 0.008), compared to 0.846 (sigma = 0.010) for a logistic regression from the same predictors and 0.836 (sigma = 0.007) for a logistic regression based on the APACHE-II score. Adding information gathered on the second day of admission improved the maximum AUC to 0.895 (sigma = 0.008). Beyond the second day, predictive ability declined. CONCLUSION: This has implications for decision making in intensive care and provides a justification for time limited trials of ICU therapy; the assessment of prognosis over more than one day may be a valuable strategy as new information on the second day helps to differentiate outcomes. New ML models based on trend data beyond the first day could greatly improve upon current risk stratification tools. PMID- 30427914 TI - The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status. AB - Autophagy has been identified as a catabolic mechanism in cells but its' role in cancer remains controversial. Autophagy has been characterized either as tumor suppressor or inducer mechanism in many tumor types. Monoclonal antibodies against EGFR (cetuximab and panitumumab) represent a major step in the treatment of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy which reveals a potential resistance mechanism to these agents. The last years immunotherapy appears to be a novel promising strategy for the treatment of patients with solid tumors, including colorectal cancer. Checkpoint inhibitors, such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab) antibodies have already been developed and applied in mCRC patients with MSI-H phenotype. The association between mtBRAF and autophagy or MSI status has already been characterized. In our study, we identify the autophagy initiation through anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma cell lines according to microsatellite status. The combination of autophagy inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors appears to be the best treatment approach for microsatellite instability high and stable colorectal cancer cell lines, respectively. Both combinatorial approaches reduce cell viability through the induction of apoptotic cell death. The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype. PMID- 30427915 TI - A novel validated method for predicting the risk of re-hospitalization for worsening heart failure and the effectiveness of the diuretic upgrading therapy with tolvaptan. AB - Increased re-hospitalization due to acute decompensated heart failure (ADHF) is a modern issue in cardiology. The aim of this study was to investigate risk factors for re-hospitalization due to worsening heart failure, and the effect of tolvaptan (TLV) on decreasing the number of re-hospitalizations. This was a multicenter, retrospective study. The re-hospitalization factors for 1191 patients with ADHF were investigated; patients receiving continuous administration of TLV when they were discharged from the hospital (n = 194) were analyzed separately. Patients were classified into 5 risk groups based on their calculated Preventing Re-hospitalization with TOLvaptan (Pretol) score. The total number of patients re-hospitalized due to worsening heart failure up to one year after discharge from the hospital was 285 (23.9%). Age >=80 years, duration since discharge from the hospital after previous heart failure <6 months, diabetes mellitus, hemoglobin <10 g/dl, uric acid >7.2 mg/dl, left ventricular ejection fraction (LVEF) <40%, left atrial volume index (LAVI) >44.7 ml/m2, loop diuretic dose >=20 mg/day, hematocrit <31.6%, and estimated glomerular filtration rate (eGFR) <50 ml/min/1.73m2 were independent risk factors for re-hospitalization for worsening heart failure. There was a significant reduction in the re hospitalization rate among TLV treated patients in the Risk 3 group and above. In conclusions, age, duration since previous heart failure, diabetes mellitus, hemoglobin, uric acid, LVEF, LAVI, loop diuretic dose, hematocrit, and eGFR were all independent risk factors for re-hospitalization for worsening heart failure. Long-term administration of TLV significantly decreases the rate of re hospitalization for worsening heart failure in patients with a Pretol score of 7. PMID- 30427916 TI - Response of Tribolium castaneum to dietary mannitol, with remarks on its possible nutritive effects. AB - Mannitol, one of the sugar alcohols, is often used as a low-calorific carbohydrate by animals. In some insects, mannitol acts as a cryoprotectant to endure coldness, but also become a poisonous agent. Adults of the red flour beetle Tribolium castaneum were shown to recognize mannitol as a factor stimulating their feeding behavior, but it remains unclear whether T. castaneum can utilize mannitol as a source of nutrition, because the enzymes needed to metabolize mannitol are unknown in this species. This study shows that T. castaneum utilizes mannitol as a nutrient in a dietary assay based on a sole carbon source added to artificial gypsum diet. The amount of mannitol excreted was less than that ingested, suggesting that it is absorbed in the insect body. The hemolymph of T. castaneum contained no mannitol but contained trehalose, a known blood sugar in insects, even after being fed mannitol. This study also revealed that dietary mannitol was metabolized to triglyceride, the main component of the fat body, forming lipid droplets. It was found that metabolites of a mannitol-supplemented diet extend the lifespan of T. castaneum, compared with those obtained by metabolizing a mannitol-free diet. Given that the insects presented transcriptional changes upon being fed carbohydrates, it might be possible to identify specific genes related to mannitol-specific metabolism by their upregulation upon mannitol intake in T. castaneum. The present study investigated mannitol-responsive gene expression using RNA-Seq. Twenty-eight genes, including those encoding trehalose-6-phosphate synthase and fatty acid synthase, were differentially expressed between beetles that were fed or not fed mannitol. The identification of upregulated genes provides us with important insights into the molecular events following mannitol intake. PMID- 30427917 TI - Dynamic integration of conceptual information during learning. AB - The development and application of concepts is a critical component of cognition. Although concepts can be formed on the basis of simple perceptual or semantic features, conceptual representations can also capitalize on similarities across feature relationships. By representing these types of higher-order relationships, concepts can simplify the learning problem and facilitate decisions. Despite this, little is known about the neural mechanisms that support the construction and deployment of these kinds of higher-order concepts during learning. To address this question, we combined a carefully designed associative learning task with computational model-based functional magnetic resonance imaging (fMRI). Participants were scanned as they learned and made decisions about sixteen pairs of cues and associated outcomes. Associations were structured such that individual cues shared feature relationships, operationalized as shared patterns of cue pair-outcome associations. In order to capture the large number of possible conceptual representational structures that participants might employ and to evaluate how conceptual representations are used during learning, we leveraged a well-specified Bayesian computational model of category learning [1]. Behavioral and model-based results revealed that participants who displayed a tendency to link experiences in memory benefitted from faster learning rates, suggesting that the use of the conceptual structure in the task facilitated decisions about cue pair-outcome associations. Model-based fMRI analyses revealed that trial-by-trial integration of cue information into higher-order conceptual representations was supported by an anterior temporal (AT) network of regions previously implicated in representing complex conjunctions of features and meaning-based information. PMID- 30427918 TI - Validity and feasibility of the Arabic version of distress thermometer for Saudi cancer patients. AB - BACKGROUND: The distress thermometer (DT) has been studied and validated as an effective screening instrument for identifying distress among cancer patients worldwide. This study aims to evaluate the validity of the Arabic version of the DT in Saudi cancer patients, to define the optimal cutoff point of the Arabic DT for detecting clinically significant distress and to determine whether there is any correlation between clinically significant distress and other demographic and Problem List variables. METHODS: The original form of the DT was translated to Arabic using a forward and backward translation method. Then, a group of 247 cancer patients who were followed up at the Outpatient Oncology Clinic at King Saud Medical City in Riyadh, Saudi Arabia, completed a socio-demographic and clinical status questionnaire, the DT and the Problem List scale, and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Receiver operating characteristic (ROC) curve analyses picked out an area under the curve of 0.76 when compared with a HADS cutoff score of 15. The DT had the best sensitivity (0.70) and specificity (0.63) with cutoff score of 4. A DT score of 4 or more was found to have a statistically significant correlation with female gender, advanced cancer stages and most of the Problem List items, including child care, work or school, treatment decision, dealing with children and partners, depression, fears, nervousness, sadness, loss of interest in usual activity, religious concerns, appearance, bathing/dressing, breathing, diarrhea, fatigue, feeling swollen, fever, getting around, indigestion, memory and concentration, nausea, dry nose, pain, and sexual problems. In contrast, a multivariate regression analysis confirmed only advanced cancer stages, treatment decision, depression, fear, sadness, worry, breathing, feeling swollen, fever, indigestion, memory and concentration, dry nose and congestion, pain and sleep as independent factors associated with distress in cancer patients. CONCLUSIONS: We found the Arabic version of the DT to be a valid instrument for screening distress in Saudi patients with cancer. Our study proposes using a cutoff score of 4 as an indicator of clinically significant distress in this population. PMID- 30427919 TI - An investigation of genotype-phenotype association in a festulolium forage grass population containing genome-spanning Festuca pratensis chromosome segments in a Lolium perenne background. AB - Alien chromosome introgression is used for the transfer of beneficial traits in plant breeding. For temperate forage grasses, much of the work in this context has focused on species within the ryegrasses (Lolium spp.) and the closely related fescues (Festuca spp.) particularly with a view to combining high forage quality with reliability and enhanced environmental services. We have analysed a L. perenne (perennial ryegrass) population containing the majority of a F. pratensis (meadow fescue) genome as introgressed chromosome segments to identify a) marker-trait associations for nutrient use and abiotic stress response across the family, and b) to assess the effects of introgression of F. pratensis genomic regions on phenotype. Using container-based assays and a system of flowing solution culture, we looked at phenotype responses, including root growth, to nitrogen and phosphorus status in the growing medium and abiotic stresses within this festulolium family. A number of significant marker/trait associations were identified across the family for root biomass on chromosomes 2, 3 and 5 and for heading date on chromosome 2. Of particular interest was a region on chromosome 2 associated with increased root biomass in phosphorus-limited conditions derived from one of the L. perenne parents. A genotype containing F. pratensis chromosome 4 as a monosomic introgression showed increased tiller number, shoot and root growth and genotypes with F. pratensis chromosome segment introgressions at different ends of chromosome 4 exhibited differential phenotypes across a variety of test conditions. There was also a general negative correlation between the extent of the F. pratensis genome that had been introgressed and root-related trait performances. We conclude that 1) the identification of alleles affecting root growth has potential application in forage grass breeding and, 2) F. pratensis introgressions can enhance quantitative traits, however, introgression can also have more general negative effects. PMID- 30427920 TI - Identification of a DNA region associated with the cool virulence of Ralstonia solancearum strain UW551 and its utilization for specific detection of the bacterium's race 3 biovar 2 strains. AB - The cool virulent Ralstonia solanacearum race 3 biovar 2 (r3b2) strains cause destructive brown rot of potato. They are quarantined pathogens in Europe and Canada and select agent pathogens in the United States. We previously identified r3b2 (sequevars 1 and 2)-unique fragments that clustered into 32 regions in the genome of R. solanacearum. In this study, we targeted five of those regions for mutagenesis in order to determine whether they are involved in cool temperature related biological functions for diagnostic purpose. Knockout mutants of four regions produced no changes to the biology of the r3b2 strain UW551. The mutation of region 13, which is 3,407 bp in size, resulted in significantly reduced twitching motility, attachment to the roots of tomato seedlings, and virulence under cool temperature conditions (18-24 degrees C), although no significant difference was found under warm temperature conditions (24-30 degrees C) as compared to the wild type strain. As a result, we designed primer pair Rs-CV-F and Rs-CV-R to target the region 13 for specific detection of r3b2 strains of R. solanacearum. Our assay specifically detected all the 34 r3b2 strains and none of the 56 non-r3b2 strains of R. solanacearum, nor any other five plant- or soil associated bacteria including Enterobacter cloacae, Pseudomonas syringae pv. syringae, Xanthomonas campestris pv. campestris, X. citri, and R. pickettii. Unexpectedly, in silico analysis predicted that a recently deposited non-sequevar 1 or 2 Brazilian R. solanacearum strain RS489 would be recognized by our assay and by previously published r3b2-specific assays, although the cool-virulent status of this strain is unclear. Our PCR assay is the first to target a DNA region associated with cool-virulence that makes r3b2 strains highly regulated pathogens for specific detection of this important group of R. solanacearum. PMID- 30427921 TI - Correction: A systematic review on the effects of resistance and plyometric training on physical fitness in youth- What do comparative studies tell us? AB - [This corrects the article DOI: 10.1371/journal.pone.0205525.]. PMID- 30427922 TI - Rapid quantification of clove (Syzygium aromaticum) and spearmint (Mentha spicata) essential oils encapsulated in a complex organic matrix using an ATR FTIR spectroscopic method. AB - Essential oils (EOs) are often encapsulated in various and complex matrices to protect them against potential degradation or to control their release. To achieve an optimum use in food products, their rapid and precise quantification after encapsulation and storage is required. Hence, a rapid ATR-FTIR method was developed and tested with two encapsulated essential oils (EOs): clove (Syzygium aromaticum) and spearmint (Mentha spicata);. Despite, the complexity of the matrix, this method coupled with univariate or multivariate regression models exhibited high potential for global quantification of the two encapsulated EOs. For clove EO, in relation to the major presence of eugenol and eugenol acetate, an analysis based on a unique band (1514 cm-1) was sufficient to obtain a good prediction with RMSEP value of 0.0173 g of EO per g of matrix. For spearmint oil which is characterized by numerous terpenoid compound, three bands (799, 885, and 1680-1676 cm-1) were suitable for a good prediction with RMSEP value of 0.0133. ATR-FTIR method was compared with a reference gas chromatography FID quantitative method in an EO release experiment and its efficiency was evaluated through modeling by the Avrami equation. Beside time saving, the ATR-FTIR method was also capable of monitoring the EO profile. This method could be easily adapted as a routine analysis in the EOs industry as quality control. PMID- 30427923 TI - Testing the generalized validity of the Emotion Knowledge test scores. AB - Differential item functioning (DIF) is of the utmost importance in order to corroborate the generalized validity of test scores in different groups. DIF indicates that an item does not function equally in different groups such as age, gender or cultural ones. Our objective was to contrast the generalized validity of the Emotion Knowledge (EK) test scores in a heterogeneous Argentinian sample composed of 100 females and 100 males (age range: 18-65). Data from the original validation sample (200 Spanish participants, half of them males) were conjointly analyzed (total n = 400). Results of the Rasch Model (RM) analysis indicated that both fit to the RM and reliability (ISR = .97, PSR = .80) were adequate. Item logit measures ranged from -3.89 to 3.68, and person logit measures ranged from 1.12 to 5.09, with a mean value of 2.36. DIF was tested for gender, age, educational level and country, with a few item contrasts found to be statistically significant. Even though small significant differences in EK scores were associated with educational level (d = .25) and country (d = -.25), they became non-significant after removing the seven country-related DIF affected items. We can conclude that there is enough evidence for the generalized validity of EK test scores in Argentina. Given that recent theories of human emotion consider conceptual knowledge supported by language as constitutive of emotions, the EK test can be used in academic or applied settings where individual differences in emotional competence might be relevant. PMID- 30427925 TI - Sex-specific genetic influence on thyroid-stimulating hormone and free thyroxine levels, and interactions between measurements: KNHANES 2013-2015. AB - BACKGROUND: Although a wide range of genetic influences on thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels have been reported, sex differences in the genetic influences have not been well described. METHODS: We assessed TSH and fT4 levels in 2,250 subjects without thyroid peroxidase antibody, with data obtained from the Korea National Health and Nutrition Examination Surveys (KNHANES) conducted from 2013 to 2015. Using variance decomposition methods, the variation of TSH and fT4 levels was divided into genetic and environmental components common to both sexes, and to males and females separately. The genetic correlation between TSH and fT4 levels was also assessed in both sexes, and in males and females separately. RESULTS: Narrow-sense heritability for TSH and fT4 were 54% and 56%, respectively. Sex-specific heritability for TSH levels was significantly higher in females than in males (75% and 41%, respectively; p = 0.037). Heritability for fT4 levels was not significantly different between males and females (62% and 52%, respectively; p = 0.335). TSH and fT4 levels showed a negative genetic correlation in females (rhog = -0.347, p = 0.040) after regressing out the influences of environmental covariates, but this correlation was not present in males (rhog = -0.160, p = 0.391). CONCLUSIONS: The genetic influences on individual TSH levels were more prominent in females than in males. In addition, female-specific pleiotropy between TSH and fT4 might be a clue that this stronger genetic influences in females would mainly affect thyroid function per se, rather than other TSH-related factors that do not primarily trigger the negative feedback loop between TSH and fT4. PMID- 30427924 TI - eHealth for people with multimorbidity: Results from the ICARE4EU project and insights from the "10 e's" by Gunther Eysenbach. AB - BACKGROUND: People with multimorbidity, especially older people, have complex health and social needs, and require an integrated care approach. In this respect, eHealth could be of support. This paper aims to describe the implementation of eHealth technologies in integrated care programs for people with multimorbidity in Europe, and to analyse related benefits and barriers according to outcomes from ICARE4EU study and within the more general conceptual framework of the "10 e's" in eHealth by Gunther Eysenbach. METHODS: In 2014, ICARE4EU project identified 101 integrated care programs in 24 European countries. Expert organizations and managers of the programs completed an on-line questionnaire addressing several aspects including the adoption of eHealth. Findings from this questionnaire were analyzed, by linking in particular benefits and barriers of eHealth with the "10 e's" by Eysenbach (Efficiency, Enhancing, Evidence-based, Empowerment, Encouragement, Education, Enabling, Extending, Ethics, and Equity). RESULTS: Out of 101 programs, 85 adopted eHealth tools, of which 42 focused explicitly on older people. eHealth could improve care integration/management, quality of care/life and cost-efficiency, whereas inadequate funding represents a major barrier. The "10 e's" by Eysenbach seem to show contact points with ICARE4EU findings, in particular when referring to positive aspects of eHealth such as Efficiency and Enhancing quality of care/life, although Empowerment/Education of patients, care Equity and Ethics issues seem crucial in this respect. Encouragement of a new relationship patient health professional, and Enabling standardized exchange of electronic information, represent further aspects impacting integration/management of care. CONCLUSIONS: Aspects of eHealth, which emerged as benefits and barriers impacting integration/management of care, as well as cost-efficiency and quality of care/life, can be identified on the basis of both ICARE4EU findings and the "10 e's" in eHealth by Eysenbach. They could represent objectives of new policies for supporting the deployment of eHealth technologies within integrated care across Europe. PMID- 30427926 TI - Severe maternal outcomes in eastern Ethiopia: Application of the adapted maternal near miss tool. AB - BACKGROUND: With the reduction of maternal mortality, maternal near miss (MNM) has been used as a complementary indicator of maternal health. The objective of this study was to assess the frequency of MNM in eastern Ethiopia using an adapted sub-Saharan Africa MNM tool and compare its applicability with the original WHO MNM tool. METHODS: We applied the sub-Saharan Africa and WHO MNM criteria to 1054 women admitted with potentially life-threatening conditions (including 28 deaths) in Hiwot Fana Specialized University Hospital and Jugel Hospital between January 2016 and April 2017. Discharge records were examined to identify deaths or women who developed MNM according to the sub-Saharan or WHO criteria. We calculated and compared MNM and severe maternal outcome ratios. Mortality index (ratio of maternal deaths to SMO) was calculated as indicator of quality of care. RESULTS: The sub-Saharan Africa criteria identified 594 cases of MNM and all the 28 deaths while the WHO criteria identified 128 cases of MNM and 26 deaths. There were 7404 livebirths during the same period. This gives MNM ratios of 80 versus 17 per 1000 live births for the adapted and original WHO criteria. Mortality index was 4.5% and 16.9% in the adapted and WHO criteria respectively. The major difference between the two criteria can be attributed to eclampsia, sepsis and differences in the threshold for transfusion of blood. CONCLUSION: The sub-Saharan Africa criteria identified all the MNM cases identified by the WHO criteria and all the maternal deaths. Applying the WHO criteria alone will cause under reporting of MNM cases (including maternal deaths) in this low-resource setting. The mortality index of 4.5% among women who fulfilled the adapted MNM criteria justifies labeling these women as having 'life threatening conditions'. PMID- 30427928 TI - Altered circulating levels of B cell growth factors and their modulation upon anti-tuberculosis treatment in pulmonary tuberculosis and tuberculous lymphadenitis. AB - B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL) are members of the tumor necrosis factor alpha (TNF) alpha family of ligands, which are essential for B cell survival, development, and modulation of the immune system. To examine the association of circulating levels of BAFF and APRIL with pulmonary tuberculosis (PTB) and tuberculous lymphadenitis (TBL), we measured the systemic levels of APRIL and BAFF in individuals with PTB, TBL, latent tuberculosis (LTB) and healthy controls (HC). Further, we also examined the pre and post-treatment plasma levels of above-mentioned parameters in PTB and TBL individuals upon completion of anti-TB chemotherapy. Next, the association of these cytokines either with extent of disease, disease severity, bacterial burden in PTB and lymph node culture grade or the lymph node size in TBL was also assessed. Finally, ROC analysis was performed to examine the discrimination capacity of APRIL and BAFF between PTB or TBL with LTB. Our study revealed significantly diminished plasma levels of APRIL in PTB and higher plasma levels of BAFF in both PTB and TBL individuals compared to LTB and HC. Furthermore, we observed a significant increase in APRIL levels in TBL and significantly decreased plasma levels of BAFF in both PTB and TBL after the completion of successful anti-TB treatment. There was no statistically positive relationship between BAFF and APRIL levels and the extent of disease, disease severity and bacterial burden in PTB. In TBL, there was a significant correlation between APRIL (but not BAFF) levels with lymph node culture grades. In contrast, APRIL in PTB and BAFF in TBL were able to clearly discriminate from LTB in ROC analysis. In summary, our results showed altered levels of BAFF/APRIL and their modulation upon chemotherapy, suggesting that these cytokines might be involved in the immune modulation of TB infection. PMID- 30427927 TI - Botulinum toxin A-induced muscle paralysis stimulates Hdac4 and differential miRNA expression. AB - At sufficient dose, intramuscular injection of Botulinum toxin A causes muscle wasting that is physiologically consistent with surgical denervation and other types of neuromuscular dysfunction. The aim of this study was to clarify early molecular and micro-RNA alterations in skeletal muscle following Botulinum toxin A-induced muscle paralysis. Quadriceps were analyzed for changes in expression of micro- and messenger RNA and protein levels after a single injection of 0.4, 2 or 4U Botulinum toxin A (/100g body weight). After injection with 2.0U Botulinum toxin A, quadriceps exhibited significant reduction in muscle weight and increased levels of ubiquitin ligase proteins at 7, 14 and 28 days. Muscle miR-1 and miR-133a/b levels were decreased at these time points, whereas a dose responsive increase in miR-206 expression at day 14 was observed. Expression of the miR-133a/b target genes RhoA, Tgfb1 and Ctfg, and the miR-1/206 target genes Igf-1 and Hdac4, were upregulated at 28 days after Botulinum toxin A injection. Increased levels of Hdac4 protein were observed after injection, consistent with anticipated expression changes in direct and indirect Hdac4 target genes, such as Myog. Our results suggest Botulinum toxin A-induced denervation of muscle shares molecular characteristics with surgical denervation and other types of neuromuscular dysfunction, and implicates miR-133/Tgf-beta1/Ctfg and miR 1/Hdac4/Myog signaling during the resultant muscle atrophy. PMID- 30427929 TI - DNA barcodes corroborating identification of mosquito species and multiplex real time PCR differentiating Culex pipiens complex and Culex torrentium in Iran. AB - Identifying mosquito species is a fundamental step in risk assessment and implementation of preventative strategies. Moreover, Culex pipiens is the most widespread mosquito vector in several regions of Iran and is the main vector for transmission of West Nile virus (WNV). Mosquitoes were collected at 14 sites in northern regions of Iran in 2015 and 2016. A subset of mosquito specimens was selected for identification confirmation using a DNA-barcoding technique. Construction of a phylogenetic tree showed clustering of mosquito sequences into three main genera: Aedes, Anopheles and Culex with individuals of a single species clustered closely together, regardless of where and when they were collected. Cx. pipiens complex and Cx. torrentium were identified and differentiated using multiplex real-time PCR targeting the gene locus for acetylcholinesterase 2 (ace2) to discriminate between Cx. pipiens pipiens and Cx. torrentium. The CQ11 microsatellite locus was used for discrimination between Cpp. biotypes. The predominant mosquito species in investigated regions were Cx. pipiens pipiens biotype pipiens, but we also detected Culex pipiens pipiens biotype molestus and hybrids of the two pipiens biotypes, as well as Cx. torrentium. The results of this study represent the first certain evidence of the presence of Cx. pipiens pipiens biotype molestus and hybrids between pipiens and molestus forms, and Cx. torrentium in Iran through a molecular identification approach. This report of a potentially important bridge vector for WNV might have key influence in the risk projections for WNV in Iran. PMID- 30427930 TI - Modelling the spatial distribution of three Portunidae crabs in Haizhou Bay, China. AB - Crab species are economically and ecologically important in coastal ecosystems, and their spatial distributions are pivotal for conservation and fisheries management. This study was focused on modelling the spatial distributions of three Portunidae crabs (Charybdis bimaculata, Charybdis japonica, and Portunus trituberculatus) in Haizhou Bay, China. We applied three analytical approaches (Generalized additive model (GAM), random forest (RF), and artificial neural network (ANN)) to spring and fall bottom trawl survey data (2011, 2013-2016) to develop and compare species distribution models (SDMs). Model predictability was evaluated using cross-validation based on the observed species distribution. Results showed that sea bottom temperature (SBT), sea bottom salinity (SBS), and sediment type were the most important factors affecting crab distributions. The relative importance of candidate variables was not consistent among species, season, or model. In general, we found ANNs to have less stability than both RFs and GAMs. GAMs overall yielded the least complex response curve structure. C. japonica was more pronounced in southwestern portion of Haizhou Bay, and C. bimaculata tended to stay in offshore areas. P. trituberculatus was the least region-specific and exhibited substantial annual variations in abundance. The comparison of multiple SDMs was informative to understand species responses to environmental factors and predict species distributions. This study contributes to better understanding the environmental niches of crabs and demonstrates best practices for the application of SDMs for management and conservation planning. PMID- 30427931 TI - Typology of patients with behavioral addictions or eating disorders during a one year period of care: Exploring similarities of trajectory using growth mixture modeling coupled with latent class analysis. AB - OBJECTIVES: Addictions are not restricted to substance-use disorders, and it is now widely recognized that they also include behavioral addictions. Certain individuals with eating disorders also experiment their disorder as an addiction. The objective was to identify typologies of patients presenting with various behavioral addictions or eating disorders according to their evolution within the framework of care, and to specify the factors associated with the differential clinical trajectories. METHODS: We included 302 patients presenting with problem gambling, sexual addiction, compulsive buying, excessive videogame use or eating disorders. The patients completed a multiaxial assessment through a face-to-face structured interview and self-administered questionnaires, including sociodemographic and addiction-related characteristics, psychiatric and addictive comorbidities and several psychological characteristics. The assessment was performed at inclusion and then repeated after 6 and 12 months. The statistical analysis included a combination of growth mixture models and latent class analysis. RESULTS: We identified five classes of patients with different profiles related to their trajectories during a one-year period of specialized care: "complex patients", "patients with impulsive psychological functioning", "patients with cooperative psychological functioning", "patients with immature psychological functioning," and "patients with resilient psychological functioning". CONCLUSIONS: The typology obtained brings interesting findings to propose patient-centered care strategies adapted to these disorders. Because the typology was independent from the type of disorder, it supports the general concept of behavioral addictions, and the similarities between eating disorders and behavioral addictions. The relevance of this model should be further examined in future studies. PMID- 30427932 TI - A meta-analysis on the role of pleiotrophin (PTN) as a prognostic factor in cancer. AB - BACKGROUND: Some researchers reported that pleiotrophin (PTN) is associated with the development and metastasis of various tumors and it is a poor prognostic factor for the tumor patients. However, the results of other researches are inconsistent with them. It is obliged to do a meta-analysis to reach a definite conclusion. METHODS: The published studies relevant to PTN were searched in the databases including PubMed, Embase and Web of Science until March 20, 2018. A meta-analysis was conducted to evaluate the role of PTN in clinicopathological characteristics and overall survival (OS) of cancer patients. RESULTS: Our meta analysis indicated that the high expression of PTN was remarkably associated with advanced TNM stage (OR = 2.79, 95%CI: 1.92-4.06, P<0.00001) and poor OS (HR = 1.77, 95%CI: 1.41-2.22, P<0.00001) in tumor patients. The expression of PTN was not associated with tumor size (OR = 1.12, 95% CI: 0.55-2.26, P = 0.76), lymph node metastasis (LNM) (OR = 1.95, 95%CI: 0.62-6.12, P = 0.25), distant metastasis (DM) (OR = 2.78, 95%CI: 0.72-10.74, P = 0.14) and histological grade (OR = 1.95, 95%CI: 0.98-3.87, P = 0.06). CONCLUSION: The high expression of PTN is significantly relevant to the advanced TNM stage and poor OS in tumor patients. PTN can serve as a promising biomarker to predict unfavorable survival outcomes, and it may be a potential target for tumor treatment. PMID- 30427933 TI - Effects of early, combined endurance and resistance training in mechanically ventilated, critically ill patients: A randomised controlled trial. AB - INTRODUCTION: Neuromuscular weakness resulting in severe functional impairment is common in critical care survivors. This study aimed to evaluate effects of an early progressive rehabilitation intervention in mechanically ventilated adults at risk. METHODS: This was a parallel, two-arm, assessor-blinded, randomised controlled trial with 6-months follow-up that was conducted in a mixed ICU of an academic centre in Switzerland. Previously independent, mechanically ventilated, critically ill adults with expected critical care stay >=72 hours (n = 115) were randomised to a control group receiving standard physiotherapy including early mobilisation or to an experimental group with early endurance and resistance training combined with mobilisation. Primary endpoints were functional capacity (6-Minute Walk Distance) and functional independence (Functional Independence Measure) at hospital discharge. Secondary endpoints including muscle strength were assessed at critical care discharge. Safety was monitored closely by standard monitoring and predefined adverse events. RESULTS: Physiotherapy started within 48 hours of critical care admission while 97% of participants were still ventilated and 68% on inotropes. Compared to the control group (n = 57), the experimental group (n = 58) received significantly more physiotherapy (sessions: 407 vs 377, p<0.001; time/session: 25min vs 18min, p<0.001) and had less days with sedation (p<0.001). Adverse events were rare (0.6%) and without consequences. There were no significant between-group differences in 6-Minute Walk Distance (experimental 123m (IQR 25-280) vs control 100m (IQR 0-300); p = 0.542) or functional independence (98 (IQR 66-119) vs 98 (IQR 18-115); p = 0.308). Likewise, no differences were found for the secondary outcomes, except a trend towards improved mental health in the experimental group after 6 months (84 (IQR 68-88) vs 70 (IQR 64-76); p = 0.023). CONCLUSIONS: Early endurance and resistance training in mechanically ventilated, intensive care patients does not improve functional capacity or independence at hospital discharge compared to early standard physiotherapy but may improve mental health 6-months after critical care discharge. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00004347, registered on 10 September 2012. PMID- 30427934 TI - HFE hemochromatosis screening in patients with severe hip osteoarthritis: A prospective cross-sectional study. AB - OBJECTIVE: Despite the high frequency of HFE gene mutations in Western Europe, widespread screening for HFE hemochromatosis is not recommended due to its variable phenotype. Joint pain and a premature osteoarthritis-like disease including the hip joints are the most frequent manifestation in patients with HFE hemochromatosis and iron overload. Therefore, screening of patients with severe osteoarthritis of the hip could identify patients with HFE hemochromatosis. METHODS: In this prospective cross-sectional study, 940 patients aged <70 years with end-stage osteoarthritis of the hip undergoing elective joint replacement surgery were screened for HFE hemochromatosis and compared to age- and sex matched controls. RESULTS: No greater prevalence of C282Y homozygosity mutation or elevated serum ferritin or transferrin saturation levels was found in the study cohort with severe osteoarthritis of the hip than in controls from the general population. CONCLUSION: Our screening approach could not identify an increased prevalence of HFE gene mutations and iron overload in younger patients with severe osteoarthritis of the hip. PMID- 30427935 TI - Adaptive plasticity in the gametocyte conversion rate of malaria parasites. AB - Sexually reproducing parasites, such as malaria parasites, experience a trade-off between the allocation of resources to asexual replication and the production of sexual forms. Allocation by malaria parasites to sexual forms (the conversion rate) is variable but the evolutionary drivers of this plasticity are poorly understood. We use evolutionary theory for life histories to combine a mathematical model and experiments to reveal that parasites adjust conversion rate according to the dynamics of asexual densities in the blood of the host. Our model predicts the direction of change in conversion rates that returns the greatest fitness after perturbation of asexual densities by different doses of antimalarial drugs. The loss of a high proportion of asexuals is predicted to elicit increased conversion (terminal investment), while smaller losses are managed by reducing conversion (reproductive restraint) to facilitate within-host survival and future transmission. This non-linear pattern of allocation is consistent with adaptive reproductive strategies observed in multicellular organisms. We then empirically estimate conversion rates of the rodent malaria parasite Plasmodium chabaudi in response to the killing of asexual stages by different doses of antimalarial drugs and forecast the short-term fitness consequences of these responses. Our data reveal the predicted non-linear pattern, and this is further supported by analyses of previous experiments that perturb asexual stage densities using drugs or within-host competition, across multiple parasite genotypes. Whilst conversion rates, across all datasets, are most strongly influenced by changes in asexual density, parasites also modulate conversion according to the availability of red blood cell resources. In summary, increasing conversion maximises short-term transmission and reducing conversion facilitates in-host survival and thus, future transmission. Understanding patterns of parasite allocation to reproduction matters because within-host replication is responsible for disease symptoms and between-host transmission determines disease spread. PMID- 30427936 TI - Iron-enriched diet contributes to early onset of osteoporotic phenotype in a mouse model of hereditary hemochromatosis. AB - Osteoporosis is associated with chronic iron overload secondary to hereditary hemochromatosis (HH), but the causative mechanisms are incompletely understood. The main objective of this study was to investigate the role of dietary iron on osteoporosis, using as biological model the Hfe-KO mice, which have a systemic iron overload. We showed that these mice show an increased susceptibility for developing a bone loss phenotype compared to WT mice, which can be exacerbated by an iron rich diet. The dietary iron overload caused an increase in inflammation and iron incorporation within the trabecular bone in both WT and Hfe-KO mice. However, the osteoporotic phenotype was only evident in Hfe-KO mice fed the iron enriched diet. This appeared to result from an imbalance between bone formation and bone resorption driven by iron toxicity associated to Hfe-KO and confirmed by a decrease in bone microarchitecture parameters (identified by micro-CT) and osteoblast number. These findings were supported by the observed downregulation of bone metabolism markers and upregulation of ferritin heavy polypeptide 1 (Fth1) and transferrin receptor-1 (Tfrc), which are associated with iron toxicity and bone loss phenotype. In WT mice the iron rich diet was not enough to promote a bone loss phenotype, essentially due to the concomitant depression of bone resorption observed in those animals. In conclusion the dietary challenge influences the development of osteoporosis in the HH mice model thus suggesting that the iron content in the diet may influence the osteoporotic phenotype in systemic iron overload conditions. PMID- 30427937 TI - How relationship status and sociosexual orientation influence the link between facial attractiveness and visual attention. AB - Facial attractiveness captures and binds visual attention, thus affecting visual exploration of our environment. It is often argued that this effect on attention has evolutionary functions related to mating. Although plausible, such perspectives have been challenged by recent behavioral and eye-tracking studies, which have shown that the effect on attention is moderated by various sex- and goal-related variables such as sexual orientation. In the present study, we examined how relationship status and sociosexual orientation moderate the link between attractiveness and visual attention. We hypothesized that attractiveness leads to longer looks and that being single as well as being more sociosexually unrestricted, enhances the effect of attractiveness. Using an eye-tracking free viewing paradigm, we tested 150 heterosexual men and women looking at images of urban real-world scenes depicting two people differing in facial attractiveness. Participants additionally provided attractiveness ratings of all stimuli. We analyzed the correlations between how long faces were looked at and participants' ratings of attractiveness and found that more attractive faces-especially of the other sex-were looked at longer. We also found that more sociosexually unrestricted participants who were single had the highest attractiveness attention correlation. Our results show that evolutionary predictions cannot fully explain the attractiveness-attention correlation; perceiver characteristics and motives moderate this relationship. PMID- 30427938 TI - Ultra-rapid near universal TB drug regimen identified via parabolic response surface platform cures mice of both conventional and high susceptibility. AB - As current treatment of tuberculosis is burdensomely long, provoking non adherence and drug resistance, effective short-course treatments are needed. Using the output-driven parabolic response surface (PRS) platform, we have identified drug regimens that treat tuberculosis more rapidly in mice than the current Standard Regimen used in humans. We show that PRS Regimen III, comprising clofazimine, SQ109, bedaquiline and pyrazinamide, rapidly sterilizes the lung both in conventionally studied BALB/c mice and in C3HeB/FeJ mice, highly susceptible mice that develop massive necrotic granulomatous lung lesions akin to those in humans, achieving relapse-free cure in only 4 weeks (p<0.0001 versus Standard Regimen). In contrast, the Standard Regimen required 16 weeks to attain lung culture negative status and 20 weeks to achieve relapse-free cure. Thus, PRS Regimen III dramatically cuts by ~80% the time to relapse-free cure in mouse tuberculosis models. PRS Regimen III, with three nonstandard drugs, can potentially treat both drug-sensitive and most drug-resistant tuberculosis. PMID- 30427940 TI - Correction: Distribution of vesicle pools in cerebellar parallel fibre terminals after depression of ectopic transmission. AB - [This corrects the article DOI: 10.1371/journal.pone.0200937.]. PMID- 30427939 TI - Movement behaviors and cardiometabolic risk in schoolchildren. AB - Growing evidence has accumulated in recent years showing that movement behaviors have important implications for health in children, especially for cardiovascular health, whose risk factors could track from childhood to adulthood. However, these findings are mixed and inconsistent in children. The aim of this study was to examine the relationship between different movement behaviors (sedentary behavior, physical activity and sleep duration) and cardiometabolic risk in schoolchildren. The study shows cross-sectional results of baseline measurement from 146 Spanish schoolchildren, aged 8-to-11 years old, participating in the MOVI-2 study. Movement behaviors were determined using accelerometry combined with self-reported sleep time. Cardiometabolic risk was assessed using a validated metabolic syndrome index. Logistic regression analysis showed that higher levels of vigorous physical activity (OR = 0.110, p = 0.004) and sleeping more than 9 hours (OR = 0.269, p = 0.015) could be protective factors against metabolic syndrome risk in children. ANCOVA analysis showed associations between vigorous physical activity and waist circumference (p < 0.001), and sleep time with insulin resistance (p = 0.017) and lipid profile (p = 0.035). No association was observed between light and moderate physical activity, sedentary behavior and metabolic syndrome (index and components). No statistically significant differences were found for blood pressure and any of the movement behaviors. Our data suggest that both the amount of vigorous physical activity accumulated and sleep duration are independently associated with higher cardiometabolic risk in children. PMID- 30427941 TI - Clinical impact of complement (C1q, C3d) binding De Novo donor-specific HLA antibody in kidney transplant recipients. AB - INTRODUCTION: Complement binding activity of donor-specific HLA antibodies (DSA) has been suggested as a new tool to stratify immunologic risk in kidney transplantation (KT). The objective of this study was to evaluate the clinical implication of C1q/C3d binding activity of de novo DSA (dnDSA) in KT recipients. MATERIAL AND METHODS: A total of 161 pretransplant DSA-negative recipients were monitored for dnDSA at the time of biopsy. C1q/C3d binding activities of dnDSA were assessed using C1qScreen assay (One lambda, USA) and Lifecodes C3d detection assay (Immucor, USA), respectively. Clinical outcomes including biopsy-proven antibody mediated rejection (AMR), C4d detection and post-biopsy graft survival were investigated. RESULTS: De-novo DSAs were detected in fifty-four (33.5%) patients (HLA class I only, n = 19; class II only, n = 29; both class I and II, n = 6). Of them, complement binding activities were detected in 26 (48.1%) patients, including 17 C1q+ and 24 C3d+ patients. Both C1q and C3d positivity were associated with increased mean fluorescence intensity values of dnDSA. Complement binding activity of dnDSA enhanced the incidence of AMR (25.0% in C1q C3d-, 36.4% in C1q+/C3d- or C1q-/C3d+, and 60.0% in C1q+/C3d+ patients) (P <0.001). The incidence of AMR was not different between patients with C1q+ and those with C3d+ dnDSA (64.7%, 11/17 versus 45.8%, 11/24, P = 0.238). In comparison between C1q and C3d assay according to HLA specificity, C1q+ HLA class I +/- II dnDSA was the best predictor for AMR (odds ratio: 27.2). C1q+/C3d+ dnDSA was associated with more C4d deposition in allograft tissue and inferior post biopsy graft survival. Clinical outcomes were not significantly different between C1q+ and C3d+ dnDSA-positive patients. CONCLUSION: Detection of complement binding activity using both C1q and C3d assays can be a further prognostic marker for predicting AMR and allograft outcome in dnDSA+ kidney transplant patients. PMID- 30427942 TI - Resonance control of acoustic focusing systems through an environmental reference table and impedance spectroscopy. AB - Acoustic standing waves can precisely focus flowing particles or cells into tightly positioned streams for interrogation or downstream separations. The efficiency of an acoustic standing wave device is dependent upon operating at a resonance frequency. Small changes in a system's temperature and sample salinity can shift the device's resonance condition, leading to poor focusing. Practical implementation of an acoustic standing wave system requires an automated resonance control system to adjust the standing wave frequency in response to environmental changes. Here we have developed a rigorous approach for quantifying the optimal acoustic focusing frequency at any given environmental condition. We have demonstrated our approach across a wide range of temperature and salinity conditions to provide a robust characterization of how the optimal acoustic focusing resonance frequency shifts across these conditions. To generalize these results, two microfluidic bulk acoustic standing wave systems (a steel capillary and an etched silicon wafer) were examined. Models of these temperature and salinity effects suggest that it is the speed of sound within the liquid sample that dominates the resonance frequency shift. Using these results, a simple reference table can be generated to predict the optimal resonance condition as a function of temperature and salinity. Additionally, we show that there is a local impedance minimum associated with the optimal system resonance. The integration of the environmental results for coarse frequency tuning followed by a local impedance characterization for fine frequency adjustments, yields a highly accurate method of resonance control. Such an approach works across a wide range of environmental conditions, is easy to automate, and could have a significant impact across a wide range of microfluidic acoustic standing wave systems. PMID- 30427943 TI - Correction: Andrographis paniculata (Chuan Xin Lian) for symptomatic relief of acute respiratory tract infections in adults and children: A systematic review and meta-analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0181780.]. PMID- 30427944 TI - Characterization of Haartman Institute snake virus-1 (HISV-1) and HISV-like viruses-The representatives of genus Hartmanivirus, family Arenaviridae. AB - The family Arenaviridae comprises three genera, Mammarenavirus, Reptarenavirus and the most recently added Hartmanivirus. Arenaviruses have a bisegmented genome with ambisense coding strategy. For mammarenaviruses and reptarenaviruses the L segment encodes the Z protein (ZP) and the RNA-dependent RNA polymerase, and the S segment encodes the glycoprotein precursor and the nucleoprotein. Herein we report the full length genome and characterization of Haartman Institute snake virus-1 (HISV-1), the putative type species of hartmaniviruses. The L segment of HISV-1 lacks an open-reading frame for ZP, and our analysis of purified HISV-1 particles by SDS-PAGE and electron microscopy further support the lack of ZP. Since we originally identified HISV-1 in co-infection with a reptarenavirus, one could hypothesize that co-infecting reptarenavirus provides the ZP to complement HISV-1. However, we observed that co-infection does not markedly affect the amount of hartmanivirus or reptarenavirus RNA released from infected cells in vitro, indicating that HISV-1 does not benefit from reptarenavirus ZP. Furthermore, we succeeded in generating a pure HISV-1 isolate showing the virus to replicate without ZP. Immunofluorescence and ultrastructural studies demonstrate that, unlike reptarenaviruses, HISV-1 does not produce the intracellular inclusion bodies typical for the reptarenavirus-induced boid inclusion body disease (BIBD). While we observed HISV-1 to be slightly cytopathic for cultured boid cells, the histological and immunohistological investigation of HISV-positive snakes showed no evidence of a pathological effect. The histological analyses also revealed that hartmaniviruses, unlike reptarenaviruses, have a limited tissue tropism. By nucleic acid sequencing, de novo genome assembly, and phylogenetic analyses we identified additional four hartmanivirus species. Finally, we screened 71 individuals from a collection of snakes with BIBD by RT-PCR and found 44 to carry hartmaniviruses. These findings suggest that harmaniviruses are common in captive snake populations, but their relevance and pathogenic potential needs yet to be revealed. PMID- 30427945 TI - The effectiveness of clove oil and two different cautery disbudding methods on preventing horn growth in dairy goat kids. AB - The effectiveness of clove oil and cautery disbudding on horn growth was evaluated in goat kids. The study used 243 Saanen doe kids (4+/-1 days old; mean+/-SD) on two goat farms that were disbudded with either (i) clove oil injection (CLOVE), (ii) a cautery iron and bud removed (BUDOFF), or (iii) a cautery iron with bud left intact (BUDON). Each kid received a different treatment per bud, which were balanced between buds (left/right) and randomly allocated. A trained observer monitored bud growth following treatment for 3 months recording either: N: no growth, H: normal horn, S: abnormal horn (scur), or SC: soft, fibrous lump (scorn). After the final observation, buds were assessed for the probability of detecting (i) success (no growth), (ii) scurs, (iii) horns or (iv) scorns [with 95% CI]. The probability of success for BUDOFF (0.77 [0.63, 0.87]) was higher than for BUDON (0.20 [0.11, 0.34]) and CLOVE (0.09 [0.04, 0.18]; P <= 0.05). Furthermore, the probability of success for BUDON was higher than for CLOVE (P <= 0.05). The probability of scurs was higher for CLOVE (0.72 [0.63, 0.80]) than BUDOFF (0.25 [0.17, 0.34]) and BUDON (0.30 [0.21, 0.39]; P <= 0.05). There was no difference in the probability of scurs for BUDOFF and BUDON (P > 0.05). The probability of horns was higher for CLOVE (0.21 [0.15, 0.29]) than BUDON (0.02 [0.01, 0.06]; P <= 0.05); horns were not observed for BUDOFF. The probability of scorns for BUDON, the only treatment that led to scorns, was 0.41 (0.25, 0.60). These results suggest that BUDOFF was more effective at preventing growth than CLOVE and BUDON and appears the most effective method, of the methods tested, for disbudding kids. Future research should explore other alternatives to cautery disbudding that may be both efficacious and cause less pain. PMID- 30427946 TI - Eocene metatherians from Anatolia illuminate the assembly of an island fauna during Deep Time. AB - Island biotas have disproportionately influenced the history and development of evolutionary biology, but understanding their genesis and evolution across geological timescales has been hindered by a poor fossil record. Here we augment the insular Eocene (~43 Ma) mammalian fauna known from the Pontide terrane of central Anatolia by describing two new metatherian taxa (stem marsupials) from the Luluk Member of the Uzuncarsidere Formation in the Orhaniye Basin. Geological and paleontological data indicate that the Pontide terrane was an island on the northern margin of Neotethys during the middle Eocene. Reflecting its geodynamic context in a region of active tectonic convergence, the Eocene Pontide terrane hosted a unique combination of Laurasian and Gondwanan mammals, including an anachronistic radiation of pleuraspidotheriids (archaic ungulates) that went extinct on the European mainland ~13 Ma earlier. Most of the mammalian clades occupying the Pontide terrane colonized it by dispersal across marine barriers rather than being stranded there through vicariance. Endemic radiations of pleuraspidotheriid ungulates and polydolopimorphian metatherians on the Pontide terrane reveal that in situ diversification was an important factor contributing to faunal assembly and evolution. The insular fauna that arose on the Pontide terrane is highly analogous to that of modern Sulawesi, which evolved under strikingly similar geological conditions. Illustrating the ephemeral nature of insular biotas across macroevolutionary timescales, the demise of the Pontide fauna coincided with paleogeographic changes enabling more cosmopolitan taxa to reach it for the first time. The high level of endemism shown by the mammalian fauna of the Uzuncarsidere Formation eliminates the Pontide terrane as a potential early Eocene dispersal corridor between western Europe and India. PMID- 30427947 TI - Creatinine- versus cystatin C-based renal function assessment in the Northern Manhattan Study. AB - BACKGROUND: Accurate glomerular filtration rate estimation informs drug dosing and risk stratification. Body composition heterogeneity influences creatinine production and the precision of creatinine-based estimated glomerular filtration rate (eGFRcr) in the elderly. We compared chronic kidney disease (CKD) categorization using eGFRcr and cystatin C-based estimated GFR (eGFRcys) in an elderly, racially/ethnically diverse cohort to determine their concordance. METHODS: The Northern Manhattan Study (NOMAS) is a predominantly elderly, multi ethnic cohort with a primary aim to study cardiovascular disease epidemiology. We included participants with concurrently measured creatinine and cystatin C. eGFRcr was calculated using the CKD-EPI 2009 equation. eGFRcys was calculated using the CKD-EPI 2012 equation. Logistic regression was used to estimate odds ratios and 95% confidence intervals of factors associated with reclassification from eGFRcr>=60ml/min/1.73m2 to eGFRcys<60ml/min/1.73m2. RESULTS: Participants (n = 2988, mean age 69+/-10yrs) were predominantly Hispanic, female, and overweight/obese. eGFRcys was lower than eGFRcr by mean 23mL/min/1.73m2. 51% of participants' CKD status was discordant, and only 28% maintained the same CKD stage by both measures. Most participants (78%) had eGFRcr>=60mL/min/1.73m2; among these, 64% had eGFRcys<60mL/min/1.73m2. Among participants with eGFRcr>=60mL/min/1.73m2, eGFRcys-based reclassification was more likely in those with age >65 years, obesity, current smoking, white race, and female sex. CONCLUSIONS: In a large, multiethnic, elderly cohort, we found a highly discrepant prevalence of CKD with eGFRcys versus eGFRcr. Determining the optimal method to estimate GFR in elderly populations needs urgent further study to improve risk stratification and drug dosing. PMID- 30427949 TI - Mechanical Behavior of Different Micro Conical Abutments in Fixed Prosthesis. AB - PURPOSE: To evaluate the biomechanical behavior between two different micro conical abutments: two-piece and one-piece abutments. MATERIALS AND METHODS: Four groups were divided according to the prosthetic connection (internal or external hexagon) and abutment type. The vertical misfit between the abutment and implant was evaluated under stereomicroscope. Next, the implants were divided into pairs and embedded in polyurethane to receive two-element prostheses. The initial removal torque was measured for abutments and for prosthesis fixation. The samples were mechanically cycled (200 N, 2 Hz, 2 * 106 cycles) before measuring the torque loss in the same regions. For stress verification, a finite element analysis was used. RESULTS: For vertical misfit, one-piece (4.70 +/- 0.26 MUm) < two-piece (16.8 +/- 0.32 MUm). For preload in abutment screw, two-piece = one piece. For prosthetic screw, a higher percentage of preload was found for two piece, but no statistical difference was observed after fatigue cycling between the groups. For stress analysis, no difference (10%) was observed for abutments, retention screw, or for the bone. CONCLUSION: The one-piece abutment maintained even amounts of preload after cyclic loading and presented less vertical misfit in comparison with the two-piece abutment for both implant connections. The use of one-piece abutments did not increase the stress and strain concentration, suggesting acceptable biomechanical behavior. PMID- 30427948 TI - The pharmacokinetics of dexmedetomidine in patients with obstructive jaundice: A clinical trial. AB - OBJECTIVES: Dexmedetomidine, a highly selective central alpha2-agonist, undergoes mainly biotransformation in the liver. The pharmacokinetics of dexmedetomidine were significantly affected by hepatic insufficiency. The clearance of dexmedetomidine in patients with severe hepatic failure decreased by 50% compared with controls. We tested the hypothesis that the pharmacokinetics of dexmedetomidine would be affected by obstructive jaundice. The prospective registration number of clinical trial is ChiCTR-IPR-15007572. METHODS: 18 patients with obstructive jaundice and 12 non-jaundiced patient controls received dexmedetomidine, 1 MUg/kg, over 10 min. Arterial blood samples were drawn before, during, and up to 5 h after the infusion. Plasma dexmedetomidine concentrations were determined by 1290 infinity high performance liquid chromatography coupled with 6470 tandem mass spectrometry. The relevant pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 7.0. RESULTS: Plasma clearance of dexmedetomidine was decreased by 33.3% in the obstructive jaundice group as compared with the control group (0.0068+/-0.0017 vs. 0.0102+/ 0.0033 L/kg/min; P = 0.002). Volume of distribution was decreased by 29.2% in the obstructive jaundice group as compared with the control group (1.43+/-0.58 vs. 2.02+/-0.84 L/kg; P = 0.041). CONCLUSIONS: This study demonstrates that the clearance and distribution volume of dexmedetomidine were decreased in patients with obstructive jaundice. It may be advisable to adjust the dose of dexmedetomidine in those patients. PMID- 30427951 TI - Accuracy of Implant Placement with a Navigation System, a Laboratory Guide, and Freehand Drilling. AB - PURPOSE: Computer-aided surgery under navigation system guidance is widely applied in dental implant procedures. However, the accuracy of drilling with such navigation systems has not been comparatively evaluated alongside those of laboratory guide-based and freehand drilling. Therefore, this study aimed to compare the accuracies of these three drilling systems. MATERIALS AND METHODS: A navigation system, a laboratory guide, and freehand drilling were used to drill 150 holes on 30 cast models. Two master models-one each for the maxilla and mandible-were prepared with the idea of placing five implants per cast. After drilling five holes on each cast, postoperative cone beam computed tomography images were acquired to measure the magnitude of errors. RESULTS: The navigation system and laboratory guide were more accurate than freehand placement with respect to total errors at the entry and apex, lateral error at the apex, and angular error. The navigation system was more accurate than the laboratory guide with respect to angular error. Laboratory guide-based drilling was more accurate than freehand drilling in terms of lateral error at entry. CONCLUSION: In comparison with the laboratory guide and freehand placement, the navigation system exhibited lower angular and axial errors. Despite its higher accuracy, the navigation system requires the operator to pay greater attention. PMID- 30427950 TI - Histologic Evaluation of Leucocyte- and Platelet-Rich Fibrin in the Inflammatory Process and Repair of Noncritical Bone Defects in the Calvaria of Rats. AB - PURPOSE: This study aimed to evaluate the effects of leucocyte- and platelet-rich fibrin (L-PRF) on the inflammatory process, tissue repair, and expression of vascular endothelial growth factor (VEGF) on bone defects in the calvaria of rats. MATERIALS AND METHODS: L-PRF was obtained from three animals submitted to cardiac puncture to prepare the membranes. Two noncritical defects with a diameter of 2 mm were created in the calvaria of 15 Wistar rats. The defects on the right side were filled with a blood clot (CTRL) and the left side with L-PRF. After 5, 15, and 30 days, the animals were euthanized and the specimens processed for histologic, histomorphometric, and immunohistochemical analyses. In order to measure the intensity of the inflammatory infiltrate and VEGF expression, scores were assigned from 0 to 3, with 0 being no expression, 1 discrete (up to 25%), 2 moderate (between 25% and 50%), and 3 intense (> 50%) expression. The area of bone neoformation at the edges of the defects was also quantified. RESULTS: A less intense inflammatory infiltrate was observed in the defects filled with L PRF compared with CTRL at all times analyzed (P < .05). At 5 days, no bone neoformation was observed in any of the groups evaluated. After 15 and 30 days, greater bone neoformation was observed in the group treated with L-PRF compared with the CTRL group (P < .05). At 15 days, 3,871.8 (1,070.15) MUm2 were recorded for the CTRL and 49,978.5 (14,360.7) MUm2 in the L-PRF. At 30 days, 62,284.5 (3,579.5) MUm2 were observed in the CTRL and 154,076.6 (31,464.9) MUm2 in the L PRF. At all evaluated times, a lower inflammatory infiltrate was observed in the group treated with L-PRF compared with the CTRL. VEGF expression was observed in the initial phase and throughout the tissue repair process in both groups. At 5 days, there was no difference in VEGF expression between the groups. VEGF was present at the initial phase and throughout the tissue repair process in both groups. In the L-PRF group, a decrease in VEGF expression was observed at 15 and 30 days compared with the CTRL group. CONCLUSION: L-PRF had a positive effect on the regenerative process of bony defects, with a reduced inflammatory response and greater bone neoformation. PMID- 30427952 TI - Evaluation of the 3D Augmented Reality-Guided Intraoperative Positioning of Dental Implants in Edentulous Mandibular Models. AB - PURPOSE: This research aimed to propose a three-dimensional (3D) augmented reality navigation method with point cloud-based image-patient registration that could merge virtual images in the real environment for dental implants using a 3D image overlay and to evaluate its feasibility. MATERIALS AND METHODS: A total of 12 rapid prototyping mandibular models were fabricated using a 3D printing method and were divided into two groups: 3D augmented reality-guided group and traditional two-dimensional (2D) image-guided group. A point cloud-based preoperative image-to-patient registration method was introduced to replace the traditional point-to-point registration. After the registration, dental implant surgery was performed in the two model groups using an augmented reality-guided navigation method and a traditional two-dimensional image-guided navigation method. The planned and actual postoperative implant positions were compared for measuring positional implantation errors. The surgery time was also recorded and compared between the two groups. RESULTS: In the model experiment, the root-mean square deviation of registration was 0.54 mm, and the implant surgery results showed < 1.5-mm mean linear deviation and < 5.5-degree angular deviation. The augmented reality-guided implantation showed smaller horizontal, vertical, and angular errors in the apical areas of the central incisor and the canine region. The surgery time using the augmented reality-guided navigation method was significantly shorter than that using the two-dimensional (2D) image-guided navigation method (P < .05). Moreover, the volunteer experiment demonstrated that the preoperative 3D models in situ accurately overlaid onto the surgical site. CONCLUSION: The proposed point cloud-based registration method can achieve excellent registration accuracy. Dental implant placement guided by the proposed 3D augmented reality navigation method showed better accuracy and applicability, as well as higher efficiency, than the traditional 2D image navigation method. PMID- 30427953 TI - In Vitro Characterization of Original and Nonoriginal Implant Abutments. AB - PURPOSE: In addition to original componentry, clinicians can choose to restore an implant using third-party parts claimed to be compatible with the original implant system. The goal of these in vitro experiments was to evaluate the performance of a selection of original and clone titanium abutments available for a widely used implant system with an internal conical connection. MATERIALS AND METHODS: Six groups of original and clone abutments compatible with NobelActive implants were compared based on the following parameters: dimensional accuracy, gap formation, circumferential strain, abutment screw preload, micromotion, abutment settling, median fatigue limit (MFL), and bacterial leakage. Each parameter was analyzed separately and compared with the original (reference) abutment applying a variety of statistical tests (alpha = .05). RESULTS: Overall, the results obtained in the different experiments showed considerable deviation from the reference abutment. Deviations in interface geometry of the abutments were inconsistent and reached up to 56.26%. Gap measurements performed on cross sections of implant-abutment assemblies were not sensitive enough for detecting consistent differences. Development of circumferential strain at the implant shoulder reached up to 1,389.30 MUm/m. Abutment screw preload ranged from 285.25 N to 397.70 N, while micromotion at the implant-abutment interface ranged from 61.68 MUm to 79.69 MUm. Abutment settling resulting from screw fixation was greater compared with settling caused by dynamic loading, reaching up to 0.09 mm. The MFL ranged from 246.00 N to 344.00 N. All implant-abutment combinations showed bacterial leakage after 6 days of incubation. CONCLUSION: While clone abutments may look similar to the original component, they display considerable differences and variations in their physico-mechanical characteristics detectable by advanced testing methods. How much these differences affect reliability and longevity of the restoration's clinical performance should be investigated in clinical studies. PMID- 30427954 TI - Citation Network Analysis of Dental Implant Literature from 2007 to 2016. AB - PURPOSE: This bibliometric study analyzed English language dental implant literature from 2007 to 2016 to evaluate and identify the terms, authors, and journals concerning dental implant articles with high citation count and the structure of their bibliometric networks. MATERIALS AND METHODS: The Web of Science database was searched to identify articles on the topic of dental implants published under the Web of Science category of Dentistry, Oral Surgery & Medicine from 2007 to 2016. The articles were first assessed using descriptive analysis concerning the authors, organizations, countries/territories, and journals. Afterward, VOSviewer was used to visualize the term map, author network, and journal network consisting of the most highly cited entities. CiteSpace II was used with default settings to identify keywords that experienced a large increase in citations received within the surveyed period of time. RESULTS: The citation analyses were based on 12,114 dental implant articles published during the survey period. The top five highly cited terms with > 500 publication counts were peri-implantitis (a mean of 20.17 citations per surveyed article [CPA]), survival rate (19.02 CPA), survival (18.74 CPA), implant failure (16.58 CPA), and success rate (16.53 CPA). The top five authors with highest average citations authored 80 papers (80/12,114 = 0.7%) that received 5,962 citations (5,962/151,404 = 3.9%) among the highly cited authors' network. Clinical Oral Implants Research had the largest total number of citation links (19,283), and hence, was in the center of the journal network, with a mean of 21.47 citations per surveyed article. CONCLUSION: The terms with high impact were related to implant success, survival, failure, and peri-implantitis. Clinical Oral Implants Research and The International Journal of Oral & Maxillofacial Implants were in the center of the journal citation network. PMID- 30427956 TI - Bone Quality and Quantity Alterations After Socket Augmentation with rhPDGF-BB or BMPs: A Systematic Review. AB - PURPOSE: The aim of this study was to systematically analyze the effect of growth factors, particularly recombinant human platelet-derived growth factor-BB (rhPDGF BB) and bone morphogenetic proteins (BMPs), on volumetric and histomorphometric changes after socket augmentation in comparison with the natural healing sockets. MATERIALS AND METHODS: An electronic search of four databases (1965 to February 2017) and a hand search of peer-reviewed journals for relevant articles were performed. Human clinical trials that reported quantitative and qualitative outcomes of soft and hard tissues in socket augmented sites with the use of rhPDGF-BB or BMPs, with a minimum five samples per group, were included. RESULTS: Eight studies, including six randomized controlled trials and two case series, were selected. Five of them used BMPs, and three used rhPDGF-BB. Regarding linear bone width change, the weighted mean difference (WMD) between the sites with and without the use of BMPs was 1.66 mm (95% confidence interval = 0.29 to 3.02 mm, P = .02), favoring the BMP group. In terms of histomorphometric outcome, the WMD of the percentage of vital bone between the sites with the use of rhPDGF-BB and with grafting materials alone was 2.16% (95% confidence interval = -4.61% to 8.93%, P = .53). CONCLUSION: This systematic review revealed that the use of BMPs in socket augmentation yields better ridge width in comparison with a natural healing socket. However, more studies are needed to warrant the effectiveness when using rhPDGF-BB in socket augmentation procedures. PMID- 30427955 TI - Effect of Bioactivation on Traditional Surfaces and Zirconium Nitride: Adhesion and Proliferation of Preosteoblastic Cells and Bacteria. AB - PURPOSE: The aim of this vitro study was to reproduce and evaluate the response of bone and bacteria to traditional and innovative implant surfaces with difference wettability. MATERIALS AND METHODS: Two hundred fifty-two samples made of grade 4 titanium with different coating (machined [MAC]; double-etched, Ti-AE; zirconium nitride [Ti-ZrN]) were used for this in vitro study. Disks were divided into test (bioactivated using plasma of argon) and control group (untreated). To assess the surface morphology of the specimens, representative images were acquired via scanning electron microscopy (SEM). Murine preosteoblasts (MC3T3-E1) were used to study the biologic response in vitro, while the quantification of protein adsorption was achieved through the incubation of the titanium samples in a 2% solution of fetal bovine serum (FBS) in phosphate-buffered saline (PBS). The sterilized titanium disks were then colonized by bacterial species from a single sputum sample obtained from a healthy volunteer. For every analysis, 24 disks were used (12 for each group). RESULTS: SEM and topographic analyses demonstrated a Sa value of 0.33 (Ti-ZrN), 0.34 (MAC), and 0.62 (Ti-AE). Compared with the control groups, plasma treatment significantly increased the protein adsorption level on all the different titanium surfaces (5.88 +/- 0.21 vs 7.85 +/- 0.21, 7.13 +/- 0.14 vs 9.74 +/- 0.65, 4.41 +/- 0.62 vs 6.13 +/- 0.52, respectively, for MAC, Ti-treated, and Ti-ZrN). Similar behavior was described for cell adhesion (27.67 +/- 2.03 vs 58.00 +/- 20.13, 116.67 +/- 12.02 vs 159.33 +/- 8.09, 52.00 +/ 4.73 vs 78.33 +/- 4.67, respectively, for MAC, Ti-treated, and Ti-ZrN). Plasma treatment significantly augmented the number of CFU only in MAC and ZrN samples. CONCLUSION: With the limitations of this in vitro study, the following conclusions could be drawn: (1) rough implant surfaces present a higher adhesion and proliferation of preosteoblastic cells and bacterial biofilm; (2) rough implant surfaces benefited the most by the plasma of argon treatment. PMID- 30427957 TI - Probability of Failure of Internal Hexagon and Morse Taper Implants with Different Bone Levels: A Mechanical Test and Probabilistic Fatigue. AB - PURPOSE: The goal of this study was to foresee the fatigue life of two implant connections, evaluate the failure probability with several bone levels, and compare the in vitro test results with finite element results. MATERIALS AND METHODS: Mechanical tests were done with 60 implants (O3.50 mm), and abutments were used. These implants were divided into two groups with 30 implants each: internal hexagon and Morse taper. Three bone levels and 10 implants for each level were analyzed. The first level was considered at the platform level, the second at 3 mm, and the last level at 5 mm above the platform resin. A quasi static loading at 30 degrees was applied to the axis of the implant in a universal machine. Six models were created and assembled to reproduce the conditions used in the laboratory testing. All models had restricted all displacement at the bone (bottom and lateral). Loads employed in the numerical test were obtained experimentally. Loads and material properties were supposed to be random. Then, failure probability was calculated by the probabilistic methodology. RESULTS: The internal hexagon group obtained the following mean fracture strengths: 2,092 N at the first level, 1,041 N at the second level, and 898 N at the third level. The mean fracture strengths for the Morse taper group were as follows: 1,687 N at the first level, 1,644 N at the second level, and 1,159 N at the third level. Results obtained by the finite element analysis are in accordance with the in vitro mechanical test results. The Morse taper group obtained a better behavior at bone levels 2 and 3 than the internal hexagon group. An important dependency between failure probability and bone level was found in the internal hexagon group. However, a similar behavior in levels 2 and 3 was obtained for the Morse taper group. CONCLUSION: In view of the mechanical results, the Morse taper group has a better behavior in bone levels 2 and 3 than the internal hexagon group. This is also in accordance with the probabilistic fatigue outcomes. PMID- 30427958 TI - Three-Dimensional Deformation and Wear of Internal Implant-Abutment Connection: A Comparative Biomechanical Study Using Titanium and Zirconia. AB - PURPOSE: The aim of this study was to investigate the influence of the abutment material and the connection geometry on deformation and wear at the internal implant-abutment connection area (IAC), using an optical scanner. MATERIALS AND METHODS: Thirty-two internal conical titanium implants, and two types of prefabricated abutments (zirconia or titanium), each (n = 8) with different connection geometries (hexagon or nonhexagon) were prepared. The inner surfaces of the implants were optically scanned before and after loading for 100,000 cycles in a simulated wet environment. The scanned data were superimposed to calculate potential three-dimensional (3D) deviations. Surfaces of the two respective implants in each group were examined using scanning electron microscopy to observe fretting wear patterns. A two-way analysis of variance (ANOVA) was used for the statistical analysis. RESULTS: The 3D deviation (deformation) was detected at the IAC in relation to the loading direction. The average 3D positive deviation and maximum positive and negative deviations at the IAC were significantly higher with zirconia abutments than with titanium abutments, regardless of connection geometries (all P < .05). However, the average 3D negative and standard 3D deviations were similar between the two materials (both P > .05). The effect of connection geometry was not significant (P > .05). After cyclic loading, an irregular wave-pattern furrow was observed on the connection area of the implant with the titanium abutment, whereas a long and straight groove was detected on that with the zirconia abutment. CONCLUSION: Based on this analysis, the deformation and the wear at the IAC could be significantly affected by the material of the prefabricated abutment. PMID- 30427959 TI - Optimization of Tilted Implant Geometry for Stress Reduction in All-on-4 Treatment Concept: Finite Element Analysis Study. AB - PURPOSE: The aim of this work was a finite element analysis of the effect of a sloped platform in tilted implants in the All-on-4 treatment concept on the level of maximum stresses in compact bone. MATERIALS AND METHODS: Finite element modeling of the stresses at tilted microthread implants with standard and sloped abutment platform under four loading conditions and two levels of osseointegration was performed. RESULTS: The sloped abutment platform in tilted implants positioned at rim bone level resulted in a two to four times reduction of the maximum von Mises stresses in the adjacent cortical bone compared with the standard platform. These stresses were well below the yield stress of the cortical bone. The main importance of the proposed sloped platform in tilted implants is substantial stress reduction in the case of immediate loading. The stress reduction also results in the reduction of the deformation of the framework of the All-on-4 concept. CONCLUSION: The suggested modification of the slope of the abutment platform on tilted implants is recommended as a technically simple and highly effective solution for significant reduction of maximum stresses in the cortical bone around the implant. PMID- 30427960 TI - An In Vivo and Cone Beam Computed Tomography Investigation of the Accuracy in Measuring Alveolar Bone Height and Detecting Dehiscence and Fenestration Defects. AB - PURPOSE: To investigate cone beam computed tomography (CBCT) accuracy in measuring facial bone height and detecting dehiscence and fenestration defects around teeth. MATERIALS AND METHODS: Patients who were treatment planned for periodontal flap or dental implant surgeries were enrolled (n = 25). CBCT imaging (Carestream CS 9300) was obtained at 0.09-mm voxels (n = 10 patients, 23 teeth) and at 0.18-mm voxels (n = 15 patients, 33 teeth). Facial bone height measurements, from cusp tip to crest of bone height along the long axis of the tooth, and presence or absence of dehiscence or fenestration defects were recorded from CBCT images in triplicates independently by two examiners. The corresponding clinical measurements were made at the time of surgery. Comparisons of CBCT and clinical measurements were made using paired t tests for teeth: anterior and posterior, maxillary and mandibular, with or without restorations, or root canal therapy. Level of agreement between investigators was assessed by concordance correlation coefficients (CCC), Pearson's correlation coefficient (PCC), and Cohen's Kappa. RESULTS: Comparing mean CBCT and clinical measurements, statistically significant differences were noted for 0.09-mm and 0.18-mm voxel sizes, for anterior and posterior teeth, for maxillary and mandibular teeth, for teeth with or without restorations, and for teeth without root canal therapy (P < .05). Clinical and CBCT measurements were similar for teeth with crowns and with root canal therapy (P > .05). CBCT measurements underestimated mean facial bone height from 0.33 +/- 0.78 to 0.88 +/- 1.14 mm (mean +/- SD) and absolute facial bone height values from 0.56 +/- 0.35 to 1.08 +/- 0.92 mm. Intraexaminer and interexaminer reliability for measuring facial bone height ranged from poor to substantial (PCC = 0.78 to 0.97 and CCC = 0.63 to 0.96, respectively). Interexaminer reliability for detection of dehiscence and fenestration defects ranged from poor to moderate (Cohen's Kappa = -0.09 to 0.66). CONCLUSION: CBCT imaging underestimated facial bone height and overestimated the presence of dehiscence and fenestration defects. PMID- 30427961 TI - A Multicenter Retrospective Clinical Study with Up-to-5-Year Follow-up Utilizing a Method that Enhances Bone Density and Allows for Transcrestal Sinus Augmentation Through Compaction Grafting. AB - PURPOSE: To evaluate the effectiveness and predictability of a novel biomechanical, minimally invasive bone instrumentation technique that enhances bone density through compaction grafting, called osseous densification, and allows for transcrestal sinus membrane elevation and augmentation with simultaneous implant placement. MATERIALS AND METHODS: Patients who were consecutively treated with the bone densification and transcrestal sinus augmentation technique and were followed up in three treatment centers between May 2012 and September 2017 were included in this retrospective study. The summary statistics are presented as means for continuous variables and percentages for categorical variables. RESULTS: In total, 222 patients with 261 implants were included in the final clinical analysis. The included follow-up period ranged from 6 to 64 months with a mean of 35 months. The subsinus residual bone height at baseline was 5.4 mm (SD: 1.9). Following the sinus augmentation, a significant vertical increase of 7 mm (SD: 2.49) was observed. No sinus membrane perforations and no late implant failures were observed from 6 up to 64 months follow-up, yielding a cumulative implant survival rate of 97%. CONCLUSION: This osseous densification technique for maxillary implant site preparation with transcrestal sinus augmentation and simultaneous implant placement led to favorable clinical outcomes with up to 64 months of follow-up. PMID- 30427962 TI - Survival of Dental Implants Replacing Previously Failed Implants: A Retrospective Study in a University Setting. AB - PURPOSE: The rate of dental implant failures ranges from 3% to 8%, with that number increasing as the number of implants placed increases. When an implant fails, the survival rate drops significantly when a second or third attempt is performed. The aim of this study was to evaluate the survival rate of an implant placed in a previously failed implant site and to explore the risk factors that might affect the outcome of the second procedure. MATERIALS AND METHODS: A retrospective chart review was conducted for patients receiving dental implants at the University of Texas, School of Dentistry from 1985 to 2017. Exclusion criteria included patients with genetic diseases, radiation and chemotherapy, or an age less than 18 years. Data on age, sex, race, tobacco use, diabetes, cardiovascular, osteoporosis, implant brand, anatomical location of the implant, implant length and width, respective information on the replacement implant, and professional maintenance were collected for analysis. RESULTS: A total of 1,234 patients with 2,742 implants were included. A chart review found that of the 247 failed implants, replacement of implants was performed in 85 patients with 99 implants. More than half of the initial implants failed within the first year of placement. Based on the 12-month performance of each brand, the initially failed implants were categorized as high, medium, or low survival rates. Based on this categorization, the replacement implants that belonged to the medium survival rate category showed higher survival rates than the high survival group of the initially failed implants. CONCLUSION: The cumulative survival rates of the replacement implants were 91% at 1 year, 88% at 5 years, and 83% at 10 years. Implant failures were more common prior to functional loading. PMID- 30427963 TI - Histomorphometric Results of a Randomized Controlled Clinical Trial Studying Maxillary Sinus Augmentation with Two Different Biomaterials and Simultaneous Implant Placement. AB - PURPOSE: Maxillary sinus augmentation has been a predictable procedure. However, in-depth analysis of tissue healing after sinus grafting with simultaneous implant placement is limited. This study aimed to compare histologic outcomes after sinus grafting with a synthetic bone graft compared with a xenograft. MATERIALS AND METHODS: A randomized controlled split-mouth study was conducted to compare bone formation around microimplants (2.00 mm, Dentium) placed at the time of maxillary sinus augmentation with a synthetic material (Osteon, Dentium) (OST) and deproteinized bovine bone (Bio-Oss) (BIO) as the control group. Four microimplants per subject (n = 13) were placed bilaterally for intrasubject comparison (two implants per side/patient). Bone cores with osseointegrated microimplants were harvested for histomorphometric analysis 6 to 8 months after sinus augmentation surgery. RESULTS: Histologic analysis revealed newly formed bone deposited on the microimplant surface and bridging to bone graft material in both groups. Further, there was no histologic evidence of signs of inflammation in all specimens. In general, bone-to-implant contact was comparable and ranged from 6.1% to 67.0% with a mean of 38.4% +/- 11.61% in OST and from 10.5% to 57.0% with a mean of 34.58% +/- 12.55% in BIO. However, a significantly higher percentage of bone-to-implant contact in the first four threads of the grafted area was noted in OST compared with BIO (P = .016). CONCLUSION: The synthetic OST was found to be equivalent to BIO in new bone formation and clinical success after sinus augmentation in conjunction with microimplant placement. Although there are some statistically significant differences in the histologic outcomes, the clinical relevance of these needs to be further evaluated. Nevertheless, the findings of this study indicate that this synthetic alloplast would be a viable alternative to an allograft material. PMID- 30427964 TI - Higher Resolution in Cone Beam Computed Tomography Is Accompanied by Improved Bone Detection in Peri-implant Bone Despite Metal Artifact Presence. AB - PURPOSE: The aim of this study was to determine the possibility and extent of artifact reduction by an optimized use of cone beam computed tomography (CBCT) parameter configuration (geometric resolution, implant geometric parameters, and image analyses). It furthermore sought to determine the distance from correctly reproduced bone tissue to an implant, where the grayscale values are equal to the pre-implantation values. MATERIALS AND METHODS: Titanium implants were inserted into pig tibia under standardized conditions. CBCT investigations in the form of bone density mapping were performed under various CBCT settings and implantation situations. The circumference of the implants was measured in order to determine the extent of metal artifacts. This was done by determining grayscale and comparing it to the bone area prior to implantation. RESULTS: Using CBCT to determine bone density postimplantation showed a correlation in dependence of CBCT parameter configuration. Higher resolution led to a better detection of correct bone density values in the peri-implant region. Normal bone density values can be recognized at a distance of 370 MUm from the implant surface, when the spatial resolution is 125 MUm. Therefore, higher resolution in CBCT is accompanied by an improved bone detection in peri-implant bone, despite the presence of metal artifacts. Peri-implant bone defects that extend 400 MUm around implants were reliably detected by using a spatial resolution of 125 MUm. In specimens, where multiple implants are present in one line, pronounced artifact formations were present. The artifacts were visible as a combination of streak like hardening and extinction effects. CONCLUSION: Bone geometric data and density values may be determined correctly in close proximity to the implant surface, and can detect peri-implant bone defects. When multiple implants are placed, the implant radiation direction geometry must be considered. PMID- 30427965 TI - Microbiologic Analysis of Immediately Loaded Full-Arch Implant-Retained Prosthesis Protocol After 2 Years of Loading: A Retrospective Study. AB - PURPOSE: The All-on-4 treatment concept has been shown to be an effective clinical procedure; however, to date, no studies have analyzed the subgingival microbiota present in these restorations. The purpose of this study was to evaluate the microbial profile of the subgingival biofilm around dental implants placed in the All-on-4 protocol and compare the microbial profile around axial and tilted implants. MATERIALS AND METHODS: Fourteen subjects treated by the All on-4 concept were evaluated clinically and microbiologically. Subgingival biofilm was collected from each patient, and the amount of 40 species of bacteria was assessed using the checkerboard DNA-DNA hybridization technique. RESULTS: The results for the indices of probing depth (PD), bleeding on probing, marginal bleeding, and visible plaque were 2.32 mm, 46%, 60%, and 57%, respectively. Tilted implants presented a significantly higher mean PD and Plaque Index compared with axial implants (P < .05). Fusobacterium nucleatum ssp vincentii, Veillonella parvula, and Fusobacterium nucleatum ssp polymorphum were found in higher levels; however, no difference in the microbial composition was observed between tilted and axial implants (P > .05). Tilted implants presented statistically higher mean levels for the orange complex in relation to the axial implants (P < .05). CONCLUSION: Despite the clinical success rate of the All-on-4 protocol, the subgingival biofilm of tilted implants presented a higher proportion for the orange complex pathogens in comparison to axial implants. These data could suggest that subjects with this modality of implant-supported restoration must be aware that they need a more rigorous maintenance protocol. PMID- 30427966 TI - 20-Year Follow-up in Maxillary Sinus Floor Elevation Using Bovine-Derived Bone Mineral: A Case Report with Histologic and Histomorphometric Evaluation. AB - Bovine-derived bone mineral demonstrated good osteoconductive properties as grating material for maxillary sinus floor elevation, but the long-term behavior of this material has not been reported. The purpose of this report was to analyze and compare histomorphometric measurements of new bone, bone graft, and medullar spaces 6 months, 12 months, and 20 years after grafting. In the grafted area, the amount of mineralized bone was 16.96% at 6 months, 22.53% at 12 months, and 22.05% at 20 years, respectively. The amount of bovine-derived bone mineral ranged from 35.87% to 4.85% in the same period. The volume of the newly formed mineralized bone does not increase over time, conversely to nonmineralized bone. PMID- 30427967 TI - Clinical Outcome of Implants Placed in Staged Maxillary Sinus Augmentation Using Bovine Bone Mineral Mixed with Autogenous Bone at Three Different Ratios: A 5 Year Prospective Follow-up Study. AB - PURPOSE: To evaluate the 5-year clinical outcomes for implants placed in a staged sinus floor elevation (SFE) procedure and to compare three patient groups with sinus grafts with three different ratios of bovine bone mineral (BBM) and autogenous bone (AB) mixture. MATERIALS AND METHODS: A 5-year prospective cohort study was conducted on 81 patients with 119 staged SFEs non-randomly distributed to three groups based on the origin of the AB and the mixture ratio with BBM: group 1 (locally harvested AB [LHB] from osteotomy sites + BBM, ratio: 1:10), 31 patients, 37 SFEs; group 2: (LHB + intraorally harvested peripheral AB [IHPB] from retromolar/chin region + BBM, ratio: 1:4), 22 patients, 29 SFEs; and group 3 (LHB + extraorally harvested peripheral AB [EHPB] from iliac crest/tibia + BBM, ratio 1:1), 28 patients, 53 SFEs. After graft healing (5 to 7 months), 284 dental implants (group 1: 76, group 2: 61, group 3: 147 [overall: 2.3 implants/sinus]) were placed. After an additional healing period (5 to 7 months), all implants placed were functionally loaded and prospectively followed by clinical and radiographic evaluations assessing implant survival/success rate as well as peri implant marginal bone level (MBL) alteration at 1, 3, and 5 years postloading. RESULTS: A total of 76/81 patients with 267/284 implants were followed for up to 5 years (dropouts: 5 patients/15 implants; implant loss = 2). The 5-year implant survival and implant success rate (group 1: 100%/98.6%; group 2: 98.3%/96.6%; group 3: 99.3%/95.7%) did not differ between the three graft mixture groups. The peri-implant marginal bone alteration (reduction) averaged over all 5 years was 1.40 +/- 0.29 mm for group 1, 1.41 +/- 0.22 mm for group 2, and 1.46 +/- 0.46 mm for group 3 (P = .187). However, over time, a continual and significant MBL reduction (P = .045) was noted for all groups presenting peri-implant MBL changes between 1 year and 5 years of -0.17 mm (group 1), -0.12 mm (group 2), and -0.24 mm (group 3), respectively. CONCLUSION: According to the clinical results obtained, dental implants inserted in grafted (staged) SFE using a mixture of BBM with a minimal amount of AB harvested from local sites provide for similarly high 5-year implant/augmentation success rates as graft mixtures with AB harvested from peripheral intraoral or extraoral donor sites, confirming no need for additional bone harvesting. PMID- 30427968 TI - Marginal Bone Loss Around Short Dental Implants Restored at Implant Level and with Transmucosal Abutment: A Retrospective Study. AB - PURPOSE: This study evaluated the effect of the level of the prosthetic construction on the marginal bone stability around extra-short implants (<= 6.5 mm in length) supporting a fixed prosthesis. MATERIALS AND METHODS: This retrospective study was performed at a private dental clinic. The patient charts were reviewed to select those who had an extra-short implant (<= 6.5 mm in length) supporting a fixed prosthesis. A transmucosal abutment (transepithelial Multi-Im, BTI Biotechnology Institute) was used in those implants that were restored at the gingival level. Otherwise, the implants were restored at the platform level. Demographic data and implant-related and prosthesis-related variables were obtained. RESULTS: Thirty-three extra-short implants in 17 patients were assessed. The patients' mean age was 61 +/- 12 years at the time of surgery. The prosthetic reconstruction was done at the platform level in 18 implants and at the gingival level (via transmucosal abutment) in 15 implants. Considering the use or not of a transmucosal abutment, there were no statistically significant differences in all studied variables except bone stability. The extra-short implants that were restored at the platform level experienced more crestal bone loss (P = .024). CONCLUSION: The extra-short implant restoration at the gingival level would increase the stability of the marginal bone. PMID- 30427969 TI - Implant Stability Outcomes After Immediate and Delayed Revascularized Free Fibula Flaps: A Preliminary Comparative Study. AB - PURPOSE: This pilot study investigated the retrospective outcomes of implants placed immediately or with a delayed protocol in revascularized free fibula flaps (FFF). MATERIALS AND METHODS: Patients undergoing FFF between 2014 and 2017 were included in the study. Implants were inserted either immediately or 23.63 +/- 10.61 months after reconstructive surgery. Resonance frequency analyses were recorded at the time of implant placement (first control) and 4 months postoperatively while uncovering and screwing the gingiva formers (second control). The statistical significance level was set at P < .05. RESULTS: Eight patients (four men, four women, mean age: 46.75 +/- 12.96 years) were included in the study. Twenty-six implants were placed in FFF (14 immediate, 12 delayed), and 28 were placed in the alveolus. All implant stability quotient (ISQ) scores were in high stability ranges. Statistically significant differences were observed between delayed (79.25 +/- 4.77) and immediate implant placement (73.14 +/- 7.42) at first controls, but not at second controls (79.17 +/- 3.59 and 76.00 +/- 6.18). The ISQ values of immediate implant placement significantly increased from first to second controls (P = .018). Bicortically placed implants showed significantly higher scores than unicortical implants (P < .05). ISQ values of FFF and alveolar bone groups were similar (P > .05). CONCLUSION: High stability scores similar to alveolar bone could be achieved by both immediate and delayed implant placement. Bicortical implantation results in better implant stability. PMID- 30427970 TI - A Within-Subject Comparison of Patient Satisfaction and Quality of Life Between a Two-Implant Overdenture and a Three-Implant-Supported Fixed Dental Prosthesis in the Mandible. AB - PURPOSE: This within-subject comparison tested the null hypothesis that there is no difference in patient satisfaction and oral health-related quality of life when an individual with an edentulous mandible is rehabilitated with a two implant overdenture or a three-implant-supported fixed dental prosthesis. MATERIALS AND METHODS: Twelve subjects with an edentulous mandible or failing dentition were rehabilitated with the use of endosseous dental implants. Three implants were placed, and were immediately loaded with a provisional fixed prosthesis with minimal cantilever. After healing for 4 months, two Locator attachments were inserted and an overdenture was trialed; then, after a further 4 months, a fixed prosthesis was placed on the three implants. The fixed prosthesis was fabricated using computer-assisted design, and a titanium framework was manufactured with a resin base and teeth. Patient satisfaction and oral health related quality of life was assessed before treatment, after wearing the provisional, and after each treatment option using a seven-item visual analog scale and a modified version of the 49-item oral health impact profile. RESULTS: Of the 12 subjects, 11 chose the fixed over the removable prosthesis. A statistically significant (P < .05) and positive effect on the overall score of both assessment tools was reported for both treatment modalities (when compared with pretreatment scores). Although no significant difference (P > .05) was found between the two options in overall scores of both surveys or in any of the seven domains of the modified oral health impact profile, the fixed prosthesis had a statistically higher score for stability, retention, and ease of chewing on a visual analog scale. CONCLUSION: Both treatment modalities provided a significant and similar improvement in patient satisfaction and oral health-related quality of life compared with a conventional complete mandibular removable dental prosthesis; however, a statistically significant higher score was reported for stability, retention, and ease of chewing for the fixed dental prostheses. Based on the 12 participants in this study, greater stability and ease of chewing with the fixed prosthesis likely influenced patient preference in most but not all subjects. PMID- 30427971 TI - Psychometric Analysis and Masticatory Efficiency of Elderly People with Single Implant Overdentures. AB - PURPOSE: The aim of this paired clinical study was to evaluate psychometric parameters (patient satisfaction and masticatory ability) and masticatory efficiency in elderly people before and after oral rehabilitation by a single implant overdenture. MATERIALS AND METHODS: This study included elderly individuals with residual alveolar bone height classified as Class III or IV according to the American College of Prosthodontics, and who wore clinically unsatisfactory complete dentures. Subjects first received new maxillary and mandibular conventional complete dentures. After 2 months of patient adaptation to the new complete dentures, subjective and objective variables were measured. Satisfaction with the new complete dentures was verified by applying a visual analog scale to rate patient satisfaction with stability, comfort, ability to chew, ability to speak, ease of cleaning, esthetics, and general satisfaction of their new complete dentures. Masticatory ability was assessed by asking participants to rate on a visual analog scale their ability to chew foods with different roughness and consistencies. Masticatory efficiency was measured by the sieving method using a silicone-based artificial test food. After evaluations were completed, each participant received one implant, which was placed in the symphysis region. After 3 months of implant osseointegration, the conventional complete dentures were transitioned to mandibular single-implant overdentures through placement of a low-profile attachment on the intaglio surface of the prostheses. Subjects used the single-implant overdentures for 2 months, and then all variables were reevaluated. Parametric t test and nonparametric Wilcoxon statistical tests were used to analyze data. RESULTS: Participants reported increased satisfaction with stability of their mandibular single-implant overdentures compared with their new conventional complete dentures. However, satisfaction with the esthetics decreased when the new complete denture was converted into the single-implant overdenture (P < .05). Masticatory ability with the rehabilitation was not different between the new conventional complete dentures and the single-implant overdentures; however, transition to the single implant overdenture greatly increased masticatory efficiency (P < .0001). CONCLUSION: Single-implant overdentures changed the patient perceptions, improving their satisfaction with stability, although decreasing satisfaction with esthetics. Despite that, masticatory efficiency of elderly individuals with decreased residual bone height was greatly improved after single-implant overdenture use. PMID- 30427972 TI - Do Penicillin-Allergic Patients Present a Higher Rate of Implant Failure? AB - PURPOSE: The aim of this clinical study was to determinate if patients allergic to penicillin present a higher incidence of dental implant failure compared with nonallergic patients. MATERIALS AND METHODS: This cross-sectional clinical study analyzed patients rehabilitated with endosseous dental implants between September 2011 and July 2015, at the University Dental Clinic, School of Dentistry, International University of Catalonia (UIC). Prophylactic antibiotic therapy was prescribed for all patients: a single dose of 2 g of amoxicillin taken orally 1 hour before implant surgery for non-penicillin-allergic patients, and 600 mg of clindamycin taken orally 1 hour before the implant surgery for penicillin allergic patients. Postsurgical antibiotics were prescribed to prevent early implant failures and postoperative infections: amoxicillin 750 mg three times a day for 7 days for nonallergic patients, and in patients with penicillin allergy, 300 mg clindamycin every 6 hours for 7 days. Implant failure was defined as the removal of the implant for any reason and was classified as early or late failure. RESULTS: A total of 1,210 patients' files were analyzed; 8.03% of nonallergic patients and 24.68% of penicillin-allergic patients presented at least one implant failure. In penicillin-allergic patients, 21.05% were classified as late implant failure and 78.95% as early implant failure, with a lack of osseointegration (80%) being the mean reason for an early implant failure. Penicillin-allergic patients demonstrated a higher risk of implant failure with a risk ratio of 3.84 (95% CI) compared with nonallergic patients. CONCLUSION: Penicillin-allergic patients treated with clindamycin presented almost four times the risk of suffering dental implant failure, although other variables such as implant brand, location, and the surgeon's skill might have influenced these results. PMID- 30427973 TI - Explantation of an Osseointegrated Titanium Implant Using Laser-Induced Thermo necrosis: A Case Report. AB - Explantation of fully or partially osseointegrated titanium implants is a complex procedure for myriad reasons and often results in major bone loss and pronounced defects of the hard and soft tissues. This may require more elaborate surgical interventions in cases of re-implantation. In this patient case, an osseointegrated titanium implant with some visible bone loss, missing attached mucosa at the buccal aspect, and a nonideal three-dimensional (3D) position had to be explanted. For this, the implant's inner connection was heated using a CO2 laser, which resulted in localized laser-induced thermo-necrosis at the bone-to implant contact. One week following laser application, explantation could be performed easily with a torque slightly more than 35 Ncm. No complications occurred during the healing period. The result was a very easily performed explantation while preserving a maximum of the surrounding bony structure. Healing was uneventful, and no further visible bone loss could be observed during the healing time. PMID- 30427975 TI - Genetic, Clinical, and Environmental Factors Associated With Persistent Atopic Dermatitis in Childhood. AB - Importance: Knowledge about factors associated with persistence of atopic dermatitis (AD) during childhood is sparse. Objective: To explore heritable, environmental, and clinical factors associated with persistent AD based on 13 years' follow-up of an at-risk birth cohort. Design, Setting, and Participants: In the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) clinical birth cohort study, 411 children born to mothers with asthma were followed up until the age of 13 years at a clinical research unit in Copenhagen, Denmark, from August 1998 to June 2015. Atopic dermatitis was diagnosed prospectively during close clinical follow-up according to the criteria of Hanifin and Rajka. Data were gathered on parental history, social circumstances, and environmental factors through parent interviews. The cohort was followed up with biannual visits to the clinic until the age of 7 years and were seen again at age 13 years. Data were analyzed from August 2015 to January 2018. Main Outcomes and Measures: Atopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by Scoring Atopic Dermatitis (SCORAD) index, with possible scores from 0 to 83, with higher scores indicating more severe AD. Results: Of the 411 children in the cohort, 203 (49.4%) were male and 186 (45.3%) were diagnosed with AD before the age of 13 years; 40 of 166 children (24.1%) had persistent AD at the age of 13 years, and 126 (76.0%) experienced remission. Factors associated with persistent AD to age 13 years included heritability, environmental exposures, asthma and allergic sensitization, clinical presentation at the time of diagnosis, the composition of Hanifin and Rajka diagnostic minor criteria, and AD severity according to SCORAD. A higher AD genetic risk score was associated with an increased the risk for persistent AD (multivariable odds ratio [OR], 1.8; 95% CI, 1.1-2.9; P = .02), together with paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02); paternal AD (multivariable OR, 6.2; 95% CI, 1.17-23.2; P = .007), and higher social circumstances (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05). Particular clinical presentations at time of diagnosis were also associated with specific minor criteria of Hanifin and Rajka (Dennie-Morgan and anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) (OR, 2.6; 95% CI, 1.1-6.2; P = .03) as well as increased severity at diagnosis (OR, 1.1; 95% CI, 1.0-1.1; P = .007). Conclusions and Relevance: In a birth cohort of children at risk for asthma who received close clinical follow-up to age 13 years, known genetic AD risk variants, paternal asthma and AD, high social circumstances, diagnostic minor criteria, and disease severity at onset were associated with persistent AD at age 13 years. These findings may be applied in clinical practice to evaluate the likely disease course for individual patients. PMID- 30427976 TI - Interpreting the Long-term Prognostic Value of Total Mesorectal Excision Plane Quality in Rectal Adenocarcinoma. PMID- 30427974 TI - Yellow fever outbreak in Brazil: the puzzle of rapid viral spread and challenges for immunisation. AB - We discuss the complex eco-social factors involved in the puzzle of the unexpected rapid viral spread in the ongoing Brazilian yellow fever (YF) outbreak, which has increased the reurbanisation risk of a disease without urban cases in Brazil since 1942. Indeed, this rapid spatial viral dissemination to the Southeast and South regions, now circulating in the Atlantic Forest fragments close to peri-urban areas of the main Brazilian megalopolises (Sao Paulo and Rio de Janeiro) has led to an exponential increase in the number of yellow fever cases. In less than 18 months, 1,833 confirmed cases and 578 deaths were recorded most of them reported in the Southeast region (99,9%). Large epizooties in monkeys and other non-human primates (NHPs) were communicated in the country with 732 YF virus (YFV) laboratory confirmed events only in the 2017/2018 monitoring period. We also discuss the peculiarities and similarities of the current outbreak when compared with previous great epidemics, examining several hypotheses to explain the recent unexpected acceleration of epizootic waves in the sylvatic cycle of the YFV together with the role of human, NHPs and mosquito mobility with respect to viral spread. We conclude that the most feasible hypothesis to explain this rapidity would be related to human behavior combined with ecological changes that promoted a significant increase in mosquito and NHP densities and their contacts with humans. We emphasize the urgent need for an adequate response to this outbreak such as extending immunisation coverage to the whole Brazilian population and developing novel strategies for immunisation of NHPs confined in selected reserve areas and zoos. Finally, we stress the urgent need to improve the quality of response in order to prevent future outbreaks and a catastrophic reurbanisation of the disease in Brazil and other South American countries. Continuous monitoring of YFV receptivity and vulnerability conditions with effective control of the urban vector Aedes aegypti and significant investments in YF vaccine production capacity and research and development for reduction of adverse effects are of the highest priority. PMID- 30427977 TI - Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of "Real-world" Evidence. AB - Importance: Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown. Objective: To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events. Data Sources: Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies. Study Selection: Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis. Data Extraction and Synthesis: PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed. Main Outcomes and Measures: Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage). Results: Omalizumab therapy was associated with an improvement in UAS7 scores ( 25.6 points, 95% CI, -28.2 to -23.0; P < .001; 15 studies, 294 patients), an improvement in UAS scores (-4.7 points, 95% CI, -5.0 to -4.4, P < .001; 10 studies, 1158 patients), an average complete response rate of 72.2% (95% CI, 66.1%-78.3%; P < .001; 45 studies, 1158 patients) with an additional average partial response rate of 17.8% (95% CI, 11.7%-23.9%; P < .001; 37 studies, 908 patients), and an average adverse event rate of 4.0% (95% CI, 1.0%-7.0%; P < .001; any level of severity, 47 studies, 1314 patients). Conclusions and Relevance: Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making. PMID- 30427978 TI - Moving the Needle Toward a More Personalized Means of Patient Care. PMID- 30427979 TI - Treating the Patient With Appendicitis, Not Just the Appendicitis. PMID- 30427980 TI - Fluorescent-Guided Lymphography in Gastric Cancer Surgery: A Useful Adjunct for a Radical Lymph Node Dissection. PMID- 30427981 TI - The High-Profile Patient-Ensuring Good Care for the Entire Hospital. PMID- 30427982 TI - The Cumulative Sex Wage Gap in Cardiology. PMID- 30427984 TI - Error in Author Byline. PMID- 30427983 TI - Nonoperative Management of Uncomplicated Appendicitis Among Privately Insured Patients. AB - Importance: Health care professionals have shown significant interest in nonoperative management for uncomplicated appendicitis, but long-term population level data are lacking. Objective: To compare the outcomes of nonoperatively managed appendicitis against appendectomy. Design, Setting, and Participants: This national retrospective cohort study used claims data from a private insurance database to compare patients admitted with uncomplicated appendicitis from January 1, 2008, through December 31, 2014, undergoing appendectomy vs nonoperative management. Coarsened exact matching was applied before multivariate analysis to reduce imbalance between groups. Data were analyzed from February 12 through May 1, 2018. Exposures: Appendectomy (control arm) or nonoperative management (treatment arm). Main Outcomes and Measures: Short-term primary clinical outcomes included emergency department visits, hospital readmission, abdominal abscess, and Clostridium difficile infections. Long-term primary clinical outcomes were small-bowel obstructions, incisional hernias, and appendiceal cancers. Nonoperative management failure was defined by hospital readmission with appendicitis diagnosis and an appendicitis-associated operation or procedure. Secondary outcomes included number of follow-up visits, length and cost of index hospitalization, and total cost of appendicitis-associated care. Covariates included age, sex, region, insurance plan type, admission year, and Charlson comorbidity index. Results: Of 58 329 patients with uncomplicated appendicitis (52.7% men; mean [SD] age, 31.9 [16.5] years), 55 709 (95.5%) underwent appendectomy and 2620 (4.5%) underwent nonoperative management. Patients in the nonoperative management group were more likely to have appendicitis-associated readmissions (adjusted odds ratio, 2.13; 95% CI, 1.63 2.77; P < .001) and to develop an abscess (adjusted odds ratio, 1.42; 95% CI, 1.05-1.92; P = .02). Patients in the nonoperative management group required more follow-up visits in the year after index admission (unadjusted mean [SD], 1.6 [6.3] vs 0.3 [1.4] visits; adjusted +1.11 visits; P < .001) and had lower index hospitalization cost (unadjusted mean [SD], $11 502 [$9287] vs $13 551 [$10 160]; adjusted -$2117, P < .001), but total cost of appendicitis care was higher when follow-up care was considered (unadjusted, $14 934 [$31 122] vs $14 186 [$10 889]; adjusted +$785; P = .003). During a mean (SD) of 3.2 (1.7) years of follow up, failure of nonoperative management occurred in 101 patients (3.9%); median time to recurrence was 42 days (interquartile range, 8-125 days). Among the patients who experienced treatment failure, 44 did so within 30 days. Conclusions and Relevance: According to results of this study, nonoperative management failure rates were lower than previously reported. Nonoperative management was associated with higher rates of abscess, readmission, and higher overall cost of care. These data suggest that nonoperative management may not be the preferred first-line therapy for all patients with uncomplicated appendicitis. PMID- 30427985 TI - User-Centered Redesign of Evidence-Based Psychosocial Interventions to Enhance Implementation-Hospitable Soil or Better Seeds? PMID- 30427986 TI - Bilateral Round Scar-like Lesions on the Face of a Young Man. PMID- 30427987 TI - Minimum Specifications for a Lifebox Surgical Headlight for Resource-Constrained Settings. PMID- 30427988 TI - The Meaning of Glutamate and the Quest for Biomarkers in the Transition to Psychosis. PMID- 30427989 TI - Reduced Itch Associated With Dupilumab Treatment In 4 Patients With Prurigo Nodularis. PMID- 30427991 TI - Error in Figure. PMID- 30427990 TI - Fluorescent Lymphography-Guided Lymphadenectomy During Robotic Radical Gastrectomy for Gastric Cancer. AB - Importance: Fluorescent imaging with indocyanine green can be used to visualize lymphatics. Peritumoral injection of indocyanine green may allow for visualization of every draining lymph node from a primary lesion on near-infrared imaging. Objectives: To evaluate the role of fluorescent lymphography using near infrared imaging as an intraoperative tool for achieving complete lymph node dissection and compare the number of lymph nodes retrieved with the use of near infrared imaging and the number of lymph nodes retrieved without the use of near infrared imaging. Design, Setting, and Participants: This prospective single-arm study was conducted among 40 patients who underwent robotic gastrectomy between August 30, 2013, and July 21, 2014, at a single-center, tertiary referral teaching hospital. After propensity score matching, the results of these 40 patients were compared with the results of 40 historical control patients who underwent robotic gastrectomy without indocyanine green injection between January 1, 2012, and August 31, 2013. Statistical analysis was performed from January 1, 2015, to July 31, 2016. Interventions: Robotic gastrectomy with systemic lymphadenectomy and retrieval of lymph nodes under near-infrared imaging after peritumoral injection of indocyanine green to the submucosal layer 1 day before surgery. Main Outcomes and Measures: The primary outcome was the number of retrieved lymph nodes in each nodal station. Results: Among the 40 patients in the study (19 women and 21 men; mean [SD] age, 52.2 [11.7] years), no complications related to indocyanine green injection or near-infrared imaging were observed. On completion of the lymphadenectomy, the absence of fluorescent lymph nodes in the dissected area was confirmed. A mean (SD) total of 23.9 (9.0) fluorescent lymph nodes were recorded among a mean (SD) total of 48.9 (14.6) overall lymph nodes retrieved. The mean number of overall lymph nodes retrieved was larger in the near-infrared group than in the historical controls (48.9 vs 35.2; P < .001), with a significantly greater number of lymph nodes retrieved at stations 2, 6, 7, 8, and 9. In the near-infrared group, 5 patients exhibited lymph node metastases, and all metastatic lymph nodes were fluorescent. Conclusions and Relevance: This study's findings suggest that fluorescent lymphography may be useful intraoperatively for identifying and retrieving all necessary lymph nodes for a complete and thorough lymphadenectomy. PMID- 30427992 TI - Implications of Medicare Coverage for Magnetic Resonance Imaging in Patients With Capped or Epicardial Leads. PMID- 30427993 TI - Association of Hippocampal Glutamate Levels With Adverse Outcomes in Individuals at Clinical High Risk for Psychosis. AB - Importance: Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum. Objective: To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes. Design, Setting, and Participants: This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom. Main Outcomes and Measures: Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale. Results: Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high risk individuals showed good overall functioning (Global Assessment of Function >=65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (beta = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (beta = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02). Conclusions and Relevance: The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes. PMID- 30427994 TI - Dupilumab Treatment for Generalized Prurigo Nodularis. PMID- 30427995 TI - Association of African Ancestry With Electrocardiographic Voltage and Concentric Left Ventricular Hypertrophy: The Dallas Heart Study. AB - Importance: Compared with white individuals, black individuals have increased electrocardiographic voltage and an increased prevalence of concentric left ventricular (LV) hypertrophy. Whether environmental or genetic factors lead to these racial differences is unknown. Objective: To determine whether proportion of genetically determined African ancestry among self-reported black individuals is associated with increased electrocardiographic voltage and concentric LV hypertrophy (LVH). Design, Setting, and Participants: The Dallas Heart Study is a probability-based cohort study of English- or Spanish-speaking Dallas County, Texas, residents, with deliberate oversampling of black individuals. Participants underwent extensive phenotyping, which included electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), and dual-energy radiography absorptiometry (DEXA) at a single center. Participants aged 18 to 65 years who enrolled in the Dallas Heart Study between July 2000 and December 2002, self identified as black (n = 1251) or white (n = 826), and had ECG, CMR, and DEXA data were included in this analysis. Data were analyzed from June 2017 to September 2018. Exposures: Proportion of African ancestry. Main Outcomes and Measures: Electrocardiographic voltage (12-lead and 9-lead) and markers of concentric LVH as assessed by CMR (LV concentricity0.67 [LV mass/end-diastolic volume0.67], LV wall thickness [LVWT], and prevalent LVH [defined by LV mass/height2.7]). Results: Of the 2077 participants included in the study, 1138 (54.8%) were women, and the mean (SD) age was 45.2 (9.9) years. Black race and African ancestry were individually associated with increased ECG voltage, LV concentricity0.67, LVWT, and prevalent LVH in multivariable analyses adjusting for age, sex, systolic blood pressure, antihypertensive medication use, and body composition. When African ancestry and black race were entered together into multivariable models, African ancestry but not black race remained associated with ECG voltage, LVWT, LV concentricity0.67, and prevalent LVH. Among black participants, African ancestry remained associated with these 4 phenotypes (12 lead voltage: beta, 0.05; P = .04; LVWT: beta, 0.05; P = .02; LV concentricty0.67: beta, 0.05; P = .045; prevalent LVH: odds ratio, 1.2; 95% CI, 1.03-1.4; P = .02). Conclusions and Relevance: Genetically determined African ancestry was associated with electrocardiographic voltage, measures of concentric LV remodeling, and prevalent LVH. These data support a genetic basis related to African ancestry for the increased prevalence of these cardiovascular traits in black individuals. PMID- 30427996 TI - Coral Dermatitis. PMID- 30427997 TI - Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study. AB - Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes. Objective: To assess if different biomarkers provide information about the risk for all-cause and cause specific mortality. Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated. Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death. Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined. Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43). Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT00391872. PMID- 30427998 TI - Association of Age With Blood Pressure Across the Lifespan in Isolated Yanomami and Yekwana Villages. PMID- 30428000 TI - A paced heart without a pacemaker. PMID- 30427999 TI - Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis. AB - Importance: Countering depressive disorders is a public health priority. Currently, antidepressants are the first-line treatment, although they show modest effects. In men, testosterone treatment is a controversial alternative or adjunct treatment option. Objectives: To examine the association of testosterone treatment with alleviation of depressive symptoms in men and to clarify moderating effects of testosterone status, depression status, age, treatment duration, and dosage. Data Sources: English-language studies published in peer reviewed journals identified from PubMed/Medline, Embase, Scopus, PsychINFO, and the Cochrane Controlled Trials Register from database inception to March 5, 2018, using the search terms testosterone, mood, administration, dosage, adverse effects, deficiency, standards, therapeutic use, therapy, treatment, and supplementation. Study Selection: Randomized placebo-controlled clinical trials (RCTs) of testosterone treatment that together cover a broad age range and hypogonadal or eugonadal men reporting depressive symptoms on psychometrically validated depression scales. Data Extraction and Synthesis: Of 7690 identified records, 469 were evaluated against full study inclusion criteria after removing duplicates, reviews, and studies that did not examine male patients or testosterone. Quality assessment and data extraction from the remaining 27 RCTs were performed. Main Outcomes and Measures: Primary outcomes were testosterone treatment effectiveness (standardized score difference after treatment), efficacy (proportion of patients who responded to testosterone treatment with a score reduction of 50% or greater), and acceptability (proportion of patients who withdrew for any reason). Results: Random-effects meta-analysis of 27 RCTs including 1890 men suggested that testosterone treatment is associated with a significant reduction in depressive symptoms compared with placebo (Hedges g, 0.21; 95% CI, 0.10-0.32), showing an efficacy of odds ratio (OR), 2.30 (95% CI, 1.30-4.06). There was no significant difference between acceptability of testosterone treatment and placebo (OR, 0.79; 95% CI, 0.61-1.01). Meta-regression models suggested significant interactions for testosterone treatment with dosage and symptom variability at baseline. In the most conservative bias scenario, testosterone treatment remained significant whenever dosages greater than 0.5 g/wk were administered and symptom variability was kept low. Conclusions and Relevance: Testosterone treatment appears to be effective and efficacious in reducing depressive symptoms in men, particularly when higher-dosage regimens were applied in carefully selected samples. However, given the heterogeneity of the included RCTs, more preregistered trials are needed that explicitly examine depression as the primary end point and consider relevant moderators. PMID- 30428001 TI - Fluoroscopy times in electrophysiology and device procedures: impact of single frame location fluoroscopy. PMID- 30428002 TI - Addressing Health-Related Misinformation on Social Media. PMID- 30428003 TI - Weightlifting unmasks high-risk coronary anomaly. PMID- 30428004 TI - CD95-Ligand contributes to abdominal aortic aneurysm progression by modulating inflammation. AB - Aims: Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltration, matrix protein degradation, and smooth muscle cell apoptosis. CD95 is an inflammatory mediator and an apoptosis inducer. Previous studies have shown elevated expression of CD95 or CD95L in the aortic tissue of AAA patients. However, how the CD95L/CD95 contributes to aneurysm degeneration and whether blocking its signaling would be beneficial to disease progression remains largely unknown. In the present study, we sought to determine the role of CD95L and its downstream target, caspase 8, in AAA progression. Methods and Results: By using the CaCl2 murine model of AAA, abdominal aortic aneurysms were induced in C57BL/6 mice. We found that both mRNA and protein levels of CD95L were increased in aneurysm tissue compared with NaCl treated normal aortic tissue. To determine whether CD95L contributes directly to aneurysm formation, we used CD95L null (CD95L-/-) mice to examine their response to CaCl2 aneurysm induction. Six weeks after periaortic application of CaCl2, aortic diameters of CD95L-/- mice were significantly smaller compared to CaCl2 treated wild type controls. Connective tissue staining of aortic sections from CaCl2-treated CD95L-/- mice showed minimal damage of medial elastic lamellae which was indistinguishable from the NaCl-treated sham control. Furthermore, CD95L deficiency attenuates macrophage and T cell infiltration into the aortic tissue. To study the role of CD95L in the myelogeous cells in AAA formation, we created chimeric mice by infusing CD95L-/- bone marrow into sub-leathally irradiated wild type mice (WT/CD95L-/-BM). As controls, wild type bone marrow were infused into sub-leathally irradiated CD95L-/- mice (CD95L-/-/WTBM). WT/CD95L-/-BM mice were resistant to aneurysm formation compared to their controls. Inflammatory cell infiltration was blocked by the deletion of CD95L on myeloid cells. Western blot analysis showed the levels of caspase 8 in the aortas of CaCl2-treated wild type mice were increased compared to NaCl-treated controls. CD95L deletion inhibited caspase 8 expression. Furthermore, a caspase 8-specific inhibitor was able to partially block aneurysm development in CaCl2-treated aneurysm models. Conclusion: These studies demonstrated that inflammatory cell infiltration during AAA formation is dependent on CD95L from myelogeous cells. Aneurysm inhibition by deletion of CD95L is mediated in part by down-regulation of caspase 8. PMID- 30428005 TI - SeQuiLa: An elastic, fast and scalable SQL-oriented solution for processing and querying genomic intervals. AB - Summary: Efficient processing of large-scale genomic datasets has recently become possible due to the application of 'big data' technologies in bioinformatics pipelines.We present SeQuiLa - a distributed, ANSI SQL compliant solution for speedy querying and processing of genomic intervals that is available as an Apache Spark package. Proposed range join strategy is significantly (~22x) faster than the default Apache Spark implementation and outperforms other state-of-the art tools for genomic intervals processing. Availability and implementation: The project is available at http://biodatageeks.org/sequila/. Supplementary Information: Supplementary data (SD) are available at Bioinformatics online. PMID- 30428006 TI - Quadriceps Lipid Content Has Sex-Specific Associations With Whole-Muscle, Cellular, and Molecular Contractile Function in Older Adults. AB - Increased adiposity is associated with reduced skeletal muscle function in older adults, but the mechanisms underlying this relationship remain unclear. To explore whether skeletal muscle properties track with adiposity, whole-muscle, cellular, and molecular function were examined in relation to adiposity measured at various anatomical levels in healthy older (60-80 years) men and women. Although women had greater absolute and relative body and thigh fat than men, quadriceps muscle attenuation, an index of intramuscular lipid content, was similar between sexes. At the whole-muscle level, greater quadriceps attenuation was associated with reduced knee extensor function in women, but not men. In women, decreased myosin heavy chain I and IIA fiber-specific force was associated with higher intramuscular lipid content, which may be explained, in part, by the reduced myofilament lattice stiffness found in myosin heavy chain IIA fibers. Longer myosin attachment times in myosin heavy chain I fibers from men and women were associated with greater amounts of adipose tissue, suggesting that fat deposits lead to slower myosin-actin cross-bridge kinetics. Our results indicate greater quantities of adipose tissue alter myofilament properties and cross bridge kinetics, which may partially explain the adiposity-induced decrements in single-fiber and whole-muscle function of older adults, especially women. PMID- 30428007 TI - Metrics for Regulated Biochemical Pathway Systems. AB - Motivation: The assessment of graphs through crisp numerical metrics has long been a hallmark of biological network analysis. However, typical graph metrics ignore regulatory signals that are crucially important for optimal pathway operation, for instance, in biochemical or metabolic studies. Here we introduce adjusted metrics that are applicable to both static networks and dynamic systems. Results: The metrics permit quantitative characterizations of the importance of regulation in biochemical pathway systems, including systems designed for applications in synthetic biology or metabolic engineering. They may also become criteria for effective model reduction. PMID- 30428008 TI - Is the PURE study pure fiction? PMID- 30428009 TI - Identify origin of replication in Saccharomyces cerevisiae using two-step feature selection technique. AB - Motivation: DNA replication is a key step to maintain the continuity of genetic information between parental generation and offspring. The initiation site of DNA replication, also called origin of replication (ORI), plays an extremely important role in the basic biochemical process. Thus, rapidly and effectively identifying the location of ORI in genome will provide key clues for genome analysis. Although biochemical experiments could provide detailed information for ORI, it requires high experimental cost and long experimental period. As good complements to experimental techniques, computational methods could overcome these disadvantages. Results: Thus, in this study, we developed a predictor called iORI-PseKNC2.0 to identify ORIs in the Saccharomyces cerevisiae (S. cerevisiae) genome based on sequence information. The pseudo k-tuple nucleotide composition (PseKNC) including 90 physicochemical properties was proposed to formulate ORI and non-ORI samples. In order to improve the accuracy, a two-step feature selection was proposed to exclude redundant and noise information. As a result, the overall success rate of 88.53% was achieved in the 5-fold cross validation test by using support vector machine (SVM). Availability: Based on the proposed model, a user-friendly webserver was established and can be freely accessed at http://lin-group.cn/server/iORI-PseKNC2.0. The webserver will provide more convenience to most of wet-experimental scholars. PMID- 30428010 TI - Predictive value of echocardiography in Type 2 diabetes. AB - Aims: Echocardiography is suggested in the diagnostic work-up of patients with Type 2 diabetes (T2D). We investigated which echocardiographic parameters that best predicted cardiovascular disease (CVD) and whether this was persistent in both genders in a large cohort of outpatients with T2D. Methods and results: We performed comprehensive echocardiography in 933 patients with T2D followed at specialized out-patients clinics in Copenhagen, Denmark. Follow-up was performed using national registries and included admission with future CVD events and non CVD death as competing risk. Median follow-up was 4.8 years and 138 CVD events occurred. In univariable and multivariable analyses, a wide range of structural, diastolic, and systolic measurements predicted CVD including mean E/e' [hazard ratio (HR) 1.06, 95% confidence interval: (1.03-1.10), P < 0.001, C-statistics 0.74 (0.70-0.78)] and global longitudinal strain (GLS) [1.10 (1.01-1.20), P = 0.03, C-statistics 0.73 (0.69-0.77)]. However, this was modified by gender. In men, mean E/e' remained the strongest predictor in multivariable analyses and performed best measured by highest C-statistics [HR 1.15, 95% confidence interval: (1.08-1.21), P < 0.001, C-statistics 0.75 (0.71-0.80)] whereas in women this was GLS [1.39 (1.14-1.70), P = 0.001, C-statistics 0.79 (0.70-0.87)]. These findings persisted when excluding patients with known heart disease and when regarding all-cause mortality as a competing risk. Conclusion: A range of echocardiographic parameters predicted CVD in patients with Type 2 diabetes, however, in multivariable analyses, mean E/e' was the strongest predictor and had the highest model performance. Importantly, this study identifies a hitherto undescribed gender interaction as mean E/e' performed best in men, whereas in women this was GLS. PMID- 30428011 TI - The coronary circulation in acute myocardial ischaemia/reperfusion injury - a target for cardioprotection. AB - The coronary circulation is both culprit and victim of acute myocardial infarction. The rupture of an epicardial atherosclerotic plaque with superimposed thrombosis causes coronary occlusion, and this occlusion must be removed to induce reperfusion. However, ischaemia and reperfusion cause damage not only in cardiomyocytes but also in the coronary circulation, including microembolisation of debris and release of soluble factors from the culprit lesion, impairment of endothelial integrity with subsequently increased permeability and oedema formation, platelet activation and leukocyte adherence, erythrocyte stasis, a shift from vasodilation to vasoconstriction, and ultimately structural damage to the capillaries with eventual no-reflow, microvascular obstruction and intramyocardial haemorrhage. Therefore, the coronary circulation is a valid target for cardioprotection, beyond protection of the cardiomyocyte. Virtually all of the above deleterious endpoints have been demonstrated to be favourably influenced by one or the other mechanical or pharmacological cardioprotective intervention. However, no-reflow is still a serious complication of reperfused myocardial infarction and carries, independently from infarct size, an unfavourable prognosis. Microvascular obstruction and intramyocardial haemorrhage can be diagnosed by modern imaging technologies, but still await an effective therapy. The current review provides an overview of strategies to protect the coronary circulation from acute myocardial ischaemia/reperfusion injury. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225. PMID- 30428012 TI - Reply to Anderson and Mori. PMID- 30428013 TI - A Drug-Side Effect Context-Sensitive Network approach for Drug Target Prediction. AB - Motivation: Computational drug target prediction has become an important process in drug discovery. Network-based approaches are commonly used in computational drug-target interactions (DTIs) predictions. Existing network-based approaches are limited in capturing the contextual information on how diseases, drugs, and genes are connected. Here, we proposed a context-sensitive network (CSN) model for DTI prediction by modeling contextual drug phenotypic relationships. Data and Methods: We constructed a Drug-Side Effect Context-Sensitive Network (DSE-CSN) of 139,760 drug-side effect pairs, representing 1480 drugs and 5868 side effects. We also built a protein-protein interaction network (PPIN) of 15,267 gene nodes and 178,972 weighted edges. A heterogeneous network was built by connecting the DSE CSN and the PPIN through 3684 known DTIs. For each drug on the DSE-CSN, its genetic targets were predicted and prioritized using a network-based ranking algorithm. Our approach was evaluated in both de novo and leave-one-out cross validation analysis using known DTIs as the gold standard. We compared our DSE CSN-based model to the traditional similarity-based network (SBN)-based prediction model. Results: The results suggested that the DSE-CSN-based model was able to rank known DTIs highly. In a de novo cross-validation, the area under the receiver operating characteristic (ROC) curve was 0.95. In a leave-one-out cross validation, the average rank was top 3.2% for known DTIs. When it was compared to the SBN-based model using the Precision-Recall curve, our CSN-based model achieved a higher mean average precision (MAP) (0.23 versus 0.19, p-value 1e-4) in a de novo cross-validation analysis. We further improved the CSN-based DTI prediction by differentially weighting the drug-side effect pairs on the network and showed a significant improvement of the MAP (0.29 versus 0.23, p-value1e-4). We also showed that the CSN-based model consistently achieved better performances than the traditional SBN-based model across different drug classes. Moreover, we demonstrated that our novel DTI predictions can be supported by published literature. Conclusion: In summary, the CSN-based model, by modeling the context specific inter-relationships among drugs and side effects, has a high potential in drug target prediction. Availability: nlp/case/edu/public/data/DSE/CSN_DTI. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30428015 TI - Menage a trois: SNPs, Ca2+ and AF. PMID- 30428014 TI - 3' Branch ligation: a novel method to ligate non-complementary DNA to recessed or internal 3'OH ends in DNA or RNA. AB - Nucleic acid ligases are crucial enzymes that repair breaks in DNA or RNA during synthesis, repair and recombination. Various genomic tools have been developed using the diverse activities of DNA/RNA ligases. Herein, we demonstrate a non conventional ability of T4 DNA ligase to insert 5' phosphorylated blunt-end double-stranded DNA to DNA breaks at 3'-recessive ends, gaps, or nicks to form a Y-shaped 3'-branch structure. Therefore, this base pairing-independent ligation is termed 3'-branch ligation (3'BL). In an extensive study of optimal ligation conditions, the presence of 10% PEG-8000 in the ligation buffer significantly increased ligation efficiency to more than 80%. Ligation efficiency was slightly varied between different donor and acceptor sequences. More interestingly, we discovered that T4 DNA ligase efficiently ligated DNA to the 3'-recessed end of RNA, not to that of DNA, in a DNA/RNA hybrid, suggesting a ternary complex formation preference of T4 DNA ligase. These novel properties of T4 DNA ligase can be utilized as a broad molecular technique in many important genomic applications, such as 3'-end labelling by adding a universal sequence; directional tagmentation for NGS library construction that achieve theoretical 100% template usage; and targeted RNA NGS libraries with mitigated structure based bias and adapter dimer problems. PMID- 30428016 TI - Monospecies and polymicrobial biofilms differentially regulate the phenotype of genotype-specific oral cancer cells. AB - Microbial infection has been shown to involve in oral carcinogenesis; however, the underlying mechanisms remain poorly understood. The present study aimed to characterize the growth of oral microorganisms as both monospecies and polymicrobial biofilms and determine the effects of their products on oral keratinocytes. Candida albicans (ALC3), Actinomyces naeslundii (AN) and Streptococcus mutans (SM) biofilms or a combination of these (TRI) were grown in flow-cell system for 24 h. The biofilms were subjected to fluorescent in situ hybridization using species-specific probes and analysed using confocal laser scanning microscopy. The effluent derived from each biofilm was collected and incubated with malignant (H357) and normal (OKF6) oral keratinocytes to assess extracellular matrix adhesion, epithelial-mesenchymal transition (EMT) and cytokines expression. Incubation of OKF6 with ALC3 and TRI effluent significantly decreased adhesion of the oral keratinocyte to collagen I, whereas incubation of H357 with similar effluent increased adhesion of the oral keratinocyte to laminin I, significantly when compared with incubation with artificial saliva containing serum-free medium (NE; P < 0.05). In OKF6, changes in E-cadherin and vimentin expression were not consistent with EMT although there was evidence of a mesenchymal to epithelial transition in malignant oral keratinocytes incubated with AN and SM effluent. A significant increase of pro-inflammatory cytokines expression, particularly interleukin (IL)-6 and IL-8, was observed when H357 was incubated with all biofilm effluents after 2- and 24-h incubation when compared with NE (P < 0.05). In conclusion, C.albicans, A.naeslundii and S.mutans form polymicrobial biofilms which differentially modulate malignant phenotype of oral keratinocytes. PMID- 30428018 TI - European Heart Journal, discussion forum. PMID- 30428017 TI - An olive oil phenolic is a new chemotype of mutant isocitrate dehydrogenase 1 (IDH1) inhibitors. AB - Mutations in the isocitrate dehydrogenase 1 (IDH1) gene confer an oncogenic gain of-function activity that allows the conversion of ?-ketoglutarate (?-KG) to the oncometabolite R-2-hydroxyglutaratye (2HG). The accumulation of 2HG inhibits ?-KG dependent histone and DNA demethylases, thereby generating genome-wide hypermethylation phenotypes with cancer-initiating properties. Several chemotypes of mutant IDH1/2-targeted inhibitors have been reported and some of them are under evaluation in clinical trials. However, the recognition of acquired resistance to such inhibitors within a few years of clinical use raises an urgent need to discover new mutant IDH1 antagonists. Here, we report that a naturally occurring phenolic compound in extra-virgin olive oil (EVOO) selectively inhibits the production of 2HG by neomorphic IDH1 mutations. In silico docking, molecular dynamics, including steered simulations, predicted the ability of the oleoside decarboxymethyl oleuropein aglycone (DOA) to preferentially occupy the allosteric pocket of mutant IDH1. DOA inhibited the enzymatic activity of recombinant mutant IDH1 (R132H) protein in the low micromolar range, whereas >10-fold higher concentrations were required to inhibit the activity of wild-type IDH1. DOA suppressed 2HG overproduction in engineered human cells expressing a heterozygous IDH1-R132H mutation. DOA restored the 2HG-suppressed activity of histone demethylases as it fully reversed the hypermethylation of H3K9me3 in IDH1-mutant cells. DOA epigenetically restored the expression of PD-L1, an immunosuppressive gene silenced in IDH1 mutant cells via 2HG-driven DNA hypermethylation. DOA selectively blocked colony formation of IDH1 mutant cells while sparing wild-type IDH1 isogenic counterparts. In sum, the EVOO-derived oleoside DOA is a new, naturally occurring chemotype of mutant IDH1 inhibitors. PMID- 30428019 TI - Potential cardiovascular implications of Janus kinase inhibitors in immune mediated diseases. PMID- 30428020 TI - Scientists on the Spot: Christoph Maack on how to measure mitochondrial parameters in cardiomyocytes. PMID- 30428022 TI - Corrigendum. PMID- 30428021 TI - Cell migration in the cardiovascular system: a force to be reckoned with? PMID- 30428023 TI - The HDAC3 Enzymatic Activity Regulates Skeletal Muscle Fuel Metabolism. AB - Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism. HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids (BCAAs) catabolism, and reduced muscle mass during aging, without changes in the muscle fiber type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance. PMID- 30428024 TI - Institutional Conflicts of Interest and Public Trust. PMID- 30428025 TI - Severe ostial coronary lesions 10 years after Cabrol procedure: a mixed blessing technique? PMID- 30428026 TI - Nomenclature of the components of the aortic root. PMID- 30428027 TI - A case of focal ventricular tachycardia with alternating endocardial and epicardial exits: utility of non-invasive mapping in predicting exits. PMID- 30428028 TI - Chlamydomonas WDR92 in association with R2TP-like complex and multiple DNAAFs to regulate ciliary dynein preassembly. AB - The motility of cilia or eukaryotic flagella is powered by the axonemal dyneins, which are preassembled in the cytoplasm by proteins termed dynein arm assembly factors (DNAAFs) before being transported to and assembled on the ciliary axoneme. Here, we characterize the function of WDR92 in Chlamydomonas. Loss of WDR92, a cytoplasmic protein, in a mutant wdr92 generated by DNA insertional mutagenesis resulted in aflagellate cells or cells with stumpy or short flagella, disappearance of axonemal dynein arms, and diminishment of dynein arm heavy chains in the cytoplasm, suggesting that WDR92 is a DNAAF. Immunoprecipitation of WDR92 followed by mass spectrometry identified inner dynein arm heavy chains and multiple DNAAFs including RuvBL1, RPAP3 and MOT48, ODA7 and DYX1C. The PIH1 domain-containing protein MOT48 formed a R2TP-like complex with RuvBL1/2 and RPAP3, while PF13, another PIH1 domain-containing protein with function in dynein preassembly, did not. Interestingly, the third PIH1 domain-containing protein TWI1 was not related to flagellar motility. WDR92 physically interacted with the R2TP-like complex and the other identified DNNAFs. Our data suggest that WDR92 functions in association with the HSP90 co-chaperone R2TP-like complex as well as linking other DNAAFs in dynein preassembly. PMID- 30428029 TI - Coverage of visible intercostal and lumbar segmental arteries can predict the volume of cerebrospinal fluid drainage in elective endovascular repair of descending thoracic and thoracoabdominal aortic disease: a pilot study. AB - OBJECTIVES: Our goal was to identify anatomical and physiological factors that could predict the amount of cerebrospinal fluid (CSF) drainage in patients undergoing elective endovascular repair of descending thoracic and thoracoabdominal aortic disease. METHODS: All consecutive elective endovascular procedures performed for descending thoracic or thoracoabdominal aortic disease between January 2015 and December 2017 were included in the study. Routine use of CSF drainage was established in all patients. The goal of drainage was to reach a spinal fluid pressure of 10-12 mmHg by draining in 5-15-ml aliquots. The number of visible intercostal and lumbar segmental arteries (SAs) was evaluated before and after endovascular repair. The covering ratio of SAs was calculated as covered preoperative SAs/total preoperative SAs. RESULTS: Twenty-four consecutive patients were included in the final analysis. The indication for the intervention was a descending thoracic aneurysm in 13 cases, a thoracoabdominal aneurysm in 4 cases and a chronic type B dissection in 7 cases. The procedure performed was thoracic endovascular aortic repair in 20 cases and fenestrated endovascular aneurysm repair in 4 cases. None of the patients developed spinal cord ischaemia. The mean volume of CSF drained was 46 ml. The mean length of aortic coverage was 231 mm. The mean number of total preoperative SAs and of covered preoperative SAs was, respectively, 22 and 9. The volume of CSF drained was significantly correlated with all these variables (length of aortic coverage, total visible SAs and covered SAs), but the most powerful correlation was individuated with the covering ratio of SAs. CONCLUSIONS: Our findings suggest that the percentage of intercostal and lumbar SAs covered by placement of a stent graft can predict the volume of CSF drained in patients undergoing elective endovascular repair of descending thoracic and thoracoabdominal aortic disease. PMID- 30428030 TI - A 5-MicroRNA Signature Identified from Serum MicroRNA Profiling Predicts Survival in Patients with Advanced Stage Non-Small Cell Lung Cancer. AB - Circulating microRNAs (miRNAs) are potential biomarkers for cancer diagnosis, screening, and prognosis. This study aimed to identify serum miRNAs as predictors of survival in patients with advanced non-small cell lung cancer (NSCLC). We profiled serum miRNAs in a pilot set of 4 patients with good survival (>24 months) and 4 patients with poor survival (<6 months). We selected 140 stably detectable miRNAs and 42 miRNAs reported in literature for further analysis. Expression of these 182 miRNAs was measured using high-throughput polymerase chain reaction assay, and their association with 3-year survival in the discovery (n=345) and validation (n=177) cohorts was assessed. Five serum miRNAs (miR-191, miR-28-3p, miR-145, miR-328, and miR-18a) were significantly associated with 3 year overall survival in both cohorts. A combined 5-miRNA risk score was created to assess the cumulative impact of these miRNAs on risk of death. Quartile analysis of the risk score showed significant association with 3-year death risk, with a 4.6-month, 6.8-month, and 9.3-month reduction in median survival time for the second, third, and fourth quartile, respectively. Survival tree analysis also identified distinct risk groups with different 3-year survival durations. Data from The Cancer Genome Atlas revealed all 5 miRNAs were differentially expressed (P<0.0001) in paired tumor and normal tissues. Pathway analysis indicated that target genes of these 5 miRNAs were mainly enriched in inflammatory/immune response pathways and pathways implicated in resistance to chemoradiotherapy and/or targeted therapy. Our results suggested that the 5-miRNA signature could serve as a prognostic predictor in advanced NSCLC patients. PMID- 30428031 TI - Zebrafish hhex-null mutant develops an intrahepatic intestinal tube due to de repression of cdx1b and pdx1. AB - The hepatopancreatic duct (HPD) system links the liver and pancreas to the intestinal tube and is composed of the extrahepatic biliary duct, gallbladder, and pancreatic duct. Haematopoietically-expressed-homeobox (Hhex) protein plays an essential role in the establishment of HPD; however, the molecular mechanism remains elusive. Here, we show that zebrafish hhex-null mutants fail to develop the HPD system characterized by lacking the biliary marker Annexin A4 and the HPD marker sox9b. The hepatobiliary duct part of the mutant HPD system is replaced by an intrahepatic intestinal tube characterized by expressing the intestinal marker fatty-acid-binding-protein 2a (fabp2a). Cell lineage analysis showed that this intrahepatic intestinal tube is not originated from hepatocytes or cholangiocytes. Further analysis revealed that cdx1b and pdx1 are expressed ectopically in the intrahepatic intestinal tube and knockdown of cdx1b and pdx1 could restore the expression of sox9b in the mutant. Chromatin immunoprecipitation analysis showed that Hhex binds to the promoters of pdx1 and cdx1b genes to repress their expression. We therefore propose that Hhex, Cdx1b, Pdx1, and Sox9b form a genetic network governing the patterning and morphogenesis of the HPD and digestive tract systems in zebrafish. PMID- 30428032 TI - EuroPrevent 2018: Report from the European Congress on Preventive Cardiology 19 21 April, 2018, in Ljubljana, Slovenia. PMID- 30428033 TI - ESH Annual Meeting 2018: Reinhold Kreutz reports on the 28th European Meeting on Hypertension and Cardiovascular Protection that took place in Barcelona, Spain, 8 11 June. PMID- 30428034 TI - EHJ 2018 Editorial Board Meeting: With EHJ now the highest-ranking cardiology journal in the world, Mark Nicholls reports from the publication's 2018 annual board meeting. PMID- 30428036 TI - Biomarkers: a window into the pathophysiology of atrial fibrillation in heart failure with reduced vs. preserved ejection fraction. PMID- 30428035 TI - The Impact Factor: sparkling or still? PMID- 30428037 TI - What is the role of gene testing in athletes with T wave inversion? PMID- 30428038 TI - This is YOUR ESC: The ESC membership community: a unique, diverse and global group of cardiologists. PMID- 30428039 TI - Lipid metabolic networks, Mediterranean diet and cardiovascular disease in the PREDIMED trial. AB - Background: Perturbed lipid metabolic pathways may play important roles in the development of cardiovascular disease (CVD). However, existing epidemiological studies have focused more on discovering individual lipid metabolites for CVD risk prediction rather than assessing metabolic pathways. Methods: This study included a subcohort of 787 participants and all 230 incident CVD cases from the PREDIMED trial. Applying a network-based analytical method, we identified lipid subnetworks and clusters from a global network of 200 lipid metabolites and linked these subnetworks/clusters to CVD risk. Results: Lipid metabolites with more double bonds clustered within one subnetwork, whereas lipid metabolites with fewer double bonds clustered within other subnetworks. We identified 10 lipid clusters that were divergently associated with CVD risk. The hazard ratios [HRs, 95% confidence interval (CI)] of CVD per a 1-standard deviation (SD) increment in cluster score were 1.39 (1.17-1.66) for the hydroxylated phosphatidylcholine (HPC) cluster and 1.24 (1.11-1.37) for a cluster that included diglycerides and a monoglyceride with stearic acyl chain. Every 1-SD increase in the score of cluster that included highly unsaturated phospholipids and cholesterol esters was associated with an HR for CVD of 0.81 (95% CI, 0.67-0.98). Despite a suggestion that MedDiet modified the association between a subnetwork that included most lipids with a high degree of unsaturation and CVD, changes in lipid subnetworks/clusters during the first-year follow-up were not significantly different between intervention groups. Conclusions: The degree of unsaturation was a major determinant of the architecture of lipid metabolic network. Lipid clusters that strongly predicted CVD risk, such as the HPC cluster, warrant further functional investigations. PMID- 30428042 TI - A primary analysis of a multicenter, prospective, single-arm, confirmatory trial of hypofractionated whole breast irradiation after breast-conserving surgery in Japan: JCOG0906. AB - Objective: To evaluate the safety of hypofractionated whole breast irradiation in Japanese women after breast-conserving surgery. Methods: Japanese women who had invasive breast cancer with a clinical tumor size <=3 cm, pN0-1c and a negative inked margin were enrolled. Hypofractionated whole breast irradiation (42.56 Gy/16 fractions) was delivered, adding boost irradiation (10.64 Gy/4 fractions) when the surgical margin was <=5 mm. The treatment course was meant to be completed within 29 days or 33 days (plus boost irradiation). The primary endpoint was the proportion of grade >=2 of pre-specified late adverse reactions, including telangiectasia, ulceration, fibrosis, fracture, pneumonitis, cardiac ischemia/infarction, pericardial effusion and breast pain, within 3 years. A sample size of 310 patients was set, with one-sided alpha of 0.05, beta of 0.1, threshold value of 8% and expected value of 4%. Secondary endpoints included the proportion of treatment completion within the recommended period and early adverse events within 90 days. Adverse events/adverse reactions were evaluated using CTCAE-3.0. Results: Between 2010 and 2012, 312 women were enrolled; 306 received hypofractionated whole breast irradiation, but 6 chose conventional fractionated WBI, with 301 patients (96.5%) treated within the recommended period. Grade 2 early adverse events were found in 38 patients (12.4%); none had grade 3/4. Among the 303 evaluable patients, 13 (4.3%; 90% CI 2.6-6.7) had grade 2/3 late adverse reactions, including one with grade 3 pneumonitis, which was under the threshold value. Conclusion: Hypofractionated whole breast irradiation is considered to be safe and one of the standard treatments for Japanese women with margin-negative invasive breast cancer after breast-conserving surgery. PMID- 30428043 TI - Associations of sperm mitochondrial DNA copy number and deletion rate with fertilization and embryo development in a clinical setting. AB - STUDY QUESTION: Are sperm mitochondrial DNA copy number (mtDNAcn) and deletion rate (mtDNAdel) associated with odds of fertilization and high embryo quality at Days 3 and 5? SUMMARY ANSWER: Higher sperm mtDNAcn and mtDNAdel were associated with lower odds of high quality Day 3 embryos and transfer quality Day 5 embryos, both of which were primarily driven by lowered odds of fertilization. WHAT IS KNOWN ALREADY: Sperm mtDNAcn and mtDNAdel have been previously associated with poor semen parameters and clinical male infertility. One prior study has shown that mtDNAdel is associated with lower fertilization rates. However, it is unknown whether these characteristics are linked with ART outcomes. STUDY DESIGN, SIZE, DURATION: This prospective observational study included 119 sperm samples collected from men undergoing ART in Western Massachusetts. ART outcomes were observed through to Day 5 post-insemination. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: As part of the Sperm Environmental Epigenetics and Development Study (SEEDS), 119 sperm samples were collected from men undergoing ART in Western Massachusetts. Sperm mtDNAcn and mtDNAdel were measured via triplex probe-based qPCR. Fertilization, Day 3 embryo quality and Day 5 embryo quality measures were fitted with mtDNAcn and mtDNAdel using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE: After adjusting for male age and measurement batches, higher sperm mtDNAcn and mtDNAdel were associated with lower odds of fertilization (P = 0.01 and P < 0.01), high quality Day 3 embryos (P = 0.02 for both) and transfer quality Day 5 embryos (P = 0.01 and P = 0.09). However, the associations of mtDNAcn and mtDNAdel with Day 3 high quality status and Day 5 transfer quality status were attenuated in models restricted to fertilized oocytes. Sperm mtDNAcn and mtDNAdel remained statistically significant in models adjusted for both male age and semen parameters, although models including both mtDNA markers generally favoured mtDNAdel. LIMITATIONS, REASONS FOR CAUTION: Our sample only included oocytes and embryos from 119 couples and thus large diverse cohorts are necessary to confirm the association of sperm mtDNA biomarkers with embryo development. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, our study is the first to assess the associations of sperm mtDNAcn and mtDNAdel with fertilization and embryo quality. The biological mechanism(s) underlying these associations are unknown. Multivariable models suggest that sperm mtDNAcn and mtDNAdel provide discrimination independent of age and semen parameters; therefore, future investigation of the utility of sperm mtDNA as a biomarker for ART outcomes is warranted. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grant (K22-ES023085) from the National Institute of Environmental Health Sciences. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A. PMID- 30428044 TI - Mitochondrial functionality modifies human sperm acrosin activity, acrosome reaction capability and chromatin integrity. AB - STUDY QUESTION: In addition to sperm motility, which major biological characteristics of sperm fertility potential are associated with mitochondrial functionality? SUMMARY ANSWER: Sperm fertilization capacities, including acrosin activity, acrosome reaction (AR) capability and chromatin integrity, are related to the mitochondria functionality as evaluated by the mitochondrial membrane potential (MMP). WHAT IS KNOWN ALREADY: Correlative studies suggest a potential role of sperm MMP in predicting sperm fertilization ability and ensuring sperm motility. However, researches characterizing other determinants of sperm fertility potential according to MMP are lacking. STUDY DESIGN, SIZE, DURATION: The sperm MMP was examined in 627 young college students in the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study in 2014. Among these participants, acrosin activity and chromatin integrity were measured in 378 and 604 subjects, respectively. These two determinants of sperm fertility potential were first compared among high-, moderate- and low-MMP groups in the college population. The effects of MMP collapse caused by carbonyl cyanide 3 chlorophenylhydrazone (CCCP) on acrosin activity, AR, DNA fragmentation, reactive oxygen species (ROS) production, and ATP content in human spermatozoa were evaluated in vitro. PARTICIPANTS/MATERIALS, SETTING, METHODS: The sperm MMP was evaluated by using JC-1 staining, acrosin activity was measured using a N-alpha benzoyl-dl-arginine-para-nitroanilide HCl (BAPNA) substrate method, the integrity of chromatin represented by DNA fragmentation index (DFI) was measured by sperm chromatin structure assay (SCSA), AR was evaluated with chlortetracycline staining, and intracellular ROS production was evaluated with dihydroethidium. ATP concentration was determined with luciferase. Measurements were performed by spectrophotometry or flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Nonparametric analysis revealed significantly higher acrosin activity and a lower DFI in subjects with moderate or high MMP compared to those with low MMP. After adjustment for potential confounders, increases of 7.9 and 44.4% in sperm acrosin activity and deceases of 12.0 and 25.2% in the sperm DFI were found in the moderate- and high-MMP groups, respectively. The MMP dissipation induced by CCCP caused significant declines in acrosin activity and AR capacity and increased DFI in human spermatozoa. Moreover, sperm MMP dissipation induced ROS overproduction and decreased ATP content. LIMITATIONS, REASONS FOR CAUTION: We cannot exclude a contribution of leukocytes to ROS production and no size gating was used to exclude these cells from the FACS measurements. No simultaneous live-dead staining was done and a contribution of dead sperm to the MMP and acrosome assays cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Mitochondrial functionality might be necessary to maintain sperm acrosin activity, AR and chromatin integrity. Tests of mitochondrial functionality should be developed and used independently of or in addition to conventional semen parameters in infertility diagnosis or risk-assessment processes. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Key Program of the National Natural Science Foundation of China (No. 81630087) and the National Natural Science Foundation of China (No. 81703254). None of the authors have any competing interests to declare. PMID- 30428045 TI - Quality of care in six sub-Saharan Africa countries: a provider-based study on adherence to WHO's antenatal care guideline. AB - Objective: Quality of care may help explain the high burden of disease in maternal, newborn and child health in low- and middle-income countries even as access to care is improved. We explored the determinants of quality of antenatal care (ANC) in sub-Saharan Africa (SSA). Design: Cross-sectional study. Multilevel Generalized Linear Latent Mixed-Effect models with logit link function were employed to obtain the adjusted odds ratios (AORs) and 95% confidence interval (CI). Setting: We used Service Provision Assessment data from six countries in SSA, including Kenya, Malawi, Namibia, Rwanda, Tanzania and Uganda. Participants: Seven thousand, five hundred and seventy seven observed antenatal clients across the six countries. Main Outcome Measures: Quality of ANC services, measured using indexes of quality of clinical care and quality of information provided. Results: Providers in facilities that had ANC guideline (AOR = 1.26; 95% CI, 1.08-1.48), were well-equipped (AOR = 1.65; 95% CI, 1.41-1.92), were classified as upper level facility (AOR = 1.32; 95% CI, 1.05-1.66), had central electricity supply (AOR = 2.19; 95% CI, 1.81-2.65), and piped water (AOR = 1.30; 95% CI, 1.09-1.55) were more likely to provide optimal quality of clinical care. Moreover, those having ANC guideline (AOR = 1.81; 95% CI, 1.43-2.28) and central electricity supply (AOR = 2.67; 95% CI, 2.01-3.44) were more likely to provide optimal information as well. Provider's qualification and experience were also important in information provision and clinical care independently. Conclusion: The lack of some very basic facility equipment and amenities compromised quality of care in sub-Saharan countries. Policy actions and investment on facility and providers will enable provision of quality services necessary to improve maternal, newborn and child health in SSA. PMID- 30428046 TI - Nucleoside supplementation modulates mitochondrial DNA copy number in the dguok-/ zebrafish. AB - Deoxyguanosine kinase (dGK) is an essential rate limiting component of the mitochondrial purine nucleotide salvage pathway, encoded by the nuclear gene DGUOK. Mutations in DGUOK lead to mitochondrial DNA (mtDNA) depletion typically in the liver and brain, causing a hepatocerebral phenotype. Previous work has shown thatin cultured DGUOK patient cellsit is possible to rescue mtDNA depletion by increasing substrate amounts for dGK. In this study we developed a mutant dguok zebrafish (Danio rerio) line using CRISPR/Cas9 mediated mutagenesis; dguok /-fish have significantly reduced mtDNA levels compared to wild-type fish. When supplemented with only one purine nucleoside (dGuo), mtDNA copy number in both mutant and wild-type juvenile animals was significantly reduced,contrasting with previous cell culture studies, possibly due to nucleotide pool imbalance. However,in adult dguok-/-fish we detected a significant increase in liver mtDNA copy number when supplemented with both purine nucleosides. This study further supports the idea that nucleoside supplementation has a potential therapeutic benefit in mtDNA depletion syndromes by substrate enhancement of the purine nucleoside salvage pathway and might improve the liver pathology in patients. PMID- 30428047 TI - A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice. PMID- 30428048 TI - Far-off and close-up feeding levels affect immunological performance in grazing dairy cows during the transition period. AB - During the peripartum period, dairy cows often have signs of inflammation. Various stresses, including infectious and metabolic diseases, have been discussed as causative for this inflammation. In this study, expression profiles for 17 immune markers were measured in whole blood preparations from 78 dairy cows over a time frame starting 1 wk before calving to 4 wk after calving. Additionally, the effects of far-off and close-up feeding on immune function of dairy cows during the peripartum period were investigated. Cows were assigned to 1 of 2 feeding levels in late lactation to achieve a low and high BCS at the time of dry-off (approximately 4.25 and 5.0 on a 10-point scale). Following dry-off, both herds were managed to achieve a BCS of 5.0 one month before calving; this involved controlled feeding (i.e., maintenance) and over-feeding of ME during the far-off dry period. Within each far-off feeding-level treatment, cows were offered 65, 90, or 120% of their pre-calving ME requirements for 3 wk pre-calving in a 2 * 3 factorial arrangement. Analysis of gene expression profiles from blood cells revealed effects of time indicating that the transition cow's immune system counteracts the peripartum inflammation, whereas later post-calving it becomes activated to provide protection against post-partum infections. Far-off feeding affected (P < 0.05) the expression of two of the investigated genes at calving. IL6 and GAPDH expression in unstimulated, peripheral leukocytes were lower (P < 0.05) in animals from the Far-Off_Over-fed group compared with the Far Off_Control-fed group. Close-up feeding had several effects on gene expression, indicating that immune function in Feed120 animals was distinct from the Feed90 and Feed65. In conclusion, feeding management pre-calving becomes an important intervention to ensure immunocompetence at and after calving. PMID- 30428049 TI - Phase 2b Study of Pimodivir (JNJ-63623872) as Monotherapy or in Combination With Oseltamivir for Treatment of Acute Uncomplicated Seasonal Influenza A: TOPAZ Trial. AB - Background: Pimodivir, a first-in-class inhibitor of influenza virus polymerase basic protein 2, is being developed for hospitalized and high-risk patients with influenza A. Methods: In this double-blinded phase 2b study, adults with acute uncomplicated influenza A were randomized 1:1:1:1 to receive one of the following treatments twice daily for 5 days: placebo, pimodivir 300 mg or 600 mg, or pimodivir 600 mg plus oseltamivir 75 mg. Antiviral activity, safety, and pharmacokinetics of pimodivir alone or in combination were evaluated. Results: Of 292 patients randomized, 223 were treated and had confirmed influenza A virus infection. The trial was stopped early because the primary end point was met; the area under the curve of the viral load, determined by quantitative reverse transcription-polymerase chain reaction analysis, in nasal secretions from baseline to day 8 significantly decreased in the active treatment groups, compared with the placebo group (300 mg group, -3.6 day*log10 copies/mL [95% confidence interval {CI}, -7.1 to -0.1]; 600 mg group, -4.5 [95%CI -8.0 to -1.0]; and combination group, -8.6 [95% CI, -12.0 to -5.1]). Pimodivir plus oseltamivir yielded a significantly lower viral load titer over time than placebo and a trend for a shorter time to symptom resolution than placebo. Pimodivir plasma concentrations increased in a dose-proportional manner. The most commonly reported adverse event was mild or moderate diarrhea. Conclusions: Pimodivir (with or without oseltamivir) resulted in significant virologic improvements over placebo, demonstrated trends in clinical improvement, and was well tolerated. Pimodivir 600 mg twice daily is in further development. Clinical Trials Registration: NCT02342249, 2014-004068-39, and CR107745. PMID- 30428050 TI - Relative contributions of prenatal complications, perinatal characteristics, neonatal morbidities and socio-economic conditions of preterm infants on the occurrence of developmental disorders up to 7 years of age. AB - Background: To investigate the relative contributions of prenatal complications, perinatal characteristics, neonatal morbidities and socio-economic conditions on the occurrence of motor, sensory, cognitive, language and psychological disorders in a large longitudinal preterm infant population during the first 7 years after birth. Methods: The study population comprised 4122 infants born at <35 weeks of gestation who were followed for an average of 74.0 months after birth. Developmental disorders, including motor, sensory, cognitive, language and psychological, were assessed at each follow-up visit from 18 months to 7 years of age. The investigated determinants included prenatal complications (prolonged rupture of membranes >24 hours, intrauterine growth restriction, preterm labour and maternal hypertension), perinatal characteristics (gender, multiple pregnancies, gestational age, birth weight, APGAR score and intubation or ventilation in the delivery room), neonatal complications (low weight gain during hospitalization, respiratory assistance, severe neurological anomalies, nosocomial infections) and socio-economic characteristics (socio-economic level, parental separation, urbanicity). Based on hazard ratios determined using a propensity score matching approach, population-attributable fractions (PAF) were calculated for each of the four types of determinants and for each developmental disorder. Results: The percentages of motor, sensory, cognitive, language and psychological disorders were 17.0, 13.4, 29.1, 25.9 and 26.1%, respectively. The PAF for the perinatal characteristics were the highest and they were similar for the different developmental disorders considered (around 60%). For the neonatal and socio-economic determinants, the PAF varied according to the disorder, with contributions of up to 17% for motor and 27% for language disorders, respectively. Finally, prenatal complications had the lowest contributions (between 6 and 13%). Conclusions: This study illustrates the heterogeneity of risk factors on the risk of developmental disorder in preterm infants. These results suggest the importance of considering both medical and psycho-social follow-ups of preterm infants and their families. PMID- 30428051 TI - Population-level mortality benefits of improved blood pressure control in Indonesia: a modelling study. AB - Background: There are few estimates of the potential gains in adult mortality from population-level improvements in systolic blood pressure (SBP) in a major low-and-middle income country (LMIC). Using nationally representative cohort data from Indonesia-the third most populous LMIC- I estimated the gains in adult life expectancy from improving SBP control among adults ages 40 and above and assessed the benefits among richer and poorer subpopulations. Methods: I used longitudinal data from 10 085 adults ages 40 and above (75 288 person-age observations) enrolled in the 2007 and 2014/15 waves of the Indonesian Family Life Survey. Next, I used Poisson-regression parametric g-formulas to directly estimate age specific mortality rates under different blood pressure control strategies and constructed period life expectancies using the observed and counterfactual mortality rates. Results: Fully controlling SBP to a population mean of under 125 mmHg was associated with a life expectancy gain at age 40 of 5.3 years [95% confidence interval (CI): 3.2, 7.4] for men and 6.0 years (95% CI: 3.6, 8.4) for women. The gains associated with blood pressure control were similar for both rich and poor subpopulations. The life expectancy gains under scenarios with imperfect blood pressure control and coverage were more modest in size and ranged between 1 and 2.5 years for a large fraction of the scenarios. Conclusions: In Indonesia, elevated SBP carries a large mortality burden, though the results suggest that realistic efforts to address hypertension will likely produce more modest gains in life expectancy. Comparing improvements from different strategies and identifying the most cost-effective ways to introduce and scale up hypertension interventions is a critical focus for both research and policy. PMID- 30428052 TI - Development of a framework to describe patient and family harm from disrespect and promote improvements in quality and safety: a scoping review. AB - Purpose: Patients and families may experience 'non-physical' harm from interactions with the healthcare system, including emotional, psychological, socio-behavioral or financial harm, some of which may be related to experiences of disrespect. We sought to use the current literature to develop a practical, improvement-oriented framework to recognize, describe and help prevent such events. Data Sources: Searches were performed in PubMed, Embase, PsychINFO, CINAHL, Health Business Elite and ProQuest Dissertations & Theses: Global: Health & Medicine, from their inception through July 2017. Study Selection: Two authors reviewed titles, abstracts, full texts, references and cited-by lists to identify articles describing approaches to understanding patient/family experiences of disrespect. Data Extraction: Findings were evaluated using integrative review methodology. Results of Data Synthesis: Three-thousand eight hundred and eighty two abstracts were reviewed. Twenty three articles were identified. Components of experiences of disrespect included: (1) numerous care processes; (2) a wide range of healthcare professional and organizational behaviors; (3) contributing factors, including patient- and professional-related factors, the environment of work and care, leadership, policies, processes and culture; (4) important consequences of disrespect, including behavioral changes and health impacts on patients and families, negative effects on professionals' subsequent interactions, and patient attrition from organizations and (5) factors both intrinsic and extrinsic to patients that can modify the consequences of disrespect. Conclusion: A generalizable framework for understanding disrespect experienced by patients/families in healthcare may help organizations better prevent non-physical harms. Future work should prospectively test and refine the framework we described so as to facilitate its integration into organizations' existing operational systems. PMID- 30428053 TI - Multitasking in Nursing Homes: Differences Between For-Profit and Nonprofit Quality Outcomes. AB - Background and Objectives: Nursing homes (NHs) in the United States face increasing pressures to admit Medicare postacute patients, given higher payments relative to Medicaid. Changes in the proportion of residents who are postacute may initiate shifts in care practices, resource allocations, and priorities. Our study sought to determine whether increases in Medicare short-stay census have an impact on quality of care for long-stay residents. Research Design and Methods: This study used panel data (2005-2010) from publicly-available sources (Nursing Home Compare, Area Health Resource File, LTCFocus.org) to examine the relationship between a 1-year change in NH Medicare census and 14 measures of long-stay quality among NHs that experienced a meaningful increase in Medicare census during the study period (N = 7,932). We conducted analyses on the overall sample and stratified by for- and nonprofit ownership. Results: Of the 14 long stay quality measures examined, only one was shown to have a significant association with Medicare census: increased Medicare census was associated with improved performance on the proportion of residents with pressure ulcers. Stratified analyses showed increased Medicare census was associated with a significant decline in performance on 3 of 14 long-stay quality measures among nonprofit, but not for-profit, facilities. Discussion and Implications: Our findings suggest that most NHs that experience an increase in Medicare census maintain long-stay quality. However, this may be more difficult to do for some, particularly nonprofits. As pressure to focus on postacute care mount in the current payment innovation environment, our findings suggest that most NHs will be able to maintain stable quality. PMID- 30428054 TI - Guatemala City youth: an analysis of health indicators through the lens of a clinical registry. AB - Background: Despite the inclusion of adolescent health in recent global frameworks, limited data exist on health indicators in low-income countries. Our objective was to identify socioeconomic measures, risk behaviors and health indicators of young people in Guatemala. Methods: We conducted a secondary data analysis of the Pan American Health Organization's Sistema Informatico del Adolescente of 2831 participants ages 10-24 y from 2008 to 2014. We examined frequencies for a core set of items, and generalized regression models assessed correlations between age, sex and ethnicity with health outcomes of interest. Results: Fewer than 17% of participants reported a history of chronic illness (16.6%) and severe psychological problems (16.8%). While 66.1% of participants' mothers and 36.6% of fathers reported job instability, far fewer families had housing instability (1.9% with no electricity, 6.3% with no running water). Fewer than one-third (29.1%) were sexually active and the majority (76.0%) routinely used condoms. About one-quarter (22.6%) reported abnormal mood. Indigenous participants were significantly more likely to have experienced psychological problems (odds ratio [OR] 1.75 [confidence interval {CI} 1.65-1.86]) and violence (OR 1.34 [CI 1.27-1.42]) compared with whites. Conclusions: The prevalence of risk behaviors and mental health concerns is low compared with other sources of national and regional data. Further work is needed to examine the benefits and limitations of this system in order to improve health surveillance. PMID- 30428055 TI - Biodiversity Pattern of Mosquitoes in Southeastern Senegal, Epidemiological Implication in Arbovirus and Malaria Transmission. AB - The composition, density, diversity, and temporal distribution of mosquito species and the influence of temperature, relative humidity, and rainfall on these data were investigated in 50 sites across five land cover classes (forest, savannah, barren, village, and agriculture) in southeastern Senegal. Mosquitoes were collected monthly in each site between June 2009 and March 2011, with three people collecting mosquitoes landing on their legs for one to four consecutive days. In total, 81,219 specimens, belonging to 60 species and 7 genera, were collected. The most abundant species were Aedes furcifer (Edwards) (Diptera: Culicidae) (20.7%), Ae. vittatus (Bigot) (19.5%), Ae. dalzieli (Theobald) (14.7%), and Ae. luteocephalus (Newstead) (13.7%). Ae. dalzieli, Ae. furcifer, Ae. vittatus, Ae. luteocephalus, Ae. taylori Edwards, Ae. africanus (Theobald), Ae. minutus (Theobald), Anopheles coustani Laveran, Culex quinquefasciatus Say, and Mansonia uniformis (Theobald) comprised >=10% of the total collection, in at least one land cover. The lowest species richness and Brillouin diversity index (HB = 1.55) were observed in the forest-canopy. The urban-indoor fauna showed the highest dissimilarity with other land covers and was most similar to the urban outdoor fauna following Jaccard and Morisita index. Mosquito abundance peaked in June and October 2009 and July and October 2010. The highest species density was recorded in October. The maximum temperature was correlated positively with mean temperature and negatively with rainfall and relative humidity. Rainfall showed a positive correlation with mosquito abundance and species density. These data will be useful for understanding the transmission of arboviruses and human malaria in the region. PMID- 30428056 TI - Reducing right ventricular pacing burden: algorithms, benefits, and risks. AB - Algorithms designed to reduce the burden of right ventricular pacing are widely available in modern implantable pacing devices. To ensure safe and optimal utilization, understanding the properties of these algorithms as well as their possible unfavourable effects is essential. In this review, we discuss in detail the technical and clinical aspects of rhythm management algorithms and update on their significant recent modifications. In addition, we highlight possible adverse phenomena that may be induced by these different pacing algorithms intended to minimize pacing. PMID- 30428057 TI - Metabolic regulation of T cell development by Sin1-mTORC2 is mediated by pyruvate kinase M2. AB - Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4-CD8- double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1-mTORC2 controls PKM2 expression through an AKT-dependent PPAR gamma nuclear translocation. Together, our study unravels a novel mTORC2-PPAR gamma-PKM2 pathway in immune-metabolic regulation of early thymocyte development. PMID- 30428058 TI - Erratum. PMID- 30428059 TI - Improvement of social support in empty-nest elderly: results from an intervention study based on the Self-Mutual-Group model. AB - Background: China has the world's largest elderly population and an increasing number of empty-nest elderly. The purpose of this study is to evaluate the effectiveness of the Self-Mutual-Group model on social support of the empty-nest elderly, thus providing reference for improving their quality of life. Methods: A intervention study was conducted between October 2016 and May 2017 at six communities in Taiyuan, Shanxi Province, China. A total of 350 empty-nest elderly aged 60-88 years were randomly assigned in the intervention group (n = 167) with a 7-month SMG-based intervention or to a control group (n = 183) with no intervention. The social support of the participating elderly (n = 350) was assessed by the Social Support Rating Scale (SSRS) at the baseline and 7 months later, respectively. Results: A 7-month follow-up showed an increasing mean scores of SSRS, objective support, subjective support and support utilization of the intervention group, and reached statistical significance (P < 0.05). Conclusions: The Self-Mutual-Group model was considered to be a positive intervention and was effective in increasing social support among the empty-nest elderly. Furthermore, future research should extend the intervention period and introduce multi-point measurement to better evaluate the intervention process and outcomes. Trial registration: Study on the 'SMG' Health Management Model Based on Community Organization Theory among empty-nest elderly (ChiCTR1800015884). PMID- 30428060 TI - Inhibiting Viral Polymerase and Neuraminidase in Treating Influenza. PMID- 30428061 TI - The Prevalence and Clinical Associations of Subclinical Sacroiliitis in Inflammatory Bowel Disease. AB - Background: Sacroiliitis, an inflammatory arthropathy associated with ankylosing spondylitis (AS), is found in patients with inflammatory bowel disease (IBD) but may go undiagnosed. The aims of this study were to assess prevalence of sacroiliitis in IBD and to determine association between clinical characteristics of IBD and sacroiliitis. Methods: Inflammatory bowel disease patients undergoing abdomino-pelvic computed tomography (CT) for any indication (2006-2015) were identified. Using standardized CT scoring, sacroiliitis was confirmed. Two blinded readers used a standardised model where presence of ankylosis or erosion score >3 indicated sacroiliitis. Inflammatory bowel disease scoring was blinded to the presence of sacroiliitis. Demographics, IBD characteristics, clinical activity (Harvey Bradshaw Index >4, Mayo >2, as denoted by attending physician), endoscopic activity (Simple Endoscopic Score for Crohn's Disease >4/Mayo subscore >1), and arthritis/extraintestinal manifestations (EIMS) were recorded. Comparisons were made between those with/without sacroiliitis. Results: Three hundred sixteen patients were included (50% male; 74% Crohn's disease [CD]). Computed tomography scoring identified 49 (16%) with sacroiliitis. Radiologists had reported sacroiliitis in 33% of these. Five patients had been to a spondylitis clinic. Thirty-three of 49 had abdominal x-rays; 64% of these fulfilled the imaging component of Modified New York criteria for AS. More than 5 sacroiliac erosions were associated with radiologist-reported sacroiliitis (P < 0.0001). There was no difference in prevalence between CD and ulcerative colitis. Sacroiliitis was associated with male sex (63.3% vs 47.9%; odds ratio [OR], 1.8; P = 0.04), known arthritis (41% vs 12%; OR, 4.7; P < 0.0001), pain as an IBD symptom (77.7% vs 56.9%; P = 0.03), and CD inflammatory phenotype (P = 0.01). Endoscopic activity, location, and extent were not associated. Conclusions: Sacroiliitis is underdiagnosed in IBD and is associated with male sex, arthritis, and inflammatory CD. Data support targeted screening in at-risk patients. PMID- 30428063 TI - Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF Melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial. AB - Backround: Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the MAPK pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised, open-label trial. Patients and Methods: Patients were randomised (1:1:1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of 6 cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and objective response rate (ORR). Results: Participants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS; (time ratio (TR), 1.47; 90% confidence interval (CI): 1.08 to 2.01, P = 0.04) and ORR (42% versus 13%; P = 0.01), but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6 month PFS; (TR, 1.36; 90% CI: 0.96 to 1.93, P = 0.14), ORR, or OS. Toxicity increased in both combination arms. Conclusion: In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS. This study was registered with the EU Clinical Trials Register, number EudraCT 2011-002545-35, and with the ISRCTN registry, number 43327231. PMID- 30428062 TI - Iatrogenic endometriosis harbors somatic cancer-driver mutations. AB - STUDY QUESTION: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 30428064 TI - Super-response to cardiac resynchronization therapy reduces appropriate implantable cardioverter-defibrillator therapy: comment. PMID- 30428065 TI - Reducing health inequalities in England: does the demise of NHS Stop Smoking Services matter? Analysis of mandatory monitoring data. AB - Background: Tobacco smoking is a key cause of mortality, morbidity and health inequalities. The unprecedented English health inequalities strategy (1999-2010) sought to reduce health inequalities, by, in part, instigating NHS Stop Smoking Services (SSS), initially targeted in deprived 'Spearhead' localities. Performance of SSS is assessed here in light of its role supporting the strategy, which evidence suggests achieved a reduction in health inequalities. Methods: SSS enrolment and four-week quits in Spearhead and non-Spearhead localities were compared during and after the strategy period, using regression models and routine monitoring data. Changes in SSS expenditure were estimated. Results: After similar increases in enrolment and quits between Spearhead and other localities between 2003/4 and 2008/9, SSS in Spearhead localities experienced a 2 fold better rate of improvement in enrolment and quit performance over the 4 years to 2011/12. Since 2011/12, SSS have dramatically reduced, and expenditure had fallen by half in Spearhead localities by 2016/17. Conclusions: SSS, particularly in Spearhead localities, were expanded up to 2011/12, and this broadly coincides with the reduction in health inequalities. This suggests that although SSS did not achieve the scale anticipated, they have important potential, and the current demise of SSS should not be tolerated. PMID- 30428066 TI - 2018 landmark papers in transplantation published in NDT: clinical research highlights in the area of kidney transplantation. PMID- 30428067 TI - Super-response to cardiac resynchronization therapy reduces appropriate implantable cardioverter-defibrillator therapy: comment-Authors' reply. PMID- 30428068 TI - The Necessity of Trauma-Informed Practice in Contemporary Social Work. PMID- 30428069 TI - Too expensive to treat? Non-treatment decisions at the margins of viability. AB - This article seeks to challenge the assumption that it is legitimate to consider the costs of premature babies' future social and educational needs when deciding what treatment, if any, to provide in the neonatal intensive care unit (NICU) . It questions the elision that is made between the claim that a particular treatment is insufficiently cost-effective and the claim that a person will be a burden on the state in the future. It discusses a series of common misunderstandings about how treatment decisions are taken in the NICU and concludes by suggesting that the claim that premature babies are too expensive to treat may depend upon regarding a premature infant as if she were not yet a person, with rights and interests of her own. PMID- 30428070 TI - Methods for estimating demography and detecting between-locus differences in the effective population size and mutation rate. AB - It is known that the effective population size (Ne) and the mutation rate (u) vary across the genome. Here we show that ignoring this heterogeneity may lead to biased estimates of past demography. To solve the problem, we develop new methods for jointly inferring past changes in population size and detecting variation in Ne and u between loci. These methods rely on either polymorphism data alone or both polymorphism and divergence data. In addition to inferring demography, we can use the methods to study a variety of questions: (1) comparing sex chromosomes to autosomes (for finding evidence for male-driven evolution, an unequal sex ratio, or sex-biased demographic changes); (2) analysing multi-locus data from within autosomes or sex chromosomes (for studying determinants of variability in Ne and u). Simulations suggest that the methods can provide accurate parameter estimates and have substantial statistical power for detecting difference in Ne and u. As an example, we use the methods to analyse a polymorphism dataset from Drosophila simulans. We find clear evidence for rapid population expansion. The results also indicate that the autosomes have a higher mutation rate than the X chromosome, and that the sex ratio is probably female biased. The new methods have been implemented in a user-friendly package. PMID- 30428071 TI - Genomic Evidence of Local Adaptation to Climate and Diet in Indigenous Siberians. AB - The indigenous inhabitants of Siberia live in some of the harshest environments on earth, experiencing extended periods of severe cold temperatures, dramatic variation in photoperiod, and limited and highly variable food resources. While the successful long-term settlement of this area by humans required multiple behavioral and cultural innovations, the nature of the underlying genetic changes has generally remained elusive. In this study, we used a three-part approach to identify putative targets of positive natural selection in Siberians. We first performed selection scans on whole exome and genome-wide SNP array data from multiple Siberian populations. We then annotated candidates in the tails of the empirical distributions, focusing on candidates with evidence linking them to biological processes and phenotypes previously identified as relevant to adaptation in circumpolar groups. The top candidates were then genotyped in additional populations to determine their spatial allele frequency distributions and associations with climate variables. Our analysis reveals missense mutations in three genes involved in lipid metabolism (PLA2G2A, PLIN1, ANGPTL8) that exhibit genomic and spatial patterns consistent with selection for cold climate and/or diet. These variants are unified by their connection to brown adipose tissue, and may help to explain previously observed physiological differences in Siberians such as low serum lipid levels and increased basal metabolic rate. These results support the hypothesis that indigenous Siberians have genetically adapted to their local environment by selection on multiple genes. PMID- 30428072 TI - The many nuanced evolutionary consequences of duplicated genes. AB - Gene duplication is seen as a major source of structural and functional divergence in genome evolution. Under the conventional models of sub- or neofunctionalizaton, functional changes arise in one of the duplicates after duplication. However, we suggest here that the presence of a duplicated gene can result in functional changes to its interacting partners. We explore this hypothesis by in-silico evolution of a heterodimer when one member of the interacting pair is duplicated. We examine how a range of selection pressures and protein structures leads to differential patterns of evolutionary divergence. We find that a surprising number of distinct evolutionary trajectories can be observed even in a simple three member system. Further, we observe that selection to correct dosage imbalance can affect the evolution of the initial function in several unexpected ways. For example, if a duplicate is under selective pressure to avoid binding its original binding partner, this can lead to changes in the binding interface of a non-duplicated interacting partner to exclude the duplicate. Hence, independent of the fate of the duplicate, its presence can impact how the original function operates. Additionally, we introduce a conceptual framework to describe how interacting partners cope with dosage imbalance after duplication. Contextualizing our results within this framework reveals that the evolutionary path taken by a duplicate's interacting partners is highly stochastic in nature. Consequently, the fate of duplicate genes may not only be controlled by their own ability to accumulate mutations but also by how interacting partners cope with them. PMID- 30428073 TI - The ecology of multilevel intervention research. AB - Behavior change research to promote health and prevent disease increasingly relies on a complex set of interacting characteristics across levels of influence such as biological, psychological, behavioral, interpersonal, and environmental. How to best develop health-related interventions that incorporate the individual, the macro-environment, and their interactions remains a challenge. This article considers a set of key dimensions that constitute what we refer to as the ecology of research across a broad context of multilevel research (MLR), spanning fundamental multilevel research (FMLR), multilevel intervention research (MLIR), and multilevel implementation science (MIS). With the goal of promoting improvements in MLIR, we describe the inherent interdependencies among aspects of research and consider how the growth and development of evidence and resources influence the cross-talk among researchers from different perspectives (e.g., disciplines and domains). We propose a framework that highlights opportunities to reduce barriers and address gaps in areas critical to generating an evidence base through MLR, MLIR, and MIS. Overall, we aim to support strategic decisions that can accelerate our understanding of ML health outcomes and interactions among factors within and across levels, with the goal of strengthening the effectiveness of ML interventions across health-related outcomes. PMID- 30428074 TI - Benchmarks for Evaluating Life Review and Reminiscence Therapy in Alleviating Depression among Older Adults. AB - The efficacy of reminiscence and life review (LR) therapy in alleviating depression among older adults is well established. However, providers in nonresearch settings might implement these interventions inadequately, and such settings rarely can evaluate their outcomes using control groups. Alternatively, evaluators in such settings can calculate a within-group effect size and then compare it with average within-group effect size benchmarks derived from the randomized clinical trials (RCTs) supporting the intervention's effectiveness. This study developed these within-group effect size benchmarks. A search of RCTs from five systematic reviews and meta-analyses, and more recent RCTs published through 2016, yielded 25 studies that met inclusion criteria. Hedge's g for LR recipients and waitlist controls were .598 and -.20, respectively, and .568 and .012 for reminiscence theory. These benchmarks offer an approach for evaluating the implementation of LR and reminiscence therapy when control groups are infeasible. PMID- 30428075 TI - BiFET: sequencing Bias-free transcription factor Footprint Enrichment Test. AB - Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g. hypergeometric) do not account for this bias and inflate false positive associations. Therefore, we developed a novel post-processing method, Bias-free Footprint Enrichment Test (BiFET), that corrects for the biases arising from the differences in chromatin accessibility levels and GC contents between target and background loci in footprint enrichment analyses. We applied BiFET on TF footprint calls obtained from EndoC-betaH1 ATAC-seq samples using three different algorithms (CENTIPEDE, HINT-BC and PIQ) and showed BiFET's ability to increase power and reduce false positive rate when compared to hypergeometric test. Furthermore, we used BiFET to study TF footprints from human PBMC and pancreatic islet ATAC-seq samples to show its utility to identify putative TFs associated with cell-type-specific loci. PMID- 30428076 TI - OSL PROPERTIES IN VARIOUS FORMS OF KCl AND NaCl SAMPLES AFTER EXPOSURE TO IONIZING RADIATION. AB - The aim of this work was to investigate the optically-stimulated luminescence (OSL) properties of potassium chloride (KCl) and its potential use in radiation dosimetry. The optimal condition for OSL readout with blue light stimulation were designated using a commercially available Riso TL/OSL reader. KCl was studied in three sample forms: crystals, powder and pellets. The following OSL characteristics were determined: signal reproducibility, OSL measurement-induced sensitivity changes, temperature dependence of OSL and signal stability over time. The results show a high reproducibility of KCl samples and strong sensitivity changes, which can be corrected for by using a test-dose. The long term OSL studies confirmed the occurrence of both inverse fading and fading phenomena in KCl. In addition, a comparison with corresponding measurements using sodium chloride (NaCl) were carried out. Although it was confirmed that NaCl is more suitable for dosimetry, there might be benefits of combining NaCl with KCl for more accurate absorbed dose determinations. PMID- 30428077 TI - Title: Functional Analysis of TM6 MADS-box gene in the Octoploid Strawberry by CRISPR/Cas9 directed mutagenesis. AB - The B-class of MADS-box transcription factors has been studied in many plant species, but remain functionally uncharacterized in Rosaceae. APETALA3 (AP3), a member of this class, controls petal and stamen identities in Arabidopsis. In this study, we identified two members of the AP3 lineage in the cultivated strawberry (Fragaria ? ananassa): FaAP3 and FaTM6. Interestingly, FaTM6, and not FaAP3, shows an expression pattern equivalent to that of AP3 in Arabidopsis. Genome editing using CRISPR/Cas9 system is becoming a robust tool for targeted and stable DNA mutagenesis. However, whether it can be efficiently used in an octoploid species such as F. ? ananassa is not yet established. Here we report the application of CRISPR/Cas9 to characterize the function of FaTM6 in strawberry flower development. An analysis by high-throughput sequencing of the FaTM6 locus spanning the target sites showed a highly efficient genome editing already in the T0 generation. The phenotypic characterization of the mutant lines indicates that FaTM6 plays a key role in anther development in strawberry. Our results validate the CRISPR/Cas9 strategy for gene functional analysis in F. ? ananassa as an octoploid species, and they offer new opportunities for engineering strawberry to improve traits of interest in breeding programs. PMID- 30428078 TI - "I Didn't Even Make My Bed": Hospital Relocations and Resident Adjustment in Long Term Care Over Time. AB - Purpose of the study: This prospective longitudinal qualitative study sought to identify the conditions that help or hinder older adults' capacities to adjust to long-term care (LTC) when relocating from hospital. Design and Methods: Informed by the principles of constructivist grounded theory, this study employed semi structured interviews with LTC home residents. Participants were interviewed 4 weeks after their initial relocation, and again every 6 months until they had either resided in their final LTC home for at least 3 months or been enrolled in the study for 2 years. Transcribed interviews were analyzed using the constant comparative method that employs the principle of comparison to guide the analytic process. Findings: A total of nine residents participated in 24 interviews and most had undergone two or more moves. Analysis of the data revealed that multiple forced moves challenged residents' capacities to find home in LTC by contributing to anxiety and uncertainty, hindering resident-staff relations, and interfering with residents' desires to connect with one another. Analysis of the data further revealed that relocation frameworks may require adaptations to more accurately reflect older adults' experiences with relocation from hospital to LTC. Implications: Hospital relocations pose many challenges to residents' capacities to find home in LTC, in part, because they initiate a process of multiple moves. Until the moving process from hospital truly acknowledges and explores residents' preferences, offers choices, and supports joint decision making, it will remain challenging for the LTC home sector to help residents find meaning, purpose, and home in LTC. PMID- 30428079 TI - Depression and occupational stress in Japanese school principals and vice principals. AB - Background: Teaching is one of the most stressful occupations. Over the last decade, about 5000 Japanese public school teachers per year have taken sick leave due to a mental illness. School principals and vice principals also face occupational stress, although few studies have examined occupational stress in these groups. Aims: To clarify the relationship between occupational stress, role problems and depressive symptoms among school principals and vice principals in Japan. Methods: We conducted a cross-sectional study in 2013 with data from 262 principals and 268 vice principals in Japan. We used the Japanese version of Zung's Self-Rating Depression Scale (SDS) to evaluate depressive symptoms and the Generic Job Stress Questionnaire to evaluate occupational stress and social support. We categorized SDS scores above 49 as indicating depression. We examined the relationship between depressive symptoms and perceived occupational stress using stepwise forward multivariate logistic regression analyses. Results: Thirty six (14%) principals and 81 (30%) vice-principals were categorized into the depressive group. Quantitative workload (odds ratio, OR = 6.62 [2.63-16.70]) and role ambiguity (OR = 4.94[1.57-15.53]) were associated with higher depressive scores in principals. Social support from supervisors (OR = 4.14 [1.97-8.68]) and role ambiguity (OR = 9.71 [4.08-23.14]) were associated with higher depressive scores in vice-principals. Conclusions: Clarifying job roles for principals and vice-principals, reducing quantitative workload for principals and increasing supervisory support for vice-principals may be important for mitigating depression for school principals and vice-principals in Japan. PMID- 30428080 TI - Occurrence and species diversity of human-pathogenic Mucorales in commercial food stuffs purchased in Paris area. AB - Mucormycoses are life-threatening fungal diseases that affect a variety of patients including those with diabetes mellitus or hematological malignancies. The responsible agents, the Mucorales, are opportunistic pathogens originating from the environment such as soil or decaying organic matter. The aim of the present study was to assess the prevalence and diversity of human-pathogenic species of Mucorales in commercially available foodstuffs in France. All food samples were purchased from January 2014 to May 2015 in France. A total of 159 dried food samples including spices and herbs (n = 68), herbal tea (n = 19), cereals (n = 19), vegetables (n = 14), and other foodstuffs (n = 39) were analyzed. Each strain of Mucorales was identified phenotypically, and molecular identification was performed by ITS sequencing. From the 28 (17.6%) samples that were culture-positive for Mucorales, 30 isolates were recovered. Among the isolates, 13 were identified as Rhizopus arrhizus var. arrhizus, 10 R. arrhizus var. delemar, two Rhizopus microsporus, one Lichtheimia corymbifera, three Lichtheimia ramosa, and one Syncephalastrum racemosum. Culture-positive samples originated from different countries (Europe, Asia) and brands. The samples most frequently contaminated by Mucorales were spices and herbs (19/68, 27.9%), followed by herbal tea (2/19, 10.5%), cereals (2/19, 10.5%), other food products (5/39, 12.8%). The present study showed that human-pathogenic Mucorales were frequently recovered from commercially available foodstuffs in France with a large diversity of species. The potential danger represented by Mucorales present in food for immunocompromised patients should be further analyzed. PMID- 30428081 TI - Arsenic may act as a pro-metastatic carcinogen through promoting tumor cell induced platelet aggregation. AB - Arsenic-associated carcinogenesis and related mortality are a major public health concern worldwide; however, the underlying mechanism of action remains unclear. Here, we demonstrated that arsenic promotes tumor metastasis by stimulating tumor cell-platelet aggregation (TCPA), which can ultimately increase cancer-related mortality. In freshly isolated human platelets in vitro, arsenic potentiated TCPA prompted by diverse cancer cell lines, which was attributable to increased platelet reactivity to TCPA with respect to thrombin generation and P-selectin, GPIIb/IIIa expression. Consistently, the co-existence of platelets and arsenic significantly enhanced tumor cell adhesion, extravasation and invasion along with increased metastasis-related markers like metallo-matrix proteinase-2 and -9 in vitro, which was attenuated by platelet activation blockers. Importantly, the exposure to arsenic-contaminated drinking water (2 ppm, 3 weeks) in mice in vivo significantly increased the metastasis of intravenously injected melanoma cells into lung. Furthermore, the exposure to arsenic-contaminated drinking water significantly reduced the survival of melanoma cell-injected mice, which was were attenuated by the pretreatment of platelet-activation blockers; aspirin and eptifibatide. All these results provide an important clue to understand the mechanism underlying arsenic-associated cancer mortality and its prevention. PMID- 30428082 TI - Macrophages alternatively activated by endometriosis-exosomes contribute to the development of lesions in mice. AB - STUDY QUESTION: Do exosomes play a role in the pathogenesis of endometriosis in a murine model? SUMMARY ANSWER: Exosomes from endometriosis (EMS) can alternatively activate macrophages and thus contribute to the development of lesions in mice. WHAT IS KNOWN ALREADY: The pathogenesis of endometriosis, an inflammatory disease, possibly involves peritoneal macrophages. Exosomes are recognized as a new communicator among cells and a key modulator in several inflammatory diseases. STUDY DESIGN SIZE, DURATION: We performed in vitro and in vivo experiments to demonstrate the role of exosomes in modulating macrophages. RAW264.7 cells (macrophages) were used to examine the effects of exosomes on macrophages in vitro. An experiment was also conducted in vivo, as follows. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n=5/group). The experimental group was injected i.p. with EMS-exosomes derived from eutopic stromal cells, starting on day-7 then every day for 1 week. )The control group received CON-exosomes from mice without endometriosis. Peritoneal macrophages were assessed over the next 6 days. On day 0, all mice were injected i.p. with endometrium to establish the endometriosis model. On day 14, all mice were sacrificed, ectopic lesions were counted and measured. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exosomes were isolated from endometrial stromal cells(ESCs) by ultracentrifugation and characterized through transmission electron microscopy, nanoparticle tracking analysis, and western blot. After treatment with exosomes, the polarization and phagocytic ability of the macrophages were detected by flow cytometry analysis.), immunofluorescent staining, and RT-PCR. C57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of endometrial segments. MAIN RESULTS AND THE ROLE OF CHANCE: After treatment with EMS-exosomes, the macrophages were polarized into an M2-like phenotype and their phagocytic ability decreased(p <0.05 versus treatment with CON-exosomes). The total weight and volume of the lesions in mice treated with EMS-exosomes significantly increased compared with those in mice treated with CON-exosomes (p<0.05). The infiltration of M2-like macrophages was enhanced in the EMS-exosome group (p <0.001 versus treatment with CON-exosomes). LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: Detection of endometriosis following exosome treatment was only performed in a murine endometriosis model. Clinical data and additional mechanism studies must be conducted to understand the role of exosomes in the pathogenesis of endometriosis. WIDER IMPLICATIONS OF THE FINDINGS: This study emphasizes the importance of EMS-exosomes in the pathogenesis of endometriosis. Further investigations on the exosome signaling pathways may contribute to the development of effective treatments for endometriosis. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by grants (Nos. 81571417 and 81771552) from the National Science Foundation of China. The authors report no conflict of interest. PMID- 30428083 TI - Oral lesions in a patient with confirmed Zika virus infection. PMID- 30428084 TI - Electrocardiographic alterations and cardiomegaly in a Bolivian migrant. PMID- 30428085 TI - Chronic constipation in a migrant from Paraguay. PMID- 30428086 TI - Beyond Continuing Education: Continuing Professional Development and the CTH. PMID- 30428087 TI - Testosterone Treatment of Depressive Disorders in Men: Too Much Smoke, Not Enough High-Quality Evidence. PMID- 30428088 TI - WD40 repeat and FYVE domain containing 3 (Wdfy3) is essential for cardiac development. AB - Aims: WD40 repeat and FYVE domain containing 3 (WDFY3) is an adaptor protein involved in selective degradation of protein aggregates by autophagy. Recent studies have revealed that Wdfy3 is critical in the regulation of brain development and osteoclastogenesis in vivo. However, the function of Wdfy3 in cardiac development remains completely unknown. In this study, we explore the role of Wdfy3 in cardiac morphogenesis using Wdfy3-deficient mice. Methods and results: Wdfy3 was expressed in the developing heart in mice and peaked at embryonic day 12.5 (E12.5). Loss of Wdfy3 in mice led to embryonic and neonatal lethality. Wdfy3-deficient mice displayed various congenital heart defects including membranous ventricular septal defect, aortic overriding, double outlet right ventricle, thinning of ventricular wall, ventricular dilation and disorganized ventricular trabeculation at E14.5. Cell proliferation was reduced in the hearts from Wdfy3-deficient mice at E12.5 and E14.5, which was associated with enhanced p21 expression. Cardiomyocyte differentiation was diminished as demonstrated by reduced Myh6 and MLC2v in Wdfy3-deficient mice at E14.5. In addition, Nkx2-5 and Mef2c, two cardiac transcription factors regulating cardiomyocyte differentiation, were decreased in Wdfy3-deficient mice at E14.5. Apoptotic cell death remained unaltered. These data suggest that reduced cell proliferation and cardiomyocyte differentiation contribute to cardiac defects in Wdfy3-deficient mice. Mechanistically, loss of Wdfy3 led to a reduction in protein levels of Notch 1 intracellular domain and its downstream targets Hes1 and Hey1, which was accompanied with enhanced full-length Notch1 protein levels. In vitro luciferase assay showed that Wdfy3 deficiency induced activity of p21 promoter, while diminished activity of Hes1 promoter through modulation of Notch1 signaling. Moreover, Wdfy3 was co-localized with Notch1 in primary embryonic cardiomyocytes. Endogenous Wdfy3 physically interacted with full-length Notch1 in the developing heart. These results suggest that Notch1 signaling is perturbed in the hearts from Wdfy3-deficient mice. No alteration of autophagy was detected in the hearts from Wdfy3-deficient mice. Conclusion: Taken together, our data suggest that Wdfy3 plays an essential role in cardiac development, which may be mediated by modulation of Notch1 signaling. PMID- 30428089 TI - Cohort Profile: TWINS study of environment, lifestyle behaviours and health. PMID- 30428090 TI - Rice protein coating in extending the shelf-life of conventional eggs. AB - The effectiveness of rice protein coatings or mineral oil on maintaining interior quality and eggshell breaking strength of fresh eggs was evaluated during storage at 20 degrees C for 8 wk. Egg quality was assessed by weight loss, Haugh unit (HU), albumen pH, yolk index (YI), shell strength, and scanning electron microscopy in uncoated eggs (control treatment) and eggs coated with mineral oil or rice protein concentrate at 5, 10, or 15%. The HU and YI were higher in coated eggs (P < 0.001). Weight loss increased (P < 0.001) during long-term storage. Uncoated eggs showed the highest weight loss (8.28%), whereas mineral oil (0.87%) and rice protein at 5% (5.60%), 10% (5.45%), 15% (5.54%) solutions were effective in preventing weight lost (P < 0.001). The use of the coatings preserved the internal quality of the eggs for up to 4 wk longer than uncoated eggs (HU, YI, and pH). Uncoated eggs had the worst (P < 0.001) HU (54.45), albumen pH (9.18), and YI (0.28) after 8 wk of storage. Among the coated eggs, the mineral oil had the best values of HU (70.54), pH (8.48), and YI (0.35) after storage. The eggs coated with 5, 10, and 15% of rice protein presented results with similar intern quality between them and intermediary quality in relation to the others treatments during all the storage period. Scanning electron microscopy demonstrated a lower surface porosity in coated eggshell, indicating that the use of the coating may provide a protective barrier against the transfer of gases and moisture. In conclusion, the use of coatings based on rice protein concentrate or mineral oil influences the internal quality of eggs during storage and may be an effective alternative for increasing the shelf-life of commercial eggs. PMID- 30428091 TI - Initial Clinical Results With a Novel Monofocal-Type Intraocular Lens for Extended Macular Vision in Patients With Macular Degeneration. AB - PURPOSE: To determine the feasibility of a novel intraocular lens (IOL) designed to improve retinal image quality at up to 10 degrees of retinal eccentricity and optionally provide retinal magnification in patients with macular disease. METHODS: In this prospective, interventional pilot study, 8 eyes of 7 patients with bilateral dry age-related macular degeneration and 1+ or less cataract underwent phacoemulsification and capsular bag implantation of a single, injectable, hydrophobic acrylic IOL. Safety and efficacy were assessed by monitoring logMAR corrected distance and near visual acuity, intraocular pressure, specular microscopy, 80-point visual field testing, and anterior segment and macular optical coherence tomography at baseline and 1 week, 1 month, and 2 months postoperatively. Microperimetry was undertaken at baseline and 1 and/or 2 months postoperatively. Reading performance was assessed at baseline and 1 month postoperatively using the Minnesota low vision reading chart (MNREAD; Precision Vision, LaSalle, IL). RESULTS: Safety outcomes were equivalent to standard monofocal IOLs. Visual acuities improved in all patients. Mean corrected distance visual acuity improved from 0.93 +/- 0.22 preoperatively to 0.59 +/- 0.25 at 2 months postoperatively. Mean reading speed increased from 28 +/- 19 to 44 +/- 31 words per minute. Mean microperimetry threshold sensitivities increased from 8.2 +/- 4.6 to 12 +/- 5.6 dB. Mean percentage of fixation points within a 4 degrees circle increased from 77% +/- 17% to 91% +/- 11% with evidence for progressive movement of preferred retinal loci away from areas of geographic atrophy. CONCLUSIONS: Initial results indicate this novel IOL has a safety profile comparable with standard IOLs. Visual benefits may exceed those obtained with existing technologies in patients with macular disease. Further work is required to determine the full potential of extended macular vision technology. [J Refract Surg. 2018;34(11):718-725.]. PMID- 30428092 TI - Corneal Surface Ablation Laser Refractive Surgery for the Correction of Myopia: A Network Meta-analysis. AB - PURPOSE: To systematically compare the efficacy, predictability, safety, postoperative haze, pain scores, and epithelial healing time of four corneal surface ablation procedures. METHODS: PubMed, Embase, Cochrane Library, and the U.S. trial registry were searched up to June 2018. Randomized controlled trials were selected. Efficacy (uncorrected distance visual acuity of 20/20 or better), predictability (refractive spherical equivalent within +/-0.50 diopters [D] of the target), and safety (loss of two or more lines of spectacle corrected distance visual acuity) were set as primary outcome measures. Haze, pain scores, and epithelial healing time were set as secondary outcome measures. RESULTS: Eighteen studies involving 1,423 eyes were included. According to the Grading of Recommendations Assessment, Development, and Evaluation, the quality of outcomes were moderate to high (70.6%). There were no differences in efficacy, predictability, safety, haze, day 1 pain, and epithelial healing time between treatments. Epithelial laser in situ keratomileusis (epi-LASIK) had statistically significantly higher pain scores on day 3 compared to photorefractive keratectomy (PRK) (weighted mean differences [WMD] = 2.2, 95% credible intervals [CrI] = 0.19 to 4.01) and transepithelial PRK (T-PRK) (WMD = 2.7, 95% CrI = 0.51 to 4.84). The surface under the cumulative ranking curve ranking results (best to worst) showed laser epithelial keratomileusis (LASEK) ranked highest for efficacy, predictability, safety, and day 1 pain scores. Epi-LASIK ranked best for grade 1 haze scores. T-PRK ranked best for haze of 0.5 or higher, haze scores day 3 pain scores, and epithelial healing time. CONCLUSIONS: Surface laser refractive surgeries are comparable in terms of efficacy, predictability, safety, and postoperative haze except for day 3 pain scores, with epi-LASIK being more painful compared to PRK and T-PRK. [J Refract Surg. 2018;34(11):726-735.]. PMID- 30428093 TI - Factors Associated With Ocular Cyclotorsion Detected by High-Speed Dual-Detection Eye Tracker During Single-Step Transepithelial Photorefractive Keratectomy. AB - PURPOSE: To determine demographic, surgical, and preoperative visual factors affecting the level of static and dynamic cyclotorsion (SC and DC) in eyes undergoing single-step transepithelial photorefractive keratectomy (TransPRK). METHODS: In this cross-sectional study, 386 patients with different types of refractive errors scheduled for single-step TransPRK were enrolled. A comprehensive profile of personal, optic, and visual characteristics of patients as surgical parameters were collected. Statistical modeling was used to explore correlates of SC and DC before and during the refractive procedure, respectively. RESULTS: There was no difference in various indices of SC and DC between right and left eyes. Lower age (beta = -0.20), uncorrected (beta = -0.99) and corrected (beta = -0.72) visual acuities, and keratometry (beta = -0.09) were significantly associated with higher ranges of DC during the laser ablation procedure. Worse mesopic contrast sensitivity (beta = 0.24) and higher (beta = 0.002, left eyes) or lower (beta = -0.002, right eyes) kappa locus also showed significant associations with a higher range of DC. In cases of SC before the procedure, amount (beta = 0.46) and axis (beta = -0.003) of the astigmatism demonstrated notable associations. CONCLUSIONS: Through comprehensive modeling, age, visual axis indices, visual acuity, and contrast sensitivity were found to be the main factors significantly associated with dynamic ocular globe cyclotorsions during single-step TransPRK. This could help identify eyes at higher risk of cyclotorsion and its potential complications in refractive surgery. [J Refract Surg. 2018;34(11):736-744.]. PMID- 30428094 TI - Implantation of a Corneal Inlay in Pseudophakic Eyes: A Prospective Comparative Clinical Trial. AB - PURPOSE: To compare the clinical outcomes of binocular cataract surgery with and without pinhole corneal inlay implantation. METHODS: In the inlay-cataract group, a small aperture corneal inlay was implanted in addition to cataract surgery in the non-dominant eye and routine cataract surgery was performed in the dominant eye. In the control group, conventional cataract surgery was performed in both eyes in separate consecutive surgeries 2 weeks apart. The target refraction was emmetropia. Visual acuity, refraction, contrast sensitivity, and visual field were analyzed 1, 4, and 12 weeks after surgery. RESULTS: Sixteen patients with advanced cataracts underwent cataract surgery on both eyes in separate surgeries. There was no statistically significant difference regarding mean age, Lens Opacities Classification System grading, and refractive outcome. The difference in uncorrected distance visual acuity between the control group and inlay cataract group was not statistically significant after 12 weeks (P = .59). Mean uncorrected intermediate visual acuity was significantly better in the inlay cataract group (P = .03). Near visual acuity was better in the inlay-cataract group, but it was not statistically significant (P = .07). There was no statistically significant difference between groups under binocular photopic and mesopic conditions with and without glare. The results of the visual field examination showed no statistically significant difference between both eyes. CONCLUSIONS: The findings demonstrate that implantation of monofocal IOLs in combination with a small aperture corneal inlay in the non-dominant eye helps to increase intermediate and near visual acuity. The implantation of small aperture corneal inlays seems to be an interesting alternative for pseudophakic patients who desire spectacle independence. [J Refract Surg. 2018;34(11):746-750.]. PMID- 30428095 TI - Incidence and Outcomes of Sterile Multifocal Inflammatory Keratitis and Diffuse Lamellar Keratitis After SMILE. AB - PURPOSE: To report the incidence outcomes of sterile multifocal inflammatory keratitis and diffuse lamellar keratitis (DLK) after small incision lenticule extraction (SMILE) in a large population. METHODS: This was a retrospective review of a population of 4,000 consecutive eyes treated by SMILE at the London Vision Clinic using the VisuMax femtosecond laser (Carl Zeiss Meditec, Jena, Germany). The inclusion criterion was to have presented with inflammatory keratitis after SMILE. In some cases after SMILE, the inflammatory keratitis presented as sterile multifocal interface keratitis uncharacteristic of classic DLK. The incidence was measured and categorized as primary or secondary by presenting appearance, grade, and time to presentation. Patients were observed for 1 year after surgery and standard outcomes analysis was performed. RESULTS: Of the 4,000 eye population, there were 18 cases (0.45%) of DLK grade 1 or 2. All cases were managed and resolved with topical steroid therapy. Of these, 12 cases (67%) were of classic appearance and 6 cases (33%) presented as sterile multifocal inflammatory keratitis. DLK was primary in nature in 11 cases (61%) and secondary in 7 cases (39%). Postoperative uncorrected distance visual acuity was 20/20 or better in 93% of eyes. No patients lost any lines of corrected distance visual acuity and there was no change in contrast sensitivity. CONCLUSIONS: DLK occurred after SMILE with an incidence of 0.45% in this population. Topical steroid therapy resolved the DLK in all cases with no sequelae and no adverse effect on refractive or visual outcome at 1 year postoperatively. A unique type of DLK presentation can occur after SMILE, characterized by multiple focal sterile inflammatory spots. Management is the same as for classic DLK, but with a lower threshold for performing an interface washout. [J Refract Surg. 2018;34(11):751-759.]. PMID- 30428096 TI - Age-Related Changes in Corneal Spherical Aberration. AB - PURPOSE: To analyze the age-related changes in corneal spherical aberration (CSA) and higher order aberrations (HOAs) and to develop a novel model to estimate the change in CSA with age. METHODS: This was a cross-sectional study of the right eyes of 3,769 patients. Anterior corneal spherical aberration (ASA), posterior corneal spherical aberration (PSA), total corneal spherical aberration (TSA), and the root mean square of corneal HOAs were measured using a Scheimpflug tomographer. Smoothed fitting curves were plotted as a function of age and the average change in spherical aberration was calculated for different ages. RESULTS: The mean magnitude of ASA, PSA, TSA, and HOAs (6 and 4 mm) were 0.270 +/ 0.111, -0.144 +/- 0.031, 0.228 +/- 0.120, 0.453 +/- 0.194, and 0.141 +/- 0.075 um, respectively. All parameters showed a statistically significant non-linear change with age. The age after which the aberrations increased at a faster rate, namely the turning points of age, were 39 years for ASA, PSA, TSA, and 6-mm HOAs (95% confidence interval [CI]: 35 to 42, 36 to 41, 36 to 42, and 35 to 56 years, respectively) and 46 years for 4-mm HOAs (95% CI: 36 to 56 years). There were significant increases in increment rates after the turning points. The average change of TSA was -0.013 um/10 years from 18 to 39 years and 0.057 um/10 years after 39 years. There were statistically significant correlations between ASA and TSA (r = 0.976, P < .001) and PSA and TSA (r = 0.192, P < .001), but not between ASA and PSA (r = -0.003, P = .835). CONCLUSIONS: CSA and HOAs increased non linearly with age and became more positive after 39 and 46 years of age, respectively. Based on the increment rates and turning points of age, a novel model is provided to help calculate the value required to compensate for the increasing CSA associated with the aging cornea. [J Refract Surg. 2018;34(11):760 767.]. PMID- 30428097 TI - Oxygen Diffusion May Limit the Biomechanical Effectiveness of Iontophoresis Assisted Transepithelial Corneal Cross-linking. AB - PURPOSE: To evaluate the impact of varying treatment time on the efficacy of iontophoresis-assisted transepithelial corneal cross-linking (I-CXL) in ex vivo porcine corneas. METHODS: One hundred twelve porcine corneas with intact epithelium were divided into 7 groups and analyzed. Groups 1, 2, and 3 received standard epitheliumoff CXL (S-CXL) with hypo-osmolaric 0.1% riboflavin and 30 minutes of ultraviolet-A (UV-A) irradiation at 3 mW/cm2, 10 minutes at 9 mW/cm2, or were not irradiated (controls). Groups 4, 5, 6, and 7 received I-CXL for either 60 minutes at 1.5 mW/cm2, 30 minutes at 3 mW/cm2, 10 minutes at 9 mW/cm2, or were not irradiated (controls). Elastic modulus and stress after relaxation of 5-mm wide corneal strips were analyzed. RESULTS: In the S-CXL groups, significant differences (P <= .05) in stress-strain extensometry were found between controls and 3 mW/cm2 for 30 minutes (group 1) and between controls and 9 mW/cm2 for 10 minutes (group 2). In the I-CXL groups, only the 1.5 mW/cm2 for 60 minutes setting (group 4) showed a significant stiffening effect. All epithelium-off groups provided a stiffening effect significantly stronger than I-CXL: with a stiffening effect of 149% and 112%, groups 1 and 4 were the groups with greater elastic modulus between the S-CXL and I-CXL groups, respectively. CONCLUSIONS: The biomechanical effect of I-CXL increased significantly when using a low irradiance/long irradiation setting. Oxygen diffusion thus represents a limiting factor even when riboflavin penetration is improved via iontophoresis. Still less effective than S-CXL, this modification may help establish transepithelial CXL as a treatment option in selected cases. [J Refract Surg. 2018;34(11):768-774.]. PMID- 30428098 TI - Flap Melting Over Corneal Inlay for Hyperopic Correction. AB - PURPOSE: To report two cases of flap melting over corneal inlays for hyperopic correction several years after implantation. METHODS: The corneal inlay (+6.00 diopters [D]; PermaVision intracorneal lens; Anamed Inc., Lake Forest, CA) was implanted underneath a LASIK flap in two patients. RESULTS: Visual acuity and slit-lamp findings of both patients were stable for several years. At 9 years postoperatively, the first patient presented with a sudden loss of corrected distance visual acuity (CDVA) due to partial flap melting over the inlay while the surrounding anterior cornea showed opacification. The inlay was explanted immediately. Three years after explantation, CDVA returned to 1.0. Similarly, the second patient presented 11 years postoperatively with loss of vision, opacification, and partial flap melting. The inlay was explanted. Two years later, CDVA recovered. CONCLUSIONS: Potentially severe biocompatibility issues of corneal inlays may occur even after several uneventful years. [J Refract Surg. 2018;34(11):775-778.]. PMID- 30428099 TI - Corneal Scarring and Hyperopic Shift After Corneal Cross-linking for Corneal Ectasia After SMILE. AB - PURPOSE: To report a case of severe corneal scarring and hyperopic shift after corneal cross-linking (CXL) for the treatment of ectasia following small incision lenticule extraction (SMILE). METHODS: Case report and literature review. RESULTS: A 35-year-old man was referred with severe unilateral corneal haze that developed after CXL. The patient had undergone SMILE 4 years earlier in both eyes. Nineteen months postoperatively, the patient presented with bilateral decrease in vision and corneal topography revealed corneal ectasia in the right eye. CXL was performed in the right eye and a deep stromal haze was observed 1 year later. Comparative maps showed progressive corneal thinning with corresponding flattening that induced hypermetropization and astigmatism. CONCLUSIONS: CXL after SMILE in this original case resulted in severe deep corneal haze and corneal flattening with hyperopic shift. [J Refract Surg. 2018;34(11):779-782.]. PMID- 30428100 TI - Comments on "Biomechanical Properties of Human Cornea Tested by Two-Dimensional Extensiometry Ex Vivo in Fellow Eyes". PMID- 30428101 TI - Good News and Bad News. PMID- 30428102 TI - Comparative Analysis of the American Board of Family Medicine and American College of Osteopathic Family Physicians In-Training Examinations. AB - BACKGROUND AND OBJECTIVES: Family medicine residency programs accredited by the Accreditation Council for Graduate Medical Education and the American Osteopathic Association typically require their residents to take the American Board of Family Medicine's In-Training Examination (ITE) and the American College of Osteopathic Family Physicians' In-Service Examination (ISE). With implementation of the single accreditation system (SAS), is it necessary to administer both examinations? This pilot study assessed whether the degree of similarity for the construct of family medicine knowledge and clinical decision making as measured by both exams is high enough to be considered equivalent and analyzed resident ability distribution on both exams. METHODS: A repeated measures design was used to determine how similar and how different the rankings of PGY-3s were with regard to their knowledge of family medicine as measured by the ISE and ITE. Eighteen third-year osteopathic residents participated in the analysis, and the response rate was 100%. RESULTS: The correlation between ISE and ITE rankings was moderately high and significantly different from zero (rs=.76, P<0.05). A Wilcoxon signed rank test indicated that the median ISE score of 62 was not statistically significantly different than the median ITE score of 71 (Z=-0.74, P=0.46, 2-tailed). CONCLUSIONS: The lack of a difference on statistical analysis of ISE scores and the ITE scores of the PGY-3 residents suggests that the cohort of osteopathic residents in family residency programs and the cohort of residents in ACGME-accredited programs seem to be of comparable ability, therefore there is no clear justification for administering both examinations. PMID- 30428103 TI - Examining an Evidence-Based Medicine Culture in Residency Education. AB - BACKGROUND AND OBJECTIVES: Reports of innovations in evidence-based medicine (EBM) training have focused on curriculum design and knowledge gained. Little is known about the educational culture and environment for EBM training and the extent to which those environments exist in family medicine residencies in the United States. METHODS: A literature review on this topic identified a validated EBM environment scale intended for learner use. This scale was adapted for completion by family medicine residency program directors (PDs) and administered through an omnibus survey. Responses to this scale were analyzed descriptively with program and PD demographics. An EBM culture score was calculated for each program and the results were regressed with the correlated demographics. RESULTS: In our adapted survey, family medicine PDs generally rated their residencies high on the EBM culture scale, but admitted to challenges with faculty feedback to residents about EBM skills, ability to protect time for EBM instruction, and clinician skepticism about EBM. In linear regression analysis, the mean summary score on the EBM scale was lower for female PDs and in programs with a higher proportion of international medical school graduates. CONCLUSIONS: To improve the culture for EBM teaching, family medicine residency programs should focus on faculty engagement and support and the allocation of sufficient time for EBM education. PMID- 30428104 TI - Perceptions of Parenting Residents Among Family Medicine Residency Directors. AB - BACKGROUND AND OBJECTIVES: Parenting during residency is increasingly common, and resident parents face unique demands on their time and emotional and cognitive resources. Physicians at all levels of training perceive negative impacts of parenting on career and family life. Surveys of program directors (PDs) in other specialties reveal concern about performance and quality of life of parenting residents. The primary aims of this study were to examine family medicine PDs' perceptions of parenting residents' performance and the adequacy of parenting support structures. METHODS: Data were collected from the 2017 Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA) Family Medicine Residency Program Directors survey. Directors provided the number and status of parenting residents and rated adequacy of parenting resources, resident performance, and impact of parenting on residents using a Likert scale. Results were compared between male/female PDs and male/female residents. RESULTS: Response rate was 57.1%. Less than half of PDs reported adequate parenting support structures in their program (46%). Over 40% of PDs reported that 81%-100% of female residents who take parental leave end up extending their residency training, the most common response category. PDs did not report gender-based differences in performance of parenting residents. PDs most often reported significantly worse well-being for female parenting residents but perceived improved well-being of male parents. CONCLUSIONS: Less than half of family medicine PDs feel their program has adequate parenting resources. Female parenting residents commonly extend residency training. PDs perceive parenting negatively impacts well-being of female residents, but not male residents. PMID- 30428105 TI - PedHITSS: A Screening Tool to Detect Childhood Abuse in Clinical Settings. AB - BACKGROUND AND OBJECTIVES: Though child abuse is prevalent and detrimental, health care providers fail to screen for abuse at sufficient rates to detect or preempt events. Current child abuse screening tools lack brevity and usefulness in clinical settings. To validate the Pediatric Hurt-Insult-Threaten-Scream-Sex (PedHITSS) screening tool, a 5-item questionnaire designed to detect and prompt provider investigation into child abuse in clinical settings, the PedHITSS was compared to the Conflict Tactics Scale: Parent-Child Version (CTSPC) screening measure. METHODS: Participants included 422 pediatric patients (n=242 nonabused; n=180 abused subsample) recruited from an ambulatory care setting, a medical center at-risk referral clinic, or homeless shelter clinic. Parents were asked to complete a cross-sectional survey, including PedHITSS and CTSPC questionnaires. Concurrent validity of PedHITSS was tested with 242 participants identified as nonabused. Construct validity was assessed with 180 participants previously identified as victims of child abuse. RESULTS: Concurrent validity between the CTSPC and PedHITSS was strong, rs=.70 (P<.01). Sensitivity and specificity for correctly identifying abuse victims (<=12 years) was optimal at a cutpoint of one or greater. There was no significant difference in sensitivity and specificity of HITSS and CTSPC in correctly identifying victims of child abuse. CONCLUSIONS: This study indicates that PedHITSS performs as well as CTSPC in identifying and differentiating victims and nonvictims of child abuse. PedHITSS allows health care providers to confidently screen and report suspected cases of child abuse and serves as a mechanism to confirm abuse status through validated means. PMID- 30428106 TI - Associations Between Integrated Care Practice and Burnout Factors of Primary Care Physicians. AB - BACKGROUND AND OBJECTIVES: Physician burnout is increasingly problematic across many health care settings. Despite this trend, little is known about whether the type of collaboration in these settings may potentially help curb this trend. We explored whether higher levels of integrated care practice are associated with reduced burnout for physicians across settings. METHODS: A national survey was sent to health care professionals who work in a variety of medical settings. Primary care physicians (n=288) were a subset of this sample and were asked about their practice demographics and perceptions of burnout. A shortened version of the Maslach Burnout Inventory (MBI) assessed for areas of burnout in physicians. RESULTS: Higher levels of integrated care were associated with higher personal accomplishment (B=1.89, 95% CI:0.47, 3.31) and lower depersonalization (B=-2.48, 95% CI:-4.54, -0.42) in routine practice on the MBI. No significant associations were found between MBI scores and both years of practice at a current site or number of providers at the site. CONCLUSIONS: While physician burnout continues to be a worsening problem, integrated care may be an additional strategy to help curb this trend. Administrators need to consider the value of integrated practice in addressing physician wellness-the potentially next big aim of health care. PMID- 30428107 TI - Advancing Oral Health Knowledge and Attitudes of Physician Assistant Students Using the Smiles for Life Oral Health Curriculum. AB - BACKGROUND AND OBJECTIVES: The purpose of this study was to determine the effectiveness of the Society of Teachers of Family Medicine's Smiles for Life: A National Oral Health Curriculum on the knowledge and attitudes of physician assistant students regarding oral health. METHODS: Seventy-two didactic year physician assistant students from one physician assistant program were surveyed to assess their knowledge and attitudes regarding oral health prior to starting the Smiles for Life oral health curriculum. The students were electronically surveyed a second time 1 week after completing all online modules in the Smiles for Life oral health curriculum. RESULTS: Precourse and postcourse survey response rates were 57% and 36%, respectively. The mean of the attitude statements increased from 3.20 on the precourse survey to 3.87 on the postcourse survey (P=.0012). The mean number of correct responses on the knowledge questions increased from 6.83 on the precourse survey to 9.85 on the postcourse survey (P<.0001). CONCLUSIONS: Statistically significant improvements in the attitudes toward oral health and oral health knowledge of physician assistant students after completion of the Smiles for Life curriculum were observed. This study illustrates the effectiveness of the Smiles for Life curriculum as an interprofessional educational experience. This curriculum can be completed online and does not require faculty expertise in oral health, thus removing previously cited barriers to incorporating oral health into the physician assistant curriculum. PMID- 30428109 TI - Nocturne. PMID- 30428108 TI - TotShots: An Innovative Pediatric Free Clinic Providing High Patient Satisfaction to the Underserved. AB - BACKGROUND AND OBJECTIVES: The University of Arizona College of Medicine-Tucson TotShots clinic is a student-developed, student-directed free clinic that provides sports physicals and vaccines to uninsured pediatric patients in Tucson, Arizona. TotShots runs under the greater umbrella of the Commitment to Underserved People Program, which aims to teach medical students how socioeconomic and cultural factors impact health and access to health care. Our objective was to study cost savings and patient satisfaction of this clinic. METHODS: Value of care provided through sports physicals and vaccine administration was calculated using the Centers for Medicare and Medicaid Services Physician Fee Schedule and Centers for Disease Control Vaccines for Children Decisions Analysis Model. In addition, patient satisfaction was measured through the utilization of an optional three-question survey completed by patients in their preferred language at the resolution of their visit. Vaccines and sports physicals were administered from April 2017 to November 2017. RESULTS: TotShots administered 51 vaccines and completed 115 sports physicals resulting in a value of $415.65 of administration fees and $5,878.80 of sports physical examinations. Sixty-three of 66 total patients completed patient satisfaction surveys. Of those patients, 57 (90.5%) were highly satisfied with their provider's communication, 58 (92%) rated their perception of the quality of medical care they received as excellent, and 54 (85.7%) of patients were highly satisfied with their overall TotShots experience. CONCLUSIONS: TotShots fills a valuable role in increasing access to vaccines and sports physicals while maintaining high patient satisfaction and high value of cost savings. PMID- 30428110 TI - How My Father's Cancer Made Me a Better Doctor. PMID- 30428111 TI - Igniting a Paradigm Shift in Family Medicine in Nigeria: Lessons From a Global Health Experience. PMID- 30428112 TI - Elvis Presley, New Technology, and Dying in the PICU. PMID- 30428113 TI - Underrepresented Minorities and Academic Difficulty During Family Medicine Residency: No Association? PMID- 30428115 TI - Moving From Uncertainty to Internal Emotional Responses. PMID- 30428114 TI - Reply to "Underrepresented Minorities and Academic Difficulty During Family Medicine Residency: No Association?" PMID- 30428117 TI - Global Health Means Listening. PMID- 30428116 TI - Reply to "Moving From Uncertainty to Internal Emotional Responses". PMID- 30428118 TI - Advances in the Biology and Management of Modern Bed Bugs. PMID- 30428119 TI - Mission Chechnya. PMID- 30428120 TI - In Shock: My Journey From Death to Recovery and the Redemptive Power of Hope. PMID- 30428121 TI - Medical-ethical guidelines: Care and treatment of people with dementia. AB - The number of people with dementia in Switzerland is currently around 150,000. The prevalence of this condition rises steeply after the age of 65. As a result of demographic changes, the number of people affected in Switzerland is thus expected to increase markedly over the coming decades.The course of dementia - which frequently occurs in combination with chronic somatic and/or mental disorders (multimorbidity) - is often protracted and is difficult to predict. Cognitive impairments mean that self-determination and alleviation of symptoms are more difficult to achieve in everyday practice. People with severe dementia generally lack capacity, and decisions then have to be made by representatives on the basis of the patient's previously expressed or presumed wishes.The management and care of patients may be complicated by disease-related behavioural disturbances.The public, as well as the individuals affected, are fearful of the loss of independence and possible changes in personality associated with progressive dementia; in addition, people are often afraid of becoming a burden on their relatives or society. Against this background, difficult decisions and significant ethical conflicts are not unusual - all the more so since life with dementia runs counter to guiding values, such as independence, productivity and rationality, which are central to our society.The aim of these guidelines is to offer practical guidance for dealing with ethical conflict situations relating to the care and treatment of people with dementia. Specific issues are addressed which may ultimately arise for all those involved in dementia care, irrespective of the setting (domestic, hospital, residential) and professional group. Which of these ethical issues is the most salient will depend largely on the stage of the condition. Once the condition has been diagnosed, management should be based on the principles that are also applicable, for example, in palliative care: a focus on quality of life, equality of care, interprofessional collaboration and continuity, open and appropriate communication, support for decision-making processes, anticipation, a multidimensional approach, and involvement of those close to the patient.These guidelines were prepared in cooperation with the Swiss Society of Gerontology (SGG SSG) as part of the National Dementia Strategy 2014 2019 (subproject 5.1: "Establishment of ethical guidelines"). PMID- 30428122 TI - Combination of flunarizine and transcutaneous supraorbital neurostimulation improves migraine prophylaxis. AB - OBJECTIVE: This study is aimed to access the efficacy and safety of combination therapy of flunarizine plus transcutaneous supraorbital neurostimulation (tSNS) compared with either flunarizine or tSNS alone for migraine prophylaxis. METHODS: Patients with episodic migraine were enrolled and randomized into three groups. Flunarizine 5 mg per day, or tSNS for 20 minutes daily or combination of both were prescribed consecutively for 3 months. The primary outcome measures were changes in migraine days and 50% responder rate of monthly migraine days. Secondary outcome measures were the changes in migraine intensity and intake of rescue medication. Finally, satisfaction to treatment and adverse effect were evaluated as well. RESULTS: A total of 154 were randomized and included in the analysis. After 3 months, the monthly migraine days was decreased in three groups and more significant in the combination group. The 50% responder rate was significantly higher (78.43%) in the combination therapy than monotherapy of flunarizine (46.15%) or tSNS (39.22%) alone. Greater reduction of migraine intensity and intake of rescue medication was observed in combination group. There was no difference of adverse events between flunarizine group and combination group (P=0.89). CONCLUSION: Adding tSNS to flunarizine can improve the therapeutic efficacy of migraine prophylaxis without increasing the adverse effects. In addition, tSNS is effective and safe for migraine treatment and can be a valid option for migraineurs who are reluctant to take oral medications or for patients who experience a low migraine frequency and/or intensity that prophylactic therapy is not indicated but desire to acquire medical intervention. This article is protected by copyright. All rights reserved. PMID- 30428123 TI - Efficacy of CoQ10 as supplementation for migraine: A meta-analysis. AB - OBJECTIVES: Migraine ranks among the most frequent neurological disorders globally. Co-enzyme Q10 (CoQ10) is a nutritional agent that might play a preventative role in migraine. This meta-analysis aimed to investigate the effects of CoQ10 as a supplemental agent in migraine. SUBJECTS AND METHODS: Web of Science, PubMed, and Cochrane Library were searched for potential articles that assessed the effects of CoQ10 on migraine. Data were extracted by two independent reviewers and analyzed with Revman 5.2 software (The Nordic Cochrane Centre, Copenhagen, Denmark). RESULTS: We included five studies with 346 patients (120 pediatric and 226 adult subjects) in the meta-analysis. CoQ10 was comparable with placebo with respect to migraine attacks/month (P = 0.08) and migraine severity/day (P = 0.08). However, CoQ10 was more effective than placebo in reducing migraine days/month (P < 0.00001) and migraine duration (P = 0.009). CONCLUSION: This is the first study to demonstrate the effects of CoQ10 supplementation on migraine. The results support the use of CoQ10 as a potent therapeutic agent with respect to migraine duration and migraine days/month. Nonetheless, more studies are needed to support the conclusions. PMID- 30428124 TI - Structural correlates of cognitive impairment in normal pressure hydrocephalus. AB - OBJECTIVES: The pathological bases for the cognitive and neuropsychiatric symptoms in normal pressure hydrocephalus (NPH) have not been elucidated. However, the symptoms may indicate dysfunction of subcortical regions. Previously, volume reductions of subcortical deep grey matter (SDGM) structures have been observed in NPH patients. The present study used automated segmentation methods to investigate whether SDGM structure volumes are associated with cognitive and neuropsychiatric measures. METHODS: Fourteen NPH patients and eight healthy controls were included in the study. Patients completed neuropsychological tests of general cognition, verbal learning and memory, verbal fluency and measures of apathy and depression pre- and postshunt surgery. Additionally, patients underwent 3 Tesla T1-weighted magnetic resonance imaging at baseline and 6 months postoperatively. Controls were scanned once. SDGM structure volumes were estimated using automated segmentation (FSL FIRST). Since displacement of the caudate nuclei occurred for some patients due to ventriculomegaly, patient caudate volumes were also estimated using manual tracing. Group differences in SDGM structure volumes were investigated, as well as associations between volumes and cognitive and neuropsychiatric measures in patients. RESULTS: Volumes of the caudate, thalamus, putamen, pallidum, hippocampus and nucleus accumbens (NAcc) were significantly reduced in the NPH patients compared to controls. In the NPH group, smaller caudate and NAcc volumes were associated with poorer performance on neuropsychological tests and increased severity of neuropsychiatric symptoms, while reduced volume of the pallidum was associated with better performance on the MMSE and reduced apathy. CONCLUSIONS: Striatal volume loss appears to be associated with cognitive and neuropsychiatric changes in NPH. PMID- 30428125 TI - Bacterial CYP154C8 catalyzes carbon-carbon bond cleavage in steroids. AB - Here, we report the first bacterial cytochrome P450, CYP154C8, that catalyzes the C-C bond cleavage reaction of steroids. A major change in product distribution is observed with CYP154C8, when the reactions are supported by NADPH and spinach redox partners ferredoxin and ferredoxin reductase, compared with previously reported reactions supported by NADH and redox partners containing putidaredoxin and putidaredoxin reductase. The NMR-based structural elucidation of reaction products reveals 21-hydroxyprednisone as the major product for prednisone, while the other product is identified as 1-dehydroadrenosterone obtained due to C-C bond cleavage. A similar pattern of product formation is observed with cortisone, hydrocortisone, and prednisone. The reaction catalyzed by CYP154C8 in the presence of oxygen surrogates also prominently shows the formation of C-C bond cleavage products. This article is protected by copyright. All rights reserved. PMID- 30428126 TI - Estimated Pulmonary Artery Systolic Pressure and Mortality in Older-Elderly Heart Failure Patients. AB - OBJECTIVES: To evaluate the association between high estimated pulmonary artery systolic pressure (ePASP) obtained by echocardiography and 1-year mortality in patients with acute heart failure (HF), comparing findings in individuals aged 80 and older with those of individuals younger than 80. DESIGN: Retrospective cohort study. SETTING: Kyorin University Hospital. PARTICIPANTS: Individuals with acute decompensated HF (N = 335). MEASUREMENTS: High ePASP was defined as a tricuspid regurgitation pressure gradient greater than 47 mmHg (ePASP >50 mmHg). Potential risk factors for 1-year mortality were selected using univariate analysis followed by multivariate Cox regression analysis with backward stepwise selection of variables with P < .10 on univariate analysis to identify significant factors. RESULTS: In individuals aged 80 and older, high ePASP (hazard ratio (HR)=3.07; 95% confidence interval (CI)=1.21-7.80), discharge medications without diuretics (HR=4.18, 95% CI=1.66-10.54), and discharge medications without renin-angiotensin aldosterone system inhibitors (HR=3.38, 95% CI=1.29-8.81) were independent risk factors for 1-year mortality. In contrast, low systolic blood pressure at admission was the sole independent risk factor for 1-year mortality (HR=0.94, 95% CI=0.89-0.99) in those younger than 80. CONCLUSION: High ePASP is a significant predictor of 1-year mortality in individuals aged 80 and older with acute HF but not in those younger than 80. Elucidation of the pathophysiological mechanisms behind these findings should facilitate the development of more effective individualized therapies for older adults with acute HF. PMID- 30428127 TI - Dynamic Molecular Metamorphism involving Palladium-Assisted Dimerization of pi Cation Radicals. AB - A dynamic supramolecular approach is developed to promote the pi-dimerization of viologen radicals at room temperature and in standard concentration ranges. It involves cis- or trans-protected palladium centers serving as inorganic hinges linking two functionalized viologens endowed with metal-ion coordinating properties. On the ground of detailed spectroscopic, electrochemical and computational data, we show that the one electron electrochemical reduction of the viologen units in different dynamic metal:ligand mixtures leads to the formation of the same intramolecular pi-dimer, regardless of the initial environment around the metallic precursor and of the relative ratio between metal and ligand initially introduced in solution. The large scale electron-triggered reorganization of the building blocks introduced in solution thus involves drastic changes in the stoichiometry and stereochemistry of the palladium/viologen complexes proceeding in some cases through a palladium centered trans ->cis isomerization of the coordinated ligands. PMID- 30428128 TI - Suppression of superoxide production by a spin-spin coupling between semiquinone and the Rieske cluster in cytochrome bc1. AB - Catalytic reactions of quinol oxidoreductases may lead to the generation of superoxide due to electron leaks from unstable semiquinone intermediates (SQ). For cytochrome bc1 , the mechanism of suppression of superoxide generation remains unknown. We analyzed conditions of formation of a spin-spin-coupled state between SQ and the Rieske cluster (SQ-FeS) associated with catalysis of the quinol oxidation site of cytochrome bc1 . We reveal that mutants that preclude direct interaction between SQ and the Rieske cluster do not form SQ-FeS and release enhanced superoxide. In the enzymes generating SQ-FeS, little or no superoxide is detected. We propose that SQ-FeS suppresses superoxide generation, becoming an element modulating superoxide release under physiologically relevant conditions slowing electron flow through the enzyme. PMID- 30428129 TI - Mast cell chymase impairs bronchial epithelium integrity by degrading cell junction molecules of epithelial cells. AB - BACKGROUND: An increased degree of mast cell (MC) degranulation and damage to the epithelial lining are prominent features of bronchial asthma. In asthmatic airways, it seems likely that epithelial cells will be exposed to increased concentrations of proteases from MC, though their actions on the epithelium are still not very clear. METHODS: Bronchial rings from human lung tissue or 16HBE cell monolayer were incubated with MC-chymase in different doses or various inhibitors. The sections of paraffin-embedded tissue were haematoxylin-eosin stained and computerized by image analysis for epithelial damage-scale evaluation; the cell viability, proliferation, adhesion, LDH release were assayed; the expressions of gelatinases, cell-junction molecules and structure proteins of 16HBE were examined. RESULTS: MC-Chymase was found to provoke profound changes in the morphology of bronchi epithelial layer. Following incubation with chymase there was 40% reduction of the length of epithelium that was intact, with detachment of columnar epithelial cells and basal cells. Chymase reduced epithelial cell proliferation and induced cell detachment, which were associated with the changes in secretion and activation of matrix metalloproteinase-2/9. In intact epithelial cell layers, immunocytochemistry study revealed that chymase reduced the expressions of occludin, claudin-4, ZO-1, E-cadherin, focal adhesion kinase and cytokeratin. Overall data of this study indicated that MC-chymase can influence tissue remodelling, disrupt epithelial cell-junctions, inhibit wound healing and impair the barrier function of epithelium, resulting in dysfunction of airway wall and ECM remodelling in pathogenesis of asthma. CONCLUSIONS: MC-chymase plays a key role in inducing the damage to bronchial epithelium in asthma. This article is protected by copyright. All rights reserved. PMID- 30428130 TI - An efficient method for synthesizing dimethylsulfonio-34 S-propionate hydrochloride from 34 S8. AB - Dimethylsulfoniopropionate (DMSP, (2-carboxyethyl)dimethylsulfonium) is a highly abundant compound in marine environments. As a precursor to the climatically active gas, dimethylsulfide (DMS), DMSP connects the marine and terrestrial sulfur cycles. However, the fate of DMSP in microbial biomass is not well understood as only a few studies have performed isotopic labeling experiments. A previously published method synthesized 34 S-labeled DMSP from 34 S8 , but the efficiency was only 26 % and required five separate reactions, expensive reagents, and purification of the products of each reaction. In this study, a method of synthesizing 34 S-labeled DMSP from 34 S8 is described. Improvements include elemental steps, inexpensive reagents, purification of only one intermediate, and less time to complete. The efficiency of this method is 65 % and results in pure DMSP with >98 % isotope enrichment as determined by 1 H-NMR and GC-MS. PMID- 30428131 TI - Investigation of combined kV/MV CBCT imaging with a high-DQE MV detector. AB - PURPOSE: Combined kV-MV cone-beam tomography (CBCT) imaging has been proposed for two potentially important image-guided radiotherapy applications: (a) scan time reduction (STR) and (b) metal artifact reduction (MAR). However, the feasibility of these techniques has been in question due to the low detective quantum efficiencies (DQEs) of commercially available electronic portal imagers (EPIDs). The goal of the work was to test whether a prototype high DQE MV detector can be used to generate acceptable quality pretreatment CBCT images at acceptable dose levels. METHODS: 6MV and 100 kVp projection data were acquired on a Truebeam system (Varian, Palo Alto, CA). The MV data were acquired using a prototype EPID containing two scintillators (a) a standard copper-gadolinium oxysulfide (Cu-GOS) screen having a zero-frequency DQE (DQE(0)) value of 1.4%, and (b) a prototype focused cadmium tungstate (CWO) pixelated "strip" with a DQE(0) = 22%. The kV data were acquired using the standard onboard imager (DQE(0) = 70%). The angular spacing of the MV projections was 0.81 degrees and the source output was 0.03 MU/projection while the kV projections were acquired with an angular spacing of 0.4 degrees at 0.3 mAs/projection. Image quality was evaluated using (a) an 18 cm diameter electron density phantom (CIRS, Norfolk, VA) with nine contrast inserts and (b) the resolution section of the 20-cm diameter Catphan phantom (The Phantom Laboratory, Greenwich, NY). For the MAR studies, two opposing CIRS phantom inserts were replaced by steel rods. The reconstruction methods were based on combining MV and kV data into one sinogram. The MAR reconstruction utilized mostly kV raw data with only those rays corrupted by metal requiring replacement with MV data (total absorbed dose = 0.7 cGy). For the STR study, projections from partially overlapping 105 degrees kV and MV acquisitions were combined to create a complete dataset that could have been acquired in 18 sec (absorbed dose = 2.5 cGy). MV-only (4.3 cGy) and kV-only (0.3 cGy) images were also reconstructed. RESULTS: The average signal-to-noise ratio (SNR) of the inserts in the MV-only CWO and GOS CIRS phantom images were 0.62* and 0.12* the SNR of the inserts in kV-only image, respectively. The limiting spatial resolutions in the MV-only GOS, MV-only CWO, and kV-only Catphan images were 3, 6, and 8 lp/cm, respectively. In the combined kV/CWO STR reconstruction, all contrast inserts were visible while only two were detectable in the kV/Cu-GOS image due to high levels of noise (average SNRs of kV/CWO and kV/GOS inserts were 0.97* and 0.18* the SNR of the kV-only inserts, respectively). In the kV-MV MAR reconstructions, streaking artifacts were substantially reduced with all inserts becoming clearly visible in the kV/CWO image while only two were visible in the kV/Cu-GOS image (average SNRs of the kV/CWO and kV/Cu-GOS CIRS with metal inserts were 0.94* and 0.35* the SNRs of the kV-only CIRS without metal inserts). CONCLUSIONS: We have demonstrated that a high-DQE MV detector can be applied to generating high-quality combined kV-MV images for SRT and MAR. Clinically acceptable doses were utilized. PMID- 30428132 TI - Less exacerbations and sustained asthma control 12 months after high altitude climate treatment (HACT) for severe asthma. PMID- 30428133 TI - How do nurses use the Early Warning Score in their practice? A Case study from an Acute Medical Unit. AB - AIMS AND OBJECTIVES: This study aimed to describe how nurses use the Early Warning Score (EWS) in an acute medical ward, their compliance with the EWS and explore their views and experiences of the EWS. BACKGROUND: EWS systems have been implemented in response to upward trends in mortality rates. Nurses play a central role in the use of EWS systems. However, barriers to their use have been identified and include behavioural, cultural and organisational approaches to adherence. Improvement strategies including education and training and electronic devices have assisted in compliance with the system. DESIGN: A holistic single descriptive case study design was used. METHODS: Data triangulation was used including non-participant observation, semi-structured interviews with nurses and document analysis. Nurses were observed using EWS and were subsequently interviewed. Data analysis was guided by systematic text condensation (STC), an approach underpinned by Giorgi's phenomenological method, where meaning units and themes are identified. The study adhered to the consolidated criteria for reporting qualitative research (COREQ) guidelines. RESULTS: Three themes with associated meaning units were found. Protocol Adherence Vs Clinical Judgement addresses nurses' knowledge, skill and experience and patient assessment. Parameter Adjustment and Escalation included parameters not being adjusted or reviewed, junior doctors not being authorised to set parameters and escalation. The final theme Culture highlighted a task driven approach and deficient communication processes. CONCLUSION: This study highlights the need for ongoing training, behavioural change and a cultural shift by health care professionals and organisations to ensure adherence with EWS escalation protocols. RELEVANCE TO CLINICAL PRACTICE: Improvements in education and training into recognition, management and communication of a deteriorating patient is required. Also, a cultural shift is needed to improve compliance and adherence with EWS practice. The potential use of electronic data should be explored. This article is protected by copyright. All rights reserved. PMID- 30428135 TI - Courses and Conferences. PMID- 30428134 TI - Assessment of hormonal parameters and psychological well-being in healthy subjects after a Taoist qigong program: An exploratory study. AB - Qigong is an ancient form of health maintenance, which is part of Traditional China Medicine. Numerous beneficial mental and physical effects have been classically ascribed to this traditional psychosomatic method. The purpose of this work has been to assess the effects of Taoist qigong practice on several hormonal parameters of the Hipotalamic-Pituitary-Adrenal axis and specific measures of psychological well-being in healthy subjects. Forty-three healthy volunteers participated in the study, of whom 22 were randomly allocated to the experimental group, and 21 were assigned to the control group. Experimental participants underwent a qigong training program for one month. Blood samples for the quantification of hormonal parameters, and several instruments to assess anxiety and depression symptoms as well as subjective sleep quality, were obtained before and after the program. Statistically significant differences were found between the experimental and control groups, with the experimental group showing lower blood levels of adrenocorticotropic hormone (ACTH). This study shows that Taoist qigong is a psychosomatic method able to exert a modulatory action on ACTH levels in healthy subjects. We consider the need to continue exploring the psychobiological modulation of this qigong method and its possible repercussion for human health care. PMID- 30428136 TI - A comparison of the uterine proteome of mares in estrus and diestrus. AB - Proteomic analysis of mare uterine flush fluid provides a minimally invasive technique for studying protein changes associated with the estrous cycle. The aim of this study was to identify differentially abundant proteins in the uterine flush fluid of mares in estrus and diestrus. In this study, uterine flush fluid samples were collected from eight reproductively healthy mares in either estrus (n=5) or diestrus (n=3). Proteomic analysis was performed using liquid chromatography- tandem mass spectrometry (LC-MS/MS). Of 172 proteins identified, six proteins [immunoglobulin lambda-like polypeptide 1 (IGLL1), hemoglobin subunit alpha (HBA), alpha-1B-glycoprotein (A1BG), serotransferrin (TF), apolipoprotein A-1 (APOA1), and hemoglobin subunit beta (HBB)] were significantly more abundant in estrus. These proteins may contribute to the endometrial defense system through roles in inflammation, immunity, or antimicrobial activity. In other species, some of these proteins have been described as immunoglobulins, negative acute phase proteins or defense agents against microorganisms. During diestrus, immunoglobulin alpha-1 chain C region-related (IGHA1-related), complement factor I (CFI), CD 109 antigen (CD109) and uterocalin (P19), were significantly more abundant. Research in other species suggests that these four proteins contribute to the immune response through proposed immunoregulatory characteristics, complement system involvement, or roles in B cell - T cell interactions. In conclusion, ten differentially abundant proteins were identified in the uterine flush fluid of mares in estrus and diestrus. Targeted studies on these proteins could elucidate their role in uterine defense mechanisms during estrous cycle in the mare. This article is protected by copyright. All rights reserved. PMID- 30428137 TI - Alcohol consumption in combination with an atherogenic diet increased indices of atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice. AB - BACKGROUND: Alcohol abuse and adherence to atherogenic diet (AD; a low carbohydrate-high-protein diet) have been positively associated with cardiovascular disease. In addition, it has been demonstrated clinically that dietary intake is increased on days when alcohol is consumed. Here, the additive effects of ethanol and AD on atherosclerosis, a major underlying cause of cardiovascular disease, were investigated in apolipoprotein E/low-density lipoprotein receptor double-knockout (KO) mice. The mechanisms, especially aortic oxidative stress damage, were highlighted. METHODS: Twelve-week-old male KO mice on AD with or without ethanol treatment were bred for 4 months. Age-matched male C57BL/6J mice on a standard chow diet without ethanol treatment served as controls. Analyses were conducted using ultrasound biomicroscopy, histopathological and fluorescence immunohistochemical examinations, Western blots, and PCR. RESULTS: KO mice on AD with ethanol treatment showed increases in aortic maximum intima media thickness, hypoechoic plaque formation, and mean Oil Red-O content. These results were associated with enhanced ratio of aortic 8 hydroxy-2'-deoxyguanosine (8-OHdG) immunopositive area to the metallothionein (MT) immunopositive area and suppression of AD-induced up-regulated aortic Mt1, Mt2, and upstream stimulatory factor 1 mRNA expressions. Moreover, 8-OHdG was expressed in the nuclei of CD31- and alpha smooth muscle actin-immunopositive cells, and the up-regulated mRNA expressions of aortic nitric oxide synthase 3 and platelet-derived growth factors were only observed in the KO mice on AD with ethanol treatment. CONCLUSIONS: Alcohol abuse and adherence to AD may promote the shift of aortic oxidative stress and anti-oxidative stress balance toward oxidative-stress predominance and reduced anti-oxidative stress, which may be partly due to the decrease in MT at the cell biological level and down-regulation of Mt at the gene level, which in turn could play a role in the up-regulation of endothelial dysfunction-related and vascular smooth muscle cell proliferation related gene expression and the progression of atherosclerosis in mice with hyperlipidemia. This article is protected by copyright. All rights reserved. PMID- 30428138 TI - Spectrum of susceptibility to air quality and weather in individual children with atopic dermatitis. AB - BACKGROUND: Exposure to air pollution aggravates symptoms of atopic dermatitis (AD) in children in the population studies. Variability in individual patient's response from individual susceptibility is needed to be explored. OBJECTIVE: This study aimed to investigate spectrum of individual variability in the associations between AD symptoms and air quality. METHODS: We enrolled 89 children aged 0-6 years with AD (22,890 person-days). Daily manifestation of symptoms was recorded for an average of 257 days (range 100-499). Both an individual analysis using logistic regression models and an overall analysis using a generalized estimating equation were performed. RESULTS: The odds ratios of an individual ranged 0.24 8.11 for particulate matter less than 10 micrometer in diameter (PM10 ), 0.09 101.92 for nitrogen oxide (NO2 ), 0.03-44.00 for ozone (O3 ), 0.11-58.30 for sulfur dioxide (SO2 ), 0.00-15.83 for carbon monoxide (CO), 0.00-39,446.94 for temperature, and 0.03-5.18 for relative humidity, demonstrating a wide individual variability. In the overall analysis, PM10 , NO2 , SO2 , and CO had a significantly positive association, whereas temperature and relative humidity were negatively associated with AD symptoms. Air pollution was responsible for aggravation of symptoms from 24.7% (O3 ) to 39.3% (SO2 ) of AD children. Overall, 71.9% of the AD children responded to at least one or more air pollution and weather. CONCLUSION: Responses of AD children to air pollution and weather were considerably variable among individuals. An individualized model would be useful to forecast and manage AD symptoms in patients. This article is protected by copyright. All rights reserved. PMID- 30428139 TI - Cord-serum per- and poly-fluoroalkyl substances and atopy and eczema at 12 months. PMID- 30428140 TI - Scheduled care - as a way of caring. A phenomenological study of being cared for when suffering from alcohol use disorders. AB - AIMS AND OBJECTIVES: The aim of this study was to elucidate the lived experience of how patients with alcohol use disorders experience being cared for when admitted to acute medical units. BACKGROUND: Alcohol use is health damaging and is identified as one of the major avoidable risk factors and alcohol use disorder is classified among the most harmful, debilitating disease categories. Patients suffering from alcohol use disorders are characterized by complex problems and health pictures spawned by chaotic lifestyles. However, the experience of the hospitalization from patients' perspective is poorly documented. DESIGN: The present study has a qualitative research design and is anchored in phenomenological and hermeneutical methodology, as described in Reflective Lifeworld Research. METHODS: The data set consists of 15 in-depth interviews with patients suffering from alcohol use disorders admitted to an acute medical unit. A purposive sampling strategy was used and the interviews were conducted as open dialogues. The study was reported in accordance with the Consolidated criteria for reporting qualitative research (COREQ). RESULTS: Being cared for when hospitalized was experienced as a two-staged process that changed throughout the hospitalization from an experience of scheduled care experienced as caring to an experience of scheduled care experienced as non-caring. Four constituents further described the variable experiences: being in a safe haven, sharing a tacit but mutual goal, being in a chaotic space, and being on your own. CONCLUSIONS: The study showed that being met in an authentic presence by nurses was a powerful tool that helped ease the hospitalization. Patients suffering from alcohol use disorders call for an intentional and distinctive attentiveness and authentic presence from the nurses throughout their hospitalization. RELEVANCE TO CLINICAL PRACTICE: Our findings highlight that patients suffering from AUD call for an intentional and distinct attentiveness from nurses throughout the hospitalization, where a possible transfer of attention is noticed and responded to in the care provided. This article is protected by copyright. All rights reserved. PMID- 30428141 TI - Bone maturation cannot be used to estimate chronological age in asylum-seeking adolescents. AB - It is important to determine the chronological ages of children and adolescent asylum seekers and physicians and researchers working in forensic medicine and paediatrics are involved in this process. However, it appears that forensic doctors in Germany (1) and Sweden, as discussed in this paper, have been ignoring high-quality research in epidemiology, paediatrics and psychology when they assess adolescents, In Sweden, the age of asylum-seeking adolescents is estimated by using radiological assessments of bone and teeth age and the risk of deportation is increased if the estimated age is 18 years or higher. In 2017, the Swedish National Board for Forensic Medicine assessed the bone age of 9,617 asylum-seeking adolescents and it maintains that its assessments were more comprehensive than any other country and that they have considerable experience when it comes to age assessments. It is therefore of international interest to examine their procedures. This article is protected by copyright. All rights reserved. PMID- 30428142 TI - Do spatial scale and life history affect fish-habitat relationships? AB - 1.Understanding how animals interact with their environment is a fundamental ecological question with important implications for conservation and management. The relationships between animals and their habitat, however, can be scale dependent. If ecologists work at suboptimal spatial scales, they will gain an incomplete picture of how animals respond to the landscape. Identifying the scale at which animal-landscape relationships are strongest (the 'scale of effect') will improve our ability to better plan management and conservation activities. 2.Several recent studies have greatly enhanced our knowledge about the scale of effect, and the potential drivers of inter-specific variability, in particular life-history traits. However, while many marine systems are inherently multi scalar, research into the scale of effect has been mainly focussed on terrestrial taxa. As the scales of observation in fish-habitat association studies are often selected based on convention rather than biological reasoning, they may provide an incomplete picture of the scales where these associations are strongest. 3.We examined fish-habitat associations across four nested spatial scales in a temperate reef system to ask: (1.) at what scale are fish-habitat associations the strongest, (2.) are habitat elements consistently important across scales, and (3.) do scale-dependent fish-habitat associations vary in relation to either body size, geographic range size or trophic level? 4.We found that: (1.) the strongest fish-habitat associations were observed when these relationships were examined at considerably larger spatial scales than usually investigated; (2.) the importance of environmental predictors varied across spatial scales, indicating that conclusions about the importance of habitat elements will depend on the scales at which studies are undertaken; and (3.) scale-dependent fish habitat associations were consistent across all life-history traits. 5.Our results highlight the importance of considering how animals relate to their environment and suggest the small scales often chosen to examine fish-habitat associations are likely to be suboptimal. Developing a more mechanistic understanding of animal-habitat associations will greatly aid in predicting and managing responses to future anthropogenic disturbances. PMID- 30428143 TI - Photo Protection against Visible Light Induced Pigmentation. AB - OBJECTIVE: This paper presents in vivo an in vitro studies demonstrating the induction of pigmentation in human skin by visible light which can be blocked by using formulation containing the correct amount of yellow iron oxide (YIO). METHODS: An in vitro absorption method was developed to determine the protection provided by a test formulation containing 4.5% YIO using an IPD UVA-VIS action spectrum. Following the development of the in vitro method and in vivo study with 10 normal healthy volunteers with Fitzpatrick skin phototypes IV to VI was conducted to verify if the predictive model. RESULTS: The in vitro model for visible light protection provided a protection factor of 2.5 using the in vitro absorption spectrum of 4.5% of YIO with a very similar result from the in vivo study with a protection factor of 3.0. Multiple daily exposures of visible light have shown increase in skin pigmentation and the application of YIO provide less development of pigmentation when compared to unprotected skin. CONCLUSION: In vitro testing of the absorbance of the pigmented formulation using a proposed action spectrum for immediate pigment darkening (IPD) response in the visible light range supports the in vivo protection observations for persistent pigment darkening (PPD) and can be used as predictor for skin pigmentation induced by visible light. This article is protected by copyright. All rights reserved. PMID- 30428144 TI - ICH: Recent Reforms as a Driver of Global Regulatory Harmonization and Innovation in Medical Products. AB - Eight years ago this journal published "The Value and Benefits of the International Conference on Harmonization to Drug Regulatory Authorities: Advancing Harmonization for Better Public Health"1 to mark the 20th anniversary of ICH. Much has happened since following the reform of ICH which culminated in 2015 with the establishment of ICH as an international non-profit association. This entailed a transformation of the collaboration between a limited number of parties in an informal setting into a formal international organization with its own legal entity. The reform was a time-consuming exercise preceded by in-depth and complex discussions where different options had to be considered and different interests balanced while ICH continued its normal harmonization work within the existing framework. However, the mission of ICH remained unchanged: advancing harmonization for better health. This article describes what triggered the reform and the work that paved the way for reaching the end result. This article is protected by copyright. All rights reserved. PMID- 30428145 TI - Prospective validation of a checklist to predict short-term death in older patients after emergency department admission in Australia and Ireland. AB - BACKGROUND: Emergency departments are pressured environment where patients with supportive and palliative care needs may not be identified. We aimed to test the predictive ability of the CriSTAL (Criteria for Screening and Triaging to Appropriate aLternative care) checklist to flag patients at risk of death within 3 months who may benefit from timely end-of-life discussions. METHODS: Prospective cohorts of >65 year-old patients admitted for at least one night via emergency departments in five Australian hospitals and one Irish hospital. Purpose-trained nurses and medical students screened for frailty using two instruments concurrently, and completed the other risk factors on the CriSTAL tool at admission. Post-discharge telephone follow-up used to determine survival status. Logistic regression and bootstrapping techniques used to test the predictive accuracy of CriSTAL for death within 90 days of admission as primary outcome. Predictability of in-hospital death was the secondary outcome. RESULTS: 1,182 patients, with median age 76-80 years (IRE-AUS). The deceased had significantly higher mean CriSTAL with Australian mean of 8.1 (95%CI 7.7-8.6 vs. 5.7 95%CI 5.1-6.2) and Irish mean 7.7 (95%CI 6.9-8.5 vs. 5.7 95%CI 5.1-6.2). The model with Fried Frailty score was optimal for the derivation (Australian) cohort but prediction with the Clinical Frailty Scale (CFS) was also good (AUROC 0.825 and 0.81 respectively). Values for the validation (Irish) cohort were AUROC 0.70 with Fried and 0.77 using CFS. A minimum of five out of 29 variables were sufficient for accurate prediction, and a cut point of 7+ or 6+ depending on the cohort was strongly indicative of risk of death. The most significant independent predictor of short-term death in both cohorts was frailty, carrying a two-fold risk of death. CriSTAL's accuracy for in-hospital death prediction was also good (AUROC 0.795 and 0.81 in Australia and Ireland respectively), with high specificity and negative predictive values. CONCLUSIONS: The modified CriSTAL tool (with CFS instead of Fried's frailty instrument) had good discriminant power to improve certainty of short-term mortality prediction in both health systems. The predictive ability of models is anticipated to help clinicians gain confidence in initiating earlier end-of-life discussions. The practicalities of embedding screening for risk of death in routine practice warrant further investigation. This article is protected by copyright. All rights reserved. PMID- 30428146 TI - Nurses' identification and reporting of medication errors. AB - AIMS AND OBJECTIVES: To investigate hospital nurses' involvement in the identification and reporting of medication errors in Turkey. BACKGROUND: Medication safety is an international priority, and medication error identification and reporting are essential for patient safety. DESIGN: A descriptive survey design consistent with the STROBE guidelines was used. METHODS: The participants were 135 nurses employed in a university hospital in Turkey. The survey instrument included 18 sample cases and respondents identified whether errors had been made and how they should be reported. Descriptive statistics were analysed using the chi-square and Fisher's exact tests. RESULTS: The sample case of "Patient given 10 mg morphine sulphate instead of 1.0 mg of morphine sulphate" was defined as a medication error by 97% of respondents, whereas the sample case of "Omitting oral/IV antibiotics because of the need to take the patient out for X-rays for 3 hr" was defined as a medication error by only 32.1%. It was found that eight sample cases (omitting antibiotics, diluting norodol drops with saline, giving aspirin preprandially, injecting clexane before colonoscopy, giving an analgesic at the nurse's discretion, dispensing undiluted morphine, preparing dobutamine instead of dopamine and administering enteral nutrition intravenously) were assessed as errors and reported, although there were significant statistical differences between the identification and reporting of these errors. CONCLUSION: Nurses are able to identify medication errors, but are reluctant to report them. Fear of the consequences was the main reason given for not reporting medication errors. When errors are reported, it is likely to be to physicians. RELEVANCE TO CLINICAL PRACTICE: The development of a commonly agreed definition of a medication error, along with clear and robust reporting mechanisms, would be a positive step towards increasing patient safety. Staff reporting medication errors should be supported, not punished, and the information provided used to improve the system. PMID- 30428148 TI - Itaconate: an emerging determinant of inflammation in activated macrophages. AB - Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites, such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct anti-microbial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of pro-inflammatory mediators in lipopolysaccharide-treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in anti-microbial defense. The mechanism for this anti-inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IkappaBzeta translation, and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro to an anti-inflammatory state to limit the damage and facilitate tissue repair under pro-inflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention. This article is protected by copyright. All rights reserved. PMID- 30428147 TI - Feasibility of the Allergy Questionnaire for Athletes (AQUA(c)) in pediatric age. AB - A burden of respiratory and allergic symptoms up to almost 60% has been observed in young and adult athletes, influencing physical performances1 . The Allergy Questionnaire for Athletes (AQUA(c)) is a validated screening tool for the prediction of the atopic status in adult athletes2 ; it was recently tested in Belgian young elite athletes (12-14 years old)3 , but its actual feasibility and suitability for children and adolescent was not evaluated. Indeed, there is evidence that children are prone to employ "satisficing" response strategies, answering every question positively/negatively, or simply not answering4 . Therefore, the present cross-sectional survey was carried out to assess feasibility of a linguistically simplified version of AQUA(c) in children and adolescents, stratifying by sport practice and focusing on the core items (12 questions, 5 to 14 and 16 to 17) related to allergy. The study was approved by the local Institutional Ethics Committee (Palermo 1, Italy, Approval Number: 07/2017), and registered on the central registration system ClinicalTrials. gov (ID: NCT03286894). This article is protected by copyright. All rights reserved. PMID- 30428149 TI - Inter-rater Reliability of the HEART Score. AB - BACKGROUND: The HEART score is a risk stratification tool for suspected acute coronary syndrome and contains several subjective components. A single previous study found good inter-rater reliability. Our objective was to assess the inter rater reliability of the HEART score in an external prospective cohort. METHODS: We prospectively collected paired, independent physician ratings of the HEART score for patients > 20 years of age presenting to the emergency department with chest pain for which an ECG and troponin were ordered. Two emergency physicians independently provided HEART scores for each unique patient. The primary outcome, the HEART score, was dichotomized by low risk (0-3) vs non- low risk (4-10). Additional outcomes included the HEART score across the entire scale (0-10) and subcomponents of the HEART score (e.g., history, electrocardiogram, risk factors; score of 0-2 for each).We calculated kappa statistics and percent agreement for all outcomes. RESULTS: We collected paired physician HEART score ratings on 311 patients from October 2017 to April 2018. The mean HEART score was 3.5 (SD 1.9). About half (49.2%) of our patients had a HEART score of <= 3, and 50.8% had a HEART score > 3. The kappa score for "low risk" (HEART <= 3) was 0.68 (95%CI: 0.60 - 0.77). There was 84.2% agreement between physicians on this variable. CONCLUSIONS: Our study demonstrates there is substantial inter-rater reliability among emergency department physicians in identifying patients at low risk of acute coronary syndrome using the HEART score. This article is protected by copyright. All rights reserved. PMID- 30428150 TI - Reduction of Computed Tomography Use for Pediatric Closed Head Injury Evaluation at a Non-pediatric Community Emergency Department. AB - OBJECTIVE: The purpose of this study was to determine if implementation of a Pediatric Emergency Care Applied Research Network (PECARN)-based closed head injury assessment tool could safely decrease computed tomography (CT) use for pediatric head injury evaluation at a non-pediatric community emergency department (ED). METHODS: A quality improvement project was initiated at a non pediatric community ED to implement an institution-specific, Pediatric Emergency Care Applied Research Network (PECARN)-based Pediatric Closed Head Injury Assessment Tool. Baseline head CT use at the participating ED was determined for children with closed head injury through retrospective chart review from March 2014 through November 2015. Head injury patients were identified using International Classification of Disease (ICD)-9 codes for head injury, unspecified (959.01) and concussion with and without loss of consciousness (850 850.9) until October 2015, after which ICD-9 was no longer used. To identify eligible patients after October 2015 lists of all pediatric patients evaluated at the participating ED were reviewed, and patients were included in the analysis if they had a physician-assigned discharge diagnosis of head injury or concussion. Exclusion criteria were age >=18 years, penetrating head trauma, history of brain tumor, ventriculoperitoneal shunt, or bleeding disorder, or presentation >24 hours post-injury. Medical history, injury mechanism, symptoms, head CT use, and disposition were recorded. Implementation of the Pediatric Closed Head Injury Assessment Tool was achieved through provider education sessions beginning in December 2015 and ending in August 2016. Head CT use was monitored for 12 months post-implementation, from September 2016 through August 2017. Patients were classified into low, intermediate, or high risk for clinically important traumatic brain injury (ciTBI) by chart review. ED length-of-stay (LOS), disposition, and ED returns within 72 hours were recorded. Categorical variables were compared using Chi-Square test or Fisher's Exact test, and continuous variables using Kruskal-Wallis test. RESULTS: A total of 252 children with closed head injury were evaluated pre-implementation (March 2014 through November 2015), 132 children were evaluated during implementation (December 2015 through August 2016), and 172 children were evaluated post-implementation (September 2016 through August 2017). Overall CT use decreased from 37.7% (95% CI, 31.7 - 43.7) pre-implementation to 16.9% (95% CI, 11.3 - 22.5) post-implementation (p <0.001). Only 1% (95% CI, 0 - 2.9) of low risk patients received a head CT post implementation compared to 22.6% (95% CI, 16.1 - 29.1) pre-implementation (p <0.001). CT use among patients >=24 months decreased from 42.9% (95% CI, 36.5 - 49.6) to 19.6% (95% CI, 13.1 - 26.1) (p <0.001) and remained low and unchanged for patients <24 months. Transfers to a pediatric trauma center and ED returns within 72 hours were unchanged, while median ED LOS improved from 1.5 hours to 1.3 hours (p = 0.03). There were no missed ciTBIs after implementation of the guideline. CONCLUSION: Implementation of the PECARN-based Pediatric Closed Head Injury Assesstment Tool reduced head CT use in a non-pediatric ED. The greatest impact was seen among children aged >=24 months at very low risk for ciTBI. This article is protected by copyright. All rights reserved. PMID- 30428151 TI - An Open Label Pilot Study of a Dexmedetomidine-Remifentanil-Caudal Anesthetic for Infant Lower Abdominal/Lower Extremity Surgery: The T REX Pilot Study. AB - BACKGROUND: Concern over potential neurotoxicity of anesthetics has led to growing interest in prospective clinical trials using potentially less toxic anesthetic regimens, especially for prolonged anesthesia in infants. Preclinical studies suggest that dexmedetomidine may have a reduced neurotoxic profile compared to other conventional anesthetic regimens; however, coadministration with either anesthetic drugs (e.g. remifentanil) and/or regional blockade is required to achieve adequate anesthesia for surgery. The feasibility of this pharmacological approach is unknown. The aim of this study was to determine the feasibility of a remifentanil/dexmedetomidine/ neuraxial block technique in infants scheduled for surgery lasting longer than 2 hours. METHODS: Sixty infants (age 1-12 months) were enrolled at seven centers over 18 months. A caudal local anesthetic block was placed after induction of anesthesia with sevoflurane. Next, an infusion of dexmedetomidine and remifentanil commenced, and the sevoflurane was discontinued. Three different protocols with escalating doses of dexmedetomidine and remifentanil were used. RESULTS: One infant was excluded due to a protocol violation and consent was withdrawn prior to anesthesia in another. The caudal block was unsuccessful in 2 infants. Of the 56 infants who completed the protocol 45 (80%) had at least one episode of hypertension (Mean Arterial Pressure >80 mmHg) and/or movement that required adjusting the anesthesia regimen. In the majority of these cases the remifentanil and/or dexmedetomidine doses were increased although six infants required rescue 0.3% sevoflurane and one required a propofol bolus. Ten infants had at least one episode of mild hypotension (Mean Arterial Pressure 40 -50 mmHg) and 4 had at least one episode of moderate hypotension (Mean Arterial Pressure <40 mmHg). CONCLUSION: A dexmedetomidine/remifentanil neuraxial anesthetic regimen was effective in 87.5% of infants. These findings can be used as a foundation for designing larger trials that assess alternative anesthetic regimens for anesthetic neurotoxicity in infants This article is protected by copyright. All rights reserved. PMID- 30428152 TI - Intergenerational Transmission of Attentional Bias and Anxiety. AB - Earlier evidence has revealed a bi-directional causal relationship between anxiety and attention biases in adults and children. This study investigated the prospective and concurrent relations between anxiety and attentional bias in a sample of 89 families (mothers, fathers, and first-born children). Parents' and children's attentional bias was measured when children were 7.5 years old, using both a visual probe task and visual search task with angry vs. happy facial expressions. Generalized and social anxiety symptoms in parents and children were measured when children were 4.5 and 7.5 years old. Anxiety in parents and children were prospectively (but not concurrently) related to their respective attentional biases to threat: All participants showed a larger attentional bias to threat in the visual search (but not in the visual probe) task if they were more anxious at the 4.5 (but not at the 7.5) year measurement. Moreover, parents' anxiety levels were prospectively predictive of the visual search attentional bias of their children after controlling for child anxiety. More anxiety in mothers at 4.5 years was related to a faster detection of angry among happy faces, while more anxiety in fathers predicted a faster detection of happy among angry faces in children at 7.5 years. We found no direct association between parental and child attentional biases. Our study contributes to the recently emerging literature on attentional biases as a potential mechanism in the intergenerational transmission of anxiety by showing that parents' anxiety rather than parents' attentional bias contributes to the intergenerational transmission of risk for child anxiety. This article is protected by copyright. All rights reserved. PMID- 30428153 TI - Robotic versus laparoscopic rectal tumour surgery: a cohort study. AB - AIM: The aim of this study was to compare robotic and laparoscopic rectal surgery in perioperative data, short-term outcome and compliance to the ERAS (Enhanced Recovery After Surgery) protocol. METHODS: In this cohort study, 224 patients scheduled for rectal resection due to cancer or adenoma between January 2011 January 2017 were evaluated. In the first time period, January 12, 2011 to April 23, 2014 47 patients (46% out of 102 patients) had laparoscopic surgery. In the second time period, April 24, 2014 to January 30, 2017 72 patients (59% out of 122 patients) had robotic surgery. Perioperative data and short-term outcome were collected from the ERAS database and patient charts. Data from the two time periods in laparoscopic and robotic surgery were compared. Primary outcome was length of stay (LOS) and secondary outcomes were compliance to the ERAS protocol, difference in postoperative complications and conversion to open surgery. RESULTS: Compliance to the ERAS protocol was 81.1% in the robotic group and 83.4% in the laparoscopic group (p=0.890). Robotic surgery was associated with shorter LOS (median 3 vs 7 days, p<0.001), lower conversion rate (11.1% vs 34.0%, p=0.002), lower rate of postoperative complications (25% vs 49%, p<0.01) and longer duration of surgery (5.8 h vs 4.5 h, p<0.001). The differences remained after multivariate analysis. CONCLUSION: Robotic surgery was associated with shorter LOS, lower conversion rates and less postoperative complications compared to laparoscopic surgery. Robotic surgery may add benefits to the ERAS protocol. This article is protected by copyright. All rights reserved. PMID- 30428154 TI - SCFbeta-TrCP ubiquitinates CHK1 in an AMPK-dependent manner in response to glucose deprivation. AB - The ATR/CHK1 pathway is a key effector of cellular response to DNA damage and therefore is a critical regulator of genomic stability. While the ATR/CHK1 pathway is often inactivated by mutations, CHK1 itself is rarely mutated in human cancers. Thus, cellular levels of CHK1 likely play a key role in the maintenance of genomic stability and preventing tumorigenesis. Glucose deprivation is observed in many solid tumors due to high glycolytic rates of cancer cells and insufficient vascularization, yet cancer cells have devised mechanisms to survive in conditions of low glucose. Although CHK1 degradation through the ubiquitin proteasome pathway following glucose deprivation has been previously reported, the detailed molecular mechanisms remain elusive. Here, we show that CHK1 is ubiquitinated and degraded upon glucose deprivation by the Skp1-Cullin-F-box (beta-TrCP) E3 ubiquitin ligase. Specifically, CHK1 contains a beta-TrCP recognizable degron domain, which is phosphorylated by AMPK in response to glucose deprivation, allowing for beta-TrCP to recognize CHK1 for subsequent ubiquitination and degradation. Our results provide a novel mechanism by which glucose metabolism regulates a DNA damage effector, and imply that glucose deprivation, which is often found in solid tumor microenvironments, may enhance mutagenesis, clonal expansion, and tumor progression by triggering CHK1 degradation. PMID- 30428155 TI - Paracoccus denitrificans Oxidative Phosphorylation: Retentions, Gains, Losses, and Lessons En Route to Mitochondria. AB - There are many similarities between the oxidative phosphorylation apparatus of mitochondria and those found in the cytoplasmic membranes of alpha proteobacteria, exemplified by Paracocus denitrificans. These similarities are reviewed here alongside consideration of the differences between mitochondrial and bacterial counterparts, as well as the loss from the modern mitochondria of many of the bacterial respiratory proteins. The assembly of c-type cytochromes is of particular evolutionary interest as the post-translational apparatus used in the alpha-proteobacteria is found in plants, and for example in eukyarotic species including algae of various kinds together with jakobids, but has been superseded by different systems in mitochondria of metazoans and trypanosomatids. All mitochondrial cytochromes c have the N-terminal sequence feature that is recognised by the metazoan system whereas the bacterial counterparts do not, suggesting that the loss of the bacterial system from eukaryotes occurred in the context of an already present recognition sequence in the eukaryotic cytochromes. Interestingly, in the case of cytochromes c1 the putative recognition features for the metazoans appear to be substantially present in the bacterial proteins. The ability to prepare from P. denitrificans inverted membrane vesicles with classic respiratory control presents a valuable system from which to draw lessons concerning the long debated topic of what controls the rates of respiration and ATP synthesis in mitochondria. (c) 2018 IUBMB Life, 70(12):1214-1221, 2018. PMID- 30428156 TI - Assessing surgical difficulty in locally advanced mid-low rectal cancer: the accuracy of two MRI-based predictive scores. AB - AIM: Predicting surgical difficulty is a critical factor in the management of locally advanced rectal cancer (LARC). This study evaluates the accuracy and external validity of a recently published morphometric score to predict surgical difficulty and additionally proposes a new score to identify preoperatively LARC patients with a high risk of having a difficult surgery. METHODS: This is a retrospective study based on the European MRI and Rectal Cancer Surgery (EuMaRCS) database, including patients with mid/low LARC who were treated with neoadjuvant chemoradiation therapy and laparoscopic total mesorectal excision (L-TME) with primary anastomosis. For all patients, pretreatment and restaging MRI were available. Surgical difficulty was graded as high and low based upon a composite outcome, including operative (e.g. duration of surgery) and postoperative variables (e.g. hospital stay). Score accuracy was assessed by estimating sensitivity, specificity and area under the receiver operating characteristic curve (AROC). RESULTS: In a total of 136 LARC patients, 17 (12.5%) were graded as high surgical difficulty. The previously published score (calculated on body mass index, intertuberous distance, mesorectal fat area, type of anastomosis) showed low predictive value (sensitivity 11.8%; specificity 92.4%; AROC 0.612). The new EuMaRCS score was developed using the following significant predictors of surgical difficulty: body mass index > 30, interspinous distance < 96.4 mm, ymrT stage >= T3b and male sex. It demonstrated high accuracy (AROC 0.802). CONCLUSION: The EuMaRCS score was found to be more sensitive and specific than the previous score in predicting surgical difficulty in LARC patients who are candidates for L-TME. However, this score has yet to be externally validated. PMID- 30428157 TI - Primary versus myocutaneous flaps closure of perineal defects following abdominoperineal resection for colorecal disease: a systematic review and meta analysis. AB - BACKGROUND: Perineal wound complications after abdominoperineal resection (APR) have become a major clinical challenge. Myocutaneous flap closure has been proposed in place of primary closure to improve wound healing. We conducted this comprehensive meta-analysis to evaluate the current scientific evidence of primary closure versus myocutaneous flaps closure of perineal defects following APR for colorectal disease. METHODS: We systematically searched the Medline, Embase, PubMed, Web of Science, Cochrane Library databases to identify all relevant studies. After data extraction from included studies, meta-analysis was performed to compare perioperative outcomes of primary closure and myocutaneous flap closure. RESULTS: Eighteen studies with a total of 17913 patients (16346 primary closure versus 1567 myocutaneous flaps closure) were included. We found that primary closure was significantly associated with higher total perineal wound complications (p=0.007), major perineal wound complications (p<0.001), and perineal wound infection (p=0.001). On the other hand, myocutaneous flap closure takes more operation time (p<0.001) and increases the risk of perineal wound dehiscence (p=0.01), deep surgical site infection (p<0.001), enterocutaneous fistulas (p=0.03), and return to operating room (p=0.0005). There were no significant differences between the two groups for other outcomes. CONCLUSIONS: This is the first systematic review with meta-analysis comparing primary closure with myocutaneous flap closure of perineal defects after APR for colorectal disease. Although taking more operation time and increased risk of specific complications, the pooled results have validated the use of myocutaneous flaps for reducing total/major perineal wound complications. More investigations are needed to draw definitive conclusion on this dilemma. This article is protected by copyright. All rights reserved. PMID- 30428158 TI - Influenza epidemics observed in primary care from 1984 to 2017 in France: a decrease of epidemic size over time. AB - BACKGROUND: Epidemiological analysis of past influenza epidemics remains essential to understand the evolution of the disease and optimize control and prevention strategies. Here, we aimed to use data collected by a primary care surveillance system over the last three decades to study trends in influenza epidemics and describe epidemic profiles according to circulating influenza viruses. METHODS: Influenza-like illness (ILI) weekly incidences were estimated using cases reported by general practitioners participating in the French Sentinelles network, between 1984 and 2017. Influenza epidemics were detected by applying a periodic regression to this time series. Epidemic (co-)dominant influenza virus (sub)types were determined using French virology data. RESULTS: During the study period, 297607 ILI cases were reported allowing the detection of 33 influenza epidemics. On average, seasonal epidemics lasted 9 weeks and affected 4.1% of the population (95%CI [3.5;4.7]). Mean age of cases was 29 years. Epidemic size decreased over time by -66 cases per 100000 population per season on average (95%CI [-132;-0.2], pval=0.049) and epidemic height decreased by -15 cases per 100000 (95%CI [-28;-2], pval=0.022). Epidemic duration appeared stable over time. Epidemics were mostly dominated by A(H3N2) (n=17, 52%), associated to larger epidemic size, higher epidemic peak and older age of cases. CONCLUSIONS: The declining trend in influenza epidemic size and height over the last 33 years might be related to several factors like increased vaccine coverage, hygiene improvements or changing in influenza viruses. However, further researches are needed to assess the impact of potential contributing factors to adapt influenza plans. This article is protected by copyright. All rights reserved. PMID- 30428160 TI - Gas exchange and water-use efficiency in plant canopies. AB - In this review, I first address the basics of gas exchange, water-use efficiency, and carbon isotope discrimination in C3 plant canopies. I then present a case study of water-use efficiency in northern Australian tree species. In general, C3 plants face a trade-off whereby increasing stomatal conductance for a given set of conditions will result in a higher CO2 assimilation rate, but a lower photosynthetic water-use efficiency. A common garden experiment suggested that tree species which are able to establish and grow in drier parts of northern Australia have a capacity to use water rapidly when it is available through high stomatal conductance, but that they do so at the expense of low water-use efficiency. This may explain why community level carbon isotope discrimination does not decrease as steeply with decreasing rainfall on the North Australian Tropical Transect as has been observed on some other precipitation gradients. Next, I discuss changes in water-use efficiency that take place during leaf expansion in C3 plant leaves. Leaf phenology has recently been recognized as a significant driver of canopy gas exchange in evergreen forest canopies, and leaf expansion involves changes in both photosynthetic capacity and water-use efficiency. Following this, I discuss the role of woody tissue respiration in canopy gas exchange and how photosynthetic refixation of respired CO2 can increase whole-plant water-use efficiency. Finally, I discuss the role of water use efficiency in driving terrestrial plant responses to global change, especially the rising concentration of atmospheric CO2 . In coming decades, increases in plant water-use efficiency caused by rising CO2 are likely to partially mitigate impacts on plants of drought stress caused by global warming. This article is protected by copyright. All rights reserved. PMID- 30428159 TI - Directional Preference of DNA-Mediated Electron Transfer in Gold-Tethered DNA Duplexes: Is DNA a Molecular Rectifier? AB - Electrical properties of self-assembling DNA nanostructures underlie the paradigm of nanoscale bioelectronics, and as such require clear understanding. DNA mediated electron transfer (ET) from a gold electrode to DNA-bound Methylene Blue (MB) shows directional preference, and it is sequence-specific. During the electrocatalytic reduction of [Fe(CN)6 ]3- catalyzed by DNA-bound MB, the ET rate constant for DNA-mediated reduction of MB reaches (1.32+/-0.2)103 and (7.09+/ 0.4)103 s-1 for (dGdC)20 and (dAdT)25 duplexes. The backward oxidation process is less efficient, making the DNA duplex a molecular rectifier. Lower rates of ET via (dGdC)20 agree well with its disturbed pi-stacked sub-molecular structure. Such direction- and sequence-specific ET may be implicated in DNA oxidative damage and repair, and be relevant to other polarized surfaces, such as cell membranes and biomolecular interfaces. PMID- 30428161 TI - Comparison between autologous and homologous blood transfusions in liver resection for biliary tract cancer: A propensity score matching analysis. AB - BACKGROUND: It remains unclear whether preoperative blood donation is truly beneficial in liver surgery. The aim of this study was to compare surgical outcomes between patients receiving autologous and homologous transfusions during liver resection for biliary tract cancer (BTC). METHODS: Patients who underwent hepatectomy for BTC were retrospectively reviewed (2006-2017). Patients who deposited autologous blood and underwent resection without homologous blood transfusion intraoperatively (Autologous-group) were compared with non-depositing patients who required homologous transfusion during hepatectomy (Homologous group). Propensity score matching analyses were performed to adjust the data for the baseline characteristics of both groups. RESULTS: During the study period, 359 patients were included in the Autologous-group, and 105 patients were in the Homologous-group. The postoperative maximum total bilirubin (T-Bil) levels and the incidence of postoperative liver failure were significantly higher in the Homologous-group than in the Autologous-group. After propensity score matching, postoperative maximum T-Bil levels were significantly higher in the Homologous group, whereas the incidence of postoperative liver failure was comparable between the two groups; between-group differences were not observed for the remaining major complications, hospital stays and mortality. CONCLUSION: Although autologous blood transfusion may minimize postoperative hyperbilirubinemia, it may not decrease the risk for mortality or morbidities following hepatectomy for BTC. This article is protected by copyright. All rights reserved. PMID- 30428162 TI - ipso-Arylative Ring-Opening Polymerization as a Route to Electron-Deficient Conjugated Polymers. AB - ipso-Arylative ring-opening polymerization of 2-bromo-8-aryl-8H-indeno[2,1 b]thiophen-8-ol monomers proceeds to Mn up to 9 kg mol-1 with conversion of the monomer diarylcarbinol groups to pendent conjugated aroylphenyl side chains (2 benzoylphenyl or 2-(4-hexylbenzoyl)phenyl), which influence the optical and electronic properties of the resulting polythiophenes. Poly(3-(2-(4 hexylbenzoyl)phenyl)thiophene) was found to have lower frontier orbital energy levels (HOMO/LUMO=-5.9/-4.0 eV) than poly(3-hexylthiophene) owing to the electron withdrawing ability of the aryl ketone side chains. The electron mobility (ca. 2*10-3 cm2 V-1 s-1 ) for poly(3-(2-(4-hexylbenzoyl)phenyl)thiophene) was found to be significantly higher than the hole mobility (ca. 8*10-6 cm2 V-1 s-1 ), which suggests such polymers are candidates for n-type organic semiconductors. Density functional theory calculations suggest that backbone distortion resulting from side-chain steric interactions could be a key factor influencing charge mobilities. PMID- 30428163 TI - LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy. AB - Xenophagy, also known as antibacterial autophagy, plays a role in host defense against invading pathogens such as Group A Streptococcus (GAS) and Salmonella. In xenophagy, autophagy receptors are used in the recognition of invading pathogens and in autophagosome maturation and autolysosome formation. However, the mechanism by which autophagy receptors are regulated during bacterial infection remains poorly elucidated. In this study, we identified LAMTOR2 and LAMTOR1, also named p14 and p18, respectively, as previously unrecognized xenophagy regulators that modulate the autophagy receptor TAX1BP1 in response to GAS and Salmonella invasion. LAMTOR1 was localized to bacterium-containing endosomes, and LAMTOR2 was recruited to bacterium-containing damaged endosomes in a LAMTOR1-dependent manner. LAMTOR2 was dispensable for the formation of autophagosomes targeting damaged membrane debris surrounding cytosolic bacteria, but it was critical for autolysosome formation, and LAMTOR2 interacted with the autophagy receptors NBR1, TAX1BP1, and p62 and was necessary for TAX1BP1 recruitment to pathogen-containing autophagosomes. Notably, knockout of TAX1BP1 caused a reduction in autolysosome formation and subsequent bacterial degradation. Collectively, our findings demonstrated that the LAMTOR1/2 complex is required for recruiting TAX1BP1 to autophagosomes and thereby facilitating autolysosome formation during bacterial infection. PMID- 30428164 TI - House passes AHCA, now fate of Obamacare is in the Senate. PMID- 30428166 TI - With CEO ousted, speculation grows Molina may be open to a takeover. PMID- 30428165 TI - Vanderbilt is a case study for the dreaded EHR conversion. AB - The new Epic system is being tailored for Vanderbilt's needs, butitremains standard enough to receive frequent company upgrades, while allowing clinicians and researchers to use a modern software system that won't feel foreign if they have to work with others outside of Vanderbilt. PMID- 30428168 TI - TOP 25 COOs IN HEALTHCARE 2017 Patricia Maryland: A COO ascends system's ranks. PMID- 30428167 TI - Fewer pharma rep visits linked to lower market share for their drugs. PMID- 30428169 TI - Shifting the mindset from being a hospital system to a health system. PMID- 30428171 TI - Outsider's question helps spur a health system COO's quest for safer patient care. AB - Sometimes it takes an outsider to point out an uncomfortable truth. I encountered that bit of wisdom early in my career, running my first hospital in central Indiana in the mid-1990s. PMID- 30428170 TI - End the slow-walk on payment reform. AB - Remember payment reform? Shared risk, bundled payments, global budgets-these baby steps are supposed to teach hospitals and physician practices how to stay on their feet financially while walking away from fee-for-service medicine. PMID- 30428172 TI - Getting to the root of loneliness. PMID- 30428173 TI - 'Our goal is to have zero serious safety events. If it's not zero, it's not acceptable'. AB - Charles Stokes, executive vice president and chief operating officer at Houston based Memorial Hermann Health System, recently began his term as chairman of the American College of Healthcare Executives. At the leadership society, Stokes will focus on providing educational tools and best practices that help the nation's healthcare organizations improve quality and accountability. He has a good personal track record. Two of Memorial Hermann's hospitals recently won the Malcolm Baldrige National Quality Award, presented every year to organizations that demonstrate excellence. Stokes was also named to Modern Healthcare's inaugural list of Top 25 COOs in Healthcare (p. 14). Modern Healthcare Southern Bureau Chief Dave Barkholz recently spoke with Stokes about his mission. The following is an edited transcript. PMID- 30428174 TI - Big Data Boot Camp. AB - Crash course invites experts from multiple fields to mingle in the world ofmedical data. PMID- 30428175 TI - Extreme measures Doctors are suffering QUALITY MEASUREMENT FATIGUE Is relief on the way?. PMID- 30428176 TI - WHERE WILL AI TAKE US? Westworld triggers reflections about radiology's future. PMID- 30428177 TI - PAGING DR. GOOGLE A patient's cyberchondriasis causes a physician to rethink her relationship with the web. PMID- 30428178 TI - Repeal without replacement is reckless. PMID- 30428179 TI - Power in numbers A math whiz explores big data's dark side. PMID- 30428180 TI - The Pokemon Go effect To motivate healthy behavior changes, take some cues from Pikachu and co. PMID- 30428181 TI - Reconsidering physician aid-in-dying As public opinion evolves, physicians and lawmakers should take note. PMID- 30428182 TI - ACA's fate will affect community health centers Repealing the Affordable Care Act would create repercussions for a significant component of Minnesota's health care safety net. PMID- 30428183 TI - Allergy, Asthma and Immunology Training in Internal Medicine Residents. AB - Common allergic conditions such as allergic rhinitis, asthma and antibiotic allergies are frequently encountered by internal medicine physicians. These conditions are a significant source of health care utilization and morbidity. However, many internal medicine residency programs offer limited training in allergy and immunology. Internal medicine residents' significant knowledge deficits regarding allergy-related content have been previously identified. We conducted a survey-based study to examine the knowledge and self-assessed clinical competency of residents at an academic medical center to determine the need for further education in allergy and immunology. Our study revealed that the majority of these residents did not feel adequately prepared to treat allergic rhinitis, urticaria, contact dermatitis, antibiotic/drug allergies or anaphylaxis; and only half felt adequately trained to treat asthma. We believe that internal medicine residency programs should provide trainees with additional education in allergy and immunology in order to improve their knowledge and clinical competency. PMID- 30428184 TI - Commentary: DON'T BLOW OFF AR Physicians should help patients with Rodney Dangerfield of respiratory diseases. PMID- 30428185 TI - Hospital-Treated Falls and Comorbidities Among Older Adults in Minnesota, 2010 2014. AB - Falls are a serious concern for older adults as they frequently result in injury, disability and even death. In older adults in Minnesota, the number and rate of hospital-treated falls have been increasing, for both males and females. The purpose of this study was to estimate trends in falls among older adults in Minnesota, and to examine whether there is an association between severe outcomes of falls and predictors. We investigated hospital-treated (both emergency department treatment and hospitalizations) falls among adults 65 years and older in Minnesota between 2010 and 2014, using hospital discharge data from the Minnesota Hospital Association. In total, 199,364 cases were identified; this represents a rate of 5,281.4/100,000 during the five-year period. We found the number of hospital-treated falls increased each year by 1,820 cases on average, for an average rate increase of 108.3/100,000 per year. The rate for falls with no comorbidities decreased, while the rate for falls with one or more comorbidities increased: Also, comorbidities were more likely among hospitalized and/ or fatal cases than among nonhospitalized and/or nonfatal cases. The most frequent principal injury diagnoses associated with falls included fractures (31.7% of total hospital-treated falls), superficial wounds/contusions (14.7%), open wounds (10.9%) and traumatic brain injuries (TBIs) (3.9%). The most frequent type of fracture was hip fracture (29.1 %). Additional complications commonly occurring during hospital treatment of injury resulting from a fall included urinarytract infection (7.2%), pneumonia (2.2%), pressure ulcer (1.2%) and sepsis (0.9%). Among these, sepsis had the highest odds ratio of 9.9 for death. These data show the burden of falls is greatest among those who are 85 and older and/or who have one or more comorbidities. PMID- 30428186 TI - What will it take to avoid a market meltdown as the GOP unravels Obamacare? PMID- 30428187 TI - The state of the ACA's risk corridors. PMID- 30428188 TI - Leaders prep for a post-ACA reality. PMID- 30428189 TI - High deductibles put some hospitals in a charitable mood. PMID- 30428191 TI - Back to abstinence-only for teens?. PMID- 30428190 TI - A tricky path to pay-for- performance drug pricing. PMID- 30428193 TI - Amid all the rhetoric over ACA repeal and replace, agenda must build on gains already achieved. PMID- 30428192 TI - Making 'more skin in the game' work. AB - Asking patients to have "more skin in the game" can work, but not through high deductible plans. Nearly 30% of the 150 million people in employer-based health insurance plans are now responsible for the first $1,000 or more of their healthcare costs. Most individual plans sold on the Obamacare exchanges have high deductibles. PMID- 30428194 TI - Blood draws without the needle. PMID- 30428195 TI - 'We have to be much closer to our customers'. AB - The movement from volume to value is a global phenomenon, according to Dr. Jan Kimpen, chief medical officer of Royal Philips in the Netherlands. The former chairman of University Medical Center Utrecht joined the company shortly after it shed its lighting division to become a pure healthcare technology provider. During the recent Radiological Society of North America trade show in Chicago, he spoke with Modern Healthcare reporter Adam Rubenfire about the changes underway in healthcare and at his new employer. The following is an edited transcript. PMID- 30428196 TI - Largest skilled-nursing providers Ranked by net revenue. PMID- 30428197 TI - Phytochemical Profile of Inula britannica from Bulgaria. AB - The flower heads of Inula britannica L. of Bulgarian origin afforded sesquiterpene lactones (gaillardin, britannin, I1, 13-dihydroinuchinenolide B, ivalin, pulchellin C), triterpenoids (3-0-palmitates of 160-hydroxylupeol, 16beta hydroxy-beta-amyrin, and faradiol) and flavonoids (quercetin, luteolin, luteolin 7-0- glucoside). All compounds are known and they were identified by spectral methods. The observed differences in the chemical content of the chloroform and methanol extracts were also reflected in their free radical scavenging activity, evaluated by DPPH and ABTS assays. Intraspecific variability of L britannica is discussed. PMID- 30428198 TI - Production of Delta7-Sterols from In Vitro Root Cultures of Endangered Gypsophila trichotoma. AB - Species from the genus Gypsophila are known for their medicinal, industrial and decorative applications. G. trichotoma Wend. is an endangered plant species for the Bulgarian flora according to the Red Data Book. Delta7-Sterols, which are unusual and rare in the plant kingdom, are present in the roots of this species. In previous studies different in vitro cultures were established from aerial parts of the species. The objective of this study was to explore the possibility for production of Delta7-sterols from in vitro cultured roots of G. trichotoma. The root cultures were grown on six modified MS media and the quantity of sterols was analyzed. These findings will serve to solve the important matter of the role of nutrients on sterols biosynthesis. PMID- 30428199 TI - Evaluation of Glaucine Content in Bulgarian Black Sea Coast Localities of Glauciumflavum Cranz. (Papaveraceae). AB - The content of the alkaloid glaucine was evaluated in Glaucium flavum plants from seven localities along the Bulgarian Black sea coast during two consecutive years, in order to select those with highest glaucine content. Some fluctuations of glaucine content were observed during the two years, and in most of the localities the alkaloid was lower in 2015. Pomorie and Ahtopol maintained high percentages of glaucine in the dry plant material in the two investigated years, being 2.3% for Pomorie in 2014 and for Ahtopol in 2015. The lowest percentages of glaucine were recorded in the plant material from Shkorpilovtsi (0.9% and 0.6%, respectively in 2014 and 2015). Fluctuations in glaucine content were probably due to some abiotic factors as light, temperature, precipitation, soil substrate, salinity, etc. PMID- 30428200 TI - Crataegus orientalis Leaves and Berries: Phenolic Profiles, Antioxidant and Anti inflammatory Activity. AB - The present study was designed to define the phenolic content, antioxidant and anti-inflammatory activity of Crateagus orientalis Pall. ex M. Bieb., traditionally used by local people in southern parts of F.Y.R. Macedonia. The presence and content of 7 phenolics in ethanolic extracts of leaves and berries were studied using HPLC-DAD, where the most dominant compounds were hyperoside, isoquercitrin and chlorogenic acid. The leaf extract was more effective as a DPPH radical scavenger (IC50 = 29.7 MUg/g) than the berry extract, as well as in the relative reducing power on Fe3+. Anti-inflammatory potential was studied by means of cyclooxygenase-1 (COX-1) and 12-lipoxygenase (12-LOX) inhibitory activity; both extracts evinced activity. Furthermore, C. orientalis leaf extract showed a concentration dependent inhibition of COX-1 pathway products 12-HHT and TXB2, reaching IC50 values below the lowest applied concentration (68.9% and 55.2% of 12-HHT and TXB2 production inhibition, respectively, at concentration of 0.4 mg/mL). Although inhibitors such as acetylsalicylic acid and quercetin showed higher activity, this study demonstrates that the investigated extracts are potential anti-inflammatory agents. PMID- 30428201 TI - Analysis of Antioxidant Polyphenols in Loquat Leaves using HPLC-based Activity Profiling. AB - Leaves of Eriobotryajaponica (loquat) have been used in Traditional Chinese Medicine with beneficial effects in numerous diseases. Extracts from loquat leaves are rich in antioxidants, containing among others: triterpenes, sesquiterpenes, flavonoids, tannins, and megastigmane glycosides. However, there is no conclusive study revealing which of these compounds are the main bioactive principles. The goal of this study was to pinpoint compounds responsible for strong antioxidant activity. Eriobotryaefolium was extracted and fractionated between solvents of increasing polarity. All extracts and fractions were screened for total polyphenols and tannins, and antioxidant activity was checked by DPPH, phosphomolybdenum and linoleic acid tests. The ethyl acetate fraction demonstrated the highest antioxidant activity and contained the largest amount of polyphenols. Applying HPLC-based activity profiling to localize antioxidants revealed that cinchonain IIb, as well as flavonoid glycosides such as hyperoside, isoquercitrin, kaempferol glycosides, quercetin-rhamnoside, as well as two tentatively identified protocatechuic acid derivatives are the main substances responsible for the strong antioxidant activity of the ethyl acetate fraction. PMID- 30428202 TI - LC/DAD/MS" and ICP-AES Assay and Correlations between Phenolic Compounds and Toxic Metals in Endemic Thymus alsarensis from the Thallium Enriched Allchar Locality. AB - Samples of Thymus alsarensis Ronniger, an endemic species for the Allchar locality, were evaluated for their polyphenolic composition and heavy metals. Allchar district is an abandoned antimony-arsenic-thallium deposit in the north west of Kozuf Mountain, R. Macedonia, with a unique mineral composition affecting the mineral composition of the flora. A systematic method for phenolic compounds characterization was developed using mass spectrometry coupled to HPLC/DAD. Analyses were focused on the polyphenolic compounds to establish a possible correlation to the region specific heavy metals As and TI in the different organs of T. alsarensis. Twenty-seven polyphenols: phenolic acid derivatives and flavonoid glycosides of luteolin, apigenin, quercetin, and kaempferol were detected; contents were higher in the leaves and flowers compared with stems and roots. Quinic acid (1), prolithospermic acid (6), salvianolic acid B (7), salvianolic acid A (8), monomethyl lithospermate (9), luteolin dihexoside (12), luteolin pentosyl-hexoside (14), luteolin acetyl pentosyl-hexoside (16), luteolin acetyl hexoside (17), luteolin dipentoside (21), luteolin pentoside (24), luteolin acetyl dipentoside (25), kaempferol pentosyl-hexoside (19) and kaempferol acetyl pentosyl-hexoside (22) were detected in T. alsarensis for the first time. To assay the content of As and TI, root, stem, leaf and flower samples were analyzed by inductively coupled plasma atomic emission spectrometry (ICP-AES). Significant accumulation of As and TI was observed with As content from 0.25 to 140 mg/kg and TI from 0.10 to 496 mg/kg. The content of As was much higher in the roots, while the content of TI was significantly higher in the roots, flowers and leaves in all T. alsarensis specimens. Comparison of the results obtained for total polyphenols and for As and TI content does not suggest any correlation (positive or negative) between the total phenolic content and the content of TI and As. On the other hand, it is evident that the soil rich with specific heavy metals (TI and As) affects the type of polyphenolic compounds produced in different organs, compared with other Thymus species growing on soil that is not contaminated. PMID- 30428203 TI - Ultrasound and Microwave-Assisted Extraction of Elecampane (Inula helenium) Roots. AB - The aim of the current research was to perform two "green chemistry" extractions (ultrasound and microwave irradiation) with methanol, 70% (v/v) ethanol and water for extraction of biologically active substances from elecampane (Inula heleniun L.) roots and to compare their contents in all extracts. The presence of carbohydrates (sugars, fructooligosaccharides and inulin), total phenols and flavonoids were established. In vitro antioxidant potential was also evaluated by four assays (DPPH, ABTS, FRAP and CUPRAC). Water extracts obtained by ultrasound assisted extraction (UAE) showed the highest value of inulin (38 g/100 g dry weight plant material). The highest antioxidant activity was possessed by the 70% (v/v) ethanol extracts obtained by UAE: DPPH - 107.2 mM TE/g dw, ABTS - 86.0 mM TE/g dw, FRAP - 67.0 mM TE/g dw and CUPRAC -173.0 mM TE/g dw, respectively. The reason for this probably depended on the highest content of total phenols in the 70% UAE ethanol extract (7.9 mg GAE/g dw, phenolic acids (chlorogenic, caffeic, p coumaric, sinapic and ferulic acids)}, especially chlorogenic acid (1.84 mg/g) and flavonoids (quercetin, kaempferol and catechin; 26.4 mg QE/g dw). UAE was evaluated as a promising approach for the simultaneous extraction of bioactive compounds (dietary fibers and antioxidants) from elecampane roots in comparison with microwave irradiation. PMID- 30428204 TI - ADME/Tox Properties and Biochemical Interactions of Silybin Congeners: In silico Study. AB - Silymarin, the active constituent of Silybum marianum (milk thistle), and its main component, silybin, are products with well-known hepatoprotective, cytoprotective, antioxidant, and chemopreventative properties. Despite substantial in vitro and in vivo investigations of these flavonolignans, their mechanisms of action and potential toxic effects are not fully defined. In this study we explored important ADME/Tox properties and biochemical interactions of selected flavonolignans using in silico methods. A quantitative structure activity relationship (QSAR) model based on data from a parallel artificial membrane permeability assay (PAMPA) was used to estimate bioavailability after oral administration. Toxic effects and metabolic transformations were predicted using the knowledge-based expert systems Derek Nexus and Meteor Nexus (Lhasa Ltd). Potential estrogenic activity of the studied silybin congeners was outlined. To address further the stereospecificity of this effect the stereoisomeric forms of silybin were docked into the ligand-binding domain of the human estrogen receptor alpha (ERa) (MOE software, CCG). According to our results both stereoisomers can be accommodated into the ERa active site, but different poses and interactions were observed for silybin A and silybin B. PMID- 30428205 TI - Comparative Study of Naphthoquinone Contents of Selected Greek Endemic Boraginaceae Plants - Antimicrobial Activities. AB - The cyclohexane (Ch) extracts of the roots of five Greek endemic Boraginaceae plants, Onosma kaheirei Teppner, 0. graeca Boiss., 0. erecta Sibth. & Sm., Alkanna sfikasiana Kit Tan, Vold and Strid and Cynoglossum columnae Ten, were investigated for the presence of alkannin/shikonin-related compounds. All species,s except C. columnae and 0. erecta, were found to contain this type of compounds. Seven compounds were obtained after several chromatographic separations from the Ch extracts of the investigated plants: deoxyalkannin (1), 2"-(S)-alpha-methylbutyrylalkannin (2), isobutyrylalkannin (3), propionylalkannin (4), acetylalkannin (5), beta-hydroxyisovalerylalkannin (6), and beta,beta dimethylacrylalkannin (7). All structures were identified by ID 1H-/13C- and 2D NMR spectroscopy, assisted also by ESI-MS. The extracts and the isolated compounds exhibiting an interesting antimicrobial profile when evaluated for their antimicrobial activity against six Gram-positive and -negative bacteria and three human pathogenic fungi. PMID- 30428206 TI - Effects of Gamma-Irradiation on the Antioxidant Potential of Traditional Bulgarian Teas. AB - Food irradiation technologies are used to reduce the risk of food bome diseases by eliminating pathogenic microorganisms, prolonging shelf life and reducing storage losses by delaying ripening, germination or sprouting. However, application of irradiation in food technology can negatively influence the biologically active compounds in foods. In this research, the effect of gamma irradiation on the antioxidant activity of Bulgarian teas was investigated. The aim of the study was to evaluate the total phenolic and tannin content and antioxidant activity of ethanolic extracts of Bulgarian herbal teas before and after gamma-irradiation. Mursalski tea (Sideritis scardica), Mashterka tea (Thymus serpyllum), Good Night tea (tea mix), Staroplaninski tea (Balkan tea mix), Trakia tea (tea mix), and Mountain tea (Planinski tea mix) were selected for this study. Gamma-irradiation was applied at the absorbed dose of 5 kGy. Antioxidant activity of non- irradiated and irradiated teas was determined by measuring antiradical activity against DPPH' and ABTS and the ability to reduce ferrous ions. The highest total-phenolic content was found in Mursalski tea (268 mg/g), and the highest tannin content in Good Night tea (168 mg/g). FRAP, TEAC and DPPH assays revealed that the most active samples were Staroplaninski (2.78 mmol Fe (II)/g), Planinski (0.87 mmol Trolox/g) and Planinski (0.032 mg/mL), respectively. The radical scavenging activity of irradiated tea samples was maintained after gamma-irradiation. The most interesting extract from irradiated tea studied was Staroplaninski, which demonstrated a higher antioxidant potential in the irradiated sample compared with the non-irradiated sample. PMID- 30428207 TI - Microelements and Heavy Metals Content in Frequently Utilized Medicinal Plants Collected from the Power Plant Area. AB - The effectiveness of medicinal plants is mainly associated with their active constituents, but one of the major quality problems frequently encountered is their high trace metals content that can be associated to extensive pollution of the environment where medicinal plants grow. Therefore the aim of this research was to evaluate the content of Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn and As in selected and frequently used medicinal plants, including chicory, broadleaf, common comfrey and dandelion. The plant material was collected from their wild habitats in the area of highly developed power plant activity during the summer of 2015. Plant analyses were done according to ICP methodology, using ICAP 6300 ICP optical emission spectrometer. The obtained results showed that the content of As, Cd, Co, Mn, Ni and Zn in the investigated medicinal plant species was below the maximum permissible concentration, while in all parts of all studied plants the concentration of Cr was toxic. The toxic concentrations of Cu were determined in root and aerial parts of chicory and common comfrey, and the toxic concentrations of Fe in root and aerial parts of dandelion and broadleaf plantain, and in aerial parts of common comfrey. However, high but not toxic content of Pb was found in aerial parts of chicory. It can be concluded that medicinal plants from the studied growing site are not appropriate for use in alternative medicine and that a determination of trace metals content in these plants must become a standard criterion for evaluation of their quality. PMID- 30428208 TI - Molecular Characterization of Verbascum anisophyllum (Scrophulariaceae) Genetic Resources Through Inter-Simple Sequence Repeat (ISSR) Markers. AB - Verbascum (Mullein) flowers are highly valued as natural remedy for various respiratory diseases. Verbascum anisophyllum Murb. is a Balkan endemic, protected by law and included in the Bulgarian Red Data Book as "Critically Endangered". Thus, a strict conservation policy and a reliable evaluation of its genetic resources are required, considering its narrow distribution range and the increasing risk from destruction of its habitats. Here, we used Inter-simple sequence repeat (ISSR) markers to characterize the genetic diversity and to assess the genetic differentiation between the existing populations of VerbascUM anisophyllum in Bulgaria. The level of genetic diversity found herein clearly indicates a long-term potential for adaptability of this endangered plant. Our findings provide important knowledge of population genetic structure of this species, thus representing a strategy for its efficient conservation and utilization. PMID- 30428209 TI - Effect of Drought and Salinity on Volatile Organic Compounds and Other Secondary Metabolites of Citrus aurantium Leaves. AB - Research was carried out in order to evaluate the effect of drought and salinity on Citrus aurantium L. plant physiological characteristics, total phenolic, flavonoid and ascorbic acid contents, and volatile organic compounds. C. aurantium plants were exposed to different levels of drought and salinity for an experimental period of 60 days. Moderate water deficit (MWD) and 100 mM NaCl increased significantly leaf total phenolic, flavonoid and ascorbic acid contents. Both drought and salinity promoted the accumulation of essential oil in leaves, while MWD and 100 mM NaCl resulted in the highest concentrations of essential oil. The main compounds of the essential oil were linalool, linalyl acetate, neryl acetate, geranyl acetate and a-terpineol. MWD and severe water deficit (SWD) reduced the concentration of hydrocarbon monoterpenes and promoted the accumulation of oxygenated compounds, while treatment with 50 and 100 Mi NaCl, promoted the accumulation of hydrocarbon monoterpenes and reduced oxygenated monoterpene concentrations in C. aurantium. PMID- 30428210 TI - Insights into the Essential Oil Compositions of Brazilian Red and Taiwanese Green Propolis. AB - The objective of the present study was to characterize chemically the essential oils of two distinct propolis types: Brazilian red and Taiwanese green. Unlike the non-volatile chemical composition of these types of propolis, which has been extensively studied, the knowledge of the essential oils is scarce or even not investigated. The essential oils were obtained by hydrodistillation of raw propolis samples using a Likens-Nickerson type apparatus and then analyzed by GC/MS. The main volatile components of Brazilian red propolis were the phenylpropanoids: elemicin (26.1-27.5%), methyl eugenol (16.3-23.8%), trans- methyl isoeugenol (9.2-11.6%), isoelemicin (6.1-7.1%) and trans-anethole (4.4 7.1%), while the major constituents of Taiwanese green propolis essential oil were: beta-eudesmol (13.9%), 6-methyl-3,5-heptadiene-2-one (12.2%), y-eudesmol (4.4%), geranial (4.1%) and 6-methyl-5-heptene-2-one (3.7%). PMID- 30428211 TI - Essential Oil Content, Composition and Bioactivity of Juniper Species in Wyoming, United States. AB - The objective of this study was to evaluate variations in leaf essential oil (EO) content and composition of Juniperus species in the Bighorn Mountains {J comimunis L. (common juniper), J. horizontalis Moench. (creeping juniper), and J scopulorum Sarg. (Rocky Mountain juniper)} in Wyoming, USA. The EO was extracted via steam distillation of fresh leaves (needles). The EO composition of the three Juniper species varied widely. Overall, the essential oil content of fresh leaves was 1.0% (0.4-1.8% range in different accessions) in J. communis, 1.3% (1.2 to 1.6% range) in J. horizontalis, and 1.1% (0.7-1.5% range) in J. scopulorln. The EO chemical profile of J. communis was very different from that of the other two species. The concentration of alpha-pinene in the oil was 67- 80% in J. communis, 2.8-6% in J. horizontalis, and 2.3-13% in J. scopulorun. The concentration of sabinene was 57-61% of the oil of J. horizontalis and 13- 59%. in oil of J. scopulorum, whereas sabinene was either below 1% or not detected in J. communis. The oils of J scopulorm and J horizontalis had higher antioxidant capacity than that of J. communis. The oils of the three junipers did not show significant antimicrobial activity against 10 organisms. The diversity of the essential oil composition of these three junipers may encourage diverse industrial applications of Juniperus leaf essential oil. PMID- 30428212 TI - Chemical Composition and Antibacterial Activity of Angelica archangelica Root Essential Oil. AB - Roots of wild growing Angelica archangelica L. from Mt. Ozren (Serbia) were subjected to hydrodistillation and GC-MS analysis. The roots contained 0.10% of essential oil with a-pinene (29.7%), 8-3-carene (14.2%), and a mixture of P phellandrene and limonene (13.2%) as main compounds. The modified resazurin microtiter-plate assay was used to evaluate the antibacterial activity of the essential oil against Staphylococcus aureus and Escherichia coli. The minimum inhibitory concentration (MIC) values were 14.2 MUL/mL for S. aureus and 28.4 MUL/mL for E. coli, while the minimum bactericidal concentrations (MBC) were 56.8 MUL/mL and 113.6 MUL/mL, respectively. According to the obtained results, the angelica root essential oil can be applied as a natural preservative in food and as a natural antibiotic for the treatment of several infectious diseases caused by these two bacteria. PMID- 30428213 TI - Gas Chromatography-Mass Spectrometry (GC-MS) Combined with Retention Index Prediction for the Rapid Identification of Halogenated monoterpenes from a Namibian Plocamium species. AB - Plocamiun species collected from the Namibian coast display morphological features similar to those of both P. rigidum and P. suhrii which makes identification of these species a difficult task. It has been reported that the major secondary metabolites found in various Plocamium species are unique to each species [1]. In this study GC-MS combined with a retention index (RI) prediction strategy was used for the rapid identification of halogenated monoterpenes characteristic of a particular Namibian Plocatnium species. The RIs of the metabolites were matched with the predicted RIs of halogenated monoterpenes for which similar MS data have been reported for the same species of Plocamium. Based on the identification of the major secondary metabolite, IE,3R,4S,5E,7Z- 1-bromo 3;4,8- trichloro-7-(dichloromethyl)-3-methylocta-1,5,7-triene [2], it was proposed that these Namibian samples are closely related to that of P. suhrii. From. this, it was determined that the proposed P. suhrii specimens collected in Namibia contain four additional metabolites (with molecular formulae C10H16Br2C2, C10H11BrCI4, C10H9BrCl6 and an unknown compound) previously not reported in P. suhrii species. In addition, a compound previously identified in South African P. suhrii was not present in the Namibian Plocamium specimens. PMID- 30428214 TI - Rapid and Efficient Extraction and HPLC Analysis of Sesquiterpene Lactones from Aucklandia lappa Root. AB - The root of Aucklandia lappa Decne, family Asteraceae, is widely used in Asian traditional medicine due to its sesquiterpene lactones. The aim of this study was the development and optimization of the extraction and analysis of these sesquiterpene lactones. The current Chinese Pharmacopoeia reports a monograph for "Aucklandiae Radix", but the extraction method is very long and tedious including maceration overnight and ultrasonication. Different extraction protocols were evaluated with the aim of optimizing the maceration period, solvent, and shaking and sonication times. The optimized method consists of only one hour of shaking plus 30 minutes of sonication using 100% MeOH as solvent. 1H NMR spectroscopy was used as a complementary analytical tool to monitor the residual presence of sesquitepene lactones in the herbal material. A suitable LC-DAD method was set up to quantify the sesquiterpene lactones. Recovery was ca. 97%, but a very high instability of constituents was found after powdering the herbal drug. A loss of about 20% of total sesquiterpenes was found after 15- 20 days; as a consequence, it is strongly endorsed to use fresh powdered herbal material to avoid errors in the quantification. PMID- 30428215 TI - Antimalarial Activity of some Kaurenes. AB - The antirnalarial activity of sixteen ent-kaurenes was assayed on male albino mice infected with Plasmodium berghei. Ent-kaur-16-en-19-oic acid (kaurenic acid), l5ialpha-hydroxy- ent-kaur-16-en-19-oic acid, 15alpha-acetoxy- ent-kaur-16 en-19-oic acid, and ent-kaur-9(11)16-en-19-oic acid, natural kaurenes isolated from two species of Espelletiinae, were modified by semisynthesis to obtain methyl esters, glucopyranosyl esters, epoxides, 17-hydroxy, and isokaurenes (compounds with a 15,16-double bond). The kaurenes were first submitted to an in vitro test to measure their capacity to inhibit the formation of beta-hematin. Compared with chloroquine (95.7%), the best effect was shown by 16,17-epoxy-ent kauran-19-oic acid alpha-D- glucopyranosyl ester (2a), which produced 92.6% inhibition. Three other kaurenes showed good inhibition levels: ent-kaur- 16-en-I 9-oic acid (1a, 73.5%), 17-hydroxy- ent-kaur- I5-en-19-oic acid methyl ester (3b, 76.5%), and 15-oxo-16,17-epoxy-ent-kaur-16-en-19-oic acid (X-D-glucopyranosyl ester (4b,76.1%). These four compounds were assayed in a four day suppressive test in vivo (Peters' test) using chloroquine as a positive control. Two hours after infection the mice received the first treatment and then every 24 hours during four consecutive days. Blood smears from the tails were prepared on the fourth day and parasitemia was determined microscopically. Survivals were followed up to the 30th day post-infection, Once again compound 2a performed best, showing 4.5% of parasitemia on the fourth day post-infection (chloroquine 0.2%) and a survival time of 25.5 days (chloroquine 29.5 days; la 18.8 days, 4b 12.7 days and 3b 10.3 days). A comparative examination of the effect of all compounds on the in vitro test permitted the inference that the presence of a C- 19 carboxylic moiety was a requirement for the antimalarial activity and that a 16,17 epoxy group enhanced such activity. PMID- 30428216 TI - Briarenol B, a New Polyoxygenated Briarane from the Octocoral Briareum excavatum. AB - A new polyoxygenated briarane diterpenoid, briarenol B (1), was isolated from the octocoral Briareum excavatun and its structure determined from spectroscopic data. In RAW264.7 cells, a macrophage-like murine cell line, briarane B (1) was found to enhance the protein expression of pro-inflammatory cyclooxygenase (COX 2) and inducible nitric oxide synthase (iNOS) in cells stimulated by lipopolysaccharide (LPS). PMID- 30428217 TI - Triterpenes with Anti-invasive Activity from Sclerotia of Inonotus obliquus. AB - The methanolic extract [inhibition (%): 61.2+/-3.8 (p<0.01) at 100 MUg/mL] and its EtOAc-soluble fraction [inhibition (%): 82.5+/-1.7 (p<0.01) at 100 MUg/mL1 from the sclerotia of Inonotus obliquus collected in Japan significantly inhibited invasion of human fibrosarcoma HT1080 cells through matrigel-coated filters. In addition, the methanolic extract significantly inhibited lung tumor formation fifteen days after injection of BI6F10 melanoma cells in mice [inhibition (%) 66.1 +/- 12:8 (p < 0.05) at 500 mg/kg/d, p.o.]. Lanostane-type triterpenes were isolated as the common principal constituents from Japanese and Russian . obliquus. Furtheremore, we examine the inhibitory effects of the constituents on the invasion of HT 1080 cells. Interestingly, 3beta hydroxylanosta-8,24-dien- 21-al [inhibition (%) 37.9 +/- 3.0 (p < 0.05) at 30 MUM] significantly inhibited the invasion, and no cytotoxic effect at 30 MUM was observed. PMID- 30428218 TI - A New Cytotoxic Cyclolanostane Triterpenoid Xyloside from Souliea vaginata. AB - A new cyclolanostane triterpenoid xyloside, soulieoside P (1), and a known oleanane-type saponin, hederasaponin B (2), were isolated from the rhizomes of Souliea vaginata. Their structures were established by extensive spectroscopic and HRESIMS analysis, as well as chemical methods. Compound 1 showed significant inhibitory effects with IC50 values of 7.6-11.2 MUM against three human cancer cell lines, while compound 2 exhibited no hepatoprotective effect on CCI4-induced injury of human HepG2 cells, in the tested range of 0.1-100 MUM. PMID- 30428219 TI - Polyhydroxy Sterols Isolated from the Red Sea Soft Coral. Lobophytum crassum and their Cytotoxic Activity. AB - One new (1) together with four known sterols (2 - 5) and a sesquiterpene (6) were isolated from a polar extract of the Red Sea soft coral Lobophytum crassum. The compounds were identified as 24-methylenecholest-5-ene-lalpha,3beta,1lalpha-triol 1-acetate (1), 24-methylenecholest-5-ene-la,3beta,llalpha-triol (2), 24- methylenecholest-5-ene-3beta-ol (3), 24-methylenecholestane la,3beta,5alpha,6beta,I la-pentol (4), 24-methylenecholestane-3beta,5alpha,6beta triol (5) and alismoxide (6) based on extensive NMR analysis. The cytotoxicity of compounds 1 - 6 was evaluated in vitro using three human cancer cell lines viz., HepG2, Hep-2 and HCT-I 16. Compound 1 showed selective cytotoxic activity against HepG2, while 3 exhibited cytotoxicity against all tested cell lines. PMID- 30428220 TI - Raphanus sativus Sprout Causes Selective Cytotoxic Effect on p53-Deficient Human Lung Cancer Cells in vitro. AB - Raphanus sativus L. (Brassicaceae) is widely consumed in many different forms worldwide. Its sprouts, in particular, are commonly consumed as a health food. R. stivus sprout has recently been shown to have anti-tumor activity on human colon cancer cells, suggesting that it may have potential use in.cancer prevention and treatment. The extent of this anti-tumor activity and its underlying mechanisms, however, remain to be investigated in other types-of cancer cells. In this study, we showed that the MeOH extract from R. sativus sprout exhibits significant but variable cytotoxic effects on human lung adenocarcinoma cells depending on their p53 status. The MeOH extract decreased the viability of p53-deleted human lung cancer cells (H1299 and Calu-6) by inducing apoptosis; this effect, however, did not occur for wild-type p53 cancer cells (A549), for cells expressing a p53 mutant lacking the C terminus (H1264), or for . non-tumor fibroblast cells (NIH3T3). Phytochemical analyses of the MeOH extract allowed us to identify and isolate 0-sitosterol as a major component of the MeOH extract. Direct treatment with P-sitosterol significantly reduced the viability of Calu-6 cells, suggesting that it may, in part, contribute to R. sativus sprout's anti-tumor activity. This work provides experimental evidence for a novel biological application of R. sativus sprout in treating human lung cancer, and it identifies the main component involved in this effect, further supporting its potential use as a functional food for cancer management. PMID- 30428221 TI - Preparative and Rapid Purification of Saponins from Asparagus racemosus Root by High Performance Centrifugal Partition Chromatography. AB - High performance centrifugal partition chromatography (HPCPC) was applied to the rapid isolation and purification of saponin glycosides in Asparagus racemosus Willd. root. A two-phase solvent system composed of CHC13-MeOH-water (4:4:2, v/v) in descending mode was used for the separation, yielding shatavarin.IX (1) and asparacoside (2) in one step. Asparanin A (3) and shatavarin V (4) were separated by repeated HPCPC fractionation using CH2Cl2- MeOH-water (4:4:2, v/v) as the solvent system, followed by either gel-filtration or TLC. Their structures were identified by NMR spectroscopy and ESI/MS'- The A. racemosus extracts and 1, 2, 3 and 4 were cytotoxic towards human hepato- and prostate-carcinoma cell lines (IC50 14-37 MUM), while primary human fibroblasts were less vulnerable (IC50 22 66 MUM), i.e., every saponin glycoside showed selectivity towards carcinoma cells compared with normal fibroblasts. HPCPC has proven rapidity to separate complex mixtures of phytochemicals yielding quantities suited to biological studies. PMID- 30428222 TI - AKR1C3 Inhibitory Potency of Naturally-occurring Amaryllidaceae Alkaloids of Different Structural Types. AB - Aldo-keto reductase 103 (AKRIC3) is an important human enzyme that participates in the reduction of steroids and prostaglandins, which leads to proliferative signaling. AKRIC3 is frequently upregulated in various cancers, and this enzyme has been suggested as a therapeutic target for the treatment of these pathological conditions. The fact that the isoquinoline alkaloid stylopine has been identified as a potent AKRIC3 inhibitor has prompted us to screen a library of diverse types of Amaryllidaceae alkaloids, which biogenetically are isoquinoline alkaloids, on a recombinant form of AKRIC3. From the tested compounds, only tazettine showed moderate AKRIC3 inhibitory potency with an IC5o value of 15.8 ? 1.2 pM. Tazettine is a common Amaryllidaceac alkaloid, which could be used as a model substance for the further development of either analogues or related compounds with better inhibition potency. PMID- 30428223 TI - Product Selectivity of Esterification of L-Aspartic Acid and L-Glutamic Acid Using Chlorotrimethylsilane. AB - TMSCI works as an acid catalyst precursor for selective esterification of L aspartic and L-glutamic acids in the presence of primary, secondary and tertiary alcohols. Although excess TMSCI was required for the completion of esterification, the resulting alkyl TMS ether could be azeotropically removed by simple evaporation with alcohol. PMID- 30428224 TI - Chemical Constituents of the Roots and Rhizomes of Saposhnikovia divaricata and their Cytotoxic Activity. AB - Phytochemical investigation of the MeOH extract of the roots and rhizomes of Saposhnikovia divaricata (Umbelliferae) resulted in the isolation of six chromons (1-6)-and five polyacetylene derivatives (7-11). Compounds 9 and 11 were isolated from S. divaricate for the first time. The chromon derivatives -(1-6) were evaluated for their cytotoxic activity against HL-60 human promyclocytic leukemia cells. Compound 1 (3'-O-angeloylhamaudol) showed the most potent cytotoxic activity with an IC50 value of 4.41 MUM and was found to induce apoptotic cell death in HL-60 cells. The loss of mitochondrial membrane potential, release of cytochrome c into the cytoplasm, and activation of caspase-9 in the 1-treated HL 60 cells suggests that I induces apoptosis through the mitochondial-dependent apoptotic pathway. PMID- 30428225 TI - Cytotoxic Activity of Compounds from Styrax obassia. AB - Cancer is a major public health burden in both developed and developing countries. Plant-derived compounds have played an important role in the development of useful anti-cancer agents. The current study was designed to evaluate the cytotoxic activity of chemical compounds from the stem bark of Styrax obassia. Seven known compounds (1-7) were isolated and identified. Compound 2 exhibited cytotoxic activity against the breast cancer cell line MCF-7 with an IC550 of 27.9 MUM, followed by the human cervical cancer cell line Hela with an IC50 of 23.3 MUM, and the human promyelocytic leukemia cell line HL-60 with an IC50 of 47.8 RM. Compound 7 exhibited cytotoxicity against Hela cells with an ICso of 16.8 pM, followed by MCF-7 cells with an IC50 of 53.5 MUM. This is the first study to investigate the significant anti-tumor properties of isolated compounds from the stem bark of S. obassia. PMID- 30428226 TI - Isolation and Characterization of Antiangiogenesis Compounds from the Fungus Aspergillus terreus Associated with Apostichopus japonicus Using Zebrafish Assay. AB - Three compouds, (+)-butyrolactone IV (1), butyrolactone I (2) and terrelactone A (3) were isolated from the fungus Aspergillus terreus associated with Apostichopusjaponicus from the Yellow Sea in China; their structures were elucidated by spectral methods. Compounds I and 2 were shown to have moderate antiangiogenesis activity when tested using-the zebrafish assay. This is the first report of butyrolactones with antiangiogenesis activity. PMID- 30428227 TI - Adsorptive Property of Food Materials and Chemicals to Cesium and Strontium. AB - In March, 2011, large amounts of radioactive materials were released from the Fukushima Daiichi nuclear power plant after the nuclear accident. Especially, for humans, internal exposure to 137Cs and 90Sr radionuclides presents very high risks because of their very long physical half-lives (137Cs: 30.2 years, 90Sr: 28.9 years). Therefore, it is important to inhibit the absorption of radioactive materials and to promote the excretion of them from the body through feces. The aim of this.study was to explore foods, their components and various chemicals showing adsorption properties to Cs and Sr. Sodium alginate (ALA-Na) strongly adsorbed Cs and Sr compared with other samples. Chondroitin sulfate, carboxymethyl cellulose sodium (CMC-Na), methyl cellulose (MC) and apple polyphenols (AP; high molecule weight) also showed adsorption potency to Cs in that order. For Sr adsorption, kelp, CMC-Na, MC, AP (high molecule weight), laminaran and Jew's mallow exhibited adsorbing effects in that order. These samples might be useful and safe tools to protect from the adverse effects induced by internal exposure to these radioactive materials. PMID- 30428228 TI - ermination and Clonal Propagation of the Endemic Shrub Corema album, a ulnerable Species with Conservation Needs and Commercial Interest. AB - In this study, we aimed to explore regeneration possibilities of Corema album (L.) D. Don by determining germination mechanisms and testing vegetative propagation methods. We analyzed seed viability under natural conditions, carried out germination treatments and a greenhouse experiment to study clonal propagation. We confirmed that C. album seeds present physiological dormancy, broken by ingestion by natural dispersers (rabbits and foxes), and that seed viability under natural conditions is lost after one year. In vitro germination was better achieved with a 200 ppm gibberellic acid treatment. Clonal propagation proved to be a successful technique for the production of C. album. Treating cuttings with IBA 0.2, w/v, at 20% resulted in the highest rooting percentage, while planting rooted cuttings in a substrate of perlite with vermiculite 1:1 was essential for plant survival. Our results show that both germination pretreatments and cutting propagation are powerful tools for the production of this valuable species. Both methods could be incorporated for population regeneration in natural habitats, and for the potential establishment of the species as a new crop for consumption and pharmacological purposes. PMID- 30428229 TI - Essential Oil Profile, Phenolic Content and Antioxidant Activity of Geranium kikianum. AB - This work presents the first phytochemical investigation of Geranium kikianum Kit Tan & G. Vold (Geraniaceae), a species endemic to the southern Peloponnese, Greece. The essential oil from aerial parts of the plant was isolated by hydrodistillation and its chemical composition characterized by GC-MS. A total of 26 compounds were identified, constituting 98.3% of the oil composition. Oxygenated sesquiterpenes were the main group of constituents (75.4%). The major component of the oil was the sesquiterpene ketone germacrone (45.6%). Eleven alcohols represented the most diverse chemical class in the volatile oil (36.3%), and phytol was the most abundant acyclic diterpene alcohol (11.4%). The volatile compounds and residual water remaining after hydrodistillation were screened for their radical-scavenging activity by the DPPH method. IC50 values ranged from 0.2+/-0.03 mg/mL for the undiluted decoction to 69.7+/-0.5 mg/mL for the essential oil. The significant antioxidant activity of the residual water, comparable with that of the widespread synthetic antioxidant BHT. (0.2+/-0.01 mg/mL), and almost tenfold higher than thymol (1.90 t 0.04 mg/mL), correlates with a high content of total phenolic compounds (100.2+/-1.7 mg GAE/g), and flavonoids (11.9+/-1.2 mg GAE/g). PMID- 30428230 TI - Integrated Analysis of the Bark Oil from Cinnamosma madagascariensis by GC(RI), GC-MS and NMR. 13C NMR data of Cyclocopacamphene and Cyclosativene. AB - The composition of leaf and bark oils of Cinnamosma madagascariensis has been investigated by a combination of GC (RI), GC-MS and 13C NMR. The leaf oil contained mainly monoterpenes: myrcene (17.9%), limonene (17.8%), Q-phellandrene (15.3%) and linalool (12.2%). The bark oil, investigated for the first time, contained P-pinene (49.9%) and a-pinene (19.5%) as major components. Special attention was paid to the identification of cyclocopacamphene, an epimer of cyclosativene. 3C NMR data of both compounds have been provided. PMID- 30428231 TI - Synergistic Activity of Essential Oils from Herbs and Spices Used on Meat Products against Food Borne Pathogens. AB - Essential oils (EOs) could be utilized as natural agents to improve the safety of meat products. However, the high concentration required to achieve an antimicrobial effect in foods might be incompatible with their sensory acceptance. To avoid this problem, combinations of EOs provide an effective approach reducing the odds of sensory rejection. In our study, 13 EOs of herbs and spices commonly used in the seasoning of meat products were assessed for their antimicrobial activity against Salmonella spp., Listeria monocytogenes, Escherichia coli and Staphylococcus aureus. However, only 7 of them were selected to study their synergistic effect based on their antimicrobial activity and minimum inhibitory concentration (MIC) against foodborne pathogens. EOs of thyme and cinnamon presented the largest antibacterial activity against foodborne pathogens. Combinations of selected EOs displayed a synergic effect against foodborne pathogens and also an important decrease in their individual MIC. Thyme EO presented the lowest individual MIC, but its utilization in combination decreased the MIC of the other EOs. Utilization of cinnamon EO also improved the reduction of the individual MICs of the EOs of cumin and parsley. Our results suggest the potential use of EO mixtures to control foodborne pathogens in meat products. Although the individual MIC values of selected EOs decreased, the sensory impact on meat products needs to be assessed. PMID- 30428232 TI - Composition, in vitro Cytotoxicity, Anti-mildew and Anti-wood-decay Fungal Activities of the Fruit Essential Oil of Liquidambarformosana from Taiwan. AB - This study investigated the chemical composition, in vitro cytotoxicity, anti mildew, and anti-wood-decay fungal activities of the essential oil isolated from the fruit of Liquidainbar formosana from Taiwan. The essential oil from the fresh fruit was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. A total of 45 compounds were identified, representing 98.5% of the essential oil. The main components identified were a pinene (16.8%), beta-caryophyllene (10.1%), tau-muurolol (8.3%), tau-cadinol (7.6%), beta-pinene (6.7%), and sabinene (5.7%). The essential oil exhibited cytotoxic activity against human oral, liver, and lung cancer cells. The active source compounds were beta-caryophyllene, tau-cadinol, and tau-muurolol. The fruit essential oil was shown to have excellent anti-mildew and anti-wood-decay fungal activities, the active compounds being evaluated as tau-cadinol and tau muurolol. PMID- 30428233 TI - Chemical Composition and Antibacterial Activity of the Bulgarian Endemic Species Achillea thracica from its Natural Habitat, and in vitro Propagated and ex vitro Established Plants. AB - The present study reports the chemical composition of headspace volatiles (HS) and acetone extracts of the endemic Bulgarian species Achillea thracica Velen. from its natural habitat (N), in vitro propagated (IN) and ex vitro established (EX) plants. Additionally, acetone extracts were tested by a disk diffusion method for antibacterial activity. Irregular monoterpenes were the most abundant HS volatile constituents, while 0,0-dimethyl quercetin was the most abundant flavonoid in the acetone extracts. The secondary metabolites of A. thracica grown in its natural habitat (N), propagated in vitro (IN) and ex vitro established (EX) showed that the qualitative composition is mutually similar, but there are differences in the quantitative composition. Considering antibacterial activity, IN and EX samples showed moderate activity against Pseudomonas aeruginosa and Escherichia coli. PMID- 30428234 TI - In vitro and in vivo Methods for the Evaluation of Natural Products against Dermatophytes. AB - Dermatomycoses are infections caused by fungi called dermatophytes; these affect 20-25% of the world population and the incidence continues to grow each year. Recently, an alternative for the treatment of these diseases is the use of natural products, thanks to the fact that they possess great chemical diversity and thus biological activity. However, to understand the therapeutic potential of natural products, their microbiological assessment presents certain limitations. Currently, there is no established reference method to determine the antifungal capacity in vitro and in vivo of natural products (i.e., essential oils). This review focuses on describing the various microbiological methods as well as the many adaptations used to evaluate the antifungal activity of natural products both in vitro and in vivo. In addition, the antifungal evaluation of natural products formulated in creams, gels, nanoemulsions, nanocapsules and solid lipid nanoparticles is included. PMID- 30428235 TI - Chemistry and Pharmacology of Tinospora cordifolia. AB - Tinospora cordifolia (Menispermaceae) is an Ayurvedic medicinal plant distributed throughout the Indian subcontinent and China. The whole plant is used in folk and the Ayurvedic system of medicine alone and in combination with other plants. Due to its commercial importance, T. cordifolia has been of intense research interest for the last four decades with the isolation of diverse compounds such as alkaloids, sesquiterpenoids, diterpenoids, phenolics, steroids, aliphatic compounds and polysaccharides, along with the discovery of a wide spectrum of pharmacological properties like immunomodulation, anticancer, hepatoprotective and hypoglycemic. Although pharmacological activities of extracts and compounds of T. cordifolia have been studied both in vitro and in vivo, only few mechanisms of action have been explored and need further elaboration. In the present review, the pharmacological activities of compounds and different extracts of T. cordifolia are highlighted, along with those of the marketed products, showing the relevance of phytochemicals and the standardization of the marketed products for medicinal use. This compilation of the extensive literature of T. cordifolia here will be a referral point for clinical study and the development of standardized phytomedicines in healthcare. PMID- 30428236 TI - Perspectives of the Apiaceae Hepatoprotective Effects - A Review. AB - The liver has the crucial role in the regulation of various physiological processes and in the excretion of endogenous waste metabolites and xenobiotics. Liver structure impairment can be caused by various factors including microorganisms, autoimmune diseases, chemicals, alcohol and drugs. The plant kingdom is. full of liver protective chemicals such as phenols, coumarins, lignans, essential oils, monoterpenes, carotenoids; glycosides, flavonoids, organic acids, lipids,- alkaloids and xanthenes. Apiaceae plants are usually used as a vegetable or as a spice, but their other functional properties are also very important. This review highlights the significance of caraway, dill, cumin, aniseed, fennel, coriander, celery, lovage, angelica, parsley and carrot, which are popular vegetables and spices, but possess hepatoprotective potential. These plants can be used for medicinal applications to patients who suffer from liver damage. PMID- 30428237 TI - Eurasian Tunnel Project: the first saturation dives during compressed-air work in Turkey. AB - The Eurasian Tunnel is a 5.64-km crossroad tunnel that connects Europe and Asia. Located under the seabed for the first time, 3.34 km of the tunnel that crosses the Bosphorus was built by advanced tunneling techniques. An exclusively designed tunnel boring machine (TBM), which has an operating pressure of 11 bars and a diameter of 13.7 meters was used for boring the seabed tunnel. The deepest point was 106 meters below sea level. One bounce diving period and seven saturation diving periods were needed for the repair and maintenance of the TBM during the project. Total time spent under pressure was 5,763 hours. A saturation decompression chamber for four divers was used for the saturation interventions, and divers breathed trimix at storage and excursion depths. The longest saturation run was the second, with storage at 10 bars and excursions to 10.4 bars. Twenty-three professional divers who were all experienced in compressed-air work were assigned to work on the project. Four dive physicians provided medical support, which included screening of divers before and during the hyperbaric interventions as well as on-site supervision. There were no diving-related accidents. A minor hand trauma, an external otitis and occasional insomnia were non-diving-related health issues that occurred during saturation and bounce diving. To our knowledge, the Eurasian Tunnel was the first project to perform TBM repair operations at such depths under the seabed and the first saturation diving in Turkey. In this report, we aimed to share our experiences of hyperbaric medical consulting in support of this type of tunneling project. PMID- 30428238 TI - Effect of rehydration schedule after four-hour head-out water immersion on running performance and recovery. AB - Introduction: Head-out water immersion (HOWI) results in diuresis, which could potentially limit performance after egress to land. We examined the effect of rehydration on endurance, cardiovascular stability, and overnight recovery following a four-hour thermoneutral HOWI on 12 subjects. Methods: Twelve males completed a crossover design consisting of no hydration, replacement of fluid loss during immersion (RD), and replacement of fluid after the immersion period (RA). Sixty minutes following immersion, subjects ran to exhaustion at ~80% maximum heart rate. After completing the run, each subject submitted to a head-up tilt test (HUTT). Vital signs and ECG were monitored overnight. Results: HOWI resulted in a transient diuresis in NH and RA, while it was sustained throughout immersion in the RD protocol, resulting in greater urine [l] output (1.27 +/- 0.48 (NH), 1.18 +/- 0.43 (RA), 2.32 +/- 0.77 (RD) (p ? 0.001). Body mass change (%) was greater in NH than RD, but not RA (-1.58 +/- 0.56 (NH), -0.66 +/- 0.47 (RD), and -0.92 +/- 0.76 (RA)). Run times were 17% versus 20% in NH compared to RD and RA, respectively, but were not statistically different. Time to orthostasis during the HUTT did not differ by condition. Overnight heart rate variability and blood pressures were not different. Conclusion: Rehydration during water immersion resulted in a large, sustained diuresis without improving performance or recovery after exiting the water. Loss of body water during thermoneutral HOWI was modest, and both rehydration strategies minimally affected aerobic performance and overnight recovery in young, healthy males. PMID- 30428239 TI - The panic triangle: onset of panic in scuba divers. AB - Panic arising from physical or psychological stress is a common issue in reported incidents and accidents in scuba diving. Due to its effect on perception, thinking and diver behavior, the panic reaction is often a significant factor in the generation or escalation of problems, potentially leading to injuries and fatalities. The instinctive behaviors associated with panic are incompatible with the constraints of scuba diving (e.g., flight response to threat, leading to rapid ascent). Although the dangers are well known, the psychological mechanisms of panic and the implications for prevention/risk reduction are not sufficiently highlighted to recreational divers. In applied psychology, there are grounded theoretical models which describe the onset and maintenance of anxiety and panic, and an evidence base for approaches to anxiety management. For example, these models are used within structured psychological approaches for people experiencing anxiety disorders; and panic attacks are resolvable. Based on these models and underlying theory, this article proposes a new, accessible model for panic in divers. The potential uses of the model are to: (1) provide a simple framework for divers to understand the onset of panic; (2) promote the need for adequate training; (3) describe the importance of staying within training standards, qualifications and personal limitations; (4) support diver and dive educator understanding of individual factors in panic reactions (e.g. psychiatric conditions) placing greater emphasis on psychological fitness to dive; and (5) draw attention to approaches to improved regulation of emotion and promote individual responsibility. PMID- 30428240 TI - Updates in diving medicine: evidence published in 2017-2018. AB - This report summarizes some of the most relevant studies during the 2017-2018 academic year of scientific literature for diving medicine. The article selection is the result of a PubMed search for "diving," as well as a manual review of the journals Undersea and Hyperbaric Medicine and Diving and Hyperbaric Medicine. Four articles were published reporting on new advances in decompression modeling. New consensus guidelines in the prehospital treatment of decompression sickness were published as well as a retrospective review of the efficacy of the U.S. Navy Treatment Tables. Several articles were published this year researching cardiovascular health and fitness to dive. A novel approach by one occupational medicine clinic for referral for hypertension may allow for early intervention of the "silent killer." Application of the Framingham risk score to commercial divers does not result in an excessive number of disqualifications. The controversy over screening and subsequent repair of a patent foramen ovale in divers was heavily researched this past year. Several groups reported their experience with closure and associated risks. Subjects diving with pre-existing conditions were surveyed and found to be fairly common, with seemingly little ill effect (albeit with a potential survivor bias). Recommendations for diving while using antidepressants were reported. Several articles were published utilizing point of care ultrasound in the diagnosis of immersion pulmonary edema (IPE). One case of a using sildenafil as a preventative medication in a triathlete with an extensive history of IPE may prove promising for further research. Finally, an extensive review article pertaining to hypercapnia in diving was published as well as the use of pulse oximetry as an early warning system to prevent hypoxia in rebreather divers. PMID- 30428241 TI - Fatty acids and sphingolipids profile in the blood plasma of experienced divers in response to hyperbaric exposure. AB - Introduction: Hyperbaric exposure mimics air-breathing scuba diving, which is reaching enormous popularity around the world. The diver's body is subjected to a broad range of divergent effects exerted by, e.g.: an increased partial pressure of inert gases, microclotting, oxidative stress and/or production of gas bubbles. However, very little is known regarding the impact of hyperbaric exposure on plasma fatty acids content and composition, together with the body's sphingolipids profile. Material and Methods: The aim of this study was to investigate the contents of major fatty acids present in the plasma as well as sphingolipids, namely: sphingosine (SPH); sphingosine-1-phosphate (S1P); sphinganine (SPA); and ceramide (CER), after hyperbaric exposure corresponding to dives conducted to the depths of 30 and 60 meters of seawater. For the plasma lipids measurements, high-performance liquid chromatography together with gas liquid chromatography were applied. Results: We demonstrated that hyperbaric exposure does not affect the content and composition of plasma fatty acids of experienced divers. Similarly, the amounts of major sphingolipids fractions were not influenced, as only the content of sphingosine-1-phosphate in the plasma was significantly decreased. Conclusions: Observed lack of significant changes in plasma lipid profile after hyperbaric exposure suggests that the procedure might be considered as secure. However, decreased sphingosine-1-phosphate content in the plasma might possibly exert some adverse effects. PMID- 30428242 TI - The cost of decompression illness: the case of lobster and sea cucumber fishery in Yucatan, Mexico. AB - Diving fisheries are an important source of income and protein for many coastal communities around the world. However, these fisheries are also the cause of both fatal and non-fatal injuries. The aim of this study is to estimate the costs of decompression sickness (DCS) in the diving small-scale fisheries that target benthic resources in the Yucatan, Mexico. The DCS cases that occurred during three fishing seasons for sea cucumber (Isostichopus badionotus) and one for spiny lobster (Panulirus argus) were used to calculate the direct medical costs. The catch data during the same fishing seasons were used to calculate the potential losses caused by disability as indirect costs. In the three years (from 2013 to 2016) the total number of fishermen treated in the region numbered 282; 116 during lobster fishing and 166 during sea cucumber season. The direct medical costs were estimated to be USD $120,269; the temporary loss of income in USD $724,377; and the permanent loss of income was USD $737,053. Considering the direct and indirect costs, the social costs of diving in both small-scale fisheries was USD $1,614,121. This is a first approach to estimate the cost of the use of diving in fisheries for the health services but for the fishing communities as well. Furthermore, this is an important first step on the road to a full economic evaluation of the benthic fisheries in order to improve their management. PMID- 30428245 TI - Session C - Diving and decompression illness. PMID- 30428244 TI - Session B - HBO2 therapy mechanisms. PMID- 30428243 TI - Session A - Diving/decompression illness: theory and mechanisms. PMID- 30428247 TI - Session E - HBO2 operations, chambers and equipment. PMID- 30428246 TI - Session D - Clinical HBO2 therapy. PMID- 30428248 TI - Session F - Top case reports. PMID- 30428250 TI - Author response to 'Disordered decompression' is not a new concept. PMID- 30428249 TI - 'Disordered decompression' is not a new concept. PMID- 30428251 TI - Scuba diving and heart rate variability. PMID- 30428252 TI - Response to 'Scuba diving and heart rate variability'. PMID- 30428253 TI - UHMS Position Statement: The Role of Hyperbaric Oxygen for Acute Traumatic Ischemias. PMID- 30428254 TI - Surfactant-Free Direct Access to Porphyrin-Cross-Linked Nanogels for Photodynamic and Photothermal Therapy. AB - Photosensitizing nanogels were obtained through a surfactant-free single-step protocol by using a porphyrin-based cross-linker for stabilizing self-assembled nanosized aggregates of thermoresponsive copolymers. Nanogels with varying amounts of porphyrin retained the singlet oxygen generation ability of the porphyrin core and were also capable of inducing temperature increase upon irradiation at 635 nm. Photoinduced killing efficiency was tested against three cell lines: human breast adenocarcinoma (MDA-MB-231 and MCF7) and pancreatic adenocarcinoma (AsPC-1) cells, and a predominant photodynamic mechanism at 450 nm and a mixed photodynamic and photothermal effect at 635 nm was observed. This innovative access to photosensitizing nanogels is a proof of concept, and opens new perspectives toward the preparation of optimized nanophotosensitizers. PMID- 30428255 TI - Advanced Electrochemical Analysis for Energy Storage Interfaces. AB - One of Wolfgang Pauli's, 1945 Nobel Prize in Physics, most popular quotes reads "God made the bulk; the surface was invented by the devil." When it comes to energy storage, interfaces - structures created between dissimilar media, such as liquids and solids, - and interphases - structures arising in between these dissimilar media- inherit this notorious reputation. This is because the high energy density chemical systems comprising the most attractive energy storage technologies are host to a plethora of dynamic processes - including electron transfer, ion transfer and migration, nucleation and dissolution, side reactions, and solvation/desolvation processes to name a few - that significantly alter their landscape. This presents a fascinating challenge to the analysis of the interfacial region, increasing its complexity from a problem of surface sensitivity, to one involving transient behavior, measurement across scales, through materials, and inherently coupled to electrochemical techniques. It is precisely these demanding characteristics that have made the creation of analytical tools and methods a priority direction in the assessment of needs for energy storage. PMID- 30428256 TI - Dipicolylamine/Metal Complexes that Promote Direct Cell-Membrane Penetration of Octaarginine. AB - Marked promotion of membrane permeation of a cell-penetrating peptide, octaarginine (R8), was attained by attachment to a single 2,2'-dipicolylamine moiety (DPA-R8) that forms 1:1 complexes with metal ions. Studies using giant unilamellar vesicles demonstrated that DPA targets phospholipids and enhances R8 binding to the membranes in the presence of metal ions. While DPA/Zn(II) complex has been most frequently employed for chelate formation with phosphates, Ni(II) had the most prominent effect on the membrane binding and penetration of DPA-R8. Facile cytosolic distribution of DPA-R8 was also attained in a few minutes in the presence of Ni(II). Analysis of the cellular uptake methods of DPA-R8/Ni(II) suggested the involvement of direct permeation through cell membrane without the use of endocytosis. The applicability of this system to the intracellular delivery of bioactive compounds was exemplified using a peptidomimetic farnesyltransferase inhibitor, FTI277. PMID- 30428257 TI - Improvements to the AMOEBA Force Field by Introducing Anisotropic Atomic Polarizability of the Water Molecule. AB - In this work, we have developed an anisotropic polarizable model for the AMOEBA force field that is derived from electrostatic fitting on a gas phase water molecule as the primary approach to improve the many-body polarization model. We validate our approach using small to large water cluster benchmark data sets and ambient liquid water properties and through comparisons to a variational energy decomposition analysis breakdown of molecular interactions for water and water ion trimer systems. We find that the accounting of anisotropy polarization for a single water molecule demonstrably improves the description of the many-body polarization energy in all cases. This study provides a proof of principle for extending our protocol for developing a general purpose anisotropic polarizable force field for other biological and material functional groups to better describe complex and asymmetric environments for which accurate polarization models are most needed. PMID- 30428258 TI - Wet-Chemical Synthesis of Chiral Colloids. AB - We disclose a method for the synthesis of chiral colloids from spontaneously formed hollow sugar-surfactant microtubes with internally confined mobile colloidal spheres. Key feature of our approach is the grafting of colloid surfaces with photoresponsive coumarin moieties, which allow for UV-induced, covalent clicking of colloids into permanent chains, with morphologies set by the colloid-to-tube diameter ratio. Subsequent dissolution of tube confinement yields aqueous suspensions that comprise bulk quantities of a variety of linear chains, including single helical chains of polystyrene colloids. These colloidal equivalents of chiral (DNA) molecules are intended for microscopic study of chiral dynamics on a single-particle level. PMID- 30428259 TI - Water, Energy, and Carbon Footprints of Bioethanol from the U.S. and Brazil. AB - Driven by biofuel policies, which aim to reduce greenhouse gas (GHG) emissions and increase domestic energy supply, global production and consumption of bioethanol have doubled between 2007 and 2016, with rapid growth in corn-based bioethanol in the U.S. and sugar cane-based bioethanol in Brazil. Advances in crop yields, energy use efficiency in fertilizer production, biomass-to-ethanol conversion rates, and energy efficiency in ethanol production have improved the energy balance and GHG emission reduction potential of bioethanol. In the current study, the water, energy, and carbon footprints of bioethanol from corn in the U.S. and sugar cane in Brazil were assessed. The results show that U.S. corn bioethanol has a smaller water footprint (541 L water/L bioethanol) than Brazilian sugar cane bioethanol (1115 L water/L bioethanol). Brazilian sugar cane bioethanol has, however, a better energy balance (17.7 MJ/L bioethanol) and smaller carbon footprint (38.5 g CO2e/MJ) than U.S. bioethanol, which has an energy balance of 11.2 MJ/L bioethanol and carbon footprint of 44.9 g CO2e/MJ. The results show regional differences in the three footprints and highlight the need to take these differences into consideration to understand the implications of biofuel production for local water resources, net energy production, and climate change mitigation. PMID- 30428260 TI - An Engineered Variant of the B1 Domain of Protein G Suppresses the Aggregation and Toxicity of Intra- and Extracellular Abeta42. AB - Intra- and extraneuronal deposition of amyloid beta (Abeta) peptides have been linked to Alzheimer's disease (AD). While both intra- and extraneuronal Abeta deposits affect neuronal cell viability, the molecular mechanism by which these Abeta structures, especially when intraneuronal, do so is still not entirely understood. This makes the development of inhibitors challenging. To prevent the formation of toxic Abeta structural assemblies so as to prevent neuronal cell death associated with AD, we used a combination of computational and combinatorial-directed evolution approaches to develop a variant of the HTB1 protein (HTB1M2). HTB1M2 inhibits in vitro self-assembly of Abeta42 peptide and shifts the Abeta42 aggregation pathway to the formation of oligomers that are nontoxic to neuroblastoma SH-SY5Y cells overexpressing or treated with Abeta42 peptide. This makes HTB1M2 a potential therapeutic lead in the development of AD targeted drugs and a tool for elucidating conformational changes in the Abeta42 peptide. PMID- 30428261 TI - Recovery of Protein Folding Funnels from Single-Molecule Time Series by Delay Embeddings and Manifold Learning. AB - The stability and folding of proteins is governed by the underlying single molecule free energy surface (smFES) mapping the free energy of the molecule as a function of configurational state. Ascertaining the smFES is of great value in understanding and engineering protein structure and function. By integrating tools from dynamical systems theory and nonlinear manifold learning, we describe an approach to reconstruct the multidimensional smFES for a protein from a time series in a single experimentally-measurable observable. We employ Takens' delay embeddings to project the time series into a high-dimensional space in which the projected dynamics are C1-equivalent to the true system dynamics, and employ diffusion maps to recover a low-dimensional reconstruction of the smFES that is equivalent to the true smFES up to a smooth and invertible transformation. We validate the approach in molecular dynamics simulations of Trp-cage, Villin, and BBA to demonstrate that landscapes recovered from univariate time series in the head-to-tail distance are topologically identical -- they precisely preserve the metastable states and folding pathways -- and topographically approximate -- the free energy barrier heights and well depths are approximately preserved -- to the true landscapes determined from complete knowledge of all atomic coordinates. We go on to show that the reconstructed landscapes reliably predict temperature denaturation and identify point mutations and groups of mutations critical to folding. These results demonstrate that protein folding funnels can be reconstructed from experimentally-measurable time series and used to understand and engineer folding. PMID- 30428262 TI - Serum Anti-Mullerian hormone (AMH) in mothers with polycystic ovary syndrome (PCOS) and their term fetuses. AB - We sought to determine serum AMH levels in the maternal circulation, and the umbilical artery and vein, in normal women and women with PCOS, and their neonates at time of delivery. This represents a cross-sectional study of 57 pregnant patients who presented to the labor and delivery suite and subsequently delivered. We obtained maternal, as well as fetal blood from both, umbilical artery and vein. We measured serum concentrations of estradiol, AMH, testosterone and FSH. A total of 30 patients delivered a female and 27 a male neonate. Of them, 18/30 and 18/27 had a diagnosis of PCOS by NIH criteria. Mean age, BMI, weight gain in pregnancy, and gestational age did not differ between the two groups of mothers. AMH serum levels were statistically higher in women with PCOS (p < 0.005) and in their fetuses, independently of gender. Testosterone was higher in women with PCOS (p < 0.001), but there was no PCOS-related difference in their fetuses. FSH levels were significantly lower in PCOS than non-PCOS mothers carrying a male (p = 0.022), but not a female, fetus. AMH was positively correlated with maternal serum testosterone (p = 0.001) and negatively with fetal serum FSH (p < 0.026). In PCOS pregnancies, AMH was negatively correlated with maternal BMI (p = 0.019), menstrual cycle length (p = 0.035), and fetal uterine vein FSH (p = 0.021). In conclusion, at time of delivery, fetuses of women with PCOS had higher AMH levels and similar testosterone levels compared to fetuses from non-PCOS mothers, irrespective of gender. Our results may help explaining developmental differences in offspring of PCOS women. PMID- 30428264 TI - CT perfusion and diffusion-weighted MR imaging of pancreatic adenocarcinoma: can we predict tumor grade using functional parameters? AB - BACKGROUND: Pancreatic adenocarcinoma is a highly lethal disease even in initially resectable patients. Functional imaging procedures such as diffusion weighted imaging (DWI) and computed tomography (CT)-perfusion might facilitate preoperative prediction of factors influencing prognosis in patients with pancreatic adenocarcinoma. PURPOSE: To evaluate CT-perfusion and DWI quantitative parameters of pancreatic adenocarcinoma and to assess their correlation with clinicopathological features. MATERIAL AND METHODS: Forty-four patients with histopathologically proven pancreatic adenocarcinoma underwent CT-perfusion and DWI for estimating blood volume (BV), blood perfusion (BF), mean transit time (MTT), time to peak (TTP), and apparent diffusion coefficient (ADC) values. The statistical analysis was performed using Wilcoxon matched-pairs test, t-test for independent samples, Spearman's rank correlation coefficient (rs), and receiver operating characteristic analysis. RESULTS: The mean CT-perfusion parameters and ADCs were significantly different in pancreatic adenocarcinoma versus healthy parenchyma. BV (2.66 +/- 0.98 mL/100g), BF (17.45 +/- 4.06 mL/min/100g), and ADCs (0.91 +/- 0.15 * 10-3mm/s2) in high-grade tumors were significantly lower in comparison to low-grade tumors (BV = 5.35 +/- 1.36 mL/100g, BF = 28.51 +/- 7.73 mL/min/100g, ADC = 1.07 +/- 0.21 * 10-3mm/s2). For prediction of high-grade tumors, the sensitivity and specificity were 79.2% and 82.4% for BF and 87.5% and 88.2% for BV, respectively. A significant negative correlation was found between BV and tumor size (rs = -0.445, P = 0.029), MTT and tumor size (rs = -0.330, P = 0.043), BV and M-stage (rs = -0.286, P = 0.049), and ADC and M-stage (rs = 0.274, P = 0.038). Moreover, BF and BV values were significantly associated with ADCs. CONCLUSION: CT-perfusion parameters and ADC values could improve preoperative assessment of pancreatic adenocarcinoma with possibility of tumor grade prediction. PMID- 30428263 TI - Advancing Translational Science for Pulmonary NTM Infections: A Roadmap for Research. AB - Multiple studies conducted since the mid-1990's indicate increasing prevalence of nontuberculous mycobacterial pulmonary disease (NTM PD) in North America, Europe, Asia, and Australia. This disease is often chronic, with lengthy treatment courses and a high risk of reinfection even after successful treatment. To identify critical gaps in diagnosis, treatment, and prevention of NTM PD, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop on September 26, 2017, bringing together diverse experts in mycobacterial disease. Panels were organized in three key areas: host/pathogen interactions; molecular epidemiology and diagnostics; and vaccine/therapeutics. Development of preventive and treatment strategies will require a more in depth understanding of host/pathogen interactions, including better understanding of 1) immune response at the NTM- lung interface, 2) biofilms, and 3) improved animal models. Improved diagnostics and treatment will require a better understanding of pathogen diversity and distribution, as well as publicly accessible, well characterized reference panels of NTM species. Additional simple-to-implement technologies may be required to leverage the diagnostic potential of markers of genetic and phenotypic variation in NTM species. Harmonization of sequencing approaches and bioinformatic analyses, as well as development of standardized clinical protocols with common data elements and case report forms will maximize the value of patient data and infrastructure. Because of its increasing prevalence and difficult diagnosis and treatment, increased research is needed for NTM pulmonary disease. Development of vaccines, drugs and diagnostics will need to be specifically tailored to the hosts and pathogens, as one size will not fit all. PMID- 30428265 TI - Letter to the Editor. PMID- 30428266 TI - How body composition may confound effect estimates of cardiorespiratory fitness. PMID- 30428267 TI - Inhibitory Process of Collaborative Inhibition: Assessment Using an Emotional Stroop Task. AB - This study investigated the inhibitory process of collaborative inhibition. An emotional Stroop task was manipulated three times after a group-recall task across three experiments. The results showed that, when participants performed an emotional Stroop task immediately after a group-recall task (Experiment 1) or between two subsequent individual-recall tasks after a group-recall task (Experiment 3), they were able to discriminate color information relating to studied but nonrecalled emotional stimuli more rapidly in the collaborative recall condition than in the nominal-recall condition. This indicated that participants experienced a stronger inhibition effect in the former condition. However, when the emotional Stroop task was performed after the final individual recall task (Experiment 2), there were no differences in discrimination between the conditions. These results suggest that the inhibition effect occurs immediately after the group-recall phase and lasts until the final individual recall task is completed (4 minutes or longer in Experiment 3). It is therefore possible to discuss retrieval inhibition as an underlying mechanism of collaborative inhibition. PMID- 30428268 TI - The Uneven Foci of Work Disability Research Across Cause-based and Comprehensive Social Security Systems. AB - This scoping review identified what kinds of work disability policy issues are critiqued in articles published in countries with cause-based versus comprehensive welfare systems. Drawing on a review of work disability policy research, we identified 74 English-language, peer-reviewed articles that focused on program adequacy and design. Articles on cause-based systems dwelled on system fairness and policies of proof of entitlement, while those on comprehensive systems focused more on system design complexities relating to worker inclusion and scope of medical certificates. Overall, we observed a clear difference in the nature of problems examined in the different systems. Gaps in work disability policy literature are identified, and challenges for comparative policy research are discussed. PMID- 30428269 TI - Reducing Health Inequalities: Comparison of Survival After Acute Myocardial Infarction According to Health Provider in Chile. AB - Health inequalities are marked in Chile. To address this situation, a health reform was implemented in 2005 that guarantees acute myocardial infarction (AMI) health care for the entire population. We evaluated if the health reform changed AMI early and long-term survival rates by hospital provider (public/private) using a longitudinal population-based study of patients >=15 years with a first AMI in Chile between 2002 and 2011. Time trends and early (within 28 days) and long-term (29-365 days) survival by age were assessed. We identified 59,557 patients: median age of 64 years; 68.9% men; 83.2% treated at public hospitals; 74.4% with public insurance. Early and long-term case-fatality was higher at public hospitals (14.6% vs 9.3%; P < .001 and 5.8% vs 3.3%; P < .001, respectively). There was a higher annual increase for early and long-term survival in public hospitals, 0.008 percentage points (95% CI: 0.006, 0.009; P < .0001) and 0.03 (0.002, 0.003; P < .0001), than in private hospitals, 0.0002 (95% CI: -0.0001, 0.005; P = .10) and 0.002 (95% CI: 0.0007, 0.003; P = .004), respectively. Being served at public hospitals affected early and long-term survival, especially in patients <70 years: hazard ratio was 2.01 (95% CI: 1.77, 2.28) and 3.11 (2.41, 4.01), respectively. Therefore, even if inequalities persist, there was a higher increase in early and long-term survival in public versus private hospitals. PMID- 30428270 TI - Detection of Pediatric Pulmonary Arterial Hypertension by School Electrocardiography Mass Screening. AB - RATIONALE: To detect pulmonary arterial hypertension (PAH) at any early stages is a promising approach to optimize the outcome. OBJECTIVES: To investigate the impact of school electrocardiography(ECG)-based screening on detecting idiopathic or heritable (I/H)-PAH in general pediatric population. METHODS: A nationwide survey of I/H-PAH patients newly diagnosed at 3 months-18years of age in Japan during 2005-12. MEASUREMENTS AND MAIN RESULTS: Eighty-seven eligible patients (age range: 1-16 years) were recruited. Among 68 (78%) patients diagnosed at >=6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (Screening group), 40 (59%) were recognized by their symptoms (n=37) or coincidental occasions (n=3) (Non-screening group). In the Screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs 60, p<.001), plasma brain natriuretic peptide level was lower (149+/-290 pg/ml vs 398+/-559, p=.045) and 6 minute walk distance was longer (420+/-109 m vs 327+/-104, p<.001) than the Non screening group, despite similar values in mean pulmonary artery pressure (58+/ 17 mmHg vs 61+/-17, p=.42), and pulmonary vascular resistance index (18+/-8 Wood units*m2 vs 21+/-11, p=.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the Screening group than the Non-screening group (14% vs 50, p=.004). CONCLUSIONS: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric I/H-PAH patients that is associated with already established pulmonary hypertension but without obvious right heart failure and warrant investigating the prognostic significance of this system. PMID- 30428271 TI - The Link between Regional Tidal Stretch and Lung Injury during Mechanical Ventilation. AB - AIM: This study aimed to assess the association between regional tidal volume (VT), regional functional residual capacity (FRC) and the expression of genes linked with ventilator-induced lung injury. METHODS: Two groups of BALB/c mice (n = 8 per group) were ventilated for 2 h using a protective or injurious ventilation strategy, with free-breathing mice as controls. Regional VT and FRC of the ventilated mice was determined from analysis of high-resolution four dimensional computed tomography (4D-CT) images, taken at baseline and after 2 h of ventilation and corrected for the volume of the region (i.e. specific [s]Vt and specific [s]FRC). RNA levels of 21 genes in ten different lung regions were quantified using qPCR array. RESULTS: sFRC at baseline varied regionally, independent of ventilation strategy, whereas sVT varied regionally depending on ventilation strategy. The expression of IL-6 (P = 0.04), Ccl2 (P < 0.01) and Ang 2 (P < 0.05) were associated with sVT but not sFRC. The expression of seven other genes varied regionally (IL-1beta and RAGE) or depended on ventilation strategy (Nfe2l2, c-fos and Wnt1) or both (TNF-alpha and CxCl2), but were not associated with regional sFRC or sVT. CONCLUSION: These observations suggest that regional inflammatory responses to mechanical ventilation are primarily driven by tidal stretch. PMID- 30428272 TI - Genetic Analysis of Copy Number Variation in Large Chorangiomas. AB - INTRODUCTION: Chorangioma (CA) is the most common nontrophoblastic, vascular tumor-like lesion of the placenta with a reported incidence of 0.5% to 1% in all examined placentas. The underlying molecular mechanisms of CAs are still poorly elucidated, and a systematic investigation of the genetic background of CAs has not previously been done. MATERIALS AND METHODS: Tissue biopsies from 8 large (>40 mm) histologically confirmed CAs and 8 unaffected matched placenta controls, along with standard control DNA samples were analyzed for large genomic deletions and duplications using array comparative genomic hybridization (array-CGH) method. RESULTS: Array-CGH analysis revealed no rare or novel copy number variants in the CA samples compared with either standard control DNA or unaffected placenta DNA from the same individual. DISCUSSION: In this study, a systematic genetic investigation of 8 large CAs failed to demonstrate any large scale pathogenic genetic changes. This lack of association might support a nongenetic, nontumorous origin of these lesions; however, additional genetic studies focusing on smaller genomic alterations are required to fully assess any possible genetic contribution. PMID- 30428274 TI - The SUPPORT for Patients and Communities Act - What Will It Mean for the Opioid Overdose Crisis? PMID- 30428273 TI - Adequacy and Accuracy of Core Biopsy in Children: A Radiologic/Pathologic Correlation Study. AB - Core biopsy (CB) is increasingly popular for assessing solid lesions in children. To date, pediatric literature is limited regarding factors contributing to diagnostically inadequate or inaccurate CB. Therefore, we retrospectively examined radiologic/pathologic factors associated with adequacy/accuracy of CB in pediatric patients. A search of the surgical pathology database for CB between January 2007 and December 2014 yielded 134 CB from 99 patients. Age, sex, anatomic site of lesion, CB diagnosis, and final diagnosis were acquired from the electronic medical record. Image guidance modality, lesion size, and CB sampling device were obtained from radiology records. CB hematoxylin and eosin slides were reviewed for fragmentation, percentage of fibrosis, and percentage of necrosis. Overall, CB length was measured using cellSens software and a DP71 camera. Groups were compared using 2-sided homoscedastic Student's t tests; 87.3% (117/134) CB were diagnostic; final diagnosis was available for 105 cases, with a concordance rate of 80.0% (84/105). Image guidance modality, lesion site (extremity vs nonextremity), and CB needle gauge did not significantly differ between diagnostic versus nondiagnostic CB or concordant versus discordant CB. Diagnostic CB had less necrosis and fibrosis than did nondiagnostic CBs (6.8% vs 29.7%, P = .0002 and 10.3% vs 29.1%, P = .0006). Nondiagnostic and discordant CB were more likely to be from bony lesions than soft tissue ( P = .01 and P = .0248). CB is valuable for diagnosing solid lesions in children, with good overall diagnostic rates regardless of lesion size, location, or imaging modality used for biopsy. Nondiagnostic and discordant CB were more often obtained from bony lesions; sampling via open biopsy may be more useful in that setting. Nondiagnostic and discordant CB have more necrosis and fibrosis, suggesting that on-site evaluation of CB tissue viability-for example, by touch imprint or fine needle aspiration may be useful in further enhancing CB utility. PMID- 30428275 TI - Disclosing Prescription-Drug Prices in Advertisements - Legal and Public Health Issues. PMID- 30428276 TI - Medicare Advantage Checkup. PMID- 30428277 TI - Venetoclax for the treatment of multiple myeloma. AB - INTRODUCTION: Treatment of multiple myeloma in the relapsed setting remains challenging, despite recent impressive advances in the management of these patients. Venetoclax (ABT-199) is a BCL-2 inhibitor recently approved by the US food and drug administration (FDA) for treatment of chronic lymphocytic leukemia but the drug has shown activity in a number of hematological malignancies. Venetoclax has broadened the treatment options for patients with relapsed or refractory multiple myeloma. Approximately 20% of myeloma patients will exhibit t (11;14) associated with high Bcl-2 expression making venetoclax an attractive therapeutic option. The efficacy of venetoclax is not uniquely restricted to this population. Areas Covered: This review will summarize the mechanism of action, toxicity profile and published data on venetoclax use in multiple myeloma, moving the field towards personalized medicine in the treatment of myeloma. Expert Commentary: Numerous phase 1/2 clinical trials are evaluating the efficacy and safety of venetoclax monotherapy and in combinations in the relapse setting. These trials show better outcomes in the subgroup of patients harboring t (11;14). PMID- 30428278 TI - HDL Cholesterol: A "Pathogen Lipid Sink" for Sepsis? PMID- 30428279 TI - Current and emerging drug therapies for the treatment of depression in adults with epilepsy. AB - INTRODUCTION: Depression is the most frequent psychiatric comorbidity among people with epilepsy. It can impact on quality of life and increases the risk of morbidity and premature mortality. Areas covered: The authors review the available data on current and emerging drug treatments for depression in epilepsy. Sources have been identified through Medline/PubMed searches while ongoing clinical trials have been identified through a ClinicalTrials.gov search. Expert opinion: SSRIs are the drug class with the largest amount of data. Though promising, the level of evidence provided by these studies is still low as the majority have relevant methodological limitations. Antiepileptic drugs under development have the unique opportunity to be of multi-use in the treatment of epilepsy and depression. The serotoninergic system has already been identified as a potential area of interest, but new targets are still needed in epilepsy and depression. For this reason, it is important that basic scientists working on these two conditions develop collaborative projects and integrate findings. PMID- 30428280 TI - Cross-Cultural Adaptation of the Developmental Coordination Disorder Questionnaire in Turkish Children. AB - The Developmental Coordination Disorder Questionnaire (DCDQ'07) is an instrument for screening children between 5 and 15 years of age. Although it is popular, this instrument has not been adapted for use with Turkish children, and there is no valid similar screening tool in Turkey. Thus, this study aimed to provide a cross-cultural adaptation of the DCDQ'07 for Turkish children. We performed the translation process using well-established cross-cultural adaptation guidelines, and we recruited 736 parents (361 males, 375 females) of typically developing children with a mean ( M) age of 9.27 years (standard deviation = 2 years 5 months, range: 5.0-14.9 years). We determined the internal consistency of the questionnaire by item and total score correlations, Cronbach's alpha and item deleted Cronbach's alpha. Intraclass correlation coefficients were used to determine test-retest reliability after an interval of 5 days. The Cronbach's alpha of the Turkish DCDQ'07 was .890 for the total questionnaire. All the item deleted Cronbach's alpha values were lower than the total value of .890, except the bull in a China shop item (Cronbach's alpha values .896). Test-retest reliability ranged from .99 to 1.00. The Turkish DCDQ is a valid and reliable screening tool for assessing the motor performance of children between 5 and 15 years of age. PMID- 30428282 TI - Melanoma in the Bronchus. PMID- 30428281 TI - Neuroprotective Effect of Nortriptyline in Overt Hepatic Encephalopathy Through Attenuation of Mitochondrial Dysfunction. AB - Hyperammonemia associated with overt hepatic encephalopathy (OHE) causes excitotoxic neuronal death through activation of the cytochrome C (CytC)-mediated mitochondria-dependent apoptotic pathway. We tested the therapeutic effect of nortriptyline (NT), a mitochondrial permeability transition pore (mPTP) blocker that can possibly inhibit mitochondrial CytC efflux to the cytosol on in vivo and in vitro OHE models. After ensuring the generation of OHE rats, established by bile duct ligation (BDL), they were intraperitoneally administered either 20 mg/kg NT (i.e., BDL+NT) or another vehicle (i.e., BDL+VEH) for 14 days. Compared with the control, BDL+VEH showed an increment of motor deficits, cell death, synaptic loss, apoptosis, and mitochondria with aberrant morphology in substantia nigra compacta dopaminergic (DA-ergic) neurons. However, the extent was significantly reversed in BDL+NT. Subsequently, we studied the neuroprotective mechanism of NT using PC-12 cells, a DA-ergic cell line, which exposed glutamate used as an excitotoxin. Compared with the control, the cells exposed to 15 mM glutamate (i.e., GLU) showed incremental cell death, apoptosis, and demise in mitochondrial respiration. Importantly, efflux of CytC from mitochondria to cytosol and the dissipation of mitochondrial membrane potential (?Psim), an indicator of mPTP opening, were prominent in GLU. However, compared with the GLU, the cells cotreated with 10 MUM NT (i.e., GLU+NT) showed a significant reduction in the aforementioned phenomenon. Together, we concluded that NT can be used for OHE therapeutics, mitigating the excitotoxic death of substantia nigra compacta DA-ergic neurons via mPTP-associated mitochondrial dysfunction inhibition. PMID- 30428283 TI - Evidence of Artemisinin-Resistant Plasmodium falciparum Malaria in Eastern India. PMID- 30428284 TI - Case Studies in Social Medicine - Attending to Structural Forces in Clinical Practice. PMID- 30428285 TI - Looking beyond Mortality in Transplantation Outcomes. PMID- 30428286 TI - Radial-Artery Grafts for Coronary-Artery Bypass Surgery. PMID- 30428287 TI - Procalcitonin-Guided Antibiotic Use. PMID- 30428288 TI - Ibrutinib and Rituximab in Waldenstrom's Macroglobulinemia. PMID- 30428289 TI - Case 35-2018: A 68-Year-Old Woman with Back Pain and a Remote History of Breast Cancer. PMID- 30428291 TI - Dengue Serostatus and Dengue Vaccine Safety and Efficacy. PMID- 30428290 TI - Prednisone for the Prevention of Paradoxical Tuberculosis-Associated IRIS. AB - BACKGROUND: Early initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients who have tuberculosis reduces mortality among patients with low CD4 counts, but it increases the risk of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS). METHODS: We conducted this randomized, double-blind, placebo-controlled trial to assess whether prophylactic prednisone can safely reduce the incidence of paradoxical tuberculosis-associated IRIS in patients at high risk for the syndrome. We enrolled HIV-infected patients who were initiating ART (and had not previously received ART), had started tuberculosis treatment within 30 days before initiating ART, and had a CD4 count of 100 cells or fewer per microliter. Patients received either prednisone (at a dose of 40 mg per day for 14 days, then 20 mg per day for 14 days) or placebo. The primary end point was the development of tuberculosis-associated IRIS within 12 weeks after initiating ART, as adjudicated by an independent committee. RESULTS: Among the 240 patients who were enrolled, the median age was 36 (interquartile range, 30 to 42), 60% were men, and 73% had microbiologically confirmed tuberculosis; the median CD4 count was 49 cells per microliter (interquartile range, 24 to 86), and the median HIV type 1 RNA viral load was 5.5 log10 copies per milliliter (interquartile range, 5.2 to 5.9). A total of 120 patients were assigned to each group, and 18 patients were lost to follow-up or withdrew. Tuberculosis-associated IRIS was diagnosed in 39 patients (32.5%) in the prednisone group and in 56 (46.7%) in the placebo group (relative risk, 0.70; 95% confidence interval [CI], 0.51 to 0.96; P=0.03). Open label glucocorticoids were prescribed to treat tuberculosis-associated IRIS in 16 patients (13.3%) in the prednisone group and in 34 (28.3%) in the placebo group (relative risk, 0.47; 95% CI, 0.27 to 0.81). There were five deaths in the prednisone group and four in the placebo group (P=1.00). Severe infections (acquired immunodeficiency syndrome-defining illnesses or invasive bacterial infections) occurred in 11 patients in the prednisone group and in 18 patients in the placebo group (P=0.23). One case of Kaposi's sarcoma occurred in the placebo group. CONCLUSIONS: Prednisone treatment during the first 4 weeks after the initiation of ART for HIV infection resulted in a lower incidence of tuberculosis associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers. (Funded by the European and Developing Countries Clinical Trials Partnership and others; PredART ClinicalTrials.gov number, NCT01924286 .). PMID- 30428292 TI - Miliary Metastases in Non-Small-Cell Lung Cancer. PMID- 30428293 TI - Closed-Loop Insulin for Glycemic Control in Noncritical Care. PMID- 30428294 TI - Clinical Course and Management of Hypertrophic Cardiomyopathy. PMID- 30428295 TI - Mosaic Effects of Growth Hormone on Fibrous Dysplasia of Bone. PMID- 30428296 TI - H4:IC31 Vaccine or BCG Revaccination for Tuberculosis. PMID- 30428297 TI - Lymphedema after Breast Cancer Treatment. PMID- 30428299 TI - Gender differences in the order of appearance of elbow ossification centres. AB - BACKGROUND: The predictable order of appearance of elbow secondary ossification centres in children is important in interpreting elbow radiographs, most commonly in the context of trauma. The usual sequence of appearance of these ossification centres is given by the acronym CRITOL, but exceptions have been described and are recognised as normal variants. AIM: To investigate the extent to which the appearance of the elbow secondary ossification centres follows a predictable sequence, and to establish the incidence of exceptions to the usual CRITOL order. METHODS: Two-stage retrospective review of 421 elbow radiographs in children at our centre. RESULTS: Of 64 children with two visible ossification centres, there was a 23% overall variant incidence (49 CR, 15 CI). Twenty-eight children had four visible ossification centres, with an overall variant incidence of 32% (19 CRIT, 9 CRIO). The variants were significantly more common in girls than in boys ( p < 0.001). CONCLUSION: Whilst the majority of radiographs remained consistent with the described CRITOL sequence, variance in this order was seen in a quarter of children with two visible ossification centres, and a third of children with four visible ossification centres. Incidence of variance was much more common in girls, reaching statistical significance. Awareness of these normal variations, particularly in girls, should help to avoid misinterpretation. PMID- 30428300 TI - Identification of differentially expressed microRNAs in outgrowth embryos compared with blastocysts and non-outgrowth embryos in mice. AB - Recurrent implantation failure (RIF) is one of the main causes for the repeated failure of IVF, and the major reason for RIF is thought to be a miscommunication between the embryo and uterus. However, the exact mechanism underlying embryo uterus cross-talk is not fully understood. The aim of the present study was to identify differentially expressed microRNAs (miRNAs) among blastocysts, non outgrowth and outgrowth embryos in mice using microarray analysis. A bioinformatics analysis was performed to predict the potential mechanisms of implantation. The miRNA expression profiles differed significantly between non outgrowth and outgrowth embryos. In all, 3163 miRNAs were detected in blastocysts and outgrowth embryos. Of these, 10 miRNA candidates (let-7b, miR-23a, miR-27a, miR-92a, miR-183, miR-200c, miR-291a, miR-425, miR-429 and miR-652) were identified as significant differentially expressed miRNAs of outgrowth embryos by in silico analysis. The expression of the miRNA candidates was markedly changed during preimplantation embryo development. In particular, let-7b-5p, miR-200c-3p and miR-23a-3p were significantly upregulated in outgrowth embryos compared with non-outgrowth blastocysts. Overall, differentially expressed miRNAs in outgrowth embryos compared with blastocysts and non-outgrowth embryos could be involved in embryo attachment, and interaction between the embryo proper and maternal endometrium during the implantation process. PMID- 30428298 TI - Medicalization and Demedicalization - A Gravely Disabled Homeless Man with Psychiatric Illness. PMID- 30428301 TI - Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP Glucuronosyltransferase Enzymes. AB - Drug resistance is a major cause of cancer-related mortality. Glucuronidation of drugs via elevation of UDP-glucuronosyltransferases (UGT1As) correlates with clinical resistance. The nine UGT1A family members have broad substrate specificities attributed to their variable N-terminal domains and share a common C-terminal domain. Development of UGT1As as pharmacological targets has been hampered by toxicity of pan-UGT inhibitors and by difficulty in isolating pure N terminal domains or full-length proteins. Here, we developed a strategy to target selected UGT1As which exploited the biochemical tractability of the C-domain and its ability to allosterically communicate with the catalytic site. By combining NMR fragment screening with in vitro glucuronidation assays, we identified inhibitors selective for UGT1A4. Significantly, these compounds selectively restored sensitivity in resistant cancer cells only for substrates of the targeted UGT1A. This strategy represents a crucial first step toward developing compounds to overcome unwanted glucuronidation thereby reversing resistance in patients. PMID- 30428302 TI - Mechanisms of Mitochondria Assembly, Dynamics and Turnover in Health and Disease. PMID- 30428303 TI - A cyclometalated iridium(III) complex-based fluorescence probe for hypochlorite detection and its application by test strips. AB - A new cyclometalated iridium(III) complex-based fluorescence probe (IrCN) for hypochlorite (ClO-) has been synthesized and characterized. The probe displayed nonfluorescent around 577 nm, while a 54-fold enhancement in fluorescence emission intensity was observed after the addition of ClO- due to the removal of C=N isomerization effect. Such "turn-on" fluorescence probe worked excellently in wide pH range (5-12) with short response time (<20 s) and the detection limit was as low as 0.11 MUM. In addition, IrCN exhibited high selectivity towards ClO- even in the presence of other competing species. Furthermore, IrCN was successfully integrated in fluorescent test strips for real-time detection of ClO . PMID- 30428304 TI - Redox-state dependent blinking of single photosystem I trimers at around liquid nitrogen temperature. AB - Efficient light harvesting in a photosynthetic antenna system is disturbed by a ragged and fluctuating energy landscape of the antenna pigments in response to the conformation dynamics of the protein. This situation is especially pronounced in Photosystem I (PSI) containing red shifted chlorophylls (red Chls) with the excitation energy much lower than the primary donor. The present study was conducted to clarify light-harvesting dynamics of PSI isolated from Synechocystis sp. PCC6803 by using single-molecule spectroscopy at liquid-nitrogen temperatures. Fluorescence emission at around 720 nm from the red Chls in single PSI trimers was monitored at 80-100 K. Intermittent variations in the emission intensities, so-called blinking, were frequently observed. Its time scale lay in several tens of seconds. The blinking amplitude depended on the redox state of the phylloquinone (A1). Electrochromic shifts of Chls induced by the negative charge on A1 were calculated based on the X-ray crystallographic structure. A Chl molecule, Chl-A839 (numbering according to PDB 5OY0), bound near A1 was found to have a large electrochromic shift. This Chl has strong exciton coupling with neighboring Chl (A838) whose site energy was predicted to be determined by interaction with an arginine residue (ArgF84) [Adolphs et al., 2010]. A possible scenario of the blinking was proposed. Conformational fluctuations of ArgF84 seesaw the excitation-energy of Chl-A838, which perturbs the branching ratio of excitation-energy between the red Chl and the cationic form of P700 as a quencher. The electrochromic shift of Chl-A839 enhances the effect of the conformation dynamics of ArgF84. PMID- 30428305 TI - Overexpression of Forkhead box C1 attenuates oxidative stress, inflammation and apoptosis in chronic obstructive pulmonary disease. AB - AIM: Chronic obstructive pulmonary disease (COPD) is a disease caused by cigarette smoke, which has been emerging as a serious health problem worldwide. The aim of this study is to explore the mRNA expression profile of lung tissues from the COPD rats and to characterize the role of Forkhead box C1 (Foxc1) in COPD. MAIN METHODS: Wistar rats were exposed to cigarette smoke during 16 weeks for COPD model establishment. The microarray was used to identify the differential gene expression in the lung of rats. Adenovirus carrying Foxc1 was administered to rats by intratracheally instillation once a week for 16 weeks. Human bronchial epithelial cell line (16HBE) cells were transfected with Foxc1 siRNA followed by incubation in the presence of CSE (10%) for 24 h. Subsequently, the pathological changes, fibrosis, apoptosis, inflammatory cytokines and oxidative stress were detected. KEY FINDINGS: Microarray results showed an upregulation of Foxc1 in lung tissues in COPD rats. Overexpression of Foxc1 mitigated the lung injury, as evidenced by reducing alveolar fusion, inflammatory cell infiltration and oxidative stress. Additionally, the apoptosis was remarkably increased in the lung in rats exposed to cigarette smoke, which was suppressed by Foxc1 overexpression. Furthermore, downregulation of Foxc1 aggravated the inflammation, oxidative stress and apoptosis in 16HBE cells with CSE treatment. SIGNIFICANCE: Overexpression of Foxc1 could prevent oxidative stress, inflammation responses and cell apoptosis and knockdown of Foxc1 has the opposite effect, suggesting that Foxc1 may be available for lung protection during COPD. PMID- 30428306 TI - Protective effects of ginsenoside Rg3 on TNF-alpha-induced human nucleus pulposus cells through inhibiting NF-kappaB signaling pathway. AB - This work aims to evaluate the effect of ginsenoside Rg3 on the apoptosis, proliferation, extracellular matrix (ECM) metabolism and oxidative stress-induced damage of human nucleus pulposus cells (NPCs) induced by TNF-alpha. The human NPCs were divided into Control, TNF-alpha, TNF-alpha + low Rg3, TNF-alpha + medium Rg3 and TNF-alpha + high Rg3 groups. Annexin V-FITC/PI, CCK-8 and flow cytometry were used to detect the apoptosis, proliferation, and cell cycle of NPCs, respectively. The expressions of ECM-related molecules were determined by qRT-PCR, ELISA and Western blotting. NF-kappaB p65 pathway and apoptosis-related proteins were evaluated by Western blotting, and the production of reactive oxygen species (ROS) was detected by DCFH-DA assay. Compared with Control group, NPCs in the TNF-alpha group had elevated proportion of apoptotic cells with up regulation of Bax and Caspase-3 and down-regulation of Bcl-2. Besides, TNF-alpha inhibited proliferation and arrested cell cycle at G1 of NPCs. Moreover, human NPCs induced by TNF-alpha presented the increase in the expressions of ECM degrading genes (MMP3 and ADAMTS5), the content of ROS and malondialdehyde (MDA), and the expression of NF-kappaB/p65 in nucleus, but showed the decrease in the expression of ECM synthesis genes (Aggrecan and COL2A1) and the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX). However, NPCs treated by both TNF-alpha and Rg3 demonstrated a certain degree of reversal in the above indexes, which became increasingly evident with the up-regulation of Rg3 concentration. Ginsenoside Rg3 may exert the effect of attenuating TNF-alpha induced NPCs impairment via blocking the NF-kappaB signaling pathway. PMID- 30428307 TI - Modular core-shell polymeric nanoparticles mimicking viral structures for vaccination. AB - Recent advances in the development of protein-based vaccines have expanded the opportunities for preventing and treating both infectious diseases as well as cancer. However, the development of readily and efficient antigen delivery systems capable of stimulating strong cytotoxic T-lymphocyte (CTL) responses remains a challenge. With the attempt to closely mimic the properties of viruses in terms of their size and molecular organization, we constructed RNA (which is a ligand for Toll-like receptor 7 (TLR7) and TLR8) and antigen-loaded nanoparticles resembling the structural organization of viruses. Cationic polymers containing either azide or bicyclo[6.1.0]nonyne (BCN) groups were synthesized as electrostatic glue that binds negatively charged single stranded RNA (PolyU) to form a self-crosslinked polyplex core. An azide-modified model antigen (ovalbumin, OVA) and a BCN-modified mannosylated or galactosylated polymer were sequentially conjugated to the RNA core via disulfide bonds using copper free click chemistry to form the shell of the polyplexes. The generated reducible virus mimicking particles (VMPs) with a diameter of 200 nm and negatively surface charge (-14 mV) were colloidally stable in physiological conditions. The immunogenicity of these VMP vaccines was evaluated both in vitro and in vivo. The surface mannosylated VMPs (VMP-Man) showed 5 times higher cellular uptake by bone marrow derived DCs (BMDCs) compared to galactosylated VMP (VMP-Gal) counterpart. Moreover, VMP-Man efficiently activated DCs and greatly facilitated MHC I Ag presentation in vitro. Vaccination of mice with VMP-Man elicited strong OVA specific CTL responses as well as humoral immune responses. These results demonstrate that the modular core-shell polymeric nanoparticles described in this paper are superior in inducing strong and durable immune responses compared to adjuvanted protein subunit vaccines and offer therefore a flexible platform for personalized vaccines. PMID- 30428308 TI - Cost minimization analysis for basic life support. AB - : The use of online teaching methodology for basic life support (BLS) courses is progressively increasing. The objective of this study was to verify whether the blended-learning methodology (virtual course with a short face-to-face complement) was more efficient than a course that followed the classical or face to-face methodology in our university. MATERIALS AND METHODS: A cost minimization analysis was performed for two BLS and automatic external defibrillation (AED) courses, one of which was conducted face-to-face (Control Group) and the second of which was conducted via blended-learning (Experimental Group). The courses had the same duration and content according to the European Resuscitation Council (ERC) recommendations. In the face-to-face course, direct costs were considered those generated by the faculty and derived from the academic activity. Other costs were those generated by the use of classrooms and the amortization of manikins and AED training. The perspective of the analysis was that of the provider, the academic, and a time horizon of six months. The costs are expressed in ? 2017. RESULTS: The savings of a course in BLS-AED based on the blended learning methodology calculated for a total of 160 university nursing and medical students were ? 2328.8 for the first year of its implementation and ? 9048.8 for its second edition compared with the same course using a face-to-face methodology. CONCLUSIONS: The blended-learning methodology supposes a cost savings for BLS-AED courses, mainly due to the reduction of expenses of the teaching staff. The blended-learning methodology seems to be more efficient than the face-to-face methodology. PMID- 30428309 TI - Differential evolution of antigenic regions of porcine reproductive and respiratory syndrome virus 1 before and after vaccine introduction. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is a widespread viral pathogen that has caused tremendous economic losses throughout most pig-producing countries. Nowadays, both PRRSV-1 and PRRSV-2 co-circulate in Korean pig populations, and commercial modified live vaccine (MLV) is predominantly used to control PRRS. Specifically, control strategy using only PRRSV-2 MLV that was used since 1995 cannot prevent the spread of PRRSV-1 and damage from its infection, which led to the first introduction of two additional PRRSV-1 vaccines in 2014. Despite the wide implementation with PRRSV-1 vaccines, there is a lack of knowledge about the currently circulating Korean PRRSV-1 strains. Whole structural genes of PRRSV-1 before (11) and after (17) the introduction of vaccine were compared to determine the genetic evolutionary features of PRRSV. Genetic and phylogenetic analysis indicated that Korean PRRSV-1 shared 91.5 +/- 1.7% nucleotide identity but formed a unique clade based on ORF2-7 phylogeny. Bioinformatics showed increased genetic heterogeneity, enhanced diversifying selection, and the emergence of novel glycosylation sites within neutralizing epitopes of minor structural proteins after vaccine introduction. Taken together, our data provide novel insight into the evolution of minor structural proteins of PRRSV-1 in the vaccination era. PMID- 30428310 TI - Lipase mediated functionalization of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with ascorbic acid into an antioxidant active biomaterial. AB - Naturally produced polyhydroxyalkanoates (PHAs) biopolymers have limited medical applications due to their brittle and hydrophobic nature. In this study poly(3 hydroxybutyrate-co-3-hydroxyvalerate) P(3HB-co-3HV) copolymer was produced using engineered Escherichia coli YJ101, and further functionalized with ascorbic acid using Candida antarctica lipase B mediated esterification. Copolymer P(3HB-co 3HV)-ascorbic acid showed lower degree of crystallinity (9.96%), higher thermal degradation temperature (294.97 degrees C) and hydrophilicity (68 degrees ) as compared to P(3HB-co-3HV). Further, P(3HB-co-3HV)-ascorbic acid biomaterial showed 14% scavenging effect on 1,1-diphenyl-2-picryl-hydrazyl (DPPH), and 1.6 fold increase in biodegradability as compared to P(3HB-co-3HV). Improvement of PHAs polymer properties by adding functional groups could be a good approach to increase their biodegradability, economic value and important applications in the medical field. PMID- 30428311 TI - Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of beta-amyloid pathology. AB - Obesity and type 2 diabetes mellitus (T2DM) are important risk factors for Alzheimer's disease (AD). Drugs originally developed for T2DM treatment, e.g., analog of glucagon-like peptide 1 liraglutide, have shown neuroprotective effects in mouse models of AD. We previously examined the neuroprotective properties of palm11-PrRP31, an anorexigenic and glucose-lowering analog of prolactin-releasing peptide, in a mouse model of AD-like Tau pathology, THY-Tau22 mice. Here, we demonstrate the neuroprotective effects of palm11-PrRP31 in double transgenic APP/PS1 mice, a model of AD-like beta-amyloid (Abeta) pathology. The 7-8-month old APP/PS1 male mice were subcutaneously injected with liraglutide or palm11 PrRP31 for 2 months. Both the liraglutide and palm11-PrRP31 treatments reduced the Abeta plaque load in the hippocampus. Palm11-PrRP31 also significantly reduced hippocampal microgliosis, consistent with our observations of a reduced Abeta plaque load, and reduced cortical astrocytosis, similar to the treatment with liraglutide. Palm11-PrRP31 also tended to increase neurogenesis, as indicated by the number of doublecortin-positive cells in the hippocampus. After the treatment with both anorexigenic compounds, we observed a significant decrease in Tau phosphorylation at Thr231, one of the first epitopes phosphorylated in AD. This effect was probably caused by elevated activity of protein phosphatase 2A subunit C, the main Tau phosphatase. Both liraglutide and palm11-PrRP31 reduced the levels of caspase 3, which has multiple roles in the pathogenesis of AD. Palm11-PrRP31 increased protein levels of the pre-synaptic marker synaptophysin, suggesting that palm11-PrRP31 might help preserve synapses. These results indicate that palm11-PrRP31 has promising potential for the treatment of neurodegenerative diseases. PMID- 30428312 TI - Effects of conflict and strategic processing on neural responses to errors in schizophrenia. AB - The error-related negativity (ERN) and error-positivity (Pe) are commonly linked to error-detection and strategic processing. Studies have documented the influence of conflict probability on ERN amplitude. However, the influence of conflict probability on ERN/Pe in schizophrenia, where such components are reduced, is unknown. A modified flanker paradigm was used to examine how the probability of conflict modulates ERN and Pe amplitudes in patients with schizophrenia (n = 33) and healthy controls (n = 25). Increased ERN was observed in response to errors on low probability, incongruent trials. No such differences were observed in Pe. While ERN and Pe showed significantly reduced amplitudes in patients relative to controls, patients showed normal condition-dependent ERN and reaction-time modulation. This suggests that while the neural mechanisms generating the ERN and Pe are compromised in schizophrenia, those modulating task performance strategy and neurophysiological responses to errors based on conflict probability are intact. PMID- 30428313 TI - Structural and Mechanistic Analyses Reveal a Unique Cas4-like Protein in the Mimivirus Virophage Resistance Element System. AB - A clustered regularly interspaced short palindromic repeats (CRISPR)-like "mimivirus virophage resistance element" (MIMIVIRE) system, which contains specific cascade genes and a CRISPR array against virophages, was reported in mimiviruses. An essential component of the MIMIVIRE system is R354, encoding a nuclease and a likely functional homolog of Cas4. Here we show that R354 is a dual nuclease with both exonuclease and endonuclease activities. Structural analysis revealed that the catalytic core domain of R354 is similar to those of Cas4 and ? exonuclease despite their low sequence identity. R354 forms a homodimer that is important for its exonuclease but not endonuclease activity. Structural comparisons between the active and semi-active states of R354 demonstrated that an activation loop adjacent to the catalytic site is critical for enzymatic activity. Overall, the results suggest that R354 belongs to a novel MIMIVIRE system involved in innate virus immunity and provides a template for the identification of new CRISPR systems in other species. PMID- 30428314 TI - Mean-Independent Noise Control of Cell Fates via Intermediate States. AB - Stochasticity affects accurate signal detection and robust generation of correct cell fates. Although many known regulatory mechanisms may reduce fluctuations in signals, most simultaneously influence their mean dynamics, leading to unfaithful cell fates. Through analysis and computation, we demonstrate that a reversible signaling mechanism acting through intermediate states can reduce noise while maintaining the mean. This mean-independent noise control (MINC) mechanism is investigated in the context of an intracellular binding protein that regulates retinoic acid (RA) signaling during zebrafish hindbrain development. By comparing our models with experimental data, we find that the MINC mechanism allows for sharp boundaries of gene expression without sacrificing boundary accuracy. In addition, this MINC mechanism can modulate noise to levels that we show are beneficial to spatial patterning through noise-induced cell fate switching. These results reveal a design principle that may be important for noise regulation in many systems that control cell fate determination. PMID- 30428315 TI - Prussian Blue Analogs for Rechargeable Batteries. AB - Non-lithium energy storage devices, especially sodium ion batteries, are drawing attention due to insufficient and uneven distribution of lithium resources. Prussian blue and its analogs (Prussian blue analogs [PBAs]), or hexacyanoferrates, are well-known since the 18th century and have been used for hydrogen storage, cancer therapy, biosensing, seawater desalination, and sewage treatment. Owing to their unique features, PBAs are receiving increasing interest in the field of energy storage, such as their high theoretical specific capacity, ease of synthesis, as well as low cost. In this review, a general summary and evaluation of the applications of PBAs for rechargeable batteries are given. After a brief review of the history of PBAs, their crystal structure, nomenclature, synthesis, and working principle in rechargeable batteries are discussed. Then, previous works classified based on the combination of insertion cations and transition metals are analyzed comprehensively. The review includes an outlook toward the further development of PBAs in electrochemical energy storage. PMID- 30428316 TI - Alternating-Magnetic-Field-Mediated Wireless Manipulations of a Liquid Metal for Therapeutic Bioengineering. AB - As emergent multifunctional materials, room temperature liquid metals (LMs) display many unique properties. Here we show that applying an external alternating magnetic field (AMF) to an LM induces various physical phenomena, such as exothermic behavior, controlled locomotion, electromagnetic levitation, and transformations of the LMs between different morphologies and configurations, in a non-contact manner. Additional interesting therapeutic bioengineering applications of LMs demonstrated herein include in vitro and in vivo effective cancer magnetic hyperthermia via wireless AMF, remote manipulation of a pill shaped microdevice based on an LM/hydrogel composite, and spatiotemporal controlled release of drug molecules from the microdevice. Overall, as an innovative therapeutic bioengineering technology, this platform and the described performance traits of LMs enable the development of biocompatible smart devices with a wide range of dynamic components that can be wirelessly controlled in a manner that solves issues related to the powering of devices and biocompatibility. PMID- 30428317 TI - Mesoporous TiO2/TiC@C Composite Membranes with Stable TiO2-C Interface for Robust Lithium Storage. AB - Transition metal oxides/carbon (TMOs/C) composites are important for high performance lithium-ion batteries (LIBs), but the development of interface-stable TMOs/C composite anodes for robust lithium storage is still a challenge. Herein, mesoporous TiO2/TiC@C composite membranes were synthesized by an in situ carbothermic reduction method. TiC nanodots with high conductivity and electrochemical inactivity at the TiO2-C interface can significantly enhance the electrical conductivity and structural stability of the membranes. Finite element simulations demonstrate that the TiO2/TiC@C membranes can effectively alleviate tensile and compression stress effects upon lithiation, which is beneficial for robust lithium storage. When used as additives and binder-free electrodes, the TiO2/TiC@C membranes show excellent cycling capability and rate performance. Moreover, a flexible full battery can be assembled by employing the TiO2/TiC@C membranes and shows good performance, highlighting the potential of these membranes in flexible electronics. This work opens an avenue to constructing interface-stable composite structures for the next-generation high-performance LIBs. PMID- 30428318 TI - Leptosphaeria maculans Effector Protein AvrLm1 Modulates Plant Immunity by Enhancing MAP Kinase 9 Phosphorylation. AB - Leptosphaeria maculans, the causal agent of blackleg disease in canola (Brassica napus), secretes an array of effectors into the host to overcome host defense. Here we present evidence that the L. maculans effector protein AvrLm1 functions as a virulence factor by interacting with the B. napus mitogen-activated protein (MAP) kinase 9 (BnMPK9), resulting in increased accumulation and enhanced phosphorylation of the host protein. Transient expression of BnMPK9 in Nicotiana benthamiana induces cell death, and this phenotype is enhanced in the presence of AvrLm1, suggesting that induction of cell death due to enhanced accumulation and phosphorylation of BnMPK9 by AvrLm1 supports the initiation of necrotrophic phase of L. maculans infection. Stable expression of BnMPK9 in B. napus perturbs hormone signaling, notably salicylic acid response genes, to facilitate L. maculans infection. Our findings provide evidence that a MAP kinase is directly targeted by a fungal effector to modulate plant immunity. PMID- 30428320 TI - Enhancing Photocurrent of Radially Polarized Ferroelectric BaTiO3 Materials by Ferro-Pyro-Phototronic Effect. AB - The pyro-phototronic effect has been utilized to modulate photoexcited carriers, to enhance the photocurrent in semiconducting nanomaterials. However, most of these materials have low pyroelectric performances. Using radially polarized ferroelectric BaTiO3 materials with a pyroelectric coefficient of about 16 nC/cm2K, we report a dramatic photocurrent enhancement due to ferro-pyro phototronic effect. The fabricated device enables a fast sensing of 365-nm light illumination with a response time of 0.5 s at the rising edge, where the output current-time curve displays a sharp peak followed by a stable plateau. By applying a heating temperature variation, the output current peak can be enhanced by more than 30 times under a light intensity of 0.6 mW/cm2. Moreover, the stable current plateau can be enhanced by 23% after utilizing a cooling temperature variation, which can be well explained by ferro-pyro-phototronic-effect-induced energy band bending. PMID- 30428319 TI - Mitochondria-Targeted Honokiol Confers a Striking Inhibitory Effect on Lung Cancer via Inhibiting Complex I Activity. AB - We synthesized a mitochondria-targeted honokiol (Mito-HNK) that facilitates its mitochondrial accumulation; this dramatically increases its potency and efficacy against highly metastatic lung cancer lines in vitro, and in orthotopic lung tumor xenografts and brain metastases in vivo. Mito-HNK is >100-fold more potent than HNK in inhibiting cell proliferation, inhibiting mitochondrial complex ?, stimulating reactive oxygen species generation, oxidizing mitochondrial peroxiredoxin-3, and suppressing the phosphorylation of mitoSTAT3. Within lung cancer brain metastases in mice, Mito-HNK induced the mediators of cell death and decreased the pathways that support invasion and proliferation. In contrast, in the non-malignant stroma, Mito-HNK suppressed pathways that support metastatic lesions, including those involved in inflammation and angiogenesis. Mito-HNK showed no toxicity and targets the metabolic vulnerabilities of primary and metastatic lung cancers. Its pronounced anti-invasive and anti-metastatic effects in the brain are particularly intriguing given the paucity of treatment options for such patients either alone or in combination with standard chemotherapeutics. PMID- 30428322 TI - Regulatory Genomic Data Cubism. AB - A regularly shaped grid is useful for analyzing data particularly at multilayer levels, where patterns can be visually represented and analytically compared conceptually similar to Picasso's cubism. Here we introduce ATLAS, featuring a suite of spatially ordered maps designed for representation and comparison of patterns seen in regulatory genomic data. It produces a landscape learned from input data and enables landscape-guided correlation with additional data. We illustrate its use for multilayer data comparison on the same cell type, and for comparisons involving different cell types, revealing information in a scientifically insightful and also visually intuitive way. The data-driven and visual-aided ability of ATLAS presents a general strategy for regulatory genomic data analysis. PMID- 30428321 TI - Base-Resistant Ionic Metal-Organic Framework as a Porous Ion-Exchange Sorbent. AB - A systematic approach has been employed to obtain a hydrolytically stable cationic metal-organic framework (MOF). The synthesized two-dimensional Ni(II) centered cationic MOF, having its backbone built from purely neutral N-donor ligand, is found to exhibit uncommon resistance over wide pH range, particularly even under highly alkaline conditions. This report presents a rare case of a porous MOF retaining structural integrity under basic conditions, and an even rarer case of a porous cationic MOF. The features of stability and porosity in this ionic MOF have been harnessed for the function of charge- and size-selective capture of small organic dye through ion-exchange process across a wide pH range. PMID- 30428323 TI - In Mitochondria ?-Actin Regulates mtDNA Transcription and Is Required for Mitochondrial Quality Control. AB - In eukaryotic cells, actin regulates both cytoplasmic and nuclear functions. However, whether actin-based structures are present in the mitochondria and are involved in mitochondrial functions has not been investigated. Here, using wild type ?-actin +/+ and knockout (KO) ?-actin ?/? mouse embryonic fibroblasts we show evidence for the defect in maintaining mitochondrial membrane potential (MMP) in ?-actin-null cells. MMP defects were associated with impaired mitochondrial DNA (mtDNA) transcription and nuclear oxidative phosphorylation (OXPHOS) gene expression. Using super-resolution microscopy we provided direct evidence on the presence of ?-actin-containing structures inside mitochondria. Large aggregates of TFAM-stained nucleoids were observed in bulb-shaped mitochondria in KO cells, suggesting defects in mitochondrial nucleoid segregation without ?-actin. The observation that mitochondria-targeted ?-actin rescued mtDNA transcription and MMP suggests an indispensable functional role of a mitochondrial ?-actin pool necessary for mitochondrial quality control. PMID- 30428324 TI - Optimal-Enhanced Solar Cell Ultra-thinning with Broadband Nanophotonic Light Capture. AB - Recent trends in photovoltaics demand ever-thin solar cells to allow deployment in consumer-oriented products requiring low-cost and mechanically flexible devices. For this, nanophotonic elements in the wave-optics regime are highly promising, as they capture and trap light in the cells' absorber, enabling its thickness reduction while improving its efficiency. Here, novel wavelength-sized photonic structures were computationally optimized toward maximum broadband light absorption. Thin-film silicon cells were the test bed to determine the best performing parameters and study their optical effects. Pronounced photocurrent enhancements, up to 37%, 27%, and 48%, respectively, in ultra-thin (100- and 300 nm-thick) amorphous, and thin (1.5-?m) crystalline silicon cells are demonstrated with honeycomb arrays of semi-spheroidal dome or void-like elements patterned on the cells' front. Also importantly, key advantages in the electrical performance are anticipated, since the photonic nano/micro-nanostructures do not increase the cell roughness, therefore not contributing to recombination, which is a crucial drawback in state-of-the-art light-trapping approaches. PMID- 30428325 TI - HOTf-Catalyzed Alkyl-Heck-type Reaction. AB - The Heck reaction, along with other cross-coupling reactions, led to a revolution in organic chemistry. In the last 50 years, metal-catalyzed, photo-induced, or base-mediated Heck and Heck-type reactions have been elegantly developed. Bronsted acid-catalyzed Heck (or Heck-type) reactions are still unknown, however. By introducing alkyl peroxides as the key intermediates, primary, secondary, and tertiary aliphatic carboxylic acids are therefore applied here in a one-pot Bronsted acid-catalyzed Heck-type reaction, to deliver E-alkenes exclusively in most cases. The use of HOTf is vital to the reaction, whose mechanism is supported by both experimental and computational results. This method can be expanded to the direct alkylation of complex natural products. PMID- 30428327 TI - Catalytic Double Cyclization Process for Antitumor Agents against Breast Cancer Cell Lines. AB - The development of efficient synthetic strategies for the discovery of novel antitumor molecules is a major goal in current research. In this context, we report here a catalytic double cyclization process leading to bicyclic heterocycles with significant antitumor activity on different human breast cancer (BC) cell lines. The products, 6,6a-dihydrofuro[3,2-b]furan-2(5H)-ones, were obtained in one step, starting from simple substrates (4-yne-1,3-diols, CO, and O2), under the catalytic action of PdI2 in conjunction with KI. These compounds have significant antiproliferative activity in vitro on human BC cell lines, both hormone receptor positive (MCF-7) and triple negative (triple-negative breast cancer [TNBC]; MDA-MB-231 and MDAMB-468), while exhibiting practically no effects on normal MCF-10A (human mammary epithelial) and 3T3-L1 (murine fibroblasts) cells. Thus, these compounds have the potential to expand the therapeutic options against BC, and in particular, against its most aggressive forms (TNBCs). Moreover, the present synthetic approach may provide an economic benefit for their production. PMID- 30428326 TI - A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1. AB - Adhesion G-protein-coupled receptors (aGPCRs) play critical roles in diverse cellular processes in neurobiology, development, immunity, and numerous diseases. The lack of molecular understanding of their activation mechanisms, especially with regard to the transmembrane domains, hampers further studies to facilitate aGPCR-targeted drug development. Latrophilin-1/ADGRL1 is a model aGPCR that regulates synapse formation and embryogenesis, and its mutations are associated with cancer and attention-deficit/hyperactivity disorder. Here, we established functional assays to monitor latrophilin-1 function and showed the activation of latrophilin-1 by its endogenous agonist peptide. Via a comprehensive mutagenesis screen, we identified transmembrane domain residues essential for latrophilin-1 basal activity and for agonist peptide response. Strikingly, a cancer-associated mutation exhibited increased basal activity and failed to rescue the embryonic developmental phenotype in transgenic worms. These results provide a mechanistic foundation for future aGPCR-targeted drug design. PMID- 30428328 TI - A Barbeque-Analog Route to Carbonize Moldy Bread for Efficient Steam Generation. AB - Sustainable reconversion of the large quantities of food waste generated every day is pivotal for a green urban development in future. Herein, we put forth a sustainable and cost-effective way to repurpose a commonly used food waste for solar steam generation, an important part of water desalination. Making use of moldy bread, a new route for steam generation is demonstrated. The moldy bread was converted into a solar absorber by a simple and cost-effective carbonization process mimicking outdoor barbeque cooking. Carbonizing food waste to facilitate better absorption of sunlight for effective evaporation of water is an unprecedented concept in this field. Interestingly, the carbonized bread repurposed from the food waste served as an effective solar steam generator with an efficiency as high as 71.4% under 1 sun illumination. The structural and thermal absorption properties of the carbonized bread facilitated efficient solar energy absorption, heat management, and water transpiration in the system. PMID- 30428329 TI - Toward a Low-Cost Alkaline Zinc-Iron Flow Battery with a Polybenzimidazole Custom Membrane for Stationary Energy Storage. AB - Alkaline zinc-iron flow battery is a promising technology for electrochemical energy storage. In this study, we present a high-performance alkaline zinc-iron flow battery in combination with a self-made, low-cost membrane with high mechanical stability and a 3D porous carbon felt electrode. The membrane could provide high hydroxyl ion conductivity while resisting zinc dendrites well owing to its high mechanical stability. The 3D porous carbon felt could serve as a guidance for the zinc stripping/plating, which can effectively suppress zinc dendrite/accumulation as well. Thus this battery demonstrates a coulombic efficiency of 99.5% and an energy efficiency of 82.8% at 160 mA cm?2, which is the highest value among recently reported flow battery systems. The battery can stably run for more than 500 cycles, showing very good stability. Most importantly, the practicability of this battery is confirmed by assembling a kilowatt cell stack with capital cost under $90/kWh. PMID- 30428331 TI - Tolerance of Perovskite Solar Cell to High-Energy Particle Irradiations in Space Environment. PMID- 30428330 TI - Structural Basis of Homology-Directed DNA Repair Mediated by RAD52. AB - RAD52 mediates homologous recombination by annealing cDNA strands. However, the detailed mechanism of DNA annealing promoted by RAD52 has remained elusive. Here we report two crystal structures of human RAD52 single-stranded DNA (ssDNA) complexes that probably represent key reaction intermediates of RAD52-mediated DNA annealing. The first structure revealed a "wrapped" conformation of ssDNA around the homo-oligomeric RAD52 ring, in which the edges of the bases involved in base pairing are exposed to the solvent. The ssDNA conformation is close to B form and appears capable of engaging in Watson-Crick base pairing with the cDNA strand. The second structure revealed a "trapped" conformation of ssDNA between two RAD52 rings. This conformation is stabilized by a different RAD52 DNA binding site, which promotes the accumulation of multiple RAD52 rings on ssDNA and the aggregation of ssDNA. These structures provide a structural framework for understanding the mechanism of RAD52-mediated DNA annealing. PMID- 30428333 TI - Blink synchronization is an indicator of interest while viewing videos. AB - The temporal pattern of spontaneous blinks changes greatly depending on an individual's internal cognitive state. For instance, when several individuals watch the same video, blinks can be synchronized at attentional breakpoints. The present study examined the degree of this blink synchronization, as reflecting an interest level, while viewing various video clips. In the first experiment, participants interested in soccer, shogi (Japanese chess), or a specific musical group watched a video clip related to each category and rated their interest level after viewing. Results revealed that blink synchronization increased with a rise in interest level in the video clips of soccer and shogi. Moreover, while blink synchronization increased when viewing preferred video clips for the soccer and music group fans, synchronization decreased when viewing videos from the other categories, except for the shogi fans. In contrast, the blink rates did not correlate with the interest level on the video content but changed with the number of shot transitions of it. In the second experiment, participants viewed a video in which a professional salesperson gave descriptions of several products for a few minutes each. When participants reported an interest in the product, blinks were synchronized to the salesperson's blinks. However, when feeling uninterested, blink synchronization did not occur. These results suggest that blink synchronization could be used as an involuntary index to assess a person's interest. PMID- 30428334 TI - Targeted delivery of intranasally administered nanoparticles-mediated neuroprotective peptide NR2B9c to brain and neuron for treatment of ischemic stroke. AB - The lack of effective therapies mandates the development of new treatment strategies for ischemic stroke. The NR2B9c peptide can prevent N-Methyl-D aspartate receptor (NMDAR)-mediated neurotoxicity induced by ischemia without affecting essential NMDAR activity and brings hope for stroke therapy. However, it is very difficult for NR2B9c to cross by itself the blood-brain barrier (BBB) and the neuron membrane. To provide a suitable delivery for unleashing the therapeutic potential of NR2B9c, in consideration of a high affinity of wheat germ agglutinin (WGA) for WGA receptors abundantly present on olfactory epithelium and neuronal surface, we developed WGA-modified nanoparticles carrying NR2B9c (NR2B9c-WGA-NPs). Following intranasal administration, NR2B9c-WGA-NPs are able to bypass the BBB and effectively transport NR2B9c into the brain and neuron, and therefore can protect neurons against excitotoxicity, reduce ischemic brain injury in rats and ameliorate their neurological function deficits. The intranasal administration of NR2B9c-WGA-NPs may serve as a practical stroke therapy. PMID- 30428332 TI - mTORC1 Negatively Regulates the Replication of Classical Swine Fever Virus Through Autophagy and IRES-Dependent Translation. AB - Classical swine fever virus (CSFV) can utilize diverse host signaling pathways for its replication; however, the cross talk between mammalian target of rapamycin (mTOR) and CSFV remains unknown. Here, we describe the potential role of mTOR complex 1 (mTORC1) in promoting CSFV replication via virus-induced hypophosphorylation of the Akt/mTORC1/S6 pathway, especially at an early stage of viral infection. Conversely, activation of mTORC1 inhibited the replication of CSFV. Furthermore, we revealed the underlying mechanisms of mTORC1 pathway in mediating CSFV replication; in addition, our data also showed that CSFV-induced transient inhibition of mTORC1 elicited a negative feedback activation of PI3K/Akt/mTORC1pathway, likely contributing to maintain the dynamic balance between viral replication and host cell survival. This study has provided strong evidence showing how CSFV utilizes mTORC1 pathway for viral replication at an early stage in the viral replicative cycle and how the mTORC1 rescues itself by eliciting a feedback loop to limit viral replication and maintain cell survival. PMID- 30428335 TI - The role of calcium-calmodulin-dependent protein kinase II in modulation of spatial memory in morphine sensitized rats. AB - It has been shown that drug addiction and memory system are related but the signaling cascades underlying this interaction is not completely revealed yet. It has been demonstrated that binding of Calcium-calmodulin-dependent protein kinase II (CaMKII) to NMDA receptor is important in the memory process. The main objective of the study was to evaluate the role of CaMKII on the spatial memory of rats which previously were sensitized by morphine. The effect of CaMKII inhibitor (KN-93) on memory changes was investigated by hippocampal microinjection of KN-93 on the morphine-sensitized rats. Also, the role of the NMDA receptor in memory retention by KN-93 on the morphine sensitized rat was investigated with NMDA agonist and antagonist. Sensitization was induced by morphine injection (once daily for 3 days) followed by 5 days free of the drug before the trial phase. For the evaluation of spatial memory, the Morris Water Maze test (MWM) was used. Results showed that pre-trial administration of morphine, induced amnesia in MWM (p < 0.05). Also, three days pretreatment with morphine (20 mg/kg) followed by five days washout period, caused to enhance memory retrieval in confront with a pre-trial challenging dose of morphine (5 mg/kg). In addition, KN-93 administration during induction phase in morphine sensitization phenomena facilitated morphine-induced memory retention. In addition, inhibition of the NMDA receptor and KN-93 during the induction phase did not improve memory. However; intra-CA1 co-administration of KN-93 and NMDA during the induction phase of morphine sensitization resulted in improving spatial memory. It can be concluded that the effect of CaMKII on memory retention in morphine-sensitized rats depends on NMDA receptor. PMID- 30428336 TI - Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches. AB - Spray drying is increasingly becoming recognized as an efficient drying and formulation technique for pharmaceutical and biopharmaceutical processing. It offers significant economic and processing advantages compared to lyophilisation/freeze-drying techniques even though the optimisation of process parameters is often a costly and time-consuming procedure. Spray Drying has primarily been used in formulating small molecule drugs with low solubility however it is increasingly being applied to the processing of large biomolecules and biopharmaceuticals. This review examines the basics of spray drying process, current technology and various components used in spray drying process. Moreover, it is focused on introducing critical formulation and processing factors in spray drying of small molecule drugs and large biomolecules, their similarities and differences. Finally, it provides an overview of the experimental optimisation strategies designed to achieve optimum spray drying results in the shortest possible timeframe while utilising minimum product. PMID- 30428337 TI - Organic cation transporter and multidrug and toxin extrusion 1 co-mediated interaction between metformin and berberine. AB - Metformin and berberine are often combined for treating diabetes. In the present study, we evaluated the drug-drug pharmacokinetic interaction between metformin and berberine after oral co-administration in vivo and the underlying mechanism. As revealed by comparison with the metformin-only group, berberine significantly decreased the maximum plasma concentration (Cmax), area under the curve from 0 to 4 h (AUC0-4h), and urinary and bile excretion, and increased the kidney tissue concentration of metformin in rats. The non-everted intestinal sac study showed that berberine inhibited the absorption of metformin, and in transfected Madin Darby canine kidney (MDCK)-rat organic cation transporter 1 (MDCK-rOCT1), MDCK rat organic cation transporter 2 (MDCK-rOCT2), and MDCK-rat multidrug and toxin extrusion 1 (MDCK-rMATE1) cells, berberine significantly inhibited metformin transport mediated by OCT1, OCT2, and MATE1 in a concentration-dependent manner with half-maximal inhibitory concentration (IC50) values of 18.8, 1.02, and 10.7 MUM, respectively. In contrast, co-administration of metformin increased the Cmax and AUC0-4h of berberine with no significant difference in pharmacokinetics parameters between co-administration and berberine-only groups. Furthermore, metformin increased kidney and liver concentrations and reduced the urinary and biliary excretion of berberine. Metformin (>=1 or >=0.3 mM) decreased berberine transport in MDCK-rOCT1, MDCK-rOCT2, and MDCK-rMATE1 cells. However, metformin did not affect berberine concentration in MDCK-multidrug resistance protein 1 cells. These results suggest that the combination of metformin and berberine induced a pharmacokinetic interaction by cooperatively inhibiting OCT and MATE1 mediated transport. PMID- 30428338 TI - The case for plerixafor to replace filgrastim as the optimal agent to mobilize peripheral blood donors for allogeneic hematopoietic cell transplantation. AB - Granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral blood progenitor cells (G-PBs) from either a related or unrelated donor continue to be the preferred donor source for most allogeneic hematopoietic cell transplantation (HCT). Recently, the American Society for Blood and Marrow Transplantation has recommended marrow instead of G-PBs as an unrelated graft source due to its lower rate of chronic graft-versus-host disease (cGVHD). However, the use of marrow is limited by both clinical considerations (slower rate of engraftment and increased donor morbidity) and logistical considerations (use of operating room resources and increased physician utilization), so this recommendation has not been widely adopted. An optimal donor source would include the rapid engraftment characteristic and the low donor morbidity associated with G-PBs and a rate of cGVHD similar to or lower than that of marrow. Recent data suggest that plerixafor mobilized PBs (P-PBs) have the rapid engraftment characteristics of G PBs in allogeneic HCT with less cGVHD. The biologic mechanism of the lower rate of cGVHD appears to be through mobilization of regulator natural killer cells and plasmacytoid dendritic cell precursors that are associated with lower acute and chronic GVHD compared with G-PBs and rapid engraftment characterized by rapid myeloid-repopulating capacity. We suggest that, based on the experience of the two Phase II clinical trials and the unique biology of plerixafor-mobilized donor product, it should be evaluated in Phase III trials as an approach to replacing G CSF mobilization for allogeneic HCT. PMID- 30428339 TI - Xrs2 and Tel1 Independently Contribute to MR-Mediated DNA Tethering and Replisome Stability. AB - The yeast Mre11-Rad50-Xrs2 (MRX) complex has structural, signaling, and catalytic functions in the response to DNA damage. Xrs2, the eukaryotic-specific component of the complex, is required for nuclear import of Mre11 and Rad50 and to recruit the Tel1 kinase to damage sites. We show that nuclear-localized MR complex (Mre11 NLS) catalyzes homology-dependent repair without Xrs2, but MR cannot activate Tel1, and it fails to tether DSBs, resulting in sensitivity to genotoxins, replisome instability, and increased gross chromosome rearrangements (GCRs). Fusing the Tel1 interaction domain from Xrs2 to Mre11-NLS is sufficient to restore telomere elongation and Tel1 signaling to Xrs2-deficient cells. Furthermore, Tel1 stabilizes Mre11-DNA association, and this stabilization function becomes important for DNA damage resistance in the absence of Xrs2. Enforcing Tel1 recruitment to the nuclear MR complex fully rescues end tethering and stalled replication fork stability, and suppresses GCRs, highlighting important roles for Xrs2 and Tel1 to ensure optimal MR activity. PMID- 30428340 TI - Origin of Gamma Frequency Power during Hippocampal Sharp-Wave Ripples. AB - Hippocampal sharp-wave ripples (SPW-Rs) support consolidation of recently acquired episodic memories and planning future actions by generating ordered neuronal sequences of previous or future experiences. SPW-Rs are characterized by several spectral components: a slow (5-15 Hz) sharp-wave, a high-frequency "ripple" oscillation (150-200 Hz), and a slow "gamma" oscillation (20-40 Hz). Using laminar hippocampal recordings and optogenetic manipulations, we dissected the origin of these spectral components. We show that increased power in the 20 40 Hz band does not reflect an entrainment of CA1 and CA3 neurons at gamma frequency but the power envelope of overlapping ripples. Spike-local field potential coupling between unit firing in CA1 and CA3 regions during SPW-Rs is lowest in the gamma band. Longer SPW-Rs are preceded by increased firing in the entorhinal cortex. Thus, fusion of SPW-Rs leads to lengthening of their duration associated with increased power in the slow gamma band without the presence of true oscillation. PMID- 30428341 TI - Single-Molecule Turnarounds of Intraflagellar Transport at the C. elegans Ciliary Tip. AB - Cilia are microtubule-based sensing hubs that rely on intraflagellar transport (IFT) for their development, maintenance, and function. Kinesin-2 motors transport IFT trains, consisting of IFT proteins and cargo, from ciliary base to tip. There, trains turn around and are transported back by IFT dynein. The mechanism of tip turnaround has remained elusive. Here, we employ single-molecule fluorescence microscopy of IFT components in the tips of phasmid cilia of living C. elegans. Analysis of the trajectories reveals that while motor proteins and IFT-A particle component CHE-11 mostly turn around immediately, the IFT-B particle component OSM-6 pauses for several seconds. Our data indicate that IFT trains disassemble into at least IFT-A, IFT-B, IFT-dynein, and OSM-3 complexes at the tip, where OSM-6 is temporarily retained or undergoes modification, prior to train reassembly and retrograde transport. The single-molecule approach used here is a valuable tool to study how directional switches occur in microtubule-based transport processes. PMID- 30428342 TI - Autophagy Ablation in Adipocytes Induces Insulin Resistance and Reveals Roles for Lipid Peroxide and Nrf2 Signaling in Adipose-Liver Crosstalk. AB - Autophagy is a homeostatic cellular process involved in the degradation of long lived or damaged cellular components. The role of autophagy in adipogenesis is well recognized, but its role in mature adipocyte function is largely unknown. We show that the autophagy proteins Atg3 and Atg16L1 are required for proper mitochondrial function in mature adipocytes. In contrast to previous studies, we found that post-developmental ablation of autophagy causes peripheral insulin resistance independently of diet or adiposity. Finally, lack of adipocyte autophagy reveals cross talk between fat and liver, mediated by lipid peroxide induced Nrf2 signaling. Our data reveal a role for autophagy in preventing lipid peroxide formation and its transfer in insulin-sensitive peripheral tissues. PMID- 30428343 TI - Two B-Box Domain Proteins, BBX18 and BBX23, Interact with ELF3 and Regulate Thermomorphogenesis in Arabidopsis. AB - Plants coordinate their growth and developmental programs with various endogenous signals and environmental challenges. Phytochrome interacting factor 4 (PIF4) plays a critical positive role in thermoresponsive gene expression and hypocotyl growth in Arabidopsis, whereas early flowering 3 (ELF3) negatively regulates the activity of PIF4 at elevated temperatures. However, it is unknown how ELF3 activity is regulated at warm temperatures. Here, we report the identification of B-box 18 (BBX18) and BBX23 as important thermomorphogenesis regulators in Arabidopsis. BBX18 and BBX23 mutations result in reduced thermoresponsive hypocotyl elongation. In contrast, BBX18 overexpression promotes hypocotyl growth at elevated temperatures, which depends on either PIF4 or constitutive photomorphogenic 1 (COP1). BBX18 and BBX23 interact with ELF3 or COP1. Knocking out BBX18 and BBX23 increases ELF3 abundance under normal and warm temperature conditions. The expression of multiple thermoresponsive genes is impaired in both a PIF4 mutant and a BBX18/BBX23 double mutant. Thus, our findings reveal an important role of B-box proteins during thermomorphogenesis and provide insights into our understanding of how warm temperature signals regulate ELF3 activity and PIF4-dependent genes. PMID- 30428344 TI - A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus. AB - Tcrb locus V(D)J recombination is regulated by positioning at the nuclear periphery. Here, we used DamID to profile Tcrb locus interactions with the nuclear lamina at high resolution. We identified a lamina-associated domain (LAD) border composed of several CTCF-binding elements that segregates active non-LAD from inactive LAD regions of the locus. Deletion of the LAD border causes an enhancer-dependent spread of histone H3 lysine 27 acetylation from the active recombination center into recombination center-proximal LAD chromatin. This is associated with a disruption to nuclear lamina association, increased chromatin looping to the recombination center, and increased transcription and recombination of recombination center-proximal gene segments. Our results show that a LAD and LAD border are critical components of Tcrb locus gene regulation and suggest that LAD borders may generally function to constrain the activity of nearby enhancers. PMID- 30428345 TI - TP63-Mediated Enhancer Reprogramming Drives the Squamous Subtype of Pancreatic Ductal Adenocarcinoma. AB - The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (DeltaNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition. PMID- 30428346 TI - Brd4's Bromodomains Mediate Histone H3 Acetylation and Chromatin Remodeling in Pluripotent Cells through P300 and Brg1. AB - The pluripotent state of embryonic stem cells (ESCs) is defined by its transcriptome and epigenome. The chromatin reader Brd4 determines ESC identity. Although Brd4 regulation in gene transcription has been well described, its contribution to the chromatin landscape is less known. Here, we show that Brd4's bromodomains partner with the histone acetyltransferase P300, increasing its enzymatic activities. Augmenting histone acetylation by Brd4-P300 interaction recruits the chromatin remodeler Brg1 altering chromatin structure. This pathway is important for maintaining the expression and chromatin patterns of pluripotency-associated genes, such as Oct4, Nanog, and the X chromosome regulatory long noncoding RNAs Tsix and Xite. Furthermore, we show that the Brd4 P300 interaction regulates the de novo formation of chromatin marks during ESC differentiation, as exemplified by controlling the master regulators of mesoderm formation. Collectively, we delineate the function of Brd4 in organizing the chromatin structure that contributes to gene transcriptional regulation and cell fate determination. PMID- 30428347 TI - Thrombopoietin Metabolically Primes Hematopoietic Stem Cells to Megakaryocyte Lineage Differentiation. AB - During acute myelosuppression or thrombocytopenia, bone marrow (BM) hematopoietic cells respond rapidly to replenish peripheral blood platelets. While the cytokine thrombopoietin (Thpo) both regulates platelet production and maintains HSC potential, whether Thpo controls megakaryocyte (Mk)-lineage differentiation of HSCs is unclear. Here, we show that Thpo rapidly upregulates mitochondrial activity in HSCs, an activity accompanied by differentiation to an Mk lineage. Moreover, in unperturbed hematopoiesis, HSCs with high mitochondrial activity exhibit Mk-lineage differentiation in vitro and myeloid lineage-biased reconstitution in vivo. Furthermore, Thpo skewed HSCs to express the tetraspanin CD9, a pattern correlated with mitochondrial activity. Mitochondria-active HSCs are resistant to apoptosis and oxidative stress upon Thpo stimulation. Thpo regulated mitochondrial activity associated with mitochondrial translocation of STAT3 phosphorylated at serine 727. Overall, we report an important role for Thpo in regulating rapid Mk-lineage commitment. Thpo-dependent changes in mitochondrial metabolism prime HSCs to undergo direct differentiation to an Mk lineage. PMID- 30428348 TI - Human COX7A2L Regulates Complex III Biogenesis and Promotes Supercomplex Organization Remodeling without Affecting Mitochondrial Bioenergetics. AB - The mitochondrial respiratory chain is organized in a dynamic set of supercomplexes (SCs). The COX7A2L protein is essential for mammalian SC III2+IV assembly. However, its function in respirasome (SCs I+III2+IVn) biogenesis remains controversial. To unambiguously determine the COX7A2L role, we generated COX7A2L-knockout (COX7A2L-KO) HEK293T and U87 cells. COX7A2L-KO cells lack SC III2+IV but have enhanced complex III steady-state levels, activity, and assembly rate, normal de novo complex IV biogenesis, and delayed respirasome formation. Nonetheless, the KOs have normal respirasome steady-state levels, and only larger structures (SCs I1-2+III2+IV2-n or megacomplexes) were undetected. Functional substrate-driven competition assays showed normal mitochondrial respiration in COX7A2L-KO cells in standard and nutritional-, environmental-, and oxidative stress-challenging conditions. We conclude that COX7A2L establishes a regulatory checkpoint for the biogenesis of CIII2 and specific SCs, but the COX7A2L dependent MRC remodeling is essential neither to maintain mitochondrial bioenergetics nor to cope with acute cellular stresses. PMID- 30428349 TI - Mitochondrial p32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation. AB - Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that p32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in p32-deficient DCs. We also found that p32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via p32-dependent PDH activity. p32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that p32 may serve as a therapeutic target for DC-related autoimmune diseases. PMID- 30428351 TI - KDEL Receptors Are Differentially Regulated to Maintain the ER Proteome under Calcium Deficiency. AB - Retention of critical endoplasmic reticulum (ER) luminal proteins needed to carry out diverse functions (e.g., protein synthesis and folding, lipid metabolism) is mediated through a carboxy-terminal ER retention sequence (ERS) and its interaction with KDEL receptors. Here, we demonstrate that depleting ER calcium causes mass departure of ERS-containing proteins from cells by overwhelming KDEL receptors. In addition, we provide evidence that KDELR2 and KDELR3, but not KDELR1, are unfolded protein response (UPR) genes upregulated as an adaptive response to counteract the loss of ERS-containing proteins, suggesting previously unknown isoform-specific functions of the KDEL receptors. Overall, our findings establish that decreases in ER calcium change the composition of the ER luminal proteome and secretome, which can impact cellular functions and cell viability. The redistribution of the ER proteome from inside the cell to the outside has implications for dissecting the complex relationship of ER homeostasis with diverse disease pathologies. PMID- 30428350 TI - Circadian Clock Regulation of Hepatic Lipid Metabolism by Modulation of m6A mRNA Methylation. AB - Transcriptional regulation of circadian rhythms is essential for lipid metabolic homeostasis, disruptions of which can lead to metabolic diseases. Whether N6 methyladenosine (m6A) mRNA methylation impacts circadian regulation of lipid metabolism is unclear. Here, we show m6A mRNA methylation oscillations in murine liver depend upon a functional circadian clock. Hepatic deletion of Bmal1 increases m6A mRNA methylation, particularly of PPaRalpha. Inhibition of m6A methylation via knockdown of m6A methyltransferase METTL3 decreases PPaRalpha m6A abundance and increases PPaRalpha mRNA lifetime and expression, reducing lipid accumulation in cells in vitro. Mechanistically, YTHDF2 binds to PPaRalpha to mediate its mRNA stability to regulate lipid metabolism. Induction of reactive oxygen species both in vitro and in vivo increases PPaRalpha transcript m6A levels, revealing a possible mechanism for circadian disruption on m6A mRNA methylation. These data show that m6A RNA methylation is important for circadian regulation of downstream genes and lipid metabolism, impacting metabolic outcomes. PMID- 30428352 TI - The Dynamics of TGF-beta Signaling Are Dictated by Receptor Trafficking via the ESCRT Machinery. AB - Signal transduction pathways stimulated by secreted growth factors are tightly regulated at multiple levels between the cell surface and the nucleus. The trafficking of cell surface receptors is emerging as a key step for regulating appropriate cellular responses, with perturbations in this process contributing to human diseases, including cancer. For receptors recognizing ligands of the transforming growth factor beta (TGF-beta) family, little is known about how trafficking is regulated or how this shapes signaling dynamics. Here, using whole genome small interfering RNA (siRNA) screens, we have identified the ESCRT (endosomal sorting complex required for transport) machinery as a crucial determinant of signal duration. Downregulation of ESCRT components increases the outputs of TGF-beta signaling and sensitizes cells to low doses of ligand in their microenvironment. This sensitization drives an epithelial-to-mesenchymal transition (EMT) in response to low doses of ligand, and we demonstrate a link between downregulation of the ESCRT machinery and cancer survival. PMID- 30428354 TI - Characterizing Speed Cells in the Rat Hippocampus. AB - Spatial navigation relies on visual landmarks as well as on self-motion information. In familiar environments, both place and grid cells maintain their firing fields in darkness, suggesting that they continuously receive information about locomotion speed required for path integration. Consistently, "speed cells" have been previously identified in the hippocampal formation and characterized in detail in the medial entorhinal cortex. Here we investigated speed-correlated firing in the hippocampus. We show that CA1 has speed cells that are stable across contexts, position in space, and time. Moreover, their speed-correlated firing occurs within theta cycles, independently of theta frequency. Interestingly, a physiological classification of cell types reveals that all CA1 speed cells are inhibitory. In fact, while speed modulates pyramidal cell activity, only the firing rate of interneurons can accurately predict locomotion speed on a sub-second timescale. These findings shed light on network models of navigation. PMID- 30428355 TI - Dissecting Molecular and Circuit Mechanisms for Inhibition and Delayed Response of ASI Neurons during Nociceptive Stimulus. AB - The mechanisms by which off-response neurons stay quiescent during stimulation are largely unknown. Here, we dissect underlying molecular and circuit mechanisms for the inhibition of off-response ASI neurons during nociceptive Cu2+ stimulation. ASIs are inhibited in parallel by sensory neurons ASER, ADFs, and ASHs. ASER activates RIC interneurons that release octopamine (OA) to inhibit ASIs through SER-3 and SER-6 receptors. ADFs release 5-HT that acts on the SER-1 receptor to activate RICs and subsequently inhibit ASIs. Furthermore, it is an inherent property of ASIs that only a delayed on response is evoked by Cu2+ stimulation even when all inhibitory neurons are silenced. Ectopic expression of the ion channel OCR-2, which functions synergistically with OSM-9, in the cilia of ASIs can induce an immediate on response of ASIs upon Cu2+ stimulation. Our findings elucidate the molecular and circuit mechanisms regulating fundamental properties of ASIs, including their inhibition and delayed response. PMID- 30428353 TI - Wnt Secretion Is Regulated by the Tetraspan Protein HIC-1 through Its Interaction with Neurabin/NAB-1. AB - The aberrant regulation of Wnt secretion is implicated in various neurological diseases. However, the mechanisms of Wnt release are still largely unknown. Here we describe the role of a C. elegans tetraspan protein, HIC-1, in maintaining normal Wnt release. We show that HIC-1 is expressed in cholinergic synapses and that mutants in hic-1 show increased levels of the acetylcholine receptor AChR/ACR-16. Our results suggest that HIC-1 maintains normal AChR/ACR-16 levels by regulating normal Wnt release from presynaptic neurons, as hic-1 mutants show an increase in secreted Wnt from cholinergic neurons. We further show that HIC-1 affects Wnt secretion by modulating the actin cytoskeleton through its interaction with the actin-binding protein NAB-1. In summary, we describe a protein, HIC-1, that functions as a neuromodulator by affecting postsynaptic AChR/ACR-16 levels by regulating presynaptic Wnt release from cholinergic motor neurons. PMID- 30428357 TI - Smchd1 Targeting to the Inactive X Is Dependent on the Xist-HnrnpK-PRC1 Pathway. AB - We and others have recently reported that the SMC protein Smchd1 is a regulator of chromosome conformation. Smchd1 is critical for the structure of the inactive X chromosome and at autosomal targets such as the Hox genes. However, it is unknown how Smchd1 is recruited to these sites. Here, we report that Smchd1 localizes to the inactive X via the Xist-HnrnpK-PRC1 (polycomb repressive complex 1) pathway. Contrary to previous reports, Smchd1 does not bind Xist or other RNA molecules with any specificity. Rather, the localization of Smchd1 to the inactive X is H2AK119ub dependent. Following perturbation of this interaction, Smchd1 is destabilized, which has consequences for gene silencing genome-wide. Our work adds Smchd1 to the PRC1 silencing pathway for X chromosome inactivation. PMID- 30428356 TI - Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression. AB - Down syndrome (DS, trisomy 21) is associated with developmental abnormalities and increased leukemia risk. To reconcile chromatin alterations with transcriptome changes, we performed paired exogenous spike-in normalized RNA and chromatin immunoprecipitation sequencing in DS models. Absolute normalization unmasks global amplification of gene expression associated with trisomy 21. Overexpression of the nucleosome binding protein HMGN1 (encoded on chr21q22) recapitulates transcriptional changes seen with triplication of a Down syndrome critical region on distal chromosome 21, and HMGN1 is necessary for B cell phenotypes in DS models. Absolute exogenous-normalized chromatin immunoprecipitation sequencing (ChIP-Rx) also reveals a global increase in histone H3K27 acetylation caused by HMGN1. Transcriptional amplification downstream of HMGN1 is enriched for stage-specific programs of B cells and B cell acute lymphoblastic leukemia, dependent on the developmental cellular context. These data offer a mechanistic explanation for DS transcriptional patterns and suggest that further study of HMGN1 and RNA amplification in diverse DS phenotypes is warranted. PMID- 30428358 TI - Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis. AB - Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. PMID- 30428361 TI - A Myogenic Double-Reporter Human Pluripotent Stem Cell Line Allows Prospective Isolation of Skeletal Muscle Progenitors. AB - Myogenic differentiation of human pluripotent stem cells (hPSCs) has been done by gene overexpression or directed differentiation. However, viral integration, long term culture, and the presence of unwanted cells are the main obstacles. By using CRISPR/Cas9n, a double-reporter human embryonic stem cell (hESC) line was generated for PAX7/MYF5, allowing prospective readout. This strategy allowed pathway screen to define efficient myogenic induction in hPSCs. Next, surface marker screen allowed identification of CD10 and CD24 for purification of myogenic progenitors and exclusion of non-myogenic cells. CD10 expression was also identified on human satellite cells and skeletal muscle progenitors. In vitro and in vivo studies using transgene and/or reporter-free hPSCs further validated myogenic potential of the cells by formation of new fibers expressing human dystrophin as well as donor-derived satellite cells in NSG-mdx4Cv mice. This study provides biological insights for myogenic differentiation of hPSCs using a double-reporter cell resource and defines an improved myogenic differentiation and purification strategy. PMID- 30428359 TI - Microanatomic Distribution of Myeloid Heme Oxygenase-1 Protects against Free Radical-Mediated Immunopathology in Human Tuberculosis. AB - Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that controls inflammatory responses and redox homeostasis; however, its role during pulmonary tuberculosis (TB) remains unclear. Using freshly resected human TB lung tissue, we examined the role of HO-1 within the cellular and pathological spectrum of TB. Flow cytometry and histopathological analysis of human TB lung tissues showed that HO 1 is expressed primarily in myeloid cells and that HO-1 levels in these cells were directly proportional to cytoprotection. HO-1 mitigates TB pathophysiology by diminishing myeloid cell-mediated oxidative damage caused by reactive oxygen and/or nitrogen intermediates, which control granulocytic karyorrhexis to generate a zonal HO-1 response. Using whole-body or myeloid-specific HO-1 deficient mice, we demonstrate that HO-1 is required to control myeloid cell infiltration and inflammation to protect against TB progression. Overall, this study reveals that zonation of HO-1 in myeloid cells modulates free-radical mediated stress, which regulates human TB immunopathology. PMID- 30428360 TI - DNA-PK Is Targeted by Multiple Vaccinia Virus Proteins to Inhibit DNA Sensing. AB - Virus infection is sensed by pattern recognition receptors (PRRs) detecting virus nucleic acids and initiating an innate immune response. DNA-dependent protein kinase (DNA-PK) is a PRR that binds cytosolic DNA and is antagonized by vaccinia virus (VACV) protein C16. Here, VACV protein C4 is also shown to antagonize DNA PK by binding to Ku and blocking Ku binding to DNA, leading to a reduced production of cytokines and chemokines in vivo and a diminished recruitment of inflammatory cells. C4 and C16 share redundancy in that a double deletion virus has reduced virulence not seen with single deletion viruses following intradermal infection. However, non-redundant functions exist because both single deletion viruses display attenuated virulence compared to wild-type VACV after intranasal infection. It is notable that VACV expresses two proteins to antagonize DNA-PK, but it is not known to target other DNA sensors, emphasizing the importance of this PRR in the response to infection in vivo. PMID- 30428363 TI - Nup133 Is Required for Proper Nuclear Pore Basket Assembly and Dynamics in Embryonic Stem Cells. PMID- 30428362 TI - In Vivo Delivery of Synthetic Human DNA-Encoded Monoclonal Antibodies Protect against Ebolavirus Infection in a Mouse Model. AB - Synthetically engineered DNA-encoded monoclonal antibodies (DMAbs) are an in vivo platform for evaluation and delivery of human mAb to control against infectious disease. Here, we engineer DMAbs encoding potent anti-Zaire ebolavirus (EBOV) glycoprotein (GP) mAbs isolated from Ebola virus disease survivors. We demonstrate the development of a human IgG1 DMAb platform for in vivo EBOV-GP mAb delivery and evaluation in a mouse model. Using this approach, we show that DMAb 11 and DMAb-34 exhibit functional and molecular profiles comparable to recombinant mAb, have a wide window of expression, and provide rapid protection against lethal mouse-adapted EBOV challenge. The DMAb platform represents a simple, rapid, and reproducible approach for evaluating the activity of mAb during clinical development. DMAbs have the potential to be a mAb delivery system, which may be advantageous for protection against highly pathogenic infectious diseases, like EBOV, in resource-limited and other challenging settings. PMID- 30428364 TI - The 10,000 Immunomes Project: Building a Resource for Human Immunology. PMID- 30428365 TI - Global profiling of megalocytivirus-induced proteins in tongue sole (Cynoglossus semilaevis) spleen identifies cellular processes essential to viral infection. AB - Megalocytivirus is a DNA virus with a broad host range among farmed fish including tongue sole (Cynoglossus semilaevis). In this study, label-free proteomics was performed to examine protein expression in tongue sole spleen induced by megalocytivirus at 8 and 12 days post infection (dpi). Compared to uninfected control fish, virus-infected fish displayed 315 up-regulated proteins and 111 down-regulated proteins at 8 dpi, and 48 up-regulated proteins and 43 down-regulated proteins at 12 dpi. The expressions of five differentially expressed proteins were confirmed by Western blot. The differentially expressed proteins were enriched in the pathways and processes associated with innate immune response and viral infection. Interference with the expression of two up regulated proteins of the ubiquitin proteasome system (UPS), i.e. proteasome assembly chaperone 2 and proteasome maturation protein, significantly reduced viral propagation in fish, whereas overexpression of these two proteins significantly enhanced viral propagation. Consistently, inhibition of the functioning of proteasome significantly impaired viral replication in vivo. This study provided the first global protein profile responsive to megalocytivirus in tongue sole, and revealed an essential role of UPS in viral infection. PMID- 30428367 TI - Neural Control of Dynamic 3-Dimensional Skin Papillae for Cuttlefish Camouflage. PMID- 30428368 TI - Transcriptional Co-activator Functions of YAP and TAZ Are Inversely Regulated by Tyrosine Phosphorylation Status of Parafibromin. PMID- 30428366 TI - N-Heterocyclic-Carbene-Catalyzed Domino Reactions via Two or More Activation Modes. AB - Organocatalytic domino processes have become a rapidly growing area of research. N-heterocyclic carbenes (NHCs) have emerged as powerful organocatalysts for various transformations and continue to have widespread application. In the last decade, domino reactions catalyzed by NHCs have seen significant progress since the different activation modes could be successfully combined in one process. The most attractive features of these domino sequences include the readily available catalysts and substrates, the simple operational procedures, and the rapid assembly of complex molecular scaffolds with excellent levels of stereocontrol under mild reaction conditions. This review covers the advances in NHC-catalyzed domino reactions by focusing on the reaction scope, limitations, and mechanism with a close attention to the features of the reaction substrates. PMID- 30428369 TI - YY1 Upregulates Checkpoint Receptors and Downregulates Type I Cytokines in Exhausted, Chronically Stimulated Human T Cells. AB - T cells infiltrate affected organs in chronic infections and malignancy, but they may fail to eradicate virus-infected cells or tumor because of exhaustion. This report describes a Yin Yang-1 (YY1)-centered mechanism for diverse components that have been correlated with exhaustion. Utilizing an in vitro reconstruction of chronic T cell activation, YY1 is shown to positively regulate the checkpoint receptors PD1, Lag3, and Tim3 and to negatively regulate the type I cytokines interleukin-2 (IL-2) (in collaboration with Ezh2 histone methyltransferase) and interferon gamma (IFN-?). Other tests suggest that IL-2 failure drives a large component of cytotoxic functional decline rather than solely checkpoint receptor ligand interactions that have been the focus of current anti-exhaustion therapies. Clinical evaluations confirm elevated YY1 and Ezh2 in melanoma tumor infiltrating lymphocytes and in PD1+ T cells in patients with HIV. Exhaustion is revealed to be an active process as the culmination of repetitive two-signal stimulation in a feedback loop via CD3/CD28?p38MAPK/JNK?YY1? exhaustion. PMID- 30428370 TI - DNA Sequence Context Controls the Binding and Processivity of the T7 DNA Primase. AB - Primases are key enzymes involved in DNA replication. They act on single-stranded DNA and catalyze the synthesis of short RNA primers used by DNA polymerases. Here, we investigate the DNA binding and activity of the bacteriophage T7 primase using a new workflow called high-throughput primase profiling (HTPP). Using a unique combination of high-throughput binding assays and biochemical analyses, HTPP reveals a complex landscape of binding specificity and functional activity for the T7 primase, determined by sequences flanking the primase recognition site. We identified specific features, such as G/T-rich flanks, which increase primase-DNA binding up to 10-fold and, surprisingly, also increase the length of newly formed RNA (up to 3-fold). To our knowledge, variability in primer length has not been reported for this primase. We expect that applying HTPP to additional enzymes will reveal new insights into the effects of DNA sequence composition on the DNA recognition and functional activity of primases. PMID- 30428371 TI - Tolerance of Perovskite Solar Cell to High-Energy Particle Irradiations in Space Environment. AB - Materials to be used in the space environment have to withstand extreme conditions, particularly with respect to cosmic particle irradiation. We report robust stability and high tolerance of organolead trihalide perovskite solar cells against high-fluence electron and proton beams. We found that methylammonium and formamidinium-based lead iodide perovskite solar cells composed of TiO2 and a conductive polymer, as electron and hole transport materials, can survive against accumulated dose levels up to 1016 and 1015particles/cm2 of electrons (1 MeV) and protons (50 KeV), respectively, which are known to completely destroy crystalline Si-, GaAS-, and InGaP/GaAs-based solar cells in spacecraft. These results justify the superior tolerance of perovskite photovoltaic materials to severe space radiations and their usefulness in satellite missions. PMID- 30428372 TI - Bioprinted 3D Primary Human Intestinal Tissues Model Aspects of Native Physiology and ADME/Tox Functions. AB - The human intestinal mucosa is a critical site for absorption, distribution, metabolism, and excretion (ADME)/Tox studies in drug development and is difficult to recapitulate in vitro. Using bioprinting, we generated three-dimensional (3D) intestinal tissue composed of human primary intestinal epithelial cells and myofibroblasts with architecture and function to model the native intestine. The 3D intestinal tissue demonstrates a polarized epithelium with tight junctions and specialized epithelial cell types and expresses functional and inducible CYP450 enzymes. The 3D intestinal tissues develop physiological barrier function, distinguish between high- and low-permeability compounds, and have functional P gp and BCRP transporters. Biochemical and histological characterization demonstrate that 3D intestinal tissues can generate an injury response to compound-induced toxicity and inflammation. This model is compatible with existing preclinical assays and may be implemented as an additional bridge to clinical trials by enhancing safety and efficacy prediction in drug development. PMID- 30428373 TI - Chemical-Chemical Combinations Map Uncharted Interactions in Escherichia coli under Nutrient Stress. AB - Of the ?4,400 genes that constitute Escherichia coli's genome, ?300 genes are indispensable for its growth in nutrient-rich conditions. These encode housekeeping functions, including cell wall, DNA, RNA, and protein syntheses. Under conditions in which nutrients are limited to a carbon source, nitrogen source, essential phosphates, and salts, more than 100 additional genes become essential. These largely code for the synthesis of amino acids, vitamins, and nucleobases. Although much is known about this collection of ?400 genes, their interactions under nutrient stress are uncharted. Using a chemical biology approach, we focused on 45 chemical probes targeting encoded proteins in this collection and mapped their interactions under nutrient-limited conditions. Encompassing 990 unique pairwise chemical combinations, we revealed a highly connected network of 186 interactions, of which 81 were synergistic and 105 were antagonistic. The network revealed signature interactions for each probe and highlighted new connectivity between housekeeping functions and those essential in nutrient stress. PMID- 30428374 TI - Morphological, Chemical, and Electronic Changes of the Conjugated Polymer PTB7 with Thermal Annealing. AB - There is considerable interest in improving the performance of organic optoelectronic devices through processing techniques. Here, we study the effect of high-temperature annealing on the properties of the semiconducting polymer PTB7 and PTB7:fullerene blends, of interest as efficient organic photovoltaic (OPV) devices. Annealing to moderate temperature improves the PTB7 morphology and optoelectronic properties. High-temperature annealing also improves morphology but results in poorer optoelectronic properties. This is a result of side chain cleavage that creates by-products that act as trap states, increasing electronic disorder and decreasing mobility. We further observe changes to the PTB7 chemical structure after thermal cleavage that are similar to those following solar irradiation. This implies that side chain cleavage is an important mechanism in device photodegradation, which is a major "burn-in" loss mechanism in OPV. These results lend insight into side chain cleavage as a method of improving optoelectronic properties and suggest strategies for improvement in device photostability. PMID- 30428375 TI - The Body-wide Transcriptome Landscape of Disease Models. AB - Virtually all diseases affect multiple organs. However, our knowledge of the body wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13-23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment. PMID- 30428376 TI - Statistical Dynamics of Spatial-Order Formation by Communicating Cells. AB - Communicating cells can coordinate their gene expressions to form spatial patterns, generating order from disorder. Ubiquitous "secrete-and-sense cells" secrete and sense the same molecule to do so. Here we present a modeling framework-based on cellular automata and mimicking approaches of statistical mechanics-for understanding how secrete-and-sense cells with bistable gene expression, from disordered beginnings, can become spatially ordered by communicating through rapidly diffusing molecules. Classifying lattices of cells by two "macrostate" variables-"spatial index," measuring degree of order, and average gene-expression level-reveals a conceptual picture: a group of cells behaves as a single particle, in an abstract space, that rolls down on an adhesive "pseudo-energy landscape" whose shape is determined by cell-cell communication and an intracellular gene-regulatory circuit. Particles rolling down the landscape represent cells becoming more spatially ordered. We show how to extend this framework to more complex forms of cellular communication. PMID- 30428377 TI - Adaptive Regulation of Nitrate Transceptor NRT1.1 in Fluctuating Soil Nitrate Conditions. AB - Plant adaptation in variable soil nitrate concentrations involves sophisticated signaling and transport systems that modulate a variety of physiological and developmental responses. However, we know very little about their molecular mechanisms. It has recently been reported that many of these responses are regulated by a transceptor NRT1.1, a transporter cum receptor of nitrate signaling. NRT1.1 displays dual-affinity modes of nitrate binding and establishes phosphorylated/non-phosphorylated states at the amino acid residue threonine 101 in response to fluctuating nitrate concentrations. Here we report that intrinsic structural asymmetries between the protomers of the homodimer NRT1.1 provide a functional basis for having dual-affinity modes of nitrate binding and play a pivotal role for the phosphorylation switch. Nitrate-triggered local conformational changes facilitate allosteric communications between the nitrate binding and the phosphorylation site in one protomer, but such communications are impeded in the other. Structural analysis therefore suggests the functional relevance of NRT1.1 interprotomer asymmetries. PMID- 30428379 TI - Photocurrent Polarity Controlled by Light Wavelength in Self-Powered ZnO Nanowires/SnS Photodetector System. PMID- 30428380 TI - Preparation of porcine enterotoxigenic Escherichia coli (ETEC) ghosts and immunogenic analysis in a mouse model. AB - Enterotoxignenic Escherichia coli (ETEC)-associated colibacillosis causes high levels of morbidity and mortality in neonatal piglets. Vaccination is among effective strategy to fight against ETEC-related diseases. Bacterial ghosts (BGs) are empty bacterial envelopes, which substain subtle antigenic comformation in bacterial outer membrane. In this study, a BG vaccine was generated using porcine ETEC isolated strain DQ061 and evaluated its safety and immunogenicity in a mouse model. The recombinant bacteria were constructed by transformation of lysis plasmid pHH43 and generation of BGs was conducted in a lysis rate of 99.93% by incubation of the recombinant bacteria at 42 degrees C for 2 h. Mice were immunized subcutaneously twice in 2-week intervals with BGs, BGs emulsified with ISA 206 adjuvant, or formalin-inactivated ETEC vaccine after safety test. Mice with either of two BG vaccines developed higher titer of antibodies, secreted higher titer of interleukin 4, gamma interferon and alpha tumor necrosis factor after 2 doses than those with formalin-inactivated ETEC vaccine or those with adjuvant placebo (P < 0.01). The quantity of CD4+ and CD8+ T lymphocyte in spleen was higher in both BG groups than that in the inactivated vaccine group or adjuvant group 2 weeks post boost immunization (P < 0.05). The vaccinated mice were challenged intraperitoneally with 10 * LD50 dose of DQ061. Mice with the BGs plus adjuvant were completely protected against challenge, compared to 60% protection of mice with the inactivated vaccine. Mice exhibited decreased tissue lesion and reduced bacterial loads in the BGs groups by comparison with those with the inactivated vaccine or adjuvant only. Our results validated that the ETEC BGs bear high safety and immunogenicity in a mouse model, suggesting a potential of further evaluation in a pig model. PMID- 30428378 TI - An Early Function of Polycystin-2 for Left-Right Organizer Induction in Xenopus. AB - Nodal signaling controls asymmetric organ placement during vertebrate embryogenesis. Nodal is induced by a leftward fluid flow at the ciliated left right organizer (LRO). The mechanism of flow sensing, however, has remained elusive. pkd2 encodes the calcium channel Polycystin-2, which is required for kidney development and laterality, and may act in flow perception. Here, we have studied the role of Polycystin-2 in Xenopus and show that pkd2 is indispensable for left-right (LR) asymmetry. Knockdown of pkd2 prevented left-asymmetric nodal cascade induction in the lateral plate mesoderm. Defects were due to failure of LRO specification, morphogenesis, and, consequently, absence of leftward flow. Polycystin-2 synergizes with the unconventional nodal-type signaling molecule Xnr3 to induce the LRO precursor tissue before gastrulation, upstream of symmetry breakage. Our data uncover an unknown function of pkd2 in LR axis formation, which we propose represents an ancient role of Polycystin-2 during LRO induction in lower vertebrates. PMID- 30428381 TI - Molecular signatures of cytotoxic effects in human embryonic kidney 293 cells treated with single and mixture of ochratoxin A and citrinin. AB - Ochratoxin A (OTA) and citrinin (CTN) are important mycotoxins, which often coexist in food and feed stuff. In this study, individual and combinative cytotoxicity of OTA and CTN were tested in human embryonic kidney (HEK) 293 cells via MTT assay, and synergistic cytotoxic effects were found following co treatment with OTA and CTN, manifested by significant accumulation of HEK293 cells in S and G2/M stages. Transcriptomic and sRNA sequencing were performed to explore molecular signatures mediating individual or combinative cytotoxicity. A total of 378 miRNAs were identified, among which 66 miRNAs targeting thousands of genes were differentially expressed in response to different treatments, and 120 differentially expressed genes (DEGs) were regulated by either individual or combinative treatments. Correlations between two representative miRNAs (hsa-miR-1 3p and hsa-miR-122-5p), and their target genes, programmed cell death 10 (PDCD10) and cyclin G1 (CCNG1), associated with apoptotic signaling and cell cycle were analyzed by luciferase assay system. Further, their expression patterns were validated by quantitative real-time PCR and western blot analysis, suggesting that both miRNA-target interactions might account for the mycotoxin-induced cell death. Taken together, these findings provide molecular evidences for synergistic cytotoxic effects of exposure to single and mixture of OTA and CTN in HEK293 cells. PMID- 30428382 TI - A Pilot Study Comparing 2- and 3-Dimensional Ultrasound Imaging for Confirmation of ESSURE(r) Fallopian Tube Pregnancy Prevention Implants. AB - STUDY OBJECTIVE: To demonstrate the feasibility of 2-dimensional ultrasound (2DUS) imaging compared to 3-dimensionnal ultrasound (3DUS) to identify the location of implants and assess if the classification developed by Simorre et al described in 2016 was applicable to the 2 types of ultrasound imaging (2D and 3D). DESIGN: A prospective study (Canadian Task Force classification II-2). SETTING: Department of obstetrics and gynecology in a teaching hospital. PATIENTS: One hundred and fifty patients who had undergone hysteroscopic sterilization with ESSURE(r) (Bayer Pharma AG Laboratory, Lyon, France) fallopian tube pregnancy prevention implants were invited by letter to participate in the study; 50 replied positively between January and August 2017. INTERVENTION: An initial 2DUS was carried out followed by a 3DUS reconstruction. The primary endpoint was to compare identification of device placement with the 2DUS and 3DUS imaging procedures, according to this new classification. Secondary considerations were to evaluate the difficulty of attaining images, the quality of implant curvature, the duration of each imaging procedure, and the number of images carried out for each technique. MEASUREMENTS AND MAIN RESULTS: 96% tubal implants were observed via 3DUS compared with 100% via 2DUS. The mean time of 2DUS was 14.64 seconds for the right fallopian tube and 15.25 seconds for the left fallopian tube compared with 25.11 seconds for the right and 31.57 seconds for the left fallopian tube in 3DUS (p < .01). The mean number of image acquisitions per patient was 1.02 (+/- 0.14 standard deviation [SD]) for 2DUS compared with 1.37 (+/- 0.64 SD) for 3DUS (p < .01). The sonographer had no difficulty performing 2DUS in 88% of cases compared with 58% of 3DUS cases. CONCLUSION: Two-dimensional ultrasound appears to be an acceptable alternative to 3DUS. We propose a 2D classification for cross-section device localization to facilitate image interpretation. PMID- 30428383 TI - N-acetyltransferase co-expression increases alpha-glucosidase expression level in Pichia pastoris. AB - Pichia pastoris is subjected to strong oxidative stress in the methanol induction phase. The oxidative stress inflicts severe injury to yeast cells, which causes cell death and reduces protein expression ability. N-acetyltransferase in Saccharomyces cerevisiae can protect yeast cells from damage caused by decreasing reactive oxygen species (ROS) in oxidative pressure environments such as ethanol treatment, freeze-thawing, or heat shock. In this study, N-acetyltransferase from P. pastoris (PpMpr1) was overexpressed for the first time to improve the anti oxidative stress ability to protect cells from strong ROS damage during the methanol induction phase. Cell viability of the PpMpr1 overexpression strain increased significantly, while biomass was increased by 22.7% at high dissolved oxygen (DO). At the same time, the heterologous alpha-glucosidase (AGL) expression level at 25% DO was increased by 21.5%. The AGL degradation was greatly relieved in the fermentation supernatant of the PpMpr1 overexpression strain. This study shows that PpMpr1 has a great potential for improvement of anti-oxidative stress ability in P. pastoris and provides a promising recombinant microorganism for industrial production of proteins. PMID- 30428384 TI - Tackling Ethical Challenges of Premature Delivery of Stem Cell-Based Therapies: ISSCR 2018 Annual Meeting Focus Session Report. AB - Clinical uses of unproven stem cell-based interventions abound, yet many patients may be harmed by receiving them, raising complex ethical, economic, and societal concerns. Regulators, scientists, clinicians, professional societies, and patient advocacy groups need to collaboratively articulate expectations related to the proper development and delivery of stem cell-based therapies. PMID- 30428385 TI - Living with Keratinocytes. AB - A feature distinguishing human hematopoietic and epithelial stem cells from other equally fascinating stem cells is perhaps their easier translation into a clinical setting. We have devoted nearly our entire scientific career in trying to turn our understanding of epithelial stem cell biology into something that could help people suffering from virtually untreatable diseases of squamous epithelia. We have done that as a team, together with our numerous students, postdocs, technicians and valuable collaborators, clinicians, regulators, and, lately, industrial partners. We had rewarding successes and burning failures, but we always did our best. This award, given by friends and colleagues deserving it more than us, has been the most important recognition of our work. Below, we summarize our story. PMID- 30428386 TI - A Prospective Analysis of Human Leukemogenesis. AB - Decades of lack of progress in treating many fatal malignancies of the blood forming system is commanding interest in new approaches. Targeting early events in the leukemogenic process has long been recognized as likely to offer the information required for these diseases. Analysis of the representation of different mutations in the leukemic cells from individual patients offers a retrospective method to infer their sequence of acquisition and associated subclonal dynamics. An alternative, prospective approach is to exploit strategies for recreating human leukemia de novo using defined genetic methods. This concept is not new, but has been historically difficult to realize. A brief review of our experience in generating insights into the properties and regulation of primitive normal human hematopoietic cells serves as a reminder of how this has enabled our recent advances in developing this approach using both primary sources of chronic myeloid leukemic cells and normal cord blood cells as targets. PMID- 30428388 TI - Microglandular Adenosis is an advanced precursor breast lesion with evidence of molecular progression to matrix-producing metaplastic carcinoma. AB - Microglandular adenosis (MGA) is a rare breast lesion reported to be associated with invasive carcinoma in up to 20-30% of cases, and has been proposed as a non obligate precursor to basal-like breast cancers. We identified a case of matrix producing metaplastic carcinoma with morphologic and immunohistochemical evidence of progression from MGA to atypical MGA (AMGA), carcinoma in situ (CIS) and invasive carcinoma. We performed whole exome sequencing of each component (MGA, AMGA, CIS and cancer) to characterize the mutational landscape of these foci. There was significant copy number overlap between all foci, including a segmental amplification of the CCND1 locus (partial chromosome 11 trisomy) and MYC (8q24.12 13). Using a bioinformatics approach, we were able to identify three putative mutational clusters and recurrent, stop-gain non-synonymous mutations in both ZNF862 and TP53 that were shared across all foci. Finally, we identified a novel deleterious splice-acceptor site mutation of chr5:5186164G>T (chromosome 5p15) encoding the gene, ADAMTS16, in the invasive component. PMID- 30428387 TI - Intestinal Stem Cells Exhibit Conditional Circadian Clock Function. AB - The circadian clock is a molecular pacemaker that produces 24-hr physiological cycles known as circadian rhythms. How the clock regulates stem cells is an emerging area of research with many outstanding questions. We tested clock function in vivo at the single cell resolution in the Drosophila intestine, a tissue that is exquisitely sensitive to environmental cues and has circadian rhythms in regeneration. Our results indicate that circadian clocks function in intestinal stem cells and enterocytes but are downregulated during enteroendocrine cell differentiation. Drosophila intestinal cells are principally synchronized by the photoperiod, but intestinal stem cell clocks are highly responsive to signaling pathways that comprise their niche, and we find that the Wnt and Hippo signaling pathways positively regulate stem cell circadian clock function. These data reveal that intestinal stem cell circadian rhythms are regulated by cellular signaling and provide insight as to how clocks may be altered during physiological changes such as regeneration and aging. PMID- 30428389 TI - Prognostic significance of Ki-67 levels and hormone receptor expression in low grade serous ovarian carcinoma: an investigation of the tumor bank ovarian cancer network. AB - Low-grade serous ovarian carcinoma (LGSOC) has recently come up as a distinct rare entity of epithelial ovarian cancer. Predictive and prognostic markers are not well studied yet. As Ki-67 and hormone receptors (HR) has been established as relevant cancer biomarkers in several malignant tumors we evaluated Ki-67 and HR expression rates by immunohistochemistry in 68 patients with LGSOC. We used standardized cutoff-finder algorithm to analyze prognostic significance for overall survival (OS) and progression free survival (PFS). Cox regression showed a significant continuous decrease in OS for higher proliferation rates with a HR per %=1.07 (CI 95% 1.01-3.67, P=.048) but not in PFS (P=.86). Cutoff finder analysis revealed the best possible cutoff for OS at 6.28% (P=.04) and for PFS at 1.85% proliferative activity (P=.04). ERs were expressed in the majority of LGSOC patients (n=61, 89.7%), PR in about half of patients (n=33, 48.5%). For both ER/PR a statistical significant cutoff for PFS could be determined, which was for ER at 75% of positive tumor cells (P=.02) and for PR at 15% of positive tumor cells (P=.03). For OS hormone receptor expression showed a tendency towards better OS for HR positive tumors, but did not turn out statistically significant. Our results show that Ki-67 is a valuable prognostic marker in the subgroup of LGSOC. We could also show, that most LGSOC not only express HRs but that this expression is associated with a better PFS, a finding valuable in times of antihormonal therapy in LGSOC. PMID- 30428390 TI - Quantification of Leydig cells and stromal hyperplasia in the postmenopausal ovary of women with endometrial carcinoma. AB - Endometrioid endometrial carcinomas (EECs) are correlated with high serum levels of androgens and estrogen. We hypothesized that Leydig cells and ovarian stromal hyperplasia contribute to postmenopausal ovarian androgen production, and are observed more frequently in EEC patients. Ovaries of postmenopausal women with EEC (n=36) or non-endometrioid endometrial carcinoma (NEEC) (n=19) were examined for the presence of hilar Leydig cells, and compared with ovaries resected for benign conditions (n=22). Leydig cells were counted manually and a Leydig cell density was calculated per mm2 hilar surface. Ovarian stromal hyperplasia was scored as atrophic, moderate hyperplastic, or marked hyperplastic. In all endometrial carcinomas (ECs), these findings were correlated with the serum levels of sex steroids and hormone receptor expression in their ECs. In EEC patients, mean number of Leydig cells was 282.8 cells compared to 76.3 cells in NEEC patients and 66.4 cells in controls. Leydig cells, marked stromal hyperplasia, and combined presence were observed more frequently in EEC patients compared to NEEC and controls. Combined presence was associated with higher serum sex steroid levels and increased tumor expression of estrogen and progesterone receptor. A cut-off value for Leydig cell hyperplasia could be proposed at a total of 300 Leydig cells bilaterally, examining a representative cross-section of both hili. Concluding, we have quantified hilar Leydig cells and demonstrated that Leydig cells may contribute to the development of EEC by increased androgen production in postmenopausal women. The correlation between sex hormone levels and Leydig cell hyperplasia may support endometrial pathology screening in these women. PMID- 30428391 TI - Validation of the international tumor budding consensus conference (ITBCC 2016) recommendations on tumor budding in stage I-IV colorectal cancer. AB - Tumor budding is a robust prognostic parameter in colorectal cancer and can be used as an additional factor to guide patient management. Though backed by large bodies of data, a standardized scoring method is essential for integrating tumor budding in reporting protocols. The International Tumor Budding Consensus Conference (ITBCC) 2016 has proposed such a scoring system. The aim of this study is to validate the ITBCC method of tumor budding assessment on a well characterized CRC cohort. 379 patients with resected Stage I-IV colorectal cancer were entered into the study. Tumor budding was scored by two pathologists according to the ITBCC recommendations on hematoxylin and eosin-stained slides and scored as BD1 (low-), BD2 (intermediate-) and BD3 (high-grade). Analysis was performed using a 3-tier approach, a 2-tier approach (BD1+2 versus BD3) and budding as a continuous variable. High-grade tumor budding was associated with adverse clinicopathological features including higher pT, higher pN stage and higher TNM stage (all P<.001) and poorer overall survival on univariate analysis (P=.0251 for BD1/2/3, P=.0106 for BD1+2 versus BD3 and P=.0195 for continuous scores (HR 1.023 (95%CI: 1.004-1.043 per bud)). In stage II cancers, BD3 was associated with poorer disease-free survival (P<.01). Tumor budding assessed by the method proposed by the ITBCC is applicable to colorectal cancer resection specimens and can be used for widespread reporting in routine. PMID- 30428392 TI - European sea bass brain DLB-1 cell line is susceptible to nodavirus: A transcriptomic study. AB - Viral diseases are responsible for high rates of mortality and subsequent economic losses in modern aquaculture. The nervous necrosis virus (NNV) produces viral encephalopathy and retinopathy (VER), which affects the fish central nervous system. It is considered one of the most serious viral diseases in marine aquaculture, the European sea bass (Dicentrarchus labrax) being amongst the most susceptible. We have evaluated the European sea bass brain derived cell line (DLB 1) susceptibility to NNV genotypes and evaluated its transcriptomic profile. DLB 1 cells supported NNV gene transcription and replication since strains belonging to the four NNV genotypes produce cytopathic effects. Afterwards, DLB-1 cells were infected with an RGNNV strain, the one which showed the highest replication, for 12 and 72 h and an RNA-seq analysis was performed to identify potential genes involved in the host-NNV interactions. Differential expression analysis showed the up-regulation of many genes related to immunity, heat-shock proteins or apoptosis but not to proteasome or autophagy processes. These data suggest that the immune response, mainly the interferon (IFN) pathway, is not powerful enough to abrogate the infection, and cells finally suffer stress and die by apoptosis liberating infective particles. GO enrichment also revealed, for the first time, the down-regulation of terms related to brain/neuron biology indicating molecular mechanisms causing the pathogenic effect of NNV. This study opens the way to understand key elements in sea bass brain and NNV interactions. PMID- 30428393 TI - Effects of Lactococcus lactis subsp. lactis JCM5805 on colonization dynamics of gut microbiota and regulation of immunity in early ontogenetic stages of tilapia. AB - The administration of probiotics during early ontogenetic stages can be an effective way to manipulate the gut microbiota of animals. Specifically, the administration of probiotics can enhance gut-colonization success and regulate the immune response. In this study, the effects of early contact with probiotic Lactococcus lactis subsp. lactis JCM5805 on the gut microbial assembly of larvae Nile tilapia were examined. The effects of JCM5805 on IFNalpha expression through the TLR7 and TLR9-dependent signal transduction pathway as well as larval disease resistance were studied. Three days postfertilization, embryos were randomly allocated into nine 30 L tanks with a concentration of 20 eggs L-1. Triplicate tanks were performed for each treatment. Treatments included a control group (C), a low probiotic concentration group (T1), where JCM5805 was added to the water at 1 * 104 cfu ml-1, and a high probiotic concentration group (T2), where JCM5805 was added to the water at 1 * 108 cfu ml-1. Probiotics were administered continuously for 15 days. qPCR was used to analyze transcript levels of the TLR7, TLR9, MyD88, IRF7 and IFNalpha genes using RNA extracted from whole embryos on day 5 and 10, and from the intestine of larvae on day 15. Transcription of these genes was also measured in the intestine, liver and spleen of larvae one month after the cessation of probiotic administration. The results showed that MyD88 and IRF7 were significantly elevated on days 5 and 10 in the T2 group. TLR9 and IFNalpha were also significantly elevated on days 5, 10 and 15 during probiotic application of T2 (P < 0.05). One month after the cessation of probiotics administration, no significant difference was observed in the expression of these genes (P > 0.05). The larvae were fed probiotics for 15 days and were infused with Streptococcus agalactiae strain WC1535 at a final concentration of 1 * 106 cfu ml-1. The survival rate of T2 was significantly higher than that of the C group (P < 0.05). Microbial characterization by Illumina HiSeq sequencing of 16S rRNA gene amplicons showed the significantly higher presence of JCM5805 in the guts of T2 after 15 days of probiotic continuous application. Although JCM5805 was below the detection level after the cessation of probiotic for 5 days, the gut microbiota of the exposed tilapia larvae in T2 remained clearly different from that of the control treatment after the cessation of probiotic administration. These data indicated that a high concentration of the probiotic strain JCM5805 upregulated the expression of IFNalpha via the TLR7/TLR9-Myd88 pathway and enhanced disease resistance of larvae. JCM5805 was only transiently detected and thus was not included in the stable larval microbiota. The early microbial exposure of tilapia larvae affects the gut microbiota at later life stages. However, whether the upregulation of related genes is related to the presence of JCM5805 strain in the intestine requires further verification. PMID- 30428394 TI - Enzymatic synthesis of non-natural trisaccharides and galactosides; Insights of their interaction with galectins as a function of their structure. AB - Galectins are a family of carbohydrate-recognizing proteins that by interacting with specific glycoepitopes can mediate important biological processes, including immune cell homeostasis and activation of tolerogenic circuits. Among the different members of this family, Galectin 1 and 3 have shown pro-tumorigenic effects, being overexpressed in numerous neoplasic diseases, proving to be relevant in tumor immune escape, tumor progression and resistance to drug-induced apoptosis. Thus, generation of specific glycosides that could inhibit their pro tumorigenic ability by blocking their carbohydrate recognition domain is one of the current major challenges in the field. Considering that galectin-ligand binding strength is closely related to the ligand structure, analysis of this relationship provides valuable information for rational design of high-affinity ligands that could work as effective galectin inhibitors. Taking profit of the ability of glycosidases to catalyze transglycosylation reactions we achieved the enzymatic synthesis of beta-d-Galp-(1 -> 6)-beta-d-Galp-(1 -> 4)-d-Glcp(2), a mixture of beta-d-Galp-(1 -> 6)-beta-d-Glcp-(1 -> 4)-d-Glcp(5) and beta-d-Galp-(1 -> 3)-beta-d-Glcp-(1 -> 4)-d-Glcp(6), and finally benzyl beta-d-galactopyranoside (9), with reaction yields between 16 and 27%. All the galactosides were purified, and characterized using 1H and 13C nuclear magnetic resonance spectroscopy. Docking results performed between the synthesized compounds and human Galectin 1 (hGal-1) and human Galectin 3 (hGal-3) showed that the replacement of a glucose moiety linked to the terminal galactose with a galactose moiety, decreases the affinity for these galectins. Moreover, regarding the interglycosidic bond the most favorable beta-Gal linkage seems to be beta(1 -> 4) followed by beta(1 -> 3) and beta(1 -> 6) for hGal-1, and beta(1 -> 4) followed by beta(1 -> 6) and beta(1 -> 3) for hGal-3. These results were in accordance with the IC50 values obtained with in vitro solid phase inhibition assays. Therefore, docking results obtained in this work proved to be a very good approximation for predicting binding affinity of novel galactosides. PMID- 30428395 TI - Chemoenzymatic radiosynthesis of 2-deoxy-2-[18F]fluoro-d-trehalose ([18F]-2 FDTre): A PET radioprobe for in vivo tracing of trehalose metabolism. AB - Trehalose analogues bearing fluorescent and click chemistry tags have been developed as probes of bacterial trehalose metabolism, but these tools have limitations with respect to in vivo imaging applications. Here, we report the radiosynthesis of the 18F-modified trehalose analogue 2-deoxy-2-[18F]fluoro-d trehalose ([18F]-2-FDTre), which in principle can be used in conjunction with positron emission tomography (PET) imaging to allow in vivo imaging of trehalose metabolism in various contexts. A chemoenzymatic method employing the thermophilic TreT enzyme from Thermoproteus tenax was used to rapidly (15-20 min), efficiently (70% radiochemical yield; >= 95% radiochemical purity), and reproducibly convert the commercially available radiotracer 2-deoxy-2-[18F]fluoro d-glucose ([18F]-2-FDG) into the target radioprobe [18F]-2-FDTre in a single step; both manual and automated syntheses were performed with similar results. Cellular uptake experiments showed that radiosynthetic [18F]-2-FDTre was metabolized by Mycobacterium smegmatis but not by various mammalian cell lines, pointing to the potential future use of this radioprobe for selective PET imaging of infections caused by trehalose-metabolizing bacterial pathogens such as M. tuberculosis. PMID- 30428397 TI - The "Fragility" of Mortality benefit of Coronary Artery Bypass Graft Surgery in Diabetics. PMID- 30428396 TI - Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events in the ODYSSEY OUTCOMES Trial. AB - BACKGROUND: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, added to high-intensity or maximum tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. OBJECTIVES: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. METHODS: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. RESULTS: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio 0.87, 95% confidence interval 0.82 to 0.93) and death (hazard ratio 0.83, 95% confidence interval 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. CONCLUSIONS: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS. PMID- 30428398 TI - Long-term Survival following Multivessel Revascularization in Patients with Diabetes (FREEDOM Follow-On Study). AB - BACKGROUND: The FREEDOM trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. OBJECTIVE: To evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. METHODS: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus or paclitaxel eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. RESULTS: Twenty-five centers (out of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range, 0 to 13.2). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio[HR], 1.36; 95% confidence interval[CI], 1.07 to 1.74; p=0.01). Of the 943 patients with extended follow-up, all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (HR, 1.32; 95%CI, 0.97 to 1.78; p= 0.076). CONCLUSIONS: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. PMID- 30428399 TI - No luck for moral luck. AB - Moral philosophers and psychologists often assume that people judge morally lucky and morally unlucky agents differently, an assumption that stands at the heart of the Puzzle of Moral Luck. We examine whether the asymmetry is found for reflective intuitions regarding wrongness, blame, permissibility, and punishment judgments, whether people's concrete, case-based judgments align with their explicit, abstract principles regarding moral luck, and what psychological mechanisms might drive the effect. Our experiments produce three findings: First, in within-subjects experiments favorable to reflective deliberation, the vast majority of people judge a lucky and an unlucky agent as equally blameworthy, and their actions as equally wrong and permissible. The philosophical Puzzle of Moral Luck, and the challenge to the very possibility of systematic ethics it is frequently taken to engender, thus simply do not arise. Second, punishment judgments are significantly more outcome-dependent than wrongness, blame, and permissibility judgments. While this constitutes evidence in favor of current Dual Process Theories of moral judgment, the latter need to be qualified: punishment and blame judgments do not seem to be driven by the same process, as is commonly argued in the literature. Third, in between-subjects experiments, outcome has an effect on all four types of moral judgments. This effect is mediated by negligence ascriptions and can ultimately be explained as due to differing probability ascriptions across cases. PMID- 30428400 TI - The role of experience for abstract concepts: Expertise modulates the electrophysiological correlates of mathematical word processing. AB - Embodied theories assign experience a crucial role in shaping conceptual representations. Supporting evidence comes mostly from studies on concrete concepts, where e.g., motor expertise facilitated action concept processing. This study examined experience-dependent effects on abstract concept processing. We asked participants with high and low mathematical expertise to perform a lexical decision task on mathematical and nonmathematical abstract words, while acquiring event-related potentials. Analyses revealed an interaction of expertise and word type on the amplitude of a fronto-central N400 and a centro-parietal late positive component (LPC). For mathematical words, we found a trend for a lower N400 and a significantly higher LPC amplitude in experts compared to nonexperts. No differences between groups were found for nonmathematical words. The results suggest that expertise affects the processing stages of semantic integration and memory retrieval specifically for expertise-related concepts. This study supports the generalization of experience-dependent conceptual processing mechanisms to the abstract domain. PMID- 30428401 TI - How can we evaluate the cost-effectiveness of health system strengthening? A typology and illustrations. AB - Health interventions often depend on a complex system of human and capital infrastructure that is shared with other interventions, in the form of service delivery platforms, such as healthcare facilities, hospitals, or community services. Most forms of health system strengthening seek to improve the efficiency or effectiveness of such delivery platforms. This paper presents a typology of ways in which health system strengthening can improve the economic efficiency of health services. Three types of health system strengthening are identified and modelled: (1) investment in the efficiency of an existing shared platform that generates positive benefits across a range of existing interventions; (2) relaxing a capacity constraint of an existing shared platform that inhibits the optimization of existing interventions; (3) providing an entirely new shared platform that supports a number of existing or new interventions. Theoretical models are illustrated with examples, and illustrate the importance of considering the portfolio of interventions using a platform, and not just piecemeal individual analysis of those interventions. They show how it is possible to extend principles of conventional cost-effectiveness analysis to identify an optimal balance between investing in health system strengthening and expenditure on specific interventions. The models developed in this paper provide a conceptual framework for evaluating the cost-effectiveness of investments in strengthening healthcare systems and, more broadly, shed light on the role that platforms play in promoting the cost-effectiveness of different interventions. PMID- 30428402 TI - Computational modelling approaches to meditation research: why should we care? AB - Computational modeling and meditation are not frequently mentioned in the same breath. However, in this article we argue that computational modeling can provide insights into the mechanisms by which meditation produces its effects on cognition. Moreover, computational modeling allows the researcher to make predictions about how effects of meditation will generalize to other contexts such as other tasks, which can be tested in subsequent experiments. In addition, computational theories can help to clarify similarities and differences between meditation practices, which is crucial for mapping out the space of contemplative practices. In short, even though computational modeling has not yet been used extensively, we think this approach can make important contributions to the field of meditation research. PMID- 30428403 TI - Ovarian stimulation with corifollitropin alfa followed by hp-hMG compared to hp hMG in patients at risk of poor ovarian response undergoing ICSI: A randomized controlled trial. AB - OBJECTIVE: To compare the results of two ovarian stimulation protocols for IVF in patients at risk of poor ovarian response: corifollitropin alfa followed by hp hMG versus daily administration of hp-hMG. We intended to demonstrate the non inferiority of the protocol with corifollitropin alfa. STUDY DESIGN: This is a prospective, randomized, non-inferiority, controlled study. We compared two ovarian stimulation protocols for IVF in 234 patients, under 40 years of age and at risk of poor ovarian response. First protocol was a single injection of 150 MUg corifollitropin alfa and the second, a daily injection of 300 IU of hp-hMG during the first week of ovarian stimulation. In both groups, if necessary, a daily injection of 300 IU of hp-hMG was dispensed until the criteria for hCG administration are met. For the primary and secondary outcomes, results were analysed by using a one-sided chi-square test or a Fisher exact test, as appropriate, with a level of significance of 0.05. For continuous variables, parametric (independent t-test) or non-parametric (Mann-Whitney test) tests were used depending on the normality of the distribution. Statistical significance was set at P < 0.05. RESULTS: The ongoing pregnancy rate, live birth rate (15.2 vs 20.2) (P = 0.33), and the cumulative live birth rate (15.2 vs 22.0) (P = 0.19) per started cycle did not show significant differences between the corifollitropin alfa and hp-hMG groups, and the difference estimated between treatments was -5% [95% CI: (-15.1, 5.0)]. CONCLUSIONS: It was not possible to probe non-inferiority of the protocol with corifollitropin alfa followed by hp hMG compared to hp-hMG in patients at risk of poor ovarian response undergoing ICSI. PMID- 30428404 TI - Downregulation of IQGAP2 Correlates with Prostate Cancer Recurrence and Metastasis. AB - IQGAP2 was recently reported as a tumor suppressor of prostate cancer (PC). Nonetheless, its clinical implications remain unknown. To address this issue, we extracted data related to IQGAP2 mRNA expression and genomic alterations from multiple large datasets within the Oncomine and cBioPortal databases and performed in silico analyses to determine a potential association of IQGAP2 mRNA expression and its genomic alterations with PC progression. In 4 cohorts consisting of 118 normal prostate tissues and 277 PCs, IQGAP2 mRNA expression was significantly elevated particularly in low-grade (primary Gleason score <=3) PCs; these changes separate PC from normal tissues with area under curve values of 0.7 0.8. Significant reductions in IQGAP2 mRNA levels and gene copy number occurred in more than 70 metastases compared to at least 230 local PCs. This duo alteration in IQGAP2 expression supports IQGAP2 elevation suppressing and its downregulation facilitating PC progression. Deletion and missense mutations were detected in 23 of 492 primary PCs; these alterations significantly associate with PC recurrence (HR=2.71; 95% CI: 1.35-5.44; P=.005) after adjusting for known risk factors and correlate with reductions in disease-free survival (DFS, P=.002). IQGAP2 (5q13.3) genomic alterations were observed in SPOP-marked PCs and co occurred with deletion in the RN7SK (16p12.2), SNORA50A (16q21), and SNORA50C (17q23.3) genes; the co-occurrence associated with reductions in DFS (P=4.14e-4). In two independent PC populations, MSKCC (n=130) and TCGA provisional (n=490), reductions in IQGAP2 mRNA expression were significantly associated with DFS. Collectively, this investigation reveals an association of IQGAP2 with PC progression. PMID- 30428405 TI - From Research to Policy Implementation: Trastuzumab in Early-Stage Breast Cancer Treatment in Thailand. AB - OBJECTIVES: To evaluate the adjuvant therapy of trastuzumab cost and quality adjusted life-years (QALYs) in lifetime horizon and describe the use of an economic evaluation in supporting policy-making decisions in the treatment of early-stage breast cancer in Thailand. METHODS: A Markov model was used to evaluate the cost effectiveness of 1-year adjuvant trastuzumab for patients with early-stage breast cancer who were considered human epidermal growth factor receptor 2/neu-positive with a societal perspective and lifetime horizon. The research variables were probability of health state change, health utility, and cost of treatment. A sensitivity analysis was conducted using probabilistic methods. A budget impact analysis was also performed. RESULTS: The results revealed that the treatment cost and QALYs in the trastuzumab group yielded 4.59 QALYs. The incremental cost-effectiveness ratio was $3387 (THB 118 572; THB = Thai baht) per QALY. On the basis of the willingness-to-pay threshold in Thailand, a 1-year adjuvant trastuzumab treatment for breast cancer was a cost effective therapy. CONCLUSIONS: A combination therapy that includes trastuzumab is a preferable choice and should be used in early-stage breast cancer treatment. The Thai government has listed trastuzumab on the National List of Essential Medicines to be used for the early stages of breast cancer since 2014. PMID- 30428406 TI - Effects of probiotics and nutrients addition on the microbial community and fermentation quality of peanut hull. AB - The objective of this study was to develop a new type of feedstuff by utilizing probiotics to transform agricultural byproducts to meet the livestock feed shortage. In this study, peanut hull powder (PHP) was used as the fermentation substrate, which was inoculated with 18 kinds of feed probiotics combined with two kinds of nutritional additives. The desired value formula was used to select the strains suitable for fermentation of PHP, and the strains were combined as multi-culture starters. We compared the changes of the chemical composition and bacterial flora before and after the fermentation, which provided a theoretical basis for the establishment and quality evaluation of the system of PHP fermentation. The result shows that inoculation with CM6 together with nutrients co-fermenting clearly raised the content of organic acid, CP and WSC in the PHP and effectively inhibited the growth of harmful microorganisms such as Enterobacter and Fusarium. PMID- 30428407 TI - Neuronal PAS domain 2 (Npas2) facilitated osseointegration of titanium implant with rough surface through a neuroskeletal mechanism. AB - Titanium (Ti) biomaterials have been applied to a wide range of implantable medical devices. When placed in bone marrow, Ti-biomaterials integrate to the surrounding bone tissue by mechanisms that are not fully understood. We have previously identified an unexpected upregulation of circadian clock molecule neuronal PAS domain 2 (Npas2) in successfully integrated implant with a rough surface. This study aimed to elucidate the molecular mechanism of osseointegration through determining the role of Npas2. Human bone marrow stromal cells (BMSC) that were cultured on a Ti disc with SLA surface exhibited increased NPAS2 expression compared to BMSC cultured on a machined surface. A mouse model was developed in which miniature Ti implants were surgically placed into femur bone marrow. The implant push-out test and bone-to-implant contact measurements demonstrated the establishment of osseointegration in 3 weeks. By contrast, in Npas2 functional knockout (KO) mice, the implant push-out value measured for SLA surface Ti implant was significantly decreased. Npas2 KO mice demonstrated normal femur bone structure surrounding the Ti implant; however, the recovered implants revealed abnormal remnant mineralized tissue, which lacked dense collagen architecture typically found on recovered implants from wild type mice. To explore the mechanisms leading to the induced Npas2 expression, an unbiased chemical genetics analysis was conducted using mouse BMSC carrying an Npas2 reporter gene for high throughput screening of Library of Pharmacologically Active Compounds. Npas2 modulating compounds were found clustered in regulatory networks of the alpha2-adrenergic receptor and its downstream cAMP/CREB signaling pathway. Mouse primary BMSC exposed to SLA Ti disc significantly increased the expression of alpha2-adrenergic receptors, but the expression of beta2-adrenergic receptor was unaffected. Our data provides the first evidence that peripheral clock gene component Npas2 plays a role in facilitating the enhanced osseointegration through neuroskeletal regulatory pathways induced by BMSC in contact with rough surface Ti implant. PMID- 30428408 TI - Chemometric analysis of porcine, bovine and ovine heparins. AB - Heparin is a polysaccharide anticoagulant drug isolated from animal tissues. There have been concerns on the safety and security of the heparin supply chain since 2007-8 when a contamination crisis led to its disruption. The current study applies a suite of modern analytical techniques to porcine, bovine and ovine intestinal mucosal heparins. These techniques include structural analysis by nuclear magnetic resonance spectrometry, disaccharide compositional analysis, bottom-up analysis of tetrasaccharides corresponding to heparin's antithrombin III binding site. Chemometric analysis was then applied to understand how these structural differences to predict the animal/tissue source of heparin and to help detect blending of heparins from various sources. PMID- 30428409 TI - A prototype tracing-technique to assess the mobility of dispersed earthworm casts on a vegetated hillslope using caesium-134 and cobalt-60. AB - Soil transport on fully vegetated land surfaces is typically detachment limited. Rates of soil and nutrient transport, and ultimately long-term landscape evolution, are controlled by processes that supply soil material for entrainment and transport. Despite their on-going nature, many such processes operate at low rates and have not been subject to detailed investigation. We present preliminary findings from a prototype tracing approach to quantify one such process; namely to determine the relative mobility of sediment from earthworm casts on a fully vegetated hillslope surface. A 0.6 * 0.5 m bounded area of pasture was prepared and fifteen intact earthworm casts representing 203 g of soil were labelled with an estimated 216 Bq of caesium-134 (134Cs) activity and evenly distributed across the upslope half of the plot, 0.3-0.6 m from the downslope outlet. A further 15 intact casts representing 190.7 g of soil were labelled with 224 Bq of cobalt-60 (60Co) activity and distributed between 0.3 and 0.0 m from the same outlet. All labelled casts were exposed to natural weather events over 76 days, during which time 186.3 mm of rainfall generated 16 runoff samples. A mass balance was used to partition labelled sediment from the unlabelled material. A total of 27.17 g of 60Co-labelled casts, equivalent to 14.2% of the original mass deployed, was recovered from a distance of <=0.3 m from their original locations. In contrast, 8.77 g of 134Cs-labelled casts, equivalent to 4.3% of the original mass deployed, was recovered from a distance >=0.3 m from their original locations. Some runoff derived samples recorded an over-enrichment of radionuclide material, which suggests that intact casts may sorb more material than the original assumption predicts. Ways in which sorption can be more accurately quantified to improve the accuracy of the tracing approach are outlined. PMID- 30428410 TI - Uptake mechanisms of perfluoroalkyl acids with different carbon chain lengths (C2 C8) by wheat (Triticum acstivnm L.). AB - Organic compounds could be taken up by plants via different pathways, depending on chemical properties and biological species, which is important for the risk assessment and risk control. To investigate the transport pathways of perfluoroalkyl acids (PFAAs) by wheat (Triticum acstivnm L.), the uptake of five perfluoroalkyl carboxylic acids (PFCAs): TFA (C2), PFPrA (C3), PFBA (C4), PFHxA (C6), PFOA (C8), and a perfluoroalkyl sulfonic acid: PFOS (C8)) were studied using hydroponic experiments. Various inhibitors including a metabolic inhibitor (Na3VO4), two anion channel blockers (9-AC, DIDS), and two aquaporin inhibitors (AgNO3, glycerol) were examined. The wheat root and shoot showed different concentration trends with the carbon chain length of PFAAs. The uptake of TFA was inhibited by Na3VO4 and 9-AC whereas PFPrA was inhibited by Na3VO4, AgNO3 and 9 AC. For the other four PFAAs, only Na3VO4 was effective. These results together with the result of concentration-dependent uptake, which followed the Michaelis Menten model, indicate that the uptake of PFAAs by wheat is mainly an energy dependent active process mediated by carriers. For the ultra-short chain PFCAs (C2 and C3), aquaporins and anion channels may also be involved. A competition between TFA and PFPrA was determined during the plant uptake but no competition was observed between these two shorter chain analogues with other analogues, neither between PFBA and PFHxA, PFBA and PFBS, PFOA and PFOS. PMID- 30428411 TI - Anthropogenic influences on emergence of vector-borne plant viruses: the persistent problem of Potato virus Y. AB - Potato virus Y (PVY) has reemerged as a serious impediment to seed potato production, responsible for reduced yields and tuber quality, as well as the majority of seed lot rejections by certification programs due to excessive virus incidence. This has led to seed shortages, especially in cultivars highly susceptible to infection. While seed certification programs have been effective at managing many virus diseases below economic thresholds, PVY has rapidly evolved in recent decades to become a complex of strains that evade many certification and farm management practices. The evolution of PVY strains is naturally occurring, but several human influences can be linked to the rapid change in PVY populations affecting the potato crop. Here we highlight the recent history and current status of PVY in potatoes and suggest some approaches for managing the virus moving forward. PMID- 30428412 TI - Impact of chronic hypertension on time to goal mean arterial pressure and clinical outcomes in critically ill patients with septic shock requiring vasopressors. AB - PURPOSE: Mean arterial pressure (MAP) reflects the adequacy of tissue perfusion. In septic shock, vasopressors are recommended to target MAP >=65 mmHg. The impact of chronic hypertension (HTN) on MAP achievement and outcomes are uncertain. MATERIALS AND METHODS: This retrospective, cohort study compared time to goal MAP in critically ill patients with septic shock admitted between May 2014 and July 2016. Between-group differences of patients with and without HTN were compared using appropriate statistical tests. To adjust for imbalances in baseline characteristics, inverse probability of treatment weighting (IPTW) procedure was performed. RESULTS: Of the 133 included patients, 75 (56.4%) had a history of HTN. Baseline characteristics were mostly similar. Patients with HTN had higher in-hospital (49.3 vs. 31.0%, p = .035) and 28-day mortality (53.3 vs. 31.0%, p = .011). After weighting and adjustment for imbalanced variables, patients with HTN achieved goal MAP more rapidly than those without (HR: 1.84, 95% CI: 1.14-2.96; p = .012). However, they also have higher odds of dying within 28 days of discharge (OR: 3.04, 95% CI: 1.11-8.38; p = .031). CONCLUSIONS: Patients with HTN achieved goal MAP more rapidly but had higher odds of mortality. PMID- 30428413 TI - A deuterohemin peptide protects a transgenic Caenorhabditis elegans model of Alzheimer's disease by inhibiting Abeta1-42 aggregation. AB - Alzheimer's disease (AD) is a progressive neurodegenerative brain disease and is the most common cause of dementia in the elderly. The main hallmark of AD is the deposition of insoluble amyloid (Abeta) outside the neuron, leading to amyloid plaques and neurofibrillary tangles in the brain. Deuterohemin-Ala-His-Thr-Val Glu-Lys (DhHP-6), a novel porphyrin-peptide, has both microperoxidase activity and cell permeability. In the present study, DhHP-6 efficiently inhibited the aggregation of Abeta and reduced the beta-sheet percentage of Abeta from 89.1% to 78.3%. DhHP-6 has a stronger affinity (KD = 100 +/- 12 MUM) for binding with Abeta at Phe4, Arg5, Val18, Glu11 and Glu22. In addition, DhHP-6 (100 MUM) significantly prolonged lifespan, alleviated paralysis and reduced Abeta plaque formation in the Abeta1-42 transgenic Caenorhabditis elegans CL4176 model of AD. Our results demonstrate that DhHP-6 is a potential drug candidate that efficiently protects a transgenic C. elegans model of Alzheimer's disease by inhibiting Abeta aggregation. PMID- 30428414 TI - Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity. AB - VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 MUM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action. PMID- 30428415 TI - New quinoline/chalcone hybrids as anti-cancer agents: Design, synthesis, and evaluations of cytotoxicity and PI3K inhibitory activity. AB - A series of quinoline-chalcone hybrids was designed as potential anti-cancer agents, synthesized and evaluated. Different cytotoxic assays revealed that compounds experienced promising activity. Compounds 9i and 9j were the most potent against all the cell lines tested with IC50 = 1.91-5.29 uM against A549 and K-562 cells. Mechanistically, 9i and 9j induced G2/M cell cycle arrest and apoptosis in both A549 and K562 cells. Moreover, all PI3K isoforms were inhibited non selectively with IC50s of 52-473 nM when tested against the two mentioned compounds with 9i being most potent against PI3K-gamma (IC50 = 52 nM). Docking of 9i and 9j showed a possible formation of H-bonding with essential valine residues in the active site of PI3K-gamma isoform. Meanwhile, Western blotting analysis revealed that 9i and 9j inhibited the phosphorylation of PI3K, Akt, mTOR, as well as GSK-3beta in both A549 and K562 cells, suggesting the correlation of blocking PI3K/Akt/mTOR pathway with the above antitumor activities. Together, our findings support the antitumor potential of quinoline-chalcone derivatives for NSCLC and CML by inhibiting the PI3K/Akt/mTOR pathway. PMID- 30428416 TI - Resistance modulatory and efflux-inhibitory activities of capsaicinoids and capsinoids. AB - Capsaicinoids are reported to have a bunch of promising pharmacological activities, among them antibacterial effects against various strains of bacteria. In this study the effect on efflux pumps of mycobacteria was investigated. The importance of efflux pumps, and the inhibition of these, is rising due to their involvement in antibiotic resistance development. In order to draw structure and activity relationships we tested natural and synthetical capsaicinoids as well as synthetical capsinoids. In an accumulation assay these compounds were evaluated for their ability to accumulate ethidium bromide into mycobacterial cells, a well known substrate for efflux pumps. Capsaicin and dihydrocapsaicin, the two most abundant capsaicinoids in Capsicum species, proved to be superior efflux pump inhibitors compared to the standard verapamil. A dilution series showed dose dependency of both compounds. The compound class of less pungent capsinoids qualified for further investigation as antibacterials against Mycobacterium smegmatis. PMID- 30428417 TI - New antibacterial and 5-lipoxygenase activities of synthetic benzyl phenyl ketones: Biological and docking studies. AB - We investigated twelve benzyl phenyl ketone derivatives which are synthetic precursors of isoflavonoids that are shown be good 5-hLOX inhibitors, especially those that have the catechol group, but these precursors never have been assayed as 5-hLOX inhibitors being a novelty as inhibitors of the enzyme, due to sharing important structural characteristics. Screening assays, half maximal inhibitory concentration (IC50) and kinetic assays of all the studied molecules (5 ug/ml in media assay) showed that 1-(2,4-dihydroxy-3-methylphenyl)-2-(3-chlorophenyl) ethanone (K205; IC50 = 3.5 uM; Ki = 4.8 uM) and 1-(2,4-dihydroxy-3-methylphenyl) 2-(2-nitrophenyl)-ethanone (K206; IC50 = 2.3 uM; Ki = 0.7 uM) were potent, selective, competitive and nonredox inhibitors of 5-hLOX. Antioxidant behavior was also assayed by DPPH, FRAP, and assessing ROS production, and those with antibacterial and antiproliferative properties relating to 1-(2,4-dihydroxy-3 methylphenyl)-2-(2-chlorophenyl)-ethanone (K208) established it as the most interesting and relevant compound studied, as it showed nearly 100% inhibition of bacterial growth of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). Finally, docking studies were done that helped to characterize how the inhibitor structures correlated to decreased 5-hLOX activity. PMID- 30428418 TI - Synthesis, characterization, crystal structure of novel bis thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes. AB - In this study, a series of novel bis-thiomethylcyclohexanone compounds (3a-3j) were synthesized by the addition of thio-Michael to the bis-chalcones under mild reaction conditions. The bis-thiomethylcyclohexanone derivatives (bis-sulfides) were characterized by 1H NMR, 13C NMR, FTIR and elemental analysis techniques. Furthermore, the molecular and crystal structures of 3h, 3i and 3j compounds were determined by single crystal X-ray diffraction studies. In this study, X-ray crystallography provided an alternative and often-complementary means for elucidating functional groups at the enzyme inhibitory site. Acetylcholinesterase (AChE) is a member of the hydrolase protein super family and has a significant role in acetylcholine-mediated neurotransmission. Here, we report the synthesis and determining of novel bis-thiomethylcyclohexanone compounds based hybrid scaffold of AChE inhibitors. The newly synthesized bis-thiomethylcyclohexanone compounds showed Ki values of in range of 39.14-183.23 nM against human carbonic anhydrase I isoenzyme (hCA I), 46.03-194.02 nM against human carbonic anhydrase II isoenzyme (hCA II), 4.55-32.64 nM against AChE and 12.77-37.38 nM against butyrylcholinesterase (BChE). As a result, novel bis-thiomethylcyclohexanone compounds can have promising anti Alzheimer drug potential and record novel hCA I, and hCA II enzymes inhibitor. PMID- 30428419 TI - Side-chain cleaved phytoecdysteroid metabolites as activators of protein kinase B. AB - Phytoecdysteroids exert their non-hormonal anabolic and adaptogenic effects in mammals, including humans, through a partially revealed mechanism of action involving the activation of protein kinase B (Akt). We have recently found that poststerone, a side-chain cleaved in vivo metabolite of 20-hydroxyecdysone, exerts potent anabolic activity in rats. Here we report the semi-synthetic preparation of a series of side-chain cleaved ecdysteroids and their activity on the Akt phosphorylation in murine skeletal muscle cells. Twelve C-21 ecdysteroids including 8 new compounds were obtained through the oxidative side-chain cleavage of various phytoecdysteroids, or through the base-catalyzed autoxidation of poststerone. The complete 1H and 13C NMR spectroscopic assignments of the new compounds are presented. Among the tested compounds, 9 could activate Akt stronger than poststerone revealing that side-chain cleaved derivatives of phytoecdysteroids other than 20-hydroxyecdysone are valuable bioactive metabolites. Thus, our results suggest that the expectable in vivo formation of such compounds should contribute to the bioactivity of herbal preparations containing ecdysteroid mixtures. PMID- 30428420 TI - 1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design, synthesis and biological evaluation. AB - A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3 triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC50s = 0.06-6.80 uM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31-155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu2+ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells. PMID- 30428421 TI - Morphology and mechanisms of a novel absorbable polymeric conduit in the pulmonary circulation of sheep. AB - BACKGROUND: Right ventricular outflow tract (RVOT) conduits used in children with congenital heart disease often degenerate rapidly or develop other complications, and they do not grow with the patient. This leads to multiple surgeries until adult-sized conduits can be implanted. We report experimental in vivo experience with an entirely synthetic absorbable graft, designed to be replaced by tissue in vivo by host cells, in a process termed Endogenous Tissue Restoration (ETR), and to grow commensurate with somatic growth. METHODS: We characterized the structure, mechanical properties, biocompatibility, and in vivo remodelling of a bioabsorbable polyester based on the self-complementary ureido-pyrimidinone (UPy) quadruple hydrogen-bonding motif. Electrospinning was used to process the polymer into a tubular graft with a highly porous wall structure, which was implanted as a pulmonary artery interposition graft in 9 adult sheep with a maximum follow-up of 1 year, followed by pathologic and mechanical analysis. RESULTS: All grafts were patent by transthoracic echocardiography. Eight were intact at post-mortem examination. One graft had aneurysmal dilation. Graft polymer resorption in vivo was consistent among specimens. Histologic examination revealed progressive tissue replacement of graft polymer, ongoing at one year, with remodeling to a structure that had some key features of native vascular wall. Burst pressures for all explants at 8 weeks and beyond were higher than those of native pulmonary artery (PA) and largely determined by newly formed tissue. CONCLUSIONS: Preclinical studies of a new, absorbable polymeric graft for PA replacement showed remodelling by endogenous cells up to one-year follow-up. Our results show that ETR leads to progressive and substantial replacement of an off-the-shelf synthetic bioabsorbable conduit by functional host tissue to one year in sheep. Thus, further development of this novel concept is warranted. PMID- 30428422 TI - Multiplex PCR for rapid identification of major lactic acid bacteria genera in cider and other fermented foods. AB - Lactobacillus, Pediococcus, Oenococcus and Leuconostoc are the main Lactic Acid Bacteria (LAB) genera present in cider as they are able to survive this hostile environment. LAB play a significant role in cider quality, for example in the process of malolactic fermentation, even though they can also be involved in spoilage of cider (production of biogenic amines, exopolysaccharides, off flavours...). In this context a better monitoring of the fermentation process is a matter of interest to guarantee cider quality. In the present study, we designed a genus-specific multiplex PCR for a rapid and simultaneous detection of the four main LAB genera involved in cider production. This multiplex PCR worked equally with purified genomic DNA of bacterial isolates and with colonies directly picked from agar plates. This new PCR method was also successfully extended to wine and dairy isolates, and thus constitutes an effective tool to quickly identify LAB associated with fermented foods. Moreover, many biodiversity studies would also benefit from this fast, cheap and reliable identification method. PMID- 30428423 TI - Dietary saturated fatty acid type impacts obesity-induced metabolic dysfunction and plasma lipidomic signatures in mice. AB - Saturated fatty acid (SFA) intake is associated with obesity, insulin resistance, and hepatic steatosis, but scant work examines the impact of SFA type upon these outcomes. We tested the hypothesis that an obesogenic diet prepared with medium chain SFA (MCSFA), mostly as lauric acid-derived from coconut oil, reduces obesity-induced outcomes compared to obesogenic diets prepared with increasing amounts long chain SFA (LCSFA), primarily palmitic acid. Mice were fed (16 weeks) a control, low fat diet or obesogenic diets prepared with differing content of MCSFA or LCSFA in which polyunsaturated and monounsaturated fatty acids (PUFA; MUFA) were kept constant. Inclusion of MCSFA in an obesogenic diet prevented hepatic lipid accumulation and lowered indices of insulin resistance. Obesogenic diets reduced hepatic levels of de novo lipogenesis proteins (SCD1 and FASN) but elevated the adipose levels of mRNA for the pro-inflammatory markers Mcp-1 and Tnfalpha. Lipidomic analysis of plasma indicated that MCSFA intake resulted in a different lipidomic signature than LCSFA intake, prevented elevation of pro inflammatory ceramides, but elevated concentrations of some lipids associated with elevated cardiovascular disease risk. Intake of the obesogenic diets in an SFA-type dependent manner elevated plasma concentrations of several phosphatidylcholine (PC) lipids having the long chain PUFA (LCPUFA) arachidonic acid (ARA) and docosahexaenoic acid (DHA), altered phospholipid ethers, and changed the triacylglyceryl environments of these LCPUFA. Our data indicate that (1) MCSFA reduce the severity of some obesogenic co-morbidities, (2) SFA-type modulates lipidomic signatures associated with cardiovascular disease and diabetes, and (3) dietary SFA type impacts LCPUFA metabolism. PMID- 30428424 TI - Omega-3 polyunsaturated fatty acids attenuate inflammatory activation and alter differentiation in human adipocytes. AB - BACKGROUND: Omega-3 polyunsaturated fatty acids, specifically the fish-oil derived eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as inflammation-resolving agents via their effects on adipose tissue. OBJECTIVE: We proposed to determine the effects of EPA and DHA on human adipocyte differentiation and inflammatory activation in vitro. METHODS: Primary human subcutaneous adipocytes from lean and obese subjects were treated with 100 MUM EPA and/or DHA throughout differentiation (differentiation studies) or for 72 h postdifferentiation (inflammatory studies). THP-1 monocytes were added to adipocyte wells for co-culture experiments. Subcutaneous and visceral adipose explants from obese subjects were treated for 72 h with EPA and DHA. Oil Red O staining was performed on live cells. Cells were collected for mRNA analysis by quantitative polymerase chain reaction, and media were collected for protein quantification by enzyme-linked immunosorbent assay. RESULTS: Incubation with EPA and/or DHA attenuated inflammatory response to lipopolysaccharide (LPS) and monocyte co-culture with reduction in post-LPS mRNA expression and protein levels of IL6, CCL2 and CX3CL1. Expression of inflammatory genes was also reduced in the endogenous inflammatory response in obese adipose. Both DHA and EPA reduced lipid droplet formation and lipogenic gene expression without alteration in expression of adipogenic genes or adiponectin secretion. CONCLUSIONS: EPA and DHA attenuate inflammatory activation of in vitro human adipocytes and reduce lipogenesis. PMID- 30428425 TI - RNAi-mediated antiviral immunity in insects and their possible application. AB - Antiviral RNA interference (RNAi) in insects is known for some time. Previously, data from the model organism Drosophila was lightly transferred to other insects. However, since more research is performed on other insects, both similarities and important differences among the RNAi pathways of insects are revealed. The piRNA pathway, for example, is suggested to have antiviral functions in mosquitoes, which is unknown for other insects. Moreover, production of viral cDNA from RNA viruses during infection and their possible incorporation into the genome hint towards potential inheritable immunity in mosquitoes. Increased knowledge of antiviral RNAi pathways has initiated efforts to engineer insects resistant to viral infections. New advances in genome editing will further stimulate this process. PMID- 30428426 TI - Chlorogenic acid protects against aluminum toxicity via MAPK/Akt signaling pathway in murine RAW264.7 macrophages. AB - Aluminum (Al), which may bring about damage to the macrophages, has been implicated in the development of immunological diseases. It has been reported that chlorogenic acid (CGA, 5-caffeoylquinic acid, chemical formula: C16H18O9) is a natural antioxidant and chelating agent with the capacity against Al (III) induced biotoxicity. The present study was carried out to investigate whether CGA could reduce AlCl3-induced cellular damage in RAW264.7 cells. After treatment with AlCl3, the inhibition rate of viability and phagocytic activity of RAW264.7 cells was 54.5% and 27.6%, respectively. Administration of CGA significantly improved the integrity and phagocytic activity, and attenuated the accumulation of intracellular Al(III) level and oxidative stress in Al(III)-treated cells. Furthermore, CGA significantly inhibited Al(III)-induced increase of phospho-Jun N-terminal kinase (p-JNK), a pro-apoptotic Bcl-2 family protein (Bad), cytochrome c and decrease of extracellular regulated protein kinases (ERK1/2), protein kinase B (Akt) protein expressions. These results showed that CGA has a protective effect against Al(III)-induced cytotoxicity through mitogen-activated protein kinase (MAPK)/Akt-mediated caspase pathways in RAW264.7 cells. PMID- 30428427 TI - Removal of Pb(II) ions from aqueous solutions using functionalized cryogels. AB - In this study, a poly(allylamine-co-methacrylamide-co-acrylic acid) (p(AA-co-MA co-AAc)) cryogel containing amine and carboxyl groups was prepared and subsequently functionalized with thiourea using methyl isothiocyanate. The functionalized p(AA-co-MA-co-AAc) cryogel was then applied to the adsorption of lead (Pb) ions from aqueous solution, and the amount of Pb adsorption was measured. The functionalized p(AA-co-MA-co-AAc) cryogel was analyzed by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM), and its chemical structure, pore shape, pore distribution and specific surface area were confirmed. To determine the effect of the solution pH and initial concentration on Pb adsorption by the functionalized p(AA-co-MA-co-AAc) cryogel, Pb adsorption tests were performed. The functionalized p(AA-co-MA-co-AAc) cryogel exhibited the highest adsorption amount at pH 7 and 400 mg L-1. The Pb adsorption process was determined to occur through chemical adsorption because the experimental data were fit well by a pseudo-second-order model. In addition, the equilibrium isotherm data fit the Langmuir isotherm better than the Freundlich model, indicating that the functionalized p(AA-co-MA-co-AAc) cryogel surfaces were uniform and that a lead adsorbate monolayer formed at equilibrium. PMID- 30428428 TI - Energy transfer phenomenon of Gd3+ to excited ground state of Eu3+ ions in Li2O BaO-Gd2O3-SiO2-Eu2O3 glasses. AB - Li2O-BaO-Gd2O3-SiO2 glasses with different concentration of Eu3+ ions were developed by the traditional melt quenching technique and characterized via FTIR, absorption, excitation, emission and CIE color coordinates analysis for visible red emission application. The FTIR shows strong band at position 740 cm-1 which is attributed to Si-O-Si symmetric stretching mode. Density and molar volume of LBGSEu glasses increases with Eu3+ ions concentration. The covalent nature of bond between the Eu3+ ions and surrounding ligands was confirmed from the bonding parameter (delta). From absorption spectra JO-parameters and oscillator strength are evaluated for LBGSEu6 glass. From JO-parameters, Eu3+ ions have asymmetric coordination environment and stronger covalency. The phonon line PSB (22,522 cm 1) confirm the phonon energy ~971 cm-1, that corresponds to the energy of one phonon associated with maximum energy of the vibrational mode couple to Eu3+ ions. Under 275 nm and 393 nm excitation, intense red emission was observed at 613 nm, we observe efficient energy transfer phenomena from Gd3+ -> Eu3+ in these glasses. Increasing trend of IR with increasing concentration of Eu2O3 indicates the asymmetric environment around Eu3+ ions in LBGS. Moreover, from JO analysis, LBGS glasses have high capability for red laser device with high lasing power and energy extraction ratio. The fluorescence lifetimes show decreasing trend in lifetime with increasing concentration of Eu2O3 is due to radiative transition. From CIE color coordinate, the CIE color coordinates of LBGSEu6 glass fall in reddish region close to orange region and can be useful for optical display devices. PMID- 30428429 TI - A sensitive colorimetric probe for detection of 6-thioguanine based on its protective effect on the silver nanoprisms. AB - In this work a non-aggregated colorimetric probe for detection of chemotherapeutic drug, 6-thioguanine (6-TG), is introduced. It is based on the protective effect of 6-TG on silver nanoprisms (AgNPRs) against the iodide induced etching reaction. Iodide ions can attack the corners of AgNPRs and etch them, leading to the morphological transition from nanoprisms to nanodiscs. As a consequence, the solution color changes from blue to pink. However, in the presence of 6-TG, due to its protective effect on the corners of AgNPRs, I- ions cannot etch the prisms and the blue color of solution remains unchanged. Using this effect, selective sensor was designed for detection of 6-TG in the range of 2.5-500 MUg L-1, with a detection limit of 0.95 MUg L-1. Since with varying the concentration of 6-TG in this range, the color variation from pink to blue can be easily observed, the designed sensing scheme can be used as a colorimetric probe. The method was used for analysis of human plasma samples. PMID- 30428430 TI - Application of stable isotope dimethyl labeling for MRM based absolute antigen quantification of influenza vaccine. AB - Determining the precursor/product ion pair and optimal collision energy are the critical steps for developing a multiple reaction monitoring (MRM) assay using triple quadruple mass spectrometer for protein quantitation. In this study, a platform consisting of stable isotope dimethyl labeling coupled with triple quadruple mass spectrometer was used to quantify the protein components of the influenza vaccines. Dimethyl labeling of both the peptide N-termini and the epsilon-amino group of lysine residues was achieved by reductive amination using formaldehyde and sodium cyanoborohydrate. Dimethylated peptides are known to exhibit dominant a1 ions under gas phase fragmentation in a mass spectrometer. These a1 ions can be predicted from the peptide N-terminal amino acids, and their signals do not vary significantly across a wide range of collision energies, which facilitates the determination of MRM transition settings for multiple protein targets. The intrinsic a1 ions provide sensitivity for acquiring MRM peaks that is superior to that of the typical b/y ions used for native peptides, and they also provided good linearity (R2 >= 0.99) at the detected concentration range for each peptide. These features allow for the simultaneous quantification of hemagglutinin and neuraminidase in vaccines derived from either embryo eggs or cell cultivation. Moreover, the low abundant ovalbumin residue originated from the manufacturing process can also be determined. The results demonstrate that the stable isotope dimethyl labeling coupled with MRM Mass spectrometry screening of a1 ions (i.e., SIDa-MS) can be used as a high-throughput platform for multiple protein quantification of vaccine products. PMID- 30428431 TI - Recent advances in magnetic fluid hyperthermia for cancer therapy. AB - Recently, magnetic fluid hyperthermia using biocompatible magnetic nanoparticles as heat mediators for cancer therapy has been extensively investigated due to its high efficiency and limited side effects. However, the development of more efficient heat nanomediators that exhibit very high specific absorption rate (SAR) value is essential for clinical application to overcome the several restrictions previously encountered due to the large quantity of nanomaterial required for effective treatment. In this review, we focus on the current progress in the development of magnetic nanoparticles based hyperthermia therapy as well as combined therapy harnessing hyperthermia with heat-mediated drug delivery for cancer treatment. We also address the fundamental principles of magnetic hyperthermia, basics of magnetism including the effect of several parameters on heating capacity, synthetic methods and nanoparticle surface chemistry needed to design and develop an ideal magnetic nanoparticle heat mediator suitable for clinical translation in cancer therapy. PMID- 30428432 TI - Synthesis of N-benzyl substituted 1,4-imino-l-lyxitols with a basic functional group as selective inhibitors of Golgi alpha-mannosidase IIb. AB - Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus is one of alternative ways to suppress growth of tumor tissue. Eight N-benzyl substituted 1,4-imino-l-lyxitols with basic functional groups (amine, amidine, guanidine), hydroxyl and fluoro groups were prepared, optimized their syntheses and tested for their ability to inhibit several alpha-mannosides from the GH family 38 (GMIIb, LManII and JBMan) as models for human Golgi and lysosomal alpha mannoside II. All compounds were found to be selective inhibitors of GMIIb. The most potent structure bearing guanidine group, inhibited GMIIb at the micromolar level (Ki = 19 +/- 2 uM) while no significant inhibition (>2 mM) of LManII and JBMan was observed. Based on molecular docking and pKa calculations this structure may form two salt bridges with aspartate dyad of the target enzyme improving its inhibitory potency compared with other N-benzyl substituted derivatives published in this and previous studies. PMID- 30428433 TI - Synthesis and biological evaluation of pyrano[4,3-b][1]benzopyranone derivatives as monoamine oxidase and cholinesterase inhibitors. AB - A series of eighteen pyrano[4,3-b][1]benzopyranone derivatives (1a-9b) were synthesized, and structure-activity relationships of their monoamine oxidase (MAO) A and B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Most of the synthesized compounds exhibited weak inhibitory activity toward MAO-A, whereas compounds 2a, 2b, 4a, 4b, 5a, 5b, 6a, 6b, 8a and 8b showed potent inhibitory activities toward MAO-B. Intriguingly, compounds 5a, 5b, and 8a showed inhibitory activities comparable to pargylin, used as a positive control for MAO-B. Substitution of butoxy at the C3 position or of chlorine at the C8 position of pyrano[4,3-b][1]benzopyranone increased the inhibitory activity of the compound toward MAO-B. The results of a molecular docking study supported this structural effect. Most of the compounds exhibited no or slight inhibitory activity toward AChE and BChE, with exo type compounds bearing a butoxy group, such as compounds 2b, 5b and 8b, showing weak but distinct inhibitory activities toward BChE. This report is the first to identify pyrano[4,3-b][1]benzopyranone derivatives as potent and selective MAO-B inhibitors. 3-Butoxy-8-chloro-pyrano[4,3-b][1]benzopyranone (5b) may be useful as a lead compound for the development of MAO-B inhibitors. PMID- 30428434 TI - Pneumatosis intestinalis a trap for the unwary: Case series and literature review. AB - INTRODUCTION: Pneumatosis Intestinalis (PI) can present with a broad range of presentations from chronic and non-specific to acute and life threatening. It is paradoxically one of the few conditions where a pneumoperitoneum found in the diagnostic workup is not necessarily an indication for laparotomy. PRESENTATION OF CASES: The first case is of a 75 year old gentlemen who attended the emergency department after several weeks of worsening abdominal pain and weight loss. At laparotomy, two segments of nodular, abnormal-looking small bowel were identified with bubbles of air seen in the small bowel mesentery. The second case is of an 86 year old man with of a 5-month history of abdominal pain, weight loss, nausea and diarrhoea. A subsequent endoscopy revealed diffuse gastritis with a small antral gastric ulcer with a small amount of blood. The CT scan demonstrated free air within the bowel wall, with a follow up scan performed 3 weeks later revealing an increase in the amount of free air. DISCUSSION: PI is a rare condition characterised by the presence of subserosal and submucosal gas filled cysts occurring anywhere in the gastrointestinal tract from the oesophagus to the anus. Numerous conditions have been associated with PI including bowel obstruction, infections, ischemia and there have been reported cases suggesting as association with Crohn's disease. CONCLUSION: PI is a condition that may manifest with a wide range of symptoms from mild abdominal pain to acute peritonitis. Its treatment is generally medical and even with radiological evidence of perforation laparotomy may not be indicated if the patient is clinically well. PMID- 30428435 TI - Correction of severe valgus deformity of knee osteoarthritis with non-constrained total knee arthroplasty implant: A case report. AB - INTRODUCTION: Knee osteoarthritis with valgus deformity presents a surgical challenge that must be solved during total knee arthroplasty (TKA). In some case whereby ligament imbalance is found, constrained implant should be used. Unfortunately, the implant is not always readily accessible in some developing countries. The objective of this paper is to provide alternative solution to such case. PRESENTATION OF CASE: We reported a 71-year-old female patient with a painful and fixed valgus deformity of her right knee. Preoperatively, the patient's right knee range of motion (ROM) was 10-145 degrees of flexion with a 32 degrees fixed valgus deformity. A constrained implant was not accessible. To balance the ligament, Medial Collateral Ligament (MCL) origin was shifted to superior and anterior. A non-constrained implant was used. The valgus deformity was corrected intraoperatively and ROM achieved 0-140 degrees of flexion. DISCUSSION: It is crucial that attention is given not only to the restoration of proper bony alignment but even more importantly to soft tissue balancing. By using the non-constrained implant, the cost can also be reduced and suitable for developing countries with limited coverage of state insurance. CONCLUSION: Three months after the surgery, the patient achieved stable and painless knee with 10 90 degrees of flexion and complete correction of her valgus deformity. PMID- 30428436 TI - Isolated Roux loop pancreaticojejunostomy versus conventional pancreaticojejunostomy after pancreaticoduodenectomy: A case-control study. AB - OBJECTIVES: The aim of this study was to compare the postoperative outcomes of isolated Roux loop pancreaticojejunostomy (IPJ) and conventional pancreaticojejunostomy (CPJ) after pancreaticoduodenectomy (PD). METHODS: Data of patients who underwent IPJ were compared with those of a pair-matched equal number of patients undergoing CPJ. The matching was performed according to age, gender, nature of the lesion indicating PD and the texture of the pancreas. The primary outcome was the rate of postoperative pancreatic fistula (POPF). Secondary outcomes included operative time, day to resumption of oral feeding, postoperative morbidity and mortality. RESULTS: Seventy patients treated by PD (35 patients in each group) were included in the study. The two groups were comparable with regards to the pre-operative and intra-operative parameters. Postoperative pancreatic fistula developed in 10 out of 35 patients in the CPJ group and 3 out of 35 patients in the IPJ group (p = 0.031). Nine CPJ patients and one IPJ patient had POPF of type B or C (p = 0.006). Re-laparotomy was significantly more frequent in the CPJ group (11.1% versus 34.6%; p = 0.04). Time to resumption of oral feeding was shorter in the IPJ group (p = 0.001). CONCLUSIONS: The use of IPJ is associated with decrease in the rate of postoperative PF in patients undergoing PD. In addition, patients with IPJ reconstruction have lesser need for re-laparotomy and early resumption of oral feeding. PMID- 30428437 TI - Reconstruction of a surgical defect in the popliteal fossa: A case report. AB - INTRODUCTION: Surgical defects of the popliteal fossa pose a reconstructive challenge to the surgeon, given the intimate relationship of this area with the knee joint and underlying vital neuro-vasculature. CASE PRESENTATION: An 88-year old woman was treated for a biopsy proven invasive squamous cell carcinoma of the right popliteal fossa with Mohs micrographic surgery. The resultant defect (4.5 * 4.3 cm) was repaired using a random patterned bilobed flap with an undersized secondary lobe and porcine xenograft with excellent functional and cosmetic outcome. DISCUSSION: Numerous approaches to reconstruction of the popliteal fossa have been proposed, including primary closure, secondary intent healing, skin grafting, random flaps, muscle flaps, fasciocutaneous flaps, freeflaps, and tissue expansion. Sub-optimal repair of the popliteal fossa can reduce mobility of the knee joint, carry a high risk of wound dehiscence and may result in significant scarring. Here, we present the use of a bilobed flap with an undersized secondary lobe, in a patient with limited tissue laxity, for the repair of the popliteal fossa. CONCLUSION: Utilizing a random pattern bilobed flap with an undersized secondary lobe is an excellent alternative for the repair of moderate sized popliteal fossa defects. PMID- 30428438 TI - Hepatectomy in a case of hepatocellular carcinoma with constitutional indocyanine green excretory defect. AB - INTRODUCTION: Constitutional indocyanine green (ICG) excretory defect is extremely rare. The indocyanine green retention rate at15 min (ICGR15) is important for estimating hepatic functional reserve and selection of the appropriate surgical procedure before hepatectomy is performed. Because of the rarity of constitutional ICG excretory defect, its clinical features are not well understood. We report here evaluation and treatment of a patient with such a disorder. PRESENTATION OF CASE: An 83-year-old man was admitted to hospital with the diagnosis of resectable hepatocellular carcinoma. The preoperative indocyanine green (ICG) retention rate at 15 min was greater than 76.2%. Despite this finding, Child-Pugh classification and 99mTc-galactosyl human serum albumin (GSA) liver scintigraphy didn't show any abnormal findings, and there was no background disease. Therefore, we diagnosed him with constitutional ICG excretory defect and performed partial hepatectomy. For patients requiring hepatectomy with this disease the indications and procedure for surgery should be considered. These should be based on liver function tests such as GSA liver scintigraphy. CONCLUSIONS: Constitutional ICG excretory defect is an extremely rare disorder. At present, the indications for surgery for this condition should be comprehensively considered. Findings of liver function tests, such as a general liver function test and GSA liver scintigraphy, are important for treating this disorder. PMID- 30428440 TI - Late presentation of vesicoureteral reflux: An unusual cause of pyelonephritis in adults. AB - INTRODUCTION: Vesicoureteral reflux (VUR) corresponds to the reflux of urine from the bladder into the upper urinary system. It can be a congenital or an acquired anomaly and although its incidence is high in children it is uncommon in the adult life. One of its presentations in the adult population is the presence of recurrent Pyelonephritis. CASE PRESENTATION: Here we report a case of an adult patient with repetitive uncomplicated pyelonephritis caused by VUR. VUR was successfully managed endoscopically with subureteral injection of a bulking agent. A literature review of adult presenting VUR was performed. DISCUSSION: The first presentation of VUR in the adult life is rare. One of the most typical presentation is the presence of recurrent uncomplicated Pyelonephritis. Although no guidelines exists to study the presence of VUR in adult patients with Pyelonephritis, in the presence of several recurrent episodes of Pyelonephritis we should think in VUR as a possible cause. Even in adults, endoscopic management of VUR is an effective treatment with low morbidity. CONCLUSION: VUR can first present in the adult life, with recurrent episodes of UTI. The diagnosis is a suspicious one and is confirmed by VUCG. VUR in adults can be effectively managed with endoscopic injection of bulking agents. PMID- 30428439 TI - Gallbladder agenesis: A case report and review of the literature. AB - INTRODUCTION: Gallbladder agenesis is a rare congenital abnormality with an incidence of 10-65 per 100,000. Approximately half of these patients are surgically operated on because of the symptoms similar to biliary colic, and correct diagnosis is established intra-operatively. We present a clinical case of gallbladder agenesis from our practice. PRESENTATION OF CASE: A 49 (forty-nine) - year- old women was admitted in the Emergency Department of our clinic. Symptoms were similar to the biliary colic. Ultrasonography showed hyperechogenic acoustic shadow on the projection of the gallbladder which was considered as constricted gallbladder and cholecystolithiasis was diagnosed. Laparoscopic cholecystectomy was considered. During laparoscopy gallbladder could not be found. Surgical operation was completed without conversion. Postoperative treatment included analgesics and antispasmodics. Pre-operative symptoms disappeared. One month later magnetic resonance cholangiopancreatography (MRCP) confirmed gallbladder agenesis diagnosis. Health condition of the patient is satisfactory, without any complications after a year of surgery. DISCUSSION: Gallbladder agenesis presented with symptoms similar to biliary colic can be diagnosed without surgical intervention. Conservative treatment consists of antispasmodic drugs. CONCLUSION: If the shrunken gallbladder is detected on the ultrasound, additional radiological examinations are required. MRCP is considered as a test of choice among the radiological investigations. If gallbladder agenesis is identified on laparoscopy, there is no need for further conversion. For postoperative follow up examination MRCP investigation is recommended. PMID- 30428442 TI - Lymphangioma of the heart as a rare tumor: A case report. AB - INTRODUCTION: Tumors of the heart are uncommon, and lymphangiomas are among the rarest of this group, with very few cases reported. These tumors consist of a benign slow-flow vascular malformation. PRESENTATION OF CASE: We report a case of a man diagnosed incidentally with a pericardial mass and our surgical approach for its treatment. DISCUSSION: The pericardial mass of our case had no cleavage plane between the myocardium and the tumor. Because of this, rather than a total resection, with very high operative risk, a biopsy was preferred. The pathology specimen showed a benign tumor and the patient was referred to the cardiologist for regular follow-up. CONCLUSION: There is no specific investigation for diagnosing cardiac lymphangiomas, and though benign, they should be considered in the differential diagnosis of other malignant diseases of the mediastinum and definitive pathologic diagnosis is mandatory. Given the increased risk of uncontrolled bleeding related to percutaneous biopsy, the definite diagnosis is usually obtained with open surgical biopsy. PMID- 30428441 TI - Intraoperative catheter directed thrombolytic therapy for the treatment of superior mesenteric and portal Vein thrombosis. AB - INTRODUCTION AND CASE PRESENTATION: Acute portal and superior mesenteric vein thrombosis(SMV) is a rare but potentially lethal condition that is often characterized by generalized and non-specific symptoms. A high index of suspicion is warranted for early diagnosis and management. We present a case of 54 year old male who presented with generalized abdominal pain which was later accompanied by hemodynamic instability and radiological diagnosis of portal vein and superior mesenteric vein thrombosis. DISCUSSION: The management of SMV can be divided into medical and surgical therapy. Patients who have clear signs of peritonitis will require emergent surgery. Interventions for life-threatening portal vein thrombosis are limited and poorly described in the literature. CONCLUSION: We report a case of extensive portal vein thrombosis(PVT) advancing proximally to involve the superior mesenteric vein. Rapid portal vein patency and improved hepatic function was achieved with the direct use of tissue plasminogen activator infusion via operatively placed middle colic vein catheter. PMID- 30428443 TI - Poor night's sleep predicts following day's salivary alpha-amylase under high but not low stress. AB - Although sleep is linked to physiological stress systems like the autonomic nervous system (ANS), research is still limited regarding night-and-day interactions between nocturnal sleep characteristics, stress, and diurnal parameters of salivary alpha-amylase (sAA) as a surrogate marker of ANS activity. Fifty healthy university students rated their chronic stress burden and completed two five-day periods of ecological momentary assessment - under everyday conditions of both low stress (beginning of semester) and high stress (final examination preparation). Participants collected saliva six times daily and reported on the previous night's sleep (quality, latency, duration, disturbances) immediately after awakening. Additionally, a sub-sample wore actigraphs recording 'time in bed'. In contrast to previous assumptions, poor sleep predicted lower sAA awakening values, more decreased awakening responses, and steeper diurnal slopes the following day only under high stress, but not under low stress. Diurnal sAA parameters did not predict the following night's sleep characteristics. The sAA profile does not seem to be sensitive to everyday occurring sleep variations, but rather seems to be an indicator of more prolonged stress induced ANS dysregulation. PMID- 30428444 TI - Course of depressive symptoms and associated factors in people aged 65+ in Europe: A two-year follow-up. AB - BACKGROUND: The epidemiology of depressive disorders presents notable differences among European countries. The objectives of the study are to determine the prevalence, incidence, persistence and remission rates of depressive symptoms and to identify risk factors and differences between four European regions. METHOD: Prospective cohort design using data from waves 5 and 6 (2013-15) of the Survey of Health, Ageing and Retirement in Europe. Sample size included 31,491 non institutionalized adults aged 65+. Depressive symptoms were assessed using the EURO-D. RESULTS: The prevalence of depressive symptoms (EURO-D >=4) was 29.8% and 31.5%in waves 5 and 6, respectively. The risk factors associated depressive symptoms were poorer self-rated health, loneliness, impairment in ADL, female gender and financial difficulties. Incidence was 6.62 (99.9% CI: 6.61-6.63)/100 person-years and the persistence and remission rates were 9.22 and 5.78, respectively. Regarding the differences between European regions, the incidence (4.93 to 7.43) and persistence (5.14 to 11.86) rates followed the same ascending order: Northern, Eastern, Continental and Southern. The remission presented higher rates in the Eastern and Southern (6.60-6.61) countries than in the Northern and Continental (4.45-5.31) ones. LIMITATIONS: The EURO-D scale is unable to distinguish between clinically relevant depressive symptoms and major depression. CONCLUSION: The risk factors related to the incidence of depressive symptoms differed across European regions. In countries of eastern and southern Europe the most important predictors were female gender and impairment in ADL. Poorer self-rated health and older age were more relevant in the Northern countries, and chronic diseases were a key factor in the Continental region. PMID- 30428445 TI - The impact of depressive comorbidity on neural plasticity following cognitive behavioral therapy in panic disorder with agoraphobia. AB - BACKGROUND: Depressive disorders are a frequent comorbidity of panic disorder with agoraphobia (PD/AG). Cognitive-behavioral therapy (CBT) for PD/AG effectively reduces anxiety and depressive symptoms, irrespective of comorbidities. However, as depressive comorbidities can confound fear circuitry activation (i.e. amygdalae, insulae, anterior cingulate cortex) in PD/AG, we investigated whether comorbid depressive disorders alter neural plasticity following CBT. METHODS: Within a randomized, controlled clinical trial on exposure-based CBT, forty-two PD/AG patients including fifteen (35.7%) with a comorbid depressive disorder (PD/AG + DEP) participated in a longitudinal functional magnetic resonance imaging (fMRI) study. A differential fear conditioning task was used as probe of interest. A generalized psycho physiological interaction analysis (gPPI) served to study functional connectivity patterns. RESULTS: After CBT, only PD/AG patients without comorbid depressive disorders (PD/AG-DEP) showed reduced activation in the left inferior frontal gyrus (IFG) extending to the insula. While PD/AG-DEP patients showed enhanced functional connectivity (FC) between the left IFG and subcortical structures (anterior cingulate cortex, thalamus and midbrain), PD/AG + DEP patients exhibited increased FC between the left IFG and cortical structures (prefrontal, parietal regions). In both groups, FC decreased following CBT. LIMITATIONS: Primary depressed and medicated patients were excluded. Major depression and dysthymia were collapsed. CONCLUSIONS: Reduced activation in the left IFG, as previously shown in PD/AG, appears to be a specific substrate of CBT effects in PD/AG-DEP patients only. Differential patterns of FC pertaining to fear circuitry networks in patients without depression vs. cognitive networks in patients with comorbid depression may point towards different pathways recruited by CBT as a function of comorbidity. PMID- 30428446 TI - Memory bias and its association with memory function in women with posttraumatic stress disorder. AB - BACKGROUND: Memory abnormalities are among a central feature of posttraumatic stress disorder (PTSD). It is suggested that individuals with PTSD exhibit memory bias; while evidence shows poor memory function in these individuals. We aimed to examine memory bias in PTSD patients relative to controls and to explore an association between memory bias and memory function. METHODS: Forty-six women with DSM-IV PTSD, most of whom developed the disorder after interpersonal violence, and 68 non-trauma-exposed healthy control women were studied. Memory bias was assessed by a recognition memory task using negative, neutral, and positive words. Memory function was assessed by a standardized neuropsychological test battery. Depression and anxiety symptoms were assessed by self-report measures. RESULTS: Compared to controls, patients showed significantly greater negative bias scores (i.e., correctly recognized rates for negative words minus those for neutral words) and poorer memory function. Negative bias scores were significantly correlated with worse memory function in patients. When patients were divided into those with lower vs. normal memory function, the former patients had significantly greater negative bias than the latter patients and controls. Memory bias scores in patients were not significantly correlated with depression or anxiety symptoms, nor were they significantly different between patients with comorbid major depressive disorder and those without. LIMITATIONS: The cross-sectional design and absence of the trauma-exposed non-PTSD group limited our findings. CONCLUSIONS: PTSD patients have greater negative memory bias, which can be associated with poorer memory function. Our findings may provide an insight into the nature of memory abnormalities in PTSD. PMID- 30428449 TI - Depression symptomology groups among middle and older adult emergency department patients. AB - INTRODUCTION: Middle and late life adults may present depression symptomology differently than the expected symptoms of depression. Clusters of common symptoms may be overlooked when determining the most appropriate treatment options, leading to a less than effective treatment. Investigation of these clusters is needed to better understand patterns of depressive symptomology among middle and late life adults. METHODS: Consent, demographics, self-report items and PHQ-9 items were administered to subjects. Latent class analysis (LCA), was used to determine groupings of patients based on PHQ-9 items. Demographics were compared across classes for additional information. RESULTS: A total of 252 subjects aged 45-85 years old were enrolled. An LCA indicated that a 3 class solution explained the clusters endorsed: Low Concerns (35%), Many Concerns (34%), and Sleep and Fatigue Concerns (31%). Patients in the Low Concerns class were more likely to have private insurance compared to those in the Many Concerns class (57% vs 34%, p = 0.003). They also reported better general health (M = 2.39 vs M = 1.58, p < 0.001), and visited their PCP less frequently (M = 1.64 visits vs M = 3.31 visits, p = 0.004). LIMITATIONS: Recall bias may have been present due to self report of symptoms which was a report based on a low threshold for endorsement of items. Future larger studies should utilize more response options. CONCLUSION: LCA suggests there are three unique groupings of symptoms as reported by the PHQ 9. These clusters may be valuable in determining treatment options and designing interventions. PMID- 30428447 TI - Inflammatory DEpression Advances in Schizophrenia (IDEAS): A precision medicine approach of the national FACE-SZ cohort. AB - BACKGROUND: Major Depressive Disorder (MDD) is a therapeutic challenge in schizophrenia (SZ). Untangling different forms of MDD appears as the best current strategy to improve remission to treatment in the so-called precision medicine approach. AIMS: The objectives of the present study were to determine (i) the prevalence of Inflammatory Depression (ID) in stabilized SZ outpatients (ii) if ID was associated with clinical or cognitive profiles that may help clinicians detecting ID (iii) if antidepressants were effective in ID and (iv) the biological correlates of ID that may orientate personalized treatments. METHOD: Participants were consecutively included and received a thorough 2 days- clinical assessment. RESULTS: 785 subjects were recruited in the FACE-SZ cohort. 289 (36.8%) were diagnosed with MDD (remitted or unremitted), of them 57 with ID (19.7%). No clinical or cognitive features were associated with ID (all p > 0.05). ID has been associated with increased abdominal perimeter (aOR = 4.48, p = 0.002) and latent Toxoplasma infection (aOR = 2.19, p = 0.04). While antidepressants were associated with decreased depressive symptoms level in ID, 44% of the subjects remained unremitted under antidepressant, with no association with CRP blood levels. CONCLUSIONS: ID may not differ from other forms of depression by its clinical symptoms but by its aetiologies. ID is associated with increased perivisceral fat and latent Toxoplasma infection that are both potentially related to gut/microbiota disturbances. Specific anti-inflammatory drugs and microbiota-targeted therapeutics appear as promising strategies in the treatment of inflammatory depression in schizophrenia. PMID- 30428448 TI - Preconception dysmenorrhea as a risk factor for psychological distress in pregnancy: The Japan Environment and Children's Study. AB - BACKGROUND: Dysmenorrhea influences emotional distress as well as physical suffering in young non-pregnant women. The aim of this study was to assess the potential association between preconception dysmenorrhea and the development of psychological distress during pregnancy. METHODS: This study was a part of the Japan Environment and Children's Study (JECS), a nationwide birth cohort study conducted between 2011 and 2014 in Japan. A total of 87,102 pregnant Japanese women with no psychological distress (Kessler 6-item psychological distress scale [K6] score <= 12) in early pregnancy were eligible. Among these, 7626 had mild and 1638 had severe preconception dysmenorrhea. The prevalence and risk of maternal psychological distress (K6 scores >= 13) in the second or third trimester were compared among preconception dysmenorrhea severity groups. RESULTS: A higher percentage of women with mild (2.6%) or severe preconception dysmenorrhea (3.6%) suffered psychological distress during pregnancy compared to that in women without dysmenorrhea (2.1%). A multilevel logistic regression model, adjusting for baseline characteristics and the K6 score at enrollment, showed that the severity of dysmenorrhea was associated with psychological distress (mild dysmenorrhea: adjusted odds ratio [aOR], 1.154; 95% confidence interval [95% CI], 0.980-1.359; and severe dysmenorrhea: aOR, 1.457; 95% CI, 1.087-1.951). LIMITATIONS: Information about dysmenorrhea was obtained during early pregnancy. The JECS did not have clear diagnostic criteria for dysmenorrhea. CONCLUSIONS: Preconception dysmenorrhea is associated with an elevated incidence of psychological distress during pregnancy. Additionally, expectant mothers with a history of severe dysmenorrhea symptoms before pregnancy have a higher risk of developing psychological distress. PMID- 30428450 TI - Spectral comparison of diffuse PAR irradiance under different tree and shrub shading conditions and in cloudy days. AB - Spectral Solar Photosynthetically Photon Flux Density (PPFD) (380 to 780 nm) reaching the surface of a plant in different lighting conditions has been analyzed in order to better understand the different photosynthetic performance of plants depending on their spatial situation and the vegetation surrounding. A comparison between the shadow of several trees in a sunny day and the case of a cloudy day in an open space has been studied. Three isolated trees (a palm tree, an olive tree and a shrub oleander) and a tipuana grove have been studied. The study has been developed in Valencia (Spain) during January and February 2017. A portable Asensetek Standard ALP-01 spectrometer with a measurement wavelength range of 380 to 780 nm, has been used. Conditions with higher PPFD received are found to be, apart from those of a sunny day, those for cloudy day (with a spectral maximum in the Green region of the spectrum), and those for individual trees and shrub shadows in a sunny day (with a spectral maximum in the Blue region). The case in which less amount of PPFD is received is that under the shadow of tipuana grove (with a spectral maximum in the Infrared region of the spectrum). In fact the order of magnitude in which the PPFD in a cloudy day exceeds the PPFD under the tipuana grove shade is up to 20. PMID- 30428451 TI - Transformation kinetics of cyclophosphamide and ifosfamide by ozone and hydroxyl radicals using continuous oxidant addition reactors. AB - The detection of pharmaceuticals in water and wastewater has triggered human and ecological health concerns. As highly toxic compounds, chemotherapy agents (CAs), such as the cyclophosphamide (CYP) and ifosfamide (IFO) structural isomers, represent a unique threat. This research elucidated the fate of CYP and IFO during ozonation and advanced oxidation by hydroxyl radicals (HO*). Novel semi batch reactors were used to determine the second-order rate constants for CYP and IFO with O3 and HO*. These reactors provided independent control of the oxidant exposure through continuous and constant aqueous ozone and peroxone (O3-H2O2) addition. The rate constants for transformation of CYP and IFO by ozone were 2.58 +/- 0.40 M-1s-1 and 6.95 +/- 0.21 M-1s-1, respectively, indicating that ozone alone is not suitable for treating CAs. Transformation of CYP and IFO by hydroxyl radicals was fast, with rate constants of 2.69(+/-0.17)*109 M-1s-1 and 2.73(+/ 0.16)*109 M-1s-1, respectively. The major transformation products formed by O3 and HO attack consisted of the 4-hydroxy-, 4-keto-, dechloroethyl-, and imino- derivatives of CYP and IFO. Low yields of the active metabolites of the CAs, namely phosphoramide mustard and isophosphoramide mustard, were detected. These findings suggest that treated water may retain the ability to alkylate DNA and confer toxicity. PMID- 30428452 TI - Autophagy in neurodegeneration and aging. PMID- 30428453 TI - The heterogeneity within Alzheimer's disease. PMID- 30428454 TI - Azithromycin and Roxithromycin define a new family of "senolytic" drugs that target senescent human fibroblasts. AB - Here, we employed a "senolytic" assay system as a screening tool, with the goal of identifying and repurposing FDA-approved antibiotics, for the targeting of the senescent cell population. Briefly, we used two established human fibroblast cell lines (MRC-5 and/or BJ) as model systems to induce senescence, via chronic treatment with a DNA-damaging agent, namely BrdU (at a concentration of 100 MUM for 8 days). Cell viability was then monitored by using the SRB assay, to measure protein content. As a consequence of this streamlined screening strategy, we identified Azithromycin and Roxithromycin as two novel clinically-approved senolytic drugs. However, Erythromycin - the very closely-related parent compound - did not show any senolytic activity, highlighting the dramatic specificity of these interactions. Interestingly, we also show that Azithromycin treatment of human fibroblasts was indeed sufficient to strongly induce both aerobic glycolysis and autophagy. However, the effects of Azithromycin on mitochondrial oxygen consumption rates (OCR) were bi-phasic, showing inhibitory activity at 50 MUM and stimulatory activity at 100 MUM. These autophagic/metabolic changes induced by Azithromycin could mechanistically explain its senolytic activity. We also independently validated our findings using the xCELLigence real-time assay system, which measures electrical impedance. Using this approach, we see that Azithromycin preferentially targets senescent cells, removing approximately 97% of them with great efficiency. This represents a near 25-fold reduction in senescent cells. Finally, we also discuss our current results in the context of previous clinical findings that specifically document the anti-inflammatory activity of Azithromycin in patients with cystic fibrosis - a genetic lung disorder that results in protein mis-folding mutations that cause protein aggregation. PMID- 30428455 TI - Intrauterine Growth Restriction and Hyperoxia as a Cause of White Matter Injury. AB - Intrauterine growth restriction (IUGR) is estimated to occur in 5% of pregnancies, with placental insufficiency being the most common cause in developed countries. While it is known that white matter injury occurs in premature infants, the extent of IUGR on white matter injury is less defined in term infants. We used a novel murine model that utilizes a thromboxane A2 (TXA2) analog (U46619), a potent vasoconstrictor, to induce maternal hypertension and mimic human placental insufficiency-induced IUGR to study the white matter. We also investigated the role of hyperoxia as an additional risk factor for white matter injury, as IUGR infants are at increased risk of respiratory comorbidities leading to increased oxygen exposure. We found that TXA2 analog-induced IUGR results in white matter injury as demonstrated by altered myelin structure and changes in the oligodendroglial cell/oligodendrocyte population. In addition, our study demonstrates that hyperoxia exposure independently results in white matter perturbation. To our knowledge, this is the first study to report single and combined effects of IUGR with hyperoxia impacting the white matter and motor function. These results draw attention to the need for close monitoring of motor development in IUGR babies following hospital discharge as well as highlighting the importance of limiting, as clinically feasible, the degree of oxygen overexposure to potentially improve motor outcomes in this population of infants. PMID- 30428456 TI - A Prospective Study of Maternal Plasma Concentrations of Retinol-Binding Protein 4 and Risk of Gestational Diabetes Mellitus. AB - BACKGROUND: The aim of this study was to investigate whether retinol-binding protein 4 (RBP4) concentrations, measured at the first prenatal visit, are associated with risk of gestational diabetes mellitus (GDM). METHODS: From July 2015 to June 2016, consecutive women who admitted to the obstetrics center of our hospital were included. At the first prenatal visit (the median gestational age was 6 [interquartile range 4-10] weeks) in the hospital, involved subjects were tested for fasting plasma glucose (FPG) and RBP4 using venous plasma samples collected after at least 8 h of fasting in the morning. Data for FPG and RBP4 concentrations at the first prenatal visit and one-step GDM screening with 75-g oral glucose tolerance test performed between 24 and 28 weeks of gestation were collected and analyzed. RESULTS: Blood at first prenatal visit was available for 827 women, among whom GDM developed in 101 (12.2%). In multivariate models comparing the second (Q2), third, and fourth quartiles against the first quartile of RBP4, concentrations of RBP4 in Q2, Q3, and Q4 were associated with GDM later developed, and increased risk of GDM by 54, 205, and 536%. There was a significant statistical difference in the area under the curve between the established risk factors alone and the addition of RBP4 concentrations (difference, 0.039 [95% CI 0.030-0.052]; p = 0.03). In the subgroup of women combined with obesity and FABP4 >=median, the measured OR was 9.83 (95% CI [4.76 16.13]; p < 0.001) for GDM compared to those without obesity and FABP4 85% of MGUS subjects, 75% of stage I MM patients, and < 15% in stage III. Likewise, a significant correlation between the dominant subclone size, secondary cytogenetic features, and changes in the expression of CD27, CD44, and CD81 was detected. The loss of intraclonal equilibrium may be an important factor related with kinetics and risk of progression not well considered to date in MFC studies. The MFC strategy used in this work can provide useful biomarkers in MGUS and MM. PMID- 30428460 TI - Rhabdomyolysis among Critically Ill Combat Casualties: Long-Term Outcomes. AB - BACKGROUND: Although rhabdomyolysis has been associated with acute kidney injury and mortality in the short term, the long-term consequences of an episode of rhabdomyolysis remain unknown. We sought to identify the long-term outcomes of rhabdomyolysis, including mortality, renal function, and incidence of hypertension (HTN), among service members initially admitted to the intensive care unit after sustaining a combat injury in Iraq or Afghanistan between February 1, 2002 and February 1, 2011. METHODS: Information on age, sex, injury severity score, mechanism of injury, serum creatinine, burn injury, presenting mean arterial pressure, and creatine kinase were retrospectively collected and analyzed for 2,208 patients. Standard descriptive tests were used to compare characteristics of patients with and without rhabdomyolysis. Competing risk Cox proportional hazards models were performed to assess the associated risk of rhabdomyolysis with both HTN and poor renal function. RESULTS: While rhabdomyolysis was associated with HTN on univariate analysis (hazard ratio [HR] 1.30, 95% CI 1.03-1.64; p = 0.029), this difference did not persist on multivariable analysis (HR 1.27, 95% CI 0.99-1.62; p = 0.058). The median estimated glomerular filtration rate (eGFR) was 119 (interquartile range [IQR] 103-128) among those with rhabdomyolysis, compared with 108 (IQR 94-121) in the group without rhabdomyolysis (p < 0.001). CONCLUSION: After adjustment, patients with rhabdomyolysis were not at an increased risk of HTN compared to patients without rhabdomyolysis. eGFR was paradoxically higher in patients with rhabdomyolysis. There was no association found between rhabdomyolysis and mortality. PMID- 30428461 TI - In-Hospital Mortality and Major Adverse Cardiovascular Events after Kidney Transplantation in the United States. AB - BACKGROUND: Kidney transplantation (KT) is the treatment of choice for end-stage kidney disease. Cardiovascular disease is a major determinant of morbidity and mortality in patients with KT. Temporal trends in perioperative cardiovascular outcomes after KT are understudied, especially in light of an aging KT waitlist population. METHODS: We performed a retrospective observational cohort study using the National Inpatient Sample for the years 2004-2013. All adult patients undergoing KT were identified using the appropriate International Classification of Diseases, 9th Revision, Clinical Modification codes. Demographic and hospital characteristics, discharge disposition, payer status, and major adverse cardiovascular events (MACEs) were summarized using summary statistics. Multivariate logistic regression was used to identify predictors of MACEs in the perioperative period of KT. RESULTS: A total of 147,431 KTs were performed between 2004 and 2013. The mean age at KT went up from 48.1 to 51.8 years from 2004 to 2013. Medicare was the primary payer for 59.6% of the KTs. Overall average perioperative mortality was 0.5%, median length of stay was 5 days, and 6.5% of patients experienced an MACE, 78% of which were heart failures (HFs). Important predictors of perioperative MACEs were age >=65 years (OR = 2.14), Medicare as primary payer (OR = 1.51), diabetes (OR = 1.46), recreational drug use (OR = 1.72), pulmonary circulation disorders (OR = 3.28), and malnutrition (OR = 1.91). CONCLUSION: Despite increases in age at the time of KT, the absolute risk of perioperative MACEs has remained stable from 2004 to 2013. HF is a major component of postoperative MACEs in KT. Malnutrition and pulmonary hypertension are major nontraditional predictors of perioperative MACE outcomes. PMID- 30428462 TI - Confocal Laser Endomicroscopy as a Guidance Tool for Transbronchial Lung Cryobiopsies in Interstitial Lung Disorder. AB - BACKGROUND: Transbronchial cryobiopsy (TBCB) of the lung parenchyma is a minimally invasive alternative for surgical lung biopsy in interstitial lung disease (ILD) patients. Drawbacks are the nondiagnostic rate and complication risk of pneumothorax and bleeding. Fluoroscopy is the current guidance tool for TBCB, which is limited by 2D imaging and a radiation dose for the patient. Confocal laser endomicroscopy (CLE) is a high-resolution imaging technique that provides immediate feedback during bronchoscopy about the elastin fiber network of peripheral lung areas. Both the visceral pleura and fibrotic lung areas consist of elastin fibers and are therefore potentially detectable with CLE. OBJECTIVES: To investigate whether CLE is capable of (1) distinguishing fibrotic from normal alveolar areas and (2) identifying the pleura. METHODS: In and ex vivo CLE imaging obtained during bronchoscopy was compared with histology of lung biopsies in 14 ILD patients. RESULTS: CLE imaging of the alveolar compartment was feasible in all patients without adverse events. Based on CLE imaging, key characteristics that influence both diagnostic yield (dense fibrotic areas) and complication rate (pleura and subpleural space) were visualized. CONCLUSIONS: CLE seems a promising alternative to fluoroscopy as a guidance tool for TBCB procedures. PMID- 30428463 TI - Local Thymosin beta4 Gel Injection Prevents Esophageal Stricture after Circumferential Endoscopic Submucosal Dissection in a Porcine Model. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is widely used in the treatment of early esophageal cancer. However, the incidence of postoperative esophageal stricture is relatively high, especially after full circumferential ESD. Previous studies have shown that thymosin beta4 (Tbeta4) has anti-fibrotic activity and prevents scar formation. In this study, we investigated the safety and therapeutic effect of Tbeta4 injection in preventing esophageal stricture after circumferential ESD in a porcine model. METHODS: A total of 8 Bama pigs underwent esophageal circumferential ESD under anesthesia (n = 4 for experimental and control group). Local injection of Tbeta4 gel was administered in the experimental group. Follow-up endoscopy was conducted, and balloon dilation (EBD) was performed to prevent the occurrence of esophageal stricture. RESULTS: Esophageal stricture developed after circumferential ESD in all pigs. Local Tbeta4 gel injection has shortened resolution of the stricture (p = 0.012) and was associated with a lesser number of EBD sessions (p = 0.002). The severity of esophageal stricture was milder in the experimental group (p = 0.046 vs. control group). No adverse events occurred in the study. CONCLUSIONS: Local Tbeta4 gel injection appeared to be safe and effective for the prevention of esophageal stricture after circumferential ESD in a porcine model. PMID- 30428464 TI - Beneficial Effects of Vaccination on Cardiovascular Events: Myocardial Infarction, Stroke, Heart Failure. AB - Influenza and pneumococcal infections have been suggested to be potential risk factors for causing adverse cardiovascular events, especially in high-risk patients. Vaccination against respiratory infections in patients with established cardiovascular disease (CVD) could serve as a potential cost-effective intervention to improve their clinical outcomes and cardiac societies have encouraged it. Previous studies have shown that influenza vaccination reduce mortality, acute coronary syndromes and hospitalization in patients with coronary heart disease (CHD) and/or heart failure (HF). However, there is a paucity of randomized prospective clinical trials in the field of the pneumococcal vaccination, and additional higher-quality evidence is needed. Furthermore, questions around the role of vaccination in the primary prevention of CVD, the optimal dose and timing are largely unanswered. The pathophysiologic mechanism in which vaccination provides cardiovascular protection may be related to the modification of the immune-inflammatory model of atherogenesis. The present review summarizes the current evidence and understanding for vaccination against influenza and streptococcus pneumoniae in CHD, HF and stroke and highlights its beneficial effect in the reduction of adverse cardiovascular events. PMID- 30428465 TI - Association of Abdominal Adiposity with Cardiovascular Mortality in Incident Hemodialysis. AB - BACKGROUND: The risk of cardiovascular mortality is high among adults with end stage renal disease (ESRD) undergoing hemodialysis. Waist-to-hip ratio (WHR), a metric of abdominal adiposity, is a predictor of cardiovascular disease (CVD) and mortality in the general population; however, no studies have examined the association with CVD mortality, particularly sudden cardiac death (SCD), in incident hemodialysis. METHODS: Among 379 participants incident (< 6 months) to hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD study, we evaluated associations between WHR and risk of CVD mortality, SCD, and non-CVD mortality in Cox proportional hazards regression models. RESULTS: At study enrollment, mean age was 55 years with 41% females, 73% African Americans, and 57% diabetics. Mean body mass index was 29.3 kg/m2, and mean WHR was 0.95. During a median follow-up time of 2.5 years, there were 35 CVD deaths, 15 SCDs, and 48 non-CVD deaths. Every 0.1 increase in WHR was associated with higher risk (hazard ratio [95% CI]) of CVD mortality (1.75 [1.06-2.86]) and SCD (2.45 [1.20 5.02]), but not non-CVD mortality (0.93 [0.59-1.45]), independently of demographics, body mass index, comorbidities, inflammation, and traditional CVD risk factors. CONCLUSIONS: WHR is significantly associated with CVD mortality including SCD, independently of other CVD risk factors in incident hemodialysis. This simple, easily obtained bedside metric may be useful in dialysis patients for CVD risk stratification. PMID- 30428466 TI - Impact of Laparoscopy to Assess Resectability in Stage IIIC Epithelial Ovarian, Tubal and Peritoneal Cancer Patients. AB - AIMS: To evaluate overall survival (OS) and progression-free survival (PFS) in patients with stage IIIC epithelial ovarian, tubal and peritoneal cancer (EOC) who underwent a laparoscopy to assess surgical resectability prior to Primary Debulking Surgery (PDS) or Interval Debulking Surgery (IDS). METHODS: Retrospective cohort study that included all women with stage IIIC EOC treated at our center between 2000 and 2010. Patients were classified in groups: PDS, neoadjuvant chemotherapy (NACT) with IDS, NACT without IDS; and then sub classified based on residual tumor (RT). A laparoscopy to assess resectability was performed before PDS and IDS. RESULTS: Among 111 patients included, 66 underwent PDS, and 45 were treated with NACT, 80% of them receiving subsequent IDS. OS was 75.6 months in the PDS group, and 52.8 months for IDS group (p = 0.100); the PFS was 30 months and 19.2 months respectively (p = 0.049). Median OS was 104.4 and 52.8 months for patients with optimal cytoreduction (RT = 0) in the PDS and IDS group respectively (p < 0.05). Laparoscopy did not modify the preoperative consideration for PDS; however, 9 laparotomies were avoided based on laparoscopic findings after NACT. CONCLUSION: Laparoscopy for the assessment of surgical resectability in stage IIIC EOC has no impact on survival; but it still could be useful for the reduction of unnecessary laparotomies after NACT. PMID- 30428467 TI - Comparison of the Accuracy of the Novel PrisMax Continuous Renal Replacement Therapy System to the Classic Prismaflex System. AB - BACKGROUND/AIMS: We assessed how the novel PrisMax continuous renal replacement therapy (CRRT) system performed in an international multicentre setting. The system has multiple novel tools aiming to increase accuracy and dose delivery. METHODS: Data was prospectively collected from 7 intensive care units in 6 countries. The PrisMax device data logs constituted the raw material and last generation Prismaflex data was used as comparison. Clinical parameters like treatment time, filter life span, downtime as well as prescribed and delivered dose were recorded. RESULTS: PrisMax delivered/prescribed effluent ratios (mean +/- SD) 0.92 +/- 0.15 vs. Prismaflex ratios 0.85 +/- 0.21, p < 0.001; delivered effluent dose (mL/kg/h) was 18.16 +/- 12.93 vs. 10.95 +/- 10.96, p < 0.0001; and (Kt/V) 0.76 +/- 0.52 vs. 0.44 +/- 0.44, p < 0.0001. Moreover, downtime was 27 minutes less for the newer device. CONCLUSION: The PrisMax CRRT device outperforms its predecessor with regard to dose delivery and accuracy. PMID- 30428468 TI - Cerebrospinal Fluid Neurofilaments May Discriminate Upper Motor Neuron Syndromes: A Pilot Study. AB - BACKGROUND: Patients presenting with upper motor neuron (UMN) signs may widely diverge in prognosis, ranging from amyotrophic lateral sclerosis (ALS) to primary lateral sclerosis (PLS) and hereditary spastic paraplegia (hSP). Neurofilaments are emerging as potential diagnostic and prognostic biomarkers for ALS, but the diagnosis of UMN syndromes still relies mostly on clinical long-term observation and on familiarity or genetic confirmation. OBJECTIVES: To test whether phosphorylated neurofilament heavy chain (pNfH) may discriminate different UMN syndromes at diagnosis and to test their prognostic role among these diseases. METHODS: We measured the cerebrospinal fluid (CSF) and serum pNfH of 30 patients presenting with UMN signs and diagnosed with ALS, hSP, and PLS, plus 9 healthy controls (HC). RESULTS: ALS patients had higher levels of pNfH in CSF and serum compared to HC (p < 0.001 and p < 0.001 in CSF and serum, respectively) and PLS (p = 0.015 and p = 0.038) and hSP (p = 0.003 and p = 0.001) patients. PLS and hSP patients had similar CSF and serum pNfH concentrations, but a higher CSF pNfH concentration, compared to HC (p = 0.002 and p = 0.003 for PLS and hSP, respectively). Receiver operating characteristic curves for discriminating ALS from PLS and hSP showed an area under the curve of 0.79 for CSF and 0.81 for serum. In multivariable survival analysis including relevant clinical factors CSF pNfH represented the strongest variable predicting survival (HR 40.43; 95% CI 3.49-467.79, p = 0.003) independently of clinical group. CONCLUSIONS: Despite some statistical instability of the results due to limitations in sample size, our study supports the role of CSF pNfH as a prognostic biomarker for motor neuron diseases presenting with UMN signs. A potential power to discriminate between ALS and other UMN syndromes at presentation, and between all of the examined MND and HC, has been detected for both CSF and serum pNfH. PMID- 30428469 TI - High Prevalence of Pathological Hydrogen Breath Tests in Patients with Functional Dyspepsia. AB - BACKGROUND/AIMS: The aim of the study is to investigate the frequency of pathological hydrogen breath tests (HBT) in patients with clinical features of functional dyspepsia (FD) meeting the Rome criteria and normal testing of upper endoscopy and abdominal sonography. METHODS: We retrospectively included patients who underwent HBT (lactose, fructose, or glucose) between 2006 and 2012 and who had symptoms of FD. Patients were divided into 2 groups according to medical history and diagnostic results: (I) patients with suspected FD according to the Rome III criteria and (II) patients with an alternative diagnosis such as gastroesophageal reflux disease (GERD) or Crohn's disease (CD). RESULTS: A total of 207/404 patients were assigned to the FD group and 44.4% of these had at least 1 positive HBT and thus more frequently than patients with GERD (20.7%; n = 111; p < 0.001) and with CD (31.7%; n = 63; p = 0.07). Lactose and fructose HBT, but not glucose HBT, occurred significantly more frequently with pathological results than in patients with GERD (p = 0.02; p = 0.002). The probability of a positive HBT increased significantly with increasing number of performed HBT (p < 0.001). CONCLUSION: We suggest that HBT should be considered in the clinical management of patients with suspected FD. In cases of positive HBTs, a potential causal therapy can be initiated. PMID- 30428470 TI - Diffusion-Weighted Magnetic Resonance Imaging: A New Tool for the Diagnosis of Bladder Pain Syndrome/Interstitial Cystitis. AB - OBJECTIVES: To determine whether diffusion-weighted magnetic resonance imaging (DWMRI), a noninvasive procedure, can contribute to the diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: The pelvic DWMRI of patients with chronic pelvic pain syndrome was selected between January 2012 and June 2017. A radiologist analyzed the bladder wall signal; he was blinded to the patients' clinical data. According to the 2008 European Society for the Study of Bladder Pain Syndrome/Interstitial Cystitis criteria, 2 groups of patients were determined: BPS/IC and no BPS/IC. The association between BPS/IC and the wall signal intensity was compared. RESULTS: In the 106 patients included, 82 had criteria for BPS/IC and 24 did not. A significant difference in the distribution of the signal was found between the 2 groups (p = 0.01). High signal intensity of the bladder wall was related to the presence of a BPS/IC with a sensitivity of 28% and a specificity of 88%. No signal intensity of the bladder wall was related to the absence of a BPS/IC with a sensitivity of 96% and a specificity of 29%. CONCLUSIONS: In -DWMRI, high bladder wall signal intensity helps to affirm a BPS/IC, whereas the absence of signal helps to exclude the diagnosis. Further studies are needed to confirm these preliminary results. PMID- 30428471 TI - Predictors of Hospitalization After Ureteroscopy Plus Elective Double-J Stent as an Outpatient Procedure. AB - PURPOSE: To evaluate the safety and feasibility of ureteroscopy plus elective double-J stent as an outpatient procedure in an unselected population with regard to the treatment for ureteral calculi and to present a multivariate analysis of factors predict hospitalization. MATERIALS AND METHODS: Ureteroscopy was performed as an outpatient procedure on 308 consecutive patients with ureteral stones. Contraindication for day case surgery was the only exclusion criteria from the study. All causes that led to immediate hospitalization were recorded; at the same time, all causes of hospitalization that occurred within 72 h from the procedure were also recorded and included in the final analysis. RESULTS: The overall stone-free rate and the rate of hospitalization were 94.5 and 9.7% respectively. Intraoperative complications were observed in 16 patients (5.1%). In terms of the variables related to hospitalization, the univariate analysis showed a statistical significant association between the American Society of Anesthesiologists (ASA) score (p < 0.001) and operative time (p = 0.018). At multivariate analysis, the only independent factor predictor of hospitalization was the ASA score (p < 0.001). CONCLUSIONS: In our experience, semirigid ureteroscopy is a safe and effective treatment that is independent of intraoperative local conditions or stone size. Elective Double-J stenting avoids major complications as the first reason for hospitalization. We suggest that ASA score > 2 should be taken into account when ureterorenoscopy is planning as an outpatient procedure. PMID- 30428472 TI - Quantitative RT-PCR Assay for Detecting Lymph Node Metastasis in Endometrial Cancer: A Preliminary Study. AB - OBJECTIVE: The detection accuracy of sentinel lymph node (SLN) metastasis by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for endometrial cancer (EC) remains unclear and was assessed in this preliminary study. METHODS: We studied primary cancer tissues and pelvic lymph nodes (PLN) from 105 patients with EC. qRT-PCR assay was performed to determine the copy numbers of CK19 mRNA in EC tissues, and negative and positive LN samples. Further, qRT-PCR results were compared with pathological findings. RESULTS: CK19 mRNA expression was detected in 98% (104/106) of the tumors, with a median copy number of 3.0 * 105/MUL. Twelve LN were diagnosed as positive by pathological examination. The median copy number of CK19 mRNA for positive and negative LN was 8.1 * 104/MUL and 90.4/uL, respectively. CK19 mRNA expression was higher in pathologically positive LN than in pathologically negative LN (p < 0.01); the pathological and qRT-PCR findings showed no discrepancy. When the cutoff value was set at 4,500 copies/uL, qRT-PCR assay using CK19 mRNA exhibited high sensitivity and specificity. CONCLUSIONS: Our results demonstrated that qRT-PCR assay, using CK19 mRNA, exhibits a high accuracy for detecting LN metastasis in EC and represents a useful alternative to conventional pathological diagnosis of EC. PMID- 30428473 TI - CXCL12 and CXCR4 in the Peripheral Blood of Patients with Parkinson's Disease. AB - OBJECTIVE: The role of CXCL12 and its receptor CXCR4 has not been fully examined in Parkinson's disease (PD). The purpose of this study was to investigate the role of CXCL12/CXCR4 in the peripheral blood of patients with PD and healthy controls. METHODS: CXCL12 serum levels and CXCR4 mRNA levels were measured in 30 PD patients and 40 controls using ELISA and real-time PCR, respectively. RESULTS: CXCL12 serum levels were significantly higher in PD patients compared to controls (p < 0.0001). Moreover, CXCR4 expression in peripheral blood mononuclear cells (PBMC) of PD patients was significantly increased compared to controls (p < 0.0001). CONCLUSIONS: Our findings provide new information on the expression of CXCL12/CXCR4 in PD. CXCR4 expression in PBMC or CXCL12 serum levels may be potential biomarkers of inflammation in PD patients. PMID- 30428474 TI - Long-Term Effect of Rifaximin with and without Lactulose on the Active Bacterial Assemblages in the Proximal Small Bowel and Faeces in Patients with Minimal Hepatic Encephalopathy. AB - BACKGROUND: Gut microbiota play an essential role in the pathogenesis of hepatic encephalopathy (HE). Treatment strategies are directed to modulate intestinal microbiota profiles and their function by the administration of the non absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin, which are required for long terms, but little is known on their long-term effect on gut microbiota composition and function. AIM: To characterize the active bacterial assemblages in duodenum and faeces in patients with minimal HE (MHE) before, during and after long-term therapy with rifaximin. METHODS: We analysed the microbiota composition in 5 patients with liver cirrhosis and MHE treated either with rifaximin 550 mg bid alone continuously for a period of 3 months or combined with lactulose 30-60 mL daily for 3 months. In addition to clinical assessments of HE, biopsies from duodenum and stool samples were analysed for their specific bacterial community applying NGS after RNA isolation before treatment, after 3 months of treatment and 3 months after the end of treatment. RESULTS: All 5 patients had a significant improvement of their MHE. Bacterial communities were different and distinct in duodenal samples and faeces. No statistically significant changes were found in the bacterial community profile at the different time points. CONCLUSION: Rifaximin therapy with and without lactulose over a period of 3 months does not affect the bacterial community composition. The improvement of HE with rifaximin is lasting also after the end of treatment and therefore a prolonged effect on microbiota metabolic function is suggested. PMID- 30428475 TI - Fatty Acid Composition of the Erythrocyte Membranes Varies between Early-Term, Full-Term, and Late-Term Infants in Japan. AB - BACKGROUND: Term infants can be categorized into 3 sub-groups: early term (37w0d to 38w6d), full term (39w0d to 40w6d), and late term (41w0d and beyond). However, the fatty acid composition among the 3 groups of term infants has not been investigated. The association between fatty acid composition and gestational period of term infants in Japan is unclear. METHODS: We assessed the fatty acid composition of maternal erythrocyte membranes in the third trimester and of cord erythrocyte membranes at birth in 212 healthy term Japanese infants using data from a prospective hospital-based cohort study. RESULTS: In maternal erythrocyte membranes, docosahexaenoic acid (DHA) levels and omega-3 index were significantly higher in the late-term group than in the early-term group. In cord erythrocyte membranes, DHA levels were not significantly different between the 3 groups; late term infants showed significantly higher DHA/arachidonic acid (ARA) and lower 20: 3n-6 and ARA levels compared to early-term infants. Gestational period positively correlated with the DHA status in maternal and cord erythrocyte membranes. CONCLUSIONS: Fatty acid composition in maternal and cord erythrocyte membranes varies between early-, full-, and late-term infants, and the greater gestational period may contribute to the relatively high n-3 polyunsaturated fatty acids status in term infants. Furthermore, maternal DHA status in the third semester directly correlates with gestational period in pregnant Japanese women. PMID- 30428476 TI - What's the Difference? 2D DIGE Image Analysis by DeCyderTM versus SameSpotsTM. AB - The efficiency and reproducibility of two-dimensional difference gel electrophoresis (2D DIGE) depends on several crucial steps: (i) adequate number of replicate gels, (ii) accurate image acquisition, and (iii) statistically confident protein abundance analysis. The latter is inherently determined by the image analysis system. Available software solutions apply different strategies for consecutive image alignment and protein spot detection. While DeCyderTM performs spot detection on single gels prior to the alignment of spot maps, SameSpotsTM completes image alignment in advance of spot detection. In this study, the performances of DeCyderTM and SameSpotsTM were compared considering all protein spots detected in 2D DIGE resolved proteomes of three different environmental bacteria with minimal user interference. Proteome map-based analysis by SameSpotsTM allows for fast and reproducible abundance change determination, avoiding time-consuming, manual spot matching. The different raw spot volumes, determined by the two software solutions, did not affect calculated abundance changes. Due to a slight factorial difference, minor abundance changes were very similar, while larger differences in the case of major abundance changes did not impact biological interpretation in the studied cases. Overall, affordable fluorescent dyes in combination with fast CCD camera-based image acquisition and user-friendly image analysis still qualify 2D DIGE as a valuable tool for quantitative proteomics. PMID- 30428477 TI - Maternal Complications following Open Fetal Myelomeningocele Repair at the Zurich Center for Fetal Diagnosis and Therapy. AB - INTRODUCTION: Despite undoubtable benefits of open fetal myelomeningocele (fMMC) repair, there are considerable maternal risks. The aim of this study was to evaluate and systematically categorize maternal complications after open fMMC repair. METHODS: We analyzed data of 40 fMMC repairs performed at the Zurich Center for Fetal Diagnosis and Therapy. Maternal complications were classified according to a 5-level grading system based on a classification of surgical complications proposed by Clavien and Dindo. RESULTS: We observed no grade 5 complication (death of a patient). Five (12.5%) women demonstrated severe grade 4 complications: 1 case of uterine rupture in a nullipara at 36 gestational weeks (GW), a third-degree atrioventricular block which needed short mechanical resuscitation, a bilateral lung embolism requiring intensive care unit (ICU) management due to low-output syndrome, and chorioamnionitis and urosepsis both requiring ICU management at 31 GW. Twenty-six (65%) women had minor (grade 1-3) complications. CONCLUSIONS: Only one grade 4 complication (uterine rupture, 2.5%) was a clear-cut direct consequence of fetal surgery. The other four grade 4 complications (10%) occurred in the context of, but cannot unequivocally be attributed to, fetal surgery, since they may occur also in other circumstances. The classification system used is a tenable step towards stringent documentation of maternal complications. PMID- 30428478 TI - Proliferative Index in Pediatric Pilocytic Astrocytoma by Region of Origin and Prediction of Clinical Behavior. AB - BACKGROUND/AIMS: Pilocytic astrocytomas are common pediatric tumors. Molecular profiles vary with location of origin. Comparisons of proliferation have not been reported. We sought to identify differences in growth by region and whether these predict clinical behavior. METHODS: A retrospective review of all patients undergoing surgery for a pilocytic astrocytoma at Children's Hospital LA from 2003 to 2015 was completed. Tumor location, determined by imaging, was stratified into infratentorial, supratentorial, or optic pathway. Proliferation was measured by Ki-67 immunostaining. A p value of 0.05 was deemed significant. RESULTS: 77 patients were identified. 51 had posterior fossa tumors, 12 had supratentorial tumors, and 14 had optic pathway tumors. Mean Ki-67 score was 3.67, 4.09, and 3.83%, respectively (p = 0.82). Ki-67 of >=4% trended towards recurrence (p = 0.11), incomplete resection (p = 0.15), and younger age at presentation (p = 0.04). Ki-67 was weakly correlated with shorter survival after surgery (r = 0.103, p = 0.41). Partial resection strongest predicted recurrence (p < 0.001; OR = 13.0). CONCLUSION: Proliferative index does not change by location. Higher cell proliferation was seen in younger patients and associated with shorter time to and a higher risk of recurrence. Further study is needed to identify predictors for clinical behavior. Importance of Study: This study provides a detailed analysis of the proliferative indices of tumors arising from characteristic locations within the brain. With recent advances in our understanding of the differences in molecular and genetic profiles despite similar histologic diagnoses, we felt that it was important to review whether there were unique components of tumor behavior that could be identified. In turn, we sought to determine whether tumor behavior could be used to predict the clinical course. This knowledge is important, given that not every tumor may undergo complete surgical resection, and that some lesions may require more aggressive upfront adjuvant therapy or be closely monitored for recurrence. PMID- 30428479 TI - Intranasal Administration of IL-27 Ameliorates Nasal Allergic Responses and Symptoms. AB - BACKGROUND: Interleukin 27 (IL-27) is an initiator of the Th1 response and inhibits inflammatory responses. In a mouse model of asthma, administration of IL 27 reduced eosinophil numbers in bronchoalveolar lavage fluid and airway hyperresponsiveness. However, it is unclear whether administration of IL-27 can inhibit symptoms of allergic diseases and allergic rhinitis as a therapeutic agent. Therefore, we investigated the in vivo effect of IL-27 on nasal symptoms and allergic rhinitis. METHODS: Mice sensitized and challenged with ovalbumin (OVA) antigen received intranasal administration of IL-27. RESULTS: Intranasal administration of IL-27 significantly suppressed the number of sneezes and nasal rubbing movements, the number of eosinophils, OVA-specific T-cell responses in cervical lymph nodes, production of IL-4 and IL-5, and OVA-specific IgE in sera, compared with the administration of PBS alone. The production of IL-10 and IL-35, the percentage of CD25+Foxp3+ cells, and the gene expression of Foxp3 in mice that received intranasal administration of IL-27 were also significantly higher than those in mice that received only PBS. CONCLUSIONS: This study showed, for the first time, that intranasal administration of IL-27 inhibited nasal allergic responses and symptoms even after the establishment of allergic rhinitis and suggested that IL-27 is useful as an intranasal therapeutic agent. PMID- 30428480 TI - Nebulized Antibiotics in Acute Exacerbation of Non-Cystic Fibrosis Bronchiectasis: Shifting the Goal Posts or a Post Too Far? PMID- 30428481 TI - Bacteria-Host Crosstalk: Sensing of the Quorum in the Context of Pseudomonas aeruginosa Infections. AB - Cell-to-cell signaling via small molecules is an essential process to coordinate behavior in single species within a community, and also across kingdoms. In this review, we discuss the quorum sensing (QS) systems used by the opportunistic pathogen Pseudomonas aeruginosa to sense bacterial population density and fitness, and regulate virulence, biofilm development, metabolite acquisition, and mammalian host defense. We also focus on the role of N-acylhomoserine lactone dependent QS signaling in the modulation of innate immune responses connected together via calcium signaling, homeostasis, mitochondrial and cytoskeletal dynamics, and governing transcriptional and proteomic responses of host cells. A future perspective emphasizes the need for multidisciplinary efforts to bring current knowledge of QS into a more detailed understanding of the communication between bacteria and host, as well as into strategies to prevent and treat P. aeruginosa infections and reduce the rate of antibiotic resistance. PMID- 30428482 TI - Epigallocatechin Gallate Is the Most Effective Catechin Against Antioxidant Stress via Hydrogen Peroxide and Radical Scavenging Activity. AB - BACKGROUND Hydrogen peroxide-induced neuronal oxidative stress is a serious threat to the nervous system. Catechins and related compounds are effective radical scavengers that protect against nerve cell damage. MATERIAL AND METHODS Here, we investigated the antioxidant property of various catechins in protecting against hydrogen peroxide, as well as their radical-scavenging activity. RESULTS We found that catechins treatment effectively protected HT22 cells against H2O2 induced cell viability by decreasing and attenuating reactive oxidative species production in different proportions. In addition, all tested catechins performed radical scavenging activity, and partially removed the free radicals. Among all investigated catechins, epigallocatechin gallate was the most effective against ROS production and had the strongest radical-scavenging activity. These results suggest that beneficial effects were strongly related with structure of catechins, mainly because of the hydroxyl and galloyl groups. CONCLUSIONS In conclusion, epigallocatechin gallate is the most effective antioxidant polyphenol against hydrogen peroxide and radical-scavenging activity. PMID- 30428483 TI - Circular and long non-coding RNAs and their role in ophthalmologic diseases. AB - Long non-coding RNAs are 200 nucleotide long RNA molecules which lack or have limited protein-coding potential. They can regulate protein formation through several different mechanisms. Similarly, circular RNAs are reported to play a critical role in post-transcriptional gene regulation. Changes in the expression pattern of these molecules are established to underline various diseases, including cancer, cardiovascular, neurological and immunological disorders. Recent studies suggest that they are differentially expressed both in healthy ocular tissues as well as in eye pathologies, such as neovascularization, proliferative vitreoretinopathy, glaucoma, cataract, ocular malignancy or even strabismus. Aetiology of ocular diseases is multifactorial and combines genetic and environmental factors, including epigenetic and non-coding RNAs. In addition, disorders like diabetic retinopathy or age-related macular degeneration lack biomarkers for early detection as well as effective treatment methods that will allow controlling the disease progression at its early stages. The newly discovered non-coding RNAs seem to be the ideal candidate for novel molecular markers and therapeutic strategies. In this review, we summarize current knowledge about gene expression regulators - long non-coding and circular RNA molecules in eye diseases. PMID- 30428486 TI - Back cover. PMID- 30428487 TI - An Evidence-Based Tool for Safe Configuration of Electronic Health Records: The eSafety Checklist. AB - BACKGROUND: Electronic health records (EHRs) are transforming the way health care is delivered. They are central to improving the quality of patient care and have been attributed to making health care more accessible, reliable, and safe. However, in recent years, evidence suggests that specific features and functions of EHRs can introduce new, unanticipated patient safety concerns that can be mitigated by safe configuration practices. OBJECTIVE: This article outlines the development of a detailed and comprehensive evidence-based checklist of safe configuration practices for use by clinical informatics professionals when configuring hospital-based EHRs. METHODS: A literature review was conducted to synthesize evidence on safe configuration practices; data were analyzed to elicit themes of common EHR system capabilities. Two rounds of testing were completed with end users to inform checklist design and usability. This was followed by a four-member expert panel review, where each item was rated for clarity (clear, not clear), and importance (high, medium, low). RESULTS: An expert panel consisting of three clinical informatics professionals and one health information technology expert reviewed the checklist for clarity and importance. Medium and high importance ratings were considered affirmative responses. Of the 870 items contained in the original checklist, 535 (61.4%) received 100% affirmative agreement among all four panelists. Clinical panelists had a higher affirmative agreement rate of 75.5% (656 items). Upon detailed analysis, items with 100% clinician agreement were retained in the checklist with the exception of 47 items and the addition of 33 items, resulting in a total of 642 items in the final checklist. CONCLUSION: Safe implementation of EHRs requires consideration of both technical and sociotechnical factors through close collaboration of health information technology and clinical informatics professionals. The recommended practices described in this checklist provide systems implementation guidance that should be considered when EHRs are being configured, implemented, audited, or updated, to improve system safety and usability. PMID- 30428488 TI - Response to: An Evidence-Based Tool for Safe Configuration of Electronic Health Records: The eSafety Checklist. PMID- 30428489 TI - Exercise in Pregnancy: The Impact of an Intervention Program in the Duration of Labor and Mode of Delivery. AB - OBJECTIVE: To access the benefits or harms of an exercise program, based on the current American College of Obstetricians and Gynecologists guidelines, on the mode of delivery, duration and onset of labor. METHODS: A study performed at the Hospital Senhora da Oliveira between October 2015 and February 2017. This was a quasi-experimental study involving 255 women divided into two groups: an intervention group engaged in a controlled and supervised exercise program during pregnancy (n = 99), and a control group that did not participate in the exercise program (n = 156). Data were collected in two stages: during the 1st trimester biochemical screening (before the beginning of the program), through a written questionnaire, and after delivery, from the medical files of the patients. The significance level in the present study was 5% (p = 0.05). RESULTS: The control group had higher odds of induced labor (odds ratio [OR] 2.71; 95% confidence interval [CI]: 1.42-5.17; p = 0.003), when compared with women who underwent the intervention. No differences were found between the groups in instrumental vaginal deliveries, cesarean rate, time until the beginning of the active phase, duration of the active phase, and duration of the second stage of labor. CONCLUSION: The implementation of a controlled and supervised exercise program in pregnancy was associated with significantly lower odds of induced deliveries. PMID- 30428490 TI - Assessment of Sensitivity and Specificity of Ultrasound and Magnetic Resonance Imaging in the Diagnosis of Placenta Accreta. AB - OBJECTIVE: To assess and compare the sensitivity and specificity of ultrasonography and magnetic resonance imaging in the diagnosis of placenta accreta in patients with placenta previa. METHODS: This retrospective cohort study included 37 women, and was conducted between January 2013 and October 2015; 16 out of the 37 women suffered from placenta accreta. Histopathology was considered the gold standard for the diagnosis of placenta accreta; in its absence, a description of the intraoperative findings was used. The associations among the variables were investigated using the Pearson chi-squared test and the Mann-Whitney U-test. RESULTS: The mean age of the patients was 31.8 +/- 7.3 years, the mean number of pregnancies was 2.8 +/- 1.1, the mean number of births was 1.4 +/- 0.7, and the mean number of previous cesarean sections was 1.2 +/- 0.8. Patients with placenta accreta had a higher frequency of history of cesarean section than those without it (63.6% versus 36.4% respectively; p < 0.001). The mean gestational age at birth among women diagnosed with placenta previa accreta was 35.4 +/- 1.1 weeks. The mean birth weight was 2,635.9 +/- 374.1 g. The sensitivity of the ultrasound was 87.5%, with a positive predictive value (PPV) of 65.1%, and a negative predictive value (NPV) of 75.0%. The sensitivity of the magnetic resonance imaging was 92.9%, with a PPV of 76.5%, and a NPV of 75.0%. The kappa coefficient of agreement between the 2 tests was 0.69 (95% confidence interval [95%CI]: (0.26-1.00). CONCLUSION: The ultrasound and the magnetic resonance imaging showed similar sensitivity and specificity for the diagnosis of placenta accreta. PMID- 30428491 TI - The Influence of Light Exposure in Ambiance during Pregnancy in Maternal and Fetal Outcomes: An Experimental Study. AB - OBJECTIVE: The aim of this study is to evaluate whether exposure to different environmental lighting conditions affects the reproductive parameters of pregnant mice and the development of their offspring. METHODS: Fifteen pregnant albino mice were divided into three groups: light/dark, light, and dark. The animals were euthanized on day 18 of pregnancy following the Brazilian Good Practice Guide for Euthanasia of Animals. Maternal and fetal specimens were measured and collected for histological evaluation. Analysis of variance (ANOVA) test was used for comparison of the groups considering p <= 0.05 to be statistically significant. RESULTS: There was no significant difference in the maternal variables between the three groups. Regarding fetal variables, significant differences were observed in the anthropometric measures between the groups exposed to different environmental lighting conditions, with the highest mean values in the light group. The histological evaluation showed the same structural pattern of the placenta in all groups, which was within the normal range. However, evaluation of the uterus revealed a discrete to moderate number of endometrial glands in the light/dark and light groups, which were poorly developed in most animals. In the fetuses, pulmonary analysis revealed morphological features consistent with the transition from the canalicular to the saccular phase in all groups. CONCLUSION: Exposure to different environmental lighting conditions had no influence on the reproductive parameters of female mice, while the offspring of mothers exposed to light for 24 hours exhibited better morphometric features. PMID- 30428492 TI - Female Genito-Pelvic Pain/Penetration Disorder: Review of the Related Factors and Overall Approach. AB - Genito-pelvic pain/penetration disorder (GPPPD) can be an extremely bothersome condition for patients, and a tough challenge for professionals regarding its assessment and treatment. The goal of the present paper is to review the etiology, assessment, and treatment of GPPPD, especially focusing on the cognitive aspects of the disease and cognitive-behavioral treatment options, through a non-systematic review of articles indexed to the Medline, Scopus and Web of Science databases, using the following MeSH queries: pelvic pain; dyspareunia; vaginismus; vulvodynia; and cognitive therapy. Altogether, 36 articles discussing the etiology, diagnosis and management of GPPPD were selected. We provide an overview of GPPPD based on biological, psychological and relational factors, emphasizing the last two. We also summarize the available medical treatments and provide strategies to approach the psychological trigger and persisting factors for the patient and the partner. Professionals should be familiarized with the factors underlining the problem, and should be able to provide helpful suggestions to guide the couple out of the GPPPD fear-avoidance circle. PMID- 30428493 TI - [Efficacy of Disease Management Programs Asthma and COPD? Results of a Cross Sectional Study]. AB - BACKGROUND: The efficacy of the German disease management programs (DMP) asthma and chronic obstructive pulmonary disease (COPD) cannot be shown with the legally bound documentations. Studies with control groups are rare. Aim of this work was to investigate in a cross-sectional study whether the disease control differs in participants (DMP+) and non-participants (DMP-) of the DMPs asthma and COPD. METHODS: The study was a prospective multicenter cross-sectional study. Primary endpoints were the Asthma Control TestTM (ACT) in the asthma part of the study and the COPD Assessment TestTM (CAT) for the COPD part. RESULTS: A total of 1038 asthma patients and 846 COPD patients were included, of whom about 70 % participated in the corresponding DMP. The ACT total score was higher in asthma DMP+ patients than in DMP- patients (mean difference 0.86; 95 %CI:0.29 - 1.43;p = 0.003), but not clinically relevant. For COPD there was no clinically relevant difference in COPD disease impact (0.52; 95 %CI:-0.71 - 1.75;p = 0.405). Although DMP patients had to be enrolled in the respective DMP for at least one year, only 60 % of these patients had participated in a structured education. We did not observe a difference in disease control in DMP patients who respectively participated and did not participate in a structured education. DISCUSSION: There was no clinically relevant difference in disease control between DMP+ and DMP- patients. The efficacy of DMPs has been demonstrated internationally in randomized controlled trials. Randomized controlled trials should be conducted in Germany for demonstrating efficacy of DMPs asthma and COPD. REGISTRATION: drks.de, DRKS00007664, Registration date: Jan 15, 2015. PMID- 30428494 TI - Association of HLA Class II alleles and Haplotypes with Type 1 Diabetes in Tunisian Arabs. AB - The molecular association of HLA class II with type 1 diabetes (T1DM) was investigated in Tunisian Arabs using 3 kinds of analyses. The first was a case control association study, using Relative Predispositional Effects method, involved 137 T1DM cases and 258 control subjects. The second was family-based association-linkage study, using Transmission Disequilibrium Test, and covering 50 Tunisian families comprising 73 T1DM patients and 100 parents. The third was a wide correlation study between 4 DRB1 alleles (DRB1*03, *04, *11, *15) and T1DM in 52 countries, using Spearman's Rho. Results from Case-control and family-based association studies showed that DRB1*03 and DRB1*04 alleles predispose to T1DM in Tunisian Arabs. Conversely, only DRB1*11 was protective for T1DM. DRB1*04-DQB1*03 haplotype was consistently associated positively with T1DM; DRB1*03/DRB1*04 genotype had the highest risk of T1DM development. Compared to DRB1*03, HLA DRB1*04 was associated with higher T1DM incidence. Thus, the contribution of HLA class II to T1DM genetic susceptibility must be evaluated with regards to specific HLA alleles, genotypes, and haplotypes, and also ethnic and racial background. PMID- 30428495 TI - Treatment of Refractory Adrenocortical Carcinoma with Thalidomide: Analysis of 27 Patients from the European Network for the Study of Adrenal Tumours Registry. AB - OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with a dismal prognosis. In advanced stages, tumour control by mitotane and cytotoxic chemotherapy is often temporary and salvage treatments are warranted. METHODS: Retrospective cohort study of participants in the prospective European Networks for the Study of Adrenal Tumours (ENSAT) registry. Main outcome measures were best response during treatment, progression-free survival (PFS), both measured according to RECIST 1.1 by two blinded radiologists, and overall survival (OS). RESULTS: Twenty-seven patients (13 males; median age 44.1 years) progressing after mitotane and a median of 4 further systemic treatments were included. Thalidomide was administered as tolerated with a starting dose of 50 mg and target dose of 200 mg /d. The median interval between treatment initiation and first imaging was 10.5 (4.4-17.5) weeks. The best response to treatment was stable disease (SD, n=2) and progressive disease (n=25), with a median PFS of 11.2 weeks and a median OS of 36.4 weeks. The first patient with SD discontinued treatment due to mild epistaxis and diarrhea after 22.3 weeks. The second patient had SD at the second treatment evaluation after 25.2 weeks and continued thalidomide but then had clinical progression and deceased after 54.3 weeks. In general, thalidomide induced only mild or moderate adverse effects (mainly fatigue and gastrointestinal complaints). CONCLUSION: Thalidomide was overall well tolerated but resulted in disease control in only 2/27 (7.4%) patients. In the absence of predictive response markers, thalidomide should only be considered in exceptional cases as a salvage therapy in ACC. PMID- 30428496 TI - Hypoglycemia and Glucagon Utilization in Insulin-Treated Diabetic Patients . AB - BACKGROUND: First choice of therapy for severe hypoglycemia outside hospital environment is glucagon injection, an undertaught and underused remedy. Aim of this study was to investigate knowledge about glucagon therapy, possession rate and usage rate in insulin-treated diabetic patients, with special emphasis on history of hypoglycemia and severe hypoglycemia episodes. METHODS: In this cross sectional study, 300 insulin-treated diabetic patients (146 males and 154 females, mean age 61.1+/-16.4 years) were recruited from comprehensive Diabetes Center in Croatia. Specialized self-administered, 13-item questionnaire regarding glucagon therapy and history of hypoglycemia was obtained from each patient, as well as data collected from medical history documentation. RESULTS: Experience of hypoglycemic episode was reported by 233 (77.7%), and severe hypoglycemia by 73 (24.3%) patients. Participants with experience of hypoglycemia have significantly longer diabetes duration (17.2+/-11.2 vs. 11.9+/-8.5 years, P<0.001) and lower BMI values (26.38+/-3.97 vs. 31.11+/-7.17 kg/m2, P<0.001). Knowledge about glucagon therapy had 55.3% patients, 44.7% obtained it from the pharmacy, while glucagon was used in 35.6% cases of severe hypoglycemia. Glucagon knowledge was better in patients that attended at least one diabetes lecture (P=0.038), while educational level showed no statistical significance (P=0.286). Main significant positive predictor of glucagon knowledge was history of severe hypoglycemia (OR 4.71, 95% CI 1.38 - 16.02, P=0.013). CONCLUSIONS: Glucagon therapy was underused in treating severe hypoglycemia. It is highly important to emphasize value of quality education as one of the fundamentals of good diabetes management. PMID- 30428497 TI - Carney Complex. AB - Carney complex is a rare, autosomal dominant, multiple endocrine neoplasia and lentiginosis syndrome, caused in most patients by defects in the PRKAR1A gene, which encodes the regulatory subunit type 1alpha of protein kinase A. Inactivating defects of PRKAR1A lead to aberrant cyclic-AMP-protein kinase A signaling. Patients may develop multiple skin abnormalities and a variety of endocrine and non-endocrine tumors. Endocrine manifestations include primary pigmented nodular adrenocortical disease, that may cause Cushing syndrome, growth hormone secreting pituitary adenoma or pituitary somatotropic hyperplasia which can result in acromegaly, as well as gonadal and thyroid tumors. Non-endocrine tumors associated with Carney complex include myxomas of the heart, breast, and other sites, psamommatous melanotic schwannomas, breast ductal adenomas, osteochondromyxomas, and a predisposition to a number of malignancies from adrenal to pancreatic and liver cancer. PMID- 30428498 TI - Evaluating Potential Distribution of High-Risk Aquatic Invasive Species in the Water Garden and Aquarium Trade at a Global Scale Based on Current Established Populations. AB - Aquatic non-native invasive species are commonly traded in the worldwide water garden and aquarium markets, and some of these species pose major threats to the economy, the environment, and human health. Understanding the potential suitable habitat for these species at a global scale and at regional scales can inform risk assessments and predict future potential establishment. Typically, global habitat suitability models are fit for freshwater species with only climate variables, which provides little information about suitable terrestrial conditions for aquatic species. Remotely sensed data including topography and land cover data have the potential to improve our understanding of suitable habitat for aquatic species. In this study, we fit species distribution models using five different model algorithms for three non-native aquatic invasive species with bioclimatic, topographic, and remotely sensed covariates to evaluate potential suitable habitat beyond simple climate matches. The species examined included a frog (Xenopus laevis), toad (Bombina orientalis), and snail (Pomacea spp.). Using a unique modeling approach for each species including background point selection based on known established populations resulted in robust ensemble habitat suitability models. All models for all species had test area under the receiver operating characteristic curve values greater than 0.70 and percent correctly classified values greater than 0.65. Importantly, we employed multivariate environmental similarity surface maps to evaluate potential extrapolation beyond observed conditions when applying models globally. These global models provide necessary forecasts of where these aquatic invasive species have the potential for establishment outside their native range, a key component in risk analyses. PMID- 30428499 TI - Forensic Performance Analysis of Load-Limiting Devices in Automotive Seat Belt Retractors. AB - The introduction of frontal airbags and seatbelt pretensioners for front seat occupants provided an opportunity to address injuries caused by seatbelt loading by introducing load-limiters, which were intended to reduce belt loading while maintaining proper restraint. Investigation and forensic analysis of real-world crashes identified that the implementation of these devices, in some circumstances, increased the potential of injury. This paper focuses on the trade offs of load-limiters, that is, the reduction loading to the occupant versus the corresponding increase in seatbelt webbing and occupant movement. If the additional webbing introduced is not controlled, the risk of injury to the occupant is increased and could result in more frequent and severe injuries rather than a reduction. This paper quantifies the webbing introduced by load limiter activation through forensic analysis of the seatbelt involved in real world crashes and testing and assesses its effect on the injuries sustained by the occupant. PMID- 30428500 TI - Wonderland and the rabbit hole: A commentary on university students' alcohol use during first year and the early transition to university. AB - For new students, university can be a wonderland of opportunity. But the first few weeks of the university experience are also typified by change, stress and uncertainty. From a health promotion perspective, the first few weeks of the university experience present an important yet understudied opportunity for alcohol misuse prevention. In this narrative review, we distinguish students' alcohol use during their first year at university from what is known about their use in the first few weeks on campus. First, we outline the developmental context of the first year experience and the descriptive epidemiology of alcohol use and consequences. Second, we highlight how distinctly different the first few weeks of the university experience are relative to the rest of the academic year and overview the limited research on alcohol use and consequences during the first few weeks. Third, we overview the limited number of strategies that have focused on reducing alcohol use during the transition to university. Finally, we offer a number of suggestions for future research. A better understanding of the nature and determinants of alcohol use and consequences during the transition to university is critical to designing effective prevention and intervention strategies. PMID- 30428501 TI - Development and evaluation of the Adaptation Support Program in Early Pregnancy after the use of assisted reproductive technology. AB - AIM: To evaluate the feasibility, acceptability, and outcome of the Adaptation Support Program in Early Pregnancy after the use of assisted reproductive technology (ART). METHODS: The participants were 57 primiparas who had undergone ART and had received the Adaptation Support Program. The data were gathered by using questionnaires before (Time 1), immediately after (Time 2), and 8 weeks after (Time 3) the intervention between August, 2014 and March, 2015. The data for the 40 women who gave valid answers were analyzed statistically. RESULTS: Of the respondents, 75% gave a positive evaluation that the program met their expectations and >80% positively evaluated it for its convenience, problem solving intentionality, satisfaction, and usefulness. The Anticipatory Anxiety for Loss Scale (AALS) and State-Trait Anxiety Inventory (STAI-J) scores decreased significantly at Times 2 and 3 and the Edinburgh Postnatal Depression Scale (EPDS) scores at Time 3. The Post-traumatic Growth Inventory-Japanese (PTGI-J) scores, showing growth as a result of infertility experience, increased significantly at Time 3. The Care Need Satisfaction Scale (CNSS) scores showed a positive correlation with the PTGI-J scores and negative correlations with the AALS and STAI-J, but did not correlate with the EPDS. CONCLUSION: This program was evaluated positively. The AALS, PTGI-J, EPDS, and STAI showed significant change after the program and the AALS, PTGI-J, and STAI-J showed significant correlations with the CNSS. PMID- 30428502 TI - Changes of computed tomography-based body composition after adrenalectomy in patients with endogenous hypercortisolism. AB - CONTEXT: Data on longitudinal changes of computed tomography (CT)-determined visceral fat area (VFA), skeletal muscle area (SMA), and skeletal muscle radiodensity (SMD) after adrenalectomy are limited in patients with hypercortisolism. OBJECTIVE: To examine the association of severity of cortisol excess and improvement of CT-based muscle and fat parameters after adrenalectomy. DESIGN: Retrospective observational cohort study. PATIENTS: One-hundred-thirty four patients with overt Cushing's syndrome (CS; n=39), mild autonomous cortisol excess (MACE; n=57), or nonfunctioning adrenal tumor (NFAT; n=38) at a tertiary endocrinology institution between 2006 and 2017 were included. MEASUREMENTS: Changes in CT-determined VFA, visceral-to-subcutaneous fat ratio (VSR), SMA, skeletal muscle index (SMI), and SMD measured at the third lumbar vertebra (L3) RESULTS: At baseline, CS patients had higher VFA, lower SMA, SMI, and SMD values, compared to NFAT or MACE patients. Compared to NFAT, significant decreases in VFA and increases in SMA, SMI, and SMD was observed in CS 1 year after adrenalectomy. In MACE, adjusted mean changes of SMD but not VFA, SMA, or SMI differ significantly compared to NFAT (+8.9% vs. -3.4%, P=0.032). In a multivariate linear regression model, the increase by 1 MUg/dL of post-dexamethasone serum cortisol at baseline was independently associated with greater reduction of VFA ( 3.95%), VSR (-3.07%), and increase in SMD (+0.92%, P<0.05 for all) after adrenalectomy. CONCLUSIONS: The severity of cortisol excess was associated with greater improvement of L3 VFA, VSR, and SMD 1 year after adrenalectomy. These CT based markers may allow more objective assessment of treatment benefit at earlier stage. This article is protected by copyright. All rights reserved. PMID- 30428503 TI - Effects of exercise training and follow-up calls at home on physical activity and quality of life after a mastectomy. AB - AIM: To determine the effects of exercise training that was supported with follow up calls at home on the postoperative level of physical activity and quality of life of women with breast cancer. METHODS: The study was carried out with a quasi experimental design. Women who had underwent an axillary dissection and mastectomy and who were receiving ongoing chemotherapy treatment in the ambulatory unit of a university hospital were included in the study. Sixty-two women were randomly assigned to an intervention (n = 31) or a control (n = 31) group. The women in the intervention group were given exercise training and then they were followed up by phone calls at home for 12 weeks in order to ensure the continuity of the exercises. RESULTS: At the end of the study, the number of "very active" individuals and the "total physical activity level" increased significantly in the intervention group but decreased significantly in the control group. In the intervention group, "future healthy function" in the functional area subscale significantly increased but "systematic therapy side effects," "breast symptoms," and "arm symptoms" in the symptom subscale increased significantly. CONCLUSION: Exercise training that is supported with home follow up calls after surgery increases the level of physical activity, which then favorably relates with a good quality of life of women with breast cancer. PMID- 30428504 TI - Initial presentation determines clinical entity in patients with anti-centromere antibody positivity. AB - AIM: Anti-centromere antibody (ACA) is often detected in patients with autoimmune diseases, including limited cutaneous systemic sclerosis (SSc), Sjogren's syndrome (SS), and primary biliary cholangitis (PBC). The association between autoimmune disease and ACA positivity remains unclear. We sought to clarify the clinical features of ACA-positive patients and their association with autoantibodies. METHOD: A total of 309 cases of a discrete-speckled pattern anti nuclear antibody (ANA) test and/or positive ACA who visited our department were retrospectively enrolled. Clinical and immunological data were collected and statistically analyzed. RESULT: A proportion of second and/or third ANA patterns were speckled (16%), homogenous (7%), cytoplasmic (3%) and/or nucleolar (3%). Of the 309 patients, 186 had Raynaud's phenomenon, 149 had sclerodactyly, and 162 had oral and/or ocular dryness. A total of 214 patients were classified into 17 autoimmune diseases based on their symptoms at the initial visit, while the other 95 patients did not meet any criteria. Most of the 214 patients were diagnosed with SSc and/or SS; 25 and 22 additional patients were diagnosed with rheumatoid arthritis and PBC, respectively. Higher titers of immunoglobulins were observed in patients diagnosed with autoimmune disease compared to patients without a diagnosis. The mean observation period was 80 months. Three additional patients received interim diagnoses based on new symptoms or organ involvement. In the other patients, the diagnosis made at the first visit was not changed over the observation period. CONCLUSION: Our study confirmed that many ACA-positive cases can be classified into an autoimmune disease type on presentation. PMID- 30428505 TI - Physiologically-based pharmacokinetic modelling to predict oprozomib CYP3A drug drug interaction potential in patients with advanced malignancies. AB - AIMS: Oprozomib is an oral, second-generation, irreversible proteasome inhibitor currently in clinical development for haematologic malignancies, including multiple myeloma and other malignancies. Oprozomib is a rare example of a small molecule drug that demonstrates cytochrome P450 (CYP) mRNA suppression. This unusual property elicits uncertainty regarding the optimal approach for predicting its drug-drug interaction (DDI) risk. The current study aims to understand DDI potential during early clinical development of oprozomib. METHODS: To support early development of oprozomib (e.g. inclusion/exclusion criteria, combination study design), we used human hepatocyte data and physiologically based pharmacokinetic (PBPK) modelling to predict its CYP3A4-mediated DDI potential. Subsequently, a clinical DDI study using midazolam as the substrate was conducted in patients with advanced malignancies. RESULTS: The clinical DDI study enrolled a total of 21 patients, 18 with advanced solid tumours. No patient discontinued oprozomib due to a treatment-related adverse event. The PBPK model prospectively predicted oprozomib 300 mg would not cause a clinically relevant change in exposure to CYP3A4 substrates (<=30%), which was confirmed by the results of this clinical DDI study. CONCLUSIONS: These results indicate oprozomib has a low potential to inhibit the metabolism of CYP3A4 substrates in humans. The study shows that cultured human hepatocytes are a more reliable system for DDI prediction than human liver microsomes for studying this class of compounds. Developing a PBPK model prior to a clinical DDI study has been valuable in supporting clinical development of oprozomib. PMID- 30428506 TI - The impact of systemic sclerosis on health-related quality of life assessed by SF 36: A systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis was to systematically review the literature to evaluate the impact of systemic sclerosis (SSc) on the health related quality of life (HRQoL) assessed by the Medical Outcomes Short-Form-36 questionnaire (SF-36). METHODS: A systematic literature search was performed on PubMed, Web of Science and Embase until April 2017 to obtain eligible studies. Random effect model was performed to summarize the scores of each domain. Scores from the SF-36 questionnaire were used as the outcome measurements, and mean differences with 95% confidence intervals were calculated. RESULTS: In total, seven studies were eligible for inclusion criteria, comprising 795 SSc patients and 1154 healthy controls. The SF-36 questionnaire score of each domain (physical function, role physical function, emotional role function, vitality, mental health, social function, body pain, general health) was lower in SSc patients than in healthy controls, meanwhile, physical component scale (PCS) and mental component scale (MCS) scores were all lower in patients with SSc than in healthy controls. Likewise, pooled mean scores of PCS and MCS ranged from 31.20 to 52.80, 37.40 to 68.30, respectively. Additionally, the score of PCS was lower than that of MCS in SSc patients. CONCLUSIONS: This meta-analysis showed that SSc patients had lower HRQoL than healthy controls, and SSc had negative influence on the HRQoL of patients. This indicates that clinical workers should pay more attention to SSc patients' HRQoL, so as to improve global health of patients with SSc. PMID- 30428507 TI - ACEM involvement in a successful African emergency medicine programme. AB - In the past 5 years Botswana graduated its first home-grown doctors and emergency medicine specialists for the country. The postgraduate emergency medicine specialist training arrangement between Botswana and South Africa was challenging in development, implementation and maintenance. Numerous varied supports from ACEM and its International Emergency Medicine Network were integral to these successes. This article encourages further investment of ACEM grants and scholarships in Africa by describing how ACEM supported significant advances in Botswana emergency medicine. PMID- 30428508 TI - von Willebrand Factor Antigen Predicts Outcomes in Patients after Liver Resection of Hepatocellular Carcinoma. AB - Background/Aims: von Willebrand factor antigen (vWF-Ag) is a noninvasive predictor of portal hypertension that serves as a negative prognostic marker in various malignancies. Increased portal hypertension is associated with higher postoperative morbidity and decreased survival after hepatectomy. The purpose of this study was to determine the correlation between vWF-Ag, postoperative morbidity and oncological outcome. Methods: This analysis includes 55 patients who underwent liver resection for hepatocellular carcinoma (HCC) between 2008 and 2015 with available preoperative vWF-Ag levels. The primary endpoints were postoperative complications and long-term outcome, including overall and disease free survival. Results: The median plasma level of vWF-Ag was 191% (range, 162.5% to 277%). There was a significant correlation between vWF-Ag levels and tumor size in the resected specimens (p=0.010, r=0.350). Patients who developed any grade of postoperative complication had significantly higher preoperative vWF-Ag levels (216% [range, 178% to 283.25%] vs 176% [range, 148% to 246%], p=0.041). Median overall survival was 39.8 months in patients with high vWF-Ag levels (>=191%) compared with 73.4 months in patients with low levels (<191%, p=0.007). Of note, there was a remarkable disparity in the number of patients who died of HCC with low versus high vWF-Ag levels (14.8% vs 28.6%, p=0.011). Conclusions: vWF-Ag may serve as a prognostic marker for the outcome of patients undergoing liver resection for HCC that is closely connected to tumor size, postoperative complication rate and long-term outcome. PMID- 30428510 TI - Filling the Gaps in Adolescent Care and School Health Policy-Tackling Health Disparities through Sports Medicine Integration. AB - The School-Based Health Centre (SBHC) model of healthcare delivery in community health is designed to address the unique needs of adolescents. Through a collaborative interprofessional approach, they aim to provide comprehensive care with the goal of reducing health disparities in underserved, at-risk adolescents. Integration of sports medicine health professionals is a novel approach to increasing available services, as well as patient utilization, while addressing multiple public health issues, including lack of athletic training services for youth athletes. PMID- 30428511 TI - The Intracellular Free Zinc Level Is Vital for Treg Function and a Feasible Tool to Discriminate between Treg and Activated Th Cells. AB - The intracellular free zinc level and zinc distribution are important for cellular function. Both are highly variable and are altered due to intrinsic zinc pool fluctuation via buffering and muffling reactions. Multiple autoimmune diseases are associated with pathologically changed zinc levels, which provoke altered signal transduction leading to changed immune responses, cell differentiation, and function. For instance, immunological tolerance can be impaired, causing autoimmune diseases because of a malfunction of regulatory T cells (Tregs). We investigated the intracellular free zinc concentration of resting and activated T helper (Th) cells and Tregs in an allogeneic graft versus host disease model using fluorescence-activated cell sorting (FACS) analysis and enlightened cell function under nontoxic zinc concentrations and zinc deficiency by detecting cytokine secretion via enzyme-linked immunosorbent assay (ELISA). We exhibited for the first time that Tregs could be explicitly discriminated from other Th cell subsets using significantly increased intracellular free zinc levels. Moreover, the intracellular free zinc level was essential in maintaining the Treg phenotype and function, since zinc deficiency favored the pro inflammatory immune response. Therefore, we hypothesize that the intracellular free zinc level in Th cells is essential in guaranteeing proper cellular function and can be used to discriminate Tregs from other Th cell subsets. PMID- 30428509 TI - Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors. AB - Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) "a single sensitizing uncommon mutation", 7 (12%) "multiple sensitizing mutations", 5 (9%) "a sensitizing mutation and a resistant uncommon mutation", and 18 (32%) "other resistant uncommon mutations". No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings. PMID- 30428512 TI - Clinically Relevant Radiation Exposure Differentially Impacts Forms of Cell Death in Human Cells of the Innate and Adaptive Immune System. AB - In cancer treatments, especially high-dose radiotherapy (HDRT) is applied. Patients suffering from chronic inflammatory diseases benefit from low-dose radiation therapy (LDRT), but exposure to very low radiation doses can still steadily increase for diagnostic purposes. Yet, little is known about how radiation impacts on forms of cell death in human immune cells. In this study, the radiosensitivity of human immune cells of the peripheral blood was examined in a dose range from 0.01 to 60 Gy with regard to induction of apoptosis, primary necrosis, and secondary necrosis. Results showed that immune cells differed in their radiosensitivity, with monocytes being the most radioresistant. T cells mainly died by necrosis and were moderately radiosensitive. This was followed by B and natural killer (NK) cells, which died mainly by apoptosis. X-radiation had no impact on cell death in immune cells at very low doses (<=0.1 Gy). Radiation doses of LDRT (0.3-0.7 Gy) impacted on the more radiosensitive NK and B cells, which might contribute to attenuation of inflammation. Even single doses applied during RT of tumors did not erase the immune cells completely. These in vitro studies can be considered as the basis to optimize individual radiation therapy schemes in multimodal settings and to define suited time points for further inclusion of immunotherapies. PMID- 30428513 TI - The Efficacy of the Tabby Improved Prevention and Intervention Program in Reducing Cyberbullying and Cybervictimization among Students. AB - Background. This article presents results from the evaluation of the Tabby Improved Prevention and Intervention Program (TIPIP) for cyberbullying and cybervictimization. TIPIP is theoretically designed to address cyberbullying and cybervictimization. It is the first program in this field developed combining the Ecological System Theory and the Threat Assessment Approach. Method. The Tabby Improved program was evaluated using an experimental design with 759 Italian students (aged 10-17 years) randomly allocated via their classes to either the Experimental or Control Group. Results. Repeated measures ANOVAs showed a significant decrease both in cyberbullying and cybervictimization among students who received the intervention with a follow-up period of six months. The program was more effective for boys than for girls. Conclusions. Because cyberbullying is a cruel problem negatively affecting those involved, validated interventions that prove their efficacy in reducing the problem using experimental designs should be widely tested and promoted, paying particular attention to implementing a program fully to increase and guarantee its effectiveness. PMID- 30428514 TI - Prediction of the Formation of Reactive Metabolites by A Novel Classifier Approach Based on Enrichment Factor Optimization (EFO) as Implemented in the VEGA Program. AB - The study is aimed at developing linear classifiers to predict the capacity of a given substrate to yield reactive metabolites. While most of the hitherto reported predictive models are based on the occurrence of known structural alerts (e.g., the presence of toxophoric groups), the present study is focused on the generation of predictive models involving linear combinations of physicochemical and stereo-electronic descriptors. The development of these models is carried out by using a novel classification approach based on enrichment factor optimization (EFO) as implemented in the VEGA suite of programs. The study took advantage of metabolic data as collected by manually curated analysis of the primary literature and published in the years 2004-2009. The learning set included 977 substrates among which 138 compounds yielded reactive first-generation metabolites, plus 212 substrates generating reactive metabolites in all generations (i.e., metabolic steps). The results emphasized the possibility of developing satisfactory predictive models especially when focusing on the first generation reactive metabolites. The extensive comparison of the classifier approach presented here using a set of well-known algorithms implemented in Weka 3.8 revealed that the proposed EFO method compares with the best available approaches and offers two relevant benefits since it involves a limited number of descriptors and provides a score-based probability thus allowing a critical evaluation of the obtained results. The last analyses on non-cheminformatics UCI datasets emphasize the general applicability of the EFO approach, which conveniently performs using both balanced and unbalanced datasets. PMID- 30428516 TI - A Novel Sensorized Heart Valve Prosthesis: Preliminary In Vitro Evaluation. AB - BACKGROUND: Recent studies have shown that subclinical valve thrombosis in heart valve prosthesis (HVP) can be responsible for reduced leaflet motion detectable only by advanced imaging diagnostics. We conceived a novel sensorized HVP able to detect earlier any thrombus formation that may alter the leaflets motion using an electric impedance measurement, IntraValvular Impedance (IVI). METHODS: For IVI measurement, dedicated electrodes are embedded in the structure of the HVP to generate a local electric field that is altered by the moving valve leaflets during their cyclic opening/closing. We present preliminary in vitro results using a first prototype of sensorized mechanical heart valve connected to an external impedance measurement system. The prototype was tested on a circulatory mock loop system and the IVI signals were recorded during both normal dynamics and experimentally induced altered working of the leaflets. RESULTS: Recordings showed a very repetitive and stable IVI signal during the normal cyclic opening/closing of the HVP. The induced alterations in leaflet motion were reflected in the IVI signal. CONCLUSIONS: The novel sensorized HVP has great potential to give early warning of possible subclinical valve thrombosis altering the valve leaflet motion, and to help in tailoring the anticoagulation therapy. PMID- 30428515 TI - Morphological, Rheological and Electromagnetic Properties of Nanocarbon/Poly(lactic) Acid for 3D Printing: Solution Blending vs. Melt Mixing. AB - The limitation of poor mechanical stability and difficulties in printing electrically conductive components can be overcome owing to the recent introduction of nanotechnology into the field of additive manufacturing (AM) and the consequent development of nonconventional polymer nanocomposites suitable for 3D printing. In the present work, different weight percentages (up to 6 wt % in total) of carbon-based nanostructures-multiwalled carbon nanotubes (MWCNTs), graphene nanoplatelets (GNPs), and a combination of both fillers (MWCNTs/GNPs) were incorporated into poly(lactic) acid (PLA, IngeoTM) in an attempt to overcome several limitations of conventional 3D manufacturing based on insulating materials. Solution blending and melt mixing were the two fabrication methods adopted for preparation of the samples under test. A comparison of the morphological, rheological, and electrical properties of the resulting nanocomposites was carried out. Moreover, for the same weight concentrations, the influence of physical and geometrical features (i.e., functionalization and aspect ratio) of the embedded fillers was also investigated. Rheological methods were applied to control the quality of fillers dispersion in PLA matrix. The rheological percolation threshold was considered as reference in order to evaluate the internal structure of nanodispersions. TEM visualization, combined with rheological characterizations, was used for efficient control of the nanofiller dispersion. DC characterization revealed that lower electrical percolation thresholds and higher values of electrical conductivity were achieved using fillers with a larger aspect ratio and melt mixing, respectively. Moreover, given the possibility of obtaining complex and appropriate shapes for electromagnetic compatibility (EC) applications, electromagnetic (EM) response of the nanocomposites at the highest filler concentration was investigated in GHz and THz regions. It was found that the electromagnetic shielding efficiency (EMI) of nanocomposites strongly depended on the aspect ratio of the nanofillers, whereas the type of processing technique did not have a significant effect. Therefore, a careful choice of methods and materials must be made to address the final application for which these materials and further 3D printed architectures are designed. PMID- 30428517 TI - Thermal and Mechanical Properties of Silica-Lignin/Polylactide Composites Subjected to Biodegradation. AB - In this paper, silica-lignin hybrid materials were used as fillers for a polylactide (PLA) matrix. In order to simulate biodegradation, PLA/hybrid filler composite films were kept in soil of neutral pH for six months. Differential scanning calorimetry (DSC) allowed analysis of nonisothermal crystallization behavior of composites, thermal analysis provided information about their thermal stability, and scanning electron microscopy (SEM) was applied to define morphology of films. The influence of biodegradation was also investigated in terms of changes in mechanical properties and color of samples. It was found that application of silica-lignin hybrids as fillers for PLA matrix may be interesting not only in terms of increasing thermal stability, but also controlled biodegradation. To the best knowledge of the authors, this is the first publication regarding biodegradation of PLA composites loaded with silica-lignin hybrid fillers. PMID- 30428518 TI - Assessment of Health-Related Quality of Life between People with Parkinson's Disease and Non-Parkinson's: Using Data Drawn from the '100 for Parkinson's' Smartphone-Based Prospective Study. AB - Background: This study aims to assess the specific difference of the health related quality of life between people with Parkinson's and non-Parkinson's. Methods: A total of 1710 people were drawn from a prospective study with a smartphone-based survey named '100 for Parkinson's' to assess health-related quality of life. The EQ-5D-5L descriptive system and the EQ visual analogue scale were used to measure health-related quality of life and a linear mixed model was used to analyze the difference. Results: The mean difference of EQ-5D-5L index values between people with Parkinson's and non-Parkinson's was 0.15 (95%CI: 0.12, 0.18) at baseline; it changed to 0.17 (95%CI: 0.14, 0.20) at the end of study. The mean difference of EQ visual analogue scale scores between them increased from 10.18 (95%CI: 7.40, 12.96) to 12.19 (95%CI: 9.41, 14.97) from baseline to the end of study. Conclusion: Data can be captured from the participants' own smart devices and support the notion that health-related quality of life for people with Parkinson's is lower than non-Parkinson's. This analysis provides useful evidence for the EQ-5D instrument and is helpful for public health specialists and epidemiologists to assess the health needs of people with Parkinson's and indirectly improve their health status. PMID- 30428519 TI - Neuroprotection Comparison of Rosmarinic Acid and Carnosic Acid in Primary Cultures of Cerebellar Granule Neurons. AB - Neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, are characterized by the progressive loss of neurons in specific regions of the brain and/or spinal cord. Neuronal cell loss typically occurs by either apoptotic or necrotic mechanisms. Oxidative stress and nitrosative stress, along with excitotoxicity and caspase activation, have all been implicated as major underlying causes of neuronal cell death. Diverse nutraceuticals (bioactive compounds found in common foods) have been shown to have neuroprotective effects in a variety of in vitro and in vivo disease models. In the current study, we compared the neuroprotective effects of two polyphenolic compounds, rosmarinic acid and carnosic acid, which are both found at substantial concentrations in the herb rosemary. The capacity of these compounds to rescue primary cultures of rat cerebellar granule neurons (CGNs) from a variety of stressors was investigated. Both polyphenols significantly reduced CGN death induced by the nitric oxide donor, sodium nitroprusside (nitrosative stress). Rosmarinic acid uniquely protected CGNs from glutamate induced excitotoxicity, while only carnosic acid rescued CGNs from caspase dependent apoptosis induced by removal of depolarizing extracellular potassium (5K apoptotic condition). Finally, we found that carnosic acid protects CGNs from 5K-induced apoptosis by activating a phosphatidylinositol 3-kinase (PI3K) pro survival pathway. The shared and unique neuroprotective effects of these two compounds against diverse modes of neuronal cell death suggest that future preclinical studies should explore the potential complementary effects of these rosemary polyphenols on neurodegenerative disease progression. PMID- 30428520 TI - Understanding #WorldEnvironmentDay User Opinions in Twitter: A Topic-Based Sentiment Analysis Approach. AB - The main objective of this exploratory study is to identify the social, economic, environmental and cultural factors related to the sustainable care of both environment and public health that most concern Twitter users. With 336 million active users as of 2018, Twitter is a social network that is increasingly used in research to get information and to understand public opinion as exemplified by Twitter users. In order to identify the factors related to the sustainable care of environment and public health, we have downloaded n = 5873 tweets that used the hashtag #WorldEnvironmentDay on the respective day. As the next step, sentiment analysis with an algorithm developed in Python and trained with data mining was applied to the sample of tweets to group them according to the expressed feelings. Thereafter, a textual analysis was used to group the tweets according to the Sustainable Development Goals (SDGs), identifying the key factors about environment and public health that most concern Twitter users. To this end, we used the qualitative analysis software NVivo Pro 12. The results of the analysis enabled us to establish the key factors that most concern users about the environment and public health such as climate change, global warming, extreme weather, water pollution, deforestation, climate risks, acid rain or massive industrialization. The conclusions of the present study can be useful to companies and institutions that have initiatives related to the environment and they also facilitate decision-making regarding the environment in non-profit organizations. Our findings will also serve the United Nations that will thoroughly review the 17 SDGs at the High-level Political Forum in 2019. PMID- 30428522 TI - TNBC Challenge: Oligonucleotide Aptamers for New Imaging and Therapy Modalities. AB - Compared to other breast cancers, triple-negative breast cancer (TNBC) usually affects younger patients, is larger in size, of higher grade and is biologically more aggressive. To date, conventional cytotoxic chemotherapy remains the only available treatment for TNBC because it lacks expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2), and no alternative targetable molecules have been identified so far. The high biological and clinical heterogeneity adds a further challenge to TNBC management and requires the identification of new biomarkers to improve detection by imaging, thus allowing the specific treatment of each individual TNBC subtype. The Systematic Evolution of Ligands by EXponential enrichment (SELEX) technique holds great promise to the search for novel targetable biomarkers, and aptamer based molecular approaches have the potential to overcome obstacles of current imaging and therapy modalities. In this review, we highlight recent advances in oligonucleotide aptamers used as imaging and/or therapeutic agents in TNBC, discussing the potential options to discover, image and hit new actionable targets in TNBC. PMID- 30428521 TI - The Timing of Activity after Eating Affects the Glycaemic Response of Healthy Adults: A Randomised Controlled Trial. AB - There is scant information on how a time lag between the cessation of eating and commencement of physical activity affects postprandial glycaemia. Starting at baseline (t = 0), participants ingested white bread containing 50 g of available carbohydrates within 10 min. Using two crossover conditions, we tested the effect over 2 h on postprandial glycaemia of participants undertaking light activity at 15 or 45 min following baseline and compared it with a sedentary control condition. The activity involved cycling on a stationary ergometer for 10 min at 40 revolutions per min with zero resistance. Seventy-eight healthy adults were randomized to the 15 or 45 min activity arm and then randomised to the order in which they undertook the active and sedentary conditions. Cycling 45 min after baseline changed the course of the blood glucose response (likelihood ratio chi square = 31.47, p < 0.01) and reduced mean blood glucose by 0.44 mmol/L (95% confidence interval 0.14 to 0.74) at 60 min when compared with the sedentary control. No differences in postprandial blood glucose response were observed when cycling started 15 min after baseline compared with the sedentary control. Undertaking activity after waiting for 30 min following eating might be optimal in modifying the glycaemic response. PMID- 30428523 TI - Preparation and Surface Properties Study of Novel Fluorine-Containing Methacrylate Polymers for Coating. AB - A new structural fluorine-containing methacrylate monomer CH2=C(CH3)COOC (CF3)2CF2CF2CF3 (5) was synthesized derived from perfluoro-2-methyl-2-pentene (D2). A homopolymer of 5 and copolymers of 5 and methacrylate with different alkyl chain length (chain length n = 1, 2, 4, 6, 8, 12, 18) were obtained. These new fluorinated acrylate polymers showed excellent water and oil repellency. The contact angle of the films of the homopolymer and part of the copolymers were similar with the corresponding polymers prepared from CH2=CHC(O)OCH(C3F7)(CF(CF3)2), but greater than that of the C6F13(CF3)CHOC(O)CH=CH2 homopolymer. The structure-property relationship research indicated that the copolymers' hydrophobicity decreased first and then increased with the increase of alkyl chain length. Td of all the polymers were greater than 220 degrees C and Tg fluctuated within the range of -51~103.8 degrees C. Contact angle and Tg could be adjusted by controlling the feed ratio of monomer to meet the requirements of technical indicators in the practical applications. The outstanding liquid repellency and thermal stability make monomer 5 a promising alternative to perfluorinated long-chain fluorosurfactants. PMID- 30428524 TI - Age Modifies the Association of Dietary Protein Intake with All-Cause Mortality in Patients with Chronic Kidney Disease. AB - Whether the effect of a low-protein diet on progression to end-stage renal disease (ESRD) and mortality risk differs between young and elderly adults with chronic kidney disease (CKD) is unclear. We conducted a retrospective CKD cohort study to investigate the association between protein intake and mortality or renal outcomes and whether age affects this association. The cohort comprised 352 patients with stage G3-5 CKD who had been followed up for a median 4.2 years, had undergone educational hospitalization, and for whom baseline protein intake was estimated from 24-h urine samples. We classified the patients into a very low protein intake (VLPI) group (<0.6 g/kg ideal body weight/day), a low protein intake (LPI) group (0.6-0.8 g), and a moderate protein intake (MPI) group (>0.8 g). Compared with the LPI group, the MPI group had a significantly lower risk of all-cause mortality (hazard ratio: 0.29; 95% confidence interval: 0.07 to 0.94) but a similar risk of ESRD, although relatively high protein intake was related to a faster decline in the estimated glomerular filtration rate. When examined per age group, these results were observed only among the elderly patients, suggesting that the association between baseline dietary protein intake and all cause mortality in patients with CKD is age-dependent. PMID- 30428525 TI - Greenspace and Atopic Sensitization in Children and Adolescents-A Systematic Review. AB - In the last decade, studies investigating greenspace have highlighted several benefits to human health. However, the effect of greenspace on allergies and atopic sensitization in children was not clear. While several studies have investigated this link, the evidence has not been systematically synthesized. We conducted a systematic search of eight databases. Study characteristics and findings were extracted from five articles covering 11 cohorts published between 2012 and 2016, and study quality assessments were performed. Due to significant heterogeneity, meta-analysis was not conducted. Findings were not consistent, possibly due to variations in exposure measurements, study populations and location, the specific allergens tested, and inclusion of confounders. Protective effects from greenspace were reported in four cohorts, while two cohorts showed an increase in sensitization related to greenspace. The other five cohorts found no significant effect of greenspace on atopic sensitization. There is limited understanding of the contributions of greenspace to specific allergens. Future research should consider amount and type of greenspace, as well as the specific allergens tested. PMID- 30428527 TI - Physiological and Fitness Adaptations after Eight Weeks of High-Intensity Functional Training in Physically Inactive Adults. AB - The purpose of this study was to characterize high-intensity functional training (HIFT) in physically inactive adults. Four men and 10 women who were inexperienced with HIFT and not performing regular physical activity performed HIFT 3 days/week for 8 weeks. Health and fitness measures were assessed before and after the intervention. Resting heart rate (73 +/- 12 vs. 68 +/- 11 bpm) and resting diastolic blood pressure (71 +/- 7 vs. 65 +/- 6 mmHg) were reduced, while resting systolic blood pressure remained unchanged. Absolute VO2max (2.53 +/- 0.68 vs. 2.69 +/- 0.66 L/min) and relative VO2max (32.51 +/- 8.84 vs. 34.31 +/- 8.63 mL/kg/min) were improved. Lean body mass (48.20 +/- 13.37 vs. 49.26 +/- 13.81 kg) was increased, but fat mass was unchanged. Performance on the leg press (164.61 +/- 54.35 vs. 201.62 +/- 67.50 kg), bench press (39.12 +/- 20.15 vs. 46.43 +/- 21.18 kg), YMCA bench press (26 +/- 13 vs. 37 +/- 16 reps), one-minute sit-up (25 +/- 9 vs. 32 +/- 10 reps), and sit-and-reach (30.36 +/- 11.36 vs. 32.14 +/- 9.66 cm) were all increased. High-intensity functional training may be useful for improving health-related physical fitness parameters in physically inactive adults. PMID- 30428526 TI - A Calcium-Deficient Diet in Dams during Gestation Increases Insulin Resistance in Male Offspring. AB - Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Osteocalcin (OC), a bone formation biomarker, acts directly on beta cells and increases insulin secretion. We determined the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in offspring. Female Wistar rats consumed either a Ca-deficient or control diet ad libitum from three weeks preconception to 21 days postparturition. Pups were allowed to nurse their original mothers until weaning. The offspring were fed a control diet beginning at weaning and were killed on day 180. Serum carboxylated OC (Gla-OC) and undercarboxylated OC (Glu-OC), insulin and adipokines in offspring were measured. In males, mean levels of insulin, glucose, and HOMA-IR were higher in the Ca deficient group than in the control group. In addition, ionized Ca (iCa) was inversely associated with serum Glu-OC and adiponectin in males. In females, mean levels of Glu-OC and Gla-OC in the Ca-deficient group were higher than in the control group. In all offspring, serum leptin levels were correlated with serum insulin levels, and inversely correlated with iCa. In conclusion, maternal Ca restriction during pregnancy and/or lactation influences postnatal offspring Ca metabolism and insulin resistance in a sex-specific manner. PMID- 30428528 TI - Genomic Analysis of the Recent Viral Isolate vB_BthP-Goe4 Reveals Increased Diversity of phi29-Like Phages. AB - We present the recently isolated virus vB_BthP-Goe4 infecting Bacillus thuringiensis HD1. Morphological investigation via transmission electron microscopy revealed key characteristics of the genus Phi29virus, but with an elongated head resulting in larger virion particles of approximately 50 nm width and 120 nm height. Genome sequencing and analysis resulted in a linear phage chromosome of approximately 26 kb, harbouring 40 protein-encoding genes and a packaging RNA. Sequence comparison confirmed the relation to the Phi29virus genus and genomes of other related strains. A global average nucleotide identity analysis of all identified phi29-like viruses revealed the formation of several new groups previously not observed. The largest group includes Goe4 and may significantly expand the genus Phi29virus (Salasvirus) or the Picovirinae subfamily. PMID- 30428529 TI - Broad-Spectrum Antiviral Activity of an Ankyrin Repeat Protein on Viral Assembly against Chimeric NL4-3 Viruses Carrying Gag/PR Derived from Circulating Strains among Northern Thai Patients. AB - Certain proteins have demonstrated proficient human immunodeficiency virus (HIV 1) life cycle disturbance. Recently, the ankyrin repeat protein targeting the HIV 1 capsid, AnkGAG1D4, showed a negative effect on the viral assembly of the HIV 1NL4-3 laboratory strain. To extend its potential for future clinical application, the activity of AnkGAG1D4 in the inhibition of other HIV-1 circulating strains was evaluated. Chimeric NL4-3 viruses carrying patient derived Gag/PR-coding regions were generated from 131 antiretroviral drug-naive HIV-1 infected individuals in northern Thailand during 2001-2012. SupT1, a stable T-cell line expressing AnkGAG1D4 and ankyrin non-binding control (AnkA32D3), were challenged with these chimeric viruses. The p24CA sequences were analysed and classified using the K-means clustering method. Among all the classes of virus classified using the p24CA sequences, SupT1/AnkGAG1D4 demonstrated significantly lower levels of p24CA than SupT1/AnkA32D3, which was found to correlate with the syncytia formation. This result suggests that AnkGAG1D4 can significantly interfere with the chimeric viruses derived from patients with different sequences of the p24CA domain. It supports the possibility of ankyrin-based therapy as a broad alternative therapeutic molecule for HIV-1 gene therapy in the future. PMID- 30428530 TI - Yield Visualization Based on Farm Work Information Measured by Smart Devices. AB - This paper proposes a new approach to visualizing spatial variation of plant status in a tomato greenhouse based on farm work information operated by laborers. Farm work information consists of a farm laborer's position and action. A farm laborer's position is estimated based on radio wave strength measured by using a smartphone carried by the farm laborer and Bluetooth beacons placed in the greenhouse. A farm laborer's action is recognized based on motion data measured by using smartwatches worn on both wrists of the farm laborer. As experiment, harvesting information operated by one farm laborer in a part of a tomato greenhouse is obtained, and the spatial distribution of yields in the experimental field, called a harvesting map, is visualized. The mean absolute error of the number of harvested tomatoes in each small section of the experimental field is 0.35. An interview with the farm manager shows that the harvesting map is useful for intuitively grasping the states of the greenhouse. PMID- 30428531 TI - Revisiting Bacterial Ubiquitin Ligase Effectors: Weapons for Host Exploitation. AB - Protein ubiquitylation plays a central role in eukaryotic cell physiology. It is involved in several regulatory processes, ranging from protein folding or degradation, subcellular localization of proteins, vesicular trafficking and endocytosis to DNA repair, cell cycle, innate immunity, autophagy, and apoptosis. As such, it is reasonable that pathogens have developed a way to exploit such a crucial system to enhance their virulence against the host. Hence, bacteria have evolved a wide range of effectors capable of mimicking the main players of the eukaryotic ubiquitin system, in particular ubiquitin ligases, by interfering with host physiology. Here, we give an overview of this topic and, in particular, we detail and discuss the mechanisms developed by pathogenic bacteria to hijack the host ubiquitination system for their own benefit. PMID- 30428532 TI - Fatigue Performance of the CA Mortar Used in CRTS I Ballastless Slab Track under Simulated Servicing Condition. AB - The cement and asphalt mortar (CA mortar) used in the China Railway Track System (CRTS) I ballastless slab track may encounter a coupling fatigue effect under the high-frequency vibration, load and high-and-low temperature cycles, and the deterioration under fatigue may happen during service of the high-speed railway. In this study, the performance degradation and its mechanism of the CA mortar with and without polymer emulsion incorporated under the coupling fatigue effects of the high-frequency vibration, load and temperature were studied by using an anti-fatigue testing device specially developed for the CA mortar used in the ballastless slab track of the high-speed railway. The results showed that the deformation capacity of the CA mortar for CRTS I slab ballastless slab track decreased after fatigue test under simulated service environment, presenting a typical brittle characteristic and an obvious reduction of the ductility and toughness. The Scanning Electron Microscopy (SEM) observation and the mercury intrusion porosimetry (MIP) analysis showed that the volume of the macropore decreased whereas that of the micropore increased after the fatigue test. The asphalt in the hardened CA mortar revealed a softening and migration from the bulk paste to fill the pore and make the structure denser and even ooze out of the CA mortar under the high-frequency vibration and high temperature. Through incorporating the polymer emulsion, the anti-fatigue property of the CA mortar was obviously improved, which can prevent the CA mortar from losing its elastic adjustment function too early. Though increase of the strength and elastic modulus for the CA mortar after severe service is beneficial to the stability of train running, the comfort level and safety of the train operation may decline due to the gradual reduction of the ductility & toughness and the gradual loss of the elastic damping adjustment function of the CA mortar between the base concrete slab and the track slab. PMID- 30428533 TI - Revisiting the Role of Ethylene and N-End Rule Pathway on Chilling-Induced Dormancy Release in Arabidopsis Seeds. AB - Dormant Arabidopsis (Arabidopsis thaliana) seeds do not germinate easily at temperatures higher than 10-15 degrees C. Using mutants affected in ethylene signaling (etr1, ein2 and ein4) and in the N-end-rule pathway of the proteolysis (prt6 and ate1-ate2) we have investigated the effects of cold and ethylene on dormancy alleviation. Ethylene (10-100 ppm) and 2-4 days chilling (4 degrees C) strongly stimulate the germination of wild type (Col-0) seeds at 25 degrees C. Two to four days of chilling promote the germination at 25 degrees C of all the mutants suggesting that release of dormancy by cold did not require ethylene and did not require the N-end-rule pathway. One mutant (etr1) that did not respond to ethylene did not respond to GA3 either. Mutants affected in the N-end rule (prt6 and ate1-ate2) did not respond to ethylene indicating that also this pathway is required for dormancy alleviation by ethylene; they germinated after chilling and in the presence of GA3. Cold can activate the ethylene signaling pathway since it induced an accumulation of ETR1, EINI4, and EIN2 transcripts, the expression of which was not affected by ethylene and GA3. Both cold followed by 10 h at 25 degrees C and ethylene downregulated the expression of PRT6, ATE1, ATE2, and of ABI5 involved in ABA signaling as compared to dormant seeds incubated at 25 degrees C. In opposite, the expression of RGA, GAI, and RGL2 encoding three DELLAs was induced at 4 degrees C but downregulated in the presence of ethylene. PMID- 30428534 TI - Photoactive ZnO Materials for Solar Light-Induced CuxO-ZnO Catalyst Preparation. AB - In this work, the solar light-induced redox photoactivity of ZnO semiconductor material was used to prepare CuxO-ZnO composite catalysts at room temperature with a control of the chemical state of the copper oxide phase. Cu2(I)O-ZnO and Cu(II)O-ZnO composite catalysts were prepared by using Cu(acac)2 in tetrahydrofuran-water and Cu(NO3)2 in water as metallic precursor, respectively. Prior to the implementation of the photon-assisted synthesis method, the most efficient photoactive ZnO material was selected from among different ZnO materials prepared by the low temperature polyol and precipitation methods with carbonates and carbamates as precipitation agents. The photocatalytic degradation of the 4-chlorophenol compound in water under simulated solar light was taken as a model reaction. The ZnO support materials were characterized by X-ray diffraction (XRD), surface area and porosimetry measurements, thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), and the synthesis method strongly influenced their photoactivity in terms of 4-chlorophenol degradation and of total organic carbon removal. The most photoactive ZnO material was prepared by precipitation with carbonates and calcined at 300 degrees C, benefitting from a high specific surface area and a small mean crystallite size for achieving a complete 4 chlorophenol mineralization within 70 min of reaction, with minimum Zn2+ released to the solution. Besides thermal catalysis applications, this work has opened a new route for the facile synthesis of Cu2O-ZnO heterojunction photocatalysts that could take place under solar light of the heterojunction built between the p-type semi-conductor Cu2O with direct visible light band gap and the ZnO semiconductor phase. PMID- 30428535 TI - Usefulness of Adenosine Deaminase Assay in Diagnosis of Patients with HIV Infection and Pleural Tuberculosis. AB - The utility of the adenosine deaminase (ADA) assay in the diagnosis of patients with pleural tuberculosis (TB) and human immunodeficiency virus (HIV) infection is controversial. Forty-eight HIV positive patients with pleural effusion were evaluated; ADA assay was obtained in forty-three of them. Twenty-five patients presented diagnosis of TB. Patients with diagnosis of TB showed a median value of ADA of 70 IU/L (interquartile range (IQR) 41-89) and the non-TB group a median of 27.5 IU/L (IQR 13.5-52). Patients with diagnosis of TB had a median cluster of differentiation 4 (CD4) count of 174 (IQR 86-274) and the non-TB group had a median of 134 (IQR 71-371). Receiver operating characteristic curve was performed with an area under the curve of 0.79. The best cut-off obtained was 35 IU/L with a sensibility of 80% and a specificity of 66%. There was no correlation between CD4 lymphocytes count and the value of ADA in the TB patient group. PMID- 30428536 TI - Challenges, Threats, Security Issues and New Trends of Underwater Wireless Sensor Networks. AB - With the advances in technology, there has been an increasing interest from researchers and industrial institutions in the use of underwater wireless sensor networks (UWSNs). Constrained by the open acoustic channel, harsh underwater environment, and their own particularities, UWSNs are vulnerable to a wide class of security threats and malicious attacks. However, most existing research into UWSNs has not taken security into consideration. Moreover, the existing relatively mature security mechanisms for WSNs cannot be directly utilized in UWSNs. For these reasons, this article aims to present a comprehensive overview of the particularities, constraints, attacks, challenges and current security mechanisms of UWSNs. In addition, challenging, open and hot research topics are outlined. PMID- 30428537 TI - Ultrasensitive and Fast Diagnostics of Viable Listeria Cells by CBD Magnetic Separation Combined with A511::luxAB Detection. AB - The genus Listeria includes foodborne pathogens that cause life-threatening infections in those at risk, and sensitive and specific methods for detection of these bacteria are needed. Based on their unrivaled host specificity and ability to discriminate viable cells, bacteriophages represent an ideal toolbox for the development of such methods. Here, the authors describe an ultrasensitive diagnostic protocol for Listeria by combining two phage-based strategies: (1) specific capture and concentration of target cells by magnetic separation, harnessing cell wall-binding domains from Listeria phage endolysins (CBD-MS); and (2) highly sensitive detection using an adaptation of the A511::luxAB bioluminescent reporter phage assay in a microwell plate format. The combined assay enabled direct detection of approximately 100 bacteria per ml of pure culture with genus-level specificity in less than 6 h. For contaminated foods, the procedure included a 16 h selective enrichment step, followed by CBD-MS separation and A511::luxAB detection. It was able to consistently detect extremely low numbers (0.1 to 1.0 cfu/g) of viable Listeria cells, in a total assay time of less than 22 h. These results demonstrate the superiority of this phage-based assay to standard culture-based diagnostic protocols for the detection of viable bacteria, with respect to both sensitivity and speed. PMID- 30428538 TI - Hsp90 Interacts with the Bacterial Effector NleH1. AB - Enterohemorrhagic Escherichia coli (EHEC) utilizes a type III secretion system (T3SS) to inject effector proteins into host cells. The EHEC NleH1 effector inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) pathway by reducing the nuclear translocation of the ribosomal protein S3 (RPS3). NleH1 prevents RPS3 phosphorylation by the IkappaB kinase-beta (IKKbeta). IKKbeta is a central kinase in the NF-kappaB pathway, yet NleH1 only restricts the phosphorylation of a subset of the IKKbeta substrates. We hypothesized that a protein cofactor might dictate this inhibitory specificity. We determined that heat shock protein 90 (Hsp90) interacts with both IKKbeta and NleH1 and that inhibiting Hsp90 activity reduces RPS3 nuclear translocation. PMID- 30428539 TI - Management of Chronic Disease and Hospitalization Due to Diabetes among Type 2 Diabetes Patients in Korea: Using the National Sample Cohort Data 2002-2013. AB - To prevent negative outcomes for diabetes patients, developing self-management skills is imperative. This study aimed to examine the association between management of chronic disease (MCD), which mainly involves educating patients about their chronic diseases for obtaining self-management skills and hospitalization due to diabetes among type 2 diabetes patients in Korea. Korean National Health Insurance Service National Sample Cohort data from 2002 to 2013 were used. A total of 54,031 type 2 diabetes patients were included in the study. If patients received the MCD within 1 year from the onset of diabetes, we categorized them as "MCD received patients" We reclassified these groups into five groups: "non-receiving", "1-3 times", "4-6 times", "7-9 times" and "10-12 times" The dependent variable of this study was hospitalization due to diabetes. Cox proportional hazard regression was used. Of the patients, 86.2% (n = 46,571) did not received the MCD within the 1 year from the onset of diabetes. The number of MCDs received increased and the hazard ratio (HR) for hospitalization due to diabetes decreased; particularly, patients who received MCD 10-12 times per annum showed the lowest HR for hospitalization due to diabetes compared to patients in the MCD non-received group (1-3 times per annum: HR: 0.81, p = 0.0001; 4-6 times per annum: HR: 0.82, p = 0.0248; 7-9 times per annum: HR: 0.75, p = 0.0054; 10-12 times per annum: HR: 0.61, p < 0.0001). Considering the importance of raising self-managing diabetes skills, the findings can aid in determining the outcomes of the MCD program. PMID- 30428540 TI - Characteristics of Climate Change and Extreme Weather from 1951 to 2011 in China. AB - It has been demonstrated that climate change is an established fact. A good comprehension of climate and extreme weather variation characteristics on a temporal and a spatial scale is important for adaptation and response. In this work, the characteristics of temperature, precipitation, and extreme weather distribution and variation is summarized for a period of 60 years and the seasonal fluctuation of temperature and precipitation is also analyzed. The results illustrate the reduction in daily and annual temperature divergence on both temporal and spatial scales. However, the gaps remain relatively significant. Furthermore, the disparity in daily and annual precipitation are found to be increasing on both temporal and spatial scales. The findings indicate that climate change, to a certain extent, narrowed the temperature gap while widening the precipitation gap on temporal and spatial scales in China. PMID- 30428542 TI - De-Extinction. AB - De-extinction projects for species such as the woolly mammoth and passenger pigeon have greatly stimulated public and scientific interest, producing a large body of literature and much debate. To date, there has been little consistency in descriptions of de-extinction technologies and purposes. In 2016, a special committee of the International Union for the Conservation of Nature (IUCN) published a set of guidelines for de-extinction practice, establishing the first detailed description of de-extinction; yet incoherencies in published literature persist. There are even several problems with the IUCN definition. Here I present a comprehensive definition of de-extinction practice and rationale that expounds and reconciles the biological and ecological inconsistencies in the IUCN definition. This new definition brings together the practices of reintroduction and ecological replacement with de-extinction efforts that employ breeding strategies to recover unique extinct phenotypes into a single "de-extinction" discipline. An accurate understanding of de-extinction and biotechnology segregates the restoration of certain species into a new classification of endangerment, removing them from the purview of de-extinction and into the arena of species' recovery. I term these species as "evolutionarily torpid species"; a term to apply to species falsely considered extinct, which in fact persist in the form of cryopreserved tissues and cultured cells. For the first time in published literature, all currently active de-extinction breeding programs are reviewed and their progress presented. Lastly, I review and scrutinize various topics pertaining to de-extinction in light of the growing body of peer-reviewed literature published since de-extinction breeding programs gained public attention in 2013. PMID- 30428541 TI - Systemic Hypertension Effects on the Ciliary Body and Iris. An Immunofluorescence Study with Aquaporin 1, Aquaporin 4, and Na+, K+ ATPase in Hypertensive Rats. AB - Aquaporin 1 (AQP1) and aquaporin 4 (AQP4) have been identified in the eye as playing an essential role in the formation of the aqueous humor along with the Na+/K+ ATPase pump. Different authors have described the relationship between blood pressure, aqueous humor production, and intraocular pressure with different conclusions, with some authors supporting a positive correlation between blood pressure and intraocular pressure while others disagree. The aim of this work was to study the effect of high blood pressure on the proteins involved in the production of aqueous humor in the ciliary body (CB) and iris. For this purpose, we used the eyes of spontaneously hypertensive rats (SHR) and their control Wistar-Kyoto rats (WKY). Immunofluorescence was performed in different eye structures to analyze the effects of hypertension in the expression of AQP1, AQP4, and the Na+/K+ ATPase alpha1 and alpha2 subunits. The results showed an increase in AQP1 and Na+/K+ ATPase alpha1 and a decrease in AQP4 and Na+/K+ ATPase alpha2 in the CB of SHR, while an increase in AQP4 and no significant differences in AQP1 were found in the iris. Therefore, systemic hypertension produced changes in the proteins implicated in the movement of water in the CB and iris that could influence the production rate of aqueous humor, which would be affected depending on the duration of systemic hypertension. PMID- 30428543 TI - Topical Administration of Bosentan Prevents Retinal Neurodegeneration in Experimental Diabetes. AB - Experimental evidence suggests that endothelin 1 (ET-1) is involved in the development of retinal microvascular abnormalities induced by diabetes. The effects of ET-1 are mediated by endothelin A- and B-receptors (ETA and ETB). Endothelin B-receptors activation mediates retinal neurodegeneration but there are no data regarding the effectiveness of ETB receptor blockage in arresting retinal neurodegeneration induced by diabetes. The main aim of the present study was to assess the usefulness of topical administration of bosentan (a dual endothelin receptor antagonist) in preventing retinal neurodegeneration in diabetic (db/db) mice. For this purpose, db/db mice aged 10 weeks were treated with one drop of bosentan (5 mg/mL, n = 6) or vehicle (n = 6) administered twice daily for 14 days. Six non-diabetic (db/+) mice matched by age were included as the control group. Glial activation was evaluated by immunofluorescence using specific antibodies against glial fibrillary acidic protein (GFAP). Apoptosis was assessed by TUNEL method. A pharmacokinetic study was performed in rabbits. We found that topical administration of bosentan resulted in a significant decrease of reactive gliosis and apoptosis. The results of the pharmacokinetic study suggested that bosentan reached the retina through the trans-scleral route. We conclude that topical administration of bosentan was effective in preventing neurodegeneration in the diabetic retina and, therefore, could be a good candidate to be tested in clinical trials. PMID- 30428545 TI - Causes and Consequences of Spatial Within-Host Viral Spread. AB - The spread of viral pathogens both between and within hosts is inherently a spatial process. While the spatial aspects of viral spread at the epidemiological level have been increasingly well characterized, the spatial aspects of viral spread within infected hosts are still understudied. Here, with a focus on influenza A viruses (IAVs), we first review experimental studies that have shed light on the mechanisms and spatial dynamics of viral spread within hosts. These studies provide strong empirical evidence for highly localized IAV spread within hosts. Since mathematical and computational within-host models have been increasingly used to gain a quantitative understanding of observed viral dynamic patterns, we then review the (relatively few) computational modeling studies that have shed light on possible factors that structure the dynamics of spatial within host IAV spread. These factors include the dispersal distance of virions, the localization of the immune response, and heterogeneity in host cell phenotypes across the respiratory tract. While informative, we find in these studies a striking absence of theoretical expectations of how spatial dynamics may impact the dynamics of viral populations. To mitigate this, we turn to the extensive ecological and evolutionary literature on range expansions to provide informed theoretical expectations. We find that factors such as the type of density dependence, the frequency of long-distance dispersal, specific life history characteristics, and the extent of spatial heterogeneity are critical factors affecting the speed of population spread and the genetic composition of spatially expanding populations. For each factor that we identified in the theoretical literature, we draw parallels to its analog in viral populations. We end by discussing current knowledge gaps related to the spatial component of within-host IAV spread and the potential for within-host spatial considerations to inform the development of disease control strategies. PMID- 30428544 TI - Childhood Obesity and Academic Outcomes in Young Adulthood. AB - The present study used nationally representative data from the National Longitudinal Study of Adolescent Health (a.k.a., Add Health) to examine the impact of childhood obesity on young adult educational attainment. In addition to weight status, independent variables included race-ethnicity, immigrant generational status, family socio-economic status (SES), preference for overweight and obese friends in school, school socio-economic and race-ethnic composition, and other important predictors. Educational attainment was measured as a categorical variable with the categories reflecting key educational benchmarks: (1) being a high school graduate; (2) having some college education; and (3) having completed a bachelor's or higher degree. The results indicate that in general, individuals who were obese as children are less likely to transition from high school to college, and even less likely to obtain a baccalaureate or more advanced degree. In line with the social network hypothesis of the obesity epidemic, we also found that having overweight and obese friends drives down the odds of educational success. Attendance at a higher SES school or a school with a lower percentage of minority students was positively associated with the odds of college attendance and obtaining a baccalaureate. Other important effects included race-ethnicity and immigrant generational status. PMID- 30428546 TI - Special Issue: Coevolution of Hosts and Their Microbiome. AB - The evolution of life-history traits in plants and animals has taken place in the midst of complex microbial communities. [...]. PMID- 30428548 TI - Effects of an Empowerment-Based Health-Promotion School Intervention on Physical Activity and Sedentary Time among Adolescents in a Multicultural Area. AB - Physical activity (PA) decreases with age, and interventions are needed to promote PA during adolescence, especially, among those in low-socioeconomic status (SES) areas. The aim of this study was to investigate whether a two-year, empowerment-based health-promotion school intervention had any effects on changes in (a) moderate-to-vigorous PA (MVPA), (b) sedentary time (SED), (c) exercise training (ET) frequency, and (d) ET duration, among adolescents. Participants (aged 12-13 years at baseline) from one intervention school and two control schools, were recruited from a multicultural area of Sweden, characterized by low SES. During the course of the two-year intervention, a total of 135 participants (43% boys) were included in the study. The intervention was developed and implemented as a result of cooperation and shared decision-making among the researchers and the participants. MVPA and SED were measured with accelerometers, and ET frequency and duration was self-reported at the beginning of the seventh, eighth, and ninth grade, respectively. There were no significant effects of the two-year, empowerment-based health-promotion school intervention on changes in the accelerometer-measured MVPA and SED, or the self-reported ET frequency and duration, among the adolescents. Overall, the intervention was unsuccessful at promoting PA and reducing SED. Several possible explanations for the intervention's lack of effects are discussed. PMID- 30428547 TI - Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer. AB - The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an overview of the patient outcomes that are associated with alternative models of genetic testing and genetic counseling for hereditary cancer, including germline only and tumor testing models. Seven databases were searched, selecting studies that were: (1) full-text articles published >=2007 or conference abstracts published >=2015, and (2) assessing patient outcomes of an alternative model of genetic counseling or testing. A total of 79 publications were included for review and synthesis. Data-charting was completed using a data-charting form that was developed by the study team for this review. Seven alternative models were identified, including four models that involved a genetic counselor: telephone, telegenic, group, and embedded genetic counseling models; and three models that did not: mainstreaming, direct, and tumor-first genetic testing models. Overall, these models may be an acceptable alternative to traditional models on knowledge, patient satisfaction, psychosocial measures, and the uptake of genetic testing; however, particular populations may be better served by traditional in-person genetic counseling. As precision medicine initiatives continue to advance, institutions should consider the implementation of new models of genetic service delivery, utilizing a model that will best serve the needs of their unique patient populations. PMID- 30428549 TI - Phenolic Profiles, Antioxidant Capacities, and Inhibitory Effects on Digestive Enzymes of Different Kiwifruits. AB - In order to obtain high-quality kiwifruits with health-promoting characteristics, physicochemical properties, phenolic profiles, antioxidant capacities, and inhibitory effects on digestive enzymes (pancreatic lipase and alpha glucosidase), of fourteen different types of kiwifruit obtained from China were systematically investigated and compared. Noticeable variations in the fruits' physicochemical properties and phenolic profiles were observed among them. The total phenolic content of Actinidia chinensis cv. Hongshi, A. chinensis cv. Jinshi, and A. chinensis cv. Jinlong were 16.52 +/- 0.26 mg GAE/g DW (dry weight), 13.38 +/- 0.20 mg GAE/g DW, and 11.02 +/- 0.05 mg GAE/g DW, respectively, which were much higher than those of the other tested kiwifruits. According to high performance liquid chromatography (HPLC) analysis, phenolic compounds, including procyanidin B1, procyanidin B2, (-)-epicatechin, chlorogenic acid, gallic acid, and quercetin-3-rhamnoside, were found to be the major compounds in kiwifruits, while procyanidin B1, procyanidin B2, and chlorogenic acid were the most abundant phenolic compounds. Furthermore, all the tested kiwifruits exerted remarkable antioxidant capacities and inhibitory effects on pancreatic lipase and alpha-glucosidase. Indeed, A. chinensis cv. Hongshi, Actinidia chinensis cv. Jinshi, and Actinidia chinensis cv. Jinlong exhibited much better antioxidant capacities and inhibitory effects on digestive enzymes than those of the other tested kiwifruits. Particularly, A. polygama showed the highest inhibitory activity on alpha-glucosidase. Therefore, Actinidia chinensis cv. Hongshi, Actinidia chinensis cv. Jinshi, and Actinidia chinensis cv. Jinlong, as well as A. polygama could be important dietary sources of natural antioxidants and natural inhibitors against pancreatic lipase and alpha-glucosidase, which is helpful for meeting the growing demand for high-quality kiwifruits with health promoting characteristics in China. PMID- 30428551 TI - Interfacing CRYSTAL/AMBER to Optimize QM/MM Lennard-Jones Parameters for Water and to Study Solvation of TiO2 Nanoparticles. AB - Metal oxide nanoparticles (NPs) are regarded as good candidates for many technological applications, where their functional environment is often an aqueous solution. The correct description of metal oxide electronic structure is still a challenge for local and semilocal density functionals, whereas hybrid functional methods provide an improved description, and local atomic function based codes such as CRYSTAL17 outperform plane wave codes when it comes to hybrid functional calculations. However, the computational cost of hybrids are still prohibitive for systems of real sizes, in a real environment. Therefore, we here present and critically assess the accuracy of our electrostatic embedding quantum mechanical/molecular mechanical (QM/MM) coupling between CRYSTAL17 and AMBER16, and demonstrate some of its capabilities via the case study of TiO2 NPs in water. First, we produced new Lennard-Jones (LJ) parameters that improve the accuracy of water-water interactions in the B3LYP/TIP3P coupling. We found that optimizing LJ parameters based on water tri- to deca-mer clusters provides a less overstructured QM/MM liquid water description than when fitting LJ parameters only based on the water dimer. Then, we applied our QM/MM coupling methodology to describe the interaction of a 1 nm wide multilayer of water surrounding a spherical TiO2 nanoparticle (NP). Optimizing the QM/MM water-water parameters was found to have little to no effect on the local NP properties, which provide insights into the range of influence that can be attributed to the LJ term in the QM/MM coupling. The effect of adding additional water in an MM fashion on the geometry optimized nanoparticle structure is small, but more evident effects are seen in its electronic properties. We also show that there is good transferability of existing QM/MM LJ parameters for organic molecules-water interactions to our QM/MM implementation, even though these parameters were obtained with a different QM code and QM/MM implementation, but with the same functional. PMID- 30428550 TI - Possible Prevention of Diabetes with a Gluten-Free Diet. AB - Gluten seems a potentially important determinant in type 1 diabetes (T1D) and type 2 diabetes (T2D). Intake of gluten, a major component of wheat, rye, and barley, affects the microbiota and increases the intestinal permeability. Moreover, studies have demonstrated that gluten peptides, after crossing the intestinal barrier, lead to a more inflammatory milieu. Gluten peptides enter the pancreas where they affect the morphology and might induce beta-cell stress by enhancing glucose- and palmitate-stimulated insulin secretion. Interestingly, animal studies and a human study have demonstrated that a gluten-free (GF) diet during pregnancy reduces the risk of T1D. Evidence regarding the role of a GF diet in T2D is less clear. Some studies have linked intake of a GF diet to reduced obesity and T2D and suggested a role in reducing leptin- and insulin resistance and increasing beta-cell volume. The current knowledge indicates that gluten, among many environmental factors, may be an aetiopathogenic factors for development of T1D and T2D. However, human intervention trials are needed to confirm this and the proposed mechanisms. PMID- 30428552 TI - The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury. AB - The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = <0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects. PMID- 30428554 TI - Cell Injection Millirobot Development and Evaluation in Microfluidic Chip. AB - We propose an innovative design of millirobot, which can achieve donor cell suction, delivery, and injection in a mammalian oocyte on a microfluidic chip. The millirobot body contains a hollow space that produces suction and ejection forces for the injection of cell nuclei using a nozzle at the tip of the robot. Specifically, a controller changes the hollow volume by balancing the magnetic and elastic forces of a membrane along with the motion of stages in the XY plane. A glass capillary attached to the tip of the robot contains a nozzle that is able to absorb and inject cell nuclei. The millirobot provides three degrees of freedom and generates micronewton forces. We demonstrate the effectiveness of the proposed millirobot through an experiment of the absorption and ejection of 20-um particles from the nozzle using magnetic control in a microfluidic chip. PMID- 30428553 TI - Satiety Factors Oleoylethanolamide, Stearoylethanolamide, and Palmitoylethanolamide in Mother's Milk Are Strongly Associated with Infant Weight at Four Months of Age-Data from the Odense Child Cohort. AB - Regulation of appetite and food intake is partly regulated by N-acylethanolamine lipids oleoylethanolamide (OEA), stearoylethanolamide (SEA), and palmitoylethanolamide (PEA), which induce satiety through endogenous formation in the small intestine upon feeding, but also when orally or systemic administered. OEA, SEA, and PEA are present in human milk, and we hypothesized that the content of OEA, SEA, and PEA in mother's milk differed for infants being heavy (high weight-for-age Z-score (WAZ)) or light (low WAZ) at time of milk sample collection. Ultra-high performance liquid chromatography-mass spectrometry was used to determine the concentration of OEA, SEA, and PEA in milk samples collected four months postpartum from mothers to high (n = 50) or low (n = 50) WAZ infants. Associations between OEA, SEA, and PEA concentration and infant anthropometry at four months of age as well as growth from birth were investigated using linear and logistic regression analyses, adjusted for birth weight, early infant formula supplementation, and maternal pre-pregnancy body mass index. Mean OEA, SEA, and PEA concentrations were lower in the high compared to the low WAZ group (all p < 0.02), and a higher concentration of SEA was associated with lower anthropometric measures, e.g., triceps skinfold thickness (mm) (beta = -2.235, 95% CI = -4.04, -0.43, p = 0.016), and weight gain per day since birth (g) (beta = -8.169, 95% CI = -15.26, -1.08, p = 0.024). This raises the possibility, that the content of satiety factors OEA, SEA, and PEA in human milk may affect infant growth. PMID- 30428555 TI - Cisplatin Loaded Multiwalled Carbon Nanotubes Induce Resistance in Triple Negative Breast Cancer Cells. AB - In this paper we developed a method for multiwalled carbon nanotubes (MWCNTs) use as carriers for a drug based on platinum in breast cancer therapy. The method of functionalization involves the carboxyl functionalization of nanotubes and encapsulation of cisplatin (CDDP) into MWCNTs. The biological properties of MWCNTs loaded with CDDP (MWCNT-COOH-CDDP) and of individual components MWCNT-COOH and free CDDP were evaluated on MDA-MB-231 cells. Various concentrations of CDDP (0.316-2.52 ug/mL) and MWCNTs (0.5-4 ug/mL) were applied on cells for 24 and 48 h. Only at high doses of CDDP (1.26 and 2.52 ug/mL) and MWCNT-COOH-CDDP (2 and 4 ug/mL) cell morphological changes were observed. The cellular viability decreased only with approx. 40% after 48 h of exposure to 2.52 ug/mL CDDP and 4 ug/mL MWCNT COOH-CDDP despite the high reactive oxygen species (ROS) production induced by MWCNTs starting with 24 h. After 48 h, ROS level dropped as a result of the antioxidant defence activation. We also found a significant decrease of caspase-3 and p53 expression after 48 h, accompanied by a down-regulation of NF-kappaB in cells exposed to MWCNT-COOH-CDDP system which promotes apoptosis escape and thus failing to overcome the triple negative breast cancer (TNBC) cells resistance. PMID- 30428556 TI - Detection of a Conspecific Mycovirus in Two Closely Related Native and Introduced Fungal Hosts and Evidence for Interspecific Virus Transmission. AB - Hymenoscyphus albidus is a native fungus in Europe where it behaves as a harmless decomposer of leaves of common ash. Its close relative Hymenoscyphus fraxineus was introduced into Europe from Asia and currently threatens ash (Fraxinus sp.) stands all across the continent causing ash dieback. H. fraxineus isolates from Europe were previously shown to harbor a mycovirus named Hymenoscyphus fraxineus Mitovirus 1 (HfMV1). In the present study, we describe a conspecific mycovirus that we detected in H. albidus. HfMV1 was consistently identified in H. albidus isolates (mean prevalence: 49.3%) which were collected in the sampling areas before the arrival of ash dieback. HfMV1 strains in both fungal hosts contain a single ORF of identical length (717 AA) for which a mean pairwise identity of 94.5% was revealed. The occurrence of a conspecific mitovirus in H. albidus and H. fraxineus is most likely the result of parallel virus evolution in the two fungal hosts. HfMV1 sequences from H. albidus showed a higher nucleotide diversity and a higher number of mutations compared to those from H. fraxineus, probably due to a bottleneck caused by the introduction of H. fraxineus in Europe. Our data also points to multiple interspecific virus transfers from H. albidus to H. fraxineus, which could have contributed to the intraspecific virus diversity found in H. fraxineus. PMID- 30428557 TI - Characterization of TrxC, an Atypical Thioredoxin Exclusively Present in Cyanobacteria. AB - Cyanobacteria form a diverse group of oxygenic photosynthetic prokaryotes considered to be the antecessor of plant chloroplast. They contain four different thioredoxins isoforms, three of them corresponding to m, x and y type present in plant chloroplast, while the fourth one (named TrxC) is exclusively found in cyanobacteria. TrxC has a modified active site (WCGLC) instead of the canonical (WCGPC) present in most thioredoxins. We have purified it and assayed its activity but surprisingly TrxC lacked all the classical activities, such as insulin precipitation or activation of the fructose-1,6-bisphosphatase. Mutants lacking trxC or over-expressing it were generated in the model cyanobacterium Synechocystis sp. PCC 6803 and their phenotypes have been analyzed. The DeltatrxC mutant grew at similar rates to WT in all conditions tested although it showed an increased carotenoid content especially under low carbon conditions. Overexpression strains showed reduced growth under the same conditions and accumulated lower amounts of carotenoids. They also showed lower oxygen evolution rates at high light but higher Fv'/Fm' and Non-photochemical-quenching (NPQ) in dark adapted cells, suggesting a more oxidized plastoquinone pool. All these data suggest that TrxC might have a role in regulating photosynthetic adaptation to low carbon and/or high light conditions. PMID- 30428558 TI - Nutritional Status of Men with Ulcerative Colitis in Remission in a Pair-Matched Case-Control Study. AB - The aim of the presented research was to analyze the nutritional status of male subjects with ulcerative colitis in remission by using body composition that was assessed by bioelectrical impedance measurement against a gender-matched control group. Forty-four male patients in remission with ulcerative colitis were recruited for the case-control study and simultaneously, a matched control group of 44 male individuals without inflammatory bowel diseases was pair-matched (general community individuals). The body composition measurement was conducted by the bioelectrical impedance method using BodyComp MF Plus and Bodygram Pro 3.0 software. Parameters assessed include body cell mass (BCM), total body water (TBW), extracellular body water (EBW), intracellular body water (IBW), fat mass (FM), fat-free mass (FFM), muscle mass (MM), and the body cell mass (BCM) index. A significant between-group difference was observed only for EBW, where subjects with ulcerative colitis were characterized by a higher mass of extracellular water (p = 0.0405). Individuals with ulcerative colitis were characterized by a lower BCM share than the control group (p = 0.0192). A comparative analysis of the body composition of male patients with ulcerative colitis with those who did not have ulcerative colitis revealed only minor differences. The risk of malnutrition, assessed using both BMI and bioelectrical impedance, in men with ulcerative colitis in remission is the same as in healthy males in the matched general population. PMID- 30428559 TI - The Combined Effects of Co-Culture and Substrate Mechanics on 3D Tumor Spheroid Formation within Microgels Prepared via Flow-Focusing Microfluidic Fabrication. AB - Tumor spheroids are considered a valuable three dimensional (3D) tissue model to study various aspects of tumor physiology for biomedical applications such as tissue engineering and drug screening as well as basic scientific endeavors, as several cell types can efficiently form spheroids by themselves in both suspension and adherent cell cultures. However, it is more desirable to utilize a 3D scaffold with tunable properties to create more physiologically relevant tumor spheroids as well as optimize their formation. In this study, bioactive spherical microgels supporting 3D cell culture are fabricated by a flow-focusing microfluidic device. Uniform-sized aqueous droplets of gel precursor solution dispersed with cells generated by the microfluidic device are photocrosslinked to fabricate cell-laden microgels. Their mechanical properties are controlled by the concentration of gel-forming polymer. Using breast adenocarcinoma cells, MCF-7, the effect of mechanical properties of microgels on their proliferation and the eventual spheroid formation was explored. Furthermore, the tumor cells are co cultured with macrophages of fibroblasts, which are known to play a prominent role in tumor physiology, within the microgels to explore their role in spheroid formation. Taken together, the results from this study provide the design strategy for creating tumor spheroids utilizing mechanically-tunable microgels as 3D cell culture platform. PMID- 30428560 TI - Visibility Graph Feature Model of Vibration Signals: A Novel Bearing Fault Diagnosis Approach. AB - Reliable fault diagnosis of rolling bearings is an important issue for the normal operation of many rotating machines. Information about the structure dynamics is always hidden in the vibration response of the bearings, and it is often very difficult to extract them correctly due to the nonlinear/chaotic nature of the vibration signal. This paper proposes a new feature extraction model of vibration signals for bearing fault diagnosis by employing a recently-developed concept in graph theory, the visibility graph (VG). The VG approach is used to convert the vibration signals into a binary matrix. We extract 15 VG features from the binary matrix by using the network analysis and image processing methods. The three global VG features are proposed based on the complex network theory to describe the global characteristics of the binary matrix. The 12 local VG features are proposed based on the texture analysis method of images, Gaussian Markov random fields, to describe the local characteristics of the binary matrix. The feature selection algorithm is applied to select the VG feature subsets with the best performance. Experimental results are shown for the Case Western Reserve University Bearing Data. The efficiency of the visibility graph feature model is verified by the higher diagnosis accuracy compared to the statistical and wavelet package feature model. The VG features can be used to recognize the fault of rolling bearings under variable working conditions. PMID- 30428561 TI - ISG15, a Small Molecule with Huge Implications: Regulation of Mitochondrial Homeostasis. AB - Viruses are responsible for the majority of infectious diseases, from the common cold to HIV/AIDS or hemorrhagic fevers, the latter with devastating effects on the human population. Accordingly, the development of efficient antiviral therapies is a major goal and a challenge for the scientific community, as we are still far from understanding the molecular mechanisms that operate after virus infection. Interferon-stimulated gene 15 (ISG15) plays an important antiviral role during viral infection. ISG15 catalyzes a ubiquitin-like post-translational modification termed ISGylation, involving the conjugation of ISG15 molecules to de novo synthesized viral or cellular proteins, which regulates their stability and function. Numerous biomedically relevant viruses are targets of ISG15, as well as proteins involved in antiviral immunity. Beyond their role as cellular powerhouses, mitochondria are multifunctional organelles that act as signaling hubs in antiviral responses. In this review, we give an overview of the biological consequences of ISGylation for virus infection and host defense. We also compare several published proteomic studies to identify and classify potential mitochondrial ISGylation targets. Finally, based on our recent observations, we discuss the essential functions of mitochondria in the antiviral response and examine the role of ISG15 in the regulation of mitochondrial processes, specifically OXPHOS and mitophagy. PMID- 30428562 TI - Developmental Stage and Shape of Embryo Determine the Efficacy of Embryo Rescue in Introgressing Orange/Yellow Color and Anthocyanin Genes of Brassica Species. AB - Vegetables in Brassica are some of the world's most commonly cultivated plants and have a wide range of consumable plant organs. Improvement of this group of vegetables is limited at the species level due to limited genetic variability. Interspecies hybridization could be a powerful alternate tool for broadening the genetic variability of target traits. Embryo rescue technique is necessarily practiced in interspecies hybridization for protecting embryos from premature abortion. However, its success depends on the age of ovaries, shape of embryos, and the effect of female genotype. In this study, we carried out a wide range of interspecies crossing for introgressing target traits (orange/yellow color in cabbage and anthocyanin in Chinese cabbage) and optimizing the appropriate age of ovaries, the shape of embryo, and the suitable genotypes of such crosses. We observed that 15 DAP (days after pollination) was the best for embryo rescue in the diploid-diploid (Brassica rapa * B. oleracea) crosses, while 20 DAP was optimum for amphidiploid-diploid (B. napus/B. juncea * B. rapa) crosses. Cotyledonary shape of embryos and genotypes of amphidiploid species were the best for successful plant regeneration in interspecies crosses. We successfully selected plants with desired orange/yellow inner leaves for cabbage and higher anthocyanin in Chinese cabbage. The results of this study have the potential to be applied for the efficient production of interspecific hybrids and to develop Brassica vegetables with new traits, which could have potential for the enrichment of the human diet. PMID- 30428563 TI - Novel Findings of Anti-Filarial Drug Target and Structure-Based Virtual Screening for Drug Discovery. AB - Lymphatic filariasis and onchocerciasis caused by filarial nematodes are important diseases leading to considerable morbidity throughout tropical countries. Diethylcarbamazine (DEC), albendazole (ALB), and ivermectin (IVM) used in massive drug administration are not highly effective in killing the long-lived adult worms, and there is demand for the development of novel macrofilaricidal drugs affecting new molecular targets. A Ca2+ binding protein, calumenin, was identified as a novel and nematode-specific drug target for filariasis, due to its involvement in fertility and cuticle development in nematodes. As sterilizing and killing effects of the adult worms are considered to be ideal profiles of new drugs, calumenin could be an eligible drug target. Indeed, the Caenorhabditis elegans mutant model of calumenin exhibited enhanced drug acceptability to both microfilaricidal drugs (ALB and IVM) even at the adult stage, proving the roles of the nematode cuticle in efficient drug entry. Molecular modeling revealed that structural features of calumenin were only conserved among nematodes (C. elegans, Brugia malayi, and Onchocerca volvulus). Structural conservation and the specificity of nematode calumenins enabled the development of drugs with good target selectivity between parasites and human hosts. Structure-based virtual screening resulted in the discovery of itraconazole (ITC), an inhibitor of sterol biosynthesis, as a nematode calumenin-targeting ligand. The inhibitory potential of ITC was tested using a nematode mutant model of calumenin. PMID- 30428564 TI - Label-Free Quantitative Proteomics in a Methylmalonyl-CoA Mutase-Silenced Neuroblastoma Cell Line. AB - Methylmalonic acidemias (MMAs) are inborn errors of metabolism due to the deficient activity of methylmalonyl-CoA mutase (MUT). MUT catalyzes the formation of succinyl-CoA from methylmalonyl-CoA, produced from propionyl-CoA catabolism and derived from odd chain fatty acids beta-oxidation, cholesterol, and branched chain amino acids degradation. Increased methylmalonyl-CoA levels allow for the presymptomatic diagnosis of the disease, even though no approved therapies exist. MMA patients show hyperammonemia, ketoacidosis, lethargy, respiratory distress, cognitive impairment, and hepatomegaly. The long-term consequences concern neurologic damage and terminal kidney failure, with little chance of survival. The cellular pathways affected by MUT deficiency were investigated using a quantitative proteomics approach on a cellular model of MUT knockdown. Currently, a consistent reduction of the MUT protein expression was obtained in the neuroblastoma cell line (SH-SY5Y) by using small-interfering RNA (siRNA) directed against an MUT transcript (MUT siRNA). The MUT absence did not affect the cell viability and apoptotic process in SH-SY5Y. In the present study, we evaluate and quantify the alterations in the protein expression profile as a consequence of MUT-silencing by a mass spectrometry-based label-free quantitative analysis, using two different quantitative strategies. Both quantitative methods allowed us to observe that the expression of the proteins involved in mitochondrial oxido reductive homeostasis balance was affected by MUT deficiency. The alterated functional mitochondrial activity was observed in siRNA_MUT cells cultured with a propionate-supplemented medium. Finally, alterations in the levels of proteins involved in the metabolic pathways, like carbohydrate metabolism and lipid metabolism, were found. PMID- 30428565 TI - Promising Tensile and Fatigue Properties of Commercially Pure Titanium Processed by Rotary Swaging and Annealing Treatment. AB - The effect of the grain refinement and texture on tensile and fatigue properties in commercially pure titanium (grade 2) processed by rotary swaging (RS) and an annealing treatment is investigated. The as-processed sample consists of band like grains on the longitudinal section and equiaxed grains on the transversal section and revealed an obvious <10-10> fiber texture with respect to the rod axis. Through this technique, a sample with a high tensile strength of 870 MPa, a high uniform elongation of 8.5%, and a high fatigue limit of 490 MPa can be achieved, and the tensile and fatigue properties are almost the same as those of a conventional Ti-6Al-4V alloy. The enhanced mechanical properties and plastic deformation mechanism are discussed in terms of the observed ultrafine-grained microstructure and strong fiber texture. PMID- 30428566 TI - Role of SCFAs for Fimbrillin-Dependent Biofilm Formation of Actinomyces oris. AB - Actinomyces oris expresses type 1 and 2 fimbriae on the cell surface. Type 2 fimbriae mediate co-aggregation and biofilm formation and are composed of the shaft fimbrillin FimA and the tip fimbrillin FimB. Short-chain fatty acids (SCFAs) are metabolic products of oral bacteria, but the effects of exogenous SCFAs on FimA-dependent biofilm formation are poorly understood. We performed two types of biofilm formation assays using A. oris MG1 or MG1.DeltafimA to observe the effects of SCFAs on FimA-dependent biofilm formation in 96-well and six-well microtiter plates and a flow cell system. SCFAs did not induce six- and 16-hour biofilm formation of A. oris MG1 and MG1.DeltafimA in saliva-coated 96-well and six-well microtiter plates in which metabolites produced during growth were not excluded. However, 6.25 mM butyric acid and 3.125 mM propionic acid induced FimA dependent biofilm formation and cell death in a flow cell system in which metabolites produced during growth were excluded. Metabolites produced during growth may lead to disturbing effects of SCFAs on the biofilm formation. The pure effects of SCFAs on biofilm formation were induction of FimA-dependent biofilm formation, but the stress responses from dead cells may regulate its effects. Therefore, SCFA may play a key role in A. oris biofilm formation. PMID- 30428567 TI - Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders. AB - The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer's disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels. PMID- 30428568 TI - Identification of Three Type II Toxin-Antitoxin Systems in Streptococcus suis Serotype 2. AB - Type II toxin-antitoxin (TA) systems are highly prevalent in bacterial genomes and have been extensively studied. These modules involve in the formation of persistence cells, the biofilm formation, and stress resistance, which might play key roles in pathogen virulence. SezAT and yefM-yoeB TA modules in Streptococcus suis serotype 2 (S. suis 2) have been studied, although the other TA systems have not been identified. In this study, we investigated nine putative type II TA systems in the genome of S. suis 2 strain SC84 by bioinformatics analysis and identified three of them (two relBE loci and one parDE locus) that function as typical type II TA systems. Interestingly, we found that the introduction of the two RelBE TA systems into Escherichia coli or the induction of the ParE toxin led to cell filamentation. Promoter activity assays indicated that RelB1, RelB2, ParD, and ParDE negatively autoregulated the transcriptions of their respective TA operons, while RelBE2 positively autoregulated its TA operon transcription. Collectively, we identified three TA systems in S. suis 2, and our findings have laid an important foundation for further functional studies on these TA systems. PMID- 30428569 TI - Evaluation and Prediction of the Ecological Footprint and Ecological Carrying Capacity for Yangtze River Urban Agglomeration Based on the Grey Model. AB - The conflict between economic development and environmental protection has become increasingly prominent in the urbanization process of the Yangtze River urban agglomeration, the most economically developed region in Jiangsu Province in China. In order to investigate the sustainable development status, and thus provide decision support for the sustainable development of this region, the ecological footprint model was utilized to evaluate and analyze the ecological footprint per capita, the ecological carrying capacity per capita, and the ecological deficit per capita for the period from 2013 to 2017. Furthermore, the Grey model is employed to predict the development trend of the ecological footprint for 2018 to 2022. The evaluation results show that the ecological footprint per capita has been increasing year by year since 2013, reaching a peak of 2.3897 hm2 in 2015 before declining again. In the same period, the available ecological carrying capacity per capita and the ecological footprint per capita basically developed in the same direction, resulting in an ecological deficit per capita and gradually increasing from 2013 to a peak of 2.0303 hm2 in 2015 before declining. It is also found that the change of ecological carrying capacity is not substantial, and the change of the ecological deficit is mainly caused by a huge change of the ecological footprint. The forecast results show that the ecological deficit per capita will reach 1.1713 hm2 in 2018, which will be another deficit peak after 2015. However, in the later period until 2022, the ecological deficit per capita will begin to decline year by year. These results can provide effective inspirations for reducing the ecological deficit of the Yangtze River urban agglomeration, thus promoting the coordinated development of the economy and environment in this area. PMID- 30428570 TI - An Ab Initio Study of Connections between Tensorial Elastic Properties and Chemical Bonds in Sigma5(210) Grain Boundaries in Ni3Si. AB - Using quantum-mechanical methods we calculate and analyze (tensorial) anisotropic elastic properties of the ground-state configurations of interface states associated with Sigma 5(210) grain boundaries (GBs) in cubic L1 2 -structure Ni 3 Si. We assess the mechanical stability of interface states with two different chemical compositions at the studied GB by checking rigorous elasticity-based Born stability criteria. In particular, we show that a GB variant containing both Ni and Si atoms at the interface is unstable with respect to shear deformation (one of the elastic constants, C 55 , is negative). This instability is found for a rectangular-parallelepiped supercell obtained when applying standard coincidence-lattice construction. Our elastic-constant analysis allowed us to identify a shear-deformation mode reducing the energy and, eventually, to obtain mechanically stable ground-state characterized by a shear-deformed parallelepiped supercell. Alternatively, we tested a stabilization of this GB interface state by Al substituents replacing Si atoms at the GB. We further discuss an atomistic origin of this instability in terms of the crystal orbital Hamilton population (COHP) and phonon dispersion calculations. We find that the unstable GB variant shows a very strong interaction between the Si atoms in the GB plane and Ni atoms in the 3rd plane off the GB interface. However, such bond reinforcement results in weakening of interaction between the Ni atoms in the 3rd plane and the Si atoms in the 5th plane making this GB variant mechanically unstable. PMID- 30428572 TI - Sleep Duration and Sleep Quality Associated with Dietary Index in Free-Living Very Old Adults. AB - The main purpose of the present study was to determine the associations between sleep duration and sleep quality with respect to dietary habits. In this cross sectional study, 810 free-living older adults aged >=85 years were recruited from six neighborhoods from the city of Zagreb. Diet, sleep duration and sleep quality were assessed using self-reported questionnaires. The associations between sleep duration and sleep quality with respect to dietary habits were examined using generalized estimating equations with Poisson regression analyses. After adjusting for body-mass index, self-rated health, psychological distress, physical activity, socioeconomic status, chronic disease/s, sex and age, we revealed that 'short' (<7 h; Rate Ratio (RR) = 0.43; 95% CI(confident interval) 0.30 to 0.64) and 'long' (>8 h; RR = 0.26; 95% CI 0.11 to 0.48) sleep durations and 'good' sleep quality (RR = 1.13; 95% CI 1.06 to 1.20) were associated with a 'moderate-to-high' healthy diet. When sleep duration and sleep quality were entered simultaneously into Model 3, 'short' (RR = 0.28; 95% CI 0.16 to 0.44 and 'long' (RR = 0.27; 95% CI 0.15 to 0.52) sleep duration and 'good' sleep quality (RR = 1.14; 95% CI 1.05 to 1.25) remained associated with a 'moderate-to-high' healthy diet. Our study shows that both 'short' and 'long' sleep duration and 'good' sleep quality are associated with 'moderate-to-high' healthy diets. PMID- 30428573 TI - Association between Sports Participation in Early Life and Arterial Intima-Media Thickness among Adults. AB - Background: Early sports practice is associated with several health benefits during childhood and adolescence, moreover, recent evidence also suggests that sports during childhood and adolescence can produce some benefits during adulthood. However, the association between early sports practice and arterial thickness is not clear. Thus, our aim was analyze the association between sports participation in childhood and adolescence, carotid/femoral intima-media thickness, and blood flow index in adulthood. Material and Methods: Sample was composed of 107 adults (64 males) between 30 years and 50 years, which were recruited from different gyms and university staff from Sao Paulo State University. Participants were divided according to sports participation in early life (engaged in sports during childhood and adolescence (n = 52) and no engagement in sports during childhood and adolescence (n = 55)). Carotid and femoral intima-media thickness were measured through Doppler ultrasonography method. Carotid and femoral index were estimated from ultrasonography measures. As covariates, the following were adopted: chronological age, sex, body fat (through dual-energy x-ray absorptiometry), c-reactive protein, HOMA, alcohol consumption, tobacco smoking, mean arterial pressure and current physical activity (pedometer). General estimating equations were used, adopting p < 0.05. Results: In the adjusted analyses, early sports participation was associated with lower carotid intima-media index (early sports participation: 0.64 mm +/- 0.14 mm vs. no early sports participation: 0.71 mm +/- 0.21 mm; p = 0.011), but not associated with femoral intima-media thickness, carotid resistive index and femoral resistive index after the adjustment by potential confounders. Conclusions: Sports participation in childhood and adolescence was associated with a reduced carotid intima-media thickness, independently of relevant confounders. PMID- 30428574 TI - The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma. AB - Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10-20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies. PMID- 30428571 TI - Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia. AB - In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk adapted post-remission chemotherapy protocols to improve their response to treatment. PMID- 30428576 TI - Delivery of Doxorubicin for Human Cervical Carcinoma Targeting Therapy by Folic Acid-Modified Selenium Nanoparticles. AB - Cancer-specific drug delivery represents an attractive approach to preventing undesirable side effects and increasing the accumulation of the drug in tumors. The surface modification of selenium nanoparticles (SeNPs) with targeting moieties thus represents an effective strategy for cancer therapy. In this study, SeNPs were modified with folic acid (FA), whose receptors were overexpressed on the surface of cancer cells, including human cervical carcinoma HeLa cells, to fabricate tumor-targeting delivery carrier FA-SeNPs nanoparticles. Then, the anticancer drug doxorubicin (DOX) was loaded onto the surface of the FA-SeNPs for improving the antitumor efficacy of DOX in human cervical carcinoma therapy. The chemical structure characterization of FA-Se@DOX showed that DOX was successfully loaded to the surface of FA-SeNPs to prepare FA-Se@DOX nanoparticles. FA-Se@DOX exhibited significant cellular uptake in human cervical carcinoma HeLa cells (folate receptor overexpressing cells) in comparison with lung cancer A549 cells (folate receptor deficiency cells), and entered HeLa cells mainly by the clathrin mediated endocytosis pathway. Compared to free DOX or Se@DOX at the equivalent dose of DOX, FA-Se@DOX showed obvious activity to inhibit HeLa cells' proliferation and induce the apoptosis of HeLa cells. More importantly, FA-Se@DOX could specifically accumulate in the tumor site, which contributed to the significant antitumor efficacy of FA-Se@DOX in vivo. Taken together, FA-Se@DOX may be one novel promising drug candidate for human cervical carcinoma therapy. PMID- 30428575 TI - Exposure to Household Air Pollution from Biomass Cookstoves and Levels of Fractional Exhaled Nitric Oxide (FeNO) among Honduran Women. AB - Household air pollution is estimated to be responsible for nearly three million premature deaths annually. Measuring fractional exhaled nitric oxide (FeNO) may improve the limited understanding of the association of household air pollution and airway inflammation. We evaluated the cross-sectional association of FeNO with exposure to household air pollution (24-h average kitchen and personal fine particulate matter and black carbon; stove type) among 139 women in rural Honduras using traditional stoves or cleaner-burning Justa stoves. We additionally evaluated interaction by age. Results were generally consistent with a null association; we did not observe a consistent pattern for interaction by age. Evidence from ambient and household air pollution regarding FeNO is inconsistent, and may be attributable to differing study populations, exposures, and FeNO measurement procedures (e.g., the flow rate used to measure FeNO). PMID- 30428577 TI - Composite Film Based on Pulping Industry Waste and Chitosan for Food Packaging. AB - Wood auto-hydrolysates (WAH) are obtained in the pulping process by the hydrothermal extraction, which contains lots of hemicelluloses and slight lignin. WAH and chitosan (CS) were introduced into this study to construct WAH-based films by the casting method. The FT-IR results revealed the crosslinking interaction between WAH and CS due to the Millard reaction. The morphology, transmittance, thermal properties and mechanical properties of composite WAH/CS films were investigated. As the results showed, the tensile strength, light transmittances and thermal stability of the WAH-based composite films increased with the increment of WAH/CS content ratio. In addition, the results of oxygen transfer rate (OTR) and water vapor permeability (WVP) suggested that the OTR and WVP values of the films decreased due to the addition of CS. The maximum value of tensile strengths of the composite films achieved 71.2 MPa and the OTR of the films was low as 0.16 cm3.MUm.m-2.24 h-1.kPa-1, these properties are better than those of other hemicelluloses composite films. These results suggested that the barrier composite films based on WAH and CS will become attractive in the food packaging application for great mechanical properties, good transmittance and low oxygen transfer rate. PMID- 30428578 TI - Halogen and Hydrogen Bonding Interplay in the Crystal Packing of Halometallocenes. AB - This paper focuses in the influence of halogen atoms in the design and structural control of the crystal packing of Group VIII halogenated metallocenes. The study is based on the present knowledge on new types of intermolecular contacts such as halogen (X?X, C-X?H, C-X?pi), pi?pi, and C-H?pi interactions. The presence of novel C-H?M interactions is also discussed. Crystal packings are analysed after database search on this family of compounds. Results are supported by ab initio calculations on electrostatic charge distributions; Hirshfeld analysis is also used to predict the types of contacts to be expected in the molecules. Special attention is given to the competition among hydrogen and halogen interactions, mainly its influence on the nature and geometric orientations of the different supramolecular motifs. Supramolecular arrangements of halogenated metallocenes and Group IV di-halogenated bent metallocenes are also compared and discussed. Analysis supports halogen bonds as the predominant interactions in defining the crystal packing of bromine and iodine 1,1'-halometallocenes. PMID- 30428580 TI - A FAST-BRISK Feature Detector with Depth Information. AB - RGB-D cameras offer both color and depth images of the surrounding environment, making them an attractive option for robotic and vision applications. This work introduces the BRISK_D algorithm, which efficiently combines Features from Accelerated Segment Test (FAST) and Binary Robust Invariant Scalable Keypoints (BRISK) methods. In the BRISK_D algorithm, the keypoints are detected by the FAST algorithm and the location of the keypoint is refined in the scale and the space. The scale factor of the keypoint is directly computed with the depth information of the image. In the experiment, we have made a detailed comparative analysis of the three algorithms SURF, BRISK and BRISK_D from the aspects of scaling, rotation, perspective and blur. The BRISK_D algorithm combines depth information and has good algorithm performance. PMID- 30428579 TI - Self-Lubricanting Slippery Surface with Wettability Gradients for Anti-Sticking of Electrosurgical Scalpel. AB - Soft tissue sticking on electrosurgical scalpels in minimally invasive surgery can increase the difficulty of operation and easily lead to medical malpractice. It is significant to develop new methods for anti-sticking of soft tissue on electrosurgical scalpels. Based on the characteristics of biomimetic ultra slippery surface, a self-lubricating slippery surface with wettability gradients on electrosurgical scalpel was designed and fabricated. Non-uniformly distributed cylindrical micro pillars, which constitute the wettability gradients, were prepared by an electrolytic etching process and the theoretic of the spontaneous liquid spreading process was analyzed. The silicophilic property of wettability gradients surface was modified by octadecyltrichlorosilane (OTS) self-assembling coat with biocompatible liquid lubricant dimethyl silicone oil. The contact angle of gradient's surface at different temperatures was measured. The transportation behaviors of both water and dimethyl silicone oil on the wettability gradient's surface were investigated; the results illustrate that the wettability gradient's slippery surface can successfully self-lubricate from regions with low pillar density to regions with high pillar density, ascribed to the unbalanced Young's force. The anti-sticking capability of the electrosurgical scalpel with self lubricating slippery surface was tested. Both the adhesion force and adhesion mass under different cycles were calculated. The results suggest that the as prepared slippery surface has excellent anti-sticking ability associated with better durability. PMID- 30428581 TI - In Vitro Efficacy of Antibiotics Released from Calcium Sulfate Bone Void Filler Beads. AB - 15 different antibiotics were individually mixed with commercially available calcium sulfate bone void filler beads. The antibiotics were: amikacin, ceftriaxone, cefuroxime, ciprofloxacin, clindamycin, colistamethate sodium, daptomycin, gentamicin, imipenem/cilastatin, meropenem, nafcillin, rifampicin, teicoplanin, tobramycin and vancomycin. The efficacy of specific released antibiotics was validated by zone of inhibition (ZOI) testing using a modified Kirby-Bauer disk diffusion method against common periprosthetic joint infection pathogens. With a subset of experiments (daptomycin, rifampin, vancomycin alone and rifampin and vancomycin in combination), we investigated how release varied over 15 days using a repeated ZOI assay. We also tested the ability of these beads to kill biofilms formed by Staphylococcus epidermidis 35984, a prolific biofilm former. The results suggested that certain antibiotics could be combined and released from calcium sulfate with retained antibacterial efficacy. The daptomycin and rifampin plus vancomycin beads showed antimicrobial efficacy for the full 15 days of testing and vancomycin in combination with rifampin prevented resistant mutants. In the biofilm killing assay, all of the antibiotic combinations showed a significant reduction in biofilm bacteria after 24 h. The exposure time was an important factor in the amount of killing, and varied among the antibiotics. PMID- 30428582 TI - Large-Scale Simulation of the Phenotypical Variability Induced by Loss-of Function Long QT Mutations in Human Induced Pluripotent Stem Cell Cardiomyocytes. AB - Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models. However, their in vitro investigation mainly relies on experiments using small numbers of cells. This is especially critical when working with cells as heterogeneous as hiPSC CMs. We aim (i) to investigate in silico the ionic mechanisms underlying LQT1 and LQT2 hiPSC-CM phenotypic variability, and (ii) to enable massive in silico drug tests on mutant hiPSC-CMs. We combined (i) data of control and mutant slow and rapid delayed rectifying K+ currents, IKr and IKs respectively, (ii) a recent in silico hiPSC-CM model, and (iii) the population of models paradigm to generate control and mutant populations for LQT1 and LQT2 cardiomyocytes. Our four populations contain from 1008 to 3584 models. In line with the experimental in vitro data, mutant in silico hiPSC-CMs showed prolonged action potential (AP) duration (LQT1: +14%, LQT2: +39%) and large electrophysiological variability. Finally, the mutant populations were split into normal-like hiPSC-CMs (with action potential duration similar to control) and at risk hiPSC-CMs (with clearly prolonged action potential duration). At risk mutant hiPSC-CMs carried higher expression of L-type Ca2+, lower expression of IKr and increased sensitivity to quinidine as compared to mutant normal-like hiPSC-CMs, resulting in AP abnormalities. In conclusion, we were able to reproduce the two most common LQT syndromes with large-scale simulations, which enable investigating biophysical mechanisms difficult to assess in vitro, e.g., how variations of ion current expressions in a physiological range can impact on AP properties of mutant hiPSC CMs. PMID- 30428583 TI - Emerging and Dynamic Biomedical Uses of Ferritin. AB - Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases. PMID- 30428584 TI - The Yellow Knight Fights Back: Toxicological, Epidemiological, and Survey Studies Defend Edibility of Tricholoma equestre. AB - Rhabdomyolysis, a condition associated with the consumption of Yellow Knight mushrooms (Tricholoma equestre), was first reported in 2001. In response, some countries began to consider the mushroom as poisonous, whereas in others it is still consumed. In the present study, a nationwide survey of Polish mushroom foragers (n = 1545) was conducted to estimate the frequency of T. equestre consumption. The epidemiological database on mushroom poisonings in Poland was analyzed from the year 2008. Hematological and biochemical parameters were followed for a week in 10 volunteers consuming 300 g of molecularly identified T. equestre. More than half the foragers had consumed T. equestre at least once in their lifetime and a quarter had consumed it consecutively. The frequency of adverse events was low and no rhabdomyolysis was reported. The toxicological database indicated that mushrooms from the Tricholoma genus caused poisonings less frequently than mushrooms with well-established edibility and not a single case of rhabdomyolysis has been reported within the last decade. The volunteers consuming T. equestre revealed no hematological or biochemical alterations and no adverse effects were observed. The findings of this study support the view that T. equestre is edible if consumed in rational amounts by healthy subjects. PMID- 30428586 TI - Simultaneous Second-Harmonic, Sum-Frequency Generation and Stimulated Raman Scattering in MgO:PPLN. AB - In this study, simultaneous second-harmonic generation (SHG), sum frequency generation (SFG), and Raman conversion based on MgO-doped periodically poled lithium niobate (MgO:PPLN) for multi-wavelength generation is demonstrated. The approach used is based on a single MgO:PPLN crystal poled with a uniform period of 10.2 um that phase matches SHG and SFG, simultaneously. Using a simplified double-pass geometry, up to 0.8 W of blue light at 487 nm is achieved by a frequency-doubling 974 nm laser diode pump, and 0.5 W of orange light at 598 nm is generated by frequency mixing 974 nm pump with C-band (1527-1565 nm) tunable laser source. At high pump powers of the 974 nm laser source, other unexpected peaks at 437, 536, 756, 815 and 1038 nm were observed, of which the 1038 nm line is due to Stimulated Raman Scattering within the MgO:PPLN crystal. The resulting multi-wavelength light source may find a wide range of applications in biomedicine and basic research. PMID- 30428587 TI - Pilot-Scale Production of Carbon Hollow Fiber Membranes from Regenerated Cellulose Precursor-Part I: Optimal Conditions for Precursor Preparation. AB - Industrial scale production of carbon membrane is very challenging due to expensive precursor materials and a multi-step process with several variables to deal with. The optimization of these variables is essential to gain a competent carbon membrane (CM) with high performance and good mechanical properties. In this paper, a pilot scale system is reported that was developed to produce CM from regenerated cellulose precursor with the annual production capacity 700 m2 of CM. The process was optimized to achieve maximum yield (>95%) of high quality precursor fibers and carbonized fibers. A dope solution of cellulose acetate (CA)/Polyvinylpyrrolidone (PVP)/N-methyl-2-pyrrolidone (NMP) and bore fluid of NMP/H2O were used in 460 spinning-sessions of the fibers using a well-known dry/wet spinning process. Optimized deacetylation of spun-CA hollow fibers (CAHF) was achieved by using 90 vol% 0.075 M NaOH aqueous solution diluted with 10 vol% isopropanol for 2.5 h at ambient temperature. Cellulose hollow fibers (CHF) dried at room temperature and under RH (80% -> ambient) overnight gave maximum yield for both dried CHF, as well as carbon fibers. The gas permeation properties of carbon fibers were also high (CO2 permeability: 50-450 Barrer (1 Barrer = 2.736 * 10-9 m3 (STP) m/m2 bar h), and CO2/CH4 selectivity acceptable (50-500). PMID- 30428588 TI - From Friend to Enemy: Dissecting the Functional Alteration of Immunoregulatory Components during Pancreatic Tumorigenesis. AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival rate of approximately 8%. More than 80% of patients are diagnosed at an unresectable stage due to metastases or local extension. Immune system reactivation in patients by immunotherapy may eliminate tumor cells and is a new strategy for cancer treatment. The anti-CTLA-4 antibody ipilimumab and anti-PD-1 antibodies pembrolizumab and nivolumab have been approved for cancer therapy in different countries. However, the results of immunotherapy on PDAC are unsatisfactory. The low response rate may be due to poor immunogenicity with low tumor mutational burden in pancreatic cancer cells and desmoplasia that prevents the accumulation of immune cells in tumors. The immunosuppressive tumor microenvironment in PDAC is important in tumor progression and treatment resistance. Switching from an immune tolerance to immune activation status is crucial to overcome the inability of self-defense in cancer. Therefore, thoroughly elucidation of the roles of various immune-related factors, tumor microenvironment, and tumor cells in the development of PDAC may provide appropriate direction to target inflammatory pathway activation as a new therapeutic strategy for preventing and treating this cancer. PMID- 30428585 TI - High Fat Programming and Cardiovascular Disease. AB - Programming is triggered through events during critical developmental phases that alter offspring health outcomes. High fat programming is defined as the maintenance on a high fat diet during fetal and/or early postnatal life that induces metabolic and physiological alterations that compromise health. The maternal nutritional status, including the dietary fatty acid composition, during gestation and/or lactation, are key determinants of fetal and postnatal development. A maternal high fat diet and obesity during gestation compromises the maternal metabolic state and, through high fat programming, presents an unfavorable intrauterine milieu for fetal growth and development thereby conferring adverse cardiac outcomes to offspring. Stressors on the heart, such as a maternal high fat diet and obesity, alter the expression of cardiac-specific factors that alter cardiac structure and function. The proper nutritional balance, including the fatty acid balance, particularly during developmental windows, are critical for maintaining cardiac structure, preserving cardiac function and enhancing the cardiac response to metabolic challenges. PMID- 30428589 TI - Membrane-Permeable Octanoyloxybenzyl-Masked cNMPs As Novel Tools for Non-Invasive Cell Assays. AB - Adenine nucleotide (AN) 2nd messengers, such as 3',5'-cyclic adenosine monophosphate (cAMP), are central elements of intracellular signaling, but many details of their underlying processes remain elusive. Like all nucleotides, cyclic nucleotide monophosphates (cNMPs) are net-negatively charged at physiologic pH which limits their applicability in cell-based settings. Thus, many cellular assays rely on sophisticated techniques like microinjection or electroporation. This setup is not feasible for medium- to high-throughput formats, and the mechanic stress that cells are exposed to raises the probability of interfering artefacts or false-positives. Here, we present a short and flexible chemical route yielding membrane-permeable, bio-reversibly masked cNMPs for which we employed the octanoyloxybenzyl (OB) group. We further show hydrolysis studies on chemical stability and enzymatic activation, and present results of real-time assays, where we used cAMP and Ca2+ live cell imaging to demonstrate high permeability and prompt intracellular conversion of some selected masked cNMPs. Based on these results, our novel OB-masked cNMPs constitute valuable precursor-tools for non-invasive studies on intracellular signaling. PMID- 30428590 TI - Development of Immunochromatographic Assay for Determination of Tetracycline in Human Serum. AB - Determining antibiotic concentration in human blood provides useful pharmacokinetic information. Commonly used methods such as ELISA require a long time to obtain results and thus cannot be applied when information is needed immediately. In this study, a novel antibody-based lateral flow technique was developed for tetracycline detection in human serum. Contrary to tests developed to analyze food samples, the features of work with serum as analyzed probe were studied for the first time here. The application of labeled and unlabeled specific antibodies was compared. For this purpose, specific and anti-species antibodies were labeled with gold nanoparticles and used for antigen-antibody interaction on the membrane surface with observed staining in the test zone. For both schemes, optimal conditions were established to provide the best sensitivity. The developed assay has a limit of visual detection as low as 35 and 11 ng/mL for the direct and indirect labeled antibodies, respectively. The limit of instrumental detection is from 0.4 to 3.5 ng/mL for diluted and undiluted sera. The use of indirect antibody labeling showed a small increase in sensitivity compared to traditional direct antibody labeling. The developed method showed no cross-reactivity with antibiotics of other classes. The method was used to test samples of serum. The results showed high correlation with the data obtained by ELISA (R2 = 0.98968). The assay provides a quick assessment of the amount of antibiotics in the blood and keeps them under control throughout the duration of therapy. PMID- 30428591 TI - From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino Fused Carbazoles and Carbolines. AB - 2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4 b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3 b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2',3':5,6] pyrido[4,3-b]indole and pyrazino[2',3':4,5]pyrido[2,3 d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition). PMID- 30428593 TI - Particle Filter Based Monitoring and Prediction of Spatiotemporal Corrosion Using Successive Measurements of Structural Responses. AB - Prediction of structural deterioration is a challenging task due to various uncertainties and temporal changes in the environmental conditions, measurement noises as well as errors of mathematical models used for predicting the deterioration progress. Monitoring of deterioration progress is also challenging even with successive measurements, especially when only indirect measurements such as structural responses are available. Recent developments of Bayesian filters and Bayesian inversion methods make it possible to address these challenges through probabilistic assimilation of successive measurement data and deterioration progress models. To this end, this paper proposes a new framework to monitor and predict the spatiotemporal progress of structural deterioration using successive, indirect and noisy measurements. The framework adopts particle filter for the purpose of real-time monitoring and prediction of corrosion states and probabilistic inference of uncertain and/or time-varying parameters in the corrosion progress model. In order to infer deterioration states from sparse indirect inspection data, for example structural responses at sensor locations, a Bayesian inversion method is integrated with the particle filter. The dimension of a continuous domain is reduced by the use of basis functions of truncated Karhunen-Loeve expansion. The proposed framework is demonstrated and successfully tested by numerical experiments of reinforcement bar and steel plates subject to corrosion. PMID- 30428592 TI - Dietary Flavonoid Intakes Are Associated with Race but Not Income in an Urban Population. AB - Flavonoids are polyphenolic phytochemicals with health-promoting properties, yet knowledge about their intake in at-risk populations is limited. This study sought to estimate intakes of total flavonoids and six flavonoid classes in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study; determine if differences in intakes exist by race (African American (AA) and White (W)) and income (< or >125% Federal poverty guidelines); and compare intakes to those of a nationally representative population with similar demographic and socioeconomic characteristics. Data transformation normalized the flavonoid intake distributions prior to conducting statistical tests. With the exception of the flavanone class, flavonoid intakes of AAs were significantly lower than those of W (p < 0.01), regardless of other potential mediating factors including sex, age, and income. Total flavonoid intakes in HANDLS did not differ from intakes in the nationally representative study, but anthocyanidin and flavone intakes were lower, and race specific differences were found for several flavonoid classes. These findings imply that benefits attributable to flavonoid consumption may not be experienced equally by AAs and Whites, nor in vulnerable populations such as that represented by HANDLS relative to the U.S. population, and may play a role in observed health disparities. PMID- 30428595 TI - Reactivity and Penetration Performance Ni-Al and Cu-Ni-Al Mixtures as Shaped Charge Liner Materials. AB - Energetic structural materials (ESMs) have many potential military applications due to their unique functions. In this work, the reactivity and penetration performance of ESMs have been examined as a shaped charge liner material. The penetration experiments of nickel-aluminum (Ni-Al) and copper-nickel-aluminum (Cu Ni-Al)-shaped charge liners (SCLs) have been designed and fired into 45# steel. The targets were recovered and analyzed by optical microscopy, electron microscopy, energy dispersive spectroscopy, and Vickers microhardness measurements. The head and tail of the crater walls penetrated by two reactive jets demonstrated unique microstructures. The jet rapidly decayed with the penetration process, but the "white" zone (a mixture of martensite and austenite) was more prominent in the tail, and the microhardness of the tail was much higher than that of the head. The results showed the continued exotherm of Ni-Al reactive jet when it was fired into the target. The addition of Cu reduced the exotherm of Ni-Al, Cu could not only increase the average crater size, but also raise the average penetration depth by 42%. These results offer valuable insight for utilizing ESM as shaped charge liner materials. PMID- 30428594 TI - CCND1 Splice Variant as A Novel Diagnostic and Predictive Biomarker for Thyroid Cancer. AB - Cyclin D1 protein is aberrantly overexpressed in thyroid cancers, but mutations of the CCND1 gene are rare in these tumors. We investigated the CCND1 rs9344 (G870A) polymorphism and the expression profiles of wild-type CCND1a and shortened oncogenic isoform CCND1b at the mRNA and protein levels in 286 thyroid tumors. Genotype AA of rs9344 was associated with high expression of CCND1b mRNA and was more frequently found in thyroid cancer than in benign tumors. The mRNA expression levels of CCND1b were higher in papillary thyroid carcinoma (PTC) than in benign or other malignant tumors. However, the expression of CCND1a mRNA showed no association with the parameters. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was distinguished from PTC by low expression of CCND1b at mRNA and protein levels. We further observed that cyclin D1b immunostaining helped to avoid the misdiagnosis of classic PTC with predominant follicular pattern as NIFTP in a separate cohort. Nuclear cyclin D1b expression was associated with aggressive clinicopathologic features in PTC. These findings suggest that cyclin D1b overexpression can be used as a diagnostic and predictive biomarker in thyroid tumors and may be functionally involved in the development and progression of the disease. PMID- 30428596 TI - Potential Causes of Titanium Particle and Ion Release in Implant Dentistry: A Systematic Review. AB - Implant surface characteristics, as well as physical and mechanical properties, are responsible for the positive interaction between the dental implant, the bone and the surrounding soft tissues. Unfortunately, the dental implant surface does not remain unaltered and changes over time during the life of the implant. If changes occur at the implant surface, mucositis and peri-implantitis processes could be initiated; implant osseointegration might be disrupted and bone resorption phenomena (osteolysis) may lead to implant loss. This systematic review compiled the information related to the potential sources of titanium particle and ions in implant dentistry. Research questions were structured in the Population, Intervention, Comparison, Outcome (PICO) framework. PICO questionnaires were developed and an exhaustive search was performed for all the relevant studies published between 1980 and 2018 involving titanium particles and ions related to implant dentistry procedures. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the selection and inclusion of the manuscripts in this review. Titanium particle and ions are released during the implant bed preparation, during the implant insertion and during the implant decontamination. In addition, the implant surfaces and restorations are exposed to the saliva, bacteria and chemicals that can potentially dissolve the titanium oxide layer and, therefore, corrosion cycles can be initiated. Mechanical factors, the micro-gap and fluorides can also influence the proportion of metal particles and ions released from implants and restorations. PMID- 30428597 TI - Health-Related Lifestyle Behavior and Religiosity among First-Generation Immigrants of Polish Origin in Germany. AB - Background: Health-related lifestyle behaviors such as smoking, alcohol consumption, physical inactivity and obesity are major cardiovascular risk factors. Previous studies have mostly demonstrated a favorable association between religiosity and these cardiovascular risk factors; however, no studies have investigated this relationship in Polish immigrants. The aim of this cross sectional study was to examine the association between health-related lifestyle behaviors and religiosity in Polish immigrants in Germany. Methods: The smoking patterns, frequency of alcohol consumption, physical activity, and presence of overweight/obesity were assessed in 257 first-generation immigrants of Polish origin living in Germany. Religiosity was measured with the Centrality of Religiosity Scale (CRS, Huber, 2003) consisting of 15 items that categorized the respondents into intrinsically, extrinsically, and not/marginally religious. Results: After adjusting for various sociodemographic, migration, and health related characteristics, intrinsic religiosity was significantly associated with a lower risk of being a smoker (odds ratios (OR) = 0.34, confidence intervals (CI) = 0.15-0.76) and was also associated with a lower risk of alcohol consumption (OR = 0.33, CI = 0.15-0.71), but a higher risk of being overweight/obese (OR = 2.53, CI = 1.15-5.56) in comparison with extrinsic/marginal religiosity. No significant relationship was found between religiosity and physical activity. Conclusions: In Polish immigrants, intrinsic religiosity acts as a protective factor against some cardiovascular risk factors (smoking and alcohol consumption). PMID- 30428598 TI - Cell Density Detector Based on Light Beam Focusing. AB - Although the lab-on-a-chip system has been successfully applied in a wide variety of fields, the goal of achieving a cell counter with simple operation, low cost, and high accuracy still attracts continuous research efforts. In this paper, the authors explore a cell counter based on light beam focusing to measure the density of adherent cells. In this sensor, the light emitted from the optical fibers is collimated by the collimating lens formed in polydimethylsiloxane (PDMS). The uniformly attached adherent cells act as a convex lens, focusing the collimated light propagated through them. The intensity of the focused light indicates the density of the adherent cells. For Hela cells, a detection limit of 8.3 * 104 cells/mL with a detection range from 0.1 * 106 cells/mL to 1.0 * 106 cells/mL is achieved. This sensor is particularly useful for drug screening, cell pathology analysis, and cancer pre-diagnosis. PMID- 30428599 TI - Study of Antiphospholipid Antibodies in Patients with Arterial Hypertension. AB - Antiphospholipid syndrome (APS) is a multifactorial, autoantibody-mediated disease. Antiphospholipid antibodies (aPL) directed against negatively charged phospholipids or various combinations of phospholipid-binding proteins seem to be an independent pathogenic factor that plays a critical role in APS. Unfortunately, their role in hypertension is not fully elucidated. The aim of our study was to determine aPL titers in hypertension patients and investigate the association of aPL with renal impairment parameters. Forty-seven patients with arterial hypertension (22 males, 46.8% and 25 females, 53.2%), aged 41-85 years old (mean 65.9 +/- 10.1 years), and 21 age-sex-matched subjects without severe hypertension as control group (8 males, 13 females, 38.1% vs. 61.9%), mean age 61 +/- 11.3 years, were enrolled in this study. Patients with other risk factors like Rheumatoid Arthritis and Systematic Lupus Erythematosus (SLE), both viral and bacterial acute infections, and cancer were excluded from the study. The aPL (anticardiolipin (ACA) and anti-b2GPI antibodies, IgG and IgM) were measured by ELISA (Aesculisa, Aesku Diagnostics, Wendelsheim, Germany) with a cutoff of 15 GPL/MPL for ACA and 15 U/mL for b2GPI. Serum Neutrophil gelatinase-associated lipocalin (sNGAL) was measured by ELISA kits (BioVendor, Brno, Czech Republic). Biochemical analysis such as serum creatinine (Cr), were measured by automated analyzer and finally estimated glomerular filtration rate (e-GFR) was calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Fifteen patients were positive for ACA IgG (31.9%), two for anti-b2GPI IgM (4.2%), and three for anti-b2GPI IgG (6.3%). Furthermore, three persons from control group were positive in anti-b2GPI IgG (14.27%). The serum level of anti-b2GPI IgG was significantly higher in patients compared to healthy controls (p = 0.013). The level of sNGAL (59.63 +/- 41.5 ng/mL vs. 45.5 +/- 21.5 ng/mL, p = 0.14) was not higher in hypertensive patients than in the age-sex-matched control group. Additionally, the sNGAL level was found to be directly and positively correlated in patients with positive ACA IgG (r2 = 0,945, p < 0.0001). These results demonstrate that autoimmunity may be one of the pathogenetic factors of hypertension and aPL antibodies might be a potential marker of renal involvement. PMID- 30428600 TI - Iss2Image: A Novel Signal-Encoding Technique for CNN-Based Human Activity Recognition. AB - The most significant barrier to success in human activity recognition is extracting and selecting the right features. In traditional methods, the features are chosen by humans, which requires the user to have expert knowledge or to do a large amount of empirical study. Newly developed deep learning technology can automatically extract and select features. Among the various deep learning methods, convolutional neural networks (CNNs) have the advantages of local dependency and scale invariance and are suitable for temporal data such as accelerometer (ACC) signals. In this paper, we propose an efficient human activity recognition method, namely Iss2Image (Inertial sensor signal to Image), a novel encoding technique for transforming an inertial sensor signal into an image with minimum distortion and a CNN model for image-based activity classification. Iss2Image converts real number values from the X, Y, and Z axes into three color channels to precisely infer correlations among successive sensor signal values in three different dimensions. We experimentally evaluated our method using several well-known datasets and our own dataset collected from a smartphone and smartwatch. The proposed method shows higher accuracy than other state-of-the-art approaches on the tested datasets. PMID- 30428601 TI - Next Generation Sequencing-Based Molecular Marker Development: A Case Study in Betula Alnoides. AB - Betula alnoides is a fast-growing valuable indigenous tree species with multiple uses in the tropical and warm subtropical regions in South-East Asia and southern China. It has been proved to be tetraploid in most parts of its distribution in China. In the present study, next generation sequencing (NGS) technology was applied to develop numerous SSR markers for B. alnoides, and 64,376 contig sequences of 106,452 clean reads containing 164,357 candidate SSR loci were obtained. Among the derived SSR repeats, mono-nucleotide was the main type (77.05%), followed by di- (10.18%), tetra- (6.12%), tri- (3.56%), penta- (2.14%) and hexa-nucleotide (0.95%). The short nucleotide sequence repeats accounted for 90.79%. Among the 291 repeat motifs, AG/CT (46.33%) and AT/AT (44.15%) were the most common di-nucleotide repeats, while AAT/ATT (48.98%) was the most common tri nucleotide repeats. A total of 2549 primer sets were designed from the identified putative SSR regions of which 900 were randomly selected for evaluation of amplification successfulness and detection of polymorphism if amplified successfully. Three hundred and ten polymorphic markers were obtained through testing with 24 individuals from B. alnoides natural forest in Jingxi County, Guangxi, China. The number of alleles (NA) of each marker ranged from 2 to 19 with a mean of 5.14. The observed (HO) and expected (HE) heterozygosities varied from 0.04 to 1.00 and 0.04 to 0.92 with their means being 0.64 and 0.57, respectively. Shannon-Wiener diversity index (I) ranged from 0.10 to 2.68 with a mean of 1.12. Cross-species transferability was further examined for 96 pairs of SSR primers randomly selected, and it was found that 48.96-84.38% of the primer pairs could successfully amplify each of six related Betula species. The obtained SSR markers can be used to study population genetics and molecular marker assisted breeding, particularly genome-wide association study of these species in the future. PMID- 30428602 TI - Transcatheter Decellularized Tissue-Engineered Heart Valve (dTEHV) Grown on Polyglycolic Acid (PGA) Scaffold Coated with P4HB Shows Improved Functionality over 52 Weeks due to Polyether-Ether-Ketone (PEEK) Insert. AB - Many congenital heart defects and degenerative valve diseases require replacement of heart valves in children and young adults. Transcatheter xenografts degenerate over time. Tissue engineering might help to overcome this limitation by providing valves with ability for self-repair. A transcatheter decellularized tissue engineered heart valve (dTEHV) was developed using a polyglycolic acid (PGA) scaffold. A first prototype showed progressive regurgitation after 6 months in vivo due to a suboptimal design and misguided remodeling process. A new geometry was developed accordingly with computational fluid dynamics (CFD) simulations and implemented by adding a polyether-ether-ketone (PEEK) insert to the bioreactor during cultivation. This lead to more belly-shaped leaflets with higher coaptation areas for this second generation dTEHV. Valve functionality assessed via angiography, intracardiac echocardiography, and MRI proved to be much better when compared the first generation dTEHV, with preserved functionality up to 52 weeks after implantation. Macroscopic findings showed no thrombi or signs of acute inflammation. For the second generation dTEHV, belly-shaped leaflets with soft and agile tissue-formation were seen after explantation. No excessive leaflet shortening occurred in the second generation dTEHV. Histological analysis showed complete engraftment of the dTEHV, with endothelialization of the leaflets and the graft wall. Leaflets consisted of collagenous tissue and some elastic fibers. Adaptive leaflet remodeling was visible in all implanted second generation dTEHV, and most importantly no fusion between leaflet and wall was found. Very few remnants of the PGA scaffold were detected even 52 weeks after implantation, with no influence on functionality. By adding a polyether-ether ketone (PEEK) insert to the bioreactor construct, a new geometry of PGA-scaffold based dTEHV could be implemented. This resulted in very good valve function of the implanted dTEHV over a period of 52 weeks. PMID- 30428603 TI - Influence of Hydroxyl Functional Group on the Structure and Stability of Xanthone: A Computational Approach. AB - The present work addresses computational research focused on the energetic and structural properties of four isomers monohydroxyxanthone, using the G3(MP2)//B3LYP method, in order to evaluate the influence of the hydroxyl (-OH moiety) functional group on the xanthone molecule. The combination of these computational results with previous experimental data of these compounds enabled the determination of their enthalpies, entropies and Gibbs energies of formation, in the gaseous phase, and consequently to infer about the relative thermodynamic stability of the four isomers. Other issues were also addressed for the hydroxyxanthone isomers, namely the conformational and the tautomeric equilibrium analysis of the optimized molecular structures, the frontier orbitals, and the electrostatic potential energy maps. Complementarily, an energetic study of the intramolecular O - H ? O hydrogen bond for 1-hydroxanthone was also performed. PMID- 30428604 TI - Root-Specific Expression of a Jacalin Lectin Family Protein Gene Requires a Transposable Element Sequence in the Promoter. AB - Transposable elements (TEs) are widespread in the plant genome and can impact on the expression of neighbouring genes. Our previous studies have identified a number of DNA demethylase-regulated defence-related genes that contain TE sequences in the promoter and show tissue-specific expression in Arabidopsis. In this study we investigated the role of the promoter TE insertions in the root specific expression of a DNA demethylase-regulated gene, AT5G38550, encoding a Jacalin lectin family protein. Using a promoter:GUS fusion reporter gene approach, we first demonstrated that the full-length promoter fragment, carrying four TE sequences, contained the essential regulatory information required for root-specific expression and DNA demethylase regulation in Arabidopsis. By successive deletion of the four TE sequences, we showed that one of the four TE insertions, a 201-bp TE fragment of the hAT DNA transposon family, was required for root-specific expression: Deletion of this TE, but not the first two TE sequences, converted the root-specific expression pattern to a constitutive expression pattern in Arabidopsis plants. Our study provides an example indicating an important role of TE insertions in tissue-specific expression of plant defence-related genes. PMID- 30428606 TI - Factors Associated with Satisfaction of Hospital Physicians: A Systematic Review on European Data. AB - BACKGROUND: Physician satisfaction is a multidimensional concept related to many factors. Despite the wide range of research regarding factors affecting physician satisfaction in different European countries, there is a lack of literature reviews analyzing and summarizing current evidence. The aim of the article is to synthetize the literature studying the factors associated with physician satisfaction. METHODS: We searched: MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library from January 2000 to January 2017. The eligibility criteria included: (1) target population: physicians working in European hospitals; (2) quantitative research aimed at assessing physician satisfaction and associated factors; (3) use of validated tools. We performed a narrative synthesis. RESULTS: After screening 8585 records, 368 full text articles were independently checked and finally 24 studies were included for qualitative analysis. The included studies surveyed 20,000 doctors from 12 European countries. The tools and scales used in the analyzed research to measure physician satisfaction varied to a large extent. We extracted all pre-specified factors, reported as statistically significant/non-significant. Analyzed factors were divided into three groups: personal, intrinsic and contextual factors. The majority of factors are modifiable and positively associated with characteristics of contextual factors, such as work-place setting/work environment. In the group of work-place related factors, quality of management/leadership, opportunity for professional development and colleague support have been deemed statistically significant in numerous studies. CONCLUSIONS: We identified more studies appraising the effect of contextual factors (such as work environment, work-place characteristics), highlighting a positive association between those factors and physician satisfaction, compared with personal and intrinsic factors. Numerous studies confirmed statistically significant associations between physician satisfaction and quality of management, professional development and colleague support/team climate. Due to the health workforce crisis, knowledge regarding physician satisfaction and associated factors is essential to healthcare managers and policy makers for more stable human resources management. PMID- 30428605 TI - The Impact of Maternal Pre-Pregnancy Body Weight and Gestational Diabetes on Markers of Folate Metabolism in the Placenta. AB - Dietary methyl donors, including folate, may modify the placenta and size at birth but the influence of maternal body weight has not been widely investigated. We therefore examined whether maternal or fetal folate status, together with indices of placental folate transport, were modulated by either maternal pre pregnancy body mass index (BMI i.e., overweight: 25 <= BMI < 30 or obesity: BMI >= 30 kg/m2) and/or gestational diabetes mellitus (GD). We utilised a sub-sample of 135 pregnant women participating in the Spanish PREOBE survey for our analysis (i.e., 59 healthy normal weight, 29 overweight, 22 obese and 25 GD). They were blood sampled at 34 weeks gestation, and, at delivery, when a placental sample was taken together with maternal and cord blood. Placental gene expression of folate transporters and DNA methyltransferases (DNMT) were all measured. Folate plasma concentrations were determined with an electro-chemiluminescence immunoassay. Food diaries indicated that folate intake was unaffected by BMI or GD and, although all women maintained normal folate concentrations (i.e., 5-16 ng/mL), higher BMIs were associated with reduced maternal folate concentrations at delivery. Umbilical cord folate was not different, reflecting an increased concentration gradient between the mother and her fetus. Placental mRNA abundance for the folate receptor alpha (FOLR1) was reduced with obesity, whilst DNMT1 was increased with raised BMI, responses that were unaffected by GD. Multi-regression analysis to determine the best predictors for placental FOLR1 indicated that pre gestational BMI had the greatest influence. In conclusion, the placenta's capacity to maintain fetal folate supply was not compromised by either obesity or GD. PMID- 30428607 TI - Changes of Left and Right Ventricle Mechanics and Function in Patients with End Stage Renal Disease Undergoing Haemodialysis. AB - Background and objectives: Chronic kidney disease (CKD) increases the risk of cardiovascular diseases even in its early stages and is associated with structural and functional cardiac abnormalities. The aim of this study was to use speckle-tracking echocardiography (STE) to evaluate left and right ventricle mechanics and function, markers of subclinical dysfunction in patients with end stage renal disease (ESRD) undergoing haemodialysis. Methods: Patients with ESRD undergoing regular haemodialysis and with preserved left ventricle (LV) ejection fraction (EF) (n = 38) were enrolled in this retrospective study. The control group consisted of 32 age-matched persons with normal kidney function (glomerular filtration rate (GFR) >90 mL/min/1.73 m2 according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)). Conventional 2D echocardiography and STE were performed in all patients. Results: 70 individuals, 31 (44.29%) males and 39 (55.71%) females, were included in the study. There were no significant differences in age, sex and body surface area between the groups. LV end diastolic diameter did not differ between the groups, while LV myocardial mass index was higher in the group of patients on haemodialysis (111.64 +/- 27.99 versus 84.21 +/- 16.99, p < 0.001) and LV diastolic dysfunction (LVDD) was found in 31 (81.6%) patients of this group. LV global longitudinal strain (GLS) (-22.43 +/- 2.71 versus -24.73 +/- 2.03, p < 0.001) and LV global circumferential strain (GCS) at the mitral valve and papillary muscles levels (-18.73 +/- 3.49 versus 21.67 +/- 2.22, p < 0.001; -18.64 +/- 2.75 versus -20.42 +/- 2.38, p = 0.005, respectively) were significantly lower in haemodialysis group patients. The parameters of the right ventricle (RV) free wall longitudinal function including RV GLS (-22.63 +/- 3.04 versus -25.45 +/- 2.48, p < 0.001), were reduced in haemodialysis patients compared with the controls. However, RV fractional area change (FAC) did not differ between the groups (p = 0.19). Conclusion: Patients with ESRD and preserved LV ejection fraction undergoing haemodialysis had a higher prevalence of LVDD and impaired LV longitudinal and circumferential deformation indices, as well as reduced RV longitudinal function and deformation parameters compared with the age-matched healthy controls. STE helps to detect subclinical LV and RV dysfunction in chronic haemodialysis patients. PMID- 30428609 TI - Ion Irradiation-Induced Microstructural Evolution of Ni-Mo-Cr Low Alloy Steels. AB - As leading candidates of sheet steels for advanced nuclear reactors, three types of Ni-Mo-Cr high-strength low alloy (HSLA) steels named as CNST1, CNST2 and CNSS3 were irradiated by 400 keV Fe+ with peak fluence to 1.4 * 1014, 3.5 * 1014 and 7.0 * 1014 ions/cm2, respectively. The distribution and morphology of the defects induced by the sample preparation method and Fe+ irradiation dose were investigated by transmission electron microscopy (TEM) and positron-annihilation spectroscopy (PAS). TEM samples were prepared with two methods, i.e., a focused ion beam (FIB) technique and the electroplating and twin-jet electropolishing (ETE) method. Point defects and dislocation loops were observed in CNST1, CNST2 and CNSS3 samples prepared via FIB. On the other hand, samples prepared via the ETE method revealed that a smaller number of defects was observed in CNST1, CNST2 and almost no defects were observed in CNST3. It is indicated that artifact defects could be introduced by FIB preparation. The PAS S-W plots showed that the existence of two types of defects after ion implantation included small-scale defects such as vacancies, vacancy clusters, dislocation loops and large-sized defects. The S parameter of irradiated steels showed a clear saturation in PAS response with increasing Fe+ dose. At the same irradiation dose, higher values of the S-parameter were achieved in CNST1 and CNST2 samples when compared to that in CNSS3 samples. The mechanism and evolution behavior of irradiation-induced defects were analyzed and discussed. PMID- 30428610 TI - High-Efficiency Automatic Recharging Mechanism for Cleaning Robot Using Multi Sensor. AB - Cleaning robot has the highest penetration rate among the service robots. This paper proposes a high-efficiency mechanism for an intelligent cleaning robot automatically returns to charging in a short time when the power is insufficient. The proposed mechanism initially combines the robot's own motor encoder with neural network linear regression to calculate the moving distance and rotation angle for the location estimation of the robot itself. At the same time, a self rotating camera is applied to scan the number of infrared spots on the docking station to find the location of the docking station so that the cleaning robot returns to charging properly in two stages, existing infrared range and extended infrared range. In addition, six-axis acceleration and ultrasound are both applied to deal with the angle error that is caused by collision. Experimental results show that the proposed recharging mechanism significantly improves the efficiency of recharging. PMID- 30428611 TI - An Investigation of the Clinical Utility of the Proposed ICD-11 and DSM-5 Diagnostic Schemes for Eating Disorders Characterized by Recurrent Binge Eating in People with a High BMI. AB - The aims of this paper were to compare (1) the proportion of participants diagnosed with threshold or subthreshold Bulimia Nervosa (BN) and Binge Eating Disorder (BED) (clinical utility), and (2) the severity of participants' clinical features and mental Health-Related Quality of Life (HRQoL) (convergent validity), when diagnosed according to either the Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) or the proposed International Classification of Diseases 11th edition (ICD-11) schemes. One hundred and seven adult men and women, with a high Body Mass Index (BMI) were evaluated by interview to confirm their eating disorder diagnoses. All participants completed self-report assessments of current symptoms and mental HRQoL. The majority of participants in either diagnostic scheme were included in the main categories of BN or BED (102/107, 95% in the ICD-11 and 85/107, 79% in the DSM-5). Fewer individuals received a subthreshold other or unspecified diagnosis with the ICD-11 compared to the DSM-5 scheme (5% vs. 21%). No significant differences in demographic, clinical features or mental HRQoL of participants with complete or partial BN or BED were found between diagnostic categories. Compared to the DSM-5, the proposed ICD-11 was not over inclusive, i.e., it did not appear to include people with less severe and potentially less clinically relevant symptoms. These results support the greater clinical utility of the ICD-11 whilst both schemes showed convergent validity. PMID- 30428608 TI - Thermo-Sensitive Nanomaterials: Recent Advance in Synthesis and Biomedical Applications. AB - Progress in nanotechnology has enabled us to open many new fronts in biomedical research by exploiting the peculiar properties of materials at the nanoscale. The thermal sensitivity of certain materials is a highly valuable property because it can be exploited in many promising applications, such as thermo-sensitive drug or gene delivery systems, thermotherapy, thermal biosensors, imaging, and diagnosis. This review focuses on recent advances in thermo-sensitive nanomaterials of interest in biomedical applications. We provide an overview of the different kinds of thermoresponsive nanomaterials, discussing their potential and the physical mechanisms behind their thermal response. We thoroughly review their applications in biomedicine and finally discuss the current challenges and future perspectives of thermal therapies. PMID- 30428612 TI - Non-Hepatic Alkaline Phosphatase, hs-CRP and Progression of Vertebral Fracture in Patients with Rheumatoid Arthritis: A Population-Based Longitudinal Study. AB - BACKGROUND: Interactions and early warning effects of non-hepatic alkaline phosphatase (NHALP) and high-sensitivity C-reactive protein (hs-CRP) on the progression of vertebral fractures (VFs) in patients with rheumatoid arthritis (RA) remain unclear. We aim to explore whether serum concentrations of NHALP and hs-CRP could serve as a promising dual biomarker for prognostic assessment of VF progression. METHODS: Unadjusted and adjusted hazard ratios (aHRs) of VF progression were calculated for different categories of serum NHALP and hs-CRP using the Cox regression model in RA patients. The modification effect between serum NHALP and hs-CRP on VF progression was determined using an interaction product term. RESULTS: During 4489 person-years of follow-up, higher NHALP (>125 U/L) and hs-CRP (>3.0 mg/L) were robustly associated with incremental risks of VF progression in RA patients (aHR: 2.2 (95% confidence intervals (CIs): 1.2-3.9) and 2.0 (95% CI: 1.3-3.3) compared to the lowest HR category, respectively). The interaction between NHALP and hs-CRP on VF progression was statistically significant (p < 0.05). In the stratified analysis, patients with combined highest NHALP and hs-CRP had the greatest risk of VF progression (aHR: 4.9 (95% CI: 2.5-9.6)) compared to the lowest HR group (NHALP < 90 U/L and hs-CRP < 1 mg/L). CONCLUSIONS: In light of underdiagnoses of VFs and misleading diagnosis by single test, NHALP and hs-CRP could serve as compensatory biomarkers to predict subclinical VF progression in RA patients. PMID- 30428614 TI - Torus Pairwise Disjoint-Path Routing. AB - Modern supercomputers include hundreds of thousands of processors and they are thus massively parallel systems. The interconnection network of a system is in charge of mutually connecting these processors. Recently, the torus has become a very popular interconnection network topology. For example, the Fujitsu K, IBM Blue Gene/L, IBM Blue Gene/P, and Cray Titan supercomputers all rely on this topology. The pairwise disjoint-path routing problem in a torus network is addressed in this paper. This fundamental problem consists of the selection of mutually vertex disjoint paths between given vertex pairs. Proposing a solution to this problem has critical implications, such as increased system dependability and more efficient data transfers, and provides concrete implementation of green and sustainable computing as well as security, privacy, and trust, for instance, for the Internet of Things (IoT). Then, the correctness and complexities of the proposed routing algorithm are formally established. Precisely, in an n dimensional k-ary torus ( n < k , k >= 5 ), the proposed algorithm connects c ( c <= n ) vertex pairs with mutually vertex-disjoint paths of lengths at most 2 k ( c - 1 ) + n ? k / 2 ? , and the worst-case time complexity of the algorithm is O ( n c 4 ) . Finally, empirical evaluation of the proposed algorithm is conducted in order to inspect its practical behavior. PMID- 30428613 TI - The Biological Efficacy of Natural Products against Acute and Chronic Inflammatory Diseases in the Oral Region. AB - The oral inflammatory diseases are divided into two types: acute and chronic inflammatory diseases. In this review, we summarize the biological efficacy of herbal medicine, natural products, and their active ingredients against acute and chronic inflammatory diseases in the oral region, especially stomatitis and periodontitis. We review the effects of herbal medicines and a biscoclaurin alkaloid preparation, cepharamthin, as a therapy against stomatitis, an acute inflammatory disease. We also summarize the effects of herbal medicines and natural products against periodontitis, a chronic inflammatory disease, and one of its clinical conditions, alveolar bone resorption. Recent studies show that several herbal medicines such as kakkonto and ninjinto reduce LPS-induced PGE 2 production by human gingival fibroblasts. Among herbs constituting these herbal medicines, shokyo (Zingiberis Rhizoma) and kankyo (Zingiberis Processum Rhizoma) strongly reduce PGE 2 production. Moreover, anti-osteoclast activity has been observed in some natural products with anti-inflammatory effects used against rheumatoid arthritis such as carotenoids, flavonoids, limonoids, and polyphenols. These herbal medicines and natural products could be useful for treating oral inflammatory diseases. PMID- 30428615 TI - Discovery of Heterotopic Bone-Inducing Activity in Hard Tissues and the TGF-beta Superfamily. AB - Bone is a unique organ because it can be experimentally induced in soft tissues by implanting a single growth factor, bone morphogenetic protein (BMP). Heterotopic bone-inducing activity was found in demineralized bone matrix in 1965. The characterization of this activity in bone enabled the purification and molecular cloning of BMPs and showed that they are members of the transforming growth factor-beta (TGF-beta) superfamily. Assay systems developed for this bone inducing activity revealed the molecular mechanisms of the intracellular signaling of members of the superfamily, including BMPs. Moreover, they are being applied to elucidate molecular mechanisms and to develop novel therapeutics for a disease caused by an abnormality in BMP signaling. PMID- 30428617 TI - Generative Adversarial Networks-Based Semi-Supervised Automatic Modulation Recognition for Cognitive Radio Networks. AB - With the recently explosive growth of deep learning, automatic modulation recognition has undergone rapid development. Most of the newly proposed methods are dependent on large numbers of labeled samples. We are committed to using fewer labeled samples to perform automatic modulation recognition in the cognitive radio domain. Here, a semi-supervised learning method based on adversarial training is proposed which is called signal classifier generative adversarial network. Most of the prior methods based on this technology involve computer vision applications. However, we improve the existing network structure of a generative adversarial network by adding the encoder network and a signal spatial transform module, allowing our framework to address radio signal processing tasks more efficiently. These two technical improvements effectively avoid nonconvergence and mode collapse problems caused by the complexity of the radio signals. The results of simulations show that compared with well-known deep learning methods, our method improves the classification accuracy on a synthetic radio frequency dataset by 0.1% to 12%. In addition, we verify the advantages of our method in a semi-supervised scenario and obtain a significant increase in accuracy compared with traditional semi-supervised learning methods. PMID- 30428616 TI - Characterisation of Monovarietal Olive Oils Obtained from Croatian cvs. Drobnica and Buza during the Ripening Period. AB - The aim of this study was the monitoring of the chemical composition of olive oil at different ripening stages to determine the appropriate harvesting time during any given crop season in the northern Adriatic region. For this purpose, from September to November, two Croatian olive cultivars (Drobnica and Buza) were taken from two different olive orchards and for the respective olive oils, prepared on a laboratory scale, the major saponifiable, unsaponifiable and phenolic compounds were determined. Based on the chemical analyses performed, the optimal harvesting time has been set in October for both cultivars. Buza had a higher oleic acid, but lower total sterols, squalene and total alkanols. Compared to the local cultivars, the studied cultivars had a high total phenolic content and antioxidant activity. The antioxidant activity and concentrations of total phenols correlated with alpha-tocopherol in oil samples taken during the ripening progress. Finally, trace minerals detected in Buza and Drobnica oil differed, which can be an indicator of oxidative stability and authenticity of oils. PMID- 30428618 TI - Robust Iterative Distributed Minimum Total MSE Algorithm for Secure Communications in the Internet of Things Using Relays. AB - In this article, we first investigate secure communications for a two-hop interference channel relay system with imperfect channel estimation in the wireless Internet of Things (IoT), where K source-destination pairs communicate simultaneously when an eavesdropper exists. We jointly conceive source, relay and destination matrices upon minimizing total mean-squared error (MSE) of all legitimate destinations while keeping the MSE at eavesdropper above a given threshold. We illuminate that the design of the source, relay and destination matrices is subject to both transmit power constraints and secrecy requirements. More specifically, we propose an efficient robust iterative distributed algorithm to simplify the process of the joint design for optimal source, relay and destination matrices. Furthermore, the convergence of the iterative distributed algorithm is described. Additionally, the performances of our proposed algorithm, such as its secrecy rate and MSE, are characterized in the form of simulation results. The simulation results reveal that the proposed algorithm is superior to the traditional approach. As a benefit, secure communications can be ensured by using the proposed algorithm for the multiple input multiple output (MIMO) interference relay IoT network in the presence of an eavesdropper. PMID- 30428619 TI - Reversal of Multidrug Resistance in Human Colon Cancer and Human Leukemia Cells by Three Plant Extracts and Their Major Secondary Metabolites. AB - Background: We studied the effect of three plant extracts (Glycyrrhiza glabra, Paeonia lactiflora, Eriobotrya japonica) and six of their major secondary metabolites (glycyrrhizic acid, 18beta glycyrrhetinic acid, liquiritigenin, isoliquiritigenin, paeoniflorin, ursolic acid) on the multidrug resistant human colon cancer cell line Caco-2 and human leukemia cell line CEM/ADR 5000 as compared to the corresponding sensitive cell line CCRF-CEM, and human colon cancer cells HCT-116, which do not over-express ATP-binding cassette (ABC) transporters. Methods: The cytotoxicity of single substances in sensitive and resistant cells was investigated by MTT assay. We also applied combinations of extracts or single compounds with the chemotherapeutic agent doxorubicin or doxorubicin plus the saponin digitonin. The intracellular retention of the ABC transporter substrates rhodamine 123 and calcein was examined by flow cytometry to explore the effect of the substances on the activity of ABC transporters P glycoprotein and MRP1. Real-time PCR was applied to analyse the gene expression changes of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 in resistant cells under the treatment of the substances. Results: All the substances moderately inhibited cell growth in sensitive and resistant cells to some degree. Whereas ursolic acid showed IC50 of 14 and 22 uM in CEM/ADR 5000 and Caco-2 cells, respectively, glycyrrhizic acid and paeoniflorin were inactive with IC50 values above 400 MUM. Except for liquiritigenin and isoliquiritigenin, all the other substances reversed MDR in CEM/ADR 5000 and Caco-2 cells to doxorubicin. Ue, ga, 18ga, and urs were powerful reversal agents. In CEM/ADR 5000 cells, high concentrations of all the substances, except Paeonia lactiflora extract, increased calcein or rhodamine 123 retention in a dose-dependent manner. In Caco-2 cells, all the substances, except liquiritigenin, retained rhodamine 123 in a dose-dependent manner. We also examined the effect of the plant secondary metabolite (PSM) panel on the expression of ABCB1, ABCC1, caspase 3, caspase 8, AhR, CYP1A1, and GSTP1 genes in MDR cells. Conclusions: The extracts and individual PSM could reverse MDR in CEM/ADR 5000 and Caco-2 cells, which overexpress ABC transporters, in two- and three-drug combinations. Most of the PSM also inhibited the activity of ABC transporters to some degree, albeit at high concentrations. Ue, ga, 18ga, and urs were identified as potential multidrug resistance (MDR) modulator candidates, which need to be characterized and validated in further studies. PMID- 30428620 TI - Engineering the Surface and Mechanical Properties of Water Desalination Membranes Using Ultralong Carbon Nanotubes. AB - In this work, novel polysulphone (PS) porous membranes for water desalination, incorporated with commercial and produced carbon nanotubes (CNT), were fabricated and analyzed. It was demonstrated that changing the main characteristics of CNT (e.g., loading in the dope solutions, aspect ratio, and functionality) significantly affected the membrane properties and performance including porosity, water flux, and mechanical and surface properties. The water flux of the fabricated membranes increased considerably (up to 20 times) along with the increase in CNT loading. Conversely, yield stress and Young's modulus of the membranes dropped with the increase in the CNT loading mainly due to porosity increase. It was shown that the elongation at fracture for PS/0.25 wt. % CNT membrane was much higher than for pristine PS membrane due to enhanced compatibility of commercial CNTs with PS matrix. More pronounced effect on membrane's mechanical properties was observed due to compatibility of CNTs with PS matrix when compared to other factors (i.e., changes in the CNT aspect ratio). The water contact angle for PS membranes incorporated with commercial CNT sharply decreased from 73 degrees to 53 degrees (membrane hydrophilization) for membranes with 0.1 and 1.0 wt. % of CNTs, while for the same loading of produced CNTs the water contact angles for the membrane samples increased from 66 degrees to 72 degrees . The obtained results show that complex interplay of various factors such as: loading of CNT in the dope solutions, aspect ratio, and functionality of CNT. These features can be used to engineer membranes with desired properties and performance. PMID- 30428621 TI - Multi-Objective Optimization for Grinding of AISI D2 Steel with Al2O3 Wheel under MQL. AB - In the present study, the machinability indices of surface grinding of AISI D2 steel under dry, flood cooling, and minimum quantity lubrication (MQL) conditions are compared. The comparison was confined within three responses, namely, the surface quality, surface temperature, and normal force. For deeper insight, the surface topography of MQL-assisted ground surface was analyzed too. Furthermore, the statistical analysis of variance (ANOVA) was employed to extract the major influencing factors on the above-mentioned responses. Apart from this, the multi objective optimization by Grey-Taguchi method was performed to suggest the best parameter settings for system-wide optimal performance. The central composite experimental design plan was adopted to orient the inputs wherein the inclusion of MQL flow rate as an input adds addition novelty to this study. The mathematical models were formulated using Response Surface Methodology (RSM). It was found that the developed models are statistically significant, with optimum conditions of depth of cut of 15 um, table speed of 3 m/min, cutting speed 25 m/min, and MQL flow rate 250 mL/h. It was also found that MQL outperformed the dry as well as wet condition in surface grinding due to its effective penetration ability and improved heat dissipation property. PMID- 30428622 TI - Superhydrophobic Water-Solid Contact Triboelectric Generator by Simple Spray-On Fabrication Method. AB - Energy harvesting is a method of converting energy from ambient environment into useful electrical energy. Due to the increasing number of sensors and personal electronics, energy harvesting technologies from various sources are gaining attention. Among energy-harvesting technologies, triboelectric nanogenerator (TENG) was introduced as a device that can effectively generate electricity from mechanical motions by contact-electrification. Particularly, liquid-solid contact TENGs, which use the liquid itself as a triboelectric material, can overcome the inevitable friction wear between two solid materials. Using a commercial aerosol hydrophobic spray, liquid-solid contact TENGs, with a superhydrophobic surface (contact angle over 160 degrees ) can be easily fabricated with only a few coating processes. To optimize the fabrication process, the open-circuit voltage of sprayed superhydrophobic surfaces was measured depending on the number of coating processes. To demonstrate the simple fabrication and applicability of this technique on random 3D surfaces, a liquid-solid contact TENG was fabricated on the brim of a cap (its complicated surface structure is due to the knitted strings). This simple sprayed-on superhydrophobic surface can be a possible solution for liquid-solid contact TENGs to be mass produced and commercialized in the future. PMID- 30428623 TI - Polypeptides Micelles Composed of Methoxy-Poly(Ethylene Glycol)-Poly(l-Glutamic Acid)-Poly(l-Phenylalanine) Triblock Polymer for Sustained Drug Delivery. AB - Methoxy-poly(ethylene glycol)-poly(l-glutamic acid)-poly(l-phenylalanine) triblock polymers with different architecture were synthesized as drug carrier to obtain sustained and controlled release by tuning the composition. These triblock polymers were prepared by ring opening polymerization and poly(ethylene glycol) was used as an initiator. Polymerization was confirmed by 1H NMR, FT-IR and gel penetration chromatography. The polymers can self-assemble to form micelles in aqueous medium and their critical micelle concentrations values were examined. The micelles were spherical shape with size of 50-100 nm and especially can arranged in a regular manner. Sorafenib was selected as the model drug and the drug loading performance was dependent on the composition of the block copolymer. In vitro drug release indicated that the polymers can realize controlled and sustained drug release. Furthermore, in vitro cytotoxicity assay showed that the polymers were biocompatible and the drug-loaded micelles can increase toxicity towards tumor cells. Confocal fluorescence microscopy assays illustrated that the micelles can be uptaken quickly and release drug persistently to inhibit tumor cell growth. PMID- 30428624 TI - Unintentional Genomic Changes Endow Cupriavidus metallidurans with an Augmented Heavy-Metal Resistance. AB - For the past three decades, Cupriavidus metallidurans has been one of the major model organisms for bacterial tolerance to heavy metals. Its type strain CH34 contains at least 24 gene clusters distributed over four replicons, allowing for intricate and multilayered metal responses. To gain organic mercury resistance in CH34, broad-spectrum mer genes were introduced in a previous work via conjugation of the IncP-1beta plasmid pTP6. However, we recently noted that this CH34-derived strain, MSR33, unexpectedly showed an increased resistance to other metals (i.e., Co2+, Ni2+, and Cd2+). To thoroughly investigate this phenomenon, we resequenced the entire genome of MSR33 and compared its DNA sequence and basal gene expression profile to those of its parental strain CH34. Genome comparison identified 11 insertions or deletions (INDELs) and nine single nucleotide polymorphisms (SNPs), whereas transcriptomic analysis displayed 107 differentially expressed genes. Sequence data implicated the transposition of IS1088 in higher Co2+ and Ni2+ resistances and altered gene expression, although the precise mechanisms of the augmented Cd2+ resistance in MSR33 remains elusive. Our work indicates that conjugation procedures involving large complex genomes and extensive mobilomes may pose a considerable risk toward the introduction of unwanted, undocumented genetic changes. Special efforts are needed for the applied use and further development of small nonconjugative broad-host plasmid vectors, ideally involving CRISPR-related and advanced biosynthetic technologies. PMID- 30428625 TI - Furanoid F-Acid F6 Uniquely Induces NETosis Compared to C16 and C18 Fatty Acids in Human Neutrophils. AB - Various biomolecules induce neutrophil extracellular trap (NET) formation or NETosis. However, the effect of fatty acids on NETosis has not been clearly established. In this study, we focused on the NETosis-inducing ability of several lipid molecules. We extracted the lipid molecules present in Arabian Gulf catfish (Arius bilineatus, Val) skin gel, which has multiple therapeutic activities. Gas chromatography-mass spectrometry (GC-MS) analysis of the lipid fraction-3 from the gel with NETosis-inducing activity contained fatty acids including a furanoid F-acid (F6; 12,15-epoxy-13,14-dimethyleicosa-12,14-dienoic acid) and common long chain fatty acids such as palmitic acid (PA; C16:0), palmitoleic acid (PO; C16:1), stearic acid (SA; C18:0), and oleic acid (OA; C18:1). Using pure molecules, we show that all of these fatty acids induce NETosis to different degrees in a dose-dependent fashion. Notably, F6 induces a unique form of NETosis that is rapid and induces reactive oxygen species (ROS) production by both NADPH oxidase (NOX) and mitochondria. F6 also induces citrullination of histone. By contrast, the common fatty acids (PA, PO, SA, and OA) only induce NOX-dependent NETosis. The activation of the kinases such as ERK (extracellular signal regulated kinase) and JNK (c-Jun N-terminal kinase) is important for long-chain fatty acid-induced NETosis, whereas, in F-acid-induced NETosis, Akt is additionally needed. Nevertheless, NETosis induced by all of these compounds requires the final chromatin decondensation step of transcriptional firing. These findings are useful for understanding F-acid- and other fatty acid-induced NETosis and to establish the active ingredients with therapeutic potential for regulating diseases involving NET formation. PMID- 30428626 TI - Stereogenic Centers. AB - The demand for chiral organic entities for different industrial purposes has grown exponentially in the last decades. [...]. PMID- 30428627 TI - Response to "Are There Non-Responders to the Ergogenic 3 Effects of Caffeine Ingestion on Exercise Performance?" AB - In response to "Letter: are there non-responders to the ergogenic effects of caffeine ingestion on exercise performance" by Grgic [...]. PMID- 30428628 TI - The Emerging Role of Epitranscriptomics in Cancer: Focus on Urological Tumors. AB - Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs. m6A has been demonstrated to play important roles in many physiological processes and several disease states, including various cancer models (from solid to liquid tumors). Tumor cells' epitranscriptome is indeed disrupted in a way to promote cancer-prone features, by means of up/downregulating m6A-related players: the so-called writers, readers and erasers. These proteins modulate m6A establishment, removal and determine mRNAs fate, acting in a context-dependent manner, so that a single player may act as an oncogenic signal in one tumor model (methyltransferase like 3 (METTL3) in lung cancer) and as a tumor suppressor in another context (METTL3 in glioblastoma). Despite recent advances, however, little attention has been directed towards urological cancer. By means of a thorough analysis of the publicly available TCGA (The Cancer Genome Atlas) database, we disclosed the most relevant players in four major urogenital neoplasms-kidney, bladder, prostate and testicular cancer for prognostic, subtype discrimination and survival purposes. In all tumor models assessed, the most promising player was shown to be Vir like m6A methyltransferase associated (VIRMA), which could constitute a potential target for personalized therapies. PMID- 30428630 TI - Polygonatum odoratum Polysaccharides Modulate Gut Microbiota and Mitigate Experimentally Induced Obesity in Rats. AB - Increasing evidence suggests that the gut microbiota plays vital roles in metabolic diseases. Polygonatum odoratum extract alleviates hyperglycemia and hyperlipidemia, but the underlying mechanism remains unclear. This study investigated the effects of P. odoratum polysaccharides (POPs) on high-fat diet (HFD)-induced obesity in rats and whether these effects were related to modulation of gut microbiota. POP treatment attenuated weight gain, fat accumulation, epididymal adipocyte size, liver triglycerides, and total liver cholesterol content in HFD-fed rats. POP administration also increased short chain fatty acids (SCFAs), including isobutyric acid, butyric acid, and valeric acid. POP upregulated the expression of genes involved in adipocyte differentiation (Pparg, Cebpa, Cebpb) and lipolysis (Ppara, Atgl), and downregulated those related to lipid synthesis (Srebpf1, Fabp4, Fas), with corresponding changes in PPARgamma and FABP4 protein expression. Finally, POP enhanced species richness and improved the gut microbiota community structure, reducing the relative abundances of Clostridium, Enterococcus, Coprobacillus, Lactococcus, and Sutterella. Principal coordinates analysis (PCoA) revealed a clear separation between HFD-fed rats and all other treatment groups. Correlation analysis identified negative and positive associations between obesity phenotypes and 28 POP-influenced operational taxonomic units (OTUs), including putative SCFA producing bacteria. Our data suggest that POP supplementation may attenuate features of obesity in HFD-fed rats in association with the modulation of gut microbiota. PMID- 30428631 TI - Predicting the Health Status of an Unmanned Aerial Vehicles Data-Link System Based on a Bayesian Network. AB - Unmanned aerial vehicles (UAVs) require data-link system to link ground data terminals to the real-time controls of each UAV. Consequently, the ability to predict the health status of a UAV data-link system is vital for safe and efficient operations. The performance of a UAV data-link system is affected by the health status of both the hardware and UAV data-links. This paper proposes a method for predicting the health state of a UAV data-link system based on a Bayesian network fusion of information about potential hardware device failures and link failures. Our model employs the Bayesian network to describe the information and uncertainty associated with a complex multi-level system. To predict the health status of the UAV data-link, we use the health status information about the root node equipment with various life characteristics along with the health status of the links as affected by the bit error rate. In order to test the validity of the model, we tested its prediction of the health of a multi-level solar-powered unmanned aerial vehicle data-link system and the result shows that the method can quantitatively predict the health status of the solar powered UAV data-link system. The results can provide guidance for improving the reliability of UAV data-link system and lay a foundation for predicting the health status of a UAV data-link system accurately. PMID- 30428629 TI - Humanization of the Prostate Microenvironment Reduces Homing of PC3 Prostate Cancer Cells to Human Tissue-Engineered Bone. AB - The primary tumor microenvironment is inherently important in prostate cancer (PCa) initiation, growth and metastasis. However, most current PCa animal models are based on the injection of cancer cells into the blood circulation and bypass the first steps of the metastatic cascade, hence failing to investigate the influence of the primary tumor microenvironment on PCa metastasis. Here, we investigated the spontaneous metastasis of PC3 human PCa cells from humanized prostate tissue, containing cancer-associated fibroblasts (CAFs) and prostate lymphatic and blood vessel endothelial cells (BVEC), to humanized tissue engineered bone constructs (hTEBC) in NOD-SCID IL2Rgammanull (NSG) mice. The hTEBC formed a physiologically mature organ bone which allowed homing of metastatic PCa cells. Humanization of prostate tissue had no significant effect on the tumor burden at the primary site over the 4 weeks following intraprostatic injection, yet reduced the incidence and burden of metastases in the hTEBC. Spontaneous PCa metastases were detected in the lungs and spleen with no significant differences between the humanized and non-humanized prostate groups. A significantly greater metastatic tumor burden was observed in the liver when metastasis occurred from the humanized prostate. Together, our data suggests that the presence of human-derived CAFs and BVECs in the primary PCa microenvironment influences selectively the metastatic and homing behavior of PC3 cells in this model. Our orthotopic and humanized prostate cancer model developed via convergence of cancer research and tissue engineering concepts provides an important platform to study species-specific PCa bone metastasis and to develop and test therapeutic strategies. PMID- 30428632 TI - From Systemic Inflammation to Neuroinflammation: The Case of Neurolupus. AB - It took decades to arrive at the general consensus dismissing the notion that the immune system is independent of the central nervous system. In the case of uncontrolled systemic inflammation, the relationship between the two systems is thrown off balance and results in cognitive and emotional impairment. It is specifically true for autoimmune pathologies where the central nervous system is affected as a result of systemic inflammation. Along with boosting circulating cytokine levels, systemic inflammation can lead to aberrant brain-resident immune cell activation, leakage of the blood-brain barrier, and the production of circulating antibodies that cross-react with brain antigens. One of the most disabling autoimmune pathologies known to have an effect on the central nervous system secondary to the systemic disease is systemic lupus erythematosus. Its neuropsychiatric expression has been extensively studied in lupus-like disease murine models that develop an autoimmunity-associated behavioral syndrome. These models are very useful for studying how the peripheral immune system and systemic inflammation can influence brain functions. In this review, we summarize the experimental data reported on murine models developing autoimmune diseases and systemic inflammation, and we explore the underlying mechanisms explaining how systemic inflammation can result in behavioral deficits, with a special focus on in vivo neuroimaging techniques. PMID- 30428633 TI - Matching SDN and Legacy Networking Hardware for Energy Efficiency and Bounded Delay. AB - Both economic and environmental costs are driving much research in the area of the energy efficiency of networking equipment. This research has produced a great amount of proposals. However, the majority of them remain unimplemented due to the lack of flexibility of current hardware devices and a certain lack of enthusiasm from commercial vendors. At the same time, Software-Defined Networking (SDN) has allowed customers to control switching decisions with a flexibility and precision previously unheard of. This paper explores the potential convergence between the two aforementioned trends and presents a promising power saving algorithm that can be implemented using standard SDN capabilities of current switches, reducing operation costs on both data centers and wired access networks. In particular, we focus on minimizing the energy consumption in bundles of energy-efficient Ethernet links leveraging SDN. For this, we build on an existing theoretical algorithm and adapt it for implementing with an SDN solution. We study several approaches and compare the resulting algorithms not only according to their energy efficiency, but also taking into account additional QoS metrics. The results show that the resulting algorithm is able to closely match the theoretical results, even when taking into account the requirements of delay-sensitive traffic. PMID- 30428634 TI - "In my day..."- Parents' Views on Children's Physical Activity and Screen Viewing in Relation to Their Own Childhood. AB - Physical activity and screen viewing are associated with cardio-metabolic risk factors, psychological wellbeing, and academic performance among children. Across the last generation, children's physical activity and screen viewing behaviours have changed, coinciding with changes to the home and neighbourhood environment. This study aimed to qualitatively explore parents' views on their 8-9-year-old child's childhood and how this compares to experiences from their own childhood, with a specific focus on physical activity and screen viewing behaviours. Semi structured telephone interviews were conducted with 51 parents (mean age = 41.2 years, range 31.5 to 51.5 years), between July and October 2016. Inductive and deductive content analyses were used to explore parents' perceptions of their child's physical activity and screen viewing behaviours in comparison to their own childhood behaviours. Interview data revealed that compared to the relative freedom they recalled as children, parents restrict their children's independent mobility and outdoor play due to concerns about safety. Despite their children having greater access to structured activities than they did as children, parents feel their children are "missing out," and perceived their own childhood as better with regards to maximising independent and outdoor play and limiting screen viewing. Innovative strategies are needed to change the social norms surrounding children's independent mobility and outdoor play. PMID- 30428635 TI - Proactive Coverage Area Decisions Based on Data Field for Drone Base Station Deployment. AB - Using the drone base station (DBS) to alleviate the network coverage supply demand mismatch is an attractive issue. Found in DBS-assisted cellular mobile networks, the deployment of DBSs to cope with the dynamic load requirements is an important problem. The authors propose a proactive DBS deployment method to enhance the DBS deployment flexibility based on network traffic. The proposed scheme uses potential value and minimum distance to decide the areas that most need to be covered, which are named as proactive coverage areas (PCAs), whereby the DBSs are assigned to cover those PCAs. Meanwhile, when the number of required DBSs is determined, the energy consumption is related to the coverage radius and the altitude of DBSs. Therefore, the proposed method further investigates the on demand coverage radius and then obtains the altitude of DBSs. Simulations show that the proposed proactive DBS deployment method provides better coverage performance with a significant complexity reduction. PMID- 30428636 TI - Crystallographic and Computational Characterization of Methyl Tetrel Bonding in S Adenosylmethionine-Dependent Methyltransferases. AB - Tetrel bonds represent a category of non-bonding interaction wherein an electronegative atom donates a lone pair of electrons into the sigma antibonding orbital of an atom in the carbon group of the periodic table. Prior computational studies have implicated tetrel bonding in the stabilization of a preliminary state that precedes the transition state in SN2 reactions, including methyl transfer. Notably, the angles between the tetrel bond donor and acceptor atoms coincide with the prerequisite geometry for the SN2 reaction. Prompted by these findings, we surveyed crystal structures of methyltransferases in the Protein Data Bank and discovered multiple instances of carbon tetrel bonding between the methyl group of the substrate S-adenosylmethionine (AdoMet) and electronegative atoms of small molecule inhibitors, ions, and solvent molecules. The majority of these interactions involve oxygen atoms as the Lewis base, with the exception of one structure in which a chlorine atom of an inhibitor functions as the electron donor. Quantum mechanical analyses of a representative subset of the methyltransferase structures from the survey revealed that the calculated interaction energies and spectral properties are consistent with the values for bona fide carbon tetrel bonds. The discovery of methyl tetrel bonding offers new insights into the mechanism underlying the SN2 reaction catalyzed by AdoMet dependent methyltransferases. These findings highlight the potential of exploiting these interactions in developing new methyltransferase inhibitors. PMID- 30428637 TI - Hemorrhagic Moyamoya Disease : A Recent Update. AB - Moyamoya disease (MMD) is a progressive cerebrovascular disease with unknown etiology, characterized by bilateral stenoocclusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network formation at the base of the brain. MMD has an intrinsic nature to convert the vascular supply for the brain from internal carotid (IC) system to the external carotid (EC) system, as indicated by Suzuki's angiographic staging. Insufficiency of this 'IC-EC conversion system' could result not only in cerebral ischemia, but also in intracranial hemorrhage from inadequate collateral anastomosis, both of which represent the clinical manifestation of MMD. Surgical revascularization prevents cerebral ischemic attack by improving cerebral blood flow, and recent evidence further suggests that extracranial-intracranial bypass could powerfully reduce the risk of re-bleeding in MMD patients with posterior hemorrhage, who were known to have extremely high re-bleeding risk. Although the exact mechanism underlying the hemorrhagic presentation in MMD is undetermined, most recent angiographic analysis revealed the characteristic angio-architecture related to high re bleeding risk, such as the extension and dilatation of choroidal collaterals and posterior cerebral artery involvement. We sought to update the current management strategy for hemorrhagic MMD, including the outcome of surgical revascularization for hemorrhagic MMD in our institute. Further investigations will clarify the optimal surgical strategy to prevent hemorrhagic manifestation in patients with MMD. PMID- 30428638 TI - Genetic Profiles Associated with Chemoresistance in Patient-Derived Xenograft Models of Ovarian Cancer. AB - Purpose: Recurrence and chemoresistance (CR) are the leading causes of death in patients with high-grade serous carcinoma (HGSC) of the ovary. The aim of this study was to identify genetic changes associated with CR mechanisms using a patient-derived xenograft (PDX) mouse model and genetic sequencing. Materials and Methods: To generate a CR HGSC PDX tumor, mice bearing subcutaneously implanted HGSC PDX tumors were treated with paclitaxel and carboplatin. We compared gene expression and mutations between chemosensitive (CS) and CR PDX tumors with whole exome and RNA sequencing and selected candidate genes. Correlations between candidate gene expression and clinicopathological variables were explored using the Cancer Genome Atlas (TCGA) database and the Human Protein Atlas (THPA). Results: Three CR and four CS HGSC PDX tumor models were successfully established. RNA sequencing analysis of the PDX tumors revealed that 146 genes were significantly up-regulated and 54 genes down-regulated in the CR group compared with the CS group. Whole exome sequencing analysis showed 39 mutation sites were identified which only occurred in CR group. Differential expression of SAP25, HLA-DPA1, AKT3, and PIK3R5 genes and mutation of TMEM205 and POLR2A may have important functions in the progression of ovarian cancer chemoresistance. According to TCGA data analysis, patients with high HLA-DPA1 expression were more resistant to initial chemotherapy (p=0.030, odds ratio, 1.845). Conclusion: We successfully established CR ovarian cancer PDX mouse models. PDX-based genetic profiling study could be used to select some candidate genes that could be targeted to overcome chemoresistance of ovarian cancer. PMID- 30428639 TI - Patient and Care Delays of Breast Cancer in China. AB - Purpose: This study differentiates patient and care delays of breast cancer and explores the related factors as well as the associations with the prognosis in Guangzhou, a southern city of China. Methods: A cohort of female incident breast cancer patients (n=1,551) was recruited from October 2008 to March 2012 and followed up until January 1, 2016 (n=1,374) in the affiliated hospitals of Sun Yat-sen University. The factors associated with patient and care delays were analyzed with multivariable logistic models. Cox proportional hazards regression models were constructed to estimate the impacts of the delays on the prognosis. Results: There were 40.4% patient delay (>=3 months) and 15.5% care delay (>=1 month). The patient delay, but not the care delay, was significantly related to the clinical stage and consequently worsened the prognosis of breast cancer (hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.91 for progression-free survival). The factors related to an increased patient delay included premenopausal status, history of benign breast disease, and less physical examination. Conclusion: Patient delay was the main type of delay in Guangzhou and resulted in higher clinical stage and poor prognosis of breast cancer. Screening for breast cancer among premenopausal women may be an effective way to reduce this delay. PMID- 30428640 TI - Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non small Cell Lung Cancer. AB - Purpose: Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications. Materials and Methods: We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival. Results: The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1-negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar's test, p<0.001). Increase in PD L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival. Conclusion: Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome. PMID- 30428641 TI - Lessons from radiation epidemiology. AB - Radiation epidemiology has developed as a specialized field and has unique characteristics compared to the other fields of epidemiology. Radiation exposure assessment is highly quantified and health risk assessment can yield precise risks per unit dose in each organ. At the same time, radiation epidemiology also emphasizes the uncertainty of the estimated doses and risks. More radiation epidemiologists work in radiation societies rather than those of epidemiology. This specialization deepens the research of radiation studies but also results in fragmentation from general epidemiology. In addition to continued involvement with radiation-related sciences, therefore, more efforts to communicate with the other fields of epidemiology are necessary for radiation epidemiology. PMID- 30428642 TI - Domestic elder abuse and associated factors in elderly women in Tehran, Iran. AB - Objectives: Elderly people often are abused in many ways with serious and pasting consequences. Elder abuse remains one of the most hidden forms of family conflict and it is anticipated that it is rising in many countries which are rapidly experiencing population aging. The purpose of study is to investigate the status of domestic elder abuse in elderly women and their related factors in Tehran. Methods: This cross-sectional study conducted in 2017 on 260 women aged 60 and older, selected through multistage random sampling. The information of abuse and its risk factors was collected through interviews with the elderly in their homes. To measure domestic elderly abuse, the standard domestic elderly abuse questionnaire was used. The ordinal logistic test was used in Stata 12 to identify the factors related to elder abuse. Results: Results showed that 90.4% of subjects have experienced at least one type of abuse, which the highest rate of abuse was authority deprivation (68.5%), and the lowest was rejection (11.2%). The ordinal logistic analysis showed that the odds of being in higher levels of abuse is significantly higher in elderly people over 72 years than older people aged 60-62 years (OR=2.07, CI: 1.03- 4.17). Conclusion: Results showed that domestic elder abuse is common in older women. Old age is an important risk factor for domestic elder abuse in elderly women in Tehran. Managing and preventing elderly abuse is an important issue that needs to be addressed. PMID- 30428643 TI - Incidences of Varicella in Children of Jeju-do, Republic of Korea, 2005-2016: Age Period-Cohort Analysis. AB - Objectives: Although the nationwide inoculation rate of varicella vaccine was about 95% in Korean children, the notified numbers of varicella cases are increasing till now, unexpectedly. To suggest some hypotheses about the gap, an age-period-cohort (APC) analysis as descriptive epidemiology study was conducted for children resident in Jeju-do, Republic of Korea (ROK). Methods: The raw data was the nationwide database for insurance claim of healthcare fee suggested by National Health Insurance Service, ROK. The selection criteria were children aged of 2 to 13 years taken any healthcare with varicella from 2005 to 2016 while resided in Jeju-do, ROK. After birth cohort-specific crude incidence rates (CIR) by age and year were calculated, intrinsic estimator (IE) method was applied to conduct APC analysis. Results: As annual CIRs were decreasing as age was increasing between 2005 and 2016, the age and period effect were decreasing in all observed years. The IE coefficients suggesting cohort effect were shifted from positive into negative in 2011 as the starting year of free varicella vaccine program in Jeju-do, ROK. Conclusion: The results suggested that inoculated varicella vaccines have preventive effect. However, researches to evaluate waning immunity would be needed. PMID- 30428644 TI - Life expectancy of HIV-positive patients after diagnosis in Iran from 1986 to 2016: A retrospective cohort study at national and sub-national levels. AB - Objectives: Little is known on the life expectancy of HIV positive patients in Iran. This study aimed to estimate the life expectancy of HIV positive patients in Iran. Methods: In this retrospective cohort study, we extracted the data from Center for Disease Control and Prevention (CDC) of the Ministry of Health and Medical Education (MOHME) and Death Registration System (DRS). We included the patients aged 20 years and older who had specified date of diagnosis. We estimated life expectancy and its 95% confidence interval (CI) using Chinag's methodology. Results: Overall life expectancy at the national level was 23.1 years (95% CI: 22.6, 23.5). Life expectancy was 21.6 years (95% CI: 21.1, 22.0) for men and 32.7 years (95% CI: 31.4, 34.0) for women. Life expectancy for patients who have received or not received Antiretroviral Therapy (ART) was 37.0 years (95% CI 36.2, 37.8) 15.5 years (95% CI: 15.1, 15.9), respectively. Life expectancy for patients with or without tuberculosis (TB) was 21.6 years (95% CI: 20.4, 22.9) and 36.5 years (95% CI: 35.7, 37.4), respectively. Conclusion: life expectancy in Iranian HIV positive patients is very low. To improve the longevity, improvement of ART coverage, control and treatment of TB is advised. Keywords: Life Expectancy, HIV, Iran. PMID- 30428645 TI - Scabies mimicking graft versus host disease in a hematopoietic cell transplant recipient. AB - Scabies is a highly contagious skin infestation caused by the mite, Sarcoptes scabiei var. hominis. Complex responses to scabies mites in the innate, humoral, and cellular immune systems can cause skin inflammation and pruritus. Diagnosis can be challenging because scabies resembles other common skin conditions. We report the first Korean case of scabies in a hematopoietic cell transplant (HCT) recipient, initially suspected of skin graft versus host disease (GVHD). A T-cell acute lymphocytic leukemia patient underwent a sibling-matched allogeneic HCT and developed pruritus after cell engraftment. Treatment for GVHD did not improve the symptoms. He was diagnosed with scabies 30 days after the onset of symptoms. PMID- 30428646 TI - Poor prognostic factors in human papillomavirus-positive head and neck cancer: who might not be candidates for de-escalation treatment? AB - Background/Aims: Since patients with human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) have favorable outcomes after treatment, treatment de-escalation for these patients is being actively investigated. However, not all HPV-positive HNSCCs are curable, and some patients have a poor prognosis. The purpose of this study was to identify poor prognostic factors in patients with HPV-positive HNSCC. Methods: Patients who received a diagnosis of HNSCC and tested positive for HPV from 2000 to 2015 at a single hospital site (n = 152) were included in this retrospective analysis. HPV typing was conducted using the HPV DNA chip assay or liquid bead microarray system. Expression of p16 in the tumors was assessed by immunohistochemistry. To determine candidate factors associated with overall survival (OS), univariate and multivariable Cox regression analyses were performed. Results: A total of 152 patients with HPV positive HNSCC were included in this study; 82.2% were male, 43.4% were current or former smokers, and 84.2% had oropharyngeal cancer. By univariate analysis, old age, performance status >= 1, non-oropharyngeal location, advanced T classification (T3-4), and HPV genotype 18 were significantly associated with poor OS. By multivariable analysis, performance status >= 1 and non-oropharyngeal location were independently associated with shorter OS (hazard ratio [HR], 4.36, p = 0.015; HR, 11.83, p = 0.002, respectively). Furthermore, HPV genotype 18 positivity was also an independent poor prognostic factor of OS (HR, 10.87, p < 0.001). Conclusions: Non-oropharyngeal cancer, poor performance status, and HPV genotype 18 were independent poor prognostic factors in patients with HPV positive HNSCC. Patients with these risk factors might not be candidates for de escalation treatment. PMID- 30428647 TI - Development of an acute pancreatitis porcine model based on endoscopic retrograde infusion of contrast medium or sodium taurocholate. AB - Background/Aims: A reproducible, endoscope-based, large animal model, of acute pancreatitis was developed to meet the need for a suitable means of preclinically testing treatments. The aim of this study was to develop an endoscope-based animal model of acute pancreatitis. Methods: This experimental study was conducted on six mini-pigs. The pancreatitis model was induced by infusing contrast medium (CM) or sodium taurocholate (TCA) under high pressure (100 mmHg) into the main pancreatic duct by endoscopic retrograde pancreatography. Animals were randomly allocated to three groups: a CM group, a 10% TCA group, and a 20% TCA group. Pancreatic injuries were evaluated histologically, and serum amylase and lipase levels were measured. Results: Acute pancreatitis was observed in all animals during hematologic and histologic examinations. Serum amylase and lipase levels were significantly higher (> 10 times baseline), and pancreatic edema, vacuolization of acinar cells, and hemorrhagic necrosis were observed. Severity of pancreatitis tended to be greater in the TCA groups than in the CM group as assessed using histologic scores, and degrees of pancreatitis were found to be dose-dependently related to TCA concentration. Conclusions: The two endoscopic procedures described are effective and safe for creating a swine model of acute pancreatitis. The authors hope the described endoscopic methods will assist in the development of a suitable treatment strategy. PMID- 30428648 TI - Association between blood pressure, inflammation and spirometry parameters in chronic obstructive pulmonary disease. AB - Background/Aims: Many systems including the cardiovascular system (ischemic heart diseases, heart failure, and hypertension) may act as comorbidities that can be seen during the course of chronic obstructive pulmonary disease (COPD). Comorbidities affect the severity and prognosis of COPD negatively. Nearly 25% of patients with COPD die due to cardiovascular diseases. In this study, we aimed to evaluate the relationship between the blood pressure, inflammation, hypoxia, hypercapnia, and the severity of airway obstruction. Methods: We included 75 COPD patients in the study with 45 control cases. We evaluated age, sex, body mass index, smoking history, C-reactive protein levels, 24-hour ambulatory blood pressure Holter monitoring, arterial blood gas, and respiratory function tests of the patient and the control groups. Results: In COPD patients, the night time systolic, diastolic blood pressures and pulse per minute and the mean blood pressures readings were significantly elevated compared to the control group (p < 0.05). In the correlation analysis, night time systolic pressure was associated with all the parameters except forced expiratory volume in 1 second (FEV1%). Diastolic blood pressure was associated with pH and HCO3 levels. The mean night time, day time pulse pressures and 24- hour pulse per minute values were also associated with all the parameters except FEV1%. Conclusions: In this study we found that parameters of systolic and diastolic blood pressures and pulse pressures were significantly elevated in COPD patients compared to the control groups. Blood pressure was associated blood gas parameters and inflammation parameters in COPD patients. This, in turn, may cause understanding of the pathophysiology of COPD and its complications. PMID- 30428649 TI - Photodynamic therapy activated by intense pulsed light in the treatment of actinic keratosis. AB - BACKGROUND: Actinic keratosis (AK), a hyperkeratotic lesion induced by solar exposure, is the precancerous lesion that most frequently develops into squamous cell carcinoma. Cryotherapy, topical fluorouracil 5, topical diclofenac 3% gel and, more recently, ingenol mebutate are used in addition to surgery. However, these treatments have varying degrees of effectiveness and are not always tolerated due to side effects. In recent years, Photodynamic Therapy (PDT), has asserted itself as a new effective and safe method for the treatment of actinic keratoses with almost no side effects. The aim of this study is to verify whether a third treatment may now be added to the "Conventional -PDT" and "Daylight-PDT": PhotoDynamic Therapy activated by Intense Pulsed Light (IPL-PDT). METHODS: 31 patients, 24 males and 7 females, in most cases elderly, were included in the trial. As in the previous methods, also in IPL-PDT, 5-methylaminolevulinic acid (MAL) was applied topically for a period of 3 hours. Thereafter, the occlusive dressing and the topical cream, were removed and the neoformation was irradiated with IPL, with a 640nm filter with variable power. Irradiation was performed in single or multiple sessions, depending on the type of keratosis, to completely cover the lesion and the apparently healthy surrounding areas, i.e. the cancerization field. RESULTS: Results were evaluated 3, 6 and 9 months after treatment. Treatment achieved a 95% complete clearance rate, with a 5% partial relapse 9 months after the last treatment. CONCLUSIONS: The above method is a valid alternative to methods already in use. The results obtained demonstrate the efficacy and tolerability of the treatment described which, due to its versatility and speed of use, is preferable to the methods used so far. PMID- 30428650 TI - Blastomycosis-like pyoderma: a diagnostic as well as therapeutic challenge. PMID- 30428651 TI - Ixekizumab for treatment of moderate to severe plaque psoriasis: real world clinical experience. AB - BACKGROUND: Data concerning clinical experience in real world setting with ixekizumab for psoriasis are still exiguous and aim of this report is to provide our experience in the use of ixekizumab in out-patient setting. METHODS: Fifteen Caucasian individuals (10 male, 5 females; mean age 58.1; range 30-75 years) affected by moderate to severe plaque psoriasis (PASI>=10 e/o DLQI>=10 e/O BSA>=10) were treated with Ixekizumab, following dosing regimen of technical data sheet and clinically evaluated both after 4 weeks (T4) and 12 weeks (T12) after. At baseline median PASI was 16.3 (range 10 -30, SD 6.0). The median BSA was 21.3 (10 - 35, SD 7.0), the median PGA was 3.4 (2 - 6, SD 1.2), the median DLQI was 18.6 (14 - 25, SD 3.6), the median m-NAPSI was 42.0 (30-56, SD 13.11). The median absolute value of PASI, BSA, PGA, DLQI and m-NAPSI showed a statistically significant decrease (p<0.05) already after 4 weeks of treatment, to testify tratment effectiveness. RESULTS: At T4, 93.3% of the patients reached PASI 50, 6.9% reached PASI75; at T12 100% ofthe patients reached PASI50, 80% reached PASI75, 13% reached PASI 90 and 6.9% reached PASI 100. One-third of observed patients reached MDA after 12 weeks of treatment. Injection site reactions were the only side effects occurring during the first 12 weeks of treatment. CONCLUSIONS: Our preliminary results seem to confirm the efficacy and safety profile provided through the UNCOVER pivotal trials (UNCOVER 1-3) although further larger observational studies are needed. PMID- 30428652 TI - Estimation of direct costs of melanoma in the Veneto Region: a budget assessment and cost-consequence analysis. AB - BACKGROUND: While many evidence-based pathways have been introduced to drive quality improvements in cancer care, most of these do not include evidence about their affordability. The main aim of this study is to provide an estimation of the overall budget to cover all the needs of melanoma patients in Veneto Region, managed according to the clinical pathway defined by the Rete Oncologica Veneta. A second objective is to conduct a cost-consequence analysis, comparing two different treatments. METHODS: A very detailed whole-disease model was developed describing the patient's pathway from diagnosis through the first year of follow up. Each procedure involved in the model was associated with a likelihood measure and a cost. The model can be used to estimate the expected direct costs associated with melanoma. RESULTS: We can observe that 0 and I stage, despite accounting for a huge percentage of new melanoma cases are characterized by a small percentage of the total costs. Stage III can be considered as the most expensive stage accounting for 54% of the total costs with a 12% of patients. Finally, the stage IV patients, although very few account for almost the 7% of the total costs. Regarding the cost-consequence analysis, it was estimated that the therapies introduced in 2016 led to an approximately 14% increase in the total costs. CONCLUSIONS: Modeling a clinical pathway with a high level of detail enables to identify the main sources of spending. The consequent analysis can thus help policy-makers to plan the future resources allocation. PMID- 30428653 TI - A case of chronic disseminated lupus erythematous in a psoriatic patient receiving ustekinumab. PMID- 30428654 TI - Pityriasis versicolor with uncommon localizations: a case report. PMID- 30428655 TI - Ectopic axillary breast tissue appeared in pregnancy and revealed by ultrasound. PMID- 30428656 TI - Patient-reported outcomes in dermatology research and practice. PMID- 30428657 TI - Unique facial cutaneous metastasis as the primary presentation of an unexpected voluminous renal cell carcinoma. PMID- 30428658 TI - Isomorphic Koebner's phenomenon or isotopic wolf's phenomenon? PMID- 30428659 TI - Extended favre-racouchot syndrome. PMID- 30428660 TI - Contact dermatitis and atopic dermatitis- Two tales, an interwoven story. AB - Atopic dermatitis is a multifactorial disease that can concomitantly occur with irritant and allergic contact dermatitis. The colloquial use of atopic dermatitis and eczema interchangeably has created confusion among patients and providers alike. Atopic skin is a complex entity that involves a defective barrier and biome, an aberrant immune response, and abnormal neural activation, while eczema is a generalized term denoting a particular appearance common to multiple diagnoses including atopic dermatitis and contact dermatitis. The conventional paradigm that simplifies atopic dermatitis and allergic contact dermatitis into distinct Th2 and Th1 processes, respectively, fails to acknowledge potential immunologic intersection points and contributes to impaired disease management. This article will review the complex interplay of atopic dermatitis and contact dermatitis and discuss treatment strategies for recalcitrant cases. PMID- 30428661 TI - Endovascular treatment for the common femoral artery: is there a challenger to open surgery? AB - Common femoral artery (CFA) atherosclerotic lesions currently remain one of the last limitations for adoption of endovascular repair as the first-line treatment. The bulky, eccentric, heavily calcified character of the CFA plaques, frequent involvement of the femoral bifurcation, easy surgical accessibility and last but not least, favorable long-term outcomes (1,2) still make CFA disease treatment part of the surgical domain. In the last 5 years, improvement of the endovascular equipment and technical skills of the operators have led to an increase in percutaneous CFA procedures. Especially the vascular mimetic implant Supera Peripheral Stent system (Abbott Vascular), with its extreme crush resistance (if correctly implanted), seems to be an ideal tool to deal with eccentric calcified plaques, crush risk and maintaining access possibilities. The multicentric, prospective, single arm VMI-CFA trial evaluates the outcome of treatment of symptomatic (Rutherford 2-4) CFA stenotic or occlusive lesions with the Supera Peripheral Stent System. A 6 months cumulative primary patency rate of 100% is noticed, up to 210 days. The cumulative freedom from TLR rate is 100%. Four patients died, not procedure or device related. From a clinical point of view, a tremendous switch from Rutherford 2-4 towards Rutherford 0-1 happened. No procedure nor device related adverse events are noticed. These short-term data confirm the safety and feasibility of an endovascular approach with the Supera stent to the "no-stent zone" CFA. Of course 12- and 24-month data are essential to bring more clarification in this interesting field. PMID- 30428662 TI - Construction of Multishelled Binary Metal Oxides via Coabsorption of Positive and Negative Ions as a Superior Cathode for Sodium-Ion Batteries. AB - Multishelled binary metal oxide, which can exert a synergetic effect of different oxides, is a promising electrochemical electrode material. However, it is challenging to synthesize this kind of binary metal oxide due to the severe hydrolysis and/or precipitation reactions of the precursors between cations and anions of different metals. Herein, by using citric acid as a chelating agent to inhibit hydrolysis and precipitation, a series of multishelled binary metal oxide hollow spheres (Fe2(MoO4)3, NiMoO4, MnMoO4, CoWO4, MnWO4, etc.) were obtained via coabsorption of negative and positive metal ions. In addition, the chelation between a metal ion and citric acid is systematically validated by NMR, MS, Raman, and UV-vis. In particular, multishelled Fe2(MoO4)3 hollow spheres show excellent electrochemical performance as cathode material for sodium-ion batteries benefited from their structural superiorities. Especially, the quintuple-shelled Fe2(MoO4)3 hollow sphere shows the highest specific capacity (99.03 mAh g-1) among all Fe2(MoO4)3 hollow spheres, excellent stability (85.6 mAh g-1 was retained after 100 cycles at a current density of 2.2 C), and outstanding rate capability (67.4 mAh g-1 can be obtained at a current density of 10 C). This general approach can be extended to the synthesis of other multishelled multielement metal oxides and greatly enrich the diversity of hollow multishelled structures. PMID- 30428663 TI - Determination of Structural Ensembles of Proteins: Restraining vs Reweighting. AB - The conformational fluctuations of proteins can be described using structural ensembles. To address the challenge of determining these ensembles accurately, a wide range of strategies have recently been proposed to combine molecular dynamics simulations with experimental data. Quite generally, there are two ways of implementing this type of approach, either by applying structural restraints during a simulation, or by reweighting a posteriori the conformations from an a priori ensemble. It is not yet clear, however, whether these two approaches can offer ensembles of equivalent quality. The advantages of the reweighting method are that it can involve any type of starting simulation and that it enables the integration of experimental data after the simulations are run. A disadvantage, however, is that this procedure may be inaccurate when the a priori ensemble is of poor quality. Here, our goal is to systematically compare the restraining and reweighting approaches and to explore the conditions required for the reweighted ensembles to be accurate. Our results indicate that the reweighting approach is computationally efficient and can perform as well as the restraining approach when the a priori sampling is already relatively accurate. More generally, to enable an effective use of the reweighting approach by avoiding the pitfalls of poor sampling, we suggest metrics for the quality control of the reweighted ensembles. PMID- 30428664 TI - High Resolution Thermochemical Study of Phase Stability and Rapid Oxygen Incorporation in YBaCo4-xZnxO7+delta 114-Cobaltites. AB - The formation thermodynamics of YBaCo4-xZnxO7+delta (x = 0, 1 and 3) oxides was determined by high temperature oxide melt solution calorimetry. All the studied oxides are thermodynamically metastable due to the tendency of cobalt to increase oxidation state under oxidizing conditions as well as to significant bond valence sum mismatch for Ba and Y in 114-oxides. Complex phase evolution in YBaCo4O7+delta at 350 - 400 degrees C upon oxygen absorption was revealed using incremental precise oxygen dosing. The calorimetric results support phase changes seen during in situ X-ray diffraction structural studies and provide high resolution measurement of the amount and energetics of oxygen absorbed by YBaCo4 xZnxO7+delta under equilibrium conditions. PMID- 30428665 TI - Recent Advances in Anti-cancer Protein/Peptide Delivery. AB - Protein/peptide drugs possess unique advantages, such as high pharmacological potency, molecular specificity, multifunctionality, and low toxicity, and thus hold great potential for use in cancer therapy. In the past decades, great achievements have been made in protein delivery systems, which can protect cargo proteins against detrimental physiological environments and efficiently deliver proteins into tumor sites and cells. In this Review, we first summarize the existing protein/peptide drugs used for cancer treatment, illustrate their anti tumor mechanisms, and point out the potential challenges/barriers against their medical utility. We then discuss the existing strategies for protein encapsulation/conjugation and survey recent advances in the development of protein delivery vehicles, including lipid-based membrane nanocarriers, polymeric carriers, metal-organic frameworks, inorganic carriers, protein/peptide-based nanocarriers, and DNA nanostructures. The design strategies, advantages in potentiating protein delivery efficiencies, and possible limitations of these delivery systems are also discussed. Finally, future opportunities and challenges in anti-cancer protein/peptide delivery are indicated. PMID- 30428666 TI - Interfacing Pathogen Detection with Smartphones for Point-of-Care Applications. AB - Infectious diseases are clinically relevant, transmissible illnesses caused by microorganisms, such as bacteria, viruses, fungi, and parasites. According to a recent report, between 1980 and 2014 more than four million people in the USA have died from various infectious diseases.1 Accurate and timely detection of infection and identification of the causative pathogen are crucial in disease prevention, treatment and monitoring.2,3 Although reliable methods of pathogen detection are well and long established, many of such detection and diagnostics techniques are still limited in use to clinical laboratories due to the need for trained and skilled personnel, and sophisticated diagnostic instruments. Accordingly, there is a pressing need for simple, affordable, and easy-to-use diagnostic tools for the specific detection of pathogens at the point of care, e.g., doctors' offices, clinics, infirmaries, and particularly in resource limited areas where medical infrastructure is lacking. PMID- 30428667 TI - Effect of Electron-Nuclear Hyperfine Interactions on Multiple-Quantum Coherences in Photogenerated Covalent Radical (Qubit) Pairs. AB - Ultrafast photodriven electron transfer reactions starting from an excited singlet state in an organic donor-acceptor molecule can generate a spin correlated radical pair (RP) with an initially entangled spin state that may prove useful as a two-qubit pair in quantum information protocols. Here we investigate the effects of modulating electron-nuclear hyperfine coupling by rapidly transferring an electron between two equivalent sites comprising the reduced acceptor of the RP. A covalent electron donor-acceptor molecule including a tetrathiafulvalene (TTF) donor, a 4-aminonaphthalene-1,8-imide (ANI) chromophoric primary acceptor, and an m-xylene bridged cyclophane having two equivalent pyromellitimides (PI2), TTF-ANI-PI2, as a secondary acceptor was synthesized along with an analogous molecule having one pyromellitimide (PI) acceptor, TTF-ANI-PI. Photoexcitation of ANI within each molecule results in sub nanosecond formation of TTF+*-ANI-PI-* and TTF+*-ANI-PI2-*. The effect of reducing electron-nuclear hyperfine interactions in TTF+*-ANI-PI2-* relative to TTF+*-ANI-PI-* on decoherence of multiple-quantum coherences has been measured by pulse-EPR spectroscopy. This contribution is especially relevant in the absence of modulation of exchange or dipolar interactions, as with the RP at a fixed distance in the molecules in this work. The theoretical prediction of the contribution from an ensemble of hyperfine interactions to decoherence in these RPs is shown to be less than the full width at half-maximum of the quantum beat frequencies measured experimentally. Pulse bandwidth and off-resonant excitation by square microwave pulses are proposed as larger contributors to decoherence in these molecules than the hyperfine interactions, and specific pulse shapes relevant to arbitrary waveform generation are introduced. PMID- 30428668 TI - Complete Generation of a 129Xe Biosensor on the Solid Support by Systematic Backbone Assembly. AB - Xenon biosensors are an emerging tool for different molecular imaging approaches. For many applications, their development requires peptide synthesis steps, followed by the selective installation of a xenon host onto the peptide backbone in solution. In this study, three different strategies were attempted for generating entire Xe biosensors on the solid support. Notably, one strategy involving CryA-da was beneficial by directly integrating this host into the growing construct on a low loaded resin via modification of the administered subcomponent equivalents and by prolonging the coupling procedure. Subsequently, installation of additional amino acids or of additional labels onto the growing construct was achieved by a procedure in which an excess amine was administered to the activated CryA-da (acid) anchored onto the resin. Further, the as generated Xe biosensor was tested for its NMR and MRI capabilities in H2O and compared to the performance of CryA-ma. Xe NMR of the biosensor indicated a clear CEST response and the Xe MR images revealed similar contrast compared to the reference host. These observations suggest that functionalizing CryA-da on both sides with multiple labels did not alter significantly its NMR capabilities. Hereby, we could show the successful and complete synthesis of a CryA-da-based xenon biosensor on the solid support without any notable side reactions and without the necessity of multiple purification steps. PMID- 30428669 TI - Specific Ion Effects in Polyampholyte Hydrogels Dialyzed in Aqueous Electrolytic Solutions. AB - Polyampholyte hydrogels (PAHs) constitute a class of physical gels with cross linking originating from inter- and intrachain ionic cross-linking between countercharged functional groups. In our previous report, we have shown that PAH has the potential to be a gel electrolyte in electrochemical energy storage devices. In this work, we further our understanding of charge-balanced PAH as a host material for gel electrolytes by studying the effect of dialysis on the mechanical properties and ionic conductivities of PAHs, whereas these properties are compared with those of poly(vinyl alcohol) (PVA)-based gel electrolytes. Here, various electrolyte solutions were investigated as dialyzing agents. The ionic species in the electrolytes form ion pairs with countercharged functional groups in PAH, whereas such interactions govern the ionic conductivity and mechanical strength of PAH in various electrolytes. For anions, the trend in ionic interactions follows the Hofmeister series in an exact manner, whereas some anomaly is observed among cations. We anticipate that our study provides a design criterion for fabricating gel electrolytes. In a broader context, this work can shed light on understanding the behavior of PAHs in various operational environments, such as under physiological conditions and in antifouling coatings for biomedical and maritime applications, respectively. PMID- 30428670 TI - Recent Advances in Petroleum Analysis by Mass Spectrometry. PMID- 30428671 TI - Uniform Symmetric and Asymmetric Polymer Nanostructures via Directed Chain Organization. AB - Polymer nanostructures can be designed with specific properties and functions, such as controlled shape, size, chemical composition, and adaptive ability to change shape or size in response to environmental cues. Precise control to organize polymer chains into uniform nonspherical symmetric and asymmetric nanostructures and at scale remains a synthetic challenge. Here, by using the temperature-directed morphology transformation (TDMT) method we show through a systematic organization of polymer chains the synthesis of well-defined asymmetric (i.e., tadpole) and symmetric (i.e., worm) nanostructures in water at high polymer concentrations. This method further allowed the production of tadpoles with controlled and uniform tail lengths, ranging from 200 to 800 nm. The organization of chains could be driven by environmental conditions to produce adaptive nanostructure systems. PMID- 30428672 TI - Structural Tunability of Multicompartment Micelles as a Function of Lipophilic Fluorophilic Block Length Ratio. AB - Structural variation in multicompartment micelles consisting of lipophilic hydrophilic-fluorophilic (hereafter referred to as BAC) triblock copolymers is investigated using the dissipative particle dynamics simulation method. It is demonstrated from our results that the structure of BAC multicompartment micelles is effectively tuned as a function of the lipophilic-fluorophilic ratio parameter, here termed [Formula: see text], of the constituent linear triblock copolymers. In particular, a morphological deviation from onion-like ABC micelles arises in BAC micelle systems as [Formula: see text] increases. The morphologies of BAC micelles with [Formula: see text] or [Formula: see text] display striking similarities, with the only notable difference being an inversion of the lipophilic and fluorophilic regions. When [Formula: see text], segmented worm like structures with multiple cores are favored in BAC micelle systems. Through this study, it is confirmed that the block length ratio is an effective control parameter to tune the structure of multicompartment micelles. PMID- 30428673 TI - Mechanistic and Synthetic Implications of the Diol-Ritter Reaction: Unexpected Yet Reversible Pathways in the Regioselective Synthesis of Vicinal-Aminoalcohols. AB - The Ritter reaction of 1,2-diolmonoesters with nitriles to 1- vic-amido-2-esters proceeds through dioxonium and nitrilium cation intermediates. To provide the basis for the reaction mechanism, novel forms of these cations were isolated, characterized, and studied by spectroscopic methods and single crystal X-ray analysis. Ground and transition state energies were determined both experimentally and theoretically. Taken together, these data suggest that the reaction proceeds via rapid formation of the dioxonium cation 9, followed by rate determining yet reversible ring opening by acetonitrile to the corresponding nitrilium cation 10 (computed Delta G? = 24.7 kcal at 50 degrees C). Rapid, irreversible hydration of the latter affords the corresponding vic-acetamido ester. Controlled addition of H2O to the dioxonium cation 9 in acetonitrile- d3 results in near-quantitative production of deuterated acetamido ester 13a. Kinetics of this conversion (9 to 13a) are biphasic, and the slow phase is ascribed to either direct cation 9 attack by acetamide to form cation 16 via O alkylation or by reversible ether formation. Deuterium labeling studies suggest O alkylated cation 16 does not directly isomerize to N-alkylated cation 18; instead, it reverts to vic-amidoester 13a via the nitrilium pathway. Preliminary results indicate high regioselectivity for primary amide formation in the diol Ritter sequence. PMID- 30428674 TI - Thermoresponsive Coatings on Hollow Particles with Mesoporous Shells Serve as Stimuli-Responsive Gates to Species Encapsulation and Release. AB - Nanoscale capsule-type particles with stimuli-respondent transport of chemical species into and out of the capsule are of significant technological interest. We describe the facile synthesis, properties, and applications of a temperature responsive silica-poly( N-isopropylacrylamide) (PNIPAM) composite consisting of hollow silica particles with ordered mesoporous shells and a complete PNIPAM coating layer. These composites start with highly monodisperse, hollow mesoporous silica particles fabricated with precision using a template-driven approach. The particles possess a high specific surface area (1771 m2/g) and large interior voids that are accessible to the exterior environment through pore channels of the silica shell. An exterior PNIPAM coating provides thermoresponsiveness to the composite, acting as a gate to regulate the uptake and release of functional molecules. Uptake and release of a model compound (rhodamine B) occurs at temperatures below the lower critical solution temperature (LCST) of 32 degrees C, while the dehydrated hydrophobic polymer layer collapses over the particle at temperatures above the LCST, leading to a shutoff of uptake and release. These transitions are also manifest at an oil-water interface, where the polymer-coated hollow particles stabilize oil-in-water emulsions at temperatures below the LCST and destabilize the emulsions at temperatures above the LCST. Cryogenic scanning electron microscopy indicates patchlike particle structures at the oil-water interface of the stabilized emulsions. The silica-PNIPAM composite therefore couples advantages from both the hollow mesoporous silica structure and the thermoresponsive polymer. PMID- 30428675 TI - Depleting Depletion: Maintaining Single-Walled Carbon Nanotube Dispersions after Graft-To Polymer Functionalization. AB - Grafting polymers onto single-walled carbon nanotubes (SWCNTs) usefully alters properties but does not typically yield stable, solvated species directly. Despite the expectation of steric stabilization, a damaging (re)dispersion step is usually necessary. Here, poly(vinyl acetate)s (PVAc's) of varying molecular weights are grafted to individualized, reduced SWCNTs at different concentrations to examine the extent of reaction and degree of solvation. The use of higher polymer concentrations leads to an increase in grafting ratio (weight fraction of grafted polymer relative to the SWCNT framework), approaching the limit of random sequentially adsorbed Flory "mushrooms" on the surface. However, at higher polymer concentrations, a larger percentage of SWCNTs precipitate during the reaction; an effect which is more significant for larger weight polymers. The precipitation is attributed to depletion interactions generated by ungrafted homopolymer overcoming Coulombic repulsion of adjacent like-charged SWCNTs; a simple model is proposed. Larger polymers and greater degrees of functionalization favor stable solvation, but larger and more concentrated homopolymers increase depletion aggregation. By using low concentrations (25 MUM) of larger molecular weight PVAc (10 kDa), up to 65% of grafted SWCNTs were retained in solution (at 65 MUg mL-1) directly after the reaction. PMID- 30428676 TI - Percolating Film of Pillared Graphene Layer Integrated with Silver Nanowire Network for Transparent and Flexible Supercapacitors. AB - Transparent and flexible supercapacitors (TFSCs) are viable power sources for next-generation wearable electronics. The ingenious design of the transparent electrode determines the performance of TFSCs. A percolating film of a pillared graphene layer integrated with a silver nanowire network as the transparent electrode was prepared, by which TFSC devices exhibit a significantly improved performance contrastively. Under the condition of the same transmittance, about 27-72% improvement in the areal capacitance can be achieved. On the one hand, the pillars of carbon nanotube (CNT) were distributed in the graphene layer uniformly, enlarging the inner distance of adjacent graphene layers and providing an open structure for extra ion transport and storage of TFSCs. On the other hand, the introduced CNT could facilitate the electron transport at the direction perpendicular to the graphene basal plane, enhancing the electronic conductivity of the graphene layer. More importantly, the formed percolating film ensures an efficient transport of electron along with the silver nanowire when it encounters the obstacle within the graphene layer, resulting in a highly conductive electrode. The TFSC device with a good compatibility indicates a reliable practicability, which provides a facile route toward the design of high performance TFSCs. PMID- 30428678 TI - Spotlights: Volume 9, Issue 22. PMID- 30428677 TI - Atom-by-Atom Construction of a Cyclic Artificial Molecule in Silicon. AB - Hydrogen atoms on a silicon surface, H-Si (100), behave as a resist that can be patterned with perfect atomic precision using a scanning tunneling microscope. When a hydrogen atom is removed in this manner, the underlying silicon presents a chemically active site, commonly referred to as a dangling bond. It has been predicted that individual dangling bonds function as artificial atoms, which, if grouped together, can form designer molecules on the H-Si (100) surface. Here, we present an artificial ring structure molecule spanning three dimer rows, constructed from dangling bonds, and verified by spectroscopic measurement of its molecular orbitals. We found that removing 8 hydrogen atoms resulted in a molecular analog to 1,4-disilylene-hexasilabenzene (Si8H8). Scanning tunneling spectroscopic measurements reveal molecular pi and pi* orbitals that agree with those expected for the same molecule in a vacuum; this is validated by density functional theory calculations of the dangling bond system on a silicon slab that show direct links both to the experimental results and to calculations for the isolated molecule. We believe the unique electronic structure of artificial molecules constructed in this manner can be engineered to enable future molecule based electronics, surface catalytic functionality, and templating for subsequent site-selective deposition. PMID- 30428679 TI - Successful Advance Care Planning in a Rural Nursing Home. AB - BACKGROUND:: Advance care planning (ACP) often culminates in the completion of advance care directives (ACD), which is a written record of informed decisions specifying the type and extent of desired medical treatment. Documentation of ACD in nursing homes in the United States indicates a 60% to 70% completion rate. There are little data on the time at which ACD are completed in relation to when the resident was admitted to the nursing home facility. OBJECTIVE:: To explore the success of advanced care planning at a large, rural long-term care (LTC) facility. METHODS:: A descriptive approach, using a retrospective chart review, of 167 residents was used to examine resident completion of health-care system documents, legal documents, predisposing factors (resident demographics and psychosocial characteristics), and the actual process of ACP as defined by the rural LTC facility. RESULTS:: This nursing home utilizes a document entitled resident preference for life-sustaining treatment (RPLST). For residents who do not have formal prepared advance directive documents, the RPLST serves to define resident and family choices for resuscitation and implementation of fluids, nutrition, medications, and antibiotics. The most striking finding was the completion rate of the RPLST within 100 days of being admitted to the nursing home. CONCLUSION:: Documentation of end-of-life preferences within 10 days of admission was achieved through the incorporation of RPLST during the resident admission process. PMID- 30428680 TI - Hospice Bereavement Service Delivery to Family Members and Friends With Bereavement-Related Mental Health Symptoms. AB - OBJECTIVES:: A sizable minority of those who lose a loved one in hospice will experience symptoms of bereavement-related mental health disorders. Though hospices offer services to bereaved informal caregivers (family members or friends) of patients, little is known about services offered or interest in them. Therefore, we sought to assess services offered by hospice staff and interest expressed by bereaved informal caregivers with symptoms of depression, anxiety, or complicated grief (CG). METHODS:: De-identified electronic bereavement care charts of 3561 informal caregivers who lost someone in a large urban metropolitan hospice from October 1, 2015, to June 30, 2016, were reviewed. RESULTS:: Of bereaved informal caregivers in the sample, 9.4% (n = 333) were positive for symptoms of depression, anxiety, or CG. The symptom-positive family members/friends were more likely than other family members/friends to be offered mailings, one-to-one counseling, telephone calls, and reference material. However, interest in most services by symptom-positive caregivers was low, with only 6% interested in one-to-one counseling and 7% interested in outside referral. DISCUSSION:: The findings suggest that hospices offer a range of services to family members or friends with symptoms of anxiety, depression, and CG, but that there can be a gap between what is offered and in the interest levels of the bereaved. Engagement with symptomatic family members and friends could be enhanced in future work. PMID- 30428681 TI - Public Health Implications of Google Searches for Sunscreen, Sunburn, Skin Cancer, and Melanoma in the United States. AB - PURPOSE:: Google Trends (GT) offers insights into public interests and behaviors and holds potential for guiding public health campaigns. We evaluated trends in US searches for sunscreen, sunburn, skin cancer, and melanoma and their relationships with melanoma outcomes. DESIGN:: Google Trends was queried for US search volumes from 2004 to 2017. Time-matched search term data were correlated with melanoma outcomes data from Surveillance Epidemiology and End Results Program and United States Cancer Statistics databases (2004-2014 and 2010-2014, respectively). SETTING:: Users of the Google search engine in the United States. PARTICIPANTS:: Google search engine users in the United States. This represents approximately 65% of the population. MEASURES:: Search volumes, melanoma outcomes. ANALYSIS:: Pearson correlations between search term volumes, time, and national melanoma outcomes. Spearman correlations between state-level search data and melanoma outcomes. RESULTS:: The terms "sunscreen," "sunburn," "skin cancer," and "melanoma" were all highly correlated ( P < .001), with sunscreen and sunburn having the greatest correlation ( r = 0.95). Sunscreen/sunburn searches have increased over time, but skin cancer/melanoma searches have decreased ( P < .05). Nationally, sunscreen, sunburn, and skin cancer were significantly correlated with melanoma incidence. At the state level, only sunscreen and melanoma searches were significantly correlated with melanoma incidence. CONCLUSIONS:: We conclude that online skin cancer prevention campaigns should focus on the search terms "sunburn" and "sunscreen," given the decreasing online searches for skin cancer and melanoma. This is reinforced by the finding that sunscreen searches are higher in areas with higher melanoma incidence. PMID- 30428682 TI - Palliative Care for Inmates in the Hospital Setting. AB - The US population of inmates continues to increase along with a rapid escalation in the number of elderly prisoners. Previous studies have demonstrated multiple barriers to providing palliative care for seriously ill inmates. The aim of this study was to assess the frequency of palliative care consultation and nature of consultation requests for inmates who died while hospitalized at a large tertiary care hospital. A retrospective chart review of all inmate decedents over a 10 year time period was conducted. The reason and timing of consultation was noted in addition to symptoms identified and interventions recommended by the palliative care team. Characteristics of patients who were transferred to the inpatient palliative care unit were also recorded. Forty-five percent of inmates were seen by palliative care prior to their death. Timing of consultation was close to the day of death. Inmates with cancer were significantly more likely to have a palliative care consultation prior to death. The most frequent intervention recommended was opiates for pain or dyspnea. Delirium was often missed by the primary team but was identified by the palliative care team. Nearly, 5000 prisoners die each year, mostly in community hospitals. These patients exhibit similar symptoms to free-living patients. Given that the inmate population has a higher rate of comorbid conditions, there is a need for more research to identify areas of need for incarcerated patients and where palliative care can best serve these individuals. PMID- 30428683 TI - Evaluation of QTc Interval Prolongation Among Patients With Cancer Using Enteral Methadone. AB - CONTEXT:: The effect of methadone on corrected QT interval (QTc) in patients with cancer pain is not well-known. OBJECTIVES:: To describe and characterize the effect of low-, moderate-, and high-dose enteral methadone on QTc interval in patients with cancer. METHODS:: Retrospective cohort study including patients prescribed enteral methadone during the 27-month study period. Participants were divided into 3 methadone daily dose groups: <30 (low dose), 30 to 59 (moderate dose), >=60 (high dose) mg. The primary outcome was the incidence of QTc prolongation (>450 ms for females and >430 ms for males). Secondary outcomes included the magnitude of change in QTc after starting methadone, the incidence of clinically significant QTc prolongation (>500 ms) and the prevalence of torsades de pointes and syncope. RESULTS:: Two hundred three patients met study inclusion criteria: 91 (45%) low dose, 52 (26%) moderate dose, and 60 (29%) high dose. Incidence of QTc prolongation for low-, moderate-, and high-dose groups was 50 (55%), 37 (71%), and 43 (72%), respectively ( P = .039, low vs high dose). Incidence of clinically significant QTc prolongation was 10 (11%), 4 (8%), and 7 (12%) for low-, moderate-, and high-dose groups. For patients without QTc prolongation prior to initiating methadone, 62% of moderate-dose patients and 67% of high-dose patients had QTc prolongation, while taking methadone. CONCLUSION:: This study found a notably high incidence of QTc prolongation in patients with cancer using enteral methadone. Future studies should aim to determine the risk of adverse cardiac effects in the cancer population and determine appropriate monitoring of methadone for pain management. PMID- 30428684 TI - French Adaptation and Validation of the Expanded Version of the Three-Factor Levenson Self-Report Psychopathy Scale. AB - The goal of this study ( N = 432 participants from a community sample) is to report on the psychometric properties of a French adaptation of the Expanded Version of the Three-Factor Levenson Self-Report Psychopathy Scale (E-LSRP), which was developed to alleviate some shortcomings of the original LSRP. A three correlated factor exploratory structural equation modeling model showed the best fits and attained satisfactory indices. There were significant, conceptually meaningful associations with measures of Dark Triad traits, pathological narcissism, empathy, impulsivity, substance misuse, and social desirability. Incremental validity over a 19-item scale proposed by Brinkley et al. was also mostly demonstrated, especially for convergent validity. Overall, the French E LSRP possesses sound psychometric properties, comparable for the most part with the original instrument, and should be seen as a useful measure of psychopathic traits in community samples. PMID- 30428686 TI - Comment: Inhaled Epoprostenol Through Noninvasive Routes of Ventilator Support Systems. PMID- 30428685 TI - Reply: Inhaled Epoprostenol Through Noninvasive Routes of Ventilator Support Systems. PMID- 30428687 TI - How to address the needs of non-responders to REACH VA: a qualitative analysis. AB - OBJECTIVE: This study used qualitative methods to understand how to further alleviate symptoms of depression and caregiver burden and address the needs of non-responders following a course of Resources for Enhancing Alzheimer's Caregiver Health in VA (REACH VA). METHODS: Semi-structured interviews with caregivers and interventionists post-treatment were coded for themes related to ways to address the needs of non-responder caregivers. RESULTS: The following suggestions recurred among non-responder caregivers and interventionists: (1) tailor skills and psychoeducation material to caregiver's needs; (2) provide greater overall support within the realm of caregiving; (3) explore and process caregiver's emotions around caregiving experience and grief; (4) address interpersonal difficulties and barriers to asking for help; (5) spend more time practicing skills to aid in implementing them at home. CONCLUSIONS: For many non responders, a longer-term treatment targeting caregivers' emotional processing, interpersonal skills, social connection, acquisition and implementation of skills is indicated. PMID- 30428688 TI - Measuring empowerment among people living with HIV: a systematic review of available measures and their properties. AB - A systematic review was conducted to identify and appraise measures of empowerment used in peer-reviewed research with people living with HIV. Thirty articles reporting on 12 scales were identified via keyword and citation searches of electronic databases and hand searching of reference lists. The instruments captured a wide range of constructs, including self-efficacy, perceived knowledge/information seeking, self-management behaviours, belief in an active patient role and tolerance of uncertainty. While the majority of instruments were focused exclusively on self-efficacy to manage HIV, the Patient Activation Measure (PAM-13 and PAM-22) and the Health Empowerment Inventory were broader in scope. Most of the identified measures had acceptable construct validity, however there were insufficient data to determine the reliability or responsiveness of many of the scales. The findings highlight the need for a more concrete definition of empowerment and for further validation of existing measures with people living with HIV. PMID- 30428689 TI - Inclusive and emancipatory approaches to occupational therapy practice in substance-use contexts. AB - BACKGROUND.: Occupational therapy practice is enhanced through clear understanding of its epistemological foundations. In the area of substance use, practices are strongly functionalist. PURPOSE.: This study unearths epistemologies through analyzing practices addressing the social needs of clients with problematic substance use. METHOD.: This study used an exploratory qualitative approach and was based on Marxist philosophies. Qualitative interviews were conducted with nine occupational therapists experienced in working with substance users. Data were analyzed through a dialectic approach to content analysis based on the Marxist theory of labour process. FINDINGS.: The occupational therapy practices were found to follow common principles: clients are agents of transformation in health processes; creativity is a strong element of practice and underlies the whole therapeutic process; and conditions of social reproduction compose the object of occupational therapy (i.e., what is transformed through occupational therapy practices). Two different approaches using these principles were uncovered according to the labour-process purposes: inclusive and emancipatory. IMPLICATIONS.: Systematization of practices based on epistemological foundations strengthens occupational therapists' ability to link actions to theories. PMID- 30428690 TI - A framework for occupational enablement to facilitate social change in community practice. AB - BACKGROUND.: Community practice in occupational therapy is becoming increasingly relevant worldwide. Moreover, a social-change approach focusing on occupational enablement is pertinent in community practice as occupational therapists endeavour to promote health, well-being, and occupational justice in communities. PURPOSE.: Drawing on theory from the fields of community development, community engagement, and occupational enablement, and based on the findings of a previous empirical, qualitative study, a framework for occupational enablement in community practice was developed. KEY ISSUES.: This article presents the background to the development of the framework, after which the framework is introduced and discussed in terms of the composition, relevance, and application of its components. The framework details outcomes and objectives that may be targeted and activities that may be utilized successfully during occupational therapy community practice engagements. It further illuminates facilitators of enablement related to contextual factors, stakeholders, and strategies that enhance the potential for enabling community practice engagements. IMPLICATIONS.: This framework can provide a strategic management guideline for occupational therapists and students who engage with communities in endeavours such as community development and service learning. PMID- 30428691 TI - The development of an end-to-end service solution to support lupus patients and improve their experience in clinical trials. AB - OBJECTIVE: To develop an end-to-end clinical trial service to improve patient experience during trials, reduce the burden of participating in a trial, and increase trial retention. METHODS: A literature search and stakeholder interviews were used to identify current challenges and unmet needs of systemic lupus erythematosus patients and other systemic lupus erythematosus clinical trial stakeholders. The results from the literature search and interviews were used to create a five-phase map describing the current clinical trial experience of all stakeholders. A set of proposed solutions were developed to address the identified unmet needs and challenges. These solutions were presented to trial experienced patients and study site personnel; any feedback obtained was used to further refine the solutions. RESULTS: Four site personnel and seven patients from three different systemic lupus erythematosus clinical trial sites were interviewed between September 2015 and December 2015. Key unmet needs and challenges were identified at each stage of the clinical trials. At the screening stage, some patients incorrectly thought they were successfully enrolled into the clinical trial. During enrollment, some patients found it difficult to keep fully informed about the trial and were unable to explain the trial process to loved ones. During the trial, patients struggled to prepare for study visits, felt overwhelmed by the trial process, and wanted someone to talk to for support. Clinical trial site personnel reported current key challenges as: delivering trial information clearly and consistently to patients, setting patient expectations, retaining enrolled patients, and providing non-clinical patient support. To address the needs of patients and site personnel, an end-to-end support service was designed, consisting of nine solutions: My Best Choice, My Eligibility, My Lupus Trial Kit, My Lupus Trial Coach, My Appointment Guide, My Clinic Compass, Our Gratitude, Building a Different Network, and My Next Chapter. CONCLUSION: The solutions proposed in this qualitative study may help improve the systemic lupus erythematosus clinical trial experience for patients, potentially helping to increase trial recruitment and retention. The solutions proposed here would also promote positive patient-trial personnel relationships, which may help site personnel identify patients at risk of early withdrawal, while ensuring that the time and resources of site personnel are used efficiently. PMID- 30428692 TI - Association of glucagon-to-insulin ratio and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. AB - OBJECTIVE:: The aim of this study is to investigate the association between glucagon-to-insulin ratio and the presence of nonalcoholic fatty liver disease on ultrasonography in participants with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS:: This cross-sectional study was performed with data obtained from 172 participants with type 2 diabetes mellitus admitted to a University hospital of Korea. Participants were assessed for serum fasting and postprandial serum glucagon-to-insulin ratio and divided into tertiles. Nonalcoholic fatty liver disease was defined as ultrasonographically detected fatty liver. RESULTS:: Prevalence of nonalcoholic fatty liver disease was significantly decreased across tertile of fasting and postprandial glucagon-to-insulin ratio ( p = 0.009 for trend, p = 0.001 for trend, respectively). Lower glucagon-to-insulin ratio was significantly associated with the presence of nonalcoholic fatty liver disease even after adjustment for potential confounding variables [fasting glucagon-to insulin ratio: odds ratio (95% confidence interval), 2.68 (1.08-6.86)], postprandial glucagon-to-insulin ratio: [2.72 (1.03-7.35)]. The participants in the lowest tertile of fasting glucagon-to-insulin ratio had higher body mass index, visceral fat thickness, subcutaneous fat thickness, homeostasis model assessment-insulin resistance and shorter duration of diabetes mellitus. CONCLUSION:: This study suggests that lower glucagon relative insulin may be independently associated with nonalcoholic fatty liver disease in participants with type 2 diabetes. PMID- 30428693 TI - Systematic Review of Real-World Studies Evaluating Characteristics Associated With or Programs Designed to Facilitate Outpatient Management of Deep Vein Thrombosis. AB - Select patients with acute deep vein thrombosis (DVT) can be managed as outpatients. We sought to conduct a systematic review of real-world studies describing either (1) the clinical characteristics associated with outpatient DVT treatment in all-comers or (2) emergency department (ED) programs designed to facilitate outpatient DVT treatment. MEDLINE and SCOPUS were searched (January 1, 2012, to May 1, 2018) to identify citations meeting the aforementioned criteria. Twenty-one real-world studies were included. The proportion of all-comer patients with DVT managed as outpatients was <=50% in 11 of 15 studies. With the exception of younger age, no characteristics were consistently associated with outpatient treatment across the 13 studies reporting these characteristics. We identified 8 studies describing ED programs aimed at facilitating DVT outpatient treatment, all of which provided education and included measures to encourage early outpatient follow-up after ED discharge. In conclusion, the proportion of patients with DVT managed as outpatients across real-world studies was low. Several ED programs aimed at facilitating this treatment have been described. It is possible that programs similar to these will increase the proportion of patients with DVT that can be safely managed as outpatients. PMID- 30428694 TI - Effect of Platelet GPIIb/IIIa Receptor Blockade With MK383 on Infarct Size and Myocardial Blood Flow in a Canine Reocclusion Model. AB - Platelet activation and aggregation during ischemia influence reperfusion-related myocyte necrosis, myocardial perfusion at the microvascular level, and thereby eventual recovery of cardiac performance. Inhibition of platelet activity therefore represents a worthwhile target to reduce cellular injury. The current study examined the effects of MK383 (tirofiban), a potent inhibitor of platelet aggregation, on infarct size and myocardial perfusion in canine subjects to either reocclusion (ie, 120-minute + 60-minute ischemia with intervening reperfusion) or prolonged occlusion (ie, 3 hours) followed by reperfusion (180 minutes). Platelet aggregation, infarct size (tetrazolium staining), coronary blood flow (flow probe), coronary vascular reserve, and myocardial perfusion (microspheres) were evaluated. MK383, administered at the time of reperfusion, produced a modest reduction of tissue necrosis (compared to saline-treated controls) in the reocclusion and prolonged occlusion studies. Blood flow in the infarct-related artery after coronary occlusion was comparable between treatment groups, as was myocardial perfusion in the deeper layers of the ischemic region; coronary vascular reserve decreased progressively during reperfusion. Of note, compensatory changes in blood flow within the adjacent nonischemic myocardium were not observed. In conclusion, we report that that limiting platelet aggregation during reperfusion impacted infarct development. Continued investigation into the mechanisms by which inhibition of platelet activity protects myocardium against ischemia-reperfusion injury and improves clinical outcomes is necessary. PMID- 30428695 TI - Circulating Biomarker Levels in Patients With Stage 5 Chronic Kidney Disease With Respect to Neurovascular Diseases. AB - The prevalence of neurocognitive deficits remains high in patients with stage 5 chronic kidney disease (CKD5D). Major contributors to such deficits include stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD). The risk of developing these dysfunctional vascular processes is facilitated by the chronic inflammation associated with renal failure. Plasma levels of 10 circulating biomarkers in patients with CKD5D (n = 78-90) were quantified using the sandwich enzyme linked immune sorbent assay method. Biomarkers for this study included kidney injury molecule-1, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), neutrophil gelatinase associated lipocalin, interleukin-18, endothelin 1, calcifediol, parathyroid hormone, platelet-derived growth factor, microparticles-expressing tissue factor, and lipoprotein(a) (Lp(a)). Of the 90 patients with CKD5D, 30 had CCAD, 24 had ICAD, and 22 had stroke. Lp(a) level was significantly elevated in patients with CKD5D with comorbid ICAD compared to those without (125.70 +/- 10.03 ng/mL vs 97.16 +/- 5.97 ng/mL; P = .0065). NT-proBNP level was also significantly elevated in patients with CKD5D with comorbid stroke diagnosis compared to those without stroke history, once patients with a diagnosis of heart failure (HF) were excluded (14.84 +/- 2.80 ng/mL vs 9.06 +/- 1.27 ng/mL; P = .0283). Profiling levels of Lp(a) and NT-ProBNP could thus be useful in the risk stratification of ICAD and stroke, respectively, in the CKD5D population. PMID- 30428696 TI - Diagnosis of Serrated Polyposis Syndrome in an Adolescent Patient. PMID- 30428697 TI - Physical activity in Indonesian University students: the contradictory roles of dispositional mindfulness and self-control. AB - Physical inactivity is now identified as one of the major risk factors for global mortality, including in Indonesia. Past research in Western settings have demonstrated the efficacy of self-determined or autonomous forms of motivation in predicting health-related behaviours, and that association between these variables could possibly be moderated by individual differences in mindfulness. In terms of mindfulness, individuals from different cultures may vary in their familiarity and acceptance of mindfulness in daily life. Moreover, the ways though which individuals exhibit qualities of mindfulness are often intertwined with their capacity for self-control. In this correlational study utilizing cloud based online survey, samples of Indonesian undergraduates (N = 411, mean age = 20.202, SD = 1.406) completed self-report measures of trait mindfulness, trait self-control, autonomous motivation, and physical activity. Bootstrap multiple regression analysis indicated that association between autonomous motivation and physical activity is strengthened by trait self-control (p = .017), but conversely, weakened by trait mindfulness (p = .024). Cultural perspective may help explain the dynamics of mindfulness, self-control, autonomous motivation, and physical activity. PMID- 30428698 TI - Predictors of the personal benefits and positive aspects of informal caregiving. AB - OBJECTIVE: We investigated a) the number of reported benefits in an informal caregiving situation and b) the factors that predict the caregiver's (CG's) experience of benefits. METHOD: In this cross-sectional study, we computed univariate analyses and a multiple regression analysis using a benefit score as the dependent variable. Participants were 734 informal CGs who provide care for a person with chronic care needs in Germany. We examined the CG's self-reported physical complaints (GBB-24), subjective burden (CSI), depressive symptoms (PHQ 9), quality of life (CarerQoL), and benefits (BIZA-D). RESULTS: Most of the CGs (87.1%) experienced benefits in at least one field. A higher experience of benefits was significantly associated with: more depressive symptoms (r = 0.10), higher burden (r = 0.17), longer duration of care (r = 0.07), longer daily care time (r = 0.21), more physical complaints (r = 0.15), and a good quality of the relationship between CG and CR (eta = 0.13). In the multivariate regression analysis, a good relationship between the CG and CR (beta = .157, P < .001), an increased amount of care time (beta = .188, P < .001), and a higher level of burden (beta = .167, P < .001) were associated with greater CG's benefits. CONCLUSION: CG benefits are a very important, often experienced, but less explored construct in caregiving research. Benefits do not seem to be on the opposite end of the same continuum as negative aspects of caregiving. Benefits appear to be a nearly distinct dimension in informal care settings. PMID- 30428699 TI - Equipping staff with the skills to maximise recovery of people with dementia after an injurious fall. AB - OBJECTIVES: People with dementia are more likely to fall and less likely to recover well after a fall than cognitively intact older people. Little is known about how best to deliver services to this patient group. This paper explores the importance of compensating for cognitive impairment when working with people with dementia. METHODS: Qualitative methods - interviews, focus groups and observation - were used to explore the views and experiences of people with dementia, family carers and professionals providing services to people with dementia following an injurious fall. A thematic, iterative analysis was undertaken in which emerging themes were identified from each individual dataset, prior to an integrative analysis. RESULTS: A key theme across all datasets was the need to deliver services in ways that compensate for cognitive impairment, such as negotiating meaningful activities that can be embedded into the routines of people with dementia. Professionals varied in their ability to adapt their practice to meet the needs of people with dementia. Negative attitudes towards dementia, a lack of knowledge and understanding of dementia limited the ability of some professionals to work in person-centred ways. CONCLUSION: Improving outcomes for people with dementia following a fall requires the principles of person-centred care to be enacted by professionals with a generic role, as well as specialist staff. This requires additional training and support by specialist staff to address the wide variability in current practice. PMID- 30428700 TI - Netflix and Chill? What Sex Differences Can Tell Us About Mate Preferences in (Hypothetical) Booty-Call Relationships. AB - The booty-call relationship is defined by both sexual characteristics and emotional involvement. In the current study, men's and women's preferences for a booty-call mate were explored. Men and women were predicted to exhibit different mate preferences depending on whether they considered a booty-call relationship a short- or long-term relationship. Participants ( N = 559, 74% women) completed an anonymous online questionnaire, designing their ideal booty-call mate using the mate dollars paradigm. Both sexes considered the physical attractiveness and kindness of a booty-call mate a necessity, expressing both short- and long-term mate preferences. The current study highlights the need to explore mate preferences outside the dichotomy of short- and long-term relationships, providing evidence of a compromise relationship. PMID- 30428702 TI - Efficacy of ultra-low-dose (0.1 mg) ranibizumab intravitreal injection for treatment of prethreshold type 1 retinopathy of prematurity: A case series. AB - AIM:: To report the results of treatment of type 1 prethreshold retinopathy of prematurity using intravitreal injection of ultra-low dose of ranibizumab (0.1 mg in 0.01 mL). DESIGN:: A retrospective observational case series study. METHODS:: Review of files of eligible infants who received this form of treatment to determine the outcome of treatment and any associated ocular or systemic side effects. RESULTS:: The study included 24 eyes of 12 preterm infants with mean gestational age of 29.75 +/- 1.54 weeks and mean birth weight of 1074.58 +/- 320.59 g. A total of 22 eyes (91.67%) had zone II disease while 2 eyes of one infant (8.33%) had zone I disease. All cases showed regression of the signs of the active retinopathy of prematurity with complete retinal vascularization. None of the cases required retreatment. Three eyes developed ocular complications. Apart from mild feeding intolerance that lasted for 24 h after injection in one infant, none of the cases developed systemic side effects. CONCLUSION:: Intravitreal injection of ultra-low-dose ranibizumab showed promising efficacy and good ocular safety. However, further large-scale studies are required to give stronger evidence about the efficacy and safety of ultra-low-dose ranibizumab. PMID- 30428701 TI - Early readmission and mortality in acute exacerbation of chronic obstructive pulmonary disease with community-acquired pneumonia. AB - Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are important causes of hospital admission and mortality. Pneumonia is a major contributor to hospitalization for AECOPD and has a close relationship with poor outcomes. We performed a prospective cohort study to evaluate the prognosis of AECOPD patients with or without community-acquired pneumonia (CAP) who hospitalized from January 2012 to December 2015. We investigated mortality and readmission rates within 6 months after the first admission between two groups and analyzed the difference of survival rate according to readmission duration (<=30 vs. >30 days) or intensive care unit (ICU) treatment. Total 308 AECOPD patients (134 with CAP and 174 without CAP) were enrolled. The mean age was 72.3 +/- 9.5 years old, and 235 patients (76.3%) were male. The 180-day mortality was higher in AECOPD with CAP than without CAP (24.6% vs. 13.2%; hazard ratio (HR): 1.982; 95% CI: 1.164-3.375; p = 0.012). However, readmission rate showed no significant difference between two groups (51.5% vs. 46.6%; HR: 1.172; 95% CI: 0.850-1.616; p = 0.333). It showed a significantly lower survival rate in AECOPD with CAP rather than without CAP when were readmitted within 30 days (HR: 1.738; 95% CI:1.063-3.017; p = 0.031). According to ICU treatment, survival rate was not significantly different between two groups. Multivariate analysis revealed the readmission within 30 days ( p < 0.001), serum hemoglobin concentration ( p = 0.010), and albumin level ( p = 0.049) were significantly associated with 180 day mortality of AECOPD with CAP. AECOPD with CAP showed lower survival rate than AECOPD without CAP during 6 months. Early readmission within 30 days was significantly associated with an increased risk of mortality. PMID- 30428704 TI - A Message from the Guest Editor. PMID- 30428703 TI - Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX). AB - Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies. PMID- 30428705 TI - How Should We Approach and Discuss Children's Weight With Parents? A Qualitative Analysis of Recommendations From Parents of Preschool-Aged Children to Physicians. AB - The primary objective of this study was to describe parents' preference for how physicians should approach diet and weight-related advice for their child. Semi structured interviews were conducted with parents (n = 40) of preschoolers, transcribed verbatim, and double-coded using an inductive thematic analysis approach. Parents identified recommendations for how physicians should approach conversations about weight. Themes included (1) Tone and Approach are Important, (2) Avoid Judgment, (3) Have Regard for Parental Expertise, (4) Consider the Timing of the Discussion with Parents, and (5) Equip Parents with Concrete and Individualized Recommendations. Future research should focus on developing brief, effective communication tools to guide discussions with parents about child nutrition and weight. Opportunities to learn about and practice the use of these brief interventions should be incorporated into medical education with the goal of providing clinicians the learning opportunities, skills/tools, and resources needed to adequately and respectfully discuss weight and diet with parents and children. PMID- 30428706 TI - Association Between Positive Occipital Sharp Transients of Sleep and Lambda Waves. AB - Positive occipital sharp transients of sleep (POSTS) and lambda waves have similar morphology and location. We studied a possible association between these 2 normal EEG patterns. We reviewed a series of consecutive unselected ambulatory EEGs during a 3-month period (October 16, 2017 to January 19, 2018) and identified records with POSTS and records with lambda waves. Statistical analysis was performed using a chi-square test. A total of 140 ambulatory EEGs were reviewed. Duration of EEGs ranged from 24 to 168 hours (mean 76 hours). The population was 34% males, with ages ranging from 3 to 93 years (mean 48 years). Of the 140 records, 30 were abnormal, including 20 with epileptiform abnormalities. A chi-square test for independence (with Yates continuity correction) indicated a significant association between POSTS and lambda waves, chi2(1, n = 140) = 69.208, p < .001, phi = 0.72. In addition, 100% of records with lambda waves had POSTS, and 72% of records with POSTS had lambda waves. There is a high association between lambda waves and POSTS. This suggests a strong similarity between the 2 waveforms, and possibly a common occipital generator. PMID- 30428707 TI - Does Parents' Own History of Child Abuse Moderate the Effectiveness of the Promoting First Relationships(r) Intervention in Child Welfare? AB - To better understand how and for whom parenting intervention may improve family outcomes in child welfare services, we examined whether parents' own history of child abuse moderated the indirect effects of the Promoting First Relationships(r) (PFR) intervention on toddlers' secure base behavior via parental sensitivity. Parents ( N = 247) and their toddlers (10-24 months) involved with child protective services were randomized to PFR or a control intervention. Results showed that the PFR group demonstrated greater parental sensitivity at postintervention than the control group, which in turn led to higher levels of toddler secure base behavior at 6-month follow-up. Findings from a moderated mediation model indicated that these intervention effects were only evident for parents who experienced physical abuse in their childhood. Parents' history of sexual or emotional abuse did not significantly moderate outcomes. These results provide evidence for a key mechanism of change in PFR informed by attachment theory and suggest that PFR intervention effects may be stronger in parents at higher risk of the intergenerational transmission of abuse. PMID- 30428708 TI - The effect of comorbidity severity on pulmonary rehabilitation outcomes in chronic obstructive pulmonary disease patients. AB - CLINICAL TRIAL NUMBER:: NCT03319108. PMID- 30428709 TI - Cancer Clinical Trials: Treatment Costs Associated With a Spanish National Health System Institution. AB - BACKGROUND:: Clinical trials should be part of routine health care. There is a common perception that enrolling patients into clinical trials results in additional costs. We conducted a retrospective cost analysis to compare medical costs attributable to participation in cancer treatment trials versus standard of care in a single Spanish institution. METHODS:: Patients recruited into cancer clinical trials between 2014 and 2016 were selected. Each research protocol was reviewed to identify trial-associated medical procedures and costs, as well as the equivalent care had the patient not been entered in the trial. Treatment cost difference was the difference between the cost of the clinical trial and that of the standard of care. RESULTS:: A total of 68 adult patients were treated in 20 different clinical trials. The overall cost treatment of the patients included in the trials was 79% lower in comparison to the standard of care. However, the load of medical procedures was 32% higher. The average treatment cost per patient and protocol ranged from an excess of ?8193 to a saving of ?59,770. CONCLUSIONS:: There is a wide range of difference in treatment costs for cancer clinical trial participants versus standard of care. Commercial trial protocols were associated with larger savings compared with the noncommercial ones, even though these may involve excess treatment costs. Overall, clinical trials provide not only the best context for progress of clinical research and health care but also creates opportunities for reducing cancer care costs. PMID- 30428710 TI - An Unusual Case of Bilateral Foot Swelling After an Online Gaming Overdose. PMID- 30428711 TI - Effect of the anisotropic permeability in the frequency dependent properties of the superficial layer of articular cartilage. AB - Articular cartilage is a tissue of fundamental importance for the mechanics of joints, since it provides a smooth and lubricated surface for the proper transfer of loads. From a mechanical point of view, this tissue is an anisotropic poroviscoelastic material: its characteristics at the macroscopic level depend on the complex microscopic architecture. With the ability to probe the local microscopic features, dynamic nanoindentation test is a powerful tool to investigate cartilage mechanics. In this work we focus on a length scale where the time dependent behaviour is regulated by poroelasticity more than viscoelasticity and we aim to understand the effect of the anisotropic permeability on the mechanics of the superficial layer of the articular cartilage. In a previous work, a finite element model for the dynamic nanoindentation test has been presented. In this work, we improve the model by considering the presence of an anisotropic permeability tensor that depends on the collagen fibers distribution. Our sensitivity analysis highlights that the permeability decreases with increasing indentation, thus making the tissue stiffer than the case of isotropic permeability, when solicited at the same frequency. With this improved model, a revised identification of the mechanical and physical parameters for articular cartilage is provided. To this purpose the model was used to simulate experimental data from tests performed on bovine tissue, giving a better estimation of the anisotropy in the elastic properties. A relation between the identified macroscopic anisotropic permeability properties and the microscopic rearrangement of the fiber/matrix structure during indentation is also provided. PMID- 30428713 TI - A Thank You From the Editor-in-Chief. PMID- 30428714 TI - Relations of civil liberties and women's health satisfaction around the globe: The explanatory power of autonomy. AB - Research on how sociopolitical factors differentially affect the health and well being of individuals is nascent and mechanisms responsible have not yet been identified. This work examined how the civil liberties afforded across 79 countries differentially affect the health satisfaction of men and women and tested one potential reason for this link: autonomy satisfaction, the experience of being choiceful, and free to express oneself. Women reported lower health satisfaction in countries that were lower in civil liberties, a relation mediated by autonomy. Implications for women and other marginalized groups most affected by a society's restrictive policies and norms are discussed. PMID- 30428712 TI - Prevalence of a Septated First Dorsal Compartment Among Patients With and Without De Quervain Tenosynovitis: An In Vivo Anatomical Study. AB - BACKGROUND: The reported prevalence of a subcompartment housing the extensor pollicis brevis (EPB) tendon within the first dorsal compartment varies widely in the literature, especially regarding the rates of occurrence between genders and among those with and without De Quervain. Based on direct intraoperative observation, we hypothesized that the prevalence of a septated compartment is far greater than previously reported, particularly in those with De Quervain disease. METHODS: A prospective analysis of consecutive patients who underwent first dorsal compartment release was carried out. Patients were divided into 2 groups: those with De Quervain tenosynovitis ("De Quervain" group) and a control cohort without a primary diagnosis of De Quervain ("non-De Quervain" group). The intraoperative findings of a single compartment or a separate subcompartment were recorded. The prevalence of a septated compartment was calculated and compared between genders and both patient groups. RESULTS: A total of 102 consecutive patients were included, with a female predominance (74.5%). Overall, 79.4% of patients had a separate subcompartment for the EPB. In the De Quervain cohort, 89.1% had 2 compartments, while 71.4% of non-De Quervain patients had a subcompartment. Men and women had a similar rate of double compartments (80% and 82.4%, respectively). CONCLUSIONS: The prevalence of a septated first dorsal compartment is considerably higher than previously reported, most notably in patients afflicted with De Quervain tenosynovitis. This higher rate of septation occurs with a similar prevalence in both men and women. Owing to its consistent presence, the dual first dorsal compartment should be regarded as an expectant anatomical component of the normal wrist. PMID- 30428715 TI - Entry Into New Therapeutic Areas: The Effect of Alliance on Clinical Trials. AB - BACKGROUND:: Entry into a new therapeutic area, that is, one in which a pharmaceutical firm lacks experience, is a considerable challenge for firms that need to overcome scientific and technological barriers. To address this issue, the present study aims to explore the potentiality of alliances in an empirical manner. METHODS:: From the clinical trials sponsored by 20 major pharmaceutical firms during 2008-2016 listed at ClinicalTrials.gov (n = 14,941 clinical trials), cases of entering a new therapeutic area for a pharmaceutical firm were extracted (n = 73), followed by statistical analyses to evaluate the effect of alliances in this regard. RESULTS:: We found that the average number of participating organizations in the cases of entering a new therapeutic area was significantly larger than that in the cases of entering an area in which firms had experience ( P < .01), suggesting that alliance has a positive effect on new therapeutic entry for these pharmaceutical firms. Second, we found that the cases of partnering with nonindustrial or nongovernmental organizations (ie, universities, research institutes, hospitals, funding agencies, and others; n = 32 of the 73) were significantly associated with these new entry trials (adjusted odds ratio = 1.1, P < .05). Furthermore, we identified that 10 of the 32 clinical trials were associated with rare diseases, which is an overrepresentation compared to the occurrence in the universe (1015 of the 14,941; P < 10-5). CONCLUSIONS:: These findings strongly suggest the importance of alliances with diversified partners in new therapeutic entry and also provide a basis for further detailed investigation of key success factors for pharmaceutical firms. PMID- 30428716 TI - Estimates of Indigenous Food Consumption and Their Contribution to Nutrient Intake in Oraon Tribal Women of Jharkhand, India. AB - INTRODUCTION:: Oraon tribes of India have high levels of undernutrition. Dietary diversification is one of the food-based interventions to ameliorate malnutrition. OBJECTIVES:: This study assessed the awareness and availability of indigenous foods and estimated dietary intakes and nutritional status with emphasis on indigenous food consumption among women in the Oraon tribal community in Jharkhand, India. DESIGN:: A cross-sectional study with a longitudinal component on dietary intake assessment to capture seasonality. SETTING:: Selected villages in Raidih block of Gumla district of Jharkhand. PARTICIPANTS:: Reproductive-age Oraon tribal women (N =143). METHODS:: Household and dietary surveys were conducted. A 24-hour dietary recall for 2 consecutive days (repeat surveys in 2 other seasons) and food frequency questionnaire were adminsitered on 1 woman per household. Anthropometric assessments were also carried out. OUTCOMES:: Socioeconomic status, awareness about indigenous foods, dietary intake pattern, and contribution of indigenous food to nutrient intake of Oraon tribal women in the reproductive age-group. RESULTS:: Comprehensive awareness about indigenous food resources was present. However, household food security and actual intake of indigenous foods were low. Higher intake of key micronutrients, calcium and iron, was observed among those who consumed indigenous foods. About 40% of the woman had various degrees of chronic energy deficiency. CONCLUSION:: Despite rich knowledge, nutrient-rich indigenous food resources remain underutilized in the Oraon tribal community of Jharkhand, India. Identifying strategies to promote dietary diversity via optimum indigenous food intake could contribute to both food and nutrition security. PMID- 30428717 TI - Obesity, stigma and reflexive embodiment: Feeling the 'weight' of expectation. AB - The dominant obesity discourse which emphasises individual moral responsibility and lifestyle modification encourages weight-based stigma. Existing research overwhelmingly demonstrates that obesity stigma is an ineffective means by which to reduce the incidence of obesity and that it promotes weight-gain. However, the sensate experiences associated with the subjective experience of obesity stigma as a reflexively embodied phenomenon have been largely unexamined. This article addresses this knowledge gap by providing a phenomenological account. Data are derived from 11 months of ethnographic participant observation and semi structured interviews with three single-sex weight-loss groups in England. Group members were predominantly overweight/obese and of low-socio-economic status. The analysis triangulates these two data sources to investigate what/how obesity stigma made group members feel. We find that obesity stigma confused participant's objective and subjective experiences of their bodies. This was primarily evident on occasions when group members felt heavier after engaging in behaviours associated with weight-gain but this 'weight' did not register on the weighing scales. We conceptualise this as the weight of expectation which is taken as illustrative of the perpetual uncertainty and morality that characterises weight-management. In addition, we show that respondents ascribed their sensate experiences of physiological responses to exercise with moral and social significance. These carnal cues provided a sense of certainty and played an important role in attempts to negotiate obesity stigma. These findings deepen the understanding of how and why obesity stigma is an inappropriate and ineffective means of promoting weight-loss. PMID- 30428718 TI - Pain in patients with chronic obstructive pulmonary disease indicated for post acute pulmonary rehabilitation. AB - Pain is a significant problem in stable chronic obstructive pulmonary disease (COPD) and is associated with other symptoms, worse health status and lower functional status. Not much is known about pain in unstable disease. The primary aim of the present study is to investigate prevalence, characteristics and relationships of pain in patients with COPD hospitalized for an acute exacerbation (AECOPD) and indicated for post-acute pulmonary rehabilitation (PR). This cross-sectional observational study included 149 patients (mean age 70.8 (+/ 7.9) years, 49% male, mean forced expiratory volume in one second as percentage of predicted value 35.3 (+/-12.6)). Pain was assessed using the brief pain inventory. Functional status and health status were measured using the six-minute walking test (6MWT), the Barthel index (BI) and the clinical COPD questionnaire (CCQ), respectively. Pain was prevalent in 39.6% of all patients. Symptom burden was high, especially in patients with pain. Although we found no difference in objective measurements of functional status (6MWT, BI), patients with pain had clinically relevant lower health status (CCQ), attributed to the functional domain. Pain in patients hospitalized for AECOPD and indicated for post-acute PR is a relevant problem and needs more attention. Incorporation of standard pain assessment during exacerbations and post-acute PR is recommended. PMID- 30428719 TI - Heat shock protein expression and autophagy after incomplete thermal ablation and their correlation. AB - OBJECTIVE: To establish a model of incomplete ablation in nude mice with hepatocellular carcinoma (HCC) and to evaluate heat shock protein (HSP) expression and autophagy and their correlation. MATERIALS AND METHODS: In the first stage, 12 nude mice with HCC were randomly divided into two groups (n = 6). A sham puncture operation was performed for one group, and palliative laser ablation was performed for the other group. All mice were sacrificed after 18 h, and HSP expression, autophagy, and apoptosis were assessed. In the second stage, 16 nude mice with HCC were randomly divided into two groups (n = 8). One group was given an HSP90 inhibitor before the operation, and the other group was given dimethyl sulfoxide (DMSO) as a control. HSP expression, autophagy and apoptosis were assessed for the two groups after palliative laser ablation. RESULTS: In the incomplete ablation model, using nude mice with HCC, HSP90, HSP70, and HSP27 expression was up-regulated, Akt and mTOR phosphorylation was enhanced, autophagy was decreased, and apoptosis was increased. After administration of the HSP90 inhibitor, HSP90, P-Akt, and P-mTOR expression was decreased, autophagy was increased, and apoptosis was further increased. CONCLUSION: Autophagy was decreased in the incomplete ablation model and might be inversely correlated with HSP expression. It is suggested that the HSP90/Akt/mTOR pathway is involved in signal transmission between autophagy and HSPs. PMID- 30428720 TI - Optimizing nature: Invoking the "natural" in the struggle over water fluoridation. AB - For the past seventy years, a host of scientific and public health bodies in the United States have strongly endorsed the practice of adding fluoride compounds to public water supplies as a prophylactic against dental caries. Throughout that period, a constant undercurrent of skepticism and outright opposition has slowed the adoption of the practice in the United States and limited its spread to just a handful of countries around the world. One of the attractions of water fluoridation is its affordability: the fluoride compounds are sourced from the phosphate and aluminum industries, for whom they would otherwise constitute an annoying toxic waste disposal problem. Despite this, proponents have nonetheless succeeded in shaping a narrative that casts fluoridation as "natural" or at least mimicking nature. I demonstrate how fluoridationists were able to persuasively argue that adding a pollutant to the water supply was safe and natural. In the process, I examine how environmental historians and historians of science approach topics such as fluoridation. I suggest that as a result of the influence of science and technology studies and an ontological turn toward hybridity, the two subdisciplines are becoming increasingly convergent. PMID- 30428721 TI - Cluster analysis identifying patients with COPD at high risk of 2-year all-cause mortality. AB - The objective of the article is to identify clusters of patients with COPD according to factors known to be associated with mortality and to verify whether clusters' assignment is associated with 2-year mortality. Patients ( n = 141) were evaluated by bioelectrical impedance, maximal inspiratory pressure (MIP), one-repetition maximum test of the quadriceps femoris (1RMQF) and BODE index (body mass index; airflow obstruction (spirometry); dyspnea (modified Medical Research Council scale); and exercise capacity (6-minute walk test (6MWT) distance). Vital status was retrospectively checked 2 years after the assessments, and time to death was quantified for those deceased in this period. K-means analysis identified two clusters. Patients in cluster one (CL I, n = 69) presented an impaired clinical status in comparison to cluster two (CL II, n = 72). Receiver operating characteristics curves identified the cutoffs discriminating patients composing CL I: forced expiratory volume in the first second <44%pred; 6MWT <479 m; 1RMQF <19 kg; and maximum inspiratory pressures <73 cmH2O (area under the curve range 0.750-0.857). During the follow-up, 19 (13%) patients deceased, 15 in CL I (22%) and 4 in CL II (0.06%) ( p = 0.005). CL I was associated with a higher risk of 2-year mortality (hazard ratio (95% confidence interval): 4.3 (1.40-12.9), p = 0.01). A cluster of patients with COPD highly associated with 2-year mortality was statistically identified, and cutoffs to identify these subjects were provided. PMID- 30428722 TI - Determinants of patient satisfaction in outpatient musculoskeletal physiotherapy: a systematic, qualitative meta-summary, and meta-synthesis. AB - PURPOSE: To identify and synthesise patient-identified factors that influence satisfaction with outpatient musculoskeletal physiotherapy (O-MSK). METHODS: A systematic, qualitative meta-summary and meta-synthesis was conducted by accessing six electronic databases: CINAHL, Embase, MEDLINE, Scopus, Web of Science, and Wiley Online Library, from inception to March 2017. Additional studies were identified by using a "berry-picking" method. Search limits were: primary studies; English language; and involving human subjects. Qualitative peer reviewed articles describing patient satisfaction in O-MSK were eligible for inclusion. Two reviewers critically appraised eligible studies independently using the critical appraisal of skills programme tool for qualitative studies. Extracted verbatim data of included studies were synthesised using the meta summary and meta-synthesis by using a purpose-designed form. RESULTS: Eleven studies were included in the article. Factors influencing patient satisfaction were grouped into six broad themes: 1) clinical outcomes; 2) physiotherapist features; 3) patient features; 4) physiotherapist-patient relationship; 5) treatment features, and 6) healthcare setting features. CONCLUSIONS: These findings suggest that patient satisfaction in O-MSK is a multidimensional construct influenced by individual patient/provider, clinical, and contextual factors. Future reviews should include a synthesis of findings from both qualitative and quantitative studies to establish a fully comprehensive understanding of this complex health phenomenon. Implications for rehabilitation Patient satisfaction in outpatient musculoskeletal physiotherapy is affected by different factors, thus reflecting a multidimensional construct; Single determinants are not sufficient to affect patient satisfaction; Patient satisfaction is influenced individual patient/provider, clinical outcomes, and contextual factors; Further studies should be designed to investigate the relationships among these factors. PMID- 30428723 TI - Coupling Between Brain Structures During Visual and Auditory Working Memory Tasks. AB - Transmission of EEG activity during a visual and auditory version of the working memory task based on the paradigm of linear syllogism was investigated. Our aim was to find possible similarities and differences in the synchronization patterns between brain structures during the same mental activity performed on different modality stimuli. The EEG activity transmission was evaluated by means of full frequency Directed Transfer Function (ffDTF) and short-time Directed Transfer Function (SDTF). SDTF provided information on dynamical propagation of EEG activity. The assortative mixing approach was applied to quantify coupling between regions of interest encompassing frontal, central and two posterior modules. The results showed similar schemes of coupling for both modalities with stronger coupling within the regions of interests than between them, which is concordant with the theories concerning efficient wiring and metabolic energy saving. The patterns of transmission showed main sources of activity in the anterior and posterior regions communicating intermittently in a broad frequency range. The differences between the patterns of transmission between the visual and auditory versions of working memory tasks were subtle and involved bigger propagation from the posterior electrodes towards the frontal ones during the visual task as well as from the temporal sites to the frontal ones during the auditory task. PMID- 30428724 TI - TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast. AB - PURPOSE: Thymic stromal lymphopoietin (TSLP) acts as a critical cytokine involved in asthmatic airway remodeling. Our study aimed to characterize the crosstalk between airway epithelial cells and fibroblasts regulated by TSLP through the signaling pathways of Mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MATERIALS AND METHODS: Human biopsy specimens and lung tissues from mice were stained with hematoxylin and eosin (H&E) and immunohistochemistry. Human lung fibroblasts were stimulated with human recombinant TSLP. The protein expression of phosphorylation of STAT3 (p STAT3) and phosphorylation of MAPK as well as the expression of collagen I and alpha-smooth muscle actin (alpha-SMA) were detected by Western blotting and immunofluorescence. Co-culture was performed to detect the influence of TSLP secreted by airway epithelial cells on fibroblasts. An ovalbumin (OVA)-induced asthmatic murine model was established with or without intraperitoneal injection of SB203580 (inhibitor of p-38). Protein expression in lung tissue was detected by immunohistochemistry and western blotting. RESULT: TSLP could activate MAPK in HLF-1. SB203580 could inhibit the activation of p38, attenuate phosphorylation of STAT3, and decrease the expression of collagen I and alpha-SMA consequently in human fibroblasts. Co-culture demonstrated that TSLP secreted by epithelial cells could promote the expression of collagen I and alpha-SMA and aggravates airway remodeling in fibroblasts. In vivo, expression of TSLP, collagen I, alpha-SMA, p p38 and p-STAT3 was upregulated in airway tissue of OVA-challenged mice and downregulated in mice which were treated by SB203580. The tissue staining showed that airway structure change was attenuated by SB203580 compared with OVA challenged mice as well. CONCLUSIONS: TSLP might promote asthmatic airway remodeling via p38 MAPK-STAT3 axis activation and the crosstalk between airway epithelial cells and fibroblasts could aggravate remodeling. Blockade of p38 could alleviate airway remodeling which might provide a new therapeutic target for asthma. PMID- 30428725 TI - Minimally invasive isolated limb perfusion - technical details and initial outcome of a new treatment method for limb malignancies. AB - OBJECTIVE: Isolated limb perfusion (ILP) and isolated limb infusion (ILI) are treatment options for patients with locally advanced melanomas and sarcomas of the extremities. ILP potentially have higher response rates, but requires open surgery for vascular access, whereas ILI is minimally invasive and easier to perform. We now present the technical details and outcome of a new approach to ILP by a minimally invasive vascular access (MI-ILP). METHODS: Six patients, five with melanoma in-transit metastases and one with squamous cell carcinoma, were included in a phase I feasibility trial. Percutaneous vascular access of the extremity vessels was performed and the inserted catheters were then connected to a perfusion system. RESULTS: All six treated patients underwent the procedure without the need for conversion to open surgery. The median operating time was 164 min and the median leakage rate was 0.1%. The complete response rate was 67%. Four patients (67%) had a Wieberdink grade II reaction and two patients (33%) had a grade III reaction. CONCLUSIONS: MI-ILP is feasible and gives the same treatment characteristics as open ILP, but with the advantage of a minimally invasive vascular access. PMID- 30428726 TI - Induction of Mitotic Catastrophe via Inhibition of Aurora B by Ionizing Radiation With Additive of Mulberry Water Extract in Human Bladder Cancer Cells. AB - Mulberry fruit water extract (MWE) has been reported to synergistically enhance the cytotoxic effect of paclitaxel by promoting mitotic catastrophe to induce apoptosis in bladder cancer cells in our previous work. The aim of this study was to evaluate and to mechanistically explore the effects of MWE on bladder cancer responses to ionizing radiation (IR) by treating TSGH 8301 bladder carcinoma cells with MWE after exposing to IR. The results of MTT assay showed a synergistic cytotoxicity of IR with the co-treatment of MWE (IR/MWE) by inducing G2/M phase arrest as demonstrated by flow cytometry analysis in TSGH 8301, HT1367 and HT1197 bladder carcinoma cells lines. The IR/MWE-treated cells expressed increased levels of the G2/M phase arrest-related proteins cdc2/cyclin B1 and displayed giant multinucleated morphology, a typical characteristic of mitotic catastrophe. Immunofluorescent confocal microscopy revealed that the combined strategy inhibited Aurora B phosphorylation through Ras/Raf/MEK/ERK signaling cascade as demonstrated by Western blotting analysis. IR/MWE also caused an inhibitory effect on Plk1 and the subsequent downstream regulator RhoA repression and Cep55 induction, which would influence cell cycle progression in the early steps of cytokinesis. A profound tumor growth suppression and inactivation of Aurora B activity in the tumor tissues by IR/MWE treatment were confirmed in the TSGH 8301 xenograft model in vivo. These data demonstrated that MWE could be an effective auxiliary to synergize with radiation on the anticancer efficacy by promoting mitotic catastrophe through inhibition of Aurora B, providing a novel and effective therapeutic option for bladder cancer management. PMID- 30428727 TI - Interprofessional education among Nigerian clinical students: implications for interprofessional care (A mixed method analysis). AB - Interprofessional education (IPE) is effective for teaching health profession students about the roles of different healthcare professionals for collaborative practice. This study was designed to investigate clinical students' awareness, knowledge, and perception of IPE. A mixed method convergent parallel design of Cross-Sectional Survey (CSS) and Focus Group Discussion (FGD) was used. Data on awareness, perception and knowledge about IPE were collected using a self developed, content-validated questionnaire and Readiness for Interprofessional Learning Scale, respectively, and was analysed using Chi-Square, and Mann-Whitney U test at alpha = 0.05. For the FGD, data were collected from 13 purposively selected students in a Nigerian university and analysed through content thematic analysis. Participants in the CSS were aged 21.9 +/- 2.0 years. Over half of the participants (57.4%) reported being unaware of IPE. More than half (73.0%) of the participants that were aware had good knowledge. Majority (93.3%) had a positive perception of IPE. There was a significant association between participants' knowledge and perception (p = 0.008) of IPE; however, there was no significant association (p = 0.051) between their awareness and perception. Also, there were no significant sex variations in the knowledge of IPE (0.371). However, there was a significant sex difference in their perception (p = 0.008). Some of the discussants in the FGD reported being aware of the term IPE. Discussants had at least fair knowledge of IPE and reported that IPE is important; and supports its formal implementation and inclusion in the curricula of study; emphasizing that it should be started early enough in their training. Awareness of interprofessional education is sub-optimal among these clinical students, however more than half of those who were aware had good knowledge. Most of them had a positive perception. There is a need to improve clinical students' awareness and knowledge about IPE by using integrated seminars and implementing IPE into the curricula of their training. PMID- 30428728 TI - Thermal ablation of pancreatic cancer: A systematic literature review of clinical practice and pre-clinical studies. AB - PURPOSE: Pancreatic cancer is a challenging malignancy with low treatment option and poor life expectancy. Thermal ablation techniques were proposed as alternative treatment options, especially in advanced stages and for unfit-for surgery patients. This systematic review describes the thermal ablative techniques -i.e., Laser (LA), Radiofrequency (RFA), Microwave (MWA) Ablation, High-Intensity Focused Ultrasound (HIFU) and cryoablation- available for pancreatic cancer treatment. Additionally, an analysis of the efficacy, complication rate and overall survival for each technique is conducted. MATERIAL AND METHODS: This review collects the ex vivo, preclinical and clinical studies presenting the use of thermal techniques in the pancreatic cancer treatment, searched up to March 2018 in PubMed and Medline. Abstracts, letters-to-the editor, expert opinions, reviews and non-English language manuscripts were excluded. RESULTS: Sixty-five papers were included. For the ex vivo and preclinical studies, there are: 12 records for LA, 8 for RFA, 0 for MWA, 6 for HIFU, 1 for cryoablation and 3 for hybrid techniques. For clinical studies, 1 paper for LA, 14 for RFA, 1 for MWA, 17 for HIFU, 1 for cryoablation and 1 for hybrid techniques. CONCLUSIONS: Important technological advances are presented in ex vivo and preclinical studies, as the real-time thermometry, nanotechnology and hybrid techniques to enhance the thermal outcome. Conversely, a lack of standardization in the clinical employment of the procedures emerged, leading to contrasting results on the safety and feasibility of some analyzed techniques. Uniform conclusions on the safety and feasibility of these techniques for pancreatic cancer will require further structured investigation. PMID- 30428729 TI - First reported case of intrahepatic cholangiocarcinoma metastasis to thecoma. PMID- 30428730 TI - Retrospective analysis of indications for termination of pregnancy. AB - This is a retrospective study of 139 termination of pregnancies (TOPs) between November 2015 and November 2017 to demonstrate the indications. We have shown that 60.4%, 34.5% and 5% of the terminations were performed because of genetic disorders, foetal or obstetrical problems, and maternal causes, respectively. Congenital abnormalities (43.8%), anhydramniosis (17.2%) and chromosomal abnormalities (15.1%) were the most frequent causes of the TOPs. The central nervous system seemed to be the most frequent indicator found in our study. The critical finding is the presence of nine (6.4%) terminations because of foetal reasons beyond the 24th gestational week. A vaginal termination occurred in 91.4% of cases, whereas a hysterotomy was performed in 8.6% of the cases. Previous uterine surgery was the most significant risk factor for a hysterotomy. Knowing the foetal indications is essential to know the aetiological and medico-legal backgrounds of the TOPs for better planning and medical counselling. Impact statement What is already known on this subject? Congenital anomalies are most common cause of termination of wanted pregnancies. Terminations beyond 24 weeks are also evaluated as unethical and create an ethical concern. The legal limitations differ between countries in terms of the legal limit in pregnancy for terminations. What do the results of this study add? We have demonstrated the congenital anomalies are the most common reason for pregnancy terminations after excluding fetal demise and unwanted pregnancies. We also showed that congenital anomalies and chromosomal abnormalities are most common indications for terminations of pregnancies beyond 24 weeks. The legal arrangements related to the termination of pregnancies in Turkey are described. Prior uterine surgery is a significant risk factor for hysterotomies in the termination of pregnancies. What are the implications of these findings for clinical practice and/or further research? It is critical to know the aetiological background of termination of pregnancies for better planning and consultation. PMID- 30428731 TI - Clinical analysis of high-intensity focussed ultrasound ablation for abdominal wall endometriosis: a 4-year experience at a specialty gynecological institution. AB - OBJECTIVE: To evaluate the long-term clinical effect of high-intensity focussed ultrasound (HIFU) as a non-invasive modality for ablation of abdominal wall endometriosis (AWE) foci. METHODS: All women who were diagnosed with cutaneous endometriosis and underwent HIFU ablation and 4-year follow-up were included. Patient symptoms, imaging performed, HIFU ablation, recurrence, lesion location, size and number were collected and analyzed. RESULTS: A total of 51 women with 57 painful abdominal wall masses with a median volume of 4.00 cm3 and a mean age of 30.5+/-2.12 years were treated with HIFU. The main symptoms were a palpable painful abdominal mass (93%), protrusion of the skin (28.1%, 16) or lack of protrusion of the skin (71.9%, 41). Ultrasound was initially performed in 100% (51) of women, whereas 6% (3) required MRI examinations to distinguish the features and range of the masses. Ablation was performed with a median 300 s of sonication time, 40 min treatment time, 150 W of power and 41800 J of total energy to treat lesions that were a median volume of 3.83 cm3. No severe complications occurred, except in one patient with a first-degree skin burn, during the 48-month follow-up period. The pooled recurrence of cutaneous endometriosis occurred in 3.9% (2) of women. CONCLUSION: The diagnosis of AWE should be confirmed with imaging of the lesion number, location, size and features before HIFU ablation. HIFU should be the first choice for the treatment of AWE as it is a non-invasive method, with high efficiency and safety and rapid postoperative recovery. PMID- 30428732 TI - Teaching NICU Fellows How to Relay Difficult News Using a Simulation-Based Curriculum: Does Comfort Lead to Competence? AB - PROBLEM: Neonatal Intensive Care Unit (NICU) clinicians must frequently relay difficult news to patient families, and the need for formal training for NICU trainees to develop this skill has been established. Although previous studies have shown improved trainee self-efficacy and comfort in handling difficult conversations after formal communication training, it remains unclear whether these interventions lead to improved objectively assessed short-term and long term performance. INTERVENTION: A simulation-based intervention emphasizing the SPIKES protocol for delivery of bad news was implemented for 15 fellows in the 3 year Baylor College of Medicine Neonatal-Perinatal Medicine fellowship program in the 2013-2014 academic year. Simulations involved video-recorded encounters between each fellow and a standardized parent (SP) involving communication of difficult news. Each fellow was evaluated before (preintervention), immediately after (postintervention), and 3-4 months after the intervention (follow-up) with an (a) evaluation of video-recorded sessions by two expert raters blinded to the timing of the encounter (blinded rater evaluation [BRE]), (b) Self-Assessment Questionnaire, (c) Content Test evaluating knowledge of taught concepts, and (d) SP evaluation (SPE). CONTEXT: The 1st- and 2nd/3rd-year fellows participated in the study at separate times in the academic year to accommodate their schedules. First-year fellows had had more prior communication training and less NICU clinical experience than the 2nd/3rd-year fellows at the time of their intervention. OUTCOME: Although all fellows displayed improved Self-Assessment and Content Test scores at postintervention with retention at the follow-up assessment, the BREs showed no statistically significant improvement in postintervention scores and showed a decline in follow-up scores. First-year fellows had higher BRE postintervention scores than the senior fellows. SPEs showed no difference in scores at all 3 assessment stages. LESSONS LEARNED: As previously described in the literature, trainee self-efficacy and knowledge may improve in the short term and long term with a simulation-based curriculum in communication of difficult news. However, these results may be inconsistent with those of objective evaluations by expert raters and standardized parents. The impact of the curriculum may be heightened if it reinforces previously learned skills, but the effect may wane over time if not reinforced frequently with additional formal training or in the clinical setting. The results of this study highlight the importance of objective assessments in evaluating the utility of a simulation-based communication curriculum and the need for longitudinal curricula to promote retention of the concepts and skills being taught. PMID- 30428733 TI - Conjoined Pacinian Corpuscles . . . or a Pacinioma In Situ? PMID- 30428734 TI - Relationship between uterine smooth muscular CPI-17-signal pathway-mediated Ca2+ sensitivity changes and uterine atony-induced postpartum haemorrhage. AB - This study aimed to investigate the changes of protein kinase C (PKC)-potentiated phosphatase inhibitor of 17 ku (CPI-17) expression, PKC activity and Rho kinase activity in the maternal uterine smooth muscle (USM), and their roles in the occurrence of uterine atony-induced postpartum haemorrhage (UAI-PPH). Sixty primiparaes who had a caesarean section performed were divided into the case group (with UAI-PPH) and the control group (the uterine contraction was good, without the PPH). The USM-p-CPI-17 (Thr38) protein levels, the activities of PKC and Rho kinase in the case group and the control group were 0.43 +/- 0.20, 4.30 +/- 0.91, 10.85 +/- 1.70 and 0.67 +/- 0.32, 0.099 +/- 0.028, 0.20 +/- 0.071, respectively (p < .05). The down-regulated expression of CPI-17 phosphorylated proteins might be one of the important factors of UAI-PPH, while the activity reduction of PKC and Rho kinase might be the reason that led to the phosphorylation level reduction of USM-CPI-17 in UAI-PPH. Impact Statement What is already known on this subject? The studies have shown that in the late pregnancy period, the total protein and phosphorylated protein of myometrial CPI 17 are significantly higher than in the non-pregnancy state, and they were all involved in regulating and enhancing the Ca2+ sensitivity of USMC during the pregnancy. The data regarding the CPI-17-signal pathway-mediated Ca2+ sensitivity in UAI-PPH is sparse. What do the results of this study add? We have shown that the down-regulated expression of CPI-17 phosphorylated proteins might be one of the important factors of UAI-PPH, while the activity reduction of PKC and Rho kinase might be the reason that led to the phosphorylation level reduction of USM CPI-17 in UAI-PPH. What are the implications of these findings for clinical practice and/or further research? Further studies are needed to confirm the pathogenesis of CPI-17-signal pathway-mediated Ca2+ sensitivity in UAI-PPH. PMID- 30428735 TI - Factors affecting effects of ultrasound guided high intensity focused ultrasound for single uterine fibroids: a retrospective analysis. AB - OBJECTIVE: To investigate factors affecting effects of ultrasound guided high intensity focused ultrasound (USgHIFU) in the treatment of single uterine fibroids (UFs) with different magnetic resonance imaging (MRI) features. METHODS: A total of 207 patients with single symptomatic UFs who were treated with HIFU were retrospectively analyzed. All UFs were grouped according to MRI features, and factors affecting HIFU ablation were set as independent variables. Non perfusion volume ratio (NPVR) and energy efficiency factor (EEF) were set as dependent variables to establish multiple linear regression models with a stepwise method. RESULTS: All patients had successful HIFU treatment, with the mean NPVR of 74.7 +/- 15.1% and the mean EEF of 7.4 +/- 5.2 j/mm3. The NPVR was negatively correlated with transmural type of UFs, hyperintense on T2 weighted image (T2WI), enhancement type on T1 weighted image (T1WI), distance from UFs ventral side to skin and posterior location of UFs, but positively correlated with anterior location of UFs, hypointense on T2WI and anteverted uterus (uterine location). The EEF was negatively correlated with size, anterior location of UFs and hypointense on T2WI, but positively correlated with distance from UFs ventral side to skin, enhancement type on T1WI and transmural type of UFs. The UFs size and enhancement type on T1WI were the greatest factors affecting the ablation effect. CONCLUSIONS: The effect of HIFU treatment for single UFs is affected by multiple factors, and the UFs of hypointense on T2WI, large size, mild enhancement on T1WI and anteverted uterus can be easily ablated with high ablation efficiency. PMID- 30428736 TI - Up-regulation of fibroblast growth factor receptor 1 due to prenatal tobacco exposure can lead to developmental defects in new born. AB - INTRODUCTION: Tobacco-smoking is one of the most important risk factor for preterm delivery, pregnancy loss, low birth weight, and fetal growth restriction. It is estimated that approximately 30% of growth-restricted neonates could be independently associated with maternal smoking. METHODS: In this study, gene expression profile, GSE11798, was chosen from GEO database with an aim to perceive change in gene expression signature in new born due to maternal smoking. Enrichment analysis was performed to annotate differentially expressed genes (DEGs) through gene ontology and pathway analysis using DAVID. Protein-protein interactions and module detection of these DEGs were carried out using cytoscape v3.6.0. Thirty umbilical cord tissue samples from 15 smokers and 15 non-smokers pregnant women were included in this analysis. RESULTS: Twenty-six differentially expressed genes (DEGs) between two groups were selected using GEO2R tool. The DEGs were observed to be participating in biological processes/pathways related to growth releasing hormone, angiogenesis, embryonic skeletal, and cardiac development. Fibroblast growth factor receptor-1 (FGFR1) was identified to be the hub node with 348 interacting partners, which regulates transcription, cell growth, differentiation, and apoptosis. The up-regulation of FGFR1 in umbilical cord tissue may lead to reproductive and developmental complications such as encephalocraniocutaneous lipomatosis, osteoglophonic dysplasia, and Pfeiffer syndrome in new-borns. CONCLUSION: The findings manifests the possibility of overcoming these adverse health effects in new born through FGFR1 modulating treatments during pregnancy. PMID- 30428737 TI - Polyethylene glycol-coated porous magnetic nanoparticles for targeted delivery of chemotherapeutics under magnetic hyperthermia condition. AB - PURPOSE: Although magnetite nanoparticles (MNPs) are promising agents for hyperthermia therapy, insufficient drug encapsulation efficacies inhibit their application as nanocarriers in the targeted drug delivery systems. In this study, porous magnetite nanoparticles (PMNPs) were synthesized and coated with a thermosensitive polymeric shell to obtain a synergistic effect of hyperthermia and chemotherapy. MATERIALS AND METHODS: PMNPs were produced using cetyltrimethyl ammonium bromide template and then coated by a polyethylene glycol layer with molecular weight of 1500 Da (PEG1500) and phase transition temperature of 48 +/- 2 degrees C to endow a thermosensitive behavior. The profile of drug release from the nanostructure was studied at various hyperthermia conditions generated by waterbath, magnetic resonance-guided focused ultrasound (MRgFUS), and alternating magnetic field (AMF). The in vitro cytotoxicity and hyperthermia efficacy of the doxorubicin-loaded nanoparticles (DOX-PEG1500-PMNPs) were assessed using human lung adenocarcinoma (A549) cells. RESULTS: Heat treatment of DOX-PEG1500-PMNPs containing 235 +/- 26 mg.g-1 DOX at 48 degrees C by waterbath, MRgFUS, and AMF, respectively led to 71 +/- 4%, 48 +/- 3%, and 74 +/- 5% drug release. Hyperthermia treatment of the A549 cells using DOX-PEG1500-PMNPs led to 77% decrease in the cell viability due to the synergistic effects of magnetic hyperthermia and chemotherapy. CONCLUSION: The large pores generated in the PMNPs structure could provide a sufficient space for encapsulation of the chemotherapeutics as well as fast drug encapsulation and release kinetics, which together with thermosensitive characteristics of the PEG1500 shell, make DOX PEG1500-PMNPs promising adjuvants to the magnetic hyperthermia modality. PMID- 30428738 TI - Combined treatment with modulated electro-hyperthermia and an autophagy inhibitor effectively inhibit ovarian and cervical cancer growth. AB - PURPOSE: Modulated electro-hyperthermia (mEHT), known as oncothermia, is an anticancer therapy that induces radiofrequency thermal damage to the cancer tissues. This study aimed to evaluate the potential effectiveness of mEHT as a therapeutic tool in ovarian and cervical cancer. MATERIALS AND METHODS: We used both tumor-bearing mice and ovarian and cervical OVCAR-3, SK-OV-3, HeLa and SNU 17 cancer cell lines to investigate the effects of mEHT in vivo and in vitro, respectively, and determine whether it was enhanced by cotreatment with an autophagy inhibitor. RESULTS: We discovered that phosphorylation of p38, a stress dependent kinase, was induced at the Thr180/Tyr182 residue in cancer cells exposed to mEHT. Apoptotic markers such as cleaved caspase-3 and poly-ADP ribose polymerase (PARP) were increased in OVCAR-3 and SNU-17 cells. Fluorescence activated cell sorting (FACS) analysis showed a significant increase in the population of sub-G1 mEHT-exposed cells, which are dying and apoptotic cells. mEHT also reduced both weight and volume of xenograft tumors in mice transplanted with ovarian and cervical cancer cells and patient-derived cancer tissues. We determined that mEHT-induced cellular damage recovery was mediated by autophagy and, therefore, expectedly, cotreatment with mEHT and 3-methyladenine (3-MA), an autophagy inhibitor, more effectively inhibited cancer cell growth than individual treatment did. CONCLUSIONS: mEHT treatment alone was sufficient to inhibit cancer growth, while a combined treatment with mEHT and an autophagy inhibitor amplified this inhibition effect. PMID- 30428739 TI - After obstetric fistula repair; willingness of women in Northern Nigeria to use family planning. AB - Utilisation of modern family planning (FP) is important for women with obstetric fistula (OF). Preventing pregnancy ensures a proper healing and the success of fistula repair. In Northern Nigeria, prevalence of OF is high while the prevalence of FP utilisation is low. This study assessed the willingness to use family planning among 420 women receiving care at obstetric fistula centres in three northern Nigerian States using a semi-structured questionnaire. Concerning family planning methods, 56.7% were aware, only three (1.3%) had ever utilised any method and 63.8% were willing to use a family planning method in the near future. Age, type of marriage and the presence of surviving children were the significant predictors of willingness to use family planning among women with fistula. There is a moderate awareness of family planning with very low utilisation rates. However, a high proportion of these women are willing to use FP. Therefore, there is a need for integration of FP services with OF services. Impact statement What is already known on this subject? Obstetric fistula remains a problem of public health significance in developing countries and emphasis is being laid on surgical repair which is successful in 80-95% of cases. What do the results of this study add? The willingness of women with OF to use FP to improve repair success rate and prevent recurrence by delaying pregnancy. What are the implications of these findings for clinical practice and/or further research? It provides a proxy for post-repair practice. It also assesses the integrated fistula repair services which include counselling and providing the use of family planning services. PMID- 30428740 TI - Diagnostic pitfalls in ovarian androgen-secreting (Leydig cell) tumours: case series. AB - Leydig cell tumours of the ovary are rare and represent a diagnostic challenge not only due to their sporadic incidence but also due to the seemingly normal imaging. We present three cases of pre- and postmenopausal women who were presented with severe clinical signs of hyperandogenism where modern imaging modalities (including computed tomography (CT), magnetic resonance imaging (MRI) and positron-emission tomography combined with computed tomography (PET-CT)) failed to identify the tumour. Two patients underwent non-expert ultrasound, CT and MRI examination with uniform conclusion that ovaries are of normal appearance. One of the two patients even had a PET-CT performed, which was inconclusive. Our case reports show the importance of examination by specialists with established skills in gynaecologic ultrasonography in the diagnosis of the Leydig cell tumours. The most useful diagnostic tool seems to be the combination of age (postmenopause), symptoms (onset of hirsutism and virilisation), high total testosterone plasma values and expert sonography. On ultrasound, these tumours are unilateral, usually small, solid intraovarian nodules of a slightly increased echogenicity in contrast to the surrounding ovarian tissue, delineated by abundant perfusion with an enhanced vascularity. The appropriate setting of the sensitive colour Doppler is crucial for the detection of intraovarian Leydig cell tumour. Impact statement What is already known on this subject? A diagnosis of Leydig cell tumours is based on ultrasound performed by a trained examiner or by MRI. CT or PET/CT are not among the primary methods of choice. According to the results of imaging investigations surgical treatment is planned. Because these tumours are usually benign and have a good prognosis the unilateral salpingo-oophorectomy is a standard procedure. What do the results of this study add? Our case series show how difficult it can be to establish the diagnosis of Leydig cell tumours by imaging, including transvaginal ultrasound, the most frequently recommended diagnostic tool. We demonstrate in three cases how easily a small hyperechogenic tumour can be overseen or interchanged for a different gynaecological pathology if transvaginal scan is not performed by an experienced examiner trained in sonographic features of gynaecologic neoplasms. What are the implications of these findings for clinical practice and/or further research? This case series demonstrate how important it is to see the patient in the whole complexity with their medical history, proper clinical symptoms evaluation, laboratory test and not to rely solely just on sophisticated high-end investigations, such as the PET-CT, a CT and an MRI. It also emphasises the importance of specialists with established skills in gynaecologic ultrasonography. Further effort should be made to define the resources for the appropriate training of such sonographers. PMID- 30428741 TI - Robot-assisted percutaneous placement of K-wires during minimally invasive interventions of the spine. AB - PURPOSE: To assess the accuracy and time requirements of image-guided percutaneous K-wire insertion in the spine using an advanced robot assistance device for needle guidance and to demonstrate a radiation-free workflow for the physician. MATERIAL AND METHODS: A planning CT-scan was acquired of a cadaver specimen and analyzed using a 3D-interventional software integrated in the robotic device. The optimal needle path was simulated and the needle holder of the robot was used for guidance during K-wire insertion. Twenty-four K-wires were inserted percutaneously in a transpedicular approach in the following vertebrae: thoracic (T) 2, 7-12 and lumbar (L) 1-5. A post-procedural CT scan was performed to analyze the accuracy of the K-wire insertion. RESULTS: All procedures were carried out without any perforation of the pedicle wall. The mean duration of planning the intervention path was 2:54 +/- 2:22 min, mean positioning time was 2:04 +/- 0:42 min and the mean time for K-wire insertion was 2:13 +/- 0:54 min. In total, the average intervention time was 7:10 +/- 3:06 min per pedicle. Compared to the planning, the K-wire position showed a mean deviation of 0.5 mm in the vertical-axis and 1.2 mm in the horizontal-axis. The average intervention path length was 8.1 cm. CONCLUSION: Our findings show a high accuracy in robot assisted K-wire insertion during spinal interventions without any exposure of the operator to radiation. PMID- 30428742 TI - Acute ischemic stroke secondary to cardiac embolus of a 'foreign body' material after a redo sternotomy for mitral valve replacement: A case report. AB - Cardiac surgery has been shown to be associated with increased risk of acute ischemic stroke. This report presents a case of a successful mechanical embolectomy procedure to treat a patient for an acute ischemic stroke, which was caused by the cardiac embolization of a 'foreign body' containing debris following a redo sternotomy procedure for mitral valve replacement and tricuspid valve annuloplasty. PMID- 30428743 TI - Recurrent incarceration of the severely retroverted uterus with successful second trimester reduction. PMID- 30428744 TI - Factors influencing MR changes associated with sacral injury after high-intensity focused ultrasound ablation of uterine fibroids. AB - PURPOSE: We investigated the risk factors influencing MR changes associated with sacral injury from ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation for uterine fibroids. METHODS: We retrospectively analyzed a total of 346 patients with symptomatic uterine fibroids who received USgHIFU ablation. All of the patients underwent contrast-enhanced magnetic resonance imaging (CE-MRI) before and after treatment. Injury to the sacrum was set as the dependent variable, while fibroid features and the treatment parameters were set as independent variables. These variables were used to assess respectively their correlation with sacral injury by using univariate and multivariate analyses. RESULTS: The results of univariate analysis revealed that the volume, distance from the fibroid to the skin, maximal diameter, distance from the fibroid to the sacrum, fibroid types, degree of enhancement, therapeutic dosimetry (TD), energy efficiency factor (EEF) and non-perfused volume (NPV) ratio manifested significant correlations with the sacral injury (p < .05). Multivariate analysis showed that the degree of enhancement, TD and EEF were independent risk factors for sacral injury (p < .05), while the distance from fibroid to sacrum and intramural or subserosal types were protective factors (p < .05). The incidence of sacral tail pain and leg pain showed a significant positive correlation with sacral injury (p < .05). CONCLUSION: As important affecting factors, the degree of enhancement, distance from fibroid to sacrum and fibroid types all possess significant correlations with MR changes associated with sacral injury. PMID- 30428745 TI - Chronic tubal ectopic pregnancy following clinically successful methotrexate treatment for an acute ectopic: a review of the literature. PMID- 30428746 TI - Main title: pulmonary vascular disease is evident in gene regulation of experimental bronchopulmonary dysplasia. AB - OBJECTIVE: To examine the gene expression regarding pulmonary vascular disease in experimental bronchopulmonary dysplasia in young mice. Premature delivery puts babies at risk of severe complications. Bronchopulmonary dysplasia (BPD) is a common complication of premature birth leading to lifelong affection of pulmonary function. BPD is recognized as a disease of arrested alveolar development. The disease process is not fully described and no complete cure or prevention is known. The focus of interest in the search for treatment and prevention of BPD has traditionally been at airspace level; however, the pulmonary vasculature is increasingly acknowledged in the pathology of BPD. The aim of the investigation was to study the gene expression in lungs with BPD with regards to pulmonary vascular disease (PVD). METHODS: We employed a murine model of hyperoxia induced BPD and gene expression microarray technique to determine the mRNA expression in lung tissue from young mice. We combined gene expression pathway analysis and analyzed the biological function of multiple single gene transcripts from lung homogenate to study the PVD relevant gene expression. RESULTS: There were n = 117 significantly differentially regulated genes related to PVD via down-regulation of contractile elements, up- and down-regulation of factors involved in vascular tone and tissue specific genes. Several genes also allowed for pinpointing gene expression differences to the pulmonary vasculature. The gene Nppa coding for natriuretic peptide, a potent vasodilator, was significantly down-regulated and there was a significant up-regulation of Pde1a (phosphodiesterase 1A), Ptger3 (prostaglandin e receptor 3) and Ptgs1 (prostaglandin-endoperoxide synthase one). CONCLUSION: The pulmonary vasculature is affected by arrest of secondary alveolarization as seen by differentially regulated genes involved in vascular tone and pulmonary vasculature suggesting BPD is not purely an airspace disease. Clues to prevention and treatment may lie in the pulmonary vascular system. PMID- 30428747 TI - The role of "improv" in health professional learning: A scoping review. AB - BACKGROUND: The use of improvizational theater ("improv") in health professional education ("medical improv") is an emerging field. However, optimal curricular design features and learning outcomes have not yet been systematically described. OBJECTIVE: To synthesize evidence on learning outcomes and curricular design elements of improvizational theater training in health professions education. METHODS: A literature search with keywords "Improv" and "Improvisational Theatre" was undertaken in January 2016 in Ovid MEDLINE, CINHAL, EMBASE, SCOPUS, Web of Science, and ERIC, with an accompanying gray literature search. Four authors coded and achieved consensus on themes relating to curricular design elements and learning outcomes, which were mapped onto the CanMEDS framework. RESULTS: Seven articles met inclusion criteria. Key curricular design features included (i) facilitators with dual clinical and theater expertise; (ii) creating a low-stakes environment; and (iii) engaging in debrief to highlight clinical relevance. Improv curricula were found to impact most CanMEDS roles, including: Medical Expert (comfort with uncertainty); Leader (team management); Scholar (feedback, self-reflection); Communicator (empathy, active listening, non-verbal communication); Collaborator (culture of trust); and Professional (resiliency and confidence). Mechanisms by which improv may promote acquisition of these professional competencies, and the utility of improv in areas such as interprofessional team development, leadership, and wellness and resiliency are discussed. PMID- 30428749 TI - Teaching empathy with literature. PMID- 30428748 TI - Peripheral tumour targeting using open-source virtual bronchoscopy with electromagnetic tracking: a multi-user pre-clinical study. AB - OBJECTIVES: The goal was to demonstrate the utility of open-source tracking and visualisation tools in the targeting of lung cancer. MATERIAL AND METHODS: The study demonstrates the first deployment of the Anser electromagnetic (EM) tracking system with the CustusX image-guided interventional research platform to navigate using an endobronchial catheter to injected tumour targets. Live animal investigations validated the deployment and targeting of peripheral tumour models using an innovative tumour marking routine. RESULTS: Novel tumour model deployment was successfully achieved at all eight target sites across two live animal investigations without pneumothorax. Virtual bronchoscopy with tracking successfully guided the tracked catheter to 2-12 mm from the target tumour site. Deployment of a novel marker was achieved at all eight sites providing a reliable measure of targeting accuracy. Targeting accuracy within 10 mm was achieved in 7/8 sites and in all cases, the virtual target distance at marker deployment was within the range subsequently measured with x-ray. CONCLUSIONS: Endobronchial targeting of peripheral airway targets is feasible using existing open-source technology. Notwithstanding the shortcomings of current commercial platforms, technological improvements in EM tracking and registration accuracy fostered by open-source technology may provide the impetus for widespread clinical uptake of electromagnetic navigation in bronchoscopy. PMID- 30428750 TI - Testing active choice for screening practitioner's gender in endoscopy among disinclined women: An online experiment. AB - OBJECTIVES: A large proportion of women have a preference for a same-gender endoscopy practitioner. We tested how information about practitioner gender affected intention to have bowel scope screening in a sample of women disinclined to have the test. METHODS: In an online experimental survey, women aged 35-54 living in England who did not intend to participate in bowel scope screening (N = 1060) were randomised to one of four experimental conditions: (1) control (practitioner's gender is unknown), (2) opposite-gender (male practitioner by default), (3) same gender (female practitioner by default), and (4) active choice (the patient could choose the gender of the practitioner). Intention was measured following the interventions. RESULTS: Of 1010 (95.3%) women who completed the survey, most were White-British (83.6%), and working (63.3%). Compared with control, both active choice and same-gender conditions increased intention among disinclined women (9.3% vs. 16.0% and 17.9%; OR: 1.85; 95% CI: 1.07-3.20 and OR: 2.07; 95% CI: 1.23-3.50). There were no differences in intention between the opposite-gender and control conditions (9.8% vs. 9.3%; OR: 1.06; 95% CI: 0.60 1.90) or the active choice and same-gender conditions (16.0% vs. 17.9%: OR: 0.89; 95% CI: 0.55-1.46, using same gender as baseline). CONCLUSIONS: Offering disinclined women a same-gender practitioner, either by choice or default, increased subsequent intention, while an opposite gender default did not negatively affect intention. Reducing uncertainty about gender of practitioner could positively affect uptake in women, and should be tested in a randomised controlled trial. PMID- 30428751 TI - A Pain Reporting Tool for School-Aged Baseball Pitchers. AB - Rates of injury to school-aged athletes are of concern to pediatric providers and can be prevented when players, coaches, and parents recognize and address pain. The aim of the present study was to evaluate the use of a pain-reporting tool. In this study, 34 baseball players aged 10-16 years reported pain surrounding 135 separate pitching experiences. Those participating in another sport on the same day as pitching rated pain intensity as significantly higher than those who did not. Approximately 19 pitches were thrown before participants noticed pain. Ice and analgesics were used appropriately to manage pain. School nurses are well positioned to discuss pain reporting and common injuries with young athletes, parents, and athletic coaches. Sharing proactive ways to elicit information about pain is suggested. Implications for future research include the study of young athlete experiences with pain and development of educational initiatives regarding the importance of reporting pain. PMID- 30428752 TI - Human keratinocytes adapt to ZnO nanoparticles induced toxicity via complex paracrine crosstalk and Nrf2-proteasomal signal transduction. AB - Zinc oxide nanoparticles (Nano-ZnO) is currently one of the most extensively used inorganic particles in a wide range of skin care and consumable products. Therefore, examining the biological effects of Nano-ZnO, especially in the non cytotoxic levels, thus holds important contemporary practical implications. Herein, our study demonstrates that long-term conditioning of human keratinocytes (HaCaTs) to non-cytoxic dose of Nano-ZnO (~100 nm) can induce an adaptive response, leading to an enhancement of the cells tolerance against cytotoxic level of Nano-ZnO. It was found that the Nano-ZnO induced adaptive alteration is mediated by a strong synergism between the generation of reactive oxygen species (ROS) flares by a sub-population of cells that are loaded with Nano-ZnO and upregulation of several pro-inflammatory transcripts. Further studies revealed activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) stress response pathway and the associated downstream sustained augmented level of chymotrypsin-like 20 s proteasome activity to be the major mechanism underpinning this phenomenon. Interestingly, these cytoprotective responses can further aid the Nano-ZnO conditioned HaCaT cells to cross-adapt to harmful effects of ultraviolet-A (UVA) by reducing radiation-induced DNA damage. Our findings have unveiled a range of previously undocumented potent and exploitable bioeffects of Nano-ZnO induced ROS mediated signaling within the framework of nano-adaptation. PMID- 30428753 TI - Special Aspects of Biologics Treatment in Psoriasis: Management in Pregnancy, Lactation, Surgery, Renal Impairment, Hepatitis and Tuberculosis. AB - : Background of the article: Biologics are modern immunomodulatory drugs, whose use in the treatment of psoriasis has led to remarkable results in psoriatic patients. The administration of these agents in special population groups, such as patients with chronic infections and renal impairment, as well as perioperative, pregnant or lactating patients, has not been thoroughly addressed, mostly because these patients are excluded from clinical studies. MATERIALS AND METHODS: This report is an updated systematic overview of the use of biologics in the above mentioned types of patients and was conducted according to the PRISMA Guidelines for systematic reviews. Articles derived from the databases PubMed, EMBASE and SCOPUS, published between 1999 and 2018, were analyzed for the study. RESULTS: Research efforts as well as clinical reporting are necessary in order to provide more insight on the management of these therapeutic dilemmas. CONCLUSION: The aim of this review, other than providing a summarized update on the clinical knowledge on this special topic, is also to raise awareness for the need to conduct larger systematic studies in order to adequately evaluate the use of biologics in these special patient categories and therefore draw definite conclusions on their safety profile. PMID- 30428754 TI - Death attitudes and truth disclosure: A survey of family caregivers of elders with terminal cancer in China. AB - BACKGROUND:: Although family caregivers play an important role in end-of-life care decisions, few studies have examined the communication between family caregivers and patients at the end of life. OBJECTIVE:: The objective was to describe family caregivers' attitudes toward death, hospice, and truth disclosure. RESEARCH DESIGN:: A quantitative method was used, and a closed-ended survey of 140 family caregivers was conducted in China. The subjects included 140 primary family caregivers of elders with terminal cancer enrolled at a hospice center from April to August 2017. PARTICIPANTS:: 140 primary family caregivers of elders with terminal cancer participated the study. RESEARCH CONTEXT:: A high proportion of cancer patients continue to receive inadequate information about their illness. Family caregivers' inhibitions about disclosing information to cancer patients have not yet been the objects of research in China. ETHICAL CONSIDERATIONS:: This study was reported to and approved by the Regional Ethics Committee in Shenzhen, China. FINDINGS:: A questionnaire survey collected information on family caregivers' background information, emotional state, personal needs, death attitudes, and truth-disclosure opinions. The results revealed that family caregivers' death attitudes and truth-disclosure opinions played an important role in the process of caring for elders with terminal cancer. DISCUSSION:: By adopting a quantitative method, the author revealed not only the general patterns of family caregivers' attitudes toward cancer diagnosis disclosure but also the reasons for their actions and the practices of family disclosure. CONCLUSION:: The findings suggested that ineffective communication concerning end-of-life issues resulted from family caregivers' lack of discussion and difficulty in hearing the news. Future studies should examine strategies for optimal communication between family caregivers and patients, especially with regard to breaking the bad news. Professional training in breaking bad news is important and is associated with self-reported truth-disclosure practices among family caregivers. PMID- 30428755 TI - Nursing students' ethical challenges in the clinical settings: A mixed-methods study. AB - BACKGROUND:: Nursing students experience ethical conflicts and challenges during their clinical education. These may lead to moral distress and disturb the learning process. OBJECTIVES:: This study aimed to explore and to evaluate the nursing students' ethical challenges in the clinical settings in Iran. RESEARCH DESIGN:: This was a mixed-methods study with an exploratory sequential design. PARTICIPANTS AND RESEARCH CONTEXT:: A total of 37 and 120 Iranian nursing students participated in the qualitative and quantitative phases, respectively. ETHICAL CONSIDERATIONS:: The ethical committee of Kerman University of Medical Sciences, Iran, approved the protocol of the study. FINDINGS:: Three main categories were extracted from qualitative data including Low attention of nurses to the patients' preferences; Lack of authority; and Inadequate support. A total of 97% of the students had more than one ethical challenge in clinical settings and 48% of them stated that their challenges did not resolve. The total score of perceived ethical challenges was 62.03 +/- 9.17, which was moderate. The highest mean score related to the "Low attention of nurses to the patients' preferences" subscale. DISCUSSION:: The finding confirmed most of the existing results of other international researches about the frequency and kinds of baccalaureate nursing students' ethical challenges. CONCLUSION:: Identifying student ethical challenges helps teachers to manage their clinical learning process better. This study may provide a view for the nurses, clinical educators, and managers toward nursing students' ethical challenges and their impact on nursing students' clinical experiences. PMID- 30428756 TI - Tetrandrine inhibits the proliferation and cytokine production induced by IL-22 in HaCaT cells. AB - OBJECTIVE: To investigate the effect of tetrandrine (Tet) on HaCaT cell proliferation and cytokine expression induced by interleukin (IL)-22, and to investigate the underlying mechanism. METHODS: The half maximal inhibitory concentration (IC50) and antiproliferation effects of Tet on IL-22-treated HaCaT cells were analysed by MTT assay. Signal transducer and activator of transcription 3 ( STAT3) expression was measured by reverse transcription plus real-time quantitative polymerase chain reaction (qPCR) and by Western blot. Phosphorylated (p)-STAT3 levels were also measured by Western blot. Cytokine production by HaCaT cells was analysed by enzyme-linked immunosorbent assay (ELISA) following administration of IL-22 and/or Tet. RESULTS: Tet displayed a dose-dependent inhibitory effect on HaCaT cell proliferation and reduced the phosphorylation level of STAT3 induced by IL-22, without affecting STAT3 mRNA and protein levels. Furthermore, co-incubation with Tet significantly down-regulated HaCaT cell production of tumour necrosis factor (TNF)-alpha, IL-1beta, IL-6, IL 20 and chemokine (C-C motif) ligand 20 (CCL20) induced by IL-22. CONCLUSIONS: Tet inhibits proliferation and cytokine production in HaCaT cells, and the process may involve the inhibition of STAT3 phosphorylation. PMID- 30428757 TI - Twelve tips for developing and running a successful women's group in international academic medicine. AB - Gender inequity in academic medicine remains an important issue worldwide. While institutional programs and policies can help promote equity in recruitment, retention, scholarship, promotion, and leadership, they often do not address the physical and social isolation that many women in international academic medicine face. Creating networking opportunities through building women's groups can provide a personal and professional support structure that decreases isolation and promotes the advancement of women. Based on a multidisciplinary literature review on change processes, group formation, and women's empowerment, as well as lessons learned from personal experience, we offer 12 tips to successfully create, maintain, and support physician women's groups, employing Kotter's change management framework. We believe that these groups can provide a structured platform for networking opportunities to advance women physicians in academic medicine worldwide. PMID- 30428758 TI - Treatment of benign and borderline bone tumors with combined curettage and bone defect reconstruction. AB - PURPOSE:: The management of bone defects following simple curettage of bone tumors is controversial and in light of the numerous emerging substitutes for bone grafts, we wished to review and report our experience with the use of cancellous allograft bone in the treatment of benign and borderline bone tumors. METHODS:: We reviewed the medical records of 164 consecutive patients with benign or borderline bone tumors treated with simple curettage at our orthopedic oncology center between 2009 and 2013. Postoperative radiological changes were evaluated by a modified Neer's classification in defects that were subsequently reconstructed with allograft bone ( n = 133). RESULTS:: Simple curettage with subsequent defect filling using allograft bone was the surgical procedure performed in the majority of our patients (81%) and was associated with a low overall 2.5-year local recurrence (LR; 9.8%) and complication rate (7.5%). The radiological appearance of the grafted defects was deemed satisfactory in 85% of cases, with signs of either complete or partial healing present 6-12 months postoperatively. With respect to pathology, we found high rates of LR in giant cell tumors (GCTs) of bone, simple cysts (SCs) in children, and preexisting local recurrent disease. We did not observe any allograft-related complications. CONCLUSIONS:: Simple curettage and bone defect reconstruction with bone allograft is a sufficient treatment for most benign bone lesions and is associated with a low complication rate. For high-risk entities, such as GCTs of bone, SCs in children, and recurrent disease, additional adjuvant treatment could be considered to avoid LR. PMID- 30428759 TI - Pharmacist-Initiated Management of a Suspected Case of Risperidone-Induced Neuroleptic Malignant Syndrome in an Aged-Care Resident. The Role of Residential Medication Management Reviews in Medication Safety. AB - A 70-year-old female aged-care resident was referred by her general practitioner for a residential medication management review after nurses reported difficulties with swallowing, episodes of hyperthermia, elevated blood pressure, and tachycardia. These symptoms were accompanied by increasing confusion and drowsiness. Risperidone had recently been prescribed to treat behavioral and psychological symptoms of dementia. This case study describes the pharmacist initiated management of the symptoms through a national medication review program. It demonstrates the valuable role collaborative medication reviews play in managing adverse drug reactions in aged-care. PMID- 30428760 TI - Impact of Physician-Pharmacist Covisits at a Primary Care Clinic in Patients With Uncontrolled Diabetes. AB - PURPOSE:: A popular method for enhancing medication management within a patient centered medical home (PCMH) is the physician-pharmacist collaborative management (PPCM) model. To improve efficiency of health-care delivery within 4 federally qualified health centers (FQHCs), the PPCM model was implemented through coordinated physician-pharmacist covisits. OBJECTIVE:: To evaluate the impact of physician-pharmacist covisits on clinical outcomes among patients with uncontrolled diabetes. METHODOLOGY:: This was a retrospective multicenter cohort study including adults (>=18 years old) with uncontrolled type 1 or type 2 diabetes (hemoglobin A1c [HbA1c] >= 8 %) who had at least one covisit between January 1, 2013, and October 1, 2016. The primary clinical metric was mean change in HbA1c from baseline to follow-up. Secondary outcomes included adherence to select American Diabetes Association (ADA) Standards of Medical Care. RESULTS:: A total of 106 patients were included in this analysis. Patients who were managed in the PPCM model experienced a significant decrease in mean change in HbA1c from baseline to follow-up (-1.75 [2.63], P < .001). There was no significant difference in the proportion of patients receiving recommended vaccinations or cardiovascular (CV) risk reduction medications. CONCLUSION:: The results suggest that physician-pharmacist covisits may improve glucose control in patients with uncontrolled diabetes. PMID- 30428761 TI - Failure of tocilizumab in treating two patients with refractory SAPHO syndrome: a case report. AB - Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare autoinflammatory disease with no standard treatment. Interleukin (IL)-6 inhibitors represent a novel therapeutic option for rheumatoid arthritis and some autoinflammatory diseases. However, the clinical utility of IL-6 inhibitors in treating SAPHO syndrome has been poorly investigated. In the present report, we describe two patients with SAPHO syndrome that was unresponsive to conventional treatment. Tocilizumab, an anti-IL-6 receptor monoclonal antibody, was putatively administered according to positive IL-6 immunohistochemical staining in biopsied bone tissues. However, the disease continued to progress, and new-onset or worsening skin lesions were noted with transient neutropenia. These cases demonstrate that tocilizumab may not be an ideal option for treating SAPHO syndrome. PMID- 30428762 TI - False memories in music listening: exploring the misinformation effect and individual difference factors in auditory memory. AB - The study of false memory has had a profound impact on our understanding of how and what we remember, as shown by the misinformation paradigm [Loftus, E. F. (2005). Planting misinformation in the human mind: A 30-year investigation of the malleability of memory. Learning & Memory, 12(4), 361-366. doi:10.1101/lm.94705]. Though misinformation effects have been demonstrated extensively within visual tasks, they have not yet been explored in the realm of non-visual auditory stimuli. Thus, the present study aimed to investigate whether post-event information can create false memories of music listening episodes. In addition, we explored individual difference factors potentially associated with false memory susceptibility in music, including age, suggestibility, personality, and musical training. In two music recognition tasks, participants (N = 151) listened to an initial music track, which unbeknownst to them was missing an instrument. They were then presented with post-event information which either suggested the presence of the missing instrument or did not. The presence of misinformation resulted in significantly poorer performance on the music recognition tasks (d = .43), suggesting the existence of false musical memories. A random forest analysis indicated that none of the individual difference factors assessed were significantly associated with misinformation susceptibility. These findings support previous research on the fallibility of human memory and demonstrate, to some extent, the generality of the misinformation effect to a non-visual auditory domain. PMID- 30428763 TI - Longitudinal melanonychia and subungual hemorrhage in a patient with systemic lupus erythematosus treated with hydroxychloroquine. AB - Hydroxychloroquine is an antimalarial agent, most commonly prescribed in the treatment of several rheumatic diseases. Although generally well tolerated, a variety of mucocutaneous adverse effects have been reported. Besides the familiar adverse effects, longitudinal melanonychia is rarely seen. Although the incidence is extremely low, systemic lupus erythematosus may also cause nail pigmentation in its own right. We report the case of a 55-year-old woman who was diagnosed with systemic lupus erythematosus and presented with longitudinal melanonychia of all 10 fingernails after 3 years of treatment with hydroxychloroquine, without mucocutaneous hyperpigmentation. The pigment of the nail lasted for more than 15 years. To the best of our knowledge, this is first published report of hydroxychloroquine-induced melanonychia without mucocutaneous hyperpigmentation. This case demonstrates that hydroxychloroquine treatment and the primary disease should be considered in the case of multiple nail changes in patients with systemic lupus erythematosus. PMID- 30428764 TI - An Investigation of Health Management Perceptions and Wellness Behaviors in African American Males in Central Texas. AB - Little is known regarding interventions that incorporate health management perceptions among African American (AA) men, to reduce the risk for developing various medical conditions. Using the Theory of Planned Behavior (TPB), the study objective was to better understand health-care perceptions of AA men by assessing participants' attitudes, subjective norms (SNs), and perceived behavioral control (PBC) regarding health management. AA adult males in Texas were recruited to participate in one of four qualitative focus groups. The TPB was used to assess participants' attitudes (advantages/disadvantages), SNs (approvers/disapprovers), and PBC (enablers/barriers) regarding health management. All four sessions were audiotaped, transcribed, and independently analyzed by researchers to identify major themes. Participants ( n = 23) were 45.2 +/- 16.2 years of age (range 24 74). Regarding attitudes toward health management, participants viewed increased longevity and avoiding future health problems as advantages; however, increased cost, lack of confidence in health care, and social pressures were disadvantages. Regarding SNs, parents and children were positive influencers, while spouses and coworkers were both positive and negative influencers. For PBC, a support system and health awareness were identified as enablers, while medical mistrust, fear, and culture were barriers. The results convey that health management behaviors in AA males are multifaceted. Health-care providers should seek to understand these factors, discuss these issues with AA males, and integrate treatment strategies that are culturally informed and patient centered. Findings from this study may be used to develop targeted interventions that improve health outcomes for AA males. PMID- 30428765 TI - Retrospective analysis of cardiac index and lactate production on cardiopulmonary bypass for a congenital cardiac patient population. AB - BACKGROUND:: Providing adequate metabolic support is the principal concern during cardiopulmonary bypass (CPB) with different strategies utilized to enhance oxygen delivery to the patient. Modifying temperature, hematocrit (Hct) and cardiac index (CI) during CPB are primary techniques which aid in this effort. Based upon surgeon preference, the study institution employs differing perfusion strategies (PS) during congenital cardiac surgery requiring CPB. One method utilizes a 2.4 L/min/m2 CI and nadir Hct of 28% (PS1) and the other a 3.0 L/min/m2 CI with a nadir Hct of 25% (PS2). METHODS:: Cardiopulmonary bypass cases during which the PS1 or PS2 strategies were applied were retrospectively examined, finding no significant difference in pre-CPB lactate, maximum lactate on CPB or maximum change in lactate on CPB. RESULTS:: While the post-CPB lactate was statistically significantly higher in the PS2 group (p=0.024), the magnitude of difference (0.15 mmol/L) was small. CONCLUSIONS:: This study illustrates that, when oxygen delivery or tissue perfusion is suspected as the primary cause of lactate production during CPB, increasing the CI to a 3.0 rather than a 2.4 CI may be more advantageous than packed red blood cell administration. PMID- 30428766 TI - Postoperative care via smartphone following carpal tunnel release. AB - INTRODUCTION: This study explores a novel smartphone application for postoperative care following carpal tunnel release (CTR). We hypothesized that a software-based 'virtual visit' for CTR could be safe, effective and convenient for the patient. METHODS: Our group developed the software application utilized in this study. Interactive steps with video instructions enabled patients to complete dressing and suture removal, capture a wound photo, answer a question about median nerve symptoms and capture a video of finger range of motion. Adult patients undergoing endoscopic or open CTR were enrolled. Prior to their scheduled postoperative visit, patients received and completed the module using their smartphone. Agreement between findings of the virtual visit and the corresponding in-person clinical visit was assessed using kappa values. RESULTS: Twenty-two patients were contacted regarding study enrolment and 17 patients were enrolled (ages 23-63, mean 48.2, 6M, 11F). Of 16 patients who participated, all completed dressing removal. Ten of 16 patients removed their sutures successfully. Fourteen patients captured a clinically adequate wound photo and 15 patients answered a question about median nerve symptoms. Fourteen patients captured a range of motion video. Software assessments of surgical wounds, nerve symptoms and physical exams agreed strongly with clinical assessments. DISCUSSION: Most patients were able to respond to a question about their symptoms, provide clinical assessment of their wound via a photo and record a video of their range of motion. Suture removal was the most difficult task. More investigation is needed to determine which patients can reliably remove their sutures. PMID- 30428767 TI - A sad thumbs up: incongruent gestures and disrupted sensorimotor activity both slow processing of facial expressions. AB - Recognising a facial expression is more difficult when the expresser's body conveys incongruent affect. Existing research has documented such interference for universally recognisable bodily expressions. However, it remains unknown whether learned, conventional gestures can interfere with facial expression processing. Study 1 participants (N = 62) viewed videos of people simultaneously producing facial expressions and hand gestures and reported the valence of either the face or hand. Responses were slower and less accurate when the face-hand pairing was incongruent compared to congruent. We hypothesised that hand gestures might exert an even stronger influence on facial expression processing when other routes to understanding the meaning of a facial expression, such as with sensorimotor simulation, are disrupted. Participants in Study 2 (N = 127) completed the same task, but the facial mobility of some participants was restricted, which disrupted face processing in prior work. The hand-face congruency effect from Study 1 was replicated. The facial mobility manipulation affected males only, and it did not moderate the congruency effect. The present work suggests the affective meaning of conventional gestures is processed automatically and can interfere with face perception, but does not suggest that perceivers rely more on gestures when sensorimotor face processing is disrupted. PMID- 30428768 TI - Infants Perceive Three-Dimensional Subjective Contours. AB - The addition of crossed horizontal disparity enhances the clarity of illusory contours compared to pictorial illusory contours and illusory contours with uncrossed horizontal disparity. Two infant-controlled habituation-dishabituation experiments explored the presence of this effect in infants 5 months of age. Experiment 1 examined whether infants are able to distinguish between a Kanizsa figure with crossed horizontal disparity and a Kanizsa figure with uncrossed horizontal disparity. Experiment 2 tested infants for their ability to differentiate between a Kanizsa figure with crossed horizontal disparity and a two-dimensional Kanizsa figure. The results provided evidence that the participants perceived the two- and the three-dimensional illusory Kanizsa contour, the illusory effect in which was strengthened by the addition of crossed horizontal disparity. PMID- 30428769 TI - Long-term effects of a memory group intervention reported by older adults. AB - The aim of this study was to examine older adults' experiences of change following a group memory intervention, the La Trobe and Caulfield Hospital (LaTCH) Memory Group programme. Semi-structured qualitative interviews were conducted with 30 individuals. Participants were healthy older adults and older adults with amnestic mild cognitive impairment (MCI) who had participated in the memory group five years previously. Transcripts were analysed for emergent themes in a workshop, using the Most Significant Change technique. The focus group derived four major themes relating to participants' experiences of change. Particularly noteworthy were themes describing a process of acceptance and normalising of memory difficulties in older age, as well as enhancement of coping and self-efficacy. The results highlight the importance of group support for older adults with and without objective memory impairment. Memory groups may use the group format to full advantage by (a) enhancing participants' experiences of universality to alleviate distress and promote coping, and (b) developing group norms to promote positive ageing, encompassing enhanced acceptance and self efficacy. PMID- 30428771 TI - Response to Letter to the Editor for "You Only Teach PE and It Doesn't Really Matter". PMID- 30428770 TI - By the Way . . . the Last-Minute International Traveler. AB - Evidence has consistently revealed international travelers are increasing in numbers every year as more folks travel for business, pleasure, humanitarian reasons, and medical tourism. Clinicians who consistently counsel travelers are well acquainted with the last-minute traveler who would benefit from a travel health assessment, vaccine administration, and health and safety information to manage travel-related issues while en route and upon arrival. Instruction in travel emergencies and packing tips, with advice to be able to address common travel issues associated health matters, are important strategies for the traveler to understand and better navigate his or her journey. To also serve the traveler are two excellent mobile apps from the Centers for Disease Control, free to the traveler, that are designed to contain travel and vaccine documents and to provide guidance in choosing foods and beverages while abroad. The occupational health nurse's role is to support and reassure the traveler. Even at the last minute, travel health risks can be significantly reduced by the traveler obtaining vaccines and observing healthy practices. PMID- 30428772 TI - TIGA-CUB-manualised psychoanalytic child psychotherapy versus treatment as usual for children aged 5-11 with treatment-resistant conduct disorders and their primary carers: results from a randomised controlled feasibility trial. AB - BACKGROUND: Parenting programmes are recommended for conduct disorders in 5-11 year olds, but ineffective for 25-33%. A feasibility trial was needed to determine whether a confirmatory trial of second-line, manualised short-term psychoanalytic child psychotherapy (mPCP) versus treatment as usual (TaU) is practicable. METHOD: This was a two-arm, pragmatic, parallel-group, multi-centre, individually-randomised controlled feasibility trial with blinded outcome assessment. Child-primary carer dyads were recruited from National Health Service Child and Adolescent Mental Health Services and mPCP delivered by routine child psychotherapists. RESULTS: Thirty-two dyads (50% of eligible, 95% CI 37 to 63%) were recruited, with 16 randomised to each arm. Eleven (69%) completed >=50% of 12 week mPCP and 13 (81%). Follow-up was obtained for 24 (75%) at 4 months and 14/16 (88%) at 8 months. Teacher follow-up was 16 (50%) >=1 session. Manual adherence was good. Baseline candidate primary outcomes were 37.4 (SD 11.4) and 18.1 (SD 15.7) on the Child Behaviour Checklist/Teacher Report Form externalising scale and 102.8 (SD 28.4) and 58.8 (SD 38.9) on the total score. Health economics data collection was feasible and the trial acceptable to participants. CONCLUSION: Recruitment, teacher follow-up and the manual need some refinement. A confirmatory trial is feasible, subject to funding of research child psychotherapists. PMID- 30428773 TI - Farnesoid X Receptor Agonist GW4064 Inhibits Aromatase and ERbeta Expression in Human Endometriotic Stromal Cells. AB - Endometriosis is an estrogen-dependent disease. Farnesoid X receptor (FXR) activation has been shown to inhibit estrogen signaling in breast cancer and testicular tumors. However, the role of FXR in endometriosis is still poorly understood. Here, we aimed to investigate whether FXR activation by its synthetic agonist GW4064 has a therapeutic effect on endometriosis and the underlying molecular mechanisms. We found that the expression of FXR (encoded by the NR1H4 gene) in endometriotic tissues and stromal cells (ESCs) was higher than that in eutopic endometrial tissues and stromal cells. The GW4064 treatment led to a dose dependent decrease in aromatase and estrogen receptor beta (ERbeta) expression and induced ERK1/2, p38, AMPK, and Stat3 activation in ESCs. In contrast, ERK1/2 inhibitor reversed the GW4064-induced reduction in aromatase expression. In addition, treatment with p38, AMPK, and Stat3 inhibitors or small interfering RNAs could also reverse the GW4064-induced reduction of ERbeta expression in ESCs. The GW4064 treatment markedly increased Stat3 phosphorylation, enhancing the binding of Stat3 to the ESR2 promoter, which resulted in the downregulation of ERbeta. Coimmunoprecipitation assay and chromatin immunoprecipitation analysis revealed that FXR was able to compete with cyclic AMP response element-binding (CREB) protein for binding to a common sequence on the aromatase promoter region after GW4064 treatment in ESCs. Moreover, treatment of endometriosis xenografts with GW4064 suppressed aromatase and ERbeta expression in nude mice. Our results suggest that FXR may represent a potential therapeutic target for future therapy. PMID- 30428774 TI - Alexithymia explains increased empathic personal distress in individuals with and without eating disorders. AB - It is often assumed that empathy impairments are common in individuals with eating disorders (EDs), but empirical work has been limited and produced mixed results, making the clinical features and treatment needs of this population difficult to determine. Alexithymia, characterised by difficulties identifying and describing one's own emotions, frequently co-occurs with EDs and is associated with atypical recognition of, and empathy for, others' emotions. This study used an existing empathy for pain paradigm to determine whether atypical empathy in EDs stems from co-occurring alexithymia, rather than EDs per se. Empathy (specifically personal distress in response to others' pain) was assessed in individuals with EDs ( N = 21) and an alexithymia-matched control group ( N = 22). Participants were simultaneously members of a high alexithymia ( N = 16) or low alexithymia ( N = 27) group, allowing the independent contributions of alexithymia and EDs to be determined. Participants judged the laterality of hands and feet in painful and non-painful situations, and the degree of empathic interference on response times was measured. Results indicated that observation of painful stimuli affected task performance in those with high levels of alexithymia more than those with low levels, but no effect of ED diagnosis was observed. These findings suggest that co-occurring alexithymia explains increased empathic personal distress in ED populations. Atypical empathy may therefore not be a core feature of EDs, and interventions aimed at improving empathy-related social functioning may only be necessary for patients who also have alexithymia. These findings emphasise the importance of determining the influence of co occurring alexithymia when assessing empathy in clinical populations. PMID- 30428775 TI - Guardianship and Predatory Crimes among Incapacitated Persons in Kentucky. AB - PURPOSE: Guardianship is a legal process intended to aid incapacitated persons unable to fully care for themselves. Guardianship in the state of Kentucky ranges from total observation (24-hour care) to informal care (such as a group home) and also includes persons who are no longer being supervised but should be. One intent of guardianship includes preventing incapacitated persons from engaging in criminal acts. However, no research has been conducted on incapacitated persons currently in guardianship and the prevalence for committing predatory crimes such as murder, fire starting, or assault. METHOD: In this study, the authors examine guardianship supervision levels and predatory crimes in the state of Kentucky. Logistic regression analysis was used to determine the variables that significantly contributed to the model. RESULTS: They find that unsupervised incapacitated persons are at higher odds of committing predatory crimes, leading to important policy recommendations for Kentucky guardians. PMID- 30428776 TI - AO principles of fracture management. PMID- 30428777 TI - Differential Regulation of Myosin Regulatory Light Chain Phosphorylation by Protein Kinase C Isozymes in Human Uterine Myocytes. AB - BACKGROUND:: Preterm birth is the most common cause of neonatal morbidity and mortality and a common precedent to lifelong disability. Current treatment has minimal efficacy. OBJECTIVE:: We assessed the role of isozymes of the protein kinase C (PKC) family in regulating the phosphorylation of myosin regulatory light chains (RLCs), which regulate uterine contractility. We also explored the mechanisms through which these isozymes function. STUDY DESIGN:: We used a previously characterized and validated quantitative in-cell Western (ICW) assay to measure site-specific phosphorylations on myosin RLC and CPI-17. Cultures of human uterine myocytes (hUM) were treated with the potent contractile stimulant oxytocin to induce uterine contractility or a pharmacological mimic of diacyl glycerol to stimulate the conventional and novel isozymes of the PKC family. Combinations of isozyme-selective inhibitors were used to determine the effects of the conventional and novel classes of isozymes. RESULTS:: Stimulation of PKC using phospho-dibutyrate caused immediate, concentration-dependent inhibition of uterine activity ex vivo. Using the ICW assay with hUM, the oxytocin-stimulated increase in the pro-contractile phosphorylations of myosin RLCs at serine19 and threonine18 was completely inhibited by prior treatment with phorbol-12-myristate 13-acetate, which stimulates both convention and novel classes of isozymes. Our results suggest that the conventional class of isozymes cause a reduction in phosphorylations at serine19 and threonine18 by reducing activity of myosin light chain kinase. The novel class of isozymes has 2 mechanisms of action: the first is activation of CPI-17 through phosphorylation at threonine38, which results in reduced activity of myosin light chain phosphatase and increased levels of activated myosin RLC; the second is increased phosphorylation of the N-terminal region of myosin RLC. CONCLUSIONS:: Specific agonists for the conventional isozymes or inhibitors of the novel isozymes of the PKC family could be useful pharmacological agents for regulation of uterine activity. PMID- 30428778 TI - Early maternal sensitivity, attachment security in young adulthood, and cardiometabolic risk at midlife. AB - Children who experience high-quality early parenting tend to have better physical health, but limited research has tested whether this association extends into adulthood using prospective, observational assessments. Likewise, mechanisms that may explain such links have not yet been illuminated. In this study, we test whether the quality of early maternal sensitivity experienced during the first 31/2 years of life predicts cardiometabolic risk at midlife (ages 37 and 39 years) via attachment representations measured in young adulthood (ages 19 and 26 years). We do so by comparing the predictive significance of two different forms of attachment representations coded from the Adult Attachment Interview (AAI): (a) secure base script knowledge and (b) coherence of mind. Using data from the Minnesota Longitudinal Study of Risk and Adaptation, we find that early maternal sensitivity is negatively associated with cardiometabolic risk at midlife. Secure base script knowledge (but not coherence of mind) partially mediated this link. These findings are consistent with the possibility that early parenting has lasting significance for physical health in part by promoting higher levels of secure base script knowledge. PMID- 30428779 TI - Carbon Monoxide Poisoning. AB - Carbon monoxide poisoning is a serious and life-threatening event. Educating workers and communities on exposure sources, symptoms, and prevention is an important role for occupational health nurses. PMID- 30428780 TI - Accurate quantification of uncertainty in epidemic parameter estimates and predictions using stochastic compartmental models. AB - Stochastic transmission dynamic models are needed to quantify the uncertainty in estimates and predictions during outbreaks of infectious diseases. We previously developed a calibration method for stochastic epidemic compartmental models, called Multiple Shooting for Stochastic Systems (MSS), and demonstrated its competitive performance against a number of existing state-of-the-art calibration methods. The existing MSS method, however, lacks a mechanism against filter degeneracy, a phenomenon that results in parameter posterior distributions that are weighted heavily around a single value. As such, when filter degeneracy occurs, the posterior distributions of parameter estimates will not yield reliable credible or prediction intervals for parameter estimates and predictions. In this work, we extend the MSS method by evaluating and incorporating two resampling techniques to detect and resolve filter degeneracy. Using simulation experiments, we demonstrate that an extended MSS method produces credible and prediction intervals with desired coverage in estimating key epidemic parameters (e.g. mean duration of infectiousness and R0) and short- and long-term predictions (e.g. one and three-week forecasts, timing and number of cases at the epidemic peak, and final epidemic size). Applying the extended MSS approach to a humidity-based stochastic compartmental influenza model, we were able to accurately predict influenza-like illness activity reported by U.S. Centers for Disease Control and Prevention from 10 regions as well as city-level influenza activity using real-time, city-specific Google search query data from 119 U.S. cities between 2003 and 2014. PMID- 30428781 TI - The $74,973 Question: Are Medicare Beneficiaries Informed Users of Private Medical Care Contracts? AB - Health-care providers are allowed to opt-out of Medicare, privately contract with beneficiaries, and require that beneficiaries pay the full cost of services. Responses from a nationally representative sample of Medicare beneficiaries reveal that they lack the knowledge necessary to make informed decisions regarding such contracts. For example, only 4.6% of participants knew the correct answer to a real-life $74,973 question, leaving a full 95.4% vulnerable to paying a large bill, even a $74,973 bill, they should not pay. In addition to advocating that Medicare effectively monitor private medical care contracts, social workers should educate beneficiaries and/or their caregivers on the implications of entering into such contracts or refer them to their State Health Insurance Assistance Program or Senior Medicare Patrol program for expert guidance. PMID- 30428782 TI - Minimally Invasive Aortobiilliofemoral Endarterectomy for Aortoiliac Occlusive Disease Is a Compelling Alternative to Bypass. AB - INTRODUCTION:: Aortobifemoral bypass is a time-honored, durable surgery allowing restoration of lower extremity blood. However, the potential for significant complications exists, impacting mortality, morbidity, and quality of life. Minimally invasive aortobiiliofemoral endarterectomy offers an alternative to prosthetic bypass and its associated complications. Here, we present a case series using remote endarterectomy for aortoiliac occlusive disease. METHODS:: Nine patients with aortoiliac occlusive disease were treated at a single institution, by a single surgeon, with direct and remote endarterectomy combination. Standard femoral access approach was used. A limited longitudinal distal aorta arteriotomy into the right common iliac artery to the hypogastric bifurcation was made. Then, an open thromboendarterectomy was performed. Circumferential common femoral endarterectomies were performed bilaterally and the plaque transected, allowing manually controlled Vollmar ring passage proximally to the iliac bifurcation on the right and the aortic bifurcation on the left. Aortoiliac arteriotomy was closed, followed by the femoral arteriotomies. Morbidity, secondary interventions, recurrent stenosis (adjacent segment velocity ratios >=2), ankle-brachial index (ABI), and patency rates were tracked postoperatively for 6 years. Kaplan-Meier life-table analysis was used to determine patency rates per the criteria of SVS and ISCS. RESULTS:: The average age was 59.1 years (54-87 years), and 88% were male. Comorbidities included hypertension (75%), former/current smokers (100%), and prior PAD surgical intervention (38%). Revascularization of 100% was achieved, with average ABI improving from 0.42 preoperatively to 0.92 postoperatively (0.91 at 8-month follow-up). Six-year patency rate was 100% without reintervention. Incidence of myocardial infarction, stroke, death, amputation, intestinal ischemia, sexual dysfunction, and aneurysmal degeneration was zero after 6 years of follow-up. CONCLUSION:: Minimally invasive aortobiiliofemoral endarterectomy is a viable alternative to aortobifemoral bypass for the treatment of aortoiliac occlusive disease, allowing reestablishment of normal anatomic anatomy while avoiding the use of prosthetic material. Patency rates in this series was 100% at 6 years, with minimal postoperative complications or morbidity. PMID- 30428783 TI - From the Masters: Lumper? Or splitter? PMID- 30428784 TI - Analyzing Factors Associated With Decisional Stage of Adoption for Colorectal Cancer Screening Among Older Korean Americans Using Precaution Adoption Process Model. AB - INTRODUCTION: For Korean Americans (KAs), colorectal cancer (CRC) screening rates remain lower than the national target. This study aimed to examine factors predicting decisional stage of CRC screening adoption among older KAs using the precaution adoption process model. METHOD: Convenience sampling was employed to recruit KAs aged 50 to 75 years from the Atlanta metropolitan area in the United States. A total of 433 KAs completed a cross-sectional survey that collects information on sociodemographics, CRC screening history, a physician's recommendation, knowledge, self-efficacy, and decisional balance pertaining CRC screening, and precaution adoption process model stage. RESULTS: Higher scores of decisional balance (odds ratio [ OR] = 1.34), having a physician's recommendation ( OR = 8.61), and having regular annual medical checkups ( OR = 4.44) were significantly associated with higher decisional stage compared with lower stage, controlling for other variables. DISCUSSION: Intervention research should incorporate consideration of individuals' decisional stage to move KAs forward from not engaging the screening to maintaining regular participation in CRC screening. PMID- 30428785 TI - TFCC Lesions in Children and Adolescents: Open Treatment. AB - BACKGROUND: There has been little discussion regarding the lesion of the TFCC in pediatric and adolescent patients. This study examines 11 cases treated with open technique. METHODS: Range of motion (ROM), strength and functional scores (QUICK DASH, PWRE, VAS pain, and NAKAMURA score) were evaluated. RESULTS: The mean postoperative flexion-extension arc was 95% of the contralateral side, the radio ulnar deviation 91% of the contralateral side and the pronation-supination arc 94% of the unaffected side. Grip strength was 85.6% of the uninjured wrist, pinch was 88%. The mean PRWE decreased from 84.4 to 9.85 postoperatively. The mean Q DASH scored 10.4. The VAS pain under stress decreased from a mean of 6.8 to a mean of 2.27, while at rest it decreased from a mean of 5 to a mean of 0.5. The final clinical results obtained by Nakamura score were 2 excellent, 6 good and 3 fair. CONCLUSIONS: This study emphasizes that open surgical TFCC repair is a safe and reliable therapeutic procedure in children and adolescent populations. PMID- 30428786 TI - The Acute Management of Unstable Intra-Articular Fractures of the Base of the Middle Phalanx: A Systematic Review. AB - BACKGROUND: Within hand trauma, the management of unstable, intra-articular fractures of the base of the middle phalanx remains highly controversial. The objective of this research was to determine which operation gives the best outcome in the management of displaced, intra-articular fractures of the base of the middle phalanx causing instability of the proximal interphalangeal joint. METHODS: A scoping study was performed to determine the evidence available and the terminology used. A Systematic Review was then performed along PRISMA guidelines. This Systematic Review looked specifically for papers available in English, published over the last ten years, with clinical data for at least five cases of acute unstable fractures of the base of the middle phalanx. There must be two years follow-up with less than 30% loss to follow-up. RESULTS: There were no Systematic Reviews or Cochrane reviews. There were no randomized controlled trials and the best studies were simply cohort studies with level III or IV evidence. There was a paucity of high quality studies, with small, heterogeneous groups, short length of follow-up and high loss to follow up. Only seven papers met the Systematic Review criteria. CONCLUSIONS: General trends show excellent return of grip strength and good function despite some ongoing pain and stiffness. There were high complication rates for all techniques and the possible reasons for different outcomes are discussed. PMID- 30428787 TI - Trends and Demographics in the Utilization of Total Wrist Arthroplasty. AB - BACKGROUND: Health disparities exist among many patient populations, with race, payer status, hospital size and access to teaching versus non-teaching hospitals potentially affecting whether certain patients have access to the benefits of total wrist arthroplasty (TWA). METHODS: The National Inpatient Sample Database (NIS) was queried from 2001 to 2013 for TWA using the ICD-9 code 81.73. Patient level data included age, sex, race, payer status, and year of discharge. Hospital level data included hospital bed size, location, teaching status, and region. RESULTS: There were 1,213 patients identified who underwent TWA between 2001 and 2013. Total number of procedures decreased from 88 TWAs in 2001 to 65 in 2013. The yearly volume ranged from 33 in 2005 to 128 in 2007. The male-female ratio was 2.5 to 1. The majority of TWA procedures were performed at urban teaching hospitals (60.8%). CONCLUSIONS: The NIS database shows a downward trend of total wrist arthroplasty utilization. The majority of total wrist arthroplasties were performed at urban teaching hospitals indicating treatment occurs most often at academic centers of excellence. PMID- 30428788 TI - A Case of Thumb Polydactyly which Ulnar Thumb Has No Active Motion in Ring Chromosome 4. AB - The objective of this study was to clarify the difference in thumb deformity between our case with ring chromosome 4 and thumb polydactyly, in which ulnar side was small and had no active motion, and other cases of ring chromosome 4, by analyzing previous reports. Our case had bilateral atypical thumb polydactyly, which was classified as type 4 on the right side and type 5 on the left side, according to the Japanese Society for Surgery of the Hand: Modified International Federation of Societies for Surgery of the Hand classification. Of the 39 cases in previous reports, 20 (51.3%) had thumb deformities. Among them, 19 cases (95%) showed radial ray deficiency and only 1 case (5%) showed bilateral thumb polydactyly. Clinodactyly was seen in 5 cases (12.8%). Foot deformities were present in 6 cases (15.4%). We discussed about thumb polydactyly with and without chromosomal deformities. PMID- 30428789 TI - Investigate the Effect of Psychological Factors in Development of Complex Regional Pain Syndrome Type I in Patients with Fracture of the Distal Radius: A Prospective Study. AB - BACKGROUND: To investigate the role of psychological factors (anxiety and depression) and pain measured on a visual analogue scale (VAS) in the development of complex regional pain syndrome type I (CRPS I) following the distal radius fracture (DRF). METHODS: A consecutive sample of patients (N=60) with a distal radius fracture was measured for signs of CRPS by Budapest criteria weekly till 8 weeks and then another follow-up one year after injury to determine the incidence and predictors of developing CRPS I in a prospective cohort study and also to discover whether there is difference between pain, depression, and anxiety level in the patients with and without CRPS I. The most of the patients were treated by Pin stabilization. The Beck depression inventoryshort form (BDI), State-Trait Anxiety Inventory, and Numerical pain rating scale were used to determine the patients' psychological features and pain intensity at the base line and 8 weeks after the fracture. RESULTS: CRPS I developed in 15 (25%) patients after eight weeks and just last in 10 (16.67%) patients after one year. No difference was found between the two groups (CRPS and non-CRPS group) in terms of state (STAI-I) and trait (STAI-II) anxiety, and BDI score. Pain at the base line was the most important risk factor in developing CRPS (odds ratio [OR] =1.52; 95% CI). CONCLUSIONS: After fracturing the distal radius, patients who have high pain intensity have a higher risk of developing CRPS I. To following these patients closely for the development of CRPS I may be advantageous for early preventative and therapeutic interventions. PMID- 30428790 TI - Atypical Presentation of Pyogenic Granuloma of the Right Index Finger: A Rare Case Report. AB - Pyogenic granuloma, also known as lobular capillary hemangioma, is a benign vascular lesion of the skin or mucous membrane with rapid growth or repetitive trauma. Rarely seen in adult, its management varies and surgical intervention is usually common. We report a case of pyogenic granuloma of the right index finger in a 46-year-old gentleman who presented with painless swelling of the right index finger after a trivial injury. Wedge biopsy confirmed the diagnosis and excision of the granuloma measuring 3 cm * 3 cm * 2 cm was done with curettage and electrocautery over the base of granuloma. The wound subsequently healed well with good functional and aesthetic outcome. PMID- 30428791 TI - Growth Factor and Intense Pulse Light in Flexor Tendon Repair: A Biomechanical Study at Strength and Gap Resistance. AB - BACKGROUND: Flexor tendon injuries are extremely common and they are usually the result of incised traumatic glass or knife injury. The process of tendon healing is a complicated and exceptionally-regimented mechanism that is originated and monitored by a vast number of diverse molecules. One of the most pivotal groups of mediators that are crucial to the healing process are growth factors (GF). Intense pulse light (IPL) can lead to evidence of new collagen formation with associated clinical improvement in tissue healing. The biological benefit of Intense pulse light (IPL) relies on judicious photothermolysis, where heat driven radiation is dissipated and focused at the cellular level. The aims of this study is to set out the effect of growth factor and IPL on healing following a tendon repair. METHODS: Bovine common digital extensor tendons (CDET) were used as an ex vivo model. 44 tendon repairs were performed by the lead author using 2.5 * magnification loupes and standard instruments. Clamped tendons were assigned into the following groups; control, IPL, GF, IPL and GF. After culturing, biomechanical testing was carried out using monotonic tensile testing with displacement-controlled uniaxial tension to failure. RESULTS: The mean values for ultimate tensile stress (UTS) for the control group was 53.51 N, for IPL it was 51.15 N, for growth factor was 70.10 N and for combined growth factor and IPL it was 75.16 N. CONCLUSIONS: This study showed significant improvement in UTS when repaired tendons were cultured with growth factor compared to control and IPL. This would suggest a biomechanical advantage for tendon healing. PMID- 30428792 TI - Persisting Complaints after Carpal Tunnel Release: Nerve Compression by the Palmaris Profundus Muscle. AB - We present the case of a 66-year-old man who had persisting complaints after initial classical open carpal tunnel release. During revision a reversed palmaris profundus muscle was identified as being the cause of residual compression of the median nerve. Neurolysis with release of the palmaris profundus muscle was performed without resection of this anatomical variant and resulted in full resolution of the complaints. PMID- 30428793 TI - Midcarpal Arthrodesis Biomechanics: Memory Staples versus Cannulated Screws. AB - BACKGROUND: Midcarpal arthrodesis is a treatment of choice in patients with midcarpal arthritis. Traditionally a four corner fusion has been favoured, however recent research has shown improved results when the triquetrum and scaphoid are excised. There is no clear evidence as to which remaining bones should be fused or which implants should be used. The purpose of this study is to compare the biomechanics of midcarpal arthrodesis after scaphoid and triquetrum excision, using memory staples or cannulated screws, in recognised construct patterns. METHODS: 36 identical sets of carpal bones were 3D printed from acetyl butyl styrene. Midcarpal arthrodeses were performed in three configurations with shape memory alloy staples or headless compression screws. This gave 6 treatment groups; lunocapitate single staple or screw, lunocapitate with 2 staples or screws, three corner fusion with 2 staples or screws. Peak torque to distraction was measured and analysed. RESULTS: The peak torque to distraction was significantly greater in almost all constructs utilizing screws compared to staples, with two lunocapitate screws having the highest peak torque at both 1 and 3 mm distraction with 244 Nmm and 749 Nmm respectively (p < 0.05). CONCLUSIONS: Constructs utilizing screws have a peak torque to distraction significantly higher when compared to staples. Our recommendation when performing a midcarpal arthrodesis after scaphoid and trapezium excision is to fuse the midcarpal joint with 2 headless compression screws. PMID- 30428794 TI - Description and Clinical Assessment of the Bone Block Tendon Interposition Technique for the Management of Thumb Carpometacarpal Joint Osteoarthritis. AB - BACKGROUND: Pellegrini's surgical technique is the most useful for thumb carpometacarpal joint osteoarthritis. The purpose of this paper is to describe the technique of a modified version using a bone block in the tunnel through which the flexor carpi radialis tendon is passed (BBTI). METHODS: Case series of patients diagnosed with osteoarthritis of the thumb carpometacarpal joint, in stage II or higher based on Eaton's classification, that were intervened using the BBTI technique for a 2-year period. Grip and pinch strength, range of motion, and 1-2 metacarpal angle were evaluated. Pain and function were measured using the visual analogue scale and the Disabilities of the Arm, Shoulder and Hand (DASH) scale. RESULTS: The study included 16 cases in 14 patients (11 women and 3 men), with an average age of 55.7 +/- 7.1 years. Encouraging results were obtained, with an average DASH score of 24.3 +/- 17.9 and a minimum VAS pain score. A total of 58% showed a grip strength of over 80% and the postoperative movement was equivalent to the contralateral limb. No cases of infection were reported, and only two minor complications were observed. CONCLUSIONS: The BBTI technique is a surgical option that incorporates an interference screw, offering good functional results for managing osteoarthritis of the thumb carpometacarpal joint, with a similar complication rate to that of the original technique. PMID- 30428795 TI - Locked Metacarpophalangeal Joint of the Little Finger in Extension Position due to the Incarceration of a Chronic Fracture Fragment: A Case Report. AB - We managed a case of locked metacarpophalangeal joint of the little finger in the extension position. Incarceration of a chronic osteochondral fracture fragment led to this unique condition. The fracture fragment partially adhered to the volar plate and ulnar collateral ligament on the joint side, which is supposed to have resulted in manually irreducible locking of the joint. We performed open reduction and achieved release of the locked joint by excising the fracture fragment. PMID- 30428796 TI - Flexor Tendon Injuries and Repairs: A Single Centre Experience. AB - BACKGROUND: Although flexor tendon injuries cause significant morbidities and socio-economic implications, there have been limited data on patient demographics, injury characteristics and surgical details. The aim of this study is to describe our experience in flexor tendon injuries and repairs. METHODS: We performed a retrospective study of all digital flexor tendon injuries that were repaired from January 2011 to December 2014. The collected data included patient demographics, injury characteristics and surgical details. RESULTS: A total of 214 patients, 308 digits with 446 flexor tendon repairs were identified. We found that males, non-residents, and 20-29 age group were most prone to flexor tendon injuries. Cleaners, labourers and related occupations were the most vulnerable. The mechanism of injury was usually work-related and mostly caused by glass. Most injuries involve both flexor digitorum profundus and flexor digitorum superficialis tendons. Concomitant digital nerve and vessel injuries were common. Most patients suffered zone 2 laceration of a single digit of the non-dominant hand. Most patients underwent procedures that lasted 1 to 2 hours, including multiple flexor tendon repairs, microsurgical repairs and other interventions. CONCLUSIONS: This study is the largest study on patient demographics, injury characteristics and surgical details on flexor tendon injuries and repairs. It could be used to plan resources and policies for the management and prevention of flexor tendon injuries. PMID- 30428797 TI - Effects of Anthropometric Measurements on Treatment Outcomes in Patients with Carpal Tunnel Syndrome. AB - BACKGROUND: The purpose of this study was to investigate the relationship between anthropometric hand/wrist measurements and outcomes following static wrist splintage in patients with mild-to-moderate carpal tunnel syndrome (CTS). METHODS: Thirty nine patients with mild-to-moderate CTS were enrolled in this study. Anthropometric measurements of hand and wrist including wrist width, wrist depth, palm length, hand length, wrist ratio (wrist depth/wrist width) and wrist/palm ratio (wrist depth/palm length) were recorded as well as body mass index and ultrasonographic cross sectional area of median nerve. Patients were treated with static wrist splints and evaluated at 2nd, 4th and 12th weeks with Boston Carpal Tunnel Questionnaire, median nerve nerve conduction studies, Visual Analog Scale for pain and Likert Scale for numbness. RESULTS: Following treatment with a static wrist splint, the wrist ratio was correlated significantly with improvements in Boston Functional Status Scale at the second and forth weeks (r = -0.354, p = 0.027 and r = -0.320, p = 0.050 respectively) and Visual Analog Scale at the forth and 12th weeks (r = -0.352, p = 0.030 and r = -0.360, p = 0.029 respectively). CONCLUSIONS: Splinting provides symptomatic improvement in mild-to moderate CTS and this study suggests that the wrist anthropometric measurements may influence treatment outcomes. PMID- 30428798 TI - An Exploratory Study Using Semi-Tabular Plate in Zone II Flexor Tendon Repair. AB - BACKGROUND: This study evaluated the feasibility of using a low-profile titanium (Ti) plate implant, also known as the Ti-button, for Zone II flexor tendon repair. We hypothesize that the use of the Ti-button can distribute the tensile force on the digital flexor tendons to achieve better biomechanical performance. METHODS: Twenty lacerated porcine flexor tendons were randomly divided into two groups and repaired using Ti-button or 6-strand modified Lim-Tsai technique. Ultimate tensile strength, load to 2 mm gap force, and mode of failure were recorded during a single cycle loading test. We also harvested twelve fingers with lacerated flexor digitorum profundus tendons from six fresh-frozen cadaver hands and repaired the tendons using either Ti-button method or modified Lim-Tsai technique. A custom-made bio-friction measurement jig was used to measure the gliding resistance and coefficient of friction of the tendon sheath interface at the A2 pulley. RESULTS: The ultimate tensile strength, load to 2 mm gap force, stiffness, and gliding resistance of the Ti-button repairs were 101.5 N, 25.7 N, 7.8 N/mm, and 2.2 N respectively. Ti-button repairs had significantly higher ultimate tensile strength and stiffness than the modified Lim-Tsai repair. However, Ti-button also increased the gliding resistance and coefficient of friction but there was no significant difference between the two repair techniques. CONCLUSIONS: Ti-button repair displayed comparable mechanical properties to the traditional repair in terms of 2-mm gap formation and gliding resistance, but with a stronger repair construct. Thus, this deepened our interest to further investigate the potential of using Ti-button implant in Zone II flexor tendon repair by studying both the mechanical and biochemical (tendon healing) properties in more in-depth. PMID- 30428799 TI - The Treatment of Distal Radius Fractures with Ipsilateral Elbow Injury. AB - BACKGROUND: The purpose of this study was to assess the functional outcomes of simultaneous distal radius fractures (DRFs) and ipsilateral elbow injuries (IEI) and to evaluate whether the DRFs and IEI affect each other's outcomes. METHODS: From February 2008 to March 2015, 29 of 846 patients treated for DRFs were found to be associated with IEI and 26 patients with follow-up over 12 months were enrolled. There were 12 men and 14 women with a mean age of 55 years (range, 17 86 years). Associated IEI was divided into fracture group (10 patients) and dislocation group (16 patients). Clinical outcomes of DRFs and IEI were evaluated using the Gartland and Werley score and Mayo Elbow Performance Score, respectively. A correlation between the wrist scoring and the elbow scoring was analyzed. In addition, the wrist scoring between fracture group and dislocation group of the elbow was compared. RESULTS: The DRFs was rated as excellent in 14 patients, good in seven patients, and fair in five patients. The IEI was rated as excellent in 12 patients, good in 11 patients, fair in two patients, and poor in one patient. Acceptable outcome rate of both DRFs and concomitant IEI was 73%, although that of DRFs and IEI was 81% and 88%, respectively. A correlation between the wrist outcome and the elbow outcome showed a negative linear relationship (Spearman rho = -0.435, p = 0.026). In addition, there was no difference in the outcome of DRFs between ipsilateral elbow fractures group and dislocation group. CONCLUSIONS: As a correlation of DRFs and ipsilateral IEI have a linear relationship, the functional outcomes of both injuries are related to each other. Therefore, we recommend that combined injuries should be managed appropriately at the same time for contended recovery of the wrist and elbow. PMID- 30428800 TI - Existing or Worsening Symptoms of Kienbock's Disease after Distal Radius Fracture: Two Case Reports. AB - We report two rare cases of existing or worsening symptoms due to Kienbock's disease after distal radius fracture (DRF). During examination, radiographs show changes in the lunate bone; there was persistent wrist pain after treatment for DRF. In each case, surgeries were performed: A combined therapy (bone marrow transfusion, bone peg graft, external fixation, and low intensity pulsed ultrasound) for one, as well as carpal coalition for another. The etiology of these case presentations suggest that a compression fracture of the lunate due to a DRF resulted in softening and sclerosis. PMID- 30428801 TI - Carpal Tunnel Syndrome and Flexor Tendon Rupture in the Wrist with Asymptomatic Scapholunate Advanced Collapse: A Case Report. AB - We experienced a rare case of carpal tunnel syndrome and rupture of the flexor digitorum profundus tendon to the index finger with a scapholunate advanced collapse wrist. We speculated that the lunate that had extruded into the carpal tunnel compressed the median nerve and caused wear of the flexor tendon following neglected perilunate subluxation. Carpal tunnel release, opponensplasty by palmaris longus tendon transfer, and a bridge graft by a half-slip of the flexor carpi radialis tendon resulted in recovery of pinch function and improvement in numbness of the hand. PMID- 30428802 TI - Simultaneous Phrenic and Intercostal Nerves Transfer for Elbow Flexion and Extension in Total Brachial Plexus Root Avulsion Injury. AB - BACKGROUND: To report the results of restoring the elbow flexion and extension in patients with total brachial root avulsion injuries by simultaneous transfer of the phrenic nerve to the nerve to the biceps and three intercostal nerves to the nerve of the long head of the triceps. METHODS: Ten patients with total brachial root avulsion injuries underwent the spinal accessory nerve transfer to the suprascapular nerve for shoulder reconstruction. Simultaneous transfer of the phrenic nerve to the nerve to the biceps via the sural nerve graft and three intercostal nerves to the nerve of the long head of the triceps was done for restoration of the elbow flexion and extension. Trunk flexion exercise program was used for all patients postoperatively. The mean follow up period was 36 months. RESULTS: For elbow flexion, there were two M4, seven M3, and one M1. For elbow extension, there were three M4, four M3, two M2, and one M1. No patient demonstrated a respiratory problem clinically postoperatively. The average FVC% decreased to 61% of the predicted value at 24 months after surgery. CONCLUSIONS: The simultaneous nerve transfer using the phrenic nerve to the nerve to the biceps and 3 intercostal nerves to the nerve of the long head of the triceps with postoperative trunk flexion exercise provide a comparable result for restoration of elbow function in total brachial plexus root avulsion injury. The patients who appear to have a respiratory problem and are unable to comply with the post operative respiratory muscles training should be contraindicated for this simultaneous transfer. PMID- 30428803 TI - Surgical Strategy for Scaphoid Nonunion Treatment. AB - Scaphoid fracture is the most common carpal fracture. Nonunion rate has been reported around 10 to 15% of scaphoid fractures. Risk factors for scaphoid nonunion are known as location, displacement, poor vascularity, time to treatment etc. The goals of surgical treatment for scaphoid nonunion are to achieve bony union, to correct carpal deformities and also to prevent progressive carpal instability and arthritis. Scaphoid nonunion can cause scaphoid nonunion advanced collapse (SNAC) which is a pattern of progressive degenerative radiocarpal and midcarpal arthritis secondary to posttraumatic pathomechanics of the scapholunate joint. Achieving bony union is essential to prevent carpal collapse or arthritis. To improve bony union, many surgical procedures including various forms of bone grafting have been developed and attempted. However, there is a controversy about which procedure is the most effective. In this review, we provide an overview of surgical treatment methods for scaphoid nonunion and discuss proper surgical strategies for scaphoid nonunion which requires surgical management. PMID- 30428804 TI - Which Factors Affect the Rate of Surgery Performed in Patients with Carpal Tunnel Syndrome? AB - BACKGROUND: Carpal tunnel release is recommended when patients have positive electrophysiologic test and their symptoms are not resolved in spite of conservative treatment. However, only some of them eventually undergo the surgery. The purposes of this study, therefore, were to evaluate the rate of carpal tunnel release performed among the patients with positive electrophysiologic test, and to identify which factors were associated with the rate of the surgery. METHODS: Subjects of this study were 865 wrists of 508 patients (90 males and 418 females) who were diagnosed as carpal tunnel syndrome between January 2013 and December 2016. The diagnosis of carpal tunnel syndrome was confirmed by electrophysiologic test, and only the patients who were followed up for more than 1 year were enrolled in this study. The average age at the time of the electrophysiologic test performed was 61.4 years, and the severity of carpal tunnel syndrome was evaluated according to the Bland scale (Gr 1-6) based on the electrophysiologic test. Whether or not the patients received carpal tunnel release was evaluated at the last follow-up visit. RESULTS: Among the 865 wrists, carpal tunnel release was performed on 528 wrists (61%). Rate of the surgery performed significantly increased in patients with more severe grades on electrophyisiologic test. More patients in female (63.3%) than in male (50.3%) and more patients with age under 60 (67.5%) than age over 60 (57.1%) received the surgery. However, there was no significant difference in the rate of carpal tunnel release according to the bilaterality or dominant hand. CONCLUSIONS: The rate of carpal tunnel release among the patients diagnosed and confirmed as carpal tunnel syndrome was not higher than we expected. We should also pay more attention to the patients who did not undergo carpal tunnel release and investigate the reasons why those patients did not undergo surgery. PMID- 30428805 TI - Corrective Osteotomy with Autogenous Bone Graft with Callus after Malunion of Distal Radius Fracture. AB - Corrective osteotomy with callus filling at fracture site for malunion after distal radius fracture is a rare technique, but it achieved a favorable postoperative outcome. The patient, 66-year-old female, visited our hospital 4 months after distal radius fracture. Corrective osteotomy of the distal radius was planned aiming at improving the wrist joint function, and was performed using a volar locking plate, then the bone defect was filled with callus as autogenous bone grafting. At 12 months after surgery, left wrist joint pain and the range of motion have improved, and the Mayo wrist score was excellent. To our knowledge, there has been no study on the treatment of bone defects by filling with callus. Since favorable bone fusion was achieved with callus, this treatment method may overcome the disadvantages of autogenous bone graft, such as pain at the donor region. PMID- 30428806 TI - Endoscopic Excision of Ganglion at Anterolateral Elbow: A Case Report. AB - Ganglion of the anterolateral elbow is rare and may be associated with compression neuropathy of the radial nerve or its branches. Open ganglionectomy implies extensive soft tissue dissection. We present a case of anterolateral elbow ganglion without any compression neuropathy. This was successfully treated with endoscopic ganglionectomy. PMID- 30428807 TI - Anatomic Pyrocarbon Hemiarthroplasty for Thumb Carpometacarpal Osteoarthritis in Patients under 65 Years: Mid Term Results. AB - BACKGROUND: To assess the midterm outcome of patients under 65 who underwent anatomic pyrocarbon hemiarthroplasty for thumb carpometacarpal (CMC) osteoarthritis. METHODS: A prospective analysis was performed of a consecutive series of active patients, less than 65 years of age, with symptomatic osteoarthritis who had undergone a CMC hemiarthroplasty using a stemmed metacarpal based, anatomic pyrolytic carbon resurfacing with an additional one third flexor carpi radialis (FCR) tendon transfer to maintain stability. The Wrightington Hand Score, Disability Arm Shoulder and Hand (DASH) Score, and the Patient Rated Wrist Evaluation Score (PRWE) were utilised. Clinical data was obtained for grip strength, pinch strength, and range of motion. RESULTS: The MEAN age was 57.6 years. MEAN follow up was 6.5 years. All patients had improvement in pain, grip strength and function. There was no significant difference in grip and pinch strengths between the individual's left and right hand. All patients stated that they would undergo the procedure again. There was one revision following a traumatic trapezium fracture. One patient underwent a neurolysis of a superficial radial nerve neuroma associated with an impinging trapezial osteophyte. CONCLUSIONS: Active patients, under 65 years of age with Eaton-Littler stage III osteoarthritis of the thumb CMC joint who are treated with anatomic pyrolytic carbon resurfacing hemiarthroplasty and stabilisation may achieve sustained improvement in pain and hand function for up to 6.5 years. PMID- 30428809 TI - Screw Length Optimization of a Volar Locking Plate Using Three Dimensional Preoperative Planning in Distal Radius Fractures. AB - BACKGROUND: A three-dimensional (3D) digital pre-operative planning system for the osteosynthesis of distal radius fracture was developed. The objective of this study was to evaluate screw choices for three-dimensional (3D) digital pre operative planning of osteosynthesis of distal radius fractures and to compare with the screw choices for the conventional method. METHODS: Distal radius fracture patients who underwent osteosynthesis using volar locking plates were evaluated. Thirty wrists in the plan group utilized 3D preoperative planning, and nineteen wrists in the control group utilized conventional preoperative assessment. In the plan group, the 3D preoperative planning was performed prior to surgery. The reduction was simulated with 3D image, and the implant choice/placement also simulated on the 3D image. In the control group, standard preoperative planning was performed using posterior-anterior and lateral view radiographs, and CT scan. After the planning, osteosynthesis was performed. During the surgery, the operator performed the reduction and the placement of the plate while comparing images between the pre-operative plan and fluoroscopy. The distal screw lengths and the anteroposterior diameter of the radius along the axis of the distal screws were measured. The ratios of the screw length and radius diameter were evaluated. The screw/radius ratios within the range of 0.75 1.00 were considered appropriate. The screw choices less than 0.75, or greater than 1.00 were considered inappropriate. The rate of appropriate screw choices were compared between plan and control groups. RESULTS: The results of appropriate screw choices were 86.1% and 74.8% in the plan group and the control group, respectively. The inappropriate screw choices were 14.0% and 25.2% in the plan group and the control group, respectively. The three-dimensional planning significantly increased appropriate screw choices compared to the conventional planning (p < 0.05). CONCLUSIONS: Three-dimensional digital preoperative planning is useful for the optimization of screw lengths in osteosynthesis of distal radius fractures. PMID- 30428808 TI - Computer-Assisted Three-Dimensional Corrective Osteotomy for Malunited Fractures of the Distal Radius Using Prefabricated Bone Graft Substitute. AB - BACKGROUND: Three-dimensional computed tomography (3D-CT) imaging has enabled more accurate preoperative planning. The purpose of this study was to investigate the results of a novel, computer-assisted, 3D corrective osteotomy using prefabricated bone graft substitute to treat malunited fractures of the distal radius. METHODS: We investigated 19 patients who underwent the computer-assisted 3D corrective osteotomy for a malunited fracture of the distal radius after the operation was stimulated with CT data. A prefabricated bone graft substitute corresponding to the patient's bone defect was implanted and internal fixation was performed using a plate and screws. We compared postoperative radiographic parameters of the patient's operated side with their sound side and analyzed clinical outcomes using Mayo wrist score. RESULTS: All patients achieved bone union on X-ray imaging at final follow-up. The mean differences of palmar tilt, radial inclination and ulnar variance between the operation side and the sound side were 4.3 degrees , 2.3 degrees and 1.2 mm, respectively. The Mayo wrist score was fair in 4 patients and poor in 15 patients before surgery. At the final follow-up after surgery, the scores improved to excellent in 3 patients, good in 11 patients and fair in 5 patients. There were two patients with correction loss at the final follow-up, but no patient complained of hand joint pain. CONCLUSIONS: We believe that computer-assisted 3D corrective osteotomy using prefabricated bone graft substitute achieved good results because it worked as a guide to the accurate angle. PMID- 30428810 TI - Cadaveric Dissection of the Axillary Nerve: An Investigation of Extra-Muscular and Intra-Muscular Branching Patterns. AB - BACKGROUND: Variations in the axillary nerve branching patterns have been reported. The aim of the study is to investigate the extra- and intra-muscular course of the axillary nerve and quantify the regional innervation of the deltoid. METHODS: In fresh frozen specimens, the origin of the axillary nerve from the posterior cord of the brachial plexus and its extra- and intra-muscular course were identified. Muscle dimensions, branching patterns and the distance from the axillary nerve origin to major branches were measured. The weights of muscle segments supplied by major branches of the axillary nerve were recorded. RESULTS: Twenty-three cadaveric dissections were completed. The axillary nerve bifurcated within the quadrangular space in all cases. The mean distance from the origin to bifurcation of the axillary nerve was 39 +/- 13 mm; from axillary nerve bifurcation to the teres minor branch was 13 +/- 6 mm; and from axillary nerve bifurcation to the middle branch of anterior division was 26 +/- 11 mm. The nerve to teres minor and superior lateral brachial cutaneous nerve originated from the posterior division or common trunk in all cases. No fibrous raphe were identified separating anterior, middle and posterior deltoid segments. The anterior division of axillary nerve supplied 85 +/- 4% of the deltoid muscle (by weight). The posterior division supplied 15 +/- 4% of the deltoid muscle (by weight). The posterior deltoid was supplied by both anterior and posterior divisions in 91.3% of cases. CONCLUSIONS: This study demonstrates a consistent branching pattern of the axillary nerve. The anterior division of the axillary nerve innervates all three deltoid segments in most instances (85% of the deltoid by weight). This study supports the concept of re-innervation of the anterior division alone in isolated axillary nerve injuries. PMID- 30428811 TI - Adventitial Cystic Disease of the Radial Artery. AB - Upper extremity adventitial cystic disease is rare, but the characteristic findings of this lesion should be known to the hand surgeon and used to guide treatment. We present a case of a young adult male who developed a painless mass in his distal forearm. Diagnostic imaging workup revealed a cystic mass that extended within and encased the radial artery. Both MRI and direct intraoperative visualization confirmed the presence of a stalk connecting the intra-mural radial artery mass to the radiocarpal joint. The mass and stalk were excised en bloc with fenestration of the volar capsule to prevent recurrence. This case demonstrates a less common example of upper extremity adventitial cystic disease and supports the articular theory of origin of these lesions. When surgical excision is performed, an attempt should be made to identify and excise the articular stalk in an effort to minimize risk of recurrence. PMID- 30428812 TI - Congenital Great Toe Hypoplasia Equivalent to a Grade 3 Hypoplastic Thumb in a Patient with VACTERL Association. AB - Lower limb malformations in VACTERL patients are extremely rare and the most common anomalies are found in the tibial ray. We present the case of a 15 month old male with VACTERL and, additionally, a hypoplastic hallucal ray of the right foot in conjunction with a floating preaxial polydactyly. The great toe hypoplasia is similar to a grade 3b thumb hypoplasia with absence of the proximal two-thirds of the first metatarsal on the plain X-ray. We would like to draw the attention of hand surgeons to anomalies of the tibial ray, which, although rare, are the most common pattern of lower limb malformations in VACTERL association. All patients with VACTERL defects should be assessed for these additional findings. PMID- 30428813 TI - Risk Factors Associated with the Outcome of Post-Traumatic Hydrocephalus. AB - BACKGROUND AND AIM:: Post-traumatic hydrocephalus is a common complication that arises after head injury. However, risk factors associated with the outcome of post-traumatic hydrocephalus have seldom been addressed. Therefore, we performed this clinical study to analyze the risk factors affecting the outcome of post traumatic hydrocephalus in patients with head injuries. METHODS:: A total of 116 post-traumatic hydrocephalus patients, admitted in our hospital between March 2012 and October 2017 were reviewed. The related factors assessed were age, gender, Glasgow Coma Score on admission, platelet count, plasma fibrinogen levels, D-dimer concentration, subarachnoid hemorrhage, subdural hygroma, cerebral hernia, cisterna ambiens, decompressive craniectomy, cranioplasty, ventriculoperitoneal shunt implantation, intracranial infection, and duration of comatous state. The patient outcomes after 6 months of treatment were evaluated by the Glasgow Outcome Scale. Risk factors for the outcome of post-traumatic hydrocephalus were evaluated by applying logistic regression analysis. RESULTS:: Poor outcome was observed in 66.4% of the patients (77/116). Univariate and multivariate analyses revealed that the disappearance of cisterna ambiens, the long duration of comatous state (>2 months), the high levels of plasma fibrinogen, and the ventriculoperitoneal shunt implantation were related to adverse outcomes (p < 0.05). CONCLUSION:: The disappearance of cisterna ambiens, the prolonged duration of comatous state (>2 months), the high plasma fibrinogen levels are the most important factors affecting the outcome of post-traumatic hydrocephalus, and the ventriculoperitoneal shunt implantation is the most critical predictor of the outcome of post-traumatic hydrocephalus. PMID- 30428815 TI - The value of participating in clinical trials: the whole is greater than the sum of its parts. PMID- 30428816 TI - What have we learnt about using digital technologies in health professional education? PMID- 30428817 TI - Acute kidney injury in an older patient. PMID- 30428818 TI - Reducing cardiovascular risk in people with diabetes and kidney disease. PMID- 30428819 TI - Planetary health: the Australian chapter. PMID- 30428821 TI - Retention of medical records of patients with high-risk medical devices. PMID- 30428820 TI - Health protection and Australian prisons, 2018. PMID- 30428822 TI - The three A's of colonoscopy referral. PMID- 30428823 TI - Hypertrophic lichen planus mistaken for squamous cell carcinoma. PMID- 30428825 TI - Calendar of conferences in Australia and New Zealand. PMID- 30428824 TI - RACGP's cream of the crop recognised. PMID- 30428826 TI - Headache attributed to aeroplane travel: the first multicentric survey in a paediatric population affected by primary headaches. AB - BACKGROUND: This multicentric survey investigates the prevalence and characteristics of Airplane Headache in children affected by primary headaches. METHODS: Patients with symptoms of Airplane Headache were recruited from nine Italian Pediatric Headache Centres. Each patient was handed a structured questionnaire which met the ICHD-III criteria. RESULTS: Among 320 children suffering from primary headaches who had flights during their lifetime, 15 (4.7%) had Airplane Headache, with mean age of 12.4 years. Most of the patients were females (80%). The headache was predominantly bilateral (80%) and localized to the frontal area (60%); it was mainly pulsating, and lasted less than 30 min in all cases. Accompanying symptoms were tearing, photophobia, phonophobia in most of the cases (73.3%). More than 30% of patients used medications to treat the attacks, with good results. CONCLUSION: Our study shows that Airplane Headache is not a rare disorder in children affected by primary headaches and highlights that its features in children are peculiar and differ from those described in adults. In children Airplane Headache prevails in females, is more often bilateral, has frequently accompanying symptoms and occurs at any time during the flight. Further studies are needed to confirm the actual frequency of Airplane Headache in the general pediatric population not selected from specialized Headache Centres, with and without other concomitant headache condition, and to better clarify the clinical characteristics, pathophysiology and potential therapies. PMID- 30428827 TI - Correction to: Skin cancer risk perception and sun protection behavior at work, at leisure, and on sun holidays: a survey for Danish outdoor and indoor workers. AB - Following publication of the original article [1], it was highlighted that Table 3 contained an error. PMID- 30428828 TI - Multi-drug resistant Salmonella enterica serovar Typhi isolates with reduced susceptibility to ciprofloxacin in Kenya. AB - BACKGROUND: Typhoid fever remains a public health concern in developing countries especially among the poor who live in informal settlements devoid of proper sanitation and clean water supply. In addition antimicrobial resistance poses a major challenge in management of the disease. This study assessed the antimicrobial susceptibility patterns of Salmonella enterica serotype Typhi (S. Typhi) isolated from typhoid fever cases (2004-2007). METHODS: A cross sectional study was conducted on 144 archived S. Typhi isolates (2004-2007) tested against 11 antimicrobial agents by quality controlled disk diffusion technique. Isolates resistant to ampicillin, chloramphenicol, and cotrimoxazole were considered Multidrug resistant (MDR). Thirty MDR isolates were selected randomly and further tested using minimum inhibitory concentration (MIC) E-test. RESULTS: Sixteen percent (23/144) of the isolates were susceptible to all the antibiotics tested while 68% were resistant to three or more of the 11 antibiotics tested. The isolates showed a high susceptibility to ceftriaxone (94%) and gentamicin (97%). A high percentage of resistance was observed for the conventional first-line antibiotics; ampicillin (72%), chloramphenicol (72%), and cotrimoxazole (70%). Sixty-nine percent of the isolates (100/144) showed reduced susceptibility to ciprofloxacin. All the 30 (100%) isolates selected for MIC test were susceptible to amoxicillin-clavulanic acid. All except one of the 30 isolates were susceptible to ceftriaxone while majority 21 (70%) recorded an intermediate susceptibility to ciprofloxacin with MIC of 0.12-0.5 MUg/mL. CONCLUSION: A large proportion of S. Typhi isolates were MDR and also showed reduced susceptibility to ciprofloxacin. Fluoroquinolone resistance is emerging and this may pose a challenge in treatment of typhoid in future. There is need for routine surveillance to monitor this phenotype in clinical settings. PMID- 30428830 TI - hsegHMM: hidden Markov model-based allele-specific copy number alteration analysis accounting for hypersegmentation. AB - BACKGROUND: Somatic copy number alternation (SCNA) is a common feature of the cancer genome and is associated with cancer etiology and prognosis. The allele specific SCNA analysis of a tumor sample aims to identify the allele-specific copy numbers of both alleles, adjusting for the ploidy and the tumor purity. Next generation sequencing platforms produce abundant read counts at the base-pair resolution across the exome or whole genome which is susceptible to hypersegmentation, a phenomenon where numerous regions with very short length are falsely identified as SCNA. RESULTS: We propose hsegHMM, a hidden Markov model approach that accounts for hypersegmentation for allele-specific SCNA analysis. hsegHMM provides statistical inference of copy number profiles by using an efficient E-M algorithm procedure. Through simulation and application studies, we found that hsegHMM handles hypersegmentation effectively with a t-distribution as a part of the emission probability distribution structure and a carefully defined state space. We also compared hsegHMM with FACETS which is a current method for allele-specific SCNA analysis. For the application, we use a renal cell carcinoma sample from The Cancer Genome Atlas (TCGA) study. CONCLUSIONS: We demonstrate the robustness of hsegHMM to hypersegmentation. Furthermore, hsegHMM provides the quantification of uncertainty in identifying allele-specific SCNAs over the entire chromosomes. hsegHMM performs better than FACETS when read depth (coverage) is uneven across the genome. PMID- 30428829 TI - Proteomic and ecophysiological responses of soybean (Glycine max L.) root nodules to Pb and hg stress. AB - BACKGROUND: Lead (Pb) and mercury (Hg) are persistent hazardous metals in industrially polluted soils which can be toxic in low quantities. Metal toxicity can cause changes at cellular and molecular level which should be studied for better understanding of tolerance mechanism in plants. Soybean (Glycine max L.) is an important oilseed crop of the world including India. Indian soils growing soybean are often contaminated by Pb and Hg. The aim of this study was to explore how soybean root nodule responds to Pb and Hg through proteomic and ecophysiological alterations in order to enhance tolerance to metal stress. RESULTS: Soybean plants were exposed to Pb (30 ppm PbCl2) and Hg (0.5 ppm HgCl2) to study histological, histochemical, biochemical and molecular response of N2 fixing symbiotic nodules. Both Pb and Hg treatment increased the level of oxidative stress in leaves and nodules. Chlorosis in leaves and morphological/anatomical changes in nodules were observed. Activities of ascorbate peroxidase, glutathione reductase and catalase were also modulated. Significant changes were observed in abundance of 76 proteins by Pb and Hg. Pb and Hg influenced abundance of 33 proteins (17 up and 16 down) and 43 proteins (33 up and 10 down), respectively. MS/MS ion search identified 55 proteins which were functionally associated with numerous cellular functions. Six crucial proteins namely catalase (CAT), allene oxide synthase (AOS), glutathione S transferase (GST), calcineurin B like (CBL), calmodulin like (CML) and rapid alkalinisation factor (RAF) were selected for transcript abundance estimation. The qRT-PCR based real time expression exhibited a positive correlation with proteomics expression except for GST and RAF. CONCLUSION: Soybean root nodule responds to metal stress by increased abundance of defence, development and repair related proteins. An efficient proteomic modulation might lead to metal induced stress tolerance in N2-fixing nodules. Although concentrations of Pb and Hg used in the study cannot be considered equimolar, yet Hg seems to induce more changes in nodule proteomic profile, and higher damage to both bacteroides and root anatomy. PMID- 30428831 TI - funcExplorer: a tool for fast data-driven functional characterisation of high throughput expression data. AB - BACKGROUND: A widely applied approach to extract knowledge from high-throughput genomic data is clustering of gene expression profiles followed by functional enrichment analysis. This type of analysis, when done manually, is highly subjective and has limited reproducibility. Moreover, this pipeline can be very time-consuming and resource-demanding as enrichment analysis is done for tens to hundreds of clusters at a time. Thus, the task often needs programming skills to form a pipeline of different software tools or R packages to enable an automated approach. Furthermore, visualising the results can be challenging. RESULTS: We developed a web tool, funcExplorer, which automatically combines hierarchical clustering and enrichment analysis to detect functionally related gene clusters. The functional characterisation is achieved using structured knowledge from data sources such as Gene Ontology, KEGG and Reactome pathways, Human Protein Atlas, and Human Phenotype Ontology. funcExplorer includes various measures for finding biologically meaningful clusters, provides a modern graphical user interface, and has wide-ranging data export and sharing options as well as software transparency by open-source code. The results are presented in a visually compact and interactive format, enabling users to explore the biological essence of the data. We compared our results with previously published gene clusters to demonstrate that funcExplorer can perform the data characterisation equally well, but without requiring labour-intensive manual interference. CONCLUSIONS: The open-source web tool funcExplorer enables scientists with high-throughput genomic data to obtain a preliminary interactive overview of the expression patterns, gene names, and shared functionalities in their dataset in a visually pleasing format. funcExplorer is publicly available at https://biit.cs.ut.ee/funcexplorer. PMID- 30428833 TI - Gout and dementia in the elderly: a cohort study of Medicare claims. AB - BACKGROUND: Conflicting data in the literature raise the question whether gout, independent of its treatment, increases the risk of dementia in the elderly. Our objective was to assess whether gout in older adults is associated with the risk of incident dementia. METHODS: We used the 5% Medicare claims data for this observational cohort study. We used multivariable-adjusted Cox proportional hazard models to assess the association of gout with a new diagnosis of dementia (incident dementia), adjusting for potential confounders/covariates including demographics (age, race, sex), comorbidities (Charlson-Romano comorbidity index), and medications commonly used for cardiac diseases (statins, beta-blockers, diuretics, and angiotensin converting enzyme (ACE)-inhibitors) and gout (allopurinol and febuxostat). RESULTS: In our cohort of 1.71 million Medicare beneficiaries, 111,656 had incident dementia. The crude incidence rates of dementia in people without and with gout were 10.9 and 17.9 per 1000 person years, respectively. In multivariable-adjusted analyses, gout was independently associated with a significantly higher hazard ratio of incident dementia, with a HR of 1.15 (95% CI, 1.12, 1.18); sensitivity analyses confirmed the main findings. Compared to age 65 to < 75 years, age 75 to < 85 and >= 85 years were associated with 3.5 and 7.8-fold higher hazards of dementia; hazards were also higher for females, black race or people with higher medical comorbidity. CONCLUSION: Gout was independently associated with a 15% higher risk of incident dementia in the elderly. Future studies need to understand the pathogenic pathways involved in this increased risk. PMID- 30428835 TI - Utilization of "prevention of mother-to-child transmission" of HIV services by adolescent and young mothers in Mulago Hospital, Uganda. AB - BACKGROUND: Prevention of mother to child transmission (PMTCT) has lowered the incidence of paediatric HIV globally. The risk of mother-to-child transmission of HIV (MTCT) remains high in Africa, where there is a high prevalence of pregnancy and poor health-seeking behaviour among young girls and women. METHODS: In this cross-sectional, mixed-methods study, we evaluated the utilization of PMTCT services and associated factors among adolescent and young postpartum mothers aged 15 to 24 years at a public urban referral hospital in Uganda. Both HIV positive and HIV-negative participants were recruited. Utilization of PMTCT services was defined as use of the PMTCT cascade of services including ever testing for HIV, receiving HIV test results; If tested negative, subsequent retesting up to 14 weeks; If tested positive, Antiretroviral drugs (ARVs) for the mother, ARVs and septrin prophylaxis for infant, safe delivery, safer infant feeding, early infant diagnosis within 6 weeks, and linkage to treatment and care. Optimal utilization of PMTCT was defined as being up to date with utilization of PMTCT services for reported HIV status at the time of being interviewed. The overall proportion of participants who optimally utilized PMTCT services was determined using descriptive statistics. Qualitative data was analyzed manually using the content thematic approach. RESULTS: Of the 418 participants, 65 (15.5%) were HIV positive. Overall, only 126 of 418 participants (30.1%) had optimally utilized PMTCT services. However, utilization of PMTCT services was better among HIV positive mothers, with 83% (54/65) having utilized the services optimally, compared to only 20% (72/353) of the HIV negative mothers (OR 18.2 (95% CI; 9.0-36.7)). The benefits of knowing ones HIV status, health of the unborn child, and counseling and support from health workers and peers, were the major factors motivating adolescent and young mothers to utilize PMTCT services, while stigma, financial constraints, non-disclosure, and lack of partner and family support were key demotivating factors. CONCLUSION: Utilization of PMTCT services by these adolescent and young mothers was suboptimal. Special consideration should be given to adolescents and young women in the design of elimination of mother to child transmission (EMTCT) programs, to improve the utilization of PMTCT services. PMID- 30428832 TI - Study protocol on Alzheimer's disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions. AB - BACKGROUND: One of the crucial challenges for the future of therapeutic approaches to Alzheimer's disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan(r), amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co existing lesions. METHODS: A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. DISCUSSION: This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan(r), PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. TRIAL REGISTRATION: NCT02052947 . PMID- 30428834 TI - Are we on the cusp of a fourth research paradigm? Predicting the future for a new approach to methods-use in medical and health services research. AB - BACKGROUND: The dominant medical and health research paradigm continues to be quantitative. While the authors sense a sea-change in opinion about mixed-method research, underpinned by two decades of highly-cited publications in medical journals, much of the medical literature still widely favours the Randomised Control Trial. MAIN BODY: This debate article examines whether it is the beginning of the end of the dominant quantitative paradigm and the interest this holds for researchers and clinicians at the forefront of care delivery. It examines the Third Research Paradigm, signifying the importance of mixed-methods, and discusses the power of the patient voice and person-focused research activity. The authors discern the coming of age of a Fourth Research Paradigm integrating mixed-methods with data collected 'on the hoof'. Within this new paradigm, the article explores the power of available, real time, and emergent data - from smart phones, wearable devices, and social media, as well as more creative approaches to data collection. The Fourth Research Paradigm will require the support of multi-disciplinary teams, moving through the world alongside their research subjects. The impact of a Fourth Research Paradigm on the health researcher is assessed, as the researcher's gaze moves away from considerations of methodological superiority to re-considerations of their role in the brave new world of research multiplicity. CONCLUSION: The Fourth Research Paradigm offers extensive opportunities to tell more complete research stories in real-time settings. It concentrates on contextual notions of everyday happenings within the ever-changing world of healthcare delivery. There will be challenges ahead, not least the management of large, complex datasets and adaptive study designs. But rigorous planning will enable unique insights into the relationships played out in the world of the patient and healthcare provider. Better care and new delivery models are likely to result, but how this will manifest is not yet clear. PMID- 30428836 TI - Quality of life and paracetamol in advanced dementia (Q-PID): protocol of a randomised double-blind placebo-controlled crossover trial. AB - BACKGROUND: No proven effective interventions on quality of life (QoL) are available for persons with dementia in a long-term care facility (LTCF). However, several interventions are effective in diminishing mediators of QoL (i.e. challenging behaviour, depressed mood, sleeping disorders), including pain treatment. Un(der)diagnosed and un(der)treated pain is a serious and frequent problem in persons with dementia. Also, although pain is difficult to assess in this group, the impact on QoL is probably considerable. There is evidence that pain has a negative impact on behaviour, mood, functioning and social participation, and benefit may be derived from use of paracetamol. Therefore, in LTCF residents with advanced dementia, this study aims to evaluate the effect of scheduled pain treatment with paracetamol on QoL, neuropsychiatric symptoms, ADL function, pain, care dependency, and (change in) use of psychotropic and pain medication. METHODS: This randomised, double-blind, placebo-controlled crossover trial will include 95 patients with: 1) age >= 65 years, 2) advanced dementia (Reisberg Global Deterioration Scale 5-7), and 3) QUALIDEM score <= 70. Exclusion criteria are the regular use of pain treatment, allergies to the study drugs, severe liver insufficiency or disease, use of > 4 units of alcohol/day, weight < 50 kg, and/or concomitant use of flucloxacillin. The two treatment periods of six weeks each (paracetamol and corresponding placebo) will be separated by a washout period of seven days. Primary outcome is effect on QoL (QUALIDEM and DS-DAT) and secondary outcome is effect on neuropsychiatric symptoms, ADL function, pain, care dependency, and (change in) use of psychotropic and pain medication (all compared to baseline). DISCUSSION: If regular treatment with paracetamol proves to be beneficial for QoL, this could have major implications for daily practice in long-term care. Information from this study may help professionals in their decision making regarding the prescription of pain medication to improve the QoL of persons with dementia and a low QoL. TRIAL REGISTRATION: The trial was registered on the Netherlands Trial Register ( NTR6766 ); Trial registration date: 20th October, 2017. PMID- 30428837 TI - Genetic diversity of drug resistant Mycobacterium Tuberculosis in local area of Southwest China: a retrospective study. AB - BACKGROUND: By 2014 although tuberculosis (TB) incidence had fallen by an average of 1.5% per year since 2000 and was 18% lower than the level of in 2000, 1.5 million people died for TB in that year. One of reason was that drug resistant Mycobacterium tuberculosis (DRTB) spread. This study aims to determine drug resistant characteristics and genotype of DRTB that isolated from patients in a tuberculosis referral hospital of southwest China. METHODS: Five hundred thirty eight drug resistant tuberculosis samples were collected from July 2013 to March 2015. All the isolates were identified by genomic deletions in region of difference 105 (RD105) and genotyped by mycobacterial interspersed repetitive unit-variable number tandem repeat typing (MIRU-VNTR). Polymorphism and cluster analysis of each locus was carried out using Bionumerics Version 3.0 and phyloviz software. RESULTS: Five hundred thirty-eight TB strains included 503 Mycobacterium tuberculosis (MTB) isolates and 35 non Mycobacterium tuberculosis (NMTB) isolates. Of 503 isolates Beijing family type was 447 (88.9%, 447/503) and non-Beijing family type was 56 (11.1%, 56/503). Five hundred three DRTB isolates were divided into 345 genotypes, of which 265 isolates were single genotype and the remaining 238 strains were classified into 80 clusters with cluster rate of 47.3% and cluster ratio of 31.4%. Sixty-nine clusters belonged to Beijing family with cluster rate was 48.3% and clustering ratio was 32.9%. The non - Beijing family had 11 clusters with a cluster rate of 39.3% and the clustering ratio of 19.6%. Beijing genotype had a significant correlation with the age (P < 0.05), the retreatment patients (P < 0.05) and the city of Chongqing (P < 0.05), not with gender (P > 0.05). In the 9 Beijing genotype clusters each cluster contained some patients who lived in the same region. CONCLUSIONS: Beijing genotype was the predominant in the patients with DRTB in our hospital. In Chongqing retreatment patients with Beijing genotype MTB may be patient with DRTB. Drug resistance test (DST), regular medication and strict follow-up are very important for patients with Beijing genotype MTB. In Chongqing control and treatment of DRTB should be paid attention. Transmission and relations of patients with DRTB need to be further research. PMID- 30428838 TI - Clinical characteristics and prognosis of serous body cavity effusions in patients with sepsis: a retrospective observational study. AB - BACKGROUND: Cavity effusion is common in patients with infectious diseases. However, the incidence rate and characteristics of serous cavity effusions (SCE) in septic patients are not clear to date. The objective of this study was to investigate the incidence and characteristics of SCE in septic patients and to explore the correlations between the bloody effusions and the illness severity/prognosis in septic patients. METHODS: From January 2010 to January 2015, a total of 214 patients with severe sepsis and septic shock were enrolled in this retrospective observational study. Thoracentesis or abdominal paracentesis was performed in 45 septic patients because of massive pleural effusions or ascites. The serum concentrations of VEGF, VEGFR, Ang, sICAM-1, sVCAM-1, E-selectin, Serpine1 and VE-cadherin in 45 septic patients underwent paracentesis were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Of the 214 septic patients, 155 (72.4%) had SCE according to imaging or ultrasound manifestations. 45 subjects with SCE underwent therapeutic thoracentesis or abdominal paracentesis. Effusion laboratory analysis showed that exudates were predominant when compared with transudates (95.6% vs. 4.4%), and 16 (35.6%) patients suffered bloody effusions. Compared with patients with non bloody effusions, those with bloody effusions showed higher critical illness scores (13 vs. 17 for APACHE II; 7 vs. 9 for SOFA), and higher mortality (6.9% vs. 62.5%). Moreover, patients with bloody effusions had delayed TT and APTT, increased D-dimer concentration, and higher serum levels of CRP and PCT (P < 0.05). In addition, the serum levels of Ang2, sVCAM-1 and E-selectin were significantly higher in patients with bloody effusions than in those with non bloody effusions (P < 0.05). However, the serum level of VEGFR2 was lower in patients with bloody fluids (P = 0.025). CONCLUSIONS: The incidence of serous cavity effusion is high in patients with sepsis. The septic patients with bloody effusions suffer a more inflammatory burden and a worse prognosis compared to septic patients with non-bloody effusions. PMID- 30428839 TI - Sedative-hypnotic initiation and renewal at discharge in hospitalized older patients: an observational study. AB - BACKGROUND: Sedative-hypnotics (SHs) are widely used in France but there are no available data addressing their prescription specifically in hospitalized older patients. The objective is thus to determine the cumulative incidence of sedative hypnotic (SH) medications initialized during a hospital stay of older patients, the proportion of SH renewal at discharge among these patients and to study associated risk factors. METHODS: We conducted a retrospective observational study in six internal medicine units and six acute geriatric units in eight hospitals (France). We included 1194 inpatients aged 65 and older without SH medications prior to hospitalization. Data were obtained from patients' electronic pharmaceutical records. Primary outcome was the cumulative incidence of SH initiation in the study units. Secondary outcomes were the proportion of SH renewal at discharge and risk factors for SH initiation and renewal at discharge (patient characteristics, hospital organization). A Cox regression model was used to study risk factors for SH initiation. A mixed effects logistic regression was used to study risk factors for SH renewal at discharge. RESULTS: SH initiation occurred in 21.5% of participants 20 days after admission. SH renewal at discharge occurred in 38.7% of patients who had initiated it during their stay and were discharged home and in 56.0% of patients discharged to rehabilitation facilities. Neither patients' characteristics nor hospital organization patterns was associated with SH initiation. SH initiation after the first six days after admission was associated with a lower risk of SH renewal in patients discharged to rehabilitation facilities (OR = 0.19, 95% CI: [0.04-0.80]). CONCLUSIONS: Hospitalization is a period at risk for SH initiation. The implementation of interventions promoting good use of SHs is thus of first importance in hospitals. Specific attention should be paid to patients discharged to rehabilitation facilities. PMID- 30428840 TI - "We know it's labour pain, so we don't do anything": healthcare provider's knowledge and attitudes regarding the provision of pain relief during labour and after childbirth. AB - BACKGROUND: Most women experience pain during labour and after childbirth. There are various options, both pharmacological and non-pharmacological, available to help women cope with and relieve pain during labour and after childbirth. In low resource settings, women often do not have access to effective pain relief. Healthcare providers have a duty of care to support women and improve quality of care. We investigated the knowledge and attitudes of healthcare providers regarding the provision of pain relief options in a hospital in Moshi, Tanzania. METHODS: Semi-structured key informant interviews (n = 24) and two focus group discussions (n = 10) were conducted with healthcare providers (n = 34) in Tanzania. Transcribed interviews were coded and codes grouped into categories. Thematic framework analysis was undertaken to identify emerging themes. RESULTS: Most healthcare providers are aware of various approaches to pain management including both pharmacological and non-pharmacological options. Enabling factors included a desire to help, the common use of non-pharmacological methods during labour and the availability of pharmacological pain relief for women who have had a Caesarean section. Challenges included shortage of staff, lack of equipment, no access to nitrous oxide or epidural medication, and fears regarding the effect of opiates on the woman and/or baby. Half of all healthcare providers consider labour pain as 'natural' and necessary for birth and therefore do not routinely provide pharmacological pain relief. Suggested solutions to increase evidence based pain management included: creating an enabling environment, providing education, improving the use of available methods (both pharmacological and non pharmacological), emphasising the use of context-specific protocols and future research to understand how best to provide care that meets women's needs. CONCLUSIONS: Many healthcare providers do not routinely offer pharmacological pain relief during labour and after childbirth, despite availability of some resources. Most healthcare providers are open to helping women and improving quality of pain management using an approach that respects women's culture and beliefs. Women are increasingly accessing care during labour and there is now a window of opportunity to adapt and amend available maternity care packages to include comprehensive provision for pain relief (both pharmacological and non pharmacological) as an integral component of quality of care. PMID- 30428841 TI - Oral acyclovir induced hypokalemia and acute tubular necrosis a case report. AB - BACKGROUND: Acyclovir is one of the most common prescribed antiviral drugs. Acyclovir nephrotoxicity occurs in approximately 12-48% of cases. It can present in clinical practice as acute kidney injury (AKI), crystal-induced nephropathy, acute tubulointerstitial nephritis, and rarely, as tubular dysfunction. Electrolytes abnormalities like hypokalemia, were previously described only when given intravenously. CASE PRESENTATION: A 54 year-old female presented with weakness and lower extremities paresis, nausea and vomiting after receiving oral acyclovir. Physical examination disclosed a decrease in the patellar osteotendinous reflexes (++ / ++++). Laboratory data showed a serum creatinine level of 2.1 mg/dL; serum potassium 2.1 mmol/L. Kidney biopsy was obtained; histological findings were consistent with acute tubular necrosis and acute tubulointerstitial nephritis. The patient was advised to stop the medications and to start with oral and intravenous potassium supplement, symptoms improved and continued until serum potassium levels were > 3.5 meq/L. CONCLUSIONS: The case reported in this vignette is unique since it is the first one to describe hypokalemia associated to acute tubular necrosis induced by oral acyclovir. PMID- 30428842 TI - Characteristics of NDM-1-producing Klebsiella pneumoniae ST234 and ST1412 isolates spread in a neonatal unit. AB - BACKGROUND: The emergence of carbapenem-resistant Klebsiella pneumoniae (CR-KP) has become a significant problem worldwide and also being a major threat to children and newborns. Here we report an outbreak of NDM-1-producing K. pneumoniae in a neonatal unit. RESULTS: Six CR-KP strains, isolated from neonates with symptoms of infection, were identified using a VITEK-2 compact system, and the clinical data were retrieved from the electronic case records. In vitro susceptibility testing with broth dilution method showed that all six K. pneumoniae isolates were resistant to carbapenems and susceptible to colistin, aminoglycosides, fluoroquinolones and tigecycline. Based on the polymerase chain reaction results, each isolate was found to be blaNDM-1 gene positive. Clonal relationships were analysed using pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) and showed that two different PFGE patterns were formed, which belonged to sequence types ST234 and ST1412. Plasmids carrying blaNDM-1 were successfully transferred from four of the six isolates to an Escherichia coli recipient through conjugative assays. S1-PFGE and Southern blot hybridization showed that four NDM-1-producing K. pneumoniae were clonal and carried blaNDM-1 on the same plasmid. The outbreak was effectively controlled by reducing the potential infection sources. All the patients were successfully treated and recovered after receiving an increased dose of carbapenems. Although the source of this outbreak was not clear, comprehensive measures were carried out and the outbreak was effectively controlled. CONCLUSIONS: ST234 and ST1412 of NDM-1-producing Klebsiella pneumoniae are the resistant clone spread in the neonatal unit, comprehensive infection control measures and optimized carbapenem therapy played an important role in controlling this NDM-1-producing K. pneumoniae outbreak. PMID- 30428843 TI - Magnitude of postpartum depression and associated factors among women in Mizan Aman town, Bench Maji zone, Southwest Ethiopia. AB - BACKGROUND: The first 12 months after childbirth may represent a high-risk time for depression. In Ethiopia there is a paucity of evidence about its magnitude and associated factors during that period. So, the aim of this study was to assess the magnitude of depression and associated factors among postpartum women in Mizan Aman town, Bench Maji Zone, Southwest Ethiopia 2017. METHODS: A community based cross- sectional study design was employed from March 15 to April 15, 2017. Four hundred sixty women were selected using multistage random sampling technique. Face to face interview were conducted using structured questionnaires and standardized scales. Bivariate logistic regression analysis was done to see crude association between each independent variable and outcome variable. Variables with p value < 0.25 in bivariate analysis were entered to multivariable logistic regression analysis to control for confounding. Adjusted odd ratios with 95%CI were calculated to identify independent predictors of postpartum depression. RESULT: Four hundred fifty-six postpartum women participated in the study giving a response rate of 99%. The magnitude of postpartum depression among the study population was 102 (22.4%, 95% CI: 19.84-24.96). Postpartum depression is relatively higher in the first 6 weeks after birth. Postpartum depression is higher among mothers with age range between 18 and 23 years (aOR 3.89 95%CI: 1.53 9.90), unplanned pregnancy (aOR 3.35 95% CI: 1.701-6.58), child having sleeping problems (aOR 3.72 95%CI: 1.79-7.72), domestic violence (aOR 2.86 95%CI 1.72 8.79), unsatisfied marital relation (aOR 2.72 95% CI 1.32-5.62), poor social support (aOR 4.30 95% CI 1.79-10.30), history of previous depression (aOR 7.38 95% CI 3.12-17.35) and substance use (aOR 5.16 95% CI 2.52-10.60). CONCLUSION: The magnitude of postpartum depression was high. This underlines health care planners' needs to incorporate screening strategies for depression following childbirth. PMID- 30428844 TI - A genome-wide association study using a Vietnamese landrace panel of rice (Oryza sativa) reveals new QTLs controlling panicle morphological traits. AB - CONTEXT: Yield improvement is an important issue for rice breeding. Panicle architecture is one of the key components of rice yield and exhibits a large diversity. To identify the morphological and genetic determinants of panicle architecture, we performed a detailed phenotypic analysis and a genome-wide association study (GWAS) using an original panel of Vietnamese landraces. RESULTS: Using a newly developed image analysis tool, morphological traits of the panicles were scored over two years: rachis length; primary, secondary and tertiary branch number; average length of primary and secondary branches; average length of internode on rachis and primary branch. We observed a high contribution of spikelet number and secondary branch number per panicle to the overall phenotypic diversity in the dataset. Twenty-nine stable QTLs associated with seven traits were detected through GWAS over the two years. Some of these QTLs were associated with genes already implicated in panicle development. Importantly, the present study revealed the existence of new QTLs associated with the spikelet number, secondary branch number and primary branch number traits. CONCLUSIONS: Our phenotypic analysis of panicle architecture variation suggests that with the panel of samples used, morphological diversity depends largely on the balance between indeterminate vs. determinate axillary meristem fate on primary branches, supporting the notion of differences in axillary meristem fate between rachis and primary branches. Our genome-wide association study led to the identification of numerous genomic sites covering all the traits studied and will be of interest for breeding programs aimed at improving yield. The new QTLs detected in this study provide a basis for the identification of new genes controlling panicle development and yield in rice. PMID- 30428845 TI - Chronic hepatitis B genotype E in African migrants: response to nucleos(t)ide treatment in real clinical practice. AB - BACKGROUND: Hepatitis B virus (HBV) genotype E is a poorly studied genotype that almost exclusively occurs in African people. It seems to harbour intrinsic potential oncogenic activity and virological characteristics of immune scape but a paucity of information is available on clinical and virological characteristic of HBV genotype E-infected patients as well as on the efficacy of anti-HBV drugs for such patients. The increasing flow of migrants from high endemic HBV sub Saharan Africa, where genotype E is the predominant one, to Western countries makes improving such knowledge critical in order to deliver proper medical care. METHODS: Prospective observational study of naive patients of sub-Saharan origin treated for chronic HBV genotype E infection at a Tropical Medicine clinic sited in Spain from February 2004 to January 2018. The aim of the study was to describe the response of chronic HBV genotype E infection to nucleos(t)ide analogues (NA), entecavir or tenofovir, in real clinical practice. RESULTS: During the study period, 2209 sub-Saharan patients were assisted at our Tropical Medicine Unit and 609 (27.6%) had chronic HBV (CHB) infection. Genotype information was available for 55 naive patients initiating treatment with NA (entecavir or tenofovir), 43 (84.3%) of them being genotype E, although 15 were excluded because they did not meet study inclusion criteria. Thus, a total of 28 CHB genotype E patients were included and followed for 24 months at least. Twenty-one patients were in HBeAg negative chronic hepatitis phase and 7 patients in HBeAg-positive chronic hepatitis phase. After one year of treatment, among those with good adherence, 89.4% (17/19) of the HBeAg-negative patients and 80% of the HBeAg-positive ones had undetectable viral loads. Response rates reached 100% in both groups after 15 18 months of follow-up. Out of the 7 HBeAg-positive patients, 6 (85.7%) presented HBeAg loss in a median time of 31.8 months. Neither serious adverse effects nor hepatocarcinoma cases happened during the study period. CONCLUSIONS: HBV genotype may influence disease progression and antiviral response. Our study provides precious information on the efficacy and safety of NA treatment for CHB genotype E infection, a fairly unknown genotype with and increasing epidemiological impact. PMID- 30428846 TI - Pandemic influenza preparedness in the WHO African region: are we ready yet? AB - BACKGROUND: Prior to the 2009 pandemic H1N1, and the unprecedented outbreak of Highly Pathogenic Avian Influenza (HPAI) caused by the H5N1 virus, the World Health Organization (WHO) called upon its Member States to develop preparedness plans in response to a new pandemic in humans. The WHO Member States responded to this call by developing national pandemic plans in accordance with the International Health Regulations (IHR) to strengthen the capabilities of Member States to respond to different pandemic scenarios. In this study, we aim to evaluate the quality of the preparedness plans in the WHO African region since their inception in 2005. METHODS: A standard checklist with 61 binary indicators ("yes" or "no") was used to assess the quality of the preparedness plans. The checklist was categorised across seven thematic areas of preparedness: preparation (16 indicators); coordination and partnership (5 indicators); risk communication (8 indicators); surveillance and monitoring (7 indicators); prevention and containment (10 indicators); case investigation and treatment (10 indicators) and ethical consideration (5 indicators). Four assessors independently scored the plans against the checklist. RESULTS: Of the 47 countries in the WHO African region, a total of 35 national pandemic plans were evaluated. The composite score for the completeness of the pandemic plans across the 35 countries was 36%. Country-specific scores on each of the thematic indicators for pandemic plan completeness varied, ranging from 5% in Cote d'Ivoire to 79% in South Africa. On average, preparation and risk communication scored 48%, respectively, while coordination and partnership scored the highest with an aggregate score of 49%. Surveillance and monitoring scored 34%, while prevention and containment scored 35%. Case investigation and treatment scored 25%, and ethical consideration scored the lowest of 14% across 35 countries. Overall, our assessment shows that pandemic preparedness plans across the WHO African region are inadequate. CONCLUSIONS: Moving forward, these plans must address the gaps identified in this study and demonstrate clarity in their goals that are achievable through drills, simulations and tabletop exercises. PMID- 30428847 TI - Comparative effectiveness of anti-viral drugs with dual activity for treating hepatitis B and HIV co-infected patients: a network meta-analysis. AB - BACKGROUND: There are randomized trials assessing a variety of antiviral drugs for hepatitis B virus (HBV), but the relative effectiveness of these drugs in the treatment of patients co-infected with human immunodeficiency virus (HIV) remains unclear. The objectives of the current study were to estimate and rank the relative effectiveness of antiviral drugs for treating HBV and HIV co-infected patients. METHODS: Randomized trials, assessing the efficacy of antiviral drugs for HBV and HIV co-infected patients were searched in health-related databases. The methodological quality of the included trials was evaluated using the Cochrane risk of bias tool. Main outcome in this meta-analysis study was the success of treatment by antivirals as determined by virologic response. We performed pairwise and network meta-analysis of these trials and assessed the quality of evidence using the GRADE approach. RESULTS: Seven randomized trials (329 participants) were included in this network meta-analysis study. A network geometry was formed with six treatment options including four antiviral drugs, adefovir (ADV), emtricitabine (FTC), lamivudine (LMV) and tenofovir disoproxil fumarate (TDF), combination treatment of TDF plus LMV, and placebo. The weighted percentage contributions of each comparison distributed fairly equally in the entire network of evidence. An assumption of consistency required for network meta-analysis was not violated (the global Wald test for inconsistency: Chi2(4) = 3.63, p = 0.46). The results of estimates showed no differences between the treatment regimens in terms of viral response for treating HBV and HIV co infected patients, which spanned both benefit and harm (e.g. LMV vs TDF plus LMV: OR: 0.37, 95%CI: 0.06-2.41). Overall, the certainty of evidence was very low in all comparisons (e.g. LMV vs TDF plus LMV: 218 fewer per 1000,121 more to 602 fewer, very low certainty). Therefore, we remained uncertain to the true ranking of the antiviral treatments in HBV/ HIV co-infected patients. CONCLUSIONS: The findings suggest that the evidence is insufficient to provide guidance to the relative effectiveness of currently available antiviral drugs with dual activity in treating co-infection of HBV/HIV. Well-designed, large clinical trials in this field to address other important outcomes from different epidemiological settings are recommended. PMID- 30428848 TI - The stability and variability of serum and plasma fibroblast growth factor-23 levels in a haemodialysis cohort. AB - BACKGROUND: Serum fibroblast growth factor 23 (FGF-23) levels are markedly elevated in haemodialysis patients and have been linked to mortality outcomes. Small studies in health and chronic kidney disease, have demonstrated marked intra- and inter-individual variability in measured FGF-23 levels, and variable degradation in serum as compared to plasma samples. In end-stage kidney disease (ESKD), the intra- and inter-individual variability of FGF-23 levels, and the optimal collection methods remain poorly characterized. In this study we assessed the variability of FGF-23 levels in a cohort of stable haemodialysis patients. Secondly, in a subset of patients, we assessed the effects of different collection methods on measured FGF-23 levels. METHODS: To assess the variability of FGF-23, pre-dialysis blood samples were collected over 3 consecutive weeks from 75 haemodialysis patients. The effects of different specimen collection methods were examined in a subset of patients (n = 23), with pre-dialysis blood collected into different tubes: plain (serum), EDTA (plasma) and EDTA with the addition of a protease inhibitor (EDTA-PI). All analyses were performed in the main cohort and repeated in each subgroup. Variability over a 3-week period was assessed using repeated measures ANOVA and random effects linear regression models. Intra-class correlation coefficients were calculated to assess agreement, and coefficients of variation were calculated to assess intra- and inter individual variability. RESULTS: Over the 3-week study period the mean FGF-23 levels were not significantly different in the serum (p = 0.26), EDTA (p = 0.62) and EDTA-PI (p = 0.55) groups. FGF-23 levels demonstrated marked intra- and inter individual variability with a CV of 36 and 203.2%, respectively. In the subgroup analysis, the mean serum FGF-23 levels were significantly lower than the EDTA (p < 0.001) or EDTA-PI (p < 0.001) groups, however there was no difference in mean FGF-23 levels between EDTA and EDTA-PI (p = 0.54). CONCLUSIONS: The measured FGF 23 levels were significantly lower in serum as compared to plasma, and the addition of a protease inhibitor did not confer an additional benefit. Importantly in this cohort of ESKD patients, FGF-23 levels showed marked intra- and inter-individual variability. The routine measurement of FGF-23 in ESKD remains challenging, however this study suggests the plasma is the optimal collection method for FGF-23 analysis. PMID- 30428849 TI - Serum levels of tumor necrosis factor alpha in patients with IgA nephropathy are closely associated with disease severity. AB - BACKGROUND: Tumor necrosis factor alpha (TNF-alpha) is considered to play an important role in the pathogenesis in IgA nephropathy (IgAN). The correlations between serum TNF-alpha and disease severity in patients with IgAN remain controversial. METHODS: Concentrations of serum TNF-alpha of 147 patients with IgAN and 126 healthy subjects were measured by chemiluminescence immunoassay. Correlations with clinicopathological features of patients with IgAN were evaluated. RESULTS: Serum levels of TNF-alpha [9.20 (7.70-10.60) pg/mL vs. 6.04 (5.11-7.23) pg/mL, P < 0.0001] were higher in patients with IgAN than that in healthy subjects. Receiver operating characteristic curve analysis revealed that TNF-alpha had better discrimination between patients with IgAN and healthy controls than estimated glomerular filtration rate [TNF-alpha: (AUC, 0.87; 95% CI, 0.83-0.91; P < 0.0001) vs. estimated glomerular filtration rate: (AUC, 0.76; 95% CI, 0.71-0.82; P < 0.0001), P = 0.007]. Multivariate linear regression analyses showed that serum levels of TNF-alpha were positively correlated with 24 h urine protein excretion (r = 0.33, P = 0.04), urinary protein to serum creatinine ratio (r = 0.33, P = 0.03), serum creatinine (r = 0.46, P < 0.0001) and Cystatin C (r = 0.59, P < 0.0001) in IgAN and negatively correlated with estimated glomerular filtration rate (r = - 0.49, P < 0.0001) after adjustment for sex, systolic blood pressure and diastolic blood pressure. Patients with higher mesangial hypercellularity or tubular atrophy/interstitial fibrosis score according to Oxford classification showed higher serum levels of TNF-alpha. CONCLUSIONS: Our data showed that serum levels of TNF-alpha detected by chemiluminescence immunoassay was a potential biomarker for evaluating the disease severity in IgAN. PMID- 30428850 TI - Field suitability and diagnostic accuracy of the Biocentric(r) open real-time PCR platform for plasma-based HIV viral load quantification in Swaziland. AB - BACKGROUND: Viral load (VL) testing is being scaled up in resource-limited settings. However, not all commercially available VL testing methods have been evaluated under field conditions. This study is one of a few to evaluate the Biocentric platform for VL quantification in routine practice in Sub-Saharan Africa. METHODS: Venous blood specimens were obtained from patients eligible for VL testing at two health facilities in Swaziland from October 2016 to March 2017. Samples were centrifuged at two laboratories (LAB-1, LAB-2) to obtain paired plasma specimens for VL quantification with the national reference method and on the Biocentric platform. Agreement (correlation, Bland-Altman) and accuracy (sensitivity, specificity) indicators were calculated at the VL thresholds of 416 (2.62 log10) and 1000 (3.0 log10) copies/mL. Leftover samples from patients with discordant VL results were re-quantified and accuracy indicators recalculated. Logistic regression was used to compare laboratory performance. RESULTS: A total of 364 paired plasma samples (LAB-1: n = 198; LAB-2: n = 166) were successfully tested using both methods. The correlation was high (R = 0.82, p < 0.01), and the Bland-Altman analysis showed a minimal mean difference (- 0.03 log10 copies/mL; 95% CI: -1.15 to 1.08). At the clinical threshold level of 3.0 log10 copies/mL, the sensitivity was 88.6% (95% CI: 78.7 to 94.9) and the specificity was 98.3% (95% CI: 96.1 to 99.4). Sensitivity was higher in LAB-1 (100%; 95% CI: 71.5 to 100) than in LAB-2 (86.4%; 95% CI: 75.0 to 94.0). Most upward (n = 8, 2.2%) and downward (n = 11, 3.0%) misclassifications occurred at the 2.62 log threshold, with LAB-2 having a 16 (95% CI: 2.26 to 113.27; p = 0.006) times higher odds of downward misclassification. After retesting of discordant leftover samples (n = 17), overall sensitivity increased to 93.5% (95% CI: 85.5 to 97.9) and 97.1% (95% CI: 90.1 to 99.7) at the 2.62 and 3.0 thresholds, and specificity increased to 98.6% (95% CI: 96.5 to 99.6) and 99.0% (95% CI: 97.0 to 99.8) respectively. CONCLUSIONS: The test characteristics of the Biocentric platform were overall comparable to the national reference method for VL quantification. One laboratory tended to misclassify VL results downwards, likely owing to unmet training needs and lack of previous hands-on practice. PMID- 30428851 TI - Analysis of sero-epidemiological characteristics of varicella in healthy children in Jiangsu Province, China. AB - BACKGROUND: In recent years, outbreaks of varicella have continued to occur, and the coverage rate of varicella vaccine in Jiangsu Province, China, remains unclear. This study aims to analyse the levels of immune antibody against varicella and obtain a comprehensive understanding of the varicella attenuated live vaccine (VarV) coverage rate in children aged 1-9 years in Jiangsu Province. METHODS: From June to October 2016, a cross-sectional survey was conducted to collect 3631 serum samples from healthy children aged 1-9 years in Jiangsu Province. The immunoglobulin G (IgG) antibody levels of varicella were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The VarV coverage rate of healthy children was only 43.1% (95% CI: 41.1-44.7%). The seroprevalence after vaccination with a single dose of VarV was only 57.1%, and the overall seropositivity and geometric antibody titre (GMC) were 43.5% and 225.4 mU/ml, respectively. The seropositivity was significantly higher in girls than in boys (chi2 = 18.82, P < 0.001). The difference in seropositivity between the 5-9 age group and 1-4 age group was statistically significant (chi2 = 84.31, P < 0.001). The difference in seropositivity between different regions was statistically significant, with the highest seropositivity in the northern area, 53.7% (chi2 = 35.64, P < 0.001). The seropositivity in the group receiving one dose of VarV was significantly higher than that of the unvaccinated group (chi2 = 205.16, P < 0.001). Linear regression analysis suggested that the GMC of varicella antibodies wanes with the time since vaccination (F = 65.01, P = 0.002). CONCLUSION: The VarV coverage rate of healthy children in Jiangsu Province was low. Sero conversion rates were also low after one dose of VarV, and the immune effectiveness of a single dose of VarV was limited. To control the spread of varicella, VarV should be included in the routine immunization program, and strengthened immunization measures for the varicella-susceptible population warrant additional consideration. PMID- 30428852 TI - Seroprevalence and distribution of leptospirosis serovars among wet market workers in northeastern, Malaysia: a cross sectional study. AB - BACKGROUND: Leptospirosis is a zoonotic disease associated with occupations which exposed workers to environments contaminated with urine of infected animals. The objective of this study was to determine the seroprevalence of leptospirosis among wet market workers in Kelantan. METHODS: A cross sectional study was conducted in two main wet markets in Kelantan and 232 wet market workers were randomly selected. Blood samples were analysed for microscopic agglutination test (MAT) against 20 live leptospirosis reference serovars. MAT titres of 1:100 or more were considered as seropositive. RESULTS: It was found that the overall seroprevalence for leptospirosis among the respondents was 33.6% (95% CI = 27.5, 39.7). The samples were tested positive against serovars Melaka (IMR LEP 1), Terengganu (IMR LEP 115), Sarawak (IMR LEP 175), Copenhageni (IMR LEP 803/11), Hardjobovis (IMR LEP 27), Australis, Autumnalis, Bataviae, Canicola, Grippotyphosa, Hardjoprajitno, Icterohaemorrhagiae, Javanica, Pyrogenes, Terrasovi, Djasiman, Patoc and Pomona. The predominant serovars was Autumnalis (18.2%). CONCLUSION: Wet markets workers were at risk for leptospirosis infection evidenced by high seroprevalence of leptospirosis in this study. Further research need to be conducted to determine factors that favours infection in this groups. PMID- 30428853 TI - Empirical assessment of the impact of sample number and read depth on RNA-Seq analysis workflow performance. AB - BACKGROUND: RNA-Sequencing analysis methods are rapidly evolving, and the tool choice for each step of one common workflow, differential expression analysis, which includes read alignment, expression modeling, and differentially expressed gene identification, has a dramatic impact on performance characteristics. Although a number of workflows are emerging as high performers that are robust to diverse input types, the relative performance characteristics of these workflows when either read depth or sample number is limited-a common occurrence in real world practice-remain unexplored. RESULTS: Here, we evaluate the impact of varying read depth and sample number on the performance of differential gene expression identification workflows, as measured by precision, or the fraction of genes correctly identified as differentially expressed, and by recall, or the fraction of differentially expressed genes identified. We focus our analysis on 30 high-performing workflows, systematically varying the read depth and number of biological replicates of patient monocyte samples provided as input. We find that, in general for most workflows, read depth has little effect on workflow performance when held above two million reads per sample, with reduced workflow performance below this threshold. The greatest impact of decreased sample number is seen below seven samples per group, when more heterogeneity in workflow performance is observed. The choice of differential expression identification tool, in particular, has a large impact on the response to limited inputs. CONCLUSIONS: Among the tested workflows, the recall/precision balance remains relatively stable at a range of read depths and sample numbers, although some workflows are more sensitive to input restriction. At ranges typically recommended for biological studies, performance is more greatly impacted by the number of biological replicates than by read depth. Caution should be used when selecting analysis workflows and interpreting results from low sample number experiments, as all workflows exhibit poorer performance at lower sample numbers near typically reported values, with variable impact on recall versus precision. These analyses highlight the performance characteristics of common differential gene expression workflows at varying read depths and sample numbers, and provide empirical guidance in experimental and analytical design. PMID- 30428854 TI - Evidence for a Robertsonian fusion in Solea senegalensis (Kaup, 1858) revealed by zoo-FISH and comparative genome analysis. AB - BACKGROUND: Solea senegalensis (Kaup, 1858) is a commercially important flatfish species, belonging to the Pleuronectiformes order. The taxonomy of this group has long been controversial, and the karyotype of the order presents a high degree of variability in diploid number, derived from chromosomal rearrangements such as Robertsonian fusions. Previously it has been proposed that the large metacentric chromosome of S. senegalensis arises from this kind of chromosome rearrangement and that this is a proto-sex chromosome. RESULTS: In this work, the Robertsonian origin of the large metacentric chromosome of S. senegalensis has been tested by the Zoo-FISH technique applied to two species of the Soleidae family (Dicologlossa cuneata and Dagetichthys lusitanica), and by comparative genome analysis with Cynoglossus semilaevis. From the karyotypic analysis we were able to determine a chromosome complement comprising 2n = 50 (FN = 54) in D. cuneata and 2n = 42 (FN = 50) in D. lusitanica. The large metacentric painting probe gave consistent signals in four acrocentric chromosomes of the two Soleidae species; and the genome analysis proved a common origin with four chromosome pairs of C. semilaevis. As a result of the genomic analysis, up to 61 genes were annotated within the thirteen Bacterial Artificial Chromosome clones analysed. CONCLUSIONS: These results confirm that the large metacentric chromosome of S. senegalensis originated from a Robertsonian fusion and provide new data about the chromosome evolution of S. senegalensis in particular, and of Pleuronectiformes in general. PMID- 30428855 TI - Three-dimensional power Doppler ultrasound evaluation of placental blood flow in normal monochorionic diamniotic twin pregnancies. AB - BACKGROUND: Monochorionic diamniotic (MCDA) twin pregnancies are at higher risk of adverse outcomes and complications, which are attributed to the influence of placental morphology in MCDA twins. Monitoring of placental function is an important index for clinical decisions. The aim of our study was to evaluate the placental blood flow estimated using three-dimensional power Doppler (3D-PD) ultrasound and the vascular indices distribution with gestational age (GA) in normal MCDA twin pregnancies. METHODS: One hundred four MCDA twin pregnancies and 106 singleton pregnancies (GA range, 14-32 weeks) were included in this prospective study. 3D-PD volume data of each fetus was obtained separately from the placenta at the site of umbilical cord insertion. We analyzed the volume data using sonobiopsy technique. The placental vascularization index (VI), flow index (FI) and vascularizationflow index (VFI), were auto-calculated. The means and standard deviation values of three vascular indices per fetus were calculated and regression analysis of the vascular indices as a function of GA was performed in twin pregnancies. The vascular indices of twin and singleton pregnancies were compared using independent t-test. RESULTS: There were no significant differences in VI, FI or VFI among the fetuses of twins (p > 0.05). These vascular indices increased over the course of pregnancy (p < 0.05). We obtained the regression equations for the indices as a function of GA in days: VI = exp. (4.369 28.533/GA) (R2 = 0.699, p < 0.05), FI = exp. (3.916-13.003/GA) (R2 = 0.511, p < 0.05), and VFI = exp. (3.577-37.468/GA) (R2 = 0.675, p < 0.05). There were no significant differences in three vascular indices between MCDA twin and singleton groups (p > 0.05). CONCLUSIONS: 3D-PD placental data using sonobiopsy technique could reflect the placental blood flow of each twin, which could be applied to the study of placental perfusion in MCDA twin pregnancies. This study also presented the vascular indices distribution with GA in normal twin pregnancies, which might be useful for early detection of MCDA complications. PMID- 30428856 TI - The effect of ranibizumab and aflibercept treatment on the prevalence of outer retinal tubulation and its influence on retreatment in neovascular age-related macular degeneration. AB - BACKGROUND: We aimed to analyze the differences in the prevalence of outer retinal tubulation (ORT) in neovascular age-related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (anti-VEGF) agents, either aflibercept or ranibizumab. Our further aim was to examine the changes in the frequency of injections of ranibizumab before and after ORT appearance. METHODS: Two hundred thirty six eyes of 230 patients were included in the study (184 eyes treated with ranibizumab by pro re nata regimen (PRN), 52 eyes with aflibercept bimonthly) and followed for 6-24 months. Using optical coherence tomography (OCT), the first appearance of ORT was documented, and fixed time point evaluations were also made every six months to determine the existence of ORT. The number of injections, the presence or absence of subretinal hyperreflective material (SHRM) at treatment initiation and visual acuity were also noted. RESULTS: The survival analysis with Cox proportional hazard model showed no significant difference between the ranibizumab and aflibercept groups in relation to the development of ORT (p = 0.79, hazard ratio 0.92). In the PRN treated ranibizumab group the number of injections showed significant decrease after ORT development (p = 0.004). When SHRM was present at treatment initiation the chance of developing ORT was 2.75 and 11.14 times higher in the ranibizumab and aflibercept groups, respectively. CONCLUSIONS: The prevalence of ORT increased over time independently from the chosen anti-VEGF drug. Our results suggest that upon the appearance of ORT a decrease in retreatments can be expected. PMID- 30428857 TI - Rare case of neglected large sacral Chordoma in a young female treated by wide En bloc resection and Sacrectomy. AB - BACKGROUND: Sacral chordoma is a locally aggressive malignant tumour originating from ectopic notochordal cells. The natural history of sacral chordoma is a slow growing tumour arising at the midline of the lower sacrum that can invade the sacrum and progressively increase in size expanding cranially and anteriorly. Metastasis is very rare even when the tumour is large. Sacral chordoma affects males more than females and is more commonly found in middle age and elderly patients. CASE PRESENTATION: A 25 years old female had neglected an extremely large midline sacral mass for 2 years. On presentation to hospital, she had been bed bound for the past 2 years. The sacral mass was so large that it prevented her from lying down supine and sitting on the wheelchair comfortably. Clinical examination showed a 40 cm * 30 cm * 20 cm hard mass over the sacrum that involved both buttocks and the gluteal fold. Neurological exam of bilateral lower limb was normal. Computed Tomography Scan of the Pelvis showed a large destructive sacrococcygeal mass measuring 43 cm * 38 cm * 27 cm with extension into the presacral space resulting in anterior displacement of the rectum, urinary bladder and uterus; and posterior extension into the dorsal soft tissue with involvement of the gluteus, piriformis, and left erector spinae muscles. Biopsy taken confirmed Chordoma. This patient was managed by a multidisciplinary team in an Oncology referral centre. The patient had undergone Wide En Bloc Resection and Sacrectomy, a complex surgery that was associated with complications namely bleeding, surgical site infection and neurogenic bowel and bladder. Six months post operatively the patient was able to lie supine and sit on wheelchair comfortably. She required extensive rehabilitation to help her ambulate in future. CONCLUSION: This is a rare case of neglected sacral chordoma in a young female treated with Wide En Bloc Resection and Sacrectomy associated with complications of this complex surgery. Nevertheless, surgery is still worthwhile to improve the quality of life and to prevent complications secondary to prolonged immobilization. A multidisciplinary approach is ideal and team members need to be prepared to address the complications once they arise. PMID- 30428859 TI - Anal human papillomavirus infection in HIV-positive men and women at two opportunistic infections clinics in Harare, Zimbabwe. AB - BACKGROUND: HIV-infected individuals are at increased risk of anal cancer; in the majority of cases this is linked to human papillomavirus (HPV) infection. Anal cancer screening is not routinely offered in Zimbabwe. METHODS: A cross-sectional study was performed on 152 patients (88 females; 64 males) attending Opportunistic Infection Clinics at 2 tertiary hospitals between November 2014 and June 2015. Demographic data, immunological parameters and behavioural characteristics were collected. An anal swab was collected from each patient for HPV genotype testing. HPV testing was performed using MY09/MY11 PCR, followed by typing using the dot blot method. RESULTS: The mean age was 39.6 years (range, 18 69 years). Median CD4 count was 375 cells/MUL. 96% were on antiretroviral therapy. Only one patient identified as a man who has sex with men. Of 122 samples tested for HPV, 54 were positive (44%). HPV was three times more common in females (60%) than males (20%). Being HPV-positive was associated with history of perianal warts, history of cervical intraepithelial neoplasia and having more than ten lifetime sexual partners. The most commonly detected high-risk HPV genotypes were HPV-58 (13%), HPV-31 (11%) and HPV-16 (9%). Nine patients harboured multiple high-risk HPV types. The two most commonly detected low-risk genotypes were HPV-11 (17%) and HPV-53 (11%). CONCLUSION: Overall anal HPV prevalence was 44% in this mostly heterosexual HIV-positive population. Oncogenic HPV types accounted for almost half of infections, supporting the need for surveillance of anal cancer in this population. PMID- 30428858 TI - Association of diet in nurseries and physical activity with zBMI in 2-4-year olds in England: a cross-sectional study. AB - BACKGROUND: Childhood obesity tracks into adulthood with detrimental effects on health. We aimed to examine the relationships of diet in childcare settings and daily physical activity (PA) of preschoolers with body mass index z-score (z BMI). METHODS: We conducted a cross-sectional study of 150 children aged 2-4 years participating in the Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC) UK study to examine the associations of their diet in childcare settings and daily PA with z-BMI. Dietary intake was observed and recorded by fieldworkers using a validated tick-list food questionnaire and diet quality was assessed based on adherence to Children's Food Trust (CFT) guidelines. PA was measured using accelerometers. We derived z-BMI scores using the UK 1990 and International Obesity Taskforce growth reference charts. Multilevel regression models were used to estimate associations between diet and PA with z-BMI separately, adjusted for age, gender, ethnicity, parental education level and clustering. RESULTS: Among children who consumed one main meal or snack at childcare, 34.4% and 74.3% met the standards on fruits and vegetables and high sugar or fat snacks, respectively. Adherence to CFT guidelines was not associated with zBMI. Only 11.4% of children met recommended UK guidelines of three hours per day of physical activity. Minutes spent in light PA (beta = 0.08, 95% CI = 0.01, 0.15) and active time (beta = 0.07, 95% CI = 0.01, 0.12) were positively associated with UK 1990 zBMI scores. CONCLUSIONS: The low proportion of children meeting the standards on fruits and vegetables and high sugar or fat snacks and recommended physical activity levels highlight the need for more work to support nurseries and parents to improve preschool children's diet and activity. In our exploratory analyses, we found children with higher zBMI were more physically active which could be attributed to fat-free mass or chance finding and so requires replication in a larger study. TRIAL REGISTRATION: ISRCTN16287377 . Registered 12 June 2014. PMID- 30428860 TI - A qualitative study of the drivers of socioeconomic inequalities in men's eating behaviours. AB - BACKGROUND: Men of low socioeconomic position (SEP) are less likely than those of higher SEP to consume fruits and vegetables, and more likely to eat processed discretionary foods. Education level is a widely used marker of SEP. Few studies have explored determinants of socioeconomic inequalities in men's eating behaviours. The present study aimed to explore intrapersonal, social and environmental factors potentially contributing to educational inequalities in men's eating behaviour. METHODS: Thirty Australian men aged 18-60 years (15 each with tertiary or non-tertiary education) from two large metropolitan sites (Melbourne, Victoria; and Newcastle, New South Wales) participated in qualitative, semi-structured, one-on-one telephone interviews about their perceptions of influences on their and other men's eating behaviours. The social ecological model informed interview question development, and data were examined using abductive thematic analysis. RESULTS: Themes equally salient across tertiary and non-tertiary educated groups included attitudes about masculinity; nutrition knowledge and awareness; 'moralising' consumption of certain foods; the influence of children on eating; availability of healthy foods; convenience; and the interplay between cost, convenience, taste and healthfulness when choosing foods. More prominent influences among tertiary educated men included using advanced cooking skills but having relatively infrequent involvement in other food-related tasks; the influence of partner/spouse support on eating; access to healthy food; and cost. More predominant influences among non-tertiary educated men included having fewer cooking skills but frequent involvement in food-related tasks; identifying that 'no-one' influenced their diet; having mobile worksites; and adhering to food budgets. CONCLUSIONS: This study identified key similarities and differences in perceived influences on eating behaviours among men with lower and higher education levels. Further research is needed to determine the extent to which such influences explain socioeconomic variations in men's dietary intakes, and to identify feasible strategies that might support healthy eating among men in different socioeconomic groups. PMID- 30428861 TI - Socioeconomic and demographic predictors of resident knowledge, attitude, and practice regarding arthropod-borne viruses in Panama. AB - BACKGROUND: We sought to identify if socioeconomic and demographic factors play a role in resident knowledge, attitude, and practice regarding Dengue, Chikungunya, and Zika in order to inform effective management procedures for disease prevention in Panama, a middle-income tropical country in Central America. All three are arthropod-borne viruses transmitted by Aedes mosquito vectors present in the focal region of Panama City, the largest city in Central America and an urban region of extreme socioeconomic polarization. METHODS: Between November 2017 and February 2018, we administered standardized, anonymous knowledge, attitude, and practice surveys to 263 residents split between two neighborhoods of high socioeconomic status (SES) and two neighborhoods of low SES. We then summed the knowledge, attitude, and practice scores respectively, and used linear and logistic regressions to quantify relationships with socioeconomic and demographic factors. RESULTS: Low-SES neighborhoods with high proportions of low income residents, residents over 70 years old had lower mean knowledge scores compared to other groups. Furthermore, residents in neighborhoods of low SES reported more mosquito biting relative to residents in neighborhoods of high SES, yet comparably lower level of concerns for disease transmission. Additionally, knowledge was lower for the more novel emergent threats of Chikungunya and Zika, compared to the endemic Dengue. CONCLUSION: Findings suggest that low-SES neighborhoods with high proportions of low income, low education, and elderly residents should be targeted for outreach programs designed to prevent DENV, CHIKV, or ZIKV in Panama City. These outcomes support our initial hypotheses as lower relative knowledge and fewer practices related to the prevention of Dengue, Chikungunya, and Zika were found in low-SES neighborhoods. There is also a widespread lack of adequate knowledge regarding these diseases as well as low levels of concern in areas of highly reported mosquito biting. We provide suggestions for taking neighborhood socioeconomic status and specific aspects resident health literacy and attitude into account for creating more effective outreach campaigns as both endemic and novel arthropod-borne disease rates continue to increase throughout Latin America. PMID- 30428862 TI - Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study. AB - BACKGROUND: In this study, the treatment of schizophrenia patients with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic setting. METHODS: This multicenter, prospective, non-interventional study included 242 patients (age = 43.1 +/- 15.1 years, 55.0% male) who were monitored during 6 months of AOM treatment. Endpoints included measurements of psychopathology (Brief Psychiatric Rating Scale, BPRS) and severity of illness scales (Clinical Global Impressions-Severity, CGI-S, and -Improvement, CGI-I). Furthermore, treatment-related adverse events (TRAEs) were recorded. RESULTS: At baseline, the mean BPRS total score was 54.1 +/- 15.6, the mean CGI-S was 4.8 +/- 0.8 and the most frequent illness category was 'markedly ill' (41.7%). Patients had been pretreated with oral aripiprazole for a mean duration of 9.7 months (SD: 22.3) and 87.9% were deemed by their clinician as "clinically stable" and for a mean of 5.9 months. The difference in global BPRS after 6 months was - 13.8 (SD: 16.0; 95% CI: [- 15.9; - 11.7]; p < 0.001). The proportion of patients with high CGI-S scores decreased and the proportion of patients with low scores increased significantly (p < 0.001, respectively). BPRS scores improved numerically especially well in younger patients <=35 years, CGI-S scores decreased significantly more in this population. TRAEs were rare, with low incidences of extrapyramidal symptoms (2.9%) or weight increase (0.4%). CONCLUSIONS: Treatment with AOM showed satisfying effectiveness in outpatients with further improvement of psychopathology after oral aripiprazole treatment for a considerable duration and even after having achieved clinically judged "stability". Our findings indicate a robust therapeutic effect of AOM and substantiate previous results from randomized controlled trials under real-world routine conditions. PMID- 30428864 TI - Negative pressure pulmonary edema after percutaneous endoscopic interlaminar lumbar discectomy-a case report. AB - BACKGROUND: Negative pressure pulmonary edema (NPPE) is a rare complication that is more prevalent in young patients. NPPE usually results from acute upper airway obstruction, which is most commonly caused by laryngospasm during extubation. NPPE is characterized by the sudden onset of coughing, hemoptysis, tachycardia, tachypnea, and hypoxia, and is dramatically improved with supportive care, which prevents severe sequelae. To our knowledge, there is no report of a patient developing NPPE after percutaneous endoscopic interlaminar lumbar discectomy. CASE PRESENTATION: Herein, we report the case of a 22-year-old amateur basketball player with L5/S1 disc herniation who developed NPPE during extubation after general anesthesia for a minimally invasive spinal surgery (percutaneous endoscopic interlaminar lumbar discectomy). The NPPE was treated by maintaining the airway patency, applying positive-pressure ventilation, administering dexamethasone and antibiotics, and limiting the volume of fluid infused. The patient had an uneventful postoperative course, and was discharged to his home on postoperative day 3. CONCLUSIONS: Although NPPE is an infrequent complication, especially in patients undergoing percutaneous endoscopic interlaminar lumbar discectomy, this case report highlights the importance of early diagnosis and prompt treatment of NPPE to prevent the development of potentially fatal complications. PMID- 30428863 TI - Protocol for evaluating the effects of a foot-ankle therapeutic exercise program on daily activity, foot-ankle functionality, and biomechanics in people with diabetic polyneuropathy: a randomized controlled trial. AB - BACKGROUND: Diabetic polyneuropathy (DPN) negatively affects foot and ankle function (strength and flexibility), which itself affects the daily physical activity and quality of life of patients. A physical therapy protocol aiming to strengthen the intrinsic and extrinsic foot muscles and increase flexibility may be a promising approach to improve lower-extremity function, prevent further complications, and improve autonomy for daily living activities in these patients. Thus, the inclusion of a specific foot-related exercises focused on the main musculoskeletal impairments may have additional effects to the conventional interventions in the diabetic foot. METHODS/DESIGN: A prospective, parallel group, outcome-assessor blinded, randomized controlled trial (RCT) will be conducted in 77 patients with DPN who will be randomly allocated to usual care (control arm) or usual care with supervised foot-ankle exercises aiming to increase strengh and flexibility twice a week for 12 weeks and remotely supervised foot-ankle exercises for a year through a web software. Patients will be evaluated 5 times in a 1 year period regarding daily physical activity level, self-selected and fast gait speeds (primary outcomes), foot ulcer incidence, ulcer risk classification, neuropathy testing, passive ankle range of motion, quality of life, foot health and functionality, foot muscle strength, plantar pressure, and foot-ankle kinematics and kinetics during gait. DISCUSSION: This study aims to assess the effect of a foot-ankle strength and flexibility program on a wide range of musculoskeletal, activity-related, biomechanical, and clinical outcomes in DPN patients. We intend to demonstrate evidence that the year-long training program is effective in increasing gait speed and daily physical activity level and in improving quality of life; foot strength, functionality, and mobility; and biomechanics while walking. The results will be published as soon as they are available. TRIAL REGISTRATION: This study has been registered at ClinicalTrials.gov as NCT02790931 (June 6, 2016) under the name "Effects of foot muscle strengthening in daily activity in diabetic neuropathic patients". PMID- 30428865 TI - Using the Health Belief Model to explore why women decide for or against the removal of their ovaries to reduce their risk of developing cancer. AB - BACKGROUND: Women at an increased risk of ovarian cancer often have to decide for or against the surgical removal of their healthy ovaries to reduce their cancer risk. This decision can be extremely difficult. Despite this, there is a lack of guidance on how to best support women in making this decision. Research that is guided by theoretical frameworks is needed to help inform clinical practice. We explored the decision-making process of women who are at an increased risk of developing ovarian cancer and had to decide for or against the removal of their ovaries. METHODS: A qualitative study of 18 semi-structured interviews with women who have attended a cancer treatment centre or cancer counselling and information service in New South Wales, Australia. Data collection and analysis were informed by the Health Belief Model (HBM). Data was analysed using qualitative content analysis. RESULTS: The paper describes women's decision making with the help of the four constructs of the HBM: perceived susceptibility, perceived severity, perceived benefits, and perceived barriers. The more anxious and susceptible women felt about getting ovarian cancer, the more likely they were to have an oophorectomy. Women's anxiety was often fuelled by witnessing family members suffer or die from cancer. Women considered a number of barriers and potential benefits to having the surgery but based their decision on "gut feeling" and experiential factors, rather than statistical risk assessment. Age, menopausal status and family commitments seemed to influence but not determine women's decisions on oophorectomy. Women reported a lack of decision support and appreciated if their doctor explained their treatment choice, provided personalised information, involved their general practitioner in the decision making process and offered a second consultation to follow-up on any questions women might have. CONCLUSIONS: These findings suggest that deciding on whether to have an oophorectomy is a highly personal decision which can be described with the help of the HBM. The results also highlight the need for tailored decision support which could help improve doctor-patient-communication and patient-centred care related to risk reducing surgery in women at an increased risk of ovarian cancer. PMID- 30428866 TI - Understanding how to improve physicians' paradigms for prescribing antibiotics by using a conceptual design framework: a qualitative study. AB - BACKGROUND: Antimicrobial resistance (AMR) is a growing public health threat. Primary care physicians are important inducers of the overuse of antimicrobials and inappropriate prescribing. Augmented reality (AR) might provide a potential educational tool in health care. The aim of this study was to identify the need for education and expectations for AR-based education in the context of improving the rational use of antibiotics by primary care physicians in China. METHODS: The study used a qualitative approach based on face-to-face interviews with eleven physicians from three community health service centers and stations in China. We used a hybrid thematic analysis approach to analyze the interview data. A conceptual design framework, mobile augmented reality education (MARE), guided the work. RESULTS: The physicians' personal prescription paradigms included problems regarding the way they diagnosed and chose treatments and prescriptions. Although the physicians mentioned that they should not treat patients with antibiotics without proof of a bacterial infection, in practice, they often did not wait for necessary test results before they prescribed antibiotics. It was also revealed that they often experienced difficulties when trying to convince patients to follow non-antibiotic treatments. Physicians' prescription of antibiotics was based on three different paths: if they thought there was a bacterial infection, if they thought preventing additional possible infections for the patient to be necessary; and if the patients requested antibiotics. The physicians expressed various learning needs for the rational use of antibiotics, and their expectations of an AR-based educational intervention included suggestions for contents, learning assets, learning environments and learning activities. CONCLUSIONS: The results showed that the physicians were not only unfamiliar with national guidelines on the use of antibiotics and local AMR patterns but also had personal paradigm issues related to the physicians' decision making. Moreover, the physicians provided meaningful insights into and expectations for possible AR-based education on AMR. In this article, we demonstrate how to apply the MARE framework to analyze the needs of educational interventions for rational use of antibiotics. PMID- 30428867 TI - Spontaneous regression of adrenal metastasis from renal cell carcinoma after sunitinib withdrawal: case report and literature review. AB - BACKGROUND: The spontaneous regression of metastatic renal cell carcinoma is a rare phenomenon, with an estimated incidence of < 1%. We report a case of post nephrectomy renal cell carcinoma adrenal metastasis, followed by the spontaneous regression of the metastasis after withdrawal of sunitinib. CASE PRESENTATION: The patient was a 55-year-old male with clear cell type renal cell carcinoma who previously underwent a left laparoscopic radical nephrectomy. After 51 months of follow up, a recurrence in the left renal fossa was observed and subsequently excised. Four months after excision, an abdominal Computerized tomography (CT) identified an adrenal metastasis of 1.6 cm. The patient was treated with sunitinib. However, the treatment was discontinued because of gastrointestinal side effects and fatigue. Eleven months after the discontinuation of sunitinib treatment, a progression in the adrenal metastasis growth (5.7 cm) was observed, whereas 16 months after the discontinuation, a regression of the adrenal metastasis growth (3.4 cm) was observed. During subsequent follow-ups, a gradual reduction in the size of the adrenal metastasis (1.8 cm) was observed. After 44 months from the discontinuation of sunitinib treatment, the patient was still alive and followed up in the outpatient department. CONCLUSIONS: Sunitinib is a multi-targeted inhibitor of vascular endothelial growth factor (VEGF) receptors. This compound reduces tumor angiogenesis and has been approved worldwide for the treatment of advanced renal cell carcinoma. To our knowledge, this is the fourth case of the spontaneous regression of metastatic renal cell carcinoma after the discontinuation of sunitinib treatment. PMID- 30428868 TI - Changes in peroxisome proliferator-activated receptor alpha target gene expression in peripheral blood mononuclear cells associated with non-alcoholic fatty liver disease. AB - OBJECTIVE: To identify differences in the expression of peroxisome proliferator activated receptor alpha (PPARalpha) target genes in human peripheral blood mononuclear cells (PBMCs) associated with non-alcoholic fatty liver disease (NAFLD) among Chinese individuals. METHODS: Thirty healthy subjects were selected as the control group (CN), and 43 patients newly diagnosed with NAFLD were subdivided into two groups, non-obese group (NF, n = 21) and obese group (OF, n = 22). Expression of PPARalpha and its target genes was determined in PBMCs. The levels of liver cell damage markers, total cholesterol (TC), triglyceride (TG), free fatty acids (FFA), glucose, and insulin were determined in serum. RESULTS: Compared to the CN group, the blood pressure and homeostasis model assessment for insulin resistance (HOMA-IR) were increased in the other groups (P < 0.05), while the systolic blood pressure (SBP) and liver cell damage markers were significantly increased in the OF group (P < 0.05). In the OF group, PPARalpha target gene expression was 2.03-3.31 times higher than that in the CN group, and a negative correlation was found between PPARalpha target gene expression and abdominal circumference (AC), body mass index (BMI), diastolic blood pressure (DBP). Additionally, solute carrier family 25 (carnitine/acylcarnitine translocase) member 20 (SLC25A20) and acyl-coenzyme A dehydrogenase 2 long chain (ACADVL) were negatively correlated with HOMA-IR; PPARalpha, acetyl-coenzyme A dehydrogenase 2 (ACAA2), and carnitine palmitoyltransferase 1A (CPT1A) were positively correlated with HOMA-IR. CONCLUSION: There is an up-expression of PPARalpha target genes in the PBMCs of NAFLD patients, possibly leading to changes in beta-oxidation and insulin resistance. PMID- 30428869 TI - Tactics employed by healthcare providers in Denmark to determine the vaccination needs of asylum-seeking children: a qualitative study. AB - BACKGROUND: Many asylum-seekers to Denmark come from war-torn countries where conflict and insufficient health care infrastructures disrupt vaccine programmes and result in very few children and their families presenting documentation of vaccinations on their arrival in asylum-centers. There is a need to explore how healthcare providers, in the absence of vaccine documentation, determine the vaccination needs of newly arrived refugee children. METHODS: To explore the tactics employed by healthcare professionals who screen and vaccinate asylum seeking children in Denmark, we conducted semi-structured interviews between December 2015 and January 2016 with six healthcare professionals, including three doctors and three public health nurses. The interviews were digitally recorded, transcribed and subjected to a thematic network analysis. RESULTS: The analysis revealed that healthcare providers adopt a number of tactics to ascertain children's immunization needs. They ask into the children's vaccination history through the use of qualified interpreters; consult WHO lists of immunization programmes worldwide; draw on tacit knowledge about country vaccination programmes; consider the background of parents; err on the side of caution and revaccinate. CONCLUSIONS: This is one of the first studies to demonstrate the tactics employed by healthcare providers to ascertain the immunization needs of asylum-seeking children in a western receiving country. The findings suggest a need for clear guidance at a national level on how to determine the vaccination needs of asylum-seeking children, and an international effort to secure reliable immunization documentation for migrant populations, for example through virtual immunization records. PMID- 30428870 TI - Recurrent epibulbar dermoid cyst treated with amniotic membrane implant a case report. AB - BACKGROUND: The dermoid cyst considered a cystic teratoma derived from embryonic germinal epithelium is a slow-growing benign tumour. Dermoid cysts may occur in the orbital and periorbital region in paediatric patients and are often recurrent. The surgical approach depends upon the site of the lesion, superficial or deep. To our knowledge, this is the first described case of a patient with resection of dermoid cyst treated with human amniotic membrane implant and topical application of 0.02% mitomycin C. CASE PRESENTATION: We present a case of a 12-year-old male with a tumour in the superotemporal region of the right eye (RE). Symptoms included decreased visual acuity (VA), burning eye, foreign body sensation, and photophobia of the affected eye. A physical examination detected blepharospasm. Ophthalmic examination of his RE, fingers count from a 1-2 m distance, showed no improvement with pinhole. Visual acuity was 20/20 on the left eye (LE). The bio-microscopic examination confirmed the presence of a tumour mass (15 mm * 12 mm) on the surface of the RE, invading the superotemporal sector. The tumour had a lobulated appearance, a shiny and vascularized surface covered by conjunctiva, a pearlescent-pink colour, a medium consistency, was renitent and painless. An ultrasound scan revealed atrophy of the pigmented retinal epithelium with scleral indentation of the RE. A computed tomography (CT) scan revealed a recurrent lesion consistent with an epibulbar dermoid cyst. Surgical excision of the lesion was performed and a human amniotic membrane (HAM) graft and topical 0.02% mitomycin C (MMC) were applied. Histopathological analysis confirmed the diagnosis of recurrent dermoid cyst. CONCLUSION: In this case report, we describe a case of recurrent epibulbar dermoid cyst treated with complete resection; topical MMC and HAM implant with good clinical outcome of the lesion and implant adhesion. Resection of a cyst of the ocular surface is not recommended when a large epibulbar dermoid tissue needs to be resected and no HAM graft is available. PMID- 30428872 TI - Paraneoplastic syndrome as the presentation of limited stage small cell carcinoma. AB - BACKGROUND: Small cell lung carcinoma (SCLC) is one of the deadliest forms of lung cancer due to its poor prognosis upon diagnosis, rapid doubling time, and affinity for metastasis. As 60-70% of patients with SCLC have disseminated disease upon presentation, it is imperative to determine the extent of disease burden for treatment. As a neuroendocrine carcinoma, clinicians must pay close attention to abnormal findings in a smoker that could lead to earlier diagnosis and better prognostication. CASE PRESENTATION: A 64 year-old 20-pack year smoker presented to the emergency department with nausea and vomiting for 3 days. No inciting events were elicited. History and review of symptoms were negative including symptoms most-commonly associated with malignancy such as fevers and weight loss. He also denied any pulmonary symptoms. Physical examination was benign except for right lung end-expiratory wheezing. Our patient was clinically euvolemic. Initial blood laboratories showed a sodium 110, serum osmolarity 227, and urine osmolarity of 579. Fluid restriction led to normalization of his sodium and resolution of nausea & vomiting. Chest radiography was obtained to follow-up on the wheezing, which was read as no acute cardiopulmonary disease by radiology. Due to high suspicion of SIADH from malignancy, a CT of the chest was performed which showed a conglomerate of nodules and opacities in the right upper lobe. Biopsy revealed SCLC. At outpatient follow-up, patient had a PET-CT showing one active mediastinal lymph node as the only site of metastasis. He received three round of chemotherapy, chest and prophylactic cranial radiation, and deemed in remission by oncology. DISCUSSION AND CONCLUSIONS: Due to its affinity for metastases, 70% of patients with SCLC present with symptoms related to the spread of cancer to affected organ systems. Given the aggressive nature of this disease, screening measures have been implemented to help diagnose limited stage SCLC. Unfortunately, in our patient and many others, screening guidelines may fail to identify appropriate patients to scan. It is therefore imperative to use our clinical index of suspicion and identify any early presentations (including paraneoplastic syndromes) which may tip off the beginning stages of SCLC. This could improve survival rates by up to 45%. PMID- 30428871 TI - Shift work and cognitive impairment in later life - results of a cross-sectional pilot study testing the feasibility of a large-scale epidemiologic investigation. AB - BACKGROUND: The effect of shift work on impairment of cognition in later life has not yet been sufficiently investigated. Therefore, we aimed at testing the feasibility of a large-scale epidemiologic study examining this putative association in a pilot study. METHODS: Between January and April 2017, a cross sectional study invited a random sample of 425 former and current employees of a German university hospital aged 55 years and older to undergo a cognitive test battery (including the Repeatable Battery for the Assessment of Neuropsychological Status, Trail Making Test, Letter-Number Span, and Vocabulary Test) and to complete a self-administered questionnaire on socio-demographic characteristics, chronotype, sleep, occupational history including shift work, and medical history. Fifty percent of the invitees were registered in the hospital's occupational records as currently working or having worked in a shift system. The feasibility of a large-scale study was evaluated by the response of the study sample and the completeness of data. In addition, we calculated the prevalence of shift work and cognitive impairment in the study population. RESULTS: Seventy five subjects (18%) completed the questionnaire, of whom 47 (11% of the total sample) participated in cognitive testing. In all but four items assessed in the questionnaire, the proportion of missing data was below 10 %, suggesting that the quality of collected data can be considered as high. Eighty percent of the participants reported that they ever worked in a shift system, indicating selective participation by exposure to shift work. With respect to chronotype, the majority of the study subjects rated themselves as rather evening type, while a quarter considered themselves as definite morning type. All cognitive tests could be carried out completely. We observed slight difficulties in at least one of the cognitive tests in 17 participants (36%) while two participants (4%) showed more pronounced signs of cognitive impairment. CONCLUSION: The present pilot study only partially supported the feasibility of the planned large-scale study. As response rates were low and depended on exposure to shift work, a better way of sampling and recruitment needs to be identified. The questionnaire and the test battery appear to be viable instruments. PMID- 30428873 TI - Changes in the nutritional quality of products sold in university vending machines since implementation of the health star rating in 2014; an environmental audit. AB - BACKGROUND: Snacking is a prevalent dietary behaviour among young adults, which could independently contribute to weight gain. Vending machines provide easy access to unhealthy snacks and beverages for young adults in universities. A voluntary front-of-pack labelling, named the Health Star Rating (HSR) system, has been implemented nationally by the Australian government as one strategy to address obesity since 2014. The primary aim of this study was to detect changes in the availability, pricing and advertising of healthy and unhealthy snacks and beverages in university vending machines after introduction of the HSR. METHODS: The study design was two cross-sectional audits of university vending machines one before (in 2014) and another after (in 2017) the implementation of the HSR. Data collections were conducted in a large urban university (> 60,000 students). Every machine was assessed; the product's name, price, portion sizes and advertisements were recorded. Products were assigned an HSR to classify as healthy (>=3.5 stars) or unhealthy (< 3.5 stars). To compare the differences of product availability between 2014 and 2017, the Chi-square test was used. RESULTS: A total of 1836 and 2458 slots were audited in 2014 and 2017, respectively. The proportion of healthy snacks and beverages increased from 7 to 14% (p < 0.001) and 38 to 44% (p < 0.05) since 2014, respectively. The mean costs of unhealthy snacks and healthy beverages increased after three years. Healthy food and drink options were more expensive than unhealthy choices in 2017. Advertisements on vending machines for unhealthy foods and drinks remained prevalent. CONCLUSION: Only small changes have been observed in the availability of healthy snacks and beverages in vending machines since implementation of the HSR system. Policy directives are indicated to encourage further improvements. PMID- 30428874 TI - Improvements in blood transfusion management: cross-sectional data analysis from nine hospitals in Zhejiang, China. AB - BACKGROUND: Since 2008, updated perioperative blood management (PoBM) guidelines have been implemented in Zhejiang, China. These guidelines ensure that the limited blood resources meet increasing clinical needs and patient safety requirements. We assessed the effects of implementing updated PoBM guidelines in hospitals in Zhejiang, China. METHODS: We performed a retrospective multicenter study that included adult patients who received blood transfusions during surgical care in the years 2007 and 2011. The volume of allogeneic red blood cells or autologous blood transfusions (cell salvage and acute normovolemic hemodilution [ANH]) for each case was recorded. The rates of performing appropriate pre-transfusion assessments during and after surgery were calculated and compared between the 2 years. RESULTS: We reviewed 270,421 cases from nine hospitals. A total of 15,739 patients received blood transfusions during the perioperative period. The rates of intraoperative allogeneic transfusion (74.8% vs. 49.9%, p < 0.001) and postoperative transfusion (51.9% vs. 44.2%, p < 0.001) both decreased from 2007 to 2011; the rates of appropriate assessment increased significantly during (63.0% vs. 78.0%, p < 0.001) and after surgery (70.6% vs. 78.4%, p < 0.001). The number of patients who received cell salvage or ANH was higher in 2011 (27.6% cell salvage; 9.3% ANH) than in 2007 (6.3% cell salvage; 0.1% ANH). CONCLUSION: Continuing education and implementation of updated PoBM guidelines resulted in significant improvements in the quality of blood transfusion management in hospitals in Zhejiang, China. PMID- 30428875 TI - A novel microemulsion-based isotonic perfusate modulated by Ringer's solution for improved microdialysis recovery of liposoluble substances. AB - BACKGROUND: Microdialysis is promising technique for dynamic microbiochemical sampling from tissues. However, the application of typical aqueous perfusates to liposoluble substances is limited. In this study, a novel microemulsion (ME) based isotonic perfusate (RS-ME) was prepared to improve the recovery of liposoluble components using microdialysis probes. RESULTS: Based on pseudo ternary phase diagrams and comparisons of the ME area, Kolliphor(r) EL and Transcutol(r) P were selected as the surfactant and co-surfactant, respectively, with a weight ratio (Km) of 2:1 and ethyl oleate as the oil phase. The ME was mixed with Ringer's solution at a 1:6 ratio (v/v) to obtain the isotonic RS-ME. The droplet size distribution of the ME in RS-ME was 78.3 +/- 9.2 nm, with a zeta potential of - 3.5 +/- 0.3 mV. By microdialysis perfusion, RS-ME achieved higher recovery rates of the poorly water-soluble compounds evodiamine (EVO) and ruthenium (RUT), i.e., 58.36 +/- 0.57% and 49.40 +/- 0.57%, respectively, than those of 20% (v/v) PEG 400 Ringer's solution (RS-PEG) and 10% (v/v) ethanol Ringer's solution (RS-EtOH). In vivo microdialysis experiments confirmed that RS ME captured EVO and RUT molecules around the dialysis membrane more efficiently and exhibited less spreading than RS-PEG and RS-EtOH. CONCLUSIONS: Owing to the nanosized droplets formed by lipid components in the RS-ME and the limited dispersion out of the dialysis membrane, we obtained good biocompatibility and reliable dialysis results, without affecting the tissue microenvironment. As a novel perfusate, RS-ME provides an easy and reliable approach to the microdialysis sampling of fat-soluble components. PMID- 30428876 TI - Vaccine hesitancy among mobile pastoralists in Chad: a qualitative study. AB - BACKGROUND: Demand side barriers to vaccination among rural and hard-to-reach populations in Chad are not yet well understood. Although innovative approaches such as linking human and animal vaccination increase vaccination uptake among mobile pastoralist communities, vaccination coverage in these communities is still lower than for rural settled populations. We hypothesize that mobile pastoralists' communities in Chad face specific demand side barriers to access vaccination services. Understanding the factors that caregivers in these communities consider, explicitly or implicitly, in order to decide whether or not to vaccinate a child, in addition to understanding the provider's perspectives, are essential elements to tailor vaccination programmes towards increasing vaccination acceptance and uptake. METHODS: We conducted a qualitative study in a rural health district in southern Chad in April 2016 with 12 key informant in depth interviews and four focus group discussions (FGDs) including 35 male and female participants. Participants in the study included caregivers, traditional chiefs, local and religious leaders from mobile pastoralist communities, and health officials and staff. We conducted a content analysis using a pre-defined set of categories for vaccine hesitancy covering issues on harmful effects of vaccination, mistrust with vaccination programmes/services, issues with the health system and other issues. RESULTS: The groups of demand side barriers reported most frequently in focus group discussions were mistrust on the expanded programme on immunization (EPI) and polio vaccination outreach services (53%, n = 94), followed by health system issues (34%, n = 94), and concerns related to potential harm of vaccines (13%, n = 94). Concerns identified by caregivers, health professionals and community leaders followed a similar pattern with issues on programme mistrust being most frequently reported and issues with harm least frequently reported. None of the health professionals reported concerns about vaccinations being potentially harmful. CONCLUSION: Mobile pastoralist communities face specific demand side barriers to vaccination. Understanding these barriers is essential to reduce vaccine hesitancy and increase vaccination uptake. Local health systems must plan for the periodic presence of pastoralist communities in their zones of responsibility and create more mutual trust. PMID- 30428877 TI - Impact of pharmacy services on initial clinical outcomes and medication adherence among veterans with uncontrolled diabetes. AB - BACKGROUND: Diabetes remains a growing public health threat but evidence supports the role that pharmacists can play in improving diabetes medication use and outcomes. To improve the quality of care, the Veterans Health Administration has widely adopted care models that integrate clinical pharmacists, but more data are needed to interpret the impact of these services. Our objective was to assess clinical pharmacy services' impact on outcomes and oral antidiabetic medication (OAD) use among veterans with uncontrolled diabetes in the first year of therapy. METHODS: This was a retrospective cohort analysis using the Veterans Affairs (VA) Corporate Data Warehouse to identify the first diagnosis of and initiation of OAD therapy for uncomplicated, uncontrolled diabetes (A1C > 7.0%) during 2002-2014. Receipt of clinical pharmacy services was identified using codes within VA electronic health records, and clinical values were obtained at or near the initial fill date and 365 days later. Use of OADs was assessed by proportion of days covered (PDC) for one year following the first filled prescription. Veterans having received clinical pharmacy services were matched 1:1 to those having not seen a clinical pharmacist in the first year of therapy, and generalized linear models assessed changes and differences in outcomes. RESULTS: The analysis included 5749 patients in each cohort. On average, patients saw a clinical pharmacist 2.5 times throughout the first year of OAD therapy. Adherence to OAD medications was higher in veterans having seen a pharmacist (84.3% vs. 82.4%, p < 0.0001) and more such patients achieved a PDC of at least 80% (72.2% vs. 68.2%, p < 0.0001). After one year of OAD therapy, mean change in hemoglobin A1C was greater among those receiving pharmacy services (- 1.5% vs. -1.4%, p < 0.0001). CONCLUSION: Pharmacist participation in diabetes patients' primary care positively affects the multifaceted needs of patients with this condition and comorbid chronic disease. PMID- 30428878 TI - Conventional and complementary cancer treatments: where do conventional and complementary providers seek information about these modalities? AB - BACKGROUND: Both conventional health care providers and complementary therapists treat cancer patients. To provide effective treatment, both types of providers should to be familiar with their own as well as alternative types of treatment. Our aim was to compare how conventional health care providers (oncology doctors, oncology nurses, family physicians) and complementary therapists (acupuncturists, reflexologists, massage therapists) seek information about conventional and complementary cancer treatments. METHOD: This analysis was conducted on the basis of feedback from 466 participants. We used self-administered questionnaires in a cross-sectional study. RESULTS: The majority of the medical doctors (96%) searched for evidence-based information regarding conventional cancer treatments. They gathered this information mostly from guidelines, which is considered best practice and is expected from Norwegian health personnel. Eighty-one percent of the nurses gather this information from evidence based resources such as UpToDate. Colleagues were asked for information by 58% of the medical doctors and 64% of the nurses. Moreover, 50% of the medical doctors and 57% of the nurses searched for evidence-based information about complementary cancer modalities. The acupuncturists gathered evidence-based information for both conventional (79%) and complementary (77%) modalities, followed by the reflexologists (54 and 54%, respectively) and massage therapists (54 and 52%, respectively). Nearly half of the acupuncturist (49%) asked a colleague for information. CONCLUSION: To provide safe cancer care, it is important that advice about complementary modalities is based on current and evidence-based evaluations. The majority of the medical doctors and nurses in this study sought information according to evidence-based medicine regarding conventional cancer treatments, and about half of them gathered evidence-based information about complementary cancer modalities. This was also true for the complementary therapists as they gathered information about complementary and conventional treatments from evidence-based evaluations. This demonstrates that since the term evidence-based medicine was first introduced in 1991, the approach has grown extensively and both conventional and complementary providers use this approach to seek information. PMID- 30428879 TI - Croton gratissimus leaf extracts inhibit cancer cell growth by inducing caspase 3/7 activation with additional anti-inflammatory and antioxidant activities. AB - BACKGROUND: Croton species (Euphorbiaceae) are distributed in different parts of the world, and are used in traditional medicine to treat various ailments including cancer, inflammation, parasitic infections and oxidative stress related diseases. The present study aimed to evaluate the antioxidant, anti-inflammatory and cytotoxic properties of different extracts from three Croton species. METHODS: Acetone, ethanol and water leaf extracts from C. gratissimus, C. pseudopulchellus, and C. sylvaticus were tested for their free radical scavenging activity. Anti-inflammatory activity was determined via the nitric oxide (NO) inhibitory assay on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages, and the 15-lipoxygenase inhibitory assay using the ferrous oxidation-xylenol orange assay. The cytotoxicity of the extracts was determined on four cancerous cell lines (A549, Caco-2, HeLa, MCF-7), and a non-cancerous African green monkey (Vero) kidney cells using the tetrazolium-based colorimetric (MTT) assay. The potential mechanism of action of the active extracts was explored by quantifying the caspase-3/- 7 activity with the Caspase-Glo(r) 3/7 assay kit (Promega). RESULTS: The acetone and ethanol leaf extracts of C. pseudopulchellus and C. sylvaticus were highly cytotoxic to the non-cancerous cells with LC50 varying between 7.86 and 48.19 MUg/mL. In contrast, the acetone and ethanol extracts of C. gratissimus were less cytotoxic to non-cancerous cells and more selective with LC50 varying between 152.30 and 462.88 MUg/mL, and selectivity index (SI) ranging between 1.56 and 11.64. Regarding the anti-inflammatory activity, the acetone leaf extract of C. pseudopulchellus had the highest NO inhibitory potency with an IC50 of 34.64 MUg/mL, while the ethanol leaf extract of the same plant was very active against 15-lipoxygenase with an IC50 of 0.57 MUg/mL. A linear correlation (r<0.5) was found between phytochemical contents, antioxidant, anti-inflammatory and cytotoxic activities of active extracts. These extracts induced differentially the activation of caspases - 3 and - 7 enzymes in all the four cancerous cells with the highest induction (1.83-fold change) obtained on HeLa cells with the acetone leaf extract of C. gratissimus. CONCLUSION: Based on their selective toxicity, good antioxidant and anti-inflammatory activities, the acetone and ethanol leaf extracts of C. gratissimus represent promising alternative sources of compounds against cancer and other oxidative stress related diseases. PMID- 30428880 TI - Impact evaluation of malaria control interventions on morbidity and all-cause child mortality in Mali, 2000-2012. AB - BACKGROUND: Major investments have been made since 2001, with intensification of malaria control interventions after 2006. Interventions included free distribution of insecticide-treated nets (ITN) to pregnant women and children under 5 years old, the introduction of artemisinin combination therapy (ACT) for malaria treatment, and indoor residual spraying of insecticides. Funders include the Government of Mali, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and the US President's Malaria Initiative. METHODS: Data from nationally representative household surveys conducted from 2000 to 2015 was used to performed the trend analysis for malaria intervention coverage, prevalence of morbidities among children under 5 years old [parasitemia and severe anaemia (< 8 g/dl)], and all-cause mortality of children under 5 (ACCM). Prevalence of contextual factors likely to contribute to ACCM were also assessed. The impact of these interventions was assessed on malaria morbidity and mortality using a plausibility argument. With the assumption that malaria contributes significantly to under-five mortality in settings with high malaria transmission, associations between malaria control interventions and all-cause under-five mortality (ACCM) were assessed taking into account other contextual factors related to child survival. RESULTS: Intervention coverage improved significantly from 2006 to 2012. Household ownership of ITN increased from 49% in 2006 to 84% in 2012. ITN use also increased over the same period, from 26% in 2006 to 69% in 2012 among children under 5 and from 28% in 2006 to 73% in 2012 among pregnant women. The coverage of intermittent preventive treatment in pregnancy (IPTp) using two or more doses of SP increased from 10% in 2006 to 29% in 2012. In 2010, 23% of febrile children under 5 received ACT, as opposed to 19% in 2012. The prevalence of Plasmodium falciparum infection increased from 2010 (38.6%) to 2012 (51.6%), followed by a decrease in 2015 (35.8%). The prevalence of severe anaemia decreased from 2010 (26.3%) to 2012 (20.6%) and continued to decline in 2015 (19.9%). An impressive decline in ACCM was observed, from 225 in 1997-2001 to 192 in 2002-2006 and 95 in 2008-2012. Changes in contextual factors such as climate, socio-economic, nutrition, and coverage of maternal and child health interventions over the evaluation period did not favour reductions in ACCM, and are therefore unlikely to explain the observed results. CONCLUSIONS: Taken as a whole, the evidence supports the conclusion that malaria control interventions substantially contributed to the observed decline in ACCM in Mali from 2000 to 2012, even in the context of continued high prevalence of parasitaemia explained by contextual factors such as climate change and political instability. PMID- 30428881 TI - Creating spaces for dialogue: a cluster-randomized evaluation of CARE's Community Score Card on health governance outcomes. AB - BACKGROUND: Social accountability interventions such as CARE's Community Score Card(c) show promise for improving sexual, reproductive, and maternal health outcomes. A key component of the intervention is creation of spaces where community members, healthcare workers, and district officials can safely interact and collaborate to improve health-related outcomes. Here, we evaluate the intervention's effect on governance constructs such as power sharing and equity that are central to our theory of change. METHODS: We randomly assigned ten matched pairs of communities to intervention and control arms, administering endline surveys to women in each arm who had given birth in the last 12 months. Forty-six governance items were reduced by factor analysis into eight underlying scales. We evaluated the intervention's impact on these constructs using local average treatment effect estimates. RESULTS: Among intervention-area women who reported a community meeting, we further evaluated the influence of the governance constructs on health-related outcomes: home visit from a community health worker, modern family planning, and satisfaction with health services. A significantly greater proportion of intervention-area women compared to control reported the existence of community groups that provide and facilitate negotiated space between community members and healthcare workers (p = .003). Several governance constructs were positively associated with the health-related outcomes. Further, active participation in the intervention was also positively associated with several governance constructs. CONCLUSIONS: CARE's Community Score Card(c) facilitated the creation and claiming of effective and inclusive negotiated spaces in which community members and healthcare workers could vocalize service delivery issues and prioritize actions for improvement. We argue that reliable measurement of governance concepts such as power sharing, equity and quality of negotiated space, collective efficacy, and mutual responsibility will enhance our ability to evaluate social accountability interventions and understand the processes by which they affect change. PMID- 30428882 TI - "There is nothing so practical as a good theory": a pragmatic guide for selecting theoretical approaches for implementation projects. AB - BACKGROUND: A multitude of theories, models and frameworks relating to implementing evidence-based practice in health care exist, which can be overwhelming for clinicians and clinical researchers new to the field of implementation science. Clinicians often bear responsibility for implementation, but may be unfamiliar with theoretical approaches designed to inform or understand implementation. MAIN TEXT: In this article, a multidisciplinary group of clinicians and health service researchers present a pragmatic guide to help clinicians and clinical researchers understand what implementation theories, models and frameworks are; how a theoretical approach to implementation might be used; and some prompts to consider when selecting a theoretical approach for an implementation project. Ten commonly used and highly cited theoretical approaches are presented, none of which have been utilised to their full potential in the literature to date. Specifically, theoretical approaches tend to be applied retrospectively to evaluate or interpret findings from a completed implementation project, rather than being used to plan and design theory-informed implementation strategies which would intuitively have a greater likelihood of success. We emphasise that there is no right or wrong way of selecting a theoretical approach, but encourage clinicians to carefully consider the project's purpose, scope and available data and resources to allow them to select an approach that is most likely to "value-add" to the implementation project. CONCLUSION: By assisting clinicians and clinical researchers to become confident in selecting and applying theoretical approaches to implementation, we anticipate an increase in theory-informed implementation projects. This then will contribute to more nuanced advice on how to address evidence-practice gaps and ultimately to contribute to better health outcomes. PMID- 30428883 TI - Offspring outcomes after prenatal interventions for common mental disorders: a meta-analysis. AB - BACKGROUND: It is presumed that pharmacological and non-pharmacological treatment of prenatal common mental disorders can mitigate associated adverse effects in offspring, yet strong evidence for the prophylactic benefits of treatment is lacking. We therefore examined the effect of prenatal treatments for common mental disorders on offspring outcomes. METHODS: For this meta-analysis, articles published up to August 31, 2017, were obtained from PubMed, PsycInfo, Embase, and Cochrane databases. Included studies needed to be randomized controlled trials (RCTs) on the effect of treatment of prenatal common mental disorders comparing an intervention to a control condition, including offspring outcome(s). Random effects models were used to calculate Hedges' g in the program Comprehensive Meta Analysis(c) (version 3.0). RESULTS: Sixteen randomized controlled trials among 2778 pregnant women compared offspring outcomes between prenatal interventions and control groups. There were zero pharmacological, 13 psychological, and three other interventions (homeopathy, relaxation interventions, and short psycho education). Birth weight (mean difference 42.88 g, g = 0.08, 95% CI -0.06 to 0.22, p = 0.27, n = 11), Apgar scores (g = 0.13, 95% CI -0.28 to 0.54, p = 0.53, n = 4), and gestational age (g = 0.03, 95% CI -0.06 to 0.54, p = 0.49, n = 10) were not significantly affected. Other offspring outcomes could not be meta analyzed due to the inconsistent reporting of offspring outcomes and an insufficient number of studies. CONCLUSIONS: Non-pharmacological interventions had no significant effect on birth outcomes, although this outcome should be considered with caution due to the risk of biases. No randomized controlled trial examined the effects of prenatal pharmacological treatments as compared to treatment as usual for common mental disorders on offspring outcomes. Present clinical guidelines may require more research evidence on offspring outcomes, including child development, in order to warrant the current recommendation to routinely screen and subsequently treat prenatal common mental disorders. TRIAL REGISTRATION: PROSPERO CRD42016047190. PMID- 30428884 TI - Overexpression of the recently identified oncogene REDD1 correlates with tumor progression and is an independent unfavorable prognostic factor for ovarian carcinoma. AB - BACKGROUND: Regulated in development and DNA damage response (REDD1), a gene responding to hypoxia or multiple DNA damage events, was recently implicated in cancer development and progression. Previously, in vivo and in vitro experiments indicated that REDD1 functions as an oncogene in ovarian cancer cells. However, the role of REDD1 in cancer cell migration and invasion and in clinical significance of prognostic values is not examined in detail. METHODS: We detected the REDD1 protein expression by immunohistochemistry in 18 normal ovarian surface epithelium or fallopian tube epithelium specimens, 24 ovarian borderline tumors, and 229 ovarian cancers. Fisher's exact test, logistic regression analysis, the Kaplan-Meier method, and the log-rank test were used to evaluate the association of REDD1 with clinical factors, overall survival and disease-free survival. The prognostic predictive value of REDD1 for ovarian cancer patients was evaluated using multivariate Cox proportional hazard regression models. REDD1 expression in HEY, HEY A8, SKOV3, SKOV3 ip1, OVCA429, OVCA433 and A2780 human ovarian epithelial cancer cell lines was detected by western blotting. The role of REDD1 in cell invasion and migration was assessed by transwell migration and invasion assays using SKOV3, A2780, HEY, HEYA8, and SKOV3-REDD1 with parental A2780-REDD1 HEY-REDD1i and HEY A8-REDD1i. RESULTS: High expression of REDD1 was observed in 35.4% of primary ovarian carcinoma samples. Overexpression of cytoplasmic REDD1 in ovarian cancer was significantly associated with serous carcinoma (P < 0.001), late-stage disease (P < 0.001), ascites (P < 0.001), and partial or non-response to chemotherapy (P < 0.001). High cytoplasmic expression of REDD1 was correlated with poorer overall survival (P < 0.001) and disease-free survival (P < 0.001). The multivariate Cox proportional hazards regression analysis indicated that patients with high cytoplasmic REDD1 expression had a high risk of death (P < 0.001) and high risk of an event (i.e., recurrence, progression, or death) (P < 0.001). REDD1 was first reported as an independent prognostic factor in ovarian cancer patients. In addition, REDD1 overexpression enhanced ovarian cancer cell migration and invasion. CONCLUSION: REDD1 is an independent unfavorable prognostic factor in ovarian carcinoma and may promote ovarian cancer metastasis. PMID- 30428886 TI - Motivators and barriers to vaccination of health professionals against seasonal influenza in primary healthcare. AB - BACKGROUND: Over the last decade, the vaccination rates amongst the general population in Slovenia were declining. According to the World Health Organisation, the vaccination rates amongst healthcare workers are also low throughout Europe. The aim of this study was to evaluate vaccination rates for seasonal flu amongst healthcare workers on the primary care level in the Koroska region and to find motivators and barriers for vaccination. METHODS: In a cross sectional study, an anonymous questionnaire was distributed to all health centres, nursing homes and private contractors, who agreed to participate. Out of 334 distributed questionnaires, 250 (74.8%) were analysed. Bivariate and multivariable statistical analyses were conducted. RESULTS: Only 12% of included health professionals were vaccinated in the 2014/15 season. The main motivators for vaccination coverage were: awareness of high risk of infection at the workplace, self-protection and protection of family members and co-workers. The main barriers for vaccination were doubt in the effectiveness of the vaccine, fear of side effects and the belief that health professionals are not at high risk of influenza infection. In the multivariable model, a positive association was found between the vaccination, older age and belief in the effectiveness against influenza, while a negative association was found between the nurses' profession and vaccination. CONCLUSION: The trend of declining rates for seasonal influenza vaccination is continuing. Protection of the patients was not among the most important reasons for vaccination. This especially endangers clients of nursing homes. The recognized motivators, barriers and other factors that were important for vaccination coverage/hesitancy could be used for designing strategies and educational programmes for health professionals to improve the vaccination coverage rates. The strategy should include the specifics of health profession groups. PMID- 30428885 TI - The usefulness of small-area-based socioeconomic characteristics in assessing the treatment outcomes of type 2 diabetes patients: a register-based mixed-effect study. AB - BACKGROUND: Assessment of the differences in the outcomes of care by socioeconomic status (SES) is beneficial for both the efficient targeting of health care services and to decrease health inequalities. This study compares the effects of three patient-based SES predictors (earned income, educational attainment, employment status) with three small-area-based SES predictors (median income, educational attainment, proportion of the unemployed) on the treatment outcomes of type 2 diabetes patients. METHODS: Mixed-effect modeling was applied to analyse how SES factors affect the treatment outcomes of type 2 diabetes patients. The treatment outcomes were assessed by the patients' latest available glycated hemoglobin A1C (HbA1c) value. We used electronic health records of type 2 diabetes patients from the regional electronic patient database, the patients' individual register-based SES information from Statistics Finland, and the SES information about the population of the postal code area of the patients from Statistics Finland. RESULTS: The effects of attained education on the treatment outcomes, both at the patient-level and the small-area-level are quite similar. Age and male gender were associated with higher HbA1c values and lower education indicated higher HbA1c values. Unemployment was not associated with HbA1c values at either the patient-level or the area-level. Income gave divergent results: high values of HbA1c were associated with low patient incomes but the median income of the postal code area did not predict the treatment outcomes of patients. CONCLUSIONS: Our comparative study of three SES factors shows that the effects of attained education on the treatment outcomes are rather similar, regardless of whether patient-based or small-area-based predictors are used. Small-area-based SES variables can be a good way to overcome the absence of individual SES information, but further research is needed to find the valid small-area factors by disease. This possibility of using more small-area-based data would be valuable in health service research and first-hand planning of health care services. PMID- 30428888 TI - Adenosine and adenosine-5'-monophosphate ingestion ameliorates abnormal glucose metabolism in mice fed a high-fat diet. AB - BACKGROUND: We have previously reported that ingestion of adenosine (ADN) and adenosine-5'-monophosphate (AMP) improves abnormal glucose metabolism in the stroke-prone spontaneously hypertensive rat model of non-obesity-associated insulin resistance. In this study, we investigated the effect of ADN and AMP ingestion on glucose metabolism in mice with high-fat diet-induced obesity. METHODS: Seven-week-old C57BL/6 J mice were administered distilled water (as a control), 10 mg/L ADN, or 13 mg/L AMP via their drinking water for 14 or 25 weeks, during which they were fed a high-fat diet. Oral glucose tolerance test (OGTT) was conducted on 21-week-old mice fasted for 16 h. Insulin tolerance test (ITT) was performed on 22-week-old mice fasted for 3 h. Blood and muscle were collected for further analysis of serum parameters, gene and protein expression levels, respectively. RESULTS: Glucose metabolism in the ADN and AMP groups was significantly improved compared with the control. OGTT and ITT showed that ADN and AMP groups lower than control group. Furthermore, phosphorylation of AMP activated protein kinase (AMPK) and mRNA levels of genes involved in lipid oxidation were enhanced in the skeletal muscle of ADN- and AMP-treated mice. CONCLUSION: These results indicate that ingestion of ADN or AMP induces activation of AMPK in skeletal muscle and mitigates insulin resistance in mice with high-fat diet-induced diabetes. PMID- 30428887 TI - Patient-specific cranio-spinal compliance distribution using lumped-parameter model: its relation with ICP over a wide age range. AB - BACKGROUND: The distribution of cranio-spinal compliance (CSC) in the brain and spinal cord is a fundamental question, as it would determine the overall role of the compartments in modulating ICP in healthy and diseased states. Invasive methods for measurement of CSC using infusion-based techniques provide overall CSC estimate, but not the individual sub-compartmental contribution. Additionally, the outcome of the infusion-based method depends on the infusion site and dynamics. This article presents a method to determine compliance distribution between the cranium and spinal canal non-invasively using data obtained from patients. We hypothesize that this CSC distribution is indicative of the ICP. METHODS: We propose a lumped-parameter model representing the hydro and hemodynamics of the cranio-spinal system. The input and output to the model are phase-contrast MRI derived volumetric transcranial blood flow measured in vivo, and CSF flow at the spinal cervical level, respectively. The novelty of the method lies in the model mathematics that predicts CSC distribution (that obeys the physical laws) from the system dc gain of the discrete-domain transfer function. 104 healthy individuals (48 males, 56 females, age 25.4 +/- 14.9 years, range 3-60 years) without any history of neurological diseases, were used in the study. Non-invasive MR assisted estimate of ICP was calculated and compared with the cranial compliance to prove our hypothesis. RESULTS: A significant negative correlation was found between model-predicted cranial contribution to CSC and MR ICP. The spinal canal provided majority of the compliance in all the age groups up to 40 years. However, no single sub-compartment provided majority of the compliance in 41-60 years age group. The cranial contribution to CSC and MR-ICP were significantly correlated with age, with gender not affecting the compliance distribution. Spinal contribution to CSC significantly positively correlated with CSF stroke volume. CONCLUSIONS: This paper describes MRI-based non-invasive way to determine the cranio-spinal compliance distribution in the brain and spinal canal sub-compartments. The proposed mathematics makes the model always stable and within the physiological range. The model-derived cranial compliance was strongly negatively correlated to non-invasive MR-ICP data from 104 patients, indicating that compliance distribution plays a major role in modulating ICP. PMID- 30428889 TI - Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature. AB - BACKGROUND: Henoch-Schonlein purpura (HSP) is a small vessel vasculitis that is characterized by non-thrombocytopenic purpura, abdominal pain, arthritis, and glomerulonephritis. Typically, HSP is self-limited requiring only supportive care, but more severe cases may require corticosteroid (CS) treatment. Rarely, a subset of these patients has persistent rash, arthritis, abdominal involvement, or renal disease despite treatment with CS, or has disease recurrence on CS tapering. Refractory HSP has been effectively treated with a variety of CS sparing therapies. For life-threatening refractory HSP, the B cell depleting agent, rituximab (RTX), has been reported as beneficial for children with substantial renal or central nervous system involvement. However, RTX use for children with less severe HSP, but chronic CS dependent disease refractory to CS sparing immunomodulatory agents, has been less well explored. Herein, we describe 8 children treated with RTX for chronic refractory HSP and report a reduction in recurrent hospitalizations and eventual CS discontinuation. METHODS: This is a retrospective analysis of eight children who were treated with RTX for chronic CS dependent HSP during the years 2006-2014 at a single institution. A chart review of the electronic medical record was performed to determine the presenting symptoms, the type and duration of treatment received, and the number of hospitalizations prior to and after RTX. The number of hospitalizations and oral corticosteroid burden were analyzed using the Wilcoxon signed rank test. RESULTS: Prior to receiving RTX, seven patients had at least one hospitalization for HSP (median 1.5, range 0-3). Following RTX, only two patients were hospitalized, each a single time for recurrent abdominal pain. The median oral CS burden was 0.345 mg/kg/day before RTX and 0 mg/kg/day at 6 months (p = 0.078), 1 year (p = 0.0625), and 2 years (p = 0.03) following RTX infusion. Seven out of eight children met remission criteria, defined as no active rash, arthritis, nephritis (hematuria and proteinuria), or gastrointestinal distress following RTX. No serious adverse events were noted. CONCLUSION: Overall, RTX effectively reduced the number of hospital admissions and oral CS burden. RTX also helped most all children achieve clinical remission. RTX appears to be an effective and safe alternative for chronic CS dependent and immunomodulatory refractory childhood HSP. PMID- 30428890 TI - Particulate matter exposure and health impacts of urban cyclists: a randomized crossover study. AB - BACKGROUND: Cycling and other forms of active transportation provide health benefits via increased physical activity. However, direct evidence of the extent to which these benefits may be offset by exposure and intake of traffic-related air pollution is limited. The purpose of this study is to measure changes in endothelial function, measures of oxidative stress and inflammation, and lung function in healthy participants before and after cycling along a high- and low- traffic route. METHODS: Participants (n = 38) bicycled for 1 h along a Downtown and a Residential designated bicycle route in a randomized crossover trial. Heart rate, power output, particulate matter air pollution (PM10, PM2.5, and PM1) and particle number concentration (PNC) were measured. Lung function, endothelial function (reactive hyperemia index, RHI), C-reactive protein, interleukin-6, and 8-hydroxy-2'-deoxyguanosine were assessed within one hour pre- and post-trial. RESULTS: Geometric mean PNC exposures and intakes were higher along the Downtown (exposure = 16,226 particles/cm3; intake = 4.54 * 1010 particles) compared to the Residential route (exposure = 9367 particles/cm3; intake = 3.13 * 1010 particles). RHI decreased following cycling along the Downtown route and increased on the Residential route; in mixed linear regression models, the (post pre) change in RHI was 21% lower following cycling on the Downtown versus the Residential route (-0.43, 95% CI: -0.79, -0.079) but RHI decreases were not associated with measured exposure or intake of air pollutants. The differences in RHI by route were larger amongst females and older participants. No consistent associations were observed for any of the other outcome measures. CONCLUSIONS: Although PNC exposures and intakes were higher along the Downtown route, the lack of association between air pollutant exposure or intake with RHI and other measures suggests other exposures related to cycling on the Downtown route may have been influential in the observed differences between routes in RHI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01708356 . Registered 16 October 2012. PMID- 30428891 TI - Motivational Interviewing as a tool to enhance access to mental health treatment in adolescents with chronic medical conditions and need for psychological support (COACH-MI): study protocol for a clusterrandomised controlled trial. AB - BACKGROUND: This cluster-randomised monocentric controlled trial focuses on improving the uptake symptoms of mental health care in adolescents with chronic medical conditions who have been identified by screening to have depression or anxiety. The study aims to determine the efficacy of motivational interviewing (MI) delivered by trained physicians to increase 12- to 20-year-old adolescents' utilisation of psychological health care for symptoms of anxiety or depression. METHODS/DESIGN: In this single-centre approach, n = 1,000 adolescents will be screened (using PHQ-9 and GAD-7), and adolescents with results indicative of anxiety or depressive symptoms (n = 162) will be advised to seek psychological health care in clusters from treating physicians in specialised outpatient departments. Participants who screen positive will receive either two sessions of MI or treatment as usual (TAU; regarded as the typical daily clinical practice), which is focused on recommending them to seek psychological health care for further evaluation. MI efficacy will be compared to the current TAU as the control condition. The primary outcome is the utilisation rate of psychological health care after counselling by an MI-trained physician vs. an untrained physician. Additionally, reasons for not claiming psychological support and changes in disease-related parameters will be evaluated in a 6-month follow-up session. DISCUSSION: This trial will evaluate the feasibility of MI as a way to improve the utilisation of mental health-care services by adolescents who need further support other than that provided by standard care for chronic diseases. Physicians offering MI to adolescents may serve as a model for optimising health care management in daily clinical practice, which may improve adolescents' long term well-being by improving adherence to medical treatment and preventing negative lifelong consequences into adulthood. TRIAL REGISTRATION: German Trials Register (DRKS), DRKS00014043 . Registered on 26 April 2018. Dusseldorf University study ID: 2017114504. PMID- 30428892 TI - The relationship between catastrophic health expenditure and health-related quality of life. AB - OBJECTIVES: The objective of our study was to investigate the relationship between catastrophic health expenditure (CHE) and health-related quality of life (HRQoL) in general population. METHODS: We used Korean Health Panel Survey data from 2011 to 2013, which included data from 8850 baseline participants of 19 years of age or older. We defined CHE as total annual out-of-pocket health payment that was 40% greater than the household's capacity to pay. HRQoL was measured using the EuroQol-visual analogue scale (EQ-VAS). We used generalized estimating equations to perform a longitudinal regression analysis. RESULTS: A total of 4.5% of the participants (n = 398) experienced CHE. Those with CHE tended to have a lower EQ-VAS index score compared with those without CHE (beta: 1.34, p = 0.013). A subgroup analysis revealed that individuals experiencing CHE had significant decreases as the number of chronic diseases increased (three or more, beta: - 1.85, p = 0.014). CONCLUSIONS: Catastrophic health expenditure influences HRQoL, which was more pronounced in patient with chronic disease. The efforts should focus on people who suffer from excessive health expenditures and chronic diseases. PMID- 30428893 TI - Analysis of influenza B virus lineages and the HA1 domain of its hemagglutinin gene in Guangzhou, southern China, during 2016. AB - BACKGROUND: Few studies have analyzed influenza B virus lineages based on hemagglutinin A (HA) gene sequences in southern China. The present study analyzed the HA gene and the lineages of influenza B virus isolates from Guangzhou during 2016, and compared our results with the WHO-recommended vaccine strain. METHODS: Ninety patients with influenza B were recruited from the First Hospital of Guangzhou Medical University. Throat swab specimens of 72 patients had high viral loads. Among these 72 isolates, the HA1 domain of the HA gene in 43 randomly selected isolates was sequenced using reverse transcription-polymerase chain reaction (RT-PCR), and analyzed using MEGA 5.05. RESULTS: Eight of the 90 patients (8.9%) also had influenza A virus infections. Analysis of the 43 influenza B virus isolates indicated that 34 (79.1%) were from the Victoria lineage and 9 (20.9%) were from the Yamagata lineage. A comparison isolates in our Victoria lineage with the B/Brisbane/60/2008 strain indicated 12 mutation sites in the HA1 domain, 4 of which (I132V, N144D, C196S, and E198D) were in antigenic epitopes. A comparison of isolates in our Yamagata lineage with the B/Phuket/3073/2013 stain indicated 5 mutation sites in the HA1 domain, none of which was in an antigenic epitope. None of the isolates had a mutation in regions of the neuraminidase gene (NA) that are known to confer resistance to NA inhibitors. CONCLUSION: In Guangzhou during 2016, most influenza B virus isolates were from the Victoria lineage, in contrast to the vaccine strain recommended by the WHO for this period. PMID- 30428894 TI - proBDNF is modified by advanced glycation end products in Alzheimer's disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processing. AB - Alzheimer disease (AD) is a complex pathology related to multiple causes including oxidative stress. Brain-derived neurotrophic factor (BDNF) is a neutrotrophic factor essential for the survival and differentiation of neurons and is considered a key target in the pathophysiology of various neurodegenerative diseases, as for example AD. Contrarily to BDNF, the precursor form of BDNF (proBDNF) induces apoptosis through the specific interaction with p75 and its co-receptor, Sortilin.We used hippocampal tissue and cerebrospinal fluid from AD patients and controls. to study the localization and the levels of proBDNF, p75 and Sortilin as well as the post-traduccional modifications of proBDNF induced by Radical Oxygen Species, by immunofluorescence and Western blot. Differentiation and survival were assessed on differentiated mouse hippocampal neurons derived from postnatal neural stem cells from WT animals or from the transgenic AD animal model APP/PS1?E9, based on mutations of familiar AD. In AD patients we observe a significative increase of proBDNF and Sortilin expression and a significative increase of the ratio proBDNF/BDNF in their cerebrospinal fluid compared to controls. In addition, the proBDNF of AD patients is modified by ROS-derived advanced glycation end products, which prevent the processing of the proBDNF to the mature BDNF, leading to an increase of pathogenicity and a decrease of trophic effects. The cerebrospinal fluid from AD patients, but not from controls, induces apoptosis in differentiated hippocampal neurons mainly by the action of AGE-modified proBDNF present in the cerebrospinal fluid of the patients. This effect is triggered by the activation and processing of p75 that stimulate the internalization of the intracellular domain (ICD) within the nucleus causing apoptosis. Induction of apoptosis and p75 ICD internalization by AD patients-derived proBDNF is further enhanced in neuron cultures from the AD model expressing the APP/PS1?E9 transgene.Our results indicate the importance of proBDNF neurotoxic signaling in AD pathology essentially by three mechanisms: i) by an increase of proBDNF stability due to ROS-induced post-traductional modifications; ii) by the increase of expression of the p75 co-receptor, Sortilin and iii) by the increase of the basal levels of p75 processing found in AD. PMID- 30428895 TI - Application of the rapid ethical assessment approach to enhance the ethical conduct of longitudinal population based female cancer research in an urban setting in Ethiopia. AB - BACKGROUND: Rapid Ethical Assessment (REA) is an approach used to design context tailored consent process for voluntary participation of participants in research including human subjects. There is, however, limited evidence on the design of ethical assessment in studies targeting cancer patients in Ethiopia. REA was conducted to explore factors that influence the informed consent process among female cancer patients recruited for longitudinal research from Addis Ababa Population-based Cancer Registry. METHODS: Qualitative study employing rapid ethnographic approach was conducted from May-July, 2017, at the Tikur Anbessa Specialized Referral Hospital. In-depth and key informants' interviews were conducted among purposively selected 16 participants. Regular de-briefings among the study team helped to identify emerging themes and ensure saturation. Interviews and debriefings were tape recorded in Amharic, and transcribed and translated to English. Coding of the transcripts was facilitated by use of NVivo software. Thematic analysis was employed to respond to the initial questions and interpret findings. RESULTS: Perceived barriers to voluntary study participation included lack of reporting back study results of previous studies, the decision making status of women, hopelessness or fatigue in the patients, shyness of the women, data collectors approach to the patient, and patient's time constraints. Most of the patients preferred oral over written consent and face-to-face interview over telephone interview. Provision of detail information about the study, using short and understandable tool, competent, compassionate and respectful enumerators of the same gender were suggested to assure participation. Due to the perceived severity, the use of the term "cancer" was associated with fear and anxiety. Alternatively, uses of phrases like "breast or cervical illness/disease" were suggested during patient interviews. CONCLUSIONS: Voluntary participation is not straight forward but affected by different factors. Using competent, compassionate and respectful enumerators, short and precise questioning tools to limit the time of the interview could improve voluntary participation. Moreover, careful consideration of the patients and families concept of the disease such as wording and information has to be taken into account. This assessment helped in improving the consent process of the ongoing project on breast and cervical cancer patients. PMID- 30428897 TI - Efficacy and safety of low-dose Sirolimus in Lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis is a rare disease caused by unregulated activation of mammalian target of rapamycin (mTOR) signalling pathway. Sirolimus showed efficacy in a phase 3 trial of patients with lymphangioleiomyomatosis, but the optimal dose remains unclear. METHODS: We investigated the efficacy and safety of low-dose compared with conventional-dose sirolimus. Clinical data of 39 patients with lymphangioleiomyomatosis (mean age, 34.8 years; median treatment period, 29.6 months) who received sirolimus were retrospectively reviewed. Low dose sirolimus was defined as any dose that maintained mean blood trough levels lower than those maintained with conventional doses (5-15 ng/mL). RESULTS: Fifty one percent of patients received low-dose therapy. The rate of decline in lung function decreased after treatment in the whole group (forced expiratory volume in 1 s [FEV1], - 0.12 +/- 0.47 [before] vs. 0.24 +/- 0.48% predicted/month [after], p = 0.027; diffusing capacity for carbon monoxide [DLco], - 0.33 +/- 0.61 vs. 0.03 +/- 0.26% predicted/month, p = 0.006) compared with before treatment. In the low-dose group, the rate of decline in FEV1 (- 0.08 +/- 0.38 [before] vs. 0.19 +/- 0.51% predicted/month [after], p = 0.264) and DLco (-0.13 +/- 0.62 vs. 0.02 +/- 0.28% predicted/month, p = 0.679) showed a numeric trend towards improvement after treatment; however, the conventional-dose group showed significant improvement in FEV1 (- 0.26 +/- 0.54 [before] vs. 0.22 +/- 0.38 [after] % predicted/month, p = 0.024) and DLco (- 0.55 +/- 0.58 vs. 0.04 +/- 0.25% predicted/month, p = 0.002) after treatment. Adverse events (AEs) occurred in 89.7% of patients and the most common AEs was hypercholesterolaemia (43.6%), followed by stomatitis (35.9%). The occurrences of AE were similar between the low- and conventional-dose groups (85.0% vs. 94.7%, p = 0.605). CONCLUSIONS: Low dose sirolimus may stabilise lung function decline in lymphangioleiomyomatosis patients, but its efficacy appears to be inferior to that of conventional-dose sirolimus. PMID- 30428898 TI - The Swedish Medical Products Agency's rules of procedure. PMID- 30428896 TI - Kinect-based assessment of proximal arm non-use after a stroke. AB - BACKGROUND: After a stroke, during seated reaching with their paretic upper limb, many patients spontaneously replace the use of their arm by trunk compensation movements, even though they are able to use their arm when forced to do so. We previously quantified this proximal arm non-use (PANU) with a motion capture system (Zebris, CMS20s). The aim of this study was to validate a low-cost Microsoft Kinect-based system against the CMS20s reference system to diagnose PANU. METHODS: In 19 hemiparetic stroke individuals, the PANU score, reach length, trunk length, and proximal arm use (PAU) were measured during seated reaching simultaneously by the Kinect (v2) and the CMS20s over two testing sessions separated by two hours. RESULTS: Intraclass correlation coefficients (ICC) and linear regression analysis showed that the PANU score (ICC = 0.96, r2 = 0.92), reach length (ICC = 0.81, r2 = 0.68), trunk length (ICC = 0.97, r2 = 0.94) and PAU (ICC = 0.97, r2 = 0.94) measured using the Kinect were strongly related to those measured using the CMS20s. The PANU scores showed good test-retest reliability for both the Kinect (ICC = 0.76) and CMS20s (ICC = 0.72). Bland and Altman plots showed slightly reduced PANU scores in the re-test session for both systems (Kinect: - 4.25 +/- 6.76; CMS20s: - 4.71 +/- 7.88), which suggests a practice effect. CONCLUSION: We showed that the Kinect could accurately and reliably assess PANU, reach length, trunk length and PAU during seated reaching in post stroke individuals. We conclude that the Kinect can offer a low-cost and widely available solution to clinically assess PANU for individualised rehabilitation and to monitor the progress of paretic arm recovery. TRIAL REGISTRATION: The study was approved by The Ethics Committee of Montpellier, France (N degrees ID-RCB: 2014-A00395-42) and registered in Clinical Trial (N degrees NCT02326688, Registered on 15 December 2014, https://clinicaltrials.gov/ct2/show/results/NCT02326688 ). PMID- 30428900 TI - Regulatory scientists' work has important ramifications for public health and should be open to public scrutiny. AB - The Swedish Medical Products Agency (MPA) objects to the fact that we occasionally refer to one of its senior ex-employees by name. However, names of individual MPA assessors, Food and Drug Administration (FDA) reviewers, and European Medicines Agency rapporteurs and co-rapporteurs are cited in regulatory documents and are a matter of public record. In our paper (Health Res Policy Syst 15:93, 2017), we in no way suggest that regulatory decisions were left to individual reviewers or assessors, although we do emphasise that individual MPA and FDA employees' scientific assessments and benefit-risk evaluations are critical to the decision-making process. In this response to the MPA, we raise a further issue - one in which the question of personal identification of individuals is relevant - and this pertains to the accountability of influential scientists and experts who contribute to public policy decisions with important ramifications for public health. In our view, it is important that interested observers are able to identify those influential individuals, and entirely appropriate that their work should be open to public scrutiny. PMID- 30428899 TI - Identification of hub genes with diagnostic values in pancreatic cancer by bioinformatics analyses and supervised learning methods. AB - BACKGROUND: Pancreatic cancer is one of the most lethal tumors with poor prognosis, and lacks of effective biomarkers in diagnosis and treatment. The aim of this investigation was to identify hub genes in pancreatic cancer, which would serve as potential biomarkers for cancer diagnosis and therapy in the future. METHODS: Combination of two expression profiles of GSE16515 and GSE22780 from Gene Expression Omnibus (GEO) database was served as training set. Differentially expressed genes (DEGs) with top 25% variance followed by protein-protein interaction (PPI) network were performed to find candidate genes. Then, hub genes were further screened by survival and cox analyses in The Cancer Genome Atlas (TCGA) database. Finally, hub genes were validated in GSE15471 dataset from GEO by supervised learning methods k-nearest neighbor (kNN) and random forest algorithms. RESULTS: After quality control and batch effect elimination of training set, 181 DEGs bearing top 25% variance were identified as candidate genes. Then, two hub genes, MMP7 and ITGA2, correlating with diagnosis and prognosis of pancreatic cancer were screened as hub genes according to above mentioned bioinformatics methods. Finally, hub genes were demonstrated to successfully differ tumor samples from normal tissues with predictive accuracies reached to 93.59 and 81.31% by using kNN and random forest algorithms, respectively. CONCLUSIONS: All the hub genes were associated with the regulation of tumor microenvironment, which implicated in tumor proliferation, progression, migration, and metastasis. Our results provide a novel prospect for diagnosis and treatment of pancreatic cancer, which may have a further application in clinical. PMID- 30428901 TI - Selective decontamination of the digestive tract in critical care: a teenage angst or coming of age issue? AB - Selective decontamination of the digestive tract (SDD) has been with us since the early days of our specialty, and in some ways it marks our progression and maturation. How we have dealt with SDD to date ranges from "thorn in our side" to "elephant in the room". With high quality multi-national studies underway, how we deal with these results will mark our final maturation to adulthood as a specialty. PMID- 30428902 TI - Assessing the value of eHealth for bariatric surgery (BePatient trial): study protocol for a randomized controlled trial. AB - BACKGROUND: The expansion of digital devices and widespread access to the Internet has opened up opportunities to provide patients with more personal information. It can be hypothesized that eHealth in addition to standard care could enhance clinical outcomes such as increased weight loss, co-morbidity reduction, and commitment to the program. The beneficial value of incorporating eHealth applications as standard postoperative care is yet to be established. In this trial, the value of different levels of eHealth are assessed. METHODS/DESIGN: Two hundred adult patients with a body mass index (BMI) >= 40 kg/m2, or >= 35 kg/m2 with obesity-related co-morbidity, undergoing sleeve gastrectomy or gastric bypass will be enrolled in this randomized controlled trial. Patients will be randomly assigned to one of the groups: receiving standard care (control group, n = 100); have access to an online eHealth platform in addition to the previous group (online group, n = 50); or receive wireless monitoring devices in addition to previous groups (device group, n = 50). The total follow-up period is two years postoperatively. Primary outcome is weight loss in terms of BMI. Secondary outcomes include: quality of life; return-to-work time; co-morbidity reduction; additional contacts; and ease of use of devices. DISCUSSION: In this trial, the value of different levels of eHealth will be assessed. This addresses an important aspect of a changing healthcare environment. TRIAL REGISTRATION: Trialregister.nl, NTR6827. Retrospectively registered on 19 November 2017. http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6827 . PMID- 30428905 TI - Effective period of conservative treatment in patients with acute calcific periarthritis of the hand. AB - BACKGROUND: Acute calcific periarthritis of the hand is a relatively uncommon painful condition involving juxta-articular deposits of amorphous calcium hydroxyapatite. Although conservative treatments have been generally considered effective, there is little evidence regarding how long they could remain effective. METHODS: We retrospectively reviewed ten patients who were diagnosed with acute calcific periarthritis of the hand from January 2015 to June 2018. We recommended the use of warm baths, nonsteroidal anti-inflammatory drugs (NSAIDs), and limited activity as initial treatments. If the pain persisted despite at least 3 months of conservative treatment, we explained surgical treatment options. If the pain improved, we recommended gradual range-of-motion exercises with the continuation of daily NSAIDs use. The visual analogue scale (VAS) score for pain at each subsequent visit (3, 6, and 9 months) was compared with that of the previous visit to investigate whether the pain had decreased during each time interval. Simple radiographs taken at each visit were compared with those taken at the previous visit to determine whether any significant changes in the amount of calcification had occurred during each time interval. RESULTS: All 10 patients with 17 affected joints continued conservative treatments for an average of 11.1 months. The average VAS score for pain at the initial visit was 7, while that at 3, 6, and 9 months was 4.3, 3.3, and 2.9, respectively. There was a significant reduction in the VAS score at 3 and 6 months, but not at 9 months (P values = 0.004, 0.008, and 0.598, respectively). The simple radiographs also showed a significant reduction in the amount of calcification at 3 and 6 months, but not at 9 months (P values = 0.020, 0.034, and 0.083, respectively). CONCLUSIONS: Patients with acute calcific periarthritis of the hand exhibited residual pain and calcification for a relatively prolonged period. Those who continued conservative treatment, including NSAIDs, showed pain relief and reduced calcification for up to 6 months. These results suggest that conservative treatment could be tried for at least 6 months before considering the surgical treatment of calcific periarthritis of the hand. PMID- 30428904 TI - Increase of CaV3 channel activity induced by HVA beta1b-subunit is not mediated by a physical interaction. AB - OBJECTIVE: Low voltage-activated (LVA) calcium channels are crucial for regulating oscillatory behavior in several types of neurons and other excitable cells. LVA channels dysfunction has been implicated in epilepsy, neuropathic pain, cancer, among other diseases. Unlike for High Voltage-Activated (HVA) channels, voltage-dependence and kinetics of currents carried by recombinant LVA, i.e., CaV3 channels, are quite similar to those observed in native currents. Therefore, whether these channels are regulated by HVA auxiliary subunits, remain controversial. Here, we used the alpha1-subunits of CaV3.1, CaV3.2, and CaV3.3 channels, together with HVA auxiliary beta-subunits to perform electrophysiological, confocal microscopy and immunoprecipitation experiments, in order to further explore this possibility. RESULTS: Functional expression of CaV3 channels is up-regulated by all four beta-subunits, although most consistent effects were observed with the beta1b-subunit. The biophysical properties of CaV3 channels were not modified by any beta-subunit. Furthermore, although beta1b subunits increased colocalization of GFP-tagged CaV3 channels and the plasma membrane of HEK-293 cells, western blots analysis revealed the absence of physical interaction between CaV3.3 and beta1b-subunits as no co immunoprecipitation was observed. These results provide solid evidence that the up-regulation of LVA channels in the presence of HVA-beta1b subunit is not mediated by a high affinity interaction between both proteins. PMID- 30428903 TI - Genomes reveal marked differences in the adaptive evolution between orangutan species. AB - BACKGROUND: Integrating demography and adaptive evolution is pivotal to understanding the evolutionary history and conservation of great apes. However, little is known about the adaptive evolution of our closest relatives, in particular if and to what extent adaptions to environmental differences have occurred. Here, we used whole-genome sequencing data from critically endangered orangutans from North Sumatra (Pongo abelii) and Borneo (P. pygmaeus) to investigate adaptive responses of each species to environmental differences during the Pleistocene. RESULTS: Taking into account the markedly disparate demographic histories of each species after their split ~ 1 Ma ago, we show that persistent environmental differences on each island had a strong impact on the adaptive evolution of the genus Pongo. Across a range of tests for positive selection, we find a consistent pattern of between-island and species differences. In the more productive Sumatran environment, the most notable signals of positive selection involve genes linked to brain and neuronal development, learning, and glucose metabolism. On Borneo, however, positive selection comprised genes involved in lipid metabolism, as well as cardiac and muscle activities. CONCLUSIONS: We find strikingly different sets of genes appearing to have evolved under strong positive selection in each species. In Sumatran orangutans, selection patterns were congruent with well-documented cognitive and behavioral differences between the species, such as a larger and more complex cultural repertoire and higher degrees of sociality. However, in Bornean orangutans, selective responses to fluctuating environmental conditions appear to have produced physiological adaptations to generally lower and temporally more unpredictable food supplies. PMID- 30428906 TI - Systematic review of incretin therapy during peri-operative and intensive care. AB - BACKGROUND: Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. By lowering blood glucose in a glucose dependent manner, incretin-based therapies represent a novel and promising intervention to treat hyperglycaemia in hospital settings. We performed a systematic review of the literature for all current applications of incretin based therapies in the peri-operative and critical care settings. METHODS: We searched MEDLINE, the Cochrane Library, and Embase databases for all randomised controlled trials using exogenous GLP-1, GLP-1 receptor agonists, exogenous GIP and dipeptidyl peptidase IV inhibitors in the setting of adult peri-operative care or intensive care. We defined no comparator treatment. Outcomes of interest included blood glucose, frequency of hypoglycaemia and insulin administration. RESULTS: Of the 1190 articles identified during the initial literature search, 38 fulfilled criteria for full-text review, and 19 single-centre studies were subsequently included in the qualitative review. Of the 18 studies reporting glycaemic control, improvement was reported in 15, defined as lower glucose concentrations in 12 and as reduced insulin administration (with similar glucose concentrations) in 3. Owing to heterogeneity, meta-analysis was possible only for the outcome of hypoglycaemia. This revealed an incidence of 7.4% in those receiving incretin-based therapies and 6.8% in comparator groups (P = 0.94). CONCLUSIONS: In small, single-centre studies, incretin-based therapies lowered blood glucose and reduced insulin administration without increasing the incidence of hypoglycaemia. TRIAL REGISTRATION: PROSPERO, CRD42017071926. PMID- 30428907 TI - Recruitment of patients with de novo Parkinson disease: successful strategies in a randomized exercise clinical trial. AB - INTRODUCTION: Recruitment of sufficient patients with Parkinson disease into clinical trials is a barrier to successful, timely study completion. Non pharmacologic studies have shown to be even more challenging for recruitment, despite some studies focusing on de novo Parkinson disease populations. This paper describes successful recruitment techniques from a randomized exercise clinical trial in Parkinson disease. METHODS: Several recruitment strategies were used to enroll de novo patients with Parkinson disease into a year-long clinical trial. Strategies focused on infrastructure included fast-track clinic scheduling, weekly research meetings, an established clinical repository, real time clinic recruitment, and outreach to the community. The nature of the study facilitated recruitment by offering a wait-listed control group, exercise at a local fitness center with a paid membership, and collection of data by shipping equipment foregoing some visits. An experienced nurse study coordinator involved in recruitment and training of the principal investigator in recruitment of minorities enhanced overall recruitment. Finally, the patient population chosen for this study, patients with de novo Parkinson disease, may be more likely to enroll in an exercise study than patients with later stage disease. RESULTS: Seventy-six patients with de novo Parkinson disease were successfully enrolled into the exercise clinical trial from a single site. CONCLUSION: Targeted recruitment strategies were successful in this study. Additional modifications to the study protocol, such as eliminating treadmill stress tests before randomization, travel to an urban downtown location for study visits, and a relatively healthy Parkinson disease population, may also have impacted this study. These strategies could all be adopted for other studies in Parkinson disease, neurodegenerative diseases, or other chronic disorders. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01506479 . Registered on 10 January 2012. PMID- 30428908 TI - Comparison between surgical and percutaneous tracheostomy effects on procalcitonin kinetics in critically ill patients. AB - Available evidence from randomized controlled trials including adult critically ill patients tends to show that percutaneous dilatational tracheostomy (PDT) techniques are performed faster and reduce stoma inflammation and infection but are associated with increased technical difficulties compared with surgical tracheostomy (ST). A recent meta-analysis found that PDT was superior to reduce risk of periprocedural stoma inflammation and infection compared with ST. WE found no differences in procalcitonin, C-reactive protein, SOFA, and SAPS II between critically ill patients with ST or PDT. PMID- 30428909 TI - A double-blind, randomized, placebo-controlled trial of a computer-based Interpretation Bias Training for youth with severe irritability: a study protocol. AB - BACKGROUND: Severe, chronic, and impairing irritability is a common presenting clinical problem in youth. Indeed, it was recently operationalized as disruptive mood dysregulation disorder (DMDD) in the DSM-5. However, to date, there are no evidence-based treatments that were specifically developed for DMDD. The current randomized controlled trial assesses the efficacy of a computer-based cognitive training intervention (Interpretation Bias Training; IBT) in youth with DMDD. IBT aims to reduce irritability by altering judgments of ambiguous face-emotions through computerized feedback. IBT is based on previous findings that youth with irritability-related psychopathology rate ambiguous faces as more hostile and fear producing. METHODS/DESIGN: This is a double-blind, randomized controlled trial of IBT in 40 youth with DMDD. Participants will be randomized to receive four IBT sessions (Active vs. Sham training) over 4 days. Active IBT provides computerized feedback to change ambiguous face-emotion interpretations towards happy interpretations. Face-emotion judgments are performed pre and post training, and for 2 weeks following training. Blinded clinicians will conduct weekly clinical ratings. Primary outcome measures assess changes in irritability using the clinician-rated Affective Reactivity Index (ARI) and Clinical Global Impressions-Improvement (CGI-I) scale for DMDD, as well as parent and child reports of irritability using the ARI. Secondary outcome measures include clinician ratings of depression, anxiety, and overall impairment. In addition, parent and child self-report measures of depression, anxiety, anger, social status, and aggression will be collected. DISCUSSION: The study described in this protocol will perform the first RCT testing the efficacy of IBT in reducing irritability in youth with DMDD. Developing non-pharmacological treatment options for youth suffering from severe, chronic irritability is important to potentially augment existing treatments. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02531893 . Registered on 25 August 2015. PMID- 30428910 TI - Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis. AB - BACKGROUND: Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. METHODS: A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo. RESULTS: Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining. CONCLUSIONS: We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC. PMID- 30428911 TI - Dysregulation of cardiac lipid parameters in high-fat high-cholesterol diet induced rat model. AB - BACKGROUND: Lipid dysregulation is a classical risk factor for cardiovascular disease (CVD), yet scanty evidence existed regarding cardiac lipid metabolism that is directly related to heart damage. Recently, the relationship between dyslipidemia and pro-inflammatory insults has led to further understanding on the CVD-predisposing effects of dyslipidemia. The aims of the present study were to investigate whether high-fat high-cholesterol (HFHC) diet-induced hyperlipidemia would cause heart damage and to study the potential role of local cardiac lipid dysregulation in the occurrence of cellular injury. METHODS: Male Sprague-Dawley rats were divided into normal chow or HFHC diet groups, and sacrificed after 2 or 4 weeks, respectively. Lipid peroxidation marker level was measured. Lipid parameters in the rat hearts were detected. Cardiac damage was evaluated. RESULTS: HFHC diet increased serum levels of cholesterol and free fatty acids (FFAs) and led to systemic oxidative stress and pro-inflammatory status. Cardiac lipid dysregulation, which was characterized by elevated levels of cholesterol and adipocyte (A)- and heart (H)-fatty acid binding proteins (FABPs), occurred after HFHC diet for 4 weeks. Cardiac damage was further evident with elevated circulating H-FABP levels, increased cardiac interstitial fibrosis and the loss of troponin I. CONCLUSION: Our data demonstrated that HFHC diet led to systemic and cardiac lipid dysregulation, accompanied by systemic oxidative and pro inflammatory stresses, and these may finally cooperate to cause a series of pathological changes of the heart tissue. Our findings suggest that maintenance of lipid regulation may be essential in the prevention of heart damage. PMID- 30428912 TI - Port site parasitic leiomyoma after laparoscopic myomectomy: a case report and review of the literature. AB - BACKGROUND: Uterine fibroids are the commonest benign gynecological tumors. Laparoscopic myomectomy is becoming increasingly popular as one of the surgical treatment options for symptomatic cases. Large tissues such as leiomyomas or even the uterus need to be morcellated in order to be retrieved from the abdominal cavity. Some of the morcellated fragments or small fibroids may be accidentally left in the abdominal cavity during the retrieval process. These may subsequently become implanted in the abdominal cavity, develop blood supply from the surrounding structures, and grow to form parasitic myomas with varied clinical presentation, depending on the location and size. CASE PRESENTATION: A 47-year old African woman presented to our hospital 6 years after laparoscopic myomectomy with a lower abdominal mass. Her work-up revealed an anterior abdominal wall mass consistent with uterine leiomyoma. She was scheduled for excision of the mass, which was subsequently histologically confirmed to be a uterine fibroid. CONCLUSIONS: Parasitic leiomyomas are a rare late complication of power morcellation following laparoscopic myomectomy or hysterectomy. Most patients present with an abdominal/pelvic mass and may need surgical excision to relieve the symptoms. Care should be taken during power morcellation to prevent excessive fragmentation of the tissues, some of which may become implanted and persist to form parasitic myomas. Moreover, effort should be made to retrieve all myoma fragments by carefully checking the abdominal cavity. Whenever possible, the morcellation should be done in a containment bag. PMID- 30428913 TI - Application of the Chinese Aircraft-shaped Sleeve system in the treatment of tibial shaft fractures using a suprapatellar approach for tibial intramedullary nailing: a randomised controlled trial. AB - BACKGROUND: The use of the suprapatellar approach for intramedullary nailing has recently become popular for the treatment of tibial fractures. This study aimed to investigate the effectiveness of using the Chinese Aircraft-shaped Sleeve (CASS) system on the clinical outcomes of tibial intermedullary nailing using a suprapatellar approach for the treatment of tibial fractures in a cohort of adult Chinese patients. METHODS: Magnetic resonance images (MRI) of the knee joints of 212 healthy adults with normal lower limb function from May 2011 to May 2015 were obtained from a level I Chinese regional trauma centre. Sixty inpatients at the same trauma centre who underwent treatment for tibial shaft fractures from June 2015 to June 2018 were enrolled. Tibial intramedullary nailing fixation of tibial shaft fractures via the suprapatellar approach was performed with either a CASS system or a conventional sleeve. The measurements of patellofemoral joint anatomy, the surgical time, the assessments of the patellofemoral joint cartilage conditions, and information of residual debris based on arthroscopic analysis were subsequently collected. RESULTS: The mean patellar angle (PA), sulcus angle (SA), sulcus width (SW) and sulcus depth (SD) were 135.40 +/- 6.20 degrees , 142.37 +/- 5.33 degrees , 33.37 +/- 2.73 mm, and 4.29 +/- 0.63 mm, respectively. The surgical time until entry reaming commencement and the irrigation time were significantly lower in the CASS group (P < 0.001). The difference in cartilage damage rate between groups was statistically significant (P = 0.031); the difference in residual debris conditions was not statistically significant (P = 0.1967). CONCLUSION: The use of the CASS system could improve clinical outcomes of intramedullary nailing via suprapatellar approach for patients with a small patellofemoral joint space. PMID- 30428914 TI - Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients. AB - BACKGROUND: Multiple endocrine neoplasia (MEN1) is a rare inherited multi-tumour syndrome, affecting specific neuroendocrine organs and non-endocrine tissues with a variable spectrum of over 20 possible different combinations, caused by inactivating heterozygote mutations of the MEN1 gene. Disease onset, penetrance, clinical presentation, course and prognosis are all extremely variable, even among individuals bearing the same causative mutation, which doesn't allow prediction of the individual clinical phenotype (based on the specific result of the genetic test), thus compelling all patients and mutation carriers to undergo a common routine general screening program. RESULTS: We performed an extensive epidemiological, clinical and genetic analysis of the Florentine MEN1 patient database, which includes 145 MEN1 patients and 20 asymptomatic MEN1 carriers, constantly followed up at the Regional Referral Centre for Inherited Endocrine Tumours of the Tuscany Region, during the last three decades. We reported, here, the results of clinical, epidemiological and genetic descriptive statistics, as well as correlation analyses between tumours and mutation types and localisation. No direct genotype-phenotype correlation was described, but the importance of the genetic testing was confirmed for an early diagnosis and the identification of asymptomatic carriers. CONCLUSIONS: As with all rare diseases, the possibility to collect and analyse data on a relatively large number of patients is important for increasing our knowledge of the epidemiologic aspects of the disease, and its natural course and prognosis of single manifestations of the syndrome, in order to set up the best diagnostic and therapeutic plans for patients. In this light, the creation and constant updating of large patient databases is fundamental. Results from database study can provide useful epidemiological, clinical and genetic information about MEN1 syndrome, which could help clinicians in the diagnostic and therapeutic management of single MEN1 patients. PMID- 30428915 TI - Characterization of tick organic anion transporting polypeptides (OATPs) upon bacterial and viral infections. AB - BACKGROUND: Ixodes scapularis organic anion transporting polypeptides (OATPs) play important roles in tick-rickettsial pathogen interactions. In this report, we characterized the role of these conserved molecules in ticks infected with either Lyme disease agent Borrelia burgdorferi or tick-borne Langat virus (LGTV), a pathogen closely related to tick-borne encephalitis virus (TBEV). RESULTS: Quantitative real-time polymerase chain reaction analysis revealed no significant changes in oatps gene expression upon infection with B. burgdorferi in unfed ticks. Synchronous infection of unfed nymphal ticks with LGTV in vitro revealed no significant changes in oatps gene expression. However, expression of specific oatps was significantly downregulated upon LGTV infection of tick cells in vitro. Treatment of tick cells with OATP inhibitor significantly reduced LGTV loads, kynurenine amino transferase (kat), a gene involved in the production of tryptophan metabolite xanthurenic acid (XA), levels and expression of several oatps in tick cells. Furthermore, bioinformatics characterization of OATPs from some of the medically important vectors including ticks, mosquitoes and lice revealed the presence of several glycosylation, phosphorylation and myristoylation sites. CONCLUSIONS: This study provides additional evidence on the role of arthropod OATPs in vector-intracellular pathogen interactions. PMID- 30428916 TI - Age and gender trends in insecticide-treated net use in sub-Saharan Africa: a multi-country analysis. AB - BACKGROUND: The degree to which insecticide-treated net (ITN) supply accounts for age and gender disparities in ITN use among household members is unknown. This study explores the role of household ITN supply in the variation in ITN use among household members in sub-Saharan Africa. METHODS: Data was from Malaria Indicator Surveys or Demographic and Health Surveys collected between 2011 and 2016 from 29 countries in sub-Saharan Africa. The main outcome was ITN use the previous night. Other key variables included ITN supply (nets/household members), age and gender of household members. Analytical methods included logistic regressions and meta regression. RESULTS: Across countries, the median (range) of the percentage of households with enough ITNs was 30.7% (8.5-62.0%). Crude analysis showed a sinusoidal pattern in ITN use across age groups of household members, peaking at 0-4 years and again around 30-40 years and dipping among people between 5-14 and 50+ years. This sinusoidal pattern was more pronounced in households with not enough ITNs compared to those with enough ITNs. ITN use tended to be higher in females than males in households with not enough ITNs while use was comparable among females and males in households with enough ITNs. After adjusting for wealth quintile, residence and region, among households with not enough ITNs in all countries, the odds of ITN use were consistently higher among children under 5 years and non-pregnant women 15-49 years. Meta-regressions showed that across all countries, the mean adjusted odds ratio (aOR) of ITN use among children under 5 years, pregnant and non-pregnant women aged 15-49 years and people 50 years and above was significantly higher than among men aged 15-49 years. Among these household members, the relationship was attenuated when there were enough ITNs in the household (dropping 0.26-0.59 points) after adjusting for geographical zone, household ITN supply, population ITN access, and ITN use:access ratio. There was no significant difference in mean aOR of ITN use among school-aged children compared to men aged 15-49 years, regardless of household ITN supply. CONCLUSIONS: This study demonstrated that having enough ITNs in the household increases level of use and decreases existing disparities between age and gender groups. ITN distribution via mass campaigns and continuous distribution channels should be enhanced as needed to ensure that households have enough ITNs for all members, including men and school-aged children. PMID- 30428917 TI - Highly clarithromycin-resistant Helicobacter pylori infection in asymptomatic children from a rural community of Cajamarca-Peru. AB - OBJECTIVE: The objective of this study was to determine the prevalence of clarithromycin-resistant Helicobacter pylori in asymptomatic children in a rural community of Cajamarca (northern Peru). RESULTS: Helicobacter pylori was detected in 17.2% (49/285) of the samples. Unboiled water consumption the most frequent associated factor in patients with positive PCR for H. pylori infection (93.9%). Clarithromycin resistant mutations were found in 79.6% (39/49) of the positive samples for H. pylori. The most frequent mutation was A2142G (46.9%), followed by the double-mutation A2142G-A2143G (28.6%). PMID- 30428919 TI - Sexuality, sexually transmitted infections and contraception among health sciences students in university of Lome, Togo. AB - OBJECTIVES: Evaluate the practice of sexuality, contraception and the risk of sexually transmitted infections among students in the Faculty of Health Sciences, University of Lome, Togo. RESULTS: Three hundred and sixteen (316) students were interviewed, with a response rate of 43.3%. The average age of students completing the form was 21.4 +/- 2.7 years and their sex ratio was 2.2. Of this number of students who completed the form, 51.8% have already had sex. The mean age of first intercourse was 17.9 +/- 3.2 years; 70.3% were heterosexual. Regarding the number of sexual partners, 48.5% of students had more than one partner, of whom 15.9% had at least 5 sexual partners. 21.5% of these students had only one sexual intercourse per month. Regarding contraception among students with the card, 67.5% of students used a method of contraception. Among those using contraceptives, it was a 55.3% condom, followed by the Ogino method at 14.1%. Some of our respondents used more than one method of contraception and 28.5% of respondents indicated that their partners used a method of contraception. For STIs, 10.8% of students completing the form were already infected. Gonorrhea was reported in 30.4% of cases, candidiasis in 26.1% of cases. PMID- 30428920 TI - "Think. Check. Submit." to avoid predatory publishing. PMID- 30428918 TI - Bone marrow mesenchymal stromal cells attenuate silica-induced pulmonary fibrosis potentially by attenuating Wnt/beta-catenin signaling in rats. AB - BACKGROUND: Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. Previous studies have shown that early intervention with bone marrow mesenchymal stem/stromal cells (BMSCs) has positive effect on anti-pulmonary fibrosis caused by silica dust. However, early intervention using BMSCs is not practical, and the therapeutic effects of BMSCs advanced intervention on pulmonary fibrosis have rarely been reported. In this study, we investigated the effects of advanced transplantation (on the 28th day after exposure to silica suspension) of BMSCs on an established rat model of pulmonary fibrosis. METHODS: Sprague Dawley (SD) rats were randomly divided into four groups including (1) control group (n = 6) which were normally fed, (2) silica model group (n = 6) which were exposed to silica suspension (1 mL of 50 mg/mL/rat), (3) BMSC transplantation group (n = 6) which received 1 mL BMSC suspension (2 * 106 cells/mL) by tail vein injection on the 28th day after exposure to silica suspension, and (4) BMSC-CM (conditioned medium) transplantation group (n = 6) which received CM from the same cell number by tail vein injection on the 28th day after exposure to silica suspension. On the 56th day after exposure to silica suspension, we used computed tomography (CT), hematoxylin and eosin (H&E), and Masson's trichrome staining to evaluate the changes in lung tissue. We examined the expression of epithelial-mesenchymal transition (EMT) and Wnt/beta-catenin pathway-related proteins in lung tissue using immunohistochemistry and western blotting. RESULTS: Successful construction of a pulmonary fibrosis model was confirmed by H&E and Masson's trichrome staining on the 28th day after exposure to silica suspension. On the 56th day after exposure, pulmonary CT examination showed a relieving effect of BMSCs on silica-induced pulmonary fibrosis which was confirmed by H&E and Masson's trichrome staining. Treatment of BMSCs increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including Vimentin (Vim) and alpha-Smooth actin (alpha-SMA) after exposure to silica suspension. Furthermore, we found that Wnt/beta-catenin signaling pathway is abnormally activated in silica-induced pulmonary fibrosis, and exogenous transplantation of BMSCs may attenuate their expression. CONCLUSIONS: BMSC transplantation inhibits the EMT to alleviate silica-induced pulmonary fibrosis in rats and the anti-fibrotic effect potentially by attenuating Wnt/beta-catenin signaling. ?: ?. PMID- 30428921 TI - Copper stress induces antioxidant responses and accumulation of sugars and phytochelatins in Antarctic Colobanthus quitensis (Kunth) Bartl. AB - BACKGROUND: In field, C. quitensis is subjected to many abiotic extreme environmental conditions, such as low temperatures, high UV-B, salinity and reduced water potentials, but not metal or metalloid high concentrations in soil, however, other members of Caryophyllaceae family have tolerance to high concentrations of metals, this is the case of Silene genre. In this work, we hypothesize that C. quitensis have the same mechanisms of Silene to tolerate metals, involving accumulation and induction of antioxidant systems, sugar accumulation and the induction of thiols such as phytochelatins to tolerate. RESULTS: The results showing an effective antioxidant defensive machinery involving non-enzymatic antioxidants such as phenolics, GSH and ascorbic acid, in another hand, GSH-related oligomers (phytochelatins) and sugars was induced as a defensive mechanism. CONCLUSIONS: Colobanthus quitensis exhibits certain mechanisms to tolerate copper in vitro demonstrating its plasticity to tolerate several abiotic stress conditions. PMID- 30428922 TI - Transcriptomic insights into the early host-pathogen interaction of cat intestine with Toxoplasma gondii. AB - BACKGROUND: Although sexual reproduction of the parasite Toxoplasma gondii exclusively occurs in the cat intestine, knowledge about the alteration of gene expression in the intestine of cats infected with T. gondii is still limited. Here, we investigated the temporal transcriptional changes that occur in the cat intestine during T. gondii infection. METHODS: Cats were infected with 100 T. gondii cysts and their intestines were collected at 6, 12, 18, 24, 72 and 96 hours post-infection (hpi). RNA sequencing (RNA-Seq) Illumina technology was used to gain insight into the spectrum of genes that are differentially expressed due to infection. Quantitative RT-PCR (qRT-PCR) was also used to validate the level of expression of a set of differentially expressed genes (DEGs) obtained by sequencing. RESULTS: Our transcriptome analysis revealed 2363 DEGs that were clustered into six unique patterns of gene expression across all the time points after infection. Our analysis revealed 56, 184, 404, 508, 400 and 811 DEGs in infected intestines compared to uninfected controls at 6, 12, 18, 24, 72 and 96 hpi, respectively. RNA-Seq results were confirmed by qRT-PCR. DEGs were mainly enriched in catalytic activity and metabolic process based on gene ontology enrichment analysis. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that transcriptional changes in the intestine of infected cats evolve over the course of infection, and the largest difference in the enriched pathways was observed at 96 hpi. The anti-T. gondii defense response of the feline host was mediated by Major Histocompatibility Complex class I, proteasomes, heat-shock proteins and fatty acid binding proteins. CONCLUSIONS: This study revealed novel host factors, which may be critical for the successful establishment of an intracellular niche during T. gondii infection in the definitive feline host. PMID- 30428924 TI - Intrathoracic fibrolipoma resected using complete thoracoscopic surgery: a case report. AB - BACKGROUND: Other than adipocytes, lipomas may contain mesodermal components such as varying proportions of fibrous tissues and blood vessels. Fibrolipoma is an uncommon variant of lipoma and comprises a high proportion of fibrous components. An intrathoracic fibrolipoma is extremely rare; to the best of our knowledge, only three such cases have been reported till date. CASE PRESENTATION: A 51-year old female presented with a left intrathoracic mass, which was confirmed to be a lipomatous tumor using computed tomography. A pedunculated tumor originating from the parietal pleura was resected using complete thoracoscopic surgery. Pathological examination indicated a diagnosis of fibrolipoma. Intrathoracic fibrolipomas are extremely rare; this is one of the first reported cases of successfully resecting an intrathoracic fibrolipoma using complete thoracoscopic surgery. CONCLUSIONS: The tumor was asymptomatic and relatively small when detected during a medical checkup. This enabled the successful resection of the tumor via complete thoracoscopic surgery. Although fibrolipomas are histologically benign, careful observation and follow-up are essential owing to the possibility of recurrence. PMID- 30428925 TI - Dog survey in Russian veterinary hospitals: tick identification and molecular detection of tick-borne pathogens. AB - BACKGROUND: Species of Canidae in Russia can be infested with up to 24 different tick species; however, the frequency of different tick species infesting domestic dogs across Russia is not known. In addition, tick-borne disease risks for domestic dogs in Russia are not well quantified. The goal of this study was to conduct a nationwide survey of ticks collected from infested dogs admitted to veterinary clinics in Russian cities and to identify pathogens found in these ticks. METHODS: Ticks feeding on dogs admitted to 32 veterinary clinics in 27 major cities across Russia were preserved in ethanol and submitted to a central facility for examination. After identification, each tick was evaluated for infection with known tick-borne pathogens using PCR. RESULTS: There were 990 individual ticks collected from 636 dogs. All collected ticks belonged to the Ixodidae (hard ticks) and represented 11 species of four genera, Dermacentor, Ixodes, Rhipicephalus and Haemaphysalis. Four most common tick species were D. reticulatus, followed by I. persulcatus, I. ricinus and R. sanguineus. Ixodes persulcatus ticks were found to be infected with 10 different pathogens, and ticks of this species were more frequently infected than either D. reticulatus or I. ricinus. Ixodes persulcatus females were also more frequently co-infected with two or more pathogens than any other tick. Pathogenic species of five genera were detected in ticks: Anaplasma centrale, A. phagocytophilum and A. marginale; Babesia canis, B. microti, B. venatorum, B. divergens, B. crassa and B. vogeli; Borrelia miyamotoi, B. afzelii and B. garinii; Ehrlichia muris, E. canis and E. ruminantum; and Theileria cervi. Anaplasma marginale, E. canis, B. crassa, B. vogeli and T. cervi were detected in I. persulcatus, and Babesia canis in D. marginatum, for the first time in Russia. CONCLUSIONS: Multiple ticks from four genera and 11 species of the family Ixodidae were collected from domestic dogs across Russia. These ticks commonly carry pathogens and act as disease vectors. Ixodes persulcatus ticks present the greatest risk for transmission of multiple arthropod-borne pathogens. PMID- 30428926 TI - Modified bolster dressing with continuous suction improves skin graft survival for an oral cavity wound. AB - BACKGROUND: Skin engraftment of intraoral defects is known to be inconsistent due to mobility of the oral structure, uneven wounds, and accumulation of saliva under the skin graft. To improve the success rate of oral skin graft, we proposed a novel and simple dressing technique for intraoral skin graft to control saliva accumulation, in comparison with the conventional bolster dressing. METHODS: We retrospectively reviewed 31 patients reconstructed with skin graft in their intraoral defect. The patients were divided into two groups; conventional bolster group (n = 21) and modified bolster group (n = 10). In the modified bolster group, a polyvinyl alcohol sponge was designed to fit the skin graft and a suction drain was inserted with tagging suture to apply continuous suction. We analyzed the success rate, the size of the skin grafts and clinical variables of each method. RESULTS: The overall success rate of oral skin graft was not different between the two groups (90.0 and 90.5%). However, partial necrosis in the engrafted skin was observed frequently in the control group (57.1% versus 20.0%). The relative engrafted area was significantly higher in the modified bolster group (55.0 +/- 11.6% versus 23.0 +/- 18.7%, p = 0.015). The duration of bolster dressing and the time to start an oral diet were shorter in the modified bolster group. CONCLUSIONS: Our modified method could be easily applied for removing saliva accumulation under a skin graft and for enhancing skin engraftment of an oral cavity wound. PMID- 30428927 TI - Patient demands for ethnic-based separation in public hospitals in Israel: patients' and practitioners' perspectives. AB - BACKGROUND: Segregation within the healthcare system is commonly associated with disparities in the utilization of health services and in the outcomes of medical care. In Israel, the Jewish majority and the Arab minority populations are treated in the same healthcare organizations. Nevertheless, demands for ethnic separation in inpatient rooms are raised at times by patients, despite the principle of prohibiting discrimination between patients on the grounds of religion, race, sex and nationality. The study sought to examine patients' attitudes regarding separation between Jews and Arabs in inpatients rooms, and to discover the coping strategies employed by healthcare practitioners. METHODS: A mixed methodology was employed. We conducted a survey of a representative sample of the Israeli population (N = 760); and held 50 in-depth interviews with nurses, physicians and managers employed in 11 public hospitals in Israel. RESULTS: In the representative sample survey, 30% of Jews and 21% of Arabs agree that patients should be allowed to choose to be placed in an inpatient room in which only patients of their own ethnic group are hospitalized. Among both Jews and Arabs, a high level of religiosity and a low level of education predict this position. Most Jews (80%) and Arabs (71%) do not agree that the entire healthcare system should be ethnically separated. The in-depth interviews revealed evidence of demands for ethnic separation made at times by Jewish patients, which are often met by the nurses. In some cases, nurses separate Jewish and Arab patients of their own accord. They do this either to promote cultural compatibility between patients or to avoid unnecessary tension and confrontations. In some cases, this step may constitute discrimination against Arab patients. Managers and senior physicians, for their part, are generally unaware of this ethnic separation, or deny that it takes place. CONCLUSIONS: Ethnic separation in inpatient rooms does take place some of the time and this runs contrary to the ethos of neutrality in medicine. We recommend implementation of a specific national policy that prohibits ethnic-based separation in hospitals' inpatient rooms. Better communication is required to ensure that policy decisions are clearly conveyed to the wards and that segregation does not become institutionalized. PMID- 30428928 TI - Is goal-directed fluid therapy based on dynamic variables alone sufficient to improve clinical outcomes among patients undergoing surgery? A meta-analysis. AB - BACKGROUND: Whether goal-directed fluid therapy based on dynamic predictors of fluid responsiveness (GDFTdyn) alone improves clinical outcomes in comparison with standard fluid therapy among patients undergoing surgery remains unclear. METHODS: PubMed, EMBASE, the Cochrane Library and ClinicalTrials.gov were searched for relevant studies. Studies comparing the effects of GDFTdyn with that of standard fluid therapy on clinical outcomes among adult patients undergoing surgery were considered eligible. Two analyses were performed separately: GDFTdyn alone versus standard fluid therapy and GDFTdyn with other optimization goals versus standard fluid therapy. The primary outcomes were short-term mortality and overall morbidity, while the secondary outcomes were serum lactate concentration, organ-specific morbidity, and length of stay in the intensive care unit (ICU) and in hospital. RESULTS: We included 37 studies with 2910 patients. Although GDFTdyn alone lowered serum lactate concentration (mean difference (MD) - 0.21 mmol/L, 95% confidence interval (CI) (- 0.39, - 0.03), P = 0.02), no significant difference was found between groups in short-term mortality (odds ratio (OR) 0.85, 95% CI (0.32, 2.24), P = 0.74), overall morbidity (OR 1.03, 95% CI (0.31, 3.37), P = 0.97), organ-specific morbidity, or length of stay in the ICU and in hospital. Analysis of trials involving the combination of GDFTdyn and other optimization goals (mainly cardiac output (CO) or cardiac index (CIx)) showed a significant reduction in short-term mortality (OR 0.45, 95% CI (0.24, 0.85), P = 0.01), overall morbidity (OR 0.41, 95% CI (0.28, 0.58), P < 0.00001), serum lactate concentration (MD - 0.60 mmol/L, 95% CI (- 1.04, - 0.15), P = 0.009), cardiopulmonary complications (cardiac arrhythmia (OR 0.58, 95% CI (0.37, 0.92), P = 0.02), myocardial infarction (OR 0.35, 95% CI (0.16, 0.76), P = 0.008), heart failure/cardiovascular dysfunction (OR 0.31, 95% CI (0.14, 0.67), P = 0.003), acute lung injury/acute respiratory distress syndrome (OR 0.13, 95% CI (0.02, 0.74), P = 0.02), pneumonia (OR 0.4, 95% CI (0.24, 0.65), P = 0.0002)), length of stay in the ICU (MD - 0.77 days, 95% CI (- 1.07, - 0.46), P < 0.00001) and in hospital (MD - 1.18 days, 95% CI (- 1.90, - 0.46), P = 0.001). CONCLUSIONS: It was not the optimization of fluid responsiveness by GDFTdyn alone but rather the optimization of tissue and organ perfusion by GDFTdyn and other optimization goals that benefited patients undergoing surgery. Patients managed with the combination of GDFTdyn and CO/CI goals might derive most benefit. PMID- 30428923 TI - A bite so sweet: the glycobiology interface of tick-host-pathogen interactions. AB - Vector-borne diseases constitute 17% of all infectious diseases in the world; among the blood-feeding arthropods, ticks transmit the highest number of pathogens. Understanding the interactions between the tick vector, the mammalian host and the pathogens circulating between them is the basis for the successful development of vaccines against ticks or the tick-transmitted pathogens as well as for the development of specific treatments against tick-borne infections. A lot of effort has been put into transcriptomic and proteomic analyses; however, the protein-carbohydrate interactions and the overall glycobiology of ticks and tick-borne pathogens has not been given the importance or priority deserved. Novel (bio)analytical techniques and their availability have immensely increased the possibilities in glycobiology research and thus novel information in the glycobiology of ticks and tick-borne pathogens is being generated at a faster pace each year. This review brings a comprehensive summary of the knowledge on both the glycosylated proteins and the glycan-binding proteins of the ticks as well as the tick-transmitted pathogens, with emphasis on the interactions allowing the infection of both the ticks and the hosts by various bacteria and tick-borne encephalitis virus. PMID- 30428931 TI - Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study. AB - OBJECTIVE: The aim of this study was to evaluate the safety of mesenchymal stem cell infusion in patients with autoimmune diseases. METHODS: A total of 404 patients with autoimmune diseases who received mesenchymal stem cell infusion between 2007 and 2016 were included in this study. Adverse events in these patients were collected, mainly including infections and malignancies. Sources of information included hospitalization records and data from outpatient visits and each follow-up. RESULTS: The mean follow-up period of all patients was 43.4 +/- 25.9 months (range 1-109). Majority of stem cells were from the umbilical cord. The most common indications for mesenchymal stem cell infusion were systemic lupus erythematosus, Sjogren's syndrome, and systemic sclerosis. The median age at infusion was 38.7 +/- 15.7 years. The 5-year and 8-year survival rates were 90.4% and 88.9%, respectively. Median follow-up of survivors was 45.1 +/- 25.7 months. The incidence rate of infections was 29.5% (119/404), and that of serious infections was 12.9% (52/404). Five patients (1.2%) experienced malignancies. Deaths occurred in 45 patients, and transplantation-related mortality was 0.2%. The most common causes of deaths in our study were disease relapse and complications associated with the underlying disease. CONCLUSION: Autoimmune disease is an emerging indication for mesenchymal stem cell infusion. Our data shows that mesenchymal stem cell infusion is a safe therapy for patients with autoimmune diseases. The incidences of adverse events, whether infections or malignancies, are acceptable in these patients. TRIAL REGISTRATION: ClinaicalTrials.gov, NCT00698191 . Registered 17 June 2008-Retrospectively registered. PMID- 30428930 TI - Low-chloride versus high-chloride hypertonic solution for the treatment of subarachnoid hemorrhage-related complications (The ACETatE trial): study protocol for a pilot randomized controlled trial. AB - BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition that results from a ruptured cerebral vessel. Cerebral edema and vasospasm are common complications and frequently require treatment with hypertonic solutions, in particular hypertonic sodium chloride (NaCl). We have previously shown that hyperchloremia in patients with aSAH given hypertonic NaCl is associated with the development of acute kidney injury (AKI), which leads to higher morbidity and mortality. Our current trial aims to study the effect of two hypertonic solutions with different chloride content on serum chloride concentrations in patients with aSAH who are at risk for AKI. METHODS: A low ChloridE hyperTonic solution for brain Edema (ACETatE) is a single center, double blinded, double-dummy pilot trial comparing bolus doses of 23.4% NaCl and 16.4% NaCl/Na-Acetate for the treatment of cerebral edema in patients with aSAH. All patients will be enrolled within 36 h following admission. Randomization will occur once patients who receive hypertonic treatment for cerebral edema develop hyperchloremia (serum Cl- concentration >= 109 mmol/L). Subsequent treatment will consist of either NaCl 23.4% or NaCl/Na-Acetate 16.4%. The primary outcome of this study will be the change in serum Cl- concentrations during treatment. Secondary outcomes will include incidence of AKI, mortality, changes in intracranial pressure, and extent of hypernatremia. DISCUSSION: In patients with aSAH, hyperchloremia is a known risk factor for subsequent development of AKI. The primary goal of this pilot study is to determine the effect of two hypertonic solutions with different Cl- content on serum Cl- concentrations in patients with aSAH who have already developed hyperchloremia. Data will be collected prospectively to determine the extent to which the choice of hypertonic saline solution affects subsequent serum Cl- concentrations and the occurrence of AKI. This approach will allow us to obtain preliminary data to design a large randomized trial assessing the effects of chloride-sparing hypertonic solutions on development of AKI in patients with SAH. This pilot study is the first to prospectively evaluate the relationship between hypertonic solution chloride content and its effect on serum electrolytes and renal function in aSAH patients at risk of AKI due to hyperchloremia. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03204955 . Registered on 28 June 2017. PMID- 30428929 TI - Coping with drought: stress and adaptive mechanisms, and management through cultural and molecular alternatives in cotton as vital constituents for plant stress resilience and fitness. AB - Increased levels of greenhouse gases in the atmosphere and associated climatic variability is primarily responsible for inducing heat waves, flooding and drought stress. Among these, water scarcity is a major limitation to crop productivity. Water stress can severely reduce crop yield and both the severity and duration of the stress are critical. Water availability is a key driver for sustainable cotton production and its limitations can adversely affect physiological and biochemical processes of plants, leading towards lint yield reduction. Adaptation of crop husbandry techniques suitable for cotton crop requires a sound understanding of environmental factors, influencing cotton lint yield and fiber quality. Various defense mechanisms e.g. maintenance of membrane stability, carbon fixation rate, hormone regulation, generation of antioxidants and induction of stress proteins have been found play a vital role in plant survival under moisture stress. Plant molecular breeding plays a functional role to ascertain superior genes for important traits and can offer breeder ready markers for developing ideotypes. This review highlights drought-induced damage to cotton plants at structural, physiological and molecular levels. It also discusses the opportunities for increasing drought tolerance in cotton either through modern gene editing technology like clustered regularly interspaced short palindromic repeat (CRISPR/Cas9), zinc finger nuclease, molecular breeding as well as through crop management, such as use of appropriate fertilization, growth regulator application and soil amendments. PMID- 30428932 TI - Herceptin(r) (trastuzumab) in HER2-positive early breast cancer: a systematic review and cumulative network meta-analysis. AB - BACKGROUND: Originator trastuzumab (Herceptin(r); H) is an antibody-targeted therapy to treat patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (EBC). We investigated the overall survival (OS) advantage conferred by the addition of H to chemotherapy for HER2+ EBC patients and how the OS advantage changed over time. METHODS: A systematic literature review (SLR) identified randomized controlled trials (RCTs) and non-randomized studies (NRSs) published from January 1, 1990 to January 19, 2017, comparing systemic therapies used in the neoadjuvant/adjuvant settings to treat HER2+ EBC patients. Bayesian cumulative network meta-analyses (cNMAs) of OS were conducted to assess the published literature over time. Heterogeneity was assessed through sensitivity and subgroup analyses. RESULTS: The SLR identified 31 unique studies (28 RCTs, 3 NRSs) included in the OS analyses from 2008 to 2016. In the reference case cNMA (RCTs alone), initial evidence demonstrated an OS advantage for H/chemotherapy compared with chemotherapy alone in HER2+ EBC patients. As additional OS data were published, the precision around this survival benefit strengthened over time. Both H/anthracycline-containing chemotherapy and H/non anthracycline-containing chemotherapy regimens provided similar OS advantages for HER2+ EBC patients. CONCLUSION: This analysis represents the most comprehensive SLR/cNMA to date of published OS data in HER2+ EBC studies. These findings demonstrate why H/chemotherapy is now the established standard of care in HER2+ EBC. In the case of H, the benefits of early patient access far outweighed the risk of waiting for more precise information. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017055763. PMID- 30428933 TI - The effects of the European e-cigarette health warnings and comparative health messages on non-smokers' and smokers' risk perceptions and behavioural intentions. AB - BACKGROUND: Article 20 of the EU Tobacco Products Directive [TPD] stipulates that e-cigarette packets and refill products must carry a nicotine addiction health warning. Although previous studies conducted in North America have found that perceived harm, addictiveness and intention to use declined following exposure to e-cigarette health warnings, possible effects of the TPD health warnings on smokers and non-smokers has not been studied. This study will investigate the effects of the EU TPD e-cigarette health warnings and a comparative harm message (COMP; developed specifically for this study) on smokers' and non-smokers' perceptions of harm, addictiveness and social acceptability of e-cigarettes. Additionally, the potential effects of the TPD warnings and the COMP on smokers' intentions to purchase and use e-cigarettes will be explored. METHODS/DESIGN: A sample of 2400 UK residents will be recruited in this experimental, randomised design, with Smoking status (Smoker vs. Non-smoker), TPD presence (TPD1 vs. TPD2 vs. No-TPD) and COMP presence (Presence vs. Absence) as between subjects independent variables, and Time (pre-post exposure of images) as a within subjects factor. Dependent variables comprise self-reported perceived harm, addictiveness, social acceptability, e-cigarettes' effectiveness, intentions to purchase and use e-cigarettes. Cigarette dependence, previous e-cigarette exposure, and baseline intentions to quit will be measured as covariates. DISCUSSION: Health warnings, such as those implemented by the TPD, may help to prevent non-smokers from e-cigarettes use, but it is possible that they may inadvertently deter smokers from initiating use and substituting their tobacco smoking for e-cigarettes use if their content is deemed too negative. It is hoped that this study will help identify the most effective message or combination of messages that encourage use among smokers without promoting use among non smokers. TRIAL REGISTRATION: ISRCTN registry ISRCTN76967031 ; date of registration: 23/10/18. PMID- 30428934 TI - Are non-high-density lipoprotein fractions associated with pediatric metabolic syndrome? The CASPIAN-V study. AB - BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) is considered as a valuable predictor for dyslipidemia and subclinical atherosclerosis which can be an appropriate index for identifying individuals with metabolic syndrome (MetS). OBJECTIVE: To evaluate the association between non-HDL-C MetS and determine the optimal cut-points of non-HDL-C fractions for identifying MetS in Iranian children and adolescents. METHODS: This nationwide study was conducted in the framework of the fifth survey of a national school-based surveillance program on children and adolescents aged 7-18 years. MetS was defined by the Adult Treatment Panel III (ATP III) criteria modified for the pediatric age group. The analysis of receiver operating characteristic (ROC) curve was applied to determine the optimal cut-points of non-HDL-C, difference between non-HDL-C and LDL-C (Diff-C) and triglycerides (TG) to HDL-C ratio (TG/HDL-C) for the prediction of MetS. RESULTS: Overall, the study participants consisted of 3843 students (52.3% boys) with mean (+/-SD) age of 12.28 (3.1) years. The odds of high LDL-C, low HDL-C and MetS were increased in subjects with higher non-HDL-C, Diff-C and TG/HDL-C (P < 0.05). Non-HDL-C, Diff-C and TG/HDL-C cut-off points for predicting MetS were 120.5 mg/dl (sensitivity: 44%, specificity: 73%), 19.9 mg/dl (sensitivity: 85%, specificity: 75%) and 2.53 (sensitivity: 82%, specificity: 79%), respectively. CONCLUSIONS: This study revealed a strong association between surrogates for serum lipid profile including non-HDL-C, TG/HDL-C and Diff-C and pediatric MetS. Our findings suggest that age- and gender-specific reference values of these markers were appropriate for both risk classification and long term control of cardiovascular events in clinical assessments. PMID- 30428936 TI - Kato-Katz thick smears as a DNA source of soil-transmitted helminths. AB - Despite the reduction in the prevalence of soil-transmitted helminthiases in many regions of the world, morbidity rates remain high in some rural regions. The Kato Katz technique is a simple, inexpensive and field-applicable tool commonly used for the diagnosis and worm-burden characterization of these infections. Molecular studies have revolutionized our understanding of the epidemiology and evolutionary genetics of parasites. In this study we recovered helminthic DNA from Kato-Katz slides (n = 93) prepared in 2011 in the Brazilian Amazon. We achieved DNA recovery by polymerase chain reaction (PCR) in 84% of cases for Ascaris sp. and 75% of cases for hookworms. The sequencing confirmed the specific species of the amplicons. The slides stored for a few years could be analysed using this methodology, allowing access to DNA from a large collection of samples. We must consider the Kato-Katz thick smears as a source of helminth DNA. This can significantly reduce logistical difficulties in the field in terms of obtaining, preserving, transporting and initial processing of samples. PMID- 30428937 TI - Okay to Stay? A new plan to help people with long-term conditions remain in their own homes. AB - AimsTo assess the 'Okay to Stay' plan to investigate if this reduces visits to emergency departments, unplanned admissions and elective admission to hospital in elderly patients with long-term health conditions. BACKGROUND: The incidence of long-term conditions is rising as the elderly population increases, resulting in more people from this group attending emergency departments and being admitted to hospital. Okay to Stay is a simple plan for people with long-term conditions to help them remain in their own home if they suffer an acute exacerbation in their health. It was co-designed with professional and patient representatives with the aim of empowering patients and their carers to more effectively manage their long term conditions. METHODS: Data from 50 patients (20 males, 30 females, mean baseline age 77.5 years) were compared 12 months before implementation of the plan and in the subsequent 12 months, with the significance of effects assessed at the 5 per cent significance level using t-tests.FindingsVisits to emergency departments were reduced by 1.86; unplanned emergency admissions were reduced by 1.28 and planned elective admissions were raised by 0.22 admissions per annum. The reduction in visits to the emergency department was significant (p = 0.009) and the reduction in emergency admissions was significant (p = 0.015). The change in elective admissions was not significant (p = 0.855). The Okay to Stay plan is effective in reducing visits to the emergency department and unplanned hospital admissions in people with long-term conditions. This is a positive step to supporting vulnerable and complex patients who are cared for at home, and facilitates the recognition by the individual of the possibility to stay at home with the support of health professionals. There are potential cost benefits to the investment of initiating an Okay to Stay plan through the avoidance of visits to the emergency department and non-elective admissions to hospital. PMID- 30428938 TI - Pure fruit juice and fruit consumption and the risk of cardiovascular diseases: The EPIC-NL Study. PMID- 30428935 TI - Non-invasive ventilation for the management of children with bronchiolitis (NOVEMBR): a feasibility study and core outcome set development protocol. AB - BACKGROUND: Bronchiolitis is an acute lower respiratory infection which predominantly affects young children. Treatment for bronchiolitis is limited to supportive therapy. Nasal oxygen therapy is part of routine care, and delivery now incorporates varying levels of non-invasive continuous positive airway pressure and/or high-flow nasal cannula oxygen therapy. Despite wide clinical use, there remains a lack of evidence on the comparative effectiveness and safety of these interventions. Furthermore, research in this field is hampered by the use of multiple outcome measures in current clinical trials. METHODS/DESIGN: This mixed methods study includes a systematic review of outcome measures, telephone interviews with parents, focus group workshops and a Delphi survey with healthcare professionals and parents. These methods will be used to identify and prioritise outcomes for inclusion in a core outcome set and to explore issues pertinent to the design of a future randomised controlled trial comparing different modes of oxygen therapy for bronchiolitis. UK hospitals will also be contacted and asked to complete a survey to provide an overview of current practice to enable assessment of capability and capacity to run a future clinical trial. DISCUSSION: This study will facilitate the design of a future clinical trial of non-invasive ventilation in children with bronchiolitis which is acceptable to important stakeholders. Furthermore, core outcome set development will improve standardisation, measurement and reporting of clinically important outcomes in bronchiolitis. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN75766048. Registered on 18 December 2017. This study was retrospectively registered in the ISRCTN Registry and on the Core Outcome Measures in Effectiveness Trials (COMET) Initiative database (15 September 2017). PMID- 30428939 TI - Dietary assessment toolkits: an overview. AB - OBJECTIVE: A wide variety of methods are available to assess dietary intake, each one with different strengths and weaknesses. Researchers face multiple challenges when diet and nutrition need to be accurately assessed, particularly in the selection of the most appropriate dietary assessment method for their study. The goal of the current collaborative work is to present a collection of available resources for dietary assessment implementation.Design/Setting/ParticipantsAs a follow-up to the 9th International Conference on Diet and Physical Activity Methods held in 2015, developers of dietary assessment toolkits agreed to collaborate in the preparation of the present paper, which provides an overview of each toolkit. The toolkits presented include: the Diet, Anthropometry and Physical Activity Measurement Toolkit (DAPA; UK); the National Cancer Institute's (NCI) Dietary Assessment Primer (USA); the Nutritools website (UK); the Australasian Child and Adolescent Obesity Research Network (ACAORN) method selector (Australia); and the Danone Dietary Assessment Toolkit (DanoneDAT; France). An at-a-glance summary of features and comparison of the toolkits is provided. RESULTS: The present review contains general background on dietary assessment, along with a summary of each of the included toolkits, a feature comparison table and direct links to each toolkit, all of which are freely available online. CONCLUSIONS: This overview of dietary assessment toolkits provides comprehensive information to aid users in the selection and implementation of the most appropriate dietary assessment method, or combination of methods, with the goal of collecting the highest-quality dietary data possible. PMID- 30428940 TI - A 25-year dynamic ecological analysis of psychiatric hospital admissions and prison committals: Penrose's hypothesis updated. AB - : AimsThere is renewed interest in the inverse association between psychiatric hospital and prison places, with reciprocal time trends shown in more than one country. We hypothesised that the numbers of admissions to psychiatric hospitals and committals to prisons in Ireland would also correlate inversely over time (i.e. dynamic measures of admission and committal rather than static, cross sectional numbers of places). METHOD: Publicly available activity statistics for psychiatric hospitals and prisons in Ireland were collated from 1986 to 2010. RESULTS: There was a reciprocal association between psychiatric admissions and prison committals (Pearson r=-0.788, p<0.001), an increase of 91 prison committals for every 100 psychiatric hospital admissions foregone. CONCLUSION: Penrose's hypothesis applies to admissions to psychiatric hospitals and prisons in Ireland over time (dynamic measures), just as it does to the numbers of places in psychiatric hospitals and prisons in Ireland and elsewhere (static, cross sectional measures). Although no causal connection can be definitively established yet, mentally disordered prisoners are usually known to community mental health services. Psychiatric services for prisons and the community should be linked to ensure that the needs of those currently accessing care through prisons can also be met in the community. PMID- 30428941 TI - Morphometrical and molecular evidence suggests cryptic diversity among hookworms (Nematoda: Uncinaria) that parasitize pinnipeds from the south-eastern Pacific coasts. AB - Hookworms of the genus Uncinaria parasitize pinniped pups in various locations worldwide. Four species have been described, two of which parasitize pinniped pups in the southern hemisphere: Uncinaria hamiltoni parasitizes Otaria flavescens and Arctocephalus australis from the South American coast, and Uncinaria sanguinis parasitizes Neophoca cinerea from the Australian coast. However, their geographical ranges and host specificity are unknown. Uncinaria spp. are morphologically similar, but molecular analyses have allowed the recognition of new species in the genus Uncinaria. We used nuclear genetic markers (internal transcribed spacer (ITS) and large subunit (LSU) rDNA) and a mitochondrial genetic marker (cytochrome c oxidase subunit I (COI)) to evaluate the phylogenetic relationships of Uncinaria spp. parasitizing A. australis and O. flavescens from South American coasts (Atlantic and Pacific coasts). We compared our sequences with published Uncinaria sequences. A Generalized Mixed Yule Coalescent (GMYC) analysis was also used to delimit species, and principal component analysis was used to compare morphometry among Uncinaria specimens. Parasites were sampled from A. australis from Peru (12 degrees S), southern Chile (42 degrees S), and the Uruguayan coast, and from O. flavescens from northern Chile (24 degrees S) and the Uruguayan coast. Morphometric differences were observed between Uncinaria specimens from both South American coasts and between Uncinaria specimens from A. australis in Peru and southern Chile. Phylogenetic and GMYC analyses suggest that south-eastern Pacific otariid species harbour U. hamiltoni and an undescribed putative species of Uncinaria. However, more samples from A. australis and O. flavescens are necessary to understand the phylogenetic patterns of Uncinaria spp. across the South Pacific. PMID- 30428942 TI - Human rabies control in Lebanon: a call for action. AB - The status of rabies as a neglected disease has made its eradication rather challenging in different parts of the world despite the availability of a successful vaccine. Lebanon, in particular, is a country endemic to the disease with several cases of rabies deaths reported over the past 30 years. The risk of rabies, however, has taken a new turn over the past few years in Lebanon with two emerging situations that have made the control of the disease rather challenging: the neighbouring Syrian war and the local garbage crisis. Both of these milestone events might have contributed to an increase in the number of disease vectors as well as individuals at risk, thus nourishing the cycle of disease transmission. In this observational study, the effect of these two events are investigated, with an update on the status of this preventable, yet often neglected, disease in the country. Both events were found to be concomitant with a notable increase in the number of dog bites and thus possible rabies exposure. Current regulations are explored through interviews with veterinarians, and custom recommendations, ranging from policies to control dog populations to awareness campaigns in high risk individuals, are then proposed to help control the disease. PMID- 30428943 TI - Evaluation of Health Care Services Provided in Political Public Meetings in Turkey: A Forgotten Detail in Politics. AB - BACKGROUND: Political parties in Turkey execute political public meetings (PPMs) during their election campaign for members of the parliament (MoP). A great number of people attend these meetings. No guidelines exist regarding preparation and organization of health care services provided during these meetings. Furthermore, there is no study evaluating health care problems encountered in previous PPMs. OBJECTIVE: Political parties arranged PPMs in 2015 during the election campaign for general election of MoP. The present study aimed to investigate the context of health care services, the distribution of assigned health staff, as well as the number and the symptoms of patients admitted in health care tents in these PPMs. METHODS: Two general elections for MoP were done in Turkey on June 7, 2015 and November 1, 2015. Health care services were provided by the City Emergency Medical Services Department (CEMSD) in the cities. Demographic characteristics, symptoms, comorbid conditions, treatment, discharge, and hospital transfer of the patients were obtained from patient medical registration records. Information about the distribution and the number of the assigned staff was received from local CEMSDs. The impact of variables such as the number of attendees, heat index, humidity, and the day of the week on the number of patients and the patient presentation rate (PPR) were analyzed. RESULTS: A total of 97 PPMs were analyzed. The number of total attendees was 5,265,450 people. The number of patients seeking medical help was 1,991. The PPR was 0.5 (0.23-0.91) patients per 1,000 attendees. Mean age of the patients was 40 (SD=19) years old while 1,174 (58.9%) of the patients were female. A total of 1,579 patients were treated in the tents and returned to the PPM following treatment. Two-hundred and three patients were transferred to a hospital by ambulance. Transfer-to-hospital ratio (TTHR) was 0.05 (0.0-0.13) patients per 1,000 attendees. None of the patients suffered sudden cardiac death (SCD) or cardiac arrest. Medical conditions were the main cause for admission. The most common symptoms were dizziness, low blood pressure, fatigue, and hypertension, respectively. The most commonly used medical agents included pain killers and myorelaxants. The number of attendees, heat index, and weekend days were positively correlated with the number of the patients. CONCLUSION: The majority of medical conditions encountered in PPMs are easily treatable in health care tents settled in the meeting area. The number of attendees, heat index, and weekend days are factors associated with the number of patients.Ceyhan MA, Demir GG, Guler GB. Evaluation of health care services provided in political public meetings in Turkey: a forgotten detail in politics. PMID- 30428944 TI - Diarrhoea, enteric pathogen detection and nutritional indicators among controls in the Global Enteric Multicenter Study, Kenya site: an opportunity to understand reference populations in case-control studies of diarrhoea. AB - Given the challenges in accurately identifying unexposed controls in case-control studies of diarrhoea, we examined diarrhoea incidence, subclinical enteric infections and growth stunting within a reference population in the Global Enteric Multicenter Study, Kenya site. Within 'control' children (0-59 months old without diarrhoea in the 7 days before enrolment, n = 2384), we examined surveys at enrolment and 60-day follow-up, stool at enrolment and a 14-day post-enrolment memory aid for diarrhoea incidence. At enrolment, 19% of controls had ?1 enteric pathogen associated with moderate-to-severe diarrhoea ('MSD pathogens') in stool; following enrolment, many reported diarrhoea (27% in 7 days, 39% in 14 days). Controls with and without reported diarrhoea had similar carriage of MSD pathogens at enrolment; however, controls reporting diarrhoea were more likely to report visiting a health facility for diarrhoea (27% vs. 7%) or fever (23% vs. 16%) at follow-up than controls without diarrhoea. Odds of stunting differed by both MSD and 'any' (including non-MSD pathogens) enteric pathogen carriage, but not diarrhoea, suggesting control classification may warrant modification when assessing long-term outcomes. High diarrhoea incidence following enrolment and prevalent carriage of enteric pathogens have implications for sequelae associated with subclinical enteric infections and for design and interpretation of case control studies examining diarrhoea. PMID- 30428945 TI - Gastropod parasitic nematodes (Phasmarhabditis sp.) are attracted to hyaluronic acid in snail mucus by cGMP signalling. AB - Phasmarhabditis hermaphrodita is a parasitic nematode of terrestrial gastropods that has been formulated into a biological control agent for farmers and gardeners to kill slugs and snails. In order to locate slugs it is attracted to mucus, faeces and volatile cues; however, there is no information about whether these nematodes are attracted to snail cues. It is also unknown how wild isolates of P. hermaphrodita or different Phasmarhabditis species behave when exposed to gastropod cues. Therefore, we investigated whether P. hermaphrodita (commercial and wild isolated strains), P. neopapillosa and P. californica were attracted to mucus from several common snail species (Cepaea nemoralis, Cepaea hortensis, Arianta arbustorum and Cornu aspersum). We also examined whether snails (C. aspersum) collected from different locations around the UK differed in their attractiveness to wild isolates of P. hermaphrodita. Furthermore, we also investigated what properties of snail mucus the nematodes were attracted to, including hyaluronic acid and metal salts (FeSO4, ZnSO4, CuSO4 and MgSO4). We found that the commercial strain of P. hermaphrodita responded poorly to snail mucus compared to wild isolated strains, and C. aspersum collected from different parts of the UK differed in their attractiveness to the nematodes. We found that Phasmarhabditis nematodes were weakly attracted to all metals tested but were strongly attracted to hyaluronic acid. In a final experiment we also showed that pharmacological manipulation of cyclic guanosine monophosphate (cGMP) increased chemoattraction to snail mucus, suggesting that the protein kinase EGL-4 may be responsible for Phasmarhabditis sp. chemoattraction. PMID- 30428946 TI - A new genus and three new species of Anthocephaliidae (Cestoda, Rhinebothriidea) from the round fantail stingray, Taeniurops grabata (Chondrichthyes, Dasyatidae) from the Mediterranean Sea and Atlantic Ocean. AB - The spiral intestines of a total of 16 round fantail stingrays Taeniurops grabata from the Mediterranean Sea off Tunisia were examined for cestodes. A new genus is erected in the Anthocephaliidae (Rhinebothridea) as Alveobothrium gen. n., with Alveobothrium grabatum sp. n. as its type species; the new genus differs from the other genera in the order in that its members possess bothridia with an apical sucker, marginal loculi and multiple staggered rows of facial loculi. Alveobothrium zarzisense sp. n. is also described. The species differ in the number of marginal loculi and in proglotid anatomy. Another anthocephaliid belonging to the genus Anthocephalum is also described from T. grabata. Anthocephalum jeancadenati sp. n. is most similar to A. alicae and A. michaeli, but differs in size of terminal proglottid and number of proglottids. All these new species are also found in formalin-preserved cestodes from T. grabata collected at Goree Island (Senegal) between 1946 and 1954 by the French ichthyologist J. Cadenat and conserved in the personal collection of the late L. Euzet. The presence of the same rhinebothriideans species parasitizing T. grabata in both the Mediterranean (Tunisia) and the eastern Atlantic (Senegal) is discussed. PMID- 30428947 TI - The role of domestic reservoirs in domestically acquired Salmonella infections in Norway: epidemiology of salmonellosis, 2000-2015, and results of a national prospective case-control study, 2010-2012. AB - In Norway, incidence of sporadic domestically acquired salmonellosis is low, and most frequently due to Salmonalla Typhimurium. We investigated the risk factors for sporadic Salmonella infections in Norway to improve control and prevention measures. Surveillance data for all Salmonella infections from 2000 to 2015 were analysed for seasonality and proportion associated with domestic reservoirs, hedgehogs and wild birds. A prospective case-control study was conducted from 2010 to 2012 by recruiting cases from the Norwegian Surveillance System for Communicable Diseases and controls from the Norwegian Population Registry (389 cases and 1500 controls). Univariable analyses using logistic regression were conducted and a multivariable model was developed using regularised/penalised logistic regression. In univariable analysis, eating snow, dirt, sand or playing in a sandbox (aOR 4.14; CI 2.15-7.97) was associated with salmonellosis. This was also the only exposure significantly associated with illness in the multivariable model. Since 2004, 34.2% (n = 354) of S. Typhimuirum cases had an MLVA profile linked to a domestic reservoir. A seasonal trend with a peak in August for all Salmonella types and in February for S. Typhimurium was observed. Indirect exposure to domestic reservoirs remains a source of salmonellosis in Norway, particularly for children. Information to the public about avoiding environmental exposure should be strengthened and initiatives to combat salmonellosis in the food chain should be reinforced. PMID- 30428948 TI - Characteristics of boli formed by dairy cows upon ingestion of fresh ryegrass, lucerne or chicory. AB - This study examined the comminution of fresh herbage, subsequent nutrient release, and the characteristics of swallowed boli from three physically and chemically contrasting forages during ingestive mastication by dairy cows. The extent and pattern of nutrient release will determine their availability to rumen microflora, and potentially influence their efficiency of use. The forages evaluated were perennial ryegrass (ryegrass, Lolium perenne L., cv Alto AR37), lucerne (Medicago sativa L., cv Torlesse) and chicory (Cichorium intybus L., cv Choice). Experimental design was a 3*3 cross-over with three forages and three consecutive 1-day measurement periods, conducted twice. Six non-lactating, pregnant, multiparous Holstein-Friesian*Jersey cows (Bos taurus) were used, with the first cross-over applied to three mature (10.1+/-0.61 years old; BW 631+/-64 kg) cows, and the second to three young (4.8+/-0.02 years; BW 505+/-19 kg) cows. Fresh cut forage was offered to the cows following partial rumen evacuation. Swallowed boli were collected directly at the cardia at the commencement, middle and end of the first feeding bout of the first meal of the day. Forage species did not affect the fresh weight of ingested boli (mean 169 g, P=0.605) but the proportion of saliva in boli varied between forage. Boli of chicory contained the greatest amount of herbage material and least amount of saliva, whereas ryegrass boli were the opposite. Boli fresh weight tended to increase as time in the meal progressed, but the age of the cow was not shown to affect any boli characteristics or nutrient release. Particle size reduction was affected by forage, with 31%, 38% and 35% of chicory, lucerne and ryegrass herbage reduced to <2 mm. There was little evidence of relationship between comminution and any physical or chemical characteristic of the forage, except in ryegrass where extent of comminution was moderately correlated with herbage strength. Proportional release of herbage soluble carbohydrate exceeded that of N during mastication. Differences in loss of N were moderately correlated with the amount of N in the herbage (R 2=0.53) but herbage comminution was not strongly correlated with release of either N or carbohydrate. These findings illustrate the complex animal*forage interactions that occur during mastication, and that it is not possible to infer nutrient loss from herbage based on herbage characteristics as the driver for this differ between species. PMID- 30428949 TI - Early post-conception maternal cortisol, children's HPAA activity and DNA methylation profiles. AB - The hypothalamic-pituitary-adrenal axis (HPAA) plays a critical role in the functioning of all other biological systems. Thus, studying how the environment may influence its ontogeny is paramount to understanding developmental origins of health and disease. The early post-conceptional (EPC) period could be particularly important for the HPAA as the effects of exposures on organisms' first cells can be transmitted through all cell lineages. We evaluate putative relationships between EPC maternal cortisol levels, a marker of physiologic stress, and their children's pre-pubertal HPAA activity (n=22 dyads). Maternal first-morning urinary (FMU) cortisol, collected every-other-day during the first 8 weeks post-conception, was associated with children's FMU cortisol collected daily around the start of the school year, a non-experimental challenge, as well as salivary cortisol responses to an experimental challenge (all Ps5% change in children's buccal epithelial cells' DNA methylation for 867 sites, while children's HPAA activity was associated with five CpG sites. Yet, no CpG sites were related to both, EPC cortisol and children's HPAA activity. Thus, these epigenetic modifications did not statistically mediate the observed physiological links. Larger, prospective peri-conceptional cohort studies including frequent bio-specimen collection from mothers and children will be required to replicate our analyses and, if our results are confirmed, identify biological mechanisms mediating the statistical links observed between maternal EPC cortisol and children's HPAA activity. PMID- 30428950 TI - Does early maternal responsiveness buffer prenatal tobacco exposure effects on young children's behavioral disinhibition? AB - Children with prenatal tobacco exposure (PTE) exhibit early self-regulatory impairments, reflecting a life-course persistent propensity toward behavioral disinhibition. Previously, we demonstrated the protective role of parental responsiveness for reducing the risk of exposure-related disruptive behavior in adolescence. Here, we expanded this line of inquiry, examining whether responsiveness moderates the relation of PTE to a broader set of behavioral disinhibition features in early childhood and testing alternative diathesis stress versus differential susceptibility explanatory models. PTE was assessed prospectively using interviews and bioassays in the Midwestern Infant Development Study (MIDS). Mother-child dyads (N = 276) were re-assessed at approximately 5 years of age in a preschool follow-up. We quantified maternal responsiveness and child behavioral disinhibition using a combination of directly observed activities in the lab and developmentally sensitive questionnaires. Results supported a diathesis-stress pattern. Children with PTE and less responsive mothers showed increased disruptive behavior and lower effortful control compared with children without PTE. In contrast, exposed children with more responsive mothers had self-regulatory profiles similar to their non-exposed peers. We did not observe sex differences. Findings provide greater specification of the protective role of maternal responsiveness for self-regulation in children with PTE and help clarify mechanisms that may underscore trajectories of exposure related behavioral disinhibition. PMID- 30428951 TI - Patient Predictors of Surgical Candidacy in Elective Spine Disorders. AB - BACKGROUND: The expansion of age-related degenerative spine pathologies has led to increased referrals to spine surgeons. However, the majority of patients referred for surgical consultation do not need surgery, leading to inefficient use of healthcare resources. This study aims to elucidate preoperative patient variables that are predictive of patients being offered spine surgery. METHODS: We conducted an observational cohort study on patients referred to our institution between May 2013 and January 2015. Patients completed a detailed preclinic questionnaire on items such as history of presenting illness, quality of-life questionnaires, and past medical history. The primary end point was whether surgery was offered. A multivariable logistical regression using the random forest method was used to determine the odds of being offered surgery based on preoperative patient variables. RESULTS: An analysis of 1194 patients found that preoperative patient variables that reduced the odds of surgery being offered include mild pain (odds ratio [OR] 0.37, p=0.008), normal walking distance (OR 0.51, p=0.007), and normal sitting tolerance (OR 0.58, p=0.01). Factors that increased the odds of surgery include radiculopathy (OR 2.0, p=0.001), patient's belief that they should have surgery (OR 1.9, p=0.003), walking distance <50 ft (OR 1.9, p=0.01), relief of symptoms when bending forward (OR 1.7, p=0.008) and sitting (OR 1.6, p=0.009), works more slowly (OR 1.6 p=0.01), aggravation of symptoms by Valsalva (OR 1.4, p=0.03), and pain affecting sitting/standing (OR 1.1, p=0.001). CONCLUSIONS: We identified 11 preoperative variables that were predictive of whether patients were offered surgery, which are important factors to consider when screening outpatient spine referrals. PMID- 30428952 TI - Age, Sex, and Genetic and Environmental Effects on Unintentional Injuries in Young and Adult Twins. AB - The aim of this study was to examine the effects of genetic and environment influences and sex on injury involvement using two sets of Finnish twin data. The younger participants were 955 twins born between 1983 and 1987, aged 20 to 24 years. The older participants were 12,428 twins born between 1930 and 1957, aged 33 to 60 years. Within-twin correlations in monozygotic and dizygotic twins suggested that genetic effects play no role in injury involvement among young twins, but do have some effect at older ages. The results indicated that environmental factors have greater importance in injury involvement than genetic factors in the younger twin data set (FT12), whereas in a middle-aged (33-60 years) twin data set, genetic effects explained about quarter of the variance in injury involvement. Sex was a strong contributing factor, with males being generally more prone to injuries than females. PMID- 30428953 TI - Does parental migration have any impact on nutritional disorders among left behind children in Bangladesh? AB - OBJECTIVE: Rates of migration have increased substantially in recent years and so has the number of left-behind children (LBC). We investigated the impact of parental migration on nutritional disorders of LBC in Bangladesh. DESIGN: We analysed data from the nationally representative cross-sectional Multiple Indicator Cluster Survey 2012-2013. Child stunting, wasting and underweight were used as measures of nutritional disorders. Descriptive statistics were used to describe characteristics of the respondents and to compare nutritional outcomes based on status of parental migration. Multivariate logistic regression models were used to examine the associations between parental migration and child nutritional disorders. SETTING: Bangladesh.ParticipantsData of 23 402 children (aged <5 years), their parents and households. RESULTS: In the unadjusted models, parental migration was found significantly protective for stunting, wasting and underweight - both separately and jointly. After potential confounders were controlled for, no difference was found between LBC and non-LBC in any of these three nutritional outcome measures. Household wealth status and maternal educational status were found to significantly influence the nutritional development of the children. CONCLUSIONS: At the population level there is no negative impact of parental migration on stunting, wasting and underweight of LBC in Bangladesh. Remittance from parental migration might enhance affordability of better foods, health care and supplies for a cleaner environment. This affordability is crucial for the poorest section of the society. PMID- 30428954 TI - Parasitic infections in relation to practices and knowledge in a rural village in Northern Thailand with emphasis on fish-borne trematode infection. AB - The present study integrates several aspects of a parasitological survey in a rural community village combining community knowledge of parasites, their potential transmission routes and health risk factors. A rural community located in Northern Thailand was surveyed for intestinal parasites, and an overall prevalence of 45.2% for helminths and 4.8% for protozoan infections was identified. Socio-demographic characteristics, customs and perceptions were compiled using individual questionnaires and interviews for participants surveyed for parasitic screening. The results allowed us to determine the knowledge and perception of local people concerning helminthic infection and transmission. Despite the fact that the participants in this community were aware of parasitic transmission routes, their widespread custom of eating raw fish and meat render the reduction of helminthiasis difficult. A detailed study on the infection of fish-borne parasitic trematodes, the most prevalent helminth, allowed us to determine that the distance from a given household to the river is a determinant of infection intensity. Health education activities organised in the local community resulted in a change in perception of risks associated with parasite transmission. PMID- 30428955 TI - 'Tailception': using neural networks for assessing tail lesions on pictures of pig carcasses. AB - Tail lesions caused by tail biting are a widespread welfare issue in pig husbandry. Determining their prevalence currently involves labour intensive, subjective scoring methods. Increased societal interest in tail lesions requires fast, reliable and cheap systems for assessing tail status. In the present study, we aimed to test the reliability of neural networks for assessing tail pictures from carcasses against trained human observers. Three trained observers scored tail lesions from automatically recorded pictures of 13 124 pigs. Nearly all pigs had been tail docked. Tail lesions were classified using a 4-point score (0=no lesion, to 3=severe lesion). In addition, total tail loss was recorded. Agreement between observers was tested prior and during the assessment in a total of seven inter-observer tests with 80 pictures each. We calculated agreement between observer pairs as exact agreement (%) and prevalence-adjusted bias-adjusted kappa (PABAK; value 1=optimal agreement). Out of the 13 124 scored pictures, we used 80% for training and 20% for validating our neural networks. As the position of the tail in the pictures varied (high, low, left, right), we first trained a part detection network to find the tail in the picture and select a rectangular part of the picture which includes the tail. We then trained a classification network to categorise tail lesion severity using pictures scored by human observers whereby the classification network only analysed the selected picture parts. Median exact agreement between the three observers was 80% for tail lesions and 94% for tail loss. Median PABAK for tail lesions and loss were 0.75 and 0.87, respectively. The agreement between classification by the neural network and human observers was 74% for tail lesions and 95% for tail loss. In other words, the agreement between the networks and human observers were very similar to the agreement between human observers. The main reason for disagreement between observers and thereby higher variation in network training material were picture quality issues. Therefore, we expect even better results for neural network application to tail lesions if training is based on high quality pictures. Very reliable and repeatable tail lesion assessment from pictures would allow automated tail classification of all pigs slaughtered, which is something that some animal welfare labels would like to do. PMID- 30428957 TI - A cross-sectional, population-based survey of U.S. adults with symptoms of chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is believed to create a substantial population-level disease burden in the UnitedStates due to its high prevalence and significant disease morbidity, but many studies of CRS epidemiology are based onadministrative or historical record sources rather than primary population sources. OBJECTIVE: To characterize CRS symptoms, burden, and patient characteristics by using a primary U.S. population- basedrepresentative sample. METHODS: A demographically and geographically representative sample of 10,336 U.S. adults recruited from a general panelof 4.3 million were obtained by using three-stage randomization. Data collected included a range of respondent-reported CRSsymptoms, symptom impact and severity, symptom duration, and treatment. RESULTS: Approximately 11.5% of the respondents (n = 1189) reported defining symptom and duration criteria for CRS. Aprevious diagnosis of nasal polyps was reported by 10% of this population. The remaining respondents reported severe (7.3%)or moderate (3.1%) symptom severity. The most frequently reported defining symptoms were nasal congestion and/orobstruction (94-97%) and drainage (89-92%). CRS participants reported a high average degree of symptom burden (e.g., ona 0-10 scale, 8.2 for CRS with nasal polyps, 8.4 for CRS without nasal polyps with severe symptoms, and 6.4 for CRS withoutnasal polyps with moderate symptoms). The participants with CRS reported high health-care use for CRS, adverse effects of CRS symptoms on multiple areas of daily life, and high dissatisfaction with currently available treatments. CONCLUSION: More than 10% of the general U.S. adult population have CRS symptoms. Most report severe symptoms, lack of satisfaction with current treatment options, and a substantial adverse impact on daily functioning. PMID- 30428956 TI - Neuroanatomical features and its usefulness in classification of patients with PANDAS. AB - OBJECTIVE: An obsessive-compulsive disorder (OCD) subtype has been associated with streptococcal infections and is called pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS). The neuroanatomical characterization of subjects with this disorder is crucial for the better understanding of its pathophysiology; also, evaluation of these features as classifiers between patients and controls is relevant to determine potential biomarkers and useful in clinical diagnosis. This was the first multivariate pattern analysis (MVPA) study on an early-onset OCD subtype. METHODS: Fourteen pediatric patients with PANDAS were paired with 14 healthy subjects and were scanned to obtain structural magnetic resonance images (MRI). We identified neuroanatomical differences between subjects with PANDAS and healthy controls using voxel-based morphometry, diffusion tensor imaging (DTI), and surface analysis. We investigated the usefulness of these neuroanatomical differences to classify patients with PANDAS using MVPA. RESULTS: The pattern for the gray and white matter was significantly different between subjects with PANDAS and controls. Alterations emerged in the cortex, subcortex, and cerebellum. There were no significant group differences in DTI measures (fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity) or cortical features (thickness, sulci, volume, curvature, and gyrification). The overall accuracy of 75% was achieved using the gray matter features to classify patients with PANDAS and healthy controls. CONCLUSION: The results of this integrative study allow a better understanding of the neural substrates in this OCD subtype, suggesting that the anatomical gray matter characteristics could have an immune origin that might be helpful in patient classification. PMID- 30428958 TI - Oral Surgery: A Primary Concern. PMID- 30428959 TI - Dean's Update. PMID- 30428960 TI - A Round-Up of the Latest Updates from Your Faculty. PMID- 30428961 TI - Primary Care Oral Surgery. PMID- 30428962 TI - Oral Surgery Facts. PMID- 30428963 TI - Dento-Legal Implications in Primary Care Oral Surgery. AB - The purpose and intention of this article is to help provide an overview and understanding of the dento-legal issues which can arise when treating patients who are undergoing oral surgery procedures in primary care. The focus will be on the initial stages of assessment, diagnosis and treatment planning, which are essential factors required to appropriately fulfil the requirement of obtaining valid consent. The importance of getting consent right has been highlighted in the context of the Montgomery case and which is further supported by the requirement and importance of accurate and full record keeping in this regard. Examples and appropriate consideration of clinical areas will be discussed with the intention of demonstrating the key points. PMID- 30428964 TI - The Use of Panoramic Radiography Prior to Oral Surgery. PMID- 30428965 TI - An Evaluation of a Practice-Based Minor Oral Surgery Service. AB - AIM To report the findings of a service evaluation of an NHS practice-based minor oral surgery service. METHOD A service evaluation including a retrospective analysis of activity and outcome data and assessment of patient and practitioner satisfaction. RESULTS 623 appointments were arranged, with a mean waiting time of 43 days. Treatment provided included: surgical removal of third molars and non third molars, surgical endodontics and other surgical and oral medicine cases (29.7%, 44.1%, 3.0% and 23.4% of cases respectively). Antibiotics were prescribed at 16.1% of treatment appointments and 1.9% required appointments for post operative complications. All participants reported overall satisfaction with their care and strongly agreed/agreed with positive attitudinal statements about the oral surgeon's communication/information giving, technical competence and understanding and acceptance; 77.5% were seen on time and none were seen more than 15 minutes late; 87.5% felt the standard of the service was better than expected than at a hospital and none felt it was worse. Over 80 of practitioners agreed that waiting times were better than expected at a hospital, urgent problems were seen quickly and the referral process was easy and understandable. All practitioners strongly agreed/agreed they that they were happy with the service provided. CONCLUSIONS A range of minor oral surgery procedures can be provided with low complication rates, acceptable waiting times and accessibility, and high patient and referring practitioner satisfaction from a practice-based specialist oral surgery service. PMID- 30428966 TI - An Update of Gorlin-Goltz Syndrome. AB - Gorlin-Goltz syndrome encompasses a variety of clinical signs and symptoms including important oral manifestations which general dental practitioners should be aware of. In light of the risk of malignancy it is important to be aware of this syndrome and recognise the need for early referral for multidisciplinary management. This paper aims to discuss Gorlin-Goltz syndrome, the pathophysiology of the condition and address the wide range of clinical manifestations. The author will pay particular attention to the oral manifestations of the condition and the management of such anomalies. PMID- 30428967 TI - The Importance of Dental Screening Prior to Commencing Anti-Resorptive Therapy for Treatment of Cancer: A Case Report and Discussion. AB - Osteonecrosis of the jaws (ONJ) can be a serious complication of radiation and anti-resorptive therapies. At present, patients due to undergo radiotherapy are required to have a dental assessment to treat current or anticipated dental disease prior to commencing treatment. However no agreed guidelines are in place for those due to start anti-resorptive therapy for cancer. More patients are now being treated with various drug therapies and new combinations of drugs with unknown long-term effects, with many patients now surviving their disease for longer periods of time. It is important to increase awareness among patients and dental professionals of the possibility of them developing medication-related osteonecrosis of the jaw (MRONJ) and to put in place effective preventative measures to help to stop such complications developing. CASE REPORT A 52-year-old patient with a complex medical history, including metastatic breast cancer, presented with generalised oral pain and tooth mobility (see Figure 1). The patient developed extensive stage III MRONJ following concurrent use of multiple anti-resorptive therapies for treatment of secondary bone disease. Dental treatment consisted of provision of antibiotics, hydrogen peroxide and chlorhexidine mouthwashes prior to the extraction of symptomatic teeth and the multiple bony sequestra. CONCLUSION Once established, stage III MRONJ can be challenging to manage for both the dental team and for the patient. This case demonstrates the importance of a comprehensive dental examination and need for preventative dental treatment prior to starting anti-resorptive therapy in order to prevent such instances. PMID- 30428968 TI - Medical Emergencies: Risk Assessment and Management. AB - Dental practitioners need to have knowledge of the risk assessment, diagnosis and management of medical emergencies. This paper deals with risk assessment and basic management principles, applicable to all emergencies. More specific aspects of medical emergency management are also discussed. PMID- 30428971 TI - Event Report. PMID- 30428969 TI - Prevention and Management of Post-Operative Pain in Oral Surgery. AB - Post-operative pain is an area of oral surgery that concerns both patients and practitioners. Adequate management of pain and anxiety in oral surgery is an essential component of any oral surgery service. In this paper, we explore the science behind pain and the drugs available to manage post-operative pain. Discussion is focussed on the analgesics available on the dental practitioners' formulary and the evidence base supporting their use. We explore the beneficial and adverse effects of these analgesics. We also discuss recent controversies relating to non-steroidal anti-inflammatory drugs and opioids. Based on the evidence available, we have developed a protocol to assist practitioners when advising and prescribing analgesics for their patients. PMID- 30428973 TI - Paramedic involvement in health education within metropolitan, rural and remote Australia: a narrative review of the literature. AB - Objective A growing body of research indicates that paramedics may have a greater role to play in health care service provision, beyond the traditional models of emergency health care. The aim of this study was to identify and synthesise the literature pertaining to the role of paramedic-initiated health education within Australia, with specific consideration of metropolitan, rural and remote contexts.Methods A literature review was undertaken using the Ovid Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE and Scopus databases. The search time frame was limited from January 2007 to November 2017. The search was performed using key paramedic search terms in combination with keywords such as health education, rural, metropolitan, remote and Australia. Reference lists from relevant papers were also reviewed.Results Fourteen articles met the inclusion criteria for synthesis. Health education in the Australian paramedic context relates largely to expanded-scope paramedics, health promotion and the role of paramedics as key members of local communities. There were no studies specifically related to the paramedic role in health education, although many papers referred to health education as one of many roles paramedics engage in today.Conclusion This review highlights a broadening of paramedicine's traditional scope of practice, and an indication of how vital paramedics could be to local communities, particularly in rural and remote areas. An expanded role may help address health workforce sustainability problems in areas where health care provision is challenged by geographical constraints and low workforce numbers.What is known about the topic? A broadening of paramedicine's traditional scope of practice has been linked to improvements in health workforce sustainability problems in areas where health care provision is challenged by geographical constraints and low workforce numbers, such as rural and remote Australia. Health education, as well as health promotion, primary health care and chronic disease management, have been proposed as potential activities that paramedics could be well placed to participate in, contributing to the health and well-being of local communities.What does this paper add? This paper identifies and synthesises literature focusing on paramedic-initiated health education in the Australian context, assessing the current health education role of paramedics in metropolitan, rural and remote areas. It provides an understanding of different geographical areas that may benefit from expanded scope prehospital practice, indicating that the involvement of paramedics in health education in Australia is significantly determined by their geographical place of work, reflecting the influence of the availability of healthcare resources on individual communities.What are the implications for practitioners? Today's paramedics fill broader roles than those encompassed within traditional models of prehospital care. Rural and remote communities facing increasing difficulty in obtaining health service provision appear to benefit strongly from the presence of expanded-scope paramedics trained in health promotion, primary injury prevention, chronic disease management and health education: this should be a consideration for medical and allied health practitioners in these areas. Australian paramedics are uniquely placed to 'fill the gaps' left by shortages of healthcare professionals in rural and remote areas of the country. PMID- 30428974 TI - Analysis of pancreatic beta cell specific CD4+ T cells reveals a predominance of proinsulin specific cells. AB - CD4+ T cell responses are thought to play a role in type 1 diabetes (T1D). However, detection and characterization of T cells that respond to beta cell epitopes in subjects with T1D has been limited by technical obstacles, including the inherently low frequencies in peripheral blood and variable responsiveness of individual subjects to single epitopes. We implemented a multicolor staining approach that allows direct ex vivo characterization of multiple CD4+ T cell specificities in a single sample. Here we demonstrate and apply that multicolor approach to directly measure the frequency and phenotype of beta cell specific CD4+ T cells in T1D patients and HLA matched controls. For this work we utilized five DR0401 restricted peptides from proinsulin, GAD65, IA-2, and IGRP, which were previously reported as disease relevant epitopes. Surprisingly, although responses to each of these peptides can be readily detected after in vitro expansion, our results indicated that only proinsulin specific T cells were consistently detectable at moderate frequencies in subjects with T1D. Characterization of beta cell specific CD4+ T cells revealed only modest differences between subjects with T1D and healthy controls. Subjects with T1D did have higher proportions of CD45RA negative epitope specific T cells than controls. In patients epitope specific T cells were often CXCR3 positive and a substantial proportion were CCR7 negative, suggesting a Th1-like effector phenotype. Finally, we demonstrated that our multicolor staining approach is compatible with class I multimer analysis, facilitating the characterization of self-reactive CD4+ and CD8+ T cells using a single sample. PMID- 30428975 TI - Past-in-the-Future. Peak detection improves targeted mass spectrometry imaging. AB - Mass spectrometry imaging is a valuable tool for visualizing the localization of drugs in tissues, a critical issue especially in cancer pharmacology where treatment failure may depend on poor drug distribution within the tumours. Proper preprocessing procedures are mandatory to obtain quantitative data of drug distribution in tumours, even at low intensity, through reliable ion peak identification and integration. We propose a simple preprocessing and quantification pipeline. This pipeline was designed starting from classical peak integration methods, developed when "microcomputers" became available for chromatography, now applied to MSI. This pre-processing approach is based on a novel method using the fixed mass difference between the analyte and its 5 d derivatives to set up a mass range gate. We demonstrate the use of this pipeline for the evaluating the distribution of the anticancer drug paclitaxel in tumour sections. The procedure takes advantage of a simple peak analysis and allows to quantify the drug concentration in each pixel with a limit of detection below 0.1 pmol mm-2 or 10 MUg g-1. Quantitative images of paclitaxel distribution in different tumour models were obtained and average paclitaxel concentrations were compared with HPLC measures in the same specimens, showing <20% difference. The scripts are developed in Python and available through GitHub, at github.com/FrancescaFalcetta/Imaging_of_drugs_distribution_and_quantifications.gi . PMID- 30428976 TI - Single-molecule catalytic hairpin assembly for rapid and direct quantification of circulating miRNA biomarkers. AB - The emergence of circulating miRNAs as potential biomarkers for cancer necessitates reliable approaches to detect miRNAs with high sensitivity and specificity. We disclose a highly sensitive method for rapid and direct quantification of circulating miRNA in serum by combining dynamic DNA circuit and single-molecule fluorescence detection. The product of DNA circuits based amplification is detected by total internal reflection fluorescence microscopy (TIRFM). The single-molecule counting allows the quantification of miRNA targets. Owing to the high sensitivity for fluorophore labeled nucleic acids of TIRFM, the products generated by 15 min amplification are sufficient for quantification. Meanwhile, the fast detection also addresses the problem of leakage because non target triggered DNA circuits is relatively slow. There miRNA biomarkers miR-141, miR-21, miR-16 were detected with remarkable sensitivity as detection limits of 0.017, 0.012, 0.006 fM, respectively. This approach was applied for the direct quantification of the circulating miRNAs in human serum. The results of 29 health samples, 18 prostate cancer samples, 23 breast cancer samples imply that miR-141 and miR-21 are up-regulated in the prostate cancer samples and the breast cancer samples, respectively, and as reference miR-16 shows no difference in health and patient samples. PMID- 30428977 TI - Exploitation of a photoelectrochemical sensing platform for catechol quantitative determination using BiPO4 nanocrystals/BiOI heterojunction. AB - A photoelectrochemical catechol sensor using BiPO4 nanocrystals/BiOI (BiPO4/BiOI) heterojunction is developed. BiPO4/BiOI heterojunction is fabricated via a simple one-step solvothermal method with KI and ionic liquid 1-octyl-3-methylimidazolium dihydrogen phosphate ([Omim]H2PO4). An enhanced photoelectrochemical separation efficiency is obtained due to the synergistic effect between the formation of BiPO4/BiOI heterojunction and shortening the transmission path of the electron to the surface caused by BiPO4 nanocrystals. Owing to the outstanding photoelectrochemical response of BiPO4/BiOI heterojunction to catechol, a photoelectrochemical sensor is constructed for monitoring catechol. The proposed sensor possesses reliable stability, anti-interference ability and a low detection limit with 2 ng mL-1. The linear range is from 6 to 1.20 * 104 ng mL-1. Notably, this work not only supplies a facile method for BiPO4 nanocrystals based binary heterojunction, but also helps to understand the relationship between BiPO4 nanocrystals and photoelectrochemical performance of binary heterojunction. Convincingly, this strategy can be extended to other BiPO4 nanocrystals based heterojunction and photoelectrochemical sensor platform associated with photoactive materials. PMID- 30428978 TI - Ultrasensitive ELISA for the detection of hCG based on assembled gold nanoparticles induced by functional polyamidoamine dendrimers. AB - Amplifying the signal of ELISA is important in the early disease diagnosis. Herein we report an ultrasensitive ELISA applying for the detection of hCG based on the assemble of AuNPs induced by functional PAMAM. The AuNP-PAMAM probe shows a competitive advantage sensitivity of 0.03 IU L-1 compared to traditional ELISA and mAb1-AuNP-HRP probe. The line range is ranged from 0.1 to 6.4 IU L-1. Moreover, the precision and reproducibility and specificity of AuNP-PAMAM probe are also eligible for the detection of hCG. The assembled AuNPs was firstly used in the signal enhancement in immunoassay. PMID- 30428979 TI - Facile synthesis of orange fluorescence carbon dots with excitation independent emission for pH sensing and cellular imaging. AB - High-efficient orange fluorescence nitrogen-doped carbon dots (N-CDs) were facilely prepared from P-phenylenediamine as a precursor via hydrothermal method. The as-prepared N-CDs with an average diameter of 3.65 nm displayed excitation independent emission at 590 nm. The N-CDs demonstrated a remarkable fluorescence enhancement behavior with the increase of pH. A sigmoidal curve was well fitted using BiDoseResp equation with pKa1 3.57 and pKa2 6.01, which can be ascribed to the unique surface properties of N-CDs. Two-segment linear ranges of 2.6-4.6 and 5.0-6.8 broaden the response range to pH of the orange-emission N-CDs to some extent. The confocal fluorescent microscopic images of SMMC7721 cells were performed successfully, which demonstrating that N-CDs possess exceptional cell membrane permeability and can implement as biosensing platform to monitor pH fluctuations in living cells. PMID- 30428980 TI - Direct sample injection from a syringe needle into a separation capillary. AB - An automatic micro-injector was developed for electrophoretic analysis of a microlitre amount of clinical samples, enabling injection of the sample from a Hamilton syringe. The outlet of the syringe needle is located directly opposite the inlet of the separation capillary at a defined distance of the order of hundreds of MUm in the injection space. During the injection, the background electrolyte is forced out by air from this space and a drop of the sample is forced out of the syringe by a micro-pump so that it is caught at the entrance to the capillary. From the drop the sample is injected into the capillary by applying a negative pressure pulse or simply by spontaneous injection. The injection space is then filled with background electrolyte, which washes away excess sample and separation is commenced. The injector was tested in electrophoretic separation of a model sample with equimolar concentrations of 100 MUM NH4+, K+, Na+, Mg2+ and Li+ in a short capillary with total/effective length of 16.5/11.5 cm. The repeatability of the migration time and peak area expressed as the RSD value is 2% and 4%, respectively. The practical applicability of the injector was verified on the determination of the antiparasitic pentamidine in 10 MUL of rat plasma. Electrophoretic separation of pentamidine was performed in 100 mM of acetic acid/NaOH at pH 4.55, the sample consumption per analysis is 125 nL, the separation time is 45 s and the attained LOQ using contactless conductivity detection is 8 MUM. PMID- 30428981 TI - Study of endocrine disrupting compound release from different medical devices through an on-line SPE UHPLC-MS/MS method. AB - The paper deals with the development of an online UHPLC-MS/MS method for the identification and determination of 25 Endocrine Disrupting Chemicals (EDCs) belonging to different chemical classes (perfluorochemicals, bisphenols, alkylphenols, phthalates, and parabens). The study regards the possible EDC migration from different medical devices of diverse materials used in the routine hospitals for blood sampling or for the parenteral nutrition therapies. In order to evaluate the release of EDCs, the equipment used for blood sampling (syringes, butterfly, cannula-needle, microcapillary tube) was put in contact with a physiological solution at a prefixed time. As regards the migration tests carried out on the medical devices used in the parenteral nutrition therapy (infusion tubes, venous catheters), the catheters were undergone to internal contact with parenteral solution and external contact with physiological one, whereas the infusion tubes were subjected only to internal migration test with parenteral solution. The results demonstrated the released of some ECDs (such as parabens at the concentration of few pg mL-1, diethylphthalate and dibutylphthlate at ng mL 1, level), when using physiological solution as the leaching agent. In addition, the presence of a PFOS structural isomer was found at 29.0 ng mL-1: this compound was released in part from the infusion tubes and mostly from the venous catheters, particularly from silicone ones. Using a more lipophilic solution, such as parenteral preparations, a greater amount of EDCs was released, among which also the diethylhexylphthalate that was quantified in all the investigated devices (without highlighting particular trends or migration from PVC devices), but its concentration remained always lower than imposed maximum threshold limit on medical device of 0.1% w/w. The releases from the infusion tubes of the same materials (polyethylene) from different manufacturers are very comparable, whereas the catheter of silicone releases greater amount of EDCs than that of polyurethane. PMID- 30428982 TI - Variation of anionic moieties of dicationic ionic liquid GC stationary phases: Effect on stability and selectivity. AB - Dicationic ionic liquids (DILs) are more and more accepted as a new class of high temperature and polar stationary phases for gas chromatography (GC). This study deals with the effect of seven different fluorosulfonyl derivatized anions associated with two dications: 1,3-di(3-methylimidazolium)-2-methylpropane [2mC3(mim)2], and 1,3-di(3-methylimidazolium)-isobutene [i-eneC4(mim)2]. Thermophysical properties of the 14 synthesized DILs were evaluated in terms of melting point, viscosity, and thermal stability. The optimal physicochemical properties of 13 DILs allowed preparing 13 GC capillary columns. Accordingly, the polarity and selectivity of the DILs were evaluated by determining the Rohrschneider-McReynolds constants and the equivalent chain lengths of C18 fatty acid methyl esters (FAMEs). The symmetrical fluoroalkylsulfonyl and the trifluorosulfonate anions seem to produce the most polar DILs. Compared to classical polyethyleneglycol phases, the DILs showed substantially decreased retention of apolar compounds and a much stronger retention of the polar ones. Unique selectivities were observed with unsaturated FAMEs, polyaromatic hydrocarbons, and bacterial specific FAMEs. The two applications presented included a biodiesel and bacterial FAME analyses. PMID- 30428983 TI - Preparation of a poly(ethyleneimine) embedded phenyl stationary phase for mixed mode liquid chromatography. AB - A poly(ethyleneimine) embedded phenyl mixed-mode stationary phase was prepared through epoxide ring opening reaction. Elemental analysis (EA), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TGA) were used to characterize whether functional groups have been modified on the surface of silica successfully. The researches of chromatographic performance for designed column were divided to four parts. The retention behavior under reversed-phase mode was studied using polycyclic aromatic hydrocarbons (PAHs), positional isomers and alkylbenzenes. The retention characteristic under hydrophilic interaction mode was studied by nucleosides, nucleobases and flavonoids. The chromatographic performance of anion exchange mode was evaluated by benzoic acids and phenols. Due to a high content of amino and phenyl groups on the stationary phase, aromatic amines were chosen for the evaluation of retention mechanisms of benzene ring attraction and amino repulsion. The investigations about effects of mobile phase constitution and pH on retention demonstrated the mixed-mode retention mechanisms of the column. Furthermore, due to amino selectivity of the column, a method for the rapid separation and determination of phenylenediamines in hair dye was established. And both linear correlation coefficients of p diaminobenzene and m-diaminobenzene in concentration range from 0.1 to 30 MUg mL 1 were over 0.999. In conclude, the prepared mixed-mode stationary phase could realize various separation modes by adjusting chromatographic conditions, and it had the potential for the rapid separation and determination of aniline compounds in various complex samples. PMID- 30428984 TI - Electrospun bimetallic Au-Ag/Co3O4 nanofibers for sensitive detection of hydrogen peroxide released from human cancer cells. AB - Bimetallic Au-Ag/Co3O4 nanofibers (Au-Ag/Co3O4NFs) were synthesized by an electrospinning method and calcination treatment. Due to the admirable synergic effect of electrocatalytic ability of Au and Ag, and the large surface-to-volume ratio of Co3O4 nanofibers caused by their rough surface, the synthesized Au Ag/Co3O4NFs were applied to a sensing platform for hydrogen peroxide oxidation. Using electrochemical techniques, the novel sensing platform based on Au Ag/Co3O4NFs shows a wide linear concentration range with high detection sensitivity of 1241.1 MUA mM-1 cm-2. This sensitive sensor was also applied to determine H2O2 from human breast cancer cells, indicating its great potential application in physiology and pathology. PMID- 30428985 TI - Electrochemical detection of dopamine by a calixarene-cellulose acetate mixed Langmuir-Blodgett monolayer. AB - The sensing performance of a Langmuir-Blodgett monolayer was significantly improved by controlling the film organization at the air-water interface. Cellulose acetate (CA) and 4-tert-butylcalix [6]arene (calix) were co-spread and formed a Langmuir film, which was efficiently transferred onto a preoxidized gold electrode, Auox. The modified gold electrode was applied as a fast, highly sensitive electrochemical sensing platform for the quantitative determination of a model molecule, dopamine (DA). The modified gold electrode, CA-calix/Auox, demonstrated better recognition and sensing ability towards dopamine as compared with electrodes modified by a single component. Under the optimized conditions, the reduction peak currents at the CA-calix/Auox increased linearly within the concentration range of dopamine from 5 to 100 and 100-7500 nM, and exhibited a very low limit of detection (LOD) of 2.54 nM (S/N = 3). These results suggest a simple, superior and efficient approach for the controllable rearrangement of Langmuir-Blodgett monolayers on a molecular level. The electroanalytical performance was optimized from the perspective of the electrode-electrolyte interface. PMID- 30428986 TI - Genomagnetic LAMP-based electrochemical test for determination of high-risk HPV16 and HPV18 in clinical samples. AB - Major cause of cervical cancer is a persistent infection with high-risk types of human papillomaviruses (HPV). For that reason, HPV testing is now becoming an important addition to standard cytological screening of cervical malignancies in women (known as Pap test). New methods are sought which could offer rapid and inexpensive detection schemes, such as those based on electrochemical (EC) readout. Here, we developed an assay for parallel detection of two most oncogenic high-risk HPV types, HPV16 and HPV18, by combining loop-mediated amplification (LAMP) of template DNA, its separation using magnetic beads and detection with amperometry at carbon-based electrode chips. Our EC-LAMP test enabled us to successfully discriminate both HPV types not only in cancer cell lines, but also using clinical material obtained from HPV-positive patient samples. PMID- 30428987 TI - SWCNTs@GQDs composites as nanocarriers for enzyme-free dual-signal amplification electrochemical immunoassay of cancer biomarker. AB - Carcinoembryonic antigen (CEA) as a typical biomarker plays a remarkable role in various human physiological processes. A sensitive and rapid method should be developed to realize the precise diagnosis of cancer at its early stage. In this work, we successfully synthesized the peroxidase-like graphene quantum dots (GQDs) and utilized it to fabricate an enzyme-free electrochemical immunosensor towards CEA by forming a single-wall carbon nanotubes@GQDs (SWCNTs@GQDs) composite. In addition to the SWCNTs@GQDs, reduced graphene oxide-Au nanoparticles (rGO-Au NPs) with the huge specific surface area and excellent conductivity were employed to modify the electrodes, leading to a dual-signal amplification result. Both the electrochemical impedance spectroscopy and cyclic voltammetry measurements were performed to evaluate the interface properties of the layer-by-layer modified electrodes. The proposed electrochemical immunosensor displayed a good specificity and sensitivity towards the detection of CEA ranging from 50 pg mL-1 to 650 pg mL-1 with a low detection limit of 5.3 pg mL-1. This simple and inexpensive immunosensor shows promising potential for the determination of other biomarkers in clinical translation. PMID- 30428988 TI - Development and validation of an open screening method for doping substances in urine by gas chromatography quadrupole time-of-flight mass spectrometry. AB - In anti-doping, a high number of classes of substances are prohibited and laboratories need to detect these at low urinary concentrations. Traditionally, testing is done using complimentary liquid chromatography mass spectrometry and gas chromatography mass spectrometry. High resolution mass spectrometric acquisition has some important advantages over triple quadrupole instruments (e.g., open screening due to full scan high resolution data acquisition with retrospectivity, compatibility with libraries and a straightforward and effortless addition and validation of new compounds in the future). Doping samples can be stored for 10 years and retrospective data analysis can be used to re-evaluate previously acquired data (e.g., searching for prohibited (designer) substances that were unknown at the initial moment of analysis). During the past decade, these advantages have led to the wide-scale transfer of liquid chromatography triple quadrupole mass spectrometry screening to liquid chromatography high resolution mass spectrometry screening for doping control purposes. Up to now, for gas chromatography a similar switch to high resolution screening has not yet occurred, because so far no method has been developed that combines sufficient sensitivity with wide-scale drug detection. In this work, the current gas chromatography triple quadrupole mass spectrometry screening method for human doping control purposes was successfully converted into an equivalent and complete gas chromatography high resolution acquisition screening method. This new screening method on a gas chromatography quadrupole time-of-flight mass spectrometer has been developed and validated. The method is compliant with the World Anti-Doping Agency requirements and allows the detection of 294 target compounds (and 14 internal standards), including diuretics, stimulants, narcotics, beta-2-agonists, beta-blockers, hormone modulators, anabolic agents and the quantification of 14 endogenous steroids in a single fast run (14.1 min). PMID- 30428989 TI - A novel approach to assess the quality and authenticity of Scotch Whisky based on gas chromatography coupled to high resolution mass spectrometry. AB - Whisky is one of the most popular spirit drinks in the world. Unfortunately, this highly valued commodity is vulnerable to fraud. To detect fraudulent practices and document quality parameters, a number of laboratory tests based on various principles including chromatography and spectroscopy have been developed. In most cases, the analytical methods are based on targeted screening strategies. Non targeted screening (metabolomics fingerprinting) of (semi)volatile substances was used in our study. Following the pre-concentration of these compounds, either by solid phase microextraction (SPME) or by ethyl acetate extraction, gas chromatography (GC) coupled to tandem mass spectrometry (Q-TOF mass analyser) was employed. Unsupervised principal component analysis (PCA) and supervised partial least squares discriminant analysis (PLS-DA) were used for evaluation of data obtained by analysis of a unique set of 171 authentic whisky samples provided by the Scotch Whisky Research Institute. Very good separation of malt whiskies according to the type of cask in which they were matured (bourbon versus bourbon and wine) was achieved, and significant 'markers' for bourbon and wine cask maturation, such as N-(3-methylbutyl) acetamide and 5-oxooxolane-2-carboxylic acid, were identified. Subsequently, the unique sample set was used to construct a statistical model for distinguishing malt and blended whiskies. In the final phase, 20 fake samples were analysed and the data processed in the same way. Some differences could be observed in the (semi)volatile profiles of authentic and fake samples. Employing the statistical model developed by PLS-DA for this purpose, marker compounds that positively distinguish fake samples were identified. PMID- 30428990 TI - Near-infrared MnCuInS/ZnS@BSA and urchin-like Au nanoparticle as a novel donor acceptor pair for enhanced FRET biosensing. AB - An enhanced near-infrared (NIR) FRET biosensing system based on the novel donor acceptor pair (MnCuInS/ZnS@BSA and urchin-like Au NPs) was developed for the sensitive detection of HER2 protein. In this strategy, MnCuInS/ZnS quantum dots (QDs) were chosen due to their NIR emission, high quantum efficiency, and low toxicity. Amounts of MnCuInS/ZnS QDs were encapsulated in BSA to form MnCuInS/ZnS@BSA nanoparticles, which can easily transfer MnCuInS/ZnS QDs from organic phase into aqueous solution, and the formed nanoparticles were applied as the energy donor which significantly enhanced the fluorescence intensity. As for the energy acceptor, urchin-like Au nanoparticles (Au NPs) with novel structure, good stability and excellent quenching ability towards NIR fluorescence were selected. Thus, the NIR MnCuInS/ZnS@BSA and urchin-like Au NPs were designed as a novel donor-acceptor pair for FRET assay. By combining the optical advantages of NIR QDs encapsulated BSA nanoparticles with the excellent fluorescence quenching ability of urchin-like Au NPs, the proposed FRET-based biosensor realized enhanced FRET effect for highly sensitive detection of HER2 in human serum samples. A wide detection range (2-100 ng mL-1) and a low detection limit (1 ng mL-1) were obtained. This sensing system can decrease the interference of other biomolecules in NIR region, can be applied to other biomarker determination in vitro, and also shows great potential for in vivo diagnosis. PMID- 30428991 TI - Point discharge microplasma reactor for high efficiency conversion of H2S to SO2 for speciation analysis of sulfide and sulfite using molecular fluorescence spectrometry. AB - A low temperature plasma integrating the merits of small size, simple operation and rich active particles has good performance in analytical chemistry. In this work, a point discharge microplasma was used as a reactor to facilitate the gaseous conversion reaction from H2S to SO2 with an excellent efficiency as high as 95%. By coupling this reactor with a fluorescence spectrometer, the speciation analysis of sulfide and sulfite was achieved in a simple, chromatographic separation-free, time-saving and practical way. Specifically, with the discharge off, only sulfite was quantified; with discharge on, both sulfide and sulfite were quantified; and with a simple subtraction, the speciation analysis could be easily attained. By the acidification process, a limit of detection of 7.7 MUM by the proposed method was obtained for both sulfide and sulfite in aqueous medium, and this method was successfully utilized to analysis of real samples. PMID- 30428992 TI - Combining DNA-stabilized silver nanocluster synthesis with exonuclease III amplification allows label-free detection of coralyne. AB - In this paper we describe a label-free biosensor for coralyne, prepared by combining DNA-stabilized silver nanoclusters (Ag NCs) with an exonuclease III amplification strategy. An artificial DNA probe having a polyadenine (poly-A) sequence at both the 3'- and 5'-ends was used as a probe to detect coralyne. In the absence of coralyne, the probe existed in a hairpin conformation that left both its 3'- and 5'-ends free. In the presence of coralyne, two adjacent adenine (A) bases in the poly-A sequence of the probe formed an A2 unit and then coordinated with coralyne through non-Watson-Crick base pairing. The DNA probe, having captured coralyne, was subsequently digested by exonuclease III, even though the distance between the A2 units in the A2-coralyne-A2 complex would be much larger than that found in common Watson-Crick base pairing. After digestion, the DNA probe became a single-stranded DNA (ssDNA) residue and released its captured coralyne. The liberated coralyne was then coordinated by another DNA probe having the hairpin conformation; as a result, many ssDNA residues formed after digestion. Two kinds of Ag NCs having different optical utilities were obtained: one corresponding to the hairpin conformational DNA probe and the other to the ssDNA residue. The difference in fluorescence intensity at 588 nm of these two kinds of Ag NCs reflected the concentration of coralyne. The linear range (on a logarithmic scale) for detecting coralyne spanned from 5 to 1000 nM, with an estimated detection limit of 1.83 nM. PMID- 30428993 TI - Sensitive and selective non-enzymatic detection of glucose by monodispersed NiO @ S-doped hollow carbon sphere hybrid nanostructures. AB - Development of selective, sensitive and non-enzymatic sensor for glucose determination is highly important for the diagnosis and management of diabetes. Herein, we have reported the novel ultra sensitive and non-enzymatic sensor development by in-situ wraped NiO nanostructures (~10-15 nm) on the sulfur-doped hollow carbon nanospheres (SDHCNSs) through hydrothermal-assisted process. The structural and morphological properties of the nanocomposites were characterized by X-ray diffraction (XRD), Raman spectroscopy, field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) techniques. The prepared NiO@SDHCNSs was directly used as an electrochemical sensor for glucose determination, and its performance was evaluated by cyclic voltammetry and amperometric techniques. The fabricated non-enzymatic biosensor was exhibited remarkably good sensitivity (1697 MUA mM-1cm-2), low detection limit (LOD) (52 nM), a wide linear range (up to 13 mM) of glucose with desirable selectivity, stability and reproducibility. Further, the constructed sensor has demonstrated an excellent anti-interference property in the presence of common interferences such as dopamine (DA), uric acid (UA) and ascorbic acid (AA). Most interestingly, the fabricated electrode is applicable for the practical analysis of glucose in the real blood serum and urine samples. The excellent electrochemical performances of NiO@SDHCNSs towards the oxidation of glucose are attributed to the increased electron transfer passage through unique hollow spherical morphology with increased redox couple of Ni(OH)2/NiOOH derived from NiO. Thus, the improved electrochemical performances of NiO@SDHCNSs can be adopted as a potential electrode for the real sample analysis. PMID- 30428994 TI - Corrigendum to "Effects of aerobic training, resistance training, or both on brain-derived neurotrophic factor in adolescents with obesity: The hearty randomized controlled trial" Physiology & Behavior, Volume 191, 1 July 2018, Pages 138-145. PMID- 30428995 TI - Response to criticisms of "Cognitive fatigue effects on physical performance: a systematic review and meta-analysis" [Physiology & Behavior, Volume 188, 1 May 2018, Pages 103-107]. PMID- 30428996 TI - [Social pain at the core of suicidal behavior]. AB - BACKGROUND: Intolerable pain is often reported in suicide notes. Moreover, the frequency of life events preceding a suicidal act is high, especially interpersonal difficulties. Such adversity is the source of psychological or social pain. METHODS: We propose a narrative review to discuss the role of pain in the suicidal process while having a focus on social ties. RESULTS: Using Ecological Momentary Assessment in suicide attempters it has been shown that being alone increased suicidal ideation while being with close others significantly reduced this risk. At a neuroanatomical level, suicidal vulnerability is associated with dysfunctional insula activation during social exclusion, a region involved in social and physical pain processing. Social pain elicited by social exclusion or devaluation shares common neurobiological patterns with physical pain. It is also an exemplar of psychological pain. Despite the complexity of its definition, higher psychological pain levels are associated with suicidal ideation and acts. Finally, intense physical pain or chronic pain are strong risk factors of suicidal ideation and act. Interestingly, suicide notes often report the existence of an intolerable pain. Presence of psychological pain and difficulties in communication predict the lethality and seriousness of suicide attempts. Moreover, presence of psychological pain is associated with more impulsive choices in suicidal patients, suggesting that a suicidal act is a means to escape intolerable suffering despite negative long term consequences (i.e. death). Analgesics are usually used to get relief from pain but are also frequently involved in suicidal overdoses. It has been shown that opioid analgesics are associated with an increased risk of suicide. Higher consumption of opioid analgesics has been shown in suicidal patients in comparison to patients with history of depression but no suicidal act and healthy controls whereas non-suicidal patients were those reporting higher presence of pain in comparison to healthy controls. It may suggest that opioids are being used by suicidal patients to get relief from psychological/social pain rather than from physical pain. Involvement of opioidergic system in suicidal process opens new therapeutic strategies. Recently, the time-limited, short-term use of very low dosages of sublingual buprenorphine (vs. placebo) was associated with decreased suicidal ideation and mental pain in severely suicidal patients without substance abuse. In a randomized controlled trial comparing a 7-week acceptance and commitment therapy (ACT) versus relaxation group, as adjunct to treatment as usual for adult outpatients suffering from a current suicidal behavior disorder, ACT has shown its effectiveness in reducing suicidal ideation and psychological pain. Evidence indicates that maintaining contact either via letter, postcard or telephone with at-risk adults following discharge from care services after a suicide attempt can reduce reattempt risk. Based on these results, a preventive program of recontact for suicide attempters, VIGILANS, has been developed in France in usual care. CONCLUSION: The approach of the suicidal issue by the angle of pain and social disconnection offers new advances to improve clinical assessment, to identify new biological pathways involved in suicidal risk, and to propose innovative therapeutic and preventive actions. PMID- 30428997 TI - [Psychological distress and caregiving burden among spouses of women with breast cancer]. AB - Breast cancer is a chronic disease that affects both patients and their caregivers. Spouses, in particular, will generally assume the role of primary caregiver and experience significant physical, social, economic and emotional stress. In the face of cancer, being the spouse of a patient is synonymous with unmet psychosocial needs and a new role assignment, that of a primary caregiver. In addition, cancer confronts spouses with fear of partner loss. This leads to a set of adverse consequences such as depression, anxiety, uncertainty, stress, etc. Several studies have shown that breast cancer reduces the quality of life of patients' spouses and increases their emotional distress, their psychosocial needs, and their responsibilities within the family. Spouses may live a complex powerful emotional experience, which is equal to or greater than that experienced by patients during the diagnosis and treatment process. These multiple solicitations contribute to the heavy symptom burden. Therefore, in the context of breast cancer, identifying vulnerable spouses and providing them with appropriate support would help ensure better adherence to the care of their wives at different stages of the disease. PMID- 30428998 TI - A review on electrochemical biosensing platform based on layered double hydroxides for small molecule biomarkers determination. AB - The development of layered double hydroxides (LDHs), also known as anionic clays with uniform distribution of metal ions and facile exchangeability of intercalated anions, are now appealing an immense deal of attention in synthesis of multifunctional materials. In electrochemical biosensors, LDHs provide stable environment for immobilization of enzymes or other sensing materials and play crucial roles in development of clinical chemistry, point-of-care devices through analysis of various small molecule metabolites excreted by biological processes which in turn serve as molecular biomarkers for medical diagnostics. In this review, we summarize the recent development in fabrication of LDH based nanoarchitectures and their electrocatalytic applications in ultrasensitive in vitro determination of conventional biomarkers, i.e., H2O2, glucose, dopamine and other biomolecules. Moreover, detailed discussion has been compiled to differentiate electrochemical enzymatic and nonenzymatic biosensors, to evaluate useful concentration ranges of H2O2 and glucose for analytical circumstances and to distinguish tumorigenic and normal cells via quantifying the released H2O2 efflux from living cells. Here, we envision that electrochemical sensing platform based on structurally integrated LDH nanohybrids with highly conducting substrates will assist as diseases diagnostic probe further enhancing diagnosis as well as therapeutic window for chronic diseases. Finally, the perspective for fabrication and assembly of LDH electrode is proposed for the future innovation of electrochemical biosensors with high performance making them more reliable for in vitro diagnostics. PMID- 30428999 TI - Antihypertensive Drugs, Incident Dementia, and the Competing Risk of Death. PMID- 30429000 TI - Response to the Letter to the Editor: "Antihypertensive Medication Regimen Intensity and Incident Dementia in an Older Population". PMID- 30429001 TI - Potentially Inappropriate Medications and Polypharmacy. PMID- 30429002 TI - Deprescribing in Geriatric Medicine: Challenges and Opportunities. PMID- 30429003 TI - Incredibly Icky Increased Intracranial Pressure. PMID- 30429004 TI - Economic analysis of osimertinib in previously untreated EGFR-mutant advanced non small cell lung cancer in Canada. AB - INTRODUCTION: Osimertinib improves progression-free survival in previously untreated EGFR-positive advanced non-small cell lung cancer (NSCLC) patients, with marked intracranial response rates. However, its cost-effectiveness in a publically funded health care system has not been established. We assessed the cost-effectiveness of first-line osimertinib from the public payer perspective in the Canadian health care system. METHODS: A Markov model was developed to project the outcomes and direct medical costs of initial treatment with osimertinib or current standard-of-care (SoC) EGFR TKIs, gefinitib or afatinib, in patients with previously untreated EGFR-mutant advanced NSCLC. Clinical and cost input estimates were informed from the available literature. Model outcomes included costs (in 2018 Canadian dollars), life years (LYs), quality-adjusted life-years (QALYs), and the cost utility of osimertinib compared to SoC EGFR TKI, or incremental cost per QALY gained. RESULTS: Initial treatment with osimertinib was associated with a gain of 0.79 QALY [95% confidence interval (CI), 0.74 to 0.83] at an incremental cost of $176,394 CAD (95% CI, 176,383 to 176,405) vs. SoC EGFR TKI (incremental cost-effectiveness ratio [ICER]: $223,133/QALY gained; 95%CI, 198,144 to 252,805). Osimertinib had a 0% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. Deterministic sensitivity analysis showed that the cost of osimertinib had the largest impact on ICER results. CONCLUSION: At the current marketed price, first-line osimertinib therapy in patients with advanced EGFR-mutant lung adenocarcinoma is not cost effective in Canada. Reduction of osimertinib cost, for example by 25%, can significantly improve the cost-effectiveness profile. PMID- 30429005 TI - Primary tracheal hyalinizing clear cell carcinoma. AB - Hyalinizing clear cell carcinomas (HCCC), now referred to as clear cell carcinomas (CCC) by the World Health Organization (WHO), are rare tumors usually arising from the salivary glands of the head and neck. We present the first case of a CCC originating from the trachea. A 66 year-old woman with history of hypertension, former smoker, presented to the emergency department reporting worsening shortness of breath. Computed chest tomography revealed a polypoid mass arising from the left posterior-lateral wall of the trachea. The patient developed worsening respiratory failure requiring mechanical ventilation. Bronchoscopy was completed which relieved a malignant airway obstruction and pathology revealed nests of cells with monomorphic nuclei and clear cytoplasm set in a hyalinized stroma. Using break apart probe fluorescence in situ hybridization testing the tissue revealed the presence of a recurring translocation of the Ewing sarcoma (EWSR1) gene, confirming the diagnosis. CCC is a rare primary airway tumor. CCC was first reported to originate in the lung in 2015. We present the first case of CCC arising from the trachea. PMID- 30429006 TI - Relationship between the number of new nodules and lung cancer probability in incidence screening rounds of CT lung cancer screening: The NELSON study. AB - BACKGROUND: New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant's number of new nodules and lung cancer probability is unknown. METHODS: Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant's new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed. RESULTS: In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8-13%) or >1 new nodule (6% [9/154], 95%CI 3-11%, P = .116). An increased number of new nodules positively correlated with a participant's largest nodule size (P < 0.001, Spearman's rho 0.177). When adjusted for largest new nodule size, the new nodule count had a significant negative association with lung cancer (odds ratio 0.59, 0.37-0.95, P = .03). CONCLUSION: A participant's new nodule count alone only has limited association with lung cancer. However, a higher new nodule count correlates with an increased largest new nodule size, while the lung cancer probability remains equivalent, and may improve lung cancer risk prediction by size only. PMID- 30429007 TI - CT-based radiomics signature for differentiating solitary granulomatous nodules from solid lung adenocarcinoma. AB - OBJECTIVES: Pulmonary granulomatous nodule (GN) with spiculated or lobulated appearance are indistinguishable from solid lung adenocarcinoma (SADC) based on CT morphological features, and partial false-positive findings on PET/CT. The objective of this study was to investigate the ability of quantitative CT radiomics for preoperatively differentiating solitary atypical GN from SADC. METHODS: 302 eligible patients (SADC = 209, GN = 93) were evaluated in this retrospective study and were divided into training (n = 211) and validation cohorts (n = 91). Radiomics features were extracted from plain and vein-phase CT images. The L1 regularized logistic regression model was used to identify the optimal radiomics features for construction of a radiomics model in differentiate solitary GN from SADC. The performance of the constructed radiomics model was evaluated using the area under curve (AUC) of receiver operating characteristic curve (ROC). RESULTS: 16.7% (35/209) of SADC were misdiagnosed as GN and 24.7% (23/93) of GN were misdiagnosed as lung cancer before surgery. The AUCs of combined radiomics and clinical risk factors were 0.935, 0.902, and 0.923 in the training cohort of plain radiomics(PR), vein radiomics, and plain and vein radiomics, and were 0.817, 0835, and 0.841 in the validation cohort of three models, respectively. PR combined with clinical risk factors (PRC) performed better than simple radiomics models (p < 0.05). The diagnostic accuracy of PRC in the total cohorts was similar to our radiologists (p >= 0.05). CONCLUSIONS: As a noninvasive method, PRC has the ability to identify SADC and GN with spiculation or lobulation. PMID- 30429008 TI - The immune checkpoint, HVEM may contribute to immune escape in non-small cell lung cancer lacking PD-L1 expression. AB - BACKGROUND: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC. METHODS: A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H score system while for PD-L1 the tumor proportion score (TPS) was used. RESULTS: HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p < 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r= 0.162, p = 0.352). CONCLUSION: HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients. PMID- 30429009 TI - Lung cancer screening - gaining consensus on next steps - proceedings of a closed workshop in the UK. AB - Lung cancer is the most common cause of cancer death in the UK, and survival from the disease is persistently poor. Efforts to improve outcomes for patients have focused on ways of reducing late diagnosis of the disease, and access to optimal treatment. Research on lung cancer screening has so far provided some evidence of an impact on lung cancer mortality, but there is some debate about whether implementation of a national screening programme should await further trial data, principally that from the NELSON trial. The ongoing poor outcomes and the belief amongst some clinicians that there is sufficient evidence has prompted several local projects testing out lung screening in their communities, sometimes referred to as lung health checks or proactive approaches to high-risk individuals. Funding from NHS England has been forthcoming to support this. Acknowledging roll-out of such activities, which effectively constitute local lung screening in the absence of a NSC recommendation, it was timely to bring key national stakeholders together with academic and clinical experts, to agree a way forward. Cancer Research UK therefore convened a closed workshop in March 2018, involving national and international expertise. This paper outlines the proceedings, key discussion points, highlighted research gaps, and areas of consensus and next steps. PMID- 30429010 TI - Detection of abundant megakaryocytes in pulmonary artery blood in lung cancer patients using a microfluidic platform. AB - OBJECTIVES: The lung was recently re-discovered as a hematopoietic organ for platelet production in mice. However, evidence for the role of the lung in thrombopoiesis in humans is still limited. In this study, we examined megakaryocytes in the pulmonary and systemic circulation, specifically in pulmonary arterial blood (PAB), venous blood (PVB) and peripheral blood using a newly developed microfluidic platform for rare cell isolation. MATERIALS AND METHODS: We analyzed 23 lung cancer patients who underwent surgery in our institute. PAB and PVB were obtained from the resected lung immediately after surgery. Blood samples were size-selected using a filtration-based microfluidic device and enriched rare cells on glass slide specimens were stained with Papanicolaou (Pap), immunocytochemistry (ICC), and immunofluorescence (IF). Lung tissues were also analyzed by immunohistochemistry. RESULTS: Pap/ICC/IF showed the presence of abundant CD61+/cytokeratin- giant cells with a megakaryocyte lineage in PAB, but only a few in PVB. These megakaryocytes were found to consist of CD61+/CD41+ immature megakaryocytes and CD61+/CD41- mature megakaryocytes with the potential to produce platelets. These findings were confirmed by the conventional hematological analysis of blood smears stained with Giemsa. In analysis of lung cancer, CD61+ megakaryocytes were observed exclusively in the capillaries of non-cancerous tissue, whereas platelets were selectively observed in the tumor blood vessels of cancerous tissue. CONCLUSIONS: These results indicate that numerous megakaryocytes migrate from systemic bone marrows to accumulate in PAs and arrest of mature megakaryocytes in the capillaries of normal lung, suggesting the possibility that the lung plays a physiological role in the systemic thrombopoiesis in lung cancer patients. PMID- 30429011 TI - Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer. AB - OBJECTIVES: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL-1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. RESULTS: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached. CONCLUSION: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC. PMID- 30429012 TI - Predictive accuracy of lepidic growth subtypes in early-stage adenocarcinoma of the lung by quantitative CT histogram and FDG-PET. AB - OBJECTIVES: The aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes. MATERIALS AND METHODS: We identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3). RESULTS: The proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p < 0.001). Multivariate analysis with CT-related parameters demonstrated that 75th percentile CT attenuation value (75th%, p < 0.001) and maximum CT attenuation value (maxCT, p = 0.009) were associated with incidence of non-LGA, whereas the value of SUVmax demonstrated a significant correlation (p < 0.001). When all patients were dichotomized according to ground glass opacities (GGO)/solid-dominancy for CT maximum diameter, a significant correlation with non-LGA was shown in patients with solid-dominant tumor on SUVmax (p < 0.001) and with GGO-dominant tumor on 75th% (p = 0.006) and maxCT (p = 0.007). The combination of one of the two significant histogram parameters and SUVmax revealed higher predictive performance for pathological high malignant features (positive pathological invasive factors, non-LGA, and the highly malignant subtype covering G2 with moderately or poorly-differentiated carcinoma and G3) than the individual use of either factor. CONCLUSION: The 75th%, maxCT, and SUVmax were highly useful in distinguishing LGA from non-LGA in c-0/I adenocarcinoma. PMID- 30429013 TI - Prospective study revealed prognostic significance of responses in leptomeningeal metastasis and clinical value of cerebrospinal fluid-based liquid biopsy. AB - OBJECTIVE: Leptomeningeal metastasis (LM) secondary to non-small cell lung cancer (NSCLC) is a devastating complication associated with poor prognosis. Diagnosis and assessment of responses in LM have been challenging due to limitation of traditional imaging tools and lack of standard evaluation criteria until very recently. To bridge this gap, we conducted the first prospective, observational study in cytologically diagnosed NSCLC-LM patients (NCT02803619). PATIENTS AND METHODS: A total of 49 NSCLC-LM patients were enrolled. LM responses were evaluated with a composite endpoint integrating neurological symptoms, cerebrospinal fluid (CSF) parameters and central nervous system (CNS) imaging. Primary outcome was overall survival (OS) after diagnosis of LM. Exploratory endpoint was the association between OS and prognostic factors. Primary tumor and CSF samples were collected for biomarker analysis. RESULTS: 93.9% of the cohort carried oncogenic drivers, and 85.7% harbored EGFR activating mutations. Median OS since LM diagnosis of the overall population was 9.7 months. EGFR mutant LM patients had a longer survival compared with wildtype ones. LM clinical responses assessed by the composite endpoint showed significant correlation with OS. Status of EGFR activating mutations was highly concordant between primary tumor and CSF. T790 M occurrence in CNS lesions was relatively rare and associated with intracranial exposure level of EGFR-TKIs. CONCLUSION: Our results supported the composite endpoint for objective response evaluation of LM was valid, suggested LM outweighed peripheral lesions on the impact to patient survival, and emphasized the urge and promise of development of CNS-penetrant targeted therapies to improve clinical outcome of NSCLC-LM patients. PMID- 30429014 TI - Characteristics, incidence, and risk factors of immune checkpoint inhibitor related pneumonitis in patients with non-small cell lung cancer. AB - OBJECTIVES: Immune checkpoint inhibitors (ICIs) can cause pneumonitis in lung cancer patients. We aimed to identify the clinical and radiologic characteristics, incidence, and risk factors of ICI-related pneumonitis in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Medical records and chest computed tomography scans of NSCLC patients treated with an ICI over a 5-year period at a tertiary hospital were retrospectively analyzed. Clinical characteristics were compared between patients with and without ICI related pneumonitis to identify risk factors. RESULTS: Data from 167 eligible patients were analyzed. The incidences of all-grade and grade 3-4 pneumonitis were 13.2% and 4.2%, respectively. The presence of preexisting interstitial lung disease [odd ratio (OR), 6.03; 95% confidence interval (CI), 1.19-30.45; P = 0.030] was associated with a higher incidence of ICI-related pneumonitis. The presence of extrathoracic metastasis [OR, 0.34; 95% CI, 0.13-0.92; P = 0.034] was associated with a lower incidence of ICI-related pneumonitis. The dominant radiologic pattern (72.7%) of ICI-related pneumonitis was organizing pneumonia. Half of the patients with pneumonitis completely recovered or improved; however, the mortality rate was 18.2%. CONCLUSION: ICIs should be used with caution when treating lung cancer patients who have underlying chronic lung disease, especially interstitial lung disease. PMID- 30429015 TI - Detection of autoantibodies against cancer-testis antigens in non-small cell lung cancer. AB - OBJECTIVES: Cancer-testis antigens (CTAs) are defined as proteins that are specifically expressed in testis or placenta and their expression is frequently activated in cancer. Due to their ability to induce an immune response, CTAs may serve as suitable targets for immunotherapy. The aim of this study was to evaluate if there is reactivity against CTAs in the plasma of non-small cell lung cancer (NSCLC) patients through the detection of circulating antibodies. MATERIALS AND METHODS: To comprehensively analyze autoantibodies against CTAs the multiplexing capacities of suspension bead array technology was used. Bead arrays were created with 120 protein fragments, representing 112 CTAs. Reactivity profiles were measured in plasma samples from 133 NSCLC patients and 57 cases with benign lung diseases. RESULTS: Altogether reactivity against 69 antigens, representing 81 CTAs, was demonstrated in at least one of the analyzed samples. Twenty-nine of the antigens (45 CTAs) demonstrated exclusive reactivity in NSCLC samples. Reactivity against cancer-testis antigen family 47; member A (CT47A) genes, P antigen family member 3 (PAGE3), variable charge X-linked (VCX), melanoma antigen family B1 (MAGEB1), lin-28 homolog B (LIN28B) and chromosome 12 open reading frame 54 (C12orf54) were only found in NSCLC patients at a frequency of 1%-4%. The presence of autoantibodies towards these six antigens was confirmed in an independent group of 34 NSCLC patients. CONCLUSION: We identified autoantibodies against CTAs in the plasma of lung cancer patients. The reactivity pattern of autoantibodies was higher in cancer patients compared to the benign group, stable over time, but low in frequency of occurrence. The findings suggest that some CTAs are immunogenic and that these properties can be utilized as immune targets. PMID- 30429016 TI - Local ablative treatment for synchronous single organ oligometastatic lung cancer A propensity score analysis of 180 patients. AB - INTRODUCTION: Local ablative treatment (LAT) improves outcome in lung cancer with oligometastatic disease (OMD) and potentially leads to long term survival. The aim of this retrospective study was to evaluate and quantify the additional benefit of LAT in synchronous OMD and to further identify prognostic factors for survival. PATIENTS AND METHODS: A propensity score-matched pairs analysis was performed on a set of patient and disease variables in 180 patients, treated for synchronous single organ OMD including non small-cell and neuroendocrine lung cancer with <=4 metastases between 2000 and 2016 in 3 lung cancer centers in Berlin, Germany. Patients either received LAT for all sites of disease (intervention group) by means of surgery or stereotactic radiotherapy, or standard chemotherapy, if necessary combined with a local treatment with palliative intent (control group). RESULTS: Median follow-up time was 32.2 and 18.8 months for the intervention and control group, respectively. Substantial benefits in median progression-free survival (PFS, 25.1 vs. 8.2 months; HR, 0.30; 95% CI, 0.21-0.43; p < 0.001) and overall survival (OS, 60.4 vs. 22.5 months; HR, 0.42; 95% CI, 0.28-0.62; p < 0.001) were associated with LAT. Histology of adenocarcinoma and T1a primaries also predicted a favorable prognosis concerning PFS and OS. More favorable nodal stage (N0-2 vs. 3) and solitary metastases were associated with an extended PFS, whereas initial ECOG-PS (0-1 vs. 2) predicted OS. CONCLUSIONS: LAT was the strongest predictor for PFS and OS in OMD with <=4 metastases. Survival in the control group identifies OMD as a subset of lung cancer with a generally more favorable prognosis. PMID- 30429017 TI - LMO7 and LIMCH1 interact with LRIG proteins in lung cancer, with prognostic implications for early-stage disease. AB - OBJECTIVES: The human leucine-rich repeats and immunoglobulin-like domains (LRIG) protein family comprises the integral membrane proteins LRIG1, LRIG2 and LRIG3. LRIG1 is frequently down-regulated in human cancer, and high levels of LRIG1 in tumor tissue are associated with favorable clinical outcomes in several tumor types including non-small cell lung cancer (NSCLC). Mechanistically, LRIG1 negatively regulates receptor tyrosine kinases and functions as a tumor suppressor. However, the details of the molecular mechanisms involved are poorly understood, and even less is known about the functions of LRIG2 and LRIG3. The aim of this study was to further elucidate the functions and molecular interactions of the LRIG proteins. MATERIALS AND METHODS: A yeast two-hybrid screen was performed using a cytosolic LRIG3 peptide as bait. In transfected human cells, co-immunoprecipitation and co-localization experiments were performed. Proximity ligation assay was performed to investigate interactions between endogenously expressed proteins. Expression levels of LMO7 and LIMCH1 in normal and malignant lung tissue were investigated using qRT-PCR and through in silico analyses of public data sets. Finally, a clinical cohort comprising 355 surgically treated NSCLC cases was immunostained for LMO7. RESULTS: In the yeast two-hybrid screen, the two paralogous proteins LMO7 and LIMCH1 were identified as interaction partners to LRIG3. LMO7 and LIMCH1 co-localized and co immunoprecipitated with both LRIG1 and LRIG3. Endogenously expressed LMO7 was in close proximity of both LRIG1 and LRIG3. LMO7 and LIMCH1 were highly expressed in normal lung tissue and down-regulated in malignant lung tissue. LMO7 immunoreactivity was shown to be a negative prognostic factor in LRIG1 positive tumors, predicting poor patient survival. CONCLUSION: These findings suggest that LMO7 and LIMCH1 physically interact with LRIG proteins and that expression of LMO7 is of clinical importance in NSCLC. PMID- 30429018 TI - Stereotactic body radiation therapy versus sublobar resection for stage I NSCLC. AB - PURPOSE: To compare sublobar resection and stereotactic body radiation therapy (SBRT) in patients with stage I non-small cell lung cancer (NSCLC). METHODS: Patients undergoing sublobar resection or SBRT for stage I NSCLC from 2007 to 2014 at Duke University Medical Center were evaluated. The primary endpoint of interest was freedom from local recurrence. Kaplan-Meier survival estimates and Cox proportional hazards multivariate analyses were performed. RESULTS: 221 patients with stage I NSCLC undergoing sublobar resection (n = 151; 105 wedge and 46 segmentectomy) or SBRT (n = 70) were evaluated. The majority (89%) of patients receiving SBRT were medically inoperable, and compared with surgical patients, were significantly older (74 vs 70 years, p = 0.019), had higher Charlson Comorbidity Indices (3.7 vs 2.7, p < 0.001), larger tumors (2.4 cm vs 1.7 cm, p < 0.001), and worse baseline pulmonary function. At 3 years, freedom from local recurrence was 90% (95% CI 82-94%) for surgery and 85% (95% CI 65-94%) for SBRT (p = 0.71). While overall survival and disease-free survival were higher in the surgical cohort, no differences were noted in cancer-specific disease-free survival (60% vs. 65%, p = 0.84). On multivariate analysis, higher Charlson Comorbidity Index (HR 1.38, 95% CI 1.19-1.61, p < 0.001) and lower diffusion capacity (HR 0.97, 95% CI 0.96-0.98, p < 0.001) were independently associated with inferior overall survival. No differences in overall survival between surgery and SBRT (HR 1.20, 95% CI 0.74-1.95, p = 0.46) were observed after correcting for baseline imbalances in prognostic factors. CONCLUSIONS: SBRT and sublobar resection provided similar rates of local tumor control and overall clinical outcomes in stage I NSCLC. PMID- 30429019 TI - Prognostic impact of preoperative comorbidities in geriatric patients with early stage lung cancer: Significance of sublobar resection as a compromise procedure. AB - OBJECTIVES: In high-risk operable geriatric patients undergoing palliative sublobar resection (SR), noncancerous comorbidities may contribute to unfavorable outcomes. The purpose of this retrospective study was to evaluate the perioperative safety and long-term survival of palliative SR in this patient population. MATERIALS AND METHODS: We reviewed 232 patients (141 male, 91 female) aged >=75 years who underwent surgical resection of clinical stage I lung cancer from 2006 to 2014. The patients were divided into two groups, lobectomy and SR, and preoperative comprehensive comorbidities were assessed using the Adult Comorbidity Evaluation 27 (ACE-27) and compared between the two groups. The operative safety was compared using the Clavien-Dindo classification. Survival rates were calculated with a Kaplan-Meier model under propensity score matching, and prognostic factors were analyzed using a Cox proportional hazard model. RESULTS: Lobectomy was performed in 156 patients and SR in 76 (segmentectomy, n = 50; wedge resection, n = 26). Age (p = 0.0137), tumor size on computed tomography (p < 0.0001), central tumor location (p = 0.0008), and high ACE-27 scores (p = 0.0202) were significantly associated with selection of SR. No mortality occurred, and the incidence of Grade 3b or greater postoperative complications in lobectomy and SR was 5.1% and 5.3%, respectively. According to the analysis of propensity score-matched patients (n = 57, tumor size = 23 mm, and consolidation/tumor ratio = 83%), the 5-year survival rate in lobectomy and SR was 81.1% and 73.5%, respectively (p = 0.4374). The ACE-27 score was a more significant prognostic factor than the type of surgical procedure, as well as consolidation/tumor ratio and nodal metastatic status. CONCLUSIONS: The severity of preoperative comorbidities is a significant prognostic factor, and SR as a compromise surgical procedure may provide promising short- and long-term outcomes in selected geriatric patients with clinical stage I lung cancer. PMID- 30429020 TI - A combination of MTAP and BAP1 immunohistochemistry is effective for distinguishing sarcomatoid mesothelioma from fibrous pleuritis. AB - OBJECTIVES: Histologic diagnosis of malignant pleural mesothelioma (MPM) is not always straightforward. Loss of BRCA1-associated protein 1 (BAP1) expression as detected by immunohistochemistry (IHC) (BAP1 IHC) and homozygous deletion (HD) of 9p21 as detected by fluorescencein situ hybridization (FISH) (9p21 FISH) are effective for distinguishing malignant mesothelial proliferation from benign proliferation. We have previously reported that immunohistochemical expression of the protein product of the methylthioadenosine phosphorylase (MTAP) gene, which is localized in the 9p21 chromosomal region, is correlated with the deletion status of 9p21 FISH in MPM tissues. In this study, we investigated whether a combination of MTAP and BAP1 IHC could distinguish sarcomatoid MPM from fibrous pleuritis. MATERIALS AND METHODS: We examined IHC expressions of MTAP and BAP1 and 9p21 FISH in sarcomatoid/desmoplastic (n = 18) and biphasic MPM (n = 12) and in fibrous pleuritis (n = 17). In biphasic MPM, only sarcomatoid components were evaluated for IHC and FISH. The sensitivity and specificity of each detection assay for discriminating MPM cases from fibrous pleuritis was determined. In addition, we compared the IHC expression of MTAP with the deletion status of 9p21 FISH. RESULTS: MTAP IHC and BAP1 IHC showed 80% and 36.7% sensitivity, respectively, and both showed 100% specificity in differentiating MPM from fibrous pleuritis. A combination of MTAP and BAP1 IHC yielded greater sensitivity (90%) than that detected for MTAP IHC alone or BAP1 IHC alone. Moreover, a high degree of concordance was observed between the results of MTAP IHC and HD of 9p21 FISH (kappa = 0.63). CONCLUSIONS: With an accurate interpretation of results, combined MTAP and BAP1 IHC is a reliable and effective method for distinguishing sarcomatoid MPM from fibrous pleuritis. PMID- 30429021 TI - Receipt of recommended surveillance with imaging in elderly survivors of early stage non-small cell lung cancer. AB - PURPOSE: Early-stage lung cancer survivorsremain at high risk for recurrence or second cancers. We measured the rates and determinants of regular surveillance imaging in early-stage non-small cell lung cancer (NSCLC) survivors. METHODS: Patients (diagnosed 2001-2011) with resected stage I and II NSCLC were identified from the Surveillance Epidemiology and End Results (SEER)-Medicare linked database. Patients were censored at recurrence/second cancer diagnosis, loss to follow-up or death. Receipt of a scan during the surveillance periods of 7-18, 19 30, 31-42 and 43-60 months from date of surgery was assessed. RESULTS: Of 10,680 survivors assessed during the 18-month surveillance period, 71% received imaging in first 18 months. Only 56% and 43% continued to receive regular imaging by 30 month and 60-month of follow-up, respectively. Survivors were less likely to receive imaging if they were older, black, unmarried, received no adjuvant therapy, had stage I disease (vs. stage II) or were diagnosed before 2006. In adjusted analysis, survivors who received recommended imaging up to 18 months from surgery experienced better survival compared to survivors who did not (HR 0.92; 95% CI 0.85-0.99). Survival benefit was also observed in survivors who underwent regular imaging up to 5 years from surgery (HR 0.68; 95% CI 0.60-0.78). CONCLUSIONS: More than half the lung cancer survivors received less than the recommended long-term surveillance imaging. Long-term adherence to surveillance is associated with improved survival. Our study provides evidence to support the current clinical guidelines for surveillance for lung cancer survivors that are primarily consensus-based at present. PMID- 30429022 TI - Pre-existing pulmonary fibrosis is a risk factor for anti-PD-1-related pneumonitis in patients with non-small cell lung cancer: A retrospective analysis. AB - OBJECTIVES: Pneumonitis related to the use of anti-programmed death 1 (PD-1) antibodies is a common immune-related adverse event that can be life-threatening. However, the relationship between pulmonary fibrosis/emphysema and the incidence of anti-PD-1-related pneumonitis is unclear. MATERIALS AND METHODS: We retrospectively reviewed data from 123 patients who were diagnosed with non-small cell lung cancer and treated with anti-PD-1 antibodies (nivolumab or pembrolizumab) at the Aichi Cancer Center Hospital, Japan, between December 17, 2015, and November 30, 2017. Patients who previously received thoracic radiotherapy to the primary lesion, mediastinum, spinal, or rib metastases were excluded from the analysis. Fibrosis score (0-5) and emphysema score (0-4) on baseline chest computed tomography (CT) were determined by two diagnostic radiologists. RESULTS: Eighteen patients (14.6%) experienced anti-PD-1-related pneumonitis, of which four (3.3%) were grade >=3. The median onset time of pneumonitis after starting anti-PD-1 therapy was 60 days (range, 6-634 days). According to the analysis of fibrosis score, pneumonitis occurred in 13 (35.1%) of the 37 patients with a fibrosis score >=1 and in 5 (5.8%) of 86 patients with a fibrosis score of 0. Univariate and multivariate logistic regression analysis revealed that fibrosis score >=1 was the only risk factor for anti-PD-1-related pneumonitis (p = 0.0008). CONCLUSION: Our results indicate that pre-existing pulmonary fibrosis significantly increases the risk of anti-PD-1-related pneumonitis. Further studies are needed to identify predictive factors of anti-PD 1-related pneumonitis in patients with fibrotic changes on CT findings. PMID- 30429023 TI - Minute ventilation-to-carbon dioxide slope is associated with postoperative survival after anatomical lung resection. AB - OBJECTIVES: The aim of the study was to identify whether ventilation-to-carbon dioxide output (VE/V CO2) slope obtained from cardiopulmonary exercise test (CPET) as part of the preoperative functional workup was an independent prognostic factor for short and long-term survival after major lung resection. PATIENTS AND METHODS: 974 consecutive patients undergoing lobectomy (n = 887) or segmentectomy (n = 87) between April 2014 to March 2018 were included. 209 (22%) underwent CPET, and pulmonary function tests and several clinical factors including age, sex, performance status and comorbidities were retrospectively investigated to identify the prognostic factors with a multivariable Cox regression analysis. RESULTS: Among the patients with measured VE/V CO2, the incidence of cardiopulmonary complications in patients with high VE/V CO2 slope (>40) was 37% (19 of 51) vs. 27% (33 of 121) in those with lower slope values (p = 0.19). The 90-day mortality in patients with high VE/V CO2 slope (n = 8) was 16% vs. 5% (n = 6) in those with lower slope values (p = 0.03). No overall difference in 2-year mortality was identified between the two groups (VE/VCO2 > 40: 70% (54-80) vs. VE/VCO2 <= 40: 72% (63-80), log-rank test, p = 0.39). In a Cox regression analysis VE/VCO2 values were associated with poorer 2-year survival (HR 1.05, 95% CI 1.01-1.10, p = 0.030). CONCLUSIONS: We found that VE/V CO2 slope was an independent prognostic factor for the 90-day mortality and 2 year survival after anatomic pulmonary resection. This finding may assist during the multidisciplinary treatment decision-making process in high-risk patients with lung cancer. PMID- 30429024 TI - Impact of serum vascular endothelial growth factor and interleukin-6 on treatment response to epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small-cell lung cancer. AB - BACKGROUND: Although EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC), responses vary within individuals. The current study aimed to investigate whether serum levels of several cytokines and their dynamic changes during TKI treatment could be used to predict the efficacy of EGFR-TKIs. MATERIALS AND METHODS: Pre treatment and one-month post-treatment serum levels of hepatocyte growth factor (HGF), interleukin-10 (IL-10), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interferon gamma (IFN-gamma) and monocyte chemotactic protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay and U-plex biomarker group assays in patients with EGFR-mutant NSCLC received first-line EGFR-TKIs. RESULTS: Patients who had lower baseline serum levels of IL-6 had better object response rate (ORR) than those with high levels (74.2% vs 42.9%, p = 0.014). PFS was significantly longer in patients with low baseline level of IL 6 (19.57 vs. 13.73 months, p = 0.003) and in those with reduced serum VEGF and HGF levels after treatment (20.30 vs. 14.33 months, p = 0.009; 22.77 vs. 14.33 months, p = 0.002; respectively). Multivariate analyses showed that lower baseline serum IL-6 level was significantly associated with longer PFS (HR = 0.469, p = 0.022) and OS (HR = 0.181, p = 0.004). Reduction of serum VEGF and HGF levels after treatment was associated with significantly longer PFS (HR = 0.447, p = 0.017; HR = 0.365, p = 0.003; respectively). Lower pre-treatment serum VEGF level was associated with dramatically longer OS (HR = 0.277, p = 0.018). CONCLUSIONS: Our study suggested that serum levels of HGF, IL-6 and VEGF and its dynamic change during TKI treatment could be used to predict the efficacy of EGFR TKIs treatment in patients with EGFR-mutant NSCLC. PMID- 30429025 TI - Multi-centre prospective study on diagnosing subtypes of lung cancer by exhaled breath analysis. AB - OBJECTIVES: Lung cancer is a leading cause of mortality. Exhaled-breath analysis of volatile organic compounds (VOC's) might detect lung cancer early in the course of the disease, which may improve outcomes. Subtyping lung cancers could be helpful in further clinical decisions. MATERIALS AND METHODS: In a prospective, multi-centre study, using 10 electronic nose devices, 144 subjects diagnosed with NSCLC and 146 healthy subjects, including subjects considered negative for NSCLC after investigation, breathed into the AeonoseTM (The eNose Company, Zutphen, Netherlands). Also, analyses into subtypes of NSCLC, such as adenocarcinoma (AC) and squamous cell carcinoma (SCC), and analyses of patients with small cell lung cancer (SCLC) were performed. RESULTS: Choosing a cut-off point to predominantly rule out cancer resulted for NSCLC in a sensitivity of 94.4%, a specificity of 32.9%, a positive predictive value of 58.1%, a negative predictive value (NPV) of 85.7%, and an area under the curve (AUC) of 0.76. For AC sensitivity, PPV, NPV, and AUC were 81.5%, 56.4%, 79.5%, and 0.74, respectively, while for SCC these numbers were 80.8%, 45.7%, 93.0%, and 0.77, respectively. SCLC could be ruled out with a sensitivity of 88.9% and an NPV of 96.8% with an AUC of 0.86. CONCLUSION: Electronic nose technology with the AeonoseTM can play an important role in rapidly excluding lung cancer due to the high negative predictive value for various, but not all types of lung cancer. Patients showing positive breath tests should still be subjected to further diagnostic testing. PMID- 30429026 TI - Comparative study of programmed cell death ligand-1 immunohistochemistry assays using 22C3 and 28-8 antibodies for non-small cell lung cancer: Analysis of 420 surgical specimens from Japanese patients. AB - OBJECTIVES: Multiple programmed cell death ligand-1 (PD-L1) immunohistochemistry assays are currently used as companion or complementary diagnostic tools for anti programmed cell death-1 immunotherapies. We aimed to characterize two PD-L1 immunohistochemistry assays (Dako 22C3 and 28-8) for non-small cell lung cancer (NSCLC) in clinical laboratories. MATERIALS AND METHODS: Surgical specimens from 420 patients with pathological stages IA to IIIA NSCLC were investigated. The archived samples were freshly cut into 5-MUm-thick sections stained with antibodies 22C3 and 28-8, and tumoral PD-L1 expression was evaluated in two clinical laboratories, respectively. Overall, positive, and negative percent agreement (OPA, PPA, and NPA, respectively) at specified PD-L1 cutoffs were calculated to assess the concordance between 22C3 and 28-8 assays. RESULTS: Tumoral PD-L1 expression of >= 1% was detected by either 22C3 or 28-8 assays in 176 cases (41.9%), whereas 22C3 revealed a significantly higher tumoral PD-L1 expression compared to 28-8 (median 30% vs. 10%, p < 0.0001). OPA was 89.0, 90.2, and 91.9% at 1, 25, and 50% cutoff levels. When 22C3 was compared to a standard assay 28-8, the PPA was 85.5, 98.3, and 94.9%, whereas NPA was 91.0, 89.0, and 91.6% at 1, 25, and 50%. On the other hand, when 28-8 was compared to 22C3, PPA was 84.4% at 1%, but it decreased to 58.3 and 53.6% at 25 and 50%; whereas NPA remained high (91.7, 99.7, and 99.4% at 1, 25 and 50%, respectively). CONCLUSION: Our analysis revealed that, despite the high OPA, there was discordance in the PPA between 22C3 as a standard assay and 28-8 as a comparator assay at 25% and 50% PD-L1 cutoff levels, indicating that the results of 28-8 could be translated to those of 22C3 but not vice versa. PMID- 30429027 TI - Use of health insurance data to identify and quantify the prevalence of main comorbidities in lung cancer patients. AB - BACKGROUND: Identifying comorbidities in lung cancer patients is a complex process in population-based studies and no gold standard exists. The current study aims to identify and measure the main comorbidities using administrative health insurance data, which were available on a population-based level. METHOD: A literature search was conducted to identify comorbidities in lung cancer patients and to select Anatomical Therapeutic Chemical codes to measure them. For each patient, the volume of delivered relevant drugs for each comorbidity in the year preceding the diagnosis of lung cancer was computed, based on the Defined Daily Doses reimbursed. Case definition rules were set by comparing the identification of comorbidities via health insurance data with the reporting of them in the medical files in a sample of hospitals. RESULTS: Four comorbidities were identified: chronic respiratory diseases, chronic cardiovascular diseases, diabetes mellitus and renal diseases. A very good to moderate agreement between the prevalence based on medical files versus health insurance data was obtained for diabetes mellitus (kappa = 0.83), chronic cardiovascular diseases (kappa = 0.64), chronic respiratory diseases (kappa = 0.48) but not for renal diseases (kappa = 0.22). Because only 27% of patients having renal diseases recorded in the medical files were identified using health insurance data, this comorbidity was not withheld. Among 12,839 lung cancer patients diagnosed in 2010-2011 in Belgium, 29.7% had chronic respiratory diseases, 57.5% had chronic cardiovascular diseases and 14.1% had diabetes mellitus. DISCUSSION: This study showed that it was possible to capture three major comorbidities in lung cancer patients using administrative health data, namely, diabetes mellitus, chronic cardiovascular diseases, and chronic respiratory diseases. However, the agreement was only moderate for the last one. A prerequisite for using this methodology is that administrative health data are available for all patients. PMID- 30429028 TI - Proposal on incorporating lymphovascular invasion as a T-descriptor for stage I lung cancer. AB - BACKGROUND: Lymphovascular invasion (LVI) and Visceral Pleural Invasion (VPI) have been reported to be risk factors for stage I Non-Small Cell Lung Cancer (NSCLC). However, only VPI was incorporated into the current 8th Tumor-Node Metastasis (TNM) classification. This study aimed to explore the prognostic effect of LVI and VPI on TNM staging in pathological stage I NSCLC. METHOD: We retrospectively reviewed 2633 consecutive p-stage I NSCLC patients in the Shanghai Chest Hospital (2008-2012). By using the Kaplan-Meier method and Cox proportional hazard regression model, we identified the correlations between LVI, VPI, and clinical outcomes in p-stage 1 NSCLC. RESULTS: Of all 2633 p-stage I NSCLC patients, 222 were pathologically diagnosed with LVI and 836 pathologically with VPI. The 5-year recurrence free survival (RFS) and overall survival (OS) rates of patients with LVI was significantly worse compared to those without LVI (61.2% vs 82.0%, p < 0.001; 73.3% vs 88.1%, p < 0.001). The same results emerged for patients with VPI (70.1% vs 85.9%, p < 0.001; 82.3% vs 90.0%, p < 0.001). Using the univariable and multivariable analysis, we found that when tumor diameter was 3 cm or smaller, LVI (RFS: hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.86-3.50; p < .001; OS: HR, 2.53; 95% CI, 1.72-3.71; p < .001) and VPI (RFS: HR, 2.14; 95% CI, 1.71-2.67; p < .001; OS: HR, 1.56; 95% CI, 1.12 2.04; p = 0.01) were significant prognostic factors for RFS and OS. When tumor size was between 3-4 cm, LVI (HR, 1.84; 95% CI, 1.03-3.29; p = 0.039) and VPI (HR, 2.56; 95% CI, 1.61-4.07; p < .001) were associated with inferior OS. CONCLUSIONS: The presence of LVI significantly affected OS and RFS in stage I NSCLC patients. Our results suggested that it might be better to incorporate LVI as a T descriptor as VPI in the further TNM classification. PMID- 30429029 TI - New risk scoring system for predicting acute exacerbation of interstitial pneumonia after chemotherapy for lung cancer associated with interstitial pneumonia. AB - BACKGROUND: Fatal acute exacerbation (AE) of interstitial pneumonia (IP) sometimes occurs after chemotherapy for lung cancer. We developed and evaluated a scoring system for assessing AE risk after chemotherapy in patients with lung cancer associated with IP. METHODS: A review of medical records identified 109 patients with primary lung cancer associated with IP who had received chemotherapy at our center during the period from June 2007 through September 2017. We developed a model to score AE risk after chemotherapy in this patient group, and logistic regression was used to evaluate the model. RESULTS: The anticancer agent score was determined by using AE rates reported in past studies. The risk score was calculated with the following formula: (1 * anticancer agent score) + (3 * smoking history [>70 pack-years]) + (4 * history of steroid use) + (3 * %diffusing capacity of lung carbon monoxide [<50%]). Patients were then classified into three groups. The AE incidence rate was 12% for a risk score of 0 5, 47% for a score of 6-10, and 66.7% for a score of >=11. The sensitivity of the scoring system was 78.6% and specificity was 67.8%. CONCLUSIONS: The present scoring system was able to identify IP patients at high risk for AE after chemotherapy for lung cancer associated with IP. PMID- 30429030 TI - Real-life treatment practice for malignant pleural mesothelioma in Belgium. AB - OBJECTIVES: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer, for which treatment is often limited to palliative combination chemotherapy. Multimodality-therapy, including radical surgery, is largely restricted to clinical trials, leaving its benefit currently unclear. This study aimed to get a comprehensive view on real-world MPM treatment at the Belgian population level, to assess survival and to identify prognostic factors. MATERIALS AND METHODS: The study period covered the incidence years 2004-2012 (N = 1453). Starting from the Belgian Cancer Registry, additional information regarding patient characteristics, diagnosis and treatment was retrieved from multiple data sources. Adjusted cox proportional-hazard regression models using time-dependent covariates were performed to assess survival in relation to treatment patterns and centre volume. RESULTS: Sixty-nine percent of patients underwent tumour directed treatment, mostly cisplatin-pemetrexed chemotherapy. Radical surgery was mainly performed in younger patients with epithelioid subtype. Centre volume, surgery and chemotherapy showed a positive relation with survival in univariable analyses, but only chemotherapy remained significantly relevant in multivariable analyses. Younger patients, females, and epithelioid subtypes also independently had a better survival. CONCLUSION: This large population-based study provides insights in MPM treatment practice in Belgium. Centre volume and surgery being related to survival in univariable analyses, only chemotherapy remained prognostic after adjustment. PMID- 30429031 TI - EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP). AB - OBJECTIVES: Contrasting other EGFR mutations (EGFRm) in lung adenocarcinomas, insertions in exon 20 (exon20ins) are generally associated with resistance to targeted therapy, limiting therapeutic options and impoverishing the prognosis compared to other EGFRm. We sought to extensively characterize exon20ins from a large cohort of lung adenocarcinomas in Hispanic patients. MATERIALS AND METHODS: This was a region-wide, observational longitudinal cohort study to evaluate characteristics and outcomes of patients with exon20ins in lung adenocarcinoma, based on a secondary analysis of electronic records from the Geno1.2-CLICaP Platform and extended genotype testing. Patients from six Latin-American countries were included (Argentina, Colombia, Costa Rica, Ecuador, Panama, and Mexico). Data obtained included the molecular spectrum (extended genotyping for mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1, as well as for EGFR amplification, ALK and PD-L1 protein expression), clinic-pathologic characteristics, prevalence and outcomes to therapeutic approach. RESULTS AND CONCLUSIONS: 4.005 patients diagnosed with stage III/IV lung adenocarcinoma from 2011 to 2016 were initially screened. Among these, 88 patients had a confirmed exon20 in. and were included; median age was 66-years, 62.5% were females, 64% were never smokers and 39% presented with brain metastases. The H773insH variant was the most frequent, making up 21.6% of cases. A common EGFRm was concomitantly found in 36.4% (del19/L858R), and 8% (G719X/L861Q/S768I) of cases. Five cases had additional mutations in PI3K, KRAS and MEK1, 26% had EGFR amplification and 81.7% had PD-L1 expression 1-50%. Overall response rate to first-line therapy was 28% and overall survival was 16.4 months. Prognosis was positively influenced by the concomitant presence of common EGFRm and response to first-line. Our results suggest that patients with EGFR exon20ins have similar clinical characteristics to those with common EGFRm but a poorer prognosis. Last, the mean PD-L1 expression in this population seems higher than for patients with common EGFRm. PMID- 30429032 TI - Pembrolizumab and platinum-based chemotherapy as first-line therapy for advanced non-small-cell lung cancer: Phase 1 cohorts from the KEYNOTE-021 study. AB - OBJECTIVES: Platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) has modest benefit overall, but has the potential to amplify immune responses. In cohorts A-C of the multicohort phase 1/2 study KEYNOTE-021 (Clinicaltrials.gov, NCT02039674), we evaluated combinations of platinum-doublet chemotherapy with the anti-programmed death 1 monocloncal antibody pembrolizumab. MATERIALS AND METHODS: Patients with previously untreated, advanced NSCLC without EGFR/ALK aberrations were randomized to pembrolizumab 2 or 10 mg/kg Q3W plus carboplatin area under the serum concentration-time curve (AUC) 6 mg/mL/min plus paclitaxel 200 mg/m2 (cohort A, any histology), carboplatin AUC 6 mg/mL/min plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg (cohort B, non-squamous), or carboplatin AUC 5 mg/mL/min plus pemetrexed 500 mg/m2 (cohort C, non-squamous) for 4 cycles followed by maintenance pembrolizumab (cohort A), pembrolizumab plus bevacizumab (cohort B), or pembrolizumab plus pemetrexed (cohort C). Response was assessed by blinded independent central review. RESULTS: Overall, 74 patients were randomized; median follow-up was 21.4, 16.4, and 17.4 months in cohorts A, B, and C, respectively. No dose-limiting toxicities occurred in any cohort at either pembrolizumab dose. Most frequent treatment-related adverse events (AEs) were alopecia, fatigue, and nausea. Treatment-related grade 3/4 AEs occurred in 40%, 42%, and 46% of patients in cohorts A, B, and C, respectively; AEs with possible immune etiology occurred in 24%, 50%, and 38% of patients, respectively. Objective response rates were 48%, 56%, and 75% in cohorts A, B, and C, respectively. CONCLUSION: Pembrolizumab in combination with carboplatin paclitaxel and with pemetrexed-carboplatin yielded encouraging antitumor activity and toxicity consistent with known toxicities of platinum-based chemotherapy or pembrolizumab monotherapy. PMID- 30429033 TI - Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer. AB - OBJECTIVE: Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. MATERIALS AND METHODS: Four patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel. RESULTS: The distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases. CONCLUSIONS: Our data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways. PMID- 30429034 TI - Predicting survival following surgical resection of lung cancer using clinical and pathological variables: The development and validation of the LNC-PATH score. AB - INTRODUCTION: The aim of this study was to develop and validate a simple prognostic scoring system using readily available clinical and pathological variables that could stratify patients according to the risk of death following lung cancer resection. We hypothesized that by using additional pathological variables not accounted for by pathological stage alone coupled with markers of overall fitness a new prognostic tool could be developed. METHODS: Multivariable logistic regression analysis of pathological and other clinical variables from patients undergoing surgical resection of non-small cell lung cancer (NSCLC) were used to determine factors independently associated with 2-year overall survival and so derive the scoring system. The model was then validated in an external multi-centre dataset. RESULTS: Using multivariable logistic regression on a large dataset (n = 1,421) the 'LNC-PATH' (Lymphovascular invasion, N-stage, adjuvant Chemotherapy, Performance status, Age, T-stage, Histology) prognostic score was devised and then validated using an external dataset (n = 402). This can be used to risk stratify patients into low, moderate and high-risk groups with a statistically significant difference between the three groups in their survival distributions. 83.8% of patients in the low-risk group survived two years after surgery compared to 55.6% in the moderate-risk group and 26.2% in the high-risk group. The score was shown to perform moderately well with an Area Under the Receiver Operating Characteristic curve (AUROC) value of 0.76 (95% CI: 0.73-0.79) and 0.70 (95% CI: 0.64-0.76) in the derivation and validation cohorts respectively. DISCUSSION: The LNC-PATH score predicts 2-year overall survival after surgery for NSCLC. This may allow the development of risk stratified follow up protocols in survivorship clinics which could be the subject of future prospective studies. PMID- 30429035 TI - Chemerin as a biomarker at the intersection of inflammation, chemotaxis, coagulation, fibrinolysis and metabolism in resectable non-small cell lung cancer. AB - OBJECTIVES: Chemerin is an emerging adipocytokine at the intersection of inflammation, chemotaxis, thrombosis, fibrinolysis and metabolism. Our aims were 1) to explore circulating chemerin in resectable non-small cell lung cancer (NSCLC) taking into account its several interfaces; 2) to study its diagnostic potential; and 3) to assess its associations with clinicopathological features of NSCLC. MATERIALS AND METHODS: In a large case-control study, serum chemerin, insulin resistance and lipid parameters, classic adipocytokines, inflammatory, coagulation, fibrinolysis and tumor biomarkers were determined in 110 consecutive patients with resectable NSCLC and 110 healthy controls matched on age (+/- 5 years), gender and date of blood draw (+/- 1 month). RESULTS: NSCLC cases exhibited significantly elevated circulating chemerin compared to controls (p < 0.001). In NSCLC cases, chemerin was positively associated with Homeostasis model assessment score of insulin resistance (HOMA-IR), fibrinogen, plasminogen activity, tumor and inflammatory biomarkers, adiponectin, number of infiltrated lymph nodes and NSCLC stage. In control participants, circulating chemerin was positively correlated with somatometric, metabolic, lipid, hemostatic and inflammatory biomarkers, and leptin. Serum chemerin was independently associated with NSCLC, above and beyond NSCLC risk factors (OR: 2.20, 95% CI: 1.09-4.40, p = 0.03). In cases, hemostatic parameters (platelet count and plasminogen activity), HOMA-IR, CYFRA 21-1, creatinine and plant food consumption emerged as independent predictors of circulating chemerin (p < 0.05). Serum chemerin greater than 220 MUg/L (cut-off point) yielded a sensitivity and a specificity of 63% and 91.8% respectively with a modest discriminative ability (AUC = 0.72, 95% C.I. 0.64 0.79) for the diagnosis of NSCLC. CONCLUSION: Chemerin may represent a potentially useful biomarker in NSCLC integrating tumor-promoting networks, inflammatory and hemostatic mechanisms, and cancer-related metabolic pathways. More preclinical, prospective and longitudinal studies highlighting the pathogenetic role of chemerin in NSCLC are needed to corroborate and extend these data. PMID- 30429036 TI - Different pattern of PD-L1, IDO, and FOXP3 Tregs expression with survival in thymoma and thymic carcinoma. AB - OBJECTIVES: The expression of immune checkpoint ligand PD-L1 has been reported in various tumors. The expression of IDO and FOXP3 Tregs are considered to be associated with tumor-induced tolerance and poor outcome. Their prognostic role in surgically treated thymoma and thymic carcinoma, however, has not been investigated. MATERIALS AND METHODS: Tissue microarray (TMA) blocks comprised of 100 surgically treated thymomas and 69 surgically treated thymic carcinomas were conducted. Tissue sections were incubated with primary antibodies against PD-L1 (clone E1L3N, 1:100), IDO (clone 10.1, 1:50), and FOXP3 (clone 236 A/E7, 1:50). Comparisons for categorical variables were performed using chi2 test and Fisher's exact test. Survival analysis was established using Kaplan-Meier method and log rank test. Univariate and multivariate analyses were performed using Cox regression model. RESULTS AND CONCLUSIONS: High expression of PD-L1, IDO, and FOXP3 Tregs were identified in 36 (36%), 13 (13%), and 16 (16%) thymoma patients, respectively. High expression of PD-L1, IDO, and FOXP3 Tregs was associated with higher grade of tumor histology (P < 0.001, P = 0.007, and 0.014, respectively). High expression of PD-L1 was also associated with advanced Masaoka staging (P < 0.001). In patients with thymic carcinoma, high expression of PD L1, IDO, and FOXP3 Tregs were identified in 25 (36%), 10 (14%), and 20 (29%) patients, respectively. Complete resection, low expression of IDO, and high expression of FOXP3 Tregs were associated with better overall survival (P = 0.001, 0.004, and 0.032, respectively), and progression-free survival (P < 0.001, P = 0.026, and 0.047, respectively) in multivariate analysis. In surgically treated thymoma, high PD-L1 expression was associated with advanced Masaoka staging. High PD-L1, IDO, and FOXP3 Tregs expression was associated with high grade histology. In surgically treated thymic carcinoma, significant survival benefit was noted in patients with complete resection, low IDO expression, and high FOXP3 Tregs expression. PMID- 30429037 TI - Three new disease-progression modes in NSCLC patients after EGFR-TKI treatment by next-generation sequencing analysis. AB - INTRODUCTION: Most non-small-cell lung cancer (NSCLC) patients who exhibit good clinical responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) will inevitably develop disease progression. Herein, through next-generation sequencing (NGS), we aimed to investigate three new disease-progression modes of NSCLC patients after EGFR-TKI treatment. MATERIALS AND METHODS: Patients with sensitive EGFR-mutations who acquired resistance to EGFR-TKIs and whose tissues were subjected to post progression NGS were enrolled. The clinical characteristics, progression-free survival (PFS), genomic alterations and expression of EGFR-mutations among the three disease-progression modes were retrospectively analyzed. RESULTS AND CONCLUSION: The sites of disease progression were as follows: primary foci in 19.5% (8/41) (Mode 1), metastatic foci in 31.7% (13/41) (Mode 2), and both primary and metastatic foci in 48.8% (20/41) (Mode 3). The median PFS in Mode 1 was 6 months (95% CI 1-8), which was significantly shorter than the 11 months (95% CI 8-14) in Mode 2 and the 10 months (95% CI 3-16) in Mode 3 (p = 0.0084). The expression of Del19 was significantly different among the three modes (p = 0.02). The numbers and species of mutant genes in Mode 3 were obviously greater than those in Modes 1 and 2, and no gene amplifications were observed in Mode 2. Mutations in the TP53 gene were the most frequent genetic alteration found in our study, and these accounted for 48.8% (20/41) of all alterations. TP53 mutations in Mode 1 were mainly in exons 6 and 8, while in Mode 2 and Mode 3, all mutations were located from exon 4 to exon 8. A significant benefit in PFS was observed in the metastatic foci progression mode and in the dual primary and metastatic foci progression mode rather than in the primary foci progression mode, which had significant value in the design of therapeutic strategies. PMID- 30429038 TI - Examining the role of access to care: Racial/ethnic differences in receipt of resection for early-stage non-small cell lung cancer among integrated system members and non-members. AB - OBJECTIVES: To examine the role of uniform access to care in reducing racial/ethnic disparities in receipt of resection for early stage non-small cell lung cancer (NSCLC) by comparing integrated health system member patients to demographically similar non-member patients. MATERIALS AND METHODS: Using data from the California Cancer Registry, we conducted a retrospective cohort study of patients from four racial/ethnic groups (White, Black, Hispanic, Asian/Pacific Islander), aged 21-80, with a first primary diagnosis of stage I or II NSCLC between 2004 and 2011, in counties served by Kaiser Permanente Northern California (KPNC) at diagnosis. Our cohort included 1565 KPNC member and 4221 non member patients. To examine the relationship between race/ethnicity and receipt of surgery stratified by KPNC membership, we used modified Poisson regression to calculate risk ratios (RR) adjusted for patient demographic and tumor characteristics. RESULTS: Black patients were least likely to receive surgery regardless of access to integrated care (64-65% in both groups). The magnitude of the black-white difference in the likelihood of surgery receipt was similar for members (RR: 0.82, 95% CI: 0.73-0.93) and non-members (RR: 0.86, 95% CI: 0.80 0.94). Among members, roughly equal proportions of Hispanic and White patients received surgery; however, among non-members, Hispanic patients were less likely to receive surgery (non-members, RR: 0.93, 95% CI: 0.86-1.00; members, RR: 0.98, 95% CI: 0.89-1.08). CONCLUSION: Disparities in surgical treatment for NSCLC were not reduced through integrated health system membership, suggesting that factors other than access to care (e.g., patient-provider communication) may underlie disparities. Future research should focus on identifying such modifiable factors. PMID- 30429040 TI - Lung cancer mortality in Australia: Projected outcomes to 2040. AB - OBJECTIVES: The aim was to develop and validate a statistical model which uses past trends for lung cancer mortality and historical and current data on tobacco consumption to project lung cancer mortality rates into the future for Australia. METHODS: We used generalized linear models (GLMs) with Poisson distribution including either age, birth cohort or period, and/or various measures of population tobacco exposure (considering cross-sectional smoking prevalence, cigarettes smoked and tar exposure per capita). Sex-specific models were fitted to data for 1956-2015 and age-standardized lung cancer mortality rates were projected forward to 2040. Possible lags of 20-30 years between tobacco exposure and lung cancer mortality were examined. The best model was selected using analysis of deviance. To validate the selected model, we temporarily re-fitted it to data for 1956-1990 and compared the projected rates to 2015 with the observed rates for 1991-2015. RESULTS: The best fitting model used information on age, birth cohort and tar exposure per capita; close concordance with the observed data was achieved in the validation. The forward projections for lung cancer mortality using this model indicate that male and female age-standardized rates will decline over the period 2011-2015 to 2036-2040 from 27.2 to 15.1 per 100,000, and 15.8 to 11.8 per 100,000, respectively. However, due to population growth and ageing the number of deaths will increase by 7.9% for males and 57.9% for females; from 41,040 (24,831 males, 16,209 females) in 2011-2015 to 52,403 (26,805 males, 25,598 females) in 2036-2040. CONCLUSION: In the context of the mature tobacco epidemic with past peaks in tobacco consumption for both males and females, lung cancer mortality rates are expected to continually decline over the next 25 years. However, the number of lung cancer deaths will continue to be substantial, and to increase, in Australia's ageing population. PMID- 30429039 TI - MET amplification increases the metastatic spread of EGFR-mutated NSCLC. AB - BACKGROUND: Five to 20% of metastatic EGFR-mutated non-small cell lung cancers (NSCLC) develop acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) through MET amplification. The effects of MET amplification on tumor and patient phenotype remain unknown. METHODS: We investigated,in vitro and in vivo, the impact of MET amplification on the biological properties of the HCC827 cell line, derived from an EGFR-mutated NSCLC. We further evaluated the time to new metastases after EGFR-TKI progression in EGFR-mutated NSCLC, exhibiting MET amplification or high MET overexpression. RESULTS: MET amplification significantly enhanced proliferation, anchorage independent growth, anoikis resistance, migration, and induced an epithelial to mesenchymal transition. In vivo, MET amplification significantly increased the tumor growth and metastatic spread. Treatment with a MET-TKI reversed this aggressive phenotype. We found that EGFR-mutated NSCLC patients exhibiting MET amplification on a re-biopsy, performed after EGFR-TKI progression, displayed a shorter time to new metastases after EGFR-TKI progression than patients with high MET overexpression but no MET amplification. CONCLUSION: MET amplification increases metastatic spread even in the context of an already pre-existing strong driver mutation such as EGFR mutation. These results prompt development of therapeutic strategies aiming at preventing emergence of MET amplification. PMID- 30429041 TI - Increased incidence, morbidity and mortality rates for lung cancer in women in Brazil between 2000 and 2014: An analysis of three types of sources of secondary data. AB - INTRODUCTION: Lung cancer is the principal cause of death from cancer worldwide. However, little is known of its epidemiological and histological profile and of the incidence and mortality rates in Brazil according to sex. OBJECTIVES: To evaluate the incidence, morbidity and mortality rates of lung cancer in Brazil from 2000 to 2014, as well as the epidemiological, clinical and morphological profile of women with lung cancer in Brazil is described. METHODS: An ecological study was conducted using three reliable sources of secondary data: population based cancer registries, hospital-based cancer registries and the national mortality database. RESULTS: The incidence rate in women increased from 7.92/100,000 in 2000 to 9.12/100,000 in 2012, while mortality increased from 6.02/100,000 in 2000 to 8.29/100,000 in 2014. In men, the incidence decreased from 23.40/100,000 in 2000 to 18.47/100,000 in 2012 and mortality also fell from 16.12/100,000 to 15.11/100,000 in 2014. There was a reduction in the male-to female ratio from 2.54 in 2000 to 1.46 in 2014. Women tended to be younger (p < 0.001), black (p < 0.001), non-smokers (p < 0.001), to have adenocarcinoma or small-cell lung cancer (p < 0.001), and to have metastatic disease (p < 0.001). In addition, the time between diagnosis and the start of cancer treatment was longer in women (p < 0.001). In relation to treatment, women were more likely to have undergone chemotherapy, surgery or surgery in combination with chemotherapy (p < 0.001) and to have response to the initial treatment (p < 0.001). CONCLUSION: Incidence, morbidity and mortality rates of lung cancer in women of Brazil increased in the most recent years. PMID- 30429042 TI - Applicability of the lung-molGPA index in non-small cell lung cancer patients with different gene alterations and brain metastases. AB - OBJECTIVES: The Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data, predicting the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic values of both DS GPA and Lung-molGPA remain undetermined, especially for patients with different molecular types. MATERIALS AND METHODS: A total of 1184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations. RESULTS: NSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models could effectively predict the outcomes of NSCLC patients with BM (P < 0.001), and the Lung-molGPA model appeared to deliver more accurate predictions. Furthermore, Lung-molGPA scores demonstrated discriminatory capability in patients with gene variations (P < 0.001), and no significant difference was reached in wild-type patients (P = 0.133). Regarding oncogene-positive NSCLC patients with BM, a modified Lung-molGPA index was established based on the prognostic factors with a C-index of 0.73 (95% CI: 0.68 0.80) to accurately calculate survival probability (P < 0.001). CONCLUSIONS: In the era of precision medicine, Lung-molGPA accurately predicted the prognosis of NSCLC patients with mutant genotypes and BM, although it did not perform well in wild-type patients. Thus, it is worthwhile to explore the prognostic model for patients with positive driving genes. PMID- 30429043 TI - Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer. AB - OBJECTIVES: EGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8+ T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS). MATERIALS AND METHODS: Tumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8+ T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD L1+/CD8+, PD-L1-/CD8+, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed. RESULTS: In patients with EGFR mutations or ALK rearrangements, proportion of PD L1+/CD8+ tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK, 14.2% (45/316) tumors were PD-L1+/CD8+ and 50.3% (159/316) tumors were PD-L1-/CD8- (P < 0.001). Median OS of EGFR-mutated or ALK-rearranged lung cancer was 78.6 months in PD-L1 positive group and 93.4 months in PD-L1 negative group (HR 0.47, 95%CI 0.23-0.76, P = 0.005). PD-L1+/CD8+ group exhibited the shortest OS, with 44.3 months, but is likely to respond to CPIs. The PD-L1-/CD8+ group exhibited the longest OS but is unlikely to respond to CPIs. CONCLUSION: Patients with EGFR mutations or ALK rearrangements exhibited lower PD-L1 and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-L1 and CD8 co expression in EGFR-mutated or ALK-rearranged lung cancer is a biomarker for poor prognosis with shorter OS. PMID- 30429044 TI - A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non small cell lung cancer patients with interstitial lung disease. AB - OBJECTIVES: The clinical benefit of chemotherapy and the appropriate regimen for non-small-cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) remain unclear. To fulfill this unmet medical need, we conducted a phase II study to elucidate the efficacy of S-1 in combination with carboplatin (CBDCA) in NSCLC patients with ILD. MATERIALS AND METHODS: A total of 33 advanced or recurrent NSCLC patients with ILD were prospectively enrolled in this multicenter, open label, phase II study. Every 4 weeks, CBDCA at a dose of AUC 5 on day 1 and S-1 at a dose of 80 mg/m2 daily for 14 days were administered. The primary endpoint was the investigator-assessed objective response rate. RESULTS: The median age at initiating chemotherapy was 70. Sixteen patients (48.5%) had squamous cell carcinoma histology. With respect to the types of ILD, the usual interstitial pneumonia pattern was dominant (66.7%). The median number of cycles administered was 3, and the overall response rate and disease control rate were 33.3% and 78.8%, respectively. The median progression-free survival, the median survival time and the 1-year survival rate were 4.8 months, 12.8 months and 51.4%, respectively. Acute exacerbation of ILD caused by chemotherapy was noted in 2 patients (6.1%). CONCLUSION: This is the first prospective study designed to evaluate the efficacy of a specific chemotherapeutic regimen as the primary endpoint in patients with advanced NSCLC with ILD. The combination of S-1 with CBDCA may be a treatment option for advanced NSCLC patients with ILD (The clinical trial registration number: UMIN000011046). PMID- 30429045 TI - In Vivo PET Tracking of 89Zr-Labeled Vgamma9Vdelta2 T Cells to Mouse Xenograft Breast Tumors Activated with Liposomal Alendronate. AB - Gammadelta T (gammadelta-T) cells are strong candidates for adoptive immunotherapy in oncology due to their cytotoxicity, ease of expansion, and favorable safety profile. The development of gammadelta-T cell therapies would benefit from non-invasive cell-tracking methods and increased targeting to tumor sites. Here we report the use of [89Zr]Zr(oxinate)4 to track Vgamma9Vdelta2 T cells in vivo by positron emission tomography (PET). In vitro, we showed that 89Zr-labeled Vgamma9Vdelta2 T cells retained their viability, proliferative capacity, and anti-cancer cytotoxicity with minimal DNA damage for amounts of 89Zr <=20 mBq/cell. Using a mouse xenograft model of human breast cancer, 89Zr labeled gammadelta-T cells were tracked by PET imaging over 1 week. To increase tumor antigen expression, the mice were pre-treated with PEGylated liposomal alendronate. Liposomal alendronate, but not placebo liposomes or non-liposomal alendronate, significantly increased the 89Zr signal in the tumors, suggesting increased homing of gammadelta-T cells to the tumors. gammadelta-T cell trafficking to tumors occurred within 48 hr of administration. The presence of gammadelta-T cells in tumors, liver, and spleen was confirmed by histology. Our results demonstrate the suitability of [89Zr]Zr(oxinate)4 as a cell-labeling agent for therapeutic T cells and the potential benefits of liposomal bisphosphonate treatment before gammadelta-T cell administration. PMID- 30429046 TI - [The American opioid overdose crisis: A threat for France?] AB - Since the 2000s, a concerning increase in opioid-analgesic-related overdoses and deaths has been reported in the United States. In contrast with opioid overdoses reported in the 80-90s mostly involving heroin, currently it is the misuse of opioid analgesics that is mainly responsible for opioid overdoses. This crisis is related to factors (not limited to the US) which occurred during the 90s and which have led to a broad prescription of opioids in non-cancer pain. In Europe and France, there is (but to a much lesser extent) an increase in strong opioid consumption and in opioid prescription related morbi-mortality. This situation, which can be described as "worrying" today, requires awareness among the French medical community, both upstream (rational prescription of opioids) and downstream (optimal management of opioid poisoning) from the opioid prescription. PMID- 30429047 TI - Radical pluralism, classificatory norms and the legitimacy of species classifications. AB - Moderate pluralism is a popular position in contemporary philosophy of biology. Despite its popularity, various authors have argued that it tends to slide off into a radical form of pluralism that is both normatively and descriptively unacceptable. This paper looks at the case of biological species classification, and evaluates a popular way of avoiding radical pluralism by relying on the shared aims and norms of a discipline. The main contention is that while these aims and norms may play an important role in the legitimacy of species classifications, they fail to fend off radical pluralism. It follows from this that the legitimacy of species classifications is also determined by local decisions about the aims of research and how to operationalize and balance these. This is important, I argue, because it means that any acceptable view on the legitimacy of classification should be able to account for these local decisions. PMID- 30429048 TI - Speed kills: Associations between methamphetamine use, HIV infection, tobacco use, and accelerated mortality among gay and bisexual men in Los Angeles, CA 20years after methamphetamine dependence treatment. AB - BACKGROUND: To better characterize mortality among methamphetamine users, we estimated rates of all-cause mortality by HIV serostatus and smoking history in gay and bisexual men (GBM) treated for methamphetamine dependence, and explored associated clinical and socio-behavioral characteristics. METHODS: We searched public records to identify deaths among men screened between 1998-2000 for a trial of outpatient therapy for GBM with methamphetamine dependence. Crude mortality rates (CMRs) were calculated, and standardized mortality ratios (SMRs) estimated, comparing data with historical information from CDC WONDER. Associations of mortality with HIV infection, tobacco use, and other factors were explored using Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: Of 191 methamphetamine-dependent GBM (median age 35 years; majority Caucasian), 62.8% had HIV infection, and 31.4% smoked tobacco at baseline. During the 20-year follow-up period, 12.6% died. Relative to controls, methamphetamine-dependent GBM had a three-fold higher 20-year SMR: 3.39, 95% CI: 2.69-4.09. Especially high mortality was observed among participants reporting tobacco use (adjusted HR 3.48, 95% CI: 1.54-7.89), club drug use prior to starting methamphetamine (2.63, 1.15-6.00), or other clinical diagnoses at baseline (3.89, 1.15-13.22). At 20 years, the CMR for HIV infected participants (7.7 per 1000 PY) was 1.5 times that for men without HIV (5.2 per 1000 PY; p = 0.22) and there was a 5-fold difference in CMRs for HIV infected tobacco smokers (16.9 per 1000 PY) compared to non-smokers (3.4 per 1000 PY; p < 0.01). CONCLUSION: In our sample of methamphetamine-dependent GBM, concomitant HIV infection and tobacco use were associated with dramatic increases in mortality. PMID- 30429049 TI - Re: Association Between the Amount of Vaginal Mesh Used with Mesh Erosions and Repeated Surgery After Repairing Pelvic Organ Prolapse and Stress Urinary Incontinence. PMID- 30429050 TI - Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. AB - BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45.7% [95% CI 28.5-67.2]; p=0.0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36.0% [95% CI 20.6-57.8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust. PMID- 30429051 TI - Stopping medication for heart failure with improved ejection fraction. PMID- 30429052 TI - P2X7 receptor-mediated leukocyte recruitment and Porphyromonas gingivalis clearance requires IL-1beta production and autocrine IL-1 receptor activation. AB - The Gram-negative bacterium Porphyromonas gingivalis is strongly associated with periodontitis. We previously demonstrated that P2X7 receptor activation by extracellular ATP (eATP) triggers elimination of intracellular pathogens, such as Leishmania amazonensis, Toxoplasma gondii and Chlamydia trachomatis. We also showed that eATP-induced IL-1beta secretion via the P2X7 receptor is impaired by P. gingivalis fimbriae. Furthermore, enhanced P2X7 receptor expression was detected in the maxilla of P. gingivalis-orally infected mice as well as in human periodontitis patients. Here, we examined the effect of P2X7-, caspase-1/11- and IL-1 receptor-mediated responses during P. gingivalis infection. P2X7 receptor played a large role in controlling P. gingivalis infection and P. gingivalis induced recruitment of inflammatory cells, especially neutrophils. In addition, IL-1beta secretion was detected at different time points only when P2X7 receptor was expressed and in the presence of eATP treatment ex vivo. Activation of P2X7 receptor and IL-1 receptor by eATP and IL-1beta, respectively, promoted P. gingivalis elimination in macrophages. Interestingly, eATP-induced P. gingivalis killing was inhibited by the IL-1 receptor antagonist (IL-1RA), consistent with autocrine activation of the IL-1 receptor for P. gingivalis elimination. In vivo, caspase-1/11 and IL-1 receptor were also required for bacterial clearance, leukocyte recruitment and IL-1beta production after P. gingivalis infection. Our data demonstrate that the P2X7-IL-1 receptor axis activation is required for effective innate immune responses against P. gingivalis infection. PMID- 30429053 TI - Exploring the response of Marchantia polymorpha: Growth, morphology and chlorophyll content in the presence of anthracene. AB - Polycyclic aromatic hydrocarbons (PAHs) were identified as hazardous contaminants that are ubiquitous and persistent in aquatic environments, where bryophytes sensu lato (mosses, liverworts and hornworts) are frequently present. Marchantia polymorpha (Class Hepaticae; thalloid liverwort) is known to respond fast to changes in the environment; it accumulates toxic substances in its tissues due to the lack of vascular and radicular systems and a reduced or absent cuticle. The objective of the present study was to quantify the effects of increasing concentrations of anthracene (0, 50 100, 280 MUM) on the germination of propagules, plant morphology and chlorophyll content index (CCI) in M. polymorpha under in vitro cultures. The results show that anthracene had no statistical effect on germination or propagula formation. However, plants exposed to anthracene for 30 days showed significantly lowered the content of chlorophyll (measured as CCI), irregular growth patterns and the induction of thalli asexual reproduction as evidenced by the production of multicellular viable propagules in gemmae cups. Results of epifluorescence microscopy also showed concomitant accumulation of anthracene in the cell walls. All of these distinctive morphological and physiological adaptive responses indicators, clearly suggest that M. polymorpha are capable of resisting high (coal tar) anthracene concentrations. PMID- 30429054 TI - The Predictive Brain as a Stubborn Scientist. AB - Bayesian theories of perception have traditionally cast the brain as an idealised scientist, refining predictions about the outside world based on evidence sampled by the senses. However, recent predictive coding models include predictions that are resistant to change, and these stubborn predictions can be usefully incorporated into cognitive models. PMID- 30429055 TI - TROP-2 exhibits tumor suppressive functions in cervical cancer by dual inhibition of IGF-1R and ALK signaling. AB - OBJECTIVE: Inactivation of tumor suppressor genes promotes initiation and progression of cervical cancer. This study aims to investigate the tumor suppressive effects of TROP-2 in cervical cancer cells and to explain the underlying mechanisms. METHODS: The tumor suppressive functions of TROP-2 in cervical cancer cells were examined by in vitro and in vivo tumorigenic functional assays. Downstream factors of TROP-2 were screened using Human Phospho Receptor Tyrosine Kinase Array. Small molecule inhibitors were applied to HeLa cells to test the TROP-2 effects on the oncogenicity of IGF-1R and ALK. Protein interactions between TROP-2 and the ligands of IGF-1R and ALK were detected via immunoprecipitation assay and protein-protein affinity prediction. RESULTS: In vitro and in vivo functional assays showed that overexpression of TROP-2 significantly inhibited the oncogenicity of cervical cancer cells; while knockdown of TROP-2 exhibited opposite effects. Human Phospho-Receptor Tyrosine Kinase Array showed that the activity of IGF-1R and ALK was stimulated by TROP-2 knockdown. Small molecule inhibitors AG1024 targeting IGF-1R and Crizotinib targeting ALK were treated to HeLa cells with and without TROP-2 overexpression, and results from cell viability and migration assays indicated that the oncogenicity of vector-transfected cells was repressed to a greater extent by the inhibition of either IGF-1R or ALK than that of the TROP-2-overexpressed cells. Immunoprecipitation assay and protein-protein affinity prediction suggested protein interactions between TROP-2 and the ligands of IGF-1R and ALK. CONCLUSIONS: Collectively, our results support that TROP-2 exhibits tumor suppressor functions in cervical cancer through inhibiting the activity of IGF-1R and ALK. PMID- 30429056 TI - Structural brain changes as a function of second language vocabulary training: Effects of learning context. AB - Recent research indicates that learning a second language (L2) results in both functional and structural brain changes. However, few studies have examined whether structural brain changes vary as a function of the context in which L2 learning takes place. The current study examines changes in cortical thickness (CT) and gray matter volume (GMV) in response to short-term L2 vocabulary learning. In particular, we compared structural changes for learning with paired picture-word (PW) association versus learning within virtual environments (VE) and non-trained controls. Both L2 training groups learned the same 90 Mandarin Chinese nouns across 7 training sessions over approximately 20 days. Our results show (a) CT and GMV increased in regions implicated in a language control network for both L2 training groups, and (b) participants in different learning contexts may rely on different structures within this language control network. In particular, CT in the right IFG was associated with L2 training performance for the PW group, whereas CT in the right IPL showed a positive correlation with L2 training performance for the VE group. Our findings indicate that short-term L2 training leads to changes in brain structure, which vary based on L2 learning contexts and individual differences in cognitive ability. PMID- 30429057 TI - Interictal psychiatric comorbidities of drug-resistant focal epilepsy: Prevalence and influence of the localization of the epilepsy. AB - Psychiatric comorbidities are 2 to 3 times more frequent in patients with epilepsy than in the general population. This study aimed to prospectively assess the following: (i) the prevalence of specific and nonspecific interictal psychiatric comorbidities in a population of patients with drug-resistant focal epilepsy and (ii) the influence of epilepsy lateralization and localization on these psychiatric comorbidities. In this prospective monocentric study, we collected demographic data, characteristics of the epilepsy, interictal psychiatric comorbidities, mood, anxiety, and alexithymia dimensions. We used criteria from Diagnostic and Statistical Manual of Mental Disorders IV ( DSM IV) (Mini International Mental Interview (MINI)), diagnosis criteria for specific comorbidities, and validated mood and anxiety scales (general and specific for epilepsy). Among the 87 enrolled patients (39 males, 48 females), 52.9% had at least one psychiatric comorbidity. The most common comorbidity was anxiety disorder (28.7% according to the MINI, and 38.4% screening by the Generalized Anxiety Disorder 7 (GAD 7)). Mood disorders were the second most frequent psychiatric comorbidity: 21.8% of our patients had interictal dysphoric disorders (IDDs), 16.1% presented major depressive disorders according to the MINI, and 17.2% screening by the Neurological Disorders Depression Inventory for Epilepsy (NDDIE). Patients with temporal lobe epilepsy had a higher prevalence of psychiatric comorbidities than patients with extratemporal lobe epilepsy (p = 0.002), which is probably related to a higher rate of anxiety disorders in this subgroup (p = 0.012). Prevalence of psychiatric disorders prior to epilepsy in patients was higher in right- than in left-sided epilepsy (p = 0.042). No difference was found according to limbic involvement at seizure onset. Overall, this article highlighted a very high proportion of anxiety disorders in these patients with drug-resistant focal epilepsy and the necessity to systematically detect them and thus lead to a specific treatment. PMID- 30429058 TI - Displaced humeral surgical neck fractures: classification and results of third generation percutaneous intramedullary nailing. AB - BACKGROUND: The high rates of complications and reoperations observed with the early designs of first-generation (unlocked) and second-generation (bent design) humeral intramedullary nail (IMNs) have discouraged their use by most surgeons. The purpose of this study was to report the results of a third-generation (straight, locking, low-profile, tuberosity-based fixation) IMN, inserted through a percutaneous approach, for the treatment of displaced 2-part surgical neck fractures. METHODS: We performed a retrospective review of 41 patients who underwent placement of a third-generation IMN to treat a displaced 2-part surgical neck fracture (AO/OTA type 11A3). The mean age at surgery was 57 years (range, 17-84 years). After percutaneous insertion through the humeral head, the IMN was used as a reduction tool. Static locking fixation was achieved after axial fracture compression ("back-slap" hammering technique). Patients were reviewed and underwent radiography with a minimum of 1 year of follow-up; the mean follow-up period was 26 months (range, 12-53 months). RESULTS: Preoperatively, 3 types of surgical neck fractures were observed: with valgus head deformity (Type A = 8 cases), shaft translation without head deformity (Type B = 19 cases), or with varus head deformity (Type C = 14 cases). At final follow up, all fractures went on to union, and the mean humeral neck-shaft angle was 132 degrees +/- 5 degrees . We observed 2 malunions and 1 case of partial humeral head avascular necrosis. No cases underwent screw migration or intra-articular penetration. At last review, mean active forward elevation was 146 degrees (range, 90 degrees -180 degrees ) and mean external rotation was 50 degrees (range, 20 degrees -80 degrees ). The mean Constant-Murley score and Subjective Shoulder Value were 71 (range, 43-95) and 80% (range, 50%-100%), respectively. CONCLUSIONS: Antegrade insertion of a third-generation IMN through a percutaneous approach provides a high rate of fracture healing, excellent clinical outcome scores, and a low rate of complications. No morbidity related to the passage of the nail through the supraspinatus muscle and the cartilage was observed. The proposed A, B, and C classification allows choosing the optimal entry point for intramedullary nailing. PMID- 30429059 TI - Rotator cuff tear incidence association with critical shoulder angle and subacromial osteophytes. AB - BACKGROUND: The concomitant presence of a heel-type osteophyte may affect the critical shoulder angle (CSA) correlation with rotator cuff tears (RCT). METHODS: We retrospectively reviewed patients with and without a full-thickness RCT who underwent magnetic resonance imaging (MRI) and radiographic imaging of the shoulder. The patients were divided into 3 groups according to the CSA as high CSA group, >38 degrees ; middle CSA group, 33 degrees -38 degrees ; and low CSA group, <33 degrees . We confirmed the presence of heel-type osteophytes, quadrangular osteophytes protruding inferiorly from the undersurface of the anterolateral acromion like the heel of a shoe, and excluded other types of osteophytes. RESULTS: Among the patients, 84.6% in the high CSA group, 60.3% in the middle CSA group, and 68.3% in the low CSA group had a RCT (P = .041). In patients without an osteophyte, 76.9% in the high CSA group, 38.5% in the middle CSA group, and 52.6% in the low CSA group had a RCT (P = .024). In patients with an osteophyte, 92.3% in the high CSA group, 80.3% in the middle CSA group, and 92.2% in the low CSA group had a RCT (P = .106). CONCLUSIONS: RCT was affected more by osteophytes than CSA when CSA and osteophytes were evaluated together as a related factor for RCT. This perhaps suggests no correlation of CSA alone with RCT. Therefore, the presence of an osteophyte must be considered when evaluating the relation of CSA to RCT. PMID- 30429060 TI - Effective healthcare cost-containment policies: A systematic review. AB - Unsustainable growth in healthcare expenditure demands effective cost-containment policies. We review policy effectiveness using total payer expenditure as primary outcome measure. We included all OECD member states from 1970 onward. After a rigorous quality appraisal, we included 43 original studies and 18 systematic reviews that cover 341 studies. Policies most often evaluated were payment reforms (10 studies), managed care (8 studies) and cost sharing (6 studies). Despite the importance of this topic, for many widely-used policies very limited evidence is available on their effectiveness in containing healthcare costs. We found no evidence for 21 of 41 major groups of cost-containment policies. Furthermore, many evaluations displayed a high risk of bias. Therefore, policies should be more routinely and rigorously evaluated after implementation. The available high-quality evidence suggests that the cost curve may best be bent using a combination of cost sharing, managed care competition, reference pricing, generic substitution and tort reform. PMID- 30429061 TI - [Abortion in Hauts-de-France: When to expect the first appointment?] AB - BACKGROUND: According to the French National Authority for Health ("Haute Autorite de sante"), the first appointment for an abortion should take place within five days of the request. Whether this deadline is met or not in the Hauts de-France region is not known. AIM: The aim of this study was to measure the time needed to get a first appointment for an abortion in Hauts-de-France. METHOD: We conducted a telephone survey of health facilities, family planning and registered practitioners practicing abortions in the Hauts-de-France region, to determine the next appointment available for a woman requesting an abortion. The calls took place between April 10 and 14, 2017. The time needed to get a first appointment (means+/-standard deviations) was calculated for the region, the departments, the districts and the health facilities and practitioners. RESULTS: We contacted 93 health facilities and practitioners and 70 were included in the study. The time needed to get a first appointment for an abortion in Hauts-de-France was measured at 5.25+/-5.20 days: 6.32+/-4.72 days for health facilities, 3.84+/-5.11 days for gynecologists, 5.22+/-5.88 days for general practitioners and 0.67+/-0.58 days for private-practice midwives. Fifty-six percent of health facilities and practitioners gave the appointment within five days. Between the districts, the average time varied from 1 to 15.5 days. CONCLUSION: The average time needed to get a first appointment for an abortion in Hauts-de-France was near the 5-day deadline recommended by the French National Authority for Health. The training of private practice midwives and general practitioners may be the first step in shortening it in some districts where access to health care is limited. PMID- 30429062 TI - [Promoting home support for elderly people with neurocognitive disorders: Caregiver perception of the help-seeking process]. AB - BACKGROUND: Caregivers play an essential role in maintaining home care for elderly people with dementia. However, it is difficult for caregivers to target their own needs as well as those of the person with neurocognitive disorders they support on a daily basis. Identifying the needed resources can also be difficult. In order to better assist caregivers in identifying resources needed to support their role, this study aims to understand the factors that influence their help seeking process. METHODS: This qualitative and descriptive study focuses on the point of view of the main people affected by this problem: caregivers. Eleven caregivers of elderly people with dementia living at home were recruited by convenience sampling. Semi-structured interviews were conducted, and the data were analyzed according to Mast's typology. RESULTS: The factors influencing caregivers help-seeking process were categorized into five themes: 1) service related (e.g. wait times); 2) personal (e.g. feeling intrusive); 3) experiential (e.g. positive use of a service); 4) relational (e.g. rejection of the elder), and 5) informational (e.g. directed to the right service). CONCLUSION: Caregivers face many challenges in their help-seeking process and want to be more proactively accompanied in a way adapted to their changing needs. PMID- 30429063 TI - Preexisting Right Ventricular Dysfunction Is Associated With Higher Postoperative Cardiac Complications and Longer Hospital Stay in High-Risk Patients Undergoing Nonemergent Major Vascular Surgery. AB - OBJECTIVES: To evaluate whether the presence of preexisting right ventricular (RV) dysfunction in high-risk patients undergoing nonemergent major vascular surgery is associated independently with higher incidents of postoperative cardiac complications and a longer length of hospital stay. DESIGN: Retrospective chart review. SETTING: Single-center university hospital setting. PARTICIPANTS: The patient population consisted of those identified as American Society of Anesthesiologists classification III and above who had a preoperative echocardiogram within 1 year of undergoing nonemergent major vascular surgery between January 2010 and May 2017. MEASUREMENTS AND MAIN RESULTS: After multivariate analyses, RV dysfunction (RVD) is associated independently with a higher incidence of postoperative major cardiac complications with an odds ratio = 6.3 (95% confidence interval [CI], 1.0-38.5; p = 0.046). In addition, patients with RVD had a 50% longer length of stay than those without RVD (incident rate ratio [95% CI], 1.5 [1.2-1.8]; p < 0.001). CONCLUSION: In this retrospective study of high-risk patients undergoing major vascular surgery, RV dysfunction was associated independently with a higher incidence of postoperative major cardiovascular events and longer length of hospital stays. Based on current findings, the prognostic value of RVD extends beyond the cardiac surgical cohort. Knowledge in management of patients with RVD in the perioperative setting should be understood by all anesthesiologists. Of note, a future study with a larger sample size is needed to validate the current findings given the small sample size of this study. PMID- 30429064 TI - Agitated saline echo testing: Two useful indications in critical care patients. PMID- 30429065 TI - Mass shootings: Are children safer in the streets than in the home? AB - PURPOSE: Though the total fatality and injury count in mass shootings is known, the burden on the pediatric population remains undefined. We sought to define the impact of domestic vs. public mass shootings in the pediatric population. METHODS: Open-source databases, Everytown for Gun Violence, and Mother Jones were cross-referenced and used to review domestic and public mass shootings from 2009 to 2016. Mass shootings were defined as four or more fatalities and any injuries. Domestic mass shootings were defined as ones that occurred in the home where the assailant was either a family member or a past or present intimate partner of a family member. Public mass shootings occurred in a public space where the shooter was unknown to the victim. The number of incidents in each group, fatalities and injuries, and effect on children <18 years were analyzed along with perpetrator characteristics. Categorical data were analyzed using Fisher's Exact test. RESULTS: There were 71 Domestic and 31 Public mass shootings accounting for 331 vs. 281 fatalities and 28 vs. 217 injuries (p < 0.0001). Children <18 years accounted for 44% of Domestic and 10% of Public fatalities (p < 0.0001) and 46% vs. 2% of all injuries (p < 0.0001). The assailant was prohibited from owning or possessing a firearm in 32% of Domestic and 39% of Public mass shootings accounting for 54 vs. 25 fatalities. CONCLUSION: The pediatric fatality rate in mass shootings is alarming, especially among Domestic shooting events. This is a public health issue and requires vigilance to protect at-risk youth. TYPE OF STUDY: Epidemiology study, retrospective review. LEVEL OF EVIDENCE: Level IV. PMID- 30429066 TI - Polyurethane scaffolds seeded with autologous cells can regenerate long esophageal gaps: An esophageal atresia treatment model. AB - BACKGROUND: Pediatric patients suffering from long gap esophageal defects or injuries are in desperate need of innovative treatment options. Our study demonstrates that two different cell sources can adhere to and proliferate on a retrievable synthetic scaffold. In feasibility testing of translational applicability, these cell seeded scaffolds were implanted into piglets and demonstrated esophageal regeneration. METHODS: Either porcine esophageal epithelial cells or porcine amniotic fluid was obtained and cultured in 3 dimensions on a polyurethane scaffold (Biostage). The amniotic fluid was obtained prior to birth of the piglet and was a source of mesenchymal stem cells (AF-MSC). Scaffolds that had been seeded were implanted into their respective Yucatan mini swine. The cell seeded scaffolds in the bioreactor were evaluated for cell viability, proliferation, genotypic expression, and metabolism. Feasibility studies with implantation evaluated tissue regeneration and functional recovery of the esophagus. RESULTS: Both cell types seeded onto scaffolds in the bioreactor demonstrated viability, adherence and metabolism over time. The seeded scaffolds demonstrated increased expression of VEGF after 6 days in culture. Once implanted, endoscopy 3 weeks after surgery revealed an extruded scaffold with newly regenerated tissue. Both cell seeded scaffolds demonstrated epithelial and muscle regeneration and the piglets were able to eat and grow over time. CONCLUSIONS: Autologous esophageal epithelial cells or maternal AF-MSC can be cultured on a 3D scaffold in a bioreactor. These cells maintain viability, proliferation, and adherence over time. Implantation into piglets demonstrated esophageal regeneration with extrusion of the scaffold. This sets the stage for translational application in a neonatal model of esophageal atresia. PMID- 30429067 TI - Barriers to complete recovery of major depression: cross-sectional, multi-centre study on clinical practice. RECORD study. AB - INTRODUCTION: To identify barriers to complete recovery in patients suffering from major depressive disorder. METHODS: A total of 461 psychiatrists participated in a cross-sectional, non-randomised, qualitative and multi-centre study based on a survey. The study questionnaire included 42 items related to management, prevalence, patient profile, impact of residual symptoms, barriers to full recovery, and strategies to increase complete recovery. RESULTS: Complete recovery was defined by 86% of participants as complete remission of symptoms plus functional recovery. A total of 83.4% of participants considered that sick leave usually lasted more than 4 months. Seventy-five percent stated that residual symptoms were the main reason for prolongation of sick leave, and 62% that between 26%-50% of patients complained of residual symptoms. Poor compliance with treatment was the most important barrier to complete recovery, followed by a lack of patient cooperation, late beginning of treatment, partial response to antidepressants, and low doses of antidepressant medication. In the case of partial response, 71.8% of participants chose to increase the dose of current treatment, and in the case of lack of response, 72.7% would switch to another antidepressant, and 22.8% would use the combination of two antidepressants, in which case 85.2% would choose agents with complementary mechanisms of action. Forty-nine percent of participants would recommend standard cognitive-behavioural psychotherapy for patients without complete response. CONCLUSIONS: Some 50% of patients did not achieve complete remission, frequently related to persistence of residual symptoms. Achievement of complete recovery should be an essential objective. PMID- 30429068 TI - Not all NAFLD patients are the same: We need to find a personalized therapeutic approach. PMID- 30429069 TI - 18F-FDG PET/CT in locally advanced cervical cancer: A review. AB - Cervical cancer is the second most common gynecological cancer worldwide. In locally advanced cervical cancer, 18F-FDG PET/CT has become important in the initial staging, particularly in the detection of nodal and distant metastasis, aspects with treatment implications and prognostic value. The aims of this study were to review the role of 18F-FDG PET/CT in uterine cervical cancer, according to the guidelines of the main scientific institutions (FIGO, NCCN, SEGO, SEOM, ESGO, and ESMO) and its diagnostic accuracy compared to conventional radiological techniques, as well as to review the acquisition protocol and its utility in radiotherapy planning, response assessment and detection of recurrence. PMID- 30429070 TI - Acute management of acetabular fractures by total hip arthroscopy using an anterior approach. AB - INTRODUCTION: Acetabular fractures in elderly patients present a therapeutic challenge, since their osteosynthesis may be hindered by comminution and poor bone quality. In certain cases, a good solution is acute total hip arthroplasty (THA) by direct anterior approach with or without minimal associated osteosynthesis. The objective of this study was to establish the indications and evaluate the clinical/functional, radiological results and complications, in the short and medium term, of acute THA using an anterior approach after acetabular fractures. MATERIAL AND METHODS: We analyzed 15 patients collecting: demographic data, classification of fractures, surgical data, clinical/functional and evolutionary radiographic evaluation, together with perioperative complications. RESULTS: The mean follow-up of the patients was 40 months with a final functional assessment of 96.5 for Harris Hip Score, and Merle D'Aubigne excellent in 93%. The radiological controls were satisfactory without prosthetic loosening. Only 2patients presented low-grade heterotopic calcifications. Ninety-four percent of the patients presented optimal postoperative recovery, with immediate loading. There was only one death for reasons unrelated to the surgery. CONCLUSIONS: Given certain acetabular fractures, acute THA using a direct anterior approach in the supine position and under scope control with a revision cup plus associated minimal osteosynthesis, if necessary, facilitates adequate fracture stabilization with full functional recovery of the patient with immediate loading and excellent results in the short and medium term with minimal complications. PMID- 30429071 TI - [Intrauterine contraception: CNGOF Contraception Guidelines]. AB - OBJECTIVE: To provide national clinical guidelines focusing on intrauterine contraception. METHODS: A systematic review of available literature was performed using Pubmed and Cochrane libraries. American, British and Canadian guidelines were considered as well. RESULTS: Intrauterine contraception (IUC) displays a wide panel of indications, including adolescents, nulliparous, patients living with HIV before AIDS (Grade B) and women with history of ectopic pregnancy (Grade C). Cervical cancer screening should not be modified in women with IUC (Grade B). Bimanual examination and cervix inspection are mandatory before device insertion (Grade B). Patients should not systematically undergo screening for sexually transmitted infections (STI) before device insertion (Grade B). Screening for STI should be preferably done before insertion but it can be performed at the time of device insertion in asymptomatic women (Grade B). Routine antibiotic prophylaxis and premedication are not recommended before insertion (Grade A). A follow-up visit may be offered several weeks after insertion (Professional consensus). Routine pelvic ultrasound examination in not recommended after device insertion (Grade B). In patients with IUC, unscheduled bleeding, when persistent or associated with pelvic pain, requires further investigation to rule out complication (Professional agreement). Suspected uterine perforation warrants radiological workup to locate the device (Professional consensus). Laparoscopic approach should be preferred for elective removal of intrauterine device from abdominal cavity (Professional consensus). In case of accidental pregnancy with intrauterine device in situ, ectopic pregnancy should be excluded (Grade B). In case of viable and desired intrauterine pregnancy, intrauterine device removal is recommended if the strings are reachable (Grade C). Detection of Actinomyces-like organisms on pap smear in asymptomatic patients with intrauterine contraception does not require further intervention (Grade B). Immediate removal of intrauterine device is not recommended in case of STI or pelvic inflammatory disease (Grade B). Device removal should be considered in the absence of clinical improvement after 48 to 72 hours of appropriate treatment (Grade B). CONCLUSION: Intrauterine contraception is a long-acting and reversible contraception method displaying great efficacy and high continuation rate. In contrast, complication rate is low. It should thus be offered to both nulliparous and multiparous women. PMID- 30429072 TI - [The sacred forests of Guinea: Between ecology and conservation]. AB - Guinea has very little ecological data available regarding its sacred forests. This study shows the important conservation role of these forests in a local context of strong human impacts. We present four representative case studies from the Sudano-Guinean zone in Upper Guinea. Our phytoecological inventories recorded a total of 431 species, 312 genera, and 87 families including 242 species, 187 genera, and 64 families in the forests. Twelve plant groups have been identified, including five in forests and seven in the surrounding vegetation. Geomorphology, texture, soil hydromorphism, microclimate, and human impacts are significant in explaining the spatial distribution of plant groups. The study reveals that in these Sudano-Guinean savannas, vegetation is dominated by micro-phanerophytes. The Guinean-Congolese flora is better represented in gallery forests. PMID- 30429073 TI - Incidence of self-inflicted burn injury in patients with Major Psychiatric Illness. AB - INTRODUCTION: Psychiatric disorders are mental illnesses that impair judgment, thought process and mood that can result in physical and emotional disability. According to DSM-IV, mental disorders increases risk of traumatic injury, particularly burn [1] (American Psychiatric Association, 2013). However, there are few studies that look at patients with pre-existing major psychiatric disorders and burn outcomes. We aim to assess the incidence and intentionality of burn injury in patients with pre-existing psychiatric disorders. METHODS: This is a retrospective study of patients admitted to the UNC Jaycee Burn Center from 2002 to 2015 and entered in the burn registry. Variables analyzed include basic demographics, insurance status, total body surface area (TBSA) of burn, Charlson comorbidity index (CCI), burn etiology, presence of inhalation injury, burn circumstance, intensive care unit (ICU) and hospital length of stay (LOS) and mortality. Chi-square, Analysis of Variance (ANOVA), Kruskal-Wallis test and Multivariate logistic regression was used to analyze the data. RESULTS: 11,650 adult and pediatric patients were entered in the burn registry from 2002 to 2015 and 494 (4.2%) adult and pediatric patients had preexisting major psychiatric illness (MPI). Within the large cohort of admitted burn patients, 90 (0.8%) patients presented with self-inflicted burn injuries. 41% of patients with SIB (n=37/90) had MPI. The incidence of self-inflicted burn injury (SIB) within the MPI (n=494) cohort was 7.5% (n=37). Mean age of patients with and without self inflicted burn injury was 35.3 (+/-11.6) vs. 41.8 (+/-17.3), respectively. Mean TBSA was significantly higher in patient with SIB at 18.6 (+/-16.5) vs. 8.5(+/ 12.2) p<0.001. Non-white race had significantly higher rate of SIB compared to white cohort. There was no significant difference in mortality rates between SIB and Non-SIB (5.4% vs. 3.7%, p=0.609), respectively. Median Hospital LOS was significantly increased in patients with SIB compared to NSIB 31 (IQR=55) vs. 9 (IQR=20) days, p=0.004. Multivariate logistic regression for predictors of self inflicted burn injury showed that minorities were more likely to incur self inflicted burn injury among patients with major psychiatric illnesses. CONCLUSION: The incidence of self-induced burn injury in patients with MPI is low and of all the self-inflicted burn patients, 60% did not have a major psychiatric illness identified. Our findings emphasize the importance of identifying patients with MPI with or without self-induced injury that may benefit from more extensive psychiatric screening after burn and counseling, particularly minority patients as they may benefit from additional mental health counseling following severe burn. PMID- 30429074 TI - Effectiveness of ECMO for burn-related acute respiratory distress syndrome. AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a complication that affects approximately 40% of burn patients and is associated with high mortality rates. Extracorporeal membrane oxygenation (ECMO) therapy is a management option for severe refractory hypoxemic respiratory failure; however, there is little literature reporting the effectiveness of this therapy in burns. Our study objective was to review patient outcomes in burns following severe ARDS treated with ECMO. METHODS: We retrospectively reviewed all patients treated with ECMO for ARDS who received their burn care at a single regional burn center between 9/1/2006 and 8/31/2016. Primary patient outcome examined was discharge disposition. RESULTS: We identified 8 patients who had ARDS secondary to burn who were placed onto ECMO during this 10-year period. The average APACHE score, SOFA score, and P/F ratio were 21+/-3, 9+/-2, and 59+/-8, respectively, at the time of decision for ECMO. No ECMO-related complications were identified. Out of the 8 patients reviewed, 1 died, 4 were discharged to acute rehabilitation or a long term acute care facility, and 3 were discharged to home. CONCLUSION: Mortality in burn patients with ARDS who are managed with ECMO is extremely low. Careful selection and timely intervention with ECMO contributed to good clinical outcomes. PMID- 30429075 TI - Keloid negatively affects body image. AB - BACKGROUND/OBJECTIVES: Keloid is a healing disorder that occurs exclusively in humans. This pathology is considered a benign cicatricial neoplasm, whose physiopathogenesis has not yet completely clarified. Its disfiguring appearance often could potentially cause a disturbance in the patient regarding his/her body image. The objective is to evaluate the impact of keloid on body image. METHODS: 61 patients with keloid in socially exposed regions of the body were included. The participants were submitted to clinical evaluation, composed of anamnesis and physical examination, and answered two questionnaires: the Body Dysmorphic Symptoms Scale (BDSS) questionnaire and the Rosenberg Self-Esteem Scale - Unifesp/EPM. RESULTS: Forty percent of the patients had negative aspects of body image (BDSS score>=6). The scores of these patients on the Rosenberg Scale reached an average of 10.5 (p<0.03). CONCLUSIONS: The presence of a keloid negatively affects body image. PMID- 30429076 TI - Determinants of the Appearance and Progression of Early-Onset Chronic Obstructive Pulmonary Disease in Young Adults. A Case-Control Study with Follow-up. AB - INTRODUCTION AND OBJECTIVES: Determinants of chronic obstructive pulmonary disease (COPD) in the early stages of its natural history are not well known. Improving our knowledge of these factors will help to design interventions that can modify prognosis. Study objectives are: a) to characterize a COPD population of young adults aged 35-50 years from a multidimensional point of view; b) to compare these patients with smokers with normal lung function; and c) to create a cohort of young adults aged 35-50 years (smokers or former smokers), with and without COPD, who will be followed in the future to improve understanding of the natural history of the disease. PARTICIPANTS AND METHOD: This is a case-control multicenter study aimed at establishing a well-characterized cohort of young adults, smokers or former-smokers, with and without COPD, for subsequent follow up. A total of 311 participants (101 cases and 210 controls) were selected from approximately 30 primary care settings and 12 hospitals in 8 Spanish regions. Subjects were smokers or former smokers (>10 pack-years) aged 35-50 years. Diagnosis of COPD was based on a post-bronchodilator result of FEV1/FVC<70%. The main study variables were: questionnaires on health, symptoms, exacerbations and daily physical activity, lung function tests, blood and sputum samples, and low dose computed tomography. In the statistical analysis, COPD patient characteristics will be described and compared with control subjects using a logistic regression analysis. PMID- 30429077 TI - More dampened monocytic Toll-like receptor 4 response to lipopolysaccharide and its association with cognitive function in Chinese Han first-episode patients with schizophrenia. AB - OBJECTIVE: Accumulating evidence suggests alterations of the innate immune system are related to schizophrenia, although the precise mechanism remains to be elucidated. In this study, we aimed to detect the monocytic toll-like receptor 4 (TLR4) expression under basal and lipopolysaccharide (LPS)-stimulated conditions in first-episode (FE) Han Chinese patients with schizophrenia, as well as its association with cognitive function. METHODS: Whole blood samples were taken in 42 FE schizophrenia patients and 36 healthy controls. Expressions of TLR4 on monocytes under basal and LPS-stimulated conditions were measured with flow cytometry. Psychopathological symptoms of schizophrenia were assessed by the Positive and Negative Syndrome Scale (PANSS) and the MATRICS Consensus Cognitive Battery (MCCB) was administered to all of the participants. RESULTS: We found no differences in percentage and mean fluorescence intensity (MFI) of TLR4 expression on monocytes between patients and controls at basal status. However, LPS challenge resulted in a lower cell-surface level of TLR4 on monocytes in FE schizophrenia patients as compared to healthy controls (TLR4+%: F = 4.092, p = 0.047; TLR4 + MFI: F = 4.820, p = 0.031). In addition, correlation analysis together with multivariate linear regression analysis identified basal percentage of TLR4 in monocytes as the beneficial factor for visual learning and working memory in FE patients with schizophrenia. CONCLUSIONS: Our findings suggested that TLR4 may be involved in the pathophysiology of schizophrenia, corroborating the role of innate immunity-related functional deficits in increased risk of schizophrenia. PMID- 30429078 TI - Social cognitive group treatment for impaired insight in psychosis: A multicenter randomized controlled trial. AB - PURPOSE: The majority of people with schizophrenia has impaired insight, which is related to a poorer outcome. In this study, we evaluate a new psychosocial intervention 'REFLEX' aimed at improving insight in people with schizophrenia. REFLEX focuses on targeting stigma-sensitivity, perspective taking and self reflection in people with schizophrenia and low insight. Primary objective is to improve insight and subsequently to improve functional outcome and symptoms. METHOD: A total of 121 people diagnosed with schizophrenia according to DSM IV criteria with impaired insight was included in 2012-2015 from seven sites in a multicenter randomized controlled trial. REFLEX was compared to an active control condition consisting of group-wise simplified cognitive remediation training. Primary outcome of the study were the preconditions of insight: internalized stigma, self-reflection, mental flexibility and perspective taking. Clinical insight and cognitive insight were secondary outcomes. RESULTS: Although perspective taking, self-reflection, mental flexibility and stigma sensitivity remained unchanged after the intervention, results showed a significant improvement of clinical insight in both conditions directly after treatment (SAI E Rater, p < .001, PANSS G12, p < .005) and at follow-up (SAI-E Rater, p < .01, SAI-E interview, p < .001, PANSS G12, p < .0001). Improvement of clinical insight directly after treatment was larger in the REFLEX condition (SAI-E Rater, p < .05). Other outcomes (self-esteem, quality of life and depression) remained unchanged. CONCLUSION: Though insight improved in both conditions, REFLEX was not superior to simplified drill-and-practice cognitive remediation training. Nevertheless, this study indicates that structured interventions can significantly improve insight. Further research on the underlying mechanisms of both conditions is needed, as insight is unlikely to improve spontaneously in chronic patients. PMID- 30429079 TI - The Association of Mediterranean Diet during Pregnancy with Longitudinal Body Mass Index Trajectories and Cardiometabolic Risk in Early Childhood. AB - OBJECTIVE: To evaluate the associations between maternal adherence to the Mediterranean diet during pregnancy and their offspring's longitudinal body mass index (BMI) trajectories and cardiometabolic risk in early childhood. STUDY DESIGN: We included mother-child pairs from the Infancia y Medio Ambiente (INMA) longitudinal cohort study in Spain. We measured dietary intake during pregnancy using a validated food frequency questionnaire and calculated the relative Mediterranean diet score (rMED). We estimated offspring's BMI z score trajectories from birth to age 4 years using latent class growth analyses (n = 2195 mother-child pairs). We measured blood pressure, waist circumference, and cardiometabolic biomarkers to construct a cardiometabolic risk score at 4 years (n = 697 mother-child pairs). We used multivariable adjusted linear and multinomial regression models. RESULTS: A higher maternal rMED in pregnancy was associated with a lower risk in offspring of larger birth size, followed by accelerated BMI gain (reference trajectory group: children with average birth size and subsequent slower BMI gain) (relative risk of high vs low rMED score, 0.68; 95% CI, 0.47-0.99). rMED score during pregnancy was not associated with the cardiometabolic risk score, its components, or related biomarkers. CONCLUSIONS: Higher adherence to the Mediterranean diet in pregnancy was associated with lower risk of having offspring with an accelerated growth pattern. This dietary pattern was not associated with the offspring's cardiometabolic risk at 4 years. PMID- 30429080 TI - Normative Trends in Physically Aggressive Behavior: Age-Aggression Curves from 6 to 24 Months. AB - OBJECTIVE: To investigate age-related trends in physically aggressive behaviors in children before age 2 years. STUDY DESIGN: A normative US sample of 477 mothers of 6- to 24-month-old children reported on the frequency of 9 interpersonally directed aggressive child behaviors, and hurting animals, in the past month. RESULTS: Almost all (94%) of the children were reported to have engaged in physically aggressive behavior in the past month. Based on 2-part regression models, the prevalences of kicking (OR, 1.70; P = .023), pushing (OR, 3.22; P < .001), and swiping (OR, 1.78; P = .018) increased with years of age, but the prevalence of hair pulling decreased with age (OR, 0.55; P = .020). The prevalences of hitting and throwing increased initially, then plateaued at age 18 20 months, and then decreased (quadratic aOR, 0.13 and 0.16; P < .001 and .010, respectively). The frequencies of hitting (R2 = .05; P < .001) and throwing (R2 = .03; P = .030) increased, and the frequencies of hair pulling (R2 = .07; P < .001) and scratching (R2 = .02; P = .042) decreased with age (P values adjusted for false discovery rate). CONCLUSIONS: Physically aggressive behavior in the 6- to 24-month age range appears to be nearly ubiquitous. Most, but not all, forms of physical aggression increase with age. These results can guide pediatricians as they educate and counsel parents about their child's behavior in the first 2 years of life. PMID- 30429081 TI - Combining functional assessment with coronary flow evaluation with vasodilator stress echocardiography in post CABG patients: Improving insight into coronary pathophysiology. PMID- 30429083 TI - How changes in column geometry and packing ratio can increase sample load and throughput by a factor of fifty in Counter-Current Chromatography. AB - This paper builds on the fact that high aspect ratio rectilinear tubing columns of the same length and outside dimensions can double column efficiency. It demonstrates that further improvements in efficiency can be made by using rectilinear tubing columns with half the wall thickness thus replacing heavy PTFE with light solvent systems and producing lighter higher capacity columns. Increases in sample loading/throughput of up to 55x are demonstrated by comparing the separation of Honokiol and Magnolol using a Hexane: Ethyl Acetate: Methanol: Water (5:2:5:2) phase system with the new thin wall rectilinear column (56 mL, 30 mL/min, 2.1 g/h in 6.5 min.) with the original optimization performed using a conventional DE-Mini column (18 mL, 0.8 mm bore circular PTFE tubing, 2.5 mL/min, 0.038 g/h in 45 min.). Honokiol is currently going through first phase clinical trials as an anti-lung cancer therapy where preparative countercurrent chromatography was used for its manufacture. To be competitive in the future it is important for the technology to become more efficient. This is the first big step in that direction. PMID- 30429082 TI - External validation of two Framingham cardiovascular risk equations and the Pooled Cohort equations: A nationwide registry analysis. AB - BACKGROUND: Cardiovascular prevention guidelines advocate the use of statistical risk equations to predict individual cardiovascular risk. However, predictive accuracy and clinical value of existing equations may differ in populations other than the one used for their development. Using baseline and follow-up data of the Austrian health-screening program, we assessed discrimination, calibration, and clinical utility of three widely recommended equations-the Framingham 1991 and 2008 general cardiovascular disease (CVD) equations, and the Pooled Cohort equations predicting atherosclerotic CVD. METHODS: The validation cohort comprised 1.7 M individuals aged 30-79, without documented CVD history who participated in the program from 2009 to 2014. CVD events were defined by a cardiovascular cause of hospitalization or death. RESULTS: The observed five-year general CVD risk was 4.66%. Discrimination c-indices (0.72-0.78) were slightly lower than those reported for the development cohorts. C-indices for women were always higher than for men. CVD risk was overestimated by the Framingham 2008 equation, but underestimated by the Pooled Cohort equations. The Framingham 1991 equation was well-calibrated, especially for individuals up to 64 years. If applied to recommend health interventions at a predicted five-year risk between 5 and 10%, the equations were clinically useful with their net benefits, weighting true positives against false positives, ranging from 0.13 to 3.43%. CONCLUSION: The equations can discriminate high-risk from low-risk individuals, but predictive accuracy (especially for high-risk individuals) might be improved by recalibration. The Framingham 1991 equation yielded the most accurate predictions. PMID- 30429084 TI - Ellipsoidal particles for liquid chromatography: Fluid mechanics, efficiency and wall effects. AB - Ellipsoidal particles are investigated as packing media for liquid chromatography using high resolution fluid mechanics and Brownian dynamics simulations. The simulations are conducted with packed capillary columns, as well as beds with periodic boundary conditions (PBCs) to study transport in the absence of wall effects. The performance of ellipsoidal particles is evaluated over a range of aspect ratios. The definition of effective diameter used to compare sphere and ellipsoidal particle performance metrics is presented and discussed along with scaling relationships which are necessary to compare sphere and ellipsoidal particle packs. Ellipsoidal particle packs are found to be inferior to sphere packs using PBCs to study chromatographic dispersion. The separation impedance was calculated with PBCs and shown to be approximately the same with ellipsoidal particles as those of spheres. Efficiency of ellipsoidal packs, as measured by plate height, is lower than spherical particle packs and the pressure drop is higher than sphere packs when using PBCs. However, a smaller wall effect is shown for ellipsoidal particles when packing cylindrical capillaries. Radial variations in packing porosity and in flow within the wall region are smaller for ellipsoidal packings. The minimum reduced plate height and the separation impedance for the packed capillaries clearly demonstrate the advantages of ellipsoidal particles compared to spherical particles. This predicted performance advantage remains to be demonstrated in actual practice. PMID- 30429085 TI - Determination of short-chain chlorinated paraffins using comprehensive two dimensional gas chromatography coupled with low resolution mass spectrometry. AB - Short-chain chlorinated paraffins (SCCPs), recently listed as Persistent Organic Pollutants (POPs) under the Stockholm Convention, are contained in commercial chlorinated paraffin (CP) products, which are used in industries such as metalworking fluids, sealants, and textiles. A novel method to determine SCCPs by comprehensive two-dimensional gas chromatography coupled with low resolution mass spectrometry was developed. Calibration curves of response factor versus chlorine content in two chlorine content ranges (R2 were 0.9544 and 0.9736, respectively) were used for quantification of SCCP total concentration. Moreover, relative concentrations of 24 congener groups were also theoretically calculated. Results showed that this method was able to detect SCCP concentration in commercial CP products and urban air samples. SCCP contribution varied largely among different CP products, which is highly determined by carbon chain distribution in paraffins. SCCP concentration in urban air ranged between 12.8-49.1 ng m-3 during nine-month sampling period. The highest SCCP concentration appeared in summer, and the lowest concentration occurred in winter. Gas phase was dominantly occupied by lighter congeners such as C10 group and Cl6 group, while heavier congeners such as C13 group and Cl7 and Cl8 groups contributed more in particle phase. PMID- 30429086 TI - Extraction and quantitative analysis of tropane alkaloids in Radix physochlainae by emulsion liquid membrane with tropine-based ionic liquid. AB - Emulsion liquid membrane (ELM) coupled with tropine-based ionic liquid was prepared and successfully adopted for the extraction and quantitative analysis of tropane alkaloids (TA) in Radix physochlainae. Effects of formation conditions of ELM were explored and then optimized; the ideal oil-water mass ratio was determined to be 1:2.5, chloroform, Span 80 and 0.05 mol L-1N-propyl-tropine hexafluorophosphate ([C3Tr][PF6]) aqueous solution were stirred for 30 min with the speed of 1500 r min-1. In order to extract and enrich TA with ELM efficiently, key factors related with their extraction efficiency such as stirring speed, volume of the extracts (feed solution), migration time and initial concentration of TA were systematically investigated. Under optimal conditions, 1.5 mL extracts containing 1.6 mg mL-1 of TA was stirred with ELM at 250 r min-1 for 5 min, the extraction efficiency of target alkaloid can reach 94.14%. Finally, the method could be used in quantitative analysis of TA in herbal material and patent medicine after demulsification. By comparison, application of ELM for the enrichment and quantitation of TA offers a more straightforward and effective strategy, which is expected to provide a meaningful reference for similar separation processes. PMID- 30429087 TI - A renal-cerebral-peripheral sympathetic reflex mediates insulin resistance in chronic kidney disease. AB - BACKGROUND: Insulin resistance (IR) complicates chronic kidney disease (CKD). We tested the hypothesis that CKD activates a broad reflex response from the kidneys and the white adipose tissue to impair peripheral glucose uptake and investigated the role of salt intake in this process. METHODS: 5/6-nephrectomized rats were administered normal- or high-salt for 3 weeks. Conclusions were tested in 100 non diabetic patients with stage 3-5 CKD. FINDINGS: High-salt in 5/6-nephrectomized rats decreased insulin-stimulated 2-deoxyglucose uptake >25% via a sympathetic nervous system (SNS) reflex that linked the IR to reactive oxygen species (ROS) and the renin-angiotensin system (RAS) in brain and peripheral tissues. Salt loading in CKD enhanced inflammation in adipose tissue and skeletal muscle, and enhanced the impairment of insulin signaling and Glut4 trafficking. Denervation of the kidneys or adipose tissue or deafferentation of adipose tissue improved IR >40%. In patients with non-diabetic CKD, IR was positively correlated with salt intake after controlling for cofounders (r = 0.334, P = 0.001) and was linked to activation of the RAS/SNS and to impaired glucose uptake in adipose tissue and skeletal muscle, all of which depended on salt intake. INTERPRETATION: CKD engages a renal/adipose-cerebral-peripheral sympathetic reflex that activates the RAS/ROS axes to promote IR via local inflammation and impaired Glut4 trafficking that are enhanced by high-salt intake. The findings point to a role for blockade of RAS or alpha-and-beta-adrenergic receptors to reduce IR in patients with CKD. FUND: National Natural Science Foundation of China. PMID- 30429088 TI - SRSF1 modulates PTPMT1 alternative splicing to regulate lung cancer cell radioresistance. AB - BACKGROUND: Radioresistance is the major cause of cancer treatment failure. Additionally, splicing dysregulation plays critical roles in tumorigenesis. However, the involvement of alternative splicing in resistance of cancer cells to radiotherapy remains elusive. We sought to investigate the key role of the splicing factor SRSF1 in the radioresistance in lung cancer. METHODS: Lung cancer cell lines, xenograft mice models, and RNA-seq were employed to study the detailed mechanisms of SRSF1 in lung cancer radioresistance. Clinical tumor tissues and TCGA dataset were utilized to determine the expression levels of distinct SRSF1-regulated splicing isoforms. KM-plotter was applied to analyze the survival of cancer patients with various levels of SRSF1-regulated splicing isoforms. FINDINGS: Splicing factors were screened to identify their roles in radioresistance, and SRSF1 was found to be involved in radioresistance in cancer cells. The level of SRSF1 is elevated in irradiation treated lung cancer cells, whereas knockdown of SRSF1 sensitizes cancer cells to irradiation. Mechanistically, SRSF1 modulates various cancer-related splicing events, particularly the splicing of PTPMT1, a PTEN-like mitochondrial phosphatase. Reduced SRSF1 favors the production of short isoforms of PTPMT1 upon irradiation, which in turn promotes phosphorylation of AMPK, thereby inducing DNA double strand break to sensitize cancer cells to irradiation. Additionally, the level of the short isoform of PTPMT1 is decreased in cancer samples, which is correlated to cancer patients' survival. CONCLUSIONS: Our study provides mechanistic analyses of aberrant splicing in radioresistance in lung cancer cells, and establishes SRSF1 as a potential therapeutic target for sensitization of patients to radiotherapy. PMID- 30429089 TI - Myeloid sirtuin 6 deficiency accelerates experimental rheumatoid arthritis by enhancing macrophage activation and infiltration into synovium. AB - BACKGROUND: We recently reported that myeloid sirtuin 6 (Sirt6) is a critical determinant of phenotypic switching and the migratory responses of macrophages. Given the prominent role of macrophages in the pathogenesis of rheumatoid arthritis (RA), we tested whether myeloid Sirt6 deficiency affects the development and exacerbation of RA. METHODS: Arthritis was induced in wild type and myeloid Sirt6 knockout (mS6KO) mice using collagen-induced and K/BxN serum transfer models. Sirt6 expression (or activity) and inflammatory activities were compared in peripheral blood mononuclear cells (PBMCs) and monocytes/macrophages obtained from patients with RA or osteoarthritis. FINDINGS: Based on clinical score, ankle thickness, pathology, and radiology, arthritis was more severe in mS6KO mice relative to wild type, with a greater accumulation of macrophages in the synovium. Consistent with these findings, myeloid Sirt6 deficiency increased the migration potential of macrophages toward synoviocyte-derived chemoattractants. Mechanistically, Sirt6 deficiency in macrophages caused an inflammation with increases in acetylation and protein stability of forkhead box protein O1. Conversely, ectopic overexpression of Sirt6 in knockout cells reduced the inflammatory responses. Lastly, PBMCs and monocytes/macrophages from RA patients exhibited lower expression of Sirt6 than those from patients with osteoarthritis, and their Sirt6 activity was inversely correlated with disease severity. INTERPRETATION: Our data identify a role of myeloid Sirt6 in clinical and experimental RA and suggest that myeloid Sirt6 may be an intriguing therapeutic target. FUND: Medical Research Center Program and Basic Science Research Program through the National Research Foundation of Korea. PMID- 30429090 TI - [Reprint of : Management of obstructive sleep apnea syndrome in people living with diabetes: context, screening, indications and treatment modalities: context, screening, indications and treatment modalities: a French position statement]. PMID- 30429091 TI - [Vaccination of COPD patients: From guidelines to routine practise]. PMID- 30429092 TI - [Systematic analysis of the scientific literature on heated tobacco]. AB - INTRODUCTION: The tobacco industry (TI) reports that heated tobacco reduces risk of tobacco use and will replace cigarettes. An analysis of the scientific literature was conducted in order to enlighten professionals and decision-makers. METHOD: After a Medline query in February 2018, a systematic analysis was conducted. RESULTS: Of the 100 papers published in 2008-2018, 75 have authors affiliated or linked to TI. Emissions contain gases, droplets and solid particles, so are smokes. The main products are: THS2.2 (Iqos(r)) which heats mini-cigarettes at 340 degrees C, the THP1.0 (Glo(r)) which heats at 240 degrees C sticks delivering about half as much nicotine, Ploom(r) which uses reconstituted tobacco microcapsules heated at 180 degrees C. Under the experimental conditions, there is a reduction of toxic emissions and biological effects, but the expected risk reduction is not demonstrated. Symptoms related to passive smoking are described. The 4 epidemiological articles report that heated tobacco is used in 10 to 45% of cases by non-smokers and demonstrate the effectiveness of TI promotion campaigns. Thus, the THS2.2 is more a gateway to smoking (20%) than an exit door (11%); moreover, it is not expected risk reduction among the 69% who are mixed users. CONCLUSIONS: While reducing emissions is documented, reducing the risk to the smoker who switches to heated tobacco remains to be demonstrated. On the other hand, the worsening of the global tobacco risk related to the promotion of the products by the TI is anticipated, justifying that the authorities take the appropriate measures to control the promotion of heated tobacco. PMID- 30429093 TI - [Patients in the IDEAL cohort: A snapshot of severe asthma in France]. AB - INTRODUCTION: This paper reports the French data from a post-hoc analysis of the international IDEAL study, which aimed to describe a recent cohort of patients with severe asthma, the impact of the disease on quality of life, as well as the population of patients eligible for treatment with omalizumab, mepolizumab and reslizumab. METHODS: Eligible patients were>=12 years of age, with severe asthma (GINA steps 4 and 5). RESULTS: A total of 129 patients were included in this post hoc analysis. Their mean age was 53 years, the majority were overweight, they were mainly women (64%) and had at least one medical comorbidity (85%). More than half had suffered from asthma for more than 25 years and were non-smokers. Lung function was moderately impaired. Blood eosinophil count was>=150 cells/MUL in 66% of patients,>=300 cells/MUL in 34% of patients, and>=500 cells/MUL in 12% of patients. One out of three patients was currently treated with omalizumab and 24% had maintenance oral corticosteroids. Asthma was poorly controlled with a negative impact on quality of life (ACQ>=1.5) in 67% of patients. In this population 40% of patients were eligible for omalizumab, 27% for mepolizumab and 2% for reslizumab. CONCLUSIONS: These findings show that a considerable proportion of patients with severe asthma remain uncontrolled and are not eligible for any of the available biological treatments. This underlines the need for therapeutic innovations in this disease. PMID- 30429094 TI - [A case report of an adult with bronchial mould infection complicated by purulent pleurisy]. AB - INTRODUCTION: Bronchial mould infection or plastic bronchitis is a rare condition, encountered at any age, but with a predilection for childhood. The clinical diagnosis is made easy by the demonstration of solid, branched expectorations. However, the aetiology is not easy to determine and investigation does not often lead to a pathological diagnosis. CASE REPORT: We report the case of a 24 year-old patient, with a history of pulmonary tuberculosis in January 2016, who had had chronic, persistent, solid and branched expectorations since January 2015. Fibreoptic bronchoscopy revealed thick white secretions plugging the bronchi. Pathological examination of the bronchial plugs showed fibrous tissue infiltrated with predominantly lymphoplasmocytic and histiocytic inflammatory cells. Investigations carried out on the pleura did not establish the aetiological diagnosis. The diagnosis of bronchial mould disease of tuberculous origin complicated by pleurisy was established. Corticosteroid therapy led to a complete regression of the moulds within six weeks. CONCLUSION: The presence of solid and branched sputum should suggest fungal bronchitis and is an indication for bronchoscopy for diagnostic and therapeutic purposes. Early management is important to avoid complications. PMID- 30429095 TI - Probing the ligand preferences of the three types of bacterial pantothenate kinase. AB - Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4' phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of PanK. PMID- 30429096 TI - Modifying aroylhydrazone prochelators for hydrolytic stability and improved cytoprotection against oxidative stress. AB - BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid. In the current study, several BSIH analogs were evaluated for their hydrolytic stability, reaction outcomes with H2O2, and prochelator-to-chelator conversion efficiency. Notably, the para-methoxy derivative (p-OMe)BSIH ((E)-N'-(5-methoxy-2-(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) and the meta-, para-double substituted (MD)BSIH ((E)-N'-((6-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)benzo[d][1,3]dioxol-5-yl)methylene)isonicotinohydrazide) showed 1.3- and 1.9-fold improved hydrolytic stability compared to BSIH, respectively, leading to a 22 and 50% increase in chelator released. Moreover, both prochelators were found to protect retinal pigment epithelial cells stressed with either H2O2 or paraquat insult. PMID- 30429097 TI - PPARgamma-sparing thiazolidinediones as insulin sensitizers. Design, synthesis and selection of compounds for clinical development. PMID- 30429098 TI - Synthesis and in vitro antitumor activity of novel alkenyl derivatives of pyridoxine, bioisosteric analogs of feruloyl methane. AB - Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase. Similar to DZG, but with higher efficiency, the leading compound was able to inhibit migration activity and, therefore, invasiveness of tumor cells. It also increased concentration of reactive oxygen species in tumor cells, induced depolarization of mitochondrial membranes and initiated apoptosis accompanied by disruption of integrity of cytoplasmic cell membranes. By contrast to DZG, the leading compound did not possess antioxidant properties. The obtained data make the described chemotype a promising starting point for the development of new anticancer agents. PMID- 30429099 TI - Matrix metalloproteinase-12 inhibitors: synthesis, structure-activity relationships and intestinal absorption of novel sugar-based biphenylsulfonamide carboxylates. AB - MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors. All the new derivatives were tested on human recombinant MMP-12 and MMP-9 in order to evaluate their affinity and the selectivity for the target enzyme. Among them, the four most promising compounds were selected to assess their intestinal permeability using an ex vivo everted gut sac model. Given the high polarity and structural similarity to glucose, compound 3 was demonstrated to cross the intestinal membrane by using the facilitative GLUT2 transport. PMID- 30429100 TI - Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors. AB - AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 MUM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl 1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization. PMID- 30429101 TI - Contralateral Subdural Hematoma Following Surgical Evacuation of Acute Subdural Hematoma: Super-Early Intervention and Clinical Implications. AB - BACKGROUND: Contralateral acute subdural hematoma (ASDH) is an uncommon but devastating complication during craniotomy and hematoma evacuation. It can lead to extremely poor outcomes if not treated properly and promptly. CASE DESCRIPTION: We present a case of a 49-year-old male who suffered contralateral ASDH during surgical evacuation of ASDH on the left side. Before the operation, we noticed slight contralateral ASDH on preoperative cranial computed tomography and were aware of its enlargement during operation. Decompression with a burr hole craniotomy promptly followed by a decompressive craniectomy was performed to prevent contralateral ASDH. Unfortunately, we found intraoperative brain swelling, which indicated the development of a contralateral hematoma. The patient was reoperated and eventually had a poor prognosis. CONCLUSIONS: We highlight that super-early intervention of contralateral hematoma is important to improve the prognosis of these patients. PMID- 30429102 TI - Laparoscopic right colectomy for adenocarcinoma (with video). PMID- 30429103 TI - Anthelmintics - From Discovery to Resistance III (Indian Rocks Beach, FL, 2018). AB - The third scientific meeting in the series "Anthelmintics: From Discovery to Resistance" was held in Indian Rocks Beach, Florida, at the end of January 2018. The meeting focused on a variety of topics related to the title, including the identification of novel targets and new leads, the mechanism of action of existing drugs and the genetic basis of resistance against them. Throughout there was an emphasis on the exploitation of new technologies and methods to further these aims. The presentations, oral and poster, covered basic, veterinary and medical science with strong participation by both academic and commercial researchers. This special issue contains selected papers from the meeting. PMID- 30429104 TI - How community pharmacists prioritize cognitive pharmaceutical services. AB - INTRODUCTION: There is broad consensus that community pharmacists should focus on the provision of pharmaceutical care. Studies, however, have shown that community pharmacists still spend a considerable amount of time on traditional activities such as dispensing instead of cognitive pharmaceutical services (CPS). It is not clear whether community pharmacists prefer their current time-utilization or if they are willing to spend more time on CPS. AIM: The aim of this study was to identify how community pharmacists ideally would prioritize CPS compared to other daily activities. METHODS: A cross-sectional study design with Q-methodology was used to identify different viewpoints regarding task prioritization. Community pharmacists were asked to rank a total of 48 daily activities. Data was collected online using FlashQ(c). Q-sorts were analyzed by principal component factor analysis and varimax rotation using PQmethod 2.35. RESULTS: In total, 166 community pharmacists participated in this study. Three distinguishing groups were found based on task prioritization explaining 59% of the total variance among respondents. All groups ranked the provision of CPS as important, in differing degrees. Group 1 ranked CPS as most important and was also the group that contained most participants. Group 2 and 3 ranked quality assurance as most important with CPS as second. Logistics and pharmacy management were ranked low by all groups. DISCUSSION AND CONCLUSION: Community pharmacists rank the provision of CPS as important. So factors, probably other than task prioritization, are keeping the pharmacist from focusing on CPS in daily practice. In other studies, time constraints are mostly mentioned as major barrier. Activities such as logistics and pharmacy management are given less priority and should be delegated to supporting staff members as much as possible, to enable pharmacists to focus their available time on activities they deem important. PMID- 30429105 TI - PAI-1 secreted from metastatic ovarian cancer cells triggers the tumor-promoting role of the mesothelium in a feedback loop to accelerate peritoneal dissemination. AB - The mesothelium, covered by a continuous monolayer of mesothelial cells, is the first protective barrier against metastatic ovarian cancer. However, mesothelial cells release tumor-promoting factors that accelerate the process of peritoneal metastasis. We identified cancer-associated mesothelial cells (CAMs) that had tumor-promoting potential. Here, we found that plasminogen activator inhibitor-1 (PAI-1) induced the formation of CAMs, after which CAMs increasingly secreted the oncogenic factors interleukin-8 (IL-8) and C-X-C motif chemokine ligand 5 (CXCL5), further promoting the metastasis of ovarian cancer cells in a feedback loop. After the formation of CAMs, PAI-1 activated the nuclear factor kappa B (NFkappaB) pathway in the CAMs, thus transcriptionally upregulating the expression of the downstream NFkappaB targets IL-8 and CXCL5. Moreover, PAI-1 correlated with peritoneal metastasis in ovarian cancer patients and indicated a poor prognosis. In both ex vivo and in vivo models, after PAI-1 expression was knocked down, the metastasis of ovarian cancer cells decreased significantly. Therefore, targeting PAI-1 may provide a potential target for future therapeutics to prevent the formation of CAMs and alleviate peritoneal metastasis in ovarian cancer patients. PMID- 30429106 TI - ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation. AB - ADAM28 has been shown to relate with tumor proliferation and prognosis. The expression of ADAM28 is up-regulated in acute myeloid leukemia (AML). However, the mechanism by which ADAM28 regulates the leukemic cell and the prognostic relevance with AML remain unknown. Here, we found that the expression level of ADAM28 was significantly elevated in AML patients suffering a relapse compared with those remaining in complete remission (CR). ADAM28 promoted the proliferation, migration and invasion in leukemic cells in vitro. Additionally, the increased expression of ADAM28 led to more IGFBP-3 degradation and IGF-I induced cell proliferation. In a xenotransplantation mouse model, knockout of ADAM28 alleviated HL-60 cells growth and dissemination. The cumulative incidence of relapse (CIR) was significantly higher in patients with high ADAM28 expression. When separately considering the impact of ADAM28 on prognosis within the risk stratifications, patients with high ADAM28 expression levels had a significantly higher CIR in the favorable and intermediate-risk group but not in poor-risk group. Taken together, these data suggest a pivotal role for ADAM28 in regulating the proliferation and invasion of leukemic cells and in the prediction of relapse in AML patients. PMID- 30429107 TI - Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers. AB - KRAS mutation is the most common type of mutation in human cancers. However, the direct pharmacological inhibition of KRAS has not been clinically successful. Trametinib (GSK1120212, Tram), a newer MEK inhibitor, inhibits RAS signaling through mitogen-activated protein kinase (MAPK) cascade suppression. The effectiveness of Tram in clinical practice is limited in KRAS mutant tumors compared to that in BRAF mutant tumors. Here, we found that Tram treatment provoked feedback activation of upstream RAS, thus causing an induction of phosphorylated MEK (pMEK) and phosphorylated ERK (pERK) rebound in KRAS mutant tumors. This failure of persistent ERK inhibition led to drug resistance. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, disrupts the biological activity of RAS by inhibiting its isoprenylation. Surprisingly, ZA overcame Tram resistance, and augmented antitumor activity was observed in KRAS mutant tumors both in vitro and in vivo. Furthermore, ZA enhanced the effect of Tram partially through the mevalonate pathway. In summary, the combination of the two FDA-approved drugs Tram and ZA may represent a novel therapeutic strategy for the treatment of KRAS mutant cancers. PMID- 30429108 TI - How would serum 25(OH)D level change in patients with inflammatory bowel disease depending on intestinal mucosa vitamin D receptor (VDR) and vitamin D1-alpha hydroxylase (CYP27B1)? AB - BACKGROUND/AIMS: To investigate how the serum 25-hydroxyvitamin D (25(OH)D) level change in patients with inflammatory bowel disease (IBD) and investigate the intestinal mucosa vitamin D receptor (VDR) and vitamin D1-alpha hydroxylase (CYP27B1) expressions. MATERIALS AND METHODS: A total of 105 patients with IBD were enrolled in the present study, including 49 cases with ulcerative colitis (UC) and 56 cases with Crohn's disease (CD), compared with 45 healthy controls (CON) during the same period by testing the permeability of the intestinal mucosa. The expressions of VDR and CYP27B1 in the intestinal mucosa were detected, so as the serum endotoxin, tumor necrosis factor (TNF)-alpha, and 25(OH)D levels. RESULTS: The lactulose and mannitol absorption ratio (LMR) and serum endotoxin and TNF-alpha levels were significantly higher in the IBD group than in the CON group (p<0.05). The levels of LMR, endotoxin, and TNF-alpha were higher in the UC group than in the CD group, but 25(OH)D was lower (p<0.05). VDR in the IBD and UC groups was down-regulated when compared with the CON group (p<0.05), but there was no significance between them (p>0.05). CYP27B1 in the IBD and CD groups was significantly up-regulated compared with the CON group (p<0.05), with no significant difference between them (p>0.05). CONCLUSION: Patients with IBD exhibit vitamin D metabolism imbalance, lower serum 25(OH)D, and lower VDR expression, but higher CYP27B1 expression in the colonic mucosa. However, VDR and CYP27B1 cannot be used to distinguish UC and CD. PMID- 30429109 TI - Sporadic nonampullary tubular adenoma of the duodenum: Prevalence and patients' characteristics. PMID- 30429110 TI - One-shot dalbavancin infusion combined with vacuum-assisted closure of Crohn's anal fistulas. PMID- 30429111 TI - An Interpretable and Expandable Deep Learning Diagnostic System for Multiple Ocular Diseases: Qualitative Study. AB - BACKGROUND: Although artificial intelligence performs promisingly in medicine, few automatic disease diagnosis platforms can clearly explain why a specific medical decision is made. OBJECTIVE: We aimed to devise and develop an interpretable and expandable diagnosis framework for automatically diagnosing multiple ocular diseases and providing treatment recommendations for the particular illness of a specific patient. METHODS: As the diagnosis of ocular diseases highly depends on observing medical images, we chose ophthalmic images as research material. All medical images were labeled to 4 types of diseases or normal (total 5 classes); each image was decomposed into different parts according to the anatomical knowledge and then annotated. This process yields the positions and primary information on different anatomical parts and foci observed in medical images, thereby bridging the gap between medical image and diagnostic process. Next, we applied images and the information produced during the annotation process to implement an interpretable and expandable automatic diagnostic framework with deep learning. RESULTS: This diagnosis framework comprises 4 stages. The first stage identifies the type of disease (identification accuracy, 93%). The second stage localizes the anatomical parts and foci of the eye (localization accuracy: images under natural light without fluorescein sodium eye drops, 82%; images under cobalt blue light or natural light with fluorescein sodium eye drops, 90%). The third stage carefully classifies the specific condition of each anatomical part or focus with the result from the second stage (average accuracy for multiple classification problems, 79%-98%). The last stage provides treatment advice according to medical experience and artificial intelligence, which is merely involved with pterygium (accuracy, >95%). Based on this, we developed a telemedical system that can show detailed reasons for a particular diagnosis to doctors and patients to help doctors with medical decision making. This system can carefully analyze medical images and provide treatment advices according to the analysis results and consultation between a doctor and a patient. CONCLUSIONS: The interpretable and expandable medical artificial intelligence platform was successfully built; this system can identify the disease, distinguish different anatomical parts and foci, discern the diagnostic information relevant to the diagnosis of diseases, and provide treatment suggestions. During this process, the whole diagnostic flow becomes clear and understandable to both doctors and their patients. Moreover, other diseases can be seamlessly integrated into this system without any influence on existing modules or diseases. Furthermore, this framework can assist in the clinical training of junior doctors. Owing to the rare high-grade medical resource, it is impossible that everyone receives high-quality professional diagnosis and treatment service. This framework can not only be applied in hospitals with insufficient medical resources to decrease the pressure on experienced doctors but also deployed in remote areas to help doctors diagnose common ocular diseases. PMID- 30429112 TI - The Mediating Role of Perceived Social Support Between Physical Activity Habit Strength and Depressive Symptoms in People Seeking to Decrease Their Cardiovascular Risk: Cross-Sectional Study. AB - BACKGROUND: Regular physical activity treatment has been advocated for the prevention and rehabilitation of patients at risk of cardiovascular diseases and depressive symptoms. How physical activity is related to depressive symptoms is widely discussed. OBJECTIVE: The aim of this internet-based study was to investigate the role of perceived social support in the relationship between physical activity habit strength and depressive symptoms. METHODS: In total, 790 participants (mean 50.9 years, SD 12.2, range 20-84 years) who were interested in reducing their cardiovascular risk were recruited in Germany and the Netherlands. Data collection was conducted via an internet-based questionnaire addressing physical activity habit strength, depressive symptoms, and perceived social support. Cross-sectional data analysis was done with SPSS version 24 using the Macro PROCESS version 2 16.3 by Hayes with bootstrapping (10,000 samples), providing 95% CIs. RESULTS: Physical activity habit strength was negatively related to depressive symptoms (r=-.13, P=.006), but this interrelation disappeared when controlling for perceived social support (beta=-.14, SE 0.09, P=.11). However, there was an indirect relationship between physical activity habit strength and depressive symptoms, which was mediated via perceived social support (beta=-.13; SE 0.04, 95% CI -0.21 to 0.06). The negative relationship between physical activity habit strength and depressive symptoms was fully mediated by perceived social support. CONCLUSIONS: We suggest that physical activity treatment in people interested in reducing their cardiovascular risk should also embed social support to target depressive symptoms. Internet-based interventions and electronic health may provide a good option for doing so. TRIAL REGISTRATION: ClinicalTrials.gov NCT01909349; https://clinicaltrials.gov/ct2/show/NCT01909349 (Archived by WebCite at http://www.webcitation.org/73Y9RfdiY). PMID- 30429113 TI - Internet-Delivered Early Interventions for Individuals Exposed to Traumatic Events: Systematic Review. AB - BACKGROUND: Over 75% of individuals are exposed to a traumatic event, and a substantial minority goes on to experience mental health problems that can be chronic and pernicious in their lifetime. Early interventions show promise for preventing trauma following psychopathology; however, a face-to-face intervention can be costly, and there are many barriers to accessing this format of care. OBJECTIVE: The aim of this study was to systematically review studies of internet delivered early interventions for trauma-exposed individuals. METHODS: A literature search was conducted in PsycINFO and PubMed for papers published between 1991 and 2017. Papers were included if the following criteria were met: (1) an internet-based intervention was described and applied to individuals exposed to a traumatic event; (2) the authors stated that the intervention was intended to be applied early following trauma exposure or as a preventive intervention; and (3) data on mental health symptoms at pre-and postintervention were described (regardless of whether these were primary outcomes). Methodological quality of included studies was assessed using the Downs and Black checklist. RESULTS: The interventions in the 7 studies identified were categorized as selected (ie, delivered to an entire sample after trauma regardless of psychopathology symptoms) or indicated (ie, delivered to those endorsing some level of posttraumatic distress). Selected interventions did not produce significant symptom improvement compared with treatment-as-usual or no intervention control groups. However, indicated interventions yielded significant improvements over other active control conditions on mental health outcomes. CONCLUSIONS: Consistent with the notion that many experience natural recovery following trauma, results imply that indicated early internet-delivered interventions hold the most promise in future prevention efforts. More studies that use rigorous methods and clearly defined outcomes are needed to evaluate the efficacy of early internet-delivered interventions. Moreover, basic research on risk and resilience factors following trauma exposure is necessary to inform indicated internet-delivered interventions. PMID- 30429114 TI - Improving Self-Management Skills Among People With Spinal Cord Injury: Protocol for a Mixed-Methods Study. AB - BACKGROUND: Most people with spinal cord injury will develop secondary complications with potentially devastating consequences. Self-management is a key prevention strategy for averting the development of secondary complications and their recurrence. Several studies have shown that self-management programs improve self-management behaviors and health outcomes in individuals living with chronic conditions such as asthma, diabetes, hypertension, and arthritis. Given the burgeoning health care costs related to secondary complications, we developed an alternative electronic health-based implementation to facilitate the development of self-management skills among people with spinal cord injury. OBJECTIVE: This study aims to evaluate the efficacy of a self-management app in spinal cord injury populations. The primary outcome is attainment of self selected, self-management goals. Secondary outcomes include increases in general and self-management self-efficacy and reductions in self-reported health events, health care utilization, and secondary complications related to spinal cord injury. This study also aims to explore how the intervention was implemented and how the app was experienced by end users. METHODS: This study will employ a mix of qualitative and quantitative methods. The quantitative portion of our study will involve a rater-blinded, randomized controlled trial with a stepped wedge design (ie, delayed intervention control group). The primary outcome is successful goal attainment, and secondary outcomes include increases in self efficacy and reductions in self-reported health events, health care utilization, and secondary conditions related to spinal cord injury. The qualitative portion will consist of semistructured interviews with a subsample of the participants. RESULTS: We expect that the mobile self-management app will help people with spinal cord injury to attain their self-management goals, improve their self efficacy, reduce secondary complications, and decrease health care utilization. CONCLUSIONS: If the results are positive, this study will produce credible new knowledge describing multiple outcomes that people with spinal cord injury realize from an app-based self-management intervention and support its implementation in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT03140501; http://clinicaltrials.gov/ct2/show/NCT03140501 (Archived by WebCite at http://www.webcitation.org/73Gw0ZlWZ). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11069. PMID- 30429115 TI - A Cardiopulmonary Monitoring System for Patient Transport Within Hospitals Using Mobile Internet of Things Technology: Observational Validation Study. AB - BACKGROUND: During intrahospital transport, adverse events are inevitable. Real time monitoring can be helpful for preventing these events during intrahospital transport. OBJECTIVE: We attempted to determine the viability of risk signal detection using wearable devices and mobile apps during intrahospital transport. An alarm was sent to clinicians in the event of oxygen saturation below 90%, heart rate above 140 or below 60 beats per minute (bpm), and network errors. We validated the reliability of the risk signal transmitted over the network. METHODS: We used two wearable devices to monitor oxygen saturation and heart rate for 23 patients during intrahospital transport for diagnostic workup or rehabilitation. To determine the agreement between the devices, records collected every 4 seconds were matched and imputation was performed if no records were collected at the same time by both devices. We used intraclass correlation coefficients (ICC) to evaluate the relationships between the two devices. RESULTS: Data for 21 patients were delivered to the cloud over LTE, and data for two patients were delivered over Wi-Fi. Monitoring devices were used for 20 patients during intrahospital transport for diagnostic work up and for three patients during rehabilitation. Three patients using supplemental oxygen before the study were included. In our study, the ICC for the heart rate between the two devices was 0.940 (95% CI 0.939-0.942) and that of oxygen saturation was 0.719 (95% CI 0.711-0.727). Systemic error analyzed with Bland-Altman analysis was 0.428 for heart rate and -1.404 for oxygen saturation. During the study, 14 patients had 20 risk signals: nine signals for eight patients with less than 90% oxygen saturation, four for four patients with a heart rate of 60 bpm or less, and seven for five patients due to network error. CONCLUSIONS: We developed a system that notifies the health care provider of the risk level of a patient during transportation using a wearable device and a mobile app. Although there were some problems such as missing values and network errors, this paper is meaningful in that the previously mentioned risk detection system was validated with actual patients. PMID- 30429116 TI - Mobile Apps for Blood Pressure Monitoring: Systematic Search in App Stores and Content Analysis. AB - BACKGROUND: Using a mobile app for self-management could make it easier for patients to get insight into their blood pressure patterns. However, little is known about the availability, quality, and features of mobile apps targeting blood pressure. OBJECTIVE: The goal of the research was to determine the availability, functionality, and quality of mobile apps that could be used for blood pressure monitoring purposes. METHODS: A systematic app search was performed based on the standards for systematic reviews. We searched the Dutch official app stores for Android and iOS platforms using predefined keywords and included all English and Dutch mobile apps targeting blood pressure. Two independent assessors determined eligibility and quality of the apps using the 5 point Mobile App Rating Scale (MARS). Quality scores of the apps with and without 17 a priori selected characteristics were compared using independent sample t tests. RESULTS: A total of 184 apps (104 Android, 80 iOS) met the inclusion criteria. The mean overall MARS score was 2.63 (95% CI 2.55-2.71) for Android and 2.64 (95% CI 2.56-2.71) for iOS. The apps Bloeddruk (4.1) and AMICOMED BP (3.6) had the highest quality scores on the Android and iOS platforms, respectively. Of the app characteristics recorded, only pricing, in-app advertisements, and local data storage were not associated with the quality scores. In only 3.8% (7/184) of the apps, involvement of medical experts in its development was mentioned, whereas none of the apps was formally evaluated with results published in a peer reviewed journal. CONCLUSIONS: This study provides an overview of the best apps currently available in the app stores and important key features for self management that can be used by health care providers and patients with hypertension to identify a suitable app targeting blood pressure monitoring. However, the majority of the apps targeting blood pressure monitoring were of poor quality. Therefore, it is important to involve medical experts in the developmental stage of health-related mobile apps to improve the quality of these apps. PMID- 30429117 TI - An mHealth Intervention to Improve Young Gay and Bisexual Men's Sexual, Behavioral, and Mental Health in a Structurally Stigmatizing National Context. AB - BACKGROUND: Young gay and bisexual men (YGBM) in some Eastern European countries, such as Romania, face high stigma and discrimination, including in health care. Increasing HIV transmission is a concern given inadequate prevention, travel to high-prevalence countries, and popularity of sexual networking technologies. OBJECTIVE: This study aimed to adapt and pilot test, in Romania, a preliminarily efficacious mobile health (mHealth) HIV-prevention intervention, created in the United States, to reduce HIV risk among YGBM. METHODS: After an intervention formative phase, we enrolled 43 YGBM, mean age 23.2 (SD 3.6) years, who reported condomless sex with a male partner and at least 5 days of heavy drinking in the past 3 months. These YGBM completed up to eight 60-minute text-based counseling sessions grounded in motivational interviewing and cognitive behavioral skills training with trained counselors on a private study mobile platform. We conducted one-group pre-post intervention assessments of sexual (eg, HIV-risk behavior), behavioral (eg, alcohol use), and mental health (eg, depression) outcomes to evaluate the intervention impact. RESULTS: From baseline to follow-up, participants reported significant (1) increases in HIV-related knowledge (mean 4.6 vs mean 4.8; P=.001) and recent HIV testing (mean 2.8 vs mean 3.3; P=.05); (2) reductions in the number of days of heavy alcohol consumption (mean 12.8 vs mean 6.9; P=.005), and (3) increases in the self-efficacy of condom use (mean 3.3 vs mean 4.0; P=.01). Participants reported significant reductions in anxiety (mean 1.4 vs mean 1.0; P=.02) and depression (mean 1.5 vs mean 1.0; P=.003). The intervention yielded high acceptability and feasibility: 86% (38/44) of participants who began the intervention completed the minimum dose of 5 sessions, with an average of 7.1 sessions completed; evaluation interviews indicated that participation was rewarding and an "eye-opener" about HIV risk reduction, healthy identity development, and partner communication. CONCLUSIONS: This first mHealth HIV risk-reduction pilot intervention for YGBM in Eastern Europe indicates preliminary efficacy and strong acceptability and feasibility. This mobile prevention tool lends itself to broad dissemination across various similar settings pending future efficacy testing in a large trial, especially in contexts where stigma keeps YGBM out of reach of affirmative health interventions. PMID- 30429118 TI - Self-Monitoring by Traffic Light Color Coding Versus Usual Care on Outcomes of Patients With Heart Failure Reduced Ejection Fraction: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Patients with heart failure (HF) reduced ejection fraction (HFrEF) have symptoms that are more severe and experience a higher rate of hospitalization compared with HF preserved ejection fraction (HFpEF) patients. However, symptom recognition cannot be made by patients based on current approaches. This problem is a barrier to effective self-care that needs to be improved by new self-monitoring instruments and strategies. OBJECTIVE: This study describes a protocol for the self-monitoring daily diaries of weight and shortness of breath (SOB) based on the traffic light system (TLS). The primary objective is to compare the self-care between the intervention and control group. Comparison of HF knowledge, HF quality of life (HFQOL), and all-cause hospitalization between the 2 groups are the secondary objectives. METHODS: A single-blind randomized controlled trial is being conducted at the HF clinic at Tehran Heart Center (Tehran, Iran). Sixty-eight adult patients of both genders will be enrolled during admission to HF clinic. Eligible subjects will be assigned to either the intervention or control group by a block balanced randomization method. Baseline surveys will be conducted before random allocation. Participants in the intervention group will receive an integrated package consisting of (1) HF self-care education by an Australian Heart Foundation booklet on HF, (2) regular home self-monitoring of weight and SOB, and (3) scheduled call follow-ups for 3 months. Patients in the control group will receive no intervention and they only complete monthly surveys. RESULTS: This study is ongoing and is expected to be completed by the end of 2018. CONCLUSIONS: This is the first trial with new self-monitoring instruments in Iran as a low and middle-income country. If the findings show a positive effect, the package will be applied in different regions with the same health care status. TRIAL REGISTRATION: Iranian Registry of Clinical Trials IRCT2017021032476N1; https://en.irct.ir/trial/25296?revision=25296 (Archived by WebCite at http://www.webcitation.org/73DLICQL8). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/9209. PMID- 30429119 TI - Response to: 'Inflammation in SLE-PAH: good news or not?' by Junyan Qian et al. PMID- 30429120 TI - Inflammation in SLE-PAH: good news or not? PMID- 30429121 TI - Response to: 'Metering the METEOR in methotrexate failure: is propensity score a falling star?' by Ahmed et al. PMID- 30429123 TI - Pollution: London's low emission zone has improved air quality but not children's lungs, study finds. PMID- 30429125 TI - Development and characterization of a new cell line derived from European eel Anguilla anguilla kidney. AB - A new cell line derived from the kidney of European eel, Anguilla anguilla, has been established and characterized. This cell line, designated as EK, has been maintained in Leibovitz's L-15 supplemented with 10% fetal bovine serum for over 24 months, and subcultured more than 60 times. This cell line consists predominantly of fibroblast-like cells, and could grow at 15-37 degrees C under an optimum temperature of 26 degrees C. The origin of this cell line was confirmed by polymerase chain reaction (PCR) amplification and 18s recombinant (r)RNA sequencing. The chromosome analysis of EK cells at passage 58 revealed an ananeuploid karyotype. The EK cells were successfully transfected with the Pegfp N1 plasmid, suggesting its potential in the genetic studies. The susceptibility test showed a significant cytopathic effect (CPE) in EK cells for Rana grylio virus, and the viral replication was evidenced with quantitative real-time PCR (qRT-PCR) assay. After poly(I:C) stimulation, the expression of the immune related molecules including interferon regulatory factor-3 (irf3), interferon regulatory factor-7 (irf7) and cytochrome P450 (CYP450) were significantly up regulated in EK cells, while the expression of transforming growth factor (TGF beta) was down-regulated. These results suggested the potential of EK cell line as a model in gene engineering, virus identification and environmental toxicology. PMID- 30429126 TI - Causes of concern for the NHS after Brexit. PMID- 30429122 TI - Prevalence of potentially inappropriate prescribing in older people in primary care and its association with hospital admission: longitudinal study. AB - OBJECTIVE: To determine whether hospital admission is associated with potentially inappropriate prescribing among older primary care patients (aged >=65 years) and whether such prescribing was more likely after hospital admission than before. DESIGN: Longitudinal study of retrospectively extracted data from general practice records. SETTING: 44 general practices in Ireland in 2012-15. PARTICIPANTS: Adults aged 65 years or over attending participating practices. EXPOSURE: Admission to hospital (any hospital admission versus none, and post admission versus pre-admission). MAIN OUTCOME MEASURES: Prevalence of potentially inappropriate prescribing assessed using 45 criteria from the Screening Tool for Older Persons' Prescription (STOPP) version 2, analysed both as rate of distinct potentially inappropriate prescribing criteria met (stratified Cox regression) and binary presence of potentially inappropriate prescribing (logistic regression) and adjusted for patients' characteristics. A sensitivity analysis used matching with propensity scores based on patients' characteristics and diagnoses. RESULTS: Overall 38 229 patients were included, and during 2012 the mean age was 76.8 (SD 8.2) years and 43% (13 212) were male. Each year, 10.4 15.0% (3015/29 077 in 2015 to 4537/30 231 in 2014) of patients had at least one hospital admission. The overall prevalence of potentially inappropriate prescribing ranged from 45.3% (13 940/30 789) of patients in 2012 to 51.0% (14 823/29 077) in 2015. Independently of age, sex, number of prescription items, comorbidity, and health cover, hospital admission was associated with a higher rate of distinct potentially inappropriate prescribing criteria met; the adjusted hazard ratio for hospital admission was 1.24 (95% confidence interval 1.20 to 1.28). Among participants who were admitted to hospital, the likelihood of potentially inappropriate prescribing after admission was higher than before admission, independent of patients' characteristics; the adjusted odds ratio for after hospital admission was 1.72 (1.63 to 1.84). Analysis of propensity score matched pairs showed a slight reduction in the hazard ratio for hospital admission to 1.22 (1.18 to 1.25). CONCLUSION: Hospital admission was independently associated with potentially inappropriate prescribing. It is important to determine how hospital admission may affect appropriateness of prescribing for older people and how potential adverse consequences of admission can be minimised. PMID- 30429124 TI - Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. AB - OBJECTIVE: To assess the association between the use of sodium glucose cotransporter 2 (SGLT2) inhibitors and seven serious adverse events of current concern. DESIGN: Register based cohort study. SETTING: Sweden and Denmark from July 2013 to December 2016. PARTICIPANTS: A propensity score matched cohort of 17 213 new users of SGLT2 inhibitors (dapagliflozin, 61%; empagliflozin, 38%; canagliflozin, 1%) and 17 213 new users of the active comparator, glucagon-like peptide 1 (GLP1) receptor agonists. MAIN OUTCOME MEASURES: The primary outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism, and acute pancreatitis, as identified from hospital records. Hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. RESULTS: Use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation (incidence rate 2.7 v 1.1 events per 1000 person years, hazard ratio 2.32, 95% confidence interval 1.37 to 3.91) and diabetic ketoacidosis (1.3 v 0.6, 2.14, 1.01 to 4.52) but not with bone fracture (15.4 v 13.9, 1.11, 0.93 to 1.33), acute kidney injury (2.3 v 3.2, 0.69, 0.45 to 1.05), serious urinary tract infection (5.4 v 6.0, 0.89, 0.67 to 1.19), venous thromboembolism (4.2 v 4.1, 0.99, 0.71 to 1.38) or acute pancreatitis (1.3 v 1.2, 1.16, 0.64 to 2.12). CONCLUSIONS: In this analysis of nationwide registers from two countries, use of SGLT2 inhibitors, as compared with GLP1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis, but not with other serious adverse events of current concern. PMID- 30429129 TI - Capmatinib Triggers Responses in NSCLC. AB - A phase II trial of the MET inhibitor capmatinib found that 72% of treatment naive patients responded to the drug, whereas the response rate for previously treated patients was 39.1%. The drug's side effects include peripheral edema, nausea, and vomiting. PMID- 30429130 TI - No deal? Not a happy prospect for life after March 2019. PMID- 30429128 TI - Capivasertib Active against AKT1-Mutated Cancers. AB - The experimental pan-AKT inhibitor capivasertib (AZD5363) helped stabilize or shrink tumor growth in most patients with metastatic AKT1-mutant tumors enrolled in the U.S.-wide NCI-MATCH trial, according to data presented at the EORTC-NCI AACR Symposium on Molecular Targets and Cancer Therapeutics. PMID- 30429131 TI - Legal representation at tribunals slashes risk of erasure, figures show. PMID- 30429127 TI - Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: randomized trial. AB - OBJECTIVE: To determine the effects of diets varying in carbohydrate to fat ratio on total energy expenditure. DESIGN: Randomized trial. SETTING: Multicenter collaboration at US two sites, August 2014 to May 2017. PARTICIPANTS: 164 adults aged 18-65 years with a body mass index of 25 or more. INTERVENTIONS: After 12% (within 2%) weight loss on a run-in diet, participants were randomly assigned to one of three test diets according to carbohydrate content (high, 60%, n=54; moderate, 40%, n=53; or low, 20%, n=57) for 20 weeks. Test diets were controlled for protein and were energy adjusted to maintain weight loss within 2 kg. To test for effect modification predicted by the carbohydrate-insulin model, the sample was divided into thirds of pre-weight loss insulin secretion (insulin concentration 30 minutes after oral glucose). MAIN OUTCOME MEASURES: The primary outcome was total energy expenditure, measured with doubly labeled water, by intention-to-treat analysis. Per protocol analysis included participants who maintained target weight loss, potentially providing a more precise effect estimate. Secondary outcomes were resting energy expenditure, measures of physical activity, and levels of the metabolic hormones leptin and ghrelin. RESULTS: Total energy expenditure differed by diet in the intention-to-treat analysis (n=162, P=0.002), with a linear trend of 52 kcal/d (95% confidence interval 23 to 82) for every 10% decrease in the contribution of carbohydrate to total energy intake (1 kcal=4.18 kJ=0.00418 MJ). Change in total energy expenditure was 91 kcal/d (95% confidence interval -29 to 210) greater in participants assigned to the moderate carbohydrate diet and 209 kcal/d (91 to 326) greater in those assigned to the low carbohydrate diet compared with the high carbohydrate diet. In the per protocol analysis (n=120, P<0.001), the respective differences were 131 kcal/d (-6 to 267) and 278 kcal/d (144 to 411). Among participants in the highest third of pre-weight loss insulin secretion, the difference between the low and high carbohydrate diet was 308 kcal/d in the intention-to-treat analysis and 478 kcal/d in the per protocol analysis (P<0.004). Ghrelin was significantly lower in participants assigned to the low carbohydrate diet compared with those assigned to the high carbohydrate diet (both analyses). Leptin was also significantly lower in participants assigned to the low carbohydrate diet (per protocol). CONCLUSIONS: Consistent with the carbohydrate-insulin model, lowering dietary carbohydrate increased energy expenditure during weight loss maintenance. This metabolic effect may improve the success of obesity treatment, especially among those with high insulin secretion. TRIAL REGISTRATION: ClinicalTrials.gov NCT02068885. PMID- 30429132 TI - Medical Financial Hardship among Cancer Survivors in the United States: What Do We Know? What Do We Need to Know? AB - Rising costs of cancer care have led to increased concerns about medical financial hardship for cancer survivors and their families in the United States. In this commentary, we provide an overview of research describing medical financial hardship and introduce a conceptual framework for identifying risk factors and research gaps at the patient and family, provider and care team, health care system, employer, and state and national policy levels. We then use this framework to highlight measurement and data infrastructure gaps related to hardship, summarize existing interventions to minimize hardship, and identify opportunities for future intervention efforts. PMID- 30429133 TI - Obstructive sleep apnoea and hypoventilation in an adult with congenital myasthenic syndrome. AB - In this case report, we describe an adult male with congenital myasthenic syndrome due to mutations in muscle-specific receptor tyrosine kinase (MuSK, c.79+2 T>G; IVS1 +2 T>G, c.2368 G>A, Val790Met) presenting with sleep apnoea and hypercapnic respiratory failure. In the intensive care unit, he required intubation followed by tracheostomy which resolved obstructive sleep apnoea. Later, due to persistent sleep-associated hypoventilation, he required nocturnal mechanical ventilation. His case illustrates how respiratory muscle weakness due to mutations in MuSK can lead to various forms of sleep disordered breathing. PMID- 30429135 TI - Agnes Binagwaho: Humour, hope, and global health. PMID- 30429136 TI - SGLT2 inhibitors for diabetes are linked to increased risk of lower limb amputation. PMID- 30429134 TI - Parry-Romberg syndrome in a patient with scleroderma. AB - Parry-Romberg syndrome (PRS) is characterised by progressive but self-limiting facial hemiatrophy. We describe a 48-year-old woman with a 3-year history of gradually worsening right facial hemiatrophy on a background of scleroderma. Her initial primary concern was alopecia. Within the last year, there was greater prominence of her right zygoma and hyperpigmentation on her forearms and left neck. She also had worsening headaches and neck stiffness in the mornings. A clinical diagnosis of PRS was made and she was subsequently treated with a course of methotrexate. She is due to be followed up by dermatology, rheumatology and maxillofacial surgery with the aim of reconstructive surgery once her symptoms stabilise. PMID- 30429137 TI - Congolese fight against Ebola. PMID- 30429138 TI - Cervical screening: GP leaders slam Capita over failure to send up to 48 500 letters. PMID- 30429140 TI - An unusual cause of right iliac fossa pain. PMID- 30429139 TI - Cutaneous Mycobacterial Infections. AB - SUMMARYHumans encounter mycobacterial species due to their ubiquity in different environmental niches. In many individuals, pathogenic mycobacterial species may breach our first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. Cutaneous mycobacterial infections may cause a wide range of clinical manifestations, which are divided into four main disease categories: (i) cutaneous manifestations of Mycobacterium tuberculosis infection, (ii) Buruli ulcer caused by Mycobacterium ulcerans and other related slowly growing mycobacteria, (iii) leprosy caused by Mycobacterium leprae and Mycobacterium lepromatosis, and (iv) cutaneous infections caused by rapidly growing mycobacteria. Clinically, cutaneous mycobacterial infections present with widely different clinical presentations, including cellulitis, nonhealing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, verrucous lesions, and other types of findings. Mycobacterial infections of the skin and subcutaneous tissue are associated with important stigma, deformity, and disability. Geography-based environmental exposures influence the epidemiology of cutaneous mycobacterial infections. Cutaneous tuberculosis exhibits different clinical phenotypes acquired through different routes, including via extrinsic inoculation of the tuberculous bacilli and dissemination to the skin from other sites, or represents hypersensitivity reactions to M. tuberculosis infection. In many settings, leprosy remains an important cause of neurological impairment, deformity, limb loss, and stigma. Mycobacterium lepromatosis, a mycobacterial species related to M. leprae, is linked to diffuse lepromatous leprosy of Lucio and Latapi. Mycobacterium ulcerans produces a mycolactone toxin that leads to subcutaneous tissue destruction and immunosuppression, resulting in deep ulcerations that often produce substantial disfigurement and disability. Mycobacterium marinum, a close relative of M. ulcerans, is an important cause of cutaneous sporotrichoid nodular lymphangitic lesions. Among patients with advanced immunosuppression, Mycobacterium kansasii, the Mycobacterium avium-intracellulare complex, and Mycobacterium haemophilum may cause cutaneous or disseminated disease. Rapidly growing mycobacteria, including the Mycobacterium abscessus group, Mycobacterium chelonei, and Mycobacterium fortuitum, are increasingly recognized pathogens in cutaneous infections associated particularly with plastic surgery and cosmetic procedures. Skin biopsies of cutaneous lesions to identify acid-fast staining bacilli and cultures represent the cornerstone of diagnosis. Additionally, histopathological evaluation of skin biopsy specimens may be useful in identifying leprosy, Buruli ulcer, and cutaneous tuberculosis. Molecular assays are useful in some cases. The treatment for cutaneous mycobacterial infections depends on the specific pathogen and therefore requires a careful consideration of antimicrobial choices based on official treatment guidelines. PMID- 30429141 TI - Association between factors related to family planning/sexual and reproductive health and contraceptive use as well as consistent condom use among internal migrant population of reproductive ages in three cities in China, based on Heckprobit selection models. AB - OBJECTIVE: With the increased population mobility and the transition in population policy, scholars are quite concerned about family planning/sexual and reproductive health (SRH) and related factors among internal migrant population of reproductive age. Therefore, the proposed study was designed to explore the association between factors related to family planning/SRH and contraceptive use as well as consistent condom use among the above-described population in China. DESIGN: Cross-sectional study. SETTING: Three municipalities in China, namely Beijing, Shanghai and Chongqing. PARTICIPANTS: Among the 6545 participants, 2099, 2414 and 2031 subjects came from Beijing, Shanghai and Chongqing, respectively. RESULTS: A total of 6545 eligible participants were included as the full sample, 6188 of whom who had intercourse in the last 3 months were selected as the subsample. Among the subsample, 80.88% (5005/6188) adopted any form of contraceptive methods and 49.14% (3041/6188) consistently used condom in the last three sexual intercourses. Meanwhile, the involved participants had a better mastery of knowledge on SRH than on contraception (p<0.0001). The results of the Heckprobit models revealed that the factors associated with both contraceptive use and consistent condom use were relationship with the first intercourse partner, communication frequency with spouse/sexual partners on sex, actual number of children and knowledge on SRH, while knowledge on contraception and age at first intercourse were associated with contraceptive use and consistent condom use, respectively (p<0.05). CONCLUSIONS: In the current study, we revealed a high level contraceptive prevalence, a relatively low-level consistent condom use and a poor mastery of knowledge on contraception and SRH. The Heckprobit selection model specified the existence of selection bias, providing evidence on the association between the factors on family planning/SRH and contraceptive use as well as consistent condom use, respectively. Our findings indicated that health institutions should offer appropriate technology and high-quality family planning/SRH services for the internal migrant population in China. PMID- 30429142 TI - Correlates and aetiological factors associated with hedonic well-being among an ageing population of US men and women: secondary data analysis of a national survey. AB - OBJECTIVE: To understand the gender-specific factors that uniquely contribute to successful ageing in a US population of men and women, 57-85 years of age. This was achieved through the examination of the correlates of subjective well-being defined by health-related quality of life (HRQoL), across several biological and psychosocial determinants of health. DESIGN: Cross-sectional study. SETTING: The National Social Life, Health and Ageing Project (NSHAP), 2010-2011 a representative sample of the US population. PARTICIPANTS: 3377 adults aged 57-85 (1538 men, 1839 women) from the NSHAP. MAIN OUTCOME MEASURES: The biopsychosocial factors of biological/physiological function, symptom status, functional status, general health perceptions and HRQoL happiness. METHOD: HRQoL was measured using the NSHAP wave 2 multistage, stratified area probability sample of US households (n=3377). Variable selection was guided by the Wilson and Cleary model (WCM) that classifies health outcomes at five main levels and characteristics. RESULTS: Our findings indicate differences in biopsychosocial factors comprised in the WCM and their relative importance and unique impact on HRQoL by gender. Women reported significantly lower HRQoL than men (t=3.5, df=3366). The most significant contributors to HRQoL in women were mental health (B=0.31; 0.22, 0.39), loneliness (B=-0.26; -0.35, -0.17), urinary incontinence (B=-0.22; -0.40, -0.05) and support from spouse/partner (B=0.27; 0.10, 0.43) and family B=0.12; 0.03, 0.20). Men indicated mental health (B=0.21; 0.14, 0.29), physical health (B=0.17; 0.10, 0.23), functional difficulties (B=0.38; 0.10, 0.65), loneliness (B=-0.20; 0.26, -0.12), depression (B=-0.36; -0.58, -0.15) and support from friends (B=0.06; 0.10, 0.11) as significant contributors. Those with greater social support had better HRQoL (F=4.22, df=4). Lack of companionship and reliance on spouse/partner were significant HRQoL contributors in both groups. CONCLUSION: Our findings offer insight into ageing, gender and subjective well-being. The results provide an opportunity to identify biopsychosocial factors to inform interventions to support successful ageing. PMID- 30429143 TI - Quality of life, loneliness and health-related characteristics among older people in Liaoning province, China: a cross-sectional study. AB - OBJECTIVES: The aim of the study was to examine the relations among quality of life (QOL), loneliness and health-related characteristics in a sample of Chinese older people. DESIGN: Cross-sectional study. SETTING: Communities in Dandong city, Liaoning province, China. PARTICIPANTS: Sample of 732 older people aged 60 and older who were living in Dandong, Liaoning province, China. METHODS: A questionnaire was administered to the participants face-to-face. The questionnaire contained four sections: demographic characteristics, health related characteristics, the EQ-5D Scale and the UCLA Loneliness Scale. The t test, F-test and multivariable linear regression analyses were performed to individually test associations between the demographic data, health-related characteristics, loneliness and QOL. RESULTS: Chronic diseases, loneliness, age and smoking status were negatively associated with QOL (p<0.05). Satisfaction with health services, income and physical activity were positively associated with QOL (p<0.05). CONCLUSIONS: Loneliness, chronic diseases and health service satisfaction were important factors related to low QOL among older people in China. The findings indicate that reducing loneliness, managing chronic diseases and improving the health service may help to improve the QOL for older people. PMID- 30429144 TI - Goal-directed fluid therapy in urgent GAstrointestinal Surgery-study protocol for A Randomised multicentre Trial: The GAS-ART trial. AB - INTRODUCTION: Intravenous fluid therapy during gastrointestinal surgery is a life saving part of the perioperative care. Too little fluid may lead to hypovolaemia, decreased organ perfusion and circulatory shock. Excessive fluid administration increases postoperative complications, worsens pulmonary and cardiac function as well as the healing of surgical wounds. Intraoperative individualised goal directed fluid therapy (GDT) and zero-balance therapy (weight adjusted) has shown to reduce postoperative complications in elective surgery, but studies in urgent gastrointestinal surgery are sparse. The aim of the trial is to test whether zero balance GDT reduces postoperative mortality and major complications following urgent surgery for obstructive bowel disease or perforation of the gastrointestinal tract compared with a protocolled standard of care. METHODS/ANALYSIS: This study is a multicentre, randomised controlled trial with planned inclusion of 310 patients. The randomisation procedure is stratified by hospital and by obstructive bowel disease and perforation of the gastrointestinal tract. Patients are allocated into either 'the standard group' or 'the zero balance GDT group'. The latter receive intraoperative GDT (guided by a stroke volume algorithm) and postoperative zero-balance fluid therapy based on body weight and fluid charts. The protocolled treatment continues until free oral intake or the seventh postoperative day.The primary composite outcome is death, unplanned reoperations, life-threatening thromboembolic and bleeding complications, a need for mechanical ventilation or dialysis. Secondary outcomes are additional complications, length of hospital stay, length of stay in the intensive care unit, length of mechanical ventilation, readmissions and time to death. Follow-up is 90 days.We plan intention-to-treat analysis of the primary outcome. ETHICS AND DISSEMINATION: The Danish Scientific Ethics Committee approved the GAS-ART trial before patient enrolment (J: SJ-436). Enrolment of patients began in August 2015 and is proceeding. We expect to publish the GAS-ART results in Summer 2019. TRIAL REGISTRATION NUMBER: EudraCT 2015-000563-14. PMID- 30429145 TI - Is the Rule of Halves framework relevant for diabetes care in Copenhagen today? A register-based cross-sectional study. AB - OBJECTIVE: The study aimed at analysing whether the 'Rule of Halves' framework applies for diabetes care in the Danish healthcare system with high levels of accessibility and equity. The Rule of Halves states that only one-half of people with a particular chronic condition are diagnosed; one-half of those diagnosed get treatment, and one-half of treated achieve desired therapeutic goals. DESIGN: The analysis is cross sectional based on available surveys, register data and clinical databases covering the adult population in Copenhagen. We analysed five levels of prevention and care including behavioural risk factors and biomarkers, prevalence of diagnosed and undiagnosed diabetes as well as how many received care according to guidelines and achieved relevant outcomes. SETTING: The study population is Copenhagen City with a population of 550 000 with 21 500 prevalent cases of diabetes. While the registers used cover the whole population, the surveys include 750 cases and the biobank data 365 cases. OUTCOME MEASURES: Outcome measures are for each level of analysis: the prevalence of high-risk individuals, prevalence of undiagnosed and diagnosed diabetes, proportion receiving treatment and proportion achieving quality and treatment targets. RESULTS: We found that the 'Rule of Halves' framework raises relevant questions on how diabetes care works in a specific population, but the actual proportions found in Copenhagen are far from halves. Our analyses showed that 74% are diagnosed and among those who are 90% are receiving care. 40%-60% have achieved target levels of treatment in terms of HbA1c level and lipid levels. 80% have received eye and foot examinations in the last 2 years. 11% have retinopathy and 25% have macrovascular complications. CONCLUSION: Copenhagen is doing much better than halves, when it comes to diagnosis and providing treatment, whereas the Rule of Halves still prevails when it comes to treatment targets. There is thus still room for improvement. PMID- 30429146 TI - Socioeconomic differences in experiences with treatment of coronary heart disease: a qualitative study from the perspective of elderly patients. AB - OBJECTIVES: This qualitative study aims to analyse socioeconomic differences in patients' experiences along the treatment pathway for coronary heart disease (CHD). DESIGN: A longitudinal qualitative study using in-depth semistructured interviews to explore patients' experiences with treatment was conducted. We analysed the transcripts of the records according to qualitative content analysis and identified differences between patients with lower and higher socioeconomic status (SES) by comparing and contrasting the narratives. SETTING: The University Hospital in Halle (Saale), Germany. PARTICIPANTS: 41 elderly patients (aged 59-80 years) who suffered from CHD. RESULTS: From various patient's experiences along the pathway of care which were found to differ according to SES we derived three major themes: (1) information: patients with higher SES had greater knowledge about treatment and could use medical records as sources of information; (2) illness perception: patients with lower SES focused on improving symptoms and survival, while patients with higher SES focused on physical performance and disease management; and (3) perceived role in healthcare: patients with lower SES tended to delegate responsibility to healthcare professionals. CONCLUSIONS: Differences in the patient's knowledge about treatment, their perceived role in healthcare and illness perception can be the factors and mechanisms that contribute to explain socioeconomic inequalities in the treatment of CHD. These factors should be considered in quantitative studies to better understand the disparities in treatment and mortality. We suggest that improving patient physician communication and patient knowledge can change the patient's understanding of CHD and their perceived role in healthcare and reduce inequalities in CHD treatment. TRIAL REGISTRATION NUMBER: DRKS00007839. PMID- 30429147 TI - Retrospective analysis of alcohol testing in trauma team activation patients at a Canadian tertiary trauma centre. AB - OBJECTIVES: Although alcohol screening is an essential requirement of level I trauma centre accreditation, actual rates of compliance with mandatory alcohol testing in trauma patients are seldom reported. Our objective was to determine the prevalence of blood alcohol concentration (BAC) testing in patients requiring trauma team activation (TTA) for whom blood alcohol testing was mandatory, and to elucidate patient-level, injury-level and system-level factors associated with BAC testing. DESIGN: Retrospective cohort study. SETTING: Tertiary trauma centre in Halifax, Canada. PARTICIPANTS: 2306 trauma patients who required activation of the trauma team. PRIMARY OUTCOME MEASURE: The primary outcome was the rate of BAC testing among TTA patients. Trends in BAC testing over time and across patient and injury characteristics were described. Multivariable logistic regression examined patient-level, injury-level and system-level factors associated with testing. RESULTS: Overall, 61% of TTA patients received BAC testing despite existence of a mandatory testing protocol. Rates of BAC testing rose steadily over the study period from 33% in 2000 to 85% in 2010. Testing varied considerably across patient-level, injury-level and system-level characteristics. Key factors associated with testing were male gender, younger age, lower Injury Severity Score, scene Glasgow Coma Scale score <9, direct transport to hospital and presentation between midnight and 09:00 hours, or on the weekend. CONCLUSIONS: At this tertiary trauma centre with a policy of empirical alcohol testing for TTA patients, BAC testing rates varied significantly over the 11-year study period and distinct factors were associated with alcohol testing in TTA patients. PMID- 30429148 TI - Compliance with pathology testing guidelines in Australian general practice: protocol for a secondary analysis of electronic health record data. AB - INTRODUCTION: In Australia, general practitioners usually are the first point of contact for patients with non-urgent medical conditions. Appropriate and efficient utilisation of pathology tests by general practitioners forms a key part of diagnosis and monitoring. However overutilisationand underutilisation of pathology tests have been reported across several tests and conditions, despite evidence-based guidelines outlining best practice in pathology testing. There are a limited number of studies evaluating the impact of these guidelines on pathology testing in general practice. The aim of our quantitative observational study is to define how pathology tests are used in general practice and investigate how test ordering practices align with evidence-based pathology guidelines. METHODS AND ANALYSIS: Access to non-identifiable patient data will be obtained through electronic health records from general practices across three primary health networks in Victoria, Australia. Numbers and characteristics of patients, general practices, encounters, pathology tests and problems managed over time will be described. Overall rates of encounters and tests, alongside more detailed investigation between subcategories (encounter year, patient's age, gender, and location and general practice size), will also be undertaken. To evaluate how general practitioner test ordering coincides with evidence-based guidelines, five key candidate indicators will be investigated: full blood counts for patients on clozapine medication; international normalised ratio measurements for patients on warfarin medication; glycated haemoglobin testing for monitoring patients with diabetes; vitamin D testing; and thyroid function testing. ETHICS AND DISSEMINATION: Ethics clearance to collect data from general practice facilities has been obtained by the data provider from the RACGP National Research and Evaluation Ethics Committee (NREEC 17-008). Approval for the research group to use these data has been obtained from Macquarie University (5201700872). This study is funded by the Australian Government Department of Health Quality Use of Pathology Program (Agreement ID: 4-2QFVW4M). Findings will be reported to the Department of Health and disseminated in peer-reviewed academic journals and presentations (national and international conferences, industry forums). PMID- 30429149 TI - Effect of beta-blocker therapy on clinical outcomes, safety, health-related quality of life and functional capacity in patients with chronic obstructive pulmonary disease (COPD): a protocol for a systematic literature review and meta analysis with multiple treatment comparison. AB - INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) who have a clinical indication for beta-blocker therapy, are often not prescribed such medication, despite evidence suggesting that beta-blockers are not associated with adverse respiratory outcomes. The primary objective of this systematic review and meta-analysis is to examine the class effect of beta-blocker use in patients with COPD. We will focus on a broad range of endpoints including, clinical, safety, and patient-centric outcomes such as health related quality of life (HRQoL) and functional capacity. A secondary objective is to explore potential within-class variation in the effects of beta-blockers among patients with COPD, and rank individual agents according to their relative benefit(s). METHODS AND ANALYSIS: MEDLINE, Embase, The Cochrane Library and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases will be systematically searched, from inception to present, to identify randomised controlled trials (RCTs) and other prospective and interventional studies of beta blocker use in patients with COPD which report on the outcomes of interest. Relative treatment effects with respect to mortality, COPD exacerbations, all cause hospitalisation, lung function, HRQoL and exercise capacity will be summarised by meta-analysis. Individual treatments (agents) will be compared in a Bayesian network meta-analysis including RCT and observational data, if feasible. ETHICS AND DISSEMINATION: The results of the study will be submitted for publication in a peer-reviewed journal. Only previously published aggregate data will be used for the purpose of this review. PROSPERO REGISTRATION NUMBER: CRD42018098983. PMID- 30429150 TI - Understanding the impact of delegated home visiting services accessed via general practice by community-dwelling patients: a realist review protocol. AB - INTRODUCTION: In western countries, early visiting services (EVS) have been proposed as a recent intervention to reduce both general practitioner workload and hospital admissions among housebound individuals experiencing a healthcare need within the community. EVS involves the delegation of the patient home visits to other staff groups such as paramedics or nursing staff. However, the principles of organising this care are unknown and it remains unclear how different contexts, such as patient conditions and the processes of organising EVS influence care outcomes. A review has been designed to understand how EVS are enacted and, specifically, who benefits, why, how and when in order to provide further insight into the design and delivery of EVS. METHODS AND ANALYSIS: The purpose of this review is to produce findings that provide explanations of how and why EVS contexts influence their associated outcomes. Evidence on EVS will be consolidated through realist review-a theory-driven approach to evidence synthesis. A realist approach is needed as EVS is a complex intervention. What EVS achieve is likely to vary for different individuals and contexts. We expect to synthesise a range of relevant data such as qualitative, quantitative and mixed-method research in the following stages: devising an initial programme theory, searching evidence, selecting appropriate documents, extracting data, synthesising and refining the programme theory. ETHICS AND DISSEMINATION: A formal ethics review is not required as this study is secondary research. Findings will be disseminated in a peer-reviewed journal, at national and international conferences and to relevant professional associations. PROSPERO REGISTRATION NUMBER: CRD42018096518. PMID- 30429151 TI - Braced for Brexit. PMID- 30429152 TI - Tackling potentially inappropriate prescribing. PMID- 30429153 TI - Addressing Disparities in Living Donor Kidney Transplantation: A Call to Action. PMID- 30429155 TI - Holding out for an apology. PMID- 30429154 TI - Long non-coding RNA PICSAR decreases adhesion and promotes migration of squamous carcinoma cells by downregulating alpha2beta1 and alpha5beta1 integrin expression. AB - Long non-coding RNAs (lncRNAs) regulate various cellular processes, and they have emerged as potential biomarkers and therapeutic targets in cancer. We have previously characterized the oncogenic role of lncRNA PICSAR (p38 inhibited cutaneous squamous cell carcinoma associated lincRNA) in cutaneous squamous cell carcinoma (cSCC), the most common metastatic skin cancer. In this study, we show that knockdown of PICSAR in cSCC cells upregulates expression of alpha2, alpha5 and beta1 integrins, resulting in increased cell adhesion and decreased cell migration on collagen I and fibronectin. In contrast, overexpression of PICSAR in cSCC cells downregulates expression of alpha2, alpha5 and beta1 integrins on cell surface, resulting in decreased cell adhesion on collagen I and fibronectin and increased cell migration. These results demonstrate a novel mechanism for regulation of the expression of collagen and fibronectin binding integrins by lncRNA PICSAR, leading to altered adhesion and migration of cSCC cells.This article has an associated First Person interview with the first author of the paper. PMID- 30429156 TI - Molecular monitoring in CML: how deep? How often? How should it influence therapy? AB - With the advent of tyrosine kinase inhibitors (TKIs), the goals of therapy in chronic myeloid leukemia (CML) are steadily shifting. Long-term disease control on TKI therapy has been the goal and expectation for most patients. More recently, treatment-free remission (TFR) has entered mainstream practice and is increasingly being adopted as the main goal of therapy. This therapeutic shift not only influences TKI selection but also, has necessitated the refinement and dissemination of highly sensitive and accurate molecular monitoring techniques. Measurement of BCR-ABL1 messenger RNA expression through reverse transcription quantitative polymerase chain reaction, reported according to the International Scale, has become the primary tool for response assessment in CML. Achieving specific time-dependent molecular milestones, as defined by global therapeutic guidelines, has been established as critical in maximizing optimal outcomes while identifying patients at risk of therapy failure. Depth and duration of a deep molecular response have become the new therapeutic targets in patients considered for TFR. Consequently, molecular monitoring in CML has become even more critical to ongoing response assessment, identifying patients with TKI resistance and poor drug adherence, and enabling TFR to be attempted safely and effectively. PMID- 30429157 TI - Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist. AB - Heavy menstrual bleeding (HMB) is frequently reported by adolescents. The role of the hematologist is threefold in the evaluation of such patients: 1) perform a clinical and laboratory evaluation for an underlying bleeding disorder based on the degree of clinical suspicion, 2) identify and manage any concomitant iron deficiency, and 3) provide input to the referring provider regarding the management of HMB, particulary for patients with identified hemostatic defects. Several clues in the menstrual history should raise suspicion for an underlying bleeding disorder, such as menses lasting >7 days, menstrual flow which soaks >5 products daily or requires product change during the night, passage of large blood clots, or failure to respond to conventional therapies. A detailed personal and family history of other bleeding symptoms should also be obtained. Iron deficiency with and without anemia is commonly found in young women with HMB. Therefore, it is important to obtain not only a hemoglobin, but also a ferritin level, when evaluating these patients. Iron supplementation is often a key component of management in the adolescent with heavy menses, and is still needed even in those who have received packed red cell transfusions due to severe anemia. Strategies for decreasing menstrual blood flow are similar between adults and adolescents with heavy menses, with combined hormonal contraceptives recommended as first-line therapy. However, adolescent-specific considerations exist for many of these agents, and must be incorporated into shared decision making when selecting the most appropriate treatment. PMID- 30429158 TI - Combinations or Sequences of Targeted Agents in CLL: Is the whole greater than the sum of its parts (Aristotle, 360 BC)? AB - The treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving. Targeted agents (TA) have demonstrated impressive single agent activity, and therefore have been replacing chemoimmunotherapy (CIT). Despite their efficacy, the optimal use of the current TAs remains challenging. Perhaps the major dilemma is whether these drugs are best-utilized in sequence, or in combinations. Most patients tolerate TA well, notably early during treatment; however, a substantial number discontinue therapy due to toxicities. Therefore, the reasons for discontinuation and, subsequently, the preferred sequence of these agents become critical issues. While TA monotherapy has revolutionized the treatment of CLL, residual disease, acquired resistance, suboptimal durability of response in patients with high-risk disease, indefinite treatment duration, and decreased compliance over time are issues of concern. To address these challenges, an increasing number of studies are evaluating different combinations of TAs; however, these studies have been mostly small single arm trials in heterogeneous patient populations using different methods for response assessment. A number of questions remain regarding the predictive value of minimal residual disease (MRD) status, durability of response, fixed treatment durations and importantly, criteria for selection of patients for the optimal combinations. Medical comorbidities, performance status, prior therapies and disease risk-profile are fundamental in determining the treatment plan for each individual patient. Furthermore, utilizing prognostic and predictive markers along with monitoring MRD can guide the development of individualized, better tolerated, time-limited and potentially curative chemo-free treatment regimens. PMID- 30429159 TI - Plateletpheresis-associated lymphopenia in frequent platelet donors. AB - Over one million apheresis platelet collections are performed annually in the United States. After two healthy plateletpheresis donors were incidentally found to have low CD4+ T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional, single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited three groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1-2, 3-19, or 20-24. CD4+ T-lymphocyte counts were below 200 cells/uL in 0/20 donors in the 1-2 sessions group, 2/20 donors in the 3-19 group and 6/20 donors in the 20-24 group (P=0.019). CD8+ T-lymphocyte counts were low in 0/20 donors in the 1-2 group, 4/20 donors in the 3-19 group, and 11/20 donors in the 20-24 group (P<0.001). The leukoreduction system chamber's lymphocyte extraction efficiency was ~15-20% for all groups. Immunophenotyping showed decreases in naive CD4+ T-lymphocyte and Th17 percentages, increases in CD4+ and CD8+ effector memory, Th1, and Treg percentages, and stable naive CD8+ and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4+ and CD8+ T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful. PMID- 30429160 TI - Variable BCL2/BCL2L1 ratio in multiple myeloma with t(11;14). PMID- 30429161 TI - The Gp1ba-Cre transgenic mouse: a new model to delineate platelet and leukocyte functions. AB - Conditional knockout (KO) mouse models are invaluable for elucidating the physiological roles of platelets. The Pf4-Cre transgenic mouse is the current model of choice for generating megakaryocyte/platelet-specific KO mice. Platelets and leukocytes work closely together in a wide range of disease settings, yet the specific contribution of platelets to these processes remains unclear. This is partially due to the Pf4-Cre transgene being expressed in a variety of leukocyte populations. To overcome this issue, we developed a Gp1ba-Cre transgenic mouse strain in which Cre expression in driven by the endogenous Gp1ba locus. By crossing Gp1ba-Cre and Pf4-Cre mice to the mT/mG dual-fluorescence reporter mouse and performing a head-to-head comparison, we demonstrate more stringent megakaryocyte lineage-specific expression of the Gp1ba-Cre transgene. Broader tissue expression was observed with the Pf4-Cre transgene, leading to recombination in many hematopoietic lineages, including monocytes, macrophages, granulocytes, dendritic, B and T cells. Direct comparison of phenotypes of Csk, Shp1 or CD148 conditional KO mice generated using either the Gp1ba-Cre or Pf4-Cre strains revealed similar platelet phenotypes. However, additional inflammatory and immunological anomalies were observed in Pf4-Cre-generated KO mice due to non specific deletion in other hematopoietic lineages. By excluding leukocyte contributions to phenotypes, the Gp1ba-Cre mouse will advance our understanding of the role of platelets in inflammation and other pathophysiological processes where platelet-leukocyte interactions are involved. PMID- 30429162 TI - Introduction to a review series on iron metabolism and its disorders. PMID- 30429164 TI - Individuals with high-risk adenomas are at elevated risk for colorectal cancer. PMID- 30429163 TI - Medical scientists and philosophers worldwide appeal to EBM to expand the notion of 'evidence'. PMID- 30429165 TI - Reciprocal healthcare arrangements after Brexit. PMID- 30429166 TI - Trends in opioid use in commercially insured and Medicare Advantage populations in 2007-16: retrospective cohort study. PMID- 30429169 TI - ? PMID- 30429168 TI - At home and away. PMID- 30429167 TI - The reporting of studies conducted using observational routinely collected health data statement for pharmacoepidemiology (RECORD-PE). PMID- 30429171 TI - Continued lack of abortion training is disheartening. PMID- 30429170 TI - The term cognition-enhancing medications is misleading. PMID- 30429172 TI - Challenges facing efforts to strengthen primary health care: The Besrour Papers: a series on the state of family medicine in Canada and Brazil. PMID- 30429173 TI - The times, are they a-changin'? PMID- 30429174 TI - Pediatric hand injuries: Practical approach for primary care physicians. AB - OBJECTIVE: To present a practical and evidence-based approach for primary care physicians to the diagnosis and initial management of common pediatric hand injuries, and to identify injuries requiring prompt referral. SOURCES OF INFORMATION: Clinical evidence and expert recommendations were identified by using MEDLINE and EMBASE for each topic presented. MAIN MESSAGE: Pediatric hand injuries are a common reason for physician consultation. The most common and potentially problematic pediatric hand injuries include fingertip injuries, phalangeal fractures, tendon injuries, and hand burns. Management is limited by difficulties in proper assessment of the hand and the paucity of evidence to guide treatment. Nevertheless, outcomes in children are typically excellent. CONCLUSION: Appropriate assessment, initial management, and, if necessary, timely referral of pediatric patients with hand injuries are paramount given the importance of the hand in function and child development. While some principles from managing adult hand injuries might apply, children often require special considerations. PMID- 30429175 TI - Trust as the foundation: thoughts on the Starfield principles in Canada and Brazil: The Besrour Papers: a series on the state of family medicine in Canada and Brazil. AB - OBJECTIVE: To compare primary care in Canada and Brazil and how both countries have embraced the Starfield principles in the design of their health care systems. COMPOSITION OF THE COMMITTEE: A subgroup of the Besrour Centre of the College of Family Physicians of Canada developed connections with colleagues in Brazil and collaborated to undertake a between-country comparison, comparing and contrasting various elements of both countries' efforts to strengthen primary care over the past few decades. METHODS: Following a literature review, the authors collectively reflected on their experiences in an attempt to explore the past and current state of family medicine in Canada and Brazil. REPORT: The Brazilian and Canadian primary care systems have both adopted and advanced the Starfield principles in various ways, with both countries showing an increasing trend toward adopting interprofessional team-based care. Access to primary care remains a challenge in rural areas in both countries, and longitudinal relationships between providers and patients appear to be more common in Canada. With the advent of technology, increasing patient engagement and expectations, the decline of paternalistic medicine, and the sheer mass of readily available information (and misinformation), to be successful, primary care systems must also be constructed to engender trust at both the local and the system levels. Both countries face challenges to maintaining trust in the context of the increasing prevalence of team-based care, and a lack of trust at the system level can be seen in patients' perceptions about the difficulty of finding a family doctor and in high rates of emergency department and urgent care centre use in both countries. Primary care reform must be implemented with the public's trust in mind. CONCLUSION: Trust is a crucial ingredient to the success of primary care and must be protected at both local and system levels. If designed with trust in mind, primary care in Canada and Brazil has the potential to meet the challenges set out by the Starfield principles. PMID- 30429176 TI - Practice organization for preventive screening. PMID- 30429178 TI - Choosing Wisely Canada recommendations. PMID- 30429177 TI - Management of asymptomatic bacteriuria in children. AB - Question I am aware of how common pediatric urinary tract infection (UTI) is, and of the potential long-term sequelae if left untreated. Therefore, in our practice we treat every child who presents with symptomatic UTI with antibiotics. However, should the same practice be applied to children with bacteriuria that is asymptomatic?Answer Historically, asymptomatic bacteriuria (ABU) was treated with antibiotics in all populations, including in children. However, more recent evidence has shown no benefit and often harm associated with the use of antibiotics to treat pediatric ABU. Some studies suggest that owing to the different microbiology associated with ABU it should not be considered in the spectrum of UTI. These children should not be treated with antibiotics unless they have received a renal transplant or have undergone invasive urologic procedures. PMID- 30429179 TI - Omega-3 supplements for dry eye. PMID- 30429180 TI - Removing a cast: Casting Immobilization Series for Primary Care. PMID- 30429182 TI - Countering countertransference. PMID- 30429183 TI - Between illness and disease: Reflections on managing medically unexplained symptoms. PMID- 30429181 TI - What are the most common conditions in primary care? Systematic review. AB - OBJECTIVE: To identify the most commonly presenting conditions in primary care globally, and to compare common reasons for visits (RFVs) as reported by clinicians and patients, as well as among countries of different economic classifications. DATA SOURCES: Twelve scientific databases were searched up to January 2016, and a dual independent review was performed to select primary care studies. STUDY SELECTION: Studies were included if they contained 20 000 visits or more (or equivalent volume by patient-clinician interactions) and listed 10 or more RFVs. Dual independent data extraction of study characteristics and RFV rankings was performed. Data analysis was descriptive, with pooled rankings of RFVs across studies. SYNTHESIS: Eighteen studies met inclusion criteria (median 250 000 patients or 83 161 visits). Data were from 12 countries across 5 continents. The 10 most common clinician-reported RFVs were upper respiratory tract infection, hypertension, routine health maintenance, arthritis, diabetes, depression or anxiety, pneumonia, acute otitis media, back pain, and dermatitis. The 10 most common patient-reported RFVs were symptomatic conditions including cough, back pain, abdominal symptoms, pharyngitis, dermatitis, fever, headache, leg symptoms, unspecified respiratory concerns, and fatigue. Globally, upper respiratory tract infection and hypertension were the most common clinician reported RFVs. In developed countries the next most common RFVs were depression or anxiety and back pain, and in developing countries they were pneumonia and tuberculosis. There was a paucity of available data, particularly from developing countries. CONCLUSION: There are differences between clinician-reported and patient-reported RFVs to primary care, as well as between developed and developing countries. The results of our review are useful for the development of primary care guidelines, the allocation of resources, and the design of training programs and curricula. PMID- 30429184 TI - Mentorship for early career family physicians: Is there a role for the First Five Years in Family Practice Committee and the CFPC? PMID- 30429185 TI - The Besrour Centre: Building a sustainable future. PMID- 30429186 TI - ? PMID- 30429187 TI - ? PMID- 30429188 TI - Linking education and practice: The Outcomes of Training project. PMID- 30429189 TI - ? PMID- 30429190 TI - ? PMID- 30429191 TI - ? PMID- 30429192 TI - ? PMID- 30429193 TI - ? PMID- 30429194 TI - Antidepressant and antipsychotic prescribing in primary care for people with dementia. AB - OBJECTIVE: To use data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN) to evaluate the prevalence of antidepressant and antipsychotic prescriptions among patients with no previous depression or psychosis diagnoses, and to identify the factors associated with the use of these drugs in this population. DESIGN: Retrospective cohort study using data derived from CPCSSN. SETTING: Primary care practices associated with CPCSSN. PARTICIPANTS: Patients who were born before 1949; who were associated with a CPCSSN primary care practitioner between October 1, 2007, and September 30, 2013; and whose electronic medical records contained data from at least 6 months before and 12 months after the date of dementia diagnosis. MAIN OUTCOME MEASURES: Prescription for an antidepressant or antipsychotic medication in the absence of a depression or psychosis diagnosis. Multivariable models were fitted to determine estimated odds ratios (ORs) and were adjusted for age and sex. RESULTS: Of the 3252 patients without a depression diagnosis, 8.5% received a new prescription for an antidepressant in the 12 months following their diagnosis of dementia. Prescribing was reduced in association with older age (OR of 0.86 per 5-year age increase, P=.001) and male sex (OR=0.77, P=.056), and prescribing increased in association with prescription of cholinesterase inhibitor medications (OR=1.57, P=.003). Of the 4262 patients without a diagnosis of psychosis, 6.1% received a new prescription for an antipsychotic in the 12 months following their diagnosis of dementia. Higher rates of antipsychotic prescriptions were reported in men (OR=1.31, P=.046), those receiving a prescription for steroids (OR=1.90, P=.037), and those diagnosed with Parkinson disease (OR 1.58, P=.051). CONCLUSION: A substantial number of patients with dementia are being prescribed antidepressant or antipsychotic medications by their primary care practitioners without evidence of depression or psychosis in their electronic medical records. PMID- 30429195 TI - Family medicine training in housecalls: Survey of residency program directors across Canada. AB - OBJECTIVE: To assess the current landscape of home-based primary care (HBPC) or home visit training for Canadian family medicine residents. DESIGN: Online survey. SETTING: Canada's 17 family medicine residency programs. PARTICIPANTS: Family medicine residency program directors. MAIN OUTCOME MEASURES: Program characteristics, current HBPC training, barriers and enablers to training, and program directors' attitudes toward training. RESULTS: There was a 76% response rate (13 of 17 program directors). Respondents' programs ranged in size from 75 to 300 residents (median 160) and closely reflected actual resident distribution of family medicine residents in Canada. Twelve of the 13 programs offered HBPC training including home visit experiences. Six programs had HBPC-related didactic lectures. None of the respondents had a formal program-wide clinical home visit curriculum, and HBPC training availability and requirements varied across programs. The most frequently cited barriers included logistical constraints, limited faculty availability, and safety concerns. Program directors generally agreed that HBPC training is essential to family medicine training, that it provides valuable learning experiences for family medicine residents, and that it effectively prepares residents in core family medicine competencies. None thought that HBPC training was too difficult to coordinate or that its barriers outweighed its educational benefits. CONCLUSION: There is increasing need for HBPC delivery in Canada, and program directors agree that HBPC training is important and worthwhile. However, barriers exist. Current HBPC training in Canada varies in its availability and requirements, and structured program-wide home visit curricula are absent. We recommend development of a central framework for a structured HBPC curriculum that is competency-based and adaptable. PMID- 30429196 TI - ? PMID- 30429197 TI - ? PMID- 30429198 TI - FLI1 exonic circular RNAs as a novel oncogenic driver to promote tumor metastasis in small cell lung cancer. AB - PURPOSE: The aberrantly upregulated Friend leukemia virus integration 1 (FLI1) is closely correlated with the malignant phenotype of small cell lung cancer (SCLC). This study attempts to examine if FLI1 exonic circular RNAs (FECRs) function as a new malignant driver that determines the metastatic phenotype in SCLC. EXPERIMENTAL DESIGN: The expression of FECRs was examined in SCLC tissues and serum exosomes. The oncogenic activity of FECRs was investigated in SCLC cell lines and animal xenograft studies. Finally, we explored the molecular mechanisms underlying these non-coding RNAs as a malignant driver. RESULTS: Therapeutic comparison of CRISPR Cas9 knockout and shRNA knockdown of FLI1 identified FECRs as a new non-canonical malignant driver in SCLC. We found that FECRs were aberrantly upregulated in SCLC tissues (p<0.0001), and was positively associated with lymph node metastasis (p<0.01). Notably, serum exosomal FECR1 was associated with poor survival and clinical response to chemotherapy. Silencing of FECRs significantly inhibited the migration in two highly aggressive SCLC cell lines and reduced tumor burden in a mouse xenograft model. Mechanistically, we uncovered that FECRs sequestered and subsequently inactivated tumor suppressor microRNA miR584-3p, leading to the activation of the Rho Associated Coiled-Coil Containing Protein Kinase 1 gene (ROCK1). CONCLUSION: This study identifies FLI1 exonic circular RNAs as a new oncogenic driver that promotes tumor metastasis through the miR584-ROCK1 pathway. Importantly, serum exosomal FECR1 may serve as a promising biomarker to track disease progression of SCLC. PMID- 30429200 TI - More is more: Semi-annual breast MRI screening in BRCA1 mutation carriers. AB - Although annual MRI-screening has improved early diagnosis of hereditary breast cancer, fast growth-rates of BRCA1-associated cancers can still lead to interval cancers, and/or node-positive disease. Using MRI with shorter screening intervals helps to effectively avoid both, interval cancers and node-positive stages, whereas there is no role for mammography in these women. PMID- 30429199 TI - Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells towards Taxanes, ATR and PARP Inhibitors in vitro and in vivo. AB - PURPOSE: The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here we present the identification and preclinical pharmacological profile of the first BUB1 kinase inhibitor with good bioavailability. EXPERIMENTAL DESIGN: The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity, physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signalling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models. RESULTS: The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared to the respective monotherapies. CONCLUSIONS: Our findings suggest clinical proof of concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors in order to enhance their efficacy and potentially overcome resistance. PMID- 30429201 TI - Introduction of Subcutaneous Depot Medroxyprogesterone Acetate (DMPA-SC) Injectable Contraception at Facility and Community Levels: Pilot Results From 4 Districts of Uganda. AB - Reproductive Health Uganda (RHU), a local NGO, introduced subcutaneous depot medroxyprogesterone acetate (DMPA-SC, brand name Sayana Press) in 4 districts of Uganda between April 2016 and March 2017. RHU trained public and private facility providers on all family planning methods including DMPA-SC; trained community health workers (known as village health teams, VHTs) to give family planning counseling, provide short-acting methods including DMPA-SC, and make referrals for long-acting and permanent methods; conducted mobile outreach and raised awareness of family planning; and provided family planning commodities. We used a retrospective cross-sectional evaluation design drawing on data from (1) in-depth interviews with 32 facility- and community-based providers; (2) key informant interviews with 7 policy makers and program staff; and (3) family planning program statistics from 4 RHU clinics, 26 mobile outreach sites, and 40 VHTs in 4 study districts. Data collection took place between April and June 2017. Over 12 months, 14,273 units of DMPA-SC were provided in RHU clinics, by mobile outreach teams, and by VHTs. DMPA-SC units were mostly administered in community settings either by VHTs (70%) or at mobile outreach events (26%). A substantial proportion (43%) of DMPA-SC units were administered to young people (<25 years), a significantly higher proportion compared with other methods provided to this age group through the project (P<.001), except condoms. In addition, a greater proportion of DMPA-SC units provided at the community level by VHTs were used by young people (45%) compared with units provided at outreach (36%) or in clinics (35%). Overall, injectables (DMPA-SC and intramuscular DMPA combined) came to represent 43% of all contraceptive methods provided, up from a baseline of 20%. This shift occurred despite significant increases in the volume of all other methods provided (P<.001). Qualitative data revealed various factors that facilitated introduction, including comprehensive training, commodity availability, strong referral links, and early community engagement. RHU's experience supports the viability of community-based delivery of DMPA-SC and identifies opportunities to strengthen this approach. There is further evidence that DMPA-SC may be popular with young people, especially in community settings. PMID- 30429202 TI - Fractional excretion of phosphorus and vascular calcification in stage 3 chronic kidney disease. AB - The role of renal excretion of Pi in relation to vascular calcification (VC) in patients in the early stages of chronic kidney disease (CKD) is controversial. Thus, we determine the relation between fractional excretion of phosphorus (FEP) and VC, measured using two methods in a cross-sectional study of patients with stage 3 CKD. We recorded demographic data, anthropometry, comorbidities and active treatment. We measured 24-hour urine FEP and, in serum, measured fibroblast growth factor 23 (FGF23), alpha-Klotho, intact parathyroid hormone (iPTH), calcium and phosphorus. VC was measured by lateral abdominal radiography (Kauppila index (KI)) and CT of the abdominal aorta (measured in Agatston units). In 57% of subjects, abnormal VC was present when measured using CT, and in only 17% using lateral abdominal radiography. Factors associated with VC using CT were age, cardiovascular risk factors, vascular comorbidity, microalbuminuria and levels of FGF23, phosphorus and calcium x phosphorus product (CaxP); although only age (OR 1.25, 95% CI 1.11 to 1.41), smoking (OR 21.2, CI 4.4 to 100) and CaxP (OR 1.21, CI 1.06 to 1.37) maintained the association in a multivariate analysis. By contrast, only age (OR 1.35, 95% CI 1.07 to 1.74), CaxP (OR 1.14, CI 1.13 to 1.92) and FEP (OR 1.07,95% CI 1004 to 1.14) were associated with abnormal VC in the lateral abdominal radiography. In conclusion, in patients with stage 3 CKD, the detection of VC by abdominal CT is more sensitive than conventional X rays. Moreover, CaxP is associated with cardiovascular risk factors and vascular comorbidity; quantification of FEPi in these patients provides additional clinical information in advanced VC detected by KI. PMID- 30429203 TI - Fifteen-minute consultation: Safety netting effectively. PMID- 30429204 TI - Abortion and deprivation: a reply to Marquis. AB - In 'Why Abortion is Immoral', Don Marquis argues that abortion is wrong for the same reason that murder is wrong, namely, that it deprives a human being of an FLO, a 'future like ours,' which is a future full of value and the experience of life. Marquis' argument rests on the assumption that the human being is somehow deprived by suffering an early death. I argue that Marquis' argument faces the 'Epicurean Challenge'. The concept of 'deprivation' requires that some discernible individual exists who can be deprived. But if death involves total annihilation, then no discernible individual exists to be so deprived. I argue that the Epicurean Challenge must be addressed before it can be proven that Marquis is correct to claim that abortion and murder are wrong because they deprive someone of an FLO. PMID- 30429205 TI - Pink and blue: the role of gender in psychiatric diagnosis. AB - Why are the diagnostic criteria of some psychiatric disorders standardised by gender while others are not? Why standardise symptom questionnaires by gender but not other personal characteristics such as ethnicity, socioeconomic class or sexual orientation? And how might our changing attitudes towards gender, born from scientific research and changing societal narratives, alter our opinion of these questions? This paper approaches these dilemmas by assessing the concept of diagnosis in psychiatry itself, before analysing two common approaches to the study of psychiatric diagnosis; the naturalist and constructivist views. The paper assesses the relative merits and significance of each, before turning its attention to the nature of gender and its relevance to psychiatry. The paper introduces a framework to approach gender-based diagnostic bias and concludes by drawing a distinction between qualitative and quantitative standardisation, arguing that gender standardisation of psychiatric diagnoses is ethically justified in the former but not the latter. PMID- 30429206 TI - EGR2 phosphatase regulates OST1 kinase activity and freezing tolerance in Arabidopsis. AB - OST1 (open stomata 1) protein kinase plays a central role in regulating freezing tolerance in Arabidopsis; however, the mechanism underlying cold activation of OST1 remains unknown. Here, we report that a plasma membrane-localized clade-E growth-regulating 2 (EGR2) phosphatase interacts with OST1 and inhibits OST1 activity under normal conditions. EGR2 is N-myristoylated by N myristoyltransferase NMT1 at 22 degrees C, which is important for its interaction with OST1. Moreover, myristoylation of EGR2 is required for its function in plant freezing tolerance. Under cold stress, the interaction of EGR2 and NMT1 is attenuated, leading to the suppression of EGR2 myristoylation in plants. Plant newly synthesized unmyristoylated EGR2 has decreased binding ability to OST1 and also interferes with the EGR2-OST1 interaction under cold stress. Consequently, the EGR2-mediated inhibition of OST1 activity is released. Consistently, mutations of EGRs cause plant tolerance to freezing, whereas overexpression of EGR2 exhibits decreased freezing tolerance. This study thus unravels a molecular mechanism underlying cold activation of OST1 by membrane-localized EGR2 and suggests that a myristoyl switch on EGR2 helps plants to adapt to cold stress. PMID- 30429207 TI - Engaging with theory: from theoretically informed to theoretically informative improvement research. PMID- 30429208 TI - Inherent DNA-binding specificities of the HIF-1alpha and HIF-2alpha transcription factors in chromatin. AB - Hypoxia-inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF-alpha isoforms, HIF-1alpha and HIF 2alpha, are progressively stabilized in response to hypoxia and form heterodimers with HIF-1beta to activate a broad range of transcriptional responses. Here, we report on the pan-genomic distribution of isoform-specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF-alpha isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell-type-specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter-proximal binding of HIF-1 and promoter distant binding of HIF-2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently. PMID- 30429209 TI - Role for intraflagellar transport in building a functional transition zone. AB - Genetic disorders caused by cilia dysfunction, termed ciliopathies, frequently involve the intraflagellar transport (IFT) system. Mutations in IFT subunits including IFT-dynein motor DYNC2H1-impair ciliary structures and Hedgehog signalling, typically leading to "skeletal" ciliopathies such as Jeune asphyxiating thoracic dystrophy. Intriguingly, IFT gene mutations also cause eye, kidney and brain ciliopathies often linked to defects in the transition zone (TZ), a ciliary gate implicated in Hedgehog signalling. Here, we identify a C. elegans temperature-sensitive (ts) IFT-dynein mutant (che-3; human DYNC2H1) and use it to show a role for retrograde IFT in anterograde transport and ciliary maintenance. Unexpectedly, correct TZ assembly and gating function for periciliary proteins also require IFT-dynein. Using the reversibility of the novel ts-IFT-dynein, we show that restoring IFT in adults (post-developmentally) reverses defects in ciliary structure, TZ protein localisation and ciliary gating. Notably, this ability to reverse TZ defects declines as animals age. Together, our findings reveal a previously unknown role for IFT in TZ assembly in metazoans, providing new insights into the pathomechanism and potential phenotypic overlap between IFT- and TZ-associated ciliopathies. PMID- 30429210 TI - Identification of TEX101-associated proteins through proteomic measurement of human spermatozoa homozygous for the missense variant rs35033974. AB - TEX101 is a germ cell-specific protein and a validated biomarker of male infertility. Mouse TEX101 was found essential for male fertility, and was suggested to function as a cell surface chaperone involved in maturation of proteins required for sperm migration and sperm-oocyte interaction. However, the precise functional role of human TEX101 is not known and cannot be studied in vitro due to the lack of human germ cell lines. Here, we genotyped 386 men for a common missense variant rs35033974 of TEX101, and identified 52 heterozygous and 4 homozygous men. We then discovered by targeted proteomics that the variant allele rs35033974 was associated with the near-complete degradation (>97%) of the corresponding G99V TEX101 form, and suggested that spermatozoa of homozygous men could serve as a knockdown model to study TEX101 function in humans. Differential proteomic profiling with label-free quantification measured 8,046 proteins in spermatozoa of eight men and identified 8 cell-surface and 9 secreted testis specific proteins significantly down-regulated in four patients homozygous for rs35033974. Substantially reduced levels of testis-specific cell-surface proteins potentially involved in sperm migration and sperm-oocyte interaction (including LY6K and ADAM29) were confirmed by targeted proteomics and western blotting assays. Since recent population-scale genomic data revealed homozygous fathers with biological children, rs35033974 is not a monogenic factor of male infertility in humans. However, median TEX101 levels in seminal plasma were found 5-fold lower (P=0.0005) in heterozygous than in wild-type men of European ancestry. We conclude that spermatozoa of rs35033974 homozygous men have substantially reduced levels of TEX101 and could be used as a model to elucidate the precise TEX101 function, which will advance biology of human reproduction. PMID- 30429211 TI - Beata Mierzwa: Bridging the divide between science and art. AB - Mierzwa studies mechanisms of cell division in different cell types and tissue contexts. PMID- 30429212 TI - PARP1 trapping by PARP inhibitors drives cytotoxicity both in cancer cells and healthy bone marrow. AB - Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone. Here we evaluate the contribution of PARP trapping to the tolerability and efficacy of PARP inhibitors in the monotherapy setting. We developed a novel implementation of the proximity ligation assay to detect chromatin-trapped PARP1 at single-cell resolution with higher sensitivity and throughput than previously reported methods. We further demonstrate that the PARP inhibitor-induced trapping appears to drive single-agent cytotoxicity in healthy human bone marrow, indicating that the toxicity of trapped PARP complexes is not restricted to cancer cells with homologous recombination deficiency (HRD). Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit comparable tumor growth inhibition at maximum tolerated doses in a xenograft model of BRCA1-mutant triple negative breast cancer. These results are consistent with emerging clinical data and suggest that the inverse relationship between trapping potency and tolerability may limit the potential therapeutic advantage of potent trapping activity. Implications: PARP trapping contributes to single agent cytotoxicity of PARP inhibitors in both cancer cells and healthy bone marrow, and the therapeutic advantage of potent trapping activity appears to be limited. PMID- 30429214 TI - Fine-Scale Resolution of Runs of Homozygosity Reveal Patterns of Inbreeding and Substantial Overlap with Recessive Disease Genotypes in Domestic Dogs. AB - Inbreeding leaves distinct genomic traces, most notably long genomic tracts that are identical by descent and completely homozygous. These runs of homozygosity (ROH) can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. Several lines of evidence have been used to show that long (> 5 megabase) ROH are disproportionately likely to harbor deleterious variation, but the extent to which long versus short tracts contribute to autozygosity at loci known to be deleterious and recessive has not been studied. In domestic dogs, nearly 200 mutations are known to cause recessive diseases, most of which can be efficiently assayed using SNP arrays. By examining genome-wide data from over 200,000 markers, including 150 recessive disease variants, we built high-resolution ROH density maps for nearly 2,500 dogs, recording ROH down to 500 kilobases. We observed over 678 homozygous deleterious recessive genotypes in the panel across 29 loci, 90% of which overlapped with ROH inferred by GERMLINE. Although most of these genotypes were contained in ROH over 5 Mb in length, 14% were contained in short (0.5 - 2.5 megabase) tracts, a significant enrichment compared to the genetic background, suggesting that even short tracts are useful for computing inbreeding metrics like the coefficient of inbreeding estimated from ROH (FROH ). In our dataset, FROH differed significantly both within and among dog breeds. All breeds harbored some regions of reduced genetic diversity due to drift or selective sweeps, but the degree of inbreeding and the proportion of inbreeding caused by short versus long tracts differed between breeds, reflecting their different population histories. Although only available for a few species, large genome-wide datasets including recessive disease variants hold particular promise not only for disentangling the genetic architecture of inbreeding depression, but also evaluating and improving upon current approaches for detecting ROH. PMID- 30429213 TI - Loss of Fas Expression and Function is Coupled with Colon Cancer Resistance to Immune Checkpoint Inhibitor Immunotherapy. AB - Despite the remarkable efficacy of immune checkpoint inhibitor (ICI) immunotherapy in various types of human cancers, colon cancer, except for the approximately 4% microsatellite-instable (MSI) colon cancer, does not respond to ICI immunotherapy. ICI acts through activating cytotoxic T lymphocytes (CTLs) that use the Fas-FasL pathway as one of the two effector mechanisms to suppress tumor. Cancer stem cells are often associated with resistance to therapy including immunotherapy, but the functions of Fas in colon cancer apoptosis and colon cancer stem cells are currently conflicting and highly debated. We report here that decreased Fas expression is coupled with a subset of CD133+CD24lo colon cancer cells in vitro and in vivo. Consistent of the lower Fas expression level, this subset of CD133+CD24loFaslo colon cancer cells exhibit decreased sensitivity to FasL-induced apoptosis. Furthermore, FasL selectively enriches CD133+CD24loFaslo colon cancer cells. CD133+CD24loFaslo colon cancer cells exhibit increased lung colonization potential in experimental metastatic mouse models, and decreased sensitivity to tumor-specific CTL adoptive transfer and ICI immunotherapies. Interesting, FasL challenge selectively enriched this subset of colon cancer cells in microsatellite-stable (MSS) but not in the MSI human colon cancer cell lines. Consistent with the down-regulation of Fas expression in CD133+CD24lo cells, lower Fas expression level is significantly correlated with decreased survival in human colon cancer patients. Implications: Our data determine that CD133+CD24loFaslo colon cancer cells are capable to evade Fas-FasL cytotoxicity of tumor-reactive CTLs and targeting this subset of colon cancer cells is potentially an effective approach to suppress colon cancer immune evasion. PMID- 30429215 TI - Obituary for Thomas A. Steitz. PMID- 30429216 TI - Neuraminidase 1-mediated desialylation of the mucin 1 ectodomain releases a decoy receptor that protects against Pseudomonas aeruginosa lung infection. AB - Pseudomonas aeruginosa (Pa) expresses an adhesin, flagellin, that engages the mucin 1 (MUC1) ectodomain (ED) expressed on airway epithelia, increasing association of MUC1-ED with neuraminidase 1 (NEU1) and MUC1-ED desialylation. The MUC1-ED desialylation unmasks both cryptic binding sites for Pa and a protease recognition site, permitting its proteolytic release as a hyperadhesive decoy receptor for Pa. We found here that intranasal administration of Pa strain K (PAK) to BALB/c mice increases MUC1-ED shedding into the bronchoalveolar compartment. MUC1-ED levels increased as early as 12 h, peaked at 24-48 h with a 7.8-fold increase, and decreased by 72 h. The a-type flagellin-expressing PAK strain and the b-type flagellin-expressing PAO1 strain stimulated comparable levels of MUC1-ED shedding. A flagellin-deficient PAK mutant provoked dramatically reduced MUC1-ED shedding compared with the wild-type strain, and purified flagellin recapitulated the wild-type effect. In lung tissues, Pa increased association of NEU1 and protective protein/cathepsin A with MUC1-ED in reciprocal co-immunoprecipitation assays and stimulated MUC1-ED desialylation. NEU1-selective sialidase inhibition protected against Pa-induced MUC1-ED desialylation and shedding. In Pa-challenged mice, MUC1-ED-enriched bronchoalveolar lavage fluid (BALF) inhibited flagellin binding and Pa adhesion to human airway epithelia by up to 44% and flagellin-driven motility by > 30%. Finally, Pa co-administration with recombinant human MUC1-ED dramatically diminished lung and BALF bacterial burden, proinflammatory cytokine levels, and pulmonary leukostasis and increased 5-day survival from 0% to 75%. We conclude that Pa flagellin provokes NEU1-mediated airway shedding of MUC1-ED, which functions as a decoy receptor protecting against lethal Pa lung infection. PMID- 30429217 TI - The ER-localized Ca2+-binding protein calreticulin couples ER stress to autophagy by associating with microtubule-associated protein 1A/1B light chain 3. AB - Autophagy is of key importance for eliminating aggregated proteins during the maintenance of cellular proteostasis in response to endoplasmic reticulum (ER) stress. However, the upstream signaling that mediates autophagy activation in response to ER stress is incompletely understood. In the study, in vivo and in vitro approaches were utilized, which include gain- and loss-of-function assays and mouse livers and human cell lines of tunicamycin-induced pharmacological ER stress. We report that calreticulin, a quality-control chaperone that binds to misfolded glycoproteins for refolding in the ER, is induced under ER stress. Calreticulin overexpression stimulated the formation of autophagosomes and increases autophagic flux. Interestingly, calreticulin was sufficient for attenuating ER stress in tunicamycin- or thapsigargin-treated HeLa cells, whereas a lentivirus-mediated shRNA calreticulin knockdown exacerbated ER stress. Mechanistically, we noted that calreticulin induces autophagy by interacting with microtubule-associated protein 1A/1B-light chain 3 (LC3). Confocal microscopy revealed that the colocalization of calreticulin and LC3 at the autophagosome was enhanced under ER stress conditions. Importantly, a conserved LC3-interacting region (LIR) was necessary for calreticulin-mediated stimulation of autophagy and for reducing ER stress. These findings indicate a calreticulin-based mechanism that couples ER stress to autophagy activation, which, in turn, attenuates the cellular stress likely by alleviating formation of aberrantly folded proteins. Pharmacological or genetic approaches that activate calreticulin-autophagy signaling may have potential for managing ER stress and related cellular disorders. PMID- 30429218 TI - Acyl chain selectivity and physiological roles of Staphylococcus aureus fatty acid binding proteins. AB - Fatty acid (FA) kinase produces acyl-phosphate for the synthesis of membrane phospholipids in Gram-positive bacterial pathogens. FA kinase consists of a kinase protein (FakA) that phosphorylates an FA substrate bound to a second module, an FA binding protein (FakB). Staphylococcus aureus expresses two distinct, but related, FakBs with different FA selectivities. Here, we report the structures of FakB1 bound to four saturated FAs at 1.6-1.93 A resolution. We observed that the different FA structures are accommodated within a slightly curved hydrophobic cavity whose length is governed by the conformation of an isoleucine side chain at the end of the tunnel. The hydrophobic tunnel in FakB1 prevents the binding of cis-unsaturated FAs, which are instead accommodated by the kinked tunnel within the FakB2 protein. The differences in the FakB interiors are not propagated to the proteins' surfaces, preserving the protein-protein interactions with their three common partners, FakA, PlsX, and PlsY. Using cellular thermal shift analyses, we found that FakB1 binds FA in vivo, whereas a significant proportion of FakB2 does not. Incorporation of exogenous FA into phospholipid in DeltafakB1 and DeltafakB2 S. aureus knockout strains revealed that FakB1 does not efficiently activate unsaturated FAs. FakB2 preferred unsaturated FAs, but also allowed the incorporation of saturated FAs. These results are consistent with a model in which FakB1 primarily functions in the recycling of the saturated FAs produced by S. aureus metabolism, whereas FakB2 activates host-derived oleate, which S. aureus does not produce but is abundant at infection sites. PMID- 30429219 TI - Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene. AB - Disruption of circadian rhythms has been implicated in an increased risk for cancer development. The Period2 (Per2) gene encodes one of the major components of the mammalian circadian clock, which plays a key role in controlling the circadian rhythms in physiology and behavior. PER2 has also been reported to suppress the malignant transformation of cells, but its role in the regulation of cancer susceptibility to chemotherapeutic drugs remains unclear. In this study, we found that oncogene- transformed embryo fibroblasts from Per2-mutant (Per2 m/m) mice, which are susceptible to both spontaneous and radiation-induced tumorigenesis, were resistant against common chemotherapeutic drugs and that this resistance is associated with up-regulation of the aldehyde dehydrogenase 3a1 (Aldh3a1) gene. Co-expression of the oncogenes H-rasV12 and SV40 large T-antigen induced malignant transformation of both wild-type and Per2 m/m cells, but the cytotoxic effects of the chemotherapeutic agents methotrexate, gemcitabine, etoposide, vincristine, and oxaliplatin were significantly alleviated in the oncogene-transformed Per2 m/m cells. Although introduction of the two oncogenes increased the expression of Aldh3a1 in both wild-type and Per2 m/m cells, the ALDH3A1 protein levels in the Per2 m/m cells were approximately 7-fold higher than in wild-type cells. The elevated ALDH3A1 levels in the oncogene-transformed Per2 m/m cells were sufficient to prevent chemo- therapeutic drug-induced accumulation of reactive oxygen species. Consequently, shRNA-mediated suppression of Aldh3a1 expression relieved the chemoresistance of the Per2m/m cells. These results suggest a role for mutated PER2 in the development of multiple drug resistance and may inform therapeutic strategies for cancer management. PMID- 30429220 TI - MAPK- and glycogen synthase kinase 3-mediated phosphorylation regulates the DEAD box protein modulator Gle1 for control of stress granule dynamics. AB - Rapid expression of critical stress response factors is a key survival strategy for diseased or stressed cells. During cell stress, translation is inhibited and a pre-existing pool of cytoplasmic mRNA-protein complexes reversibly assembles into cytoplasmic stress granules (SGs). Gle1 is a conserved modulator of RNA dependent DEAD-box proteins required for mRNA export, translation, and stress responses. Proper Gle1 function is critical, as reflected by some human diseases such as developmental and neurodegenerative disorders and some cancers linked to gle1 mutations. However, the mechanism by which Gle1 controls SG formation is incompletely understood. Here, we show that human Gle1 is regulated by phosphorylation during heat shock stress. In HeLa cells, stress-induced Gle1 hyperphosphorylation was dynamic, primarily in the cytoplasmic pool, and followed changes in translation factors. MS analysis identified 14 phosphorylation sites in the Gle1A isoform, 6 of which clustered in an intrinsically disordered, low complexity N-terminal region flanking the coil-coiled self-association domain. Of note, two mitogen-activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), phosphorylated the Gle1A N-terminal domain, priming it for phosphorylation by glycogen synthase kinase 3 (GSK3). A phosphomimetic gle1A6D variant (in which six putative Ser/Thr phosphorylation sites were substituted with Asp) perturbed self-association and inhibited DEAD-box helicase 3 (X-linked) (DDX3) ATPase activity. Expression of alanine-substituted, phospho-deficient GFP-gle1A6A promoted SG assembly, whereas GFP-gle1A6D enhanced SG disassembly. We propose that MAPKs and GSK3 phosphorylate Gle1A and thereby coordinate SG dynamics by altering DDX3 function. PMID- 30429221 TI - Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL. AB - In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation, DNA fragmentation, GST pull-down, and apoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73-TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3 interacting domain death agonist (BID). In particular, we found that a 16-mer p73 TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD. We observed that the alpha-helical p73-TAD16 peptide binds to a non-canonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptotic BH3 peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a non-canonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy. PMID- 30429222 TI - Bombyx mori transcription factors FoxA and Sage divergently regulate the expression of wing cuticle protein gene 4 during metamorphosis. AB - Stage-specific gene expression governs metamorphosis of the silkworm, Bombyx mori. B. mori wing cuticle protein gene 4 (BmWCP4) is an essential gene for wing disc development expressed specifically during pupation. BmWCP4 transcription is suppressed at the larval stage by unknown mechanisms, which we sought to elucidate here. Bioinformatics analysis predicted seven potential Forkhead box (Fox) cis-regulatory elements (CRE) in the BmWCP4 promoter region, and we found that Fox CRE6 contributes to suppression of BmWCP4 expression. Electrophoretic mobility shift (EMSA) and DNA pull-down assays revealed that BmFoxA suppressed activity at the BmWCP4 promoter by specifically binding to the Fox CRE6. The expression level of BmFoxA in the wing discs was higher during the larval stage than at the pupal stage. In contrast, expression of another transcription factor, BmSage, increased over the course of development. Of note, the hormone 20 hydroxyecdysone (20E), which governs molting in insects, suppressed BmFoxA expression in the wing discs and up-regulated that of BmSage. EMSA and cell co transfection assays indicated that BmSAGE interacts with BmFoxA and suppressed its binding to the Fox CRE6, thereby releasing BmFoxA-mediated suppression of BmWCP4. In summary, higher BmFoxA expression during the larval stage suppresses BmWCP4 expression by binding to the Fox CRE6 on the BmWCP4 promoter. During metamorphosis, BmSAGE forms a complex with BmFoxA to relieve this repression, initiating BmWCP4 expression. Taken together, this study reveals a switch-like role for BmFoxA in regulating BmWCP4 expression and provides new insights into the regulatory regulation of wing disc development in insects. PMID- 30429223 TI - Analysis of two new arabinosyltransferases belonging to the carbohydrate-active enzyme (CAZY) glycosyl transferase family 1 provides insights into disease resistance and sugar donor specificity. AB - Glycosylation of small molecules is critical for numerous biological processes in plants, including hormone homeostasis, neutralization of xenobiotics, and synthesis and storage of specialized metabolites. Glycosylation of plant natural products is usually carried out by uridine diphosphate-dependent glycosyltransferases (UGTs). Triterpene glycosides (saponins) are a large family of plant natural products that determine important agronomic traits such as disease resistance and flavor and have numerous pharmaceutical applications. Most characterised plant natural product UGTs are glucosyltransferases, and little is known about enzymes that add other sugars. Here we report the discovery and characterization of AsAAT1 (UGT99D1), which is required for biosynthesis of the antifungal saponin avenacin A-1 in oat. This enzyme adds L-arabinose to the triterpene scaffold at the C-3 position, a modification critical for disease resistance. The only previously reported plant natural product arabinosyltransferase is a flavonoid arabinosyltransferase from Arabidopsis. We show that AsAAT1 has high specificity for UDP-beta-L-arabinopyranose, identify two amino acids required for sugar donor specificity, and through targeted mutagenesis convert AsAAT1 into a glucosyltransferase. We further identify a second arabinosyltransferase potentially implicated in the biosynthesis of saponins that determine bitterness in soybean. Our investigations suggest independent evolution of UDP-arabinose sugar donor specificity in arabinosyltransferases in monocots and eudicots. PMID- 30429224 TI - The Peroxidative Cleavage of Kaempferol Contributes to the Biosynthesis of the Benzenoid Moiety of Ubiquinone in Plants. AB - Land plants possess the unique capacity to derive the benzenoid moiety of the vital respiratory cofactor, ubiquinone (coenzyme Q), from phenylpropanoid metabolism via beta-oxidation of p-coumarate to form 4-hydroxybenzoate. Approximately half of the ubiquinone in plants comes from this pathway; the origin of the rest remains enigmatic. In this study, Phe-[Ring-13C6] feeding assays and gene network reconstructions uncovered a connection between the biosynthesis of ubiquinone and that of flavonoids in Arabidopsis thaliana. Quantification of ubiquinone in Arabidopsis and tomato (Solanum lycopersicum) mutants in flavonoid biosynthesis pinpointed the corresponding metabolic branch point as lying between flavanone-3-hydroxylase and flavonoid-3'-hydroxylase. Further isotopic labeling and chemical rescue experiments demonstrated that the B ring of kaempferol is incorporated into ubiquinone. Moreover, heme-dependent peroxidase activities were shown to be responsible for the cleavage of B-ring of kaempferol to form 4-hydroxybenzoate. In contrast, kaempferol 3-beta-D glucopyranoside, dihydrokaempferol, and naringenin were refractory to peroxidative cleavage. Collectively, these data indicate that kaempferol contributes to the biosynthesis of a vital respiratory cofactor, resulting in an extraordinary metabolic arrangement where a specialized metabolite serves as a precursor for a primary metabolite. Evidence is also provided that the ubiquinone content of tomato fruits can be manipulated via deregulation of flavonoid biosynthesis. PMID- 30429225 TI - Echinocandin-Induced Microevolution of Candida parapsilosis Influences Virulence and Abiotic Stress Tolerance. AB - Candida species are a major cause of life-threatening bloodstream infections worldwide. Although Candida albicans is responsible for the vast majority of infections, the clinical relevance of other Candida species has also emerged over the last twenty years. This shift might be due in part to changes in clinical guidelines, as echinocandins became the first line of therapeutics for the treatment. Candida parapsilosis is an emerging non-albicans Candida species that exhibits lower susceptibility levels to these drugs. Candida species frequently display resistance to echinocandins, and the mechanism for this is well-known in C. albicans and Candida glabrata, where it is mediated by amino acid substitutions at defined locations of the beta-1,3-glucan synthase, Fks1p. In C. parapsilosis isolates, Fks1p harbors an intrinsic amino acid change at position 660 of the hot spot 1 (HS1) region, which is thought to be responsible for the high MIC values. Less is known about acquired substitutions in this species. In this study, we used directed evolution experiments to generate C. parapsilosis strains with acquired resistance to caspofungin, anidulafungin, and micafungin. We showed that cross-resistance was dependent on the type of echinocandin used to generate the evolved strains. During their characterization, all mutant strains showed attenuated virulence in vivo and also displayed alterations in the exposure of inner cell wall components. The evolved strains harbored 251 amino acid changes, including three in the HS1, HS2, and HS3 regions of Fks1p. Altogether, our results demonstrate a direct connection between acquired antifungal resistance and virulence of C. parapsilosis IMPORTANCE Candida parapsilosis is an opportunistic fungal pathogen with the ability to cause infections in immunocompromised patients. Echinocandins are the currently recommended first line of treatment for all Candida species. Resistance of Candida albicans to this drug type is well characterized. C. parapsilosis strains have the lowest in vitro susceptibility to echinocandins; however, patients with such infections typically respond well to echinocandin therapy. There is little knowledge of acquired resistance in C. parapsilosis and its consequences on other characteristics such as virulence properties. In this study, we aimed to dissect how acquired echinocandin resistance influences the pathogenicity of C. parapsilosis and to develop explanations for why echinocandins are clinically effective in the setting of acquired resistance. PMID- 30429226 TI - Nucleolar Relocalization of RBM14 by Influenza A Virus NS1 Protein. AB - Viruses utilize a number of host factors in order to carry out their replication cycles. Influenza A virus (IAV) and human respiratory syncytial virus (RSV) both infect the tissues of the respiratory tract, and as such we hypothesize that they might require similar host factors. Several published genome-wide screens have identified putative IAV host factors; however, there is significant discordance between their hits. In order to build on this work, we integrated a variety of "OMICS" data sources using two complementary network analyses, yielding 51 genes enriched for both IAV and RSV replication. We designed a targeted small interfering RNA (siRNA)-based assay to screen these genes against IAV under robust conditions and identified 13 genes supported by two IAV subtypes in both primary and transformed human lung cells. One of these hits, RNA binding motif 14 (RBM14), was validated as a required host factor and furthermore was shown to relocalize to the nucleolus upon IAV infection but not with other viruses. Additionally, the IAV NS1 protein is both necessary and sufficient for RBM14 relocalization, and relocalization also requires the double-stranded RNA (dsRNA) binding capacity of NS1. This work reports the discovery of a new host requirement for IAV replication and exposes a novel example of interplay between IAV NS1 and the host protein, RBM14.IMPORTANCE Influenza A virus (IAV) and respiratory syncytial virus (RSV) present major global disease burdens. There are high economic costs associated with morbidity as well as significant mortality rates, especially in developing countries, in children, and in the elderly. There are currently limited therapeutic options for these viruses, which underscores the need for novel research into virus biology that may lead to the discovery of new therapeutic approaches. This work extends existing research into host factors involved in virus replication and explores the interaction between IAV and one such host factor, RBM14. Further study to fully characterize this interaction may elucidate novel mechanisms used by the virus during its replication cycle and open new avenues for understanding virus biology. PMID- 30429228 TI - Knock down lncRNA HOTAIR sensitize breast cancer cells to ionizing radiation through activating miR-218. AB - Radiotherapy is a major therapeutic strategy for breast cancer, while cancer radioresistance remains an obstacle for the successful control of the tumor. Novel radiosensitizing targets are to be developed to overcome radioresistance. Recently, long non-coding RNAs (lncRNAs) were proved to play critical roles in cancer progression. Among all, lncRNA HOTAIR was found to participate in cancer metastasis and chemoresistance. In the present study, we aimed to investigate the radiosensitizing effects of targeting HOTAIR and the underlying mechanism. Our data showed that HOTAIR was upregulated in breast cancer cells and tissues, and the expression of HOTAIR increased following irradiation. Knockdown of HOTAIR inhibited cell survival and increased cell apoptosis in response to ionizing radiation. Moreover, compared with control group, radiation induced more DNA damage and cell cycle arrest in HOTAIR knockdown cells. Finally, we found that the radiosentizing effects of HOTAIR was related to the upregulation of miR218, a ceRNA of HOTAIR. In conclusion, our finding showed that HOTAIR inhibition sensitizes breast cancer cells to ionizing radiation, induced severe DNA damage and activated apoptosis pathways, suggesting a possible role of HOTAIR as a novel target for breast cancer radiosensitization. PMID- 30429227 TI - The Protective Role of Bacteroides fragilis in a Murine Model of Colitis Associated Colorectal Cancer. AB - Many patients with chronic inflammation of the gut, such as that observed in inflammatory bowel disease (IBD), develop colorectal cancer (CRC). Recent studies have reported that the development of IBD and CRC partly results from an imbalanced composition of intestinal microbiota and that intestinal inflammation in these diseases can be modulated by the microbiota. The human commensal Bacteroides fragilis is best exemplified playing a protective role against the development of experimental colitis in several animal disease models. In this study, we found that gut inflammation caused by dextran sulfate sodium (DSS) treatment was inhibited by B. fragilis colonization in mice. Further, we reveal a protective role of B. fragilis treatment against colon tumorigenesis using an azoxymethane (AOM)/DSS-induced model of colitis-associated colon cancer in mice and demonstrate that the decreased tumorigenesis by B. fragilis administration is accompanied by inhibited expression of C-C chemokine receptor 5 (CCR5) in the gut. We show direct evidence that the inhibition of tumor formation provided by B. fragilis in colitis-associated CRC animals was dependent on the production of polysaccharide A (PSA) from B. fragilis and that Toll-like receptor 2 (TLR2) signaling was responsible for the protective function of B. fragilis IMPORTANCE The incidence of colorectal cancer (CRC) is rapidly growing worldwide, and there is therefore a greater emphasis on studies of the treatment or prevention of CRC pathogenesis. Recent studies suggested that consideration of the microbiota is unavoidable to understand inflammation and tumorigenesis in the gastrointestinal tract. We demonstrate, using a mouse model of colitis-associated CRC, that human commensal B. fragilis protects against colon tumorigenesis. The protective role against tumor formation provided by B. fragilis is associated with inhibition of expression of the chemokine receptor CCR5 in the colon. The molecular mechanism for protection against CRC provided by B. fragilis is dependent on polysaccharide A production and is mediated by TLR2 signaling. Our results suggest that the commensal microorganism B. fragilis can be used to prevent inflammation associated CRC development and may provide an effective therapeutic strategy for CRC. PMID- 30429229 TI - Long non-coding RNA ABHD11-AS1 promotes colorectal cancer development through regulation of miR-133a/SOX4 axis. AB - Recently, lncRNA has been verified to regulate the development and progression of tumor. LncRNA ABHD11-AS1 has been proven to serve as an oncogene in several cancer. However, the role of ABHD11-AS1 in colorectal cancer remains totally unkown. In this study, qRT-PCR assay revealed that ABHD11-AS1 expression was markedly higher in colorectal cancer tissues and cell lines. In addition, patients who displayed overexpression of ABHD11-AS1 showed a significantly poorer progression free survival (PFS) and overall survival (OS) by Kaplan-Meier analysis. Loss-of-function experiments suggested that silencing of ABHD11-AS1 expression could significantly reduce the proliferation, colony formation, migration and invasion of colorectal cancer cells, and increase cell apoptosis. Moreover, bioinformatics analysis, biotin pull-down assay, luciferase reporter assay, and RIP assay disclosed that ABHD11-AS1 straightly interacted with miR 133a. We also found that SOX4 was a downstream target of miR-133a and ABHD11-AS1 subsequently exerted its biological effects via modulating the expression of SOX4 in colorectal cancer cells. Collectively, these findings manifested that the ABHD11-AS1/miR-133a/SOX4 axis might be a cogitable and promising therapeutic target for colorectal cancer. PMID- 30429230 TI - Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han Population. AB - BACKGROUND: This research aimed to study the associations between XPD (G751A, rs13181), hOGG1 (C326G, rs1052133) and XRCC4 (G1394T, rs6869366) gene polymorphisms and the risk of colorectal cancer (CRC) in a Chinese Han population. METHOD: A total of 225 Chinese Han patients with CRC were selected as the study group, and 200 healthy subjects were recruited as the control group. The polymorphisms of XPD G751A, hOGG1 C326G and XRCC4 G1394T loci were detected by the RFLP-PCR technique in the peripheral blood of all subjects. RESULTS: Compared with individuals carrying the XPD751 GG allele, the A allele carriers (GA/AA) had a significantly increased risk of CRC (adjusted OR=2.109, 95%CI=1.352 3.287, p =0.003). Similarly, the G allele (CG/GG) of hOGG1 C326G locus conferred increased susceptibility to CRC (adjusted OR=2.654, 95%CI=1.915-3.685, p <0.001). In addition, the T allele carriers (GT/TT) of the XRCC4 G1394T locus have an increased risk of developing CRC (adjusted OR=4.512, 95%CI=2.785-7.402, p< 0.001). The risk of CRC was significantly increased in individuals with both the XPD locus A allele and the hOGG1 locus G allele (adjusted OR=1.543, 95%CI=1.302 2.542, p =0.002). Furthermore, individuals with both the hOGG1 locus G allele and the XRCC4 locus T allele were predisposed to CRC development (adjusted OR=3.854, 95%CI=1.924-7.123, p <0.001). Conclusion: Our results suggest that XPD G751A, hOGG1 C326G and XRCC4 G1394T gene polymorphisms might play an important role in colorectal carcinogenesis and increase the risk of developing CRC in the Chinese Han population. The interaction between smoking and these gene polymorphisms would increase the risk of CRC. PMID- 30429231 TI - Single nucleotide polymorphism rs731384 is associated with plasma lipid levels and the risk of-coronary artery disease in Chinese populations. AB - AIMS: To investigate the relationship between the miR-130a polymorphism rs731384 and coronary artery disease (CAD) and to further explore the molecular mechanism of the pathogenesis of CAD, an observational single-center study was conducted. METHOD: A total of 876 subjects were recruited in this study. Four milliliters of venous blood was drawn after 12 hours of fasting to perform biochemical assays. CAD patients and controls were distinguished by coronary angiography. Rs731384 was genotyped on the Agena MassARRAY system according to the manufacturer's user guide. Statistical analysis was conducted using SPSS 16.0 software. RESULTS: The study found that the plasma levels of TC (p=0.006), LDL-C (p=0.030), ApoA (p=0.038), and ApoB (p=0.022) distributed differently in patients with various alleles. Additionally, the AA genotype of rs731384 was found to be a protective factor against CAD in a recessive model (AA:AG+GG, OR=0.408, 95% CI=0.171-0.973, p=0.043). A significant association was found between the gene-environment interaction and CAD risk. The AA genotype along with HDL-C level>=1.325 mmol/L significantly decreased the CAD risk (AA:AG+GG, OR=0.117, 95% CI=0.023-0.588, p=0.009). CONCLUSION: The mutant AA genotype of rs731384 seems to be a protective factor against CAD, and rs731384 plays an important role in the human metabolism of plasma lipids. PMID- 30429232 TI - Anticancer effects and underlying mechanism of Colchicine on human gastric cancer cell lines in vitro and in vivo. AB - This study investigated the effects of Colchicine on gastric carcinoma (GC) cells and explored its possible mechanisms underlying such effects. The results of MTT and colony formation assays showed that Colchicine (2, 5 and 10ng/ml) markedly inhibited the proliferation of AGS and NCI-N87 cells in a dose-dependent manner. It also led to a reduction of cell migration in both GC cells as determined by Transwell migration assay. Mover, data form Hoechst 33342 staining and flow cytometry assay indicated that Colchicine (2, 5 and 10ng/ml) promoted the apoptosis of NCI-N87 cells. In addition, the release of cytochrome C, the activation of bax, and the inhibition of bcl-2 were observed in NCI-N87 cells treated with Colchicine. Furthermore, the in vivo experiment further confirmed that Colchicine administration remarkably suppressed the tumor growth in nude mice via induction of apoptosis at 0.05 and 0.1 mg/kg. In addition, no visible toxicity was observed in liver and renal tissue of mice. This finding suggests that Colchicine-induced apoptosis is associated with caspase-3 mediated mitochondrial apoptotic pathways. PMID- 30429233 TI - Chemotherapy-induced miR-141/MAP4K4 signaling suppresses progression of colorectal cancer. AB - BACKGROUND AND AIM: one of the treatment failures for colorectal cancer(CRC) is resistance to chemotherapy drugs. microRNAs (miRs) have been demonstrated to be a new regulator of pathobiological processes in various tumours. While, few studies have explored the specific role of microRNA-141(miR-141) in mediating 5 fluorouracil (5-FU) sensitivity of CRC cells. This study aimed to detect the contribution of miR-141 in 5-FU sensitivity. METHODS: the CRC cells viability was measured by MTS assay and cell colony forming. The expression of miR-141 and its downstream targets were assessed by RT-qPCR, western blotting and immunohistochemistry. The functional assays were conducted using CRC cells and nude mice. RESULTS: At the present study, we found overexpression of miR-141 could inhibit proliferation, migration, tumour forming and invasive potential of CRC cells in vitro and mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was verified as a directed target of miR-141. The combination treatment of miR-141 with 5-FU, directly targeting MAP4K4, could better inhibit invasion and metastasis of colorectal cancer cells colony than either one alone. Furthermore, overexpression of miR-141, targeting MAP4K4, enhanced the effected of 5-FU and suppressed the malignant biological behaviors, in vivo. Our findings showed that 5-FU inhibited malignant behavior of human colorectal cancer cells in vitro and in vivo by enhancing the efficiency of miR-141. CONCLUSIONS: our data suggested that targeting the miR-141/MAP4K4 signaling pathway could be a potential molecular target that may enhance chemotherapeutic efficacy in the treatment of CRC. PMID- 30429234 TI - The association of auditory integration training in children with autism spectrum disorders among Chinese: A meta-analysis. AB - Randomized controlled trials (RCTs) have reported an inconsistent relationship about the auditory integration training (AIT) in children with autism spectrum disorders (ASD) among Chinese. The current study was to investigate the efficacy of AIT for children with ASD compared to those in control group by using meta analysis. Relevant trials published were identified by an electronic search of PubMed, CENTRAL, EMBASE, WanFang, CNKI, and SinoMed databases up to December 31th, 2017. Outcome of interest included childhood autism rating scale (CARS), autism behavior checklist (ABC), intelligence quotient (IQ), and autism treatment evaluation checklist (ATEC). Standardized mean difference (SMD) with 95% confidence intervals (CI) was calculated using a random-effect model. Thirteen RCTs with 976 children with ASD were included for analysis. The pooled SMD showed that children with ASD had significantly lower ABC scores [summary SMD = -0.58, 95%CI= -0.79 to -0.38] and ATEC scores [summary SMD= -0.75, 95%CI= -1.05 to 0.45] in AIT group compared to that in control group. The analysis of pooled statistics put forward AIT could increase the IQ score when compared to that in control group [summary SMD= 0.59, 95%CI= 0.41 to 0.77]. A negative association was found about CARS scores between AIT group and control group. No publication bias was found and no single study had essential effect on the pooled results. In conclusions, AIT can reduce the score of ABC and ATEC and can increase the IQ score among children with ASD in Chinese. Therefore, it is recommended for Chinese children with ASD to receive AIT. PMID- 30429235 TI - QRREM method for the isolation of high quality RNA from the complex matrices of coconut. AB - Complex plant tissues vary in hardness, i.e. some are succulent, while others are complex to break. Besides, plant metabolites, such as polysaccharides, proteins, polyphenols and lipids can greatly interfere with the RNA extraction. So, in order to obtain a high quality RNA from the complex tissues (like coconut endosperm, coconut apple and coconut leaf bud) rich in secondary metabolites, a robust method is demanded. Several methods (MRIP, CTAB and TRIZOL) have been used previously for the isolation of quality RNA from the coconut tissues, but without any success. This paper will provide with the details of a new method (Quick and Reliable RNA Extraction Method or QRREM), which have efficiently isolated the intact RNA form the complex tissues of coconut compared to CTAB, Trizol and RNAplant. The method has been validated for the isolation of high quality intact RNA from the other available plant species (Areca/betel nut, mint and spring onion). The method has various advantages over the other methods in terms of time and cost effectiveness. Furthermore, the resulted RNA from various tissues of coconut performed well in the downstream experiments, i.e. reverse transcription and PCR for the production and amplification of cDNA. PMID- 30429236 TI - LncRNA GAS8-AS1 suppresses papillary thyroid carcinoma cell growth through the miR-135b-5p/CCND2 axis. AB - The aim of this study was to investigate the potential role of GAS8-AS1 in papillary thyroid carcinoma(PTC). PcDNA3.1-GAS8-AS1 and si-GAS8-AS1, miR-135b-5p mimic and si-CCND2 were transfected into PTC cells. Cell proliferation was evaluated by Cell Counting Kit-8(CCK-8). QRT-PCR was used to determine expressions of GAS8-AS1, miR-135b-5p and CCND2, and western blot were detected protein level of CCND2. The miRNA target gene prediction site TargetScan was used to predict potential targets of GAS8-AS1 and miR-135b-5p. Cell cycle progression was analyzed by flow cytometry. We found that GAS8-AS1 was downregulated in PTC cell lines and inhibited proliferation and cycle of PTC cell. GAS8-AS1 directly targets miR-135b-5p, and GAS8-AS1 could regulate a downstream target of miR-135b 5p, CCNG2, in a miR-135b-5p-mediated manner. In addition, we also proved overexpression GAS8-AS1 inhibited tumor formation in vivo. GAS8-AS1 suppresses PTC cell growth through the miR-135b-5p /CCND2 axis. PMID- 30429237 TI - Association between inflammatory-response gene polymorphisms and risk of acute kidney injury in children. AB - In this study, we investigated the association of 12 polymorphisms in six inflammatory-response genes ( TNF, IL6, IL10, IL18, NFKB1 and NFKBIA ) with risk of acute kidney injury (AKI) in children. The polymorphisms were genotyped in 1138 children with AKI and 1382 non-AKI controls. Logistic regression analysis was performed to calculate the odds ratio for estimating the risk association. After accounting for Bonferroni correction and adjustment for potential confounders, significant association was observed for NFKB1 rs28362491, NFKBIA rs2233406 and NFKBIA rs696 polymorphisms (P < 0.004). All three polymorphisms were associated with a reduced risk of AKI. For rs28362491 polymorphism, the OR for ID vs. II comparison was 0.75 (95%CI=0.58-0.83) while that for DD vs. II was 0.44 (95%CI=0.30-0.67). For rs2233406 polymorphism, the CT vs. CC comparison showed an OR of 0.90 (95%CI=0.39-0.99), while the TT vs. CC comparison showed an OR of 0.43 (95%CI=0.33-0.80). For rs696 polymorphism, the OR for AG vs. AA comparison was 0.71 (95%CI=0.43-0.89), while the GG vs. AA comparison showed an OR of 0.39 (95%CI=0.21-0.71). In conclusion, NFKB1 rs28362491, NFKBIA rs2233406 and NFKBIA rs696 polymorphisms may serve as biomarkers for predicting risk of AKI in children. PMID- 30429238 TI - Yanghe Huayan Decoction inhibit the capability of trans-endothelium and angiogenesis of HER2+ breast cancer via pAkt signaling. AB - BACKGROUND: Yanghe Huayan Decoction (YHD), a traditional Chinese medicine, is one of the most common complementary medicine currently used in the treatment of breast cancer. It has been recently linked to suppressing precancerous lesion and tumor development. The current study sought to explore the role of Yanghe Huayan Decoction on trans-endothelium and angiogenesis of breast cancer. METHODS: HER2+ breast cancer cells were treated with YHD, Trastuzumab or the combination in vitro and in vivo to compare the effects of them on trans-endothelium and angiogenesis features. This study also investigated the potential molecular mechanism of YHD in inhibiting angiogenesis of breast cancer. RESULTS: YHD significantly suppressed the invasion and angiogenesis of breast cancer cells via elevated pAkt signaling. Administration of YHD in vivo also strikingly repressed angiogenesis in tumor grafts. CONCLUSION: YHD could partially inhibit and reverse tumorigenesis of breast cancer. It also could inhibit Akt activation and angiogenesis in vitro and in vivo Its effect was superior to trastuzumab. Thus it was suitable in prevention and treatment for breast cancer. PMID- 30429239 TI - Synthetic bovine lactoferrin peptide Lfampin kills Entamoeba histolytica trophozoites by necrosis and resolves amoebic intracecal infection in mice. AB - Amoebiasis caused by the protozoan parasite Entamoeba histolytica remains a public health problem in developing countries. Previously, we have shown that lactoferrin (Lf) and several Lf-derived peptides exhibit in vitro anti-amoebic activity independently of their iron-binding activity. Here, we evaluated the amoebicidal effect of synthetic Lf-derived peptides Lfcin-B, Lfcin 17-30 and Lfampin, analyzed the mechanism of death induced by the peptides and determined their therapeutic effects on murine intestinal amoebiasis. MTT assays in trophozoite cultures of E. histolytica exposed to each peptide (1 - 1000 MUM) showed that Lfampin is far more amoebicidal than Lfcins. Lfampin killed 80% of trophozoites at doses higher than 100 MUM in 24 h, and FACs analysis using Annexin V/PI showed that death occurred mainly by necrosis. In contrast, Lfcin-B and Lfcin 17-30 appeared to have no significant effect on amoebic viability. FACs and confocal microscopy analysis using FITC-labeled peptides showed that all three peptides are internalized by the amoeba, mainly via an endosomal-/lysosomal independent pathway. Docking studies identified cholesterol in the amoeba's plasma membrane as a possible target of Lfampin. Oral treatment of intracecally infected mice with the abovementioned peptides at 10 mg/kg for 4 days showed that Lfampin resolved 100% of the cases of intestinal amoebiasis, whereas Lfcin 17-30 and Lfcin-B were effective in resolving infection in 80 and 70% of cases, respectively. These data show that although synthetic bovine Lf-derived peptides exhibit varying amoebicidal potentials in vitro , they do resolve murine intestinal amoebiasis efficiently, suggesting that they may be useful as a therapeutic treatment. PMID- 30429240 TI - Inflammatory Cytokine Profiles in Eyes with Primary Angle-Closure Glaucoma. AB - Acute primary angle-closure (APAC) eyes show an early "acute inflammatory" condition, while the inflammation condition has not been fully elucidated in the development of primary angle-closure glaucoma (PACG). To evaluate the roles of inflammatory cytokines in the pathogenesis of PACG, this cross-sectional study involved 40 eyes of 32 PACG patients who required trabeculectomy and 24 eyes of 24 patients who required cataract surgery. The aqueous humor samples were collected at the time of surgery. Fifteen inflammatory cytokines were detected using the multiplex bead immunoassay technique, and the clinical information was recorded for the correlation analysis. Eight of the 15 cytokines were all detectable in both groups, including granulocyte colony-stimulating factor (G CSF), interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, MCP-3, macrophage-derived chemokine (MDC), macrophage inflammatory protein (MIP)-1beta, and vascular endothelial growth factor (VEGF). When compared with the cataract patients, the MCP-3, MDC, and VEGF levels were elevated in the PACG patients, while the MCP-1 and MIP-1beta levels were decreased. However, the G-CSF, IL-6, and IL-8 levels were similar between the two groups. The MCP-1 concentration was elevated accordingly as the disease progressed in the PACG patients. Our results suggest the PACG eyes retained a "mild inflammation" condition in the aqueous humor, and MCP-1 may play an important role in the progression of this disease. PMID- 30429241 TI - The association between peroxisome proliferator-activated receptor delta (PPARD) rs3777744, rs3798343 and rs6922548 and coronary artery disease. AB - OBJECTIVE: The aim of this study is to investigate the association between the single nucleotide polymorphism sites of peroxisome proliferator-activated receptor delta and the risk of coronary artery disease. To this end, a prospective observational single-center study of the clinical data from 880 subjects in a Chinese population was conducted. METHODS: A total of 880 subjects, including 609 coronary artery disease patients and 271 control subjects, were selected for this study. All inpatients had 4 mL of venous blood drawn after 12 hours of fasting, and then clinical tests were conducted to obtain the biochemical parameters. CAD patients and Controls were distinguished by coronary angiography. Statistical analysis was conducted with SPSS software (Ver 16.0). RESULTS: A significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased risk for CAD was found. Moreover, we found and interaction between high HDL-C serum levels, low serum glucose levels and these genotypes, ultimately decreasing the risk of coronary artery disease. Haplotype analysis was conducted on the three SNP sites, rs3777744 and rs3798343 to form a block [r2=0.79, D'=0.99). The A-C haplotypes were associated with an increased risk of CAD (OR, 95% CI: 1.321 (1.060-1.647), p=0.013], and the G-G haplotypes were associated with a decreased risk [OR, 95% CI: 0.714 (0.567-0.849), p=0.004]. CONCLUSIONS: Our study indicates a significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased CAD risk. In addition, genotypes interact with high serum HDL-C levels and low serum glucose levels, resulting in decreased prevalence of CAD. PMID- 30429242 TI - The structure of temperate phage-bacteria infection networks changes with the phylogenetic distance of the host bacteria. AB - With their ability to integrate into the bacterial chromosome and thereby transfer virulence or drug-resistance genes across bacterial species, temperate phage play a key role in bacterial evolution. Thus, it is paramount to understand who infects whom to be able to predict the movement of DNA across the prokaryotic world and ultimately the emergence of novel (drug-resistant) pathogens. We empirically investigated lytic infection patterns among Vibrio spp. from distinct phylogenetic clades and their derived temperate phage. We found that across distantly related clades, infections occur preferentially within modules of the same clade. However, when the genetic distance of the host bacteria decreases, these clade-specific infections disappear. This indicates that the structure of temperate phage-bacteria infection networks changes with the phylogenetic distance of the host bacteria. PMID- 30429243 TI - Soil inorganic carbon in mangroves of tropical China: patterns and implications. AB - Soil inorganic carbon (IC) is neglected in most blue carbon studies despite the globally significant role of the calcium carbonate cycle in ocean C balance and climate change. We sampled soils to 1 m depth from seven mangrove reserves in Hainan Island, China. Only 45 out of 509 samples were rich in IC (greater than 10 mg cm-3). Most of the IC-rich samples were found at the outer part of Qinglan Bay, which is adjacent to the largest coral reef zone of Hainan Island. Soil IC concentration ranged from 0 to 66 g kg-1 (or 0-67 mg cm-3), accounting for 0-92% of total C. IC concentration increased with soil depth where it was abundant. Soil pH was low (2.36-6.59) in IC-depleted soils, but increased to 5.67-7.99 in IC-rich soils. Soil total C stock and IC stock in mangroves of Hainan amounted to 0.76*106 and 0.12*106 Mg, respectively, with IC accounting for 16% of total C. Our study finds that carbonate concentrations can be high in mangrove soils but their spatial distribution indicates they are largely allochthonous in origin. Evidence of carbonate dissolution in mangroves suggests mangroves may increase total alkalinity to buffer acidification in seawater. PMID- 30429244 TI - Aeroecology of a solar eclipse. AB - Light cues elicit strong responses from nearly all forms of life, perhaps most notably as circadian rhythms entrained by periods of daylight and darkness. Atypical periods of darkness, like solar eclipses, provide rare opportunities to study biological responses to light cues. By using a continental scale radar network, we investigated responses of flying animals to the total solar eclipse of 21 August 2017. We quantified the number of biological targets in the atmosphere at 143 weather radar stations across the continental United States to investigate whether the decrease in light and temperature at an atypical time would initiate a response like that observed at sunset, when activity in the atmosphere usually increases. Overall, biological activity decreased in the period leading to totality, followed by a short low-altitude spike of biological activity during totality in some radars. This pattern suggests that cues associated with the eclipse were insufficient to initiate nocturnal activity comparable to that occurring at sunset but sufficient to suppress diurnal activity. PMID- 30429245 TI - Negative biotic interactions drive predictions of distributions for species from a grassland community. AB - Understanding the factors that determine species' geographical distributions is important for addressing a wide range of biological questions, including where species will be able to maintain populations following environmental change. New methods for modelling species distributions include the effects of biotic interactions alongside more commonly used abiotic variables such as temperature and precipitation; however, it is not clear which types of interspecific relationship contribute to shaping species distributions and should therefore be prioritized in models. Even if some interactions are known to be influential at local spatial scales, there is no guarantee they will have similar impacts at macroecological scales. Here we apply a novel method based on information theory to determine which types of interspecific relationship drive species distributions. Our results show that negative biotic interactions such as competition have the greatest effect on model predictions for species from a California grassland community. This knowledge will help focus data collection and improve model predictions for identifying at-risk species. Furthermore, our methodological approach is applicable to any kind of species distribution model that can be specified with and without interspecific relationships. PMID- 30429246 TI - Pollinivory and the diversification dynamics of bees. AB - Pollinivory-the consumption of pollen rather than arthropod prey-is a defining feature of bees (Anthophila; the flower lovers). In virtually all bee species, larvae consume a diet composed of pollen mixed with nectar or floral oils. Bees arose from within a group of solitary, carnivorous, apoid wasps in the Early to Mid-Cretaceous, coincident with the rapid rise of flowering plants. It is assumed that the switch from carnivory to pollen-feeding was a key innovation that led to the rapid diversification of bees, but this has never been examined empirically. Here, we explore the hypothesis that pollinivory led to the increased diversification of bees. In contrast to common perception, we find that the switch to pollen-feeding per se does not explain their extensive diversification. Rather, our results indicate that pollinivory was a necessary but not sufficient condition for diversification, and that other complementary innovations, such as a broadening of host-plant diet, allowed the diversification of the major bee lineages. Our results have broad implications for understanding tempo and mode of bee diversification dynamics in light of their floral resources. PMID- 30429247 TI - Correction to 'Lionfish predators use flared fin displays to initiate cooperative hunting'. PMID- 30429248 TI - The conduit system exports locally secreted IgM from lymph nodes. AB - Immunoglobulin M (IgM) is the first type of antibody produced during acute infections and thus provides an early line of specific defense against pathogens. Being produced in secondary lymphoid organs, IgM must rapidly be exported to the blood circulation. However, it is currently unknown how such large pentameric molecules are released from lymph nodes (LNs). Here, we show that upon immunization, IgM transiently gains access to the luminal side of the conduit system, a reticular infrastructure enabling fast delivery of tissue-derived soluble substances to the LN parenchyma. Using microinjections of purified IgM, we demonstrate that conduit-associated IgM is delivered by neither the afferent lymph nor the blood, but is locally conveyed by conduits. Exploiting in vivo models, we further demonstrate that conduit-associated IgM is locally and transiently produced by activated, antigen-specific B cells migrating in the T cell zone. Thus, our study reveals that the conduit system is coopted by B cells to rapidly export secreted IgM out of LNs. PMID- 30429250 TI - Evaluation of Vitek MSTM for the differentiation of Cryptococcus neoformans and Cryptococcus gattii genotypes. AB - Cryptococcus neoformans and Cryptococcus gattii are the main pathogenic species of invasive cryptococcosis among the Cryptococcus species. Taxonomic studies have shown that these two taxa have different genotypes or molecular types with biological and eco-epidemiological peculiarities. MALDI-TOF mass spectrometry (MS) has been proposed as an alternative method for labor-intensive methods for C. neoformans and C. gattii genotypes differentiation. However, Vitek MSTM, one of the commercial MALDI-TOF MS instruments, has not been yet been evaluated for this purpose. Thus, we constructed an in-house database with reference strains belonging to the different C. neoformans (VNI, VNII, VNIII, VNIV) and C. gattii major molecular types (VGI, VGII, VGIII, VGIV) by using the software Saramis PremiumTM (Biomerieux, Marcy L'Etoile, France). Then, this new database was evaluated for discrimination of the different genotypes. Our in-house database provided correct identification for all C. neoformans and C. gattii genotypes, however, due to the inter-genotypic mass spectra similarities, a careful post analytic evaluation is necessary to provide correct genotype identification. PMID- 30429251 TI - Clinical performance of the BioPlex 2200 Syphilis Total & RPR assay at a tertiary medical center with a high rate of syphilis. AB - Manual treponemal and nontreponemal serologic testing has historically been used for the diagnosis of syphilis. This approach is simple and reproducible but labor intensive. Recently, the FDA cleared the fully automated BioPlex 2200 Syphilis Total and RPR assay for the detection of treponemal and nontreponemal antibodies. We evaluated the clinical performance of this assay at a tertiary medical center with high syphilis prevalence. Prospective consecutively collected (n = 400) and known RPR-positive specimens (n = 100) were compared using predicate manual RPR and FTA methods and the BioPlex 2200 Syphilis Total and RPR assay. Positive and negative percent agreement (PPA and NPA) between the assays was calculated. The PPA and NPA between the manual and BioPlex 2200 RPR results for the prospective population was 85% (17/20, 95% CI 69-100%) and 98% (373/380, 95% CI: 97-99%), respectively. PPA for the manual RPR-positive population was 88% (88/100; 95% CI: 82-94%). Overall, the manual and BioPlex 2200 RPR titers demonstrated 78% (99/127) concordance within +/- 1 dilution and 94% (120/127) within +/- 2 dilutions. Interpretation of the syphilis serologic profile using the traditional algorithm showed a concordance of 99.5% in the prospective population and 85% in the manual RPR-positive cohort. The performance of the BioPlex 2200 Syphilis Total & RPR assay is comparable to manual methods. The high NPA of this assay combined with the ability to automate a historically labor-intensive assay is an appealing attribute for syphilis screening in a high volume laboratory. PMID- 30429249 TI - PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt. AB - Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation. PMID- 30429252 TI - Mycobacterium talmoniae: A potential pulmonary pathogen isolated from multiple patients with bronchiectasis in the United States including the first case of clinical disease in a patient with Cystic Fibrosis. AB - We characterize three respiratory isolates of the recently described species Mycobacterium talmoniae recovered in Texas, Louisiana, and Massachusetts, including the first case of disease in a patient with underlying cystic fibrosis. The three isolates had a 100% match to M. talmoniae NE-TNMC-100812T by complete 16S rRNA, rpoB- region V, and hsp65 gene sequencing. Core genomic comparisons between one isolate and the type strain revealed an average nucleotide identity of 99.8%. The isolates were susceptible to clarithromycin, amikacin and rifabutin, while resistance was observed for tetracyclines, ciprofloxacin and linezolid. M. talmoniae should be added to the list of potential pulmonary pathogens, including in the setting of cystic fibrosis. PMID- 30429253 TI - Evaluation of the CosmosID Bioinformatics Platform for Prosthetic Joint Associated Sonicate Fluid Shotgun Metagenomic Data Analysis. AB - We previously demonstrated that shotgun metagenomic sequencing can detect bacteria in sonicate fluid, providing a diagnosis of prosthetic joint infection (PJI). A limitation of the approach we used is that data analysis was time consuming and specialized bioinformatics expertise was required, both barriers to routine clinical use. Fortunately, automated commercial analytic platforms that can "interpret" shotgun metagenomic data are emerging. In this study, we evaluated the CosmosID bioinformatics platform using shotgun metagenomic sequencing data derived from 408 sonicate fluids from our prior study, with the goal of evaluating the platform vis-a-vis bacterial detection and antibiotic resistance gene detection for predicting staphylococcal antibacterial susceptibility. Samples were divided into a derivation set and a validation set, each consisting of 204 samples; results from the derivation set were used to establish cutoffs which were then tested in the validation set for identifying pathogens and predicting staphylococcal antibacterial resistance. Metagenomic analysis detected bacteria in 94.8% (109/115) of sonicate culture-positive PJIs and 37.8% (37/98) of sonicate culture-negative PJIs. Metagenomic analysis showed sensitivities ranging from 65.7 to 85.0% for predicting staphylococcal antibacterial resistance. In conclusion, the CosmosID platform has the potential to provide fast, reliable bacterial detection and identification from metagenomic shotgun sequencing data derived from sonicate fluid for diagnosis of PJI. Strategies for metagenomic detection of antibiotic resistance genes for predicting staphylococcal antibacterial resistance need further development. PMID- 30429254 TI - Combination of non-structural protein 1-based enzyme-linked immunosorbent assays can detect and distinguish various dengue virus and Zika virus infections. AB - The recent outbreaks of Zika virus (ZIKV) and associated birth defects in dengue virus (DENV)-endemic regions emphasize the need for sensitive and specific serodiagnostic tests. We reported previously that enzyme-linked immunosorbent assays (ELISAs) based on the nonstructural protein 1 (NS1) of DENV serotype 1 (DENV1) and ZIKV can distinguish primary DENV1, secondary DENV and ZIKV infections. Whether ELISA based on NS1 proteins of other DENV serotypes can discriminate various DENV and ZIKV infections remains unknown. We herein developed DENV2-, DENV3- and DENV4-NS1 IgG ELISAs to test convalescent- and post convalescent-phase samples from reverse-transcription-polymerase-chain reaction confirmed cases, including 25 primary DENV1, 24 primary DENV2, 10 primary DENV3, 67 secondary DENV, 36 primary West Nile virus, 38 primary ZIKV, and 35 ZIKV with previous DENV infections as well as 55 flavivirus-naive samples. Each ELISA can detect primary DENV infection with a sensitivity of 100% for the same serotype and of 23.8 to 100% for different serotypes. IgG ELISA using a mixture of DENV1-4 NS1 proteins can detect different primary and secondary DENV infections with a sensitivity of 95.6% and specificity of 89.5%. The ZIKV-NS1 IgG ELISA can detect ZIKV infection with a sensitivity of 100% and specificity of 82.9%. Based on the relative optical density ratio, combination of DENV1-4 and ZIKV-NS1 IgG ELISAs can distinguish ZIKV with previous DENV and secondary DENV infections with a sensitivity of 91.7-94.1% and specificity of 87.0-95.0%. These findings have important applications to serodiagnosis, serosurveillance and monitoring of both DENV and ZIKV infections in endemic regions. PMID- 30429255 TI - It is not about the assay - Preanalytical screening is the key to reduce Clostridioides difficile infection. AB - Clostridioides difficile (formerly Clostridium difficile) infection (CDI) is one of the most common healthcare-associated infections in the United States resulting in significant morbidity, mortality, and economic burden (1)..... PMID- 30429256 TI - CRISPR-Cas Biology and Infectious Diseases Applications. AB - Infectious diseases remain a global threat contributing to excess morbidity and mortality annually with persistent potential for destabilizing pandemics. Improved understanding of the pathogenesis of bacteria, viruses, fungi, and parasites, along with rapid diagnosis and treatment of human infections are essential to improving infectious diseases outcomes worldwide. Genomic loci in bacteria and archea, termed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR associated (Cas) proteins, function as an adaptive immune system for prokaryotes protecting against foreign invaders. CRISPR-Cas9 is now routinely applied for efficient gene editing contributing to advances in biomedical science. In the past decade improved understanding of other diverse CRISPR-Cas systems has expanded CRISPR applications, including in the field of infectious diseases. In this review, we summarize the biology of CRISPR-Cas systems and discuss existing and emerging applications to evaluate mechanisms of host-pathogen interactions, to develop accurate and portable diagnostics, and to advance prevention and treatment of infectious diseases. PMID- 30429257 TI - MODS-Wayne: A colorimetric adaptation of the MODS assay for the detection of Mycobacterium tuberculosis pyrazinamide resistance from sputum samples. AB - Although pyrazinamide (PZA) is a key component of first and second line tuberculosis treatment regimens, there is no gold standard to determine PZA resistance. Approximately 50% of multidrug-resistant tuberculosis (MDR-TB) and over 90% of extensively drug resistant tuberculosis (XDR-TB) strains are also PZA resistant. pncA sequencing is the endorsed test to evaluate PZA susceptibility. However, molecular methods have limitations for their wide application.In this study we standardized and evaluated a new method to determine PZA resistance: MODS-Wayne. MODS-Wayne is based on the detection of pyrazinoic acid, the hydrolysis product of PZA, directly in the supernatant of sputum cultures by detecting a color change following addition of 10% ferrous ammonium sulfate. Using a PZA concentration of 800 ug/mL, sensitivity and specificity were evaluated at three time different periods of incubation (Reading 1, reading 2, reading 3)) using a composite standard (MGIT-PZA, pncA sequencing, and the classic Wayne test).MODS-Wayne was able to detect PZA resistance with a sensitivity and specificity of 92.7% and 99.3% respectively at Reading 3. MODS Wayne had an agreement of 93.8% and a kappa index of 0.79 compared to the classic Wayne test, agreement of 95.3% and kappa index of 0.86 compared to MGIT-PZA, and agreement of 96.9% and kappa index of 0.90 compared to pncA sequencing. In conclusion, MODS-Wayne is a simple, fast, accurate, and inexpensive approach to detect PZA resistance, making this an attractive assay especially for low resource countries, where TB is a major public health problem. PMID- 30429258 TI - Rapid microbiological diagnostics from explanted heart valves by a multiplex PCR assay. AB - Infective endocarditis (IE) is a life-threatening disease with high morbidity and mortality (1)..... PMID- 30429259 TI - Initial scaffold thickness affects the emergence of a geometrical and mechanical equilibrium in engineered cardiovascular tissues. AB - In situ cardiovascular tissue-engineering can potentially address the shortcomings of the current replacement therapies, in particular, their inability to grow and remodel. In native tissues, it is widely accepted that physiological growth and remodelling occur to maintain a homeostatic mechanical state to conserve its function, regardless of changes in the mechanical environment. A similar homeostatic state should be reached for tissue-engineered (TE) prostheses to ensure proper functioning. For in situ tissue-engineering approaches obtaining such a state greatly relies on the initial scaffold design parameters. In this study, it is investigated if the simple scaffold design parameter initial thickness, influences the emergence of a mechanical and geometrical equilibrium state in in vitro TE constructs, which resemble thin cardiovascular tissues such as heart valves and arteries. Towards this end, two sample groups with different initial thicknesses of myofibroblast-seeded polycaprolactone-bisurea constructs were cultured for three weeks under dynamic loading conditions, while tracking geometrical and mechanical changes temporally using non-destructive ultrasound imaging. A mechanical equilibrium was reached in both groups, although at different magnitudes of the investigated mechanical quantities. Interestingly, a geometrically stable state was only established in the thicker constructs, while the thinner constructs' length continuously increased. This demonstrates that reaching geometrical and mechanical stability in TE constructs is highly dependent on functional scaffold design. PMID- 30429260 TI - Variability in life-history switch points across and within populations explained by Adaptive Dynamics. AB - Understanding the factors that shape the timing of life-history switch points (SPs; e.g. hatching, metamorphosis and maturation) is a fundamental question in evolutionary ecology. Previous studies examining this question from a fitness optimization perspective have advanced our understanding of why the timing of life-history transitions may vary across populations and environments. However, in nature we also often observe variability among individuals within populations. Optimization theory, which typically predicts a single optimal SP under physiological and environmental constraints for a given environment, cannot explain this variability. Here, we re-examine the evolution of a single life history SP between juvenile and adult stages from an Adaptive Dynamics (AD) perspective, which explicitly considers the feedback between the dynamics of population and the evolution of life-history strategy. The AD model, although simple in structure, exhibits a diverse range of evolutionary scenarios depending upon demographic and environmental conditions, including the loss of the juvenile stage, a single optimal SP, alternative optimal SPs depending on the initial phenotype, and sympatric coexistence of two SP phenotypes under disruptive selection. Such predictions are consistent with previous optimization approaches in predicting life-history SP variability across environments and between populations, and in addition they also explain within-population variability by sympatric disruptive selection. Thus, our model can be used as a theoretical tool for understanding life-history variability across environments and, especially, within species in the same environment. PMID- 30429261 TI - Emergence of form in embryogenesis. AB - The development of form in an embryo is the result of a series of topological and informational symmetry breakings. We introduce the vector-reaction-diffusion drift (VRDD) system where the limit cycle of spatial dynamics is morphogen concentrations with Dirac delta-type distributions. This is fundamentally different from the Turing reaction-diffusion system, as VRDD generates system wide broken symmetry. We developed 'fundamental forms' from spherical blastula with a single organizing axis (rotational symmetry), double axis (mirror symmetry) and triple axis (no symmetry operator in three dimensions). We then introduced dynamics for cell differentiation, where genetic regulatory states are modelled as a finite-state machine (FSM). The state switching of an FSM is based on local morphogen concentrations as epigenetic information that changes dynamically. We grow complicated forms hierarchically in spatial subdomains using the FSM model coupled with the VRDD system. Using our integrated simulation model with four layers (topological, physical, chemical and regulatory), we generated life-like forms such as hydra. Genotype-phenotype mapping was investigated with continuous and jump mutations. Our study can have applications in morphogenetic engineering, soft robotics and biomimetic design. PMID- 30429262 TI - Multiscale modelling of the human lumbar facet capsular ligament: analysing spinal motion from the joint to the neurons. AB - Due to its high level of innervation, the lumbar facet capsular ligament (FCL) is suspected to play a role in low back pain (LBP). The nociceptors in the lumbar FCL may experience excessive deformation and generate pain signals. As such, understanding the mechanical behaviour of the FCL, as well as that of its underlying nerves, is critical if one hopes to understand its role in LBP. In this work, we constructed a multiscale structure-based finite-element (FE) model of a lumbar FCL on a spinal motion segment undergoing physiological motions of flexion, extension, ipsilateral and contralateral bending, and ipsilateral axial rotation. Our FE model was created for a generic FCL geometry by morphing a previously imaged FCL anatomy onto an existing generic motion segment model. The fibre organization of the FCL in our models was subject-specific based on previous analysis of six dissected specimens. The fibre structures from those specimens were mapped onto the FCL geometry on the motion segment. A motion segment model was used to determine vertebral kinematics under specified spinal loading conditions, providing boundary conditions for the FCL-only multiscale FE model. The solution of the FE model then provided detailed stress and strain fields within the tissue. Lastly, we used this computed strain field and our previous studies of deformation of nerves embedded in fibrous networks during simple deformations (e.g. uniaxial stretch, shear) to estimate the nerve deformation based on the local tissue strain and fibre alignment. Our results show that extension and ipsilateral bending result in largest strains of the lumbar FCL, while contralateral bending and flexion experience lowest strain values. Similar to strain trends, we calculated that the stretch of the microtubules of the nerves, as well as the forces exerted on the nerves' membrane are maximal for extension and ipsilateral bending, but the location within the FCL of peak microtubule stretch differed from that of peak membrane force. PMID- 30429263 TI - Experimental degradation of helicoidal photonic nanostructures in scarab beetles (Coleoptera: Scarabaeidae): implications for the identification of circularly polarizing cuticle in the fossil record. AB - Scarab beetles (Coleoptera: Scarabaeidae) can exhibit striking colours produced by pigments and/or nanostructures. The latter include helicoidal (Bouligand) structures that can generate circularly polarized light. These have a cryptic evolutionary history in part because fossil examples are unknown. This suggests either a real biological signal, i.e. that Bouligand structures did not evolve until recently, or a taphonomic signal, i.e. that conditions during the fossilization process were not conducive to their preservation. We address this issue by experimentally degrading circularly polarizing cuticle of modern scarab beetles to test the relative roles of decay, maturation and taxonomy in controlling preservation. The results reveal that Bouligand structures have the potential to survive fossilization, but preservation is controlled by taxonomy and the diagenetic history of specimens. Further, cuticle of specific genus (Chrysina) is particularly decay-prone in alkaline conditions; this may relate to the presence of certain compounds, e.g. uric acid, in the cuticle of these taxa. PMID- 30429264 TI - Pillar versus dimple patterned surfaces for wettability and adhesion with varying scales. AB - Inspired by biological topographical surfaces, micropatterned elastomeric surfaces with square pillars and dimples of different geometry scales were fabricated. Their wettability and adhesion properties with various liquids were systematically investigated and compared with flat surfaces. Interesting results were obtained in the case of silicone oil (the toe-pad-like wetting case) in that the scale-dependent wettability and adhesion performed inversely for pillars and dimples. Micropillars significantly enhanced the surface wettability with a geometry scale dependence, whereas the dimples suppressed the wettability independent of the geometry scale. The adhesion force of the micropillars increased with an increase of the geometry scale. However, in the case of the micro-dimples, the adhesion force obviously decreased with an increase of the geometry scale. This behaviour was attributed to the fact that pillars are 'open' to oil but dimples are 'close' to oil, presenting different orientations to the solid-liquid interface. PMID- 30429265 TI - The future of quantum biology. AB - Biological systems are dynamical, constantly exchanging energy and matter with the environment in order to maintain the non-equilibrium state synonymous with living. Developments in observational techniques have allowed us to study biological dynamics on increasingly small scales. Such studies have revealed evidence of quantum mechanical effects, which cannot be accounted for by classical physics, in a range of biological processes. Quantum biology is the study of such processes, and here we provide an outline of the current state of the field, as well as insights into future directions. PMID- 30429266 TI - Cellular geometry controls the efficiency of motile sperm aggregates. AB - Sperm that swim collectively to the fertilization site have been observed across several vertebrate and invertebrate species, with groups ranging in size from sperm pairs to massive aggregates containing hundreds of cells. Although the molecular mechanisms that regulate sperm-sperm adhesion are still unclear, aggregation can enhance sperm motility and thus offer a fertilization advantage. Here, we report a thorough computational investigation on the role of cellular geometry in the performance of sperm aggregates. The sperm head is modelled as a persistent random walker characterized by a non-trivial three-dimensional shape and equipped with an adhesive region where cell-cell binding occurs. By considering both, a simple parametric head shape and a computer reconstruction of a real head shape based on morphometric data, we demonstrate that the geometry of the head and the structure of the adhesive region crucially affects both the stability and motility of the aggregates. Our analysis further suggests that the apical hook commonly found in the sperm of muroid rodents might serve to shield portions of the adhesive region and promote efficient alignment of the velocities of the interacting cells. PMID- 30429267 TI - Marital status and cardiovascular disease risk. PMID- 30429268 TI - Further studies needed before using renin-angiotensin-aldosterone system blockade for atrial fibrillation prevention in hypertrophic cardiomyopathy. PMID- 30429269 TI - Reply: further studies needed before using renin-angiotensin-aldosterone system blockade for atrial fibrillation prevention in hypertrophic cardiomyopathy. PMID- 30429270 TI - Reply to 'Marital status and risk of cardiovascular diseases: a systematic review and meta-analysis'. PMID- 30429271 TI - Repeated Percutaneous Treatment of Massive Hepatic Cystic Echinococcosis in a Child. AB - Because of mostly asymptomatic cyst growth and often-neglected nonspecific low grade symptoms, many cases of cystic echinococcosis (CE) caused by Echinococcus granulosus in the pediatric population are diagnosed at school age, in an advanced and even complicated stage. In 2003, after 5 months of intermittent dull upper-right abdominal pain and nausea, a 13-year-old boy was diagnosed with massive liver CE, with ~20 round-shaped double-walled medium-sized infective cysts, which permeated the whole liver. Because of their wide distribution across the liver tissue and the risky superficial position of some cysts, liver transplantation emerged as the optimal therapeutic option. Despite being described as only an exceptionally used method for CE, we subjected our patient on 4 occasions to a radiofrequency energy thermoablation (RFT) procedure similar to the one used for malignant neoplasms. In total, 9 superficially situated cysts were initially treated with RFT by using a 14-gauge outer needle and a temperature of 70 degrees C for 8 minutes per cyst, and the remaining cysts were treated with the puncture-aspiration-instillation-reaspiration procedure, along with albendazole (15 mg/kg per day) therapy, for a period of 20 months. After 2 years of follow-up, 4 residual small-sized semisolidified cysts were seen in the liver, and the patient showed no signs of relapse. Although not routinely used, RFT, along with puncture-aspiration-instillation-reaspiration and prolonged albendazole therapy, has shown good tolerability and long-term efficacy in the treatment of multiple infective CE, which could suggest the usefulness of the RFT method beyond salvage situations in pediatric patients. PMID- 30429272 TI - Sex Differences in Mortality and Morbidity of Infants Born at Less Than 30 Weeks' Gestation. AB - OBJECTIVE: To examine whether changes in mortality and morbidities have benefited male more than female infants. METHODS: Infants of gestational ages 22 to 29 weeks born between January 2006 and December 2016 at a Vermont Oxford Network center in the United States were studied. We examined mortality and morbidity rate differences and 95% confidence intervals by sex and birth year. We tested temporal differences in mortality and morbidity rates between boys and girls by means of a likelihood ratio test (LRT) on nested binomial regression models with log links. RESULTS: A total of 205 750 infants were studied; 97 048 (47.2%) infants were girls. The rate for mortality and chronic lung disease decreased over time faster for boys than for girls (LRT P < .001 for mortality; P = .006 for lung disease). Restricting to centers that remained throughout the entire study period did not change all the above but additionally revealed a significant year-sex interaction for respiratory distress syndrome, with a faster decline among boys (LRT P = .04). Morbidities, including patent ductus arteriosus, necrotizing enterocolitis, early-onset sepsis, late-onset sepsis, severe intraventricular hemorrhage, severe retinopathy of prematurity, and pneumothorax, revealed a constant rate difference between boys and girls over time. CONCLUSIONS: Compared with girls, male infants born at <30 weeks' gestation experienced faster declines in mortality, respiratory distress syndrome, and chronic lung disease over an 11-year period. Future research should investigate which causes of death declined among boys and whether their improved survival has been accompanied by a change in their neurodevelopmental impairment rate. PMID- 30429273 TI - White matter abnormalities in the corpus callosum with cognitive impairment in Parkinson disease. AB - OBJECTIVE: To evaluate microstructural characteristics of the corpus callosum using diffusion tensor imaging (DTI) and their relationships to cognitive impairment in Parkinson disease (PD). METHODS: Seventy-five participants with PD and 24 healthy control (HC) participants underwent structural MRI brain scans including DTI sequences and clinical and neuropsychological evaluations. Using Movement Disorder Society criteria, PD participants were classified as having normal cognition (PD-NC, n = 23), mild cognitive impairment (PD-MCI, n = 35), or dementia (PDD, n = 17). Cognitive domain (attention/working memory, executive function, language, memory, visuospatial function) z scores were calculated. DTI scalar values, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were established for 5 callosal segments on a midsagittal plane, single slice using a topographically derived parcellation method. Scalar values were compared among participant groups. Regression analyses were performed on cognitive domain z scores and DTI metrics. RESULTS: Participants with PD showed increased AD values in the anterior 3 callosal segments compared to healthy controls. Participants with PDD had significantly increased AD, MD, and RD in the anterior 2 segments compared to participants with PD-NC and most anterior segment compared to participants with PD-MCI. FA values did not differ significantly between participants with PD and participants with HC or among PD cognitive groups. The strongest associations for the DTI metrics and cognitive performance occurred in the most anterior and most posterior callosal segments, and also reflected fronto-striatal and posterior cortical type cognitive deficits, respectively. CONCLUSIONS: Microstructural white matter abnormalities of the corpus callosum, as measured by DTI, may contribute to PD cognitive impairment by disrupting information transfer across interhemispheric and callosal-cortical projections. PMID- 30429274 TI - Body mass index, but not vitamin D status, is associated with brain volume change in MS. AB - OBJECTIVE: To determine whether body mass index (BMI) or vitamin D status is associated with MRI measures of neurodegeneration in a cohort of individuals with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS). METHODS: Expression, Proteomics, Imaging, Clinical (EPIC) is a longitudinal multiple sclerosis (MS) cohort study at the University of California, San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. We evaluated patients with CIS or RRMS at baseline. In multivariate repeated-measures analyses adjusted for age, sex, ethnicity, smoking status, and use of MS treatments, annual 25-hydroxyvitamin D levels and BMI were evaluated for their association with subsequent brain volumes (normalized gray matter [nGMV], brain parenchymal [nBPV], and white matter volumes, as determined by Structural Image Evaluation using Normalization of Atrophy-X). RESULTS: Among 469 participants, each 1-kg/m2 higher BMI was independently associated with reduced nGMV in multivariate models (-1.1 mL, 95% confidence interval [CI] -1.8 to -0.5, p = 0.001). BMI was likewise independently associated with nBPV (nBPV per 1-kg/m2 greater BMI: -1.1 mL, 95% CI -2.1 to -0.05, p = 0.039). Vitamin D levels did not appear to be meaningfully associated with brain volumes. CONCLUSIONS: Higher BMI appears to be associated with greater reductions in nGMV and nBPV, which is relevant because, in particular, nGMV loss portends greater longer-term disability. Because obesity is modifiable, further studies should explore these relationships in detail, and evaluating the effect of reducing BMI on imaging and clinical outcomes in MS may be warranted. PMID- 30429275 TI - Ultrastructural mechanisms of macrophage-induced demyelination in CIDP. AB - Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent advances in the search for autoantibodies against components expressed at nodal regions, such as the nodes of Ranvier and paranodes, have substantially contributed to clarifying the pathogenesis of CIDP in a subpopulation of patients. In particular, immunoglobulin G4 (IgG4) antibodies to paranodal junction proteins, including neurofascin-155 and contactin-1, have attracted the attention of researchers. Paranodal dissection resulting from the attachment of IgG4 at paranodal junctions and the absence of macrophage-induced demyelination are characteristic pathologic features in patients who have these antibodies. By contrast, the mechanisms of neuropathy in cases with classical macrophage-induced demyelination remain unclear despite the long-standing recognition of this process in CIDP. In addition to complement-dependent damage provoked by autoantibodies, recent studies have shed light on antibody-dependent phagocytosis by macrophages without participation of complements. However, a direct association between specific autoantibodies and macrophage-induced demyelination has not been reported. Electron microscopic examination of longitudinal sections of sural nerve biopsy specimens suggested that macrophages recognize specific sites of myelinated fibers as the initial target of demyelination. The site that macrophages select to initiate myelin breakdown is located around the nodal regions in some patients and internode in others. Hence, it seems that the components that distinguish between the nodal regions and internode play a pivotal role in the behavior of macrophages that initiate phagocytosis of myelin. Further studies are needed to elucidate the mechanisms underlying macrophage induced demyelination from this perspective. PMID- 30429276 TI - Prediagnostic plasma branched chain amino acids and the risk of amyotrophic lateral sclerosis. AB - OBJECTIVE: To assess whether prediagnostic levels of plasma branched-chain amino acids (BCAAs) are associated with amyotrophic lateral sclerosis (ALS) risk. METHODS: We included participants from 5 large cohort studies-The Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition, the Multiethnic Cohort Study, and the Women's Health Initiative-and identified 275 individuals who developed ALS during follow-up. Two controls were randomly selected for each case, matched on cohort, age, sex, fasting status, and time of blood draw. We measured metabolites using liquid chromatography-mass spectrometry and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for the association of individual BCAAs with ALS risk. RESULTS: None of the 3 BCAAs was associated with a higher ALS risk. The risk estimates were similar for leucine (RR top vs bottom quartile: 0.87, 95% CI 0.57-1.33), isoleucine (RR top vs bottom quartile: 0.81, 95% CI 0.52 1.24), and valine (RR top vs bottom quartile: 0.80, 95% CI 0.52-1.23) in a multivariable analysis adjusted for body mass index, smoking, level of education, and physical activity. The estimates did not vary significantly by sex, fasting status, or time interval between blood draw and disease onset. CONCLUSION: The results from this study do not support the hypothesis that BCAAs are risk factors for ALS. PMID- 30429277 TI - CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. AB - Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions. PMID- 30429279 TI - Obesity and brain volume loss in multiple sclerosis. PMID- 30429278 TI - Migraine with visual aura a risk factor for incident atrial fibrillation: A cohort study. AB - OBJECTIVE: Migraine with visual aura is associated with cardioembolic stroke risk. The aim of this study was to test association between migraine with visual aura and atrial fibrillation (AF), in the Atherosclerosis Risk in Communities study. METHODS: In the Atherosclerosis Risk in Communities study, a longitudinal, community-based cohort study, participants were interviewed for migraine history in 1993-1995 and were followed for incident AF through 2013. AF was adjudicated using ECGs, discharge codes, and death certificates. Multivariable Cox proportional hazards models were used to study the relation between migraine and its subtypes with incident AF, compared with controls without headaches. Mediation analysis was conducted to test whether AF was a mediator of migraine with visual aura-associated stroke risk. RESULTS: Of 11,939 participants assessed for headache and without prior AF or stroke, 426 reported migraines with visual aura, 1,090 migraine without visual aura, 1,018 nonmigraine headache, and 9,405 no headache. Over a 20-year follow-up period, incident AF was noted in 232 (15%) of 1,516 with migraine and 1,623 (17%) of 9,405 without headache. After adjustment for multiple confounders, migraine with visual aura was associated with increased risk of AF compared to no headache (hazard ratio 1.30, 95% confidence interval 1.03-1.62) as well as when compared to migraine without visual aura (hazard ratio 1.39, 95% confidence interval 1.05-1.83). The data suggest that AF may be a potential mediator of migraine with visual aura-stroke risk. CONCLUSIONS: Migraine with aura was associated with increased risk of incident AF. This may potentially lead to ischemic strokes. PMID- 30429280 TI - Migraine with visual aura, incident AF, and stroke risk: Is migraine with aura an embolic TIA? PMID- 30429281 TI - Context-dependent spindle pole focusing. AB - The formation of a robust, bi-polar spindle apparatus, capable of accurate chromosome segregation, is a complex process requiring the co-ordinated nucleation, sorting, stabilization and organization of microtubules (MTs). Work over the last 25 years has identified protein complexes that act as functional modules to nucleate spindle MTs at distinct cellular sites such as centrosomes, kinetochores, chromatin and pre-existing MTs themselves. There is clear evidence that the extent to which these different MT nucleating pathways contribute to spindle mass both during mitosis and meiosis differs not only between organisms, but also in different cell types within an organism. This plasticity contributes the robustness of spindle formation; however, whether such plasticity is present in other aspects of spindle formation is less well understood. Here, we review the known roles of the protein complexes responsible for spindle pole focusing, investigating the evidence that these, too, act co-ordinately and differentially, depending on cellular context. We describe relationships between MT minus-end directed motors dynein and HSET/Ncd, depolymerases including katanin and MCAK, and direct minus-end binding proteins such as nuclear-mitotic apparatus protein, ASPM and Patronin/CAMSAP. We further explore the idea that the focused spindle pole acts as a non-membrane bound condensate and suggest that the metaphase spindle pole be treated as a transient organelle with context-dependent requirements for function. PMID- 30429282 TI - TAPping into the treasures of tubulin using novel protein production methods. AB - Microtubules are cytoskeletal elements with important cellular functions, whose dynamic behaviour and properties are in part regulated by microtubule-associated proteins (MAPs). The building block of microtubules is tubulin, a heterodimer of alpha- and beta-tubulin subunits. Longitudinal interactions between tubulin dimers facilitate a head-to-tail arrangement of dimers into protofilaments, while lateral interactions allow the formation of a hollow microtubule tube that mostly contains 13 protofilaments. Highly homologous alpha- and beta-tubulin isotypes exist, which are encoded by multi-gene families. In vitro studies on microtubules and MAPs have largely relied on brain-derived tubulin preparations. However, these consist of an unknown mix of tubulin isotypes with undefined post translational modifications. This has blocked studies on the functions of tubulin isotypes and the effects of tubulin mutations found in human neurological disorders. Fortunately, various methodologies to produce recombinant mammalian tubulins have become available in the last years, allowing researchers to overcome this barrier. In addition, affinity-based purification of tagged tubulins and identification of tubulin-associated proteins (TAPs) by mass spectrometry has revealed the 'tubulome' of mammalian cells. Future experiments with recombinant tubulins should allow a detailed description of how tubulin isotype influences basic microtubule behaviour, and how MAPs and TAPs impinge on tubulin isotypes and microtubule-based processes in different cell types. PMID- 30429283 TI - Bridging centrioles and PCM in proper space and time. AB - Throughout biology, specifying cellular events at the correct location and time is necessary for ensuring proper function. The formation of robust microtubule organizing centers (MTOCs) in mitosis is one such event that must be restricted in space to centrosomes to prevent ectopic MTOC formation elsewhere in the cell, a situation that can result in multipolar spindle formation and aneuploidy. The process of reaching maximum centrosome MTOC activity in late G2, known as centrosome maturation, ensures accurate timing of nuclear envelope breakdown and proper chromosome attachment. Although centrosome maturation has been recognized for over a century, the spatial and temporal regulatory mechanisms that direct MTOC activation are poorly understood. Here, we review Sas-4/CPAP, Asterless/Cep152, Spd-2/Cep192, and PLP/Pericentrin, a group of proteins we refer to as 'bridge' proteins that reside at the surface of centrioles, perfectly positioned to serve as the gatekeepers of proper centrosome maturation at the perfect place and time. PMID- 30429284 TI - Indole-3-Pyruvic Acid, an Aryl Hydrocarbon Receptor Activator, Suppresses Experimental Colitis in Mice. AB - Aryl hydrocarbon receptor (AHR) agonists are promising immunomodulators that potentially maintain immune tolerance. In this study, we examined the ability of indole-3-pyruvic acid (IPA), a major precursor of microbiota-derived AHR agonists and a proagonist of AHR, to activate AHR. The anti-inflammatory effects of IPA were also evaluated in a mouse model of colitis in comparison with other aromatic pyruvic acids (phenylpyruvic acid and 4-hydroxyphenylpyruvic acid). Among them, IPA showed the strongest ability to activate AHR in vitro and in vivo, and only IPA improved chronic inflammation in an experimental colitis model. IPA attenuated the expression of genes encoding Th1 cytokines and enhanced Il-10 gene expression in the colon. Oral administration of IPA decreased the frequency of IFN-gamma+ IL-10- CD4+ T cells and increased that of IFN-gamma- IL-10+ CD4+ T cells in the colon lamina propria in a T cell-mediated colitis model. IPA directly promoted the differentiation of type 1 regulatory T cells in vitro. Furthermore, IPA administration attenuated the ability of dendritic cells (DCs) in the mesenteric lymph nodes (MLN) to induce IFN-gamma-producing T cells, increased the frequency of CD103+ CD11b- DCs, and decreased the frequency of CD103- CD11b+ DCs in the MLN. Adoptive transfer of MLN CD103+ CD11b- DCs significantly improved the severity of colon inflammation. Treatment with an AHR antagonist inhibited IPA-induced differentiation of type 1 regulatory T cells and the IPA-induced increase in CD103+ CD11b- DCs and attenuated the anti inflammatory effect of IPA. These findings suggest that IPA potently prevents chronic inflammation in the colon by activating AHR. PMID- 30429285 TI - Deregulated AUF1 Assists BMP-EZH2-Mediated Delayed Wound Healing during Candida albicans Infection. AB - Tissue repair is a complex process that necessitates an interplay of cellular processes, now known to be dictated by epigenetics. Intriguingly, macrophages are testimony to a large repertoire of evolving functions in this process. We identified a role for BMP signaling in regulating macrophage responses to Candida albicans infection during wound repair in a murine model. In this study, the RNA binding protein, AU-rich element-binding factor 1, was posttranslationally destabilized to bring about ubiquitin ligase, NEDD4-directed activation of BMP signaling. Concomitantly, PI3K/PKCdelta mobilized the rapid phosphorylation of BMP-responsive Smad1/5/8. Activated BMP pathway orchestrated the elevated recruitment of EZH2 at promoters of genes assisting timely wound closure. In vivo, the repressive H3K27 trimethylation was observed to persist, accompanied by a robust upregulation of BMP pathway upon infection with C. albicans, culminating in delayed wound healing. Altogether, we uncovered the signaling networks coordinated by fungal colonies that are now increasingly associated with the infected wound microbiome, resulting in altered wound fate. PMID- 30429286 TI - The Length Distribution and Multiple Specificity of Naturally Presented HLA-I Ligands. AB - HLA-I molecules bind short peptides and present them for recognition by CD8+ T cells. The length of HLA-I ligands typically ranges from 8 to 12 aa, but variability is observed across different HLA-I alleles. In this study we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples. PMID- 30429287 TI - Complement Inhibitor CRIg/FH Ameliorates Renal Ischemia Reperfusion Injury via Activation of PI3K/AKT Signaling. AB - Complement activation is involved in the pathogenesis of ischemia reperfusion injury (IRI), which is an inevitable process during kidney transplantation. Therefore, complement-targeted therapeutics hold great potential in protecting the allografts from IRI. We observed universal deposition of C3d and membrane attack complex in human renal allografts with delayed graft function or biopsy proved rejection, which confirmed the involvement of complement in IRI. Using FB , C3-, C4-, C5-, C5aR1-, C5aR2-, and C6-deficient mice, we found that all components, except C5aR2 deficiency, significantly alleviated renal IRI to varying degrees. These gene deficiencies reduced local (deposition of C3d and membrane attack complex) and systemic (serum levels of C3a and C5a) complement activation, attenuated pathological damage, suppressed apoptosis, and restored the levels of multiple local cytokines (e.g., reduced IL-1beta, IL-9, and IL 12p40 and increased IL-4, IL-5, IL-10, and IL-13) in various gene-deficient mice, which resulted in the eventual recovery of renal function. In addition, we demonstrated that CRIg/FH, which is a targeted complement inhibitor for the classical and primarily alternative pathways, exerted a robust renoprotective effect that was comparable to gene deficiency using similar mechanisms. Further, we revealed that PI3K/AKT activation, predominantly in glomeruli that was remarkably inhibited by IRI, played an essential role in the CRIg/FH renoprotective effect. The specific PI3K antagonist duvelisib almost completely abrogated AKT phosphorylation, thus abolishing the renoprotective role of CRIg/FH. Our findings suggested that complement activation at multiple stages induced renal IRI, and CRIg/FH and/or PI3K/AKT agonists may hold the potential in ameliorating renal IRI. PMID- 30429288 TI - Predicting Humoral Alloimmunity from Differences in Donor and Recipient HLA Surface Electrostatic Potential. AB - In transplantation, development of humoral alloimmunity against donor HLA is a major cause of organ transplant failure, but our ability to assess the immunological risk associated with a potential donor-recipient HLA combination is limited. We hypothesized that the capacity of donor HLA to induce a specific alloantibody response depends on their structural and physicochemical dissimilarity compared with recipient HLA. To test this hypothesis, we first developed a novel computational scoring system that enables quantitative assessment of surface electrostatic potential differences between donor and recipient HLA molecules at the tertiary structure level [three-dimensional electrostatic mismatch score (EMS-3D)]. We then examined humoral alloimmune responses in healthy females subjected to a standardized injection of donor lymphocytes from their male partner. This analysis showed a strong association between the EMS-3D of donor HLA and donor-specific alloantibody development; this relationship was strongest for HLA-DQ alloantigens. In the clinical transplantation setting, the immunogenic potential of HLA-DRB1 and -DQ mismatches expressed on donor kidneys, as assessed by their EMS-3D, was an independent predictor of development of donor-specific alloantibody after graft failure. Collectively, these findings demonstrate the translational potential of our approach to improve immunological risk assessment and to decrease the burden of humoral alloimmunity in organ transplantation. PMID- 30429289 TI - Effect of one session of mirror therapy on phantom limb pain and recognition of limb laterality in military traumatic lower limb amputees: a pilot study. AB - Up to 70 % of military amputees suffer phantom limb pain (PLP), which is difficult to treat. PLP has been attributed to cortical reorganisation and associated with impaired laterality. Repeated sessions of mirror therapy (MT) can benefit PLP; however, anecdotal evidence suggests one MT session could be effective. In a one-group pretest and post-test design, 16 UK military unilateral lower limb amputees (median age: 31.0, 95% CI 25.0 to 36.8 years) undertook one 10 min MT session. Visual analogue scale (VAS) pain and laterality (accuracy and reaction time) measurements were taken pre-MT and post-MT. Median VAS PLP did not differ significantly between pre-MT 15 mm (2-53 mm) and post-MT 12 mm (1-31) (p=0.875) scores. For the amputated limb, there were no significant differences between pre-MT and post-MT scores for laterality accuracy, 95.3%, 95% CI 90.5% to 97.6% and 96.7%, 95% CI 90.0% to 99.4%, respectively (p=0.778), or reaction time, 1.42 s, 95% CI 1.11 to 2.11 s and 1.42 s, 95% CI 1.08 to 2.02 s, respectively (p=0.629). Laterality was also not different between limbs for accuracy, p=0.484, or reaction time, p=0.716, and did not correlate with PLP severity. No confounding variables predicted individual responses to MT. Therefore, one 10 min MT session does not affect laterality and is not effective as standard treatment for PLP in military lower limb amputees. However, substantial PLP improvement for one individual and resolution of a stuck phantom limb for another infers that MT may benefit specific patients. No correlation found between PLP and laterality implies associated cortical reorganisation may not be the main driver for PLP. Further research, including neuroimaging, is needed to help clinicians effectively target PLP. PMID- 30429290 TI - Role of research psychology in defence and security. AB - The following article provides an overview of the research psychology capabilities within MOD's Defence Science Technology Laboratory (Dstl). An explanation is provided of the role of Dstl psychologists and the way they work to deliver impacting applied scientific research to address 'real world' defence and security challenges. Three short case studies are provided to illustrate the range of work they delivered. PMID- 30429291 TI - Four years of orthopaedic activities in Chinese Role 2 Hospital of eastern Mali peacekeeping area. AB - INTRODUCTION: The Chinese Role 2 Hospital (CHN-Role 2H) Medical Treatment Facility (MTF) was founded in July 2013 as part of the Chinese commitment to Multidimensional Integrated Stabilization Mission in Mali (MINUSMA). It provides medical care for approximately 5200 personnel of the whole Sector East of MINUSMA including UN military personnel, UN police and UN civilian staff. The aim of this study was to determine the orthopaedic surgical activity over a 4-year period to facilitate the training of future Chinese military surgical teams. MATERIALS AND METHODS: Surgical records of all patients operated on at the CHN-Role 2H between 28 March 2014 to 28 March 2018 were identified, and all orthopaedic activity were analysed. RESULTS: During this period, 1190 patients underwent 2024 surgical procedures. Orthopaedic procedures represented 961/2024 (47.5%) of all the procedures. Battle injury (BI) represented 43% of patients. Improvised explosive devices (IEDs) were responsible for 15.8 % casualties. Fractures (49%) and soft tissue injures (43%) were the most common injuries, with 61% of the fractures being open. Damage control surgery including debridement (23.52%) and external fixation (17.90%) were the most frequently performed interventions. CONCLUSION: Orthopaedic surgery is the most frequently performed surgery in the CHN-Role 2H in Mali. The complexity and severity of injuries demonstrate the urgent need for tailored training and extended skill sets for deploying military orthopaedic surgeons. PMID- 30429292 TI - Medical support to military training and operations. Starkey KJ, Lyon J, Sigman E, Pynn H, Nordman G. J R Army Med Corps 2018;(164):92-5. PMID- 30429293 TI - Aviation medicine considerations in parachuting operations. PMID- 30429294 TI - Energy availability and nutrition during a Special Force Qualification Course (Q Course). AB - INTRODUCTION: The Special Forces (SF) are an elite military group usually engaged in physically demanding field operations, resulting among others in high daily energy requirements. Optimising energy supply and nutritional requirements is therefore mandatory for success. The aim of this study was to estimate energy availability and nutrition during a Qualification Course (Q-Course) for Belgian SF. METHODS: 21 participants recorded all foods and beverages consumed during four days in a structured food diary. Energy expenditure was measured with an accelerometer and fat mass measured with quadripolar impedance. Energy availability was calculated by the following formula: (energy intake by foods and beverages - energy expenditure for physical activity)/kg FFM/day (FFM, fat-free mass). RESULTS: The mean (SD) total energy expenditure was 4926 kcal/day (238), with a minimum of 4645 kcal/day and a maximum of 5472 kcal/day. The mean (SD) total energy consumption was 4186 kcal/day (842), giving an energy balance ranging from -2005 kcal/day to 1113 kcal/day. The mean (SD) energy availability was 17 kcal/kg FFM/day, with a minimum of 1 kcal/kg FFM/day and a maximum of 44 kcal/kg FFM/day. The mean (SD) intake of carbohydrates was 6.8 g/kg body weight/day (1.5). CONCLUSIONS: During this studied Q-Course, energy intake was not optimal as demonstrated by an overall negative energy balance and low energy availability. High interindividual variations in energy intake were found, highlighting the importance of providing SF members nutritional education. PMID- 30429295 TI - Updated Diploma in Immediate Medical Care: applicability to military and civilian clinicians. AB - The Diploma in Immediate Medical Care (DipIMC) is the entry-level interprofessional civilian qualification for prehospital emergency care (PHEC) in the UK. It is designed to test the knowledge, skills and behaviours of PHEC practitioners. Military personnel are eligible to enter, dependent on the level of PHEC experience they have. The DipIMC examination has changed in recent years; this paper aims to update aspiring candidates on the application process, recommended preparation and skill-set required to pass. PMID- 30429296 TI - Three cusps are better than two: bicuspid aortic valve and implications for military service. AB - Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. It is an aortopathy and is associated with other congenital heart disease. Although there is no mortality increase with BAV, the natural history increases the risk of aortic valve disease, aortic dilatation and infective endocarditis over the time frame of a full military career. Military service theoretically increases the risk of aortic dilatation and endocarditis in BAV. Conversely, there are some who have BAV who would not suffer any complications during their military career. Currently, potential UK Army recruits undergo personal/family history and physical examination plus an ECG and, although this goes beyond American Heart Association guidelines, it does not screen specifically for BAV. This would necessitate a transthoracic echo for each potential recruit but would be a considerable increase in resources-both time and financial. In addition to the recruitment medical, military personnel undergo frequent medicals, which could identify those who develop significant valvular disease. Those with mild valve disease are at lowest risk of complication. Those with aortic dilatation only remain a concern. PMID- 30429297 TI - Myopericarditis: recognition and impact in the military population. AB - We present a case of a fit and well British Army officer with sudden-onset chest pain following a viral illness, on a background of arduous skiing over an 8-week period. This resulted in a 6-month downgrade with no clearly defined plan for return to full fitness and deployability. The diagnosis and differentiation of myopericarditis from other causes of chest pain is reviewed. The treatment and management of myopericarditis is summarised and commentary is made on the paucity of evidence underpinning the return to fitness guidelines. The impact of this condition primarily affecting young fit individuals, commonly exacerbated by viral illness and arduous activity, is discussed in the context of individual employability and operational capability in a military setting. PMID- 30429298 TI - Neonatal mice exposed to a high-fat diet in utero influence the behaviour of their nursing dam. AB - The behaviour of a nursing dam influences the development, physiology, and behaviour of her offspring. Maternal behaviours can be modulated both by environmental factors, including diet, and by physical or behavioural characteristics of the offspring. In most studies of the effects of the environment on maternal behaviour, F0 dams nurse their own F1 offspring. Because the F1 are indirectly exposed to the environmental stressor in utero in these studies, it is not possible to differentiate between effects on maternal behaviour from direct exposure of the dam and those mediated by changes in the F1 as a consequence of in utero exposure. In this study, we used a mouse model of high-fat (HF) diet feeding, which has been shown to influence maternal behaviours, combined with cross-fostering to discriminate between these effects. We tested whether the diet of the F0 dam or the exposure experienced by the F1 pups in utero is the most significant predictor of maternal behaviour. Neither factor significantly influenced pup retrieval behaviours. However, strikingly, F1 in utero exposure was a significant predictor of maternal behaviour in the 15 min immediately following pup retrieval while F0 diet had no discernable effect. Our findings suggest that in utero exposure to HF diet programmes physiological changes in the offspring which influence the maternal behaviours of their dam after birth. PMID- 30429299 TI - Carbon limitation of lake productivity. AB - Phytoplankton productivity in lakes controls the rate of synthesis of organic matter that drives energy flow through the food webs and regulates the transparency and oxygen conditions in the water. Limitation of phytoplankton productivity and biomass by nutrients and light availability is an established paradigm for lake ecosystems, whereas invasion of atmospheric CO2 has been assumed to cover the high demands of dissolved inorganic carbon (DIC) during intense organic productivity. We challenge this paradigm, and show up to a 5-fold stimulation of phytoplankton productivity and biomass in outdoor mesocosms enriched with DIC, compared to mesocosms with lower DIC concentrations. High DIC supported phytoplankton productivity by direct algal uptake of bicarbonate, through the release of CO2 coupled to calcification and by inducing high pH that greatly enhances atmospheric CO2 invasion. Comparisons of 204 natural Danish lakes supported mesocosm experiments showing higher phytoplankton biomass and pH levels in hard water than soft water lakes for the same nutrient and light availabilities. The most productive lakes are nutrient-rich, hard water lakes that attain surface pHs of 10-11 and chemically enhance atmospheric CO2 uptake 10 15-fold. Our results will help understand natural variations of lake productivity along gradients in nutrients, DIC and pH. PMID- 30429300 TI - Experimental disturbances reveal group-level costs of social instability. AB - In group-living species, social stability is an important trait associated with the evolution of complex behaviours such as cooperation. While the drivers of stability in small groups are relatively well studied, little is known about the potential impacts of unstable states on animal societies. Temporary changes in group composition, such as a social group splitting and recombining (i.e. a disturbance event), can result in individuals having to re-establish their social relationships, thus taking time away from other tasks such as foraging or vigilance. Here, we experimentally split socially stable groups of captive zebra finches (Taeniopygia guttata), and quantified the effects of repeated disturbance events on (1) group foraging efficiency, and (2) co-feeding associations when subgroups were recombined. We found that the efficiency of groups to deplete a rich, but ephemeral, resource patch decreased after just a single short disturbance event. Automated tracking of individuals showed that repeated disturbances reduced efficiency by causing social relationships to become more differentiated and weaker, resulting in fewer individuals simultaneously accessing the patch. Our experiment highlights how short-term disturbances can severely disrupt social structure and group functionality, revealing potential costs associated with group instability that can have consequences for the evolution of animal societies. PMID- 30429301 TI - Calcium transfer across the outer mantle epithelium in the Pacific oyster, Crassostrea gigas. AB - Calcium transport is essential for bivalves to be able to build and maintain their shells. Ionized calcium (Ca2+) is taken up from the environment and eventually transported through the outer mantle epithelium (OME) to the shell growth area. However, the mechanisms behind this process are poorly understood. The objective of the present study was to characterize the Ca2+ transfer performed by the OME of the Pacific oyster, Crassostrea gigas, as well as to develop an Ussing chamber technique for the functional assessment of transport activities in epithelia of marine bivalves. Kinetic studies revealed that the Ca2+ transfer across the OME consists of one saturable and one linear component, of which the saturable component fits best to Michaelis-Menten kinetics and is characterized by a K m of 6.2 mM and a V max of 3.3 nM min-1 The transcellular transfer of Ca2+ accounts for approximately 60% of the total Ca2+ transfer across the OME of C. gigas at environmental Ca2+ concentrations. The use of the pharmacological inhibitors: verapamil, ouabain and caloxin 1a1 revealed that voltage-gated Ca2+-channels, plasma-membrane Ca2+-ATPase and Na+/Ca2+-exchanger all participate in the transcellular Ca2+ transfer across the OME and a model for this Ca2+ transfer is presented and discussed. PMID- 30429302 TI - Early bursts of disparity and the reorganization of character integration. AB - 'Early bursts' of morphological disparity (i.e. diversity of anatomical types) are common in the fossil record. We typically model such bursts as elevated early rates of independent character change. Developmental theory predicts that modules of linked characters can change together, which would mimic the effects of elevated independent rates on disparity. However, correlated change introducing suboptimal states should encourage breakup (parcellation) of character suites allowing new (or primitive) states to evolve until new suites arise (relinkage). Thus, correlated change-breakup-relinkage presents mechanisms for early bursts followed by constrained evolution. Here, I analyse disparity in 257 published character matrices of fossil taxa. For each clade, I use inverse-modelling to infer most probably rates of independent change given both time-homogeneous and separate 'early versus late' rates. These rates are used to estimate expected disparity given both independent change models. The correlated change-breakup relinkage model also predicts elevated frequencies of compatible character state pairs appearing out of order in the fossil record (e.g. 01 appearing after 00 and 11; = low stratigraphic compatibility), as one solution to suboptimal states induced by correlated change is a return to states held before that change. As predicted by the correlated change-breakup-relinkage model, early disparity in the majority of clades both exceeds the expectations of either independent change model and excess early disparity correlates with low stratigraphic compatibility among character-pairs. Although it is possible that other mechanisms for linking characters contribute to these patterns, these results corroborate the idea that reorganization of developmental linkages is often associated with the origin of groups that biologists recognize as new higher taxa and that such reorganization offers a source of new disparity throughout the Phanerozoic. PMID- 30429303 TI - The hidden cost of sexually selected traits: the metabolic expense of maintaining a sexually selected weapon. AB - Sexually selected weapons are among the most exaggerated traits in nature. Sexual selection theory frequently assumes a high cost of this exaggeration; yet, those costs are rarely measured. We know very little about the energetic resources required to maintain these traits at rest and the difference in energetic costs for the largest individuals relative to the smallest individuals. Knowledge in this area is crucial; resting metabolic rate can account for 30-40% of daily energy expenditure in wild animals. Here, we capitalized on the phenomenon of autotomy to take a unique look at weapon maintenance costs. Using Leptoscelis tricolor (Hemiptera: Coreidae), we measured CO2 production rates before and after a weapon was shed. Males in this insect species use enlarged hind femora as weapons in male-male combat, and yet can shed them readily, without regeneration, upon entrapment. We found that metabolic rate decreased by an average of 23.5% in males after leg loss and by 7.9% in females. Notably, larger males had less of a drop in metabolic rate per gram of weapon lost. Our findings suggest that sexually selected weapons contribute to a large portion of resting metabolic rate in males, but these costs do not scale in direct proportion to size; larger males can have larger weapons for a reduced metabolic cost. These energetic maintenance costs may be integral to the evolution of the allometries of sexually selected weapons, and yet they remain largely unexplored. PMID- 30429304 TI - Real or fake? Natural and artificial social stimuli elicit divergent behavioural and neural responses in mangrove rivulus, Kryptolebias marmoratus. AB - Understanding how the brain processes social information and generates adaptive behavioural responses is a major goal in neuroscience. We examined behaviour and neural activity patterns in socially relevant brain nuclei of hermaphroditic mangrove rivulus fish (Kryptolebias marmoratus) provided with different types of social stimuli: stationary model opponent, regular mirror, non-reversing mirror and live opponent. We found that: (i) individuals faced with a regular mirror were less willing to interact with, delivered fewer attacks towards and switched their orientation relative to the opponent more frequently than fish exposed to a non-reversing mirror image or live opponent; (ii) fighting with a regular mirror image caused higher expression of immediate-early genes (IEGs: egr-1 and c-Fos) in the teleost homologues of the basolateral amygdala and hippocampus, but lower IEG expression in the preoptic area, than fighting with a non-reversing mirror image or live opponent; (iii) stationary models elicited the least behavioural and IEG responses among the four stimuli; and (iv) the non-reversing mirror image and live opponent drove similar behavioural and neurobiological responses. These results suggest that the various stimuli provide different types of information related to conspecific recognition in the context of aggressive contests, which ultimately drive different neurobiological responses. PMID- 30429305 TI - Exploring mechanisms and origins of reduced dispersal in island Komodo dragons. AB - Loss of dispersal typifies island biotas, but the selective processes driving this phenomenon remain contentious. This is because selection via, both indirect (e.g. relaxed selection or island syndromes) and direct (e.g. natural selection or spatial sorting) processes may be involved, and no study has yet convincingly distinguished between these alternatives. Here, we combined observational and experimental analyses of an island lizard, the Komodo dragon (Varanus komodoensis, the world's largest lizard), to provide evidence for the actions of multiple processes that could contribute to island dispersal loss. In the Komodo dragon, concordant results from telemetry, simulations, experimental translocations, mark-recapture, and gene flow studies indicated that despite impressive physical and sensory capabilities for long-distance movement, Komodo dragons exhibited near complete dispersal restriction: individuals rarely moved beyond the valleys they were born/captured in. Importantly, lizard site-fidelity was insensitive to common agents of dispersal evolution (i.e. indices of risk for inbreeding, kin and intraspecific competition, and low habitat quality) that consequently reduced survival of resident individuals. We suggest that direct selection restricts movement capacity (e.g. via benefits of spatial philopatry and increased costs of dispersal) alongside use of dispersal-compensating traits (e.g. intraspecific niche partitioning) to constrain dispersal in island species. PMID- 30429306 TI - Of molecules, memories and migration: M1 acetylcholine receptors facilitate spatial memory formation and recall during migratory navigation. AB - Many animals use complex cognitive processes, including the formation and recall of memories, for successful navigation. However, the developmental and neurological processes underlying these cognitive aspects of navigation are poorly understood. To address the importance of the formation and recollection of memories during navigation, we pharmacologically manipulated turtles (Chrysemys picta) that navigate long distances using precise, complex paths learned during a juvenile critical period. We treated freely navigating turtles both within and outside of their critical learning period with a specific M1 acetylcholine receptor antagonist, a drug known to disrupt spatial cognition. Experienced adult turtles lost all navigational ability under the influence of the drug, while naive juveniles navigated successfully. We retested these same juveniles the following year (after they had passed their critical period). The juveniles that initially navigated successfully under the influence of the antagonist (but were unable to form spatial memories) were unable to do so subsequently. However, the control animals (who had the opportunity to form memories previously) exhibited typical navigational precision. These results suggest that the formation of spatial memories for navigation occur during a critical period, and successful navigation after the critical period is dependent upon the recall of such memories. PMID- 30429307 TI - Microbial-tubeworm associations in a 440 million year old hydrothermal vent community. AB - Microorganisms are the chief primary producers within present-day deep-sea hydrothermal vent ecosystems, and play a fundamental role in shaping the ecology of these environments. However, very little is known about the microbes that occurred within, and structured, ancient vent communities. The evolutionary history, diversity and the nature of interactions between ancient vent microorganisms and hydrothermal vent animals are largely undetermined. The oldest known hydrothermal vent community that includes metazoans is preserved within the Ordovician to early Silurian Yaman Kasy massive sulfide deposit, Ural Mountains, Russia. This deposit contains two types of tube fossil attributed to annelid worms. A re-examination of these fossils using a range of microscopy, chemical analysis and nano-tomography techniques reveals the preservation of filamentous microorganisms intimately associated with the tubes. The microfossils bear a strong resemblance to modern hydrothermal vent microbial filaments, including those preserved within the mineralized tubes of the extant vent polychaete genus Alvinella The Yaman Kasy fossil filaments represent the oldest animal-microbial associations preserved within an ancient hydrothermal vent environment. They allude to a diverse microbial community, and also demonstrate that remarkable fine-scale microbial preservation can also be observed in ancient vent deposits, suggesting the possible existence of similar exceptionally preserved microfossils in even older vent environments. PMID- 30429308 TI - Multiple paternity and number of offspring in mammals. AB - Many cooperative social attributes are being linked to characteristics of mating systems, particularly to the rate of multiple paternity that typifies a population. Under the logic that greater offspring production by females should engender greater competition among males to mate with females, it is predicted that multiple paternity should increase with litter sizes. We tested the predicted positive association of multiple paternity and litter size with a meta analysis of 59 species of mammals. The probability of multiple paternity and mean litter size were positively correlated, but not significantly (Zr = 0.202). Also, the mean number of sires of litters increased with mean litter size, but not significantly (Zr = 0.235). We developed a combinatorial formula for the influence of number of male mates and litter size on the probability of multiple paternity. We used Bayesian Markov chain Monte Carlo simulations to generate an expectation for the form of the relationship between the probability of multiple paternity and mean litter size. Under the assumption of random samplings of numbers of mates, the expected association of the probability of multiple paternity and mean litter sizes among species was positive, curvilinear and relatively high. However, the empirical probabilities of multiple paternities were much less than expected, suggesting that behavioural factors (such as mating associated behaviours) or ecological characteristics (such as population density) probably limit the number of male mates for reproductive females. The probability of multiple paternity in a population is an estimate of mating patterns that does not closely reflect the number of sires of individual litters. We suggest use of the estimated probability of mating success for males as an alternative measure of their contribution to the mating system. PMID- 30429309 TI - Adaptation, speciation and extinction in the Anthropocene. AB - Humans have dramatically altered the planet over the course of a century, from the acidity of our oceans to the fragmentation of our landscapes and the temperature of our climate. Species find themselves in novel environments, within communities assembled from never before encountered mixtures of invasives and natives. The speed with which the biotic and abiotic environment of species has changed has already altered the evolutionary trajectory of species, a trend that promises to escalate. In this article, I reflect upon this altered course of evolution. Human activities have reshaped selection pressures, favouring individuals that better survive in our built landscapes, that avoid our hunting and fishing, and that best tolerate the species that we have introduced. Human altered selection pressures have also modified how organisms live and move through the landscape, and even the nature of reproduction and genome structure. Humans are also shaping selection pressures at the species level, and I discuss how species traits are affecting both extinction and speciation rates in the Anthropocene. PMID- 30429310 TI - Comparative biogeography: innovations and the rise to dominance of the North Pacific biota. AB - The North Pacific is the largest cold-water source of lineages spreading to other modern marine temperate biotas. How this status was achieved remains unclear. One hypothesis is that functional innovations of large effect, defined as departures from the norm in temperate clades and which confer competitive or defensive benefits, increase resource availability, and raise performance standards in the biota as a whole, evolved earlier and more frequently in the North Pacific than elsewhere in the temperate zone. In support of this hypothesis, phylogenetic and fossil evidence reveals 47 temperate marine innovations beginning in the latest Eocene, of which half arose in the North Pacific. Of the 22 innovations of large effect, 13 (39%) evolved in the North Pacific, including basal growth in kelps and bottom-feeding herbivory and durophagy in mammals. Temperate innovations in the Southern Hemisphere and the North Atlantic appeared later and were less consequential. Most other innovations arose in refuges where the risks of predation and competition are low. Among temperate marine biotas, the North Pacific has the highest incidence of unique innovations and the earliest origins of major breakthroughs, five of which spread elsewhere. PMID- 30429311 TI - Insights into the roles of CMK-1 and OGT-1 in interstimulus interval-dependent habituation in Caenorhabditis elegans. AB - Habituation is a ubiquitous form of non-associative learning observed as a decrement in responding to repeated stimulation that cannot be explained by sensory adaptation or motor fatigue. One of the defining characteristics of habituation is its sensitivity to the rate at which training stimuli are presented-animals habituate faster in response to more rapid stimulation. The molecular mechanisms underlying this interstimulus interval (ISI)-dependent characteristic of habituation remain unknown. In this article, we use behavioural neurogenetic and bioinformatic analyses in the nematode Caenorhabiditis elegans to identify the first molecules that modulate habituation in an ISI-dependent manner. We show that the Caenorhabditis elegans orthologues of Ca2+/calmodulin dependent kinases CaMK1/4, CMK-1 and O-linked N-acetylglucosamine (O-GlcNAc) transferase, OGT-1, both function in primary sensory neurons to inhibit habituation at short ISIs and promote it at long ISIs. In addition, both cmk-1 and ogt-1 mutants display a rare mechanosensory hyper-responsive phenotype (i.e. larger mechanosensory responses than wild-type). Overall, our work identifies two conserved genes that function in sensory neurons to modulate habituation in an ISI-dependent manner, providing the first insights into the molecular mechanisms underlying the universally observed phenomenon that habituation has different properties when stimuli are delivered at different rates. PMID- 30429312 TI - Metrics matter: the effect of parasite richness, intensity and prevalence on the evolution of host migration. AB - Parasites have long been thought to influence the evolution of migration, but precisely determining the conditions under which this occurs by quantifying costs of infection remains a challenge. Here we developed a model that demonstrates how the metric used to describe infection (richness/diversity, prevalence or intensity) shapes the prediction of whether migration will evolve. The model shows that predictions based on minimizing richness yield opposite results compared to those based on minimizing prevalence, with migration only selected for when minimizing prevalence. Consistent with these findings, empirical studies that measure parasite diversity typically find that migrants are worse off than residents, while those measuring prevalence or intensity find the opposite. Our own empirical analysis of fish parasite data finds that migrants (of all types) have higher parasite richness than residents, but with no significant difference in either prevalence or intensity. PMID- 30429314 TI - Epithelial Cell Chirality Revealed by Three-Dimensional Spontaneous Rotation. AB - Our understanding of the left-right (LR) asymmetry of embryonic development, in particular the contribution of intrinsic handedness of the cell or cell chirality, is limited due to the confounding systematic and environmental factors during morphogenesis and a ack of physiologically relevant in vitro 3D platforms. Here we report an efficient two-layered biomaterial platform for determining the chirality of individual cells, cell aggregates, and self-organized hollow epithelial spheroids. This bioengineered niche provides a uniform defined axis allowing for cells to rotate spontaneously with a directional bias toward either clockwise or counterclockwise directions. Mechanistic studies reveal an actin dependent, cell-intrinsic property of 3D chirality that can be mediated by actin cross-linking via alpha-actinin-1. Our findings suggest that the gradient of extracellular matrix is an important biophysicochemical cue influencing cell polarity and chirality. Engineered biomaterial systems can serve as an effective platform for studying developmental asymmetry and screening for environmental factors causing birth defects. PMID- 30429316 TI - Grassland fire ecology has roots in the late Miocene. AB - That fire facilitated the late Miocene C4 grassland expansion is widely suspected but poorly documented. Fire potentially tied global climate to this profound biosphere transition by serving as a regional-to-local driver of vegetation change. In modern environments, seasonal extremes in moisture amplify the occurrence of fire, disturbing forest ecosystems to create niche space for flammable grasses, which in turn provide fuel for frequent fires. On the Indian subcontinent, C4 expansion was accompanied by increased seasonal extremes in rainfall (evidenced by delta18Ocarbonate), which set the stage for fuel accumulation and fire-linked clearance during wet-to-dry seasonal transitions. Here, we test the role of fire directly by examining the abundance and distribution patterns of fire-derived polycyclic aromatic hydrocarbons (PAHs) and terrestrial vegetation signatures in n-alkane carbon isotopes from paleosol samples of the Siwalik Group (Pakistan). Two million years before the C4 grassland transition, fire-derived PAH concentrations increased as conifer vegetation declined, as indicated by a decrease in retene. This early increase in molecular fire signatures suggests a transition to more fire-prone vegetation such as a C3 grassland and/or dry deciduous woodland. Between 8.0 and 6.0 million years ago, fire, precipitation seasonality, and C4-grass dominance increased simultaneously (within resolution) as marked by sharp increases in fire-derived PAHs, delta18Ocarbonate, and 13C enrichment in n-alkanes diagnostic of C4 grasses. The strong association of evidence for fire occurrence, vegetation change, and landscape opening indicates that a dynamic fire-grassland feedback system was both a necessary precondition and a driver for grassland ecology during the first emergence of C4 grasslands. PMID- 30429313 TI - Site occupancy calibration of taxane pharmacology in live cells and tissues. AB - Drug receptor site occupancy is a central pharmacology parameter that quantitatively relates the biochemistry of drug binding to the biology of drug action. Taxanes and epothilones bind to overlapping sites in microtubules (MTs) and stabilize them. They are used to treat cancer and are under investigation for neurodegeneration. In cells, they cause concentration-dependent inhibition of MT dynamics and perturbation of mitosis, but the degree of site occupancy required to trigger different effects has not been measured. We report a live cell assay for taxane-site occupancy, and relationships between site occupancy and biological effects across four drugs and two cell lines. By normalizing to site occupancy, we were able to quantitatively compare drug activities and cell sensitivities independent of differences in drug affinity and uptake/efflux kinetics. Across all drugs and cells tested, we found that inhibition of MT dynamics, postmitotic micronucleation, and mitotic arrest required successively higher site occupancy. We also found interesting differences between cells and drugs, for example, insensitivity of the spindle assembly checkpoint to site occupancy. By extending our assay to a mouse xenograft tumor model, we estimated the initial site occupancy required for paclitaxel to completely prevent tumor growth as 80%. The most important cellular action of taxanes for cancer treatment may be formation of micronuclei, which occurs over a broad range of site occupancies. PMID- 30429315 TI - Metabolic programming a lean phenotype by deregulation of RNA polymerase III. AB - As a master negative regulator of RNA polymerase (Pol) III, Maf1 modulates transcription in response to nutrients and stress to balance the production of highly abundant tRNAs, 5S rRNA, and other small noncoding RNAs with cell growth and maintenance. This regulation of Pol III transcription is important for energetic economy as mice lacking Maf1 are lean and resist weight gain on normal and high fat diets. The lean phenotype of Maf1 knockout (KO) mice is attributed in part to metabolic inefficiencies which increase the demand for cellular energy and elevate catabolic processes, including autophagy/lipophagy and lipolysis. A futile RNA cycle involving increased synthesis and turnover of Pol III transcripts has been proposed as an important driver of these changes. Here, using targeted metabolomics, we find changes in the liver of fed and fasted Maf1 KO mice consistent with the function of mammalian Maf1 as a chronic Pol III repressor. Differences in long-chain acylcarnitine levels suggest that energy demand is higher in the fed state of Maf1 KO mice versus the fasted state. Quantitative metabolite profiling supports increased activity in the TCA cycle, the pentose phosphate pathway, and the urea cycle and reveals changes in nucleotide levels and the creatine system. Metabolite profiling also confirms key predictions of the futile RNA cycle hypothesis by identifying changes in many metabolites involved in nucleotide synthesis and turnover. Thus, constitutively high levels of Pol III transcription in Maf1 KO mice reprogram central metabolic pathways and waste metabolic energy through a futile RNA cycle. PMID- 30429318 TI - Intracellular transport is accelerated in early apoptotic cells. AB - Intracellular transport of cellular proteins and organelles is critical for establishing and maintaining intracellular organization and cell physiology. Apoptosis is a process of programmed cell death with dramatic changes in cell morphology and organization, during which signaling molecules are transported between different organelles within the cells. However, how the intracellular transport changes in cells undergoing apoptosis remains unknown. Here, we study the dynamics of intracellular transport by using the single-particle tracking method and find that both directed and diffusive motions of endocytic vesicles are accelerated in early apoptotic cells. With careful elimination of other factors involved in the intracellular transport, the reason for the acceleration is attributed to the elevation of adenosine triphosphate (ATP) concentration. More importantly, we show that the accelerated intracellular transport is critical for apoptosis, and apoptosis is delayed when the dynamics of intracellular transport is regulated back to the normal level. Our results demonstrate the important role of transport dynamics in apoptosis and shed light on the apoptosis mechanism from a physical perspective. PMID- 30429317 TI - Skin as a window to body-clock time. PMID- 30429319 TI - "Fragile" equilibrium between translation and transcription. PMID- 30429320 TI - Indirect reciprocity with private, noisy, and incomplete information. AB - Indirect reciprocity is a mechanism for cooperation based on shared moral systems and individual reputations. It assumes that members of a community routinely observe and assess each other and that they use this information to decide who is good or bad, and who deserves cooperation. When information is transmitted publicly, such that all community members agree on each other's reputation, previous research has highlighted eight crucial moral systems. These "leading eight" strategies can maintain cooperation and resist invasion by defectors. However, in real populations individuals often hold their own private views of others. Once two individuals disagree about their opinion of some third party, they may also see its subsequent actions in a different light. Their opinions may further diverge over time. Herein, we explore indirect reciprocity when information transmission is private and noisy. We find that in the presence of perception errors, most leading-eight strategies cease to be stable. Even if a leading-eight strategy evolves, cooperation rates may drop considerably when errors are common. Our research highlights the role of reliable information and synchronized reputations to maintain stable moral systems. PMID- 30429322 TI - Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice. AB - Obesity is frequently associated with metabolic disease. Here, we show that obesity changes the miRNA profile of plasma exosomes in mice, including increases in miR-122, miR-192, miR-27a-3p, and miR-27b-3p Importantly, treatment of lean mice with exosomes isolated from obese mice induces glucose intolerance and insulin resistance. Moreover, administration of control exosomes transfected with obesity-associated miRNA mimics strongly induces glucose intolerance in lean mice and results in central obesity and hepatic steatosis. Expression of the candidate target gene Ppara is decreased in white adipose tissue but not in the liver of mimic-treated (MIMIC) mice, and this is accompanied by increased circulating free fatty acids and hypertriglyceridemia. Treatment with a specific siRNA targeting Ppara transfected into exosomes recapitulates the phenotype induced by obesity associated miRNAs. Importantly, simultaneously reducing free fatty acid plasma levels in MIMIC mice with either the lipolysis inhibitor acipimox or the PPARalpha agonist fenofibrate partially protects against these metabolic alterations. Overall, our data highlight the central role of obesity-associated exosomal miRNAs in the etiopathogeny of glucose intolerance and dyslipidemia. PMID- 30429321 TI - Microstructural properties of the vertical occipital fasciculus explain the variability in human stereoacuity. AB - Stereopsis is a fundamental visual function that has been studied extensively. However, it is not clear why depth discrimination (stereoacuity) varies more significantly among people than other modalities. Previous studies have reported the involvement of both dorsal and ventral visual areas in stereopsis, implying that not only neural computations in cortical areas but also the anatomical properties of white matter tracts connecting those areas can impact stereopsis. Here, we studied how human stereoacuity relates to white matter properties by combining psychophysics, diffusion MRI (dMRI), and quantitative MRI (qMRI). We performed a psychophysical experiment to measure stereoacuity and, in the same participants, we analyzed the microstructural properties of visual white matter tracts on the basis of two independent measurements, dMRI (fractional anisotropy, FA) and qMRI (macromolecular tissue volume; MTV). Microstructural properties along the right vertical occipital fasciculus (VOF), a major tract connecting dorsal and ventral visual areas, were highly correlated with measures of stereoacuity. This result was consistent for both FA and MTV, suggesting that the behavioral-structural relationship reflects differences in neural tissue density, rather than differences in the morphological configuration of fibers. fMRI confirmed that binocular disparity stimuli activated the dorsal and ventral visual regions near VOF endpoints. No other occipital tracts explained the variance in stereoacuity. In addition, the VOF properties were not associated with differences in performance on a different psychophysical task (contrast detection). These series of experiments suggest that stereoscopic depth discrimination performance is, at least in part, constrained by dorso-ventral communication through the VOF. PMID- 30429323 TI - TRPA1 ankyrin repeat six interacts with a small molecule inhibitor chemotype. AB - TRPA1, a member of the transient receptor potential channel (TRP) family, is genetically linked to pain in humans, and small molecule inhibitors are efficacious in preclinical animal models of inflammatory pain. These findings have driven significant interest in development of selective TRPA1 inhibitors as potential analgesics. The majority of TRPA1 inhibitors characterized to date have been reported to interact with the S5 transmembrane helices forming part of the pore region of the channel. However, the development of many of these inhibitors as clinical drug candidates has been prevented by high lipophilicity, low solubility, and poor pharmacokinetic profiles. Identification of alternate compound interacting sites on TRPA1 provides the opportunity to develop structurally distinct modulators with novel structure-activity relationships and more desirable physiochemical properties. In this paper, we have identified a previously undescribed potent and selective small molecule thiadiazole structural class of TRPA1 inhibitor. Using species ortholog chimeric and mutagenesis strategies, we narrowed down the site of interaction to ankyrinR #6 within the distal N-terminal region of TRPA1. To identify the individual amino acid residues involved, we generated a computational model of the ankyrinR domain. This model was used predictively to identify three critical amino acids in human TRPA1, G238, N249, and K270, which were confirmed by mutagenesis to account for compound activity. These findings establish a small molecule interaction region on TRPA1, expanding potential avenues for developing TRPA1 inhibitor analgesics and for probing the mechanism of channel gating. PMID- 30429325 TI - Parametric amplification of optical phonons. AB - We use coherent midinfrared optical pulses to resonantly excite large-amplitude oscillations of the Si-C stretching mode in silicon carbide. When probing the sample with a second pulse, we observe parametric optical gain at all wavelengths throughout the reststrahlen band. This effect reflects the amplification of light by phonon-mediated four-wave mixing and, by extension, of optical-phonon fluctuations. Density functional theory calculations clarify aspects of the microscopic mechanism for this phenomenon. The high-frequency dielectric permittivity and the phonon oscillator strength depend quadratically on the lattice coordinate; they oscillate at twice the frequency of the optical field and provide a parametric drive for the lattice mode. Parametric gain in phononic four-wave mixing is a generic mechanism that can be extended to all polar modes of solids, as a means to control the kinetics of phase transitions, to amplify many-body interactions or to control phonon-polariton waves. PMID- 30429324 TI - Epstein-Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus. AB - Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi's sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein-Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV+ single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV+/EBV+ PEL cell lines with an EBV-specific CRISPR/Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein-Barr nuclear antigen 1 (EBNA-1) in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression. PMID- 30429327 TI - Episodic organic carbon fluxes from surface ocean to abyssal depths during long term monitoring in NE Pacific. AB - Growing evidence suggests substantial quantities of particulate organic carbon (POC) produced in surface waters reach abyssal depths within days during episodic flux events. A 29-year record of in situ observations was used to examine episodic peaks in POC fluxes and sediment community oxygen consumption (SCOC) at Station M (NE Pacific, 4,000-m depth). From 1989 to 2017, 19% of POC flux at 3,400 m arrived during high-magnitude episodic events (>=mean + 2 sigma), and 43% from 2011 to 2017. From 2011 to 2017, when high-resolution SCOC data were available, time lags between changes in satellite-estimated export flux (EF), POC flux, and SCOC on the sea floor varied between six flux events from 0 to 70 days, suggesting variable remineralization rates and/or particle sinking speeds. Half of POC flux pulse events correlated with prior increases in EF and/or subsequent SCOC increases. Peaks in EF overlying Station M frequently translated to changes in POC flux at abyssal depths. A power-law model (Martin curve) was used to estimate abyssal fluxes from EF and midwater temperature variation. While the background POC flux at 3,400-m depth was described well by the model, the episodic events were significantly underestimated by ~80% and total flux by almost 50%. Quantifying episodic pulses of organic carbon into the deep sea is critical in modeling the depth and intensity of POC sequestration and understanding the global carbon cycle. PMID- 30429326 TI - Genetic variant at coronary artery disease and ischemic stroke locus 1p32.2 regulates endothelial responses to hemodynamics. AB - Biomechanical cues dynamically control major cellular processes, but whether genetic variants actively participate in mechanosensing mechanisms remains unexplored. Vascular homeostasis is tightly regulated by hemodynamics. Exposure to disturbed blood flow at arterial sites of branching and bifurcation causes constitutive activation of vascular endothelium contributing to atherosclerosis, the major cause of coronary artery disease (CAD) and ischemic stroke (IS). Conversely, unidirectional flow promotes quiescent endothelium. Genome-wide association studies (GWAS) have identified chromosome 1p32.2 as strongly associated with CAD/IS; however, the causal mechanism related to this locus remains unknown. Using statistical analyses, assay of transposase accessible chromatin with whole-genome sequencing (ATAC-seq), H3K27ac/H3K4me2 ChIP with whole-genome sequencing (ChIP-seq), and CRISPR interference in human aortic endothelial cells (HAECs), our results demonstrate that rs17114036, a common noncoding polymorphism at 1p32.2, is located in an endothelial enhancer dynamically regulated by hemodynamics. CRISPR-Cas9-based genome editing shows that rs17114036-containing region promotes endothelial quiescence under unidirectional shear stress by regulating phospholipid phosphatase 3 (PLPP3). Chromatin accessibility quantitative trait locus (caQTL) mapping using HAECs from 56 donors, allelic imbalance assay from 7 donors, and luciferase assays demonstrate that CAD/IS-protective allele at rs17114036 in PLPP3 intron 5 confers increased endothelial enhancer activity. ChIP-PCR and luciferase assays show that CAD/IS-protective allele at rs17114036 creates a binding site for transcription factor Kruppel-like factor 2 (KLF2), which increases the enhancer activity under unidirectional flow. These results demonstrate that a human SNP contributes to critical endothelial mechanotransduction mechanisms and suggest that human haplotypes and related cis-regulatory elements provide a previously unappreciated layer of regulatory control in cellular mechanosensing mechanisms. PMID- 30429329 TI - DksA-DnaJ redox interactions provide a signal for the activation of bacterial RNA polymerase. AB - RNA polymerase is the only known protein partner of the transcriptional regulator DksA. Herein, we demonstrate that the chaperone DnaJ establishes direct, redox based interactions with oxidized DksA. Cysteine residues in the zinc finger of DksA become oxidized in Salmonella exposed to low concentrations of hydrogen peroxide (H2O2). The resulting disulfide bonds unfold the globular domain of DksA, signaling high-affinity interaction of the C-terminal alpha-helix to DnaJ. Oxidoreductase and chaperone activities of DnaJ reduce the disulfide bonds of its client and promote productive interactions between DksA and RNA polymerase. Simultaneously, guanosine tetraphosphate (ppGpp), which is synthesized by RelA in response to low concentrations of H2O2, binds at site 2 formed at the interface of DksA and RNA polymerase and synergizes with the DksA/DnaJ redox couple, thus activating the transcription of genes involved in amino acid biosynthesis and transport. However, the high concentrations of ppGpp produced by Salmonella experiencing oxidative stress oppose DksA/DnaJ-dependent transcription. Cumulatively, the interplay of DksA, DnaJ, and ppGpp on RNA polymerase protects Salmonella from the antimicrobial activity of the NADPH phagocyte oxidase. Our research has identified redox-based signaling that activates the transcriptional activity of the RNA polymerase regulator DksA. PMID- 30429328 TI - Histone tails decrease N7-methyl-2'-deoxyguanosine depurination and yield DNA protein cross-links in nucleosome core particles and cells. AB - Monofunctional alkylating agents preferentially react at the N7 position of 2' deoxyguanosine in duplex DNA. Methylated DNA, such as that produced by methyl methanesulfonate (MMS) and temozolomide, exists for days in organisms. The predominant consequence of N7-methyl-2'-deoxyguanosine (MdG) is widely believed to be abasic site (AP) formation via hydrolysis, a process that is slow in free DNA. Examination of MdG reactivity within nucleosome core particles (NCPs) provided two general observations. MdG depurination rate constants are reduced in NCPs compared with when the identical DNA sequence is free in solution. The magnitude of the decrease correlates with proximity to the positively charged histone tails, and experiments in NCPs containing histone variants reveal that positively charged amino acids are responsible for the decreased rate of abasic site formation from MdG. In addition, the lysine-rich histone tails form DNA protein cross-links (DPCs) with MdG. Cross-link formation is reversible and is ascribed to nucleophilic attack at the C8 position of MdG. DPC and retarded abasic site formation are observed in NCPs randomly damaged by MMS, indicating that these are general processes. Histone-MdG cross-links were also detected by mass spectrometry in chromatin isolated from V79 Chinese hamster lung cells treated with MMS. The formation of DPCs following damage by a monofunctional alkylating agent has not been reported previously. These observations reveal the possibility that such DPCs may contribute to the cytotoxicity of monofunctional alkylating agents, such as MMS, N-methyl-N-nitrosourea, and temozolomide. PMID- 30429330 TI - Dynamic interactions of type I cohesin modules fine-tune the structure of the cellulosome of Clostridium thermocellum. AB - Efficient degradation of plant cell walls by selected anaerobic bacteria is performed by large extracellular multienzyme complexes termed cellulosomes. The spatial arrangement within the cellulosome is organized by a protein called scaffoldin, which recruits the cellulolytic subunits through interactions between cohesin modules on the scaffoldin and dockerin modules on the enzymes. Although many structural studies of the individual components of cellulosomal scaffoldins have been performed, the role of interactions between individual cohesin modules and the flexible linker regions between them are still not entirely understood. Here, we report single-molecule measurements using FRET to study the conformational dynamics of a bimodular cohesin segment of the scaffoldin protein CipA of Clostridium thermocellum We observe compacted structures in solution that persist on the timescale of milliseconds. The compacted conformation is found to be in dynamic equilibrium with an extended state that shows distance fluctuations on the microsecond timescale. Shortening of the intercohesin linker does not destabilize the interactions but reduces the rate of contact formation. Upon addition of dockerin-containing enzymes, an extension of the flexible state is observed, but the cohesin-cohesin interactions persist. Using all-atom molecular dynamics simulations of the system, we further identify possible intercohesin binding modes. Beyond the view of scaffoldin as "beads on a string," we propose that cohesin-cohesin interactions are an important factor for the precise spatial arrangement of the enzymatic subunits in the cellulosome that leads to the high catalytic synergy in these assemblies and should be considered when designing cellulosomes for industrial applications. PMID- 30429331 TI - Aberrant IP3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29. AB - Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital ataxia characterized by early-onset motor delay, hypotonia, and gait ataxia. Recently, heterozygous missense mutations in an intracellular Ca2+ channel, inositol 1,4,5 trisphosphate (IP3) receptor type 1 (IP3R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mutations affect IP3R1 activity and Ca2+ dynamics. Ca2+ imaging using IP3R-null HeLa cells generated by genome editing revealed that all SCA29 mutations identified within or near the IP3-binding domain of IP3R1 completely abolished channel activity. Among these mutations, R241K, T267M, T267R, R269G, R269W, S277I, K279E, A280D, and E497K impaired IP3 binding to IP3R1, whereas the T579I and N587D mutations disrupted channel activity without affecting IP3 binding, suggesting that T579I and N587D compromise channel gating mechanisms. Carbonic anhydrase-related protein VIII (CA8) is an IP3R1-regulating protein abundantly expressed in cerebellar Purkinje cells and is a causative gene of congenital ataxia. The SCA29 mutation V1538M within the CA8-binding site of IP3R1 completely eliminated its interaction with CA8 and CA8-mediated IP3R1 inhibition. Furthermore, pathological mutations in CA8 decreased CA8-mediated suppression of IP3R1 by reducing protein stability and the interaction with IP3R1. These results demonstrated the mechanisms by which pathological mutations cause IP3R1 dysfunction, i.e., the disruption of IP3 binding, IP3-mediated gating, and regulation via the IP3R modulatory protein. The resulting aberrant Ca2+ homeostasis may contribute to the pathogenesis of cerebellar ataxia. PMID- 30429333 TI - Mechanism of selective benzene hydroxylation catalyzed by iron-containing zeolites. AB - A direct, catalytic conversion of benzene to phenol would have wide-reaching economic impacts. Fe zeolites exhibit a remarkable combination of high activity and selectivity in this conversion, leading to their past implementation at the pilot plant level. There were, however, issues related to catalyst deactivation for this process. Mechanistic insight could resolve these issues, and also provide a blueprint for achieving high performance in selective oxidation catalysis. Recently, we demonstrated that the active site of selective hydrocarbon oxidation in Fe zeolites, named alpha-O, is an unusually reactive Fe(IV)=O species. Here, we apply advanced spectroscopic techniques to determine that the reaction of this Fe(IV)=O intermediate with benzene in fact regenerates the reduced Fe(II) active site, enabling catalytic turnover. At the same time, a small fraction of Fe(III)-phenolate poisoned active sites form, defining a mechanism for catalyst deactivation. Density-functional theory calculations provide further insight into the experimentally defined mechanism. The extreme reactivity of alpha-O significantly tunes down (eliminates) the rate-limiting barrier for aromatic hydroxylation, leading to a diffusion-limited reaction coordinate. This favors hydroxylation of the rapidly diffusing benzene substrate over the slowly diffusing (but more reactive) oxygenated product, thereby enhancing selectivity. This defines a mechanism to simultaneously attain high activity (conversion) and selectivity, enabling the efficient oxidative upgrading of inert hydrocarbon substrates. PMID- 30429334 TI - The Autographa californica multiple nucleopolyhedrovirus ac51 gene is required for efficient nuclear egress of nucleocapsids and is essential for in vivo virulence. AB - Alphabaculoviruses are lepidopteran-specific nucleopolyhedroviruses that replicate within the nucleus; however, the anterograde transport of the nucleocapsids of these viruses, which is an obligatory step for progeny virion production, is not well understood. In the present study, a unique Alphabaculovirus gene with unknown function, namely, the Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac51 gene, was found to be required for efficient nuclear egress of AcMNPV nucleocapsids. Our results indicate that ac51 is a late gene, and Ac51 protein was detectable from 24 to 72 h postinfection using an antibody raised against Ac51. Ac51 is distributed in both the cytoplasm and nuclei of infected cells. Upon ac51 deletion, budded virion (BV) production by 96 h posttransfection was reduced by approximately 1,000-fold compared with that of wild-type AcMNPV. Neither viral DNA synthesis nor viral gene expression was affected. Ac51 was demonstrated to be a nucleocapsid protein of BVs, and ac51 deletion did not interrupt nucleocapsid assembly and ODV formation. However, BV production in the supernatants of transfected cells during a viral life cycle was substantially decreased when ac51 was deleted. Further analysis showed that compared with wild-type AcMNPV, ac51 deletion decreased nucleocapsid egress, while the numbers of nucleocapsids in the nuclei were comparable. Deletion of ac51 also eliminated the virulence of AcMNPV in vivo Taken together, our results support the conclusion that ac51 plays an important role in the nuclear egress of nucleocapsids during BV formation and is essential for the in vivo virulence of AcMNPV.IMPORTANCE Little is known about the mechanism underlying the nuclear egress of baculovirus nucleocapsids. In particular, the mechanism by which nucleocapsids of alphabaculoviruses efficiently egress from the nucleus to produce high levels of BVs in cultured cells is not known. Some genes that are conserved in all baculoviruses have been identified as essential for not only the nuclear egress of nucleocapsids but also ODV formation. In this study, we show that ac51, a unique Alphabaculovirus gene, encodes a nucleocapsid protein of BVs and is required for high levels of BV production. Deletion of this gene impaired efficient nuclear egress of nucleocapsids but not nucleocapsid assembly or ODV formation, which is similar to the phenotype observed for ac141 or ac66 deletion. This result indicated that Ac51 is the third nucleocapsid protein that promotes the nuclear egress of nucleocapsids by a common pathway with Ac141 and Ac66. PMID- 30429332 TI - Global impacts of chromosomal imbalance on gene expression in Arabidopsis and other taxa. AB - Changes in dosage of part of the genome (aneuploidy) have long been known to produce much more severe phenotypic consequences than changes in the number of whole genomes (ploidy). To examine the basis of these differences, global gene expression in mature leaf tissue for all five trisomies and in diploids, triploids, and tetraploids of Arabidopsis thaliana was studied. The trisomies displayed a greater spread of expression modulation than the ploidy series. In general, expression of genes on the varied chromosome ranged from compensation to dosage effect, whereas genes from the remainder of the genome ranged from no effect to reduced expression approaching the inverse level of chromosomal imbalance (2/3). Genome-wide DNA methylation was examined in each genotype and found to shift most prominently with trisomy 4 but otherwise exhibited little change, indicating that genetic imbalance is generally mechanistically unrelated to DNA methylation. Independent analysis of gene functional classes demonstrated that ribosomal, proteasomal, and gene body methylated genes were less modulated compared with all classes of genes, whereas transcription factors, signal transduction components, and organelle-targeted protein genes were more tightly inversely affected. Comparing transcription factors and their targets in the trisomies and in expression networks revealed considerable discordance, illustrating that altered regulatory stoichiometry is a major contributor to genetic imbalance. Reanalysis of published data on gene expression in disomic yeast and trisomic mouse cells detected similar stoichiometric effects across broad phylogenetic taxa, and indicated that these effects reflect normal gene regulatory processes. PMID- 30429335 TI - The endosomal Toll-like receptors 7 and 9 cooperate in detection of MHV68 infection. AB - Murine gammaherpesvirus 68 (MHV68) is an amenable small animal model for study of the human pathogens Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. Here, we have characterized the roles of the endosomal TLR escort protein UNC93B, endosomal TLR7, 9, and 13, and cell surface TLR2 in MHV68 detection. We found that the interferon alpha (IFNalpha) response of plasmacytoid dendritic cells (pDC) to MHV68 was reduced in Tlr9-/- cells compared to wildtype (WT), but not completely lost. Tlr7-/- pDC responded similarly to WT. However, we found that in Unc93b-/- pDC, as well as in Tlr7/Tlr9-/- double knockout pDC, the IFNalpha response to MHV68 was completely abolished. Thus, the only pattern recognition receptors contributing to the IFNalpha response to MHV68 in pDC are TLR7 and TLR9, but the contribution of TLR7 is masked by the presence of TLR9. To address the role of UNC93B and TLR for MHV68 infection in vivo, we infected mice with MHV68. Lytic replication of MHV68 after intravenous infection was enhanced in the lungs, spleen, and liver of UNC93B-deficient mice, in the spleen of TLR9 deficient mice, and in the liver and spleen of Tlr7/Tlr9-/- mice. The absence of TLR2 or TLR13 did not affect lytic viral titers. We then compared reactivation of MHV68 from latently infected WT, Unc93b-/- , Tlr7/Tlr9-/- , Tlr7-/-, and Tlr9-/- splenocytes. We observed enhanced reactivation and latent viral loads, particularly from Tlr7/Tlr9-/- splenocytes, compared to WT. Our data show that UNC93B-dependent TLR7 and TLR9 cooperate in and contribute to detection and control of MHV68 infection.IMPORTANCE STATEMENT The two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), can cause aggressive forms of cancer. These herpesviruses are strictly host specific and therefore their murine homolog murid gammaherpesvirus 4 strain 68 (MHV68) is a widely used model to obtain in vivo insights into the interaction between these two gammaherpesviruses and their host. Like EBV and KSHV, MHV68 establishes lifelong latency in B cells. The innate immune system serves as one of the first lines of host defense, with pattern recognition receptors such as the Toll-like receptors playing a crucial role in mounting a potent antiviral immune response to various pathogens. Here we shed light on a yet unanticipated role of Toll-like receptor 7 in the recognition of MHV68 in a subset of immune cells called plasmacytoid dendritic cells, as well as the control of this virus in its host. PMID- 30429337 TI - Cellular zinc finger protein 622 hinders human adenovirus lytic growth and limits binding of the viral pVII protein to virus DNA. AB - Human adenovirus (HAdV) encodes a multifunctional DNA-binding protein pVII, which is involved in virus DNA packaging and extracellular immune signaling regulation. Although the pVII is an essential viral protein, its exact role in the virus life cycle and interplay with cellular proteins have remained to a large extent unclear. We have recently identified the cellular zinc finger protein 622 (ZNF622) as a potential pVII-interacting protein. In this study, we describe the functional consequences of the ZNF622-pVII interplay and the role of ZNF622 in the HAdV life cycle. ZNF622 protein expression increased and it accumulated similarly to the pVII protein in the nucleus of virus-infected cells. Lack of the ZNF622 protein specifically increased pVII binding to viral DNA in the infected cells and elevated the pVII protein levels in the purified virions. In addition, ZNF622 knock out cells showed an increased cell lysis and enhanced accumulation of the infectious virus particles. Protein interaction studies revealed that ZNF622 forms a trimeric complex with the pVII protein and the cellular histone chaperon protein nucleophosmin 1 (NPM1). The integrity of this complex is important since ZNF622 mutations and NPM1 deficiency changed pVII ability to bind viral DNA. Collectively, our results implicate that ZNF622 may act as a cellular anti-viral protein hindering lytic HAdV growth and limiting pVII protein binding to viral DNA.IMPORTANCE Human adenoviruses (HAdVs) are common human pathogens causing a wide range of acute infections. To counteract viral pathogenicity, cells encode a variety of anti-viral proteins and non-coding RNAs to block virus growth. In this study, we show that the cellular zinc finger protein 622 (ZNF622) interacts with an essential HAdV protein known as pVII. This mutual interaction limits pVII binding to viral DNA. Further, ZNF622 has a role in HAdV life cycle since the lack of ZNF622 correlates with increased lysis of the infected cells and accumulation of the infectious virions. Together, our study reveals a novel cellular anti-viral protein ZNF622, which may impede lytic HAdV growth. PMID- 30429336 TI - RNA sequencing of the in vivo human herpesvirus 6B transcriptome to identify targets for clinical assays distinguishing between latent and active infections. AB - Human herpesvirus 6B (HHV-6B) DNA is frequently detected in human samples. Diagnostic assays distinguishing HHV-6B reactivation from latency are limited. This has impaired strategies to diagnose and treat HHV-6B-associated diseases. We used RNA sequencing to characterize and compare the HHV-6B transcriptome in multiple sample types, including 1) whole blood from hematopoietic cell transplant (HCT) recipients with and without HHV-6B plasma viremia; 2) tumor tissue samples from subjects with large B cell lymphoma infected with HHV-6B; 3) lymphoblastoid cell lines (LCLs) from subjects with inherited chromosomally integrated HHV-6B or latent infection with HHV-6B; and 4) HHV-6B Z29 infected SupT1 CD4+ T cells. We demonstrated substantial overlap in the HHV-6B transcriptome observed in in vivo and in vitro samples, although there was variability in the breadth and quantity of gene expression across samples. The HHV-6B viral polymerase gene U38 was the only HHV-6B transcript detected in all RNA-seq data sets and was one of the most highly expressed genes. We developed a novel reverse transcription PCR assay targeting HHV-6B U38, which identified U38 messenger RNA in all tested whole blood samples from patients with concurrent HHV 6B viremia. No HHV-6B U38 transcripts were detected by RNA-seq or RT-qPCR in whole blood samples from subjects without HHV-6B plasma detection or from latently infected LCLs. A RT-qPCR assay for HHV-6B U38 may be useful to identify lytic HHV-6B infection in non-plasma samples and samples from individuals with inherited chromosomally integrated HHV-6B. This study also demonstrates the feasibility of transcriptomic analyses in HCT recipients.IMPORTANCE Human herpesvirus 6B (HHV-6B) is a DNA virus that infects most children within the first few years of life. After primary infection, HHV-6B persists as a chronic, latent infection in many cell types. Additionally, HHV-6B can integrate into germline chromosomes, resulting in individuals with viral DNA in every nucleated cell. Given that PCR to detect viral DNA is the mainstay for diagnosing HHV-6B infection, the characteristics of HHV-6B infection complicate efforts to distinguish between latent and active viral infection, particularly in immunocompromised patients who have frequent HHV-6B reactivation. In this study, we used RNA sequencing to characterize the HHV-6B gene expression profile in multiple sample types, and our findings identified evidence-based targets for diagnostic tests that distinguish between latent and active viral infection. PMID- 30429338 TI - A measles virus-based vaccine candidate mediates protection against Zika virus in an allogenic mouse pregnancy model. AB - The impact of the Zika virus (ZIKV) epidemic highlights the need for vaccines that reduce or prevent infection and reliably prevent teratogenic complications. The live-attenuated measles virus (MV) vaccine strains are a promising vaccine platform since they induce robust humoral and cellular immune responses against additional antigens and have an excellent safety record. To explore its potential to protect against ZIKV, we compared a recombinant Schwarz strain MV that encodes ZIKV prM and soluble E proteins (MV-Zika-sE) with a prototypic alum-adjuvanted whole-inactivated ZIKV particle vaccine. Analysis of MV-Zika-sE-infected cells confirmed antigen expression, and the virus replicated with vaccine strain characteristics. Immunized IFNAR-/--CD46Ge mice developed E protein-specific and neutralizing antibodies, and ZIKV E-specific cellular immune responses were observed by IFN-gamma ELISpot and in vitro T cell proliferation assays. To analyze protective efficacy, vaccinated female mice were challenged with ZIKV after allogenic mating. In MV-Zika-sE-vaccinated mice, weight gain was similar to uninfected mice, while no plasma viremia was detectable in the majority of the animals. In contrast, infected control animals gained less weight and experienced about 100-fold higher viremia over at least 3 days. Moreover, vaccination with MV Zika-sE reduced ZIKV load in different organs, the placentas, and prevented infection of the fetus. Consequently, no fetal growth retardation, anemia, and death due to ZIKV infection were seen in MV-Zika-sE-vaccinated dams. In contrast, the inactivated ZIKV vaccine had little to no effect in our studies. Therefore, the MV-derived ZIKV vaccine is a promising candidate for further preclinical and clinical development.IMPORTANCE Zika virus (ZIKV) is a mosquito-borne flavivirus, which causes a variety of neurological complications, including congenital birth defects. Despite the urgent need, no ZIKV vaccine is licensed yet. Recombinant vaccine strain-derived measles viruses (MV) constitute a promising vector platform to induce immunity against foreign pathogens by expressing antigens from additional transcription units, while at the same time possessing a remarkable safety profile. This concept has already been validated against different pathogens including at least 3 other flaviviruses, and our data illustrate that vaccination with the MV expressing soluble ZIKV E protein significantly diminishes infection and prevents fetal loss or damage in an allogenic mouse pregnancy model. It can thus be regarded as a promising emergency vaccine candidate with the potential for inclusion in routine vaccination settings in endemic areas to prevent teratogenic effects of circulating ZIKV during pregnancy, comparable to standard rubella vaccination. PMID- 30429339 TI - An HIV-1 broadly neutralizing antibody from a clade C infected pediatric elite neutralizer potently neutralizes the contemporaneous and autologous evolving viruses. AB - Broadly neutralizing antibodies (bNAbs) have demonstrated protective effects against HIV-1 in primate studies and recent human clinical trials. Elite neutralizers are potential candidates for isolation of HIV-1 bNAbs. The coexistence of bNAbs such as BG18 with neutralization susceptible autologous viruses in an HIV-1 infected adult elite controller has been suggested to control viremia. Disease progression is faster in HIV-1 infected children than adults. Plasma bNAbs with multiple epitope specificities are developed in HIV-1 chronically infected children with more potency and breadth than in adults. Therefore, we evaluated the specificity of plasma neutralizing antibodies of an antiretroviral naive HIV-1 clade C chronically infected pediatric elite neutralizer AIIMS_330. The plasma antibodies showed broad and potent HIV-1 neutralizing activity with >87% (29/33) breadth, median inhibitory dilution (ID50) value of 1246 and presence of N160 and N332-supersite dependent HIV-1 bNAbs. The sorting of BG505.SOSIP.664.C2 T332N gp140 HIV-1 antigen-specific single B cells of AIIMS_330 resulted in the isolation of an HIV-1 N332-supersite dependent bNAb AIIMS-P01. The AIIMS-P01 neutralized 67% of HIV-1 cross-clade viruses; exhibited substantial indels despite limited somatic hypermutations; interacted with native-like HIV-1 trimer as observed in negative stain electron microscopy and demonstrated high binding affinity. In addition, AIIMS-P01 neutralized the coexisting and evolving autologous viruses suggesting the coexistence of vulnerable autologous viruses and HIV-1 bNAbs in AIIMS_330 pediatric elite neutralizer. Such pediatric elite-neutralizers can serve as potential candidates for isolation of novel HIV-1 pediatric bNAbs and for understanding the coevolution of virus and host immune response.ImportanceMore than 50% of the HIV-1 infections globally are caused by clade C viruses. Till date, there is no effective vaccine to prevent HIV-1 infection. Based on the structural information of the currently available HIV-1 bNAbs, attempts are underway to design immunogens that can elicit correlates of protection upon vaccination. Here we report the isolation and characterization of an HIV-1 N332 supersite dependent bNAb AIIMS-P01 from a clade C chronically infected pediatric elite neutralizer. The N332-supersite is an important epitope and is one of the current HIV-1 vaccine targets. AIIMS-P01 potently neutralized the contemporaneous and autologous evolving viruses and exhibits substantial indels despite low somatic hypermutations. Taken together with the information on infant bNAbs, further isolation and characterization of bNAbs contributing to the plasma breadth in HIV-1 chronically infected children may help to better understand their role in controlling HIV-1 infection. PMID- 30429341 TI - Recessive host range mutants and unsusceptible cells that inactivate virions without genome penetration: ecological and technical implications. AB - Although microviruses do not possess a visible tail structure, one vertex rearranges after interacting with host lipopolysaccharides. Most examinations of host range, eclipse, and penetration were conducted before this "host-induced" unique vertex was discovered and before DNA sequencing became routine. Consequently, structure-function relationships dictating host range remain undefined. Biochemical and genetic analyses were conducted with two closely related microviruses, alpha3 and ST-1. Despite ~90% amino acid identity, the natural host of alpha3 is E. coli C; whereas ST-1 is a K12-specific phage. Virions attached and eclipsed to both native and unsusceptible hosts; however, they breached only the native host's cell wall. This suggests that unsusceptible host-phage interactions promote off-pathway reactions that can inactivate viruses without penetration. This phenomenon may have broader ecological implications. To determine which structural proteins conferred host range specificity, chimeric virions were generated by individually interchanging the coat, spike, or DNA pilot proteins. Interchanging the coat protein switched host range. However, host range expansion could be conferred by single point mutations in the coat protein. The expansion phenotype was recessive: genetically mutant progeny from co infected cells did not display the phenotype. Thus, mutant isolation required populations generated in low MOI environments: a phenomenon that may have impacted past host range studies in both prokaryotic and eukaryotic systems. The resulting genetic and structural data were consistent enough that host range expansion could be predicted, broadening the classical definition of antireceptors to include interfaces between protein complexes within the capsid.ImportanceTo expand host range, viruses must interact with unsusceptible host cell surfaces, which could be detrimental. As observed in this study, virions were inactivated without genome penetration. This may be advantageous to potential new hosts; culling the viral population from which an expanded host range mutant could emerge. When identified, altered host range mutations were recessive. Accordingly, isolation required populations generated in low MOI environments. However, in laboratory settings, viral propagation includes high MOI conditions. Typically, infected cultures incubate until all cells produce progeny. Thus, coinfections dominate later replication cycles, masking recessive host range expansion phenotypes. This may have impacted similar studies with other viruses. Lastly, structural and genetic data could be used to predict site directed mutant phenotypes, which may broaden the classic antireceptor definition to include interfaces between capsid complexes. PMID- 30429340 TI - Replication-competent NYVAC-KC yields improved immunogenicity to HIV-1 antigens in rhesus macaques, compared to non-replicating NYVAC. AB - As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 Phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain, NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here we report a side-by-side comparison of replication restricted NYVAC and replication-competent NYVAC-KC in a non-human primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC C-KC express the HIV-1 antigens gp140 and Gag/Gag-Pol-Nef-derived VLPs from clade C and were used as the prime, with recombinant virus plus envelope protein as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than did NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.ImportanceThough the RV144 Phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in non-human primates an attenuated, but replication competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication-restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate. PMID- 30429342 TI - Ubiquitination is essential for avibirnavirus replication by supporting VP1 Polymerase activity. AB - Ubiquitination is critical for several cellular physical processes. However, ubiquitin modification in virus replication is poorly understood. Therefore, the present study aimed to determine the presence and effect of ubiquitination on polymerase activity of viral protein 1 (VP1) of avibirnavirus. We reported that the replication of avibirnavirus is regulated by ubiquitination of its VP1 protein, the RNA-dependent RNA polymerase of infectious bursal disease virus (IBDV). In vivo detection revealed the ubiquitination of VP1 protein in IBDV infected target organs and different cells, but not in purified IBDV particles. Further analysis of ubiquitination confirms that VP1 is modified by K63-linked ubiquitin chain. Point mutation screening showed that the ubiquitination site of VP1 was at the K751 residue in the C-terminus. The K751 ubiquitination is independent of VP1's interaction with VP3 and eukaryotic initiation factor-4A II. Polymerase activity assays indicated that the K751 ubiquitination at the C terminus of VP1 enhanced its polymerase activity. The K751 to R mutation of VP1 protein did not block the rescueing of IBDV, but decreased the replication ability of IBDV. Our data demonstrated that the ubiquitination of VP1 is crucial to regulate its polymerase activity and IBDV replication.IMPORTANCEAvibirnavirus protein VP1, the RNA-dependent RNA polymerase, is responsible for IBDV genome replication, gene expression and assembly. However, little is known about its chemical modification relating to its polymerase activity. In this study, we revealed the molecular mechanism of ubiquitin modification of VP1 via a K63 linked ubiquitin chain during infection. Lysine (K) residue 751 at the C-terminus of VP1 is the target site for ubiquitin and its ubiquitination is independent of VP1's interaction with VP3 and eukaryotic initiation factor-4A II. The K751 ubiquitination promotes the polymerase activity of VP1 and unubiquitinated VP1 mutant IBDV significantly impairs virus replication. We concluded that VP1 is the ubiquitin-modified protein and revealed the mechanism by which VP1 promotes avibirnavirus replication. PMID- 30429343 TI - Priming with a potent HIV-1 DNA vaccine frames the quality of immune responses prior to a poxvirus and protein boost. AB - The use of heterologous immunization regimens and improved vector systems has led to increases in immunogenicity of HIV-1 vaccine candidates in non-human primates. In order to resolve interrelations between different delivery modalities, three different poxvirus boost regimens were compared. Three groups of rhesus macaques were each primed with the same DNA vaccine encoding for Gag, PolNef, and gp140. The groups were then boosted either with the vaccinia virus strain NYVAC or a variant with improved replication competence in human cells termed NYVAC-KC. The latter was either administered by scarification or intramuscularly. Finally, macaques were boosted with adjuvanted gp120 protein to enhance humoral responses. The regimen elicited very potent CD4+ and CD8+ T cell responses in a well balanced manner, peaking two weeks after the boost. T cells were broadly reactive and polyfunctional. All animals exhibited antigen-specific humoral responses already after the poxvirus boost that further increased following protein administration. Polyclonal reactivity of IgG antibodies was highest against HIV-1 clade C Env-proteins with considerable cross-reactivity to other clades. Substantial effector functional activities (ADCC and ADCVI) were observed in sera obtained after the last protein boost. Notably, major differences between the groups were absent, indicating that the potent priming induced by the DNA vaccine initially framed the immune responses in such a way that the subsequent boosts with NYVAC and protein only led to an increase in the response magnitudes without skewing the quality. This study highlights the importance of selecting the best combination of vector systems in heterologous prime-boost vaccination regimens.ImportanceThe evaluation of HIV vaccine efficacy trials indicates that protection would most likely correlate with a polyfunctional immune response involving several effector functions from all arms of the immune system. Heterologous prime-boost regimens have been shown to elicit vigorous T cell and antibody responses in non-human primates that, however, qualitatively and quantitatively differ depending on the respective vector systems used. The present study evaluated a DNA prime, poxvirus and protein boost regimen, and compared how two poxvirus vectors with varying degrees of replication capacity and two different delivery modalities - conventional intramuscular delivery and percutaneous delivery by scarification - impact several immune effectors. It was found that despite the different poxvirus boosts, the overall immune responses in the three groups were similar, suggesting the potent DNA priming as the major determining factor of immune responses. These findings emphasize the importance of selecting optimal priming agents in heterologous prime-boost vaccination settings. PMID- 30429344 TI - Two families of Env antibodies efficiently engage Fc-gamma receptors and eliminate HIV-1-infected cells. AB - HIV-1 conceals epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies (Abs), including anti-co-receptor binding site (CoRBS) and anti cluster A, preferentially recognize Env in its "open" conformation. The binding of anti-CoRBS Abs has been shown to induce conformational changes that further opens Env allowing interaction of anti-cluster A antibodies. We explored the possibility that CoRBS Abs synergize with anti-cluster A Abs to engage Fc-gamma receptors to mediate ADCC. We found that binding of anti-CoRBS and anti-cluster A Abs to the same gp120 is required for interaction with soluble dimeric FcgammaRIIIa in ELISA assays. We also show that Fc regions of both Abs are required to optimally engage FcgammaRIIIa and mediate robust ADCC. Altogether, our results indicate that these two families of Abs act together in a sequential and synergistic fashion to promote FcgammaRIIIa engagement and ADCC.IMPORTANCE The "open" CD4-bound conformation of HIV-1 envelope glycoproteins is the primary target of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies present in HIV+ sera, such as anti-co-receptor binding site and anti-cluster A antibodies. Here we report that the binding of these two families of antibodies is required to engage FcgammaRIIIa and mediate ADCC. PMID- 30429345 TI - Conformational Differences Between Functional Human Immunodeficiency Virus (HIV 1) Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. AB - Binding to the receptor, CD4, triggers entry-related conformational changes in the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120/gp41)3). Soluble versions of HIV-1 Env trimers (sgp140 SOSIP.664) stabilized by a gp120-gp41 disulfide bond and a change (I559P) in gp41 have been structurally characterized. Here we use crosslinking/mass spectrometry to evaluate the conformations of functional membrane Env and sgp140 SOSIP.664. Differences were detected in the gp120 trimer association domain and C-terminus and in the gp41 heptad repeat (HR1) region. Whereas the membrane Env trimer exposes the gp41 HR1 coiled coil only after CD4 binding, the sgp140 SOSIP.664 HR1 coiled coil was accessible to the gp41 HR2 peptide even in the absence of CD4. Our results delineate differences in both gp120 and gp41 subunits between functional membrane Env and the sgp140 SOSIP.664 trimer, and provide distance constraints that can assist validation of candidate structural models of the native HIV-1 Env trimer.IMPORTANCE The human immunodeficiency virus (HIV-1) envelope glycoprotein spikes mediate the entry of the virus into host cells and are a major target for vaccine-induced antibodies. Soluble forms of the envelope glycoproteins that are stable and easily produced have been characterized extensively and are being considered as vaccines. Here we present evidence that these stabilized soluble envelope glycoproteins differ in multiple respects from the natural HIV-1 envelope glycoproteins. By pinpointing these differences, our results can guide the improvement of envelope glycoprotein preparations to achieve greater similarity to the viral envelope glycoprotein spike, potentially increasing their effectiveness as a vaccine. PMID- 30429346 TI - The Dietary Restriction-Like (drl-1) Gene, a Putative Serine/Threonine Kinase, is Essential for Orsay Virus Infection in Caenorhabditis elegans. AB - Orsay virus is the only known natural virus pathogen of Caenorhabditis elegans, and its discovery has enabled virus-host interactions studies in this model organism. Host genes required for viral infection remain understudied. We previously established a forward genetic screen based on a virus-inducible GFP transcriptional reporter to identify novel host factors essential for virus infection. Here we report the essential role in Orsay virus infection of the Dietary Restriction-Like (drl-1) gene, which encodes a serine/threonine kinase similar to the mammalian MEKK3 kinase. Ablation of drl-1 led to a >10,000-fold reduction in Orsay virus RNA levels, which could be rescued by ectopic expression of DRL-1. DRL-1 was dispensable for Orsay replication from an endogenous transgene replicon, suggesting that DRL-1 affects a pre-replication stage of the Orsay life cycle. Thus, this study demonstrates the power of C. elegans as a model to identify novel virus-host interactions essential for virus infection.IMPORTANCE The recent discovery of Orsay virus, the only known natural virus of Caenorhabditis elegans, provides a unique opportunity to study virus host interactions that mediate infection in a genetically tractable multicellular model organism. As viruses remain a global threat to human health, better insights into cellular components that enable virus infection and replication can ultimately lead to the development of new targets for antiviral therapeutics. PMID- 30429347 TI - Tetherin inhibits Nipah virus but not Ebola virus replication in fruit bat cells. AB - Ebola virus (EBOV) and Nipah virus (NiV) infection of humans can cause fatal disease and constitutes a public health threat. In contrast, EBOV and NiV infection of fruit bats, the putative (EBOV) or proven (NiV) natural reservoir, is not associated with disease and it is currently unknown how these animals control the virus. The human interferon (IFN)-stimulated antiviral effector protein tetherin (CD317, BST-2) blocks release of EBOV- and NiV-like particles from cells and is counteracted by the EBOV glycoprotein (GP). In contrast, it is unknown whether fruit bat tetherin restricts virus infection and is susceptible to GP-driven antagonism. Here, we report the sequence of fruit bat tetherin and show that its expression is IFN-stimulated and associated with strong antiviral activity. Moreover, we demonstrate that EBOV-GP antagonizes tetherin orthologues of diverse species but fails to efficiently counteract fruit bat tetherin in virus-like particle (VLP) release assays. However, unexpectedly, tetherin was dispensable for robust IFN-mediated inhibition of EBOV spread in fruit bat cells. Thus, the VLP-based model system mimicking tetherin-mediated inhibition of EBOV release and its counteraction by GP seems not to adequately reflect all aspects of EBOV release from IFN-stimulated fruit bat cells, potentially due to differences in tetherin expression levels that could not be resolved by the present study. In contrast, tetherin expression was essential for IFN-dependent inhibition of NiV infection, demonstrating that IFN-induced fruit bat tetherin exerts antiviral activity and may critically contribute to control of NiV and potentially other highly virulent viruses in infected animals.IMPORTANCE Ebola virus and Nipah virus (EBOV, NiV) can cause fatal disease in humans. In contrast, infected fruit bats do not develop symptoms but can transmit the virus to humans. Why fruit bats but not humans control infection is largely unknown. Tetherin is an antiviral host cell protein and is counteracted by the EBOV glycoprotein in human cells. Here, employing model systems, we show that tetherin of fruit bats displays higher antiviral activity than human tetherin and is largely resistant against counteraction by the Ebola virus glycoprotein. Moreover, we demonstrate that induction of tetherin expression is critical for interferon-mediated inhibition of NiV but, for at present unknown reasons, not EBOV spread in fruit bat cells. Collectively, our findings identify tetherin as an antiviral effector of innate immune responses in fruit bats, which might allow these animals to control infection with NiV and potentially other viruses that cause severe disease in humans. PMID- 30429348 TI - Chikungunya virus fidelity variants exhibit differential attenuation and population diversity in cell culture and adult mice. AB - Chikungunya virus (CHIKV) is a re-emerging global health threat that produces debilitating arthritis in people. Like other RNA viruses with high mutation rates, CHIKV produces populations of genetically diverse genomes within a host. While several known CHIKV mutations influence disease severity in vertebrates and transmission by mosquitoes, the role of intrahost diversity in chikungunya arthritic disease is not studied. In this study, high and low fidelity CHIKV variants, previously characterized by altered in vitro population mutation frequencies, were used to evaluate how intrahost diversity influences clinical disease, CHIKV replication, and antibody neutralization in immunocompetent adult mice inoculated in the rear footpads. Both high and low fidelity mutations were hypothesized to attenuate CHIKV arthritic disease, replication, and neutralizing antibody levels compared to wildtype (WT) CHIKV. Unexpectedly, high fidelity mutants elicited more severe arthritic disease than WT despite comparable CHIKV replication, whereas a low fidelity mutant produces attenuated disease and replication. Serum antibody developed against both high and low fidelity CHIKV exhibited reduced neutralization of WT CHIKV. Using next-generation sequencing (NGS), the high fidelity mutations were demonstrated to be genetically stable, but produce more genetically diverse populations than WT CHIKV in mice. This enhanced diversification was subsequently reproduced after serial in vitro passage. The NGS results contrast with previously reported population diversities for fidelity variants, which focused mainly on part of the E1 gene, and highlight the need for direct measurements of mutation rates to clarify CHIKV fidelity phenotypes.IMPORTANCE Chikungunya virus (CHIKV) is a re-emerging global health threat that elicits debilitating arthritis in humans. There are currently no commercially available CHIKV vaccines. Like other RNA viruses, CHIKV has a high mutation rate and is capable of rapid intrahost diversification during an infection. In other RNA viruses, virus population diversity associates with disease progression; however, potential impacts of intrahost viral diversity on CHIKV arthritic disease have not been studied. Using previously characterized CHIKV fidelity variants, we addressed whether CHIKV population diversity influences the severity of arthritis and host antibody response in an arthritic mouse model. Our findings show that CHIKV populations with greater genetic diversity can cause more severe disease and stimulate antibody responses with reduced neutralization of low diversity virus populations in vitro The discordant high fidelity phenotypes in this study highlight the complexity of inferring replication fidelity indirectly from population diversity. PMID- 30429349 TI - The Plant Non-canonical Antiviral Resistance Protein JAX1 Inhibits Potexviral Replication by Targeting the Viral RNA-dependent RNA Polymerase. AB - Understanding the innate immune mechanisms of plants is necessary for breeding of disease-resistant lines. Previously, we identified the antiviral resistance gene JAX1 from Arabidopsis thaliana, which inhibits infection by potexviruses. JAX1 encodes a unique jacalin-type lectin protein. In this study, we analyzed the molecular mechanisms of JAX1-mediated resistance. JAX1 restricted the multiplication of a potexviral replicon lacking movement-associated proteins, suggesting inhibition of viral replication. Therefore, we developed an in vitro potato virus X (PVX) translation/replication system using vacuole- and nucleus free lysates from tobacco protoplasts, and revealed that JAX1 inhibits viral RNA synthesis but not translation of the viral RNA-dependent RNA polymerase (RdRp). JAX1 did not affect the replication of a resistance-breaking mutant of PVX. Blue native-polyacrylamide gel electrophoresis of fractions separated by sucrose gradient sedimentation showed that PVX RdRp constituted the high-molecular-weight complex that seems to be crucial for viral replication. JAX1 was detected in this complex of wild-type PVX replicon, but not in that of the resistance-breaking mutant. In addition, JAX1 interacted with the RdRp of the wild-type virus, but not with that of virus with a point mutation at the resistance-breaking residue. These results suggest that JAX1 targets RdRp to inhibit potexvirus replication.IMPORTANCE Resistance genes play a crucial role in plant antiviral innate immunity. The roles of conventional nucleotide binding-leucine rich repeat (NLR) proteins and the associated defense pathways have long been studied. In contrast, recently discovered resistance genes that do not encode NLR proteins (non-NLR resistance genes) have not been investigated extensively. Here we report that the non-NLR resistance factor JAX1, a unique jacalin-type lectin protein, inhibits potexviral de novo RNA synthesis by targeting the huge complex of viral replicase. This is unlike other known antiviral resistance mechanisms. Molecular elucidation of the target in lectin-type protein-mediated antiviral immunity will enhance our understanding of the plant non-NLR-mediated resistance system. PMID- 30429350 TI - Elicitation of protective antibodies against 20 years of future H3N2 co ciruculating influenza virus variants in ferrets preimmune to historical H3N2 influenza viruses. AB - The vast majority of people already have pre-existing immune responses to influenza viruses from one or more subtypes. However, almost all preclinical studies evaluate new influenza vaccine candidates in immunologically naive animals. Recently, our group demonstrated that priming naive ferrets with broadly reactive H1 COBRA HA based vaccines boosted pre-existing antibodies induced by wild-type H1N1 virus infections. These H1 COBRA HA antigens induced antibodies with HAI activity against multiple antigenically different H1N1 viral variants. In this study, ferrets, preimmune to historical H3N2 viruses, were vaccinated with virus-like particle (VLP) vaccines expressing either an HA from a wild-type H3 influenza virus or a COBRA H3 HA antigen (T6, T7, T10, or T11). The elicited antisera had the ability to neutralize virus infection against a panel of viruses representing vaccine strains selected by the World Health Organization (WHO), or a set of viral variants that co-circulated during the same time period. Preimmune animals vaccinated with H3 COBRA T10 HA antigen elicited sera with higher HAI antibody titers than antisera elicited by VLP vaccines with wild-type HA VLPs in preimmune ferrets. However, while the T11 COBRA vaccine did not elicit HAI activity, the elicited antibodies did neutralize antigenically distinct H3N2 influenza viruses. Overall, H3 COBRA-based HA vaccines were able to neutralize both historical H3 and comtemporary, as well as future H3N2 viruses with higher titers than vaccines with wild-type H3 HA antigens. This is the first report demonstrating the effectiveness of a broadly reactive H3N3 vaccine in a preimmune ferret model.IMPORTANCE Following influenza virus exposure, the host generates neutralizing anti-hemagglutinin antibodies against that specific infecting influenza strain. These antibodies can also neutralize some, but not all, co circulating strains. The goal of next generation influenza vaccines, such as HA head-based COBRA, is to stimulate broadly protective neutralizing antibodies against all strains circulating within a subtype, in particular those that persist over multiple influenza seasons, without requiring an update to the vaccine. To mimic the human condition, COBRA HA virus-like particle vaccines were tested in ferrets that were previously exposed to historical H3N2 influenza viruses. In this model, these vaccines elicited broadly protective antibodies that neutralized co-circulating H3N2 influenza viruses isolated over a 20-year period. This is the first study to show the effectiveness of H3N3 COBRA HA vaccines in a host with pre-existing immunity to influenza. PMID- 30429351 TI - Infection of cell lines derived from diffuse large B-cell lymphoma (DLBCL) with the Epstein-Barr virus (EBV) alters the miRNA loading of the Ago2-complex. AB - Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid tumor which is occasionally Epstein-Barr virus (EBV)-positive and is further subtyped as activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL, which has implications for prognosis and treatment.We performed Ago2-RNA immunoprecipitation followed by high throughput RNA sequencing (Ago2-RIP-Seq) to capture functionally active miRNAs in EBV-negative ABC-DLBCL and GC-DLBCL cell lines and their EBV-infected counterparts. In parallel, total miRNomes of these cells were sequenced to capture the cellular miRNA profile for comparison with the functionally active profile. Selected miRNAs with differential abundance were validated using RT-qPCR and Northern Blot. We found 6 miRNAs with differential abundance (2 upregulated and 4 downregulated miRNAs) between EBV-neg. and pos. ABC-DLBCL, and 12 miRNAs with differential abundance (3 upregulated and 9 downregulated miRNAs) between EBV-neg and -pos GC-DLBCL. Eight and twelve miRNAs were confirmed using RT-qPCR in ABC-DLBCL and GC-DLBCL, respectively. Selected miRNs were analyzed in additional type I/II vs. type III EBV latency DLBCL cell lines. Furthermore, up regulation of miR-221-3p and down regulation of let-7c-5p in ABC-DLBCL and up regulation of miR-363-3p and down regulation of 423-5p in GC DLBCL was verified using RIP-Northern blot.Our comprehensive sequence analysis of the DLBCL miRNomes identified sets of deregulated miRNAs in the Ago2-RIP-seq. Our Ago2-IP-seq miRNomes profile could be considered as an important data set for detection of deregulated functionally active miRNAs in DLBCL and could possibly lead to identification of miRNAs as biomarkers for classification of DLBCL or even as targets for personalized targeted treatment.Importance: Diffuse large B cell lymphoma (DLBCL) is a highly aggressive tumor of lymphoid origin which is occasionally Epstein-Barr virus (EBV)-positive. MicroRNAs are found in most multicellular organisms and even in viruses such as EBV. They regulate the synthesis of proteins by binding to their cognate messenger RNA (mRNA). MicroRNAs are tethered to their target mRNAs by "Argonaute" proteins. Here we compared the overall content of by differential loading of the Ago2-complex in comparison to the overall content of miRNAs in two DLBCL cell lines and their EBV-converted counterparts. In all cell lines, the Ago2-load was different from the overall expression of miRNAs. In addition, the loading of the Ago2-complex was changed upon infection with EBV. This indicates that the virus changes not only the overall content of miRNAs but also influences the expression of proteins by affecting the Ago-complexes. PMID- 30429352 TI - Enterovirus-A71 Infection Activates Human Immune Responses and Induces Pathological Changes in Humanized Mice. AB - Since the discovery of enterovirus-A71 (EV-A71) half a century ago, it has caused large-scale outbreaks of hand-foot-and-mouth disease worldwide, in particular in the Asia-Pacific region, causing a great concern of public health and economic burden. Detailed mechanisms on the modulation of immune responses after EV-A71 infection have not been fully known, and the lack of appropriate models hinders the development of promising vaccines and drugs. In the present study, NOD-scid IL2Rgamma-/- (NSG) mice with human immune system (humanized mice) at the age of four-week-old were found to be susceptible to a human isolate of EV-A71 infection. After infection, humanized mice displayed limb weakness, which is similar to the clinical features found in some of the EV-A71-infected patients. Histopathological examination indicated the presence of vacuolation, gliosis or meningomyelitis in brain stem and spinal cord, which were accompanied by high viral loads detected in these organs. The numbers of activated human CD4+ and CD8+ T cells were upregulated after EV-A71 infection and EV-A71-specific human T cell responses were found. Furthermore, the secretion of several proinflammatory cytokines, such as human IFN-gamma, IL-8 and IL-17A was elevated in the EV-A71 infected humanized mice. Taken together, our results suggested that the humanized mouse model permits insights into the human immune responses and the pathogenesis of EV-A71 infection, which may provide a platform for the evaluation of anti-EV A71 drug candidates in the future.IMPORTANCE Despite causing self-limited hand food-and-mouth disease in younger children, EV-A71 is consistently associated with severe forms of neurological complications and pulmonary edema. Nevertheless, only limited vaccines and drugs have been developed over the years, which is possibly due to a lack of models that can more accurately recapitulate human specificity, since human is the only natural host for wild type EV-A71 infection. Our humanized mouse model did not only mimic histological symptoms in patients, but also allows us to investigate the function of human immune system during the infection. It was found that human T cell responses were activated, accompanied by an increase in the production of proinflammatory cytokines in EV A71-infected humanized mice, which might contribute to the exacerbation of disease pathogenesis. Collectively, this model allows us to delineate the modulation of human immune responses during EV-A71 infection and may provide a platform to evaluate anti-EV-A71 drug candidates in the future. PMID- 30429353 TI - Cell and fluid sampling microneedle patches for monitoring skin-resident immunity. AB - Important cell populations reside within tissues and are not accessed by traditional blood draws used to monitor the immune system. To address this issue at an essential barrier tissue, the skin, we created a microneedle-based technology for longitudinal sampling of cells and interstitial fluid, enabling minimally invasive parallel monitoring of immune responses. Solid microneedle projections were coated by a cross-linked biocompatible polymer, which swells upon skin insertion, forming a porous matrix for local leukocyte infiltration. By embedding molecular adjuvants and specific antigens encapsulated in nanocapsules within the hydrogel coating, antigen-specific lymphocytes can be enriched in the recovered cell population, allowing for subsequent detailed phenotypic and functional analysis. We demonstrate this approach in mice immunized with a model protein antigen or infected in the skin with vaccinia virus. After vaccination or infection, sampling microneedles allowed tissue-resident memory T cells (TRMs) to be longitudinally monitored in the skin for many months, during which time the antigen-specific T cell population in systemic circulation contracted to low or undetectable counts. Sampling microneedles did not change the immune status of naive or antigen-exposed animals. We also validated the ability of cell sampling using human skin samples. This approach may be useful in vaccines and immunotherapies to temporally query TRM populations or as a diagnostic platform to sample for biomarkers in chronic inflammatory and autoimmune disorders, allowing information previously accessible only via invasive biopsies to be obtained in a minimally invasive manner from the skin or other mucosal tissues. PMID- 30429355 TI - Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early stage lung adenocarcinoma. AB - The diagnostic definition of indeterminate lung nodules as malignant or benign poses a major challenge for clinicians. We discovered a potential marker, the sodium-dependent glucose transporter 2 (SGLT2), whose activity identified metabolically active lung premalignancy and early-stage lung adenocarcinoma (LADC). We found that SGLT2 is expressed early in lung tumorigenesis and is found specifically in premalignant lesions and well-differentiated adenocarcinomas. SGLT2 activity could be detected in vivo by positron emission tomography (PET) with the tracer methyl 4-deoxy-4-[18F] fluoro-alpha-d-glucopyranoside (Me4FDG), which specifically detects SGLT activity. Using a combination of immunohistochemistry and Me4FDG PET, we identified high expression and functional activity of SGLT2 in lung premalignancy and early-stage/low-grade LADC. Furthermore, selective targeting of SGLT2 with FDA-approved small-molecule inhibitors, the gliflozins, greatly reduced tumor growth and prolonged survival in autochthonous mouse models and patient-derived xenografts of LADC. Targeting SGLT2 in lung tumors may intercept lung cancer progression at early stages of development by pairing Me4FDG PET imaging with therapy using SGLT2 inhibitors. PMID- 30429356 TI - Patents and drug insurance: Clash of the Titans? PMID- 30429354 TI - Commensal bacteria contribute to insulin resistance in aging by activating innate B1a cells. AB - Aging in humans is associated with increased hyperglycemia and insulin resistance (collectively termed IR) and dysregulation of the immune system. However, the causative factors underlying their association remain unknown. Here, using "healthy" aged mice and macaques, we found that IR was induced by activated innate 4-1BBL+ B1a cells. These cells (also known as 4BL cells) accumulated in aging in response to changes in gut commensals and a decrease in beneficial metabolites such as butyrate. We found evidence suggesting that loss of the commensal bacterium Akkermansia muciniphila impaired intestinal integrity, causing leakage of bacterial products such as endotoxin, which activated CCR2+ monocytes when butyrate was decreased. Upon infiltration into the omentum, CCR2+ monocytes converted B1a cells into 4BL cells, which, in turn, induced IR by expressing 4-1BBL, presumably to trigger 4-1BB receptor signaling as in obesity induced metabolic disorders. This pathway and IR were reversible, as supplementation with either A. muciniphila or the antibiotic enrofloxacin, which increased the abundance of A. muciniphila, restored normal insulin response in aged mice and macaques. In addition, treatment with butyrate or antibodies that depleted CCR2+ monocytes or 4BL cells had the same effect on IR. These results underscore the pathological function of B1a cells and suggest that the microbiome monocyte-B cell axis could potentially be targeted to reverse age-associated IR. PMID- 30429358 TI - Erratum for the Research Article: "mTORC1 Inhibition Is Required for Sensitivity to PI3K p110alpha Inhibitors in PIK3CA-Mutant Breast Cancer" by M. Elkabets, S. Vora, D. Juric, N. Morse, M. Mino-Kenudson, T. Muranen, J. Tao, A. B. Campos, J. Rodon, Y. H. Ibrahim, V. Serra, V. Rodrik-Outmezguine, S. Hazra, S. Singh, P. Kim, C. Quadt, M. Liu, A. Huang, N. Rosen, J. A. Engelman, M. Scaltriti, J. Baselga. PMID- 30429357 TI - Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist. AB - Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon like peptide-1 analog, coformulated with the absorption enhancer sodium N-[8-(2 hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that absorption of semaglutide takes place in the stomach, is confined to an area in close proximity to the tablet surface, and requires coformulation with SNAC. SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. The mechanism of absorption is shown to be compound specific, transcellular, and without any evidence of effect on tight junctions. These data have implications for understanding how highly efficacious and specific therapeutic peptides could be transformed from injectable to tablet-based oral therapies. PMID- 30429360 TI - Cross-sectional study on emergency department management of sepsis. AB - INTRODUCTION: Emergency departments (EDs) play an important role in the early identification and management of sepsis. Little is known about local EDs' processes of care for sepsis, adoption of international recommendations, and the impact of the new Sepsis-3 definitions. METHODS: Structured telephone interviews based on the United Kingdom Sepsis Trust 'Exemplar Standards for the Emergency Management of Sepsis' were conducted from January to August 2017 with nominated representatives of all responding public hospital EDs in Hong Kong, followed by a review of hospital/departmental sepsis guidelines by the investigators. RESULTS: Sixteen of the 18 public EDs in Hong Kong participated in the study. Among various time-critical medical emergencies such as major trauma, sepsis was perceived by the interviewees to be the leading cause of in-hospital mortality and the second most important preventable cause of death. However, only seven EDs reported having departmental guidelines on sepsis care, with four adopting the Quick Sequential Organ Failure Assessment score or its modified versions. All responding EDs reported that antibiotics were stocked within their departments, and all EDs with sepsis guidelines mandated early intravenous antibiotic administration within 1 to 2 hours of detection. Reported major barriers to optimal sepsis care included lack of knowledge and experience, nursing human resources shortages, and difficulty identifying patients with sepsis in the ED setting. CONCLUSION: There are considerable variations in sepsis care among EDs in Hong Kong. More training, resources, and research efforts should be directed to early ED sepsis care, to improve patient outcomes. PMID- 30429361 TI - Transcriptional trajectories of human kidney injury progression. AB - BACKGROUND: The molecular understanding of the progression from acute to chronic organ injury is limited. Ischemia/reperfusion injury (IRI) triggered during kidney transplantation can contribute to progressive allograft dysfunction. METHODS: Protocol biopsies (n = 163) were obtained from 42 kidney allografts at 4 time points after transplantation. RNA sequencing-mediated (RNA-seq-mediated) transcriptional profiling and machine learning computational approaches were employed to analyze the molecular responses to IRI and to identify shared and divergent transcriptional trajectories associated with distinct clinical outcomes. The data were compared with the response to IRI in a mouse model of the acute to chronic kidney injury transition. RESULTS: In the first hours after reperfusion, all patients exhibited a similar transcriptional program under the control of immediate-early response genes. In the following months, we identified 2 main transcriptional trajectories leading to kidney recovery or to sustained injury with associated fibrosis and renal dysfunction. The molecular map generated by this computational approach highlighted early markers of kidney disease progression and delineated transcriptional programs associated with the transition to chronic injury. The characterization of a similar process in a mouse IRI model extended the relevance of our findings beyond transplantation. CONCLUSIONS: The integration of multiple transcriptomes from serial biopsies with advanced computational algorithms overcame the analytical hurdles related to variability between individuals and identified shared transcriptional elements of kidney disease progression in humans, which may prove as useful predictors of disease progression following kidney transplantation and kidney injury. This generally applicable approach opens the way for an unbiased analysis of human disease progression. FUNDING: The study was supported by the California Institute for Regenerative Medicine and by the Swiss National Science Foundation. PMID- 30429362 TI - Role of a TRIM72 ADP-ribosylation cycle in myocardial injury and membrane repair. AB - Mono-ADP-ribosylation of an (arginine) protein catalyzed by ADP ribosyltransferase 1 (ART1) - i.e., transfer of ADP-ribose from NAD to arginine - is reversed by ADP-ribosylarginine hydrolase 1 (ARH1) cleavage of the ADP-ribose arginine bond. ARH1-deficient mice developed cardiomyopathy with myocardial fibrosis, decreased myocardial function under dobutamine stress, and increased susceptibility to ischemia/reperfusion injury. The membrane repair protein TRIM72 was identified as a substrate for ART1 and ARH1; ADP-ribosylated TRIM72 levels were greater in ARH1-deficient mice following ischemia/reperfusion injury. To understand better the role of TRIM72 and ADP-ribosylation, we used C2C12 myocytes. ARH1 knockdown in C2C12 myocytes increased ADP-ribosylation of TRIM72 and delayed wound healing in a scratch assay. Mutant TRIM72 (R207K, R260K) that is not ADP-ribosylated interfered with assembly of TRIM72 repair complexes at a site of laser-induced injury. The regulatory enzymes ART1 and ARH1 and their substrate TRIM72 were found in multiple complexes, which were coimmunoprecipitated from mouse heart lysates. In addition, the mono-ADP ribosylation inhibitors vitamin K1 and novobiocin inhibited oligomerization of TRIM72, the mechanism by which TRIM72 is recruited to the site of injury. We propose that a mono-ADP-ribosylation cycle involving recruitment of TRIM72 and other regulatory factors to sites of membrane damage is critical for membrane repair and wound healing following myocardial injury. PMID- 30429363 TI - NF-kappaB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification. AB - BACKGROUND: Inflammation helps regulate normal growth and tissue repair. Although bone morphogenetic proteins (BMPs) and inflammation are known contributors to abnormal bone formation, how these pathways interact in ossification remains unclear. METHODS: We examined this potential link in patients with fibrodysplasia ossificans progressiva (FOP), a genetic condition of progressive heterotopic ossification caused by activating mutations in the Activin A type I receptor (ACVR1/ALK2). FOP patients show exquisite sensitivity to trauma, suggesting that BMP pathway activation may alter immune responses. We studied primary blood, monocyte, and macrophage samples from control and FOP subjects using multiplex cytokine, gene expression, and protein analyses; examined CD14+ primary monocyte and macrophage responses to TLR ligands; and assayed BMP, TGF-beta activated kinase 1 (TAK1), and NF-kappaB pathways. RESULTS: FOP subjects at baseline without clinically evident heterotopic ossification showed increased serum IL-3, IL-7, IL-8, and IL-10. CD14+ primary monocytes treated with the TLR4 activator LPS showed increased CCL5, CCR7, and CXCL10; abnormal cytokine/chemokine secretion; and prolonged activation of the NF-kappaB pathway. FOP macrophages derived from primary monocytes also showed abnormal cytokine/chemokine secretion, increased TGF-beta production, and p38MAPK activation. Surprisingly, SMAD phosphorylation was not significantly changed in the FOP monocytes/macrophages. CONCLUSIONS: Abnormal ACVR1 activity causes a proinflammatory state via increased NF-kappaB and p38MAPK activity. Similar changes may contribute to other types of heterotopic ossification, such as in scleroderma and dermatomyositis; after trauma; or with recombinant BMP-induced bone fusion. Our findings suggest that chronic antiinflammatory treatment may be useful for heterotopic ossification. PMID- 30429364 TI - Complement serves as a switch between CD4+ T cell-independent and -dependent RBC antibody responses. AB - RBC alloimmunization represents a significant immunological challenge for patients requiring lifelong transfusion support. The majority of clinically relevant non-ABO(H) blood group antigens have been thought to drive antibody formation through T cell-dependent immune pathways. Thus, we initially sought to define the role of CD4+ T cells in formation of alloantibodies to KEL, one of the leading causes of hemolytic transfusion reactions. Unexpectedly, our findings demonstrated that KEL RBCs actually possess the ability to induce antibody formation independent of CD4+ T cells or complement component 3 (C3), two common regulators of antibody formation. However, despite the ability of KEL RBCs to induce anti-KEL antibodies in the absence of complement, removal of C3 or complement receptors 1 and 2 (CR1/2) rendered recipients completely reliant on CD4+ T cells for IgG anti-KEL antibody formation. Together, these findings suggest that C3 may serve as a novel molecular switch that regulates the type of immunological pathway engaged following RBC transfusion. PMID- 30429365 TI - Carbon monoxide-induced metabolic switch in adipocytes improves insulin resistance in obese mice. AB - Obesity is characterized by accumulation of adipose tissue and is one the most important risk factors in the development of insulin resistance. Carbon monoxide releasing (CO-releasing) molecules (CO-RMs) have been reported to improve the metabolic profile of obese mice, but the underlying mechanism remains poorly defined. Here, we show that oral administration of CORM-401 to obese mice fed a high-fat diet (HFD) resulted in a significant reduction in body weight gain, accompanied by a marked improvement in glucose homeostasis. We further unmasked an action we believe to be novel, by which CO accumulates in visceral adipose tissue and uncouples mitochondrial respiration in adipocytes, ultimately leading to a concomitant switch toward glycolysis. This was accompanied by enhanced systemic and adipose tissue insulin sensitivity, as indicated by a lower blood glucose and increased Akt phosphorylation. Our findings indicate that the transient uncoupling activity of CO elicited by repetitive administration of CORM 401 is associated with lower weight gain and increased insulin sensitivity during HFD. Thus, prototypic compounds that release CO could be investigated for developing promising insulin-sensitizing agents. PMID- 30429366 TI - The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle. AB - The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. In skeletal muscle, MCU links Ca2+ signaling to energy production by directly enhancing the activity of key metabolic enzymes in the mitochondria. Here, we examined the role of MCU in skeletal muscle development and metabolic function by generating mouse models for the targeted deletion of Mcu in embryonic, postnatal, and adult skeletal muscle. Loss of Mcu did not affect muscle growth and maturation or otherwise cause pathology. Skeletal muscle specific deletion of Mcu in mice also did not affect myofiber intracellular Ca2+ handling, but it did inhibit acute mitochondrial Ca2+ influx and mitochondrial respiration stimulated by Ca2+, resulting in reduced acute exercise performance in mice. However, loss of Mcu also resulted in enhanced muscle performance under conditions of fatigue, with a preferential shift toward fatty acid metabolism, resulting in reduced body fat with aging. Together, these results demonstrate that MCU-mediated mitochondrial Ca2+ regulation underlies skeletal muscle fuel selection at baseline and under enhanced physiological demands, which affects total homeostatic metabolism. PMID- 30429367 TI - Concomitant SK current activation and sodium current inhibition cause J wave syndrome. AB - The mechanisms of J wave syndrome (JWS) are incompletely understood. Here, we showed that the concomitant activation of small-conductance calcium-activated potassium (SK) current (IKAS) and inhibition of sodium current by cyclohexyl-[2 (3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine (CyPPA) recapitulate the phenotypes of JWS in Langendorff-perfused rabbit hearts. CyPPA induced significant J wave elevation and frequent spontaneous ventricular fibrillation (SVF), as well as sinus bradycardia, atrioventricular block, and intraventricular conduction delay. IKAS activation by CyPPA resulted in heterogeneous shortening of action potential (AP) duration (APD) and repolarization alternans. CyPPA inhibited cardiac sodium current (INa) and decelerated AP upstroke and intracellular calcium transient. SVFs were typically triggered by short-coupled premature ventricular contractions, initiated with phase 2 reentry and originated more frequently from the right than the left ventricles. Subsequent IKAS blockade by apamin reduced J wave elevation and eliminated SVF. beta-Adrenergic stimulation was antiarrhythmic in CyPPA-induced electrical storm. Like CyPPA, hypothermia (32.0 degrees C) also induced J wave elevation and SVF. It facilitated negative calcium-voltage coupling and phase 2 repolarization alternans with spatial and electromechanical discordance, which were ameliorated by apamin. These findings suggest that IKAS activation contributes to the development of JWS in rabbit ventricles. PMID- 30429368 TI - Spatial and phenotypic immune profiling of metastatic colon cancer. AB - Paramount to the efficacy of immune checkpoint inhibitors is proper selection of patients with adequate tumor immunogenicity and a robust but suppressed immune infiltrate. In colon cancer, immune-based therapies are approved for patients with DNA mismatch repair (MMR) deficiencies, in whom accumulation of genetic mutations results in increased neoantigen expression, triggering an immune response that is suppressed by the PD-L1/PD-1 pathway. Here, we report that characterization of the microenvironment of MMR-deficient metastatic colorectal cancer using multiplex fluorescent immunohistochemistry (mfIHC) identified increased infiltration of cytotoxic T lymphocytes (CTLs), which were more often engaged with epithelial cells (ECs) and improved overall survival. A subset of patients with intact MMR but a similar immune microenvironment to MMR-deficient patients was identified and found to universally express high levels of PD-L1, suggesting that they may represent a currently untreated, checkpoint inhibitor responsive population. Further, PD-L1 expression on antigen-presenting cells (APCs) in the tumor microenvironment (TME) resulted in impaired CTL/EC engagement and enhanced infiltration and engagement of Tregs. Characterization of the TME by mfIHC highlights the interconnection between immunity and immunosuppression in metastatic colon cancer and may better stratify patients for receipt of immunotherapies. PMID- 30429369 TI - Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. AB - BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy. METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses. RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher's exact test). CONCLUSION: EBV specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527. FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous. PMID- 30429370 TI - Early expansion of donor-specific Tregs in tolerant kidney transplant recipients. AB - Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early after CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT. We expanded Tregs with several different protocols. Using functional analyses and T cell receptor sequencing, we found that expanding sorted Tregs with activated donor B cells identified the broadest Treg repertoire with the greatest potency and donor specificity of suppression. This method outperformed both alloantigen stimulation with CTLA4Ig and sequencing of CFSElo cells from the primary mixed lymphocyte reaction. In 3 tolerant and 1 nontolerant CKBMT recipients, we sequenced donor-specific Tregs before transplant and tracked them after transplant. Preexisting donor-specific Tregs were expanded at 6 months after CKBMT in tolerant patients and were reduced in the nontolerant patient. These results suggest that early expansion of donor-specific Tregs is involved in tolerance induction following CKBMT. PMID- 30429371 TI - Elevated circulating MMP-9 is linked to increased COPD exacerbation risk in SPIROMICS and COPDGene. AB - BACKGROUND: Matrix metalloprotease 9 (MMP-9) is associated with inflammation and lung remodeling in chronic obstructive pulmonary disease (COPD). We hypothesized that elevated circulating MMP-9 represents a potentially novel biomarker that identifies a subset of individuals with COPD with an inflammatory phenotype who are at increased risk for acute exacerbation (AECOPD). METHODS: We analyzed Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene) cohorts for which baseline and prospective data were available. Elevated MMP-9 was defined based on >95th percentile plasma values from control (non-COPD) sample in SPIROMICS. COPD subjects were classified as having elevated or nonelevated MMP-9. Logistic, Poisson, and Kaplan-Meier analyses were used to identify associations with prospective AECOPD in both cohorts. RESULTS: Elevated MMP-9 was present in 95/1,053 (9%) of SPIROMICS and 41/140 (29%) of COPDGene participants with COPD. COPD subjects with elevated MMP-9 had a 13%-16% increased absolute risk for AECOPD and a higher median (interquartile range; IQR) annual AECOPD rate (0.33 [0 0.74] versus 0 [0-0.80] events/year and 0.9 [0.5-2] versus 0.5 [0-1.4] events/year for SPIROMICS and COPDGene, respectively). In adjusted models within each cohort, elevated MMP-9 was associated with increased odds (odds ratio [OR], 1.71; 95%CI, 1.00-2.90; and OR, 3.03; 95%CI, 1.02-9.01), frequency (incidence rate ratio [IRR], 1.45; 95%CI, 1.23-1.7; and IRR, 1.24; 95%CI, 1.03-1.49), and shorter time-to-first AECOPD (21.7 versus 31.7 months and 14 versus 21 months) in SPIROMICS and COPDGene, respectively. CONCLUSIONS: Elevated MMP-9 was independently associated with AECOPD risk in 2 well-characterized COPD cohorts. These findings provide evidence for MMP-9 as a prognostic biomarker and potential therapeutic target in COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01969344 (SPIROMICS) and NCT00608764 (COPDGene). FUNDING: This work was funded by K08 HL123940 to JMW; R01HL124233 to PJC; Merit Review I01 CX000911 to JLC; R01 (R01HL102371, R01HL126596) and VA Merit (I01BX001756) to AG. SPIROMICS (Subpopulations and Intermediate Outcomes in COPD Study) is funded by contracts from the NHLBI (HHSN268200900013C, HHSN268200900014C,HHSN268200900015C HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, and HHSN268200900020C) and a grant from the NIH/NHLBI (U01 HL137880), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals Inc.; Chiesi Farmaceutici; Forest Research Institute Inc.; GlaxoSmithKline; Grifols Therapeutics Inc.; Ikaria Inc.; Novartis Pharmaceuticals Corporation; Nycomed GmbH; ProterixBio; Regeneron Pharmaceuticals Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan. COPDGene is funded by the NHLBI (R01 HL089897 and R01 HL089856) and by the COPD Foundation through contributions made to an Industry Advisory Board composed of AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. PMID- 30429372 TI - Functional heterogeneity of human tissue-resident memory T cells based on dye efflux capacities. AB - Tissue-resident memory T cells (TRMs) accelerate pathogen clearance through rapid and enhanced functional responses in situ. TRMs are prevalent in diverse anatomic sites throughout the human lifespan, yet their phenotypic and functional diversity has not been fully described. Here, we identify subpopulations of human TRMs based on the ability to efflux fluorescent dyes [efflux(+) TRMs] located within mucosal and lymphoid sites with distinct transcriptional profiles, turnover, and functional capacities. Compared with efflux(-) TRMs, efflux(+) TRMs showed transcriptional and phenotypic features of quiescence including reduced turnover, decreased expression of exhaustion markers, and increased proliferative capacity and signaling in response to homeostatic cytokines. Moreover, upon activation, efflux(+) TRMs secreted lower levels of inflammatory cytokines such as IFN-gamma and IL-2 and underwent reduced degranulation. Interestingly, analysis of TRM subsets following activation revealed that both efflux(+) and efflux(-) TRMs undergo extensive transcriptional changes following TCR ligation but retain core TRM transcriptional properties including retention markers, suggesting that TRMs carry out effector function in situ. Overall, our results suggest a model for tissue-resident immunity wherein heterogeneous subsets have differential capacities for longevity and effector function. PMID- 30429373 TI - Loss of complement regulatory proteins on uninfected erythrocytes in vivax and falciparum malaria anemia. AB - Anemia is a major complication of malaria, driven largely by loss of uninfected RBCs during infection. RBC clearance through loss of complement regulatory proteins (CRPs) is a significant contributor to anemia in Plasmodium falciparum infection, but its role in Plasmodium vivax infection is unknown. CRP loss increases RBC susceptibility to macrophage clearance, a process that is also regulated by CD47. We compared CRPs and CD47 expression on infected and uninfected RBCs in adult patients with vivax and falciparum malaria and different anemia severities from Papua, Indonesia. Complement activation and parasite specific complement-fixing antibodies were measured by ELISA. Levels of CR1 and CD55 were reduced in severe anemia in both falciparum and vivax malaria. Loss of CRPs and CD47 was restricted to uninfected RBCs, with infected RBCs having higher expression. There was no association among complement-fixing antibodies, complement activation, and CRP loss. Our findings demonstrate that CRP loss is a pan-species, age-independent mechanism of malarial anemia. Higher levels of CRP and CD47 expression on infected RBCs suggest that parasites are protected from complement-mediated destruction and macrophage clearance. Lack of associations between protective antibodies and CRP loss highlight that complement pathogenic and protective pathways are distinct mechanisms during infection. PMID- 30429374 TI - Tyro3 is a podocyte protective factor in glomerular disease. AB - Our previous work demonstrated a protective role of protein S in early diabetic kidney disease (DKD). Protein S exerts antiinflammatory and antiapoptotic effects through the activation of TYRO3, AXL, and MER (TAM) receptors. Among the 3 TAM receptors, we showed that the biological effects of protein S were mediated largely by TYRO3 in diabetic kidneys. Our data now show that TYRO3 mRNA expression is highly enriched in human glomeruli and that TYRO3 protein is expressed in podocytes. Interestingly, glomerular TYRO3 mRNA expression increased in mild DKD but was suppressed in progressive DKD, as well as in focal segmental glomerulosclerosis (FSGS). Functionally, morpholino-mediated knockdown of tyro3 altered glomerular filtration barrier development in zebrafish larvae, and genetic ablation of Tyro3 in murine models of DKD and Adriamycin-induced nephropathy (ADRN) worsened albuminuria and glomerular injury. Conversely, the induction of TYRO3 overexpression specifically in podocytes significantly attenuated albuminuria and kidney injury in mice with DKD, ADRN, and HIV associated nephropathy (HIVAN). Mechanistically, TYRO3 expression was suppressed by activation of TNF-alpha/NF-kappaB pathway, which may contribute to decreased TYRO3 expression in progressive DKD and FSGS, and TYRO3 signaling conferred antiapoptotic effects through the activation of AKT in podocytes. In conclusion, TYRO3 plays a critical role in maintaining normal podocyte function and may be a potential new drug target to treat glomerular diseases. PMID- 30429375 TI - Dysregulated NK cell PLCgamma2 signaling and activity in juvenile dermatomyositis. AB - Juvenile dermatomyositis (JDM) is a debilitating pediatric autoimmune disease manifesting with characteristic rash and muscle weakness. To delineate signaling abnormalities in JDM, mass cytometry was performed with PBMCs from treatment naive JDM patients and controls. NK cell percentages were lower while frequencies of naive B cells and naive CD4+ T cells were higher in JDM patients than in controls. These cell frequency differences were attenuated with cessation of active disease. A large number of signaling differences were identified in treatment-naive JDM patients compared with controls. Classification models incorporating feature selection demonstrated that differences in phospholipase Cgamma2 (PLCgamma2) phosphorylation comprised 10 of 12 features (i.e., phosphoprotein in a specific immune cell subset) distinguishing the 2 groups. Because NK cells represented 5 of these 12 features, further studies focused on the PLCgamma2 pathway in NK cells, which is responsible for stimulating calcium flux and cytotoxic granule movement. No differences were detected in upstream signaling or total PLCgamma2 protein levels. Hypophosphorylation of PLCgamma2 and downstream mitogen-activated protein kinase-activated protein kinase 2 were partially attenuated with cessation of active disease. PLCgamma2 hypophosphorylation in treatment-naive JDM patients resulted in decreased calcium flux. The identification of dysregulation of PLCgamma2 phosphorylation and decreased calcium flux in NK cells provides potential mechanistic insight into JDM pathogenesis. PMID- 30429376 TI - AAV-mediated follistatin gene therapy improves functional outcomes in the TIC DUX4 mouse model of FSHD. AB - Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There is currently no pharmacological treatment. The emergence of DUX4 enabled development of cell and animal models that could be used for basic and translational research. Since DUX4 is toxic, animal model development has been challenging, but progress has been made, revealing that tight regulation of DUX4 expression is critical for creating viable animals that develop myopathy. Here, we report such a model - the tamoxifen-inducible FSHD mouse model called TIC-DUX4. Uninduced animals are viable, born in Mendelian ratios, and overtly indistinguishable from WT animals. Induced animals display significant DUX4-dependent myopathic phenotypes at the molecular, histological, and functional levels. To demonstrate the utility of TIC-DUX4 mice for therapeutic development, we tested a gene therapy approach aimed at improving muscle strength in DUX4-expressing muscles using adeno-associated virus serotype 1.Follistatin (AAV1.Follistatin), a natural myostatin antagonist. This strategy was not designed to modulate DUX4 but could offer a mechanism to improve muscle weakness caused by DUX4-induced damage. AAV1.Follistatin significantly increased TIC-DUX4 muscle mass and strength even in the presence of DUX4 expression, suggesting that myostatin inhibition may be a promising approach to treat FSHD-associated weakness. We conclude that TIC-DUX4 mice are a relevant model to study DUX4 toxicity and, importantly, are useful in therapeutic development studies for FSHD. PMID- 30429377 TI - Targeting the CALR interactome in myeloproliferative neoplasms. AB - Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57, and CALR to the MPL promoter to enhance transcription. Consistent with a critical role for CALR-mediated JAK/STAT activation, we confirmed the efficacy of JAK2 inhibition on CALR-mutant cells in vitro and in vivo. Due to the altered interactome induced by CALR mutations, we hypothesized that CALR-mutant MPNs may be vulnerable to disruption of aberrant CALR protein complexes. A synthetic peptide designed to competitively inhibit the carboxy terminal of CALR specifically abrogated MPL/JAK/STAT signaling in cell lines and primary samples and improved the efficacy of JAK kinase inhibitors. These findings reveal what to our knowledge is a novel potential therapeutic approach for patients with CALR mutant MPN. PMID- 30429378 TI - A nanoparticle-incorporated STING activator enhances antitumor immunity in PD-L1 insensitive models of triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) has few therapeutic options, and alternative approaches are urgently needed. Stimulator of IFN genes (STING) is becoming an exciting target for therapeutic adjuvants. However, STING resides inside the cell, and the intracellular delivery of CDNs, such as cGAMP, is required for the optimal activation of STING. We show that liposomal nanoparticle-delivered cGAMP (cGAMP-NP) activates STING more effectively than soluble cGAMP. These particles induce innate and adaptive host immune responses to preexisting tumors in both orthotopic and genetically engineered models of basal-like TNBC. cGAMP-NPs also reduce melanoma tumor load, with limited responsivity to anti-PD-L1. Within the tumor microenvironment, cGAMP-NPs direct both mouse and human macrophages (M), reprograming from protumorigenic M2-like phenotype toward M1-like phenotype; enhance MHC and costimulatory molecule expression; reduce M2 biomarkers; increase IFN-gamma-producing T cells; augment tumor apoptosis; and increase CD4+ and CD8+ T cell infiltration. Activated T cells are required for tumor suppression, as their depletion reduces antitumor activity. Importantly, cGAMP-NPs prevent the formation of secondary tumors, and a single dose is sufficient to inhibit TNBC. These data suggest that a minimal system comprised of cGAMP-NP alone is sufficient to modulate the tumor microenvironment to effectively control PD-L1 insensitive TNBC. PMID- 30429379 TI - Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265P mutations. PMID- 30429380 TI - Pseudomonas aeruginosa - Difficult to outmanoeuvre. PMID- 30429381 TI - An update on antimicrobial resistance and the role of newer antimicrobial agents for Pseudomonas aeruginosa. AB - Infections due to Pseudomonas aeruginosa is a major health concern, especially hospital-acquired infections, in critically ill individuals. Antimicrobial resistance (AMR) increases the morbidity and mortality rates associated with pseudomonal infections. In this review, we aim to address two major aspects of P. aeruginosa. The first part of the review will focus on the burden of AMR and its prevailing mechanisms seen in India, while the second part will focus on the challenges and approaches in the management with special emphasis on the role of newer antimicrobial agents. PMID- 30429382 TI - Hepatitis E virus infection: An old virus with a new story! AB - Hepatitis E virus (HEV) infection is an important public health problem. HEV infection has been identified as a major cause of enterically transmitted acute sporadic hepatitis in India especially in adult age group. India is hyperendemic for HEV, with the disease presenting both as outbreaks and as cases of acute sporadic viral hepatitis. Most of these outbreaks can be traced to contamination of drinking water supplies with human fecal matter. The last decade has witnessed tremendous change in our understanding of the virus in its epidemiology, clinical features, diagnostic approaches, treatment options and the need for vaccination. With the identification of culture systems for HEV and development of animal models for its replication, knowledge regarding its replication and pathogenesis has evolved. This review attempts to discuss the nuances in our understanding of this virus, its pathogenesis and diagnosis, especially with reference to the Indian scenario. PMID- 30429383 TI - Legionella and Legionnaires' disease: Time to explore in India. AB - Legionella pneumophila was first recognised as a fatal cause of pneumonia more than four decades ago, during the 1976-American Legion convention in Philadelphia, USA. Legionella spp. continue to cause disease outbreaks of public health significance, and at present, Legionnaires' disease (LD) has emerged as an important cause of community and hospital-acquired pneumonia. Parallel to this, the understanding of LD has also increased exponentially. However, the disease is likely to be underreported in many countries because of the dearth of common definitions, diagnostic tests and active surveillance systems. In this review, we outline the basic concepts of Legionella including clinical presentations, epidemiology, laboratory diagnosis and the status of LD in India. This article also summarises the progress of research related to Legionella in this country, identifying the research gaps and discussing priorities to explore this unexplored pathogen in India. PMID- 30429384 TI - Newer beta-Lactam/beta-Lactamase inhibitor for multidrug-resistant gram-negative infections: Challenges, implications and surveillance strategy for India. AB - Antimicrobial resistance (AMR) is a major public health concern across the globe, and it is increasing at an alarming rate. Multiple classes of antimicrobials have been used for the treatment of infectious diseases. Rise in the AMR limits its use and hence the prerequisite for the newer agents to combat drug resistance. Among the infections caused by Gram-negative organisms, beta-lactams are one of the most commonly used agents. However, the presence of diverse beta-lactamases hinders its use for therapy. To overcome these enzymes, beta-lactamase inhibitors are being discovered. The aim of this document is to address the burden of AMR in India and interventions to fight against this battle. This document addresses and summarises the following: The current scenario of AMR in India (antimicrobial susceptibility, resistance mechanisms and molecular epidemiology of common pathogens); contentious issues in the use of beta-lactam/beta-lactamase inhibitor as an carbapenem sparing agent; role of newer beta-lactam/beta-lactamase inhibitor agents with its appropriateness to Indian scenario and; the Indian Council of Medical Research interventions to combat drug resistance in terms of surveillance and infection control as a national response to AMR. This document evidences the need for improved national surveillance system and country-specific newer agents to fight against the AMR. PMID- 30429385 TI - Dominance of international high-risk clones in carbapenemase-producing Pseudomonas aeruginosa: Multicentric molecular epidemiology report from India. AB - Background: Pseudomonas aeruginosa is one of the most common opportunistic pathogens that cause severe infections in humans. The burden of carbapenem resistance is particularly high and is on the rise. Very little information is available on the molecular mechanisms and its clonal types of carbapenem resistant P. aeruginosa seen in Indian hospitals. This study was undertaken to monitor the beta-lactamase profile and to investigate the genetic relatedness of the carbapenemase-producing (CP) P. aeruginosa collected across different hospitals from India. Materials and Methods: A total of 507 non-duplicate, carbapenem-resistant P. aeruginosa isolated from various clinical specimens collected during 2014-2017 across seven Indian hospitals were included. Conventional multiplex polymerase chain reaction for the genes encoding beta lactamases such as extended-spectrum beta-lactamase (ESBL) and carbapenemase were screened. A subset of isolates (n = 133) of CP P. aeruginosa were genotyped by multilocus sequence typing (MLST) scheme. Results: Of the total 507 isolates, 15%, 40% and 20% were positive for genes encoding ESBLs, carbapenemases and ESBLs + carbapenemases, respectively, whilst 25% were negative for the beta-lactamases screened. Amongst the ESBL genes, blaVEB is the most predominant, followed by blaPER and blaTEM, whilst blaVIM and blaNDM were the most predominant carbapenemases seen. However, regional differences were noted in the beta lactamases profile across the study sites. Genotyping by MLST revealed 54 different sequence types (STs). The most common are ST357, ST235, ST233 and ST244. Six clonal complexes were found (CC357, CC235, CC244, CC1047, CC664 and CC308). About 24% of total STs are of novel types and these were found to emerge from the high-risk clones. Conclusion: This is the first large study from India to report the baseline data on the molecular resistance mechanisms and its association with genetic relatedness of CP P. aeruginosa circulating in Indian hospitals. blaVIM- and blaNDM-producing P. aeruginosa is the most prevalent carbapenemase seen in India. Majority of the isolates belongs to the high-risk international clones ST235, ST357 and ST664 which is a concern. PMID- 30429386 TI - Hepatitis C virus infection in a tertiary care hospital in Mumbai, India: Identification of a mixed and novel genotype. AB - Purpose: Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). HCV being a ribonucleic acid virus has considerable sequence variability. Assessment of viral load and genotype is necessary for designing treatment strategies and monitoring for viral resistance among HCV-infected cases. HCC is the most common form of liver cancer, often occurring in people with chronic hepatitis B or C. We undertook this study to observe genotype distribution of the virus in HCV patients from Mumbai. Materials and Methods: Between January 2017 and December 2017, the study was conducted on 120 chronic hepatitis outpatients from a tertiary care hospital, Mumbai, after obtaining ethics approval. All these diagnosed cases of HCV were subjected to molecular diagnosis in a research institute, Mumbai, by real-time polymerase chain reaction-based techniques. Results: Males were more preponderant than females with HCV infection, and the highest number of HCV-infected cases was observed in the age group of 41-50 years. Genotype 3 (n = 70; 58.3%) accounted for the highest number of cases followed by genotypes 1b (n = 29; 24.2%) and then 1a (n = 14; 11.7%). Mixed genotypes 1b + 3 and individual genotype 4 were found in two cases each (1.7%). A total of three samples (2.5%) were found with untypeable genotype. Conclusion: The major HCV genotype observed was 3 which is difficult to treat with direct-acting antivirals, owing to the more rapid progression of liver disease, increased rates of steatosis (non-alcoholic fatty liver disease), a higher risk for cancer (HCC). We believe this study is the first one to address the prevalence of mixed genotypes and untypeable genotype from India. PMID- 30429387 TI - Diagnostic accuracy of Xpert MTB/RIF assay in extrapulmonary tuberculosis. AB - Introduction: The WHO endorsed Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay, has been evaluated for pulmonary TB in a number of studies but very few have investigated it for extrapulmonary specimens. The present study evaluates the performance of Xpert MTB/RIF assay in the diagnosis of extrapulmonary TB (EPTB). Aim and Objectives: The aim of the study is to determine sensitivity and specificity of Xpert MTB/RIF assay for diagnosis of EPTB and RIF resistance in comparison to culture on Lowenstein-Jensen (LJ) medium and proportion method (PM), respectively. Materials and Methods: A total of 738 specimens from clinically suspected cases of EPTB were subjected to Ziehl-Neelsen staining, Xpert MTB/RIF assay and culture on LJ medium. PM was done on MTB isolates. Results: The sensitivity, specificity of Xpert MTB/RIF assay for diagnosis of EPTB were 84.91% (95% confidence interval [CI] 72.41%-93.25%) and 86.72% (95% CI 83.94%-89.17%) and for RIF resistance detection were 60.00% (95% CI 32.29%-83.66%) and 94.74% (95% CI 73.97%-99.87%), respectively. Among culture positive cases, the sensitivity of Xpert MTB/RIF assay was 94.12% in smear positive and 80.56% in smear-negative cases. Xpert MTB/RIF showed maximum sensitivity of MTB detection from lymph node specimens (100% [95% CI 54.07% 100.00%]) and other body fluids (100% [95% CI 15.81%-100.00%]). Conclusion: The present study establishes Xpert MTB/RIF assay as a promising tool in the rapid diagnosis of EPTB and detection of RIF resistance. PMID- 30429388 TI - Changing virulence factors among vaginal non-albicans Candida species. AB - Background: Vulvovaginal candidiasis (VVC) is caused by overgrowth of Candida species in the female lower genital tract and most commonly caused by Candida albicans. The production of various virulence factors may attribute to their pathogenicity. Hence, this study was aimed to determine the production of various virulence factors of Candida spp. causing VVC. Materials and Methods: A total of 51 Candida spp. were isolated prospectively from 50 patients among 211 clinically suspected cases of VVC. The haemolytic activity, biofilm production, proteinase activity, phospholipase activity and esterase activity were detected by standard methods. Statistical analysis was performed using OpenEpi version 3.01. Results: Haemolytic activity was observed in 42 Candida isolates (82.4%), biofilm activity in 21 Candida isolates (41.2%), proteinase and esterase activity in 19 Candida isolates (37.3%) each and phospholipase activity in 15 Candida isolates (29.4%). Phospholipase activity was observed in all of the C. albicans strains, whereas all strains of Candida krusei were able to produce biofilm. All strains of Candida parapsilosis and 87% strains of Candida glabrata were haemolytic. Five of the eight C. glabrata strains were found to produce strong proteinase (Prz score <=0.63). About 30.4% strains of C. glabrata and 20% strains of C. krusei were found to be positive for esterase activity. This is one of the few studies which revealed esterase activity among C. glabrata and C. krusei strains. Conclusions: This study highlighted that there is a change in the virulence factors among the non-albicans Candida species, especially C. glabrata strains which were haemolytic and produce strong proteinase activity and esterase activity. It may be one of the explanation of the most common causative agent of VVC in our study. Multicentric studies from this area might be required to get a more generalised conclusion. PMID- 30429390 TI - Hepatitis C virus and its genotypes in chronic liver disease patients from Meghalaya, Northeast India. AB - Background and Objectives: Hepatitis C virus (HCV) is an important cause of chronic liver disease (CLD). Although Northeast India is believed to be a HCV hotspot, the proportion of HCV infection and the distribution of HCV genotypes in CLD cases from the region are not known. The objectives of the study were to determine the proportion of HCV infection in newly diagnosed CLD patients from Meghalaya, Northeast India, and further investigate the HCV genotype distribution in those patients. Materials and Methods: The aetiology of CLD was evaluated in 196 newly diagnosed patients, recruited consecutively over a period of 1 year in a medical college hospital from Meghalaya. Those positive for HCV infection were genotyped, and the mode of transmission of the virus was investigated. Results: A considerable proportion (43 patients, 21.9%) of CLD patients were positive for HCV (95% confidence interval [CI]: 16.7%-28.2%). Other leading causes of CLD were alcohol (36.32%) and hepatitis B virus infection (39.3%). Genotype 3 was the most prevalent (48.7%, 95% CI: 33.9%-63.8%), followed by genotype 6 (30.8%, 95% CI: 18.6%-46.6%) and genotype 1 (20.5%, 95% CI: 10.8%-35.5%). The frequency of genotype 6 was remarkably higher than in the other regions of India. Injecting drug use appeared to be the most common mode (28 patients) of acquiring HCV. This was true irrespective of the genotype. Conclusions: The presence of HCV in newly diagnosed CLD cases from Meghalaya was considerable. The genotype distribution of HCV was distinct from the other regions of India. PMID- 30429389 TI - Rapid detection of the commonly encountered carbapenemases (New Delhi metallo beta-lactamase, OXA-48/181) directly from various clinical samples using multiplex real-time polymerase chain reaction assay. AB - Background: Resistance due to New Delhi metallo-beta-lactamase (NDM) and OXA 48/181 continues to emerge as a threat which is associated with nosocomial outbreaks and is a serious healthcare concern. Phenotypic detection being laborious and time-consuming requires rapid detection of NDM and OXA-48/181, which is achieved through real-time polymerase chain reaction (RT-PCR). Materials and Methods: In this study, RT-PCR assay was developed to simultaneously detect NDM and OXA-48/181. The assay was validated on 102 non-duplicate, phenotypically characterised clinical samples. Results: The assay showed a sensitivity and specificity of 97% and 100% for the detection of carbapenemases in comparison to conventional PCR. The in-house developed multiplex RT-PCR would help to rule-in the presence of NDM and OXA-48/181. Conclusions: Rapid detection of these carbapenemases would be assist in better patient management, in terms of accurate antimicrobial treatment, help in cohorting infected from uninfected patient to prevent spread. PMID- 30429391 TI - Incidence, epidemiology and control of Clostridium difficile infection in a tertiary care private hospital in India. AB - Purpose: Clostridium difficile infection (CDI) is a serious healthcare-associated infection (HAI) now being increasingly reported from hospitals across India. However, there is a paucity of data on the incidence of and impact of control measures on CDI in India. Materials and Methods: This is a retrospective study conducted at a tertiary care hospital in Mumbai from January 2016 to December 2017. All patients with healthcare-onset diarrhoea were tested for C. difficile by glutamate dehydrogenase (GDH)/toxin assay or nucleic acid amplification test (NAAT). CDI was defined as either GDH and toxin positive or NAAT positive. The incidence of CDI was calculated per 1000 patient days. Demographic features of patients with CDI including age, sex, duration of hospitalisation before onset of CDI, antibiotic use and treatment administered were summarised. Results: A total of 67 patients had CDI in the study period with a mean incidence of 0.2/1000 patient days. A halving of the CDI incidence was seen after intensification of the CDI prevention bundle. The mean age of affected patients was 64 years and CDI occurred at a median duration of 2 weeks after hospitalisation. Eighty-seven per cent of the patients were on antibiotics at the time of diagnosis of CDI. The crude mortality rate was 22%. Conclusions: CDI is an emerging HAI in India. All hospitals need to set up policies for surveillance, testing, treatment and prevention of CDI based on recent international guidelines and local infrastructure/logistics. PMID- 30429392 TI - Evaluation of an in-house LipL32 polymerase chain reaction for diagnosis of leptospirosis and its correlation with various serological diagnostic techniques. AB - Background: Leptospirosis is a zoonotic disease of ubiquitous distribution. During rainy seasons, in spring and summer and also during harvest times, the risk of leptospirosis increases as there are chances of frequent contact with infected rat population which is common in Karnataka as farming is a main source of income to the people here. There is a paucity of data regarding the prevalent serovars from Karnataka. This study was undertaken as an attempt to compare a battery of tools such as immunochromatographic test (ICT), microscopic agglutination test (MAT), immunoglobulin M (IgM) enzyme-linked immunosorbent assay (ELISA) and in-house polymerase chain reaction (PCR) to detect leptospirosis. Settings and Design: This study using consecutive sampling technique was conducted in a tertiary care centre, Mysore, Karnataka. Subjects and Methods: Samples from 783 suspected cases of leptospirosis in and around Mysore between April 2013 and April 2016 were processed. Samples from 783 patients suspected of leptospirosis were subjected to ICT, IgM ELISA, MAT and in house PCR. Statistical Analysis Used: The statistical analysis was carried out using SPSS software version. Results: Among 783 samples tested, only 14 (1.7%) were positive by ICT, 341 (44%) were positive by IgM ELISA, 368 (47%) were positive by MAT and 393 (50.2%) were positive by in-house PCR. Conclusions: Mysore can be considered endemic for leptospirosis. The in-house PCR based on LipL32 gene proved to be useful in the early diagnosis of leptospirosis. PMID- 30429393 TI - Expanded diagnostic approach to hepatitis E virus detection in patients with acute-on-chronic liver failure: A pilot study. AB - Introduction: Acute decompensation of pre-existing chronic liver disease (CLD), known as acute-on-chronic liver failure (ACLF), is associated with high mortality. Hepatitis E virus (HEV) as a potential cause was studied. Objectives: The objectives of this study are to evaluate the role of HEV in ACLF patients using an IgM anti-HEV antibody enzyme-linked immunosorbent assay (ELISA), HEV antigen ELISA, and a quantitative HEV polymerase chain reaction (PCR). Materials and Methods: In this prospective cross-sectional study, blood samples were collected from 50 ACLF (cases) as defined by the standard guidelines (APASL, 2014) and 50 patients with stable CLD (controls) from January 2015 to August 2016, after obtaining informed consent. Two IgM ELISAs (MP Diagnostics HEV IgM ELISA 3.0, Singapore and Wantai HEV IgM ELISA, Beijing, China) were compared using plasma from cases and controls. In addition, an HEV antigen detection by ELISA (Wantai, Beijing, China) and a real-time PCR for quantification of HEV RNA in plasma and stool were employed. Results: Ethanol was the leading cause of acute insult in ACLF (54%) cases. HEV infection accounted for 20% of cases. Ten ACLF patients (20%) had 1-3 markers of HEV versus two (4%) among controls (P = 0.0138). Among ACLF cases, one had HEV viraemia (403 IU/ml), faecal shedding (2790 IU/ml) and detectable HEV antigenaemia. Agreement between the two anti-HEV IgM ELISAs was 0.638 (kappa value). Conclusion: This study shows that alcohol is a major contributing factor for both underlying CLD and ACLF while HEV is the most common infectious cause for ACLF, suggesting a need for a vaccination in such patients, whenever made available. PMID- 30429394 TI - Evaluation of immune response to hepatitis B vaccine in healthcare workers at a tertiary care hospital. AB - Purpose: Healthcare workers (HCWs) are at high risk of acquiring hepatitis B virus (HBV) infection through occupational exposure which is preventable through hepatitis B vaccination. In the current study, the response to HBV surface antigen (HBsAg) vaccine was assessed in a selected group of HCWs by testing for antibodies against HBsAg (anti-HBs). Methods: Blood samples were collected in all HCWs, who have received the complete schedule of hepatitis B vaccination and anti HBs levels, were assessed quantitatively in sera using ELISA. Results: The age range of the study participants was 20-55 years. The mean months after the last dose of vaccination were 60.36. Among the 85 participants, 96.5% (n = 82) have protective immunity to hepatitis B. The anti-Hbs response was similar in both male and female (P > 0.05). There was a decline in immune response as the age was increasing (P < 0.05). The results of the study found a significant decline in the immune response with time (P < 0.05). The anti-Hbs response was declined with smoking habit (P < 0.05) and with increasing body mass index (P < 0.05). Conclusion: Post-HBsAg vaccination immunity to hepatitis B was 96.5% in HCW and was similar to that of global rates. Increasing age, time period, smoking habit, and overweight were associated with decreased immunity. Many studies are needed in developing newer HBV vaccines with very high immunogenicity. Giving highly immunogenic vaccine to HCWs will ensure safety at work by reducing nosocomial transmission which is very much desired in a resource-limited country. PMID- 30429395 TI - Microbiological and chest X-ray studies on influenza B virus-associated pneumonia. AB - Introduction: The signs and symptoms of influenza B are commonly ignored. Therefore, very few clinical reports are available. This study is an attempt to evaluate the clinical features and characteristics of influenza B virus associated pneumonia patients. Objective: The aim of this study is to investigate the microbiological and characteristics of influenza B virus-associated pneumonia patients. Methodology: Patients with <16 years old with a clinical diagnosis of influenza B virus infection and who had chest radiography within 2 days were enrolled. A total of 49 patients were categorised as the pneumonia group by clinical symptoms and chest X-ray (CXR) findings, whereas 107 patients were categorised as the non-pneumonia group based on the laboratory data and normal CXR findings. Results: The study observed that the age of the patients in the pneumonia group was significantly younger than the non-pneumonia group. The white blood cell (WBC) count of the pneumonia group was also higher. However, the haemoglobin (Hgb) level was lower in the pneumonia group. The C-reactive protein (CRP) level of the pneumonia group was also significantly high. The CXR findings revealed that 28.57% of patients had alveolar consolidation, 32.65% had interstitial infiltration and 40.82% had ground glass opacity. Conclusions: High clinical suspicion is required to detect pneumonia in influenza B virus patients. Based on the CXR findings, the study also suggests that patients with pleural effusion and positive bacterial culture need more attention for the severity of clinical outcome. Moreover, critical care should be given to paediatric patients having higher WBC count, higher CRP level and lower Hgb. These parameters would be helpful to differentiate primary pneumonia from non-pneumonic influenza. PMID- 30429396 TI - Comparing the profile of respiratory fungal pathogens amongst immunocompetent and immunocompromised hosts, their susceptibility pattern and correlation of various opportunistic respiratory fungal infections and their progression in relation to the CD4+T-cell counts. AB - Introduction: Invasive fungal infections are increasingly common in the nosocomial setting. Materials and Methods: The patients were divided into two groups immunocompetent and immunocompromised that is, patients with significant neutropenia <500 neutrophils/MUl for longer than 10 days. microscopy, culture, identification of isolates were done and some specilised tests on serum and BAL for antigen detection were performed. Results: Majority of the patients were young adult males in this study. A higher prevalence of 26.7% was seen in immunocompromised patients. Amongst yeasts, Candida albicans was the predominant species followed by the National AIDS Control that is, Candida glabrata, Candida dubliniensis, Candida parapsilosis and Candida tropicalis in the same order. Amongst moulds, Aspergillus fumigatus was the most common species followed by Aspergillus flavus and Aspergillus niger. Mucor and Penicillium marneffei were seen in a lower prevalence. By Broth microdilution method, isolates of Candida spp. were most sensitive to caspofungin, amphotericin B, ketoconazole and fluconazole in the same order. Isolates of Aspergillus spp. were most sensitive to caspofungin, amphotericin B and itraconazole in the same order. By disc diffusion method, resistance to fluconazole was observed in 6.9% isolates of C. albicans. 50% of C. dubliniensis and 20% of C. glabrata showed resistance to fluconazole. A total mortality of 27.7% was observed during this study. This was distributed as 24.1%, 26.7%, 50%, 50%, 100% and 0% among by patients of candidiasis, aspergillosis, cryptococcosis, pneumocystosis, mucormycosis and penicilliosis. Fifteen per cent were lost to follow-up. Conclusion: Patterns of invasive fungal infections are changing in many ways. In the midst of these evolving trends, IFI of the respiratory tractcontinue to remain important causes of morbidity and mortality. Diagnostic tools can be adequately used only if the treating physician is aware of the propensity of patients to acquire a fungal infection. Thus, continuous awareness and education is crucial for successful management of patients. Judicious use of antifungal medications as prophylactic measures must be employed, particularly in the critically ill and patients of HIV. PMID- 30429397 TI - Changes in hepatitis C virus genotype distribution in chronic hepatitis C infection patients. AB - Purpose: Identification of hepatitis C virus (HCV) genotypes is very important in the selection of antiviral treatment, dose adjustment of antiviral agents, determining the treatment duration and following-up of treatment response. We aimed to determine the distribution pattern of HCV genotypes in chronic hepatitis C infection (CHC) patients. Materials and Methods: We have included 106 CHC patients who were positive in the anti-HCV and HCV-RNA tests performed in our hospital during the 16-month period. Anti-HCV assays were performed on device using a chemiluminescent microparticle immunoassay, while HCV-RNA tests and HCV genotyping assays were performed by real-time polymerase chain reaction. Results: Of the 106 cases; genotype 1b was detected in 67.0%, genotype 3 was detected in 16.0%, genotype 1a was detected in 14.2% and genotype 2 was detected in 2.8% patients. Genotypes 4, 5 and 6 were not detected in our study group. There were no statistically significant differences between the gender and age groups according to the HCV genotype distribution. The genotype 3 detection rate (16%) was the highest rate among the studies compared with the other studies in our country. Conclusions: Events that cause social changes such as war and immigration and intense commercial and touristic activities affect and alter the HCV genotype distribution in HCV-infected patients. For this reason, further multicentre studies are required reflecting all the regions in order to determine the genotype distribution in HCV-infected patients at regular intervals. PMID- 30429398 TI - Use of eschar for the molecular diagnosis and genotypic characterisation of Orientia tsutsugamushi causing scrub typhus. AB - Scrub typhus caused by Orientia tsutsugamushi presents as an acute febrile illness with a varied presentation from mild illness to fatal disease in the absence of appropriate antibiotic treatment. Performing polymerase chain reaction (PCR) on eschar sample acts a rapid diagnostic tool in the early stage of scrub typhus when blood is negative. A total of eight patients from whom both whole blood and eschar samples were collected and tested by nested PCR targeting 56 kDa trichostatin A (TSA) gene to detect O. tsutsugamushi DNA. All (100%) eschar samples and three whole blood samples tested positive. Genetic analysis of the 56 kDa TSA gene sequences showed that the majority were related to Karp reference strains, while one clustered with Kawasaki strain. When present, eschar should be favoured as a diagnostic sample over whole blood in the early phase of infection. PMID- 30429399 TI - The prevalence of occult hepatitis B infection among the blood donors in a tertiary care hospital, Puducherry. AB - Occult hepatitis B infection (OBI) is a cause of concern while screening the blood donors to prevent transfusion-related transmission of infection. This study was conducted to assess the prevalence of OBI using total anti-HBc by ELISA and DNA detection by real time polymerase chain reaction (PCR). The samples included were negative for HBs Ag by ELISA. Out of 1102 samples tested, 156 were positive for total anti-hepatitis B core antigen and 52/156 by real-time PCR. Overall, the prevalence was found to be 4.71% (52/1102). The results indicate that nucleic acid-based testing should be an essential part of screening procedure to prevent missing of OBI. PMID- 30429400 TI - Serotyping of dengue viruses circulating during 2014-2015 in Assam, India. AB - Dengue has become endemic in India with outbreaks caused by all the four serotypes occurring almost every year. Dengue cases have been increasing alarmingly in Assam also. This study aimed to identify the dengue serotypes circulating in Assam. Clinically suspected dengue fever cases were included in the study. Viral RNA was extracted using QIAamp Viral RNA Mini Kit (Qiagen). Nested reverse transcriptase polymerase chain reaction was done for serotyping. The frequency of dengue was 25.23% with a peak during the period from September (22.56%) to October (26.22%). Two serotypes were detected, DEN-1 (72.7%) and DEN 2 (12.1%) and dual infection in 15.1%. PMID- 30429401 TI - Clinical and laboratory characteristics of patients with toxocariasis encountered at a tertiary care centre in North India. AB - Toxocariasis is a neglected soil-transmitted helminthic infection caused by either Toxocara canis or Toxocara cati where humans get infected by accidental ingestion of embryonated eggs, and the definitive hosts are dogs and cats. This study aims to analyse the clinical and laboratory characteristics of Toxocara infected patients and assessment of response to standard treatment with review of literature. The clinical details of patients with Toxocara serology positive for IgG antibodies by ELISA in 5 years (2013-2017) were retrospectively analysed. A total of 29 patients with clinical features and serology suggestive of Toxocara infection were evaluated. A complete history of 14 patients was available for the analysis. Majority (13/14; 96.5%) of cases were children <15 years, males (79%) and belonged to lower socioeconomic status (64.3%). The most common clinical presentation was fever (78.5%) with respiratory symptoms (57%) followed by gastrointestinal features (35.7%). All the patients had eosinophilia (range 8.3% 85%) and raised total IgE levels. Toxocariasis is more common in children, and the true prevalence may be underestimated. In endemic areas, Toxocara workup should be considered in patients with eosinophilia presenting with respiratory and gastrointestinal features. PMID- 30429402 TI - Bioassay and molecular study for detection of insecticide resistance dengue causing mosquito vectors. AB - Nowadays, dengue infection creates a major problem across the country. The vector species carrying dengue infection has progressively started to developed resistance against most of the currently used insecticides. Hence, a study was carried out in dengue-endemic areas of Assam and Arunachal Pradesh to find the current situation of insecticide susceptibility status of dengue vectors. Based on the previous history of dengue incidence, Aedes mosquitoes were collected from Dibrugarh, Kamrup, Sivasagar, Tezpur and Tinsukia districts in Assam and Pasighat district in Arunachal Pradesh to test the insecticide resistance status through bioassay and molecular methods. The WHO standard bioassay test kits were used to detect insecticide susceptibility status among dengue vectors. In molecular study, allele-specific polymerase chain reaction (PCR) method was done for the detection of mutations in paratype voltage-gated sodium channel gene of Aedes aegypti and Aedes albopictus mosquitoes. In bioassay method, 100% A. aegypti mosquitoes were found to be resistant towards dichlorodiphenyltrichloroethane (DDT), 8% towards pyrethroid and 4% towards malathion. Similarly, 92% A. albopictus mosquitoes have shown resistance competency towards DDT, 12% towards pyrethroid and 8% towards malathion. In allele-specific PCR methods, V1016G heterozygous mutations were detected from the field collected A. aegypti and A. albopictus mosquitoes of Tinsukia, Dibrugarh and Sivasagar district. Similarly, F1534C heterozygous mutations were observed from A. aegypti mosquitoes of Tezpur, Tinsukia and Sivasagar district and A. albopictus mosquitoes of Tinsukia, Dibrugarh and Sivasagar district. From the study, it was concluded that the Aedes mosquitoes have progressively started to developed resistance towards commonly used insecticides. PMID- 30429403 TI - Fatal Cryptococcus gattii meningitis with negative cryptococcal antigen test in a HIV-non-infected patient. AB - Cryptococcus gattii predominantly causes central nervous system and pulmonary infection in both immunocompromised and immunocompetent patients with substantial morbidity. We report a case of rapidly fatal meningitis by C. gattii in an HIV non-infected man with CD4 lymphopenia who tested negative for cryptococcal antigen. This case may serve as an alert to its wider occurrence and less explored risk factors. PMID- 30429404 TI - Herpes simplex virus type 2 and cytomegalovirus perigenital ulcer in an HIV infected woman. AB - We report a case of mucocutaneous Herpes Simplex Virus (HSV)-2 and Cytomegalovirus (CMV) infection in a 39-year-old female with acquired immunodeficiency syndrome, who presented with a perigenital ulcer. The patient was receiving antiretroviral treatment (ART) for 3 months before presentation. Scraping from the perigenital ulcer was positive for HSV-2 and Treponema pallidum using polymerase chain reactions (PCR). The extent and duration of the lesions led us to consider the possibility of coinfection with CMV. The patient also tested positive for CMV by PCR. On subsequent follow-up after 8 weeks, the genital lesions had healed completely. This is possibly ascribable to the ART, which led to significant immune reconstitution. PMID- 30429405 TI - Fatal aspergillosis of the renal vasculature in a combined liver-kidney transplant recipient. AB - Invasive aspergillosis remains a problem in solid organs and haematopoietic stem cell transplants. We report a case of 12-year-old female with primary hyperoxaluria with regular haemodialysis for the end-stage renal disease. She underwent a combined liver and renal transplantation which got infected by aspergillosis. In this case study, it is speculated that the most likely source of Aspergillus was contaminated preservative solution (perfusate), resulting in infection within the donor kidney and subsequent systemic infection in the recipient. This case study calls for critical analysis and needs for the routine culture of the preservative solution before transplantation, to detect any fungal contamination and manage it prophylactically. PMID- 30429406 TI - Cutaneous botryomycosis of the foot: A case report and review of literature. AB - Botryomycosis is a chronic bacterial infection that manifests clinically as tumours or plaques that are often ulcerated and have discharging sinuses draining small white-coloured granules. Therefore, they closely mimic mycetoma or other fungal infections. It is most commonly caused by Staphylococcus aureus. It can present as cutaneous or visceral disease. The cutaneous form can invade deep tissue leading to extensive destruction and disfigurement. A 31-year-old female presented with progressive swelling of her right foot over a period of 8 years. She had a disfigured right foot with multiple sinuses discharging pus. X-ray and magnetic resonance imaging of the foot showed invasion and destruction of the deep layers of the foot including the bone. Deep biopsy from the foot showed an abscess cavity with Gram-positive cocci within and bacterial culture grew S. aureus establishing the diagnosis of botryomycosis. Botryomycosis is a rare presentation of a common pathogen and needs to be considered while evaluating a chronic invasive subcutaneous infection. PMID- 30429407 TI - The Release of Monocyte-Derived Tissue Factor-Positive Microparticles Contributes to a Hypercoagulable State in Idiopathic Membranous Nephropathy. AB - AIM: Idiopathic membranous nephropathy (IMN) is an immune-mediated inflammatory disease characterized by a high risk of thromboembolic complications. Microparticles (MPs), a type of extracellular vesicles, have procoagulant properties, especially when they display tissue factor (TF). This study aimed to investigate whether circulating TF-positive MPs contributed to the hypercoagulable state in patients with IMN. METHODS: Twenty adult IMN patients and fourteen healthy subjects were included in the study. The basic indexes of a routine biochemical examination and coagulative function were determined. The plasma levels of MPs were detected by flow cytometry, and TF activity of MPs was examined using an assay kit. The plasma levels of lipopolysaccharide (LPS) were measured by an enzyme-linked immunosorbent assay. RESULTS: Total circulating MPs were not increased in patients with IMN compared with healthy controls. Circulating CD14+/TF+MPs were significantly increased in IMN patients, but this achieved significance was not observed in CD41+/TF+MPs between the two groups. Interestingly, the circulating TF-positive MPs were increased significantly. Plasma MPs TF assays revealed high procoagulant activity, which was positively associated with the D-dimer level in IMN. In addition, circulating LPS in IMN patients were significantly higher than those in the controls. Furthermore, after two hours' incubation with healthy whole blood, LPS enhanced the release of circulating TF-positive MPs and the TF activity of MPs. CONCLUSION: Increased circulating LPS may mediate the release of monocyte-derived TF-positive MPs, which further contributes to the hypercoagulable state in IMN patients. These findings provide an additional mechanism by which patients with IMN have a higher risk of thromboembolic complication. PMID- 30429408 TI - Prestroke Aspirin Use is Associated with Clinical Outcomes in Ischemic Stroke Patients with Atherothrombosis, Small Artery Disease, and Cardioembolic Stroke. AB - AIM: To evaluate the effect of prestroke aspirin (PA) use on initial stroke severity, early neurologic deterioration (END), stroke recurrence, hemorrhagic transformation (HT), and functional outcome in patients with ischemic stroke (IS). METHODS: This was a prospective, observational, multicenter cohort study. The acute IS patients with atherothrombosis (AT), small artery disease (SAD), or cardioembolic (CE) stroke within 24 hours of symptom onset were identified. National Institutes of Health Stroke Scale (NIHSS) scores on admission, clinical outcomes (END, recurrent ischemic stroke [RIS], myocardial infarction [MI], death, and hemorrhagic episodes), and functional outcome (modified Rankin Scale [mRS] scores) at three months after admission were compared between PA users and nonusers. RESULTS: Among the 1,862 patients, 401 (21.5%) reported PA use. The PA users had a significantly lower initial NIHSS score than the non-PA users. The effect was evident in AT stroke, but not in other subtypes. PA use was independently associated with the decreased risk of END. PA use increased the risk of HT; however, it was only associated with increased risk for asymptomatic HT, not for symptomatic HT. PA use was associated with better functional outcomes (mRS scores <=2 points) irrespective of stroke subtypes at three months after admission, despite the increased risk of HT. CONCLUSIONS: PA use may reduce initial stroke severity in AT stroke and the risk of END, and can improve functional outcome at three months irrespective of stroke subtypes. PMID- 30429409 TI - Eukaryotic elongation factor 2 kinase inhibitor, A484954 inhibits noradrenaline induced acute increase of blood pressure in rats. AB - Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) inhibits protein translation through the phosphorylation of its specific substrate, eEF2. We previously demonstrated that eEF2K expression increases in superior mesenteric artery from spontaneously hypertensive rats (SHR) and that eEF2K mediates development of hypertension in SHR. In addition, we recently revealed that A484954, a selective eEF2K inhibitor induced relaxation via opening smooth muscle inward rectifier K+ (Kir) channel in rat isolated superior mesenteric artery. Here, we further examined the effects of A484954 on contractility and blood pressure (BP) in rats. Isometric contraction of rat isolated superior mesenteric artery was measured. BP was measured by a carotid cannulation method. A484954 (10 MUM) inhibited noradrenaline (NA)-induced contraction in a biphasic manner (magnitude of inhibition higher at high dose NA). A484954 also inhibited an alpha1-receptor agonist, phenylephrine-induced contraction, while it was not biphasic. Specifically, a beta-receptor antagonist, propranolol (1 MUM) prevented the A484954-mediated inhibition of NA (high-dose)-induced contraction. A484954 (10 MUM) potentiated a beta-receptor agonist, isoproterenol-induced relaxation, which was completely prevented by BaCl2 (1 mM), a Kir channel blocker. In vivo, A484954 (122 MUg/kg) inhibited NA-induced increase of BP in rats. Another eEF2K inhibitor, NH125 (22 MUg/kg) also inhibited the NA-induced BP increase in rats. In summary, it was concluded that A484954 lowers NA-induced BP rise perhaps through activation of beta2-receptor-Kir channel and subsequent vasorelaxation via inhibiting eEF2K activity. PMID- 30429411 TI - Effects of Ghrelin on the Apoptosis of Rheumatoid Arthritis Fibroblast-Like Synoviocyte MH7A Cells. AB - Ghrelin is a circulating peptide hormone, which involved in promoting feeding and regulating energy metabolism in human and rodents. Abnormal synovial hyperplasia is the most important pathologic hallmark of rheumatoid arthritis (RA), which is characterised by tumor-like expansion. Existing studies indicated that there may exist some relation between the decreased ghrelin and the abnormally proliferating synovial cells in RA. Therefore, the aim of this study is to explore the apoptotic effects of ghrelin on MH7A synovial cells in vitro. MTT assay was used to evaluate the effects of ghrelin on the viability of MH7A cells. TUNEL and flow cytometry were used to test the apoptotic effects of ghrelin. At last, western blot and real-time PCR were performed to explore the expression of caspase -8, -9, -3 after the treatment of ghrelin. MTT experiments showed that ghrelin could inhibit viability of MH7A cells. The results of flow cytometry and TUNEL showed that ghrelin could induce apoptosis of MH7A synovial cells. Western blot showed that expression of cleaved-caspase -8, -9 and -3 were increased in ghrelin stimulation group compared with the control group, while expression of pro-caspase -8, -9, -3 had no significant difference. In mRNA levels, ghrelin can decrease pro-caspase -8, -9, -3 mRNA expression, which confirmed the results of protein levels. Then these apoptotic effects were significantly reversed by [D Lys3] GHRP-6 (ghrelin receptor antagonist). This study found that ghrelin can induce apoptosis of MH7A cells through caspase signaling pathways. PMID- 30429410 TI - Effects of a diet with or without physical activity on angiopoietin-like protein 8 concentrations in overweight/obese patients with newly diagnosed type 2 diabetes: a randomized controlled trial. AB - Angiopoietin-like protein 8 (ANGPTL8) is a newly discovered adipokine plays an important role in energy homoeostasis, obesity and type 2 diabetes (T2D). Although lifestyle modification in obesity and T2D is known to offer metabolic benefits, there is paucity of comprehensive data on change in ANGPTL8. We investigated the effect of lifestyle intervention on ANGPTL8 concentrations. 384 obese/overweight adults with newly diagnosed T2D were randomly assigned (1:1:1) to diet (n = 128), diet + activity (n = 128) or usual care (control, n = 128) groups. All patients received usual care. Besides, the diet group received a calorie-restricted diet aiming for a weight loss of 5-10%. The diet + activity group additionally received a pedometer-based walking program. Primary outcome was change in ANGPTL8 concentration at 6 months. Data were analyzed according to intention-to-treat. From baseline to 6 months, the median ANGPTL8 level changed from 804.38 pg/mL to 792.86 pg/mL in control group. Compared with control, ANGPTL8 decreased with diet (baseline-adjusted between-group difference was 121.00 pg/mL, 95% CI -177.47 to -64.53; p < 0.0001) and diet + activity (-126.16 pg/mL, -181.21 to -71.11; p < 0.0001). There was no greater effect of diet + activity compared with diet (-5.16 pg/mL, - 53.63 to 43.31; p = 0.8348). Both effects disappeared after adjusting for change in body fat, but did not differ significantly when adjusting for physical activity. A 6-month intervention inducing weight loss by a calorie-restricted diet or diet + activity, resulted in significant decrease on ANGPTL8 concentration. These effects were established by change in total body fat, and not by change in physical activity. PMID- 30429413 TI - Effects of storytelling on the childhood brain: near-infrared spectroscopic comparison with the effects of picture-book reading. AB - In children, storytelling provides many psychological and educational benefits, such as enhanced imagination to help visualize spoken words, improved vocabulary, and more refined communication skills. However, the brain mechanisms underlying the effects of storytelling on children are not clear. In this study, the effects of storytelling on the brains of children were assessed by using near-infrared spectroscopy (NIRS). Results indicated significant decreases of the blood flow in the bilateral prefrontal areas during picture-book reading when the subjects were familiarized in comparison to the cases of the subject naive to the stories. However, no significant differences in the blood flow were found during storytelling between the subjects naive and familiarized to the stories. The results indicated more sustained brain activation to storytelling in comparison with picture-book reading, suggesting possible advantages of storytelling as a psychological and educational medium in children. PMID- 30429412 TI - Second-Generation Cryoballoon Ablation for Atrial Fibrillation - A Detailed Analysis of the Impact of Left Atrial Volume Index on Clinical Outcome. AB - BACKGROUND: Pulmonary vein isolation (PVI) by means of cryoballoon is increasingly being used for the treatment of atrial fibrillation (AF). This study assessed whether the left atrial volume index (LAVI) predicts AF recurrence following PVI by means of 2nd-generation cryoballoon (Cryoballoon Advance; CB-A) when comparing persistent AF (PeAF) and paroxysmal AF (PAF). Methods and Results: Patients with drug-resistant AF and undergoing preprocedural computed tomography (CT) and PVI with CB-A were included. LAV was estimated from 3D CT images. A total of 417 patients with AF were included (95 PeAF, 322 PAF patients). After a mean of 22.1+/-9.4 months follow-up, 45/95 (47%) PeAF patients and 254/322 (79%) PAF patients had no recurrence. LAVI was an independent predictor for AF recurrence in PeAF patients (hazard ratio 1.042 per 1 mL/m2; 95% confidence interval 1.006-1.080, P=0.02), but not in PAF patients. In PeAF patients with LAVI <=61 mL/m2, the freedom from recurrence was 78.5% vs. 22.2% in those with LAVI >61 mL/m2 (hazard ratio 5.771, 95% confidence interval 2.434-13.682, P<0.001), and the mid-term success rate was comparable with PAF patients. CONCLUSIONS: LAVI predicted AF recurrence after PVI using CB-A in PeAF patients but not in PAF patients. If LAVI was <=61 mL/m2, the mid-term efficacy among PeAF patients was equivalent to that for PAF patients. PMID- 30429414 TI - Pterostilbene alleviates hydrogen peroxide-induced oxidative stress via nuclear factor erythroid 2 like 2 pathway in mouse preimplantation embryos. AB - Pterostilbene (PTS) in blueberries is a phytoalexin with antioxidant properties. PTS exerts strong cytoprotective effects on various cells via Nuclear Factor Erythroid 2 like 2 (NFE2L2) pathway. We evaluated the antioxidant PTS treatment in mouse preimplantation embryos. In vitro culture media were supplemented with different concentrations of PTS. Treatment of zygotes with 0.25 MUM PTS improved the development of day 4 blastocysts (P < 0.05). Moreover, H2O2 treatment significantly increased the reactive oxygen species level and reduced the glutathione level in mouse blastocyst, whereas PTS treatment counteracted these effects. The fluorescence intensity of apoptotic positive cell was higher in the H2O2 group than in the PTS group. Furthermore, PTS-treated embryos significantly increased the protein expression of NFE2L2 in the nucleus and decreased Kelch like ECH-associated protein1 (KEAP1). PTS treatment significantly increased the expression of downstream target genes involved in the NFE2L2 pathway, such as catalase (CAT), heme oxygenase1 (HMOX1), glutathione peroxidase (GPX), and superoxide dismutase (SOD); these genes confer cellular protection. In addition, PTS treatment significantly increased the expression of anti-apoptotic B-cell lymphoma 2 (BCL2), with a concomitant reduction in the apoptotic Bcl-2-associated X protein (BAX) and Caspase-3 genes in the embryo. PTS treatment also increased the protein expression of BCL2 and reduced the protein expression of BAX in the mouse embryo. In conclusion, PTS activated NFE2L2 signaling pathway in the development of mouse embryos by altering downstream expression of genes involved in the antioxidant mechanisms and apoptosis. PMID- 30429415 TI - Rationale and Design of a Randomized Phase 2 Trial of Gefitinib Plus Bevacizumab vs Gefitinib Alone in Patients with Epidermal Growth Factor Receptor Mutant Non Squamous Non-Small-Cell Lung Cancer: Study Protocol. AB - Combination chemotherapy with platinum preparations is the standard first-line treatment for stage IIIB/IV non-small-cell lung cancer. However, the median survival in patients receiving this therapy is 8 to 10 months, and it is essential to improve the results of chemotherapy in non-small-cell lung cancer. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors hinder EGFR signal transmission by binding to the adenosine triphosphate binding site of intracellular tyrosine kinase and inhibiting the autophospholylation of EGFR. They are a standard initial treatment option in EGFR gene mutation-positive patients. In Japan, gefitinib is routinely used. A combination of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and another antineoplastic drug may be a strategy to further improve treatment outcomes. We planned a randomized phase 2 trial to assess the efficacy and safety of gefitinib plus bevacizumab in such patients. In this study, subjects will be assigned to receive monotherapy with gefitinib (GEF group) or combination therapy with gefitinib and beva cizumab (GEF+BEV group) as the initial treatment at a ratio of 1:1. EGFR gene mutations are frequently detected in Asian patients with non-small cell lung cancer. This study may be significant for establishing a new standard treatment. PMID- 30429416 TI - [Establishment of Test Methods for Overall Migration Test into Vegetable Oil Applied to Food Contact Materials Intended for Contact with Oils and Fatty Foods]. AB - The evaporation residue test designated in the Japanese Food Sanitation Act is used to determine the total migration amount of substances that food contact materials release into foods. Vegetable oil would be the most suitable food simulant for oils and fatty foods, but it is difficult to remove by heating due to its high boiling point, so heptane and 20% ethanol are used as substitute food simulants in the test for plastics and rubbers. The EU has introduced an overall migration test into olive oil for plastics intended to come into contact with oils and fatty foods. This test method is described in European Standard EN1186 2. However, this method has several problems. Therefore, we improved the procedures for weighing samples in a desiccator containing 43% sulfuric acid, extraction of the absorbed vegetable oil using the soaking method with an internal standard, methyl esterification of vegetable oil using sodium methoxide, and the GC conditions for the determination of vegetable oil. The improved method is simpler and much quicker than the original method, and the harmfulness of the reagents is reduced. It can be applied to both plastics and rubbers. Comparative trials showed that the results obtained with this method and EN1186-2 method are equivalent. PMID- 30429418 TI - [Determination of Cyromazine in Livestock Products by LC-MS/MS on an Anion-Cation Exchange Mode ODS Column]. AB - Cyromazine in livestock products was determined using a validated LC-MS/MS method. There are three key points in our methods. First, the extraction was performed with two solutions, methanol and pH 3.0 McIlvaine buffer. The process was optimized for each type of sample. Secondly, cleanup was performed using a reversed-phase and strong cation exchange mixed-mode cartridge. The cartridge was washed with 0.14% ammonium solution. Thirdly, the chromatographic separation was performed on an anion-cation exchange mode ODS column. There was no matrix effect on the extraction and determination for five livestock products. The quantification was carried out using an external standard calibration curve. This new method satisfies the Japanese guideline criteria. Recovery ranged from 77.2 to 92.1%, the relative standard deviation of repeatability (RSDr) was under 2.2%, and RSDwr was under 6.1%. Residual cyromazine was detected in raw milks and eggs. PMID- 30429417 TI - Development of Enzyme-Linked Immunosorbent Assay for Analysis of Total Aflatoxins Based on Monoclonal Antibody Reactive with Aflatoxins B1, B2, G1 and G2. AB - A direct competitive enzyme-linked immunosorbent assay (dc-ELISA) was developed for the determination of total amount of aflatoxin B1, B2, G1 and G2 (AFB1, AFB2, AFG1 and AFG2), using a mouse monoclonal antibody that shows similar reactivity to each of these AFs. The working range of the developed dc-ELISA was 50-230 pg/mL for AFB1, 50-270 pg/mL for AFB2, 60-390 pg/mL for AFG1 and 65-700 pg/mL for AFG2. The recovery of AFs from spiked roasted peanuts was 98%. Further, when 4 samples actually contaminated with AFB1, AFB2, AFG1 and AFG2 were examined, the results of dc-ELISA were highly correlated with the values assigned by the Food Analysis Performance Assessment Scheme. The developed dc-ELISA appears to be suitable for the determination of total AFs at concentrations around the maximum permitted level (10 MUg/kg for all foods) in Japan. PMID- 30429419 TI - [A Screening Analysis Method for Stevia Sweetener in Processed Foods by LC MS/MS]. AB - A LC-MS/MS-based screening method was developed for stevia sweetener in processed foods. After extraction of stevia sweetener from processed foods by dialysis, the dialysate was diluted with water, and stevia sweetener was measured by LC-MS/MS. Recovery from 5 kinds of processed foods spiked with 10 mg/kg of stevioside (SS), 10 mg/kg of rebaudioside A (RS), or 100 mg/kg of alpha-glu-cosyltransferase treated stevia (Gts) product was excellent, and no interfering peak was observed. Thirty-six commercial processed foods indicated as containing "stevia" were analyzed using this established method. Among them, 33 contained SS, 33 contained RS, and 11 contained Gts. Five products contained both stevia extract and Gts. PMID- 30429420 TI - Differentiation of Laboratory Strains of Red Flour Beetle Tribolium castaneum Collected from Various Areas. AB - We recently reported polymorphism in the mitochondrial genes of Tribolium castaneum, a stored grain pest. Here, we show that T. castaneum samples from the main island of Japan can be easily differentiated from samples from other areas by using real-time PCR with minor groove binding (MGB) TaqMan probes containing a single nucleotide polymorphism (SNP) to amplify a 179-bp fragment. This assay was also applicable to samples stored at room temperature for 5 months after natural death, and samples whose DNA was artificially degraded by heat, pressure, or gamma-ray irradiation. PMID- 30429421 TI - [Verification and Improvement of an Official Method for Determining Chlorophyll Decomposition Products Including Pheophorbide]. AB - The official method described in Direction Notification Kanshoku No. 99 (May 8, 1981) for the determination of chlorophyll decomposition products including pheophorbide was verified and improved in order to overcome several problems. Firstly, extraction with a mortar required improvement because of the difficulty of maintaining equal power for a long time. Secondly, the saturated sodium sulfate reagent caused a red-shift of the absorption maximum wavelength from the measured wavelength given in the official method; consequently, the absorption was decreased and a new absorption peak was detected around 729 nm. As a result, chlorophyll decomposition products including pheophorbide were underestimated. Lastly, it was impossible to make up the volume of the diethyl ether layer accurately to 20 mL before measuring the absorption. These points were improved in the modified method, and a validation test was performed. The mean recovery was 82.7% and the within-laboratory reproducibility was 5.8%. PMID- 30429422 TI - [Chlorpyrifos-Methyl, Pirimiphos-Methyl and Fenitrothion Residues in Commercial Wheat Products]. AB - We measured the concentrations of organophosphorus pesticide (chlorpyrifos methyl, pirimiphos-methyl and fenitrothion) residues in domestic and imported commercial wheat products (flour, noodles, cookies) collected from 2008 to 2016. Chlorpyrifos-methyl and fenitrothion in domestic flour samples were detected in 16 out of 34 samples at levels of <0.001 to 0.016 ppm, and in 14 out of 34 samples at levels of <0.001 to 0.004 ppm. Chlorpyrifos-methyl was detected in 22 out of 38 domestic cookies at levels of <0.001 to 0.054 ppm (median: 0.001 ppm). Relatively high concentrations of chlorpyrifos-methyl (0.005 to 0.054 ppm) were found in six domestic cookies containing wheat bran. Pirimiphos-methyl was detected in 32 out of 68 cookies from foreign countries at levels of <0.001 to 0.11 ppm. Pirimiphos-methyl was detected frequently in products imported from Europe. PMID- 30429423 TI - Surveillance of Chlorantraniliprole Residues in Vegetables and Fruits Using LC MS/MS. AB - We measured the residual amounts of chlorantraniliprole in various vegetables and fruits. Sample solutions were prepared according to our routine procedure based on the QuEChERS method and analyzed by LC-MS/MS. Performance characteristics were evaluated for 8 kinds of food samples by means of recovery tests of 5 replicates at the concentration of 10 ng/g. Recoveries and RSDs (%) ranged from 50.2 to 93.4% and from 2.1 to 9.7%, respectively. Application of this method to survey 207 vegetables and 163 fruits gave detection rates of 8.2 and 1.2%, respectively. In vegetables, detection rates were high in okra (4 out of 10 samples), paprika (4 out of 23 samples) and tomato (2 out of 6 samples), and leaf vegetables such as lettuce, mizuna, spinach and wrinkled greens also contained high concentrations of chlorantraniliprole. The highest residual concentration was 571 ng/g in mizuna. The samples containing chlorantraniliprole seemed to be mainly from Asian countries, including samples of domestic Japanese origin. However, none of them contained more than the MRL, which suggests that the use of chlorantraniliprole has been properly controlled. PMID- 30429424 TI - [Concentration of Radioactive Cesium in Domestic Foods Collected from the Japanese Market in Fiscal Years 2014-2016]. AB - Between fiscal years 2014 and 2016, we surveyed the concentration of radioactive cesium in commercial foods produced in areas where there is a risk of radiation contamination due to the Fukushima Daiichi nuclear disaster. The number of samples with a concentration of radioactive cesium that exceeded the regulatory limit (100 Bq/kg for general foods) was 9 out of 1,516 (0.6%) in fiscal 2014, 12 out of 900 (1.3%) in fiscal 2015, and 10 out of 654 (1.5%) in fiscal 2016. Even though some samples were expected to be contaminated with radioactive cesium, because wild mushrooms and edible wild plants were intentionally included in this survey, the percentage of samples that exceeded the regulatory limit was only around 1%. The surveillance results confirmed that the pre-shipment food monitoring conducted by local governments was properly and efficiently performed, although continuous monitoring of the concentration of radioactive cesium in cultivated and wild mushrooms, edible wild plants, and wild animal meats is still required. PMID- 30429425 TI - [Development of LC-MS and LC-MS/MS Methods for Free Asparagine in Grains]. AB - New analytical methods for the determination of free asparagine (Asn), which is a precursor of acrylamide, in grains were developed using LC-MS and LC-MS/MS. Asn was extracted from a sample with 5% (w/v) aqueous trichloroacetic acid solution, appropriately diluted with 0.1% (v/v) formic acid solution, and then analyzed by LC-MS or LC-MS/MS. HPLC separation was performed by isocratic elution on a Penta Fluoro Phenyl (PFP) column using 0.1% (v/v) formic acid and acetonitrile mixture as the mobile phase. The calibration curve was linear in the range of 0.005-0.1 MUg/mL. The mean recoveries from potato starch, non-glutinous rice flour and whole wheat flour ranged from 95.4 to 100.9%, repeatability (RSD) ranged from 0.9 to 6.0%, and within-laboratory reproducibility (RSDwr) ranged from 2.8 to 7.1%. Limits of quantitation (LOQs) were 7 mg/kg for potato starch, and 5 mg/kg for non glutinous rice flour. In addition, an inter-laboratory study was performed in 10 laboratories using 5 kinds of grains (non-glutinous brown rice flour, corn flour, strong flour, whole wheat flour, and whole rye flour), which naturally contained free asparagine. The HORRATR values ranged from 0.4 to 1.0. These results are within the range of the procedural manual of the Codex Alimentarius Commission, confirming the effectiveness of the developed procedures. PMID- 30429426 TI - Low-field magnetic resonance imaging and computed tomography of a calf with aqueductal stenosis caused by web: comparison with normal calves. AB - A 6-day-old female Holstein displayed a dome-shaped skull and cardiac murmur on physical examination. Neurological abnormalities included progressive ataxia, decreased pupillary light reflex, and blindness soon after birth. On diagnostic imaging, CT identified expanded ventricles and thyroid hypoplasia on the left side. MRI detected expanded ventricles, especially in the rostral cerebrum at the mesencephalic aqueduct, compared with normal calves, so we suspected hydrocephalus causing stenosis of the mesencephalic aqueduct. Postmortem examination revealed a structure in the mesencephalic aqueduct resembling the "web" type of aqueductal stenosis described in humans. This case report indicates the utility of describing mesencephalic aqueductal stenosis by web and detection of other malformations on CT and MRI for antemortem diagnosis in calves. PMID- 30429427 TI - Comparison of alfaxalone-medetomidine and tiletamine-zolazepam in rescued common palm civets (Paradoxurus musangus). AB - Forty rescued common palm civets were anesthetized. Twenty animals received intramuscular injections of alfaxalone 5 mg/kg and medetomidine 0.05 mg/kg (A-M group), whereas twenty animals received 5 mg/kg of tiletamine and zolazepam (T-Z group). The A-M group was reversed with atipamazole 0.25 mg/kg. There were no significant differences in the time from anesthetic injection to induction and intubation between the A-M and T-Z groups. The time from the injection of reversal in the A-M group and the time from cessation of isoflurane in the T-Z group to extubation, first response to recovery and ambulation were longer (P<0.05) in the T-Z group. The T-Z group recorded lower (P<0.05) rectal temperatures compared to the A-M group. This study showed that both drug combinations can be used effectively for the immobilization of civets. The A-M combination provided better anesthetic depth, but with higher incidence of bradycardia and hypoxemia. The recovery time was reduced significantly as atipamezole was used as a reversal agent in the A-M combination. PMID- 30429428 TI - Multicenter, Prospective Study on Respiratory Stability During Recovery From Deterioration of Chronic Heart Failure. AB - BACKGROUND: The respiratory instability frequently observed in advanced heart failure (HF) is likely to mirror the clinical status of worsening HF. The present multicenter study was conducted to examine whether the noble respiratory stability index (RSI), a quantitative measure of respiratory instability, reflects the recovery process from HF decompensation. Methods and Results: Thirty six of 44 patients hospitalized for worsening HF completed all-night measurements of RSI both at deterioration and recovery phases. Based on the signs, symptoms, and laboratory data during hospitalization, the Central Adjudication Committee identified 22 convalescent patients and 14 patients with less extent of recovery in a blinded manner without any information on RSI or other respiratory variables. The all-night RSI in the convalescent patients was increased from 27.8+/-18.4 to 34.6+/-15.8 (P<0.05). There was no significant improvement of RSI, however, in the remaining patients with little clinical improvement. Of the clinical and laboratory variables, on stepwise linear regression modeling, body weight, peripheral edema, and lung congestion were closely related to the RSI of recovered patients and accounted for 56% of the changes in RSI (coefficient of determination, R2=0.56). CONCLUSIONS: All-night RSI, a quantitative measure of respiratory instability, could faithfully reflect congestive signs and clinical status of HF during the recovery process from acute decompensation. PMID- 30429429 TI - Pro-Arrhythmogenic Effects of Heterogeneous Tissue Curvature - A Suggestion for Role of Left Atrial Appendage in Atrial Fibrillation. AB - BACKGROUND: The arrhythmogenic role of complex atrial morphology has not yet been clearly elucidated. We hypothesized that bumpy tissue geometry can induce action potential duration (APD) dispersion and wavebreak in atrial fibrillation (AF). Methods and Results: We simulated a 2D-bumpy atrial model by varying the degree of bumpiness, and 3D-left atrial (LA) models integrated by LA computed tomographic (CT) images taken from 14 patients with persistent AF. We also analyzed wave-dynamic parameters with bipolar electrograms during AF and compared them with LA-CT geometry in 30 patients with persistent AF. In the 2D-bumpy model, APD dispersion increased (P<0.001) and wavebreak occurred spontaneously when the surface bumpiness was greater, showing phase transition-like behavior (P<0.001). The bumpiness gradient 2D-model showed that spiral wave drifted in the direction of higher bumpiness, and phase singularity (PS) points were mostly located in areas with higher bumpiness. In the 3D-LA model, PS density was higher in the LA appendage (LAA) compared with other parts of the LA (P<0.05). In 30 persistent-AF patients, the surface bumpiness of LAA was 5.8-fold that of other LA parts (P<0.001), and exceeded critical bumpiness to induce wavebreak. Wave dynamics complexity parameters were consistently dominant in the LAA (P<0.001). CONCLUSIONS: Bumpy tissue geometry promoted APD dispersion, wavebreak, and spiral wave drift in in-silico human atrial tissue, and corresponded to clinical electroanatomical maps. PMID- 30429430 TI - Structure-Activity Relationship of Biakamide, Selective Growth Inhibitors under Nutrient-starved Condition from Marine Sponge. AB - The tumor microenvironment is considered as one of the important targets for anticancer drug discovery. In particular, nutrient deficiency may be observed in tumor microenvironment; biakamides A-D (1-4) isolated from marine sponge Petrosaspongia sp. as growth inhibitors against cancer cells adapted to glucose deprived conditions have potential as new drugs and tools for elucidating adaptation mechanisms to these conditions. In this paper, we investigated structure-activity relationship (SAR) of biakamide to create easily accessible analog and gain insights about participation of the substructures to growth inhibitory activity toward development of anticancer drug. This work revealed that 14,15-dinor-biakamide C (5), which is easily accessible, has similar activity to natural biakamide C (3). In addition, detailed SAR study showed the terminal acyl chain is important for interacting with target molecule and amide part including thiazole ring has acceptability to convert structures without losing activity. PMID- 30429432 TI - In-Hospital Electrical Storm in Acute Myocardial Infarction - Clinical Background and Mechanism of the Electrical Instability. AB - BACKGROUND: Recurrent ventricular tachycardia (VT) and fibrillation (VF), the so called "electrical storm" (ES) occurs at various stages of acute myocardial infarction (AMI), but its incidence, background, and short-term prognosis remain unclear. Methods and Results: A retrospective observational study was performed using the registry database of the Tokyo CCU Network. The individual data of 6,003 patients with AMI during 2011-2012 was corrected. ES was defined as more than 3 episodes of sustained VT/VF during a 24-h period as first documented after hospitalization. ES occurred in 55 patients after admission (0.9%). The ES(+) group had more severe heart failure (Killip class >III), more extensive MI (peak CK), greater inflammatory reaction (CRP), history of diabetes, and more frequent application of hemodialysis as compared with the ES(-) group (n=5,865). When the ES patients were divided into Early-ES (n=37: ES occurred <=48 h after the onset of MI) and Late-ES (n=15 >48 h after onset of MI) groups, logistic regression analysis revealed that Early-ES was associated with severity of MI, whereas Late ES was related to systemic disorders, including inflammation, renal dysfunction, or diabetes. Late-ES was an independent predictor of in-hospital death. CONCLUSIONS: In-hospital ES was a rare clinical manifestation of AMI. The features and background of the ES varied as time elapsed after admission for MI. PMID- 30429431 TI - Specialty-Related Differences in the Acute-Phase Treatment and Prognosis in Patients With Acute Heart Failure - Insights From REALITY-AHF. AB - BACKGROUND: The aim of this study was to assess specialty-related differences in the treatment for patients with acute heart failure (AHF) in the acute phase and subsequent prognostic differences. Methods and Results: We analyzed hospitalizations for AHF in REALITY-AHF, a multicenter prospective registry focused on very early presentation and treatment in patients with AHF. All patients were classified according to the medical specialty of the physicians responsible for contributed most to decisions regarding the initial diagnosis and treatment after the emergency department (ED) arrival. Patients initially managed by emergency physicians (n=614) or cardiologists (n=911) were analyzed. After propensity-score matching, vasodilators were used less often by emergency physicians than by cardiologists at 90 min after ED arrival (29.8% vs. 46.1%, P<0.001); this difference was also observed at 6, 24, and 48 h. Cardiologists administered furosemide earlier than emergency physicians (67 vs. 102 min, P<0.001). However, the use of inotropes, noninvasive ventilation, and endotracheal intubation were similar between groups. In-hospital mortality did not differ between patients managed by emergency physicians and those managed by cardiologists (4.1% vs. 3.8%, odds ratio 1.12; 95% confidence interval 0.58 2.14). CONCLUSIONS: Despite differences in initial management, no prognostic difference was observed between emergency physicians and cardiologists who performed the initial management of patients with AHF. PMID- 30429433 TI - Change in Pericardial Fat Volume and Cardiovascular Risk Factors in a General of Japanese Men. PMID- 30429434 TI - Methotrexate-associated Lymphoproliferative Disorder of the Stomach Presumed to Be Mucosa-associated Lymphoid Tissue Lymphoma. AB - The number of patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) is increasing. We describe a case of MTX-LPD of the stomach. After treatment with methotrexate for rheumatoid arthritis, the patient developed left cervical lymphadenopathy and an ulcerative lesion in the stomach, which was presumed to be a mucosa-associated lymphoid tissue (MALT) lymphoma. However, we suspected MTX-LPD, based on the clinical course and the positivity of in situ hybridization for the detection of the Epstein-Barr encoding region. After the cessation of MTX, the left cervical lymphadenopathy and the gastric lesion disappeared. This is first report of gastric MTX-LPD that was presumed to be MALT lymphoma. PMID- 30429435 TI - Retrospective clinical study of 296 patients with mass lesions of the tongue. AB - To better understand the clinical features of mass lesions of the tongue, we retrospectively evaluated frequency, recurrence rate, and complications in 296 patients who had undergone surgery for such lesions. The diagnoses were fibroma (43.6%), mucous cyst (14.2%), papilloma (11.8%), hemangioma (7.8%), granuloma (6.4%), lipoma (1.4%), schwannoma (1.0%), ectopic tonsil (0.7%), and other (13.2%). Recurrence was noted in two patients (0.7%). Twenty-two patients (7.4%) developed surgical complications, including lingual nerve paralysis (6.4%), glossodynia (0.6%), and postoperative infection (0.3%). Lingual nerve paralysis was observed in the ventral portion (42.1%) of the tongue, apex (36.8%), lateral border (10.5%), and dorsum (10.5%). When all sites were considered together, there was no significant difference in the number of patients presenting with lingual nerve paralysis (P = 0.075). However, there were significant differences in lingual nerve paralysis at the lateral border (P < 0.05), apex (P < 0.05), and dorsum (P < 0.001) but not at the ventral portion (P > 0.05) in the size of the patients with versus without it which suggests that the risk of lingual nerve paralysis is higher at the ventral tongue, regardless of tumor size. These results shed light on the clinical features of mass lesions of the tongue. PMID- 30429436 TI - Differential dendritic cell responses to cell wall mannan of Candida albicans, Candida parapsilosis, and Candida dubliniensis. AB - Mannan (mannosylated glycoproteins) in the outermost layer of the Candida cell wall may be the first molecules that interact with host dendritic cells (DCs) and activate immune responses that determine disease outcomes. However, little is known about how different mannan structures of common oral Candida species affect DC activation. The effects of heat-inactivated (HI) yeast cells and soluble mannan of Candida albicans, Candida parapsilosis, and Candida dubliniensis on bone marrow-derived DC (BMDC) responses were compared. HI Candida and the mannan exhibited different effects on BMDC activation and functions, which could be due to other carbohydrate compositions in the yeast cell wall. Among Candida mannan, the C. albicans mannan was the weakest stimulus and induced only interferon (IFN) gamma production. This suggests the possibility that C. albicans mannan may skew T helper (Th) responses from protective Th17 toward Th1. In contrast, C. parapsilosis mannan caused strong BMDC activation and high production of several proinflammatory cytokines which possibly promote hyperinflammation. Meanwhile, C. dubliniensis mannan induced moderate BMDC responses, which may correlate with its lower pathogenicity. Therefore, mannan of each Candida species play distinct roles in DC responses and may be involved in the immunopathogenesis and disease severity of oral candidiasis as well as other Candida infection. PMID- 30429437 TI - Expression of the Forkhead box transcription factor Foxo3a in human periapical granulomas. AB - It has been reported that Forkhead box transcription factor class O3a (Foxo3a) is expressed in rheumatoid arthritis, a chronic inflammatory condition accompanied by bone resorption, and plays a role in its pathology. However, it has remained unclear whether Foxo3a is involved in the pathogenesis of periapical granulomas. The present study was performed to compare the expression of Foxo3a in periapical granulomas and healthy gingival tissues. Samples were obtained surgically from patients, and subjected to hematoxylin-eosin staining for histopathologic diagnosis. Two-color immunofluorescence staining was also performed using antibodies against Foxo3a and markers for three types of inflammatory cells: neutrophils, T lymphocytes, and B lymphocytes. This revealed that Foxo3a was expressed in all three cell types in periapical granulomas but not in healthy gingival tissues. Foxo3a was expressed in 82.1%, 78.3%, and 77.5% of neutrophils, T lymphocytes, and B lymphocytes, respectively, and statistical analysis using the Kruskal-Wallis test followed by the Steel-Dwass test showed no significant difference of Foxo3a expression among the three cell types. Our results suggest that Foxo3a transcription factors may be involved in the pathogenesis of periapical granulomas. PMID- 30429438 TI - Effects of xylitol-containing chewing gum on the oral microbiota. AB - In this interventional study, a randomized controlled trial was used to evaluate the short-term effects of xylitol-containing chewing gum on the salivary microbiota. In total, 70 healthy adult men recruited from the Japan Ground Self Defense Force participated in the study during a 2-day training at Yamaguchi camp, Yamaguchi Prefecture, Japan. The men were randomly divided into two groups: one group chewed two pieces of xylitol-containing chewing gum 7 times/day for 2 days (n = 34) and the other did not (n = 36). Baseline and follow-up stimulated saliva samples were collected and the salivary microbial composition was assessed using the 16S rRNA gene next-generation sequencing analysis. The total salivary bacterial count was quantified using a quantitative real-time PCR system. No statistically significant difference was found between the two groups regarding any parameter analyzed in the baseline samples; however, the follow-up samples of the test group showed significantly lower total salivary bacterial count than those of the control group. Conversely, no significant difference was observed in the overall composition of the salivary microbiota between the baseline and follow-up samples of the two groups. These results indicate that xylitol containing chewing gum inhibits the increase in total salivary bacteria over a short time during which the salivary microbial composition is not affected. PMID- 30429439 TI - Metabolism of Natural Highly Unsaturated Fatty Acid, Tetracosahexaenoic Acid (24:6n-3), in C57BL/KsJ-db/db Mice. AB - Tetracosahexaenoic acid (THA; 24:6n-3) is a natural, n-3 highly unsaturated fatty acid (n-3HUFA) that exists in fish, including Baltic herring (Clupea harengus) and the flathead flounder (Hippoglossoides dubius). In this study, natural n 3HUFAs, i.d. eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and THA were administrated to C57BL/KsJ-db/db mice for 4 weeks and the liver and serum lipid profiles, hepatic enzyme activity, expression of mRNA related to lipid metabolism, and adiponectin serum levels were then analyzed. The results showed that THA had the highest activity in suppressing hepatic triglyceride (TG) accumulation and increase in liver weight among the test groups. Furthermore, THA increased adiponectin levels in serum. These results indicate that THA is an excellent natural n-3HUFA that can suppress the development of metabolic syndromes and circulatory system diseases. The order of the n-3HUFA activity was THA > DHA > EPA in almost all the factors examined here. In a previous study of ours, the order was DHA > DPA > EPA, so the final order was summarized as THA > DHA > DPA > EPA. This order clearly translates to the rule that "the number of double bonds and carbon atoms in the n-3HUFA structure relates to their clinical functions". PMID- 30429440 TI - Role of Borage Seed Oil and Fish Oil with or without Turmeric and Alpha- Tocopherol in Prevention of Cardiovascular Disease and Fatty Liver in Rats. AB - The aim of the present research was to Study the prevention of dyslipidemia, oxidative stress, inflammation and fatty liver as risk factors for cardiovascular disease via intervention by borage oil (B) and fish oil (F) with or without turmeric (T) and alpha-tocopherols (TC). Fatty acids were assessed in both oils while curcuminoids were determined in turmeric. Rats were divided into; first group fed on balanced diet and designated as normal control (NC), second fed on dyslipidemic and steatohepatitis (DS) inducer diet which represented the DS control group and groups 3-6 fed on DS inducer diet with daily oral administration of B, B+T+TC, F and F+T+TC; respectively for 5 weeks. Liver fat and plasma lipid profile, oxidative stress and inflammatory biomarker and liver and heart histopathology were assessed. Results showed gamma linolenic to be 21.01% in B. F contained eicosapentaenoic as 22.768% and docosahexaenoic acid as 13.574%.Total curcuminoids were 4.63 mg/g turmeric. The DS control group showed significant dyslipidemia, elevated malondialdehyde (MDA), tumor necrosis factor alpha and liver fat with significant reduction in total antioxidant capacity (TAC) compared to NC. The different treatments produced significant improvement in all the parameters and histopathology. F was superior to B in ameliorating liver histopathological changes while B was more efficient in elevating TAC. B was more promising in improving lipid profile and liver fat compared to B + T + TC, while the latter was superior in improving MDA and liver histopathology. Fish oil was more efficient than F+TC+T except for TAC and high density lipoprotein cholesterol which were more improved on addition of TC and T. Conclusion: Borage and fish oil with or without antioxidants protect from cardiovascular and fatty liver diseases with variable degrees. PMID- 30429441 TI - Portable Mid-Infrared Device and Chemometrics for the Prediction of Low (0.5%) Total Trans Fat Content in Fast Foods. AB - The ruling that partially hydrogenated oils (PHO) are no longer "generally recognized as safe (GRAS)," has accelerated the replacement of PHO ingredients with fat alternatives having increasingly lower or no trans fat content. In the present study, we developed a Fourier-transform infrared (FTIR) spectroscopic procedure in conjunction with multivariate partial least squares regression (PLSR) and found it suitable for the accurate prediction of low (0.5%) total trans fat content, as percentage of total fat, measured as fatty acid methyl esters (FAME), in the lipids extracted from 24 representative fast foods. This multivariate data analysis approach is relevant because the precision of the current univariate FTIR official method (AOCS Cd 14-09) is reportedly poor below 2% of total fat, while PLSR has allowed us to accurately predict the concentration of low trans fat in fast foods. The performance of a portable FTIR device was also evaluated and compared to that of a benchtop FTIR spectrometer. For both infrared data sets, PLSR-predicted concentrations of total trans FAME, ranging from approximately 0.47% to 11.40% of total FAME, were in good agreement with those determined by a primary reference gas chromatography (GC) method (R2>0.99); high prediction accuracy was also evidenced by low root mean square error of cross-validation (RMSECV) values. The lowest RMSECV error of 0.12% was obtained with the portable device. The lowest total trans FAME concentration, determined by GC to be 0.42%, was accurately predicted by the portable FTIR/PLSR procedure as 0.47% of total FAME. PMID- 30429442 TI - Insecticidal Activities and Chemical Composition of the Essential Oils of Ajania nitida and Ajania nematoloba from China. AB - In this work, we investigated insecticidal and repellent activities of the essential oils extracted from Ajania nitida and Ajania nematoloba against Tribolium castaneum and Lasioderma serricorne adults. The components of essential oils were analyzed by GC-MS. The main components of A. nitida oil were camphor (20.76%), thujone (18.64%), eucalyptol (13.42%), borneol (8.32%) and those of A. nematoloba oil were beta-pinene (34.72%), eucalyptol (24.97%) and verbenol (20.39%). The results showed that the two essential oils possessed insecticidal and repellent activities against two species of insects. A. nitida oil possessed contact and fumigant toxicity against T. castaneum (LD50 = 30.10 ug/adult and LC50 = 21.07 mg/L air) and L.serricorne (LD50 = 17.51 ug/adult and LC50 = 11.23 mg/L air). A.nematoloba oil showed contact and fumigant toxicity against T. castaneum (LD50 = 102.29ug/adult and LC50 = 69.45 mg/L air) and contact toxicity against L.serricorne (LD50 = 53.43 ug/adult), but no obvious fumigant effect was observed against L.serricorne. Both of essential oils possessed strong repellent activity against T. castaneum and certain repellent activity against L.serricorne. Especially, A. nematoloba oil showed the same level percentage repellency as DEET(the positve control) against T. castaneum. The results indicated that the essential oils of A. nitida and A. nematoloba had the potential to be developed as natural insecticides and repellents for the control of T. castaneum and L.serricorne. PMID- 30429443 TI - Application of Glycolipid Biosurfactants as Surface Modifiers in Bioplastics. AB - Surface properties of cast films of poly(lactic acid) (PLA) containing 1 wt% of several glycolipid-type biosurfactants (BSs) were investigated. The wettability of PLA films containing a homologue of mannosylerythritol lipids (MEL-B), lactone form sophorolipid (LSL), or cellobiose lipid (CL) was drastically higher than that of untreated PLA and several synthetic surfactants-containing PLA. Surface wettability was also dependent on the hydrophilicity of the substrate used during solvent casting of the PLA films. The wetting behavior of the opposing sides of MEL-B-containing films prepared on glass substrates differed significantly; the contact angle on the side of the film that had been in contact with the glass surface was significantly lower than that obtained on the side of the film that had been in contact with air. Time-of-flight secondary ion mass spectrometry (TOF SIMS) analysis results showed that the MEL in MEL-B-containing thin PLA cast films was localized to a thin surface layer. These results suggest self-assembly of MEL-B and micro-phase separation between the PLA matrix and MEL-B domains. This resulted in the localization and orientation of MEL-B at the surface of the cast PLA film, which determined its specific wetting behavior. PMID- 30429444 TI - TLC Screening Profile of Secondary Metabolites and Biological Activities of Salisapilia tartarea S1YP1 Isolated from Philippine Mangroves. AB - The Salisapilia species are estuarine oomycetes of the mangrove and saltmarsh ecosystem. To date, reports on the secondary metabolites and biological activities of these microorganisms are wanting. In this study, secondary metabolites in broth ethyl acetate extracts (BEAE) and mycelial ethyl acetate extracts (MEAE) of Salisapilia tartarea S1YP1 isolated from yellow senescent mangrove leaves were screened by Thin Layer Chromatography (TLC). Extracts were assayed for antioxidant, antibacterial, alpha- glucosidase inhibition, and cytotoxic activity. The TLC detected anthraquinones, anthrones, flavonoids, phenols, and triterpenes in both BEAE and MEAE. Coumarins were detected in BEAE but not in MEAE. Quantifying the total phenolics and total flavonoids content of the extracts in terms of gallic acid and quercetin equivalents, respectively shows that BEAE has higher total phenolic and flavonoid contents than MEAE. BEAE exhibited significant antioxidant activities through measurements of free radical scavenging activity against DPPH, hydroxyl, nitric oxide, and superoxide anion radicals as well as the ability to chelate Fe2+ metal ion. BEAE significantly inhibited in a dose-dependent manner alpha-glucosidase activity and selectively inhibited HepG2 cell proliferation. Antioxidant, alpha- glucosidase inhibitory, and cytotoxic activities have not been observed for MEAE. Both BEAE and MEAE do not have antibacterial activity. PMID- 30429445 TI - The Antioxidation of Different Fractions of Dill (Anethum graveolens) and Their Influences on Cytokines in Macrophages RAW264.7. AB - Dill (Anethum graveolens L.) has been shown strong antioxidative and immune propertise, but the precise potency and action mechanisms remain largely elusive. This study is to dissect the different fractions' antioxidant power and antiinflammatory function. We extracted 4 fractions from China original dill with ether (DI-E), ethyl acetate (DI-EA), n-butanol (DI-B) and water (DI-W), and performed 4 different kinds of antioxidative analysis together with vitamine C (Vc): DPPH, ABTS, reducing power and TPTZ-FRAP. For correlated compounds in antioxidant assays Folin-Ciocalteu's analysis was performed. For antiinflammation, cell proliferation by MTT, NO molecules and interleukin-1 and 6 in supernatant were detected by Griess reaction and Elisa, respectively, and gene expression of inducible nitric oxide synthase (iNOS) was analyzed by RT-PCR. The strength of antioxidant activity was Vc > DI-EA > DI-B > DI-W > DI-E. Folin Ciocalteu's analysis showed that antioxidant power was correlated to phenolic compounds. However, in antiinflammatory assays DI-E was most active one by cell proliferation, iNOS's gene expression, and secretion of interleukin IL-1 and 6 in macrophage RAW264.7. The antioxidant fraction and antiinflammatory fraction of the dill were determined. The certain fractions of dill may be strong at antioxidation, but weak at antiinflammation, vice versa. Thus dill has anti ageing and anticancer potential, a good resource for functional food and ancillary drugs of rehabilitation. PMID- 30429446 TI - High Internal Phase Emulsion Gels Stabilized by Natural Casein peptides. AB - The surface and interfacial properties of casein-hydrolyzed peptides were evaluated using measurement of surface and interfacial tensions, surface viscosity, dynamic light scattering (DLS), and freeze-fracture transmission electron microscopy (FF-TEM). In this study, high internal oil phase emulsion (HIPE) gels were successfully prepared, using the surface and interfacial properties of casein peptides. The casein peptides exhibited surface and interfacial activities. The estimated critical micelle concentration (CMC) and gammaCMC values were 3.0 mg/mL and 47.8 mN/m, and the average size of casein peptide micelles was 13.2 +/- 1.7 nm. The surface shear viscosity of an aqueous casein peptide solution at 10 mg/mL was 1603 uPa ms, which is fifteen times larger than that of sodium dodecyl sulfate (SDS, 106 uPa ms). The larger surface viscosity of casein peptide adsorbed layer could stabilize emulsions and prevent flocculation and coalescence. High internal oil phase gel emulsions were then prepared by slowly adding oil and polyisobutene into an aqueous casein peptide solution/glycerol mixture with different compositions. Based on the pseudo ternary 15 wt% aqueous casein peptide solution/polyisobutene/glycerol phase diagram, the HIPE containing the maximum 88.1 wt% (91.5 vol%) of oil is obtained by the addition of 0.36 wt% of casein peptides. The use of only a small amount of protein-hydrolyzed peptides instead of the commonly used synthetic surfactants for HIPE preparation has great advantages for the widespread application of HIPE technology. PMID- 30429447 TI - Effects of beta-Sitosteryl Sulfate on the Properties of DPPC Liposomes. AB - The effect of beta-sitosteryl sulfate (PSO4) on the liposomal size, stability, fluidity, and dispersibility of DPPC liposomes prepared by vortex mixing, bath sonication, and probe-sonication has been studied. PSO4 significantly decreases the particle size of the multilamellar liposomes (MLVs). The sizes of the vortexmixed and the bath-sonicated liposomes vary as a function of PSO4 concentration. On the other hand, PSO4 has only little effect on the particle sizes of probe sonicated liposomes. In some cases, the liposomal stability at higher PSO4 concentrations depends on the preparation method. PSO4 improves the dispersibility of the DPPC liposomes and enhances their hydration. It also increases the fluidity of the liposomes prepared by each method. Our results suggest that liposomes consisting of DPPC and PSO4 can be suitable as a cosmetic or pharmaceutical ingredient for the effective delivery of the active components into the body. PMID- 30429449 TI - Comparison of Rearranged During Transfection (RET) Gene Rearrangements in Primary Versus Metastatic Non-Small Cell Lung Cancer (NSCLC). AB - BACKGROUND RET rearrangements have been reported in 30% of papillary thyroid carcinomas and 1-2% of non-small cell lung cancer (NSCLC). In these tumors, RET gene fusion product provides a constitutively active tyrosine kinase (TKR), leading to uncontrolled cellular proliferation, differentiation, and migration. In this investigation we assessed the positivity rate of RET gene rearrangement in primary and metastatic non-small cell lung cancer and explored their relationships. MATERIAL AND METHODS Between January 2013 and May 2015, we collected 384 cases of primary metastatic non-small cell lung cancer, which included 246 matched metastatic tumors cases from multiple centers. The RET rearrangement uniformity in metastatic lymph nodes and tumor specimens were contrasted and the relationships between RET rearrangement and patients' clinical features were investigated. RESULTS For those 384 cases, 7 (1.82%) cases had tumors with identified RET rearrangement. Among the 246 paired cases, 3 (1.22%) cases of primary tumor had identified RET rearrangement and 2 (0.81%) cases of metastases had identified RET rearrangement. The sensitivity was 66.67% (2/3) and the specificity was 100% (243/243). CONCLUSIONS The results of this research indicate that the metastases of non-small cell lung cancer can predict RET rearrangement of the primary tumor tissue in the majority of cases. Testing for RET rearrangement in metastases can be used as an alternative to testing of primary tumor tissue if it is inaccessible. PMID- 30429450 TI - An Unusual Case of Intestinal Malrotation Causing Duodenal Obstruction by a Looped Appendix. AB - BACKGROUND Bowel obstruction is a mechanical or functional obstruction of the intestines which prevents the normal movement of the products of digestion. Intestinal malrotation is one of the rarest causes of mechanical bowel obstruction. In adults, the incidence rate is 0.2%, and 15% of all patients with confirmed diagnosis remain asymptomatic throughout life. Surgery is generally required when the patient is symptomatic. CASE REPORT A 30-year-old man with multiple admissions for chronic intermittent colicky abdominal pain since childhood, was admitted for symptoms suggestive of proximal small bowel obstruction. Tomographic imaging identified a midgut malrotation and a duodenal obstruction by a non-diseased displaced appendix. Laparoscopic liberation of the duodenum and the terminal ilium was done successfully. CONCLUSIONS Intestinal malrotation is infrequently encountered in the adult population, but it should be kept in mind as a differential diagnosis whenever a case of acute intestinal obstruction in an adult presents without any significant past surgical history. PMID- 30429451 TI - Glucocorticoid-mediated ER-mitochondria contacts reduce AMPA receptor and mitochondria trafficking into cell terminus via microtubule destabilization. AB - Glucocorticoid, a major risk factor of Alzheimer's disease (AD), is widely known to promote microtubule dysfunction recognized as the early pathological feature that culminates in memory deficits. However, the exact glucocorticoid receptor (GR)-mediated mechanism of how glucocorticoid triggers microtubule destabilization and following intracellular transport deficits remains elusive. Therefore, we investigated the effect of glucocorticoid on microtubule instability and cognitive impairment using male ICR mice and human neuroblastoma SH-SY5Y cells. The mice group that was exposed to corticosteroid, the major glucocorticoid form of rodents, showed reduced trafficking of alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) 1/2 and mitochondria, which are necessary for memory establishment, into the synapse due to microtubule destabilization. In SH-SY5Y cells, cortisol, the major glucocorticoid form of humans, also decreased microtubule stability represented by reduced acetylated alpha-tubulin to tyrosinated alpha-tubulin ratio (A/T ratio), depending on the mitochondria GR-mediated pathway. Cortisol translocated the Hsp70-bound GR into mitochondria which thereafter promoted GR-Bcl-2 interaction. Increased ER-mitochondria connectivity via GR-Bcl-2 coupling led to mitochondrial Ca2+ influx, which triggered mTOR activation. Subsequent autophagy inhibition by mTOR phosphorylation increased SCG10 protein levels via reducing ubiquitination of SCG10, eventually inducing microtubule destabilization. Thus, failure of trafficking AMPAR1/2 and mitochondria into the cell terminus occurred by kinesin-1 detachment from microtubules, which is responsible for transporting organelles towards periphery. However, the mice exposed to pretreatment of microtubule stabilizer paclitaxel showed the restored translocation of AMPAR1/2 or mitochondria into synapses and improved memory function compared to corticosterone-treated mice. In conclusion, glucocorticoid enhances ER mitochondria coupling which evokes elevated SCG10 and microtubule destabilization dependent on mitochondrial GR. This eventually leads to memory impairment through failure of AMPAR1/2 or mitochondria transport into cell periphery. PMID- 30429452 TI - Inhibition of STAT5A promotes osteogenesis by DLX5 regulation. AB - The regulation of osteogenesis is important for bone formation and fracture healing. Despite advances in understanding the molecular mechanisms of osteogenesis, crucial modulators in this process are not well-characterized. Here we demonstrate that suppression of signal transducer and activator of transcription 5A (STAT5A) activates distal-less homeobox 5 (DLX5) in human bone marrow-derived stromal cells (hBMSCs) and enhances osteogenesis in vitro and in vivo. We show that STAT5A negatively regulates expression of Dlx5 in vitro and that STAT5A deletion results in increased trabecular and cortical bone mass and bone mineral density in mice. Additionally, STAT5A deletion prevents age-related bone loss. In a murine fracture model, STAT5A deletion was found to significantly enhance bone remodeling by stimulating the formation of a fracture callus. Our findings indicate that STAT5A inhibition enhances bone formation by promoting osteogenesis of BMSCs. PMID- 30429453 TI - Clinical significance of APOB inactivation in hepatocellular carcinoma. AB - Recent findings from The Cancer Genome Atlas project have provided a comprehensive map of genomic alterations that occur in hepatocellular carcinoma (HCC), including unexpected mutations in apolipoprotein B (APOB). We aimed to determine the clinical significance of this non-oncogenetic mutation in HCC. An Apob gene signature was derived from genes that differed between control mice and mice treated with siRNA specific for Apob (1.5-fold difference; P < 0.005). Human gene expression data were collected from four independent HCC cohorts (n = 941). A prediction model was constructed using Bayesian compound covariate prediction, and the robustness of the APOB gene signature was validated in HCC cohorts. The correlation of the APOB signature with previously validated gene signatures was performed, and network analysis was conducted using ingenuity pathway analysis. APOB inactivation was associated with poor prognosis when the APOB gene signature was applied in all human HCC cohorts. Poor prognosis with APOB inactivation was consistently observed through cross-validation with previously reported gene signatures (NCIP A, HS, high-recurrence SNUR, and high RS subtypes). Knowledge based gene network analysis using genes that differed between low-APOB and high APOB groups in all four cohorts revealed that low-APOB activity was associated with upregulation of oncogenic and metastatic regulators, such as HGF, MTIF, ERBB2, FOXM1, and CD44, and inhibition of tumor suppressors, such as TP53 and PTEN. In conclusion, APOB inactivation is associated with poor outcome in patients with HCC, and APOB may play a role in regulating multiple genes involved in HCC development. PMID- 30429454 TI - Selective blockade of spinal D2DR by levo-corydalmine attenuates morphine tolerance via suppressing PI3K/Akt-MAPK signaling in a MOR-dependent manner. AB - Morphine tolerance remains a challenge in the management of chronic pain in the clinic. As shown in our previous study, the dopamine D2 receptor (D2DR) expressed in spinal cord neurons might be involved in morphine tolerance, but the underlying mechanisms remain to be elucidated. In the present study, selective spinal D2DR blockade attenuated morphine tolerance in mice by inhibiting phosphatidylinositol 3 kinase (PI3K)/serine-threonine kinase (Akt)-mitogen activated protein kinase (MAPK) signaling in a MU opioid receptor (MOR)-dependent manner. Levo-corydalmine (l-CDL), which exhibited micromolar affinity for D2DR in D2/CHO-K1 cell lines in this report and effectively alleviated bone cancer pain in our previous study, attenuated morphine tolerance in rats with chronic bone cancer pain at nonanalgesic doses. Furthermore, the intrathecal administration of l-CDL obviously attenuated morphine tolerance, and the effect was reversed by a D2DR agonist in mice. Spinal D2DR inhibition and l-CDL also inhibited tolerance induced by the MOR agonist DAMGO. l-CDL and a D2DR small interfering RNA (siRNA) decreased the increase in levels of phosphorylated Akt and MAPK in the spinal cord; these changes were abolished by a PI3K inhibitor. In addition, the activated Akt and MAPK proteins in mice exhibiting morphine tolerance were inhibited by a MOR antagonist. Intrathecal administration of a PI3K inhibitor also attenuated DAMGO-induced tolerance. Based on these results, l-CDL antagonized spinal D2DR to attenuate morphine tolerance by inhibiting PI3K/Akt dependent MAPK phosphorylation through MOR. These findings provide insights into a more versatile treatment for morphine tolerance. PMID- 30429455 TI - Rescue from galactose-induced death of Leigh Syndrome patient cells by pyruvate and NAD. AB - Cell models of mitochondrial complex I (CI) deficiency display activation of glycolysis to compensate for the loss in mitochondrial ATP production. This adaptation can mask other relevant deficiency-induced aberrations in cell physiology. Here we investigated the viability, mitochondrial morphofunction, ROS levels and ATP homeostasis of primary skin fibroblasts from Leigh Syndrome (LS) patients with isolated CI deficiency. These cell lines harbored mutations in nuclear DNA (nDNA)-encoded CI genes (NDUFS7, NDUFS8, NDUFV1) and, to prevent glycolysis upregulation, were cultured in a pyruvate-free medium in which glucose was replaced by galactose. Following optimization of the cell culture protocol, LS fibroblasts died in the galactose medium, whereas control cells did not. LS cell death was dose-dependently inhibited by pyruvate, malate, oxaloacetate, alpha-ketoglutarate, aspartate, and exogenous NAD+ (eNAD), but not by lactate, succinate, alpha-ketobutyrate, and uridine. Pyruvate and eNAD increased the cellular NAD+ content in galactose-treated LS cells to a different extent and co incubation studies revealed that pyruvate-induced rescue was not primarily mediated by NAD+. Functionally, in LS cells glucose-by-galactose replacement increased mitochondrial fragmentation and mass, depolarized the mitochondrial membrane potential (Deltapsi), increased H2DCFDA-oxidizing ROS levels, increased mitochondrial ATP generation, and reduced the total cellular ATP content. These aberrations were differentially rescued by pyruvate and eNAD, supporting the conclusion that these compounds rescue galactose-induced LS cell death via different mechanisms. These findings establish a cell-based strategy for intervention testing and enhance our understanding of CI deficiency pathophysiology. PMID- 30429457 TI - Restriction of Zika virus infection and transmission in Aedes aegypti mediated by an insect-specific flavivirus. AB - Previous studies demonstrated an insect-specific flavivirus, Nhumirim virus (NHUV), can suppress growth of West Nile virus (WNV) and decrease transmission rates in NHUV/WNV co-inoculated Culex quinquefasciatus. To assess whether NHUV might interfere with transmission of other medically important flaviviruses, the ability of NHUV to suppress viral growth of Zika virus (ZIKV) and dengue-2 virus (DENV-2) was assessed in Aedes albopictus cells. Significant reductions in ZIKV (100,000-fold) and DENV-2 (10,000-fold) were observed in either cells concurrently inoculated with NHUV or pre-inoculated with NHUV. In contrast, only a transient 10-fold titer reduction was observed with an alphavirus, chikungunya virus. Additionally, restricted in vitro mosquito growth of ZIKV was associated with lowered levels of intracellular ZIKV RNA in NHUV co-inoculated cultures. To assess whether NHUV could modulate vector competence for ZIKV, NHUV-inoculated Aedes aegypti were orally exposed to ZIKV. NHUV-inoculated mosquitoes demonstrated significantly lower ZIKV infection rates (18%) compared to NHUV unexposed mosquitoes (51%) (p < 0.002). Similarly, lower ZIKV transmission rates were observed for NHUV/ZIKV dually intrathoracically inoculated mosquitoes (41%) compared to ZIKV only inoculated mosquitoes (78%) (p < 0.0001), suggesting that NHUV can interfere with both midgut infection and salivary gland infection of ZIKV in Ae. aegypti. These results indicate NHUV could be utilized to model superinfection exclusion mechanism(s) and to study the potential for the mosquito virome to impact transmission of medically important flaviviruses. PMID- 30429456 TI - Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine. AB - The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non target stimuli (discrimination sensitivity, or d'). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0-1.0 mg/kg, i.p.) dose-dependently improved d' in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d' impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure. PMID- 30429458 TI - MiR-27b regulates podocyte survival through targeting adenosine receptor 2B in podocytes from non-human primate. AB - MicroRNAs are a group of small non-coding RNAs that play key roles in almost every aspect of mammalian cell. In kidney, microRNAs are required for maintaining normal function of renal cells, disruption of which contributes to pathogenesis of renal diseases. In this study, we investigated the potential role of miRNAs as key regulators of podocyte survival by using a primary cell culture model from non-human primates (NHPs). Through microRNA profile comparison in glomeruli from mouse, rat and NHP, miR-27b was found to be among a list of glomeruli-enriched miRNA conserved across species. In NHP primary podocyte culture, significant downregulation of miR-27b was observed during treatment of puromycin aminonucleoside (PAN), a classic nephrotoxin. Overexpression of miR-27b enhanced PAN-induced apoptosis and cytoskeleton destruction in podocytes while its inhibition had a protective effect. Target identification analysis identified Adora2b as a potential direct target of miR-27b. Ectopic expression of miR-27b suppressed both Adora2b mRNA and protein expression, whereas inhibition of miR 27b increased the transcript and protein expression levels of Adora2B. Dual luciferase assay further confirmed Adora2b as a direct target of miR-27b. Furthermore, knockdown of Adora2b by siRNAs enhanced PAN-induced apoptosis, similar to the phenotypes we had observed with miR-27b overexpression. In addition, stimulating the adenosine signaling by an Adora2b agonist, NECA, improved podocyte survival upon PAN treatment. Taken together, our data identified a novel role of miR-27b-adora2b axis in primary podocyte survival upon injury and suggested a critical role of adenosine signaling pathway in podocyte protection. PMID- 30429459 TI - Sulforaphane metabolites reduce resistance to paclitaxel via microtubule disruption. AB - Long treatment with paclitaxel (PTX) might increase resistance and side-effects causing a failure in cancer chemotherapy. Here we uncovered that either sulforaphane-cysteine (SFN-Cys) or sulforaphane-N-acetyl-cysteine (SFN-NAC) induced apoptosis via phosphorylated ERK1/2-mediated upregulation of 26 S proteasome and Hsp70, and downregulation of betaIII-tubulin, XIAP, Tau, Stathmin1 and alpha-tubulin causing microtubule disruption in human PTX-resistant non-small cell lung cancer (NSCLC) cells. Knockdown of either betaIII-tubulin or alpha tubulin via siRNA increased cell sensitivity to PTX, indicating that these two proteins help cells increase the resistance. Tissue microarray analysis showed that overexpression of betaIII-tubulin correlated to NSCLC malignant grading. Immunofluorescence staining also showed that SFN metabolites induced a nest-like microtubule protein distribution with aggregation and disruption. Co immunoprecipitation showed that SFN metabolites reduced the interaction between betaIII-tubulin and Tau, and that between alpha-tubulin and XIAP. The combination of PTX with SFN metabolites decreased the resistance to PTX, and doses of both PTX and SFN metabolites, and enhanced apoptosis resulting from activated Caspase 3-caused microtubule degradation. Importantly, the effective dose of SFN metabolites combined with 20 nM PTX will be low to 4 MUM. Thus, we might combine SFN metabolites with PTX for preclinical trial. Normally, more than 20 MUM SFN metabolites only leading to apoptosis for SFN metabolites hindered their applications. These findings will help us develop a low-resistance and high efficiency chemotherapy via PTX/SFN metabolites combination. PMID- 30429460 TI - Stem cell-secreted 14,15- epoxyeicosatrienoic acid rescues cholesterol homeostasis and autophagic flux in Niemann-Pick-type C disease. AB - We previously demonstrated that the direct transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the dentate gyrus ameliorated the neurological symptoms of Niemann-Pick type C1 (NPC1)-mutant mice. However, the clinical presentation of NPC1-mutant mice was not fully understood with a molecular mechanism. Here, we found 14,15-epoxyeicosatrienoic acid (14,15 EET), a cytochrome P450 (CYP) metabolite, from hUCB-MSCs and the cerebella of NPC1-mutant mice and investigated the functional consequence of this metabolite. Our screening of the CYP2J family indicated a dysregulation in the CYP system in a cerebellar-specific manner. Moreover, in Purkinje cells, CYP2J6 showed an elevated expression level compared to that of astrocytes, granule cells, and microglia. In this regard, we found that one CYP metabolite, 14,15-EET, acts as a key mediator in ameliorating cholesterol accumulation. In confirming this hypothesis, 14,15-EET treatment reduced the accumulation of cholesterol in human NPC1 patient-derived fibroblasts in vitro by suppressing cholesterol synthesis and ameliorating the impaired autophagic flux. We show that the reduced activity within the CYP system in the cerebellum could cause the neurological symptoms of NPC1 patients, as 14,15-EET treatment significantly rescued cholesterol accumulation and impaired autophagy. We also provide evidence that the intranasal administration of hUCB-MSCs is a highly promising alternative to traumatic surgical transplantation for NPC1 patients. PMID- 30429461 TI - The role of FGF-2 in smoke-induced emphysema and the therapeutic potential of recombinant FGF-2 in patients with COPD. AB - Although the positive effects of recombinant fibroblast growth factor-2 (rFGF-2) in chronic obstructive pulmonary disease (COPD) have been implicated in previous studies, knowledge of its role in COPD remains limited. The mechanism of FGF2 in a COPD mouse model and the therapeutic potential of rFGF-2 were investigated in COPD. The mechanism and protective effects of rFGF-2 were evaluated in cigarette smoke-exposed or elastase-induced COPD animal models. Inflammation was assessed in alveolar cells and lung tissues from mice. FGF-2 was decreased in the lungs of cigarette smoke-exposed mice. Intranasal use of rFGF-2 significantly reduced macrophage-dominant inflammation and alveolar destruction in the lungs. In the elastase-induced emphysema model, rFGF-2 improved regeneration of the lungs. In humans, plasma FGF-2 was decreased significantly in COPD compared with normal subjects (10 subjects, P = 0.037). The safety and efficacy of inhaled rFGF-2 use was examined in COPD patients, along with changes in respiratory symptoms and pulmonary function. A 2-week treatment with inhaled rFGF-2 in COPD (n = 6) resulted in significantly improved respiratory symptoms compared with baseline levels (P < 0.05); however, the results were not significant compared with the placebo. The pulmonary function test results of COPD improved numerically compared with those in the placebo, but the difference was not statistically significant. No serious adverse events occurred during treatment with inhaled rFGF-2. The loss of FGF-2 production is an important mechanism in the development of COPD. Inhaling rFGF-2 may be a new therapeutic option for patients with COPD because rFGF-2 decreases inflammation in lungs exposed to cigarette smoke. PMID- 30429462 TI - Correction: A multicenter retrospective study aiming to identify patients who respond well to adsorptive granulomonocytapheresis in moderately to severely active ulcerative colitis. AB - This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly. PMID- 30429463 TI - Restoration of FBP1 suppressed Snail-induced epithelial to mesenchymal transition in hepatocellular carcinoma. AB - Fructose-1,6-bisphosphatase (FBP1), one of the rate-limiting gluconeogenic enzymes, plays critical roles in several cancers and is treated as a tumour suppressor. However, its role in hepatocellular carcinoma (HCC) is unclear. Here, we demonstrated that FBP1 was significantly inhibited during Snail-induced epithelial to mesenchymal transition (EMT) and tissues in HCC. Restoration of FBP1 expression in HCC cancer cells suppressed EMT phenotype, tumour migration and tumour growth induced by Snail overexpression in SMMC-7721 cells. Gene set enrichment analyses revealed significantly enriched terms, including WNT, Notch, ESC, CSR and PDGF, in the group with high Snail and low FBP1 compared with those with low Snail and high FBP1. Low FBP1 expression was significantly correlated with higher AFP level, satellite nodules, portal vein tumour thrombus, and advanced tumour stage. Survival analyses showed that FBP1 was an independent prognostic factor for overall survival and recurrence-free survival. In conclusion, our study revealed a vital role for FBP1 in Snail-induced EMT and prognostic prediction in HCC. PMID- 30429464 TI - Correction: Immune Checkpoint Inhibitor-Associated Colitis and Hepatitis. AB - The original version of this Article contained an error in the spelling of colitis in the article title. It was incorrectly spelt as "colits". This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30429465 TI - Sound identity is represented robustly in auditory cortex during perceptual constancy. AB - Perceptual constancy requires neural representations that are selective for object identity, but also tolerant across identity-preserving transformations. How such representations arise in the brain and support perception remains unclear. Here, we study tolerant representation of sound identity in the auditory system by recording neural activity in auditory cortex of ferrets during perceptual constancy. Ferrets generalize vowel identity across variations in fundamental frequency, sound level and location, while neurons represent sound identity robustly across acoustic variations. Stimulus features are encoded with distinct time-courses in all conditions, however encoding of sound identity is delayed when animals fail to generalize and during passive listening. Neurons also encode information about task-irrelevant sound features, as well as animals' choices and accuracy, while population decoding out-performs animals' behavior. Our results show that during perceptual constancy, sound identity is represented robustly in auditory cortex across widely varying conditions, and behavioral generalization requires conserved timing of identity information. PMID- 30429466 TI - Mettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. AB - N6-methyladenosine (m6A) is the most abundant epigenetic modification in eukaryotic mRNAs and is essential for multiple RNA processing events during mammalian development and disease control. Here we show that conditional knockout of the m6A methyltransferase Mettl3 in bone marrow mesenchymal stem cells (MSCs) induces pathological features of osteoporosis in mice. Mettl3 loss-of-function results in impaired bone formation, incompetent osteogenic differentiation potential and increased marrow adiposity. Moreover, Mettl3 overexpression in MSCs protects the mice from estrogen deficiency-induced osteoporosis. Mechanistically, we identify PTH (parathyroid hormone)/Pth1r (parathyroid hormone receptor-1) signaling axis as an important downstream pathway for m6A regulation in MSCs. Knockout of Mettl3 reduces the translation efficiency of MSCs lineage allocator Pth1r, and disrupts the PTH-induced osteogenic and adipogenic responses in vivo. Our results demonstrate the pathological outcomes of m6A mis-regulation in MSCs and unveil novel epitranscriptomic mechanism in skeletal health and diseases. PMID- 30429467 TI - Multicenter validation of the flow measurement of classical monocyte fraction for chronic myelomonocytic leukemia diagnosis. AB - Peripheral blood monocytes include three subsets defined by CD14 and CD16 surface markers. An increase in the CD14++CD16- classical monocyte fraction >= 94% of the total monocytes was proposed to rapidly and efficiently distinguish chronic myelomonocytic leukemia from reactive monocytosis. The robustness of this assay required a multicenter validation. The flow cytometry assay designed to quantify peripheral blood monocyte subsets was implemented by multiple diagnosis laboratories in France. A nationwide survey was performed to evaluate its performance. All the 48 French laboratories answered the questionnaire, revealing that 63% use this assay routinely. Central blind reanalysis of 329 cytometry files collected from five laboratories demonstrated an excellent correlation in classical monocyte fraction measurement (r = 0.93; p < 0.0001). The cutoff value of 94% classical monocytes being the critical readout for diagnosis, we then compared 115 patients with classical monocytes >= 94% and 214 patients with a fraction < 94% between initial analysis and reanalysis. An agreement was obtained in 311 files. Finally, an overt diagnosis, available for 86 files, confirmed a good sensitivity (93.6%) and specificity (89.7%). This survey demonstrates the robustness of the flow assay with limited variability of classical monocyte percentage between centers, validates the 94% cutoff value, and confirms its sensitivity and specificity. PMID- 30429468 TI - MR imaging tracking of inflammation-activatable engineered neutrophils for targeted therapy of surgically treated glioma. AB - Cell-based drug delivery systems have shown promising capability for tumor targeted therapy owing to the intrinsic tumor-homing and drug-carrying property of some living cells. However, imaging tracking of their migration and bio effects is urgently needed for clinical application, especially for glioma. Here, we report the inflammation-activatable engineered neutrophils by internalizing doxorubicin-loaded magnetic mesoporous silica nanoparticles (ND-MMSNs) which can provide the potential for magnetic resonance (MR) imaging tracking of the drug loaded cells to actively target inflamed brain tumor after surgical resection of primary tumor. The phagocytized D-MMSNs possess high drug loading efficiency and do not affect the host neutrophils' viability, thus remarkably improving intratumoral drug concentration and delaying relapse of surgically treated glioma. Our study offers a new strategy in targeted cancer theranostics through combining the merits of living cells and nanoparticle carriers. PMID- 30429469 TI - PhiCrAss001 represents the most abundant bacteriophage family in the human gut and infects Bacteroides intestinalis. AB - CrAssphages are an extensive and ubiquitous family of tailed bacteriophages, predicted to infect bacteria of the order Bacteroidales. Despite being found in ~50% of individuals and representing up to 90% of human gut viromes, members of this viral family have never been isolated in culture and remain understudied. Here, we report the isolation of a CrAssphage (PhiCrAss001) from human faecal material. This bacteriophage infects the human gut symbiont Bacteroides intestinalis, confirming previous in silico predictions of the likely host. DNA sequencing demonstrates that the bacteriophage genome is circular, 102 kb in size, and has unusual structural traits. In addition, electron microscopy confirms that PhicrAss001 has a podovirus-like morphology. Despite the absence of obvious lysogeny genes, PhicrAss001 replicates in a way that does not disrupt proliferation of the host bacterium, and is able to maintain itself in continuous host culture during several weeks. PMID- 30429470 TI - Myths and reality of HPbI3 in halide perovskite solar cells. AB - All-inorganic perovskites have a special place in halide perovskite family because of their potential for better stability. However, the representative cesium lead iodide (CsPbI3) is metastable and spontaneously converts to the non perovskite structure at room temperature. Here, we demonstrate that what appears to be all-inorganic CsPbI3 stabilized in its perovskite form using the purported intermediate known as hydrogen lead iodide (HPbI3) is, in fact, the hybrid perovskite cesium dimethylammonium lead iodide (Cs1-xDMAxPbI3, x = 0.2 to 0.5). Thus, many of the reported all-inorganic perovskites are actually still hybrid organic-inorganic perovskites, as strongly evidenced by a wide battery of experimental techniques presented here. Solar cells based on the representative composition Cs0.7DMA0.3PbI3 can achieve an average power conversion efficiency of 9.27 +/- 1.28% (max 12.62%). These results provide an alternative angle to look at previous results pertaining all-inorganic CsPbI3 while the DMA cation is now revealed as an alternative A site cation. PMID- 30429471 TI - Scalable high performance radio frequency electronics based on large domain bilayer MoS2. AB - Atomically-thin layered molybdenum disulfide (MoS2) has attracted tremendous research attention for their potential applications in high performance DC and radio frequency electronics, especially for flexible electronics. Bilayer MoS2 is expected to have higher electron mobility and higher density of states with higher performance compared with single layer MoS2. Here, we systematically investigate the synthesis of high quality bilayer MoS2 by chemical vapor deposition on molten glass with increasing domain sizes up to 200 MUm. High performance transistors with optimized high-kappa dielectrics deliver ON-current of 427 MUA MUm-1 at 300 K and a record high ON-current of 1.52 mA MUm-1 at 4.3 K. Moreover, radio frequency transistors are demonstrated with an extrinsic high cut off frequency of 7.2 GHz and record high extrinsic maximum frequency of oscillation of 23 GHz, together with gigahertz MoS2 mixers on flexible polyimide substrate, showing the great potential for future high performance DC and high frequency electronics. PMID- 30429472 TI - Conformational ensemble of the human TRPV3 ion channel. AB - Transient receptor potential vanilloid channel 3 (TRPV3), a member of the thermosensitive TRP (thermoTRPV) channels, is activated by warm temperatures and serves as a key regulator of normal skin physiology through the release of pro inflammatory messengers. Mutations in trpv3 have been identified as the cause of the congenital skin disorder, Olmsted syndrome. Unlike other members of the thermoTRPV channel family, TRPV3 sensitizes upon repeated stimulation, yet a lack of structural information about the channel precludes a molecular-level understanding of TRPV3 sensitization and gating. Here, we present the cryo electron microscopy structures of apo and sensitized human TRPV3, as well as several structures of TRPV3 in the presence of the common thermoTRPV agonist 2 aminoethoxydiphenyl borate (2-APB). Our results show alpha-to-pi-helix transitions in the S6 during sensitization, and suggest a critical role for the S4-S5 linker pi-helix during ligand-dependent gating. PMID- 30429473 TI - Presenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity. AB - Mutations of the intramembrane protease presenilin (PS) or of its main substrate, the amyloid precursor protein (APP), cause early-onset form of Alzheimer disease. PS and APP interact with proteins of the neurotransmitter release machinery without identified functional consequences. Here we report that genetic deletion of PS markedly decreases the presynaptic levels of the Ca2+ sensor synaptotagmin 7 (Syt7) leading to impaired synaptic facilitation and replenishment of synaptic vesicles. The regulation of Syt7 expression by PS occurs post-transcriptionally and depends on gamma-secretase proteolytic activity. It requires the substrate APP as revealed by the combined genetic invalidation of APP and PS1, and in particular the APP-Cterminal fragments which interact with Syt7 and accumulate in synaptic terminals under pharmacological or genetic inhibition of gamma secretase. Thus, we uncover a role of PS in presynaptic mechanisms, through APP cleavage and regulation of Syt7, that highlights aberrant synaptic vesicle processing as a possible new pathway in AD. PMID- 30429475 TI - Publisher Correction: Complex virome in feces from Amerindian children in isolated Amazonian villages. AB - In the original version of this Article, the affiliation details for Eric Delwart were incorrectly given as 'Blood Systems Research Institute, San Francisco, CA 94118, USA and Amazonic Center for Research and Control of Tropical Diseases (CAICET), Puerto Ayacucho 7101, Venezuela'. The correct affiliations are 'Blood Systems Research Institute, San Francisco, CA 94118, USA and Department of Laboratory Medicine, University of California at San Francisco, San Francisco, CA 94118, USA'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30429474 TI - Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma. AB - BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR impairment as a strategy to overcome melanoma resistance. PMID- 30429476 TI - Author Correction: The prognostic effects of somatic mutations in ER-positive breast cancer. AB - The original version of this Article contained errors in the depiction of confidence intervals in the NF1 BCSS data illustrated in Figure 3b. These have now been corrected in both the PDF and HTML versions of the Article. The incorrect version of Figure 3b is presented in the associated Author Correction. PMID- 30429479 TI - Microfluidic active loading of single cells enables analysis of complex clinical specimens. AB - A fundamental trade-off between flow rate and measurement precision limits performance of many single-cell detection strategies, especially for applications that require biophysical measurements from living cells within complex and low input samples. To address this, we introduce 'active loading', an automated, optically-triggered fluidic system that improves measurement throughput and robustness by controlling entry of individual cells into a measurement channel. We apply active loading to samples over a range of concentrations (1-1000 particles MUL-1), demonstrate that measurement time can be decreased by up to 20 fold, and show theoretically that performance of some types of existing single cell microfluidic devices can be improved by implementing active loading. Finally, we demonstrate how active loading improves clinical feasibility for acute, single-cell drug sensitivity measurements by deploying it to a preclinical setting where we assess patient samples from normal brain, primary and metastatic brain cancers containing a complex, difficult-to-measure mixture of confounding biological debris. PMID- 30429477 TI - Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer. AB - Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3' UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3' UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy. PMID- 30429478 TI - Colorectal cancer liver metastatic growth depends on PAD4-driven citrullination of the extracellular matrix. AB - Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is recognized in rheumatoid arthritis, but largely undocumented in cancer. Here we show that citrullination of the extracellular matrix by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases from colorectal cancer (CRC). Using proteomics, we demonstrate that liver metastases exhibit higher levels of citrullination and PAD4 than unaffected liver, primary CRC or adjacent colonic mucosa. Functional significance for citrullination in metastatic growth is evident in murine models where inhibition of citrullination substantially reduces liver metastatic burden. Additionally, citrullination of a key matrix component collagen type I promotes greater adhesion and decreased migration of CRC cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition and liver metastasis. Overall, our study reveals the potential for PAD4-dependant citrullination to drive the progression of CRC liver metastasis. PMID- 30429481 TI - An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules. AB - Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to many biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck in ubiquitin research. Here, we present an E2-thioester-driven identification (E2~dID) method for the targeted identification of substrates of specific E2 and E3 enzyme pairs. E2~dID exploits the central position of E2-conjugating enzymes in the ubiquitination cascade and provides in vitro generated biotinylated E2~ubiquitin thioester conjugates as the sole source for ubiquitination in extracts. This enables purification and mass spectrometry-based identification of modified proteins under stringent conditions independently of the biological source of the extract. We demonstrate the sensitivity and specificity of E2-dID by identifying and validating substrates of APC/C in human cells. Finally, we perform E2~dID with SUMO in S. cerevisiae, showing that this approach can be easily adapted to other ubiquitin-like modifiers and experimental models. PMID- 30429482 TI - Two-step self-assembly of a spider silk molecular clamp. AB - Web spiders synthesize silk fibers of unique strength and extensibility through the controlled self-assembly of protein building blocks, so-called spidroins. The spidroin C-terminal domain is highly conserved and connects two polypeptide chains through formation of an all-helical, intertwined dimer. Here we use contact-induced fluorescence self-quenching and resonance energy transfer in combination with far-UV circular dichroism spectroscopy as three orthogonal structural probes to dissect the mechanism of folding and dimerization of a spidroin C-terminal domain from the major ampullate gland of the nursery web spider Euprosthenops australis. We show that helices forming the dimer core assemble very rapidly and fold on association. Subsequently, peripheral helices fold and dock slowly onto the preformed core. Lability of outer helices facilitates formation of a highly expanded, partially folded dimer. The high end to-end distance of chain termini in the partially folded dimer suggests an extensibility module that contributes to elasticity of spider silk. PMID- 30429480 TI - Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. AB - The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis. PMID- 30429483 TI - Author Correction: Bi-directional cell-pericellular matrix interactions direct stem cell fate. AB - In the original version of this Article the dataset identifier in the Data Availability statement was incorrect. The correct dataset identifier is PXD009500. This has been corrected in the HTML and PDF versions of this Article. PMID- 30429484 TI - Superconductivity in a 122-type Fe-based compound (La,Na,K)Fe2As2. AB - We synthesized a Fe-based superconductor (FeSC), (La,Na,K)Fe2As2, and characterized its superconducting properties. It was found that (La,Na,K)Fe2As2 has a 122-type (ThCr2Si2-type) structure with a space group I4/mmm (No. 139), identical to (Ba,K)Fe2As2 and (La,Na)Fe2As2 but distinct from so-called 1144-type FeSCs such as CaKFe4As4 and (La,Na)CsFe4As4. The results demonstrate that the formation of the 1144-type phase necessitates the large ionic radius mismatch among the so-called A-site constituent elements of the AFe2As2 formula. The lattice constants are a = 3.850(1) A and c = 13.21(1) A. The La, Na, and K ions occupy the same atomic site of Wyckoff position 1a. Electrical resistivity and magnetic susceptibility show the superconducting transition at 22.5 K. The transition temperature (Tc) of (La,Na,K)Fe2As2 is comparable with that of 122 type (La,Na)Fe2As2 and 1144-type (La,Na)AFe4As4 (A = Rb, Cs), while being more than 10 K lower than those of typical 122- and 1144-type FeSCs. The results suggest that the random distribution of La3+ and Na+ ions is the main reason for lower Tc in the AE = (La,Na) 122-type and 1144-type FeSCs. PMID- 30429485 TI - Regional variations in human milk oligosaccharides in Vietnam suggest FucTx activity besides FucT2 and FucT3. AB - Breastfeeding is the normal way of providing young infants with the nutrients they need for healthy growth and development (WHO). Human milk oligosaccharides (hMOS) constitute a highly important class of nutrients that are attracting strong attention in recent years. Several studies have indicated that hMOS have prebiotic properties, but also are effective in anti-adhesion of pathogens, modulating the immune system and providing nutrients for brain growth and development. Most of the latter functions seem to be linked to the presence of fucose-containing immunodeterminant epitopes, and Neu5Ac-bearing oligosaccharides. Analysis of hMOS isolated from 101 mothers' milk showed regional variation in Lewis- and Secretor based immunodeterminants. Lewis negative milk groups could be sub-divided into two sub-groups, based on the activity of a third and hitherto unidentified fucosyltransferase enzyme. Analysis of hMOS remaining in faeces showed three sub-groups based on hMOS surviving passage through the gut, full consumption, specific partial consumption and non specific partial consumption, fitting previous findings. PMID- 30429486 TI - The 2.1 A structure of protein F9 and its comparison to L1, two components of the conserved poxvirus entry-fusion complex. AB - The poxvirus F9 protein is a component of the vaccinia virus entry fusion complex (EFC) which consists of 11 proteins. The EFC forms a unique apparatus among viral fusion proteins and complexes. We solved the atomic structure of the F9 ectodomain at 2.10 A. A structural comparison to the ectodomain of the EFC protein L1 indicated a similar fold and organization, in which a bundle of five alpha-helices is packed against two pairs of beta-strands. However, instead of the L1 myristoylation site and hydrophobic cavity, F9 possesses a protruding loop between alpha-helices alpha3 and alpha4 starting at Gly90. Gly90 is conserved in all poxviruses except Salmon gill poxvirus (SGPV) and Diachasmimorpha longicaudata entomopoxvirus. Phylogenetic sequence analysis of all Poxviridae F9 and L1 orthologs revealed the SGPV genome to contain the most distantly related F9 and L1 sequences compared to the vaccinia proteins studied here. The structural differences between F9 and L1 suggest functional adaptations during evolution from a common precursor that underlie the present requirement for each protein. PMID- 30429488 TI - Superhydrophobic and Compressible Silica-polyHIPE Covalently Bonded Porous Networks via Emulsion Templating for Oil Spill Cleanup and Recovery. AB - We synthesize porous polyHIPE networks with silanol functionalities in the polyHIPE backbone. These silanol functionalities are used for covalent bonding with silica aerogels embedded in the polyHIPE. Covalent bonding between silica and polyHIPE networks are confirmed using Fourier-transform infrared spectroscopy and scanning electron microscopy. Silica aerogels covalently bonded with polyHIPE network show macroporous and mesoporous morphologies and possess excellent properties like high bendability, high elasticity, superhydrophobicity (~160 degrees ), low density (~0.128 g/cm3), and low thermal conductivity (~0.045 W/m.K). Oil absorption from water/oil mixtures and recovery of the absorbed oil (by squeezing) from flexible silica-polyHIPE networks is studied. The silica polyHIPE is shown to absorb crude oil ~16-times its own weight and can be reused multiple times after recovery. Hence, such materials are very important for oil spill cleanup applications from aqueous systems. PMID- 30429487 TI - NTG-101: A Novel Molecular Therapy that Halts the Progression of Degenerative Disc Disease. AB - The tremendous cost, pain and disability associated with degenerative disc disease (DDD) makes the development of a biological agent that can mitigate the course of DDD, a critical unmet need. We have identified and reported that a single injection of a combination of recombinant human (rh) Transforming growth factor beta 1 (TGF-beta1) and Connective tissue growth factor (CTGF) proteins into the injured intervertebral disc (IVD) nucleus pulposus (NP) can mediate DDD in a pre-clinical rodent model. In this study, we developed and evaluated the efficacy of a novel molecular therapy (NTG-101) containing rhTGF-beta1 and rhCTGF proteins suspended in an excipient solution using in vivo models of DDD including rat-tail and chondrodystrophic (CD) canines. Needle puncture injury in CD-canine NPs resulted in loss of hydration, disc height and showed radiographic evidence of DDD like humans. However, NTG-101-injected IVDs maintained disc height and demonstrated retention of viscoelastic properties as compared to IVDs injected with phosphate buffer saline (PBS, 1X, pH = 7.2). In addition, a single intra discal injection of NTG-101 into the injured IVD-NPs resulted in sustained expression of healthy extra-cellular matrix (ECM) proteins (aggrecan, collagen 2A1) and reduced expression of inflammation associated proteins and molecules (IL 1beta, IL-6, IL-8, MMP-13, Cox-2 and PGE2) as compared to vehicle controls. In conclusion, we demonstrated that a single intra-discal injection of the novel formulation, NTG-101 confers a robust anti-inflammatory, anti-catabolic and pro anabolic effects in pre-clinical models of DDD thereby restoring homeostasis. These findings suggest the therapeutic potential of NTG-101 for clinical use. PMID- 30429489 TI - Shape oscillations of single blood drops: applications to human blood and sickle cell disease. AB - Sickle cell disease (SCD) is an inherited blood disorder associated with severe anemia, vessel occlusion, poor oxygen transport and organ failure. The presence of stiff and often sickle-shaped red blood cells is the hallmark of SCD and is believed to contribute to impaired blood rheology and organ damage. Most existing measurement techniques of blood and red blood cell physical properties require sample contact and/or large sample volume, which is problematic for pediatric patients. Acoustic levitation allows rheological measurements in a single drop of blood, simultaneously eliminating the need for both contact containment and manipulation of samples. The technique shows that the shape oscillation of blood drops is able to assess blood viscosity in normal and SCD blood and demonstrates an abnormally increased viscosity in SCD when compared with normal controls. Furthermore, the technique is sensitive enough to detect viscosity changes induced by hydroxyurea treatment, and their dependence on the total fetal hemoglobin content of the sample. Thus this technique may hold promise as a monitoring tool for assessing changes in blood rheology in sickle cell and other hematological diseases. PMID- 30429490 TI - Spatial pattern of plutonium and radiocaesium contamination released during the Fukushima Daiichi nuclear power plant disaster. AB - Plutonium and radiocaesium are hazardous contaminants released by the Fukushima Daiichi nuclear power plant (FDNPP) disaster and their distribution in the environment requires careful characterisation using isotopic information. Comprehensive spatial survey of 134Cs and 137Cs has been conducted on a regular basis since the accident, but the dataset for 135Cs/137Cs atom ratios and trace isotopic analysis of Pu remains limited because of analytical challenges. We have developed a combined chemical procedure to separate Pu and Cs for isotopic analysis of environmental samples from contaminated catchments. Ultra-trace analyses reveal a FDNPP Pu signature in environmental samples, some from further afield than previously reported. For two samples, we attribute the dominant source of Pu to Reactor Unit 3. We review the mechanisms responsible for an emergent spatial pattern in 134,135Cs/137Cs in areas northwest (high 134Cs/137Cs, low 135Cs/137Cs) and southwest (low 134Cs/137Cs, high 135Cs/137Cs) of FDNPP. Several samples exhibit consistent 134,135Cs/137Cs values that are significantly different from those deposited on plant specimens collected in previous works. A complex spatial pattern of Pu and Cs isotopic signature is apparent. To confidently attribute the sources of mixed fallout material, future studies must focus on analysis of individual FDNPP-derived particles. PMID- 30429491 TI - Elevated ADAMTS13 Activity is Associated with Poor Postoperative Outcome in Patients Undergoing Liver Resection. AB - Recently, von-Willebrand-Factor (vWF) has been shown to correlate with postoperative liver dysfunction (LD). Accordingly, "disintegrin-like metalloprotease with thrombospondin type1 motif" (ADAMTS13) is known to cleave vWF in less active fragments. Thus, we aimed to evaluate the diagnostic potential of ADAMTS13-activity (ADAMTS13-AC) to identify patients with postoperative LD after hepatectomy. Accordingly 37 patients undergoing hepatectomy for different neoplastic entities were included in this study. Plasma ADAMTS13-AC and vWF-Ag were measured 1 day prior to (preOP), 1 and 5 days (POD1/5) after hepatectomy. In accordance to the ISGLS-criteria LD was prospectively recorded. In this context, perioperative ADAMTS13-AC- and vWF-Ag/ADAMTS13-AC-ratio- levels revealed a significant increase after hepatectomy. Accordingly, elevated vWF-Ag/ADAMTS13-AC ratio significantly predicted LD (preOP AUC: 0.75, p = 0.02; POD1 AUC: 0.80, p = 0.03). Patients who fulfilled our perioperative vWF-Ag/ADAMTS13-AC-ratio cut-off levels (preOP: >=116, POD1: >=165) suffered from significantly higher incidences of LD (preOP: 70% vs. 30%, p = 0.01; POD1: 83% vs. 17%, p = 0.001). In conclusion, perioperative ADAMTS13-AC measurement may serve as a useful parameter to early detect high-risk patients developing postoperative LD prior to liver resection in patients suffering from hepatic malignancies. Indeed, further investigations have to be performed to consolidate its role as a predictive marker for LD. PMID- 30429492 TI - Sub-micron level investigation reveals the inaccessibility of stabilized carbon in soil microaggregates. AB - Direct evidence-based approaches are vital to evaluating newly proposed theories on the persistence of soil organic carbon and establishing the contributions of abiotic and biotic controls. Our primary goal was to directly identify the mechanisms of organic carbon stabilization in native-state, free soil microaggregates without disrupting the aggregate microstructure using scanning transmission x-ray microscopy coupled with near edge x-ray absorption fine structure spectroscopy (STXM-NEXAFS). The influence of soil management practices on microaggregate associated-carbon was also assessed. Free, stable soil microaggregates were collected from a tropical agro-ecosystem in Cruz Alta, Brazil. The long-term experimental plots (>25 years) comparing two tillage systems: no-till and till with a complex crop rotation. Based on simultaneously collected multi-elemental associations and speciation, STXM-NEXAFS successfully provided submicron level information on organo-mineral associations. Simple organic carbon sources were found preserved within microaggregates; some still possessing original morphology, suggesting that their stabilization was not entirely governed by the substrate chemistry. Bulk analysis showed higher and younger organic carbon in microaggregates from no-till systems than tilled systems. These results provide direct submicron level evidence that the surrounding environment is involved in stabilizing organic carbon, thus favoring newly proposed concepts on the persistence of soil organic carbon. PMID- 30429493 TI - Integrated Population Modeling Provides the First Empirical Estimates of Vital Rates and Abundance for Polar Bears in the Chukchi Sea. AB - Large carnivores are imperiled globally, and characteristics making them vulnerable to extinction (e.g., low densities and expansive ranges) also make it difficult to estimate demographic parameters needed for management. Here we develop an integrated population model to analyze capture-recapture, radiotelemetry, and count data for the Chukchi Sea subpopulation of polar bears (Ursus maritimus), 2008-2016. Our model addressed several challenges in capture recapture studies for polar bears by including a multievent structure reflecting location and life history states, while accommodating state uncertainty. Female breeding probability was 0.83 (95% credible interval [CRI] = 0.71-0.90), with litter sizes of 2.18 (95% CRI = 1.71-2.82) for age-zero and 1.61 (95% CRI = 1.46 1.80) for age-one cubs. Total adult survival was 0.90 (95% CRI = 0.86-0.92) for females and 0.89 (95% CRI = 0.83-0.93) for males. Spring on-ice densities west of Alaska were 0.0030 bears/km2 (95% CRI = 0.0016-0.0060), similar to 1980s-era density estimates although methodological differences complicate comparison. Abundance of the Chukchi Sea subpopulation, derived by extrapolating density from the study area using a spatially-explicit habitat metric, was 2,937 bears (95% CRI = 1,552-5,944). Our findings are consistent with other lines of evidence suggesting the Chukchi Sea subpopulation has been productive in recent years, although it is uncertain how long this will continue given sea-ice loss due to climate change. PMID- 30429494 TI - Macrophages mediate corticotomy-accelerated orthodontic tooth movement. AB - Clinical evidence has suggested that surgical corticotomy of the alveolar bone can accelerate local orthodontic tooth movement (OTM), but the underlying cell and molecular mechanisms remain largely unclear. The present study examined the role of macrophages played in corticotomy-assisted OTM. Orthodontic nickel titanium springs were applied to the left maxillary first molars of rats or mice to induce OTM with or without corticotomy. Corticotomy enhanced OTM distance by accelerating movement through induction of local osteoclastogenesis and macrophage infiltration during OTM. Further analysis showed that macrophages were polarized toward an M1-like phenotype immediately after corticotomy and then switched to an M2-like phenotype during OTM. The microenvironment of corticotomy induced macrophage infiltration and polarization through the production of TNF alpha. More importantly, the amount of OTM induced by corticotomy was significantly decreased after mice were depleted of monocyte/macrophages by injection of liposome-encapsulated clodronate. Further experiments by incubating cultured macrophages with fresh tissue suspension obtained from post-corticotomy gingiva switched the cells to an M1 phenotype through activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway, and to an M2 phenotype through activation of the JAK/STAT3 signaling pathway. Our results suggest that corticotomy induces macrophage polarization first by activating the NF-kappaB signaling pathway and later by activating the JAK/STAT3 signaling pathway, and that these processes contribute to OTM by triggering production of inflammatory cytokines and osteoclastogenesis. PMID- 30429496 TI - The beneficial effects of Lactobacillus reuteri ADR-1 or ADR-3 consumption on type 2 diabetes mellitus: a randomized, double-blinded, placebo-controlled trial. AB - Probiotics have been reported to ameliorate symptoms of type 2 diabetes mellitus (T2DM) in animal models and human studies. We previously demonstrated that oral administration of Lactobacillus reuteri ADR-3 reduced insulin resistance in high fructose-fed (HFD) rats. In the present study, we first identified another L. reuteri strain, ADR-1, which displayed anti-diabetes activity that reduced the levels of serum HbA1c and cholesterol and that increased antioxidant proteins in HFD rats. We further performed a randomized, double-blinded, placebo-controlled trial with a total of 68 T2DM patients to examine the beneficial effects of oral consumption of L. reuteri strains ADR-1 and ADR-3 and to investigate the associated changes in intestinal flora using a quantitative PCR method to analyze 16 S rRNA in fecal specimens. Significant reductions in HbA1c and serum cholesterol were observed in participants in the live ADR-1 consumption group (n = 22) after 3 months of intake when compared with those in the placebo group (n = 22). Although there was no significant difference in the HbA1c serum level among participants who consumed heat-killed ADR-3 (n = 24), the systolic blood pressure and mean blood pressure were significantly decreased after 6 months of intake. There was no obvious change in serum inflammatory cytokines or antioxidant proteins in participants after intaking ADR-1 or ADR-3, except for a reduction in IL-1beta in the ADR-3 consumption group after 6 months of intake. With the analysis of fecal microflora, we found that L. reuteri or Bifidobacterium spp. were significantly increased in the ADR-1 and ADR-3 consumption groups, respectively, after 6 months of intake. Interestingly, a significant reduction in HbA1c was observed in the ADR-1 and ADR-3 consumption participants who displayed at least an 8-fold increase in fecal L. reuteri. We also observed that there was a significantly positive correlation between Bifidobacterium spp. and Lactobacillus spp. in participants with increased levels of fecal L. reuteri. In the ADR-1 intake group, the fecal Lactobacillus spp. level displayed a positive correlation with Bifidobacterium spp. but was negatively correlated with Bacteroidetes. The total level of fecal L. reuteri in participants in the ADR-3 consumption group was positively correlated with Firmicutes. In conclusion, L. reuteri strains ADR-1 and ADR-3 have beneficial effects on T2DM patients, and the consumption of different strains of L. reuteri may influence changes in intestinal flora, which may lead to different outcomes after probiotic intake. PMID- 30429495 TI - Radiation-induced premature cellular senescence involved in glomerular diseases in rats. AB - Currently, cellular senescence has emerged as a fundamental contributor to chronic organ diseases. Radiation is one of the stress factors that induce cellular senescence. Although the kidney is known as a radiosensitive organ, whether and how radiation-induced cellular senescence is associated with kidney diseases remains unclear. In this study, we performed experiments on 7-8-week-old male rats that received a single dose of 18-Gy radiation in the unilateral kidney. The irradiated kidneys showed hallmarks of cellular senescence, including increased SA-beta-gal activity, upregulation of cyclin-dependent kinase inhibitor (p53, p21, and p16), and absence of DNA proliferation marker (Ki-67). Furthermore, combined with in-vitro experiments, we demonstrated that radiation induced senescent glomerular endothelial cells acquired altered gene expression, namely, senescence-associated secretory phenotype (particularly, IL-6), which might be triggered by NF-kB signaling pathway. Pathological analysis suggested severe glomerular endothelial cell injury, as evidenced by thrombotic microangiopathy, collapsing glomeruli, and reduced endothelial cell numbers. We suggested that glomerular endothelial cells were more susceptible to radiation induced cellular senescence. In conclusion, the current study is the first to identify the important role of radiation-induced cellular senescence, mainly derived from glomerular endothelial cells, for the development of glomerular injury. PMID- 30429497 TI - CRISPR/Cas9-mediated mutagenesis of homologous genes in Chinese kale. AB - The clustered regulatory interspaced short palindromic repeat-associated protein 9 (CRISPR/Cas9) system has developed into a powerful gene-editing tool that has been successfully applied to various plant species. However, studies on the application of the CRISPR/Cas9 system to cultivated Brassica vegetables are limited. Here, we reported CRISPR/Cas9-mediated genome editing in Chinese kale (Brassica oleracea var. alboglabra) for the first time. A stretch of homologous genes, namely BaPDS1 and BaPDS2, was selected as the target site. Several stable transgenic lines with different types of mutations were generated via Agrobacterium-mediated transformation, including BaPDS1 and BaPDS2 double mutations and BaPDS1 or BaPDS2 single mutations. The overall mutation rate reached 76.47%, and these mutations involved nucleotide changes of fewer than 10 bp. The clear albino phenotype was observed in all of the mutants, including one that harbored a mutation within an intron region, thereby indicating the importance of the intron. Cleavage in Chinese kale using CRISPR/Cas9 was biased towards AT-rich sequences. Furthermore, no off-target events were observed. Functional differences between BaPDS1 and BaPDS2 were also assessed in terms of the phenotypes of the respective mutants. In combination, these findings showed that CRISPR/Cas9-mediated targeted mutagenesis can simultaneously and efficiently modify homologous gene copies of Chinese kale and provide a convenient approach for studying gene function and improving the yield and quality of cultivated Brassica vegetables. PMID- 30429498 TI - Pathophysiological and molecular mechanisms involved in renal congestion in a novel rat model. AB - Increased central venous pressure in congestive heart failure causes renal dysfunction; however, the underlying mechanisms are unclear. We created a rat renal congestion model and investigated the effect of renal congestion on hemodynamics and molecular mechanisms. The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion in the left kidney only. Left kidney congestion reduced renal blood flow, glomerular filtration rate, and increased renal interstitial hydrostatic pressure. Tubulointerstitial and glomerular injury and medullary thick ascending limb hypoxia were observed only in the congestive kidneys. Molecules related to extracellular matrix expansion, tubular injury, and focal adhesion were upregulated in microarray analysis. Renal decapsulation ameliorated the tubulointerstitial injury. Electron microscopy captured pericyte detachment in the congestive kidneys. Transgelin and platelet-derived growth factor receptors, as indicators of pericyte-myofibroblast transition, were upregulated in the pericytes and the adjacent interstitium. With the compression of the peritubular capillaries and tubules, hypoxia and physical stress induce pericyte detachment, which could result in extracellular matrix expansion and tubular injury in renal congestion. PMID- 30429499 TI - Fecal chromogranins and secretogranins are linked to the fecal and mucosal intestinal bacterial composition of IBS patients and healthy subjects. AB - Altered fecal levels of chromogranins (Cg) and secretogranins (Sg) are demonstrated in irritable bowel syndrome (IBS), but their role in IBS pathophysiology remains unknown. This study aimed to determine if granins are associated with bacterial composition, immune activation and IBS symptoms. Protein levels of fecal granins (CgA, CgB, SgII and SgIII) were analysed with immunoassays. Mucosal mRNA expression of granins, TPH1 and immune markers were evaluated with RT-qPCR. 16S rRNA gene sequencing was performed on fecal and mucosal bacteria. The intestinal granin profile, based on fecal protein levels and mucosal mRNA expression, could not discriminate between IBS patients (n = 88) and healthy subjects (HS, n = 33). IBS patients dominated by high fecal or mucosal granin levels, respectively, did not differ in symptom or immune profiles. Fecal-dominated and mucosal-dominated granin clusters of IBS patients and HS, demonstrated separate fecal and mucosal bacterial profiles and high fecal abundance of granins were associated with a less diverse bacterial composition and the Bacteroides enterotype. The intestinal granin profiles of IBS patients and HS are linked to the intestinal bacterial composition, diversity and enterotypes. These findings suggest that granins may be one of several host produced factors regulating the microbiota composition of the intestine. PMID- 30429500 TI - Diet-dependent gene expression highlights the importance of Cytochrome P450 in detoxification of algal secondary metabolites in a marine isopod. AB - Isopods of the genus Idotea have an unusual ability to feed on algae containing high amounts of chemical defense molecules, such as species of the genera Fucus and Ulva. In this study, we compared gene expression patterns of Idotea balthica individuals fed with Fucus vesiculosus to individuals fed with Ulva lactuca. We generated the first-ever transcriptome assembly for this species, and found 3,233 differentially expressed genes across feeding regimes. However, only a handful of biological functions were enriched with regard to differentially expressed genes, the most notable being "alkaloid metabolic process". Within this category, we found eight differentially expressed cytochrome P450 (CYP) unigenes, all of which had a higher expression in the U. lactuca diet treatment. A phylogenetic analysis showed that the differentially expressed CYP genes are closely related to a CYP gene described from the hepatopancreas of the spiny lobster Panulirus argus, and we hypothesize that these transcripts are involved in metabolite detoxification. This is a first step in the understanding of this algae-grazer interaction, and will form a basis for future work to characterize cytochrome P450 functioning in marine crustaceans. PMID- 30429501 TI - Transcriptomic changes with increasing algal symbiont reveal the detailed process underlying establishment of coral-algal symbiosis. AB - To clarify the establishment process of coral-algal symbiotic relationships, coral transcriptome changes during increasing algal symbiont densities were examined in juvenile corals following inoculation with the algae Symbiodinium goreaui (clade C) and S. trenchii (clade D), and comparison of their transcriptomes with aposymbiotic corals by RNA-sequencing. Since Symbiodinium clades C and D showed very different rates of density increase, comparisons were made of early onsets of both symbionts, revealing that the host behaved differently for each. RNA-sequencing showed that the number of differentially expressed genes in corals colonized by clade D increased ca. two-fold from 10 to 20 days, whereas corals with clade C showed unremarkable changes consistent with a slow rate of density increase. The data revealed dynamic metabolic changes in symbiotic corals. In addition, the endocytosis pathway was also upregulated, while lysosomal digestive enzymes and the immune system tended to be downregulated as the density of clade D algae increased. The present dataset provides an enormous number of candidate symbiosis-related molecules that exhibit the detailed process by which coral-algal endosymbiosis is established. PMID- 30429502 TI - Improving visualization and quantitative assessment of choriocapillaris with swept source OCTA through registration and averaging applicable to clinical systems. AB - Choriocapillaris (CC) visualization and quantification remains challenging. We propose an innovative three-step registration and averaging approach using repeated swept source optical coherence tomography angiography (SS-OCTA) scans to conduct automatic quantitative assessment on CC. Six subjects were enrolled, each imaged at several locations with SS-OCTA from macular to equatorial regions using 3 mm * 3 mm scanning pattern. Five repeated volumes were collected for each subject. The complex optical microangiography (OMAG) algorithm was applied to identify blood flow in CC slab. An automatic three-step registration of translation, affine and B-Spline was applied to en face OCTA images of CC, followed with averaging. A fuzzy clustering approach was used to segment vasculature and flow deficits from the averaged images. The improvement in visualization of CC was evaluated and the average intercapillary distance was estimated by calculating the averaged capillary lumen spacing. A series of quantitative indices of flow deficit density, number, size, complexity index and aspect ratio index (FDD, FDN, FDS, FDCI and FDARI) were designed and validated with the increase of repeated scan numbers for averaging. Quantitative assessment was applied and compared on CC in macular and equatorial regions. The intercapillary distance was observed to be around 24 um at macula and increased toward equatorial regions. All five quantitative indices (FDD, FDN, FDS, FDCI and FDARI) showed significant changes with multiple averaging and tend to become stable with repeated number of 4. Our proposed registration and averaging algorithm significantly improved the visualization of CC with SS-OCTA. The designed five indices for CC provide more options in the quantitative assessment of CC and are of great potentials in assisting the understanding of disease pathology, early diagnosis and treatment monitoring. PMID- 30429504 TI - Simulated performances of pixelated CsI(Tl) scintillation screens with different micro-column shapes and array structures in X-ray imaging. AB - The performances of the pixelated CsI(Tl) scintillation screens based on oxidized silicon micro-pore array templates with different CsI(Tl) micro-column shapes and array structures in X-ray imaging were simulated using the Geant4 Monte Carlo simulation code. The shapes of the micro-columns include square, hexagonal and circular, and the array structures include square and hexagonal arrangements. The pitch size of the pixelated CsI(Tl) scintillation screens was set to 4 um, and the incident X-ray energy was set to 20 keV. The ratios of the number of scintillation photons that propagate along the CsI(Tl) micro-columns to the total number of scintillation photons of the micro-columns gradually decrease with the increase in total reflection time on the lateral surfaces of the micro-columns. However, these ratios are closely related to the shapes of the micro-columns and the incident positions of X-ray on the cross-sections of the micro-columns, especially for the circular micro-column. The sequence of bottom light outputs stimulated by a uniform flood field of X-ray from high to low corresponds to the circular, square and hexagonal CsI(Tl) micro-columns with the same cross-section areas. In addition, all spatial resolutions in terms of modulation transfer functions (MTFs) for the pixelated CsI(Tl) scintillation screens with square and hexagonal array structures are over 100 lp/mm. However, the resolution for the pixelated screen with the hexagonal array structure is approximately 8.5% higher than that for the screen with the square array structure. Moreover, the former screen has a higher detective quantum efficiency (DQE) than the latter screen at the same thickness. The pixelated CsI(Tl) scintillation screen with circular micro-column and hexagonal array structure in X-ray imaging has superior performance compared to other pixelated screens in this work. PMID- 30429503 TI - Statin-induced metabolic reprogramming in head and neck cancer: a biomarker for targeting monocarboxylate transporters. AB - Prognosis of HPV negative head and neck squamous cell carcinoma (HNSCC) patients remains poor despite surgical and medical advances and inadequacy of predictive and prognostic biomarkers in this type of cancer highlights one of the challenges to successful therapy. Statins, widely used for the treatment of hyperlipidaemia, have been shown to possess anti-tumour effects which were partly attributed to their ability to interfere with metabolic pathways essential in the survival of cancer cells. Here, we have investigated the effect of statins on the metabolic modulation of HNSCC cancers with a vision to predict a personalised anticancer therapy. Although, treatment of tumour-bearing mice with simvastatin did not affect tumour growth, pre-treatment for 2 weeks prior to tumour injection, inhibited tumour growth resulting in strongly increased survival. This was associated with increased expression of the monocarboxylate transporter 1 (MCT1) and a significant reduction in tumour lactate content, suggesting a possible reliance of these tumours on oxidative phosphorylation for survival. Since MCT1 is responsible for the uptake of mitochondrial fuels into the cells, we reasoned that inhibiting it would be beneficial. Interestingly, combination of simvastatin with AZD3965 (MCT1 inhibitor) led to further tumour growth delay as compared to monotherapies, without signs of toxicity. In clinical biopsies, prediagnostic statin therapy was associated with a significantly higher MCT1 expression and was not of prognostic value following conventional chemo-radiotherapy. These findings provide a rationale to investigate the clinical effectiveness of MCT1 inhibition in patients with HNSCC who have been taking lipophilic statins prior to diagnosis. PMID- 30429506 TI - Indentation of a surface-stiffened elastic substrate. AB - The paper deals with the problem of the indentation of a substrate in the form of an isotropic elastic halfspace that is reinforced at the surface by a bonded layer, which has flexibility characteristic of a Poisson-Kirchhoff-Germain thin plate. The presence of the reinforcing layer changes the characteristics of the indentation problem, in that the techniques that are applicable for the solution of the direct indentation of the halfspace cannot be applied to develop a load displacement relationship for the indenter. The integro-differential equation governing the indentation of the surface reinforced halfspace is solved using a discretization approach and numerical results are presented to demonstrate the influence of the stiffness of the reinforcing layer on the Boussinesq indention problem. PMID- 30429505 TI - Microbiomes and chemical components of feed water and membrane-attached biofilm in reverse osmosis system to treat membrane bioreactor effluents. AB - Reverse osmosis (RO) system at a stage after membrane bioreactor (MBR) is used for the wastewater treatment and reclamation. One of the most serious problems in this system is membrane fouling caused by biofilm formation. Here, microbiomes and chemical components of the feed water and membrane-attached biofilm of RO system to treat MBR effluents were investigated by non-destructive confocal reflection microscopy, excitation-emission fluorescence spectroscopy and high throughput sequencing of 16S rRNA genes. The microscopic visualization indicated that the biofilm contained large amounts of microbial cells (0.5 +/- 0.3~3.9 +/- 2.3 um3/um2) and the extracellular polysaccharides (3.3 +/- 1.7~9.4 +/- 5.1 um3/um2) and proteins (1.0 +/- 0.2~1.3 +/- 0.1 um3/um2). The spectroscopic analysis identified the humic and/or fulvic acid-like substances and protein-like substances as the main membrane foulants. High-throughput sequencing showed that Pseudomonas spp. and other heterotrophic bacteria dominated the feed water microbiomes. Meanwhile, the biofilm microbiomes were composed of diverse bacteria, among which operational taxonomic units related to the autotrophic Hydrogenophaga pseudoflava and Blastochloris viridis were abundant, accounting for up to 22.9 +/- 4.1% and 3.1 +/- 0.4% of the total, respectively. These results demonstrated that the minor autotrophic bacteria in the feed water played pivotal roles in the formation of polysaccharide- and protein-rich biofilm on RO membrane, thereby causing membrane fouling of RO system. PMID- 30429507 TI - KLF2 regulates osteoblast differentiation by targeting of Runx2. AB - Osteoblast differentiation plays a critical role in bone formation and maintaining balance in bone remodeling. Runt-related transcription factor 2 (Runx2) is a central transcription factor regulating osteoblast differentiation and promoting bone mineralization. Until now, the molecular regulatory basis and especially the gene regulatory network of osteogenic differentiation have been unclear. Kruppel-like factor 2 (KLF2) is a zinc finger structure and DNA-binding transcription factor. The current study aimed to investigate the physiological function of KLF2 in osteoblast differentiation. Our results indicate that KLF2 is expressed in pre-osteoblast MC3T3-E1 cells and primary osteoblasts. Interestingly, KLF2 expression is increased in osteoblasts during the osteoblastic differentiation process. Overexpression of KLF2 in MC3T3-E1 cells promoted the expression of the osteoblastic differentiation marker genes Alp, Osx, and Ocn, and stimulated mineralization by increasing Runx2 expression at both the mRNA and protein levels. In contrast, knockdown of KLF2 produced the opposite effects. Importantly, we found that KLF2 could physically interact with Runx2. KLF2 promoted osteoblast differentiation by regulating Runx2 and physically interacting with Runx2. Taken together, the findings of this study identify KLF2 as a novel regulator of osteoblast differentiation. Our findings suggest that KLF2 might be a new therapeutic target for bone disease. PMID- 30429508 TI - Geological evidence for AD 1008 tsunami along the Kachchh coast, Western India: Implications for hazard along the Makran Subduction Zone. AB - The 2004 Sumatra-Andaman tsunami emphasized the catastrophic nature of such disasters and exposed our knowledge gap of the historical and palaeo events. In the aftermath of this deadly event, the thrust in palaeotsunami studies was restricted to areas in the Indian Ocean, affected by this tsunami. The northern Arabian Sea, which hosts a similar tsunamigenic source i.e. the Makran Subduction Zone (MSZ), has so far remained 'Terra-Incognita'. Here, for the first time, we report geological evidence of the 1008 AD tsunami, also mentioned as 'an enigma' in the historical reports, by identifying a >250 km long sand sheet with a landward extent of more than 250 m from the Indian coastline. Detailed sedimentology and geochemistry reveals an offshore origin of this sand sheet, from where it was eroded by a high energy wave and deposited in a supratidal environment. Optical and AMS 14C chronology constrains its age of deposition around 1000 AD. The shear size of the sand sheet, laterally and across the coast, along with grain size, a characteristically different provenance, are some of the major indicators, which can be useful in palaeotsunami/palaeostorm deposit distinction. Our report of the AD 1008 event from the Indian coastline, also supports the claim that the Western MSZ, albeit at longer intervals, has experienced major thrust earthquakes (Mw > 8) in the historical past. The proximity of this sand sheet to the shoreline does not discount the role of extremely unlikely, large storms as its causal mechanism. PMID- 30429509 TI - Apparent strength versus universality in glasses of soft compressible colloids. AB - Microgel colloids, solvent swollen hydrogel particles of microscopic size, are in osmotic equilibrium with their surroundings. This has a profound effect on the behaviour of dense solutions of these polymeric colloids, most notably their ability to swell and deswell depending on the osmotic pressure of the system as a whole. Here we develop a minimal simulation model to treat this intrinsic volume regulation in order to explore the effects this has on the properties of dense solutions close to a liquid-solid transition. We demonstrate how the softness dependent volume regulation of particles gives rise to an apparent change in the fragility of the colloidal glass transition, which can be scaled out through the use of an adjusted volume fraction that accounts for changes in particle size. Moreover, we show how the same model can be used to explain the selective deswelling of soft microgels in a crystalline matrix of harder particles leading to robust crystals free of defects. Our results not only highlight the non trivial effects of osmotic regulation in governing the apparent physics of microgel suspensions, but also provides a platform to efficiently account for particle deswelling in simulations. PMID- 30429510 TI - Correlation between dynamic recrystallization and formation of rare earth texture in a Mg-Zn-Gd magnesium alloy during extrusion. AB - The trace addition of rare earth (RE) elements in Mg alloys can modify the extrusion texture, leading to the formation of RE texture and thus improved formability. The interrupted extrusion experiment as well as electron back scatter diffraction (EBSD) characterization was conducted in Mg-1.5Zn-0.5Gd (wt.%) alloy to unveil the dominant dynamic recrystallization (DRX) mechanism and its correlation with the formation of RE texture during extrusion. The results indicate that continuous DRX (CDRX) dominated the microstructural development. Fresh DRXed grains with 30 degrees [0001] grain boundaries preferentially nucleated in unDRXed grains with [10[Formula: see text]0] basal fiber orientation via CDRX, showing preferred selection of [2[Formula: see text][Formula: see text]0] basal fiber orientation rather than RE texture orientation. Consequently, CDRX contributed to the weakening of [10[Formula: see text]0] basal fiber texture and had a more significant effect on the formation of [2[Formula: see text][Formula: see text]0] basal fiber component than that of RE texture component. Besides, the preferred growth of recrystallized grains with RE texture orientation was confirmed to occur during static annealing after extrusion, which is inferred as the key reason for the formation of RE texture in dilute Mg-RE alloys. PMID- 30429511 TI - Long-term use of a neural prosthesis in progressive paralysis. AB - Brain-computer interfaces (BCIs) enable communication with others and allow machines or computers to be controlled in the absence of motor activity. Clinical studies evaluating neural prostheses in amyotrophic lateral sclerosis (ALS) patients have been performed; however, to date, no study has reported that ALS patients who progressed from locked-in syndrome (LIS), which has very limited voluntary movement, to a completely locked-in state (CLIS), characterized by complete loss of voluntary movements, were able to continue controlling neural prostheses. To clarify this, we used a BCI system to evaluate three late-stage ALS patients over 27 months. We employed steady-state visual evoked brain potentials elicited by flickering green and blue light-emitting diodes to control the BCI system. All participants reliably controlled the system throughout the entire period (median accuracy: 83.3%). One patient who progressed to CLIS was able to continue operating the system with high accuracy. Furthermore, this patient successfully used the system to respond to yes/no questions. Thus, this CLIS patient was able to operate a neuroprosthetic device, suggesting that the BCI system confers advantages for patients with severe paralysis, including those exhibiting complete loss of muscle movement. PMID- 30429513 TI - Author Correction: Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30429512 TI - Gene expression profile of muscle adaptation to high-intensity intermittent exercise training in young men. AB - High-intensity intermittent exercise training (HIIT) has been proposed as an effective approach for improving both, the aerobic and anaerobic exercise capacity. However, the detailed molecular response of the skeletal muscle to HIIT remains unknown. We examined the effects of the HIIT on the global gene expression in the human skeletal muscle. Eleven young healthy men participated in the study and completed a 6-week HIIT program involving exhaustive 6-7 sets of 20 s cycling periods with 10-s rests. In addition to determining the maximal oxygen uptake ([Formula: see text]), maximal accumulated oxygen deficit, and thigh muscle cross-sectional area (CSA), muscle biopsy samples were obtained from the vastus lateralis before and after the training to analyse the skeletal muscle transcriptome. The HIIT program significantly increased the [Formula: see text], maximal accumulated oxygen deficit, and thigh muscle CSA. The expression of 79 genes was significantly elevated (fold-change >1.2), and that of 73 genes was significantly reduced (fold-change <0.8) after HIIT. Gene ontology analysis of the up-regulated genes revealed that the significantly enriched categories were "glucose metabolism", "extracellular matrix", "angiogenesis", and "mitochondrial membrane". By providing information about a set of genes in the human skeletal muscle that responds to the HIIT, the study provided insight into the mechanism of skeletal muscle adaptation to HIIT. PMID- 30429515 TI - Automatic Detection of Prostate Tumor Habitats using Diffusion MRI. AB - A procedure for identification of optimal Apparent Diffusion Coefficient (ADC) thresholds for automatic delineation of prostatic lesions with restricted diffusion at differing risk for cancer was developed. The relationship between the size of the identified Volumes of Interest (VOIs) and Gleason Score (GS) was evaluated. Patients with multiparametric (mp)MRI, acquired prior to radical prostatectomy (RP) (n = 18), mpMRI-ultrasound fused (MRI-US) (n = 21) or template biopsies (n = 139) were analyzed. A search algorithm, spanning ADC thresholds in 50 um2/s increments, determined VOIs that were matched to RP tumor nodules. Three ADC thresholds for both peripheral zone (PZ) and transition zone (TZ) were identified for estimation of VOIs at low, intermediate, and high risk of prostate cancer. The determined ADC thresholds for low, intermediate and high risk in PZ/TZ were: 900/800; 1100/850; and 1300/1050 um2/s. The correlation coefficients between the size of the high/intermediate/low risk VOIs and GS in the three cohorts were 0.771/0.778/0.369, 0.561/0.457/0.355 and 0.423/0.441/0.36 (p < 0.05). Low risk VOIs mapped all RP lesions; area under the curve (AUC) for intermediate risk VOIs to discriminate GS6 vs GS >= 7 was 0.852; for high risk VOIs to discriminate GS6,7 vs GS >= 8 was 0.952. In conclusion, the automatically delineated volumes in the prostate with restricted diffusion were found to strongly correlate with cancer aggressiveness. PMID- 30429514 TI - Terminal restriction fragment length polymorphism is an "old school" reliable technique for swift microbial community screening in anaerobic digestion. AB - The microbial community in anaerobic digestion has been analysed through microbial fingerprinting techniques, such as terminal restriction fragment length polymorphism (TRFLP), for decades. In the last decade, high-throughput 16S rRNA gene amplicon sequencing has replaced these techniques, but the time-consuming and complex nature of high-throughput techniques is a potential bottleneck for full-scale anaerobic digestion application, when monitoring community dynamics. Here, the bacterial and archaeal TRFLP profiles were compared with 16S rRNA gene amplicon profiles (Illumina platform) of 25 full-scale anaerobic digestion plants. The alpha-diversity analysis revealed a higher richness based on Illumina data, compared with the TRFLP data. This coincided with a clear difference in community organisation, Pareto distribution, and co-occurrence network statistics, i.e., betweenness centrality and normalised degree. The beta diversity analysis showed a similar clustering profile for the Illumina, bacterial TRFLP and archaeal TRFLP data, based on different distance measures and independent of phylogenetic identification, with pH and temperature as the two key operational parameters determining microbial community composition. The combined knowledge of temporal dynamics and projected clustering in the beta diversity profile, based on the TRFLP data, distinctly showed that TRFLP is a reliable technique for swift microbial community dynamics screening in full-scale anaerobic digestion plants. PMID- 30429517 TI - Publisher Correction: A functional variant in the OAS1 gene is associated with Sjogren's syndrome complicated with HBV infection. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30429516 TI - The development of a new parameter for tracking post-transcriptional regulation allows the detailed map of the Pseudomonas aeruginosa Crc regulon. AB - Bacterial physiology is regulated at different levels, from mRNA synthesis to translational regulation and protein modification. Herein, we propose a parameter, dubbed post-transcriptional variation (PTV), that allows extracting information on post-transcriptional regulation from the combined analysis of transcriptomic and proteomic data. We have applied this parameter for getting a deeper insight in the regulon of the Pseudomonas aeruginosa post-transcriptional regulator Crc. P. aeruginosa is a free-living microorganism, and part of its ecological success relies on its capability of using a large number of carbon sources. The hierarchical assimilation of these sources when present in combination is regulated by Crc that, together with Hfq (the RNA-binding chaperon in the complex), impedes their translation when catabolite repression is triggered. Most studies on Crc regulation are based either in transcriptomics or in proteomics data, which cannot provide information on post-transcriptional regulation when analysed independently. Using the PTV parameter, we present a comprehensive map of the Crc post-transcriptional regulon. In addition of controlling the use of primary and secondary carbon sources, Crc regulates as well cell respiration, c-di-GMP mediated signalling, and iron utilization. Thus, besides controlling the hyerarchical assimilation of carbon sources, Crc is an important element for keeping bacterial homeostasis and, consequently, metabolic robustness. PMID- 30429518 TI - Legumain is an independent predictor for invasive recurrence in breast ductal carcinoma in situ. AB - Legumain is a proteolytic enzyme that plays a role in the regulation of cell proliferation in invasive breast cancer. Studies evaluating its role in ductal carcinoma in situ (DCIS) are lacking. Here, we aimed to characterize legumain protein expression in DCIS and evaluate its prognostic significance. Legumain was assessed immunohistochemically in a tissue microarray of a well-characterized cohort of DCIS (n = 776 pure DCIS and n = 239 DCIS associated with invasive breast cancer (DCIS-mixed)). Legumain immunoreactivity was scored in tumor cells and surrounding stroma and related to clinicopathological parameters and patient outcome. High legumain expression was observed in 23% of pure DCIS and was associated with features of high-risk DCIS including higher nuclear grade, comedo necrosis, hormone receptor negativity, HER2 positivity, and higher proliferation index. Legumain expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher legumain expression than the DCIS component (p < 0.0001). Legumain was an independent predictor of shorter local recurrencefree interval for all recurrences (p = 0.0003) and for invasive recurrences (p = 0.002). When incorporated with other risk factors, legumain provided better patient risk stratification. High legumain expression is associated with poor prognosis in DCIS and could be a potential marker to predict DCIS progression to invasive disease. PMID- 30429519 TI - Nucleation and growth of TiAl3 intermetallic phase in diffusion bonded Ti/Al Metal Intermetallic Laminate. AB - A novel nucleation and growth phenomenon for TiAl3 intermetallic phase in Ti/Al diffusion couple is proposed based on diffusion kinetics. The interdiffusion and intrinsic diffusion co-efficients are calculated to make evident of dominant diffusion of Al towards Ti in Ti/Al diffusion couple obtained by solid state diffusion bonding. It was surprising to observe that the diffusion rate of Al was around 20 times higher than Ti with the formation of Kirkendall pores near the Al/TiAl3 interface. With such dominant diffusion of Al towards Ti, the nucleation and growth of TiAl3 intermetallic phase in Ti/Al couple happens mainly at the Ti/TiAl3 interface rather than Al/TiAl3 interface which is evident by the presence of very fine nearly nano-sized TiAl3 nuclei/grains near the Ti/TiAl3 interface. Even though the intermetallic phase is expected to nucleate at Al/TiAl3 interface, the relatively larger TiAl3 grains near that interface depicts grain growth with minimal nucleation. The theoretical calculations on diffusion parameters are in accordance with experimental observations of TiAl3 intermetallic growth phenomenon in Ti/Al system. PMID- 30429521 TI - Source evaluation of 137Cs in foodstuffs based on trace 134Cs radioactivity measurements following the Fukushima nuclear accident. AB - We performed gamma-ray analysis to determine the amount of radioactive cesium-134 (134Cs) and cesium-137 (137Cs) in 259 foodstuffs five years after the Fukushima nuclear accident of 2011. Using measurements of trace 134Cs radioactivity, we investigated the contribution ratio of 137Cs derived from the Fukushima accident on 2011 and pre-Fukushima. The median detected concentration of radiocesium (134Cs + 137Cs) in foodstuffs was 0.33 Bq/kg-raw, a much lower radioactivity than the Japanese regulatory limit. However, a few samples had particularly high radioactivity, including some dried mushrooms sold in Iwate Prefecture that had a 137Cs radioactivity concentration as high as 441 Bq/kg. Our analysis showed that 75.5% of the 137Cs detected in these mushrooms originated from the Fukushima accident, and 24.5% was originated before the Fukushima event. Our study clarified the 137Cs contamination in 75 of all 259 food samples before and after the Fukushima nuclear accident, showing that not only mushrooms but also fish had been contaminated before the Fukushima accident. PMID- 30429522 TI - Polythermal structure of a Himalayan debris-covered glacier revealed by borehole thermometry. AB - Runoff from high-elevation debris-covered glaciers represents a crucial water supply for millions of people in the Hindu Kush-Himalaya region, where peak water has already passed in places. Knowledge of glacier thermal regime is essential for predicting dynamic and geometric responses to mass balance change and determining subsurface drainage pathways, which ultimately influence proglacial discharge and hence downstream water availability. Yet, deep internal ice temperatures of these glaciers are unknown, making projections of their future response to climate change highly uncertain. Here, we show that the lower part of the ablation area of Khumbu Glacier, a high-elevation debris-covered glacier in Nepal, may contain ~56% temperate ice, with much of the colder shallow ice near to the melting-point temperature (within 0.8 degrees C). From boreholes drilled in the glacier's ablation area, we measured a minimum ice temperature of -3.3 degrees C, and even the coldest ice we measured was 2 degrees C warmer than the mean annual air temperature. Our results indicate that high-elevation Himalayan glaciers are vulnerable to even minor atmospheric warming. PMID- 30429520 TI - Revised role for Hfq bacterial regulator on DNA topology. AB - Hfq is a pleiotropic regulator that mediates several aspects of bacterial RNA metabolism. The protein notably regulates translation efficiency and RNA decay in Gram-negative bacteria, usually via its interaction with small regulatory RNA. Besides these RNA-related functions, Hfq has also been described as one of the nucleoid associated proteins shaping the bacterial chromosome. Therefore, Hfq appears as a versatile nucleic acid-binding protein, which functions are probably even more numerous than those initially suggested. For instance, E. coli Hfq, and more precisely its C-terminal region (CTR), has been shown to induce DNA compaction into a condensed form. In this paper, we establish that DNA induces Hfq-CTR amyloidogenesis, resulting in a change of DNA local conformation. Furthermore, we clarify the effect of Hfq on DNA topology. Our results evidence that, even if the protein has a strong propensity to compact DNA thanks to its amyloid region, it does not affect overall DNA topology. We confirm however that hfq gene disruption influences plasmid supercoiling in vivo, indicating that the effect on DNA topology in former reports was indirect. Most likely, this effect is related to small regulatory sRNA-Hfq-based regulation of another protein that influences DNA supercoiling, possibly a nucleoid associated protein such as H-NS or Dps. Finally, we hypothesise that this indirect effect on DNA topology explains, at least partially, the previously reported effect of Hfq on plasmid replication efficiency. PMID- 30429523 TI - Achieving acoustic topological valley-Hall states by modulating the subwavelength honeycomb lattice. AB - Topological valley-contrasting physics is attracting increasing attention because of its potentials as a promising information carrier in electrics and classical systems. In this work, we reveal the valley-Hall effect and the valley projected edge states in two-dimensional sonic crystals with modulated acoustic honeycomb lattice. The sonic crystals are arranged by soft-material rods and thereby in a sub-wavelength scale, of which the lattice constant is only 0.267 times the wavelength and can be modulated to almost 0.1 times the wavelength. The degenerated valley states are lifted by breaking the inversion symmetry through introducing the refractive-index difference to the rods. The unidirectional excitation of valley chiral bulk state and the non-diffracting Bessel beams are realized by sources carrying orbital angular momentum with proper chirality. Furthermore, we demonstrate that the sub-wavelength valley creation can also be achieved by embedding modulated rubber rods with the mingled steel in a water background, which has significant potential in hydroacoustics, such as underwater communications, sound trapping and directional radiation. PMID- 30429524 TI - Administration of hydrogen-rich water prevents vascular aging of the aorta in LDL receptor-deficient mice. AB - The main cause of arteriosclerosis is atherosclerosis in the aorta. Atherosclerosis is recognized as a chronic inflammatory condition that begins with the dysfunction or activation of arterial endothelium. Low-density lipoprotein (LDL) and especially its oxidized form play a key role in endothelial dysfunction and atherogenesis. Recent studies showed that senescent cells are involved in the development and progression of atherosclerosis, and eliminating senescent cells suppresses the senescence-associated secretory phenotype. We previously reported that molecular hydrogen-rich water (HW) has antioxidant and anti-inflammatory effects in numerous diseases. Here, we used LDL receptor deficient mice fed a high-fat diet (HFD) for 13 weeks as a model for atherosclerosis and evaluated the effects of continuous administration of HW. The numbers of endothelial cells in the atheroma expressing the senescence factors p16INK4a and p21 decreased in HFD-fed mice given HW compared with HFD-fed mice given control water. Furthermore, macrophage infiltration and Tnfalpha expression in the atheroma were also suppressed. These results suggest that vascular aging can be suppressed by HW. PMID- 30429525 TI - Evidence for mitigation of coral bleaching by manganese. AB - Unprecedented mass coral bleaching events due to global warming and overall seawater pollution have been observed worldwide over the last decades. Although metals are often considered as toxic substances for corals, some are essential at nanomolar concentrations for physiological processes such as photosynthesis and antioxidant defenses. This study was designed to elucidate, the individual and combined effects of nanomolar seawater enrichment in manganese (Mn) and iron (Fe), on the main physiological traits of Stylophora pistillata, maintained under normal growth and thermal stress conditions. We provide, for the first time, evidence that Mn is a key trace element for coral symbionts, enhancing cellular chlorophyll concentrations, photosynthetic efficiency and gross photosynthetic rates at ambient temperature. Our experiment also highlights the key role of Mn in increasing coral resistance to heat stress-induced bleaching. While Mn enriched corals did not bleach and did not reduce their rates of photosynthesis and calcification, control corals experienced significant bleaching. On the contrary to Mn, Fe enrichment not only impaired calcification but induced significant bleaching. Such information is an important step towards a better understanding of the response of corals to seawater enrichment in metals. It can also explain, to some extent, species susceptibility to environmental stress. PMID- 30429526 TI - Anomalously high geothermal flux near the South Pole. AB - Melting at the base of the Antarctic Ice Sheet influences ice dynamics and our ability to recover ancient climatic records from deep ice cores. Basal melt rates are affected by geothermal flux, one of the least constrained properties of the Antarctic continent. Estimates of Antarctic geothermal flux are typically regional in nature, derived from geological, magnetic or seismic data, or from sparse point measurements at ice core sites. We analyse ice-penetrating radar data upstream of South Pole revealing a ~100 km long and 50 km wide area where internal ice sheet layers converge with the bed. Ice sheet modelling shows that this englacial layer configuration requires basal melting of up to 6 +/- 1 mm a-1 and a geothermal flux of 120 +/- 20 mW m-2, more than double the values expected for this cratonic sector of East Antarctica. We suggest high heat producing Precambrian basement rocks and hydrothermal circulation along a major fault system cause this anomaly. We conclude that local geothermal flux anomalies could be more widespread in East Antarctica. Assessing their influence on subglacial hydrology and ice sheet dynamics requires new detailed geophysical observations, especially in candidate areas for deep ice core drilling and at the onset of major ice streams. PMID- 30429527 TI - Ciliary defects caused by dysregulation of O-GlcNAc modification are associated with diabetic complications. PMID- 30429529 TI - Penile traction therapy - efficacy in PD. PMID- 30429530 TI - TECs support the SSC niche. PMID- 30429528 TI - Two Contrasting Patterns and Underlying Genes for Coadaptation of Seed Dormancy and Flowering Time in Rice. AB - Association between seed dormancy (SD) and flowering time (FT) may generate a synergy in plant adaptation. This research aimed to identify patterns and underlying genes of the association in rice (Oryza sativa). Four F2 and two BC1F1 populations from crosses of weedy/cultivated rice, and two families of progeny lines from backcrosses were evaluated for variations in time to flowering and germination ability. The two measurements were correlated negatively in the F2 and BC1F1 populations, but positively in advanced generations of the progeny lines. The negative correlations were resulted from linkage disequilibria between SD and FT loci at 7-40 cM apart. The positive correlations arose from co-located SD and FT loci undetectable in the BC1F1 population. Two independent sets of co localized loci were isolated as single Mendelian factors, and haplotypes that promote flowering and reduce germination derived from weedy and cultivated rice, respectively. The presence of negative and positive correlations indicates that the rice complex has maintained two contrasting patterns of SD-FT coadaptation, with the positive being "recessive" to the negative pattern. Modeling with isogenic lines suggests that a negative pattern could generate a greater synergy (difference between haplotype variants) than the positive one for seedbank persistence, or enhanced plant adaptation to seasonal changes in temperature or moisture. However, the early-flowering dormant genotype of a positive pattern could also have a selective advantage over its counterpart for weeds to avoid harvesting. The isolated haplotypes could be used to manipulate cultivars simultaneously for germination ability and growth duration. PMID- 30429531 TI - High-affinity CD16-polymorphism and Fc-engineered antibodies enable activity of CD16-chimeric antigen receptor-modified T cells for cancer therapy. AB - BACKGROUND: CD16-chimeric antigen receptors (CAR) T cells recognise the Fc portion of therapeutic antibodies, which can enable the selective targeting of different antigens. Limited evidence exists as to which CD16-CAR design and antibody partner might be most effective. We have hypothesised that the use of high-affinity CD16 variants, with increased Fc-terminus antibody affinity, combined with Fc-engineered antibodies, would provide superior CD16-CAR T cell efficacy. METHODS: CD16-CAR T (wild-type or variants) cells were co-cultured with Panc-1 pancreatic cancer, Raji lymphoma or A375 melanoma cells in the presence or absence of anti-CD20, anti-MCSP, wild-type or the glycoengineered antibody variants. The endpoints were proliferation, activation, and cytotoxicity in vitro. RESULTS: The CD16 158 V variant of CD16-CAR T cells showed increased cytotoxic activity against all the tested cancer cells in the presence of the wild-type antibody directed against MCSP or CD20. Glycoengineered antibodies enhanced CD16-CAR T cell activity irrespective of CD16 polymorphisms as compared with the wild-type antibody. The combination of the glycoengineered antibodies with the CD16-CAR 158 V variant synergised as seen by the increase in all endpoints. CONCLUSION: These results indicate that CD16-CAR with the high affinity CD16 variant 158 V, combined with Fc-engineered antibodies, have high anti-tumour efficacy. PMID- 30429532 TI - Platelet biology and functions: new concepts and clinical perspectives. AB - Platelets - blood cells continuously produced from megakaryocytes mainly in the bone marrow - are implicated not only in haemostasis and arterial thrombosis, but also in other physiological and pathophysiological processes. This Review describes current evidence for the heterogeneity in platelet structure, age, and activation properties, with consequences for a diversity of platelet functions. Signalling processes of platelet populations involved in thrombus formation with ongoing coagulation are well understood. Genetic approaches have provided information on multiple genes related to normal haemostasis, such as those encoding receptors and signalling or secretory proteins, that determine platelet count and/or responsiveness. As highly responsive and secretory cells, platelets can alter the environment through the release of growth factors, chemokines, coagulant factors, RNA species, and extracellular vesicles. Conversely, platelets will also adapt to their environment. In disease states, platelets can be positively primed to reach a pre-activated condition. At the inflamed vessel wall, platelets interact with leukocytes and the coagulation system, interactions mediating thromboinflammation. With current antiplatelet therapies invariably causing bleeding as an undesired adverse effect, novel therapies can be more beneficial if directed against specific platelet responses, populations, interactions, or priming conditions. On the basis of these novel concepts and processes, we discuss several initiatives to target platelets therapeutically. PMID- 30429534 TI - Publisher Correction: Environment spectrum and coherence behaviours in a rare earth doped crystal for quantum memory. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30429533 TI - Correlative Light-Electron Microscopy detects lipopolysaccharide and its association with fibrin fibres in Parkinson's Disease, Alzheimer's Disease and Type 2 Diabetes Mellitus. AB - Many chronic diseases, including those classified as cardiovascular, neurodegenerative, or autoimmune, are characterized by persistent inflammation. The origin of this inflammation is mostly unclear, but it is typically mediated by inflammatory biomarkers, such as cytokines, and affected by both environmental and genetic factors. Recently circulating bacterial inflammagens such as lipopolysaccharide (LPS) have been implicated. We used a highly selective mouse monoclonal antibody to detect bacterial LPS in whole blood and/or platelet poor plasma of individuals with Parkinson's Disease, Alzheimer's type dementia, or Type 2 Diabetes Mellitus. Our results showed that staining is significantly enhanced (P < 0.0001) compared to healthy controls. Aberrant blood clots in these patient groups are characterized by amyloid formation as shown by the amyloid selective stains thioflavin T and AmytrackerTM 480 or 680. Correlative Light Electron Microscopy (CLEM) illustrated that the LPS antibody staining is located in the same places as where amyloid fibrils may be observed. These data are consistent with the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis in which bacterial inflammagens such as LPS are responsible for anomalous blood clotting as part of the aetiology of these chronic inflammatory diseases. PMID- 30429536 TI - TRPV2 is required for mechanical nociception and the stretch-evoked response of primary sensory neurons. AB - Mechanotransduction plays important roles in many sensory processes, including touch, pain, hearing, and proprioception. However, the molecular mechanisms of mechanical nociception have remained unclear. Here, we showed that elimination of transient receptor potential vanilloid 2 (TRPV2) in mice resulted in the deficit of mechanical nociception due to the lack of mechanosensitivity in a subclass of adult primary sensory neurons (PSNs). The PSN-specific TRPV2-deficient mice showed behavioural impairment of mechanical nociception in tail-pressure and von Frey hair tests, without defects in axonal growth and neuronal composition. Conversely, the mice displayed normal behaviour to noxious heat and non-noxious tactile stimuli. Furthermore, based on the stretch-evoked Ca2+ response of cultured PSNs, we characterised two types of stretch-activated neurons in normal mice; fast-decay high-threshold and slow-decay low-threshold mechanosensitive. The cultured neurons from TRPV2-deficient mice lacked stretch-evoked Ca2+ responses by fast-decay neurons normally activated by high-threshold mechanical stimulation. These results demonstrated that TRPV2 has a critical role in mechanical nociception in the adult somatosensory system. PMID- 30429535 TI - Cerebral Motor Functional Connectivity at the Acute Stage: An Outcome Predictor of Ischemic Stroke. AB - Sixty-seven patients with first acute ischemic stroke onset between 3 to 7 days and 25 age- and sex- matched controls were analyzed for the performance of a resting-state functional MRI to investigate whether the functional connectivity (FC) of the motor network in acute ischemic stroke is independently associated with functional outcomes. The FC of cortical motor network and default mode network was analyzed. The FC was compared between controls, patients with favorable outcomes (modified Rankin Scale, mRS <=1), and patients with unfavorable outcomes (mRS >=2) at 3 months. Of the 67 patients, 23 (34%) exhibited unfavorable outcomes. In multivariate analysis, the FC between ipsilesional primary motor cortex (M1) and contralesional dorsal premotor area (PMd) <=0.63, were independently associated with unfavorable outcomes (odds ratio = 6.32, P = 0.032), whereas the FC of default mode network was not different between groups. The interhemispheric FC of the motor network is an independent predictor of functional outcomes in patients with acute ischemic stroke. PMID- 30429538 TI - Antioxidants: good, bad or indifferent. PMID- 30429537 TI - Blocking nuclear export of HSPA8 after heat shock stress severely alters cell survival. AB - The nuclear translocation of endogenous heat shock cognate protein HSPA8 is a requisite for cell survival during oxidative and heat shock stress. Upon these events, cytoplasmic HSPA8 is thought to concentrate within the nucleus and nucleolus. When the situation returns to normal, HSPA8 is released from its nuclear/nucleolar anchors and redistributes into the cytoplasm. By using different stress conditions and a 21-mer phosphopeptide tool called P140, which binds HSPA8 and hampers its chaperone properties, we deciphered the cellular and molecular effects arising during this vital cytoplasmic-nuclear-cytoplasmic shuttling process. Using the non-metastatic fibroblastoid cell line MRL/N-1 derived from a MRL/MpTn-gld/gld lupus-prone mouse, we discovered that P140 treatment neutralized the egress of HSPA8 from nucleus to cytoplasm in the cell recovery phase. This lack of relocation of HSPA8 into the cytoplasm of heat shocked MRL/N-1 cells altered the ability of these cells to survive when a second mild oxidative stress mimicking inflammatory conditions was applied. Crosslinking experiments followed by proteomics studies showed that P140 binds regions close to nuclear import and export signal sequences encompassed within the HSPA8 structure. These data are consistent with HSPA8 having a crucial cell protective role against reactive oxygen species (ROS) production by mitochondria during inflammatory conditions. PMID- 30429539 TI - Non-mercaptalbumin, Oxidized Form of Serum Albumin, Significantly Associated with Renal Function and Anemia in Chronic Kidney Disease Patients. AB - Oxidative stress plays a major role in development of cardiovascular disease in patients with chronic kidney disease (CKD). Human mercaptalbumin (HMA), a reduced form of serum albumin, and non-mercaptalbumin (HNA), an oxidized form of serum albumin, are known as indicators for evaluating oxidative stress in systemic circulation, including end-stage renal disease cases. We investigated factors associated with fraction of HNA [f(HNA)] in 112 pre-dialysis CKD patients (63.6 +/- 14.0 years old; 59 males, 53 females) using a newly established anion exchange column packed with hydrophilic polyvinyl alcohol gel as well as high performance liquid chromatography. Mean f(HNA) in our CKD patients was 30.0 +/- 6.1%, higher than that previously reported for healthy subjects. In multiple regression analysis, age (beta = 0.200, p = 0.014), eGFR (beta = -0.238, p = 0.009), hemoglobin (beta = -0.346, p < 0.001), and ferritin (beta = 0.200, p = 0.019) were significantly and independently associated with f(HNA) (R2 = 0.356, p < 0.001). In addition, factors related to CKD-mineral and bone disorder (CKD MBD), including intact-PTH (beta = 0.218, p = 0.049) and 1,25-dihydroxyvitamin D (1,25(OH)2D) (beta = -0.178, p = 0.040), were significantly and independently associated with serum f(HNA) (R2 = 0.339, p < 0.001), whereas fibroblast growth factor-23 was not. These findings indicate the importance of management of hemoglobin and ferritin levels, as well as appropriate control of CKD-MBD factors for a better redox state of serum albumin in CKD patients. PMID- 30429541 TI - Health effects of seasonal variation in cardiovascular hemodynamics among workers in forest environments. AB - Seasonal variation in cardiovascular functions (CVFs) associated with climatic changes is an important emerging public health issue. The objectives of this study were to demonstrate seasonal variation in CVFs by comparing intra individual differences between winter and summer among people working in a forest environment and to discuss the possible mechanisms accounting for the health effects of seasonal variation in cardiovascular hemodynamics. A total of 72 staff members of the Experimental Forest of National Taiwan University were recruited for continuous health monitoring during two seasons to investigate the intra individual seasonal variation in CVFs, complete blood counts, and biochemical examinations. CVFs were assessed by measuring the arterial pressure waveform by a cuff sphygmomanometer using an oscillometric blood pressure device, and aortic stiffness was measured by brachial-ankle pulse wave velocity (baPWV). The results showed that cholesterol levels, white and red blood cell counts, and platelet counts were higher in winter than in summer. Subjects showed not only higher vascular stress, as indicated by higher levels of brachial systolic and diastolic blood pressure (SBP and DBP), central end-SBP and DBP, systemic vascular resistance (SVR), and baPWV, but also lower cardiac activities, including lower levels of heart rate, left ventricular contractility, and cardiac output in winter than in summer. The central and brachial BP, cardiac output, SVR, and baPWV were significantly associated with temperature changes in seasonal variation after controlling related confounding factors. This study provides evidence of higher vascular stress and susceptibility to atherothrombosis during winter compared with summer. PMID- 30429540 TI - Genome-wide discovery of DNA polymorphisms among chickpea cultivars with contrasting seed size/weight and their functional relevance. AB - Seed size/weight is a major agronomic trait which determine crop productivity in legumes. To understand the genetic basis of seed size determination, we sought to identify DNA polymorphisms between two small (Himchana 1 and Pusa 362) and two large-seeded (JGK 3 and PG 0515) chickpea cultivars via whole genome resequencing. We identified a total of 75535 single nucleotide polymorphisms (SNPs), 6486 insertions and deletions (InDels), 1938 multi-nucleotide polymorphisms (MNPs) and 5025 complex variants between the two small and two large-seeded chickpea cultivars. Our analysis revealed 814, 244 and 72 seed specific genes harboring DNA polymorphisms in promoter or non-synonymous and large-effect DNA polymorphisms, respectively. Gene ontology analysis revealed enrichment of cell growth and division related terms in these genes. Among them, at least 22 genes associated with quantitative trait loci, and those involved in cell growth and division and encoding transcription factors harbored promoter and/or large-effect/non-synonymous DNA polymorphisms. These also showed higher expression at late-embryogenesis and/or mid-maturation stages of seed development in the large-seeded cultivar, suggesting their role in seed size/weight determination in chickpea. Altogether, this study provided a valuable resource for large-scale genotyping applications and a few putative candidate genes that might play crucial role in governing seed size/weight in chickpea. PMID- 30429542 TI - Publisher Correction: A patient-level pooled analysis of treatment-shortening regimens for drug-susceptible pulmonary tuberculosis. AB - The version of this article originally published was not open access. This article should have been open access. The error has been fixed, and the article is now open access. PMID- 30429544 TI - Emergence of multi-body interactions in a fermionic lattice clock. AB - Alkaline-earth atoms have metastable 'clock' states with minute-long optical lifetimes, high-spin nuclei and SU(N)-symmetric interactions, making them powerful platforms for atomic clocks1, quantum information processing2 and quantum simulation3. Few-particle systems of such atoms provide opportunities to observe the emergence of complex many-body phenomena with increasing system size4. Multi-body interactions among particles are emergent phenomena, which cannot be broken down into sums over underlying pairwise interactions. They could potentially be used to create exotic states of quantum matter5,6, but have yet to be explored in ultracold fermions. Here we create arrays of isolated few-body systems in an optical clock based on a three-dimensional lattice of fermionic 87Sr atoms. We use high-resolution clock spectroscopy to directly observe the onset of elastic and inelastic multi-body interactions among atoms. We measure the frequency shifts of the clock transition for varying numbers of atoms per lattice site, from n = 1 to n = 5, and observe nonlinear interaction shifts characteristic of elastic multi-body effects. These measurements, combined with theory, elucidate an emergence of SU(N)-symmetric multi-body interactions, which are unique to fermionic alkaline-earth atoms. To study inelastic multi-body effects, we use these frequency shifts to isolate n-occupied sites in the lattice and measure the corresponding lifetimes of the clock states. This allows us to access the short-range few-body physics without experiencing the systematic effects that are encountered in a bulk gas. The lifetimes that we measure in the isolated few-body systems agree very well with numerical predictions based on a simple model for the interatomic potential, suggesting a universality in ultracold collisions. By connecting these few-body systems through tunnelling, the favourable energy and timescales of the interactions will allow our system to be used for studies of high-spin quantum magnetism7,8 and the Kondo effect3,9. PMID- 30429543 TI - Three-dimensional collective charge excitations in electron-doped copper oxide superconductors. AB - High-temperature copper oxide superconductors consist of stacked CuO2 planes, with electronic band structures and magnetic excitations that are primarily two dimensional1,2, but with superconducting coherence that is three-dimensional. This dichotomy highlights the importance of out-of-plane charge dynamics, which has been found to be incoherent in the normal state3,4 within the limited range of momenta accessible by optics. Here we use resonant inelastic X-ray scattering to explore the charge dynamics across all three dimensions of the Brillouin zone. Polarization analysis of recently discovered collective excitations (modes) in electron-doped copper oxides5-7 reveals their charge origin, that is, without mixing with magnetic components5-7. The excitations disperse along both the in plane and out-of-plane directions, revealing its three-dimensional nature. The periodicity of the out-of-plane dispersion corresponds to the distance between neighbouring CuO2 planes rather than to the crystallographic c-axis lattice constant, suggesting that the interplane Coulomb interaction is responsible for the coherent out-of-plane charge dynamics. The observed properties are hallmarks of the long-sought 'acoustic plasmon', which is a branch of distinct charge collective modes predicted for layered systems8-12 and argued to play a substantial part in mediating high-temperature superconductivity10-12. PMID- 30429545 TI - Metal-free ribonucleotide reduction powered by a DOPA radical in Mycoplasma pathogens. AB - Ribonucleotide reductase (RNR) catalyses the only known de novo pathway for the production of all four deoxyribonucleotides that are required for DNA synthesis1,2. It is essential for all organisms that use DNA as their genetic material and is a current drug target3,4. Since the discovery that iron is required for function in the aerobic, class I RNR found in all eukaryotes and many bacteria, a dinuclear metal site has been viewed as necessary to generate and stabilize the catalytic radical that is essential for RNR activity5-7. Here we describe a group of RNR proteins in Mollicutes-including Mycoplasma pathogens that possess a metal-independent stable radical residing on a modified tyrosyl residue. Structural, biochemical and spectroscopic characterization reveal a stable 3,4-dihydroxyphenylalanine (DOPA) radical species that directly supports ribonucleotide reduction in vitro and in vivo. This observation overturns the presumed requirement for a dinuclear metal site in aerobic ribonucleotide reductase. The metal-independent radical requires new mechanisms for radical generation and stabilization, processes that are targeted by RNR inhibitors. It is possible that this RNR variant provides an advantage under metal starvation induced by the immune system. Organisms that encode this type of RNR-some of which are developing resistance to antibiotics-are involved in diseases of the respiratory, urinary and genital tracts. Further characterization of this RNR family and its mechanism of cofactor generation will provide insight into new enzymatic chemistry and be of value in devising strategies to combat the pathogens that utilize it. We propose that this RNR subclass is denoted class Ie. PMID- 30429546 TI - The metabolite dimethylsulfoxonium propionate extends the marine organosulfur cycle. AB - Algae produce massive amounts of dimethylsulfoniopropionate (DMSP), which fuel the organosulfur cycle1,2. On a global scale, several petagrams of this sulfur species are produced annually, thereby driving fundamental processes and the marine food web1. An important DMSP transformation product is dimethylsulfide, which can be either emitted to the atmosphere3,4 or oxidized to dimethylsulfoxide (DMSO) and other products5. Here we report the discovery of a structurally unusual metabolite, dimethylsulfoxonium propionate (DMSOP), that is synthesized by several DMSP-producing microalgae and marine bacteria. As with DMSP, DMSOP is a low-molecular-weight zwitterionic metabolite that carries both a positively and a negatively charged functional group. Isotope labelling studies demonstrate that DMSOP is produced from DMSP, and is readily metabolized to DMSO by marine bacteria. DMSOP was found in near nanomolar amounts in field samples and in algal culture media, and thus represents-to our knowledge-a previously undescribed biogenic source for DMSO in the marine environment. The estimated annual oceanic production of oxidized sulfur from this pathway is in the teragram range, similar to the calculated dimethylsulfide flux to the atmosphere3. This sulfoxonium metabolite is therefore a key metabolite of a previously undescribed pathway in the marine sulfur cycle. These findings highlight the importance of DMSOP in the marine organosulfur cycle. PMID- 30429547 TI - Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. AB - Protein misfolding is linked to a wide array of human disorders, including Alzheimer's disease, Parkinson's disease and type II diabetes1,2. Protective cellular protein quality control (PQC) mechanisms have evolved to selectively recognize misfolded proteins and limit their toxic effects3-9, thus contributing to the maintenance of the proteome (proteostasis). Here we examine how molecular chaperones and the ubiquitin-proteasome system cooperate to recognize and promote the clearance of soluble misfolded proteins. Using a panel of PQC substrates with distinct characteristics and localizations, we define distinct chaperone and ubiquitination circuitries that execute quality control in the cytoplasm and nucleus. In the cytoplasm, proteasomal degradation of misfolded proteins requires tagging with mixed lysine 48 (K48)- and lysine 11 (K11)-linked ubiquitin chains. A distinct combination of E3 ubiquitin ligases and specific chaperones is required to achieve each type of linkage-specific ubiquitination. In the nucleus, however, proteasomal degradation of misfolded proteins requires only K48-linked ubiquitin chains, and is thus independent of K11-specific ligases and chaperones. The distinct ubiquitin codes for nuclear and cytoplasmic PQC appear to be linked to the function of the ubiquilin protein Dsk2, which is specifically required to clear nuclear misfolded proteins. Our work defines the principles of cytoplasmic and nuclear PQC as distinct, involving combinatorial recognition by defined sets of cooperating chaperones and E3 ligases. A better understanding of how these organelle-specific PQC requirements implement proteome integrity has implications for our understanding of diseases linked to impaired protein clearance and proteostasis dysfunction. PMID- 30429549 TI - Water input into the Mariana subduction zone estimated from ocean-bottom seismic data. AB - The water cycle at subduction zones remains poorly understood, although subduction is the only mechanism for water transport deep into Earth. Previous estimates of water flux1-3 exhibit large variations in the amount of water that is subducted deeper than 100 kilometres. The main source of uncertainty in these calculations is the initial water content of the subducting uppermost mantle. Previous active-source seismic studies suggest that the subducting slab may be pervasively hydrated in the plate-bending region near the oceanic trench4-7. However, these studies do not constrain the depth extent of hydration and most investigate young incoming plates, leaving subduction-zone water budgets for old subducting plates uncertain. Here we present seismic images of the crust and uppermost mantle around the central Mariana trench derived from Rayleigh-wave analysis of broadband ocean-bottom seismic data. These images show that the low mantle velocities that result from mantle hydration extend roughly 24 kilometres beneath the Moho discontinuity. Combined with estimates of subducting crustal water, these results indicate that at least 4.3 times more water subducts than previously calculated for this region3. If other old, cold subducting slabs contain correspondingly thick layers of hydrous mantle, as suggested by the similarity of incoming plate faulting across old, cold subducting slabs, then estimates of the global water flux into the mantle at depths greater than 100 kilometres must be increased by a factor of about three compared to previous estimates3. Because a long-term net influx of water to the deep interior of Earth is inconsistent with the geological record8, estimates of water expelled at volcanic arcs and backarc basins probably also need to be revised upwards9. PMID- 30429548 TI - Single-cell reconstruction of the early maternal-fetal interface in humans. AB - During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success. PMID- 30429550 TI - Anthropogenic influences on major tropical cyclone events. AB - There is no consensus on whether climate change has yet affected the statistics of tropical cyclones, owing to their large natural variability and the limited period of consistent observations. In addition, projections of future tropical cyclone activity are uncertain, because they often rely on coarse-resolution climate models that parameterize convection and hence have difficulty in directly representing tropical cyclones. Here we used convection-permitting regional climate model simulations to investigate whether and how recent destructive tropical cyclones would change if these events had occurred in pre-industrial and in future climates. We found that, relative to pre-industrial conditions, climate change so far has enhanced the average and extreme rainfall of hurricanes Katrina, Irma and Maria, but did not change tropical cyclone wind-speed intensity. In addition, future anthropogenic warming would robustly increase the wind speed and rainfall of 11 of 13 intense tropical cyclones (of 15 events sampled globally). Additional regional climate model simulations suggest that convective parameterization introduces minimal uncertainty into the sign of projected changes in tropical cyclone intensity and rainfall, which allows us to have confidence in projections from global models with parameterized convection and resolution fine enough to include tropical cyclones. PMID- 30429551 TI - Urbanization exacerbated the rainfall and flooding caused by hurricane Harvey in Houston. AB - Category 4 landfalling hurricane Harvey poured more than a metre of rainfall across the heavily populated Houston area, leading to unprecedented flooding and damage. Although studies have focused on the contribution of anthropogenic climate change to this extreme rainfall event1-3, limited attention has been paid to the potential effects of urbanization on the hydrometeorology associated with hurricane Harvey. Here we find that urbanization exacerbated not only the flood response but also the storm total rainfall. Using the Weather Research and Forecast model-a numerical model for simulating weather and climate at regional scales-and statistical models, we quantify the contribution of urbanization to rainfall and flooding. Overall, we find that the probability of such extreme flood events across the studied basins increased on average by about 21 times in the period 25-30 August 2017 because of urbanization. The effect of urbanization on storm-induced extreme precipitation and flooding should be more explicitly included in global climate models, and this study highlights its importance when assessing the future risk of such extreme events in highly urbanized coastal areas. PMID- 30429553 TI - How to turn your interests into a career. PMID- 30429554 TI - Say it with mastodons. PMID- 30429555 TI - Governments should unite to curb meat consumption. PMID- 30429556 TI - Networks and mentors help female scientists in Africa and Middle East. PMID- 30429552 TI - A candidate super-Earth planet orbiting near the snow line of Barnard's star. AB - Barnard's star is a red dwarf, and has the largest proper motion (apparent motion across the sky) of all known stars. At a distance of 1.8 parsecs1, it is the closest single star to the Sun; only the three stars in the alpha Centauri system are closer. Barnard's star is also among the least magnetically active red dwarfs known2,3 and has an estimated age older than the Solar System. Its properties make it a prime target for planetary searches; various techniques with different sensitivity limits have been used previously, including radial-velocity imaging4 6, astrometry7,8 and direct imaging9, but all ultimately led to negative or null results. Here we combine numerous measurements from high-precision radial velocity instruments, revealing the presence of a low-amplitude periodic signal with a period of 233 days. Independent photometric and spectroscopic monitoring, as well as an analysis of instrumental systematic effects, suggest that this signal is best explained as arising from a planetary companion. The candidate planet around Barnard's star is a cold super-Earth, with a minimum mass of 3.2 times that of Earth, orbiting near its snow line (the minimum distance from the star at which volatile compounds could condense). The combination of all radial velocity datasets spanning 20 years of measurements additionally reveals a long term modulation that could arise from a stellar magnetic-activity cycle or from a more distant planetary object. Because of its proximity to the Sun, the candidate planet has a maximum angular separation of 220 milliarcseconds from Barnard's star, making it an excellent target for direct imaging and astrometric observations in the future. PMID- 30429558 TI - Paying PIs from grants blocks talent and diversity. PMID- 30429557 TI - Written lab agreements improve mentoring. PMID- 30429559 TI - 3D print so more scholars can access unique specimens. PMID- 30429560 TI - A key piece in the exoplanet puzzle. PMID- 30429562 TI - Water takes a deep dive into an oceanic tectonic plate. PMID- 30429563 TI - Lymphoma. PMID- 30429561 TI - Cell atlas reveals the landscape of early pregnancy. PMID- 30429564 TI - Solving lymphoma's stem-cell problem. PMID- 30429565 TI - The cost of surviving cancer. PMID- 30429566 TI - Precision therapies take aim at non-Hodgkin's lymphoma. PMID- 30429567 TI - Towards the better diagnosis of lymphoma. PMID- 30429568 TI - Genetically modified T cells target lymphoma. PMID- 30429569 TI - How dogs are teaching researchers new tricks for treating cancer. PMID- 30429570 TI - Building a better lymphoma vaccine. PMID- 30429571 TI - Lymphoma: 4 big questions. PMID- 30429572 TI - In the Palestinian territories, science struggles against all odds. PMID- 30429573 TI - Keystone pipeline blocked, statistics prize and horse cull. PMID- 30429574 TI - Uneven distribution of cobamide biosynthesis and dependence in bacteria predicted by comparative genomics. AB - The vitamin B12 family of cofactors known as cobamides are essential for a variety of microbial metabolisms. We used comparative genomics of 11,000 bacterial species to analyze the extent and distribution of cobamide production and use across bacteria. We find that 86% of bacteria in this data set have at least one of 15 cobamide-dependent enzyme families, but only 37% are predicted to synthesize cobamides de novo. The distribution of cobamide biosynthesis and use vary at the phylum level. While 57% of Actinobacteria are predicted to biosynthesize cobamides, only 0.6% of Bacteroidetes have the complete pathway, yet 96% of species in this phylum have cobamide-dependent enzymes. The form of cobamide produced by the bacteria could be predicted for 58% of cobamide producing species, based on the presence of signature lower ligand biosynthesis and attachment genes. Our predictions also revealed that 17% of bacteria have partial biosynthetic pathways, yet have the potential to salvage cobamide precursors. Bacteria with a partial cobamide biosynthesis pathway include those in a newly defined, experimentally verified category of bacteria lacking the first step in the biosynthesis pathway. These predictions highlight the importance of cobamide and cobamide precursor salvaging as examples of nutritional dependencies in bacteria. PMID- 30429578 TI - The immunological anatomy of the skin. AB - The skin is the outermost organ of the body and is continuously exposed to external pathogens. Upon inflammation, various immune cells pass through, reside in or are recruited to the skin to orchestrate diverse cutaneous immune responses. To achieve this, immune cells interact with each other and even communicate with non-immune cells, including peripheral nerves and the microbiota. Immunologically important anatomical sites, such as skin appendages (for example, hair follicles and sweat glands) or postcapillary venules, act as special portal sites for immune cells and for establishing tertiary lymphoid structures, including inducible skin-associated lymphoid tissue. Here, we provide an overview of the key findings and concepts of cutaneous immunity in association with skin anatomy and discuss how cutaneous immune cells fine-tune physiological responses in the skin. PMID- 30429577 TI - Sendai Virus Infection Induces Expression of Novel RNAs in Human Cells. AB - Innate antiviral immune responses are driven by virus-induced changes in host gene expression. While much research on antiviral effectors has focused on virus inducible mRNAs, recent genome-wide analyses have identified hundreds of novel target sites for virus-inducible transcription factors and RNA polymerase. These sites are beyond the known antiviral gene repertoire and their contribution to innate immune responses is largely unknown. In this study, RNA-sequencing of mock infected and Sendai virus-infected cells was performed to characterize the virus inducible transcriptome and identify novel virus-inducible RNAs (nviRNAs). Virus inducible transcription was observed throughout the genome resulting in expression of 1755 previously RefSeq-annotated RNAs and 1545 nviRNAs. The previously-annotated RNAs primarily consist of protein-coding mRNAs, including several well-known antiviral mRNAs that had low sequence conservation but were highly virus-inducible. The previously-unannotated nviRNAs were mostly noncoding RNAs with poor sequence conservation. Independent analyses of nviRNAs based on infection with Sendai virus, influenza virus, and herpes simplex virus 1, or direct stimulation with IFNalpha revealed a range of expression patterns in various human cell lines. These phylogenetic and expression analyses suggest that many of the nviRNAs share the high inducibility and low sequence conservation characteristic of well-known primary antiviral effectors and may represent dynamically evolving antiviral factors. PMID- 30429579 TI - Effects of metformin mediated by gut microbiota. PMID- 30429576 TI - Author Correction: Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome. AB - In the version of this article originally published, the main-text sentence "In three patients of European ancestry, we identified the germline variant encoding p.Ile97Met in TIM-3, which was homozygous in two (P12 and P13) and heterozygous in one (P15) in the germline but with no TIM-3 plasma membrane expression in the tumor" misstated the identifiers of the two homozygous individuals, which should have been P13 and P14. The error has been corrected in the HTML, PDF and print versions of the paper. PMID- 30429581 TI - Can electronic health records revive central nervous system clinical trials? PMID- 30429580 TI - Correction: A pilot randomised blinded placebo-controlled trial of paracetamol for later treatment of a patent ductus arteriosus. AB - In the published version of this paper the author Yan Chen was missed out of the author list. This has now been corrected in the HTML and PDF versions of the paper. PMID- 30429582 TI - Activation of alpha7 Nicotinic Acetylcholine Receptor Ameliorates Zymosan-Induced Acute Kidney Injury in BALB/c Mice. AB - Zymosan, a natural compound, provokes acute peritonitis and multiple organ dysfunction that affects the kidney, beside other organs via exaggerated inflammatory response. The aim of the present study is to test the role of cholinergic anti-inflammatory pathway (CAP) in alleviating acute kidney injury (AKI) induced by zymosan in BALB/c mice, using galantamine, a cholinesterase inhibitor, known to act via alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) to stimulate CAP. Galantamine verified its anti-inflammatory effect by elevating acetylcholine (ACh) level, while abating the interleukin-6/ janus kinase 2 (Y1007/1008)/ signal transducer and activator of transcription 3 (Y705) (IL-6/ pY(1007/1008)-JAK2/ pY705-STAT3) inflammatory axis, with a consequent inhibition in suppressor of cytokine signaling 3 (SOCS3). This effect entails also the nuclear factor-kappa B (p65)/ high mobility group box protein-1/ (NF kappaB (p65)/ HMGB-1) signaling pathway. Furthermore, the reno-curattive effect of galantamine was associated by a reduction in plasma creatinine (Cr), cystatin (Cys)-C, IL-18, and renal neutrophil gelatinase-associated lipocalin (NGAL), as well as an improved histopathological structure. Blocking the alpha7 nAChR by methyllycaconitine abolished the beneficial effect of galantamine to document the involvement of this receptor and the CAP in the amelioration of AKI induced by zymosan. PMID- 30429584 TI - Cancer chromatin accessed. PMID- 30429583 TI - Bacteria-mediated delivery of RNAi effector molecules against viral HPV16-E7 eradicates oral squamous carcinoma cells (OSCC) via apoptosis. AB - Delivery of RNAi-mediating shRNA molecules for gene silencing via bacteria, i.e. by transkingdom RNAi (tkRNAi) technology, is suggested to be a powerful alternative technique. In this work, the efficiency of bacterial delivery of shRNAs directed against HPV16-E7-specific mRNA to oral squamous carcinoma cells (OSCCs) was evaluated. E. coli were transfected with a plasmid encoding the inv locus and the Hlya gene to enable the bacteria to enter carcinoma cells and to escape from endocytotic vesicles. The bacterial penetration to the target cells was confirmed by DAPI staining. The HPV16-E7 mRNA expression in bacteria-treated OSCCs dropped to 61% of the controls as measured by qRT-PCR. Corresponding inhibition of the HPV16-E7 protein was confirmed by western blotting. The IC50 of bacteria-treated OSCCs was reduced to more than 75%. Flow cytometry assays showed higher total apoptosis and caspase-3 activation (6.6-fold and 8.4-fold respectively) in OSCCs following exposure to anti-HPV-E7 bacteria compared to anti-GFP bacteria (2-fold and 2.9-fold, respectively). In conclusion, it was demonstrated for the first time that tkRNAi technology is also useful for treatment of squamous carcinoma cells. Anti-HPV16-E7 shRNA-encoding bacteria can efficiently deliver RNAi effectors to OSCCs mediating a strong and specific gene silencing associated with triggering cell death. PMID- 30429585 TI - New pathways in development of liver cancer. PMID- 30429587 TI - CXCL12 limits podocyte regeneration. PMID- 30429586 TI - Tales from the crypt: new insights into intestinal stem cells. AB - The intestinal epithelium withstands continuous mechanical, chemical and biological insults despite its single-layered, simple epithelial structure. The crypt-villus tissue architecture in combination with rapid cell turnover enables the intestine to act both as a barrier and as the primary site of nutrient uptake. Constant tissue replenishment is fuelled by continuously dividing stem cells that reside at the bottom of crypts. These cells are nurtured and protected by specialized epithelial and mesenchymal cells, and together constitute the intestinal stem cell niche. Intestinal stem cells and early progenitor cells compete for limited niche space and, therefore, the ability to retain or regain stemness. Those cells unable to do so differentiate to one of six different mature cell types and move upwards towards the villus, where they are shed into the intestinal lumen after 3-5 days. In this Review, we discuss the signals, cell types and mechanisms that control homeostasis and regeneration in the intestinal epithelium. We investigate how the niche protects and instructs intestinal stem cells, which processes drive differentiation of mature cells and how imbalance in key signalling pathways can cause human disease. PMID- 30429588 TI - A central anti-oncogenic pathway in ccRCC. PMID- 30429589 TI - PIEZOs in baroreceptor reflex. PMID- 30429590 TI - Diagnosis and Management of Primary Biliary Cholangitis. AB - Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC. PMID- 30429591 TI - New Onset of Inflammatory Bowel Disease in Three Patients Undergoing IL-17A Inhibitor Secukinumab: A Case Series. PMID- 30429592 TI - Durability and Decay of Treatment Benefit of Cognitive Behavioral Therapy for Irritable Bowel Syndrome: 12-Month Follow-Up. AB - BACKGROUND: There is a need for safe and effective IBS treatments that provide immediate and sustained improvement of IBS symptoms, particularly among more severe patients. The aim was to assess long-term clinical response of cognitive behavioral therapy (CBT) with reference to IBS education. METHODS: A total of 436 Rome III-diagnosed IBS patients (80% F, M age = 41 years) were randomized to: 4 session home-based CBT (minimal contact (MC-CBT)), 10 session clinic-based CBT (standard (S-CBT)), or 4 session IBS education (EDU). Follow-up occurred at 2 weeks and 3, 6, 9, and 12 months following treatment completion. Treatment response was based a priori on the Clinical Global Improvement Scale (global IBS symptom improvement) and IBS Symptom Severity Scale (IBS-SSS). RESULTS: Post treatment CGI gains were generally maintained by MC-CBT patients at quarterly intervals through 12-month follow-up with negligible decay. For MC-CBT and S-CBT, 39 and 33% of respondents maintained treatment response at every follow-up assessment. The corresponding percent for EDU was 19%, which was significantly lower (p < 0.05) than for the CBT groups. On the IBS-SSS, therapeutic gains also showed a pattern of maintenance with trends towards increased efficacy over time in all conditions, with the mean unit reductions between baseline and follows-up being approximately -76 at immediate and approximately -94 at 12 months (-50 = clinically significant). CONCLUSION: For treatment-refractory IBS patients, home- and clinic-based CBT resulted in substantial and enduring relief of multiple IBS symptoms that generally extended to 12-month post treatment. PMID- 30429593 TI - Evidence for Local and Systemic Immune Activation in Functional Dyspepsia and the Irritable Bowel Syndrome: A Systematic Review. AB - BACKGROUND: Subtle histopathologic features such as eosinophilia and increased mast cells have been observed in functional gastrointestinal disorders (FGIDs), including functional dyspepsia (FD) and the irritable bowel syndrome (IBS). The mechanisms that drive recruitment of these cells to the gastrointestinal tract remain unexplained, largely due to the heterogeneity in phenotypes among patients diagnosed with such conditions. We aimed to systematically review the literature and collate the evidence for immune activation in FD and IBS, and where possible, detail the nature of activation. METHODS: Seven literature databases were searched using the keywords: 'functional gastrointestinal disorder', FGID, 'functional dyspepsia', 'non-ulcer dyspepsia', 'idiopathic dyspepsia', 'irritable bowel syndrome', IBS and 'immun*'. RESULTS: Fifty-one papers reporting discordant immune features met the selection criteria for this review. Changes in lymphocyte populations, including B and T lymphocyte numbers and activation status were reported in IBS and FD, in conjunction with duodenal eosinophilia in FD and increased colonic mast cells in IBS. Increases in circulating alpha4+beta7+ gut homing T cells appear to be linked to the pathophysiology of both FD and IBS. Studies in the area are complicated by poor phenotyping of patients into subgroups and the subtle nature of the immune activity involved in FD and IBS. CONCLUSIONS: Alterations in proportions of gut-homing T lymphocytes in both FD and IBS indicate that a loss of mucosal homeostasis may drive the symptoms of FD and IBS. There is indirect evidence that Th17 responses may play a role in FGIDs, however the evidence for a Th2 immune phenotype in FD and IBS is limited. Although immune involvement is evident, large, well-characterised patient cohorts are required to elucidate the immune mechanisms driving the development of FGIDs. PMID- 30429594 TI - The role of Prostate Imaging Reporting and Data System score in Gleason 3 + 3 active surveillance candidates enrollment: a diagnostic meta-analysis. AB - BACKGROUND: The contemporary active surveillance (AS) criteria may result in an unsatisfactory misclassification rate, which may delay curative treatment for prostate cancer patients. The magnetic resonance imaging (MRI), not included in any AS criteria, provides useful information for prostate cancer diagnosis. Our goal is to evaluate the diagnostic performance of Prostate Imaging Reporting and Data Systems (PI-RADS) score, a standardized MRI reporting system, in AS candidates enrollment. METHODS: We searched Cochrane CENTRAL, PubMed, and Embase for pertinent studies through June 2018. The standard methods recommended for meta-analyses of diagnostic evaluation were employed. We draw the summary receiver operating characteristic (SROC) curve. Meta-regression analysis was performed to evaluate the effects of confounding factors. RESULTS: From the resulting 168 studies, 5 provided the diagnostic data on PI-RADS score and pathological results; 834 patients were included. All AS candidates in these studies were defined by Prostate Cancer Research International: Active Surveillance (PRIAS) criterion. The pooled estimates of PI-RADS 4 or 5 on adverse pathological features at radical prostatectomy (RP) among AS candidates were: sensitivity, 0.77 (95% confidence interval (CI), 0.71-0.82); specificity, 0.63 (95% CI, 0.55-0.71); positive predictive value, 0.72 (95% CI, 0.64-0.79); negative predictive value, 0.68 (95% CI, 0.63-0.73); and diagnostic odds ratio, 6 (95% CI, 4-8). The SROC curve was positioned toward the desired upper left corner of the curve, the area under the curve was 0.77 (95% CI, 0.73-0.80). The P-value for heterogeneity was <0.01. The pathological outcomes and endorectal coils contributed to the heterogeneity of sensitivity. The evidences supporting the advantage of PI-RADS v2 over v1 were not sufficient yet. CONCLUSION: AS candidates with PI-RADS 4 or 5 may be unsuitable for AS even though they fulfill current AS criteria. Those with PI-RADS 3 or less indicated relative safety for AS enrollment. PMID- 30429595 TI - Immediate treatment vs. active-surveillance in very-low-risk prostate cancer: the role of patient-, tumour-, and hospital-related factors. AB - BACKGROUND: To provide insight in the treatment variation of very-low-risk prostate cancer patients and to assess the role of hospital-related factors. METHODS: All patients diagnosed with very-low-risk prostate cancer (cT1c-cT2a, PSA < 10 ng/ml, Gleason score <7 and <3 positive cores) in 2015 and 2016 were identified through the population-based Netherlands Cancer Registry. Multilevel logistic regression analyses were performed to examine the crude and case-mix adjusted probability of immediate treatment vs. active-surveillance (AS) according to hospital of diagnosis and to evaluate the effect of patient-, tumour , and hospital-related factors. RESULTS: In all, 2047 (85.4%) of the 2396 patients with very-low-risk prostate cancer were managed with AS. The crude proportion of patients with AS varied from 33.3 to 100% between hospitals. Case mix adjusted probability varied from 71 to 97%. Tumour stage cT2a vs. cT1c (OR 2.0, 95%CI 1.1-3.6), two vs. one positive core (OR 2.8, 95%CI 1.6-4.7), diagnostic MRI (OR 2.8, 95%CI 1.5-5.2), discussion of a patient in a multi disciplinary team (OR 2.2, 95%CI 1.1-4.5), discussion of treatment options with the patient (OR 3.3, 95%CI 1.5-7.4) and type of hospital (non-university referral hospital vs. community hospital: OR 0.5, 95%CI 0.2-0.9) were associated with immediate treatment. CONCLUSION: The majority of Dutch very-low-risk prostate cancer patients is managed with AS but variation between hospitals exists. Part of the variation is explained by patient- and tumour characteristics but also hospital-related factors play a role. This implies that clinical practice could be improved. PMID- 30429596 TI - In vitro conversion of adult murine endothelial cells to hematopoietic stem cells. AB - The ability to generate hematopoietic stem cells (HSCs) in vitro would have an immeasurable impact on many areas of clinical practice, including trauma, cancer, and congenital disease. In this protocol, we describe a stepwise approach that converts adult murine endothelial cells (ECs) to HSCs, termed 'reprogrammed ECs into hematopoietic stem and progenitor cells' (rEC-HSPCs). The conversion, which is achieved without cells transitioning through a pluripotent state, comprises three phases: induction, specification, and expansion. Adult ECs are first isolated from Runx1-IRES-GFP; Rosa26-rtTa mice and maintained in culture under EC growth factor stimulation and Tgfbeta inhibition. In the first (induction) phase of conversion (days 0-8), four transcription factors (TFs)-FosB, Gfi1, Runx1, and Spi1 (FGRS)-are expressed transiently, which results in endogenous Runx1 expression. During the second (specification) phase (days 8-20), endogenous Runx1+ FGRS-transduced ECs commit to a hematopoietic fate and no longer require exogenous FGRS expression. Finally, the vascular niche drives robust proliferation of rEC-HSPCs during the expansion phase (days 20-28). The resulting converted cells possess a transcriptomic signature and long-term self-renewal capacity indistinguishable from those of adult HSCs. In this protocol, we also describe functional in vitro and in vivo assays that can be used to demonstrate that rEC-HSPCs are competent for clonal engraftment and possess multi-lineage reconstitution potential, including antigen-dependent adaptive immune function. This approach thus provides a tractable strategy for interrogating the generation of engraftable hematopoietic cells, advancing the mechanistic understanding of hematopoietic development and HSC self-renewal. PMID- 30429597 TI - Application and optimization of CRISPR-Cas9-mediated genome engineering in axolotl (Ambystoma mexicanum). AB - Genomic manipulation is essential to the use of model organisms to understand development, regeneration and adult physiology. The axolotl (Ambystoma mexicanum), a type of salamander, exhibits an unparalleled regenerative capability in a spectrum of complex tissues and organs, and therefore serves as a powerful animal model for dissecting mechanisms of regeneration. We describe here an optimized stepwise protocol to create genetically modified axolotls using the CRISPR-Cas9 system. The protocol, which takes 7-8 weeks to complete, describes generation of targeted gene knockouts and knock-ins and includes site-specific integration of large targeting constructs. The direct use of purified CAS9-NLS (CAS9 containing a C-terminal nuclear localization signal) protein allows the prompt formation of guide RNA (gRNA)-CAS9-NLS ribonucleoprotein (RNP) complexes, which accelerates the creation of double-strand breaks (DSBs) at targeted genomic loci in single-cell-stage axolotl eggs. With this protocol, a substantial number of F0 individuals harboring a homozygous-type frameshift mutation can be obtained, allowing phenotype analysis in this generation. In the presence of targeting constructs, insertions of exogenous genes into targeted axolotl genomic loci can be achieved at efficiencies of up to 15% in a non-homologous end joining (NHEJ) manner. Our protocol bypasses the long generation time of axolotls and allows direct functional analysis in F0 genetically manipulated axolotls. This protocol can be potentially applied to other animal models, especially to organisms with a well-characterized transcriptome but lacking a well characterized genome. PMID- 30429598 TI - Failure to convert. PMID- 30429575 TI - Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. AB - In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper. PMID- 30429599 TI - Metal Enterococcus equipment. PMID- 30429600 TI - Transcriptional recorder. PMID- 30429601 TI - Devilish diatoms. PMID- 30429603 TI - Expanding the terpenoid kingdom. PMID- 30429602 TI - Identification of Chaoborus kairomone chemicals that induce defences in Daphnia. AB - Infochemicals play important roles in aquatic ecosystems. They even modify food web interactions, such as by inducing defenses in prey. In one classic but still not fully understood example, the planktonic freshwater crustacean Daphnia pulex forms specific morphological defenses (neckteeth) induced by chemical cues (kairomones) released from its predator, the phantom midge larva Chaoborus. On the basis of liquid chromatography, mass spectrometry, and chemical synthesis, we report here the chemical identity of the Chaoborus kairomone. The biologically active cues consist of fatty acids conjugated to the amino group of glutamine via the N terminus. These cues are involved in Chaoborus digestive processes, which explains why they are consistently released despite the disadvantage for its emitter. The identification of the kairomone may allow in-depth studies on multiple aspects of this inducible defense system. PMID- 30429604 TI - Disrupting the CD95-PLCgamma1 interaction prevents Th17-driven inflammation. AB - CD95L is a transmembrane ligand (m-CD95L) that is cleaved by metalloproteases to release a soluble ligand (s-CD95L). Unlike m-CD95L, interaction between s-CD95L and CD95 fails to recruit caspase-8 and FADD to trigger apoptosis and instead induces a Ca2+ response via docking of PLCgamma1 to the calcium-inducing domain (CID) within CD95. This signaling pathway induces accumulation of inflammatory Th17 cells in damaged organs of lupus patients, thereby aggravating disease pathology. A large-scale screen revealed that the HIV protease inhibitor ritonavir is a potent disruptor of the CD95-PLCgamma1 interaction. A structure activity relationship approach highlighted that ritonavir is a peptidomimetic that shares structural characteristics with CID with respect to docking to PLCgamma1. Thus, we synthesized CID peptidomimetics abrogating both the CD95 driven Ca2+ response and transmigration of Th17 cells. Injection of ritonavir and the CID peptidomimetic into lupus mice alleviated clinical symptoms, opening a new avenue for the generation of drugs for lupus patients. PMID- 30429605 TI - Synthesis of 11-carbon terpenoids in yeast using protein and metabolic engineering. AB - One application of synthetic biology is the redesign of existing biological systems to acquire new functions. In this context, expanding the chemical code underlying key biosynthetic pathways will lead to the synthesis of compounds with new structures and potentially new biological activities. Terpenoids are a large group of specialized metabolites with numerous applications. Yet, being synthesized from five-carbon units, they are restricted to distinct classes that differ by five carbon atoms (C10, C15, C20, etc.). To expand the diversity of terpenoid structures, we engineered yeast cells to synthesize a noncanonical building block with 11 carbons, and produced 40 C11 terpene scaffolds that can form the basis for an entire terpenoid class. By identifying a single-residue switch that converts C10 plant monoterpene synthases to C11-specific enzymes, we engineered dedicated synthases for C11 terpene production. This approach will enable the systematic expansion of the chemical space accessed by terpenoids. PMID- 30429606 TI - Similar cranial trauma prevalence among Neanderthals and Upper Palaeolithic modern humans. AB - Neanderthals are commonly depicted as leading dangerous lives and permanently struggling for survival. This view largely relies on the high incidences of trauma that have been reported1,2 and have variously been attributed to violent social behaviour3,4, highly mobile hunter-gatherer lifestyles2 or attacks by carnivores5. The described Neanderthal pattern of predominantly cranial injuries is further thought to reflect violent encounters with large prey mammals, resulting from the use of close-range hunting weapons1. These interpretations directly shape our understanding of Neanderthal lifestyles, health and hunting abilities, yet mainly rest on descriptive, case-based evidence. Quantitative, population-level studies of traumatic injuries are rare. Here we reassess the hypothesis of higher cranial trauma prevalence among Neanderthals using a population-level approach-accounting for preservation bias and other contextual data-and an exhaustive fossil database. We show that Neanderthals and early Upper Palaeolithic anatomically modern humans exhibit similar overall incidences of cranial trauma, which are higher for males in both taxa, consistent with patterns shown by later populations of modern humans. Beyond these similarities, we observed species-specific, age-related variation in trauma prevalence, suggesting that there were differences in the timing of injuries during life or that there was a differential mortality risk of trauma survivors in the two groups. Finally, our results highlight the importance of preservation bias in studies of trauma prevalence. PMID- 30429607 TI - Autophagy maintains tumour growth through circulating arginine. AB - Autophagy captures intracellular components and delivers them to lysosomes, where they are degraded and recycled to sustain metabolism and to enable survival during starvation1-5. Acute, whole-body deletion of the essential autophagy gene Atg7 in adult mice causes a systemic metabolic defect that manifests as starvation intolerance and gradual loss of white adipose tissue, liver glycogen and muscle mass1. Cancer cells also benefit from autophagy. Deletion of essential autophagy genes impairs the metabolism, proliferation, survival and malignancy of spontaneous tumours in models of autochthonous cancer6,7. Acute, systemic deletion of Atg7 or acute, systemic expression of a dominant-negative ATG4b in mice induces greater regression of KRAS-driven cancers than does tumour-specific autophagy deletion, which suggests that host autophagy promotes tumour growth1,8. Here we show that host-specific deletion of Atg7 impairs the growth of multiple allografted tumours, although not all tumour lines were sensitive to host autophagy status. Loss of autophagy in the host was associated with a reduction in circulating arginine, and the sensitive tumour cell lines were arginine auxotrophs owing to the lack of expression of the enzyme argininosuccinate synthase 1. Serum proteomic analysis identified the arginine-degrading enzyme arginase I (ARG1) in the circulation of Atg7-deficient hosts, and in vivo arginine metabolic tracing demonstrated that serum arginine was degraded to ornithine. ARG1 is predominantly expressed in the liver and can be released from hepatocytes into the circulation. Liver-specific deletion of Atg7 produced circulating ARG1, and reduced both serum arginine and tumour growth. Deletion of Atg5 in the host similarly released circulating arginine and suppressed tumorigenesis, which demonstrates that this phenotype is specific to autophagy function rather than to deletion of Atg7. Dietary supplementation of Atg7 deficient hosts with arginine partially restored levels of circulating arginine and tumour growth. Thus, defective autophagy in the host leads to the release of ARG1 from the liver and the degradation of circulating arginine, which is essential for tumour growth; this identifies a metabolic vulnerability of cancer. PMID- 30429608 TI - Sensitive tumour detection and classification using plasma cell-free DNA methylomes. AB - The use of liquid biopsies for cancer detection and management is rapidly gaining prominence1. Current methods for the detection of circulating tumour DNA involve sequencing somatic mutations using cell-free DNA, but the sensitivity of these methods may be low among patients with early-stage cancer given the limited number of recurrent mutations2-5. By contrast, large-scale epigenetic alterations which are tissue- and cancer-type specific-are not similarly constrained6 and therefore potentially have greater ability to detect and classify cancers in patients with early-stage disease. Here we develop a sensitive, immunoprecipitation-based protocol to analyse the methylome of small quantities of circulating cell-free DNA, and demonstrate the ability to detect large-scale DNA methylation changes that are enriched for tumour-specific patterns. We also demonstrate robust performance in cancer detection and classification across an extensive collection of plasma samples from several tumour types. This work sets the stage to establish biomarkers for the minimally invasive detection, interception and classification of early-stage cancers based on plasma cell-free DNA methylation patterns. PMID- 30429609 TI - POLAR-guided signalling complex assembly and localization drive asymmetric cell division. AB - Stomatal cell lineage is an archetypal example of asymmetric cell division (ACD), which is necessary for plant survival1-4. In Arabidopsis thaliana, the GLYCOGEN SYNTHASE KINASE3 (GSK3)/SHAGGY-like kinase BRASSINOSTEROID INSENSITIVE 2 (BIN2) phosphorylates both the mitogen-activated protein kinase (MAPK) signalling module5,6 and its downstream target, the transcription factor SPEECHLESS (SPCH)7, to promote and restrict ACDs, respectively, in the same stomatal lineage cell. However, the mechanisms that balance these mutually exclusive activities remain unclear. Here we identify the plant-specific protein POLAR as a stomatal lineage scaffold for a subset of GSK3-like kinases that confines them to the cytosol and subsequently transiently polarizes them within the cell, together with BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL), before ACD. As a result, MAPK signalling is attenuated, enabling SPCH to drive ACD in the nucleus. Moreover, POLAR turnover requires phosphorylation on specific residues, mediated by GSK3. Our study reveals a mechanism by which the scaffolding protein POLAR ensures GSK3 substrate specificity, and could serve as a paradigm for understanding regulation of GSK3 in plants. PMID- 30429611 TI - Hemimastigophora is a novel supra-kingdom-level lineage of eukaryotes. AB - Almost all eukaryote life forms have now been placed within one of five to eight supra-kingdom-level groups using molecular phylogenetics1-4. The 'phylum' Hemimastigophora is probably the most distinctive morphologically defined lineage that still awaits such a phylogenetic assignment. First observed in the nineteenth century, hemimastigotes are free-living predatory protists with two rows of flagella and a unique cell architecture5-7; to our knowledge, no molecular sequence data or cultures are currently available for this group. Here we report phylogenomic analyses based on high-coverage, cultivation-independent transcriptomics that place Hemimastigophora outside of all established eukaryote supergroups. They instead comprise an independent supra-kingdom-level lineage that most likely forms a sister clade to the 'Diaphoretickes' half of eukaryote diversity (that is, the 'stramenopiles, alveolates and Rhizaria' supergroup (Sar), Archaeplastida and Cryptista, as well as other major groups). The previous ranking of Hemimastigophora as a phylum understates the evolutionary distinctiveness of this group, which has considerable importance for investigations into the deep-level evolutionary history of eukaryotic life ranging from understanding the origins of fundamental cell systems to placing the root of the tree. We have also established the first culture of a hemimastigote (Hemimastix kukwesjijk sp. nov.), which will facilitate future genomic and cell biological investigations into eukaryote evolution and the last eukaryotic common ancestor. PMID- 30429610 TI - Enhanced strength and ductility in a high-entropy alloy via ordered oxygen complexes. AB - Oxygen, one of the most abundant elements on Earth, often forms an undesired interstitial impurity or ceramic phase (such as an oxide particle) in metallic materials. Even when it adds strength, oxygen doping renders metals brittle1-3. Here we show that oxygen can take the form of ordered oxygen complexes, a state in between oxide particles and frequently occurring random interstitials. Unlike traditional interstitial strengthening4,5, such ordered interstitial complexes lead to unprecedented enhancement in both strength and ductility in compositionally complex solid solutions, the so-called high-entropy alloys (HEAs)6-10. The tensile strength is enhanced (by 48.5 +/- 1.8 per cent) and ductility is substantially improved (by 95.2 +/- 8.1 per cent) when doping a model TiZrHfNb HEA with 2.0 atomic per cent oxygen, thus breaking the long standing strength-ductility trade-off11. The oxygen complexes are ordered nanoscale regions within the HEA characterized by (O, Zr, Ti)-rich atomic complexes whose formation is promoted by the existence of chemical short-range ordering among some of the substitutional matrix elements in the HEAs. Carbon has been reported to improve strength and ductility simultaneously in face-centred cubic HEAs12, by lowering the stacking fault energy and increasing the lattice friction stress. By contrast, the ordered interstitial complexes described here change the dislocation shear mode from planar slip to wavy slip, and promote double cross-slip and thus dislocation multiplication through the formation of Frank-Read sources (a mechanism explaining the generation of multiple dislocations) during deformation. This ordered interstitial complex-mediated strain-hardening mechanism should be particularly useful in Ti-, Zr- and Hf containing alloys, in which interstitial elements are highly undesirable owing to their embrittlement effects, and in alloys where tuning the stacking fault energy and exploiting athermal transformations13 do not lead to property enhancement. These results provide insight into the role of interstitial solid solutions and associated ordering strengthening mechanisms in metallic materials. PMID- 30429612 TI - The hippocampus is crucial for forming non-hippocampal long-term memory during sleep. AB - There is a long-standing division in memory research between hippocampus dependent memory and non-hippocampus-dependent memory, as only the latter can be acquired and retrieved in the absence of normal hippocampal function1,2. Consolidation of hippocampus-dependent memory, in particular, is strongly supported by sleep3-5. Here we show that the formation of long-term representations in a rat model of non-hippocampus-dependent memory depends not only on sleep but also on activation of a hippocampus-dependent mechanism during sleep. Rats encoded non-hippocampus-dependent (novel-object recognition6-8) and hippocampus-dependent (object-place recognition) memories before a two-hour period of sleep or wakefulness. Memory was tested either immediately thereafter or remotely (after one or three weeks). Whereas object-place recognition memory was stronger for rats that had slept after encoding (rather than being awake) at both immediate and remote testing, novel-object recognition memory profited from sleep only three weeks after encoding, at which point it was preserved in rats that had slept after encoding but not in those that had been awake. Notably, inactivation of the hippocampus during post-encoding sleep by intrahippocampal injection of muscimol abolished the sleep-induced enhancement of remote novel object recognition memory. By contrast, muscimol injection before remote retrieval or memory encoding had no effect on test performance, confirming that the encoding and retrieval of novel-object recognition memory are hippocampus independent. Remote novel-object recognition memory was associated with spindle activity during post-encoding slow-wave sleep, consistent with the view that neuronal memory replay during slow-wave sleep contributes to long-term memory formation. Our results indicate that the hippocampus has an important role in long-term consolidation during sleep even for memories that have previously been considered hippocampus-independent. PMID- 30429613 TI - Widespread but heterogeneous responses of Andean forests to climate change. AB - Global warming is forcing many species to shift their distributions upward, causing consequent changes in the compositions of species that occur at specific locations. This prediction remains largely untested for tropical trees. Here we show, using a database of nearly 200 Andean forest plot inventories spread across more than 33.5 degrees latitude (from 26.8 degrees S to 7.1 degrees N) and 3,000-m elevation (from 360 to 3,360 m above sea level), that tropical and subtropical tree communities are experiencing directional shifts in composition towards having greater relative abundances of species from lower, warmer elevations. Although this phenomenon of 'thermophilization' is widespread throughout the Andes, the rates of compositional change are not uniform across elevations. The observed heterogeneity in thermophilization rates is probably because of different warming rates and/or the presence of specialized tree communities at ecotones (that is, at the transitions between distinct habitats, such as at the timberline or at the base of the cloud forest). Understanding the factors that determine the directions and rates of compositional changes will enable us to better predict, and potentially mitigate, the effects of climate change on tropical forests. PMID- 30429614 TI - Linking a cell-division gene and a suicide gene to define and improve cell therapy safety. AB - Human pluripotent cell lines hold enormous promise for the development of cell based therapies. Safety, however, is a crucial prerequisite condition for clinical applications. Numerous groups have attempted to eliminate potentially harmful cells through the use of suicide genes1, but none has quantitatively defined the safety level of transplant therapies. Here, using genome-engineering strategies, we demonstrate the protection of a suicide system from inactivation in dividing cells. We created a transcriptional link between the suicide gene herpes simplex virus thymidine kinase (HSV-TK) and a cell-division gene (CDK1); this combination is designated the safe-cell system. Furthermore, we used a mathematical model to quantify the safety level of the cell therapy as a function of the number of cells that is needed for the therapy and the type of genome editing that is performed. Even with the highly conservative estimates described here, we anticipate that our solution will rapidly accelerate the entry of cell based medicine into the clinic. PMID- 30429616 TI - IRC +10216 as a spectroscopic laboratory: improved rotational constants for SiC2, its isotopologues, and Si2C. AB - This work presents a detailed analysis of the laboratory and astrophysical spectral data available for 28SiC2, 29SiC2,30SiC2, Si13CC, and Si2C. New data on the rotational lines of these species between 70 and 350 GHz have been obtained with high spectral resolution (195 kHz) with the IRAM 30m telescope in the direction of the circumstellar envelope IRC +10216. Frequency measurements can reach an accuracy of 50 kHz for features observed with a good signal to noise ratio. From the observed astrophysical lines and the available laboratory data new rotational and centrifugal distortion constants have been derived for all the isotopologues of SiC2, allowing to predict their spectrum with high accuracy in the millimeter and submillimeter domains. Improved rotational and centrifugal distortion constants have also been obtained for disilicon carbide, Si2C. This work shows that observations of IRC +10216 taken with the IRAM 30m telescope, with a spectral resolution of 195 kHz, can be used for any molecular species detected in this source to derive, or improve, its rotational constants. Hence, IRC +10216 in addition to be one the richest sources in molecular species in the sky, can also be used as a state-of-the-art spectroscopy laboratory in the millimeter and submillimeter domains. PMID- 30429617 TI - High-speed molecular cloudlets around the Galactic center's supermassive black hole. AB - We present 1"-resolution ALMA observations of the circumnuclear disk (CND) and the interstellar environment around Sgr A*. The images unveil the presence of small spatial scale 12CO (J=3-2) molecular "cloudlets" (?20,000 AU size) within the central parsec of the Milky Way, in other words, inside the cavity of the CND, and moving at high speeds, up to 300 km s-1 along the line-of-sight. The 12CO-emitting structures show intricate morphologies: extended and filamentary at high negative-velocities (vLSR ?-150 km s-1), more localized and clumpy at extreme positive-velocities (vLSR ?+200 km s-1). Based on the pencil-beam 12CO absorption spectrum toward Sgr A* synchrotron emission, we also present evidence for a diffuse molecular gas component producing absorption features at more extreme negative-velocities (vLSR <-200 km s-1). The CND shows a clumpy spatial distribution traced by the optically thin H13CN (J=4-3) emission. Its motion requires a bundle of non-uniformly rotating streams of slightly different inclinations. The inferred gas density peaks, molecular cores of a few 105 cm-3, are lower than the local Roche limit. This supports that CND cores are transient. We apply the two standard orbit models, spirals vs. ellipses, invoked to explain the kinematics of the ionized gas streamers around Sgr A*. The location and velocities of the 12CO cloudlets inside the cavity are inconsistent with the spiral model, and only two of them are consistent with the Keplerian ellipse model. Most cloudlets, however, show similar velocities that are incompatible with the motions of the ionized streamers or with gas bounded to the central gravity. We speculate that they are leftovers of more massive molecular clouds that fall into the cavity and are tidally disrupted, or that they originate from instabilities in the inner rim of the CND that lead to fragmentation and infall from there. In either case, we show that molecular cloudlets, all together with a mass of several 10 M ?, exist around Sgr A*. Most of them must be short-lived, ?104 yr: photoevaporated by the intense stellar radiation field, G 0?105.3 to 104.3, blown away by winds from massive stars in the central cluster, or disrupted by strong gravitational shears. PMID- 30429618 TI - Whats New in Emergencies Trauma and Shock? Autopsy in Fatal Head Injuries. PMID- 30429619 TI - Smooth Transitions in Critical Care. PMID- 30429615 TI - Improved reference genome of Aedes aegypti informs arbovirus vector control. AB - Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector. PMID- 30429620 TI - The New Paradigm in Community-Based Care: Managing Mindset and Expectations. PMID- 30429621 TI - Magnitude and Spectrum of Injuries Sustained in Road Traffic Accidents Among Two Wheeler Riders and Correlation with Helmet Use. AB - Background: Helmet, as a protective gear to prevent fatal injuries while riding two-wheelers, needs to be evaluated by quality data. The aim of the study was to find out spectrum of injuries sustained with downstream outcomes in relation to acceptable ways of use of crash-proof helmet among motorized two-wheeler riders compared to nonuse following road traffic accidents. Methods: The present study was an analytical cross-sectional multicentric study conducted at three dedicated trauma care centers of India: (a) Jai Prakash Narayan Apex Trauma Center, All India Institute of Medical Sciences, New Delhi, (b) King George's Medical University, Lucknow, Uttar Pradesh, and (c) Narayana Medical College and Hospital, Nellore, Andhra Pradesh. Detailed information was collected on correct use of crash-proof helmets versus nonusers. Results: Among 317 traumatic brain injury victims (mean age 31.4 +/- 12.5 years; range 11-70 years; highest (38%) in the 21-30 years age group), majority were from urban areas (84%), were brought directly to trauma center (76%), and were "Drivers" (73.50%), and their vision was "normal with or without using corrective lenses" (96%). Two-thirds of the victims were carrying "Formal driving licenses," one-thirds were "Primary earning member of the family," and one-tenths were under influence of alcohol. Half of the two-wheeler riders were using helmet, still lesser fastened helmet properly (45%), and few others used ISI quality "Crash proof" (38.5%). Helmet use during accidents had significantly better outcomes and significantly low clinical symptoms such as loss of consciousness, vomiting, ear/nose/oral bleed, headache, seizures with associated bony, abdominal, and chest injuries. Conclusions: Helmets have protective effects on riders if helmets are of crash-proof quality, fastened properly, and consistently used even for short spells and distances of rides. PMID- 30429622 TI - The Incidence and Outcome Differences in Severe Sepsis with and without Lactic Acidosis. AB - Introduction: To compare the incidence, characteristics, and outcomes of lactate expressors and nonexpressors in patients with severe sepsis and septic shock. Methods: This is a retrospective cohort study of patients with severe sepsis and septic shock who presented over a 40-month period to an academic tertiary care center. Primary outcome of interest was in-hospital mortality. Secondary outcomes were hospital length of stay (LOS), Intensive Care Unit (ICU) LOS, and escalation of care. Results: Three hundred and thirty-eight patients met inclusion criteria and were divided into a lactate expressor group (n = 197; initial lactate >=2.5 mmol/L) and a nonexpressor group (n = 141; lactate <2.5 mmol/L). The mortality rate was 46.2% for lactate expressors and 24.8% for nonexpressors. There were no significant differences in hospital or ICU LOS. The escalation-of-care rate in the severe sepsis nonexpressor group was more than double that found in the expressor group: 16.5% versus 6.2% (P = 0.040). The two groups had baseline differences: expressor group had a higher median Acute Physiology and Chronic Health Evaluation II (APACHE II) illness severity score, and nonexpressors had an increased prevalence of comorbid conditions. APACHE II score (odds ratio [OR] 1.10 (1.07-1.14), P < 0.001) and being in the expressor group (OR 1.72 [1.03 2.89], P = 0.039) increased the odds of mortality. Conclusions: In patients with severe sepsis and septic shock, lactate nonexpressors are common. Although the mortality in this cohort is less than its counterparts who present with lactate elevation, it is still significant which warrants vigilance in their care. PMID- 30429623 TI - Patterns of Zygomatic Complex Bone Fracture in Saudi Arabia. AB - Introduction: Zygomatic bone (ZB), also known as the cheekbone, articulates with the maxilla, temporal sphenoid, and the frontal bones. It forms the prominence of the cheek and part of the orbit, and because of its prominence, it is susceptible to trauma. The aim of this study was to present the pattern of ZB fracture in a country in the Middle East. Patients and Methods: The medical records of all trauma cases admitted to the Department of Oral and Maxillofacial Surgery Ward, Riyadh Dental Centre, King Saud Medical City, Riyadh, Saudi Arabia, were reviewed and all cases with ZB fractures were included in this study from December 2002 to December 2012. Data were analyzed using SPSS version 16 (SPSS Inc., Chicago, IL, USA). The results were presented as simple frequencies and percentages. Results: A total of 1487 patients had maxillofacial trauma and 306 cases were diagnosed with ZB fractures during the study. There were 271 (88.6%) males and 35 (11.4%) females with male: female ratio of 7.7:1. Age group of 21-30 years has the highest number of fracture cases (133 [43.5%]). Road traffic accident (RTA) remained the leading etiology of zygomatic complex fracture (ZMCF; 221 [72.2%]). August has been observed to be associated with the highest cases of ZMCF (40 [13.1%]). The years 2005 and 2006 recorded the highest frequency of ZMCF cases (46 [15.0%] and 44 [14.4%], respectively). Conclusion: The results of this study showed that RTA is the leading cause of ZB fractures followed by assaults. The most commonly fractured site was the zygomaticomaxillary. Proper road traffic regulation is paramount to help reduce maxillofacial trauma. PMID- 30429624 TI - Road Traffic Injuries and Fatalities among Drivers Distracted by Mobile Devices. AB - Context: With increasing ownership of mobile devices (i.e., cell phones and smartphones), it is important to better understand the role of these devices in motor vehicle collision (MVC)-related trauma. Aims: The primary objective was to synthesize evidence on the proportion of drivers injured or killed in an MVC attributed to driver distraction by a mobile device. As a secondary objective, we assessed for associations between injury risk and mobile device use while driving. Settings and Design: This study was a systematic review. Subjects and Methods: We searched five electronic databases (PubMed, Embase, CINAHL, TRIS, and Web of Science) and the gray literature to identify reports of drivers injured (regardless of the severity) or killed in MVCs attributed to mobile device related distraction by the driver. We evaluated study and driver characteristics, as well as associations between injury risk and mobile device use by drivers. Statistical Analysis Used: Descriptive statistics were used to report study characteristics. The proportion of injuries related to driver distraction by mobile devices was calculated for each study. Results: Overall, 4907 articles were screened, of which 13 met eligibility criteria. The median proportion of distracted-driving-related trauma was 3.4% (range: 0.04% to 44.7%). Three studies evaluated the association between mobile device use and road traffic injury; all found use of a mobile device while driving significantly increased crash risk. Conclusions: The proportion of road traffic injuries and fatalities attributed to driver distraction by a mobile device ranges from 0.04% to 44.7%. Studies were subject to limitations in the collection of reliable data on distraction-related MVCs. PMID- 30429625 TI - Resuscitation of Out-of-Hospital Cardiac Arrest Victims in Lebanon: The Experience and Views of Prehospital Providers. AB - Background: The survival rate of out-of-hospital cardiac arrest (OHCA) victims in Lebanon is much lower than those seen internationally. In this study, we examined the attitudes and practices of prehospital providers in resuscitation. Methods: We devised a cross-sectional survey with questions adopted from the literature including a study out of Lebanon. Questionnaires were mailed to 300 volunteers who were recruited from 10 centers of local emergency medical services (EMS). Results: A total of 258 questionnaires were returned (86% response rate). Most participants (>80%) were younger than 30 years, and males (60%). Over half reported witnessing up to 10 arrests per year, with 72.5% reporting prehospital return of spontaneous circulation in <6% of cases. Futile resuscitation was frequently (91%) practiced. Participants believed resuscitation should be withdrawn when prolonged (55.4%) or in the presence of advanced directives (34.1%) or terminal illness (27.5%). Reported resuscitation challenges were related to the reaction of witnesses (70.1%), to delay in calling EMS (84.4%), and to traffic delays (30%). Participants recommended training lay persons in resuscitation (79%), training prehospital providers in advanced airway management (68.2%) and intravenous skills (60.1%), providing medications in ambulances (57.7%), and adjusting traffic laws (52%). Conclusion: Prehospital providers in Lebanon face several challenges in their resuscitation practices. A multi-faceted strategy to improve resuscitation practices is needed in Lebanon. In addition to policy development, structural changes should be put in place for improved outcomes in OHCA victims. PMID- 30429626 TI - From Emergency Department to Intensive Care Unit, Does The Delay Matter to Trauma Patients? AB - Introduction: Emergency department (ED) overcrowding with critically ill trauma patients has been a major concern globally. It has been shown that longer stays in the hospital before Intensive Care Unit (ICU) admission have a higher mortality rate. Objective: The objective of this study was to find whether the delay in ICU admission from ED is associated with significant mortality in a trauma patient. Methods: A prospective trauma registry data of 232 patients collected from the ED of JPNATC trauma center between September 2015 and March 2016 were used in the study. The study participants were all admitted trauma patients. Dead-on-arrival patients were excluded from the study. Results: All included patients had a blunt injury at the time of arrival. Of 232 patients, 66 died during treatment and 166 were discharged. Of these, 196 (84.5%) were male and 36 (15.5%) were female. Most of the patients among 66 who died were referred from different hospitals; however, most survivors arrived directly at JPNATC as compared to another group (P < 0.001). Waiting time in ED was calculated by the difference between arrival time and ED disposition time. There was statistically significant difference found in ED waiting time in both the groups (P = 0.015); however, the odds ratio is closer to 1, that is, 0.998. Similarly, age, gender, oxygen saturation, Glasgow Coma Scale, ICU stay days, heart rate, referring status, and injury severity score were found to be significant at the level of 25% under univariate analysis. Conclusion: The ED delay is not associated with adverse outcome in terms of mortality. Other factors may play a much greater role in determining the prognosis. PMID- 30429627 TI - The Effect of Head Rotation on the Relative Vascular Anatomy of the Neck: Implications for Central Venous Access. AB - Context: Previous studies have shown that safe venous cannulation is difficult when the internal jugular vein (IJV) overlies the carotid artery (CA) as the probability of inadvertent arterial penetration is greatly increased. Aims: The goal of this study was to examine the anatomical relationships of the IJV and CA as a function of the degree of head rotation in order to minimize the risk for CA puncture. Settings and Design: Our study was a prospective study using a sample of 496 Emergency Department patients. Methods and Material: The anatomic relationships of the right and left IJVs and CAs were recorded with head rotation at three different positions. Patients who had the IJV in a 45 to 135 degree relationship to the CA were deemed to be in the high-risk zone for arterial puncture. Statistical Analysis: Chi square, ANOVA. Results: Right IJVs were in the high risk zone for 39.5%, 47.8% and 60.9% of cases at 0, 45 and 80 degrees of head rotation, respectively (P < 0.001). Left IJVs were in the high risk zone for 59.1%, 69.2% and 80.0% at 0, 45 and 80 degrees of head rotation, respectively. (P < 0.001). Conclusions: Head rotation should be minimized during IJV cannulation to decrease the overlap of CA by IJV. Cannulation of the left IJV appears to carry a higher degree of risk as compared to the right IJV. Placing the head in neutral position, avoiding rotation, and using ultrasound guidance are recommended to minimize complications during central venous access. PMID- 30429628 TI - Functional Outcomes in Moderate-to-Severe Traumatic Brain Injury Survivors. AB - Introduction: We aimed to analyze the functional outcomes based on the admission characteristics in individuals with moderate-to-severe traumatic brain injury (TBI) over a 5-year period. Methods: A retrospective cohort study was conducted to assess the cognitive, physical, and functional outcomes based on traditional and novel metrics used in potential outcome prediction. Results: A total of 201 participants were enrolled with a mean age of 31.9 +/- 11.9 years. Glasgow Coma Score (GCS) at emergency department did not correlate with the functional independence measure (FIM) score or Ranchos Los Amigos (RLA) scores at discharge. The absolute functional gain was significantly higher in individuals who sustained TBI with RLA 4-5 (34.7 +/- 18.8 vs. 26.5 +/- 15.9, P = 0.006). Participants with RLA 4-5 on admission to rehabilitation showed good correlation with the absolute FIM gain. On multivariate regression analysis, only age (odds ratio 0.96; 95% confidence interval: 0.93-0.98; P = 0.005) was found to be the independent predictor of good functional outcome. Conclusions: Initial GCS is not a predictor of functional outcome in individuals who sustained TBI. Consideration of age and development of novel functional measures might be promising to predict the outcomes in individuals with moderate-to-severe TBI. PMID- 30429629 TI - Clinical Profile and Autopsy Findings in Fatal Head Injuries. AB - Aims: This study aims to correlate the autopsy findings with the clinical picture and imaging report in fatal head injury patients. Settings and Design: A descriptive study conducted at tertiary care hospital in South India from July 2015 to December 2016. Patients and Methods: All patients with head injuries who were admitted to our Emergency and Trauma Centre and underwent autopsy were included in the study. A structured pro forma was used for collecting information. Autopsy findings were considered as a gold standard to correlate with antemortem findings in fatal head injury. The data were analyzed with EpiData and OpenEpi statistical analyzing software. Results: Of the 303 fatal head injury patients, a majority were males and age group between 21 and 40 years. Eighty-eight percent (267/303) of fatal head injuries were due to road traffic accidents. Twenty-five of the 303 patients reached our center within 1 h (golden hour) of trauma. Of the 303 fatal head injuries, 153 (50.5%) died within 24 h of reaching our center. The most common autopsy finding in this study was subarachnoid hemorrhage (SAH) (247/303, 81.3%). Diagnostic accuracy of Epi dural hemorrhage (EDH) antemortem had the highest value (98.35%). SAH had least diagnostic accuracy value (45.72). subdural hemorrhage (SDH) had highest sensitivity (57.02%). EDH had higher specificity (100%). Significant SDH, SAH, and brain contusions were not detected during antemortem evaluation. Conclusions: Our study revealed that among fatal head injury patients, half of them died within first 24 h after reaching to tertiary care center. Diagnostic accuracy to detect extradural hemorrhage antemortem had the highest value and SAH had least diagnostic accuracy value. Significant subdural hemorrhage, subarachniod hemorrhage, and brain contusion were not detected during antemortem evaluation. Expertise in interpretation of imaging, adequate clinical examination, proper documentation, and early resuscitation may reduce the chances of missed injuries in head injury patients. PMID- 30429630 TI - Utility of Clot Waveform Analysis in Russell's Viper Bite Victims with Hematotoxicity. AB - Introduction: In Russell's viper bites, due to the lack of a better alternative, whole blood clotting test (WBCT) remains the standard test even though its reliability and sensitivity has been shown to be low. Activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA) is an optic absorbance assay that can be used as a global clotting test. In this study, the objective was to assess the changes in CWA and to compare CWA to WBCT and aPTT in patients with Russell's viper envenomation. Methods: The datum was collected prospectively over 2 months as a pilot observational study in a tertiary care center. All proven cases of Russell's viper-envenomated individuals with preliminary CWA data and WBCT were included in the study. The clot wave (CW) of the five individuals, which met all the stringent inclusion criteria, was analyzed and interpreted. Results: CW absorbance sigmoid waveform was deranged in all 5 cases, of which 4 showed a change in CWA even before an abnormal aPTT. Three of the 5 had a normal WBCT but showed early changes in CWA. Atypical biphasic waveform reported in disseminated intravascular coagulation in other prior studies is seen in venom-induced consumptive coagulopathy also. In all patients where a second derivative was plotted, the second (lower) phase of the second derivative showed a slow rise to baseline. Conclusion: CWA showed changes which provided information earlier than the conventional coagulation studies in the snakebite victims studied. While aPTT or WBCT reflects clotting time, CWA conveys the dynamic process of clot formation and stabilization. CWA may reveal disorders of clotting in snakebite victims before the conventional tests become abnormal. Future research should assess the speed and accuracy of the test in diagnosing hemotoxic envenomation and its potential role in guiding antivenom therapy. PMID- 30429632 TI - Assessment and Management of Hypotension in the Elderly Patient. AB - Introduction: Elderly patients often present to the emergency department (ED) with nonspecific signs of infection and excessive fluid loss, with limited research into their management. The purpose of this audit was to assess the initial management of hypotensive elderly patients in the ED: observations within 15 min, fluid challenge within 1 h, time to assessment by a physician, and initial management of septic shock. Subjects and Methods: Online patient systems were reviewed to find 40 patients >65 years old who were hypotensive (systolic blood pressure <100 mmHg or diastolic blood pressure <60 mmHg) in the ED between 1st October 2015 and 16th November 2015. This data were used to perform a retrospective audit to assess their management. Results: Forty hypotensive patients were identified with an average age of 79.6, with 55% being male. Eighty three percent had their observations recorded within 15 min of presentation, 35% had their observations repeated within 1 h, and 35% were fluid challenged within 1 h. Nearly 60% patients were reviewed within 1 h by a physician. About 33% patients were in septic shock with 41% receiving IVF within 1 h, and all 40 patient receiving antibiotics. Discussion: The majority of patients had their observations performed within 15 min; however, a smaller percentage was fluid challenged within 1 h with their observations rechecked. Despite a sepsis pathway, hypotensive patients were still not receiving fluids within the hour. Conclusion: Developing a fast-track protocol for hypotensive elderly patients in the ED could improve initial rehydration management and ensure observations are reported in a timely manner. PMID- 30429631 TI - Impact of Automated External Defibrillator as a Recent Innovation for the Resuscitation of Cardiac Arrest Patients in an Urban City of Japan. AB - Context/Aims: We retrospectively analyzed the characteristics of prehospital care for cardiopulmonary arrest (CPA) to identify the predictors of a good recovery (GR) among the recent changes in the management of Japanese prehospital care. Settings and Design: This study was a retrospective medical chart review. Subjects and Methods: We reviewed the transportation records written by emergency medical technicians and the characteristics of prehospital management of out-of hospital (oh) CPA described by the Sunto-Izu Fire Department from April 2016 to March 2017. The cases were divided into two groups: a GR group (cerebral performance category of 1-3 at 1 month after CPA) and a poor recovery (PR) group. Results: During the analysis period, there were 545 cases of CPA. The average age in the GR group (n = 19) was significantly younger than that in the PR group. The proportions of patients with witnessed collapse, automated external defibrillator (AED) executed by a bystander, ventricular fibrillation during prehospital cardiopulmonary resuscitation (CPR), defibrillation-induced cardioversion, cardiogenic arrest, and oh-return of spontaneous circulation (ROSC) were significantly greater in the GR group than in the PR group. The proportions of telephone CPR conducted by operator, instrumentally secured airways, and administration of epinephrine were significantly smaller in the GR group than in the PR group. A multivariate analysis showed that the significant predictors of GR were bystander AED, ROSC, not instrumentally secured airway, and younger age. Conclusions: This study showed that patients with CPA who were younger, underwent AED executed by a bystander, and obtained oh-ROSC had a higher chance of a favorable outcome. PMID- 30429633 TI - An Unusual Case of Commotio Cordis Resulting in Ventricular Flutter. AB - A 16-year-old male developed palpitations immediately following chest impact with a soccer ball. The patient was noted to have ventricular flutter in a delayed presentation that was successfully treated. While ventricular fibrillation is the predominant arrhythmia following commotio cordis, ventricular flutter may occur as well. Ventricular flutter may be better tolerated in a young athletic individual with structurally normal heart and may lead to a delayed presentation. PMID- 30429634 TI - Camphor Poisoning: A Rare Cause of Acute Symptomatic Seizures in Children. AB - Camphor is a toxic compound easily available over the counter, which can cause fatal seizures in children when ingested. It is available in several forms and is commonly used in Indian households, especially for religious rituals and for its cough-suppressive and nasal-decongestant effect. The toxic effect remains unknown in most homes. Seizures are usually well controlled with intravenous benzodiazepines, and recurrences of seizures are rarely reported. PMID- 30429635 TI - Fatal Acute Myocardial Infarction after Multiple Blunt Injuries Involving the Chest. AB - The patient was a 60-year-old male fell whose head and left chest hit the ground after falling from a height of 2 m. He complained of the left shoulder and chest pain after regaining consciousness. On arrival, he showed left bloody otorrhea, left chest tenderness, and a limited range of motion due to the left shoulder pain. Emergency chest roentgenography revealed multiple left rib fractures, left clavicular fracture with decreased radiolucency in the left lung field, suggesting lung contusion. When the patient was being transported for computed tomography, he suddenly displayed ventricular tachycardia with pulse and subsequently became VF storm, which required percutaneous cardiopulmonary support. The coronary angiogram showed complete obstruction of the branch of the anterior descending artery. Coronary angioplasty resulted in recanalization; however, massive hemorrhage from the left ear was recognized. Computed tomography revealed traumatic subarachnoid hemorrhage and left massive hemothorax requiring thoracostomy. Massive hemorrhage from the left ear and left thoracic cavity continued after the patient was transported to the coronary care unit. He underwent massive transfusion; however, he died on the same day. PMID- 30429636 TI - A Rare Case of Spontaneous Massive Retroperitoneal Hemorrhage Due to Idiopathic lumbar Artery Bleed. PMID- 30429637 TI - Current Role of Active Surveillance in the Management of a Small Renal Mass. AB - Renal cell carcinoma accounts for 3-4% of adult malignant neoplasms and over 65,000 new cases of kidney cancer were diagnosed in the USA in 2013 [1, 2]. Widespread use of abdominal imaging is leading to an increased incidence in the detection of small renal masses (SRMs) among other causes [1-4]. In light of recent literature on the role of percutaneous renal mass biopsy and retrospective data analysis, surveillance for renal masses <=4 cm is likely to become more common especially in patients with less aggressive pathology, advanced age and multiple medical comorbidities. PMID- 30429638 TI - Human factors analysis, design, and evaluation of Engage, a consumer health IT application for geriatric heart failure self-care. AB - Human factors and ergonomics (HFE) and related approaches can be used to enhance research and development of consumer-facing health IT systems, including technologies supporting the needs of people with chronic disease. We describe a multiphase HFE study of health IT supporting self-care of chronic heart failure by older adults. The study was based on HFE frameworks of "patient work" and incorporated the three broad phases of user-centered design: study or analysis; design; and evaluation. In the study phase, data from observations, interviews, surveys, and other methods were analyzed to identify gaps in and requirements for supporting heart failure self-care. The design phase applied findings from the study phase throughout an iterative process, culminating in the design of the Engage application, a product intended for continuous use over 30 days to stimulate self-care engagement, behavior, and knowledge. During the evaluation phase, we identified a variety of usability issues through expert heuristic evaluation and laboratory-based usability testing. We discuss the implications of our findings regarding heart failure self-care in older adults and the methodological challenges of rapid translational field research and development in this domain. PMID- 30429639 TI - Comprehensive screening of CYP4V2 in a cohort of Chinese patients with Bietti crystalline dystrophy. AB - Purpose: Bietti crystalline dystrophy (BCD) is an autosomal recessive retinal degeneration disorder caused by mutations in CYP4V2. The aim of this study is to describe the genetic and clinical findings in 128 unrelated Chinese patients diagnosed with BCD. Methods: Ophthalmological evaluations were performed in all patients. All coding regions of CYP4V2 were amplified and sequenced directly. Real-time quantitative PCR was performed to detect copy number variations. Haplotype analysis was performed in 70 patients with c.802-8_810del17insGC and in 93 normal controls. Results: A total of 28 mutations in CYP4V2, including eight novel mutations, were identified in 125 patients. The most common mutation was c.802-8_810del17insGC, with an allele frequency of 62.6%, followed by p.H331P (8.7%) and c.1091-2A>G (7.5%). A novel large deletion encompassing exon 8 of CYP4V2 was detected. Haplotype analysis revealed four common haplotypes in patients with c.802-8_810del17insGC. A 17.6 kb haplotype CT(delCT)TA(Indel)A was the most common and was observed in 34.5% of the c.802-8_810del17insGC mutant alleles. The patients with mutations in CYP4V2 showed wide intra- and interfamilial variability in clinical severity. Conclusions: The findings expand the mutational spectrum of CYP4V2 and further confirm the c.802-8_810del17insGC mutation was due to a founder effect in a large cohort of Chinese patients. PMID- 30429642 TI - Index to Abstracts / Index Des Resumes. PMID- 30429640 TI - TGF-beta-induced IOP elevations are mediated by RhoA in the early but not the late fibrotic phase of open angle glaucoma. AB - Purpose: Elevations in intraocular pressure (IOP) are associated with the development of glaucoma and loss of sight. High transforming growth factor-beta (TGF-beta) 1 levels in the eye's anterior chamber can lead to dysfunctional contractions through RhoA signaling in trabecular meshwork (TM) cells and IOP spikes. Sustained high TGF-beta levels leads to TM fibrosis and sustained increases in IOP. We investigated whether inhibiting RhoA, using a siRNA-mediated RhoA (siRhoA), controls IOP by altering TM expression of fibrosis and contractility-related proteins in a rodent model of glaucoma. Methods: TGF-beta was injected intracamerally twice a week into adult Sprague Dawley rats, and IOP was recorded with tonometry. Animals were euthanized on day 7 and 35 with TM expression of fibrosis and contractility-related proteins, as well as survival of retinal ganglion cells (RGCs) assessed with immunohistochemistry. siRNA against RhoA or enhanced green fluorescent protein (EGFP) was also injected intracamerally into select animals. Successful RhoA knockdown was determined with quantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, and the effects of the knockdown on the parameters above analyzed. Results: TGF-beta caused increased TM contractile proteins and IOP spikes by day 7, sustained increases in IOP from day 15, and TM fibrosis at day 35. siRhoA abolished the transient 7 day IOP rise but not the later sustained IOP increase (due to fibrosis). At 35 days, TGF-beta-related RGC loss was not prevented with siRhoA treatment. Conclusions: We conclude that RhoA signaling mediates the early IOP rise induced by TM cellular changes associated with contractility but not the sustained IOP elevation caused by TM fibrosis. Thus, RhoA therapies offer a clinically relevant opportunity for IOP management, likely through the modulation of TM contractility, but appear to be ineffective in the amelioration of fibrosis. PMID- 30429644 TI - Circadian Regulation by REV-ERBalpha Mediates Hippocampal E-LTP in a Time dependent Manner. AB - Circadian rhythms are driven by circadian oscillators, and these rhythms result in the biological phenomenon of 24-h oscillations. Previous studies suggest that learning and memory are affected by circadian rhythms. One of the genes responsible for generating the circadian rhythm is Rev-erbalpha. The REV-ERBalpha protein is a nuclear receptor that acts as a transcriptional repressor, and is a core component of the circadian clock. However, the role of REV-ERBalpha in neurophysiological processes in the hippocampus has not been characterized yet. In this study, we examined the time-dependent role of REV-ERBalpha in hippocampal synaptic plasticity using Rev-erbalpha KO mice. The KO mice lacking REV-ERBalpha displayed abnormal NMDAR-dependent synaptic potentiation (E-LTP) at CT12~CT14 (subjective night) when compared to their wild-type littermates. However, Rev erbalpha KO mice exhibited normal E-LTP at CT0~CT2 (subjective day). We also found that the Rev-erbalpha KO mice had intact late LTP (L-LTP) at both subjective day and night. Taken together, these results provide evidence that REV ERBalpha is critical for hippocampal E-LTP during the dark period. PMID- 30429645 TI - iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia. AB - Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Abeta was dramatically increased in PS1 E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery. PMID- 30429646 TI - Fatty Acid Increases cAMP-dependent Lactate and MAO-B-dependent GABA Production in Mouse Astrocytes by Activating a Galphas Protein-coupled Receptor. AB - Medium-chain fatty acids (MCFAs) are mostly generated from dietary triglycerides and can penetrate the blood-brain barrier. Astrocytes in the brain use MCFAs as an alternative energy source. In addition, MCFAs have various regulatory and signaling functions in astrocytes. However, it is unclear how astrocytes sense and take up MCFAs. This study demonstrates that decanoic acid (DA; C10), a saturated MCFA and a ligand of Galphas protein-coupled receptors (Galphas-GPCRs), is a signaling molecule in energy metabolism in primary astrocytes. cAMP synthesis and lactate release were increased via a putative Galphas-GPCR and transmembrane adenylyl cyclase upon short-term treatment with DA. By contrast, monoamine oxidase B-dependent gamma-aminobutyric acid (GABA) synthesis was increased in primary cortical and hypothalamic astrocytes upon long-term treatment with DA. Thus, astrocytes respond to DA by synthesizing cAMP and releasing lactate upon short-term treatment, and by synthesizing and releasing GABA upon long-term treatment, similar to reactive astrocytes. Our data suggest that astrocytes in the brain play crucial roles in lipid-sensing via GPCRs and modulate neuronal metabolism or activity by releasing lactate via astrocyte neuron lactate shuttle or GABA to influence neighboring neurons. PMID- 30429647 TI - Ubiquitin C-terminal Hydrolase L1 Regulates Lipid Raft-dependent Endocytosis. AB - Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is highly expressed in neurons, and gathering evidence indicates that UCH-L1 may play pathogenic roles in many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease (PD). Additionally, lipid rafts have attracted interest in neurodegeneration as playing a common role in many neurodegenerative diseases. In the present study, we demonstrated that UCH-L1 associates with lipid rafts as with other PD-associated gene products. In addition, UCH-L1 regulates lipid raft-dependent endocytosis and it is not dependent on the expression and degradation of caveolin-1 or flotillin-1. Finally, UCH-L1 regulates cell-to-cell transmission of alpha-synuclein. This study provides evidence that many PD associated gene products share common signaling pathways to explain the pathogenesis of PD. PMID- 30429643 TI - Sex-specific Behavioral Features of Rodent Models of Autism Spectrum Disorder. AB - Sex is an important factor in understanding the clinical presentation, management, and developmental trajectory of children with neuropsychiatric disorders. While much is known about the clinical and neurobehavioral profiles of males with neuropsychiatric disorders, surprisingly little is known about females in this respect. Animal models may provide detailed mechanistic information about sex differences in autism spectrum disorder (ASD) in terms of manifestation, disease progression, and development of therapeutic options. This review aims to widen our understanding of the role of sex in autism spectrum disorder, by summarizing and comparing behavioral characteristics of animal models. Our current understanding of how differences emerge in boys and girls with neuropsychiatric disorders is limited: Information derived from animal studies will stimulate future research on the role of biological maturation rates, sex hormones, sex-selective protective (or aggravating) factors and psychosocial factors, which are essential to devise sex precision medicine and to improve diagnostic accuracy. Moreover, there is a strong need of novel strategies to elucidate the major mechanisms leading to sex-specific autism features, as well as novel models or methods to examine these sex differences. PMID- 30429648 TI - A Group of Descending Glutamatergic Neurons Activated by Stress in Corticolimbic Regions Project to the Nucleus Accumbens. AB - The nucleus accumbens (NAc) is the major component of the ventral striatum that regulates stress-induced depression. The NAc receives dopaminergic inputs from the ventral tegmental area (VTA), and the role of VTA-NAc neurons in stress response has been recently characterized. The NAc also receives glutamatergic inputs from various forebrain structures including the prelimbic cortex (PL), basolateral amygdala (BLA), and ventral hippocampus (vHIP), whereas the role of those glutamatergic afferents in stress response remains underscored. In the present study, we investigated the extent to which descending glutamatergic neurons activated by stress in the PL, BLA, and vHIP project to the NAc. To specifically label the input neurons into the NAc, fluorescent-tagged cholera toxin subunit B (CTB), which can be used as a retrograde neuronal tracer, was injected into the NAc. After two weeks, the mice were placed under restraint for 1 h. Subsequent histological analyses indicated that CTB-positive cells were detected in 170~680 cells/mm2 in the PL, BLA, and vHIP, and those CTB-positive cells were mostly glutamatergic. In the PL, BLA, and vHIP regions analyzed, stress-induced c-Fos expression was found in 20~100 cells/mm2. Among the CTB positive cells, 2.6% in the PL, 4.2% in the BLA, and 1.1% in the vHIP were co labeled by c-Fos, whereas among c-Fos-positive cells, 7.7% in the PL, 19.8% in the BLA, and 8.5% in the vHIP were co-labeled with CTB. These results suggest that the NAc receives a significant but differing proportion of glutamatergic inputs from the PL, BLA, and vHIP in stress response. PMID- 30429649 TI - Differential Expression of Ca2+-buffering Protein Calretinin in Cochlear Afferent Fibers: A Possible Link to Vulnerability to Traumatic Noise. AB - The synaptic contacts of cochlear afferent fibers (CAFs) with inner hair cells (IHCs) are spatially segregated according to their firing properties. CAFs also exhibit spatially segregated vulnerabilities to noise. The CAF fibers contacting the modiolar side of IHCs tend to be more vulnerable. Noise vulnerability is thought to be due to the absence of neuroprotective mechanisms in the modiolar side contacting CAFs. In this study, we investigated whether the expression of neuroprotective Ca2+-buffering proteins is spatially segregated in CAFs. The expression patterns of calretinin, parvalbumin, and calbindin were examined in rat CAFs using immunolabeling. Calretinin-rich fibers, which made up ~50% of the neurofilament (NF)-positive fibers, took the pillar side course and contacted all IHC sides. NF-positive and calretinin-poor fibers took the modiolar side pathway and contacted the modiolar side of IHCs. Both fiber categories juxtaposed the C terminal binding protein 2 (CtBP2) puncta and were contacted by synaptophysin puncta. These results indicated that the calretinin-poor fibers, like the calretinin-rich ones, were afferent fibers and probably formed functional efferent synapses. However, the other Ca2+-buffering proteins did not exhibit CAF subgroup specificity. Most CAFs near IHCs were parvalbumin-positive. Only the pillar-side half of parvalbumin-positive fibers coexpressed calretinin. Calbindin was not detected in any nerve fibers near IHCs. Taken together, of the Ca2+ buffering proteins examined, only calretinin exhibited spatial segregation at IHC CAF synapses. The absence of calretinin in modiolar-side CAFs might be related to the noise vulnerability of the fibers. PMID- 30429650 TI - The Novel Neuroprotective Compound KMS99220 Has an Early Anti-neuroinflammatory Effect via AMPK and HO-1, Independent of Nrf2. AB - We have previously reported a novel synthetic compound KMS99220 that prevented degeneration of the nigral dopaminergic neurons and the associated motor deficits, suggesting a neuroprotective therapeutic utility for Parkinson's disease. Microglia are closely associated with neuroinflammation, which plays a key role in the pathogenesis of neurodegenerative diseases. In this study, we investigated the effects of KMS99220 on the signaling involving AMP-activated protein kinase (AMPK) and heme oxygenase-1 (HO-1), the enzymes thought to regulate inflammation. KMS99220 was shown to elevate the enzyme activity of purified AMPK, and phosphorylation of cellular AMPK in BV2 microglia. It increased the level of HO-1, and this was attenuated by AMPK inhibitors. KMS99220 lowered phosphorylation of IkappaB, nuclear translocation of NFkappaB, induction of inducible nitric oxide synthase, and generation of nitric oxide in BV2 cells that had been challenged with lipopolysaccharide. This anti-inflammatory response involved HO-1, because both its pharmacological inhibition and knockdown of its expression abolished the response. The AMPK inhibitors also reversed the anti inflammatory effects of KMS99220. The induction of HO-1 by KMS99220 occurred within 1 h, and this appeared not to involve the transcription factor Nrf2, because Nrf2 knockdown did not affect the compound's HO-1 inducing- and anti inflammatory effects in this time window. These findings indicated that KMS99220 leads to AMPK-induced HO-1 expression in microglia, which in turn plays an important role in early anti-inflammatory signaling. Together with its neuroprotective property, KMS99220 may serve as a feasible therapeutic agent against neuroinflammation and neurodegeneration. PMID- 30429652 TI - HDAC3 Inhibition Promotes Alternative Activation of Macrophages but Does Not Affect Functional Recovery after Spinal Cord Injury. AB - After spinal cord injury (SCI), monocyte derived macrophages play a detrimental role. Histone deacetylases (HDACs) are central epigenetic regulators of macrophage-polarization. We hypothesized that HDAC3 inhibition suppresses the pro inflammatory macrophage phenotype (M1), promotes the anti-inflammatory phenotype (M2) and improves functional recovery after SCI. Therefore, two inhibitors of HDAC3 were selected, namely scriptaid and RGFP966. The impact on macrophage polarization was studied by investigating the effect on gene and protein expression of selected M1 and M2 markers. We show that scriptaid differentially influences M1 and M2 markers. It increases CD86 and iNOS gene expression and decreases GPR18, CD38, FPR2 and Arg-1 gene expression as well as the production of IL-6 and NO. RGFP966 primarily increased the expression of the M2 markers Arg 1 and Ym1 and reduced the production of IL-6 (M1). RGFP966 and scriptaid reduced the formation of foamy macrophages. Finally, to investigate the impact of HDAC3 inhibition on functional recovery after SCI, we studied the effects of RGFP966 and scriptaid in an in vivo T-cut hemisection SCI model. Histological analyses were performed on spinal cord sections to determine lesion size and astrogliosis, demyelinated area and selected infiltrating immune cells. RGFP966 and scriptaid did not affect functional recovery or histopathological outcome after SCI. In conclusion, these results indicate that specific HDAC3 inhibition with RGFP966 promotes alternative activation of macrophages and reduces the formation of foamy macrophages, but does not lead to a better functional recovery after SCI. PMID- 30429651 TI - Chronic Treatment with Combined Chemotherapeutic Agents Affects Hippocampal Micromorphometry and Function in Mice, Independently of Neuroinflammation. AB - Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy. PMID- 30429653 TI - Fulfilling the taxonomic consequence after DNA Barcoding: Carychiumpanamaense sp. n. (Eupulmonata, Ellobioidea, Carychiidae) from Panama is described using computed tomographic (CT) imaging. AB - Five years ago, the Panamanian evolutionary lineage (EL) C12 was uncovered along with four other ELs in an integrative phylogenetic investigation of worldwide Carychiidae. Since EL C12 lacked shell material post-molecular analysis to serve as a museum voucher, it remained undescribed. Now, after recent collection efforts of C12 and the congener, Carychiumzarzaae Jochum & Weigand, 2017 at their original Panamanian sites, C12 is morphologically described and formally assigned the name, Carychiumpanamaense Jochum, sp. n. In sync with recent taxonomic treatment of the genus, computed tomography (CT) is used in this work to differentiate shells of C.panamaense sp. n. from geographically-proximal, Caribbean, North and Central American congeners. Recent material of topotypic Carychiumjardineanum (Chitty, 1853) and undamaged C.zarzaae were additionally CT scanned and assessed in the comparative analyses. PMID- 30429654 TI - Sparsorythussescarorum, new species from Mindoro, Philippines (Ephemeroptera, Tricorythidae). AB - A new mayfly species, Sparsorythussescarorum sp. n. (Tricorythidae) is described from Mindoro Island, Philippines. Nymphs are characterized by the combination of the following characters: compound eyes of approximately equal size in both sexes, shape and setation of legs, presence of rudimentary gills on abdominal segment VII, and some details of mouthparts. Male imagines are characterized by the coloration pattern of wings and details of genitalia. The developmental stages are matched by DNA barcodes. PMID- 30429655 TI - Cnestusquadrispinosus, a new species of xyleborine ambrosia beetle from Thailand and Borneo (Coleoptera, Curculionidae, Scolytinae, Xyleborini). AB - A new species, Cnestusquadrispinosus, is described from Thailand, Brunei Darussalam, and East Malaysia (Sabah). It is compared to three related species of Cnestus which lack a mycangial tuft of hairs on the pronotum, and have an impressed elytral declivity. PMID- 30429656 TI - A new species of frog-biting midge from Papua New Guinea with a key to the described Corethrellidae of the Australopapuan region (Diptera, Corethrellidae, Corethrella). AB - Corethrellaoppositophila Kvifte & Bernal, sp. n. is described based on one male and six female specimens collected at 2200 m a.s.l. on Mount Wilhelm, Papua New Guinea. The species is the fourth species of frog-biting midge described from this country and appears similar to Corethrellasolomonis Belkin based on pigmentation of legs and abdominal tergites. It differs from C.solomonis, however, in the shape of female flagellomeres I-III, and in the thorax which has a dark brown vertical stripe. The new species is named for its sexually dimorphic flagellomeres, which are short and squat in the female and elongate in the male. These differences in morphological characters are discussed in light of the likely sexual differences in functional uses of the antennae, as males use them for mating only whereas females use them both for mating and prey location. An emended key is presented to the described Australopapuan species of Corethrellidae. PMID- 30429657 TI - Imaging natural history museum collections from the bottom up: 3D print technology facilitates imaging of fluid-stored arthropods with flatbed scanners. AB - Availability of 3D-printed laboratory equipment holds promise to improve arthropod digitization efforts. A 3D-printed specimen scanning box was designed to image fluid-based arthropod collections using a consumer-grade flatbed scanner. The design was customized to accommodate double-width microscope slides and printed in both Polylactic Acid (PLA) and nylon (Polyamide). The workflow with two or three technicians imaged Trichoptera lots in batches of six scanning boxes. Individual images were cropped from batch imagess using an R script. PLA and nylon both performed similarly with no noticeable breakdown of the plastic; however, dyed nylon leeched color into the ethanol. The total time for handling, imaging, and cropping was ~8 minutes per vial, including returning material to vials and replacing ethanol. Image quality at 2400 dpi was the best and revealed several diagnostic structures valuable for partial identifications with higher utility if structures of the genitalia were captured; however, lower resolution scans may be adequate for natural history collection imaging. Image quality from this technique is similar to other natural history museum imaging techniques; yet, the scanning approach may have wider applications to morphometrics because of lack of distortion. The approach can also be applied to image vouchering for biomonitoring and other ecological studies. PMID- 30429658 TI - Chroma+, a new automontage method of image background selection for Insects and other structurally complex objects. AB - Obtaining taxonomic-grade images is a vital part of probably every present-day morphological study of insects, even though the task itself is perceived as a "necessary evil" due to high investment of both time and effort to produce representable images. Cleaning the background and making it appear as a solid color of known properties is probably one of the most time-demanding tasks. Several techniques have been developed to reduce the time requirement; the most convenient and cost-effective one presumably being the chroma isolation. This method uses a green background that can be isolated and conveniently replaced with another picture or solid color, as used in the film industry. However, the main drawback of this technique is spilling of color onto the object, which is unavoidable and can be corrected only by sacrificing the true color of the object to some extent. Our improved Chroma+ method is based on classical chroma isolation workflow and helps to overcome this problem by taking an additional image of the object with a neutral color background and applying a selection obtained from the chroma-isolated picture on it. This technique is, in terms of the resulting image quality, superior to classical chroma isolation, while the time difference between these two methods is negligible. Furthermore, it does not require any additional equipment (hardware or software), thus being accessible to both employed taxonomists, low budget laboratories, and enthusiasts. PMID- 30429659 TI - A broadly distributed species instead of an insular endemic? A new find of the poorly known Hainan gymnure (Mammalia, Lipotyphla). AB - The Hainan gymnure Neohylomyshainanensis (Mammalia, Lipotyphla), endemic to Hainan Island (China), is one of the rarest and least-known species within the family Galericidae. The IUCN Red List inferred it as an endangered species due to ongoing population decline caused by natural habitat loss. A recent biodiversity survey has revealed N.hainanensis to be rather common in northern Vietnam. This is the first record of the species outside Hainan Island. New data have allowed us to re-assess the conservation status of this poorly known mammal. The occurrence of N.hainanensis in mainland Vietnam also supports the hypothesis that Hainan Island could have been previously connected to Guangxi and northern Vietnam rather than to neighbouring Guangdong. PMID- 30429660 TI - Two new species of Hiptage (Malpighiaceae) from Yunnan, Southwest of China. AB - Hiptagepauciflora Y.H. Tan & Bin Yang and Hiptageferruginea Y.H. Tan & Bin Yang, two new species of Malpighiaceae from Yunnan, South-western China are here described and illustrated. Morphologically, H.pauciflora Y.H. Tan & Bin Yang is similar to H.benghalensis (L.) Kurz and H.multiflora F.N. Wei; H.ferruginea Y.H. Tan & Bin Yang is similar to H.calcicola Sirirugsa. The major differences amongst these species are outlined and discussed. A diagnostic key to the two new species of Hiptage and their closely related species is provided. PMID- 30429661 TI - A new large-flowered species of Andeimalva (Malvaceae, Malvoideae) from Peru. AB - Andeimalvaperuviana Dorr & C.Romero, sp. nov., the third Peruvian endemic in a small genus of five species, is described and illustrated from a single collection made at high elevation on the eastern slopes of the Andes. Molecular phylogenetic analyses of nuclear ribosomal ITS sequence data resolve a group of northern species of Andeimalva found in Bolivia and Peru from the morphologically very different southern A.chilensis. The new species bears the largest flowers of any Andeimalva and is compared with Bolivian A.mandonii. A revised key to the genus is presented. PMID- 30429662 TI - Poasecunda J. Presl (Poaceae): a modern summary of infraspecific taxonomy, chromosome numbers, related species and infrageneric placement based on DNA. AB - Poasecunda J. Presl. s.l. is a morphologically highly variable bunchgrass that is a valuable forage species in western North America. There has been much controversy as to whether multiple taxa should be recognised and at what rank in this taxonomically challenging apomictic complex. Here we propose an infraspecific classification for Poasecunda of six varieties within two subspecies, juncifolia and secunda. New combinations are P.secunda vars. ampla, gracillima, juncifolia, nevadensis and scabrella. Conflicting plastid and nrDNA phylogenies show that P.sect.Secundae is of ancient hybrid origin. Based on this and its distinct morphology, the section is raised to the rank of subgenus. A key is presented for P.secunda infraspecies and closely related non-arctic species. Suppl. materials are provided of chromosome counts for Secundae taxa and D.D. Keck specimen annotations of taxa here included in P.secunda. PMID- 30429663 TI - VernoniasubgenusAustrovernonia, a new subgenus from South America (Compositae, Vernonieae, Vernoniinae). AB - Vernoniaincana Less. and V.echioides Less. are two semi-aquatic species from southern South American that are referred to as "the semi-aquatic Vernonia of South America" and they have been, until now, retained as members of Vernonia mostly because each had some unusual characters that made them hard to place. Based on an ongoing molecular study, we can now say that V.incana is the sister taxon to all true Vernonia and can therefore be responsibly left in Vernonia but, because of its morphological and geographic differences, it is now assigned to its own subgenus: Vernonia subg. Austrovernonia. Vernoniaechioides is not closely related to V.incana and is now part of a separate investigation. This placement of V.incana as sister to the true Vernonia species brings up the possibility of a South American root for the Vernonia clade and perhaps indicates a propensity in the lineage for growing in or near water. The species V.incana is lectotypified. PMID- 30429664 TI - A new species of the lichenised genus Anamylopsora (Baeomycetaceae, Baeomycetales) from Tengger Desert of China. AB - The monotypic lichenised genus Anamylopsora (Baeomycetaceae, Baeomycetales), with its single species A.pulcherrima, is distributed in the arid areas of the Northern Hemisphere, including China. In this paper, we introduce another species new to science, Anamylopsorapruinosa. The new species is characterised by a densely pruinose upper surface, abundantly thick and strong rhizines and terricolous habitat. It is also strongly supported by the phylogenetic and species delimitation analyses based on nrDNA ITS sequences, in which A.pruinosa forms well-supported clade separated from A.pulcherrima. PMID- 30429665 TI - Informed consent and ethics committee approval in laboratory medicine. AB - Informed consent is a process in which a human subject who is to participate in research needs to give his or her consent after being properly informed of the expected benefits as well as the potential harm of the research that will be performed. The function and purpose of the research ethics committee is to ensure that the research that will take place is in accordance with the relevant ethical standards. This means that the committee must assess the appropriateness of the design of the study reviewed. Research in the field of laboratory medicine has specific features, i.e. the use of samples that remain after routine analysis, data collection from databases containing patient information, data mining, collection of laboratory management data, method/instrument comparisons and validation, etc. As most of such research is either retrospective or not directly associated with patients, the question arises as to whether all types of research require informed consent and ethics committee approval. This article aims to clarify what is specific about obtaining informed consent and ethical approval in laboratory medicine, to provide general guidance on informed consent and ethical approval requirements based on the type of study, and what information should be included in applications for ethical approval and informed consent. This could also provide some guidance for future contributors to the Biochemia Medica. PMID- 30429666 TI - "Ultra-sensitive" cardiac troponins: Requirements for effective implementation in clinical practice. AB - The measurement of cardiac troponins, either cardiac troponin I or T, has become the culprit of clinical decision making in patients with suspected acute coronary syndrome (ACS), especially in those with non-ST elevation myocardial infarction (NSTEMI). The leading analytical mainstays of cardiac troponin immunoassays include the limit of blank (LoB), limit of detection (LoD), functional sensitivity, the 99th percentile of a healthy reference population, along with the percentage of "ostensibly healthy" subjects displaying measurable values < 99th percentile. The latest generation of cardiac troponin immunoassays, conventionally defined as "high-sensitive" (HS), is characterized by a LoD over 100-fold lower compared to the first commercialized techniques and a percentage of measurable values consistently > 50% in the general healthy population. The very recent commercialization of methods with further improved analytical sensitivity (i.e., "ultra-sensitive" assays), which allow to measure cardiac troponin values in the vast majority of healthy subjects, is now challenging the diagnostic paradigm based on early rule-out of subjects with cardiac troponin values comprised between the 99th percentile and LoD. New diagnostic strategies, entailing assay-specific cut-offs, must hence be developed and validated in large multicenter studies. The aim of this article is to provide an update on commercially available HS and "ultra"-sensitive techniques for measuring cardiac troponins, along with possible implications of increasingly enhanced analytical sensitivity on diagnostic algorithms for evaluating patients with suspected ACS. PMID- 30429667 TI - Red blood cell distribution width in pregnancy: a systematic review. AB - Anisocytosis has been associated with the severity and prognosis of several acute and chronic diseases, as well as physiological conditions such as pregnancy. Anisocytosis is quantified by the red blood cell distribution width (RDW), expressed as the ratio, multiplied by 100, between the standard deviation (SD) of red blood cell volumes and the mean corpuscular volume, or as the SD of erythrocyte volumes (RDW-SD). The aim of the present review was to report the state of the art on the physiological values and the putative diagnostic and prognostic roles of RDW in complicated pregnancy. Literature research for articles published in the last ten years was conducted in Pubmed, Web of Science, ClinicalTrials.gov, and Scopus databases. Abstracts were independently screened by two investigators. If relevant, full articles were retrieved. References, in these articles, citing relevant reviews or original studies were also accessed to identify additional eligible studies. Any disagreement between the reviewers was resolved by a third investigator. A total of 28 studies were included in the review. These studies reported changes in RDW values during physiological pregnancy, and associations between the RDW and several pregnancy complications including anaemia, preeclampsia, gestational diabetes, and recurrent miscarriage. This review provides background information for establishing physiological and pathological RDW values in pregnancy for diagnostic and prognostic use in clinical practice. PMID- 30429668 TI - Improvement of neutrophil gelatinase-associated lipocalin sensitivity and specificity by two plasma measurements in predicting acute kidney injury after cardiac surgery. AB - Introduction: Acute kidney injury (AKI) remains among the most severe complication after cardiac surgery. The aim of this study was to evaluate the neutrophil gelatinase-associated lipocalin (NGAL) as possible biomarker for the prediction of AKI in an adult cardiac population. Materials and methods: Sixty nine consecutive patients who underwent cardiac surgeries in our hospital were prospectively evaluated. In the intensive care unit (ICU) NGAL was measured as a new biomarker of AKI besides serum creatinine (sCrea). Patients with at least two factors of AKI risk were selected and samples collected before the intervention and soon after the patient's arrival in ICU. As reference standard, sCrea measurements and urine outputs were evaluated to define the clinical AKI. A Triage Meter for plasma NGAL fluorescence immunoassay was used. Results: Acute kidney injury occurred in 24 of the 69 patients (35%). Analysis of post-operative NGAL values demonstrated an AUC of 0.71, 95% CI (0.60 - 0.82) with a cut-off = 154 ng/mL (sensitivity = 76%, specificity = 59%). Moreover, NGAL after surgery had a good correlation with the AKI stage severity (P <= 0.001). Better diagnostic results were obtained with two consecutive tests: sensitivity 86% with a negative predictive value (NPV) of 87%. At 10-18 h after surgery sCrea measurement, as confirmatory test, allowed to reach a more sensitivity and specificity with a NPV of 96%. Conclusions: The assay results showed an improvement of NGAL diagnostic accuracy evaluating two tests. Consequently, NGAL may be useful for a timely treatment or for the AKI rule out in ICU patients. PMID- 30429670 TI - Significance of LDL and HDL subclasses characterization in the assessment of risk for colorectal cancer development. AB - Introduction: Dyslipidaemia contributes to the occurrence of colorectal cancer (CRC). We hypothesized that qualitative changes of lipoproteins are associated with the risk for CRC development. This study analyses low-density lipoprotein (LDL) and high-density lipoprotein (HDL) diameters, as well as distribution of LDL and HDL subclasses in patients with CRC, with an aim to determine whether advanced lipid testing might be useful in predicting the risk for the onset of this malignancy. Materials and methods: This case-control study included 84 patients with newly diagnosed CRC and 92 controls. Gradient gel electrophoresis was applied for separation of lipoprotein subclasses and for LDL and HDL diameters determination. Lipid parameters were measured using routine enzymatic methods. Results: Total cholesterol, HDL and LDL-cholesterol were significantly lower in CRC patients compared to controls (4.47 mmol/L vs. 5.63 mmol/L; 0.99 mmol/L vs. 1.27 mmol/L; 2.90 mmol/L vs. 3.66 mmol/L; P < 0.001, respectively). Patients had significantly smaller LDL (25.14 nm vs. 26.92 nm; P < 0.001) and HDL diameters (8.76 nm vs. 10.17 nm; P < 0.001) and greater proportion of small, dense LDL particles (54.0% vs. 52.9%; P = 0.044) than controls. Decreased LDL and HDL diameters were independent predictors of CRC (OR = 0.5, P = 0.001 and OR = 0.5, P = 0.008, respectively), and alongside with age and HDL-cholesterol concentrations formed the optimal cost-effective model, providing adequate discriminative abilities for CRC (AUC = 0.89) and correct patients classification (81%). Conclusions: Patients with CRC have decreased LDL and HDL diameters and increased proportion of smaller particles. LDL and HDL diameters determination could be useful in assessing the risk for CRC development. PMID- 30429669 TI - Association of abdominal aortic aneurysm diameter with insulin resistance index. AB - Introduction: Epidemiological studies have highlighted a negative association between diabetes and abdominal aortic aneurysm (AAA). The aim of this study was to investigate the association between insulin resistance and AAA size. Materials and methods: This prospective cross sectional monocentric study analysed fasting blood samples from 55 patients with AAA eligible for surgical repair. They were divided into 2 groups according to the median AAA diameter: diameter < 50 mm (N = 28) and diameter > 50 mm (N = 27). The median ages were respectively 73 years (62 - 79) and 72 years (67 - 81). Glucose and fructosamine concentrations were determined by spectrophotometry; insulin and C-peptide using chemiluminescent technology. Homeostasis model assessment 2 calculator was used to estimate insulin resistance index (HOMA2 IR). Results: There was no significant difference for fasting glucose concentration between the groups (6.1 vs. 5.9 mmol/L, P = 0.825). C-peptide and insulin concentrations, as well as HOMA2 IR index were significantly higher in patients with AAA > 50 mm (0.82 vs. 0.54 nmol/L, P = 0.012; 9 vs. 5 mU/L, P = 0.019 and 1.72 vs. 1.26, P = 0.028, respectively). No linear correlation was identified between AAA diameter and HOMA2 IR. Fructosamine concentration was lower in patients with AAA > 50 mm (225.5 vs. 251 MUmol/L, P = 0.005) and negatively correlated with AAA diameter (r = - 0.54, P < 0.001). Conclusion: This study evidenced an association between AAA diameter and insulin resistance. Further studies are required to determine a causal link between insulin resistance and AAA development. PMID- 30429671 TI - Detection of annexin A8 antibodies in serum of patients with antiphospholipid syndrome. AB - Introduction: Antibodies specific for annexin A8 (AnxA8) have not been investigated in patients suffering from antiphospholipid syndrome (APS) yet. The aim of this study was to compare the presence of AnxA8 antibodies in serum of APS patients with that of age-matched healthy controls and to investigate whether AnxA8 antibodies are potential biomarkers for APS. Materials and methods: We enrolled 22 APS patients and 22 healthy controls in this case-control study. We used sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblot to investigate the presence of AnxA8 antibodies, and we applied enzyme-linked immunosorbent assay to investigate the presence of cardiolipin (CL) and beta-2 glycoprotein I (beta2GPI) antibodies. Results: The serum of 9/22 APS patients showed AnxA8 IgG isotype antibody reactivity compared to serum of 2/22 healthy controls (P = 0.034). When we also included weak immunoblot signals, 12/22 APS patients exhibited AnxA8 IgG isotype antibody reactivity compared to 3/22 healthy controls (P = 0.005). We also investigated the presence of AnxA8 IgM isotype antibodies in the serum of APS patients but found no statistically significant difference between the APS patient group and healthy control group (P = 0.500). We further investigated the presence of beta2GPI and CL IgG and IgM isotype antibodies. AnxA8 IgG isotype antibodies were present in APS patients in a similar frequency as the APS "criteria" antibody against CL (P = 0.764). Conclusion: We demonstrated that AnxA8 IgG isotype antibodies are potential biomarkers for the diagnosis of APS. PMID- 30429672 TI - Haematology specimen acceptability: a national survey in Chinese laboratories. AB - Introduction: Specimen adequacy is a crucial preanalytical factor affecting accuracy and usefulness of test result. The aim of this study was to determine the frequency and reasons for rejected haematology specimens, preanalytical variables which may affect specimen quality, and consequences of rejection, and provide suggestions on monitoring quality indicators as to obtain a quality improvement. Materials and methods: A cross-sectional survey was conducted and a questionnaire was sent to 1586 laboratories. Participants were asked to provide general information about institution and practices on specimen management and record rejections and reasons for rejection from 1st to 31st July. Results: A total survey response rate was 56% (890/1586). Of 10,181,036 tubes received during the data collection period, 11,447 (0.11%) were rejected, and the sigma (sigma) was 4.6. The main reason for unacceptable specimens was clotted specimen (57%). Rejected specimens were related to source department, container type, container material type, transportation method and phlebotomy personnel. The recollection of 84% of the rejected specimens was required. The median specimen processing delay in inpatient, outpatient and emergency department were 81.0 minutes, 57.0 minutes and 43.3 minutes, respectively. Conclusions: Overall, rejection rate was a slightly lower than previously published data. In order to achieve a better quality in the preanalytical phase, haematology laboratories in China should pay more attention on training for phlebotomy and sample transportation, identify main reasons for clotted specimen and take effective measures. The platform in the study will be helpful for long-term monitoring, but simplification and modification should be introduced in the following investigation. PMID- 30429673 TI - Effect of sample processing and time delay on cell count and chemistry tests in cerebrospinal fluid collected from drainage systems. AB - Introduction: Cerebrospinal fluid (CSF) from extra-ventricular drainage (EVD) systems is routinely analysed to diagnose EVD-related bacterial meningitis. We investigated the effect of time delay and sample processing on cell count and basic biochemistry results in EVD CSF to define optimal turnaround time and whether manual and automated cell counting are comparable in such samples. Materials and methods: In total, 32 EVD CSF samples were analysed. Baseline testing included cell counting (Fuchs-Rosenthal chamber and Sysmex XE5000) and biochemistry analyses (glucose, lactate, proteins). Manual cell counting was also performed at intervals of 61-90 and 91-150 minutes from baseline in the residual sample. Biochemistry analyses were performed in samples before and after centrifugation at baseline and at 91-150 minutes interval. Results: At 91-150 minutes total cell count (P < 0.001), large lymphocytes (P = 0.007), neutrophils (P < 0.001) and phagocytes (P = 0.006) obtained by manual counting decreased and the number of disintegrated cells count increased (P = 0.016) compared to the baseline values. Considering method comparison, proportional difference between methods for all cell (sub)groups was obtained, whereas polymorphonuclears also showed the constant difference (y = 11.21 + 1.22x). Compared to centrifuged CSF, lower concentration of glucose and lactates were obtained in uncentrifuged samples (P < 0.001) at baseline. Conclusions: Manual cell counting should be performed within 60 minutes as any delay can alter results. The same counting technique should be used to obtain longitudinally assessable results. Biochemistry tests are stable in uncentrifuged CSF up to 2.5 hours. PMID- 30429674 TI - Computer physician order entry (CPOE) as a strategy to estimate laboratory activity and costs associated with cancer clinical trials. AB - Introduction: Most of clinical laboratories are not properly reimbursed for their activity related to clinical trials (CTs) conducted in their institutions due to a lack of measurement strategies. We implemented a specific computer physician order entry (CPOE) environment for CTs in order to facilitate ordering to providers and estimate the associated costs to be compared with the standard of care (SOC). Materials and methods: Four specific electronic formularies, restricted to two new virtual CTs clinical services (onco - CT and haemo - CT), were implemented in January 2015. For each clinical trial displayed in the panels there were several box-cells that contained several profiles based on the different phase of the trials. Tests included in the profiles were the tests required by protocol. Laboratory costs (?) per patient were compared between the CTs services and their regular outpatients clinical services (onco - Out and haemo - Out, considered the SOC) for three years. Results: Costs per patient were higher for CTs services and increased progressively each year (25%, 70% and 70% and 0.6%, 2.7% and 17% in 2015, 2016 and 2017 for Oncology and Haematology, respectively). Taking into account all these differences and the number of patients attending a total difference in expense of + 130,377.7 ? for the period 2015-2017 was obtained between CTs and outpatients services. Conclusions: Strategies through CPOE systems based on restricted and specific profiles for CTs ordering are a promising tool that can improve laboratory associated costs estimation and provide robust evidence in reimbursement negotiation processes with CTs sponsors. PMID- 30429675 TI - Analysis of selected T cell subsets in peripheral blood after exhaustive effort among elite soccer players. AB - Introduction: Physical exercise induces developing of naive T lymphocyte subsets into polarised effector ones by immune system. The aim of the study was to examine the influence of exhaustive effort on the selected Th cell subsets and inflammation markers among soccer players. Materials and methods: Fourteen soccer players aged 18 (16-21) years old performed the progressive efficiency test on mechanical treadmill. Th and Tc memory lymphocytes' subsets and selected cytokine concentrations pre-exercise, post-exercise and in recovery were analysed by flow cytometry. Results: Physical effort induced changes in Th cell percentages. Increase in recovery Treg and Th17 cell subsets' percentages in comparison to pre exercise values were observed (10.98 (9.83-14.07) vs. 3.95 (3.15-5.53), P < 0.001 in autumn; 10.58 (7.54-12.67) vs. 4.83 (3.73-6.81), P < 0.010 in spring for Treg and 29.21 (26.34-32.16) vs. 21.64 (18.48-25.76) in autumn; 27.15 (24.60-29.16) vs. 17.43 (15.83-19.77) in spring, both P < 0.010; for Th17, respectively). Increases in Th1 cell percentages post-exercise (31.86 (28.72-33.72) in autumn, 25.60 (21.50-29.19) in spring, both P < 0.010) and in recovery (34.64 (31.21 38.20) in autumn; 26.68 (25.17-28.07) in spring, both P < 0.001) compared to pre exercise (22.70 (21.21-26.74) for autumn and 15.64 (14.38-19.63) for spring, respectively) were found. Interestingly, no changes in Th2 cell subsets were found. Post-exercise and recovery changes in IL-6, IL-8, TNF-alpha and IL-10 were also observed. Conclusions: It seems that the given effort in the progressive test induced an anabolic effect being related not only with cytokine profile but also with CD4+ T cells' differentiation and peripheral distribution. PMID- 30429676 TI - Evaluation of the analytical performances of the Cobas c513 analyser for HbA1c assay. AB - Introduction: Haemoglobin A1c (HbA1c) is considered to be the gold standard for the follow-up of glycaemic control in patients with diabetes mellitus and is also a diagnostic tool. Accordingly, reliable and efficient methods must be used for its quantification. Roche Diagnostics have recently adapted the Tina-quant(r) HbA1c Third Generation immunoassay on a fully dedicated analyser, the Cobas c513, which allows a high throughput of up to 400 samples per hour. The present article deals with the evaluation of the analytical performances of this system which has been recently introduced to the market. Materials and methods: Precision, comparison with two ion-exchange high-performance liquid chromatography (HPLC) methods (Variant II and D-100 systems, BioRad Laboratories) using Passing Bablok and Bland-Altman analyses, accuracy and interference of the most frequent haemoglobin (Hb) variants on HbA1c measurement were evaluated. Results: Precision was high, with coefficients of variation lower than 1.1% (HbA1c values expressed in National Glycohemoglobin Standardization Program units, 1.7% for values expressed in International Federation of Clinical Chemistry and Laboratory Medicine [IFCC] units). The comparison study showed similar results with the two HPLC systems. The analysis of samples with IFCC-assigned values showed high methodological accuracy. Finally, no interference of bilirubin, triglycerides and common Hb variants (Hb AC, AD, AE, AS) was observed. Conclusions: This evaluation showed that the analytical performance of the Cobas c513 analyser for HbA1c assay makes it suitable for a routine use in clinical chemistry laboratories. PMID- 30429677 TI - Reducing test request for anti-thyroglobulin and anti-thyroid peroxidase antibodies: trends before and after interventions based on rejection rules and profile management. AB - Introduction: The objective of this study was to identify trends in requests for anti-thyroid peroxidase antibodies (TPOab) and anti-thyroglobulin antibodies (TGab) tests before and after applying set of interventions based on rejection rules and profile management. Materials and methods: Trend analysis was made at semester time intervals (from May-October 2010 to May-October 2017), before and after the intervention semester (May-October 2016). Number of tests (N) TPOab and TGab / 1000 total requests based on total N of both tests and total N of biochemical analysis laboratory requests, was calculated. To find out where the interventions had more impact we distinguished N of requests between Primary Care (PC) and Specialized Care (SC). A joinpoint regression analysis was used to determine time segments and time points in these indicators where the trend changed. Results: Trend analysis of the request of TPOab and TGab showed two clearly differentiated trend lines with a statistically significant Joinpoint (P < 0.001) with an increase in each semester from May 2010 of 7.4% and 7.5% respectively, to the semester of the interventions where there was a decrease of 45% and - 61% located mainly in PC. Trend analysis in SC setting did not show any Joinpoint and any trend line. Conclusions: Results showed that applied interventions enabled change of trend for TPOab and TGab test requests, especially in PC where the interventions proved to be the most successful. PMID- 30429678 TI - Calcium-stimulated calcitonin - The "new standard" in the diagnosis of thyroid C cell disease - clinically relevant gender-specific cut-off levels for an "old test". AB - Introduction: Pentagastrin (Pg) stimulated calcitonin (sCT) was used to enhance accuracy in medullary thyroid cancer (MTC) diagnosis. As it is now unavailable, calcium (Ca) has been recommended as an alternative. The aim of this study was to define gender-specific cut-off values to predict MTC in patients with elevated basal CT (bCT) following Pg-sCT and Ca-sCT stimulation and to compare the time courses of CT release during stimulation. Materials and methods: The stimulation tests were applied in 62 consecutive patients with thyroid nodules. Basal calcitonin was measured by chemiluminescent immunometric assay. All patients underwent thyroidectomy and bilateral central neck dissection. C-cell pathology was confirmed by histological and immunohistochemical evaluation. Results: In 39 (0.63) patients MTC was documented while isolated C-cell hyperplasia (CCH) was identified in 23 (0.37) patients. Medullary thyroid cancer was predicted in males with bCT values > 43 pg/mL or sCT concentrations > 470 pg/mL (Pg-sCT) or > 1500 pg/mL (Ca-sCT), and in females with bCT concentrations > 23 pg/mL or sCT concentrations > 200 pg/mL (Pg-sCT) or > 780 pg/mL (Ca-sCT), respectively. Pg-sCT correctly predicted MTC in 16 (0.66) compared to 13 (0.54) after Ca-sCT in males and in 12 (0.80) compared to 11 (0.73) in females; without statistical significance. In patients with CCH or low tumor burden, there was a tendency of faster CT release after Ca stimulation (CT peak after 3min in > 60%) compared to patients with advanced MTC (CT peak after 3min in < 10%). Conclusions: Using gender-specific cut-off values, Ca could replace Pg to predict MTC with similar diagnostic power. PMID- 30429679 TI - A collaborative study by the Working Group on Hemostasis and Thrombosis of the Italian Society of Clinical Biochemistry and Clinical Molecular Biology (SIBioC) on the interference of haemolysis on five routine blood coagulation tests by evaluation of 269 paired haemolysed/non-haemolysed samples. AB - Introduction: Haemolysis is the leading cause of sample rejection in laboratory haemostasis. Most studies focused on artificially haemolysed samples. The aim of this study was a prospective assessment of spontaneous haemolysis on haemostasis tests, by comparing results of haemolysed (H) versus new, non-haemolysed (NH) specimens, collected within 4hrs. As new coagulometers can identify interfering substances, visual assessment of haemolysis was also compared with instrumental haemolysis index and stratified in subclasses. Materials and methods: Two hundred and sixty nine paired samples were collected and analysed using ACL TOP750-CTS (Instrumentation Laboratory, Bedford, USA), for prothrombin time (PT), activated partial thromboplastin time (aPTT), D-Dimer (DD), fibrinogen (Fib) and antithrombin (AT). Bias between H and NH was calculated and compared with the respective critical difference (CD). Results: Mean bias was - 0.1 s for PT (P = 0.057), - 1.1 s for aPTT (P < 0.001), 1025 ng/mL for DD (P < 0.001), - 0.04 g/L for Fib (P = 0.258) and 1.4% for AT (P = 0.013). Bias exceeding the CD varied according to the method, with larger differences for aPTT (36.1%) and DD (17.1%) and < 8% for PT, Fib and AT. No correlation emerged between free haemoglobin values and difference in haemostasis tests in H and NH samples for any tests. Moderate/severe haemolysis involved > 95% of samples. The agreement between visual assessment and instrumental evaluation of haemolysis was 0.62. Conclusion: Spurious haemolysis deeply influences aPTT and DD, and to a lesser extent AT and Fib. Prothrombin time seems only slightly influenced, suggesting that PT can be accepted also in haemolysed samples. Although a good inter-observer correlation of haemolysis evaluation was found, the instrumental assessment of haemolysis seems recommendable. PMID- 30429680 TI - The diagnostic accuracy of clinical and laboratory parameters in the diagnosis of acute appendicitis in the adult emergency department population - a case control pilot study. AB - Introduction: The evaluation of patients with suspected appendicitis strives to identify all patients with presenting symptoms while minimizing negative appendectomy rate. The aim of the study was to identify the optimal combination of clinical and laboratory parameters that should facilitate the emergency department surgeon's definite decision. Materials and methods: The study group comprised 120 patients with suspicion of acute appendicitis (AA). In 60 patients the AA diagnosis was confirmed intraoperatively and by histological analysis. Clinical parameters included: appetite, vomiting, diarrhea, dysuria, signs of localized peritonitis and pain migration. Measured laboratory parameters were: C reactive protein (CRP), complete blood count (CBC) and the urine test strip. Results: The control group of patients were more likely to present following symptoms: no changes in appetite (P < 0.001), diarrhea (P = 0.009) and dysuria (P = 0.047). CRP and white blood cell count (WBC) were significantly higher in the group with confirmed AA compared to the control group (44.7 vs. 6.6, and 13.6 +/- 3.9 vs. 9.0 +/- 3.4, respectively; P < 0.001). The multivariate logistic regression analysis identified lack of appetite (P = 0.013), absence of diarrhea (P = 0.004), and positive finding of signs of localized peritonitis (P = 0.013), as well as WBCs (P < 0.001) and negative urine test strip results (P = 0.009) as statistically significant predictors of AA. The highest percentage of correctly classified cases (82%) was achieved by combination of common clinical exam and basic inexpensive laboratory parameters (WBCs and urine test strip). Conclusions: Acute appendicitis in the emergency setting may be successfully ruled in based on elevated WBCs and negative urine test strip in combination with signs of localized peritonitis, lack of appetite and absence of diarrhea. Since CRP did not contribute to the overall diagnostic accuracy, its use in AA diagnostic protocols is of no value. PMID- 30429681 TI - Metabolic follow-up of a Croatian patient with gyrate atrophy and a new mutation in the OAT gene: a case report. AB - Gyrate atrophy (GA) of the choroid and retina is a rare autosomal recessive disorder that occurs due to deficiency of the mitochondrial enzyme ornithine aminotransferase (OAT). Hyperornithinemia causes degeneration of the retina with symptoms like myopia, reduced night vision and progressive vision loss. Our patient is a 10-year-old girl with impaired vision and strabismus. As part of the metabolic work-up, plasma amino acid analysis revealed significantly increased concentration of ornithine (1039 MUmol/L; reference interval 20 - 155 MUmol/L). Molecular genetic analysis revealed homozygous mutation in exon 7 of the OAT gene that has not been reported previously (c.868_870delCTT p.(Leu290del)). This in frame deletion was predicted to be deleterious by in silico software analysis. Our patient was treated with pyridoxine (vitamin B6 in a dose of 2 x 100 mg/day), low-protein diet (0.6 g/kg/day) and L-lysine supplementation which resulted in a significant reduction in plasma ornithine concentrations to 53% of the initial concentration and the ophthalmologic findings showed significant improvement. We conclude that low protein diet and lysine supplementation can lead to long-term reduction in plasma ornithine concentrations and, if started at an early age, notably slow the progression of retinal function loss in patients with GA. The effect of therapy can be reliably monitored by periodical measurement of plasma ornithine concentration. To our knowledge, this is the first report of OAT deficiency in Croatia. PMID- 30429682 TI - Biotin and high-sensitivity cardiac troponin T assay. AB - Introduction: The high-sensitivity cardiac troponin T assay of Roche Diagnostics is known to have interference with high concentrations of biotin as this assay uses biotin-streptavidin binding as detection method. As studies so far have not shown if different biotin concentrations could have diverse influence on various troponin concentrations and whether interference could be removed by available protocol within corresponding turnaround time we aimed to investigate it. Materials and methods: Plasma samples were spiked with different concentration of biotin solution. Troponin T concentrations were tested on a Roche Cobas(r) 8000 module 602 analyser. Final concentrations of biotin and troponin T were 50, 100, 500 and 1000 MUg/L and 18, 59, 201 and 6423 ng/L, respectively. Impact of different incubation times following biotin neutralization protocol described by Piketty et al. was also tested. Results: We observed a mean of negative biases of 24, 56, 97, and 98% of the troponin T expected value at biotin concentrations of 50, 100, 500, 1000 MUg/L. Neutralization protocol was applied on the sample with initial concentration of TnT of 59 ng/L at a biotin concentration of 1000 MUg/L. Same results across different incubation times from 60 to 0 minutes were obtained (mean value 56.8 ng/L, coefficient of variation of 1.31%). We demonstrated that neutralization process had a dilution effect of the troponin concentration (loss of 4.5% to 9.6% of initial troponin value). Conclusions: Biotin interference is not dependent of initial troponin value. Interference could be successfully neutralized within a time frame compatible with emergency but results still should be carefully interpreted due to possible dilution effect. PMID- 30429683 TI - Effect of cold agglutinins on red blood cell parameters in a trauma patient: a case report. AB - The presence of cold agglutinins (CAs) in samples intended for complete blood count (CBC) using automated haematology analysers might cause serious preanalytical errors. In this report we describe the case of a 90-year old female patient admitted to the Emergency department following trauma injuries. A blood testing on admission revealed surprisingly low red blood cell count (0.99 x 1012/L), low haematocrit (0.102 L/L) which did not correlate with haemoglobin concentration (100 g/L), and high erythrocytes indices (mean corpuscular haemoglobin, 101 pg; mean corpuscular haemoglobin concentration, 980 g/L). In the second sample, after repeated collection, almost equal results were observed. Blood smear examination under the microscope revealed clusters of erythrocytes. Cold agglutinins presence was suspected and, in order to get valid results, sample was warmed to 37 degrees C. Correction of CBC was observed. Furthermore, we performed some additional analysis to confirm the presence of CAs in this patient. The aim of this report was to present the laboratory findings in a case of CAs and propose a laboratory procedure for whole blood samples with suspected CAs. PMID- 30429685 TI - Geriatric Depression in Family Medicine. AB - Introduction: Elderly persons often suffer from depression, without anyone around them noticing. Depression is more common at physically ill elderly person then at their physically healthy contemporary. It is important mental health problem of developed society, because it is still faintly revealed thus insufficiently treated. Objective: To explore the existence of geriatric depression in elderly persons living on their own and those who live in family environment. Materials and methods: The research included 200 elderly respondents, experimental group made of elderly persons (>65 years) living alone. Control group included elderly persons living in a family environment. Universal geriatric questionnaire was made for this research. To assess the presence of depression at respondents we used "The scale of geriatric depression". Results: The average age (+/-SD) was 75,4+/-6,2 years in the experimental group, while in the control group the average age was 74,9+/-5,6 years. In the experimental group there is significantly larger number of elderly persons that are neglected (p=0,001). Elderly respondents surrounded by loneliness are more depressive than elderly living in the family environment. Statistically geriatric depression is significantly connected with inability for everyday activities, with decreased result of cognitive abilities and indicated result of dementia (P=0.001). Conclusion: Depression is an important mental health problem of the developed society, because it is still faintly discovered and by that insufficiently treated. Organizing approach to different aspects of geriatric health, doctors of the primary protection can improve care of their elderly patients. PMID- 30429686 TI - Screening for Latent Tuberculosis Infection in Patients with Autoimmune Diseases Before Initiating TNF-alpha Inhibitors Therapy. AB - Introduction: QFT-GIT is more sensitive than TST in patients under immunosuppressive therapy, but TST detects more cases of LTBI. TST remains an inexpensive test worldwide, which does not need laboratory equipment. Material and Methods: Overall, 457 patients having autoimmune diseases were referred. Of those referred, 158 patients were screened with QFT-GIT and TST. No patient in the present study was known to be HIV positive, or had a history of tuberculosis contact the last year. Additionally, neither of the two methods distinguish latent from active TB, and neither one is better at recognizing patients with autoimmune diseases who could avail from preventive chemoprophylaxis. Results: QFT-GIT is more sensitive than TST in patients under immunosuppressive therapy, but TST detects more cases of LTBI. TST remains an inexpensive test worldwide, which does not need laboratory equipment. Conclusion: Since the literature for the economic evaluation of LTBI screening has not clearly defined which test is ultimately more cost-effective, low income countries like Greece should continue using TST as the primary method for diagnosis of LTBI. PMID- 30429687 TI - An Instrument for Rating Quality of Life Related to Sore Throat in Patients Suffering from Acute Pharyngitis or Tonsillitis. AB - Introduction: Quality of life in patients with acute pharyngitis or tonsillitis is significantly lower than in healthy persons, and it should be taken into account when efficacy of new therapeutic options is investigated. Objective: The aim of this study was to develop and validate a reliable instrument that can measure quality of life in adult outpatients with sore throat caused by acute pharyngitis or acute tonsillitis. Method: The study was of a cross-sectional type, and assessed reliability and validity of newly developed questionnaire for measurement of quality of life in adult outpatients with sore throat (STQoL) caused by acute pharyngitis or acute tonsillitis. It was conducted on a sample of 282 patients, with mean age 39.0 +/- 14.8 years, male/female ratio 104/178 (36.9%/63.1%). Results: Final version of the STQoL scale with 21 items showed excellent reliability, with Cronbach's alpha 0.949. It was temporally stable, and both divergent and convergent validity tests had good results. Factorial analysis revealed three domains, Social/psychic aspects, Physical aspects and Environmental aspects of sore throat related quality of life. Conclusions: The STQoL scale is reliable and valid specific instrument for measuring sore throat related quality of life, which is an important treatment outcome in patients with acute pharyngitis or tonsillitis. PMID- 30429689 TI - Assessing the Understanding of Pediatric-Oriented Medication Education Materials Versus Standard Available Education Materials. AB - OBJECTIVES: The objective of this study was to determine if education material targeting children would improve understanding of medication indication, administration, and common side effects in pediatric subjects. METHODS: This cross-sectional pilot study included students 7 to 11 years old from a suburban elementary school. Study participants were read either the US Food and Drug Administration-approved adult medication leaflet or a pediatric medication leaflet created at a first-grade reading level for levetiracetam (Keppra, UCB, Inc, Atlanta, GA). Students were asked a set of standardized survey questions to evaluate comprehension of side effects, medication indication, dosing frequency, administration, and overall impression of the leaflet. RESULTS: Fifty-eight children were included. Fifty percent of the children were male, 79% were Caucasian, and the average age was 9 years. There was no statistical difference for demographics in the adult leaflet versus the pediatric leaflet group. Children correctly stated the indication for the medication in 30% of participants (9/30) in the adult leaflet group and 79% of participants (22/28) in the pediatric leaflet group, p = 0.002. The administration frequency question was answered correctly in 93% of the pediatric leaflet group (26/28) as compared to 73% in the adult leaflet group (22/30), p = 0.05. For questions about side effects and how to administer the medication, there was no difference between the groups. The responses regarding readability and understanding of the leaflets were significantly different in the pediatric leaflet group compared to the adult leaflet group, p = 0.001 and p = 0.001, respectively. CONCLUSIONS: Leaflets designed for pediatric patients resulted in an improvement in the understanding of the indication for levetiracetam. PMID- 30429688 TI - Evolving Pharmacotherapeutic Strategies for Type 1 Diabetes Mellitus. AB - Despite pharmacotherapeutic advancements in the management of type 1 diabetes mellitus during the past several decades, patients struggle to achieve glycemic goals. Additionally, hypoglycemia, especially in extremes of age, decreases quality of life. The lack of optimal glycemic control and risk for hypoglycemia are multifactorial. Nevertheless, endeavors aiming to develop pharmacotherapeutic options with enhanced pharmacokinetic, pharmacodynamic, and clinical profiles continue. This review article discusses recent ventures in 3 categories of insulin, non-insulin, and glucagon products. PMID- 30429690 TI - Poractant Alfa Versus Beractant for Neonatal Respiratory Distress Syndrome: A Retrospective Cost Analysis. AB - OBJECTIVES: The objectives of this study were to determine the average medication cost per patient of poractant alfa and beractant, and to compare the outcomes of treatment with these agents. METHODS: We conducted a retrospective, observational, cohort study of patients who received surfactant, before and after an institutional formulary change from beractant to poractant alfa. The primary outcome was the average medication cost per case. Secondary measures were clinical outcomes, including duration of respiratory support, length of hospital stay, and the occurrence of complications. RESULTS: A total of 114 patients were enrolled; 38 were treated with poractant alfa and 76 patients were treated with beractant. Baseline characteristics were similar between groups. The average medication cost per patient was $1756.44 +/- $1030.06 and $1329.78 +/- $705.64 for poractant alfa and beractant, respectively (p = 0.011). Patients treated with poractant alfa had a shorter length of stay (45.0 +/- 30.5 days) than patients treated with beractant (65.1 +/- 37.1 days) (p = 0.010). Rates of pneumothoraces, pulmonary hemorrhage, necrotizing enterocolitis, intraventricular hemorrhage, and mortality did not differ significantly between groups. CONCLUSIONS: We found an unanticipated increase in drug cost with poractant alfa compared to beractant. PMID- 30429691 TI - Pediatric Antiviral Stewardship: Defining the Potential Role of Ribavirin in Respiratory Syncytial Virus-Associated Lower Respiratory Illness. AB - OBJECTIVES: Although no longer included in the American Academy of Pediatrics guideline, ribavirin was shown to be beneficial in a subset of adult patients with severe respiratory syncytial virus (RSV)-associated bronchiolitis. This study aimed to investigate risk factors for progression to severe acute respiratory tract infections in hospitalized pediatric patients with RSV associated bronchiolitis to identify which patients may benefit from inhaled ribavirin therapy, despite its substantial cost, diffcult administration, and potential complications. METHODS: Patients were identified by ICD-9 codes for RSV bronchiolitis and were only included if they had a confirmed positive result for RSV via polymerase chain reaction for detection and typing of respiratory viruses. Patient characteristics, including underlying conditions and comorbidities, were analyzed for the risk of severe acute respiratory tract infection. RESULTS: A total of 299 patients were included in the study population. Ninety-six patients (32%) were admitted to the pediatric intensive care unit, and almost half of those patients (46%) required mechanical ventilation. Weight and presence of atrial septal defect were the only factors significantly associated with the need for mechanical ventilation, as identified by univariate analysis. Two patients required extracorporeal membrane oxygenation (ECMO), and a total of 5 patients, including one who received ECMO, died with RSV infection as the primary cause. Of these patients, all were less than 1 year of age. Two had a history of prematurity; however, no variables were associated with mortality. CONCLUSIONS: Given the side effect profile and expense of ribavirin therapy, it is prudent to limit use to patients at risk for significant morbidity and mortality from RSV disease. Because we were unable to identify patients who would most likely benefit from ribavirin antiviral therapy, we cannot recommend the routine use of ribavirin to prevent mechanical ventilation, ECMO, or death from RSV bronchiolitis in our institution. PMID- 30429693 TI - Azithromycin Induces Migrating Motor Complexes in Pediatric Patients Undergoing Antroduodenal Motility Studies. AB - OBJECTIVE: Erythromycin (ERY) is used in the treatment of gastroparesis; however, this medication is associated with serious side effects, such as cardiac arrhythmias and consequent cardiorespiratory arrest. Azithromycin (AZM) has been suggested as an alternative to ERY as a result of its improved safety profile. Intravenous ERY (1 mg/kg) is administered during antroduodenal motility studies to induce migrating motor complexes (MMCs), the presence or absence of which helps diagnose motility disorders like gastroparesis and gastrointestinal dysmotility. However, there are no pediatric studies comparing the effects of AZM and ERY on antroduodenal pressure profiles. The goal of this study is to determine if AZM is comparable in inducing MMCs in pediatric patients undergoing antroduodenal motility studies. METHODS: We performed a retrospective chart analysis of gastric and small bowel manometric data in 2 adolescent patients, both age 15 years, who were given AZM (1 mg/kg) during antroduodenal motility studies. The pressure profiles obtained during motility studies were compared to those of patients of similar age and symptomology who were given the standard intravenous ERY dose during motility studies. We then compared the total duration of effect, mean amplitude of contractions, number of cycles per minute, and duration of highest antral and duodenal contractions. RESULTS: Intravenous AZM induces migrating motor contractions in the stomach followed by contractions in the small intestine. The mean amplitude of the stomach contractions was 259 mm Hg in patients who received AZM vs 241 mm Hg in patients who received ERY. The mean amplitude of small intestinal MMCs was 68 mm Hg in patients who received AZI and 72 mm Hg in patients who received ERY. Additionally, the frequency and duration of stomach and small intestinal contractions were also similar in the 2 groups. CONCLUSIONS: Intravenous AZM has similar prokinetic effects to intravenous ERY. Our study suggests that AZM is a suitable alternative to ERY in inducing MMCs without the concerning side effects related to ERY and may potentially be used in the management of gastroparesis and other small bowel motility disorders. However, larger prospective studies are required to better understand the long term efficacy of AZM. PMID- 30429692 TI - Relationship of Pulmonary Outcomes, Microbiology, and Serum Antibiotic Concentrations in Cystic Fibrosis Patients. AB - OBJECTIVES: To determine the frequency of subtherapeutic exposure to intravenously administered beta-lactam antibiotics in a cohort of cystic fibrosis (CF) patients who were treated for a pulmonary exacerbation, and its impact on pulmonary function. METHODS: Nineteen CF patients between the ages of 5 and 21 years treated at Children's National Health System for a pulmonary exacerbation were followed between March 2015 and August 2016 in a prospective, longitudinal study. Pharmacokinetic modeling and minimum inhibitory concentrations (MICs) of the involved pathogens were used to determine therapeutic or subtherapeutic beta lactam antibiotic exposure based on the time the antibiotic concentration was above the MIC. Clinical outcomes were measured by spirometry values. RESULTS: The 19 participants were treated with a total of 29 courses of antibiotics. The most common beta-lactam antibiotics used in a treatment course were ceftazidime (62%) and meropenem (45%). There was no difference in age, CF genotype, or creatinine clearance between the 9 participants (47%) who reached therapeutic concentrations versus the 10 (53%) who did not. Those who achieved sufficiently high antibiotic exposure had more significant improvement of their pulmonary function tests. CONCLUSIONS: We found that sufficient antibiotic exposure during treatment of CF pulmonary exacerbations was associated with improved pulmonary function. Moreover, it was impossible to predict, solely from the dosing regimen used, which patients were going to reach therapeutic beta-lactam antibiotic serum concentrations. This suggests that CF patients may benefit from closer monitoring of their beta-lactam exposure and bacterial MIC for optimal clinical outcomes. PMID- 30429694 TI - Use of Intravenous Acetaminophen in Children for Analgesia After Spinal Fusion Surgery: A Randomized Clinical Trial. AB - OBJECTIVES: Opioid pharmacotherapy is the cornerstone of postoperative analgesia. Despite its effectiveness, it has a variety of potential adverse effects. Therefore, a multimodal approach with non-opioid analgesics would be optimal. The aim of this study was to determine if intravenous (IV) acetaminophen would reduce opioid requirements and improve clinical outcomes in children after surgery. METHODS: A single-center, randomized, double-blind study was conducted in 57 children (10-18 years old) undergoing posterior spine fusion surgery between July 2011 to May 2014. All subjects received either acetaminophen or placebo at the end of surgery, followed by repeated doses every 6 hours for a total of 8 doses. RESULTS: In the first 24 postoperative hours, the average opioid consumption was lower for the active group compared with the placebo group (p = 0.02). The total unadjusted time to patient controlled analgesia (PCA) discontinuation was also longer in the placebo group than the active group (90 hours vs. 73 hours, p = 0.02); however, this was not statistically significant after normalizing for body weight. Additionally, time to first solid intake was longer without the use of acetaminophen (69 hours vs. 49 hours, p = 0.01). CONCLUSIONS: Postoperative use of IV acetaminophen was associated with earlier time to diet advancement and discontinuation of IV analgesics and may result in lower opioid consumption. PMID- 30429695 TI - Effectiveness of Antimicrobial Preservation of Extemporaneous Diluted Simple Syrup Vehicles for Pediatrics. AB - OBJECTIVES: Extemporaneous or magistral formulation of active pharmaceutical ingredients using traditional compounding techniques is a common practice when no commercial form is available for pediatrics. For this vulnerable group of patients, the formulation must be prepared with the minimum quantity and lowest proportion of excipients approved for pediatrics, avoiding the use of preservatives. Often the vehicles used for these preparations are dilutions of simple syrup with water. The objective of this study is to assess the effectiveness of antimicrobial preservation in simple syrup diluted with aqua conservans (conserved water), without propylene glycol or with a reduced proportion of parabens. METHODS: The European Pharmacopoeia test of efficacy of antimicrobial preservation was applied to 5 trial vehicles prepared with simple syrup diluted with water. RESULTS: Simple syrup is stable during 14 days. Vehicles prepared with simple syrup diluted with purified water did not meet the microbiological quality criteria, but when they are diluted with water that incorporates propylene glycol and parabens (aqua conservans), then they meet the criteria. In addition, if the water is prepared with parabens and without propylene glycol, the criteria for the dilution are met. Nevertheless, if the dilution is done with water prepared with an insufficient proportion of parabens to act as preservatives, the dilution does not meet the pharmacopoeia microbiological criteria. CONCLUSIONS: Dilution of simple syrup (50:50 v/v) to prepare a vehicle for extemporaneous or magistral preparation is microbiologically safe when water with methylparaben and propylparaben is used in a proportion of 0.08% and 0.02% (w/w), respectively, avoiding the use of propylene glycol as a solvent and thus its toxic effects in pediatrics. PMID- 30429696 TI - Assessment of Outcomes With a Sedation Protocol During Laser Photocoagulation in Preterm Infants With Retinopathy of Prematurity. AB - OBJECTIVES: To evaluate the success of a sedation protocol of fentanyl and midazolam infusions for infants undergoing laser photocoagulation for retinopathy of prematurity. METHODS: This retrospective study included infants receiving a sedation protocol for laser photocoagulation during a 4-year period. The primary objective was protocol success, defined as completion without interruption, absence of protocol dose deviations, and absence of interventions. Secondary objectives compared outcomes between those with and without opioid/benzodiazepine exposure. A logistic regression was used to assess the effect of prior opioid/benzodiazepine exposure on requirement for fentanyl infusion increases. RESULTS: Twenty-six infants were included. Seven (26.9%) had protocol success. Sixteen (61.5%) had protocol success, excluding dose deviations. Seventeen (65.4%) experienced >=1 cardiopulmonary adverse events. Photocoagulation was completed in all cases. CONCLUSIONS: Most achieved protocol success, when eliminating dosing deviations. These data indicate that flexibility is needed in fentanyl and midazolam infusion titration, based on clinical response. PMID- 30429697 TI - Severe Neuropathic Pain With Concomitant Administration of Vincristine and Posaconazole. AB - Vincristine is a chemotherapeutic agent with a potential toxicity of sensorimotor peripheral neuropathy. Patients receiving chemotherapy are in an immunocompromised state and may require antifungal agents. Triazole antifungals are known inhibitors of cytochrome P450 (CYP) enzymes. Vincristine is a known CYP3A4 and CYP3A5 substrate, and concomitant administration with fluconazole or voriconazole has been reported to increase vincristine toxicity and peripheral neuropathy, but there is limited literature on posaconazole in this regard. This 5-year-old girl with pre-B-cell acute lymphoblastic leukemia received vincristine while receiving posaconazole for a mucormycosis infection and developed unexpectedly severe peripheral neuropathy. After recovery, the child continued on mucormycosis prophylaxis with posaconazole with instructions to hold for 2 days before and on the day of vincristine administration. This case illustrates the potentiating effect that posaconazole had on vincristine-associated neurotoxicity, and our approach to mitigating that negative interaction. PMID- 30429698 TI - Craniofacial and cutaneous findings in Noonan, Costello and LEOPARD syndromes. AB - Noonan, Costello and LEOPARD syndromes belong to a family of cardiofaciocutaneous disorders and share common genetic traits. As they are associated with a germline mutation in genes encoding proteins involved in RAS/MAPK, patients suffering from these syndromes are at a greater risk of cancer and abnormal myelopoiesis in infancy. Patients with cardio faciocutaneous syndromes share some clinically overlapping syndromes, therefore differential diagnosis can be problematic. In this paper we aim at demonstrating distinctive craniofacial and cutaneous manifestations of Noonan, Costello and LEOPARD syndromes which can be useful for clinicians who aim at treatment of children with rare diseases. PMID- 30429699 TI - Cellulite: a cosmetic or systemic issue? Contemporary views on the etiopathogenesis of cellulite. AB - Cellulite (also known as gynoid lipodystrophy or orange peel syndrome) is one of the most common lipodystrophy syndromes, which affects millions of post adolescent women. Cellulite is manifested by topographic disorders of subcutaneous tissue such as nodules, edema, and abnormal fibrosis. It is located mainly on the pelvic area, especially on the buttocks. Its pathogenesis is complexed and unclear. There are several theories about its pathophysiology. Hormonal disorders, endothelial dysfunction and genetic predispositions are taken under consideration. PMID- 30429700 TI - Male and female genital lichen sclerosus. Clinical and functional classification criteria. AB - Introduction: Lichen sclerosus (LS) is a chronic inflammatory disease affecting mainly the genital mucous membranes in both sexes. In the past, different terms were used to describe the disease, rendering a unique and specific clinical classification impossible. Aim: New therapeutic approaches are being defined, which may contribute to a proper clinical management, however, a stage classification is essential to better define appropriate treatment for every stage of the disease. Material and methods: One hundred and fifteen patients (50 women and 65 men) with a diagnosis of LS were enrolled between January 2014 and September 2016. All patients underwent cutaneous biopsy to confirm the clinical diagnosis of LS. Clinical and symptomatological parameters were used in order to put the patients into the correct stage of LS. The Dermatology Life Quality Index (DLQI) was used to classify patients based on subjective symptoms. Different cutaneous alterations and structural modifications of the genital mucosa were also taken into consideration in order to assign every patient to a specific stage. Conclusions: Lichen sclerosus is clinically described differently in females and in males and every form of LS is put into one of two stages according to the degree of severity: early and late stages. Within the clinical practice, it is useful to screen patients for groups of early or late forms of the disease in order to obtain a uniform subdivision of patients: those who may benefit from localized treatments, require a systemic drug and must undergo physical treatments (surgical, stem cells infiltrations). PMID- 30429701 TI - Comparison of ultrasound therapy and radial shock wave therapy in the treatment of venous leg ulcers - clinical, pilot study. AB - Introduction: Venous insufficiency and venous leg ulcers each year affect more and more people, especially in developed countries. The challenge of our time is to find an effective method of treating venous leg ulcers, which will further shorten treatment time and reduce the cost of treatment. Aim: To compare the effects of treating venous leg ulcers using ultrasound therapy, radial shock wave therapy and standard care. Material and methods: Group A consisted of 17 patients. Patients were treated with ultrasound therapy US power density 0.5 W/cm2, pulsed wave with a duty cycle of 1/5, and 1 MHz frequency. Group B consisted of 17 patients. Patients were treated with the radial shock wave R-ESWT using surface energy density 0.17 mJ/mm2, 100 impulses/cm2, frequency of 5 Hz and a pressure of 0.2 MPa. Group C (control group) consisted of 17 patients. Patients in this group received standard care: gauze dressing saturated in 0.9% sodium chloride and elastic bandages changed daily for 4 weeks. Results: Ultrasound therapy with 1 MHz and energy power density 0.5 W/cm2 for 4 weeks resulted in an average reduction of 68% of the area of ulceration. We used for venous leg ulcers 4-week treatment with radial shock wave therapy resulting in a 38% mean percentage reduction of the ulceration area. Standard care reduces the area of ulceration by only 16%. Conclusions: The use of ultrasound therapy for the treatment of venous leg ulcers is more effective than the use of radial shock wave therapy or standard care alone. PMID- 30429702 TI - Sputum interleukin-25 correlates with asthma severity: a preliminary study. AB - Introduction: Interleukin 25 is an epithelial-derived cytokine associated with allergic Th2 inflammation. However, little is known about the role of IL-25 in different asthma phenotypes and its relationship with disease severity. Aim: To evaluate and compare the mRNA and protein expression of IL-25 in patients with mild-to moderate/severe asthma and cough variant asthma (CVA). Material and methods: Thirty-eight patients with stable asthma (11 patients with mild-to moderate asthma, 14 patients with severe asthma and 13 patients with CVA) and 14 control subjects were enrolled. IL-25 protein concentration was measured in induced sputum (IS) supernatants by ELISA and IL-25 mRNA expression was evaluated in IS cells by real time PCR. Results: No differences in IS IL-25 mRNA and IL-25 concentration between controls and the whole asthma group were found. In the detailed analysis, a lower IL-25 mRNA expression in sputum cells was observed in severe asthma compared to CVA and controls. IL-25 protein concentration in sputum supernatants was elevated in patients with severe asthma compared to controls, CVA and mild-to-moderate asthma. A sputum IL-25 level was increased in atopic vs. non-atopic asthma patients. The elevated IL-25 mRNA expression and protein concentration was associated with a lower eosinophil and higher neutrophil percentage in asthmatic airways. Conclusions: Our results suggest that IL-25 is particularly associated with severe asthma. The relationship between IL-25 and neutrophilic airway inflammation suggests the pleiotropic role of IL-25 in the immune response in this disease. PMID- 30429703 TI - Morphea and antithyroid antibodies. AB - Introduction: Morphea, also known as localized scleroderma, is an autoimmune skin disease which is characterized by excessive accumulation of collagen that leads to the thickening of the dermis and subcutaneous tissue. There is an unclear relationship between morphea and other autoimmune diseases, especially related to the thyroid gland. Aim: To determine the occurrence of increased antithyroid antibodies in patients with morphea in relation to the clinical manifestations of the disease. Material and methods: Forty-two Caucasian patients with different forms of morphea were included into the study. To determine the thyroid status, thyrotropin (TSH), anti-peroxidase antibodies (TPO-Ab), anti-thyroglobulin antibodies (Tg-Ab) were evaluated with the use of the electrochemiluminescence method and TSH receptor autoantibodies (TRAb) - with the use of the radioimmunoassay method. Results: Increased levels of antithyroid antibodies were observed in 6 cases in relation to TPO-Ab (14.3%), in 4 cases in relation to of Tg-Ab (9.5%) and in 1 patient in relation to TRAb (2.3%). There was no difference in the level of antithyroid antibodies between circumscribed and generalized forms of morphea. Conclusions: Although morphea is an autoimmune disease, it does not seem to be associated with increased prevalence of positive antithyroid antibodies. We conclude that there is no need to perform routine laboratory tests for thyroid disorders in patients with morphea. PMID- 30429704 TI - Evaluation of quantitative changes in regulatory T cells in peripheral blood of kidney transplant recipients with skin cancer after conversion to mTOR inhibitors. AB - Introduction: Immunosuppressive therapy, necessary for graft survival, has its clinical consequences with an increased risk of developing malignancies being one of them. It seems that the maintenance of a proper balance between cytotoxic and regulatory activity of the immune system may prevent graft rejection, and with a lower risk of cancer. Aim: To assess the quantitative changes in regulatory T cells (Tregs) in peripheral blood of kidney transplant recipients with post transplantation skin neoplasm after conversion to mTOR inhibitors (mTORi) and to assess the incidence of secondary skin cancer in that group of patients. Material and methods: Fourteen patients with post-transplant cutaneous malignancies converted to mTORi were included into the study. The control group consisted of eighteen patients maintained on immunosuppressive regimens without mTORi. The level of Tregs with a phenotype defined as CD4lowCD25high was measured before, and 6 months after, mTORi introduction. Results: In all cases, 6 months after conversion, a significant decrease in the ratio of CD4+CD25+ to CD4lowCD25high from 6.52 to 4.29 was detected (p = 0.035). One patient converted to mTORi developed subsequent skin cancer, while in the control group, subsequent skin cancer was recognized in eight patients. Moreover, introducing mTORi significantly improved progression-free survival in this group of patients (p = 0.016). Conclusions: Introducing mTORi to the immunosuppressive regimen resulted in an increase in the number of regulatory cells without increasing the incidence of secondary skin cancer in the investigated group of patients. PMID- 30429705 TI - HIV infection and sex in sex-on-premises venues are associated with a higher risk of syphilis reinfection among men who have sex with men. AB - Introduction: Recent outbreaks of syphilis occurred predominantly in men who have sex with men (MSM). A significant proportion of syphilis cases occur in MSM who had more than one episode of syphilis. This group may play an important role in syphilis transmission. Aim: To identify factors associated with the risk of syphilis reinfection. Material and methods: Forty-four MSM patients with the first episode of syphilis who were treated at the Department of Dermatology at the Jagiellonian University School of Medicine in Krakow, Poland were included in this study. After completing the treatment, the RPR testing was done every 3 months for 2 years in every patient. In the study period, we identified 12 (22%) cases of syphilis reinfection, eight of which were asymptomatic. Clinical, demographic and behavior data from patients with only one episode of syphilis were compared with those collected from repeaters. Results: Individuals with syphilis reinfection had concomitant HIV infection more frequently, reported a higher number of sexual partners and had sex in sex on premises venues more frequently (p < 0.05). In the multivariate analysis, we found that being HIV infected MSM and having sex in sex on premises venues independently correlated with a higher risk of syphilis reinfection (OR = 9.6, 95% CI: 2.2-42.5 and OR = 5.6, 95% CI: 1.4-22.5, respectively). Conclusions: Results of our study highlight a strong need for frequent and repeated screening among MSM patients (especially those with concomitant HIV infection) with the first episode of syphilis and taking detailed patient's history regarding also demographic and behavior data. We should also improve prevention policies to reduce risk behaviors in this population. PMID- 30429706 TI - Chitinase-3-like protein 1 (YKL-40) is a biomarker of severity of joint involvement in psoriatic arthritis. AB - Introduction: Psoriasis is an inflammatory disease of a complex pathogenesis and arthritis is one of its most common complications. The biological role of chitinase-3-like protein 1 remains unknown. It is suggested that this protein takes part in processes such as proliferation, inflammation and tissue remodelling. Aim: To determine whether YKL-40 can be a useful biomarker in psoriatic arthritis. Material and methods: The study was performed on 42 patients with psoriatic arthritis: 28 men and 14 women, aged from 24 to 71 years. All patients met the diagnostic criteria (CASPAR) for psoriatic arthritis. The severity of psoriatic arthritis was assessed using 28-joint Disease Activity Score with CRP. The assessment of skin lesions was performed by Psoriasis Area and Severity Index (PASI) and, additionally, the Body Surface Area (BSA) was calculated. Blood samples were taken to measure the serum concentration of YKL 40, as well as C-reactive protein, erythrocyte sedimentation rate, white blood cell count and neutrophil count. Results: YKL-40 serum levels were significantly higher in patients with psoriatic arthritis, compared to the control group. Moreover, a significant positive correlation between the activity of psoriatic arthritis measured by DAS 28 and serum level of YKL-40 was found. There was a positive correlation between serum YKL-40 and BSA, as well as a distinct trend towards significance between YKL-40 and PASI score. Conclusions: YKL-40 can be a useful biomarker for both diagnosing and monitoring joint involvement in psoriatic patients. PMID- 30429707 TI - Acrodermatitis chronica atrophicans: various faces of the late form of Lyme borreliosis. AB - Introduction: Acrodermatitis chronica atrophicans (ACA) is probably the most common late and chronic manifestation of the Lyme borreliosis seen in European patients. Aim: To analyze epidemiological data, and to investigate the effects of treatment of patients with ACA. Material and methods: Nine patients were included in the study. All patients had serological examinations (ELISA and Western blot) and histopathological examination of the skin lesions performed. Eight patients had PCR in the skin biopsy performed. Results: The duration of symptoms ranged from 2 months to 2 years. In 7 patients, skin lesions were located on lower limbs, in 2 patients - in a non-typical body area - abdomen. In 1 patient, scleroderma and in 3 patients, diabetes mellitus was diagnosed. Borrelia burgdorferi DNA was detected in 25% of the skin biopsy specimens. IgG anti-B. burgdorferi specific antibodies were present in serum of all patients (confirmed by Western blot). In all cases, the diagnosis was confirmed by histopathological examination. The response to ceftriaxone therapy varied. In 5 cases, the lesions resolved completely, in others they faded. Conclusions: Despite raising awareness of Lyme borreliosis, late forms of the disease such as ACA are still observed. Acrodermatitis chronica atrophicans skin lesions may be located in non characteristic areas, e.g. abdominal skin. Symptoms are not irritating or painful, therefore patients do not seek medical help. The effect of antibiotic treatment varies. PMID- 30429708 TI - Omalizumab improves forced expiratory volume in 1 second in patients with severe asthma. AB - Introduction: Asthma is a multiphenotypic disease, and therapeutic managenment in patients with severe asthma is particulary difficult, with conventional treatment of severe asthma showing poor efficacy. Aim: To analyse forced expiratory volume in 1 s (FEV1) following the adminstration of omalizumab. Material and methods: Six patinents (mean age: 50 +/-12.6) with severe, uncontrolled asthma according to the GINA guidelines were enrolled in the study. Results: Treatment with omalizumab increased in all subjects FEV1 by 17.28 +/-13.4% after months and 18.57 +/-13.4% after 12 months of treatment. Conclusions: These results provides further evidence that therapy with omalizumab improves spiromtric parameters in severe asthma. PMID- 30429709 TI - Dynamic thiol/disulphide homeostasis in vitiligo patients. AB - Introduction: Vitiligo is an acquired depigmentation disorder with melanocyte destruction. Aim: To examine the thiol/disulphide balance in vitiligo patients and to compare the results with a healthy control group. Material and methods: Thirty-two patients with vitiligo and 35 healthy individuals were included in the study. Native thiol, disulfide and total thiol levels in plasma were evaluated using a new and automated spectrophotometric method. Disulphide/total thiol, disulphide/native thiol and native thiol/total thiol levels were measured. Results: There was no statistically significant difference between the two groups when the patient and control groups were compared in terms of thiol/disulphide balance (p > 0.05). There was no statistically significant difference in native thiol, disulphide and total thiol levels for vitiligo when compared with the control group (p > 0.005). Conclusions: In recent years, there have been numerous studies on the role of oxidative stress in the etiopathogenesis of vitiligo. In this study, we investigated in vitiligo patients whether thiol/disulphide balance is a new oxidative stress marker. The results were compared with a healthy control group. We measured the thiol/disulphide balance by a new method developed by Erel and Neselioglu. The serum thiol/disulphide levels were similar in the vitiligo patients and the control subjects, which indicated that the thiol/disulphide balance was not affected by vitiligo. We are of the opinion that new investigations to determine serum levels of thiol/disulphide may shed light on the possible roles of these molecules in vitiligo. PMID- 30429711 TI - The effect of omalizumab treatment on severe allergic asthma and allergic comorbidities: real-life experience from the Czech Anti-IgE Registry. AB - Introduction: Omalizumab is indicated for the treatment of severe allergic asthma (SAA) and chronic spontaneous urticaria, although a number of studies have confirmed the effectiveness of this therapy also for other IgE-mediated diseases. Aim: To assess the impact of anti-IgE therapy on SAA and comorbid IgE-mediated allergic diseases in patients treated with omalizumab for SAA enrolled in the CAR (Czech Anti-IgE Registry). Material and methods: Three hundred and ten patients with SAA treated with omalizumab were enrolled in the CAR. Two hundred and twenty nine individuals were evaluated after 12 months of omalizumab treatment for asthma control test (ACT), examination of fractional exhaled nitric oxide (FENO), forced expiratory volume in 1 s (FEV1), the use of systemic corticosteroids, side effects of treatment and clinical effect of omalizumab on allergic comorbidities (allergic rhinitis, chronic urticaria, atopic dermatitis and food allergy). Results: After 12 months of treatment with omalizumab, patients experienced a significant improvement of ACT and FEV1, reduction of FENO, use of systemic corticosteroids for asthma exacerbations and dose of maintenance oral corticosteroid therapy. The positive effect of treatment with omalizumab was observed in 82.2% of patients with allergic rhinitis, in 85.7% of patients with chronic urticaria, in 82.1% of patients with atopic dermatitis, and in 67.3% of patients with food allergy. Conclusions: In the CAR registry, patients with SAA treated with omalizumab showed a significant positive effect of anti-IgE therapy not only on the asthma control, but also on allergic comorbidities. PMID- 30429710 TI - Variances in the mRNA expression profile of TGF-beta1-3 isoforms and its TGF betaRI-III receptors during cyclosporin a treatment of psoriatic patients. AB - Introduction: Psoriasis is a chronic, immunologic, multi-factor inflammatory skin disease, strongly associated with a higher level of a number of cytokines, such as isoforms of transforming growth factor beta (TGF-beta1-3) and its receptors (TGF-betaRI-III). One of the most popular and important drugs used to treat this disease is cyclosporin A (CsA). Aim: The aim of this study was to investigate the expression of genes encoding the transforming growth factor (TGF)-beta isoforms and receptors of the cytokine TGF-betaRs in psoriatic patients during an 84-day long observation of the effects of cyclosporin A therapy. It made an attempt to determine the usefulness of testing mRNA expression of TGF-beta1-3 and its receptors TGF-betaRI-III as the supplementary molecular markers of lost sensitivity to the medicine. Material and methods: The study group consisted of 32 patients with psoriasis (20 men and 12 women) treated with cyclosporin A. The changes in expression patterns of TGF-beta1-3 and TGF-betaRI-III were performed by real-time quantitative reverse transcription PCR (RTqPCR). Results: The expression of TGF-beta1-3 and TGF-betaRI-III were detected in the whole period of therapy with CsA. Changes in transcriptional activities of TGF-beta1-3 and TGF betaRI-III during pharmacotherapy were observed. Differences in the expression of these genes were found before and after 42 and 84 days of using CsA. Conclusions: The changes in expression profiles of TGF-beta1-3 and TGF-betaRI-III during CsA therapy can be a useful molecular marker of lost sensitivity to the medicine. PMID- 30429712 TI - The effect of omalizumab treatment on IgE and other immunoglobulin levels in patients with chronic spontaneous urticaria and its association with treatment response. AB - Introduction: Suppression of free immunoglobulin E (IgE) levels and an increase in total IgE levels are observed during omalizumab treatment. However, whether omalizumab has any effect on other immunoglobulins is unknown. Aim: To investigate the effect of omalizumab treatment on serum IgE and other immunoglobulins, and demonstrate any association with response to treatment in patients with chronic spontaneous urticaria (CSU). Material and methods: The study included 41 patients diagnosed with CSU. Baseline and post-12-week treatment total IgE, IgA, IgM, and IgG levels and blood eosinophil, neutrophil, lymphocyte and platelet levels were compared. Patients were grouped based on weekly urticaria activity score (UAS-7) responses and these parameters were compared. Results: There was a significant increase in baseline and post-12-week treatment total IgE levels, while there was no significant difference in other immunoglobulin levels. A significant reduction was found in neutrophil counts after the treatment, whereas there was no significant difference in eosinophil, lymphocyte and platelet levels. There was no difference in these parameters between groups with complete response and without complete response. Conclusions: Omalizumab treatment can also be used in patients with immunoglobulin deficiency. Due to the observed reduction in neutrophil counts after the treatment, patients must be closely followed for whole blood parameters. PMID- 30429713 TI - The importance of specific IgE antibodies in epidemiology of allergic rhinitis and asthma - the Epidemiology of Allergic Diseases in Poland (ECAP) survey: part one. Influence of allergy risk factors on concentration of specific IgE antibodies in serum. AB - Introduction: Specific immunoglobulins E (sIgE) are important parameters to estimate severity of allergic diseases. Aim: To determine the influence of allergy risk factors on the concentration of specific IgE antibodies in serum. Material and methods: The concentration of sIgE antibodies against allergens Dermatophagoides pteronyssinus, cat dander, timothy grass, Alternaria alternata were determined in serum of 4077 respondents randomly selected from 9 regions (ECAP study). The positive results of sIgE (>= 0.35 IU/ml) were correlated to answers in questionnaires ECRHSII and ISAAC. Results: sIgE are more frequently detected in respondents declaring an allergic disease of a father than of a mother (D. pteronyssinus p < 0.05, A. alternata p < 0.01). An early beginning to attend school, kindergarten or nursery increases the frequency of sIgE detection (p < 0.05). If the number of children who slept in the same room as a respondent before the respondent was five years old, was lower, sIgE antibodies are more frequently detected (p < 0.05). Relating to: 1) all 4 allergens, sIgE are the most frequently detected in respondents declaring absence of a carpet/rug at home (p < 0.05), 2) cat dander - less frequently detected in respondents who have a cat at home at the age of 1-4 years (p < 0.005). Conclusions: Carpets/rugs capture a portion of mite, epidermal, mould allergens located at home, wherefore absence of a carpet or rug causes greater stimulation of an immune system by these allergens; as a consequence, IgE antibodies are the most frequently detected in respondents. Household contacts of the respondents, at the age of 1-4 years, with cats induced partial immune tolerance to cat dander. PMID- 30429714 TI - Delayed allergy to acyclovir revealed by lymphocyte proliferation test. PMID- 30429715 TI - Acute urticaria: an extremely rare adverse effect of levonorgestrel-releasing intrauterine system as a possible manifestation of progestogen hypersensitivity syndrome. PMID- 30429716 TI - Mycobacterium tuberculosis and pemphigus vulgaris. PMID- 30429717 TI - Multiple disseminated keratoacanthoma-like nodules: a rare form of distant metastases to the skin. PMID- 30429718 TI - Allergic contact dermatitis to dorzolamide and benzalkonium chloride. PMID- 30429719 TI - Editorial. PMID- 30429720 TI - Hereditary Hemochromatosis and Iron Metabolism. PMID- 30429721 TI - A Common Calibrator Does Not Secure Harmonisation of Commercial t-PA and PAI-1 Antigen Measurements. AB - : There is no common standardisation of different commercially available kits for both t-PA and PAI-1 antigen. AIM: The aim of this project was to study whether the exchange of the kit calibrator with the common calibration materials of the WHO would harmonise the results produced by five different commercially available t-PA and PAI-1 antigen kits when analysing the SSC secondary standard. METHODS: WHO international standards were used as calibrator and the SSC secondary standard and a commercially available plasma standard were used as test plasma in 5 commercially available kits measuring total t-PA and PAI-1 antigen. For t-PA only, the SSC secondary standard was spiked with purified t-PA and recovery was studied. RESULTS: There was a large variation in the concentrations of t-PA antigen (ranging from <0.5 to 6.6 ng/ml for the SSC secondary standard and from 3.3 to 10.9 ng/ml for the commercial plasma standard, respectively) produced by the different kits. Also, PAI-1 antigen results of the different kits showed a large variation (ranging from 20.3 to 51.2 ng/ml for the SSC secondary standard and from 41.8 to 89.7 ng/ml for the commercial plasma standard, respectively). Results of the two test samples and spiking with t-PA were not in agreement in all methods, indicating differences in specificity of tests. Data point to a specific effect of the matrix of standards. CONCLUSIONS: The use of a common calibration material does only marginally harmonise data for t-PA and PAI-1 antigen assays. There is a need for improvement of methods to cope with standards and standardisation. PMID- 30429722 TI - Iohexol Clearance for the Determination of Glomerular Filtration Rate: 15 Years' Experience in Clinical Practice. PMID- 30429724 TI - Criteria for the Specific Measurement of Plasmin Inhibitor Activity Using an Enzymatic Procedure. AB - There is a lack of well-established criteria for the specific measurement of fibrinolytic parameters. On behalf of the SSC, the subcommittee on Fibrinolysis started a process to develop criteria for the specific measurement of fibrinolytic variables. This report describes the criteria for the specific measurement of plasmin inhibitor activity. In summary, a plasma deficient in plasmin inhibitor should show an activity close to 0%. Plasma containing only the non-plasminogen binding form of plasmin inhibitor should show an activity nearby the activity of a plasma deficient for plasmin inhibitor. Other inhibitors of plasmin, like a 2 -macroglobulin, antithrombin in the presence of heparin, and C1 esterase inhibitor should not interfere in the assay at the level usually found in pathological conditions or at the higher normal level. PMID- 30429723 TI - The Clinical Value of Serum Transferrin Measurements. PMID- 30429726 TI - Welcome Message. PMID- 30429725 TI - IFCC Professional Scientific Exchange Programme: Paroxonase and its Role in Cardiovascular Disease. PMID- 30429727 TI - Caveat scriptor. PMID- 30429728 TI - Video-assisted subpleural block: A description of a novel technique. PMID- 30429729 TI - Turning of the tides: Saudi Arabia sits a top in the academic impact factor race in the region. PMID- 30429730 TI - Using propranolol in traumatic brain injury to reduce sympathetic storm phenomenon: A prospective randomized clinical trial. AB - Background: Traumatic brain injury (TBI) correlated with increased sympathetic activity on the expense of parasympathetic system due to loss of cortical control after brain injury. Manifestations of sympathetic storm include tachycardia, hypertension, tachypnea, and hyperthermia. The neuroprotective effects via reducing cerebral metabolism and lowering O2 and glucose consumption are the targets early after trauma. Beta-blockers reduce sympathetic activity. Objectives: We suppose that using propranolol blunts the sympathetic storming phenomenon as it is a nonselective beta inhibitor and has a lipophilic property to steadily penetrate blood-brain barrier. Patients and Methods: Sixty patients allocated randomly into two groups, each consisting of 30 patients. Group A started propranolol and Group B received placebo within first 24 h. Primary outcome was catecholamine levels on day 7, and the secondary outcomes were physiological measures (heart rate [HR], respiratory rate [RR], mean arterial blood pressure [MABP], temperature, random blood sugar, and follow-up Glasgow coma score [GCS] and sedation score). Results: Analysis of outcomes demonstrated that Group A tended to have lower catecholamine levels in comparison to Group B in day 7 (norepinephrine 206.87 +/- 44.44 vs. 529.33 +/- 42.99 pg/ml, P = <0.001), epinephrine level (69.00 +/- 8.66 vs. 190.73 +/- 16.48 pg/ml, P < 0.001), and dopamine level (32.90 +/- 4.57 vs. 78.00 +/- 3.48 pg/ml P < 0.001). GCS of the patients in Group A improved and was statistically significant compared to Group B in day 7 (13 vs. 10, P = 0.006), with percent change interquartile range (20.0 vs. 8.33, P = 0.006). Regarding hemodynamic parameters between the two groups MABP, HR, RR, and temperature, there was no statistically significant difference on day 1, while on day 7, there is high statistical significance and significant percent change (P < 0.001). Conclusion: Early usage of propranolol after TBI controls hemodynamics and blood sugar with decreased catecholamine levels correlated with the improvement of GCS. PMID- 30429731 TI - Emergency department visits for paroxysmal supraventricular tachycardia in Saudi Arabia. AB - Purpose: The present study aimed to compare the demographic, medical history, clinical features, and treatment management of paroxysmal supraventricular tachycardia (PSVT) in the emergency department of a teaching hospital in Riyadh, Saudi Arabia. A secondary purpose was to evaluate Adenosine response among numerous variables that might be used as predictors of the conversion. Methods: All PSVT cases presented to the Department of Emergency Medicine at King Khalid University Hospital, during the period from January 1, 2016, until December 31, 2016, were included in the study. Patients were assigned into two groups: adenosine sensitive (AS-group) and adenosine resistant (AR-group) according to adenosine conversion response. Results: A total of 38 patients were admitted during the study period. Fisher's exact test results showed that there were no significant (P > 0.05) differences among the AS-group and AR-group in the demographics, past medical history and clinical features, and post-ablation condition, except for the previous usage of the other anti-arrhythmic drugs to convert the last PSVT in the AR-group. The first bolus of adenosine had higher sensitivity and specificity, compared to the second bolus. Further, the second bolus of adenosine was not specific for short-term treatment of PSVT. Conclusions: Differences in adenosine sensitivity among PSVT patients were independent of demographic, past medical history, and clinical features of PSVT patients. Thus, the difference in adenosine response among groups may be attributed to the heterozygosity in conducting pathways. The first bolus of adenosine had high sensitivity and specificity, compared to the second bolus, and their optimal levels were predictable by HR deceleration. PMID- 30429732 TI - Enteral nutrition with omega-3 fatty acids in critically ill septic patients: A randomized double-blinded study. AB - Purpose: The present study was done to investigate the effect of the enteral omega-3 fatty acids on critically ill septic patients. Methods: A total of 110 critically ill septic patients were divided into two groups, 55 patients in each. Group A received enteral nutrition with 1000 mg omega-3 three times daily and Group B received enteral nutrition without omega-3. Demographic data, sepsis characteristics, number of patients required invasive ventilation, ventilation days, Intensive Care Unit (ICU) sequential organ failure assessment (SOFA) score, organ failure-free days, hemodynamic failure-free days, ICU stay, ICU, and hospital outcome were recorded. Results: Leukocytic count and C-reactive protein were higher in Group B during ICU stay (P = 0.010 and 0.003, respectively). The number of organ and hemodynamic failure-free days was higher in Group A (P < 0.05). Overall, ICU SOFA score was higher in Group B (P = 0.03). There was no difference in the number of patients requiring mechanical ventilation (P = 0.41). ICU stay was longer in Group B (P = 0.019); however, post-ICU hospital stay was similar in both groups. There were no differences regarding ICU and hospital survivors (P > 0.05). Conclusions: Enteral nutrition with omega-3 can improve organ function and decrease ICU stay in septic patients. Omega-3 fatty acids do not affect ICU mortality or decrease the post-ICU hospital stay. PMID- 30429733 TI - Comparison of I-gel for general anesthesia in obese and nonobese patients. AB - Context: I-gel is a second-generation supraglottic airway device. Despite several studies on i-gel, there are very few studies on the use of i-gel in obese patients. Aims: The aim of the study was to compare the clinical performance of i gel between obese and nonobese patients. Settings and Design: Prospective, controlled, nonrandomized, hospital-based study. Subjects and Methods: After obtaining informed consent, patients were divided into two groups of 16 patients each: group O consisted of patients with body mass index (BMI) >30 kg/m2 and Group C consisted of patients with BMI 18.5-29.9 kg/m2. I-gel was inserted after induction of anesthesia and muscle relaxation. Oropharyngeal leak pressure (OLP) (primary outcome variable), leak fraction, time taken to insert the device, ease of insertion, fiberoptic view of glottis through i-gel's airway tube, and adverse effects were recorded. Statistical Analysis Used: Data were analyzed using SPSS 20. Continuous, ordinal, and categorical variables were analyzed using students t test, Mann-Whitney U-test, and Fischer's exact test, respectively. Results: OLP was slightly higher in Group O (25.38 +/- 4.79 cm H2O) but was not statistically different than Group C (27.38 +/- 4.38 cm H2O). Other parameters except weight and BMI (which were higher in Group O) were statistically similar in both groups. There was no statistical difference in side effects. Conclusions: We concluded that i-gel is as effective in obese patients as in nonobese patients when used for securing the airway for surgical procedures. PMID- 30429734 TI - International internship experience for emergency medical service paramedic students. AB - Introduction: The purpose of this study is to delineate the training activities in the internship program, describe students' clinical and emergency medical service field hours and skills performance, and compare between internship students groups in their skills performance. Methods: This is a retrospective, descriptive, and analytical study based on an interpretive observational documentary review of internship reports received on internship students. Results: Three groups of internship students participated in various training activities in 3 years. Students in Group A (2015) completed 4610 h and contact 1600 patients. They completed the following clinical skills: 712 medication administrations, 652 intravenous (IV) access, 174 team leads (TLs), 4 live patient endotracheal intubations, and 13 ventilations. Students in Group B (2016) completed 2424 h and contact 797 patients. They completed several clinical skills including 256 medication administrations, 249 IV access, 16 TLs, 1 live patient endotracheal intubation, and 8 ventilations. Students in Group C (2017) completed 5700 h and contact 1200 patients. They completed several skills including 673 medication administrations, 650 IV access, 198 TLs, 11 live patient endotracheal intubations, and 27 ventilations. The study revealed significant differences and superiority in skills performance in Groups A (2015) and C (2017) over Group B (2016). Conclusion: Internship students have exposure opportunities to patients and have more opportunities to perform medication administration, IV activities, and serve as TLs. As expected, internship students have few opportunities to perform live tube insertions and ventilation. There are statistical significant differences in skills performance within the group of students in each year and among the three groups of internship students. PMID- 30429735 TI - Comparative evaluation of analgesic sparing efficacy between dexmedetomidine and clonidine used as adjuvant to ropivacaine in thoracic paravertebral block for patients undergoing breast cancer surgery: A prospective, randomized, double blind study. AB - Introduction: Thoracic paravertebral block (TPVB) is an effective method for intra- and post-operative pain management in thoracic surgeries. For a long time, various adjuvants have been tried for prolonging the duration of TPVB. Objective: In this prospective study, we have compared the analgesic sparing efficacy of dexmedetomidine and clonidine, two alpha2 adrenergic agonists, administered along with ropivacaine for TPVB for breast cancer surgery patients. Materials and Methods: Forty-four breast cancer surgery patients undergoing general anesthesia (GA) were randomly divided into Group C and Group D (n = 44 each) receiving preoperative TPVB at T3-5 level with 0.5% ropivacaine solution admixture with clonidine and dexmedetomidine, respectively. Cancer surgery was performed under GA. Intraoperative fentanyl and propofol requirement was compared. Visual analogue scale was used for pain assessment. Total dose and mean time to administration of first rescue analgesic diclofenac sodium was noted. Side effects and hemodynamic parameters were also noted. Results: Intraoperative fentanyl and propofol requirement was significantly less in dexmedetomidine group than clonidine. The requirement of diclofenac sodium was also significantly less and later in Group D than Group C. Hemodynamics, and side effects were comparable among two groups. Conclusion: Dexmedetomidine provided better intraoperative as well as postoperative analgesia than clonidine when administered with ropivacaine in TPVB before breast cancer surgery patients without producing remarkable side effects. PMID- 30429736 TI - Is body mass index >=50 kg/m2 a predictor of higher morbidity for patients who have undergone laparoscopic sleeve gastrectomy? AB - Background: Super-morbid obese (SMO) patients (body mass index [BMI] >50 kg/m2) carry a higher risk for bariatric surgery. Despite several studies addressing this patient group, the number of patients included tends to be relatively small. Methods: We reviewed 708 patients who underwent laparoscopic sleeve gastrectomy between 2009 and 2015 and compared the outcome of SMO (BMI >=50 kg/m2) patients with MO (BMI <50 kg/m2) patients. Results: Of 708 patients, 217 were SMO and 491 were MO. Both groups had homogeneous baseline characteristics and comorbidities, except sleep apnea which was higher in SMO group. There was no significant difference for the duration of operation, length of stay, or recovery room time. The mean number of trocars was four for both groups. There were no conversions to open or documented intraoperative complications in either group. Postoperative complications occurred in 13 (6%) SMO patients (3 patients with leakage and 10 with bleeding). Postoperative complications occurred in 21 (4.3%) MO patients (11 patients with leakage and 10 with bleeding). No reoperation was done in both groups. There was no surgical mortality. Conclusion: We detected no significant difference in the duration of operation and intra- or postoperative complication between SMO and MO groups. The possibility of the safety of this procedure in SMO group can be adopted. PMID- 30429737 TI - Evaluation of thoracolumbar interfascial plane block for postoperative analgesia after herniated lumbar disc surgery: A randomized clinical trial. AB - Background: Thoracolumbar interfascial plane (TLIP) block involves injection of local anesthetics between multifidus and longissimus muscles at the 3rd lumbar vertebral level assuming that it can block the dorsal rami of thoracolumbar nerves. Objective: The objective of this study was to evaluate the analgesic effects gained after performing TLIP block (analogous to the transversus abdominis plane [TAP] block, but intended for the back) in patients undergoing lumbar discectomy. Methodology: This was a prospective, randomized, double blinded, controlled clinical trial. Computer-generated randomization numbers were used to allocate patients into two groups. A total of 102 patients scheduled for lumbar discectomy were considered eligible, of these 70 patients were randomly included in the analysis: 35 patients (control group) received the standard general anesthetic technique and 35 patients (TLIP group) received TLIP block with 20 ml mixture of 0.25% bupivacaine and 1% lidocaine on each side. The primary outcome was to compare the two groups with regard to pain scores, whereas the secondary outcomes included the time to first analgesic (TFA), 24-h morphine consumption, and side effects associated with morphine such as nausea, vomiting, and sedation. Results: TLIP group compared with the control group showed a significant reduction in the postoperative Visual Analog Scale for pain score both on rest and movement, with no statistically significant difference at 24 h during movement. TFA was significantly shorter in the control group compared to the TLIP group (82.00 +/- 69.01 vs. 442.7 +/- 126.47 min, P < 0.001). TLIP group had lower cumulative morphine consumption than control group of statistically significant difference (9.7 +/- 6.38 vs. 25.88 +/- 5.17 mg, P < 0.001). TLIP block group compared with the control group showed a significant reduction of nausea and a lower incidence of sedation. Conclusion: TLIP block is an effective and safe method for postoperative analgesia after lumbar discectomy. PMID- 30429738 TI - Ultrasound-guided serratus anterior plane block versus thoracic paravertebral block for perioperative analgesia in thoracotomy. AB - Background: Thoracotomy needs adequate powerful postoperative analgesia. This study aims to compare the safety and efficacy of ultrasound (US)-guided serratus anterior plane block (SAPB) and thoracic paravertebral block (TPVB) for perioperative analgesia in cancer patients having lung lobectomy. Patients and Methods: This clinical trial involved 90 patients with lung cancer scheduled for lung lobectomy randomly divided into three groups according to the type of preemptive regional block. Group TPVB received US-guided TPVB. In Group SAPB, US guided SAPB was performed. The patients of the control Group received general anesthesia alone. The outcome measures were postoperative visual analog scale (VAS) score, intraoperative fentanyl consumption, time of first rescue analgesic, total dose postoperative analgesic, and drug-related adverse effects. Results: Analgesia was adequate in TPVB and SAPB groups up to 24 h. VAS score was comparable in TPVB and SAPB groups and significantly lower compared to control group up to 9 h postoperatively. At 12 and 24 h, TPVB group had significantly lower VAS score relative to SAPB and control groups. Total intraoperative fentanyl consumption was significantly lower in TPVB and SAPB Groups compared to control group. The majority of TPVB Group cases did not need rescue morphine, while the majority of control group needed two doses (P < 0.001). The hemodynamic variables were stable in all patients. Few cases reported trivial adverse effects. Conclusion: Preemptive TPVB and SAPB provide comparable levels of adequate analgesia for the first 24 h after thoracotomy. TPVB provided better analgesia after 12 h. The two procedures reduce intraoperative fentanyl and postoperative morphine consumption. PMID- 30429739 TI - 2% lidocaine versus 3% prilocaine for oral and maxillofacial surgery. AB - Objective: To investigate the speed of action and injection discomfort of 2% lidocaine and 3% prilocaine for upper teeth extractions. Materials and Methods: Forty-six patients were included in the prilocaine 3% group, and 46 in the lidocaine 2% control group. After all injections, soft and hard tissue numbness was objectively gauged by dental probe at intervals of 15 s. Moreover, the pain of the injections was recorded by the patients after each treatment on standard 100 mm visual analog scales, tagged at the endpoints with "no pain" (0 mm) and "unbearable pain" (100 mm). Results: There were no significant differences in the meantime of first numbness to associated buccal, palatal mucosa, and tooth of patients in the lidocaine and prilocaine buccal infiltration groups (P = 0.56, 0.37, and 0.33). However, clinically, the patients in prilocaine group recorded earlier buccal, palatal mucosa, and teeth numbness than those in lidocaine group. With regards to the discomfort of the needle injections, there was a significant difference for lidocaine and prilocaine groups when comparing the post buccal scores with the post palatal injection scores (t-test: P < 0.001). Lidocaine and prilocaine buccal injections were significantly more comfortable than palatal injections. Conclusions: Using 2% lidocaine and 3% prilocaine for extractions of upper maxillary teeth produces similarly successful anesthesia. Clinically, prilocaine has slightly rapid onset of action, earlier buccal mucosa, hard palate, and teeth numbness. Prilocaine and lidocaine buccal injection was significantly more comfortable than palatal injection. PMID- 30429740 TI - Ultrasonographic assessment of internal jugular vein diameter and its relationship with the carotid artery at the apex, middle, and base of the triangle formed by two heads of sternocleidomastoid muscle: A pilot study in healthy volunteers. AB - Background: Anteroposterior (AP) diameter of internal jugular vein (IJV) and its relative position with carotid artery (CA) varies in the triangle formed by two heads of sternocleidomastoid muscle, which is the site of insertion of needle for IJV cannulation. This study assessed the maximum AP diameter of the IJV in supine and Trendelenburg positions and during Valsalva maneuver (supine position) at the apex, middle, and base of the triangle and to study the relationship of the IJV with the CA. Materials and Methods: Twenty-five healthy volunteers were included and ultrasonography of IJV was performed in supine and Trendelenburg positions and during Valsalva maneuver (supine position) at the apex, middle, and base of the triangle bilaterally. The AP diameter of IJV was measured. The relative anatomical position of IJV was assessed as anterior (A), anterolateral (AL), or lateral (L) to CA in neutral head position and 30 degrees , 45 degrees , and 90 degrees head rotation to the contralateral side in supine position. Results: The difference in right IJV diameter was significant (P = 0.001) between supine vs. Trendelenburg position at the base of the triangle. Within one position there was significant difference between apex and base of the triangle. The left IJV diameter was significantly different between supine vs. Trendelenburg position at the apex (P = 0.004), middle (P = 0.003), and base of the triangle (P-value = 0.001). There was significant difference between supine vs. Valsalva maneuver at the middle (P = 0.011) and base (P = 0.014) of the triangle. The right IJV was more L or AL to the CA in apex with head in neutral or 30 degrees rotation. The left IJV was more L or AL to the CA in middle with head in neutral position. Conclusion: Trendelenburg and Valsalva increase diameter of IJV on both right and left side. Diameter of IJV is greater at the base of the triangle. IJV is lateral or anterolateral when the head is either neutral or turned 30 degrees to the contralateral side. PMID- 30429741 TI - The utility of limited trans-thoracic echocardiography in the stratification of pulse pressure variation: A feasibility study in major open abdominal surgery. AB - Background and Aim: Limitation in use of pulse pressure variation (PPV) in predicting fluid responsiveness (FR) in hypotensive patients is encountered when values are in the "gray zone" (8-13%). Dynamic arterial elastance (E adyn= PPV/SVV) can be used in such situations to predict arterial pressure response to volume expansion (VE). In our study, we used respiratory variation of ascending aorta velocity time integral (AoVTI) calculated from suprasternal window as a surrogate of stroke volume variation (SVV). Fluids/vasopressors were administered to hypotensive patients intraoperatively based on value of E adyn. Aim was to assess feasibility and utility of suprasternal echocardiography in the above mentioned subset of patients. Materials and Methods: Hemodynamic data were monitored and respiratory variation in AoVTI was recorded using suprasternal echocardiography at all time points when patients developed hypotension (systolic blood pressure <90 mm Hg/<20% of baseline for 5 min) and at randomly selected time intervals when hemodynamic stability was maintained. VE with 250 ml of Ringer lactate (RL) was done in hypotensive patients with PPV value of 8-13% and E adyn>0.9. Increase of >15% in AoVTI after VE defined "fluid responsiveness." Results: Twenty-eight patients were enrolled, but three were excluded in view of left ventricular systolic dysfunction detected during preinduction echocardiography. Hemodynamic and echocardiographic data were recorded at 538 observation points in 25 adults. Hypotension occurred in 247 data sets, and in 168 data sets, value of PPV was 8-13%. VE was carried out in only those 131 data sets in which the value of E adyn was >0.9. Area under the curve (AUC) for VE as an intervention in the indeterminate (PPV 8-13%) group was 0.574 (0.49-0.68, 95% CI, P < 0.049), and in the observation set with PPV >13, the AUC value was 0.7 (0.59-0.98, 95% CI, P < 0.01). Conclusions: Echocardiography using the suprasternal window in the operating room during abdominal surgery is feasible, but the utility of E adyn in stratification of patients with PPV 8-13% is inconclusive. PMID- 30429743 TI - A comparative study between interlaminar nerve root targeted epidural versus infraneural transforaminal epidural steroids for treatment of intervertebral disc herniation. AB - Background: Low back pain (LBP) is one of the most common musculoskeletal abnormalities. Epidural corticosteroid injections (ESIs) have been used long time ago for treatment of lumbar radiculopathy or discogenic back pain in case of failed medical and conservative management. Different techniques for ESIs include the interlaminar, the caudal, and the transforaminal approaches. Purpose: The aim of our study is to compare between the efficacy of infraneural transforaminal ESI and lumbar paramedian nerve root targeted interlaminar steroid injection in reduction of unilateral radicular pain secondary to disc prolapse. Patients and Methods: This prospective double-blind randomized study was performed on 40 patients randomized into two equal groups, each of 20: the infraneural transforaminal ESI (IN group) and the interlaminar parasagittal ESI (IL group). Patients with backache without leg radiation, or with focal motor neurological deficit, previous spine surgery, S1 radiculopathy, lumbar ESI in the past month, systemic steroid used recently within 4 weeks before the procedure, allergy to any medication or addiction to opioids, and pregnancy were excluded from the study. The duration and efficacy of pain relief (defined as >=40% reduction of pain perception) by 0-10 visual analog scale (VAS) is the primary outcome. Functional assessment using Modified Oswestry Disability Questionnaire (MODQ) and possible side effects and complications are the secondary outcomes. Results: The VAS and MODQ scores were significantly lower in both groups in comparison with the basal values. There was also a lower VAS in the infraneural group than the parasagittal (IL) group up to 6 months after injection. Conclusion: The infraneural (IN) epidural steroid is more favorable than the parasagittal (IL) interlaminar epidural steroid owing to its long-term improvement in physical function than the parasagittal technique with no serious side effects. PMID- 30429742 TI - Surgically-assisted abdominal wall blocks for analgesia after abdominoplasty: A prospective randomized trial. AB - Background: Abdominoplasty is a common aesthetic procedure. The transversus abdominis plane block (TAPB) and rectus sheath block (RSB) have proven efficacy as analgesic modality for abdominal surgeries. This study demonstrates post abdominoplasty analgesic duration consequent to the three surgically infiltrated local anesthetic techniques: bilateral TAPB, bilateral RSB, and subcutaneous infiltration (SCI) of 0.25% bupivacaine. Methods: In this prospective randomized study, 48 adult patients scheduled for abdominoplasty were randomized into three groups: TAPB group (n = 16), RSB group (n = 16), and SCI group (n = 16) utilizing 40 mL of 0.25% bupivacaine for each block. In both TAPB and RSB groups, the block was performed bilaterally after plication of anterior abdominal wall, while in SCI group, the surgical incisional area was infiltrated before skin closure. Main outcome measures included visual analogue scale (VAS), at rest and during movement; the analgesic duration; and the total required doses of morphine in the first postoperative day. Results: A statistically significant longer analgesia was recorded in the TABP group compared with both the RSB and SCI groups. Statistically significant higher VAS scores in the SCI group 4 hours postoperatively was recorded, both at rest and during movement, compared with both TABP and RSB groups. Significant higher morphine consumption in the SCI group was compared with the other two groups. Conclusions: Among the surgically infiltrated anesthetic techniques for abdominoplasty, bilateral TAPB was associated with longer postoperatively analgesic duration with lower morphine consumption in the first 24 hours compared with RSB and SCI. PMID- 30429744 TI - Assessment of effectiveness of cricoid pressure in preventing gastric insufflation during bag and mask ventilation: A randomized controlled trial. AB - Background: Rapid sequence induction and intubation (RSII) with application of "Cricoid pressure" and avoidance of "facemask ventilation" (FMV) is believed to minimize the risk of pulmonary aspiration of gastric contents during general anesthesia. However, some patients may be at risk of developing hypoxemia and may benefit from FMV during RSII. The purpose of this study was to assess the effectiveness of "cricoid pressure" in preventing gastric insufflation during FMV using gastric ultrasonography. Materials and Methods: Eighty-four adult patients were randomized to receive cricoid pressure (CP) or no cricoid pressure (NCP), during FMV after induction of general anesthesia. Gastric antral cross-sectional area (CSA) was measured with ultrasonography before and after FMV in supine and right lateral decubitus positions (LDP). Appearance of "comet tail" artifacts created by acoustic shadows of gas in the gastric antrum was noted. Results: The incidence of insufflation indicated by "comet tail" artifacts during FMV was lower in group CP (17 vs 71%; P < 0.001). The lowest P aw at which gastric insufflation occurred was higher in group CP (20 vs 14 cmH2O). The change in mean gastric antral CSA was significantly lower in group CP than in group NCP in supine (0.02 vs 0.36 cm2, P = 0.012) and right LDP (0.03 vs 0.67 cm2, P < 0.001). Conclusion: Cricoid pressure is effective in preventing gastric insufflation during FMV at P aw less than 20 cmH2O. Observation of comet tail artifacts in gastric antrum along with measurement of change in antral CSA on ultrasound examination is a feasible and reliable method to detect gastric insufflation. PMID- 30429745 TI - General versus local anesthesia for carotid endarterectomy: Special considerations. AB - Anesthesia for carotid endarterectomy (CEA), general or locoregional, has been an issue of debate in literature ever since the first Cochrane review in 1991. The largest available study on the subject, the GALA trial, has not shown any difference in patient's outcome - incidence of stroke and 30-day-mortality postsurgery. However, increasing evidence favors regional anesthesia as an independent factor of reduced morbidity after CEA. The advantages and disadvantages of general versus regional anesthesia for CEA have been well established. Cervical plexus blocks (CPBs) are safe and effective anesthetic techniques, but they may also present adverse effects that we must be aware of. Optimal cerebral function monitoring remains a problem to be solved. Cerebral oximetry may prove to be a reliable tool in predicting neurological impairment. This narrative review intends to highlight the latest implemented anesthetic modalities for CEA, including CPB under ultrasound guidance, and to outline the main limitations of general versus regional anesthesia. Following the appropriate anesthetic, modality necessitates a thorough preoperative consultation among the patient, the surgeon, and the anesthetist. The anesthetic plan should be made on an individual basis, taking into consideration patient's comorbidities and wish. PMID- 30429747 TI - Emergent airway management in a patient with in situ tracheal stent: A lesson learned. AB - The prevalence of in situ tracheal stents has increased in the past two decades for the management of malignant and benign central airway diseases for either palliation or definitive therapy. Recent placement of a tracheal stent has been associated with edema of the upper airway; therefore, these patients are at a great risk for airway collapse, especially within the days most recent to the procedure. The authors present the case of a morbidly obese patient with a tracheal stent admitted to the Intensive Care Unit who developed acute respiratory failure and was found to be "unable to ventilate, unable to intubate." Surgical airway approach through a cricothyroidotomy failed to provide a patent airway and the patient subsequently developed cardiac arrest and expired. The presence of tracheal stent poses a high challenge during emergent airway interventions; thus, carefully planned airway manipulation in such patients is paramount in order to avoid catastrophic outcomes. PMID- 30429748 TI - A case series of different anesthesia approaches for single ventricular physiology patients in various stages of palliation underwent noncardiac procedures. AB - Patients with single ventricle physiology (SVP) are a particularly challenging population with congenital heart disease (CHD); they will go for staged, palliation ending in the Fontan circulation. Nowadays, with improvement in surgical procedures for CHD, these patients become growing population, and noncardiac surgeries become not uncommon. The authors report different anesthesia approaches for four pediatric patients with SVP underwent ten noncardiac procedures done under general anesthesia following the different stages of palliation at King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia, between 2009 and 2015 and do a brief review of the literature on this topic. The aim of this study is to highlight that anesthesia approach for patients with SVP varies according to the patient physical situation at the time of the procedure, stage of palliation, and type of surgery. Therefore, every anesthesiologist should have thorough knowledge about SVP, different stages of palliative surgery, anesthesia concern in each one and risk factors associated with perioperative morbidity before anesthetizing patients for a noncardiac procedure to keep patient safety as well as avoiding unnecessary cancellation, rescheduling, and admissions to the ward or the Intensive Care Unit. PMID- 30429746 TI - Pain relief after ambulatory surgery: Progress over the last decade. AB - The concept of fast-track or ambulatory surgery appeared to facilitate early recovery and discharge from the hospital and early resumption of normal daily activities after elective surgical procedures as well to reduce the health-care costs. Multimodal/balanced analgesia is an increasingly popular approach for this. The use of conventional modalities including central neuraxial blockade and opioids cannot be extended to patients undergoing fast-track surgery. Hence, an aggressive perioperative analgesic regimen/protocol is required for effective pain relief, with minimal side effects and which could be managed easily by the patient or the relatives at home away from the hospital setting. Pharmacological therapy and regional anesthesia techniques have been utilized for postoperative pain management. The use of perineural, incisional, and intra-articular catheters and local anesthetic administration through elastomeric and electronic pumps is promising approach for effective pain management at home. The key to successful pain management of such procedures requires individually tailored education to patients or caregivers including information on treatment options for postoperative pain and use of multimodal analgesia. This review provides an overview of the current armamentarium of drugs and modalities available for effective management of patients undergoing day care surgeries and sheds light on newer modalities available. PMID- 30429749 TI - Anesthetic considerations and successful management of a patient with permanent pacemaker for cervical spine instrumentation. AB - Patients with permanent pacemaker posted for cervical spine instrumentation pose special challenges for modern-day anesthesiologist since the field of surgery is in proximity to the pacing apparatus. The important considerations in this regard are pacemaker dependency, prior reprogramming to asynchronous mode, perioperative interference with pacemaker function due to electrolyte, acid-base disturbances, and electromagnetic interference leading to pacemaker failure and hemodynamic compromise. We report successful anesthetic management of a patient of postlaminectomy kyphosis with compressive myelopathy with permanent pacemaker in situ who underwent C5-C6 corpectomy and instrumentation under general anesthesia. PMID- 30429750 TI - A novel out plane technique of midpoint transverse process to pleura block in breast surgery: A case report. AB - Regional anesthetic techniques have gradually revolutionized the perioperative analgesia in breast surgeries. Recently, midpoint transverse process to pleura block has been described and found to provide excellent opioid-sparing analgesia. We performed the block in a novel out-of-plane technique to decrease the patient needle interaction time and at the same time achieving good analgesia. The immediate postoperative Numeric Pain Rating Scale score was 0/10 both at rest and on movement, and patient reported a score of 5/10 after 12 h, which get subsided with single dose of nonopioid analgesic. PMID- 30429751 TI - Multidisciplinary team approach for an atypical presentation of postpartum thrombotic thrombocytopenic purpura and severe preeclampsia in the Intensive Care Unit. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare hematologic syndrome during pregnancy with overlapping features of severe preeclampsia and is associated with high morbidity and mortality. We present a case of postpartum TTP, associated with severe preeclampsia. Therapeutic approach for this case included corticosteroids, plasma exchange therapy, and immunomodulatory therapy. We describe the pathophysiology of TTP in pregnancy and its similarities with other disorders that constitute the thrombotic microangiopathy syndrome, as well as other clinical factors which made the final diagnosis challenging. In addition, we highlight the value of a multidisciplinary team care approach to assure an optimal outcome for this clinical scenario. PMID- 30429752 TI - Endovascular aspiration of clot in a 3-year-old child with embolic infarct of right middle cerebral artery. AB - Stroke in children is common and is associated with long-term morbidity. The incidence of stroke is 13/100,000 in children above 1 month, with higher incidences in neonates and premature infants. It has to be differentiated from other diseases which have a similar presentation. We present a case of a 3-year old female child with embolic stroke of right middle cerebral artery managed with endovascular clot retrieval done under general anesthesia. PMID- 30429753 TI - Crack in the epidural catheter filter port. PMID- 30429754 TI - Giant vallecular cyst excision in infant: Should we proceed without a definite airway? PMID- 30429755 TI - An innovative way of monitoring end-tidal carbon dioxide during endoscopic retrograde cholangiopancreatography. PMID- 30429756 TI - Prolonged neuromuscular blockade in a middle-eastern female patient homozygous for atypical plasma cholinesterase. PMID- 30429757 TI - Intra-tracheal extension of hilar mass mimicking severe asthma: Anesthesiologist perspective. PMID- 30429758 TI - Aortic root abscess and the lost art of the physical exam. PMID- 30429759 TI - Effect of prophylactic ondansetron and/or continuous infusion of phenylephrine on spinal anesthesia-induced hypotension. PMID- 30429760 TI - Comments on the article "Intraoperative fluid management: Past and future, where is the evidence?" PMID- 30429761 TI - Puzzling postoperative toxin-induced acute liver failure after nonhepatobiliary surgery. PMID- 30429762 TI - Anesthetic management of a case of nesidioblastosis. PMID- 30429763 TI - Retraction: Evaluation of gabapentin and dexamethasone alone or in combination for pain control after adenotonsillectomy in children. AB - [This retracts the article on p. 317 in vol. 8, PMID: 25191179.]. PMID- 30429764 TI - BDNF-Related Imbalance of Copine 6 and Synaptic Plasticity Markers Couples With Depression-Like Behavior and Immune Activation in CUMS Rats. AB - Chronic stress is a contributing risk factor in the pathogenesis of depression. Although the mechanisms are multifaceted, the relationship can be ascribed partly to stress-related alterations in immune activation and brain plasticity. Considering the increasing evidence regarding the role of Copine 6 in the regulation of synaptic plasticity, the aim of the present study is to investigate Copine 6 expression in the hippocampus and the prefrontal cortex (PFC) in a stress-induced depression rat model. The behavior of the rats was evaluated via the open field test, saccharin preference test, elevated plus maze test, tail suspension test, Morris water maze, and forced swimming test. The plasma concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the protein expressions of brain-derived neurotrophic factor (BDNF), Copine 6, and synaptic plasticity markers in the hippocampus and the PFC were also detected. The results showed that chronic unpredictable mild stress (CUMS) induces depression-like behavior in rats, accompanied by increased plasma concentrations of CRP and IL-6. Moreover, the protein expressions of BDNF, Copine 6, and synapsin I were decreased in both the hippocampus and the PFC of CUMS rats, and the protein expression of synaptotagmin I was decreased in the hippocampus. Furthermore, Pearson's test revealed a potential relationship between the depression-like behavior, the plasma CRP concentration, and the protein expressions of BDNF, Copine 6, synapsin I, or synaptotagmin I in the hippocampus or the PFC. Together with our previous results, the current findings suggest that apart from immune activation, the BDNF-related imbalance of Copine 6 expression in the brain might play a crucial role in stress-associated depression like behaviors and synaptic plasticity changes. PMID- 30429765 TI - Transcriptomic Characterization of the Human Habenula Highlights Drug Metabolism and the Neuroimmune System. AB - Due to size and accessibility, most information about the habenula is derived from rodent studies. To better understand the molecular signature of the habenula we characterized the genes that have high expression in the habenula. We compared anatomical expression profiles of three normal adult human brains and four fetal brains. We used gene set enrichment analyses to determine if genes annotated to specific molecular functions, cellular components, and biological processes are enriched in the habenula. We also tested gene sets related to depression and addiction to determine if they uniquely involve the habenula. As expected, we observed high habenular expression of GPR151, nicotinic cholinergic receptors, and cilia-associated genes (medial division). Genes identified in genetic studies of smoking and associated with nicotine response were enriched in the habenula. Genes associated with major depressive disorder did not have enriched expression in the habenula but genes negatively correlated with hedonic well-being were, providing a link to anhedonia. We observed enrichment of genes associated with diseases that are comorbid with addictions (hematopoiesis, thrombosis, liver cirrhosis, pneumonia, and pulmonary fibrosis) and depression (rheumatoid arthritis, multiple sclerosis, and kidney disease). These inflammatory diseases mark a neuroimmune signature that is supported by genes associated with mast cells, acute inflammatory response, and leukocyte migration. We also found enrichment of cytochrome p450 genes suggesting the habenula is uniquely sensitive to endogenous and xenobiotic compounds. Our results suggest the habenula receives negative reward signals from immune and drug processing molecules. This is consistent with the habenular role in the "anti-reward" system and suggests it may be a key bridge between autoimmune disorders, drug use, and psychiatric diseases. PMID- 30429766 TI - Understanding the Effects of Both CD14-Mediated Innate Immunity and Device/Tissue Mechanical Mismatch in the Neuroinflammatory Response to Intracortical Microelectrodes. AB - Intracortical microelectrodes record neuronal activity of individual neurons within the brain, which can be used to bridge communication between the biological system and computer hardware for both research and rehabilitation purposes. However, long-term consistent neural recordings are difficult to achieve, in large part due to the neuroinflammatory tissue response to the microelectrodes. Prior studies have identified many factors that may contribute to the neuroinflammatory response to intracortical microelectrodes. Unfortunately, each proposed mechanism for the prolonged neuroinflammatory response has been investigated independently, while it is clear that mechanisms can overlap and be difficult to isolate. Therefore, we aimed to determine whether the dual targeting of the innate immune response by inhibiting innate immunity pathways associated with cluster of differentiation 14 (CD14), and the mechanical mismatch could improve the neuroinflammatory response to intracortical microelectrodes. A thiol-ene probe that softens on contact with the physiological environment was used to reduce mechanical mismatch. The thiol-ene probe was both softer and larger in size than the uncoated silicon control probe. Cd14-/- mice were used to completely inhibit contribution of CD14 to the neuroinflammatory response. Contrary to the initial hypothesis, dual targeting worsened the neuroinflammatory response to intracortical probes. Therefore, probe material and CD14 deficiency were independently assessed for their effect on inflammation and neuronal density by implanting each microelectrode type in both wild-type control and Cd14-/- mice. Histology results show that 2 weeks after implantation, targeting CD14 results in higher neuronal density and decreased glial scar around the probe, whereas the thiol-ene probe results in more microglia/macrophage activation and greater blood-brain barrier (BBB) disruption around the probe. Chronic histology demonstrate no differences in the inflammatory response at 16 weeks. Over acute time points, results also suggest immunomodulatory approaches such as targeting CD14 can be utilized to decrease inflammation to intracortical microelectrodes. The results obtained in the current study highlight the importance of not only probe material, but probe size, in regard to neuroinflammation. PMID- 30429767 TI - A Neuro-Inspired System for Online Learning and Recognition of Parallel Spike Trains, Based on Spike Latency, and Heterosynaptic STDP. AB - Humans perform remarkably well in many cognitive tasks including pattern recognition. However, the neuronal mechanisms underlying this process are not well understood. Nevertheless, artificial neural networks, inspired in brain circuits, have been designed and used to tackle spatio-temporal pattern recognition tasks. In this paper we present a multi-neuronal spike pattern detection structure able to autonomously implement online learning and recognition of parallel spike sequences (i.e., sequences of pulses belonging to different neurons/neural ensembles). The operating principle of this structure is based on two spiking/synaptic neurocomputational characteristics: spike latency, which enables neurons to fire spikes with a certain delay and heterosynaptic plasticity, which allows the own regulation of synaptic weights. From the perspective of the information representation, the structure allows mapping a spatio-temporal stimulus into a multi-dimensional, temporal, feature space. In this space, the parameter coordinate and the time at which a neuron fires represent one specific feature. In this sense, each feature can be considered to span a single temporal axis. We applied our proposed scheme to experimental data obtained from a motor-inhibitory cognitive task. The results show that out method exhibits similar performance compared with other classification methods, indicating the effectiveness of our approach. In addition, its simplicity and low computational cost suggest a large scale implementation for real time recognition applications in several areas, such as brain computer interface, personal biometrics authentication, or early detection of diseases. PMID- 30429768 TI - Effects of High-Definition and Conventional Transcranial Direct-Current Stimulation on Motor Learning in Children. AB - Background: Transcranial direct current stimulation (tDCS) can improve motor learning in children. High-definition approaches (HD-tDCS) have not been examined in children. Objectives/Hypothesis: We hypothesized that primary motor cortex HD tDCS would enhance motor learning but be inferior to tDCS in children. Methods: Twenty-four children were recruited for a randomized, sham-controlled, double blinded interventional trial (NCT03193580, clinicaltrials.gov/ct2/show/NCT03193580) to receive (1) right hemisphere (contralateral) primary motor cortex (M1) 1 mA anodal conventional 1 * 1 tDCS (tDCS), (2) right M1 1 mA anodal 4 * 1 HD-tDCS (HD-tDCS), or (3) sham. Over five consecutive days, participants trained their left hand using the Purdue Pegboard Test (PPTL). The Jebsen-Taylor Test, Serial Reaction Time Task, and right hand and bimanual PPT were also tested at baseline, post-training, and 6-week retention time (RT). Results: Both the tDCS and HD-tDCS groups demonstrated enhanced motor learning compared to sham with effects maintained at 6 weeks. Effect sizes were moderate-to-large for tDCS and HD-tDCS groups at the end of day 4 (Cohen's d tDCS = 0.960, HD-tDCS = 0.766) and day 5 (tDCS = 0.655, HD-tDCS = 0.851). Enhanced motor learning effects were also seen in the untrained hand. HD tDCS was well tolerated and safe with no adverse effects. Conclusion: HD-tDCS and tDCS can enhance motor learning in children. Further exploration is indicated to advance rehabilitation therapies for children with motor disabilities such as cerebral palsy. Clinical Trial Registration: clinicaltrials.gov, identifier NCT03193580. PMID- 30429769 TI - Dbx1-Derived Pyramidal Neurons Are Generated Locally in the Developing Murine Neocortex. AB - The neocortex (NCx) generates at the dorsal region of the pallium in the forebrain. Several adjacent structures also contribute with neurons to NCx. Ventral pallium (VP) is considered to generate several populations of neurons that arrive through tangential migration to the NCx. Amongst them are the Cajal Retzius cells and some transient pyramidal neurons. However, the specific site and timing of generation, trajectory of migration and actual contribution to the pyramidal population remains elusive. Here, we investigate the spatio-temporal origin of neuronal populations from VP in an in vivo model, using a transposase mediated in utero electroporation method in embryonic mouse. From E11 to E14 cells born at the lateral corner of the neocortical neuroepithelium including the VP migrated ventro-laterally to settle all areas of the ventral telencephalon. Specifically, neurons migrated into amygdala (Ag), olfactory cortices, and claustrum (Cl). However, we found no evidence for any neurons migrating tangentially toward the NCx, regardless the antero-posterior level and developmental time of the electroporation. Our results challenge the described ventral-pallial origin of the transient pyramidal neuron population. In order to find the exact origin of cortical neurons that were previously Dbx1-fate mapped we used the promoter region of the murine Dbx1 locus to selectively target Dbx1 expressing progenitors and label their lineage. We found these progenitors in low numbers in all pallial areas, and not only in the ventral pallial ventricular zone. Our findings on the local cortical origin of the Dbx1-derived pyramidal neurons reconcile the observation of Dbx1-derived neurons in the cortex without evidence of dorsal tangential migration from VP and provide a new framework for the origin of the transient Dbx1-derived pyramidal neuron population. We conclude that these neurons are born locally within the dorsal pallial neuroepithelium. PMID- 30429770 TI - Role of Oscillations in Auditory Temporal Processing: A General Model for Temporal Processing of Sensory Information in the Brain? AB - We review the role of oscillations in the brain and in the auditory system showing that the ability of humans to distinguish changes in pitch can be explained as a precise analysis of temporal information in auditory signals by neural oscillations. The connections between auditory brain stem chopper neurons construct neural oscillators, which discharge spikes at various constant intervals that are integer multiples of 0.4 ms, contributing to the temporal processing of auditory cochlear output. This is subsequently spatially mapped in the inferior colliculus. Electrophysiological measurements of auditory chopper neurons in different species show oscillations with periods which are integer multiples of 0.4 ms. The constant intervals of 0.4 ms can be attributed to the smallest synaptic delay between interconnected simulated chopper neurons. We also note the patterns of similarities between microcircuits in the brain stem and other parts of the brain (e.g., the pallidum, reticular formation, locus coeruleus, oculomotor nuclei, limbic system, amygdala, hippocampus, basal ganglia and substantia nigra), dedicated to the processing of temporal information. Similarities in microcircuits across the brain reflect the importance of one of the key mechanisms in the information processing in the brain, namely the temporal coupling of different neural events via coincidence detection. PMID- 30429771 TI - Influence of Sex on Cognition and Peripheral Neurovascular Function in Diabetic Mice. AB - Cognition impairment and peripheral neuropathy (DPN) are two major complications of diabetes. The aim of the present study is to investigate the effect of sex differences on cognition and DPN in diabetic mice. Male and female BKS.Cg m+/+Leprdb/J (db/db) and db/m mice were used. At ages of 20 and 30 weeks, all animals were subjected to learning, memory and neurological function tests. Regional blood flow in footpad and sciatic nerves were measured using laser Doppler flowmetry. Our data showed that male db/db mice aged 20 weeks and 30 weeks spent significantly more time to locate the hidden platform in the correct quadrant and spent significantly less time exploring the cage with a new stranger mouse compared to aged-matched female db/db mice. Electrophysiological recordings showed that male db mice aged 30 weeks had significantly reduced motor and sensory nerve conduction velocity compared with females. Hot plate and tactile allodynia tests revealed that males exhibited significantly higher thermal and mechanical latency than females. Male db mice aged 30 weeks displayed significantly reduced blood perfusion in sciatic nerve and footpad tissues compared with females. In addition, compared with male and female non-diabetic db/m mice, db/db mice exhibited increased time spent on locating the hidden platform, decreased time spent on exploring the novel odor bead and an unfamiliar mouse, as well as showed significantly lower levels of blood flow, lower velocity of MCV and SCV, higher thermal and mechanical latencies. Blood glucose levels and body weight were not significantly different between male and female diabetic animals (age 30 weeks), but male db mice showed a higher serum total cholesterol content. Together, our data suggest that males develop a greater extent of diabetes-induced cognition deficits and peripheral neurovascular dysfunction than females. PMID- 30429774 TI - Editorial: Neuroglia Molecular Mechanisms in Psychiatric Disorders. PMID- 30429772 TI - Implicit Grasp Force Representation in Human Motor Cortical Recordings. AB - In order for brain-computer interface (BCI) systems to maximize functionality, users will need to be able to accurately modulate grasp force to avoid dropping heavy objects while also being able to handle fragile items. We present a case study consisting of two experiments designed to identify whether intracortical recordings from the motor cortex of a person with tetraplegia could predict intended grasp force. In the first task, we were able classify neural responses to attempted grasps of four objects, each of which required similar grasp kinematics but different implicit grasp force targets, with 69% accuracy. In the second task, the subject attempted to move a virtual robotic arm in space to grasp a simple virtual object. For each trial, the subject was asked to grasp the virtual object with the force appropriate for one of the four objects from the first experiment, with the goal of measuring an implicit representation of grasp force. While the subject knew the grasp force during all phases of the trial, accurate classification was only achieved during active grasping, not while the hand moved to, transported, or released the object. In both tasks, misclassifications were most often to the object with an adjacent force requirement. In addition to the implications for understanding the representation of grasp force in motor cortex, these results are a first step toward creating intelligent algorithms to help BCI users grasp and manipulate a variety of objects that will be encountered in daily life. Clinical Trial Identifier: NCT01894802 https://clinicaltrials.gov/ct2/show/NCT01894802. PMID- 30429773 TI - No Plasmatic Proteomic Signature at Clinical Disease Onset Associated With 11 Year Clinical, Cognitive and MRI Outcomes in Relapsing-Remitting Multiple Sclerosis Patients. AB - Background: The clinical course of relapsing-remitting multiple sclerosis (RRMS) is highly heterogeneous and prognostic biomarkers at time of diagnosis are lacking. Objective: We investigated the predictive value of the plasma proteome at time of diagnosis in RRMS patients. Methods: The plasma proteome was interrogated using a novel aptamer-based proteomics platform, which allows to measure the levels of a predefined set of 1310 proteins. Results: In 67 clinically and radiologically well characterized RRMS patients, we found no association between the plasma proteome at diagnosis and clinical, cognitive or MRI outcomes after 11 years. Conclusions: Proteomics studies on cerebrospinal fluid may be better suited to identify prognostic biomarkers in early RRMS. PMID- 30429775 TI - A Novel Perspective Linkage Between Kidney Function and Alzheimer's Disease. AB - It has long been believed that kidney function is linked to brain activity. Clinical studies demonstrate that patients with chronic kidney disease (CKD) are more prone to cognitive impairment and Alzheimer's disease (AD), and the degree of cognitive impairment is closely related to CKD progression and renal failure. Moreover, the fact that cognitive function in CKD patients is significantly improved after successful kidney transplantation reveals a linkage between CKD and AD. However, the mechanisms behind this linkage are unclear. The physiological function of the kidney is to maintain the stability of the internal environment, including the cerebrovascular circulation, whereas abnormal kidney function often leads to ischemia and hypoxia. Many CKD patients experience chronic hypoxia, and many urinary toxins accumulate after renal function is impaired. In this mini review, we will propose a novel perspective on the association between AD and CKD and the connection between the kidney and brain. PMID- 30429776 TI - Mice With Decreased Number of Interneurons Exhibit Aberrant Spontaneous and Oscillatory Activity in the Cortex. AB - GABAergic (gamma-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities in oscillatory activity, especially in the gamma frequency range (30-80 Hz). We investigated the functional changes in cortical network activity in response to developmentally reduced inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays ~50% fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells [Rac1 conditional knockout (cKO) mice], to examine how this developmental loss of cortical interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity, and neuronal oscillations in the adult BC. The decrease in the number of interneurons increased basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio (PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit enhanced sensitivity and susceptibility to emergent spontaneous activity. We also find that this developmental decrease in the number of cortical interneurons results in local neuronal networks with alterations in neuronal oscillations, exhibiting decreased power in low frequencies (delta, theta, alpha) and gamma frequency range (30-80 Hz) with an extra aberrant peak in high gamma frequency range (80-150 Hz). Therefore, our data show that disruption in GABAergic inhibition alters synaptic properties and plasticity, while it additionally disrupts the cortical neuronal synchronization in the adult BC. PMID- 30429777 TI - Functional Topography and Development of Inhibitory Reticulothalamic Barreloid Projections. AB - The thalamic reticular nucleus (TRN) is the main source of inhibition to the somatosensory thalamus (ventrobasal nucleus, VB) in mice. However, the functional topography and development of these projections with respect to the VB barreloids has been largely unexplored. In this respect, to assist in the study of these projections, we have utilized a vesicular gamma-aminobutryic acid (GABA) transporter (VGAT)-Venus transgenic mouse line to develop a brain slice preparation that enables the rapid identification of inhibitory neurons and projections. We demonstrate the utility of our in vitro brain slice preparation for physiologically mapping inhibitory reticulothalamic (RT) topography, using laser-scanning photostimulation via glutamate uncaging. Furthermore, we utilized this slice preparation to compare the development of excitatory and inhibitory projections to VB. We found that excitatory projections to the barreloids, created by ascending projections from the brain stem, develop by postnatal day 2 3 (P2-P3). By contrast, inhibitory projections to the barreloids lag ~5 days behind excitatory projections to the barreloids, developing by P7-P8. We probed this lag in inhibitory projection development through early postnatal whisker lesions. We found that in whisker-lesioned animals, the development of inhibitory projections to the barreloids closed by P4, in register with that of the excitatory projections to the barreloids. Our findings demonstrate both developmental and topographic organizational features of the RT projection to the VB barreloids, whose mechanisms can now be further examined utilizing the VGAT Venus mouse slice preparation that we have characterized. PMID- 30429778 TI - Restoration and Efficiency of the Neural Processing of Continuous Speech Are Promoted by Prior Knowledge. AB - Sufficiently noisy listening conditions can completely mask the acoustic signal of significant parts of a sentence, and yet listeners may still report the perception of hearing the masked speech. This occurs even when the speech signal is removed entirely, if the gap is filled with stationary noise, a phenomenon known as perceptual restoration. At the neural level, however, it is unclear the extent to which the neural representation of missing extended speech sequences is similar to the dynamic neural representation of ordinary continuous speech. Using auditory magnetoencephalography (MEG), we show that stimulus reconstruction, a technique developed for use with neural representations of ordinary speech, works also for the missing speech segments replaced by noise, even when spanning several phonemes and words. The reconstruction fidelity of the missing speech, up to 25% of what would be attained if present, depends however on listeners' familiarity with the missing segment. This same familiarity also speeds up the most prominent stage of the cortical processing of ordinary speech by approximately 5 ms. Both effects disappear when listeners have no or little prior experience with the speech segment. The results are consistent with adaptive expectation mechanisms that consolidate detailed representations about speech sounds as identifiable factors assisting automatic restoration over ecologically relevant timescales. PMID- 30429779 TI - Effects of Trauma in Adulthood and Adolescence on Fear Extinction and Extinction Retention: Advancing Animal Models of Posttraumatic Stress Disorder. AB - Evidence for and against adolescent vulnerability to posttraumatic stress disorder (PTSD) is mounting, but this evidence is largely qualitative, retrospective, or complicated by variation in prior stress exposure and trauma context. Here, we examine the effects of development on trauma vulnerability using adult post-natal (PN) day 61, early adolescent (PN23) and mid adolescence (PN34) rats and two types of trauma: an established animal model of PTSD, single prolonged stress (SPS), and a novel composite model-SPS predation (SPSp) version. We demonstrate that early and mid adolescent rats are capable of fear conditioning and fear extinction, as well as extinction retention. Our results also demonstrate that both types of trauma induced a deficit in the retention of fear extinction in adulthood, a hallmark of PTSD, but not after early or mid adolescence trauma, suggesting that adolescence might convey resilience to SPS and SPSp traumas. Across all three life stages, the effects of SPS exposure and a novel predation trauma model, SPSp, had similar effects on behavior suggesting that trauma type did not affect the likelihood of developing PTSD-like symptoms, and that SPSp is a predation-based trauma model worth exploring. PMID- 30429780 TI - Behavioral Plasticity of Audiovisual Perception: Rapid Recalibration of Temporal Sensitivity but Not Perceptual Binding Following Adult-Onset Hearing Loss. AB - The ability to accurately integrate or bind stimuli from more than one sensory modality is highly dependent on the features of the stimuli, such as their intensity and relative timing. Previous studies have demonstrated that the ability to perceptually bind stimuli is impaired in various clinical conditions such as autism, dyslexia, schizophrenia, as well as aging. However, it remains unknown if adult-onset hearing loss, separate from aging, influences audiovisual temporal acuity. In the present study, rats were trained using appetitive operant conditioning to perform an audiovisual temporal order judgment (TOJ) task or synchrony judgment (SJ) task in order to investigate the nature and extent that audiovisual temporal acuity is affected by adult-onset hearing loss, with a specific focus on the time-course of perceptual changes following loud noise exposure. In our first series of experiments, we found that audiovisual temporal acuity in normal-hearing rats was influenced by sound intensity, such that when a quieter sound was presented, the rats were biased to perceive the audiovisual stimuli as asynchronous (SJ task), or as though the visual stimulus was presented first (TOJ task). Psychophysical testing demonstrated that noise-induced hearing loss did not alter the rats' temporal sensitivity 2-3 weeks post-noise exposure, despite rats showing an initial difficulty in differentiating the temporal order of audiovisual stimuli. Furthermore, consistent with normal-hearing rats, the timing at which the stimuli were perceived as simultaneous (i.e., the point of subjective simultaneity, PSS) remained sensitive to sound intensity following hearing loss. Contrary to the TOJ task, hearing loss resulted in persistent impairments in asynchrony detection during the SJ task, such that a greater proportion of trials were now perceived as synchronous. Moreover, psychophysical testing found that noise-exposed rats had altered audiovisual synchrony perception, consistent with impaired audiovisual perceptual binding (e.g., an increase in the temporal window of integration on the right side of simultaneity; right temporal binding window (TBW)). Ultimately, our collective results show for the first time that adult-onset hearing loss leads to behavioral plasticity of audiovisual perception, characterized by a rapid recalibration of temporal sensitivity but a persistent impairment in the perceptual binding of audiovisual stimuli. PMID- 30429783 TI - Human-Robotic Variable-Stiffness Grasps of Small-Fruit Containers Are Successful Even Under Severely Impaired Sensory Feedback. AB - Application areas of robotic grasping extend to delicate objects like groceries. The intrinsic elasticity offered by variable-stiffness actuators (VSA) appears to be promising in terms of being able to adapt to the object shape, to withstand collisions with the environment during the grasp acquisition, and to resist the weight applied to the fingers by a lifted object during the actual grasp. It is hypothesized that these properties are particularly useful in the absence of high quality sensory feedback, which would otherwise be able to guide the shape adaptation and collision avoidance, and that in this case, VSA hands perform better than hands with fixed stiffness. This hypothesis is tested in an experiment where small-fruit containers are picked and placed using a newly developed variable-stiffness robotic hand. The grasp performance is measured under different sensory feedback conditions: full or impaired visual feedback, full or impaired force feedback. The hand is switched between a variable stiffness mode and two fixed-stiffness modes. Strategies for modulating the stiffness and exploiting environmental constraints are observed from human operators that control the robotic hand. The results show consistently successful grasps under all stiffness and feedback conditions. However, the performance is affected by the amount of available visual feedback. Different stiffness modes turn out to be beneficial in different feedback conditions and with respect to different performance criteria, but a general advantage of VSA over fixed stiffness cannot be shown for the present task. Guidance of the fingers along cracks and gaps is observed, which may inspire the programming of autonomously grasping robots. PMID- 30429782 TI - The Effect of Unihemispheric Concurrent Dual-Site Transcranial Direct Current Stimulation of Primary Motor and Dorsolateral Prefrontal Cortices on Motor Function in Patients With Sub-Acute Stroke. AB - It is believed that unihemispheric concurrent dual-site transcranial direct current stimulation (tDCSUHCDS) of the primary motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC) causes an increase in motor cortex excitability. However, the clinical effect of this type of stimulation on patients with neurological conditions is not yet known. The aim of the present study was to assess the effect of anodal-tDCSUHCDS (a-tDCSUHCDS) on upper limb motor function in subacute stroke patients. Fifteen patients participated in this sham-controlled crossover study. The main outcome measures were the reaction time (RT) to visual stimuli, completion time of a nine-pin pegboard (9-PPB), and the scores from the Fugl-Meyer assessment (FMA) for the upper limb of the involved side before and after three brain stimulation conditions. For a-tDCSUHCDS, the anodal electrodes were placed on the M1 and the DLPFC, while for a-tDCS, the anodal electrode was placed on the M1. For the sham stimulation, the tDCS was turned off after 30 s. For brain stimulation, the selected current was 1 mA for 20 min. After a-tDCSUHCDS, there was a significant reduction in the RT and completion time of the 9-PPB compared with the times after a-tDCS and the sham stimulation: p = 0.013 and p = 0.022, respectively). However, there was no significant difference in the FMA scores after the three types of stimulations (p = 0.085). Compared with a-tDCS, a-tDCSUHCDS temporarily improved the RT and dexterity of the involved hand in subacute stroke patients. Clinical Trial Registration: Iranian Registry of Clinical Trials (IRCT), identifier IRCT2015012520787N1. PMID- 30429781 TI - State-Dependent Memory: Neurobiological Advances and Prospects for Translation to Dissociative Amnesia. AB - In susceptible individuals, overwhelming traumatic stress often results in severe abnormalities of memory processing, manifested either as the uncontrollable emergence of memories (flashbacks) or as an inability to remember events (dissociative amnesia, DA) that are usually, but not necessarily, related to the stressful experience. These memory abnormalities are often the source of debilitating psychopathologies such as anxiety, depression and social dysfunction. The question of why memory for some traumatic experiences is compromised while other comparably traumatic experiences are remembered perfectly well, both within and across individuals, has puzzled clinicians for decades. In this article, we present clinical, cognitive, and neurobiological perspectives on memory research relevant to DA. In particular, we examine the role of state dependent memory (wherein memories are difficult to recall unless the conditions at encoding and recall are similar), and discuss how advances in the neurobiology of state-dependent memory (SDM) gleaned from animal studies might be translated to humans. PMID- 30429784 TI - Primary Disruption of the Memory-Related Subsystems of the Default Mode Network in Alzheimer's Disease: Resting-State Functional Connectivity MRI Study. AB - Background: Recent studies have indicated that the default mode network (DMN) comprises at least three subsystems: The medial temporal lobe (MTL) and dorsal medial prefrontal cortex (DMPFC) subsystems and a core comprising the anterior MPFC (aMPFC) and posterior cingulate cortex (PCC). Additionally, the disruption of the DMN is related to Alzheimer's disease (AD). However, little is known regarding the changes in these subsystems in AD, a progressive disease characterized by memory impairment. Here, we performed a resting-state functional connectivity (FC) analysis to test our hypothesis that the memory-related MTL subsystem was predominantly disrupted in AD. Method: To reveal specific subsystem changes, we calculated the strength and number of FCS in the DMN intra- and inter subsystems across individuals and compared the FC of the two groups. To further examine which pairs of brain regional functional connections contributed to the subsystem alterations, correlation coefficients between any two brain regions in the DMN were compared across groups. Additionally, to identify which regions made the strongest contributions to the subsystem changes, we calculated the regional FC strength (FCS), which was compared across groups. Results: For the intra subsystem, decreased FC number and strength occurred in the MTL subsystem of AD patients but not in the DMPFC subsystem or core. For the inter-subsystems, the AD group showed decreased FCS and number between the MTL subsystem and PCC and a decreased number between the PCC and DMPFC subsystem. Decreased inter-regional FCS were found within the MTL subsystem in AD patients relative to controls: The posterior inferior parietal lobule (pIPL) showed decreased FC with the hippocampal formation (HF), parahippocampal cortex (PHC) and ventral MPFC (vMPFC). Decreased inter-regional FCS of the inter-subsystems were also found in AD patients: The HF and/or PHC showed decreased FC with dMPFC and TPJ, located in the DMPFC subsystem, and with PCC. AD patients also showed decreased FC between the PCC and TLC of the dMPFC subsystem. Furthermore, the HF and PHC in the MTL subsystem showed decreased regional FCS. Conclusion: Decreased intrinsic FC was mainly associated with the MTL subsystem of the AD group, suggesting that the MTL subsystem is predominantly disrupted. PMID- 30429785 TI - Hyperhomocysteinemia as a Risk Factor for Vascular Contributions to Cognitive Impairment and Dementia. AB - Behind only Alzheimer's disease, vascular contributions to cognitive impairment and dementia (VCID) is the second most common cause of dementia, affecting roughly 10-40% of dementia patients. While there is no cure for VCID, several risk factors for VCID, such as diabetes, hypertension, and stroke, have been identified. Elevated plasma levels of homocysteine, termed hyperhomocysteinemia (HHcy), are a major, yet underrecognized, risk factor for VCID. B vitamin deficiency, which is the most common cause of HHcy, is common in the elderly. With B vitamin supplementation being a relatively safe and inexpensive therapeutic, the treatment of HHcy-induced VCID would seem straightforward; however, preclinical and clinical data shows it is not. Clinical trials using B vitamin supplementation have shown conflicting results about the benefits of lowering homocysteine and issues have arisen over proper study design within the trials. Studies using cell culture and animal models have proposed several mechanisms for homocysteine-induced cognitive decline, providing other targets for therapeutics. For this review, we will focus on HHcy as a risk factor for VCID, specifically, the different mechanisms proposed for homocysteine-induced cognitive decline and the clinical trials aimed at lowering plasma homocysteine. PMID- 30429786 TI - A Randomized Controlled Trial: Regenerative Effects, Efficacy and Safety of Erythropoietin in Burn and Scalding Injuries. AB - In adult's burn injuries belong to the top 15 causes of injury. Annually more than a million patients receive specialized treatment. Improving burned patients' outcomes is still a challenge. Effects of erythropoietin (EPO) are reported to be pro-angiogenic, pro-regenerative, anti-inflammatory, immunomodulatory and hypoxia/ischemia protective. Study objectives were to demonstrate cytoprotective and regenerative effects of EPO in burned patients in terms of improved wound healing, reduced morbidity and mortality. This was a prospective, placebo controlled, randomized, double-blind trial. The trial was conducted in 13 specialized burn care centers in Germany. Adult Patients with 2b degrees or 3 degrees burn injuries were included. Patients received state of the art burn care including obligatory split skin graft transplantation. Study medication was EPO or placebo every other day for 21 days. Between 12/08 and 06/14, 116 patients were randomized, 84 received study medication (EPO 45, Placebo 39). Primary endpoint analysis revealed inconclusive results, as only a minority of patients reached the primary endpoint [100% re-epithelialization: EPO: 23% (9/40); Placebo 30% (11/37)]. Several secondary endpoints such as SOFA score (morbidity), EPO level in blood and wound healing onset revealed clinical, and statistically significant results in favor of the EPO group. Adverse Events (AEs) and Severe Adverse Events (SAEs) were in expected ranges; AEs EPO: 80%, (36/45), Placebo: 77%, (30/39); SAEs EPO: 24%, (11/45), Placebo: 24%, (8/39). Out of 84 patients two died, one per group, thus mortality was lower than expected. Results (SOFA score) indicate a lower morbidity of the EPO group, suggesting pro-regenerative effects of EPO in burned patients. Higher EPO levels might influence the faster onset of re-epithelialization in the first 10 days of the treatment. Both effects could reveal new therapeutic options. Clinical Trial Registration: ISRCT Number: ISRCTN95777824 and EudraCT Number: 2006-002886-38, Protocol Number: 0506. PMID- 30429788 TI - Qingchang Suppository Ameliorates Colonic Vascular Permeability in Dextran Sulfate-Sodium-Induced Colitis. AB - Ulcerative colitis (UC), with a long course and repeated attack, severely affects patient's life quality and increases economic burden all over the world. However, the concrete causes and mechanisms of UC are still unclear, but it is generally considered that many factors participate in this process. Qingchang Suppository (QCS) has been used in treating rectitis and colitis for about 30 years in Shanghai, China. Its satisfactory clinical effects have been proved. The aim of this study is to investigate the effect and mechanisms of QCS on colonic vascular endothelial barrier in dextran sulfate sodium (DSS)-induced colitis. The results indicated that increased vascular permeability (VP) appeared earlier than increased intestinal epithelial permeability (EP) in the process of DSS-induced colitis. QCS attenuated colonic tissue edema, vascular congestion and inflammatory cell infiltration. QCS inhibited the elevation of MPO, TNF-alpha, and IL-6 levels in colon tissues and alleviated the microvascular damage induced by DSS. QCS also improved colonic hypoxia and decreased the expression of VEGF, HIF-1alpha, and iNOS. These results revealed that QCS can reduce colonic VP and can improve vascular endothelial barrier function maybe by regulating the VEGF/HIF-1alpha signaling pathway. PMID- 30429789 TI - Pien Tze Huang Alleviates Relapsing-Remitting Experimental Autoimmune Encephalomyelitis Mice by Regulating Th1 and Th17 Cells. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by infiltrating inflammatory cells and demyelinating lesions, and T helper (Th) cells play critical roles in the pathogenesis of MS. There is still lack of effective treatments currently. Pien Tze Huang (PZH), a traditional Chinese medicine formula, has been proved to have anti-inflammatory, neuroprotective, and immunoregulatory effects. However, whether PZH can be used to treat MS is still obscure. This study aimed to investigate the possible therapeutic effect and the underlying action mechanism of PZH in relapsing remitting experimental autoimmune encephalomyelitis (RR-EAE) mice. Female SJL/J mice were immunized with myelin proteolipid protein 139-151 (PLP139-151) and pertussis toxin to establish RR-EAE model. Mice were then randomly divided into normal group, model group, PZH group and positive control group (fingolimod, FTY 720), and drugs were orally administered for 60 days from the day 10 after immunization. Sera of mice were collected for ELISA detection. Tissues of CNS were harvested for hematoxylin-eosin (H-E) and luxol fast blue (LFB) staining. Furthermore, Th1, Th17 cells and their related cytokines in the CNS were detected by flow cytometry and quantitative real-time PCR, respectively. Proteins involved in STAT and NF-kappaB signaling pathways were detected by western blot. The results showed that PZH-treated mice displayed mild or moderate clinical symptoms compared with untreated EAE mice that exhibited severe clinical symptoms. PZH remarkably reduced inflammatory cell infiltration and myelin damage in the CNS of EAE mice. It markedly down-regulated the levels of IFN-gamma and IL-17A in sera of EAE mice. Moreover, PZH could reduce the percentages of Th1 and Th17 cells. It also suppressed the production of transcription factors ROR-gammat and T-bet as well as the mRNA levels of their downstream pro-inflammatory cytokines, such as IFN-gamma and IL-17A. Furthermore, PZH could inhibit the phosphorylation of some key proteins in the STAT and NF-kappaB signaling pathways. In conclusion, the study demonstrated that PZH had a therapeutic effect on RR-EAE mice, which was associated with the modulation effect on Th1 and Th17 cells. PMID- 30429791 TI - Drug Shortages From the Perspectives of Authorities and Pharmacy Practice in the Netherlands: An Observational Study. AB - Background: Drug shortages are a potential threat to public health. Reliable data on drug shortages is limited. The objective was to examine the extent and nature of potential drug shortages signaled by authorities and pharmacy practice in the Netherlands Materials and Methods: The primary working systems of Dutch authorities (Medicines Evaluation Board and Health and Youth Care Inspectorate) and the archives of pharmacy practice (Royal Dutch Pharmacists Association) from 2012 to 2015 were searched for number, characteristics, overlap, and date of signals on potential drug shortages. Also, the product characteristics of the potential drug shortages were analyzed from the two different sources Results: Authorities detected 2.6 times more signals on potential shortages than pharmacy practice. Only 438 (8%) out of 5,731 potential drug shortages were detected by both authorities and pharmacy practice. Signals were detected later by authorities than by pharmacy practice, especially on potential permanent shortages (median difference -180 days (IQR: -4 to -405 days)). Authorities detected by majority (72%) signals related to permanent shortages with relative overrepresentation of rectal products and anti-infectives for systemic use. In contrast, pharmacy practice detected by majority (71%) signals related to temporary shortages with relative overrepresentation of ocular and cutaneous products, anti-infectives for systemic use, products for sensory organs and dermatologicals. Conclusions: Authorities and pharmacy practice detected different signals on potential drug shortages with little overlap. Combining data from both authorities and pharmacy practice seems to be necessary in order to gain a more complete overview and maximum insight in potential drug shortages at a national level. Moreover, the finding that authorities were informed later than pharmacy practice causes concerns in terms of opportunities for authorities to assist pharmacy practice to find solutions for shortages. PMID- 30429790 TI - The Lipid Mediator Resolvin D1 Reduces the Skin Inflammation and Oxidative Stress Induced by UV Irradiation in Hairless Mice. AB - UV irradiation-induced oxidative stress and inflammation contribute to the development of skin diseases. Therefore, targeting oxidative stress and inflammation might contribute to reduce skin diseases. Resolvin D1 (RvD1) is a bioactive metabolite generated during inflammation to actively orchestrate the resolution of inflammation. However, the therapeutic potential of RvD1 in UVB skin inflammation remains undetermined, which was, therefore, the aim of the present study. The intraperitoneal treatment with RvD1 (3-100 ng/mouse) reduced UVB irradiation-induced skin edema, myeloperoxidase activity, matrix metalloproteinase 9 activity, and reduced glutathione depletion with consistent effects observed with the dose of 30 ng/mouse, which was selected to the following experiments. RvD1 inhibited UVB reduction of catalase activity, and hydroperoxide formation, superoxide anion production, and gp91phox mRNA expression. RvD1 also increased the Nrf2 and its downstream targets NQO1 and HO-1 mRNA expression. Regarding cytokines, RvD1 inhibited UVB-induced production of IL 1beta, IL-6, IL-33, TNF-alpha, TGF-beta, and IL-10. These immuno-biochemical alterations by RvD1 treatment had as consequence the reduction of UVB-induced epidermal thickness, sunburn and mast cell counts, and collagen degradation. Therefore, RvD1 inhibited UVB-induced skin oxidative stress and inflammation, rendering this resolving lipid mediator as a promising therapeutic agent. PMID- 30429787 TI - Tumor Microenvironment Targeted Nanotherapy. AB - Recent developments in nanotechnology have brought new approaches to cancer diagnosis and therapy. While enhanced permeability and retention effect promotes nano-chemotherapeutics extravasation, the abnormal tumor vasculature, high interstitial pressure and dense stroma structure limit homogeneous intratumoral distribution of nano-chemotherapeutics and compromise their imaging and therapeutic effect. Moreover, heterogeneous distribution of nano chemotherapeutics in non-tumor-stroma cells damages the non-tumor cells, and interferes with tumor-stroma crosstalk. This can lead not only to inhibition of tumor progression, but can also paradoxically induce acquired resistance and facilitate tumor cell proliferation and metastasis. Overall, the tumor microenvironment plays a vital role in regulating nano-chemotherapeutics distribution and their biological effects. In this review, the barriers in tumor microenvironment, its consequential effects on nano-chemotherapeutics, considerations to improve nano-chemotherapeutics delivery and combinatory strategies to overcome acquired resistance induced by tumor microenvironment have been summarized. The various strategies viz., nanotechnology based approach as well as ligand-mediated, redox-responsive, and enzyme-mediated based combinatorial nanoapproaches have been discussed in this review. PMID- 30429792 TI - Determining the Balance Between Drug Efficacy and Safety by the Network and Biological System Profile of Its Therapeutic Target. AB - One of the most challenging puzzles in drug discovery is the identification and characterization of candidate drug of well-balanced profile between efficacy and safety. So far, extensive efforts have been made to evaluate this balance by estimating the quantitative structure-therapeutic relationship and exploring target profile of adverse drug reaction. Particularly, the therapeutic index (TI) has emerged as a key indicator illustrating this delicate balance, and a clinically successful agent requires a sufficient TI suitable for it corresponding indication. However, the TI information are largely unknown for most drugs, and the mechanism underlying the drugs with narrow TI (NTI drugs) is still elusive. In this study, the collective effects of human protein-protein interaction (PPI) network and biological system profile on the drugs' efficacy safety balance were systematically evaluated. First, a comprehensive literature review of the FDA approved drugs confirmed their NTI status. Second, a popular feature selection algorithm based on artificial intelligence (AI) was adopted to identify key factors differencing the target mechanism between NTI and non-NTI drugs. Finally, this work revealed that the targets of NTI drugs were highly centralized and connected in human PPI network, and the number of similarity proteins and affiliated signaling pathways of the corresponding targets was much higher than those of non-NTI drugs. These findings together with the newly discovered features or feature groups clarified the key factors indicating drug's narrow TI, and could thus provide a novel direction for determining the delicate drug efficacy-safety balance. PMID- 30429795 TI - Editorial: Hidden Secrets and Lessons From the Crystal Structures of Integral Membrane Proteins: Channels, Pumps and Receptors. PMID- 30429793 TI - High-Intensity Interval Training Improves Markers of Oxidative Metabolism in Skeletal Muscle of Individuals With Obesity and Insulin Resistance. AB - Background: The excess body fat characteristic of obesity is related to various metabolic alterations, which includes insulin resistance (IR). Among the non pharmacological measures used to improve insulin sensitivity are aerobic physical training, such as high-intensity interval training (HIIT). This study investigated the effects of 8 weeks of HIIT on blood and skeletal muscle markers related to IR and oxidative metabolism in physically inactive individuals with obesity and compared the changes between insulin resistant and non-insulin resistant phenotypes. Methods: Initially to investigate the effect of obesity and IR in the analyzed parameters, insulin-sensitive eutrophic volunteers (CON; n = 9) and obese non-insulin (OB; n = 9) and insulin-resistant (OBR; n = 8) were enrolled. Volunteers with obesity completed 8 weeks of HIIT in a cycle ergometer. Venous blood and vastus lateralis muscle samples were obtained before and after the HIIT. Body composition and peak oxygen consumption (VO2peak) were estimated before and after HIIT. Results: HIIT reduced IR assessed by the homeostatic model assessment of insulin resistance (HOMA-IR) in OBR (4.4 +/- 1.4 versus 4.1 +/- 2.2 MUU L-2), but not in OB (HOMA-IR 1.8 +/- 0.5 versus 2.3 +/- 1.0 MUU L-2) volunteers. HIIT increased VO2peak with no change in body fat in both groups. In skeletal muscle, HIIT increased the phosphorylation of IRS (Tyr612), Akt (Ser473), and increased protein content of beta-HAD and COX-IV in both groups. There was a reduction in ERK1/2 phosphorylation in OBR after HIIT. Conclusion: Eight weeks of HIIT increased the content of proteins related to oxidative metabolism in skeletal muscle of individuals with obesity, independent of changes total body fat. PMID- 30429794 TI - Chronic Nicotine Exposure Induces Murine Aortic Remodeling and Stiffness Segmentation-Implications for Abdominal Aortic Aneurysm Susceptibility. AB - Aim: Arterial stiffness is a significant risk factor for many cardiovascular diseases, including abdominal aortic aneurysms (AAA). Nicotine, the major active ingredient of e-cigarettes and tobacco smoke, induces acute vasomotor effects that may temporarily increase arterial stiffness. Here, we investigated the effects of long-term nicotine exposure on structural aortic stiffness. Methods: Mice (C57BL/6) were infused with nicotine for 40 days (20 mg/kg/day). Arterial stiffness of the thoracic (TS) and abdominal (AS) aortic segments was analyzed using ultrasound (PWV, pulse wave velocity) and ex vivo pressure myograph measurements. For mechanistic studies, aortic matrix-metalloproteinase (MMP) expression and activity as well as medial elastin architecture were analyzed. Results: Global aortic stiffness increased with nicotine. In particular, local stiffening of the abdominal segment occurred after 10 days, while thoracic aortic stiffness was only increased after 40 days, resulting in aortic stiffness segmentation. Mechanistically, nicotine exposure enhanced expression of MMP-2/-9 and elastolytic activity in both aortic segments. Elastin degradation occurred in both segments; however, basal elastin levels were higher in the thoracic aorta. Finally, MMP-inhibition significantly reduced nicotine-induced MMP activity, elastin destruction, and aortic stiffening. Conclusion: Chronic nicotine exposure induces aortic MMP expression and structural aortic damage (elastin fragmentation), irreversibly increasing aortic stiffness. This process predominantly affects the abdominal aortic segment, presumably due in part to a lower basal elastin content. This novel phenomenon may help to explain the role of nicotine as a major risk factor for AAA formation and has health implications for ECIGs and other modes of nicotine delivery. PMID- 30429796 TI - Osmolality Selectively Offsets the Impact of Hyperthermia on Mouse Skeletal Muscle in vitro. AB - Hyperthermia and dehydration can occur during exercise in hot environments. Nevertheless, whether elevations in extracellular osmolality contributes to the increased skeletal muscle tension, sarcolemmal injury, and oxidative stress reported in warm climates remains unknown. We simulated osmotic and heat stress, in vitro, in mouse limb muscles with different fiber compositions. Extensor digitorum longus (EDL) and soleus (SOL) were dissected from 36 male C57BL6J and mounted at optimal length in tissue baths containing oxygenated buffer. Muscles were stimulated with non-fatiguing twitches for 30 min. Four experimental conditions were tested: isotonic-normothermia (285 mOsm*kg-1 and 35 degrees C), hypertonic-normothermia (300 mOsm*kg-1 and 35 degrees C), isotonic-hyperthermia (285 mOsm*kg-1 and 41 degrees C), and hypertonic-hyperthermia (300 mOsm*kg-1 and 41 degrees C). Passive tension was recorded continuously. The integrity of the sarcolemma was determined using a cell-impermeable fluorescent dye and immunoblots were used for detection of protein carbonyls. In EDL muscles, isotonic and hypertonic-hyperthermia increased resting tension (P < 0.001). Whereas isotonic-hyperthermia increased sarcolemmal injury in EDL (P < 0.001), this effect was absent in hypertonic-hyperthermia. Similarly, isotonic hyperthermia elevated protein carbonyls (P = 0.018), a response not observed with hypertonic-hyperthermia. In SOL muscles, isotonic-hyperthermia also increases resting tension (P < 0.001); however, these effects were eliminated in hypertonic hyperthermia. Unlike EDL, there were no effects of hyperthermia and/or hyperosmolality on sarcolemmal injury or protein carbonyls. Osmolality selectively modifies skeletal muscle response to hyperthermia in this model. Fast glycolytic muscle appears particularly vulnerable to isotonic-hyperthermia, resulting in elevated muscle tension, sarcolemmal injury and protein oxidation; whereas slow-oxidative muscle exhibits increased tension but no injury or protein oxidation under the conditions and duration tested. PMID- 30429797 TI - Syzygium cumini Nectar Supplementation Reduced Biomarkers of Oxidative Stress, Muscle Damage, and Improved Psychological Response in Highly Trained Young Handball Players. AB - The purpose of this study was to investigate the effects of Syzygium cumini (SC) nectar supplementation on performance, markers of oxidative stress, muscle damage, and psychological response in Handball players. Twenty-five young athletes (age = 18.6 +/- 2.4 years) from an elite high school national level Brazilian Handball team were randomized into two study groups: SC/Jamelon nectar (SC, n = 12) and placebo (n = 13). The subjects ingested 10 mL/kg/day of Jamelon nectar or placebo 30 min before the training sessions and immediately after training cessation, for 28 days. Body mass index (BMI) and percentage of fat mass were assessed using bioelectrical impedance analysis. Biomarkers of oxidative stress were measured by lipid peroxidation, which was quantified by malondialdehyde (MDA). Total antioxidant capacity (TAC), creatine kinase (CK) activity, and lactate dehydrogenase (LDH) were determined. The 20 m shuttle run test, vertical jump, and running anaerobic sprint test were assessed to verify performance and the fatigue index was calculated. The Profile of Mood States (POMS) questionnaire was used for psychological evaluation. Both groups demonstrated improved vertical jump performance and a decreased fatigue index over time but without significant differences between them regarding performance. There was statistically significance only for SC in CK, LDH, and MDA, and TAC was greater in the SC compared to placebo. Furthermore, only the SC group demonstrated improved mood disturbance and confusion after the intervention. In conclusion, the present study suggests that SC nectar supplementation reduced biomarkers of oxidative stress and muscle damage, and improved psychological response in young handball players. PMID- 30429798 TI - Aortic Response to Strength Training and Spirulina platensis Dependent on Nitric Oxide and Antioxidants. AB - Studies have shown that supplementation with Spirulina platensis improves vascular reactivity. However, it is unclear whether in association with strength training this effect can be enhanced. Thus, this study aimed to determine the effects of strength training and S. platensis on the reactivity of the aorta from Wistar rat and the possible mechanisms involved. The animals were supplemented with S. platensis and divided into sedentary (SG, SG50, SG150, and SG500) and trained groups (TG, TG50, TG150, and TG500). Nitrite, malondialdehyde (MDA) and antioxidant activity were determined by biochemical assays. To evaluate vascular response, cumulative concentration-response curves to phenylephrine (PHE) and acetylcholine (ACh) were constructed. L-NAME was used to assess the participation of nitric oxide (NO). It was observed that the PHE contractile potency was reduced in TG50, TG150, and TG500 groups compared to SG50, SG150, and SG500 groups, respectively. However, the presence of L-NAME increased the contractile response in all groups. Strength training potentiated the increase in relaxing activity induced by S. platensis, where the pCE50 values of ACh increased in TG150 and TG500. These responses were accompanied by increased nitrite production, MDA reduction and increased antioxidant activity in the aorta of both TG150 and TG500 groups. Thus, the present study demonstrated that combined with strength training, S. platensis potentiates vascular improvement through the participation of NO and reduction of oxidative stress. PMID- 30429799 TI - Effects of Kinesiology Tape on Non-linear Center of Mass Dispersion During the Y Balance Test. AB - Static taping of the ankle or knee joint is a common method of reducing risk of injury by providing mechanical stability. An alternative taping technique employs kinesiology tape, which has the additional benefit of improving functionality by stimulating proprioception. There is substantial disagreement whether kinesiology tape shows significant differences in proprioception and postural stability as compared to rigid/static tape when applied at the lower limb. The current study investigated the effects of kinesiology tape and static tape during a Y Balance Test on center of mass as an indicator for postural stability. Forty-one individuals, free of injury, performed the Y Balance Test under the three conditions; no tape, kinesiology tape, and static tape applied at the lower limb to the quadriceps, triceps surae and ankle joint. All participants completed the Y Balance Test to determine whether any significant differences could be observed using center of mass movement as a surrogate measure for balance and proprioception. The Minkowski-Bouligand and box-counting fractal dimension analyses were used as measures of the dynamic changes in the center of mass whilst undertaking the Y Balance Test. Statistical analyses included the Kruskal Wallis test to allow for non-normally distributed data and a Bonferroni corrected pairwise T-test as a post hoc test to ascertain pairwise differences between the three taping conditions. Significance was set at 0.05. The fractal analyses of the dynamic changes in center of mass showed significant differences between the control and both the static tape and kinesiology tape groups (p = 0.021 and 0.009, respectively). The current study developed a novel measure of dynamic changes in the center of mass during a set movement that indicated real-time processing effects during a balance task associated with the type of taping used to enhance postural stability. PMID- 30429800 TI - Coronary Smooth Muscle Cell Calcium Dynamics: Effects of Bifurcation Angle on Atheroprone Conditions. AB - This work investigates the effect of arterial bifurcation angulation on atherosclerosis development through in-silico simulations of coupled cell dynamics. The computational model presented here combines cellular pathways, fluid dynamics, and physiologically-realistic vessel geometries as observed in the human vasculature. The coupled cells model includes endothelial cells (ECs) and smooth muscle cells (SMCs) with ion dynamics, hetero and homotypic coupling, as well as electro-diffusive coupling. Three arterial bifurcation surface models were used in the coupled cells simulations. All three simulations showed propagating waves of Ca2+ in both the SMC and EC layers, following the introduction of a luminal agonist, in this case ATP. Immediately following the introduction of ATP concentration Ca2+ waves propagate from the area of high ATP toward the areas of low ATP concentration, forming complex patterns where waves interact with eachother, collide and fade. These dynamic phenomena are repeated with a series of waves of slower velocity. The underlying motivation of this research was to examine the macro-scale phenomena, given that the characteristic length scales of atherosclerotic plaques are much larger than a single cell. The micro-scale dynamics were modeled on macro-scale arterial bifurcation surfaces containing over one million cells. The results of the simulations presented here suggest that susceptibility to atherosclerosis development depends on the bifurcation angulation. In conjunction with findings reported in the literature, the simulation results demonstrate that arterial bifurcations containing wider angles have a more prominent influence on the coupled cells pathways associated with the development of atherosclerosis, by means of disturbed flow and lower SMC Ca2+ concentrations. The discussion of the results considers the findings of this research within the context of the potential link between information transport through frequency encoding of Ca2+ wave dynamics and development of atheroprone conditions. PMID- 30429802 TI - Disease Severity in Treatment Resistant Schizophrenia Patients Is Mainly Affected by Negative Symptoms, Which Mediate the Effects of Cognitive Dysfunctions and Neurological Soft Signs. AB - This post-hoc study was aimed at assessing whether disease severity was higher in a sample of Treatment Resistant Schizophrenia patients (TRS) compared to schizophrenia patients responsive to antipsychotics (non-TRS). Determinants of disease severity were also investigated in these groups. Eligible patients were screened by standardized diagnostic algorithm to categorize them as TRS or non TRS. All patients underwent the following assessments: CGI-S; PANSS; DAI; NES; a battery of cognitive tests. Socio-demographic and clinical variables were also recorded. TRS patients exhibited significantly higher disease severity and psychotic symptoms, either as PANSS total score or subscales' scores. A preliminary correlation analysis ruled out clinical and cognitive variables not associated with disease severity in the two groups. Hierarchical linear regression showed that negative symptoms were the clinical variable explaining the highest part of variation in disease severity in TRS, while in non-TRS patients PANSS-General Psychopathology was the variable explaining the highest variation. Mediation analysis showed that negative symptoms mediate the effects of verbal fluency dysfunctions and high-level neurological soft signs (NSS) on TRS' disease severity. These results show that determinants of disease severity sharply differ in TRS and non-TRS patients, and let hypothesize that TRS may stem from cognitive disfunctions and putatively neurodevelopmental aberrations. PMID- 30429803 TI - Multiple Myeloma, Misdiagnosed As Somatic Symptom Disorder: A Case Report. AB - Here we report on a case of a 57-year-old woman with pain and discomfort in multiple sites of upper body who was diagnosed as somatic symptom disorder after completing a partial examinations of relevant parts which turned out to be negative. Finished imageological examinations of all painful parts, she was eventually diagnosed with multiple myeloma after 6-month being misdiagnosed as somatic symptom disorder. This case highlights the importance of completing imageological examinations of all the painful parts of the patient to exclude the possibility of multiple myeloma especially when symptoms are associated with objective signs and treatment has been ineffective; and it is as well as significant to notice characteristics of symptoms and to pay excessive attention directed toward the symptoms in the diagnosis of somatic symptom disorder. PMID- 30429801 TI - Mouse Microbiota Models: Comparing Germ-Free Mice and Antibiotics Treatment as Tools for Modifying Gut Bacteria. AB - As the intestinal microbiota has become better appreciated as necessary for maintenance of physiologic homeostasis and also as a modulator of disease processes, there has been a corresponding increase in manipulation of the microbiota in mouse models. While germ-free mouse models are generally considered to be the gold standard for studies of the microbiota, many investigators turn to antibiotics treatment models as a rapid, inexpensive, and accessible alternative. Here we describe and compare these two approaches, detailing advantages and disadvantages to both. Further, we detail what is known about the effects of antibiotics treatment on cell populations, cytokines, and organs, and clarify how this compares to germ-free models. Finally, we briefly describe recent findings regarding microbiota regulation of infectious diseases and other immunologic challenges by the microbiota, and highlight important future directions and considerations for the use of antibiotics treatment in manipulation of the microbiota. PMID- 30429804 TI - Emotion Norms, Display Rules, and Regulation in the Akan Society of Ghana: An Exploration Using Proverbs. AB - Proverbs are widely used by the Akan of West Africa. The current study thematically analyzed an Akan proverb compendium for proverbs containing emotion references. Of the identified proverbs, a focus on negative emotions was most typical. Emotion-focused proverbs highlighted four emotion regulation strategies: change in cognition, response modulation, situation modification, and situation selection. A subset of proverbs addressed emotion display rules restricting the expression of emotions such as pride, and emotional contagion associated with emotions such as shame. Additional themes including: social context influences on the expression and experience of emotion; expectations of emotion limits; as well as the nature of emotions were present in the proverb collection. In general, Akan emotion-related proverbs stress individual-level responsibility for affect regulation in interpersonal interactions and societal contexts. PMID- 30429806 TI - Multilingual Competence Influences Answering Strategies in Italian-German Speakers. AB - The present study aims at analyzing the role of nativeness, the amount of input in L1 acquisition and the multilingual competence in the performance of Italian German bilingual speakers. We compare novel data from the performance of adult L2 learners (L1: Italian; late L2: German) and that of heritage speakers (heritage language: Italian; majority language: German) to previous data from monolingual speakers of Italian. The comparison deals with the produced word order at the syntax-discourse interface in sentences containing New Information Subjects in answers to questions that prompt the identification of the clausal subject. Overall, adult L2 speakers and heritage speakers perform alike but crucially differently from Italian monolinguals. These data reveal that multilingual proficiency determines an increased variety in the adopted answering strategies; in particular, the German-like strategy is active in Italian. Nativeness alone is thus no guarantee for a homogeneous performance across groups, nor do we find similar patterns of performance in speakers who grew up as monolinguals. Data also show heritage speakers' sensitivity to verb classes, with answering strategies varying in accordance with the verb argument structure. Participants' productions reveal an interesting relation in sentences with transitive verbs between subject position (pre-/postverbal) and object form (lexical DP/clitic pronoun). PMID- 30429807 TI - Accelerated rTMS: A Potential Treatment to Alleviate Refractory Depression. AB - Three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS) has yielded one clear treatment indication in psychiatry for major depression disorder (MDD). Although the clinical response equals the standard treatment algorithms, the effect sizes on the beneficial outcome remain rather modest. Over the last couple of years, to improve the efficacy in resistant depression, two new avenues have been developed: personalization and intensifying rTMS treatment. For the latter, we retrospectively compared accelerated high-frequency rTMS (arTMS) with accelerated intermittent theta burst stimulation (aiTBS) in the refractory depressed state. Although the clinical efficacy was not significantly different between both protocols, our observations substantiate the potential of the accelerated stimulation to shorten the treatment duration from the depressed state to the response state. Any time gain from the depressed state to the recovered state is in the patients' interest. PMID- 30429808 TI - Keep Your Eye on the Ball; the Impact of an Anticipatory Fixation During Successful and Unsuccessful Soccer Penalty Kicks. AB - The success of a sporting task requiring an object to be kicked or hit toward a target (e.g., kicking a ball into a goal) is impacted by the length of the Quiet Eye (QE). Limitations in the ocular motor system mean that after impact, these fast moving objects are not tracked using smooth pursuit eye movements. Rather, anticipatory fixations are used to re-fixate ahead of the moving object.Using a soccer penalty kick, the current study investigated whether striking a stationary object to generate high ball velocity results in an anticipatory fixation prior to ball contact and if this occurs at detriment to the QE period and task success.Facing a goalkeeper, 12 participants produced a successful (scored) and unsuccessful (saved) penalty whilst wearing a mobile eye tracker.QE was longer in the successful compared to unsuccessful penalty (p = 0.036) and was due to QE offset ending later in the successful compared to unsuccessful penalty (p = 0.008). An anticipatory fixation occurred later (p = 0.025) and was shorter (p = 0.005) in successful compared to unsuccessful penalties. The football was kicked wider (more accurately) within the goal during the successful compared to unsuccessful penalty (p < 0.001). Results highlight the importance of the QE period in successfully executing a soccer penalty kick. Unsuccessful penalties were associated with shorter QE length and earlier QE offset, which was due to initiating an anticipatory fixation in prediction of tracking the fast moving football, resulting in kicking the ball more centrally in the goal, making it easier for the goalkeeper to save. PMID- 30429805 TI - The Neural Mechanism Underlying Cognitive and Emotional Processes in Creativity. AB - Creativity is related to both cognition and emotion, which are the two major mental processes, interacting with each other to form psychological processes. Emotion is the major driving force of almost all creativities, sometimes in an unconscious way. Even though there are many studies concerning the relationship between creativity and cognition, there are few studies about the neural mechanisms of the emotional effects on creativity. Here, we introduce a novel model to explain the relationship between emotions and creativities: Three Primary Color model, which proposes that there are four major basic emotions; these basic emotions are subsided by three monoamines, just like the three primary colors: dopamine-joy, norepinephrine-stress (fear and anger), and serotonin-punishment. Interestingly, these three neuromodulators play similar roles in creativity, whose core features are value and novelty (surprise), like the characteristics of the core features of basic emotions (hedonic value and arousal value). Dysfunctions of these neuromodulators may be the reasons for both psychopathology and creativity, in that they can change the thinking styles such as novelty seeking behavior, hyper-connectivity of brain areas, and/or cognitive disinhibition to induce both creativity and psychopathology. This new model will not only help researchers understand the dynamics of basic emotion elements, it can also bring an entirely new perspective into the relationship between psychopathology and creativity. PMID- 30429809 TI - Measurement Invariance of the Depression Anxiety Stress Scales-21 Across Gender in a Sample of Chinese University Students. AB - The Depression Anxiety Stress Scales-21 (DASS-21) has three 7-item subscales (depression, anxiety, and stress). The current study aims assess the gender-based measurement invariance of the DASS-21 questionnaire in a Chinese university student sample from five different cities. The sample was composed of 13208 participants (62.3% female, mean age of 19.7 years, and SD age = 1.8). Multi group confirmatory factor analysis supported full measurement invariance for the three subscales. The findings support the measurement invariance of DASS-21 scores across gender. Future research on the DASS should include additional validation across ethnicities and testing of all versions of the DASS. PMID- 30429811 TI - Outcome-Focused Dance Movement Therapy Assessment Enhanced by iPad App MARA. AB - Healthcare and human services are increasingly required to demonstrate effectiveness and efficiency of their programs, with assessment and evaluation processes more regularly part of activity cycles. New approaches to service delivery, such as the National Disability Insurance Scheme (NDIS) scheme in Australia, require outcome-focused reporting that is responsive to the perspectives of clients. Eco-systematic approaches to service delivery and assessment consider the client as part of an interconnected web of stakeholders who all have responsibility for and contribute to their development and progress. These imperatives provide challenges for modalities for which there are not well established assessment approaches. Dance movement therapists face particular difficulties in this respect, as they have few assessment tools that are practical for regular use. Existing dance movement therapy (DMT) assessment approaches largely do not yet prioritize input from clients. This article addresses these challenges in reporting a trial of iPad app MARA (Movement Assessment and Reporting App) developed for assessment in DMT. MARA is applied in a program for adults with intellectual disability (ID) over 16 weeks. Assessment data is gathered utilizing the app's features: two researcher-therapists undertake quantitative scoring that MARA aggregates into graphs, substantiated by qualitative note-taking, photos, and videos; and clients provide feedback about their progress stimulated by viewing photos and videos. A sample graph generated by MARA and supporting notes and a report drawn from data are provided. Responses to reports from program stakeholders (12 participants, 12 families, 11 center staff) gathered through interviews and focus groups are discussed, and researcher therapists' reflections are detailed. The benefits of using MARA reported by researcher-therapists include strengthened capacity to focus on participant outcomes, assess efficiently, plan and make decisions for the program, and communicate participants' progress to stakeholders. Family members perceive reports drawn from data gathered in MARA to be useful in enabling better understanding of the DMT program and participant outcomes and potentially to support NDIS service planning. Managers perceive the potential value of data in these reports for quality control and resource decisions, while other staff confirm the therapists' perspective that reports offer the possibility of improved communication and collaboration between center staff. PMID- 30429810 TI - A P5 Approach to m-Health: Design Suggestions for Advanced Mobile Health Technology. AB - In recent years, technology has been developed as an important resource for health care management, especially in regard to chronic conditions. In the broad field of eHealth, mobile technology (mHealth) is increasingly used to empower patients not only in disease management but also in the achievement of positive experiences and experiential growth. mHealth tools are considered powerful because, unlike more traditional Internet-based tools, they allow patients to be continuously monitored and followed by their own mobile devices and to have continual access to resources (e.g., mobile apps or functions) supporting health care management activities. However, the literature has shown that, in many cases, such technology not accepted and/or adopted in the long term by its users. To address this issue, this article reviews the main factors influencing mHealth technology acceptance/adoption in health care. Finally, based on the main aspects emerging from the review, we propose an innovative approach to mHealth design and implementation, namely P5 mHealth. Relying on the P5 approach to medicine and health care, this approach provides design suggestions to address mHealth adoption issues already at the initial stages of development of the technologies. PMID- 30429812 TI - Regular Distribution Inhibits Generic Numerosity Processing. AB - This study investigated the role of pattern regularity in approximate numerical processing. Experiment 1 demonstrated that the change in stimulus size has a distinct effect on the adaptation aftereffect for random and regular patterns. For regular patterns, adapting to large patterns and being tested with small patterns caused stronger aftereffects than the reverse treatment, in which the participants adapted to small patterns and were tested with large patterns. For random patterns, this effect was absent. Experiment 2 revealed a distinct connectedness effect on the numerosity processing of random and regular patterns. For random patterns, reference stimuli were perceived to contain fewer items when the dots were connected by lines than when they were not connected, and the number of items in the connected reference was further underestimated when the participants adapted to unconnected patterns with the same number of dots. For regular patterns, this effect was absent. Distinct mechanisms were thus suggested for the numerosity coding of random and regular patterns. For random patterns, the change in primary texture features would be abstracted from numerosity processing, while connectedness could affect this coding by affecting the processing of numerical unit individuation. For regular patterns, generic numerosity processing is inhibited, and numerical judgments appear to be inferred from the visual processing results of texture features such as dot size or the distance between adjacent dots. PMID- 30429813 TI - The Principles of Art Therapy in Virtual Reality. AB - In recent years, the field of virtual reality (VR) has shown tremendous advancements and is utilized in entertainment, scientific research, social networks, artistic creation, as well as numerous approaches to employ VR for psychotherapy. While the use of VR in psychotherapy has been widely discussed, little attention has been given to the potential of this new medium for art therapy. Artistic expression in VR is a novel medium which offers unique possibilities, extending beyond classical expressive art mediums. Creation in VR includes options such as three-dimensional painting, an immersive creative experience, dynamic scaling, and embodied expression. In this perspective paper, we present the potentials and challenges of VR for art therapy and outline basic principles for its implementation. We focus on the novel qualities offered by this creative medium (the virtual environment, virtual materials, and unreal characteristics) and on the core aspects of VR (such as presence, immersivity, point of view, and perspective) for the practice of art therapy. PMID- 30429815 TI - Effects of Sleep Fragmentation and Induced Mood on Pain Tolerance and Pain Sensitivity in Young Healthy Adults. AB - Background: Experimental research exploring the sleep/pain-relationship has typically focused on total or partial sleep deprivation, hereby failing to reproduce the mere fragmented sleep pattern typically observed in patients with chronic pain. Further, little research is done on how affect moderates the sleep pain relationship after sleep fragmentation. The present study sought to clarify the relationship between pain, sleep and positive and negative affect. Methods: In an experimental counterbalanced crossover design, 35 healthy young adults were subjected to several pain measures after one night of fragmented sleep, compared to one control night of normal sleep, both conducted in their own homes, and respectively, positive and negative affect induction using validated film clips and facial feedback procedures. Sleep was monitored using sleep diaries. Results: Increased pain sensitivity after one night of experimentally induced sleep fragmentation was found, compared to after one control night of undisturbed sleep. No main effects of induced affect on pain were found, and sleep x induced affect interaction was not significant. Conclusion: The present study supports the adverse effect of sleep fragmentation on pain sensitivity, however, affect was not found to be a moderator in the sleep-pain relationship. The results underline the need for further research within this field. PMID- 30429816 TI - Effectiveness of Online Mindfulness-Based Interventions on Psychological Distress and the Mediating Role of Emotion Regulation. AB - Online mindfulness-based intervention as a feasible and acceptable approach has received mounting attention in recent years, yet more evidence is needed to demonstrate its effectiveness. The primary objective of this study was to examine the effects of online mindfulness-based programs on psychological distress (depression and anxiety). The randomized controlled intervention design consisted of four conditions: group mindfulness-based intervention (GMBI), self-direct mindfulness-based intervention (SDMBI), discussion group (DG) and blank control group (BCG). The program lasted 8 weeks and a total of 76 participants completed the pre- and post-test. Results showed that participants in GMBI and SDMBI had significant pre- and post-test differences on mindfulness, emotion regulation difficulties, and psychological distress, with medium to large effect sizes. In addition, ANCOVA results indicated significant effects of group membership on post-test scores of mindfulness, depression and anxiety when controlling the pretest scores, with medium to large effect sizes. The GMBI appeared to exert the greatest effects on outcome variables in comparison with other groups. In addition, changes in emotion regulation difficulties across groups could mediate the relationship between changes in mindfulness dimensions (Observing and Describing) and changes in psychological distress across groups. These results provided encouraging evidence for the effectiveness of online mindfulness-based interventions in reducing psychological distress, and the possible mediating role of emotion regulation, while also underlining the importance of group discussion in online mindfulness-based interventions. PMID- 30429817 TI - How Do Infants Disaggregate Referential and Affective Pitch? AB - Infants are faced with a challenge of disaggregating functions of pitch in the ambient language into affective, pragmatic or referential (the latter in tone languages only). This mini review discusses several factors that might facilitate the disaggregation of referential and affective pitch in infancy: acoustic characteristics of infant-directed speech, recognition of vocal affect, facial cues accompanying affective prosody, and lateralization of affective and referential prosody in the brain. It proposes two hypotheses concerning the role of audiovisual cues and brain lateralization. PMID- 30429814 TI - Rapid Eye Movements in Sleep Furnish a Unique Probe Into Consciousness. AB - The neural correlates of rapid eye movements (REMs) in sleep are extraordinarily robust; including REM-locked multisensory-motor integration and accompanying activation in the retrosplenial cortex, the supplementary eye field and areas encompassing cholinergic basal nucleus (Hong et al., 2009). The phenomenology of REMs speaks to the notion that perceptual experience in both sleep and wakefulness is a constructive process - in which we generate predictions of sensory inputs and then test those predictions through actively sampling the sensorium with eye movements. On this view, REMs during sleep may index an internalized active sampling or 'scanning' of self-generated visual constructs that are released from the constraints of visual input. If this view is correct, it renders REMs an ideal probe to study consciousness as "an exclusively internal affair" (Metzinger, 2009). In other words, REMs offer a probe of active inference - in the sense of predictive coding - when the brain is isolated from the sensorium in virtue of the natural blockade of sensory afferents during REM sleep. Crucially, REMs are temporally precise events that enable powerful inferences based on time series analyses. As a natural, task-free probe, (REMs) could be used in non-compliant subjects, including infants and animals. In short, REMs constitute a promising probe to study the ontogenetic and phylogenetic development of consciousness and perhaps the psychopathology of schizophrenia and autism, which have been considered in terms of aberrant predictive coding. PMID- 30429818 TI - Evolutionary Psychology of Eating Disorders: An Explorative Study in Patients With Anorexia Nervosa and Bulimia Nervosa. AB - Prior research on non-clinical samples has lent support to the sexual competition hypothesis for eating disorders (SCH) where the drive for thinness can be seen as an originally adaptive strategy for women to preserve a nubile female shape, which, when driven to an extreme, may cause eating disorders. Restrictive versus impulsive eating behavior may also be relevant for individual differences in allocation of resources to either mating effort or somatic growth, reflected in an evolutionary concept called "Life History Theory" (LHT). In this study, we aimed to test the SCH and predictions from LHT in female patients with clinically manifest eating disorders. Accordingly, 20 women diagnosed with anorexia nervosa (AN), 20 with bulimia nervosa (BN), and 29 age-matched controls completed a package of questionnaires comprising measures for behavioral features and attitudes related to eating behavior, intrasexual competition, life history strategy, executive functioning and mating effort. In line with predictions, we found that relatively faster life history strategies were associated with poorer executive functioning, lower perceived own mate value, greater intrasexual competition for mates but not for status, and, in part, with greater disordered eating behavior. Comparisons between AN and BN revealed that individuals with BN tended to pursue a "fast" life history strategy, whereas people with AN were more similar to controls in pursuing a "slow" life history strategy. Moreover, intrasexual competition for mates was significantly predicted by the severity of disordered eating behavior. Together, our findings lend partial support to the SCH for eating disorders. We discuss the implications and limitations of our study findings. PMID- 30429820 TI - The Neuromodulatory Impact of Subthalamic Nucleus Deep Brain Stimulation on Gait and Postural Instability in Parkinson's Disease Patients: A Prospective Case Controlled Study. AB - Background: Subthalamic nucleus deep brain stimulation (STN-DBS) has been an established method in improvement of motor disabilities in Parkinson's disease (PD) patients. It has been also claimed to have an impact on balance and gait disorders in PD patients, but the previous results are conflicting. Objective: The aim of this prospective controlled study was to evaluate the impact of STN DBS on balance disorders in PD patients in comparison with Best-Medical-Therapy (BMT) and Long-term-Post-Operative (POP) group. Methods: DBS-group consisted of 20 PD patients (8F, 12M) who underwent bilateral STN DBS. POP-group consisted of 14 post-DBS patients (6F, 8M) in median 30 months-time after surgery. Control group (BMT-group) consisted of 20 patients (11F, 9M) who did not undergo surgical intervention. UPDRS III scale and balance tests (Up And Go Test, Dual Task- Timed Up And Go Test, Tandem Walk Test) and posturography parameters were measured during 3 visits in 9 +/- 2months periods (V1, V2, V3) 4 phases of treatment (BMT ON/OFF, DBS-ON/OFF). Results: We have observed the slowdown of gait and postural instability progression in first 9 post-operative months followed by co-existent enhancement of balance disorders in next 9-months evaluation (p < 0.05) in balance tests (Up and Go, TWT) and in posturography examination parameters (p < 0.05). The effect was not observed neither in BMT-group nor POP-group (p > 0.05): these groups revealed constant progression of static and dynamic instability (p > 0.05). Conclusions: STN-DBS can have modulatory effect on static and dynamic instability in PD patients: it can temporarily improve balance disorders. mainly during first 9 post-operative months, but with possible following deterioration of the symptoms in next post-operative months. PMID- 30429821 TI - Homotopic Connectivity in Early Pontine Infarction Predicts Late Motor Recovery. AB - Connectivity-based methods are essential to explore brain reorganization after a stroke and to provide meaningful predictors for late motor recovery. We aim to investigate the homotopic connectivity alterations during a 180-day follow-up of patients with pontine infarction to find an early biomarker for late motor recovery prediction. In our study, resting-state functional MRI was performed in 15 patients (11 males, 4 females, age: 57.87 +/- 6.50) with unilateral pontine infarction and impaired motor function during a period of 6 months (7, 14, 30, 90, and 180 days after stroke onset). Clinical neurological assessments were performed using the Fugl-Meyer scale (FM).15 matched healthy volunteers were also recruited. Whole-brain functional homotopy in each individual scan was measured by voxel-mirrored homotopic connectivity (VMHC) values. Group-level analysis was performed between stroke patients and normal controls. A Pearson correlation was performed to evaluate correlations between early VMHC and the subsequent 4 visits for behavioral measures during day 14 to day 180. We found in early stroke (within 7 days after onset), decreased VMHC was detected in the bilateral precentral and postcentral gyrus and precuneus/posterior cingulate cortex (PCC), while increased VMHC was found in the hippocampus/amygdala and frontal pole (P < 0.01). During follow-up, VMHC in the precentral and postcentral gyrus increased to the normal level from day 90, while VMHC in the precuneus/PCC presented decreased intensity during all time points (P < 0.05). The hippocampus/amygdala and frontal pole presented a higher level of VMHC during all time points (P < 0.05). Negative correlation was found between early VMHC in the hippocampus/amygdala with FM on day 14 (r = -0.59, p = 0.021), day 30 (r = 0.643, p = 0.01), day 90 (r = -0.693, p = 0.004), and day 180 (r = -0.668, p = 0.007). Furthermore, early VMHC in the frontal pole was negatively correlated with FM scores on day 30 (r = -0.662, p = 0.013), day 90 (r = -0.606, p = 0.017), and day 180 (r = -0.552, p = 0.033). Our study demonstrated the potential utility of early homotopic connectivity for prediction of late motor recovery in pontine infarction. PMID- 30429822 TI - How Physical Activities Affect Mental Fatigue Based on EEG Energy, Connectivity, and Complexity. AB - Many studies have verified that there is an interaction between physical activities and mental fatigue. However, few studies are focused on the effect of physical activities on mental fatigue. This study was to analyze the states of mental fatigue based on electroencephalography (EEG) and investigate how physical activities affect mental fatigue. Fourteen healthy participants participated in an experiment including a 2-back mental task (the control) and the same mental task with cycling simultaneously (physical-mental task). Each experiment consisted of three 20 min fatigue-inducing sessions repeatedly (mental fatigue for mental tasks or mental fatigue plus physical activities for physical-mental tasks). During the evaluation sessions (before and after the fatigue-inducing sessions), the states of the participants were assessed by EEG parameters. Wavelet Packet Energy (WPE), Spectral Coherence Value (SCV), and Lempel-Ziv Complexity (LZC) were used to indicate mental fatigue from the perspectives of activation, functional connectivity, and complexity of the brain. The indices are the beta band energy Ebeta , the energy ratio Ealpha/beta , inter-hemispheric SCV of beta band SCVbeta and LZC. The statistical analysis shows that mental fatigue was detected by Ebeta , Ealpha/beta , SCVbeta , and LZC in physical-mental task. The slopes of the linear fit on these indices verified that the mental fatigue increased more fast during physical-mental task. It is concluded form the result that physical activities can enhance the mental fatigue and speed up the fatigue process based on brain activation, functional connection, and complexity. This result differs from the traditional opinion that physical activities have no influence on mental fatigue, and finds that physical activities can increase mental fatigue. This finding helps fatigue management through exercise instruction. PMID- 30429823 TI - Mononucleosis: A Possible Cause of Idiopathic Hypersomnia. AB - Idiopathic hypersomnia (IH) is a rare central hypersomnia of unknown physiopathology. In this study, we determine if the presence of infectious mononucleosis evaluated by serological markers of Epstein Barr virus infection plays a role in this hypersomnia. Ten patients with a suspicion of IH underwent to clinical assessment, 24 h polysomnography, and serologic testing for mononucleosis including Viral Capside Antigen (VCA) IgG, the VCA IgM, and the EBV nuclear antigen (EBNA). None of the patients reported neurological inflammatory disease and viral infection prior the onset of the disease. Compared to the laboratory serological reference values, all patients had high levels of VCA IgG and EBNA with lower level of VCA IgM, overall indicating past infection. This study shows that prior infectious mononucleosis may predispose some subjects to idiopathic hypersomnia suggesting the role of inflammatory and immunological processes in this sleep disorder. PMID- 30429819 TI - The Glymphatic System in Diabetes-Induced Dementia. AB - The glymphatic system has emerged as an important player in central nervous system (CNS) diseases, by regulating the vasculature impairment, effectively controlling the clearance of toxic peptides, modulating activity of astrocytes, and being involved in the circulation of neurotransmitters in the brain. Recently, several studies have indicated decreased activity of the glymphatic pathway under diabetes conditions such as in insulin resistance and hyperglycemia. Furthermore, diabetes leads to the disruption of the blood-brain barrier and decrease of apolipoprotein E (APOE) expression and the secretion of norepinephrine in the brain, involving the impairment of the glymphatic pathway and ultimately resulting in cognitive decline. Considering the increased prevalence of diabetes-induced dementia worldwide, the relationship between the glymphatic pathway and diabetes-induced dementia should be investigated and the mechanisms underlying their relationship should be discussed to promote the development of an effective therapeutic approach in the near future. Here, we have reviewed recent evidence for the relationship between glymphatic pathway dysfunction and diabetes. We highlight that the enhancement of the glymphatic system function during sleep may be beneficial to the attenuation of neuropathology in diabetes-induced dementia. Moreover, we suggest that improving glymphatic system activity may be a potential therapeutic strategy for the prevention of diabetes-induced dementia. PMID- 30429824 TI - Inhibition of p38 MAPK Signaling Regulates the Expression of EAAT2 in the Brains of Epileptic Rats. AB - Seizures induce the release of excitatory amino acids (EAAs) from the intracellular fluid to the extracellular fluid, and the released EAAs primarily comprise glutamic acid (Glu) and asparaginic acid (Asp). Glu neurotransmission functions via EAA transporters (EAATs) to maintain low concentrations of Glu in the extracellular space and avoid excitotoxicity. EAAT2, the most abundant Glu transporter subtype in the central nervous system (CNS), plays a key role in the regulation of glutamate transmission. Previous studies have shown that SB203580 promotes EAAT2 expression by inhibiting the p38 mitogen-activated protein kinase (MAPK) signaling pathway, but whether SB203580 upregulates EAAT2 expression in epileptic rats is unknown. This study demonstrated that EAAT2 expression was increased in the brain tissue of epileptic rats. Intraperitoneal injection of a specific inhibitor of p38 MAPK, SB203580, reduced the time to the first epileptic seizure and attenuated the seizure severity. In addition, SB203580 treatment increased the EAAT2 expression levels in the brain tissue of epileptic rats. These results suggest that SB203580 could regulate epileptic seizures via EAAT2. PMID- 30429825 TI - Evaluation of Balance Disorders in Parkinson's Disease Using Simple Diagnostic Tests-Not So Simple to Choose. AB - Background: Balance disorders are one of the main symptoms in parkinson's Disease (PD)-patients have a tendency to fall, related traumas and also a significant restriction of mobility. Numerous tools may be used to evaluate the balance, but it is difficult to choose the proper one. The aim of this review was to compare simple diagnostic tools for PD and emphasize those characterized by a high reliability and sensitivity. Methods: The global literature search was conducted in PubMED, Scopus, Science Direct, Web of Science, Cochrane, and Google Scholar for publications in English and Polish. Results: According to the literature some scales and functional tests in which clinimetric properties had been assessed in PD population were selected and described. Conclusion: Basing on current knowledge, psychometric properties, and clinical experience, the authors suggest the BESTest with its shortened versions and the Fullerton Advanced Balance Scale to be used for comprehensive balance assessment of parkinson's disease patients. These tests are easy in administration, not time-consuming and provide a professional diagnosis allowing to plan individual therapy for the patient being examined. PMID- 30429826 TI - Benchmarks of Diabetes Care in Men Living With Treated HIV-Infection: A Tertiary Center Experience. AB - Treated human immunodeficiency virus (HIV) infection is associated with high rates of type 2 diabetes mellitus (DM), metabolic syndrome and central obesity/body fat partitioning disorders. To our knowledge, there are no available data comparing diabetes care in people with both HIV+DM vs. DM alone (DM controls) within the same service and evaluating if benchmarked standards of care are being met in people with HIV+DM. This study evaluated the frequency that people with HIV+DM met the benchmarked American Diabetes Association (ADA) standards of care in diabetes (targets for HbA1c, blood pressure, lipid levels, complication screening, and healthy weight), compared to age- and sex- matched controls with diabetes, in an urban teaching hospital. The frequency of diabetes complications and rates of obesity and metabolic syndrome were also examined. All participants were male; individuals with HIV+DM (n = 30) were similar to DM controls (n = 30) for age, diabetes duration and smoking status, but were more frequently non-obese compared to DM controls (92 vs. 55%, respectively, p = 0.003). Only 41% of HIV+DM met HbA1c targets, compared with 70% of DM-controls (p = 0.037). Blood pressure targets were poorly met in both HIV+DM and DM-controls: 43 vs. 23%, respectively (p = 0.12); LDL cholesterol targets were met in 65 vs. 67% (p = 1.0). Benchmarked complication screening rates were similar between HIV+DM vs. DM-controls for annual foot examination (53 vs. 67%, respectively, p = 0.29); biennial retinal examination (83 vs. 77%, respectively, p = 0.52); and annual urinary albumin measurement (77 vs. 67%, respectively, p = 0.39). The prevalence of diabetes complications was similar between HIV+DM compared to DM controls: macrovascular complications were present in 23% in both groups (p = 1.0); the prevalence of microvascular complications was 40 vs. 30%, respectively (p = 0.51). Achieving the standard of care benchmarks for diabetes in people with both HIV-infection and diabetes is of particular importance to mitigate against the accelerated cardiometabolic outcomes observed in those with treated HIV infection. HIV+DM were less likely to achieve HbA1c targets than people with diabetes, but without HIV. People with HIV+DM may require specific strategies to ensure care benchmarks are met. PMID- 30429827 TI - Verapamil Ameliorates Hepatic Metaflammation by Inhibiting Thioredoxin Interacting Protein/NLRP3 Pathways. AB - Activation of thioredoxin-interacting protein (TXNIP)/nod-like receptor protein 3 (NLRP3) inflammasome plays a critical role in pathogenesis of non-alcoholic fatty liver disease. This study investigated the protective effects of verapamil on hepatic metaflammation in a rodent model of high-fat (HF) diet-induced obesity (DIO). DIO was induced in a subset of mice provided with HF diet (45% kcal fat). After 10 weeks of HF diet, verapamil was administered by intraperitoneal injection. The experimental groups included the following: (1) normal diet group, (2) normal diet + treatment with verapamil (VER) group, (3) HF control group, (4) HF+VER (25 mg/kg/day) group. After 1 week of each treatment, blood and liver tissues were collected, and glucose control, serum triglyceride (TG) level, inflammation, and TXNIP/NLRP3 inflammasome were analyzed. Verapamil administration caused no alteration in food intake. HF diet impaired glucose control and increased body weight and serum TG levels. Hepatic inflammation was aggravated in HF-fed mice, as demonstrated by increased levels of pro inflammatory markers interleukin-1beta (IL-1beta) and IL-18 in the liver. On the other hand, verapamil administration significantly improved glucose control, body weight, and serum TG levels. Verapamil treatment also reduced pro-inflammatory marker levels. These improvements were accompanied by alterations in activation of TXNIP/NLRP3 inflammasome. The observed results demonstrate that verapamil ameliorates hepatic metaflammation by inhibiting TXNIP/NLRP3 pathways. PMID- 30429828 TI - The Orexin-A-Regulated Akt/mTOR Pathway Promotes Cell Proliferation Through Inhibiting Apoptosis in Pancreatic Cancer Cells. AB - The orexin-A and its receptors are associated with many physiological processes in peripheral organs and the central nervous system and play important roles in a series of human diseases, including narcolepsy, obesity, and drug addiction. Increasing evidence has indicated high expression of orexin-A and OX1 receptor (OX1R) in malignant tumors, suggesting that the stimulation of OX1R might be essential for tumorigenesis. Here, we attempted to clarify the correlation between orexin-A expression and malignancy in pancreatic cancer. Our results indicated that the stimulation of OX1R promotes cell proliferation in pancreatic cancer PANC1 cells. Additionally, orexin-A treatment can protect PANC1 cells from apoptosis, whereas inhibition of the stimulation of OX1R results in apoptosis through regulating pancreatic cancer cell expression levels of Bcl-2, caspase-9, and c-myc, which are key apoptotic factors. Further investigation revealed that orexin-A treatment activates theAkt/mTOR signaling pathway to promote cell proliferation byinhibiting Bcl-2/caspase-9/c-myc-mediated apoptosis in pancreatic cancer cells. Our findings revealed that the stimulation of OX1R might be important for tumorigenesis in pancreatic cancer and is a potential target for the treatment of patients with pancreatic cancer. PMID- 30429830 TI - PGE2 Augments Inflammasome Activation and M1 Polarization in Macrophages Infected With Salmonella Typhimurium and Yersinia enterocolitica. AB - Eicosanoids are cellular metabolites, which shape the immune response, including inflammatory processes in macrophages. The effects of these lipid mediators on inflammation and bacterial pathogenesis are not clearly understood. Certain eicosanoids are suspected to act as molecular sensors for the recruitment of neutrophils, while others regulate bacterial uptake. In this study, gene expression analyses indicated that genes involved in eicosanoid biosynthesis including COX-1, COX-2, DAGL, and PLA-2 are differentially regulated in THP-1 human macrophages infected with Salmonella enterica Typhimurium or Yersinia enterocolitica. By using targeted metabolomics approach, we found that the eicosanoid precursor, arachidonic acid (AA) as well as its derivatives, including prostaglandins (PGs) PGF2alpha or PGE2/PGD2, and thromboxane TxB2, are rapidly secreted from macrophages infected with these Gram-negative pathogenic bacteria. The magnitude of eicosanoid biosynthesis in infected host cells depends on the presence of virulence factors of Y. enterocolitica and S. Typhimurium strains, albeit in an opposite way in Y. enterocolitica compared to S. Typhimurium infection. Trials with combinations of EP2/EP4 PGE2 receptor agonists and antagonists suggest that PGE2 signaling in these infection models works primarily through the EP4 receptor. Downstream of EP4 activation, PGE2 enhances inflammasome activation and represses M2 macrophage polarization while inducing key M1-type markers. PGE2 also led to a decreased numbers of Y. enterocolitica within macrophages. To summarize, PGE2 is a potent autocrine/paracrine activator of inflammation during infection in Gram-negative bacteria, and it affects macrophage polarization, likely controlling bacterial clearance by macrophages. PMID- 30429829 TI - Timing of Exposure and Bisphenol-A: Implications for Diabetes Development. AB - Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDCs). It is used as the base compound in the production of polycarbonate and other plastics present in many consumer products. It is also used as a building block in epoxy can coating and the thermal paper of cash register receipts. Humans are consistently exposed to BPA and, in consequence, this compound has been detected in the majority of individuals examined. Over the last decade, an enlarging body of evidence has provided a strong support for the role of BPA in the etiology of diabetes and other metabolic disorders. Timing of exposure to EDCs results crucial since it has important implications on the resulting adverse effects. It is now well established that the developing organisms are particularly sensitive to environmental influences. Exposure to EDCs during early life may result in permanent adverse consequences, which increases the risk of developing chronic diseases like diabetes in adult life. In addition to that, developmental abnormalities can be transmitted from one generation to the next, thus affecting future generations. More recently, it has been proposed that gestational environment may also program long-term susceptibility to metabolic disorders in the mother. In the present review, we will comment and discuss the contributing role of BPA in the etiology of diabetes. We will address the metabolic consequences of BPA exposure at different stages of life and comment on the final phenotype observed in different whole-animal models of study. PMID- 30429831 TI - Selection Pressure Pathways and Mechanisms of Resistance to the Demethylation Inhibitor-Difenoconazole in Penicillium expansum. AB - Penicillium expansum causes blue mold, the most economically important postharvest disease of pome fruit worldwide. Beside sanitation practices, the disease is managed through fungicide applications at harvest. Difenoconazole (DIF) is a new demethylation inhibitor (DMI) fungicide registered recently to manage postharvest diseases of pome fruit. Herein, we evaluated the sensitivity of 130 P. expansum baseline isolates never exposed to DIF and determined the effective concentration (EC50) necessary to inhibit 50% germination, germ tube length, and mycelial growth. The respective mean EC50 values of 0.32, 0.26, and 0.18 MUg/ml indicate a high sensitivity of P. expansum baseline isolates to DIF. We also found full and extended control efficacy in vivo after 6 months of storage at 1 degrees C. We conducted a risk assessment for DIF-resistance development using ultraviolet excitation combined with or without DIF-selection pressure to generate and characterize lab mutants. Fifteen DIF-resistant mutants were selected and showed EC50 values of 0.92 to 1.4 MUg/ml and 1.7 to 3.8 MUg/ml without and with a DIF selection pressure, respectively. Resistance to DIF was stable in vitro over a 10-week period without selection pressure. Alignment of the full CYP51 gene sequences from the three wild-type and 15 mutant isolates revealed a tyrosine to phenylalanine mutation at codon 126 (Y126F) in all of the 15 mutants but not in the wild-type parental isolates. Resistance factors increased 5 to 15-fold in the mutants compared to the wild-type-isolates. DIF resistant mutants also displayed enhanced CYP51 expression by 2 to 14-fold and was positively correlated with the EC50 values (R 2 = 0.8264). Cross resistance between DIF and fludioxonil, the mixing-partner in the commercial product, was not observed. Our findings suggest P. expansum resistance to DIF is likely to emerge in commercial packinghouse when used frequently. Future studies will determine whether resistance to DIF is qualitative or quantitative which will be determinant in the speed at which resistance will develop and spread in commercial packinghouses and to develop appropriate strategies to extend the lifespan of this new fungicide. PMID- 30429832 TI - Changes in the Drinking Water Microbiome: Effects of Water Treatments Along the Flow of Two Drinking Water Treatment Plants in a Urbanized Area, Milan (Italy). AB - While safe and of high quality, drinking water can host an astounding biodiversity of microorganisms, dismantling the belief of its "biological simplicity." During the very few years, we are witnessing an exponential growth in scientific publications, exploring the ecology hidden in drinking water treatment plants (DWTPs) and drinking water distribution system (DWDS). We focused on what happens to the microbial communities from source water (groundwater) throughout the main steps of the potabilization process of a DWTP, located in an urbanized area in Northern Italy. Samples were processed by a stringent water filtration to retain even the smallest environmental bacteria and then analyzed with High-Throughput DNA Sequencing (HTS) techniques. We showed that carbon filters harbored a microbial community seeding and shaping water microbiota downstream, introducing a significant variation on incoming (groundwater) microbial community. Chlorination did not instantly affect the altered microbiota. We were also able to correctly predict (through machine learning analysis) samples belonging to groundwater (overall accuracy was 0.71), but the assignation was not reliable with carbon filter samples, which were incorrectly predicted as chlorination samples. The presence and abundance of specific microorganisms allowed us to hypothesize their role as indicators. In particular, Candidatus Adlerbacteria (Parcubacteria), together with microorganisms belonging to Alphaproteobacteria and Gammaproteobacteria, characterized treated water, but not raw water. An exception, confirming our hypothesis, is given by the samples downstream the filters renewal, which had a composition resembling groundwater. Volatility analysis illustrated how carbon filters represented an ecosystem that is stable over time, probably bearing the environmental conditions that promote the survival and growth of this peculiar microbial community. PMID- 30429833 TI - FLO1, FLO5 and FLO11 Flocculation Gene Expression Impacts Saccharomyces cerevisiae Attachment to Penicillium chrysogenum in a Co-immobilization Technique. AB - A reoccurring flaw of most yeast immobilization systems that limits the potential of the technique is leakage of the cells from the matrix. Leakage may be due to weakly adherent cells, deterioration of the matrix, or to new growth and loss of non-adherent daughter cells. Yeast biocapsules are a spontaneous, cost effective system of immobilization whereby Saccharomyces cerevisiae cells are attached to the hyphae of Penicillium chrysogenum, creating hollow spheres that allow recovery and reutilization. This attachment is based on naturally occurring adherent properties of the yeast cell surface. We hypothesized that proteins associated with flocculation might play a role in adherence to fungal hyphae. To test this hypothesis, yeast strains with overexpressed and deleted flocculation genes (FLO1, FLO5, and FLO11) were evaluated for biocapsule formation to observe the impact of gene expression on biocapsule diameter, number, volume, dry mass, and percent immobilized versus non-immobilized cells. Overexpression of all three genes enhanced immobilization and resulted in larger diameter biocapsules. In particular, overexpression of FLO11 resulted in a five fold increase of absorbed cells versus the wild type isogenic strain. In addition, deletion of FLO1 and FLO11 significantly decreased the number of immobilized yeast cells compared to the wild type BY4742. These results confirm the role of natural adherent properties of yeast cells in attachment to fungal hyphae and offer the potential to create strongly adherent cells that will produce adherent progeny thereby reducing the potential for cell leakage from the matrix. PMID- 30429835 TI - Genome Sequence and Metabolic Analysis of a Fluoranthene-Degrading Strain Pseudomonas aeruginosa DN1. AB - Pseudomonas aeruginosa DN1, isolated from petroleum-contaminated soil, showed excellent degradation ability toward diverse polycyclic aromatic hydrocarbons (PAHs). Many studies have been done to improve its degradation ability. However, the molecular mechanisms of PAHs degradation in DN1 strain are unclear. In this study, the whole genome of DN1 strain was sequenced and analyzed. Its genome contains 6,641,902 bp and encodes 6,684 putative open reading frames (ORFs), which has the largest genome in almost all the comparative Pseudomonas strains. Results of gene annotation showed that this strain harbored over 100 candidate genes involved in PAHs degradation, including those encoding 25 dioxygenases, four ring-hydroxylating dioxygenases, five ring-cleaving dioxygenases, and various catabolic enzymes, transcriptional regulators, and transporters in the degradation pathways. In addition, gene knockout experiments revealed that the disruption of some key PAHs degradation genes in DN1 strain, such as catA, pcaG, pcaH, and rhdA, did not completely inhibit fluoranthene degradation, even though their degradative rate reduced to some extent. Three intermediate metabolites, including 9-hydroxyfluorene, 1-acenaphthenone, and 1, 8-naphthalic anhydride, were identified as the dominating intermediates in presence of 50 MUg/mL fluoranthene as the sole carbon source according to gas chromatography mass spectrometry analysis. Taken together, the genomic and metabolic analysis indicated that the fluoranthene degradation by DN1 strain was initiated by dioxygenation at the C-1, 2-, C-2, 3-, and C-7, 8- positions. These results provide new insights into the genomic plasticity and environmental adaptation of DN1 strain. PMID- 30429834 TI - A Neglected Animal Model for a Neglected Disease: Guinea Pigs and the Search for an Improved Animal Model for Human Brucellosis. AB - Brucellosis is a bacterial disease caused by species of the Brucella genus and affects a wide variety of domestic and wildlife species and is also an important zoonosis. The global burden of disease is difficult to assess but Brucella spp. have a worldwide distribution and are endemic in the Middle East, Africa, South America, and Asia. The clinical signs of fever and malaise are non-specific, and the available serological diagnostic tests lack a high degree specificity in endemic regions compared to other important public health diseases such as malaria. A better understanding of the pathogenesis of brucellosis through discoveries in animal models could lead to improved diagnostics and potentially a vaccine for human use. Mouse models have played an important role in elucidating the pathogenesis but do not replicate key features of the disease such as fever. Guinea pigs were instrumental in exploring the pathogenesis of brucellosis in the early nineteenth century and could offer an improvement on the mouse model as a model for human brucellosis. PMID- 30429836 TI - Seasonal Genetic Drift of Human Influenza A Virus Quasispecies Revealed by Deep Sequencing. AB - After a pandemic wave in 2009 following their introduction in the human population, the H1N1pdm09 viruses replaced the previously circulating, pre pandemic H1N1 virus and, along with H3N2 viruses, are now responsible for the seasonal influenza type A epidemics. So far, the evolutionary potential of influenza viruses has been mainly documented by consensus sequencing data. However, like other RNA viruses, influenza A viruses exist as a population of diverse, albeit related, viruses, or quasispecies. Interest in this quasispecies nature has increased with the development of next generation sequencing (NGS) technologies that allow a more in-depth study of the genetic variability. NGS deep sequencing methodologies were applied to determine the whole genome genetic heterogeneity of the three categories of influenza A viruses that circulated in humans between 2007 and 2012 in France, directly from clinical respiratory specimens. Mutation frequencies and single nucleotide polymorphisms were used for comparisons to address the level of natural intrinsic heterogeneity of influenza A viruses. Clear differences in single nucleotide polymorphism profiles between seasons for a given subtype also revealed the constant genetic drift that human influenza A virus quasispecies undergo. PMID- 30429837 TI - A Putative Zn2Cys6 Transcription Factor Is Associated With Isoprothiolane Resistance in Magnaporthe oryzae. AB - Isoprothiolane (IPT), a systemic fungicide, has been applied to control rice blast since the 1970s. Although resistance to IPT has been observed, the mechanism of resistance still has not been fully elucidated. In this study, nucleotide polymorphisms were detected between two IPT-resistant mutants generated in the lab, and their parental wild type isolates using a whole-genome sequencing approach. In the genomes of the two resistant mutants, single point mutations were identified in a gene encoding a Zn2Cys6 transcription factor-like protein. Notably, either knocking out the gene or replacing the wild type allele with the mutant allele (R343W) in a wild type isolate resulted in resistance to IPT, indicating that the gene is associated with IPT resistance, and thus was designated as MoIRR (Magnaporthe oryzae isoprothiolane resistance related). Along with point mutations R343W in mutant 1a_mut, and R345C in 1c_mut, a 16 bp insertion in 6c_mut was also located in the Fungal_TF_MHR domain of MoIRR, revealing that this domain may be the core element for IPT resistance. In addition, IPT-resistant mutants and transformants showed cross-resistance with iprobenfos (IBP), which was consistent with previous observations. These results indicated that MoIRR is strongly connected to resistance to choline biosynthesis inhibitor (CBI), and further work should focus on investigating downstream effects of MoIRR. PMID- 30429838 TI - Cross-Protective Shigella Whole-Cell Vaccine With a Truncated O-Polysaccharide Chain. AB - Shigella is a highly prevalent bacterium causing acute diarrhea and dysentery in developing countries. Shigella infections are treated with antibiotics but Shigellae are increasingly resistant to these drugs. Vaccination can be a countermeasure against emerging antibiotic-resistant shigellosis. Because of the structural variability in Shigellae O-antigen polysaccharides (Oag), cross protective Shigella vaccines cannot be derived from single serotype-specific Oag. We created an attenuated Shigella flexneri 2a strain with one rather than multiple Oag units by disrupting the Oag polymerase gene (Deltawzy), which broadened protective immunogenicity by exposing conserved surface proteins. Inactivated Deltawzy mutant cells combined with Escherichia coli double mutant LT(R192G/L211A) as adjuvant, induced potent antibody responses to outer membrane protein PSSP-1, and type III secretion system proteins IpaB and IpaC. Intranasal immunization with the vaccine preparation elicited cross-protective immunity against S. flexneri 2a, S. flexneri 3a, S. flexneri 6, and Shigella sonnei in a mouse pneumonia model. Thus, S. flexneri 2a Deltawzy represents a promising candidate strain for a universal Shigella vaccine. PMID- 30429839 TI - Biogas Biocatalysis: Methanotrophic Bacterial Cultivation, Metabolite Profiling, and Bioconversion to Lactic Acid. AB - Anaerobic digestion (AD) of waste substrates, and renewable biomass and crop residues offers a means to generate energy-rich biogas. However, at present, AD derived biogas is primarily flared or used for combined heat and power (CHP), in part due to inefficient gas-to-liquid conversion technologies. Methanotrophic bacteria are capable of utilizing methane as a sole carbon and energy source, offering promising potential for biological gas-to-liquid conversion of AD derived biogas. Here, we report cultivation of three phylogenetically diverse methanotrophic bacteria on biogas streams derived from AD of a series of energy crop residues. Strains maintained comparable central metabolic activity and displayed minimal growth inhibition when cultivated under batch configuration on AD biogas streams relative to pure methane, although metabolite analysis suggested biogas streams increase cellular oxidative stress. In contrast to batch cultivation, growth arrest was observed under continuous cultivation configuration, concurrent with increased biosynthesis and excretion of lactate. We examined the potential for enhanced lactate production via the employ of a pyruvate dehydrogenase mutant strain, ultimately achieving 0.027 g lactate/g DCW/h, the highest reported lactate specific productivity from biogas to date. PMID- 30429840 TI - Organic Amendment Under Increasing Agricultural Intensification: Effects on Soil Bacterial Communities and Plant Productivity. AB - The soil microbiome is a complex living network that plays essential roles in agricultural systems, regardless of the level of intensification. However, the effects of agricultural management on the soil microbiome and the association with plant productivity remain largely unclear. Here, we studied the responses of three soil systems displaying distinct levels of agriculture intensiveness (i.e., natural, organic, and conventional soil management regimes) to experimentally manipulated organic farming amendments (i.e., dung and earthworms). We aimed at (i) identifying the effect on plant productivity and (ii) elucidating the degree of shifts in bacterial communities in response to the applied organic amendments. We found plant productivity to be lower with increasing agricultural intensification. Bacterial communities shifted distinctively for each soil management regime to the organic amendments applied. In brief, greater changes were observed in the Conventional management comparatively to the Organic and Natural management, an effect largely driven by dung addition. Moreover, we found evidence that the level of agricultural intensiveness also affects the timespan for these shifts. For instance, while the Natural system reached a relatively stable community composition before the end of the experiment, treatments on the conventional soil management regime did not. Random forest analyses further revealed an increasing impact of introduced taxa from dung addition aligned with increasing agricultural intensification. These analyses suggested that earthworms regulate the introduction of species from dung into the soil bacterial community. Collectively, our results contribute to a better understanding of the outcomes of organic amendments on soils under distinct levels of agriculture intensiveness, with implications for further development in soil restorations practices. PMID- 30429841 TI - Different Selectivity in Fungal Communities Between Manure and Mineral Fertilizers: A Study in an Alkaline Soil After 30 Years Fertilization. AB - Fertilizer application has contributed substantially to increasing crop yield. Despite the important role of soil fungi in agricultural production, we still have limited understanding of the complex responses of fungal taxonomic and functional groups to organic and mineral fertilization in long term. Here we report the responses of the fungal communities in an alkaline soil to 30-year application of mineral fertilizer (NP), organic manure (M) and combined fertilizer (NPM) by the Illumina HiSeq sequencing and quantitative real-time PCR to target fungal internal transcribed spacer (ITS) genes. The results show: (1) compared to the unfertilized soil, fertilizer application increased fungal diversity and ITS gene copy numbers, and shifted fungal community structure. Such changes were more pronounced in the M and NPM soils than in the NP soil (except for fungal diversity), which can be largely attributed to the manure induced greater increases in soil total organic C, total N and available P. (2) Compared to the unfertilized soil, the NP and NPM soils reduced the proportion of saprotrophs by 40%, the predominant taxa of which may potentially affect cellulose decomposition. (3) Indicator species analysis suggested that the indicator operational taxonomic units (OTUs) in the M soil occupied 25.6% of its total community, but that only accounted for 0.9% in the NP soil. Our findings suggest that fertilization-induced changes of total fungal community were more responsive to organic manure than mineral fertilizer. The reduced proportion of cellulose decomposition-related saprotrophs in mineral fertilizer treatments may potentially contribute to increasing their soil C stocks. PMID- 30429842 TI - Characterization of a Protein Phosphatase Type-1 and a Kinase Anchoring Protein in Plasmodium falciparum. AB - With its multiple regulatory partners, the conserved Protein Phosphatase type-1 (PP1) plays a central role in many functions of the biology of eukaryotic cells, including Plasmodium falciparum. Here, we characterized a protein named PfRCC PIP, as a major partner of PfPP1. We established its direct interaction in vitro and its presence in complex with PfPP1 in the parasite. The use of Xenopus oocyte model revealed that RCC-PIP can interact with the endogenous PP1 and act in synergy with suboptimal doses of progesterone to trigger oocyte maturation, suggesting a regulatory effect on PP1. Reverse genetic studies suggested an essential role for RCC-PIP since no viable knock-out parasites could be obtained. Further, we demonstrated the capacity of protein region containing RCC1 motifs to interact with the parasite kinase CDPK7. These data suggest that this protein is both a kinase and a phosphatase anchoring protein that could provide a platform to regulate phosphorylation/dephosphorylation processes. PMID- 30429843 TI - Contribution of Host Genetics to the Variation of Microbial Composition of Cecum Lumen and Feces in Pigs. AB - Pigs are a perfect model for studying the interaction between host genetics and gut microbiome due to the high similarity of gastrointestine and digestive system with humans, and the easily controlled feeding conditions. In this study, two pig populations which were raised in uniformed farm conditions and provided with the same commercial formula diet were used as the experimental animals. A systematical investigation of host genetic effect on the gut microbial composition was separately performed in porcine cecum lumen and feces samples through the comparison of microbial composition among full-sibs, half-sibs and unrelated members, heritability estimate (h 2), and genome-wide association study (GWAS). The results showed that full-sib members had a higher similarity of microbial composition than unrelated individuals. A significant correlation was observed between the microbial composition-based kinship and the host SNP-based kinship in both populations (P < 9.9 * 10-5). We identified 81 and 67 microbial taxa having h 2 > 0.15 in fecal and cecum luminal samples, respectively, including 31 taxa with h 2 > 0.15 in both types of samples. GWAS identified 40 and 34 significant associations between host genomic loci and the abundance or presence/absence of bacterial taxa in the fecal and cecum luminal samples. Functional classifications of host candidate genes related to microbial taxa are mainly associated with metabolism, immunity functions and response, and signal transduction. The high similarity of heritable taxa and functional categories of candidate genes among pig, human and mouse suggests the similar mechanism of the host genetic effect on gut microbiome across mammalian species. The results from this study provided another evidence that host genetics contributes significantly to the gut microbiome. PMID- 30429844 TI - Gene Expression Profiling of Lacrimal Glands Identifies the Ectopic Expression of MHC II on Glandular Cells as a Presymptomatic Feature in a Mouse Model of Primary Sjogren's Syndrome. AB - Ectopic expression of MHC II molecules on glandular cells is a feature of primary Sjogren's syndrome (pSS). However, the cause of this ectopic expression and its potential role in the pathogenesis of the disease remains elusive. Here, we report that ectopic expression of MHC II molecules on glandular cells represents an early presymptomatic event in a mouse model of pSS induced by immunization of Ro60_316-335 peptide emulsified in TiterMax(r) as an adjuvant. Ectopic expression of MHC II was induced by TiterMax(r) but not by complete freund's adjuvant (CFA). Furthermore, immunization with Ro60_316-335 peptide emulsified in TiterMax(r), but not in CFA, induced a pSS-like disease in mice. Our results suggests that ectopic expression of MHC II molecules on glandular cells represents a presymptomatic feature of pSS and that such ectopic expression can be induced by exogenous factors. In addition, this study also provides a novel mechanism how adjuvants can amplify immune responses. PMID- 30429846 TI - A CARD9 Founder Mutation Disrupts NF-kappaB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation. AB - Background: Inherited CARD9 deficiency constitutes a primary immunodeficiency predisposing uniquely to chronic and invasive fungal infections. Certain mutations are shown to negatively impact CARD9 protein expression and/or NF kappaB activation, but the underlying biochemical mechanism remains to be fully understood. Objectives: To investigate a possible founder origin of a known CARD9 R70W mutation in five families of Turkish origin. To explore the biochemical mechanism of immunodeficiency by R70W CARD9. Methods: We performed haplotype analysis using microsatellite markers and SNPs. We designed a model system exploiting a gain-of-function (GOF) CARD9 L213LI mutant that triggers constitutive NF-kappaB activation, analogous to an oncogenic CARD11 mutant, to study NF-kappaB signaling and signalosome formation. We performed reporter assays, immunoprecipitation and confocal imaging on HEK cells overexpressing different CARD9 variants. Results: We identified a common haplotype, thus providing evidence for a common Turkish founder. CARD9 R70W failed to activate NF kappaB and abrogated NF-kappaB activation by WT CARD9 and by GOF CARD9. Notably, R70W CARD9 also exerted negative effects on NF-kappaB activation by CARD10, CARD11, and CARD14. Consistent with the NF-kappaB results, the R70W mutation prevented GOF CARD9 to pull down the signalosome partner proteins BCL10 and MALT1. This reflected into drastic reduction of BCL10 filamentous assemblies in a cellular context. Indeed, structural analysis revealed that position R70 in CARD9 maps at the putative interface between successive CARD domains in CARD9 filaments. Conclusions: The R70W mutation in CARD9 prevents NF-kappaB activation by inhibiting productive interactions with downstream BCL10 and MALT1, necessary for assembly of the filamentous CARD9-BCL10-MALT1 signalosome. PMID- 30429845 TI - Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress. AB - Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation. PMID- 30429847 TI - Benchmarking Tree and Ancestral Sequence Inference for B Cell Receptor Sequences. AB - B cell receptor sequences evolve during affinity maturation according to a Darwinian process of mutation and selection. Phylogenetic tools are used extensively to reconstruct ancestral sequences and phylogenetic trees from affinity-matured sequences. In addition to using general-purpose phylogenetic methods, researchers have developed new tools to accommodate the special features of B cell sequence evolution. However, the performance of classical phylogenetic techniques in the presence of B cell-specific features is not well understood, nor how much the newer generation of B cell specific tools represent an improvement over classical methods. In this paper we benchmark the performance of classical phylogenetic and new B cell-specific tools when applied to B cell receptor sequences simulated from a forward-time model of B cell receptor affinity maturation toward a mature receptor. We show that the currently used tools vary substantially in terms of tree structure and ancestral sequence inference accuracy. Furthermore, we show that there are still large performance gains to be achieved by modeling the special mutation process of B cell receptors. These conclusions are further strengthened with real data using the rules of isotype switching to count possible violations within each inferred phylogeny. PMID- 30429848 TI - Fueling Defense: Effects of Resources on the Ecology and Evolution of Tolerance to Parasite Infection. AB - Resource availability is a key environmental constraint affecting the ecology and evolution of species. Resources have strong effects on disease resistance, but they can also affect the other main parasite defense strategy, tolerance. A small but growing number of animal studies are beginning to investigate the effects of resources on tolerance phenotypes. Here, we review how resources affect tolerance strategies across animal taxa ranging from fruit flies to frogs to mice. Surprisingly, resources (quality and quantity) can increase or reduce tolerance, dependent upon the particular host-parasite system. To explore this seeming contradiction, we recast predictions of models of sterility tolerance and mortality tolerance in a resource-dependent context. Doing so reveals that resources can have very different epidemiological and evolutionary effects, depending on what aspects of the tolerance phenotype are affected. Thus, it is critical to consider both sterility and mortality in future empirical studies of how behavioral and environmental resource availability affect tolerance to infection. PMID- 30429849 TI - Absence of Regulatory T Cells Causes Phenotypic and Functional Switch in Murine Peritoneal Macrophages. AB - Tissue macrophages are important components of tissue homeostasis and inflammatory pathologies. In the peritoneal cavity, resident macrophages interact with a variety of immune cells and can exhibit broad range of phenotypes and functions. Forkhead-box-P3 (FOXP3)+ regulatory T cells (Tregs) play an indispensable role in maintaining immunological tolerance, yet whether, and how the pathological condition that results from the lack of functional Tregs affects peritoneal macrophages (PM) is largely unknown. We used FOXP3-deficient scurfy (Sf) mice to investigate PM behavior in terms of the missing crosstalk with Tregs. Here, we report that Treg deficiency induced a marked increase in PM numbers, which was reversed after adoptive transfer of CD4+ T cells or neutralization of macrophage colony-stimulating factor. Ex vivo assays demonstrated a pro-inflammatory state of PM from Sf mice and signs of excessive activation and exhaustion. In-depth immunophenotyping of Sf PM using single-cell chipcytometry and transcriptome analysis revealed upregulation of molecules involved in the initiation of innate and adaptive immune responses. Moreover, upon transfer to non-inflammatory environment or after injection of CD4+ T cells, PM from Sf mice reprogramed their functional phenotype, indicating remarkable plasticity. Interestingly, frequencies, and immune polarization of large and small PM subsets were dramatically changed in the FOXP3-deficient mice, suggesting distinct origin and specialized function of these subsets in inflammatory conditions. Our findings demonstrate the significant impact of Tregs in shaping PM identity and dynamics. A better understanding of PM function in the Sf mouse model may have clinical implication for the treatment of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, and other forms of immune-mediated enteropathies. PMID- 30429850 TI - Rainbow Trout Erythrocytes ex vivo Transfection With a DNA Vaccine Encoding VHSV Glycoprotein G Induces an Antiviral Immune Response. AB - Fish red blood cells (RBCs), are integral in several biologic processes relevant to immunity, such as pathogen recognition, pathogen binding and clearance, and production of effector molecules and cytokines. So far, one of the best strategies to control and prevent viral diseases in aquaculture is DNA immunization. DNA vaccines (based on the rhabdoviral glycoprotein G [gpG] gene) have been shown to be effective against fish rhabdoviruses. However, more knowledge about the immune response triggered by DNA immunization is necessary to develop novel and more effective strategies. In this study, we investigated the role of fish RBCs in immune responses induced by DNA vaccines. We show for the first time that rainbow trout RBCs express gpG of viral hemorrhagic septicaemia virus (VHSV) (GVHSV) when transfected with the DNA vaccine ex vivo and modulate the expression of immune genes and proteins. Functional network analysis of transcriptome profiling of RBCs expressing GVHSV revealed changes in gene expression related to G-protein coupled receptor (GPCR)-downstream signaling, complement activation, and RAR related orphan receptor alpha (RORA). Proteomic profile functional network analysis of GVHSV-transfected RBCs revealed proteins involved in the detoxification of reactive oxygen species, interferon-stimulated gene 15 (ISG15) antiviral mechanisms, antigen presentation of exogenous peptides, and the proteasome. Conditioned medium of GVHSV-transfected RBCs conferred antiviral protection and induced ifn1 and mx gene expression in RTG-2 cells infected with VHSV. In summary, rainbow trout nucleated RBCs could be actively participating in the regulation of the fish immune response to GVHSV DNA vaccine, and thus may represent a possible carrier cells for the development of new vaccine approaches. PMID- 30429851 TI - Induced B Cell Development in Adult Mice. AB - We employed the B-Indu-Rag1 model in which the coding exon of recombination activating gene 1 (Rag1) is inactivated by inversion. It is flanked by inverted loxP sites. Accordingly, B cell development is stopped at the pro/pre B-I cell precursor stage. A B cell-specific Cre recombinase fused to a mutated estrogen receptor allows the induction of RAG1 function and B cell development by application of Tamoxifen. Since Rag1 function is recovered in a non-self-renewing precursor cell, only single waves of development can be induced. Using this system, we could determine that B cells minimally require 5 days to undergo development from pro/preB-I cells to the large and 6 days to the small preB-II cell stage. First immature transitional (T) 1 and T2 B cells could be detected in the bone marrow at day 6 and day 7, respectively, while their appearance in the spleen took one additional day. We also tested a contribution of adult bone marrow to the pool of B-1 cells. Sublethally irradiated syngeneic WT mice were adoptively transferred with bone marrow of B-Indu-Rag1 mice and B cell development was induced after 6 weeks. A significant portion of donor derived B-1 cells could be detected in such adult mice. Finally, early VH gene usage was tested after induction of B cell development. During the earliest time points the VH genes proximal to D/J were found to be predominantly rearranged. At later time points, the large family of the most distal VH prevailed. PMID- 30429853 TI - Auto-Reactive Th17-Cells Trigger Obsessive-Compulsive-Disorder Like Behavior in Mice With Experimental Autoimmune Encephalomyelitis. AB - Th17-lymphocytes are well known for their deleterious role in autoimmunity. But does the notoriety of this repertoire extend beyond autoimmunity? In the present study we employed experimental autoimmune encephalomyelitis as model system to study the role auto-reactive Th17 cells in neuropsychiatric disorders. The mice with experimental autoimmune encephalomyelitis exhibited exaggerated grooming activity. The observed behavioral anomaly resembled obsessive compulsive disorder (OCD) upon analysis of grooming microstructure, induced grooming, marble burying and nestlet shredding. The observed OCD like behavior was relieved upon Th17 cell depletion; alternatively, it could alone be induced by adoptive transfer of myelin oligodendrocyte glycoprotein (35-55) reactive Th17 in B6.Rag1 -/- mice. The observed OCD like behavior was also alleviated upon treatment with a selective serotonin reuptake inhibitor, fluoxetine. PMID- 30429854 TI - Early Induction of Human Regulatory Dermal Antigen Presenting Cells by Skin Penetrating Schistosoma Mansoni Cercariae. AB - Following initial invasion of Schistosoma mansoni cercariae, schistosomula reside in the skin for several days during which they can interact with the dermal immune system. While murine experiments have indicated that exposure to radiation attenuated (RA) cercariae can generate protective immunity which is initiated in the skin stage, contrasting non-attenuated cercariae, such data is missing for the human model. Since murine skin does not form a reliable marker for immune responses in human skin, we used human skin explants to study the interaction with non-attenuated and RA cercariae with dermal innate antigen presenting cells (APCs) and the subsequent immunological responses. We exposed human skin explants to cercariae and visualized their invasion in real time (initial 30 min) using novel imaging technologies. Subsequently, we studied dermal immune responses and found an enhanced production of regulatory cytokine interleukin (IL)-10, pro inflammatory cytokine IL-6 and macrophage inflammatory protein (MIP)-1alpha within 3 days of exposure. Analysis of dermal dendritic cells (DDCs) for their phenotype revealed an increased expression of immune modulators programmed death ligand (PD-L) 1 and 2, and increased IL-10 production. Ex vivo primed DDCs suppress Th1 polarization of naive T-cells and increase T-cell IL-10 production, indicating their regulatory potential. These immune responses were absent or decreased after exposure to RA parasites. Using transwells, we show that direct contact between APCs and cercariae is required to induce their regulatory phenotype. To the best of our knowledge this is the first study that attempts to provide insight in the human dermal S. mansoni cercariae invasion and subsequent immune responses comparing non-attenuated with RA parasites. We reveal that cercariae induce a predominantly regulatory immune response whereas RA cercariae fail to achieve this. This initial understanding of the dermal immune suppressive capacity of S. mansoni cercariae in humans provides a first step toward the development of an effective schistosome vaccine. PMID- 30429852 TI - Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease. AB - Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4+ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4+ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4+ T cells can contribute to intestinal inflammation. PMID- 30429855 TI - High-Dimensional Profiling Reveals Heterogeneity of the Th17 Subset and Its Association With Systemic Immunomodulatory Treatment in Non-infectious Uveitis. AB - Background: Non-infectious uveitis (NIU) is a severe intra ocular inflammation, which frequently requires prompt systemic immunosuppressive therapy (IMT) to halt the development of vision-threatening complications. IMT is considered when NIU cannot be treated with corticosteroids alone, which is unpredictable in advance. Previous studies have linked blood cell subsets to glucocorticoid sensitivity, which suggests that the composition of blood leukocytes may early identify patients that will require IMT. Objective: To map the blood leukocyte composition of NIU and identify cell subsets that stratify patients that required IMT during follow-up. Methods: We performed controlled flow cytometry experiments measuring a total of 37 protein markers in the blood of 30 IMT free patients with active non-infectious anterior, intermediate, and posterior uveitis, and compared these to 15 age and sex matched healthy controls. Results from manual gating were validated by automatic unsupervised gating using FlowSOM. Results: Patients with uveitis displayed lower relative frequencies of Natural Killer cells and higher relative frequencies of memory T cells, in particular the CCR6+ lineages. These results were confirmed by automatic gating by unsupervised clustering using FlowSOM. We observed considerable heterogeneity in memory T cell subsets and abundance of CXCR3-CCR6+ (Th17) cells between the uveitis subtypes. Importantly, regardless of the uveitis subtype, patients that eventually required IMT in the course of the study follow-up exhibited increased CCR6+ T cell abundance before commencing therapy. Conclusion: High-dimensional immunoprofiling in NIU patients shows that clinically distinct forms of human NIU exhibit shared as well as unique immune cell perturbations in the peripheral blood and link CCR6+ T cell abundance to systemic immunomodulatory treatment. PMID- 30429856 TI - Macrophage Polarization in Leishmaniasis: Broadening Horizons. AB - Leishmaniasis is a vector-borne neglected tropical disease that affects more than 700,000 people annually. Leishmania parasites cause the disease, and different species trigger a distinct immune response and clinical manifestations. Macrophages are the final host cells for the proliferation of Leishmania parasites, and these cells are the key to a controlled or exacerbated response that culminates in clinical manifestations. M1 and M2 are the two main macrophage phenotypes. M1 is a pro-inflammatory subtype with microbicidal properties, and M2, or alternatively activated, is an anti-inflammatory/regulatory subtype that is related to inflammation resolution and tissue repair. The present review elucidates the roles of M1 and M2 polarization in leishmaniasis and highlights the role of the salivary components of the vector and the action of the parasite in the macrophage plasticity. PMID- 30429858 TI - Silencing of the Wheat Protein Phosphatase 2A Catalytic Subunit TaPP2Ac Enhances Host Resistance to the Necrotrophic Pathogen Rhizoctonia cerealis. AB - Eukaryotic type 2A protein phosphatases (protein phosphatase 2A, PP2A) consist of a scaffold subunit A, a regulatory subunit B, and a catalytic subunit C. Little is known about the roles of PP2Ac proteins that are involved in plant responses to necrotrophic fungal pathogens. Sharp eyespot, caused by the necrotrophic fungus Rhizoctonia cerealis, is a destructive disease of wheat (Triticum aestivum), an important staple food crop. Here, we isolated TaPP2Ac-4D from wheat, which encodes a catalytic subunit of the heterotrimeric PP2A, and characterized its properties and role in plant defense response to R. cerealis. Based on the sequence alignment of TaPP2Ac-4D with the draft sequences of wheat chromosomes from the International Wheat Genome Sequencing Consortium (IWGSC), it was found that TaPP2Ac-4D gene is located on the long arm of the wheat chromosome 4D and has two homologs assigned on wheat chromosomes 4A and 4B. Sequence and phylogenetic tree analyses revealed that the TaPP2Ac protein is a typical member of the PP2Ac family and belongs to the subfamily II. TaPP2Ac-4B and TaPP2Ac-4D displayed higher transcriptional levels in the R. cerealis-susceptible wheat cultivar Wenmai 6 than those seen in the resistant wheat line CI12633. The transcriptional levels of TaPP2Ac-4B and TaPP2Ac-4D were significantly elevated in wheat R. cerealis after infection and upon H2O2 treatment. Virus-induced gene silencing results revealed that the transcriptional knockdown of TaPP2Ac-4D and TaPP2Ac-4B significantly increased wheat resistance to R. cerealis infection. Meanwhile, the transcriptional levels of certain pathogenesis-related (PR) and reactive oxygen species (ROS)-scavenging enzyme encoding genes were increased in TaPP2Ac-silenced wheat plants. These results suggest that TaPP2Ac-4B and TaPP2Ac 4D negatively regulate defense response to R. cerealis infection possibly through modulation of the expression of certain PR and ROS-scavenging enzyme genes in wheat. This study reveals a novel function of the plant PP2Ac genes in plant immune responses. PMID- 30429857 TI - Polymicrobial Sepsis Chronic Immunoparalysis Is Defined by Diminished Ag-Specific T Cell-Dependent B Cell Responses. AB - Immunosuppression is one hallmark of sepsis, decreasing the host response to the primary septic pathogens and/or secondary nosocomial infections. CD4 T cells and B cells are among the array of immune cells that experience reductions in number and function during sepsis. "Help" from follicular helper (Tfh) CD4 T cells to B cells is needed for productive and protective humoral immunity, but there is a paucity of data defining the effect of sepsis on a primary CD4 T cell-dependent B cell response. Using the cecal ligation and puncture (CLP) mouse model of sepsis induction, we observed reduced antibody production in mice challenged with influenza A virus or TNP-KLH in alum early (2 days) and late (30 days) after CLP surgery compared to mice subjected to sham surgery. To better understand how these CD4 T cell-dependent B cell responses were altered by a septic event, we immunized mice with a Complete Freund's Adjuvant emulsion containing the MHC II restricted peptide 2W1S56-68 coupled to the fluorochrome phycoerythrin (PE). Immunization with 2W1S-PE/CFA results in T cell-dependent B cell activation, giving us the ability to track defined populations of antigen-specific CD4 T cells and B cells responding to the same immunogen in the same mouse. Compared to sham mice, differentiation and class switching in PE-specific B cells were blunted in mice subjected to CLP surgery. Similarly, mice subjected to CLP had reduced expansion of 2W1S-specific T cells and Tfh differentiation after immunization. Our data suggest CLP-induced sepsis impacts humoral immunity by affecting the number and function of both antigen-specific B cells and CD4 Tfh cells, further defining the period of chronic immunoparalysis after sepsis induction. PMID- 30429859 TI - A Stepwise NaHSO3 Addition Mode Greatly Improves H2 Photoproduction in Chlamydomonas reinhardtii. AB - NaHSO3 addition greatly increases the yield of H2 photoproduction in a unicellular green alga Chlamydomonas reinhardtii through removing O2 and activating hydrogenase but significantly impairs the activity of PSII, an electron source for H2 photoproduction. Here, a stepwise addition mode of total 13 mM NaHSO3, an optimal concentration for H2 photoproduction of C. reinhardtii identified in a previous one step addition method, significantly improved H2 photoproduction. Such improvement was believed to be the result of increased residual PSII activity in an anaerobic background, but was at least independent of two alternative electron sinks for H2 photoproduction, cyclic electron transport around PSI and CO2 assimilation. Based on the above results, we propose that increased residual PSII activity in an anaerobic environment is an efficient strategy to enhance H2 photoproduction in C. reinhardtii, and the stepwise NaHSO3 addition mode is a case study in the strategy. PMID- 30429860 TI - Adaptation of a Fungal Pathogen to Host Quantitative Resistance. AB - Impact of host quantitative resistance on pathogen evolution is still poorly documented. In our study, we characterized the adaptation of the pathogenic fungus Colletotrichum gloeosporioides, to the quantitative resistance of its host, the water yam (Dioscorea alata). Genetic and pathogenic diversities of C. gloeosporioides populations were specified at the field scale. We used nuclear markers to describe fungal population structuring within and between six fields of three cultivars differently susceptible to the fungus. Strain aggressiveness was then quantified in the laboratory through cross-inoculation tests. The high level of genetic diversity and significant linkage disequilibrium revealed a significant influence of clonal reproduction in the C. gloeosporioides evolution. The recorded fungal migration between fields was weak (evidence for a dispersion mode via tubers rather than splashing dispersal), which provides the first molecular evidence for limited C. gloeosporioides migration via yam tuber exchanges. C. gloeosporioides's populations are adapted to their host resistance. The aggressiveness of the fungal clones seems to have evolved toward an accumulation of components specific to each host cultivar. Despite the remaining marks of adaptation to the former widely cultivated host, adaptation to current cultivars was clearly depicted. PMID- 30429861 TI - Mapping and QTL Analysis of Gynoecy and Earliness in Bitter Gourd (Momordica charantia L.) Using Genotyping-by-Sequencing (GBS) Technology. AB - A high-density, high-resolution genetic map was constructed for bitter gourd (Momordica charantia L.). A total of 2013 high quality SNP markers binned to 20 linkage groups (LG) spanning a cumulative distance of 2329.2 cM were developed. Each LG ranging from 185.2 cM (LG-12) to 46.2 cM (LG-17) and average LG span of 116.46 cM. The number of SNP markers mapped in each LG varied from 23 markers in LG-20 to 146 markers in LG-1 with an average of 100.65 SNPs per LG. The average distance between markers was 1.16 cM across 20 LGs and average distance between the markers ranged from 0.70 (LG-4) to 2.92 (LG-20). A total of 22 QTLs for four traits (gynoecy, sex ratio, node and days at first female flower appearance) were identified and mapped on 20 LGs. The gynoecious (gy-1) locus is flanked by markers TP_54865 and TP_54890 on LG 12 at a distance of 3.04 cM to TP_54890 and the major QTLs identified for the earliness traits will be extremely useful in marker development and MAS for rapid development of various gynoecious lines with different genetic background of best combiner for development of early and high yielding hybrids in bitter gourd. PMID- 30429862 TI - Genetic Variability Induced by Gamma Rays and Preliminary Results of Low-Cost TILLING on M2 Generation of Chickpea (Cicer arietinum L.). AB - In order to increase genetic variability for chickpea improvement, the Kabuli genotype, variety Ghab4, was treated with 280 Grays of gamma rays (Cobalt 60). Field characterization began with the M2 generation. A total of 135 M2 families were sown in the field resulting in approximately 4,000 plants. Traits related to phenology (days to flowering, days to maturity), plant morphology of vegetative parts (plant height, height of first pod, number of primary branches per plant) and yield (number of seeds per pod, total number of pods per plant, total number of seeds per plant, seed yield and hundred seed weight) were recorded and analyzed to evaluate genetic variability. An evaluation of the efficacy of low cost TILLING (Targeting Induced Local Lesions IN Genomes) to discover mutations in the M2 generation was undertaken. Mutation screening focused on genes involved in resistance to two important diseases of chickpea; Ascochyta blight (AB) and Fusarium wilt (FW), as well as genes responsible for early flowering. Analysis of variance showed a highly significant difference among mutant families for all studied traits. The higher estimates of genetic parameters (genotypic and phenotypic coefficient of variation, broad sense heritability and genetic advance) were recorded for number of seeds per plant and yield. Total yield was highly significant and positively correlated with number of pods and seeds per plant. Path analysis revealed that the total number of seeds per plant had the highest positive direct effect followed by hundred seed weight parameter. One cluster from nine exhibited the highest mean values for total number of pods and seeds per plant as well as yield per plant. According to Dunnett's test, 37 M2 families superior to the control were determined for five agronomical traits. Pilot experiments with low-cost TILLING show that the seed stock used for mutagenesis is homogeneous and that small mutations do not predominate at the dosage used. PMID- 30429863 TI - Recent Fragmentation May Not Alter Genetic Patterns in Endangered Long-Lived Species: Evidence From Taxus cuspidata. AB - Forestland fragmentation caused by overexploitation of forest resources can in principle reduce genetic diversity, limit gene flow and eventually lead to species developing strong genetic structure. However, the genetic consequences of recent anthropogenic fragmentation of tree species remain unclear. Taxus cuspidata, which has extremely small populations distributed mainly in Changbai Mt. in Northeast (NE) China, has recently endured severe habitat fragmentation. Here, we investigate the pattern of genetic diversity and structure, identify risk factors, predict the future distribution and finally provide guidelines for the conservation and management of this species. We used three chloroplast and two mitochondrial DNA fragments, which are both paternally inherited in yews but differ in mutation rates, to genotype a total of 265 individuals from 26 populations covering the distribution of the species in China. Both chloroplast and mitochondrial data showed high degrees of genetic diversity, extensive gene flow over the entire geographical range and historical stability of both effective population size and distribution of the species. However, ecological niche modeling suggests a decrease in suitable areas for this species by the years 2050 and 2070. The maintenance of high genetic diversity and the existence of sufficient gene flow suggest that recent fragmentation has not affected the genetic composition of the long-lived tree T. cuspidata. However, severe impacts of anthropogenic activities are already threatening the species. Conservation and management strategies should be implemented in order to protect the remnant populations. PMID- 30429864 TI - Dissecting the Genetic Architecture of Melon Chilling Tolerance at the Seedling Stage by Association Mapping and Identification of the Elite Alleles. AB - Low temperature is an important abiotic stress that negatively affects morphological growth and fruit development in melon (Cucumis melo L.). Chilling stress at the seedling stage causes seedling injury and poor stand establishment, prolonging vegetative growth and delaying fruit harvest. In this study, association mapping was performed for chilling tolerance at the seedling stage on an expanded melon core collection containing 212 diverse accessions by 272 SSRs and 27 CAPSs. Chilling tolerance of the melon seedlings was evaluated by calculating the chilling injury index (CII) in 2016 and 2017. Genetic diversity analysis of the whole accession panel presented two main groups, which corresponded to the two subspecies of C. melo, melo, and agrestis. Both the subspecies were sensitive to chilling but with agrestis being more tolerant. Genome-wide association study (GWAS) was conducted, respectively, on the whole panel and the two subspecies, totally detecting 51 loci that contributed to 74 marker-trait associations. Of these associations, 35 were detected in the whole panel, 21 in melo, and 18 in agrestis. About half of the associations identified in the two subspecies were also observed in the whole panel, and seven associations were shared by both the subspecies. CMCT505_Chr.1 was repeatedly detected in different populations with high phenotypic contribution and could be a key locus controlling chilling tolerance in C. melo. Nine loci were selected for evaluation of the phenotypic effects related to their alleles, which identified 11 elite alleles contributing to seedling chilling tolerance. Four such alleles existed in both the subspecies and six in either of the two subspecies. Analysis of 20 parental combinations for their allelic status and phenotypic values showed that the elite alleles collectively contributed to enhancement of the chilling tolerance. Tagging the loci responsible for chilling tolerance may simultaneously favor dissecting the complex adaptability traits and elevate the efficiency to improve chilling tolerance using marker-assisted selection in melon. PMID- 30429865 TI - Radial Growth and Wood Density Reflect the Impacts and Susceptibility to Defoliation by Gypsy Moth and Climate in Radiata Pine. AB - Drought stress causes a reduction in tree growth and forest productivity, which could be aggravated by climate warming and defoliation due to moth outbreaks. We investigate how European gypsy moth (Lymantria dispar dispar L., Lepidoptera: Erebidae) outbreak and related climate conditions affected growth and wood features in host and non-host tree species in north-western Spain. There, radiata pine (Pinus radiata D. Don) plantations and chestnut (Castanea sativa Mill.) stands were defoliated by the moth larvae, whereas Maritime pine (Pinus pinaster Ait.) was not defoliated. The gypsy moth outbreak peaked in 2012 and 2013, and it was preceded by very warm spring conditions in 2011 and a dry-warm 2011-2012 winter. Using dendrochronology we compared growth responses to climate and defoliation of host species (radiata pine, chestnut) with the non-host species (Maritime pine). We also analyzed wood density derived from X-ray densitometry in defoliated and non-defoliated trees of radiata pine. We aimed to: (i) disentangle the relative effects of defoliation and climate stress on radial growth, and (ii) characterize defoliated trees of radiata pine according to their wood features (ring-width, maximum and minimum density). Radial growth during the outbreak (2012-2013) decreased on average 74% in defoliated (>50% of leaf area removed) trees of radiata pine, 43% in defoliated trees of chestnut, and 4% in non defoliated trees of Maritime pine. After applying a BACI (Before-After-Control Impact) type analysis, we concluded that the difference in the pattern of radial growth before and during the defoliation event was more likely due to the differences in climate between these two periods. Radiata pines produced abundant latewood intra-annual density fluctuations in 2006 and 2009 in response to wet summer conditions, suggesting a high climatic responsiveness. Minimum wood density was lower in defoliated than in non-defoliated trees of radiata pine prior to the outbreak, but increased during the outbreak. The pre-outbreak difference in minimum wood density suggests that the trees most affected by the outbreak produced tracheids with wider lumen and were more susceptible to drought stress. Results of this study illustrate (i) that the pattern of radial growth alone may be not a good indicator for reconstructing past defoliation events and (ii) that wood variables are reliable indicators for assessing the susceptibility of radiata pine to defoliation by the gypsy moth. PMID- 30429866 TI - Characterization of Selenium Accumulation, Localization and Speciation in Buckwheat-Implications for Biofortification. AB - Buckwheat is an important crop species in areas of selenium (Se) deficiency. To obtain better insight into their Se metabolic properties, common buckwheat (Fagopyrum esculentum) and tartary buckwheat (F. tataricum) were supplied with different concentrations of Se, supplied as selenate, selenite, or Astragalus bisulcatus plant extract (methyl-selenocysteine). Se was supplied at different developmental stages, with different durations, and in the presence or absence of potentially competing ions, sulfate, and phosphate. The plants were analyzed for growth, Se uptake, translocation, accumulation, as well as for Se localization and chemical speciation in the seed. Plants of both buckwheat species were supplied with 20 MUM of either of the three forms of Se twice over their growth period. Both species accumulated 15-40 mg Se kg-1 DW in seeds, leaves and stems, from all three selenocompounds. X-ray microprobe analysis showed that the Se in seeds was localized in the embryo, in organic C-Se-C form(s) resembling selenomethionine, methyl-selenocysteine, and gamma-glutamyl-methylselenocysteine standards. In short-term (2 and 24 h) Se uptake studies, both buckwheat species showed higher Se uptake rate and shoot Se accumulation when supplied with plant extract (methyl-selenocysteine), compared to selenite or selenate. In long-term (7 days) uptake studies, both species were resistant to selenite up to 50 MUM. Tartary buckwheat was also resistant to selenate up to 75 MUM Se, but >30 MUM selenate inhibited common buckwheat growth. Selenium accumulation was similar in both species. When selenite was supplied, Se levels were 10-20-fold higher in root (up to 900 mg Se kg-1 DW) than shoot, but 4-fold higher in shoot (up to 1,200 mg Se kg-1 DW) than root for selenate-supplied plants. Additionally, sulfate and phosphate supply affected Se uptake, and conversely selenate enhanced S and P accumulation in both species. These findings have relevance for crop Se biofortification applications. PMID- 30429867 TI - A Genome-Wide Association Study of Wheat Spike Related Traits in China. AB - Rapid detection of allelic variation and identification of advantage haplotypes responsible for spike related traits play a crucial role in wheat yield improvement. The released genome sequence of hexaploid wheat (Chinese Spring) provides an extraordinary opportunity for rapid detection of natural variation and promotes breeding application. Here, selection signals detection and genome wide association study (GWAS) were conducted for spike related traits. Based on the genotyping results by 90K SNP chip, 192 common wheat samples from southwest China were analyzed. One hundred and forty-six selective windows and one hundred and eighty-four significant SNPs (51 for spike length, 28 for kernels per spike, 39 for spikelet number, 30 for thousand kernel weight, and 36 for spike number per plant) were detected. Furthermore, tightly linkage and environmental stability window clusters and SNP clusters were also obtained. As a result, four SNP clusters associated with spike length were detected on chromosome 2A, 2B, 2D, and 6A. Two SNP clusters correlated to kernels per spike were detected on 2A and 2B. One pleiotropy SNP cluster correlated to spikelet number and kernels per spike was detected on 7B. According to the genome sequence, these SNP clusters and their overlapped/flanking QTLs which have been reported previously were integrated to a physical map. The candidate genes responsible for spike length, kernels per spike and spikelet number were predicted. Based on the genotypes of cultivars in south China, two advantage haplotypes associated with spike length and one advantage haplotype associated with kernels per spike/spikelet number were detected which have not been effectively transited into cultivars. According to these haplotypes, KASP markers were developed and diagnosed across landraces and cultivars which were selected from south and north China. Consequently, KASP assay, consistent with the GWAS results, provides reliable haplotypes for MAS in wheat yield improvement. PMID- 30429868 TI - Neural Net Classification Combined With Movement Analysis to Evaluate Setaria viridis as a Model System for Time of Day of Anther Appearance. AB - In many plant species, the time of day at which flowers open to permit pollination is tightly regulated. Proper time of flower opening, or Time of Day of Anther Appearance (TAA), may coordinate flowering opening with pollinator activity or may shift temperature sensitive developmental processes to cooler times of the day. The genetic mechanisms that regulate the timing of this process in cereal crops are unknown. To address this knowledge gap, it is necessary to establish a monocot model system that exhibits variation in TAA. Here, we examine the suitability of Setaria viridis, the model for C4 photosynthesis, for such a role. We developed an imaging system to monitor the temporal regulation of growth, flower opening time, and other physiological characteristics in Setaria. This system enabled us to compare Setaria varieties Ames 32254, Ames 32276, and PI 669942 variation in growth and daily flower opening time. We observed that TAA occurs primarily at night in these three Setaria accessions. However, significant variation between the accessions was observed for both the ratio of flowers that open in the day vs. night and the specific time of day where the rate is maximal. Characterizing this physiological variation is a requisite step toward uncovering the molecular mechanisms regulating TAA. Leveraging the regulation of TAA could provide researchers with a genetic tool to improve crop productivity in new environments. PMID- 30429869 TI - Deep Intraspecific Divergence in the Endemic Herb Lancea tibetica (Mazaceae) Distributed Over the Qinghai-Tibetan Plateau. AB - Qinghai-Tibetan Plateau (QTP) is an important biodiversity hub, which is very sensitive to climate change. Here in this study, we investigated genetic diversity and past population dynamics of Lancea tibetica (Mazaceae), an endemic herb to QTP and adjacent highlands. We sequenced chloroplast and nuclear ribosomal DNA fragments for 429 individuals, collected from 29 localities, covering their major distribution range at the QTP. A total of 19 chloroplast haplotypes and 13 nuclear genotypes in two well-differentiated lineages, corresponding to populations into two groups isolated by Tanggula and Bayangela Mountains. Meanwhile, significant phylogeographical structure was detected among sampling range of L. tibetica, and 61.50% of genetic variations was partitioned between groups. Gene flow across the whole region appears to be restricted by high mountains, suggesting a significant role of geography in the genetic differences between the two groups. Divergence time between the two lineages dated to 8.63 million years ago, which corresponded to the uplifting of QTP during the late Miocene and Pliocene. Ecological differences were found between both the lineages represent species-specific characteristics, sufficient to keep the lineages separated to a high degree. The simulated distribution from the last interglacial period to the current period showed that the distribution of L. tibetica experienced shrinkage and expansion. Climate changes during the Pleistocene glacial-interglacial cycles had a dramatic effect on L. tibetica distribution ranges. Multiple refugia of L. tibetica might have remained during the species history, to south of the Tanggula and north of Bayangela Mountains, both appeared as topological barrier and contributed to restricting gene flow between the two lineages. Together, geographic isolation and climatic factors have played a fundamental role in promoting diversification and evolution of L. tibetica. PMID- 30429871 TI - Research and Global Health Emergencies: On the Essential Role of Best Practice. AB - This article addresses an important, overlooked regulatory challenge during global health emergencies (GHEs). It provides novel insights into how, and why, best practice can support decision makers in interpreting and implementing key guidance on conducting research during GHEs. The ability to conduct research before, during and after such events is crucial. The recent West-African Ebola outbreaks and the Zika virus have highlighted considerable room for improvement in meeting the imperative to research and rapidly develop effective therapies. A means of effectively capturing these experiences and folding them into future decision-making is lacking; the need for effective practical translational measures remains. The challenge for the research community lies in extracting meaningful action-guiding content from pre-existing guidelines-which draw upon practical examples of guidelines 'in action'-that assist in determining how to act in a particular (future) situation. Insights are provided into the role of best practice as a means to do so; such examples can provide invaluable support to decision makers in interpreting high-level guidance; overarching guidelines retain their necessary level of generality and flexibility, whilst corresponding best practice examples-which incorporate important lessons learned-illustrate how such guidelines can be interpreted at a practical level. PMID- 30429870 TI - FGF10 and Human Lung Disease Across the Life Spectrum. AB - Lung diseases impact patients across the lifespan, from infants in the first minutes of life through the aged population. Congenital abnormalities of lung structure can cause lung disease at birth or make adults more susceptible to chronic disease. Continuous inhalation of atmospheric components also requires the lung to be resilient to cellular injury. Fibroblast growth factor 10 (FGF10) regulates multiple stages of structural lung morphogenesis, cellular differentiation, and the response to injury. As a driver of lung airway branching morphogenesis, FGF10 signaling defects during development lead to neonatal lung disease. Alternatively, congenital airway abnormalities attributed to FGF10 mutations increase the risk of chronic airway disease in adulthood. FGF10 also maintains progenitor cell populations in the airway and promotes alveolar type 2 cell expansion and differentiation following injury. Here we review the cellular and molecular mechanisms linking FGF10 to multiple lung diseases, from bronchopulmonary dysplasia in extremely preterm neonates, cystic fibrosis in children, and chronic adult lung disorders. Understanding the connections between FGF10 and lung diseases may lead to exciting new therapeutic strategies. PMID- 30429872 TI - Doing 'Upstream' Priority-Setting for Global Health with Justice: Moving from Vision to Practice? AB - The vision of global health with justice which Larry Gostin articulates in his book Global Health Law envisages a switch to 'upstream' priority-setting for expenditure on health, with a focus upon social determinants and a goal of redressing health inequalities. This article explores what is meant by this proposal and offers a critical evaluation of it. It is argued that difficulties arise in respect of the ethical and evidential bases for such an approach to the setting of priorities, while significant challenges may also arise in the necessary modification of structures of governance. PMID- 30429873 TI - Ethical Considerations for Global Health Decision-Making: Justice-Enhanced Cost Effectiveness Analysis of New Technologies for Trypanosoma brucei gambiense. AB - We sought to assess formally the extent to which different control and elimination strategies for human African trypanosomiasis Trypanosoma brucei gambiense (Gambiense HAT) would exacerbate or alleviate experiences of societal disadvantage that traditional economic evaluation does not take into account. Justice-enhanced cost-effectiveness analysis (JE-CEA) is a normative approach under development to address social justice considerations in public health decision-making alongside other types of analyses. It aims to assess how public health interventions under analysis in comparative evaluation would be expected to influence the clustering of disadvantage across three core dimensions of well being: agency, association and respect. As a case study to test the approach, we applied it to five strategies for Gambiense HAT control and elimination, in combination with two different other evaluations: a cost-effectiveness analysis and a probability of elimination analysis. We have demonstrated how JE-CEA highlights the ethical importance of adverse social justice impacts of otherwise attractive options and how it indicates specific modifications to policy options to mitigate such impacts. JE-CEA holds promise as an approach to help decision makers and other stakeholders consider social justice more fully, explicitly and systematically in evaluating public health programs. PMID- 30429874 TI - Platelet bio-nanobubbles as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics. AB - Since the expected therapeutic results of ischemic stroke are strictly time dependent, early and accurate diagnosis as well as short intervals between diagnosis and treatment are key factors for the survival of stroke patients. In this study, we fabricated platelet (PLT) membrane-derived biomimetic nanobubbles (PNBs) for timely perfusion intervention and ultrasound imaging of acute ischemic stroke. Methods: The PNBs are fabricated by sonication-assisted reassembly of repeatedly freeze-thawed live platelet-derived PLT membrane vesicles (PMVs). The TEM, SEM, EDS and DLS were used to analyze the morphology and physicochemical properties of PNBs. The HPLC and LC-MS/MS were applied to confirm the lipid and protein compositions of PNBs. The in vitro macrophage uptake and platelet aggregation of PNBs were designed to examine the immune escape and thrombotic response characteristics. Furthermore, based on a photothrombotic ischemic stroke mouse model, the biodistribution, stroke microvascular network change, as well as cerebral blood flow of PNBs were studied by using near-infrared fluorescence imaging, multimodal optical imaging, and full-field laser perfusion imager. Finally, we assessed the brain ultrasound imaging of PNBs with a high-resolution micro-imaging system using both B-mode and contrast mode. Results: The natural lipid and protein components isolated from PLT membrane endow the PNBs with accurate lesion-targeting ability. The preferentially accumulated PNBs exhibit microvascular bio-remodeling ability of the stroke lesion, which is critical for recanalization of the obstructed vessels to protect the neural cells around the ischemic region of the stroke. Furthermore, with the increased accumulation of PNBs clusters in the lesion, PNBs in the lesion can be monitored by real-time contrast-enhanced ultrasound imaging to indicate the severity and dynamic development of the stroke. Conclusions: In summary, platelet membrane-based nanobubbles for targeting acute ischemic lesions were developed as microvascular recanalization nanoformulation for acute ischemic stroke lesion theranostics. This biomimetic PNBs theranostic strategy will be valuable for ischemic stroke patients in the future. PMID- 30429875 TI - Enhanced bioreduction-responsive diselenide-based dimeric prodrug nanoparticles for triple negative breast cancer therapy. AB - Efficient drug accumulation in tumor is essential for chemotherapy. We developed redox-responsive diselenide-based high-loading prodrug nanoparticles (NPs) for targeted triple negative breast cancer (TNBC) treatment. Method: Redox-responsive diselenide bond (Se-Se) containing dimeric prodrug (PTXD-Se) was synthesized and co-precipitated with TNBC-targeting amphiphilic copolymers to form ultra-stable NPs (uPA-PTXD NPs). The drug loading capacity and redox-responsive drug release behavior were studied. TNBC targeting effect and anti-tumor effect were also evaluated in vitro and in vivo. Results: On-demand designed paclitaxel dimeric prodrug could co-precipitate with amphiphilic copolymers to form ultra-stable uPA PTXD NPs with high drug loading capacity. Diselenide bond (Se-Se) in uPA-PTXD NPs could be selectively cleaved by abnormally high reduced potential in tumor microenvironment, releasing prototype drug, thus contributing to improved anti cancer efficacy. Endowed with TNBC-targeting ligand uPA peptide, uPA-PTXD NPs exhibited reduced systemic toxicity and enhanced drug accumulation in TNBC lesions, thus showed significant anti-tumor efficacy both in vitro and in vivo. Conclusion: The comprehensive advantage of high drug loading, redox-controlled drug release and targeted tumor accumulation suggests uPA-PTXD NPs as a highly promising strategy for effective TNBC treatment. PMID- 30429876 TI - Two-stage oxygen delivery for enhanced radiotherapy by perfluorocarbon nanoparticles. AB - Tumors are usually hypoxic, which limits the efficacy of current tumor therapies, especially radiotherapy in which oxygen is essential to promote radiation-induced cell damage. Herein, by taking advantage of the ability of perfluorocarbon (PFC) to promote red blood cell penetration, we developed a simple but effective two stage oxygen delivery strategy to modulate the hypoxic tumor microenvironment using PFC nanoparticles. Methods: We first examined the two-stage oxygen delivery ability of PFC nanoparticles on relieving tumor hypoxia through platelet inhibition. To evaluate the effect of PFC nanoparticles on radiation sensitization, CT26 tumor and SUM49PT tumor model were used. Results: In this study, PFC was encapsulated into albumin and intravenously injected into tumor bearing mice without hyperoxic breathing. After accumulation in the tumor, PFC nanoparticles rapidly released the oxygen that was physically dissolved in PFC as the first-stage of oxygen delivery. Then, PFC subsequently promoted red blood cell infiltration, which further released O2 as the second-stage of oxygen delivery. Conclusion: The hypoxic tumor microenvironment was rapidly relieved via two-stage oxygen delivery, effectively increasing radiotherapy efficacy. The safety of all substances used in this study has been clinically demonstrated, ensuring that this simple strategy could be rapidly and easily translated into clinical applications to solve the clinical problems associated with tumor hypoxia. PMID- 30429877 TI - Blood exosomes regulate the tissue distribution of grapefruit-derived nanovector via CD36 and IGFR1 pathways. AB - Tumor-specific delivery of therapeutics is challenging. One of the major hurdles for successfully delivering targeted agents by nanovectors is the filtering role of the liver in rapidly sequestering nanovectors from the circulation. Exosomes, a type of endogenous nanoparticle, circulate continuously in the peripheral blood and play a role in intercellular communication. The aim of this study was to determine whether the level of endogenous exosomes has an effect on nanovector delivery efficiency of targeted agents. Methods: Exosomes were isolated from peripheral blood and intravenously (I.V.) injected into tumor-bearing mice. Subsequently, 1,1-dioctadecyl-3,3,3'3'-tetramethylindotricarbocyanine-iodide (DiR) fluorescent dye-labeled nanoparticles, including grapefruit nanovectors (GNV) and standard liposomes, were I.V. injected in the mice. The efficiency of redirecting GNVs from liver to other organs of injected mice was further analyzed with in vivo imaging. The concentration of chemo drugs delivered by GNV was measured by HPLC and the anti-lung metastasis therapeutic effects of chemo drugs delivered by GNVs in mouse breast cancer and melanoma cancer models were evaluated. Results: We show that tail vein-injected exosomes isolated from mouse peripheral blood were predominately taken up by liver Kupffer cells. Injection of peripheral blood-derived exosomes before I.V. injection of grapefruit-derived nanovector (GNV) decreased the deposition of GNV in the liver and redirected the GNV to the lung and to the tumor in breast and melanoma tumor-bearing mouse models. Enhanced therapeutic efficiency of doxorubicin (Dox) or paclitaxel (PTX) carried by GNVs for lung metastases was demonstrated when there was an I.V. injection of exosomes before therapeutic treatment. Furthermore, we found that CD36 and IGFR1 receptor-mediated pathways played a critical role in the exosome mediated inhibitory effect of GNV entry into liver macrophages. Conclusions: Collectively, our findings provide a foundation for using autologous exosomes to enhance therapeutic vector targeted delivery to the lung. PMID- 30429879 TI - Efficacy of chronic BACE1 inhibition in PS2APP mice depends on the regional Abeta deposition rate and plaque burden at treatment initiation. AB - Beta secretase (BACE) inhibitors are promising therapeutic compounds currently in clinical phase II/III trials. Preclinical [18F]-florbetaben (FBB) amyloid PET imaging facilitates longitudinal monitoring of amyloidosis in Alzheimer's disease (AD) mouse models. Therefore, we applied this theranostic concept to investigate, by serial FBB PET, the efficacy of a novel BACE1 inhibitor in the PS2APP mouse, which is characterized by early and massive amyloid deposition. Methods: PS2APP and C57BL/6 (WT) mice were assigned to treatment (PS2APP: N=13; WT: N=11) and vehicle control (PS2APP: N=13; WT: N=11) groups at the age of 9.5 months. All animals had a baseline PET scan and follow-up scans at two months and after completion of the four-month treatment period. In addition to this longitudinal analysis of cerebral amyloidosis by PET, we undertook biochemical amyloid peptide quantification and histological amyloid plaque analyses after the final PET session. Results: BACE1 inhibitor-treated transgenic mice revealed a progression of the frontal cortical amyloid signal by 8.4 +/- 2.2% during the whole treatment period, which was distinctly lower when compared to vehicle-treated mice (15.3 +/ 4.4%, p<0.001). A full inhibition of progression was evident in regions with <3.7% of the increase in controls, whereas regions with >10% of the increase in controls showed only 40% attenuation with BACE1 inhibition. BACE1 inhibition in mice with lower amyloidosis at treatment initiation showed a higher efficacy in attenuating progression to PET. A predominant reduction of small plaques in treated mice indicated a main effect of BACE1 on inhibition of de novo amyloidogenesis. Conclusions: This theranostic study with BACE1 treatment in a transgenic AD model together with amyloid PET monitoring indicated that progression of amyloidosis is more effectively reduced in regions with low initial plaque development and revealed the need of an early treatment initiation during amyloidogenesis. PMID- 30429878 TI - Theranostics based on AIEgens. AB - The utilization of luminogens with aggregation-induced emission (AIE) characteristics has recently been developed at a tremendous pace in the area of theranostics, mainly because AIE luminogens (AIEgens) hold various distinct advantages, such as good biocompatibility, excellent fluorescence properties, simple preparation and modification, perfect size of nano-aggregation for enhanced permeability and retention effect, promoted efficiencies of photodynamic and photothermal therapies, efficient photoacoustic imaging, and ready constructions of multimodal imaging and therapy. Significant breakthroughs and developments of theranostics based on AIEgens have been achieved in the past few years, and great progress has been witnessed in many theranostic modalities, indicating that AIEgens remarkably complement conventional theranostic materials and promote the development of theranostics. This review provides theoretical insights into the advantages of AIEgens in theranostics, and systematically summarizes the basic concepts, seminal studies, recent trends and perspectives in theranostics based on AIEgens. We believe that AIEgens would be promising multifunctional theranostic platforms in clinical fields and facilitate significant advancements in this research-active area. PMID- 30429880 TI - Sonodynamic therapy-induced foam cells apoptosis activates the phagocytic PPARgamma-LXRalpha-ABCA1/ABCG1 pathway and promotes cholesterol efflux in advanced plaque. AB - In advanced atherosclerotic plaques, defective efferocytosis of apoptotic foam cells and decreased cholesterol efflux contribute to lesion progression. In our previous study, we demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (SDT) could induce foam cells apoptosis via the mitochondrial caspase pathway. In the current research, we sought to explore ALA-SDT-induced apoptosis of phagocytes and the effects of cholesterol efflux and efferocytosis in advanced apoE-/- mice plaque. Methods: apoE-/- mice fed western diet were treated with ALA-SDT and sacrificed at day 1, day 3, day 7 and day 28 post treatment. THP-1 macrophage-derived foam cells were treated with ALA-SDT. 5 hours later, the supernatant was collected and added to fresh foam cells (phagocytes). Then, the lipid area, efferocytosis, cholesterol efflux, anti-inflammatory reactions and PPARgamma-LXRalpha-ABCA1/ABCG1 pathway were detected in plaque in vivo and in phagocytes in vitro. Results: We found that ALA-SDT induced foam cells apoptosis coupled with efferocytosis and upregulation of Mer tyrosine kinase (MerTK) both in vivo and in vitro. The lipid content in plaque decreased as early as 1 day after ALA-SDT and this tendency persisted until 28 days. The enhancement of phagocytes cholesterol efflux was accompanied by an approximately 40% decrease in free cholesterol and a 24% decrease in total cholesterol in vitro. More importantly, anti-inflammatory factors such as TGFbeta and IL-10 were upregulated by ALA-SDT treatment. Finally, we found that PPARgamma-LXRalpha ABCA1/ABCG1 pathway was activated both in vivo and in vitro by ALA-SDT, which could be blocked by PPARgamma siRNA. Conclusions: Activation of PPARgamma LXRalpha-ABCA1/ABCG1 pathway induced by ALA-SDT treatment engages a virtuous cycle that enhances efferocytosis, cholesterol efflux and anti-inflammatory reactions in advanced plaque in vivo and in phagocytes in vitro. PMID- 30429881 TI - Early prediction of revascularisation by angiomotin-targeting positron emission tomography. AB - This study aimed to develop a PET imaging agent of angiomotin (AMOT) expression, a potential biomarker of functional tissue regeneration in post-ischaemic conditions. Methods: Hindlimb ischaemia was induced by ligature and resection of the right femoral artery in mice, and clinical score and limb perfusion were evaluated up to 30 days after surgery. AMOT expression was evaluated by histology and Western blot analysis. NODAGA-conjugates of AMOT ligand, sCD146, were designed, synthesised and radiolabelled with gallium-68. 68Ga-sCD146 microPET/CT imaging was performed from day 1 to day 30 after ischaemia. 68Ga-sCD146 specificity for AMOT was evaluated by autoradiography. Results: Immunohistochemistry showed a significant endothelial overexpression of AMOT from day 5 up to day 10 in the ischaemic hindlimb. 68Ga-sCD146 PET signal intensity correlated significantly with AMOT immunohistochemistry evaluation. 68Ga-sCD146 PET imaging showed a significant uptake in the ischaemic hindlimb from day 2 to day 15, peaking on day 5 (ipsi/contralateral ratio = 2.4 +/- 1.3, P = 0.0005) and significantly decreased after pharmacological blocking (62.57 +/- 11% decrease in PET signal P = 0.032). Finally, we observed a significant correlation between day 5 68Ga-sCD146 PET signal intensity and clinical recovery (day 28) or hindlimb perfusion recovery (day 30). Conclusions: This work reports for the first time an early and sustained increase in AMOT expression after hindlimb ischaemia in mice. We therefore developed an AMOT-targeting imaging agent, 68Ga-sCD146, and showed its specific uptake up to 21 days after ischaemic hindlimb using microPET imaging. Correlation of early post-ischaemic PET signal with both delayed perfusion recovery and clinical outcome allows us to postulate that 68Ga-sCD146 represents a promising radiotracer for tissue angiogenesis assessment. PMID- 30429882 TI - Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling. AB - Despite initial progress in preclinical models, most known histone deacetylase inhibitors (HDACis) used as a single agent have failed to show clinical benefits in nearly all types of solid tumours. Hence, the efficacy of HDACis in solid tumours remains uncertain. Herein, we developed a hybrid HDAC inhibitor that sensitized solid tumours to HDAC-targeted treatment. Methods: A hybrid molecule, Roxyl-zhc-84 was designed and synthesized with novel architecture. The pharmacokinetics and toxicity of Roxyl-zhc-84 were analysed. The antitumour effects of Roxyl-zhc-84 on solid tumours were investigated by assessing cell growth, apoptosis and cell cycle in vitro and in three in vivo mouse models and compared to those of corresponding control inhibitors alone or in combination. Gene set enrichment analysis was performed, and relevant JAK1-STAT3-BCL2 signalling was identified in vitro and in vivo in mechanistic studies. Results: Roxyl-zhc-84 showed excellent pharmacokinetics and low toxicity. The novel hybrid inhibitor Roxyl-zhc-84 induced cell apoptosis and G1-phase arrest in breast cancer and ovarian cancer cell lines. In three mouse models, oral administration of Roxyl-zhc-84 led to significant tumour regression without obvious toxicity. Moreover, Roxyl-zhc-84 dramatically improved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance. Roxyl-zhc-84 treatment exhibited vastly superior efficacy than the combination of HDAC and JAK1 inhibitors both in vitro and in vivo. Conclusion: Concurrent inhibition of HDAC and CDK using Roxyl-zhc-84 with additional JAK1 targeting resolved the limited response of traditional HDAC inhibitors in solid tumours via overcoming JAK1-STAT3-BCL2-mediated drug resistance, providing a rational multi-target treatment to sensitize solid tumours to HDACi therapy. PMID- 30429883 TI - Multimodal imaging of the receptor for advanced glycation end-products with molecularly targeted nanoparticles. AB - The receptor for advanced glycation end-products (RAGE) is central to multiple disease states, including diabetes-related conditions such as peripheral arterial disease (PAD). Despite RAGE's importance in these pathologies, there remains a need for a molecular imaging agent that can accurately assess RAGE levels in vivo. Therefore, we have developed a multimodal nanoparticle-based imaging agent targeted at RAGE with the well-characterized RAGE ligand, carboxymethyllysine (CML)-modified human serum albumin (HSA). Methods: A multimodal tracer (64Cu-Rho G4-CML) was developed using a generation-4 (G4) polyamidoamine (PAMAM) dendrimer, conjugated with both rhodamine and copper-64 (64Cu) chelator (NOTA) for optical and PET imaging, respectively. First, 64Cu-Rho-G4-CML and its non-targeted analogue (64Cu-Rho-G4-HSA) were evaluated chemically using techniques such as dynamic light scattering (DLS), electron microscopy and nuclear magnetic resonance (NMR). The tracers' binding capabilities were examined at the cellular level and optimized using live and fixed HUVEC cells grown in 5.5-30 mM glucose, followed by in vivo PET-CT imaging, where the probes' kinetics, biodistribution, and RAGE targeting properties were examined in a murine model of hindlimb ischemia. Finally, histological assessment of RAGE levels in both ischemic and non-ischemic tissues was performed. Conclusions: Our RAGE-targeted probe demonstrated an average size of 450 nm, a Kd of 340-390 nM, rapid blood clearance, and a 3.4 times greater PET uptake in ischemic RAGE-expressing hindlimbs than their non-ischemic counterpart. We successfully demonstrated increased RAGE expression in a murine model of hindlimb ischemia and the feasibility for non-invasive examination of cellular, tissue, and whole-body RAGE levels with a molecularly targeted tracer. PMID- 30429884 TI - Novel skin patch combining human fibroblast-derived matrix and ciprofloxacin for infected wound healing. AB - Skin injuries are frequently encountered in daily life, but deep wounds often poorly self-heal and do not recover completely. In this study, we propose a novel skin patch that combines antibiotic, cell-derived extracellular matrix (ECM) and biocompatible polyvinyl alcohol (PVA) hydrogel. Methods: Decellularized human lung fibroblast-derived matrix (hFDM) was prepared on tissue culture plate (TCP) and PVA solution was then poured onto it. After a freeze-thaw process, PVA was peeled off from TCP along with hFDM tightly anchored to PVA. Subsequently, ciprofloxacin (Cipro)-incorporated PVA/hFDM (PVA/Cipro/hFDM) was fabricated via diffusion-based drug loading. Results: In vitro analyses of PVA/Cipro/hFDM show little cytotoxicity of ciprofloxacin, stability of hFDM, rich fibronectin in hFDM, and good cell attachment, respectively. In addition, hFDM proved to be beneficial in promoting cell migration of dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) using transwell inserts. The antibacterial drug Cipro was very effective in suppressing colony growth of gram-negative and positive bacteria as identified via an inhibition zone assay. For animal study, infected wound models in BALB/c mice were prepared and four test groups (control, PVA, PVA/Cipro, PVA/Cipro/hFDM) were administered separately and their effect on wound healing was examined for up to 21 days. The results support that Cipro successfully reduced bacterial infection and thus encouraged faster wound closure. Further analysis using histology and immunofluorescence revealed that the most advanced skin regeneration was achieved with PVA/Cipro/hFDM, as assessed via re-epithelialization, collagen texture and distribution in the epidermis, and skin adnexa (i.e., glands and hair follicles) regeneration in the dermis. Conclusion: This work demonstrates that our skin patch successfully consolidates the regenerative potential of ECM and the antibacterial activity of Cipro for advanced wound healing. PMID- 30429885 TI - Increased recruitment of endogenous stem cells and chondrogenic differentiation by a composite scaffold containing bone marrow homing peptide for cartilage regeneration. AB - Even small cartilage defects could finally degenerate to osteoarthritis if left untreated, owing to the poor self-healing ability of articular cartilage. Stem cell transplantation has been well implemented as a common approach in cartilage tissue engineering but has technical complexity and safety concerns. The stem cell homing-based technique emerged as an alternative promising therapy for cartilage repair to overcome traditional limitations. In this study, we constructed a composite hydrogel scaffold by combining an oriented acellular cartilage matrix (ACM) with a bone marrow homing peptide (BMHP)-functionalized self-assembling peptide (SAP). We hypothesized that increased recruitment of endogenous stem cells by the composite scaffold could enhance cartilage regeneration. Methods: To test our hypothesis, in vitro proliferation, attachment and chondrogenic differentiation of rabbit mesenchymal stem cells (MSCs) were tested to confirm the bioactivities of the functionalized peptide hydrogel. The composite scaffold was then implanted into full-thickness cartilage defects on rabbit knee joints for cartilage repair, in comparison with microfracture or other sample groups. Stem cell recruitment was monitored by dual labeling with CD29 and CD90 under confocal microcopy at 1 week after implantation, followed by chondrogenic differentiation examined by qRT-PCR. Repaired tissue of the cartilage defects was evaluated by histological and immunohistochemistry staining, microcomputed tomography (micro-CT) and magnetic resonance imaging (MRI) at 3 and 6 months post-surgery. Macroscopic and histological scoring was done to evaluate the optimal in vivo repair outcomes of this composite scaffold. Results: The functionalized SAP hydrogels could stimulate rabbit MSC proliferation, attachment and chondrogenic differentiation during in vitro culture. At 7 days after implantation, increased recruitment of MSCs based on CD29+ /CD90+ double-positive cells was found in vivo in the composite hydrogel scaffold, as well as upregulation of cartilage-associated genes (aggrecan, Sox9 and type II collagen). After 3 and 6 months post-surgery, the articular cartilage defect in the composite scaffold-treated group was fully covered with cartilage like tissue with a smooth surface, which was similar to the surrounding native cartilage, according to the results of histological and immunohistochemistry staining, micro-CT and MRI analysis. Macroscopic and histological scoring confirmed that the quality of cartilage repair was significantly improved with implantation of the composite scaffold at each timepoint, in comparison with microfracture or other sample groups. Conclusion: Our findings demonstrated that the composite scaffold could enhance endogenous stem cell homing and chondrogenic differentiation and significantly improve the therapeutic outcome of chondral defects. The present study provides a promising approach for in vivo cartilage repair without cell transplantation. Optimization of this strategy may offer great potential and benefits for clinical application in the future. PMID- 30429886 TI - Tumor-specific activated photodynamic therapy with an oxidation-regulated strategy for enhancing anti-tumor efficacy. AB - Photodynamic therapy relies on photosensitizers to generate cytotoxic reactive oxygen species (ROS) resulting in the apoptois of tumor cells. However, there is an antioxidant system that impedes the elevation of oxidation levels in tumor cells. Thus, photodynamic therapy may exhibit insufficient curative effects due to ungenerous reactive oxygen species levels. Herein, we describe tumor-specific activated photodynamic therapy using an oxidation-regulating strategy. Methods: We first synthesised a reactive oxygen species-sensitive amphipathic prodrug of gambogic acid-grafted hyaluronic acid (HA-GA). The hydrophobic photosensitizer chlorin e6 (Ce6) was then loaded into HA-GA by hydrophobic interactions between GA and Ce6, forming amphipathic nanomicelles (HA-GA@Ce6). The ROS-responsive behavior, cytotoxicity, cell uptake, tumor cell killing, in vivo biodistribution and in vivo anti-tumor efficacy of HA-GA@Ce6 were investigated. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model. Results: We validated that the micelles of HA-GA@Ce6 showed stronger cell uptake in 4T1 tumor cells and lower cytotoxicity in normal cells compared with free Ce6 and GA, which exhibited the benefits of nanomicelles on enhancing the tumor cell acumulation and reducing the side effects on normal cells synchronously. Additionally, the cytotoxic free radicals of photodynamic therapy were generated after irradiation and the high oxidation levels activated the ROS sensitive GA prodrug efficiently, which killed the tumor cells and depleted intracellular glutathione (GSH), thereby impairing antioxidant levels and enhancing photodynamic therapy. Conclusion: With the successfully eradicated tumor growth in vivo. Our work represents a new photodynamic therapy concept, achieving superior anti-tumor efficacy by reducing intracellular antioxidant levels. PMID- 30429888 TI - Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy. AB - Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas. Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP (MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo. Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo. Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas. PMID- 30429887 TI - The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging lethal tumors and has a very poor prognosis. In addition to cancer cells, the tumor microenvironment created by a repertoire of resident and recruited cells and the extracellular matrix also contribute to the acquisition of hallmarks of cancer. Among these factors, cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. CAFs originate from the activation of resident fibroblasts and pancreatic stellate cells, the differentiation of bone marrow-derived mesenchymal stem cells and epithelial-to-mesenchymal transition. CAFs acquire an activated phenotype via various cytokines and promote tumor proliferation and growth, accelerate invasion and metastasis, induce angiogenesis, promote inflammation and immune destruction, regulate tumor metabolism, and induce chemoresistance; these factors contribute to the acquisition of major hallmarks of PDAC. Therefore, an improved understanding of the impact of CAFs on the major hallmarks of PDAC will highlight the diagnostic and therapeutic values of these targeted cells. PMID- 30429889 TI - Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: Curative treatment of HER2-positive breast carcinoma. AB - In recent reports, we have shown that optimized pretargeted radioimmunotherapy (PRIT) based on molecularly engineered antibody conjugates and 177Lu-DOTA chelate (DOTA-PRIT) can be used to cure mice bearing human solid tumor xenografts using antitumor antibodies to minimally internalizing membrane antigens, GPA33 (colon) and GD2 (neuroblastoma). However, many solid tumor membrane antigens are internalized after antibody binding and it is generally believed that internalizing tumor membrane antigens are not suitable targets for PRIT. In this study, we tested the hypothesis that DOTA-PRIT can be performed successfully to target HER2, an internalizing membrane antigen widely expressed in breast, ovarian, and gastroesophageal junction cancers. Methods: DOTA-PRIT was carried out in athymic nude mice bearing BT-474 xenografts, a HER2-expressing human breast cancer, using a three-step dosing regimen consisting of sequential intravenous administrations of: 1) a bispecific IgG-scFv (210 kD) format (BsAb) carrying the IgG sequence of the anti-HER2 antibody trastuzumab and the scFv "C825" with high-affinity, hapten-binding antibody for Bn-DOTA (metal) (BsAb: anti-HER2-C825), 2) a 500 kD dextran-based clearing agent, followed by 3) 177Lu DOTA-Bn. At the time of treatment, athymic nude mice bearing established subcutaneous BT-474 tumors (medium- and smaller-sized tumors with tumor volumes of 209 +/- 101 mm3 and ranging from palpable to 30 mm3, respectively), were studied along with controls. We studied single- and multi-dose regimens. For groups receiving fractionated treatment, we verified quantitative tumor targeting during each treatment cycle using non-invasive imaging with single-photon emission computed tomography/computed tomography (SPECT/CT). Results: We achieved high therapeutic indices (TI, the ratio of radiation-absorbed dose in tumor to radiation-absorbed dose to critical organs, such as bone marrow) for targeting in blood (TI = 28) and kidney (TI = 7), while delivering average radiation-absorbed doses of 39.9 cGy/MBq to tumor. Based on dosimetry estimates, we implemented a curative fractionated therapeutic regimen for medium-sized tumors that would deliver approximately 70 Gy to tumors, which required treatment with a total of 167 MBq 177Lu-DOTA-Bn/mouse (estimated absorbed tumor dose: 66 Gy). This regimen was well tolerated and achieved 100% complete responses (CRs; defined herein as tumor volume equal to or smaller than 4.2 mm3), including 62.5% histologic cure (5/8) and 37.5% microscopic residual disease (3/8) at 85 days (d). Treatment controls showed tumor progression to 207 +/- 201% of pre-treatment volume at 85 d and no CRs. Finally, we show that treatment with this curative 177Lu regimen leads to a very low incidence of histopathologic abnormalities in critical organs such as bone marrow and kidney among survivors compared with non-treated controls. Conclusion: Contrary to popular belief, we demonstrate that DOTA-PRIT can be successfully adapted to an internalizing antigen-antibody system such as HER2, with sufficient TIs and absorbed tumor doses to achieve a high probability of cures of established human breast cancer xenografts while sparing critical organs of significant radiotoxicity. PMID- 30429890 TI - Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer. AB - In ultrasound molecular imaging (USMI), ligand-functionalized microbubbles (MBs) are used to visualize vascular endothelial targets. Netrin-1 is upregulated in 60% of metastatic breast cancers and promotes tumor progression. A novel netrin-1 interference therapy requires the assessment of netrin-1 expression prior to treatment. In this study, we studied netrin-1 as a target for USMI and its potential as a companion diagnostic in breast cancer models. Methods: To verify netrin-1 expression and localization, an in vivo immuno-localization approach was applied, in which anti-netrin-1 antibody was injected into living mice 24 h before tumor collection, and revealed with secondary fluorescent antibody for immunofluorescence analysis. Netrin-1 interactions with the cell surface were studied by flow cytometry. Netrin-1-targeted MBs were prepared using MicroMarker Target-Ready (VisualSonics), and validated in in vitro binding assays in static conditions or in a flow chamber using purified netrin-1 protein or netrin-1 expressing cancer cells. In vivo USMI of netrin-1 was validated in nude mice bearing human netrin-1-positive SKBR7 tumors or weakly netrin-1-expressing MDA-MB 231 tumors using the Vevo 2100 small animal imaging device (VisualSonics). USMI feasibility was further tested in transgenic murine FVB/N Tg(MMTV/PyMT634Mul) (MMTV-PyMT) mammary tumors. Results: Netrin-1 co-localized with endothelial CD31 in netrin-1-positive breast tumors. Netrin-1 binding to the surface of endothelial HUVEC and cancer cells was partially mediated by heparan sulfate proteoglycans. MBs targeted with humanized monoclonal anti-netrin-1 antibody bound to netrin-1-expressing cancer cells in static and dynamic conditions. USMI signal was significantly increased with anti-netrin-1 MBs in human SKBR7 breast tumors and transgenic murine MMTV-PyMT mammary tumors compared to signals recorded with either isotype control MBs or after blocking of netrin-1 with humanized monoclonal anti-netrin-1 antibody. In weakly netrin-1-expressing human tumors and normal mammary glands, no difference in imaging signal was observed with anti-netrin-1- and isotype control MBs. Ex vivo analysis confirmed netrin-1 expression in MMTV-PyMT tumors. Conclusions: These results show that USMI allowed reliable detection of netrin-1 on the endothelium of netrin-1-positive human and murine tumors. Significant differences in USMI signal for netrin-1 reflected the significant differences in netrin-1 mRNA & protein expression observed between different breast tumor models. The imaging approach was non-invasive and safe, and provided the netrin-1 expression status in near real-time. Thus, USMI of netrin-1 has the potential to become a companion diagnostic for the stratification of patients for netrin-1 interference therapy in future clinical trials. PMID- 30429891 TI - Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression. AB - High levels of angiogenesis are associated with poor prognosis in patients with gliomas. However, the molecular mechanisms underlying tumor angiogenesis remain unclear. Methods: The effect of homeobox C10 (HOXC10) on tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) and on chicken chorioallantoic membranes (CAMs) was examined. An animal xenograft model was used to examine the effect of HOXC10 on xenograft angiogenesis or the effect of bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), on HOXC10-overexpressing xenografts. A chromatin immunoprecipitation assay was applied to investigate the mechanism in which HOXC10 regulated VEGFA expression. Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result. We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors. Mechanistically, HOXC10 could transcriptionally upregulate VEGFA expression by binding to its promoter. Strikingly, treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited the growth of HOXC10 overexpressing tumors and efficiently impaired angiogenesis. Protein arginine methyltransferase 5 (PRMT5) and WD repeat domain 5 (WDR5), both of which regulate histone post-translational modifications, were required for HOXC10-mediated VEGFA upregulation. Importantly, a significant correlation between HOXC10 levels and VEGFA expression was observed in a cohort of human gliomas. Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas. PMID- 30429892 TI - Mussel-inspired conductive nanofibrous membranes repair myocardial infarction by enhancing cardiac function and revascularization. AB - The controversy between polypyrrole's (Ppy) biocompatibility and its aggregation on nanofibers impedes application of conductive Ppy-incorporated nanofibers to create engineered cardiac microenvironments. The purpose of this study was to fabricate a functional scaffold for engineering cardiac patches (ECP) using a high concentration of methyl acrylic anhydride-gelatin (GelMA)-Ppy nanoparticles, mussel-inspired crosslinker, and electrospun (ES)-GelMA/polycaprolactone (PCL) nanofibrous membrane. Methods: First, spherical GelMA-Ppy nanoparticles were obtained when the methacrylate groups of GelMA formed a self-crosslinked network through oxidative polymerization of Ppy. Second, GelMA-Ppy nanoparticles were uniformly crosslinked on the ES-GelMA/PCL membrane through mussel-inspired dopamine-N'N'-methylene-bis-acrylamide (dopamine-MBA) crosslinker. Finally, the feasibility of the dopa-based conductive functional ECP scaffold was investigated in vitro and in vivo. Results: The GelMA-Ppy nanoparticles displayed excellent biocompatibility at a high concentration of 50 mg/mL. The massive GelMA-Ppy nanoparticles could be uniformly distributed on the ES nanofibers through dopamine-MBA crosslinker without obvious aggregation. The high concentration of GelMA-Ppy nanoparticles produced high conductivity of the dopamine-based (dopa based) conductive membrane, which enhanced the function of cardiomyocytes (CMs) and yielded their synchronous contraction. GelMA-Ppy nanoparticles could also modify the topography of the pristine ES-GelMA/PCL membrane to promote vascularization in vitro. Following transplantation of the conductive membrane derived ECP on the infarcted heart for 4 weeks, the infarct area was decreased by about 50%, the left ventricular shortening fraction percent (LVFS%) was increased by about 20%, and the neovascular density in the infarct area was significantly increased by about 9 times compared with that in the MI group. Conclusion: Our study reported a facile and effective approach to developing a functional ECP that was based on a mussel-inspired conductive nanofibrous membrane. This functional ECP could repair infarct myocardium through enhancing cardiac function and revascularization. PMID- 30429894 TI - Relationships Between Isokinetic Shoulder Evaluation and Fitness Characteristics of Elite French Female Water-Polo Players. AB - Swimming and throwing are involved in water-polo player performance. These movements have a common biomechanical basis in the use of the internal shoulder rotation and adductor muscles. The aim of the study was to evaluate the relationship between shoulder isokinetic evaluation and throwing velocity as well as swimming performance in female water-polo players. Fifteen high level water polo players completed two isokinetic shoulder evaluations to determine peak torque of shoulder rotators of the dominant shoulder (concentric and eccentric movements at an angular velocity of 60 degrees .s-1 and concentric movements at an angular velocity of 240 degrees .s-1) and shoulder extensors of both arms (concentric movements at an angular velocity of 60 degrees .s-1 and 240 degrees .s-1). Throwing velocity was measured using a radar gun placed 5 m behind the goal post. Front crawl swimming velocity was determined at 25 m, 100 m and 400 m distances. Concentric peak torque at 60 degrees .s-1 and 240 degrees .s-1 of internal rotators and eccentric peak torque at 60 degrees .s-1 of external rotators were predictors of throwing velocity. The best model to explain the relationship between isokinetic evaluations and throwing velocity was obtained with concentric IR peak torque at 60 degrees .s-1 and eccentric ER peak torque at 60 degrees .s-1 (r2 = 0.52, p = 0.012). Relative total work done and peak torque of shoulder extensors were predictors of 25 m swimming velocity. Shoulder isokinetic evaluations correlate significantly with swimming performance and throwing velocity of female water-polo players. The results may help coaches to develop new strategies such as eccentric dry land training programs to increase both shoulder external rotators strength and throwing velocity. PMID- 30429893 TI - Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRbeta aptamer. AB - While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor beta (PDGFRbeta) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition. Methods: Immunohistochemical analysis for PDGFRbeta expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal like TNBC cells to investigate the effect of a previously validated PDGFRbeta aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near infrared (NIR) dye and its binding specificity to PDGFRbeta was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRbeta aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer. Results: Here, we present novel data showing that tumor cell expression of PDGFRbeta identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRbeta in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRbeta aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases. Conclusions: We propose PDGFRbeta as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRbeta aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC. PMID- 30429895 TI - Do Strike Patterns or Shoe Conditions have a Predominant Influence on Foot Loading? AB - This study aimed to explore the effects of strike patterns and shoe conditions on foot loading during running. Twelve male runners were required to run under shoe (SR) and barefoot conditions (BR) with forefoot (FFS) and rearfoot strike patterns (RFS). Kistler force plates and the Medilogic insole plantar pressure system were used to collect kinetic data. SR with RFS significantly reduced the maximum loading rate, whereas SR with FFS significantly increased the maximum push-off force compared to BR. Plantar pressure variables were more influenced by the strike patterns (15 out of 18 variables) than shoe conditions (7 out of 18 variables). The peak pressure of midfoot and heel regions was significantly increased in RFS, but appeared in a later time compared to FFS. The influence of strike patterns on running, particularly on plantar pressure characteristics, was more significant than that of shoe conditions. Heel-toe running caused a significant impact force on the heel, whereas wearing cushioned shoes significantly reduced the maximum loading rate. FFS running can prevent the impact caused by RFS. However, peak plantar pressure was centered at the forefoot for a long period, thereby inducing a potential risk of injury in the metatarsus/phalanx. PMID- 30429896 TI - Comparative Study of Kinematics and Muscle Activity Between Elite and Amateur Table Tennis Players During Topspin Loop Against Backspin Movements. AB - This study investigated differences of lower limb kinematics and muscle activity during table tennis topspin loop against backspin movements between elite players (EPs) and amateur players (APs). Ten EPs and ten APs performed crosscourt backhand loop movements against the backspin ball with maximal power. Vicon motion analysis and a MEGA ME6000 system was used to capture kinematics and surface EMG data. The motion was divided into two phases, including the backswing and swing. The joints' flexion and extension angle tendency between EPs and APs differed significantly. The coefficient of multiple correlation (CMC) values for EPs were all beyond 0.9, indicating high similarity of joint angles change. APs presented moderate similarity with CMC values from 0.5 to 0.75. Compared to APs, EPs presented larger ankle eversion, knee and hip flexion at the beginning moment of the backswing. In the sEMG test, EPs presented smaller standardized AEMG (average electromyography) of the lower limb muscles in the rectus femoris and tibia anterior on both sides. Additionally, the maximum activation of each muscle for EPs was smaller and MPF (mean power frequency) of the lower limb was greater during the whole movement. The present study revealed that EPs could complete this technical motion more economically than APs, meanwhile, EPs were more efficient in muscle usage and showed better balance ability. PMID- 30429897 TI - Changes in Muscle Stiffness of the Trapezius Muscle After Application of Ischemic Compression into Myofascial Trigger Points in Professional Basketball Players. AB - The study aimed to assess the effects of compression trigger point therapy on the stiffness of the trapezius muscle in professional basketball players (Part A), and the reliability of the MyotonPRO device in clinical evaluation of athletes (Part B). Twelve professional basketball players participated in Part A of the study (mean age: 19.8 +/- 2.4 years, body height 197 +/- 8.2 cm, body mass: 91.8 +/- 11.8 kg), with unilateral neck or shoulder pain at the dominant side. Part B tested twelve right-handed male athletes (mean +/- SD; age: 20.4 +/- 1.2 years; body height: 178.6 +/- 7.7 cm; body mass: 73.2 +/- 12.6 kg). Stiffness measurements were obtained directly before and after a single session trigger point compression therapy. Measurements were performed bilaterally over 5 points covering the trapezius muscle. The effects were evaluated using a full-factorial repeated measure ANOVA and the Bonferroni post-hoc test for equal variance. A p value < .05 was considered significant. The RM ANOVA revealed a significant decrease in muscle stiffness for the upper trapezius muscle. Specifically, muscle stiffness decreased from 243.7 +/- 30.5 to 215.0 +/- 48.5 N/m (11.8%), (p = .008) (Part A). The test-retest relative reliability of trapezius muscle stiffness was found to be high (ICC from 0.821 to 0.913 for measurement points). The average SEM was 23.59 N/m and the MDC 65.34 N/m, respectively (Part B). The present study showed that a single session of compression trigger point therapy can be used to significantly decrease the stiffness of the upper trapezius among professional basketball players. PMID- 30429898 TI - Relationship Between Toe Muscular Strength and the Ability to Change Direction in Athletes. AB - This study aimed to investigate the relationship between toe muscular strength and the ability to change direction in athletes. Seventeen collegiate American football players participated in the study (age 19.9 +/- 0.9 years, competition experience 7.3 +/- 1.7 years). Two types of measurements were performed to evaluate toe muscular strength: toe flexor strength with the metatarsophalangeal joint in the planter flexed position and toe-pushing force with the metatarsophalangeal joint in the dorsiflexed position. The ability to change direction was evaluated using the pro-agility and 3-cone tests and change of direction deficits, calculated by subtracting the sprint times from the pro agility and 3-cone times. There were significant correlations between toe-pushing force and the results of the pro-agility and 3-cone tests, but no significant correlations between toe flexor strength and the pro-agility and 3-cone tests. Neither toe-pushing force nor toe flexor strength was significantly correlated with the sprint test results. Furthermore, toe-pushing force was significantly correlated with the 3-cone test deficit, but toe flexor strength was not. The ability to change direction is more strongly affected by toe muscular strength (measured as toe-pushing force) with the metatarsophalangeal joint in the dorsiflexed angle than by toe muscular strength (measured as toe flexor strength) with the metatarsophalangeal joint in the plantar flexed angle. Our results suggest that athletes can improve their ability to change direction with toe muscular strength training with the metatarsophalangeal joint in the dorsiflexed position. PMID- 30429900 TI - Biomechanical Comparisons of One-Legged and Two-Legged Running Vertical Jumps. AB - The purpose of this study was to determine the differences in biomechanical characteristics between one- and two-legged running vertical jumps (1-LRVJ and 2 LRVJ). Ten male college volleyball players voluntarily participated in this study. Two running vertical jumps used in volleyball were randomly performed. Three trials for each type of the running vertical jump were recorded for each participant. Data were collected using six infra-red Qualisys motion-capture cameras at a 180-Hz sampling rate and two AMTI force platforms at an 1800-Hz sampling rate. Jump height in the 2-LRVJ was significantly higher than that in the 1-LRVJ (p < 0.05). In the take-off phase, knee and hip extension impulses for the 1-LRVJ were significantly greater than those for the 2-LRVJ (p < 0.05). These results suggest that the 1-LRVJ produced greater leg stiffness than the 2-LRVJ did. We found that the 1-LRVJ caused greater lower-extremity stiffness and impulse compared to the 2-LRVJ, which is beneficial in the stretch-shortening cycle, and thus the more focus on practicing 1-LRVJs is recommended for coaches and athletes. PMID- 30429899 TI - Reproducibility of the Evolution of Stride Biomechanics During Exhaustive Runs. AB - Running biomechanics and its evolution that occurs over intensive trials are widely studied, but few studies have focused on the reproducibility of stride evolution in these runs. The purpose of this investigation was to assess the reproducibility of changes in eight biomechanical variables during exhaustive runs, using three-dimensional analysis. Ten male athletes (age: 23 +/- 4 years; maximal oxygen uptake: 57.5 +/- 4.4 ml02.min-1.kg-1; maximal aerobic speed: 19.3 +/- 0.8 km.h-1) performed a maximal treadmill test. Between 3 to 10 days later, they started a series of three time-to-exhaustion trials at 90% of the individual maximal aerobic speed, seven days apart. During these trials eight biomechanical variables were recorded over a 20-s period every 4 min until exhaustion. The evolution of a variable over a trial was represented as the slope of the linear regression of these variables over time. Reproducibility was assessed with intraclass correlation coefficients and variability was quantified as standard error of measurement. Changes in five variables (swing duration, stride frequency, step length, centre of gravity vertical and lateral amplitude) showed moderate to good reproducibility (0.48 <= ICC <= 0.72), while changes in stance duration, reactivity and foot orientation showed poor reproducibility (-0.71 <= ICC <= 0.04). Fatigue-induced changes in stride biomechanics do not follow a reproducible course across the board; however, several variables do show satisfactory stability: swing duration, stride frequency, step length and centre of gravity shift. PMID- 30429901 TI - The Acute Effects of Different Forms of Suspension Push-Ups on Oxygen Consumption, Salivary Testosterone and Cortisol and Isometric Strength. AB - Suspension exercise systems are being used in strength and conditioning facilities, fitness centers, rehabilitation centers and home gyms. Though some evidence exists regarding the impact of training with these systems, more work is needed for a better understanding. The purpose of the present investigation was to examine the acute effects of an exercise session with 2 (hands only) and 4 straps (hands and feet) in the push-up exercise compared to a work-matched bench press exercise session. The participants for this repeated measures, cross-over investigation were 18 healthy college-aged males (age: 24.8 +/- 3.5 yrs, body mass: 81.8 +/- 7.8 kg, body height: 178.9 +/- 4.5 cm). The conditions were 6 sets of 10 repetitions of suspension push-ups using two straps (DUAL) for the hands, fours straps (QUAD) for hands and feet and a traditional bench press exercise matched to the average resistance during the suspension push-up. The participants performed all repetitions at a controlled cadence. Expired gases, and heart rate were monitored continuously during the exercise session. Pre and post exercise saliva samples were collected to quantify changes in testosterone and cortisol. Upper body isometric strength tests ( UBIST) were performed (Post, 1 hr, 24 hr, 48 hr) to evaluate changes in force production during recovery. Data analysis via repeated measures ANOVA revealed a significant trend for increased oxygen consumption in the QUAD condition compared to the bench press (p = 0.019). Additionally, both suspension conditions resulted in a reduced respiratory exchange ratio as compared to the bench press (p < 0.05). A significant main effect was noted for time in all conditions regarding isometric strength (p < 0.001), but no differences between conditions were revealed. Testosterone and cortisol responses did not differ between conditions. Based upon these data, it appears that when matched for work, suspension exercise results in equivalent reductions in muscle force, but greater oxygen consumption compared to isotonic exercise. PMID- 30429902 TI - Polygenic Study of Endurance-Associated Genetic Markers NOS3 (Glu298Asp), BDKRB2 (-9/+9), UCP2 (Ala55Val), AMPD1 (Gln45Ter) and ACE (I/D) in Polish Male Half Marathoners. AB - The purpose of this study was to investigate individually and in combination the association between the ACE (I/D), NOS3 (Glu298Asp), BDKRB2 (-9/+9), UCP2 (Ala55Val) and AMPD1 (Gln45Ter) variants with endurance performance in a large, performance-homogenous cohort of elite Polish half marathoners. The study group consisted of 180 elite half marathoners: 76 with time < 100 minutes and 104 with time > 100 minutes. DNA of the subjects was extracted from buccal cells donated by the runners and genotyping was carried out using an allelic discrimination assay with a C1000 Touch Thermal Cycler (Bio-Rad, Germany) instrument with TaqMan(r) probes (NOS3, UCP2, and AMPD1) and a T100TM Thermal Cycler (Bio-Rad, Germany) instrument (ACE and BDKRB2). We found that the UCP2 Ala55Val polymorphism was associated with running performance, with the subjects carrying the Val allele being overrepresented in the group of most successful runners (<100 min) compared to the >100 min group (84.2 vs. 55.8%; OR = 4.23, p < 0.0001). Next, to assess the combined impact of 4 gene polymorphisms, all athletes were classified according to the number of 'endurance' alleles (ACE I, NOS3 Glu, BDKRB2 -9, UCP2 Val) they possessed. The proportion of subjects with a high (4-7) number of 'endurance' alleles was greater in the better half marathoners group compared with the >100 min group (73.7 vs. 51.9%; OR = 2.6, p = 0.0034). These data suggest that the likelihood of becoming an elite half marathoner partly depends on the carriage of a high number of endurance-related alleles. PMID- 30429903 TI - Influence of Autonomic Control on the Specific Intermittent Performance of Judo Athletes. AB - Judo is a high-intensity intermittent combat sport which causes cardiac adaptations both morphologically and related to the autonomic nervous system (ANS). Therefore, this study aims to verify the correlation between heart rate variability (HRV) at rest with performance in the Special Judo Fitness Test (SJFT) and whether groups with different RR values at rest show different performance in the SJFT and during post-test recovery. Sixteen judo athletes with 7.2 +/- 3.9 years of training experience participated in the study. Before and after the SJFT execution HRV and lactate measurements were conducted. For HRV analysis, we used the mean interval RR, the standard deviation of the RR interval (SDNN), the root mean square of successive differences in RR intervals (RMSSD), the low frequency (LF) and high frequency (HF) in normalized and absolute units. The sample was split into two groups (low RR and high RR) to verify if this variable could differentiate between specific performance. For the SDNN, a significant and moderate correlation (r = 0.53) was found with the total number of throws and throws in the series A (r = 0.56) and B (r = 0.54) and for the RMSSD a correlation with throws during series B (r = 0.59) in the SJFT. However, the groups did not differ in performance and recovery. Therefore, HRV is related to intermittent judo performance; however, it cannot differentiate between judokas at different levels of performance. PMID- 30429904 TI - Effects of Probiotic Supplementation on Selected Parameters of Blood Prooxidant Antioxidant Balance in Elite Athletes: A Double-Blind Randomized Placebo Controlled Study. AB - A randomized, double-blind, placebo-controlled study was conducted, in order to evaluate if Lactobacillus helveticus Lafti(r) L10 (Lallemand Health Solutions, Montreal, Canada) supplementation during three months could influence oxidative markers in the population of elite athletes: triathletes, cyclists and endurance athletes. Twenty-two elite athletes were randomized to either placebo (n = 12) or probiotic (n = 10) groups. The probiotic group received 2x1010 colony forming units of Lafti(r) L10. Before and after the supplementation serum samples were collected. Markers of oxidative stress and anti-oxidative defense: superoxide dismutase (SOD), paraoxonase (PON), advanced oxidation protein products (AOPP), malondialdehyde (MDA), total antioxidant status, total oxidant status, pro oxidant-antioxidant balance, oxidative stress index, bilirubin, uric acid and albumin were determined in serum. Parameters of lipid status, as well as susceptibility to copper-induced oxidation of LDL particles in vitro were also determined. There was a significant interaction effect for MDA (p = 0.039), with a decrease in MDA in the probiotic group only (p = 0.049). There was a significant interaction effect for AOPP (p = 0.037), with a significant decrease in the probiotic group (p = 0.045). Interaction effect for SOD was approaching to formal significance (p = 0.108) and the post-hoc test showed a significant decrease in the probiotic group (p = 0.041) only. A significant correlation between AOPP and SOD (p = 0.012, r = -0.40) was found in the probiotic group at the end of the study. PON1 activity was decreased in both the probiotic (p = 0.032) and placebo group (p = 0.035). No significant changes in the remainder of the evaluated parameters were noted. In conclusion, probiotic strain Lafti(r) L10 exerts certain antioxidant potential, but further research is needed. PMID- 30429905 TI - Training-Induced Variations in Haematological and Biochemical Variables in Adolescent Athletes of Arab Origin Throughout an Entire Athletic Season. AB - The purpose of this study was to observe and report variations in several haematological and biochemical markers throughout an entire athletic season in a large cohort of adolescent athletes of Arab origin. Blood samples were collected from 72 adolescent male athletes at 4 selected time points during their training season. Results expressed in relation to plasma volume were corrected accordingly and significant variations in several variables emerged. Initial uncorrected haematological results revealed that haematocrit (Hct) and mean cell volume (MCV) concentrations noticeably increased at the competitive period (T3) and before the start of the following preseason (T4), whereas reticulocytes equivalent (Ret-He) only rose at T4 phase (p < 0.01). Conversely, corrected red blood cells (RBC), haemoglobin (Hb) and mean cell haemoglobin concentration (MCHC) progressively decreased over the year (p < 0.001). From the electrolytes panel, sodium and chloride considerably reduced at the peak of the training period (T2) to the start of the next preseason (T4), while a significant fall in potassium was mainly observed during the competitive period (T3) (p < 0.001). Coaches and sport scientists could use the results of this study to evaluate typical variations of each age group in order to diagnose potential adverse effects of high training loads, assist in the design of training programs and/or clinical interventions that will safeguard athletes' health, and consider the important role of plasma volume for the interpretation of results. PMID- 30429906 TI - Physiological and Psychological Adaptations of Trained Cyclists to Spring Cycling Camps. AB - The purpose of our study was to assess physiological adaptations and measure mood outcomes following a cycling training camp in competitive athletes. Fourteen competitive athletes (8 males, 6 females) performed 2 incremental tests to exhaustion before and after a training camp. Volume and intensity (load) of the training regimen were recorded. Submaximal and maximal metabolic data were analysed, as well as economy variables (gross mechanical efficiency and cycling economy). Skeletal muscle adaptations were assessed using near infrared spectroscopy (NIRS). For both genders (n = 14), peak power output, peak power output-W/kg ratio and peak power output-B[La] were significantly increased (p < 0.05) after the cycling training camp (p < 0.05). Significant increases occurred for gross mechanical efficiency measured at the lactate threshold (+4.9%) and at the same precamp lactate threshold power output (+2.9%). At the lactate threshold and Post Camp Lactate Threshold Power, cycling economy increased by 5.2 and 2.9%, respectively (p < 0.05). These power measurements were significantly correlated with individual fluctuations in deoxyhaemoglobin in the vastus lateralis for male cyclists only. Profile of Mood State questionnaire results showed that subcategories "Tension-Anxiety", "Confusion", "Fatigue" and "Total Global Score" significantly decreased after the training camp. Cycling training camps were associated with positive adaptations (increased cycling economy, gross mechanical efficiency and power output) as well as some mental benefits. This indicates that despite some significant physiological adaptations participants probably did not overreach during their CTC. PMID- 30429907 TI - Successful and Unsuccessful Offensive Sequences Ending in a Shot in Professional and Elite Under-16 Basketball. AB - Following observational methodology, we analyzed successful and unsuccessful offensive attacks by professional and elite under-16 (U16) basketball players in Spain using an adapted ad hoc observation instrument designed to study efficiency in basketball. We identified both similarities and differences between how players from both categories built their attacks. The synchronic statistical analysis based on frequency counts showed that shots were more efficient in professional basketball and that U16 basketball was less static and had a higher frequency of fast breaks. Diachronic analysis, which consisted of T-pattern detection using Theme software, allowed us to identify characteristic successful and unsuccessful offensive sequences in professional and elite U16 basketball. These results have practical implications as they can be used to design training drills and prepare for competitions in U16 and professional basketball. PMID- 30429908 TI - Relationship Between Tactical Performance, Somatic Maturity and Functional Capabilities in Young Soccer Players. AB - The aim of the study was to investigate the relationship between tactical performance, somatic maturity, and functional capabilities in young soccer players. Study participants were 48 soccer players (14.80 +/- 1.5 years) belonging to an extension project at the State University of Maringa - Brazil. Anthropometric measurements of body mass, body height, and sitting height were carried out. The number of years to peak height velocity (PHV) was used as an index of maturation. Evaluations of functional fitness included the following tests: sit-and-reach, Yo-Yo Intermittent Recovery Test Level 1, handgrip test, modified abdominal test, and vertical jumps (Counter Movement Jump and Jump Squat). Tactical performance was assessed through the System of Tactical Assessment in Soccer (FUT-SAT). Multiple Linear Regression models were used to estimate the relative contributions of functional and maturational capacities to tactical performance. The results indicated weak associations between the tactical performance indices and somatic maturity, functional capacity, and anthropometric attributes (r < 0.40). The Yo-Yo Test contributed to 36% of the defensive tactic performance variation in the under 13 category. These results suggest that the level of maturity, growth status, and functional fitness have limited impact on tactical performance of young soccer players. PMID- 30429909 TI - Influence of the Varied Pitch Shape on Soccer Players Physiological Responses and Time-Motion Characteristics During Small-Sided Games. AB - The aim of this study was to investigate the effect of pitch shape modifications on heart rate responses and time-motion characteristics in soccer players during 5-a-side small-sided games (SSGs). Players completed four different SSG dimensions: (1) short narrow pitch (SN; 40 * 25 m), (2) short wide pitch (SW; 66 * 25 m), (3) long narrow pitch (LN; 40 * 50 m), and (4) long wide pitch (LW; 66 * 50 m). Twenty amateur soccer players (age: 21 +/- 5 yr; stature: 176.8 +/- 1.9 cm; body mass: 72.7 +/- 3.7 kg) were monitored using a heart rate monitor and a 10 Hz GPS device. Mean maximum heart rate (%HRmax), rating of perceived exertion (RPE), peak running speed, total distance covered (TD), distance covered in four speed categories, number of moderate and high accelerations (Ac), decelerations (Dc), changes of direction (COD) and player load were recorded. Increasing the pitch length had a greater effect compared to increasing the pitch width especially on RPE (3.8, 6.3, 4.9 and 6.6 AU to SN, LN, SW and LW, respectively) and time-motion characteristics such as TD (101, 127, 108 and 131 m.min-1 to SN, LN, SW and LW, respectively), peak speed (4.8, 6.1, 5.2 and 6.2 m.s-1 to SN, LN, SW and LW, respectively), and the number of accelerations, decelerations, and changes of direction. The data demonstrates that increasing the length rather than the width of 5-a-side SSG has a greater impact on players' responses in terms of increasing workloads. PMID- 30429910 TI - The Impact of Rule Modifications on Elite Basketball Teams' Performance. AB - Rule modifications in basketball are used to develop the sport, and FIBA changes the basketball regulations periodically and constantly in search of a more attractive game. The objectives of this study were as follows: i) to characterise and identify the technical-tactical performance indicators which discriminated the game style according to the effect of rule modifications; and ii) to analyse the persistence of these indicators according to rule modifications over time. Analyses were made of all the editions of the current competition system of the Copa Del Rey in Spanish basketball. One hundred and forty matches were analysed, starting from the 1995-96 to the 2014-15 season. Data were gathered from the official competition web page (www.acb.com) The variables analysed included rule modifications, the number of ball possessions, points scored, one, two and 3 point field goals made and attempted, total rebounds, defensive and offensive rebounds, assists, steals, turnovers, blocked shots, dunks and committed and received personal fouls, score differences, as well as one, two and 3-point field goal percentages. Several analyses were carried out: descriptive analysis to characterise the sample; ANOVA to identify differences between periods; discriminant analysis to determine technical-tactical performance indicators which best discriminated between each competition term and rule change period; and finally autocorrelation function and cross-correlation were used to estimate the persistency of performance indicators over time. Results show that rule changes affect the way basketball is played. Nevertheless, players and coaches are the ones who determine functional behavior in basketball. PMID- 30429911 TI - The Effects of Two Different Resisted Swim Training Load Protocols on Swimming Strength and Performance. AB - This study used a power rack device to evaluate the effects of 2 different approaches to resisted swim training loads on swimming strength and performance. Sixteen male, youth national-level swimmers (mean age, 16.22 +/- 2.63 years; body height, 169 +/- 10.20 cm; body mass, 61.33 +/- 9.90 kg) completed a 6-week specific strength-training program, and were then randomly assigned to one of the two groups: a standard training group (GS, n = 8) and a flat pyramid-loading pattern group (GP, n = 8). Strength and power tests along with specific swimming tests (50-m crawl and 50-m competition-style time trials) were conducted at baseline (pre-test), before the third week (mid-test), and after 6 weeks of intervention (post-test). Isokinetic swim bench tests were conducted to obtain measurements of force production and power, and 1RM tests with the power rack system were conducted to measure the maximum drag load (MDL) and specific swimming power. Following 6 weeks of intervention, the mean MDL increased (p < 0.05) by 13.94%. Scores for the 50-m competition style and 50-m crawl time trials improved by 0.32% and 0.78%, respectively, in the GP; however, those changes were not statistically significant. The GS significantly increased their time in the 50-m competition style by 2.59%, and their isokinetic force production decreased by 14.47% (p < 0.05). The 6-week strength-training program performed with the power rack device in a pyramidal organization was more effective than a standard linear load organization in terms of producing improvements in the MDL; however, it did not produce significant improvements in performance. The use of a strength training program with a pyramidal organization can be recommended for specific strength-training in young swimmers during a preparatory period. However, in our study, that program did not produce significant changes in 50-m crawl and main competition style performance. PMID- 30429912 TI - Acceleration and Speed Performance of Brazilian Elite Soccer Players of Different Age-Categories. AB - This study aimed to compare vertical jump ability (squat-jump [SJ] and countermovement-jump [CMJ]), relative to body mass mean propulsive power in the jump-squat (MPP-REL JS), and the 0-5, 5-10, and 10-20 m acceleration and speed among soccer players from the same professional club, divided into age-categories (U15 [n = 20], U17 [n = 53], U20 [n = 22] and senior [n = 25] players). The tests were performed at the start of the preseason in indoor facilities. The magnitude based inference approach and the standardized differences (based on effect sizes) were used to compare the age-groups. The SJ, CMJ, and MPP-REL JS increased across the age-groups up to U20, the latter being similar to senior players. Interestingly, the 0-5 m acceleration was likely and possibly higher in U15 players compared to U17 and senior players. Although soccer athletes improve their unloaded and loaded jump abilities across the age-categories (plateauing during adulthood), the same does not hold true for acceleration capacity, from the early phases of players' development (i.e., U15). Strength and conditioning professionals should seek effective strategies to minimize impairment in maximal acceleration performance of elite soccer players throughout their prospective training programs. PMID- 30429913 TI - Suggestions for Judo Training with Pacing Strategy and Decision Making by Judo Championship Phases. AB - The present study aimed to compare pacing and decision making of athletes competing in judo, with particular attention paid to effort-pause ratios occurring in the championship phases of the Olympic Games and non-Olympic Games. The sample was composed of 53,403 sequential actions analyzed during 611 performances of the non-Olympic Games (eliminatory n = 330, quarterfinals n = 60, semi-final n = 88, repechage n = 21, third place playoff n = 26, and final n = 79) and 163 from the Olympic Games (eliminatory n = 71, quarterfinals n = 13, semi-final n = 26, repechage n = 20, third place playoff n = 24, and final n = 14). The analysis of effort-pause ratios included separating bouts into states of approach, gripping, attack, groundwork and pause, according to frequency and time. A Markov multi-state model and analysis of variance were applied (p <= 0.05). Approach time presented differences of the eliminatory Olympic Games (7.3 +/- 3.2 s) versus final non-Olympic Games (6.0 +/- 2.2s), and the third place playoff Olympic Games (8.1 +/- 2.3 s) versus semi-final (6.2 +/- 2.4 s) and third place playoff (5.9 +/- 2.1 s) of the non-Olympic Games, and the semi-final Olympic Games (8.6 +/- 2.3 s) versus eliminatory (6.5 +/- 2.3 s), quarter-finals (6.5 +/- 1.7 s), semi-final (6.2 +/- 2.4 s), repechage (6.2 +/- 2.2 s), third place playoff (5.9 +/- 2.1 s), and final (6.0 +/- 2.0 s) of the non-Olympic Games. Pause time presented differences of the semi-final Olympic Games (6.8 +/- 2.1 s) versus eliminatory (5.1 +/- 3.1 s). The present data suggest a focus on pacing strategy during championship phases, which mimic the requirements of judo combats. PMID- 30429914 TI - Rethinking Monolithic Pathways to Success and Talent Identification: The Case of the Women's Japanese Volleyball Team and Why Height is not Everything. AB - The aim of the present study was to analyse the Japanese National Women's Volleyball Team and to identify items differentiating it from other teams. All fifteen matches between the six National Teams (i.e., Japan, Brazil, China, Belgium, Turkey and Russia) competing at the Women's Volleyball World Grand Prix Finals of 2014 were analyzed, in a total of 56 sets and 7,176 situations of ball possession. Data suggested the existence of differences between Japan's and the other five teams' gameplay, namely the likelihood of more gameplay with utilization of the float jump serve (20.42; +/- 3.79%, very large magnitude) and attack tempo 2 (61.89; +/- 29.67%, large magnitude), while exhibiting less gameplay with zero blockers opposing the attack (-42.06; +/- 21.28%, large magnitude). Based on these findings, it was concluded that sports success could be achieved even when a core feature of mainstream performance models (e.g., height in volleyball) was lacking. PMID- 30429915 TI - Performance Indicators of Winning and Defeated Female Handball Teams in Matches of the 2012 Olympic Games Tournament. AB - The aim of the study was to determine performance indicators of winning and defeated women teams of the 2012 Olympic Games handball tournament. The sample of entities consisted of 27 games played during the preliminary round of the competition. The sample of variables consisted of the completed and unsuccessfully executed technical and tactical handball elements in attacking and defensive actions during handball matches (14 variables describing performance in attack and three variables related to defensive play). The differences between the winning and defeated teams in performance variables were determined using the Mann-Whitney U-test. The results showed statistically significant differences between the winning and defeated teams in the following variables: successful fast-break shots (5.11 +/- 2.79 vs. 3.00 +/- 1.88), unsuccessful wing shots (2.33 +/- 1.24 vs. 3.67 +/- 1.98), unsuccessful long-range shots (10.70 +/- 3.98 vs. 13.37 +/- 4.33), steals (5.48 +/- 2.28 vs. 4.04 +/- 2.07), and assists (13.81 +/- 4.04 vs. 11.37 +/- 3.59). The winning teams were better in the variables defining offensive performance effectiveness, especially with regard to successful performance of counter attacks; they also had higher efficiency of attacking actions with a strict selection of distance shots and wing shots, as well as a higher number of assists and steals. PMID- 30429916 TI - Analysis of Scoring Sequences in Matches of the Portuguese Premier League. AB - The aim of this study was to examine the sequences of the first two goals scored in soccer matches in accordance with a range of different match contexts. Data from 1506 matches played in the Portuguese Premier League during six consecutive competitive seasons (2009-10 to 2014-2015) were analysed using descriptive statistics and the chi-square test in order to verify the association between variables and a Cox regression analysis was used to predict the time the second goal was scored in function of the time of the first goal scored in the match and the scoreline. The results revealed a higher frequency of the second goals being scored in the second half of a match (58%) and in the last 5 min periods of each half. A positive association was found for home teams and score-doubling goals (58%), as well as for away teams and score-equalizing goals (56%). For home and away teams the score-doubling goal of a match was strongly and positively associated with a win outcome for home (93%) and away teams (92%), while the score-equalizing goals were associated with a draw (home and away teams: 44%) and loss outcome (home: 33% and away teams: 32%). Finally, the Cox model showed that if the first goal was scored in the second half of the match, the probability of the second goal being scored was three times higher compared to the first half. PMID- 30429917 TI - The Relative Age Effect in Poland's Elite Youth Soccer Players. AB - The relative age effect (RAE) is related to discrimination against youth athletes born in the last quarter of the calendar year. The current study presents research on the RAE in elite youth soccer players in Poland. Players in the Central Junior League (CLJ) finals represent 0.59% of the 25,756 players under 20 years old (U20). This study analyzed the post-game protocols of the CLJ knockout stage from the 2013/2014 and 2014/2015 seasons as well as the U17-U21 teams during 2015, including only players who played on the field for at least one minute (n = 395). The results revealed the existence of RAE in the examined groups ( CLJ 2013/2014, chi23 = 15.441, p < 0.01, CLJ 2014/2015, chi23 = 20.891, p < 0.001 U17-U21, chi23 = 25.110, p < 0.001). In addition, the results differed by monthly birth distribution in the Polish population (PP) between 1995 and 1999. This study is the first to examine the RAE in youth soccer in Poland. The occurrence of the RAE with regard to the most promising youth and national team players suggests that a similar effect exists among younger age categories. To reduce the RAE related to identifying soccer talent, tools should be implemented to optimize the player-selection process, such as those that consider the biological development of a player. PMID- 30429918 TI - Differences in Physical Performance According to the Competitive Level in Futsal Players. AB - The purpose of the present study was to describe performance in acceleration capacity, change of direction ability, vertical jump, horizontal jump, repeated sprint ability, and endurance (Yo-Yo Intermittent Recovery Test Level 1) in futsal players, and analyze the differences according to competitive categories or levels. The total sample (n = 40) was divided into three groups depending on the category in which the participants competed: Second Division B (n = 15), Third Division (n = 12) and juniors (n = 13). All the tests were performed with participants' regular competition shoes and on the usual playing surface, in an indoor pavilion with a floating wood floor. The results of the study did not show significant differences in acceleration capacity (5 and 15 m) or change of direction ability among the different categories. In contrast, significant differences were found among the categories with regard to horizontal jump and vertical jump capacity (p < 0.05); but not in all the variables analyzed. Performance in repeat sprint ability varied significantly among the different categories in 30 m (p < 0.01) but not in 5 m (p > 0.05). The distance covered in the Yo-Yo Intermittent Recovery Test Level 1 by the Second Division B and the Third Division groups was greater than that covered by the junior group. In the light of these results repeated sprint ability and aerobic endurance could be two discriminating qualities of the competitive level among different futsal categories. PMID- 30429919 TI - Substance Use, Homelessness, Mental Illness and Medicaid Coverage: A Set-up for High Emergency Department Utilization. AB - Introduction: Frequent users of emergency departments (ED) account for 21-28% of all ED visits nationwide. The objective of our study was to identify characteristics unique to patients with psychiatric illness who are frequent ED users for mental health care. Understanding unique features of this population could lead to better care and lower healthcare costs. Methods: This retrospective analysis of adult ED visits for mental healthcare from all acute care hospitals in California from 2009-2014 used patient-level data from California's Office of Statewide Health Planning and Development. We calculated patient demographic and visit characteristics for patients with a primary diagnosis of a mental health disorder as a percentage of total adult ED visits. Frequent ED users were defined as patients with more than four visits in a 12-month period. We calculated adjusted rate ratios (aRR) to assess the association between classification as an ED frequent user and patient age, sex, payer, homelessness, and substance use disorder. Results: In the study period, 846,867 ED visits for mental healthcare occurred including 238,892 (28.2%) visits by frequent users. Patients with a primary mental health diagnosis and a co-occurring substance use diagnosis in the prior 12 months (77% vs. 37%, aRR [4.02], 95% confidence interval [CI] [3.92 4.12]), homelessness (2.9% vs 1.1%, odds ratio [1.35], 95% [CI] [1.27-1.43]) were more likely to be frequent users. Those covered by Medicare (aRR [3.37], 95% CI [3.20-3.55]) or the state's Medicaid program Medi-Cal (aRR [3.10], 95% CI [2.94 3.25]) were also more likely to be frequent users compared with those with private insurance coverage. Conclusion: Patients with substance use disorders, homelessness and public healthcare coverage are more likely to be frequent users of EDs for mental illness. Substance use and housing needs are important factors to address in this population. PMID- 30429920 TI - Analysis of Patients with Ventricular Assist Devices Presenting to an Urban Emergency Department. AB - Introduction: Left ventricular assist device (LVAD) insertion is an increasingly common intervention for patients with advanced heart failure; however, published literature on the emergency department (ED) presentation of this population is limited. The objective of this study was to characterize ED presentations of patients with LVADs with a focus on device-specific complications to inform provider education and preparation initiatives. Methods: This was a retrospective chart review of all patients with LVADs followed at an urban academic medical center presenting to the ED over a five-year period (July 1, 2009, to June 30, 2014). Two abstractors reviewed 45 randomly selected charts to standardize the abstraction process and establish a priori categories for reason for presentation to the ED. Remaining charts were then divided evenly for review by one of the two abstractors. Primary outcomes for this study were (1) frequency of and (2) reason for presentation to the ED by patients with LVADs. Results: Of 349 patients with LVADs identified, 143 (41.0%) had ED encounters during the study period. There were 620 total ED encounters, (range 1 to 32 encounters per patient, median=3, standard deviation=5.3). Among the encounters, 431 (69.5%) resulted in admission. The most common reasons for presentation were bleeding (e.g., gastrointestinal, epistaxis) (182, 29.4%); infection (127, 20.5%); heart failure exacerbation (68, 11.0%); pain (56, 9.0%); other (45, 7.3%); and arrhythmias (40, 6.5%). Fifty-two encounters (8.4%) were device-specific; these patients frequently presented with abnormal device readings (37, 6.0%). Interventions for device-specific presentations included anticoagulation regimen adjustment (16/52, 30.8%), pump exchange (9, 17.3%), and hardware repair (6, 11.5%). Pump thrombosis occurred in 23 cases (3.7% of all encounters). No patients required cardiopulmonary resuscitation or died in the ED. Conclusion: This is the largest study known to the investigators to report the rate of ED presentations of patients with LVADs and provide analysis of device-specific presentations. In patients who do have device-specific ED presentations, pump thrombosis is a common diagnosis and can present without device alarms. Specialized LVAD education and preparation initiatives for ED providers should emphasize the recognition and management of the most common and critical conditions for this patient population, which have been identified in this study as bleeding, infection, heart failure, and pump thrombosis. PMID- 30429921 TI - Predictors of Admission in Adult Unscheduled Return Visits to the Emergency Department. AB - Introduction: The 72-hour unscheduled return visit (URV) of an emergency department (ED) patient is often used as a key performance indicator in emergency medicine. We sought to determine if URVs with admission to hospital (URVA) represent a distinct subgroup compared to unscheduled return visits with no admission (URVNA). Methods: We performed a retrospective cohort study of all 72 hour URVs in adults across 10 EDs in the Edmonton Zone (EZ) over a one-year period (January 1, 2015 - December 31, 2015) using ED information-system data. URVA and URVNA populations were compared, and a multivariable analysis identified predictors of URVA. Results: Analysis of 40,870 total URV records, including 3,363 URVAs, revealed predictors of URVA on the index visit including older age (>65 yrs, odds ratio [OR] 3.6), higher disease acuity (Canadian Emergency Department Triage and Acuity Scale [CTAS] 2, OR 2.6), gastrointestinal presenting complaint (OR 2.2), presenting to a referral hospital (OR 1.4), fewer annual ED visits (<4 visits, OR 2.0), and more hours spent in the ED (>12 hours, OR 2.0). A decrease in CTAS score (increase in disease acuity) upon return visit also increased the risk of admission (-1 CTAS level, OR 2.6). ED crowding at the index visit, as indicated by occupancy level, was not a predictor. Conclusion: We demonstrate that URVA patients comprise a distinct subgroup of 72-hour URV patients. Risk factors for URVA are present at the index visit suggesting that patients at high risk for URVA may be identifiable prior to admission. PMID- 30429922 TI - Social Disconnection Among Older Adults Receiving Care in the Emergency Department. AB - Introduction: Social disconnection is a public health problem in older adults, as it can lead to decreased quality of life for this population. This study describes the prevalence of social disconnection and patient interest in social resources to address social disconnection among older adults receiving emergency department (ED) care. Methods: We conducted a cross-sectional survey of community dwelling older adults (>=65 years) receiving care at two U.S. EDs. We described participant characteristics (demographic, social, and health variables), social disconnection prevalence, and desire for social resources using percentages and 95% confidence intervals. Then, we performed Chi Square tests and logistic regression to determine factors associated with positive screens for social disconnection. Results: Of 289 participants, 51% were female and the median age was 72 (interquartile range: 69-78). Most (76%) engaged with the community regularly, and 68% reported driving. Regarding social disconnection, a substantial minority of participants reported feeling as if they were burdensome to others (37%); as if they didn't belong (27%); or that people would be better off if they were gone (15%); 52% reported at least one of these. In separate regression analyses, the perceptions of being a burden or better off if gone were each significantly associated with needing help with routine tasks (odds ratio [OR] [5.87, 5.90]); perceived burden was associated with hospitalization in the prior month (OR [2.09]); and low belonging was associated with not engaging in the community regularly (OR [2.50]), not seeing family regularly (OR [3.82]), and difficulty affording food (OR [2.50]). Regarding potential ED referrals, most participants were interested in transportation options (68%), food assistance (58%), and mental health resources (55%). Participants experiencing difficulties affording food were interested in food and housing assistance (p=.03; p=.01). Conclusion: Over half of this sample of older ED patients reported feeling socially disconnected. Social and functional health problems are often related and both must be addressed to optimize older ED patient quality of life. Future research should consider the impact of social disconnection on older adults discharged from the ED and work to develop ED services that could refer this population to programs that may decrease social disconnection. PMID- 30429923 TI - Characterizing Highly Frequent Users of a Large Canadian Urban Emergency Department. AB - Introduction: Highly frequent users (HFU) of the emergency department (ED) are a poorly defined population. This study describes patient and visit characteristics for Canadian ED HFU and patient subgroups with mental illness, substance misuse, or >= 30 yearly ED visits. Methods: We reviewed health records from a random selection of adult patients whose visit frequency comprised the 99th percentile of yearly ED visits to The Ottawa Hospital. We excluded scheduled repeat ED assessments. We collected the following: 1) patient characteristics - age, sex, and comorbidities; and 2) ED visit characteristics - diagnosis category, length of stay, presentation time, consultation services, and final disposition. Two reviewers collected data, and we performed an inter-rater review to measure agreement. Results: We analyzed 3,164 ED visits for 261 patients in all subgroups overall. Within the HFU random selection, mean age was 53.4 +/- 1.3, and 55.6% were female. Most patients had a fixed address (88.9%), and family physician (87.2%). Top ED diagnoses included musculoskeletal pain (9.6%), alcohol intoxication (8.5%), and abdominal pain (8.4%). Allied health (social work, geriatric emergency medicine, or community care access centre) was consulted for 5.9% of visits. In 52.7% of these cases, allied health services were not available at the time of presentation. Conclusion: HFU are a complex population who represent a marked proportion of annual ED visits. Our data indicate that there are opportunities to improve the current approaches to care. Future work examining ED-based screening and multi-disciplinary approaches for HFU may help reduce frequent ED presentations, and better serve this vulnerable population. PMID- 30429924 TI - Obtaining History with a Language Barrier in the Emergency Department: Perhaps not a Barrier After All. AB - Introduction: Patients with limited English proficiency may be at risk for incomplete history collection, potentially a patient safety issue. While federal law requires qualified medical interpreters be provided for these patients, little is known about the quality of information obtained in these encounters. Our study compared the medical histories obtained by physicians in the emergency department (ED) based on whether the patients primarily spoke English or Spanish. Methods: This was a prospective, observational study conducted at a single, urban, academic ED during a six-month time period. Resident and faculty physicians caring for adult patients with a chief complaint of chest or abdominal pain were eligible for participation. Patient encounters were directly observed by medical students who had been trained using simulated encounters. Observers documented which key historical data points were obtained by providers, including descriptions of pain (location, quality, severity, radiation, alleviating/aggravating factors), past medical/family/surgical history, and social history, in addition to the patient's language in providing history. Providers, interpreters, and observers were blinded to the nature of the study. We used chi-square analyses to examine differences in whether specific elements were collected based on the primary language of the patient. Results: Encounters with 753 patients were observed: 105 Spanish speaking and 648 English speaking. Chi-square analyses found no statistically significant differences in any history questions between Spanish-speaking and English-speaking patients, with the exception that questions regarding alleviating factors were asked more often with Spanish-speaking patients (45%) than English-speaking patients (30%, p=.003). The average percentages of targeted history elements obtained in Spanish and English encounters were 60% and 57%, respectively. Conclusion: In this study at a large, urban, academic ED, the medical histories obtained by physicians were similar between English-speaking and Spanish-speaking patients. This suggests that the physicians sought to obtain medical histories at the same level of detail despite the language barrier. One limitation to consider is the Hawthorne effect; however, providers and observers were blinded to the nature of the study in an attempt to minimize the effect. PMID- 30429925 TI - Emergency Department Patient Satisfaction with Treatment of Low-risk Pulmonary Embolism. AB - Introduction: Many emergency department (ED) patients with acute pulmonary embolism (PE) who meet low-risk criteria may be eligible for a short length of stay (LOS) (<24 hours), with expedited discharge home either directly from the ED or after a brief observation or hospitalization. We describe the association between expedited discharge and site of discharge on care satisfaction and quality of life (QOL) among patients with low-risk PE (PE Severity Index [PESI] Classes I-III). Methods: This phone survey was conducted from September 2014 through April 2015 as part of a retrospective cohort study across 21 community EDs in Northern California. We surveyed low-risk patients with acute PE, treated predominantly with enoxaparin bridging and warfarin. All eligible patients were called 2-8 weeks after their index ED visit. PE-specific, patient-satisfaction questions addressed overall care, discharge instruction clarity, and LOS. We scored physical and mental QOL using a modified version of the validated Short Form Health Survey. Satisfaction and QOL were compared by LOS. For those with expedited discharge, we compared responses by site of discharge: ED vs. hospital, which included ED-based observation units. We used chi-square and Wilcoxon rank sum tests as indicated. Results: Survey response rate was 82.3% (424 of 515 eligible patients). Median age of respondents was 64 years; 47.4% were male. Of the 145 patients (34.2%) with a LOS<24 hours, 65 (44.8%) were discharged home from the ED. Of all patients, 89.6% were satisfied with their overall care and 94.1% found instructions clear. Sixty-six percent were satisfied with their LOS, whereas 17.5% would have preferred a shorter LOS and 16.5% a longer LOS. There were no significant differences in satisfaction between patients with LOS<24 hours vs. >=24 hours (p>0.13 for all). Physical QOL scores were significantly higher for expedited-discharge patients (p=0.01). Patients with expedited discharge home from the ED vs. the hospital had no significant difference in satisfaction (p>0.20 for all) or QOL (p>0.19 for all). Conclusion: ED patients with low-risk PE reported high satisfaction with their care in follow-up surveys. Expedited discharge (<24 hours) and site of discharge were not associated with differences in patient satisfaction. PMID- 30429926 TI - American Heart Association/American Stroke Association Deletes Sections from 2018 Stroke Guidelines. AB - The updated American Heart Association (AHA)/American Stroke Association (ASA) Guidelines for the Early Management of Patients with Acute Ischemic Stroke were published in January 2018.1 The purpose of the guidelines is to provide an up-to date, comprehensive set of recommendations for clinicians caring for adult patients with acute arterial ischemic stroke in a single document. The guidelines detail new and updated recommendations that reflect and incorporate the most recent literature in the evaluation and management of acute ischemic stroke. Some sections of the latest guidelines have sparked debate in the medical community. Debate with regard to deciding the optimal diagnostic and treatment strategy for patients is healthy and anticipated with the release of new medical literature or recommendations. However, what is somewhat puzzling and unanticipated with the release of these new guidelines is that within two months of their release the AHA/ASA rescinded its recently released guidelines, publishing a "correction" in which several parts of the document have been deleted.2 An action such as this at the guideline level is unprecedented in recent history and has left stakeholders in the medical community somewhat confused as to the rationale for its occurrence. This article will inform the emergency medicine (EM) healthcare professional of the recent correction of the updated stroke guidelines, identify which sections have been removed (deleted), and will provide a brief summary of the pertinent updates (that have not been deleted) to the 2018 stroke guidelines that have particular relevance to the EM community. PMID- 30429927 TI - Low-dose Ketamine Does Not Improve Migraine in the Emergency Department: A Randomized Placebo-controlled Trial. AB - Introduction: Patients frequently present to the emergency department (ED) with migraine headaches. Although low-dose ketamine demonstrates analgesic efficacy for acute pain complaints in the ED, headaches have historically been excluded from these trials. This study evaluates the efficacy and safety of low-dose ketamine for treatment of acute migraine in the ED. Methods: This randomized, double-blinded, placebo-controlled trial evaluated adults 18 to 65 years of age with acute migraine at a single academic ED. Subjects were randomized to receive 0.2 milligrams per kilogram of intravenous (IV) ketamine or an equivalent volume of normal saline. Numeric Rating Scale (NRS-11) pain scores, categorical pain scores, functional disability scores, side effects, and adverse events were assessed at baseline (T0) and 30 minutes post-treatment (T30). The primary outcome was between-group difference in NRS score reduction at 30 minutes. Results: We enrolled 34 subjects (ketamine=16, placebo=18). Demographics were similar between treatment groups. There was no statistically significant difference in NRS score reductions between ketamine and placebo-treated groups after 30 minutes. Median NRS score reductions at 30 minutes were 1.0 (interquartile range [IQR] 0 to 2.25) for the ketamine group and 2.0 (IQR 0 to 3.75) for the placebo group. Between-group median difference at 30 minutes was 1.0 (IQR -2 to 1, p=0.5035). No significant differences between treatment groups occurred in categorical pain scores, functional disability scores, rescue medication request rate, and treatment satisfaction. Side Effect Rating Scale for Dissociative Anesthetics scores in the ketamine group were significantly greater for generalized discomfort at 30 minutes (p=0.008) and fatigue at 60 minutes (p=0.0216). No serious adverse events occurred in this study. Conclusion: We found that 0.2mg/kg IV ketamine did not produce a greater reduction in NRS score compared to placebo for treatment of acute migraine in the ED. Generalized discomfort at 30 minutes was significantly greater in the ketamine group. Overall, ketamine was well tolerated by migraine-suffering subjects. To optimize low-dose ketamine as an acute migraine treatment, future studies should investigate more effective dosing and routes of administration. PMID- 30429928 TI - Risk Factors in Pediatric Blunt Cervical Vascular Injury and Significance of Seatbelt Sign. AB - Introduction: Computed tomography angiography (CTA) is used to screen patients for cerebrovascular injury after blunt trauma, but risk factors are not clearly defined in children. This modality has inherent radiation exposure. We set out to better delineate the risk factors associated with blunt cervical vascular injury (BCVI) in children with attention to the predictive value of seatbelt sign of the neck. Methods: We collected demographic, clinical and radiographic data from the electronic medical record and a trauma registry for patients less than age 18 years who underwent CTA of the neck in their evaluation at a Level I trauma center from November 2002 to December 2014 (12 years). The primary outcome was BCVI. Results: We identified 11,446 pediatric blunt trauma patients of whom 375 (2.7%) underwent CTA imaging. Fifty-three patients (0.4%) were diagnosed with cerebrovascular injuries. The average age of patients was 12.6 years and included 66% males. Nearly half of the population was white (52%). Of those patients who received CTA, 53 (14%) were diagnosed with arterial injury of various grades (I V). We created models to evaluate factors independently associated with BCVI. The independent predictors associated with BCVI were Injury Severity Score >/= 16 (odds ratio [OR] [2.35]; 95% confidence interval [CI] [1.11-4.99%]), infarct on head imaging (OR [3.85]; 95% CI [1.49-9.93%]), hanging mechanism (OR [8.71]; 95% CI [1.52-49.89%]), cervical spine fracture (OR [3.84]; 95% CI [1.94-7.61%]) and basilar skull fracture (OR [2.21]; 95% CI [1.13-4.36%]). The same independent predictors remained associated with BCVI when excluding hanging mechanism from the multivariate regression analysis. Seatbelt sign of the neck was not associated with BCVI (p=0.68). Conclusion: We have found independent predictors of BCVI in pediatric patients. These may help in identifying children that may benefit from screening with CTA of the neck. PMID- 30429929 TI - Factors Affecting Family Presence During Fracture Reduction in the Pediatric Emergency Department. AB - Introduction: Asking family members to leave during invasive procedures has historically been common practice; however, evidence-based recommendations have altered the trend of family presence during pediatric procedures. The aim of this study was to determine factors related to family members' choice to be present or absent during fracture reductions in a pediatric emergency department (ED), and their satisfaction with that choice. Methods: We administered role-specific, anonymous surveys to a convenience sample of patients' family members in the ED of a Level I pediatric trauma center. All family members were given a choice of where to be during the procedure. Results: Twenty-five family members of 18 patients completed surveys. Seventeen family members chose to stay in the room. Family member satisfaction with their decision to be inside or outside the room during the procedure (median = very satisfied) was almost uniformly high and not associated with any of the following variables: previous presence during a medical procedure; provider-reported procedure difficulty, or anxiety levels. Family member perception of procedure success (median = extremely well) was also high and not associated with other variables. Location during the procedure was associated with a desire to be in the same location in the future (Fisher's exact test, p=0.001). Common themes found among family members' reasons for their location decisions and satisfaction levels were a desire to support the patient, high staff competence, and their right as parents to choose their location. Conclusion: Family members self-select their location during their child's fracture reduction to high levels of satisfaction, and they considered the ability to choose their location as important. PMID- 30429930 TI - Tranexamic Acid in Civilian Trauma Care in the California Prehospital Antifibrinolytic Therapy Study. AB - Introduction: Hemorrhage is one of the leading causes of death in trauma victims. Historically, paramedics have not had access to medications that specifically target the reversal of trauma-induced coagulopathies. The California Prehospital Antifibrinolytic Therapy (Cal-PAT) study seeks to evaluate the safety and efficacy of tranexamic acid (TXA) use in the civilian prehospital setting in cases of traumatic hemorrhagic shock. Methods: The Cal-PAT study is a multi centered, prospective, observational cohort study with a retrospective comparison. From March 2015 to July 2017, patients >= 18 years-old who sustained blunt or penetrating trauma with signs of hemorrhagic shock identified by first responders in the prehospital setting were considered for TXA treatment. A control group was formed of patients seen in the five years prior to data collection cessation (June 2012 to July 2017) at each receiving center who were not administered TXA. Control group patients were selected through propensity score matching based on gender, age, Injury Severity Scores, and mechanism of injury. The primary outcome assessed was mortality recorded at 24 hours, 48 hours, and 28 days. Additional variables assessed included total blood products transfused, the hospital and intensive care unit length of stay, systolic blood pressure taken prior to TXA administration, Glasgow Coma Score observed prior to TXA administration, and the incidence of known adverse events associated with TXA administration. Results: We included 724 patients in the final analysis, with 362 patients in the TXA group and 362 in the control group. Reduced mortality was noted at 28 days in the TXA group in comparison to the control group (3.6% vs. 8.3% for TXA and control, respectively, odds ratio [OR]=0.41 with 95% confidence interval [CI] [0.21 to 0.8]). This mortality difference was greatest in severely injured patients with ISS >15 (6% vs 14.5% for TXA and control, respectively, OR=0.37 with 95% CI [0.17 to 0.8]). Furthermore, a significant reduction in total blood product transfused was observed after TXA administration in the total cohort as well as in severely injured patients. No significant increase in known adverse events following TXA administration were observed. Conclusion: Findings from the Cal-PAT study suggest that TXA use in the civilian prehospital setting may safely improve survival outcomes in patients who have sustained traumatic injury with signs of hemorrhagic shock. PMID- 30429931 TI - Burnout and Exposure to Critical Incidents in a Cohort of Emergency Medical Services Workers from Minnesota. AB - Introduction: Very little quantitative data on occupational burnout and exposure to critical incidents are available from contemporary United States emergency medical services (EMS) cohorts. Given that burnout has been associated positively with turnover intentions and absenteeism in EMS workers, studies that uncover correlates of burnout may be integral to combating growing concerns around retention in the profession. Methods: We administered a 167-item electronic survey that included the Maslach Burnout Inventory (MBI) and a modified version of the Critical Incident History Questionnaire (n=29 incident types) to paramedics, emergency medical technicians (EMTs), and dispatchers of a single ambulance service. We defined the presence of burnout as a high score on either the emotional exhaustion or depersonalization subscales of the MBI. Results: Survey respondents who provided regular 911 response at the time of the survey and completed the MBI portion of the survey were included in our analysis (190 paramedics/EMTs, 19 dispatchers; 54% response). The overall prevalence of burnout was 18%, with prevalence reaching 32% among dispatchers. The seven pediatric critical incident types presented in the survey accounted for seven of the top eight rated most difficult to cope with, and severity ratings for pediatric critical incidents did not differ by parental status (all p>0.30). A significant number of respondents reported that they had been threatened with a gun/weapon (43%) or assaulted by a patient (68%) at least once while on duty. Being over the age of 50, a parent, or in a committed relationship was associated with reduced odds of burnout in unadjusted models; however, these associations did not remain statistically significant in multivariate analysis. Increasing tertile of career exposure to critical incidents was not associated with burnout. Conclusion: Medical dispatchers may be an EMS subgroup particularly susceptible to burnout. These data also demonstrate quantitatively that in this EMS agency, responders find pediatric critical incidents especially distressing and that violence against responders is commonplace. In this study, a simple measure of career exposure to potentially critical incidents was not associated with burnout; however, individual reactions to incidents are heterogeneous, and assessment tools that more accurately enumerate encounters that result in distress are needed. PMID- 30429932 TI - Scholarship in Emergency Medicine: A Primer for Junior Academics Part I: Writing and Publishing. AB - The landscape of scholarly writing, publishing, and university promotion can be complex and challenging. Mentorship may be limited. To be successful it is important to understand the key components of writing and publishing. In this article, we provide expert consensus recommendations on four key challenges faced by junior faculty: writing the paper; selecting contributors and the importance of authorship order; journal selection and indexing; and responding to critiques. After reviewing this paper, the reader should have an enhanced understanding of these challenges and strategies to successfully address them. PMID- 30429933 TI - Measuring Scholarly Productivity: A Primer for Junior Faculty. Part III: Understanding Publication Metrics. AB - There are approximately 78 indexed journals in the specialty of emergency medicine (EM), making it challenging to determine which is the best option for junior faculty. This paper is the final component of a three-part series focused on guiding junior faculty to enhance their scholarly productivity. As an EM junior faculty's research career advances, the bibliometric tools and resources detailed in this paper should be considered when developing a publication submission strategy. The tenure and promotion decision process in many universities relies at least in part on these types of bibliometrics. This paper provides an understanding of new, alternative metrics that can be used to promote scientific progress in a transparent and timely manner. PMID- 30429934 TI - Student Experience with a Quality Improvement Project in the Emergency Department. PMID- 30429935 TI - Deaf and Hard-of-Hearing Learners in Emergency Medicine. AB - Approximately 23% of Americans over age 12 have some level of hearing loss.1 Emergency departments can reduce healthcare barriers for deaf and hard-of-hearing (DHoH) patients through improved patient-physician communication. DHoH students, once they become physicians, may provide one mechanism for reducing existing healthcare disparities and communication barriers for DHoH patients, and may be more adept with patients facing other communication barriers. A renewed interest in disability access and a commitment to social justice has increased efforts toward the inclusion of individuals with disabilities in medical education and training. Despite this increased interest and a growing number of DHoH students entering medical education, DHoH students continue to be dissuaded from specialty careers such as emergency medicine (EM) over concerns regarding effective communication and ability. Given the academic medicine communities' commitment to diversity, a recounting of the successful inclusion of DHoH students in EM can benefit medical education and practice. In this account, the authors reflect on the successful experiences of a visiting DHoH medical student in an academic EM rotation at a Level I trauma hospital that serves a diverse population, and they identify the potential challenges for DHoH students in an EM setting, offer solutions including reasonable accommodations, and provide commentary on the legal requirements for providing full and equal access for DHoH students. We secured permission from the student to share the contents of this article prior to publication. PMID- 30429936 TI - Standardized Patients to Assess Resident Interpersonal Communication Skills and Professional Values Milestones. AB - It has been a challenge to assess communication and professional values Milestones in emergency medicine (EM) residents using standardized methods, as mandated by the Accreditation Council for Graduate Medical Education (ACGME). This paper outlines an innovative method of assessing these Milestones using an established instructional method. EM faculty mapped the communication and professional values Milestones to an existing communication and interpersonal skills scale. We identified six communication-focused scenarios: death notification; informed consent; medical non-compliance; medical error; treatment refusal; and advanced directives. In a pilot, 18 EM residents completed these six standardized patient (SP) encounters. Our experience suggests SP encounters can support standardized direct observation of residents' achievement of ACGME Milestones. Further effort can be made to create a tailored, behaviorally anchored tool that uses the Milestones as the conceptual framework. PMID- 30429937 TI - Gun Violence: A Biopsychosocial Disease. AB - Gun violence is a complex biopsychosocial disease and as such, requires a multidisciplinary approach to understanding and treatment. Framing gun violence as a disease places it firmly within medical and public health practice. By applying the disease model to gun violence, it is possible to explore the host, agent, and environment in which gun violence occurs, and to identify risk factors to target for prevention. This approach also provides an opportunity to address scientifically inaccurate assumptions about gun violence. In addition, there are many opportunities for medical communities to treat gun violence as a disease by considering and treating the biologic, behavioral, and social aspects of this disease. The medical community must answer recent calls to engage in gun violence prevention, and employing this model of gun violence as a biopsychosocial disease provides a framework for engagement. PMID- 30429938 TI - Analgesic Administration for Patients with Renal Colic in the Emergency Department Before and After Implementation of an Opioid Reduction Initiative. AB - Introduction: We aimed to evaluate the patterns of analgesic prescribing for emergency department (ED) patients suffering from pain of renal colic before, during, and after implementation of an opioid reduction initiative. We hypothesized that this initiative based on the concept of channels/enzymes/receptors-targeted analgesia would result in overall decrease in opioid utilization in the ED and at discharge. Methods: We performed a retrospective analysis of ED electronic medical record of patients presenting with renal colic who received analgesics in the ED and at discharge over a five year period. Patients were divided into three groups based on the following periods: 2012-2014 (pre-implementation phase); 2014-2015 (implementation phase); and 2015-2017 (post-implementation). Results: A total of 4,490 patients presented to the ED with renal colic over a five-year study period. Analgesics were administered to 3,793 ED patients of whom 1,704 received opioids and 2,675 received non-opioid analgesics. A total of 3,533 ED patients received a prescription for analgesic(s) upon discharge from the ED: 2,692 patients received opioids, and 2,228 received non-opioids. We observed a 12.7% overall decrease from the pre-implementation to post-implementation time period in opioid prescribing in the ED and a 25.5% decrease in opioid prescribing at discharge, which translated into 432 and 768 fewer patients receiving opioids, respectively. Conclusion: Implementation of an opioid-reduction initiative based on patient specific, pain syndrome-targeted opioid alternative protocols resulted in a reduction in opioid administration in the ED by 12.7% and at prescriptions at discharge by 25.5%. Adoption of similar ED initiatives nationwide has the potential to foster effective non-opioid analgesic practices for ED patients presenting with renal colic and to reduce physicians' reliance on administering and prescribing opioids. PMID- 30429939 TI - The Emergency Department as an Opportunity for Naloxone Distribution. AB - Introduction: Substance use disorders, including opioid use disorders, are a major public health concern in the United States. Between 2005 and 2014, the rate of opioid-related emergency department (ED) visits nearly doubled, from 89.1 per 100,000 persons in 2005 to 177.7 per 100,000 persons in 2014. Thus, the ED presents a distinctive opportunity for harm-reduction strategies such as distribution of naloxone to patients who are at risk for an opioid overdose. Methods: We conducted a systematic review of all existing literature related to naloxone distribution from the ED. We included only those articles published in peer-reviewed journals that described results relating to naloxone distribution from the ED. Results: Of the 2,286 articles we identified from the search, five met the inclusion criteria and had direct relevance to naloxone distribution from the ED setting. Across the studies, we found variation in the methods of implementation and evaluation of take-home naloxone programs in the ED. In the three studies that attempted patient follow-up, success was low, limiting the evidence for the programs' effectiveness. Overall, in the included studies there is evidence that distributing take-home naloxone from the ED has the potential for harm reduction; however, the uptake of the practice remained low. Barriers to implementation included time allocated for training hospital staff and the burden on workflow. Conclusion: This systematic review of the best evidence available supports the ED as a potential setting for naloxone distribution for overdose reversal in the community. The variability of the implementation methods across the studies highlights the need for future research to determine the most effective practices. PMID- 30429940 TI - Use of Fine-scale Geospatial Units and Population Data to Evaluate Access to Emergency Care. AB - Introduction: Time to facility is a crucial element in emergency medicine (EM). Fine-scale geospatial units such as census block groups (CBG) and publicly available population datasets offer a low-cost and accurate approach to modeling geographic access to and utilization of emergency departments (ED). These methods are relevant to the emergency physician in evaluating patient utilization patterns, emergency medical services protocols, and opportunities for improved patient outcomes and cost utilization. We describe the practical application of geographic information system (GIS) and fine-scale analysis for EM using Ohio ED access as a case study. Methods: Ohio ED locations (n=198), CBGs (n=9,238) and 2015 United States Census five-year American Community Survey (ACS) socioeconomic data were collected July-August 2016. We estimated drive time and distance between population-weighted CBGs and nearest ED using ArcGIS and 2010 CBG shapefiles. We examined drive times vs. ACS characteristics using multinomial regression and mapping. Results: We categorized CBGs by centroid-ED travel time in minutes: <10 (73.4%; n=6,774), 10-30 (25.1%; n=2,315), and >30 (1.5%; n=141). CBGs with increased median age, Hispanic and non-Hispanic Black population, and college graduation rates had significantly decreased travel time. CBGs with increased low-income populations (adjusted odds ratio [AOR] [1.03], 95% confidence interval [CI] [1.01-1.04]) and vacant housing (AOR [1.06], 95% CI [1.05-1.08]) had increased odds of >30 minute travel time. Conclusion: Use of fine-scale geographic analysis and population data can be used to evaluate geographic accessibility and utilization of EDs. Methods described offer guidance to approaching questions of geographic accessibility and have numerous ED and pre hospital applications. PMID- 30429941 TI - Bundled HIV and Hepatitis C Testing in the Emergency Department: A Randomized Controlled Trial. AB - Introduction: An estimated 25% of the 1.2 million individuals living with human immunodeficiency virus (HIV) in the U.S. are co-infected with hepatitis C (HCV). The Centers for Disease Control and Prevention recommends HCV testing for high risk groups. Our goal was to measure the impact of bundled HIV and HCV testing vs. HIV testing alone on test acceptance and identification of HCV and HIV. Methods: We conducted a two-armed, randomized controlled trial on a convenience sample of 478 adult patients in the Jacobi Medical Center emergency department from December 2012 to May 2013. Participants were randomized to receive either an offer of bundled HIV/HCV testing or HIV testing alone. We compared the primary outcome, HIV test acceptance, between the two groups. Secondary outcomes included HIV and HCV prevalence, and HCV test acceptance, refusal, risk, and knowledge. Results: We found no significant difference in HIV test acceptance between the bundled HCV/HIV (91.8%) and HIV-only (90.6%) groups (p=0.642). There were also no significant differences in test acceptance based on gender, race, or ethnicity. A majority of participants (76.6%) reported at least one HCV risk factor. No participants tested positive for HIV, and one (0.5%) tested positive for HCV. Conclusion: Integrating bundled, rapid HCV/HIV testing into an established HIV testing program did not significantly impact HIV test acceptance. Future screening efforts for HCV could be integrated into current HIV testing models to target high-risk cohorts. PMID- 30429942 TI - Implementation of a Collaborative HIV and Hepatitis C Screening Program in Appalachian Urgent Care Settings. AB - Introduction: With the current hepatitis C (HCV) epidemic in the Appalachian region and the risk of human immunodeficiency virus (HIV) co-infection, there is a need for increased secondary prevention efforts. The purpose of this study was to implement routine HIV and HCV screenings in the urgent care setting through the use of an electronic medical record (EMR) to increase a provider's likelihood of testing eligible patients. Methods: From June 2017 through May 2018, EMR-based HIV and HCV screenings were implemented in three emergency department-affiliated urgent care settings: a local urgent care walk-in clinic; a university-based student health services center; and an urgent care setting located within a multi specialty clinic. EMR best practice alerts (BPA) were developed based on Centers for Disease Control and Prevention (CDC) guidelines and populated on registered patients who qualified to receive HIV and/or HCV testing. Patients were excluded from the study if they chose to opt out from testing or the provider deemed it clinically inappropriate. Upon notification of a positive HIV and/or HCV test result through the EMR, patient navigators (PNs) were responsible for linking patients to their first medical appointment. Results: From June 2017 through May 2018, 48,531 patients presented to the three urgent care clinics. Out of 27,230 eligible patients, 1,972 patients (7.2%) agreed to be screened for HIV; for HCV, out of 6,509 eligible patients, 1,895 (29.1%) agreed to be screened. Thirty-one patients (1.6%) screened antibody-positive for HCV, with three being ribonucleic acid confirmed positives. No patients in either setting were confirmed positive for HIV; however, two initially screened HIV-positive. PNs were able to link 17 HCV antibody-positive patients (55%) to their first appointment, with the remainder having a scheduled future appointment. Conclusion: Introducing an EMR based screening program is an effective method to identify and screen eligible patients for HIV and HCV in Appalachian urgent care settings where universal screenings are not routinely implemented. PMID- 30429943 TI - Erratum: This Article Corrects: "Coronary Disease in Emergency Department Chest Pain with Recent Negative Stress Testing". AB - [This corrects the article on p. 384 in vol. 11, PMID: 21079714.]. PMID- 30429944 TI - Upper Vault Septal Anatomy and Short Nasal Bone Syndrome: Implications for Rhinoplasty. AB - Introduction: This is a diagnostic study that investigates the clinical significance between patients with short and long nasal bones and the variation in upper septal composition that would delineate propensity for middle vault collapse. Methods: Computed tomographic scans of 16 female patients undergoing evaluation with sinus films were analyzed. Two measurements were taken from each scout image: nasal bone length and total nasal length. Patient scans were separated into 2 groups; patients whose nasal bone length was less than one-half their total nasal length were defined as patients with "short nasal bone" (n = 8), and those with nasal bones longer than one-half the length of their noses were defined as patients with "long nasal bone" (n = 8). Results: Key differences were identified between patients with short and long nasal bones. Total septal area in the upper vault was decreased in the short nasal bone group relative to that of the long nasal bone group (5.7 +/- 0.6 cm2 vs 8.1 +/- 1.0 cm2, P = .002). This was mainly the result of the decreased ethmoid bone component in the short nasal bone group when compared with the long nasal bone group (1.6 +/- 0.6 cm2 vs 3.2 +/- 0.8 cm2, P = .007). PMID- 30429945 TI - Transforming Computational Drug Discovery with Machine Learning and AI. AB - In this Viewpoint, we discuss the current progress in applications of machine learning (ML) and artificial intelligence (AI) to meet the challenges of computational drug discovery. We identify several areas where existing methods have the potential to accelerate pharmaceutical research and disrupt more traditional approaches. PMID- 30429946 TI - Daedal Facets of Splice Modulator Optimization. AB - The spliceosome has been shown to be a promising target for the development of new anticancer therapeutics. Synthetic and chemical biological efforts directed toward the development of natural product-based splice modulators (SPLMs) have shown that the potency of these compounds derives from their ability to selectively affect the alternate splicing of apoptotic genes in tumor cells. However, questions remain regarding the mechanistic understanding of splice modulation as well as the selectivity with which SPLMs impact certain genes. PMID- 30429947 TI - Kinase Inhibitors for Treatment of Cancer and Inflammation. PMID- 30429948 TI - Optimization of Phenyl Indole Inhibitors of the AAA+ ATPase p97. AB - Optimization of the side-chain of a phenyl indole scaffold identified from a high throughput screening campaign for inhibitors of the AAA+ ATPase p97 is reported. The addition of an N-alkyl piperazine led to high potency of this series in a biochemical assay, activity in cell-based assays, and excellent pharmaceutical properties. Molecular modeling based on a subsequently obtained cryo-EM structure of p97 in complex with a phenyl indole was used to rationalize the potency of these allosteric inhibitors. PMID- 30429949 TI - Discovery and Pharmacology of a Novel Somatostatin Subtype 5 (SSTR5) Antagonist: Synergy with DPP-4 Inhibition. AB - We report new SSTR5 antagonists with enhanced potency, subtype selectivity, and minimal off-target activities as compared to previously reported compounds. Starting from the reported SSTR5 antagonist 1, we systematically surveyed changes in the central core and head piece while maintaining the diphenyl tail group constant. From this study the azaspirodecanone 10 emerged as a new highly potent and selective SSTR5 antagonist. Compound 10 lowered glucose excursion by 94% in an oral glucose tolerance test (OGTT) in mice following a 3 mg/kg oral dose. The compound increased both total and active circulating incretin hormone GLP-1 levels in mice at a dose of 10 mg/kg. A synergistic effect was also demonstrated when compound 10 was coadministered with a DPP-4 inhibitor, substantially increasing circulating active GLP-1[7-36] amide and insulin in response to a glucose challenge. PMID- 30429950 TI - Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5 Selective Antagonists. AB - A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound 1 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 13 demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies. In this Communication, we discuss the relationship among structure, in vitro and in vivo activity, metabolic stability, and ultimately the potential of these compounds as therapeutic agents for the treatment of type 2 diabetes. Furthermore, we show how the use of focused libraries significantly expanded the structural class and provided new directions for structure-activity relationship optimization. PMID- 30429951 TI - Interaction of Half Oxa-/Half cis-Platin Complex with Human Superoxide Dismutase and Induced Reduction of Neurotoxicity. AB - The formation of amorphous protein aggregates containing human superoxide dismutase (hSOD1) is thought to be involved in amyotrophic lateral sclerosis onset. cis-Platin inhibits the oligomerization of apo hSOD1, but its toxicity precludes any possible use in therapy. Herein, we propose a less toxic platinum complex, namely oxa/cis-platin, as hSOD1 antiaggregation lead compound. Oxa/cis platin is able to interact with hSOD1 in the disulfide oxidized apo form by binding cysteine 111 (Cys111). The mild neurotoxic phenomena induced in vitro and in vivo by oxa/cis-platin can be successfully reverted by using lypoyl derivatives, which do not interfere with the antiaggregation properties of the platin derivative. PMID- 30429952 TI - 2-Aminoadipic Acid-C(O)-Glutamate Based Prostate-Specific Membrane Antigen Ligands for Potential Use as Theranostics. AB - The design and synthesis of prostate specific membrane antigen (PSMA) ligands derived from 2-aminoadipic acid, a building block that has not previously been used to construct PSMA ligands, are reported. The effects of both the linker length and of an N-substituent of our PSMA ligands were probed, and X-ray structures of five of these ligands bound to PSMA were obtained. Among the ligands disclosed herein, 13b showed the highest inhibitory activity for PSMA. As ligand 13b can readily be radiolabeled since its fluorine atom is adjacent to the nitrogen atom of its pyridine ring, the use of this and related compounds as theranostics can be pursued. PMID- 30429953 TI - Synthesis of Cyanoenone-Modified Diterpenoid Analogs as Novel Bmi-1-Mediated Antitumor Agents. AB - Bmi-1 is overexpressed in colorectal cancer (CRC) and served as a novel therapeutic target for the treatment of CRC. A series of novel cyanoenone modified diterpenoid analogs was synthesized and investigated for their antiproliferative activity against CRC cells. The results showed that most of these compounds exhibited potent antiproliferative and Bmi-1 inhibitory activity. Among them, the most active compound 33 (SH498) showed more potent antiproliferative activity than the positive control compound PTC-209. These synthetic diterpenoid analogs were less toxic for normal human fibroblasts (HAF) than for CRC cells. Especially 33, its selectivity index (SI) between HAF and tumor cells was 7.3-13.1, which was much better than PTC-209. The polycomb repressive complex 1 (PRC1) complex, transwell migration, colony formation, cancer stem cell proliferation, and apoptosis assays of 33 were performed on CRC cell lines. The in vivo antitumor effect of 33 was also observed in HCT116 tumor bearing mice. PMID- 30429954 TI - Structure-Property Relationship Studies of Influenza A Virus AM2-S31N Proton Channel Blockers. AB - Majority of current circulating influenza A viruses carry the S31N mutation in their M2 genes, rendering AM2-S31N as a high profile antiviral drug target. With our continuous interest in developing AM2-S31N channel blockers as novel antivirals targeting both oseltamivir-sensitive and -resistant influenza A viruses, we report herein the structure-property relationship studies of AM2-S31N inhibitors. The goal was to identify lead compounds with improved microsomal stability and membrane permeability. Two lead compounds, 10d and 10e, were found to have high mouse and human liver microsomal stability (T 1/2 > 145 min) and membrane permeability (>200 nm/s). Both compounds also inhibit both currently circulating oseltamivir-sensitive and -resistant human influenza A viruses (H1N1 and H3N2) with EC50 values ranging from 0.4 to 2.8 MUM and a selectivity index of >100. We also showed for the first time that AM2-S31N channel blockers such as 10e inhibited influenza virus replication at both low and high multiply of infection (102-106 pfu/mL) and the inhibition was not cell-type dependent. Overall, these studies have identified two promising lead candidates for further development as antiviral drugs against drug-resistant influenza A viruses. PMID- 30429955 TI - Discovery of 4-Azaindole Inhibitors of TGFbetaRI as Immuno-oncology Agents. AB - The multifunctional cytokine TGFbeta plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFbeta signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFbeta receptor kinase inhibitors with excellent selectivity for TGFbeta receptor 1 kinase. The combination of compound 3f and an antimouse-PD-1 antibody demonstrated significantly improved antitumor efficacy compared to either treatment alone in a murine tumor model. PMID- 30429956 TI - Discovery of JND3229 as a New EGFRC797S Mutant Inhibitor with In Vivo Monodrug Efficacy. AB - EGFRC797S mutation inducing resistance against third generation EGFR inhibitor drugs is an emerging "unmet clinical need" for nonsmall cell lung cancer patients. The pyrimidopyrimidinone derivative JND3229 was identified as a new highly potent EGFRC797S inhibitor with single digit nM potency. It also exhibited good in vitro and in vivo monodrug anticancer efficacy in a xenograft mouse model of BaF3/EGFR19D/T790M/C797S cells. A high-resolution X-ray crystallographic structure was also determined to elucidate the interactions between JND3229 and EGFRT790M/C797S. Our study provides an important structural and chemical basis for future development of new generation EGFRC797S inhibitors as anticancer drugs. PMID- 30429957 TI - Synthesis of Artemisinin-Estrogen Hybrids Highly Active against HCMV, P. falciparum, and Cervical and Breast Cancer. AB - Artemisinin-estrogen hybrids were for the first time both synthesized and investigated for their in vitro biological activity against malaria parasites (Plasmodium falciparum 3D7), human cytomegalovirus (HCMV), and a panel of human malignant cells of gynecological origin containing breast (MCF7, MDA-MB-231, MDA MB-361, T47D) and cervical tumor cell lines (HeLa, SiHa, C33A). In terms of antimalarial efficacy, hybrid 8 (EC50 = 3.8 nM) was about two times more active than its parent compound artesunic acid (7) (EC50 = 8.9 nM) as well as the standard drug chloroquine (EC50 = 9.8 nM) and was, therefore, comparable to the clinically used dihydroartemisinin (6) (EC50 = 2.4 nM). Furthermore, hybrids 9-12 showed a strong antiviral effect with EC50 values in the submicromolar range (0.22-0.38 MUM) and thus possess profoundly stronger anti-HCMV activity (approximately factor 25) than the parent compound artesunic acid (7) (EC50 = 5.41 MUM). These compounds also exerted a higher in vitro anti-HCMV efficacy than ganciclovir used as the standard of current antiviral treatment. In addition, hybrids 8-12 elicited substantially more pronounced growth inhibiting action on all cancer cell lines than their parent compounds and the reference drug cisplatin. The most potent agent, hybrid 12, exhibited submicromolar EC50 values (0.15-0.93 MUM) against breast cancer and C33A cell lines. PMID- 30429959 TI - Evaluation of Enzyme Substrate Radiotracers as PET/MRS Hybrid Imaging Agents. AB - The development of a positron emission tomography (PET)/magnetic resonance spectroscopy (MRS) hybrid imaging agent allows for functional imaging by both methods with a single imaging agent. Enzyme substrates that are cleaved to form two metabolites present an interesting opportunity, as the unique metabolites generated might each be detected by a different modality. To be successful, such enzyme substrates would require administration of doses that (a) reach the in vivo target tissue at concentrations necessary for MRS imaging, (b) do not show substrate inhibition of tissue uptake or enzymatic activity, and (c) provide PET images that still reflect the action of the enzyme. We report in vitro and in vivo proof-of-concept studies of a carbon-11 small molecule substrate for brain monoamine oxidases that, upon enzyme-mediated cleavage, produces two metabolites, one detectable by PET and the other by MRS. PMID- 30429958 TI - Prediction of Drug-Target Binding Kinetics by Comparative Binding Energy Analysis. AB - A growing consensus is emerging that optimizing the drug-target affinity alone under equilibrium conditions does not necessarily translate into higher potency in vivo and that instead binding kinetic parameters should be optimized to ensure better efficacy. Therefore, in silico methods are needed to predict the kinetic parameters and the mechanistic determinants of drug-protein binding. Here we demonstrate the application of COMparative BINding Energy (COMBINE) analysis to derive quantitative structure-kinetics relationships (QSKRs) for the dissociation rate constants (k off) of inhibitors of heat shock protein 90 (HSP90) and HIV-1 protease. We derived protein-specific scoring functions by correlating k off rate constants with a subset of weighted interaction energy components determined from the energy-minimized structures of drug-protein complexes. As the QSKRs derived for these sets of chemically diverse compounds have good predictive ability and provide insights into important drug-protein interactions for optimizing k off, COMBINE analysis offers a promising approach for binding kinetics-guided lead optimization. PMID- 30429960 TI - B-973, a Novel alpha7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation. AB - We report here the total synthesis of B-973 (five steps), a recently identified alpha7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X ray crystallography studies revealed its absolute "S" stereochemistry. B-973B was effective in attenuating pain behavior and decreasing paw edema (formalin test), and its analgesic effects were mediated through alpha7 nAChR. PMID- 30429961 TI - Mandibular Midline Distraction Osteogenesis with a Bone-borne, Tooth-borne or Hybrid Distraction Appliance: a Systematic Review. AB - Objectives: The objective of the present systematic review was to assess the transverse skeletal and dental arch expansion and relapse after mandibular midline distraction osteogenesis with a bone-borne, tooth-borne or hybrid distraction appliance. Material and Methods: A MEDLINE (PubMed), Embase and Cochrane library search in combination with a hand-search of relevant journals was conducted. Human studies published in English until the 3rd of July, 2018 were included. Results: Two comparative and seven non-comparative studies characterized by high risk of bias fulfilled the inclusion criteria. Transverse mandibular widening was achieved with the different types of distraction appliance displaying a horizontal V-shaped opening with larger anterior transverse expansion declining progressively towards the posterior part of the mandible. Bone-borne and hybrid appliance facilitate more skeletal expansion compared with tooth-borne appliance, whereas comparable dental arch expansion was achieved with the different types of distraction appliance. Skeletal and dental arch relapse with the different type of appliance was limited and comparable. However, frequency of complications was higher with bone-borne appliance compared with tooth-borne or hybrid appliance. Conclusions: Mandibular midline distraction osteogenesis with bone-borne, tooth-borne or hybrid distraction appliance is an effective treatment modality to correct severe transverse mandibular discrepancies, although the skeletal and dental arch expansion pattern was dissimilar with the different types of appliance. However, dissimilar evaluation methods, different outcome measures, various methodological confounding factors posed serious restrictions reviewing the literature in a quantitative systematic manner. Hence, well-designed long-term randomized controlled trials applying three-dimensional technology, patient-related outcome measures and an economic perspective are needed before definite conclusions can be provided. PMID- 30429962 TI - Dental Implant Placement in Patients on Bisphosphonate Therapy: a Systematic Review. AB - Objectives: The review aims to study dental implant placement purposefulness for patients who have been treated or are on treatment with bisphosphonate medication. Material and Methods: Structured search strategy was applied on electronic databases: MEDLINE, PubMed, PubMed Central and ResearchGate. Scientific publications in English between 2006 and 2017 were identified in accordance with inclusion, exclusion criteria. Publication screening, data extraction, and quality assessment were performed. Outcome measures included implant failure or implant-related osteonecrosis of the jaw. Results: In total, 32 literature sources were reviewed, and 9 of the most relevant articles that are suitable to the criteria were selected. Heterogeneity between the studies was found and no meta-analysis could be done. Five studies analysed intraoral bisphosphonate medication in relation with implant placement, three studies investigated intravenous bisphosphonate medication in relation with implant placement and one study evaluated both types of medication given in relation with implant placement. Patients with intraoral therapy appeared to have a better implant survival (5 implants failed out of 423) rate at 98.8% vs. patients treated intravenously (6 implants failed out of 68) at 91%; the control group compared with intraoral bisphosphonate group appeared with 97% success implant survival rate (27 implants failed out of 842), showing no significant difference in terms of success in implant placement. Conclusions: Patients treated with intravenous bisphosphonates seemed to have a higher chance of developing implant related osteonecrosis of the jaw. The intraorally treated patient group appeared to have more successful results. Implant placement in patients treated intraorally could be considered safe with precautions. PMID- 30429963 TI - Effect of Implant Location on Palateless Complete Overdenture Retention: an In Vitro Study. AB - Objectives: The purpose of this in vitro study was to evaluate effect of implant location on initial retention values of palateless complete overdentures retained by four o-rings at different inter-implant distances. Material and Methods: Two standard acrylic models representing completely edentulous maxillary arches were used. Four single piece ball type implants were placed in each model. Models were divided into two groups according to the distance between anterior and posterior implants. Two canine implants with 32 mm inter-implant distance were placed in both models. In one model (G1), two posterior implants were placed in second premolar region away from canine implants by 14 mm on both sides, while in the other model (G2), the two posterior implants were placed in first molar region away from canine implants by 22 mm on both sides. Eighteen palateless complete overdentures were constructed for each model. Overdentures were retained by four o-rings. Initial axial (central), and para-axial (anterior, posterior, and lateral) retention values of overdentures were estimated and compared using a universal testing machine. Results: Independent t-test revealed that implant location has a significant role in palateless complete overdenture retention with a level of significance set at P < 0.05. Conclusions: For in vitro simulated palateless implant overdentures retained by four o-rings, increasing the inter implant distance between anterior and posterior implants is favourable for a more retentive prosthesis. PMID- 30429964 TI - Short Dental Implants (6 mm) Versus Standard Dental Implants (10 mm) Supporting Single Crowns in the Posterior Maxilla and/or Mandible: 2-Year Results from a Prospective Cohort Comparative Trial. AB - Objectives: The purpose of present study was to compare short (6 mm) with longer implants with the same surface use in the posterior maxilla and/or mandible. Material and Methods: A total of 110 implants of 6 or 10 mm in length were placed with an internal hex (n = 60) and with a conical connection (n = 50) but the same material, surface and design, supporting single crowns in the posterior maxilla and/or mandible. Outcomes measured were implant survival and marginal bone level changes up to 24 months after loading. Results: Final group consisted of 105 implants: 6 mm (n = 58) and 10 mm (n = 47). Success rate after 24 months was similar between treatment groups (98.3% vs. 100%; P = 0.361). Failure rates of the short implants in mandible (1/18, 5.6%) and in maxilla (0/40, 0%) were also not significantly different (P = 0.133). Success rate after 2 years was similar between internal hex vs. conical connection implants (100% vs. 97.7%; P = 0.233). Subjects lost statistically significant marginal peri-implant bone in both groups, but without differences (6 mm group: 0.38 mm [95% CI = 0.09 to 0.67] vs. 10 mm group: 0.43 mm [95% CI = 0.15 to 0.61]; P = 0.465 at 24 months), in relation also to type of implant (internal hex vs. conical, P = 0.428 at 24 months) or operator (P = 0.875 at 24 months). Conclusions: Short implants may be successful in the posterior areas during the first 24 months of loading, with similar outcomes to 10 mm long implants, supporting their use as a valid option in selected cases. However, larger and longer follow-ups of 5 years or more are needed. PMID- 30429965 TI - Is Articaine More Potent than Mepivacaine for Use in Oral Surgery? AB - Objectives: To investigate the potency and speed of action of 4% articaine and 2% mepivacaine for maxillary teeth extractions. Material and Methods: Ninety-four patients, aged between 16 to 70 years old, were recruited in this study. Two regimens were randomly administered over one visit. Patients of treatment group 1 received mepivacaine 2% with 1:100,000 adrenaline, whereas treatment group 2 - articaine 4% with 1:100,000 adrenaline. The onset time of pulp anaesthesia for maxillary teeth indicated for extraction was determined by electronic pulp testing. At any point of trial (10 minutes), the anesthetized tooth becomes unresponsive for maximal pulp stimulation (64 reading), the extraction was carried out. Results: In this study, 85 patients had successful local anaesthetic followed by extraction within the study duration time (10 min). However, 5 patients had failed dental extraction (4 in mepivacaine group and 1 in articaine group). Patients in the articaine buccal infiltration group recorded faster onset time of action regarding anaesthesia and teeth extraction than patients in mepivacaine buccal infiltration group (P = 0.03). Conclusions: Articaine is an effective anaesthetic with a rapid onset, comparable to mepivacaine in infiltrative techniques used for maxillary teeth extraction. However, articaine has clinically achieved faster dental anaesthesia and earlier teeth extraction than mepivacaine. So, articaine can be the local anaesthetic of first choice in oral surgery. PMID- 30429966 TI - Porphyrins as ligands for 64copper: background and trends. AB - Porphyrins and 64Cu have emerged as a novel synergic option for applications in PET molecular imaging. Both the characteristics and photophysical properties of macrocyclic porphyrins and the relatively long half-life of the copper isotope, in addition to the increased tumor-specific uptake of porphyrins compared to normal cells, make this complex an attractive option not only for diagnosis but also for therapeutic applications. Herein, we present an overview of the latest results on the development of PET agents based on porphyrins and 64Cu, including methods used to improve the selectivity of these macrocycles when conjugated with biological units such as monoclonal antibodies, peptides or proteins. PMID- 30429968 TI - Identification of an auxiliary druggable pocket in the DNA gyrase ATPase domain using fragment probes. AB - Discovery of new drug binding sites on well-established targets is of great interest as it facilitates the design of new mechanistic inhibitors to overcome the acquired drug resistance. Small chemical fragments can easily enter and bind to the cavities on the protein surface. Thus, they can be used to probe new druggable pockets in proteins. DNA gyrase plays indispensable roles in DNA replication, and both its GyrA and GyrB subunits are clinically validated antibacterial targets. New mechanistic GyrB inhibitors are urgently desired since the withdrawal of novobiocin from the market by the FDA due to its reduced efficiency and other reasons. Here, a fragment library was screened against the E. coli GyrB ATPase domain by combining affinity- and bioactivity-based approaches. The following X-ray crystallographic efforts were made to determine the cocrystal structures of GyrB with ten fragment hits, and three different binding modes were disclosed. Fortunately, a hydrophobic pocket which is previously unknown was identified by two fragments. Fragments that bind to this pocket were shown to inhibit the ATPase activity as well as the DNA topological transition activity of DNA gyrase in vitro. A set of fragment analogs were screened to explore the binding capacity of this pocket and identify the better starting fragments for lead development. Phylogenetic analysis revealed that this pocket is conserved in most Gram-negative and also many Gram-positive human pathogenic bacteria, implying a broad-spectrum antibacterial potential and a lower risk of mutation. Thus, the novel druggable pocket and the starting fragments provide a novel basis for designing new GyrB-targeting therapeutics. PMID- 30429967 TI - Medicinal chemistry of acridine and its analogues. AB - 'Acridine' along with its functional analogue 'Acridone' is the most privileged pharmacophore in medicinal chemistry with diverse applications ranging from DNA intercalators, endonuclease mimics, ratiometric selective ion sensors, and P glycoprotein inhibitors in countering the multi-drug resistance, enzyme inhibitors, and reversals of neurodegenerative disorders. Their interaction with DNA and ability of selectively identifying numerous biologically useful ions has cemented exploitability of the acridone nucleus in modern day therapeutics. Additionally, most derivatives and salts of acridine are planar, crystalline, and stable displaying a strong fluorescence which, when coupled with their marked bio selectivity and low cytotoxicity, enables the studying and monitoring of several biochemical, metabolic, and pharmacological processes. In this review, a detailed picture covering the important therapeutic aspects of the acridone nucleus and its functional analogues is discussed. PMID- 30429969 TI - Platinum(ii) complexes with rutaecarpine and tryptanthrin derivatives induce apoptosis by inhibiting telomerase activity and disrupting mitochondrial function. AB - Four new platinum(ii) complexes, [Pt(Rut)(DMSO)Cl2] (Rut-Pt), [Pt(Try)(DMSO)Cl2] (Try-Pt), [Pt(ITry)(DMSO)Cl2] (ITry-Pt) and [Pt(BrTry)(DMSO)Cl2] (BrTry-Pt), with rutaecarpine (Rut), tryptanthrin (Try), 8-iodine-tryptanthrin (ITry) and 8-bromo tryptanthrin (BrTry) as ligands were synthesized and fully characterized. In these complexes, the platinum(ii) adopts a four-coordinated square planar geometry. The inhibitory activity evaluated by the MTT assay showed that BrTry-Pt (IC50 = of 0.21 +/- 0.25 MUM) could inhibit the growth of T-24 tumor cells (human bladder cancer cell line) more so than the other three complexes. In addition, all of these Pt complexes exhibited low toxicity against non-cancerous HL-7702 cells. BrTry-Pt induced cell cycle arrest in the S phase, leading to the down regulation of cyclin A and CDK2 proteins. BrTry-Pt acts as a telomerase inhibitor targeting the c-myc promoter. In addition, BrTry-Pt also caused mitochondrial dysfunction. Importantly, the in vitro anticancer activity of BrTry-Pt was higher than those of Rut-Pt, Try-Pt and ITry-Pt, and it was more selective for T-24 cells than for non-cancerous HL-7702 cells. PMID- 30429971 TI - Copper(ii) complexes based on quinoline-derived Schiff-base ligands: synthesis, characterization, HSA/DNA binding ability, and anticancer activity. AB - Three copper(ii) complexes, [Cu(L1)(NO3)2] (C1), [Cu(L2)Cl2] (C2) and [Cu(L2)SO4]2.H2O (C3), were designed and synthesized by the reaction of Cu(NO3)2.3H2O, CuCl2.2H2O and CuSO4.5H2O with a quinoline-derived Schiff base ligand, L1 or L2, prepared by the condensation of quinoline-8-carbaldehyde with 4 aminobenzoic acid methyl ester or 4-aminobenzoic acid ethyl ester (benzocaine). The efficient bindings of the C1-C3 complexes with human serum albumin (HSA) and calf thymus DNA (CT-DNA) were analyzed by spectroscopy and molecular docking. These complexes could significantly quench the fluorescence of HSA through the static quenching process, and hydrophobic interactions with HSA through the sub domain IIA and IIIA cavities. The complexes bind to DNA via the intercalative mode and they fit well into the curved contour of the DNA target in the minor groove region. Furthermore, the interaction abilities of the Cu(ii) complexes with HSA/DNA were greater as compared to their corresponding ligands. Interestingly, C1-C3, particularly C3, exhibited more cytotoxicity toward HeLa cells compared to normal HL-7702 cells and three other tumor cell lines (Hep-G2, NCI-H460, and MGC80-3). Their cytotoxicity toward the HeLa cell lines was 1.9-3.5 fold more potent than cisplatin. Further studies indicated that these complexes arrested the cell cycle in the G0/G1 phase and promoted tumor cell apoptosis via a reactive oxygen species (ROS)-mediated mitochondrial pathway. PMID- 30429972 TI - On the inhibition of capsaicin response in dorsal root ganglion neurons by nobilamide B and analogues: a structure-activity relationship study. AB - Nobilamide B, a TRPV1 antagonist, and a series of Ala-substituted analogues were synthesized and their neuroactivity was assessed in a primary culture of dorsal root ganglion (DRG) neurons. Analogues 4, 6, and 7 showed comparable activity, affecting capsaicin response in neurons, in contrast to 2, 3, and 5 which showed minimal blocking. Compounds 2, 3, and 5 correspond to analogues in which d-Phe, d Leu and d-allo-Thr have been substituted with Ala, respectively. The observed loss of bioactivity in these three analogues highlights the importance of d amino acids in the primary structure of nobilamide B. PMID- 30429970 TI - Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents. AB - The natural products colchicine and combretastatin A-4 (CA4) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on beta-tubulin. A water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as KGP03) and a similar aroyl ring (referred to as KGP413) were potent inhibitors of tubulin polymerization (IC50 = 1.0 and 1.2 MUM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water solubility for in vivo evaluation, the corresponding phosphate prodrug salts (KGP04 and KGP152, respectively) were synthesized. In a preliminary in vivo study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of KGP152 (200 mg kg-1) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of KGP04 (15 mg kg-1). PMID- 30429973 TI - Novel 1,3,4-thiadiazole-chalcone hybrids containing catechol moiety: synthesis, antioxidant activity, cytotoxicity and DNA interaction studies. AB - Hybrid compounds that combine the 1,3,4-thiadiazole-containing catechol moiety with a chalcone motif were synthesized and examined for their antioxidant activity, cytotoxicity, and DNA-binding activity. A series of thirteen compounds showed strong antioxidant and cytotoxic effects on human acute promyelocytic leukemia HL-60 cells. Several compounds exerted good cytotoxic activities on cervical adenocarcinoma HeLa cells. The treatment of HeLa cells with IC50 and double IC50 concentrations of the compounds 5a, 5c, 5f, and 5m induced a statistically significant increase in the percentage of cells within a subG1 cell cycle phase. The examined compounds caused G2/M cell cycle arrest in HeLa cells. Each of these compounds triggered apoptosis in HeLa cells through activation of caspase-3, the main effector caspase, caspase-8, which is involved in the extrinsic apoptotic pathway, and caspase-9, which is involved in the intrinsic apoptotic pathway. All of the examined compounds decreased the expression levels of MMP2 in HeLa cells and levels of protumorigenic miR-133b. Compounds 5a and 5m lowered the expression level of oncogenic miR-21 in HeLa cells. In addition, compounds 5a, 5f, and 5m decreased the expression levels of oncogenic miR-155 while the treatment of HeLa cells with compounds 5a, 5c, and 5f increased expression of tumor-suppressive miR-206. Observed effects of these compounds on expression levels of four examined miRNAs suggest their prominent cancer suppressive activity. An investigation by absorption and fluorescence spectroscopy showed more efficient calf thymus DNA binding activity of the compound 5m in comparison to other tested compounds. Results of a pUC19 plasmid cleavage study and comet assay showed DNA damaging activities of compounds 5a and 5c. PMID- 30429974 TI - Structural optimization and antibacterial evaluation of rhodomyrtosone B analogues against MRSA strains. AB - Methicillin-resistant Staphylococcus aureus (MRSA) infections are well-known as a significant global health challenge. In this study, twenty-two congeners of the natural antibiotic rhodomyrtosone B (RDSB) were synthesized with the aim of specifically enhancing the structural diversity through modifying the pendant acyl moiety. The structure-activity relationship study against various MRSA strains revealed that a suitable hydrophobic acyl tail in the phloroglucinol scaffold is a prerequisite for antibacterial activity. Notably, RDSB analogue 11k was identified as a promising lead compound with significant in vitro and in vivo antibacterial activities against a panel of hospital mortality-relevant MRSA strains. Moreover, compound 11k possessed other potent advantages, including breadth of the antibacterial spectrum, rapidity of bactericidal action, and excellent membrane selectivity. The mode of action study of compound 11k at the biophysical and morphology levels disclosed that 11k exerted its MRSA bactericidal action by membrane superpolarization resulting in cell lysis and membrane disruption. Collectively, the presented results indicate that the novel modified RDSB analogue 11k warrants further exploration as a promising candidate for the treatment of MRSA infections. PMID- 30429975 TI - 7-Deacetyl-10-alkylthiocolchicine derivatives - new compounds with potent anticancer and fungicidal activity. AB - A series of new semi-synthetic 7-deacetyl-10-alkylthiocolchicne derivatives with ethyl, n-propyl, i-propyl and n-butyl substituents were synthesised and characterised by spectroscopic methods, elemental analysis, DFT calculations and molecular docking simulations. All the synthesized compounds have been tested for fungicidal and anticancer activities against SKOV-3, LoVo, MCF-7, MDA-MB-231 and the lung-derived fibroblast CCD39Lu. All the new colchicine derivatives exhibit significantly higher cytotoxicity towards the SKOV-3 tumour cell line than the natural product - colchicine. The most effective cytotoxic agents were 7-deacetyl 10-n-buthylthiocolchicine and 7-deacetyl-10-i-propylthiocolchicine. Among all the compounds tested, 7-deacetyl-10-n-buthylthiocolchicine exhibited the highest fungicidal activity. Molecular modeling indicated that several mutations found in the beta-tubulin unit of the tested fungal strains are crucial for antifungal activity and selectivity of 7-deacetyl-10-n-buthylthiocolchicine. The obtained results may be useful for the development of selective colchicine derivatives as effective fungicidal and/or anticancer drugs. PMID- 30429976 TI - Protective effects of astragaloside IV against hypoxic pulmonary hypertension. AB - The present study aimed to evaluate the protective effects of astragaloside IV (As-IV) against hypoxic pulmonary hypertension (HPH) and its mechanisms of action. Sprague-Dawley rats were used in a model of HPH induced by chronic hypoxia. After hypoxia, the mean pulmonary arterial pressure (mPAP), right ventricular pressure (RVP), and right ventricular hypertrophy index (RVHI) were monitored. Relaxation of the pulmonary artery in response to As-IV was measured. The levels of endothelin-1 (ET-1), angiotensin II (Ang II), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) in serum were assessed. Cell proliferation was detected by the cell counting kit-8 (CCK-8) assay. Treatment with As-IV significantly decreased mPAP, RVP and RV/(LV + S) and attenuated the development of HPH. Moreover, As-IV time-dependently relaxed the pulmonary arteries from HPH rats. In addition, As-IV decreased the levels of ET-1, Ang II, TNF-alpha, and IL-6 in serum of HPH rats. In vitro experiments demonstrated that As-IV also significantly inhibited the proliferation of pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia. Our findings suggested the therapeutic potential of As-IV in the treatment of pulmonary hypertension. PMID- 30429978 TI - Antiplasmodial imidazopyridazines: structure-activity relationship studies lead to the identification of analogues with improved solubility and hERG profiles. AB - 3,6-Diarylated imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go go-related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure-activity relationship studies of new imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency. While we identified new analogues with potent antiplasmodial activity (IC50 = 0.031 MUM against the NF54 drug-sensitive strain, and IC50 = 0.0246 MUM against the K1 multidrug resistant strain), hERG inhibition remained an issue. Excitingly, on the other hand, new analogues with a substantially improved hERG inhibition profile (IC50 = 7.83-32.3 MUM) with sub-micromolar antiplasmodial activity (NF54, IC50 = 0.151-0.922 MUM) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60-200 MUM) while also displaying sub-micromolar antiplasmodial potency (NF54, IC50 = 0.136-0.99 MUM). PMID- 30429977 TI - Novel hybrids derived from aspirin and chalcones potently suppress colorectal cancer in vitro and in vivo. AB - Colorectal cancer (CRC) remains the fourth leading cause of cancer deaths around the world despite the availability of many approved small molecules for treatment. The issues lie in the potency, selectivity and targeting of these compounds. Therefore, new strategies and targets are needed to optimize and develop novel treatments for CRC. Here, a group of novel hybrids derived from aspirin and chalcones were designed and synthesized based on recent reports of their individual benefits to CRC targeting and selectivity. The most active compound 7h inhibited proliferation of CRC cell lines with better potency compared to 5-fluorouracil, a currently used therapeutic agent for CRC. Importantly, 7h had 8-fold less inhibitory activity against non-cancer CCD841 cells. In addition, 7h inhibited CRC growth via the inhibition of the cell cycle in the G1 phase. Furthermore, 7h induced apoptosis by activating caspase 3 and PARP cleavage, as well as increasing ROS in CRC cells. Finally, 7h significantly retarded the CRC cell growth in a mouse xenograft model. These findings suggest that 7h may have potential to treat CRC. PMID- 30429979 TI - Synthesis and antiviral activity of camphor-based 1,3-thiazolidin-4-one and thiazole derivatives as Orthopoxvirus-reproduction inhibitors. AB - The Orthopoxvirus genus belongs to the Poxviridae family and includes variola virus (smallpox), cowpox virus, monkeypox virus and vaccinia virus (VV). Smallpox is considered one of the great epidemic disease scourges in human history. It has currently been eradicated; however, it remains a considerable threat as a biowarfare or bioterrorist weapon. The poxvirus, VV, serves as a model virus from which new antiviral therapies against Orthopoxviruses can be identified. Here, a series of nitrogen-sulphur containing heterocycles such as 1,3-thiazolidin-4-one and thiazoles containing a 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold were synthesized and screened for their antiviral activity. The bioassay results showed that the 4b, 4c and 4e thiazoles, which contained a substituted benzene ring, were able to inhibit VV reproduction with IC50 values in the 2.4-3.7 micromolar range whilst exhibiting moderate cytotoxicity. Among the thiazolidin-4 one derivatives, compound 8b, which contained a 4-methylbenzylidene group, displayed good inhibitory activity (IC50 = 9.5 MUM) and moderate toxicity. PMID- 30429980 TI - A zwitterionic near-infrared dye linked TrkC targeting agent for imaging metastatic breast cancer. AB - Much effort has been devoted to targeting agents for imaging and chemotherapy of tumors in cancer research, but there remain significant unmet needs in that area. We have reported a series of preclinical TrkC targeting agents for diagnoses and treatment of metastatic breast cancer; however, with respect to optical imaging, there are limitations to the agents already disclosed. In this work, a TrkC targeting fragment was equipped with a zwitterionic cyanine dye to give a near infrared probe for in vivo imaging of metastatic breast tumors, with excitation and emission wavelengths of 760 and 780 nm, respectively, and facilitate the aqueous dissolution of the final design. To our delight, the newly developed probe maintained the specific targeting to TrkC+ 4T1 metastatic breast tumor cells as well as the TrkC+ metastatic breast tumor tissue. Upon injection into 4T1-tumor-bearing mice, the tumor was visualized in vivo and ex vivo through the fluorescence signal of the probe. These data seem to encourage further investigations toward developing a TrkC targeting agent for the diagnosis of metastatic breast tumors. PMID- 30429981 TI - Development of a [68Ga]-ghrelin analogue for PET imaging of the ghrelin receptor (GHS-R1a). AB - The ghrelin receptor is a member of the growth hormone secretagogue receptor (GHS R) family and is present at low concentrations in tissues such as the brain, kidney, cardiovascular system, and prostate. The ghrelin receptor plays an important role in cellular proliferation, apoptosis, invasion, and migration associated with the progression of many cancers, including prostate, breast, ovarian, testicular, and intestinal carcinomas. Ghrelin, the endogenous ligand, is a 28 amino acid peptide (IC50 = 3.1 nM) known to have poor in vivo stability. Herein, we report the synthesis and evaluation of [Dpr3(octanoyl),Lys19(Ga DOTA)]ghrelin(1-19). This new ghrelin analogue has a binding affinity (IC50 = 5.9 nM) comparable to that of natural ghrelin. Preliminary in vivo evaluation shows higher uptake of [Dpr3(octanoyl),Lys19(68Ga-DOTA)]ghrelin(1-19) in HT1080/GHSR-1a xenografts than the non-transfected HT1080 xenografts in NOD-SCID mice, although considerable uptake is observed in the kidneys. This is the first example of ghrelin receptor PET imaging in a xenograft model using a peptide derived directly from the endogenous ligand and serves as motivation for developing more effective ghrelin-based radiopeptides. PMID- 30429983 TI - Double layer 3D codes: fluorescent supramolecular polymeric gels allowing direct recognition of the chloride anion using a smart phone. AB - Reported here is a two-layer gel construct that permits the on-site detection of the chloride anion by means of a hand-held UV-vis lamp and a smart phone "app". To prepare this system, eight fluorescent polymeric gels G1-G8 were synthesized. Gels G1-G4 containing C4P/imidazolium-F- anion recognition motifs were used to construct a fluorescent pattern (Code A) that may be read out by a smart phone as a 3D color code (Info A). Gels G5-G8, which are based on C4P/imidazolium-Br- anion interactions, were used to construct an array (Code B) that may be read as Info B. Code B was then adhered to the surface of Code A to produce an adhered double layer code system stabilized by interfacial C4P/imidazolium-Br- anion interactions. Readout of the top layer (Code B) could be achieved without interference from Code A. Treatment with a Cl- anion source was found to delaminate the top layer and leave intact the more robust bottom layer, allowing the bottom layer (Code A) to be read out. The disparate information content associated with Codes A and B thus permits the on-site recognition of Cl-. The present sensing strategy does not rely on elaborate instrumentation and could provide a new application for elaborated soft materials. PMID- 30429984 TI - Anion identification using silsesquioxane cages. AB - Anthracene-conjugated octameric silsesquioxane (AnSQ) cages, prepared via Heck coupling between octavinylsilsesquioxane (OVS) and 9-bromoanthracene, thermodynamically display intramolecular excimer emissions. More importantly, these hosts are sensitive to each anionic guest, thereby resulting in change of anthracene excimer formation, displaying the solvent-dependent fluorescence and allowing us to distinguish up to four ions such as F-, OH-, CN- and PO4 3- by fluorescence spectroscopy. Depending on the solvent polarity, for example, both F and CN- quenched the fluorescence emission intensity in THF, but only F- could enhance the fluorescence in all other solvents. The presence of PO4 3- results in fluorescence enhancements in high polarity solvents such as DMSO, DMF, and acetone, while OH- induces enhancements only in low polarity solvents (e.g. DCM and toluene). A picture of the anion recognizing ability of AnSQ was obtained through principal component analysis (PCA) with NMR and FTIR confirming the presence of host-guest interactions. Computational modeling studies demonstrate the conformation of host-guest complexation and also the change of excimer formation. Detection of F-, CN- and OH- by AnSQ hosts in THF is noticeable with the naked eye, as indicated by strong color changes arising from charge transfer complex formation upon anion addition. PMID- 30429982 TI - Charge carrier injection and transport engineering in two-dimensional transition metal dichalcogenides. AB - Ever since two dimensional-transition (2D) metal dichalcogenides (TMDs) were discovered, their fascinating electronic properties have attracted a great deal of attention for harnessing them as critical components in novel electronic devices. 2D-TMDs endowed with an atomically thin structure, dangling bond-free nature, electrostatic integrity, and tunable wide band gaps enable low power consumption, low leakage, ambipolar transport, high mobility, superconductivity, robustness against short channel effects and tunneling in highly scaled devices. However, the progress of 2D-TMDs has been hampered by severe charge transport issues arising from undesired phenomena occurring at the surfaces and interfaces. Therefore, this review provides three distinct engineering strategies embodied with distinct innovative approaches to optimize both carrier injection and transport. First, contact engineering involves 2D-metal contacts and tunneling interlayers to overcome metal-induced interface states and the Fermi level pinning effect caused by low vacancy energy formation. Second, dielectric engineering covers high-k dielectrics, ionic liquids or 2D-insulators to screen scattering centers caused by carrier traps, imperfections and rough substrates, to finely tune the Fermi level across the band gap, and to provide dangling bond free media. Third, material engineering focuses on charge transfer via substitutional, chemical and plasma doping to precisely modulate the carrier concentration and to passivate defects while preserving material integrity. Finally, we provide an outlook of the conceptual and technical achievements in 2D TMDs to give a prospective view of the future development of highly scaled nanoelectronic devices. PMID- 30429985 TI - Luminescent mesoporous nanorods as photocatalytic enzyme-like peroxidase surrogates. AB - Herein we report on a novel inorganic peroxidase-mimicking nanocatalyst activated under blue LED photoirradiation. A novel flash-pyrolysis method has been developed for the generation of strong blue photoluminescence (PL) centers attributed to silicon and carbon-based sites within a mesoporous SBA-15 silica nanorod platform. The type of centers and their PL response can be controlled by varying the flash thermal treatment conditions. By tailoring the operating conditions the system can be driven towards the preferential generation of carbon based luminescent centers, with or without the simultaneous generation of silicon based centers. The properties and the nature of these luminescent centers within the mesoporous nanorods have been thoroughly corroborated by a battery of characterization techniques including fluorescence spectroscopy, X-ray photoelectron spectroscopy (XPS) and electron energy loss spectroscopy (EELS) at the local level of the structures combined with scanning transmission electron microscopy (STEM) imaging. In addition, these luminescent mesoporous nanorods have been successfully tested as robust photocatalysts able to display peroxidase like activity and indirect glucose sensing in a wider range of pH conditions compared to the natural enzyme, especially when carbogenic dots and oxygen deficient silica centers are simultaneously present in the structure. PMID- 30429986 TI - High yield accelerated reactions in nonvolatile microthin films: chemical derivatization for analysis of single-cell intracellular fluid. AB - The identification of trace components from biological media can require derivatization under mild conditions for successful analysis by mass spectrometry (MS). When aqueous droplets (ca. 500 nL) containing a sugar and an amine as reagents are allowed to evaporate they may form long-lasting microthin films in which derivatization reactions can occur fast relative to reaction rates in bulk solution. Evidence is presented that these reactions are heterogeneous in nature and comparisons are made with reactions in pastes and in neat reagent mixtures. Moreover, these thin film reactors can be made stable for the long periods of time that may be necessary to give high product yields. The situation is typified by imine formation from reducing sugars which have reaction times of much more than 1 hour provided that small concentrations (e.g. 20 ppm) of nonvolatile solvents are included. After evaporation of almost all the water, the reaction occurs at an approximately constant rate for the first hour. The rate is two orders of magnitude faster than the reaction in the corresponding homogeneous saturated bulk solution. Conversion of the reagent to the Schiff base product is 67% to 96% efficient in these long-lasting thin films, in sharp contrast to the corresponding derivatization efficiencies in the bulk of less than 1%. This method was used to chemically derivatize and thus to identify, using tandem mass spectrometry, 29 reducing sugars in ca. 1 nL of intracellular fluid from a single onion epidermis cell. A formal description of the kinetics of reversible and irreversible second order reactions in thin films is provided. The effects of thermodynamic and kinetic factors are separated and the measured apparent acceleration factor is shown to represent the ratio of intrinsic rate constants for the microthin film reactor relative to the bulk reaction. PMID- 30429987 TI - Conformation of intrazeolitic choline ions and the framework topology of zeolite hosts. AB - The host-guest interactions in as-made zeolites Y, UZM-4, UZM-22, offretite, ferrierite, phillipsite, EU-12 and levyne, all of which were synthesized using choline as an organic structure-directing agent, have been investigated by a combination of different experimental techniques, including Raman, 1H-13C CP MAS NMR and variable-temperature IR spectroscopies, together with theoretical calculations. The conformation of this asymmetric quaternary ammonium cation was shown to differ significantly according to the pore topology of the zeolite host and the intrazeolitic location of the organic guest molecule. Theoretical calculations using the pure-silica zeolite model reveal that among its three representative conformers (i.e., gauche, trans and trans' forms), the conformer, which was experimentally found to dominantly or exclusively exist in zeolite structures studied, always has a lower interaction energy with the surrounding zeolite framework. Our work provides the first example in which the conformation of organic structure-directing agents plays an important kinetic role in governing the phase selectivity during zeolite nucleation. PMID- 30429988 TI - A chemical reporter facilitates the detection and identification of lysine HMGylation on histones. AB - Lysine 3-hydroxyl-3-methylglutarylation (HMG-K) is a newly identified PTM that can occur non-enzymatically in mitochondria. However, the substrate scope of this new PTM remains insufficiently explored, which has greatly hindered the progress in interpreting its regulatory mechanisms and cellular functions. Here, we report the development of an alkyne-functionalized chemical reporter (HMGAM-yne), for the detection and identification of cellular HMGylated proteins. HMGAM-yne is cell-permeable and metabolically incorporated into proteins in living cells. Subsequent biorthogonal conjugation enables fluorescence visualization and identification of the protein substrates of HMG-K. Using HMGAM-yne, we also identified Sirt5 as an 'eraser' that regulates HMGylation in cells. In addition to the known mitochondrial HMG-K proteins, HMGAM-yne facilitates the discovery of multiple nuclear proteins, including histones, as novel substrates of lysine HMGylation. PMID- 30429989 TI - A DNA nanowire based localized catalytic hairpin assembly reaction for microRNA imaging in live cells. AB - Here, we have developed a localized catalytic hairpin assembly (LCHA) strategy for intracellular miR-21 imaging by using DNA nanowires confining both hairpin probes in a compact space. The LCHA is constructed by interval hybridization of DNA hairpin probe pairs to a DNA nanowire with multiplex footholds generated by alternating chain hybridization. Compared to the conventional catalytic hairpin assembly (CHA) strategy, the LCHA significantly shortens the reaction time and enhances the sensitivity. Moreover, the proposed LCHA can serve as a carrier for delivery of probes into live cells as well as protect the probes from nuclease degradation and enhances the stability. We anticipate that this design can be widely applied in facilitating basic biomedical research and disease diagnosis. PMID- 30429990 TI - Understanding complex supramolecular landscapes: non-covalent macrocyclization equilibria examined by fluorescence resonance energy transfer. AB - As molecular self-assembled systems increase in complexity, due to a large number of participating entities and/or the establishment of multiple competing equilibria, their full understanding becomes likewise more complicated, and the use of diverse analytical techniques that can afford complementary information is required. We demonstrate in this work that resonance excitation energy transfer phenomena, measured by fluorescence spectroscopy in combination with other optical spectroscopies, can be a valuable tool to obtain supplementary thermodynamic data about complex supramolecular landscapes that other methods fail to provide. In particular, noncovalent macrocyclization processes of lipophilic dinucleosides are studied here by setting up a competition between intra- and intermolecular association processes of Watson-Crick H-bonding pairs. Multiwavelength analysis of the monomer emission changes allowed us to determine cyclotetramerization constants and to quantify chelate cooperativity, which was confirmed to be substantially larger for the G-C than for the A-U pair. Furthermore, when bithiophene-BODIPY donor-acceptor energy transfer probes are employed in these competition experiments, fluorescence and circular dichroism spectroscopy measurements in different regions of the visible spectrum additionally reveal intermolecular interactions occurring simultaneously at both sides of the macrocyclization reaction: the cyclic product, acting as a host for the competitor, and the monomer reactant, ultimately leading to macrocycle denaturation. PMID- 30429991 TI - Phosphorescent cationic iridium(iii) complexes dynamically bound to cyclodextrin vesicles: applications in live cell imaging. AB - We report cationic Ir(iii) complexes functionalized with adamantyl groups designed to bind to beta-cyclodextrin vesicles (CDV) with high affinity (K a = 1 * 106 M-1). The emission of the complexes is tuned by changing the nature of the cyclometalating ligands. The host-guest adduct of CDV and Ir(iii) complexes shows increased and significantly blue-shifted emission due to the lower mobility of the Ir(iii)-complexes residing in the less polar environment of the vesicle surface. Ir(iii)-decorated CDV are efficiently taken up by cells and can be used in live cell imaging. The CDV act as carriers to transport the phosphorescent complexes into cells where they selectively stain mitochondria. PMID- 30429992 TI - Rational design of red AIEgens with a new core structure from non-emissive heteroaromatics. AB - The development of new aggregation-induced emission (AIE) systems is a hot research topic, from which functional materials with diversified structures and properties are derived. Here, based on rare, non-emissive and highly electron withdrawing heteroaromatics of 1,4,5,8-tetraazaanthracene (TAA), experimental and theoretical studies reveal that attaching phenyl rotors to TAA is crucial to creating a new N-type AIE core structure. Furthermore, by covalent attachment of electron-donating aromatic amines to the peripheries of the AIE core, red AIEgens could be obtained readily, which exhibit excellent photostability for long-term lysosome tracking. This work not only provides a new strategy to design heterocycle-containing AIEgens from non-emissive heteroaromatics but also stimulates more their applications as bio-imaging materials. PMID- 30429993 TI - Live-cell labeling of endogenous proteins with nanometer precision by transduced nanobodies. AB - Accurate labeling of endogenous proteins for advanced light microscopy in living cells remains challenging. Nanobodies have been widely used for antigen labeling, visualization of subcellular protein localization and interactions. To facilitate an expanded application, we present a scalable and high-throughput strategy to simultaneously target multiple endogenous proteins in living cells with micro- to nanometer resolution. For intracellular protein labeling, we advanced nanobodies by site-specific and stoichiometric attachment of bright organic fluorophores. Their fast and fine-tuned intracellular transfer by microfluidic cell squeezing enabled high-throughput delivery with less than 10% dead cells. This strategy allowed for the dual-color imaging of distinct endogenous cellular structures, and culminated in super-resolution imaging of native protein networks in genetically non-modified living cells. The simultaneous delivery of multiple engineered nanobodies does not only offer exciting prospects for multiplexed imaging of endogenous protein, but also holds potential for visualizing native cellular structures with unprecedented accuracy. PMID- 30429994 TI - Selective C-H halogenation over hydroxylation by non-heme iron(iv)-oxo. AB - Non-heme iron based halogenase enzymes promote selective halogenation of the sp3 C-H bond through iron(iv)-oxo-halide active species. During halogenation, competitive hydroxylation can be prevented completely in enzymatic systems. However, synthetic iron(iv)-oxo-halide intermediates often result in a mixture of halogenation and hydroxylation products. In this report, we have developed a new synthetic strategy by employing non-heme iron based complexes for selective sp3-C H halogenation by overriding hydroxylation. A room temperature stable, iron(iv) oxo complex, [Fe(2PyN2Q)(O)]2+ was directed for hydrogen atom abstraction (HAA) from aliphatic substrates and the iron(ii)-halide [FeII(2PyN2Q)(X)]+ (X, halogen) was exploited in conjunction to deliver the halogen atom to the ensuing carbon centered radical. Despite iron(iv)-oxo being an effective promoter of hydroxylation of aliphatic substrates, the perfect interplay of HAA and halogen atom transfer in this work leads to the halogenation product selectively by diverting the hydroxylation pathway. Experimental studies outline the mechanistic details of the iron(iv)-oxo mediated halogenation reactions. A kinetic isotope study between PhCH3 and C6D5CD3 showed a value of 13.5 that supports the initial HAA step as the RDS during halogenation. Successful implementation of this new strategy led to the establishment of a functional mimic of non-heme halogenase enzymes with an excellent selectivity for halogenation over hydroxylation. Detailed theoretical studies based on density functional methods reveal how the small difference in the ligand design leads to a large difference in the electronic structure of the [Fe(2PyN2Q)(O)]2+ species. Both experimental and computational studies suggest that the halide rebound process of the cage escaped radical with iron(iii)-halide is energetically favorable compared to iron(iii) hydroxide and it brings in selective formation of halogenation products over hydroxylation. PMID- 30429995 TI - Activity-based ubiquitin-protein probes reveal target protein specificity of deubiquitinating enzymes. AB - Ubiquitination is an essential eukaryotic post-translational modification that regulates various cellular processes. The removal of ubiquitin from its target protein is catalyzed by deubiquitinating enzymes (DUBs). Although it was proposed that many DUBs specifically interact and recognize ubiquitinated proteins as substrates, more direct evidence is needed to support this notion. Here we report protein-targeting activity-based DUB probes that allowed the identification of DUBs recognizing monoubiquitinated proliferating cell nuclear antigen (PCNA) in Saccharomyces cerevisiae. This new class of DUB probes contain a Michael acceptor as a warhead between ubiquitin and the target protein PCNA through a linkage that mimics the native isopeptide bond. We selected two known and biologically relevant ubiquitination sites on PCNA to generate the DUB probes. This allowed us to interrogate the site-specific deubiquitination of a target protein by DUBs. DUBs were profiled in yeast cell lysates using the two Ub-PCNA DUB probes in conjunction with two control probes that contain a noncleavable linkage but no warhead. We identified yeast DUBs through pulldown coupled with quantitative mass spectrometry analysis of the pulled down proteins. Our results showed that specific yeast DUBs recognize monoubiquitinated PCNA and corroborated previous genetic study. We also identified DUBs as potential new deubiquitinase of PCNA. Remarkably, identified DUBs clearly distinguish the different modification sites on PCNA, thus supporting a high level of DUB specificity beyond the target protein identity. PMID- 30429996 TI - Alternating oligo(o,p-phenylenes) via ruthenium catalyzed diol-diene benzannulation: orthogonality to cross-coupling enables de novo nanographene and PAH construction. AB - Ruthenium(0) catalyzed diol-diene benzannulation is applied to the conversion of oligo(p-phenylene vinylenes) 2a-c, 5 and 6 to alternating oligo(o,p-phenylenes) 10a-c, 11-13. Orthogonality with respect to conventional palladium catalyzed biaryl cross-coupling permits construction of p-bromo-terminated alternating oligo(o,p-phenylenes) 10b, 11-13, which can be engaged in Suzuki cross-coupling and Scholl oxidation. In this way, structurally homogeneous nanographenes 16a-f are prepared. Nanographene 16a, which incorporates 14 fused benzene rings, was characterized by single crystal X-ray diffraction. In a similar fashion, p-bromo terminated oligo(p-phenylene ethane diol) 9, which contains a 1,3,5 trisubstituted benzene core, is converted to the soluble, structurally homogeneous hexa-peri-hexabenzocoronene 18. A benzothiophene-terminated pentamer 10c was prepared and subjected to Scholl oxidation to furnish the helical bis(benzothiophene)-fused picene derivative 14. The steady-state absorption and emission properties of nanographenes 14, 16a,b,d,e,h and 18 were characterized. These studies illustrate how orthogonality of ruthenium(0) catalyzed diol-diene benzannulation with respect to classical biaryl cross-coupling streamlines oligophenylene and nanographene construction. PMID- 30429998 TI - Multinuclear iron-phenyl species in reactions of simple iron salts with PhMgBr: identification of Fe4(MU-Ph)6(THF)4 as a key reactive species for cross-coupling catalysis. AB - The first direct syntheses, structural characterizations, and reactivity studies of iron-phenyl species formed upon reaction of Fe(acac)3 and PhMgBr in THF are presented. Reaction of Fe(acac)3 with 4 equiv. PhMgBr in THF leads to the formation of [FePh2(MU-Ph)]2 2- at -80 degrees C, which can be stabilized through the addition of N-methylpyrrolidone. Alternatively, at -30 degrees C this reaction leads to the formation of the tetranuclear iron-phenyl cluster, Fe4(MU-Ph)6(THF)4. Further synthetic studies demonstrate that analogous tetranuclear iron clusters can be formed with both 4-F-PhMgBr and p-tolylMgBr, illustrating the generality of this structural motif for reactions of simple ferric salts and aryl Grignard reagents in THF. Additional studies isolate and define key iron species involved in the synthetic pathway leading to the formation of the tetranuclear iron-aryl species. While reaction studies demonstrate that [FePh2(MU-Ph)]2 2- is unreactive towards electrophile, Fe4(MU Ph)6(THF)4 is found to rapidly react with bromocyclohexane to selectively form phenylcyclohexane. Based on this reactivity, a new catalytic reaction protocol has been developed that enables efficient cross-couplings using Fe4(MU Ph)6(THF)4, circumventing the current need for additives such as TMEDA or supporting ligands to achieve effective cross-coupling of PhMgBr and a secondary alkyl halide. PMID- 30429997 TI - Chemically stable ionic viologen-organic network: an efficient scavenger of toxic oxo-anions from water. AB - Detoxification of water has been demonstrated with a viologen-based cationic organic network (compound-1), which was stable not only in water, but also in acidic and basic media. The presence of free exchangeable Cl- ions inside the network of compound-1 and a high physiochemical stability of the materials offered a suitable scope for the capture of hazardous anionic pollutants from water. Rapid removal of the toxic water pollutant and carcinogenic chromate (CrO4 2-) from water was shown with compound-1. Furthermore, the oxo-anion of the radioactive isotope of technetium (99Tc), i.e. the TcO4 - ion, also counts as a toxic water pollutant and by using surrogate anions (MnO4 - and ReO4 -), a model capture study was performed. Notably, compound-1 showed high capacity values for each of the oxo-anions and these were comparable to some of the well-performing compounds reported in the literature. Furthermore, to check the real time aspect, removal of all of the aforementioned anions from water was demonstrated, even in the presence of other concurrent anions. PMID- 30429999 TI - Facile saccharide-free mimetics that recapitulate key features of glycosaminoglycan sulfation patterns. AB - Controlling glycosaminoglycan (GAG) activity to exploit its immense potential in biology ultimately requires facile manipulation of sulfation patterns associated with GAGs. However, satisfying this requirement in full remains challenging, given that synthesis of GAGs is technically arduous while convenient GAG mimetics often produce sulfation patterns that are uncharacteristic of GAGs. To overcome this, we develop saccharide-free polyproline-based GAG mimetics (PGMs) that can be facilely assembled via amide coupling chemistry. Molecular dynamics simulations show that PGMs recapitulate key GAG structural features (i.e. ~9 A sized repeating units, periodicity and helicity) and as with GAGs, can be tuned to introduce systematic variations in sulfate clustering and spacing. Functionally, a variety of PGMs control various GAG activities (concerning P selectin, neurotrophic factors and heparinase) and exhibit GAG-like characteristics such as progressive modulation, comparable effectiveness with heparins, need for different sequences to suit different activities and the presence of a "minimal bioactive length". Furthermore, PGMs produce consistent effects in vivo and successfully provide therapeutic benefits over cancer metastasis. Taken together with their high level of biosafety, PGMs answer the long-standing need for an effective and practicable strategy to manipulate GAG appropriate sulfation patterns and exploit GAG activity in medicine and biotechnology. PMID- 30430000 TI - Ultrafast interligand electron transfer in cis-[Ru(4,4'-dicarboxylate-2,2' bipyridine)2(NCS)2]4- and implications for electron injection limitations in dye sensitized solar cells. AB - Interligand electron transfer (ILET) of the lowest metal-to-ligand charge transfer (MLCT) state of N712 (cis-[Ru(dcb)2(NCS)2]4-, where dcb = 4,4' dicarboxylate-2,2'-bipyridine) in a deuterated acetonitrile solution has been studied by means of femtosecond transient absorption anisotropy in the mid-IR. Time-independent B3LYP density functional calculations were performed to assign vibrational bands and determine their respective transition dipole moments. The transient absorption spectral band at 1327 cm-1, assigned to a symmetric carboxylate stretch, showed significant anisotropy. A rapid anisotropy increase (tau 1 ~ 2 ps) was tentatively assigned to vibrational and solvent relaxation, considering the excess energy available after the excited singlet-triplet conversion. Thereafter, the anisotropy decayed to zero with a time constant tau 2 ~ 240 ps, which was assigned to the rotational correlation time of the complex in deuterated acetonitrile. No other distinctive changes to the anisotropy were observed and the amplitude of the slow component at time zero agrees well with that predicted for a random mixture of MLCT localization on either of the two dcb ligands. The results therefore suggest that MLCT randomization over the two dcb ligands occurs on the sub-ps time scale. This is much faster than proposed by previous reports on the related N3 complex [Benko et al., J. Phys. Chem. B, 2004, 108, 2862, and Waterland et al., J. Phys. Chem. A, 2001, 105, 4019], but in agreement with that found by Wallin and co-workers [J. Phys. Chem. A, 2005, 109, 4697] for the [Ru(bpy)3]2+ (bpy = 2,2'-bipyridine) complex. This suggests that electron injection from the excited dye into TiO2 in dye-sensitized solar cells is not limited by ILET. PMID- 30430001 TI - A one-step method for covalent bond immobilization of biomolecules on silica operated in aqueous solution. AB - A simple, one-step method for covalent bond immobilization of biomolecules on silica operated in water is described. In the approach, an NHS-ester linked methallylsilane is utilized as a bifunctional linker to couple the biomolecule to the silica surface. Weak organic acid such as acetic acid activates the silica surface enough to react with bifunctional linker without destroying activity of biomolecule. PMID- 30430002 TI - Graininess of RGB-Display Space. AB - RGB-display space, that is, the 'RGB-cube', was sampled at 3,000 locations, uniformly and randomly distributed. Fifty observers contributed 60 samples each. At each location, participants synthesised a copy of the target, using a generic colour picker. The statistical distributions of errors as a function of location are used to define an overall measure of graininess. A smooth field of interpolated three-dimensional covariance ellipsoids represents an explicit, empirical Riemannian metric. The unit step size is about 20 times larger than the size of the classical MacAdam ellipses. We speculate that this metric might be found useful in various settings involving applications, because it reflects typical fuzziness encountered in generic tasks involving colour patterns such as images. Some of the more obvious applications are discussed. PMID- 30430004 TI - Crystal structures of a llama VHH antibody BCD090-M2 targeting human ErbB3 receptor. AB - Background: The ability of ErbB3 receptor to functionally complement ErbB1-2 and induce tumor resistance to their inhibitors makes it a unique target in cancer therapy by monoclonal antibodies. Here we report the expression, purification and structural analysis of a new anti-ErbB3 single-chain antibody. Methods: The VHH fragment of the antibody was expressed in E. coli SHuffle cells as a SUMO fusion, cleaved by TEV protease and purified to homogeneity. Binding to the extracellular domain of ErbB3 was studied by surface plasmon resonance. For structural studies, the antibody was crystallized by hanging-drop vapor diffusion in two different forms. Results: We developed a robust and efficient system for recombinant expression of single-domain antibodies. The purified antibody was functional and bound ErbB3 with K D = 1 MUM. The crystal structures of the VHH antibody in space groups C2 and P1 were solved by molecular replacement at 1.6 and 1.9 A resolution. The high-quality electron density maps allowed us to build precise atomic models of the antibody and the putative paratope. Surprisingly, the CDR H2 existed in multiple distant conformations in different crystal forms, while the more complex CDR H3 had a low structural variability. The structures were deposited under PDB entry codes 6EZW and 6F0D. Conclusions: Our results may facilitate further mechanistic studies of ErbB3 inhibition by single-chain antibodies. Besides, the solved structures will contribute to datasets required to develop new computational methods for antibody modeling and design. PMID- 30430005 TI - shinySISPA: A web tool for defining sample groups using gene sets from multiple omics data. AB - As opposed to genome-wide testing of several hundreds of thousands of genes on very few samples, gene panels target as few as tens of genes and enable the simultaneous testing of many samples. For example, some cancer gene panels test for 50 genes that can affect tumor growth and potentially identify treatment options directed against the genetic mutation. The increasing popularity of gene panel testing has spurred the technological development of panels that test for diverse data types such as expression and mutation. Once samples are tested, there is the desire to examine clinical associations based on the panel and for this purpose, one would like to identify, among the samples tested, which show support for a molecular profile (e.g., presence of mutation with increased expression) versus those samples that do not among the genes tested. With user specified molecular profile of interest, and gene panel data matrices (e.g., gene expression, variants, etc.) that define the profile, shinySISPA (Sample Integrated Set Profile Analysis) is a web-based shiny tool to define two sample groups with and without profile support based on our previously published method from which clinical associations may be readily examined. The shinySISPA can be accessed from http://shinygispa.winship.emory.edu/shinySISPA/. PMID- 30430003 TI - Towards personalized medicine in Meniere's disease. AB - Meniere's disease (MD) represents a heterogeneous group of relatively rare disorders with three core symptoms: episodic vertigo, tinnitus, and sensorineural hearing loss involving 125 to 2,000 Hz frequencies. The majority of cases are considered sporadic, although familial aggregation has been recognized in European and Korean populations, and the search for familial MD genes has been elusive until the last few years. Detailed phenotyping and cluster analyses have found several clinical predictors for different subgroups of patients, which may indicate different mechanisms, including genetic and immune factors. The genes associated with familial MD are COCH, FAM136A, DTNA, PRKCB, SEMA3D, and DPT. At least two mechanisms have been involved in MD: (a) a pro-inflammatory immune response mediated by interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and IL-6, and (b) a nuclear factor-kappa B (NF-kappaB)-mediated inflammation in the carriers of the single-nucleotide variant rs4947296. It is conceivable that microbial antigens trigger inflammation with release of pro inflammatory cytokines at different sites within the cochlea, such as the endolymphatic sac, the stria vascularis, or the spiral ligament, leading to fluid imbalance with an accumulation of endolymph. Computational integration of clinical and "omics" data eventually should transform the management of MD from "one pill fits all" to precise patient stratification and a personalized approach. This article lays out a proposal for an algorithm for the genetic diagnosis of MD. This approach will facilitate the identification of new molecular targets for individualized treatment, including immunosuppressant and gene therapy, in the near future. PMID- 30430006 TI - Enterobacter hormaechei subsp. hoffmannii subsp. nov., Enterobacter hormaechei subsp. xiangfangensis comb. nov., Enterobacter roggenkampii sp. nov., and Enterobacter muelleri is a later heterotypic synonym of Enterobacter asburiae based on computational analysis of sequenced Enterobacter genomes. AB - Background: The predominant species in clinical Enterobacter isolates is E. hormaechei. Many articles, clinicians, and GenBank submissions misname these strains as E. cloacae. The lack of sequenced type strains or named species/subspecies for some clades in the E. cloacae complex complicate the issue. Methods: The genomes of the type strains for Enterobacter hormaechei subsp. oharae, E. hormaechei subsp. steigerwaltii, and E. xiangfangensis, and two strains from Hoffmann clusters III and IV of the E. cloacae complex were sequenced. These genomes, the E. hormaechei subsp. hormaechei type strain, and other available Enterobacter type strains were analysed in conjunction with all extant Enterobacter genomes in NCBI's RefSeq using Average Nucleotide Identity (ANI). Results: There were five recognizable subspecies of E. hormaechei: E. hormaechei subsp. hoffmannii subsp. nov., E. hormaechei subsp. xiangfangensis comb. nov., and the three previously known subspecies. One of the strains sequenced from the E. cloacae complex was not a novel E. hormaechei subspecies but rather a member of a clade of a novel species: E. roggenkampii sp. nov.. E. muelleri was determined to be a later heterotypic synonym of E. asburiae which should take precedence. Conclusion: The phylogeny of the Enterobacter genus, particularly the cloacae complex, was re-evaluated based on the type strain genome sequences and all other available Enterobacter genomes in RefSeq. PMID- 30430007 TI - Osteogenic potential of gingival stromal progenitor cells cultured in platelet rich fibrin is predicted by core-binding factor subunit-alpha1/Sox9 expression ratio ( in vitro). AB - Background: Alveolar bone defect regeneration has long been problematic in the field of dentistry. Gingival stromal progenitor cells (GSPCs) offer a promising solution for alveolar bone regeneration. In order to optimally differentiate and proliferate progenitor cells, growth factors (GFs) are required. Platelet rich fibrin (PRF) has many GFs and can be easily manufactured. Core-binding factor subunit-alpha1 (CBF-alpha1) constitutes a well-known osteogenic differentiation transcription factor in SPCs. Sox9, as a chondrogenic transcription factor, interacts and inhibits CBF-alpha1, but its precise role in direct in vitro osteogenesis remains unknown. GSPCs cultured in vitro in PRF to optimally stimulate osteogenic differentiation has been largely overlooked. The aim of this study was to analyze GSPCs cultured in PRF osteogenic differentiation predicted by CBF-alpha1/Sox9. Methods: This study used a true experimental with post-test only control group design and random sampling. GPSCs isolated from the lower gingiva of four healthy, 250-gram, 1-month old, male Wistar rats ( Rattus Novergicus) were cultured for two weeks, passaged every 4-5 days. GSPCs in passage 3-5 were cultured in five M24 plates (N=108; n=6/group) for Day 7, Day 14, and Day 21 in three different mediums (control negative group: alphaModified Eagle Medium; control positive group: High Glucose-Dulbecco's Modified Eagle Medium (DMEM-HG) + osteogenic medium; Treatment group: DMEM-HG + osteogenic medium + PRF). CBF-alpha1 and Sox9 were examined with ICC monoclonal antibody. A one-way ANOVA continued with Tukey HSD test (p<0.05) based on Kolmogorov-Smirnov and Levene's tests (p>0.05) was performed. Results: The treatment group showed the highest CBF-alpha1/Sox9 ratio (16.00+/-3.000/14.33+/-2.517) on Day 7, while the lowest CBF-alpha1/Sox9 ratio (3.33+/-1.528/3.67+/-1.155) occurred in the control negative group on Day 21, with significant difference between the groups (p<0.05). Conclusion: GSPCs cultured in PRF had potential osteogenic differentiation ability predicted by the CBF-alpha1/sox9 ratio. PMID- 30430008 TI - Effect of a multifaceted stewardship intervention on antibiotic prescribing and outcomes for acute bacterial skin and skin structure infections. AB - Background: Acute bacterial skin and skin structure infections (ABSSSI) are a leading cause of hospitalization, but are often treated inappropriately in the inpatient setting. A multifaceted stewardship intervention was implemented to encourage prescribing of guideline-concordant therapy (GCT). Objective: To examine the impact of this initiative on antimicrobial prescribing practices and patient outcomes. Methods: This was a single-center, retrospective study of adult inpatients admitted with a primary or secondary diagnosis of ABSSSI, classified by type and severity based on signs of systemic infection. Patients treated during the pre-intervention period (pre-IP) were compared with patients treated during the post-intervention period (post-IP). The primary endpoint was receipt of GCT. Secondary endpoints included receipt of anti-anaerobic antibiotic (AAA) or broad-spectrum antibiotics (BSA). Results: A total of 125 patients were included, 64 in the pre-IP and 61 in the post-IP. There was a statistically significant increase in prescribing of GCT during the post-IP compared with the pre-IP (14% versus 56%, p < 0.0001) and a decrease in use of AAA (56% versus 34%, p = 0.01). No difference was observed with use of BSA (16% versus 15%, p = 0.89). Use of the computerized order set during the post-IP was low (18%). There was a numerical, but non-significant reduction in 30-day readmission (14.1% versus 6.6%, p = 0.17). Conclusion: The multifaceted intervention was effective for improving prescribing of GCT for ABSSSI. Given low use of the computerized order set, improved prescribing seemed to be driven by provider education. Strategies around ongoing education may be key to sustain positive results of stewardship interventions. PMID- 30430009 TI - Extended duration vancomycin in recurrent Clostridium difficile infection: a systematic review. AB - Clostridium difficile infections have a high recurrence rate following acute treatment. Extended duration vancomycin (EDV) is a mainstay for the treatment of recurrent Clostridium difficile infections (rCDI). Clinical disease guidelines recommend a variety of different vancomycin treatment regimens though based on weak, low-quality evidence. Patients typically receive an initial vancomycin treatment course of 7-14 days for the acute infection, followed by an extended duration vancomycin course. Multiple publications on the utility of EDV regimens have been published but few include reported effectiveness outcomes associated with a prescribed treatment regimen. The purpose of this review is to evaluate the safety and efficacy data on extended duration vancomycin regimens used in recurrent clostridium treatment. Five articles, three case series and two randomized open-label clinical trials, were identified which included both elements. Outcomes were evaluable in 174 patients, 31 from randomized trials, with prior average recurrent episodes ranging from 3 to 4. Vancomycin dose ranged from 3500 to >6800 mg with therapy durations extending from 21 days to over 60 days. Follow-up duration ranged from 10 weeks to 12 months. Case series reported success rates for EDV in rCDI from 61% to 100%, while randomized trials found lower success rates from 26% to 58%. Taper and pulse regimens reported superior outcomes compared to pulse-only regimens, 58-100% versus 26-81%, respectively. Comparative EDV data is limited. Current available data supports an EDV regimen which includes both a daily dosing taper followed by an every 48 or 72 h pulse. PMID- 30430011 TI - Patient-derived organoids: a promising model for personalized cancer treatment. PMID- 30430012 TI - Diagnosis and management of floppy pouch complex. AB - Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for patients with refractory ulcerative colitis, colitis-associated dysplasia or familial adenomatous polyposis. There are various pouch disorders and associated complications. Floppy pouch complex is defined as the presence of pouch prolapse, afferent limb syndrome, enterocele, redundant loop and folding pouch on pouchoscopy, gastrografin pouchogram or defecography. Common clinical presentation includes dyschezia, bloating, abdominal pain, straining or the sense of incomplete evacuation. Each disorder has its own unique endoscopic, radiographic and manometry findings. A range of therapeutic options are available for the management of the various causes of a pouch. PMID- 30430010 TI - Variation among populations in the immune protein composition of mother's milk reflects subsistence pattern. AB - Lay Summary: Adaptive immune proteins in mothers' milk are more variable than innate immune proteins across populations and subsistence strategies. These results suggest that the immune defenses in milk are shaped by a mother's environment throughout her life. Background and objectives: Mother's milk contains immune proteins that play critical roles in protecting the infant from infection and priming the infant's developing immune system during early life. The composition of these molecules in milk, particularly the acquired immune proteins, is thought to reflect a mother's immunological exposures throughout her life. In this study, we examine the composition of innate and acquired immune proteins in milk across seven populations with diverse disease and cultural ecologies. Methodology: Milk samples (n = 164) were collected in Argentina, Bolivia, Nepal, Namibia, Philippines, Poland and the USA. Populations were classified as having one of four subsistence patterns: urban-industrialism, rural shop, horticulturalist-forager or agro-pastoralism. Milk innate (lactalbumin, lactoferrin and lysozyme) and acquired (Secretory IgA, IgG and IgM) protein concentrations were determined using triple-quadrupole mass spectrometry. Results: Both innate and acquired immune protein composition in milk varied among populations, though the acquired immune protein composition of milk differed more among populations. Populations living in closer geographic proximity or having similar subsistence strategies (e.g. agro-pastoralists from Nepal and Namibia) had more similar milk immune protein compositions. Agro-pastoralists had different milk innate immune protein composition from horticulturalist-foragers and urban-industrialists. Acquired immune protein composition differed among all subsistence strategies except horticulturist-foragers and rural-shop. Conclusions and implications: Our results reveal fundamental variation in milk composition that has not been previously explored in human milk research. Further study is needed to understand what specific aspects of the local environment influence milk composition and the effects this variation may have on infant health outcomes. PMID- 30430013 TI - Management of chronic hepatitis B during pregnancy. AB - Chronic hepatitis B is globally prevalent and is a major cause of cirrhosis and hepatocellular carcinoma. Despite immunoprophylaxis against hepatitis B in pregnancy, perinatal transmission still occurs in at least 10% of the children born to a mother with high level of viremia. Decisions regarding hepatitis B therapy during pregnancy must take into account the benefits and safety for both the mother and the unborn baby. In this review, we summarize the current treatment options for chronic hepatitis B with a focus on management during pregnancy and the evidence-based strategies to prevent vertical transmission of hepatitis B virus (HBV). PMID- 30430014 TI - Colorectal cancer resection rates in patients with inflammatory bowel disease: a population-based study. AB - Background and objective: Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC). This study aimed to analyse the trends in rates of resection for IBD-related CRC in the USA. Methods: We used the Nationwide Inpatient Sample from 1995 to 2012. Temporal trends in age-adjusted rates of resection for CRC in the setting of IBD were analysed using multivariate Joinpoint regression models. The primary outcome was surgical resection of CRC in the setting of IBD. Results: We included 3 597 168 IBD discharges in the present study, of which 275 479 underwent CRC resection between 1995 and 2012. The annual CRC resection rates among IBD population decreased significantly from 1995 to 2012. This decrease was significant in all age groups with an annual decrease of 393 (P < 0.001), 359 (P < 0.001), 293 (P < 0.001) and 159 (P < 0.001) per 100 000 IBD discharges between 1995 and 2012 for age groups 18-39, 40-49, 50-74 and >75 years, respectively. The annual IBD-CRC resection rate per 100 000 IBD discharges for proximal CRC decreased by 149 (P < 0.001), 130 (P < 0.001), 95 (P < 0.001) and 50 (P < 0.001), respectively, and the annual distal CRC resections per 100 000 IBD discharges decreased by 104 (P < 0.001), 123 (P < 0.001), 123 (P < 0.001) and 82 (P < 0.001), respectively, for age groups 18-39, 40-49, 50-74 and >75 years, between 1995 and 2012. On multivariate Poisson regression analysis, after adjustment for age and sex, CRC resections decreased by 3.9% each year from 1995 to 2012. Conclusions: CRC resection rates among IBD patients have continued to decrease annually from 1995 to 2012. There is a population-level decrease in resection of both proximal and distal CRC reflecting a decreasing incidence of IBD-related CRC incidence in the USA. PMID- 30430015 TI - Prognostic and predictive value of interstitial cells of Cajal populations following stapled transanal rectal resection (STARR) in patients with obstructed defecation syndrome. AB - Objective: The present study was designed to evaluate the functional outcome of stapled transanal rectal resection (STARR) and to examine the relationship between the population density of the interstitial cells of Cajal (ICC) and the efficacy of the STARR operation in the management of obstructed defecation syndrome (ODS) patients. Methods: Full-thickness rectal samples were obtained from 50 ODS patients who underwent STARR. Samples were analysed using ICC immunohistochemistry. Clinical and functional parameters obtained with defecography and anorectal manometry were compared with 20 controls. Results: ICCs were significantly decreased in patients in the submucosal (SM), intramuscular (IM) and myenteric (MY) regions when compared with the control group (P < 0.05). The mean pre-operative Cleveland Constipation Score (CCS) was 24.2 +/- 4.1, whilst the CCS at 1, 2, 3, 4 and 5 years post-operatively decreased significantly (P < 0.05). At 3 post-operative years, 58.3% (28/48) of the patients reported a favorable outcome (CCS <= 10). On univariate analysis, the functional results were worse in those with pre-operative digitation (P = 0.017), a decreased ICC-MY cell population (P = 0.067), a higher resting anal canal pressure (P = 0.039) and a higher rectal sensory threshold (P = 0.073). Multivariate analysis showed the decreased ICC-MY cell population was an independent predictor for low unfavorable functional outcome (odds ratio = 0.097, 95% confidence interval: 0.012-0.766). Conclusions: STARR achieved acceptable results at the cost of a slight deterioration over a more prolonged follow-up. Patients with a decreased ICC number in the rectal specimen showed an unfavorable functional outcome where pre-operative histological assessment of a full thickness rectal sample might predict for the functional outcome following STARR. PMID- 30430016 TI - Is adjuvant chemotherapy necessary for patients with ypT0-2N0 rectal cancer treated with neoadjuvant chemoradiotherapy and curative surgery? AB - Background and objective: The benefit from adjuvant chemotherapy for patients treated with neoadjuvant chemoradiotherapy (NCRT) and curative surgery remains controversial, particularly among those responding well to NCRT. This retrospective study aimed to clarify the benefits of adjuvant chemotherapy in terms of the oncological outcomes of patients with ypT0-2N0 rectal cancer after NCRT and curative surgery. Methods: All patients with ypT0-2N0 rectal cancer after NCRT and curative resection between 2005 and 2014 were examined. The oncological outcomes between patients treated with adjuvant chemotherapy and those without any chemotherapy were compared. Results: The clinicopathological characteristics of 110 patients were reviewed in this study; one patient was excluded due to lack of follow-up. Of the 109 patients included, 58 (53.2%) underwent adjuvant chemotherapy (chemo group), whereas the remaining 51 (46.8%) did not receive any chemotherapy (non-chemo group). After a median follow-up of 50 months, there were no significant differences in the 5-year overall survival (OS) or recurrence-free survival (RFS) rates between the groups (OS: 92.1 vs 86.3%, P = 0.375; RFS: 80.9 vs 74.7%, P = 0.534). Subgroup analysis also demonstrated no significant differences in 5-year OS and RFS rates between patients with ypT0N0 rectal cancer (P = 0.712 and P = 0.599, respectively) and those with ypT1-2N0 disease (P = 0.255 and P = 0.278, respectively). Conclusions: These results indicate that patients with ypT0-2N0 rectal cancer after NCRT followed by curative surgery may not derive significant benefit from adjuvant chemotherapy. However, further prospective randomized trials, with larger sample sizes, are warranted to confirm this conclusion. PMID- 30430017 TI - Well-controlled autoimmune hepatitis treatment withdrawal may be safely accomplished without liver-biopsy guidance. AB - Background: Autoimmune hepatitis may flare up after treatment withdrawal, especially in those who had not achieved histological remission but had normal liver enzymes. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) Guidelines recommend performing liver biopsy before treatment withdrawal. The aim of the study is to define the outcome of treatment withdrawal in adults with well-controlled disease for 2 years with and without liver-biopsy guidance. Methods: A retrospective observational study was conducted on biopsy-proven autoimmune hepatitis patients who were treated for 2 years and with persistently normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) or nearly so for 6 months prior to treatment withdrawal. Exclusions were: juvenile onset autoimmune hepatitis and prior treatment or use of agents other than corticosteroids and azathioprine. The primary endpoint was to define freedom from flare-ups for 1 year after treatment withdrawal. Results: Thirty-four consecutive subjects meeting study criteria were identified. Treatment withdrawal was accomplished in 24 subjects without liver-biopsy guidance and 10 had pre-treatment withdrawal liver biopsy. Demographics, immunosuppressive usage, pre-treatment cirrhosis and pre-treatment liver enzymes were similar between the two groups, and 25% had an enzyme flare-up within 12 months after treatment withdrawal, which was similar in the two groups (20.8 vs 30.0%, P = 0.57). Conclusions: Adults with autoimmune hepatitis and excellent response to therapy for 2 years are candidates for treatment withdrawal without the need for liver biopsy. PMID- 30430018 TI - Ileal transposition rapidly improves glucose tolerance and gradually improves insulin resistance in non-obese type 2 diabetic rats. AB - Background: Many studies have confirmed that ileal transposition can improve type 2 diabetes mellitus (T2DM), accompanied by increased glucagon-like peptide-1 (GLP 1). We performed the experiment on diabetic rats to evaluate the effects and mechanisms of ileal transposition on the glycemic metabolism. Methods: Twenty Goto-Kakizaki (GK) rats were randomly divided into the ileal transposition group (IT group) and the sham operation group (Sham group). Weight, food intake, fasting plasma glucose (FPG), fasting insulin (F-ins), oral glucose tolerance test (OGTT) and GLP-1 were determined at baseline and 1, 4, 8, 16 and 24 weeks post-operatively. The homeostasis model assessment-insulin resistance (HOMA-IR) index and the area under the curve (AUC) during OGTT were measured. Histological determination of the GLP-1 receptor (GLP-1R) was performed on the pancreas and ileum 24 weeks post-operatively. Results: In comparison with the Sham group, the IT group showed a higher GLP-1 level and lower AUC at 4, 8, 16 and 24 weeks post operatively (all P < 0.05) and a lower FPG, F-ins levels and HOMA-IR at 8, 16 and 24 weeks post-operatively (all P < 0.05). Compared with baseline levels, the plasma GLP-1, AUC and FPG levels decreased significantly at each post-operative time point in the IT group (all P < 0.05), but not in the Sham group (all P > 0.05); F-ins and HOMA-IR significantly decreased at 8, 16 and 24 weeks post operatively in the IT group (all P < 0.05). GLP-1R expression in the IT group was significantly higher than that of the Sham group in both the pancreas and the ileum at 24 weeks post-operatively (P < 0.05). Conclusions: Ileal transposition ameliorated glucose metabolism without reduction in weight or food intake in GK rats, which may be induced by the increased GLP-1 expression. However, the delayed improvement of insulin resistance, accompanied by decreased plasma insulin levels, might not directly result from the increased GLP-1. PMID- 30430019 TI - The role of visceral adipose tissue on improvement in insulin sensitivity following Roux-en-Y gastric bypass: a study in Chinese diabetic patients with mild and central obesity. AB - Background: Most Chinese patients with type 2 diabetes mellitus (T2DM) have mild obesity and central obesity. Central obesity is combined with insulin resistance. The aim of this study was to assess the effect of abdominal adipose tissue on insulin-sensitivity improvement after Roux-en-Y gastric bypass (RYGB) in Chinese diabetic patients with mild and central obesity. Methods: Seventeen T2DM patients with a mean body mass index of 30.3 kg/m2 were scheduled for laparoscopic RYGB. A hyperinsulinemic-euglycemic clamp and dual-energy X-ray absorptiometry were performed prior to surgery and 3 months after RYGB. The primary end points were the correlations between insulin sensitivity and abdominal adipose tissue, including visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), before and 3 months after RYGB. Results: Indices of peripheral insulin sensitivity, including glucose-disposal rate (M value) and glucose infusion rate, were significantly increased after RYGB. Body-fat mass, VAT and SAT were significantly reduced after RYGB. The pre-operative M value was significantly correlated with VAT mass (r = -0.57, P = 0.02), but not correlated with SAT mass. M value changes after RYGB were highly correlated with changes in VAT mass (r = 0.59, P = 0.01), percentage of VAT mass (r = -0.66, P < 0.01), VAT area (r = 0.56, P = 0.02) and percentage of VAT area (r = -0.57, P = 0.02). Conclusions: A significant correlation was observed between increased peripheral insulin sensitivity and decreased VAT following RYGB in Chinese patients with mild and central obesity. VAT and SAT were significantly decreased with improved insulin sensitivity after RYGB. VAT mass may be considered as an indication for gastric bypass during patient selection. PMID- 30430020 TI - Serum zinc level is associated with liver dysfunction caused by white smoke inhalation. AB - Background: White smoke bomb exposure in the military setting could result in organ injuries, which is uncommon and has been rarely described in previous studies. The aim of this study is to observe whether serum zinc levels are associated with liver function after white smoke inhalation. Methods: Fifteen patients with white smoke exposure were the subjects in this study. The clinical manifestations, liver function tests and the serum zinc levels were analysed. Results: The level of serum zinc was increased in the moderate or severe group (n = 4) compared with that in the mild group (n = 11). The four cases in the moderate or severe group had delayed impairment of liver function with an elevation of alanine transaminase. Additionally, increased blood concentrations of hyaluronic acid were found in three patients in the moderate or severe group. But no hexachloroethane or trichloropropane was detected. Conclusion: This study suggested that serum zinc levels may be associated with the severity of liver injuries after white smoke inhalation. PMID- 30430021 TI - Morbidity and mortality of elderly patients with advanced gastric cancer after laparoscopy-assisted or open distal gastrectomy: a randomized-controlled trial. AB - Laparoscopy-assisted distal gastrectomy (LDG) combined with D2 lymphadenectomy may be safely performed in patients with advanced gastric cancer (AGC) by experienced surgeons at specialized high-volume institutions as shown in the Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS)-01. However, studies focusing on the use of LDG in patients with gastric cancer older than 65 years are rare. This study was designed to investigate the morbidity and mortality of elderly patients with gastric cancer who underwent laparoscopic-assisted or open distal gastrectomy (ODG). In this prospective, randomized, open, parallel controlled trial, patients older than 65 years with tumor located at the middle or lower part of the stomach will be enrolled in this study. Patients will be randomly divided into a laparoscopic group and an open surgery group. The early post-operative complications, intra-operative complications and post-operative recovery will be compared between the two groups. This trial will provide valuable clinical evidence for the objective assessment of the feasibility, short term safety, and potential benefits of LDG compared with ODG for gastric cancer in the elderly patients. This trial has been registered on ClinicalTrials.gov. (Identifier: NCT02246153.) in September 22, 2014. PMID- 30430022 TI - Erratum: Radiation therapy-induced aortoesophageal fistula: a case report and review of literature. AB - [This corrects the article DOI: 10.1093/gastro/gou081.]. PMID- 30430023 TI - Report from the ESMO 2018 presidential symposium-Radiotherapy to the primary tumour for men with newly diagnosed metastatic prostate cancer: survival results from STAMPEDE. PMID- 30430024 TI - Biosimilars in oncology. PMID- 30430025 TI - Osimertinib therapy as first-line treatment before acquiring T790M mutation: from AURA1 trial. PMID- 30430026 TI - Extended sleeve lobectomy: its place in surgical therapy for centrally located non-small cell lung cancer and a review of technical aspects. PMID- 30430027 TI - Neoadjuvant PD-1 blockade in non-small cell lung cancer: what else do we need to do? PMID- 30430028 TI - Peri-procedural myocardial infarction is all the same? PMID- 30430029 TI - Sortilin as a new membrane inhibitor of EGFR trafficking for overcoming resistance to EGFR inhibitors in non-small cell lung cancer. PMID- 30430030 TI - Editorial on "current state of empyema management". PMID- 30430031 TI - Disadvantaged Status and Health Matters Networks among Low-Income African American Women. AB - A significant gap in current network research relates to understanding the factors that shape the health matters (HM) networks of marginalized, socially disadvantaged populations. This is noteworthy, given that these networks represent a critical resource for mitigating the adverse health effects of both acute and chronic strains associated with marginalized status. Further, research has suggested that the networks of such populations-especially low-income African American women-are unique, and may operate in substantively different ways than those of other groups. Using two waves of data from a sample of low-income African American women, this research identifies the demographic, health status, and health behavior measures at time one that correspond to HM network characteristics at time two, six months later. This study offers preliminary insights on the relationship between key sociodemographic and health status characteristics of low-income African American women and their HM networks, including criminal justice involvement. Findings reveal that though poorer health status and criminal justice involvement correspond to smaller health matters networks, they also correspond to more active and supportive networks. PMID- 30430032 TI - A Systematic Review of Molecular Autopsy Studies in Sudden Infant Death Cases. AB - Sudden unexpected death is an upsetting event, which can remain unexplained even after post-mortem investigation. Internationally, molecular autopsies have shown to resolve up to 44% of unexplained cases; however, it is currently unclear how many of these were infants. This systematic literature review showed that significantly fewer infant cases were resolved (median: 4%) compared with cohorts of 1 to 45 years old (median: 32%). Further, no study involving indigenous African participants has yet been published. Overall, molecular autopsies hold immense value to living family members and is motivation to explore new avenues in infant cohorts. PMID- 30430033 TI - Co-occurrence of Noonan and Cardiofaciocutaneous Syndrome Features in a Patient with KRAS Variant. AB - We report the case of a 3-year-old girl, who is the third child of nonconsanguineous parents, with short stature, hypertrophic cardiomyopathy, and mild dysmorphic features; all suggestive of Noonan syndrome. In addition, the patient presents with feeding difficulties, deep palmar and plantar creases, sparse hair, and delayed psychomotor and language development, all characteristics frequently observed in cardiofaciocutaneous syndrome. Molecular analysis of the Ras/ MAPK pathway genes using high-resolution melting curve analysis and gene sequencing revealed a de novo KRAS amino acid substitution of leucine to tryptophan at codon 53 (p.L53W). This substitution was recently described in an Iranian patient with Noonan syndrome. The findings described in this report expand the phenotypic heterogeneity observed in RASopathy patients harboring a KRAS substitution, and advocate for the inclusion of genes with low mutational frequency in genetic screening protocols for Noonan syndrome and other RASopathies. PMID- 30430035 TI - A Familial Case of Multicentric Carpotarsal Osteolysis Syndrome and Treatment Outcome. AB - Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder caused by heterozygous mutations in the MAFB gene (v-maf musculoaponeurotic fibrosarcoma oncogene ortholog B). This is an autosomal dominant condition with a high frequency of sporadic cases. MCTO is characterized by osteolysis of the carpal, metacarpal, and tarsal bones beginning in early childhood with musculoskeletal rheumatologic symptoms such as pain and disability. Renal involvement can be seen in more than half of the patients; from ages 16 months to 42 years and manifests from proteinuria to end-stage renal failure requiring renal transplantation. The association of MAFB gene mutations with this genetic condition has aided in understanding the pathophysiology of the disease. We report here a 7-year-old Caucasian boy and his 33-year-old mother diagnosed with MCTO, with the boy having concomitant juvenile idiopathic arthritis. He was initially diagnosed with arthritis at age 5 years based on bilateral wrist synovial swelling, morning stiffness, and weakness with family history of his mother being diagnosed with erosive psoriatic arthritis leading to limb deformities. Initial therapy for the boy included methotrexate and infliximab with moderate response. Later, during the course of his disease, he underwent a genetic evaluation at age 7 years for history of learning disabilities and dysmorphic features. Maternal evaluation and radiographic examination led to a clinical diagnosis of MCTO in the mother, and subsequent testing for MAFB gene in the son revealed a mutation at c.206C > T (p.Ser69Leu), the most commonly reported genetic change in MCTO. Nevertheless, further imaging still confirmed ongoing arthritis, and therapy was adjusted based on its progression including abatacept, tocilizumab, and pamidronate. Our report highlights the possibility of concomitant inflammatory arthropathy in MCTO. PMID- 30430034 TI - Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm. AB - Wolf-Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1 , CTBP1 , NSD2 , FGFR3 , CPLX1 , MAEA , CTBP1-AS2 , and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH. PMID- 30430036 TI - Infantile Onset Hypertrophic Cardiomyopathy Secondary to PRKAG2 Gene Mutation is Associated with Poor Prognosis. AB - Hypertrophic cardiomyopathy (HCM) is the second most prevalent form of cardiomyopathy in children. The etiology of the HCM is heterogeneous, so is the age of onset of symptoms. The HCM associated with metabolic disorders and genetic syndromes presents early in childhood. There are very few case reports of early onset infantile HCM secondary to the PRKAG2 gene. Here, we report a case of HCM in a neonate diagnosed prenatally and eventually diagnosed with a missense mutation in the PRKAG2 gene. PMID- 30430037 TI - Osteogenesis Imperfecta and Extra-/Intradural Hematomas: A Case Report and Review of the Literature. AB - Osteogenesis imperfecta, also named as brittle bone disease, is characterized by fragile bones and short stature caused by mutations in the collagen gene. Subdural and intraparenchymal hematomas are defined and associated with trauma, vascular causes, and systemic bleeding diathesis. Skull fragility may lead to epidural hematoma, which is a life-threatening situation. Vascular fragility and intrinsic platelet defects are the causes of bleeding in patients with osteogenesis imperfecta, which is a major management challenge for neurosurgeons. Here, we reported on a 5-year-old boy with osteogenesis imperfecta with epidural hematoma and skull fracture following a trivial trauma, and made a literature review of 28 cases with extra-/intradural hematoma. PMID- 30430038 TI - A Data-driven Process Recommender Framework. AB - We present an approach for improving the performance of complex knowledge-based processes by providing data-driven step-by-step recommendations. Our framework uses the associations between similar historic process performances and contextual information to determine the prototypical way of enacting the process. We introduce a novel similarity metric for grouping traces into clusters that incorporates temporal information about activity performance and handles concurrent activities. Our data-driven recommender system selects the appropriate prototype performance of the process based on user-provided context attributes. Our approach for determining the prototypes discovers the commonly performed activities and their temporal relationships. We tested our system on data from three real-world medical processes and achieved recommendation accuracy up to an F1 score of 0.77 (compared to an F1 score of 0.37 using ZeroR) with 63.2% of recommended enactments being within the first five neighbors of the actual historic enactments in a set of 87 cases. Our framework works as an interactive visual analytic tool for process mining. This work shows the feasibility of data driven decision support system for complex knowledge-based processes. PMID- 30430039 TI - Exploratory Profiling of Urine MicroRNAs in the dy2J/dy2J Mouse Model of LAMA2 CMD: Relation to Disease Progression. AB - Circulating microRNAs (miRNAs) are being considered as non-invasive biomarkers for disease progression and clinical trials. Congenital muscular dystrophy with deficiency of laminin alpha2 chain (LAMA2-CMD) is a very severe form of muscular dystrophy, for which no treatment is available. In order to identify LAMA2-CMD biomarkers we have profiled miRNAs in urine from the dy2J /dy2J mouse model of LAMA2-CMD at three distinct time points (representing asymptomatic, initial and established disease). We demonstrate that unique groups of miRNAs are differentially expressed at each time point. We suggest that urine miRNAs can be sensitive biomarkers for different stages of LAMA2-CMD. PMID- 30430040 TI - Comparison of incisional complications between skin closures using a simple continuous or intradermal pattern: a pilot study in horses undergoing ventral median celiotomy. AB - Background: Development of incisional complications following ventral median celiotomy might depend on suture pattern for skin closure. Methods: In this prospective study, 21 healthy male horses underwent celiotomy. Skin closure was either performed via a continuous percutaneous pattern (CO group; 5 warmbloods/5 ponies) or an intradermal pattern (ID group; 5 warmbloods/6 ponies). Follow-up examination of the incisional site included daily monitoring for edema, dehiscence, and drainage. Transcutaneous ultrasound was performed at Days 3, 6, and 10 as well as on Week 8 and 12 to evaluate size of edema and presence or absence of sinus formation, and hernia formation. Prevalence of incisional infection on base of positive microbiological analysis at any time up to Day 10 was evaluated and compared between ID and CO group. Furthermore, edema size was analysed by a linear mixed-effect model for group and time dependency. Results: Observed incisional complications included edema (9/10 in CO, 10/11 in ID), suture sinus formation (2/10 in CO, 1/11 in ID), surgical site infection (2/10 in CO, 0/11 in ID), and incisional hernia (1/10 in CO, 0/11 in ID). The overall prevalence of incisional infection was 9.5% without significant differences between both groups (20% in CO, 0% in ID; p = 0.214). Edema size was not dependent on time or group (p = 0.545 and p = 0.627, respectively). Discussion: CO and ID suture pattern are appropriate for skin closure following ventral median celiotomy in horses. None of the animals in the continuous ID group developed surgical site infections, even without the use of antibiotics. PMID- 30430041 TI - A real-time PCR assay for quantification of parasite burden in murine models of leishmaniasis. AB - Eukaryotic parasites in the genus Leishmania place approximately 350 million people per year at risk of disease. In addition to their global health significance, Leishmania spp. have served as an important model for delineating basic concepts in immunology such as T-helper cell polarization. There have been many qPCR-based assays reported for measuring parasite burden in humans and animals. However, these are largely optimized for use in clinical diagnosis and not specifically for animal models. This has led several of these assays to have suboptimal characteristics for use in animal models. For example, multi-copy number genes have been frequently used to increase sensitivity but are subject to greater plasticity within the genome and thus may confound effects of experimental manipulations in animal models. In this study, we developed a sybr green based quantitative touchdown PCR assay for a highly conserved and single copy putative RNA-binding protein, DRBD3. With primers that share greater than 90% sequence identity across all sequenced Leishmania spp., we demonstrate that this assay has a lower limit of detection of 100 fg of parasite DNA for Leishmania major, L. donovani, L. venezuelensis, and L. panamensis. Using C57BL6/J mice, we used this assay to monitor parasite burden over 1 month of infection with two strains of L. major (Seidman and Friedlin), and L. venezeuelensis. These characteristics rival the sensitivity of previously reported qPCR based methods of parasite quantitation while amplifying a stable, single copy gene. Use of this protocol in the future will lead to improved accuracy in animal based models and help to tease apart differences in biology of host-parasite interactions. PMID- 30430042 TI - Nutrition of marine mesograzers: integrating feeding behavior, nutrient intake and performance of an herbivorous amphipod. AB - Consumers can regulate the acquisition and use of nutrients through behavioral and physiological mechanisms. Here, we present an experimental approach that simultaneously integrates multiple nutritional traits, feeding assays, and juvenile performance to assess whether a marine herbivore (the amphipod Ampithoe valida) regulates the intake of elements (carbon and nitrogen), macronutrients (protein and non-protein) or both when offered freeze-dried tissues of seaweeds varying in nutritional content. We assessed behavioral regulation of nutrients in three ways. First, during no-choice assays, we found that amphipods ingested similar amounts of carbon, but not nitrogen, non-protein and protein, across algal diets. Second, herbivore intake rates of carbon, protein and non-protein components across no-choice assays was similar to intake rates when offered a choice of foods. Third, variation in intake rates of carbon and non-protein components among algal diets was significantly greater than was tissue content of these components, while variation in intake rates of nitrogen was significantly lower; differences in protein intake variation was equivocal. While these analytical approaches are not uniformly consistent, carbon and nitrogen seem to emerge as the nutrient components that are more strongly regulated by A. valida. Juveniles reared on single diets shown patterns of survivorship, growth and reproduction that could not be predicted by these feeding preferences, nor nutrient content. We conclude that an integrative approach that considers the intake of multiple nutrients potentially yields insights into feeding behavior and its performance consequences. PMID- 30430044 TI - Editorial Trends and Challenges in Translation of Point-of-Care Technologies in Healthcare. AB - Point-of-Care Technologies (POCT) in Healthcare have emerged as a potential pathway in global and resource-limited environments towards improving access to healthcare with emphasis on preventive, personalized and precision medicine. The potential uses for POC technologies by patients or clinicians are many-from home based monitoring to semi-managed and clinical inpatient healthcare. However, it is yet to be proven precisely what technologies are necessary or how they should be used to make an impact in improving access to quality healthcare. Although there is great potential for the application of new technologies in healthcare, physicians are skeptical about POCT since they fear it will generate large amounts of unreliable and overwhelming information of unknown benefit. Because the benefits and acceptance of POCT are unknown, a necessary first step in its development is performing market research of patients and clinicians to determine what POCT protocols would be most beneficial and acceptable. Research into POCT involves first understanding what the needs are of patients and clinicians, and then researching the best way to apply new technology to improve clinical care based on the understanding of these needs. The conference featured 5 keynote, 8 panel and 4 breakout sessions involving leaders from several stakeholder groups, including technology research, federal funding and regulatory agencies, industry and clinical healthcare. Through numerous presentations and group discussions, the conference participants concluded that the future of POCT depends upon facilitation of collaborative translational research towards development and meaningful validation of POCT in addressing specific healthcare and clinical needs with clear benefits and user acceptance. PMID- 30430043 TI - Interaction between Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis. AB - Background: Cystic fibrosis (CF) is a disease characterized by chronic airway infection with a high incidence and poor prognosis. Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens commonly found in CF patients. Clinically, these two microorganisms often coexist in the airway of CF patients. Combined infection with P. aeruginosa and A. fumigatus results in worsening lung function and clinical condition. Methods: In this review, we focus on the mutual inhibition and promotion mechanisms of P. aeruginosa and A. fumigatus in CF patients. We also summarized the mechanisms of the interaction between these pathogenic microorganisms. Results: P. aeruginosa inhibits A. fumigatus growth through the effects of phenazines, the quorum sensing system, iron competition, bacteriophages, and small colony variants. P. aeruginosa induces A. fumigatus growth through volatile organic compounds and subbacteriostatic concentrations of phenazines. A. fumigatus interferes with P. aeruginosa, affecting its metabolic growth via phenazine metabolic transformation, gliotoxin production, and reduced antibiotic sensitivity. Discussion: Coexistence of P. aeruginosa and A. fumigatus can lead to both mutual inhibition and promotion. In different stages of CF disease, the interaction between these two pathogenic microorganisms may shift between promotion and inhibition. A discussion of the mechanisms of P. aeruginosa and A. fumigatus interaction can be beneficial for further treatment of CF patients and for improving the prognosis of the disease. PMID- 30430046 TI - Osteopoikilosis Demonstrating Multiple Joint Involvement in an Adult Male: An Incidental Radiographic Finding. AB - Osteopoikilosis is a rare condition that is characterized by multiple small non aggressive appearing sclerotic foci in a periarticular distribution. Typically, it does not cause any symptoms and is diagnosed incidentally on imaging studies done for other reasons. We present a case of osteopoikilosis in a 37-year-old male, which was diagnosed incidentally on radiographs. PMID- 30430045 TI - A Case of Amitriptyline-induced Myocarditis. AB - Amitriptyline is a widely prescribed tricyclic antidepressant (TCA) with a very concerning cardiotoxicity profile, but it is one that has not been discussed much in literature. Here, we present a case of amitriptyline toxicity presenting as myocarditis with pericardial involvement. A 21-year-old male with no previous cardiac history presented to the emergency department (ED) with a decreased level of consciousness after an amitriptyline overdose as a suicidal attempt. For concerns with airway protection, the patient was intubated and subsequently admitted to the intensive care unit (ICU). An electrocardiogram (EKG) showed sinus tachycardia, prolonged QRS complex, prolonged QTc interval, and nonspecific ST-T wave changes. Intravenous fluid resuscitation and sodium bicarbonate were administered with a target blood pH of 7.5 to 7.55. Two days later, the patient was taken off mechanical ventilation and improved clinically. However, troponin levels began to rise with a peak level of 4.08 ug/L. He then began having fevers, elevated white blood cell counts (WBCs), and elevated inflammatory markers. Transthoracic echo (TTE) revealed an ejection fraction (EF) of 45%-50%, no wall segment motion abnormalities, and a mild-to-moderate pericardial effusion. Cardiac magnetic resonance (CMR) was done, which revealed changes indicative of acute myocarditis, moderate pericardial effusion, a calculated EF of 45% with a moderate left ventricular dilation, and no coronary artery stenosis or anomalous coronary artery origin. Given the patient's age, the absence of cardiac risk factors, and the presence of an amitriptyline overdose along with his EKG, TTE, and CMR findings, we hypothesize that this myocarditis with pericardial involvement is due to amitriptyline-induced direct toxicity. PMID- 30430047 TI - Primary Gastrointestinal Diffuse Large B-cell Lymphoma. AB - Primary gastrointestinal lymphoma is a rare neoplasm that accounts for less than 5% of all gastrointestinal malignancies. We present a case of a 37-year-old woman positive for human immunodeficiency virus who presented with abdominal pain and vomiting for three months. She underwent endoscopic biopsy and was found to have high-grade diffuse large B-cell lymphoma in the jejunum. This report discusses her treatments and includes a brief literature review highlighting the rarity of this entity, the etiological agents implicated in its pathogenesis, and the lack of specific guidelines for treatment. PMID- 30430048 TI - Conservative Follow-up of Severely Displaced Distal Radial Metaphyseal Fractures in Children. AB - Introduction Distal radius fractures are the most frequent fractures seen in pediatric population and usually treated with closed reduction and casting. However, there is a risk of reduction loss and/or angulations in distal radial metaphyseal fractures. The purpose of this study is to evaluate the radiological and functional results of pediatric patients with distal radius metaphyseal fractures in which excessive displacement and/or angulations were accepted and to question upper acceptable limits in light of current literature. Methods Patients between five and 15 years of age with displaced distal radius fractures who were treated conservatively with significant angulation or translation were included in this study. Patients' demographic data were gathered from hospital's digital database. Clinical and radiological evaluations of all patients were done prospectively based on the last outpatient clinic control. Range of motion of wrist and elbow joint was measured with a goniometry, neurovascular status was documented, muscle strength was assessed and finally existing deformity measurements were performed clinically. Radiological evaluation was performed on pre-reduction, post-reduction, cast removal, 6th and 12th months and final examination radiographs. All measured values were compared with uninjured side. Radiologically, the percentage of translation, the amount of angulations, the distance from the fracture to the epiphyseal line, and the radius lengths were measured. Radial inclination and palmar tilt angles as well as ulnar variance and residual angulation were measured in both antero-posterior (AP) and lateral forearm radiographs. The Mann-Whitney U test was used to compare the variables in SPSS version 21. p < 0.05 was considered statistically significant. Results Twenty-nine patients with a mean age of 8.8 +/- 3.1 years were included in this study. The mean follow-up duration was 17.4 +/- 6.7 months. Compared to the uninjured side, in 24 (83%) patients, there were no limitations on wrist movements except five patients in forearm pronation clinically. In patients with re-displacement, the mean displacement occurrence time was 13.3 +/- 4.9 (7-21) days. The translational and/or angulations in AP and lateral radiographs fully remodeled at the end of 6th month. Conclusion This study demonstrates that radial and dorsal angular deformities up to 39 degrees and 22 degrees volar angulation and complete displacement correct fully in children up to 10 years old. In children between 10 and 15 years, the dorsal angulation up to 38 degrees , radial angulation up to 23 degrees , and volar angulation up to 16 degrees are acceptable for remodeling capacity of the child. PMID- 30430050 TI - Right Ventricular Outflow Obstruction Due to Metastatic Neuroendocrine Tumor. AB - Neuroendocrine tumors (NETs) are rare malignant tumors that arise from neuroendocrine cells of the gastrointestinal tract and often metastasize to the liver, lung, and bone. Cardiac metastasis of NETs is uncommon. We report a patient with a past medical history of a neuroendocrine tumor of the left femur presenting with signs and symptoms of new onset heart failure. Transthoracic echocardiogram and cardiac magnetic resonance showed a large mass within the right ventricle causing right ventricular outflow obstruction. A positron emission tomographic/computed tomographic scan (PET-CT) revealed increased uptake of fluorodeoxyglucose (FDG) activity within the right ventricle consistent with metastasis. Cardiac biopsy of the right ventricular mass revealed metastatic nonfunctioning neuroendocrine tumor. In view of the fact that it was a tumor that caused the right ventricular obstruction, the patient was started on chemotherapy with improvement of symptoms. This case highlights that in patients with a history of neuroendocrine tumor presenting with heart failure, cardiac metastasis should be included in the differential. PMID- 30430049 TI - Medical Needling: Effect on Skin Erythema of Hypertrophic Burn Scars. AB - Background Burn scars frequently tend to have pathological discolorations, which is manifested in the development of persistent erythema. Affected people suffer from psychological and physiological issues when they are restricted or rejected in their daily life. In this context, medical needling seems to be an efficient therapy for erythematous scars with a relatively low-risk rate of postoperative complications. Study research has already shown significant improvements in the scar quality with reference to the parameters "moisture and transepidermal water loss." Clinical data is up-to-date and provides an innovative therapy outcome of scar treatment with medical needling. Objective The aim of our study was to examine the influence of medical needling on the pathological and persistent erythema of hypertrophic burn scars. By means of reliable measurement methods, we were able to prove positive and sustainable outcomes for normal and healthy skin. The patient cohort included 20 patients with an average age of 34.63 years. Our examinations involved scars that were at least two years old and had healed by secondary intent. Every scar showed the pathological values of persistent erythema according to the participation requirements. Methods For the practical implementation of medical needling or percutaneous collagen induction (PCI), we used a roller covered with needles of 3 mm length. The needling device is rolled over the scar alternatively in a vertical, horizontal, and diagonal orientation. Multiple micro-wounds at a close distance cause intradermal bleeding, which evokes modified skin regeneration provoked by the effects of medical needling. Every patient has been followed up for 12 months postoperatively. Further on, valid results have been evaluated objectively as well as subjectively by the patient and observer. Results Our study has shown that persistent erythema of hypertrophic scars can be considered as an indication of PCI. The needling procedure influences vascularization by stimulating angiogenesis in the post needling wound healing cascade. As the method is based on percutaneous collagen induction, the synthesis of collagen improves the vital thickness of the epidermis, which is directly associated with less transparency. Examined scars showed a significant reduction of erythema and were less reddened after treatment. Based on the outcomes of objective measurements, medical needling achieves a normalization of the skin color and an adjustment to healthy skin after repetitive treatments. Conclusion Medical needling seems to be a suitable therapy approach for treating erythematous, hypertrophic burn scars. PMID- 30430051 TI - Radiographic Evaluation of Meniscal Extrusion. AB - Background Magnetic resonance imaging (MRI) is well established as the preferred noninvasive tool for meniscal evaluation. To our knowledge, there has been no study examining the utility of diagnosing meniscal extrusion from radiography alone. We hypothesize that with appropriate window settings, meniscal extrusion may be diagnosed on radiography with high sensitivity and specificity. Materials and methods We included 190 patients with MRI of the knee performed within three months of knee radiography. As defined within the literature, we utilized the MRI criteria of meniscal extrusion as meniscal tissue extending 3 mm or greater beyond the tibial plateau, excluding osteophytes. Two attending radiologists blindly and independently identified the absence or presence, in millimeters, of medial meniscal extrusion on plain film radiography. Kappa test and Pearson correlation coefficient were calculated to assess the extent of inter-reader agreement and correlation. Sensitivity and specificity were calculated for each reader, assuming the concurrent MRI served as the gold standard. Results Ninety six patients had medial meniscal extrusion and 94 had no medial extrusion by MRI. Kappa test for inter-reader agreement = 0.61. Pearson coefficient for inter reader measurement correlation = 0.69. Reader A had sensitivity of 0.59 (95% CI 0.49-0.69) and specificity of 0.88 (95% CI 0.79-0.94). Reader B had sensitivity of 0.61 (95% CI 0.51-0.71) and specificity of 0.85 (95% CI 0.76-0.91). Conclusion There is substantial inter-reader agreement and high correlation of meniscal extrusion measurement between readers. Our results suggest that while radiographs have low sensitivity for evaluation of meniscal extrusion, their high specificity may be of clinical utility. PMID- 30430052 TI - A Case of Pseudo-pneumothorax with Complications. AB - Pseudo-pneumothorax occurs after inappropriately diagnosing a pneumothorax based on a chest X-ray. This can be attributed to skin folds, bed sheets, previous pneumothorax, heating blankets, clothes, and other circumstances that may mimic the radiographic findings of a pneumothorax. We present a case where a patient underwent a tube thoracostomy due to the diagnosis of a pneumothorax that was not, in fact, present. The unnecessary intervention was complicated by hemoptysis and cardiac arrest. PMID- 30430053 TI - Endoscopic Removal of Large Sharp-edged Foreign Bodies in the Gastrointestinal Tract Using an Innovative Modification of the Overtube. AB - Foreign body ingestion is commonly encountered in clinical practice. According to standard guidelines, urgent therapeutic endoscopy should be performed in cases involving sharp objects to prevent complications. Although several extraction methods are available, few cases may still pose a therapeutic challenge. This report describes a novel endoscopic technique utilizing modification of the standard overtube to facilitate the removal of a large razor blade. This technique offers a minimally invasive approach for rapid retrieval of large sharp edged foreign bodies, obviating the need for a surgical exploration. Additionally, this article compares various imaging modalities for prompt detection of gastrointestinal foreign bodies to avoid unnecessary delays in endoscopic intervention. PMID- 30430054 TI - The Spectrum of Beta-thalassemia Mutations in Couples Referred for Chorionic Villus Sampling at Bahawal Victoria Hospital, Bahawalpur. AB - Introduction The prevalence of beta-thalassemia mutations is different in various castes, regions, and ethnic groups. By knowing this prevalence, we can conduct a targeted screening of only the high-risk population and only for the specific mutations that are prevalent in each group. Objective The purpose of this study was to determine the regional, caste-wise, and ethnic spectrum of beta thalassemia mutations in couples referred for a prenatal diagnosis. Methods A cross-sectional analytical study was conducted at the thalassemia unit, Bahawal Victoria Hospital, Bahawalpur, from October 1, 2015, to May 15, 2018. After obtaining informed consent, chorionic villus sampling (CVS) was performed in 144 women having a gestational age of 12 to 16 weeks. We took blood samples of the couples. A chromosomal analysis for 13 mutations was done at Punjab Thalassaemia Prevention Programme (PTPP), Lahore. The researchers filled a questionnaire with all the details of couples like ethnicity, caste, and region. Results The most common mutation was Fr 8-9(+G), accounting for 29.8%, followed by IVS 1-5(G-C), which was 28.9%. We did not find three mutations in any chromosome. Fr 8-9 (+G) was the most common mutation among Punjabis and Pakhtoons. IVS 1-5 (G-C) was the most common mutation among Saraikis and Urdu-speaking people. In Rajputs, Arains, Jatts, and Pathans, Fr 8-9 (+G) was the most common mutation. IVS 1-5 (G-C) was the most common mutation among Sheikhs, Balochs, Syeds, and Miscellaneous. IVS 1 5 (G-C) was the most common mutation in the Bahawalpur division and Ghotki (Sindh) while Fr 8-9 (+G) was the most common mutation in the Multan division. The p-value of all the results was <0.001. Conclusion There is an ethnic, caste wise, and regional distribution of mutations. We can conduct a targeted screening of the population and provide counseling about chorionic villus sampling by using this local data. PMID- 30430055 TI - Non-insidious Large Joint Manifestation of Severe Cachectic Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disorder in which constitutional symptoms typically occur before joint swelling becomes a true clinical phenomenon. Weight loss, although common, is generally mild in nature and occurs after long standing inflammation. While large joints do become inflamed, RA has a much stronger predilection for the small joints. Our case is a rarity in the fact that there was initial large joint swelling without long standing inflammation. Additionally, the weight loss was cachectic in nature and extreme. Furthermore, while extra-articular manifestations do commonly occur, spontaneous pneumothorax is certainly atypical. The content of this manuscript serves to enlighten hospitalist physicians and residents, as to the odd way in which a case like this may present. PMID- 30430056 TI - Ventricular Fibrillation Cardiac Arrest in African American Male with Apical Hypertrophic Cardiomyopathy. AB - Apical hypertrophic cardiomyopathy (AHCM) is a rare form of non-obstructive hypertrophic cardiomyopathy. It is rarely reported in African American patients, and more commonly reported in Japanese patients. AHCM involves hypertrophy of the apex of the left ventricle. It is considered to have a benign prognosis in terms of cardiovascular mortality, however arrhythmias and sudden cardiac death have been reported. We report a case of a 49-year-old African American male with a history of hypertension, who presented to the emergency department after in field defibrillation for ventricular fibrillation cardiac arrest with return of spontaneous circulation after 10 minutes of cardiopulmonary resuscitation. Features of left ventricular hypertrophy and deep T-wave inversions in V3-V6 were noted on a 12-lead electrocardiogram which were suggestive of AHCM. Left heart catheterization with left ventriculography and coronary angiography confirmed the diagnosis of AHCM with the classic "ace of spades" sign. This case highlights the rare occurrence of AHCM with ventricular fibrillation cardiac arrest in an African American male, treated with hypertension management, aspirin, atorvastatin and automated implantable cardioverter-defibrillator placement. PMID- 30430057 TI - Autoimmune Thyroiditis with Hypothyroidism Induced by Sugar Substitutes. AB - The use of sugar substitutes (artificial sweeteners or non-nutritive sweeteners) has increased dramatically in the past few decades. They have been used as a substitute for sucrose (table sugar) in various diet-related disorders. Their excessive use has been linked to hyperphagia and obesity-related disorders. Hashimoto's thyroiditis (chronic autoimmune thyroiditis) is a disease that involves the immune-mediated destruction of the thyroid gland, gradually leading to its failure. Animal studies report that artificial sweeteners affect the immune system. Moreover, animal studies show that sucralose diminishes the thyroid axis activity. We are presenting the case of a 52-year-old female with autoimmune thyroiditis with hypothyroidism (Hashimoto's thyroiditis) induced by an excessive intake of beverages containing non-nutritive sweeteners. She was ruled out for any other autoimmune disorder. The association between Hashimoto's thyroiditis and the excessive consumption of sugar substitutes is shown by the quick return of thyroid stimulating hormone and antibody levels to normal after eliminating the use of sugar substitutes. Thus, it suggests that the sugar substitutes were the culprit in the development of Hashimoto's thyroiditis in our patient. PMID- 30430058 TI - Cognitive Decline in Adults Aged 65 and Older in Cumbaya, Quito, Ecuador: Prevalence and Risk Factors. AB - Objective To assess the prevalence of and risk factors for cognitive decline and dementia in individuals greater than 65 years of age in Cumbaya, Quito, Ecuador. Methods This is a cross-sectional observational study that was carried out in adults over age 65. The Mini Mental State Examination (MMSE), Ascertain Dementia Eight-Item Informant Questionnaire (AD8), and Mini Nutritional Assessment (MNA) were used to assess the cognitive status and nutritional habits of this population. Results A total of 144 patients (mean age 75.3 years, 77.1% female) participated in this study. Forty percent of patients had AD8 and MMSE scores consistent with cognitive impairment and possible dementia. Age (p < 0.01), lower educational level (p < 0.01), history of stroke (p < 0.01), history of intracerebral hemorrhage (p < 0.01), diabetes mellitus (p < 0.01), and malnutrition (p < 0.01) were statistically significant risk factors for cognitive impairment. Exercise was found to be protective against cognitive decline in our study group (p < 0.03). Gender, ethnicity, location, head trauma, Parkinson disease, hypercholesterolemia, myocardial infarction, thyroid disease, depression, anxiety, and family history of dementia were not found to be associated with cognitive decline in this population. Conclusions The prevalence of cognitive impairment and possible dementia is 18-21% at age 65 and 54-60% at age 85 in Cumbaya, Quito, Ecuador. The major risk factors for cognitive impairment in this population are age, low educational level, malnutrition, prior stroke, prior intracerebral hemorrhage, and diabetes. Protective factors for cognitive decline include exercise and possibly modest consumption of alcohol. PMID- 30430059 TI - Mal de Debarquement Syndrome: A Case Report. AB - Mal de Debarquement syndrome (MdDS) is an uncommon neurological disorder seen in women, mostly in their fourth decade of life. It is characterized by a constant sensation of swaying or motion after one disembarks from a vehicle such as a ship or plane following a lengthy trip. These symptoms temporarily subside when the patient is subjected again to passive motion like driving a car. There are no definitive diagnostic tests for Mal de Debarquement syndrome. It is a diagnosis of exclusion and does not have an effective treatment. The symptoms usually resolve spontaneously in about a year. We report a case of a 47-year-old female who presented with a feeling of imbalance following about a four-week cruise, which temporarily subsides during a bicycle ride or a car drive. We report this case, as this condition may not be well-known and probably under-reported. Prospective travelers should be warned and patients can perhaps be cautiously reassured. PMID- 30430060 TI - The Role of Primary Care Physicians in Curtailing Harmful Social Media Trends. AB - Social media platforms, such as YouTube and Instagram, have become the latest medium for communication with a vast potential for influencing society. With their rise, a virtual market now exists where attention in the form of "likes," "views," and "followers" is traded for a monetary and psychological benefit. Amid this trade, physically risky behaviors have arisen to become a new attraction for attention, leading to numerous "trends" that encourage the same risk-taking behavior. Such trends, even those with a positive goal, have simultaneously led to injuries and fatalities, which highlights the necessity of a proactive approach to curtail the same. While media outlets and some non-governmental organizations usually highlight the risks of participating in these trends, the healthcare community has yet to have a collective and organized response to extreme social media participation. As such, a collaborative effort involving multiple tiers of the healthcare community is required to successfully prevent vulnerable populations from falling prey to the virtual attention-based economy of extreme social media participation. PMID- 30430061 TI - Conservative treatment of fingertip injuries in children - first experiences with a novel silicone finger cap that enables woundfluid analysis. AB - Introduction: Human fingertips are able to regenerate soft tissue and skin after amputation injuries with excellent cosmetic and functional results when treated with semiocclusive dressings. Despite bacterial colonizations, proceeding infections are not reported with this management. The underlying mechanisms for this form of regenerative healing as well as for the resilience to infections are not known. Due to the lack of mechanical protection, the leakage of maloderous woundfluid and the sometimes challenging application, conventional film dressings have their problems, especially in treating young children. We therefore treated selected patients with a novel silicone finger cap with an integrated wound fluid reservoir that enables atraumatic routine wound fluid aspiration. Methods: We report on 34 patients in between 1 and 13 years with traumatic fingertip amputations primarily treated with occlusive dressings. 12 patients were treated with a novel silicone finger cap. We summarized clinical data for each patient. This included photographs and microbiological results from wound fluid analyses, whenever available. Results: The results of both, conventional film dressing and silicone finger cap treatment, were excellent with no hypersensitivity and no restrictions in sensibility and motility. Even larger pulp defects were rearranged in a round shape and good soft tissue coverage of the distal phalanx was achieved. Nail deformities were not observed. We detected a wide spectrum of both aerobic and anaerobic bacteria in the wound fluids but infections were not observed. Epithelialization times did not differ significantly and no severe complications were seen in all primarily conservatively treated patients. Conclusion: This study provides preliminary data demonstrating that the treatment with the silicone finger cap leads to excellent clinical results in wound healing. Interestingly, the wounds were colonized with a wide range of bacteria including species that may cause wound infections. However, we saw no proceeding inflammation and the regeneration was undisturbed. In the future, the efficacy of this new management should be evaluated in randomized, controlled clinical trials to confirm the results under standard conditions and get more insight into the role of the wound microbiome as well as other factors that may promote regeneration. The aspirable Reservoir of the finger cap will enable easy atraumatic sampling of wound fluids both for diagnostic and for research purposes as well as possibly allowing direct administration of pro-regenerative drugs in the future. PMID- 30430062 TI - The Relationship between Salivary Total Antioxidant Capacity and Dental Caries in Children: A Meta-Analysis with Assessment of Moderators. AB - Objective: There has been variation reported in literature examining the relationship between dental caries and total antioxidant capacity (TAC) of saliva in children. This study aimed to systematically review the literature and conduct a meta-analysis of the association between dental caries and TAC in children. Methodology: A systematic review of literature was done using the PubMed, Medline, and EBSCO libraries. Of the total of 68 records found, 11 studies were qualitatively assessed in the final analysis. These studies yielded a total of 13 comparisons to be included in the meta-analysis. The type of dentition of the child and the test used to measure TAC were assigned as moderators. A meta analysis was done of the mean TAC levels, while a meta-regression was formulated using the moderators. All analyses were performed using OpenMetaAnalystTM meta analysis software (Brown University, RI, USA). Results: The meta-analysis showed significant increase in TAC in children with dental caries when compared to their caries-free counterparts (P < 0.001). The meta-analysis showed high levels of heterogeneity (I 2= 99.48). The meta-regression revealed that, while the type of dentition was a significant moderating factor (P = 0.002), the method used to assess the TAC was not (P = 0.053). Conclusion: There is a significant increase in TAC in children with dental caries when compared to their caries-free counterparts. PMID- 30430063 TI - Nickel-Titanium Rotary Instruments: Development of the Single-File Systems. AB - Over the past two decades, the nickel-titanium (NiTi) rotary instruments have highly improved the quality of the cleaning and shaping of the root canals. The superelasticity and shape memory of these instruments reduce the possibility of the canal transportation along with saving the time for both the patients and the clinicians. Several commercial types of these instruments, produced by different manufacturers, have currently become available by modifying the characteristics of the wonder NiTi alloy and also the cross-sectional shapes, cutting edges, tapering and numbers and distances of the flutes of the instruments. Up to this date, five generations for NiTi rotary instruments have been described according to the time of introduction, properties, and method of application. The aim of this article is to review the evolution of these five generations of NiTi rotary instruments since their inception. PMID- 30430064 TI - Effect of Hyaluronic Acid Added to Suture Material and its Relationship with Bacterial Colonization: An In vitro Study. AB - Aims and Objectives: The aims of this study were to evaluate the presence of Staphylococcus aureus and Escherichia coli, in polyglycolic acid (PGA) 4-0 and silk sutures, with or without hyaluronic acid (HA) treatment. Materials and Methods: This in vitro study measured S. aureus and E. coli growth on PGA and silk sutures, through incubation in agar media for 24 h. The suture length was 10 cm and divided into three parts: A (8 h), B (16 h), and C (24 h), which were observed every 8 h, followed by suspension on a microscopic slide. This was repeated thrice. The number of S. aureus and E. coli cells was recorded and compared between the suture types. Results: The mean S. aureus colony forming units (CFUs) differed at each time point between non-HA and HA-PGA sutures (P = 0.0016), with a greater number of CFUs on non-HA-PGA. The mean S. aureus CFUs were significantly higher on non-HA silk than on HA-silk sutures (P = 0.008). There was a significant increase in E. coli CFUs on non-HA silk than on HA-silk sutures (P = 0.008). E. coli CFUs were higher on non-HA-PGA than on HA-PGA sutures (P = 0.006). We performed repeated measures two-way ANOVA (SPSS version 13.0) for comparison between group factors and time points and Posthoc analysis using independent samples t-test. Conclusions: HA reduced wicking in both PGA and silk sutures. PMID- 30430065 TI - Evaluation of the Prevalence of Oral Mucosal Lesions in a Population of Eastern Coast of South India. AB - Objective/Aim: The aim of this study is to measure the association between oral mucosal lesions (OMLs) and habit of tobacco and alcohol in the population of Guntur city, Andhra Pradesh, South India. Material and Method: A cross-sectional study was conducted on 300 participants in Guntur city with the habit of tobacco and alcohol consumption in various forms who were selected by stratified cluster random sampling technique. Guntur city was divided into four zones, that is, North, East, South, and West; and two administrative wards were randomly selected from each zone as clusters. Information was obtained by interviewing the participant regarding various tobacco-related habits followed by standardized clinical examination in the field. Clinical data were collected using a modified 1980 WHO Pro forma where the basis for diagnosis was established as per the criteria provided by the epidemiology guide for the diagnosis of oral mucosal diseases (WHO). Statistical tests such as Pearson Chi-square were exercised to test the significance, using SPSS version 19.0 with 0.05 as cutoff level of significance. Results: Overall oral soft-tissue lesions were found in 42.4% of the study participants including nicotinic stomatitis, tobacco pouch keratosis, smokers melanosis, mild keratosis of the palate, and chewer's mucosa. In this study, nicotinic stomatitis was found to be the most common soft-tissue lesion among men, while leukoplakia was found to be the most common premalignant lesion with the prevalence being 5.7%. While oral submucous fibrosis was found to be the most common premalignant condition among women. It was found that 13.2% of illiterates (53) were having leukoplakia. In the present study, the lower labial mucosa and buccal mucosa were found to be the most common sites of occurrence of leukoplakia and oral submucous fibrosis. Conclusion: This study gives information on the association of OML in smokers, chewers, alcoholics, and those with mixed habits. This study highlighted six habit-related OML which included potentially malignant disorders such as leukoplakia and oral submucous fibrosis. Future case control or cohort studies for individual lesions and with larger sample size are necessary to evaluate the risk for OML including potentially malignant conditions and oral cancer resulting from smoking and chewing habits. PMID- 30430066 TI - A Preliminary Investigation into the Dietary and Oral Practices Associated with Fractured Teeth and Prostheses in a Trinidadian Population. AB - Objectives: This preliminary study seeks to determine the relationship between fractured teeth, restorations, prostheses, and specific dietary practices. Methodology: Anonymous questionnaires were randomly distributed to a convenience sample of Trinidadian adults at various locations around the country, after gaining consent. Data were analyzed using the software; Statistical Package for the Social Sciences for significant associations between various types of food and broken teeth or prosthesis using odds ratios. Results: Three hundred questionnaires were completed. Seventy-five percent of the patients preferred crunchy or hard foods and 51% of the respondents liked crushing bones, mostly chicken bones. It was observed that respondents with a dietary preference for fried whole chana, split chana, crab, and sugarcane were significantly associated with broken dentures. Respondents eating whole chana also had a significant association with broken teeth and broken dentures. Associations were found between some dietary preferences, ethnicities, and age groups. Conclusions: Significant associations between age, ethnicity, sex, and certain dietary practices and habits were found. There also appears to be a significant relationship between patients with fractured teeth, restorations, and prostheses with certain dietary preferences. PMID- 30430067 TI - Comparison of Light-Emitting Diode-Curing Unit and Halogen-Based Light-Curing Unit for the Polymerization of Orthodontic Resins: An In vitro Study. AB - Aims and Objectives: Conventionally, composites are cured using halogen-based light-curing units (LCUs). However, recently, light-emitting diode (LED) LCUs have been introduced commercially, claiming many advantages, yet producing comparable bond strength even when cured with single LED LCUs. This present study was undertaken to compare the shear bond strength of orthodontic brackets bonded to teeth with conventional halogen LCU (3M ESPE Elipar 2500) and LED LCU (3M ESPE Elipar FreeLight 2) and to determine the site of bond failure. Materials and Methods: Fifty extracted human bicuspid teeth were randomly divided into two groups of 25 each. All the teeth were etched and primed. Then, orthodontic brackets were bonded onto the teeth with the light-cured adhesive (Transbond XT, 3M Unitek), and the adhesive was cured with halogen LCU and LED LCU for Group I and Group II, respectively. The brackets were then subjected to shear stress using a Hounsfield universal testing machine at a crosshead speed of 1 mm/min. The force was recorded in Kgf and converted to MPa. The residual adhesive was scored based on the modified adhesive remnant index (ARI) using an optical stereomicroscope. The data were analyzed using the Student's t-test and the Mann Whitney test at a significance level of 0.05. Results: The results have shown that there is no significant difference between the shear bond strengths and the ARI scores of both the groups. Conclusion: From this study, it can be concluded that (1) LED LCUs containing even only a single LED can cure the composite as well as a halogen-based LCU; (2) there is no statistically significant difference in the shear bond strengths of the two groups; and (3) the ARI scores show no significant difference. PMID- 30430068 TI - Bite Force Evaluation in Complete Denture Wearer with Different Denture Base Materials: A Randomized Controlled Clinical Trial. AB - Aim: The aim of this study is to evaluate the maximum bite force (MBF) with different denture base materials in completely edentulous patients. Materials and Methods: MBF was evaluated in randomly selected 100 completely edentulous patients. Patients were selected from the Outpatient Clinic, College of Dentistry, Aljouf University, Saudi Arabia. The patients were randomly divided into two equal groups: Group I (control group): Patient received a conventional heat-cured acrylic complete denture (VertexTM Regular, Vertex-Dental B.V., The Netherlands) and Group II (experimental group): Patient received a thermoplastic complete denture (VertexTM ThermoSens, Vertex-Dental B.V., The Netherlands). MBF measurements were taken at the time of new denture placement and after 6 months of denture use. Statistics were analyzed using independent t-test to compare the MBF measurements between both groups. Results: At the time of denture placement, there was no significant difference in bite force measurements between both groups. Bite force is increasing considerably after 6 months of denture use, and it was higher than MBF recorded at the time of new prosthesis placement in the same group. The MBF values were considerably higher in patients with a thermoplastic denture than patients with conventional acrylic denture with statistically significant difference after 6 months of denture use. Conclusion: After 6 months of denture use, patients with a thermoplastic denture have a higher biting force than patients with a conventional acrylic denture. Therefore, it could be considered a treatment plan option according to the ridge nature and quality to solve the problem of diminished bite force in old age patients. PMID- 30430069 TI - Histopathological Evaluation of Dental Pulp of Primary Teeth Pulpotomized with Formocresol with/without a Capping Agent: A Randomized Clinical Trial. AB - Objectives: This study aimed to assess the reaction of dental pulp of pulpotomized teeth with/without applying a capping agent. This study was performed as randomized clinical trial. Materials and Methods: This split-mouth clinical trial was conducted on eight pairs of primary canine teeth scheduled for extraction as part of orthodontic treatment. The teeth were randomly assigned to the intervention and control groups. In the intervention group, canine teeth were restored with amalgam after pulpotomy with formocresol. In the control group, zinc oxide eugenol paste was applied as the capping agent after pulpotomy with formocresol, and the teeth were then restored with amalgam. After 1 month, the teeth were extracted in both groups and stained with hematoxylin and eosin for histological analysis. Pulp reaction was assessed in terms of pathological parameters. Data were analyzed using the Mann-Whitney U-test and Fisher's exact test. The statistical analysis software was SPSS 16. Results: No significant difference was found between the two groups in terms of inflammation, vitality, internal resorption, bleeding, presence of osteoclasts and dentinoclasts, and internal regeneration. Dentinal bridge did not form in any group. Conclusion: According to the results of this study, formocresol pulpotomy of primary teeth can be completed without the application of a capping agent. PMID- 30430070 TI - Efficacy of a Self-Designed Mobile Application to Improve Child Dental Health Knowledge among Parents. AB - Objectives: The objective of the study is to develop a mobile-based application and assess its efficacy in improving child dental health knowledge of parents. Subjects and Methods: A mobile-based application (Your child's smile) was developed and made available on application-store and play store. This application provided all essential information to parents on child dental health prepartum and from infancy to adolescence. To assess improvement in parent's knowledge two similar pretested questionnaires were incorporated within the application, one to be filled at initial registration and other after the parents had utilized the application. Responses were entered into MS excel sheet and analyzed using IBM SPSS statistics version 20.0. Results: Within the 15 days' research period, the application was downloaded by 230 parents out of whom 110 answered only the 1st and 120 both questionnaires. Out of the 120 who responded to both majority showed highly significant (P < 0.01) or significant (P < 0.05) improvement in their knowledge on tooth development, importance of deciduous teeth, importance of regular dental check-up, pit and fissure sealants, bedtime bottle use, and consequence of early loss of deciduous teeth. Confidence in child dental health knowledge was also evident in other areas with more parents opting for agreeing, strongly agree, or disagree options. A majority 75% of parents favored the use of mobile applications as an effective child dental health knowledge tool. Conclusion: Within the limitations of the study, we can conclude that mobile based applications are an effective tool for providing child oral health knowledge to parents and significant improvement in knowledge is evident after parents utilized the mobile-based application. PMID- 30430071 TI - Factors Affecting Access to Oral Health Care among Adults in Abha City, Saudi Arabia. AB - Aims and Objectives: To investigate the self-reported access problems to dental care among adults in Abha city, KSA. Materials and Methods: A cross-sectional descriptive survey was carried out among adults in Abha city, Saudi Arabia. A structured, close-ended, self-administered questionnaire elicited the access and utilization of dental care among a sample of adults. Data were collected and analyzed using SPSS version 21.0 statistical software. The descriptive statistics and logistic regression analysis were performed to predict the variables associated with access and utilization of dental care. Results: A total of 499 adults (male = 270, female = 229) participated in the study. More than half (289, 57.9%) of the participants utilized dental services and emergency services (283, 56.7%) were the most common reason to visit dentist. For most of the participants (281, 57.1%), the last dental visit was less than 1 year. Majority (409, 82%) of the participants self-funded for their treatment in private dental clinics (382, 76.6%). More than half (258, 51.7%) of the participants received restorative treatment during their last visit to dentist. Cost (39.1%) and lack of time (28.7%) were the main barriers to accessing dental care. Education and income were all involved in predicting nonutilization of dental services among the study participants. Conclusion: Access to and utilization of dental care are the multidimensional concepts influenced by many factors. Cost and lack of time were the predominant barriers to utilization of dental services. Access to dental care is a multidimensional issue with education and income, were considered as the significant predictors of nonutilization of dental services. Similarly, income and transportation problems significantly predicted the use of private dental services. Marital status, transportation problem, health problems, and difficulty in movement were all concerned with multiple barriers to accessing dental services among the study participants. PMID- 30430072 TI - Comparison of Cheiloscopy and Rugoscopy in Karnataka, Kerala, and Manipuri Population. AB - Aims and Objectives: The aim of the study was to evaluate and compare lip prints and palatal rugae pattern in Kerala, Karnataka, and Manipuri population. Materials and Methods: The study involved 180 individuals (60 each from Karnataka, Kerala, and Manipuri population). Lipstick was used to record lip prints, which were visualized by magnifying lens. Palatal rugae were recorded on maxillary casts of all subjects and analyzed following Kapali S et al.' s classification. Statistical Package for the Social Sciences version 20 for Windows software was used for analysis. Results: Among the study population, most frequent lip print pattern was Type 3 and least was Type 1'. When patterns were compared between groups, Type 3 was the most common in Manipuri and Kerala and Type 3 in Karnataka groups. In the entire population, males showed Type 3 and females showed Type 1. On analysis of overall rugae wavy, forward and divergence patterns were predominant. On comparison of gender, males demonstrated greater number of wavy and perpendicular rugae, and females had curved, straight, forward, and backward. Conclusion: Both cheiloscopy and rugoscopy have the prospective to recognize an individual. Cheiloscopy is more reliable than rugoscopy in making out the group and gender of an individual. PMID- 30430073 TI - Biomechanical Behavior of an Implant System Using Polyether Ether Ketone Bar: Finite Element Analysis. AB - Aim and Objectives: This study assessed, through finite element analysis, the biomechanical behavior of an implant system using the All-on-Four(r) technique with nickel-chromium (M1) and polyether ether ketone (PEEK) bars (M2). Materials and Methods: Implants and components were represented in three-dimensional (3D) geometric models and submitted to three types of load: axial, oblique, and load on all teeth. The 3D models were exported to a computer-aided design-like software such as Solidworks 2016 (Dassault Systemes, Solidworks Corps, USA) for editing and Nonuniform Rational Basis Splines parametrization. Results: Data were analyzed according to system's areas of action: peri-implant bone, implant, intermediates, intermediates' screws, prostheses' screws, and bars. Largest peak stress was shown in M2. Conclusion: PEEK is a promising material for use in dentistry; however, further studies are necessary to evaluate its performance. PMID- 30430074 TI - A Comparative Immunohistochemical Study of Presence and Distribution Pattern of Stromal Myofibroblast in Oral Dysplasia and in Different Grades of Oral Squamous Cell Carcinoma. AB - Aims and Objectives: Squamous cell carcinoma (SCC) is a common oral malignancy with a poor survival rate. Early tumorigenesis is marked by transdifferentiation of fibroblasts to myofibroblasts (MFs), which is supported by growth factors and cytokines expressed by tumor cells. The expression of alpha-smooth muscle actin (alphaSMA) marker correlates with the activation of MFs. This study was undertaken to compare the frequency and distribution of alphaSMA immunoexpression in oral epithelial dysplasia (OED) and OSCC. Materials and Methods: This study was conducted on samples collected from patients with oral epithelial dysplasia and oral SCC who visited Rajarajeswari Dental College and Hospital, Bengaluru. Tissue sections were subjected to Immunohistochemistry using alphaSMA marker, and cells were counted. The obtained data was subjected to Kruskal-Wallis test and Mann-Whitney U-test. Results: On performing Kruskal-Wallis test and Mann-Whitney U-test between the three groups (normal oral mucosa, OED, and OSCC) statistically significant result was found in the frequency between OED and OSCC and between normal tissue and OSCC. On comparing the distribution pattern, statistically significant result was found between OED and OSCC and between normal tissue and OSCC. Conclusion: The expression of MFs increases as the disease progresses from high-grade epithelial dysplasia to invasive OSCC. Poorly differentiated SCC showed more attendance of positive MFs in the stroma than other grades of OSCC. The rise in the number of alphaSMA-positive MFs and change in distribution pattern in OSCC can be associated with tumor invasive characteristics. Thus, the proliferation of MFs may be used as a stromal marker of premalignancy and malignancy. PMID- 30430075 TI - Effect of Recasting on Physical Properties of Base Metal Alloys: An In Vitro Study. AB - Aims and Objectives: This study aims to establish the outcome of recasting on tensile strength, modulus of elasticity, and hardness of Nickel-chromium alloys. Materials and Methods: Fifty wax patterns were fabricated, using the lost wax technique, the measurements of which were standardized. They were categorized into five groups of ten each. Group I included samples casted with new alloy alone. Group II samples consisted of 75% new alloy and 25% once casted alloy. Group III was casted with 50% of each. Group IV with 25% new metal and 75% previous alloy and samples of Group V samples were casted with once casted alloy alone. Modulus of elasticity and tensile strength were measured by universal testing machine, whereas hardness using microhardness tester. The values were statistically analysed. IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. IBM Corp, Armonk, NY, USA. for Windows software was used for analysis. Results: We found a slight variation in mean tensile strength and modulus of elasticity, which was statistically insignificant variation among the groups. However, there was a significant difference in mean hardness between Groups III, IV, and V. Conclusion: It is prudent to use pure alloy alone for casting. However, in view of environment and economical factors, addition of <50% reused alloy to pure alloy is satisfactory clinically. PMID- 30430076 TI - Knowledge, Attitude, and Practice toward Impression Technique and Materials for Recording Impression in Implant Placement among Dental Practitioners in Patna City, Bihar. AB - Objectives: The present study is conducted to explore the knowledge, attitude, and practice towards impression technique and materials for recording impression in implant placement among general dental practitioners. Materials and Methods: The present study is a cross-sectional questionnaire study. The study was conducted among general dental practitioners in Patna city in November-December 2017. Patna city was divided into five directions, which are north, south, east, west, and central. From each direction, 20 clinics were selected randomly, and dental practitioners from there clinics were interviewed. A closed-ended questionnaire consists of 19 items was prepared, the questionnaire was divided into four parts. Results: Majority of study participants (58 [34%]) were above the age of 40 years. 96 (56%) of study participants were male. Most of the study participants (89 [50%]) were having MDS degree. Knowledge, attitude, and behavior scores among study participants. About 43% of study participants have good knowledge scores regarding impression technique and material in implant placement while 50% of study participants had fair attitude score. About 58% of study participants had fair practice score. There was statistically significant correlation (P <= 0.05*) between knowledge and attitude of study participants. Conclusion: It was concluded that there was good knowledge, fair attitude, and practice among the dental professionals regarding the impression technique and materials for recording impression in implant placement. There was statistically significant correlation between knowledge and attitude of study participants. There was statistically significant correlation between some demographic variables and knowledge, attitude, and practice of study participants. PMID- 30430077 TI - Four-Year Follow-up of Increased Vertical Dimension of Occlusion using Resin Composites. AB - The objectives of this case report were to treat a severe loss of the vertical dimension of occlusion with indirect composite and to evaluate the durability of the restorations. A 55-year-old male complains from severe wear of teeth, leading to a change in normal occlusal plane. Two major treatment modalities were proposed to this patient; a conventional invasive crown placement with root canal treatments or a minimally invasive approach relying on adhesion. The latter was adopted and used to treat this patient. This paper describes a step-by-step approach of the different treatment phases starting with teeth preparation, then provisional prostheses, and ending with the placement of indirect anterior veneers and posterior onlays, all made with laboratory resin composite. Satisfactory clinical results were observed over the 4-year follow-up, with minimum failures limited to one partial fracture of inlay treated with direct adhesive repair. PMID- 30430078 TI - A Meta-Analysis of Vascular Endothelial Growth Factor for Nasopharyngeal Cancer Prognosis. AB - Background: Vascular endothelial growth factor (VEGF) has been reported to serve as a promising prognostic marker in several cancers. This meta-analysis aims to assess the prognostic significance of VEGF in nasopharyngeal cancer (NPC). Methods: We conducted a systematic literature search of PubMed, Embase, and the Cochrane Library for observational studies published until June, 2018 to identify observational studies on the prognostic effect of tissue VEGF expression or serum VEGF level on the survival of NPC. The primary outcome measure assessed was overall survival (OS). The secondary outcomes included disease-free survival (DFS) or progression-free survival (PFS). Summary hazard ratio (HR) and its 95% confidence interval (95% CI) were derived using a random-effects model. Results: Out of 840 retrieved citations, 16 studies inclusive of 1,345 patients were included in the analysis of tissue VEGF expression and cancer survival. The pooled HRs for OS and DFS in patients with high VEGF expression were 2.07 (95% CI: 1.32-3.25) and 5.99 (95% CI: 2.66-13.48), respectively, with significant heterogeneity between studies (I2 = 79.1% for OS and 50.2% for DFS). Tissue high VEGF expression was not significantly associated with short RFS, PFS, or MFS. Five studies also investigated the prognostic effect between serum VEGF level and patient survival and found that high serum VEGF level was significantly associated with short OS for patients with NPC (HR 2.47, 95% CI 1.16-5.28), but not with short PFS (HR 1.47, 95% CI 0.92-2.35). Conclusions: Determination of tissue VEGF expression and serum VEGF level have the potential to serve as biomarkers and add prognostic information in NPC. Prospective analyses of associated data on VEGF expression and serum VEGF level in large NPC cohorts could be further conducted to advance our understanding of the relationship between VEGF and NPC outcomes. PMID- 30430079 TI - CD44 Expression Profile Varies According to Maturational Subtypes and Molecular Profiles of Pediatric T-Cell Lymphoblastic Leukemia. AB - CD44 is a glycoprotein expressed in leucocytes and a marker of leukemia initiating cells, being shown to be important in the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL). In this study, we have (i) identified the aberrant antigenic pattern of CD44 and its isoform CD44v6 in T-ALL; (ii) tested the association with different T-cell subtypes and genomic alterations; (iii) identified the impact of CD44 status in T-ALL outcome. Samples from 184 patients (123 T-ALL and 61 AML; <19 years) were analyzed throughout multiparametric flow cytometry. Mutations in N/KRAS, NOTCH1, FBXW7 as well as STIL-TAL1 and TLX3 rearrangements were detected using standard molecular techniques. CD44 expression was characterized in all T-ALL and AML cases. Compared with AML samples in which the median fluorescence intensity (MFI) was 79.1 (1-1272), T-ALL was relatively low, with MFI 43.2 (1.9-1239); CD44v6 expression was rarely found, MFI 1 (0.3 3.7). T-ALL immature subtypes (mCD3/CD1aneg) had a lower CD44 expression, MFI 57.5 (2.7-866.3), whereas mCD3/TCRgammadeltapos cases had higher expressions, MFI 99.9 (16.4-866.3). NOTCH1 mut and STIL-TAL1 were associated with low CD44 expression, whereas N/KRAS mut and FBXW7 mut cases had intermediate expression. In relation to clinical features, CD44 expression was associated with tumor infiltrations (p = 0.065). However, no association was found with initial treatment responses and overall survival prediction. Our results indicate that CD44 is aberrantly expressed in T-ALL being influenced by different genomic alterations. Unraveling this intricate mechanism is required to place CD44 as a therapeutic target in T-ALL. PMID- 30430080 TI - GEMO, a National Resource to Study Genetic Modifiers of Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Pathogenic Variant Carriers. PMID- 30430081 TI - Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma. AB - Objective: Cathepsin D (CTSD) is a pivotal orchestrator in the occurrence and development of tumors. Recently, CTSD was detected in salivary adenoid cystic carcinoma (SACC). However, its functional role in perineural invasion (PNI) of SACC remained elusive. We conducted the present study to detect the expression of CTSD in SACC, analyze the correlation between CTSD expression and prognosis of SACC patients and elucidate the role of CTSD in occurrence of PNI in SACC to lay the foundation for further studies. Methods: Immunohistochemical analysis was conducted to assess CTSD and Ki67 expression in 158 SACC samples and 20 normal salivary gland samples adjacent to carcinoma. Meanwhile, the correlation between CTSD and PNI of SACC specimens was analyzed using Wilcoxon test. QRT-PCR, immunofluorescence and western blot analysis were used to examine the levels of CTSD mRNA and protein in SACC-LM cell line. SiRNA-mediated CTSD silence was performed. Scratch wound healing assay, transwell invasion assay and DRG co culture assay of PNI was used to detect the ability of migration, invasion and PNI. FITC-phalloidin was used to detect cytoskeletal organization. Results: Our data demonstrated that the positive expression of CTSD was observed in 74.1% (117/158) of SACC cases, and the expression of CTSD was significantly correlated with the PNI (p < 0.05). The ability of migration, invasion, and PNI could be inhibited significantly by siRNA-mediated CTSD silence (p < 0.01). Furthermore, siRNA-mediated CTSD silence inhibited cytoskeletal organization and pseudo foot formation in SACC-LM cells. Conclusion: Our results suggested that an association between PNI and expression of CTSD existed. CTSD may promote PNI of SACC accompanied by cytoskeletal organization and pseudo foot formation. PMID- 30430082 TI - Association of One-Carbon Metabolism-Related Vitamins (Folate, B6, B12), Homocysteine and Methionine With the Risk of Lung Cancer: Systematic Review and Meta-Analysis. AB - Background: Studies on serum one-carbon metabolism factors (folate, B6, B12, homocysteine, and methionine) with lung cancer (LC) risk have produced inconsistent results. We aimed to systematically evaluate the association between them. Methods: This study was reported in accordance with the PRISMA Statement and was registered with PROSPERO (no. CRD42018086654). Relevant studies were searched in PubMed, Embase, MEDLINE, and CNKI up to February 2018. Random-effects models were used to estimate the pooled standardized mean differences (SMD) or odds ratios (OR), as well as their 95% confidence interval (CI). Sensitivity and subgroup analysis were performed to identify the source of heterogeneity. Publication bias was also assessed. Results: A total of 14 articles (8,097 patients) were included. The concentration of serum folate and vitamin B6 of LC patients were lower than the controls [SMD -0.53, 95% CI (-0.70, -0.35), p = 0.001 and SMD -0.28, 95%CI (-0.53, -0.02), p = 0.001, respectively]. While the concentration of homocysteine of the cases was higher than the controls [SMD 0.41, 95% CI (0.24, 0.59), p = 0.001]. However, there were no significant differences between LC patients and the controls in terms of vitamin B12 and methionine [SMD -0.09, 95% CI (-0.27, 0.09), p = 0.202 and SMD -0.13, 95% CI ( 0.36, 0.10), p = 0.001]. Subgroup analysis showed that these results were more significant in Europe, Asia, former and current smokers, and the male population (p-value < 0.05). Conclusions: Serum folate and vitamin B6 might be protective factors against lung carcinogenesis and homocysteine could contribute to LC risk. PMID- 30430083 TI - Management of Intracranial Metastatic Disease With Laser Interstitial Thermal Therapy. AB - Treatment approaches for metastatic brain tumors continue to evolve, with increasing recent emphasis on focal therapies whenever possible. MRI-guided Laser Interstitial Thermal Therapy (LITT) is a minimally invasive surgical option that has broadened the capability of the neurosurgeon in treating difficult-to-treat intracranial lesions. This technology uses image-guided delivery of laser to the target lesion to generate heat and thereby ablate pathological tissue and has expanded the neurosurgical armamentarium for surgical treatment of brain metastases. In this study, we describe the indications for LITT in the management of intracranial metastatic disease and report our institutional experience with LITT. PMID- 30430084 TI - Community-based study on the knowledge, awareness, and practices of females towards breast cancer in Buraimi, Oman. AB - Background: In Oman, a higher proportion of patients presented with breast cancer are relatively young age and with an advanced stage. This could be due to lack of awareness and knowledge about breast cancer among young women. Aim: To assess the breast cancer knowledge, awareness and factors associated with the practice of breast self-examination (BSE) among females in Buraimi, Oman. Methods: A cross sectional survey was conducted among females attending the two days health exhibition event at a polyclinc, in Al-Buraimi, governorate. A pretested questionnaire to assess their knowledge, awareness and practices concerned to breast cancer was used. The collected data was categorized, analyzed using descriptive statistics and logistic regression model. All the statistical analysis was performed using SPSS 21.0 version. Results: Out of the total of one hundred and eighty nine (189) participants, 80% had information of breast cancer. Participants had better knowledge of symptoms but less knowledge about risk factors. When probed about BSE, only 43% performed it and only 21% of them do it monthly on regular basis. The main reasons for regular monthly BSE is mainly because of fear of breast cancer (9%), doctor's advice (6%) and awareness through media (5%). Conclusion: Our study participants showed insufficient knowledge in some areas related to sign and symptoms and risk factors of breast cancer and identified a negative influence of low knowledge on the practice of BSE. Thus, educational interventions need to be emphasized to provide comprehensive information of breast cancer. PMID- 30430085 TI - Chryseobacterium indologenes: An emerging uropathogen among hematological malignancy patients. PMID- 30430086 TI - Modified 5-fluorouracil/leucovorin/irinotecan as a feasible and efficacious second-line chemotherapeutic regimen in advanced gastric cancers. AB - Background: Modified 5-fluorouracil/leucovorin/irinotecan (mFOLFIRI) is a commonly used combination second-line chemotherapeutic regimen in advanced gastric cancer (AGC). Materials and Methods: Patients diagnosed with AGC, receiving biweekly mFOLFIRI between July 2013 and June 2016, as second-line chemotherapy were retrospectively analyzed for tolerance, prognostic factors, event-free survival (EFS), and overall survival (OS). Results: Overall, 91 patients were administered a median of 6 cycles of therapy. Response rate was 29.7% and clinical benefit rate was 57.2%. With a median follow-up of 11.5 months, median EFS was 3.98 months (95% confidence interval [CI]: 2.54-5.41) and median OS was 7.73 months (95% CI: 5.30-10.15). Common Grade 3 and Grade 4 adverse events were neutropenia (18.7%), febrile neutropenia (9.9%), thrombocytopenia (7.7%), and vomiting (4.4%). Nearly 33% of patients required dose modification during therapy. Conclusions: mFOLFIRI regimen as a second-line therapy in AGCs appears feasible and efficacious in clinical practice. PMID- 30430087 TI - Chronic myelomonocytic leukemia presenting as upper limb gangrene. PMID- 30430088 TI - Retrospective study of oxaliplatin, leucovarin and 5 fluoruracil regimen in patients with advanced gastric cancer with poor performance status: A study at a tertiary center of South India. AB - Background: Gastric carcinoma is the leading cause of cancer in south India. Gastric cancer is frequently diagnosed in locally advanced or metastatic setting in Indian scenario and has a poor survival. There is no standard chemotherapy regimen which can be used in advanced gastric cancer (AGC) patients. Objective: The aim of this study was to assess the clinical activity and toxicity of oxaliplatin with infusional 5-fluorouracil and leucovorin administered every 3 weeks in patients with locally advanced and inoperable gastric cancer. Patients and Methods: In this retrospective study, the case records of 25 patients who have received OLF regimen were analyzed. Results: The median number of cycles for patients was 6 (range: 4-12 cycles). Overall response rate was 36%, with all patients having stable disease. Median survival of patients was 6 months (7 months in locally advanced). Compared to other regimens, there was less toxicity (less hematologic toxicity, less nausea and vomiting, no hair loss, no renal toxicity, no hand foot syndrome, and lesser admissions). Conclusions: OLF regimen is an acceptable regimen in poor performance status AGC patients with adequate response and an acceptable toxicity profile. PMID- 30430089 TI - Treatment outcomes of metastatic nonclear cell renal cell carcinoma: A single institution retrospective analysis. AB - Introduction: Nonclear cell (NCC) metastatic renal cell carcinoma (mRCC) is a biologically heterogeneous entity. We report the outcomes of NCC mRCC treated with first-line vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin (mTOR) inhibitors at our institute. This is first such report from India. Methods: This is a retrospective analysis of the 40 consecutive patients of NCC mRCC treated between January 2013 and June 2015 in routine clinical practice at our institute. The primary endpoint analyzed was overall survival (OS) with respect to the type of first-line treatment and tumor histology. Results: The most common histological subtype was papillary in 25 patients (62.5%) followed by sarcomatoid in six (15%), chromophobe in 5 (12.5%), translocation-associated in one patient, and other nonspecified in three patients. First-line treatment was sorafenib in 14 (35%), sunitinib in 9 (22.5%), pazopanib in 8 (20%), everolimus in seven (17.5%), and best-supportive care (BSC) in two (5%) patients. Partial response, stable disease, and progression was observed in six (15%), 13 (32.5%), and nine (22.5%) cases, respectively, as the best response to first-line treatment. The median OS was 11.7 months and median event-free survival was 6.1 months in the whole cohort. The median OS in months for different first-line treatments were as follows: sorafenib (16.2), sunitinib (11.7), pazopanib (not reached, mean-23.9 +/- 6.0), everolimus (4.1) and BSC (0.6) and for different histological subtypes were as follows: papillary (9.8), chromophobe (not reached, mean-30.3 +/- 8.4), sarcomatoid (4.1), and others (7.9). Conclusions: Chromophobe histology has a better outcome compared to other histological subtypes, and anti-VEGF tyrosine kinase inhibitors are preferable first-line agents compared to mTOR inhibitors. PMID- 30430090 TI - Treatment of locally advanced carcinoma cervix with special emphasis on brachytherapy: A practice pattern survey among young radiation oncologist of India. AB - Background: Carcinoma cervix is one of the two most common cancers of Indian women with very high morbidity and mortality burden. Although India probably is the leading country in numbers patients of cervix treated radically with combination of teletherapy and brachytherapy (BT), there is presumed diversity of practice across the country due to the inequality of available infrastructure, absence of uniform the training of the radiation oncologists, and absence of any national guidelines. The present survey was conducted to determine current practice patterns in management of locally advanced carcinoma cervix with regard to gynecologic high-dose-rate among the radiation oncologist across the country. Methodology: A 25-item survey was undertaken to study the standard management pattern of Stage IIB-IIIB cervical cancer with special emphasis on the BT practice patterns among various young radiation oncologist working across the country. The survey was undertaken in person in the form of interview questionnaire among the younger members of association of radiation oncologist of India during two national conferences, along with telephonic interview of other members as obtained from the national directory. Results: About 57 young radiation oncologists from 57 centers across the country were surveyed. 25 of them represented private nonacademic centers, 24 represented government academic centers, the rest were from private academic, nongovernmental organization (NGO) run and other centers. The most common teletherapy dose prescribed was 46 Gy/23# for Stage II, and50 Gy/25 # for Stage III disease. HDR after loader with 192Ir is the most common machine (82.6%) in use and computed tomography scan is the most commonly (30/57) used imaging for planning. The most common intracavitary dose pattern for all stages was 7 Gy * 3 fractions (30/57s) and 9 Gy * 2 (12/57) fractions. Although in most centers, computed tomography-based delineation of organs at risk is done routinely; however, target volume delineation and dose prescription/optimization for the same is routinely done in handful of centers (5/57). The mean planned dose to Point A for combined external-beam radiation and BT (EQD210) was about 77.5 Gy for Stage IIIB and 72.6 Gy for Stage II disease. Conclusion: Although fractionation patterns may vary, the overall mean dose administered for cervical cancer is similar across the country, which is slightly lower than the recommended doses as per stage by various international guidelines. PMID- 30430091 TI - Expression of p16INK4a and human papillomavirus 16 with associated risk factors in cervical premalignant and malignant lesions. AB - Introduction: Human papilloma virus (HPV) which is causative factor for cervical cancer may interact with p16 leading to malignant transformation of cervical epithelial cells. The present study was conducted to assess the immunoexpression of p16 INK4a in premalignant and malignant lesions of cervix and to correlate it with HPV 16 expression. It was also intended to study the various risk factors which may be associated with cervical cancer in this north Himalayan region of India. Material and Methods: The study included 50 cases of premalignant and malignant cervical lesions and 50 controls diagnosed on histopathology over a period of one year. All the relevant clinical details were noted and both cases and controls were subjected to HPV 16 and p16 INK4a immunohistochemical staining. Results: 67% of subjects (including cases and controls) and 94% of the cases were positive for HPV 16 expression. p16 INK4a expression was negative in all the controls, positive in 96% of invasive cancer, 66.6% in HSIL and 37.5% in LSIL. Conclusion: Cervical cancer is associated with low socio economic status, illiteracy, smoking, early age of marriage and conception in north Himalayan region of India. HPV 16 infection is positive in both cases and controls indicating high prevalence of HPV 16 in this region. Neoplastic transformation by HPV is identified by over expression of p16 INK4a in premalignant and malignant cases. The immunopositivity of p16 INK4a increases with the severity of cervical lesions and thus may play an important role in stratification of premalignant and malignant lesions. PMID- 30430092 TI - Age-adjusted charlson comorbidity index and 30-day morbidity in pelvic surgeries. AB - Introduction: Charlson comorbidity index (CCI) is a validated tool enabling clinicians for prediction of adverse events posttherapy. In this study, we planned to estimate the predictive value of age-adjusted CCI (ACCI) in assessing the perioperative complication in oncological patients undergoing major pelvic surgeries. Methods: This was a single arm, prospective, observational study, in which adult patients with pelvic malignancies undergoing pelvic surgeries were selected. The relationship between the ACCI and Grade 3-5 adverse events were tested using Fisher's test. Results: The rate of Grade 3-5 adverse event rate was 16.7% (11 patients, n = 66). Among the whole cohort, 11 patients (16.7%) had high score on ACCI. The rate of Grade 3-5 adverse events was higher in the cohort of patients with high ACCI score (45.5% vs. 10.9%, P = 0.014). The sensitivity, specificity and negative and positive predictive values were 45.5%, 89.1%, 89.1%, and 45.5%, respectively. Conclusion: ACCI can predict for postsurgical adverse events. It has a high negative predictive value for nonoccurrence of adverse events. PMID- 30430093 TI - Population-based cancer screening through community participation: Outcome of a district wide oral cancer screening program from rural Kannur, Kerala, India. AB - Background: Oral cancer is a major public health challenge, and about one-fifth of all oral cancer cases reported globally are from India. In spite of the potential for early detection by simple visual examination, the majority of patients report in later stages of the disease, especially in low and middle income countries. We report the results from a district level population-based oral cancer screening program. Methods: A cross-sectional survey was carried out among people aged >15 years in 48 panchayats of Kannur district in Kerala, India. This comprehensive multi-stakeholder district-wide screening was carried out in six stages including planning, sensitization, recruiting of community volunteers and training, survey, organization of specialist camps and referring to cases to cancer center. The descriptive statistical analysis was performed using EpiData analysis software (Version 2.2.2.180). Results: Among the 1,061,088 people in 265,272 houses surveyed, 2507 of them attended the screening camps, and 13 oral cancers and 174 oral precancers were detected. Majority of the oral cancer patients were male (69%), with primary education or illiterate (62%) and low socioeconomic status (61%). Five of the patients diagnosed with early-stage cancer are alive and have good oral health-related quality of life. Conclusion: Detection of precancerous and early-stage cancers should be a priority of oral cancer screening programs. The possible key for addressing cancer screening needs of the rural population is to equip the primary health centers in cancer screening activities with available human resources while adapting to local context. PMID- 30430094 TI - Quality of life and quality-adjusted time without toxicity in palliatively treated head-and-neck cancer patients. AB - Background: Quality-adjusted time without toxicity (Q-TWiST) and quality of life (QOL) are indicators of benefit provided by different chemotherapy regimens. Methods: This was a prospective study, in which adult head-and-neck (H and N) cancer patients, treated with metronomic chemotherapy were enrolled. The Functional Assessment of Cancer Therapy-General H and N (FACT-G and H and N) version 4 pro formas were self-administered before the start of chemotherapy and then at 2, 4, and 6 months. FACT QOL and Q-TWiST analysis were then performed. Results: There was an improvement in the social well-being (P = 0.370), emotional well-being (P = 0.000), functional well-being (P = 0.000), H and N cancer subscale (P = 0.001), FACT H and N trial outcome index (P = 0.000), FACT G-total score (P = 0.000), and FACT H and N total score (P = 0.000) with palliative chemotherapy. The QTWiST value for a utility score of 0.25 for toxicity and relapse state was 145.93 days. Conclusion: Metronomic chemotherapy is associated with improvement in QOL and has a low duration of time spent in toxicity state. PMID- 30430095 TI - Safety and efficacy of weekly versus three-weekly paclitaxel plus platinum neoadjuvant chemotherapy in patients with locally advanced squamous cell head and neck carcinoma: A pilot study. AB - Background: Squamous cell carcinoma of head and neck (SCCHN) is one of the most common cancers seen in India and also the world. Majority of patients present in locally advanced (LA) disease where neoadjuvant combination chemotherapy with a taxane plus platinum with/without 5-Fluorouracil is the standard of care treatment. There are no/few prospective trials of weekly paclitaxel in SCCHN in spite of convincing evidence regarding safety and tolerability in other solid tumors such as breast, ovary, and lung carcinoma. In the present study, we prospectively assessed the safety and efficacy of weekly versus three-weekly paclitaxel plus platinum neoadjuvant chemotherapy in patients with LA-SCCHN. Materials and Methods: We included 50 newly diagnosed patients of LA-SCCHN in the study and randomized them into two groups to receive either low-dose weekly (80 mg/sq. m) or standard three-weekly (175 mg/sq. m) paclitaxel along with standard dose carboplatin (AUC 5) and assessed response rates and toxicities. Results: Age and sex were evenly matched in both groups. Oral and oropharyngeal cancers were the most common sites. Hematological toxicities were significantly more in the three-weekly group. Nonhematological toxicities, especially neuropathy, were also more in this group. The overall response rate (complete response + partial response) in the three-weekly arm was 36% versus 52% in the weekly arm. Conclusion: Data from our small study suggest that weekly paclitaxel plus platinum neoadjuvant chemotherapy may be superior to the standard every 3 weeks' administration in terms of safety as well as efficacy in patients with LA-SCCHN. PMID- 30430097 TI - A rare case of pinealoblastoma in adult with complete response to treatment. PMID- 30430096 TI - Comparative analysis of the Sokal, Euro and European Treatment and Outcome Study score in prognostication of Indian chronic myeloid leukemia-chronic phase patients on imatinib. AB - Introduction: The ultimate goal for CML management is risk stratification of the patients to design the appropriate treatment approach. The Sokal, Euro and EUTOS risk scores were established to prognosticate the patients on therapy. Aim: To perform a comparative assessment of the Sokal, Euro and EUTOS prognostic score in Indian CML-CP patients on imatinib. Methods: This is a retrospective study performed in 260 Ph+ CML-CP patients who were administered oral imatinib (400 mg/day). Results: 166/260 were males and 94/260 were females (M: F::1.6:1) with median age 35 years (range 20-70). 92 (35.38%), 125 (48.07%) and 43 (16.5%) patients were divided into low, intermediate and high risk Sokal score respectively. 102 (39.23%), 106 (40.76%) and 52 (20%) patients were discriminated into low, intermediate and high risk Euro score respectively. 210 (80.7%) and 50 (19.2%) patients were divided into low and high risk EUTOS score. Cumulative incidence of MMR for low, intermediate and high-risk Sokal score was 87%, 76% and 84% respectively (P = 0.016). Incidence of MMR in low, intermediate and high-risk Euro score was 93%, 85% and 68% respectively (P = 0.001). Incidence of MMR was 80 % and 81% for low and high risk EUTOS score (P = 0.764). Both EFS and OS are significantly correlated with Sokal score (P = 0.004, P = 0.007) and Euro score (P = 0.009, P = 0.001) but not with EUTOS score (P = 0.581, P = 0.927). Conclusion: The present study highlights the significant prognostic role of Sokal and Euro score in predicting the treatment outcome of the CML- CP patients on imatinib. PMID- 30430098 TI - Impact of cytogenetics on outcomes in pediatric acute lymphoblastic leukemia. AB - Context: In acute lymphoblastic leukemia (ALL), the most important prognostic factors are age, leukocyte count at presentation, immunophenotype, and cytogenetic abnormalities. The cytogenetic abnormalities are associated with distinct immunologic phenotypes of ALL and characteristic outcomes. Aims: The present study was primarily aimed at analyzing the impact of cytogenetics on postinduction responses and event-free survival (EFS) in pediatric patients with ALL. The secondary objective was to study the overall survival (OS). Subjects and Methods: A total of 240 patients with age <18 years and diagnosed with ALL between January 2011 and June 2016 were retrospectively analyzed. Cytogenetics was evaluated with conventional karyotyping or reverse transcriptase polymerase chain reaction. Based on cytogenetic abnormalities, the patients were grouped into five categories, and the outcomes were analyzed. Results: Of the 240 patients, 125 (52%) patients had evaluable cytogenetics. Of these, 77 (61.6%) patients had normal cytogenetics, 19 (15.2%) had t(9;22) translocation, 10 (8%) had unfavorable cytogenetics which included t(9;11), hypodiploidy, and complex karyotype, 10 (8%) had favorable cytogenetics which included t(12;21), t(1;19), and high hyperdiploidy, 9 (7.2%) had miscellaneous cytogenetics. Seventy-one percent of patients were treated with MCP 841 protocol, while 29% of patients received BFM-ALL 95 protocol. The 3-year EFS and OS of the entire group were 52% and 58%, respectively. On univariate analysis, EFS and OS were significantly lower in t(9;22) compared to normal cytogenetics (P = 0.033 and P = 0.0253, respectively) and were not significant for other subgroups compared to normal cytogenetics. On multivariate analysis, EFS was significantly lower for t(9;22) and unfavorable subgroups. Conclusions: Cytogenetics plays an important role in the molecular characterization of ALL defining the prognostic subgroups. Patients with unfavorable cytogenetics and with t(9;22) have poorer outcomes. PMID- 30430099 TI - Clinical and endoscopic response to high dose rate endobronchial brachytherapy in malignant lung tumors: A single centre experience. AB - Purpose: The aim of the study was to evaluate the short-term clinical, endoscopic response, and acute toxicities in endobronchial cancer treated with high-dose rate endobronchial brachytherapy (HDR-EB). Materials and Methods: Thirty patients of advanced endobronchial cancers were treated with HDR-EB. Brachytherapy was delivered at a depth of 1 cm from the source axis at weeks 1, 2, and 3 with 7 Gy per fraction. All patients were evaluated before treatment and at 1 month after completion of therapy. Using Speiser's scoring criteria, the severity of symptoms (dyspnea, cough, hemoptysis, and postobstructive pneumonia) and degree of obstruction were graded. Results: Symptomatic response for cough, dyspnea, and hemoptysis was seen in 88%, 75%, and 96%, respectively, with a significant P value (<0.05). Obstructive pneumonia was resolved in 94% of patients. Endoscopic response in terms of degree of obstruction was seen in 84% of patients. Acute toxicities in the form of radiation bronchitis were seen in 32% of patients, whereas 8% of patients experienced esophagitis. Bronchospasm was seen in one patient during treatment. Conclusion: HDR brachytherapy is a highly effective, safe, convenient therapy in alleviating symptoms of endobronchial obstruction with endoscopic response in the majority of cases. Thus, HDR-BT is a promising treatment for palliation of patients presenting with symptoms of endobronchial obstruction with an acceptable rate of complications. PMID- 30430100 TI - Clinicopathological features, treatment and survival outcomes of synovial sarcoma. AB - Introduction: Synovial sarcoma (SS) is a malignant mesenchymal tumor. It is most common among children and adults. The data on SS from India are scarce. In this study, we analyzed the clinicopathological treatment parameters and survival outcomes of SS patients. Materials and Methods: A total of 57 histologically proven SS diagnosed from 2010 to 2016 were retrospectively analyzed. Results: The median age was 23 years with a male-to-female ratio of 1.28:1. Localized disease was seen in 44 patients (77%) and 13 patients (23%) had metastasis. The primary sites of involvement such as lower limb, upper limb, thorax, and abdomen were seen in 60%, 28%, 7%, and 5% patients, respectively. Surgery was done in 39 patients and 18 patients had unresectable disease. Adjuvant chemotherapy with doxorubicin-based regimen was given in 30 patients and adjuvant radiotherapy in 21 patients. Palliative chemotherapy with anthracycline-based or gemcitabine based regimen was used in 17 and 2 patients, respectively. The median event-free survival (EFS) was 30 months with 3 years and EFS rate was 36%; median progression-free survival (PFS) was 11.5 months and 1 year; and PFS rate was 38%. On univariate analysis, resection and performance status were significantly associated with survival. There is no impact of grade and size of the tumor on survival. In metastatic patients, the lung is the most common site. Conclusion: SS is the most common soft-tissue sarcoma among adults. Resectability and performance status were impacting the survival. PMID- 30430101 TI - Three-dimensional analysis of the anterior loop of the inferior alveolar nerve in relation to the growth pattern of the mandibular functional subunit. AB - Background: The purpose of the present study was to investigate the differences in the position and shape of the anterior loop of the inferior alveolar nerve (ALIAN) in relation to the growth pattern of the mandibular functional subunit. Methods: The study was conducted on 56 patients among those who had undergone orthognathic surgery at the Gangnam Severance Hospital between January 2010 and December 2015. Preoperative computerized tomography (CT) images were analyzed using the Simplant OMS software (ver.14.0 Materialise Medical, Leuven, Belgium). The anterior and inferior lengths of ALIAN (dAnt and dInf) and each length of the mandibular functional subunits were measured. The relationship between dAnt, dInf, and the growth pattern of the mandibular subunits was analyzed. Results: The length of the anterior portion of ALIAN (dAnt) reached 3.34 +/- 1.59 mm in prognathism and 1.00 +/- 0.97 mm in retrognathism. The length of the inferior portion of ALIAN (dInf) reached 6.81 +/- 1.33 mm in prognathism and 5.56 +/- 1.34 mm in retrognathism. The analysis of Pearson's correlation coefficiency on all samples showed that the lengths of functional subunits were positively correlated with the loop depth. The length of the symphysis area in prognathic patients was positively correlated with the anterior loop depth (p = 0.005). Conclusions: Both the anterior and inferior length of ALIAN are longer in prognathic patients. Especially, it seems to be associated with the growth of the symphysis area. PMID- 30430102 TI - Individualized Fortification Influences the Osmolality of Human Milk. AB - Background: Fortification of human milk (HM) increases its osmolality, which is associated with an increased risk of necrotizing enterocolitis. The impact of new fortifiers on osmolality is not well-known, nor are the kinetics regarding the increase in osmolality. Aim: To determine the optimum fortifier composition for HM fortification by measuring the osmolality of fortified HM made with three powder multicomponent fortifiers (MCFs) and a protein fortifier (PF). Methods: The osmolality of HM was assessed at 2 (H2) and 24 (H24) h after fortification to compare the effects of MCF (MCF1-3) and PF used in quantities that ensured that infants' nutrient needs would be met (MCF: 4 g/100 ml HM; PF: 0.5 g or 1 g/100 ml HM). To evaluate the early kinetics associated with the osmolality increase, the osmolality of HM fortified with MCF1 or MCF2 was also measured at 0, 1, 5, 10, 15, 20, 30, 40, 50, 60, 90, and 120 min after fortification. Results: The osmolality increased significantly immediately after fortification, depending on the type of fortification used and the quantity of MCF and PF used, rather than the time elapsed after fortification. The maximum value at H24 was 484 mOsm/kg. The mean increase in osmolality between H2 and H24 was 3.1% (p < 0.01) (range: 0.2-10.8%). Most of the increase (>70%) occurred immediately after fortification. Conclusion: When choosing a fortifier, its effect on HM osmolality should be considered. As most of the increase in osmolality occurred immediately, bedside fortification is not useful to prevent the increase in osmolality, and further research should focus on improving fortifier composition. PMID- 30430103 TI - A Decision Tree for Donor Human Milk: An Example Tool to Protect, Promote, and Support Breastfeeding. AB - Despite decades of breastfeeding promotion, exclusive breastfeeding rates for the first 6 months of life remain low: around 40% globally. Infants that are admitted to a neonatal ward are even less likely to be exclusively breastfed. Lactogenesis is frequently delayed in mothers that deliver early, with the added burden of separation of the unstable newborn and mother. For such vulnerable infants, donor human milk is recommended by the World Health Organization, UNICEF, and professional organizations as the next best alternative when mother's own milk is unavailable and can serve as a bridge to full feeding with mother's own milk. Hospital support of optimal breastfeeding practices is essential with thoughtful integration of donor human milk policies for those infants that need it most. We propose a decision tree for neonatal wards that are considering the use of donor human milk to ensure donor human milk is used to replace formula, not to replace mothers' own milk. By first evaluating barriers to full feeding with mother's own milk, healthcare workers are encouraged to systematically consider the appropriateness of donor human milk. This tool also seeks to prevent overuse of donor human milk, which has the potential to undermine successful lactation development. In settings where donor human milk supplies are limited, prioritization of infants by medical status is also needed. Readily available and easy-to-use tools are needed to support healthcare staff and mothers in order to improve lactation development and neonatal nutrition. PMID- 30430104 TI - High Pressure Balloon Dilatation of Primary Obstructive Megaureter in Children: A Multicenter Study. AB - Aim of the Study: We described the initial experience of four referral centers in the treatment of primary obstructive megaureter (POM) in children, by high pressure balloon dilatation (HPBD) of the ureterovesical junction with double JJ stenting. We managed a retrospective multicenter study to assess its effectiveness in long-term. Methods: We reviewed the medical records of all children who underwent HPBD for POM that require surgical treatment from May 2012 to December 2017 in four different institutions. The primary outcome measured was ureterohydronephrosis (UHN) and its degree of improvement after the procedure. Secondary outcomes were postoperative complications and resolution of preoperative symptomatology. Main Results: Forty-two ureters underwent HPBD for POM in 33 children, with a median age of 14.7 months - (range: 3 months -15 years). Ureterohydronephrosis improves in 86% of ureters after one endoscopic treatment. Three cases required a second HPBD. Four patients required surgical treatment for worsening of UHN after endoscopic treatment. The post-operative complication rate was 50% (21 ureters). In 13 cases (61%), they were related to double J stent. The median follow-up was 24 months (2 months -5 years) and all patients were symptom-free. Conclusion: We reported the first multicenter study and the largest series of children treated with HPBD, with an overall success rate of 92%. Endoscopic treatment can be a definitive treatment of POM since it avoided reimplantation in 90% of cases. Complications are mainly due to double J stent. PMID- 30430105 TI - Rare Earth Doped Ceria: The Complex Connection Between Structure and Properties. AB - The need for high efficiency energy production, conversion, storage and transport is serving as a robust guide for the development of new materials. Materials with physical-chemical properties matching specific functions in devices are produced by suitably tuning the crystallographic- defect- and micro-structure of the involved phases. In this review, we discuss the case of Rare Earth doped Ceria. Due to their high oxygen diffusion coefficient at temperatures higher than ~500 degrees C, they are very promising materials for several applications such as electrolytes for Solid Oxide Fuel and Electrolytic Cells (SOFC and SOEC, respectively). Defects are integral part of the conduction process, hence of the final application. As the fluorite structure of ceria is capable of accommodating a high concentration of lattice defects, the characterization and comprehension of such complex and highly defective materials involve expertise spanning from computational chemistry, physical chemistry, catalysis, electrochemistry, microscopy, spectroscopy, and crystallography. Results coming from different experimental and computational techniques will be reviewed, showing that structure determination (at different scale length) plays a pivotal role bridging theoretical calculation and physical properties of these complex materials. PMID- 30430106 TI - Purification of the Recombinant Green Fluorescent Protein Using Aqueous Two-Phase System Composed of Recyclable CO2-Based Alkyl Carbamate Ionic Liquid. AB - The formation of aqueous two-phase system (ATPS) with the environmentally friendly and recyclable ionic liquid has been gaining popularity in the field of protein separation. In this study, the ATPSs comprising N,N-dimethylammonium N',N'-dimethylcarbamate (DIMCARB) and thermo-responsive poly(propylene) glycol (PPG) were applied for the recovery of recombinant green fluorescent protein (GFP) derived from Escherichia coli. The partition behavior of GFP in the PPG + DIMCARB + water system was investigated systematically by varying the molecular weight of PPG and the total composition of ATPS. Overall, GFP was found to be preferentially partitioned to the hydrophilic DIMCARB-rich phase. An ATPS composed of 42% (w/w) PPG 1000 and 4.4% (w/w) DIMCARB gave the optimum performance in terms of GFP selectivity (1,237) and yield (98.8%). The optimal system was also successfully scaled up by 50 times without compromising the purification performance. The bottom phase containing GFP was subjected to rotary evaporation of DIMCARB. The stability of GFP was not affected by the distillation of DIMCARB, and the DIMCARB was successfully recycled in three successive rounds of GFP purification. The potential of PPG + DIMCARB + water system as a sustainable protein purification tool is promising. PMID- 30430107 TI - ctDNA Detection Based on DNA Clutch Probes and Strand Exchange Mechanism. AB - Circulating tumor DNA (ctDNA), originating directly from the tumor or circulating tumor cells, may reflect the entire tumor genom and has gained considerable attention for its potential clinical diagnosis and prognosis throughout the treatment regimen. However, the reliable and robust ctDNA detection remains a key challenge. Here, this work designs a pair of DNA clutch separation probes and an ideal discrimination probes based on toehold-mediated strand displacement reaction (TSDR) to specifically recognize ctDNA. First, the ctDNAs were denatured to form ssDNAs, the pair of DNA clutch separation probes [one of which modified onto the magnetic nanoparticles (MNPs)] are used to recognize and hybridize with the complemental chains and prevent reassociation of denatured ssDNAs. The complemental chains are removed in magnetic field and left the wild and mutant ssDNA chains in the supernatant. Then, the TSDR specificity recognizes the target mutant sequence to ensure only the mutated strands to be detection. The proposed assay exhibited good sensitivity and selectivity without any signal amplification. The proposed assay displayed a linear range from 2 to100 nM with a limit of detection (LOD) of 0.85 nM, and it was useful for ctDNA biomedical analysis and clinic theranostic. PMID- 30430108 TI - Tin Nanoparticles Encapsulated Carbon Nanoboxes as High-Performance Anode for Lithium-Ion Batteries. AB - One of the crucial challenges for applying Sn as an anode of lithium-ion batteries (LIBs) is the dramatic volume change during lithiation/delithiation process, which causes a rapid capacity fading and then deteriorated battery performance. To address this issue, herein, we report the design and fabrication of Sn encapsulated carbon nanoboxes (denoted as Sn@C) with yolk@shell architectures. In this design, the carbon shell can facilitate the good transport kinetics whereas the hollow space between Sn and carbon shell can accommodate the volume variation during repeated charge/discharge process. Accordingly, this composite electrode exhibits a high reversible capacity of 675 mAh g-1 at a current density of 0.8 A g-1 after 500 cycles and preserves as high as 366 mAh g 1 at a higher current density of 3 A g-1 even after 930 cycles. The enhanced electrochemical performance can be ascribed to the crystal size reduction of Sn cores and the formation of polymeric gel-like layer outside the electrode surface after long-term cycles, resulting in improved capacity and enhanced rate performance. PMID- 30430110 TI - High Expression of Glycolytic Genes in Cirrhosis Correlates With the Risk of Developing Liver Cancer. AB - A marked increase in the rate of glycolysis is a key event in the pathogenesis of hepatocellular carcinoma (HCC), the main type of primary liver cancer. Liver cirrhosis is considered to be a key player in HCC pathogenesis as it precedes HCC in up to 90% of patients. Intriguingly, the biochemical events that underlie the progression of cirrhosis to HCC are not well understood. In this study, we examined the expression profile of metabolic gene transcripts in liver samples from patients with HCC and patients with cirrhosis. We found that gene expression of glycolytic enzymes is up-regulated in precancerous cirrhotic livers and significantly associated with an elevated risk for developing HCC. Surprisingly, expression levels of genes involved in mitochondrial oxidative metabolism are markedly increased in HCC compared to normal livers but remain unchanged in cirrhosis. Our findings suggest that key glycolytic enzymes such as hexokinase 2 (HK2), aldolase A (ALDOA), and pyruvate kinase M2 (PKM2) may represent potential markers and molecular targets for early detection and chemoprevention of HCC. PMID- 30430109 TI - Advances in the Biofabrication of 3D Skin in vitro: Healthy and Pathological Models. AB - The relevance for in vitro three-dimensional (3D) tissue culture of skin has been present for almost a century. From using skin biopsies in organ culture, to vascularized organotypic full-thickness reconstructed human skin equivalents, in vitro tissue regeneration of 3D skin has reached a golden era. However, the reconstruction of 3D skin still has room to grow and develop. The need for reproducible methodology, physiological structures and tissue architecture, and perfusable vasculature are only recently becoming a reality, though the addition of more complex structures such as glands and tactile corpuscles require advanced technologies. In this review, we will discuss the current methodology for biofabrication of 3D skin models and highlight the advantages and disadvantages of the existing systems as well as emphasize how new techniques can aid in the production of a truly physiologically relevant skin construct for preclinical innovation. PMID- 30430111 TI - Nutrition Trends in Kidney Transplant Recipients: the Importance of Dietary Monitoring and Need for Evidence-Based Recommendations. AB - Many physiological properties of the renal system influence nutrient metabolism, elimination, and homeostasis. Kidney failure poses significant challenges to maintaining adequate nutrition, most of which transplantation ameliorates. Comprehensive recommendations for managing nutritional derangements for patients with chronic kidney disease and end stage renal disease exist; however, there are only sparse guidelines for post-transplant malnutrition and adverse outcomes. Not only are guidelines limited, but little is known about dietary trends of post kidney transplant recipients. This review describes guidelines for prevalent metabolic and nutritional complications post-kidney transplantation and also evaluates changes in caloric intake and diet composition after transplantation. This topic is important because nutrition influences allograft function and a number of cardiovascular risk factors including blood pressure, dyslipidemia, weight, and diabetes. In addition, many dietary recommendations and modifiable lifestyle changes should be tailored for specific complications of transplant patients, namely immunosuppression side effects, dietary restrictions, and electrolyte imbalances. PMID- 30430112 TI - Infection of Wildlife by Mycobacterium bovis in France Assessment Through a National Surveillance System, Sylvatub. AB - Mycobacterium bovis infection was first described in free-ranging wildlife in France in 2001, with subsequent detection in hunter-harvested ungulates and badgers in areas where outbreaks of bovine tuberculosis (TB) were also detected in cattle. Increasing concerns regarding TB in wildlife led the French General Directorate for Food (DGAL) and the main institutions involved in animal health and wildlife management, to establish a national surveillance system for TB in free-ranging wildlife. This surveillance system is known as "Sylvatub." The system coordinates the activities of various national and local partners. The main goal of Sylvatub is to detect and monitor M. bovis infection in wildlife through a combination of passive and active surveillance protocols adapted to the estimated risk level in each area of the country. Event-base surveillance relies on M. bovis identification (molecular detection) (i) in gross lesions detected in hunter-harvested ungulates, (ii) in ungulates that are found dead or dying, and (iii) in road-killed badgers. Additional targeted surveillance in badgers, wild boars and red deer is implemented on samples from trapped or hunted animals in at risk areas. With the exception of one unexplained case in a wild boar, M. bovis infection in free-living wildlife has always been detected in the vicinity of cattle TB outbreaks with the same genotype of the infectious M. bovis strains. Since 2012, M. bovis was actively monitored in these infected areas and detected mainly in badgers and wild boars with apparent infection rates of 4.57-5.14% and 2.37-3.04%, respectively depending of the diagnostic test used (culture or PCR), the period and according to areas. Sporadic infection has also been detected in red deer and roe deer. This surveillance has demonstrated that M. bovis infection, in different areas of France, involves a multi-host system including cattle and wildlife. However, infection rates are lower than those observed in badgers in the United Kingdom or in wild boars in Spain. PMID- 30430113 TI - Role of bile acids in colon carcinogenesis. AB - Bile acids (BAs) are cholesterol derivatives synthesized in the liver and then secreted into the intestine for lipid absorption. There are numerous scientific reports describing BAs, especially secondary BAs, as strong carcinogens or promoters of colon cancers. Firstly, BAs act as strong stimulators of colorectal cancer (CRC) initiation by damaging colonic epithelial cells, and inducing reactive oxygen species production, genomic destabilization, apoptosis resistance, and cancer stem cells-like formation. Consequently, BAs promote CRC progression via multiple mechanisms, including inhibiting apoptosis, enhancing cancer cell proliferation, invasion, and angiogenesis. There are diverse signals involved in the carcinogenesis mechanism of BAs, with a major role of epidermal growth factor receptor, and its down-stream signaling, involving mitogen activated protein kinase, phosphoinositide 3-kinase/Akt, and nuclear factor kappa light-chain-enhancer of activated B cells. BAs regulate numerous genes including the human leukocyte antigen class I gene, p53, matrix metalloprotease, urokinase plasminogen activator receptor, Cyclin D1, cyclooxygenase-2, interleukin-8, and miRNAs of CRC cells, leading to CRC promotion. These evidence suggests that targeting BAs is an efficacious strategies for CRC prevention and treatment. PMID- 30430114 TI - Update on global epidemiology of viral hepatitis and preventive strategies. AB - Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers. Every year 1.4 million people die from viral hepatitis-related cirrhosis and liver cancer. However, the majority of the infected population are unaware of their condition. This population have significant obstacles to overcome such as lack of awareness, vulnerability, increased migration, disease stigma, discrimination, as well as poor health resources, conflict in policy development and program implementation. Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive. This study aims to present the current global prevalence status and examines potential elimination strategies. The information for this research were obtained through a systematic review, published scientific literatures, the official websites of various government organisations, international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and 2018. PMID- 30430115 TI - Iron metabolism disorders in patients with hepatitis B-related liver diseases. AB - AIM: To investigate the relationship between levels of iron metabolism markers and hepatitis B virus (HBV)-related chronic liver diseases. METHODS: This case control study with 318 participants included 78 cases of chronic hepatitis B, 85 cases of HBV-related liver cirrhosis, 77 cases of HBV-related hepatocellular carcinoma, and 78 healthy controls. Markers of iron metabolism were detected in participants. Hematological and biochemical parameters and HBV-DNA were assessed. Child-Pugh grade and Barcelona Clinic Liver Cancer stage were determined for each hepatocellular carcinoma patient. Perls' staining was performed on liver sections. The SPSS program was used for all statistical analyses, and statistical significance was considered if a P-value < 0.05. RESULTS: Significantly higher serum ferritin and lower serum hepcidin levels were detected in all groups of HBV infected patients compared with healthy controls. Serum iron, total iron binding capacity, and serum transferrin levels were significantly lower in patients with cirrhosis and hepatocellular carcinoma, whereas the hepcidin level was higher than that in chronic hepatitis B patients. Correlation analysis indicated that serum hepcidin was negatively correlated with HBV-DNA load (P < 0.01). Serum ferritin and transferrin saturation levels increased proportionally to the extent of liver cirrhosis and poorer Child-Pugh scores (P < 0.05). The decreased serum iron and transferrin saturation levels were significantly correlated with a smaller hepatocellular carcinoma tumor burden according to Barcelona Clinic Liver Cancer staging. Liver histology showed a clearly increasing trend in iron deposition in the liver tissues with increased fibrosis, which became prominent at stages 3 (severe liver fibrosis) and 4 (cirrhosis). CONCLUSION: Iron metabolism disorders occur in patients with HBV-related liver diseases. The serum markers of iron metabolism disorders vary in different stages of HBV-related liver diseases. PMID- 30430116 TI - Impact of an acute hemodynamic response-guided protocol for primary prophylaxis of variceal bleeding. AB - AIM: To evaluate the long-term outcome of an acute hemodynamic response-guided protocol in which acute responders to intravenous propranolol received traditional nonselective beta-blockers (NSBBs) and acute nonresponders received carvedilol. METHODS: Retrospective review of a protocol for primary prophylaxis of variceal bleeding guided by the acute hemodynamic response to intravenous propranolol. Fifty-two acute responders treated with traditional NSBB (i.e. propranolol or nadolol) were compared with 24 acute nonresponders receiving carvedilol. A second hemodynamic study was performed in 27 and 13 patients, respectively. The primary endpoint was development of first or further decompensation. Secondary endpoints included death from any cause, association between acute and chronic hemodynamic response, and baseline clinical and laboratory variables related to the acute hemodynamic response. RESULTS: Acute responders and acute nonresponders presented similar 1, 2, and 3-year probabilities of first decompensation (NSBB: 0%, 13.7%, 26.1% vs carvedilol: 0%, 20%, 20%, P = 0.968) or further decompensation (21.2%, 26.1%, 40.9% vs 21.2%, 50.0%, 50.0%, P = 0.525). A previous episode of hepatic encephalopathy was the only independent predictor of decompensation [hazard ratio (95% confidence interval): 8.03 (2.76-23.37)]. Mortality rates were similar in acute responders and acute nonresponders with compensated (P = 0.428) or decompensated cirrhosis (P = 0.429). No clinical, laboratory, endoscopic or hemodynamic parameter predicted the acute hemodynamic response. In patients receiving traditional NSBB, the acute and chronic changes of hepatic venous pressure gradient were correlated (r = 0.59, P = 0.001). Up to 69.2% of acute nonresponders gained chronic response with carvedilol. CONCLUSION: Early identification and treatment with carvedilol of acute nonresponders to intravenous propranolol improves the clinical outcome of this high-risk group of patients, probably due to its greater effects for reducing portal pressure. PMID- 30430117 TI - Effect of a region-wide incorporation of an algorithm based on the 2012 international consensus guideline on the practice pattern for the management of pancreatic cystic neoplasms in an integrated health system. AB - AIM: To examine the practice pattern in Kaiser Permanente Southern California (KPSC), i.e., gastroenterology (GI)/surgery referrals and endoscopic ultrasound (EUS), for pancreatic cystic neoplasms (PCNs) after the region-wide dissemination of the PCN management algorithm. METHODS: Retrospective review was performed; patients with PCN diagnosis given between April 2012 and April 2015 (18 mo before and after the publication of the algorithm) in KPSC (integrated health system with 15 hospitals and 202 medical offices in Southern California) were identified. RESULTS: 2558 (1157 pre- and 1401 post-algorithm) received a new diagnosis of PCN in the study period. There was no difference in the mean cyst size (pre- 19.1 mm vs post- 18.5 mm, P = 0.119). A smaller percentage of PCNs resulted in EUS after the implementation of the algorithm (pre- 45.5% vs post- 34.8%, P < 0.001). A smaller proportion of patients were referred for GI (pre- 65.2% vs post- 53.3%, P < 0.001) and surgery consultations (pre- 24.8% vs post- 16%, P < 0.001) for PCN after the implementation. There was no significant change in operations for PCNs. Cost of diagnostic care was reduced after the implementation by 24%, 18%, and 36% for EUS, GI, and surgery consultations, respectively, with total cost saving of 24%. CONCLUSION: In the current healthcare climate, there is increased need to optimize resource utilization. Dissemination of an algorithm for PCN management in an integrated health system resulted in fewer EUS and GI/surgery referrals, likely by aiding the physicians ordering imaging studies in the decision making for the management of PCNs. This translated to cost saving of 24%, 18%, and 36% for EUS, GI, and surgical consultations, respectively, with total diagnostic cost saving of 24%. PMID- 30430118 TI - Usefulness of colonic tattooing using indocyanine green in patients with colorectal tumors. AB - AIM: To prove that tattooing using indocyanine green (ICG) is feasible in laparoscopic surgery for a colon tumor. METHODS: From January 2012 to December 2016, all patients who underwent laparoscopic colonic surgery were retrospectively screened, and 1010 patients with colorectal neoplasms were included. Their lesions were tattooed with ICG the day before the operation. The tattooed group (TG) included 114 patients, and the non-tattooed group (NTG) was selected by propensity score matching of subjects based on age, sex, tumor staging, and operation method (n = 228). In total, 342 patients were enrolled. Between the groups, the changes in [Delta (Delta), preoperative-postoperative] the hemoglobin and albumin levels, operation time, hospital stay, oral ingestion period, transfusion, and perioperative complications were compared. RESULTS: Preoperative TG had a shorter operation time (174.76 +/- 51.6 min vs 192.63 +/- 59.9 min, P < 0.01), hospital stay (9.55 +/- 3.36 d vs 11.42 +/- 8.23 d, P < 0.01), and post-operative oral ingestion period (1.58 +/- 0.96 d vs 2.81 +/- 1.90 d, P < 0.01). The Delta hemoglobin (0.78 +/- 0.76 g/dL vs 2.2 +/- 1.18 g/dL, P < 0.01) and Delta albumin (0.41 +/- 0.44 g/dL vs 1.08 +/- 0.39 g/dL, P < 0.01) levels were lower in the TG. On comparison of patients in the "N0" and "N1 or N2" groups, the N0 colon cancer group had a better operation time, length of hospital stay, oral ingestion period, Delta hemoglobin, and Delta albumin results than those of the N1 or N2 group. The operation methods affected the results, and laparoscopic anterior resection (LAR) showed similar results. However, for left and right hemicolectomy, both groups showed no difference in operation time or hospital stay. CONCLUSION: Preoperative tattooing with ICG is useful for laparoscopic colectomy, especially in the N0 colon cancer group and LAR. PMID- 30430121 TI - Successful rescue of acute liver failure and hemophagocytic lymphohistiocytosis following varicella infection: A case report and review of literature. AB - Herein we report a case of acute liver failure (ALF) and hemophagocytic lymphohistiocytosis (HLH) induced by varicella infection, successfully rescued by a combination therapy of acyclovir, supportive care, and immunosuppression with dexamethasone and etoposide. A previously healthy 16-year-old boy presented with generalized rash, fever, severe abdominal pain, and abnormal liver function within 4 d. Chickenpox was suspected, and acyclovir and intravenous immunoglobulin were started on admission. However, the patient's condition deteriorated overnight with soaring transaminases, severe coagulopathy and encephalopathy. On the fourth day of admission, pancytopenia emerged, accompanied by hypofibrinogenemia and hyperferritinemia. The patient was diagnosed with ALF. He also met the diagnostic criteria of HLH according to the HLH-2004 guideline. Polymerase chain reaction (PCR) amplifications of varicella-zoster virus (VZV) were positive, confirming that VZV was a causative trigger for ALF and HLH. In view of the devastating immune activation in HLH, immunosuppression therapy with dexamethasone and etoposide was administered, in addition to high dose acyclovir. The patient's symptoms improved dramatically and he finally made a full recovery. To our knowledge, this is only the second report of a successful rescue of ALF associated with HLH, without resorting to liver transplantation. The first case was reported in a neonate infected by herpes simplex virus-1. However, survival data in older children and adults are lacking, most of whom died or underwent liver transplantation. Our report emphasizes the clinical vigilance for the possible presence of HLH, and the necessity of extensive investigation for underlying etiologies in patients presenting with indeterminate ALF. Early initiation of specific therapy targeting the underlying etiology, and watchful immunosuppression such as dexamethasone and etoposide, together with supportive therapy, are of crucial importance in this life-threatening disorder. PMID- 30430119 TI - Helicobacter pylori may be an initiating factor in newly diagnosed ulcerative colitis patients: A pilot study. AB - AIM: To directly visualize Helicobacter pylori (H. pylori) by the highly sensitive and specific technique of immunohistochemical staining in colonic tissue from patients newly diagnosed with ulcerative colitis (UC). METHODS: Colonoscopic biopsies from thirty patients with newly diagnosed UC and thirty controls were stained with Giemsa stain and immunohistochemical stain for detection of H. pylori in the colonic tissue. Results were confirmed by testing H. pylori Ag in the stool then infected patients were randomized to receive either anti H. pylori treatment or placebo. RESULTS: Twelve/30 (40%) of the UC patients were positive for H. pylori by Giemsa, and 17/30 (56.6%) by immunohistochemistry stain. Among the control group 4/30 (13.3%) and 6/30 (20 %) were positive for H. pylori by Giemsa and immunohistochemistry staining respectively. H. pylori was significantly higher in UC than in controls (P = 0.04 and 0.007). All Giemsa positive patients and controls were positive by immunohistochemical stain. Four cases of the control group positive for H. pylori also showed microscopic features consistent with early UC. CONCLUSION: H. pylori can be detected in colonic mucosa of patients with UC and patients with histological superficial ulcerations and mild infiltration consistent with early UC. There seems to be an association between UC and presence of H. pylori in the colonic tissue. Whether this is a causal relationship or not remains to be discovered. PMID- 30430120 TI - Photodynamic therapy for middle-advanced stage upper gastrointestinal carcinomas: A systematic review and meta-analysis. AB - AIM: To determine the therapeutic effect of photodynamic therapy (PDT) for middle advanced stage upper gastrointestinal carcinomas. METHODS: We searched PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, and Wanfang Database from inception to April 2018 for randomized controlled studies. These studies compared PDT with other palliative therapies (radiotherapy, chemotherapy, or Nd:YAG laser) and compared PDT, radiotherapy, or chemotherapy alone with PDT combined with chemotherapy/radiotherapy. In our meta-analysis, both fixed and random effects models were used to estimate the risk ratio (RR) for dichotomous outcomes (the response rate and one-year survival rate). RESULTS: Ten random controlled clinical studies with 953 patients were included in the analysis. The effective rate for PDT was better than that of radiotherapy or Nd:YAG laser for the treatment of middle-advanced upper gastrointestinal carcinomas [RR = 1.36; 95% confidence interval (CI): 1.13-1.65; P = 0.001]. In addition, PDT combined with chemotherapy had significantly better efficacy and a higher one-year survival rate than PDT or chemotherapy alone (significant remission rate, RR = 1.62; 95%CI: 1.34-1.97; P < 0.00001; one-year survival rate, RR = 1.81; 95%CI: 1.13 2.89; P = 0.01). CONCLUSION: PDT is a useful method for the treatment of middle advanced stage upper gastrointestinal carcinomas. PDT combined with chemotherapy or radiotherapy can enhance its efficacy and prolong survival time. PMID- 30430122 TI - Bilateral thoracic kidneys combined with inferior vena cava located behind the anterior abdominal wall: A case report and review of literature. AB - Ectopic thoracic kidneys are the rarest form of renal ectopia. Moreover, congenital abnormality of a primary anterior inferior vena cava (IVC) located behind the anterior abdominal wall is extremely rare. To date, only one such case has been reported. Herein, we report a rare case of a 55-year-old Chinese male with bilateral thoracic kidneys combined with an anterior IVC, a malformed liver, and a large-round-folds navel. The classification, clinical characteristics, and management options of a thoracic kidney was also summarized by literature review. To our best knowledge, the simultaneous detection of such multiple complex abnormalities has not been reported. PMID- 30430123 TI - Incident hepatocellular carcinoma developing during tenofovir alafenamide treatment as a rescue therapy for multi-drug resistant hepatitis B virus infection: A case report and review of the literature. AB - Tenofovir disoproxil fumarate (TDF) is a potent nucleotide analogue with high barrier to resistance, which is recommended for multi-drug resistant hepatitis B virus (HBV) infection. However, nephrotoxicity has been reported during TDF treatment, and tenofovir alafenamide (TAF), which has comparable efficacy to TDF and improves bone and renal safety, can be used as a replacement strategy. Herein, we describe a clinical case concerning a 60-year-old individual suffering liver cirrhosis and renal dysfunction, and being infected with multidrug resistant HBV. When failing treatment with TDF, he received TAF as a rescue therapy. TAF effectively inhibited HBV replication without worsening renal function or serum phosphorus abnormality. Furthermore, hepatocellular carcinoma (HCC) occurred during TAF treatment despite controlling the viral load. The risk of HCC could not be eliminated and should be monitored during TAF treatment. PMID- 30430124 TI - Possible connection between elevated serum alpha-fetoprotein and placental necrosis during pregnancy: A case report and review of literature. AB - Placenta previa is the main cause of bleeding throughout pregnancy, and it is associated with serious complications, such as infection, that lead to a poor prognosis. Gynecological sonography is recommended as the first-line examination technique for the surveillance and determination of vaginal bleeding and for early intervention. We report the case of a patient with gradually expanded hypoechoic lesion and extremely high serum alpha-fetoprotein level during her third trimester, and discuss their potential relationship in evaluating the progression of placental necrosis. PMID- 30430125 TI - Laparoscopic pancreatic duct incision and stone removal and T-type tube drainage for pancreatic duct stone: A case report and review of literature. AB - To study a more micro-invasive procedure for patients having pancreatic duct stones (PDS). Till now, there has been no report of laparoscopic pancreatic duct incision and stone removal and T-type tube drainage for PDS in the English literature. An 82-year-old man suffered from subxiphoid pain associated with a dilated pancreatic duct (7 mm) containing one stone, but without a mass in the head of the pancreas. Laparoscopic pancreatic duct incision, stone removal, and T type tube drainage were successfully performed without intraoperative or postoperative complications. An uneventful operation was performed with laparoscopically completed procedures in 160 min. The intraoperative loss of blood was around 50 mL. After patient a discharge on day 11, complete relief from the subxiphoid pain was reported at a follow-up visit 15 mo later. Laparoscopic pancreatic duct incision with stone removal and T-type tube drainage is applicable in carefully selected patients and can be effectively and safely used for the treatment of the abdominal pain of chronic pancreatitis. PMID- 30430126 TI - Detection of a unicentric type of Castleman-like mass at the site of adrenal grand: A case report and review of literature. AB - We present a case of adrenal CD in a 26-year-old female. The patient was referred to our hospital because of left flank pain for 1 wk. A computed tomography scan revealed a 4 cm * 3 cm well-defined mass, considered as a paraganglioma. A preoperative diagnosis of left adrenal neoplasm and urinary tract infection was made. The patient underwent anti-inflammatory therapy followed by an open operation to remove the mass in the left adrenal. Through analysis of the morphological pattern and immunohistochemical markers, a diagnosis of CD was made. During the 12-mo follow-up, there was no evidence of metastasis or recurrence. This case reminds clinicians that CD should be considered in the evaluation of an adrenal mass. Surgery is suggested for its therapeutic management. PMID- 30430127 TI - Systemic lupus erythematosus complicated by noncirrhotic portal hypertension: A case report and review of literature. AB - A 48 year-old Chinese woman suffering from polyarthritis, irregular fever and trichomadesis was admitted to the hospital. A diagnosis of systemic lupus erythematosus (SLE) was made based on polyarthritis, pancytopenia, reduced complement 3, multiple positive autoantibodies, a positive Coomb's test and protein in her urine. In addition, splenomegaly was detected during physical examination and confirmed by abdominal ultrasonography and magnetic resonance imaging, indicating that the patient had SLE and portal hypertension. Further negative investigations ruled out the possibility of cirrhosis. The patient was diagnosed with active SLE complicated by noncirrhotic portal hypertension (NCPH) without liver histopathology, due to the patient's refusal for liver biopsy. Portal vein diameter and splenomegaly decreased following treatment with methylprednisolone, hydroxychloroquine and metoprolol tartrate. To date, SLE complicated by NCPH has rarely been reported, as it is under-recognized clinically as well as pathologically. Here we describe a case of SLE complicated by NCPH and review the literature for its characteristics, which may contribute to improving the recognition of NCPH and reducing missed and delayed diagnosis of this disorder. PMID- 30430128 TI - Natural killer/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion: A case report and review of literature. AB - We report a case of natural killer (NK)/T-cell lymphoma with concomitant syndrome of inappropriate antidiuretic hormone secretion (SIADH). The patient was a 64 year-old woman with a history of nasopharyngeal carcinoma of over 30 years. She was admitted with a chief complaint of intermittent fever for 2 mo. Palpation after admission indicated a swollen lymph node below the left jaw. Multiple imaging examinations on admission indicated multiple enlarged lymph nodes throughout the body. We performed a left submandibular lymph node biopsy, and the results revealed NK/T-cell lymphoma. A biochemical examination indicated Epstein Barr virus positivity. At the same time, the patient developed hyponatremia. Based on her laboratory examination and clinical manifestation, decreased plasma osmolality, urine osmolality greater than plasma osmolality, lack of skin swelling, normal blood pressure, normal renal function, no adrenal function detected on serology, and no abnormalities in imaging examination of the adrenal glands, the likelihood of SIADH in the patient was high. After fluid restriction and administration of sodium chloride, the patient's blood sodium level gradually increased. Subsequently, the immune function of the patient declined, there were severe symptoms of infection, and she died of respiratory failure. NK/T-cell lymphoma associated with SIADH has not, to our knowledge, been previously reported in PubMed. This case emphasizes the importance of monitoring serum ion levels, especially serum sodium, in patients with NK/T-cell lymphoma. PMID- 30430129 TI - Successful treatment of pyoderma gangrenosum with concomitant immunoglobulin A nephropathy: A case report and review of literature. AB - Pyoderma gangrenosum (PG) is an uncommon ulcerative cutaneous condition of an unknown etiology and is often associated with immune diseases. However, PG rarely shows visceral involvement, especially in the kidney. A 20-year-old female presented with pedal edema and skin ulceration of both lower limbs. The skin lesion began as an erythematous plaque and then became a blister. She also complained of abdominal distension and a decreasing urine volume. Laboratory data showed high proteinuria, hypoalbuminemia and hyperlipidemia. Her skin and kidney were biopsied. The pathological results indicated PG and immunoglobulin A (IgA) nephropathy. The patient was finally cured with prednisolone in combination with cyclosporine A (CsA). PMID- 30430130 TI - Highlighting the importance of early diagnosis in progressive multi-organ involvement of IgG4-related disease: A case report and review of literature. AB - IgG4-related disease (IgG4-RD) is an increasingly recognized pathological entity that tends to involve multiple organs with an elevated level of serum IgG4, which is easily misdiagnosed owing to sharing common clinical features with a variety of other diseases. Here, we report an interesting IgG4-RD case of a woman with progressive multi-organ involvement for over 19 years, started with swollen eyelids, dry eye and mouth, and polydipsia and hydruria. Imaging diagnosis revealed diffuse enlargement of the parotid glands, enlargement of the head of the pancreas, pulmonary infection and interstitial lung. Serological tests showed a remarkable elevation of the serum IgG4, and cytological analysis further revealed a large amount of lymphoplasmacytic infiltration into the focal lobule, and IgG4-positive cell infiltration in bladder mucosa. Therapeutically, the patient responded well to steroid therapy, and thus, she was diagnosed as IgG4-RD suspicious. This report highlights the importance of an early diagnosis in this autoimmune disease and suggests that patients with a clinically unclear cause of inflammation, swelling and refractory glands, rhinitis, pancreatitis, hypophysitis, and/or interstitial pneumonia should be considered for IgG4-RD. The plasma IgG4 level and lymphoplasmacytic infiltration may be useful indexes for screening, and a low dose of steroid maintaining therapy may offer benefits for patients with IgG4-RD. PMID- 30430131 TI - Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin in Patients With Chronic Hepatitis C Virus Genotype 1 Infection Receiving Opioid Substitution Therapy: A Post Hoc Analysis of 12 Clinical Trials. AB - Background: We evaluated the impact of opioid substitution therapy (OST) on the completion, adherence, efficacy, and safety of the 3-direct-acting antiviral regimen of ombitasvir, paritaprevir (identified by AbbVie and Enanta) co-dosed with ritonavir, and dasabuvir +/- ribavirin among patients infected with hepatitis C virus (HCV) genotype (GT) 1, with or without compensated cirrhosis. Methods: Data were pooled from GT1-infected patients enrolled in 12 phase II/III/IIIb clinical trials and categorized by use of OST. Patients with ongoing drug use were excluded. HCV treatment completion, treatment adherence (>=90%), sustained virologic response at post-treatment week 12 (SVR12), and adverse events were assessed. Results: Of 4747 patients, 3% (n = 149) received OST. Among patients receiving OST vs those not receiving OST, 82% (n = 122) vs 52% (n = 2409) had GT1a infection; 76% (n = 113) vs 61% (n = 2792) were treatment naive; and 17% (n = 25) vs 18% (n = 830) had cirrhosis, respectively. The proportion of patients completing HCV treatment did not differ between those receiving and not receiving OST (97% [n = 144] vs 98% [n = 4510], respectively), whereas adherence to treatment was reduced in patients receiving vs those not receiving OST (88% [n = 105] vs 97% [n = 4057], respectively). SVR12 was similar between patients receiving and not receiving OST (94% [n = 140] vs 96% [n = 4405], respectively; P = .273). Treatment was well tolerated. Conclusions: Although treatment adherence was lower in patients receiving OST vs those not receiving OST, treatment completion and SVR12 were similar between groups. These data support the use of direct-acting antiviral therapies in patients receiving OST. PMID- 30430132 TI - Toward all-day wearable health monitoring: An ultralow-power, reflective organic pulse oximetry sensing patch. AB - Pulse oximetry sensors have been playing a key role as devices to monitor elemental yet critical human health states. Conventional pulse oximetry sensors, however, have relatively large power consumption, impeding their use as stand alone, continuous monitoring systems that can easily be integrated with everyday life. Here, we exploit the design freedom offered by organic technologies to realize a reflective patch-type pulse oximetry sensor with ultralow power consumption. On the basis of flexible organic light-emitting diodes and organic photodiodes designed via an optical simulation of color-sensitive light propagation within human skin, the proposed monolithically integrated organic pulse oximetry sensor heads exhibit successful operation at electrical power as low as 24 MUW on average. We thereby demonstrate that organic devices not only have form factor advantages for such applications but also hold great promise as enablers for all-day wearable health monitoring systems. PMID- 30430133 TI - An ion redistributor for dendrite-free lithium metal anodes. AB - Lithium (Li) metal anodes have attracted considerable interest due to their ultrahigh theoretical gravimetric capacity and very low redox potential. However, the issues of nonuniform lithium deposits (dendritic Li) during cycling are hindering the practical applications of Li metal batteries. Herein, we propose a concept of ion redistributors to eliminate dendrites by redistributing Li ions with Al-doped Li6.75La3Zr1.75Ta0.25O12 (LLZTO) coated polypropylene (PP) separators. The LLZTO with three-dimensional ion channels can act as a redistributor to regulate the movement of Li ions, delivering a uniform Li ion distribution for dendrite-free Li deposition. The standard deviation of ion concentration beneath the LLZTO composite separator is 13 times less than that beneath the routine PP separator. A Coulombic efficiency larger than 98% over 450 cycles is achieved in a Li | Cu cell with the LLZTO-coated separator. This approach enables a high specific capacity of 140 mAh g-1 for LiFePO4 | Li pouch cells and prolonged cycle life span of 800 hours for Li | Li pouch cells, respectively. This strategy is facile and efficient in regulating Li-ion deposition by separator modifications and is a universal method to protect alkali metal anodes in rechargeable batteries. PMID- 30430134 TI - Extremely flat band in bilayer graphene. AB - We propose a novel mechanism of flat band formation based on the relative biasing of only one sublattice against other sublattices in a honeycomb lattice bilayer. The mechanism allows modification of the band dispersion from parabolic to "Mexican hat"-like through the formation of a flattened band. The mechanism is well applicable for bilayer graphene-both doped and undoped. By angle-resolved photoemission from bilayer graphene on SiC, we demonstrate the possibility of realizing this extremely flattened band (< 2-meV dispersion), which extends two dimensionally in a k-space area around the K- point and results in a disk-like constant energy cut. We argue that our two-dimensional flat band model and the experimental results have the potential to contribute to achieving superconductivity of graphene- or graphite-based systems at elevated temperatures. PMID- 30430135 TI - Coalescence-induced jumping of droplets on superomniphobic surfaces with macrotexture. AB - When two liquid droplets coalesce on a superrepellent surface, the excess surface energy is partly converted to upward kinetic energy, and the coalesced droplet jumps away from the surface. However, the efficiency of this energy conversion is very low. In this work, we used a simple and passive technique consisting of superomniphobic surfaces with a macrotexture (comparable to the droplet size) to experimentally demonstrate coalescence-induced jumping with an energy conversion efficiency of 18.8% (i.e., about 570% increase compared to superomniphobic surfaces without a macrotexture). The higher energy conversion efficiency arises primarily from the effective redirection of in-plane velocity vectors to out-of plane velocity vectors by the macrotexture. Using this higher energy conversion efficiency, we demonstrated coalescence-induced jumping of droplets with low surface tension (26.6 mN m-1) and very high viscosity (220 mPa.s). These results constitute the first-ever demonstration of coalescence-induced jumping of droplets at Ohnesorge number >1. PMID- 30430136 TI - Enhanced quantum coherence in exchange coupled spins via singlet-triplet transitions. AB - Manipulation of spin states at the single-atom scale underlies spin-based quantum information processing and spintronic devices. These applications require protection of the spin states against quantum decoherence due to interactions with the environment. While a single spin is easily disrupted, a coupled-spin system can resist decoherence by using a subspace of states that is immune to magnetic field fluctuations. Here, we engineered the magnetic interactions between the electron spins of two spin-1/2 atoms to create a "clock transition" and thus enhance their spin coherence. To construct and electrically access the desired spin structures, we use atom manipulation combined with electron spin resonance (ESR) in a scanning tunneling microscope. We show that a two-level system composed of a singlet state and a triplet state is insensitive to local and global magnetic field noise, resulting in much longer spin coherence times compared with individual atoms. Moreover, the spin decoherence resulting from the interaction with tunneling electrons is markedly reduced by a homodyne readout of ESR. These results demonstrate that atomically precise spin structures can be designed and assembled to yield enhanced quantum coherence. PMID- 30430137 TI - Magnetic and defect probes of the SmB6 surface state. AB - The impact of nonmagnetic and magnetic impurities on topological insulators is a central focus concerning their fundamental physics and possible spintronics and quantum computing applications. Combining scanning tunneling spectroscopy with transport measurements, we investigate, both locally and globally, the effect of nonmagnetic and magnetic substituents in SmB6, a predicted topological Kondo insulator. Around the so-introduced substitutents and in accord with theoretical predictions, the surface states are locally suppressed with different length scales depending on the substituent's magnetic properties. For sufficiently high substituent concentrations, these states are globally destroyed. Similarly, using a magnetic tip in tunneling spectroscopy also resulted in largely suppressed surface states. Hence, a destruction of the surface states is always observed close to atoms with substantial magnetic moment. This points to the topological nature of the surface states in SmB6 and illustrates how magnetic impurities destroy the surface states from microscopic to macroscopic length scales. PMID- 30430138 TI - Evidence for a quantum spin Hall phase in graphene decorated with Bi2Te3 nanoparticles. AB - Realization of the quantum spin Hall effect in graphene devices has remained an outstanding challenge dating back to the inception of the field of topological insulators. Graphene's exceptionally weak spin-orbit coupling-stemming from carbon's low mass-poses the primary obstacle. We experimentally and theoretically study artificially enhanced spin-orbit coupling in graphene via random decoration with dilute Bi2Te3 nanoparticles. Multiterminal resistance measurements suggest the presence of helical edge states characteristic of a quantum spin Hall phase; the magnetic field and temperature dependence of the resistance peaks, x-ray photoelectron spectra, scanning tunneling spectroscopy, and first-principles calculations further support this scenario. These observations highlight a pathway to spintronics and quantum information applications in graphene-based quantum spin Hall platforms. PMID- 30430139 TI - Flexible elastomer patch with vertical silicon nanoneedles for intracellular and intratissue nanoinjection of biomolecules. AB - Vertically ordered arrays of silicon nanoneedles (Si NNs), due to their nanoscale dimension and low cytotoxicity, could enable minimally invasive nanoinjection of biomolecules into living biological systems such as cells and tissues. Although production of these Si NNs on a bulk Si wafer has been achieved through standard nanofabrication technology, there exists a large mismatch at the interface between the rigid, flat, and opaque Si wafer and soft, curvilinear, and optically transparent biological systems. Here, we report a unique methodology that is capable of constructing vertically ordered Si NNs on a thin layer of elastomer patch to flexibly and transparently interface with biological systems. The resulting outcome provides important capabilities to form a mechanically elastic interface between Si NNs and biological systems, and simultaneously enables direct imaging of their real-time interactions under the transparent condition. We demonstrate its utility in intracellular, intradermal, and intramuscular nanoinjection of biomolecules into various kinds of biological cells and tissues at their length scales. PMID- 30430140 TI - H3Africa: crucial importance of knowledge on human demographic history in strategies for data exploitation - an analysis of the Luhya in Webuye, Kenya population from the 1000 Genomes Project. AB - Paucity of data from African populations has restricted understanding of the heritable human genome variation. Although under-represented in human genetic studies, Africa has sizeable genetic, cultural and linguistic diversity. The Human Heredity and Health in Africa (H3Africa) initiative is aimed at understanding health problems relevant to African populations, and titling the scales of data deficit and lacking expertise in health-related genomics among African scientists. We emphasise that careful consideration of the sampled populations in the H3Africa projects is required to maximise the prospects of identifying and fine-mapping novel risk variants in indigenous populations. H3Africa which considers national and within-continental cohorts must have well thought out documented protocols that carefully consider human demographic history. PMID- 30430141 TI - Interaction between opposing modes of phospho-regulation of the proneural proteins Ascl1 and Ngn2. AB - From the relatively simple nervous system of Drosophila to the elaborate mammalian cortex, neurogenesis requires exceptional spatial and temporal precision to co-ordinate progenitor cell proliferation and subsequent differentiation to a diverse range of neurons and glia. A limited number of transiently expressed proneural basic-helix-loop-helix (bHLH) transcription factors, for example achaete-scute-complex (as-c) and atonal (ato) in Drosophila and the vertebrate homologues Ascl1 and Neurogenin2 (Ngn2), are able to orchestrate the onset of neuronal determination, context-dependent subtype selection and even influence later aspects of neuronal migration and maturation. Within the last decade, two models have emerged to explain how the temporal activity of proneural determination factors is regulated by phosphorylation at distinct sites. One model describes how cell-cycle associated phosphorylation on multiple sites in the N and C termini of vertebrate proneural proteins limits neuronal differentiation in cycling progenitor cells. A second model describes phosphorylation on a single site in the bHLH domain of Drosophila atonal that acts as a binary switch, where phosphorylation terminates proneural activity. Here we combine activating mutations of phosphorylation sites in the N- and C- termini with an inhibitory phospho-mimetic mutation in the bHLH domain of Ascl1 and Ngn2 proteins, and test their functions in vivo using Xenopus embryos to determine which mode of phospho-regulation dominates. Enhancing activity by preventing N- and C terminal phosphorylation cannot overcome the inhibitory effect of mimicking phosphorylation of the bHLH domain. Thus we have established a hierarchy between these two modes of proneural protein control and suggest a model of temporal regulation for proneural protein activity. PMID- 30430142 TI - Sonographic Volumetric Assessment Is a More Accurate Measure Than Maximum Diameter Alone in Papillary Thyroid Cancer. AB - Background: Tumor size is an important prognostic factor in papillary thyroid cancer (PTC). Management guidelines, staging systems, and pathological definitions use maximum diameter (Dmax) as a surrogate marker of tumor size. However, PTC nodules are three-dimensional (3D) structures, with behavior reflective of tumor cell count, which is directly proportional to volume. We explored the relationship between sonographically determined Dmax, volume, and lymph node status (LNS) in a cohort of patients with PTC. Methods: All patients treated for PTC between 2003 and 2015 in our institution who had sonographic 3D nodule measurements available were evaluated. We examined the relationship between diameter, volume, and LNS. Results: A total of 159 nodules in 153 patients met the inclusion criteria. Mean nodule dimensions were 2.4 * 1.9 * 1.5 cm, giving "ideal" nodule dimensions of y * 0.78y * 0.62y, where y is the Dmax. Observed volumes differed from predicted nodule volumes by an average of 26.2%. For PTC <=2 cm, the coefficient of variation was 26.7%. Dmax did not correlate with the presence of lymph node metastases (Pearson coefficient 0.08), whereas volume very weakly correlated with LNS (Pearson coefficient 0.22). However, both Dmax and volume correlated very strongly with the number of nodal metastases (Pearson coefficients 0.93 and 0.89, respectively). Conclusions: PTC nodules demonstrated significant volume heterogeneity, rendering Dmax an inaccurate marker of true tumor size. Although there was little difference between Dmax and volume in predicting nodal status or nodal disease burden, we propose that a prospective, randomized trial might demonstrate a clear clinical advantage of 3D sonographic nodule measurement over Dmax alone. PMID- 30430143 TI - Assessing Sex Steroid Influence on Kisspeptin Responsiveness in Idiopathic Hypogonadotropic Hypogonadism. AB - Context: Individuals with idiopathic hypogonadotropic hypogonadism (IHH), even those with evidence of some hypothalamic reproductive endocrine activity, fail to complete puberty and fail to respond to physiologic doses of kisspeptin. Objective: This case series examined whether treatment with sex steroids could stimulate kisspeptin responsiveness in patients with IHH. Design: This was a case series. Setting: This study was conducted at an academic medical center. Participants: Seven patients with IHH were studied. Interventions: Participants, both on and off sex steroid therapy, underwent frequent blood sampling to measure LH at baseline, in response to kisspeptin and GnRH. Main Outcome Measures: The main outcome measure was LH responses to kisspeptin on and off sex steroids. Results: All participants responded to exogenous GnRH, but no participant responded to exogenous kisspeptin. Sex steroid treatment did not modify responsiveness to kisspeptin. Conclusions: The functional impairment of the GnRH neuronal network in patients with IHH, as evidenced by their inability to respond to a physiologic dose of kisspeptin, is observed in both sex steroid- deficient and sex steroid-replete states. In this case series, a normalized sex steroid milieu does not appear capable of overcoming the kisspeptin resistance of these patients. PMID- 30430144 TI - Depression in Nonclassical Hypogonadism in Young Men. AB - The specific objective of this study was to test the clinically derived hypothesis associating a high prevalence of depression in young men with nonclassical hypogonadism. We studied the entire population of men aged 18 to 40 years who had an outpatient visit at an academic health system in the years 2013 to 2015. The study group comprised 186 patients with a diagnosis of eugonadotropic hypogonadism and a testosterone value below 10.4 nmol/L with no apparent cause. We compared their demographic factors, other diagnoses, and treatments with those of (i) the entire population, (ii) a matched population of 930 controls, and (iii) 404 controls with normal testosterone determinations, and no hypogonadism diagnosis. Depression, defined as either an International Classification of Diseases, Ninth Revision (ICD-9) diagnosis or treatment with an antidepressant medication, was found in 22.6% of cases vs 6.6% of population controls [P < 0.001; OR: 1.13 (1.09 to 1.17); 95% CI]. Obesity was also higher in the cases (P < 0.001). The matched controls had a depression rate of 13.4% compared with the case rate of 22.6% [P < 0.002; OR 1.14 (1.08 to 1.17)]. Controls with normal testosterone determinations had a depression rate of 16.8% [P = 0.121; OR: 1.04 (0.96 to 1.12)], suggesting that clinicians may have ordered a testosterone determination because of symptoms consistent with both depression and hypogonadism. The high incidence of depression in nonclassical hypogonadism in young men, although only associative, supports a depression evaluation and treatment as appropriate as well as investigation of the proximate causes of this form of hypogonadism. PMID- 30430145 TI - Hyperglycemia in the Posttransplant Period: NODAT vs Posttransplant Diabetes Mellitus. AB - Objective: To characterize the types of hyperglycemia that occur up to 1 year following liver transplant and to clarify the nomenclature for posttransplant hyperglycemia. Design: We analyzed 1-year glycemic follow-up data in 164 patients who underwent liver transplant and who had been enrolled in a randomized controlled trial comparing moderate to intensive insulin therapy to determine if patients had preexisting known diabetes, transient hyperglycemia, persistent hyperglycemia, or new-onset diabetes after transplantation (NODAT). Results: Of 119 patients with posttransplant hyperglycemia following hospital discharge, 49 had preexisting diabetes, 5 had insufficient data for analysis, 48 had transient hyperglycemia (16 resolved within 30 days and 32 resolved between 30 days and 1 year), 13 remained persistently hyperglycemic out to 1 year and most likely had preexisting diabetes that had not been diagnosed or insulin resistance/insulinopenia prior to transplant, and 4 had NODAT (i.e., patients with transient hyperglycemia after transplant that resolved but then later truly developed sustained hyperglycemia, meeting criteria for diabetes). Conclusions: Distinct categories of patients with hyperglycemia following organ transplant include known preexisting diabetes, persistent hyperglycemia (most likely unknown preexisting diabetes or insulin resistance/insulinopenia), transient hyperglycemia, and NODAT. Those with preexisting diabetes for many years prior to transplant may well have very different long-term outcomes compared with those with true NODAT. Therefore, it would be prudent to classify patients more carefully. Long-term outcome studies are needed to determine if patients with true NODAT have the same poor prognosis as patients with preexisting diabetes (diagnosed and undiagnosed) undergoing transplant. PMID- 30430146 TI - Evaluation of Trace Alignment Quality and its Application in Medical Process Mining. AB - Trace alignment algorithms have been used in process mining for discovering the consensus treatment procedures and process deviations. Different alignment algorithms, however, may produce very different results. No widely-adopted method exists for evaluating the results of trace alignment. Existing reference-free evaluation methods cannot adequately and comprehensively assess the alignment quality. We analyzed and compared the existing evaluation methods, identifying their limitations, and introduced improvements in two reference-free evaluation methods. Our approach assesses the alignment result globally instead of locally, and therefore helps the algorithm to optimize overall alignment quality. We also introduced a novel metric to measure the alignment complexity, which can be used as a constraint on alignment algorithm optimization. We tested our evaluation methods on a trauma resuscitation dataset and provided the medical explanation of the activities and patterns identified as deviations using our proposed evaluation methods. PMID- 30430148 TI - A DR4 capturer with AKT siRNA for the synergetic enhancement of death receptor mediated apoptosis. AB - A graphene-based nanocarrier modified with death receptor 4 (DR4) antibody and AKT siRNA has been developed, which can synergistically strengthen death receptor mediated apoptosis and enhance the cancer therapeutic effect in vivo. PMID- 30430147 TI - Volume-Based Analysis of 6-Month-Old Infant Brain MRI for Autism Biomarker Identification and Early Diagnosis. AB - Autism spectrum disorder (ASD) is mainly diagnosed by the observation of core behavioral symptoms. Due to the absence of early biomarkers to detect infants either with or at-risk of ASD during the first postnatal year of life, diagnosis must rely on behavioral observations long after birth. As a result, the window of opportunity for effective intervention may have passed when the disorder is detected. Therefore, it is clinically urgent to identify imaging-based biomarkers for early diagnosis and intervention. In this paper, for the first time, we proposed a volume-based analysis of infant subjects with risk of ASD at very early age, i.e., as early as at 6 months of age. A critical part of volume-based analysis is to accurately segment 6-month-old infant brain MRI scans into different regions of interest, e.g., white matter, gray matter, and cerebrospinal fluid. This is actually very challenging since the tissue contrast at 6-month-old is extremely low, caused by inherent ongoing myelination and maturation. To address this challenge, we propose an anatomy-guided, densely-connected network for accurate tissue segmentation. Based on tissue segmentations, we further perform brain parcellation and statistical analysis to identify those significantly different regions between autistic and normal subjects. Experimental results on National Database for Autism Research (NDAR) show the advantages of our proposed method in terms of both segmentation accuracy and diagnosis accuracy over state-of-the-art results. PMID- 30430150 TI - Two-photon imaging of the endoplasmic reticulum thiol flux in the brains of mice with depression phenotypes. AB - Depression is a common mental illness with high morbidity and mortality. Mounting evidence suggests that an imbalance of the oxidant-antioxidant defence system is strongly correlated with depression and the dysfunction of the endoplasmic reticulum (ER) is strongly related to the oxidative stress. Therefore, as vital and abundant antioxidants in the ER, biothiols may contribute to the etiology of depression. However, ideal two-photon (TP) fluorescent probes for in vivo imaging of ER-associated thiols in the brains of mice with depression phenotypes are still lacking. Hence, we describe a fluorescent probe (ER-SH) to visualize thiols in living systems. ER-SH displays high sensitivity, excellent ER-targeting ability, outstanding TP properties and low cytotoxicity. Using this ER-SH probe, we succeeded in revealing an increase in the endogenous thiol levels under ER stress induced by DTT. Significantly, TP in vivo imaging showed for the first time that the thiol levels are reduced in brains of mice with depression phenotypes. Collectively, this work can assist in further understanding the molecular mechanism of depression and offers a crucial dimension for diagnosis and anti-depression treatments. PMID- 30430152 TI - Cell membrane camouflaged magnetic nanoparticles as a biomimetic drug discovery platform. AB - We report a novel biomimetic drug discovery platform using high expression epidermal growth factor receptor (EGFR) HEK 293 cell membrane camouflaged magnetic nanoparticles. The EGFR/magnetic cell membrane nanoparticles (MCMNs) integrated desirable magnetic features and special binding bioaffinity. Application of this drug-targeting concept is expected to pave ways to a new drug discovery strategy. PMID- 30430153 TI - Ultrasensitive SERS detection of highly homologous miRNAs by generating 3D organic-nanoclusters and a functionalized chip with locked nucleic acid probes. AB - Herein, a new finding is reported that 3D organic-nanoclusters (3DONs) with superior SERS properties as an original reporter could accurately and sensitively distinguish microRNAs (miRNAs) with highly similar sequences, even with a single nucleotide difference, as a result of a functionalized chip with locked nucleic acid probes (LNAP-chip) and rolling circle replication (RCA). Furthermore, the innovative SERS-method could be used to broadly discriminate cancer cells from normal cells and evaluate changes in the expression levels of intracellular miRNAs. PMID- 30430154 TI - Covalent capture of OGT's active site using engineered human-E. coli chimera and intrastrand DNA cross-links. AB - O 6-Alkylguanine DNA alkyltransferases (AGTs) are proteins found in most organisms whose role is to remove alkylation damage from the O6- and O4-positions of 2'-deoxyguanosine (dG) and thymidine (dT), respectively. Variations in active site residues between AGTs from different organisms leads to differences in repair proficiency: The human variant (hAGT) has a proclivity for removal of alkyl groups at the O6-position of guanine and the E. coli OGT protein has activity towards the O4-position of thymine. A chimeric protein (hOGT) that our laboratory has engineered with twenty of the active site residues mutated in hAGT to those found in OGT, exhibited activity towards a broader range of substrates relative to native OGT. Among the substrates that the hOGT protein was found to act upon was interstrand cross-linked DNA connected by an alkylene linkage at the O6-position of dG to the complementary strand. In the present study the activity of hOGT towards DNA containing alkylene intrastrand cross-links (IaCL) at the O6- and O4-positions respectively of dG and dT, which lack a phosphodiester linkage between the connected residues, was evaluated. The hOGT protein exhibited proficiency at removal of an alkylene linkage at the O6-atom of dG but the O4 position of dT was refractory to protein activity. The activity of the chimeric hOGT protein towards these IaCLs to prepare well defined DNA-protein cross-linked conjugates will enable mechanistic and high resolution structural studies to address the differences observed in the repair adeptness of O4-alkylated dT by the OGT protein relative to other AGT variants. PMID- 30430156 TI - Inhibition of arsenite methylation induces synergistic genotoxicity of arsenite and benzo(a)pyrene diol epoxide in SCC-7 cells. AB - As is well-known, arsenite (As(iii)) is a human carcinogen associated with many human cancers. As(iii) can act as a co-carcinogen to induce DNA damage with other carcinogens. Benzo(a)pyrene diol epoxide (BPDE) is one of the most-studied environmental carcinogens, which exists ubiquitously in our daily life. The elucidation of the mechanism of As(iii) as a co-carcinogen with BDPE in cells causing genotoxicity is beneficial for the evaluation of its bioeffect. In this study, a comprehensive analytical system is used for DNA damage evaluation, BPDE DNA adduct detection, arsenic speciation and gene expression analysis. Based on the experimental results, it can be inferred that BPDE and As(iii) synergistically cause genotoxicity, and the possible mechanism is that BPDE inhibits arsenic methylation, leading to cellular As(iii) enrichment. As(iii) inhibits nucleotide excision repair (NER) of the DNA adduct damage caused by BPDE. The synergistic effect of BPDE and As(iii) causes DNA strand break damage, which further results in carcinogenesis. PMID- 30430158 TI - Temperature dependence of the spin state and geometry in tricobalt paddlewheel complexes with halide axial ligands. AB - Trinuclear cobalt paddlewheel complexes, [Co3(dpa)4X2] (dpa = the anion of 2,2' dipyridylamine, X = Cl-, Br-, -NCS-, -CN-, (NC)2N-), are known to demonstrate a thermally-induced spin-crossover (SCO). Despite a wealth of structural and magnetic information about such complexes, the role of the axial ligand on the characteristic SCO temperature (T1/2) remains ambiguous. The situation is complicated by the observation that the solid state geometry of the complexes, symmetric or unsymmetric, with respect to the central cobalt ion, also appears to influence the SCO behavior. In order to seek trends in the relationship between the nature of the axial ligand, geometry and magnetic properties, we have prepared the first examples of tricobalt paddlewheel complexes with axial fluorido and iodido ligands, as well as two new chlorido and bromido solvates. Their SCO properties are discussed in the context of an examination of previously reported chlorido and bromido adducts. The main conclusions are: (1) T1/2 values follow the trend I- < Br- ~ Cl- < F-; (2) while the molecular geometry is predominantly guided by crystal packing for the Cl-, Br- and I- derivatives, the presence of an axial fluoride may favor a more symmetric core; (3) the magnetic characterization of a second example of an unsymmetric complex supports the observation that they display dramatically lower T1/2 values than their symmetric analogues; and (4) SCO in crystallographically symmetric compounds apparently occurs without loss of molecular or crystallographic symmetry, while a gradual geometric transformation linking the temperature dependence of quasi-symmetric to unsymmetric in crystallographically unconstrained compounds was found. PMID- 30430159 TI - A nonpolar solvent effect by CH/pi interaction inside zeolites: characterization, mechanism and concept. AB - The acidity enhancement induced by the nonpolar solvent effect of naphthalene inside zeolites was unambiguously identified. The mechanism of such an effect due to the CH/pi interaction in the nonpolar environment has been revealed based on the advanced 2D 1H-13C correlation NMR technique and DFT calculations for the first time. PMID- 30430160 TI - Vibrationally induced metallisation of the energetic azide alpha-NaN3. AB - As initiation of an energetic material requires rupture of a covalent bond, and therefore population of antibonding electronic states, consideration of the electronic band gap has dominated initiation mechanisms for solid state materials. Most prominent are models based on metallisation, where static mechanical perturbation leads to closing of the electronic band gap. This work explores an alternative mechanism for the dynamic metallisation of a model energetic material, where vibrational excitation resulting from mechanical impact is found to induce transient metallisation of alpha-NaN3. The normal coordinates associated with bending the azido anion close the electronic band gap, facilitating the formation of highly reactive species important for initiation of energetic materials. The DFT simulated vibrational spectrum of alpha-NaN3 exhibits excellent reproduction of the experimental low-temperature inelastic neutron scattering spectrum (INS). PMID- 30430161 TI - Desferrioxamine:gallium-pluronic micelles increase outer membrane permeability and potentiate antibiotic activity against Pseudomonas aeruginosa. AB - The outer membrane of Pseudomonas aeruginosa functions primarily as a permeability barrier and imparts a broad spectrum of intrinsic antibiotic resistance. Herein, we describe the synthesis, characterization, and antimicrobial evaluation of a targeted polymeric micelle that specifically permeabilizes the outer membrane and potentiates antibiotic activity against P. aeruginosa. PMID- 30430162 TI - Toward reliable characterization of energetic materials: interplay of theory and thermal analysis in the study of the thermal stability of tetranitroacetimidic acid (TNAA). AB - The thermal stability of energetic materials, being of the utmost importance for safety issues, is often considered in terms of kinetics, e.g., the Arrhenius parameters of the decomposition rate constant. The latter, in turn, are commonly determined using conventional thermoanalytical procedures with the use of simple Kissinger or Ozawa methods for kinetic data processing. However, thermal decomposition of energetic materials typically occurs via numerous exo- and endothermal processes including fast parallel reactions, phase transitions, autocatalysis, etc. This leads to numerous drawbacks of simple approaches. In this paper, we proposed a new methodology for characterization of the thermochemistry and thermal stability of melt-cast energetic materials, which is comprised of a complementary set of experimental and theoretical techniques in conjunction with a suitable kinetic model. With the aid of the proposed methodology, we studied in detail a novel green oxidizer, tetranitroacetimidic acid (TNAA). The experimental mass loss kinetics in the melt was perfectly fitted with a model comprised of zero-order reaction (sublimation or evaporation) and first-order thermal decomposition of TNAA with the effective Arrhenius parameters Ea = 41.0 +/- 0.2 kcal mol-1 and log(A/s-1) = 20.2 +/- 0.1. We rationalized the experimental findings on the basis of highly accurate CCSD(T)-F12 quantum chemical calculations. Computations predict that thermolysis of TNAA involves an intricate interplay of multiple decomposition channels of the three tautomers, which are equilibrated via either monomolecular reactions or concerted double hydrogen atom transfer in the H-bonded dimers; the calculated Arrhenius parameters of the effective rate constant coincide well with experiment. Most importantly, calculations provide detailed mechanistic evidence missing in the thermoanalytical experiment and explain formation of the experimentally observed primary products N2O and NO2. Along with the kinetics and mechanism of decomposition, the proposed approach yields accurate thermochemistry and phase change data of TNAA. PMID- 30430176 TI - Surface charge engineering of nanosized CuS via acidic amino acid modification enables high peroxidase-mimicking activity at neutral pH for one-pot detection of glucose. AB - Surface charge engineering of nanosized CuS via acidic amino acid modification is proved to be an efficient strategy to realize high peroxidase-mimicking catalytic activity at neutral pH. As a proof-of-concept application, one-pot high performance colorimetric sensing of glucose by coupling the engineered nanozyme with glucose oxidase is realized. PMID- 30430177 TI - New 3,5-dimethylorsellinic acid-based meroterpenoids with BACE1 and AchE inhibitory activities from Aspergillus terreus. AB - Chemical investigation of the extracts of Aspergillus terreus resulted in the identification of terreusterpenes A-D (1-4), four new 3,5-dimethylorsellinic acid based meroterpenoids. The structures and absolute configurations of 1-4 were elucidated by spectroscopic analyses including HRESIMS and 1D- and 2D-NMR, chemical conversion, and single crystal X-ray diffraction. Terreusterpenes A (1) and B (2) featured 2,3,5-trimethyl-4-oxo-5-carboxy tetrahydrofuran moieties. Terreusterpene D (4) was characterized by a 4-hydroxy-3-methyl gamma lactone fragment that was generated by accident from the rearrangement of 3 in a mixed tetrahydrofuran-H2O-MeOH solvent. All these compounds were evaluated for the beta site amyloid precursor protein-cleaving enzyme 1 (BACE1) and acetylcholinesterase (AchE) inhibitory activities. Among them, compounds 1 and 2 showed potentially significant BACE1 inhibitory activity, with IC50 values of 5.98 and 11.42 MUM, respectively. Interestingly, compound 4 exhibited promising BACE1 and AchE inhibitory activities, with IC50 values of 1.91 and 8.86 MUM, respectively, while 3 showed no such activity. Taken together, terreusterpenes A and B could be of great importance for the development of new BACE1 inhibitors, while terreusterpene D could serve as the first dual-targeted 3,5-dimethylorsellinic acid-based meroterpenoid for the treatment of Alzheimer's disease. PMID- 30430182 TI - Iron(iii) chloride-catalyzed activation of glycosyl chlorides. AB - Glycosyl chlorides have historically been activated using harsh conditions and/or toxic stoichiometric promoters. More recently, the Ye and the Jacobsen groups showed that glycosyl chlorides can be activated under organocatalytic conditions. However, those reactions are slow, require specialized catalysts and high temperatures, but still provide only moderate yields. Presented herein is a simple method for the activation of glycosyl chlorides using abundant and inexpensive ferric chloride in catalytic amounts. Our preliminary results indicate that both benzylated and benzoylated glycosyl chlorides can be activated with 20 mol% of FeCl3. PMID- 30430183 TI - Correction: Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach. AB - Correction for 'Unique perforated graphene derived from Bougainvillea flowers for high-power supercapacitors: a green approach' by Rajendra P. Panmand et al., Nanoscale, 2017, 9, 4801-4809. PMID- 30430184 TI - Abnormal eyeblink conditioning is an early marker of cerebellar dysfunction in preclinical SCA3 mutation carriers. AB - BACKGROUND: Spinocerebellar ataxias (SCAs) are a group of autosomal dominantly inherited degenerative diseases. As the pathological process probably commences years before the first appearance of clinical symptoms, preclinical carriers of a SCA mutation offer the opportunity to study the earliest stages of cerebellar dysfunction and degeneration. Eyeblink classical conditioning (EBCC) is a motor learning paradigm, crucially dependent on the integrity of the olivocerebellar circuit, and has been shown to be able to detect subtle alterations of cerebellar function, which might already be present in preclinical carriers. METHODS: In order to acquire conditioned responses, we performed EBCC, delay paradigm, in 18 preclinical carriers of a SCA3 mutation and 16 healthy, age-matched controls by presenting repeated pairings of an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms. RESULTS: Preclinical carriers acquired significantly less conditioned eyeblink responses than controls and learning rates were significantly reduced. This motor learning defect was, however, not associated with the predicted time to onset. CONCLUSIONS: EBCC is impaired in preclinical carriers of a SCA3 mutation, as a result of impaired motor learning capacities of the cerebellum and is thus suggestive of cerebellar dysfunction. EBCC can be used to detect but probably not monitor preclinical cerebellar dysfunction in genetic ataxias, such as SCA3. PMID- 30430185 TI - Main anatomical features of the calcarine sulcus: a 3D magnetic resonance imaging at 3T study. AB - OBJECTIVE: The purpose of our study was to determine the main anatomical features of the calcarine sulcus using a 3-T MRI. METHODS: Fifty human brains have been explored using an MRI 3-T in Doctors Center in Beirut (Lebanon). RESULTS: The calcarine sulcus was identified in 100% of cases. In most cases, it had a continuous aspect with several peaks. In all our specimens, the calcarine sulcus crosses the parieto-occipital fissure. The majority of their collateral branches and their connections with other sulci were located at the level of the calcarine sulcus properly. In the majority of specimens, the deepest part of the anterior calcarine sulcus forms a protrusion in the occipital horn of the lateral ventricle called calcar avis. CONCLUSION: Our study emphasizes the fact that the course patterns of the calcarine sulcus are highly variable. The description of the main anatomical features of the calcarine sulcus obtained from our study can be used as a reference for fMRI exploration and is useful for brain surgery. PMID- 30430186 TI - A Novel Brain Injury Biomarker Correlates with Cyanosis in Infants with Congenital Heart Disease. AB - Cyanotic heart lesions are a complex subset of congenital heart disease (CHD) in which patients are desaturated until surgical repair or palliation. We hypothesized that a direct relationship would exist between degree of desaturation and presence of systemic inflammation and brain injury in unrepaired patients less than 1 year of age. The pre-operative desaturation with augmented systemic inflammation would predict a more complex post-operative course. Fifty patients with CHD were enrolled in this study and classified as cyanotic (O2 <= 90%) or acyanotic (O2 > 90%) based on SpO2. Serum inflammatory mediators measured included interleukins (IL)-6, IL-8, IL-12p70, IL-10, IL-1beta, tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma; macrophage inhibitory factor (MIF) and a novel brain biomarker, phosphorylated neurofilament heavy subunit (pNF-H). Twenty-two cyanotic and 28 acyanotic subjects were enrolled with SpO2 of 78 +/- 18% and 98 +/- 2% (p < 0.001), respectively, and mean age of 72 days (range 2 303) and 102 days (range 1-274), respectively. Cyanotic vs acyanotic subjects had elevated serum IL-6 (6.6 +/- 7.6 vs 2.9 +/- 2.9 pg/ml, p = 0.019) and pNF-H (222 +/- 637 vs 57 +/- 121 pg/ml, p = 0.046), and both biomarkers correlated with degree of desaturation (Spearman rank-order correlation rho = - 0.30, p = 0.037 and rho = - 0.29 p = 0.049, respectively). Post-operative inotrope scores at 24 h and duration of mechanical ventilation correlated inversely with pre-operative oxygen saturation (rho = - 0.380, p = 0.014 and rho = - 0.362, p = 0.020, respectively). The degree of pre-operative desaturation correlated with a more complicated post-operative course supporting the need for advanced peri-operative therapy in this population. PMID- 30430187 TI - Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. AB - Male reproductive development is intricately dependent on fetal androgen action. Consequently, disrupted androgen action during fetal life can interfere with the development of the reproductive system resulting in adverse effects on reproductive function later in life. One biomarker used to evaluate fetal androgen action is the anogenital distance (AGD), the distance between the anus and the external genitalia. A short male AGD is strongly associated with genital malformations at birth and reproductive disorders in adulthood. AGD is therefore used as an effect readout in rodent toxicity studies aimed at testing compounds for endocrine activity and anti-androgenic properties, and in human epidemiological studies to correlate fetal exposure to endocrine disrupting chemicals to feminization of new-born boys. In this review, we have synthesized current data related to intrauterine exposure to xenobiotics and AGD measurements. We discuss the utility of AGD as a retrospective marker of in utero anti-androgenicity and as a predictive marker for male reproductive disorders, both with respect to human health and rodent toxicity studies. Finally, we highlight four areas that need addressing to fully evaluate AGD as a biomarker in both a regulatory and clinical setting. PMID- 30430188 TI - Highlight report: the need of 'fit-for-purpose' controls for cell lines used in toxicity assays. PMID- 30430189 TI - Bariatric Surgery Versus Lifestyle Intervention in Class I Obesity: 7-10-Year Results of a Retrospective Study. AB - INTRODUCTION: The American Society of Metabolic and Bariatric Surgery (ASMBS) and the International Federation of Surgery for Obesity (IFSO) have both stated that bariatric surgery (BS) should not be denied in Class I patients. However, lifestyle intervention (LI), such as diet plus gym programs, is still considered the preferred approach for subjects with a BMI ranging from 30 to 35 kg/m2. The aim of this study was to retrospectively compare results of LI and BS in patients in Class I obesity. METHODS: Retrospective analysis of prospective maintained databases of two centers for the "Interdisciplinary Treatment of Obesity" was performed. All patients in Class I obesity and follow-up >7 years were included in the study. Subjects were divided into two groups: BS group that included patients who had undergone surgery and LI group that included patients who underwent lifestyle intervention (LI). Percentage of excess body mass index loss (%EBMIL) and comorbidities remission were recorded. RESULTS: Seventy-six patients were included in the study. Fifty-six subjects were submitted to surgery (BS group); 20 subjects were treated with nonsurgical approach (LI group). In BS group, 34 underwent laparoscopic adjustable gastric band, 13 laparoscopic sleeve gastrectomy (LSG), and 9 laparoscopic Roux-en-Y gastric bypass. EWL% resulted significantly higher in BS group at 1, 3, 5, 7 and 10 years (p < 0.01). CONCLUSION: Bariatric surgery is more effective than LI for patients in Class I obesity. Due to its versatility, low-risk profile and high-effectiveness LSG could be the standard intervention for these patients. PMID- 30430190 TI - [Brain stimulation for the selective treatment of schizophrenia symptom domains : Non-invasive and invasive concepts]. AB - Given that one third of patients with schizophrenia (SZ) only show limited response to established treatments, alternative therapeutic strategies such as non-invasive/invasive brain stimulation approaches have emerged as an adjunctive treatment option for distinct SZ symptom domains (e.g. acoustic hallucinations, negative/positive symptoms and cognitive impairment). aking comparative interventional studies and standardized technical parameters into consideration, current meta-analyses indicate that adjunctive electroconvulsive therapy, repetitive transcranial magnetic stimulation and transcranial direct current stimulation have a positive effect. Invasivedeep brain stimulation and MR-guided ultrasound brain ablation procedures represent treatment modalities that are currently being clinically tested. Supplementary preinterventional investigation methods (e.g. electrophysiology, neuroimaging and molecular inflammatory profiling) have been recommended in order to identify symptom-tailored predictive measures for diagnosis and treatment. PMID- 30430191 TI - Copanlisib, a novel phosphoinositide 3-kinase inhibitor, combined with carfilzomib inhibits multiple myeloma cell proliferation. AB - Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kalpha and delta inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110alpha and delta catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells. PMID- 30430192 TI - Indications for the monosegmental stabilization of thoraco-lumbar spine fractures. AB - PURPOSE: To evaluate the efficacy and to underline the right indications of the posterior monosegmental stabilization for the treatment of thoraco-lumbar spine fractures. METHOD: Twenty patients underwent a monosegmental stabilization at our Institution and were retrospectively reviewed with a minimum follow-up of two years. All the patients had a clinical and radiological assessment before, after the surgery and at final follow-up. All data were evaluated by one independent observer. Data collected were Denis pain and work scale, somatic kyphosis (SK), somatic height (SH), and compression percentage (CP). RESULTS: The mean pre operative SK angle measured between the upper and lower end plate of the fractured vertebra was 23.6 degrees . The mean SK immediately after surgery was 12.8 degrees and at final follow-up was 13.9 degrees . The mean pre-operative SH was 21.9 mm, the mean value after surgery was 26.5 mm, and at final follow-up was 24.8 mm. The mean pre-operative CP was 66.7%, the mean value after surgery was 80.9%, and at final follow-up was 75.3%. At final follow-up, 75% of the patients had no pain or moderate pain and 95% of the patients returned to a full time work. CONCLUSIONS: Monosegmental stabilization with fusion is a safe and effective method to treat well selected thoracolumbar spine fractures. The right indications are type A1, type B2, and type A3 with a load sharing of less than 7 points and some very well selected type C fractures in which there is not lateral and rotatory displacement. PMID- 30430193 TI - Analysis of PM10 and PM2.5 Concentrations in an Urban Atmosphere in Northern Spain. AB - This work analyses levels of particles PM10 and PM2.5 recorded at four air quality monitoring stations located in the urban area of Valladolid (Spain) during 2015-2016. To achieve this, the evolution of particle concentrations at different time scales was determined. Average concentrations ranged from 15.3 to 17.6 ug m-3 for PM10 and between 8.9 and 14.8 ug m-3 for PM2.5. The highest monthly means were recorded in autumn and winter. The difference between mean concentrations at weekends and on weekdays for PM10 was around 3 ug m-3 at most of the measuring stations and was 1 ug m-3 for PM2.5. Two concentration peaks were found during the day, one in the morning and the other in the evening, which evidenced the influence of traffic and other anthropogenic activities on PM concentrations. Their mean values were approximately 21 and 17-21 ug m-3, respectively, for PM10. Mean maximum values for PM2.5 were 12 ug m-3, except at one of the measuring sites, with 17 ug m-3 for the morning maximum and 1 ug m-3 more for the nocturnal peak. In addition, the impact of long-distance transport of air masses in the study area was analysed by applying a HYSPLIT trajectory model, taking into account backward trajectories of European, African, and Atlantic origins as well as local conditions. In particular, high concentration events due to Saharan dust intrusions are presented. Finally, background levels of particle concentrations estimated at most sampling areas were around 15 and 7.7 ug m-3 for the PM10 and PM2.5 particle fractions, respectively. PMID- 30430194 TI - Deauville score: the Phoenix rising from ashes. PMID- 30430195 TI - [Radiologic diagnosis of the gallbladder and bile ducts - part 2 : Acute and chronic cholecystitis, primary sclerosing cholangitis (PSC), benign and malignant masses of the biliary system]. AB - Upper abdominal pain, icterus and cholestasis are the symptoms leading to evaluation of the biliary tract. Together with its complications biliary stone disease is the main reason for inflammation of the biliary system. A distinction is made between acute and chronic variants. In chronic bile duct inflammation primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) and more recently IgG4-associated sclerosing cholangitis are of particular importance. Besides benign and tumor-like-lesions, malignant entities as gallbladder carcinoma and cholangiocarcinoma (CCC) in its three locations have to be mentioned. Despite all recent improvements, specificity of bile-tract imaging still remains limited, especially regarding malignant masses. Therefore the final diagnosis is made in many cases by histological analysis. PMID- 30430196 TI - Assessing the Microbiota of Black Soldier Fly Larvae (Hermetia illucens) Reared on Organic Waste Streams on Four Different Locations at Laboratory and Large Scale. AB - This study aimed to gain insight into the microbial quality, safety and bacterial community composition of black soldier fly larvae (Hermetia illucens) reared at different facilities on a variety of organic waste streams. For seven rearing cycles, both on laboratory-scale and in large-scale facilities at several locations, the microbiota of the larvae was studied. Also samples of the substrate used and the residue (= leftover substrate after rearing, existing of non-consumed substrate, exuviae and faeces) were investigated. Depending on the sample, it was subjected to plate counting, Illumina Miseq sequencing and/or detection of specific food pathogens. The results revealed that the substrates applied at the various locations differed substantially in microbial numbers as well as in the bacterial community composition. Furthermore, little similarity was observed between the microbiota of the substrate and that of the larvae reared on that substrate. Despite substantial differences between the microbiota of larvae reared at several locations, 48 species-level operational taxonomic units (OTUs) were shared by all larvae, among which most belonged to the phyla Firmicutes and Proteobacteria. Although the substrate is assumed to be an important source of bacteria, our results suggest that a variety of supposedly interacting factors-both abiotic and biotic-are likely to affect the microbiota in the larvae. In some larvae and/or residue samples, potential foodborne pathogens such as Salmonella and Bacillus cereus were detected, emphasising that decontamination technologies are required when the larvae are used in feed, just as for other feed ingredients, or eventually in food. PMID- 30430197 TI - Molecular basis of primary hyperoxaluria: clues to innovative treatments. AB - Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic end-product that is eliminated by urine. The main symptoms are related to the precipitation of calcium oxalate crystals in the urinary tract with progressive renal damage and, in the most severe form named Primary Hyperoxaluria Type I (PH1), to systemic oxalosis. The therapies currently available for PH are either poorly effective, because they address the symptoms and not the causes of the disease, or highly invasive. In the last years, advances in our understanding of the molecular bases of PH have paved the way for the development of new therapeutic strategies. They include (i) substrate-reduction therapies based on small-molecule inhibitors or the RNA interference technology, (ii) gene therapy, (iii) enzyme administration approaches, (iv) colonization with oxalate-degrading intestinal microorganisms, and, in PH1, (v) design of pharmacological chaperones. This paper reviews the basic principles of these new therapeutic strategies and what is currently known about their application to PH. PMID- 30430198 TI - Mitochondrial functions and melatonin: a tour of the reproductive cancers. AB - Cancers of the reproductive organs have a strong association with mitochondrial defects, and a deeper understanding of the role of this organelle in preneoplastic-neoplastic changes is important to determine the appropriate therapeutic intervention. Mitochondria are involved in events during cancer development, including metabolic and oxidative status, acquisition of metastatic potential, resistance to chemotherapy, apoptosis, and others. Because of their origin from melatonin-producing bacteria, mitochondria are speculated to produce melatonin and its derivatives at high levels; in addition, exogenously administered melatonin accumulates in the mitochondria against a concentration gradient. Melatonin is transported into tumor cell by GLUT/SLC2A and/or by the PEPT1/2 transporters, and plays beneficial roles in mitochondrial homeostasis, such as influencing oxidative phosphorylation and electron flux, ATP synthesis, bioenergetics, calcium influx, and mitochondrial permeability transition pore. Moreover, melatonin promotes mitochondrial homeostasis by regulating nuclear DNA and mtDNA transcriptional activities. This review focuses on the main functions of melatonin on mitochondrial processes, and reviews from a mechanistic standpoint, how mitochondrial crosstalk evolved in ovarian, endometrial, cervical, breast, and prostate cancers relative to melatonin's known actions. We put emphasis on signaling pathways whereby melatonin interferes within cancer cell mitochondria after its administration. Depending on subtype and intratumor metabolic heterogeneity, melatonin seems to be helpful in promoting apoptosis, anti-proliferation, pro-oxidation, metabolic shifting, inhibiting neovasculogenesis and controlling inflammation, and restoration of chemosensitivity. This results in attenuation of development, progression, and metastatic potential of reproductive cancers, in addition to lowering the risk of recurrence and improving the life quality of patients. PMID- 30430199 TI - Endoplasmic reticulum-targeting doxorubicin: a new tool effective against doxorubicin-resistant osteosarcoma. AB - Doxorubicin is one of the most effective drugs for the first-line treatment of high-grade osteosarcoma. Several studies have demonstrated that the major cause for doxorubicin resistance in osteosarcoma is the increased expression of the drug efflux transporter ABCB1/P-glycoprotein (Pgp). We recently identified a library of H2S-releasing doxorubicins (Sdox) that were more effective than doxorubicin against resistant osteosarcoma cells. Here we investigated the molecular mechanisms of the higher efficacy of Sdox in human osteosarcoma cells with increasing resistance to doxorubicin. Differently from doxorubicin, Sdox preferentially accumulated within the endoplasmic reticulum (ER), and its accumulation was only modestly reduced in Pgp-expressing osteosarcoma cells. The increase in doxorubicin resistance was paralleled by the progressive down regulation of genes of ER-associated protein degradation/ER-quality control (ERAD/ERQC), two processes that remove misfolded proteins and protect cell from ER stress-triggered apoptosis. Sdox, that sulfhydrated ER-associated proteins and promoted their subsequent ubiquitination, up-regulated ERAD/ERQC genes. This up regulation, however, was insufficient to protect cells, since Sdox activated ER stress-dependent apoptotic pathways, e.g., the C/EBP-beta LIP/CHOP/PUMA/caspases 12-7-3 axis. Sdox also promoted the sulfhydration of Pgp that was subsequently ubiquitinated: this process further enhanced Sdox retention and toxicity in resistant cells. Our work suggests that Sdox overcomes doxorubicin resistance in osteosarcoma cells by at least two mechanisms: it induces the degradation of Pgp following its sulfhydration and produces a huge misfolding of ER-associated proteins, triggering ER-dependent apoptosis. Sdox may represent the prototype of innovative anthracyclines, effective against doxorubicin-resistant/Pgp-expressing osteosarcoma cells by perturbing the ER functions. PMID- 30430200 TI - Diagnostic/classification criteria in pediatric Behcet's disease. AB - Behcet's disease (BD) is a variable vessel vasculitis characterized by recurrent oral and genital aphthosis accompanied by skin, ocular, gastrointestinal, neurologic, and articular involvement. BD is not common in childhood and the disease characteristics considerably differ between adults and children. 18 diagnostic/classification criteria have been published for BD to date. The pediatric BD (PEDBD) criteria, published in 2015, focused on pediatric BD, while the others mainly based on adult studies and are not validated for children. The aim of this review is to summarize the data about diagnostic/classification criteria for BD and to discuss the use and performance of the current criteria in pediatric BD. The covered topics are the characteristics of the diagnostic/classification criteria sets for BD, the factors restricting the universal use/acceptance of these criteria, and pediatric studies testing the performance of BD criteria sets. Having valid and universally accepted criteria with high performance is very important in pediatric BD as they help us determine patients for our studies and guide us through our clinical practice. There are less than 10 pediatric studies testing the performances of BD diagnostic/classification criteria. Their results suggest that revised ICBD (The International Criteria for BD) has the highest sensitivity, while ISG (The International Study Group) criteria remain as the most specific criteria set. Larger multinational pediatric BD cohorts with adequate control groups are required to compare the performance of the different criteria sets in children and to improve the performance of the existing PEDBD criteria. PMID- 30430201 TI - The effects of 8-week water-running program on exercise capacity in children with juvenile idiopathic arthritis: a controlled trial. AB - Exercise capacity has been reported to be lower in children with Juvenile Idiopathic Arthritis (JIA). Therefore, the aim was to investigate the effects of an 8-week water-based exercise program on exercise capacity in children with JIA. Forty-two children with JIA were divided into two groups as: exercise group [n = 21, water-running, moderate-intensity exercise (60-70%), two times/week], and control group (n = 21, no additional treatment other than the prescribed medication). All children were assessed at baseline and post-intervention in terms of physical and disease-related characteristics, pain at rest and in activity (visual analog scale), range of motion (Escola Paulista de Medicina Range of Motion Scale), aerobic exercise capacity (cycle ergometer), and anaerobic exercise capacity (Wingate Test). Anaerobic exercise capacity was found to be improved in the exercise group [baseline: 5.54 W/kg (IQR 25/75: 4.07/6.88 W/kg) vs. post-intervention: 6.0 W/kg (IQR 25/75: 4.8/7.4 W/kg), p = 0.002], while no improvements were observed in the control group [baseline: 5.29 W/kg (IQR 25/75: 4.75/5.85 W/kg) vs. post-intervention: 5.5 watts/kg (IQR 25/75: 5.0/6.1 W/kg), p = 0.076]. The amount of the changes related to anaerobic exercise capacity were higher in the exercise group [exercise group: 0.6 W/kg (IQR 25/75: 0.3/1.3 W/kg) vs. control group: 0.2 W/kg (IQR 25/75: - 0.1/0.5 W/kg), p = 0.024]. No changes were detected related to aerobic exercise capacity in any of the groups (p > 0.05). An 8-week water-running program might be beneficial to improve anaerobic exercise capacity, but it is not enough to improve the aerobic exercise capacity in children with JIA. PMID- 30430202 TI - Strengthening the quadriceps femoris muscle versus other knee training programs for the treatment of knee osteoarthritis. AB - People with knee osteoarthritis have atrophy of the muscles surrounding the knee joint. Therefore, exercise programs primarily have been focused on the strengthening of quadriceps femoris muscle (QFM). Primary aim of this systematic review was to determine which exercise increases strength of the QFM and describe the details of the training programs. Secondary aim was to determine effectiveness of strengthening of the QFM alone on pain and dysfunction in patient with knee osteoarthritis. PubMed, PEDro, and Cochrane were searched. PEDro for methodological quality of randomized controlled trials and Cochrane Collaborations' tool for risk of bias were used. A total of 1128 articles were identified from the database searches. Ten studies which were moderate-to-high level of evidence were included. In the comparison of different strengthening exercises of the QFM, significant difference was not found between training groups. However, strengthening of the QFM exercise training was superior to proprioceptive training. Additional hot packs plus shortwave diathermy or ultrasound or transcutaneous electrical nerve stimulation had superiority to isokinetic strengthening of the QFM alone. Only additional Russian electrical stimulation showed the significant difference compared with strengthening of the QFM exercise. Most of the included studies showed that strengthening of the QFM exercises has an effect on pain reduction and improvement of function. This review indicated that the strengthening of QFM training compared with other knee exercises provided muscle strengthening, pain reduction, and improved function while combination with other electrotherapy modalities or combination with Russian electrical stimulation had superiority to alone strengthening QFM training. PMID- 30430203 TI - [Cancer screening: yes or no? Aspects of a complex response]. PMID- 30430204 TI - Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly. AB - Aging immune deterioration and Epstein-Barr (EBV) intrinsic mechanisms play an essential role in EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly (EBV + DLBCLe) pathogenesis, through the expression of viral proteins, interaction with host molecules and epigenetic regulation, such as miR-155, required for induction of M1 phenotype of macrophages. This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patients. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to EBV-negative DLBCL. In EBV-negative DLBCL, CD163/CD68 ratio was higher among advanced-staged/high-tumor burden disease and overexpression of miR-155 was associated with decreased polarization to the M2 phenotype of macrophages. The opposite was observed in EBV + DLBCLe patients: we found a positive association between miR-155 relative expression and CD163/CD68 ratio, which was not significant after outlier exclusion. We believe that the higher CD163/CD68 ratio in this group is probably due to the presence of the EBV since it directly affects macrophage polarization towards M2 phenotype through cytokine secretion in the tumor microenvironment. Therapeutic strategies modulating miR-155 expression or preventing immuno-regulatory and pro-tumor macrophage polarization could be adjuvants in EBV + DLBCLe therapy since this entity has a rich infiltration of M2 macrophages in its tumor microenvironment. PMID- 30430206 TI - Intensive care medicine in 2050: clinical trials designs. PMID- 30430205 TI - A phase I clinical study of a cocktail vaccine of Wilms' tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma. AB - PURPOSE: The safety and clinical efficacy of WT1 human leukocyte antigen (HLA) class I peptide vaccine have been established, but the safety of a cocktail vaccine of WT1 HLA class I and II peptides has not. To verify its safety, we performed a phase I clinical trial for patients with recurrent malignant gliomas and assessed the immunological responses and survival data. PATIENTS AND METHODS: Fourteen HLA-A*24:02-positive patients with recurrent malignant glioma (2 with grade 3, 12 with grade 4) were enrolled. Every week, the patients received alternately a vaccine containing 3 mg of WT1 HLA-A*24:02-restricted (HLA class I) peptide and a cocktail vaccine of the HLA class I peptide and one of 0.75, 1.5 or 3 mg of the WT1 HLA class II peptide. For patients who showed no significant adverse effects within 6 weeks, the WT1 vaccine was continued at 2-4-week intervals. RESULTS: Eleven of the 14 patients completed WT1 vaccination for 6 weeks, while 3 patients dropped out earlier due to disease progression. All patients showed grade I level of skin disorders at the injection sites. No grade III/IV toxicity or dose-limiting toxicity was observed for any dose of WT1 HLA class II peptide. Six of the 14 patients had stable disease at 6 weeks. Median OS and 1-year OS rates were 24.7 weeks and 36%, respectively. CONCLUSION: The safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma. PMID- 30430207 TI - Percutaneous versus surgical femoro-femoral veno-arterial ECMO: a propensity score matched study. AB - PURPOSE: Femoral artery surgical cannulation is the reference for venoarterial extracorporeal membrane oxygenation (VA-ECMO) in adults. However, the less invasive percutaneous approach has been associated with lower rates of complications. This retrospective study compared complication rates and overall survival in a large series of patients who received surgical or percutaneous peripheral VA-ECMO. METHODS: All consecutive patients implanted with VA-ECMO between January 2015 and December 2017 in a high ECMO-volume university hospital were included. Surgical cannulation was the only approach until late 2016 after which the percutaneous approach became the first line strategy. Propensity score framework analyzes were used to compare outcomes of percutaneous and surgical groups while controlling for confounders. RESULTS: Among the 814 patients who received VA-ECMO (485 surgical and 329 percutaneous), propensity-score matching selected 266 unique pairs of patients with similar characteristics. Percutaneous cannulation was associated with fewer local infections (16.5% versus 27.8%, p = 0.001), similar rates of limb ischemia (8.6% versus 12.4%, p = 0.347) and sensory motor complications (2.6% versus 2.3%, p = 0.779) and improved 30-day survival (63.8% versus 56.3%, p = 0.034). However, more vascular complications following decannulation (14.7% versus 3.4%, p < 0.001), mainly persistent bleeding requiring surgical revision (9.4% vs. 1.5%, p < 0.001), occurred after percutaneous cannulation. CONCLUSIONS: Compared to the surgical approach, percutaneous cannulation for peripheral VA-ECMO was associated with fewer local infections, similar rates of ischemia and sensory-motor complications and improved 30-day survival. The higher rate of vascular complications following decannulation suggests that improvements in cannula removal techniques are needed to further improve patients' outcomes after percutaneous cannulation. PMID- 30430208 TI - Tracheal transplantation. PMID- 30430210 TI - Nasogastric tube ending in the right pleura of an intubated patient. PMID- 30430209 TI - Targeting two different levels of both arterial carbon dioxide and arterial oxygen after cardiac arrest and resuscitation: a randomised pilot trial. AB - PURPOSE: We assessed the effects of targeting low-normal or high-normal arterial carbon dioxide tension (PaCO2) and normoxia or moderate hyperoxia after out-of hospital cardiac arrest (OHCA) on markers of cerebral and cardiac injury. METHODS: Using a 23 factorial design, we randomly assigned 123 patients resuscitated from OHCA to low-normal (4.5-4.7 kPa) or high-normal (5.8-6.0 kPa) PaCO2 and to normoxia (arterial oxygen tension [PaO2] 10-15 kPa) or moderate hyperoxia (PaO2 20-25 kPa) and to low-normal or high-normal mean arterial pressure during the first 36 h in the intensive care unit. Here we report the results of the low-normal vs. high-normal PaCO2 and normoxia vs. moderate hyperoxia comparisons. The primary endpoint was the serum concentration of neuron specific enolase (NSE) 48 h after cardiac arrest. Secondary endpoints included S100B protein and cardiac troponin concentrations, continuous electroencephalography (EEG) and near-infrared spectroscopy (NIRS) results and neurologic outcome at 6 months. RESULTS: In total 120 patients were included in the analyses. There was a clear separation in PaCO2 (p < 0.001) and PaO2 (p < 0.001) between the groups. The median (interquartile range) NSE concentration at 48 h was 18.8 ug/l (13.9-28.3 ug/l) in the low-normal PaCO2 group and 22.5 ug/l (14.2-34.9 ug/l) in the high-normal PaCO2 group, p = 0.400; and 22.3 ug/l (14.8 27.8 ug/l) in the normoxia group and 20.6 ug/l (14.2-34.9 ug/l) in the moderate hyperoxia group, p = 0.594). High-normal PaCO2 and moderate hyperoxia increased NIRS values. There were no differences in other secondary outcomes. CONCLUSIONS: Both high-normal PaCO2 and moderate hyperoxia increased NIRS values, but the NSE concentration was unaffected. REGISTRATION: ClinicalTrials.gov, NCT02698917. Registered on January 26, 2016. PMID- 30430211 TI - Albumin fluid resuscitation in patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy is associated with improved survival. PMID- 30430212 TI - This is not a drill. PMID- 30430213 TI - De novo assembly and comparative transcriptome analysis: novel insights into terpenoid biosynthesis in Chamaemelum nobile L. AB - KEY MESSAGE: Analysis of terpenoids content, transcriptome from Chamaemelum nobile showed that the content of the terpenoids in the roots was the highest and key genes involved in the terpenoids synthesis pathway were identified. Chamaemelum nobile is a widely used herbaceous medicinal plant rich in volatile oils, mainly composed of terpenoids. It is widely used in food, cosmetics, medicine, and other fields. In this study, we analyzed the transcriptome and the content and chemical composition of the terpenoids in different organs of C. nobile. Gas chromatography-mass spectrometry analysis showed that the total content of the terpenoids among C. nobile organs was highest in the roots, followed by the flowers. Illumina HiSeq 2500 high-throughput sequencing technology was used to sequence the transcripts of roots, stems, leaves, and flowers of C. nobile. We obtained 139,757 unigenes using the Trinity software assembly. A total of 887 unigenes were annotated to secondary metabolism. In total, 55,711 differentially expressed genes were screened among different organs of C. nobile. We identified 16 candidate genes that may be involved in the terpenoid biosynthesis from C. nobile and analyzed their expression patterns using real-time PCR. Results showed that the expression pattern of these genes was tissue-specific and had significant differential expression levels in different organs of C. nobile. Among these genes, 13 were expressed in roots with the highest levels. Furthermore, the transcript levels of these 13 genes were positively correlated with the content of alpha-pinene, beta-phellandrene, 1,8 cineole, camphor, alpha-terpineol, carvacrol, (E,E)-farnesol and chamazulene, suggesting that these 13 genes may be involved in the regulation of the synthesis of the volatile terpenoids. These results laid the foundation for the subsequent improvement of C. nobile quality through genetic engineering. PMID- 30430214 TI - Pharmacokinetics of free and total mycophenolic acid in adult lupus nephritis patients-implications for therapeutic drug monitoring. AB - PURPOSE: To evaluate the relationship between total and free MPA pharmacokinetic (PK) parameters and renal outcome markers, and to verify whether conducting therapeutic drug monitoring (TDM) in lupus nephritis (LN) patients would be of value in routine clinical practice. METHODS: Eighty-four samples were collected from sixteen LN patients. Total and free MPA concentrations were measured at predose, 0.5 and 2 h after mycophenolate mofetil (MMF) intake. Area under the concentration time curve from 0 to 2 h (AUC0-2) and free fraction were calculated. RESULTS: High between-patient variability was observed (CV% of 53.5% for dose-normalized total MPA AUC0-2). A significant but weak correlation between dose-normalized total C0 and AUC0-2 was noted (r = 0.5699). Dose-normalized total C0 above 2.76 MUg/mL.g may indicate patients with eGFR < 81 mL/min with sensitivity of 83.3% and specificity of 75.0%. Hypoalbuminemic LN patients demonstrated significantly elevated MPA free fraction when compared with patients with serum albumin concentration >= 3.5 g/dL (1.49 +/- 0.64% vs 1.08 +/- 0.75%). CONCLUSION: This study examined relationship between free and total pharmacokinetic MPA parameters as well as the effect of hypoalbuminemia on MPA plasma protein binding in adult LN patients. The study results suggest that TDM of MPA in LN seems to be a more reasonable approach than the fixed-dose protocol. Moreover, predose total MPA concentration may be a possible estimation of MPA exposure, while monitoring free rather than total MPA may be more beneficial in hypoalbuminemic patients. PMID- 30430215 TI - Statin-associated immune-mediated necrotizing myopathy: a retrospective analysis of individual case safety reports from VigiBase. AB - PURPOSE: Statins represent an effective treatment for hyperlipidaemia. Immune mediated necrotising myopathy (IMNM), a form of statin myopathy, has recently been described, and is characterized by elevated creatine kinase, presence of antibodies against HMG-CoA and no improvement after drug discontinuation, even with immunosuppressive treatment. Information on IMNM is mainly from case reports and small case series. Therefore, all reported cases of IMNM in VigiBase, the WHO global database of individual case safety reports (ICSRs) including the underlying reporting patterns, were analysed to characterize more detailed this adverse drug reaction. METHODS: ICSRs of IMNM up to October 1, 2016 were extracted from VigiBase. Corresponding case narratives were requested from responsible national authorities to maximize the available data. The reports were analysed in terms of reporting criteria, co-reported terms, patient demographics, clinical data, administered medication, latency time, seriousness of the reaction and outcome. RESULTS: One hundred one deduplicated ICSRs of IMNM were reported from 17 countries until October 2016. Approximately two thirds of the cases were from the year 2016. Slightly more males than females were affected (52 [57%] males vs 39 [42%] females). Median reported patient age was 68 years (range 16 - 87 years). Ninety-one cases (99%) were classified as serious. Median latency time was 26 months (range 1 - 288 months). Median creatine kinase value was 6860 U/L (range 576 - 35,000 U/L). In total, eight patients (9%) had recovered from IMNM. Atorvastatin was the most frequently reported statin in 80% of cases. CONCLUSIONS: The number of IMNM reports has increased in recent years. IMNM associated with statin treatment seems to occur worldwide. Most IMNM cases were reported with atorvastatin. No dose dependency of statin-associated IMNM pathogenesis was identified. PMID- 30430216 TI - CD8+ T cell/IL-33/ILC2 axis exacerbates the liver injury in Con A-induced hepatitis in T cell-transferred Rag2-deficient mice. AB - BACKGROUND: Previous studies showed that CD4+ T cells play a critical role in Con A-induced hepatitis in wild-type mice. However, the role of CD8+ T cells in the setting of Con A-induced hepatitis is enigmatic. The aim of study is to investigate the function of CD8+ T cells in the context of Con-A-induced hepatitis. MATERIALS AND SUBJECTS: Two different mouse models of Con A-induced hepatitis, T cell-transferred Rag2-/- mice and wild-type C57BL/6 mice, were used in the present study. IL-33 gene knockout mice were used to confirm the role of alarmin in Con A-induced hepatitis. RESULTS: Opposing to the previous results obtained in wild-type mice, transferred CD4+ T cells alone into Rag2-knockout mice cannot cause hepatitis upon Con A challenge. In stark contrast, transferred CD8+ T cells play an important role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Furthermore, we found that hepatocytes injured by perforin-based CD8+ T cell cytotoxicity release the alarmin IL-33. This cytokine promotes ST2+ ILC2 development and the secretion of cytokines IL-5 and IL-13 to mediate liver inflammation triggered by Con A challenge. In addition, these type 2 cytokines, including those originated from CD4+ T cells, result in eosinophils accumulation in liver to exacerbate the liver injury after Con A administration. CONCLUSION: Our data for the first time revealed that CD8+ T cells play an indispensable role in the pathogenesis of Con A-induced liver injury in T cell-transferred Rag2-deficient mice. Therefore, the CD8+ T cell/IL-33/ILC2 axis is a potential therapeutic target for acute immune mediated liver injury. PMID- 30430217 TI - MVPTM Micro Vascular Plug Systems for the Treatment of Pulmonary Arteriovenous Malformations. AB - PURPOSE: To describe our institutional experience with MVPTM micro vascular plug systems for the treatment of pulmonary arteriovenous malformations (PAVMs). MATERIALS AND METHODS: We performed a retrospective medical record review of 52 patients with 119 PAVMs treated exclusively with MVPTM systems (69 procedures/153 MVPTM systems) between July 2014 and July 2018. All patients had PAVMs with feeding artery diameters >= 2 mm. MVPTM systems were deployed according to physician preference. We collected patient demographic information; procedural data (including size of feeding artery, size and number of embolics used per PAVM, fluoroscopy time, contrast administration), technical success rates, complications, and persistence. Persistence was assessed using computed tomography angiography (CTA) performed 1-3 months and 3-5 years after embolization per clinical protocol. RESULTS: All procedures were technically successful without major complications. Mean feeding artery diameter was 3.3 +/- 1.2 mm. Mean fluoroscopy time per procedure and contrast volume administered per procedure were 35 +/- 16 min and 217 +/- 101 mL, respectively. A mean of 1.3 +/- 0.8 MVPTM systems was used per PAVM. There were no instances of persistence during a mean follow-up time of 328 +/- 258 days (range 26 to 914 days). CONCLUSIONS: For PAVMs with feeding artery diameters of 2 to 7.9 mm (mean 3.3 +/- 1.2 mm), MVPTM systems are safe and effective given their high technical success rates and lack of persistence. Further prospective work will be required to elucidate the advantages and disadvantages of these MVPTM systems for PAVM embolization. LEVEL OF EVIDENCE: Level III. PMID- 30430218 TI - 12-Month Results from the Multicenter LOCOMOTIVE Study: Should We All Jump on this Bandwagon? PMID- 30430219 TI - A mathematical formalism for natural selection with arbitrary spatial and genetic structure. AB - We define a general class of models representing natural selection between two alleles. The population size and spatial structure are arbitrary, but fixed. Genetics can be haploid, diploid, or otherwise; reproduction can be asexual or sexual. Biological events (e.g. births, deaths, mating, dispersal) depend in arbitrary fashion on the current population state. Our formalism is based on the idea of genetic sites. Each genetic site resides at a particular locus and houses a single allele. Each individual contains a number of sites equal to its ploidy (one for haploids, two for diploids, etc.). Selection occurs via replacement events, in which alleles in some sites are replaced by copies of others. Replacement events depend stochastically on the population state, leading to a Markov chain representation of natural selection. Within this formalism, we define reproductive value, fitness, neutral drift, and fixation probability, and prove relationships among them. We identify four criteria for evaluating which allele is selected and show that these become equivalent in the limit of low mutation. We then formalize the method of weak selection. The power of our formalism is illustrated with applications to evolutionary games on graphs and to selection in a haplodiploid population. PMID- 30430220 TI - The detached stump of the torn anterior cruciate ligament adheres to the femoral notch wall and then to the posterior cruciate ligament within 6 months from injury. AB - PURPOSE: To evaluate the progressive changes in the morphology of traumatic ruptures of the anterior cruciate ligament (ACL) over time. A secondary objective was evaluating their correlation with meniscal tears or chondral lesions. METHODS: The study included one hundred and one patients who underwent ACL reconstruction surgery of the knee after a definite date of injury. The torn ACL remnant morphological pattern was assessed and classified during arthroscopy. A correlation analysis was performed between the pathological features of the remnant and the time length from injury. In addition, correlation between ACL remnant subtypes and meniscal tears or chondral lesions was evaluated. RESULTS: At surgery there were four distinct ACL tear morphological patterns that were correlated to the time span from injury (r = 0.61, p < 0.001) and ended with scarring of the femoral remnant to the posterior cruciate ligament. The early pattern was noticed within median time of 2.6 months from injury and appeared as a separate stump with no scar tissue. The following two patterns appeared within 6 months from injury and were characterized by adhesion of scar tissue to different locations in the femoral notch. The last morphological pattern appeared as adherence of the ACL stump to the posterior cruciate ligament. This pattern was seen in some patients within 6 months from injury but was the dominant pattern later on and was also correlated with meniscal tears. CONCLUSIONS: During the first 3 months from injury the gross morphological features of the torn ACL remnant showed no scar. This phase was followed by scarring of the femoral remnant at first to the femoral notch, and eventually to the posterior cruciate ligament within 6 months from injury and later on. Therefore, further research on the healing potential of the human ACL stump and its biological environment should be focused on the first 3 months from injury. STUDY DESIGN: Case series; Level of evidence, 4. PMID- 30430221 TI - Medial femoral epicondyle upsliding osteotomy with posterior stabilized arthroplasty provided good clinical outcomes such as constrained arthroplasty in primary total knee arthroplasty with severe valgus deformity. AB - PURPOSE: A modified technique referred to as a medial femoral epicondyle upsliding osteotomy was proposed to address severe valgus deformity with unconstrained posterior stabilized (PS) arthroplasty. The study compared the effectiveness of the technique and PS arthroplasty with constrained arthroplasty during primary total knee arthroplasty (TKA). METHODS: Fifty-three patients presenting with valgus knees with a mean valgus angle (VA) greater than 30 degrees were prospectively randomized and divided into two groups, and both groups received primary TKA. Upsliding osteotomy with PS arthroplasty was performed on the knees of 27 patients (group A), while the remaining 26 patients (group B) received a constrained arthroplasty. The Knee Society function score (KSF), Hospital for Special Surgery knee score (HSS), range of motion (ROM), mediolateral stability and hospitalization expenses were recorded. The hip-knee ankle angle (HKA), femorotibial angle (FTA) and VA were analysed. Complications were also recorded. RESULTS: The patients received follow-up care for more than 50 months. The postoperative KSF, HSS and ROM showed marked improvement in both groups (p < 0.05). Radiological assessments showed that HKA, FTA and VA for group A were restored to (179.9 +/- 3.0) degrees , (173.0 +/- 2.4) degrees and (7.0 +/ 2.4) degrees , respectively. For group B, the HKA, FTA and VA were restored to (181.5 +/- 2.3) degrees , (172.5 +/- 2.3) degrees and (7.5 +/- 2.3) degrees , respectively. Only two patients from group A demonstrated mild medial laxity in their knees, and the remaining patients from both groups were stable medially and laterally. However, the total hospitalization expenses and material expenses of group A were less than those of group B because of the more expensive constrained prosthesis and stems. No late-onset loosening or recurrent valgus deformity was displayed. CONCLUSIONS: Both medial femoral epicondyle upsliding osteotomy with PS arthroplasty and constrained arthroplasty showed good outcomes for the restoration of neutral limb alignment and soft tissue balance, which are demonstrated to be safe and effective techniques for correcting severely valgus knees. Therefore, the clinically important finding of this study is that medial femoral epicondyle upsliding osteotomy with PS arthroplasty can be an alternative method for correcting severe valgus knees. LEVEL OF EVIDENCE: II. PMID- 30430222 TI - Extended Water-Level Drawdowns in Dammed Rivers Enhance Fish Habitat: Environmental Pool Management in the Upper Mississippi River. AB - Environmental Pool Management (EPM) can improve ecosystem function in rivers by restoring aspects of the natural flow regime lost to dam construction. EPM recreates summer baseflow conditions and promotes the growth of terrestrial vegetation which is inundated in the fall, thereby improving habitat heterogeneity for many aquatic taxa. A three-year experiment was conducted wherein terrestrial floodplain areas were dewatered through EPM water-level reductions and the resulting terrestrial vegetation was (1) allowed to remain or (2) removed in paired plots in Mississippi River pool 25. Fish assemblage and abundance were quantified in paired plots after inundation. Abundances of many fish species were greater in vegetated plots, especially for species that utilize vegetation during portions of their life history. Fish assemblages varied more between plot types when the magnitude of EPM water-level drawdowns was greater, which produced greater vegetation growth. Young-of-year individuals, especially from small, early maturing species and/or species reliant on vegetation for refuge, feeding, or life history, utilized vegetated plots more than devegetated plots. Vegetation growth produced under EPM was heavily used by river fishes, including young-of-year individuals, which may ultimately positively influence recruitment. Increased habitat heterogeneity may mitigate some of the negative impacts of dam construction and water-level regulation on river fishes. Annual variability in vegetation responses that occurs under EPM enhances natural environmental variability which could ultimately contribute to increased fish diversity. Low-cost programs like EPM can be implemented as a part of adaptive management plans to help maintain biodiversity and ecosystem health in anthropogenically altered rivers. PMID- 30430223 TI - ? PMID- 30430224 TI - [MagicTube: new possibilities for completely internal bone segmental transport and optional lengthening : New additional module for motorized lengthening nails for treatment of large bone defects]. AB - Segmental bone transport is an effective method of treatment for segmental defects but the previous need for external fixation constructs during the transport phase is a great disadvantage, especially in the femur. In order to avoid external fixation, a new cylindrical combitube segmental transport (CKTST, MagicTube) module for combination with a commercially available motorized lengthening nail was developed by the author. This MagicTube module enables completely internal segmental bone transport and also enables optional lengthening if needed. The concept and surgical technique of MagicTube are described, illustrated, discussed and exemplified by clinical cases involving the tibia and femur. PMID- 30430225 TI - [Motorized intramedullary lengthening nails]. PMID- 30430227 TI - Pharmacokinetics of liposomal curcumin (LipocurcTM) infusion: effect of co medication in cancer patients and comparison with healthy individuals. AB - PURPOSE: Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of LipocurcTM (liposomal curcumin). METHODS: Correlation analysis was used to determine the impact of co medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with LipocurcTM to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals. RESULTS: Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with LipocurcTM. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals. CONCLUSION: Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as LipocurcTM) in cancer patients. PMID- 30430228 TI - Role of the HDAC6/STAT3 pathway in regulating PD-L1 expression in osteosarcoma cell lines. AB - Histone deacetylases (HDACs), initially described as histone modifiers, have more recently been verified to target various other proteins unrelated to the chromatin environment. On this basis, findings of the current study demonstrates that the pharmacological or genetic abrogation of HDAC6 in osteosarcoma cell lines down-regulates the expression of program death receptor ligand-1 (PD-L1), an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T cells. As shown by our results, the mechanism by which HDAC6 regulated PD-L1 expression was mediated by the transcription factor STAT3. In addition, we observed that selective HDAC6 inhibitors could inhibit tumor progression in vivo. Crucially, these results provide an essential pre-clinical rationale and justification for the necessity of further research on HDAC6 inhibitors as potential immuno-modulatory agents in osteosarcoma. PMID- 30430229 TI - Long-term outcome of patients with advanced pancreatic cancer treated with sequential chemotherapies before the era of modern combination therapy protocols. AB - INTRODUCTION: Patients (pts) with locally advanced (LAPC) or metastatic pancreatic ductal adenocarcinoma (mPDAC) have a dismal prognosis. Recently, new combination chemotherapies such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated superiority over gemcitabine monotherapy. However, a substantial proportion of pts cannot tolerate these intensive front-line protocols. Moreover, the long-term superiority of multiagent protocols over less intensive strategies remains to be shown. To provide a benchmark for future studies, we analyzed the outcome of patients with LAPC or mPDAC treated at the West German Cancer Center before the FOLFIRINOX/nab-paclitaxel + gemcitabine era. METHODS: This retrospective analysis included 201 consecutive pts with LAPC and mPDAC treated between 2007 and 2011. Efficacy parameters were correlated with type of chemotherapy, number of treatment lines and clinicopathological parameters. RESULTS: Gemcitabine monotherapy was given as first-line therapy in 51.1%, whereas 48.9% received combination chemotherapies such as gemcitabine/oxaliplatin or FOLFOX. Patients received a median of two lines of treatment, with 54.8% receiving second-line and 37.9% receiving third- and further-line therapies. There was no significant difference between gemcitabine monotherapy and combination therapies. Despite moderate activity of first-line treatment, median overall survival for LAPC was 11.3 months and 8.7 months for mPDAC. Multivariate analysis identified age and number of treatment lines as prognostic markers. CONCLUSION: The long-term outcome of unselected pts with LAPC and mPDAC treated before the introduction of aggressive multiagent chemotherapy protocols compares favorably with the results of contemporary benchmark trials. This suggests a multifactorial benefit from interdisciplinary care provided over sequential treatment lines at high volume expert centers. PMID- 30430231 TI - Safety and efficacy of short- and long-term inspiratory muscle training in late onset Pompe disease (LOPD): a pilot study. AB - BACKGROUND: In patients with late-onset Pompe disease, progressive respiratory muscle weakness with predominantly diaphragmatic involvement is a frequent finding at later stages of the disease. Respiratory muscle training (RMT) is an established therapy option for patients with several neuromuscular disorders including Duchenne muscular dystrophy. Forced voluntary muscle contractions of inspiration and/or expiration muscles enhance ventilation by increasing respiratory coordination, endurance, and strength. Efficacy of RMT in LOPD is rarely examined, and the clinical studies performed are difficult to compare because of different training programs and protocols. This impedes a useful statement and recommendation about the safety and efficacy of respiratory muscle training. METHODS: We conducted a monocentric unblinded single-arm pilot study in patients with LOPD to evaluate the safety and efficacy of inspiratory muscle training (IMT). The primary objective was to determine the efficacy of a 6-week repetitive IMT with a gradual increase of inspiratory resistance, measured by MIP (maximum inspiratory pressure) in the upright position. For statistical analysis, we used an A-B-C single subject design. The 6-week training-period A was followed by a 6-week non-training period B and an optional training period of 40 weeks in period C. The total study duration for the periods A, B and C was 52 weeks. Throughout the study, spirometry assessments (FCV, FEV1) and measurements of respiratory strength (MIP, MEP) were performed at defined time points, as well as capillary oximetry and capnometry, motor function test and patient's questionnaires for quality of life and dyspnea, measured by St. George's Respiratory Questionnaire (SGRQ) and MMRC-Dyspnea scale. For the cross-sectional comparison, a paired two-sided t test, and for the longitudinal comparison, a two sample, two-sided t test were used. When data were not normally distributed, a Wilcoxon-Mann-Whitney test was added. Finally, the annual decline in FVC and FEV1 before and after IMT was compared. FINDINGS: 11 subjects were included in this pilot study. Overall, IMT was well tolerated. In four subjects, a total of six adverse events related to the study procedures were noticed. Training compliance was excellent in the first weeks of training, but declined continuously in the extension period. There was a significant increase in our primary outcome measure MIP within the 6-week period of frequent IMT with a mean of 15.7% (p =0.024; d =0.402). A significant increase was also seen after week 52 by a mean of + 26.4% (mean + 13.4 cmH2O, p =0.001, d =0.636). In the 6-week non-training interim period (period B), the values remained stable, and there was no clinically meaningful decline in secondary outcome measures. The increase in MIP did not have any effect on secondary outcome measures like spirometry tests (FVC, FEV1), capillary blood gas analysis, motor function tests, patient's perceived quality of life or any significant change in dyspnea score. CONCLUSIONS: Frequent IMT improves MIP and thereby stabilizes and decelerates the decline of the diaphragm strength. The gradual increase of inspiratory resistance is well tolerated without any increase of side effects, as long as IMT is supervised and resistance is individually adjusted to the patient's perceived grade of exhaustion. Although we could not detect a significant impact on secondary outcome measures, IMT should be offered to all LOPD patients, especially to those who demonstrate a progressive decline in respiratory muscle function or are unable to receive ERT. PMID- 30430230 TI - Surgical anatomy of the external branch of the superior laryngeal nerve: a systematic review and meta-analysis. AB - PURPOSE: To provide a comprehensive evidence-based assessment of the anatomical characteristics of the external branch of the superior laryngeal nerve (EBSLN). MATERIALS AND METHODS: A thorough systematic search was performed on the major electronic databases PubMed, EMBASE, Cochrane library, and ScienceDirect to identify eligible studies. Data were extracted and pooled into a meta-analysis. The primary outcomes were the EBSLN identification rate (total number of EBSLN identified divided by the total number of dissected hemilarynges) and the prevalence of various EBSLN types. RESULTS: A total of 56 studies (n = 13,444 hemilarynges) were included. The overall pooled EBSLN identification rate was 89.24% (95% CI 85.49-92.49). This rate was higher for cadaveric (95.00%; 95% CI 89.73-99.35) compared to that reported in intraoperative studies (86.99%; 95% CI 82.37-91.01). Significantly higher identification rates were reported for studies in which intraoperative nerve monitoring was used (95.90%; 95% CI 94.30-97.25) compared to those which only relied on direct visual identification of the EBSLN (76.56%; 95% CI 69.34-83.08). Overall, Cernea type IIa (nerves crossing the superior thyroid artery less than 1 cm above the upper edge of the superior thyroid pole) and Friedman type 1 (nerves running their entire course superficial to the inferior pharyngeal constrictor) were the most prevalent (41.84%; 95% CI 33.28-48.08 and 50%; 95% CI 29.90-65.62, respectively). The combined prevalence of Cernea IIa and IIb (nerves crossing the superior thyroid artery below the upper edge of the superior thyroid pole) was higher in intraoperative studies compared to that in cadaveric studies (64.3% vs 49.4%). The EBSLN coursed medial to the superior thyroid artery in 70.98% (95% CI 55.14-84.68) of all cases. CONCLUSION: The use of intraoperative nerve monitoring improves EBSLN identification rates. In light of the highly variable anatomical patterns displayed by the EBSLN, thorough pre-operative knowledge of its anatomy can be crucial in minimizing incidences of its iatrogenic injury. PMID- 30430232 TI - Burden of disease in patients with chronic hepatitis C in the Austrian REAL study. AB - BACKGROUND: The direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) +/- dasabuvir (DSV) +/- ribavirin (RBV) is approved to treat patients with chronic hepatitis C (CHC) infection genotypes 1 or 4, including compensated cirrhosis. The aim of the prospective, multicenter, observational REAL study was to provide evidence of the effectiveness of this regimen in an Austrian real-world setting and to determine the impact on patient-reported outcomes (PROs). METHODS: Effectiveness was defined as sustained virologic response 12 weeks after the end of treatment (SVR12). EuroQol 5 Dimension 5 Level (EQ-5D-5L) and Work Productivity and Activity Impairment HepC v2.0 (WPAI) questionnaires were used to assess PROs. RESULTS: A total of 173 patients were enrolled. The SVR12 was 95.9% (140/146) in the core population with sufficient follow-up (i. e. patients without SVR12 data not due to efficacy/safety reasons, such as lost to follow-up, were excluded) and 84.8% (140/165) in the core population (CP). Data at all timepoints for the EQ-5D 5L index score and visual analog scale and the total activity impairment score of the WPAI were available for 88, 95 and 72 patients, respectively. All PROs remained generally unaltered during treatment with OBV/PTV/r +/- DSV +/- RBV but showed a statistically significant (p < 0.01) improvement 12 weeks after the end of treatment versus baseline. CONCLUSIONS: These are the first data on PROs in a real-world setting with OBV/PTV/r +/- DSV +/- RBV treatment; this study demonstrated that treatment did not negatively impact quality of life. Results from the Austrian REAL study support the effectiveness of OBV/PTV/r +/- DSV +/- RBV in patients with CHC genotype 1 and 4 in everyday clinical practice. PMID- 30430233 TI - Resolving tradeoffs among crypsis, escape behavior, and microhabitat use in sexually dichromatic species. AB - Variation in color pattern between populations of cryptic animals is common and typically attributed to selection pressures from visual predators combined with variation in substrate composition. However, little is known about how cryptic color pattern relates to varied rates of predation, and few studies simultaneously analyze patterns of escape behavior and microhabitat use along with variation in color pattern, even though these traits evolve in tandem. Here, we use a combination of calibrated photographs and spectrometry to examine the influence of spatial heterogeneity in rates of predation on dorsal brightness in the Florida scrub lizard (Sceloporus woodi), a cryptic and sexually dimorphic species. Simultaneously, we analyze patterns of escape behavior and microhabitat use measured in the field. The results of this study indicate that populations inhabiting environments of increased predation have less color variation and more closely match the color of local substrate than populations sampled in environments of relaxed predation. Populations exposed to increased predation also show more pronounced escape behavior and are more selective in their use of microhabitat. Interestingly, geographic variation of dorsal brightness, escape behavior, and microhabitat use were greater for females than for males. Our results not only provide empirical evidence for theories of adaptive coloration, but suggest that sexual dichromatism can be maintained by selection pressures related to predation. PMID- 30430234 TI - A review on animal-robot interaction: from bio-hybrid organisms to mixed societies. AB - Living organisms are far superior to state-of-the-art robots as they have evolved a wide number of capabilities that far encompass our most advanced technologies. The merging of biological and artificial world, both physically and cognitively, represents a new trend in robotics that provides promising prospects to revolutionize the paradigms of conventional bio-inspired design as well as biological research. In this review, a comprehensive definition of animal-robot interactive technologies is given. They can be at animal level, by augmenting physical or mental capabilities through an integrated technology, or at group level, in which real animals interact with robotic conspecifics. Furthermore, an overview of the current state of the art and the recent trends in this novel context is provided. Bio-hybrid organisms represent a promising research area allowing us to understand how a biological apparatus (e.g. muscular and/or neural) works, thanks to the interaction with the integrated technologies. Furthermore, by using artificial agents, it is possible to shed light on social behaviours characterizing mixed societies. The robots can be used to manipulate groups of living organisms to understand self-organization and the evolution of cooperative behaviour and communication. PMID- 30430235 TI - ? PMID- 30430236 TI - [Erdheim-Chester disease : An important differential diagnosis and its main symptoms]. AB - BACKGROUND: During the last 3 years 4 patients were admitted to this hospital with a wide variety of different symptoms, in whom Erdheim-Chester disease (ECD) was diagnosed via different diagnostic pathways. OBJECTIVE: Based on four clinical cases of ECD and using additional information from the literature, this article presents the symptoms of ECD. Furthermore, similarities and differences in comparison to important rheumatological differential diagnoses are presented. RESULTS: The ECD is a multi-organ orphan disease. Typical for the disease are long bone involvement, periarterial inflammation especially of the aorta, retroperitoneal and perirenal fibrosis with so-called hairy kidneys in abdominal computed tomography (CT) scans. Treatment is increasingly directed towards the presence of a BRAF mutation, which enables targeted and effective treatment with BRAF inhibitors. CONCLUSION: The ECD is a rare differential diagnosis to rheumatic diseases that causes various and often nonspecific symptoms. Due to modern diagnostic methods with imaging procedures and biopsies it is possible to establish a precise diagnosis and provide a targeted and effective treatment. PMID- 30430237 TI - In memorium Herbert B. Tanowitz, MD, FIDSA, FACP, FRSTMH 6 September 1941 - 17 July 2018. AB - With deep regret and sadness, we report the death of Professor Herbert B. Tanowitz, Professor of Pathology, Division of Parasitology and Professor of Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York. He is survived by his children Pam, Meredith, and Jill, and their families. PMID- 30430238 TI - Persistent postoperative step-off of the posterior malleolus leads to higher incidence of post-traumatic osteoarthritis in trimalleolar fractures. AB - BACKGROUND: Traditionally, size of the posterior fragment is considered the most important indicator for fixation in trimalleolar fractures. It remains unclear which factors contribute to worse functional and radiological outcome. This study was designed to determine predictors for the development of posttraumatic osteoarthritis and worse functional outcome in trimalleolar fractures. METHODS: This retrospective cohort study evaluated outcomes of 169 patients with a trimalleolar fracture treated between 1996 and 2013 in a level-1 trauma hospital in the Netherlands after a mean follow-up of 6.3 (range 2.4 to 15.9) years. The average fragment size was 17%. Twenty patients had a posterior fragment smaller than 5% of the intra-articular surface, 119 patients a fragment of 5-25% and 30 patients a posterior fragment larger than 25%. In total, 39 patients (23%) underwent fixation of the posterior fragment. RESULTS: Clinical union was achieved in all 169 patients. The median AOFAS score after follow-up was 93 (interquartile range 76-100) and the median AAOS score was 92 (interquartile range 81-98). A persistent postoperative step-off larger than 1 mm was found in 65 patients (39%) and osteoarthritis was present in 49 patients (30%). Higher age and postoperative step-off > 1 mm were independent, significant risk factors for the development of osteoarthritis. Osteoarthritis and BMI were independent, significant risk factors for worse functional outcome. CONCLUSION: It is advisable to correct intra-articular step-off of intraarticular posterior malleolar fragments to reduce the risk of developing osteoarthritis and, consequently, the risk of worse functional outcome after long-term follow-up. LEVEL OF EVIDENCE: Level IIB. PMID- 30430239 TI - Determinants of low measles vaccination coverage in children living in an endemic area. AB - Measles outbreaks were recently reported in Europe due to low immunization rates. In this scenario, identifying the reasons of no vaccination is crucial to set up strategies to improve immunization rate. A cross-sectional study was conducted to investigate the determinants of missed vaccination in children living in Southern Italy, during the 2016 outbreak. A standardized face-to-face questionnaire was used to record demographic data, immunization status, and reasons for missed vaccination. A total of 1141 children (median age 86 months, male 47.2%) was enrolled, 77.8% of the children were adequately vaccinated for age, 6.3% were incompletely vaccinated for age, and 15.9% did not receive any vaccine dose. Vaccination rate and reasons for not vaccinating significantly varied according to age, with children <= 24 months showing the lowest rate (67.8%). Reasons for not vaccinating included fear for side effects (51%), presence of underlying chronic conditions (12.2%), skip scheduled appointment (12.2%), refusal of vaccination (10.3%), acute illnesses (7.2%), and allergy to eggs (4.6%). The presence of underlying condition was a risk factor for inadequate immunization (p < 0.0001). Only 4.7% of conditions were true contraindications to vaccine administration.Conclusion: We reported inadequate measles immunization rate in Southern Italy, with lowest rates in children <= 2 years or with underlying conditions. Only a minority had true contraindications to vaccine uptake. Implementation strategies addressed to health-care professionals and families should focus on the reported determinants to increase measles vaccination coverage. What is Known: * Measles is a viral, highly communicable disease, preventable by vaccine. * Measles elimination in Europe failed as demonstrated by outbreaks in several countries, due to low immunization rates. What is New: * Inadequate measles immunization rate due to false contraindications in Southern Italy, with lowest rates in children <= 2 years. * The presence of underlying disease is a risk factor for inadequate immunization. PMID- 30430241 TI - Choanal polyps in children and adults: 10-year experience from a tertiary care hospital. AB - PURPOSE: Choanal polyps (CPs) are benign, solitary, soft-tissue lesions extending towards the junction between the nasal cavity and the nasopharynx through the choana. The aim of this retrospective study was to evaluate clinical and histological characteristics of CPs in children comparing to adult patients. METHODS: Characteristics of CPs treated in our hospital (demography, main complaints, side, localization, surgical approach, histological characteristics, accompanying paranasal sinus diseases, association with allergic rhinitis, postoperative follow-up period, and recurrence rates) were retrospectively reviewed. RESULTS: Seventy-eight patients with CPs were included, 22 (28%) patients in children and 56 (72%) patients in adults. We found no differences in the prevalence of main nasal complaints (nasal obstruction, rhinorrhea, snoring, and epistaxis) between the child and adult. In 27% children and in 7% adults, we found the oropharyngeal extension of CPs (p < 0.01). In 18% children and in 5.3% adults, we found the histological characteristics of an angiomatous CP (p < 0.05). The association with allergic rhinitis was more frequent in children (32%) than in adults (18%) (p < 0.05). In 32% pediatric patients and in 14% adult patients, we found the association with ipsilateral chronic maxillary rhinosinusitis without nasal polyps (CRSsNP) (p < 0.05). After the surgical treatment, we found the recurrence in 3 (14%) pediatric and in 5 (8%) adult patients, without the significant difference. CONCLUSION: Our results suggest some specificities of CPs in children comparing to adults. Oropharyngeal extension, association with allergic rhinitis and ipsilateral CRS, and the presence of angiomatous histological type of CPs are more frequent in the pediatric population. PMID- 30430240 TI - Expression of hyaluronan synthases upregulated by thyroid hormone is involved in intestinal stem cell development during Xenopus laevis metamorphosis. AB - During amphibian intestinal remodeling, thyroid hormone (TH) induces adult stem cells, which newly generate the absorptive epithelium analogous to the mammalian one. We have previously shown that hyaluronan (HA) is newly synthesized and plays an essential role in the development of the stem cells via its major receptor CD44 in the Xenopus laevis intestine. We here focused on HA synthase (HAS) and examined how the expression of HAS family genes is regulated during natural and TH-induced metamorphosis. Our quantitative RT-PCR analysis indicated that the mRNA expression of HAS2 and HAS3, but not that of HAS1 and HAS-rs, a unique Xenopus HAS-related sequence, is upregulated concomitantly with the development of adult epithelial primordia consisting of the stem/progenitor cells during the metamorphic climax. In addition, our in situ hybridization analysis indicated that the HAS3 mRNA is specifically expressed in the adult epithelial primordia, whereas HAS2 mRNA is expressed in both the adult epithelial primordia and nearby connective tissue cells during this period. Furthermore, by treating X. laevis tadpoles with 4-methylumbelliferone, a HA synthesis inhibitor, we have experimentally shown that inhibition of HA synthesis leads to suppression of TH upregulated expression of leucine-rich repeat-containing G protein-coupled 5 (LGR5), an intestinal stem cell marker, CD44, HAS2, HAS3, and gelatinase A in vivo. These findings suggest that HA newly synthesized by HAS2 and/or HAS3 is required for intestinal stem cell development through a positive feedback loop and is involved in the formation of the stem cell niche during metamorphosis. PMID- 30430242 TI - Costs of sialendoscopy and impact on health-related quality of life. AB - PURPOSE: To analyse costs related to the diagnosis and treatment of patients with sialolithiasis and sialadenitis managed with sialendoscopy, and to prospectively evaluate the impact of sialendoscopy on health-related quality of life (HRQoL) in a longitudinal follow-up study. METHODS: All patients undergoing sialendoscopy or sialendoscopy-assisted surgery at a tertiary care university hospital between January 2014 and May 2016 were identified from a surgical database, and the direct hospital costs were retrospectively evaluated from 1 year before to 1 year after the sialendoscopy. The 15D HRQoL questionnaire and a questionnaire exploring the use of health care services during the preceding 3 months were mailed to the patients before sialendoscopy as well as at 3 and 12 months after the operation. RESULTS: A total of 260 patients were identified. Mean total hospital costs, costs related to the sialendoscopy, and complications were significantly higher in sialolithiasis patients than in patients with other diagnoses. 74 patients returned the baseline 15D questionnaire, and 51 patients all three 15D questionnaires. At baseline, the dimensions "discomfort and symptoms" and "distress" were lower in patients than in age- and gender standardised general population, but the total 15D score did not differ significantly. The dimension "discomfort and symptoms" improved significantly at 3 and 12 months postoperatively, and the mean total HRQoL score improved in patients with sialolithiasis at 3 months postoperatively. CONCLUSIONS: The costs related to sialendoscopy are substantial and the cost-effectiveness of sialendoscopy warrants further studies. However, sialendoscopy seems to reduce patients' discomfort and ailments and to improve HRQoL at least in patients with sialolithiasis. PMID- 30430243 TI - Body surface area at birth and later risk for gestational diabetes mellitus among primiparous women. AB - AIMS: To assess the relationship between body surface area (BSA) at birth and future risk for gestational diabetes mellitus (GDM). METHODS: This is an observational cohort study from Vantaa, Finland. The cohort included 1548 Finnish primiparous women, aged 15-28 years, without pre-existing diabetes, who gave birth 2009-2015. All women were born full-term and had complete information about their birth weight and length, from the Finnish Medical Birth Register. Additional data for the study were provided by individual patient health records and Statistics Finland. Study participants were divided into five levels (I-V) according to BSA at birth, based on normal distribution. RESULTS: There was an inverse association between BSA at birth and risk for GDM (p = 0.015 for linearity, after adjustments for age, educational attainment, pre-pregnancy BMI and smoking). The odds ratio (OR) for GDM in level V, with the largest BSA at birth, compared with level I, with the smallest BSA at birth, was 0.43 [95% confidence interval (CI) 0.22-0.83]; adjusted for age, educational attainment, pre-pregnancy body mass index and smoking. The OR for GDM was 0.8 (95% CI 0.68 0.95, p = 0.009) for each one standard deviation increase in BSA at birth, adjusted for the same confounders. BSA at birth correlated with adult anthropometry: correlation coefficients were r = 0.16 (95% CI 0.11-0.21) for weight, r = 0.31 (95% CI 0.26-0.35) for height, and r = 0.06 (95% CI 0.01-0.11) for BMI. CONCLUSIONS: Body surface area at birth is inversely associated with future risk for GDM in primiparous women. PMID- 30430244 TI - Correction to: Short-term outcome of emergency colorectal cancer surgery: results from Bi-National Colorectal Cancer Audit. AB - The publisher regret that a typographical error was present in the Table 1 of the original version of this article. The value "20,032" should have been "2" in the Variable column under T stage. The correct table is now presented correctly in this article. PMID- 30430246 TI - The PINCH-Phone: a new screenings method for recurrent incisional hernias. AB - BACKGROUND: Debate persists on the optimal management of incisional hernias due to paucity of accurate recurrence rates. Reoperation rates implicate a severe underestimation of the risk of a recurrence. Therefore, long-term postoperative clinic visits allowing physical examination of the abdomen are deemed necessary. However, these are time and costs consuming. Aim of this study was to develop and evaluate a new screenings method for recurrent hernias, the 'PINCH-Phone' (Post INCisional-Hernia repair-Phone). METHODS: The PINCH-Phone is a telephone questionnaire. In this multicenter prospective study, the PINCH-Phone was answered by patients after incisional hernia repair. Afterwards the patients were seen at the clinic and physical examination was done to detect any recurrences. RESULTS: The PINCH-Phone questions were answered by 210 patients with a median postoperative follow-up of 36 months. Fifty-six patients were seen after multiple incisional hernia repairs. In 137 patients who had replied positively to one or more questions, 28 recurrent incisional hernias were detected at physical examination. Six recurrences were noted in 73 patients who had replied negatively to all questions. The overall sensitivity and specificity of the PINCH-Phone were 82% and 38%, respectively. CONCLUSION: The PINCH-Phone appears a simple and valuable screenings method for recurrences after incisional hernia repair and, hence, is recommended for implementation. PMID- 30430245 TI - MR angiogram confirms sustained blood flow in 1,2 ICSR artery of vascularized bone grafting in scaphoid nonunion treatment. AB - PURPOSE: To evaluate the functioning of 1,2 intercompartmental supraretinacular artery (ICSRA) in vascularized bone grafting (VBG) of scaphoid nonunions with avascular necrosis of proximal pole. MATERIALS AND METHODS: Fourteen patients with scaphoid nonunion were treated operatively with 1,2 ICSRA VBG. Viability of the pedicle artery was evaluated by MR angiography with intravenous contrast agent. RESULTS: In 13 out of 14 patients, the 1,2 ICSR artery was found to be patent and functional. Revascularization of scaphoid proximal pole was revealed in all cases, and nonunion healing was confirmed as well. CONCLUSION: 1,2 ICSRA VBG in scaphoid nonunion is an effective surgical technique. It combines the advantages of bone grafting and vascular supply via the transferred pedicle artery which seems to be functional postoperatively if a meticulous operative technique is used. PMID- 30430247 TI - Complex reproductive secretions occur in all extant gymnosperm lineages: a proteomic survey of gymnosperm pollination drops. AB - KEY MESSAGE: Complex protein-containing reproductive secretions are a conserved trait amongst all extant gymnosperms; the pollination drops of most groups include carbohydrate-modifying enzymes and defence proteins. Pollination drops are aqueous secretions that receive pollen and transport it to the ovule interior in gymnosperms (Coniferales, Cycadales, Ginkgoales, Gnetales). Proteins are well established as components of pollination drops in conifers (Coniferales) and Ephedra spp. (Gnetales), but it is unknown whether proteins are also present in the pollination drops of cycads (Cycadales), Ginkgo (Ginkgoales), Gnetum (Gnetales), or in the pollination drops produced by sterile ovules occurring on pollen plants in the Gnetales. We used liquid chromatography-tandem mass spectrometry followed by database-derived protein identification to conduct proteomic surveys of pollination drops collected from: Ceratozamia hildae, Zamia furfuracea and Cycas rumphii (Cycadales); Ginkgo biloba (Ginkgoales); Gnetum gnemon and Welwitschia mirabilis, including pollination drops from both microsporangiate and ovulate plants (Gnetales). We identified proteins in all samples: C. hildae (61), Z. furfuracea (40), C. rumphii (9), G. biloba (57), G. gnemon ovulate (17) and sterile ovules from microsporangiate plants (25) and W. mirabilis fertile ovules (1) and sterile ovules from microsporangiate plants (138). Proteins involved in defence and carbohydrate modification occurred in the drops of most groups, indicating conserved functions for proteins in pollination drops. Our study demonstrates that all extant gymnosperm groups produce complex reproductive secretions containing proteins, an ancient trait that likely contributed to the evolutionary success of seed plants. PMID- 30430248 TI - Adapting INTACT to analyse cell-type-specific transcriptomes and nucleocytoplasmic mRNA dynamics in the Arabidopsis embryo. AB - In the early embryo of vascular plants, the different cell types and stem cells of the seedling are specified as the embryo develops from a zygote towards maturity. How the key steps in cell and tissue specification are instructed by genome-wide transcriptional activity is poorly understood. Progress in defining transcriptional regulation at the genome-wide level in plant embryos has been hampered by difficulties associated with capturing cell-type-specific transcriptomes in this small and inaccessible structure. We recently adapted a two-component genetic nucleus labelling system called INTACT to isolate nuclei from distinct cell types at different stages of Arabidopsis thaliana embryogenesis. We have used these to generate a transcriptomic atlas of embryo development following microarray-based expression profiling. Here, we present a general description of the adapted INTACT procedure, including the two-component labelling system, seed isolation, nuclei preparation and purification, as well as transcriptomic profiling. We also compare nuclear and cellular transcriptomes from the early Arabidopsis embryo to assess nucleocytoplasmic differences and discuss how these differences can be used to infer regulation of gene activity. PMID- 30430250 TI - Reply to the letter to the editor of L. Russo et al. concerning "Relationship between sagittal spinal curves geometry and isokinetic trunk muscle strength in adults" by W. Elsayed, A. Farrag, Q. Muaidi, N. Almulhim (2018) Eur Spine J 27:2014-2022. PMID- 30430249 TI - Identification of Phenotypes in People with COPD: Influence of Physical Activity, Sedentary Behaviour, Body Composition and Skeletal Muscle Strength. AB - INTRODUCTION: People with chronic obstructive pulmonary disease (COPD) present high prevalence of physical inactivity that leads to a negative effect on health related quality of life (HRQoL). The present study investigated COPD phenotypes according to their levels of physical activity and sedentary behaviour, as well as body composition and skeletal muscle strength. METHODS: This is an observational and cross-sectional study. Anthropometric data and COPD clinical control were collected and all participants underwent assessments of lung function, HRQoL, dyspnoea, levels of physical activity and sedentary behaviour, body composition and skeletal muscle strength. Participants were classified using hierarchical cluster analysis. Age, dyspnoea and obstruction (ADO) index was used to determine prognosis and calculated for each cluster. RESULTS: One hundred and fifty-two participants were included. Three distinct phenotypes were identified. Participants in phenotype 1 were more physically active, less sedentary and had better body composition and lower ADO index (p < 0.0001 for all variables). Overall, participants in phenotypes 2 and 3 were less physically active, more sedentary having a higher ADO index. However, participants in phenotype 2 were older, whereas participants in phenotype 3 had worse HRQoL, clinical control and body composition. Lung function did not differ across the three phenotypes. CONCLUSIONS: Our results show that physical activity, sedentary behaviour and body composition should be considered to determine phenotypes in people with COPD and are involved in the prognosis of the disease. Less sedentary patients have better prognosis while age, body composition and clinical control seems to differentiate physically inactive patients. PMID- 30430251 TI - The effect of patient positioning on the relative position of the aorta to the thoracic spine. AB - PURPOSE: Detailed knowledge of the anatomy of the thoracic aorta is crucial for thoracolumbar spinal surgery. The purpose of the present study is to describe the relative displacement of the aorta to the spine in supine, prone and prone position with padding. Improved understanding of the magnitude and direction of this often-overlooked change could benefit preoperative planning and decision making. METHODS: A total of 200 patients underwent CT scan of the thoracic spine in the standard supine, prone and prone position with padding. Axial CT images from T4 to T12, in all three different positions, were selected and the following parameters were measured: (a) distance B connecting left pedicle entry point to the edge of the aortic wall and (b) projections Bx and By, representing the minimum AP depth and horizontal displacement of the aortic wall relative to the left pedicle entry point O. RESULTS: There was a significant difference in the distance B between the three different positions across all thoracic vertebrae levels, confirming that positioning significantly affects aorta's relative position. Moreover, in the prone position with padding at the level of T6, the aortic wall lies at a minimum distance from the left pedicular axis and thus from the typical screw trajectory. CONCLUSION: The results of this study show that prone positioning for posterior thoracolumbar approach affects significantly the anatomic relationship of the aorta to the spine. Surgeons should be aware that standard supine CT evaluation represents a static technique, which can differ considerably from surgical reality. These slides can be retrieved from electronic supplementary material. PMID- 30430252 TI - A reinterpretation of "Homing pigeons' flight over and under low stratus" based on atmospheric propagation modeling of infrasonic navigational cues. AB - Pigeons flying above temperature inversion and related low-stratus layers appear to lack important navigational cues, and a reinterpretation of Wagner's 1978 study suggests that these cues are low-frequency acoustic signals (infrasound). Wagner released homing pigeons above opaque stratus over the Swiss Plateau to determine whether they could locate their loft beneath it. Birds above the clouds appeared lost, while those that descended beneath them returned home directly. Atmospheric propagation modeling of infrasonic waves virtually transmitted from the loft area shows that these signals would have been ducted beneath the inversion layer, and would not have reached the release sites above it. The absence of homeward infrasonic cues above temperature inversions could explain the disorientation of Wagner's birds, especially if such signals are the predominant cues used by pigeons to home. The possible generation of infrasonic navigational signals in the loft area and recent queries concerning the infrasound navigational "map" hypothesis are also discussed. PMID- 30430254 TI - ? PMID- 30430253 TI - Systematic review and cumulative analysis of the managements for proximal impacted ureteral stones. AB - PURPOSE: To compare the efficacy and safety of different treatment options for the management of proximal impacted ureteral stones (PIUS). METHODS: A systematic literature search using Pubmed, Medline, Embase and Cochrane Library was conducted to obtain studies concerning different managements for PIUS up to Jan 2018. Summary odds ratios (ORs), standard mean differences (SMDs) or weighted mean differences with their 95% confidence intervals (CIs) were calculated to compare the efficacy and safety of all included treatment methods, registered in PROSPERO under number CRD42018092745. RESULTS: A total of 15 comparative studies with 1780 patients were included. Meta-analyses of final stone-free rate (SFR) favored percutaneous nephrolithotomy (PCNL) over ureteroscopic lithotripsy (URL) (OR 10.35; 95% CI 5.26-20.35; P < 0.00001), laparoscopic ureterolithotomy over URL (OR 0.11; 95% CI 0.05-0.25; P < 0.00001) and URL over extracorporeal shockwave lithotripsy (OR 0.47; 95% CI 0.28-0.77; P = 0.003). As to complications, PCNL had a significantly higher blood transfusion rate (OR 7.47; 95% CI 1.3-42.85; P = 0.02) and a lower ureteral injury rate (OR 0.15; 95% CI 0.04-0.52; P = 0.003) compared with URL. It also shared a significantly lower stone-retropulsion rate (OR 0.03; 95% CI 0.01-0.15; P < 0.0001) and higher treatment costs (SMD = 2.71; 95% CI 0.71-4.70; P = 0.008) than URL. CONCLUSIONS: Our meta-analysis suggested that PCNL might be the best option for PIUS owing to its higher successful rate. Complications such as hemorrhage could be decreased by the application on mini-PCNL. PMID- 30430255 TI - Gunshot residue on dark materials: a comparison between infrared photography and the use of an alternative light source. AB - The pattern of gunshot residue (GSR) includes important information about muzzle target distance since a larger GSR distribution diameter indicates a larger shooting distance. GSR may not be visible to the naked eye when, for example, it is located on dark textiles. In such cases, further procedures need to be performed in order to visualize the pattern of GSR. Besides chemical procedures, an alternative light source or infrared photography can be utilized for non destructive GSR visualization. In the work presented, these two techniques are compared based on shooting experiments using 26 different dark textiles. Within the range of the alternative light source, the use of a 440-nm light in combination with an orange-colored filter led to the best visualization of GSR in the form of fluorescent particles. Infrared photography, on the other hand, visualized GSR as dark particles, whereas-ideally-the dark textile reflected the infrared light and appeared bright. The comparison of both techniques revealed that the GSR distribution visualized by infrared photography was not identical to the GSR distribution visualized with 440-nm illumination in combination with an orange-colored filter. We concluded that infrared photography visualizes the inner powder soot zone, whereas illumination at 440 nm leads to fluorescence of the outer powder soot zone, which can be visualized using an orange-colored filter. Knowledge of this difference in visualization of the two powder soot zones is important for forensic practitioners assessing firing distances. In the literature, however, this difference is not noted as clearly. PMID- 30430256 TI - Prediction of Incident Delirium Using a Random Forest classifier. AB - Delirium is a serious medical complication associated with poor outcomes. Given the complexity of the syndrome, prevention and early detection are critical in mitigating its effects. We used Confusion Assessment Method (CAM) screening and Electronic Health Record (EHR) data for 64,038 inpatient visits to train and test a model predicting delirium arising in hospital. Incident delirium was defined as the first instance of a positive CAM occurring at least 48 h into a hospital stay. A Random Forest machine learning algorithm was used with demographic data, comorbidities, medications, procedures, and physiological measures. The data set was randomly partitioned 80% / 20% for training and validating the predictive model, respectively. Of the 51,240 patients in the training set, 2774 (5.4%) experienced delirium during their hospital stay; and of the 12,798 patients in the validation set, 701 (5.5%) experienced delirium. Under-sampling of the delirium negative population was used to address the class imbalance. The Random Forest predictive model yielded an area under the receiver operating characteristic curve (ROC AUC) of 0.909 (95% CI 0.898 to 0.921). Important variables in the model included previously identified predisposing and precipitating risk factors. This machine learning approach displayed a high degree of accuracy and has the potential to provide a clinically useful predictive model for earlier intervention in those patients at greatest risk of developing delirium. PMID- 30430257 TI - Anterior communicating artery division in the endoscopic endonasal translamina terminalis approach to the third ventricle: an anatomical feasibility study. AB - BACKGROUND: Endonasal endoscopic approaches (EEA) to the third ventricle are well described but generally use an infrachiasmatic route since the suprachiasmatic translamina terminalis corridor is blocked by the anterior communicating artery (AComA). The bifrontal basal interhemispheric translamina terminalis approach has been facilitated with transection of the AComA. The aim of the study is to describe the anatomical feasibility and limitations of the EEA translamina terminalis approach to the third ventricle augmented with AComA surgical ligation. METHODS: Endoscopic dissections were performed on five cadaveric heads injected with colored latex using rod lens endoscopes attached to a high definition camera and a digital video recorder system. A stepwise anatomical dissection of the endoscopic endonasal transtuberculum, transplanum, translamina terminalis approach to the third ventricle was performed. Measurements were performed before and after AComA elevation and transection using a millimeter flexible caliper. RESULTS: Multiple comparison statistical analysis revealed a statistically significant difference in vertical exposure between the control condition and after AComA elevation, between the control condition and after AComA division and between the AComA elevation and division (p < 0.05). The mean difference in exposed surgical area was statistically significant between the control and after AComA division and between elevation and AComA division (p < 0.01), whereas it was not statistically significant between the control condition and AComA elevation (NS). CONCLUSION: The anatomical feasibility of clipping and dividing the AComA through an EEA has been demonstrated in all the cadaveric specimens. The approach facilitates exposure of the suprachiasmatic optic recess within the third ventricle that may be a blind spot during an infrachiasmatic approach. PMID- 30430258 TI - De novo cavernous malformation arising in the wall of vestibular schwannoma following stereotactic radiosurgery: case report and review of the literature. AB - We report a novel case of a radiation-induced cavernous malformation developing in a vestibular schwannoma previously treated with stereotactic radiosurgery. Eleven years after treatment, the patient presented with a large predominantly cystic lesion in the cerebellopontine angle. We performed surgery, and a solid vascular lesion was identified within the schwannoma, which was determined to be a cavernous malformation after histopathological analysis. We review the literature of radiation-induced cavernous lesions, illustrating that while rare, these lesions do pose concern as a long-term complication of brain radiation therapy. We also discuss the possibility that radiation-induced cavernous malformation-like lesions are pathologically distinct from cavernous malformations. PMID- 30430259 TI - CGRP Discovery and Timeline. AB - Calcitonin gene-related peptide (CGRP) was discovered over about 35 years ago through molecular biological techniques. Its activity as a vasodilator and the proposal that it was involved in pain processing were then soon established. Today, we are in the interesting situation of having the approval for the clinical use of antagonists and antibodies that have proved to block CGRP activities and benefit migraine. Despite all, there is still much to learn concerning the relevance of the vasodilator and other activities as well as further potential applications of CGRP agonists and blockers in disease. This review aims to discuss the history and present knowledge and to act as an introductory chapter in this volume. PMID- 30430260 TI - Nociceptin/Orphanin FQ and Urinary Bladder. AB - Following identification as the endogenous ligand for the NOP receptor, nociceptin/orphanin FQ (N/OFQ) has been shown to control several biological functions including the micturition reflex. N/OFQ elicits a robust inhibitory effect on rat micturition by reducing the excitability of the afferent fibers. After intravesical administration N/OFQ increases urodynamic bladder capacity and volume threshold in overactive bladder patients but not in normal subjects. Moreover daily treatment with intravesical N/OFQ for 10 days significantly reduced urine leakage episodes. Different chemical modifications were combined into the N/OFQ sequence to generate Rec 0438 (aka UFP-112), a peptide NOP full agonist with high potency and selectivity and long-lasting duration of action. Rec 0438 mimicked the robust inhibitory effects of N/OFQ on rat micturition reflex; its action is solely due to NOP receptor stimulation, does not show tolerance liability after 2 weeks of treatment, and can be elicited by intravesical administration. Collectively the evidence summarized and discussed in this chapter strongly suggests that NOP agonists are promising innovative drugs to treat overactive bladder. PMID- 30430261 TI - The Nociceptin/Orphanin FQ System and the Regulation of Memory. AB - Nociceptin/orphanin FQ (N/OFQ) is an endogenous neuropeptide of 17 amino acids, related to opioid peptides but with its own receptor, distinct from conventional opioid receptors, the ORL1 or NOP receptor. The NOP receptor is a G protein coupled receptor which activates Gi/o proteins and thus induces an inhibition of neuronal activity. The peptide and its receptor are widely expressed in the central nervous system with a high density of receptors in regions involved in learning and memory. This review describes the consequences of the pharmacological manipulation of the N/OFQ system by NOP receptor ligands on learning processes and on the consolidation of various types of long-term memory. We also discuss the role of endogenous N/OFQ release in the modulation of learning and memory. Finally we propose several putative neuronal mechanisms taking place at the level of the hippocampus and amygdala and possibly underlying the behavioral amnestic or promnesic effects of NOP ligands. PMID- 30430262 TI - The effect of the severity of parental alcohol abuse on mental and behavioural disorders in children. AB - Many studies have shown that children of alcohol abusing parents have a higher risk for mental and behavioural disorders compared to other children. Using a retrospective population-based cohort study, based on health care and social welfare registers that include children born in Finland in 1997 and their biological parents, we evaluated whether the severity of parental alcohol abuse is related to these disorders in children. We examined (1) differences in the incidence of mental and behavioural disorders over time among the children of parents with no alcohol problems, parents with less severe alcohol problems and parents with severe alcohol problems, and (2) associations between mother's and father's alcohol abuse and children's risk of disorders. Children were followed up until the age of 15. A diagnosis of mental or behavioural disorders during the follow-up was received by 15.4% of the boys and 9.0% of the girls. Both less severe alcohol abuse (HR = 1.36, 95% CI 1.14-1.61) and severe alcohol abuse (HR = 1.29, 95% CI 1.11-1.49) in mothers increased the risk of these disorders in their offspring. The corresponding figures among fathers were HR = 1.19, 95% CI 0.92 1.54 and HR = 1.16, 95% CI 1.02-1.32. Our results indicate that both maternal alcohol abuse and paternal alcohol abuse, regardless of severity, are associated with an increased risk of mental and behavioural disorders in children. It is crucial for professionals working with children to pay attention to all children whose parents have any alcohol abuse problems. PMID- 30430263 TI - Identification and quantification of 19 pharmaceutical active compounds and metabolites in hospital wastewater in Cameroon using LC/QQQ and LC/Q-TOF. AB - Human pharmaceutical residues are a serious environmental concern. They have been reported to have eco, geno, and human toxic effects, and thus their importance as micropollutants cannot be ignored. These have been studied extensively in Europe and North America. However, African countries are still lagging behind in research on these micropollutants. In this study, the wastewaters of the University Teaching Hospital of Yaounde (UTHY) were screened for the presence of active pharmaceutical ingredients and their metabolites. The screening was carried out using two methods: high-performance liquid chromatography coupled to a triple quadrupole analyzer (LC/QQQ) and high-performance coupled to a mass spectrometer with a time of flight analyzer (LC/Q-TOF). A total of 19 active pharmaceutical ingredients and metabolites were identified and quantified. The compounds identified include paracetamol (211.93 MUg/L), ibuprofen (141 MUg/L), tramadol (76 MUg/L), O-demethyltramadol (141 MUg/L), erythromycinanhydrate (7 MUg/L), ciprofloxacin (24 MUg/L), clarinthromycine (0.088 MUg/L), azitromycine (0.39 MUg/L), sulfamethoxazole 0.16 MUg/L), trimetoprime (0.27 MUg/L), caffeine (5.8 MUg/L), carnamaeepine (0.94 MUg/L), atenolol (0.43 MUg/L), propranolol (0.3 MUg/L), cimetidine (34 MUg/L), hydroxy omeprazole (5 MUg/L), diphenhydramine (0.38 MUg/L), metformine (154 MUg/L), and sucralose (13.07 MUg/L). PMID- 30430265 TI - Development of sesbania mosaic virus nanoparticles for imaging. AB - The capsids of viruses have a high degree of symmetry. Therefore, virus nanoparticles (VNPs) can be programmed to display many imaging agents precisely. Plant VNPs are biocompatible, biodegradable and non-infectious to mammals. We have carried out bioconjugation of sesbania mosaic virus (SeMV), a well characterized plant virus, with fluorophores using reactive lysine-N hydroxysuccinimide ester and cysteine-maleimide chemistries. Monitoring of cellular internalization of labelled SeMV nanoparticles (NPs) by confocal microscopy and flow cytometry showed that the particles have a natural preference for entry into MDA-MB-231 (breast cancer) cells, although they could also enter various other cell lines. The fluorescence of SeMV NPs labelled via the cysteines with Cy5.5 dye was found to be more stable and was detectable with greater sensitivity than that of particles labelled via the lysines with Alexa Fluor. Live-cell imaging using SeMV internally labelled with Cy5.5 showed that it could bind to MDA-MB-231 cells in less than 5 minutes and enter the cells within 15 minutes. The particles undergo endolysosomal degradation by 6 h as evidenced by their co-localization with LAMP-1. Far-western blot analysis with a HeLa cell membrane protein fraction showed that SeMV interacts with 54-, 35- and 33-kDa proteins, which were identified by mass spectrometry as vimentin, voltage dependent anion-selective channel protein (VDAC1), and annexin A2 isoform 2 (ANXA2), respectively, suggesting that the particles may bind and enter the cell through these proteins. The results presented here demonstrate that the SeMV NPs provide a new platform technology that could be used to develop in vivo imaging and targeted drug delivery agents for cancer diagnosis and therapy. PMID- 30430264 TI - Survival outcomes after minimally invasive thymectomy for early-stage thymic carcinoma. AB - Minimally invasive surgery (MIS) has occasionally been used for selected patients with thymoma, but there is little information on the MIS approach for thymic carcinoma. The aim of this study was to evaluate survival outcomes after MIS for early-stage (Masaoka stage I-II) thymic carcinoma and thymic neuroendocrine carcinoma. A retrospective chart review of the cases recorded in our multi institutional database was performed to identify patients who underwent resection for thymic carcinoma between 1995 and 2017. MIS thymectomy was performed in 17 cases (VATS, n = 14; RATS, n = 3. male, 41%; median age, 72 years). The median follow-up period was 32.7 (range 7.4-106) months. The five-year overall survival and relapse-free survival rates were 84.4% and 77.8%, respectively. The present study demonstrated encouraging preliminary results regarding MIS for the treatment of early-stage thymic carcinoma and thymic neuroendocrine carcinoma. Further studies with a larger sample size are required to evaluate the indications for this surgery. PMID- 30430266 TI - Effects of oral ingestion on physical functions before tube feeding in adults with severe motor and intellectual disabilities. AB - This study aimed to determine the significance of oral ingestion in tube-fed adults. Six males and three females (mean age 48.1 +/- 12.4 years) with severe motor and intellectual disabilities were included in this study. The subjects were monitored for cerebral blood flow (CBF) by functional near-infrared spectroscopy imaging, gastric motor function by electrogastrography, and arterial oxygen saturation (SpO2) and pulse rate with a biological data monitoring device. The subjects were divided into two groups, settings A and B. In setting A, after resting for 30 min, the subjects were tube fed a routinely used enteral nutrient solution. In Setting B, the subjects received 10 cc of thickened enteral nutrient solution prior to tube feeding. Cerebral function as measured by CBF significantly increased after tube feeding under setting A (without oral ingestion), as compared to the resting state. Under setting B (with oral ingestion), CBF significantly increased after oral ingestion and after tube feeding. SpO2 significantly decreased under setting B after oral ingestion and after tube feeding. Gastric motor function showed no significant change after tube feeding in either setting. The pulse rate significantly increased before tube feeding as compared to that in the resting state, after feeding as compared to before feeding and after feeding as compared to the resting state. Our data suggest that introducing oral ingestion, at least partially, in tube-fed individuals with severe dysphagia is beneficial in that it can stimulate cerebral function. PMID- 30430267 TI - Correction to: Psoriasis in systemic lupus erythematosus: a single-center experience. AB - Prof. Ari Polachek on of the author of the published version of this article missed to add his second affiliation which is the Department of Rheumatology, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. The new affiliation is now added and presented correctly in this article. PMID- 30430268 TI - Assessment using CFD of the wind direction on the air discharges caused by natural ventilation of a poultry house. AB - Air inside poultry houses must be removed on a regular basis to prevent excess of heat, particles and noxious gases that can imperil animals. To cope with this issue, natural ventilation could be an effective method when assisted by accurate predictions. This study investigates air discharges caused by natural ventilation of a poultry house by means of a three-dimensional computational fluid dynamics (CFD) model. It solves the governing equations of momentum, heat and mass transport, radiative transfers and animal-generated heat. Wind directions of 0 degrees , 36 degrees and 56 degrees (0 degrees corresponds to a wind blowing perpendicular to the ridgeline) were investigated; the CFD model predictions achieved a RMSE of 1.2 degrees C and 0.6 g[H2O] kg-1 [dry air] for internal temperature and absolute humidity, respectively, when air blew with an angle of 36 degrees . Air renewal rates (ARR) were 39.5 (+/- 1.9), 34.9 (+/- 2.2) and 33.6 (+/- 1.7) volumes of the building per hour, when air blew at 0 degrees , 36 degrees and 56 degrees , respectively. Such ARR predictions served to know how the gases contained in air would likely spread downstream from the building in order to define regions of potentially high gas concentration that could endanger neighbouring habitable facilities. PMID- 30430269 TI - ICU physicians' and internists' survival predictions for patients evaluated for admission to the intensive care unit. AB - BACKGROUND: A higher chance of survival is a key justification for admission to the intensive care unit (ICU). This implies that physicians should be able to accurately estimate a patient's prognosis, whether cared for on the ward or in the ICU. We aimed to determine whether physicians' survival predictions correlate with the admission decisions and with patients' observed survival. Consecutive ICU consultations for internal medicine patients were included. The ICU physician and the internist were asked to predict patient survival with intensive care and with care on the ward using 5 categories of probabilities (< 10%, 10-40%, 41-60%, 61-90%, > 90%). Patient mortality at 28 days was recorded. RESULTS: Thirty ICU physicians and 97 internists assessed 201 patients for intensive care. Among the patients, 140 (69.7%) were admitted to the ICU. Fifty-eight (28.9%) died within 28 days. Admission to intensive care was associated with predicted survival gain in the ICU, particularly for survival estimates made by ICU physicians. Observed survival was associated with predicted survival, for both groups of physicians. The discrimination of the predictions for survival with intensive care, measured by the area under the ROC curve, was 0.63 for ICU physicians and 0.76 for internists; for survival on the ward the areas under the ROC curves were 0.69 and 0.74, respectively. CONCLUSIONS: Physicians are able to predict survival probabilities when they assess patients for intensive care, albeit imperfectly. Internists are more accurate than ICU physicians. However, ICU physicians' estimates more strongly influence the admission decision. Closer collaboration between ICU physicians and internists is needed. PMID- 30430270 TI - Phase-Selective Synthesis of CIGS Nanoparticles with Metastable Phases Through Tuning Solvent Composition. AB - I-III-VI2 compounds have shown great interests in the application of functional semiconductors. Among them, Cu(In,Ga)S2 has been a promising candidate due to its excellent optoelectronic properties. Although the polymorphs of Cu(In,Ga)S2 have been attracted extensive attentions, the efforts to developing the methodologies for phase-controlled synthesis of them are rare. In this paper, we reported a phase-selective synthesis of CIGS nanoparticles with metastable phases via simply changing the composition of solvents. For the wet chemistry synthesis, the microstructure of the initial nuclei is decisive to the crystal structure of final products. In the formation of Cu(In,Ga)S2, the solvent environment is the key factor, which could affect the coordination of monomers and influence the thermodynamic conditions of Cu-S nucleation. Moreover, wurtzite and zincblende Cu(In,Ga)S2 nanoparticles are selectively prepared by choosing pure en or its mixture with deionized water as reaction solvent. The as-synthesized wurtzite Cu(In,Ga)S2 possess a band gap of 1.6 eV and a carrier mobility of 4.85 cm2/Vs, which indicates its potential to construct a heterojunction with hexagonal structured CdS for solar cells. PMID- 30430272 TI - Combined transcriptomics-metabolomics profiling of the heat shock response in the hyperthermophilic archaeon Pyrococcus furiosus. AB - Pyrococcus furiosus is a remarkable archaeon able to grow at temperatures around 100 degrees C. To gain insight into how this model hyperthermophile copes with heat stress, we compared transcriptomic and metabolomic data of cells subjected to a temperature shift from 90 degrees C to 97 degrees C. In this study, we used RNA-sequencing to characterize the global variation in gene expression levels, while nuclear magnetic resonance (NMR) and targeted ion exchange liquid chromatography-mass spectrometry (LC-MS) were used to determine changes in metabolite levels. Of the 552 differentially expressed genes in response to heat shock conditions, 257 were upregulated and 295 were downregulated. In particular, there was a significant downregulation of genes for synthesis and transport of amino acids. At the metabolite level, 37 compounds were quantified. The level of di-myo-inositol phosphate, a canonical heat stress solute among marine hyperthermophiles, increased considerably (5.4-fold) at elevated temperature. Also, the levels of mannosylglycerate, UDP-N-acetylglucosamine (UDPGlcNac) and UDP-N-acetylgalactosamine were enhanced. The increase in the pool of UDPGlcNac was concurrent with an increase in the transcript levels of the respective biosynthetic genes. This work provides the first metabolomic analysis of the heat shock response of a hyperthermophile. PMID- 30430273 TI - Importance of the physical exam: double-blind randomized controlled trial of radiologic interpretation of ventral hernias after selective clinical information. AB - PURPOSE: Increasingly, radiologic imaging is obtained as part of the pathway in diagnosing ventral hernias. Often, radiologists receive incomplete or incorrect clinical information from clinicians. OBJECTIVE: The aim of the study is to determine if clinical exam findings alter radiological interpretation of ventral hernias on CT. METHODS: This is a single-institution double-blind, randomized trial. All patients with a recent abdominal/pelvic CT scan seen in various surgical clinics were enrolled. A surgeon blinded to the CT scan findings performed a standardized physical examination and assessed for the presence of a ventral hernia. Seven independent radiologists blinded to the study design reviewed the scans. Each radiologist received one of three types of clinical exam data per CT: accurate (correct), inaccurate (purposely incorrect), or none. Allocation was random and stratified by the presence of clinical hernia. The primary outcome was the proportion of radiologic hernias detected, analyzed by chi square. RESULTS: 115 patients were enrolled for a total of 805 CT scan reads. The proportion of hernias detected differed by up to 25% depending on if accurate, no, or inaccurate clinical information was provided. Inaccurate clinical data in patients with no hernia on physical exam led to a significant difference in the radiologic hernia detection rate (54.3% versus 35.7%, p = 0.007). No clinical data in patients with a hernia on physical exam led to a lower radiologic hernia detection rate (75.0% versus 93.8%, p = 0.001). CONCLUSIONS: The presence and accuracy of clinical information provided to radiologists impacts the diagnosis of abdominal wall hernias in up to 25% of cases. Standardization of both clinical and radiologic examinations for hernias and their reporting are needed. TRIAL REGISTRATION: Clinicaltrials.gov, Number NCT03121131, https://clinicaltrials.gov/ct2/show/NCT03121131 . PMID- 30430271 TI - Activated sludge bacterial communities of typical wastewater treatment plants: distinct genera identification and metabolic potential differential analysis. AB - To investigate the differences in activated sludge microbial communities of different wastewater treatment plants (WWTPs) and understand their metabolic potentials, we sampled sludge from every biological treatment unit of 5 full scale waste water treatment systems in 3 typical Chinese municipal WWTPs. The microbial communities and overall metabolic patterns were not only affected by influent characteristics but also varied between different biological treatment units. Distinct genera in different wastewater treatment systems were identified. The important microorganisms in domestic sewage treatment systems were unclassified SHA-20, Caldilinea, Dechloromonas, and unclassified genera from Rhodospirilaceae and Caldilineaceae. The important microorganisms in dyeing wastewater treatment systems were Nitrospira, Sphingobacteriales, Thiobacillus, Sinobacteraceae and Comamonadaceae. Compared with the obvious differences in microbial community composition, the metabolic potential showed no significant differences. PMID- 30430275 TI - The Mediterranean Diet: Lost in Translation. AB - PURPOSE OF REVIEW: Despite substantive evidence documenting the efficacy of the Mediterranean diet to reduce cardiovascular events, underutilization is common. An overview of the data set supporting the role of the Mediterranean diet as confirmed in both observational and interventional trials should stimulate greater clinician interest in the diet. Additionally, the availability of patient friendly tools that enable prompt and easy adoption of the Mediterranean diet, that are able to be used by clinicians who claim no special expertise in diet knowledge, should simplify the path to successful dietary change. RECENT FINDINGS: A large recently published (2018) prospective study of the Mediterranean diet for primary prevention of cardiovascular events confirmed that compared to control, Mediterranean diet is associated with reduced risk for cardiovascular events in high risk patients. Of the tools available to clinicians that might reduce cardiovascular risk, dietary intervention is the one least utilized. The evidence supports the value of dietary intervention with the Mediterranean diet, and methods to effectively employ it within the confines of typical office practice are readily at hand. PMID- 30430274 TI - Gene correction of HBB mutations in CD34+ hematopoietic stem cells using Cas9 mRNA and ssODN donors. AB - BACKGROUND: beta-Thalassemia is an inherited hematological disorder caused by mutations in the human hemoglobin beta (HBB) gene that reduce or abrogate beta globin expression. Although lentiviral-mediated expression of beta-globin and autologous transplantation is a promising therapeutic approach, the risk of insertional mutagenesis or low transgene expression is apparent. However, targeted gene correction of HBB mutations with programmable nucleases such as CRISPR/Cas9, TALENs, and ZFNs with non-viral repair templates ensures a higher safety profile and endogenous expression control. METHODS: We have compared three different gene-editing tools (CRISPR/Cas9, TALENs, and ZFNs) for their targeting efficiency of the HBB gene locus. As a proof of concept, we studied the personalized gene-correction therapy for a common beta-thalassemia splicing variant HBBIVS1-110 using Cas9 mRNA and several optimally designed single stranded oligonucleotide (ssODN) donors in K562 and CD34+ hematopoietic stem cells (HSCs). RESULTS: Our results exhibited that indel frequency of CRISPR/Cas9 was superior to TALENs and ZFNs (P < 0.0001). Our designed sgRNA targeting the site of HBBIVS1-110 mutation showed indels in both K562 cells (up to 77%) and CD34+ hematopoietic stem cells-HSCs (up to 87%). The absolute quantification by next-generation sequencing showed that up to 8% site-specific insertion of the NheI tag was achieved using Cas9 mRNA and a chemically modified ssODN in CD34+ HSCs. CONCLUSION: Our approach provides guidance on non-viral gene correction in CD34+ HSCs using Cas9 mRNA and chemically modified ssODN. However, further optimization is needed to increase the homology directed repair (HDR) to attain a real clinical benefit for beta-thalassemia. PMID- 30430277 TI - Social Media and Allergy. AB - PURPOSE OF REVIEW: Social media services dominate online consumption of information and play an ever expanding role in our lives. They are not only used to connect with friends and family but also to educate and recruit colleagues and patients, and to stay up-to-date with the new developments in the field of allergy and immunology. RECENT FINDINGS: There are known risks to social media user by health care professionals mostly related to breaches of patient confidentiality, professionalism, and privacy. Malpractice and liability risks have been linked to irresponsible use of social media. This review provides a comprehensive overview of the current social media tools in allergy. We recommend a pragmatic approach to maximize social media tools for the allergy practice. PMID- 30430276 TI - Review of Immune Therapies Targeting Ovarian Cancer. AB - OPINION STATEMENT: The rise of immunotherapy is the greatest advance in oncology to occur over the last several years, but applications in gynecologic malignancies lag behind other tumors. The term "immunotherapy" envelops monoclonal antibodies as receptor mediators, including immune checkpoint inhibitors (ICPI), cancer vaccines, and adoptive immunotherapies alone or in combination with other therapeutic approaches. The purpose of this review is to summarize the status of immunotherapy trials in ovarian cancer and to specifically highlight data published in the last 1-2 years. PMID- 30430278 TI - Effect of different knee flexion angles with a constant hip and knee torque on the muscle forces and neuromuscular activities of hamstrings and gluteus maximus muscles. AB - PURPOSE: This study examined the effect of different knee flexion angles with a constant hip and knee torque on the muscle force and neuromuscular activity of the hamstrings and gluteus maximus. METHODS: Twenty healthy males lay in prone position and held their lower limb with hip flexion at 45 degrees and knee flexion at either 10 degrees or 80 degrees . At these angles, the hip and knee torques are identical. Under three load conditions: passive (referred to as Unloaded), active (Loaded), and active with 3-kg weight added to the shank (Loaded + 3 kg), the muscle stiffness (i.e., an indicator of muscle force) and neuromuscular activity of the hamstrings and gluteus maximus were measured using shear wave elastography and surface electromyography. RESULTS: The muscle stiffness and neuromuscular activity of the hamstrings and gluteus maximus increased significantly with the load. Muscle stiffness in the hamstrings was significantly lower at knee flexion of 80 degrees than at 10 degrees for Unloaded, but not for either Loaded or Loaded + 3 kg. The neuromuscular activity of the hamstrings was significantly greater at knee flexion of 80 degrees than at 10 degrees for both Loaded and Loaded + 3 kg. The muscle stiffness or neuromuscular activity of the gluteus maximus showed no significant differences between knee angles. CONCLUSIONS: When the passive force in the hamstrings decreases with knee flexion, sufficient muscle force to maintain the hip and knee torques against an external load is generated by preferentially increasing the neuromuscular activity of the hamstrings, rather than increasing the synergetic muscle force. PMID- 30430279 TI - Effect of ciliary-muscle contraction force on trapezius muscle activity during computer mouse work. AB - The present study aimed to identify whether or not an increase in ciliary-muscle contraction force, when the eye-lens is adjusted for viewing at a near distance, results in an increase in trapezius muscle activity, while performing a natural work task. Twelve participants, ranging in age from 21 to 32 years, performed a computer-mouse work task during free gaze conditions. A moving visual target was tracked with a computer mouse on a screen placed at two different distances from the eyes, 25 cm and 50 cm. Tracking performance, eye accommodation, and bilateral trapezius muscle activity were measured continuously. Ciliary-muscle contraction force was computed according to a formula which takes into account the age dependent, non-linear relationship between the contraction force of the ciliary muscle and the produced level of eye accommodation. Generalized estimating equations analyses were performed. On the dominant hand side and for the nearest screen distance, there was a significant effect of ciliary-muscle contraction force on the trapezius muscle activity (p < 0.001). No other effects were significant (p > 0.05). The results support the hypothesis that high visual demands, during computer mouse work, increase ciliary muscle contraction force and contribute to a raise of the sustained level of trapezius muscle activity. The current study specifically clarifies the validity of the relationship between ciliary-muscle contraction force and trapezius muscle activity and demonstrates that this relationship is not due to a general personality trait. We conclude that a high level of ciliary muscle contraction force can contribute to a development of musculoskeletal complaints in the neck-shoulder area. PMID- 30430280 TI - Induction of angiogenic and inflammation-associated dermal biomarkers following acute UVB exposure on bio-engineered pigmented dermo-epidermal skin substitutes in vivo. AB - PURPOSE: Ultraviolet (UV) radiation adversely affects skin health at cellular and molecular levels. Hence, UV radiation can directly induce inflammatory responses in the dermis by inducing erythema, edema, inflammation, dermal fibroblasts alterations, and extracellular matrix modifications. METHODS: Human keratinocytes, melanocytes, and fibroblasts were isolated from skin biopsies, cultured, and expanded in vitro. Fibroblasts were seeded into collagen type I hydrogels that were subsequently covered by keratinocytes and melanocytes. These pigmented dermo-epidermal skin substitutes (pigmDESS) were transplanted for 5 weeks onto full-thickness skin wounds on the back of immuno-incompetent rats, exposed to a single UVB dose of 250 mJ/cm2 or unexposed and excised after 1 week. The effects onto the dermis were assessed regarding cell number, cell phenotype, and cell proliferation. Local inflammation by granulocytes (HIS48) or macrophages (CD11b, iNOS) was analyzed by immunohistochemistry staining. RESULTS: We observed a significantly enhanced ingrowth rate of blood capillaries, but not of lymphatic capillaries at 1 week post-irradiation. Moreover, the enhanced vascularization of pigmDESS after UVB exposure was concomitant with a high infiltration of granulocytes and monocytes/macrophages to the dermal part of grafts. In addition, a heterogeneous expression of HIF-1alpha and TNFalpha was detected at this early phase after UVB exposure. In local cellular response examination, results only show a moderate cell proliferation in the dermis. CONCLUSIONS: We were able to define early markers of UVB-induced effects in the dermis of pigmDESS. Overall, a single UVB dose induces temporary acute angiogenic and immune responses during the early post-irradiation phase in vivo. PMID- 30430281 TI - Age-dependent outcomes in asymptomatic umbilical hernia repair. AB - PURPOSE: Umbilical hernias are common in young children. Many resolve spontaneously by age four with very low risk of symptoms or incarceration. Complications associated with surgical repair of asymptomatic umbilical hernias have not been well elucidated. We analyzed data from one hospital to test the hypothesis that repair at younger ages is associated with increased complication rates. METHODS: A retrospective chart review of all umbilical hernia repairs performed during 2007-2015 was conducted at a tertiary care children's hospital. Patients undergoing repairs as a single procedure for asymptomatic hernia were evaluated for post-operative complications by age, demographics, and co morbidities. RESULTS: Of 308 umbilical hernia repairs performed, 204 were isolated and asymptomatic. Postoperative complications were more frequent in children < 4 years (12.3%) compared to > 4 years (3.1%, p = 0.034). All respiratory complications (N = 4) and readmissions (N = 1) were in children < 4 years. CONCLUSIONS: Age of umbilical hernia repair in children varied widely even within a single institution, demonstrating that timing of repair may be a surgeon dependent decision. Patients < 4 years were more likely to experience post operative complications. Umbilical hernias often resolve over time and can safely be monitored with watchful waiting. Formal guidelines are needed to support delayed repair and prevent unnecessary, potentially harmful operations. PMID- 30430282 TI - Recurrent ACTG2 gene variation in African degenerative visceral leiomyopathy. AB - INTRODUCTION: Visceral myopathies remain difficult and frustrating clinical entities, a distinctive form of acquired degenerative visceral myopathy, African degenerative leiomyopathy, a myogenic functional intestinal obstruction without aganglionosis which affects smooth muscle of the intestine, in young indigenous African children. The Actin G2 gene is the main gene encoding smooth muscle actin found in enteric tissues. Recent research has identified Actin G2 alpha gene variation as an important causative biomarker in visceral myopathies and megacystis microcolon. This study of the Actin G2 gene (ACTG2) in an African population explores a possible molecular basis abnormal muscle function in a visceral myopathy. PATIENTS AND METHODS: Following ethical permission and informed consent, DNA was extracted from whole blood samples in five patients with histologically proven African degenerative leiomyopathy. PCR amplification of ACTG2 alpha gene products by semi-automated bi-directional sequencing analysis. Results were analysed using FinchTV Sequence Alignment Software and predicting bioinformatic investigation by PolyPhen 2 software. RESULTS: Five new patients with the ADL phenotypes were prospectively investigated for variation in the Actin G2 gamma gene (ACTG2). ACTG2 gene variation occurred in exon 5 (c.463 A>G K119R), in three (60%). In addition, intronic variation t > c-IVS3 was identified in three with the K119 mutation plus further g > c -IVS12 and t > c + IVS16(2), suggesting a possible haplotype. Bioinformatic modelling showed that these ACTG2 gene variations are highly non-conservative altering protein expression. CONCLUSIONS: Recurrent Actin G2 smooth muscle gene variation in African degenerative visceral leiomyopathy is associated with abnormal muscle actin development. PMID- 30430283 TI - Commentary to "Fact or myth? The long shared common wall between the fistula and the urethra in male anorectal malformations with urethral bulbar fistula". PMID- 30430284 TI - Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. AB - Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 degrees C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-alpha alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible. PMID- 30430285 TI - Amorphous Vanadium Oxide Thin Films as Stable Performing Cathodes of Lithium and Sodium-Ion Batteries. AB - Herein, we report additive- and binder-free pristine amorphous vanadium oxide (a VOx) for Li- and Na-ion battery application. Thin films of a-VOx with a thickness of about 650 nm are grown onto stainless steel substrate from crystalline V2O5 target using pulsed laser deposition (PLD) technique. Under varying oxygen partial pressure (pO2) environment of 0, 6, 13 and 30 Pa, films bear O/V atomic ratios 0.76, 2.13, 2.25 and 2.0, respectively. The films deposited at 6-30 Pa have a more atomic percentage of V5+ than that of V4+ with a tendency of later state increased as pO2 rises. Amorphous VOx films obtained at moderate pO2 levels are found superior to other counterparts for cathode application in Li- and Na ion batteries with reversible capacities as high as 300 and 164 mAh g-1 at 0.1 C current rate, respectively. At the end of the 100th cycle, 90% capacity retention is noticed in both cases. The observed cycling trend suggests that more is the (V5+) stoichiometric nature of a-VOx better is the electrochemistry. PMID- 30430286 TI - MUW researcher of the month. PMID- 30430287 TI - Guidelines for imaging reach a new quality level towards computer-assisted diagnosis. PMID- 30430288 TI - Veranstaltungstipps. PMID- 30430290 TI - Methods to handle missing values and missing individuals. PMID- 30430291 TI - Automated projection spectroscopy in solid-state NMR. AB - Given that solid-state NMR is being used for protein samples of increasing molecular weight and complexity, higher-dimensionality methods are likely to be more and more indispensable for unambiguous chemical shift assignments in the near future. In addition, solid-state NMR spectral properties are increasingly comparable with solution NMR, allowing adaptation of more sophisticated solution NMR strategies for the solid state in addition to the conventional methodology. Assessing first principles, here we demonstrate the application of automated projection spectroscopy for a micro-crystalline protein in the solid state. PMID- 30430292 TI - Estimation method for sound velocity distribution for high-resolution ultrasonic tomographic imaging. AB - PURPOSE: With commercial ultrasonic equipment, the sound velocity is fixed to a constant value of 1530 or 1540 m/s, which is used for beam formation. However, the assumption of a constant sound velocity is not optimal, as the sound velocity in a living body is heterogeneous. In this study, a novel method was proposed to estimate the distribution of the sound velocity in a region of interest. METHODS: The sound velocity distribution was estimated by fitting the theoretical propagation time of the ultrasonic wave from the scatterer to each of the probe elements with measured values. RESULTS: In a phantom experiment, the sound velocity distribution was estimated by the proposed method with a maximum estimation error of 0.6%, and the resultant local sound velocity values successfully improved the quality of the ultrasonic image. CONCLUSION: The proposed method has the potential to improve ultrasonic image quality in in vivo experiments by estimating the sound velocity distribution. PMID- 30430289 TI - Basophil Activation Test: Old and New Applications in Allergy. AB - PURPOSE OF REVIEW: The basophil activation test (BAT) using flow cytometry has supplanted traditional methods of measuring basophil degranulation using histamine and other mediator release, and can be used for clinical applications as well as to explore the immune mechanisms of effector cell response to allergen. This review discusses the advancements made in clinical, diagnostic and laboratory research of allergy utilizing an ever-evolving BAT. RECENT FINDINGS: Being an in vitro surrogate of the allergic reaction that happens in vivo in the sick patient, the BAT can be used to support the diagnosis of various allergic conditions, such as food, drug, respiratory and insect venom allergies, and the assessment of clinical response to allergen-specific immunotherapy and other immunomodulatory treatments. The BAT can also be used for research purposes to explore the mechanisms of allergy and tolerance at the level of the basophil, for instance by manipulating IgE and IgG and their receptors and by studying intracellular signalling cascade in response to allergen. This review covers the applications of the BAT to the clinical management of allergic patients and the increased understanding of the mechanisms of immune response to allergens as well as technological advancements made in recent years. PMID- 30430293 TI - Assessment of single beat end-systolic elastance methods for quantifying ventricular contractility. AB - Multi-beat end-systolic elastance (EMB) is considered a gold-standard index of ventricular contractility. However, it is difficult to measure clinically due to the need for transient manipulation of ventricular preload or afterload. We compared the performance of 5 'single-beat' methods that do not require loading interventions, for estimating the equivalent of EMB. In 7 sheep instrumented with a micromanometer/conductance catheter, single-beat methods were compared with EMB, obtained after transiently decreasing preload or increasing afterload under a broad range of heart rates and inotropic conditions. The single-beat elastance (ESB) method described by Shishido et al. (Circulation 102(16):1983-1989, 2000) had the highest correlation (R = 0.69, y = 0.52x + 0.43) with EMB, although the absolute accuracy was poor. Interestingly, for all methods tested, a higher correlation was observed when EMB was obtained with an afterload increase (R = 0.47 - 0.78) rather than a preload reduction (R = 0.07-0.57). Within-animal regression coefficients were higher than those obtained from pooled data, with excellent within-animal correlation observed for Shishido et al. method (0.73 <= R <= 0.96) when using afterload increase as the loading intervention. We conclude that (1) current methods perform better when using an afterload increase to obtain reference EMB, (2) intra-individual ESB comparisons may be more reliable than inter-individual comparisons and (3) Shishido et al.'s method demonstrated the strongest correlation with EMB. Current ESB methods have limited and variable accuracy, but may hold promise for tracking relative changes in ventricular contractility in individuals. PMID- 30430294 TI - Impact of vascular access site on procedural time of endomyocardial biopsy. AB - Endomyocardial biopsy (EMB) is widely used for the diagnosis of unexplained ventricular dysfunction and for assessment of cardiac allograft rejection. But, the impact of vascular access site on procedural time of EMB is not well-known. From February 2014 to May 2016, consecutive patients requiring EMB were prospectively enrolled in this study. Vascular access, by either the jugular or femoral vein, was randomly assigned. EMB was randomly performed by 3 pre identified physicians based on practical experience in EMB. Each case was required to obtain at least 3 samples. The primary endpoint was to compare the total time spent in acquiring EMB from the right ventricular septum between the jugular and femoral vein access groups. The secondary endpoints were evaluation of each set (1st to 3rd attempt) of EMB times and safety. In addition, factors affecting the EMB procedural times were evaluated. A total of 49 consecutive patients requiring EMB (3.9 attempts/patient) were enrolled (the jugular group: 23, the femoral group: 26), and 156 myocardial samples (3.2 samples/patient) were obtained. There were no significant differences in total biopsy procedural time between the 2 groups (16.3 +/- 7.4 vs. 20.8 +/- 9.9 min, p = 0.075). Independent predictors for longer procedural time of the 1st attempt included femoral access, non-expert operators, and larger right atrium according to multiple linear regression analysis. The complication rates were not significantly different between the 2 groups, except for catheter kinking as a technical factor. Total biopsy time was not significantly different between the jugular and femoral venous access groups. However, the 1st attempt EMB procedural time by non-expert operators was longer when using the femoral approach, especially in cases involving a larger right atrium diameter. PMID- 30430295 TI - Variations in the eicosapentaenoic acid-arachidonic acid ratio associated with age in acute myocardial infarction patients undergoing primary percutaneous coronary intervention. AB - Acute myocardial infarction (AMI) is a life-threatening disease, and its incidence has been increasing even in the young population. Although a low eicosapentaenoic acid (EPA)-arachidonic acid (AA) ratio is associated with an increased risk of coronary artery disease, the effect of age on EPA/AA ratios in AMI patients remains unclear. This study aimed to clarify the independent polyunsaturated fatty acid (PUFA)-related determinants of age in younger and older AMI patients. A total of 153 consecutive patients who underwent primary percutaneous coronary interventions (PCIs) for de novo AMIs were enrolled in this study. Patients' background data, including PUFA and lipid profiles during PCI, were evaluated retrospectively. The EPA/AA ratio correlated positively with age (r = 0.21; P = 0.011) and increased markedly from age 60 years. Patients aged < 60 years (n = 35) had a lower mean EPA/AA ratio (0.25 +/- 0.16) than patients aged >= 60 years (n = 118) (0.38 +/- 0.25) (P < 0.001). The AA level was more dependent on age than on EPA level (r = - 0.34, P < 0.001 vs. r = 0.12, P = 0.16). The multivariate analysis revealed that a 0.1 EPA/AA ratio increase (odds ratio 1.50; 95% confidence interval 1.09-2.06), body mass index, triglyceride level, and aspirin administration were independently associated with the age stratification of AMI patients. The EPA/AA ratio was higher in younger AMI patients who have undergone primary PCIs than in older patients. Younger population at risk for AMI should be managed with multiple interventions including PUFA profiling. PMID- 30430296 TI - Altered drug efflux under iron deprivation unveils abrogated MmpL3 driven mycolic acid transport and fluidity in mycobacteria. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) is a global threat to human health hence better understanding of the MTB pathogenesis for improved therapeutics requires immediate attention. Emergence of drug-resistant strains has stimulated an urgent need for adopting new strategies that could be implemented to control TB. One of the contributing mechanisms by which MTB evades drug doses is overexpression of drug efflux pumps. Thus blocking or modulating the functionality of efflux pumps represents an attractive approach to combat drug resistance. Iron is a critical micronutrient required for MTB survival and not freely available inside the host. In this study, we demonstrated that iron deprivation impairs drug efflux pump activity and confers synergism for anti-TB drugs in presence of efflux pump inhibitors against MTB. Mechanistic insights revealed that iron deprivation inhibit resistance nodulation division superfamily transporter activity. This was evident from enhanced Nile red accumulation and reduced expression of MmpL3, a transmembrane promising target involved in mycolic acid transport across membrane. Furthermore, iron deprivation led to abrogated MA transport particularly of class methoxy-MA which was confirmed by TLC and mass spectrometry based lipidome analysis. Additionally, iron deprivation leads to enhanced membrane fluidity in MTB. Together, MmpL3 being a promiscuous anti-TB target, metal chelation strategy could be adopted to boost the effectiveness of current anti-TB drug regimes to combat drug resistance TB. PMID- 30430297 TI - Nonalcoholic Fatty Liver Disease and Bone Mineral Density in Children and Adolescents: Specific Considerations for Future Studies. PMID- 30430298 TI - Acidic Pharyngeal Reflux Does Not Correlate with Symptoms and Laryngeal Injury Attributed to Laryngopharyngeal Reflux. AB - BACKGROUND: Laryngopharyngeal reflux (LPR) is suspected when the symptoms are attributed to the penetration of acidic gastroesophageal reflux (GER) into the larynx. However, the relationships between the intensity of LPR and symptoms and laryngeal injury have not been elucidated. Several factors confound the study of LPR, namely pH is monitored in the pharynx (pharyngeal reflux) but the pharyngeal acidity (pH) required to induce laryngeal injury is unknown, the GER origin of pharyngeal acid is not always established, and a recent treatment with proton pump inhibitors (PPI) confounds the analysis. AIMS: We aimed to limit these confounding factors to analyze the relationship between LPR and symptoms and laryngeal injury. METHODS: We used dual pharyngeal and distal esophageal 24-h pH/impedance monitoring to establish GER origin of pharyngeal reflux, we used an unbiased approach to analysis by evaluating a whole range of acidity (pH < 6, pH < 5.5, pH < 5.0, pH < 4.5 and pH < 4.0) in patients with suspected LPR without PPI for > 30 days. RESULTS: Pharyngeal reflux was (median[IQR]) 14[8-20.5] and 4[1.5-6.5] pharyngeal reflux episodes with pH < 6.0 and pH < 5.5, respectively. Pharyngeal reflux with pH < 5.0 was rare. Comprehensive analysis did not reveal any correlation between symptoms (reflux symptom index) or laryngeal injury (reflux finding score) and the number of pharyngeal reflux episodes or duration of pharyngeal acid exposure at any pH level. CONCLUSION: Unbiased comprehensive approach did not reveal any relationship between acidic pharyngeal reflux and the symptoms or laryngeal injury attributed to LPR. Limited clinical usefulness of pharyngeal monitoring reported by others is unlikely due to confounding factors. PMID- 30430299 TI - Correction to: The impact of social-emotional context in chronic cancer pain: patient-caregiver reverberations. AB - The last 4 authornames in the original manscript was inadvertently inverted and is now corrected in this article. PMID- 30430300 TI - Factors influencing neck and shoulder function after oral oncology treatment: a five-year prospective cohort study in 113 patients. AB - BACKGROUND: The aim of this study was to identify factors influencing shoulder and/or neck function in patients up to five years after treatment. MATERIALS AND METHODS: Lateral flexion of the neck, ipsilateral forward flexion, and abduction of the shoulder were measured. Potential factors were entered into a linear mixed model analysis to create a multivariate model for describing the results. RESULTS: Predicted neck and shoulder function was negatively influenced by higher age before intervention. Contralateral flexion of the neck was lower for patients undergoing surgery and radiotherapy compared to surgery. Ipsilateral flexion of the neck is influenced by a higher age at baseline. Ipsilateral shoulder abduction is lower for female gender, bone graft/flap reconstruction, and more extensive neck dissection. Ipsilateral forward flexion of the shoulder is lower for bone graft/flap reconstruction and better for patients with a T2 tumor in comparison to T3 and T4 tumors, as predicted. CONCLUSION: By our five-year follow up outcomes of this study, neck and/or shoulder impairments can be found for high risk patients by physiotherapists. PMID- 30430301 TI - 'I want to know why and need to be involved in my own care...': a qualitative interview study with liver, bile duct or pancreatic cancer patients about their experiences with involvement in care. AB - PURPOSE: Patients' involvement in their own care is important for those with upper abdominal tumours. Care is often conducted according to standardized fast track care programs (FTCP), and a shorter hospital stay is one of the goals. However, there is no research providing an in-depth perspective on patients' experiences of involvement in care. In this qualitative study, we explored experiences of involvement among patients who had surgery for upper abdominal tumours and were cared for according to an FTCP. METHODS: Qualitative in-depth face-to-face interviews about patient involvement in care were conducted with 20 patients who had surgery for the liver, bile duct, or pancreatic cancer using an open-interview guide. RESULTS: The most important findings are that customized information and active dialogue about care decisions stimulate patient involvement. We identified three themes from the analysed data: involvement depended on the quality of information, communication and involvement during the care period, and safety at discharge. CONCLUSIONS: Individualized care and continuous information about treatment and care goals in the FTCP during the care process create trust between patients and healthcare professionals and increase patient experiences of involvement. PMID- 30430302 TI - The intron 3 16 bp duplication polymorphism of p53 (rs17878362) is not associated with increased risk of developing triple-negative breast cancer. AB - PURPOSE: Very little is known about the genetic risk factors associated with triple-negative breast cancer (TNBC), an aggressive clinical subtype characterised by the absence of ER, PR and HER2. p53, the tumour suppressor gene, is essential for maintaining genomic stability in response to cellular stress. In breast cancer, the mutation rates of TP53 vary depending on the subtype, such that ER-negative tumours have a high rate, and in ER-positive tumours they are less common. Previous studies have implicated the intronic polymorphism in TP53 (rs17878362; or PIN3) with an increased risk of developing breast cancer, although little has been discerned on its prevalence in different subtypes. In this study, we investigated the prevalence of the PIN3 genotype in the blood of cohorts with ER-positive and the ER-negative subtype TNBC, and assessed its association with outcome. METHODS: We genotyped 656 TNBC and 648 ER-positive breast cancer patients, along with 436 controls, and compared the prevalence of polymorphism rs17878362 in these cohorts. RESULTS: We found there to be no differences in the prevalence of the PIN3 genotype between the ER-positive and TNBC cohorts. Furthermore, no statistically significant difference was observed in the outcome of patients in either cohort with respect to their PIN3 genotype. CONCLUSIONS: Taken together, our results do not support an association of the PIN3 genotype with increased breast cancer risk, either in ER-positive or ER negative patients. PMID- 30430303 TI - Effect of Bacillus cereus on the ecotoxicity of metal-based fungicide spiked soils: Earthworm bioassay. AB - Soil microorganisms exhibit varying levels of metal tolerance across a diverse range of environmental conditions. The use of metal-based fungicides such as mancozeb and copper oxychloride could potentially result in increased levels of manganese, zinc and copper which may adversely affect soil mesofauna. Under standardized earthworm bioassay conditions (temperature, pH, soil type and water content), we investigated the effect of Bacillus cereus on mancozeb and copper oxychloride ecotoxicity towards Eisenia andrei. A metal-tolerant Bacillus cereus strain previously isolated from a gold mining site was introduced into fungicide spiked soils. Earthworms were exposed to bacterial inoculated and non-inoculated substrates of mancozeb (8, 44, 800 and 1250 mg kg-1) and copper oxychloride (200, 450, 675 and 1000 mg kg-1). Experimental trials assessed avoidance-behavior, growth and reproduction utilizing standardized protocols (ISO and OECD). In the avoidance-behavior, E. andrei showed significant (p < 0.05) preference for inoculated substrates. Further, significant (p < 0.05) increases in biomass, survival, cocoons, juveniles and lower soil and tissue Mn, Cu and Zn contents were recorded at 8 and 44 mg kg-1 mancozeb and copper oxychloride 200 and 450 mg kg-1 inoculated soils compared to non-inoculated. However, at 800 and 1250 mg kg 1 mancozeb and 675 and 1000 mg kg-1 copper oxychloride concentrations, reproductive success in both inoculated and non-inoculated treatments was negatively (p < 0.05) affected. In conclusion, Bacillus cereus decreased the ecotoxicity of metal-based fungicides towards Eisenia andrei at 8 and 44 mg kg-1 mancozeb and 200 and 450 mg kg-1 copper oxychloride concentrations. The outcome observed with the inoculated substrates at elevated fungicides concentrations maybe as a result of the environmental conditions (pH and temperature). PMID- 30430304 TI - Milan M. Cirkovic: The Great Silence: The Science and Philosophy of Fermi's Paradox : Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, United Kingdom, 2018, (ISBN 9780199646302) USD 32.95, 432 pages. PMID- 30430308 TI - The complete genome sequence of a second alphabaculovirus from the true armyworm, Mythimna unipuncta: implications for baculovirus phylogeny and host specificity. AB - The Mythimna unipuncta nucleopolyhedrovirus isolate KY310 (MyunNPV-KY310) is an alphabaculovirus isolated from a true armyworm (Mythimna unipuncta) population in Kentucky, USA. Occlusion bodies of this virus were examined by electron microscopy and the genome sequence was determined by 454 pyrosequencing. MyunNPV KY310 occlusion bodies consisted of irregular polyhedra measuring 0.8-1.8 um in diameter and containing multiple virions, with one to six nucleocapsids per virion. The genome sequence was determined to be 156,647 bp with a nucleotide distribution of 43.9% G+C. 152 ORFs and six homologous repeat (hr) regions were annotated for the sequence, including the 38 core genes of family Baculoviridae and an additional group of 26 conserved alphabaculovirus genes. BLAST queries and phylogenetic inference confirmed that MyunNPV-KY310 is most closely related to the alphabaculovirus Leucania separata nucleopolyhedrovirus isolate AH1, which infects Mythimna separata. In contrast, MyunNPV-KY310 did not exhibit a close relationship with Mythimna unipuncta nucleopolyhedrovirus isolate #7, an alphabaculovirus from the same host species. MyunNPV-KY310 lacks the gp64 envelope glycoprotein, which is a characteristic of group II alphabaculoviruses. However, this virus and five other alphabaculoviruses lacking gp64 are placed outside the group I and group II clades in core gene phylogenies, further demonstrating that viruses of genus Alphabaculovirus do not occur in two monophyletic clades. Potential instances of MyunNPV-KY310 ORFs arising by horizontal transfer were detected. Although there are now genome sequences of four different baculoviruses from M. unipuncta, comparison of their genome sequences provides little insight into the genetic basis for their host specificity. PMID- 30430305 TI - Biomarker and Drug Target Discovery Using Quantitative Proteomics Post Intracerebral Hemorrhage Stroke in the Rat Brain. AB - The pathological mechanisms of acute intracerebral hemorrhage (ICH) remain unknown and unverified. In the present study, we used quantitative proteomics to elucidate the pathological mechanisms and to identify novel biomarker and therapeutic target candidates via tissue proteome in a rat model of acute ICH. Rats were experimentally induced with ICH (n = 6) or Sham (n = 6), and their brain tissue was obtained by 24 h. The TMT-LC-MS/MS-based proteomics approach was used to quantify the differential proteomes across brain tissue, and the results were further analyzed by ingenuity pathway analysis to explore canonical pathways and the relationship involved in the uploaded data. Upon quantification, we found that 96 secreted proteins that were identified in the ICH 24-h group were significantly different those in the control group (P < 0.05); among these proteins, 57 increased and 39 decreased in abundance. Bioinformatic analyses of differentially expressed proteins demonstrated that the protein localization and ERK1 and ERK2 cascade were the top two biological processes with the highest concentrations of differentially proteins. The top protein-protein action network with high confidence levels of protein was the albumin and ERK signaling pathways. Albumin, ERK, and p-ERK were assessed in brain tissue by western blot analysis, and higher expression levels of albumin and p-ERK were observed in the ICH group. Our proteomic results highlight important change in the biological processes of ERK1 and ERK2 cascade, which are possible targets for future interventions of ICH. To our knowledge, this study provides in-depth analysis of ICH in brain tissue, and we propose 96 new biomarker candidates for ICH, including albumin and ERK. PMID- 30430306 TI - The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons. AB - The metabotropic glutamate (mGlu) receptor 5 is a G protein-coupled receptor and is densely expressed in the mammalian brain. Like other glutamate receptors, mGlu5 receptors are tightly regulated by posttranslational modifications such as phosphorylation, although underlying mechanisms are incompletely investigated. In this study, we investigated the role of a prime kinase, extracellular signal regulated kinase 1 (ERK1), in the phosphorylation and regulation of mGlu5 receptors in vitro and in striatal neurons. We found that recombinant ERK1 proteins directly bound to the C-terminal tail (CT) of mGlu5 receptors in vitro. Endogenous ERK1 also interacted with mGlu5 receptor proteins in adult rat striatal neurons in vivo. The kinase showed the ability to phosphorylate mGlu5 receptors. A serine residue in the distal region of mGlu5 CT was found to be a primary phosphorylation site sensitive to ERK1. In functional studies, we found that pharmacological inhibition of ERK with an inhibitor U0126 reduced the efficacy of mGlu5 receptors in stimulating production of cytoplasmic inositol 1,4,5-triphosphate, a major downstream conventional signaling event, in striatal neurons under normal conditions. These results identify mGlu5 as a new biochemical substrate of ERK1. The kinase can interact with and phosphorylate an intracellular domain of mGlu5 receptors in striatal neurons and thereby control its signaling efficacy. PMID- 30430310 TI - Long-term results of stapled hemorrhoidectomy. PMID- 30430309 TI - Transanal total mesorectal excision for rectal cancer with indocyanine green fluorescence angiography. AB - BACKGROUND: The aim of this study was to evaluate the impact of fluorescence angiography (FA) on any change in proximal resection margin and/or anastomotic leak (AL) following transanal total mesorectal excision (TaTME) for rectal cancer (RC). METHODS: This retrospective cohort study was conducted at two centers by three senior surgeons. Both institutions' prospectively maintained Institutional Review Board-approved databases were retrospectively queried for all consecutive patients between July 2015 and May 2017 who had laparoscopic hybrid trans abdominal total mesorectal excision (TME) and TaTME for RC with colorectal or coloanal anastomosis < 10 cm from the anal verge. All patients had intraoperative FA to assess colonic perfusion of the planned proximal resection margin before bowel transection and after construction of the anastomosis. Primary outcomes measured any changes in proximal resection margins and AL rates. RESULTS: Fifty four patients (31 males; mean age 63 +/- 12 years) were included; 30 (55%) of whom received neoadjuvant chemoradiation. The average anastomotic height was 3.6 cm from the anal verge and 8 (14.5%) patients required intersphincteric dissection. Forty-six patients (85%) had loop ileostomy. FA led to a change in the proximal resection margin in 10 patients (18.5%), one of whom had AL on postoperative day 3 requiring diagnostic laparoscopy and loop ileostomy. A second patient, without a change in the proximal resection margin, also had an AL. The overall AL rate was 3.7%. CONCLUSIONS: FA changed the planned proximal resection margin in 18.5% of patients, possibly accounting for the relatively low AL rate. FA is imperfect, and subjective but does have the potential to improve outcomes. PMID- 30430311 TI - Robotic pelvic lymph node dissection for rectal cancer. PMID- 30430313 TI - Single blastomeres as a source of mouse embryonic stem cells: effect of genetic background, medium supplements, and signaling modulators on derivation efficiency. AB - PURPOSE: To assess the role of the genetic background, the culture medium supplements, and the presence of modulators of signaling pathways on mouse embryonic stem cell derivation from single blastomeres from 8-cell embryos. METHODS: Mice from permissive and non-permissive genetic backgrounds, different culture media supplements, knockout serum replacement (KSR) and N2B27, and the presence or absence of 2i treatment were used to derive mouse embryonic stem cells (mESC) from single blastomeres isolated from 8-cell embryos and from control embryos at the blastocyst stage. After the sixth passage, the putative mESC were analyzed by immunofluorescence to assess their pluripotency and, after in vitro differentiation induction, their ability to differentiate into derivatives of the three primary germ layers. Selected mESC lines derived from single blastomeres in the most efficient culture conditions were further characterized to validate their stemness. RESULTS: In control embryos, high mESC derivation efficiencies (70-96.9%) were obtained from permissive backgrounds or when embryos were cultured in medium complemented with 2i regardless of their genetic background. By contrast, only blastomeres isolated from embryos from permissive background cultured in KSR-containing medium complemented with 2i were moderately successful in the derivation of mESC lines (22.9-24.5%). Moreover, we report for the first time that B6CBAF2 embryos behave as permissive in terms of mESC derivation. CONCLUSIONS: Single blastomeres have higher requirements than whole blastocysts for pluripotency maintenance and mESC derivation. The need for 2i suggests that modulation of signaling pathways to recreate a commitment towards inner cell mass could be essential to efficiently derive mESC from single blastomeres. PMID- 30430312 TI - What is the evidence for the use of parenteral nutrition (PN) in critically ill surgical patients: a systematic review and meta-analysis. AB - BACKGROUND: Malnutrition is associated with poor outcomes in surgical patients and corrective enteral feeding may not be possible. This is a particular problem in the acute setting where malnutrition is prevalent. The aim of this systematic review was to evaluate the use of parenteral nutrition (PN) in critically ill surgical patients. METHODS: This review was registered with PROSPERO (CRD42017079567). Searches of the CENTRAL, EMBASE, and MEDLINE databases were performed using a predefined strategy. Randomised trials published in English since 1995, reporting a comparison of PN vs any comparator in a critically ill surgical population were included. The primary outcome was mortality. Risk of bias was assessed using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development and Evaluation assessment. Meta-analysis was performed using a random effects model to assess variation in mortality and length of stay. RESULTS: Fourteen RCTs were identified; standard PN was compared vs other forms of PN in ten studies, to PN with variable dose amino acids in one, and to enteral nutrition (EN) in three. In trials comparing glutamine supplemented PN (PN-GLN) to PN, a non-significant reduction in mortality was noted (risk difference - 0.08. 95% CI - 0.17, 0.01, p = 0.08). A trend for a reduction in length of stay was seen in PN-GLN to PN comparator (mean reduction - 2.4, 95% CI - 7.19 to 2.32 days, I2 = 92%). Impact on other outcome measures varied in direction of effect. CONCLUSIONS: PN may offer benefit in critically ill surgical patients. The size and quality of studies lead to uncertainty around the estimates of clinical effect, meaning a robust trial is required. PMID- 30430314 TI - Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes. AB - PURPOSE: To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque. METHODS: Cycling female rhesus macaques (N = 8) received vehicle through one menstrual (control) cycle, followed by daily injections of PGL1001, a SSTR-2 antagonist, for three menstrual (treatment) cycles. Main endpoints include overall animal health and ovarian hormones (e.g., estradiol [E2], progesterone [P4], and anti-Mullerian hormone [AMH]), ovarian circumference, numbers of oocytes and their maturation status following controlled ovarian stimulation (COS), as well as oocyte fertilization and subsequent blastocyst rates that were assessed in control and PGL1001 treatment cycles. Circulating PGL1001 levels were assessed at baseline as well as 6, 60, and 90 days during treatment. RESULTS: PGL1001 treatment did not impact overall animal health, menstrual cycle length, or circulating levels of ovarian hormones (E2, P4, and AMH) in comparison to vehicle treatment during natural cycles. PGL1001 treatment increased (p ? 0.05) ovarian circumference and the day 8 to day 1 ratio of AMH levels (p ? 0.05) during a COS protocol, as well as oocyte fertilization rates compared to the vehicle treatment interval. Blastocyst development rates were not significantly different between vehicle and PGL1001 treatment groups. CONCLUSION: Prolonged treatment with PGL1001 appears to be safe and does not affect rhesus macaque general health, menstrual cycle length, or ovarian hormone production. Interestingly, PGL1001 treatment increased the fertilization rate of rhesus macaque oocytes collected following ovarian stimulation. PMID- 30430315 TI - Management of acute ischemic stroke, thrombolysis rate, and predictors of clinical outcome. AB - BACKGROUND AND AIMS: Monitoring the quality of acute ischemic stroke (AIS) management is increasingly important since patient outcome could be improved with better access to evidence-based treatments. In this scenario, the aim of our study was to identify thrombolysis rate, reasons for undertreatment, and factors associated with better outcome. METHODS: From January to December 2016, individuals diagnosed with AIS at the Policlinic San Martino Hospital in Genoa, Italy, were prospectively included. Severity of stroke, site of occlusion, rate and time related in-hospital management of systemic thrombolysis, and mechanical thrombectomy were recorded. Safety and clinical outcomes were compared between different subgroups. RESULTS: Of 459 AIS patients (57.3% females, mean age 78.1), 111 received i.v. thrombolysis (24.4%) and 50 received mechanical thrombectomy (10.9%). Apart from arrival behind the therapeutic window, which was the first limitation to thrombolysis, the main reason of undertreatment was minor stroke or stroke in rapid improvement. Baseline NIHSS >= 8 was associated with unfavorable clinical outcome (mRS > 2) (OR 20.1; 95% CI, 1.1-387.4, p = 0.047). Age older than 80 years (OR 5.0; 95% CI, 1.4-64.1, p = 0.01), baseline NIHSS >= 7 (OR 20.1; 95% CI, 1.1-387.4, p = 0.047), and symptomatic intracranial hemorrhage (OR 22.9; 95% CI, 2.0-254.2, p = 0.01) proved independently associated with mortality. CONCLUSIONS: i.v. thrombolysis and mechanical thrombectomy rate was higher than that of previous reports. Minor stroke or stroke in rapid improvement was a major reason for exclusion from thrombolysis of eligible patients. Higher NIHSS proved an independent predictor of unfavorable clinical outcome and death. Strategies to avoid in-hospital delays need to be enforced. PMID- 30430316 TI - Case report: hypertrophic pachymeningitis associated with Sjogren's syndrome. PMID- 30430318 TI - Autistic-Like Traits in Pena-Shokeir Syndrome. AB - Pena-Shokeir syndrome (PSS) is a rare, early lethal disease. PSS is characterized by fetal growth restriction, craniofacial deformities, multiple ankyloses and pulmonary hypoplasia. Because of the primary concern of physical health problems, psychiatric evaluation is frequently underestimated in PSS patients. Our case report describes a child with PSS who presented with autistic spectrum disorder symptoms. PMID- 30430317 TI - Intrathecal nusinersen treatment for SMA in a dedicated neuromuscular clinic: an example of multidisciplinary and integrated care. AB - Nusinsersen is now available in Italy for all SMA types. We describe the experience with intrathecal treatment with nusinersen in 50 patients with SMA at the NEMO Center (NEuroMuscular Omniservice Clinical Center) in Milan, a neuromuscular patient-centered clinic hosted within Niguarda Hospital, a National Public General Hospital. Our results indicate that the pathway of care described outweighs the burden due to the repeated intrathecal injections. Irrespective of age and severity, the treatment is feasible, accessible, and replicable provided that there is a multidisciplinary team having experience and training in SMA. PMID- 30430319 TI - Digital Books with Dynamic Text and Speech Output: Effects on Sight Word Reading for Preschoolers with Autism Spectrum Disorder. AB - Despite the importance of literacy in today's educational curriculum, learning to read is a challenge for many children with autism spectrum disorder (ASD). One of the foundational skills of early literacy learning is the ability to recognize sight words. This study used a single-subject, multiple-probe, across participants design, to investigate the effects of a new software feature, dynamic text and speech output, on the acquisition of sight words by three pre literate preschoolers with ASD during shared digital book reading experiences. All participants demonstrated successful acquisition of the target sight words with minimal exposure to the words. Limitations and future research directions are discussed, including the importance of investigating how the new software feature can be integrated into a more comprehensive literacy curriculum. PMID- 30430320 TI - Prevalence and Predictors of Anxiety Disorders in Adolescent and Adult Males with Autism Spectrum Disorder and Fragile X Syndrome. AB - Anxiety disorders affect ~ 15-20% of youths without neurodevelopmental disorders, with persons having autism spectrum disorder (ASD) and fragile X syndrome (FXS) at elevated risk for anxiety disorders. Few studies have compared rates and predictors of anxiety disorders in adolescents with FXS or ASD. This study directly compares rates, predictors, and medication of anxiety disorders between age-matched, male adolescents with FXS (n = 31) or ASD (n = 20). Results indicate that 51.6% of FXS and 50.0% of ASD adolescents met criteria for an anxiety disorder. Cognitive scores and ASD severity did not predict anxiety. Of those with anxiety, ~ 40% of the FXS and 20% of the ASD participants were prescribed medications for anxiety. PMID- 30430321 TI - Social Conformity in Autism. AB - Humans are extremely susceptible to social influence. Here, we examine whether this susceptibility is altered in autism, a condition characterized by social difficulties. Autistic participants (N = 22) and neurotypical controls (N = 22) completed a memory test of previously seen words and were then exposed to answers supposedly given by four other individuals. Autistic individuals and controls were as likely to alter their judgements to align with inaccurate responses of group members. These changes reflected both temporary judgement changes (public conformity) and long-lasting memory changes (private conformity). Both groups were more susceptible to answers believed to be from other humans than from computer algorithms. Our results suggest that autistic individuals and controls are equally susceptible to social influence when reporting their memories. PMID- 30430322 TI - Landslide susceptibility mapping in an area of underground mining using the multicriteria decision analysis method. AB - Landslides are geomorphological phenomena that affect anthropogenic and natural features on the Earth's surface. Many previous studies have identified several factors that have contributed to landslides. Among these factors are physical characteristics, such as slope, aspect, and land cover, of Earth's surface. Moreover, landslides can be triggered by human activities such as underground mining. This study aims to identify landslide susceptibility areas by analyzing landslide-related factors, including land subsidence triggered by underground mining. The area of interest was Kozlu, Turkey, where underground mining has been in progress for the past 100 years. Thus, to identify landslide risk zones, the multicriteria decision analysis method, together with the analytical hierarchy method, was used. The datasets included were topography, land cover, geological settings, and mining-induced land subsidence. The spatial extent of land subsidence was estimated using a previously published model. A landslide susceptibility map (LSM) was developed using a purposely developed GIS-based software. The results were compared with a terrain deformation map, which was developed in a separate study using the differential synthetic aperture radar interferometry (DInSAR) technique. The results showed a substantial correlation between the LSM and DInSAR map. Furthermore, it was found that ~ 88% of the very high and high landslide risk areas coincided with location of the past landslide events. These facts suggest that the algorithm and data sources used were sufficient to produce a sufficiently accurate LSM, which may be used for various purposes such as urban planning. PMID- 30430323 TI - ASO Author Reflections: Staging Laparoscopy Improves Overall Survival of Patients with Pancreatic Adenocarcinoma Found to Have Occult Metastatic Disease. PMID- 30430324 TI - Neoadjuvant Androgen Deprivation Therapy Prior to Radical Prostatectomy: Recent Trends in Utilization and Association with Postoperative Surgical Margin Status. AB - PURPOSE: In this study, we sought to describe the contemporary trends in utilization of neoadjuvant androgen deprivation therapy (ADT). As a secondary endpoint, we assessed the community-level effect of neoadjuvant ADT on positive surgical margins after radical prostatectomy (RP). METHODS: Using the National Cancer Database (2004-2014), we identified patients with clinically localized prostate cancer (PCa) [cT1-4N0M0] treated with RP. The estimated annual percentage change (EAPC) mixed linear regression methodology was used for temporal trend analysis of neoadjuvant ADT. Observed differences in baseline characteristics between patients treated with neoadjuvant ADT versus those who were not were then controlled for using an inverse probability of treatment weighting (IPTW) approach. IPTW-adjusted analyses were then performed to examine the odds of positive surgical margins. RESULTS: Overall, 8184 (2.12%) and 377,843 (97.88%) individuals with PCa were treated with neoadjuvant ADT prior to RP versus RP only, respectively. There was a consistent trend in decreasing use of neoadjuvant ADT over time, with a nadir observed in 2011 [EAPC - 8.08; 95% confidence interval (CI) - 11.7 to - 4.32; p < 0.05]. In IPTW-adjusted analyses, the odds of positive surgical margins were lower in patients receiving neoadjuvant ADT with low-risk [odds ratio (OR) 0.65; 95% CI 0.51-0.84; p < 0.001] and intermediate-risk [OR 0.76; 95% CI 0.69-0.85; p < 0.001] PCa. CONCLUSIONS: After a period of steady decline, there appears to be a modest trend towards increased utilization of neoadjuvant ADT in more recent years. We found an association between neoadjuvant ADT and decreased odds of positive surgical margins among low- and intermediate-risk patients. PMID- 30430325 TI - Neoadjuvant Chemoradiation Versus Upfront Esophagectomy in Clinical Stage II and III Esophageal Squamous Cell Carcinoma. AB - BACKGROUND: The benefits of neoadjuvant chemoradiation (NCRT) compared to upfront esophagectomy (UE) in esophageal squamous cell carcinoma (ESCC) is controversial. Our purpose was to determine whether clinical stages based on the 8th edition American Joint Committee on Cancer Tumor-Node-Metastasis staging system could guide treatment decision. METHODS: Data from 2503 patients with clinical stages II and III ESCC diagnosed between 2008 and 2014 were obtained from a nationwide database. Propensity score matching was used to identify well-balanced pairs of patients. Cox proportional hazards regression and log-rank test were used in the survival analysis. The outcomes of patients receiving "NCRT followed by surgery" or "UE" strategies were compared. RESULTS: The treatment modality (UE or NCRT) was not a prognostic factor in clinical stage II ESCC (HR: 0.97; p = 0.778). In contrast, the UE group demonstrated a significantly worse outcome compared with the NCRT group in clinical stage III ESCC (HR: 1.39; p < 0.001). After matching, patients who underwent UE for clinical stage II ESCC had median survival/3-year overall survival (OS) rates of 27.8 months/39.2% compared with 32.7 months/49.8% in the NCRT group (p = 0.508). The patients who underwent UE for clinical stage III ESCC had median survival/3-year OS rates of 17.9 months/28.2% in the UE group compared with 24.0 months/41.8% in the NCRT group (p < 0.001). CONCLUSIONS: Our data suggest that NCRT strategy improved survival compared with UE in clinical stage III ESCC but not in clinical stage II tumors. PMID- 30430326 TI - Effect of image quality on accuracy of two-dimensional strain echocardiography for diagnosing ischemic chest pain: a 2DSPER multicenter trial substudy. AB - Few data exist regarding the effect of image quality on measurements of two dimensional longitudinal strain (2DLS). In the 2DLS for Diagnosing Chest Pain in the Emergency Room (2DSPER) multicenter study, 2DLS was not useful for ruling out acute coronary syndromes (ACS) in the emergency department (ED). The aim of this substudy was to determine the effect of 2D image quality on the diagnostic accuracy of 2DLS for ACS. We reviewed apical views used for 2DLS analysis in all 605 patients included in the 2DSPER study. Studies with the best image quality (HighQ, n = 177), were compared to the lower quality group (LowQ, n = 428). Abnormal 2DLS was defined as PSS20% > - 17% (PSS20% being the peak left ventricular systolic strain value identifying the 20% worst strain values). Global longitudinal strain (GLS) and PSS20% were significantly worse in LowQ compared to HighQ patients. LowQ independently predicted abnormal 2DLS (OR 1.9, 95% CI 1.3-2.9, P = 0.003). The sensitivity of PSS20% > - 17% for ACS was 85% for LowQ vs. 73% for HighQ (P = 0.2), specificity 22% vs. 38% (P < 0.0001) and overall accuracy 29% vs. 44% (P = 0.0004). Despite better overall accuracy in the HighQ group there was no significant difference between the receiver operating characteristic curves of either GLS or PSS20% in the two groups and abnormal 2DLS did not predict ACS even in HighQ patients (OR 1.7, 95% CI 0.7-4.3, P = 0.3). LowQ echo is associated with worse 2DLS. Abnormal 2DLS was not clinically useful for excluding ACS in the ED even in patients with optimal 2D image quality. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01163019. PMID- 30430327 TI - Increased fractal dimension of left ventricular trabeculations is associated with subclinical diastolic dysfunction in patients with type-2 diabetes mellitus. AB - The aim of this study was to investigate the relationship among left ventricular (LV) concentric hypertrophy, endocardial remodeling, and myocardial deformation in type-2 diabetes mellitus (T2DM). Fifty-three T2DM patients with normotension and 36 healthy controls underwent cardiovascular magnetic resonance imaging to assess for LV concentric hypertrophy (LV myocardial mass index, LVMMi; LVMMi-to LV end-diastolic volume index ratio, MVR), endocardial remodeling (fractal dimension of trabeculations, FD), and myocardial deformation (global longitudinal, radial and circumferential strain, systolic and diastolic strain rate). When compared with healthy controls, T2DM was associated with LV concentric hypertrophy (LVMMi: T2DM, 52.7 +/- 8.9 g/m2; controls, 48.7 +/- 8.4 g/m2, p = 0.032; MVR: T2DM, 0.88 +/- 0.19 g/mL; controls, 0.77 +/- 0.16 g/mL, p = 0.007), endocardial remodeling (max. apical FD: T2DM, 1.265 +/- 0.056; controls, 1.233 +/- 0.055, p = 0.008; mean apical FD: T2DM, 1.198 +/- 0.043; controls, 1.176 +/- 0.043, p = 0.020), and subtle diastolic dysfunction (peak longitudinal diastolic strain rate, PDSRL: T2DM, 1.1 +/- 0.2/s; controls, 1.2 +/- 0.3/s, p = 0.031). In the stepwise multivariable regression model, the MVR was an independent determinant of the maximum apical FD (standardized beta, sbeta = 0.525, p < 0.001) and mean apical FD (sbeta = 0.568, p < 0.001). The mean apical FD was an independent determinant of the PDSRL (p = 0.004). LV concentric hypertrophy is an independent determinant of endocardial remodeling, a process that may contribute to subtle LV diastolic dysfunction in T2DM patients. PMID- 30430328 TI - The predictive value of global longitudinal strain on late infarct size in patients with anterior ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention. AB - Late infarct size (IS) after ST segment elevation myocardial infarction (STEMI) is a determinant of subsequent mortality. Late Gadolinium enhancement in cardiac magnetic resonance imaging (LGE-CMRI) is the gold standard for IS measurement, however, it is not readily accessible in many areas. We aimed to evaluate the value of early baseline 2D-echocardiographic global longitudinal strain (GLS) for the prediction of late IS after STEMI. From October 2017 to July 2018, we studied 100 patients with their 1st anterior STEMI treated with primary percutaneous coronary intervention. Baseline GLS calculation was performed within 48 h of admission. In addition, the average value of the nine segments supplied by the LAD was assessed separately (anterior GLS). Infarct size was assessed 3 months later using LGE-CMRI, and large infarcts were defined as >= 20% LV myocardium covered by scar. Based on CMRI, we defined two groups; 57 patients with large infarcts (group I) and 43 patients with small infarcts (group II). Both groups were matched in all baseline demographics and risk factors. There was a good and significant correlation between GLS and late IS (r = - 0.840, P < 0.001). This correlation was even higher for anterior GLS (r = - 0.867, P < 0.001). ROC analysis showed a cut-off point of GLS (- 13%) that identified large late IS with a sensitivity and specificity of 66.7% and 88.4% respectively (AUC = 0.85). For anterior GLS, the cut-off point was - 9.6% (Sensitivity 94%, specificity 86%, AUC = 0.9). We concluded that baseline GLS significantly predicts late IS after anterior STEMI. PMID- 30430329 TI - Multi-parametric "on board" evaluation of right ventricular function using three dimensional echocardiography: feasibility and comparison to traditional two-and three dimensional echocardiographic measurements. AB - Three-dimensional echocardiographic (3DE) of right ventricle (RV) has been validated in many clinical settings. However, the necessity of complicated and off-line dedicated software has reduced its diffusion. A new simplified "on board" 3DE software (OB) has been developed to obtain RV volumes and ejection fraction (EF) together with several conventional parameters automatically derived from 3DE: tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), longitudinal strain (LS). Aims of this study were to evaluate feasibility and accuracy of OB RV analysis. A complete 2DE and 3DE with OB 3DRV evaluation was obtained in 35 normal subjects and 105 patients with different pathologies. Results were compared with the conventional off-line software (OFL) and with the 2D-derived corresponding values. A subgroup of 22 patients underwent also cardiac CMR. OB 3DRV was feasible in 133/140 cases (95%) in a mean time of 97.5 +/- 33 s lower than OFL analysis (129 +/- 52 s plus dataset loading 80 +/- 24 s). Imaging quality was good in 84%. OB and OFL 3DE RV volumes and EF were similar. 3DE derived FSA and LS (but not TAPSE) were similar to 2DE values and correlated with tissue Doppler systolic peak velocity, dP/dt, systolic pulmonary pressure and myocardial performance index. OB RV volumes and EF well correlated with CMR. (bias + SD: - 21.5 +/- 20 mL for EDV; - 8.2 +/- 12.4 mL for ESV; - 1 +/ 5.9% for EF). OB 3DE method is feasible, simple, time saving. It easily provides 3DE RV volumes and multiple functional parameters. Off-line operator border adjustment may improve accuracy of 3DE TAPSE. PMID- 30430330 TI - Mutation and Selection in Bacteria: Modelling and Calibration. AB - Temporal evolution of a clonal bacterial population is modelled taking into account reversible mutation and selection mechanisms. For the mutation model, an efficient algorithm is proposed to verify whether experimental data can be explained by this model. The selection-mutation model has unobservable fitness parameters, and, to estimate them, we use an Approximate Bayesian Computation algorithm. The algorithms are illustrated using in vitro data for phase variable genes of Campylobacter jejuni. PMID- 30430331 TI - Development and validation of a rapid reversed-phase liquid chromatography method for CnAMP1 peptide quantification in human intestinal cell lines. AB - Plant foods are rich sources of biologically active peptides that may have a role in the prevention of diseases. Coconut water is a valuable beverage due to its nutrient composition and the presence of bioactive compounds, such as the peptide CnAMP1. It is unknown if CnAMP1 can be absorbed into intestinal cells. We, therefore, aimed to develop and validate a simple reversed-phase liquid chromatographic method to quantify the peptide in Caco-2 and LS180 cell lysates. CnAMP1 standards (1-200 umol/L) and spiked cell lysates were injected onto a Reprosil-Pur 120 C18-AQ column (4.6 * 250 mm) using acetonitrile:water:trifluoroacetic acid (14.0:85.9:0.1, by volume) as mobile phase in isocratic mode at flow rate of 1 mL/min. The method achieved rapid separation (total run time of 6 min), with linear response, good sensitivity (limit of detection, 8.2 ng; lower limit of quantification, 30.6 ng) and no interfering peaks. Best recoveries (84-96%), accuracies (7.6-14.8%) and precision (1.5-8%) were found for LS180 cell lysates spiked with medium (50 umol/L) and high (100 umol/L) amounts of the peptide. Uptake assays detected no peptides in the cell lysates; however, after the first 15-min incubation CnAMP1 underwent partial hydrolysis upon incubation with LS180 cells (29%) and extensive hydrolysis with Caco-2 cells (93%). PMID- 30430332 TI - Proapelin is processed extracellularly in a cell line-dependent manner with clear modulation by proprotein convertases. AB - Apelin is a peptide hormone that binds to a class A GPCR (the apelin receptor/APJ) to regulate various bodily systems. Upon signal peptide removal, the resulting 55-residue isoform, proapelin/apelin-55, can be further processed to 36-, 17-, or 13-residue isoforms with length-dependent pharmacological properties. Processing was initially proposed to occur intracellularly. However, detection of apelin-55 in extracellular fluids indicates that extracellular processing may also occur. To test for this, apelin-55 was applied exogenously to HEK293A cells overexpressing proprotein convertase subtilisin kexin 3 (PCSK3), the only apelin processing enzyme identified thus far, and to differentiated 3T3 L1 adipocytes, which endogenously express apelin, PCSK3 and other proprotein convertases. Analysis of culture media constituents from each cell type by high performance liquid chromatography-mass spectrometry and western blot demonstrated a time-dependent decrease in apelin-55 levels. This decrease was partially, but not fully, attenuated by PCSK inhibitor treatment in both cell lines. Comparison of the resulting apelin-55-derived peptide profile between the two cell lines demonstrated distinct processing patterns, with apelin-36 production apparent in 3T3-L1 adipocytes vs. detection of the prodomain of a shorter isoform (likely the apelin-13 prodomain, observed after additional proteolytic processing) in PCSK3 transfected HEK293A cells. Extracellular processing of apelin, with distinct cell type dependence, provides an alternative mechanism to regulate isoform-mediated physiological effects of apelin. PMID- 30430333 TI - Correction to: Autolysis of Pichia pastoris induced by cold. AB - The original version of this article (Bartolo-Aguilar et al. 2017) was written and published including the first construction strategy of pLGC09, but not the final one. This error was pointed out by a reader and an analysis of sequences of parts of the plasmid corroborated this. The final construction strategy was reanalysed and confirmed the error. This error affected the text, Table 2, Fig. 1 and Additional files, but did not affect the results and conclusions stated in the paper. The authors regret that this error occurred in the original publication of the article. The corrected text, Table 2 and Fig. 1, and Additional files (Additional file 1. Construction strategy of pLGC09 and Additional file 2. Plasmid pLGC09) are given in this correction. PMID- 30430334 TI - Decreased beta-Cell Function is Associated with Cardiovascular Autonomic Neuropathy in Chinese Patients Newly Diagnosed with Type 2 Diabetes. AB - The influence of beta-cell function on cardiovascular autonomic neuropathy (CAN), an important diabetes-related complication, is still unclear. In this study, we aimed to investigate the association between residual beta-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN+ group (diabetic patients with CAN, n = 20) and a CAN- group (diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured. Homeostasis model assessment-beta cells (HOMA-B) and HOMA-insulin resistance (IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN- group, the CAN+ group had significantly lower fasting plasma insulin (6.60 +/- 4.39 vs 10.45 +/- 7.82 MU/L, P = 0.029), fasting C-peptide (0.51 +/- 0.20 vs 0.82 +/- 0.51 nmol/L, P = 0.004), and HOMA-B (21.44 +/- 17.06 vs 44.17 +/- 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio (r = 0.24, P = 0.043) and the 30:15 test (r = 0.26, P = 0.023). Further analysis showed that fasting C-peptide (OR: 0.041, 95% CI 0.003-0.501, P = 0.012) and HOMA-B (OR: 0.965, 95% CI 0.934-0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values < 0.67 nmol/L were more likely to have CAN than those with C-peptide levels >=0.67 nmol/L (OR: 6.00, 95% CI 1.815-19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased beta-cell function was closely associated with CAN in this population. PMID- 30430335 TI - Proceedings of the RAMI Section of Radiology incorporating the Faculty of Radiologists, RCSI: Professionalism and Clinical Effectiveness training : 14 th February 2018 and 14 th March 2018. PMID- 30430336 TI - Evaluation of the natural course of thyroid nodules in patients with acromegaly. AB - PURPOSE: To investigate the nodular thyroid disease (NTD) and the natural course of thyroid nodules in patients with acromegaly. METHODS: 138 patients with acromegaly (73 F/65 M), whose initial thyroid ultrasonography performed in our university hospital, were included in this study. The frequencies of NTD, papillary thyroid cancer (PTC) and associated factors on nodule formation were investigated at initial assessment. Patients who had NTD continued to follow-up (n = 56) were re-evaluated with a ultrasonography performed after a mean 7-years follow-up period. The nodule size changes were compared with the initial data and the factors affecting nodule growth were investigated. RESULTS: The frequency of NTD was found 69%. Patients with NTD were older (p = 0.05), with higher baseline IGF-1%ULN (upper limit of normal) (p = 0.01). In patients with NTD, the majority had similar nodule size (45%), decreased nodule size in 30% and nodule growth in 25%. In patients with active acromegaly at last visit, nodule growth was more significant (p < 0.001). For one unit change in the IGF-1 levels, nodule growth increased by 1.01 folds and presence of active acromegaly disease was related with ninefolds increase in nodule growth. The frequency of PTC was 14% in patients with nodule growth and PTC was diagnosed 11% of all acromegalic patients. CONCLUSION: Both NTD and nodule growth is more frequent in active acromegalic patients. Thyroid nodules may show dynamic changes according to the disease activity and nodule growth should be closely monitored due to the risk of malignancy in patients with active acromegaly disease. PMID- 30430337 TI - Influence of polycystic ovary syndrome on the periodontal health of Indian women visiting a secondary health care centre. AB - OBJECTIVES: Periodontal disease and polycystic ovary syndrome (PCOS) share risk factors like obesity, insulin resistance, and dyslipidemia, along with evidence of chronic inflammation in the two conditions. Evaluating the influence of PCOS on periodontal health would, therefore, identify a possible association. MATERIALS AND METHODS: Sixty women, divided into equal groups of PCOS and healthy patients, were clinically examined for periodontal parameters like probing depth (PD), plaque index (PI), modified gingival index (mGI), and bleeding on probing (BOP). Fasting blood sugar (FBS), insulin (FI), triglycerides (TG), and free testosterone along with serum and gingival crevicular fluid (GCF) levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were the biochemical parameters evaluated. RESULTS: Women with PCOS had statistically significant differences in mGI, PI, testosterone, FBS, and TG when compared with healthy women (p < 0.05). MDA levels in serum and GCF between women with PCOS and controls were also significantly different. BOP and mGI showed a moderate positive correlation (r = 0.45 and 0.44) with serum levels of MDA. Relatively greater gingival inflammation was observed in patients with PCOS compared to healthy controls, independent of the risk factors present. CONCLUSION: PCOS seemed to have an impact on gingival inflammation, in addition to the effect of dental plaque and other local factors in the oral cavity, in PCOS patients when compared with healthy individuals. CLINICAL RELEVANCE: Women diagnosed with PCOS may have probabaility of co existing gingival inflammation. Therefore, emphasis on medical treatment for PCOS and periodic screening for periodontal disease may be warranted. PMID- 30430338 TI - In vivo evaluation of the genotoxicity and oxidative damage in individuals exposed to 10% hydrogen peroxide whitening strips. AB - OBJECTIVE: This study assessed the impact of 10% hydrogen peroxide whitening strip exposure on the genotoxicity and oxidative damage by means of the buccal micronucleus cytome assay by counting nuclear abnormalities (NAs) in buccal mucosa and attached gingiva cells and by analyzing in whole saliva the molecule 8 hydroxy-2'-deoxyguanosine (8-OHdG). MATERIALS AND METHODS: The study was conducted on 113 subjects divided into two groups: group 1 or control (n = 53), non-whitening strip exposed, and group 2 (n = 60), whitening strip exposed (Crest(r) 3D Whitestrips(r) premium plus, 10% hydrogen peroxide). Oral epithelial cells and whole saliva samples were taken at the beginning and 30 days later for group 1 and immediately before bleaching and 15 and 30 days after the end of the bleaching for group 2. RESULTS: An increased frequency of NAs (p < 0.05) and higher levels of 8-OHdG (p < 0.05) were observed after bleaching exposure. Also, a positive correlation exists between oxidative stress produced by hydrogen peroxide and micronuclei was found. CONCLUSION: Individuals exposed to 10% hydrogen peroxide whitening strips exhibit NAs increased in oral epithelial cells and 8-OHdG in saliva, which is directed related to nuclear and oxidative DNA damage, respectively. CLINICAL SIGNIFICANCE: Hydrogen peroxide is the active agent of tooth whitening and this compound induced DNA damage. Individuals exposed to whitening strips with 10% hydrogen peroxide exhibit increased genotoxic and oxidative damage. Therefore, self-application of bleaching agents should be handled carefully since it could be a risk to human health. PMID- 30430339 TI - Breast cancer risk associated with BRCA1/2 variants in the Pakistani population. AB - BACKGROUND: Majority of the BRCA1 and BRCA2 mutations are associated with the risk of sporadic and familial breast cancer. Since these genes are significant in DNA repair mechanisms, we focused homology-directed DNA repair (HDDR) and BRCA complex. METHODS: We selected BRCA1 variant (rs80356932, 4491C/T) and BRCA2 variant (rs80359182, 319T/C) from the interaction region of BRCA complex and studied in 100 breast cancer patients and 100 controls using tetra-ARMS-PCR. RESULTS: Here we show that BRCA1 and BRCA2 variants are significantly associated with high breast cancer risk (BRCA1 rs80356932; Genotype T/T OR 8.66, 95% CI 3.16 23.71, p < 0.0001; Allele-T, OR 2.48, 95% CI 1.62-3.81, p < 0.0001 and BRCA2 rs80359182; Genotype C/C OR 4.32, 95% CI 1.95-9.53, p = 0.0001; Allele-C, OR 2.19, 95% CI 1.43-3.34, p = 0.0002). Additionally, bioinformatics analysis showed that BRCA2-tryptophan > arginine substitutions result in altered interaction of BRCA1/PALB2/BRCA2/protein complex and impaired HDDR pathway. We also observed that breast cancer risk was significantly increased in over-weighted and obese women. CONCLUSIONS: Our results indicate that high risk of breast cancer is significantly associated with BRCA1 and BRCA2 variants, and mutations may alter the protein interactions of BRCA complex that results in tumor genesis. PMID- 30430340 TI - An Integrated Examination of County- and Individual-Level Factors in Relation to HIV Pre-exposure Prophylaxis Awareness, Willingness to Use, and Uptake Among Men Who Have Sex with Men in the US. AB - This study explored the extent to which county- and individual-level factors were associated with awareness, willingness to use, and use of pre-exposure prophylaxis (PrEP) among US men who have sex with men (MSM). We conducted multilevel analyses using a sample of 8338 MSM residing in 1257 US counties drawn from the 2014-2015 American Men's Internet Survey to examine these associations, with focuses on variation in PrEP outcomes across counties and proportion variation explained by county-level factors (HIV prevalence, racial composition, median household income, income inequality, health insurance coverage). Results showed that PrEP awareness varied moderately across counties (intraclass correlation coefficients [ICC] = 7.7%), willingness to use did not vary; however, the actual use varied substantially (ICC = 20.7%). Half of the variation in awareness and use was explained by county-level factors. Higher median household income was associated with greater likelihood of awareness and use. Higher income inequality was associated with greater likelihood of PrEP awareness. Findings can inform the development of multilevel interventions to address PrEP uptake among MSM and identify communities where structural intervention is most needed. PMID- 30430341 TI - Network Modeling of PrEP Uptake on Referral Networks and Health Venue Utilization Among Young Men Who Have Sex with Men. AB - The objective of this study is to identify individual-level factors and health venue utilization patterns associated with uptake of pre-exposure prophylaxis (PrEP) and to evaluate whether PrEP uptake behavior is further diffused among young men who have sex with men (YMSM) through health venue referral networks. A sample of 543 HIV-seronegative YMSM aged 16-29 were recruited in 2014-2016 in Chicago, IL, and Houston, TX. Stochastic social network models were estimated to model PrEP uptake. PrEP uptake was associated with more utilization of health venues in Houston and higher levels of sexual risk behavior in Chicago. In Houston, both Hispanic and Black YMSM compared to White YMSM were less likely to take PrEP. No evidence was found to support the spread of PrEP uptake via referral networks, which highlights the need for more effective PrEP referral network systems to scale up PrEP implementation among at-risk YMSM. PMID- 30430342 TI - Enrollment in HIV Care and Treatment Clinic and Associated Factors Among HIV Diagnosed Patients in Magu District, Tanzania. AB - HIV care and treatment clinics (CTC) are important for management of HIV morbidity and mortality, and to reduce HIV transmission. Enrollment in HIV care and treatment clinics remains low in many developing countries. We followed up 632 newly diagnosed HIV patients aged 15 years and above from Magu District, Tanzania. Logistic regression was used to assess factors significantly associated with enrollment for CTC services. Kaplan-Meier plots and log-rank tests were used to evaluate differences in timing uptake of services. Among 632 participants, 214 (33.9%) were enrolled in CTC, and of those enrolled 120 (56.6%) took longer than 3 months to enroll. Those living in more rural villages were less likely to be enrolled than in the villages with semi-urban settings (OR 0.36; 95% CI 0.17 0.76). Moreover, those with age group 35-44 years and with age group 45 years and above were 2 times higher odds compared to those with age group 15-24 years, (OR 2.03; 95% CI 1.05-3.91) and (OR 2.69; 95% CI 1.40-5.18) respectively. Enrollment in the CTC in Tanzania is low. To increase uptake of antiretroviral therapy, it is critical to improve linkage between HIV testing and care services, and to rollout these services into the primary health facilities. PMID- 30430343 TI - Moderated Mediation of Perceived Intoxication and Sexual Arousal on Determinants of Sexual Risk Behavior in Men Who Have Sex with Men. AB - Behavioral interventions remain the preferred strategy for reducing HIV-related risk behavior among men who have sex with men (MSM), one of the populations most affected by HIV. To improve intervention efforts, research is needed to identify cognitive-motivational factors that may play a role in sexual risk behaviors among MSM. This study sought to replicate and extend previous work from a heterosexual population that identified a serial mediation effect of perceived intoxication and subjective sexual arousal in the relationship between alcohol consumption and determinants of sexual risk in a population of MSM. Exploratory moderated mediation analyses tested subjective sexual arousal as a moderator of the indirect effect of alcohol consumption on determinants of sexual risk via perceived intoxication. Participants (N = 117 MSM, ages 21-50) were randomly assigned to one of six experimental conditions based on two manipulations: beverage condition (alcohol, placebo, or control) and sexual arousal (low or high). Dependent measures were likelihood to engage in risky sex and condom negotiation skills. Results did not support the serial mediation effect but showed some support for the moderated mediation model in the prediction of behavioral skills. Implications for alcohol and arousal myopia theories of risky behavior and HIV prevention efforts are discussed. PMID- 30430344 TI - One-Step Immobilization and Stabilization of a Recombinant Enterococcus faecium DBFIQ E36 L-Arabinose Isomerase for D-Tagatose Synthesis. AB - A recombinant L-arabinose isomerase from Enterococcus faecium DBFIQ E36 was immobilized onto multifunctional epoxide supports by chemical adsorption and onto a chelate-activated support via polyhistidine-tag, located on the N-terminal (N His-L-AI) or on the C-terminal (C-His-L-AI) sequence, followed by covalent bonding between the enzyme and the support. The results were compared to reversible L-AI immobilization by adsorption onto charged agarose supports with improved stability. All the derivatives presented immobilization yields of above 75%. The ionic interaction established between agarose gels containing monoaminoethyl-N-aminoethyl structures (MANAE) and the enzyme was the most suitable strategy for L-AI immobilization in comparison to the chelate-activated agarose. In addition, the immobilized biocatalysts by ionic interaction in MANAE showed to be the most stable, retaining up to 100% of enzyme activity for 60 min at 60 degrees C and with Km values of 28 and 218 mM for MANAE-N-His-L-AI and MANAE-C-His-L-AI, respectively. PMID- 30430345 TI - Effect of Diets, Familial History, and Alternative Therapies on Genomic Instability of Breast Cancer Patients. AB - This study evaluates a correlation between family history, micronutrients intake, and alternative therapies with genetic instability, before and during breast cancer treatment. For this study, a total of 150 women were selected. Among those, 50 women were breast cancer patients on chemotherapy, while 50 breast cancer patients were on radiotherapy, and 50 were healthy females. All the participants signed the informed consent form and answered the public health questionnaire. Samples of buccal epithelial and peripheral blood cells were collected and analyzed through micronucleus and comet assays. The cells were evaluated for apoptosis and DNA damage. Results showed the association of patients' family history with an increase in toxicogenetic damage before and during cancer therapy. On the other hand, patients with late-onset cancer also presented genetic instability before and during therapy, along with those who did not take sufficient vegetables and alternative therapies. A positive correlation was observed between the genetic instability and alternative therapies, while inverse correlation was recorded with the vegetable consumption. Results clearly explain that the nutritional aspects and alternative therapies influence the genetic instability before and during cancer therapies especially in radiotherapy treated patients. Our data could be used for the monitoring therapies and management of breast cancer patients. PMID- 30430346 TI - Enhanced Production of 6-(N-Hydroxyethyl)-Amino-6-Deoxy-alpha-L-Sorbofuranose by Immobilized Gluconobacter oxydanson Corn Stover with a pH Control Strategy in a Bubble Column Bioreactor. AB - 6-(N-Hydroxyethyl)-amino-6-deoxy-alpha-L-sorbofuranose (6NSL) is a key intermediate in the synthesis of miglitol. Biotransformation of N-2-hydroxyethyl glucamine (NHEG) to 6NSL was performed by immobilized Gluconobacter oxydans, which was prepared by cultivating the cells in a home-made bubble column bioreactor where corn stover particles were loaded. The optimal carrier addition and aeration rate for 6NSL production by immobilized cells in the bioreactor were determined to be 25 g/L and 2.5 vvm respectively. The supplementation of NH4Cl was conducive to the biotransformation of NHEG and was performed by adding aqueous ammonia and HCl, which was taken as the pH controlling agents as well. An optimal pH control strategy using the mixture of aqueous ammonia and NaOH was applied, resulting in a 9.9% increased production of 6NSL, while repeated batches of biotransformation increased from three times to four times. Finally, the 6NSL concentration and the conversion rate of NHEG to 6NSLreached 44.2 +/- 1.5 g/L and 88.4 +/- 2.0%, respectively, in average after four cycles of biotransformation under the optimized condition. PMID- 30430347 TI - Probing the Dynamic Mechanism of Uncommon Allosteric Inhibitors Optimized to Enhance Drug Selectivity of SHP2 with Therapeutic Potential for Cancer Treatment. AB - There is currently considerable interest in SHP2 as a potential target for treatment of cancer. Mutation in SHP2, particularly the E76A mutation, has been found to seriously confer the phosphatase high activity. Recently, two compounds, 1 and 23, have been reported as potent allosteric inhibitors of both SHP2 wild type (SHP2WT) and the E76A mutant (SHP2E76A), with higher activity than other inhibitors. However, the structural and dynamic implications of their inhibitory mechanisms are yet unexplored which deserve further attention. Herein, the MD simulation applies to gain insight into the atomistic nature of each binding mode of inhibitors 1 and 23 in both SHP2WT and SHP2E76A. The comparative analysis reveals inhibitor 1 can freeze SHP2WT and SHP2E76A in their auto-inhibited conformation better than 23, in agreement with experimental data. GLU250 in both SHP2WT and SHP2E76A and ARG111 and ARG229 in SHP2E76A play a crucial role in the higher activity of 1 compared to 23. The mutation E76A increases the binding affinity of 1 and 23 compared to the wild type, implying that the two inhibitors have been well adopted by the E76A mutant. The findings here can substantially shed light on new strategies for developing novel classes of SHP2 inhibitors with increased potency. PMID- 30430348 TI - Contrast between what is expected and what occurs increases pigeon's suboptimal choice. AB - When pigeons are given a choice between 50% signaled reinforcement and 100% reinforcement they typically do not choose optimally, sometimes even preferring 50% reinforcement. Smith and Zentall (J Exp Psychol Anim Behav Process 42:212 220, 2016) proposed that choice depends primarily on the predictive value of the signal for reinforcement associated with each alternative (both 100% reinforcement) and not the frequency of the signal for reinforcement (50% vs. 100%). With extended training, however, Case and Zentall (Behav Process, 2018) found that pigeons actually show a reliable preference for the 50% reinforcement alternative. They suggested that contrast between the expected outcome at the time of choice (50% reinforcement) and the value of the signal for reinforcement (100% reinforcement) is the mechanism responsible for the preference for the suboptimal alternative (for the optimal alternative there should be no contrast). In the present research, we tested the contrast hypothesis by increasing the probability of reinforcement for choice of the suboptimal alternative to 75%, thereby reducing the contrast between expected and obtained reinforcement and found a reduced preference for the suboptimal alternative. That is, increasing the probability of reinforcement for choice of the suboptimal alternative decreased suboptimal choice. Thus, preference for the suboptimal alternative appears to result from two mechanisms: (1) the value of the signal for reinforcement that follows choice of the alternative and (2) positive contrast between the expected and obtained probability of reinforcement. We compared this interpretation with other hypotheses. PMID- 30430349 TI - "Real-life" continuous flash suppression (CFS)-CFS with real-world objects using augmented reality goggles. AB - Continuous flash suppression (CFS) is a popular method for suppressing visual stimuli from awareness for relatively long periods. Thus far, this method has only been used for suppressing two-dimensional images presented on screen. We present a novel variant of CFS, termed "real-life" CFS, in which a portion of the actual immediate surroundings of an observer-including three-dimensional, real life objects-can be rendered unconscious. Our method uses augmented reality goggles to present subjects with CFS masks to the dominant eye, leaving the nondominant eye exposed to the real world. In three experiments we demonstrated that real objects can indeed be suppressed from awareness for several seconds, on average, and that the suppression duration is comparable to that obtained using classic, on-screen CFS. As supplementary information, we further provide an example of experimental code that can be modified for future studies. This technique opens the way to new questions in the study of consciousness and its functions. PMID- 30430350 TI - Availability of Safe Childbirth Supplies in 284 Facilities in Uttar Pradesh, India. AB - Objectives Vital to implementation of the World Health Organization (WHO) Safe Childbirth Checklist (SCC), designed to improve delivery of 28 essential birth practices (EBPs), is the availability of safe birth supplies: 22 EBPs on the SCC require one or more supplies. Mapping availability of these supplies can determine the scope of shortages and need for supply chain strengthening. Methods A cross-sectional survey on the availability of functional and/or unexpired supplies was assessed in 284 public-sector facilities in 38 districts in Uttar Pradesh, India. The twenty-three supplies were categorized into three non mutually exclusive groups: maternal (8), newborn (9), and infection control (6). Proportions and mean number of supplies available were calculated; means were compared across facility types using t-tests and across districts using a one-way ANOVA. Log-linear regression was used to evaluate facility characteristics associated with supply availability. Results Across 284 sites, an average of 16.9 (73.5%) of 23 basic childbirth supplies were available: 63.4% of maternal supplies, 79.1% of newborn supplies, and 78.7% of infection control supplies. No facility had all 23 supplies available and only 8.5% had all four medicines assessed. Significant variability was observed by facility type and district. In the linear model, facility type and distance from district hospital were significant predictors of higher supply availability. Conclusions for Practice In Uttar Pradesh, more remote sites, and primary and community health centers, were at higher risk of supply shortages. Supply chain management must be improved for facility-based delivery and quality of care initiatives to reduce maternal and neonatal harm. PMID- 30430351 TI - Development of a nonlinear hierarchical model to describe the disposition of deuterium in mother-infant pairs to assess exclusive breastfeeding practice. AB - The World Health Organization recommends exclusive breastfeeding (EBF) for the first 6 months after birth. The deuterium oxide dose-to-the-mother (DTM) technique is used to distinguish EBF based on a cut-off (< 25 g/day) of water intake from sources other than breastmilk. This value is based on a theoretical threshold and has not been verified in field studies. The aim of this study was to estimate the water intake cut-off value that can be used to define EBF practice. One hundred and twenty-one healthy infants, aged 2.5-5.5 months who were deemed to be EBF were recruited. After administration of deuterium to the mothers, saliva was sampled from mother and infant pairs over a 14-day period. Validation of infant feeding practices was conducted via home observation over six non-consecutive days with caregiver recall. A fully Bayesian framework using a gradient-based Markov chain Monte Carlo approach implemented in Stan was used to estimate the cut-off of non-milk water intake of EBF infants. From the original data set, 113 infants were determined to be EBF and provided 1500 paired mother-infant observations. The deuterium saliva concentrations were best described by two linked 1-compartment models (mother and infant), with body weight as a covariate on the mother's volume of distribution and infant's body weight on infant's water clearance rate. The cut-off value was based on the 90th percentile of the posterior distribution of non-milk water intake and was 86.6 g/day. This cut-off value can be used in future field studies in other geographic regions to determine exclusivity of breast feeding practices in order to determine their potential public health needs. PMID- 30430352 TI - Overexpression of CAV3 facilitates bone formation via the Wnt signaling pathway in osteoporotic rats. AB - PURPOSE: Osteoporosis is a condition characterized by decreased bone density and bone strength, commonly observed among older individuals. Caveolin-3 (CAV3) is a principal structural protein of the caveolae membrane domains, which has been reported to participate in cell signaling as well as the maintenance of cell structure. The aim of the current study was to investigate the effects involved with the silencing of CAV3 on bone formation among osteoporotic rat models via the Wnt signaling pathway. METHODS: Osteoporosis was initially induced by means of ovariotomy among rat models in order to determine the expression of CAV3. Then, to confirm the specific function and mechanism of CAV3 from an osteoporosis perspective, the CAV3 expression vector was constructed and transfected into the osteoblasts of the osteoporotic rats. Afterward, the mRNA and protein expressions of CAV3, beta-catenin, low-density lipoprotein receptor-related protein 5 (LRP5), T-cell factor (TCF), and Wnt3a in addition to cell proliferation and apoptosis were detected accordingly. RESULTS: Positive expression of CAV3 exhibited diminished levels in the bone tissues of osteoporotic rats. The osteoblasts of the osteoporotic rats treated with overexpressed CAV3 displayed elevated mRNA and protein expression levels of beta-catenin, LRP5, TCF, and Wnt3a. Increased cell proliferation and decreased cell apoptosis were also observed, while the osteoblasts of the osteoporotic rats treated with si-CAV3 exhibited an opposite result. CONCLUSION: Overexpressed CAV3 promotes bone formation and suppresses the osteoporosis progression via the activation of the Wnt signaling in rat models, suggesting CAV3 as a potential target biomarker in the treatment of osteoporosis. PMID- 30430353 TI - Larger ascending aorta in primary aldosteronism: a 3-year prospective evaluation of adrenalectomy vs. medical treatment. AB - OBJECTIVE: Primary aldosteronism is associated with higher cardiovascular morbidity as compared with essential hypertension. Vascular complications encompass myocardial infarction and cerebrovascular events. Aortic damage in primary aldosteronism has never been explored, although a few cases of ascending aorta aneurisms have been reported. DESIGN AND METHODS: We consecutively enrolled patients affected by primary aldosteronism (n = 45) and compared them with patients affected by essential hypertension (n = 47), on an outpatient setting. Echocardiographic data of patients with primary aldosteronism were collected during a mean follow-up of 3 years, in subjects who underwent adrenal surgery (n = 12) and those on mineralocorticoid receptor antagonists (n = 33). RESULTS AND CONCLUSION: We found that patients with primary aldosteronism had larger ascending aorta diameters than those with essential hypertension before starting any specific treatment. Patients with primary aldosteronism did not show significant changes in the size of ascending aorta during a mean of 3 years of follow-up, irrespective of the type of treatment (medical vs. surgical treatment). A longer follow-up will better clarify if worsening of the aortic damage may be better prevented by surgery rather than by mineralocorticoid receptor antagonists. PMID- 30430354 TI - Correction to: Chronic Aichi Virus Infection in a Patient with X-Linked Agammaglobulinemia. AB - The original version of this article unfortunately did not display the appropriate captions in the figure. The correct version is displayed below. PMID- 30430355 TI - Identification of Radiofrequency Ablation Catheter Parameters That May Induce Intracardiac Steam Pops: Direct Visualization of Elicitation in Reanimated Swine Hearts. AB - Radiofrequency, a common ablation modality, is used clinically to terminate cardiac arrhythmias. With excessive heating, complications sometimes occur when the applied energy generates steam pops, which cause release of energy in the form of tissue and/or air emboli. In this study, we investigated numerous parameters potentially associated with intracardiac steam pops including (1) wattage, (2) catheter tip temperature, (3) catheter irrigation, (4) anatomic site, and (5) repeat ablations at a given site. Using unique Visible Heart(r) methodologies in reanimated swine hearts, we visualized 539 ablations; steam pops developed in 140 of these ablations. The incidence of steam pops significantly increased for both nonirrigated and irrigated ablations at 40 W (p < 0.005), and for nonirrigated ablations with catheter contact angles perpendicular to the tissue or that encompassed larger surface areas (p < 0.05). To minimize the incidence of steam pops, clinicians performing radiofrequency ablations must consider catheter parameters. PMID- 30430356 TI - Purinergic implication in amyotrophic lateral sclerosis-from pathological mechanisms to therapeutic perspectives. AB - Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by degeneration of upper motor neurons in the brainstem and lower motor neurons in the spinal cord. Multiple mechanisms of motor neuron injury have been implicated, including more than 20 different genetic factors. The pathogenesis of ALS consists of two stages: an early neuroprotective stage and a later neurotoxic. During early phases of disease progression, the immune system through glial and T cell activities provides anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a rapidly succeeding neurotoxic phase develops. A well-orchestrated purine-mediated dialog among motor neurons, surrounding glia and immune cells control the beneficial and detrimental activities occurring in the nervous system. In general, low adenosine triphosphate (ATP) concentrations protect cells against excitotoxic stimuli through purinergic P2X4 receptor, whereas high concentrations of ATP trigger toxic P2X7 receptor activation. Finally, adenosine is also involved in ALS progression since A2A receptor antagonists prevent motor neuron death. Given the complex cellular cross-talk occurring in ALS and the recognized function of extracellular nucleotides and adenosine in neuroglia communication, the comprehensive understanding of purinome dynamics might provide new research perspectives to decipher ALS and help to design more efficient and targeted drugs. This review will focus on the purinergic players involved in ALS etiology and disease progression and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity. PMID- 30430357 TI - Erratum to: Structural aspects of human lactoferrin in the iron-binding process studied by molecular dynamics and small-angle neutron scattering. AB - The original article was published electronically on SpringerLink on 20 September 2018 without Open Access. The copyright of the article changed on 16 November 2018 with the author(s)' decision to opt for Open Choice. PMID- 30430359 TI - Follicular Dendritic Cell Sarcoma of Gastrointestinal Tract: an Uncommon Lesion, Commonly Missed. AB - INTRODUCTION: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm, accounting for only 0.4% of soft-tissue sarcomas. It shows both nodal and extranodal involvement. Considering the rarity and difficulties in diagnosing this tumor, we consider it very important to share our experience of diagnosing FDCS. Its correct diagnosis cannot be overemphasized as the treatment and prognosis of FDCS are very much different from tumors which come in its differential diagnosis. MATERIAL AND METHODS: We are presenting eight cases of extranodal FDCS in gastrointestinal tract diagnosed at our center in a period of 3 years (Feb 2015 to Feb 2018). Presenting complaints, demographic details, gross description, histologic features, immunostain results, and clinical follow-up were evaluated. RESULTS: Four patients were females and four were males. Tumor ranged in size from 5.5 to 35 cm. In five cases, tumor cells were arranged in storiform and whorling pattern. Lymphocytes were seen sprinkled in between these cells. In one case, lymphocytic infiltrate was extensive. Giant cells and frequent mitoses were noted in two cases. One case showed extensive necrosis. Tumor cells were strongly and diffusely positive for CD21 and CD35. Mean follow up of 11.8 months (range 01 to 24 months) was noted. CONCLUSION: FDCS is a rare tumor having distinct morphology and phenotype which if known can be correctly diagnosed. Therefore, knowledge of its varied location, morphology, and phenotype is very important to correctly diagnose this tumor and to prevent misdiagnosis and mistreatment. PMID- 30430358 TI - Metal, magnet or transplant: options in primary sclerosing cholangitis with stricture. AB - Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree of unknown etiology leading to stricturing and dilation. There is currently no effective medical therapy for PSC and liver transplantation (LT) remains the ultimate treatment for severe disease defined as repeated episodes of cholangitis, decompensated biliary cirrhosis or in exceptional cases, cholangiocarcinoma (CCA). Patients often present with a "dominant" stricture and the therapeutic endoscopist plays an important role in management to improve biliary patency using a variety of techniques that involve sampling, balloon dilation and temporary stenting. Newer modalities such as self-expanding metal stents or magnetic compression anastomosis that have been used in other diseases may have a role to play in PSC but should remain investigational. Liver transplantation for PSC is curative in most cases but the optimal timing remains unclear. The lifetime risk of CCA is 10-15% in PSC patients and LT is often not possible at the time of diagnosis. Multiple studies have tried to identify risk factors and to diagnose CCA at an early stage when surgical resection may be possible or LT can be performed. However, deceased donor organs for LT remain in short supply throughout the world so even identifying PSC patients with CCA at an early stage may not be beneficial unless a live donor organ is available. PMID- 30430360 TI - Adhesion Capacity of Weissella cibaria to Bovine Mammary Tissue and the Effect of Bio-Sealant Topical Application on Physicochemical Properties of Milk. AB - The ability of a probiotic strain (Weissella cibaria) to adhere on tissue and the effect of its topical application in nipples of lactating cows on physicochemical characteristics of milk were evaluated. An ex vivo model was used to demonstrate the adhesion capacity of W. cibaria. Tissue samples were randomly distributed in three different solutions corresponding to three treatments (a nipple bio-sealant formulation, sterile PBS solution and biomass of W. cibaria, sterile PBS solution without microorganism addition). The number of bacteria adhered in tissue was quantified and observed using electron microscopy. Additionally, a bio-sealant prepared with W. cibaria was topically applied to nipples of dairy cows. Milk samples were taken every 7 days for 60 days. Two controls were used. California mastitis test (CMT), somatic cell count, electrical conductivity, pH, density, and acidity were evaluated. The adhesion capacity of W. cibaria strain to epithelial cells of bovine teat tissue samples was demonstrated. When the strain was added as a bio-sealant, the adhesion capacity of W. cibaria was 80.44%. The response variables did not show significant differences among treatments; these results indicate the safety of the topical application of W. cibaria on the bovine mammary gland. In this study, a new safe way of administering probiotic microorganisms in nipples of lactating cows was demonstrated. W. cibaria adheres to the bovine mammary tissue and can be topically applied in nipples of lactating cows without affecting the physicochemical characteristics of milk. PMID- 30430361 TI - Combining MRF-based deformable registration and deep binary 3D-CNN descriptors for large lung motion estimation in COPD patients. AB - PURPOSE: Deep convolutional neural networks in their various forms are currently achieving or outperforming state-of-the-art results on several medical imaging tasks. We aim to make these developments available to the so far unsolved task of accurate correspondence finding-especially with regard to image registration. METHODS: We propose a two-step hybrid approach to make deep learned features accessible to a discrete optimization-based registration method. In a first step, in order to extract expressive binary local descriptors, we train a deep network architecture on a patch-based landmark retrieval problem as auxiliary task. As second step at runtime within a MRF-regularised dense displacement sampling, their binary nature enables highly efficient similarity computations, thus making them an ideal candidate to replace the so far used handcrafted local feature descriptors during the registration process. RESULTS: We evaluate our approach on finding correspondences between highly non-rigidly deformed lung CT scans from different breathing states. Although the CNN-based descriptors excell at an auxiliary learning task for finding keypoint correspondences, self-similarity based descriptors yield more accurate registration results. However, a combination of both approaches turns out to generate the most robust features for registration. CONCLUSION: We present a three-dimensional framework for large lung motion estimation based on the combination of CNN-based and handcrafted descriptors efficiently employed in a discrete registration method. Achieving best results by combining learned and handcrafted features encourages further research in this direction. PMID- 30430362 TI - 1,25-Dihydroxy Vitamin D3 Attenuates the Oxidative Stress-Mediated Inflammation Induced by PM2.5 via the p38/NF-kappaB/NLRP3 Pathway. AB - Vitamin D3 is reported to be involved in the regulation of inflammatory processes. In this study, biomarkers related to oxidative stress and inflammation were investigated to clarify the protective effects and possible mechanism of 1,25-dihydroxy vitamin D3 (1,25-(OH)2D3) on PM2.5-induced inflammatory response. In the in vitro study using human bronchial epithelial (HBE) cells, aqueous extracts of PM2.5 could induce oxidative damage which is characterized by significant increases in production of reactive oxygen species, malonaldehyde concentration, and protein expression of HSPA1A and HO-1. Meanwhile, PM2.5 caused secretion of inflammatory factors (IL-6, IL-8) in the culture medium as well as phosphorylation of p38, nuclear factor-kappa B (NF-kappaB) inhibitor alpha (IkappaBalpha), and NF-kappaB p65 proteins. Increases in NLRP3 expression was also observed in HBE cells after PM2.5 exposure. However, all these biomarkers were remarkably attenuated by a 24-h pretreatment of 1 nM 1,25-(OH)2D3. Furthermore, 1,25-(OH)2D3 also reduced transcriptional activation of NF-kappaB induced by PM2.5 as indicated by a significant decrease in luciferase activity in HBE cells stably transfected with the NF-kappaB response element (RE)-driven luciferase reporter. Taken together, our findings provided novel experimental evidences supporting that vitamin D3 could reduce the predominantly oxidative stress-mediated inflammation induced by PM2.5 via the p38/NF-kappaB/NLRP3 signaling pathway. PMID- 30430364 TI - Inhibitory effect of Carnosol on UVB-induced inflammation via inhibition of STAT3. AB - Ultraviolet B (UVB) irradiation causes sunburn, inflammatory responses, dysregulation of immune function, oxidative stress, DNA damage and photocarcinogenesis on skin. Rosemary (Rosmarinus officinalis L.) has been reported to inhibit inflammation. Carnosol, a major component of Rosemary, has prominent anti-inflammatory effects. However, its protective effect on UVB induced inflammatory skin responses has not yet been reported. Here, we investigated the effectiveness of carnosol on UVB-induced inflammation. We examined the anti-inflammation effect of topical application of carnosol (0.05 ug/cm2) on UVB (540 mJ/cm2, for 3 successive days)-induced skin inflammation in HR1 mice. Topical application of carnosol inhibited UVB-induced erythema, epidermal thickness, inflammatory responses in HR1 mice. Carnosol reduced the level of Immunoglobulin-E and IL-1beta in blood serum of UVB-induced mice. Carnosol also significantly inhibited the UVB-induced expression of inflammatory marker protein (iNOS and COX-2) in back skin of mice. In addition, carnosol treated skin decreased activation of STAT3, a transcriptional factor regulating inflammatory genes. Our study suggested that carnosol has protective effects on skin inflammatory skin damages by UVB. PMID- 30430363 TI - Desiccation Resistance and Micro-Climate Adaptation: Cuticular Hydrocarbon Signatures of Different Argentine Ant Supercolonies Across California. AB - Cuticular hydrocarbons (CHCs), the dominant fraction of the insects' epicuticle and the primary barrier to desiccation, form the basis for a wide range of chemical signaling systems. In eusocial insects, CHCs are key mediators of nestmate recognition, and colony identity appears to be maintained through a uniform CHC profile. In the unicolonial Argentine ant Linepithema humile, an unparalleled invasive expansion has led to vast supercolonies whose nestmates can still recognize each other across thousands of miles. CHC profiles are expected to display considerable variation as they adapt to fundamentally differing environmental conditions across the Argentine ant's expanded range, yet this variation would largely conflict with the vastly extended nestmate recognition based on CHC uniformity. To shed light on these seemingly contradictory selective pressures, we attempt to decipher which CHC classes enable adaptation to such a wide array of environmental conditions and contrast them with the overall CHC profile uniformity postulated to maintain nestmate recognition. n-Alkanes and n alkenes showed the largest adaptability to environmental conditions most closely associated with desiccation, pointing at their function for water-proofing. Trimethyl alkanes, on the other hand, were reduced in environments associated with higher desiccation stress. However, CHC patterns correlated with environmental conditions were largely overriden when taking overall CHC variation across the expanded range of L. humile into account, resulting in conserved colony-specific CHC signatures. This delivers intriguing insights into the hierarchy of CHC functionality integrating both adaptation to a wide array of different climatic conditions and the maintenance of a universally accepted chemical profile. PMID- 30430365 TI - Characterization of circulating tumor cells in breast cancer patients by spiral microfluidics. AB - Circulating tumor cells (CTCs) have important application prospects in the early diagnosis, treatment evaluation, and prognostic prediction of tumors. In this study, we enrolled a total of 65 patients with different stages and molecular subtypes of breast cancer and isolated and enriched for CTCs from peripheral blood using the ClearCell FX1 platform, which is based on a label-free spiral microfluidic method. The ClearCell platform can successfully isolate CTCs from peripheral blood with different detection rates in breast cancer patients. We also compared the difference between the ClearCell and CellSearch platforms for isolating CTCs. To further determine the genetic information of CTCs, we performed single-cell whole-exome sequencing (WES) in three CTCs isolated from one patient. The sequencing results indicated the presence of a few hundreds of single-nucleotide variants (SNVs) in each CTC, with only 16 SNVs being shared by all three CTCs. These shared SNVs may have a crucial impact on the development of breast cancer. Here, we report, for the first time, the complete process and results of performing single-cell WES on CTCs isolated by the ClearCell FX1 platform. PMID- 30430366 TI - Incidence of Diabetes in the Working Population in Spain: Results from the ICARIA Cohort. AB - INTRODUCTION: Our objective was to evaluate the incidence of type 2 diabetes mellitus (T2DM) in a working population in Spain and to assess associations between its development and several risk factors. METHODS: The ICARIA (Ibermutuamur CArdiovascular RIsk Assessment) cohort (n = 627,523) includes ~3% of Spanish workers. This analysis was undertaken in individuals whose glycaemic status during the index period (May 2004-December 2007) was determined to be normal or indicative of prediabetes [fasting plasma glucose (FPG) 100-125 mg/dl] and who had at least one FPG measurement taken 9 months after a first measurement during follow-up (May 2004-June 2014) (n = 380,366). T2DM patients were defined as those with an FPG >= 126 mg/day and those who had already been diagnosed with T2DM or were taking antihyperglycaemic medications. RESULTS: The incidence rate of T2DM was 5.0 [95% confidence interval (CI) 4.9-5.1] cases per 1000 person years. Under multivariate logistic regression analysis, the factor showing the strongest association with the occurrence of T2DM was the baseline FPG level, with the likelihood of T2DM almost doubling for every 5 mg/dl increase in baseline FPG between 100 and < 126 mg/dl. The presence of other cardiometabolic risk factors and being a blue-collar worker were also significantly associated with the occurrence of T2DM. CONCLUSIONS: The incidence of T2DM in the working population was within the range encountered in the general population and prediabetes was found to be the strongest risk factor for the development of diabetes. The workplace is an appropriate and feasible setting for the assessment of easily measurable risk factors, such as the presence of prediabetes and other cardiometabolic factors, to facilitate the early detection of individuals at higher risk of diabetes and the implementation of diabetes prevention programmes. FUNDING: Eli Lilly and Co. PMID- 30430367 TI - Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors. AB - Current unmet needs in haemophilia A patients with inhibitors include the need for intravenous infusion of replacement therapy and the high burden of treatment associated with prophylaxis. Emicizumab is a humanised bispecific monoclonal antibody designed to address these unmet needs and has completed phase III clinical trials in adolescents/adults (HAVEN 1) and paediatric (HAVEN 2) inhibitor populations. In HAVEN 1, there was an 80% bleed reduction across all bleeds, 89% reduction in treated joint bleeds, 92% reduction in treated spontaneous bleeds, and 95% reduction in treated target joint bleeds on emicizumab compared with no prophylaxis. In HAVEN 2, there was a 63% reduction in all bleeds, 94.7% reduction in treated bleeds, 94.7% reduction in treated spontaneous bleeds, 100% reduction in treated joint bleeds, and 100% reduction in treated target joint bleeds on emicizumab prophylaxis when compared with no prophylaxis. For patients on bypassing agent prophylaxis, emicizumab resulted in a 68% reduction in bleeds in HAVEN 1 and a 100% reduction in bleed rates in HAVEN 2. In HAVEN 1, three patients developed thrombotic microangiopathy (TMA) and two developed thrombosis when emicizumab was used together with an activated prothrombin complex concentrate (aPCC) at high or frequent doses. When the combination was avoided in HAVEN 2, no patient developed TMA or thrombosis. In both studies, no anti-emicizumab antibodies developed and the pharmacokinetic profile of emicizumab was similar. Emicizumab use is currently being explored in haemophilia A patients without inhibitors as well as in combination with other haemophilia A replacement therapies. The role of emicizumab in combination with current factor VIII replacement therapies and evolving non-replacement therapies remains to be established. PMID- 30430368 TI - Duvelisib: First Global Approval. AB - Duvelisib (CopiktraTM) is a small-molecule inhibitor of phosphatidylinositol-3 kinase that has been developed as an oral treatment for various cancer indications. In September 2018, duvelisib received its first global approval in the USA for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) after at least two prior therapies. Duvelisib was also granted accelerated approval in the USA for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after at least two prior systemic therapies. Clinical development for various haematological malignancies is ongoing worldwide, as well as preclinical development for solid tumours in the USA. This article summarizes the milestones in the development of duvelisib leading to these first approvals for CLL/SLL and FL. PMID- 30430369 TI - Correction to: Elagolix: First Global Approval. AB - The original article can be found online. PMID- 30430370 TI - Robotic distal pancreatectomy with selective closure of pancreatic duct: surgical outcomes. AB - Pancreatic fistula is the main post-operative complication of distal pancreatectomy associated with other further complications, such as intra abdominal abscesses, wound infection, sepsis, electrolyte imbalance, malabsorption and hemorrhage. Surgeons have tried various techniques to close the stump of the remaining pancreas, but the controversy regarding the impact of stapler closure and suture closure of the pancreatic stump is far from resolved. In this study, we reported our technique and results of robotic assisted distal pancreatectomy with ultrasound identification and consequent selective closure of pancreatic duct. Twenty-one patients underwent consecutive robotic-assisted distal pancreatectomy were included in our study. We describe our technique and analyzed the operative and peri-operative data including mean operative time, intra-operative bleeding, blood transfusions necessity, conversion rate, mortality and morbidity rate, pancreatic fistula rate and grade, time of refeeding and canalization, length of hospital stay and readmission. Median operative time was 260 min. No conversion occurred. Estimated blood loss was 100 mL (range 50-200). No blood transfusions were performed. Mortality rate was 0%. One (5%) patient had a major complication, while 9 (43%) patients had minor complications (grade I). Three (14%) patients developed pancreatic fistula (grade B), while two (10%) patients had a biochemical leak. No late pancreatic fistula and re-operation occurred. The refeeding was started at second day (range 1^-6^) and the median canalization time was 4 days (range 2-7). The median hospital stay was 6 days (range 3-25) with a readmission rate of 0%. Robotic distal pancreatectomy can be considered safe and feasible. Our technique is easily reproducible, with good surgical results. PMID- 30430371 TI - Head-to-nerve analysis of electromechanical impairments of diffuse axonal injury. AB - The aim was to investigate mechanical and functional failure of diffuse axonal injury (DAI) in nerve bundles following frontal head impacts, by finite element simulations. Anatomical changes following traumatic brain injury are simulated at the macroscale by using a 3D head model. Frontal head impacts at speeds of 2.5 7.5 m/s induce mild-to-moderate DAI in the white matter of the brain. Investigation of the changes in induced electromechanical responses at the cellular level is carried out in two scaled nerve bundle models, one with myelinated nerve fibres, the other with unmyelinated nerve fibres. DAI occurrence is simulated by using a real-time fully coupled electromechanical framework, which combines a modulated threshold for spiking activation and independent alteration of the electrical properties for each three-layer fibre in the nerve bundle models. The magnitudes of simulated strains in the white matter of the brain model are used to determine the displacement boundary conditions in elongation simulations using the 3D nerve bundle models. At high impact speed, mechanical failure occurs at lower strain values in large unmyelinated bundles than in myelinated bundles or small unmyelinated bundles; signal propagation continues in large myelinated bundles during and after loading, although there is a large shift in baseline voltage during loading; a linear relationship is observed between the generated plastic strain in the nerve bundle models and the impact speed and nominal strains of the head model. The myelin layer protects the fibre from mechanical damage, preserving its functionalities. PMID- 30430372 TI - Efficacy of vitamin D replacement therapy in restless legs syndrome: a randomized control trial. AB - PURPOSE: Restless legs syndrome is a movement sleep disorder that may be linked to dopaminergic dysfunction and in which vitamin D may play a role. This 12-week randomized, placebo-controlled trial elucidated the efficacy of vitamin D supplements in decreasing restless legs syndrome symptom severity. METHODS: Thirty-five subjects with restless legs syndrome, diagnosed using the International Restless Legs Syndrome Study Group criteria, were enrolled. The subjects were randomized to orally receive either vitamin D (50,000 IU caplets) or a placebo. All medications were administered weekly using a direct observation technique. Clinical assessments, including those for restless legs syndrome severity, were conducted at baseline and the end of the study using the International Restless Legs Syndrome Study Group rating scale. The serum vitamin D levels and bone profiles were measured at baseline and every 4 weeks. The primary endpoint was the change in the restless legs syndrome severity score from baseline to week 12. There were 17 and 18 patients in the vitamin D and placebo groups, respectively. RESULTS: The groups did not differ with respect to age, sex, restless legs syndrome severity, or vitamin D levels. Participants in the vitamin D group showed no significant change in the mean restless legs syndrome severity score compared with the placebo group. CONCLUSIONS: The results suggest that vitamin D supplementation does not improve restless legs syndrome symptoms. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov : NCT02256215 (available from: https://clinicaltrials.gov/ct2/show/NCT02256215 ). PMID- 30430373 TI - Successful upper airway stimulation therapy in an adult Down syndrome patient with severe obstructive sleep apnea. AB - PURPOSE: The aim of this study was to report on the successful application of upper airway stimulation (UAS) therapy in an adult Down syndrome (DS) patient with severe obstructive sleep apnea (OSA) and continuous positive airway pressure (CPAP) intolerance. METHODS: Baseline polysomnography (PSG) in a 23-year-old male OSA patient (body mass index (BMI) 24.4 kg/m2) revealed an apnea/hypopnea index (AHI) of 61.5 events/h and oxygen desaturation index (ODI) of 39.7 events/h. Based on the clinical examination, PSG and drug-induced sleep endoscopy, the patient fulfilled the formal inclusion criteria for UAS therapy: AHI between 15 and 65 events/h, BMI < 32 kg/m2, and no complete concentric collapse at the level of the velopharynx. RESULTS: Implantation of the hypoglossal nerve stimulator in the adult patient with DS resulted in a substantial subjective as well as objective improvement of OSA (63 to 81% decrease in AHI and 77% decrease in ODI), translating into an overall satisfactory outcome. CONCLUSION: Research on the long-term effectiveness of UAS therapy in a larger group of patients with DS is needed. However, based on the available literature and our presented case, respiration-synchronized electrostimulation of the hypoglossal nerve using UAS therapy may have a potential value in well-selected OSA patients with DS who are non-compliant to CPAP therapy. PMID- 30430374 TI - The Varieties of Procrastination: with Different Existential Positions Different Reasons for it. AB - Instead of considering procrastination as a unitary construct we argue that it takes different forms and has multiple explanations and determinants. While it is fair to consider procrastination a cognitive focusing issue, we posit that the motivational sources for this vary depending on where someone can be located with regard to the "existential" developmental positions that have been explicated over many years by Object Relations clinical theorists: the autistic-contiguous, paranoid-schizoid, depressive, and transcendental. These positions generate different understandings of what motivates procrastination and in turn, effects the interventions we offer. We note both clinical and commonplace examples. PMID- 30430375 TI - Sociodemographic and clinical factors associated with acceptance of outpatient parenteral antibiotic therapy in a Singapore tertiary hospital from 2014 to 2017. AB - Outpatient parenteral antibiotic therapy (OPAT) can facilitate early discharge; however, not all offered OPAT can accept. We assessed factors associated with acceptance of OPAT in a large Asian tertiary hospital cohort. From 2014 to 2017, we reviewed all referrals to Singapore General Hospital's (SGH) Outpatient Parenteral Antibiotic Therapy (OPAT) service. We compared differences in sociodemographic and clinical factors between patients who opted for OPAT and those who declined, using chi-square test for univariate analysis and logistic regression for multivariate analysis. From 2014 to 2017, a total of 1406 OPAT referrals were made. Of these, 95.9% (1349/1406) were deemed suitable for OPAT. Amongst those suitable, 90.0% (1213/1349) accepted OPAT treatment. On multivariate analysis, being independently ambulant (aOR = 3.46, 95%CI = 2.21 5.37) was independently associated with higher odds of acceptance for OPAT; whereas, patients with peripheral vascular disease had lower odds of accepting OPAT (aOR = 0.32, 95%CI = 0.16-0.62). Lower socioeconomic status (SES) was closely associated with rejection of OPAT, with markers of both individual-level SES (subsidized ward class) and area-level SES (staying in a public rental flat) being independently associated with lower odds of OPAT preference. Distance and travel time were not associated with OPAT acceptance. The top reasons for rejecting OPAT were lack of caregiver (n = 35), mobility issues (n = 24), financial issues (n = 24), and difficulty caring for the line (n = 21). Comorbidities, mobility, and financial issues are important factors to consider when determining suitability for OPAT. More can be done to improve accessibility of OPAT amongst lower-income patients and those staying in lower-SES areas. PMID- 30430376 TI - Culturing periprosthetic tissue in blood culture bottles results in isolation of additional microorganisms. AB - Despite low sensitivity, culture of periprosthetic tissue (PPT) specimens on agars and in broths has traditionally been used for the detection of causative microorganisms in patients suspected for prosthetic joint infection (PJI). The aim of this study was to evaluate the added diagnostic value of culturing PPT in blood culture bottles (BCB) over the conventional combination of standard agar and broth alone. This prospective cohort study was conducted over a 12-month period and included consecutive patients undergoing revision arthroplasty. Overall, 113 episodes from 90 subjects were studied; 45 subjects (50.0%) met the Infectious Diseases Society of America (IDSA) criteria for PJI, of whom the majority (75.6%) had an acute infection. Sensitivity and specificity of culture were assessed using IDSA criteria for PJI as gold standard. Although the increase in sensitivity from 84.44 (CI 70.54; 93.51) to 93.33% (81.73; 98.60) was not significant, added diagnostic value of culturing PPT in BCBs was demonstrated by the significantly higher number of detected pathogens in culture sets with BCBs compared to culture without BCBs (61 pathogens in conventional set versus 89 when BCBs were included for 57 PJI episodes, P = <0.0001). In 17 (29.8%) episodes, microorganisms were cultured from BCBs only, and in 9 (52.9%) of these episodes, virulent pathogens were found. This study demonstrates that PPT culture in BCBs leads to isolation of additional microorganisms, both virulent and low-virulent, which were not cultured with use of agars and broths alone. Isolation of additional causative microorganisms has serious consequences for the treatment strategy in PJI. PMID- 30430377 TI - Left-sided infective endocarditis caused by Streptococcus agalactiae: rare and serious. AB - A comparative study of the behaviour of left-sided infective endocarditis (left sided IE) due to Streptococcus agalactiae (GBS) with left-sided IE caused by Staphylococcus aureus (SA). A prospective, multicentre cohort study in eight public hospitals in Spain, from January 1984 to December 2015; comparative analysis and factors associated with mortality. In total, there were 1754 episodes of left-sided IE; 41 (2.3%) caused by GBS vs. 344 (19.6%) due to SA, definitive IE 39 vs. 324 cases, males, 25 vs. 213, respectively. There were no differences in age or comorbidity, and healthcare-associated acquirement was 10% vs. 43%, p 0.001. Transthoracic echocardiogram (TTE) was performed in 95% vs. 96.8% and a transesophageal echocardiogram (TEE) in 61% vs. 56%. Vegetations were detected in 80% and measured > 1 cm in a similar proportion. It affected native valves in 85.4% vs. 82.6% and late prosthetic valve in 14.6% vs. 9.6%. The course was acute in both groups. There were more skin manifestations in SA left-sided IE, 7.3% vs. 32%, p 0.001. Both groups had similar complications, but in SA, there was more renal failure, 24% vs. 45%, p 0.010. Surgical risk and operated patients were similar. Mortality was proportionally higher in the SA group, without significance 29% vs. 43% (150), p 0.09. Heart failure, septic shock and neurological deterioration conditioned mortality: HR 1.96, 1.69 and 1.37 (CI 95% 1.40-2.73; 1.19-2.39 and 0.99-1.88 respectively) and to a lesser degree SA as aetiology agent and age. Left-sided IE caused by GBS is similar in severity to left-sided IE caused by SA. PMID- 30430378 TI - Muller Cells Derived from Adult Chicken and Mouse Retina Neurospheres Acquire the Dopaminergic Phenotype. AB - Neurospheres prepared from multipotent progenitors in the retina obtained from postnatal mice differentiate into neurons and Muller glia (De Melo Reis et al., in Cell Mol Neurobiol 31:835-846, 2011). Here, we investigated whether neurospheres prepared from adult chickens (ciliary marginal zone, CMZ) or (ciliary body) retina could also lead to differentiated neurons and glia. Neurospheres were prepared from post-hatched chickens or from adult mice after 7 days in the presence of mitogenic factors (FGFb, insulin, and EGF), generating neurons and glial cells. In addition, Muller (2M6 or glutamine synthetase positive cells) derived from post-hatch chicken CMZ neurospheres displayed the dopaminergic phenotype. Furthermore, we observed that Muller cells derived from adult chickens and mice retina neurospheres released significant amounts of dopamine as well as of its metabolites. Taken together, our data lead us to conclude that as for embryonic (chick) or newborn (mouse), the dopaminergic phenotype is a default condition of Muller glial cells obtained from neurospheres prepared from mature retina. Our data raise the possibility that Muller cells from differentiated tissue could be used to ameliorate neurodegenerative diseases involving dopaminergic dysfunction as in Parkinson's disease as shown previously (Stutz et al., in J Neurochem 128:829-840, 2014). PMID- 30430379 TI - Diversity and mycotoxin production by Fusarium temperatum and Fusarium subglutinans as causal agents of pre-harvest Fusarium maize ear rot in Poland. AB - Maize ear rot is a common disease found worldwide, caused by several toxigenic Fusarium species. Maize ears and kernels infected by Fusarium subglutinans contained significant amounts of beauvericin, fusaproliferin, moniliformin, and enniatins. In 2011, F. subglutinans sensu lato has been divided into two species: Fusarium temperatum sp. nov. and F. subglutinans sensu stricto, showing different phylogeny and beauvericin production within the populations of maize pathogens in Belgium. Isolates of the new species-F. temperatum-were also identified and characterized in Spain, Argentina, Poland, France, and China as one of the most important pathogens of maize. Moreover, F. temperatum was proved to be pathogenic to maize seedlings and stalks. We identified Fusarium isolates obtained from diseased maize ears collected between 2013 and 2016 in Poland (321 isolates). Based on morphological analyses, six Fusarium species were identified. Molecular identification performed on the set of selected isolates (42 isolates) revealed 34 isolates to be F. temperatum and only five to be F. subglutinans. Interestingly, the phylogenetic analysis showed that the population of F. temperatum infecting maize in Poland remained quite uniform for over 30 years with only a few exceptions. For the first time, a single isolate of Fusarium ramigenum was detected from the area of Poland. Significant amounts of BEA were found in Fusarium-damaged kernels. The same kernel samples contained also enniatins A1, A, B1, and B. The results clearly demonstrate the occurrence of F. temperatum as maize pathogen in Poland for over the last three decades. PMID- 30430380 TI - Expansion-Prone Hematoma: Defining a Population at High Risk of Hematoma Growth and Poor Outcome. AB - BACKGROUND: Noncontrast computed tomography (CT) markers are increasingly used for predicting hematoma expansion. The aim of our study was to investigate the predictive value of expansion-prone hematoma in predicting hematoma expansion and outcome in patients with intracerebral hemorrhage (ICH). METHODS: Between July 2011 and January 2017, ICH patients who underwent baseline CT scan within 6 h of symptoms onset and follow-up CT scan were recruited into the study. Expansion prone hematoma was defined as the presence of one or more of the following imaging markers: blend sign, black hole sign, or island sign. The diagnostic performance of blend sign, black hole sign, island sign, and expansion-prone hematoma in predicting hematoma expansion was assessed. Predictors of hematoma growth and poor outcome were analyzed using multivariable logistical regression analysis. RESULTS: A total of 282 patients were included in our final analysis. Of 88 patients with early hematoma growth, 69 (78.4%) had expansion-prone hematoma. Expansion-prone hematoma had a higher sensitivity and accuracy for predicting hematoma expansion and poor outcome when compared with any single imaging marker. After adjustment for potential confounders, expansion-prone hematoma independently predicted hematoma expansion (OR 28.33; 95% CI 12.95 61.98) and poor outcome (OR 5.67; 95% CI 2.82-11.40) in multivariable logistic model. CONCLUSION: Expansion-prone hematoma seems to be a better predictor than any single noncontrast CT marker for predicting hematoma expansion and poor outcome. Considering the high risk of hematoma expansion in these patients, expansion-prone hematoma may be a potential therapeutic target for anti-expansion treatment in future clinical studies. PMID- 30430381 TI - The Role of Glycerol-Containing Drugs in Cerebral Microdialysis: A Retrospective Study on the Effects of Intravenously Administered Glycerol. AB - BACKGROUND: Cerebral microdialysis (CMD) is a valuable tool for monitoring compounds in the cerebral extracellular fluid (ECF). Glycerol is one such compound which is regarded as a marker of cell membrane decomposition. Notably, in some acutely brain-injured patients, CMD-glycerol levels rise without any other apparent indication of cerebral deterioration. The aim of this study was to investigate whether this could be due to an association between CMD-glycerol levels and the administration of glycerol-containing drugs. METHODS: Microdialysis data were retrospectively retrieved from the hospital's intensive care unit patient data management system (PDMS). All patients who were monitored with CMD for >= 96 h were included. Administered drug doses were retrieved from the PDMS and converted to exact doses of glycerol. Cross-correlation analyses were performed between the free, metabolized as well as total administered dose of glycerol and the detrended and differenced CMD-glycerol concentration. These analyses were repeated for two sets of subgroups based upon the individual catheter's graphical trend and its location in relation to the lesion. RESULTS: There was no significant correlation between the differenced CMD-glycerol levels and drug-administered glycerol. Furthermore, there was no significant correlation between CMD-glycerol and catheter location or graphical trend. However, if the CMD-glycerol levels were detrended, significant but clinically non-relevant correlations were identified (maximum correlation coefficient of 0.1 (0.04-0.15, 95% CI) at a lag of 7 h using the total administered dose of glycerol). CONCLUSIONS: Glycerol-containing drugs routinely administered intravenously in the clinical setting appear to have a minimal and clinically insignificant effect on levels of glycerol in the cerebral ECF. PMID- 30430382 TI - Tailored One Anastomosis Gastric Bypass: 3-Year Outcomes of 94 Patients. AB - BACKGROUND: One anastomosis gastric bypass (OAGB) claims its place among bariatric operations, proving itself a safe and effective procedure. METHODS: This is a retrospective analysis of prospectively collected data regarding 94 patients who underwent surgery in a single surgical unit. Tailoring of the biliopancreatic limb length decided upon preoperative BMI was applied. Patients' excess weight loss and resolution of comorbidities were evaluated. Data on patients' nutritional status is also presented. RESULTS: Mean BMI reduction at 36 months postoperatively was 21.7 +/- 6.3 kg/m2. Mean excess weight loss (%EWL) was 83.6%, 91.8%, and 92.5% at 12, 24, and 36 months postoperatively, respectively. When controlling for preoperative BMI, a 36-month %EWL of 89.1% for the 2-m subgroup, a 95.3% for the 2.5-m subgroup, and a 104.7% for the 3-m subgroup were found. Operation's success, defined as %EWL greater than 50%, was 97.9% 36 months postoperatively. All patients suffering from hypertension, diabetes, and dyslipidemia achieved full remission. Furthermore, the percentage of patients with obstructive sleep apnea and gastroesophageal reflux disease, achieving full remission was 91.7% and 86.7%, respectively. An incidence of 5.3% new onset regurgitation was noted. Iron deficiency presented in 26 (27.7%) patients postoperatively, vitamin B12 deficiency in 13 (13.8%), folic acid deficiency in 18 (19.1%), and mild hypoalbuminemia in 7 (7.4%). Major early postoperative complications (Clavien-Dindo grade >= 3) were reported in 1.7% of our patients. One (1.1%) patient developed marginal ulcer and two (2.2) patients had late dumping. CONCLUSIONS: OAGB is a safe and efficient technique; however, careful selection of patients and postoperative surveillance with respect to weight regain and nutritional deficiencies are mandatory for optimal results. PMID- 30430384 TI - Evaluation of Italian radiotherapy research from 1985 to 2005: preliminary analysis. AB - AIM: The difficulty in conducting meaningful clinical research is a multifactorial issue, involving political, financial and cultural problems, which can lead to unexpected negative long-term consequences, in terms of knowledge advancement and impact on patient care. The aims of the present review were to evaluate the publications of Italian radiotherapy (RT) groups during a 20-year period and to verify whether research is still appealing to young radiation oncologists (ROs) in Italy. METHODS: PubMed database was searched for English language articles published by Italian groups from January 1985 to December 2005. Analyzed variables were: publication/year, kind of study, geographical area and age of the first author. RESULTS: The systematic review identified 3291 articles: 1207 papers fulfilled the inclusion criteria. The number of Italian published papers increased during the examined period. Retrospective analyses, prospective phase I-II trials and literature reviews were 44, 20 and 14.5% of all published manuscripts, respectively. Randomized trials showed a mild increase from 2000 to 2005, but their absolute number remained low respect to other types of studies (4%). Northern Italy produced the very most of Italian research papers (58.7%). The age of the first/second author was evaluated on 716 papers: In more than 50% of cases, the first author was younger than 40. CONCLUSION: Despite a general gradual improvement, RT clinical research suffers in Italy (as elsewhere) from insufficient funding, with a negative impact on evidence production. It is worth noting that clinical research is still appealing and accessible to junior Italian RO. PMID- 30430383 TI - Exploring the Patient-Reported Impact of the Pharmacist on Pre-bariatric Surgical Assessment. AB - BACKGROUND: The effects of surgical procedures and the need for life-long nutrient supplementation may impact on medication regimes, requiring changes to dosage and formulation of medicines, which can be difficult for patients following surgery. Our pre-surgical assessment pathway involves a pharmacist with specialist knowledge of bariatric surgery, to help prepare patients for these changes. OBJECTIVE: To explore the patient-reported impact of the specialist bariatric pharmacist in pre-surgical assessment. SETTING: National Health Service Hospital, United Kingdom. METHODS: A two phased, retrospective study design using participants recruited from pre-surgical clinic lists. The first phase consisted of confidential, face to face semi-structured interviews. A constant comparative analytic framework informed the construction of the second phase, which consisted of a confidential survey to test the generalizability of the findings with a larger cohort of patients. RESULTS: A total of 40 participants (12 interviews, 28 surveys) were recruited to the study. The majority of participants were female (n = 33), mean age 50 years, mean pre-surgical weight 124 kg (n = 38). The most common comorbidity was type 2 diabetes. Participants on medication had at least one comorbidity, with the majority of conditions improved or eliminated after surgery. CONCLUSIONS: The pre-surgical consultation with the pharmacist was highly valued by the participants, providing information and support which helped prepare for medication changes after bariatric surgery. Many felt that a post surgical appointment with the pharmacist would provide support and improve compliance with vitamins and medications. Future research into the role of pharmacists in the bariatric multi-disciplinary team and patient support are recommended. PMID- 30430385 TI - Whole-body magnetic resonance imaging (WB-MRI) in oncology: recommendations and key uses. AB - The past decade has witnessed a growing role and increasing use of whole-body magnetic resonance imaging (WB-MRI). Driving these successes are developments in both hardware and software that have reduced overall examination times and significantly improved MR imaging quality. In addition, radiologists and clinicians have continued to find promising new applications of this innovative imaging technique that brings together morphologic and functional characterization of tissues. In oncology, the role of WB-MRI has expanded to the point of being recommended in international guidelines for the assessment of several cancer histotypes (multiple myeloma, melanoma, prostate cancer) and cancer-prone syndromes (Li-Fraumeni and hereditary paraganglioma-pheochromocytoma syndromes). The literature shows growing use of WB-MRI for the staging and follow up of other cancer histotypes and cancer-related syndromes (including breast cancer, lymphoma, neurofibromatosis, and von Hippel-Lindau syndromes). The main aim of this review is to examine the current scientific evidence for the use of WB-MRI in oncology. PMID- 30430386 TI - The Tree of Life. PMID- 30430389 TI - Integrative Analysis of CD133 mRNA in Human Cancers Based on Data Mining. AB - CD133 is a wildly used cancer stem cell marker. The purpose of this study was to explore the significance of CD133 mRNA in human cancers mainly based on The Cancer Genome Atlas (TCGA) database. Bioinformatic analyses were done by using public repositories, including BioGPS, SAGE Genie tools, Oncomine analysis, Regulome Explorer, COSMIC analysis, and Kaplan-Meier Plotter. The main findings in this study were: 1) High CD133 mRNA was correlated with a benign survival rate of gastric cancer and lung cancer; 2) Transmembrane protein 125 (TMEM125) in bladder urothelial carcinoma and intercellular adhesion molecule 2 (ICAM2) in ovarian serous cystadenocarcinoma were closely related to CD133 expression; 3) The location and the topological structure of CD133 protein were not determined by its transcript variant in cancer cells; 4) CD38 and CD200 may be used as novel surface markers for solid cancers. However, the mechanism of these findings is not completely clear, further studies have to be performed in the future. PMID- 30430390 TI - Parental Cognitions and Motivation to Engage in Psychological Interventions: A Systematic Review. AB - This paper reviews the available research on the predictors of parental engagement in preventive and therapeutic psychological interventions that target mental health problems in children. Based on previous literature, seven predictors concerning parental motivation to engage are considered: perceived child problems, perceived parenting, attributions of problems, self-efficacy, expectations about treatment, perceived obstacles and global motivation to engage. PRISMA guidelines for systematic review were used to conduct the literature search. Thirty-seven studies that examined prospective relations between parental cognitions evaluated at the beginning of the intervention and parental engagement during the intervention were included. Most studies focused on the parents' perception of the child's problems and of parenting, with fewer studies examining the role of the other parental cognitions. The results suggest that the psychological dimensions proposed in motivational models may play an important role in understanding parental engagement in preventive and therapeutic psychological interventions. PMID- 30430391 TI - Investigating the impact of dynamic and static secondary tasks on task-switch cost. AB - Many researchers have employed secondary tasks, which have to be performed in parallel with a primary task requirement, to examine how successful task selection is accomplished in the context of task switching. The influence of such a secondary task on the observed switch cost (i.e., the cost arising when the currently relevant task differs from the task performed most recently) is seen as indicative that cognitive processes such as self-instruction are involved. Most secondary tasks chosen so far have required the repeated utterance of a word or syllable or a rhythmic movement of the foot. In the present study, we manipulated the dynamics of the to-be-performed secondary task (i.e., a repeated utterance or movement, or a static task that involved similar muscles-holding a spattle in the mouth or pressing keys). Additionally, we tested for modality-specific influences by asking participants to perform a dynamic or nondynamic (i.e., static) secondary task with two effector systems, namely oral and manual. Overall, our secondary tasks led to a reduced (rather than an increased) switch cost, as compared to a control condition without any secondary task. This reduction in switch cost was dependent on the secondary-task dynamics but independent of the effectors involved, showing larger switch-cost reductions for dynamic secondary tasks. To explain this finding, we suggest that performing secondary tasks interferes with the formation of episodic-memory traces that would lead to retrieval benefits in the case of a task repetition, so that our reduced task switch costs actually represent reduced repetition benefits. PMID- 30430388 TI - LC-ESI-IT-MS/MS and MALDI-TOF Approach: Identification of Natural Polymers from Rhizophora mangle Barks and Determination of Their Analgesic and Anti inflammatory Properties. AB - We recognize the chemical composition of the acetonic extract of Rhizophora mangle barks (AERM) using mass spectrometry analysis [liquid chromatography (LC) ESI-IT-MS/MS and matrix-assisted laser desorption/ionization-time of flight-MS (MALDI-TOF)]. Analgesic activity was evaluated by formalin and tail-flick experimental assays. Anti-inflammatory activity was performed by paw edema test induced by carrageenan and 48/80 compounds. The first series of experiments involved [LC]-FIA-IT-MS/MS with 11 separated catechins derivatives until degree of polymerization 3 (DP3). The spectra obtained by MALDI-TOF analysis of the AERM presented two homologous series: one based on polymers of m/z 288 Da increments (up to DP12) and another series based on polymers of m/z [288 + 162] Da increments (up to DP11). In addition to these series of flavan-3-ol, each DP had a subset of masses with a variation of - 16 Da (homologous series of afzelechins m/z 873-3465 Da) and + 16 Da (homologous series of gallocatechins-m/z 905-3497 Da). A similar pattern with homologous series of gallocatechins and afzelechins could also be observed for a fifth and a sixth monohexoside series: glucogallocatechins (m/z 779-3371) and glucoafzelechins (m/z 747-3339). The intraperitoneal administration of different doses of AERM (50, 150 and 300 ug mL 1) have a morphine-like effect and intense anti-inflammatory activity. PMID- 30430392 TI - LGBT-Specific Education in General Psychiatry Residency Programs: a Survey of Program Directors. AB - OBJECTIVE: Lesbian, gay, bisexual, transgender (LGBT) and other sexual minority individuals are at higher risk than non-LGBT individuals for multiple psychiatric conditions and suicide. However, little is known regarding LGBT-specific training among psychiatric residents. The authors sought to characterize LGBT-specific training among adult psychiatry residency programs. METHODS: An anonymous, cross sectional survey was electronically distributed to U.S.-based adult psychiatry program directors between February and April 2018. Survey topics included program demographics, characteristics of LGBT-specific training, perceived barriers to implementation, and anticipated needs. RESULTS: Seventy-two program directors (30.8%) provided complete survey responses. Over half (55.6%) of these programs had <= 5 h of LGBT-specific training ("lower-hour programs"). Lower- and higher hour (> 5 h of LGBT-specific education) programs were similar on measured demographic variables, but lower-hour programs covered fewer LGBT-specific topics and program directors were more likely to report lack of interested or topic expert faculty as a barrier to enhancing LGBT-specific training. CONCLUSIONS: Results of this survey suggest a need for the development and implementation of LGBT-specific educational curricula for use in U.S.-based adult psychiatry programs. In addition, future research may explore effective ways for programs to recruit, retain, and support teaching faculty with LGBT-specific expertise. PMID- 30430395 TI - Do locally advanced and metastatic human epithelial cancers evolve in 'placental/decidual-like microenvironments'? AB - Successful tumor microenvironments eventually kill the host. They are not only meant to nourish and protect tumor development, but to give them the right "soil" for perpetual malignant properties such as tissue invasion and metastasis. This can only be achieved if cancers avoid immune vigilance. A similar situation occurs in mammalian placental pregnancy but feto-maternal tolerance is required for a correct physiological process only until birth. Once a cancer microenvironment has acquired the genetic and epigenetic "placental immune editing switches" (PIES) phenotype, it seems likely that it will keep them "available", whenever needed, for the rest of its development, because it gives cellular clones a competitive advantage to pass unnoticed by the host's immune system. This allows primary cancers and their metastasis to continue growing in spite of new and changing antigenic landscapes. PMID- 30430393 TI - Effects of Cannabidiol on Diabetes Outcomes and Chronic Cerebral Hypoperfusion Comorbidities in Middle-Aged Rats. AB - Diabetes and aging are risk factors for cognitive impairments after chronic cerebral hypoperfusion (CCH). Cannabidiol (CBD) is a phytocannabinoid present in the Cannabis sativa plant. It has beneficial effects on both cerebral ischemic diseases and diabetes. We have recently reported that diabetes interacted synergistically with aging to increase neuroinflammation and memory deficits in rats subjected to CCH. The present study investigated whether CBD would alleviate cognitive decline and affect markers of inflammation and neuroplasticity in the hippocampus in middle-aged diabetic rats submitted to CCH. Diabetes was induced in middle-aged rats (14 months old) by intravenous streptozotocin (SZT) administration. Thirty days later, the diabetic animals were subjected to sham or CCH surgeries and treated with CBD (10 mg/kg, once a day) during 30 days. Diabetes exacerbated cognitive deficits induced by CCH in middle-aged rats. Repeated CBD treatment decreased body weight in both sham- and CCH-operated animals. Cannabidiol improved memory performance and reduced hippocampal levels of inflammation markers (inducible nitric oxide synthase, ionized calcium-binding adapter molecule 1, glial fibrillary acidic protein, and arginase 1). Cannabidiol attenuated the decrease in hippocampal levels of brain-derived neurotrophic factor induced by CCH in diabetic animals, but it did not affect the levels of neuroplasticity markers (growth-associated protein-43 and synaptophysin) in middle-aged diabetic rats. These results suggest that the neuroprotective effects of CBD in middle-aged diabetic rats subjected to CCH are related to a reduction in neuroinflammation. However, they seemed to occur independently of hippocampal neuroplasticity changes. PMID- 30430394 TI - Prognostic factors in neoadjuvant treatment followed by surgery in stage IIIA-N2 non-small cell lung cancer: a multi-institutional study by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society). AB - PURPOSE: To evaluate the prognostic factors associated with survival in patients treated with neoadjuvant treatment [chemoradiotherapy (CRT) or chemotherapy] followed by surgery (CRTS) in patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). METHODS: A retrospective study was conducted of 118 patients diagnosed with stage T1-T3N2M0 NSCLC and treated with CRTS at 14 hospitals in Spain between January 2005 and December 2014. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox regression analysis was performed. RESULTS: Surgery consisted of lobectomy (74.5% of cases), pneumectomy (17.8%), or bilobectomy (7.6%). Neoadjuvant treatment was CRT in 62 patients (52.5%) and chemotherapy alone in 56 patients (47.5%). Median follow-up was 42.5 months (5 128 months). 5-year OS and PFS were 51.1% and 49.4%, respectively. The following variables were independently associated with worse OS and PFS: pneumonectomy (vs. lobectomy); advanced pathologic T stage (pT3 vs. pT0-pT2); and presence of persistent N2 disease (vs. ypN0-1) in the surgical specimen. CONCLUSIONS: In this sample of patients with stage IIIA-N2 NSCLC treated with CRTS, 5-year survival (both OS and PFS) was approximately 50%. After CRTS, the patients with the best prognosis were those whose primary tumour and/or mediastinal nodal metastases were downstaged after induction therapy and those who underwent lobectomy. These findings provide further support for neoadjuvant therapy followed by surgery in selected patients. PMID- 30430396 TI - Opioidergic Agents as Antidepressants: Rationale and Promise. AB - Research concerning psychiatric issues relating to opioid drugs currently focuses primarily on their role in reinforcing addictive behaviors, given the recent proliferation of lethal abuse of illicit opiates in the United States and around the world. In contrast, this article will review the mechanism of action of opioids in affective disorders and the available evidence and potential for their use, especially in the treatment of resistant major depression. Buprenorphine is the opioid derivative of special interest; we review this and other opioid derivatives, highlighting the growing role of opioids in treating depressive illnesses and other related psychopathologies. PMID- 30430397 TI - Molecular mechanisms of apoptosis and autophagy elicited by combined treatment with oridonin and cetuximab in laryngeal squamous cell carcinoma. AB - Combined oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, and cetuximab (Cet), an anti-EGFR monoclonal antibody, have been reported to exert synergistic anti-tumor effects against laryngeal squamous cell carcinoma (LSCC) both in vitro and in vivo by our group. In the present study, we further found that ORI/Cet treatment not only resulted in apoptosis but also induced autophagy. AMPK/mTOR signaling pathway was found to be involved in the activation of autophagy in ORI/Cet-treated LSCC cells, which is independent of p53 status. Additionally, chromatin immunoprecipitation (ChIP) assay showed that ORI/Cet significantly increased the binding NF-kappaB family member p65 with the promotor of BECN 1, and p65-mediated up-regulation of BECN 1 caused by ORI/Cet is coupled to increased autophagy. On the other hand, we demonstrated that either Beclin 1 SiRNA or autophagy inhibitors could increase ORI/Cet induced apoptosis, indicating that autophagy induced by combination of the two agents plays a cytoprotective role. Interestingly, 48 h after the combined treatment, autophagy began to decrease but apoptosis was significantly elevated. Our findings suggest that autophagy might be strongly associated with the antitumor efficacy of ORI/Cet, which may be beneficial to the clinical application of ORI/Cet in LSCC treatment. PMID- 30430398 TI - Daptomycin-associated myopathy induced by concomitant administration of mirabegron. PMID- 30430399 TI - Vaccine strain Listeria monocytogenes bacteremia occurring 31 months after immunization. AB - BACKGROUND: Listeria monocytogenes is a food-borne, facultative intracellular bacterium that causes severe diseases such as sepsis and meningoencephalitis in immunocompromised hosts. Because it stimulates robust T-lymphocyte-mediated responses, attenuated L. monocytogenes are candidate vaccine vectors for tumor immunotherapy. CASE: We report a case of bacteremia caused by vaccine strain L. monocytogenes (Axalimogene filolisbac) occurring 31 months after immunization against human papilloma virus (HPV) associated cervical cancer. CONCLUSION: Receipt of a L. monocytogenes-based vaccine is a novel risk factor for delayed L. monocytogenes bacteremia. PMID- 30430401 TI - The Reliability and Validity of the Religious Health Fatalism Scale in Turkish Language. AB - This study aimed to conduct the reliability and validity study of the Religious Health Fatalism Scale in Turkish language. The study carried out in methodological type and consisted of 500 individuals. The basic component analysis was applied to the 17-item scale, and it was decided that the Turkish version of the scale would have one sub-dimension. Factor loads were over 0.30 for all items, and the explained variance of the scale was found 42.70%. The Cronbach's alpha coefficient was determined to be 0.91. Consequently, it was determined that the Religious Health Fatalism Scale had one dimension in the Turkish language, and it was a highly valid and reliable tool. It was determined that the elderly, females, housewives, illiterate, people with no health insurance, married individuals, those with low income, and people with chronic diseases had higher health fatalism scores. PMID- 30430400 TI - In silico studies, synthesis and anticancer activity of novel diphenyl ether based pyridine derivatives. AB - A series of novel 2-amino-4-(3-hydroxy-4-phenoxyphenyl)-6-(4-substituted phenyl) nicotinonitriles were synthesized and evaluated against HepG2, A-549 and Vero cell lines. Compounds 3b (IC50 16.74 +/- 0.45 uM) and 3p (IC50 10.57 +/- 0.54 uM) were found to be the most active compounds against A-549 cell line among the evaluated compounds. Further 3b- and 3p-induced apoptosis was characterized by AO/EB (acridine orange/ethidium bromide) nuclear staining method and also by DNA fragmentation study. A decrease in cell viability and initiation of apoptosis was clearly evident through the morphological changes in the A-549 cells treated with 3b and 3p when stained with this method. Fragmentation of DNA into nucleosomes was observed which further confirmed the cell apoptosis in cells treated with compound 3b. Flow cytometry studies confirmed the cell cycle arrest at G2/M phase in A549 cells treated with compound 3b. Further in silico studies performed supported the in vitro anticancer activity of these compounds as depicted by dock score and binding energy values. PMID- 30430402 TI - Hormonal control of vas deferens fluid volume and aquaporin expression in rats. AB - Precise regulation of vas deferens fluid volume which is important for sperm survival might be influenced by testosterone. In order to investigate changes in vas deferens fluid volume and aquoporins (AQP) isoforms expression under testosterone influence, orchidectomized Sprague-Dawley rats were given 125 and 250 ug/kg/day testosterone with or without flutamide, an androgen receptor blocker or finasteride, a 5alpha-reductase inhibitor for seven consecutive days. Following treatment completion, vas deferens was perfused and changes in the fluid secretion rate and osmolality were determined in the presence of acetazolamide. Rats were then sacrificed and vas deferens was harvested for histology, tissue expression and distribution analyses of AQP-1, AQP-2, AQP-5, AQP-7 and AQP-9 proteins by Western blotting and immunohistochemistry, respectively. Our findings indicate that testosterone causes vas deferens fluid secretion rate to increase, which was antagonized by acetazolamide. Fluid osmolality increased following testosterone treatment and further increased when acetazolamide was given. Co-administration of flutamide or finasteride with testosterone causing both fluid secretion rate and osmolality to decrease. Histology revealed increased size of vas deferens lumen with increased thickness of vas deferens stroma. Expression of AQP-1, AQP-2 and AQP-9 were detected in vas deferens but not AQP-5 and AQP-7, and the levels of these proteins were increased by testosterone treatment mainly at the apical membrane of vas deferens epithelium. In conclusion, increased in vas deferens fluid secretion rate under testosterone influence mediated via the up-regulation of AQP-1, 2 and 9 might be important for vas deferens fluid homeostasis in order to ensure normal male fertility. PMID- 30430403 TI - The Care and Learn Model: a Practice and Research Model for Improving Healthcare Quality and Outcomes. AB - The Agency for Healthcare Research and Quality conducted internal work to formulate a model that could be used to analyze the Agency's research portfolio, identify gaps, develop and prioritize its research agenda, and evaluate its performance. Existing models described the structure and components of the healthcare system. Instead, we produced a model of two functions: caring and learning. Central to this model is the commitment to and participation of people patients, communities, and health professionals-and the organization of systems to respond to people's problems using evidence. As a product of caring, the system produces evidence that is then used to adapt and continuously improve this response, closely integrating caring and learning. The Agency and the health services research and improvement communities can use this Care and Learn Model to frame an evidence-based understanding of vexing clinical, healthcare delivery, and population health problems and to identify targets for investment, innovation, and investigation. PMID- 30430404 TI - Inequalities in Young Adult Health Insurance Coverage Post-federal Health Reform. AB - BACKGROUND: Uninsurance for young adults (YAs) was greatly reduced by the Affordable Care Act (ACA). However, reforms may not be equally beneficial for all YAs and certain policies may exacerbate, rather than resolve, pre-existing disparities. OBJECTIVE: To investigate inequalities in YAs' insurance coverage pre- (2000-2010) and post-federal health reforms (dependent coverage expansion, 2010-2013, and Medicaid/Marketplace expansions, 2014-2016), among a nationally representative sample. DESIGN: A difference-in-differences estimator (controlling for sociodemographics) was used to determine the effects of the ACA for young adults (ages 19-25) compared to adolescents (ages 13-18) and older YA (ages 26 30) counterparts; triple-difference estimators quantified differential policy effects by sociodemographics. PARTICIPANTS: Three hundred eighty-seven thousand six hundred thirty-five participants in the 2000-2016 National Health Interview Survey. MAIN MEASURES: Respondents reported their health insurance coverage types during the last 12 months, reasons uninsured, and detailed sociodemographics. KEY RESULTS: An adjusted difference-in-differences estimator quantified a 12.3 percentage point increase (p < 0.0001) in full-year coverage post-ACA for YAs compared to older counterparts, driven by increases in employer-sponsored private insurance while younger and older youth saw larger gains in Medicaid coverage. Triple-difference estimators identified subgroups experiencing less beneficial dependent coverage expansion effects, including females, lower socioeconomic status, non-citizens, non-English speakers, and several racial/ethnic minority groups. Later ACA reforms (Marketplace/Medicaid expansions) mitigated many of these widening disparities. CONCLUSION: While the ACA significantly impacted YA insurance coverage, these gains were not of equal magnitude for all YAs and disparities remain. As such, more work needs to be done to ensure optimal and equitable access to high-quality, affordable insurance for all YAs. PMID- 30430405 TI - The challenge and potential of photosynthesis: unique considerations for metabolic flux measurements in photosynthetic microorganisms. AB - Photosynthetic microorganisms have the potential for sustainable production of chemical feedstocks and products but have had limited success due to a lack of tools and deeper understanding of metabolic pathway regulation. The application of instationary metabolic flux analysis (INST-MFA) to photosynthetic microorganisms has allowed researchers to quantify fluxes and identify bottlenecks and metabolic inefficiencies to improve strain performance or gain insight into cellular physiology. Additionally, flux measurements can also highlight deviations between measured and predicted fluxes, revealing weaknesses in metabolic models and highlighting areas where a lack of understanding still exists. In this review, we outline the experimental steps necessary to successfully perform photosynthetic flux experiments and analysis. We also discuss the challenges unique to photosynthetic microorganisms and how to account for them, including: light supply, quenching, concentration, extraction, analysis, and flux calculation. We hope that this will enable a larger number of researchers to successfully apply isotope assisted metabolic flux analysis (13C MFA) to their favorite photosynthetic organism. PMID- 30430407 TI - Societal causes of, and responses to, ocean acidification. AB - Major climate and ecological changes affect the world's oceans leading to a number of responses including increasing water temperatures, changing weather patterns, shrinking ice-sheets, temperature-driven shifts in marine species ranges, biodiversity loss and bleaching of coral reefs. In addition, ocean pH is falling, a process known as ocean acidification (OA). The root cause of OA lies in human policies and behaviours driving society's dependence on fossil fuels, resulting in elevated CO2 concentrations in the atmosphere. In this review, we detail the state of knowledge of the causes of, and potential responses to, OA with particular focus on Swedish coastal seas. We also discuss present knowledge gaps and implementation needs. PMID- 30430408 TI - Seasonal fire management by traditional cattle ranchers prevents the spread of wildfire in the Brazilian Cerrado. AB - The use of fire by cattle ranchers is a major source of conflict between conservationists and local communities in tropical savannas. We evaluate the role of traditional pastoral management in wildfire prevention in two protected areas within the Brazilian savanna. Fine-grain field data from transect walks and interviews were combined with geospatial data at landscape scale to compare fire regimes in community-managed areas with those in government-managed areas. Local pastoral management creates seasonal mosaic patterns of burnings performed for productive activities and for deliberate landscape management, i.e. to protect fire-sensitive vegetation and avoid wildfires. Whereas government-managed areas were affected by large biennial late dry season wildfires, community-managed areas with a regular fire regime suffered less damage. These systems are under threat and poorly understood by researchers and environmental managers. In order to improve fire management in tropical savannas, greater understanding of pastoral management practices and their spatiotemporal dimensions is required. PMID- 30430406 TI - Atheroprotective effect of novel peptides from Porphyridium purpureum in RAW 264.7 macrophage cell line and its molecular docking study. AB - OBJECTIVE: To explore the atherogenic foam cell prevention efficiency of two dipeptides purified from Porphyridium purpureum on RAW 264.7 cell line and to study its molecular interaction through molecular docking. RESULT: P. purpureum consists of 29.9% protein and 2.98% phycoerythrin on a dry weight basis. The two dipeptides namely of Histidine-Glutamic acid (HE) and Glycine-Proline (GP) isolated from the total protein and purified phycoerythrin of P. purpureum respectively, were evaluated for atherogenic foam cell prevention capacity in RAW 264.7 cell line. The IC5O values of peptides were found to be 91.2 +/- 1.81 ug/ml (GP), 103.3 +/- 4.8 ug/ml (HE) in MTT assay. The two peptides reduce the foam cell formation, intracellular lipid accumulation (cholesterol and triglycerides) and the secretion of TNF-alpha and IL-6 which are inflammatory cytokines in RAW 264.7 cell line at non-cytotoxic concentrations. A molecular interaction study proposed the binding pose for GP and HE peptides targeting the scavenging receptors CD36, SRA1, and Map Kinase p38 (a protein mediator). CONCLUSIONS: The cell line and molecular docking study indicated that among the two dipeptides, peptide GP has the highest atherogenic foam cell prevention efficiency. PMID- 30430409 TI - Analytics of Cerebrospinal Fluid MicroRNA Quantitative PCR Studies. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate post-transcriptional gene expression. Recent studies have shown that human disease states correlate with measurable differences in the level of circulating miRNAs relative to healthy controls. Thus, there is great interest in developing clinical miRNA assays as diagnostic or prognostic biomarkers for diseases, and as surrogate measures for therapeutic outcomes. Our studies have focused on miRNAs in human cerebral spinal fluid (CSF) as biomarkers for central nervous system (CNS) diseases. Our objective here was to examine factors that may affect the outcome of quantitative PCR (qPCR) studies on CSF miRNAs, in order to guide planning and interpretation of future CSF miRNA TaqMan(r) low-density array (TLDA) studies. We obtained CSF from neurologically normal (control) donors and used TLDAs to measure miRNA expression. We examined sources of error in the TLDA outcomes due to (1) nonspecific amplification of products in total RNA, (2) variations in RNA isolations performed on different days, (3) miRNA primer probe efficiency, and (4) variations in individual TLDA cards. We also examined the utility of card-to card TLDA corrections and use of an unchanged "reference standard" to remove batch processing effects in large-scale studies. PMID- 30430410 TI - Maternal Gestational Immune Response and Autism Spectrum Disorder Phenotypes at 7 Years of Age in the Seychelles Child Development Study. AB - Findings from observational and experimental studies suggest that maternal inflammation during pregnancy is associated with autism spectrum disorder (ASD). We report the first study in humans to examine this association in a large prospective birth cohort. We studied 788 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2. Thirteen inflammatory markers were measured in mothers' serum at 28 weeks' gestation, along with the sum of T-helper 1 (Th1) and 2 (Th2) cytokines. The Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were administered at age 7 years to obtain information on ASD phenotype. We evaluated associations between maternal inflammatory markers and ASD phenotype using multivariable linear regression. For the SCQ, increased MCP-1 (a chemokine that is upregulated in response to pro inflammatory cytokines) was associated with fewer ASD symptoms (B = - 0.40; 95% CI = - 0.72, - 0.09). Increased IL-4 (a cytokine that is typically associated with an enhanced anti-inflammatory response) was associated with more ASD symptoms (B = 2.10; 95% CI = 0.78, 3.43). For the SRS, higher concentrations of the anti-inflammatory cytokine IL-10 were associated with fewer ASD symptoms (B = - 0.18; 95% CI = - 0.35, - 0.01), but only after removal of outliers. No associations were observed for other markers. These findings suggest that a shift in the maternal immune balance during pregnancy may be associated with ASD symptomatology. While the use of well-established measures that capture ASD phenotypic variability is a strength of the study, measurement of peripheral immune markers only once during gestation is a limitation. Our results should be confirmed using maternal immune markers measured throughout gestation. PMID- 30430411 TI - Transcranial direct current stimulation reconstructs diminished thalamocortical connectivity during prolonged resting wakefulness: a resting-state fMRI pilot study. AB - Reductions in the alertness and information processing capacity of individuals due to sleep deprivation (SD) were previously thought to be related to dysfunction of the thalamocortical network. Previous studies have shown that transcranial direct current stimulation (tDCS) can restore vigilance and information processing after SD. However, the underlying neural mechanisms of this phenomenon remain unclear. The purpose of this study was to investigate the neurocognitive mechanisms of tDCS following SD, by comparing changes in the brain network, especially the thalamocortical network, after tDCS and sham stimulation following 24 h of SD. Sixteen healthy volunteers were tested in a sham controlled, randomized crossover design experiment. Resting-state functional magnetic resonance imaging was conducted during resting wakefulness and again after either active tDCS or sham stimulation to the right dorsolateral prefrontal cortex (1.0 mA, 20 min) immediately following 24 h of SD. Seed-based correlations and graph theory analysis were used to determine functional connectivity within the brain thalamocortical network. When tDCS was used, the functional connectivity of the thalamus with the temporal lobe and left caudate was higher than that when the sham stimulation was used. Analysis using graph theory showed that compared with sham stimulation, tDCS administration was associated with a significant improvement in not only the number of connections but also the global efficiency of the thalamus itself. Our study reveals a modulation of the activity of the intrinsic thalamus networks after tDCS. The effects may help explain earlier reports of improvements in the cognitive performance after anodal-tDCS. PMID- 30430412 TI - Fibroblast growth factor 21 in chronic kidney disease. AB - Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF family that acts as a metabolic regulator of both glucose and lipid metabolism. Similar to fibroblast growth factor 23 (FGF23), serum FGF21 levels rise progressively with the loss of renal function, reaching 20 times normal values in end-stage renal disease. In patients with chronic kidney disease (CKD), higher serum FGF21 levels correlate with poorer metabolic profile, higher inflammatory markers, more comorbidities, and higher mortality. The high serum FGF21 levels are above and beyond what can be explained by the loss of FGF21 renal clearance, suggesting increased production and/or impaired non-renal clearance. In diabetic nephropathy, serum FGF21 levels correlate with the severity of albuminuria and faster loss of glomerular filtrate rate and can potentially be a biomarker of poor prognostic. The observational and associative human data contrast sharply with in vitro and in vivo preclinical experimental data, which is more in line with a protective role of FGF21 in chronic nephropathies. We here review the physiology of FGF21, and the literature regarding its behavior in CKD with particular focus on diabetic nephropathy. Finally, we speculate on the role of FGF21 in CKD. PMID- 30430413 TI - Pregnancy in women with diabetic nephropathy. AB - The number of pregnancies in women with pregestational diabetes has been steadily increasing worldwide. These pregnancies are associated with an increased risk of a variety of complications, including miscarriages, congenital malformations, macrosomia, fetal growth restriction, preeclampsia, preterm delivery and stillbirth. In pregnant women with diabetic nephropathy it is important to evaluate both the effect of pregnancy on kidney function and the effect of kidney disease on pregnancy outcomes. Pregnant women with normal renal function and microalbuminuria have a low risk of loss of kidney function during pregnancy, while women with GFR < 60 ml/min and/or proteinuria >= 3 g/24 h at the beginning of pregnancy are at risk of permanent kidney damage. The risk of fetal and maternal complications is associated with the severity of chronic kidney disease and glycemic control. Advances in prenatal care have improved fetal and maternal outcomes and preconception counseling has become key for a successful pregnancy in all women with diabetes and especially in those with diabetes and chronic kidney disease. PMID- 30430414 TI - Special Section: Social Insects in the Neotropics. PMID- 30430415 TI - Response Mechanism of Oviposition and Relevant Protein Expression of Bactrocera cucurbitae (Coquillet) to Short-Term High-Temperature Conditions. AB - Bactrocera cucurbitae (Coquillett) (Diptera: Tephritidae) is an important pest of vegetables in Asia, the Middle East, Africa, and Hawaii. High temperature can significantly influence B. cucurbitae reproduction. The effect of short-term high temperature exposure on proteins that affect oviposition was analyzed by proteomics. Among six key target genes for oviposition, the expression of Vitellogenin-1, Vitellogenin-2, and Vitellogenin receptor was similar in B. cucurbitae exposed to higher temperature compared to controls. However, levels of Vitellogenin-3 were reduced. Juvenile hormone (Jh)-inducible protein was downregulated and then upregulated, while the expression of Jh-epoxide hydrolase 2 showed the opposite Jh-inducible protein trend. Therefore, short-term high temperature stress can cause differential expression of proteins related to oviposition in B. cucurbitae, which in turn further triggers the hormesis of oviposition. High-temperature conditions have become more frequent because of climate warming and are predicted to continue. The data indicate that climate effects on insect reproduction pose a significant threat to agriculture in a world of increasing population. PMID- 30430416 TI - Immunolocalization of Cancer Stem Cells Marker ALDH1 and its Association with Tumor Budding in Oral Squamous Cell Carcinoma. AB - Tumor budding is a prognostic marker for oral squamous cell carcinoma (OSCC) characterized by the presence of isolated or small clusters of neoplastic cells at the tumor invasive front. Aldehyde dehydrogenase-1 (ALDH1) is associated with tumorigenesis, linked to treatment resistance and shown to identify cancer stem cells (CSC)-like cells. This study aimed to evaluate the expression of ALDH1 and its association with tumor budding in OSCC. Immunohistochemistry was employed in 163 OSCC samples to identify pancytokeratin (AE1/AE3) and ALDH1. While pancytokeratin (AE1/AE3) identified squamous tumor buds, the CSC-like cells were identified using ALDH1. A Chi square test was used to evaluate association between ALDH1 expression and tumor budding, while McNemar's test was used to identify differences in ALDH1 expression between the budding area and the area outside the budding. A positive expression of ALDH1 was observed in 47.24% of the samples and in 70% of anatomic locations affected. No association was observed between ALDH1 expression and tumor budding (p > 0.05). In tumors with high intensity tumor budding, ALDH1 expression was higher in the budding area than in the area outside the budding (p < 0.05). The finding that tumor bud cells in OSCC show phenotypic characteristics of CSC-like cells reinforces the relevance of tumor budding in determining the biological behavior of this malignant neoplasm. Moreover, the presence of CSC-like cells in nearly half of evaluated samples of OSCC and in most of the affected anatomic locations is in accordance with the CSC model of oral carcinogenesis. PMID- 30430418 TI - The Combined Effects of Cr(III) Supplementation and Iron Deficiency on the Copper and Zinc Status in Wistar Rats. AB - The aim of the study was to assess the combined effects of chromium(III) supplementation and iron deficiency on the copper (Cu) and zinc (Zn) status in female rats. The Cr, Fe, Cu and Zn dietary and tissular levels were measured by Atomic Absorption Spectrometry (AAS) method. The data show that chromium(III) supplementation compensated for the negative effects of Fe deficiency on the Cu content but it deepened the effect on Zn levels in the female rats. Detailed data on the status of trace elements and their interactions in healthy subjects and patients with metabolic disorders (e.g. anaemia, diabetes mellitus) are strongly required for effective nutritional and therapeutic strategies. PMID- 30430417 TI - Systematic Review of the Effects of Chromium(III) on Chickens. AB - Chromium supplementation has been proposed to have beneficial effects in farm animals, particularly when under stress. The last two decades, in particular, have seen an emphasis on examining the effects of supplemental chromium on a variety of variables in chicks and chickens. Thus, given the recent approval of a Cr(III) compound for use in chicken feed in the United States and the recent surge in papers on the use of Cr in chicken feed, the need for a systematic review of studies utilizing chickens is extremely urgent and timely. With the exception of studies on cold-stressed laying hens, the results of studies of Cr supplementation of chickens, whether broilers or laying hens, were found to be too inconsistent for any firm conclusions to be drawn other than that Cr supplementation generally leads to accumulation of Cr in tissues. Few potential trends in terms or beneficial or deleterious effects from Cr supplementation were found regardless of strain of chicken, Cr source, Cr dose, duration of supplementation, or variable examined. Hence, in summary, no recommendation for the use of Cr as a supplement for the diet of chickens can be made at this time. PMID- 30430420 TI - Human germline editing: Insights to future clinical treatment of diseases. PMID- 30430419 TI - Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma. AB - High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a >= 2 prognostic index for T-cell lymphoma (P < 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and > 60 years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of >= 2 at ASCT (P < 0.001), receiving >= 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and > 60 years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT. PMID- 30430421 TI - Phosphorylation of PLIN3 by AMPK promotes dispersion of lipid droplets during starvation. PMID- 30430422 TI - An extensive study for binary characterisation of adrenal tumours. AB - On adrenal glands, benign tumours generally change the hormone equilibrium, and malign tumours usually tend to spread to the nearby tissues and to the organs of the immune system. These features can give a trace about the type of adrenal tumours; however, they cannot be observed all the time. Different tumour types can be confused in terms of having a similar shape, size and intensity features on scans. To support the evaluation process, biopsy process is applied that includes injury and complication risks. In this study, we handle the binary characterisation of adrenal tumours by using dynamic computed tomography images. Concerning this, the usage of one more imaging modalities and biopsy process is wanted to be excluded. The used dataset consists of 8 subtypes of adrenal tumours, and it seemed as the worst-case scenario in which all handicaps are available against tumour classification. Histogram, grey level co-occurrence matrix and wavelet-based features are investigated to reveal the most effective one on the identification of adrenal tumours. Binary classification is proposed utilising four-promising algorithms that have proven oneself on the task of binary-medical pattern classification. For this purpose, optimised neural networks are examined using six dataset inspired by the aforementioned features, and an efficient framework is offered before the use of a biopsy. Accuracy, sensitivity, specificity, and AUC are used to evaluate the performance of classifiers. Consequently, malign/benign characterisation is performed by proposed framework, with success rates of 80.7%, 75%, 82.22% and 78.61% for the metrics, respectively. Graphical abstract ?. PMID- 30430423 TI - Promoter Mutation Analysis of ALDOA Gene in Solid Tumors and Acute Leukemias. PMID- 30430424 TI - Investigating Potential Molecular Mechanisms of Carcinogenesis and Genes as Biomarkers for Prognosis of Gastric Cancer Based on Integrated Bioinformatics Analysis. AB - Gastric cancer, as the fifth most common malignancy worldwide, is a deadly disease afflicting nearly a million people. Researchers have devoted much to study the mechanisms of carcinogenesis and progression, but the exact information of tumor initiation and progression is remained largely unknown. Here, we hypothesized several differentially expressed genes and possible pathways by employing integrated bioinformatics analysis. We fully analyzed four gastric cancer-related microarray datasets to screen differentially expressed mRNAs (DEMs), miRNAs (DEMis) and lncRNAs (DELs). The functional enrichment analysis was deeply construed, PPI network and ceRNA regulatory network were constructed to investigate potential mechanisms of tumorigenesis and progression. Furthermore, survival analysis was performed to identify critical lncRNAs that may significantly affect pathogenesis of gastric cancer. QRT-PCR was applied to verify our result. We identified two hub subnetworks that may explain the progression, metastasis and poor prognosis of gastric cancer. Meanwhile, several potential significant lncRNAs were identified. In summary, we ascertained several significantly changed KEGG pathways in the tumor initiation and progression. We also hypothesized several lncRNAs that contribute to poor prognosis of gastric cancer via integrated bioinformatics, which deserve further investigation. PMID- 30430425 TI - Gene Promoter Methylation in Endometrial Carcinogenesis. AB - Up to 60% of untreated atypical hyperplastic endometrium will develop into endometrial carcinoma (EC), and for those who underwent a hysterectomy a coexisting EC is found in up to 50%. Gene promoter methylation might be related to the EC development. The aim of this study is to determine changes in gene promoter profiles in normal endometrium, atypical hyperplasia (AH) and EC in relation to K-Ras mutations. A retrospective study was conducted in patients diagnosed with endometrial hyperplasia with and without subsequent EC. Promoter methylation of APC, hMLh1, O6-MGMT, P14, P16, RASSF1, RUNX3 was analysed on pre operative biopsies, and correlated to the final histological diagnosis, and related to the presence of K-Ras mutations. In the study cohort (n=98), differences in promoter methylation were observed for hMLH1, O6-MGMT, and P16. Promoter methylation of hMLH1 and O6-MGMT gradually increased from histologically normal endometrium to AH to EC; 27.3, 36.4% and 38.0% for hMLH1 and 8.3%, 18.2% and 31.4% for O6-MGMT, respectively. P16 promoter methylation was significantly different in AH (7.7%) compared to EC (38%). K-Ras mutations were observed in 12.1% of AH, and in 19.6% of EC cases. No association of K-Ras mutation with promoter methylation of any of the tested genes was found. In conclusion, hMLH1 and O6-MGMT promoter methylation are frequently present in AH, and thus considered to be early events in the carcinogenesis of EC, whereas P16 promoter methylation was mainly present in EC, and not in precursor lesions supporting a late event in the carcinogenesis. PMID- 30430426 TI - From Some to None? Fertility Expectation Dynamics of Permanently Childless Women. AB - Permanent childlessness is increasingly acknowledged as an outcome of a dynamic, context-dependent process, but few studies have integrated a life course framework to investigate the complex pathways leading to childlessness. This study focuses on an understudied yet revealing dimension of why individuals remain childless: stated fertility expectations over the life course. Using data from the National Longitudinal Survey of Youth 1979 cohort, I use a combination of sequence analysis, data-driven clustering techniques, and multivariable regression models to identify and describe groups of permanently childless women who follow similar trajectories of stated fertility expectations. Results indicate that a little more than one-half (56 %) of eventually childless women fall into a cluster where childlessness is expected before age 30. Women in the remaining clusters (44 %) transition to expecting childlessness later in the life course but are differentiated by the types of trajectories that precede the emergence of a childless expectation. Results from multivariable regression show that several respondent characteristics, including race/ethnicity, education, and marital history, predict cluster membership. Taken together, these findings add to a growing body of literature that provides a more nuanced description of permanently childless women and motivates further research that integrates interdependencies between life course domains and fertility expectations and decision-making of those who remain childless. PMID- 30430427 TI - Prospective, Non-randomized, 36-Month Study of Second-Generation Trabecular Micro Bypass Stents with Phacoemulsification in Eyes with Various Types of Glaucoma. AB - INTRODUCTION: The aim of this study was to assess 36-month outcomes after cataract surgery and implantation of two second-generation trabecular micro bypass stents (iStent inject, Glaukos Corporation, San Clemente, CA, USA) into eyes with predominantly primary open-angle glaucoma (POAG) or pseudoexfoliative glaucoma (PEX). METHODS: This prospective, non-randomized, consecutive cohort study included eyes with POAG (n = 60), PEX (n = 15), appositional narrow-angle (n = 4), pigmentary (n = 1), or neovascular (secondary) (n = 1) glaucoma and cataract requiring surgery. All eyes (n = 81) underwent ab interno iStent inject implantation following cataract surgery. Effectiveness endpoints through 36 months included intraocular pressure (IOP), number of medications, and proportion of eyes with >= 20% IOP reduction, IOP <= 18 mmHg, and IOP <= 15 mmHg. Safety measures included corrected distance visual acuity (CDVA), adverse events, and secondary surgeries. Outcomes were evaluated for the overall cohort, and for the POAG and PEX subgroups. RESULTS: Preoperatively, 32.1% of eyes had undergone prior glaucoma surgery, 56% were on 3-4 medications, and 1 eye (1%) was medication-free. At 36 months postoperatively, mean IOP reduced by 37% (14.3 +/- 1.7 mmHg versus 22.6 +/- 6.2 mmHg preoperatively), and mean medication burden decreased by 68% (0.8 +/- 0.9 versus 2.5 +/- 1.1 medications preoperatively). IOP reduced by >= 20% in 78% of eyes; 100% of eyes reached IOP <= 18 mmHg and 71% reached <= 15 mmHg. Medication burden reduced considerably: 22 eyes (54%) were medication-free compared to 1 eye (1%) preoperatively; 1 eye (2%) required >= 3 medications compared to 45 eyes (56%) preoperatively; and 92.7% of eyes required reduced medications postoperatively. From 3 through 36 months, mean IOP remained <= 15.0 mmHg, and mean number of medications remained <= 0.9. Outcomes in the POAG and PEX subgroups included 33% and 32% lower IOP, and 68% and 64% fewer medications, respectively. iStent inject showed a favorable safety profile, including no intraoperative complications, minimal adverse events, and a stable CDVA. CONCLUSION: This real-world cohort of eyes with various types of glaucoma and considerable disease burden exhibited durable and safe IOP and medication reductions through 36 months following iStent inject implantation with cataract surgery. Outcomes were similarly beneficial in eyes with POAG and PEX. FUNDING: Article processing charges were funded by Glaukos Corporation (San Clemente, CA, USA). PMID- 30430428 TI - Radiomics and liquid biopsy in oncology: the holons of systems medicine. AB - Radiomics is a process of extraction and analysis of quantitative features from diagnostic images. Liquid biopsy is a test done on a sample of blood to look for cancer cells or for pieces of tumourigenic DNA circulating in the blood. Radiomics and liquid biopsy have great potential in oncology, since both are minimally invasive, easy to perform, and can be repeated in patient follow-up visits, enabling the extraction of valuable information regarding tumour type, aggressiveness, progression, and response to treatment. Both methods are in their infancy, with major evidence of application in lung and gastrointestinal cancer, while still undergoing evaluation in other cancer types. In this paper, the main oncologic applications of radiomics and liquid biopsy are reviewed, and a synergistic approach incorporating both tests for cancer diagnosis and follow-up is discussed within the context of systems medicine. TEACHING POINTS: * Radiomics is a process of extraction and analysis of quantitative features from diagnostic images. * Most clinical applications of radiomics are in the field of oncologic imaging. * Radiomics applies to all imaging modalities. * A cluster of radiomic features is a "radiomic signature". * Machine learning may improve the efficacy of radiomics analysis. PMID- 30430429 TI - A novel heteroplasmic mutation in mitochondrial tRNAArg gene associated with non dystrophic myotonias. AB - Non-dystrophic myotonias (NDM) are rare diseases caused by defects in skeletal muscle chloride and sodium ion channels. It is well established that high-energy consuming tissues such as muscular and nervous systems are exclusively dependent on the ATP generation by mitochondria. The mitochondrial dysfunction, which is caused by mitochondrial DNA mutations, played an important role in the pathogenesis of non-dystrophic myotonias. The purpose of this study is to identify mitochondrial tRNA mutations in non-dystrophic myotonias patients. In this study, 45 Iranian patients with non-dystrophic myotonia were investigated for intracellular ATP content and the mutation screening in all the mitochondrial tRNA genes by DNA sequencing. Our findings showed that lymphocyte intracellular ATP is significantly decreased in NDM patients compared with control subjects (p = 0.001). We found nine mutations in mitochondrial tRNA genes, including m.4454 T > C (in the TpsiC loop of tRNAMet), m.5568 A > G (tRNATrp), m.5794 T > C (in the anticodon loop of tRNACys), novel m.10438 A > T, and m.10462 T > C (in anticodon loop and ACC stem of tRNAArg), m.12308 A > G (tRNALeu(CUN)) and m.15907 A > G, m.15924 A > G, and m.15928 G > A (in the anticodon stem of tRNAThr) in 31 NDM patients. These results suggest that novel m.10438 A > T mutation is involved in NDM patients and reinforces the significant association between this mutation in mitochondrial tRNAArg Gene and NDM patients (p = 0.008). PMID- 30430430 TI - Current status of endovascular treatment for dural arteriovenous fistulae in the tentorial middle region: a literature review. AB - The tentorial middle region (TMR) includes the midline and paramedian tentorium. TMR dural arteriovenous fistulae (DAVFs) are complex. We performed a review of the literature on TMR DAVFs. TMR DAVFs are divided into the following four types: incisural DAVF, Galenic DAVF, straight sinus DAVF and torcular DAVF. TMR DAVFs often drain into pial veins; therefore, most TMR DAVFs are classified as Borden II-III and Cognard types IIb-IV, whose characteristics cause TMR DAVFs to be prone to hemorrhage. TMR DAVFs have a very disappointing natural progression, and treatment is necessary. TMR DAVFs have extensive arterial supply and complex venous drainages, making them difficult to treat. Currently, for TMR DAVF, endovascular treatment (EVT) has become a better option. In EVT, transarterial embolization is the first-line treatment. Many complications can occur when treating TMR DAVFs, but complete EVT can generally achieve good clinical outcomes. In this review, three educational cases with demonstrating figures are provided to elaborate TMR DAVFs. PMID- 30430431 TI - Metabolic Syndrome Is a Significant Predictor of Postoperative Morbidity and Mortality Following Bariatric Surgery. AB - INTRODUCTION/PURPOSE: Metabolic syndrome is commonly demonstrated in patients with morbid obesity undergoing bariatric surgery. The purpose of this study was to determine the effect of metabolic syndrome on morbidity and mortality following bariatric surgery. MATERIALS AND METHODS: The National Surgical Quality Improvement Program (NSQIP) dataset was queried for patients who underwent bariatric surgical procedures between 2012 and 2014. Patient demographics, comorbid conditions, bariatric procedure type, and postoperative complications were analyzed. Metabolic syndrome was defined as having a body mass index > 30 kg/m2 in the presence of the comorbid conditions of hypertension and diabetes. Regression analysis was used to determine the relationship between metabolic syndrome and postoperative morbidity and mortality. RESULTS: During the study interval, 59,404 patients underwent bariatric surgery (Roux-en-Y gastric bypass = 28,263, sleeve gastrectomy = 30,239, revision = 422, and biliopancreatic diversion = 480). The mean body mass index was 45.9 kg/m2, and the mean age was 45 years. Of the cohort, 30,104 (50.6%) patients had a diagnosis of hypertension, 16,558 (27.8%) had diabetes mellitus, and 12,803 (21.5%) met the criteria for metabolic syndrome. Patients with metabolic syndrome were more likely to have Roux-en-Y gastric bypass procedure, a history of congestive heart failure, severe COPD, renal failure, and diminished functional status (p < 0.0001). Morbidity was greater for patients with metabolic syndrome (7.5% vs. 5%; p < 0.0001), and patients in this subset also had a 3.2-fold increased risk of mortality (p < 0.0001). DISCUSSION: Metabolic syndrome is prevalent in patients who undergo bariatric surgery. We have demonstrated that patients with the constellation of comorbid conditions defining metabolic syndrome are at an increased risk of morbidity and mortality following bariatric surgery. Patients and surgeons should be informed of the potential increased risk in this patient population. PMID- 30430432 TI - Long-Term Quality of Life Assessment After Successful Endoscopic Vacuum Therapy of Defects in the Upper Gastrointestinal Tract Quality of Life After EVT. AB - BACKGROUND: Accumulating evidence indicates that anastomotic leakages and perforations of the upper gastrointestinal tract (uGIT) can be treated successfully with endoscopic vacuum therapy (EVT). So far, no data is available regarding the long-term quality of life (QoL) after successful EVT of defects in the uGIT. METHODS: We present a prospective survey on long-term Qol of 52 patients treated by EVT for defects of the uGIT. Results are compared with 63 of 221 patients treated by esophagectomy without anastomotic insufficiency (w/o EVT) between 12/2011 and 12/2015. The Gastrointestinal Quality of Life-Index (GIQLI) score was determined by a 36-item questionnaire of 25 respondents with EVT and 50 respondents w/o EVT. RESULTS: The response rate was 78.95% (75/95) including 25 survey respondents who were treated with EVT for anastomotic insufficiency secondary to esophagectomy or gastrectomy (n = 19), iatrogenic esophageal perforation (n = 4), and Boerhaave syndrome (n = 2) and 50 respondents with complication-free esophagectomy w/o EVT. The median follow-up was 19 months for EVT patients and 21 months for patients w/o EVT. Except for "social function" (p = 0.009) in favor for patients w/o EVT, the median GIQLI score did not differ significantly between both study groups concerning the categories 'symptoms', 'emotions', 'physical functions', and 'medical treatment' resulting in a total median GIQLI score of 83 in EVT versus 96.5 in patients w/o EVT (p = 0.185). Spearman Rho analysis revealed that a high GIQLI score correlated with a low ASA score (p < 0.001), a benign pathology (p = 0.001), and a hospital stay less than 21 days (p < 0.001). CONCLUSION: EVT in the uGIT is well tolerated by the patients and accompanied by a satisfactory long-term QoL. PMID- 30430433 TI - Laparoscopic Complete Mesocolic Excision for Right-Sided Colon Cancer: Analysis of Feasibility and Safety from a Single Western Center. AB - BACKGROUND: Colectomies performed according to complete mesocolic excision (CME) principles have demonstrated an improvement in the quality of surgical specimen and a potential improvement of long-term results. Laparoscopic CME right hemicolectomy is considered a demanding procedure and adopted in few centers from the West. The main purpose of this paper is to present a video showing our technique for laparoscopic CME right hemicolectomy and to analyze our short-term results to prove its safety. METHODS: Data from 38 patients operated on at the Division of General and Hepatobiliary Surgery, University of Verona Hospital Trust, between September 2014 and February 2017, were included in the study. RESULTS: In the present series, 37% of patients were >=75 years old, 32% of patients were ASA class 3, 46% of patients had >=2 comorbidities, 30% of patients had BMI >28 and 17% of patients had >=2 previous abdominal surgeries. Despite these unfavorable clinic characteristics, no mortality was observed, Clavien Dindo >=3 complications occurred in 13.1% and redo surgery in 5.3%. Good quality specimens were obtained with a mean (SD) length of 34.5+/-7.5 cm, a proximal margin of 16.8+/-9.2 cm and a distal margin of 14.3+/-6.4 cm. The mean (SD) number of harvested lymph nodes was 24.3 (8.3). CONCLUSIONS: When implemented in a Western center, laparoscopic CME right hemicolectomy is feasible and safe and allows obtaining good quality specimens. PMID- 30430434 TI - Retraction Note to: Changes of Absorptive and Secretory Transporting System of (1 -> 3) beta-D-glucan Based on Efflux Transporter in Indomethacin-induced Rat. AB - The Editor-in-Chief has retracted this article [1] based on an investigation by the Ministry of Education, Culture, Sports, Science and Technology, Japan, which found that the article contained overlap with a previously published article by Kalitsky-Szirtes J, et al. [2]. PMID- 30430435 TI - A Focus Honoring Carol Robinson's Election to the National Academy of Sciences. PMID- 30430436 TI - Effects of Individual Ion Energies on Charge Measurements in Fourier Transform Charge Detection Mass Spectrometry (FT-CDMS). AB - A method to correct for the effect of ion energy on charge measurements of individual ions trapped and weighed with charge detection mass spectrometry (CDMS) is demonstrated. Ions with different energies induce different signal patterns inside an electrostatic ion trap. The sum of the amplitudes of the fundamental and second harmonic frequencies in the Fourier transform of the induced signal, which has been used to obtain the ion charge, depends on both ion energy and charge. The amplitudes of the fundamental frequencies of ions increase over time as ions lose energy by collisions with background gas and solvent loss from larger ions. Model ion signals are simulated with the same time-domain amplitude at different energies and frequencies and the resulting fundamental frequency amplitudes are used to normalize real ion signals for energy and frequency effects. The fundamental frequency amplitude decreases dramatically below 20 kHz and increases by ~ 17% from the highest energy to lowest energy that is stable with a given trap potential at all frequencies. Normalizing the fundamental frequency amplitude with the modeled amplitudes removes the systematic changes in the charge measurement of polyethylene glycol (PEG) and other ions and makes it possible to signal average the amplitude over long times, which reduces the charge uncertainty to 0.04% for a PEG ion for a 500-ms measurement. This method improves charge measurement accuracy and uncertainty, which are important for high-accuracy mass measurement with CDMS. Graphical abstract ?. PMID- 30430437 TI - Development of a Post-Column Liquid Chromatographic Chiral Addition Method for the Separation and Resolution of Common Mammalian Monosaccharides. AB - The first solely MS-based methodology for the identification and resolution of the ten common mammalian monosaccharides is presented. Based on Cooks' fixed ligand kinetic method, this technique is effective on multiple classes of monosaccharides and includes the first example of two fixed ligand combinations used in a single multiplexed experiment. Subsequently, a post-HPLC chiral addition method is used in conjunction with this newly developed MS methodology for the separation and identification of mixtures of common neutral mammalian monosaccharides. This proposed technique is able to overcome a limitation of present carbohydrate analysis methods, namely the simultaneous isomeric resolution of multiple monosaccharides in a mixture. Graphical Abstract ?. PMID- 30430439 TI - Validity evidence for programmatic assessment in competency-based education. AB - INTRODUCTION: Competency-based education (CBE) is now pervasive in health professions education. A foundational principle of CBE is to assess and identify the progression of competency development in students over time. It has been argued that a programmatic approach to assessment in CBE maximizes student learning. The aim of this study is to investigate if programmatic assessment, i. e., a system of assessment, can be used within a CBE framework to track progression of student learning within and across competencies over time. METHODS: Three workplace-based assessment methods were used to measure the same seven competency domains. We performed a retrospective quantitative analysis of 327,974 assessment data points from 16,575 completed assessment forms from 962 students over 124 weeks using both descriptive (visualization) and modelling (inferential) analyses. This included multilevel random coefficient modelling and generalizability theory. RESULTS: Random coefficient modelling indicated that variance due to differences in inter-student performance was highest (40%). The reliability coefficients of scores from assessment methods ranged from 0.86 to 0.90. Method and competency variance components were in the small-to-moderate range. DISCUSSION: The current validation evidence provides cause for optimism regarding the explicit development and implementation of a program of assessment within CBE. The majority of the variance in scores appears to be student-related and reliable, supporting the psychometric properties as well as both formative and summative score applications. PMID- 30430438 TI - C-O Bond Dissociation and Induced Chemical Ionization Using High Energy (CO2)n+ Gas Cluster Ion Beam. AB - A gas cluster ion beam (GCIB) source, consisting of CO2 clusters and operating with kinetic energies of up to 60 keV, has been developed for the high resolution and high sensitivity imaging of intact biomolecules. The CO2 molecule is an excellent molecule to employ in a GCIB source due to its relative stability and improved focusing capabilities, especially when compared to the conventionally employed Ar cluster source. Here we report on experiments aimed to examine the behavior of CO2 clusters as they impact a surface under a variety of conditions. Clusters of (CO2)n+ (n = 2000~10,000) with varying sizes and kinetic energies were employed to interrogate both an organic and inorganic surface. The results show that C-O bond dissociation did not occur when the energy per molecule is less than 5 eV/n, but that oxygen adducts were seen in increasing intensity as the energy is above 5 eV/n, particularly, drastic enhancement up to 100 times of oxygen adducts was observed on Au surface. For Irganox 1010, an organic surface, oxygen containing adducts were observed with moderate signal enhancement. Molecular dynamics computer simulations were employed to test the hypothesis that the C-O bond is broken at high values of eV/n. These calculations show that C-O bond dissociation occurs at eV/n values less than the C-O bond energy (8.3 eV) by interaction with surface topological features. In general, the experiments suggest that the projectiles containing oxygen can enhance the ionization efficiency of surface molecules via chemically induced processes, and that CO2 can be an effective cluster ion source for SIMS experiments. Graphical Abstract ?. PMID- 30430440 TI - An observational study of end-tidal carbon dioxide trends in general anesthesia. AB - PURPOSE: Despite growing evidence supporting the potential benefits of higher end tidal carbon dioxide (ETCO2) levels in surgical patients, there is still insufficient data to formulate guidelines for ideal intraoperative ETCO2 targets. As it is unclear which intraoperative ETCO2 levels are currently used and whether these levels have changed over time, we investigated the practice pattern using the Multicenter Perioperative Outcomes Group database. METHODS: This retrospective, observational, multicentre study included 317,445 adult patients who received general anesthesia for non-cardiothoracic procedures between January 2008 and September 2016. The primary outcome was a time-weighted average area under-the-curve (TWA-AUC) for four ETCO2 thresholds (< 28, < 35, < 45, and > 45 mmHg). Additionally, a median ETCO2 was studied. A Kruskal-Wallis test was used to analyse differences between years. Random-effect multivariable logistic regression models were constructed to study variability. RESULTS: Both TWA-AUC and median ETCO2 showed a minimal increase in ETCO2 over time, with a median [interquartile range] ETCO2 of 33 [31.0-35.0] mmHg in 2008 and 35 [33.0-38.0] mmHg in 2016 (P <0.001). A large inter-hospital and inter-provider variability in ETCO2 were observed after adjustment for patient characteristics, ventilation parameters, and intraoperative blood pressure (intraclass correlation coefficient 0.36; 95% confidence interval, 0.18 to 0.58). CONCLUSIONS: Between 2008 and 2016, intraoperative ETCO2 values did not change in a clinically important manner. Interestingly, we found a large inter-hospital and inter-provider variability in ETCO2 throughout the study period, possibly indicating a broad range of tolerance for ETCO2, or a lack of evidence to support a specific targeted range. Clinical outcomes were not assessed in this study and they should be the focus of future research. PMID- 30430441 TI - The reliability of a portfolio of workplace-based assessments in anesthesia training. AB - PURPOSE: Competency-based anesthesia training programs require robust assessment of trainee performance and commonly combine different types of workplace-based assessment (WBA) covering multiple facets of practice. This study measured the reliability of WBAs in a large existing database and explored how they could be combined to optimize reliability for assessment decisions. METHODS: We used generalizability theory to measure the composite reliability of four different types of WBAs used by the Australian and New Zealand College of Anaesthetists: mini-Clinical Evaluation Exercise (mini-CEX), direct observation of procedural skills (DOPS), case-based discussion (CbD), and multi-source feedback (MSF). We then modified the number and weighting of WBA combinations to optimize reliability with fewer assessments. RESULTS: We analyzed 67,405 assessments from 1,837 trainees and 4,145 assessors. We assumed acceptable reliability for interim (intermediate stakes) and final (high stakes) decisions of 0.7 and 0.8, respectively. Depending on the combination of WBA types, 12 assessments allowed the 0.7 threshold to be reached where one assessment of any type has the same weighting, while 20 were required for reliability to reach 0.8. If the weighting of the assessments is optimized, acceptable reliability for interim and final decisions is possible with nine (e.g., two DOPS, three CbD, two mini-CEX, two MSF) and 15 (e.g., two DOPS, eight CbD, three mini-CEX, two MSF) assessments respectively. CONCLUSIONS: Reliability is an important factor to consider when designing assessments, and measuring composite reliability can allow the selection of a WBA portfolio with adequate reliability to provide evidence for defensible decisions on trainee progression. PMID- 30430442 TI - Effects of pH Variability on Peracetic Acid Reduction of Human Norovirus GI, GII RNA, and Infectivity Plus RNA Reduction of Selected Surrogates. AB - With increasing interest in peracetic acid (PAA) as a disinfectant in water treatment processes, this study determined PAA treatment effects on human noroviruses (hNoVs) genotype I (GI) and genotype II (GII) as well as effects on bacteriophage MS2 and murine norovirus (MNV) in relation to pH. Across all pH conditions, PAA achieved between 0.2 and 2.5 log10 reduction of hNoVs over 120 min contact time in buffer solution as measured by reverse transcription-qPCR (RT qPCR). The PAA treatments produced similar RT-qPCR reductions of MS2 and MNV, in the range of 0.2-2.7 log10. Infectivity assays achieved > 4 log10 reduction of both MS2 and MNV in buffer solution after 120 min contact time. Comparing PAA activity across varying pH, disinfection at pH 8.5, in general, resulted in less reduction of infectivity and molecular signals compared to pH conditions of 6.5 and 7.5. This difference was most pronounced for reductions in infectivity of MNV and MS2, with as much as 2.7 log10 less reduction at pH 8.5 relative to lower pH conditions. This study revealed that PAA was an effective disinfectant for treatment of hNoV GI and GII, MS2 and MNV, with greatest virus reduction observed for MS2 and MNV infectivity. RT-qPCR reductions of MS2 and MNV were lower than concurrent MS2 and MNV infectivity reductions, suggesting that observed hNoV RT qPCR reductions may underestimate reductions in hNoV infectivity achieved by PAA. Although virus disinfection by PAA occurred at all evaluated pH levels, PAA is most effective at pH 6.5-7.5. PMID- 30430443 TI - Correction to: The Three-Dimensional Culture of Epithelial Organoids Derived from Embryonic Chicken Intestine. AB - Erratum to: The Three-Dimensional Culture of Epithelial Organoids Derived from Embryonic Chicken Intestine. PMID- 30430444 TI - Antibody-Based Therapies for Cutaneous T-Cell Lymphoma. AB - Cutaneous T-cell lymphomas (CTCLs) are a group of non-Hodgkin's lymphomas that present in the skin. In early-stage disease, the course is generally chronic and indolent; however, in advanced stages of disease, therapies rarely provide long lasting responses, and the only potential curative therapy is allogeneic hematopoietic stem-cell transplantation. This has led to the search for novel targeted therapies to better treat more advanced stages of CTCLs that cannot be controlled by typical treatment regimens. One area of advancement has been the development of antibodies specifically targeted to cell types that are known to be involved in CTCL. At present, brentuximab vedotin, an antibody-drug conjugate composed of an anti-cluster of differentiation (CD)-30 antibody covalently linked to monomethyl auristatin E, is approved for the treatment of CD30+ lymphoproliferative disorders [lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (pc-ALCL)] as well as transformed CD30+ mycosis fungoides (MF). Additionally, mogamulizumab, an anti-chemokine receptor 4 (CCR4) monoclonal antibody, is approved for patients with MF or Sezary syndrome (SS) for whom one prior systemic therapy has failed. Trials are underway looking into the use of immune checkpoint inhibitors in the treatment of CTCLs. As we continue to research CTCL, and as antibody-based therapies continue to advance, more antibody specific targeted therapy could provide alternative treatment regimens for patients with advanced CTCL. PMID- 30430445 TI - Pollutants from fish feeding recycled for microalgae production as sustainable, renewable and valuable products. AB - Trash fish feeding of cage fish can result in marine pollution. Whole and chopped trash fish can leach pollutants such as ammonia, phosphate and protein into surrounding waters. Reduction of pollution can be achieved by recycling the wastewater generated from trash fish feeding for cultivation of microalgae. Microalgae are potent candidates for the production of renewable and sustainable products such as feed and food, health and pharmaceutical, cosmeceutical, industrial products, and biofuel. Two microalgae, Chlorella saccharophila and Nannochloropsis sp., have the potential to produce high amounts of polyunsaturated fatty acids. Furthermore, high oil content ranging from 10.7 to 13.6% is found in Chlorella saccharophila and up to 9.3% for Nannochloropsis sp. Moreover, these microalgae can also be utilized as a biofuel to give a mean calorific value of 5364 Cal/g which is higher than that of wood for Chlorella saccharophila and 6132 Cal/g which is equivalent to that of coal for Nannochloropsis sp. An alternative biofuel derived from microalgae is feasible due to the fact that they do not compete for arable land for cultivation and land crops for feed and food. This study discusses the synergistic coupling of microalgae mass production with wastewater treatment and carbon sequestration potential for mitigation of environmental impacts and a technically viable alternative energy resource. Additionally, the de-oiled biomass byproduct after oil extraction or its whole biomass can be converted into sustainable and renewal industrial products such as bioplastic, biopaint, bioasphalt, and biobuilding components. PMID- 30430446 TI - Statistical assessment of nonpoint source pollution in agricultural watersheds in the Lower Grand River watershed, MO, USA. AB - The water quality in many Midwestern streams and lakes is negatively impacted by agricultural activities. Although the agricultural inputs that degrade water quality are well known, the impact of these inputs varies as a function of geologic and topographic parameters. To better understand how a range of land use, geologic, and topographic factors affect water quality in Midwestern watersheds, we sampled surface water quality parameters, including nitrate, phosphate, dissolved oxygen, turbidity, bacteria, pH, specific conductance, temperature, and biotic index (BI) in 35 independent sub-watersheds within the Lower Grand River Watershed in northern Missouri. For each sub-watershed, the land use/land cover, soil texture, depth to bedrock, depth to the water table, recent precipitation area, total stream length, watershed shape/relief ratio, topographic complexity, mean elevation, and slope were determined. Water quality sampling was conducted twice: in the spring and in the late summer/early fall. A pairwise comparison of water quality parameters acquired in the fall and spring showed that each of these factors varies considerably with season, suggesting that the timing is critical when comparing water quality indicators. Correlation analysis between water quality indicators and watershed characteristics revealed that both geologic and land use characteristics correlated significantly with water quality parameters. The water quality index had the highest correlation with the biotic index during the spring, implying that the lower water quality conditions observed in the spring might be more representative of the longer-term water quality conditions in these watersheds than the higher quality conditions observed in the fall. An assessment of macroinvertebrates indicated that the biotic index was primarily influenced by nutrient loading due to excessive amounts of phosphorus (P) and nitrogen (N) discharge from agricultural land uses. The PCA analysis found a correlation between turbidity, E. coli, and BI, suggesting that livestock grazing may adversely affect the water quality in this watershed. Moreover, this analysis found that N, P, and SC contribute greatly to the observed water quality variability. The results of this study can be used to improve decision-making strategies to improve water quality for the entire river basin. PMID- 30430447 TI - Destabilization of polyethylene and polyvinylchloride structure by marine bacterial strain. AB - Plastics are recalcitrant and inert to degrade, and destabilization leads to accumulate in the terrestrial and marine ecosystems; need for the development of strategies for reducing these plastic wastes in a sustainable manner would be revolutionary. We studied the bacterial adherence, degradation and destabilization of polyvinylchloride (PVC), low-density polyethylene (LDPE), and high-density polyethylene (HDPE) by marine bacterial strain AIIW2 by a series of analytical and microscopic observations over 3 months. Based on 16S rRNA gene sequence and the phylogenetic analysis of the strain AIIW2, it showed 97.39% similarity with Bacillus species. Degradation of plastics was determined by the weight loss after 90 days with bacterial strain which detected up to 0.26 +/- 0.02, 0.96 +/- 0.02, and 1.0 +/- 0.01% for PVC, LDPE, and HDPE films, respectively over initial weights. The mineralization of plastic film was found to be maximum in LDPE followed by HDPE and PVC. Bacterial interaction had increased roughness and deteriorated the surface of plastics which is revealed by the scanning electron microscope and atomic force microscope. Bending vibrations of the alkane rock chain (-CH2 and -CH3) and carbonyl (-CO) regions in LDPE and HDPE films, while there was slight stretching in the hydroxyl (-OH) regions of carboxylic acid in PVC which is evidenced through Fourier transform infrared spectral studies, suggested the oxidative activities of the bacteria. Though, the bacterial activity was higher on the LDPE and HDPE than PVC film which may be due to the presence of chlorine atom in PVC structure making it more versatile. The results of the present study revealed the ability of marine bacterial strain for instigating their colonization over plastic films and deteriorating the polymeric structure. PMID- 30430448 TI - Assessment of heavy metal release into the soil after mine clearing in Halgurd Sakran National Park, Kurdistan, Iraq. AB - The aim of this study was to assess the heavy metal pollution in soils after mine clearance and disposal through controlled explosions in dugout pits during demining operations at two hotspot areas, in the Halgurd-Sakran National Park (HSNP). This investigation was undertaken in order to reveal the concentration level, migration and enrichment in various heavy metals present in polluted soils. Eighteen samples, nine sampling positions at each site, were collected. The current study used inductively coupled plasma-emission spectroscopy (ICP-ES) methodology to determine the concentration levels of Cu, Pb, Zn, Ni, Co, Mn, As and Cr in the soil samples as important toxic contaminants resulting from the demining process. The results show concentration levels of 63.33, 16.22, 116.44, 328, 32.66, 1594.33, 7 and 291.55 ppm in site 1 for Cu, Pb, Zn, Ni, Co, Mn, As and Cr, respectively, while site 2 gave 72.55, 17, 102.55, 296.55, 32, 1851.88, 9.11 and 308.77 ppm. Soil enrichment factor (EF) in sites 1 and 2 of the heavy metals Ni, Cr, Mn, Co and Cu ranged from extremely high enrichment to moderate high enrichment, respectively. The geo-accumulation (I-geo) index indicated contamination levels that ranged from very strongly to moderately contaminated soil for Ni, Cr, Mn, Co and Cu, respectively. On the other hand, the pollution load index (PLI) showed all values from all samples in both sites were above 1 indicating totally contaminated areas. However, the most polluting heavy metals in the soil at both sites are Ni and Cr with high contamination levels attributed to the controlled mines' detonations. In conclusion, these mines' detonations are producing residual heavy metals in the soil that are potentially harmful to the vegetation cover, animals and ultimately humans. PMID- 30430449 TI - Distinctive impact of polystyrene nano-spherules as an emergent pollutant toward the environment. AB - The increasing load of nanoplastic pollution in the environment has become a major concern toward human and environmental safety. The current investigation mainly focused on assessing the toxic behavior of nanoplastics (polystyrene nano spheres (PNS)) toward blood cells and marine crustacean. The study also investigated the temporal stability of PNS under different water matrices and its size-dependent sedimentation behavior in the sea water dispersion. The nano dispersion showed mean particle size of 561.4 +/- 0.80 and 613.7 +/- 0.11 nm for PNS 1 and 781.4 +/- 0.80 and 913.7 +/- 0.11 nm for PNS 2 in lake and seawater, respectively after 48-h incubation, which is ~ 8-fold increase from its original size. The LC50 value against Artemia salina and lymphocytes were found to be 4.82 and 8.79 MUg/mL, and 75 MUg/mL, respectively for PNS 1 and PNS 2. The genotoxic study reveals that around 50% of lymphocytes were affected by both PNS at 50 MUg/mL concentration, whereas the cytotoxic studies on RBC and lymphocytes showed 50% toxicity only at 100 MUg/mL concentration. The genotoxic study displayed numerous tri- and multi-nucleated cells. The biochemical profile of A. salina exposed to lethal concentration demonstrated a significant decrease in the total protein, reduced glutathione, and catalase activity and increase in lipid peroxidation activity as a result of PNS permeation to tissues. In conclusion, the present study demonstrated that the polystyrene nano-spheres are emerging pollutant in the environment and are hazardous to humans. PMID- 30430450 TI - Interference mechanism of Sophora alopecuroides L. alkaloids extract on host finding and selection of the Asian citrus psyllid Diaphorina citri Kuwayama (Hemiptera: Psyllidae). AB - Manipulating insect behavior through the deployment of semiochemicals offers a promising opportunity for protecting crops in a sustainable manner. Therefore, there is still a significant opportunity for the development of natural crop protectants as eco-friendly tools in pest management. In this context, the aim of the current investigation is to find a novel prophylactic against the Asian citrus psyllid (ACP) and to gain a better understanding of the host-finding and selection ability of the ACP towards Murraya paniculata seedlings treated with Sophora alopecuroides alkaloids extract (SAAE). Our results indicate that foliar application of SAAE influences the psyllid host-finding and selection process. The behavioral assay with M. paniculata seedlings treated with 15 and 30 mg/mL of SAAE, with masked visual cues, revealed that only 6.6 and 10.4% psyllids were able to locate the host in the vials. The results also indicate that citrus psyllids mainly rely on both visual and olfaction in host-finding and selection. In choice settling experiments, psyllids settled almost completely on control seedlings rather than on seedlings treated with SAAE at a concentration of 30 mg/mL. Chemical analyses of the alkaloids extract revealed the presence of sophocarpine (33.90%), sophoridine (6.23%), anagyrine (2.77%), matrine (2.38%), lupanine (1.68%) aphylline (0.89%), and sophoramine (0.75%). In further behavioral bioassays with the dominant alkaloids sophocarpine and sophoridine, the alkaloids repelled ACP at higher concentrations of 50 and 70 mg/mL as compared to SAAE. Furthermore, the 50 mg/mL (1:1, v/v) combination of sophocarpine and sophoridine displayed a synergistic effect and showed the maximum behavioral effect as compared to the individual alkaloid. Based on our results, SAAE makes M. paniculata seedlings unattractive to the psyllids, and therefore, alkaloids could be used in reducing the colonization of citrus plants, subsequently curtailing HLB infection. PMID- 30430451 TI - Albumin nano-encapsulation of caffeic acid phenethyl ester and piceatannol potentiated its ability to modulate HIF and NF-kB pathways and improves therapeutic outcome in experimental colitis. AB - Hypoxia inducible factor and nuclear factor-kappa beta pathways have been proposed as therapeutic targets for several inflammatory diseases. Caffeic acid phenethyl ester (CAPE) and piceatannol (PIC) are natural anti-inflammatory compounds; however, poor bioavailability and limited understanding of biomolecular mechanistic limits its clinical use. The aims of this study are to enhance bioavailability and investigate their impact on nuclear p65 and HIF 1alpha for the first time in experimental colitis.Dextran sulphate sodium was used to induce colitis in mice and effect of either free CAPE/PIC or CAPE/PIC loaded albumin nanoparticles treatment was observed on disease development and levels of cellular p65 and HIF-1alpha.Our results indicate that albumin nano encapsulation of CAPE/PIC not only enhances its anti-inflammatory potential but also potentiates its ability to effectively modulate inflammation related biomolecular pathways. Hence, combining nanotechnology with natural compounds could result in development of new therapeutic options for IBD. PMID- 30430452 TI - Macrophage ghost entrapped amphotericin B: a novel delivery strategy towards experimental visceral leishmaniasis. AB - Leishmania donovani, an intracellular parasite, poses many challenges against attempted chemotherapy. After the resistance towards the first-line antileishmanial drug, amphotericin B has become the treatment of choice against visceral leishmaniasis, a fatal tropical disease. However, unfavorable toxicity profile, severe side effects, and prolonged parenteral administration limit its use. Lack of available specific delivery system also makes this drug unsafe for long-term use. In the current study, a "ghost cell" strategy based on macrophage membrane-derived nanovesicle has been introduced as a specific carriage for amphotericin B. Membrane proteins of macrophage ghost play a crucial role in the dissemination of infection in host by communicating between infected neutrophil macrophage system and non-infected macrophages. These membrane proteins are the basis of specificity of the drug delivery to the infected tissues in this current macrophage ghost cell carrier. This cheap and biocompatible delivery vehicle has significantly improved the toxicity profile and lowered LD50 value of the drug compared to traditional way of its direct administration and widely accepted antileishmanial therapy, AmBisome. PMID- 30430453 TI - Topical delivery of 3,5,4'-trimethoxy-trans-stilbene-loaded microemulsion-based hydrogel for the treatment of osteoarthritis in a rabbit model. AB - The aim of this study was to develop a microemulsion-based hydrogel (MBH) formulation of 3,5,4'-trimethoxy-trans-stilbene (BTM) as topical delivery system for the treatment of osteoarthritis (OA). The pseudo-ternary phase diagrams were constructed to optimize the microemulsion (ME) formulation. The ME formulation containing 18.8% Cremopher EL35 (surfactant), 9.4% Transcutol HP (co-surfactant), 3.1% LABRAFIL M 1944 CS (oil), and 68.7% water was selected. The obtained BTM loaded ME (BTM-ME) had a spherical morphology (17.5 +/- 1.4 nm), with polydispersity index (PDI) value of 0.068 +/- 0.016 and zeta potential of - 11.8 +/- 0.5 mV, and was converted into BTM-loaded MBH (BTM-MBH) using Carbopol 940. Ex vivo skin permeation study showed that both ME and MBH formulations significantly enhanced the amount of BTM permeated. The cumulative amount of BTM permeated after 12 h (Q12) for ME, and MBH formulations were 3.25- and 1.96-fold higher than that for emulsion gel (EG). Pharmacokinetic study showed that the AUC of BTM suspension (oral) was three times higher than that of BTM-MBH (topical). Topical delivery of BTM-MBH demonstrated remarkable anti-OA effect in a rabbit model of OA induced by papain, with decreased levels of pro-inflammatory cytokines. The developed MBH formulation might be a promising strategy for topical delivery of BTM for treatment of OA. PMID- 30430454 TI - Uncertainty related to multigene panel testing for cancer: a qualitative study on counsellors' and counselees' views. AB - Multigene panel testing is mainly used to improve identification of genetic causes in families with characteristics fitting multiple possible cancer syndromes. This technique may yield uncertainty, for example when variants of unknown significance are identified. This study explores counsellors' and counselees' experiences with uncertainty, and how they discuss uncertainties and decide about multigene panel testing. Six focus groups were conducted including 38 counsellors. Twelve counselees who had received genetic counselling about a multigene panel test were interviewed. The focus group sessions and interviews were audio-recorded and transcribed verbatim. Transcripts were analysed inductively by two independent coders and data were examined to obtain a comprehensive list of themes. Counsellors identified several uncertainties, e.g. finding a variant of unknown significance, or detecting an unsolicited finding. Most difficulty was experienced in deciding what uncertain information to communicate to counselees and how to do so. The extent and manner of providing uncertain information differed between centres and between counsellors. Counsellors attached more value to counselees' preferences in decision making compared to less extended tests. Counselees experienced difficulty in recalling which uncertainties had been discussed during genetic counselling. They primarily reported to have experienced uncertainty about their own and their relatives' risk of developing cancer. Counselees felt they had had a say in the decision. This study showed that counsellors need more guidance on whether and how to convey uncertainty. Undesirable practice variation in the communication of uncertainty may be prevented by determining what information should minimally be discussed to enable informed decision making. PMID- 30430455 TI - "This could be me": exploring the impact of genetic risk for Huntington's disease young caregivers. AB - Huntington's disease (HD) is a predominantly adult-onset, genetic, neurodegenerative condition. Children of affected individuals have a 50% risk of inheriting HD and often assume caregiving roles for their parent. Studies specifically focused on HD young caregivers have proposed that the genetic risk component of HD "exacerbates" the caregiving experience and identified common responsibilities, burdens, and support needs, but none have explored the relationship between the caregiving role and perception of genetic risk. In an attempt to understand this relationship, we conducted a qualitative study to explore the interaction between a young caregiver's perception of genetic risk, the caregiving experience, and thoughts about and plans for predictive testing. Thirteen individuals between 15 and 25 years who provided care for a parent with HD were recruited from two HD youth groups and local support groups. Interviews were recorded, transcribed, and analyzed thematically. Two themes emerged: (1) caregiving and thoughts about risk and (2) caregiving and perceived opinions towards genetic testing. Our findings suggest that the genetic risk colors the caregiving experience by evoking feelings about the future and a potential diagnosis of HD, in addition to impacting plans for predictive testing. Genetic counselors can use these findings to inform their understanding of caregiver experiences, which can aid them when helping patients explore their motivations for testing during a genetic counseling session. Future studies should explore the extent to which health care providers acknowledge the work of young caregivers in the home and provide support to these individuals. PMID- 30430456 TI - Healthcare Experience and their Relationship with Demographic, Disease and Healthcare-Related Variables: A Cross-Sectional Survey of Patients with Chronic Diseases Using the IEXPAC Scale. AB - BACKGROUND: Patient experience is acknowledged as a principal aspect of quality healthcare delivery, and it has implications with regard to outcomes. OBJECTIVES: Our objective was to evaluate the healthcare experience of patients with chronic diseases to identify patient-perceived healthcare gaps and to assess the influence of demographic and healthcare-related variables on patient experiences. METHODS: A cross-sectional survey was delivered to adult patients with chronic diseases: diabetes mellitus (DM), human immunodeficiency virus (HIV) infection, inflammatory bowel disease (IBD) or rheumatic diseases. Patient experiences were assessed with the Instrument for Evaluation of the Experience of Chronic Patients (IEXPAC) questionnaire, with possible scores ranging from 0 (worst) to 10 (best experience). RESULTS: Of the 2474 patients handed the survey, 1618 returned it (response rate 65.4%). Patients identified gaps in healthcare related mainly to access to reliable information and services, interaction with other patients and continuity of healthcare after hospital discharge. The mean +/- standard deviation (SD) IEXPAC score was 6.0 +/- 1.9 and was higher for patients with HIV (6.6 +/- 1.7) than for those with rheumatic disease (5.5 +/- 2.0), IBD (5.9 +/- 2.0) or DM (5.9 +/- 1.9) (p < 0.001). In multivariate models, better overall IEXPAC experience was associated with follow-up by the same physician, follow-up by a nurse, receiving healthcare support from others and treatment with subcutaneous or intravenous drugs. The multivariate model that confirmed patients with HIV or DM had better experience than did those with rheumatic diseases. CONCLUSIONS: Through IEXPAC, patients identified aspects for healthcare quality improvements and circumstances associated with better experience, which may permit greater redirection of healthcare toward patient-centered goals while facilitating improvements in social care and long-term healthcare quality. PMID- 30430457 TI - Multifunctional roles of tropomodulin-3 in regulating actin dynamics. AB - Tropomodulins (Tmods) are proteins that cap the slow-growing (pointed) ends of actin filaments (F-actin). The basis for our current understanding of Tmod function comes from studies in cells with relatively stable and highly organized F-actin networks, leading to the view that Tmod capping functions principally to preserve F-actin stability. However, not only is Tmod capping dynamic, but it also can play major roles in regulating diverse cellular processes involving F actin remodeling. Here, we highlight the multifunctional roles of Tmod with a focus on Tmod3. Like other Tmods, Tmod3 binds tropomyosin (Tpm) and actin, capping pure F-actin at submicromolar and Tpm-coated F-actin at nanomolar concentrations. Unlike other Tmods, Tmod3 can also bind actin monomers and its ability to bind actin is inhibited by phosphorylation of Tmod3 by Akt2. Tmod3 is ubiquitously expressed and is present in a diverse array of cytoskeletal structures, including contractile structures such as sarcomere-like units of actomyosin stress fibers and in the F-actin network encompassing adherens junctions. Tmod3 participates in F-actin network remodeling in lamellipodia during cell migration and in the assembly of specialized F-actin networks during exocytosis. Furthermore, Tmod3 is required for development, regulating F-actin mesh formation during meiosis I of mouse oocytes, erythroblast enucleation in definitive erythropoiesis, and megakaryocyte morphogenesis in the mouse fetal liver. Thus, Tmod3 plays vital roles in dynamic and stable F-actin networks in cell physiology and development, with further research required to delineate the mechanistic details of Tmod3 regulation in the aforementioned processes, or in other yet to be discovered processes. PMID- 30430459 TI - Racial Disparities in Community Mental Health Service Use Among Juvenile Offenders. AB - PURPOSE: Investigate differences in community mental health service utilization by race among a sample of juvenile offenders in the time surrounding adjudication for a serious offense. It was predicted that racial minority youth would demonstrate lower utilization of these services. METHODS: The Pathways to Desistance data were used in analyses. This consisted of the responses of 1354 juvenile offenders. Wave 1 of the data was used in analyses. Logistic regression models were used to examine the relevance of racial identification and control covariates for predicting odds of receiving community mental health services during the prior 6 months. RESULTS: Results indicate that Black youth had lower odds of receiving all types of community mental health services, relative to White participants. Hispanic juvenile offenders had lower odds of receiving several types of services also, relative to White juvenile offenders. DISCUSSION: Findings indicate that minority justice-involved youth utilize community mental health services in the time surrounding adjudication at lower rates than White juvenile offenders do, a net of all effects. This may be indicative of additional barriers to service use and possible institutionalized racism which restrict mandating of services which may reduce mental health symptom severity and risk for recidivism among minority juvenile offenders. PMID- 30430458 TI - Conducting an observational study during an economic crisis: analysis of the treatment and follow-up phase of Greek patients participating in the ExFOS study. AB - OBJECTIVE: We present the subanalysis of the Greek cohort of the Extended Forsteo Observational Study (ExFOS), a multicenter, non-interventional, prospective, observational study evaluating the effect of teriparatide on fractures, back pain (BP), health-related quality of life (HR-QoL), and safety and compliance, in patients with osteoporosis treated for up to 24 months, with a post-treatment follow-up of at least 18 months. DESIGN: A total of 439 osteoporotic patients (92.2% female) were enrolled in Greece. New or worsened fractures, based on their physicians' assessment, as well as patients' self-assessment of HR-QoL and BP, compliance, and safety profile, were captured by validated questionnaires. RESULTS: In the ExFOS Greek cohort, fracture rates were low and mean bone mineral density (BMD) was numerically improved. Compliance with teriparatide remained high throughout the study, with 81.5% of subjects completing treatment. Only 0.7% of patients reported discontinuation due to adverse effects. A sustainable improvement in patient-perceived BP and HRQoL throughout treatment and follow-up was similar to that achieved by the European Forsteo Observational Study (EFOS). A lower than expected percentage of patients using antiresorptives following teriparatide was recorded. CONCLUSIONS: ExFOS reproduces the outcomes of EFOS, with a 6.5-year time interval between studies, in comparable cohorts of osteoporotic patients. Data should be interpreted in the context of observational study data collection, although summary statistics computed at each time point may overstate drug effect. PMID- 30430460 TI - Psychological Therapy in Secondary Mental Health Care: Access and Outcomes by Ethnic Group. AB - OBJECTIVE: To explore the differences in access to, and outcomes of, psychological therapy for different ethnic groups across a South London Mental Health Trust. METHOD: This study used Trust data to explore the proportions of ethnic groups accessing psychological therapy as a proportion of all patients supported by the Trust, as well as their outcomes within broad diagnostic clusters. RESULTS: Compared to proportions in the local population, there were significantly more White/White British patients and significantly fewer patients from 'other ethnic groups' in the Trust (p < .05). There was also significantly greater proportion of Black/Black British patients with schizophrenia diagnoses compared to the proportion of Black/Black British people in the local population (p < .001). Of those accessing psychological therapy, there were significantly more White/White British and 'other ethnic group' patients and significantly fewer Black/Black British patients (p < .05). For schizophrenia diagnoses, significantly fewer Black/Black British and 'other ethnic group' patients were accessing psychological therapy (p < .05); however for behavioural and emotional disorders, there were significantly higher proportions of 'other ethnic group' and White/White British patients. Outcomes varied by diagnosis; Black/Black British patients experienced significantly higher distress scores at the beginning of therapy for depression and neurotic diagnoses (p < .05), with the latter persisting at the end of treatment. CONCLUSIONS: Across the Trust, there were significant differences in the proportion of ethnic groups in accessing psychological therapy, as well as in outcomes. More research is needed to understand the factors that may underlie these disparities. PMID- 30430461 TI - The Affordable Care Act's Effect on Discharge Disposition of Racial Minority Trauma Patients in the United States. AB - BACKGROUND: Our aim was to examine the US trauma population before and after the Affordable Care Act (ACA), specifically examining racial disparities in insurance status as well as access to post-hospitalization care in the trauma population. MATERIALS AND METHODS: The National Trauma Data Bank was queried for all non-burn patients age 18 to 64. The patient data was grouped into pre-ACA (2012-2013) and post-ACA (2014-2015). Regression analysis was controlled for age, sex, race (when applicable), type of injury (blunt vs penetrating), ISS, shock, head injury, and mechanical ventilation and clustered by hospital. RESULTS: After ACA implementation, mortality decreased (2.4% from 2.6%, P < 0.001) and the number of patients discharged to acute care, nursing homes, and rehabilitation also decreased. Adjusting for age, sex, race, and injury-related variables associated with post-hospital care, the likelihood of discharge to acute care, skilled nursing, and rehab facilities decreased significantly post-ACA for all insurance and discharge destinations except those patients with private insurance discharging to rehab facilities. All uninsured patients as well as Caucasians with public insurance were more likely to die from their injuries than Caucasians with private insurance. After ACA, other minorities with private insurance had a higher mortality than privately-insured Caucasians. CONCLUSIONS: Despite an increase in the rate of insured trauma patients, after implementation of the affordable care act there was no increase in post-hospital care facility utilization, particularly for minorities. Uninsured trauma patients, who are more likely to be minorities, have not only decreased access to rehabilitation resources but also higher mortality. PMID- 30430462 TI - Quality of Diabetes Care Among Recent Immigrants to the USA. AB - BACKGROUND: This study investigated the relationship between immigration status and quality of care for patients with diabetes. METHODS: We used the Medical Expenditure Panel (MEPS) dataset between 2002 and 2011 to examine the association between quality of care and immigration status. Quality of care was measured by report of dilated eye exam, foot exam, A1C test, an annual doctor's visit, and having blood pressure checked. Immigration status was defined as US born, non-US born but living in the USA for less than 15 years, and non-US born but living in the USA for more than 15 years. Bivariate analyses were used to compare receiving quality of care and immigration status. Multiple logistic regression was used to examine the association of immigration status with quality of care, adjusting for demographic and medical variables. RESULTS: Bivariate analyses showed significant differences for all quality of care measures compared to immigration status. However, after adjusting for sociodemographic factors and comorbidities, the only quality of care measures that were significantly associated with immigration status was having blood pressure checked (OR = 0.37 for < 15 years and 0.90 for > 15 years compared to US born, p < 0.001) and having dilated eye exam (OR = 0.77 for < 15 years and 0.89 for > 15 years compared to US born, p = 0.046). CONCLUSIONS: After adjustment for socioeconomic and comorbidity factors, blood pressure testing and dilated eye exams were the only measures significantly associated with immigration status. The highest risk was in the first 15 years after entering the USA and should be a target for interventions. PMID- 30430463 TI - Self-to-others and self-to-self relationships: paths to understanding the valence of body image and eating attitudes in emerging adult women. AB - PURPOSE: Interpersonal and intrapersonal factors contributing to body appreciation in emerging adult women remain poorly explored. Thus, the present study aimed to test the impact of early memories of warmth and safeness with peers, self-compassion, and social safeness, in body appreciation and in disordered eating attitudes and behaviours. METHODS: A total of 387 women aged between 18 and 25 completed a set of self-report questionnaires. Data were analysed through descriptive and correlation statistics, and the suitability of a theoretical model was explored via path analysis. Self-report instruments assessed participants' weight and height, early memories of warmth and safeness with peers, self-compassion, social safeness, body appreciation, as well as disordered eating. RESULTS: Early memories of warmth and safeness with peers associated with higher self-compassion and feelings of social safeness, which were both positively linked to body appreciation. Body appreciation associated with a lower display of disordered eating. CONCLUSION: It seems that childhood and adolescent experiences may have an important influence on the development of self-to-self and self-to-others secure relationships, with consequences on the way women behave and relate with their unique body characteristics. The pertinence of developing self-compassion and affiliative skills to promote positive body image among females is suggested, as well as of applying compassion based strategies when clinically approaching symptoms of eating disorders. LEVEL OF EVIDENCE: Cross-sectional descriptive study, Level V. PMID- 30430464 TI - Spirituality and eating disorder risk factors in African American women. AB - PURPOSE: The increased prevalence of body dissatisfaction and eating disordered behaviors (EDBs) among African American women warrants further examination of critical factors that may contribute to this recent trend. This study sought to investigate whether ethnic identification, spirituality, and internalization of the thin ideal would be associated with decreased body dissatisfaction and EDBs. METHOD: A convenience sample of 55 African American college women was recruited from a college campus. The Eating Attitudes Test, Eating Disorders Inventory, Multigroup Ethnic Identity Measure, Sociocultural Attitudes toward Appearance Questionnaire, Life Regard Index-R, and Spiritual Transcendence Index were administered. RESULTS: Body dissatisfaction and internalization of the thin ideal were positively associated with EDBs. Higher scores on meaning in life were negatively associated with body dissatisfaction. Spiritual transcendence and internalization of the thin ideal were positively associated with body dissatisfaction. Spiritual transcendence was positively associated with meaning in life. CONCLUSIONS: These findings highlight the importance of exploring spirituality and ethnic identification in efforts to understand the relationships among the internalization of a thin ideal, body dissatisfaction, and EDBs in African American women. LEVEL OF EVIDENCE: Level V, Evidence obtained from a cross-sectional descriptive study. PMID- 30430465 TI - The relationship between risk of eating disorders, age, gender and body mass index in medical students: a meta-regression. AB - PURPOSE: Age, gender and body mass index (BMI) are commonly described risk factors for the development of eating disorders. However, the magnitude of these factors (individually and together) is still not well-defined in some populations. METHODS: A systematic search was performed for studies that reported the prevalence of eating disorder risk among medical students using the Eating Attitudes Test-26 (EAT-26) and age, gender and BMI as risk factors. We included studies published in English peer-reviewed journals between 1982 and 2017. A total of 14 studies were included in the analyses, and the meta-regression analyses were performed using mean age (years), gender (proportion of female subjects), and mean BMI (kg/m2) as moderators with the risk of eating disorders measured using EAT-26 as an outcome variable. Four interaction terms were created (1) age * gender (2) age * BMI (3) gender * BMI and (4) age * gender * BMI to assess if two or more independent variables simultaneously influence the outcome variable. RESULTS: Utilizing the EAT-26, the pooled prevalence of at risk for eating disorders among medical students (k = 14, N = 3520) was 10.5% (95% CI 7.3 13.7%). Meta-regression model of age, gender and BMI alone revealed poor predictive capabilities. Meta-regression model of age * gender * BMI interaction revealed statistically significant results with a covariate coefficient of 0.001 and p value of 0.044. CONCLUSION: Results from this sample of medical students provided evidence for the role of interactions between risk factors (e.g., age * gender * BMI) in predicting individuals at risk for eating disorders, whereas these variables individually failed to predict eating disorders. LEVEL OF EVIDENCE: Level I, systematic review and meta-analysis. PMID- 30430466 TI - The role of mindful parenting and children's weight in mothers' child-feeding practices. AB - PURPOSE: This study explores whether mindful parenting dimensions and children's body mass index (BMI) z-scores are associated with mothers' concern about child weight and child-feeding practices (i.e., responsibility for child feeding, pressure to eat, restriction, food reward, and monitoring). METHODS: The sample included 576 mothers of children/adolescents (7-18 years old) with normal weight (BMI = 3-85th percentiles) and 490 mothers of children/adolescents with overweight/obesity (BMI >= 85th percentile; 59% undergoing nutritional treatment). Mothers completed the Portuguese versions of the Interpersonal Mindfulness on Parenting Scale and the Child Feeding Questionnaire. RESULTS: Mothers of children with overweight/obesity undergoing nutritional treatment presented lower levels of emotional awareness of the child, nonjudgmental acceptance of parental functioning, and pressure to eat and higher levels of concern about child weight, restriction and monitoring than the other groups presented. Almost all mindful parenting dimensions and children's zBMI were significantly associated with mothers' concern and child-feeding practices. CONCLUSIONS: Mindful parenting dimensions and children's weight seem to be important predictors of mothers' child-feeding practices and of their concern about child weight, which suggests that a mindful approach in parenting might help mothers adopt more adaptive and weight-adapted child-feeding practices. LEVEL OF EVIDENCE: Level III, case-control analytic study. PMID- 30430467 TI - Weight Reduction and Pioglitazone are Cost-Effective for the Treatment of Non Alcoholic Fatty Liver Disease in Thailand. AB - INTRODUCTION: This study evaluated lifetime liver-related clinical outcomes, costs of treatment, and the cost-effectiveness of treatment options for non alcoholic fatty liver disease (NAFLD) in Thailand. METHODS: A cost-utility analysis using a lifetime Markov model was conducted among Thai patients with NAFLD, from a societal perspective. Pioglitazone, vitamin E, a weight reduction program, and usual care were investigated, with the outcomes of interest being the number of cirrhosis and hepatocellular carcinoma (HCC) cases, life expectancy, quality-adjusted life-years (QALYs), lifetime costs, and the incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were performed. RESULTS: When compared with usual care, a weight reduction program can prevent cirrhosis and HCC cases by 13.91% (95% credible interval [CrI] 0.97, 20.59) and 2.12% (95% CrI 0.43, 4.56), respectively; pioglitazone can prevent cirrhosis and HCC cases by 9.30% (95% CrI 2.52, 15.24) and 1.42% (95% CrI -0.18, 3.74), respectively; and vitamin E can prevent cirrhosis and HCC cases by 7.32% (95% CrI -4.64, 15.56) and 1.12% (95% CrI -0.81, 3.44), respectively. Estimated incremental life expectancy and incremental QALYs for all treatment options compared with usual care were approximately 0.06 years and 0.07 QALYs, respectively. The lifetime costs of both a weight reduction program and pioglitazone were less than usual care, while vitamin E was $3050 (95% CrI 2354, 3650). The weight reduction program dominated all other treatment options. The probability of being cost-effective in Thailand's willingness-to-pay threshold ($4546/QALY gained) was 76% for the weight reduction program, 22% for pioglitazone, 2% for usual care, and 0% for vitamin E. CONCLUSIONS: A weight reduction program can prevent cirrhosis and HCC occurrences, and dominates all other treatment options. Pioglitazone and vitamin E demonstrated a trend towards decreasing the number of cirrhosis and HCC cases. PMID- 30430468 TI - Script concordance test as a sanctionnal evaluation in cardiology. AB - INTRODUCTION: Sanctioning evaluation in cardiology is carried out using multiple choice questions, short-answer questions, clinical cases and editorial questions. However, these methods do not assess clinical reasoning in a context of uncertainty in contrast with script concordance tests (SCT). AIM: To compare the scores obtained by the students in the 3rd year of medicine with the SCT versus the sanctioning test of cardiology and to study the correlation between these two evaluation methods. METHODS: This is a prospective study including 31 3rd year students who completed their cardiology clerckship in the Cardiology Department of the HabibThameur Hospital during the first half of 2016. We compared the scores obtained in the 13 SCT test (39 items) with those of the cardiology normative test. RESULTS: Students 'mean score at SCT was significantly lower than that of experts (66.6 +/- 10.2 vs 86 +/- 6.7%, p <0.0001). The mean score obtained by students at the SCT was significantly higher than that of the cardiology sanctioning test (p <0.001). Cronbach alpha coefficient was 0.71. There was no correlation between the two tests (r = 0.329; p= 0.07). CONCLUSION: The evaluation of our students by the SCT showed mean score statistically higher than the questions of a classic test, without correlation between them. This should encourage us to incorporate SCT into our assessment methods to promote clinical reasoning. PMID- 30430469 TI - The determinants of therapeutic observance in open-angle glaucoma. AB - Adherence to medical treatment in primary open angle glaucoma is key to the success of the treatment. Most of the work show that glaucoma patients are poor observant. Poor adherence is multifactorial. The analysis of these factors is crucial. That is why the author wanted to expose, through a literature review, the main determinants of adherence in glaucoma. PMID- 30430470 TI - Rare retro peritoneal tumor in infants. AB - Lipoblastoma is a rare mesenchymal tumor, occuring in less than three-year-old infants in 90% of the cases and in 40% of the cases in chidren aged less than one year. It can be present at birth. It is a benign tumor, with defined margins, that can be locally aggressive, without metastases. We report the case of retroperitoneal lipoblastomatosis, with a neonatal diagnosis made by ultrasonographic and CT features. PMID- 30430471 TI - Tuberculosis and non-pulmonary malignancies : study of ten cases. AB - INTRODUCTION: Tuberculosis (TBC) is a major public health problem with high mortality especially in developing countries. It is associated with a higher risk of developing pulmonary and non-pulmonary malignancies including solid and hematologic cancers. Association between TBC and nonpulmonary malignancies is rarely described in the literature. AIM: To describe the epidemiological, clinical, therapeutic modalities and the evolutive aspects of patients treated for cancer and TBC. METHODS: This is a retrospective study conducted over a period of 19 years (between 1993 and 2012), including 10 patients followed up for cancer and tuberculosis at the department of oncology and the department of infectious disease, CHU Habib Bourguiba Hospital and CHU HediChaker, Sfax, Tunisia. RESULTS: The average age of patients was 55 years old. The sex ratio was 1. The different locations of cancer were represented by the breast (4 cases), the nasopharynx (1 case), the colon (1 case), the kidney (1 case) the gum (1 case), the endometrium (1 case) and the blood (1 case).TBC and cancer were synchronous in 5 cases. Concerning the metachronous presentation that interested 5 patients, the average time betweenthe onset of TBC after cancer diagnosis was 3.5 years. Three of these patients were treated by chemotherapy with radiation therapy. TBClocalization was nodal in 6 cases, spinal one case, nasopharyngeal in one case, peritoneal in one case and urogenital in one case. The diagnosisof TBC was made incidentally in two cases during axillary lymph node dissection. The therapeutic management of cancer was based on surgery,chemotherapy and / or radiotherapy. All patients received anti TBC treatment for at least six months. Surgery was indicated in one case(laminectomy). A complete remission of cancer was observed in 9 patients. Concerning TBC, recovery was observed in 8 patients, 1 patient hada spinal recurrence and 1 patient is being treated. CONCLUSION: Chronic inflammation during TBC can lead to cancer development. The etiopathogenesis of this association is still imperfectly known. Association between TBC and non-pulmonary cancer, although rare, should be always kept in mind in order to handle in time these two diseases in order provide the best chances of recovery for patients. PMID- 30430473 TI - Metabolic syndrome and physical activity measured by pedometer among adolescents. AB - AIM: To describe the prevalence of metabolic syndrome and to study the association of physical activity measured by pedometer with the metabolic syndrome components, in a sample of overweight and obese adolescents from Sfax City. METHODS: This study concerned 51 obese and overweight adolescents (28 girls and 23 boys), between the ages of 15 and 18 years, recruited by the unit of obesity and metabolic syndrome department of endocrinology, Hedi Chaker Hospital, University of Sfax, between december 2012 and october 2013. Metabolic syndrome was defined with the International Diabetes Federation (IDF) criteria. Physical activity was monitored with pedometer (Digi-Walker SW-200; Yamax Co, Tokyo, Japan). RESULTS: The frequency of metabolic syndrome was 21.6%. It was significantly higher in obese (25%) than in overweight (15,81%) adolescents (p=0.04). The most common component, associated with abdominal obesity, was hypoHDLemia observed in 58.8 % of the sample. The average steps / day measured by pedometer was significantly higher in subjects without metabolic syndrome than with (9648, 25+/-2297, 726 vs 7365, 91+/-1505, 65 steps/day; p=0, 03). Pedometer determined steps/day was inversely correlated with waist circumference (P<0.05), blood pressure (P<0.05) and triglycerides (P<0.05). CONCLUSION: Metabolic syndrome is prevalent in our young population. A more physically active lifestyle appears to be associated with lower probability of metabolic syndrome. PMID- 30430472 TI - Influenza A/H1N1 pdm 09 in children's Hospital Bechir Hamza of Tunis. AB - BACKGROUND: Influenza A (H1N1) is a contagious acute respiratory infection caused a pandemic in 2009. The outcome was variable among populations. AIM: To describe a clinical spectrum and the outcome of Tunisian children with pandemic H1N1/09 influenza virus. METHODS: This is a retrospective, descriptive study of children with pandemic H1N1/09 influenza virus hospitalized in the children's hospital of tunis, between November 2009 and February 2010. The diagnosis was made on positive rapid test or PCR. RESULTS: thirty two children were included. The median age was 12 months. The most frequently symptoms were: fever (87,5%), digestive disorders ( 59,4%) and dyspnea (15,6%). The mean length of stay was 3,8 days. The outcome was complicated by a bacterial infection (56,3%), and one death. CONCLUSION: Mild form of H1N1/influenza virus is the most common presentation; however severe forms can be observed especially in infants. PMID- 30430474 TI - Diagnosis of fetal occiput position using transperineal ultrasound. AB - OBJECTIVE: To compare Transperineal (TP) and Transabdominal (TA) ultrasound in the assessment of fetal head position during the second stage of labor. METHOD: A prospective comparative Study including low risk parturients. The assessment of fetal head position was performed for each patient at full dilation. The ultrasound examination was performed by one examiner using TP technique first then TA. A routine digital vaginal examination was performed by a different examiner blinded to ultrasound findings. Considering TA as reference, the three methods were compared. RESULTS: Fifty two patients were enrolled in the study group. Agreement between the clinical examination and TA ultrasound was average with Kappa index = 0.579. Agreement between TA and TP Ultrasound was good with Kappa index = 0.766. TP technique was accurate in the diagnosis of fetal head position (sensitivity =91.3%, specificity=98.38%, PPV=87.5%, NPV=98.91%). TA ultrasound was the most reliable method in case of high presentations. For lower fetal presentations, the TP approach was more relevant. CONCLUSIONS: Assuming that an accurate diagnosis of fetal head position is required before any instrumental delivery where, by definition, fetal presentation is engaged, the TP ultrasound is advised. In a single time this technique provides the necessary information about the station, and the position of the fetal head. PMID- 30430475 TI - Assessment of the quality of the change of surgical wound dressings by the nursing staff in a university hospital of Tunis. AB - BACKGROUND: Infection of surgical wounds is the main cause of nosocomial infections. In the event of a defect in the care chain, in particular, during the change of the postoperative dressings, the infectious risk would be increased. AIM: To evaluate the gestures of change of dressing practiced by nurses of a university hospital department of surgery, in order to observe the insufficiencies. METHODS: We conducted a two-month-duration prospective, descriptive study having a qualitative approach, consisting of a protocol for observing nursing procedures carried out during the implementation of postoperative dressings in a university hospital surgery department from Tunis. A five-item observation grid was developed based on the nursing procedures that should be performed during dressing rehabilitation. RESULTS: This observation was made on 48 changes of dressings made by 13 nurses (eight women and five men). Inadequacies were noted during the preparation of the gesture, the preparation of the equipment, the execution of the act, the storage of the equipment and the transmission of the care to the rest of the nursing staff. CONCLUSION: The results of our study are consistent with a deficiency of the quality of repair of wounds by the nurses. They show a poor application of the rules of asepsis when repairing surgical wounds. This would be only partly due to inadequate staff training, as the majority of participating nurses were found to be familiar with the basics of the means and methods used to prevent infection of a wound. Other causes are lack of staff and work overload, lack of adequate material for the given care as well as lack of self-responsibility for its nursing practice. The resolution of these problems requires the setting up of an epidemiological surveillance system and the in-service training of the staff involved. PMID- 30430476 TI - Functional repercussion of polyarthrosis of the elderly in tunisia. AB - INTRODUCTION: Osteoarthritis (OA) is the most common degenerative joint disease in the elderly. The often multifocal location at this age can be a source of pain, limitation of everyday activities, thus affecting their quality of life. AIM: To evaluate functional status of aged people with generalized OA in Tunisia, and to detect the main factors associated with a poor function in order to optimize their medical care. METHODS: A cross-sectional, descriptive study done between January and March 2017. Fifty patients were included, aged 65 years and over followed for generalized osteoarthritis. The functional repercussions of polyarthrosis was assessed by functional independence measure (FIM), the Lequesne Algofunctional Index, the Womac index for hip and knee OA, and the Oswestry questionnaire for low back pain. RESULTS: The mean age of patients was 71.94 +/- 0.8 years with a sex ratio of 0.42.The functional status of patients with polyarthrosis were altered to varying degrees. The most impaired dimensions of FIM were self-care, transfers and locomotion. Activities of daily living of the Lequesne index was the most impaired section with an average of 5.28. The three dimensions of the Womac index were affected, particularly the pain section with an average of 49.18/100. The Oswestry index was altered with an average of 18.89 / 40. Factors associated with poor functional status were: Female gender (p<0,05), age of development (p<0,05), spinal arthrosis (p<0,05) and history of falls(p<0,05). CONCLUSION: Polyarthrosis is accompanied by functional impairment in the elderly. Factors associated with functional impairment should be considered in the Patient Management Program. PMID- 30430477 TI - Prognostic factors of survival during hepatocellular carcinoma. AB - INTRODUCTION: Despite advances in diagnostic and therapeutic means,mortality of hepatocellular carcinoma (HCC) on liver cirrhosis remainsheavy in the absence of curative treatment. AIM: To evaluate survival and to identify prognostic factors during HCC. METHODS: A mono centric retrospective study over a period of13 years (January 2002-October 2015), including all patients with HHConcirrhotic liver was performed. Survival analysis was performed accordingto the Kaplan-Meier method. The prognostic factors of survival weredetermined by the Log Rank test. RESULTS: Ninety four patients wereincluded (meanage 66.18 years, sexratio 1.65). Cirrhosiswassecondary to hepatitis B or C in 73.6%). Twentytwo patients responded to the MILAN criteria. Cirrhosiswasrated Child A,B and C in 30.9%, 46.8% and 22.3% of patients, respectively. A Curativetreatment was possible for only 10 patients (11.2%). In our study, meansurvival was 15.1 months and overall survival at 1 year and 2 years were25.5% and 21.3%, respectively. Nine factors associated with shortersurvival were identified : a Child-Pugh stage B or C; the absence ofscreening; an AFP level of> 400ng / ml; the existence of vascularthrombosis; a CHC evolved according to the classification of Milan; anOKUDA III score; CLIP score >= 3; a BCLC stage C or D; palliative orsymptomatic treatment. CONCLUSION: Although the best treatment of HCC remainspreventive, theuse of new prognostic scores couldimprove the management of patientsifintegrated in therapeuticalgorithms. PMID- 30430478 TI - Factors associated with poor medication compliance in hypertensive patients. AB - INTRODUCTION: Hypertension is a major cause of cardiovascular morbidity and mortality. Despite therapeutic advances, only one-third of patients achieve blood pressure targets. Poor compliance is one of the main causes. AIM: To study the factors associated with poor compliance in hypertensive patients. METHODS: We conducted a descriptive prospective study including 200 hypertensive patients treated and followed out between March and April 2017. The Girerd medication adherence questionnaire was submitted to patients during an semi-directed interview. RESULTS: Patients meanagewas of 63.28 +/- 9.62 years-old and sex ratio of 0.92. The predominant risk factor was dyslipidemia in 45% of cases, followed by smoking 36.5% and diabetes 25.5%. A previous history of acute coronary syndrome was found in 33.5% of cases and atrial fibrillation in 13%. Fifteen percent of our patients consumed alcohol regularly and 9.5% practiced regular physical activity. Fifty-five percent of our patients were on low sodium diet. The prevalence of poor medication adherence was 20.5%. In multivariate analysis, independent factors related to poor medication adherence were: the number of treating specialist physicians greater than 1 (OR = 3.444, p = 0.008) and the absence of information received on hypertension (OR = 4.345; p= 0.003). CONCLUSION: The improvement of medication adherence for our patients must be based on information on hypertension and its risks and the harmonization of care between treating physicians. PMID- 30430479 TI - Giant urethral diverticulum calculus revealed by peri-urethral abscess. AB - Urethral diverticulum of the male is uncommon. We report a case of bulbar urethraldiverticulum with contained giant calculus presenting as left inguino scrotal swellingsecondary to peri-urethral abscess in a 40 year-old male. In the light of this case Weemphasize the importance of investigation for the presence of urethral diverticulum in youngmale individuals presenting with voiding disturbances to preventrelated complications. PMID- 30430480 TI - Chronic gastric volvulus. AB - Gastric volvulus is an abnormal rotation of the stomach around his axis. The chronic presenting, as the acute one, is considered as a surgical emergency. We report 4 cases of chronic gastic volvulus. In 2 cases, it was a mesenterico-axial volvulus while in the 2 other cases it was an organo-axial volvulus. The barium enema made the diagnosis in all cases. The volvulus was secondary to a hernia in 3 cases and an agenesis of left diaphragmatic dome with ligament laxity in 1 case. All the patients underwent surgery. The laparoscopic approach was used in two patients. PMID- 30430481 TI - Orbital disorder revealing a lung cancer: a case report. AB - INTRODUCTION: Orbital metastases are rare and they are even rarer to be the first sign of the disease, which can lead to misdiagnosis and delay of management. OBSERVATION: Our patient consulted for a diplopia and a ptosis of the upper eyelid of the right eye since one month, without any other systemic symptoms. After ophthalmological examination and orbital tomography, the diagnosis of orbital metastasis was suspected. Lung cancer was revealed by thoracic tomography and confirmed by an anatomopahological examination. CONCLUSION: Because of the increased incidence of neoplasia, the diagnosis of orbital metastasis should be considered in any elderly patient who consults for symptomatology related to orbital involvement. PMID- 30430482 TI - Training of Tunisian future urologists: how to improve it ? AB - BACKGROUND: The lack of continuous evaluation of training tools in medicine, especially in developing countries, represents a brake to the development of the latter. AIM: To establish an inventory of the training facilities available to residents in urology in Tunisia, to assess their satisfaction and their expectations, and to propose solutions to improve residents training. METHODS: An anonymous questionnaire was sent by E-mail in 2015 to all residents in urology in Tunisia. The questionnaire addressed demographic characteristics, educational resources used and desired, the current medical and university curriculum and evaluation of the training. RESULTS: Among 33 residents, 66.6% responded to the survey. Medical staff, courses organized by the national college of urology, reading french-language articles and daily activity in operating room were the most used pedagogic resources. Training was judged unsatisfactory by 59.1% of respondents because of a lack of theoretical training in 18.1% of cases, a lack of practical training in 13.6% of cases and both of them in 27.2% of cases. Training on animals and simulator, creation of an educational booklet, use of online course materials, and the institution of a mentoring process during residency were rated favorable by the majority of respondents. CONCLUSION: The majority of residents in urology in Tunisia believe their training is unsatisfactory. The E-learning, improved access to surgical training in animals and simulator, better information on existing resources and strengthening of companionship through tutoring should enhance satisfaction. PMID- 30430483 TI - Chronic gastritis classifications. AB - Chronic gastritis are inflammatory diseases of the gastric mucosa whose diagnosis depends on pathological examination. They are frequent and cover a significant part of the daily activity of pathologists. Their origin is often infectious, particularly by Helicobacter Pylori. Several classifications of chronic gastritis were proposed but in order to achieve standardization in the drafting of pathological reports of gastric biopsies, pathologists currently following the recommendations of the revisted Sydney System. OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link for Gastritis Intestinal metaplasia Assessment) stages are increasingly used since they allow the clinicians to select patients with " high risk " chronic gastritis, which require special monitoring. The aim of this paper was to perform a review of the different classifications of chronic gastritis currently available to pathologists. PMID- 30430484 TI - Bibliometric profile of Tunisian medical publications written in English and indexed in Medline. AB - BACKGROUND: English is becoming nowadays the universal language of science. Rresearch published in English can be considered as a bibliometric indicator of the scientific productivity. AIM: We sought to describe the evolution of the Tunisian medical publications written in English over the period from 2004 to 2014. METHODS: Medline's database was consulted using a research query associating the names of the country and the main university cities both in French and in English. The articles with a Tunisian health affiliation were retained but the articles of dentistry, pharmacy and non-medical fields were not included. RESULTS: We counted 979 English language Tunisian medical articles published during the three tracer years of the study: 2004, 2009 and 2014. The increase rate was about 38% between 2004 and 2014. The contribution of medical fields in English language publications was important but showed a clear decrease over time. The retrieved articles did not have the same distribution according to the specialties and the institutions. The distribution according to the journals showed that these articles were mainly published by foreign journals with an increasing impact factors between 2004 and 2014. CONCLUSION: The English language Tunisian medical productivity had shown an important increase over time but many specialties and institutions still not enough implicated in this production.Therefore, increasing research funding, improving the physicians' research methodology and English writing capacities are likely needed to improve the Tunisian medical output. PMID- 30430485 TI - Atopic dermatitis and mother-child interaction: a comparative study of 48 dyads. AB - BACKGROUND: Psychological factors and family environment may play a role in the pathogenesis and the persistence of atopic dermatitis (AD). AIM: To evaluate the interactions between mothers and their children suffering from AD and to look for the presence of maternal depression and anxiety. METHODS: A sample of 24 children with AD and their mothers and 24 matched control dyads participated in the study. Maternal depression and anxiety were assessed using the Beck Depression Inventory short form (BDI) and the Hamilton Anxiety Rating Scale (HAM-A). The mother-child interaction was evaluated by video recording, and through scores established after analyses of the video: M-score for the mother's attitude towards the child and C-score for the child's behavior. RESULTS: AD group mothers showed significantly higher scores on the HAM-A,but not on the BDI. The analysis of the video recording conveyed a significant difference in M-scores between the two groups but no difference in C-scores.. M-score was correlated with the mother's anxiety. CONCLUSION: Our study found evidence in favor of a disturbance of the mother- child interaction in the case of AD, noted on the mother's side, and more anxiety in AD group mothers than in the control group. Our findings suggest the need for psychological support for mothers of children suffering from AD. PMID- 30430486 TI - Management of perforated duodenal peptic ulcer treated by suture. AB - BACKGROUND: Laparoscopic surgery has become the gold standard for many procedures owing to its advantages such as a shorter post-operative stay, a faster recovery and less postoperative pain. However, choosing laparoscopic approach in an emergency situationsuch as in the management of a perforated duodenal peptic ulcer is still debated because of the absence of significant benefits. This study aimed to assess the management of perforated duodenal peptic ulcer treated by suture. METHODS: It's a retrospective study enrolling 81 patients operated on for duodenal perforated peptic ulcer between June 1st, 2012 and December 31st, 2016 who underwent surgery in the surgical department B of Charles Nicolle's Hospital. RESULTS: Our retrospective study showed that laparoscopic approach had shorter post-operative duration (3 [1-5] versus 4 [1-16] days, respectively, p< 0.001), shorter mortality rate (3% versus 19%, p=0.032) and more uneventful post operative course (97% versus 74%, p=0.004) comparing to the open approach. Patients who were not admitted in the intensive care unit during the first 48 hours had 9.901 more chance to be operated by laparoscopic approach. Patients who were operated on by a senior had 3.240 times more chance to be operated by laparoscopic approach. There was no predictive variable for conversion. Mortality rate was 11%. Age was the only predictive independent factor of mortality with a cut-off point of 47 years. CONCLUSIONS: Laparoscopic approach is routinely practised in the perforated duodenal ulcer. In our study, we showed that laparoscopic approach had less post-operative complications, a lower rate of mortality and a shorter post-operative duration comparing to the open approach. The main limitation of our study was non-randomization and lack of laparoscopic expertise. The decision for either open or laparoscopic approach was then dependent on senior surgeon's availability. PMID- 30430487 TI - Evaluation of concordance of Gleason score between prostate biopsy and radical prostatectomy. AB - BACKGROUND: Histological Gleason score grading is a main determinant of prostate cancer treatment. However, the final histological examination may reveal that concordance rates between biopsy and pathological Gleason sums are inadequate. AIM: To evaluate the concordance of Gleason score between prostate biopsy and radical prostatectomy specimen and to study factors predictive of up-grading of Gleason score at radical prostatectomy. METHODS: We conducted a descriptive and retrospective study including cases of patients who underwent prostatectomy between 2008 and 2015. We proceeded to a histological examination of 30 cases of radical prostatectomy and 17 corresponding biopsies. The data of the remaining 13 prostate biopsies, not performed in our hospital, have been picked from detailed histological reports. RESULTS: Our results showed that the concordance in the Gleason score was 43% (kappa = 0.11, poor agreement).Gleason score was upgraded in 54% of the cases. At radical prostatectomy, it increased by two points in one case and by one point in 14 cases. The Gleason score was under-graded on prostatic biopsies in an only 1 case. Using the new classification ISUP 2014, the concordance rate was 26% (kappa = 0.04, very poor agreement). Gleason score was upgraded in 78% of the cases for Group 1 (SG 3 + 3) and 63% for group 2 (SG 3 + 4). The concordance rate was highest for Group 4 (4 + 3). Variables as age, serum PSA (prostate specific antigen) , numbre of cores, percentage of positive cores, or prostate volume were not significant predictors of upgrading of Gleason score on radical prostatectomy specimen. CONCLUSION: Thus, the high rate of discordance of Gleason score between prostate biopsy and radical prostatectomy specimen implies an understanding of factors predictive of discordance of this score allowing urologists, pathologists and oncologists to support patients in a more suitable way, choosing the appropriate therapeutic modality for each patient. PMID- 30430488 TI - Chemo-embolization in the treatment of hepatocellular carcinoma: should we switch to charged particles in our countries? About 102 procedures of a North African radiology center. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a public health problem in african countries. The chemoembolization (CE) could represent the only therapeutic strategy. Two methods can be proposed: charged microparticles and lipiodol chemoembolization. The purpose of this study was to compare results, morbidity and survival between charged microparticles and lipiodol chemoembolization. METHODS: A 5 years retrospective, study was conducted including 62 patients with HCC treated by chemioembolization. The efficacy of the treatment was evaluated for patients by performing a computed tomography four to six weeks after the act. We used " European Association for Study of the Liver " criteria to evaluate the therapeutic outcome. RESULTS: A total of 102 sessions of chemoembolization were performed. This was a with charged microparticles in 70 cases (68.6%) and lipiodol chemoembolization in 32 cases (31.3 %). The difference was not significant between the two CE techniques (lipiodol and charged microparticles) in terms of complete and objective response and complications. The mean survival rate was 30 months +/- 4 for all techniques combined, with no statistically significant difference in terms of survival time without recurrence between the two chemoembolization techniques. CONCLUSION: The efficacy, morbidity and survival of the two CE techniques to lipiodol or microfilled particles are comparable. The selectivity of the technique is to be taken into consideration. For economic health purposes, the CE lipiodolee appears to be more adapted to the context of the developing African countries. PMID- 30430489 TI - Primary glomerulonephritis with predominant mesangial Immunoglobulin G deposits. AB - BACKGROUND: Glomerular deposits are a major pathologic feature of a wide range of human glomerulonephritis and may be located in the mesangial, subepithelial, and subendothelial regions. Rare cases of primary glomerulonephritis definied by exclusive or predominant mesangial IgG deposits were reported. We reviewed the pathologic findings for the 848 renal biopsies examined in our department between 2007 and 2016, one case of primary mesangial IgG glomerulonephritis (MIG) in the absence of any evidence of systemic lupus erythematous (SLE), of other systemic diseases or of Infections. REPOTED CASE: Male patient aged 55 years consults for nephrotic syndrome (proteinuria=7g/1.73m2/day; Albuminemia=14g/L) with hematuria.. The serum creatinine concentration was 88 umol/l, and the creatinine clearance was on MDRD at 82 ml/min/1.73m2. He had a renal biopsy showing the absence of proliferative lesions and the presence of exclusive mesangial IgG deposit. CH50, C3 and C4 levels were normal and antinuclear antibody and anti-DNA antibody assays remained negative during the follow-up period. A full dose corticosteroid was initiated (1mg/Kg/day). The interval from onset of steroid therapy to remission was 2 months. During follow-up; the patient had developed 2 relapsing nephrotic syndrome episods. Then he was switched to Mycophenolate mofetil with remission after 2 months. CONCLUSION: MIG is a very rare but distinct type of primary glomerulonephritis that is characterized by exclusive or predominant mesangial IgG deposits. Its renal prognosis may be less favorable than previously reported because of the possibility of steroids resistance of the nephrotic syndrome and the recurrence after renal transplantation. PMID- 30430490 TI - Successful management of acquired uterine arteriovenous malformation. AB - Uterine arteriovenous malformation (UAVM) is uncommon. They are usually acquired, due to previous intra uterine trauma. We report a case of acquired UAVM in a 28 years-old patient after a medical abortion, diagnosed with ultrasonography and successfully managed with uterine artery embolization. PMID- 30430491 TI - Atrial flutter ablation by femoral approach in a woman with azygos continuation of an interrupted inferior vena cava and dual chamber pacemaker. AB - This report describes a case of isthmus-dependent atrial flutter ablation by the femoral approach in a 54-year-old woman with a previously unknown absence of the inferior vena cava (IVC) and dual chamber pacemaker. Despite looping of the catheters, ablation and termination of atrial flutter were performed successfully without function alteration of the pacemaker leads. This is the first report of an inferior-to-superior approach for ablation of atrial flutter in the absence of the perihepatic IVC with the presence of chronic indwelling leads in the area targeted for radiofrequency. PMID- 30430492 TI - About a lymphoepithelioma-like carcinoma of the lung with an endotracheal localization. AB - INTRODUCTION: Lympho-epithelioma like carcinoma is a rare lung tumour that acounts for less than 1% of non small cell lung carcinomas. It is defined as a special entity among the 2015 World Health Organization. AIM: Our aim was to describe a completely illustrated new case of lymhpo-epithelioma like carcinoma. We describe a new case diagnosed in our Department of Pathology. CASE PRESENTATION: The authors describe a case of a 22-year-old woman without a particular past medical history who presented non specific respiratory symptoms. Radiologic investigations revealed a tracheal tumor with enlarged mediastinal lumph nodes. A first biopsy was performed revealing a malignant tumor with a squamous differentiation highlighted by immunohischemistry. A surgical biopsy was performed and the final microscopic diagnosis revealed a lymphoepithelioma-like carcinoma of the lung. This diagnosis was retained after ruling out a possible metastasis of a nasopharyngeal carcinoma whose microscopic features are similar to this subtype of lung tumor. CONCLUSION: This case points out the rarity of this diagnosis, especially in a young and caucasian patient and highlights the diagnostic dilemma caused by this kind of tumor. PMID- 30430493 TI - Primary aldosteronism diagnosed in a patient with severe renal disease. AB - Although initially considered a rarity, primary aldosteronism now is one of the more common causes of secondary hypertension. Based on older data, it was originally estimated that primary aldosteronism accounted for less than 1% of all patients with hypertension. Subsequent data, however, indicated that it may actually occur in as many as 5-15% of patients with hypertension. Here we present a 66-year-old patient with a history of hypertension who was diagnosed with primary hyperaldosteronism at the time he had developed a severe renal failure secondary to a vascular nephropathy. This case report illustrates the difficulties in diagnosis of primary hyperaldosteronism, and highlights the effects of the delay of diagnosis on renal survival and on patient quality of life. PMID- 30430494 TI - Successful resolution of Hemophagocytic lymphohistiocytosis associated to brucellosis in the adult. AB - Hemophagocyticlymphohistocytosis (HLH) is a proliferation of histiocytes with importanthemophagocytosisoccurring in different organs such as the spleen and the bone marrow. HLH is now increasingly diagnosed in the context of infections, malignancies and connective tissue diseases. Although brucellosis is an endemic infection in Tunisia, its association with HLH is a very rare condition which should be considered in patients with splenomegaly and cytopenia. Here, we describe brucellosis associated HLH in a 31 year-old man. The patient was admitted to our hospital with fever, sweating, and fatigue. Physical and laboratory findings revealed splenomegaly, pancytopenia, elevated serum transaminases, triglycerides, lactate dehydrogenase, and ferritin, and bone marrow hemophagocytosis. The Brucella agglutination test was positive. The patient improved after treatment with Rifampin and doxycyclin. PMID- 30430495 TI - Secondary biliary cirrhosis due to percholecystectomy bile duct injury : report of three cases. PMID- 30430496 TI - Von hippel lindau disease revealed by bilateral renal tumor. PMID- 30430497 TI - Evaluation of an interactive teaching method in the teaching of Pulmonology. AB - INTRODUCTION: For several years, interactive teaching has proved its effectiveness in learning. At the Faculty of Medicine of Tunis (FMT), the interactive sessions are sessions of clarification, illustration, application, and participation (CIAP). AIM: To evaluate pneumology CIAP session in the acquisition of learning by first-year students of the second cycle of medical studies (SCMS1). METHODS: It was a cross-sectional study carried out at the FMT during the academic year 2016-2017 and included students from SCMS1. CIAP session subject was "The chronic respiratory failure". A pre-test and a post-test, with the same subject, were distributed during the session. Knowledge acquisition was evaluated by comparing the scores assigned to the tests. An evaluation of the students' satisfaction with the session progress was made. RESULTS: Ten students attended the CIAP session. The mean score of the pre-test was 2.1 +/- 0.7 over 10 points. A statistically significant (p = 0.003) increase in the score was observed for the post-test, which increased to 4.8 +/- 0.2. For the evaluation of the session by the students, the best scores were assigned for the items evaluating the achievement of objectives and the facilitation of the session by the teacher (1.9 points).The lowest score was given for the item evaluating the time required for the session (1 point). CONCLUSION: The interactive teaching method "CIAP" was beneficial in terms of learning, as demonstrated by the statistically significant improvement of the post-test score compared to the pre test and the satisfaction of the students at the end of the session. Moreover, the involvement of all the stakeholders (students, teachers, and institutions) is necessary for the success of this teaching. PMID- 30430498 TI - Midshaft clavicle fracture synthesis with twisted one-third tubular plate with anterior-inferior approach. AB - BACKGROUND: Fractures of the clavicle are common and usually treated as minor injuries. The middle-third fractures account for 80% of all clavicle fractures. For many years, these fractures have been treated conservatively. After recent studies, this traditional approach has been reconsidered pointing the need to operate in some cases. AIM: To describe functional and radiological outcome of midclavicular fractures fixation using one-third tubular molded plate through an anterior inferior incision and to compare it to the outcome in the literature. METHODS: It was a retrospective study, using data gathered in 40 months from 38 cases of mid-shaft clavicle fractures treated operatively using one-third tubular molded plate with minimum perspective of 12 months. RESULTS: The mean age of the patients was 27 years with a sex ratio of 4.42. 8% of patients were suffering from diabetes. 58% were manual workers. 89% of fractures occurred on the side of the dominant limb, mostly after a domestic accident. In 2/3 of cases, the fracture occurred on the right side after an indirect injury. No vascular or neurological complications were reported. Fractures were most frequently classified Allman type I, AO type A1 and A2 and Edinburgh type 2A2 and 2B1. The mean operative time was 55 minutes. Immobilization with a sling were recommended for 24 hours. The mean consolidation time was 53 days. There was no postoperative complications and none of our patients underwent plate removal for infection. The mean Constant score at last follow up was 90. CONCLUSION: Operative treatment of mid-shaft clavicle fractures using one-third tubular molded plate allows avoiding neurovascular and skin complications with a low financial cost and helps patients, especially manual workers and young athletics, recover a normal shoulder function and return sooner to their usual activities. PMID- 30430499 TI - Primary bone lymphoma: tunisian multicentric retrospective study about 32 cases. AB - AIM: To report the epidemiologic, clinical features, treatment modalities and prognosis of primary bone lymphomas (PBL) within a retrospective Tunisian series. METHODS: We collected cases of histologically confirmed PBL in 3 medical oncology departments from northern and central Tunisia andwe analyzed their characteristics. RESULTS: From January 1990 to July 2014, we collected 32 patients with histologically proven PBL, having a median age of 53 years. They affected mainly the long bones and diagnosed at early stages. 91% of the PBL were large cell B lymphoma. All patients received CHOP or CHOP-likeChemotherapy (CT), associated to Rituximab in the last 9 cases, with 14/32 patients received loco regional radiotherapy and one patient had a resection-reconstruction surgery. We observed 90% of objective responses after primary CT.With a median follow-up of 38.5 months (1 to 192), the 5-year overall survival OS rate was 63%.18 patients relapsed and 14 remain alive in complete remission. CONCLUSION: PBL remains a rare disease lately diagnosed in Tunisia. However, most of the patients had early stages tumors. Furthermore, the efficacy of CT and introduction of Rituximab leads to a high rate of complete/objective responses, improving the survival rate. PMID- 30430501 TI - Radiology department performance: case study of CT scan at Sahloul Hospital (Tunisia). AB - BACKGROUND: The privileged recourse to CT-scan prescription in our current medical practice engender massive request which can alter not only the stability of the operating budgets of the public hospitals but also the clinical and managerial performance of these medical-technical departments. AIM: To audit the quality of CT-scan delivery in radiology Department at University Hospital of Sahloul in 2013. METHODS: Five quality indicators for the CT scan delivery were measured, three of which refer to period of time: A (deposit), B (perform CT Scan) and C (final report recovery), and two evaluating the conformity of the radiological documents of the CT scan (request form and radiological report) using two grids composed of 12 iso-weighted items (one point), and was found satisfactory beyond 10 points. RESULTS: A total of 1141 CT scan request forms were included in the study which 1 111 (97%) were from Sahloul hospital departments and particularly from urology (16,2 %). Filling of CT- scan application form was conform only in 25.6 % of cases. For outpatient clinics the means (+/-SD) of period of time (in days) were: A: 0.2+/- 1.8. B: 59+/- 24.6. C: 14+/-9.2. D: 69.9+/-30.3 and E: 70+/- 30.1 versus A: 0.2+/- 1.8; B: 4.4+/- 3.9; C: 4.7 +/- 6.5; D: 7.9+/- 8.6 and E: 8+/- 8.8 for hospital departments. Final reports were satisfactory in 87% and 52% of cases respectively in outpatient clinics and emergency. CONCLUSION: The performance of the CT scan examination, at Sahloul University Hospital, was limited mainly by excessive times of its realization and unsatisfactory quality of the final reports, hence there is a need of a radiology information system. PMID- 30430500 TI - Mercurial hospital waste: management, becoming and recommendations. AB - INTRODUCTION AND PURPOSE: In hospitals, the use of medical instruments and products containing mercury and the management of mercury waste (MW) collected are regulated in developed countries. In Tunisia, MW end up in landfill and no strategy has so far been adopted. The objective of this study was to quantify MW in two university hospitals in Tunis and to indicate the elimination pathways used and to propose certain recommendations. METHODS: This was a descriptive retrospective study conducted from February to August 2016 and quantifying the MWs from medical products and instruments used by two university hospitals in Tunis during 2015. Semi-structured interviews and focus groups enabled the collection of informations on MW management methods for these products and instruments and their waste and to identify the weaknesses of this management. RESULTS: In 2015, 2,443 mercury thermometers were used by Habib Thameur hospital (HHT) and 7,439 by La Rabta hospital (HLR), releasing 19,764 g of mercury. For dental amalgams, 1,440 g were used at HHT. Their residues (320.4 g) were stored in the original capsules. At HLR, 1,320 g were used but residues, estimated at one-third of the total amount (440g), were discharged into the cuspidor. The total amount released from the amalgams was 380.2g, knowing that half of the volume was mercury. The broken tensiometers (26 at HHT and 113 at HLR) released 183.5g of mercury, the roasted fluorescent lamps (1,627 at HHT and 1,722 at the HLR) 167.4g, Harris Hematoxylin (15 liters at HHT and 18 liters at HLR) 82.5g and used batteries (1,258 at the HHT and 914 at the HLR) 54,3g. In total, with the exception of mercury vapors, the amount of mercury released in 2015 at the two hospitals was approximately 20,632 g. These MW have borrowed the household waste stream (51% of HHT MW and 47% of HLR MW), waste from infectious care activities (47% HHT and 46% of the HLR MW), electrical and electronic waste (1% of HHT and HLR MW), and sewage (1% of HHT MW and 6% of the HLR MW). CONCLUSION: The main supplier of hospital MW is the mercury thermometer (95.8%). The managerial authorities would benefit from the promulgation of a regulatory framework, like the European law of 1998, prohibiting their use on a territorial scale and, by subsidies, replace them with electronic thermometers. PMID- 30430502 TI - Medical practice assessment during the phlebotomy: clinical audit of blood sampling. AB - INTRODUCTION: Phlebotomy is taking a venous blood sample for a medical biology analysis .If the taking of a sample is poorly executed, the results for this sample may be inaccurate and mislead the clinician, or the inconvenience of the patient having to undergo a new levy. The three main problems associated with errors in the collection are: hemolysis, contamination and mislabelling. We conduct clinical audit to evaluate compliance of activities in relation to the recommendations. Our objective was to determine the compliance rate of the different steps of the phlebotomy procedure and propose corrective actions. METHODS: it is an observational study which follows a forward-looking approach based on direct observation of blood collection procedures in 2015. RESULTS: 330 acts of phlebotomy were audited in 11 services. The overall compliance rate phlebotomy was 57.7%. The overall compliance rate ''patient prescribing and preparation "was 94.4%; "equipment preparation" was 85.3%. There was a lack of tourniquets, holders and hydro-alcoholic solutions. The overall compliance rate "collection procedure" was 45.1%, the overall compliance rate for hand hygiene is low (28%), wearing gloves (20%) and the use of antiseptics (44.4%). The overall compliance rate "sample identification"quot; was 61.3% (tube labeling (45.7%) and compliance of the laboratory worksheet (76.9%). the overall compliance rate "Transport" was 49.4%. There was a lack of bag or holders for transport. CONCLUSION: The results obtained allowed to propose an improvement plan to improve this practice. In fact, the ultimate purpuse of medical practice assessment is to improve the quality of care. PMID- 30430503 TI - Outcome of total knee arthroplasty following closing wedge high tibialosteotomy: a review of 40 cases. AB - INTRODUCTION: Total knee replacement after high tibial osteotomy becomes more and more indicated. This intervention needs to identify some pearls and pitfalls. AIM: To evaluate results of total knee arthroplasty after closing wedge high tibial osteotomy. METHOD: Fourty total knee arthroplasty following closing wedge high tibial osteotomy were identified. Demographic features, tibiofemoral alignment and radiolucent lines were documented on postoperatively. Clinical and functional evaluations were performed preoperatively and postoperatively according IKSS score. RESULTS: The average duration of follow-up was 11,5 years. The mean function score increased from 39 points to 70,4 points postoperatively. The mean knee score increased from 40 points to 84,9 points postoperatively. The mean average tibio-femoral angle was 177,7 degrees in preoperatively and 178 degrees (min 176 degrees , max 185 degrees ) at the last follow-up. CONCLUSION: The closing wedge high tibial osteotomy does not compromise subsequent total knee replacement. Knowing pearls and pitfalls lead to better outcome. PMID- 30430504 TI - Predictive factors for major amputation of lower limb in diabetic foot: about 430 patients. AB - BACKGROUND: Major amputation of the lower limb is defined by a leg or thigh amputation. The aim of our work was identifying predictive factors for lower limb major amputation in patients with diabetes admitted on for foot lesions through using an administrative data base. METHODS: It was a retrospective study ranging from June 1st, 2008 to December 31st, 2011, which included all the patients admitted on for an infected diabetic foot to the surgery unit B of Charles Nicolle hospital in Tunis. The main judgement criterion was the major amputation of the lower limb. We have done a descriptive and a comparative study, with univariate and multivariate analysis. RESULTS: We have enrolled 319 men and 111 women. The average age was 60.5 +/- 12 years. Ninety five patients (24%) had a major amputation. Former inpatient, patient readmitted within one month post operatively, stay in intensive care, admission in intensive care within 48hours after admission, age >= 65 years, presence of kidney problem, preoperative stay and length of intervention were identified as predictive factors of major amputation in the univariate analysis. Age was the only independent variable predictive for major amputation which appeared from the multivariate analysis (p=0.004). The age cut-off >= 65 years has a specificity of 69 % and a sensitivity of 47% [p=0.004, OR=1.971, IC 95% : 1.239-3.132]. CONCLUSIONS: Age was the only independent predictive factor for major amputation of the lower limb in the diabetic foot with a threshold value higher or equal to 65 years. Patients aged more than 65 had 1.9 time more risk to undergo major amputation of the lower limb. PMID- 30430505 TI - Cold abscess in the immunocompetent subject. AB - INTRODUCTION: Tuberculous cold abscesses are a rare and unusual form, accounting for 1% of extrapulmonary tuberculosis (TB). AIM: To describe clinical, diagnostic, therapeutic and prognostic aspects of cold tuberculous abscesses. METHODS: Retrospective multicentre study of 26 patients followed for cold abscesses tuberculous in respiratory departments of AbderrahmenMami hospital between 2009 and 2017. RESULTS: We included 24 patients. Mean age was 36.9 years. Six patients had a personal history of pulmonary TB. Circumstances of the discovery were chronic pain (n = 15), parietal swelling (n = 7) and parietal fistulization (n = 2). The mean duration of the symptoms was 2.8 months. Fever was absent in 15 patients. The cold abscess was multifocal in 3 patients, associated with pleuropulmonary TB in 16 patients and extrapulmonary TB in 9 patients. Thoracic wall was the most frequent localization (n=13), followed by subcutaneous and intramuscular localization (n = 6). The surgical flattening of the abscess with biopsy of the edges was performed in 15 patients. The positive diagnosis was pathological in 15 patients and bacteriological in 12 patients. GeneXpert was positive in 2 patients. All patients received anti-tuberculosis treatment. The mean duration of TB was 10.7 months. Evolution was marked by the cure of 20 patients and tuberculous relapse in 1 patient after 6 months. CONCLUSION: Tuberculous cold abscess should be evoked in front of any chronique collection occurring especially in a context of risk factors of TB. Early diagnosis is the best guarantee of a cure without complications. PMID- 30430506 TI - Cephalic tetanus: about two cases. AB - Tetanus is still a common problem in developing countries. Localized tetanus remains a rare clinical presentation dominated by cephalic localization. Head, neck or ear infection strongly guide the diagnosis. A trismus and one or several cranial nerve impairment are the major symptoms. We report two cases of cephalic tetanus associating a trismus with involvement of the cranial nerves. Diagnosis was difficult because the neurological damage preceded the trismus. PMID- 30430507 TI - Mycobacterium fortuitum infection associated with achalasia. AB - The association achalasia and non tuberculous Mycobacteria lung infection is described in the literature. Most of the time Mycobacterium Fortuitum is responsible of aspiration pneumonia that didn't respond to usual antibiotic therapy. We report a new case about a 15 year-old woman with Allgrove's syndrome history. The chest imaging showed a right pulmonary condensation and the diagnosis was bacteriological. Mycobacterium Fortuitum resistant to Rifampicin, isoniazid, Pyrazinamide and ethamabutol was isolated. She was treated by cotrimoxazole, ciprofloxacin and clarithromycin for 12 months, with a good clinical, radiological and bacteriological evolution. With the purpose to prevent the relapse the patient was treated by cardiomyotomy. PMID- 30430508 TI - Self extrusion on an ingested foreign body: a case report. AB - Foreign body ingestion is a frequent issue in paediatrician's practice. Foreign bodies often pass the gastro-intestinal tract spontaneously but can sometimes generate complications (1% of the cases). The migration of ingested foreign bodies is rare, but their spontaneous extrusion through the skin is even rarer and was previously described only in the neck. We report an unusual case of a spontaneous extrusion of an ingested foreign body through the skin of the lower abdomen. Observation: A 2 year-old boy, presented with a 2cm inflammatory swelling of the hypogastric region. Laboratory analysis showed hyperleukocytosis (16 7770 /mm3) and high C reactive protein level at 12mg/L. Ultrasonography and computed tomography allowed us to diagnose a parietal foreign body extruding through the skin and to eliminate associated complication (perforation, vascular fistula...). The foreign body was extracted by a surgical incision. This observation is very rare but it is also uncommon because of the nature of the ingested foreign body which was a wooden piece. Its ingestion was explained by a paediatric mental disorder. PMID- 30430509 TI - Aneurysm of a splenic artery originating from the superior mesenteric artery.About a case. AB - INTRODUCTION: Digestive arterial aneurysms are rare. The splenic artery aneurysm (SA) is the most common visceral artery aneurysm (60% of cases). The origin of SA from the superior mesenteric artery (SMA) is an exceptional anatomical variation. The rupture of this aneurysm leads to death in 10 to 25% of cases. OBSERVATION: This is a 40-year-old adult presenting with abdominal pain associated with fever. An abdominal ultrasound shows a vascular mass projecting into the celiac region. CT angiography shows an aneurysm of SA. The patient is operated on and benefits from selective ligation and resection of the aneurysm with preservation of the spleen. The nascent SA of the SMA has been respected. The immediate postoperative course was simple. The abdominal pain stopped. The patient was placed under medical supervision externally. CONCLUSION: These arterial aneurysms should be followed regularly and should be treated by conventional surgery or better by endovascular procedure when the technical means are available. PMID- 30430510 TI - Atypical form of peritoneal tuberculosis. AB - It was a 48-year-old woman with a right flank mass. On examination there was a hard and painful mass of the right side, centered by a fistula orifice with a diameter of 5 mm. Abdominal computed tomography showed an intraperitoneal tissue structure in relation to the parietal peritoneum in the left hypochondria. A scanno-guided biopsy was performed. Pathological examination revealed non specific inflammatory lesions. The evolution was marked by the appearance of a purulent fistula in the puncture site. A biopsy of the margins of the fistulous orifice of the left hypochondria was performed. Pathological examination found a granular infiltrate with caseous necrosis confirming the diagnosis of tuberculosis. The patient was put under anti-tuberculosis treatment with a good clinical and radiological evolution. PMID- 30430511 TI - Primitive Burkitt lymphoma in testis in non-endemic area: A report of a case. PMID- 30430512 TI - Tow cases of tracheocele revealed by haemoptysis. PMID- 30430513 TI - Resistant hypertension secondary to coexisting primary hyperaldosteronism and renal artery stenosis. PMID- 30430514 TI - Kaposi's varicelliform eruption revealing Darier's disease. PMID- 30430515 TI - The practice of the mental image tool for the training of hand hygiene with Hydro alcoholics solutions: randomized trial. AB - INTRODUCTION: Mental image (or mental practice), a psychological representation of a task to be carried out, is a technique that could enhance skills in several areas areas including medicine. OBJECTIVE: To evaluate the practice of the mental image tool for the training of hand hygiene with Hydro-alcoholics solutions among students of DCEM2. METHODS: Randomized trial including DCEM2 students in Neonatology and Pediatrics at Charles Nicolle Hospital during the same period. Group1: group training in the mental image, Group 2 of reference. The assessment of student achievement was evaluated in terms of obtained scores. RESULTS: The total number of students was 37. The overall score in group 1 was 17.17 +/- 3.82 versus 11.58 +/- 4.05 in group 2, p <10 -3. The friction duration of hands in group 1 was 30.56 S +/- 4.52S versus 24 +/- 5.17 in group 2, p <10-3. CONCLUSION: Mental practice may be a time- and cost-effective strategy that improves hand hygiene with Hydro-alcoholics solutions. PMID- 30430516 TI - Assessment of premature ventricular beats in athletes. AB - INTRODUCTION: Premature ventricular complexes (PVC) are generally considered as a benign electrocardiographic abnormality in the athleticpopulation. However it may be indicative of underlying heart disease which may increase the risk of sudden death. This implies the need forcardiological evaluation before indicating the ability to practice competitive sports. AIM: The aim of this study was to evaluate an athlete population with PVC and establish underlying etiologies in order to take a decisionregarding practicing sports. METHODS: This is a prospective study which included athletes examined in the Tunisian National Centre of Sports Medicine and Sports Science (TNCSM) from January 2013 to June 2015 who presented PVC on an electrocardiogram RESULTS: 5798 athletes were referred to the TNCSM . We identified 42 athletes having PVC with a prevalence of 1.8%. The average age of thestudy population was 21.6 +/- 5.99 years. 83% were men. 88% were asymptomatic the electrocardiogram was considered normal in 62% ofthe athletes according to the Seattle criteria, At the Holter monitoring, the average number of PVC was 920 PVC / 24 hours. Thirteen athleteshad doublets and 11 had triplets. One patient had polymorphic PVC and an R/T phenomenon. The transthoracic echocardiography (TTE) wasnormal in 71 % of cases. Three athletes had hypertrophic cardiomyopathy (HCM). All patients underwent a stress test. The PVC disappearedin 12% of athletes. MRI was performed in 10 athletes confirming the three cases of HCM and revealing a case of arrhythmogenic rightventricular dysplasia and a case of compression of the right ventricle by pectusexacavatum. CONCLUSION: After this assessment, five athletes were not allowed to practice sport. This study shows the necessity of a thorough cardiological assessment of athletes with ventricular arrhythmia in order to detect underlying heart disease and prevent sudden death in this young apparentlyhealthy population. PMID- 30430517 TI - Early outcomes of cardiac surgery in elderly patients. AB - BACKGROUND: Due to the increase in average life expectancy and the higher incidence of cardiovascular disease, more elderly patients present for cardiac surgery nowadays. At the same time, age has been considered a predictor of morbidity and mortality. AIM: To evaluate the short-term outcomes of cardiac surgery in elderly patients. METHODS: We conducted a descriptive retrospective study including elderly patients who underwent cardiac surgery from January 2012 to 31st of December 2016. All patients were hospitalized before and after cardiac surgery in the cardiology department of Habib Thameur Hospital. RESULTS: Our study included 55 patients. Average age was 72+/-6 years old and sex-ratio was two. Eighty-five percent presented with angina, 18% with dyspnea and one patient with an aortic prosthetic valve endocarditis. Mean left ventricular function was 54 +/-9 %. Mean EuroSCORE II was 1.91+/-1.18. Twenty-six per-cent had an urgent surgery. Mean extracorporeal circulation time was of 77+/-26 min and mean extubation time was 8+/-6 h. Eighty-four per cent had a coronary artery bybass grafting and 16% a valve replacement. Four per cent had a redux and 4% a combined surgery. Stay in surgical department varied between 3 and 10 days with average of 4.6+/-1.2 days. Early mortality rate was of 2% and 98% had complications. Ninety eight complications occurred after surgery: 35 reintervention for mediastinal bleeding or tamponade, 28 bleedings requiring transfusions, eight heart rhythm disorders, an atrioventricular conduction block requiring ventricular, five atrial fibrillation, two ventricular tachycardias, a ventricular fibrillation, eight low cardiac outpout, seven prolonged mechanical ventilation and eight pneumonias. In univariate analysis, recent myocardial infarction and chronic kidney disease were predictive of early complications. CONCLUSION: Our data shows cardiac surgery is feasible in elderly patients with acceptable risk in terms of mortality and an increased morbidity due to their frailty. Careful patient selection is needed for the success of cardiac surgery in elderly patients. PMID- 30430518 TI - Laparoscopy for perforated duodenal ulcer: A morbidity score based on a cohort study of 384 patients. AB - BACKGROUND: The Laparoscopic treatment of perforated ulcer is accompanied by a lesser morbidity and mortality compared with treatment by laparotomy. However, the morbidity of the laparoscopic approach is not nil (4%). It is influenced by pre and intraoperative factors. The aim of our work is to establish a morbidity score in patients undergoing laparoscopic surgery for acute peritonitis with perforated duodenal ulcer. METHODS: This is a retrospective study conducted in a General Surgery Department. We included 384 cases of perforated duodenal ulcer operated laparoscopically over a fourteen-year period ranging from January 2000 to December 2014. We conducted a multivariate logistical regression analysis by step-by-step-descending method. From these independent factors we established a score using the ROC curves. The threshold with the best sensitivity and specificity for predicting morbidity was investigated. In all statistical tests, the significance level was set at 0.05. RESULTS: The overall morbidity rate of our patients was 3.38% (13 patients). Multivariate analysis has identified five independent morbidity risk factors: temperature higher than 37.6 degrees C, renal failure, age> 45 years, a number of stitches of two or higher and operating time to 75 minutes or longer. Our morbidity score took into account these 5 factors by integrating the intrinsic value of each factor. The threshold of the score having the best torque sensitivity specificity to predict morbidity was 10. CONCLUSION: A morbidity score for perforated duodenal ulcer surgery performed by laparoscopy may be useful to organize the post-operativecare of these patients usually young and active. A lower score than the threshold predictive of morbidity could allow a rapid rehabilitation of these patients and a one day hospitalization management. PMID- 30430519 TI - Estimation of the prevalence of obstructive sleep apnea in non alcoholic fatty liver disease. AB - INTRODUCTION: The prevalence of non alcoholic fatty liver disease is increasing in parallel with the epidemic of obesity and metabolic syndrome. Recent data have shown frequent association between non alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea. AIM: To estimate the prevalence of sleep disorders, to search an obstructive sleep apnea syndrome by conducting a ventilator polygraphy and to search the particularities of obstructive sleep apnea when its exists, in patients with NAFLD. METHODS: A prospective study, conducted over a period of 6 months, including patients followed for non-alcoholic fatty liver disease. We performed in all patients a Berlin questionnaire that assesses the risk of obstructive sleep apnea syndrome, an Epworth score that estimates the degree of daytime sleepiness and a ventilator polygraphy. RESULTS: We collected 37 patients. The mean age was 50,41+/-13,7 years. The sex ratio (M/F) was 0,42. Type 2 diabetes mellitus, arterial hypertension or dyslipidemia were recorded respectively in 37,8%, 40,5% and 37,8% of cases. Snoring was noted in 75,7% of cases and excessive daytime sleepiness in 34,2% of cases. Obesity was observed in 73% and metabolic syndrome in 43,2% of cases. The Berlin Questionnaire was positive in 64,9% of cases. The average score of Epworth scale was 9,22+/-4,02 and 43,2% of patients had a score> 10. Ventilatorypolygraphy was positive in 13 cases (35,1%) with a mean AHI of 7,02+/-10,08.In these patients, obstructive sleep apnea was mild, moderate and severe in respectively 61,5%, 15,4% and 23,1% of cases. In univariate analysis, subjects with positive ventilator polygraphy had a significantly higher waist circumference (118,00 versus 109,58, p=0,05). Arterial hypertension was significantly associated with increased daytime sleepiness (p=0,018). In multivariate analysis, the only independent variable associated with excessive daytime sleepiness was arterial hypertension (OR=5,33 p=0,021). CONCLUSION: In our study, the prevalence of obstructive sleep apnea syndrome is high in patients with non alcoholic fatty liver disease. The only independent variable associated with excessive daytime sleepiness was arterial hypertension. PMID- 30430522 TI - Target therapy for metastatic breast cancer. AB - Breast cancer is the first cancer in women worldwide. Since the previous estimates of WHO in 2008, incidence is increasing and it is estimated that 30% of women will develop immediately a metastatic form. However, advances in molecular biology and the discovery of new therapies have extended significantly the survival of patients and improved the quality of life of patients with metastatic breast cancer. The study of gene expression and protein profile has resulted in a finer classification of breast cancer and adapt the treatment of patients according to their molecular profiles. The purpose of our work is to describe the different targeted therapies used in the MBC and their action's mechanism referring to various therapeutic trials described in the literature. PMID- 30430521 TI - Oral Communication Abstracts of the 18th Pan Arab Cancer Congress. TUNISIA. April 19-21, 2018. PMID- 30430524 TI - Impact of smoking on the severity of Obstructive Sleep Apnea Hypopnea Syndrome. AB - BACKGROUND: Smoking is an established risk factor of several respiratory and extra respiratory diseases. However, the effect of smoking on obstructive sleep apnea syndrome (OSAS) is not well characterized. The purpose of this work is to study the influence of smoking on the severity of OSAS. METHODS: We performed a retrospective study, which included patients with an obstructive sleep apnea syndrome diagnosed in the pulmonology department of Charles Nicolle Hospital in Tunis, during the period from January 2008 to December 2014. RESULTS: We collected 104 patients with obstructive sleep apnea syndrome. The average age of patients was 49,4 years (14-81 years). The majority of patients were women (53,8%). Thirty two patients were smokers with an average consumption of 27 PA. The reasons for consultation were nocturnal snoring (90%), daytime sleepiness (77%), respiratory pauses (53%), nocturia (35%), daytime fatigue (34%) and headache (29% ). The average weight was 92 kg. The average BMI was 33 kg / m2. The average waist circumference was 98 cm. On average, the Epworth score was 12. The apnea hypopnea index was on average 32 / h. A slight OSAS was noted in 28,8% of cases, moderate OSAS in 14,4% of cases and severe OSAS in 53,8% of cases. The number of desaturations averaged 155. The CPAP treatment was fixed in 61 patients (58%) and self-controlled in 5 patients (4,8%). Adherence was checked in 48 patients (46%) and it was good in 85% of cases. The comparison between the smoking and non-smoking subjects was about; the Epworth scale, FEV, AHI, mean SpO2 and observance of treatment but no significant difference was found. CONCLUSION: Although our study did not find any difference between smokers and non smokers, smoking cessation takes an important place for management of a patient with OSAS. PMID- 30430523 TI - Hypoparathyroidism in children: a study of eight cases. AB - BACKGROUND: Hypoparathyroidism is a rare pediatric endocrine disease, which is caused by low circulating levels of PTH or insensitivity to its action in the target tissues. AIM: To report the clinical and biochemical characteristics and theoutcome of 8 patients with hypoparathyroidism. METHODS: We analyzed retrospectively the results of clinical, biochemical, radiological findings of patients with hypoparathyroidism diagnosed in pediatric department of Hedi Chaker Hospital during the period 1994-2013. RESULTS: Eight patients (5 females and 3 males) were diagnosed with hypoparathyroidism during 20 years's period. The median age at the onset of first symptoms was 17,5 months (15 days- 5 years and 10 months). Seizures were the most commonly presenting symptom and were seen in seven cases. Eight patients were diagnosed with hypoparathyroidism (Di-Georges syndrome: one case, Sanjad Sakati syndrome: 3 case, kearns sayre syndrome: 1 case, autoimmune polyendocrinopathy candidiasis- ectodermal dystrophy: one case, idiopathic hypoparathyroidism: two cases. Conventional treatment was based on calcium and vitamin D analogs. The average of follow up was 5 years. Nephrocalcinosis was noted in two patients. The death occurred in five patients; it was related to hypocalcaemia in one patient. CONCLUSION: The diagnosis of hyperparathyroidism is easy; it's established on the association of hypocalcaemia and hyperphosphatemia. Etiologic approach is based on molecular findings. Vitamin D analog treatment of hypoparathyroidism in children involves the challenge, of adjusting treatment dosage to minimize both symptomatic hypocalcemia and asymptomatic, but potentially kidney-damaging, hypercalciuria causing nephrocalcinosis and renal insufficiency. PMID- 30430525 TI - Epidemiological situation of enterobacteriaceae resistant to cephalosporins third generation in the region of Mahdia, Tunisia (2002-2014). AB - OBJECTIVES: To determine the prevalence and to monitor the trends of resistance to broad-spectrum cephalosporins among various species of enterobacteria in the region of Mahdia (Tunisia) from 2002 to 2014. METHODS: A retrospective study was carried out in the microbiology laboratory at Tahar Sfar Teaching Hospital in Mahdia. Data concerning a thirteen-year period (2002-2014). All clinical isolates of enterobacteriaceae were identified with the API 20 E system. Antimicrobial susceptibilities were determined by disk diffusion on Mueller Hinton agar according to CA-SFM recommendations. RESULTS: During the study period, 25040 non duplicate clinical strains of enterobacteriacae were identified. 2584 (10,3%) clinical isolates showed acquired resistance to third generation cephalosporins (3rdGC). The overall frequency of resistance increased from 8% in 2002 to 16,3% in 2014. This increase was statistically significant. High prevalence rates of 3rdGC resistance have been observed in pediatric (25,1%), in gynecologyobstetrics (21,9%) and medecine (17,4%). E. coli (21,6%), K. pneumoniae (28,6%) and E. cloacae (30,5%) showed high prevalence rates of broad-spectrum cephalosporin resistance. CONCLUSION: The resistance rates ERC3G in our region seems to be increasing. Implementation of infection control measures and identification of the mechanism responsible for third generation cephalosporins resistance are necessary to limit the spreading of these resistant enterobacteriaceae in hospitals and community settings. PMID- 30430526 TI - Fahr's syndrome in Southern Tunisia: A broad spectrum of clinical and etiological features. AB - AIM: We describe the clinical and etiological profile of patients with Fahr's syndrome (FS). METHODS: Charts of sixteen patients diagnosed with FS between 1999 and 2014 were retrospectively assessed. RESULTS: The mean age at diagnosis was 44.68 years (11-67 years). The most main presenting neurological features were seizures in 6 cases, headaches in 5 cases and parkinson's syndrome in 3 cases. Psychiatric disorders were observed in 2 patients including memory loss and iritability. Hypocalcemia clinical features were observed in 7 cases. The mean value of hypocalcemia was 1.69 mmol/l. Etiologies included idiopathic hypoparathyroidism in 4 patients, pseudohypoparathyroidism in 5 cases, secondary hypoparathyroidism, isolated hypovitaminosis D and cerebral radiotherapy in one case for each and Fahr's disease in 4 patients. Oral calcium and vitamin D substitution were started in patients with parathyroid disturbances with favorable outcome. CONCLUSION: In this report, we propose to discuss the clinical manifestations of FS, its etiologies especially parathyroid disturbances and its therapeutic modalities. PMID- 30430527 TI - Xanthogranulomatous pyelonephritis in adults: clinical, biological, radiological and therapeutic main findings in diffuse and focal forms. About 42 cases. AB - INTRODUCTION: Xanthogranulomatous pyelonephritis (XGPN) is a particular form of chronic renal suppuration characterized by the destruction of renal parenchyma and its replacement by a granulomatous tissue containing xanthomatous cells. OBJECTIVE: To report and describe the main clinical, biological, radiological and therapeutic aspects of xanthogranulomatous pyelonephritis in adults in focal and diffuse forms. METHODS: This was a monocentric retrospective study involving 42 cases of XGPN operated and histologically confirmed between 2005 and 2015. We included in our study the patients belonging to any age, of both sexes, with a preoperative CT and whose XGPN diagnosis was confirmed histologically. Clinical, biological, bacteriological, radiological data and surgical procedures were collected and analyzed. RESULTS: The mean age was 50 years (34-79) with a sex ratio of 0.61. The XGPN was diffuse in 88% and focal in 12% of cases. Clinical symptoms were dominated by low back pain (95%), fever (64%) and recurrent urinary tract infections (41%). Urine culture was positive in 67% of cases and Escherichia Coli was the most isolated germ (36%). 64% of patients had inflammatory anemia and 57% of patients had an inflammatory biological syndrome. Ultrasound and CT revealed obstruction of the urinary tract in all cases: a lithiasic cause in 90% of cases and the rest were isolated cases of retroperitoneal fibrosis, abnormal pyelo-ureteral junction, ureteral stenosis and pyelo-ureteric duplicity. A peri-renal abscess and / or psoas was associated in 6 cases (14%). The preoperative diagnosis was often pyonephrosis (50%). Neoplasia was suspected in 4 cases. The treatment consisted in a radical nephrectomy for all patients preceded by drainage of the excretory pathways in 41% of the cases and drainage of a collection in 21% of the cases. CONCLUSION: The XGPN is a rare entity whose diagnosis is difficult. This is suspected on a cluster of clinical and biological arguments and can be evoked on the preoperative CT. The kidney cancer is the main differential diagnosis. PMID- 30430528 TI - Sensitivity to pain in autistic spectrum disorders: Its links with self gressivity. AB - OBJECTIVES: To investigate the link between pain sensitivity in autism spectrum disorders (ASD) and self-aggressive behavior. METHODS: we performed a cross sectional study which involved 50 children fulfilling DSM-V criteria for ASD; confirmed by the Autism Diagnostic Interview Revised. The severity of autism was determined using the Childhood Autism Rating Scale (CARS).The psycho-educational profile (PEP-R) was used to assess the age of development and perception. Sensitivity to pain was assessed with item IX of the CARS. Self-aggressive behavior was assessed by the Behavior Problems Inventory. RESULTS: Pain sensitivity was lowered in 40% and elevated in 4% of children. In the univariate analysis, no statistically significant association was found between normal sensitivity or hyper sensitivity to pain and the presence of auto-aggressiveness. A significant association was found between the presence of hypo-sensitivity to pain and the following variables: auto-aggression (p = 0.007, OR = 5.8, 95% CI = 1.5-21) , frequency of self-aggression (p = 0.001), intensity of self-aggression (p = 0.05), location of auto-aggressiveness at head and (P = 0.007, OR = 7.6, 95% CI = 1.8-14), higher score at CARS, and lower perception score at PEP-R (p = 0.012). Multiple-varied analysis identified risk factors for hypo-sensitivity to pain: lower perceptual score (p = 0.003, adjusted OR = 4.3, 95% CI = 1.9-54) and location of self-aggression at head and hands (p = 0.001, adjusted OR = 1.09, 95% CI = 1.02-1.09). CONCLUSION: It would be interesting to develop tools allowing a fine and precise evaluation of the painful sensation. PMID- 30430529 TI - Edinburgh questionnaire in the screening for peripheral artery disease in type 2 diabetic patients. AB - AIM: to analyze Edinburgh questionnaire (EQ) screening performance for peripheral artery disease (PAD) in type 2 diabetic patients. METHODS: Cross sectional study including 150 type 2 diabetic patients without PAD history. All patients responded to EQ and had peripheral pulse checkup and measurement of the ankle/brachial index (ABI). PAD was considered to be present when the ABI was <= 0.9 Results: Participants mean age was 57.46 +/- 8.04 years and sex-ratio (men/women) was 1.3. EQ has revealed intermittent claudication in 18 patients (12%). On examination, 42 patients (28%) had at least one weakened or abolished pulse in upper limbs. ABI has revealed the presence of PAD in 16% of patients. The EQ sensibility specificity, positive and negative predictivevalueswere 29, 91,39 and 87%, respectively. Among patients with false negative results (n=17), nine had peripheral neuropathy. CONCLUSION: In diabetic patients, EQ had a very low sensibility for the PAD screening. In fact, the important false negative rate, due to the coexisting of peripheral neuropathy, had limited the use of this questionnaire. PMID- 30430530 TI - Extremely preterm infants in Tunisia: Where are we now? AB - BACKGROUND: Extremely preterm infants are newborns born before 28 weeks of gestation. Survival of these immature newborns depends on resuscitation and the quality of care during hospitalization. OBJECTIVE: To determine survival and neurologic outcomes at2 years after extremely preterm birth. METHODS: It is a retrospective multicentric study in 5 neonatal intensive care units (NICU) in 2012-2013.All live births less than 28 weeks gestation were included. RESULTS: A total of 109 births were recorded. Prenatal corticosteroids were given in 47% of cases. Mean weight was 989g and mean age was 26 weeks gestation. Ninety percent of patients had respiratory distress syndrome and 67% of them needed respiratory support. Surfactant was given to 29% of newborns. The mortality rate atdischarge was 76%.The first cause of mortality was nosocomial infections. At thecorrected age of 2 years, 27% of survivors had abnormal neurologic outcome. CONCLUSION: In our study, survival and neurologic outcomes ofextremely preterm infants were poor.In this high-risk population, improving perinatal care remains a challenge to improve long-term outcome in Tunisia. PMID- 30430531 TI - Particularities of neonatal isthmic aortic coarctation (A Tunisian study). AB - METHODS: This is a retrospective study including 47 patients with isthmic coarctation (CoA) diagnosed in ante et postnatal period, hospitalized in pediatric cardiology departement of la Rabta Hospital-Tunisia during the period from 2000 to 2017. RESULTS: They were 36 girls and 11 boys with an average age of 14 days. The diagnosis of CoA was suspected during the antenatalperiod in eight cases. In postnatal period heart failure was observed in (38.5%), abolition of femoral pulse (74%), a tension asymetry was found in all patients. Antenatal echocardiography suspected indicators of fetal coarctation especially ventriculo arterial asymmetryechocardiography confirmed the diagnosis of CoA ,The ejection fraction was impaired in 31% of the cases.The abnormalities associated with coarctation were dominated by the patent ductus arteriosus (68%), atrial septal defect (55.5%), aortic hypoplasia, bicuspidia in respectively in 34% and 31% coarctation syndrome in (23.4%). Prostaglandin wasneccessary in (89.3%). forty two patients were operated with good immediateresults. the early postoperative mortality was 12.5%. In the long term, we deplored two late deaths, six cases of recoarctation with a follow-up of 14 months treated by percutaneous angioplasty with a result considered good in all cases. CONCLUSION: Coarctation of the aorta in neonates is a special form of aorticcoarctaion that differs from the child and adult forms in clinical, echocardiographic, and therapeutic characteristics . His clinical diagnosis must be early, if possible in antenatal , to asssure optimal management. PMID- 30430532 TI - Primitive necrotizing fasciitis of the thoracic wall: Fatal complication of diabetic patient. AB - INTRODUCTION: necrotizing fasciitis of the chest wall is a rare condition in subcutaneous tissues and deep fascia. Primary thoracic involvement is exceptional and is a diagnostic and therapeutic emergency. AIM: To report our experience in the management of this rare pathology of which clinical picture is unknown by most practitioners. METHODS: This is a retrospective study carried out over a period of 07 years, compiling 07 cases of primitive necrotizing fasciitis of the thoracic wall at the department of thoracic surgery at the CHU Hassan II in Fez. RESULTS: Patients were five men and two women, with an average age of 58 years. All our patients were known to have poorly balanced diabetes. The reason for consultation was a swelling of the chest wall with fever in all patients. On the results of thoracic computed tomography (CT), the presence of a deep collection of soft tissue was found in all patients. The treatment was a large necrosectomy, taking away the skin as well as the adjacent muscle. Postoperative follow-up was favorable in five patients. We noted two deceased patients due to postoperaive septic shock. CONCLUSION: Necrotizing chest wall fasciitis is a medical and surgical emergency, requiring early diagnosis and rapid and appropriate management which will determine the prognosis. PMID- 30430533 TI - Bilateral congenital macular coloboma: Swept-source optical coherence tomography findings. AB - A 15-year-old male presented with decreased vision and nystagmus from childhood. Best-corrected visual acuity was limited to 0,05/10 in both eyes. Fundus examination revealed a well-demarcated macular excavation of 2 discs diameter, baring of the underlying sclera, surrounded by a pigmented rim and hypopigmented retinal areas. Autofluorescence images showed a central hypoautofluorescent lesion with patchy hypoautofluorescent areas corresponding to retinal pigmented epithelium (RPE) and photoreceptor atrophy. Swept-source optical coherence tomography showed a crater-like depression with atrophy of the neurosensory retina and the absence of RPE and choroid except some large choroidal vessels. Anti-toxoplasma antibody was negative. These findings are suggestive of a congenital macular coloboma. Similar lesions have to be excluded such as toxoplasmosis macular scar and North Carolina dystrophy. PMID- 30430534 TI - What is the interest of the electroencephalogram in the syndromic diagnosis? AB - INTRODUCTION: The identification of the epileptic syndrome is a challenge particularly in childhood epilepsies. In fact, the diagnosis may need several years to be fulfilled. OBSERVATION: Our patient presented at the age of 3 years 6 months atypical absence. His electroencephalogram (EEG) showed generalized spikes and waves andpolyspikes and waves. At age 6, he has developed other types of seizures: slow fall of the head, shoulders jerks,slow fall to the side and loss of consciousness. All these phenomena were organized in a fortuitous and variable association from one period to another over 2 years. Meanwhile, the child developed cognitive impairment. EEG showed fast rhythms in sleep and waking. It was only at the age of 8years, whenthe child developedtonic seizures,that we made the diagnosis of Lennox-Gastaut syndrome. CONCLUSION: In the absence of Specific Markers, syndromic diagnosis in epilepsy remains Electro- clinical. PMID- 30430535 TI - Pituitary tuberculosis presented with pituitary coma. AB - BACKGROUND: Pituitary tuberculosis is very rare. Its diagnosis is difficult unless a bacteriological or histological evidence of tuberculosis. OBSERVATION: We report the case of a 54 years old woman who presented with a pituitary coma that occurred two weeks after the initiation of antituberculous therapy for cervical lymph node tuberculosis. Resonance magnetic imaging showed a pseudotumoral aspect of the pituitary gland. She had hormonal replacement and anti-tuberculous therapy. Outcome was favourable with the normalization of both the pituitary function and the pituitary volume. However, an acute hypopituitarism happened eight months after the withdrawal of antituberculous, which were taken during 12 months. The re initiation of anti tuberculous therapy and its extension to two years leaded to a prolonged remission. CONCLUSION: the three-phase outcome confirms the tuberculous origin of the hypophysitis in our patient. PMID- 30430536 TI - Epiphyseal pseudotumor of the tibia:an uncommon presentation of osteoarthritis. AB - Epiphyseal pseudotumor secondary to osteoarthritis are rare in patients under 50 years. We report here the case of a 48-year-old woman who complained of pain in the medial side of the left knee for three years. X-rays of the left knee showed a large lytic lesion containing multiple septae, with sclerotic margins at the upper end of the tibia, associated with knee osteoarthritis. An epiphyseal tumor of the left tibia was suspected. CT scan of the left knee concluded in a giant subchondral cyst secondary to osteoarthritis. Subchondral cysts or geodes are a common finding in patients with knee osteoarthritis. Nevertheless, some unusual aspects of the lesions may lead to diagnosis difficulties. PMID- 30430537 TI - A robust RUV-testing procedure via gamma-divergence. AB - Identification of differentially expressed genes (DE genes) is commonly conducted in modern biomedical research. However, unwanted variation inevitably arises during the data collection process, which can make the detection results heavily biased. Various methods have been suggested for removing the unwanted variation while keeping the biological variation to ensure a reliable analysis result. Removing Unwanted Variation (RUV) has recently been proposed for this purpose, which works by virtue of negative control genes. On the other hand, outliers frequently appear in modern high-throughput genetic data, which can heavily affect the performances of RUV and its downstream analysis. In this work, we propose a robust RUV-testing procedure (a robust RUV procedure to remove unwanted variance, followed by a robust testing procedure to identify DE genes) via gamma divergence. The advantages of our method are twofold: (i) it does not involve any modeling for the outlier distribution, which makes it applicable to various situations; (ii) it is easy to implement in the sense that its robustness is controlled by a single tuning parameter of gamma-divergence, and a data-driven criterion is developed to select gamma. When applied to real data sets, our method can successfully removed unwanted variation, and was able to identify more DE genes than conventional methods. This article is protected by copyright. All rights reserved. PMID- 30430538 TI - Complement, Hidradenitis Suppurativa and Pathogen-Driven Positive Selection. AB - The precise pathogenesis of Hidradenitis Suppurativa (HS) remains unclear. Kanni et al1 provides novel data implicating C5a and the membrane attack complex in HS pathogenesis. This opens the possibility of therapeutic blockade of C5a for the treatment of HS, although the results do require replication in larger patient cohorts. The current HS pathogenic paradigm involves dysregulation of the Th17:T reg axis with contribution from genetic polymorphisms, metabolic syndrome, the microbiome and smoking, so data implicating complement is somewhat unexpected, stimulating the need for reconsideration of the current pathogenic paradigm. This article is protected by copyright. All rights reserved. PMID- 30430539 TI - Sickle cell screening in Europe: the time has come. PMID- 30430540 TI - Exact Inference on the Random-Effects Model for Meta-Analyses with Few Studies. AB - We describe an exact, unconditional, non-randomized procedure for producing confidence intervals for the grand mean in a normal-normal random effects meta analysis. The procedure targets meta-analyses based on too few primary studies, <= 7; say, to allow for the conventional asymptotic estimators, e.g., DerSimonian and Laird 1986, or non-parametric resampling-based procedures, e.g., Liu, Lee, and Xie 2007. Meta-analyses with such few studies are common, with one recent sample of 22,453 heath-related meta-analsyes finding a median of 3 primary studies per meta-analysis (Davey et al. (2011)). Reliable and efficient inference procedures are therefore needed to address this setting. The coverage level of the resulting CI is guaranteed to be above the nominal level, up to Monte Carlo error, provided the meta-analysis contains more than 1 study and the model assumptions are met. After employing several techniques to accelerate computation, the new CI can be easily constructed on a personal computer. Simulations suggest that the proposed CI typically is not overly conservative. We illustrate the approach on several contrasting examples of meta-analyses investigating the effect of calcium intake on bone mineral density. This article is protected by copyright. All rights reserved. PMID- 30430520 TI - Poster abstracts of the 18th Pan Arab Cancer Congress. TUNISIA. April 19-21, 2018. PMID- 30430541 TI - Convex Clustering Analysis for Histogram-Valued Data. AB - In recent years, there has been increased interest in symbolic data analysis, including for exploratory analysis, supervised and unsupervised learning, time series analysis, etc. Traditional statistical approaches that are designed to analyze single-valued data are not suitable because they cannot incorporate the additional information on data structure available in symbolic data, and thus new techniques have been proposed for symbolic data to bridge this gap. In this paper, we develop a regularized convex clustering approach for grouping histogram valued data. The convex clustering is a relaxation of hierarchical clustering methods, where prototypes are grouped by having exactly the same value in each group via penalization of parameters. We apply two different distance metrics to measure (dis)similarity between histograms. Various numerical examples confirm that the proposed method shows better performance than other competitors. This article is protected by copyright. All rights reserved. PMID- 30430542 TI - Gastro-intestinal involvement in Stevens-Johnson syndrome and toxic epidermal necrolysis : a retrospective case series. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by extensive skin and mucosal membrane detachment together with specific visceral involvement. While respiratory tract2 and ear, nose, and throat1 mucosal lesions have been comprehensively described, gastro-intestinal (GI) involvement, although previously reported, has been less investigated. Clinical manifestations are non-specific, including ileus, emesis, diarrhea, hematemesis, melena/rectal bleeding, abdominal pain, or dysphagia. This article is protected by copyright. All rights reserved. PMID- 30430543 TI - Causal inference accounting for unobserved confounding after outcome regression and doubly robust estimation. AB - Causal inference with observational data can be performed under an assumption of no unobserved confounders (unconfoundedness assumption). There is, however, seldom clear subject-matter or empirical evidence for such an assumption. We therefore develop uncertainty intervals for average causal effects based on outcome regression estimators and doubly robust estimators, which provide inference taking into account both sampling variability and uncertainty due to unobserved confounders. In contrast with sampling variation, uncertainty due to unobserved confounding does not decrease with increasing sample size. The intervals introduced are obtained by modeling the treatment assignment mechanism and its correlation with the outcome given the observed confounders, allowing us to derive the bias of the estimators due to unobserved confounders. We are thus also able to contrast the size of the bias due to violation of the unconfoundedness assumption, with bias due to misspecification of the models used to explain potential outcomes. This is illustrated through numerical experiments where bias due to moderate unobserved confounding dominates misspecification bias for typical situations in terms of sample size and modeling assumptions. We also study the empirical coverage of the uncertainty intervals introduced and apply the results to a study of the effect of regular food intake on health. An R package implementing the inference proposed is available. This article is protected by copyright. All rights reserved. PMID- 30430545 TI - Management of vulval melanoma in situ with imiquimod. AB - A 75 year old lady presented to her local hospital with vulval pigmentation that she noticed six months previously. She was generally in good health with a past medical history of hypertension, migraine and hypercholesterolemia treated with Indapamide, Simvastatin, Aspirin and Amitryptyline. On examination, there was an extensive area of pigmentation affecting both labia minora and the right labium majus. The pigmentation did not extend into the vagina or the urethral orifice. A punch biopsy from the left labium minus confirmed melanoma in situ, and wide local excision was recommended. Therefore, both labia minora were excised and histology showed melanoma in situ extending to the peripheral margins. This article is protected by copyright. All rights reserved. PMID- 30430544 TI - Successful therapy with secukinumab in a patient with generalized pustular psoriasis carrying homozygous IL36RN p.His32Arg mutation. PMID- 30430546 TI - Development and Validation of a Multivariable Risk Prediction Model for Serious Infection in Patients with Psoriasis Receiving Systemic Therapy. AB - BACKGROUND: Patients with psoriasis are often concerned about the associated risk of serious infection with systemic psoriasis treatments. OBJECTIVES: To develop and externally validate a prediction model for serious infection in patients with psoriasis within one year of starting systemic therapies. METHODS: The risk prediction model was developed using the British Association of Dermatologists Biologic Interventions Register (BADBIR) and the German Psoriasis Registry PsoBest was used as the validation dataset. Model discrimination and calibration was assessed internally and externally using the C-statistic, the calibration slope, and the calibration in the large. RESULTS: 175 (1.7%) out of 10033 participants from BADBIR and 41 (1.7%) out of 2423 participants from PsoBest developed a serious infection within one year of therapy initiation. Selected predictors in a multiple logistic regression model included 9 baseline covariates, and starting infliximab was the strongest predictor. Evaluation of model performance showed a bootstrap optimism-corrected C-statistic of 0.64 (95% C.I. 0.60, 0.69), calibration in the large of 0.02 (95% confidence interval -0.14 to 0.17) and calibration slope of 0.88 (0.70, 1.07), while external validation performance was poor [C-statistic 0.52 (95% C.I. 0.42 to 0.62), calibration in the large of 0.06 (95% C.I. -0.25 to 0.37), calibration slope 0.36 (95% C.I. 0.24, 0.97)]. CONCLUSIONS: We present first results of the development of a multivariable prediction model that may help patients and dermatologists in the United Kingdom and the Republic of Ireland identify modifiable risk factors and inform therapy choice in a shared decision-making process. This article is protected by copyright. All rights reserved. PMID- 30430547 TI - Evaluation of the Dermatology Life Quality Index scoring modification, the DLQI-R score, in two independent populations. AB - The 10-item Dermatology Life Quality Index (DLQI) is an easily administered health-related quality of life instrument often utilized in dermatologic studies, including clinical trials for psoriasis. However, there have been questions regarding how best to score 'not relevant' responses (NRRs) on the DLQI since these can be common and could lead to underestimation of the impact on quality of life. Recently, Rencz and colleagues proposed a scoring modification for the DLQI, the DLQI-R score, in which the traditional DLQI score is multiplied by a conversion factor that increases with the number of NRRs. In their reanalysis of 242 patients involved in two cross-sectional surveys conducted in Hungary, they found that the DLQI-R displayed moderate correlation with Psoriasis Area Severity Index (PASI) scores and EQ-5D-3L index values, with higher correlation coefficients than the traditional DLQI score. This article is protected by copyright. All rights reserved. PMID- 30430548 TI - Composite Kernel Machine Regression based on Likelihood Ratio Test for Joint Testing of Genetic and Gene-environment Interaction Effect. AB - Most common human diseases are a result from the combined effect of genes, the environmental factors and their interactions such that including gene-environment (GE) interactions can improve power in gene mapping studies. The standard strategy is to test the SNPs, one-by-one, using a regression model that includes both the SNP effect and the GE interaction. However, the SNP-by-SNP approach has serious limitations, such as the inability to model epistatic SNP effects, biased estimation and reduced power. Thus, in this paper, we develop a kernel machine regression framework to model the overall genetic effect of a SNP-set, considering the possible GE interaction. Specifically, we use a composite kernel to specify the overall genetic effect via a nonparametric function and we model additional covariates parametrically within the regression framework. The composite kernel is constructed as a weighted average of two kernels, one corresponding to the genetic main effect and one corresponding to the GE interaction effect. We propose a likelihood ratio test (LRT) and a restricted likelihood ratio test (RLRT) for statistical significance. We derive a Monte Carlo approach for the finite sample distributions of LRT and RLRT statistics. Extensive simulations and real data analysis show that our proposed method has correct type I error and can have higher power than score-based approaches under many situations. This article is protected by copyright. All rights reserved. PMID- 30430549 TI - Long-term clinical safety of Clindamycin and Rifampicin combination for the treatment of Hidradenitis Suppurativa: strategy to reduce side effects, improving patients' compliance. AB - We read with great interest the article by Albrecht et al.1 regarding the long term clinical safety of Clindamycin and Rifampicin combination for the treatment of Hidradenitis Suppurativa (HS). The authors discuss carefully whether Clindamycin and Rifampicin could be safely continued beyond a 10 week course, analyzing long term toxicity of these drugs. This article is protected by copyright. All rights reserved. PMID- 30430550 TI - BRAF V600E expression in juvenile xanthogranuloma occurring after Langerhans cell histiocytosis. AB - Histiocytosis are a heterogenous group of diseases resulting from the abnormal proliferation of cells derived from macrophages-monocytes or dendritic cells at various sites, including bones, soft tissues and skin. Histiocytosis comprises the Langerhans group (L group), including Langerhans cell histiocytosis (LCH), the cutaneous and mucocutaneous histiocytosis (C group), comprising juvenile xanthogranuloma (JXG) and the group of Rosai-Dorfman disease and related histioctytosis (R group). JXG is the most common form of non-Langerhans cell histiocytosis (nLCH), and generally is self-limiting and non-aggressive. Some reports have documented cases of children with LCH who have developed JXG after chemotherapy. This article is protected by copyright. All rights reserved. PMID- 30430551 TI - Evolutionary stability of the lysis-lysogeny decision: why be virulent? AB - Lytic viruses infect and kill host cells, producing a large number of viral copies. Temperate viruses, in contrast, are able to integrate viral genetic material into the host cell DNA, leaving a viable host cell. The evolutionary advantage of this strategy, lysogeny, has been demonstrated in complex environments that include spatial structure, oscillating population dynamics, or periodic environmental collapse. Here, we examine the evolutionary stability of the lysis-lysogeny decision, that is, we predict the long-term outcome of the evolution of lysogeny rates. We demonstrate that viruses with high rates of lysogeny are stable against invasion by more virulent viral strains even in simple environments, as long as the pool of susceptible hosts is not unlimited. This mirrors well-known results in both r-K selection theory and virulence evolution: although virulent viruses have a faster potential growth rate, temperate strains are able to maintain positive growth on a lower density of the limiting resource, susceptible hosts. We then outline scenarios in which the rate of lysogeny is predicted to evolve either toward full lysogeny or full lysis. Finally, we demonstrate conditions under which intermediate rates of lysogeny, as observed in temperate viruses in nature, can be sustained long-term. In general, intermediate lysogeny rates persist when the coupling between susceptible host density and virus density is relaxed. PMID- 30430552 TI - Rifampin alone may be enough. Is it time to abandon the classic oral clindamycin rifampicin combination for hidradenitis suppurativa? AB - In this issue, a "Critically Appraised Topic" assesses the long-term safety of clindamycin and rifampicin in hidradenitis suppurativa (HS). 1 It concludes that the long-term use of these drugs is generally safe. As described in the CAT, the treatment approach with rifampicin was adapted from a case of dissecting cellulitis successfully treated with rifampicin as a monotherapy. 1 Based on hypothetical thinking, clindamycin was added to rifampicin to prevent the possible resistance development of Staphylococcus aureus, that was considered the pathophysiological essential bacteria of dissecting cellulitis. This article is protected by copyright. All rights reserved. PMID- 30430553 TI - The Single-Index/Cox Mixture Cure Model. AB - In survival analysis it often happens that a certain fraction of the subjects under study never experience the event of interest, i.e. they are considered 'cured'. In the presence of covariates, a common model for this type of data is the mixture cure model, which assumes that the population consists of two subpopulations, namely the cured and the non-cured ones, and it writes the survival function of the whole population given a set of covariates as a mixture of the survival function of the cured subjects (which equals one), and the survival function of the non-cured ones. In the literature one usually assumes that the mixing probabilities follow a logistic model. This is however a strong modeling assumption, which might not be met in practice. Therefore, in order to have a flexible model which at the same time does not suffer from curse-of dimensionality problems, we propose in this paper a single-index model for the mixing probabilities. For the survival function of the non-cured subjects we assume a Cox proportional hazards model. We estimate this model using a maximum likelihood approach. We also carry out a simulation study, in which we compare the estimators under the single-index model and under the logistic model for various model settings, and we apply the new model and estimation method on a breast cancer data set. This article is protected by copyright. All rights reserved. PMID- 30430554 TI - Paradoxical exacerbation of latent interstitial pneumonia by secukinumab in a patient with psoriasis vulgaris. AB - In a recent article by Chijiwa et al.1 , anti-IL-17A antibody (secukinumab; SEC) administration was reported to reduce the elevated levels of serum KL-6 in patients with psoriasis. We have encountered a unique case of psoriasis vulgaris with increased serum KL-6 levels and paradoxical development of interstitial pneumonia (IP) after the introduction of SEC administration. A 66-year-old male with a 20-year history of psoriasis vulgaris was referred to our department. At initial presentation, multiple scaly erythematous plaques were scattered on the trunk and extremities (Fig. 1a). Blood tests revealed increased serum KL-6 level (1,408 U/mL; normal range <500 U/mL), while surfactant protein-D level was within the normal range. This article is protected by copyright. All rights reserved. PMID- 30430555 TI - Familial frontal fibrosing alopecia: A cross-sectional study of 20 cases from nine families. AB - BACKGROUND/OBJECTIVES: Frontal fibrosing alopecia (FFA) is a scarring alopecia whose prevalence is increasing. The pathogenesis of this disease is not well known. Genetic, environmental, hormonal and autoimmunity related factors have been considered; however, only a few cases of familial frontal fibrosing alopecia have been reported. MATERIAL AND METHODS: A cross-sectional study was performed at University Hospital in Granada (Spain). Twenty patients with frontal fibrosing alopecia belonging to nine different families were included, and clinical and dermoscopic features were analysed. RESULTS: Overall, 90% of the patients studied were women (mean age 61.4 years). About 50% of the patients had grade II frontal fibrosing alopecia at the time of diagnosis, whilst 35% had grades III or V. Mean recession was 2.83 cm in the frontal area and 1.99 cm in the temporo-parietal area. Daughters presented a shorter recession area and earlier debut of the disease than mothers. Androgenetic alopecia was found in only two patients (10%). The dermoscopic signs most commonly found were perifollicular erythema (85%), hyperkeratosis (85%), and absence of vellus hair in the hairline (78.9%). CONCLUSION: This study adds to the growing evidence that there is a genetic component to frontal fibrosing alopecia. The clinical pattern of frontal fibrosing alopecia was not different from that found in non-familial cases, but the debut of the disease in daughters of mothers with frontal fibrosing alopecia may be earlier. PMID- 30430556 TI - Interim FDG-PET does not predict outcome in advanced-stage Hodgkin lymphoma patients treated with BEACOPP. PMID- 30430559 TI - Suggestions for Streamlining and Optimizing Clinical End-Point Bioequivalence Studies for US Abbreviated New Drug Application Submissions. PMID- 30430557 TI - Topology of Psoriasis in Routine Care - Results from a High-resolution Analysis in 2,009 Patients. AB - BACKGROUND: In psoriasis, a variety of different phenotypes have been described. However, little details are known about the topology in patients from routine care. OBJECTIVES: To characterize the frequency and distribution of body sites affected by psoriasis in Germany based on high-resolution analysis. METHODS: Data from a national cross-sectional study (PsoHealth2) were analysed. Each practice consecutively recruited 20 patients independently of treatment. The topical distribution was identified with a detailed grid scheme of 1,424 squares filled by the patient. Psoriasis history, clinical findings, comorbidity and patient reported outcomes were obtained. RESULTS: A total of 2,009 patients with psoriasis were observed. 19% of patients had psoriatic arthritis, 65.4% scalp involvement, 35.6% nail involvement and in 40.5% first-degree relatives also had psoriasis. 1,927 (95.9%) provided complete grid data. The mean number of grids marked was 152.4+193.2 which corresponds with 10.7% of body surface. The most frequently affected body areas were the elbows, knees, lower legs and scalp (between 65% and 78%). In a linear regression analysis (corrected R2=0,093) the strongest predictors of health-related quality of life (HRQoL), as measured by the DLQI, were the affection of the hands (Beta=0,147; p=0,000), the arms (Beta=0,097; p=0,008), the genitals (Beta=0,080; p=0,010), the neck (Beta=-0,072; p=0,043), the scalp (Beta=0,068; p=0,010) and the nails (Beta=0,064; p=0,005). CONCLUSIONS: Typical psoriatic lesions as described in the textbooks are found in real-world care. However, also smaller areas, in particular in visible regions and in the genitals, are important determinants of HRQoL reductions. This article is protected by copyright. All rights reserved. PMID- 30430560 TI - The immunopathogenesis of fibrosis in systemic sclerosis. AB - Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterised by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterised by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc including: T cells, B cells, dendritic cells, mast cells, and macrophages. How these different cell types interact to contribute to SSc is complicated and can involve cell to cell interactions and communication via cytokines including TGF-beta, IL-6 and IL-4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis. This article is protected by copyright. All rights reserved. PMID- 30430561 TI - Progression-free survival and one-year milestone survival as surrogates for overall survival in previously treated advanced non-small cell lung cancer. AB - The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non-small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second-line NSCLC trials. Here, we aimed to assess the surrogacy of progression free survival (PFS) and milestone survival for OS in second-line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active-controlled, second-line NSCLC trials. The milestone time point was set at one-year based on pre-analysis. A two-stage meta analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HRPFS ), 1yr milestone ratio (Ratio1y-SUR ) and HROS . Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One-year survival strongly correlated with OS (R2 [95% confidence interval]: one-year survival -median OS=0.707 [0.704-0.708]; Ratio1y-SUR -HROS =0.829 [0.828-0.831]). No correlation was established between PFS and OS (median PFS-median OS=0.100 [0.098-0.101]; HRPFS -HROS =0.064 [0.059-0.069]), except in immunotherapy subgroup (HRPFS -HROS =0.835 [0.791-0.918]). In subgroup analyses, surrogacy of one-year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One-year milestone survival showed strong surrogacy for OS in second-line NSCLC trials. Although no association was identified between PFS and OS, the strong HRPFS -HROS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies. This article is protected by copyright. All rights reserved. PMID- 30430562 TI - Structure of the external auditory meatus of the Bowhead whale (Balaena mysticetus) and its relation to their seasonal migration. AB - The external auditory meatus (EAM) in many species of mysticete whales is filled with a waxy ear plug. Though this lamellated structure is often used to age a whale, its formation and development remain undescribed. It is thought that growth layer groups (GLGs) are laid down annually, thereby increasing the size of this structure. Since some mysticete whales are migratory and many undergo molting, we hypothesized that the cyclical production of these GLGs may be related to these processes. The epithelia of both EAM and glove finger (a part of the tympanic membrane protruding into the EAM) of one juvenile and multiple adult bowhead whales from both fall (October: non-molting) and spring (May: molting) seasons were dissected and examined anatomically and histologically. These tissue samples were compared with the adult oral epithelia at the same time periods. These epithelia shared a similar basic broad structure, though there were differences in thickness and presence of intraepithelial structures. All epithelia in the October specimens were rich in both glycogen and lipid. The parakeratinized epithelium of the oral cavity in the juvenile and some May specimens shed via the production of several superficial epithelial fissures. Other adult May specimens exhibited deep epithelial fissures, reminiscent of pressure ulcers, which would cause the detachment of the entire epithelium from the dermis. We propose that sloughed epithelial lining is the source of the GLGs in the ear plug. Correlating a potential molting sequence with these observations explained the presence of epidermal glycogen, deep epidermal fissures and dermal glycolipid, and to some extent calls into question the origin and structure of the ear plug itself. Further morphological characterization of ear plugs in bowheads is needed to better understand cell origin and ear plug formation. PMID- 30430563 TI - A systematic review of quality measures used in primary care dentistry. AB - INTRODUCTION: 'Quality' in primary care dentistry is poorly defined. There are significant international efforts focussed on developing quality measures within dentistry. The aim of this research was to identify measures used to assess quality in primary care dentistry and categorise them according to which dimensions of quality they attempt to measure. METHODS: Quality measures were identified from the peer-reviewed and grey literature. Peer-reviewed papers describing the development and validation of measures were identified using a structured literature search. Measures from the grey literature were identified using structured searches and direct contact with dental providers and institutions. Quality measures were categorised according to domains of structure, process and outcome and by disaggregated dimensions of quality. RESULTS: From 22 studies, 11 validated measure sets (comprising nine patient satisfaction surveys and two practice assessment instruments) were identified from the peer-reviewed literature. From the grey literature, 24 measure sets, comprising 357 individual measures, were identified. Of these, 96 addressed structure, 174 addressed process and 87 addressed outcome. Only three of these 24 measure sets demonstrated evidence of validity testing. The identified measures failed to address dimensions of quality, such as efficiency and equity. CONCLUSIONS: There has been a proliferation in the development of dental quality measures in recent years. However, this development has not been guided by a clear understanding of the meaning of quality. Few existing measures have undergone rigorous validity or reliability testing. A consensus is needed to establish a definition of quality in dentistry. Identification of the important dimension of quality in dentistry will allow for the production of a core quality measurement set. PMID- 30430564 TI - DANCR contributed to hepatocellular carcinoma malignancy via sponging miR-216a-5p and modulating KLF12. AB - Long noncoding RNA (lncRNA) differentiation antagonizing nonprotein coding RNA (DANCR) has been identified as an oncogene in several cancers. However, the biological function and role of DANCR in hepatocellular carcinoma (HCC) remain unclear. Our current study aimed to investigate the detailed mechanism of DANCR in HCC. We found that DANCR was significantly upregulated in HCC cell lines in comparison to LO2 cells. Then, we observed that knockdown of DANCR could greatly inhibit Huh7 and HepG2 cell proliferation. In addition, HCC cell apoptosis was increased by silence of DANCR and meanwhile, cell cycle progression was blocked in G1 phase. Apart from these, downregulation of DANCR repressed HCC cell migration and invasion ability obviously. As predicted by the bioinformatics analysis, microRNA-216a-5p (miR-216a-5p) could serve as a direct target of DANCR. MiR-216a-5p has been reported to be involved in many cancers. Here, the correlation between miR-216a-5p and DANCR was confirmed using dual-luciferase reporter assay and radioimmunoprecipitation assay. Subsequently, Kruppel-like factor 12 (KLF12) exerts an important role in different tumor types. KLF12 can function as a downstream target of miR-216a-5p. Finally, the in vivo experiments were used and the data proved that DANCR also strongly suppressed HCC tumor growth in vivo via targeting miR-216a-5p and KLF12. In conclusion, our study indicated that DANCR might provide a new perspective for HCC treatment. PMID- 30430566 TI - Measuring angle of progression by transperineal ultrasonography to predict successful instrumental and cesarean deliveries during prolonged second stage of labor. AB - OBJECTIVE: To compare the angle of progression (AoP) measured by transperineal ultrasonography before indicating an instrumental delivery or cesarean delivery. METHODS: A prospective observational study was conducted among women with singleton term pregnancies with prolonged second stage of labor at Kwong Wah Hospital, Hong Kong, China, between May 16, 2011, and May 25, 2016. Transabdominal and transperineal ultrasonography were performed to determine fetal head position and AoP, respectively, both at rest and during uterine contraction with pushing. Mode of delivery was decided after vaginal examination without relying on ultrasonography. RESULTS: Of 143 women, 116 underwent successful instrumental delivery and 27 underwent cesarean delivery. Median AoP was 153.0 degrees in the instrumental group versus 139.0 degrees in the cesarean group at rest (P<0.001), and 182.5 degrees in the instrumental group versus 156.5 degrees in the cesarean group during contraction (P<0.001). The best predictive cutoff AoP for successful instrumental delivery was 138.7 degrees at rest (sensitivity 86.2%, specificity 51.9%) and 160.9 degrees during contraction (sensitivity 87.1%, specificity 74.1%). No between-group differences in AoP were found for ease of vacuum extraction at rest (P=0.457) or during contraction with pushing (P=0.095). CONCLUSION: The AoP predicted approximately 80% of successful instrumental deliveries performed for prolonged second stage of labor. PMID- 30430565 TI - Ih contributes to increased motoneuron excitability in restless legs syndrome. AB - KEY POINTS: Restless legs patients complain about sensory and motor symptoms leading to sleep disturbances. Symptoms include painful sensations, an urge to move and involuntary leg movements. The responsible mechanisms of restless legs syndrome are still not known, although current studies indicate an increased neuronal network excitability. Reflex studies indicate the involvement of spinal structures. Peripheral mechanisms have not been investigated so far. In the present study, we provide evidence of increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated inward rectification in motor axons. The excitability of sensory axons was not changed. We conclude that, in restless legs syndrome, an increased HCN current in motoneurons may play a pathophysiological role, such that these channels could represent a valuable target for pharmaceutical intervention. ABSTRACT: Restless legs syndrome is a sensorimotor network disorder. So far, the responsible pathophysiological mechanisms are poorly understood. In the present study, we provide evidence that the excitability of peripheral motoneurons contributes to the pathophysiology of restless legs syndrome. In vivo excitability studies on motor and sensory axons of the median nerve were performed on patients with idiopathic restless legs syndrome (iRLS) who were not currently on treatment. The iRLS patients had greater accommodation in motor but not sensory axons to long-lasting hyperpolarization compared to age-matched healthy subjects, indicating greater inward rectification in iRLS. The most reasonable explanation is that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open at less hyperpolarized membrane potentials, a view supported by mathematical modelling. The half-activation potential for HCN channels (Bq) was the single best parameter that accounted for the difference between normal controls and iRLS data. A 6 mV depolarization of Bq reduced the discrepancy between the normal control model and the iRLS data by 92.1%. Taken together, our results suggest an increase in the excitability of motor units in iRLS that could enhance the likelihood of leg movements. The abnormal axonal properties are consistent with other findings indicating that the peripheral system is part of the network involved in iRLS. PMID- 30430567 TI - Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches. AB - OBJECTIVE AND BACKGROUND: Chronic myeloid leukemia (CML) is a neoplastic disease whose genetic and cytogenetic changes play important roles in prognosis and treatment strategies. Philadelphia (Ph) translocation t(9;22)(q34;q11) is a diagnostic and prognostic biomarker in CML. METHODS: Pubmed and Google Scholar databases were searched for English language articles from 1975 to 2017 containing the terms CML; Additional chromosomal abnormalities; Philadelphia translocation; Prognosis; and Treatment. DISCUSSION: Approximately 10-12% of CML patients exhibit additional chromosomal aberrations (ACAs) in chronic phase and blast crisis. ACAs emergence may cause different features in CML patients according to Ph pattern. For instance, deletion of chromosome 9 derivation is associated to patient's bad survival, whereas monosomy 7 develops myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) in CML patients with Ph negative pattern. And ACAs in Ph-positive CML is considered as a failure in the management of CML with imatinib. CONCLUSION: CML classification using different features such as Ph and ACAs can play a decisive role in the evaluation of treatment responses in patients, for example, CML patients with Ph negative and monosomy 7 develop MDS or CML patient -Y and extra copy of Ph have a good response to tyrosine kinase inhibitors, therefore, classifications according to Ph and ACAs play an important role in choosing better treatment protocols and therapeutic strategies. Karyotype analysis in CML patients with complex karyotype shows unrandom pattern so ACAs can be great clue in medical guidelines. PMID- 30430568 TI - Comparison of lycopene changes between open-field processing and fresh market tomatoes during ripening and postharvest storage by using a non-destructive reflectance sensor. AB - BACKGROUND: Accumulation and stability of tomato lycopene markedly depends on the cultivar, plant growing and storage conditions. To estimate lycopene in open field cultivated processing and fresh market tomatoes, we used a calibrated spectral reflectance portable sensor. RESULTS: Lycopene accumulation in fruits attached to the plant, starting from the Green ripening stage, followed a sigmoidal function. It was faster and reached higher levels in processing (cv. Calista) than fresh market (cv. Volna) tomatoes (90 and 62 mg kg-1 FW, respectively). During storage at 12, 20 and 25 degrees C, Red tomatoes retained about 90% of harvest lycopene for 3 weeks. Pink tomatoes increased lycopene during the first week of storage, but never reached the lycopene values of Red tomatoes ripened on the vine. Storability at 12 degrees C retaining the highest quality in Red tomatoes was limited to 14 and 7 days for Calista and Volna cvs., respectively. CONCLUSION: Significant differences in lycopene accumulation and stability between processing and fresh market tomatoes were precisely established following with time the very same fruits by a non-destructive optical tool. It can be useful in agronomical and postharvest physiological studies and can be of interest for producers oriented to the niche nutraceutical market. This article is protected by copyright. All rights reserved. PMID- 30430569 TI - Association and Genome Analyses to Propose Putative Candidate Genes for Malt Quality Traits. AB - BACKGROUND: We studied the genetics of nine malt quality traits using association genetics in a panel of North Dakota, ICARDA, and Ethiopian barley lines. Grain samples harvested from Bekoji in 2011 and 2012 were used. RESULTS: The mapping panel revealed strong population structure explained by inflorescence-type, geographic origin, and breeding history. North Dakota germplasm were superior in malt quality traits and they can be donors to improve malt quality properties. We identified 106 MTAs for the nine traits, representing 81 genomic regions across all barley chromosomes. Chromosomes 3H, 5H, and 7H contained most of the MTAs (58.5%). Nearly 18.5% of these genomic regions contained to 2-3 malt quality traits. Within +/-250 kb of 81 genomic regions, we recovered 348 barley genes, with some potential impacting malt quality. These include invertase, beta fructofuranosidase, alpha-glucosidase, serine carboxypeptidase, and bidirectional sugar transporter SWEET14-like protein. Eighteen of these genes were also previously reported in the Hordeum Toolbox, and 17 of them highly expressed during the germination process. CONCLUSION: The results from this study invite further follow-up functional characterization experiments to relate the genes with individual malt quality traits with higher confidence. It also provides germplasm resources for malt barley improvement. This article is protected by copyright. All rights reserved. PMID- 30430570 TI - HSR Commentary: Linking VA and Non-VA Data to Address Important US Veteran Health Services Research Issues. AB - OBJECTIVE: This commentary summarizes the methods and topics addressed in the special issue of HSR focused on linkage of United States Department of Veterans Affairs (VA) and non-VA datasets. The issue illustrates that researchers are increasingly linking diverse datasets as a valuable method for obtaining outcomes, treatments, and covariates to evaluate and examine health care delivery that includes non-VA services. The issue serves as a reference to VA and non-VA investigators alike who employ data linkage methods to address high-impact clinical and health policy evaluations that span different care systems and different datasets. PMID- 30430571 TI - Do racial and ethnic disparities in health care use vary with health? AB - OBJECTIVE: To determine the relationship between health status and the magnitude of black-white and Hispanic-white disparities in the likelihood of having any office-based or hospital outpatient department visits, as well as number of visits. DATA SOURCE: 2010-2014 Medical Expenditure Panel Survey. STUDY DESIGN: The probability of having a visit is modeled using a Probit model, and the number of visits using a negative binomial model. We use a nonlinear rank-and-replace method to adjust minority health status to be comparable to that of whites, and predict utilization at different levels of health by fixing an indicator of health status. We compare estimated differences in predicted utilization across racial/ethnic groups for each level of health status to map out the relationship between the racial/ethnic disparity and health status, also stratifying by health insurance coverage. EXTRACTION METHODS: We subset to nonelderly adults. PRINCIPAL FINDINGS: We find that Hispanic-white differences in the probability of having an office-based or hospital outpatient department were widest among adults in excellent health (27 percentage points, 95% CI: [23, 31]) and narrowest when reporting poor or fair health (15 p.p. [13, 17]). Black-white and Hispanic-white differences in the number of visits were wider for adults who report poor or fair health (5.3 visits [4.0, 6.6] and 5.7 [4.3, 7.0], respectively) compared to excellent health (1.7 [1.2, 2.1] and 1.5 [1.1, 2.0], respectively) among adults who are full-year privately insured. CONCLUSIONS: The magnitudes of racial/ethnic disparities vary with level of health. PMID- 30430572 TI - Protein matrices ensure safe and functional delivery of rosmarinic acid from marjoram (Origanum majorana) extracts. AB - BACKGROUND: To understand the interactions between carriers and functional ingredients is crucial when designing delivery systems, to maximize bioefficacy and functionality. In this study, two different protein matrices were evaluated as means to protect the extract isolated from marjoram leaves (Origanum majorana), casein micelles from fresh skim milk and soy protein isolate (SPI). RESULTS: Marjoram extract was obtained from pressurization of ethanol andwater solvent. Protein dispersions of casein and SPI (5 g L-1 each) with or without marjoram extract (0.1-3 mg mL-1 ) were prepared and homogenized. The physicochemical characterization of charge and entrapment efficiency were conducted. The results demonstrated that entrapment efficiency was highly dependent on the carrier itself where SPI formulations showed 20% higher affinity when compared to casein micelles. To investigate the physiological behaviour of the marjoram-protein dispersions, human macrophages were employed. A non-specific inflammatory response of macrophages stimulated with bacterial lipopolysaccharide was measured for TNF-alpha, IL-1beta and IL-6 cytokine secretion. CONCLUSION: Casein and SPI protein formulations warranted high bioefficacy of marjoram extract, showing their potential as safe carriers. This article is protected by copyright. All rights reserved. PMID- 30430573 TI - Inflammation induces endothelial-to-mesenchymal transition and promotes vascular calcification through downregulation of BMPR2. AB - Endothelial-to-mesenchymal transition (EndMT) has been unveiled as a common cause for a multitude of human pathologies, including cancer and cardiovascular disease. Vascular calcification is a risk factor for ischemic vascular disorders and slowing calcification may reduce mortality in affected patients. The absence of early biomarkers hampers the identification of patients at risk. EndMT and vascular calcification are induced upon cooperation between distinct stimuli, including inflammatory cytokines and transforming growth factor beta (TGF-beta) family members. However, how these signaling pathways interplay to promote cell differentiation and eventually vascular calcification is not well understood. Using in vitro and ex vivo analysis in animal models and patient-derived tissues, we have identified that the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) induce EndMT in human primary aortic endothelial cells, thereby sensitizing them for BMP-9-induced osteogenic differentiation. Downregulation of the BMP type II receptor BMPR2 is key event in this process. Rather than compromising BMP canonical signal transduction, loss of BMPR2 results in decreased JNK signaling in ECs, thus enhancing BMP-9-induced mineralization. Altogether, our results point at the BMPR-JNK signaling axis as a key pathway regulating inflammation-induced EndMT and contributing to calcification. PMID- 30430574 TI - The Dual-Domain Porosity Apparatus: Characterizing Dual Porosity at the Sediment/Water Interface. AB - The characterization of pore-space connectivity in porous media at the sediment/water interface is critical to understanding contaminant transport and reactive biogeochemical processes in zones of groundwater and surface-water exchange. Previous in situ studies of dual-domain (i.e., mobile/less-mobile porosity) studies have been limited to solute tracer injections at scales of meters to 100s of meters and subsequent numerical model parameterization using fluid concentration histories. Pairing fine-scale (e.g., sub-meter) geoelectrical measurements with fluid tracer data over time alleviates dependence on flowpath scale experiments, enabling spatially targeted characterization of shallow sediment/water interface media where biogeochemical reactivity is often high. The Dual-Domain Porosity Apparatus is a field-tested device capable of variable rate controlled downward flow experiments. The Dual-Domain Porosity Apparatus facilitates meter-scale inference of dual-domain parameters, i.e., mobile/less mobile exchange rate coefficient and the ratio of less mobile to mobile porosity. The Dual-Domain Porosity Apparatus experimental procedure uses water electrical conductivity as a conservative tracer of differential loading and flushing of pore spaces within the region of measurement. Variable injection rates permit the direct quantification of the flow-dependence of dual-domain parameters, which has been theorized for decades but remains challenging to assess using existing experimental methodologies. This article is protected by copyright. All rights reserved. PMID- 30430575 TI - Canine urethral sphincter pressure profile under incremental inflation of an artificial cuff: a cadaver study. AB - OBJECTIVES: To determine whether artificial urethral sphincter filling volume is proportional to peak pressure exerted on the urethra. MATERIALS AND METHODS: Urethral pressure profilometry was performed in five female, medium-sized, mixed breed canine cadavers following artificial urethral sphincter placement. Maximum urethral pressure was recorded following sequential incremental inflation of 0.15 mL and compared to baseline pressure and between dogs using two-way analysis of variance. RESULTS: Artificial urethral sphincter placement in cadavers was associated with an increase in urethral pressure, which was significantly correlated with inflation volume. The correlation was non-linear and demonstrated considerable individual variation. Maximum urethral pressures after artificial urethral sphincter placement exceeded those reported in conscious continent dogs within a narrow volume range, in which a 0.15 mL infusion more than doubled maximal urethral pressures. CLINICAL SIGNIFICANCE: Rapid increases in urethral pressure from the artificial urethral sphincter over a small range of filling volumes (0.15 mL increments) might explain why some clinical cases can become suddenly dysuric following incremental inflations. We suggest that smaller increments of filling (0.05 to 0.1 mL) may achieve finer pressure control. PMID- 30430576 TI - Effect of cryoconcentration process on phenolic compounds and antioxidant activity in apple juice. AB - BACKGROUND: Freeze concentration is an alternative process where bioactive compounds are preserved during the processing of juice concentrates. This study proposed a simple and cheaper cryoconcentration process assisted by centrifugation in apple juice. RESULTS: The levels of phenolics increased significantly (p < 0.05) with each freeze concentration cycle that was performed. Furthermore, the process resulted in an average increase in the concentration of phenolics of 1.9, 2.9 and 3.8 times for the first, second and third steps of the concentration, respectively. In relation to phenolics, the antioxidant potential, which was evaluated by radical scavenging activity and reduction power, also increased with the cryoconcentration steps. The influence of the phenolics on the in vitro antioxidant activity was confirmed by a significant correlation between the antioxidant assays and total phenolics, flavonoids, flavan-3-ols, and flavonols (r > 0.70). CONCLUSION: The increase in antioxidant activity may have been attributed to the increase in the phenolic compounds in the apple juices because of the cryoconcentration process. Therefore, could be an excellent natural product to supplement and enriching blends, juices, ciders, smoothies, and jams in order to improve the sensorial, nutritional and antioxidant properties. This article is protected by copyright. All rights reserved. PMID- 30430577 TI - Intraductal patient derived xenografts of estrogen receptor alpha positive (ER+) breast cancer recapitulate the histopathological spectrum and metastatic potential of human lesions. AB - Estrogen receptor alpha positive (ER+ ) or "luminal" breast cancers (BC) were notoriously difficult to establish as patient-derived xenografts (PDXs). We and others recently demonstrated that the microenvironment is critical for ER+ tumor cells; when grafted as single cells into milk ducts of NOD Scid gamma (NSG) females >90% of ER+ tumors can be established as xenografts and recapitulate many features of the human disease in vivo. This intra-ductal (ID) approach holds promise for personalized medicine, yet human and murine stroma are organized differently and this and other species specificities may limit the value of this model. Here, we analyzed 21 ER+ ID-PDXs histopathologically. We find that ID-PDXs vary in extent and define four histopathological patterns: flat, lobular, in situ, and invasive, which occur in pure and combined forms. The ID-PDXs replicate earlier stages of tumor development than their clinical counterparts. Micrometastases are already detected when lesions appear in situ. Tumor extent, histopathological patterns and micrometastatic load correlate with biological properties of their tumors of origin. Our findings add evidence to the validity of the intraductal model for in vivo studies of ER+ breast cancer and raise the intriguing possibility that tumor cell dissemination may occur earlier than currently thought. This article is protected by copyright. All rights reserved. PMID- 30430579 TI - Fungal beta-1,3-1,4-glucanases: Production, proprieties and biotechnological applications. AB - beta-1,3-1,4-glucanases (or lichenases, EC 3.2.1.73) are one of the main enzymes used in industry during the last decades. These enzymes hydrolyze beta-glucans containing beta -1,3 and beta -1,4 linkages such as cereal beta-glucans and lichenan. The beta-1,3-1,4-glucanases are known to be produced by a variety of bacteria, fungi, plants, and animals. A large number of microbial beta-1,3-1,4 glucanases have a potential application in industrial processes such as feed, food and detergent industries. This present review summarizes the studies on beta 1,3-1,4-glucanases production conditions, enzyme biochemical properties, and potential industrial applications. This article is protected by copyright. All rights reserved. PMID- 30430578 TI - Single-cell sequencing defines genetic heterogeneity in pancreatic cancer precursor lesions. AB - Intraductal papillary mucinous neoplasms (IPMNs) are precursors to pancreatic cancer; however, little is known about genetic heterogeneity in these lesions. The objective of this study was to characterize genetic heterogeneity in IPMNs at the single-cell level. We isolated single cells from fresh tissue from ten IPMNs, followed by whole genome amplification and targeted next generation sequencing of pancreatic driver genes. We then determined single-cell genotypes using a novel multi-sample mutation calling algorithm. Our analyses revealed that different mutations in the same driver gene frequently occur in the same IPMN. Two IPMNs had multiple mutations in the initiating driver gene KRAS that occurred in unique tumor clones, suggesting the possibility of polyclonal origin or an unidentified initiating event preceding this critical mutation. Multiple mutations in later occurring driver genes were also common and were frequently localized to unique tumor clones, raising the possibility of convergent evolution of these genetic events in pancreatic tumorigenesis. Single-cell sequencing of IPMNs demonstrated genetic heterogeneity with respect to early and late occurring driver gene mutations, suggesting a more complex pattern of tumor evolution than previously appreciated in these lesions. PMID- 30430580 TI - Effects of a mental fitness positive psychology intervention program on inpatients with schizophrenia in South Korea: A feasibility study. AB - PURPOSE: This study investigated the effects of a mental fitness positive psychology intervention program on the self-esteem and interpersonal relationship ability of inpatients with schizophrenia. DESIGN AND METHODS: A pretest-posttest nonequivalent control group quasi-experimental design was used. Participants (N = 60) completed scales measuring self-esteem and interpersonal relationship ability. FINDINGS: The program effectively improved participants' self-esteem and interpersonal relationship ability. PRACTICE IMPLICATIONS: Psychiatric nurses can use this program as a nursing intervention to enhance the self-esteem and interpersonal skills of inpatients with schizophrenia in mental health facilities. PMID- 30430581 TI - Psychiatric nurses' knowledge, attitudes, and practice towards the use of physical restraints. AB - PURPOSE: This study examines the knowledge, attitudes, and practice of psychiatric nurses towards the use of physical restraint in Saudi Arabia. DESIGN AND METHODS: Descriptive explanatory cross-sectional design, 101 participants were invited to complete a set of questionnaires to assess the knowledge, attitude, and practice towards the use of physical restraint. FINDINGS: Participants had a moderate knowledge and attitude as well as practice in using physical restraint. Less than half reported that they recognized alternative approaches to physical restraint and most of them did not understand the reasons for the restraint. PRACTICE IMPLICATIONS: This study highlights some important misunderstandings of nurses about using physical restraint. The findings serve as a supporting reason for recognizing the importance of educating nurses about its use. PMID- 30430582 TI - Relation of High-Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High-Density Lipoprotein-Related Genes in Mononuclear Cells to the HDL-Cholesterol Level. AB - The heterogeneity and content of human plasma high-density lipoprotein (HDL) related to their atheroprotective properties determined by various molecular and cellular mechanisms still remain to be completely clarified. For 29 atherosclerosis-free male subjects, we studied the relationship of plasma lipid levels and the content of apolipoprotein A-I (apoA-I)-containing HDL with prebeta electrophoretic mobility, the efficiency of BODIPY-cholesterol efflux from RAW 264.7 macrophages to apolipoprotein B (apoB)-deficient plasma, and the expression level of 22 genes related to HDL metabolism in mononuclear cells. A significant decrease in the absolute content of apoA-I in prebeta-HDL was found in subjects with hypoalphalipoproteinemia compared with the subjects with hyperalphalipoproteinemia. The prebeta-to-alpha-ratio of the apoA-I content was constant within the HDL-cholesterol (HDL-C) range 0.59 to 2.24 mM. However, this ratio was significantly increased with an increase in the plasma triacylglycerol (TAG) content from 0.59 to 3.42 mM. A correlation of the level of prebeta-HDL with the basal and ABCA1-mediated efflux of cholesterol is shown. The transcript levels for six HDL-metabolizing genes (LDLR, LCAT, ABCA1, SCARB1, ZDHHC8, and BMP1) were decreased, while the transcript level of APOA1 gene was increased in mononuclear cells of subjects with hyperalphalipoproteinemia as compared with subjects with hypoalphalipoproteinemia. A reduction of the intracellular cholesterol level and inhibition of the expression of cholesterol transporters by nascent HDL in mononuclear cells from subjects with hyperalphalipoproteinemia are suggested. Hyperalphalipoproteinemia can be a driving force of the decreased flux of cholesteryl ester to the liver and the increased TAG hydrolysis. The atheroprotective effect of prebeta-HDL in hypertriglyceridemia is proposed. PMID- 30430583 TI - Physical, mechanical, and water barrier properties of yuba films incorporated with various types of additives. AB - BACKGROUND: To apply yuba as an edible film, we evaluated film properties after adding various additives, including plasticizer (glycerol [G] and sorbitol [S]), cross-linking agent (oxidized ferulic acid [OX-FA]), emulsifier (sodium pyrophosphate [SP]), thicker (sodium carboxymethyl cellulose [CMC]), and lipid (beeswax [BW]) alone or in combinations (SP and S [SPS], CMC and G [CMCG], and BW and G [BWG]). RESULTS: Addition of BX and OX-FA enhanced water resistance of the film, showing decreased solubility in water and swelling ratio. The results for tensile strength and elongation showed opposite trends except for S, SP and CMCG. Tensile strength of CMC (9.3 MPa) was increased compared to that of yuba without additive (3.5 MPa). Elongation was increased in G (132%) compared to that in Con (8%). Water vapor permeability decreased in all samples by 0.7 to 8 times compared to that of Con. X-ray diffraction analysis found that blending additives influenced the crystalline degree and second structure of the film. Atomic force microscopy revealed that Con (37 nm) and CMCG (47 nm) exhibited smooth surface and lower roughness values compared to G (84 nm) and CMCG (87 nm). CONCLUSION: Our results confirmed that yuba could be used as edible film with a wide range of applications depending on types of additive and purpose of use. Results of this study revealed that CMCG added yuba film had exceptional edible film properties, including water resistance, elongation, and water vapor permeability based on principal component analysis. This article is protected by copyright. All rights reserved. PMID- 30430584 TI - Depressive symptoms during pregnancy and postpartum: a prospective cohort study. AB - PURPOSE: The aim was to determine the prevalence and risk factors of postpartum depression, and changes over time from pregnancy to postpartum period. DESIGN AND METHODS: A prospective cohort study was conducted in 23 cities in Turkey, with 497 pregnant women. FINDINGS: Of women, 13.5% had a high level of depressive symptoms during pregnancy and 4.8% during the postpartum period. Significant relationships emerged between total Edinburgh Postnatal Depression Scale score and mean age of participants and their husbands, duration of marriage, parity, and history of receiving professional psychological support. PRACTICE IMPLICATIONS: Family planning education could be an important intervention to prevent depression in young couples. PMID- 30430585 TI - Combining culture and microbead-based immunoassay for the early and generic detection of bacteria in platelet concentrates. AB - BACKGROUND: Despite current preventive strategies, bacterial contamination of platelets is the highest residual infectious risk in transfusion. Bacteria can grow from an initial concentration of 0.03-0.3 colony-forming units (CFUs)/mL up to 108 to 109 CFUs/mL over the product shelf life. The aim of this study was to develop a cost-effective approach for an early, rapid, sensitive, and generic detection of bacteria in platelet concentrates. STUDY DESIGN AND METHODS: A large panel of bacteria involved in transfusion reactions, including clinical isolates and reference strains, was established. Sampling was performed 24 hours after platelet spiking. After an optimized culture step for increasing bacterial growth, a microbead-based immunoassay allowed the generic detection of bacteria. Antibody production and immunoassay development took place exclusively with bacteria spiked in fresh platelet concentrates to improve the specificity of the test. RESULTS: Antibodies for the generic detection of either gram-negative or gram-positive bacteria were selected for the microbead-based immunoassay. Our approach, combining the improved culture step with the immunoassay, allowed sensitive detection of 1 to 10 CFUs/mL for gram-negative and 1 to 102 CFUs/mL for gram-positive species. CONCLUSION: In this study, a new approach combining bacterial culture with immunoassay was developed for the generic and sensitive detection of bacteria in platelet concentrates. This efficient and easily automatable approach allows tested platelets to be used on Day 2 after collection and could represent an alternative strategy for reducing the risk of transfusion transmitted bacterial infections. This strategy could be adapted for the detection of bacteria in other cellular products. PMID- 30430586 TI - The effect of a course on violence against women on the attitudes of student midwives and nurses towards domestic violence against women, their occupational roles in addressing violence, and their abilities to recognize the signs of violence. AB - AIM: The aim of this study was to determine the effect of a course on violence against women on the attitudes of student midwives and nurses towards violence against women and their abilities to recognize the signs of violence. METHODS: This study used a pretest-posttest quasi-experimental design with experimental and control groups and was conducted with student midwives and nurses. RESULTS: The results indicated that the difference between pretest and posttest scores averaged across three scales was statistically significant for students in the experimental group (P < 0.001) and not statistically significant for students in the control group ( P > 0.05). PRACTICE IMPLICATIONS: The traditional attitudes of students who enrolled in the course on violence against women decreased, and their levels of knowledge of signs of violence increased. PMID- 30430587 TI - Sensitization to fragrances in Spain: A 5-year multicentre study (2011-2015). AB - BACKGROUND: Fragrance chemicals constitute the second most frequent cause of contact allergy in Spain. There are no data available concerning the individual fragrances that are most frequently involved. OBJECTIVES: To describe the diagnostic contribution provided by specific fragrance series to the results obtained with baseline series fragrance markers by correlating the results of both series. MATERIALS AND METHODS: We performed a 5-year retrospective study of fragrance marker-positive patients tested with specific fragrance series in 23 Spanish centres. We collected the demographic and clinical characteristics, and compared the results of patch tests obtained from different suppliers. RESULTS: Of 19 588 patients patch tested with the Spanish baseline series, 1590 (8.1%) reacted positively to a fragrance marker. Of these, 1013 (63.7%) were patch tested with a fragrance series, and 664 patients reacted positively to at least one individual fragrance other than hydroxyisohexyl 3-cyclohexene carboxaldehyde. Geraniol was the most frequent allergen. Positive reactions to substances not included in fragrance mix (FM) I or FM II were found in 230 patients. Of the 436 FM I-positive patients and the 419 FM II-positive patients, 184 (42%) and 64 (39.1%), respectively, had no positive reactions to fragrance series. In the case of FM I, negative results were more common when individual fragrances were patch tested at low concentrations. CONCLUSIONS: We recommend patch testing all patients positive for any fragrance marker with a specific fragrance series. The correlation between the results of baseline series and fragrance series could be improved by increasing the concentrations of individual fragrances. PMID- 30430588 TI - A novel colorimetric immunosensor based on PtNPs immobilized on Power Vision as signal probes and Fe3 O4 @beta-cyclodextrin as capture probes for ractopamine detection in pork. AB - BACKGROUND: A novel colorimetric immunosensor was developed for the simple, sensitive, and selective detection of ractopamine (RAC) based on using beta cyclodextrin-modified Fe3 O4 particles (Fe3 O4 @beta-CD) as capture probes and complex platinum colloid nanomaterials (PtNPs-PV) composed of platinum colloid nanomaterials (PtNPs) and polymerase chelate PowerVision (PV) as signal probes. RESULTS: PtNPs-PV double catalyzed the chromogenic substrate 3,3' diaminobenzidine (DAB), which induced changes in DAB's color and chromogenic absorbance. Incubation temperature, pH, and incubation time were systematically optimized, and under optimum conditions, the measured absorbance values exhibited a linear relationship with the RAC concentrations in the range of 0.03 to 8.1 ng mL-1 . The detection limit was 0.01 ng mL-1 . The sensor exhibited high sensitivity and specificity, which was demonstrated by testing structurally similar organic compounds such as salbutamol (SAL), clenbuterol (CLE), and dopamine (DOA). The practicality of the developed colorimetric immunosensor was supported by the successful detection of RAC in pork samples with recovery ranging from 94.00% to 106.00%. CONCLUSION: We designed a novel sandwich-type noncompetitive colorimetric immunoassay for the detection of trace levels of RAC in pork. The proposed method can also be used for the detection of toxins in food products by using PtNPs-PV amplification. This article is protected by copyright. All rights reserved. PMID- 30430589 TI - Factors related to malnutrition in community-dwelling patients with schizophrenia. AB - PURPOSE: This study aims to identify demographic, clinical, and nutritional factors related to malnutrition in community-dwelling patients with schizophrenia. DESIGN AND METHODS: We used a descriptive cross-sectional design. Between June and July 2016, 188 community-dwelling patients with schizophrenia were included in this study. FINDINGS: Of the 188 participants, 4.3% were classified as malnourished, and 40.4% were at risk of malnutrition. Living status, body weight, and appetite were significant factors related to malnutrition in community-dwelling patients with schizophrenia. PRACTICE IMPLICATION: Assessment of nutritional status should be considered along with demographic and nutritional factors in community-dwelling patients with schizophrenia. PMID- 30430590 TI - Escape mapping to achieve bidirectional block: A case series. AB - Escape mapping is a novel technique that can be used to locate sites of persistent conduction and achieve exit block during an atrial fibrillation ablation. This method allows for mapping solely with the ablation catheter in the left atrium by annotating to a catheter in the coronary sinus. We illustrate the utility escape mapping during an atrial fibrillation ablation where entrance block is achieved without exit block. We further expand upon this technique by describing the first reported case of escape mapping being used to achieve bidirectional block during an atrial flutter ablation. PMID- 30430591 TI - Preparation of Microcapsule Antioxidative Wall Materials of Pine Nut Oil by the Maillard Reaction. AB - BACKGROUND: Maillard reaction products contribute to the amelioration of the biological functions or physical properties of foods and can be used to make dependable antioxidant wall materials for microcapsules of pine nut oil. The objective of this paper was to analyze the effects of temperature on the Maillard reaction of dry heat processes using gelatin/gum Arabic (GE/GA)or gelatin/gum Arabic/Maltodextrin (GE/GA/MD) models and the products of Maillard reaction (MRPs) as encapsulants to protect pine nut oil as well as to evaluate the characteristics of the microcapsules. RESULTS: The grafting degree of the product increased with the temperature increments during the Maillard reaction. Polyacrylamide gel electrophoresis (SDS-PAGE) showed that the polysaccharide covalently linked to the protein. The antioxidant capability of the Maillard products at 80 degrees C was the highest. The DPPH radical-scavenging activity, lipid peroxidation-inhibiting activity and reducing power of the GE/GA/MD model were higher than those of the GE/GA model. With the in vitro digestion of Maillard products, GE/GA/MD pine nut oil microcapsules exhibited more oil release in artificial gastric and enteric juices. Microencapsulated pine nut oil had more stable oxygen, which protected the oil, compared to unencapsulated pine nut oil. CONCLUSION: Temperature affects the degree of the Maillard reaction on GE/GA and GE/GA/MD models. This article is protected by copyright. All rights reserved. PMID- 30430592 TI - Effects of Physical Activity Program on cognitive function and sleep quality in elderly with mild cognitive impairment: A randomized controlled trial. AB - AIM: The aim of this study is to determine the effect of a 20-week Physical Activity Program for elderly individuals with mild cognitive impairment (MCI) on their cognitive functions and sleep quality. METHODS: A randomized controlled trial research design was used in this experimental pretest-posttest study. The data were analyzed using SPSS 21.0. RESULTS: This study showed that the Physical Activity Program improved the cognitive functions and sleep quality of elderly individuals (p < 0.05). CONCLUSION AND PRACTICE IMPLICATIONS: The findings of this study showed that the cognitive functions and sleep quality of elderly individuals improved thanks to a 20-week Physical Activity Program. It is recommended that physical activities should be included in nursing interventions for elderly people with MCI. PMID- 30430593 TI - Revealing the regional distribution of soybean lunasin content in China and the effects of climate factors by sampling extensively. AB - BACKGROUND: Lunasin is a novel therapeutic peptide that was initially isolated from soybean. In this study, we quantified the variations in lunasin content in a total of 413 soybean samples that were collected from four major regions in China and harvested in 2014 and 2015 to reveal the regional distribution of soybean lunasin content in China and the effects of climate factors. RESULTS: The results showed that the cultivar Changmidou 30 collected from Jilin province and harvested in 2015 had the highest lunasin content (3.25 g kg-1 dry seeds). The data from both 2014 and 2015 showed that the lunasin content in soybean collected from northern China was significantly higher (p<0.05) than that from south China. There was a positive correlation (p<0.01) between lunasin content and hours of sunshine (HS) as well as diurnal temperature range (DTR); however, there was a negative correlation (p<0.01) between lunasin content and rainfall (RF). In addition, combined analysis of data from 2014 and 2015 demonstrated that DTR was the dominant factor that affected lunasin content with a direct path-coefficient of 0.301. CONCLUSIONS: These results were anticipated to contribute to guiding the cultivation of soybean with high lunasin content. This article is protected by copyright. All rights reserved. PMID- 30430594 TI - Implementing a brief healthy-lifestyle group program on a psychiatric inpatient unit. AB - PURPOSE: This paper describes a project to assess the feasibility of a brief healthy lifestyle health education group (HE) program and its effects on patient outcomes. DESIGN AND METHODS: Forty adult inpatients were enrolled in the HE program, which featured a one-group, pretest or posttest design deployed in an adult psychiatric unit. Outcomes comprised (1) feasibility and acceptability of the program and (2) changes in patient knowledge and weight. FINDINGS: The HE program demonstrates not only feasibility, but also improvement in patient outcomes related to maintaining a healthy lifestyle. PRACTICE IMPLICATIONS: Requisite changes in practice are necessary for the success of the HE program deployed in a typical, inpatient psychiatric unit. PMID- 30430595 TI - Dermatitis caused by Olanedine (olanexidine gluconate) and povidone iodine. AB - Olanedine (Ohtsuka Pharmaceutical Factory, Tokushima, Japan) is a biguanide antiseptic for external use released in 2015 [1]. The active ingredient is olanexidine gluconate, which has been shown to demonstrate a significant bactericidal effect against various gram-positive and -negative bacteria and also against MRSA, VRE, Pseudomonas aeruginosa [2,3] and Cepacia resistant to other antiseptics [4]. It has been reported that use of Olanedine as a skin disinfectant is associated with almost no systemic side effects [5]. PMID- 30430596 TI - OCCURRENCE AND SEASONALITY OF AFLATOXIN M1 IN MILK IN TWO DIFFERENT CLIMATE ZONE. AB - BACKGROUND: Aflatoxin M1 (AFM1) is a mycotoxin that can be found in milk as a result of the ingestion of aflatoxin B1 (AFB1) by dairy cattle. Due to its carcinogenic properties, the control of its occurrence in dairy products is of great importance. We evaluated the occurrence and seasonality of AFM1 in milk from farms with subtropical and temperate climates, where occur a significant milk production. Forty samples of raw milk were collected from expansion cooling tanks during the summer (5 samples from subtropical climate and 14 from temperate) and winter (6 samples from subtropical climate and 15 from temperate) months of 2017, and analyzed using the ELISA method (detection limit 5 ng/L). Data from 8 random samples were compared between liquid chromatography with mass spectrometry detection (HPLC-MS/MS) and ELISA. A significant correlation was observed. RESULTS: The presence of AFM1 was detected in 87.50% (35) of the analyzed samples (mean 16.66 ng/L and median 12.42 ng/L in positive samples); however, its concentration in all samples was below the maximum limit allowed by European (50 ng/L) and Brazilian (500 ng/L) legislations. There were no significant differences in the levels of AFM1 between the properties located in the two climate zones, in both summer and winter. The estimated daily intake of AFM1 based on the analyzed milk was 0.0107 ng/kg/day for adolescents, 0.0072 ng/kg/day for adults, and 0.0098 ng/kg/day for the elderly. CONCLUSION: The present work demonstrated low exposure to AFM1. This article is protected by copyright. All rights reserved. PMID- 30430597 TI - A review of non-glove personal protective equipment-related occupational dermatoses reported to EPIDERM between 1993 and 2013. AB - BACKGROUND: Personal protective equipment (PPE) is defined as equipment that protects the wearer's body against health/safety risks at work. Gloves are a cause of many dermatoses. Non-glove PPE constitutes a wide array of garments. Dermatoses resulting from these have hitherto not been documented. OBJECTIVES: To determine the incidence and types of non-glove PPE-related dermatoses. PATIENTS/METHODS: We analysed incident case reports from dermatologists of non glove PPE-related dermatoses to a UK-wide surveillance scheme (EPIDERM) between 1993-2013. RESULTS: The dermatoses associated with non-glove PPE accounted for 0.84% of all occupational skin disease. Of all PPE-related cases 194 (9.2%) were due to non-glove PPE. Of these, 132 (68.0%) occurred in men and the median age (both male and female) was 42 years (range 18-82 years). The non-glove PPE related dermatoses were diagnosed as: allergic contact dermatitis (47.4%), irritant contact dermatitis (16.0%), friction (11.3%), occlusion (11.3%), unspecified dermatitis (8.8%), acne (3.1%), infections (1.5) and contact urticaria (0.52%). The industries most associated with non-glove PPE-related dermatoses were manufacturing (18.6%), public administration and defence (17.0%), health and social work (15.5%) and transport, storage and communication (9.8%). CONCLUSIONS: Clothing, footwear, facemasks and headgear need to be recognised as causes of dermatoses occurring at body sites less commonly associated with occupational skin disease. PMID- 30430598 TI - Generalized bullous fixed drug eruption due to ibuprofen. AB - Ibuprofen can cause a wide variety of cutaneous reactions with a relatively high frequency, but establishing the causal relationship is usually difficult [1]. We report a case of a skin drug reaction due to ibuprofen, confirmed by positive patch test results. PMID- 30430599 TI - Methylchloroisothiazolinone and methylisothiazolinone contact allergy: A retrospective cohort study from a tertiary dermatology clinic in Turkey. AB - Isothiazolinones, methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI), are widely used preservatives in cosmetic, industrial and household products owing to their strong biocidal effects.1 Following an epidemic of contact allergy to MCI/MI (Kathon CG) and subsequent regulatory measures on the use of MCI/MI, the use of MI as a monopreservative has increased. This article is protected by copyright. All rights reserved. PMID- 30430600 TI - Evaluating perceptions of risk in mosquito experts and identifying undocumented pathways for the introduction of invasive mosquito species into Europe. AB - In several reported cases of the entry of invasive mosquito species (IMSs) into Europe, the introduction was associated with a specific pathway of introduction or dispersal. The identification of potential pathways for the introduction of IMSs and evaluations of the importance of the different pathways are key to designing proper surveillance strategies to promptly detect and control introductions in non-infested areas. The main goals of the present study were to identify other, previously undocumented, pathways of introduction into Europe, and to identify mosquito experts' perceptions regarding control measures against IMS introductions via different documented pathways. At the European Mosquito Control Association (EMCA) conference in Montenegro in March 2017, a questionnaire was distributed among meeting participants to collect expert data. Results showed that ground transportation (by cars, trucks, etc.), passive natural dispersal and the shipping of used tyres are perceived as the most likely pathways. Introduction via aircraft did not appear to be well known and was not perceived as probable. This study shows that there were no pathways unknown to European experts that could lead to cryptic introductions into the experts' countries. Furthermore, the findings demonstrated that the perceived efficacy of surveillance and control is key to overcoming the constraints experienced and to supporting the implementation of actions against introductions. PMID- 30430601 TI - Impaired electron transfer accounts for the photosynthesis inhibition in wheat seedlings (Triticum aestivum L.) subjected to ammonium stress. AB - No single mechanism can provide an adequate explanation for the inhibition of photosynthesis when plants are supplied with ammonium (NH4 + ) as the sole nitrogen (N) source. We performed a hydroponic experiment using two N sources [5 mM NH4 + and 5 mM nitrate (NO3 - )] to investigate the effects of NH4 + stress on the photosynthetic capacities of two wheat cultivars (NH4 + -sensitive AK58 and NH4 + -tolerant XM25). NH4 + significantly inhibited the growth and light saturated photosynthesis (Asat ) of both cultivars, but the extent of such inhibition was greater in the NH4 + -sensitive AK58. The CO2 concentration did not limit CO2 assimilation under NH4 + nutrition; though both stomatal and mesophyll conductance were significantly suppressed. Carboxylation efficiency (CE), light-saturated potential rate of electron transport (Jmax ), the quantum efficiency of PSII (FPSII ), electron transport rate through PSII [Je(PSII)], and Fv/Fm were significantly reduced by NH4 + . As a result, NH4 + nutrition resulted in a significant increase in the production of hydrogen peroxide (H2 O2 ) and superoxide anion radicals (O2 *- ), but these symptoms were less severe in the NH4 + -tolerant XM25, which had a higher capacity of removing elevated reactive oxygen species (ROS). Thus, NH4 + N sources might decreased electron transport efficiency and increased the production of ROS, exacerbating damage to the the electron transport chain, leading to a reduced plant photosynthetic capacity. This article is protected by copyright. All rights reserved. PMID- 30430602 TI - Differential responses of molecular mechanisms and physiochemical characters in wild and cultivated soybeans against invasion by the pathogenic Fusarium oxysporum Schltdl. AB - Cultivated soybean (Glycine max) was derived from the wild soybean (Glycine soja), which has genetic resources that can be critically important for improving plant stress resistance. However, little information is available pertaining to the molecular and physiochemical comparison between the cultivated and wild soybeans in response to the pathogenic Fusarium oxysporum Schltdl.. In this study, we first used comparative phenotypic and paraffin section analyses to indicate that wild soybean is indeed more resistant to F. oxysporum than cultivated soybean. Genome-wide RNA-sequencing approach was then used to elucidate the genetic mechanisms underlying the differential physiological and biochemical responses of the cultivated soybean, and its relative, to F. oxysporum. A greater number of genes related to cell wall synthesis and hormone metabolism were significantly altered in wild soybean than in cultivated soybean under F. oxysporum infection. Accordingly, a higher accumulation of lignins was observed in wild soybean than cultivated soybean under F. oxysporum infection. Collectively, these results indicated that secondary metabolites and plant hormones may play a vital role in differentiating the response between cultivated and wild soybeans against the pathogen. These important findings may provide future direction to breeding programs to improve resistance to F. oxysporum in the elite soybean cultivars by taking advantage of the genetic resources within wild soybean germplasm. This article is protected by copyright. All rights reserved. PMID- 30430603 TI - Modulatory effects of methanolic fruit fraction of Pedalium murex on sulphasalazine-induced male reproductive disruption. AB - Pedalium murex is widely practiced in Ayurveda for the treatment of sexual disorders, but their detailed scientific evaluations are still unexplored. Therefore, the present study was conducted to assess the effect of methanolic fruit fraction of P. murex (MfPm) against sulphasalazine (SSZ) induced male reproductive disruption. MfPm and Clomiphene citrate were orally administered to SSZ (100 mg/kg b.wt) induced infertile rats at the dose of 50 and 10 mg/kg b.wt, respectively, for 60 days. MfPm treatment promoted a significant (p < 0.01) improvement in fertility (~70%), sperm motility (21%), and sperm density (11.20% and 12.30%). MfPm administration restored the serum luteinizing hormone, follicle stimulating hormone, and testosterone levels back to their normal range in a significant (p < 0.01) manner and also significantly (p < 0.01) altered the level of biochemical parameters in treated rats. Furthermore, histological examination showed an improvement in spermatogenesis, as well as regeneration in the testicular architecture observed with increased germinal and interstitial cell count in response to MfPm treated rats. In conclusion, the results suggest that MfPm showed a significant modulatory effect against SSZ induced male reproductive disruption via possible mode of action such as spermatogenic and androgenic nature, therefore, justifying the traditional use of this plant in the treatment of reproductive disruption. PMID- 30430604 TI - Brentuximab vedotin in multifocal cutaneous anaplastic large cell lymphoma in a patient with human immunodeficiency virus following Hodgkin lymphoma. PMID- 30430605 TI - Randomised clinical trial: emricasan versus placebo significantly decreases ALT and caspase activation in subjects with non-alcoholic fatty liver disease. AB - BACKGROUND: Lipotoxicity leading to excessive caspase-mediated apoptosis and inflammation is believed to drive liver damage in NAFLD. Emricasan is a pan caspase inhibitor that decreased serum ALT and apoptotic and inflammatory markers in subjects with chronic hepatitis. AIMS: To assess whether 28 days of emricasan would reduce elevated levels of serum ALT, AST, cleaved cytokeratin-18, full length cytokeratin-18, and caspase 3/7 in subjects with NAFLD and raised aminotransferases. METHODS: Double-blind, placebo-controlled, office-practice study assessed the efficacy, safety, and tolerability of emricasan in subjects with NAFLD and ALT levels >=1.5 x ULN during screening. Subjects were randomised to emricasan 25 mg twice daily or matching placebo. Subjects with cirrhosis and other causes for raised aminotransferases were excluded. The primary endpoint was the change in ALT at day 28 in the emricasan group vs placebo. RESULTS: 38 subjects were randomised, 19 each to emricasan or placebo. Baseline disease factors were well balanced except for lower median ALT values in emricasan subjects. Three subjects randomised to placebo discontinued prior to day 28. ALT values decreased significantly in emricasan-treated subjects vs placebo at days 7 (P < 0.0001) and 28 (P = 0.02). cCK18 (day 7), flCK18 (days 7 and 28), and caspase 3/7 (day 7) were also significantly decreased in emricasan-treated subjects vs placebo. Emricasan treatment was generally safe and well tolerated. CONCLUSIONS: Emricasan decreased ALT and biomarkers in subjects with NAFLD and raised aminotransferases after 28 days. These results support the further development of emricasan in patients with NAFLD. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02077374. PMID- 30430606 TI - Lupus erythematous mimicking mycosis fungoides: CD123+ plasmacytoid dendritic cells as a useful diagnostic clue. AB - Mycosis fungoides (MF) is a primary cutaneous lymphoma, characterized by a clonal proliferation of T cell helper memory cells in the skin [1]. Various benign conditions, such as chronic inflammatory dermatoses, may mimic MF, either clinically or histologically. Distinguishing MF from dermatologic conditions mimicking MF may be challenging. Clinicopathological correlation is fundamental to support the diagnosis, which is essential to ensure proper treatment and to provide an accurate prognosis [2]. This article is protected by copyright. All rights reserved. PMID- 30430608 TI - Neutrophilic Figurate Erythema of Infancy: A Diagnostic Challenge. AB - Neutrophilic figurate erythema of infancy (NFEI) is a rare variant of annular erythema of infancy. It is characterized by annular erythematous plaques, occasionally with a polycyclic configuration. The main challenge is to differentiate this rare entity from other figurate erythemas associated with serious diseases such as neonatal lupus erythematosus. We present the case of a 9 month-old female admitted with a skin rash of unclear etiology. The rash started on her face at the age of 3 months and gradually spread to her extremities. She had no constitutional symptoms, and her health and development were otherwise unremarkable since birth. This persistent skin eruption consisted of many ill defined erythematous papules and annular plaques. Histologic examination revealed perivascular neutrophils and eosinophils with abundant nuclear dust without signs of vasculitis. NFEI is a diagnostic enigma both clinically and histologically. Absence of an underlying cause, dermal neutrophilic infiltrate with leukocytoclasis, and lack of vascular damage are the keys to diagnosis. This article is protected by copyright. All rights reserved. PMID- 30430607 TI - Loss of CCAAT-enhancer-binding protein alpha (CEBPA) is linked to poor prognosis in PTEN deleted and TMPRSS2:ERG fusion type prostate cancers. AB - BACKGROUND: The transcription factor CCAAT-enhancer-binding protein alpha (CEBPA) is a crucial regulator of cell proliferation and differentiation. Expression levels of CEBPA have been suggested to be prognostic in various tumor types. METHODS: Here, we analyzed the immunohistochemical expression of CEBPA in a tissue microarray containing more than 17 000 prostate cancer specimens with annotated clinical and molecular data including for example TMPRSS2:ERG fusion and PTEN deletion status. RESULTS: Normal prostate glands showed moderate to strong CEBPA staining, while CEBPA expression was frequently reduced (40%) or lost (30%) in prostate cancers. Absence of detectable CEBPA expression was markedly more frequent in ERG negative (45%) as compared to ERG positive cancers (20%, P < 0.0001). Reduced CEBPA expression was linked to unfavorable phenotype (P < 0.0001) and poor prognosis (P = 0.0008). Subgroup analyses revealed, that the prognostic value of CEBPA loss was entirely driven by tumors carrying both TMPRSS2:ERG fusions and PTEN deletions. In this subgroup, CEBPA loss was tightly linked to advanced tumor stage (P < 0.0001), high Gleason grade (P < 0.0001), positive nodal stage (0.0003), and early biochemical recurrence (P = 0.0007), while these associations were absent or markedly diminished in tumors with normal PTEN copy numbers and/or absence of ERG fusion. CONCLUSIONS: CEBPA is down regulated in about one third of prostate cancers, but the clinical impact of CEBPA loss is strictly limited to the subset of about 10% prostate cancers carrying both ERG fusion and deletions of the PTEN tumor suppressor. Our findings challenge the concept that prognostic molecular markers may be generally applicable to all prostate cancers. PMID- 30430609 TI - High Concordance of BRAF Mutational Status in Matched Primary and Metastatic Melanoma. AB - BACKGROUND: Techniques for the accurate identification of activating mutations of BRAF in metastatic melanoma are of great clinical importance, due to the availability of targeted therapies for these tumours. There is uncertainty regarding the frequency with which BRAF status differs between primary and metastatic sites. METHODS: Between 2011 and 2016, 219 melanoma cases underwent BRAF testing in our institution. In 53 of these, paired primary and metastatic specimens were available for PCR and immunohistochemical evaluation. RESULTS: 52 out of 53 cases (98%) showed concordant BRAF status between primary and metastatic site by IHC. In one case, a metastasis and its matched primary were positive by IHC but the metastasis was negative on PCR. On further investigation, PCR was positive in the primary and repeat PCR in the metastasis was positive, following macrodissection. CONCLUSIONS: Our results suggest that discordance of BRAF mutational status between primaries and metastases is a rare occurrence. In one case, immunohistochemistry provided strong evidence that initial PCR testing had provided a false negative result due to low tumour volume. Thus, in cases where tissue is is difficult to obtain from a metastasis or unavailble, the primary tumour can be used with confidence. This article is protected by copyright. All rights reserved. PMID- 30430610 TI - Semiparametric additive rates model for recurrent events data with intermittent gaps. AB - Statistical methods for analyzing recurrent events have attracted significant attention. The majority of existing works consider situations in which subjects are observed over time periods and events of interest that occurred during the course of follow-up are recorded. In some applications, a subject may leave the study for a period of time and then resume due to various reasons. During the absence, which is referred to as an intermittent gap in this study, it may be impossible to observe a recording of the event. A naive analysis disregards gaps and considers events to be a typical recurrent event dataset. However, this may result in biased estimations and misleading results. In this study, we build an additive rates model for recurrent event data considering intermittent gaps. We provide the asymptotic theories behind the proposed model, as well as the goodness of fit between observed and modeled values. Simulation studies reveal that the estimations perform well if intermittent gaps are taken into account. In addition, we utilized the longitudinal cohort of elderly patients who have type 2 diabetes and at least one record of a severe recurrent complication, hypoglycemia, from the National Health Insurance Research Database in Taiwan to demonstrate the proposed method. PMID- 30430611 TI - A solitary chest nodule. PMID- 30430612 TI - Outer electronic shell visualization by NMR chemical shift laplacian of a helium probe. AB - A new method of visualization of lone pairs is proposed using fluorine atoms in fluoroacetylene, trifluoroethylene, and fluoroform (sp, sp2 , and sp3 hybridized carbons) as an example. The space around fluorines was probed by a helium atom and at each point 3 He NMR chemical shift deltaHe and its Laplacian ?2 deltaHe were calculated. The ?2 deltaHe isosurfaces have symmetrical toroidal shapes along CF axes; the maximum values of ?2 deltaHe are reached at about 1.5 A from fluorine atom center in the direction roughly coinciding with the lone pair localization. The absolute values of the ?2 deltaHe could be used to quantify the electron-rich regions of lone pairs. The results are compared with more common visualization methods-3D maps of the molecular electrostatic potential and the electron localization function. We show that a helium atom could be used for evaluation of fine features of molecular electronic shell, since 3 He NMR spectral characteristics remain sensitive at relatively large distances. (c) 2018 Wiley Periodicals, Inc. PMID- 30430613 TI - Prediction intervals for penalized longitudinal models with multisource summary measures: An application to childhood malnutrition. AB - In many global health analyses, it is of interest to examine countries' progress using indicators of socio-economic conditions based on national surveys from varying sources. This results in longitudinal data where heteroscedastic summary measures, rather than individual level data, are available. Administration of national surveys can be sporadic, resulting in sparse data measurements for some countries. Furthermore, the trend of the indicators over time is usually nonlinear and varies by country. It is of interest to track the current level of indicators to determine if countries are meeting certain thresholds, such as those indicated in the United Nations Sustainable Development Goals. In addition, estimation of confidence and prediction intervals are vital to determine true changes in prevalence and where data is low in quantity and/or quality. In this article, we use heteroscedastic penalized longitudinal models with survey summary data to estimate yearly prevalence of malnutrition quantities. We develop and compare methods to estimate confidence and prediction intervals using asymptotic and parametric bootstrap techniques. The intervals can incorporate data from multiple sources or other general data-smoothing steps. The methods are applied to African countries in the UNICEF-WHO-The World Bank joint child malnutrition data set. The properties of the intervals are demonstrated through simulation studies and cross-validation of real data. PMID- 30430614 TI - Aquaporins in brain edema. AB - Brain edema is a common feature of brain injuries, which leads to increased intracranial pressure (ICP) and ischemia that worsen outcome. Current management of edema focuses on reduction of ICP, but there are no treatments targeting the molecular players directly involved in edema process. The perivascular astrocyte endfeet are critical in maintaining brain homeostasis with ionic and water exchange; in this context, aquaporins (AQPs), astrocyte water channels, have emerged as privileged targets for edema modulation. However, AQPs can facilitate either accumulation or drainage of water, depending on the osmotic gradients between extra-intracellular space; and thus inhibition of AQPs leads to different outcomes depending on specific tissue characteristics and time post-injury. Most of this knowledge has been gathered from the study of AQP4, the best characterized AQP and the one that has the biggest impact on water movement. In addition to the level of expression, the ratio of AQP4 isoforms (m1, m23 or mz), the spatial distribution of AQP4 into orthogonal arrays of particles, and the interaction of AQP4 with neighboring ionic channels and gap junctions could directly impact edema formation. Although there are no specific AQP4 pharmacological blockers, the development of AQP4 siRNA offers a promising therapeutic tool. Given the complex dynamics of AQP4, therapies targeting AQP4 should carefully take into account the particular features of the injury (e.g., hemorrhagic vs. non-hemorrhagic) and different times after injury (e.g., phase of edema formation vs. resolution). PMID- 30430615 TI - Incidence and predictors of new persistent opioid use following inflammatory bowel disease flares treated with oral corticosteroids. AB - BACKGROUND: Opioids are commonly prescribed to manage pain associated with inflammatory bowel disease (IBD). It is unknown what percentage of patients develop new persistent opioid use following a steroid-treated IBD flare. AIM: To identify the incidence and the predictors of new persistent opioid use following an IBD flare. METHODS: We used a national insurance claim dataset to identify patients with IBD who received an opioid medication around the time of a corticosteroid-treated IBD flare. Patients were stratified as previously opioid naive, intermittent users, or chronic users. The incidence of persistent opioid use among the opioid-naive cohort was evaluated along with associated predictors. RESULTS: We identified 15 119 IBD patients who received opioids around the time of a flare. 5411 (35.8%) were opioid-naive patients of which 35.0% developed persistent opioid use after the flare. Factors associated with new persistent opioid use include a history of depression (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13-1.47), substance abuse (HR 1.36, 95% CI 1.2-1.54), chronic obstructive pulmonary disease (COPD) (HR 1.17, 95% CI 1.04-1.3), as well as, Crohn's disease (HR 1.26, 95% CI 1.14-1.4) or indeterminate colitis (HR 1.6, 95% CI 1.36-1.88). CONCLUSIONS: New persistent opioid use is common in IBD patients who experience a flare, especially among those with mental health disorders, COPD, and Crohn's disease or indeterminate colitis. These findings can be helpful in risk-stratifying patients when choosing an acute pain therapy and providing counselling before choosing to prescribe opioids to opioid-naive patients experiencing an IBD flare. PMID- 30430616 TI - Measles antibody trough levels after treatment with immunoglobulin products and predicted levels assuming lower measles antibody specifications. AB - BACKGROUND: Widespread vaccination against measles has resulted in decreasing measles antibody levels in human immune globulin (IG) products. As levels continue to decline, it needs to be determined whether the release specifications for measles antibody levels in IG products can be lowered and still provide protection against infection for patients who receive IG treatment for primary immunodeficiency disease. STUDY DESIGN AND METHODS: Trough level measles neutralizing antibodies were measured in 10 pediatric patients with primary immunodeficiency disease (ages 2-16) treated with IG administered both by intravenous and subcutaneous infusion. The results were used to model worst-case (lowest) serum measles antibody levels in two cases: 1) the current case with intravenous dosage at 300 mg/kg at a measles antibody level of 0.48* Center for Biologics Evaluation and Research Reference 176 and 2) a future case with intravenous dosage at 400 mg/kg and 0.30* Center for Biologics Evaluation and Research Reference 176. RESULTS: Serum trough measles neutralizing antibody levels were an average of 11-fold or greater above minimum protective levels for immunocompetent individuals of 0.12 IU/mL in both the intravenous and subcutaneous phases of the study. Modeling using both the current worst-case dose and future case shows average levels for IG intravenous/subcutaneous infusion of 3.9/4.8- and 3.2/4.0-fold above 0.12 IU/mL for the two cases, respectively. CONCLUSION: Lowering the measles antibody level specification to 0.30* Center for Biologics Evaluation and Research Reference 176 in IG products will still provide trough serum antibody levels against measles infection of greater than 0.12 IU/mL when dosed at 400 mg/kg or higher. PMID- 30430617 TI - Paroxysmal acral haematoma is a more appropriate name for Achenbach syndrome. PMID- 30430618 TI - Atypical presentation of dyschromatosis universalis hereditaria with a novel ABCB6 mutation. PMID- 30430619 TI - The challenges of detecting progress in generic competencies in the clinical setting. AB - CONTEXT: Competency-based medical education has spurred the implementation of longitudinal workplace-based assessment (WBA) programmes to track learners' development of competencies. These hinge on the appropriate use of assessment instruments by assessors. This study aimed to validate our assessment programme and specifically to explore whether assessors' beliefs and behaviours rendered the detection of progress possible. METHODS: We implemented a longitudinal WBA programme in the third year of a primarily rotation-based clerkship. The programme used the professionalism mini-evaluation exercise (P-MEX) to detect progress in generic competencies. We used mixed methods: a retrospective psychometric examination of student assessment data in one academic year, and a prospective focus group and interview study of assessors' beliefs and reported behaviours related to the assessment. RESULTS: We analysed 1662 assessment forms for 186 students. We conducted interviews and focus groups with 21 assessors from different professions and disciplines. Scores were excellent from the outset (3.5 3.7/4), with no meaningful increase across blocks (average overall scores: 3.6 in block 1 versus 3.7 in blocks 2 and 3; F = 8.310, d.f. 2, p < 0.001). The main source of variance was the forms (47%) and only 1% of variance was attributable to students, which led to low generalisability across forms (Erho2 = 0.18). Assessors reported using multiple observations to produce their assessments and were reluctant to harm students by consigning anything negative to writing. They justified the use of a consistent benchmark across time by citing the basic nature of the form or a belief that the 'competencies' assessed were in fact fixed attributes that were unlikely to change. CONCLUSIONS: Assessors may purposefully deviate from instructions in order to meet their ethical standards of good assessment. Furthermore, generic competencies may be viewed as intrinsic and fixed rather than as learnable. Implementing a longitudinal WBA programme is complex and requires careful consideration of assessors' beliefs and values. PMID- 30430620 TI - Thinking in new and deeper ways about clinical reasoning. PMID- 30430621 TI - Direct observation in postgraduate training: making it happen and making it work. PMID- 30430623 TI - Operationalising complexity in health professions education. PMID- 30430625 TI - Cutaneous sebaceous tumours and Lynch syndrome: long-term follow-up of 60 patients. AB - BACKGROUND: Sebaceous neoplasms (SN) may appear sporadically in the general population but may also be part of the Muir-Torre variant of Lynch syndrome (MT LS). There are few studies in southern Europe on the incidence of MT-LS in the population of patients with SN. AIM: To retrospectively review patients with SN and to analyse their clinical features and the incidence of MT-LS. METHODS: Patients with SN diagnosed between 1995 and 2015 were enrolled in the study. The diagnosis of MT-LS was made according to established clinical criteria and, whenever possible, was confirmed by germline mutation analysis. RESULTS: In 60 patients (32 men, 28 women, mean age 69.22 years), 96 SN were diagnosed: 65 adenomas (67.7%), 16 sebaceomas (16.7%) and 15 carcinomas (15.6%). Of the 60 patients, 50 (83.3%) had a single SN and 10 (16.7%) had multiple lesions. Patients diagnosed with MT-LS (12 patients, 20%) were younger (63.25 years vs. 70.71 years), and had a higher incidence of extrafacial SN (4/12 patients, 33.3%), and were significantly (P < 0.001) more likely to have multiple SNs (8/12, 75%) and keratoacanthomas (KAs) (6/12, 50%). CONCLUSION: Our study confirms that all patients with SN should be investigated, as 20% of our patients were diagnosed with MT-LS. The most specific features of SN associated with MT-LS in our study were the presence of multiple lesions and association with KAs. PMID- 30430626 TI - Lidocaine inhibits melanoma cell proliferation by regulating ERK phosphorylation. AB - The melanoma is responsible for the majority of all skin cancer-related deaths worldwide. Evidence suggests that local anesthetics provide some benefit in the treatment of cancer via inhibition of cellular proliferation, invasion and migration. However, the potential antiproliferative effects of local anesthetics in the treatment of melanoma remain to be elucidated. In this study, we investigated the antiproliferative effects and underlying mechanism of the commonly used local anesthetic (lidocaine) on melanoma cells. A375 melanoma cells were treated by lidocaine or vemurafenib. Cell Counting Kit-8, histological staining, flow cytometric analysis, immunohistochemical staining, and Western blot analyses were carried out to test the effects of lidocaine and vemurafenib on A375 cells. BALB/C-nu/nu mice intraperitoneally injected with A375 cells were treated by lidocaine, and then tumor volume and weight were calculated. Lidocaine exhibited vemurafenib-like effects totally. Lidocaine inhibited A375 melanoma cell proliferation in a dose- and time-dependent manner and colony formation also showed a dose-dependent inhibition. Lidocaine treatment resulted in the arrest of cell-cycle progression in the G1 phase and inhibited Ki-67 expression in a dose dependent manner. This effect was associated with inhibited extracellular signal regulated kinase (ERK) phosphorylation. In vivo experiments revealed that intravenous injections of lidocaine suppressed tumor volume and weight. Lidocaine inhibits melanoma cell proliferation in a dose- and time-dependent manner via a mechanism that may involve inhibition of the ERK signaling pathway. Thus, lidocaine may provide some benefit for the treatment of melanoma. PMID- 30430627 TI - Combination therapy of sirolimus and acitretin in solid organ transplant recipients: a new cutaneous adverse event. PMID- 30430628 TI - Constituents of effective support for homecare workers providing care to people with dementia at end of life. AB - OBJECTIVE: The aim of this study was to enhance understanding about homecare workers providing care to people with dementia at end of life by exploring homecare workers' perceptions of challenges and the support they needed and sometimes received. METHODS: Qualitative semi-structured interviews were conducted with 29 homecare workers and 13 homecare managers in England. Framework analysis was used to analyse the data. FINDINGS: Four overarching challenges were identified: working with clients with dementia, including clients' sometimes unpredictable responses, communication difficulties, and mood changes; caring for the dying; conflict with family members; and working alone, which often left homecare workers at risk of exhaustion, fatigue, and a sense of isolation. When their work entailed high levels of emotion, such as a client's death or getting embroiled in a client's family conflict, they felt emotionally drained, under prepared and overwhelmed. Supportive elements include receiving encouragement and learning from experienced peers and their feelings being acknowledged by managers at their employing homecare agency. Some workers were offered time off or encouraged to attend the client's funeral as a means of supporting the process of bereavement. CONCLUSIONS: Peer and manager support are essential and effective in coping with work pressures. There is a need to develop models of effective support to alleviate staff's practical, emotional and interpersonal pressures. However, due to the isolating nature of homecare work, managers may not recognise early signs of their staff finding stress unmanageable and miss the opportunity to mitigate these negative effects. PMID- 30430629 TI - Effects of multicopper oxidase orientation in multiwalled carbon nanotube biocathodes on direct electron transfer. AB - In this study, multicopper oxidase (MCO) was immobilized on multiwalled carbon nanotubes (MWCNTs) at two different orientations, and the electrochemical properties of the resulting cathodes were investigated. Using N- or C-terminal His-tagged MCO and MWCNTs, we constructed two types of cathodes. We assumed that the distance between the type 1 (T1)Cu of the C-terminal His-tagged MCO and the MWCNT surface was lesser than that between the T1Cu of the N-terminal His-tagged MCO and the MWCNT surface. In addition, in the C-terminal His-tagged MCO, T1Cu was expected to be closer to the MWCNT surface than the type 2/type 3 Cu site. The current density of the modified electrode with a C-terminal His-tagged MCO immobilized on an MWCNT surface was 1.3-fold higher than that of the electrode with an N-terminal His-tagged MCO immobilized on an MWCNT surface. In addition, the amount of H2 O2 produced by the N-terminal His-tagged MCO immobilized MWCNT modified electrodes was 2.3-fold higher than that produced by the C-terminal His tagged MCO immobilized MWCNT electrodes. In direct electron transfer (DET)-type biocathodes, both the MCO orientation and the distance between the T1Cu of MCO and the electrode surface are important. The authors succeeded in constructing highly efficient DET-type electrodes. PMID- 30430630 TI - Food Is Medicine: A Qualitative Analysis of Patient and Institutional Barriers to Successful Surgical Nutrition Practices in an Enhanced Recovery After Surgery Setting. AB - BACKGROUND: Close adherence to the Enhanced Recovery After Surgery (ERAS) program is associated with improved outcomes. A nutrition-focused qualitative analysis of patient experience and of ERAS implementation across our province was conducted to better understand the barriers to successful adoption of ERAS nutrition elements. METHODS: Enrolled colorectal patients (n = 27) were asked to describe their surgical experience. Narrative interviews (n = 20) and focus groups (n = 7) were transcribed verbatim and analyzed inductively for food and nutrition themes. Qualitative data sources (n = 198 documents) collected throughout our implementation of ERAS were categorized as institutional barriers that impeded the successful adoption of ERAS nutrition practices. RESULTS: We identified patient barriers related to 3 main themes. The first theme, Mistaken nutrition facts & beliefs, describes how information provision was a key barrier to the successful adoption of nutrition elements. Patients held misconceptions and providers tended to provide them with contradictory nutrition messages, ultimately impeding adequate food intake and adherence to ERAS elements. The second theme, White bread is good for the soul?, represents a mismatch between prescribed medical diets and patient priorities. The third theme, Food is medicine, details patient beliefs that food is healing; the perception that nutritious food and dietary support was lacking produced dissatisfaction among patients. Overall, the most important institutional barrier limiting successful adoption of nutrition practices was the lack of education for patients and providers. CONCLUSION: Applying a patient-centered model of care that focuses on personalizing the ERAS nutrition elements might be a useful strategy to improve patient satisfaction, encourage food intake, correct previously held beliefs, and promote care adherence. PMID- 30430631 TI - Identification of key lncRNAs in the carcinogenesis and progression of colon adenocarcinoma by co-expression network analysis. AB - Colon adenocarcinoma (COAD) is one of the most common cancers, and its carcinogenesis and progression is influenced by multiple long non-coding RNAs (lncRNA), especially through the miRNA sponge effect. In this study, more than 4000 lncRNAs were re-annotated from the microarray datasets through probe sequence mapping to obtain reliable lncRNA expression profiles. As a systems biology method for describing the correlation patterns among genes across microarray samples, weighted gene co-expression network analysis was conducted to identify lncRNA modules associated with the five stepwise stages from normal colonic samples to COAD (n = 94). In the most relevant module (R2 = -0.78, P = 4E-20), four hub lncRNAs were identified (CTD-2396E7.11, PCGF5, RP11-33O4.1, and RP11-164P12.5). Then, these four hub lncRNAs were validated using two other independent datasets including GSE20916 (n = 145) and GSE39582 (n = 552). The results indicated that all hub lncRNAs were significantly negatively correlated with the three-stage colonic carcinogenesis, as well as TNM stages in COAD (one way analysis of variance P < 0.05). Kaplan-Meier survival curve showed that patients with higher expression of each hub lncRNA had a significantly higher overall survival rate and lower relapse risk (log-rank P < 0.05). In conclusion, through co-expression analysis, we identified and validated four key lncRNAs in association with the carcinogenesis and progression of COAD, and these lncRNAs might have important clinical implications for improving the risk stratification, therapeutic decision and prognosis prediction in COAD patients. PMID- 30430632 TI - The recency ratio is related to CSF Amyloid Beta 1-42 levels in MCI-AD. AB - OBJECTIVE: As anti-amyloid therapeutic interventions shift from enrolling patients with Alzheimer's disease (AD) dementia to individuals with pre-clinical disease, the need for sensitive measures that allow for non-invasive, fast, disseminable and cost-effective identification of preclinical status increases in importance. The recency ratio (Rr) is a memory measure that relies on analysis of serial position performance, which has been found to predict cognitive decline and conversion to early mild cognitive impairment (MCI). The aim of this study was to test Rr's sensitivity to cerebrospinal fluid (CSF) levels of the core AD biomarkers in individuals with MCI-AD and controls. METHODS: Baseline data from 126 (110 controls and 16 MCI-AD) participants from the Wisconsin Alzheimer's Disease Research Center were analysed. Partial correlations adjusting for demographics were carried out between CSF measure of amyloid beta (Abeta40, Abeta42 and the 40/42 ratio) and tau (total and phosphorylated), and memory measures (Rr, delayed recall and total recall) derived from the Rey's Auditory Verbal Learning Test. RESULTS: Results indicated that Rr was the most sensitive memory score to Abeta42 levels in MCI-AD, while no memory score correlated significantly with any biomarker in controls. CONCLUSIONS: This study shows that Rr is a sensitive cognitive index of underlying Amyloid beta pathology in MCI-AD. PMID- 30430633 TI - Effect of microRNA-141 on the development of diabetic nephropathy through regulating AKT/AMPK signaling pathway by targeting insulin receptor substrate 2. AB - OBJECTIVE: The aim of this study was to explore the effect of microRNA-141 (miR 141) on the development of diabetic nephropathy (DN) and its potential mechanism. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of miR-141 in peripheral blood of DN patients. Cell apoptosis was measured by flow cytometry. The expression levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were detected by enzyme-linked immunosorbent assay. The expression level of insulin receptor substrate 2 (IRS2) was analyzed by RT-qPCR and Western blot analysis. The targeting regulatory sites were predicted by Targetscan and luciferase assay was conducted to confirm the relationship between miR-141 and IRS2. The expression levels of protein kinase B (AKT)/adenosine monophosphate protein kinase (AMPK)-related proteins were investigated by Western blot analysis. RESULTS: MiR-141 was upregulated in peripheral blood of DN patients (P < 0.05). Upregulation of miR-141 significantly promoted apoptosis ( P < 0.05) and the expression of TNF-alpha and IL-6 ( P < 0.05). However, downregulation of miR-141 inhibited cell apoptosis ( P < 0.05) and productions of TNF-alpha and IL-6 ( P < 0.05). Moreover, miR-141 displayed a negatively regulatory effect on IRS2 abundance, and overexpression of IRS2 reversed the inhibitory effect of miR-141 on development of DN cells ( P < 0.05). Besides, knockdown of miR-141 significantly promoted the expressions of AKT/AMPK related proteins ( P < 0.05), which was attenuated by inhibition of IRS2 ( P < 0.05). CONCLUSION: MiR-141 promoted DN progression through regulating AKT/AMPK signaling pathway by targeting IRS2. PMID- 30430634 TI - Long noncoding RNA HAGLROS regulates apoptosis and autophagy in colorectal cancer cells via sponging miR-100 to target ATG5 expression. AB - The aim of this study was to explore the relationship between the expression of HOXD antisense growth-associated long noncoding RNA (HAGLROS) and prognosis of patients with colorectal cancer (CRC), as well as the roles and regulatory mechanism of HAGLROS in CRC development. The HAGLROS expression in CRC tissues and cells was detected. The correlation between HAGLROS expression and survival time of CRC patients was investigated. Moreover, HAGLROS was overexpressed and suppressed in HCT-116 cells, followed by detection of cell viability, apoptosis, and the expression of apoptosis-related proteins and autophagy markers. Furthermore, the association between HAGLROS and miR-100 and the potential targets of miR-100 were investigated. Besides, the regulatory relationship between HAGLROS and PI3K/AKT/mTOR pathway was elucidated. The results showed that HAGLROS was highly expressed in CRC tissues and cells. Highly expression of HAGLROS correlated with a shorter survival time of CRC patients. Moreover, knockdown of HAGLROS in HCT-116 cells induced apoptosis by increasing the expression of Bax/Bcl-2 ratio, cleaved-caspase-3, and cleaved-caspase-9, and inhibited autophagy by decreasing the expression of LC3II/LC3I and Beclin-1 and increasing P62 expression. Furthermore, HAGLROS negatively regulated the expression of miR-100, and HAGLROS controlled HCT-116 cell apoptosis and autophagy through negatively regulation of miR-100. Autophagy related 5 (ATG5) was verified as a functional target of miR-100 and miR-100 regulated HCT-116 cell apoptosis and autophagy through targeting ATG5. Besides, HAGLROS overexpression activated phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. In conclusion, a highly expression of HAGLROS correlated with shorter survival time of CRC patients. Downregulation of HAGLROS may induce apoptosis and inhibit autophagy in CRC cells by regulation of miR 100/ATG5 axis and PI3K/AKT/mTOR pathway. PMID- 30430635 TI - Does social interaction influence the effect of cognitive intervention program? A randomized controlled trial using Go Game. AB - OBJECTIVES: The purpose of this study is to clarify the influence of social interaction on the effect of a cognitive intervention program using Go. METHODS: A single-blind, randomized controlled trial using a classical board game "Go" was conducted. A total of 72 community-dwelling older adults, without previous experience playing Go, were randomly assigned to three groups: 1) a face-to-face group (FG) in which members attended 12 Go group lessons held once a week; 2) a non-face-to-face group (NFG) in which members individually underwent the same Go lessons as the FG using a tablet computer; or 3) a health education control group (CG). The main outcome variable, working memory, was assessed before and after the interventions using the Visual Memory Span Test (VMST) and the Visual Memory Span Backward task (VMSB). Go performance and additional cognitive domains were also examined. RESULTS: Analysis of covariance revealed that VMST scores significantly improved after the intervention in both the FG and NFG (both P<.05). Compared with the CG, the effect size of the FG (Cohen's d = 0.89) was greater than that of the NFG (Cohen's d = 0.67). Although VMSB scores significantly improved after the intervention in the FG (P<.05), no significant changes were observed in other groups. CONCLUSIONS: This study showed that Go game could improve visual working memory regardless of social interaction. Furthermore, findings suggested that playing board games face-to-face with others is more effective for cognitive function than playing alone. PMID- 30430636 TI - A dual target of Plasmepsin IX and X: Unveiling the atomistic superiority of a core chemical scaffold in malaria therapy. AB - Plasmepsin IX and X, members of the prominent aspartic family of proteases whose function were hitherto unknown have only recently been established as key mediators of erythrocyte invasion and egress of the virulent malarial parasite. Inhibitor 49c, a potent antimalarial peptidomimetic inhibitor initially developed to target Plasmepsin II has lately been proven to exhibit potent inhibitory activity against Plasmepsin IX and X. However, the molecular and structural dynamics supporting its inhibitory activity remain inconclusive. Hindering the motion of the flap and hinge region of an aspartic protease remains essential for disabling the catalytic activity of the enzyme. Integrating molecular dynamic simulations coupled with other advanced biocomputational tools, we reveal the enhanced structural mechanistic competence of 49c in complex with Plasmepsin IX and X relative to Pepstatin. Pepstatin, a known aspartic protease inhibitor which actively hinders the opening and closing of the flap tip and flexible loop and consequently limits access to the catalytic aspartic residues, however, its administration has been related to elevated levels of toxicity. Thermodynamic calculations reveal a higher relative binding free energy associated with Plasmepsin IX and X in complex with 49c as opposed to Pepstatin. A relatively compact and structurally rigid 49c bound complexes sequel into the restriction of the flap and hinge residues by restraining cohesive movement, consequently hindering their "twisting motion" from transpiring. Findings unveil an atomistic perspective into the structural superiority of 49c in complex with Plasmepsin IX and X. PMID- 30430637 TI - Nivolumab PD-1 inhibitor immunotherapy associated with vulvar, perineal and perianal lichen sclerosus. PMID- 30430638 TI - Substances Involved in Suicidal Poisonings in the United States. AB - OBJECTIVE: This study investigated specific substances most commonly involved in suicidal poisonings, causing severe clinical effects, and leading to intensive treatments. METHOD: Suicidal poisoning cases for individuals >=13 years old were obtained from the National Poison Data System for 2011-2015. The most common products involved in single and multiple-product poisonings were identified. Single product cases were used to calculate substances causing the largest numbers of serious clinical effects and leading to intensive treatments. RESULTS: More than half of reported cases involved only a single product (54.4%), but this frequency was higher at the extremes of age (66.7% in adolescents 13-19 years old and 70.5% in individuals >=90 years old) and among pregnant women (65.8%). The top three substances involved in single-product poisonings were over-the-counter (OTC) medications, while alcohol and prescription sedatives were most common in multiple-product poisonings. One OTC medication, diphenhydramine, was a frequent cause of several serious clinical effects and intensive treatments. CONCLUSIONS: Single product suicidal poisonings were more frequent with extremes of age and in pregnancy. OTC products were more frequently used in single product attempts. Products causing serious clinical effects can be targeted for suicide prevention efforts as well as education of health care providers. PMID- 30430639 TI - Response to Economic Shock: The Impact of Recession on Rural-Urban Suicides in the United States. AB - OBJECTIVE: This study examines the effect of economic recession on the suicide differential between rural and urban counties. METHODS: A negative binomial regression model and county mortality data are used to estimate the effect of recession and rurality on county-level suicides from 2002-2016. RESULTS: After accounting for differences in population, urban counties have more female suicides than rural counties, but urban counties experience smaller increases in female suicide numbers during periods of recession than rural counties. Long-term factors such as high chronic poverty or unemployment have a greater impact on male suicide rates, while short-term economic crises have a larger impact on female suicides. Higher percentages of children in the county have an increasing effect on male suicides, but a decreasing effect on female suicides. Finally, farm-dependent counties have fewer suicides than non-farm-dependent counties. This holds true for both males and females. CONCLUSIONS: Periods of recession impact suicide numbers; however, this effect is most noticeable for females, with rural counties having larger increases in female suicide numbers than their urban counterparts during recession years. PMID- 30430640 TI - An Integrative Review of Acupressure Interventions for Older people: A focus on sleep quality, depression, anxiety and agitation. AB - OBJECTIVES: This integrative review aimed to synthesize studies that investigated the effects of acupressure on sleep quality, depression, anxiety, and agitation in older people, and to describe the acupressure procedures and techniques applied in the included studies. METHODS: A literature search was conducted using electronic databases including CINAHL, Cochrane Library, EMBASE, and MEDLINE. The inclusion criteria for the review were studies examining the effect of acupressure in older people aged 60 years and above, measured the outcomes for sleep quality, depression, anxiety or agitation, applied body acupressure, and published in English language. The exclusion criteria were studies using auricular acupoints only, and articles published in any language other than English. Methodological quality of studies were assessed using the critical appraised tools developed by the Joanna Briggs Institute. The information about study design, findings and description of acupressure intervention were extracted, summarised and synthesized. RESULTS: A total of 225 articles were identified from the search and as well one article from cross-references. From there, a total of 19 studies were included in this review. Nine studies consistently showed positive effects of acupressure on sleep quality, and four studies consistently showed that acupressure reduced depression. The outcomes of acupressure on anxiety and agitation showed inconsistent findings, in which three studies measured anxiety and five studies measured agitation. There was also variation of acupressure techniques applied in the reviewed studies. CONCLUSION: This review found some emerging evidences that acupressure can be beneficial for older people who suffer from sleep problems and depression. Use of specific acupressure points, with standardised acupressure treatment protocols, may improve sleep quality and possibly psychological wellbeing of older people. Future research with well-designed mixed method studies are required to produce stronger evidence, as well as in-depth understanding of acupressure intervention in aged care context. PMID- 30430641 TI - Should Measures of Health Care Availability be Based on the Providers or the Procedures? A Case Study with Implications for Rural Colorectal Cancer Disparities. AB - PURPOSE: Patients with colorectal cancer (CRC) living in rural areas have lower survival rates than those in urban areas, potentially because of lack of access to quality CRC screening and treatment. The purpose of this study was to compare traditional physician density (ie, colonoscopy provider availability per capita) against a new physician density measure using an example case of colonoscopy volume and quality. The latter is particularly relevant for rural providers, who may have fewer patients and are more frequently nongastroenterologists. METHODS: We conducted a secondary data analysis of the 2014 Medicare Provider Utilization and Payment Database and the National Cancer Institute State Cancer Profile Database. Volume-weighted physician density scores at the state and county levels were created, accounting for (1) the physician's annual colonoscopy volume and (2) whether the physician performs >=100 procedures per year. We compared volume weighted versus traditional density, overall and by rurality, and examined their correlation with CRC screening, incidence, and mortality rates. FINDINGS: The difference between volume-weighted and traditional density scores was particularly large in rural parts of the West and Midwest, and it was most similar in the Northeast. Although weak, correlations with CRC outcomes were stronger for volume-weighted density, and they did not differ by rurality. CONCLUSIONS: Our new method is an improvement over traditional methods because it considers the variation of physician procedure volume, and it has a stronger correlation with population health outcomes. Weighted density scores portray a more realistic picture of physician supply, particularly in rural areas. PMID- 30430642 TI - Using electronic health records to estimate the prevalence of agitation in Alzheimer's disease/dementia. AB - BACKGROUND: Agitation is a common neuropsychiatric symptom of Alzheimer's disease (AD). Data are scarce regarding agitation prevalence among community-dwelling patients with AD. OBJECTIVE: To estimate agitation prevalence in a sample of US patients with AD/dementia overall and by AD/dementia disease severity, using data from electronic health records (EHR). METHODS: This retrospective database study examined community-dwelling patients with >=1 EHR record indicating AD/dementia from January 2008 - June 2015 and no evidence of non-AD dementia during the 12 month pre- and post-index periods. Agitation was identified using diagnosis codes for dementia with behavioral disturbance, and EHR abstracted notes records indicating agitation symptoms compiled from the International Psychogeriatric Association provisional consensus definition. RESULTS: Of 320,886 eligible patients (mean age 76.4 years, 64.7% female), 143,160 (44.6%) had evidence of agitation during the observation period. Less than 5% of patients with agitation had a diagnosis code for behavioral disturbance. The most prevalent symptom categories among patients with agitation, pre-index and post-index, were agitation (31.4% and 41.3%), falling (22.6% and 21.7%), and restlessness (18.3% and 23.3%). Among the 78,827 patients (24.6%) with known AD/dementia severity, agitation prevalence was 61.3%. Agitation during the observation period was most prevalent for moderate-to-severe and severe AD/dementia (74.6% and 68.3%, respectively) and lowest for mild AD/dementia (56.4%). CONCLUSIONS: Agitation prevalence was 44.6% overall and 61.3% among patients with staged AD/dementia. Behavioral disturbance appeared to be underdiagnosed. While agitation has previously been shown to be highly prevalent in the long-term care setting, this study indicates that it is also common among community-dwelling patients. PMID- 30430643 TI - Regional Rural-Urban Differences in E-Cigarette Use and Reasons for Use in the United States. AB - PURPOSE: To determine whether there are rural/urban differences in e-cigarette use and reasons for use that vary across the 10 Health & Human Services (HHS) regions. METHODS: Age-adjusted bivariate and multivariable analyses were conducted for n = 225,413 respondents to the 2014-2015 Tobacco Use Supplement Current Population Survey to estimate the prevalence of e-cigarette use. Reasons for e-cigarette use were collected from n = 16,023 self-respondents who reported ever using e-cigarettes. FINDINGS: While nationally rural residents appeared more likely to use e-cigarettes, adjusted results indicated that current e-cigarette use was significantly less likely across the northern and western regions (New England, East North Central, Heartland, North Central Mountain, Northwest, and Southwest Pacific regions). Reasons for e-cigarette use differed by urban/rural status and region; for example, the rationale to use e-cigarettes as a smoking cessation aid was significantly more common among rural compared to urban adults in the New England and New York/New Jersey regions, but less common in the Southeast. CONCLUSIONS: For several regions, there were no significant rural/urban differences in e-cigarette use and reasons for use. Yet those regions that present differences face the need to develop public health approaches to minimize urban/rural disparities in health education, services, and outcomes related to tobacco use, particularly where access to health care is limited. Public health campaigns and guidance for clinical care within HHS regions should be tailored to reflect regional differences in beliefs about e-cigarettes. PMID- 30430644 TI - Metabolic syndrome rates in older patients with severe mental illness after five years of follow-up and the association with mortality. AB - OBJECTIVES: To establish the course of metabolic syndrome (MS) rates in older patients with severe mental illness (SMI) after five-year follow-up and evaluate whether MS at baseline is associated with mortality or diabetes at follow-up. METHODS: Patients (>60 years of age) with SMI (N=100) were included at a specialized mental health outpatient clinic. Metabolic parameters were collected from patients' medical files at baseline and after five-year follow-up. RESULTS: Follow-up data were available of 98 patients (98%), nine patients had died. Parameters of MS were available of 76 patients, 34.2% were diagnosed with MS. This was not significantly different compared with baseline (46.1%). MS at baseline was not significantly associated with mortality or development of diabetes at follow-up. CONCLUSIONS: In older patients with SMI the rates of MS may reach a plateau. Screening for MS in older patients treated at a specialized mental health outpatient clinic may generate attention for their somatic health and treatment for the components of MS that may in turn have a positive effect on their outcome. However, further research with larger sample sizes is needed in order to confirm these findings. PMID- 30430645 TI - The effects of particle density in moxa smoke on the ultrastructure of knee cartilage and expressions of TNF-alpha, IL-1b, BAX, and Bcl-2 mRNA in a rat model for osteoarthritis. AB - BACKGROUND: The effectiveness of smokeless moxa and other means to reduce exposure are extensively investigated with regards to the health consequences of inhalation of moxa smoke, and clinical studies indicate that classical moxibustion is superior to smokeless moxa. This study aims to quantify the effects of particle density in moxa smoke on the clinical outcome with an established model, demonstrated to be effective for classical moxibustion. OBJECTIVES: The purpose of this study is to explore the effects of particle density in moxa smoke on the ultrastructure of knee cartilage and expression of cytokine, tissue necrosing factor-alpha (TNF-alpha), interleukin 1 beta (IL-1b), apoptosis regulator, B-cell lymphoma-2 (Bcl-2), and BAX in a rat model for inflammatory joint disease. METHODS: Fifty healthy experimental rats were randomly divided into five groups, including normal control, model control, and moxa exposure groups with low, medium, and high particle density, and n = 10/group. In addition, a knee osteoarthritis model was duplicated in the model control and moxa exposure groups. Finally, the ultrastructure of knee cartilage was observed using transmission electron microscopy, and messenger RNA (mRNA) expressions of TNF-alpha, IL-1b, BAX, and Bcl-2 were determined with quantitative fluorescence methodology. RESULTS: In the model control and moxa exposure groups, knee cartilage indicated that histologic changes with the degree of injury were inversely proportional to moxa smoke density. The mRNA expressions of TNF-alpha, IL-1b, and BAX in synovial fluid, as an acute phase reactant, were similarly inversely related to moxa smoke density, but significantly increased. In contrast, Bcl-2, as an antiapoptotic, was substantially decreased in the model, while its levels were directly proportional to moxa smoke density. Besides, the ratio of Bcl-2/BAX mRNA was sharply decreased in the model group, but with levels proportional to moxa smoke density. CONCLUSIONS: A correlation was found between the particle density in moxa smoke and degree of injury to knee cartilage, favoring higher particle densities. This can be partially related to the suppression of the inflammatory effects of TNF-alpha, IL-1b, enhancement of the antiapoptotic effects of Bcl-2, and, nevertheless, suppression of the apoptotic effects of BAX. Finally, the protective effect of antiapoptotic is one of the key mechanisms for an ambient moxa smoking environment. PMID- 30430646 TI - The use of direct care in nursing home residents: a longitudinal cohort study over three years. AB - OBJECTIVES: To evaluate the trend in the use of direct care in a cohort of Nursing home (NH) residents and explore its association with resident characteristics and organizational factors. METHODS/DESIGN: A total of 696 NH residents from 47 Norwegian NHs were included at admissions at NH. In 537 residents the use of direct care was assessed every 6 months over a course of three years. A multiple model was estimated to identify demographic, clinical and organizational characteristics associated with the use of direct care time. RESULTS: Six months after admission, on average, 76.2 hours of direct care were rendered to each resident per month, while this number was reduced to 50.3 hours per month at the end of the study period. Most residents (92%) showed a stable use of direct care time, while a small group of residents displayed a much higher and varying use of direct care time. Increasing dementia, neuropsychiatric symptoms and decreasing function in activities of daily living were associated with higher use of direct care time. Direct care time constituted about 50% of the staff's working time. CONCLUSION: In Norwegian NHs, high use of direct care time was associated with younger age, more severe dementia and severe neuropsychiatric symptoms. By identifying factors that impact on direct care time, preventive measures might be put in place to the benefit of the residents and possibly to improve resource use. Further research should explore the association between direct care time, quality of care and the residents' quality of life. PMID- 30430647 TI - Total necrosis after sequential treatment with pazopanib followed by nivolumab in a patient with renal cell carcinoma involving the inferior vena cava. PMID- 30430648 TI - Comparative study of electrical and rheological properties of different solutions used in EMR. AB - BACKGROUND AND AIM: The study of electrical and rheological properties of solutions to perform endoscopic resection procedures could determinate the best candidate. An ex vivo study with porcine stomachs was conducted to analyze electrical resistivity (R) and rheological properties (temperature, viscosity, height and lasting of the cushion) of different substances used in these techniques. METHODS: Tested solutions were: 0.9% Saline (S), platelet-rich plasma (PRP), Gliceol(r) (GC), Hyaluronic acid 2% (HA), Pluronic-F127 20% (PL), Glucosated serum 10% (GS), Gelaspan (GP), TriBio (TB) and PRP with TB (PRP+TB). Measurements of electrical and rheological properties were done at 0, 15, 30, 45 and 60 minutes after submucosal injection RESULTS: Solutions showed a wide variability of trans-epithelial R after submucosal injection. Substances able to long-term maintain the highest R after 60 min postinjection were TB (7x104 Omega), HA (7x104 Omega) and PL (7x104 Omega). Protective solutions against deep thermal injury (Ta lower than 60 degrees C) were PL (47.6 degrees C), TB (55 degrees C) and HA (56.63 degrees C). Shortest time to perform resections were observed with GC (17.66''), PRP (20.3'') and GS (23.45''). Solutions with less cushion descrease (<25%) after 60 min were: TB (11.74%), PL (18.63%) and PRP (22.12%) CONCLUSIONS: TB, PL and HA were the best solutions with long-term protective effects (trans-epithelial R, lower thermal injury and less cushion descrease). Solutions with quicker resection time were GC, PRP and GS. This article is protected by copyright. All rights reserved. PMID- 30430649 TI - Effects of Lactobacillus rhamnosus HN001 in early life on the cumulative prevalence of allergic disease to 11 years. AB - BACKGROUND: In a two-centre randomized placebo-controlled trial of Lactobacillus rhamnosus HN001 (HN001) (6 * 109 colony-forming units [cfu]) or Bifidobacterium lactis HN019 (HN019) (9 * 109 cfu) taken daily from 35-week gestation to 6 months' post-partum in mothers while breastfeeding and from birth to age 2 years in infants, we showed that HN001 significantly protected against eczema development at 2, 4 and 6 years and atopic sensitization at 6 years. There was no effect of HN019. We report here the findings for 11 year outcomes. METHODS: At age 11 years, eczema was defined as previously using the UK Working Party's Diagnostic Criteria. Asthma, wheeze, hay fever and rhinitis were defined based on the International Study of Asthma and Allergies in Childhood (ISAAC) questions. Atopic sensitization was defined as one or more positive responses (mean wheal diameter >=3 mm) to a panel of food and aeroallergens. Analysis was intention-to treat using hazard ratios to assess probiotic effects on the 11-year lifetime prevalence and relative risks for point or 12-month prevalence at 11 years. RESULTS: Early childhood HN001 supplementation was associated with significant reductions in the 12-month prevalence of eczema at age 11 years (relative risk [RR] = 0.46, 95% CI 0.25-0.86, P = 0.015) and hay fever (RR = 0.73, 95% CI 0.53 1.00, P = 0.047). For the lifetime prevalence, HN001 was associated with a significant reduction in atopic sensitization (hazard ratio [HR] = 0.71, 95% CI 0.51-1.00, P = 0.048), eczema (HR = 0.58, 95% CI 0.41-0.82, P = 0.002) and wheeze (HR = 0.76, 95% CI 0.57-0.99, P = 0.046). HN019 had no significant effect on these outcomes. CONCLUSION: This is the first early probiotic intervention to show positive outcomes for at least the first decade of life across the spectrum of allergic disease. PMID- 30430651 TI - Editorial Comment from Dr Iwami to Clinical impact of glomerular basement membrane thickness on post-donation renal function in living donors. PMID- 30430650 TI - LncRNA CRNDE promotes the epithelial-mesenchymal transition of hepatocellular carcinoma cells via enhancing the Wnt/beta-catenin signaling pathway. AB - Colorectal neoplasia differentially expressed (CRNDE) is a significantly upregulated long noncoding RNA in hepatocellular carcinoma (HCC). CRNDE could promote cell proliferation, migration, and invasion, while its molecular mechanisms were still largely unclear. In this study, we investigated the expression and function of CRNDE. CRNDE was significantly upregulated in tumor tissues compared with adjacent normal tissues. In vitro, we revealed that knockdown of CRNDE inhibited cell proliferation, migration, and cell invasion capacities in HCC. Animal studies indicated that CRNDE knockdown represses both growth and metastasis of HCC tumors in vivo. Moreover, knockdown of CRNDE suppressed the cell epithelial-mesenchymal transition (EMT) process by increasing the expression of E-cadherin and ZO-1, whereas, decreasing the expression of N cadherin, slug, twist, and vimentin in HCC cells. We also revealed that knockdown of CRNDE suppressed the Wnt/beta-catenin signaling in HCC. Thus, CRNDE could modulate EMT of HCC cells and knockdown of CRNDE impaired the mesenchymal properties. CRNDE increased invasion of HCC cells might be through activating the Wnt/beta-catenin signaling pathway. PMID- 30430652 TI - Astrocyte-neuron lactate shuttle sensitizes nociceptive transmission in the spinal cord. AB - Astrocytes play a key role in the maintenance of synaptic transmission by producing L-lactate via the astrocyte-neuron lactate shuttle (ANLS). Astrocyte activation in the spinal cord is involved in the expression of neuropathic pain. We investigated the role of the ANLS in the spinal cord on hyperalgesia in neuropathic pain in mice. Specific activation of dorsal horn astrocytes induced mechanical hyperalgesia, which was attenuated by alpha-cyano-4-hydroxycinnamate (4-CIN), an inhibitor of monocarboxylate transporters that deliver L-lactate from astrocytes to neurons. Intrathecal L-lactate administration lowered the mechanical nociceptive threshold, which was attenuated by pretreatment with 4-CIN and isosafrole (a lactate dehydrogenase inhibitor), but not gliotoxin. Intrathecal L-lactate administration significantly upregulated c-Fos and cofilin phosphorylation, which was reversed by 4-CIN. The lowered mechanical nociceptive threshold was significantly attenuated by intrathecal fluorocitrate (an astrocyte specific Krebs cycle inhibitor), 4-CIN, and isosafrole treatment. Thus, these results suggested that, in neuropathic pain, mechanical hyperalgesia was maintained by excessive L-lactate supplied by activated astrocytes via an aberrant ANLS. PMID- 30430653 TI - Transperitoneal versus retroperitoneal laparoscopic adrenalectomy for large pheochromocytoma: Comparative outcomes. AB - OBJECTIVES: To evaluate operative and oncological outcomes of laparoscopic adrenalectomy through a transperitoneal approach and retroperitoneal approach for large (>5 cm in diameter) pheochromocytomas. METHODS: We retrospectively compared the results of a transperitoneal approach with those of a retroperitoneal approach in 22 patients (mean age 57.5 years, range 38-76 years) with unilateral large pheochromocytomas (12 right, 10 left). The mean body mass index, operation time, pneumoperitoneum time, estimated blood loss, fluctuation in blood pressure and complication rate were compared between the two approaches. RESULTS: The mean tumor diameter (range) was 7.0 cm (range 5.2-15.5 cm), and no significant differences were observed between the transperitoneal approach and retroperitoneal approach in any baseline clinical parameter. For right-sided procedures, significant differences were found for operation time (113 vs 85 min), pneumoperitoneum time (93 vs 64 min) and estimated blood loss (96 vs 23 mL; P < 0.05, transperitoneal approach and retroperitoneal approach, respectively). No open conversion or recurrence was reported, but one right transperitoneal approach case required blood transfusion. No difference in these parameters was noted on the left side. CONCLUSIONS: For right side procedures, the retroperitoneal approach is feasible, safer and faster than the transperitoneal approach for large pheochromocytomas. Early transection of the feeding artery is beneficial for managing the tumor and reducing the risk of bleeding. PMID- 30430654 TI - Variation in bucco-palatal maxillary sinus width does not permit a meaningful sinus classification. AB - OBJECTIVES: The bucco-palatal sinus width (SW) appears as relevant factor for graft consolidation after maxillary sinus (MS) floor augmentation. The present study aimed to assess (a) SW at different height levels of posterior teeth, (b) possible factors influencing SW, and (c) whether a simple/meaningful sinus classification based on SW is possible. METHODS: The following parameters were recorded on computed tomographies of 76 edentulous and 86 partially edentulous maxillary quadrants displaying 383 tooth sites in total: (a) alveolar ridge height, (b) -area, (c) -width 2 mm apical to the alveolar crest, (d) -width at the sinus floor, and (e) SW and sinus area at a level 2, 4, 6, 8, and 10 mm above the sinus floor. The possible influence of gender, tooth position [i.e., premolar (PM); molar (M)], tooth-gap extent, and residual alveolar ridge dimensions on SW was assessed. Further, based on percentiles of average values or on the frequency distribution of SW <10, 10-15, or >15 mm, it was attempted to classify the sinus at each given site into narrow, average, or wide. RESULTS: Gender and tooth-gap extent presented no relevant impact on MS dimensions; however, significant differences were observed among the various tooth positions regarding all evaluated parameters. The lower the residual alveolar ridge, the wider the MS at 4-10 mm height, while the wider the residual alveolar ridge, the wider the MS. Large variation in SW classes among the different height levels within the same tooth position and among tooth positions within the same person was observed, irrespective of the threshold applied. Further, at a MS height of 10 mm at PM1, PM2, M1, and M2, SW was <10 mm in 68%, 33%, 0%, and 7% of the cases, respectively, while in 3%, 21%, 65%, and 57%, respectively, SW was >15 mm. CONCLUSIONS: There is a large variation in SW depending on the height level within the sinus and on tooth position, which does not permit a simple/meaningful classification of each sinus as "narrow," "average," or "wide." Nevertheless, narrow sinuses (<10 mm) are rather prevalent in the premolar region, while wide sinuses (>15 mm) in the molar region; further, a wider and shorter residual alveolar ridge is associated with a wider SW. PMID- 30430655 TI - Long-term follow-up of single crowns supported by short, moderately rough implants-A prospective 10-year cohort study. AB - OBJECTIVES: To evaluate prospectively the clinical and radiographic outcomes after ten years of short (6 mm) implants with a moderately rough surface supporting single crowns in the posterior region. MATERIAL AND METHODS: Forty 6 mm modified sandblasted large-grit acid-etched (mod-SLA), soft tissue level implants were installed in the distal segments of 35 consecutive patients. After 6 weeks of healing, abutments were tightened, and single porcelain-fused-to-metal crowns were cemented. Implant survival, marginal bone loss, and clinical crown/implant ratio were evaluated at various time intervals up to 10 years after loading. RESULTS: Two out of the 40 implants were lost before loading, one implant was lost after 7 years because of peri-implantitis. One patient with two implants died and was excluded from analysis. Two patients did not come at the 10 year follow-up and were considered as drop out (2 implants). The survival rate was 91.7% (n = 36). Thirty-three implants were available for marginal bone loss evaluation. A mean marginal bone loss after 10 years of function was 0.8 +/- 0.7 mm. Between 5 and 10 years, the loss was 0.2 +/- 0.4 mm. No technical complications were registered during the 10-year period. The clinical crown/implant ratio increased with time from 1.6 at the delivery of the prosthesis to 2.0 after 10 years of loading with no increase between 5 and 10 years. CONCLUSION: Short (6 mm) implants with a moderately rough surface supporting single crowns in the posterior region and loaded after 6-7 weeks maintained full function for at least 10 years with low marginal bone resorption. PMID- 30430656 TI - Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination. AB - Remyelination in the adult CNS depends on activation, differentiation, and functional integration of resident oligodendroglial precursor cells (OPCs) and constitutes the only spontaneous neuroregenerative process able to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis. The proteins encoded by p57kip2- and by human endogenous retrovirus type W (pHERV-W) envelope genes were previously identified as negative regulators of OPC maturation. We here focused on the activity of the ENV protein and investigated how it can be neutralized for an improved myelin repair. We could demonstrate that myelination in vitro is severely affected by this protein but that application of an anti-ENV neutralizing antibody, currently investigated in clinical trials, can rescue the generation of internodes. We then compared p57kip2 and ENV dependent inhibitory mechanisms and found that a dominant negative version of the p57kip2 protein can equally save OPCs from myelination failure in response to ENV-mediated TLR4 activation. Additional experiments addressing p57kip2's underlying mode of action revealed a direct interaction with ATP6v1d, a central component of a vascular ATPase. Its pharmacological blocking was then shown to exert an analogous myelination rescue effect in presence of the ENV protein. Therefore, our study provides mechanistic insights into oligodendroglial inhibition processes and presents three different means to counteract the anti-myelination effect of the ENV protein. These observations are therefore of interest in light of understanding the complexity of the numerous oligodendroglial inhibitors and might promote the establishment of novel regenerative therapies. PMID- 30430657 TI - Hearing loss and incident psychosis in later life: The Health in Men Study (HIMS). AB - OBJECTIVE: To determine if hearing loss is associated with increased risk of incident psychosis in later life. METHODS: Longitudinal cohort study of a community-representative sample of 38 173 men aged 65 to 85 years at the start of the follow-up period of 18 years. We used the Western Australian Data Linkage System to ascertain the presence of hearing loss and of psychotic disorders according to the International Classification of Diseases (ICD) (versions 8, 9, and 10). We also collected information on concurrent morbidities: cancer and diseases of the cardiovascular, respiratory, digestive, and renal systems. RESULTS: One thousand four hundred forty-two (3.8%) and 464 (1.2%) men had a recorded diagnosis of hearing loss and psychosis at the start of follow-up. After excluding the 464 participants with prevalent psychosis, 37 709 men were available for the longitudinal study, and of these, 252 (0.7%) developed a psychotic disorder. Competing risk regression showed that hearing loss was associated incident psychosis (subhazard ratio = 2.03, 95% CI, 1.24-3.32; after statistical adjustment for age and concurrent morbidities). CONCLUSIONS: Hearing loss is associated with double the risk of incident psychosis in older men. Available evidence suggests that this link could be causal, although conclusive evidence is still missing from randomized controlled trials designed to test the effect of correction of hearing loss on the prevalence and incidence of psychosis. PMID- 30430658 TI - Intracranial vascular calcification with extensive white matter changes in an autopsy case of pseudopseudohypoparathyroidism. AB - We herein report an autopsy case of a 69-year-old man with pseudopseudohypoparathyroidism. The patient suffered from mental retardation and spastic tetraparesis and had all the features of Albright's hereditary osteodystrophy with a normal response to parathyroid hormone in the Ellsworth Howard test. Computed tomography demonstrated symmetrical massive brain calcification involving the bilateral basal ganglia, thalami, dentate nuclei and cerebral gray/white matter junctions, which was consistent with Fahr's syndrome. Magnetic resonance imaging revealed extensive white matter changes sparing the corpus callosum. Severe ossification of the posterior longitudinal ligament of the cervical spine was also demonstrated. A neuropathological examination revealed massive intracranial calcification within the walls of the blood vessels and capillaries with numerous calcium deposits. The calcium deposits aligned along the capillaries, and deposits in the vessel wall at the initial stage were confined to the border between the tunica media and adventitia. The vascular calcification in the basal ganglia continuously spread over the surrounding white matter into the cortex. The area of vascular calcification in the white matter was very well correlated with the area of the attenuated myelin staining. Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification. We should recognize the continuous area of vascular calcification and its correlation with extensive white matter changes as possible causes of neuropsychiatric symptoms in pseudopseudohypoparathyroidism with Fahr's syndrome. PMID- 30430659 TI - Ultrafast Sodium Full Batteries Derived from X?Fe (X = Co, Ni, Mn) Prussian Blue Analogs. AB - Exploring high-rate electrode materials with excellent kinetic properties is imperative for advanced sodium-storage systems. Herein, novel cubic-like X?Fe (X = Co, Ni, Mn) Prussian blue analogs (PBAs), as cathodes materials, are obtained through as-tuned ionic bonding, delivering improved crystallinity and homogeneous particles size. As expected, Ni-Fe PBAs show a capacity of 81 mAh g-1 at 1.0 A g 1 , mainly resulting from their physical-chemical stability, fast kinetics, and "zero-strain" insertion characteristics. Considering that the combination of elements incorporated with carbon may increase the rate of ion transfer and improve the lifetime of cycling stability, they are expected to derive binary metal-selenide/nitrogen-doped carbon as anodes. Among them, binary Ni0.67 Fe0.33 Se2 coming from Ni-Fe PBAs shows obvious core-shell structure in a dual-carbon matrix, leading to enhanced electron interactions, electrochemical activity, and "metal-like" conductivity, which could retain an ultralong-term stability of 375 mAh g-1 after 10 000 loops even at 10.0 A g-1 . The corresponding full-cell Ni-Fe PBAs versus Ni0.67 Fe0.33 Se2 deliver a remarkable Na-storage capacity of 302.2 mAh g-1 at 1.0 A g-1 . The rational strategy is anticipated to offer more possibilities for designing advanced electrode materials used in high-performance sodium-ion batteries. PMID- 30430660 TI - Mobility Deception in Nanoscale Transistors: An Untold Contact Story. AB - Mobility is a critical parameter that is routinely used for benchmarking the performance of field-effect transistors (FETs) based on novel nanomaterials. In fact, mobility values are often used to champion nanomaterials since high performance devices necessitate high mobility values. The current belief is that the contacts can only limit the FET performance and hence the extracted mobility is an underestimation of the true channel mobility. However, here, such misconception is challenged through rigorous experimental effort, backed by numerical simulations, to demonstrate that overestimation of mobility occurs in commonly used geometries and in nanomaterials for which the contact interface, contact doping, and contact geometry play a pivotal role. In particular, dual gated FETs based on multilayer MoS2 and WSe2 are used as case studies in order to elucidate and differentiate between intrinsic and extrinsic contact effects manifesting in the mobility extraction. The choice of 2D layered transition metal dichalcogenides (TMDCs) as the semiconducting channel is motivated by their potential to replace and/or coexist with Si-based aging FET technologies. However, the results are equally applicable to nanotube- and nanowire-based FETs, oxide semiconductors, and organic-material-based thin-film FETs. PMID- 30430661 TI - Hollow-Structured Metal Oxides as Oxygen-Related Catalysts. AB - Metal oxide hollow structures with large surface area, low density, and high loading capacity have received great attention for energy-related applications. Acting as oxygen-related catalysts, hollow-structured transition metal oxides offer low overpotential, fast reaction rate, and excellent stability. Herein, recent progress in the oxygen-related catalysis (e.g., oxygen evolution reaction (OER), oxygen reduction reaction (ORR), and metal-air batteries) of hollow structured transition metal oxides is discussed. Through a comprehensive outline of hollow-structured spinels, perovskites, rutiles, etc., a rational design strategy is provided for an enhanced oxygen-related catalysis performance from the viewpoint of crystal structures. Urgent challenges and further research directions are presented for hollow-structured transition metal oxides toward excellent oxygen-related catalysis. PMID- 30430662 TI - Tract creation using plasma vaporization versus metal dilatation in percutaneous nephrolithotomy: A propensity score-matched analysis. AB - OBJECTIVES: To share our 10-year experience of tract creation by using plasma vaporization compared with metal dilatation in percutaneous nephrolithotomy. METHODS: We retrospectively reviewed the medical records of 230 patients who had undergone 244 percutaneous nephrolithotomy procedures at Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, from January 2007 to December 2016, and divided the patients into the plasma (n = 130) and metal (n = 114) groups. All patients underwent percutaneous nephrolithotomy by either a bipolar resectoscope mounted with a plasma vaporization button electrode or metal dilatation for tract creation. Propensity score matching was applied to reduce selection bias. Perioperative and postoperative data analysis included procedure time, length of hospital stay, blood transfusion rate, any early and late complications, stone free rate, renal function, and time of need for pain control. RESULTS: Before propensity score matching, there were significantly shorter hospital stay (2.6 vs 3.8 days, P < 0.01), less operating time (66.1 vs 108.1 min, P < 0.01) and no blood transfusion rate (0 vs 4 [3.5%], P = 0.031) in the plasma vaporization group. After propensity score matching, there was no statistically significant difference in the patients' baseline characteristics. There were significantly shorter hospital stay (odds ratio 0.46, 95% confidence interval 0.32-0.66; P < 0.001) and shorter average operating time (odds ratio 0.98, 95% confidence interval 0.97-0.99, P < 0.001) in the plasma vaporization group. CONCLUSIONS: In comparison with metal dilatation, the plasma vaporization technique is a safe and effective method for creating the nephrostomy tract for percutaneous nephrolithotomy, based on shorter postoperative stay, less operating time, zero blood transfusion rate, acceptable stone-free rate and no major complications. PMID- 30430663 TI - Clinical impact of glomerular basement membrane thickness on post-donation renal function in living donors. PMID- 30430664 TI - Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging. AB - BACKGROUND: Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI). PURPOSE: To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics. STUDY TYPE: Prospective. POPULATION: Twenty ME/CFS patients and 23 healthy controls were recruited. FIELD STRENGTH/SEQUENCE: Three-b value DWI (b-values = 0, 1000, and 2000 sec/mm2 ) and 3D T1 -weighted images were at 3.0T. ASSESSMENT: Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated. STATISTICAL TESTING: The two sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups. RESULTS: In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05). Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05). DATA CONCLUSION: Right SLF abnormalities may be a diagnostic marker for ME/CFS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430665 TI - Intracortical astrocyte subpopulations defined by astrocyte reporter Mice in the adult brain. AB - Although historically regarded as a homogeneous cell population, astrocytes in different brain regions exhibit differences in their physiological properties, such as gap-junction coupling, glutamate uptake dynamics, and intracellular Ca2+ response. Recent in vivo RNA profiles have further demonstrated the molecular heterogeneity of astrocytes in the adult CNS. Astrocyte heterogeneity exists not only inter-regionally but also intra-regionally. Despite the characteristic laminal organization of cortical layers and multiple sources of radial glia progenitors for (astro)gliogenesis, the molecular profile and functional properties of astroglial subpopulations in the adult cerebral cortex remain essentially undefined. Using two astrocyte reporter mouse lines: eaat2-tdTomato and Bac aldh1l1-eGFP, we identified tdT- eGFP+ , tdTlow eGFP+ , and tdThigh eGFP+ astroglial subpopulations (in an approximate 1:7:2 ratio) within the cortex. The tdT- eGFP+ astrocyte population is selectively localized at layers I-II and exhibits increased resting membrane potential and membrane resistance but reduced functional expression of the potassium channel Kir4.1. We also isolated individual astrocyte subpopulations through fluorescence activated cell sorting (FACS) and examined their transcriptome differences by RNA-seq. We found that the whole-genome transcriptional profiles of tdT- eGFP+ astrocytes are drastically different from that of tdTlow eGFP+ and tdThigh eGFP+ astrocytes. Particularly, elevated levels of several nonastrocyte genes that are typically specific to other glial cells, such as mog, mobp, Iba1, and pdgfralpha, are observed in tdT- eGFP+ astrocytes, suggesting a less-specific molecular identity of these astrocytes. Overall, our study has unveiled molecular differences between adult cortical astroglial subpopulations, shedding new light on understanding their unique functions in the adult cortex. PMID- 30430666 TI - Three Certified Sugar Reference Materials for Carbon Isotope Delta Measurements. AB - RATIONALE: For isotope delta analysis, it is preferable to have at least two matrix-matched reference materials whose isotope delta values encompass those of the samples to be analyzed. The National Research Council Canada (NRC) has developed three sugar Certified Reference Materials (CRMs), BEET-1 (beet sugar), GALT-1 (galactose), and FRUT-1 (fructose), to be collectively used for carbon isotope delta measurements in sugars, and other organic materials. METHODS: All materials were homogenized and packaged in glass ampules. All three sugar materials were analyzed at the NRC using elemental analysis-isotope ratio mass spectrometry (EA-IRMS). Six additional laboratories also provided EA-IRMS measurements. Data from all laboratories were re-normalized using three international secondary reference materials (IAEA-CH-6, USGS40, and USGS62) included as blind samples in the inter-laboratory comparison, thus providing added quality control and robustness to the study. RESULTS: Re-normalized carbon isotope delta values from each laboratory were combined using a random laboratory effects statistical model with accounting of the correlations between the laboratory results due to the use of the same reference materials for calibration. The consensus delta(13 C) values and combined standard uncertainties which include effects due to characterization, homogeneity, and stability for BEET-1, GALT-1, and FRUT-1 are -26.02(7) 0/00, -21.41(5) 0/00, and -10.98(5) 0/00, respectively, on the VPDB scale. CONCLUSIONS: Three new delta(13 C) sugar CRMs (BEET-1, GALT-1, and FRUT-1) were developed and are available from NRC. These three CRMs can be utilized as a set for daily delta(13 C) scale normalization of sugar-based or other organic materials in order to produce reliable delta(13 C) measurements. PMID- 30430667 TI - Progressive muscle relaxation therapy to relieve dental anxiety: a randomized controlled trial. AB - Dental anxiety causes patients to refuse or delay treatment, which may exacerbate oral diseases. The aim of the current randomized controlled trial was to determine whether progressive muscle relaxation therapy could relieve dental anxiety. The trial included 68 periodontal patients with dental anxiety scores of >=13 who were randomly assigned to either an intervention group or a control group (n = 34 per group). The intervention group was administered progressive muscle relaxation therapy for 20 min and oral health education for 15 min before periodontal treatment once per week for 4 wk. The control group was provided with oral health education only, for the same duration. Changes in dental anxiety, depression symptoms, blood pressure, heart rate, and salivary cortisol were evaluated 4 wk and 3 months after the intervention. The intervention group exhibited statistically significantly greater reductions in dental anxiety scores than did the control group at the 4-wk (-3.82 vs. -0.89) and 3-month (-4.22 vs. 0.28) assessments. They also exhibited significantly greater reductions in depression symptoms, systolic and diastolic blood pressure, pulse rate, and salivary cortisol levels at both time-points. Progressive muscle relaxation therapy relieves tension and anxiety in dental patients. PMID- 30430668 TI - Management of Cytological Material, Pre-Analytical Procedures and Bio-Banking in Effusion Cytopathology. AB - Serous effusion fluid is one of the most commonly encountered specimens in routine cytopathology practice. It provides invaluable information about the patient and the clinical status; but to get the most of it, specimen handling and processing must be carried out properly. Cytomorphology is the basis of a successful analysis which should complemented by ancillary tests when needed. A wide spectrum of ancillary techniques - ranging from immunocytochemistry and flow cytometry to different assays of molecular pathology - can be applied to serous effusions. This article describes the acquisition and management of serous effusion fluids, methods for preservation and transportation, different techniques of cytopreparation, application of immunocytochemistry, flow cytometry, and fluorescence in-situ hybridization (FISH), as well as DNA extraction for polymerase chain reaction (PCR) and next generation sequencing (NGS). Principles of bio-banking of effusion samples are also discussed which is getting more important in correlation with the developments in personalized medicine. This article is protected by copyright. All rights reserved. PMID- 30430669 TI - Editorial Comment from Dr Hotta to Clinical impact of glomerular basement membrane thickness on post-donation renal function in living donors. PMID- 30430670 TI - Characterizing and Alleviating Ion Suppression Effects in Atmospheric Pressure Matrix-Assisted Laser Desorption/Ionization (AP-MALDI). AB - RATIONALE: As a powerful ambient ion source, atmospheric pressure (AP)-MALDI enables direct analysis at atmospheric pressure/temperature and minimal sample preparation. With the increasing usage of AP-MALDI sources with Orbitrap instruments, systematic characterization of the extent of ion suppression effect (ISE) in AP-MALDI-Orbitrap mass spectrometry imaging (MSI) is desirable. Recently, a new low-pressure MALDI platform has been introduced that reportedly provided better sensitivity. While extensive research efforts have been devoted to improving spatial resolution, fewer studies focused on the characterization and sensitivity improvement of these MALDI platforms that, coupled with high resolution Orbitraps, provide powerful strategy for MS imaging. METHODS: Here, we compared the analytical performance of AP and low-pressure (subatmospheric) MALDI sources to study the effect of pressure control in the ion source. Using a model peptide/protein mixture, we systematically evaluated the factors influencing ISE. Furthermore, the effect of laser spot size was evaluated through tissue imaging analysis of lipids and neuropeptides. The effects of ion suppression and laser spot size have also been examined by comparing the number of identified molecular species during MSI analysis. RESULTS: Several key operating parameters including source pressure, laser energy, laser repetition rate, and microscopic slide coating materials were optimized to minimize the ISE. Under the optimal conditions, the subatmospheric AP-MALDI-Orbitrap platform with high spatial and mass spectral resolution enabled significantly improved coverage of several lipid and neuropeptide families in the MS analysis of mouse brain tissue sections. CONCLUSIONS: The new SubAP-MALDI source coupled with an Orbitrap mass spectrometer was established as a viable platform for in situ endogenous biomolecular analysis with increased sensitivity compared to conventional AP MALDI sources as evidenced by the confident identification of neuropeptides from mouse brain imaging analyses. The alleviated ISE was key to substantial performance improvement due to optimized intermediate pressure conditions and better ion collection by the ion funnel. PMID- 30430671 TI - Selective Encapsulation and Separation of Dihalobenzene Isomers with Discrete Heterometallic Macrocages. AB - A series of metallosupramolecular architectures have been prepared, including rectangles, prisms and cages, that feature half-sandwich rhodium(III) fragments at the vertices. Remarkably, a stable cage-like heteropolymetallic complex possessing eight rhodium(III) and two silver(I) metal ions (3) has been obtained following a multistep procedure. The RhIII /AgI mixed macrocage enables the separation of dihalogenated benzene derivatives with high selectivity. Furthermore, a detailed X-ray crystallographic study confirmed that the discriminative encapsulation of para-dihalobenzene (dichlorobenzene, dibromobenzene and diiodobenzene) is favored by Ag-pi interactions and steric effects. PMID- 30430672 TI - Increased salivary AKR1B10 level: association with progression and poor prognosis of oral squamous cell carcinoma. AB - BACKGROUND: Aldo-keto reductase family 1 member B10 (AKR1B10) expression in oral squamous cell carcinoma (OSCC) tissue specimens is correlated with the progression and prognosis of OSCC. METHODS: Saliva samples were obtained from 35 normal controls and 86 patients with OSCC before cancer surgery. The AKR1B10 levels were determined using enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean salivary AKR1B10 levels were significantly higher in the patients with OSCC than in the normal controls (P < .001). Higher salivary AKR1B10 levels were significantly associated with larger tumor size, more advanced clinical stage, and areca quid chewing habit. Patients with OSCC with a higher salivary AKR1B10 level (>646 pg/mL) had a significantly poorer survival than those with a lower (<=646 pg/mL) salivary AKR1B10 level (P = .026). CONCLUSION: The salivary AKR1B10 level may be a promising biomarker for screening high-risk patients with OSCC and monitoring the progression of OSCC. PMID- 30430673 TI - Discussing alcohol in medicines use reviews: experiences of patients in a community pharmacy context. AB - OBJECTIVES: Although pharmacist-led medicines use reviews (MURs) are effective for medicines management, little is understood about patients' experiences of alcohol-related advice delivered therein. Sampling a population at high risk for misuse (within an area of socio-economic deprivation), we explored patient experiences of alcohol-related MURs. METHODS: Two focus groups were conducted with patients who had discussed alcohol in an MUR in the preceding 3 months (n = 9). Data were analysed thematically. KEY FINDINGS AND CONCLUSION: Patients were open to discussing alcohol in the MUR context. The absence of practitioner patient power asymmetry and pharmacists' sensitivity to cultural contexts were critical to patient engagement. PMID- 30430675 TI - Violence towards Emergency Nurses. The 2016 Italian National Survey: a cross sectional study. AB - AIM: To analyse the dimensions and characteristics of Violence towards Emergency Nurses in a national context (Italy). BACKGROUND: Nurses are the most exposed to workplace violence, especially in Emergency Department contexts. METHODS: A cross sectional study was conducted in all Italian regions. Descriptive analyses were used to examine violence from patients and relatives (Type II violence) concerning personal characteristics of the emergency nurses and perpetrators, environmental and organisational factors. Multinomial logistic regression analysis was used to investigate risk factors. RESULTS: 76.0% of Emergency nurses experienced verbal violence, 15.5% both verbal and physical violence and only 8.5% denied having experienced either. Older age and more experience in Emergency settings are protective factors. Whilst working in the South of Italy significantly increases the probability of being exposed. DISCUSSION: There are many factors explaining violence, but some correlations are not clear. CONCLUSION: The following factors can have a positive effect on this problem: Providing specific training for the youngest nurses, creating a strong alliance between users and health personnel to restore a relationship of trust between the parties and investing in physical barriers and adopting appropriate architectural measures. This article is protected by copyright. All rights reserved. PMID- 30430676 TI - Surveillance, anticipation and firefighting in hospital: Perspectives of patient safety from a New Zealand case study. AB - AIM: This study explored how doctors, nurses and managers working in a New Zealand tertiary hospital understand patient safety. BACKGROUND: Despite healthcare systems implementing proven safety strategies from high reliability organisations, such as aviation and nuclear power, these have not been uniformly adopted by healthcare professionals with concerns raised about clinician engagement. DESIGN: Instrumental, embedded case study design using qualitative methods. METHODS: The study used purposeful sampling and data was collected using focus groups and semi-structured interviews with doctors (n=31); registered nurses (n=19); and senior organisational managers (n=3) in a New Zealand tertiary hospital. RESULTS: Safety was described as a core organisational value. Clinicians appreciated proactive safety approaches characterised by anticipation and vigilance, where they expertly recognised and adapted to safety risks. Managers trusted evidence-based safety rules and approaches that recorded, categorised and measured safety. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: It is important that nurse managers hold a more refined understanding about safety. Organisations are more likely to support safe patient care if cultural complexity is accounted for. Recognising how different occupational groups perceive and respond to safety, rather than attempting to reinforce a uniform set of safety actions and responsibilities, is likely to bring together a shared understanding of safety, build trust and nurture safety culture. This article is protected by copyright. All rights reserved. PMID- 30430677 TI - Amide proton transfer imaging to evaluate the grading of squamous cell carcinoma of the cervix: A comparative study using 18 F FDG PET. AB - BACKGROUND: Amide proton transfer (APT) imaging has shown great potential value in the diagnosis of cancer, but has yet not been applied in cervical carcinoma patients. PURPOSE: To investigate the utility of APT imaging in estimating histologic grades of squamous cell carcinoma of the cervix (SCCC), compared with the standardized uptake value (SUV). STUDY TYPE: Prospective. POPULATION: Thirty one patients with SCCC (median age 51 years) were included. FIELD STRENGTH/SEQUENCE: Ingenia 3.0 T CX, Axial T1 -weighted imaging (T1 WI), Axial T2 WI, 3D turbo spin echo sequence for APT imaging. ASSESSMENT: Patient pathology was confirmed by surgery and the patients were divided into three groups based on histologic grades: Grade 1 (n = 9), Grade 2 (n = 12), and Grade 3 (n = 10). The APT signal intensity (APT SI), maximum SUV (SUVmax ) and mean SUV (SUVmean ) for each grade were assessed by experienced radiologists in a blinded manner. STATISTICAL TESTS: The obtained parameters were compared by one-way analysis of variance with Tukey honest significant difference post-hoc test. The correlations between the parameters and histologic grades were analyzed by Spearman's correlation coefficient. The Pearson correlation coefficients of the APT SI with the SUVmax and SUVmean were also calculated. RESULTS: The APT SIs for the three grades were significantly different (P = 0.0002). The APT SIs of Grade 2 and Grade 3 had significant differences (P = 0.009). The Spearman correlation coefficients for the correlations between the parameters and histological grade were as follows: APT SI: 0.684 (P = 0.00002), SUVmax : 0.318 (P = 0.082), and SUVmean : 0.261 (P = 0.157). The Pearson correlation coefficients of the APT SI with the SUVmax and SUVmean were 0.108 (P = 0.564) and 0.178 (P = 0.337), respectively. DATA CONCLUSION: The APT SI was positively correlated with the SCCC grades. APT imaging maybe a promising method for predicting SCCC histologic grades. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430679 TI - To command is to serve: Senior leadership and policy-making predict hospital ward functioning in emergency. AB - AIM: To examine personal, ward, and organizational factors related to the functioning of general hospital staff under missile attack. BACKGROUND: The summer of 2014 is remembered in Israel for missile attacks from the Gaza Strip targeting the civilian population of southern Israel. METHODS: The study was carried out in two steps: (1) Qualitative - a focus group to identify the issues faced by the staff of a hospital under fire, (2) Quantitative - a cross-sectional study among 409 hospital workers to explore: a) personal involvement in decision making, b) clarity of directives, c) coping with emergency on the ward and on d) the management level, e) personal professional functioning. RESULTS: A statistically significant positive correlation was found between personal involvement in decision- and policy-making, the clarity of directives, and hospital ward functioning. A regression analysis demonstrated that executive management and leadership, clarity of directives, and workers' personal functioning statistically significantly explained 46.1% (R2 =.461) of the variance in ward functioning during emergency. CONCLUSION: Clarity of directives and executive management and leadership in emergency were positively associated with ward functioning and coping with emergency. This article is protected by copyright. All rights reserved. PMID- 30430678 TI - Adverse pregnancy and perinatal outcome in patients with recurrent pregnancy loss: Multiple imputation analyses with propensity score adjustment applied to a large-scale birth cohort of the Japan Environment and Children's Study. AB - PROBLEM: Several studies have reported the increased risk of preterm birth, premature rupture of membranes and low birth weight in patients with recurrent pregnancy loss (RPL). There have been a limited number of large population-based studies examining adverse pregnancy and perinatal outcome after RPL. Multiple imputed analyses (MIA) adjusting for biases due to missing data is also lacking. METHOD OF STUDY: A nationwide population-based birth cohort study known as the "Japan Environment and Children's Study (JECS)" was conducted by the Ministry of the Environment. The subjects consisted of 104,102 registered children (including fetuses or embryos). RESULTS: No increased risk of a congenital anomaly, aneuploidy, neonatal asphyxia or a small for date infant was observed among the children from women with a history of RPL. A novel increased risk of placental adhesion and uterine infection was found. The adjusted ORs using MIA in women with three or more PL were 1.76 (95% CI, 1.04-2.96) for a stillbirth, 1.68 (1.12 2.52) for a pregnancy loss, 2.53 (1.17-5.47) for placental adhesion, 1.87 (1.37 2.55) and 1.60 (0.99-2.57) for mild and severe hypertensive disorders of pregnancy, respectively, 1.94 (1.06-3.55) for uterine infection, 1.28 (1.11-1.47) for caesarean section and 0.86 (0.76-0.98) for a male infant. CONCLUSION: MIA better quantified the risk, which could encourage women who might hesitate to attempt a subsequent pregnancy. This article is protected by copyright. All rights reserved. PMID- 30430680 TI - Sex differences in own and other body perception. AB - Own body perception, and differentiating and comparing one's body to another person's body, are common cognitive functions that have relevance for self identity and social interactions. In several psychiatric conditions, including anorexia nervosa, body dysmorphic disorder, gender dysphoria, and autism spectrum disorder, self and own body perception, as well as aspects of social communication are disturbed. Despite most of these conditions having skewed prevalence sex ratios, little is known about whether the neural basis of own body perception differs between the sexes. We addressed this question by investigating brain activation using functional magnetic resonance imaging during a Body Perception task in 15 male and 15 female healthy participants. Participants viewed their own body, bodies of same-sex, or opposite-sex other people, and rated the degree that they appeared like themselves. We found that men and women did not differ in the pattern of brain activation during own body perception compared to a scrambled control image. However, when viewing images of other bodies of same-sex or opposite-sex, men showed significantly stronger activations in attention-related and reward-related brain regions, whereas women engaged stronger activations in striatal, medial-prefrontal, and insular cortices, when viewing the own body compared to other images of the opposite sex. It is possible that other body images, particularly of the opposite sex, may be of greater salience for men, whereas images of own bodies may be more salient for women. These observations provide tentative neurobiological correlates to why women may be more vulnerable than men to conditions involving own body perception. PMID- 30430681 TI - IL-33 guides osteogenesis and increases proliferation and pluripotency marker expression in dental stem cells. AB - OBJECTIVES: Soluble IL-33 (interleukin (IL)-1-like cytokine) acts as endogenous alarm signal (alarmin). Since alarmins, besides activating immune system, act to restore tissue homeostasis, we investigated whether IL-33 exerts beneficial effects on oral stem cell pull. MATERIALS AND METHODS: Clonogenicity, proliferation, differentiation and senescence of stem cells derived from human periodontal ligament (PDLSCs) and dental pulp (DPSCs) were determined after in vitro exposure to IL-33. Cellular changes were detected by flow cytometry, Western blot, immunocytochemistry and semiquantitative RT-PCR. RESULTS: IL-33 stimulated proliferation, clonogenicity and expression of pluripotency markers, OCT-4, SOX-2 and NANOG, but it inhibited ALP activity and mineralization in both PDLSCs and DPSCs. Higher Ki67 expression and reduced beta-galactosidase activity in IL-33-treated cells were demonstrated, whereas these trends were more conspicuous in osteogenic medium. However, after 7-day IL-33 pretreatment, differentiation capacity of IL-33-pretreated cells was retained, and increased ALP activity was observed in both cell types. Results showed that IL-33 regulates NF-kappaB and beta-catenin signalling, indicating the association of these molecules with changes observed in IL-33-treated PDLSCs and DPSCs, particularly their proliferation, pluripotency-associated marker expression and osteogenesis. CONCLUSIONS: IL-33 treatment impairs osteogenesis of PDLSCs and DPSCs, while increases their clonogenicity, proliferation and pluripotency marker expression. After exposure to IL-33, osteogenic capacity of cells stayed intact. NF-kappaB and beta-catenin are implicated in the effects achieved by IL-33 in PDLSCs and DPSCs. PMID- 30430682 TI - Use of tumor necrosis factor-alpha inhibitors during pregnancy among women who delivered live born infants. AB - PURPOSE: To describe the use of tumor necrosis factor-alpha inhibitors (TNFis) among pregnancies ending in a live birth and with a diagnosis of ankylosing spondylitis (AS), Crohn's disease (CD), juvenile idiopathic arthritis (JIA), psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ulcerative colitis (UC). METHODS: We identified pregnancies among women aged 15 to 54 years between 01/01/2004 and 09/30/2015 from 16 health plans participating in Sentinel. We inferred indication using ICD-9-CM codes in the 183-day period before conception. We assessed proportion of infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab by calendar year, indication, and maternal age, and compared them to proportions in an age-matched, indication-matched, and date matched non-pregnant cohort. RESULTS: Among 19 681 pregnancies with at least one chronic inflammatory condition, 2990 (15.2%) received a TNFi. In both pregnancies and matched non-pregnant cohort, TNFi use was highest (34.4%; 55.8%) for PsA patients and lowest (6.2%; 13.4%) for PsO patients. Etanercept was most frequently used among AS/JIA/PsA/PsO/RA patients, while infliximab was the preferred TNFi for CD/UC patients. Except for infliximab and certolizumab, TNFi use during pregnancy decreased after the first trimester. Pregnancies among older pregnant women (45-54 years) were more likely to be treated compared with the matched non-pregnant cohort. CONCLUSION: There was a preference for etanercept among pregnancies with AS/JIA/PsA/PsO/RA, despite the availability of other TNFis. Decline in TNFi use after the first trimester may be related to the desire to reduce TNFis transplacental transfer and to minimize infection risk to the fetus or baby associated with live vaccine immunizations after birth. PMID- 30430683 TI - Resonant electron capture by uridine and deoxyuridine molecules: Fragmentation with charge transfer. AB - RATIONALE: Charge transfer via DNA plays an important role in physical and chemical processes in biological systems, and is used in biomolecular electronics. The present study considers the resonant interaction of free electrons with nucleosides, which is important for an understanding of the processes of electron transport in DNA. METHODS: Resonant electron capture negative ion mass spectrometry was used to study the processes of low-energy electron attachment to two uracil nucleosides, uridine and deoxyuridine, while density functional theory (DFT) calculations were used to analyze the energy aspects of ion formation and decay. RESULTS: Short-lived molecular ions, formed via mechanisms of pi* shape resonances, were found in the energy region below 5 eV. The fragmentation channels of these resonances and the structures of the charged and neutral products formed were determined. CONCLUSIONS: These results suggest that the formation of some fragment negative ions occurs through intramolecular charge transfer. PMID- 30430684 TI - Accuracy and precision of proton density fat fraction measurement across field strengths and scan intervals: A phantom and human study. AB - BACKGROUND: Complex-based chemical shift imaging-based magnetic resonance imaging (CSE-MRI) is emerging as a preferred method for noninvasively quantifying proton density fat fraction (PDFF), a promising quantitative imaging biomarker (QIB) for longitudinal hepatic steatosis measurement. PURPOSE: To determine linearity, bias, repeatability, and reproducibility of the PDFF measurement using CSE-MRI (CSE-PDFF) across scan intervals, MR field strengths, and readers in phantom and nonalcoholic fatty liver disease (NAFLD) patients. STUDY TYPE: Institutional Review Board (IRB)-approved prospective. SUBJECTS: Fat-water phantom and 20 adult patients. FIELD STRENGTH/SEQUENCE: 1.5 T and 3.0 T MR systems and a commercially available CSE-MRI sequence (IDEAL-IQ). ASSESSMENT: Two independent readers measured CSE-PDFF of fat-water phantom and NAFLD patients across two field strengths and scan intervals (same-day and 2-week) each and in a combination of both. MR spectroscopy-based PDFF (MRS-PDFF) was used as the reference standard for phantom PDFF. STATISTICAL TESTS: Linearity and bias of measurement were evaluated by linear regression analysis and Bland-Altman plots, respectively. Repeatability and reproducibility were assessed by coefficient of variance and repeatability / reproducibility coefficients (RC). The intraclass correlation coefficient was used to validate intra- and interobserver agreements. RESULTS: CSE-PDFF showed high linearity and small bias (-0.6-0.4 PDFF%) with 95% limits of agreement within +/-2.9 PDFF% across field strengths, 2-week interscan period, and readers in the clinical scans. CSE-PDFF was highly repeatable and reproducible both in phantom and clinical scans, with the largest observed RC across field strengths and 2-week interscan period being 3 PDFF%. DATA CONCLUSION: CSE-PDFF is a robust QIB with high linearity, small bias, and excellent repeatability/reproducibility. A change of more than 3 PDFF% across field strengths within 2 weeks of scan interval likely reflects a true change, which is well within the clinically acceptable range. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430685 TI - Melatonin protects mesenchymal stem cells from autophagy-mediated death under ischaemic ER-stress conditions by increasing prion protein expression. AB - OBJECT: The purpose of this study was to explore whether melatonin could protect mesenchymal stem cells (MSCs) against ischaemic injury, by inhibiting endoplasmic reticulum (ER) stress and autophagy both in vivo and in vitro. MATERIALS AND METHODS: To confirm the protective effect of melatonin against ER stress in MSCs, markers of cell viability, apoptosis and autophagy were analysed. To further investigate the regenerative effect of melatonin-treated MSCs in ischaemic tissues, a murine hindlimb ischaemic model was established. RESULTS: Under oxidative stress conditions, treatment with melatonin suppressed the activation of ER stress-associated proteins and autophagy-associated proteins acting through upregulation of cellular prion protein (PrPC ) expression. Consequently, inhibition of apoptotic cell death occurred. Melatonin also promoted the activation of MnSOD and catalase activities in MSCs. In a murine hindlimb ischaemia model, melatonin-treated MSCs also enhanced the functional limb recovery as well as neovascularization. These beneficial effects of melatonin were all blocked by knock-down of PrPC expression. CONCLUSION: Melatonin protects against ER stress/autophagy-induced apoptotic cell death by augmenting PrPC expression. Thus, melatonin-treated MSCs could be a potential cell-based therapeutic agent for ER stress-induced ischaemic diseases, and melatonin-induced PrPC might be a key molecule in ameliorating ER stress and autophagy. PMID- 30430686 TI - A Triple-Classification Radiomics Model for the Differentiation of Primary Chordoma, Giant Cell Tumor, and Metastatic Tumor of Sacrum Based on T2-Weighted and Contrast-Enhanced T1-Weighted MRI. AB - BACKGROUND: Preoperative differentiation between primary sacral chordoma (SC), sacral giant cell tumor (SGCT), and sacral metastatic tumor (SMT) is important for treatment decisions. PURPOSE: To develop and validate a triple-classification radiomics model for the preoperative differentiation of SC, SGCT, and SMT based on T2-weighted fat saturation (T2w FS) and contrast-enhanced T1-weighted (CE T1w) MRI. STUDY TYPE: Retrospective. POPULATION: A total of 120 pathologically confirmed sacral patients (54 SCs, 30 SGCTs, and 36 SMTs) were retrospectively analyzed and divided into a training set (n = 83) and a validation set (n = 37). FIELD STRENGTH/SEQUENCE: The 3.0T axial T2w FS and CE T1w MRI. ASSESSMENT: Morphology, intensity, and texture features were assessed based on Formfactor, Haralick, Gray-level co-occurrence matrix (GLCM), Gray-level run-length matrix (GLRLM), histogram. STATISTICAL TESTS: Analysis of variance, least absolute shrinkage and selection operator (LASSO), Pearson correlation, Random Forest (RF), area under the receiver operating characteristic curve (AUC) and accuracy analysis. RESULTS: The median age of SGCT (33.5, 25.3-45.5) was significantly lower than those of SC (58.0, 48.8-64.3) and SMT (59.0, 46.3-65.5) groups (chi2 = 37.6; P < 0.05). No significant difference was found when compared in terms of genders, tumor locations, and tumor sizes of SC, SGCT, and SMT ( DATA CONCLUSION: Our 3.0T MRI-based triple-classification radiomics model is feasible to differentiate SC, SGCT, and SMT, which may be applied to improve the precision of preoperative diagnosis in clinical practice. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430688 TI - Correlation of quantitative pancreatic T1 value and HbA1c value in subjects with normal and impaired glucose tolerance. AB - BACKGROUND: Signal intensity on T1 -weighted images (T1 WI) is associated with pancreatic fibrosis and HbA1c levels. PURPOSE: To evaluate the feasibility of the pancreatic T1 value for assessment of subjects with normal and impaired glucose tolerance (IGT). STUDY TYPE: A prospective single-institution study. POPULATION: In all, 95 consecutive patients with a known or suspected pancreatic disease. FIELD STRENGTH/SEQUENCES: 3T/fast pancreatic T1 mapping using a modified Look Locker sequence. ASSESSMENT: Following the American Diabetes Association criteria, patients were classified into three groups, as follows: no-diabetes subject, HbA1c < 5.7%; prediabetes, 5.7% <= HbA1c < 6.5%; and type 2 diabetes mellitus (T2DM), HbA1c >= 6.5%. Pancreatic T1 value and signal intensity ratio (SIR = SIpancreas /SImuscle ) using T1 WI were compared with the HbA1c values. STATISTICAL TESTS: Quantitative data were assessed with one-way analysis of variance, Fisher's and Mann-Whitney U tests, and receiver-operating characteristic analysis. RESULTS: The pancreatic T1 value was significantly longer in T2DM than in no-diabetes and prediabetes subjects (P < 0.05) and was significantly longer in prediabetes than in no-diabetes subjects (P < 0.05). The mean pancreatic T1 value was significantly lower in the low-value group (HbA1c < 5.7%) (906.3 msec) compared with the high-value group (HbA1c >= 6.5%) (993.8 msec) (P < 0.0001). SIR on T1 WI was significantly higher in the low-value group compared with the high-value group (P = 0.029). The sensitivities, specificities, and area under the receiver-operating characteristic curve (AUCs) for differentiating the low- and high-value groups were 74.1%, 83.8%, and 0.82 in the pancreatic T1 values and 77.8%, 54.4%, and 0.63 in SIR on T1 WI, respectively. The specificity (P < 0.0001) and AUC (P = 0.0020) were significantly higher in the pancreatic T1 values than in SIR on T1 WI. DATA CONCLUSION: Pancreatic T1 value has the potential of being an imaging biomarker for the assessment of IGT. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430687 TI - Gradual acquisition of visuospatial associative memory representations via the dorsal precuneus. AB - Activation of parietal cortex structures like the precuneus is commonly observed during explicit memory retrieval, but the role of parietal cortices in encoding has only recently been appreciated and is still poorly understood. Considering the importance of the precuneus in human visual attention and imagery, we aimed to assess a potential role for the precuneus in the encoding of visuospatial representations into long-term memory. We therefore investigated the acquisition of constant versus repeatedly shuffled configurations of icons on background images over five subsequent days in 32 young, healthy volunteers. Functional magnetic resonance imaging was conducted on Days 1, 2, and 5, and persistent memory traces were assessed by a delayed memory test after another 5 days. Constant compared to shuffled configurations were associated with significant improvement of position recognition from Day 1 to 5 and better delayed memory performance. Bilateral dorsal precuneus activations separated constant from shuffled configurations from Day 2 onward, and coactivation of the precuneus and hippocampus dissociated recognized and forgotten configurations, irrespective of condition. Furthermore, learning of constant configurations elicited increased functional coupling of the precuneus with dorsal and ventral visual stream structures. Our results identify the precuneus as a key brain structure in the acquisition of detailed visuospatial information by orchestrating a parieto occipito-temporal network. PMID- 30430689 TI - The developmental neural substrates of item and serial order components of verbal working memory. AB - Behavioral and developmental studies have made a critical distinction between item and serial order processing components of verbal working memory (WM). This functional magnetic resonance imaging (fMRI) study determined the extent to which item and serial order WM components are characterized by specialized neural networks already in young children or whether this specialization emerges at a later developmental stage. Total of 59 children aged 7-12 years performed item and serial order short-term probe recognition tasks in an fMRI experiment. While a left frontoparietal network was recruited in both item and serial order WM conditions, the right intraparietal sulcus was selectively involved in the serial order WM condition. This neural segregation was modulated by age, with both networks becoming increasingly separated in older children. Our results indicate a progressive specialization of networks involved in item and order WM processes during cognitive development. PMID- 30430690 TI - Technique to Confirm Occlusal Contact Using an Articulating Paper Holder Equipped with Tongue Depressor. AB - This technical report describes a simple procedure for verifying occlusal contact with the use of a new device that combines the functions of a tongue depressor and an articulating paper holder. Verifying occlusal contact and/or the maxillomandibular relationship record can be expected to be simpler and easier with this device compared to the conventional holder, especially for patients with tongue hypertrophy or obesity and those treated under general anesthesia, among others. PMID- 30430691 TI - Beware detrending: Optimal preprocessing pipeline for low-frequency fluctuation analysis. AB - Resting-state functional magnetic resonance imaging (rs-fMRI) offers the possibility to assess brain function independent of explicit tasks and individual performance. This absence of explicit stimuli in rs-fMRI makes analyses more susceptible to nonneural signal fluctuations than task-based fMRI. Data preprocessing is a critical procedure to minimise contamination by artefacts related to motion and physiology. We herein investigate the effects of different preprocessing strategies on the amplitude of low-frequency fluctuations (ALFFs) and its fractional counterpart, fractional ALFF (fALFF). Sixteen artefact reduction schemes based on nuisance regression are applied to data from 82 subjects acquired at 1.5 T, 30 subjects at 3 T, and 23 subjects at 7 T, respectively. In addition, we examine test-retest variance and effects of bias correction. In total, 569 data sets are included in this study. Our results show that full artefact reduction reduced test-retest variance by up to 50%. Polynomial detrending of rs-fMRI data has a positive effect on group-level t values for ALFF but, importantly, a negative effect for fALFF. We show that the normalisation process intrinsic to fALFF calculation causes the observed reduction and introduce a novel measure for low-frequency fluctuations denoted as high-frequency ALFF (hfALFF). We demonstrate that hfALFF values are not affected by the negative detrending effects seen in fALFF data. Still, highest grey matter (GM) group-level t-values were obtained for fALFF data without detrending, even when compared to an exploratory detrending approach based on autocorrelation measures. From our results, we recommend the use of full nuisance regression including polynomial detrending in ALFF data, but to refrain from using polynomial detrending in fALFF data. Such optimised preprocessing increases GM group-level t-values by up to 60%. PMID- 30430692 TI - Nuclear factor-kappa B-dependent X-box binding protein 1 signalling promotes the proliferation of nucleus pulposus cells under tumour necrosis factor alpha stimulation. AB - OBJECTIVES: Tumour necrosis factor alpha (TNF-alpha) expressed by nucleus pulposus cells (NPCs) plays a critical role in intervertebral disc (IVD) degeneration. A key unfolded protein response (UPR) component, X-box binding protein 1 (XBP1) and nuclear factor-kappa B (NF-kappaB) are essential for cell survival and proliferation. The aim of our study was to elucidate the roles of XBP1 and NF-kappaB in IVD degeneration (IDD). MATERIALS AND METHODS: Rat NPCs were cultured with TNF-alpha in the presence or absence of XBP1 and NF-kappaB-p65 small interfering RNA. The associated genes and proteins were evaluated through quantitative real-time PCR, Western blot analyses and immunofluorescence staining to monitor UPR and NF-kappaB signalling and identify the regulatory mechanism of p65 by XBP1. Cell counting kit-8 assay, cell cycle analysis and related gene and protein expression were performed to examine the proliferation of NPCs. RESULTS: The acute exposure of TNF-alpha accelerated the proliferation of rat NPCs by activating the UPR/XBP1 pathway. XBP1 signalling favoured the phosphorylation and nuclear translocation of p65 subunit of NF-kappaB. The activation of NF-kappaB in the later phase also enhanced NPC proliferation. CONCLUSIONS: Unfolded protein response reinforces the survival and proliferation of NPCs under TNF-alpha stimulation by activating the XBP1 pathway, and NF-kappaB serves as a vital mediator in these events. The XBP1 signalling of UPR can be a novel therapeutic target in IDD. PMID- 30430693 TI - Photo-Modulating Multicolor Photoluminescence Including White-Light Emission from a Photochromic Copolymer. AB - Organic photochromic materials have always been a hot topic among scientists, ascribed to its broad applications and characteristic properties of photo modulating multicolor photoluminescence. Meanwhile, white-light emission of organic materials has drawn considerable attention in recent years. Herein, these two concepts are combined together to make an achievement in a photochromic copolymer with white-light emission. A novel amorphous polyacrylamide copolymer consisting of tetraphenylethylene (TPE) and spiropyran (SP) monomers is synthesized, which is capable of emitting fluorescence with tunable colors including white-light one with Commission Internationale de L'eclairage coordinates (0.33, 0.33). This new concept provides an available approach to obtain white-light emission materials which will exert far-reaching influence in its further development. PMID- 30430694 TI - Reactivity of Highly Lewis-Acidic Diborane(4) toward C=N and N=N Bonds: Uncatalyzed Addition and N=N Bond-Cleavage Reactions. AB - The diboration of the C=N bond in organic nitriles, and the N=N bond in azobenzene and pyridazine, by the highly Lewis-acidic tetra(o-tolyl)diborane(4) are reported. In the reactions with nitriles, azobenzene, and pyridazine, the addition of diborane(4) to the C=N and N=N bonds was observed. Conversely, the N=N bond in phthalazine was cleaved by an addition/rearomatization sequence. PMID- 30430695 TI - Identifying and treating obstructive sleep apnea in sleepy drivers: Everybody wins. PMID- 30430696 TI - Differences in barriers to birth and death registration in Guinea-Bissau: implications for monitoring national and global health objectives. AB - OBJECTIVE: Improving civil registration and vital statistics (CRVS) systems is essential to monitoring health objectives locally and globally. The barriers to birth and particularly death registration in low- and middle-income countries are however poorly understood. METHODS: We conducted a survey among women of reproductive age in Bissau, the capital of Guinea-Bissau. We asked women with a birth in the past two years whether their child had been registered and had obtained a birth certificate. We elicited the sources of information about birth registration and asked respondents to list their reasons for (not) registering a birth. If their child had died, we asked similar questions about death registration. RESULTS: Most women (86%) had received messages about birth registration, but few women whose child had died had heard about the need to register deaths (22%). The primary sources of information about birth registration were messages broadcast on the radio or displayed at health facilities. Information about death registration was primarily obtained through informal social networks. Only 16% of births, and 2% of deaths, had been registered. The main barriers to birth registration were administrative pre requisites and paternal absence. The main reasons for not registering a death were lack of knowledge about death registration and lack of perceived benefits. CONCLUSION: Strengthening CRVS systems requires addressing the specific barriers preventing birth and death registration. In Bissau, interventions to improve knowledge about death registration are needed. Simplifying registration procedures, as well as providing additional incentives, might help improve the coverage of birth registration. PMID- 30430697 TI - Neuronal dynamics enable the functional differentiation of resting state networks in the human brain. AB - Intrinsic brain activity is organized in spatial-temporal patterns, called resting-state networks (RSNs), exhibiting specific structural-functional architecture. These networks presumably reflect complex neurophysiological processes and have a central role in distinct perceptual and cognitive functions. In this work, we propose an innovative approach for characterizing RSNs according to their underlying neural oscillations. We investigated specific electrophysiological properties, including spectral features, fractal dimension, and entropy, associated with eight core RSNs derived from high-density electroencephalography (EEG) source-reconstructed signals. Specifically, we found higher synchronization of the gamma-band activity and higher fractal dimension values in perceptual (PNs) compared with higher cognitive (HCNs) networks. The inspection of this underlying rapid activity becomes of utmost importance for assessing possible alterations related to specific brain disorders. The disruption of the coordinated activity of RSNs may result in altered behavioral and perceptual states. Thus, this approach could potentially be used for the early detection and treatment of neurological disorders. PMID- 30430698 TI - Back to the future? Late Holocene marine food web structure in a warm climatic phase as a predictor of trophodynamics in a warmer South-Western Atlantic Ocean. AB - Stable carbon and nitrogen isotope ratios in the skeletal elements of both ancient and modern marine species from the Beagle Channel were used to compare the structure of Late Holocene and modern food webs, and predict potential changes as a result of a Sea Surface Temperature (SST) increase in the region. Complementary, ancient and modern shells of limpets and mussels were isotopically analysed to explore changes in the isotopic baseline and compare marine food webs through time after an appropriate correction for baseline shifts. Results confirmed a declining pattern of marine primary productivity during the Late Holocene in the Beagle Channel. In general, the isotopic niches overlapped largely in the ancient food web in comparison to the current marine one, with the exception of that of cormorants (Phalacrocorax sp.). Our data suggest that all the species that have undergone intense human exploitation (Arctocephalus australis, Otaria flavescens and Merluccius sp.) significantly increased their trophic levels. The most important finding of this work was the very high isotopic overlap between snoek (Thyrsites atun) and hake (Merluccius sp.) during the Late Holocene. Increasing SST as a result of global warming could favour the recolonization of the southern South-Western Atlantic Ocean by snoek from the South-Eastern Pacific Ocean, with a potential impact on the landings of the economically important Argentine and Austral hake. These findings highlight the relevance of using zooarchaeological remains for providing predictions about marine food webs changes in the near future. This article is protected by copyright. All rights reserved. PMID- 30430699 TI - Effects of climate and demography on reproductive phenology of a harvested marine fish population. AB - Shifts in phenology are a well-documented ecological response to changes in climate, which may or may not be adaptive for a species depending on the climate sensitivity of other ecosystem processes. Furthermore, phenology may be affected by factors in addition to climate, which may accentuate or dampen climate-driven phenological responses. In this study, we investigate how climate and population demographic structure jointly affect spawning phenology of a fish species of major commercial importance: walleye pollock (Gadus chalcogrammus). We use 32 years of data from ichthyoplankton surveys to reconstruct timing of pollock reproduction in the Gulf of Alaska and find that the mean date of spawning has varied by over 3 weeks throughout the last >3 decades. Climate clearly drives variation in spawn timing, with warmer temperatures leading to an earlier and more protracted spawning period, consistent with expectations of advanced spring phenology under warming. However, the effects of temperature were nonlinear, such that additional warming above a threshold value had no additional effect on phenology. Population demographics were equally as important as temperature: An older and more age-diverse spawning stock tended to spawn earlier and over a longer duration than a younger stock. Our models suggest that demographic shifts associated with sustainable harvest rates could shift the mean spawning date 7 days later and shorten the spawning season by 9 days relative to an unfished population, independent of thermal conditions. Projections under climate change suggest that spawn timing will become more stable for walleye pollock in the future, but it is unknown what the consequences of this stabilization will be for the synchrony of first-feeding larvae with production of zooplankton prey in spring. With ongoing warming in the world's oceans, knowledge of the mechanisms underlying reproductive phenology can improve our ability to monitor and manage species under changing climate conditions. PMID- 30430700 TI - Characterization of clinical human prostate cancer lesions using 3.0-T sodium MRI registered to Gleason-graded whole-mount histopathology. AB - BACKGROUND: Overtreatment of prostate cancer (PCa) is a healthcare issue. Development of noninvasive imaging tools for improved characterization of prostate lesions might reduce overtreatment. PURPOSE: To measure the distribution of tissue sodium concentration (TSC), proton T2 -weighted signal, and apparent diffusion coefficient (ADC) values in human PCa and to test the presence of a correlation between regional differences in imaging metrics and the Gleason grade of lesions determined from histopathology. STUDY TYPE: Cross-sectional. SUBJECTS: Ten men with biopsy-proven PCa. SEQUENCES/FIELD STRENGTH: Sodium, proton T2 weighted, and diffusion-weighted MRI data were acquired using Broad-Band 3D-Fast Gradient-Recalled, 3D Cube (Isotropic 3D-Fast-Turbo-Spin-Echo acquisition) and 2D Spin-Echo sequences, respectively, with a 3.0T MR scanner. ASSESSMENT: All imaging data were coregistered to Gleason-graded postprostatectomy histology, as the standard for prostate cancer lesion characterization. Regional TSC and T2 data were assessed using percent changes from healthy tissue of the same patient (denoted DeltaTSC, DeltaT2 ). STATISTICS: Differences in DeltaTSC, ADC, and DeltaT2 as a function of Gleason score were analyzed for each imaging contrast using a one-way analysis of variance or a nonparametric t-test. Correlations between imaging data measures and Gleason score were assessed using a Spearman's ranked correlation. RESULTS: Evaluation of the correlation of DeltaTSC, ADC, and DeltaT2 datasets with Gleason scoring revealed that only the correlation between DeltaTSC and Gleason score was statistically significant (rs = 0.791, p < 0.01), whereas the correlations of ADC and DeltaT2 with Gleason score were not (rs = 0.306, p = 0.079 and r s = -0.069, p = 0.699, respectively). In addition, all individual patients showed monotonically increasing DeltaTSC with Gleason score. DATA CONCLUSION: The results of this preliminary study suggest that changes in TSC, assessed by sodium MRI, has utility as a noninvasive imaging assay to accurately characterize PCa lesions. Sodium MRI may provide useful complementary information on mpMRI, which may assist the decision-making of men choosing either active surveillance or treatment. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30430701 TI - Assessing climate change associated sea level rise impacts on sea turtle nesting beaches using drones, photogrammetry and a novel GPS system. AB - Climate change associated sea level rise (SLR) is expected to have profound impacts on coastal areas, affecting many species including sea turtles which depend on these habitats for egg incubation. Being able to accurately model beach topography using digital terrain models (DTMs) is therefore crucial to project SLR impacts and develop effective conservation strategies. Traditional survey methods are typically low-cost with low accuracy or high-cost with high accuracy. We present a novel combination of drone-based photogrammetry and a low-cost and portable real-time kinematic (RTK) GPS to create DTMs which are highly accurate (<10 cm error) and visually realistic. This methodology is ideal for surveying coastal sites, can be broadly applied to other species and habitats, and is a relevant tool in supporting the development of Specially Protected Areas. Here we applied this method as a case-study to project three SLR scenarios (0.48, 0.63 and 1.20 m) and assess the future vulnerability and viability of a key nesting habitat for sympatric loggerhead (Caretta caretta) and green turtle (Chelonia mydas) at a key rookery in the Mediterranean. We combined the DTM with 5 years of nest survey data describing location and clutch depth, to identify (1) regions with highest nest densities, (2) nest elevation by species and beach, and (3) estimated proportion of nests inundated under each SLR scenario. On average, green turtles nested at higher elevations than loggerheads (1.8 m vs. 1.32 m, respectively). However, because green turtles dig deeper nests than loggerheads (0.76 m vs. 0.50 m, respectively), these were at similar risk of inundation. For a SLR of 1.2 m, we estimated a loss of 67.3% for loggerhead turtle nests and 59.1% for green turtle nests. Existing natural and artificial barriers may affect the ability of these nesting habitats to remain suitable for nesting through beach migration. This article is protected by copyright. All rights reserved. PMID- 30430702 TI - Bottom-up and top-down effects of browning and warming on shallow lake food webs. AB - Productivity and trophic structure of aquatic ecosystems result from a complex interplay of bottom-up and top-down forces that operate across benthic and pelagic food web compartments. Projected global changes urge the question how this interplay will be affected by browning (increasing input of terrestrial dissolved organic matter), nutrient enrichment and warming. We explored this with a process-based model of a shallow lake food web consisting of benthic and pelagic components (abiotic resources, primary producers, grazers, carnivores), and compared model expectations with the results of a browning and warming experiment in nutrient-poor ponds harboring a boreal lake community. Under low nutrient conditions, the model makes three major predictions. (1) Browning reduces light and increases nutrient supply; this decreases benthic and increases pelagic production, gradually shifting productivity from the benthic to the pelagic habitat. (2) Because of active habitat choice, fish exert top-down control on grazers and benefit primary producers primarily in the more productive of the two habitats. (3) Warming relaxes top-down control of grazers by fish and decreases primary producer biomass, but effects of warming are generally small compared to effects of browning and nutrient supply. Experimental results were consistent with most model predictions for browning: light penetration, benthic algal production, and zoobenthos biomass decreased, and pelagic nutrients and pelagic algal production increased with browning. Also consistent with expectations, warming had negative effects on benthic and pelagic algal biomass and weak effects on algal production and zoobenthos and zooplankton biomass. Inconsistent with expectations, browning had no effect on zooplankton and warming effects on fish depended on browning. The model is applicable also to nutrient rich systems, and we propose that it is a useful tool for the exploration of the consequences of different climate change scenarios for productivity and food web dynamics in shallow lakes, the worldwide most common lake type. This article is protected by copyright. All rights reserved. PMID- 30430704 TI - A natural heating experiment: Phenotypic and genotypic responses of plant phenology to geothermal soil warming. AB - Under global warming, the survival of many populations of sedentary organisms in seasonal environments will largely depend on their ability to cope with warming in situ by means of phenotypic plasticity or adaptive evolution. This is particularly true in high-latitude environments, where current growing seasons are short, and expected temperature increases large. In such short-growing season environments, the timing of growth and reproduction is critical to survival. Here, we use the unique setting provided by a natural geothermal soil warming gradient (Hengill geothermal area, Iceland) to study the response of Cerastium fontanum flowering phenology to temperature. We hypothesized that trait expression and phenotypic selection on flowering phenology are related to soil temperature, and tested the hypothesis that temperature-driven differences in selection on phenology have resulted in genetic differentiation using a common garden experiment. In the field, phenology was related to soil temperature, with plants in warmer microsites flowering earlier than plants at colder microsites. In the common garden, plants responded to spring warming in a counter-gradient fashion; plants originating from warmer microsites flowered relatively later than those originating from colder microsites. A likely explanation for this pattern is that plants from colder microsites have been selected to compensate for the shorter growing season by starting development at lower temperatures. However, in our study we did not find evidence of variation in phenotypic selection on phenology in relation to temperature, but selection consistently favoured early flowering. Our results show that soil temperature influences trait expression and suggest the existence of genetically-based variation in flowering phenology leading to counter-gradient local adaptation along a gradient of soil temperatures. An important implication of our results is that observed phenotypic responses of phenology to global warming might often be a combination of short term plastic responses and long-term evolutionary responses, acting in different directions. This article is protected by copyright. All rights reserved. PMID- 30430703 TI - Genetic architecture of hippocampal subfields on standard resolution MRI: How the parts relate to the whole. AB - The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images. PMID- 30430705 TI - Insights into the Biosynthesis of Cyclic Guanidine Alkaloids from Crambeidae Marine Sponges. AB - Among the outstanding chemical diversity found in marine sponges, cyclic guanidine alkaloids, present in species of the family Crambeidae, are particularly attractive, not only because of their unique chemical features, but also due to a broad range of biological activities. Despite a growing interest in these natural products as therapeutic agents, their metabolic pathway has not been experimentally investigated. Ex situ feeding experiments using radiolabeled precursors performed on the Mediterranean sponge Crambe crambe suggest arginine and fatty acids as precursors in the metabolic pathway of crambescins. A subsequent bio-inspired approach supported the change of paradigm in the metabolic pathway of cyclic guanidine alkaloids. A large part of the chemical diversity of this family would therefore originate from a tethered Biginelli-like reaction between C-2/C-3 activated fatty acids and a central guanidinylated pyrrolinium. PMID- 30430706 TI - Addressing challenges of high spatial resolution UHF fMRI for group analysis of higher-order cognitive tasks: An inter-sensory task directing attention between visual and somatosensory domains. AB - Functional MRI at ultra-high field (UHF, >=7 T) provides significant increases in BOLD contrast-to-noise ratio (CNR) compared with conventional field strength (3 T), and has been exploited for reduced field-of-view, high spatial resolution mapping of primary sensory areas. Applying these high spatial resolution methods to investigate whole brain functional responses to higher-order cognitive tasks leads to a number of challenges, in particular how to perform robust group-level statistical analyses. This study addresses these challenges using an inter sensory cognitive task which modulates top-down attention at graded levels between the visual and somatosensory domains. At the individual level, highly focal functional activation to the task and task difficulty (modulated by attention levels) were detectable due to the high CNR at UHF. However, to assess group level effects, both anatomical and functional variability must be considered during analysis. We demonstrate the importance of surface over volume normalisation and the requirement of no spatial smoothing when assessing highly focal activity. Using novel group analysis on anatomically parcellated brain regions, we show that in higher cognitive areas (parietal and dorsal-lateral prefrontal cortex) fMRI responses to graded attention levels were modulated quadratically, whilst in visual cortex and VIP, responses were modulated linearly. These group fMRI responses were not seen clearly using conventional second-level GLM analyses, illustrating the limitations of a conventional approach when investigating such focal responses in higher cognitive regions which are more anatomically variable. The approaches demonstrated here complement other advanced analysis methods such as multivariate pattern analysis, allowing UHF to be fully exploited in cognitive neuroscience. PMID- 30430707 TI - Construction of Bovine Serum Albumin/AIE-Based Quaternary Complexes for Efficient Gene Transfection. AB - High transfection efficiency and superior cell imaging are required for cationic polymers-based gene delivery system to afford high therapeutic effect but its high toxicity and unstable cell imaging are easily ignored. In this study, cationic amino poly(glycerol methacrylate) derivative (PGMA-EDA) is used to incorporate bovine serum albumin (BSA) and aggregation-induced emission (AIE) molecular (tetraphenylethylene derivatives, TPE) as an efficient carrier for gene transfection and intracellular imaging. The obtained polymer/pDNA-TPE/BSA (PDTB) quaternary nanoparticles (NPs) not only exhibit efficient gene transfection but also show excellent biocompatibility. After inclusion of TPE/BSA (TB) NPs, BSA promoted dissociation of the complexes upon being protonated and the lipophilic TPE-reduced endosomal membrane stability, which enhanced endosomal escape of pDNA payload, finally resulting in an excellent gene transfection. On the other hand, less positive surface charge of PDTB NPs than that of the binary PD complexes, as well as the addition of biocompatible BSA, both factors contribute to the improved cell viability. Moreover, the AIE feature of TPE compared to aggregation caused quenching character of conventional fluorophores enables the complex with stably tracking the delivery of pDNA into cancer cells. Therefore, the newly developed PDTB complexes may be a promising candidate vector for traceable, safe, and effective gene delivery. PMID- 30430708 TI - Right hippocampus atrophy is independently associated with Alzheimer's disease with psychosis. AB - AIM: The purpose of this study was to determine whether regionally distributed medial temporal cortex thickness (or hippocampal volume) and frontal lobe volume are independently associated with the onset of Alzheimer's disease (AD) with psychosis. METHODS: We identified 26 AD patients with psychosis (AD+P) and 48 AD patients without psychosis (AD-P) from the Memory Impairment Clinic at Pusan National University Hospital in South Korea. They were matched for age, gender, duration of AD, and Clinical Dementia Rating sum of box score. All participants met the National Institute of Neurological and Communication Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria for probable AD. Psychosis was diagnosed according to Jeste and Finkel's proposed diagnostic criteria for psychosis of AD. All participants underwent 3-T magnetic resonance imaging, and 3-D magnetization-prepared rapid gradient echo sequence was acquired for each. The FreeSurfer version 5.1 software package was used to analyze cortical thickness and volume on 3-D T1 -weighted images. anova was used to investigate the differences in cortical thickness and the volume of the total frontal cortex, total temporal cortex, and subregions of the medial temporal cortex between groups after age, gender, years of education, Clinical Dementia Rating sum of box score, duration of AD, and total intracranial volume were controlled for. Furthermore, we added the total frontal volume as an additional variable to investigate whether the association between the medial temporal cortex and AD+P is independent of the frontal cortex. RESULTS: We found that both left and right hippocampal volume were smaller in AD+P than in AD-P. In particular, there was a significant difference in right hippocampal volume between the AD+P and AD-P groups after total frontal volume was added as an additional variable. CONCLUSION: We found that more severe hippocampal atrophy is associated with AD+P than with AD-P. In addition, atrophy of the right hippocampus remained significant among AD+P after adjustment for frontal volume. These findings suggest that right hippocampal atrophy is independently associated with AD+P. PMID- 30430709 TI - Crystal Structure of Regularly Th -Symmetric [U(NO3 )6 ]2- Salts with Hydrogen Bond Polymers of Diamide Building Blocks. AB - Hexanitratouranate(IV), [U(NO3 )6 ]2- , has been crystallized with anhydrous H+ involving hydrogen bond polymers connected by selected diamide building blocks. Thanks to the significant moderation of electrostatic interactions between the anions and cations, the molecular structure of [U(NO3 )6 ]2- in these compounds is regularly Th -symmetric. The f-f transitions stemming from 5f2 configuration of U4+ are strictly forbidden by the Laporte selection rule in such a centrosymmetric system, so that the obtained compounds are nearly colourless in contrast to other UIV species usually coloured in green. PMID- 30430710 TI - High pressure synthesis of A2NiO2Ag2Se2 (A = Sr, Ba) with a high spin Ni2+ in square planar coordination. AB - Square-planar coordinate Ni2+ ions in oxides are exclusively limited to a low spin state (S = 0) owing to extensive crystal field splitting. Here we report layered oxychalcogenides A2NiIIO2Ag2Se2 (A = Sr, Ba) with the S = 1 NiO2 square lattice. The structural analysis revealed that the Ni2+ ion is underbonded by a significant tensile strain from neighboring Ag2Se2 layers, leading to a reduction of the crystal field energy. Ba2NiO2Ag2Se2 exhibits a G-type spin order at 130 K, indicating fairly strong in-plane interactions. The high-pressure synthesis employed here possibly assists the expansion of NiO2 square lattice by taking the advantage of a difference in compressibility in oxide and selenide layers. PMID- 30430711 TI - Machine learning of brain gray matter differentiates sex in a large forensic sample. AB - Differences between males and females have been extensively documented in biological, psychological, and behavioral domains. Among these, sex differences in the rate and typology of antisocial behavior remains one of the most conspicuous and enduring patterns among humans. However, the nature and extent of sexual dimorphism in the brain among antisocial populations remains mostly unexplored. Here, we seek to understand sex differences in brain structure between incarcerated males and females in a large sample (n = 1,300) using machine learning. We apply source-based morphometry, a contemporary multivariate approach for quantifying gray matter measured with magnetic resonance imaging, and carry these parcellations forward using machine learning to classify sex. Models using components of brain gray matter volume and concentration were able to differentiate between males and females with greater than 93% generalizable accuracy. Highly differentiated components include orbitofrontal and frontopolar regions, proportionally larger in females, and anterior medial temporal regions proportionally larger in males. We also provide a complimentary analysis of a nonforensic healthy control sample and replicate our 93% sex discrimination. These findings demonstrate that the brains of males and females are highly distinguishable. Understanding sex differences in the brain has implications for elucidating variability in the incidence and progression of disease, psychopathology, and differences in psychological traits and behavior. The reliability of these differences confirms the importance of sex as a moderator of individual differences in brain structure and suggests future research should consider sex specific models. PMID- 30430712 TI - Affective temperaments are associated with the white matter microstructure in healthy participants. AB - OBJECTIVES: Five affective temperaments are regarded as potential precursors of bipolar disorder. These are depressive, cyclothymic, hyperthymic, irritable, and anxious temperaments. However, the neural substrates underlying these temperaments have not been identified. The aim of this study was to determine whether these temperaments are associated with specific neural substrates related to the brain white matter integrity in healthy participants. METHODS: We conducted a cross-sectional neuroimaging study of 71 healthy participants (38 males and 33 females) with affective temperaments. All participants screened for past and present psychiatric disorders. The scores of the five affective temperaments were measured by the temperament scale of Memphis, Pisa, Paris, and San Diego-autoquestionnaire. We analyzed the association between the fractional anisotropy (FA) and mean diffusivity (MD) of the brain white matter and these affective temperaments using tract-based spatial statistics (TBSS). RESULTS: The cyclothymic temperament score had a significant positive association with the FA and a significant negative association with the MD in the white matter in the right frontal part of brain. The hyperthymic temperament score was negatively associated with the MD in a wide area of the brain white matter. The anxious temperament score was positively associated with the FA in the bilateral frontal, temporal, and parietal regions of the brain white matter. The depressive and irritable temperament scores were not associated with either the FA or the MD. CONCLUSION: The present findings suggest that cyclothymic, hyperthymic, and anxious temperaments are associated with brain white matter integrity in healthy participants. This article is protected by copyright. All rights reserved. PMID- 30430713 TI - Seed banking of terrestrial orchids: evaluation of seed quality in Anacamptis following 4-year dry storage. AB - Good-quality dry seeds of some orchids have the potential to survive for decades under conventional seed-bank conditions, but further research is needed to fill existing gaps in knowledge regarding seed behaviour under long-term dry storage. The objectives of this study were to evaluate germination ability on two asymbiotic culture media with different nitrogen source; to assess seed desiccation tolerance needed for the storage at sub-zero temperatures; to study the effects of dry storage at low temperature. Asymbiotic seed germination tests of four Anacamptis species were carried out to evaluate the effects of different culture media, dehydration, and dry storage on germination ability. Viability of 4-year-stored seeds was assessed by means of tetrazolium test. Generalised Linear Models (GLM) analysis detected significant effects (P < 0.01) of the species, medium, and storage time on total germination, while dehydration did not significantly affect it. Except for A. palustris, germination percentage had a minimum after 1-month storage and increasing values with longer storage periods. Tetrazolium viability tests detected high percentages of viable seeds (> 90%) following 4-year storage, in three out of four species. Seeds of the four Anacamptis species showed to be desiccation tolerant and to have an orthodox storage behaviour. The consequence of these findings is of interest to practical conservation approaches of orchids as seed-banking. The results highlight the importance of multiple assessments of seed quality, both viability and germination, to understand seed storage behaviour. This article is protected by copyright. All rights reserved. PMID- 30430715 TI - Recovery of myocardial perfusion after percutaneous coronary intervention of chronic total occlusions is comparable to hemodynamically significant non occlusive lesions. AB - BACKGROUND: The benefits of chronic coronary total occlusion (CTO) percutaneous coronary intervention (PCI) are being questioned. The aim of this study was to assess the effects of CTO PCI on absolute myocardial perfusion, as compared with PCI of hemodynamically significant non-CTO lesions. METHODS: Consecutive patients with a preserved left ventricular ejection fraction (>=50%) and a CTO or non-CTO lesion, in whom [15 O]H2 O positron emission tomography was performed prior and after successful PCI, were included. Change in quantitative (hyperemic) myocardial blood flow (MBF), coronary flow reserve (CFR) and perfusion defect size (in myocardial segments) were compared between CTOs and non-CTO lesions. RESULTS: In total 92 patients with a CTO and 31 patients with a non-CTO lesion were included. CTOs induced larger perfusion defect sizes (4.51 +/- 1.69 vs. 3.23 +/- 2.38 segments, P < 0.01) with lower hyperemic MBF (1.30 +/- 0.37 vs. 1.58 +/- 0.62 mL.min-1 .g-1 , P < 0.01) and similarly impaired CFR (1.66 +/- 0.75 vs. 1.89 +/- 0.77, P = 0.17) compared with non-CTO lesions. After PCI both hyperemic MBF and CFR increased similarly between groups (P = 0.57 and 0.35) to normal ranges with higher hyperemic MBF values in non-CTO compared with CTO (2.89 +/- 0.94 vs. 2.48 +/- 0.73 mL.min-1 .g-1 , P = 0.03). Perfusion defect sizes decreased similarly after CTO PCI and non-CTO PCI (P = 0.14), leading to small residual defect sizes in both groups (1.15 +/- 1.44 vs. 0.61 +/- 1.45 segments, P = 0.054). CONCLUSIONS: Myocardial perfusion findings are slightly more hampered in patients with a CTO before and after PCI. Percutaneous revascularization of CTOs, however, improves absolute myocardial perfusion similarly to PCI of hemodynamically significant non-CTO lesions, leading to satisfying results. PMID- 30430714 TI - Barrett's oesophagus: A qualitative study of patient burden, care delivery experience and follow-up needs. AB - BACKGROUND: Barrett's oesophagus (BO), a precursor to oesophageal adenocarcinoma, requires long-term endoscopic surveillance. The rising incidence of this chronic disease has implications for service provision and patient burden. Few studies have explored BO patients' personal burden, care delivery experience and participation in health-care delivery decisions. OBJECTIVE: To identify and explore factors impacting BO patients' health-related quality of life, follow-up needs and views on new models of follow-up care. DESIGN: An exploratory qualitative approach was adopted using semi-structured, in-depth, one-to-one interviews, audio-recorded and transcribed verbatim. Patients undergoing BO surveillance, at a single NHS hospital, were recruited using purposive sampling with the aim of achieving maximum variation. Data were analysed using framework analysis approach, supported by NVivo Pro 11. RESULTS: Data saturation occurred after 20 participant interviews. Ten subthemes and three main themes emerged from the analysis: (a) burden of disease-symptom control, worry of oesophageal cancer and surveillance endoscopy; (b) follow-up experiences-follow-up care, at this NHS hospital, was found to be inconsistent and often inadequate to meet patients' needs, in particular a lack of disease-specific information; and (c) follow-up needs-participants sought enhanced communication, organization and structure of care. They highly valued face-to-face interaction with a specialist, and the concept of direct secondary care access in-between endoscopies was reassuring to participants. CONCLUSIONS: This qualitative research provides an in-depth account of the patients' perspective of BO, the effectiveness of follow-up care and patient opinion on new follow-up systems. PMID- 30430716 TI - Approaches to communication assessment with children and adults with profound intellectual and multiple disabilities. AB - Communication assessment of people with profound intellectual and multiple disabilities (PIMD) has seldom been investigated. Here, we explore approaches and decision making in undertaking communication assessments in this group of people. A questionnaire was sent to UK practitioners. The questionnaire elicited information about assessment approaches used and rationales for assessment choices. Fifty-five speech and language therapists (SLTs) responded. Findings revealed that the Preverbal Communication Schedule, the Affective Communication Assessment and the Checklist of Communication Competence were the most frequently used published assessments. Both published and unpublished assessments were often used. Rationales for assessment choice related to assessment utility, sensitivity to detail and change and their applicability to people with PIMD. Underpinning evidence for assessments was seldom mentioned demonstrating the need for more empirical support for assessments used. Variability in practice and the eclectic use of a range of assessments was evident, underpinned by practice-focused evidence based on tacit knowledge. PMID- 30430717 TI - Deficiency of sterol regulatory element-binding protein-1c induces schizophrenia like behavior in mice. AB - Schizophrenia is a hereditary disease that approximately 1% of the worldwide population develops. Many studies have investigated possible underlying genes related to schizophrenia. Recently, clinical studies suggested sterol regulatory element-binding protein (SREBP) as a susceptibility gene in patients with schizophrenia. SREBP controls cellular lipid homeostasis by three isoforms: SREBP 1a, SREBP-1c and SREBP-2. This study used SREBP-1c knockout (KO) mice to examine whether a deficiency in SREBP-1c would affect their emotional and psychiatric behaviors. Altered mRNA expression in genes downstream from SREBP-1c was confirmed in the brains of SREBP-1c KO mice. Schizophrenia-like behavior, including hyperactivity during the dark phase, depressive-like behavior, aggressive behavior and deficits in social interaction and prepulse inhibition, was observed in SREBP-1c KO mice. Furthermore, increased volume of the lateral ventricle was detected in SREBP-1c KO mice. The mRNA levels of several gamma aminobutyric acid (GABA)-receptor subtypes and/or glutamic acid decarboxylase 65/67 decreased in the hippocampus and medial prefrontal cortex of SREBP-1c KO mice. Thus, SREBP-1c deficiency may contribute to enlargement of the lateral ventricle and development of schizophrenia-like behaviors and be associated with altered GABAergic transmission. PMID- 30430718 TI - Cleft mitral leaflets and severe mitral regurgitation: Testing the limits of percutaneous mitral valve repair. AB - Repair of mitral regurgitation (MR) with the MitraClip device (Abbot Vascular, Menlo Park, CA) to treat degenerative MR is associated with improved acute and long-term outcomes. There is an increasing adoption of the device and operators are now testing the limits of the therapy even for unfavorable anatomies. Isolated cleft mitral leaflets are rare but represent a challenge to percutaneous repair. We present two cases of successful repair of severe MR and cleft mitral leaflets. In the first case, a 52-year-old male with a dilated cardiomyopathy and an ejection fraction (EF) of 15% presented in decompensated heart failure. Workup revealed a pseudo-cleft anterior mitral leaflet and a cleft posterior leaflet. A strategy to treat the restricted posterior leaflet lateral of the posterior cleft with a provisional second clip resulted in trace residual MR with only one clip, and an EF improvement to 50% at 2-month follow-up. In the second case, an 80-year old male with a history of obstructive CAD with a normal EF but severe MR and a restricted anterior leaflet presented with severe shortness of breath. An initial strategy to grasp the middle of the valve was unsuccessful due to the cleft. Instead, two clips were placed side-by-side on either side of the cleft resulting in trivial residual MR. Despite challenging anatomy percutaneous repair can allow for dramatic reduction in MR, resulting in significant left ventricular remodeling and improvement of EF and cardiac output. PMID- 30430719 TI - Basic Salt-Lake Brine: An Efficient Catalyst for the Transformation of CO2 into Quinazoline-2,4(1 H,3 H)-diones. AB - The efficient transformation of CO2 into value-added chemicals with green, abundant, and cheap catalysts is an interesting and challenging topic in both green and sustainable chemistry. In this study, a series of salt-lake brines were used for the first time to catalyze the reaction of CO2 and a broad range of 2 aminobenzonitriles to form the corresponding quinazoline-2,4(1 H,3 H)-diones. It was found that the abundant, available, and inexpensive Zhabuye basic salt-lake brine could efficiently promote the reaction of 2-aminobenzonitriles under low pressure of CO2 . Very high yields of value-added products were obtained. Further studies indicated that the basic carbonate and borate ions in the brine play key roles in accelerating the reactions. PMID- 30430720 TI - Use of Gray Sunglasses to Alleviate Hypomanic State in Two Patients with Bipolar II Disorder. AB - There is evidence to suggest that darkness may have therapeutic effects for mania. For example, darkness therapy with 14 hours of enforced darkness and rest from 6 p.m. to 8 a.m. in a light-sealed isolation room of the ward was proven effective for alleviating manic symptoms in a pilot study1 . Subsequently, a placebo-controlled trial examined the use of blue-blocking (BB) glasses as an add on treatment for reducing symptoms of mania2 because wearing orange glasses (blue blockers) in white-light environments has been shown to preserve melatonin production3 . Patients with mania were assigned to BB glasses or placebo (clear glasses) groups from 6 p.m. to 8 a.m. for 7 days. Although BB glasses were significantly more effective than placebo glasses in reducing manic symptoms, there was no difference in sleep between the two groups2 , suggesting that anti manic effects may not be derived from preserving melatonin production, but from blockade of ambient light. If this is the case, wearing gray sunglasses in the daytime may be effective. Here, we report the cases of two patients with hypomania who responded to treatment with gray sunglasses. This article is protected by copyright. All rights reserved. PMID- 30430721 TI - Products of Early and Advanced Glycation in the Soy Milk Proteome. AB - SCOPE: Thermal processing of soy milk kills pathogens and denatures anti nutrition factors warranting microbiological safety, better digestibility, and longer storage. Additionally, Maillard reactions are triggered, yielding glycated proteins (Amadori/Heyns products) and a heterogeneous group of advanced glycation end-products (AGEs). These modifications alter the nutritional value, antigenicity, and digestibility of proteins. They also raise concerns about potentially toxic effects. This study aims at characterizing these modifications in proteins from different soy milk products. METHODS AND RESULTS: Here, glycation and AGE-modification sites in the proteome of ultrahigh-temperature treated natural soy milk, soy milk sweetened with hexose (fructose)-containing sweeteners (SSM), and sucrose as well as soy-based infant formulas (SIFs) from different manufacturers are reported for the first time. A bottom-up proteomic approach based on nano reversed-phase high-perfomance liquid chromatography electrospray ionization-tandem mass spectrometry (nanoRP-HPLC-ESI-MS/MS) (collision-induced dissociation (CID) and electron transfer dissociation modes) identified 229 glycated peptides and 128 AGE-modified peptides resembling 53 proteins. The glycation sites are mainly derived from hexoses, whereas Ndelta carboxyethylarginine and methylglyoxal-derived hydroimidazolone are the main AGEs in soy milk. CONCLUSION: The qualitative and quantitative data obtained here indicate that early glycation increases with harsher processing conditions (SIFs) and the addition of hexose-containing sweeteners (SSMs), whereas the latter sweeteners (but not the harsher processing) triggered more AGE modifications. PMID- 30430722 TI - Causes of childhood low vision and blindness in New Zealand. AB - IMPORTANCE: This is the first national study on childhood visual impairment in a developed nation, New Zealand; describing prevalence, aetiology and preventable causes of low vision and blindness in children. BACKGROUND: Causes of childhood blindness varies between regions. This study aimed to present region-specific data on epidemiology of childhood blindness affecting a developed nation, New Zealand. DESIGN: Retrospective data analysis PARTICIPANTS: All children enrolled with the Blind and Low Vision Education Network (BLENNZ) with best corrected visual acuity =<6/18, or binocular visual field <10 degrees. METHODS: 1000 out of 1321 children with visual impairment enrolled with BLENNZ were included. The principal cause of visual loss was determined, and the severity of visual loss categorized as low vision, or blindness according to the WHO criteria. MAIN OUTCOME MEASURES: Main outcome measures were degree of visual impairment, aetiology of visual impairment and treatment modalities for visual rehabilitation. RESULTS: The calculated prevalence of childhood blindness and low vision was 0.05% and 0.06%. Principle causes of blindness were: cortical visual impairment (31.5%), optic nerve atrophy (16.5%) and optic nerve hypoplasia (9.0%). The main preventable causes of blindness were neonatal trauma/asphyxia (31.5%), retinopathy of prematurity (18.2%) and non-accidental injury (10.3%). CONCLUSIONS AND RELEVANCE: This is the first national report on prevalence of childhood low vision and blindness in New Zealand. The prevalence and leading causes of low vision and blindness found in this study were comparable to other developed nations; however, preventable causes of low vision and blindness appeared unique to New Zealand. PMID- 30430723 TI - Feasibility study of a synchronized diastolic injection with low contrast volume for proper quantitative assessment of aortic regurgitation in porcine models. AB - OBJECTIVES: To evaluate the in vivo feasibility of aortography with one accurately timed diastolic low-volume contrast injection for quantitative assessment of aortic regurgitation (AR) post transcatheter aortic valve replacement (TAVR). BACKGROUND: With the rise of a minimalistic approach for TAVR, aortography (re)emerges as a pragmatic tool for AR assessment. In a mock circulation system, we have validated the accuracy of a single diastolic injection triggered by electrocardiogram (ECG) with low-contrast volume. METHODS: Two-phase experiment: first, a series of aortograms were performed in a porcine model, with 8 mL of contrast using the synchronized (SYNC) and the conventional non-synchronized (NS) injections. In a second phase, we developed a model of AR by inserting partially unsheathed Wallstents of 6-10 mm of diameter across the pig's aortic valve, performing SYNC injections with 8 mL of contrast and NS injections with 8 mL and 15 mL (rate: 20 mL/sec). Respective accuracies of SYNC vs. NS were assessed using Passing-Bablock regression. An angiography core laboratory performed quantitative AR assessment with videodensitometry (VD-AR). RESULTS: The SYNC injections produced higher opacification of the aortic root compared with NS injections (P = 0.04 for density). In the second phase, a regression line for predicting VD-AR based on the SYNC injection resulted in a lower intercept and a slope closer to the line of identity (y = 11.9 + 0.79x, P < 0.001, r2 = 0.94) with the NS-8 mL than with the NS-15 mL injection (y = 26.5 + 0.55x, P < 0.001, r2 = 0.81). CONCLUSION: Synchronized diastolic injection with low contrast volume produced denser images in the aortic root and more accurate than the conventional injection; thus, may be an appealing alternative for assessment of AR post TAVR. PMID- 30430724 TI - The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: a randomized controlled trial. AB - Essentials Perioperative blood loss and inflammatory response can significantly affect recovery after surgery. We studied the effects of multiple-dose oral tranexamic acid on blood loss and inflammatory response. A postoperative four dose regimen brought about maximum reduction in postoperative blood loss. A postoperative four-dose regimen reduced inflammatory response and promoted early rehabilitation. SUMMARY: Background Tranexamic acid (TXA) can reduce blood loss and the inflammatory response at multiple doses in total knee arthroplasty patients. However, the optimal regimen has not been determined. Objectives To identify the most effective regimen for achieving maximum reductions in blood loss and the inflammatory response. Patients/Methods Two hundred and seventy-five patients were randomized to receive a placebo (group A), a single 2-g oral dose of TXA 2 h preoperatively followed by 1 g of oral TXA 3 h postoperatively (group B), a single dose followed by 1 g of oral TXA 3 h and 7 h postoperatively (group C), a single dose followed by 1 g of oral TXA 3 h, 7 h and 11 h postoperatively (group D), or a single dose followed by 1 g of oral TXA 3 h, 7 h, 11 h and 15 h postoperatively (group E). The primary outcome was total blood loss on postoperative day (POD) 3. Secondary outcomes included a decrease in the hemoglobin level, coagulation parameters, inflammatory marker levels, and thromboembolic complications. Results Groups D and E had significantly lower blood loss and smaller decreases in hemoglobin level than groups A, B, and C, with no significant difference on POD 3 between groups D and E. Significantly enhanced coagulation was identified for the four multiple-dose regimens; however, all thromboelastographic parameters remained within normal ranges. Group E had the lowest inflammatory marker levels and pain, and the greatest range of motion. No thromboembolic complications were identified. Conclusion The four-dose regimen yielded the maximum reductions in blood loss and inflammatory response, improved analgesia, and promoted early rehabilitation. Further studies are required to ensure that these findings are reproducible. PMID- 30430725 TI - Fluoride movement into and out of Bacillus spores and growing cells and effects of fluoride accumulation on spore properties. AB - AIMS: To investigate effects of fluoride ion (F- ) on, and kinetics of its movement into and out of, spores and growing cells of Bacillus species. METHODS AND RESULTS: Effects of F- on Bacillus cell growth, spore germination and outgrowth and heat resistance were investigated, as well as F- movement into and out of spores using 19 F NMR. F- inhibited Bacillus subtilis spore germination and outgrowth, and YhdU, now named FluC, was crucial to prevent F- accumulation in growing cells and to minimize F- inhibition of spore germination. Dormant wild type, yhdU and coat defective B. subtilis spores, and Bacillus cereus spores incubated in 40 mmol l-1 NaF for 48 h accumulated 2-2.6 mol l-1 F- and its movement into Bacillus spores was highest at low pH. B. subtilis spores lacking Ca-dipicolinic acid accumulated higher F- levels than wild-type spores. CONCLUSIONS: These results are consistent with F- incorporation into the dormant spore core, and as either HF and/or NaF, but not CaF2 . YhdU played no significant role in F- uptake or efflux in dormant spores, but assisted in F- export early in spore germination. SIGNIFICANCE AND IMPACT OF STUDY: This knowledge provides new insight into effects of F- on Bacillus cells and spores and how this anion moves into, and out of spores. This article is protected by copyright. All rights reserved. PMID- 30430726 TI - The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. PMID- 30430728 TI - Intrinsic Carrier Transport of Phase-Pure Homologous 2D Organolead Halide Hybrid Perovskite Single Crystals. AB - This work reveals the intrinsic carrier transport behavior of 2D organolead halide perovskites based on phase-pure homologous (n = 1, 2, and 3) Ruddelsden Popper perovskite (RPP) (BA)2 (MA)n -1 Pbn I3n+1 single crystals. The 2D perovskite field effect transistors with high-quality exfoliated 2D perovskite bulk crystals are fabricated, and characteristic output and transfer curves are measured from individual single-crystal flakes with various n values under different temperatures. Unipolar n-type transport dominated the electrical properties of all these 2D RPP single crystals. The transport behavior of the 2D organolead halide hybrid perovskites exhibits a strong dependence on the n value and the mobility substantially increases as the ratio of the number of inorganic perovskite slabs per organic spacer increases. By extracting the effect of contact resistances, the corrected mobility values for n = 1, 2, and 3 are 2 * 10 3 , 8.3 * 10-2 , and 1.25 cm2 V-1 s-1 at 77 K, respectively. Furthermore, by combining temperature-dependent electrical transport and optical measurements, it is found that the origin of the carrier mobility dependence on the phase transition for 2D organolead halide perovskites is very different from that of their 3D counterparts. Our findings offer insight into fundamental carrier transport behavior of 2D organic-inorganic hybrid perovskites based on phase-pure homologous single crystals. PMID- 30430727 TI - Crystal structures of VIM-1 complexes explain active site heterogeneity in VIM class metallo-beta-lactamases. AB - Metallo-beta-Lactamases (MBLs) protect bacteria from almost all beta-lactam antibiotics. Verona integron-encoded MBL (VIM) enzymes are among the most clinically important MBLs, with VIM-1 increasing in carbapenem-resistant Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae) that are among the hardest bacterial pathogens to treat. VIM enzymes display sequence variation at residues (224 and 228) that in related MBLs are conserved and participate in substrate binding. How they accommodate this variability, while retaining catalytic efficiency against a broad substrate range, has remained unclear. Here, we present crystal structures of VIM-1 and its complexes with a substrate mimicking thioenolate inhibitor, ML302F, that restores meropenem activity against a range of VIM-1 producing clinical strains, and the hydrolysed product of the carbapenem meropenem. Comparison of these two structures identifies a water mediated hydrogen bond, between the carboxylate group of substrate/inhibitor and the backbone carbonyl of the active site zinc ligand Cys221, that is common to both complexes. Structural comparisons show that the responsible Cys221-bound water is observed in all known VIM structures, participates in carboxylate binding with other inhibitor classes, and thus effectively replicates the role of the conserved Lys224 in analogous complexes with other MBLs. These results provide a mechanism for substrate binding that permits the variation at positions 224 and 228 that is a hallmark of VIM MBLs. ENZYMES: EC 3.5.2.6 DATABASES: Co ordinates and structure factors for protein structures described in this manuscript have been deposited in the Protein Data Bank (www.rcsb.org/pdb) with accession codes 5N5G (VIM-1), 5N5H (VIM-1:ML302F complex) and 5N5I (VIM-1 hydrolysed meropenem complex). PMID- 30430730 TI - 10 Years of Soft Nanomaterials Research and Training at the Adolphe Merkle Institute. PMID- 30430729 TI - Aerobic Toluene Oxidation Catalyzed by Subnano Metal Particles. AB - Subnanocatalysts (SNCs) containing various noble metals (Cu, Ru, Rh, Pd, or Pt) with sizes of approximately 1 nm were synthesized using dendritic poly(phenylazomethine)s as a macromolecular template. These materials exhibit high catalytic performance during toluene oxidation without the use of harmful solvents or explosive oxidants, resulting in the formation of valuable organic products, including benzoic acid as the major product. In particular, Pt19 SNC with a narrow particle size distribution exhibits extraordinary catalytic activity, with a turnover frequency of 3238 atom-1 h-1 , which is 1700 times greater than that obtained by commercial Pt/C catalysts. PMID- 30430731 TI - Interleukin 10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown aetiology. According to the role of interleukin 10 (IL10) in SLE pathogenesis, the genetic alterations in its promoter region could be associated with elevated IL10 levels and exacerbated disease. Here, we investigated the association of genotype and haplotype frequencies of three IL10 gene promoter polymorphisms with susceptibility to SLE, IL10 plasma levels and disease activity of patients in an Iranian population. A total of 116 SLE patients and 131 healthy subjects were enrolled. The PCR-RFLP technique was used to detect IL10 promoter genotypes at the positions of -1082 (G/A), -819 (C/T) and -592 (C/A) in association with IL10 plasma levels and SLEDAI scores. The GG genotype of -1082 polymorphism was associated with the increased risk of SLE [OR = 2.65, 95% CI (1.21-5.82), p-value = 0.046]. The CC genotype in -819 region was associated with SLE susceptibility [OR = 3.38, 95% CI (1.26-9.07), p-value = 0.034] and C allele was introduced as risk allele [OR = 1.86, 95% CI (1.15-3.01), p-value = 0.009] in this region. IL10 plasma levels were overexpressed in CC genotype carriers of -592 SNP and decreased in AA genotype carriers of -1082. IL10 was also increased in SLE patients with CGT (-592/-1082/-819) haplotype. The SLEDAI score was higher among CC genotype carriers at the position of -592 and TT genotype carriers at the region of -819. SLEDAI was also elevated among patients with CGC (-592/-1082/ 819) and CAC (p = 0.011) haplotypes. The present study suggests that the IL10 819(C/T), -1082(G/A) and -592(C/A) polymorphisms and the haplotypes are associated with SLE susceptibility, increased disease activity and elevated IL10 levels. While this is the first time to report such an association in an Iranian population, further studies are needed to confirm these findings. PMID- 30430732 TI - Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain. AB - Myosin regulatory light chain (RLC) phosphorylation is important for cardiac muscle mechanics/function as well as for the Ca2+ -troponin/tropomyosin regulation of muscle contraction. This study focuses on the arginine to glutamine (R58Q) substitution in the human ventricular RLC (MYL2 gene), linked to malignant hypertrophic cardiomyopathy in humans and causing severe functional abnormalities in transgenic (Tg) R58Q mice, including inhibition of cardiac RLC phosphorylation. Using a phosphomimic recombinant RLC variant where Ser-15 at the phosphorylation site was substituted with aspartic acid (S15D) and placed in the background of R58Q, we aimed to assess whether we could rescue/mitigate R58Q induced structural/functional abnormalities in vitro. We show rescue of several R58Q-exerted adverse phenotypes in S15D-R58Q-reconstituted porcine cardiac muscle preparations. A low level of maximal isometric force observed for R58Q- versus WT reconstituted fibers was restored by S15D-R58Q. Significant beneficial effects were also observed on the Vmax of actin-activated myosin ATPase activity in S15D R58Q versus R58Q-reconstituted myosin, along with its binding to fluorescently labeled actin. We also report that R58Q promotes the OFF state of myosin, both in reconstituted porcine fibers and in Tg mouse papillary muscles, thereby stabilizing the super-relaxed state (SRX) of myosin, characterized by a very low ATP turnover rate. Experiments in S15D-R58Q-reconstituted porcine fibers showed a mild destabilization of the SRX state, suggesting an S15D-mediated shift in disordered-relaxed (DRX)<->SRX equilibrium toward the DRX state of myosin. Our study shows that S15D-phosphomimic can be used as a potential rescue strategy to abrogate/alleviate the RLC mutation-induced phenotypes and is a likely candidate for therapeutic intervention in HCM patients. PMID- 30430733 TI - Cytotoxicity and Cellular Responses of Gold Nanorods to Smooth Muscle Cells Dependent on Surface Chemistry Coupled Action. AB - Gold nanorods (AuNRs), with their unique physicochemical properties, are recognized as promising materials for biomedical applications. Chemical modification of their surfaces is attracting increasing attention with regard to cytotoxicity and cellular uptake. Herein, the toxicological effects of three types of polymer-coated AuNRs, which are cetyltrimethylammonium bromide-coated AuNRs, polystyrene sulphonate-coated AuNRs, and poly(diallyldimethyl ammonium chloride-coated AuNRs (PDDAC-AuNRs), on vascular smooth muscle cells (VSMCs) are investigated. The results show significantly different effects on VSMCs with different surface coatings. PDDAC-AuNRs, which were nontoxic in cancer cells in previous reports, display extreme toxicity to VSMCs. Initial contact between AuNRs and cell membranes is the important step in AuNRs cellular uptake. Force spectroscopy based on atomic force microscopy is exploited to study interactions between AuNRs and VSMCs membrane in the absence or presence of a corona on the AuNRs surface. The results show that the binding force and binding probability between AuNRs and membranes are closely related to cytotoxicity and cellular responses. These findings highlight the importance of assessing nanoparticle cytotoxicity in somatic cells for medical applications. PMID- 30430734 TI - Effectiveness of non-pharmacological nursing interventions to improve the quality of life of patients with idiopathic pulmonary fibrosis: A systematic review. AB - AIM: To evaluate whether non-pharmacological nursing interventions improve the quality of life, including both physical and psychosocial states, for patients with idiopathic pulmonary fibrosis, compared to patients receiving the usual care visit or not receiving routine nursing. METHODS: A comprehensive search was conducted of the following electronic databases in English and Japanese: PubMed, MEDLINE, EMBASE, CINAHL, The Cochrane Central Register Controlled Trials (CENTRAL), NPO Japan Medical Abstracts Society's Ichushi - Web database, National Institute of Informatics' Scholarly and Academic Information Navigator (CiNii) database, Grants-in-Aid for Scientific Research (KAKEN) database, and Database of Health Labor Sciences Research Grants. The keywords were as follows: [interstitial lung disease], [interstitial pulmonary fibrosis], [idiopathic pulmonary fibrosis] AND [nurse OR nurses' role OR nursing]. A search method was used based on the eligibility criteria without including words, such as "randomized controlled trial" (RCT). Three categories defined the search parameters: (i) patients with idiopathic pulmonary fibrosis; (ii) non pharmacological nursing interventions; and (iii) RCT. RESULTS: Three-hundred-and ninety-four articles were reviewed. Two articles met all the eligibility criteria. The nursing interventions were "disease management program" and "community case conference," both involving nurse specialists. The quality-of life scores decreased after 6 weeks of intervention with the disease management program. The quality-of-life scores improved after 4 weeks of intervention with the community case conferences. The risk of bias for these two studies was high. CONCLUSION: There was limited evidence of non-pharmacological nursing interventions improving the quality of life of patients with idiopathic pulmonary fibrosis. PMID- 30430735 TI - B7 Liquid Crystal Filament Growth in Presence of Carbon Nanotubes. AB - Liquid crystal phases formed from bent-core mesogens have attracted much interest of the liquid crystal research community, due to the manifestation of chirality effects from achiral molecules. One of the most elusive of the bent-core phases is the B7 phase, which at its early stage often forms in a helical filament fashion. We investigate the growth of such filaments in the presence of single walled nanotubes to elucidate possible effects on the growth dynamics and helicity of B7 helical filaments. It is found that the filament width slightly decreases in comparison to the neat B7 material, suggesting a more tightly bound structure around the nanotubes, with the nanotubes likely acting as the core of the helical filament. No effects on pitch or periodicity of the helical superstructure is observed. The filament growth velocity quickly decreases as nanotubes are added to the B7 phase, indicating that a more tightly bound structure needs a longer time of formation. An observed buckling instability is of interest as a microscopic example for the study of nonlinear dynamics theories of filaments. The present investigation is thus of general importance for nanoparticle directed growth of filaments, which has applications in biomolecular growth and high tensile strength fibres. PMID- 30430736 TI - Cooperativity in proton sensing by PIP aquaporins. AB - One of the most intriguing properties of plasma membrane intrinsic protein (PIP) aquaporins (AQPs) is their ability to modulate water transport by sensing different levels of intracellular pH through the assembly of homo- and heterotetrameric molecular species in the plasma membrane. In this work, using a phenomenological modeling approach, we demonstrate that cooperativity in PIP biological response cannot be directly attributed to a cooperative proton binding, as it is usually considered, since it could also be the consequence of a cooperative conformation transition between open and closed states of the channel. Moreover, our results show that, when mixed populations of homo- and heterotetrameric PIP channels are coexpressed in the plasma membrane of the same cell, the observed decrease in the degree of positive cooperativity would result from the simultaneous presence of molecular species with different levels of proton sensing. Indeed, the random mixing between different PIP paralogues as subunits in a single tetramer, plus the possibility of mixed populations of homo- and heterotetrameric PIP channels widen the spectrum of cooperative responses of a cell membrane. Our approach offers a deep understanding of cooperative transport of AQP channels, as members of a multiprotein family where the relevant proton binding sites of each member have not been clearly elucidated yet. PMID- 30430737 TI - Renal Epithelial Monolayer Formation on Monomeric and Polymeric Catechol Functionalized Supramolecular Biomaterials. AB - Induction of a functional, tight monolayer of renal epithelial cells on a synthetic membrane to be applied in a bioartificial kidney device requires for bio-activation of the membrane. The current golden standard in bio-activation is the combination of a random polymeric catechol (L-DOPA) coating and collagen type IV (Col IV). Here the possibility of replacing this with defined monomeric catechol functionalization on a biomaterial surface using supramolecular ureido pyrimidinone (UPy)-moieties is investigated. Monomeric catechols modified with a UPy-unit are successfully incorporated and presented in supramolecular UPy polymer films and membranes. Unfortunately, these UPy-catechols are unable to improve epithelial cell monolayer formation over time, solely or in combination with Col IV. L-DOPA combined with Col IV is able to induce a tight monolayer capable of transport on electrospun supramolecular UPy-membranes. This study shows that a random polymeric catechol coating cannot be simply mimicked by defined monomeric catechols as supramolecular additives. There is still a long way to go in order to synthetically mimic simple natural structures. PMID- 30430738 TI - MicroRNA fingerprints in serum and whole blood of sarcoid-affected horses as potential non-invasive diagnostic biomarkers. AB - Serum and whole blood microRNA (miRNA) fingerprints have been proposed as a new class of non-invasive human cancer biomarkers. In this study, we compared equine sarcoid (ES) disease-specific serum and whole blood miRNA fingerprints and correlated them to miRNA expression in sarcoid tissue. After high throughput sequencing, miRNA differential expression analysis between six ES-affected and five control horses was carried out in serum and whole blood using a DESeq algorithm, accounting for the influence of hemolysis and the white blood cell count. Target gene, pathway prediction and enrichment analyses were conducted using TarBase, mirPath and GeneCodis. After exclusion of 4 hemolyzed out of a total of 11 serum samples, 9 miRNAs were found to be differentially expressed in serum of ES vs control horses. In whole blood, all 11 samples showed normal white blood cell counts and 19 miRNAs were found to be differentially expressed. A total of 2/9 serum and 7/19 whole blood differentially expressed miRNAs were also highly expressed at the tissue level and their predicted target genes were associated with cancer pathways. Serum and whole blood miRNA expression allowed discrimination between ES and control horses and merits further validation in a larger study cohort. The use of whole blood might be superior because it has higher miRNA content and is less influenced by pre-analytical variables compared to serum. Concurrent dysregulation of single miRNAs in tissue and blood suggests a possible biological function of circulating miRNAs. PMID- 30430739 TI - Pencil-Drawing Skin-Mountable Micro-Supercapacitors. AB - In this study, integrated plaster-like micro-supercapacitors based on medical adhesive tapes are fabricated by a simple pencil drawing process combined with a mild solution deposition of MnO2 . These solid micro-supercapacitors not only exhibit excellent stretchability, flexibility, and biocompatibility, but also possess outstanding electrochemical performances, such as exceptional rate capability and cycling stability. Hence they may act as skin-mountable and thin film energy storage devices of high efficiency to power miniaturized and wearable electronic devices. PMID- 30430740 TI - Is postponed laparoscopic appendectomy justified for patients with acute appendicitis? AB - INTRODUCTION: Recent meta-analyses revealed that laparoscopic appendectomy (LA) is a feasible procedure even for patients with complicated appendicitis. More than a few patients with acute appendicitis arrive at the hospital during night shifts and have their operation postponed for various reasons. However, the feasibility and disadvantages of this so-called "postponed laparoscopic appendectomy" (PLA) remain controversial. METHODS: We included 149 patients who underwent LA for acute appendicitis within 48 h of diagnosis between January 2013 and May 2018. Patients were divided into an immediate LA group (patients who underwent LA within 4 h of diagnosis, n = 84) and a PLA group (patients who underwent LA 4-48 h after diagnosis, n = 65). Comparisons were made between these groups. RESULTS: The preoperative characteristics of the patients in the immediate LA and PLA groups were not significantly different. Operative time was significantly longer in the PLA group than in the LA group (92.5 +/- 40.8 vs 78.1 +/- 29.7 min, P = 0.012). The incidence of postoperative complications (grade II or higher) was significantly greater in the PLA group than in the LA group (32.3% vs 17.8%, P = 0.041). Multivariate analysis revealed that a preoperative CT finding of periappendiceal fluid (P = 0.005, odds ratio = 4.71) and surgery 4-48 h after diagnosis (P = 0.005, odds ratio = 4.425) were independent risk factors of postoperative complications (grade II or higher). CONCLUSIONS: For patients with acute appendicitis, surgeons should perform immediate LA, if that is the patient's preferred surgical treatment, as long as there is no special reason to postpone surgery. PMID- 30430741 TI - Discovery and analysis of a novel-type serine biosynthetic enzyme, phosphoserine phosphatase in Thermus thermophilus. AB - Studying the diversity of extant metabolisms and enzymes, especially those involved in the biosynthesis of primary metabolites including amino acids, is important to shed light on the evolution of life. Many organisms synthesize serine from phosphoserine via a reaction catalyzed by phosphoserine phosphatase (PSP). Two types of PSPs, belonging to distinct protein superfamilies, have been reported. Genomic analyses have revealed that the thermophilic bacterium Thermus thermophilus lacks both homologs while still having the ability to synthesize serine. Here, we purified a protein from T. thermophilus which we biochemically identified as a PSP. A knockout mutant of the responsible gene (TT_C1695) was constructed, which showed serine auxotrophy. These results indicated the involvement of this gene in the serine biosynthesis of T. thermophilus. TT_C1695 was originally annotated as a protein with unknown function belonging to the haloacid dehalogenase-like hydrolase (HAD) superfamily. The HAD superfamily, which comprises phosphatases having a variety of substrates, includes also the classical PSP as a member. However, the amino acid sequence of the TT_C1695 was more similar to phosphatases against non-phosphoserine substrates than classical PSP, therefore blastp search and phylogenetic analysis failed to predict TT_C1695 as a PSP. Our results strongly suggest that the T. thermophilus PSP and classical PSP evolved specificity for phosphoserine independently. This article is protected by copyright. All rights reserved. PMID- 30430743 TI - Evaluating insecticide coverage in almond and pistachio for control of navel orangeworm (Amyelois transitella) (Lepidoptera: Pyralidae). AB - BACKGROUND: Insecticide application is essential to control navel orangeworm (Amyelois transitella) in California almond and pistachios. Coverage is difficult because of tree height and applicator practices. Studies were conducted to characterize insecticide deposition by both ground and air, and to develop alternatives to the use of water sensitive cards to assess spray coverage. RESULTS: We used almond challenge bioassays to demonstrate that insecticide application failed first in the upper canopy (5.2-6.1 m) when application speed exceeded 2.9 kph. In pistachios we used filter paper and insecticide extraction from hulls to demonstrate that deposition increased with application volume. Typically, in ground applications coverage decreased with height while for application by air coverage was greatest at the top of the canopy (6 m) and decreased as the spray penetrated the canopy. In the best ground applications there was no loss over height. We were able to demonstrate a dose-response relationship for methoxyfenozide using contact toxicity bioassays. CONCLUSION: Coverage was best at or below the recommended speed of 3.2 kph and improved when water volume increased. There was a 50% loss in insecticide efficacy at the height of 4 - 4.8 m; we suggest that future monitoring concentrate in this portion of the canopy. The best ground application provided uniform deposition throughout the canopy while the applications by air were most effective in the upper canopy. The use of filter paper can both provide information for chemical deposition as well as enable contact toxicity bioassays, while water sensitive paper cannot do this. This article is protected by copyright. All rights reserved. PMID- 30430742 TI - Late diagnosis, delayed presentation and late presentation among persons enrolled in a clinical HIV cohort in Ontario, Canada (1999-2013). AB - OBJECTIVES: Timely HIV diagnosis and presentation to medical care are important for treatment and prevention. Our objective was to measure late diagnosis, delayed presentation and late presentation among individuals in the Ontario HIV Treatment Network Cohort Study (OCS) who were newly diagnosed in Ontario. METHODS: The OCS is a multi-site clinical cohort study of people living with HIV in Ontario, Canada. We measured prevalence of late diagnosis [CD4 count < 350 cells/MUL or an AIDS-defining condition (ADC) within 3 months of HIV diagnosis], delayed presentation (>= 3 months from HIV diagnosis to presentation to care), and late presentation (CD4 count < 350 cells/MUL or ADC within 3 months of presentation). We identified characteristics associated with these outcomes and explored their overlap. RESULTS: A total of 1819 OCS participants were newly diagnosed in Ontario from 1999 to 2013. Late diagnosis (53.0%) and presentation (54.0%) were common, and a quarter (23.1%) of participants were delayed presenters. In multivariable models, the participants of delayed presentation decreased over calendar time, but that of late diagnosis/presentation did not. Late diagnosis contributed to the majority (> 87%) of late presentation, and the prevalence of delayed presentation was similar among those diagnosed late versus early (13.4 versus 13.4%, respectively; P = 0.99). Characteristics associated with higher odds of late diagnosis/presentation in multivariable analyses included older age at diagnosis/presentation; African, Caribbean and Black race/ethnicity; Indigenous race/ethnicity; female sex; and being a male who did not report sex with men. There were lower odds of late diagnosis/presentation among participants who had ever injected drugs. In contrast, delayed presentation risk factors included younger age at diagnosis and having ever injected drugs. CONCLUSIONS: Late presentation is common in Ontario, as it is in other high income countries. Our findings suggest that efforts to reduce late presentation should focus on facilitating earlier diagnosis for the populations identified in this analysis. PMID- 30430744 TI - Receipt of radiotherapy after mastectomy in women with breast cancer: Population based cohort study in New Zealand. AB - PURPOSE: To investigate the receipt of postmastectomy radiotherapy (PMRT) in breast cancer patients in New Zealand for whom radiotherapy is strongly recommended in current clinical guidelines. METHOD: This study involved all women who were diagnosed with primary invasive breast cancer in two health regions, had undergone a mastectomy, and met the "strong recommendation" criteria for PMRT based on New Zealand National Guidelines. We performed logistic regression analyses to identify demographic and clinical factors associated with the receipt of PMRT. RESULTS: Of the 1455 patients with stage II to III cancers included in this analysis, 1195 (82%) received radiotherapy. The receipt of PMRT decreased with increasing age, and was significantly lower in rural residents, Maori and Pacific women, those with more comorbidity, those who received primary cancer care in a public facility, and those diagnosed with stage III cancer. Although not significant, the receipt was also lower in patients who resided in more deprived neighborhood, and those with comorbidities. The findings restricted to stage III patients (n = 1325), and to those diagnosed since 2010 (n = 422), after the current guidelines were published, which were very similar to the whole cohort. CONCLUSION: Disparities exist in the receipt of PMRT in breast cancer patients in New Zealand, underscoring the need for a greater equity focus in management of breast cancer. PMID- 30430745 TI - Randomized controlled trial of mechanical bowel preparation for laparoscopy assisted colectomy. AB - INTRODUCTION: The benefit of mechanical bowel preparation (MBP) before open colon surgery has been debated over the last decade. The aim of this randomized controlled trial was to evaluate the effect of MBP on the outcome of patients who underwent elective laparoscopic colectomy. METHODS: Patients who were scheduled to undergo elective laparoscopic colon resection with primary anastomosis were randomly allocated to a preoperative MBP group (either two bottles of sodium phosphate or 2-L polyethylene glycol) or a no-MBP group. Anastomotic leakage and other complications such as surgical-site infection and extra-abdominal complications were recorded postoperatively. RESULTS: In this study, 122 patients were recruited and randomly allocated to the MBP group (n = 62) or the no-MBP group (n = 60). Demographic and clinical characteristics were not significantly different between the two groups. The rate of abdominal complications, including anastomotic leak and surgical-site infection, was 16.2% in the MBP group and 18.3% in the no-MBP group (P = 0.747). Anastomotic leakage occurred in four patients (6.5%) in the MBP group and in two patients (3.3%) in no-MBP group (P = 0.680). About 29% of patients in the MBP group still had either liquid or solid content in the bowel. No significant difference was found between the length of hospital stay in the MBP group and the no-MBP group (9.0 +/- 2.9 vs 8.4 +/- 1.9 days, P = 0.180). CONCLUSIONS: Elective laparoscopic colectomy without MBP is safe and offers acceptable postoperative morbidity. PMID- 30430746 TI - Autophagy and aging: Maintaining the proteome through exercise and caloric restriction. AB - Accumulation of dysfunctional and damaged cellular proteins and organelles occurs during aging, resulting in a disruption of cellular homeostasis and progressive degeneration and increases the risk of cell death. Moderating the accrual of these defunct components is likely a key in the promotion of longevity. While exercise is known to promote healthy aging and mitigate age-related pathologies, the molecular underpinnings of this phenomenon remain largely unclear. However, recent evidences suggest that exercise modulates the proteome. Similarly, caloric restriction (CR), a known promoter of lifespan, is understood to augment intracellular protein quality. Autophagy is an evolutionary conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This housekeeping system has been reliably linked to the aging process. Moreover, autophagic activity declines during aging. The target of rapamycin complex 1 (TORC1), a central kinase involved in protein translation, is a negative regulator of autophagy, and inhibition of TORC1 enhances lifespan. Inhibition of TORC1 may reduce the production of cellular proteins which may otherwise contribute to the deleterious accumulation observed in aging. TORC1 may also exert its effects in an autophagy-dependent manner. Exercise and CR result in a concomitant downregulation of TORC1 activity and upregulation of autophagy in a number of tissues. Moreover, exercise-induced TORC1 and autophagy signaling share common pathways with that of CR. Therefore, the longevity effects of exercise and CR may stem from the maintenance of the proteome by balancing the synthesis and recycling of intracellular proteins and thus may represent practical means to promote longevity. PMID- 30430747 TI - Psychomotor Dysfunction in Rett Syndrome: Insights into the Neurochemical and Circuit Roots. AB - Rett syndrome (RTT) is a monogenic neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Patients with RTT develop symptoms after 6-18 months of age, exhibiting characteristic movement deficits, such as ambulatory difficulties and loss of hand skills, in addition to breathing abnormalities and intellectual disability. Given the striking psychomotor dysfunction, numerous studies have investigated the underlying neurochemical and circuit mechanisms from different aspects. Here, I review the evidence linking MeCP2 deficiency to alterations in neurotransmission and neural circuits that govern the psychomotor function and discuss a recently identified pathological origin underlying the psychomotor deficits in RTT. PMID- 30430748 TI - Lymph nodes as barriers to T-cell rejuvenation in aging mice and nonhuman primates. AB - In youth, thymic involution curtails production of new naive T cells, placing the onus of T-cell maintenance upon secondary lymphoid organs (SLO). This peripheral maintenance preserves the size of the T-cell pool for much of the lifespan, but wanes in the last third of life, leading to a dearth of naive T cells in blood and SLO, and contributing to suboptimal immune defense. Both keratinocyte growth factor (KGF) and sex steroid ablation (SSA) have been shown to transiently increase the size and cellularity of the old thymus. It is less clear whether this increase can improve protection of old animals from infectious challenge. Here, we directly measured the extent to which thymic rejuvenation benefits the peripheral T-cell compartment of old mice and nonhuman primates. Following treatment of old animals with either KGF or SSA, we observed robust rejuvenation of thymic size and cellularity, and, in a reporter mouse model, an increase in recent thymic emigrants (RTE) in the blood. However, few RTE were found in the spleen and even fewer in the lymph nodes, and SSA-treated mice showed no improvement in immune defense against West Nile virus. In parallel, we found increased disorganization and fibrosis in old LN of both mice and nonhuman primates. These results suggest that SLO defects with aging can negate the effects of successful thymic rejuvenation in immune defense. PMID- 30430749 TI - A two-step multicomponent synthetic approach and anti-inflammatory evaluation of N-substituted 2-oxopyrazines. AB - Inflammation is widely reported as a main factor for the development of chronic diseases such as cancer, diabetes and even metabolic syndrome. Thus, the search for novel anti-inflammatory compounds is required. Herein, we describe the synthesis of a collection of peptidic pyrazinones by a convenient approach which involved a multicomponent isocyanide-based reaction followed by a tandem deprotection/oxidative cyclization step. The series was tested for its potential anti-inflammatory capacity in an in vivo murine model, where 4 compounds were identified that inhibited tetradecanoylphorbol acetate-induced (TPA) edema more than 75%. The two most active compounds having a methyl (10o) and trifluoromehtyl (10x) groups were also able to reduce the MPO activity and leukocyte infiltration; Moreover, 10x promoted the reduction of the thickness of TPA treated ear as observed in the histological analysis of tissues. PMID- 30430750 TI - 18 F-Labeled Derivatives of Irbesartan for Angiotensin II Receptor PET Imaging. AB - The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18 F-labeled derivative of the drug irbesartan, one of the most prescribed angiotensin II type 1 receptor (AT1 R) antagonists, for in vivo positron emission tomography (PET). This allows the in vivo measurement of AT1 R expression, and thus the evaluation of functional changes in its expression under pathophysiological conditions. We followed various synthetic approaches optimized for the introduction of fluorine into different positions of the aliphatic side chain of irbesartan. Radioligand binding studies revealed that fluorine atoms at specified positions (alpha position (IC50 =6.6 nm) and delta-position (IC50 =8.5 nm) of the aliphatic side chain) do not alter the binding properties of irbesartan (IC50 =1.6 nm). After successful radiolabeling with fluorine-18 in a radiochemical yield of 11 %, we observed high renal uptake in healthy rats and pigs, which could be decreased by pretreatment with the parent compound irbesartan. PMID- 30430751 TI - Involvement of the long noncoding RNA NEAT1 in carcinogenesis. AB - Altered expression levels of the long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) have been reported in different types of cancer. More than half of the NEAT1 studies in cancer have been published within the last 2 years. In this review, we discuss very recent developments and insights into NEAT1 contribution to carcinogenesis. Summarizing the literature, it becomes obvious that NEAT1 is a lncRNA highly de-/upregulated in a variety of cancer entities, in which it primarily acts as a competing endogenous RNA (ceRNA) which sponges tumor-suppressive microRNA (miRNA). The sponged miRNA lose their ability to degrade, silence, or hamper translation of their downstream-mostly oncogenic target transcripts, ultimately promoting carcinogenesis. This role of NEAT1 function in tumorigenesis suggests it may be a prognostic biomarker as well as potential therapeutic target, pending the completion of further studies into the underlying mechanisms. PMID- 30430752 TI - Avoiding bites and scratches? Understanding the public health implication of human-bat interactions in Ghana. AB - Zoonotic pathogens cause an estimated 70% of emerging and re-emerging infectious diseases in humans, affecting various aspects of human development on a global scale. The significance of bats as a source of emerging infectious diseases is being progressively appreciated. This study was undertaken post-Ebola virus disease in West Africa and assessed the public health implications of human-bat interactions by exploring the reasons for contact between humans and bats, as well as reported actions taken upon experiencing bat bites or scratches. The paper highlights the nuances of human-bat interactions, stressing zoonotic disease risk awareness as well as the sources of information. The study used questionnaires to solicit information from 788 respondents in five communities with significant bat populations. We show that bat consumption was one of the main reasons for human-bat interactions. More men across the various communities ate bat meat. Only a small number of respondents (4.4%) reported being bitten by a bat, and 6.1% had been scratched by a bat. More than 21% had come into direct contact with bat blood. An even lower number went to the hospital after been bitten or scratched by bats. There was little knowledge on post-exposure management. The most common places human-bat interactions occurred were at home and on farms. Seventy-three per cent of the respondents believed that bats carried diseases, with Ebola virus disease being the most mentioned. Respondents indicated that the way they interacted with bats had not changed, even though they believed bats carried diseases and 46% stated that they had not changed the way they interacted with bats over the last two years. Apart from providing information on avoiding bites and scratches, a more holistic framework is needed to reduce human-bat interactions. The paper recommends a comprehensive and coordinated approach to optimizing an effective response to a potential bat-borne zoonotic disease spillover. PMID- 30430753 TI - Spectrofluorimetric investigation with green analytical procedures for estimation of bambuterol and terbutaline: Application to pharmaceutical dosage forms and content uniformity testing. AB - Bambuterol (BAM) and terbultaline (TER) are well known and effective bronchodilators. In this article highly sensitive, green and cost-effective spectrofluorimetric methods are designed to determine low concentrations of such drugs. The proposed methods are based on an investigation of the native fluorescence properties of aqueous solutions of BAM at 298 nm after excitation at 263 nm and of TER at 313 nm after excitation at 275 nm. Under optimum conditions, the plots of the relative fluorescence intensity versus concentration were rectilinear over the range 0.1-1.2 MUg/mL for BAM and 0.05-0.5 MUg/mL for TER with a limit of quantitation of 0.067 MUg/mL for BAM and 0.018 MUg/mL for TER. The methods are simple and hence suitable for application to the quantification of BAM and TER in syrups and tablets without interference from common excipients. Furthermore, based on United States Pharmacopeia (USP) guidelines, the application was extended to determine the content uniformity of the cited drugs in low dose tablets. The developed methods were fully validated according to the guidelines of the International Conference on Harmonization (ICH). PMID- 30430754 TI - Dysregulated Translation in Neurodevelopmental Disorders: An Overview of Autism Risk Genes Involved in Translation. AB - Regulated local translation-whereby specific mRNAs are transported and localized in subcellular domains where they are translated in response to regional signals allows for remote control of gene expression to concentrate proteins in subcellular compartments. Neurons are highly polarized cells with unique features favoring local control for axonal pathfinding and synaptic plasticity, which are key processes involved in constructing functional circuits in the developing brain. Neurodevelopmental disorders are caused by genetic or environmental factors that disturb the nervous system's development during prenatal and early childhood periods. The growing list of genetic mutations that affect mRNA translation raises the question of whether aberrant translatomes in individuals with neurodevelopmental disorders share common molecular features underlying their stereotypical phenotypes and, vice versa, cause a certain degree of phenotypic heterogeneity. Here, we briefly give an overview of the role of local translation during neuronal development. We take the autism-risk gene list and discuss the molecules that (perhaps) are involved in mRNA transport and translation. Both exaggerated and suppressed translation caused by mutations in those genes have been identified or suggested. Finally, we discuss some proof-of principle regimens for use in autism mouse models to correct dysregulated translation. PMID- 30430755 TI - Two-Photon Polymerization as a Tool for Studying 3D Printed Topography-Induced Stem Cell Fate. AB - Geometric topographies are known to influence cellular differentiation toward specific phenotypes, but to date the range of features and type of substrates that can be easily fabricated to study these interactions is somewhat limited. In this study, an emerging technology, two-photon polymerization, is used to print topological patterns with varying feature-size and thereby study their effect on cellular differentiation. This technique offers rapid manufacturing of topographical surfaces with good feature resolution for shapes smaller than 3 um. Human-induced pluripotent stem cells, when attached to these substrates or a non patterned control for 1 week, express an array of genetic markers that suggest their differentiation toward a heterogeneous population of multipotent progenitors from all three germ layers. Compared to the topographically smooth control, small features (1.6 um) encourage differentiation toward ectoderm while large features (8 um) inhibit self-renewal. This study demonstrates the potential of using two-photon polymerization to study and control stem cell fate as a function of substrate interactions. The ability to tailor and strategically design biomaterials in this way can enable more precise and efficient generation or maintenance of desired phenotypes in vitro and in vivo. PMID- 30430756 TI - Neuroprotective effects on the morphology of somatic motoneurons following the death of neighboring motoneurons: A role for microglia? AB - Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone protects motoneurons from induced dendritic atrophy. We explored a potential mechanism for this induced atrophy and protection by testosterone, examining the microglial response to partial depletion of motoneurons. Motoneurons innervating the vastus medialis muscles of adult male rats were killed by intramuscular injection of cholera toxin-conjugated saporin; some saporin-injected rats were treated with testosterone. Microglia were later visualized via immunohistochemical staining, classified as monitoring or activated, and counted stereologically. Partial motoneuron depletion increased the number of activated microglia in the quadriceps motor pool, and this increase was attenuated with testosterone treatment. The attenuation in microglial response could reflect an effect of testosterone on suppressing microglia activation, potentially sparing motoneuron dendrites. Alternatively, testosterone could be neuroprotective, sparing motoneuron dendrites, secondarily resulting in reduced microglial activation. To discriminate between these hypotheses, following partial motoneuron depletion, rats were treated with minocycline to inhibit microglial activation. Motoneurons innervating the ipsilateral vastus lateralis muscle were later labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed. Reduction of microglial activation by minocycline did not prevent induced dendritic atrophy following partial motoneuron depletion. Further, reduction of microglial activation by minocycline treatment resulted in dendritic atrophy in intact animals. Together, these findings indicate that the neuroprotective effect of testosterone on dendrites following motoneuron death is not due inhibiting microglial activation, and that microglial activity contribute to the normal maintenance of dendritic arbors. This article is protected by copyright. All rights reserved. PMID- 30430757 TI - Effectiveness of Traditional Chinese Medicine Jinlida Granules as an Add-on Therapy for Type 2 Diabetes: A System Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Jinlida granules is the commonly-prescribed oral medication to lower blood- glucose combination with anti-diabetic drugs in China. We aimed to systematically identify and pool the findings of randomized controlled trials for evaluating effectiveness and safety of Jinlida as an add-on therapy for glycaemic control in T2DM. METHODS: The CNKI; Wang Fang; PUBMED; CBM and VIP databases were searched for papers regarding the effects of Jinlida granules for T2DM published before 1 July 2018. Data were independently extracted by two authors. A pooled analysis of data was performed using random-effects models. RESULTS: A total of 1810 individuals retrieved from 15 studies were involved. Participants in Jinlida granules add-on groups achieved a lower glucose decreases(HAb1c)than those in control groups (n=1820; MD, -0.66; 95% CI,[-0.72 to -0.60]; p<0.00001; I2=38%). Jinlida granules add-on groups also reduced BMI and benefited HOMA-beta,HOMA-IR regulation. Furthermore, No obvious adverse events occurred. CONCLUSIONS: Findings from this meta-analysis demonstrated additional benefits of Jinlida granules as an add-on therapy for type 2 Diabetes and Jinlida granules were generally safe. Treatment with Jinlida granules provided clinically and statistically significant reductions in FPG, 2hPG, HbA1Clevels in patients with T2DM. However, the findings should be interpreted with caution due to the small sample size and study limitations. This article is protected by copyright. All rights reserved. PMID- 30430758 TI - Ultrastable and antibacterial two-dimension tungsten disulfide lamellar membrane for water filtration. AB - Two-dimensional (2D) lamellar membranes restacked by tungsten disulfide (WS2) nanosheets have shown excellent separation properties for water filtration. This paper is aimed to evaluate the stability, anti-fouling properties and antibacterial activities of WS2 laminar membranes from the point of practical application. We discovered that the separation properties of the WS2 laminar membranes changed slightly after soaking in water for 28 days as well as that of a 45 h-cross-flow filtration, demonstrating an extraordinary operational stability of the WS2 laminar membranes. The remarkable stability is related to its dominant van der Waals interactions between WS2 nanosheets including the hydrogen bonding bridging via water molecules. In addition, the WS2 laminar membranes exhibited striking antibacterial properties against S. aureus and E. coli with antibacterial rates of 91.3% and 89.7%, respectively. These newly revealed properties of the WS2 laminar membranes make them promising candidates for water filtration. PMID- 30430759 TI - Knowledge, attitudes and practice of physicians toward evidence-based medicine: A systematic review. AB - AIM: To assess knowledge, attitude, and practice of graduate physicians toward evidence-based medicine (EBM) and the barriers to the implementation of EBM worldwide. METHODS: Relevant databases were searched systematically with appropriate search terms up to September 2017. References of the articles detected by the search were screened for any new articles. Risk of bias was assessed by two independent reviewers. Data were extracted from the full-text articles based on the study summary measures and were collected in a data table. RESULTS: Fifty-seven articles were finally included in this systematic review. The studies were of variable and moderate quality. Based on our results, physicians have a generally positive attitude toward EBM and most of them believe that its implementation improves patient care. However, their self-reported awareness and knowledge regarding EBM concepts and the main databases are generally poor. The major barriers to the practice of EBM were related to patient overload and lack of personal time, knowledge, and skills rather than a lack of facilities and resources. However, this pattern varied among the studies. Most of the physicians in the included studies referred to their colleagues and textbooks to answer most of their clinical questions. CONCLUSION: Although many physicians have poor EBM knowledge and skills, the majority of them have a positive attitude toward the implication of EBM. To overcome the barriers against the evidence based practice, it is recommended that appropriate policies be adopted to decrease physicians' workload and to provide them with preappraised evidence. PMID- 30430760 TI - Assessment of Middle Ear Anatomy Teaching Methodologies Using Microscopy versus Endoscopy: A Randomized Comparative Study. AB - Teaching methodologies for the anatomy of the middle ear have not been investigated greatly due to the middle ear's highly complex structure and hidden location inside of the temporal bone. The aim of this randomized study was to quantitatively compare the suitability of using microscope- and endoscope-based methods for teaching the anatomy of the middle ear. We hypothesize that the endoscopic approach will be more efficient compared to the microscopic approach. To answer the study questions, 33 sixth-year medical students, residents and otorhinolaryngology specialists were randomized either into the endoscopy or the microscopy group. Their anatomical knowledge was assessed using a structured anatomical knowledge test before and after each session. Each participant received tutoring on a human cadaveric specimen using one of the two methods. They then performed a hands-on dissection. After 2-4 weeks, the same educational curriculum was repeated using the other technique. The mean gains in anatomical knowledge for the specialists, residents, and medical students were +19.0%, +34.6%, and +23.4%, respectively. Multivariate analyses identified a statistically significant increase in performance for the endoscopic method compared to the microscopic technique (P < 0.001). For the recall of anatomical structures during dissection, the endoscopic method outperformed the microscopic technique independently of the randomization or the prior training level of the attendees (P < 0.001). In conclusion, the endoscopic approach to middle ear anatomy education is associated to an improved gain in knowledge as compared to the microscopic approach. The participants subjectively preferred the endoscope for educational purposes. PMID- 30430761 TI - Screening of Lipopeptide-Producing Strains of Bacillus sp. Using a New Automated and Sensitive Fluorescence Detection Method. AB - Lipopeptides, such as surfactins are important biosurfactants produced by Bacillus sp. that find applications in many areas (environment, medicine, and food industries). Giving their importance, the use of simple detection methods will facilitate screening and quantification. In the present work, the authors describe a completely automated workflow for the screening of lipopeptide producing strains, including quantification. First, isolated colonies from environmental samples are automatically picked and inoculated in 96 wells growth plate. After overnight incubation, surfactin produced in the broth is quantified, using a new sensitive fluorescent method. The method uses fluorescein (FL), which is an anionic dye at neutral to alkaline pH and forms a stable complex with the cationic surfactant cetylpiridinium chloride (CPC), quenching fluorescence. Upon addition of surfactin or other lipopeptides, fluorescein is released from the CPC FL complex and quantified. The robustness of this method is assessed by comparing the quantification results to those conventionally measured by RP-UPLC and the results of strain screening are confirmed by MALDI-ToF analysis. The authors report for the first time the successful application of this analytical method for high-throughput screening of novel lipopeptide-producing strains. PMID- 30430762 TI - Corrigendum. PMID- 30430763 TI - Identification of the new HLA-DRB5*01:01:01:02 allele in a Chinese individual. AB - DRB5*01:01:01:02 differs from DRB5*01:01:01 by four nucleotide changes in intron 2. PMID- 30430764 TI - Fast turbidimetric assay for analyzing the enzymatic hydrolysis of polyethylene terephthalate model substrates. AB - Synthetic plastics such as polyethylene terephthalate (PET) can be cooperatively degraded by microbial polyester hydrolases and carboxylesterases, with the latter hydrolyzing the low-molecular-weight degradation intermediates. For the identification of PET-degrading enzymes, efficient and rapid screening assays are required. Here we report a novel turbidimetric method in a microplate format for the fast screening of enzyme activities against the PET model substrates with two ester bonds bis-(2-Hydroxyethyl) terephthalate (BHET) and ethylene glycol bis-(p methylbenzoate) (2PET). The carboxylesterase TfCa from Thermobifida fusca KW3 was used for validating the method. High correlation and regression coefficients between the experimental and fitted data confirmed the accuracy and reproducibility of the method and its feasibility for analyzing the kinetics of the enzymatic hydrolysis of the PET model substrates. A comparison of the hydrolysis of BHET and 2PET by TfCa using a kinetic model for heterogeneous catalysis indicated that the enzyme preferentially hydrolyzed the less bulky molecule BHET. The high-throughput assay will facilitate the detection of novel enzymes for the biocatalytic modification or degradation of PET. PMID- 30430765 TI - Maternal immune activation, central nervous system development and behavioral phenotypes. AB - Maternal immune activation (MIA) refers to a maternal immune system triggered by infectious or infectious-like stimuli. A cascade of cytokines and immunologic alterations are transmitted to the fetus, resulting in adverse phenotypes most notably in the central nervous system. Epidemiologic studies implicate maternal infections in a variety of neuropsychiatric disorders, most commonly autism spectrum disorders and schizophrenia. In animal models, MIA causes neurochemical and anatomic changes in the brain that correspond to those found in humans with the disorders. As our understanding of the interactions between environment, genetics, and immune system grows, the role of alternative, noninfectious risk factors, such as prenatal stress, obesity, and the gut microbiome also becomes clearer. This review considers how infectious and noninfectious etiologies activate the maternal immune system. Their impact on fetal programming and neuropsychiatric disorders in offspring is examined in the context of human and animal studies. PMID- 30430767 TI - The energy requirements and metabolic benefits of wilderness hunting in Alaska. AB - The purported healthy aspects of subsistence foods have led to the popularity of the Paleo diet. There has been very little focus, surprisingly, on health benefits derived from the nomadic nature of humans during the Paleolithic era. The purpose of our study was to examine total energy expenditure (TEE), total energy intake (TEI), body composition, blood lipids, and intrahepatic lipid in humans during a 12-day Alaskan backcountry expeditionary hunting (ABEH) immersion. Four healthy men (age: 42 +/- 3 year, BMI: 27 +/- 1 kg/m2 ) were recruited for the study. TEE was measured using the doubly labeled water method and a food diary was utilized to assess TEI. Body composition was measured using dual energy X-ray absorptiometry (DXA); cross-sectional area of the thigh (XT) and intrahepatic lipid (IHL) were measured using molecular imaging. Blood samples were collected for the measurement of blood lipids. DXA, XT, IHL, and blood data were collected pre- and immediately post-ABEH. Results were analyzed using paired t-tests and considered significant at P < 0.05. TEE and TEI averaged 18.1 +/- 1.2 and 9.1 +/- 2.5 MJ/day, respectively, indicating substantial negative energy balance (-9.0 +/- 1.3 MJ/day). There was a reduction in percent body fat (?-3.3 +/- 0.2%), total fat mass (?-3.3 +/- 0.4 kg), and visceral fat volume (Delta-261 +/- 188 cm3 ). Lean tissue mass and XT was unchanged. There was a decrease in IHL (Delta-0.5 +/- 0.1% water peak), and a trend (P = 0.055) toward reduction in LDL cholesterol. We conclude that constancy of physical activity during negative energy balance may provide metabolic benefits above and beyond variations in diet that exist with the hunter-gatherer lifestyle. PMID- 30430766 TI - Effects of hypoestrogenism and/or hyperaldosteronism on myocardial remodeling in female mice. AB - We investigated the potential adverse effects of hyperaldosteronism and/or hypoestrogenism on cardiac phenotype, and examined their combined effects in female mice overexpressing cardiac aldosterone synthase (AS). We focused on some signaling cascades challenging defensive responses to adapt and/or to survive in the face of double deleterious stresses, such as Ca2+ -homeostasis, pro/anti hypertrophic, endoplasmic reticulum stress (ER stress), pro- or anti-apoptotic effectors, and MAP kinase activation, and redox signaling. These protein expressions were assessed by immunoblotting at 9 weeks after surgery. Female wild type (FWT) and FAS mice were fed with phytoestrogen-free diet; underwent ovariectomy (Ovx) or sham-operation (Sham). Ovx increased gain weight and hypertrophy index. Transthoracic echocardiograghy was performed. Both Ovx-induced heart rate decrease and fractional shortening increase were associated with collagen type III shift. Cardiac estrogen receptor (ERalpha, ERbeta) protein expression levels were downregulated in Ovx mice. Hypoestrogenism increased plasma aldosterone and MR protein expression in FAS mice. Both aldosterone and Ovx played as mirror effects on up and downstream signaling effectors of calcium/redox homeostasis, apoptosis, such as concomitant CaMKII activation and calcineurin down-regulation, MAP kinase inhibition (ERK1/2, p38 MAPK) and Akt activation. The ratio Bcl2/Bax is in favor to promote cell survivor. Finally, myocardium had dynamically orchestrated multiple signaling cascades to restore tolerance to hostile environment thereby contributing to a better maintenance of Ca2+ /redox homeostasis. Ovx-induced collagen type III isoform shift and its upregulation may be important for the biomechanical transduction of the heart and the recovery of cardiac function in FAS mice. OVX antagonized aldosterone signaling pathways. PMID- 30430768 TI - DSCAM-AS1 regulates the G1 /S cell cycle transition and is an independent prognostic factor of poor survival in luminal breast cancer patients treated with endocrine therapy. AB - DSCAM-AS1 is one of the few intensively studied lncRNAs with high specific expression in luminal breast cancer. It is directly regulated by estrogen receptor alpha (ERalpha) and plays vital roles in tumor proliferation, invasion, and tamoxifen resistance. However, the detailed function of DSCAM-AS1 in tumor progression and its clinical significance remain unclear. We reveal that DSCAM AS1 regulates cell proliferation and colony formation by inducing the G1/S transition. RNA-seq analysis demonstrated that DSCAM-AS1 participates in crucial biological processes, including DNA replication, the G1/S phase transition, sister chromatid cohesion, chromosome segregation, protein localization to the chromosome and DNA recombination. Most importantly, in the retrospectively registered clinical analysis, high expression of DSCAM-AS1 is a poor prognostic factor in patients with luminal breast cancer treated with endocrine therapy. In conclusion, DSCAM-AS1 is a promising clinical therapeutic target that may prolong survival of luminal breast cancer patients treated with endocrine therapy. PMID- 30430769 TI - The power of tumor sizes in predicting the survival of solitary hepatocellular carcinoma patients. AB - BACKGROUND: Vascular invasion, rather than tumor size, was applied into the 7th edition of the AJCC TNM staging system to predict survival of solitary hepatocellular carcinoma (HCC) patients. However, does this mean tumor size is of little value in prognostic prediction? The current study was designed to explore the prognostic ability of tumor sizes in solitary HCC. METHODS: A total of 18 591 patients with solitary HCC categorized as T1 and T2 were retrieved from the Surveillance Epidemiology and End Results (SEER) database. The Cox proportional hazards regression model was adopted to evaluate the impact of tumor sizes on overall survival (OS) and disease-specific survival (DSS) in general and in subgroups stratified by vascular invasion and surgery type. RESULTS: Large tumor sizes (>39 mm) were associated with unfavorable clinicopathologic characteristics. Compared with tumors <=30 mm, tumors between 31-50 mm and tumors >50 mm showed significantly worse OS and DSS in general using multivariate analysis (all P < 0.001). In subgroup analyses, for patients without vascular invasion, tumor size was a notable prognostic indicator for OS in the radiofrequency ablation group (P < 0.001), rather than in the liver resection or transplantation group. Nevertheless, for patients with vascular invasion, tumor sizes exhibited a notable impact on OS in the liver resection and transplantation group. CONCLUSIONS: The AJCC TNM staging system for solitary HCC would be more comprehensive if tumor sizes were integrated into the T2 classification. Additionally, for T1 patients, tumor sizes play no role in the choice between resection and transplantation. PMID- 30430770 TI - Early fetal echocardiography. AB - OBJECTIVES: To explore the technical aspects and clinical utility of early fetal echocardiography and screening of the fetal heart in early pregnancy. Also, to document differences in cardiac structure and function which can be demonstrated in the late first/early second trimesters. METHODS: In addition to summarizing our own experiences of late first/early second trimester fetal echocardiography, we reviewed the literature to explore clinical indications for, technical aspects, safety, accuracy, strengths and weaknesses of early fetal echocardiography. RESULTS: In the current era, an increasing number of fetuses are identified as being at risk of congenital heart disease from as early as the late first trimester. In experienced hands, early fetal echocardiography can pick up a high proportion of congenital heart disease with good reliability for the majority of lesions. Early fetal echocardiography is relatively poor at assessing pulmonary veins, the atrioventricular valves and lesions that typically occur later or progress during the course of pregnancy. There is increasing interest in widespread implementation of an early obstetric anomaly screen which includes an assessment of the fetal heart for all pregnancies. There are a variety of hemodynamic differences in the late first/early second trimester compared with later in pregnancy. CONCLUSION: Early fetal echocardiography is has become an established tool for detection of congenital heart disease. It affords opportunities to learn about the true spectrum and progression of congenital heart disease in-utero. Operators should be mindful of safety issues, technical aspects and hemodynamic findings which differ when performing echocardiograms at this stage of pregnancy. PMID- 30430771 TI - Long non-coding RNA H19 promotes TDRG1 expression and cisplatin resistance by sequestering miRNA-106b-5p in seminoma. AB - The role of TDRG1 in tumorigenesis and the progression of seminoma, as well as its role in regulating chemosensitivity of seminoma to cisplatin through the PI3K/Akt/mTOR signaling pathway, has been previously defined. However, the detailed mechanism underlying TDRG1 expression and concomitant chemoresistance conditions are unknown. Furthermore, it has been reported that non-protein-coding RNAs play an important role in a variety of vital processes including cellular chemosensitivity. However, the role of non-protein-coding RNAs in regulating the chemosensitivity of seminoma remains unknown. In this study, using microarray analysis, we found that long non-coding RNA H19 was upregulated while miRNA-106b 5p was downregulated in an established cisplatin-resistant TCam-2 cell line. Moreover, H19 acts as a miRNA-106b-5p sponge and thus impairs the function of miRNA-106b-5p on its target gene, TDRG1. Based on these findings, we propose that H19 promotes the expression of TDRG1 by sequestering miRNA-106b-5p and uses this mechanism to facilitate cell survival in cisplatin-based chemotherapeutic conditions. These findings elucidate the mechanisms, at least partially, applied to deregulate TDRG1 and cisplatin sensitivity, and may provide new therapeutic possibilities for chemoresistant seminoma. PMID- 30430772 TI - Cis-AB, the Blood Group of Many Faces, Is a Conundrum to the Novice Eye. AB - Cis-AB, a rare ABO variant, is caused by a gene mutation that results in a single glycosyltransferase enzyme with dual A and B glycosyltransferase activities. It is the most frequent ABO subgroup in Korea, and it occurs more frequently in the East Asian region than in the rest of the world. The typical phenotype of cis-AB is A2B3, but it can express various phenotypes when paired with an A or B allele, which can lead to misclassification in the ABO grouping and consequently to adverse hemolytic transfusion reactions. While cis-AB was first discovered as having an unusual inheritance pattern, it was later found that both A and B antigens are expressed from the same allele inherited from a single parent; hence, the name cis-AB. Earlier studies relied on serological and familial investigation of cis-AB subjects, but its detection has become much easier with the introduction of molecular methods. This review will summarize the serological variety, genetic basis and inheritance pattern, laboratory methods of investigation, clinical significance, and the blood type of choice for transfusion for the cis-AB blood group. PMID- 30430773 TI - Reducing Diagnostic Errors Worldwide Through Diagnostic Management Teams. AB - A major challenge facing most countries is the growing cost of healthcare. Laboratory testing costs constitute approximately 3% of all clinical costs, while waste of funds due to inappropriate admissions to clinical departments is reported to be as high as 15%. A frequently used approach to save money in healthcare is random reduction of laboratory budgets, focusing on decreasing the number of unnecessary laboratory tests. The World Health Assembly has approached this problem by publishing a list of essential in vitro diagnostic tests, to achieve a global rationalization of the problem. A much more thoughtful strategy to reducing healthcare expenditure is to improve the efficiency of the diagnostic process. Decreasing the time to a correct diagnosis provides considerable financial and clinical benefits. Additionally, reducing both overutilization and underutilization of laboratory tests while achieving the correct diagnosis is of great benefit to challenged healthcare budgets. Examining the situation in the United States and Italy, this review presents an opportunity for reducing diagnostic error and increasing the efficiency of diagnostic testing worldwide. One approach taken to achieve major savings in healthcare in the United States, which can be applied in Italy and other countries, is the creation of "diagnostic management teams," comprising experts in specialty areas of medicine, primarily based in the clinical laboratory, who can advise physicians on the selection of necessary tests and the interpretation of complex test results. PMID- 30430774 TI - T-Cell Receptor Rearrangements Determined Using Fragment Analysis in Patients With T-Acute Lymphoblastic Leukemia. AB - BACKGROUND: Chromosomal abnormalities and common genetic rearrangements related to T-acute lymphoblastic leukemia (T-ALL) are not clear. We investigated T-cell receptor (TCR) rearrangement in Korean T-ALL patients by fragment analysis, examining frequency, association between clinicopathologic characteristics and TCR clonality, and feasibility for detecting minimal residual disease (MRD). METHODS: In 51 Korean patients diagnosed as having T-ALL, TCR rearrangement was analyzed using the IdentiClone TCR gene clonality assay (InVivoScribe Technologies, San Diego, CA, USA) from archived bone marrow specimens. Limit of detection (LOD) and clonal stability at relapse were evaluated. The association between clinical prognosis and TCR clonality was examind by age and immunophenotypic classification. RESULTS: Thirty-eight patients (74.5%) had 62 clonal products of TCRbeta, TCRgamma, and/or TCRdelta rearrangements at diagnosis. Children with T-ALL (<12 years) showed a higher frequency of clonality (93.8%) than adolescents/adults (65.7%; >=12 years). Patients with a mature immunophenotype (84.4%) showed a relatively higher frequency of clonality than those with the immature immunophenotype (57.9%). Survival and event-free survival were not influenced by immunophenotype or TCR clonality. The LOD was 1%. Clonal evolution at the relapse period was noted. CONCLUSIONS: The overall detection rate of TCR clonality was 74.5%. Survival did not differ by TCR clonality or immunophenotype and age group. Fragment analysis of TCR rearrangement cannot be used to assess MRD due to low sensitivity. Further research on the relationship between prognosis and frequency of TCR rearrangements is needed, using more sensitive methods to detect clonality and monitor MRD. PMID- 30430776 TI - Development of a Novel Flow Cytometry-Based System for White Blood Cell Differential Counts: 10-color LeukoDiff. AB - BACKGROUND: Flow cytometry (FCM) is commonly used to identify many cell populations. We developed a white blood cell (WBC) differential counting system for detecting abnormal cells using FCM incorporating 10 colors and 11 antibodies in a single tube, called "10-color LeukoDiff," and evaluated its performance. METHODS: Ninety-one EDTA-anti-coagulated peripheral blood samples from 76 patients were analyzed using 10-color LeukoDiff. We compared 10 color LeukoDiff results with the results of manual differential count (manual diff). WBCs were classified into 17 cell populations: neutrophils, total lymphocytes, T lymphocytes, B lymphocytes, CD5 and CD19 co-expressing lymphocytes, natural killer cells, total monocytes, 16+ monocytes, eosinophils, immature granulocytes, basophils, myeloblasts, B-blasts, T-blasts, myeloid antigen-positive B-blasts, CD19- plasma cells, and 19+ plasma cells. RESULTS: The correlations between the 10-color LeukoDiff and manual diff results were strong (r>0.9) for mature neutrophils, lymphocytes, eosinophils, immature granulocytes, and blasts and moderate for monocytes and basophils (r=0.86 and 0.74, respectively). There was no discrepancy in blast detection between 10-color LeukoDiff and manual diff results. Furthermore, 10-color LeukoDiff could differentiate the lineage of the blasts and separately count chronic lymphocytic leukemic cells and multiple myeloma cells. CONCLUSIONS: The 10-color LeukoDiff provided an accurate and comprehensive WBC differential count. The most important ability of 10-color LeukoDiff is to detect blasts accurately. This system is clinically useful, especially for patients with hematologic diseases, such as acute leukemia, chronic lymphocytic leukemia, and multiple myeloma. Application of this system will improve the development of FCM gating strategy designs. PMID- 30430777 TI - Comparison of High Sensitivity and Conventional Flow Cytometry for Diagnosing Overt Paroxysmal Nocturnal Hemoglobinuria and Detecting Minor Paroxysmal Nocturnal Hemoglobinuria Clones. AB - BACKGROUND: High sensitivity flow cytometry (HS-FCM) was recently developed for diagnosing paroxysmal nocturnal hemoglobinuria (PNH). We compared its performance with conventional flow cytometry (C-FCM) for diagnosing overt PNH and detecting minor (0.1-1%) PNH clones in aplastic anemia (AA)/low-grade myelodysplastic syndrome (MDS) patients. METHODS: C-FCM and HS-FCM were performed simultaneously on 41 samples from healthy controls and 23 peripheral blood samples from 15 AA/low-grade MDS and eight PNH patients, using a Navios flow cytometer (Beckman Coulter, Miami, FL, USA). Results were compared. RESULTS: No healthy control samples had PNH clone size >0.01%. For granulocytes, C-FCM detected a smaller PNH clone size than HS-FCM (mean difference: 0.7-1.7%). In AA/low-grade MDS patients, three samples showed >1% PNH clones with C-FCM but not with HS-FCM. Seven samples showed minor PNH clones by C-FCM, but HS-FCM showed negative results for all these samples. In PNH patients, C-FCM detected a smaller PNH clone size than HS FCM (mean difference: 1.9-5.0%). For red blood cells, C-FCM detected a greater PNH clone size than HS-FCM (mean difference: 1.5%). In AA/low-grade MDS patients, C-FCM showed >1% PNH clones in six samples, but HS-FCM showed >1% PNH clones in none of the samples. C-FCM detected minor PNH clones in nine samples, but six of them were negative by HS-FCM. In PNH patients, C-FCM detected a greater PNH clone size than HS-FCM (mean difference: 2.5%). CONCLUSIONS: HS-FCM can sensitively detect minor PNH clones and reduce false-positive C-FCM minor PNH clone cases in AA/low-grade MDS patients. PMID- 30430775 TI - Increased Prevalence of Thalassemia in Young People in Korea: Impact of Increasing Immigration. AB - BACKGROUND: Thalassemia is highly prevalent in Southeast Asia but is rare in Korea; however, Southeast Asian immigrant population is recently rising in Korea. We investigated the prevalence of thalassemia in Korea in the context of increasing immigration. METHODS: This prospective, observational, multicenter study was conducted between September 2015 and August 2017. A total of 669 subjects <30 years living in Korea were grouped into the multiethnic (N=314) and Korean (N=355) groups. Hb electrophoresis and complete blood count (CBC) were performed. If low mean corpuscular volume with high red blood cell distribution width coefficient of variation or a high fetal Hb (HbF) or Hb alpha 2 (HbA2) level was observed, genetic testing of the alpha- and beta-globin genes was performed. In addition, the number of potential thalassemia carriers in Korea was estimated by multiplying the prevalence of thalassemia in a specific ethnicity by the number of immigrants of that ethnicity. RESULTS: Twenty-six multiethnic and 10 Korean subjects showed abnormal results for Hb electrophoresis and CBC. Eighteen multiethnic subjects and four Korean subjects were tested for alpha globin and beta-globin gene mutations. Within the multiethnic group, five subjects (1.5%) were alpha-thalassemia carriers, and six (1.9%) were beta thalassemia minor. The SEA deletion in HBA1 and HBA2, and c. 126_129delCTTT (p.Phe42Leufs*19) mutation of HBB were the dominant inherited mutations. CONCLUSIONS: The prevalence of thalassemia in young people in Korea is increasing due to the increasing number of Southeast Asian immigrants. PMID- 30430778 TI - Impact of Community-Onset Methicillin-Resistant Staphylococcus aureus on Staphylococcus aureus Bacteremia in a Central Korea Veterans Health Service Hospital. AB - BACKGROUND: No study has examined the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in Korean veterans' hospitals. We investigated the microbiological and clinical epidemiology of S. aureus bacteremia at the central Veterans Health Services (VHS) hospital in Korea. METHODS: Patients with S. aureus bacteremia were consecutively enrolled from February to August 2015. Bacteremia was classified as hospital-acquired (HA), community-onset healthcare-associated (COHA), or community-acquired (CA). MRSA bacteremia risk factors were analyzed. Species identification, antimicrobial susceptibility, and presence of luk and tst were tested. Staphylococcal cassette chromosome mec (SCCmec) typing, spa sequence typing agr polymorphism typing, and multilocus sequence typing were performed. Biofilm production and delta-hemolysin activity were measured to determine agr function. RESULTS: In total, 60 patients were enrolled (30 HA, 23 COHA, and seven CA bacteremia); 44 (73.3%) had MRSA bacteremia (26 HA, 16 COHA, and two CA). MRSA bacteremia occurred more frequently in non-CA patients and those who had received antibiotic treatment within the past month (P<0.05). The major MRSA strains comprised 24 ST5-agr2-SCCmecII, 11 ST72-agr 1-SCCmecIV, and five ST8-agr1-SCCmecIV strains. Of 26 agr2-SCCmecII strains, including two MSSA strains, 25 were multidrug-resistant, 18 were tst positive, and 13 were agr-defective, whereas only five of the 18 agr1-SCCmecIV strains were multidrug-resistant, and all were tst-negative and agr-intact. agr1 SCCmecIV and ST8-agr1-SCCmecIV strains were more likely than agr2-SCCmecII strains to be COHA. CONCLUSIONS: MRSA was highly prevalent in both COHA and HA bacteremia. The introduction of virulent CA-MRSA strains may be an important cause of increased HA-MRSA bacteremia in VHS hospitals. PMID- 30430779 TI - Identification and Characterization of NDM-1-producing Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae in China. AB - BACKGROUND: Carbapenem-resistant hypervirulent (hypermucoviscous) Klebsiella pneumoniae (CR-HMKP) poses a significant public health challenge. We investigated its epidemiology and molecular characteristics in a tertiary care hospital in eastern China. METHODS: CR-HMKP were identified among 106 non-duplicated carbapenem-resistant K. pneumoniae isolates (from June 2013 to September 2017) using the string test. The pulsotype (PT) and sequence type (ST) of CR-HMKP isolates were determined using pulsed-field gel electrophoresis and multilocus sequence typing. Resistance determinants, capsular serotypes, and virulence genes were detected by PCR and sequencing. Representative isolates from each PT were selected, and their virulence phenotypes were established using the serum killing and Galleria mellonella lethality assays. RESULTS: Of the 106 isolates, 13 (12.3%) were CR-HMKP. Seven were positive for blaNDM-1 and shared the same genotype (PT5/ST1764); the others were positive for blaKPC-2, belonged to ST11, and were divided into four different PTs. The serotype of all blaNDM-1-positive isolates was K64, while that of blaKPC-2-positive isolates were K47 (N=4) and K64 (N=2). The NDM-1-producing HMKP isolates were positive for aerobactin, exhibited high serum resistance, and elicited significantly increased larval mortality compared with the other isolates. All patients had received invasive treatment prior to infection by NDM-1-producing HMKP. The infections occurred between July and August 2016 and were hospital-acquired. CONCLUSIONS: NDM-1-producing HMKP ST1764 isolates were identified; this is the first report worldwide on an outbreak of nosocomial infection caused by these isolates. Effective surveillance and strict infection control strategies should be implemented to prevent CR-HMKP dissemination. PMID- 30430780 TI - Comparative Evaluation Between the RealStar Pneumocystis jirovecii PCR Kit and the AmpliSens Pneumocystis jirovecii (carinii)-FRT PCR Kit for Detecting P. jirovecii in Non-HIV Immunocompromised Patients. AB - BACKGROUND: Real-time PCR is more sensitive than microscopic examination for detecting Pneumocystis jirovecii. We compared the performance of two assays for detecting P. jirovecii DNA: the RealStar Pneumocystis jirovecii PCR Kit 1.0 CE (Altona Diagnostics, Hamburg, Germany) and the AmpliSens Pneumocystis jirovecii (carinii)-FRT PCR kit (InterLabService Ltd., Moscow, Russia). METHODS: We used 159 samples from the lower respiratory tract (112 bronchoalveolar lavage [BAL] fluid, 37 sputum, and 10 endotracheal aspirate [ETA] samples) of non-HIV immunocompromised patients. Nested PCR and sequencing were used to resolve discordant results. The performance of the two assays was evaluated according to clinical categories (clinical Pneumocystis pneumonia [PCP], possible PCP, or unlikely PCP) based on clinical and radiological observations. RESULTS: The positive and negative percent agreement values were 100% (95% confidence interval [CI], 85.4-100%) and 96.6% (95% CI, 90.9-98.9%), respectively, and kappa was 0.92 (95% CI, 0.84-0.99). P. jirovecii DNA load was significantly higher in the clinical PCP group than in the other groups (P<0.05). When stratified by sample type, the positive rate for BAL fluids from the clinical PCP group was 100% using either assay, whereas the positive rate for sputum/ETA samples was only 20%. CONCLUSIONS: The two assays showed similar diagnostic performance and detected low P. jirovecii burden in BAL fluids. Both assays may be useful as routine methods for detecting P. jirovecii DNA in a clinical laboratory setting, though their results should be interpreted considering sample type. PMID- 30430781 TI - An Excel Macro for Determining Allelic and Sequence Types of Bacterial Clones in Multilocus Sequence Typing. AB - BACKGROUND: Multilocus sequence typing (MLST) was designed to overcome the low discriminatory power and poor reproducibility of previous molecular typing schemes, and it is useful for inter-laboratory, inter-regional, and inter national comparison of pathogenic clones. MLST includes labor-intensive sequencing processes and meticulous allelic/sequence type (ST) determination processes, often prone to error. We developed a free automated MLST determination program (MLST typer) based on the Visual Basic for Applications macro, which runs on Microsoft Excel. METHODS: MLST typer imports sequence data in the FASTA format, converts reverse complement counterparts of the reverse sequences, assembles forward and reverse-complement converted sequences, and returns allelic numbers for each gene and ST of each isolate. To evaluate the performance of MLST typer, we tested the sequence data from 200 clinical isolates, each consisting of seven housekeeping gene sequences, with a total of 1,400 allelic number determinations. The results were compared with manual assessment. RESULTS: MLST typer comprises three worksheets: the Main page, Result page, and Summary page. The Main page console operates the process according to user-specified parameters. The Result and Summary pages provide the allelic type and ST determinations. It took approximately 12 minutes to analyze the sequence data from 200 clinical isolates. Compared with manual assessment, the rate of correct identification was 97.2% (1,361/1,400). CONCLUSIONS: MLST typer can be widely used for epidemiological studies owing to its thoroughness in repetitive functions, good compatibility with FASTA type data files, and easy-to-understand outputs for allelic and ST determinations. PMID- 30430782 TI - Antimicrobial Susceptibility Patterns of Anaerobic Bacterial Clinical Isolates From 2014 to 2016, Including Recently Named or Renamed Species. AB - BACKGROUND: Anaerobic bacterial resistance trends may vary across regions or institutions. Regional susceptibility patterns are pivotal in the empirical treatment of anaerobic infections. We determined the antimicrobial resistance patterns of clinically important anaerobic bacteria, including recently named or renamed anaerobes. METHODS: A total of 521 non-duplicated clinical isolates of anaerobic bacteria were collected from a tertiary-care hospital in Korea between 2014 and 2016. Anaerobes were isolated from blood, body fluids, and abscess specimens. Each isolate was identified by conventional methods and by Bruker biotyper mass spectrometry (Bruker Daltonics, Leipzig, Germany) or VITEK matrix assisted laser desorption ionization time-of-flight mass spectrometry (bioMerieux, Marcy-l'Etoile, France). Antimicrobial susceptibility was tested using the agar dilution method according to the CLSI guidelines. The following antimicrobials were tested: piperacillin-tazobactam, cefoxitin, cefotetan, imipenem, meropenem, clindamycin, moxifloxacin, chloramphenicol, tetracycline, and metronidazole. RESULTS: Most Bacteroides fragilis isolates were susceptible to piperacillin-tazobactam, imipenem, and meropenem. The non-fragilis Bacteroides group (including B. intestinalis, B. nordii, B. pyogenes, B. stercoris, B. salyersiae, and B. cellulosilyticus) was resistant to meropenem (14%) and cefotetan (71%), and Parabacteroides distasonis was resistant to imipenem (11%) and cefotetan (95%). Overall, the Prevotella and Fusobacterium isolates were more susceptible to antimicrobial agents than the B. fragilis group isolates. Anaerobic gram-positive cocci exhibited various resistance rates to tetracycline (6-86%). Clostridioides difficile was highly resistant to penicillin, cefoxitin, imipenem, clindamycin, and moxifloxacin. CONCLUSIONS: Piperacillin-tazobactam, cefoxitin, and carbapenems are highly active beta-lactam agents against most anaerobes, including recently named or renamed species. PMID- 30430783 TI - Cluster Containing More Than 20 CD3-Positive Cells in Bone Marrow Biopsy Is a Candidate Prognostic Indicator in Peripheral T-Cell Lymphoma, Not Otherwise Specified. AB - Assessment of bone marrow (BM) involvement in peripheral T-cell lymphoma, not otherwise specified (PTCL) is straightforward in cases of extensive involvement but difficult in cases of minimal to partial involvement. We evaluated the usefulness of CD3 as an immunohistochemical marker for assessing BM involvement in PTCL patients. BM biopsies of 92 PTCL patients were immunohistochemically stained for CD3, CD4, CD8, CD20, and CD56, and evaluated by two hematopathologists. CD3 positivity was graded according to the proportion of CD3 positive cells and the number of CD3-positive cells in a cluster. These criteria were used to determine the cut-offs at which significant differences in progression-free survival (PFS) and overall survival (OS) were observed. Multivariate analysis controlling the International Prognostic Index (IPI) score and its individual factors revealed that >20 CD3-positive cells in a cluster adversely affected PFS (relative risk [RR], 2.1; 95% confidence interval [CI], 1.0-4.3; P=0.047) and OS (RR, 2.4; 95% CI, 1.1-5.1; P=0.028) independent of IPI score. A cluster with >20 CD3-positive cells is a candidate indicator for BM involvement in PTCL. PMID- 30430784 TI - Estimated Glomerular Filtration Rates Show Minor but Significant Differences Between the Single and Subgroup Creatinine-Based Chronic Kidney Disease Epidemiology Collaboration Equations. AB - The creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation can be calculated according to race, sex, and creatinine concentration (subgroup equation) or in the form expressed by one equation (single equation). Minor differences in the constants used in the CKD-EPI equations (subgroup vs single equations) could result in a significant difference in the estimated glomerular filtration rate (eGFR). We evaluated the impact of this difference in 79,709 Korean patients. The eGFR was calculated as an integer using the single and subgroup CKD-EPI equations. The differences in eGFR and GFR categories between the equations were analyzed. eGFR was higher in the subgroup equation than the single equation by 1 mL/min/1.73 m2 for 12,476 (27.4%) Korean females. The GFR category based on the subgroup equation was reclassified using the single equation for 352 (0.77%) females. Based on the results, the constant of the single equation was optimized. There was no difference in eGFR values between equations using a multiplier of 1.0213 instead of 1.018 for the "white or other" females constant in the single CKD-EPI equation. Clinicians should carefully apply the CKD-EPI equation because eGFR values may differ by 1 mL/min/1.73 m2 depending on the manner of calculation. To minimize these differences, the constants of the single equation should be revised. PMID- 30430786 TI - Simultaneous Detection of Clostridioides difficile Glutamate Dehydrogenase and Toxin A/B: Comparison of the C. DIFF QUIK CHEK COMPLETE and RIDASCREEN Assays. AB - Various commercial assays have recently been developed for detecting glutamate dehydrogenase (GDH) and/or toxin A/B to diagnose Clostridioides difficile infection (CDI). We compared the performance of two assays for the simultaneous detection of C. difficile GDH and toxin A/B, using 150 stool samples: C. DIFF QUIK CHEK COMPLETE (QCC; TechLab, Blacksburg, VA, USA) and RIDASCREEN Clostridium difficile GDH (RC-GDH) and Toxin A/B (RC-Toxin A/B; R-Biopharm, Darmstadt, Germany). For GDH detection, QCC and RC-GDH showed satisfactory sensitivity (95.7% and 94.3%, respectively) and specificity (92.5% and 93.8%, respectively) compared with C. difficile culture. For toxin A/B detection, QCC showed higher sensitivity than RC-Toxin A/B (60.0% vs 33.3%, P<0.001) compared with toxigenic C. difficile culture. When the results of QCC or RC-GDH+RC-Toxin A/B were used as the first step of a two-step algorithm for diagnosing CDI, QCC permitted more accurate discrimination than RC of positive or negative results for CDI (77.3% and 65.3%, respectively). QCC is useful for the simultaneous detection of C. difficile GDH and toxin A/B as a part of the two-step algorithm for diagnosing CDI. PMID- 30430785 TI - Hemoglobin A1c Levels Are Slightly but Significantly Lower in Normoglycemic Subjects With the Hemoglobin E Phenotype. AB - Hb mutations can alter the structure, behavior, stability, or quantity of the globin chain produced. Some Hb variants shorten the erythrocyte life span, resulting in physiologically lower hemoglobin A1c (HbA1c) levels. The hemoglobin E (HbE) phenotype involves a single-nucleotide polymorphism that reduces beta globin chain synthesis. We compared the HbA1c levels of subjects with normal Hb (HbAA; N=131) and HbE (N=148) phenotypes, examining potential hematological and biochemical factors contributing to differences in HbA1c levels. All had normal fasting plasma glucose (<5.6 mmol/L), AST, ALT, and creatinine levels. Mean+/-SD HbA1c levels differed between HbAA and HbE subjects: 5.5+/-0.3% and 5.3+/-0.3% (P<0.001) according to an immunoassay, and 5.5+/-0.3% and 5.3+/-0.3% (P<0.001) according to cation-exchange HPLC, respectively. In multiple logistic regression, only mean corpuscular volume (P<0.001) contributed to the difference in HbA1c levels between groups. Although a 0.2% difference in HbA1c is relatively small and unlikely to alter clinical decisions, epidemiologically, this can lead to misclassification of a significant proportion of the population, especially since the threshold of non-diabetes HbA1c (<=5.6%) falls very close to the HbA1c median of the general population. PMID- 30430787 TI - Red Blood Cell Alloimmunization in Korean Patients With Myelodysplastic Syndrome and Liver Cirrhosis. AB - Red blood cell (RBC) alloimmunization varies across human populations and ethnic groups. We evaluated the characteristics of RBC alloimmunization and compared the risk of alloimmunization in Korean patients with myelodysplastic syndrome (MDS) and liver cirrhosis (LC), two representative diseases in which chronic transfusion is required. In total, 115 MDS patients and 202 LC patients transfused with RBCs between 2013 and 2015 were retrospectively included. Twenty patients (6.3%) were newly alloimmunized (five MDS patients, 4.3%; 15 LC patients, 7.4%). The median number of RBC units transfused in alloimmunized patients was nine (interquartile range, 4-15 units). As the number of transfused RBC units increased, the cumulative risk of alloimmunization was higher in LC than in MDS patients (P=0.001). The most common alloantibody detected in patients was anti-E (45%), followed by anti-c (17%), anti-e (10%), anti-C (7%), anti-Fyb (7%), and anti-Jka (7%). The present data indicate the need for matching of extended RBC antigens (Rh, Duffy, and Kidd systems) for chronically transfused patients with MDS and LC in Korea. PMID- 30430788 TI - Reconstructed Three-Dimensional Images and Parameters of Individual Erythrocytes Using Optical Diffraction Tomography Microscopy. PMID- 30430789 TI - Centromere Protein-F-like Pattern in a Patient With Rheumatoid Arthritis. PMID- 30430790 TI - The First Case of Congenital Prekallikrein Deficiency in Korea With a Novel Pathogenic Variant (c.1198G>T). PMID- 30430791 TI - Advantages of Array Comparative Genomic Hybridization Using Buccal Swab DNA for Detecting Pallister-Killian Syndrome. PMID- 30430792 TI - Erratum: Novel 4-bp Intronic Deletion (c.1560+3_1560+6del) in LEMD3 in a Korean Patient With Osteopoikilosis. AB - This corrects the article on p. 540 in vol. 37, PMID: 28840995. PMID- 30430793 TI - Adverse Drug Event Rate in Israeli Hospitals: Validation of an International Trigger Tool and an International Comparison Study. AB - BACKGROUND: Adverse drug events (ADEs) are a major cause of morbidity and mortality worldwide. Hence, identifying and monitoring ADEs is of utmost importance. The Trigger Tool introduced by the Institute of Healthcare Improvement in the United States has been used in various countries worldwide, but has yet to be validated in Israel. OBJECTIVES: To validate the international Trigger Tool in Israel and to compare the results with those generated in various countries. METHODS: A retrospective descriptive correlative analysis surveying four general hospitals in Israel from different geographical regions was conducted. Patient medical charts (n=960) were screened for 17 established triggers and confirmed for the presence of an ADE. Trigger incidence was compared to the actual ADE rate. Further comparison among countries was conducted using published literature describing Trigger Tool validation in various countries. RESULTS: A total of 421 triggers in 279 hospitalizations were identified, of which 75 ADEs in 72 hospitalizations (7.5%) were confirmed. In addition, two ADEs were identified by chart review only. Mean positive predictive value was 17.81% and overall sensitivity was 97%. We found 1.54 ADEs for every 100 hospitalization days, 7.8 ADEs per 100 admissions, and 1.81 ADEs for every 1000 doses of medication. Of the 77 ADEs identified, 22.7% were defined as preventable. CONCLUSIONS: Our results support the Trigger Tool validity in Israel as a standardized method. Further studies should evaluate between hospital and region differences in ADE rate, in particular for the preventable events. PMID- 30430794 TI - Hoarding among Jewish Holocaust Survivors: Moving Toward a Theoretical Model. AB - BACKGROUND: Previously described as a subcategory of obsessive compulsive disorder (OCD), hoarding disorder was added to the fifth Diagnostic and Statistical Manual of Mental Disorders (DSM-V) as a stand-alone diagnosis for the first time. The first formal research in the 1990s surprisingly found no connection between material deprivation early in life and hoarding; however, later studies linked early traumatic life experiences with hoarding. Subsequent familial studies demonstrated a genetic predisposition for hoarding. Emerging evidence suggests a link between a post-traumatic stress disorder (PTSD) and hoarding in Jewish Holocaust survivors. OBJECTIVES: To evaluate the literature on PTSD among Jewish Holocaust survivors for associations between PTSD and hoarding. METHODS: A systematic search of selected databases, including PubMed, Google Scholar, NCBI, Psych Info, and EBSCO Host was conducted from 1 March 2017 to 15 July 2018 using the following search terms: hoarding, hoarding disorder, obsessive compulsive disorder, OCD, compulsive hoarding, Jewish Holocaust survivors, Shoa, post-traumatic stress disorder, and PTSD. Inclusion criteria included peer reviewed research published on adults in English since 1990. Because no publications linking hoarding and PTSD in Jewish Holocaust survivors were found, references in retained papers were also searched for any relevant published work. RESULTS: Seven articles linking PTSD and hoarding were identified for this review. However, no articles were found linking PTSD and hoarding in Jewish Holocaust survivors. CONCLUSIONS: A relationship between PTSD and hoarding in Jewish Holocaust survivors is conceivable and should be explored to effectively diagnose and care for affected individuals. PMID- 30430795 TI - Surgical Biopsy of Pathologically Enlarged Lymph Nodes: A Reappraisal. AB - BACKGROUND: Enlarged lymph nodes (ELN) pose a great diagnostic challenge. They may represent the first clinical finding of a hematologic disease or other malignancy and may be an indication of a wide range of infectious and non infectious diseases. Because many patients undergo percutaneous biopsy, surgical excisional biopsy is not often considered. OBJECTIVES: To analyze indications for a patient's referral for surgical biopsy of ELN and diagnostic steps to follow until referral, and to determine the number of ELN. METHODS: A retrospective study was conducted of prospectively collected data of patients who underwent surgical biopsy of ELN from January 2004 to December 2013. RESULTS: Of 118 patients who underwent surgical biopsy of ELN, only 52 (44%) had needle biopsy (NB) before referral. Lymphoma was diagnosed by NB in 24 (46%) of the referred patients. In patients with a previous diagnosis of lymphoma, NB of ELN yielded a sensitivity of 67% and specificity of 79%. In patients with lymphadenopathy but with no previous history of malignancy, sensitivity for lymphoma was 68% and specificity was 71%. The investigative time period until final diagnosis was 3 months in patients who had NB but only 1.25 months in patients who were referred directly for surgery (P < 0.0001). CONCLUSIONS: Surgical biopsy of ELN still has a place in the clinical evaluation of patients with ELN. Surgery may significantly reduce the length of investigation and prevent unnecessary diagnostics, especially in patients with suspected lymphoma recurrence. PMID- 30430796 TI - Clinical and Molecular Characteristics of Eight Israeli Families with Thyroid Hormone Receptor Beta Mutations. AB - BACKGROUND: Reduced sensitivity to thyroid hormone (RSTH) syndrome describes a group of rare heterogeneous genetic disorders. Precise diagnosis is essential to avoid unnecessary treatment. OBJECTIVES: To identify and characterize previously undiagnosed patients with RSTH in Israel. METHODS: Patients with suspected RSTH throughout Israel were referred for study. After clinical evaluation, genomic DNA was obtained and all coding exons of the thyroid hormone receptor beta (THRB) gene were sequenced. If mutations were found, all available blood relatives were evaluated. The common polymorphism rs2596623, a putative intronic regulatory variant, was also genotyped. Genotype/phenotype correlations were sought, and the effect of mutation status on pregnancy outcome was determined. RESULTS: Eight mutations (one novel; two de-novo, six dominant) were identified in eight probands and 13 family members. Clinical and genetic features were similar to those reported in other populations. Previous suggestions that rs2596623 predicts clinical features were not confirmed. There was no evidence of increased risk of miscarriage or fetal viability. Mothers carrying a THRB mutation tended to have increased gestational hypertension and low weight gain during pregnancy. Their affected offspring had increased risk of small-for-gestational age and poor postnatal weight gain. CONCLUSIONS: Clinical heterogeneity due to THRB mutations cannot be explained by the variant rs2596623. Mothers and newborns with THRB mutations seem to be at increased risk of certain complications, such as gestational hypertension and poor intrauterine and postnatal growth. However, these issues are usually mild, suggesting that routine intervention to regulate thyroid hormone levels may not be warranted in these patients. PMID- 30430797 TI - Factors Associated with Recurrence of Tracheoesophageal Fistula. AB - BACKGROUND: Recurrence of tracheoesophageal fistula (TEF) is reported in 8-20% patients. Factors that may influence recurrence of fistula beyond the postoperative period are not clear. OBJECTIVES: To evaluate possible factors associated with recurrence of TEF beyond the immediate postoperative period. METHODS: A single center, retrospective comparison of patients with and without recurrence of TEF was conducted. Medical records of patients previously operated for TEF who were followed in our pediatric pulmonary institute between January 2007 and December 2016 were reviewed. RESULTS: The medical records of 74/77 patients previously operated for TEF were evaluated. Nine patients (12%) had a recurrence of TEF and 65 did not. These groups had similar age and gender distribution and similar prevalence of VACTERL association. In addition, they had similar length of atretic gap, rates of thoracoscopic surgery, rates of prolonged need for respiratory assistance post-surgery, and frequency of gastrointestinal symptoms. Notably, the patients who had recurrent TEF had significantly more hospitalizations for respiratory symptoms (P = 0.011) and significantly more episodes of clinical bronchiolitis per patient (P < 0.0001). In addition, the patients with recurrent TEF had significantly more episodes of positive polymerase chain reaction for viruses (P = 0.009). CONCLUSIONS: Hospitalizations for respiratory symptoms as well as clinical and/or viral bronchiolitis are associated with recurrence of TEF. Even though cause and effect cannot be established, these patients should undergo meticulous evaluation for the possibility of recurrence of TEF. PMID- 30430798 TI - Short-term Adherence with Discharge Recommendation for Insulin Treatment among Patients with Type 2 Diabetes. AB - BACKGROUND: Basal-bolus (BB) insulin treatment is increasingly used in poorly controlled diabetes patients during hospitalization and is commonly recommended at discharge; however, the extent of adherence with this recommendation is unknown. OBJECTIVES: To determine short-term adherence of type 2 diabetes mellitus (T2DM) patients discharged from internal medicine wards with recommendation for BB insulin treatment. METHODS: Prescription (primary physician adherence) and purchase (patient adherence) of long-acting and short-acting insulins during the first month following discharge from internal medicine wards was determined in 153 T2DM patients. Adherence was defined as full if prescription/purchase of both basal (long-acting) and bolus (short-acting) insulin was completed, and as partial if only one kind of insulin (basal or bolus) was prescribed/purchased. Association between demographic and clinical parameters and adherence was determined. RESULTS: Full adherence with discharge instructions was higher for primary physicians than for patients )79.1% vs. 69.3%, respectively, P = 0.0182). Pre-hospitalization hemoglobin A1C was significantly associated with adherence by both patients and primary physicians (full-adherence group 9.04% +/- 2.04%; no-adherence group 7.51% +/- 1.35%, P = 0.002). Age was negatively associated with adherence of both primary physicians and patients; however, this association did not reach statistical significance. Patients with certain background diseases such as atrial fibrillation, coronary heart disease, and chronic heart failure had significantly worse adherence (P < 0.05). When the sole cause of admission was diabetes, full adherence (100%) of both primary physicians and patients was found. CONCLUSIONS: Short-term adherence with discharge recommendation for BB insulin treatment is associated with pre hospitalization patient characteristics. PMID- 30430799 TI - NOD2/CARD15 Mutations among Bedouin Arabs with Inflammatory Bowel Disease: Frequency and Phenotype Correlation. AB - BACKGROUND: Inflammatory bowel disease (IBD) prevalence is increasing among Bedouin Arabs in Israel. This population is known to have a high rate of consanguinity. NOD2/CARD15 mutations are well-studied in IBD. OBJECTIVES: To investigate the frequency of NOD2/CARD15 mutations in IBD Bedouin patients and their relevance to disease phenotype. METHODS: The IBD-Arab cohort in southern Israel included 68 patients, of which 25 Crohn's disease (CD) patients and 25 ulcerative colitis (UC) patients consented to participate (72%). Blood samples were obtained from all participants who were genotyped for NOD2/CARD15 variants Arg702Trp, Gly908Arg, and Leu1007fsinsC. RESULTS: The NOD2/CARD15 mutation frequency was higher in Crohn's disease than in ulcerative colitis patients. Carrier frequency for the Gly908Arg mutation in CD and UC patients was 8/25 (32%) and 3/25 (12%), respectively (P = 0.08). Neither the Arg702Trp nor Leu1007fsinsC mutation was found in our cohort. No homozygous/compound heterozygote mutations were found. Genotype-phenotype analysis revealed that CD patients carrying the Gly908Arg mutation were younger at diagnosis, 22.8 +/- 4.5 vs. 28.82 +/- 9.1 years (P = 0.04). All carriers were males, compared with 41.2% in non-carriers (P = 0.005). NOD2/CARD15 mutation carriers with UC were older, 67.0 +/- 24.5 years compared with 41.2 +/- 12.3 years (P = 0.006). No other associations regarding disease localization or other clinical parameter were found. CONCLUSIONS: The frequency of NOD2/CARD15 gene mutations is high in CD and UC among Bedouin Arab IBD patients and is associated with younger age at onset in CD and male gender. PMID- 30430800 TI - Comparison of the Clinical Utility in the Detection of Anti-Nuclear Antibodies Between the Elia CTD Screen and Indirect Immunofluorescence on Hep-2 Cells: A Review of the Literature. PMID- 30430801 TI - Primary Immunodeficiency: The Israeli Connection. PMID- 30430802 TI - The Use of FDG PET/CT in the Diagnosis and Monitoring of Disseminated Aspergillosis. PMID- 30430803 TI - Treatment of Resistance to Thyroid Hormone in Pregnancy: How to Address the Challenge. PMID- 30430804 TI - Pyoderma Gangrenosum and Extensive Aseptic Chest Wall Abscess in a Patient with Inflammatory Bowel Disease. PMID- 30430805 TI - ASIA Syndrome Following Breast Implant Placement. PMID- 30430806 TI - Detection of Disseminated Aspergillosis on FDG PET/CT in a Patient with Acute Lymphoblastic Leukemia. PMID- 30430807 TI - Post-Myocardial Infarction Ventricular Septal Defect: Still a Deadly Complication 30 Years after the First Transcatheter Closure. PMID- 30430808 TI - Patient Involvement in the Design and Policy in Healthcare: Highlights from the 4th Annual Conference on Therapeutic Patient Education in Diabetes OTZMA, 21 March 2018. PMID- 30430809 TI - Potential Impact of Active Helicobacter pylori Infection with or without Concomitant Metabolic Syndrome on Colorectal Cancer Invasion and Mortality. PMID- 30430810 TI - The Association of Helicobacter pylori Seropositivity and Colorectal Cancer. PMID- 30430811 TI - Application of meta-summary to derive a measurement instrument from the literature: a method exemplar. AB - BACKGROUND: Measurement tools are a common method to collect data in observational and survey research. Nurse researchers have developed numerous scales and instruments, many derived from published literature. However, few studies report systematic or replicable approaches to analysing the literature from which measures were derived. This is a significant challenge to construct validity. AIM: To provide a method exemplar of meta-summary and categorical factor analysis to refine scale items and establish construct definition. DISCUSSION: A rigorous method for deriving items from the literature is largely absent from nursing literature. This exemplar addresses the often-cited limitation of scales that authors rarely assure content validity before experts assess their newly derived scales. CONCLUSION: Without sufficient methodological rigour, practitioners and researchers must speculate about the content validity of newly derived instruments. Meta-summary provides a useful approach to developing scales from the literature. IMPLICATIONS FOR PRACTICE: The method detailed here is of use when deriving measurement instruments from the literature. It provides a systematic and replicable strategy that assures construct validity. PMID- 30430812 TI - Isochemotopic response: the first case on a scar. PMID- 30430813 TI - Extramammary Paget disease of the vulva (VEMPD) with perianal involvement: a 30 year experience. PMID- 30430814 TI - Development of a prenatal program for adults with personal histories of childhood abuse or neglect: a Delphi consensus consultation study. AB - INTRODUCTION: Pregnancy and the birth of a child present particular challenges for adults with personal histories of childhood abuse or neglect. However, few prenatal interventions address the specific needs of this population. This research aims to determine a list of actions that should be achieved during group interventions designed for expectant parents who experienced childhood trauma. METHODS: Fifteen stakeholders representing nine different Quebec health care and community organizations that work with families and/or trauma survivors participated in a Delphi process in two rounds. In round 1, three project leaders identified, from clinical and empirical literature, a set of 36 actions relevant for expectant parents who experienced childhood trauma. Using an anonymized online survey, stakeholders coded how important they considered each action and whether they were already conducting similar interventions in their clinical setting. Stakeholders subsequently participated in a one-day in-person meeting during which they discussed the pertinence of each action, proposed new ones and refined them. This was followed by a second anonymized online survey (round 2). A consensus was reached among the stakeholders regarding a final list of 22 actions. RESULTS: Two central clusters of actions emerged from the consultation process: actions aiming to support mentalization about self and parenthood, and actions aiming to support mentalization of trauma. CONCLUSION: The Delphi process helped to identify what should be the core of a prenatal intervention targeting adults who experienced childhood trauma, from the viewpoint of professionals who will ultimately deliver such a program. PMID- 30430815 TI - Factors associated with sleep duration across life stages: results from the Canadian Health Measures Survey. AB - INTRODUCTION: Sleep is essential for both physical and mental well-being. This study investigated sociodemographic, lifestyle/behavioural, environmental, psychosocial and health factors associated with sleep duration among Canadians at different life stages. METHODS: We analyzed nationally representative data from 12 174 Canadians aged 3-79 years in the Canadian Health Measures Survey (2009 2013). Respondents were grouped into five life stages by age in years: preschoolers (3-4), children (5-13), youth (14-17), adults (18-64) and older adults (65-79). Sleep duration was classified into three categories (recommended, short and long) according to established guidelines. Logistic regression models were used to identify life stage-specific correlates of short and long sleep. RESULTS: The proportion of Canadians getting the recommended amount of sleep decreased with age, from 81% of preschoolers to 53% of older adults. Statistically significant factors associated with short sleep included being non White and having low household income among preschoolers; being non-White and living in a lone-parent household among children; and second-hand smoke exposure among youth. Boys with a learning disability or an attention deficit/hyperactivity disorder and sedentary male youth had significantly higher odds of short sleep. Among adults and older adults, both chronic stress and arthritis were associated with short sleep. Conversely, mood disorder and poor/fair self-perceived general health in adults and weak sense of community belonging in adults and older men were associated with long sleep. CONCLUSION: Our population-based study identified a wide range of factors associated with short and long sleep at different life stages. This may have implications for interventions aimed at promoting healthy sleep duration. PMID- 30430816 TI - Promotion of physical activity in rural, remote and northern settings: a Canadian call to action. AB - INTRODUCTION: The lack of policy, practice and research action on physical activity and features of the physical (built and natural) environments in rural, remote and northern settings is a significant threat to population health equity in Canada. This paper presents a synthesis of current evidence on the promotion of physical activity in non-urban settings, outcomes from a national priority setting meeting, and a preliminary call to action to support the implementation and success of population-level initiatives targeting physical activity in non urban settings. METHODS: We conducted a "synopses of syntheses" scoping review to explore current evidence on physical activity promotion in rural, remote, northern and natural settings. Next, we facilitated a collaborative priority setting conference with 28 Canadian experts from policy, research and practice arenas to develop a set of priorities on physical activity in rural, remote and northern communities. These priorities informed the development of a preliminary Canadian call to action. RESULTS: We identified a limited number of reviews that focused on physical activity and the built environment in rural, remote and northern communities. At the prioritysetting conference, participants representing rural, remote and northern settings identified top priorities for policy, practice and research action to begin to address the gaps and issues noted in the literature. These priorities include self-identifying priorities at the community level; compiling experiences; establishing consistency in research definitions and methods; and developing mentorship opportunities. CONCLUSION: Coordinated action across policy, practice and research domains will be essential to the success of the recommendations presented in this call to action. PMID- 30430817 TI - How to facilitate laparoscopic extraperitoneal suture? AB - To show a simplified technique of extraperitoneal laparoscopic suture. Step-by step explanation of the technique using an educative video and pictures. This technique of extraperitoneal laparoscopic suture is highlighted through two laparoscopic procedures: a sacrocolpopexy (mesh fixation) for a pelvic organ prolapse and an ovariopexy after hysterectomy without adnexectomy (fibromatous uterus). This method avoids the need for repetitive use of the knot-pusher in performing extraperitoneal knots. Time saved in the operating room and limited gestures can theoretically contribute to decrease cost and improve safety. Although our intimate conviction goes in this direction, further studies are needed to better evaluate this procedure. Rehabilitating a process historically used during laparotomic procedures, this technique avoids iterative intra abdominal gestures and expedites the knot-tying steps. PMID- 30430818 TI - Erratum PMID- 30430819 TI - Highly Stretchable Fiber-Shaped Supercapacitors Based on Ultrathin Gold Nanowires with Double-Helix Winding Design. AB - The ability of developing highly durable fiber-shaped electronic devices is crucial for next-generation smart textile electronics. Past several years have witnessed encouraging progress made in stretchable fiber-shaped supercapacitors using carbon materials, transition metal oxides, and conducting polymers. Here, we report a dry-spun strategy to produce scalable ultrathin gold nanowire-based fibers, which can lead to highly stretchable fiber-based supercapacitors using a double-helix winding design. Hildebrand's and Hansen's solubility parameters of gold nanowire-binding oleylamine ligands match those of styrene-ethylene/butylene styrene and tetrahydrofuran, enabling the formation of high-quality dry-spun fibers. In conjunction with conductivity enhancement by electroless plating and pseudocapacitance by polyaniline, we obtained fiber-shaped supercapacitors stretchable up to 360% with a capacitance of 16.80 mF cm-2. The capacitance retention is about 85% after 2000 cycles of 0-200-0% stretching/releasing. Our fiber capacitors can be woven into an everyday glove, with negligible capacitance changes for normal finger movements. PMID- 30430820 TI - Realizing an Asymmetric Supercapacitor Employing Carbon Nanotubes Anchored to Mn3O4 Cathode and Fe3O4 Anode. AB - A facile route to anchor pseudocapacitive materials on multiwalled carbon nanotubes (CNTs) to realize high-performance electrode materials for asymmetric supercapacitors (ASCs) is reported. The anchoring process is developed after direct decomposition of metal-hexacyanoferrate complex on the CNT surface. Transmission electron microscopy (TEM) analysis reveals that the nanoparticles (NPs) are discretely attached over the CNT surface without forming a uniform layer, thus making most of the entire NP surface available for electrochemical reactions. Accordingly, CNT-Mn3O4 nanocomposite cathode shows significantly improved capacitive performance as compared to pristine CNT electrode, validating the efficacy of designing the composite electrode. With CNT-Fe3O4 nanocomposite as the paired anode, the hybrid ASC delivers a specific capacitance of 135.2 F/g at a scan rate of 10 mV/s within a potential window of 0-1.8 V in the aqueous electrolyte and retains almost 100% of its initial capacitance after 15,000 cycles. The serially connected ASCs can power commercial light-emitting diodes (LEDs) and mobile phones, reflecting their potential in next-generation storage applications. PMID- 30430821 TI - Plasmonic Conducting Metal Oxide-Based Optical Fiber Sensors for Chemical and Intermediate Temperature-Sensing Applications. AB - The demand for real-time sensors in harsh environments at elevated temperature is significant and increasing. In this manuscript, the chemical and temperature sensing using the optical response through the practical fiber platform is demonstrated, and principle component analysis is coupled with targeted experimental film characterization to understand the fundamental sensing layer properties, which dominate measured gas sensing responses in complex gas mixtures. More specifically, tin-doped indium oxide-decorated sensors fabricated with the sol-gel method show stable and stepwise transmission responses varying over a wide range of H2 concentration (5-100%) at 250-350 degrees C as well as responses to CH4 and CO to a lesser extent. Measured responses are attributed to modifications to the surface plasmon resonance absorption in the near-infrared range and are dominated by the highest concentrations of the most-reducing analyte based upon systematic mixed gas stream experiments. Principal component analysis is utilized for this type of sensor to improve the quantitative and qualitative understanding of responses, clearly identifying that the dominant principle component (PC #1) accounts for ~78% of total data variance. Correlations between PC #1 and the experimentally derived free carrier concentration confirm that this material property plays the strongest role on the ITO gas sensing mechanism, while correlations between the free carrier mobility and the second most important principle component (PC #2) suggest that this quantity may play a significant but secondary role. As such, the results presented here clarify the relationship between generalized principle components and fundamental sensing materials properties thereby suggesting the pathway toward improved multicomponent gas speciation through sensor layer engineering. The work presented represents a significant step toward the ultimate objective of optical waveguide sensors integrated with multivariate data analytics for multiparameter monitoring with a single sensor element. PMID- 30430822 TI - Perovskite-Polymer Blends Influencing Microstructures, Nonradiative Recombination Pathways, and Photovoltaic Performance of Perovskite Solar Cells. AB - Solar cells based on organic-inorganic halide perovskites are now leading the photovoltaic technologies because of their high power conversion efficiency. Recently, there have been debates on the microstructure-related defects in metal halide perovskites (grain size, grain boundaries, etc.) and a widespread view is that large grains are a prerequisite to suppress nonradiative recombination and improve photovoltaic performance, although opinions against it also exist. Herein, we employ blends of methylammonium lead iodide perovskites with an insulating polymer (polyvinylpyrrolidone) that offer the possibility to tune the grain size in order to obtain a fundamental understanding of the photoresponse at the microscopic level. We provide, for the first time, spatially resolved details of the microstructures in such blend systems via Raman mapping, light beam induced current imaging, and conductive atomic force microscopy. Although the polymer blend systems systematically alter the morphology by creating small grains (more grain boundaries), they reduce nonradiative recombination within the film and enhance its spatial homogeneity of radiative recombination. We attribute this to a reduction in the density of bulk trap states, as evidenced by an order of magnitude higher photoluminescence intensity and a significantly higher open circuit voltage when the polymer is incorporated into the perovskite films. The solar cells employing blend systems also show nearly hysteresis-free power conversion efficiency ~17.5%, as well as a remarkable shelf-life stability over 100 days. PMID- 30430823 TI - Fe3+-induced synchronous formation of composite hydrogels for effective synergistic tumor therapy in NIR-I/II biowindows. AB - Alginate-Ca2+ hydrogel has been used to immobilize photothermal materials as well as chemotherapy drugs at lesion sites to prevent their entry into the bloodstream. However, the alginate-Ca2+ gelation mechanism may result in hardening of the blood vessels due to Ca2+ migration to the lesion site. In this study, a unique and facile one-pot formation of chemotherapeutic (doxorubicin, DOX) and polypyrrole (PPy)-containing alginate hydrogel was designed by introducing Fe3+, which can synchronously induce the polymerization of pyrrole and gelatinization of alginate, into the DOX/pyrrole/alginate solution. The formed composite hydrogel was endowed with superior photothermal conversion properties in both the NIR-I (650-950 nm) and NIR-II (1000-1700 nm) biowindows and light-to-heat conversion efficiency higher than 50%, which enabled effective tumor hyperthermia treatment. Besides, NIR irradiation could be used as a remote controller to trigger the DOX-release due to the heat generation, thus achieving continuous and on-demand tumor chemotherapy. The composite polymer hydrogels exhibited favorable hemo-, cyto-, and histocompatibility, as well as simple and cost-effective preparation and good clinical prospects. PMID- 30430824 TI - Preparation and Characterization of Te/Poly(3,4 ethylenedioxythiophene):Poly(styrenesulfonate)/Cu7Te4 Ternary Composite Films for Flexible Thermoelectric Power Generator. AB - In this work, Te/poly(3,4-ethylenedioxythiophene) (PEDOT):poly(styrenesulfonate) (PSS)/Cu7Te4 ternary thermoelectric (TE) nanocomposite films were successfully fabricated by physical mixing and then drop casting. An optimum power factor of 65.3 MUW/mK2 was acquired from a composite film containing 95 wt % PEDOT:PSS coated Te (PC/Te) nanorods at 300 K, which was about 5 times as large as that of the PC/Cu7Te4 nanorod film and about 3 times as large as that of the PC/Te nanorod film. The power factor reached 112.3 MUW/mK2 when the temperature was 380 K. Scanning transmission electron microscopy (STEM) and high-resolution STEM were used to observe the detailed internal microstructure of the composite film, revealing that the Te nanorods were single crystalline and the Cu7Te4 rods polycrystalline. The composite film was in fact a three-dimensional network interconnected with the PC/Te and PC/Cu7Te4 nanorods. The enhancement of the TE properties was ascribed to the synergetic effect of the two kinds of nanorods and the double-carrier filtering effect at the two heterointerfaces of Te/PEDOT:PSS and Cu7Te4/PEDOT:PSS. An eight single-leg flexible TE device consisting of the optimized composite film was fabricated, which produced a voltage of 31.2 mV and a maximum output power of 94.7 nW at a temperature gradient of 39 K. PMID- 30430825 TI - Interface States in Bilayer Graphene Encapsulated by Hexagonal Boron Nitride. AB - The threshold voltages at the onset of conduction for electron and hole branches can provide information on band gap values or interface states in a gap. We measured conductivity of bilayer graphene encapsulated by hexagonal boron nitride as a function of back and top gates, where another bilayer graphene is used as a top gate. From the measured conductivity the transport gap values were extracted assuming zero interface trap states, and they are close to the theoretically expected gap values. From a little discrepancy an average density of interface states per energy within a band gap ( Dit) is also estimated. The data clearly show that Dit decreases as a bilayer graphene band gap increases rather than being constant. Despite the decreasing trend of Dit, interestingly the total interface states within a gap increases linearly as a band gap increases. This is because of ~2 * 1010 cm-2 interface states localized at band edges even without a band gap, and other gap states are equally spread over the gap. PMID- 30430826 TI - Binding Affinity and Function of the Extremely Disordered Protein Complex Containing Human Linker Histone H1.0 and Its Chaperone ProTalpha. AB - It was recently reported that human linker histone H1.0 and its chaperone prothymosin-alpha (ProTalpha) form an extremely disordered 1:1 complex with an ultrahigh affinity (equilibrium dissociation constant KD of ~2 * 10-12 M) measured using a single-molecule Forster resonance energy transfer method. It was hypothesized that the ultrahigh affinity and extreme disorder may be required for the chaperone function of ProTalpha, in which it displaces the linker histone from condensed chromatin. Here, we measure the binding affinity for the ProTalpha H1.0 complex using isothermal titration calorimetry and report a KD value of (4.6 +/- 0.5) * 10-7 M. In addition, we show that ProTalpha facilitates the formation of the H1.0-nucleosome complex in vitro. The results of our study contrast with those of the previous report and provide new insights into the chaperone function of ProTalpha. Possible causes for the observed discrepancy in binding affinity are discussed. PMID- 30430827 TI - Ultrastable Luminescent Organic-Inorganic Perovskite Quantum Dots via Surface Engineering: Coordination of Methylammonium Bromide and Covalent Silica Encapsulation. AB - Encapsulation of luminescent perovskite quantum dots (QDs) into a solid matrix has been approved to be an efficient way to improve their stability. In this work, we reported a green encapsulation method to produce ultrastable CH3NH3PbBr3 QDs incorporated into the SiO2 matrix. Specifically, fresh-prepared CH3NH3PbBr3 QDs were covalently embedded into silica by an aqueous sol-gel method assisted with CH3NH3Br, which not only effectively inhibited the water-driven degradation of QDs through surface coordination, but also strongly stabilized the QDs in solid powder via concentration gradient. As far as we know, this silica encapsulation of perovskite QDs in aqueous environments is reported for the first time. Luminescent properties of perovskite QDs during the course of gelation as well as in resulting composite powder were investigated using steady-state and time-resolved spectroscopies, and a 2 wt % QD-doped sample treated with 11.5 mM of CH3NH3Br was demonstrated to be the optimal phosphor. The green-emissive phosphor had a PLQY of 60.3% and a full width at half maxima of ~25 nm, exhibiting ultrahigh stability tested by cycle heating (120 degrees C), continuous heating (80 degrees C, 60 h), and light irradiation (450 nm light, 350 h). The phosphor was readily blended with polymers and applied as a color converting layer on blue light-emitting diodes. PMID- 30430828 TI - Non-Fullerene Based Printed Organic Photodiodes with High Responsivity and MHz Detection Speed. AB - Digitally printed organic photodiodes (OPDs) are of great interest for the cost efficient additive manufacturing of single and multi-device detection systems with full freedom of design. Recently reported high-performance non-fullerene acceptors (NFAs) can address the crucial demands of future applications in terms of high operational speed, tunable spectral response as well as device stability. Here, we present the first demonstration of inkjet and aerosol-jet printed OPDs based on the high-performance NFA, IDTBR, in combination with poly(3 hexylthiophene) (P3HT) exhibiting a spectral response up to the NIR. These digitally printed devices reach record responsivities up to 300 mA/W in the visible and NIR spectrum competing with current commercially available technologies based on Si. Furthermore, their fast dynamic response with cut-off frequencies surpassing 2 MHz outperforms most of the state-of the-art organic photodiodes. The successful process translation from spincoating to printing is highlighted by the marginal loss in performance compared to the reference devices, which reach responsivities of 400mA/W and detection speeds of more than 4 MHz. The achieved high device performance and the industrial relevance of the developed fabrication process provide NFAs with an enormous potential for the development of printed photodetection systems. PMID- 30430829 TI - The Singular NMR Fingerprint of a Polyproline II Helical Bundle. AB - Polyproline II (PPII) helices play vital roles in biochemical recognition events and structures like collagen and form part of the conformational landscapes of intrinsically disordered proteins (IDPs). Nevertheless, this structure is generally hard to detect and quantify. Here, we report the first thorough NMR characterization of a PPII helical bundle protein, the Hypogastrura harveyi "snow flea" antifreeze protein (sfAFP). J-couplings and nuclear Overhauser enhancement spectroscopy confirm a natively folded structure consisting of six PPII helices. NMR spectral analyses reveal quite distinct Halpha2 versus Halpha3 chemical shifts for 28 Gly residues as well as 13Calpha, 15N, and 1HN conformational chemical shifts (Deltadelta) unique to PPII helical bundles. The 15N Deltadelta and 1HN Deltadelta values and small negative 1HN temperature coefficients evince hydrogen-bond formation. 1H-15N relaxation measurements reveal that the backbone structure is generally highly rigid on ps-ns time scales. NMR relaxation parameters and biophysical characterization reveal that sfAFP is chiefly a dimer. For it, a structural model featuring the packing of long, flat hydrophobic faces at the dimer interface is advanced. The conformational stability, measured by amide H/D exchange to be 6.24 +/- 0.2 kcal.mol-1, is elevated. These are extraordinary findings considering the great entropic cost of fixing Gly residues and, together with the remarkable upfield chemical shifts of 28 Gly 1Halpha, evidence significant stabilizing contributions from CalphaHalpha ||| O?C hydrogen bonds. These stabilizing interactions are corroborated by density functional theory calculations and natural bonding orbital analysis. The singular conformational chemical shifts, J-couplings, high hNOE ratios, small negative temperature coefficients, and slowed H/D exchange constitute a unique set of fingerprints to identify PPII helical bundles, which may be formed by hundreds of Gly-rich motifs detected in sequence databases. These results should aid the quantification of PPII helices in IDPs, the development of improved antifreeze proteins, and the incorporation of PPII helices into novel designed proteins. PMID- 30430830 TI - Remarkable Bifunctional Oxygen and Hydrogen Evolution Electrocatalytic Activities with Trace-Level Fe Doping in Ni- and Co-Layered Double Hydroxides for Overall Water-Splitting. AB - Large-scale H2 production from water by electrochemical water-splitting is mainly limited by the sluggish kinetics of the nonprecious-based anode catalysts for oxygen evolution reaction (OER). Here, we report layer-by-layer in situ growth of low-level Fe-doped Ni-layered double hydroxide (Ni1- xFe x-LDH) and Co-layered double hydroxide (Co1- xFe x-LDH), respectively, with three-dimensional microflower and one-dimensional nanopaddy-like morphologies on Ni foam, by a one step eco-friendly hydrothermal route. In this work, an interesting finding is that both Ni1- xFe x-LDH and Co1- xFe x-LDH materials are very active and efficient for OER as well as hydrogen evolution reaction (HER) catalytic activities in alkaline medium. The electrochemical studies demonstrate that Co1- xFe x-LDH material exhibits very low OER and HER overpotentials of 249 and 273 mV, respectively, at a high current density of 50 mA cm-2, whereas Ni1- xFe x-LDH exhibits 297 and 319 mV. To study the overall water-splitting performance using these electrocatalysts as anode and cathode, three types of alkaline electrolyzers are fabricated, namely, Co1- xFe x-LDH(+)?Co1- xFe x-LDH(-), Ni1- xFe x-LDH(+)?Ni1- xFe x-LDH(-), and Co1- xFe x-LDH(+)?Ni1- xFe x-LDH(-). These electrolyzers require only a cell potential ( Ecell) of 1.60, 1.60, and 1.59 V, respectively, to drive the benchmark current density of 10 mA cm-2. Another interesting finding is that their catalytic activities are enhanced after stability tests. Systematic analyses are carried out on both electrodes after all electrocatalytic activity studies. The developed three types of electrolyzers to produce H2, are very efficient, cost-effective, and offer no complications in synthesis of materials and fabrication of electrolyzers, which can greatly enable the realization of clean renewable energy infrastructure. PMID- 30430831 TI - Triptycene 1,2-Quinones and Quinols: Permeable Crystalline Redox-Active Molecular Solids. AB - Suitably designed quinones and quinols are promising modules for the programmed construction of ordered redox-active molecular solids. To explore this potential, we have synthesized compounds 1-4, in which multiple 1,2-benzoquinone and 1,2 quinol units are attached to a triptycene core. The resulting molecules have topologies that disfavor efficient packing, and structural studies show that they crystallize to form open networks held together by characteristic attractive intermolecular forces, including O-H...O hydrogen bonds, C-H...O interactions, pi stacking, and dipolar interactions. Remarkably, the resulting solids are permeable and can undergo reversible redox reactions without loss of crystallinity. Our work may thereby help lead to the design of robust carbon based batteries with electrodes derived from quinones, quinols, and other redox active molecules abundantly produced by nature. PMID- 30430832 TI - Bond Dissociation Triggering Molecular Disorder in Amorphous H2O. AB - We developed a system to deposit H2O molecules onto ultrathin silicon nitride substrates in situ using time-resolved transmission electron diffraction apparatus and performed ultrafast time-resolved electron diffraction measurements in the noncrystalline (amorphous) H2O under near-ultraviolet photoexcitation. The observed dynamics directly represent O-H bond dissociation via multiphoton absorption and charge transfer, which trigger ionization and intermolecular disorder in the amorphous H2O. Our results illustrate the intriguing nature of light-matter and matter-matter interactions in H2O molecules. PMID- 30430833 TI - Selective, Catalytic, and Dual C(sp3)-H Oxidation of Piperazines and Morpholines under Transition-Metal-Free Conditions. AB - By using cheap and innocuous reagents, such as NaClO2, NaOCl, and catalytic amounts of TEMPO, a new environmentally friendly protocol for the selective and catalytic TEMPO C(sp3)-H oxidation of piperazines and morpholines to 2,3 diketopiperazines (2,3-DKP) and 3-morpholinones (3-MPs), respectively, has been developed. This novel direct access to 2,3-DKP from piperazines provides significant advantages over the traditional N-monoacylation/intramolecular C-N cyclization procedure. Additionally, by modulating the amounts of TEMPO, 2 alkoxyamino-3-morpholinone can be prepared from morpholine derivatives, which would enable further functionalization at the C2 position of the morpholine skeleton. PMID- 30430834 TI - Autonomous Damage Detection in Multilayered Coatings via Integrated Aggregation Induced Emission Luminogens. AB - Detection and assessment of small-scale damage at early stages are essential for polymeric materials to extend lifetime, avoid catastrophic structural failure, and improve cost-efficiency. Previous self-reporting coatings provide visual indication of surface damage but have been limited to a single layer without information on the depth of crack penetration. Here, we present a novel strategy for autonomous indication of damage in multilayered polymeric materials using aggregation-induced emission luminogens (AIEgens). Three different AIEgens are encapsulated and layered into polymeric coatings. When scratches of varying depths penetrate the coating layers, different combinations of AIEgens are activated to visually detect the depth of damage based on the corresponding fluorescent colors. The AIEgen-based detection mechanism makes this system a powerful tool for damage indication in a variety of polymeric coatings. PMID- 30430836 TI - Ubiquity of cis-Halide -> Isocyanide Direct Interligand Interaction in Organometallic Complexes. AB - We recently reported a density functional theory (DFT) analysis of the Nb(V)-C bond in various NbCl5(L) complexes, discovering that the carbon ligand L receives electronic density from the metal (classical back-donation) and from the chlorides in the cis position (direct interligand interaction). Here we report the synthesis and the structural characterization of two new coordination compounds of niobium pentahalides, i.e., NbX5(CNXyl) (X = Cl, Br; Xyl = 2,6 C6H3Me2), and the corresponding DFT analyses of the Nb(V)-C bond using the Natural Orbitals for Chemical Valence-Charge Displacement (NOCV-CD) approach, confirming the presence of a cis-halide -> isocyanide direct interligand interaction. To verify whether the latter is limited to Nb complexes or not, we performed a NOCV-CD analysis on a series of several organometallic complexes based on Ti(IV), Nb(V), Ta(V), Rh(III), Pd(II), and Au(III), all of which bear one halide ligand and m-xylyl-isocyanide in a mutual cis position, revealing that the cis-halide -> isocyanide interaction is always present. PMID- 30430835 TI - Switching the Spin State of Pentafluorophenylnitrene: Isolation of a Singlet Arylnitrene Complex. AB - The chemistry of arylnitrenes is dominated by their triplet ground states and excited open-shell singlet states. This results in radical-type reactions and unwanted rearrangements, which diminish the use of arylnitrenes as intermediates in organic synthesis. While the closed-shell singlet states of arylnitrenes are expected to undergo useful chemical transformations (comparable to the closed shell singlet states of carbenes), these states are too high in energy to be chemically accessible. When triplet pentafluorophenylnitrene is interacting with the Lewis acid BF3 under the conditions of matrix isolation, a Lewis acid-base complex consisting of the closed-shell singlet state of the nitrene and two molecules of BF3 is formed. Although the closed-shell singlet state of pentafluorophenylnitrene is calculated (CCSD(T)) to lie more than 25 kcal/mol above its triplet ground state, the reaction with BF3 results in switching the spin state from triplet to singlet. The formation of the singlet complex was monitored by IR, UV-vis, and EPR spectroscopy. DFT, CCSD(T), and CASPT2 calculations confirm the experimental findings. PMID- 30430837 TI - Binding-Induced DNA Dissociation Assay for Small Molecules: Sensing Aflatoxin B1. AB - We describe a new fluorescence turn-on sensor for homogeneous detection of aflatoxin B1 (AFB1), a potent low molecular weight mycotoxin. A key innovation is the binding-induced intramolecular interaction involving the following two sets of probes: (1) a gold nanoparticle (AuNP) immobilized with hundreds of assistant oligonucleotides (AO) and dozens of anti-AFB1 monoclonal antibodies (mAb), and (2) the AFB1-BSA antigen conjugated with fluorophore-labeled signal oligonucleotides (SO) that contained a short sequence complementary to AO. Specific binding of AFB1-BSA to the antibody brought the fluorophore very close to the surface of the AuNP through a stable intramolecular hybridization between AO and SO, resulting in efficient quenching of fluorescence. The improved fluorescence quenching substantially reduced the background, due to the binding induced intramolecular hybridization, and improved the signal-to-background ratio by 390%. In the presence of AFB1 in a sample, competitive binding of AFB1 in the sample to the antibodies immobilized on the AuNP caused the release of the fluorophore-labeled AFB1-BSA from the AuNP, turning on fluorescence. A detection limit of 2.3 nM was achieved, which meets the requirement for AFB1 detection at regulatory levels. Analyses of rice samples using this assay showed recoveries of 86-102%. Incorporating appropriate antibody probes could extend the assay to the detection of other small molecules. PMID- 30430838 TI - The changing epidemiological profile of HIV-1 subtype B epidemic in Ukraine. AB - BACKGROUND: While HIV-1 subtype B has caused a large epidemic in the western world, its transmission in Ukraine remains poorly understood. We assessed the genetic diversity of HIV-1 subtype B viruses circulating in Ukraine, characterized transmission group structure, and estimated key evolutionary and epidemiological parameters. METHODS: We analysed 120 HIV-1 subtype B pol sequences (including 46 newly generated) sampled from patients residing in 11 regions of Ukraine between 2002-2017. Phylogenies were estimated using maximum likelihood and Bayesian phylogenetic methods. A Bayesian molecular clock coalescent analysis was used to estimate effective population size dynamics and to date the most recent common ancestors of identified clades. A phylodynamic birth-death model was used to estimate the effective reproductive number (Re) of these clades. RESULTS: We identified two phylogenetically distinct predominantly Ukrainian (>=75%) clades of HIV-1 subtype B. We found no significant transmission group structure for either clade, suggesting frequent mixing among transmission groups. The estimated dates of origin of both subtype B clades were around early 1970s, similar to the introduction of HIV-1 subtype A into Ukraine. Re for Clade 1 was estimated to be 1.42 (95% HPD 1.26-1.56) and 1.69 (95% HPD 1.49-1.84) for Clade 2. DISCUSSION: The subtype B epidemic in the country is no longer concentrated in specific geographical regions or transmission groups. The study results highlight the necessity for strengthening preventive and monitoring efforts to reduce the further spread of HIV-1 subtype B. PMID- 30430839 TI - Evaluating the relationship between adherence to Highly Active Antiretroviral Therapy (HAART) and social and clinical characteristics in Chinese patients with HIV. AB - This study investigated the adherence rate of Highly Active Antiretroviral Therapy (HAART) in patients with HIV infection in China. The research also examined the adherence rate related to demographic and clinical characteristics with these patients. A total of 516 patients with HIV infection were enrolled from the Wuhan Provincial Center for Disease Control and Prevention. Patients reported their one-month HAART adherence rate, as well as their demographic and clinical characteristics. Using the >=95% HAART one-month adherence rate, the patients were divided into an adherence group and a non-adherence group. The two groups were compared to identify differences. Compared to the adherence group (92.2%), the non-adherence patients (7.8%) experienced greater perceived stigma as measured by Berger Stigma Scale, and tended to have more homosexual sexual partners. Logistic regression analyses revealed that having less confidence in HAART treatment (p = 0.04, OR = 0.2, 95% CI = 0.03-0.9) and more homosexual sex partners (p = 0.049, OR = 1.5, 95% CI = 1.0-2.3) were independently associated with HAART non-adherence. More attention should be paid to patients with HIV infection who did not adherence to HAART treatment. Regular screening and psychological and social support should be considered as an intervention with non adherence patients living with HIV. PMID- 30430841 TI - Clinical and Investigative Endocrinology and Diabetes. PMID- 30430840 TI - Vitamin D deficiency and course of frailty in a depressed older population. AB - OBJECTIVE: To study the association between vitamin D levels and frailty, its components and course in a depressed sample. METHODS: Baseline and two-year follow-up data from the depressed sample of the Netherlands Study of Depression in Older persons (NESDO), a prospective observational cohort study, were analyzed. The 378 participants (aged 60-93) had a diagnosis of depression according to DSM-IV criteria. Frailty was defined according to Fried's physical phenotype. 25-OH vitamin D measurement was performed by liquid chromatography - tandem mass spectrometry. Linear and logistic regression analyses were performed, adjusted for covariates. RESULTS: Higher vitamin D levels were cross-sectionally associated with lower prevalence of frailty (OR 0.64 [95%-CI 0.45 - 0.90], p = .010), predicted a lower incidence of frailty among non-frail depressed patients (OR 0.51 [95%-CI 0.26 - 1.00], p=.050), and, surprisingly, the persistence of frailty among frail depressed patients (OR 2.82 [95%-CI 1.23 - 6.49], p=.015). CONCLUSIONS: In a depressed population, higher vitamin D levels were associated with lower prevalence and incidence of frailty. Future studies should examine whether the favorable effect of low vitamin D levels on the course of frailty can be explained by confounding or whether unknown pathophysiological mechanisms may exert protective effects. PMID- 30430842 TI - Completeness of HIV nucleotide sequence ascertainment and its potential impact on understanding HIV transmission - Maryland, 2011-2013. AB - HIV nucleotide sequences generated through routine drug resistance testing (DRT) and reported to Maryland's Molecular HIV Surveillance system are most effective for elucidating transmission patterns and identifying outbreaks if DRT is ordered promptly and sequences are reported completely. Among reported cases of HIV infection newly diagnosed during 2011-2013 in Maryland residents aged >=13 years, we assessed sequence ascertainment completeness. To better understand which populations were most likely to have a sequence, we examined associations between sequence ascertainment and clinical and demographic characteristics. During 2011 2013, 4423 new HIV infection diagnoses were reported; sequences were ascertained for 1282 (29.0%). Among 3267 cases with complete data, odds for having a sequence ascertained were highest for cases in persons living inside Maryland's Central Region with initial CD4 counts <=500 cells/mm3 (adjusted odds ratio [aOR] 2.4, 95% confidence interval [CI] 1.9-3.1). Sequence ascertainment did not vary significantly by patient age, sex, race/ethnicity or HIV transmission category. Educational interventions, policy changes and improved processes to increase timely DRT and subsequent sequence reporting with a focus on testing at entry to care, particularly for those with higher CD4 counts and those living outside the Central Region, might improve ascertainment completeness. PMID- 30430843 TI - Moderate to high levels of pre-treatment HIV drug resistance in KwaZulu-Natal Province, South Africa. AB - INTRODUCTION: There is evidence of increasing levels of pre-treatment HIV drug resistance (PDR) in Southern Africa. We used data from two large population-based HIV surveillance studies to estimate prevalence of PDR in KwaZulu-Natal, the province with the highest HIV prevalence in South Africa. METHODS: Sanger sequencing was performed on samples obtained from a longitudinal HIV surveillance programme (study A, 2013-2014) and the HIV Incidence Provincial Surveillance System (study B, 2014-2015). Sequences were included for adult HIV positive participants (age >=15 years for study A, age 15-49 years for study B) with no documented prior exposure to ART. Overall and drug class-specific PDR was estimated using the World Health Organization 2009 surveillance drug resistance mutation (SDRM) list and phylogenetic analysis was performed to establish evidence of drug resistance transmission linkage. RESULTS: One thousand eight hundred and forty-five (1845) sequences were analysed (611 study A; 1234 study B). An overall PDR prevalence of 9.2% (95% confidence interval (CI): 7.0-11.7) was observed for study A and 11.0% (95% CI 8.9-13.2) for study B. In study B, the prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) PDR exceeded 10% for sequences collected in 2014 (10.2%, 95% CI 7.5-12.9). The most prevalent SDRMs were K103NS (7.5%), M184VI (2.4%) and V106AM (1.4%). There was no evidence of large transmission chains of drug-resistant virus. CONCLUSION: High level NNRTI-PDR (>10%) suggests a need to modify the standard first-line ART regimen and to focus attention on improving the quality of HIV prevention, treatment and care. PMID- 30430844 TI - Quantifying differences between passive and task-evoked intrinsic functional connectivity in a large-scale brain simulation. AB - Establishing a connection between intrinsic and task-evoked brain activity is critical because it would provide a way to map task-related brain regions in patients unable to comply with such tasks. A crucial question within this realm is to what extent the execution of a cognitive task affects the intrinsic activity of brain regions not involved in the task. Computational models can be useful to answer this question because they allow us to distinguish task from non task neural elements while giving us the effects of task execution on non-task regions of interest at the neuroimaging level. The quantification of those effects in a computational model would represent a step towards elucidating the intrinsic versus task-evoked connection. Here we used computational modeling and graph theoretical metrics to quantify changes in intrinsic functional brain connectivity due to task execution. We used our Large-Scale Neural Modeling framework to embed a computational model of visual short-term memory into an empirically derived connectome. We simulated a neuroimaging study consisting of ten subjects performing passive fixation (PF), passive viewing (PV) and delay match-to-sample (DMS) tasks. We used the simulated BOLD fMRI time-series to calculate functional connectivity (FC) matrices and used those matrices to compute several graph theoretical measures. After determining that the simulated graph theoretical measures were largely consistent with experiments, we were able to quantify the differences between the graph metrics of the PF condition and those of the PV and DMS conditions. Thus, we show that we can use graph theoretical methods applied to simulated brain networks to aid in the quantification of changes in intrinsic brain functional connectivity during task execution. Our results represent a step towards establishing a connection between intrinsic and task-related brain activity. PMID- 30430845 TI - Are Dietitians Documenting Malnutrition Based on Subjective Global Assessment Category? AB - PURPOSE: This study reports on dietitian use of the Nutrition Care Process Terminology (NCPT) diagnosis of malnutrition based on Subjective Global Assessment (SGA). METHODS: Nutrition assessment reports for adults in medical, surgical, and cardiac units in 13 Canadian hospitals were retrospectively examined for a 6-week period in 2014. Reports with a SGA and NCPT diagnosis were included regardless of why the patient was seen by the dietitian. RESULTS: Of the 932 nutrition assessment reports, 857 (92%) included an SGA. Based on SGA, the prevalence of mild to moderate malnutrition (SGA B) and severe malnutrition (SGA C) was 53.4% (n = 458) and 10.0% (n = 86), respectively. When categorized as severely malnourished, the most common NCPT diagnoses were "malnutrition" (n = 55, 72.4%), "inadequate oral intake" (n = 11, 14.5%), and "inadequate protein energy intake" (n = 10,13.1%). Among those with SGA B and C, the assignment of the NCPT malnutrition diagnosis was 19.8% (n = 95). CONCLUSIONS: Dietitians play a key role in the prevention, identification, and treatment of malnutrition in the hospitalized patient and are well positioned to take a leadership role in improving its documentation. Ongoing audits, staff support, and training regarding NCPT use may improve the application of the malnutrition diagnosis. Future research examining dietitian barriers to using the malnutrition diagnosis would be valuable. PMID- 30430846 TI - Performance and function meet structure: A white matter connection tuned for vocal production. AB - Contemporary imaging techniques have increased the potential for establishing how brain regions interact during spoken language. While some imaging methods report bilateral changes in brain activity during speech, another approach finds that the relationship between individual variability in speech measures and individual variability in brain activity more closely resembles clinical observations. This approach has repeatedly demonstrated that speaking rate for phonological and lexical items can be predicted by an inverse relationship between cerebral blood flow in the left inferior frontal region and the right caudate nucleus. To determine if morphology contributes to this relationship, we examined ipsilateral and contralateral white matter connections between these structures using diffusion tensor imaging, and further assessed possible relationships between morphology and selected acoustic measures of participants' vocal productions. The ipsilateral connections between the inferior frontal regions and the caudate nuclei had higher average fractional anisotropy and mean diffusivity values than the contralateral connections. Neither contralateral connection between inferior frontal and caudate regions showed a significant advantage on any of the average morphology measures. However, individual differences in white matter morphology were significantly correlated with individual differences in vocal amplitude and frequency stability in the left frontal-right caudate connection. This cortical striatal connection may be "tuned" for a role in the coordination of cortical and subcortical activity during speech. The structure-function relationship in this cortical-subcortical pathway supports the previous observation of a predictive pattern of cerebral blood flow during speech and may reflect a mechanism that ensures left-hemisphere control of the vocal expression of propositional language. PMID- 30430847 TI - Later-life trajectories of cognitive functioning among immigrants of Mexican origin: implications of age at immigration and social resources. AB - OBJECTIVE: This study examines age-at-immigration disparities in later-life trajectories of cognitive functioning among immigrant men and women of Mexican descent. This study also considers the role of socioeconomic resources, family status, and church attendance in these disparities. METHODS: This study draws on eight waves of the Hispanic Established Populations for the Epidemiologic Study of the Elderly and employs growth curve models. This study distinguished between immigrants who moved from Mexico to the U.S. in early life (before age 19), midlife (between ages 20 and 49; reference category), and late life (beyond age 50). The analyses were conducted separately for men and women. The final analytic sample consisted of 2,030 repeated observations from 639 men and 2,883 observations from 884 women. RESULTS: Compared to midlife immigration, late-life immigration was associated with lower cognitive functioning at baseline among both men and women, whereas early- as well as late-life immigration was related to faster cognitive decline over time only among men. Adjusting for socioeconomic resources reduced cognitive disadvantages among late-life immigrants, regardless of gender. Family status also partially accounted for poorer cognitive functioning among late-life immigrant women. CONCLUSION: This study demonstrates that later-life cognitive functioning among immigrant men and women of Mexican descent might be contingent on age at immigration. By highlighting the importance of individuals' social resources for overall cognitive functioning and for age-at immigration disparities, this study also suggests that social programs and interventions to improve cognitive health in this population group should address later-life disadvantages related to low educational attainment, being unmarried, and less frequent religious participation. PMID- 30430848 TI - Diversity and Equity in Dietetics and Undergraduate Nutrition Education in Manitoba. AB - PURPOSE: The objectives of this study were (i) to describe ethnicity, tuition funding sources, and living arrangements during degree among Registered Dietitian (RD) and non-RD alumni of the University of Manitoba's undergraduate nutrition program and (ii) to describe barriers to obtaining an internship among those who did not become an RD. METHODS: A 31-item, self-administered, online questionnaire was distributed to nutrition graduates. Binary logistic regression was used to test for predictors of RD status (vs. non-RD). RESULTS: Of the 195 participants who completed the survey (37% response rate), 68% identified as an RD and 31% did not. White students had 3.8 times higher odds of being an RD (P < 0.001) compared with students of an ethnic minority. Those who had received a student loan (P = 0.033) or lived with their parents during their degree (P = 0.004) also had significantly lower odds of being an RD. The most common barrier for not completing the dietetic internship by non-RDs was that the application process was too stressful. CONCLUSIONS: Results from this study highlight the need for the dietetics field to address systemic barriers for students of ethnic minorities and low socioeconomic backgrounds, including barriers during the degree program and in the internship selection process. PMID- 30430849 TI - Is greenery associated with mental health among residents of aged care facilities? A systematic search and narrative review. AB - OBJECTIVES: Older adults living in residential aged care facilities (RACFs) may be vulnerable to mental health issues. Evidence suggests greenery is beneficial for adults' mental health in community settings. This review aims to summarise evidence of associations between greenery in RACFs and residents' mental health. METHOD: Six databases were searched with three sets of terms related to: (1) exposure (e.g. garden, green); (2) outcome (e.g. mental health, well-being); and (3) setting (e.g. aged care, nursing home). The inclusion criteria were peer reviewed journal articles published in English up to 2017, reporting quantitative/qualitative associations between greenery and mental health in RACFs. RESULTS: Of the nine articles identified, seven reported positive associations between greenery (in particular, garden use) at RACFs and some aspect of residents' mental well-being (e.g. quality of life); however, four out of seven studies used observations and perceptions of staff and relatives. One study examined depression and reported reduction in depression following garden use, while one examined physiological indicators of stress (blood pressure, heart rate) and found no association with garden use. Seven studies examined garden use and four examined the presence of greenery (two examined both exposures). CONCLUSION: Exposure to greenery and use of greenspace in RACFs show promise for promoting mental health. However, the findings relied mainly on non-validated measures of mental health. More robust evidence based on valid and reliable mental health measures is needed. Future studies also need to examine the effect of visual exposure to greenery and the effect of greenery on stress reduction. PMID- 30430851 TI - Nutrition Care of Critically Ill Patients with Leukemia: A Retrospective Study. AB - Adults with acute leukemia (AL) are at high risk of malnutrition due to their disease and treatment side effects and may be admitted to the intensive care unit (ICU), further increasing the risk of malnutrition. Although ICU care includes some form of nutrition, patients typically receive less than prescribed energy and protein. Our objective was to characterize the nutrition care for critically ill patients with AL. We completed a retrospective review of adults with AL admitted to the Medical/Surgical ICU >24 hours. Descriptive statistics were performed on collected data including: demographics, APACHE II and Nutric scores, nutrition therapy, reasons for withholding nutrition, and mortality status at discharge. Data were collected on 154 AL patients with an average APACHE II score of 27 and Nutric score of 5.96. ICU mortality was 36%. Enteral nutrition (EN) was most commonly prescribed. Patients on EN received 55% of energy and 51% of protein prescribed. EN was commonly withheld for airway management and gastrointestinal impairment. Patients with AL received low amounts of energy and protein in the ICU and had a high Nutric score. Strategies and barriers to improve protein intake in this population are identified. PMID- 30430850 TI - Fear of falling and emotional regulation in older adults. AB - OBJECTIVES: Fear of falling is common amongst older adults with and without a prior experience of falling. It is related to decreased quality of life, isolation, and institutionalisation. It also poses a risk for future falls when activity is avoided because of fear of falling and muscle deconditioning occurs. Relatively little is known about the psychological factors underpinning fear of falling. This study explored the relationship between emotion regulation and fear of falling in community dwelling older adults. METHOD: A sample of 117 older adults (>65 years) were recruited from community based exercise classes, falls reduction classes, NHS and charity organisations. Self-reported measures included the Falls Efficacy Scale-International (FES-I), the Fear of Falling Behaviour Questionnaire (FFABQ), the Difficulties in Emotion Regulation Scale (DERS) and the Hospital and Anxiety Depression Scale (HADS). RESULTS: A significant positive correlation was found between emotion regulation and fear of falling, as well as between emotional regulation and fear-related avoidance behaviour. A regression model found that after controlling for depression and age, emotion regulation was no longer significantly related to fear of falling. CONCLUSIONS: Fear of falling is associated with emotion regulation difficulties in community dwelling older adults. However, this link no longer exists once depression is controlled for. The key clinical implication is the importance of the assessment of depression in older adults with a fear of falling. Future research should use a longitudinal design to further unpick the causal relationships between these variables. PMID- 30430852 TI - Kaurenoic acid and its sodium salt derivative: antibacterial activity against Porphyromonas gingivalis and their mechanism of action. AB - AIM: To evaluate the antibacterial activity of 12 kaurane-type diterpenes against a panel of bacteria that cause endodontic infection. METHODS & MATERIALS: We conducted tests against bacteria in the planktonic or in the sessile mode, cytotoxic assays for the most promising compounds against human normal lung fibroblast cells, and Porphyromonas gingivalis (ATCC 33277) proteomic analysis. RESULTS & CONCLUSION: Kaurenoic acid and its salt exhibited satisfactory antibacterial action against the evaluated bacteria. Proteomic analysis suggested that these compounds might interfere in bacterial metabolism and virulence factor expression. Kaurane-type diterpenes are an important class of natural products and should be considered in the search for new irrigating solutions to treat endodontic infections. PMID- 30430853 TI - Histopathologic Features of Chronic Sinusitis Precipitated by Odontogenic Infection. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a heterogeneous disease process that can arise in the context of odontogenic disease from the maxillary teeth. The histopathologic features of odontogenic CRS (CRSo) have yet to be determined and may have important implications on disease management and need for escalation of therapy. OBJECTIVES: The objectives of this study are to characterize the histopathologic features of CRSo and determine whether the inflammatory profile of CRSo contributes to its recalcitrance to medical therapy and need for surgery in a subset of patients with this disease. METHODS: A structured histopathology report was used to analyze sinus tissue removed during functional endoscopic sinus surgery (FESS). Histopathology variables, Lund-Mackay scores (LMS), and Sinonasal Outcome Test-22 scores were compared among CRSo patients, CRS without nasal polyps (CRSsNP) patients, and CRS with nasal polyps (CRSwNP) patients. RESULTS: Twenty-three CRSo, 38 CRSwNP, and 53 CRSsNP patients who underwent FESS were analyzed. Compared to CRSsNP, CRSo exhibited increased moderate-severe inflammation (73.9% vs 41.5%, P < .009). Compared to CRSwNP, CRSo had decreased squamous metaplasia (0.0% vs 18.4%, P < .03) and decreased fibrosis (26.1% vs 63.2%, P < .005). Eosinophilia was prevalent in CRSo but to a lesser extent than in CRSwNP (39.1% vs 63.2%, P < .05). CRSo cases had significantly lower mean LMS compared to CRSwNP (7.83 +/- 2.77 vs12.18 +/- 6.77, P < .005). CONCLUSION: CRSo exhibits histopathologic features similar to those of CRSsNP with more severe inflammation. Moreover, eosinophilia, which is not typically considered to coexist with CRSo, was present in a large portion of CRSo patients. These findings may help explain at the inflammatory level why select cases of CRSo may be recalcitrant to medical and dental therapy. PMID- 30430854 TI - The Predictive Value of Preoperative High-Sensitive C-Reactive Protein/Albumin Ratio in Systemic Inflammatory Response Syndrome after Percutaneous Nephrolithotomy. AB - Objective The aim of the study was to evaluate the predictive value of preoperative high-sensitive C-reactive protein/albumin (hs-CRP/Alb) ratio in systemic inflammatory response syndrome (SIRS) after percutaneous nephrolithotomy (PCNL). Materials and Methods We retrospectively reviewed 556 patients who underwent PCNL at our institution between August 2015 and February 2018. The primary endpoint for the study was the development of SIRS after operation. A univariate and multivariate logistic regression analysis was used to identify the independent factors associated with the post-PCNL SIRS. Receiver operating characteristic (ROC) curves were constructed and the areas under the curve (AUC) werewas calculated to compare the discriminatory ability of the systemic inflammation biomarkers. Results Among the 556 patients who underwent PCNL, 123 patients(22.1%) developed to SIRS. Multivariate analysis revealed that female gender (OR 1.691 95%CI 1.045-2.735 P=0.032), positive urine culture (OR 1.972 95%CI 1.204-3.231 P<0.01), hs-CRP/Alb ratio (OR 6.925 95%CI 4.244-11.300 P<0.01), NLR (OR 2.476 95%CI 1.471-4.167 P<0.01), PNI (OR 0.559 95%CI 0.338-0.924 P=0.023) were independent predictors of post-PCNL SIRS. The optimal cutoff value of the hs CRP/Alb ratio was 0.06 from the ROC analysis. The elevated hs-CRP/Alb ratio was significantly associated with female gender, positive urine culture, hs-CRP, albumin, leukocyte, neutrophil, monocyte, platelet, hemoglobin, creatinine, NLR, LMR, PLR, PNI, hs-mGPS, development of sepsis, ICU admission and length of stay (all P<0.05). Additionally, the hs-CRP/Alb ratio had a higher AUC (0.791) with a sensitivity of 76.4% and a specificity of 73.2% than NLR(0.669), LMR(0.633), PLR(0.594), PNI(0.629) and Hs-mGPS(0.739). Conclusions The preoperative hs CRP/Alb ratio is independently predictive for the development of SIRS after PCNL. Moreover, compared with other systemic inflammation biomarkers, the preoperative hs-CRP/Alb ratio shows better predictive value. PMID- 30430855 TI - The Impact of Canadian School Food Programs on Children's Nutrition and Health: A Systematic Review. AB - The quality of children's diets has declined over the past few decades, giving rise to a variety of health-related consequences. In response to this trend, school food programs have become an increasingly effective method to support nutrition and lifelong healthy eating habits. This systematic review synthesizes current academic literature pertaining to school nutrition programs in Canada to identify existing interventions and their impacts on children's nutritional knowledge, dietary behaviour, and food intake. The review was conducted through a search of the following databases: ERIC, Education Source, CINAHL, PubMed, SagePub, SCOPUS, EMBASE, and CBCA. Information extracted from the articles included the program objectives, intervention design and components, research evaluation, and primary outcomes. A total of 11 articles evaluating Canadian school nutrition programs were identified. The programs incorporated a variety of intervention components including policy, education, family and community involvement, and/or food provision. These multi-component interventions were positively associated with children's development of nutrition knowledge, dietary behaviour changes, and intake of healthy foods; however, barriers associated with intervention duration, intensity, and availability of resources may have influenced the extent to which these programs impacted children's diets and overall health. PMID- 30430857 TI - Evaluation of a Patient Experience Tool in Dietetic Practice: Validation and Clinical Usage of the Assessment of Registered Dietitian Care Survey (ARCS). AB - PURPOSE: The study aim was to evaluate a patient experience survey, the Assessment of Registered Dietitian Care Survey (ARCS), that is aligned with a nutrition counselling approach (NCA) and evidence-based chronic disease care for use in outpatient registered dietitian (RD) practice. METHODS: Criterion and construct validity were examined using Pearson correlation coefficients and principal components analyses, respectively. Reliability was examined using Pearson correlations and Cronbach's alpha. Acceptability was evaluated by survey response rate and readability. Kruskall-Wallis test was used to detect differences between RD scores. RESULTS: A total of 479 survey packages were returned (46% response rate). Criterion validity indices were high (r = 0.91 and 0.94, P < 0.001) between Patient Assessment of Chronic Illness Care (PACIC) and NCA subscales, respectively, and lower with overall patient satisfaction (r = 0.63-0.65, P < 0.001). Construct validity revealed 2 factors for PACIC and NCA subscales. There was high internal reliability for the PACIC, 5As, and NCA (Cronbach's alpha > 0.7) and test-retest reliability showed an adequate consistency over time (r = 0.70, P < 0.05). The tool was able to detect differences in scores between RDs (P < 0.05). CONCLUSIONS: More research is warranted to explore ceiling effects and sensitivity to intervention in similar practice settings. The NCA subscale has acceptable reliability and validity to measure patient experience of RD care. PMID- 30430856 TI - Perceived Age Discrimination and Job Satisfaction Among Older Employed Men in Japan. AB - The present study examined the additive effects of age discrimination, as well as the buffering effects of psychosocial resources in reducing the negative impact of age discrimination on job satisfaction, among older employed men in Japan. Data were obtained from a national survey administered in 2016 to a probability based sample of men aged 55 to 64 years ( n = 514). The results indicated that perceived age discrimination at work was associated with a lower level of job satisfaction. Moreover, a high level of social support from supervisors and coworkers decreased the negative impact of perceived age discrimination on job satisfaction. Our findings suggest that organizational-level interventions might be necessary to mitigate age discrimination and increase social support for keeping older employees in the workforce beyond their conventional retirement age. PMID- 30430858 TI - Exploring the experience of the disclosure of a dementia diagnosis from a clinician, patient and carer perspective: a systematic review and Meta ethnographic synthesis. AB - OBJECTIVES: The objective of this review was to identify, appraise and synthesise qualitative research that explores the experience of the disclosure of a dementia diagnosis from the perspectives of clinicians, patients and carers. METHOD: A systematic search of four databases, grey literature and reference lists identified 13 studies, which met the required criteria to be included in the review. All were appraised using a quality appraisal tool. Data were extracted and synthesised using a meta-ethnographic approach. RESULTS: Five key themes were developed from an interpretation of the results: the clinician's approach; how to tell people the diagnosis is dementia; the importance of the clinician offering hope; level of understanding; and who should attend the disclosure meeting. The process can be improved through a compassionate clinician offering hope, answers to patient and carer questions, and written and/or visual information to support understanding of the diagnosis. These features could be included in guidance to clinicians. There was a large amount of variance in the quality of the studies. Future qualitative research could focus on clinician compassion, giving hope, the management of dynamics within sessions, supporting information and follow-up sessions. CONCLUSION: Clinical practice can be informed by a body of literature but there is much work to be done to develop evidence-based detailed guidance for improving the dementia diagnosis experience for all parties, and supporting clinicians to manage inherent tensions in this process. Further research is required on this topic to addresses the shortcomings highlighted in this review. PMID- 30430859 TI - Employment Outcomes among Registered Dietitians following Graduation in Manitoba. AB - PURPOSE: The study objectives were to (i) describe employment outcomes among Registered Dietitians (RDs) who graduated from the University of Manitoba, (ii) test for differences in employment outcomes according to graduation year, and (iii) compare preferred area of practice and geography prior to employment with past and current employment. METHODS: Graduates of the Human Nutritional Sciences program (2006-2015) were invited to participate in an online survey. Data on respondent demographics, education, and employment outcomes were collected. RESULTS: Overall, 133 (68%) respondents self-identified as RDs. RDs who had graduated between 2006 and 2011 were significantly more likely to secure employment within 6 months post-graduation compared with RDs that graduated between 2012 and 2015. Geographically, although 56% of RDs did not wish to gain experience in rural/remote communities upon graduating, 44% of these respondents reported working part- or full-time in a rural/remote location at some point during their career. CONCLUSION: Findings indicate that a substantial number of RDs in Manitoba are employed in a rural or remote location despite acknowledging that it is not a preferred location. Future research is needed to explore the views and experiences of new and established RDs toward rural or remote practice, including preparedness for practice. PMID- 30430860 TI - Exploring Nutrition Labelling of Food and Beverages in Vending Machines in Canadian Recreational Sport Settings. AB - PURPOSE: To evaluate whether interpretive "health" labels placed in vending machines in recreation centres represented products' nutrient content when compared with provincial nutrition guidelines. METHODS: A cross-sectional audit (November 2015 - April 2016) of 139 vending machines in recreation facilities found 525 foods and beverages in 17 machines labelled by vendors according to healthfulness. Product nutrient content was compared with provincial nutrition guideline criteria. Cross-tabulation and weighted Cohen's kappa evaluated agreement between vendor interpretive labels and guideline ranks. Descriptive statistics evaluated how mislabelled products deviated from recommended nutrient content. Mann-Whitney tests compared nutrient content of "healthy" and "unhealthy" labelled products. RESULTS: Almost one-third of all products were mislabelled by vendors with 72% of those labelled healthier than their actual guideline rank. Energy, total fat, sugar, and sodium contents exceeded recommended levels in one-third to one-half of mislabelled products. Overall, products labelled healthy by vendors were significantly lower in energy, sodium, and fat compared with those labelled unhealthy; however, not for all food types (e.g., bars, fruit snacks, nuts). CONCLUSIONS: For certain product categories, vendor interpretive nutrition labels poorly represented products' nutrient content according to provincial nutrition guidelines. Dietitians may be a valuable resource to help implement nutrition guidelines to create credible interpretive product labelling systems. PMID- 30430861 TI - Reducing demand for ineffective health remedies: overcoming the illusion of causality. AB - OBJECTIVE: We tested a novel intervention for reducing demand for ineffective health remedies. The intervention aimed to empower participants to overcome the illusion of causality, which otherwise drives erroneous perceptions regarding remedy efficacy. DESIGN: A laboratory experiment adopted a between-participants design with six conditions that varied the amount of information available to participants (N = 245). The control condition received a basic refutation of multivitamin efficacy, whereas the principal intervention condition received a full contingency table specifying the number of people reporting a benefit vs. no benefit from both the product and placebo, plus an alternate causal explanation for inefficacy over placebo. MAIN OUTCOME MEASURES: We measured participants' willingness to pay (WTP) for multivitamin products using two incentivized experimental auctions. General attitudes towards health supplements were assessed as a moderator of WTP. We tested generalisation using ratings of the importance of clinical-trial results for making future health purchases. RESULTS: Our principal intervention significantly reduced participants' WTP for multivitamins (by 23%) and increased their recognition of the importance of clinical-trial results. CONCLUSION: We found evidence that communicating a simplified full contingency table and an alternate causal explanation may help reduce demand for ineffective health remedies by countering the illusion of causality. PMID- 30430862 TI - Trajectories of public psycho-behavioural responses relating to influenza A(H7N9) over the winter of 2014-15 in Hong Kong. AB - OBJECTIVE: To explore trajectories of public psycho-behavioural responses over one influenza A(H7N9) epidemic wave, and examine the interplays among social norm influence, disease worry and protective behaviours. METHODS: Participants were 464 adults who completed the baseline and at least two follow-up assessments on their H7N9-related Perceived Susceptibility, Perceived Severity, Perceived Efficacy, Worry, Social Norms influence and Protective Behaviours in a five-phase longitudinal survey over one H7N9 epidemic wave. Latent growth modelling (LGM) identified trajectories of these psycho-behavioural responses while multi-process LGM examined the inter-relationships among trajectories of Social Norms influence, Worry and Protective Behaviours. RESULTS: Trajectories of Perceived Susceptibility, Worry, Social Norms and Protective Behaviours increased initially but declined as the epidemic decayed, while Perceived Severity increased linearly and Perceived Efficacy remained stable across the epidemic. Change in Social Norms influence was significantly associated with change in Worry (beta = 0.65) which was significantly associated with change in Protective Behaviours (beta = 0.62). CONCLUSION: The public's threat appraisal but not efficacy appraisal may have been well-informed by epidemic-related information. Social Norms may be important contributors of public emotional response to an epidemic. Communication via social networks during an epidemic could be important for regulating public emotional response and guiding their behavioural change. PMID- 30430863 TI - Decomposing the within-person and between-person sources of variation in physical activity-cognition associations for low-active older adults. AB - OBJECTIVES: To examine within-person and between-person sources of variation in the relationship between physical activity and cognition in older adults participating in a walking program. To explore whether demographic, health and fitness variables, and their interactions with activity, are significant predictors of cognition. DESIGN: Brief longitudinal burst design. PARTICIPANTS: 118 participants (91 females, mean age = 72.81 + 5.24 years). MAIN OUTCOME MEASURES: Cognition, self-reported moderate-to-vigorous walking and self-reported moderate-to-vigorous physical activity were assessed at baseline and 6, 9, 12 and 16 weeks follow-up. Attendance at weekly walks was also recorded. RESULTS: Within persons, changes in physical activity were related to select measures of executive functioning, with increased activity predictive of better cognition (three of four cognitive functions, p<.05). Between-persons, activity was also associated with cognition (two of four cognitive functions, p<.05). Younger age and higher education were related to better cognition. Interactions of demographic, health, and fitness variables with changes in within-person activity were generally non-significant. CONCLUSION: The results highlight the importance of distinguishing within- from between-person effects in longitudinal analyses of the association between physical activity and cognition. This stringent within person test of association underscores the potential value of simple physical activity interventions for improving cognitive function. PMID- 30430864 TI - Neutrophil-to-lymphocyte ratio is superior to platelet-to-lymphocyte ratio as a prognostic predictor in advanced non-small-cell lung cancer treated with first line platinum-based chemotherapy. AB - AIM: We aimed to investigate the prognostic impact of the neutrophil-to lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in advanced non small-cell lung cancer treated with first-line platinum-based chemotherapy and determine which of the two was a better predictor of prognosis. MATERIALS & METHODS: We conducted multivariate Cox regression analysis to assess the independent effects of the NLR and PLR on patient survival. RESULTS: In multivariate Cox regression analysis, the NLR was an independent risk factor predicting poor prognostic factor (HR: 2.464; 95% CI: 1.305-4.652; p = 0.005) and overall survival (HR: 1.954; 95% CI: 1.172-3.257; p = 0.01); however, the PLR was not a prognostic factor (progression-free survival; p = 0.105; overall survival; p = 0.239). CONCLUSION: The NLR was a better prognostic indicator than the PLR for advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy. PMID- 30430866 TI - RE: Inclusive Dietetic Practice. PMID- 30430865 TI - Young adults' barriers and enablers to healthy eating. PMID- 30430867 TI - Epidemiology of amyotrophic lateral sclerosis in Friuli-Venezia Giulia, North Eastern Italy, 2002-2014: a retrospective population-based study. AB - OBJECTIVES: To describe the epidemiology of Amyotrophic Lateral Sclerosis (ALS) in Friuli-Venezia Giulia (FVG) region, Italy, over a 13-year period (2002-2014), estimating ALS (a) incidence, prevalence, and clinical features; (b) mortality, also comparing Udine municipality to the rest of FVG. METHODS: We conducted a retrospective population-based study. ALS incident cases were ascertained using multiple sources and validated through expert review. We calculated crude and standardized incidence rate (IR), point prevalence and mortality rate (MR), each with 95% confidence interval. Standardized incidence (SIR) and mortality (SMR) ratio were calculated to compare Udine to FVG. RESULTS: Among 444 incident cases (50.0% men, median age 68.5 years), onset was bulbar in 30.2%, spinal in 59.9%, mixed in 9.9%; 3.6% had familial ALS. Crude and 2000 European population standardized IR was respectively 2.81 (2.56-3.09) and 2.09 (1.89-2.29) per 100,000 person-years. Standardized male-to-female incidence ratio was 1.05. IR peaked at age 65-74 years (men: 9.93, 8.04-12.32; women: 7.74, 6.18-9.67) and decreased thereafter. Prevalence was 8.36 (6.74-9.97) cases per 100,000 inhabitants on 30 June 2009 and 7.98 (6.40-9.56) on 30 June 2014. SIR was 1.20 and SMR 1.11. CONCLUSIONS: When assessed over a long period, incidence of ALS was in the range of Italian and European population-based registries and showed a consistent pattern by age and sex. IR and MR were only slightly higher in Udine vs. FVG. PMID- 30430869 TI - Research on the Effects of Levetirasetam in Spinal Cord Injury Model. PMID- 30430868 TI - Wish to die and reasons for living among patients with amyotrophic lateral sclerosis. AB - OBJECTIVE: In Amyotrophic lateral sclerosis (ALS), disease severity, ineffective treatment, and increasing dependence on caregivers may give rise to hopelessness and suicidal ideation among patients. In clinical practice, the desire for death among patients with ALS often accompanies the desire to live and fear of death. Thus, we decided to study suicidal ideation among patients with ALS and examine protective factors and reasons for living. METHODS: We conducted a prospective, observational cohort study that recruited patients during routine visits to the outpatient multidisciplinary reference center for ALS. Depression was measured using the Beck Depression Inventory, suicidal ideation was assessed using the Columbia Suicide Severity Rating Scale, and reasons for living were assessed using the Reasons for Living inventory for adults. RESULTS: Among the 71 patients included, 39% expressed either passive (wish to die) or active suicidal ideation. Patients who expressed suicidal ideation were more likely to report depressive symptoms and have worse disability scores. A significant difference in the survival and coping beliefs subscore of the RFL inventory, which was negatively associated with suicidal ideation, had been found between those who did and did not have suicidal ideation. CONCLUSION: These findings have stressed the need for caregivers to recognize depression and other distressing expressions as well as provide adequate treatment. Therefore, close attention should be given to those suffering from depression while providing optimal care in terms of not only drug treatment but also psychological support. PMID- 30430870 TI - Chromones: privileged scaffolds for the production of multi-target-directed ligand agents for the treatment of Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder responsible for the great majority of age-related dementias affecting daily life through memory loss and cognitive impairment. From a molecular point of view, the most common neuropathological characteristics found in AD patients are abnormal protein deposits, particularly senile plaques (SP) and neurofibrillary tangles (NFT). Furthermore, the currently available pharmacological treatment only provides short-term improvements and is focused on the use of cholinesterase (ChEs) inhibitors or memantine, an approved medicine that is a glutamatergic N-methyl-D-aspartate (NMDA) receptor blocker. Areas covered: This review is focused on the relevance of chromones for future AD treatment. Structure-activity relationship (SAR) studies which look at the inhibition of amyloid-beta (Abeta) plaque formation and aggregation and the inhibition of both acetylcholinesterase (AChE) and butyrylcholinesterase are also discussed. Expert opinion: SAR studies are a useful strategy for the elucidation of structural features that improve compound-specific AD-related activities. The development of multi-target-directed ligands (MTDLs) represents an exciting challenge for organic chemists. As such, recently developed chromone-type compounds have a potential use as MTDLs for the treatment of AD. PMID- 30430871 TI - Acute kidney injury induced by thrombotic microangiopathy in two cases of Bothrops envenomation. AB - CONTEXT: Bothrops snakes are the most frequent agents of snakebites in South and Central America. Acute kidney injury (AKI) is one of its complications and has multifactorial origin. Thrombotic microangiopathy (TMA)-induced AKI in snakebites is uncommon and is not described in Bothrops envenomation. CASE DETAILS: We report two cases of patients bitten by young Bothrops jararaca who developed AKI induced by TMA. Both patients evolved with mild envenomation and received the specific antivenom within 4 h after the snakebite. None of them had hypotension or shock, bleeding or secondary infection. Patient 1 (P1) was diabetic and using oral hypoglycemic drugs, and patient 2 (P2) was hypertensive without regular use of medication. On admission, both patients had levels of fibrinogen lower than 35 mg/dL, D-dimer higher than 10,000 ng/mL. They evolved with AKI, thrombocytopenia, normal coagulation assays, anemia, lactate dehydrogenase (LDH) elevation, low haptoglobin levels, negative direct antiglobulin test, and presence of schizocytes in peripheral blood. Only P1 required renal replacement therapy, and plasmapheresis was not required. Both patients were discharged and did not require outpatient dialysis, and subsequently had normal creatinine levels. DISCUSSION: TMA may occur in Bothrops jararaca envenomation, even in mild cases that received early specific antivenom. PMID- 30430873 TI - ALSUntangled 46: penicillin G/hydrocortisone. PMID- 30430874 TI - Designer benzodiazepines: a report of exposures recorded in the National Poison Data System, 2014-2017. AB - IMPORTANCE: Exposures to novel psychoactive substances are reported with increasing frequency in both the medical literature and the lay press. While the majority of reports describe synthetic cannabinoids and cathinones, a lesser understood family is the "designer benzodiazepines". The current literature describing human exposures to these compounds is comprised of case reports and small case series. OBJECTIVE: The primary objectives of this study are to describe epidemiologic trends and clinical effects of designer benzodiazepine use. METHODS: Data regarding single agent exposures to designer benzodiazepines between 1 January 2014 and 31 December 2017 was obtained from the National Poison Data System. Substances queried include: adinazolam, clonazolam, cloniprazepam, diclazepam, etizolam, flubromazepam, flubromazolam, meclonazepam, nifoxipam, norflurazepam, and pyrazolam. Data was summarized descriptively. RESULTS: 234 single agent exposures in 40 states were reported during the study period. The annual number of exposures increased each year, from 26 in 2014 to 112 in 2017, amounting to a 330% increase. The most common exposures were etizolam (n = 162) and clonazolam (n = 50). The most common clinical effects were drowsiness/lethargy (65%), and slurred speech (17%). 3% required intubation, 36% of cases required hospital admission, 22% to the intensive care unit. There was 1 death in the study population. CONCLUSIONS: The incidence of exposures to designer benzodiazepines is rising. Clinical effects are generally consistent with a sedative-hypnotic toxidrome. Severe effects, including death, seemed relatively uncommon in the study population. PMID- 30430872 TI - Intramuscular cobinamide versus saline for treatment of severe hydrogen sulfide toxicity in swine. AB - INTRODUCTION: Hydrogen sulfide (H2S) is found in petroleum, natural gas, and decaying organic matter. Terrorist groups have attempted to use it in enclosed spaces as a chemical weapon. Mass casualty scenarios have occurred from industrial accidents and release from oil field sites. There is no FDA approved antidote for sulfide poisoning. We have previously reported that intravenous cobinamide is effective for sulfide poisoning. A rapid-acting antidote that is easy to administer intramuscularly (IM) would be ideal for use in a prehospital setting. In this study, we assessed survival in sulfide-poisoned swine treated with IM cobinamide. METHODS: Eleven swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. After stabilization, anesthesia was adjusted such that animals ventilated spontaneously with a FiO2 of 0.21. Sodium hydrosulfide (NaHS, 8 mg/mL) was infused intravenously at 0.9 mg/kg.min until apnea or severe hypotension. Animals were randomly assigned to receive cobinamide (4 mg/kg), or no treatment at the apnea/hypotension trigger. The NaHS infusion rate was sustained for 1.5 min post trigger, decreased to 0.2 mg/kg.min for 10 min, and then discontinued. RESULTS: The amount of NaHS required to produce apnea or hypotension was not statistically different in both groups (cobinamide: 9.0 mg/kg +/-6.1; saline: 5.9 mg/kg +/-5.5; mean difference: -3.1, 95% CI: -11.3, 5.0). All of the cobinamide treated animals survived (5/5), none of the control (0/6) animals survived (p < .01). Mean time to return to spontaneous ventilation in the cobinamide treated animals was 3.2 (+/-1.1) min. Time to return to baseline systolic blood pressure (+/-5%) in cobinamide-treated animals was 5 min. CONCLUSION: Intramuscular cobinamide was effective in improving survival in this large swine model of severe hydrogen sulfide toxicity. PMID- 30430875 TI - Potential combination topical therapy of anal fissure: development, evaluation, and clinical study?. AB - To treat anal fissure, internal anal sphincterotomy may be associated with surgical risks and incidence of incontinence. Botulinum toxin injection into the anal sphincter is invasive and expensive. Headache and hypotension hindered topical treatment with glyceryl trinitrate. Greater patient compliance, potentiated efficacy, reduced side effects, and lower cost are the major advantages offered by the combination therapy. Therefore, combination topical gels of nifedipine (NIF), lidocaine hydrochloride (LDH) and betamethasone valerate (BMV) were prepared and evaluated regarding viscosity, pH, drug content, and in vitro release. Compatibility study of drug-drug and drug-excipient mixtures preceded the formulation. Stability study was performed. A prospective randomized clinical trial was conducted for six weeks to assess the efficacy of the optimized formula in the treatment of anal fissure either acute (AAF, 37 patients) or chronic (CAF, 34 patients) in comparison with three single drug market products. The compatibility was indicated except in case of LDH with each of poloxamer 407 (P407), methylparaben, and propylparaben as well as BMV with P407. The gels showed acceptable viscosity ranges, tolerated pH values, and drugs content limits complying with the pharmacopeial limit. The gel containing 10% Transcutol(r) (F2) was selected as optimized formula due to the significant (p < 0.05) enhancement in NIF release. The recommended storage temperature was 8 degrees C. In comparison with the market products, the optimized gel can be represented as a potential combination therapy of acute and chronic anal fissures as suggested by significantly increased healing% and significantly reduced pain, bleeding, anal discharge and itching without side effects. PMID- 30430876 TI - Comprehensive genotyping of the C9orf72 hexanucleotide repeat region in 2095 ALS samples from the NINDS collection using a two-mode, long-read PCR assay. AB - OBJECTIVE: Expansion of the G4C2 repeat tract in the C9orf72 gene is linked to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we provide comprehensive genotyping of the C9orf72 repeat region for the National Institute of Neurological Disorders and Stroke (NINDS) ALS collection (n = 2095), using a novel bimodal PCR assay capable of amplifying nearly 100% GC-rich sequences. METHODS: A single-tube 3-primer PCR assay mode, resolved using capillary electrophoresis, was used for sizing up to 145 repeats with single repeat accuracy, for detecting expansions irrespective of their overall size, and for flagging confounding 3' sequence variations (SVs). A modified two-primer PCR mode, resolved via agarose gel electrophoresis, provided further size information for hyper-expanded samples (>145 repeats) up to ~5.8 kb amplicons (~950 G4C2 repeats). RESULTS: Within the evaluated cohort, 177 (8.4%) samples were expanded, with 175 (99%) samples being hyper-expanded. 3'-SVs were identified in 64 (3.1%) samples, and were most common in expanded alleles. Genotypes of all 606 (29%) homozygous samples were confirmed using an orthogonal PCR assay. CONCLUSION: This study and PCR method may improve and standardize molecular characterization of the C9orf72 locus, and have the potential to inform phenotype-genotype correlations and therapeutic development in ALS/FTD. PMID- 30430877 TI - Early clinical features and risk factors for cesarean scar pregnancy: a retrospective case-control study. AB - The aim of this study was to investigate early clinical features and risk factors for cesarean scar pregnancy (CSP). Study group of 206 CSP patients out of 6853 women with early pregnancies, diagnosed from 2014 to 2016 was compared with a randomly selected control group of 412 patients. Early clinical features for CSP were vaginal bleeding (OR: 9.65; 95% CI: 5.67-16.41), lower abdominal pain (OR: 3.8; 95% CI: 1.52-9.54) and increased white blood cells (OR: 1.30; 95% CI: 1.12 1.50). Important risk factors for CSP were artificial abortion within the last pregnancy (OR: 4.13; 95% CI: 2.23-7.66), 0 ~ 1 year and 2 ~ 3 year interval between present and last pregnancy (OR: 2.27; 95% CI: 1.11-4.67 and OR: 2.15; 95% CI: 1.15-4.03). Pregnancy problems are important issues within the scope of 'Gynecological Endocrinology'. Vaginal bleeding and lower abdominal pain, although unspecific, could be early clinical symptoms of CSP, especially if main risk factors exist such as abortion within the last pregnancy and short interval to the last pregnancy. Knowing this can help for prevention and early diagnosis CSP which can reduce life-threatening complications such as massive hemorrhage and can avoid hysterectomy. Consequence also must be to avoid unwanted pregnancies by using effective contraception, especially in risk patients. PMID- 30430878 TI - The Efficacy of Recombinant Platelet-Derived Growth Factor on Beta-Tricalcium Phosphate to Regenerate Femoral Critical Sized Segmental Defects: Longitudinal In Vivo Micro-CT Study in a Rat Model. AB - BACKGROUND AND OBJECTIVES: Beta-tricalcium phosphate (beta-TCP) has been used for bone regeneration. The objective of this study was to assess longitudinally, the regeneration of critical sized segmental defects (CSSD) in rat femur using beta TCP with or without recombinant platelet-derived growth factor (PDGF) through in vivo micro-computed tomography (micro-CT). MATERIALS AND METHODS: Following ethical approval unilateral femoral CSSD measuring 5 mm was surgically created, under general anesthesia, in 30 male Wistar-Albino rats (aged 12-18 months; weighing 450-500 g). CSSD was stabilized using titanium mini-plate (4 holes, 1.0 mm thick with 8 mm bar). Depending upon biomaterial used for regeneration, the animals were randomly divided into: Control group (N = 10): CSSD covered with resorbable collagen membrane (RCM) only; Beta-TCP group (N = 10): CSSD filled with beta-TCP and covered by RCM; Beta-TCP + PDGF group (N = 10): CSSD filled with beta-TCP soaked in recombinant PDGF and covered by RCM. Longitudinal in vivo micro-CT analysis of the CSSD was done postoperatively at baseline, 2nd, 4th, 6th, and 8th weeks to assess volume and mineral density of newly formed bone (NFB) and beta-TCP. RESULTS: Significant increase in NFB volume (NFBV) and mineral density (NFBMD) were observed from baseline to 8-weeks in all groups. Based on longitudinal in vivo micro-CT at 8-weeks, beta-TCP + PDGF group had significantly higher (p < 0.01) NFBV (38.98 +/- 7.36 mm3) and NFBMD (3.72 +/- 0.32 g/mm3) than the beta-TCP (NFBV-31.15 +/- 6.68 mm3; NFBMD-2.28 +/- 0.86g/mm3) and control (NFBV: 5.60 +/- 1.06 mm3; NFBMD: 0.27 +/- 0.02 g/mm3) groups. Significantly, higher reduction in beta-TCP volume (TCPV) and mineral density (TCPMD) were 1 observed in the beta-TCP + PDGF group when compared to the beta TCP group. CONCLUSION: Addition of recombinant PDGF to beta-TCP enhanced bone regeneration within rat femoral CSSD and increased resorption rates of beta-TCP particles. PMID- 30430880 TI - Response to Letter to Editor RE: Comparison of the 2 Tight Rope Technique and Clavicular Hook Plate for the Treatment of Rockwood 3 Type III Acromioclavicular Joint Dislocation. PMID- 30430879 TI - Making Cancer Visible: Unmasking Patients' Subjective Experiences. AB - The Face of Cancer, an article and patient's painting published nearly 15 years ago, has contributed in significant ways to a body of research focusing on communication during oncology interviews. Impacts from this painting helped to create a sensitivity for analyzing naturally occurring video recordings, including moments when patients' subjective experiences are raised and responded to. Analysis begins with how a melanoma patient's facial expression bears striking resemblance to the painting, vocal and other visible social actions (e.g., gaze, gesture), and how patient's story about a friend's metastatic cancer reveals her primal fears and hopes about cancer. Actions displayed by other patients (breast, testicular, abdominal, and leukemia) are also examined to unmask how their faces and bodies make cancer visible, doctors' responses, and the complexities of how patients' stressful stories get constructed. Implications are raised for improving patient-provider relationships by offering more personalized care. Understanding how patients display their concerns and emotions, through spoken and embodied actions, enhances discernment about how best to provide tailored and supportive responses to patients' life-world experiences especially, but not exclusively, when dealing with the stresses and angst of cancer. PMID- 30430881 TI - An outbreak of synthetic cannabinoid exposures reported to a regional poison center: "K2" identified as 5F-ADB. PMID- 30430882 TI - Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update. AB - INTRODUCTION: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent. Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing 20 potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development. Expert opinion: So far, 20 compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long noncoding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents. PMID- 30430883 TI - GnRH antagonist versus follicular-phase single-dose GnRH agonist protocol in patients of normal ovarian responses during controlled ovarian stimulation. AB - OBJECTIVE: This study aims to explore the differences of the ovarian stimulation (OS) characteristics, laboratory, and clinical outcomes between follicular-phase single-dose gonadotropin-releasing hormone (GnRH) agonist protocol and GnRH antagonist protocol during controlled ovarian hyperstimulation (COH). METHODS: About 1883 consecutive IVF/ICSI fresh cycles of normal ovarian responders were retrospectively analyzed, with 1229 in the single-dose GnRH agonist protocol group and 654 in the GnRH antagonist protocol group at Reproductive Medical Center of Tongji Hospital from 1 January 2014 to 31 December 2017. RESULTS: The follicular-phase single-dose GnRH agonist group showed significantly more oocytes obtained, higher implantation rate and pregnancy rate, as well as lower luteinizing hormone (LH) level and estradiol (E2)/oocyte ratio on the day of human chorionic gonadotropin (hCG) administration. However, differences were not significant in meiosis II (MII) oocyte rate, two pronuclear zygote (2PN) embryo rate, viable embryo rate or high-quality embryo rate, compared with the GnRH antagonist group. Further comparison of clinical outcomes in the first frozen thawed cycles did not show significant difference in either implantation or clinical pregnancy rate between the two protocol groups. CONCLUSIONS: Follicular phase single-dose GnRH agonist protocol may achieve better clinical outcomes in normal ovarian responders, which could be explained more by positive effect on endometrial receptivity rather than embryo quality. PMID- 30430884 TI - There is limited existing evidence to support the common assumption that strenuous endurance exercise bouts impair immune competency. PMID- 30430885 TI - Budget impact analysis of comprehensive genomic profiling in patients with advanced non-small cell lung cancer. AB - AIMS: Broad molecular profiling of patients with advanced non-small cell lung cancer (NSCLC) is strongly advised to optimize genomic matching with available targeted treatment options or investigational agents. Unlike conventional molecular diagnostic testing, or smaller hotspot panels, comprehensive genomic profiling (CGP) identifies genomic alterations across hundreds of clinically relevant cancer genes from a single tissue specimen. The present study sought to estimate the budget impact of increased use of CGP using a 324-gene panel (FoundationOne(r)) versus non-CGP (represented by a mix of conventional molecular diagnostic testing and smaller NGS hotspot panels) and the number needed to test with CGP to gain 1 life year. MATERIALS AND METHODS: A decision analytic model was developed to assess the budget impact of increased CGP in advanced NSCLC from a US private payer perspective. Model inputs were based on published literature (epidemiology and treatment outcomes), real-world data (testing and rates, medical service costs), list prices for CGP and anticancer drugs, and assumptions for clinical trial participation. RESULTS: Among 2 million covered lives, 532 had advanced NSCLC; 266 underwent molecular diagnostic testing. An increase in CGP among those tested, from 2% to 10%, was associated with $0.02 per member per month budget impact, of which $0.013 was attributable to costs of prolonged drug treatment and survival and $0.005 to testing cost. Approximately 12 patients would need to be tested with CGP to add 1 life year. LIMITATIONS: The model incorporated certain assumptions to account for inputs with a limited evidence profile and simplify the possible post-CGP treatments. CONCLUSIONS: An increase in CGP utilization from 2% to 10% among patients with advanced NSCLC undergoing molecular diagnostic testing was associated with modest budget impact, most of which was attributable to increased use of more effective treatments and prolonged survival. PMID- 30430886 TI - Pediatric Bronchogenic Cysts: A Case Series of Six Patients Highlighting Diagnosis and Management. AB - PURPOSE: To present six cases of bronchogenic cysts while highlighting the diagnosis and management of this anomaly. MATERIALS AND METHODS: A retrospective chart review was conducted using our institution's Pathology database. The database was queried for "bronchogenic cyst." From 2006 through 2017, six unusual cases were identified. RESULTS: The six cases of bronchogenic cysts were located in the neck (two cases), chest wall, mediastinum (two cases), and thyroid. All six of our patients underwent complete excision and did not experience recurrence or other complications. CONCLUSION: Although rare, bronchogenic cysts should be considered in the differential diagnosis of peculiar cystic masses in the pediatric population. Considering the crucial regional anatomy that may be associated with bronchogenic cysts, intimate knowledge of surgical anatomy using preoperative imaging is critical in most cases for their safe and effective excision. PMID- 30430887 TI - A Novel Method of Damage Control for Multiple Discontinuous Intestinal Injuries with Hemorrhagic Shock: A Controlled Experiment. AB - AIM: In this study, we examined the effects of branched silicon tube (BST) and temporary closed circle (TCC) in a Beagle dog model of multiple transection of small intestine and discontinuities suspected intestinal necrosis with hemorrhagic shock. MATERIALS AND METHODS: Ten male Beagle dogs were randomly divided into two groups. Hemorrhagic shock was induced by bleeding. Intestine was severed. Suspected intestinal necrotic model by ligating the mesenteric vessels was established, with a small tertiary mesenteric vessel reserved. Fracted intestines were ligated (IL group, n = 5) or reconnected with BST (IR group, n = 5). The abdominal cavity was temporarily closed with TCC. Definitive surgery was conducted after 24 h. RESULTS: There was no statistical difference between two groups in the weight of dogs, their blood loss, fluid resuscitation, operation time of early emergency treatment (EET). After definitive surgery, all dogs in IR group and 3 dogs in IL groups were alive. 18 (90%) suspicious necrotic intestinal segments in IL group became necrotic, but 20 (80%) segments in IR group didn't develop obvious changes (p < 0.01). From 2 h after EET, the endotoxin concentration in IL group was significantly higher than that in IR group (133.87 +/- 43.73 vs. 56.31 +/- 24.70 pg/ml, p < 0.01). Microscopic examination revealed that much more severe damage occurred in the suspicious necrotic intestinal segments in IL group. CONCLUSION: Both reconnecting intestine with BST and temporary abdominal closure with TCC are viable methods of damage control for multiple discontinuous intestinal injuries. PMID- 30430888 TI - Effects of Isolated Impaired Fasting Glucose on Brain Injury During Cardiac Surgery Under Cardiopulmonary Bypass. AB - OBJECTIVE: To evaluate the effects of isolated impaired fasting glucose (IIFG) on brain injury in patients undergoing cardiopulmonary bypass (CPB) surgery. METHODS: Patients with rheumatic heart valve disease who underwent elective mitral valve replacement were included and divided into control and IIFG groups. Pre-, intra-, and postoperative blood glucose levels, serum insulin levels, insulin resistance index (HOMA-IR), lactic acid levels, and neuron-specific enolase (NSE) and S100B levels were measured. The cerebral oxygen extraction ratio (OER) was calculated. Cognitive function was assessed via the Mini-Mental State Examination (MMSE). RESULTS: HOMA-IR levels were higher in the IIFG group than the control group 30 min after the beginning of CPB, at the termination of CPB, and 2 h after the termination of CPB. Cerebral OER and lactic acid increased intraoperatively in both groups, especially in the IIFG group. NSE and S100B levels were higher in the IIFG group than in the control group at the termination of CPB, 2 h after the termination of CPB, and at 24 h postoperatively. The MMSE scores did not significantly differ between the two groups. Delirium occurred in two patients in the IIFG group, and one in the control group. No other signs and symptoms of brain injuries were detected in either group. CONCLUSIONS: The increased postoperative NSE and S100B levels in the IIFG group compared with controls may be associated with severe insulin resistance and stress hyperglycemia. However, the IIFG group did not have clinical manifestations of brain injuries, including cognitive impairment. PMID- 30430889 TI - Networks of E-cadherin, beta1 integrin, and focal adhesion kinase in the pathogenesis of tubal pregnancy. AB - E-cadherin, beta1 integrin, and focal adhesion kinase (FAK) are reported to involved in eutopic implantation by mediating cell adhesion. However, less is documented about their roles in ectopic implantation. This study was undertaken to evaluate the roles and networks of E-cadherin, beta1 integrin, and FAK in tubal pregnancy. A total of 31 Fallopian tube specimens were obtained from tubal pregnant women. Immunohistochemistry and western blot were used to analyze the distributions and levels of E-cadherin, beta1 integrin and phosphorylated-FAK (Pho-FAK) in the Fallopian tube epithelium. Normal Fallopian tube samples derived from non-pregnant women with benign genital diseases were used for comparison. E cadherin presented in the cytomembrane of tubal epithelial cells and beta1 integrin mainly expressed in the cytoplasm. A lowest-level of E-cadherin was detected in the implantation site (0.63 +/- 0.29) when compared with the non implantation site (0.95 +/- 0.37) and the controls (0.89 +/- 0.33) (P < 0.05). beta1 integrin, as well as Pho-FAK in the implantation site (0.81 +/- 0.35; 0.72 +/- 0.24), showed a higher-level than that in the non-implantation site (0.59 +/- 0.26; 0.48 +/- 0.27) or the control group (0.38 +/- 0.19; 0.36 +/- 0.25) (p < .05). The decreased E-cadherin and increased beta1 integrin are implicated in tubal pregnancy. The involvement of beta1 integrin maybe depends on beta1 integrin/FAK signaling. PMID- 30430890 TI - Association of Frailty with Delayed Recovery of Gastrointestinal Function after Elective Colorectal Cancer Resections. AB - Frailty is characterized by a state of vulnerability to poor resolution of homoeostasis after a stressor event and is a consequence of age-related decline in many physiological systems during a lifetime. To access the association between frailty and delayed recovery of gastrointestinal function in patients undergoing elective colorectal cancer resections, 241 patients who had undergone elective colorectal cancer resections from July 2015 to August 2017 were investigated. The association of frailty with delayed recovery of gastrointestinal function, length of stay (LOS), and whether or not to transfer into intensive care unit (ICU) were analyzed. For the entire cohort, 164 (68.0%) of total patients experienced the early recovery of gastrointestinal function, 67 (27.8%) delayed recovery, and 10 (4.1%) patients occurred postoperative ileus (POI) or anastomotic leakage (AL). Low Modified Frailty Index (mFI) score was associated with statistically decreased odds ratios of 0.276 (95% CI, 0.095 0.808; p = 0.019) for delayed recovery of gastrointestinal function or even the occurrence of POI or AL, and shorter LOS of 1.058 (95%CI, 1.024-1.216; p = 0.039) compared with those of high mFI scores. However, mFI scores were not predictive of transferring into ICU (OR, 1.103; 95% CI, 0.808-1.507; p = 0.44). Frailty was associated with increased odds of delayed gastrointestinal function recovery or even the occurrence of POI or AL. Moreover, higher mFI was also associated with longer LOS, but was not predictive of whether or not transferring into ICU. PMID- 30430891 TI - Immune Correlates of Protection Induced by Virus-Like Particles Containing 2009 H1N1 Pandemic Influenza HA, NA or M1 Proteins. AB - Influenza virus-like particle (VLPs) vaccines are a promising alternative to conventional egg-based vaccines. Evaluation of vaccine efficacy induced by HA-M1 VLPs, NA-M1 VLPs or M1 VLPs against virus challenge infection would provide important insight into vaccine design strategy. In this study, we generated VLPs containing hemagglutinin (HA), neuraminidase (NA) or M1 proteins derived from the A/California/04/09. Mice were immunized intramuscularly with HA-M1, NA-M1 or M1 VLPs and protective immunity was evaluated by assessing lung virus loads against low (5LD50) or high (100LD50) lethal dose of homologous virus challenges. High levels of virus-specific serum IgG antibody responses were induced in mice after HA-M1 VLPs immunization, whereas low or no IgG antibody responses were detected from immunization with NA-M1 VLPs or M1 VLPs, independently. Mice that were immunized with HA-M1 VLPs showed below the limit of detection on lung virus loads against low dose (5LD50) of challenge and significant reduction against high dose (100LD50) of challenge infection. Mice that were immunized with NA-M1 or M1 VLPs also displayed reduced lung viral loads compared to naive control. In vitro cultures of cells from mouse spleen and bone marrow revealed that HA-M1 VLPs and NA-M1 VLPs induced higher levels of antibody-secreting cell (ASC) responses compared to naive control, whereas M1 VLPs showed no ASC responses. HA-M1, NA-M1 or M1 VLPs immunization demonstrated varying degree of protection with respect to body weight changes and survival rates, which are consistent with the levels of antibody responses in sera and ASC responses from spleen and bone marrow. PMID- 30430893 TI - Imatinib for right heart failure in COPD. AB - Severe pulmonary hypertension (PH) is rare in chronic obstructive pulmonary disease (COPD). Pulmonary arterial hypertension drugs are vasodilators and may cause severe side effects in these patients. Hence, they are not recommended except in right heart failure on an individual basis. Imatinib, a tyrosine-kinase inhibitor, has no direct vasodilator effects but significantly improved hemodynamics and exercise capacity in PAH but its use was associated with an increased risk for subdural hematomas in anticoagulated patients. We report on a COPD patient with right heart failure who did not recover with a phosphodiesterase-5-inhibitor or a soluble-guanylate-cyclasestimulator alone but with imatinib as add-on therapy. After one year of treatment, pulmonary vascular resistance (10.8 WU to 2.9 WU), NT-proBNP (4144 pg/mL to 363 pg/mL), and symptoms (WHO FC IV to III, 6MWD bedridden to 303 m) improved without major side effects. Imatinib may be a therapy option in patients with severe PH due to lung disease and right heart failure where other drugs have failed. PMID- 30430892 TI - A case of fatal invasive aspergillosis in a patient with neurosarcoidosis treated with infliximab. AB - INTRODUCTION: CNS involvement in sarcoidosis is seen in 5-10% of cases. Long term treatment involves steroids and other immunomodulatory agents, including infliximab. Chronic immunosuppression can result in increased patient susceptibility to opportunistic infections. We present a case of fatal aspergillosis in a patient with neurosarcoidosis treated with infliximab. CASE REPORT: A 55-year-old woman with neurosarcoidosis on infliximab (started 4 months prior) and dexamethasone, presented with progressive cognitive decline. Exam revealed impaired attention and disorientation with preserved language. Brain MRI showed multiple, bilateral cortical and subcortical ring-enhancing lesions. We held immunosuppression due to suspicion of infection; empiric Amphotericin B was given early in the hospital course. The patient rapidly deteriorated from a neurological and respiratory standpoint, requiring intubation. CSF analysis showed elevated protein of 511 and normal glucose of 104 (67% serum), with lymphocytic pleocytosis (25 cells, 96% lymphocytes). Systemic and CNS microbiological studies were negative. On hospital day 13, bronchial fluid grew Aspergillus fumigatus, prompting a switch to voriconazole. Despite early empiric antifungal treatment, she died from respiratory failure; autopsy revealed systemic and CNS aspergillosis with multiple brain abscesses. DISCUSSION: This case represents an example of a fatal complication of infliximab therapy, which was recently shown to be effective in neurosarcoidosis in one study. It also serves to highlight the challenges faced in diagnosing ring-enhancing lesions, especially in patients with pre-existing brain disorders. Finally, it highlights the difficulty in treating invasive aspergillosis. Further studies are needed to identify risks associated with infliximab therapy and potential early interventions to improve outcomes. PMID- 30430894 TI - Proximal pulmonary arterial wall disease in patients with persistent pulmonary hypertension after successful left-sided valve replacement according to the hemodynamic phenotype. AB - Regression of pulmonary hypertension (PH) is often incomplete after successful left-sided valve replacement (LSVR). Proximal pulmonary arterial (PPA) wall disease can be involved in patients with persistent-PH after LSVR, affecting the right ventricular to pulmonary arterial (RV-PA) coupling. Fifteen patients underwent successful LSVR at least one year ago presenting PH by echo (> 50 mmHg). Prosthesis-patient mismatch and left ventricular dysfunction were discarded. All patients underwent hemodynamic and intravascular ultrasound (IVUS) study. We estimated PPA stiffness (elastic modulus [EM]) and the relative area wall thickness (AWT). Acute vasoreactivity was assessed by inhaled nitric oxide (iNO) testing. RV-PA coupling was estimated by the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure ratio. Patients were classified as isolated post-capillary PH (Ipc-PH; pulmonary vascular resistance [PVR] <= 3 WU and/or diastolic pulmonary gradient [DPG] < 7 mmHg) and combined post- and pre-capillary PH (Cpc-PH; PVR > 3 WU and DPG >= 7 mmHg). Both Ipc-PH and Cpc-PH showed a significant increase of EM and AWT. Despite normal PVR and DPG, Ipc-PH had a significant decrease in pulmonary arterial capacitance and RV PA coupling impairment. Cpc-PH had worse PA stiffness and RV-PA coupling to Ipc PH ( P < 0.05). iNO decreased RV afterload, improving the cardiac index and stroke volume only in Cpc-PH ( P < 0.05). Patients with persistent PH after successful LSVR have PPA wall disease and RV-PA coupling impairment beyond the hemodynamic phenotype. Cpc-PH is responsive to iNO, having the worse PA stiffness and RV-PA coupling. The PPA remodeling could be an early event in the natural history of PH associated with left heart disease. PMID- 30430895 TI - Value of lung perfusion scintigraphy in patients with idiopathic pulmonary arterial hypertension: a patchy pattern to consider. AB - The ventilation/perfusion lung scan is recommended to exclude chronic thromboembolic pulmonary hypertension in the diagnostic algorithm of pulmonary hypertension, but its role in pulmonary arterial hypertension (PAH) has not been well explored. We characterized the lung perfusion pattern assessed by lung perfusion scintigraphy in idiopathic PAH (IPAH) patients and evaluate the potential prognostic significance of the patchy pattern perfusion defect. A total of 318 patients with IPAH confirmed by right heart catheterization who performed lung perfusion scintigraphy were included. On lung perfusion scintigraphy, 134 patients had normal lung perfusion and 184 patients showed patchy perfusion defects. In comparison to patients with normal lung perfusion, patients with patchy perfusion defects experienced significantly higher mean pulmonary arterial pressure (58.0 +/- 15.4 mmHg vs. 54.1 +/- 16.2 mmHg, P = 0.027) and total pulmonary resistance (1192.6 +/- 533.7 dyn.s.cm-5 vs. 1067.2 +/- 549.3 dyn.s.cm 5, P = 0.042). During a median follow-up period of 884.0 days, 53 patients reached the primary endpoint of all-cause mortality. On univariate Cox analysis, the patchy pattern of perfusion defect was significantly associated with the all cause mortality (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.32 4.63, P = 0.005). Patients with patchy perfusion defects had a worse outcome (log rank = 8.605, P = 0.003). On multivariate analysis, the patchy pattern remained as a significant independent predictor of the endpoint (HR = 2.30, 95% CI = 1.22 4.31, P = 0.010). IPAH patients presented with heterogeneity in lung perfusion and the patchy pattern of lung perfusion defect commonly existed. Patients with patchy pattern identified by lung perfusion scintigraphy were associated with more severe disease and worse outcome. PMID- 30430896 TI - Serum Interleukin-6 Level in Children With Attention-Deficit Hyperactivity Disorder (ADHD). AB - INTRODUCTION:: Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder in children, but its specific etiology and pathophysiology are still incompletely understood. OBJECTIVES:: This case-control study aimed to measure the level of serum interleukin-6 (IL-6) as a predictor of the immunologic status in children with ADHD, and to study its correlation with severity of symptoms. SUBJECTS AND METHODS:: 60 ADHD children who met the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria for ADHD and 60 control children were subjected to complete history taking, clinical examination, and psychometric tests. Serum interleukin-6 of ADHD patients and control children was measured by enzyme-linked immunosorbent assay. RESULTS:: The mean serum level of IL-6 was 22.35 (95% confidence interval [CI], 17.68-26.99) in ADHD patients, and it was 5.44 (95% CI, 4.81-6.06) in controls. A significantly higher level of IL-6 was reported in ADHD patients compared with controls ( P = .001). No significant correlation was found between serum IL-6 level and either the Intelligence Quotient (IQ) or the Conners' Parent Rating Scale score. CONCLUSION:: Serum IL-6 values were significantly higher in ADHD patients compared to healthy control children. Increased production of IL-6 may play a role in the pathogenesis of ADHD. PMID- 30430897 TI - Epibulbar osseous choristoma within a dermolipoma: case report and literature review. AB - A healthy 18-year-old girl presented with a superotemporal epibulbar mass that was present since birth. Computed tomography revealed a cystic mass with fat-like low-density and a central oval-shaped mass that was isodense to the bone in the superotemporal region of the globe. Histopathology of the excised tumour revealed osseous choristoma and dermolipoma. Our review of literature yielded nine reported cases of epibulbar osseous choristoma within a dermolipoma and we reviewed these cases. PMID- 30430899 TI - Evaluation of pesticides residues distribution in fresh and smoked body parts of Clarias gariepinus and assessment of possible health risks in Nigeria. AB - Pesticides residues in fresh and smoked body parts of Clarias gariepinus were investigated to evaluate their contamination status and risks to human health. The results gave an overview of the contamination levels of these (head, body trunk and liver) fish parts. The pesticides [organochlorine (OC), organophosphorus (OP), pyrethroids (PY) and others like: guazatine, methoprene, metalaxyl and imidachloprid] concentration in the fresh and smoked body parts ranged from 0.002 to 0.221 ug/kg and 0.002 to 0.175 ug/kg, with mean concentration of 0.002-0.218 ug/kg and 0.002-0.126 ug/kg, respectively. Smoking was observed to reduce the overall pesticide concentration as follows: head (0.23 ug/kg or 17.3%), liver (0.34 ug/kg or 29.8%) and muscles (0.41 ug/kg or 27.2%). The pesticides contents were significantly lower than standard daily intake and the risk associated with consumption of the fish also showed that the fish posed no potential threat to consumers. PMID- 30430898 TI - SphK1/S1P mediates TGF-beta1-induced proliferation of pulmonary artery smooth muscle cells and its potential mechanisms. AB - The upregulation of Sphingosine kinase 1 (SphK1) expression and accompanied sphingosine-1-phosphate (S1P) production have been reported to contribute to the proliferation of pulmonary artery smooth muscle cells (PASMC) and pulmonary arterial remodeling. However, the molecular mechanisms of SphK1/S1P upregulation in PASMC and the specific mechanisms of how SphK1/S1P pathway promotes PASMC proliferation remain largely unclear. This study aims to address these issues. Here, we demonstrated that TGF-beta1 significantly upregulated SphK1 expression and S1P production by promoting the phosphorylation of Smad2/3 in PASMC. Further study indicated that SphK1/S1P pathway mediated TGF-beta1-induced Notch3 activation in PASMC. In addition, we showed that TGF-beta1 significantly induced proliferation of PASMC, while pre-inhibition of Smad2/3 phosphorylation with SB431542 or silencing SphK1 using small interfering RNA in advance, or pre blocking Notch3 pathway with N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S phenylglycine t-butyl ester (DAPT), attenuated TGF-beta1-induced PASMC proliferation. Taken together, our study indicates that Smad2/3/SphK1/S1P/Notch3 pathway mediates TGF-beta1-induced PASMC proliferation and suggests this pathway as a potential therapeutic target in the prevention and treatment of pulmonary hypertension. PMID- 30430900 TI - Beneficial effects of Kaempferol after developmental TBI is through protection of mitochondrial function, oxidative metabolism and neural viability. AB - Oxidative energy metabolism is depressed after mild/moderate TBI during early development, accompanied by behavioral debilitation and secondary neuronal death. TBI metabolome analysis revealed broad effects with a striking impact on energy metabolism. Our studies on mitochondrial modulators and their effects on brain function have shown that Kaempferol, a stimulator of the mitochondrial Ca2+ uniporter channel (mCU), enhanced neural and neurovascular activity in the normal and improved stimulus-induced brain activation and behavior after TBI during early development. Since Kaempferol enhances mitochondrial Ca2+ uptake and cycling, with protective effects after TBI, we tested the hypothesis that Kaempferol treatment during the acute/subacute stage after TBI (0-72 hours) acted upon mitochondria in improving TBI outcome. Developmental age rats (P31) were subjected to TBI and treated with vehicle or Kaempferol, (1mg/Kg i.p) in 3 doses at 1, 24 and 48 hours after TBI. Brains were harvested at 72 hours and subjected to Liquid Chromatography Mass Spectrometric (LC/MS) measurements. Decrease in pyruvate and TCA cycle flux were observed in the untreated and vehicle-treated group, consistent with previously established energy metabolic decline after TBI. Kaempferol improved TCA cycle flux, maintained mitochondrial functional integrity as observed by decreased acyl carnitines, improved neural viability as evidenced by higher NAA levels. The positive outcomes of Kaempferol on metabolic profile corresponded with improved sensorimotor behavior. PMID- 30430901 TI - In vitro and in vivo evaluation of desmopressin-loaded poly(D,L-lactic-co glycolic acid) nanoparticles for its potential use in cancer treatment. AB - AIM: To develop and characterize the antitumor activity of poly(D,L-lactic-co glycolic acid) nanoparticles loaded with hemostatic and anticancer drug desmopressin (dDAVP). MATERIALS & METHODS: After full physicochemical characterization, anticancer activity of dDAVP-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (NPdDAVP) was evaluated in vitro and in vivo on a highly aggressive breast cancer model. RESULTS: After efficiently loading desmopressin in poly(D,L-lactic-co-glycolic acid) matrix, NPdDAVP exhibited suitable physicochemical characteristics for biomedical applications. NPdDAVP displayed a potent cytostatic effect in vitro, inhibiting tumor cell proliferation and colony forming ability. Moreover, intravenous treatment using nanoparticulated-dDAVP inhibited tumor progression and prolonged survival in animals bearing rapidly growing mammary tumors. CONCLUSION: Within the framework of promising dDAVP repurposing studies, these findings support further preclinical development of the NPdDAVP for the management of highly aggressive cancer. PMID- 30430902 TI - Electrophysiological guidance of epidural electrode array implantation over the human lumbosacral spinal cord to enable motor function after chronic paralysis. AB - Epidural electrical stimulation (EES) of the spinal cord has been shown to restore function after spinal cord injury (SCI). Characterization of EES-evoked motor responses has provided a basic understanding of spinal sensorimotor network activity related to EES-enabled motor activity of the lower extremities. However, the use of EES-evoked motor responses to guide EES system implantation over the spinal cord and their relation to post-operative EES-enabled function in humans with chronic paralysis due to SCI has yet to be described. Herein, we describe the surgical and intraoperative electrophysiological approach used, followed by initial EES-enabled results observed in two human subjects with motor complete paralysis who were enrolled in a clinical trial investigating the use of EES to enable motor functions after SCI. The 16-contact electrode array was initially positioned under fluoroscopic guidance. Then, EES-evoked motor responses were recorded from select leg muscles and displayed in real-time to determine electrode array proximity to spinal cord regions associated with motor activity of the lower extremities. Acceptable array positioning was determined based on achievement of selective proximal or distal leg muscle activity, as well as bilateral muscle activation. Motor response latencies were not significantly different between intraoperative recordings and post-operative recordings, indicating array positioning remained stable. Additionally, EES enabled intentional control of step-like activity in both subjects within the first five days of testing. These results suggest that the use of EES-evoked motor responses may guide intraoperative positioning of epidural electrodes to target spinal cord circuitry to enable motor functions after SCI. PMID- 30430903 TI - Effects of thymol and carvacrol, alone or in combination, on fermentation and microbial diversity during in vitro culture of bovine rumen microbes. AB - Two essential oils (EO), thymol and carvacrol, were used in six ratio (100:00, 80:20, 60:40, 40:60, 20:80 and 00:100) combinations of both EO and in a dose of 0.2 g L-1 in bovine ruminal culture medium, 24-h cultures, to evaluate effects on total gas production (TGP), methane production, in vitro dry matter digestibility (IVDMD) and in vitro culture population dynamics of methanogenic and total bacteria. Total DNA extracted from ruminal microorganisms was subjected to denaturing gradient gel electrophoresis (DGGE)-polymerase chain reaction (PCR) to examine effects on bacterial populations. The effect of EO on TGP and IVDMD were assessed by comparison to untreated control cultures. In general, methane production by the microbial populations appeared to be higher with treatments containing the highest concentration of thymol than with treatments containing more carvacrol resulting in a tendency for greater methane-inhibiting activity achieved as the thymol concentration in the thymol:carvacrol mixtures decreased linearly. The population of total bacteria with a 74.5% Dice similarity coefficient for comparison of DGGE band patterns indicating shifts in bacterial constituents as EO ratios changed. No effects on TGP, IVDMD while only slight shifts in the methanogenic populations were seen with an overall 91.5% Dice similarity coefficient. PMID- 30430905 TI - How Do Waterpipe Smoking Establishments Attract Smokers? Implications for Policy. AB - BACKGROUND: Given the unique social nature of waterpipe smoking, an important factor contributing to its popularity is the spread of waterpipe establishments. OBJECTIVES: With a focus on implications for regulations, we conducted a qualitative assessment of customers' online reviews on Yelp.com to gain insight into their positive and negative perceptions about waterpipe establishments and products, and identify features that are most important to them. METHODS: In June 2016, an online search of Yelp was conducted to identify waterpipe establishments in Miami, Florida. First, we collected information from the websites on establishments' characteristics and their marketing practices. Then we selected customers' waterpipe-related reviews and used an inductive qualitative method to code and identify key themes associated with positive and negative customers' experiences. Thematic analysis was completed upon reaching saturation. The final coding scheme consisted of 32 codes within eight themes. RESULTS: The homepage of the establishment was used to promote special discounts and events, while the online waterpipe menu was used to promote the waterpipe products. Our thematic analysis indicated that the variety of flavored tobacco was the most rated positive factor to customers, while the low-quality charcoal and high price were the most negative factors. Conclusions/Importance: Waterpipe online advertisements and promotions should be monitored and restricted. The availability of flavored tobacco, innovative device/accessories, affordable pricing, and charcoal quality are important domains for waterpipe establishments policy/regulation. Regulatory framework for waterpipe establishments should address the complex context of waterpipe including the venue (i.e., physical, website, menu), the tobacco, the device/accessories, and charcoal. PMID- 30430904 TI - Prevalence of temporomandibular disorders (TMD) among Finnish prisoners: cross sectional clinical study. AB - OBJECTIVE: The aim of the present study was to evaluate the prevalence of self reported temporomandibular disorders (TMD) symptoms and clinically diagnosed TMD among Finnish prisoners. MATERIAL AND METHODS: Altogether 100 prisoners from the Pelso Prison, Vaala, Finland, underwent dental and TMD clinical examinations performed by a calibrated and well-trained dentist. Symptom Questionnaire and clinical examination according to a Finnish pre-final version of the DC/TMD (Diagnostic Criteria for Temporomandibular Disorders) Axis I protocol were used to evaluate the prevalence of TMD sub-diagnoses. RESULTS: The most common TMD symptoms were facial pain (54.0%), temporomandibular joint noises (43.0%) and headache (37.0%). The prevalence of joint-related TMD diagnoses was four and a half times higher than diagnoses attributed with pain (76.0% vs. 17.0%). The most common TMD diagnoses were degenerative joint disease (33.0%) and disc displacement with reduction (33.0%). CONCLUSIONS: The prevalence of self-reported TMD symptoms and clinical assessed TMD, especially join-related TMD diagnoses, is high among Finnish prisoners. Examination and treatment of TMD should become a common practice also in prison dental care. PMID- 30430906 TI - Exposure assessment of operators to pesticides in Kongou, a sub-watershed of Niger River valley. AB - The use of pesticides in horticultural sector in Niger has become an integral part of modern agriculture. Nevertheless, their inappropriate use can generate negative health effects to operators. A study was carried out among Kongou farmers in order to assess their potential dermal exposure (PDE). The UK-POEM model was used to quantify the PDE during mixing/loading and application according to the local practices. In order to determine which parts of the operator body are subject to most contamination during spraying and to validate the theoretical model used, a patch method was used with a tartrazine dye. The deposits of the tartrazine on patches were measured by colorimetry thanks to the absorbance value determined after their extraction in water and a calibration curve. A total of ten spraying trials (five trials with the hand-held sprayer and five others with the backpack sprayer) were performed by different producers at 0.5 and 1 m height for each trial. The survey shows that 92% of the farmers are illiterate and the most common active substances identified are organophosphate or pyrethroids insecticides. Seventy percent of operators do not use any personal protective equipment (PPE) during mixing/loading or spraying. The predictive systemic exposure levels vary from 0.0027 mg kg-1 bw per day to 0.7692 mg kg-1 bw per day for backpack sprayer and from 0.0261 mg kg-1 bw per day to 0.9788 mg kg-1 bw per day for hand-held sprayer, several times higher the Acceptable Operator Exposure Level (AOEL) for some actives substances. Theoretical modeling indicates more exposure of operator by a hand-held sprayer than a backpack sprayer. The patch method results show that the deposits of dye increase when the position of sprayer nozzle increases from 0.5 to 1 m for the two sprayers. All parts of the operator body are contaminated but lower body parts and chest are the most exposed. The patch method results also show that hand spraying contaminates operator more than backpack spraying, confirming the results of the theoretical model. PMID- 30430907 TI - Incidence and characteristics of injury in under-19 academy level rugby league match play: A single season prospective cohort study. AB - Academy rugby league competition is an important step along the pathway to professional status, but little is known about injury at this level of the game. The aim of this research was to establish the nature, incidence and burden of injury in English academy rugby league. Using an observational prospective cohort study design, and a time-loss injury definition, the injury outcomes of three professional rugby league academies were recorded during the 2017 season. A total of 87 injuries occurred in 59 matches for an overall injury incidence of 85 (95%CI 67-103) injuries per 1000 hours played. The mean severity of injury was 22 +/- 19 days resulting in an overall injury burden of 1898 (95%CI 1813-1983) days lost per 1000 hours. The tackle event was the most common cause of injury (77% of all injuries). Forwards sustained a greater proportion of injuries than backs (forwards 67% vs. backs 33% of injuries). Concussion (13 (6-20) per 1000 hours) and ankle sprains (11 (4-17) per 1000 hours) were the most commonly diagnosed injuries. The shoulder joint was the most commonly injured site (17 (9-25) per 1000 hours). The incidence of injury for academy rugby league is similar to senior professional rugby league. PMID- 30430908 TI - The severity of NAFLD is associated with the risk of urolithiasis. AB - BACKGROUND AND AIMS: Population-based studies suggest a strong association between the presence of nonalcoholic fatty liver disease (NAFLD) and an increased risk of urolithiasis. However, the available information on the association of the severity of NAFLD with urolithiasis is limited. We hypothesised a link between the severity of NAFLD and the risk of urolithiasis. METHODS: We recruited 1527 adult patients with NAFLD who completed a comprehensive health checkup. The severity of NAFLD was measured with AST to platelet ratio (APRI score). Logistic regression analysis was used to detect the association of APRI score with the risk of urolithiasis among NAFLD patients. ROC analysis was used to assess the diagnostic value of APRI score for identifying urolithiasis among NAFLD patients. RESULTS: Multivariate analysis showed three independent risk factors for urolithiasis, including obesity (OR, 2.06 95%CI 1.35-3.13), APRI score (OR 1.29 95%CI 1.05-1.59), and serum uric acid (OR 1.07 95%CI 1.05-1.09), suggesting an independent association between the noninvasive staging of liver fibrosis and the risk of urolithiasis in NAFLD patients. A three-variable model (obesity, APRI score, and serum uric acid) with an AUROC of 0.73 (95% CI 0.70-0.75) was superior in identifying urolithiasis among patients with NAFLD. CONCLUSIONS: The severity of NAFLD is associated with the risk of urolithiasis among NAFLD patients. Moreover, a three-variable model (obesity, APRI score, serum uric acid) could serve as a useful tool for identifying individuals at high risk for urolithiasis in patients with NAFLD. PMID- 30430909 TI - Key somatic variables in young backstroke swimmers. AB - The purpose of this study was to estimate the optimal body size, limb-segment length, girth or breadth ratios for 100-m backstroke mean speed performance in young swimmers. Sixty-three young swimmers (boys [n = 30; age: 13.98 +/- 0.58 years]; girls [n = 33; age: 13.02 +/- 1.20 years]) participated in this study. To identify the optimal body size and body composition components associated with 100-m backstroke speed performance, we adopted a multiplicative allometric log linear regression model, which was refined using backward elimination. The multiplicative allometric model exploring the association between 100-m backstroke mean speed performance and the different somatic measurements estimated that biological age, sitting height, leg length for the lower-limbs, and two girths (forearm and arm relaxed girth) are the key predictors. Stature and body mass did not contribute to the model, suggesting that the advantage of longer levers was limb-specific rather than a general whole-body advantage. In fact, it is only by adopting multiplicative allometric models that the abovementioned ratios could have been derived. These findings highlighted the importance of considering somatic characteristics of young backstroke swimmers and can help swimming coaches to classify their swimmers and enable them to suggest what might be the swimmers' most appropriate stroke (talent identification). PMID- 30430910 TI - Differences in Cortical Gray Matter Atrophy of Paraplegia and Tetraplegia after Complete Spinal Cord Injury. AB - Anatomical studies of SCI using Magnetic Resonance Imaging (MRI) report diverging observations, from 'no changes' to 'tissue atrophy in motor and non-motor regions.' These discrepancies among studies can be attributed to heterogeneity in extent, level and post-injury duration observed within the SCI population. But, no studies have investigated structural changes associated with different levels of injury (paraplegia vs. tetraplegia). High-resolution MRI images were processed using Voxel-Based Morphometry technique to compare regional GM volume (GMV) between 16 complete paraplegia and 7 complete tetraplegia SCI subjects scanned within two years of injury when compared to 22 age-matched healthy controls using one-way Analysis of Covariance (ANCOVA). A post-hoc analysis using region of interest based approach was employed to quantify GMV differences between healthy controls and subgroups of SCI. A voxel-wise one sample t-test was also performed to evaluate the mean effect of post-injury duration on GMV of SCI group. ANCOVA resulted in altered GMV in inferior frontal gyrus, bilateral mid orbital gyrus extending to rectal gyrus and anterior cingulate cortex. Post-hoc analysis, in general, indicated GM atrophy after SCI but tetraplegia showed a greater decrease in GMV when compared to paraplegia and healthy controls. Further, the GMV of the middle frontal gyrus, superior frontal gyrus, inferior frontal gyrus, insula, mid orbital gyrus and middle temporal gyrus was positively correlated with post injury duration in both paraplegia and tetraplegia groups. GM atrophy after SCI is affected by the level of cord injury, with higher levels of injury resulting in greater loss of GMV. The magnitude of GMV loss in the frontal cortex after SCI also appears to be dynamic within the first two years of injury. Understanding the effect of injury level and injury duration on structural changes following SCI can help better understand the mechanisms leading to positive and negative clinical outcome in SCI patients. PMID- 30430911 TI - Domino effect of IL-15 and CD8 T cell-mediated neuronal apoptosis in experimental traumatic brain injury. AB - The effects of local factors on the activation of immune cells infiltrating the CNS in rat model of traumatic brain injury (TBI) remains to be defined. The cytokine IL-15 is crucial in the development and activation of CD8 T lymphocytes, a prominent lymphocytic population identified in TBI lesions. We investigated whether IL-15 originates from astrocytes as well as evoke the CD8 T lymphocyte response in TBI. We observed that astrocytes were activated in TBI rat model, with IL-15 overexpressed on the astrocytic surface. Furthermore, the infiltrating CD8 T lymphocytes in the TBI lesions were adjacent to the IL-15-expressing astrocytes. Subsequently, CD8 T lymphocytes released Gra-b, which in turn activated Caspase-3 and cleaved PARP, and ultimately induced neuronal apoptosis. Conversely, inhibition of astrocytes by fluorocitrate (FC) pretreatment resulted in the improved neurological function and memory, as well as downregulation of IL 15 and CD8 T cells, and decreased neuronal apoptosis. In contrast, recombinant rat IL-15 (rIL-15) pretreatment upregulated the levels of CD8 T cells and Gra-b, and induced neuronal apoptosis. We concluded that IL-15 could induce neuronal apoptosis by enhancing CD8 T cell function in the rat model of TBI. PMID- 30430912 TI - Physiological determinants of elite mountain bike cross-country Olympic performance. AB - Detailed physiological phenotyping was hypothesized to have predictive value for Olympic distance cross-country mountain bike (XCO-MTB) performance. Additionally, mean (MPO) and peak power output (PPO) in 4 * 30 s all-out sprinting separated by 1 min was hypothesized as a simple measure with predictive value for XCO-MTB performance. Parameters indicative of body composition, cardiovascular function, power and strength were determined and related to XCO-MTB national championship performance (n = 11). Multiple linear regression demonstrated 98% of the variance (P < 0.001) in XCO-MTB performance (tXCO-MTB; [min]) is explained by maximal oxygen uptake relative to body mass (VO2peak,rel; [ml/kg/min]), 30 s all-out fatigue resistance (FI; [%]) and with a minor contribution from quadriceps femoris maximal torque (Tmax; [Nm]): tXCO-MTB = -0.217* VO2peak,rel.-0.201* FI+ 0.012* Tmax+ 85.4. Parameters with no additional predictive value included hemoglobin mass, leg peak blood flow, femoral artery diameter, knee-extensor peak workload, jump height, quadriceps femoris maximal voluntary contraction force and rate of force development. Additionally, multiple linear regression demonstrated parameters obtained from 4x30s repeated sprinting explained 88% of XCO-MTB variance (P < 0.001) with tXCO-MTB = -5.7* MPO+ 5.0* PPO+ 55.9. In conclusion, XCO-MTB performance is predictable from VO2peak,rel and 30 s all-out fatigue resistance. Additionally, power variables from a repeated sprint test provides a cost-effective way of monitoring athletes XCO-MTB performance. PMID- 30430913 TI - [Hospital nurses' perspective on academic nursing education: a cross-sectional study in hospitals in the northwestern part of Germany]. AB - : Hospital nurses' perspective on academic nursing education: a cross-sectional study in hospitals in the northwestern part of Germany Abstract. BACKGROUND: Currently, there is an increasing need for highly qualified nurses in Germany. Against this background, an academic nursing education is frequently demanded in order to meet the high level of competences nurses must fulfil. AIM: This cross sectional study aimed to explore nurses' attitudes towards academic nursing education as well as their self-reported scientific competences. METHODS: Based on a standardized questionnaire, we surveyed 547 hospital nurses from six different hospitals in the northwestern part of Germany. By means of a bivariate analysis and two multivariate regression models, we examined the influence of the independent variables "professional position", "degree of academic education", "age" and "gender" on the dependent variables "attitude towards academic nursing education" and "scientific competences". The multivariate analysis included three co-variates analysing different ways of support of academic nursing education within the hospitals. RESULTS: Especially nursing staff who has completed a study programme, is currently studying or hold executive positions has a more positive attitude towards academic education than its colleagues have. Moreover, opportunities for advancement within the hospitals influence the staff's attitude positively. With regard to the assessment of scientific competences, the analysis shows that a completed or currently conducted study programme as well as an executive position have a positive influence. In addition, male nursing staff, young nursing staff and staff with access to scientific articles assess their scientific skills more positively than their colleagues do. CONCLUSIONS: The attitudes towards academic education are still heterogeneous and influenced by different factors. Accordingly, the worth of academic education needs to be demonstrated. PMID- 30430914 TI - Genetic polymorphism contributes to 131I radiotherapy-induced toxicities in patients with differentiated thyroid cancer. AB - AIM: To investigate the association between SNPs in DNA damage response pathways and toxicities following 131I radiotherapy of differentiated thyroid cancer (DTC). Materials & methods: We identified 22 functional SNPs of genes in DNA damage response pathways. MassArray was used to sequence SNP genotypes in 203 DTC patients. Hardy-Weinberg equilibrium and the associations between the two alleles of each SNP and toxicity reactions were evaluated using chi2 analysis. RESULTS: Ataxia-telangiectasia mutated (ATM) rs620815 T-allele carriers were at increased risk of 131I radiation-induced gastrointestinal reaction compared with C allele carriers. TNFalpha rs1800629 GA genotype may increase the incidence of neck pain compared with GG genotype. Furthermore, TNFalpha rs1800629, ATM rs11212570, NF kappabeta rs230493, and TGF-beta rs1800469, rs2241716 were associated with throat pain following 131I radiotherapy. CONCLUSION: The identified SNPs might serve as novel biomarkers for DTC treated with 131I radiotherapy. PMID- 30430915 TI - Enhanced phenanthrene removal in aqueous solution using modified biochar supported nano zero-valent iron. AB - The present work investigated the removal behaviour of phenanthrene (PHE) by nano zero-valent iron immobilized on alkali modified biochar (nZVI/MB). Batch studies showed that nZVI/MB enhanced PHE removal by 4.9 times that of the nZVI and 1.2 times that of modified biochar (MB) alone, due to the greater surface area and the inhibited aggregation of nZVI on the surface of MB. Transmission electron microscopy images revealed that the spherical nZVI particulates with an average diameter of 32 nm uniformly dispersed on the surface of MB. The PHE removal fitted well with the pseudo-second-order model (R2>0.98) was an endothermic and spontaneous process. The forces of pi-pi interaction, hydrophobic interaction and reduction of supported nZVI were contributed to PHE removal process. In addition, the PHE degradation products in solution were determined by gas chromatograph mass spectrometer after reaction with nZVI/MB. PMID- 30430916 TI - Empowering a Community from the Inside Out: Evaluation of a Yoga Teacher Training Program for Adults in Custody. AB - The current study evaluated a yoga teacher training program to understand the effect of bringing yoga psychology (as an integrated eight-limbed system) to adults in custody (AIC), who were trained to become yoga teachers who will in turn teach other AICs. The study used quantitative and qualitative measures to assess the yoga teacher training program's impact on individuals, their relationships, and the overall prison environment. The study included assessments and interviews with 12 AICs and nine yoga teacher volunteers, as well as key informant interviews with two correctional officers and five administrators who work within or directly with the Department of Corrections on the implementation of the program. Quantitative results revealed significant enhancements and sustainability in all key outcome variables (self-compassion, mindfulness, perceived stress, understanding of yoga philosophy, and teaching skills) from pretest to program completion and from completion to 3-month follow-up. Additionally, AIC yoga teachers became more similar on all outcome measures to the volunteer teachers from pretest to program completion and from completion to follow-up. Qualitative methods (used for 31 key informant and focus group interviews) revealed themes that illuminated positive effects on the prison community regarding participants' personal experiences, attitudes and values, behaviors, relationships, yoga philosophy in prison, culture, and future directions. Implications and recommendations are provided to support sustaining the current program and to help with the creation of new programs to infuse yoga philosophy into corrections departments. PMID- 30430917 TI - Combined Effects of Low-Dose Proton Radiation and Simulated Microgravity on the Mouse Retina and the Hematopoietic System. AB - The purpose of the current study was to characterize the effects of simulated microgravity and radiation-induced changes in retina and retinal vasculature, and to assess the accompanying early changes in immune cells and hematological parameters. To better understand the effects of spaceflight, we used a combination of treatments designed to simulate both the radiation and low-gravity aspects of space conditions. To simulate the broad energy spectrum of a large solar particle event (SPE) and galactic cosmic ray (GCR) radiation, male C57BL/6J mice were exposed to whole-body irradiation using fully modulated beams of 150 MeV protons containing particles of energy from 0 to 150 MeV and a uniform dose vs.-depth profile. The mice were also hindlimb-unloaded (HLU) by tail suspension. Mice were unloaded for 7 days, exposed to 50 cGy, unloaded for an additional 7 days and then sacrificed for tissue isolation at days 4 and 30 after the combined treatments. Increases in the number of apoptotic cells were observed in the endothelial cells of mice that received radiation alone or with HLU compared to controls at both days 4 and 30 ( P < 0.05). Endothelial nitric oxide synthase (eNOS) levels were significantly elevated in the retina after irradiation only or combined with HLU compared to controls at the 30-day time point ( P < 0.05). The most robust changes were observed in the combination group, suggesting a synergistic response to radiation and unloading. For hematopoietic parameters, our analysis indicated the main effects for time and radiation at day 4 after treatments (day 11 postirradiation) ( P < 0.05), but a smaller influence of HLU for both white blood cell and lymphocyte counts. The group treated with both radiation and HLU showed greater than 50% reduction in lymphocyte counts compared to controls. Radiation-dependent differences were also noted in specific lymphocyte subpopulations (T, B, natural killer cells). This study shows indications of an early effect of low-dose radiation and spaceflight conditions on retina and immune populations. PMID- 30430918 TI - Specific Members of the Gut Microbiota are Reliable Biomarkers of Irradiation Intensity and Lethality in Large Animal Models of Human Health. AB - The development of effective biomarkers for detecting the magnitude of radiation exposure and resiliency of host response is crucial to identifying appropriate treatment strategies after radiation exposure. We hypothesized that the gastrointestinal resident bacteria would demonstrate predictable, dose-dependent changes after radiation exposure across two large animal models of acute radiation syndrome. Here, Gottingen minipigs (GMP) (n = 50) and rhesus macaques (n = 48) were exposed to five dose levels (resulting in mortality rates of 33 100% and 25-68.7%, respectively). Fecal samples taken prior to and after irradiation (day 0 for GMP; day 0, 3 and 14 for macaques) were used for 16S rRNA gene sequence amplicon high-throughput sequencing. Baseline gut microbiota profiles were dissimilar between GMP and macaques, however, radiation appeared to have similar effect at the phylum level, resulting in Bacteroidetes decrease and Firmicutes increase in both models. The abundance of the main Bacteroidetes genus ( Bacteroides for GMP, Prevotella for macaques) was profoundly decreased by irradiation. Intracellular symbionts [Elusimicrobia in GMP, Treponema (Spirochaetes) in macaques] consistently increased after irradiation, suggesting their use as potential biomarkers of intestinal injury, and potential negative effect on health. Prevotella, Lactobacillus, Clostridium XIVa, Oscillibacter and Elusimicrobium/ Treponema abundances were found to be very significantly correlated with radiation intensity. Furthermore, Prevotella, Enterorhabdus and Ruminococcus and Enterorhabdus maintenance was strongly associated with survival in GMP, while Prevotella, Oscillibacter and Treponema were strongly associated with survival and Streptococcus with death in macaques. Overall, we found that a wide range of gut bacterial genera known to be abundant in the human gut microbiota are excellent biomarkers of radiation intensity and resilience in animal models, and that detrimental effects can be monitored, and potentially prevented, by targeting selected genera. PMID- 30430920 TI - Editorial. PMID- 30430921 TI - Pattern recall, decision making and talent identification in rugby union. AB - The ability to make fast, accurate decisions is an essential skill for all who play sport. However, measuring this ability has proved difficult for coaches and talent identification practitioners. Pattern recognition (a key factor in decision making) has commonly been measured using pattern recall tasks. This study aimed to understand whether accuracy when recalling rugby union patterns is a valid measure of on-field decision making performance. In Study 1, professional players recalled structured patterns of players from still images (N = 20) viewed for 5 s. On-field decision-making markers, including coaches' rankings of decision-making ability, playing position, number of years playing professionally and total number of years playing rugby union, were used as predictor variables of recall accuracy. Results showed that only total number of years playing rugby union was correlated with recall accuracy, suggesting that caution is necessary when adopting these tasks for talent identification purposes. The structured stimuli used in Study 1 were not representative of a true rugby union game, so Study 2 tested novice and expert players on a pattern recall task that included structured, semi-structured and unstructured rugby union patterns. Experts were significantly more accurate than novices when recalling structured and semi structured patterns; however, there were no differences when recalling unstructured patterns. It was concluded that structured and semi-structured patterns should be used in future studies to test whether pattern recall tasks can be used for talent identification in rugby union. PMID- 30430919 TI - Involvement of nerve growth factor in mouse hippocampal neuronal cell line (HT22) differentiation and underlying role of DNA methyltransferases. AB - DNA methylation is an epigenetic event involved in regulation of gene transcription during cell differentiation. DNA methyltransferases (DNMT) play a role in differentiation of neural stem cells into neurons. The aim of this study was to determine whether nerve growth factor (NGF) was involved in differentiation of mouse hippocampal neuronal cell line (HT22) as assessed by IncuCyte. Quantitative PCR and western blot were used to measure gene and protein expression of DNMT as well as the activity of DNMTs. Treatment with NGF was found to upregulate both gene and protein expressions as well as total activity of DNMTs in differentiating HT22 cells. Compared to undifferentiating cells, the percentage of differentiating cells at S phase increased significantly when incubated with NGF. In undifferentiated cells, NGF failed to induce gene and protein expressions and activity of DNMTs. Data demonstrate that differentiation of HT22 cells by exposure to NGF involve the activation of DNMTs pathway. PMID- 30430922 TI - A High-Throughput Workflow to Study Remodeling of ECM-Based Microtissues. AB - Changes to the cellular microenvironment are an integral characteristic of numerous pathologies including cancer, fibrosis, and autoimmune disease. Current in vitro methodologies available to study 3D tissue remodeling are ill suited for high-throughput studies as they are not scalable for large-scale experiments. Combining droplet microfluidics and patterned low-adhesion culture surfaces, we have engineered a workflow to incorporate cell-ECM interactions in a versatile and high-throughput platform that is compatible with existing high throughput liquid handling systems, enables long-term experiments (>1 month), and is well-suited for traditional and novel biological measurements. With our platform, we demonstrate the feasibility of high-throughput ECM remodeling studies with collagen microtissues as one application of a tissue-level function. In this study, we use our workflow to examine ECM remodeling at the tissue, cell, and subcellular levels, leveraging assays ranging from immunohistochemistry and live-cell imaging, to proliferation and contraction assays. With our unique culture system, we can track individual constructs over time and evaluate remodeling on several scales for large populations. Finally, we demonstrate the ability to cryopreserve our microtissues while retaining high viability and cell function, an invaluable method that could allow for dissemination and freezing of microtissues after mass production. Using these methods, our ECM-based system becomes a viable platform for modeling diseases characterized by tissue reorganization as well as a scalable method to conduct in vitro cell-based assays for drug screening and high-throughput biological discovery. PMID- 30430923 TI - Family caregivers' perceptions of maltreatment of older adults with dementia: findings from the northwest of Spain. AB - Dementia is a neurocognitive disorder that implies a risk factor of maltreatment by family caregivers. In this study, we analyzed both informal caregiver's perceptions of maltreatment and aspects of the caregiver and caregiving behavior that may be associated with maltreatment. We conducted five focus groups (FGs) in three Spanish cities: Segovia, Soria and Leon. The themes that were identified were related to two levels of maltreatment: (a) relational and (b) institutional. At the relational level, we observed the justification of maltreatment of Older Adults with Dementia (OAswD) by family caregivers during the occurrence of behavioral symptoms. At the institutional level, we noted that lack of support from the government was considered a type of maltreatment. These themes suggest that policy issues related to healthcare should be considered. PMID- 30430924 TI - The protective mechanism underlying total flavones of Dracocephalum (TFD) effects on rat cerebral ischemia reperfusion injury. AB - Previously, total flavones of Dracocephalum (TFD), derived from Dracocephalum, were found to exert protective effects in cerebral ischemia reperfusion injury (CIRI) in middle cerebral artery occlusion (MCAO) rat model. However, the mechanisms underlying these observed effects of TFD on MCAO-induced rats still remain to be determined. Therefore, the aim of this study was to examine whether TFD alleviated MCAO through mechanisms involving anti-inflammatory and anti apoptotic using MCAO rats. The following parameters were measured: (1) percentage (%) area of brain infarction; (2) serum levels of inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) and (3) expression protein levels of caspase-3 and AMP-activated protein kinase (AMPK). Results showed that MCAO significantly increased the % area of brain infarction, while TFD administration in these animals markedly reduced % area of brain infarction. A significant elevation on serum levels of TNF-alpha and IL-6 was noted with MCAO which was markedly reduced by TFD. In addition, MCAO produced a significant rise in protein expression levels of caspase-3 and AMPK. In contrast, TFD markedly lowered protein expression levels of caspase-3 and AMPK. Data suggest that the protective effects of TFD in MCAO model animals may involve inhibition of inflammatory mediator release associated with apoptosis through down regulation of AMPK signaling pathway. PMID- 30430926 TI - Isolation, molecular identification, and characterization of a unique toxic cyanobacterium Microcystis sp. found in Hunan Province, China. AB - Global proliferation of cyanobacterial blooms associated with climate change and eutrophication constitutes a serious environmental threat. In Hunan Province a freshwater pond located in Changsha City was found to contain high concentrations of cyanobacteria, however, the characteristics of these cyanobacteria at present are not known. This study thus aimed to isolate, identify the most common bloom forming cyanobacteria in this region and determine the toxigenic characteristics of the predominant cyanobacteria. The cyanobacteria were isolated by serial dilution and identified using polymerase chain reaction (PCR). The cyanotoxins generated by the cyanobacterium were detected using high-performance liquid chromatography with an ultra-high resolution LTQ Orbitrap Velos Pro ETD mass spectrometry equipped with electrospray ionization interface (HPLC-ESI-MS). One species of cyanobacterium was isolated and identified as Microcystis sp. YFM1 according to the sequence of the 16S ribosome deoxyribonucleic acid (16S rDNA). It was found that this cyanobacterium contained microcystin synthetase B gene (mcyB) and produced three types of cyanotoxins including microcystin-LR, RR and YR. Our findings indicate that the Microcystis sp. YFM1 isolated from the freshwater pond in Hunan Province exhibits unique characteristics distinguishable from other known cyanobacteria. PMID- 30430927 TI - ABSTRACTPerformance of the new Illumigene(r) Mycoplasma LAMP assay for detection of M. pneumonia. PMID- 30430928 TI - Ecological impact of isolated cognitive relapses in MS. AB - Isolated cognitive relapses (ICRs) are transient deficits in cognitive performance that are the only presentation of a multiple sclerosis (MS) relapse. Here, we evaluated the impact of ICRs on cognitive difficulties in daily activities (assessed with the Multiple Sclerosis Neuropsychological Screening Questionnaire, Informant Version (MSNQ-I)) to characterize ICRs' clinical relevance. We used 2-year-long retrospective data to compare 15 relapsing remitting MS (RRMS) patients with ICRs with 57 RRMS patients presenting an asymptomatic gadolinium enhancing lesion (and no-ICRs). ICRs were associated not only with neuropsychological performance decline but also with an increase in the daily cognitive difficulties. These findings support the ecological relevance of ICRs. PMID- 30430925 TI - The protective mechanism underlying phenylethanoid glycosides (PHG) actions on synaptic plasticity in rat Alzheimer's disease model induced by beta amyloid 1 42. AB - Phenylethanoid glycosides (PHG), derived from Herba cistanche, were found to exert protective effects on cognitive dysfunctions by improving synaptic plasticity in Alzheimer's disease (AD) rat model. However, the mechanisms underlying these effects of PHG on synaptic plasticity remain to be determined. Thus the aim of this study was to examine the influence of PHG on synaptic plasticity in male AD rat model induced by bilateral central nervous system ventricle injections of beta amyloid 1-42 oligomers (Abeta1-42). The following parameters were measured: (1) number of intact pyramidal cells in hippocampal CA1 region by Nissl staining, (2) post synaptic density 95 (PSD-95), phosphorylated N methyl-D-aspartate receptor-1(p-NMDAR1) and (3) phosphorylated Tau protein (p Tau) by immunohistochemistry and western blot. In addition, the content of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Abeta1-42 lowered the number of intact pyramidal cells in hippocampal CA1 region. In contrast, treatment with PHG significantly elevated this cell number. Abeta1-42 significantly diminished protein expression levels of PSD-95 accompanied by elevated protein expression levels of p-NMDAR1 and p-Tau. PHG markedly increased protein expression levels of PSD-95, but significantly reduced protein expression levels of p-NMDAR1 and p Tau. Further, Abeta1-42 markedly increased MDA content concomitantly with reduced activities of SOD and GSH-Px. PHG significantly decreased MDA content accompanied by elevated activities of SOD and GSH-Px. Data suggest that the protective effects of PHG on synaptic plasticity may involve inhibition of cytotoxicity mediated by Abeta-1-42 administration and reduction of oxidant stress. PMID- 30430929 TI - Special Section on Productive Aging & Retirement. PMID- 30430930 TI - Analysis of long non-coding RNA profiled following MC-LR-induced hepatotoxicity using high-throughput sequencing. AB - The occurrence of microcystin-LR(MC-LR) variant a known hepatotoxin constitutes a global public health concern. However, the molecular mechanisms underlying MC-LR induced hepatotoxicity remain to be determined. The aim of this study was to investigate whether long noncoding RNAs (lncRNA) were involved in MC-LR-mediated hepatotoxicity using human normal liver cell line HL7702 to profile lncRNAs after 24 hr treatment with MC-LR. With the use of high-throughput sequencing techniques, data showed that the expression levels of 37, 33, 34, 35 lncRNA were significantly altered following exposure to 1, 2.5, 5, or 10 MUM MC-LR, respectively. In particular, the expression levels of LINC00847, MIR22HG and LNC_00027 were markedly increased in all treatment groups. It is of interest that LNC_00027 was identified as a novel lncRNA. Quantitative real-time PCR (qPCR) was employed to determine the differentially expressed lncRNA levels. Analysis using Gene Ontology (GO) enrichment identified the functions of target genes involved in systems development, metabolism, and protein binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated that MC-LR exposure upregulated some important signaling pathways including pathway in cancer, PI3K AKT signaling and MAPK pathway. In summary, data indicate that the MC-LR-induced alterations in lncRNA may be associated with hepatotoxicity and that upregulation of LINC00847, MIR22HG and LNC_00027 may play important roles in the observed MC mediated liver damage. PMID- 30430931 TI - Classification-based QSAR models for the prediction of the bioactivity of ACE inhibitor peptides. AB - Local classification models were used to establish quantitative structure activity relationships (QSARs) of bioactive di-, tri- and tetrapeptides, with their capacity to inhibit Angiotensin Converting Enzyme (ACE). These discrete models can thus predict this activity for other peptides obtained from functional foods. These types of peptides allow some foods to be considered nutraceuticals. A database of 313 molecules of di, tri- and tetra-peptides was investigated and antihypertensive activities of peptides, expressed as log (1/IC50), were separated into two qualitative classes: low activity (inactive) was associated with experimental values under the 66th percentile and active peptides with values above this threshold. Chemicals were divided into a training set, including 70% of the peptides, and a test set for external validation. Genetic algorithm variable subset selection coupled with the kNN and N3 local classifiers were applied to select the best subset of molecular descriptors from a pool of 953 Dragon descriptors. Both models were validated on the test peptides. The N3 model turned out to be superior to the kNN model when the classification focused on identifying the most active peptides. PMID- 30430932 TI - Building on Success: A Bright Future for Peptide Therapeutics. AB - The primary aim of this review article is to highlight current exciting and future looking areas of research in peptide science as applied to the discovery and development of novel therapeutics. Among the strengths of peptides as drug candidates are their high potency, specificity, and good safety profile. These positive attributes of peptides along with advances in drug delivery technologies have generated renewed interest in the discovery, optimization, and development of peptides as therapeutics. The intent of this review is to demonstrate that peptides have broad applicability in many therapeutic areas by examining some of the most compelling indications and targets for peptide therapeutics. For example, target selection for peptide therapeutics is challenging due to the inherent properties of peptides, therefore, identifying a clear differentiation strategy for a new peptide program over a small molecule or antibody program from the outset is critical for successful navigation of drug development hurdles. In this review, some of the latest techniques that accentuate the advantages and overcome the drugability limitations of peptides will be covered. Emerging technologies for enhancing the pharmacokinetics of peptides to achieve sufficient in vivo half-lives will be described and evaluated, as well as novel technologies for getting peptides across cell membranes to reach intracellular targets and across the blood-brain-barrier to reach central nervous system targets. PMID- 30430933 TI - Heterologous expression and functional characterization of catalytic subunit of rice acetohydroxyacid synthase. AB - Acetohydroxyacid synthase (AHAS) is the first enzyme in the biosynthesis pathway of the branched chain amino acids (valine, lleucine and isoleucine). AHAS is the common target site of five herbicide chemical groups: sulfonylurea, imidazolinone, triazolopyrimidine, pyrimidinyl-thiobenzoates, and sulfonyl aminocarbonyl-triazolinone. The gene encoding catalytic subunit of rice AHAS (cOsAHAS) without part of the chloroplast transit sequence was cloned into the bacterial expression vector pET41a and heterologously expressed in Escherichia coli as carboxy-terminal extensions of glutathione-S-transferase (GST). The optimum pH and temperature for GST-cOsAHAS activity was 8.0 and 37 degrees C, respectively. The specific activity and Km value of this enzyme toward pyruvate were 0.08 U/mg and 30 mM, respectively. GST-cOsAHAS was inhibited by herbicides tribenuron, sulfosulfuron, nicosulfuron and bensulfuron. These results suggest that the recombinant form of GST-cOsAHAS is functionally active and carries the binding site for sulfynylurea herbicides. Furthermore, GST-cOsAHAS was insensitive to feed back inhibition by endproducts which indicates the existence of a regulator subunit in rice AHAS as previously has been described in other plant AHASs. PMID- 30430934 TI - Diverse effects of different "protein-based" vehicles on the stability and bioavailability of curcumin: Spectroscopic evaluation of the antioxidant activity and cytotoxicity in vitro. AB - Curcumin is a natural polyphenolic compound with anti-cancer, anti-inflammatory, and anti-oxidation properties. Low water solubility and rapid hydrolytic degradation are two challenges limiting use of curcumin. In this study, the roles of the native/modified forms of bovine serum albumin (BSA), beta-lactoglobulin (beta-lg) and casein, as food-grade biopolymers and also protein chemical modification, in stabilizing and on biological activity of curcumin were surveyed. Investigation of curcumin stability indicated that curcumin binding to the native BSA and modified beta-lg were stronger than those of the modified BSA and native beta-lg, respectively and hence, the native BSA and modified beta-lg could suppress water-mediated and light-mediated curcumin degradation, significantly. Moreover, in the presence of the native proteins (BSA and casein), curcumin revealed elevated in vitro anti-cancer activity against MCF-7 (human breast carcinoma cell line) and SKNMC (human neuroblastoma cell line). As well, curcumin, in the presence of the unmodified "BSA and beta-lg", was more potent to decrease ROS generation by hydrogen peroxide (H2O2) whereas it led to an inverse outcome in the presence of native casein. Overall, in the presence of the protein bound curcumin, increased anti-cancer activity and decreased ROS generation by H2O2 in vitro were documented. It appears that "water exclusion" is major determinant factor for increased stability/efficacy of the bound curcumin so that some protein-curcumin systems may provide novel tools to increase both food quality and the bioavailability of curcumin as health promoting agent. PMID- 30430935 TI - Identification and characterization of a novel gene-encoded antioxidant peptide from odorous frog skin. AB - Amphibian skin plays an essential role in protecting organisms from harmful external factors such as UV radiation. How amphibians protect themselves from reactive oxygen species following long-term sun exposure is an important and interesting question. Amphibian skins possess a novel antioxidant system composed of various antioxidant peptides (AOPs), which maintain redox homeostasis. However, only a few AOPs have been identified so far. Using peptidomics and genomics, we characterized a novel gene-encoded antioxidant peptide (herein named OA-VI12) from Odorrana andersonii skin secretions, which was produced by the post translational processing of a 59-residue prepropeptide. The amino acid sequence of the peptide was 'VIPFLACRPLGL', with a molecular mass of 1298.65 Da and no observed post-transcriptional modifications. Functional analysis demonstrated that OA-VI12 was capable of scavenging ABTS+, DPPH, Fe3+, and NO free radicals. We determined that the C7 amino acid was responsible for ABTS+ and Fe3+ scavenging, the F4, C7, and P9 amino acids were crucial for DPPH scavenging, and the P9 amino acid was responsible for NO scavenging. Unlike several other amphibian peptides, OA-VI12 did not accelerate wound healing in a full-thickness skin-wound mouse model and did not demonstrate direct microbial killing. Here, we identified and named a novel gene-encoded antioxidant peptide from the skin secretions of an odorous frog species, which may assist in the development of potential antioxidant candidates. This study will help improve our understanding of the molecular basis of amphibian adaptation to environments experiencing long term UV radiation. PMID- 30430936 TI - Immunodominant IgE epitopes of Der p 5 Allergen. AB - BACKGROUND: Der p 5 is an important allergen of Dermatophagoides pteronyssinus that plays a key role in allergic airway diseases. Its three dimensional structure (PDB 3MQ1) consists of three anti-parallel alpha-helices arranged in a helical bundle. Aggregation of Der p5 can modulate its allergenicity. This study aimed to identify the key residues of IgE binding epitopes of Der p 5. METHODS: IgE binding epitopes of Der p 5 were characterized as follow. An in silico prediction of the epitope was performed with the help of SEPPA program. We also made a mapping of the epitope by using an overlapping library of peptides that encompass the sequence of mature Der p 5. Finally, an alanine scanning mutagenesis allowed us to define the key residues of the allergen involved in its interaction with IgE. The integrity of the structure of the different protein's mutants was assessed by far UV circular dichroism. RESULTS: The presented data indicate that the major epitope sequence of Der p 5 is 90DRLMQRKDLDIFEQYNLEM108. Residues L98, D99, I100, F101, E102 and Y104 appear to be important for IgE binding. CONCLUSIONS: This study highlighted the residues of Der p 5 essential for IgE binding. The identification of the major residues epitope of Der p 5 allergen may participate in the selection and engineering of new hypoallergens used in immunotherapy. PMID- 30430938 TI - Antifungal activity, mode of action, docking prediction and anti-biofilm effects of (+)-beta-pinene enantiomers against Candida spp. AB - AIMS: The objective of this study was to investigate the effectiveness of (+) beta-pinene inhibition onCandida spp. growth,aiming at elucidation of the mechanism of action; to determinefungal cell enzymebinding activity (through molecular docking simulations) and its effects on biofilm reduction. METHODOLOGY: Candidastrains (n=26)from referencedand clinical origins, eithersusceptible or resistant to standard clinical antifungals, were tested for determination of Minimum Inhibitory Concentration (MIC); Minimum Fungicidal Concentration (MFC); and microbial death curves upon treatment with (+)-beta-pinene; the effects of (+)-beta-pinene on the cell wall (sorbitol assay), membrane ergosterol binding, and effects on biofilm wereevaluatedby microdilution techniques. We also evaluated the interactions between (+)-beta-pinene and cell wall and membrane enzymes of interest. RESULTS: The MIC values of (+)-beta-pinene ranged from <56.25 to 1800 umol/L. The MIC of (+)-beta-pinene did not increase when ergosterol was added to the medium, however it did increase in the presence of sorbitol, leading to a doubled MIC for C. tropicalis and C. krusei. The results of the molecular docking simulationsindicatedbetter interactionwith delta-14 sterol reductase (-51 kcal/mol). (+)-beta-pinene presents anti-biofilm activity againstmultiples species of Candida. CONCLUSION: (+)-beta-pinene has antifungal activityand most likely acts throughinterference with the cell wall; through molecular interaction with Delta-14-sterol reductase and, to a lesser extent, with the 1,3-beta-glucan synthase.This molecules was also found to effectively reduceCandida biofilm adhesion. PMID- 30430939 TI - Anxiety assessment in pre-clinical tests and in clinical trials: a critical review. AB - The identification of anxious symptoms is crucial to diagnose anxiety disorders, as well as to monitor their treatment in clinical practice and research. The aim of this review is to discuss the different ways of assessing anxiety in clinical research, including clinical trials, and the different kinds of animal behavioral tests used to study anxiety and test the efficacy of anxiolytics in pre-clinical studies. In clinical practice a categorical classification (such as the Diagnostic and Statistical Manual of Mental Disorders and the International Statistical Classification of Diseases and Related Health Problems) distinguishes the cases of the disease versus non-disease. Some structured and semi-structured interviews can be used to arrive at these diagnoses. On the other hand, anxiety can also be assessed using a dimensional approach, through self-report or hetero evaluation questionnaires. Regarding the assessment of anxiety in animals, several behavioral tests are described and evaluated, namely the Social Interaction Test, Elevated Plus Maze and Open Field Test. Under a critical view, these two approaches are presented and discussed, in order to improve the outcome of research in this field. PMID- 30430937 TI - Antioxidant components of Brassica vegetables including turnip and the influence of processing and storage on their anti-oxidative properties. AB - Brassica vegetables, particularly turnip, are a rich source of natural antioxidants. This review focuses on antioxidant components and the effect of processing and storage conditions on antioxidant activities of some Brassica vegetables including turnip. Long storage times had an adverse effect on antioxidant value of turnip. Also during cooking, the antioxidant activity of Brassica vegetables might be influenced by qualitative changes, antioxidant breakdown and leaching into surrounding water. Heat treatment influences the antioxidant activity of Brassica vegetables and it has been observed lower antioxidant capacity in processed samples versus raw vegetables. Industrial processing such as blanching, canning, sterilizing and freezing, as well as cooking methods probably affect the yield, chemical composition and bioavailability of antioxidants in Brassica vegetables. Cooking methods such as steaming and microwaving are proper methods for a short time. Consumption of raw or slightly blanched turnip is an appropriate way to maximize its health benefits. PMID- 30430940 TI - Anxiety disorders: sex differences in serotonin and tryptophan metabolism. AB - INTRODUCTION: Anxiety disorders manifest in women more than in men by almost twofold. This narrative review aims to summarize the sex-related biological factors, which underpin anxiety, focusing on the interactions of sex and tryptophan/serotonin with anxiety. METHODS: A literature search was conducted using Google Scholar, PubMed/MEDLINE, Scopus, and EMBASE databases from inception until December 31, 2017. RESULTS: This review shows that sex may interact with many serotonin functions thereby modulating anxiety, including 5-HT1A and 5-HT2C receptors, 5-HT transporter and central 5-HT concentrations and metabolism. Sex steroids modulate the expression of serotonin transporter genes, creating a difference in serotonin availability. Sex and estrous cycle phases lead to varying anxiety responses to tryptophan depletion. Testosterone, progesterone and estrogen are important factors in mediating sex differences in serotonin responses to anxiety-generating behavioral tests. At prenatal levels, there are sex-related differences in the reciprocal relationships between serotonin and the HPA-axis, which modulate anxiety-like behaviors. Activated immune-inflammatory pathways induce indoleamine-2,3-dioxynease (IDO) and the tryptophan catabolite (TRYCAT) pathway thereby increasing tryptophan degradation and increasing the production of TRYCATs including kynurenine and quinolinic acid, which may create an overall anxiogenic effect. The effects of immune activation on IDO are significantly more pronounced in women than men and therefore females may show increased levels of anxiogenic TRYCAT following immune challenge. Aberrations in the IDO-activated TRYCAT pathway are found in pregnant females and parturients and are associated with increased anxiety levels in the postnatal period. CONCLUSIONS: The results of this review underscore the necessity of studying the associations between serotonin and anxiety in both sexes taking into account the effects of immune activation on IDO and production of anxiogenic TRYCATs. Future anxiety research should focus on the interactions between serotonin/tryptophan and sex, sex hormones, the menstrual cycle, pregnancy, the HPA axis and the immune system through production of anxiogenic TRYCATs. PMID- 30430941 TI - Common environmental factors may underpin the comorbidity between generalized anxiety disorder and mood disorders via activated nitro-oxidative pathways. AB - Generalized anxiety disorder (GAD) commonly co-occurs with mood disorders, especially major depressive disorder (MDD) and bipolar disorder (BD), which are accompanied by activated neuro-immune and neuro-oxidative pathways. The aim of this narrative review is to review the phenomenological similarities and dissimilarities and the shared pathways between GAD and mood disorders. We searched PubMed, Scopus, and Google Scholar for articles published in English from 1980 to present. GAD and mood disorders, either MDD or BD, show some phenomenological overlaps and a high degree of comorbidity, especially between GAD and MDD. Both GAD and mood disorders are also frequently comorbid with other anxiety disorders, substance use disorders and medical conditions, including cardio-vascular disorder (CVD). Mood disorders have a worse prognosis when GAD is present. GAD and mood disorders are associated with female sex and may partly share genetic variants of risk. Moreover, both GAD and mood disorders frequently share similar environmental risks factors including early life time trauma (ELT) and psychological stressors in adulthood (PSA). Increased nitro-oxidative stress and lipid peroxidation coupled to lowered lipid-associated antioxidant defenses are evident in GAD, MDD and type I bipolar patients. Patients with comorbid GAD and MDD show significantly higher nitro-oxidative biomarkers as compared with patients presenting with either GAD or MDD as well as patients with BD with or without co-occurring GAD. Activated immune-inflammatory processes characterized by increased levels of CRP and pro-inflammatory cytokines are other shared pathways that underpin GAD and mood disorders. Moreover, these pathways may explain comorbidities with medical disorders including CVD. Aberrations in HPA axis, GABA and glutamate neurotransmission, NMDA and mu opioid-receptors and neuroimaging fields have yielded more inconsistent findings. In conclusion, here we propose a new model explaining GAD and the comorbidity between GAD and mood disorders. Common triggers such as ELT/PSA may underpin GAD and its comorbidity with mood disorders via activated neuro-oxidative, neuro-nitrosative and neuro immune pathways. PMID- 30430942 TI - Depression assessment in clinical trials and pre-clinical tests: a critical review. AB - Depression is deeply rooted in human behavior, but the development of new antidepressants demanded the creation of animal models to investigate new drugs, which potentially could work as antidepressants. The aim of this review is to discuss the different ways of assessing depression in clinical research, including clinical trials, and the different animal behavioral tests used to study depression and test the efficacy of antidepressants in pre-clinical studies. In clinical practice a categorical classification, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the International Statistical Classification of Diseases and Related Health Problems (ICD) can be used for diagnosis, through the use of structured and semi-structured interviews. On the other hand, depression can also be assessed using a dimensional approach, through self- or clinician-rated questionnaires. Regarding the assessment of the efficacy of antidepressants in animal models, several tests are routinely used, namely the Forced Swim Test, the Modified Forced Swim Test, the Tail Suspension Test and the Sucrose Preference Test. These tests are informative, providing that the following rules are taken into account: 1) more than one test is used, with coherent results; 2) secondary drug effects, the most frequent being putative changes in motor activity, are taken into account and properly controlled with specific tests run concomitantly; 3) each test and specific protocol is validated with data from at least a gold standard antidepressant drug. We herein briefly discuss the potential and limitations of each of those tests. PMID- 30430943 TI - Exploration of Umbelliferone based Derivatives as Potent MAO inhibitors: Dry Vs Wet lab Evaluation. AB - BACKGROUND: Monoamine oxidase inhibitors are potential drug candidates within therapeutics of different neuropsychological and neurodegenerative disorders including anxiety, depression and Parkinson's disease. OBJECTIVE: We investigated the MAO inhibitory effects of the umbelliferone based derivatives for the treatment of neurological disorders. The potential antioxidant effects of the derivatives were evaluated by DPPH and H2O2 scavenging methods. METHOD: A series of different umbelliferone derivatives was designed and synthesized, for hMAO-A and hMAO-B inhibition the derivatives were screened. Moreover, the mechanistic insight for enzyme-compound infractions was achieved by docking simulation. The antioxidant potential was dually assessed by two spectrophotometric titrations methods. RESULTS: Compound 5 with bromo 5-bromo-isatin exhibited remarkable hMAO A inhibitory potential (7.473+/-0.035 uM and the selectivity index of 0.14) revealed the impact of hybrid coumarin and 5-bromo-2-oxoindolin-3-yl ring with hydrazine linker for the hMAO-A active site. Compound 13 exhibited significant hMAO-B inhibition with an IC50 value of 10.32+/-0.044uM with an exceptional selectivity index of 8.55. Incorporation of 2-hydroxy-2-phenylacetate moiety on 2 oxo-2H-chromen ring led the important binding infractions within the hMAO active site. CONCLUSION: Our findings revealed a good correlation between experimental MAO inhibition and docking score by computational studies. Notably, the compounds with remarkable MAO inhibitory potential were also observed as potential antioxidants. PMID- 30430944 TI - Recognizing the leaky gut as a trans-diagnostic target for neuro-immune disorders using clinical chemistry and molecular immunology assays. AB - BACKGROUND: Increased intestinal permeability with heightened translocation of Gram-negative bacteria, also known as "leaky gut", is associated with the pathophysiology of neuroimmune disorders, such as major depressive disorder (MDD), chronic fatigue syndrome (CSF) and (deficit) schizophrenia, as well as with general medical disorders, including irritable bowel syndrome. This review aims to summarize clinical biochemistry and molecular immunology tests that may aid in the recognition of leaky gut in clinical practice. METHODS: We searched online libraries, including PubMed/MEDLINE, Google Scholar and Scopus, with the key words "diagnosis" or "biomarkers" and "leaky gut", "bacterial translocation", and "intestinal permeability" and focused on papers describing tests that may aid in the clinical recognition of leaky gut. RESULTS: To evaluate tight junction barrier integrity, serum IgG/IgA/IgM responses to occludin and zonulin and IgA responses to actomyosin should be evaluated. The presence of cytotoxic bacterial products in serum can be evaluated using IgA/IgM responses to sonicated samples of common Gram-negative gut commensal bacteria and assays of serum lipopolysaccharides (LPSs) and other bacterial toxins, including cytolethal distenting toxin, subunit B. Major factors associated with increased gut permeability, including gut dysbiosis and yeast overgrowth, use of NSAIDs and alcohol, food hypersensitivities (IgE-mediated), food intolerances (IgG mediated), small bacterial overgrowth (SIBO), systemic inflammation, psychosocial stressors, some infections (e.g., HIV) and dietary patterns, should be assessed. Stool samples can be used to assay gut dysbiosis, gut inflammation and decreased mucosal defenses using assays of fecal growth of bacteria, yeast and fungi and stool assays of calprotectin, secretory IgA, beta-defensin, alpha-antitrypsin, lysozyme and lactoferrin. Blood and breath tests should be used to exclude common causes of increased gut permeability, namely, food hypersensitivities and intolerances, SIBO, lactose intolerance and fructose malabsorption. DISCUSSION: Here, we propose strategies to recognize "leaky gut" in a clinical setting using the most adequate clinical chemistry and molecular immunology assays. PMID- 30430945 TI - Structure-based virtual screening for the identification of high affinity small molecule towards STAT3 for the clinical treatment of Osteosarcoma. AB - According to DCEG investigation, the compared results of the osteosarcoma incidences in different continents, reported it to be mostly diagnosed in adolescents and adults above 60 yrs. old. Less than 15% number of patients get cured with surgery alone but addition of chemotherapy to the treatment increases the survival rate of patient by 58%-76%. Surgical resection and aggressive chemotherapy protocols are effective to an extent, but have failed to improve the 5-year overall survival rate. Indubitably, new drugs and new therapeutic targets are required to improve the outcome as well as to diminish the long-term toxicities associated with the current benchmark of treatment. STAT3 appears to be an important mediator of chemo resistance in osteosarcoma. Experimental evidences clearly demonstrate the disruption of STAT3 signaling which inhibits the survival and proliferation of osteosarcoma and decreases the growth of disease. This prevailing study approach is by molecular docking, virtual screening to elucidate inhibitor with superior affinity against STAT3 to have a cautious pharma profile. To rectify the best established drug with high affinity, Mol dock algorithm is executed. The compound Sorafenib (Pub CID 216239) having high affinity scores is subjected to another similarity search to retrieve the drugs with similar properties. The virtual screened compound with PubChem CID 44815014 as per BOILED-Egg plot reveals its high affinity. Comparative study and ADMET study both showed the compounds to have equivalent properties, whereas interestingly the virtual screened compound having PubChem CID-44815014 is seen to have the lowest rerank score. These drugs are identified to have high potential to act as STAT3 inhibitors and probably can be considered for further studies in wet lab analysis. PMID- 30430946 TI - The Development of Epigenetics and Related Inhibitors for Targeted Drug Design in Cancer Therapy. AB - Epigenetics process is the heritable change in gene function that does not involve changes in the DNA sequence. Until now, several types of epigenetic mechanisms have been characterized, including DNA methylation, histone modification (acetylation, methylation, etc.), nucleosome remodeling, and noncoding RNAs. With the biological investigations of these modifiers, some of them are identified as promoters in the process of various diseases, such as cancer, cardiovascular disease and virus infection. Epigenetic changes may serve as potential "first hits" for tumorigenesis. Hence, targeting epigenetic modifiers is being considered as a promising way for disease treatment. To date, six agents in two epigenetic target classes (DNMT and HDAC) have been approved by the US Food and Drug Administration (FDA). Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the treatment of solid tumor. Due to the rapid development of epigenetics and epigenetics targeted drugs, it is becoming an emerging area in targeted drug design. PMID- 30430948 TI - Withdrawn: Controlling HCV infection by targeting its translation initiation site in PBMCs using siRNA; In Vitro. AB - The manuscript has been withdrawn by the publisher. PMID- 30430947 TI - Development of Betamethasone Dipropionate-Loaded Nanostructured Lipid Carriers for Topical and Transdermal Delivery. AB - Betamethasone dipropionate is a highly effective corticosteroid anti inflammatory. However, the main drawback of its topical use is the limited skin penetration into deeper skin layers. Also, its systemic use has shown many side effects. The goal of this research was to formulate betamethasone dipropionate in nanostructured lipid carriers (NLC) formulae that contain oleic acid to aid its penetration to deeper skin layers and to aid absorption to local regions upon topical application.NLC formulae were prepared by high shear homogenization then sonication. Formulae were characterized for their particle size, size distribution, electric potential, occlusion factor, entrapment efficiency, drug loading, transmission electron microscopy, in vitro drug release, and ex vivo skin penetration. Compatibility of ingredients with drug was tested using differential scanning calorimetry. Formulae were shown to have appropriate characteristics. NLC formulae were superior to traditional topical formulation in drug release. Upon testing ex vivo skin penetration, betamethasone dipropionate prepared in NLC formulae was shown to penetrate more efficiently into skin layers than when formulated as a traditional cream. NLC formulation that contained higher percentage of oleic acid showed higher penetration and higher amount of drug to pass through skin. In general, NLC with lower oleic acid percentage was shown to deliver betamethasone dipropionate more efficiently into deeper skin layers while that of a higher oleic acid percentage was shown to deliver the drug more efficiently into deeper skin layers and through the skin, transdermally. PMID- 30430949 TI - Extending Arms of Insulin Resistance from Diabetes to Alzheimer's disease: Identification of Potential Therapeutic Targets. AB - Type 3 diabetes (T3D) is chronic brain insulin resistant state which has shared pathology with sporadic Alzheimer's disease (sAD). Insulin signaling is a highly conserved pathway in the living systems that orchestrate cell growth, repair, maintenance, energy homeostasis and reproduction. Although insulin is primarily studied as a key molecule in diabetes mellitus, its role has recently been implicated in the development of Alzheimer's disease (AD) pathology. Severe brain complications are observed in diabetic patients and metabolically compromised brain status is evident in AD patients. Underlying shared pathology of these two disorders draws a trajectory from peripheral insulin resistance to insulin unresponsiveness in the central nervous system (CNS). As insulin has a pivotal role in AD, it is not an overreach to address brain diabetic condition in AD as T3D. Insulin signaling is indispensable for nervous system and is vital for neuronal growth, repair, and maintenance of chemical milieu at synapses. Downstream mediators of insulin signaling pathway work as a regulatory hub for aggregation and clearance of unfolded proteins like Abeta and tau. In this review, we will discuss the regulatory roles of insulin as a pivotal molecule in brain with current understanding of defective insulin signaling as a key pathological mechanism in sAD. This also highlights ongoing trials of targeting insulin signaling as a therapeutic manifestation to treat brain diabetic condition. PMID- 30430950 TI - The Unprecedented Role of Gold Nonmaterial in Diabetes Management. AB - BACKGROUND: Gold nanoparticles possess unique mechanical, chemical, photo-optical and biological properties and have been an interesting field of research and development in life sciences. Research efforts in this area have resulted in innovative nanodevices and nanostructures useful in the diagnostics, biosensing, therapeutics, and targeted drug delivery. OBJECTIVE: In this review, the unique potential aspects of gold nanoparticles/ nanoformulations/ or devices related to diabetes management have been discussed together with the recent patent on the gold nanoparticles / or developed for diabetes management. The first part of this review will focus on recent strategies for the treatment of hyperglycemia and its management with the help of gold nanoparticles and the second part of the review reports recent patents on gold nanoparticles useful in the diabetes management. CONCLUSION: Gold nanoparticles have proved themselves useful in diabetes therapeutics and diagnostics. Due to low inherent toxicity, and high surface area, gold nanoparticles have become a unique aspect of the delivery approach. The key issue that needs to be addressed is the bio pharmaceutics, biocompatibility, and potential clinical applications. PMID- 30430951 TI - Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial - Corrigendum. PMID- 30430952 TI - Treatment outcomes for anorexia nervosa: a systematic review and meta-analysis of randomized-controlled trials - CORRIGENDUM. PMID- 30430953 TI - Predictors of vitamin A status among pregnant women in Western Brazilian Amazon. AB - Determining the predictors of serum retinol at mid-pregnancy is relevant for planning interventions aimed at improving vitamin A status of pregnant women and their offspring. This prospective study assessed predictors of serum retinol at the beginning of the third trimester of pregnancy. We enrolled 442 pregnant women living in the urban area of Cruzeiro do Sul, Western Brazilian Amazon. Demographic, socio-economic, environmental and clinical characteristics as well as obstetric history, anthropometric, dietary and biochemical data, including serum retinol, were gathered between 16 and 20 gestational weeks. Serum retinol also measured at the beginning of the third trimester of pregnancy (approximately 28 gestational weeks) was the outcome of interest. Multiple linear regression models were used to evaluate associations with the outcome. Overall, the following variables explained serum retinol at the beginning of the third trimester of pregnancy in the adjusted model (R 2 = 11.1 %): seasonality (winter season - November to April; beta=0.134; 95 % CI 0.063, 0.206), weekly consumption of Amazonian fruits (beta=0.087; 95 % CI 0.012, 0.162) and retinol concentrations between 16 and 20 gestational weeks (beta=0.045; 95 % CI 0.016, 0.074) were positively associated, whereas having a smoker in the house was negatively associated (beta=-0.087; 95 % CI: -0.166, -0.009). Consumption of pro-vitamin A rich fruits by pregnant women should be encouraged. Passive smoking may play a role in decreasing vitamin A status as a proxy of smoking exposure during pregnancy. PMID- 30430954 TI - Species and site contributions to beta-diversity in fleas parasitic on the Palearctic small mammals: ecology, geography and host species composition matter the most. AB - The beta-diversity of fleas parasitic on small mammals in 45 regions of the Palearctic was partitioned into species [species contributions to beta-diversity (SCBD)] and site ( = assemblage) contributions [local contributions to beta diversity (LCBD)]. We asked what are the factors affecting SCBD and LCBD and tested whether (a) variation in ecological, morphological, life history and geographic traits of fleas can predict SCBD and (b) variation in flea and host community metrics, off-host environmental factors, host species composition of flea assemblages can predict LCBD. We used spatial variables to describe geographic distribution of flea assemblages with various LCBD values. SCBD significantly increased with an increase in abundance and a decrease in phylogenetic host specificity of a flea as well as with size and latitude of its geographic range, but was not associated with any morphological/life history trait. LCBD of flea assemblages did not depend on either flea or host species richness or environmental predictors, but was significantly affected by compositional uniqueness ( = LCBD) of regional host assemblages and variables describing their species composition. In addition, variation in LCBD was also explained by broad-to-moderate-scale spatial variables. We conclude that SCBD of fleas could be predicted via their ecological and geographic traits, whereas LCBD of their assemblages could be predicted via host composition. PMID- 30430955 TI - Model systems for investigating disease processes in neurocysticercosis. AB - Neurocysticercosis (NCC) occurs following brain infection by larvae of the cestode Taenia solium. It is the leading cause of preventable epilepsy worldwide and therefore constitutes a critical health challenge with significant global relevance. Despite this, much is still unknown about many key pathogenic aspects of the disease, including how cerebral infection with T. solium results in the development of seizures. Over the past century, valuable mechanistic insights have been generated using both clinical studies and animal models. In this review, we critically assess model systems for investigating disease processes in NCC. We explore the respective strengths and weaknesses of each model and summarize how they have contributed to current knowledge of the disease. We call for the continued development of animal models of NCC, with a focus on novel strategies for understanding this debilitating but often neglected disorder. PMID- 30430956 TI - Laterality of a short-term peripheral intravenous catheter does not affect complications or patient satisfaction: a subanalysis of the One Million Global Peripheral Intravenous Catheter Study. PMID- 30430957 TI - Diets high in n-3 fatty acids are associated with lower arterial stiffness in patients with rheumatoid arthritis: a latent profile analysis. AB - Supplementation with n-3 fatty acids can influence inflammation and markers of arterial stiffness that are increased in patients with rheumatoid arthritis (RA). However, it is unknown whether specific patterns of dietary fatty acid intake are similarly associated. In a longitudinal study, eighty-six RA patients reported their dietary intake and had arterial stiffness measured using the augmentation index (AIx) at baseline and 8 months. Latent profile analysis (LPA) was performed to characterise patterns of fatty acid intake using sixteen major fatty acids. Models for two to six profiles were compared using the Akaike and Bayesian information criteria. Associations between AIx and the profiles were adjusted for age, sex, disease activity, fish oil supplementation, medications, physical activity and socio-economic status. LPA identified five distinct profiles. Profile 1 subjects (n 7) reported significantly higher intake of palmitoleic acid (16 : 1), arachidonic acid (20 : 4n-6), EPA (20 : 5n-3), DHA (22 : 6n-3) and docosapentaenoic acid (22 : 5n-3) (P<0.001 for each) than profiles 2 (n 14), 3 (n 19), 4 (n 23) and 5 (n 23) and significantly higher grilled and tinned fish consumption. The AIx varied significantly across the five profiles (P=0.023); subjects in profile 1 had a significantly lower AIx than those in profile 3 (beta=-7.2 %; 95 % CI -11.5, -2.9; P=0.001) who had the lowest reported intake of n-3 fatty acids. Fish oil supplementation was also independently associated with lower AIx (beta=-4.15 %; 95 % CI -6.73, -1.56; P=0.002). A diet characterised by a higher reported intake of n-3 fatty acids, palmitoleic acid (16 : 1) and arachidonic acid (20 : 4n-6) is associated with a lower AIx in RA patients. PMID- 30430958 TI - Incidence and Outcomes after Out-of-Hospital Medical Emergencies in Gambia: A Case for the Integration of Prehospital Care and Emergency Medical Services in Primary Health Care. AB - BACKGROUND: The Gambia is going through a rapid epidemiologic transition with a dual disease burden of infections and non-communicable diseases occurring at the same time. Acute, time-sensitive, medical emergencies such as trauma, obstetric emergencies, respiratory failure, and stroke are leading causes of morbidity and mortality among adults in the country.ProblemData on medical emergency care and outcomes are lacking in The Gambia. Data on self-reported medical emergencies among adults in a selection of Gambian communities are presented in this report. METHODS: A total of 320 individuals were surveyed from 34 communities in the greater Banjul area of The Gambia using a survey instrument estimating the incidence of acute medical emergencies in an adult population. Self-reported travel time to a health facility during medical emergencies and patterns of health-seeking behavior with regard to type of facility visited and barriers to accessing emergency care, including cost and medical insurance coverage, are presented in this report. RESULTS: Of the 320 individuals surveyed, 262 agreed to participate resulting in a response rate of 82%. Fifty-two percent of respondents reported an acute medical emergency in the preceding year that required urgent evaluation at a health facility. The most common facility visited during such emergencies was a health center. Eighty-seven percent of respondents reported a travel time of less than one hour during medical emergencies. Out-of-pocket cost of medications accounted for the highest expenditure during emergencies. There was a low awareness and willingness to subscribe to health insurance among individuals surveyed. CONCLUSION: There is a high incidence of acute medical emergencies among adults in The Gambia which are associated with adverse outcomes due to a combination of poor health literacy, high out-of-pocket expenditures on medications, and poor access to timely prehospital emergency care. There is an urgent need to develop prehospital acute care and Emergency Medical Services (EMS) in the primary health sector as part of a strategy to reduce mortality and morbidity in the country.Touray S, Sanyang B, Zandrow G, Touray I. Incidence and outcomes after out-of-hospital medical emergencies in Gambia: a case for the integration of prehospital care and Emergency Medical Services in primary health care. PMID- 30430959 TI - Identifying key targets for interventions to improve psychological wellbeing: replicable results from four UK cohorts. AB - BACKGROUND: An increasing importance is being placed on mental health and wellbeing at individual and population levels. While there are several interventions that have been proposed to improve wellbeing, more evidence is needed to understand which aspects of wellbeing are most influential. This study aimed to identify key items that signal improvement of mental health and wellbeing. METHODS: Using network analysis, we identified the most central items in the graph network estimated from the well-established Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Results were compared across four major UK cohorts comprising a total of 47,578 individuals: the Neuroscience in Psychiatry Network, the Scottish Schools Adolescent Lifestyle and Substance Use Survey, the Northern Ireland Health Survey, and the National Child Development Study. RESULTS: Regardless of gender, the three items most central in the network were related to positive self-perception and mood: 'I have been feeling good about myself'; 'I have been feeling confident'; and 'I have been feeling cheerful'. Results were consistent across all four cohorts. CONCLUSIONS: Positive self-perception and positive mood are central to psychological wellbeing. Psychotherapeutic and public mental health interventions might best promote psychological wellbeing by prioritising the improvement of self-esteem, self-confidence and cheerfulness. However, empirical testing of interventions using these key targets is needed. PMID- 30430960 TI - Emergency with Resiliency Equals Efficiency - Challenges of an EMT-3 in Nepal. AB - The 7.8 MW (moment magnitude scale) earthquake that hit Nepal on April 25, 2015 caused significant casualties and serious damage to infrastructure.The Israeli Emergency Medical Team (IEMT; later verified as EMT-3) was deployed 80 hours after the earthquake. A Forward Disaster Scout Team (FDST) that was dispatched to the disaster area a few hours after the disaster relayed pre-deployment information.The EMT staff was comprised of 42 physicians. A total of 1,668 patients were treated. The number of non-trauma cases increased as the days went by. The hospitalization rate was 31%. Wound debridement procedures were the most common operations performed.Yitzhak A, Merin O, Halevy J, Tarif B. Emergency with resiliency equals efficiencychallenges of an EMT-3 in Nepal. PMID- 30430961 TI - Prediction of remission in pharmacotherapy of untreated major depression: development and validation of multivariable prediction models. AB - BACKGROUND: Depression is increasingly recognized as a chronic and relapsing disorder. However, an important minority of patients who start treatment for their major depressive episode recover to euthymia. It is clinically important to be able to predict such individuals. METHODS: The study is a secondary analysis of a recently completed pragmatic megatrial examining first- and second-line treatments for hitherto untreated episodes of non-psychotic unipolar major depression (n = 2011). Using the first half of the cohort as the derivation set, we applied multiply-imputed stepwise logistic regression with backward selection to build a prediction model to predict remission, defined as scoring 4 or less on the Patient Health Quetionnaire-9 at week 9. We used three successively richer sets of predictors at baseline only, up to week 1, and up to week 3. We examined the external validity of the derived prediction models with the second half of the cohort. RESULTS: In total, 37.0% (95% confidence interval 34.8-39.1%) were in remission at week 9. Only the models using data up to week 1 or 3 showed reasonable performance. Age, education, length of episode and depression severity remained in the multivariable prediction models. In the validation set, the discrimination of the prediction model was satisfactory with the area under the curve of 0.73 (0.70-0.77) and 0.82 (0.79-0.85), while the calibration was excellent with non-significant goodness-of-fit chi2 values (p = 0.41 and p = 0.29), respectively. CONCLUSIONS: Patients and clinicians can use these prediction models to estimate their predicted probability of achieving remission after acute antidepressant therapy. PMID- 30430962 TI - Provincial Differences in the Diagnosis and Care of Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease resulting in muscle weakness, dysarthria and dysphagia, and ultimately respiratory failure leading to death. Half of the ALS patients survive less than 3 years, and 80% of the patients survive less than 5 years. Riluzole is the only approved medication in Canada with randomized controlled clinical trial evidence to slow the progression of ALS, albeit only to a modest degree. The Canadian Neuromuscular Disease Registry (CNDR) collects data on over 140 different neuromuscular diseases including ALS across ten academic institutions and 28 clinics including ten multidisciplinary ALS clinics. METHODS: In this study, CNDR registry data were analyzed to examine potential differences in ALS care among provinces in time to diagnosis, riluzole and feeding tube use. RESULTS: Significant differences were found among provinces, in time to diagnosis from symptom onset, in the use of riluzole and in feeding tube use. CONCLUSIONS: Future investigations should be undertaken to identify factors contributing to such differences, and to propose potential interventions to address the provincial differences reported. PMID- 30430963 TI - Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study. AB - This open study investigated the clinical effects of 10-week selegiline administration in six patients in vegetative state and in four patients in a minimally conscious state, at least 6 months after onset. Clinical outcome was assessed by Coma Recovery Scale-Revised once a week during selegiline administration and 1 month later. Three patients stopped treatment because of possible side effects. After treatment and at 1 month of follow-up, four patients showed improvements in clinical diagnosis, and three patients showed an increase in arousal level only. Selegiline might represent a relatively safe option to enhance arousal and promote recovery in brain-injured patients with disorders of consciousness. PMID- 30430964 TI - Neuromuscular Ultrasound: Clinical Applications and Diagnostic Values. AB - Advances in high-resolution ultrasound have provided clinicians with unique opportunities to study diseases of the peripheral nervous system. Ultrasound complements the clinical and electrophysiology exam by showing the degree of abnormalities in myopathies, as well as spontaneous muscle activities in motor neuron diseases and other disorders. In experienced hands, ultrasound is more sensitive than MRI in detecting peripheral nerve pathologies. It can also guide needle placement for electromyography exam, therapeutic injections, and muscle biopsy. Ultrasound enhances the ability to detect carpal tunnel syndrome and other focal nerve entrapment, as well as pathological nerve enlargements in genetic and acquired neuropathies. Furthermore, ultrasound can potentially be used as a biomarker for muscular dystrophy and spinal muscular atrophy. The combination of electromyography and ultrasound can increase the diagnostic certainty of amyotrophic lateral sclerosis, aid in the localization of brachial plexus or peripheral nerve trauma and allow for surveillance of nerve tumor progression in neurofibromatosis. Potential limitations of ultrasound include an inability to image deeper structures, with lower sensitivities in detecting neuromuscular diseases in young children and those with mitochondrial myopathies, due to subtle changes or early phase of the disease. As well, its utility in detecting critical illness neuromyopathy remains unclear. This review will focus on the clinical applications of neuromuscular ultrasound. The diagnostic values of ultrasound for screening of myopathies, neuropathies, and motor neuron diseases will be presented. PMID- 30430965 TI - Concussion, Cagney, Captains of the Clouds. AB - The case of James Cagney adds interesting details to the history of concussion. It is underappreciated that a movie-star of Cagney's stature incurred multiple concussions over many years. Moreover, the fact that he sustained one of these concussions in Canada while filming Captains of the Clouds, a major Hollywood film, is essentially unknown, and was seldom discussed by Cagney despite his willingness to discuss his many other concussions. The scene showing this concussion was left in the final released version of the movie, making it one of the earliest filmed concussions and the first concussion ever filmed in Technicolor. PMID- 30430966 TI - An Evaluation of the Family Informal Caregiver Stroke Self-Management Program. AB - BACKGROUND: Caregivers are often unprepared and overwhelmed with the responsibilities of providing care to stroke survivors, which can lead to negative physical and psychological effects. PURPOSE: To evaluate the impact of the Family Informal Caregiver Stroke Self-Management (FICSS) program on burden and life changes resulting from providing care among family caregivers of stroke survivors. METHODS: A prospective pre-test and post-test design using quantitative and qualitative data was used to evaluate the program with a convenience sample of 42 caregivers. The four-module facilitated program consisted of small group-guided discussion. Quantitative evaluations were completed at baseline, 2 weeks and 6 months (post-intervention), and qualitative data were collected at 2 weeks and 6 months. Life changes and burden were measured using the Bakas Caregiving Outcome Scale (BCOS) and the Oberst Caregiving Burden Scale (OCBS), respectively. RESULTS: The BCOS scores increased consistently over time, showing significant differences at 6 months compared with 2 weeks (mean difference: 5.29, 95% confidence interval [CI]: 0.30-10.28, p=0.04) and baseline (mean difference: 7.58, 95% CI: 2.92-12.23, p=0.001). The OCBS time scores decreased consistently over time, showing a significant difference at 6 months compared with baseline (mean difference: -5.20, 95% CI: -0.96 to -9.44, p=0.02). The OCBS difficulty scores fluctuated over time, resulting in no overall difference from baseline to 6 months. Qualitative themes were consistent with the positive quantitative findings. CONCLUSION: Study results suggest that the FICSS program may result in reduced caregiver burden and improved life changes resulting from providing care. PMID- 30430967 TI - Cerebral Perfusion Pressure Targets in Traumatic Brain Injury: The "Fuzzy" Spots Above Optimal Cerebral Perfusion Pressure. PMID- 30430968 TI - Low-Intensity Ultrasound Decreases Ischemia-Induced Edema by Inhibiting N-Methyl d-Aspartic Acid Receptors. AB - BACKGROUND: We have previously shown that low-intensity ultrasound (LIUS), a noninvasive mechanical stimulus, inhibits brain edema formation induced by oxygen and glucose deprivation (OGD) or treatment with glutamate, a mediator of OGD induced edema, in acute rat hippocampal slice model in vitro. METHODS: In this study, we treated the rat hippocampal slices with N-methyl-d-aspartic acid (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) to determine whether these different glutamate receptor agonists induce edema. The hippocampal slices were then either sonicated with LIUS or treated with N-methyl-d-aspartic acid receptor (NMDAR) antagonists, namely, MK-801 and ketamine, and observed their effects on edema formation. RESULTS: We observed that treatment with NMDA, an agonist of ionotropic glutamate receptors, induced brain edema at similar degrees compared with that induced by OGD. However, treatment with DHPG, an agonist of metabotropic glutamate receptors, did not significantly induce brain edema. Treatment with the NMDAR antagonists MK-801 or ketamine efficiently prevented brain edema formation by both OGD and NMDA in a concentration-dependent manner. N Methyl-d-aspartic acid-induced brain edema was alleviated by LIUS in an intensity dependent manner when ultrasound was administered at 30, 50, or 100 mW/cm2 for 20 minutes before the induction of the edema. Furthermore, LIUS reduced OGD- and NMDA-induced phosphorylation of NMDARs at Y1325. CONCLUSION: These results suggest that LIUS can inhibit OGD- or NMDA-induced NMDAR activation by preventing NMDAR phosphorylation, thereby reducing a subsequent brain edema formation. The mechanisms by which LIUS inhibits NMDAR phosphorylation need further investigation. PMID- 30430969 TI - Research Priorities for Optimizing Long-term Community Integration after Brain Injury. AB - OBJECTIVE: This paper reports on a funded summit, which convened a multidisciplinary group of experts to provide consensus on the research priorities necessary for improving long-term community integration of individuals with traumatic brain injury (TBI) and their caregivers. METHODS: The 2-day summit was directed using the World Cafe Methodology, to engage stakeholders and collaboratively arrive at a consensus on the problems to be targeted in research. Participants (n=54), drawn from two Canadian provinces, included an interdisciplinary group of researchers, clinicians, representatives from brain injury associations, individuals with TBI, and caregivers. In small groups, participants discussed challenges to long-term community integration and potential initiatives that would address these barriers. Field notes from the discussions were analyzed using qualitative content analysis. RESULTS: The consensus on prioritized research directions included developing interventions to optimize the functioning and participation of individuals with TBI, reducing caregiver burden, and evaluating how emerging technology can facilitate delivery of care. CONCLUSIONS: The World Cafe Methodology was an effective method for developing research priorities. The breadth of expertise of participants and the collegial environment allowed for the identification of a broad perspective on important future research directions with potential to enhance the long-term community integration of individuals with brain injury. PMID- 30430970 TI - Endoscopic Retrieval of Flanged Ventricular Catheters. AB - Flanged ventricular catheters are now used infrequently. Many patients with longstanding hydrocephalus still harbor these catheters, either as their current ventricular catheter, or as a retained catheter from a prior implant. The removal of flanged ventricular catheters is sometimes necessary, and may be challenging due to intraventricular adhesions. We describe the use of an endoscopic technique for the successful retrieval of flanged ventricular catheters in two patients. The technique described in this report may be helpful for patients that have flanged ventricular catheters that must be removed. PMID- 30430972 TI - Recurrent Amoxicillin-Induced Aseptic Meningitis. PMID- 30430971 TI - Epilepsy, Physical Activity and Sports: A Narrative Review. AB - People with epilepsy (PWE) are less physically active compared with the general population. Explanations include prejudice, overprotection, unawareness, stigma, fear of seizure induction and lack of knowledge of health professionals. At present, there is no consensus on the role of exercise in epilepsy. This paper reviews the current evidence surrounding the risks and benefits associated with physical activity (PA) in this group of patients. In the last decade, several publications indicate significant benefits in physiological and psychological health parameters, including mood and cognition, physical conditioning, social interaction, quality of life, as well as potential prevention of seizure presentation. Moreover, experimental studies suggest that PA provides mechanisms of neuronal protection, related to biochemical and structural changes including release of beta-endorphins and steroids, which may exert an inhibitory effect on the occurrence of abnormal electrical activity. Epileptic discharges can decrease or disappear during exercise, which may translate into reduced seizure recurrence. In some patients, exercise may precipitate seizures. Available evidence suggests that PA should be encouraged in PWE in order to promote wellbeing and quality of life. There is a need for prospective randomized controlled studies that provide stronger clinical evidence before definitive recommendations can be made. PMID- 30430973 TI - Atypical Clinical Presentation and Imaging Findings of Central Nervous System Tuberculosis. PMID- 30430974 TI - Testing a novel audit and feedback method for hand hygiene compliance: A multicenter quality improvement study. AB - OBJECTIVE: Although most hospitals report very high levels of hand hygiene compliance (HHC), the accuracy of these overtly observed rates is questionable due to the Hawthorne effect and other sources of bias. In the study, we aimed (1) to compare HHC rates estimated using the standard audit method of overt observation by a known observer and a new audit method that employed a rapid (<15 minutes) "secret shopper" method and (2) to pilot test a novel feedback tool. DESIGN: Quality improvement project using a quasi-experimental stepped-wedge design. SETTING: This study was conducted in 5 acute-care hospitals (17 wards, 5 intensive care units) in the Midwestern United States. METHODS: Sites recruited a hand hygiene observer from outside the acute-care units to rapidly and covertly observe entry and exit HHC during the study period, October 2016-September 2017. After 3 months of observations, sites received a monthly feedback tool that communicated HHC information from the new audit method. RESULTS: The absolute difference in HHC estimates between the standard and new audit methods was ~30%. No significant differences in HHC were detected between the baseline and feedback phases (OR, 0.92; 95% CI, 0.84-1.01), but the standard audit method had significantly higher estimates than the new audit method (OR, 9.83; 95% CI, 8.82 10.95). CONCLUSIONS: HHC estimates obtained using the new audit method were substantially lower than estimates obtained using the standard audit method, suggesting that the rapid, secret-shopper method is less subject to bias. Providing feedback using HHC from the new audit method did not seem to impact HHC behaviors. PMID- 30430975 TI - Mentorship Training is Essential to Advancing Global Health Research. AB - Mentorship Training is Essential to Advancing Global Health Research. PMID- 30430976 TI - Global Health Research Mentoring Competencies for Individuals and Institutions in Low- and Middle-Income Countries. AB - Mentoring is beneficial to mentors, mentees, and their institutions, especially in low- and middle-income countries (LMICs), that are faced with complex disease burdens, skills shortages, and resource constraints. Mentoring in global health research can be enhanced by defining key competencies, to enable the skill set required for effective mentoring, determine training needs for local research mentors, and facilitate institutional capacity building to support mentors. The latter includes advocating for resources, institutional development of mentoring guidelines, and financial and administrative support for mentoring. Nine core global health research mentoring competencies were identified: maintaining effective communication; aligning expectations with reasonable goals and objectives; assessing and providing skills and knowledge for success; addressing diversity; fostering independence; promoting professional development; promoting professional integrity and ethical conduct; overcoming resource limitations; and fostering institutional change. The competencies described in this article will assist mentors to sharpen their cognitive skills, acquire or generate new knowledge, and enhance professional and personal growth and job satisfaction. Similarly, the proposed competencies will enhance the knowledge and skills of mentees, who can continue and extend the work of their mentors, and advance knowledge for the benefit of the health of populations in LMICs. PMID- 30430977 TI - Mentoring the Mentors: Implementation and Evaluation of Four Fogarty-Sponsored Mentoring Training Workshops in Low-and Middle-Income Countries. AB - A growing body of evidence highlights the importance of competent mentoring in academic research. We describe the development, implementation, and evaluation of four regional 2-day intensive workshops to train mid- and senior-level investigators conducting public health, clinical, and basic science research across multiple academic institutions in low- and middle-income countries (LMICs) on tools and techniques of effective mentoring. Sponsored by the Fogarty International Center, workshops included didactic presentations, interactive discussions, and small-group problem-based learning and were conducted in Lima, Peru; Mombasa, Kenya; Bangalore, India; and Johannesburg, South Africa, from 2013 to 2016. Mid- or senior-level faculty from multiple academic institutions within each region applied and were selected. Thirty faculty from 12 South America-based institutions, 29 faculty from eight East Africa-based institutions, 37 faculty from 14 South Asia-based institutions, and 36 faculty from 13 Africa-based institutions participated, with diverse representation across disciplines, gender, and academic rank. Discussions and evaluations revealed important comparisons and contrasts in the practice of mentoring, and specific barriers and facilitators to mentoring within each cultural and regional context. Specific regional issues related to hierarchy, the post-colonial legacy, and diversity arose as challenges to mentoring in different parts of the world. Common barriers included a lack of a culture of mentoring, time constraints, lack of formal training, and a lack of recognition for mentoring. These workshops provided valuable training, were among the first of their kind, were well-attended, rated highly, and provided concepts and a structure for the development and strengthening of formal mentoring programs across LMIC institutions. PMID- 30430978 TI - Evaluating Academic Mentorship Programs in Low- and Middle-Income Country Institutions: Proposed Framework and Metrics. AB - A growing number of low- and middle-income country (LMIC) institutions have developed and implemented formal programs to support mentorship. Although the individual-level benefits of mentorship are well established, such activities can also sustainably build institutional capacity, bridge inequities in health care, and catalyze scientific advancement. To date, however, evaluation of these programs remains limited, representing an important gap in our understanding about the impact of mentoring. Without rigorous and ongoing evaluation, there may be missed opportunities for identifying best practices, iteratively improving program activities, and demonstrating the returns on investment in mentorship. In this report, we propose a framework for evaluating mentorship programs in LMIC settings where resources may be constrained. We identify six domains: 1) mentor mentee relationship, 2) career guidance, 3) academic productivity, 4) networking, 5) wellness, and 6) organizational capacity. Within each, we describe specific metrics and how they may be considered as part of evaluation plans. We emphasize the role of measurement and evaluation at the institutional level, so that programs may enhance their mentoring capacity and optimize the management of their resources. Although we advocate for a comprehensive approach to evaluation, we recognize that-depending on stage and relative maturity-some domains may be prioritized to address short- and medium-term program goals. PMID- 30430979 TI - The Evolution of Mentorship Capacity Development in Low- and Middle-Income Countries: Case Studies from Peru, Kenya, India, and Mozambique. AB - Following the Fogarty International Center-supported "Mentoring the Mentors" workshops in South America, Africa, and Asia, approaches and guidelines for mentorship at institutions within these low- and middle-income country (LMIC) contexts, appropriate for the respective regional resources and culture, were implemented. Through the presentation of case studies from these three geographic regions, this article illustrates the institutional mentorship infrastructure before the workshop and the identified gaps used to implement strategies to build mentorship capacity at the Universidad Peruana Cayetano Heredia (Peru), Kenya Medical Research Institute (Kenya), Saint John's Research Institute (India), and Eduardo Mondlane University (Mozambique). These case studies illustrate three findings: first, that mentorship programs in LMICs have made uneven progress, and institutions with existing programs have exhibited greater advancement to their mentoring capacity than institutions without formal programs before the workshops. Second, mentoring needs assessments help garner the support of institutional leadership and create local ownership. Third, developing a culture of mentorship that includes group mentoring activities at LMIC institutions can help overcome the shortage of trained mentors. Regardless of the stage of mentoring programs, LMIC institutions can work toward developing sustainable, culturally effective mentorship models that further the partnership of early career scientists and global health. PMID- 30430980 TI - Mentorship and Ethics in Global Health: Fostering Scientific Integrity and Responsible Conduct of Research. AB - Addressing ethical issues through mentorship is key to encouraging scientific integrity and increasing research capacity. Across the global health arena, mentorship requires helping mentees understand and negotiate the regulatory aspects of research-which can substantially differ even between countries with similar resources. Mentorship support spans across the research framework from obtaining ethical approval and ensuring scientific integrity, to determining authorship and disseminating study results-providing multiple opportunities to model ethical behavior for mentees. The power imbalances between the global north and south in accessing funding resources produce further challenges in setting the research agenda and for ensuring equity in the dissemination of research findings. Gender further complicates the aspiration for equity; the proportion of women in high administrative or research positions remains low. This study explores four specific mentoring case scenarios commonly encountered in the global health research field in low- and middle-income institutions. PMID- 30430981 TI - Global Health Mentoring Toolkits: A Scoping Review Relevant for Low- and Middle Income Country Institutions. AB - Capacity building in low- and middle-income country (LMIC) institutions hinges on the delivery of effective mentorship. This study presents an overview of mentorship toolkits applicable to LMIC institutions identified through a scoping review. A scoping review approach was used to 1) map the extent, range, and nature of mentorship resources and tools available and 2) to identify knowledge gaps in the current literature. To identify toolkits, we collected and analyzed data provided online that met the following criteria: written in English and from organizations and individuals involved in global health mentoring. We searched electronic databases, including PubMed, Web of Science, and Google Scholar, and Google search engine. Once toolkits were identified, we extracted the available tools and mapped them to pre-identified global health competencies. Only three of the 18 identified toolkits were developed specifically for the LMIC context. Most toolkits focused on individual mentor-mentee relationships. Most focused on the domains of communication and professional development. Fewer toolkits focused on ethics, overcoming resource limitations, and fostering institutional change. No toolkits discussed strategies for group mentoring or how to adapt existing tools to a local context. There is a paucity of mentoring resources specifically designed for LMIC settings. We identified several toolkits that focus on aspects of individual mentor-mentee relationships that could be adapted to local contexts. Future work should focus on adaptation and the development of tools to support institutional change and capacity building for mentoring. PMID- 30430982 TI - Strengthening Mentoring in Low- and Middle-Income Countries to Advance Global Health Research: An Overview. AB - Mentoring is a proven path to scientific progress, but it is not a common practice in low- and middle-income countries (LMICs). Existing mentoring approaches and guidelines are geared toward high-income country settings, without considering in detail the differences in resources, culture, and structure of research systems of LMICs. To address this gap, we conducted five Mentoring-the Mentor workshops in Africa, South America, and Asia, which aimed at strengthening the capacity for evidence-based, LMIC-specific institutional mentoring programs globally. The outcomes of the workshops and two follow-up working meetings are presented in this special edition of the American Journal of Tropical Medicine and Hygiene. Seven articles offer recommendations on how to tailor mentoring to the context and culture of LMICs, and provide guidance on how to implement mentoring programs. This introductory article provides both a prelude and executive summary to the seven articles, describing the motivation, cultural context and relevant background, and presenting key findings, conclusions, and recommendations. PMID- 30430983 TI - Conceptual Framework of Mentoring in Low- and Middle-Income Countries to Advance Global Health. AB - Although mentoring is not a common practice in low- and middle-income countries (LMICs), there is a strong need for it. Conceptual frameworks provide the structure to design, study, and problem-solve complex phenomena. Following four workshops in South America, Asia, and Africa, and borrowing on theoretical models from higher education, this article proposes two conceptual frameworks of mentoring in LMICs. In the first model, we propose to focus the mentor-mentee relationship and interactions, and in the second, we look at mentoring activities from a mentees' perspective. Our models emphasize the importance of an ongoing dynamic between the mentor and mentee that is mutually beneficial. It also emphasizes the need for institutions to create enabling environments that encourage mentorship. We expect that these frameworks will help LMIC institutions to design new mentoring programs, clarify expectations, and analyze problems with existing mentoring programs. Our models, while being framed in the context of global health, have the potential for wider application geographically and across disciplines. PMID- 30430984 TI - Effect of Intensity Level and Speech Stimulus Type on the Vestibulo-Ocular Reflex. AB - BACKGROUND: Accurate vestibulo-ocular reflex (VOR) measurement requires control of extravestibular suppressive factors such as visual fixation. Although visual fixation is the dominant suppressor and has been extensively studied, the mechanisms underlying suppression from nonvisual factors of attention and auditory stimulation are less clear. It has been postulated that the nonvisual suppression of the VOR is the result of one of two mechanisms: (1) activation of auditory reception areas excites efferent pathways to the vestibular nuclei, thus inhibiting the VOR or (2) cortical modulation of the VOR results from directed attention, which implies a nonmodality-specific process. PURPOSE: The purpose of this research was to determine if the VOR is affected by the intensity level and/or type of speech stimulus. RESEARCH DESIGN: A repeated measures design was used. The experiment was single-blinded. STUDY SAMPLE: Participants included 17 adults (14 females, three males) between the ages of 18-34 years who reported normal oculomotor, vestibular, neurological, and musculoskeletal function. DATA COLLECTION AND ANALYSIS: Each participant underwent slow harmonic acceleration testing in a rotational chair. VOR gain was assessed at 0.02, 0.08, and 0.32 Hz in quiet (baseline). VOR gain was also assessed at each frequency while a forward running speech stimulus (attentional) or a backward running speech stimulus (nonattentional) was presented binaurally via insert earphones at 42, 62, and 82 dBA. The order of the conditions was randomized across participants. VOR difference gain was calculated as VOR gain in the auditory condition minus baseline VOR gain. To evaluate auditory efferent function, the medial olivocochlear reflex (MOCR) was assayed using transient-evoked otoacoustic emissions (right ear) measured in the presence and absence of broadband noise (left ear). Contralateral acoustic reflex thresholds were also assessed using a broadband noise elicitor. A three-way repeated measures analysis of variance was conducted to evaluate the effect of frequency, intensity level, and speech type on VOR difference gain. Correlations were conducted to determine if difference gain was related to the strength of the MOCR and/or to the acoustic reflex threshold. RESULTS: The analysis of variance indicated that VOR difference gain was not significantly affected by the intensity level or the type of speech stimulus. Correlations indicated VOR difference gain was not significantly related to the strength of the MOCR or the acoustic reflex threshold. CONCLUSIONS: The results were in contrast to previous research examining the effect of auditory stimulation on VOR gain as auditory stimulation did not produce VOR suppression or enhancement for most of the participants. Methodological differences between the studies may explain the discrepant results. The removal of an acoustic target from space to attend to may have prevented suppression or enhancement of the VOR. Findings support the hypothesis that VOR gain may be affected by cortical modulation through directed attention rather than due to activation of efferent pathways to the vestibular nuclei. PMID- 30430985 TI - Optimum Response Filter Setting for Air Conduction-Induced Ocular Vestibular Evoked Myogenic Potential. AB - BACKGROUND: A wide range of normative values of amplitude and latencies can be noticed in the publications on ocular vestibular evoked myogenic potential (oVEMP), possibly because of the inconsistent use of various stimulus and acquisition-related parameters such as response filter, gaze angle, onset polarity of stimulus, etc. One major nonuniform parameter across studies is the response filter. Several band-pass response filters such as 0.5-500, 1-1000, 5 500, 5-800, 10-750, 20-2000, 100-3000, and 200-1000 Hz have been used across published studies, and a wide range of normative values can be noticed. However, there is paucity of literature evidence to show that variations in response filters could cause alterations in oVEMP response. PURPOSE: This study aimed to investigate the effects of changes in response filter setting on oVEMP. RESEARCH DESIGN: Normative study using repeated measures research design. STUDY SAMPLE: Young adults in the age range of 18-35 years (N = 150) and older adults in the age range of 60-70 years (N = 10). INTERVENTION: Contralateral air conduction oVEMP. DATA COLLECTION AND ANALYSIS: Contralateral air conduction oVEMP was obtained from only one ear of all participants. Low-pass filters (LPFs) of 500, 700, 1000, 1500, 2000, and 3000 Hz and high-pass filters (HPFs) of 0.1, 1, 10, and 30 Hz were used in all possible combinations of one LPF and one HPF to create band-pass filters. Latencies, peak-to-peak amplitude, and signal-to-noise ratio (SNR) were obtained for each response and comparison was made between various band-pass filters. RESULTS: In young adults, there was a significant reduction in n1 and p1 latencies with increasing HPF and LPF (p < 0.01) and a significant reduction in peak-to-peak amplitude with increasing HPF (p < 0.008). The peak-to peak amplitude was significantly not affected by changes in LPF (p > 0.05). In older adults, the response rate was better for 0.1- to 1000-Hz than 1- to 1000-Hz band-pass filters. CONCLUSIONS: The optimum band-pass filter is 0.1-1000 Hz for recording oVEMP as it produces the largest amplitude oVEMP without compromising on SNR and causes improved response rate in older adults compared with 1- to 1000 Hz filters. Therefore, clinical recording of oVEMP should use 0.1-1000 Hz for obtaining large amplitude potentials and improving the chances of response detection in clinical population. PMID- 30430986 TI - Speech Recognition in Noise in Single-Sided Deaf Cochlear Implant Recipients Using Digital Remote Wireless Microphone Technology. AB - BACKGROUND: Previous research in cochlear implant (CI) recipients with bilateral severe-to-profound sensorineural hearing loss showed improvements in speech recognition in noise using remote wireless microphone systems. However, to our knowledge, no previous studies have addressed the benefit of these systems in CI recipients with single-sided deafness. PURPOSE: The objective of this study was to evaluate the potential improvement in speech recognition in noise for distant speakers in single-sided deaf (SSD) CI recipients obtained using the digital remote wireless microphone system, Roger. In addition, we evaluated the potential benefit in normal hearing (NH) participants gained by applying this system. RESEARCH DESIGN: Speech recognition in noise for a distant speaker in different conditions with and without Roger was evaluated with a two-way repeated-measures design in each group, SSD CI recipients, and NH participants. Post hoc analyses were conducted using pairwise comparison t-tests with Bonferroni correction. STUDY SAMPLE: Eleven adult SSD participants aided with CIs and eleven adult NH participants were included in this study. DATA COLLECTION AND ANALYSIS: All participants were assessed in 15 test conditions (5 listening conditions * 3 noise levels) each. The listening conditions for SSD CI recipients included the following: (I) only NH ear and CI turned off, (II) NH ear and CI (turned on), (III) NH ear and CI with Roger 14, (IV) NH ear with Roger Focus and CI, and (V) NH ear with Roger Focus and CI with Roger 14. For the NH participants, five corresponding listening conditions were chosen: (I) only better ear and weaker ear masked, (II) both ears, (III) better ear and weaker ear with Roger Focus, (IV) better ear with Roger Focus and weaker ear, and (V) both ears with Roger Focus. The speech level was fixed at 65 dB(A) at 1 meter from the speech presenting loudspeaker, yielding a speech level of 56.5 dB(A) at the recipient's head. Noise levels were 55, 65, and 75 dB(A). Digitally altered noise recorded in school classrooms was used as competing noise. Speech recognition was measured in percent correct using the Oldenburg sentence test. RESULTS: In SSD CI recipients, a significant improvement in speech recognition was found for all listening conditions with Roger (III, IV, and V) versus all no-Roger conditions (I and II) at the higher noise levels (65 and 75 dB[A]). NH participants significantly benefited from the application of Roger in noise for higher levels, too. In both groups, no significant difference was detected between any of the different listening conditions at 55 dB(A) competing noise. There was also no significant difference between any of the Roger conditions III, IV, and V across all noise levels. CONCLUSIONS: The application of the advanced remote wireless microphone system, Roger, in SSD CI recipients provided significant benefits in speech recognition for distant speakers at higher noise levels. In NH participants, the application of Roger also produced a significant benefit in speech recognition in noise. PMID- 30430987 TI - Identification and confirmation of diuretics and masking agents in urine by turbulent flow online solid-phase extraction coupled with liquid chromatography triple quadrupole mass spectrometry for doping control. AB - Diuretics can be misused to force diuresis to achieve weight loss or to mask the intake of a prohibited substance and are therefore prohibited by the World Anti Doping Agency (WADA). For similar reasons other masking agents (vaptans, probenecid, etc.) are also prohibited by the WADA. The currently employed methods to detect diuretics in urine use extraction or dilute-and-shoot, combined with 1D liquid chromatography (LC) high resolution mass spectrometry (MS) or LC-triple quadrupole MS. Dilute-and-shoot methods save time and work, but these methods encounter some problems (e.g., peak drift and matrix effect). Therefore, a 2D-LC MS/MS application was developed, validated and evaluated as an alternative. The effect of a turbulent flow rate was studied by loading samples under different conditions and the turbulent flow rate was found to be more effective in removing matrix interferences. A correlation with the specific gravity was observed. A turbulent flow online solid phase extraction (SPE) method combined with LC-MS/MS for the detection of 50 diuretics and masking agents was developed and validated for identification purposes. This method combines the advantages of dilute-and shoot while solving the issues of matrix effect and retention time shift. Furthermore, the presented method is compliant with WADA's identification criteria and can hence be used for screening and/or confirmation. PMID- 30430988 TI - Non-protein A purification platform for continuous processing of monoclonal antibody therapeutics. AB - Protein A capture chromatography, the core of a mAb purification platform, is known to account for more than 50% of downstream processing costs along with other limitations including lack of complete stability to alkaline cleaning solutions, relatively lower binding capacity, and ligand leaching. Researchers have explored alternatives to protein A chromatography, both chromatographic and non-chromatographic, but with limited success. In this paper, we propose a non protein A purification platform for continuous processing of monoclonal antibodies (mAbs). The proposed platform consists of precipitation in coiled flow inverter reactor, cation exchange chromatography for capture, multimodal chromatography and a salt tolerant anion exchange membrane as polishing steps. The versatility of the proposed platform has been successfully demonstrated for three different mAbs. In all cases, acceptable process yield was obtained (70-80 %) and the product quality attributes of the final unformulated drug substance were consistent and well within accepted limits (HCP < 100 ppm, DNA < 10 ppb, % aggregate content < 1%) along with desired charge variant composition. PMID- 30430989 TI - Development and validation of a multiclass method for the determination of organohalogen disinfectant by-products in water samples using solid phase extraction and gas chromatography-tandem mass spectrometry. AB - An analytical method employing solid phase extraction (SPE) and gas chromatography-tandem mass spectrometry (GC-MS/MS) has been developed for quantitative determination of twenty-six organohalogen disinfectant by-products (OXBPs) in water samples. Target analytes include four trihalomethanes (THMs), four iodohalomethanes (I-HMs), one haloacetaldehyde (HAL), six haloketones (HKs), four halonitromethanes (HNMs), and seven haloacetonitriles (HANs). The sample preparation procedure includes pretreatment with ascorbic acid to quench residual oxidants, followed by analyte enrichment using solid-phase extraction. Five SPE sorbents were tested. The best results for the majority of target analytes were obtained using a styrene-divinylbenzene copolymer phase and methyl tert-butyl ether (MTBE) as the elution agent. GC-MS analysis was performed using electron ionization (EI) and selected reaction monitoring (SRM) for analyte detection. The performance of the method was assessed according to the French standard NF T90 210. The method showed LOQs ranging from 3 to 3000 ng L-1. The applicability of the method has been demonstrated by analyzing both river water and tap water samples. The OXBPs detected most often in the tap water were dibromochloromethane (in 100% of the samples, 4.3-4.7 MUg L-1), bromodichloromethane (100%, 1.3-1.7 MUg L-1), tribromomethane (100%, 0.8-4.4 MUg L-1), trichloromethane (100%, 0.6 0.7 MUg L-1), dibromoacetonitrile (75%, 0.5-0.9 MUg L-1), with dichloroacetonitrile and 1,1,1-trichloro-2-propanone detected at concentrations around the LOQ levels. In the treated river water samples, the only OXBPs measured at levels above the limit of quantification were trichloromethane and 1,1,1-trichloro-2-propanone. To the best of our knowledge, this is the first SPE GC-MS/MS method enabling the analysis of an extensive list of OXBPs. PMID- 30430990 TI - Extraction of Hyssopus officinalis L. essential oil using instant controlled pressure drop process. AB - To determine the optimum condition for the extraction of Hyssopus officinalis L. essential oil (EO) by instant controlled pressure drop (in French: Detente Instantanee Controlee or DIC), the influential parameters of pressure, heating time per cycle, number of cycles, mean particle diameter of the herb, and water concentration in the steam generator feed were evaluated using response surface methodology (RSM). The impact of using an ethanol-water mixture to generate the required vapor in the DIC process on EO extraction was investigated. The optimum condition was found to be at pressure = 1 bar, heating time = 100 s, cycles = 12, particle diameter = 1 mm, and water concentration = 80 v%. The addition of ethanol turned out to be more efficient at higher heating times and cycle numbers. The optimum yield in DIC was highest compared with hydrodistillation (HD), ultrasound-assisted extraction (UAE), and Soxhlet (SOX) methods; their values, expressed as total area percentages per internal standard area percentage, were 39.04, 10.98, 1.58, and 7.71, respectively. Comparison of the four methods also indicated that the DIC-EO was of a superior quality. The analysis of the DIC-treated residual herb in the optimum experiment revealed that unlike the low amount of valuable oxygenated monoterpenes, the availability of sesquiterpenes increased, which proved that DIC performs selectively while extracting more valuable EO components. The DIC-EO and its extract were examined for total phenolic content (TPC) and antioxidant activity using Folin-Ciocalteu and DPPH assay, respectively. Comparison of these results with those obtained from HD demonstrated higher TPC and antioxidant activity of the DIC-EO. Moreover, scanning electron microscopy (SEM) of the raw material and residual herb in the optimum experiment showed significant structure modifications induced by the DIC process. PMID- 30430991 TI - [Daratumumab for multiple myeloma]. AB - Daratumumab is a monoclonal antibody that targets CD38. It has an anti-tumor action on the myeloma cell and an immunomodulatory action. For relapsing and/or refractory myeloma patients, daratumumab is effective both alone and in combination and significantly improves progression-free survival. Daratumumab has been approved in 2016 in France for treatment of relapses or refractory multiple myeloma. PMID- 30430993 TI - Clostridium difficile infection in hospitalized patients with COPD in Spain (2001 2015). AB - BACKGROUND: The objectives of this study were to examine incidence and in hospital outcomes of Clostridium difficile infection (CDI) among patients with COPD, to compare clinical variables among COPD patients with matched non-COPD patients hospitalized with CDI, and to identify factors associated with in hospital mortality (IHM) among COPD patients. METHODS: We performed a retrospective study using the Spanish National Hospital Discharge Database from 2001 to 2015. We included patients aged 40 years or over with a primary or secondary diagnosis of CDI. For each COPD patient, we selected a sex, age, readmission status and year-matched non-COPD patient. RESULTS: We identified 44,695 patients with CDI (19.36% with COPD). Incidence of CDI has increased significantly from 2001 to 2015 besides COPD status. Incidence was higher in COPD patients than in patients without this disease (IRR 2.24; 95%CI 2.18-2.29). IHM decreased significantly over time in patients without COPD (from 13.98% in 2001 03 to 10.99% in 2013-15), but there were no changes in those with COPD (from 12.93% in 2001-03 to 13.37% in 2013-15). In COPD patients, higher mortality rates were associated with older age, comorbidities, severe CDI, longer length of hospital stay and readmission. Primary diagnosis of CDI was associated with lower IHM in this group of patients (OR 0.66; 95%CI 0.56-0.77) in comparison with secondary diagnosis. CONCLUSIONS: Incidence of CDI was twice higher in COPD patients than in matched non-COPD controls and is increasing overtime in both groups. Our results suggest that the management of CDI has improved in Spain during the study period. PMID- 30430994 TI - Health policy and system support to optimise community health worker programmes: an abridged WHO guideline. AB - Optimising community health worker (CHW) programmes requires evidence-based policies on their education, deployment, and management. This guideline aims to inform efforts by planners, policy makers, and managers to improve CHW programmes as part of an integrated approach to strengthen primary health care and health systems. The development of this guideline followed the standard WHO approach to developing global guidelines. We conducted one overview of reviews, 15 systematic reviews (each one on a specific policy question), and a survey of stakeholders' views on the acceptability and feasibility of the interventions under consideration. We assessed the quality of systematic reviews using the AMSTAR tool, and the certainty of the evidence using the GRADE methodology. The overview of reviews identified 122 eligible articles and the systematic reviews identified 137 eligible primary studies. The stakeholder perception survey obtained inputs from 96 respondents. Recommendations were developed in the areas of CHW selection, preservice education, certification, supervision, remuneration and career advancement, planning, community embeddedness, and health system support. These are the first evidence-based global guidelines for health policy and system support to optimise community health worker programmes. Key considerations for implementation include the need to define the role of CHWs in relation to other health workers and plan for the health workforce as a whole rather than by specific occupational groups; appropriately integrate CHW programmes into the general health system and existing community systems; and ensure internal coherence and consistency across different policies and programmes affecting CHWs. PMID- 30430995 TI - [The challenge of antitrombotic treatment prescription in older adults with atrial fibrillation. Does age justify the anti-thrombotic strategy in elderly patients with atrial fibrillation?] PMID- 30430996 TI - [Self-care: New evidence for its measurement in older adults]. AB - INTRODUCTION: A major challenge in today's society is getting older people, not only live longer, but to have a better life, and achieve successful aging. Self care has been identified as relevant construct in its relation to physical, psychological, and social health. Therefore, this paper aims to provide first evidence of the psychometric properties of a scale to assess self-care in older people. MATERIAL AND METHODS: The sample consisted of 443 people aged between 60 and 80years (M=66.11, SD=4.72), all of them currently participating in lifelong learning programs. There were 64.2% women, and most participants were married (73.7%). They were asked to complete the Self-Care for Older People Scale (SCOPS), the SF-8 Health Perception scale and, the Life Satisfaction scale (SWLS). Data were analysed using confirmatory factor analysis, and scale correlations between self-care and variables from its nomological network. RESULTS AND CONCLUSIONS: The tested model provided an adequate fit to the data: chi2(23)=64.257 (P<.001); comparative fit index (CFI)=.936; Tucker Lewis Index (TLI) =.899; standardized root mean square residual (SRMR) =.070; root mean square error of approximation (RMSEA) =.064 (.046-.083), supporting the original structure of three factors: physical, social, and internal self-care. These factors also showed statistically significant correlations with two important variables of their nomological network, perceived health and life satisfaction. PMID- 30430998 TI - Why some surgeons no longer systematically operate cases of papillary thyroid carcinoma. PMID- 30430997 TI - [Domiciliary intervention by occupational therapy after hospital discharge in order to prevent re-admission in the elderly: Study protocol for a randomised clinical trial]. AB - BACKGROUND AND OBJECTIVE: Re-admission to hospital by the elderly is a frequent event that is associated with complications. The aim of this article is to describe a randomised clinical trial protocol which has the aim of describing and comparing the impact of a home-based intervention by Occupational Therapists (OT) in the likelihood of re-admission at 6 months. MATERIAL AND METHOD: Randomised controlled trial conducted in medical units of the "Hospital Clinico de la Universidad de Chile" and "Hospital de la Fuerza Aerea de Chile", with 217 patients aged 60 years or older admitted for acute or decompensated chronic disease, provided that they have a person of reference after hospital discharge. The control group consists of the usual care regarding post-discharge patients. This will be compared to the experimental group that includes a home visit from OT on two occasions over a six-month period, who will apply a multicomponent intervention. Informed consent will be requested with the sociodemographic and hospital admission information, functional (Barthel index; Lawton & Brody Scale) and cognitive performance (Short Portable Mental Status Questionnaire; Functional Activities Questionnaire; Confusion Assessment Method), and comorbidity (Cumulative Illness Rating Scale for Geriatrics). Both groups will receive a telephone follow-up at 4, 12 and 24 weeks after hospital discharge. RESULTS: The intervention will reduce the rate of hospital re-admissions by at least 40% at 6 months compared with usual care. CONCLUSION: It will be useful to know the components that reduce the risk of hospital re-admissions and improve hospital discharge healthcare for elderly. PMID- 30430999 TI - Transoral robotic surgery of the tongue base for obstructive sleep apnea: Preliminary results. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a major public health issue. Robotic tongue-base reduction surgery is being developed, but needs assessment. The present study reports clinical and polygraphic results at 6 months' follow-up. METHOD: Single-center prospective study of 8 patients undergoing transoral robotic surgery (TORS) for severe OSAS. RESULTS: Mean age was 47 years. M/F sex ratio was 5:3. Initial body-mass index ranged from 18 to 35kg/m2. Mean Epworth score was 12. Mean preoperative apnea-hypopnea index (AHI) was 47 (range, 36-60). At 6 months, only 1 patient did not meet usual success criteria (AHI<20 with>50% decrease); 2 patients had residual AHI between 10 and 20; the other 5 had non-significant event rates. CONCLUSION: TORS tongue-base reduction showed promising results, which need confirmation on long-term multicenter studies. PMID- 30431000 TI - Impact of cochlear implantation on peripheral vestibular function in adults. AB - OBJECTIVE: Cochlear implantation may have a detrimental effect on vestibular function and residual hearing. Our goal was to investigate the impact of cochlear implantation on peripheral vestibular function and the symptomatology that ensues. MATERIAL AND METHODS: A prospective observational study included all adults undergoing cochlear implantation by the same operator between July 2014 and December 2015, with pre- and postoperative (4 months) neurovestibular balance examination comprising a questionnaire and clinical tests [head impulse test (HIT), head-shaking test (HST), skull vibration test (SVT)] and instrumental tests [caloric test of the lateral semicircular canal and cervical vestibular evoked myogenic potentials (cVEMP)]. RESULTS: Twenty-two patients were included, with a mean age of 62 years and sex-ratio of 1.2. Before implantation, 50% of subjects (n=11) reported at least one episode of vertigo associated with balance disorder during their life. After implantation, there were 11 cases of vertigo but only one patient described persistent discomfort related to vertigo 4 months after surgery. Patients with impaired vestibular function after 4 months, taking all symptoms together, were all aged more than 75 years. HIT was abnormal in 18% of cases before implantation and in 59% after (P=NS). HST showed nystagmus in one patient both before and after surgery. Only 18% of patients showed nystagmus induced by SVT before surgery, increasing to one-third after surgery (P=NS). Caloric test of the lateral canal showed hypofunction in 50% of cases before surgery, including 10% of cases with areflexia. This rate increased after surgery to 58%, with 18% areflexia (P=NS). cVEMPs were not detected in 68% of cases before implantation and this rate increased to 86% after surgery (P=NS). There were no significant associations (P>0.05) between test results and symptoms. CONCLUSIONS: In the medium term, although older subjects more frequently presented vestibular disorder, cochlear implantation induced little vertigo or balance disorder, sometimes even improving vestibular function. However, vestibular disorders were frequent preoperatively and increased postoperatively. We tested vestibular function on different stimulation frequencies and yet found no correlation between postoperative test results and postoperative vertigo. PMID- 30431001 TI - Human single-chain variable fragment antibody expressed in E. coli with optimal in vitro cross-neutralizing and no enhancing activity. AB - Single chain fragment variable (scFv) is a small molecule antibody comprising of only the variable region of heavy and light chain responsible for antigen binding. For dengue disease, the Fc region of antibody molecule was reported to be involved with dengue complication caused by Antibody-dependent enhancement (ADE). We attempted to produce small molecule scFv human monoclonal antibody (HuMAb), which lacking the Fc portion to eliminate the ADE effect of the IgG. This scFv antibody was produced in Escherichia coli. The biologically active form of scFv antibody was successfully generated. 23-1C2D2-scFv showed neutralizing activity similar to the IgG obtained from parental hybridoma, but lacked enhancing activity in all studied concentrations. This antibody was targeted to the 101WXN103 motif of dengue envelop protein domain II, studied by western blot analysis with truncated E protein and random peptide phage display. This scFv is verified as a candidate for further development as therapeutic candidate for DENV infection. PMID- 30431002 TI - A framework for research on vaccine effectiveness. AB - The need for a systematic approach to research on vaccine effectiveness (VE) is increasing with growing numbers of vaccines and complexity of immunization programs. The diverse scientific fields that investigate how vaccines work and why they fail continue to evolve, yet definitions related to such advances have not kept pace. Researchers in disciplines ranging from basic science through immunopathology, clinical and epidemiological research, and mathematical modelling need more precise definitions to promote communication and interdisciplinary VE research to ensure that studies are designed to appropriately address relevant questions. To meet these aims, we suggest standardized definitions, consider models of vaccine failure, and offer general approaches for incorporation into study design. We further propose a framework for conducting VE research that builds on the traditional epidemiological triad of host, pathogen and environment, and also includes additional elements such as characteristics of both the vaccine and vaccinee, the effect of time on likelihood of exposure and protection, and the impact of environment and pathogen, as well as how outcomes of interest and study design may impact observed vaccine effectiveness. The framework is relevant to researchers in all disciplines who investigate the effectiveness of vaccines and vaccination programs and why they may fail. Stronger research in this field will help policy makers optimise decision-making on vaccination programs, ensuring we maximize the health benefits of vaccines. It is also important for clinicians communicating the benefits of vaccines to the public. PMID- 30431003 TI - Introduction of inactivated poliovirus vaccine in the Philippines: Effect on health care provider and infant caregiver attitudes and practices. AB - BACKGROUND: The introduction of inactivated poliovirus vaccine (IPV) to the Philippines' national immunization schedule meant the addition of a third injectable vaccine at a child's 14-week immunization visit. Although previous studies have shown that providing multiple vaccines at the same time affected neither the risk of severe adverse events nor vaccine efficacy, concerns were raised that providing three injections at a single visit, with two injections in one leg, might be unacceptable to health care providers (HCP) and infant caregivers. METHODS: We conducted pre- and post-IPV introduction surveys on the acceptance and acceptability of the additional injectable vaccine in three of the Philippines' 17 administrative regions. Regions 3 and 6 were included in the pre introduction phase and Regions 3, 6 and 10 were included in the post-introduction phase. Thirty public health centers (PHCs) were randomly sampled from each region. HCPs and infant caregivers were interviewed. In addition, vaccination records from a minimum of 20 eligible children pre-introduction and 10 children post-introduction per PHC were reviewed. RESULTS AND DISCUSSION: We interviewed 89 HCPs and 286 infant caregivers during the pre-introduction phase and 137 HCPs and 455 caregivers during the post-introduction phase. Among 986 vaccination records reviewed post-introduction, 84% (n = 826) of children received all three recommended injections at one visit, with a range from 61% (209/342) in Region 10 to 100% (328/328) in Region 3. The proportion of HCPs reporting that they had administered three or more injectable vaccines and the proportion of caregivers that would be comfortable with their child receiving three or more injectable vaccines at one visit increased from pre- to post-introduction (p < 0.0001 for both). Eighty-seven percent of HCPs that had administered three or more injectable vaccines post-introduction reported being comfortable or very comfortable with the number of vaccines they had administered. PMID- 30431004 TI - A prospective randomized comparative study to determine appropriate edoxaban administration period, to prevent deep vein thromboembolism in patients with total knee arthroplasty. AB - BACKGROUND: This study aimed to determine the appropriate administration duration of edoxaban 15 mg (a factor Xa inhibitor) for the prevention of deep vein thrombosis (DVT) after total knee arthroplasty (TKA). METHODS: Our study comprised 202 patients who underwent TKA (excluding bilateral TKA) at our institution between 2014 and 2015. The subjects received edoxaban 15 mg daily for 1 (n = 93) or 2 (n = 109) weeks; group assignment was random. B-mode ultrasonography was performed 7 and 14 days post-TKA for the detection of DVT. We compared the incidence of DVT between the groups and examined for side effects. RESULTS: The demographic data of the patients in the 1- and 2-week administration groups were similar at baseline. DVT incidence did not differ significantly between the groups at 1 week post-TKA. However, it was significantly lower in the 2-week administration group (n = 0) than in the 1-week administration group (n = 7; p = 0.004) at 2 weeks post-DVT. Neither group exhibited symptomatic DVT. A total of six patients withdrew during the study period because of hepatic dysfunction. CONCLUSIONS: Our results show that the administration of edoxaban 15 mg is more effective in preventing DVT after TKA when administered for 2 weeks than for 1 week. PMID- 30431005 TI - The effects of bisphosphonate on pain-related behavior and immunohistochemical analyses in hindlimb-unloaded mice. AB - OBJECTIVE: The aim of this study was to evaluate skeletal pain associated with immobility-induced osteoporosis and to examine the inhibitory effect of bisphosphonate (BP) administration on pain in hindlimb-unloaded (HU) mice. METHODS: The mechanism of osteoporotic pain in HU mice was evaluated through an examination of pain-related behavior, as well as immunohistochemical findings. In addition, the effects of alendronate (ALN), a potent osteoclast inhibitor, on these parameters were assessed. RESULTS: HU mice with tail suspension developed bone loss and mechanical hyperalgesia in the hindlimbs. The HU mice showed an increase in the number of calcitonin gene-related peptide (CGRP)-immunoreactive neurons and in transient receptor potential channel vanilloid subfamily member 1 (TRPV1)-immunoreactive neurons in the dorsal root ganglions (DRGs) innervating the hindlimbs. Furthermore, administration of ALN prevented HU-induced bone loss, mechanical hyperalgesia, and upregulation of CGRP and TRPV1 expressions in DRG neurons of immobility-induced osteoporotic animal models. CONCLUSIONS: HU mice appear to be a useful model for immobility-induced osteoporotic pain and hindlimb unloading-induced bone loss, as well as upregulation of CGRP and TRPV1 expressions in DRG neurons, and BP treatment prevented bone loss and mechanical hyperalgesia. The inhibitory effect of BP on osteoclast function might contribute to improving osteoporosis-related pain. PMID- 30431006 TI - Effect of osteoporosis on the clinical and radiological outcomes following one level posterior lumbar interbody fusion. AB - BACKGROUND: Cage subsidence or pedicle screw loosening following lumbar fusion surgery is frequently reported in osteoporotic patients. However, few studies have analyzed clinical as well as radiological outcomes after such surgeries as a function of bone mineral density. We aimed to evaluate the impact of osteoporosis on the clinical and radiological outcomes of patients who underwent one-level posterior lumbar interbody fusion (PLIF). METHODS: Fifty-five non-osteoporotic (T score >= -1.0) and 31 osteoporotic (T-score <= -2.5) patients who underwent one level PLIF were followed up for >2 years. Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and EuroQol 5-Dimension (EQ-5D) parameters were assessed. Fusion success was identified with dynamic plain radiographs and computed tomography. Pedicle screw loosening and cage subsidence were evaluated. The clinical and radiological parameters were compared between osteoporotic and non osteoporotic patients. Subgroup analysis was performed on cage subsidence or screw loosening. RESULTS: Although VAS score for back pain was higher in osteoporotic patients than in non-osteoporotic patients at 6 months postoperatively (3.3 vs. 2.2, P = 0.062), this difference disappeared at 1 year postoperatively (2.9 vs. 2.5, P = 0.606). However, no differences were noted between the groups in ODI and EQ-5D grades. Cage subsidence (65.4% vs. 17.6%, P < 0.001) and screw loosening rates (32.3% vs. 12.7%, P = 0.029) were significantly higher in osteoporotic patients than in non-osteoporotic patients, but fusion rate did not differ between the groups. Although clinical outcomes did not differ between those who had cage subsidence or screw loosening and those who did not, fusion rate was lower in those who showed screw loosening than those who did not (71.4% vs. 93.9%, P = 0.038). CONCLUSIONS: Higher cage subsidence and pedicle screw loosening rates in osteoporotic patients did not significantly affect the clinical outcomes, but screw loosening, which occurred more frequently in older patients, significantly reduced the fusion success rate. Thus, PLIF procedure may be a good surgical treatment option to achieve good clinical outcomes, even in osteoporotic patients despite higher rates of cage subsidence and pedicle screw loosening. However, surgeons should monitor screw loosening because of its significant association with non-union. PMID- 30431007 TI - Alteration in stress distribution patterns through the elbow joint in professional and college baseball pitchers: Using computed tomography osteoabsorptiometry. AB - BACKGROUND: Long-term pitching activities change the stress distribution across the elbow joint surface in living subjects, however the influence of the different strength of stress on the stress distribution patterns remain unclear. The aims of this study were to evaluate the distribution of subchondral bone density across the elbow joint in different levels of pitchers, and to reveal the influence of the strength of stress on the elbow joint surface under long-term loading conditions of baseball pitching. METHODS: The current analysis was performed using computed tomography (CT) image data obtained from the throwing side elbow of 12 nonthrowing athletes (controls), 15 college baseball pitchers (college group) and 13 professional baseball pitchers (professional group). The distribution patterns of subchondral bone density through the articular surface of the elbow joints were assessed using a CT osteoabsorptiometry method. The quantitative analysis was based on location and percentages of high-density area on the articular surface. RESULTS: High-density area in the college and professional groups were found in the anterior part of the captellum, posterior part of the trochlea and radial head. In the professional group, the percentages of high-density area in the anterior part of the capitellum, posterior part of the trochlea, radial head and olecranon were significantly greater than in the college group. CONCLUSIONS: Stress distribution on the articular surface of the elbow joint was affected by pitching abilities or competitive levels. Our analysis indicates that high strength of stress in professional baseball players produce potential risk of elbow injuries. PMID- 30431008 TI - Opioid administration via epidural catheter is a risk factor for postoperative nausea and vomiting in total hip arthroplasty: A retrospective study. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) may lead to extended hospital stay due to severe discomfort and restriction of patient activity. We retrospectively studied PONV incidence following total hip arthroplasty (THA) to evaluate the effect of opioid administration via epidural catheter. METHODS: Our study included 155 affected joints in 136 patients who underwent a first THA from 2011 to 2016. For postoperative analgesia, an epidural catheter was preoperatively placed and used for continuous analgesic delivery into the epidural space up to 2 days after surgery. We analyzed patient age, sex, body mass index (BMI), opioid use via epidural catheter, amount of opioid used intraoperatively, amount of opioid used immediately before the end of the operation, anesthesia duration, and amount of opioid used postoperatively. RESULTS: PONV was reported for 51 affected joints. Opioid was infused via epidural catheter in 114 affected joints, but not in 41 affected joints. Logistic regression analysis for PONV occurrence revealed a significant difference according to sex (P < 0.05), BMI (P < 0.01), and opioid use via epidural catheter (P < 0.05). Correlation analysis evaluating the occurrence of PONV and BMI using the chi2 test demonstrated a significantly higher incidence of PONV in the subgroup of patients with a BMI <=20 kg/m2 (P < 0.01). CONCLUSIONS: These results indicate that without using opioid or other action should be considered when epidural catheter is used in female patients with a BMI <=20 kg/m2. PMID- 30431009 TI - Whether Dirofilaria repens parasites from South India belong to zoonotic Candidatus Dirofilaria hongkongensis (Dirofilaria sp. hongkongensis)? AB - The canine and zoonotic dirofilarioses are arthropod-borne parasitic infections caused by nematodes of the genus Dirofilaria, infecting canines, felines and humans throughout the world. Dirofilaria repens was considered as the most common cause of human dirofilariosis in Kerala. In the present study, molecular characterization of Dirofilaria isolates causing dirofilariosis in humans, dogs and jackal from Kerala, South India was undertaken by performing sequence and phylogenetic analysis based on cytochrome oxidase subunit I (COI) gene. The live worms from swellings/ nodules in subconjunctiva or subcutaneous tissue or scrotum were recovered from humans (n = 3), dogs (n = 4) and one jackal. The PCRs targeting a repetitive fragment, 18S rRNA and COI genes yielded products of ~246 bp, ~875 bp and ~350 bp respectively in all the samples. The sequence analysis of 18S rRNA gene revealed the closest identity (98 to 99%) with an already published sequence of D. repens isolated from a human in Japan. However, based on the sequence and phylogenetic analysis of partial sequences of COI gene, the Dirofilaria infecting both animals (dogs, jackal) and humans native to Kerala, South India were identified as genetically conserved and closely related to Dirofilaria sp. hongkongensis. Hence, the results of the present study suggested the existence of Candidatus Dirofilaria hongkongensis (Dirofilaria sp. hongkongensis) in Kerala, South India causing zoonotic filariosis in canines and humans. PMID- 30431010 TI - Suppression of isoproterenol-induced cardiotoxicity in rats by raspberry ketone via activation of peroxisome proliferator activated receptor-alpha. AB - The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) controls the lipid and glucose metabolism and also affects inflammation, cell proliferation and apoptosis during cardiovascular disease. Raspberry ketone (RK) is a red raspberry (Rubusidaeus, Family-Rosaceae) plant constituent, which activates PPAR alpha. This study was conducted to assess the cardioprotective action of RK against isoproterenol (ISO)-induced cardiotoxicity. Wistar rats were randomly divided into six groups (six rats/group). Rats were orally administered with RK (50, 100 and 200 mg/kg, respectively) and fenofibrate (standard, 80 mg/kg) for 28 days and ISO was administered (85 mg/kg, subcutaneously) on 27th and 28th day. Administration of ISO in rats significantly altered hemodynamic and electrocardiogram patterns, total antioxidant capacity, PPAR-alpha, and apolipoprotein C-III levels. These myocardial aberrations were further confirmed during infarct size, heart weight to body weight ratio and immunohistochemical assessments (caspase-3 and nuclear factor-kappaB). RK pretreatment (100 and 200 mg/kg) significantly protected rats against oxidative stress, inflammation, and dyslipidemia caused by ISO as demonstrated by change in hemodynamic, biochemical and histological parameters. The results so obtained were quite comparable with fenofibrate. Moreover, RK was found to have binding affinity with PPAR-alpha, as confirmed by docking analysis. PPAR-alpha expression and concentration was also found increased in presence of RK which gave impression that RK probably showed cardioprotection via PPAR-alpha activation, however direct binding study of RK with PPAR-alpha is needed to confirm this assumption. PMID- 30431011 TI - Ulixertinib (BVD-523) antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance. AB - Ulixertinib (BVD-523) is a highly potent, selective, and reversible ERK1/2 inhibitor and is currently in clinical development for the treatment of advanced solid tumors. In this study, we investigated whether ulixertinib could antagonize multidrug resistance (MDR) mediated by ATP-binding cassette (ABC) transporters. The results showed that ulixertinib, at non-toxic concentrations, significantly reversed ATP-binding cassette subfamily B member 1 (ABCB1)- and ATP-binding cassette subfamily G member 2 (ABCG2)-mediated MDR. In ABCB1-overexpressing cells, ulixertinib antagonized MDR by attenuating the efflux function of ABCB1. Similarly, in ABCG2-overexpressing cells, ulixertinib inhibited the efflux activity of ABCG2 and reversed resistance to substrate anticancer drugs. The reversal effects of ulixertinib were not related to the down-regulation or change of subcellular localization of ABCB1 or ABCG2. Mechanistic investigations revealed that ulixertinib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and the in silico docking study predicted that ulixertinib could interact with the substrate-binding sites of both ABCB1 and ABCG2. Our finding provides a clue into a novel treatment strategy: a combination of ulixertinib with anticancer drugs to attenuate MDR mediated by ABCB1 or ABCG2 in cancer cells overexpressing these transporters. PMID- 30431012 TI - Intratympanic Methylprednisolone versus Dexamethasone for the Primary Treatment of Idiopathic Sudden Sensorineural Hearing Loss. AB - OBJECTIVES: The aim of the present study was to compare the therapeutic effectiveness of intratympanic (IT) methylprednisolone and dexamethasone in the initial treatment of patients with idiopathic sudden sensorineural hearing loss (ISSHL). MATERIALS AND METHODS: A total of 46 patients with ISSHL who had been treated with IT methylprednisolone or dexamethasone were included in the present study. Dexamethasone (4 mg/mL) and methylprednisolone (20 mg/mL) were given transtympanically to 22 and 24 patients, respectively, one dosage per day for 5 consecutive days. Audiologic evaluations were performed pretreatment, daily in inpatient clinics, and in the first week and second month after discharge, using four-frequency pure-tone average (PTA) and speech discrimination score (SDS). Audiologic improvement was classified according to the Furuhashi criteria. RESULTS: According to the Furuhashi criteria, the therapeutic success rate was 62.5% (complete improvement 16.7% and marked improvement 45.8%) in the methylprednisolone group, whereas it was 54.6% (complete improvement 27.3% and marked improvement 27.3%) in the dexamethasone group. Therapeutic success was higher in the methylprednisolone group; however, it was not statistically significant. When the audiologic improvement was accepted as >10 dB in PTA, the therapeutic success rates were 83.3% in the methylprednisolone group and 72.8% in the dexamethasone group. The mean (+/-SD) improvement of PTA before and after treatment was 30.8+/-21.4 in the methylprednisolone group and 24.7+/-2.5 in the dexamethasone group. The mean improvement in SDS was 32.6+/-25 in the methylprednisolone group and 23.7+/-26.9 in the dexamethasone group. CONCLUSION: IT steroids are safe, effective, and well-tolerated agents in the initial treatment of patients with ISSHL. Despite having different pharmacokinetic characteristics, IT methylprednisolone and dexamethasone have no superiorities over each other in the primary treatment in patients with ISSHL. PMID- 30431013 TI - Auditory Reasoning Skills of Cochlear Implant Users. AB - OBJECTIVES: This study compared the auditory reasoning skills of school-going children with early and late cochlear implantation and assessed the relationship between auditory reasoning skills, language development, vocabulary knowledge, and communication skills. MATERIALS AND METHODS: In this case series study, 90 pre-lingually deaf children aged 7-10 years were assessed. Children were divided into two groups: early-implanted group with children who received cochlear implants before 3 years of age (mean, 23.45; 12-35 months) and late-implanted group with children implanted after 3 years of age (mean, 50.54; 36-84 months). Tests were performed in the auditory-visual condition. Correlational analyses were used to assess the relationships between daily communication skills, language development performances, vocabulary knowledge, and auditory reasoning skills of both the groups. RESULTS: Auditory reasoning skills were better in the early-implanted group than in the late-implanted group (Mann-Whitney U test=518, p<0.05). Language performances of the early-implanted group were significantly better than those of the late-implanted group (receptive language performances: Mann-Whitney U=522, p<0.05; expressive language performances: Mann-Whitney U=552, p<0.05). Stepwise regression analysis showed that expressive language performances, vocabulary knowledge, and chronological age could predict 82% of the variance. CONCLUSION: Reasoning skills of children with cochlear implants should be supported during the language-learning process. PMID- 30431014 TI - Middle Ear Osteoma Causing Mixed Hearing Loss: A Case Report. AB - Osteomas of the middle ear are rare benign tumors. Their consequences and symptoms are due to their specific location, such as the promontory or the epitympanum and their contact with the facial nerve, the semicircular canal, the ossicles, and the oval or round windows. We report a very unusual case of middle ear osteoma (MEO) in a 23-year-old male patient causing a right mixed hearing loss by contacting and overwhelming the incus and stapes. The lesion was also closely attached to the tympanic portion of the fallopian canal. Since the stapes was not clearly visible behind the lesion, careful observation was preferred to surgery owing to the high risk of inner ear damage and facial palsy with removal of the lesion. MEOs are rarely situated at this critical site. Regular clinical and computerized tomography monitoring is warranted to check their growth. This case also supports the etiological theory of chronic middle ear inflammation causing osteomas. PMID- 30431015 TI - Axial Mesodermal Dysplasia Complex with a Unique Abnormal Course of Vestibulocochlear Nerve. AB - Axial mesodermal dysplasia complex (AMDC) is a combination of multiple congenital malformations arising due to the mesodermal cell migration, neural tube fusion, and rhombencephalon segmentation. Here, we present the imaging findings of a 15 year-old boy with AMDC who has bilateral inner ear malformations associated with a vestibulocochlear nerve extending to Meckel cave, cystic lesion in prepontine cisterna, cervical vertebral segmentation anomalies, and maxillar bone anomalies. PMID- 30431016 TI - Canal Wall Up versus Canal Wall down Mastoidectomy: Considerations for the New Age Otologists. PMID- 30431017 TI - Simulation study on the translocation of polyelectrolyte through conical nanopores. AB - Experiments have suggested that the conical nanopore may be a reasonable sensor for the biopolymer analysis as it can provide high-resolution current signal. In this paper, we use Langevin dynamics simulation to study the translocation of charged polymer (polyelectrolyte) through three different conical nanopores, a single-conical nanopore with large entry and small exit (pore I), a single conical nanopore with small entry and large exit (pore II), and a double-conical nanopore with the tip (narrowest place) at the middle (pore III). Simulation shows that the detailed translocation behaviors are of pore structure dependence. Pore I might be the most reasonable one for the polyelectrolyte analysis, especially at strong monomer-pore attraction, since it can efficiently reduce the polyelectrolyte speed at the tip. The simulation results are interpreted by the free energy profiles of the polyelectrolyte translocation through different pores and the time of individual monomer passing through the tips. PMID- 30431018 TI - Ultrafast formation and dynamics of interlayer exciton in a large-area CVD-grown WS2/WSe2 heterostructure. AB - A WS2/WSe2 heterostructure is constructed by stacking a WS2 monolayer on the top of WSe2 monolayer fabricated with chemical vapor deposition (CVD) method. Ultrafast transient spectroscopy is used to demonstrate the ultrafast charge transfer and interlayer exciton dynamics in the heterostructure. When the WS2/WSe2 heterostructure was photoexcitated at 617 nm (2.01 eV) to excite the A exciton transition of WS2, an ultrafast photobleaching was observed around the WSe2 A-exciton transition at 749 nm. The bleaching signal lasts several nanoseconds, which is much longer than the A-exciton lifetime in both the WS2 and WSe2 monolayer film. Moreover, by selectively photoexciting the A-exciton of WSe2 at 749 nm in the heterostructure, an ultrafast photobleaching occurs around the WS2 A-exciton transition, the recovery of the bleaching shows a single exponential relaxation with typical time constant of ~1.8 ps. The very fast relaxation in the heterostructure probing around 620 nm is indicative that rich defect states exist below the conduction band in WS2, which can efficiently trap these electrons transferred from the WSe2 upon photoexcitation. Our spectroscopic results reveal that our CVD-grown WS2/WSe2 bilayer film has a type II heterostructure in nature at room temperature. With photoexcitation, electrons and holes can be separately confined in the WS2 and WSe2 layer, respectively; as a result, interlayer excitons are formed. PMID- 30431019 TI - Giant magnetoresistance control and nontrivial metallic state manipulation in a transition-metal dichalcogenide spin-valve using a gate voltage. AB - Here, we have theoretically studied the valley- and spin-resolved transport in a monolayer transition metal dichalcogenides based spin valve device, where both the Rashba spin orbit interaction and a gate voltage coexist in the central lead. In contrast to conventional semiconductor, nontrivial metallic states, such as, normal Rashba metal state (NRMS), anomalous Rashba metal state (ARMS), and Rashba ring metal state (RRMS), can be generated and manipulated by Rashba spin orbit interaction without the magnetic effect. For a nonferromagnetic double junction, it was found that the valley- and spin-resolved tunneling conductance can be effectively tuned by the incident energy, the junction length, the Rashba spin orbit interaction strength, and the gate voltage. Due to the spin texture and the Fermi wavevectors in the central lead, both the tunneling coefficient and the tunneling conductance all exhibit the remarkable characteristic features which enable us to diagnose the special states. For a ferromagnetic spin valve device, the resulting nontrivial metallic groundstates in the central lead also demonstrate directly in the giant magnetoresistance with notable unique features. We have further revealed that a perfect valley and spin giant magnetoresistance stems from the spin splitting and the spin-valley coupling. These valley- and spin-resolved phenomena are interesting for both fundamental research and applications. PMID- 30431020 TI - Heat transfer in rough nanofilms and nanowires using full band ab initio Monte Carlo simulation. AB - The Boltzmann transport equation is one of the most relevant frameworks to study the heat transport at the nanoscale, beyond the diffusive regime and up to the micrometer-scale. In the general case of 3D devices, the particle Monte Carlo approach of phonon transport is particularly powerful and convenient, and requires reasonable computational resources. In this work, we propose an original and versatile particle Monte Carlo approach parametrized by using ab initio data. Both the phonon dispersion and the phonon-phonon scattering rates have been computed by DFT calculation in the entire 3D Brillouin zone. To treat the phonon transport at rough interfaces, a combination of specular and diffuse reflections has been implemented in phase space. Thermal transport has been investigated in nanowires and thin films made of cubic and hexagonal Silicon, including edge roughness, in terms of effective thermal conductivity, phonon band contributions and heat flux orientation. It is shown that the effective thermal conductivity in quasi-ballistic regime obtained from our Monte Carlo simulation cannot be accurately fitted by simple semi-analytical Matthiessen-like models and that spectral approaches are mandatory to get good results. Our full band approach shows that some phonon branches exhibiting a negative group velocity in some parts of the Brillouin zone may contribute negatively to the total thermal flux. Besides, the thermal flux clearly appears to be oriented along directions of high density of states. The resulting anisotropy of the heat flux is discussed together with the influence of rough interfaces. PMID- 30431021 TI - Crystal structure and physical properties of the two stannides EuPdSn2 and YbPdSn2. AB - We report on synthesis, crystal structure and physical properties of the isotypic compounds YbPdSn2 and EuPdSn2 crystallizing in the MgCuAl2-type structure. In both stannides a divalent state of respective rare earth element was found from analysis of the magnetic susceptibilities. Whereas in YbPdSn2 only weak paramagnetic behaviour is observed, in EuPdSn2 a long-range magnetic phase transition occurs at 12.5 K with complex magnetic behaviour evidenced by magnetic susceptibity and specific heat measurements. Under the influence of magnetic field, the magnetic behaviour was found to evolve from an antiferromagnetic to a ferromagnetic state as a consequence of a re-arrangement of magnetic moments. PMID- 30431022 TI - Perfusable and stretchable 3D culture system for skin-equivalent. AB - This study describes a perfusable and stretchable culture system for a skin equivalent. The system is comprised of a flexible culture device equipped with connections that fix vascular channels of the skin-equivalent and functions as an interface for an external pump. Furthermore, a stretching apparatus for the culture device can be fabricated using rapid prototyping technologies, which allows for easy modifications of stretching parameters. When cultured under dynamically stretching and perfusion conditions, the skin-equivalent exhibits improved morphology. The epidermal layer becomes thicker and more differentiated than that cultured without the stretching stimuli or under statically-stretched conditions, and the dermal layer was more densely populated with dermal fibroblasts than that cultured without perfusion due to the nutrient and oxygen supply by perfusion via the vascular channels. Therefore, the system is useful for the improvement and biological studies of skin-equivalents. PMID- 30431023 TI - Low energy excitations in NiO based on a direct Delta-SCF approach. AB - This paper reports calculated energies and electronic structures of nineteen excited states in NiO based on a Delta-SCF approach reported previously for the [Formula: see text] transitions in NiO and Sr2CuO2Cl2. They are the spin-flip: [Formula: see text]; eight [Formula: see text]: (one electron) 3A2g -> 3 T 2g , (two electron) 3A2g -> 3 T 1g , 3A2g -> a 1 E g , 3A2g -> 1 T 2g , 3A2g -> 1 T 1g , 3A2g -> b1 E g , 3A2g -> b1 T 2g ; two O(2p) -> Ni(3d); seven Ni(3d) -> O(2p) (including two spin-flip) and the O(2s) -> Ni(3d) charge transfer excitations, which span an energy range from 0.25 eV to 17.53 eV, and include the fundamental band gap associated with an excitonic O(2p) -> Ni(3d) transition at 4.23 eV. These are compared to absorption and emission spectra, and previous calculations. In the case of the O(2p) -> Ni(3d) excitations, comparisons are given for gap and Gamma-point energies derived from HF, PBE0, HSE06, B3LYP, B1WC, GGA and LDA one-electron approximations. Finally, the directly calculated Stokes shifts and associated luminescence energies for the two O(2p) -> Ni(3d) transitions are reported, where the excitonic value is found to be in good agreement with the recently reported experimental value. PMID- 30431024 TI - Dynamics on next-neighbour distances in liquid and undercooled gallium. AB - Density fluctuations of liquid and 20 K undercooled gallium have been studied by neutron spectroscopy. The decay of density fluctuations has been recorded at the structure factor maximum over a wide temperature range up to twice the melting temperature. The amplitude of the scattering function falls off with rising temperature in a nonlinear way with a changing slope around [Formula: see text]. The derived generalized longitudinal viscosity shows an upturn with decreasing temperature in the same temperature range. This increase in viscosity can be understood that liquid gallium transforms from a more fluid liquid metal to a more viscous liquid metal in that temperature range upon cooling. The change in the amplitude shows a remarkable agreement with results from liquid aluminium, lead and rubidium. This study suggests a universal crossover in dynamics of liquid monatomic metals, despite the many peculiar properties of gallium. PMID- 30431025 TI - Astrocyte Elevated Gene 1 (AEG-1) Acts as a Promoter Gene in Clear Cell Renal Cell Carcinoma Cell Growth and Metastasis. AB - BACKGROUND Clear cell renal cell carcinoma (ccRCC) is usually incurable once it progresses to metastatic stage. Hence, in-depth investigations to reveal the precise molecular mechanisms behind the metastasis of ccRCC are required to improve the therapeutic outcome of ccRCC. MATERIAL AND METHODS The level of astrocyte elevated gene 1 (AEG-1) in ccRCC tissues and cell lines was determined by quantitative real-time PCR (qRT-PCR) assay. The MTS, colony formation, wound healing, and Transwell invasion assays were used to assess the role of AEG-1 in ccRCC cells growth, migration, and invasion in vitro, respectively. Xenograft model and lung metastasis models were constructed to analyze the functions of AEG 1 in ccRCC cells growth and metastasis in vivo. RESULTS We found that AEG-1 was overexpressed in ccRCC and was associated with the progression of ccRCC. Knocked down AEG-1 impaired the migration and invasion of ccRCC cells in vitro. Furthermore, under-expression of AEG-1 caused complete inhibition of ccRCC cells growth and metastasis in vivo. In contrast, overexpression of AEG-1 significantly increased the migration and invasion ability of ccRCC cells in vitro. Finally, we revealed that AEG-1 boosted the metastatic ability of ccRCC cells via regulating Notch homolog 1 (Notch1). CONCLUSIONS The AEG-1/Notch1 signaling axis plays a vital role in ccRCC cell growth and metastasis. PMID- 30431026 TI - Actinide-transition metal bonding in heterobimetallic uranium- and thorium molybdenum paddlewheel complexes. AB - We report the preparation of four heterobimetallic uranium- and thorium molybdenum paddlewheel complexes. The characterisation data suggest the presence of Mo -> An sigma-interactions in all cases. These complexes represent unprecedented actinide-group 6 metal-metal bonds, where before heterobimetallic uranium-metal bonds were restricted to group 7-11 metals. PMID- 30431027 TI - Helicity adaptation within a quadruply stranded helicate by encapsulation. AB - The helicity of a quadruply stranded M2L4 helicate consisting of an aromatic amide bidendate ligand is flexible due to the twisting of the amide moieties and can be tuned by the encapsulated anions. This study reveals the multiple interplays and complementarities between the anions as well as between the anions and the helicate, which are synthetically responsive to the ultimate conformation of the helicate. PMID- 30431028 TI - Emissive intelligent supramolecular gel for highly selective sensing of Al3+ and writable soft material. AB - A fluorine-containing acylhydrazone was newly designed and found to form gels in a mixed solvent of DMSO-ethylene glycol. The gelator could show brilliant blue light upon mixing with Al3+, which could be erased by F- ions and thus forming an erasable gel. PMID- 30431029 TI - Ruthenium(ii)-polypyridyl doped zirconium(iv) metal-organic frameworks for solid state electrochemiluminescence. AB - Solid-state electrochemiluminescence (ECL) has drawn increasing attention due to its advantages over solution-phase ECL, such as reducing the consumption of expensive reagents and enhancing the ECL signal. Herein we report a ruthenium(ii) polypyridyl doped zirconium(iv) metal-organic framework (MOF) film, UiO-67 Ru@FTO, for solid-state electrochemiluminescence. With tripropylamine (TPA) as a coreactant, UiO-67-Ru@FTO exhibited high ECL intensity and good stability. A linear relationship was found between the ECL intensity and TPA concentration in a wide range of 0.04-20 mM. Additionally, UiO-67-Ru@FTO was successfully used for dopamine detection, implying its great potential in real-life applications. PMID- 30431030 TI - Measurement of cytokine biomarkers using an aptamer-based affinity graphene nanosensor on a flexible substrate toward wearable applications. AB - We present an approach for the label-free detection of cytokine biomarkers using an aptamer-functionalized, graphene-based field effect transistor (GFET) nanosensor on a flexible, SiO2-coated substrate of the polymer polyethylene naphthalate (PEN). The nanosensor conforms to the underlying nonplanar surface and performs GFET-based rapid transduction of the aptamer-biomarker binding, thereby potentially allowing the detection of cytokine biomarkers that are sampled reliably from human bodily fluids (e.g., sweat) in wearable sensing applications. In characterizing the suitability of the nanosensor for wearable applications, we investigate the effects of substrate bending on the equilibrium dissociation constant between the aptamer and the biomarker as well as the graphene transconductance. The utility of the nanosensor is demonstrated by the detection of tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine biomarker. Experimental results show that the flexible nanosensor can specifically respond to changes in the TNF-alpha concentration within 5 minutes with a limit of detection as low as 26 pM in a repeatable manner. PMID- 30431031 TI - Multi-modal, ultrasensitive, wide-range humidity sensing with Ti3C2 film. AB - Gravimetric, direct-current electrical, and electrical impedance sensing modes were used to measure response of high surface area 2D Ti3C2 MXene film to water vapor pressures spanning 3 orders of magnitude (20 mTorr-20 Torr). The Ti3C2 film exhibited reproducible reversible response in 0.1%-95% relative humidity (RH) range with a detection limit of <20 mTorr H2O partial pressure (<0.1% RH). DC electrical current-based sensing with 3 mV operating voltage and 0.8 pW power consumption was demonstrated. The highest normalized sensitivity was shown for gravimetric sensing modalities which scale with the overtone number, reaching highest sensitivity of about 12 Hz/% RH at the 9th crystal overtone (45 MHz oscillation). PMID- 30431032 TI - A method to directly assay circRNA in real samples. AB - A method to directly assay circular RNA (circRNA) is proposed in this work by utilizing the 'microRNA (miRNA) sponge' nature of circRNA and by taking the advantage of duplex-specific nuclease. Moreover, miRNA absorption site-mediated hairpin DNA unfolding and nuclease-assisted target recycling have also been designed in this method to amplify the signal readout, thus sensitive assay of circRNA can be achieved in real samples. PMID- 30431033 TI - Assembly of glycoamino acid building blocks: a new strategy for the straightforward synthesis of heparan sulfate mimics. AB - A new strategy that enables a modular straightforward synthesis of heparan sulfate oligosaccharide mimics by the assembly of simple glycoamino acid building blocks is described. The coupling between units is readily carried out by an amidation reaction. Several glycoamino acid oligomers were prepared and their interaction with the FGF2 protein was analyzed. PMID- 30431034 TI - Implementing one-shot multiple-FID acquisition into homonuclear and heteronuclear NMR experiments. AB - Multiple-FID acquisition (MFA) within the same scan is applied to acquire simultaneously multiple 2D spectra from a single NMR experiment. A discussion on the incorporation of the MFA strategy in several homonuclear and heteronuclear 2D pulse sequences is presented. As a proof of concept, a set of novel COSY, TOCSY and HMBC experiments are reported as a time-efficient solution in small-molecule NMR spectroscopy. PMID- 30431035 TI - Phosphomolybdic acid as an efficient hole injection material in perovskite optoelectronic devices. AB - Efficient perovskite devices consist of a perovskite film sandwiched between charge selective layers, in order to avoid non-radiative recombination. A common metal oxide used as a p-type or hole transport layer is molybdenum oxide. MoO3 is of particular interest for its very large work function, which allows it to be used both as an interfacial charge transfer material and a dopant for organic semiconductors. However, high quality and high work function MoO3 is typically thermally evaporated in a vacuum. An alternative solution-processable high work function material is phosphomolybdic acid (PMA), which is stable, commercially available and environmentally friendly. In this Communication, we show the first application of PMA in efficient vacuum processed perovskite devices. We found that the direct growth of perovskite films onto PMA leads to strong charge carrier recombination, hindering the solar cell photovoltage. Using an energetically suitable selective transport layer placed between PMA and the perovskite film, solar cells with efficiency >13% as well as LEDs with promising quantum efficiency can be obtained. PMID- 30431036 TI - Spirulina platensis and silicon-enriched spirulina equally improve glucose tolerance and decrease the enzymatic activity of hepatic NADPH oxidase in obesogenic diet-fed rats. AB - The prevalence of metabolic syndrome components, such as obesity, glucose intolerance and hepatic steatosis, is rapidly increasing and becoming a major issue of public health. The present work was designed to determine the effects of Spirulina platensis (Sp) algae and silicon-enriched Sp on major metabolic syndrome components in obesogenic diet-fed rats. Forty male Wistar rats were divided into 4 groups. Ten rats were fed a control diet and 30 rats were fed a high fat (HF) diet. The HF groups were divided into three groups and supplemented with placebo or Sp or Si-enriched Sp for 12 weeks. Dietary intake and body weight were recorded. Oral glucose tolerance test and surrogate metabolic syndrome (insulin, leptin, adiponectin and lipids), mitochondrial function (enzymatic activity of respiratory chain complexes and beta-hydroxyacyl-CoA dehydrogenase), NADPH oxidase activity and several long-established oxidative stress markers were measured in the blood and liver. The HF diet induced obesity, glucose intolerance, hepatic steatosis and huge metabolic alterations, associated with higher NADPH oxidase activity and lower hepatic sulfhydryl group and glutathione contents. Otherwise, the Sp and Sp + Si supplements showed some interesting effects on rat characteristics and particularly on blood and hepatic metabolic parameters. Indeed, the intake of Sp or Sp + Si mainly improved glucose tolerance and decreased the enzymatic activity of hepatic NADPH oxidase. Overall, Si supplementation of spirulina does not appear to have more beneficial effects than spirulina alone. Other experiments with different species of rats/mice, different diets or different durations of diet intake should be undertaken to confirm or invalidate these results. PMID- 30431038 TI - Manipulating three-dimensional bending to extraordinarily stiffen two-dimensional membranes by interference colors. AB - We have provided a no-touch and inexpensive technique to present the three dimensional (3D) structure of two-dimensional (2D) films, based on the equal thickness interference fringes. In these experiments, the interference colors were obtained by an optical microscope without contact with the sample, and the 3D structures of curved 2D membranes were reconstructed by MATLAB programs in real time. The theoretical model and experimental results both showed that natural bending can improve the stiffness of 2D materials by more than 10 times. By using micro-droplets as the workbench, the 3D bending orientation and curvature of the 2D material could be manipulated and detected at the same time. The selected 3D curved shapes of cylindrical, ellipsoid and saddle surfaces can increase the bending stiffness over 10 000 times based on theoretical calculation. A saddle-shaped 3D structure (classic crisps shape) is predicted to obtain the maximum bending stiffness. Herein, a simple and practical method to comprehensively detect the basic deformation of 2D membranes is proposed, which should be promoted to explore the out-of-plane mechanical properties of 2D materials under external fields. PMID- 30431037 TI - Porous platinum-silver bimetallic alloys: surface composition and strain tunability toward enhanced electrocatalysis. AB - Promoting surface strains in heterogeneous catalysts and heteroatomic interactions in alloying offer an effective strategy for the development of electrocatalysts with greatly enhanced activity. In this work, we design platinum silver nanotubes (PtAg NTs) with tunable surface compositions by a controlled galvanic replacement reaction of well-defined Ag nanowires (NWs). The optimized and porous PtAg NTs (PtAg-4 NTs), with the Pt5Ag3 surface composition and (111) facet-dominant surface features, exhibit an extraordinary oxygen reduction reaction (ORR) activity that reaches a specific activity of 1.13 mA cm-2 and a mass activity of 0.688 A mg-1Pt at 0.9 V versus a reversible hydrogen electrode (RHE), which are 4.5 times and 4.3 times those of commercial Pt/C catalysts (0.25 mA cm-2 and 0.16 A mg-1Pt). Moreover, PtAg-4 NTs/C can endure under the ORR conditions over the course of 10 000 cycles with negligible activity decay. Remarkably, density functional theory simulations reveal that the porous PtAg-4 NTs exhibit enhanced adsorption interaction with adsorbates, attributed to the catalytically active sites on high-density (111) facets and modulation of the surface strain, further boosting the ORR activity and durability. PMID- 30431039 TI - Probing the SERS brightness of individual Au nanoparticles, hollow Au/Ag nanoshells, Au nanostars and Au core/Au satellite particles: single-particle experiments and computer simulations. AB - Different classes of plasmonic nanoparticles functionalized with the non-resonant Raman reporter molecule 4-MBA are tested for their SERS signal brightness at the single-particle level: gold nanoparticles, hollow gold/silver nanoshells, gold nanostars, and gold core/gold satellite particles. Correlative SERS/SEM experiments on a set of particles from each class enable the unambiguous identification of single particles by electron microscopy as well as the characterization of both their elastic (LSPR) and inelastic (SERS) scattering spectra. Experimental observations are compared with predictions from FEM computer simulations based on 3D models derived from representative TEM/SEM images. Single gold nanostars and single gold core/gold satellite particles exhibit a detectable SERS signal under the given experimental conditions, while single gold nanoparticles and single hollow gold/silver nanoshells are not detectable. PMID- 30431040 TI - Materials and design of nanostructured broadband light absorbers for advanced light-to-heat conversion. AB - Light-to-heat conversion systems have been attracting growing research interest in the last few decades, due to their highly intriguing photothermal properties and their wide applications ranging from biomedical applications to solar energy harvesting to mechanical actuators. In general, because the light-to-heat conversion efficiency depends strongly on the absorbing material, significant efforts have been focused on fabricating broadband light absorbers. However, there are several challenges associated with the design and fabrication of light absorbers, such as minimizing heat loss, and optimizing the broadband light absorption and omnidirectional light absorption. Thus, the rational design of enhanced light absorbers is critical to achieve efficient light absorption over a broad wavelength range. In this paper, we introduce the basic theory of light absorption and heat transfer, then summarize fundamental understanding of representative light-to-heat conversion agents including carbon-based, semiconductor-based and plasmonic metal-based materials and structures, and highlight state-of-the-art structural designs towards the development of broadband light absorbers. In addition, the practical applications of these materials and designs are also discussed. PMID- 30431041 TI - Enhanced thermal conductivity in percolating nanocomposites: a molecular dynamics investigation. AB - In this work we present a molecular dynamics investigation of thermal transport in a silica-gallium nitride nanocomposite. A surprising enhancement of the thermal conductivity for crystalline volume fractions larger than 5% is found, which cannot be predicted by an effective medium approach, not even including percolation effects, the model systematically leading to an underestimation of the effective thermal conductivity. The behavior can instead be reproduced if an effective volume fraction twice larger than the real one is assumed, which translates into a percolation effect surprisingly stronger than the usual one. Such a scenario can be understood in terms of a phonon tunneling between inclusions, enhanced by the iso-orientation of all particles. Indeed, if a misorientation is introduced, the thermal conductivity strongly decreases. We also show that a percolating nanocomposite clearly stands in a different position than other nanocomposites, where thermal transport is dominated by the interface scattering and where parameters such as the interface density play a major role, differently from our case. PMID- 30431042 TI - Low-defectiveness exfoliation of MoS2 nanoparticles and their embedment in hybrid light-emitting polymer nanofibers. AB - Molybdenum disulfide (MoS2) has been attracting extraordinary attention for its intriguing optical, electronic and mechanical properties. Here, we demonstrate hybrid, organic-inorganic light-emitting nanofibers based on MoS2 nanoparticle dopants obtained through a simple and inexpensive sonication process in N-methyl 2-pyrrolidone and successfully encapsulate the nanofibers in polymer filaments. The gentle exfoliation method used to produce the MoS2 nanoparticles results in low defectiveness and preserves the stoichiometry. The fabricated hybrid fibers are smooth, uniform and flawless and exhibit bright and continuous light emission. Moreover, the fibers show significant capability for waveguiding self emitted light along their longitudinal axes. These findings suggest that emissive MoS2 fibers formed by gentle exfoliation are novel and highly promising optical materials for sensing surfaces and photonic circuits. PMID- 30431043 TI - Customizable 3D-printed architecture with ZnO-based hierarchical structures for enhanced photocatalytic performance. AB - ZnO-based hierarchical structures including nanoparticles (NPs), nanorods (NRs) and nanoflowers (NFs) on a 3D-printed backbone were effectively fabricated via the combination of the fused deposition modelling (FDM) 3D-printing technique and hydrothermal reaction. The photocatalytic performance of the ZnO-based hierarchical structures on the 3D-backbone was verified via the degradation of the organic pollutant methylene blue, which was monitored by UV-vis spectroscopy. The new photocatalytic architectures used in this investigation give an effective approach and wide applicability to overcome the limitation of photocatalysts such as secondary removal photocatalyst processes. PMID- 30431044 TI - Eco-friendly synthesis of N,S co-doped hierarchical nanocarbon as a highly efficient metal-free catalyst for the reduction of nitroarenes. AB - Heteroatom-doped carbon nanomaterials are effective metal-free catalysts for organic reactions. However, S-doped carbocatalysts are relatively unexplored due to challenges related to the synthesis of S-doped nanocarbon. Herein, we employed a facile, low-cost and eco-friendly approach to construct a N,S co-doped hierarchical carbon nanomaterial (NSHC) via the pyrolysis of an azo-sulphonate dye pollutant intercalated layered double hydroxide. The as-prepared NSHC possesses a two-dimensional hierarchical porous structure with ultrathin carbon nanosheets uniformly distributed on hexagonal carbon nanoplates, endowing the material with a high specific surface area of 1260 m2 g-1. Attributed to the synergistic effects of N,S co-doping, the high specific surface area and the interconnected porous architecture, NSHC demonstrates excellent catalytic activity and selectivity in the reduction of nitroarenes. Among the reported carbocatalysts for nitrobenzene reduction using hydrazine hydrate, NSHC shows the highest turnover frequency value of 4.89 h-1. Furthermore, NSHC exhibits remarkable recyclability and generality for the reduction of various aromatic nitro compounds. PMID- 30431045 TI - Mimicking biological neurons with a nanoscale ferroelectric transistor. AB - Neuron is the basic computing unit in brain-inspired neural networks. Although a multitude of excellent artificial neurons realized with conventional transistors have been proposed, they might not be energy and area efficient in large-scale networks. The recent discovery of ferroelectricity in hafnium oxide (HfO2) and the related switching phenomena at the nanoscale might provide a solution. This study employs the newly reported accumulative polarization reversal in nanoscale HfO2-based ferroelectric field-effect transistors (FeFETs) to implement two key neuronal dynamics: the integration of action potentials and the subsequent firing according to the biologically plausible all-or-nothing law. We show that by carefully shaping electrical excitations based on the particular nucleation limited switching kinetics of the ferroelectric layer further neuronal behaviors can be emulated, such as firing activity tuning, arbitrary refractory period and the leaky effect. Finally, we discuss the advantages of an FeFET-based neuron, highlighting its transferability to advanced scaling technologies and the beneficial impact it may have in reducing the complexity of neuromorphic circuits. PMID- 30431050 TI - Nanoscale tracking plasmon-driven photocatalysis in individual nanojunctions by vibrational spectroscopy. AB - Plasmonic metal nanoparticles (NPs) are promising catalysts in photocatalytic reactions. Understanding the exact role of sites where two particles are approaching (hot spots) is important to achieve higher efficiency of photocatalysis, and promote the development of advanced plasmon-driven photocatalytic systems. Surface-enhanced Raman spectroscopy was employed to probe photocatalytic coupling reactions occurring at individual plasmonic nanojunctions that trap light to nanoscale while serving as nanoreactors. Compared with nanocavities fabricated using the small Ag NPs (70 nm or 82 nm), the 102 nm Ag NP molecule-Au thin film nanojunction demonstrated enhanced reaction kinetics and catalytic efficiency. On the basis of the experimental results and theoretical modeling, it was concluded that the photochemical reaction dynamics and yields showed direct correlation with the local electric field enhancement at the nanojunction hot spot. The largely enhanced electric field generates increased hot plasmonic electrons, promoting chemical transformations of the adsorbed molecules. PMID- 30431051 TI - Influence of protein charge patches on the structure of protein-polyelectrolyte complexes. AB - We employ a combination of the single chain in mean field simulation approach with the solution of Poisson's equation to study the influence of charge heterogeneities on the structure of protein-polyelectrolyte complexes. By adopting a coarse-grained model of representing proteins as charged nanoparticles, we studied the influence of the pattern of charge heterogeneities, net charge, ratio of positive to negative charges on the patches, and the volume fraction of the particles on the structural and aggregation characteristics of proteins in polyelectrolyte solutions. Our results demonstrate that the pattern of charge heterogeneities can exert a significant influence on the resulting characteristics of the aggregates, in some cases leading to a transformation from polymer-bridged complexes into direct particle aggregates driven by the attraction between oppositely charged patches. PMID- 30431052 TI - A removable functional group strategy for regiodivergent Wittig rearrangement products. AB - [1,2] and [2,3] Wittig rearrangements are competing reaction pathways, often leading to uncontrollable product distribution. We employ a single removable functional group to fulfill the dual role of attaining a reversible [2,3] and stabilizing radical intermediate for the [1,2] path to obtain both the Wittig products selectively for a broad range of substrates. PMID- 30431054 TI - Transistor configuration yields energy level control in protein-based junctions. AB - The incorporation of proteins as functional components in electronic junctions has received much interest recently due to their diverse bio-chemical and physical properties. However, information regarding the energies of the frontier orbitals involved in their electron transport (ETp) has remained elusive. Here we employ a new method to quantitatively determine the energy position of the molecular orbital, nearest to the Fermi level (EF) of the electrode, in the electron transfer protein Azurin. The importance of the Cu(ii) redox center of Azurin is demonstrated by measuring gate-controlled conductance switching which is absent if Azurin's copper ions are removed. Comparing different electrode materials, a higher conductance and a lower gate-induced current onset is observed for the material with smaller work function, indicating that ETp via Azurin is LUMO-mediated. We use the difference in work function to calibrate the difference in gate-induced current onset for the two electrode materials, to a specific energy level shift and find that ETp via Azurin is near resonance. Our results provide a basis for mapping and studying the role of energy level positions in (bio)molecular junctions. PMID- 30431055 TI - Guanine and nucleotide binding protein 3 promotes odonto/osteogenic differentiation of apical papilla stem cells via JNK and ERK signaling pathways. AB - Odonto/osteogenic differentiation of stem cells from the apical papilla (SCAPs) is a key process in tooth root formation and development. However, the molecular mechanisms underlying this process remain largely unknown. In the present study, it was identified that guanine and nucleotide binding protein 3 (GNAI3) was at least in part responsible for the odonto/osteogenic differentiation of SCAPs. GNAI3 was markedly induced in mouse tooth root development in vivo and in human SCAPs mineralization in vitro. Notably, knockdown of GNAI3 by lentiviral vectors expressing short-hairpin RNAs against GNAI3 significantly inhibited the proliferation, cell cycle progression and migration of SCAPs, as well as odonto/osteogenic differentiation of SCAPs in vitro, suggesting that GNAI3 may play an essential role in tooth root development. The promotive role of GNAI3 in odonto/osteogenic differentiation was further confirmed by downregulation of odonto/osteogenic makers in GNAI3-deficient SCAPs. In addition, knockdown of GNAI3 effectively suppressed activity of c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) signaling pathways that was induced during SCAPs differentiation, suggesting that GNAI3 promotes SCAPs mineralization at least partially via JNK/ERK signaling. Taken together, the present results implicate GNAI3 as a critical regulator of odonto/osteogenic differentiation of SCAPs in tooth root development, and suggest a possible role of GNAI3 in regeneration processes in dentin or other tissues. PMID- 30431056 TI - Exosome-mediated microRNA-138 and vascular endothelial growth factor in endometriosis through inflammation and apoptosis via the nuclear factor-kappaB signaling pathway. AB - Endometriosis (Ems) is a condition that refers to the ectopic implantation and growth of endometrial tissue outside the uterine cavity. The aim of the present study was to investigate the role of microRNA-138 (miR-138) in Ems and the possible underlying mechanism. Flow cytometry was measured CD11b level, cell proliferation was measured using MTT assay and lactate dehydrogenase (LDH) assays was analyzed using LDH activity kits. Cell apoptosis was measured using Annexin V FITC/PI double staining apoptosis detection kit and DAPI assays. ELISA assay and western blot analysis were used to measure protein expression determination. It was first observed that miR-138 expression was markedly downregulated and the CD11b level was reduced in Ems mice compared with the control group. Subsequently, miR-138 expression was downregulated in the uterine endothelial cells co-cultured with THP-1 cells, which resulted in decreased apoptosis and increased inflammation in the uterine endothelial cells. By contrast, upregulation of miR-138 by mimic transfection increased the proliferation and reduced inflammation in uterine endothelial cells. In addition, in the co-culture of uterine endothelial and THP-1 cells, downregulation of miR-138 induced the expression of nuclear factor (NF)-kappaB and vascular endothelial growth factor (VEGF) proteins in THP-1 cells. Furthermore, treatment with an NF-kappaB inhibitor and downregulation of miR-138 in the co-culture of uterine endothelial and THP-1 cells reduced inflammation. VEGF inhibitor treatment and downregulation of miR-138 in this cell co-culture promoted the proliferation of uterine endothelial cells. These results suggested that uterine endothelial cells promoted miR-138 to induce exosome-mediated inflammation and apoptosis in Ems through the VEGF/NF-kappaB signaling pathway. PMID- 30431057 TI - Neuroprotective effects of midazolam on focal cerebral ischemia in rats through anti-apoptotic mechanisms. AB - Stroke is a cerebrovascular circulatory disorder and its high mortality rate represents a prominent threat to human health. Subsequent apoptosis and cytotoxicity are the main causes underlying the poor prognosis. Midazolam (MDZ) is a benzodiazepine drug that is clinically used during surgical procedures and for the treatment of insomnia, with a potential ability to treat stroke. The protective effect of MDZ was investigated on glutamate-induced cortical neuronal injuries in vitro and transient middle cerebral artery occlusion (tMCAO) rat models in vivo. Western blot analysis and semi quantitative RT-PCR were used to evaluate the potential underlying mechanisms. In vitro studies revealed that MDZ regulated apoptosis-associated gene expression and inhibited lactate dehydrogenase (LDH) release, protecting against neuronal damage. In vivo studies revealed that MDZ reduced LDH-induced neuronal damage by reducing LDH release from the peripheral blood, and brain tissue staining revealed that MDZ protected neurons during tMCAO. MDZ protected neurons under an ischemic environment by inhibiting LDH release and regulating apoptosis-associated gene expression to reduce cytotoxicity and apoptosis. These results provide a reliable basis for further studies on the effect of MDZ, to improve the prognosis of cerebral infarction. PMID- 30431058 TI - Propofol attenuates inflammatory damage on neurons following cerebral infarction by inhibiting excessive activation of microglia. AB - The overall incidence rate of stroke is increasing worldwide. Inflammatory damage following a stroke is a leading cause for the poor prognosis and high disability rate observed in stroke patients. Microglia are considered to be the main causative agents of inflammatory injury following cerebral infarction, as they secrete various inflammatory cytokines and cytotoxic factors. The aim of the present study was to identify novel methods for attenuating inflammatory injury and improving the prognosis of stroke patients. Lipopolysaccharide-stimulated microglia were treated using propofol in vitro and a transient middle cerebral artery occlusion/reperfusion model was constructed in rats. Expression of cytotoxic factors, microglia proliferation and the neuroprotective effects of propofol were measured in vitro and in vivo. The in vitro studies demonstrated that propofol inhibits the expression of multiple cytotoxic factors, prevents structural changes to cytoskeletal proteins, and suppresses microglial migration via the adenosineA2b receptors. The results of the in vivo experiments revealed that propofol inhibits the abnormal proliferation of microglia, as well as reduces the expression levels of interleukin (IL)-6, IL-1beta, tumor necrosis factor alpha, and the cytotoxic factor nitric oxide through the A2b receptor. In conclusion, propofol inhibited the excessive activation of microglia through the A2b receptor and attenuated the inflammatory injury following cerebral infarction. The current study may provide a reliable basis for further clinical studies on propofol and its putative role in improving the prognosis of patients with cerebral infarction. PMID- 30431059 TI - Overexpression of microRNA-183 promotes apoptosis of substantia nigra neurons via the inhibition of OSMR in a mouse model of Parkinson's disease. AB - The present study aimed to investigate the effect of microRNA-183 (miR-183) on substantia nigra neurons by targeting oncostatin M receptor (OSMR) in a mouse model of Parkinson's disease (PD). The positive expression rates of OSMR and the apoptosis of substantia nigra neurons were detected by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling, respectively. Substantia nigra neurons in normal and PD mice were cultured in vitro. The association between miR-183 and OSMR was verified using a dual luciferase reporter gene assay. The expression of miR-183 and the phosphoinositide 3-kinase-Akt signaling pathway-associated genes were detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Cell apoptosis was detected by flow cytometry. OSMR is the target gene of miR-183. The number of OSMR-positive cells and the apoptotic rate of substantia nigra neurons were increased in the PD group. Neurons transfected with miR-183 mimic exhibited elevated expression levels of miR-183, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and caspase-9 and increased apoptotic rate, and reduced expression levels of OSMR, Akt, phosphorylated (p )Akt, glycogen synthase kinase-3 (GSK-3beta), p-GSK-3beta, Bcl-2, insulin-like growth factor 1 (IGF-1), mammalian target of rapamycin (mTOR) and p-mTOR. The miR 183 inhibitor decreased the expression levels of miR-183, Bax and caspase-9 and the apoptotic rate; however, increased the expression of OSMR, Akt, p-Akt, GSK 3beta, p-GSK-3beta, Bcl-2, IGF-1, mTOR and p-mTOR. The results of the present study provide evidence that the overexpression of miR-183 promotes the apoptosis of substantia nigra neurons by inhibiting the expression of OSMR. PMID- 30431060 TI - Overexpression of CDCA8 promotes the malignant progression of cutaneous melanoma and leads to poor prognosis. AB - Cutaneous melanoma is very aggressive and results in high mortality rates for cancer patients. Determining molecular targets is important for developing novel therapies for cutaneous melanoma. Cell division cycle associated 8 (CDCA8) is a putative oncogene that is upregulated in multiple types of cancer. The present study aimed to examine the role of CDCA8 in cutaneous melanoma, with a focus on the association of its expression to prognosis and metastasis. First, the mRNA expression of CDCA8 in cutaneous melanoma tissues was investigated using the ONCOMINE and Gene Expression Omnibus (GEO) databases. Furthermore, the relationship between the expression of CDCA8 and cutaneous melanoma patient survival was analyzed using a Kaplan-Meier plot and Log Rank test. In addition, the effects of CDCA8 on proliferation, migration and invasion of cutaneous melanoma cell lines were investigated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Cell Counting kit-8, colony formation assay, wound healing and Matrigel assay. Finally, the expression levels of key proteins related to the Rho-associated coiled-coil-containing protein kinase (ROCK) signaling pathway were measured by western blot assay. The results demonstrated that CDCA8 was overexpressed in cutaneous melanoma tissues and cells lines compared with normal tissues, and high expression of CDCA8 was significantly associated with poorer prognosis in patients with cutaneous melanoma. In in vitro experiments, CDCA8 knockdown inhibited A375 and MV3 cell proliferation, migration and invasion. In addition, CDCA8 knockdown reduced the phosphorylation levels of ROCK1 and myosin light chain, two downstream effector proteins of the ROCK pathway. In summary, the present findings suggested that CDCA8 may be a promising therapeutic target for the treatment of cutaneous melanoma. PMID- 30431061 TI - Quercetin-3-O-alpha-L-rhamnopyranoside derived from the leaves of Lindera aggregata (Sims) Kosterm. evokes the autophagy-induced nuclear factor erythroid 2 related factor 2 antioxidant pathway in human umbilical vein endothelial cells. AB - Quercetin-3-O-alpha-L-rhamnopyranoside (QI) is derived from the leaves of Lindera aggregata (Sims) Kosterm. And exhibits multiple biological activities, including an antioxidant activity. However, the detailed molecular mechanism of its antioxidant activity remains unknown. The aim of the present study was to investigate the antioxidant activity of QI and the underlying molecular mechanism in human umbilical vein endothelial cells (HUVECs). An oxidative stress model was established in HUVECs using H2O2, and cells were then treated with different concentrations of QI. The results revealed that the exposure of HUVECs to QI protected these cells from H2O2-induced damage. QI treatment also increased the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione (GSH) in the cell culture medium. In addition, QI inhibited H2O2-induced apoptosis by decreasing the expression levels of cleaved Caspase-9 and poly(ADP ribose) polymerase. QI also inhibited the production of DNA fragments and reactive oxygen species induced by H2O2. Furthermore, QI decreased the oxidative stress by promoting the nuclear transfer of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 by activating autophagy, and inhibited the competition of Bach1 from Nrf2. Finally, QI significantly improved the activities of T-SOD and GSH, and decreased the content of malondialdehyde in the serum and heart tissue of aging rats. These data support the use of QI as a health supplement to alleviate oxidative stress or further development of this compound as an antioxidant drug. PMID- 30431063 TI - Mechanism of extracellular-superoxide dismutase DNA methylation in a hyperhomocysteinemia-induced atherosclerosis in a mouse model. AB - The effect of homocysteine (Hcy) on extracellular-superoxide dismutase (EC-SOD) methylation levels in the aorta of mice was observed and the underlying mechanism of THP-1 monocyte-derived macrophages was investigated. The key targets of Hcy induced EC-SOD methylation changes were identified. ApoE-/- mice were fed different diets for 15 weeks and the concentrations of Hcy and lipids were subsequently detected using an automatic biochemistry analyzer. Serum levels of Hcy and lipids were significantly higher in the Meth group compared with the control group. EC-SOD and DNA methyltransferase (DNMT)1 mRNA and protein expression levels were detected by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, respectively. EC-SOD methylation levels were assessed using nested touchdown methylation-specific PCR (ntMS-PCR). Oxidative stress was measured using chromatometry. Recombined vectors overexpressing and silencing EC-SOD were transfected into macrophages. Following the transfection of macrophages with pEGFP-N1-DNMT1, the methylation levels of EC SOD were detected. Furthermore, EC-SOD DNA methylation levels were significantly decreased in the Meth group. The promoter activity of EC-SOD was increased following transfection with -1/-1100 fragment and DNMT1 mRNA expression was significantly decreased in the Meth group. Following transfection with the recombinant plasmid, DNMT1 protein expression was significantly increased. ntMS PCR results revealed that EC-SOD methylation levels significantly decreased in the Meth group, while they increased in N1-DNMT1 groups compared with the controls. In conclusion, Hcy may alter the DNA methylation status and DNMT1 acts as the essential enzyme in the methyl transfer process to disturb the status of EC-SOD DNA methylation, leads to a decrease in the expression of EC-SOD to promote oxidative stress and AS. PMID- 30431062 TI - miR-181b-5p suppresses starvation-induced cardiomyocyte autophagy by targeting Hspa5. AB - This study aimed to investigate the role of microRNA-181b-5p (miR-181b-5p) in starvation-induced cardiomyocyte autophagy by targeting heat shock protein family A member 5 (Hspa5). For this purpose, H9c2 cardiomyocytes and neonatal rat ventricular myocytes (NRVMs) were glucose-starved in Earle's Balanced Salt Solution (EBSS) for different periods of time (0, 2, 4, 6 and 8 h). RT-qPCR analysis was performed to examine the expression of miR-181b-5p in the different groups. Immunofluorescence was performed to detect the expression of LC3. In addition, the H9c2 cardiomyocytes and NRVMs were transfected with miR-181b-5p mimic, miR-181b-5p inhibitor, siHspa5 or their respective controls. An MTT assay was performed to measure cell proliferation in the different groups. Western blot analysis was performed to determine the expression of Beclin-1, Hspa5, phosphorylated phosphoinositide 3-kinase PI3K (p-PI3K), phosphorylated Akt (p Akt), phosphorylated mammalian target of rapamycin (p-mTOR), Bcl-2, Bax and cleaved caspase-3. Flow cytometry was performed to assess cell apoptosis. A luciferase reporter assay was performed to determine whether Hspa5 is a direct target of miR-181b-5p. The results revealed that the downregulation of miR-181b 5p promoted cell autophagy in the cardiomyocytes. Moreover, miR-181b-5p negatively regulated Beclin-1 and Hspa5. Beclin-1 is a well-known autophagy- and apoptosis-related protein. In addition, cell apoptosis was attenuated by the decreased expression of miR-181b-5p in the cardiomyocytes. Bcl-2 prevented apoptosis and autophagy by binding to Bax and Bcl-2, respectively. The upregulation of miR-181b-5p inhibited autophagy and promoted apoptosis via Hspa5. miR-181b-5p inhibition promoted p-mTOR, p-Akt and p-PI3K expression via Hspa5. The results of luciferase reporter assay also confirmed that Hspa5 is a direct target of miR-181b-5p. On the whole, the findings of this study suggest that miR 181b-5p contributes to starvation-induced autophagy and apoptosis in cardiomyocytes by directly targeting Hspa5 via the PI3K/Akt/mTOR signaling pathway. PMID- 30431065 TI - lncRNA MEG3 promotes hepatic insulin resistance by serving as a competing endogenous RNA of miR-214 to regulate ATF4 expression. AB - MicroRNA (miR)-214 has been demonstrated to suppress gluconeogenesis by targeting activating transcription factor 4 (ATF4), which regulates gluconeogenesis by affecting the transcriptional activity of forkhead box protein O1 (FoxO1). Our previous study revealed that the upregulation of maternally expressed gene 3 (MEG3), a long noncoding RNA, enhanced hepatic insulin resistance via increased FoxO1 expression. The present study aimed to explore whether miR-214 and ATF4 were involved in the MEG3-mediated increase of FoxO1 expression. MEG3, miR-214 and ATF4 expression were examined by reverse transcription quantitative polymerase chain reaction and western blot analysis. The interaction among MEG3, miR-214 and ATF4 was analysed using the luciferase reporter assay. MEG3-targeting small interference RNAs were injected into high-fat diet (HFD)-fed mice to verify the role of MEG3 in hepatic insulin resistance in vivo. MEG-3 and ATF4 were demonstrated to be upregulated and miR-214 was indicated to be downregulated in the livers of HFD-fed and ob/ob mice. In mouse primary hepatocytes, palmitate time-dependently increased MEG3 and ATF4 but decreased miR-214 expression levels. Furthermore, MEG3 served as a competing endogenous RNA (ceRNA) for miR-214 to facilitate ATF4 expression, while miR-214 inhibition and ATF4 overexpression reversed the MEG3 knockdown-mediated decrease in the expression of FoxO1 and FoxO1-downstream targets phosphoenolpyruvate carboxykinase and glucose-6 phosphatase catalytic subunit. In HFD-fed mice, MEG3 knockdown substantially improved impaired glucose and insulin tolerance, while downregulating HFD-induced ATF4 expression and upregulating HFD-suppressed miR-214 expression. In conclusion, MEG3 promoted hepatic insulin resistance by serving as a ceRNA of miR 214 to facilitate ATF4 expression. These data provide insight into the molecular mechanism of MEG3 involvement in the development of type 2 diabetes mellitus. PMID- 30431064 TI - High-pressure carbon dioxide pneumoperitoneum induces oxidative stress and mitochondria-associated apoptotic pathway in rabbit kidneys with severe hydronephrosis. AB - The primary aim of the present study was to investigate the potential effect of high-pressure carbon dioxide (CO2) pneumoperitoneum on kidneys with severe hydronephrosis and to investigate the possible underlying mechanism. A total of 18 rabbits underwent a surgical procedure inducing severe hydronephrosis. Rabbits were then divided at random into three groups (n=6 each) and subjected to intraabdominal pressure of 0, 8 or 18 mmHg, respectively. CO2 inflation lasted for 90 min in the pneumoperitoneum groups. Oxidative stress was assessed by measurements of reactive oxygen species (ROS). Activation of apoptosis was analyzed by western blot analysis of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated x protein (Bax), cytochrome c (Cyt c), caspase-3 and caspase-9 levels. In addition, TUNEL assay, hematoxylin and eosin (H&E) staining, measurement of mitochondrial membrane potential (MMP) and detection of changes to kidney ultramicrostructure were performed. In the 0 and 8 mmHg groups, all results were normal and similar. However, in the 18 mmHg group, the kidneys suffered oxidative damage and mitochondrial injuries, and increased ROS levels, lower MMP and mitochondrial vacuolization were observed. Furthermore, the mitochondrial/caspase dependent pathway of apoptosis was activated, as indicated by the apoptotic index, and the expression levels and translocation of Bax, Bcl-2, Cyt c, caspase 3 and caspase-9. Therefore, it is concluded that high-pressure CO2 pneumoperitoneum induces oxidative damage and apoptosis in rabbit kidneys with severe hydronephrosis, which is associated with the mitochondrial apoptotic pathway. PMID- 30431067 TI - 'Governor vessel-unblocking and mind-regulating' acupuncture therapy ameliorates cognitive dysfunction in a rat model of middle cerebral artery occlusion. AB - Acupuncture is a traditional Chinese medicinal therapy, which is used for the amelioration of cognitive dysfunction. The aim of this study was to investigate the effectiveness and relevancy mechanisms of 'governor vessel-unblocking and mind-regulating' acupuncture therapy for cognitive dysfunction in rats with ischemia. For this purpose, we used the middle cerebral artery occlusion (MCAO) method to induce cognitive dysfunction in rats. The behavioral changes in the rats were examined using the Morris water maze (MWM) test. The effects of the treatment on oxidative stress response and the function of the mitochondria in brain tissues were also assessed. The results revealed that 'governor vessel unblocking and mind-regulating' acupuncture therapy markedly improved the cognitive ability of the rats with cognitive dysfunction. The production of pro oxidative stress factors, including nitric oxide (NO) and inducible nitric oxide synthase (iNOS), was also blocked along with the amelioration of cognitive function, while the production of adenosine triphosphate (ATP), superoxide dismutase (SOD) and cyclooxygenase (COX) was restored. At the molecular level, the accumulation of amyloid beta (Abeta) in the mitochondria was suppressed by 'governor vessel-unblocking and mind-regulating' acupuncture therapy, which may be attributed to the inhibition of the function of translocase of outer mitochondrial membrane 40 (TOMM40) and translocase of inner mitochondrial membrane 17A (TIMM17A). On the whole, the findings of the present study confirm the effects of 'governor vessel-unblocking and mind-regulating' acupuncture therapy on cognitive dysfunction induced by brain ischemia in rats, and that the mechanisms underlying the effects of this treatment might be mediated through the inhibition of TOMM40 and TIMM17A synthesis, which can relieve mitochondrial dysfunction from the accumulation of Abeta. PMID- 30431066 TI - Bioinformatics-based study to detect chemical compounds that show potential as treatments for pulmonary thromboembolism. AB - The objectives of the present study comprised the recognition of major genes related to pulmonary thromboembolism (PTE) and the evaluation of their functional enrichment levels, in addition to the identification of small chemical molecules that may offer potential for use in PTE treatment. The RNA expression profiling of GSE84738 was obtained from the Gene Expression Omnibus database. Following data preprocessing, the differently expressed genes (DEGs) between the PTE group and the control group were identified using the Linear Models for Microarray package. Subsequently, the protein-protein interaction (PPI) network of these DEGs was examined using the Search Tool for the Retrieval of Interacting Genes/Proteins database, visualized via Cytoscape. The most significantly clustered modules in the network were identified using Multi Contrast Delayed Enhancement, a plugin of Cytoscape. Subsequently, functional enrichment analysis of the DEGs was performed, using the Database for Annotation Visualization and Integrated Discovery tool. Furthermore, the chemical-target interaction networks were investigated using the Comparative Toxicogenomics Database as visualized via Cytoscape. A total of 548 DEGs (262 upregulated and 286 downregulated) were identified in the PTE group, compared with the control group. The upregulated and downregulated genes were enriched in Gene Ontology terms related to inflammation and eye sarcolemma, respectively. Tumor necrosis factor (TNF) and erb-b2 receptor tyrosine kinase 2 (ERBB2) were upregulated genes that ranked higher in the PPI network (47 and 40 degrees, respectively) whereas C-JUN was the most downregulated gene (46). Small chemical molecules ethinyl (135), cyclosporine (126), thrombomodulin precursor (113) and tretinoin (111) had >100 degrees in the DEG-chemical interaction network. In addition, ethinyl targeted to TNF, whereas TNF and ERBB2 were targeted by cyclosporine, and tretinoin was a targeted chemical of ERBB2. Therefore, cyclosporine, ethinyl, and tretinoin may be potential targets for PTE treatment. PMID- 30431068 TI - Inhibitory role of AMP-activated protein kinase in necroptosis of HCT116 colon cancer cells with p53 null mutation under nutrient starvation. AB - Simultaneous induction of other types of programmed cell death, alongside apoptosis, in cancer cells may be considered an attractive strategy for the development of more effective anticancer therapies. The present study aimed to investigate the role of AMP-activated protein kinase (AMPK) in nutrient/serum starvation-induced necroptosis, which is a programmed form of necrosis, in the presence or absence of p53. The present study detected higher cell proliferation and lower cell death rates in the HCT116 human colon cancer cell line containing a p53 null mutation (HCT116 p53-/-) compared with in HCT116 cells harboring wild type p53 (HCT116 p53+/+), as determined using a cell viability assay. Notably, western blot analysis revealed a relatively lower level of necroptosis in HCT116 p53-/- cells compared with in HCT116 p53+/+ cells. Investigating the mechanism, it was revealed that necroptosis may be induced in HCT116 p53+/+ cells by significantly increasing reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), whereas little alterations were detected in HCT116 p53-/- cells. Unexpectedly, a much lower level of ATP was detected in HCT116 p53-/- cells compared with in HCT116 p53+/+ cells. Accordingly, AMPK phosphorylation on the Thr172 residue was markedly increased in HCT116 p53-/- cells. Furthermore, western blot analysis and ROS measurements indicated that AMPK inhibition, using dorsomorphin dihydrochloride, accelerated necroptosis by increasing ROS generation in HCT116 p53-/- cells. However, AMPK activation by AICAR did not suppress necroptosis in HCT116 p53+/+ cells. In conclusion, these data strongly suggested that AMPK activation may be enhanced in HCT116 p53-/- cells under serum-depleted conditions via a drop in cellular ATP levels. In addition, activated AMPK may be at least partially responsible for the inhibition of necroptosis in HCT116 p53-/- cells, but not in HCT116 p53+/+cells. PMID- 30431069 TI - Long non-coding RNA HOTAIR mediates the switching of histone H3 lysine 27 acetylation to methylation to promote epithelial-to-mesenchymal transition in gastric cancer. AB - HOX transcript antisense intergenic RNA (HOTAIR), a well-known long non-coding RNA, plays an important role in the regulation of epithelial-to-mesenchymal transition (EMT). In this study, we propose a novel mechanism through which HOTAIR promotes EMT by switching histone H3 lysine 27 acetylation to methylation at the E-cadherin promoter, which induces the transcriptional inhibition of E cadherin. HOTAIR recruits polycomb repressive complex 2 (PRC2) to catalyze H3K27me3; however, whether HOTAIR is associated with the acetylation of histone H3 lysine 27, a marker of transcriptional activation, and the mechanisms through which HOTAIR triggers the metastasis of gastric cancer (GC) by epigenetic regulation remain largely unknown. In this study, HOTAIR knockdown significantly reversed EMT by increasing the expression of E-cadherin in GC cells. Additionally, the loss of PRC2 activity induced by HOTAIR knockdown resulted in a global decrease in H3K27 methylation and an increase in H3K27 acetylation. Furthermore, HOTAIR recruits PRC2 (which consists of H3K27 methyltransferase EZH2, SUZ12 and EED), which may inhibit the reaction between the acetyltransferase CBP and H3K27 acetylation. On the whole, the findings of this study suggested that the HOTAIR-mediated acetylation to methylation switch was associated with the transcriptional inhibition of E-cadherin. HOTAIR can promote the development of GC through the epigenetic regulation of E-cadherin, switching the state of the E-cadherin promoter from the transcriptionally active to the transcriptionally repressive state. PMID- 30431070 TI - beta-glucan, a dectin-1 ligand, promotes macrophage M1 polarization via NF kappaB/autophagy pathway. AB - Pro-inflammatory (M1) macrophages have key roles in atherogenesis. As beta-glucan has been demonstrated to exert pro-inflammatory effects, the present study examined whether beta-glucan exerts atherogenic effects via converting macrophages into M1 phenotype. The results from reverse transcription quantitative polymerase chain reaction, flow cytometry, western blotting and transmission electron microscope indicated that M1 macrophage markers inducible nitric oxide synthase and cluster of differentiation 80 were upregulated, dectin 1 (a receptor for beta-glucan) expression and nuclear factor (NF)-kappaB nuclear translocation were promoted, and autophagy level was inhibited following beta glucan treatment of macrophages. Additionally, dectin-1 small interfering RNA (siRNA), autophagy inducer rapamycin and NF-kappaB inhibitor SN50 reversed the effects of beta-glucan on autophagy level and macrophage M1 polarization, suggesting that dectin-1 and NF-kappaB are upstream of autophagy in beta-glucan induced macrophage M1 polarization. Notably, simultaneous treatment with dectin-1 siRNA and SN50 exhibited similar effects on beta-glucan-reduced autophagy compared with dectin-1 siRNA treatment alone. These findings demonstrate that dectin-1 may mediate beta-glucan-reduced autophagy through NF-kappaB in macrophages. Accordingly, results from hematoxylin and eosin staining, western blotting and immunofluorescence staining demonstrated that beta-glucan accelerated the progress of atherosclerosis in apolipoprotein E-deficient mice and modulated expression of dectin-1, beclin-1 and light chain 3II/I in aortas similarly to that observed in macrophages. These results indicate that dectin-1 activation by beta-glucan exerts atherogenic effects via converting macrophages into M1 phenotype in an NF-kappaB-autophagy-dependent pathway. PMID- 30431071 TI - Proteolysis is the most fundamental property of malignancy and its inhibition may be used therapeutically (Review). AB - The mortality rates of cancer patients decreased by ~1.5% per year between 2001 and 2015, although the decrease depends on patient sex, ethnic group and type of malignancy. Cancer remains a significant global health problem, requiring a search for novel treatments. The most common property of malignant tumors is their capacity to invade adjacent tissue and to metastasize, and this cancer aggressiveness is contingent on overexpression of proteolytic enzymes. The components of the plasminogen activation system (PAS) and the metalloproteinase family [mainly matrix metalloproteinases (MMPs)] are overexpressed in malignant tumors, driving the local invasion, metastasis and angiogenesis. This is the case for numerous types of cancer, such as breast, colon, prostate and oral carcinoma, among others. Present chemotherapeutics agents typically attack all dividing cells; however, for future therapeutic agents to be clinically successful, they need to be highly selective for a specific protein(s) and act on the cancerous tissues without adverse systemic effects. Inhibition of proteolysis in cancerous tissue has the ability to attenuate tumor invasion, angiogenesis and migration. For that purpose, inhibiting both PAS and MMPs may be another approach, since the two groups of enzymes are overexpressed in cancer. In the present review, the roles and new findings on PAS and MMP families in cancer formation, growth and possible treatments are discussed. PMID- 30431072 TI - Identification of key candidate genes and miRNA-mRNA target pairs in chronic lymphocytic leukemia by integrated bioinformatics analysis. AB - Chronic lymphocytic leukemia (CLL) is a malignant clonal proliferative disorder of B cells. Inhibition of cell apoptosis and cell cycle arrest are the main pathological causes of this disease, but its molecular mechanism requires further investigation. The purpose of the present study was to identify biomarkers for the early diagnosis and treatment of CLL, and to explore the molecular mechanisms of CLL progression. A total of 488 differentially expressed genes (DEGs) and 32 differentially expressed microRNAs (miRNAs; DEMs) for CLL were identified by analyzing the gene chips GSE22529, GSE39411 and GSE62137. Functional and pathway enrichment analyses of DEGs demonstrated that DEGs were mainly involved in transcriptional dysregulation and multiple signaling pathways, such as the nuclear factor-kappaB and mitogen-activated protein kinase signaling pathways. In addition, Cytoscape software was used to visualize the protein-protein interactions of these DEGs in order to identify hub genes, which could be used as biomarkers for the early diagnosis and treatment of CLL. Cytoscape software was also used to analyze the association between the predicted target mRNAs of DEMs and DEGs and increase knowledge about the miRNA-mRNA regulatory network associated with the progression of CLL. Taken together, the present study provided a bioinformatics basis for advancing our understanding of the pathogenesis of CLL by identifying differentially expressed hub genes, miRNA-mRNA target pairs and molecular pathways. In addition, hub genes may be used as novel biomarkers for the diagnosis of CLL and to guide the selection of CLL drug combinations. PMID- 30431073 TI - miR-494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene. AB - Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. Novel prognostic and predictive factors are required. The C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor 4 (CXCR4) axis is involved in tumour development and metastatic spread in many types of cancer and previous data have demonstrated a pivotal role of CXCR4 in SS cell migration and invasion. Bioinformatics and biological data indicated CXCR4 is a possible candidate target of miR-494.3p, known to be involved in tumour progression. In this study, we analysed the expression of miR-494.3p and its potential target, CXCR4, in a series of SS specimens. A significantly lower miR-494.3p expression was found in the tumour compared to normal tissue associated with higher levels of CXCR4 both at the gene and protein level. The role of CXCR4 as a potential target of miR 494.3p was assessed in two SS cell lines (SW982 and SYO-I). Transfection with miR 494.3p expression plasmid led to a marked decrease in CXCR4 gene and protein expression, concomitant with a transitory decrease in cell proliferation and migration. The SYO-I cells also responded with an increased apoptotic fraction. The data of this study also demonstrate that the downregulation of miR-494.3p in SS surgical specimens, concomitant with an increased expression of its potential target, CXCR4, was more evident in the metastatic subset. In vitro experiments confirmed that miR-494.3p functioned as a tumour suppressor through the involvement of CXCR4 and ongoing studies are directed to better clarify its role in SS therapeutic strategies. PMID- 30431074 TI - Overexpression of lncRNA EGFR-AS1 is associated with a poor prognosis and promotes chemotherapy resistance in non-small cell lung cancer. AB - Chemoresistance is one of the most important biological elements affecting the progression and prognosis of cancer. Long non-coding RNAs (lncRNAs) are important regulators and are aberrantly expressed in various types of cancer in humans, including non-small cell lung cancer (NSCLC). The present study aimed to investigate the effect of lncRNAs on NSCLC resistance to chemotherapy. The relative expression level of epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) was quantified by reverse transcription-quantitative polymerase chain reaction analysis in NSCLC tissues, paired adjacent normal tissues, patient plasma and NSCLC cell lines, and its association with prognosis was assessed by multivariate analysis. The biological functions of EGFR-AS1 in NSCLC cells were determined in vitro. It was found that EGFR-AS1 was abnormally upregulated in NSCLC tissues compared with adjacent normal lung tissues. Furthermore, patients with NSCLC with increased expression of EGFR-AS1 had a poor prognosis. EGFR-AS1 knockdown significantly inhibited NSCLC malignancy in vitro, including cell proliferation and chemoresistance. Furthermore, the expression levels of EGFR-AS1 were increased in plasma samples from patients with cisplatin-based chemotherapy resistance. Bioinformatics analysis and a luciferase reporter assay confirmed that EGFR-AS1 mediated cell proliferation and chemoresistance through directly binding to microRNA-223. Therefore, EGFR-AS1 overexpression-induced chemoresistance can contribute to poor prognosis in NSCLC. PMID- 30431075 TI - Serum PGLYRP-1 is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis. AB - Peptidoglycan recognition protein-1 (PGLYRP-1) is a part of the innate immune system. It is well-known that dysregulation of innate immune responses is present in patients with rheumatoid arthritis (RA). However, the role of Pglyrp1/PGLYPR-1 in RA is poorly understood. Reverse transcription-quantitative polymerase chain reaction was used to detect the level of Pglyrp1 in peripheral blood mononuclear cells. An ELISA was used to measure the level of PGLYPR-1 in the serum, and correlation analysis was performed to analyze the association between the level of PGLYPR-1 in the serum and clinical characteristics. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of PGLYPR-1 in serum. The expression of PGLYPR-1 in the serum of healthy controls compared with PGLYPR-1 in the serum from patients with RA was significantly increased compared with patients with systemic lupus erythematosus (SLE). The level of PGLYPR-1 in serum was correlated with rheumatoid factor and anti-cyclic citrullinated peptide. ROC curve analysis suggested that PGLYPR-1 in the serum may have significant value for RA diagnosis. In addition, the risk score based on PGLYPR-1 in the serum also significantly discriminated the patients with RA from the disease controls (SLE). The present study suggested that increased expression of PGLYPR-1 in the serum from patients with RA may serve as a potential biomarker for RA diagnosis. PMID- 30431076 TI - Luteolin sensitizes human liver cancer cells to TRAIL-induced apoptosis via autophagy and JNK-mediated death receptor 5 upregulation. AB - The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a dynamic cytokine that initiates the apoptosis of cancer cells, but exhibits little or no toxicity in normal cells. Luteolin is a flavonoid compound frequently used in the treatment of cancer. In the current study, we demonstrate that treatment with luteolin and TRAIL exerts a synergistic effect and the mechanisms on TRAIL resistant Huh7 cells. The results demonstrated that luteolin induced an autophagic flux in human liver cancer cells. The attenuation of the autophagic flux by applying the specific inhibitor of autophagy, chloroquine, significantly suppressed DR5 expression. Treatment with genetically modified autophagy-related 5 siRNA abrogated the luteolin-mediated sensitizing effect of TRAIL. Furthermore, pre-treatment with the c-Jun N-terminal kinase (JNK) inhibitor, SP600125, significantly attenuated the luteolin-induced upregulation of DR5 expression, thereby suggesting that JNK activation promotes DR5 expression. Our findings also revealed that Akt phosphorylation was required for TRAIL sensitization. On the whole, the findings of this study indicated that luteolin effectively enhanced TRAIL-initiated apoptosis, and that these effects were likely to be mediated by autophagy and JNK-mediated DR5 expression. PMID- 30431078 TI - SENP2 exerts an anti-tumor effect on chronic lymphocytic leukemia cells through the inhibition of the Notch and NF-kappaB signaling pathways. AB - Chronic lymphocytic leukemia (CLL) is one of the most often diagnosed hematological malignant tumors in the Western world and a type of inert B-cell lymphoma that commonly attacks the elderly. Small ubiquitin related modifier (SUMO)-specific protease 2 (SENP2) can act as a suppressor in various types of cancer by regulating the stability of beta-catenin to affect the Notch signaling pathway; however, it has a low expression level in CLL cells. In this study, we firstly used western blot analysis and RT-qPCR to detect the protein and mRNA expression levels of SENP2 in the peripheral blood of patients with CLL and healthy volunteers. Secondly, we overexpressed or knocked down the expression of SENP2 in CLL cells and then determined the cell invasive and chemotactic ability in a Transwell assay and chemotaxis assay. We examined the sensitivity of the cells to cytarabine and dexamethasone via a CCK-8 assay and determined the cell apoptotic condition and the expression of the Notch signaling pathway using flow cytometry and western blot analysis. The results demonstrated that the patients with CLL had relatively low expression levels of SENP2. The overexpression of SENP2 in the CLL cells decreased their invasive and proliferative ability, as well as their chemotactic response and enhanced their sensitivity to cytarabine and dexamethasone, while it promoted cell apoptosis. The silencing of SENP2 in the CLL cells generally produced the opposite results. We thus hypothesized that the overexpression of SENP2 downregulated beta-catenin expression, thus inhibiting the Notch signaling pathway in CLL cells. Moreover, the nuclear factor (NF)-kappaB signaling pathway was also regulated by the overexpression of SENP2. On the whole, the findings of this study indicate tha SENP2 can act as a tumor suppressor in CLL cells, and may thus prove to be a novel target for CLL treatment in clinical practice. PMID- 30431077 TI - Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma. AB - Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance. PMID- 30431079 TI - Biopanning of mouse bone marrow mesenchymal stem cell affinity for cyclic peptides. AB - Osteonecrosis of the femoral head (ONFH) is a refractory disease present worldwide. In the development of therapies for this disease, mesenchymal stem cells (MSC) are a promising candidate cell source in tissue engineering (TE) and regenerative medicine. MSCs harvested from bone marrow (BM) are the gold standard. A significant barrier for BMMSC-based therapies is the inability and decreased number of BMMSCs in the tissues of interest. The ability to recruit BMMSCs efficiently to defective or injured sites in tissues or organs, for example the necrotic area of the femoral head in vivo, has been a major concern. In the present study, a peptide sequence (CDNVAQSVC), termed D7, was identified through phage display technology using C57BL/6 mouse BMMSCs. Subsequent analysis suggested that the identified loop-constrained heptapeptide exhibited a high specific affinity for mouse BMMSCs. Due to this specific affinity for BMMSCs, the present study provides a selective method to improve MSC-based TE strategies for the treatment of ONFH. PMID- 30431080 TI - Long-term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse. AB - Salicylate is widely used to produce animal models of tinnitus in mice and/or rats. The side effects on auditory function, including hearing loss and tinnitus, are considered the results of the auditory nerve dysfunction. A recent study indicated that chronic treatment with salicylate for several weeks reduces compressed action potential amplitude, which is contradictory to the studies reporting excessive activation of N-methyl-D-aspartate receptors (NMDAR) in tinnitus-induced animals. The specific aims of the experiment were to detect the effect of salicylate on the inner hair cells (IHCs), ribbon synapse, as well as the association between the hearing threshold and the number of mismatched ribbon synapses. In the present study, mice were injected intraperitoneally with a low dose of salicylate (200 mg/kg) for 14 days. The auditory brainstem response and otoacoustic emission were measured to assess auditory function of the mice. The postsynaptic regions of IHC were identified with two types of immunostaining targets: Postsynaptic density protein 95 and Glu2/3. The number of spheres was counted and the synapses were reconstructed in 3-dimensional images. Increases in distortion product otoacoustic emissions amplitudes of the salicylate group were detected, however, an elevation in the hearing threshold was also observed. A mismatch between pre-and post-ribbon synapses was observed. In addition, the cochlear components, including the numbers of outer hair cells and IHCs, were unlikely to be affected by salicylate. IHC ribbon synapses were more susceptible to salicylate stimuli. Furthermore, mismatch of pre- and post-ribbon synapses may indicate a competitive inhibition between NMDAR and alpha-amino-3-hydroxy-5 methyl-4-isoxa-zole-propionate receptors and dysfunction of ribbon synapses. PMID- 30431081 TI - DOK7V1 influences the malignant phenotype of lung cancer cells through PI3K/AKT/mTOR and FAK/paxillin signaling pathways. AB - Downstream of tyrosine kinase 7 transcript variant 1 (DOK7V1) is a docking protein mediating signal transduction between receptors and intracellular downstream molecules. Our previous study indicated that DOK7V1 was decreased in lung cancer and its lower expression was associated with a decreased survival rate. The 5-year overall survival rate for patients with lung cancer was 20.2 and 18.6% for high and low DOK7 expression, respectively; the 5-year disease-free survival rate for patients with lung cancer was 14.3 and 16.9% for high and low DOK7 expression, respectively. DOK7V1 inhibited proliferation and migration, but enhanced adhesion, of lung cancer cells. In the present study, the effect of DOK7V1 and its domains [pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domain] on the malignant phenotype and associated signaling pathway in lung cancer cells was investigated. The results indicated that truncation of DOK7V1 domains (DOK7V1Delta-PH and DOK7V1Delta-PTB) inhibited the proliferation and migration of lung cancer cells which exhibited the same trend as DOK7V1, whereas DOK7V1Delta-PH and DOK7V1Delta-PTB exhibited different functions from those of DOK7V1 in cell matrix adhesion. Consistently, DOK7V1 overexpression in lung cancer cells suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathways, but activated the focal adhesion kinase (FAK)/paxillin signaling pathway. Taken together, these results indicate that DOK7V1 may inhibit proliferation and migration via negatively regulating the PI3K/AKT/mTOR signaling pathway, and increase adhesion by upregulating the FAK/paxillin signaling pathway in lung cancer cells. PMID- 30431082 TI - ERp57-small interfering RNA silencing can enhance the sensitivity of drug resistant human ovarian cancer cells to paclitaxel. AB - ERp57 has been identified to be associated with the chemoresistance of human ovarian cancer. However, its biological roles in the chemoresistance phenotype remain unclear. In the present study, the association of ERp57 with paclitaxel resistant cellular behavior was investigated and the sensitivity enhancement of chemoresistant human ovarian cancer cells to paclitaxel was examined using ERp57 small interfering (si)RNA silencing. Cell viability, cell proliferation, cell apoptosis and cell migration were detected using an MTT assay, clonogenic assay, flow cytometry analysis and transwell assay. Furthermore, mRNA expression levels of ERp57 and protein expression levels of ERp57, STAT3, phosphorylated STAT3, PCNA, nucelolin, TUBB3, P-gp, vimentin, Bcl-2, Bax, Bcl-xl, p53, MMP1, MMP2 and MMP9 of paclitaxel-sensitive human SKOV3 ovarian cancer cells were compared with paclitaxel-resistant counterpart SKOV3/tax using the real-time PCR and western blot analysis. ERp57 was highly expressed in the paclitaxel-resistant SKOV3/tax cells, and experimental results concluded that the paclitaxel-resistance phenotype was due primarily to the activation of the STAT3 signaling pathway. ERp57 overexpression by lentiviral particle infection decreased the sensitivity of SKOV3 cells to paclitaxel. Furthermore, ERp57-siRNA silencing restored paclitaxel sensitivity of SKOV3/tax cells. Notably, the IC50 value of ERp57-siRNA silenced SKOV3/tax cells was reduced to the original level and colony survival was significantly decreased in comparison with that of SKOV3/tax cells. Additionally, co-treatment of ERp57-siRNA silencing and paclitaxel could inhibit the STAT3 signaling pathway and downregulate the expression levels of downstream proteins. Notably, ERp57-siRNA and 100 nM paclitaxel co-treatment downregulated Bcl-2, Bcl-xl, MMP2, MMP9, TUBB3 and P-gp expression levels and upregulated the expression of Bax protein. Furthermore, co-treatment promoted change of the isoform of p53 to p53/p47. Bioinformatics analyses supported the experimental observations that ERp57 was associated with drug resistance in ovarian cancer. The present study implies that ERp57 is a potential therapeutic target for the treatment of paclitaxel-resistant human ovarian cancer. PMID- 30431084 TI - Downregulation of NLRP2 inhibits HUVEC viability by inhibiting the MAPK signaling pathway. AB - Nucleotide-binding oligomerization domain (NOD)-like receptor proteins (NLRPs) are a subfamily of NOD-like receptors (NLRs) that mainly participate in innate immunity. Among the 14 NLRPs, studies on NLRP2 are few and mostly focus on its functions in reproduction and embryonic development. To the best of the authors' knowledge, there has been no research on the function of NLRP2 in human umbilical vein endothelial cells (HUVECs). The present study knockdown the expression of NLRP2 by transfecting a short interfering (si)RNA (siNLRP2) into HUVECs and investigating its effects on HUVECs. It was identified using a Cell Counting kit 8 assay that knockdown of NLRP2 can inhibit cell proliferation in HUVECs. The results of wound healing and Transwell assays indicated that migration and invasion were also suppressed by siNLRP2 transfection in HUVECs. Flow cytometry demonstrated that siNLRP2 induced cell cycle arrest and apoptosis in HUVECs. Western blot analysis revealed that the expression levels of cell cycle and apoptosis-associated proteins were markedly changed. In addition, knockdown of NLRP2 inhibited the mitogen-activated protein kinase (MAPK) signaling pathway by elevating extracellular signal-regulated kinase phosphorylation levels and reducing proto-oncogene serine/threonine-protein kinase expression. Taken together, it was concluded that NLRP2 served an important role in maintaining cell viability, proliferation and motility in HUVECs, mainly by promoting the MAPK signaling pathway. PMID- 30431083 TI - EGFR mutation decreases FDG uptake in non-small cell lung cancer via the NOX4/ROS/GLUT1 axis. AB - [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) is a functional imaging modality based on glucose metabolism. The association between the maximum standardized uptake value (SUVmax) from 18F-FDG PET-CT scanning and epidermal growth factor receptor (EGFR) mutation status has, to the best of our knowledge, not previously been fully elucidated, and the potential mechanisms by which EGFR mutations alter FDG uptake are largely unknown. A total of 157 patients who were pathologically diagnosed with non-small cell lung cancer (NSCLC) who underwent EGFR mutation testing and PET-CT pretreatment between June 2015 and October 2017 were retrospectively analyzed. chi2 and univariate analyses were performed to identify the contributors to EGFR mutation. The receiver operating characteristic (ROC) curve was analyzed, and the area under the curve (AUC) was calculated. Glucose transporter 1 (GLUT1) and NADPH oxidase 4 (NOX4) expression, and reactive oxygen species (ROS) activity were detected in the A549 (wild-type), PC-9 (EGFR mutation-positive, EGFR exon 19del) and NCI-H1975 (EGFR mutation-positive, combined with L858R and T790M substitution) cell lines. A total of 109 patients who met the criteria were enrolled, and 63 of those tested as EGFR mutation-positive. The SUVmax values were significantly lower in patients with EGFR mutations (mean, 6.52+/-0.38) compared with in patients with wild-type EGFR (mean, 9.37+/-0.31; P<0.001). Using univariate analysis, EGFR mutation status was significantly associated with sex, smoking status, tumor histology and SUVmax of the primary tumor. In the multivariate analysis, smoking status (never-smoking), histopathology (adenocarcinoma) and SUVmax (<=9.91) were the statistically significant predictors of EGFR mutations. ROC curve analysis identified that the SUVmax cut off point was 9.92, for which the AUC was 0.75 (95% confidence interval, 0.68 0.83). Reverse transcription-polymerase chain reaction indicated that the GLUT1 mRNA decreased in the PC-9 and NCI-H1975 cell lines compared with the A549 cell line (0.82+/-0.07 and 0.72+/-0.04 vs. 0.98+/-0.04, respectively; P<0.05) and decreased ROS activity was observed in the PC-9 cell line. Furthermore, the expression of NOX4 mRNA decreased by 20% in PC-9 (P<0.01) and by 14% (P<0.05) in NCI-H1975 cells. In addition, NOX4 protein expression decreased by 13% in PC-9 and by 16% in NCI-H1975 cells (both P<0.05) compared with the A549 cell line. The SUVmax could be considered to effectively predict EGFR mutation status of patients with NSCLC, and the EGFR mutation status may alter FDG uptake partially via the NOX4/ROS/GLUT1 axis. PMID- 30431085 TI - Progranulin protects the mouse retina under hypoxic conditions via inhibition of the Toll-like receptor-4-NADPH oxidase 4 signaling pathway. AB - To investigate the function of progranulin on the retina under hypoxic conditions, 8-week-old C57BL/6 mice were divided into normal condition and hypoxic condition groups (n=24 mice/group). The hypoxia model was established through intravitreal injection of 9 mM cobalt chloride. Subsequently, 10 mM progranulin and an equal amount of PBS were injected into the right and left eyes, respectively. Photoreceptor function was examined using electroretinogram (ERG) analysis. Morphological alterations were examined using immunofluorescence co-localization, retinal vascular inflammation was examined using the leukostasis assay, and signaling pathways were screened using immunoblotting. The results revealed that ERG amplitude was significantly lower under hypoxic conditions compared with under normal conditions. Furthermore, the amplitude was significantly reduced in the PBS-injected eyes compared with in the progranulin injected eyes. Morphological examination demonstrated that the number of rods in the PBS-injected eyes was decreased compared with in the progranulin-injected eyes under hypoxic conditions. In addition, the arrangement of the cones was sparse and the morphology of the outer segments was short and small. Although the number of adherent leukocytes in the progranulin-injected eyes was higher in the hypoxic mice compared with in those under normal conditions, the number was only 52.31% of the number detected in the PBS-injected eyes. Analysis of the signaling pathways demonstrated that the protective effects of progranulin on retinas under hypoxic conditions were regulated by the Toll-like receptor 4 (TLR4)-NADPH oxidase 4 (NOX4) pathway, instead of the caspase and Wnt/beta-catenin pathways. In conclusion, progranulin exerted protective effects on the function and morphology of photoreceptors in a hypoxic environment, and could reduce retinal vascular inflammation, through inhibition of the TLR4-NOX4 pathway. PMID- 30431086 TI - Activation of the Notch-Nox4-reactive oxygen species signaling pathway induces cell death in high glucose-treated human retinal endothelial cells. AB - Diabetic retinopathy (DR) occurs in almost all patients with diabetes and remains as one of the major causes of vision loss worldwide. Nevertheless, the molecular mechanisms underlying the pathogenesis of DR remain elusive. The present study aimed to investigate the role and association of Notch signaling and NADPH oxidase 4 (Nox4)-mediated oxidative stress in high glucose (HG)-treated retinal cells. Human retinal endothelial cells were cultured for various durations in RPMI-1640 medium containing 30 mM glucose (HG) or 30 mM mannitol (MN) as an osmotic control; apoptotic cell death and reactive oxygen species (ROS) levels were assessed, respectively. Alterations in the expression profiles of Nox and Notch proteins were evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Knockdown of Nox4 and recombination signal-binding protein J (RBPj) was generated by transfection with specific small interfering (siRNA). Persistent activation of Notch signaling was induced via the overexpression of Notch intracellular domain (NICD). In the present study, time dependent increases in ROS production and cell death were detected in HG-treated cells. Depletion of ROS by diphenyleneiodonium decreased HG-induced cell death, and suppressed increases in caspase 3 activity and B-cell lymphoma 2-associated X protein levels. In HG-treated cells, Nox4 expression was upregulated at the mRNA and protein levels, and inhibition of Nox4 by GKT137831 or knockdown of expression by siRNA Nox4 significantly reduced ROS levels and cell death. In the presence of HG, Notch1 expression levels were elevated, and increased NICD abundance was detected in whole cell lysates and nuclear fractions. Additionally, HG-induced cell death was decreased by treatment with gamma-secretase inhibitor (GSI), but increased via the overexpression of NICD. The application of GSI or knockdown of RBPj by siRNA RBPj prevented increases in Nox4 expression within HG treated cells. The findings of the present study demonstrated that Nox4-mediated ROS serves an important role in HG-induced retinal cell damage, in which the activation of Notch signaling may be responsible for Nox4 upregulation. Therefore, inhibition of Notch signaling or Nox4 expression may be considered as potential therapeutic targets in patients with DR. PMID- 30431087 TI - c-Jun N-terminal kinase inhibition attenuates early brain injury induced neuronal apoptosis via decreasing p53 phosphorylation and mitochondrial apoptotic pathway activation in subarachnoid hemorrhage rats. AB - Early brain injury (EBI)-induced neuronal apoptosis is primarily responsible for the subsequent complications of aneurysmal subarachnoid hemorrhage (aSAH), which may increase the risk of mortality in patients with aSAH. c-Jun N-terminal kinase (JNK) has been demonstrated to be a promoter of EBI-induced cell apoptosis, although the mechanism has yet to be fully elucidated. The present study aimed to explore whether the role of JNK1 is associated with tumor protein p53 (p53), which is one of the most important factor that triggers cell apoptosis. JNK1 expression was downregulated via in vivo small interfering RNA transfection in an aSAH rat model in order to assess differences in the behavior, survival times, morphology and genetics of the experimental animals. The results revealed that JNK1 inhibition improved the neurological scores and survival times of SAH rats by interrupting cascaded neuronal apoptosis. The interruption of EBI-induced neuronal apoptosis may originate from a decrease in the level of p53 phosphorylation and deactivation of the downstream mitochondrial apoptotic pathway. Taken together, these results suggest that JNK1 may be a promising target for improving the prognosis of patients with aSAH. PMID- 30431088 TI - PARP inhibitor re-sensitizes Adriamycin resistant leukemia cells through DNA damage and apoptosis. AB - Resistance to Adriamycin (ADR) is an increasing problem in the treatment of leukemia and the development of novel therapeutic strategies is becoming increasingly important. Olaparib is a poly (adenosine diphosphate-ribose) polymerase (PARP) 1 inhibitor, which has promising antitumor activity in patients with metastatic breast cancer and germline BRCA mutations. Previously published studies have indicated that Olaparib is able to overcome drug resistance in cancer; however, its underlying mechanism of action is yet to be elucidated. The aim of the present study was to explore the mechanism underlying re sensitization. Annexin V-propidium iodide staining indicated that the percentage of apoptotic ADR resistant cells was markedly increased and the cell cycle was blocked at the G2/M-phase following treatment with ADR combined with Olaparib, when compared with the control group. The alkaline comet assay demonstrated that ADR combined with Olaparib significantly upregulated the induction of the DNA damage response in ADR-resistant cells. Western blot analysis revealed that the protein expression of gamma-H2A histone family member X, cleaved PARP, caspase 3 and cleaved caspase 3 was markedly enhanced, while the cell cycle-associated protein cyclin B1 was downregulated in K562/ADR cells following treatment with a combination of ADR and Olaparib. Similar synergistic cytotoxicity was observed in blood mononuclear cells, which were isolated from patients with chemotherapy resistant leukemia. As Olaparib is available for clinical use, the results of the present study provide a rationale for the development of Olaparib combinational therapies for cases of ADR resistant leukemia. PMID- 30431090 TI - MicroRNA-409 may function as a tumor suppressor in endometrial carcinoma cells by targeting Smad2. AB - MicroRNAs (miRNAs) are frequently dysregulated in human cancer and can act as either potent oncogenes or tumor suppressor genes. The aberrant expression of miRNA-409 (miR-409) has been found in certain types of cancer, however, its expression and potential biological role in endometrial cancer remain to be fully elucidated. In the present study, a total of 16 pairs of tissue samples from 16 patients with endometrial cancer were used in the present study, each of which consisted of human endometrial cancer tissue and matched adjacent normal tissue from the same patient. The expression of miR-409 of the tissue were detected and its associations with Ishikawa and HEC-1B human endometrial cancer cell lines were studied. The results of the present study demonstrated that miR-409 was downregulated in human endometrial cancer, and it suppressed the growth of Ishikawa and HEC-1B human endometrial cancer cell lines. Bioinformatics analysis indicated that small mothers against decapentaplegic 2 (Smad2) was a putative target of miR-409. In a luciferase reporter system, it was confirmed that Smad2 was a direct target gene of miR-409. It was also demonstrated that Smad2 was upregulated in human endometrial cancer tissues, and this was inversely correlated with the expression of miR-409. These findings indicated that miR-409 targeted the Smad2 transcript and suppressed endometrial cancer cell growth, suggesting that miR-409 has a tumor suppressive role in the pathogenesis of human endometrial cancer. PMID- 30431089 TI - VEGI174 protein and its functional domain peptides exert antitumour effects on renal cell carcinoma. AB - Vascular endothelial growth inhibitor (VEGI) has been identified as an anti angiogenic cytokine. However, the effects of VEGI174 protein, and its functional domain peptides V7 and V8, on renal cell carcinoma (RCC) remain unknown. In the present study, the protein and peptides were biosynthesised as experimental agents. The A498 and 786-O RCC cell lines, and an established mouse xenograft model, were separately treated with VEGI174, V7 or V8. Cellular functions, including proliferation, migration and invasion, were subsequently detected. Cell migration and invasion were monitored using the xCELLigence system. Furthermore, tumour growth and mouse behaviours, including mobility, appetite and body weight, were assessed. The results demonstrated that VEGI174, V7 and V8 inhibited the proliferation, migration and invasion of A498 and 786-O cell lines when administered at concentrations of 1 and 100 pM, 10 nM and 1 uM. The inhibitory effects exhibited dose- and time-dependent antitumour activity. Furthermore, VEGI174, V7 and V8 inhibited tumour growth in A498 and 786-O xenograft mice. In the A498 xenografts, the tumour growth inhibition (TGI) rates in the VEGI174-, V7 and V8-treated groups were 71, 20 and 31%, respectively. In the 786-O xenografts, the TGI rates in the VEGI174-, V7- and V8-treated groups were 34, 26 and 31%, respectively. There was no significant loss in body weight and no cases of mortality were observed for all treated mice. In conclusion, VEGI174, V7 and V8 exhibited potential antitumour effects and were well tolerated in vivo. V7 and V8, as functional domain peptides of the VEGI174 protein, may be studied for the future treatment of RCC. PMID- 30431091 TI - Meta-analysis of current chemotherapy regimens in advanced pancreatic cancer to prolong survival and reduce treatment-associated toxicities. AB - Unresectable advanced pancreatic cancer (APC) is a highly lethal malignancy. Although numerous chemotherapeutic regimens are available, evidence regarding the survival extension, the life quality improvement, the associated risks and occurrence rates of adverse effects, is required. The effects of 19 chemotherapy regimens on survival and treatment-associated toxicities in the context of APC treatment were comparatively assessed. A total of 23 randomized controlled trials were included in this network meta-analysis. For overall survival, five regimens, Gemcitabine (Gem)+radiotherapy (Radio), Gem+cisplatin (Cis), Gem+erlotinib (Erl)+bevacizumab (Bev), Gem+capecitabine (Cap)+Erl, and Gem+exatecan, were the most effective treatments, according to their respective high surface under the cumulative ranking (SUCRA) probabilities. Regarding the progression-free survival, five regimens, including Gem+Radio, Gem+Erl+Bev, Gem+Cis, Gem+Cap+Erl and Gem+pemetrexed, were the most effective treatments based on their SUCRA probabilities. Each regimen exhibited advantages and disadvantages, and 14 common treatment-associated toxicities were present in different proportions. The three principal toxic effects included haematological, gastrointestinal and constitutional symptoms. To improve survival, chemotherapy regimens with high SUCRA probabilities require prioritizing. Although treatment-associated toxicities are unavoidable, the regimens presented toxicities in distinct proportions. Therefore, clinicians should assess the disease status of the patients, and balance the benefits and risks of the selected treatment. PMID- 30431092 TI - Screening and clinical significance of tumor markers in head and neck squamous cell carcinoma through bioinformatics analysis. AB - In order to identify potential diagnostic and prognostic biomarkers, and treatment targets for head and neck squamous cell carcinoma (HNSCC), the present study obtained the gene expression profiles in HNSCC through public data mining, and core genes were identified using a series of bioinformatics analysis methods and databases. A total of nine hub genes (SPP1, ITGA6, TMPRSS11D, MMP1, LAMC2, FAT1, ACTA1, SERPINE1 and CEACAM1) were identified to be significantly correlated with HNSCC. Furthermore, overall survival analysis demonstrated that the expression values of hub genes were associated with overall survival in HNSCC. Furthermore, certain of the identified genes, including, TMPRSS11D, ACTA1 and CEACAM1, have not been thoroughly investigated in HNSCC previously. Taken together, the nine hub genes obtained by screening in the present study may serve as potential tumor markers and important prognostic indicators for HNSCC. PMID- 30431093 TI - Osteocalcin-GPRC6A: An update of its clinical and biological multi-organic interactions (Review). AB - Osteocalcin is no longer regarded as a molecule exclusive to bone remodeling and osteogenesis, but as a hormone with manifold functions. The discovery of the interaction of osteocalcin with the G protein-coupled receptor family C group 6 member A (GPRC6A) receptor has accompanied the characterization of several roles that this peptide serves in body regulation and homeostasis. These roles include the modulation of memory in the brain, fertility in the testis, fat accumulation in the liver, incretins release in the intestine and adaptation to exercise in muscle, in addition to the well-known effects on beta-cell proliferation, insulin release and adiponectin secretion. The aim of the present review was to provide a practical update of the multi-organ effects that osteocalcin exerts through its interaction with GPRC6A and the clinical implications of this. PMID- 30431094 TI - Involvement of endothelial nitric oxide synthase pathway in IGF-1 protects endothelial progenitor cells against injury from oxidized LDLs. AB - A high level of oxidized low-density lipoproteins (oxLDLs) is an independent risk factor for cardiovascular disease. The aim of the present study was to investigate whether insulin-like growth factor-1 (IGF-1) protected endothelial progenitor cells (EPCs) from injury caused by ox-LDLs, and whether the endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) pathway was involved in this process. EPCs were isolated from human peripheral blood and characterized. In order to evaluate the effect of IGF-1 on EPCs, cells were incubated with ox-LDLs (100 mg/ml) for 24 h to induce a model of EPC dysfunction in vitro, which demonstrated a decrease in the number of EPCs, concomitant with increased apoptosis and decreased proliferation rates. IGF-1 dose-dependently increased the number of EPCs. Concurrently, IGF-1 decreased the levels of apoptosis of EPCs and improved EPCs proliferation following ox-LDLs challenge. In addition, IGF-1 significantly increased NO levels in ox-LDLs-treated EPCs, accompanied by an upregulation in eNOS expression. The protective effects of IGF 1 on EPCs and NO production were abolished by L-NAME, a specific eNOS inhibitor. These results suggested that IGF-1 protects EPCs from dysfunction induced by oxLDLs through a mechanism involving the eNOS/NO pathway. PMID- 30431096 TI - C1QTNF6 is overexpressed in gastric carcinoma and contributes to the proliferation and migration of gastric carcinoma cells. AB - In the present study, proteins differentially expressed between gastric cancer tissue and para-tumoral normal gastric tissues were screened, and the function of the highly expressed protein C1QTNF6 in gastric carcinoma was investigated. The differential expression of mRNAs extracted from the tumor and adjacent tissues was analyzed using GeneChip assay. An AGS si-C1QTNF6 cell line was constructed using shRNA-C1QTNF6 lentivirus. The cell invasion and migration ability of C1QTNF6-knockdown cells were determined by Transwell chamber migration and wound healing assays, respectively. The effects of C1QTNF6 on AGS cell cycle distribution and apoptosis were detected using a FACScan flow cytometer. The results demonstrated that the expression of 109 genes was increased and the expression of 129 was decreased in tumor tissues. Among these genes, the C1QTNF6 gene was highly expressed in tumor tissues and the AGS7901 cell line. C1QTNF6 knockdown decreased the cell growth, and the proliferative and migration ability, as well as increasing the apoptosis of gastric carcinoma cells. In addition, the number of AGS cells in the G2/M phase was significantly increased after 5 days of C1QTNF6-shRNA lentivirus infection. The results of the present study indicated that C1QTNF6 serves an important role in the development of gastric carcinoma. C1QTNF6 is involved in promoting the proliferation and migration, and in reducing the apoptosis of gastric carcinoma cells. These results provided a potential therapeutic target for the treatment of gastric carcinoma. PMID- 30431095 TI - Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults. AB - Fatty acids (FAs) play critical roles in health and disease. The detection of FA imbalances through metabolomics can provide an overview of an individual's health status, particularly as regards chronic inflammatory disorders. In this study, we aimed to establish sensitive reference value ranges for targeted plasma FAs in a well-defined population of healthy adults. Plasma samples were collected from 159 participants admitted as outpatients. A total of 24 FAs were analyzed using gas chromatography-mass spectrometry, and physiological values and 95% reference intervals were calculated using an approximate method of analysis. The differences among the age groups for the relative levels of stearic acid (P=0.005), the omega-6/omega-3 ratio (P=0.027), the arachidonic acid/eicosapentaenoic acid ratio (P<0.001) and the linoleic acid-produced dihomo gamma-linolenic acid (P=0.046) were statistically significant. The majority of relative FA levels were higher in males than in females. The levels of myristic acid (P=0.0170) and docosahexaenoic acid (P=0.033) were significantly different between the sexes. The reference values for the FAs examined in this study represent a baseline for further studies examining the reproducibility of this methodology and sensitivities for nutrient deficiency detection and investigating the biochemical background of pathological conditions. The application of these values to clinical practice will allow for the discrimination between health and disease and contribute to early prevention and treatment. PMID- 30431097 TI - CagA increases DNA methylation and decreases PTEN expression in human gastric cancer. AB - Gastric cancer is one of the leading causes of cancer-associated mortality worldwide. Cytotoxin-associated gene A (CagA) has been reported to be associated with gastric diseases. Phosphatase and tensin homolog (PTEN) and tet methylcytosine dioxygenase 1 (Tet1) are important tumor-suppressor genes. The present study aimed to investigate the underlying functions of CagA in human gastric cancer, and to explore the associations between CagA, PTEN and Tet1 in gastric cancer. For that purpose, CagA overexpression and Tet1 interference recombinant lentiviral plasmids were constructed. Quantitative polymerase chain reaction (qPCR) was utilized to screen gene expression in HGC-27 human gastric cancer cells overexpressing CagA. qPCR and western blotting were used to detect gene and protein expression, respectively. In addition, the methylation status of PTEN was detected by methylation-specific PCR. The expression levels of PTEN, Tet1, apolipoprotein B mRNA editing enzyme catalytic subunit (APOBEC)3A, APOBEC3C and APOBEC3F were significantly decreased in the CagA overexpression group compared with in the negative control group in HGC-27 cells. Compared with in the negative control group, the mRNA and protein expression levels of PTEN were markedly decreased in cells with Tet1 interference. The decreased expression of PTEN was associated with increased methylation levels in the cells. In addition, the protein expression levels of PTEN were significantly decreased in HGC-27 cells when CagA was overexpressed. The expression levels of PTEN and Tet1 were also markedly decreased in CagA+ gastric cancer tissues compared with in non cancerous tissues. The decreased expression of PTEN in CagA+ gastric cancer tissues was associated with increased methylation levels. In conclusion, overexpression of CagA significantly decreased the expression of PTEN, Tet1, APOBEC3A, APOBEC3C and APOBEC3F in human gastric cancer. In addition, CagA increased DNA methylation and decreased PTEN expression, which was reversed by Tet1 overexpression. The present study may facilitate future therapeutic approaches targeting human gastric cancer. PMID- 30431098 TI - PEDF protects human retinal pigment epithelial cells against oxidative stress via upregulation of UCP2 expression. AB - To investigate the protective function of pigment epithelium-derived factor (PEDF) against oxidative stress (OS) in ARPE-19 cells, ARPE-19 cells were divided into different OS groups and treated with various concentrations of H2O2 (0, 75, 150 and 200 umol/l) for 24 h. To establish the protective group, 200 ng/ml of PEDF was administered to ARPE-19 cells. Cell Counting Kit-8 assays and cell growth curve experiments were performed to determine levels of cell viability; lactate dehydrogenase and propidium iodide (PI) staining assays were also performed. The expression levels of genes associated with apoptosis as well as uncoupling protein 2 (UCP2) were detected by reverse transcription-quantitative, or semi-quantitative polymerase chain reaction. Furthermore, an OS injury animal model was established in both C57BL/6 and BALB/c mice via injection of 5 ug of PEDF in the vitreous cavity and subsequent injection of 150 uM H2O2 following a 24 h time interval. Hematoxylin and eosin (H&E) staining, as well as UCP2 immunofluorescent labeling were also performed. One-way analysis of variance was used to determine statistically significant differences, followed by multiple comparison analysis using the Newman Keuls method. The results of cell viability assays demonstrated that the numbers of apoptotic cells were increased following treatment with H2O2 in a dose-dependent manner; however, this effect was reversed following treatment with PEDF. The expression levels of caspase 3 and B cell lymphoma (Bcl2) associated X genes associated with apoptosis were inhibited, whereas levels of the anti-apoptotic gene Bcl2 were enhanced following treatment with PEDF in different passages of ARPE-19 cells. Significant differences were demonstrated in the levels of UCP2 gene expression between the PEDF+ H2O2 treated group and cells treated with H2O2 alone. Labeling of the UCP2 detector in the confocal images demonstrated decreased UCP2 protein staining in the retinal pigment epithelium (RPE) cells and RPE layers following H2O2 injury; however, this effect was inhibited following treatment with PEDF. H&E staining was performed to investigate the thickness of the RPE layers, and the results revealed that thicknesses were significantly increased in sections treated with PEDF during OS, due to increased numbers of RPE cells. Furthermore, PEDF was demonstrated to increase UCP2 gene expression in ARPE-19 cells and animal RPE layers under OS, which suggested that PEDF may protect RPE cells and tissues during oxidative injury. PMID- 30431099 TI - FOXC1 silencing inhibits the epithelial-to-mesenchymal transition of glioma cells: Involvement of beta-catenin signaling. AB - Glioma is a type of malignant brain tumor. Forkhead box C1 (FOXC1) is a conserved transcription factor that is involved in tumorigenesis; however, the function of FOXC1 in glioma remains unclear. The present study aimed to investigate the effects of FOXC1 silencing on the epithelial-to-mesenchymal transition (EMT) of glioma cells. FOXC1-specific small interfering RNAs were employed to downregulate the expression levels of FOXC1 in glioma cells. The proliferation, migration and invasion of glioma cells were assessed by MTT assay, wound healing assay and Transwell assay. Western blot analysis was performed to reveal the effects of FOXC1 on EMT-associated proteins and beta-catenin signaling. The results revealed that, following FOXC1 silencing, the proliferation, migration and invasion of glioma cells were decreased. The expression levels of EMT-associated proteins were also affected. Further examination demonstrated that beta-catenin signaling was involved in the effects of FOXC1 on glioma cells. Previous results suggested that overexpression of beta-catenin reversed the effects of FOXC1 silencing on glioma cells. The present study demonstrated that FOXC1 may regulate the EMT of glioma cells, potentially via beta-catenin signaling. Therefore, FOXC1 may be a potential therapeutic target for the treatment of glioma. PMID- 30431100 TI - Genistein attenuates renal fibrosis in streptozotocin-induced diabetic rats. AB - The present study aimed to investigate the antifibrogenic effects of genistein (GEN) on the kidney in streptozotocin (STZ)-induced diabetic rats and to determine the associated mechanisms. Rats were randomized into four groups: Normal control (N), STZ (S), L (STZ + low-dose GEN) and H (STZ + high-dose GEN). After 8 weeks, the fasting blood glucose (FBG) level, the ratio of kidney weight to body weight (renal index), 24-h urine protein, blood urea nitrogen (BUN), serum creatinine (SCr), renal total antioxidant capacity (T-AOC), superoxide dismutase (SOD), lipid peroxidation (LPO), malondialdehyde (MDA) and hydroxyproline (Hyp) contents were measured. The histomorphology and ultrastructure of the kidney were also assessed. In addition, mRNA expression levels of transforming growth factor-beta1 (TGF-beta1) and protein expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), TGF-beta1, mothers against decapentaplegic homolog 3 (Smad3), phosphorylated (p)-Smad3 and collagen IV were estimated. Compared with group N, the levels of FBG, renal index, 24-h urine protein, BUN, SCr, LPO, MDA and Hyp were increased, whereas the levels of T-AOC and SOD were decreased in group S. The structure of renal tissue was damaged, and the expression of Nrf2, HO-1 and NQO1 were reduced, whereas the expression of TGF beta1, Smad3, p-Smad3 and collagen IV were increased in group S. Compared with group S, the aforementioned indices were improved in groups L and H. In conclusion, GEN exhibited reno-protective effects in diabetic rats and its mechanisms may be associated with the inhibition of oxidative stress by activating the Nrf2-HO-1/NQO1 pathway, and the alleviation of renal fibrosis by suppressing the TGF-beta1/Smad3 pathway. PMID- 30431101 TI - L-carnitine ameliorates peripheral neuropathy in diabetic mice with a corresponding increase in insulin-like growth factor-1 level. AB - Diabetic peripheral neuropathy (DPN) is one of the common complications in diabetes, affecting more than half of patients with diabetes. L-carnitine (LC) was recently demonstrated to serve a positive role in ameliorating DPN. Therefore, the aim of the present study was to investigate the underlying mechanisms of LC in ameliorating DPN. Male Kunming mice were randomly assigned into five groups, including the control group, diabetes mellitus group, pre treatment group, treatment group and post-treatment group. Type 2 diabetes was induced in mice using a combination of high-fat diet and streptozotocin injection. Subsequently, peripheral neuropathy was measured and the levels of LC, insulin and insulin-like growth factor-1 (IGF-1) were detected. When diabetic mice were treated with LC, the levels of IGF-1 in the plasma and pancreas were increased. In addition, hyperalgesia, as determined by the tail-flick test as well as food intake, body weight and blood glucose levels were decreased. An amelioration of demyelination, axonal atrophy and mitochondria swelling in the nerve fibres of diabetic mice was also observed. The present study demonstrated that LC ameliorated peripheral neuropathy in type 2 diabetic mice and the effect of LC may in part be mediated by an increase in local and circulatory IGF-1 levels. PMID- 30431102 TI - miR-494-3p promotes the progression of endometrial cancer by regulating the PTEN/PI3K/AKT pathway. AB - MicroRNAs (miRs) are essential regulators in the development and progression of cancer. The role of miR-494-3p in endometrial cancer (EC) has not yet been investigated. In the present study, the expression levels of miR-494-3p were significantly upregulated in EC tissues compared with adjacent normal tissues. Furthermore, upregulation of miR-494-3p in patients with EC indicated poorer prognosis; miR-494-3p overexpression significantly promoted the proliferation, migration and invasion of HHUA and JEC cells in vitro. Consistently, inhibition of miR-494-3p in HHUA cells significantly suppressed tumor growth in vivo in a xenograft model. Additionally, phosphatase and tensin homolog (PTEN) was revealed to be a direct target of miR-494-3p in EC cells. Furthermore, overexpression of miR-494-3p inhibited PTEN expression and consequently activated the downstream phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signialing pathway. Restoration of PTEN or inhibition of PI3K/AKT pathway also abolished miR-494-3p mediated proliferation, migration and invasion of HHUA and JEC cells. In summary, the results of the present study revealed the importance of the miR-494 3p/PTEN/PI3K/AKT axis in the progression of EC, which may provide novel insight into potential therapeutic targets for the treatment of EC. PMID- 30431103 TI - Inhibition of cell proliferation and migration in non-small cell lung cancer cells through the suppression of LYPLA1. AB - Lysophospholipase1 (LYPLA1) also known as acyl-protein thioesterase1 (APT1) belongs to the superfamily of alpha/beta hydrolase. It has been found to have the properties of a homodimer by manifesting depalmitoylation as well as lysophospholipase activity. LYPLAs are under the control of both microRNAs, miR 138 and miR-424. They were observed to be significantly overexpressed in chronic lymphocytic leukemia cells. To date, LYPLAs are the sole enzymes recognized to activate depalmitoylation. In this study, we provide the expression pattern of LYPLA1 in non-small cell lung cancer (NSCLC) using four different NSCLC cell lines. Western blot analysis and RT-PCR were performed to detect the protein expression and mRNA expression of LYPLA1 in NSCLC cell lines. We detected the highest LYPLA1 protein expression level in SPC-A-1 cells followed by A549 cells, and the highest LYPLA1 mRNA expression level was detected in the SPC-A-1 cells followed by the H1299 cell line. We found that suppression of LYPLA1 expression using small-interfering RNA significantly inhibited proliferation, migration and invasion of the LYPLA1-transfected NSCLC cells. Furthermore, we explored the involvement of LYPLA1 in the regulation of epithelial-mesenchymal transition (EMT). The epithelial marker E-cadherin was significantly increased, while mesenchymal markers N-cadherin, vimentin and SNAIL were markedly decreased in the LYPLA1-silenced cells. Collectively the results of the present study suggest that the LYPLA1 gene plays a tumor-promotor role in NSCLC cells in vitro. PMID- 30431104 TI - Long non-coding RNA MALAT1 correlates with cell viability and mobility by targeting miR-22-3p in renal cell carcinoma via the PI3K/Akt pathway. AB - Renal cell carcinoma (RCC) is one of the most common types of cancer of the urinary tract in the world. Long non-coding RNA MALAT1 (lncR-MALAT1) is upregulated in RCC and is associated with the proliferation and migration of RCC. The present study aimed to investigate the regulating role of lncR-MALAT1 in RCC as well as the possible underlying mechanisms. The relative expression of MALAT1 and miR-22-3p in RCC tumor tissues and cell lines was detected by qRT-PCR. CCK-8 and wound healing assay were used to evaluate cell proliferation and migration ability. Western blot analysis was used to detect the expression of Ki-67, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase-3 (MMP-3), migration and invasion inhibitory protein (MIIP), p-PI3K and p-Akt. The relationship between MALAT1 and miR-22-3p was examined by bioinformatic prediction analysis and luciferase reporter assay. Immunofluorescence was used to detect the activation of Akt. MALAT1 was highly expressed and the expression of miR-22-3p was suppressed in RCC tissues and cell lines. ShRNA-mediated knockdown of MALAT1 significantly inhibited the viability and mobility of RCC cells in vitro and in vivo. Further experiments revealed that miR-22-3p was a target of MALAT1 and that miR-22-3p inhibitor abolished the effect of MALAT1 shRNA on cell proliferation, migration and inactivation of PI3K/AKT pathway. In conclusion, lncR-MALAT1 affected the proliferation and migration of RCC cells by targeting miR-22-3p through the inactivation of the PI3K/Akt signaling pathway. PMID- 30431105 TI - HIF-1alpha contributes to tube malformation of human lymphatic endothelial cells by upregulating VEGFR-3. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is upregulated in various tumors and associated with lymphangiogenesis and angiogenesis during tumor development and metastasis. However, the role of HIF-1alpha in cystic lymphatic malformations (cLM) remains unclear. In the present study, expression of HIF-1alpha and vascular endothelial growth factor receptor 3 (VEGFR-3) was evaluated in 20 pairs of cLM specimens from patients who accepted curative surgery at Children's Hospital of Nanjing Medical University (Nanjing, China). Additionally, a stable HIF-1alpha-overexpressing human lymphatic endothelial cell (HLEC) line was established. Overexpression and silencing of HIF-1alpha were used to investigate the biological role in colony formation, migration and lymphatic tube formation. HIF-1alpha and VEGFR-3 were upregulated in cLM specimens compared with adjacent normal tissues. In addition, HIF-1alpha effectively induced HLEC colony formation and migration. Furthermore, lymphatic malformation of HLECs was promoted in vitro by overexpression of HIF-1alpha. HIF-1alpha overexpression upregulated VEGFR-3 during lymphangiogenesis. Additionally, expression of lymphatic endothelial markers prospero homeobox protein 1 and lymphatic vessel endothelial hyaluronan receptor 1 increased significantly during lymphatic tube malformation. The presented data demonstrated that HIF-1alpha overexpression in HLECs promoted colony formation, migration and tube malformation via upregulation of VEGFR-3. These findings may assist in the development of HIF-1alpha-targeted cLM therapeutics in the future. PMID- 30431106 TI - Aortic constriction induces hypertension and cardiac hypertrophy via (pro)renin receptor activation and the PLC-beta3 signaling pathway. AB - The (pro)renin receptor [(P)RR] serves an important role in cardiovascular complications. However, the precise mechanisms of (P)RR in the heart remain obscure. The authors hypothesized that overexpression of (P)RR would be associated with activation of the relevant signal pathway which could lead to organ injury. The aim of the present study was to test the role of cardiac (P)RR and its potential signaling pathway components including phospholipase C (PLC), protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2 and Raf-1 proto-oncogene, serine/threonine kinase (Raf-1). Hypertension and cardiac hypertrophy were induced by partial abdominal aortic ligation in Sprague-Dawley rats. The expression levels of cardiac (P)RR, PLC-beta3, PKC, ERK1/2 and Raf-1 were measured following administration of the handle region peptide (HRP) and PLC beta3 inhibitor U73122. The expression of (P)RR and PLC-beta3 significantly increased in the left ventricle (P<0.05). Levels of PKC-alpha, ERK1/2 and Raf-1 in the heart rose significantly (P<0.05). HRP and U73122 significantly decreased the levels of cardiac (P)RR and PLC-beta3. Furthermore, levels of PKC-alpha, ERK1/2 and Raf-1 were also decreased (P<0.05). Cardiac parameters, blood pressure and plasma Angiotensin (Ang) I and Ang II levels were altered significantly (P<0.05). The results demonstrated that hypertension induced by aortic restriction activated the (P)RR in the heart. This action led to hypertension and cardiac hypertrophy via the (P)RR-PLC-beta3-PKC-ERK1/2-Raf-1 signaling pathway. These results provide a mechanism by which elevated (P)RR levels in hypertension may contribute to the development of cardiac remodeling. PMID- 30431107 TI - MicroRNA-584 directly targets CCND1 and inhibits cell proliferation and invasion in pancreatic cancer. AB - Multiple previous studies have demonstrated that the dysregulation of microRNAs (miRNAs) is implicated in the occurrence and development of pancreatic cancer. Therefore, a further characterisation of deregulated miRNAs in pancreatic cancer may provide novel insight into the oncogenesis and progression of pancreatic cancer, which may facilitate the identification of effective therapeutic targets for treating patients with this disease. In the present study, reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the expression level of miRNA-584-5p (miR-584) was significantly decreased in pancreatic cancer tissues and cell lines. It was demonstrated that restoration of miR-584 expression significantly suppressed the proliferative and invasive ability of pancreatic cancer cells. Bioinformatics analysis predicted that cyclin D1 (CCND1) was a putative target of miR-584. Subsequent experiments demonstrated that CCND1 was a direct target gene of miR-584 in pancreatic cancer cells. Furthermore, the inhibition of CCND1 mimicked the suppressive effect of miR-584 overexpression in pancreatic cancer cells. The restoration of CCND1 expression significantly abolished the inhibitory effects of miR-584 overexpression on pancreatic cancer cells. Collectively, the present results demonstrated that miR 584 inhibited the development of pancreatic cancer by directly targeting CCND1, suggesting that this miRNA may represent a potential therapeutic target for this fatal disease. PMID- 30431109 TI - Enhanced adhesion and proliferation of bone marrow mesenchymal stem cells on beta tricalcium phosphate modified by an affinity peptide. AB - Mesenchymal stem cells (MSCs) are often used in orthopedic tissue engineering, and bone marrow-derived mesenchymal stem cells (BMSCs) are currently considered the gold standard. One of the most important issues in MSC-based tissue engineering therapy is the low number of MSCs in pathological tissues. Achieving efficient recruitment of MSCs to defective or damaged tissues in vivo has been a difficult hurdle. The aim of the present study was to construct a biomaterial that can effectively recruit BMSCs to facilitate the repair of pathological tissues. So functional beta-tricalcium phosphate (beta-TCP) was synthesized using the BMSC affinity peptide DPIYALSWSGMA (DPI) adsorbed onto beta-TCP through an adsorption/freeze-drying strategy. C57BL/6 mouse-derived BMSCs were seeded onto the DPI peptide-modified beta-TCP (beta-TCP-DPI); in vitro experiments demonstrated that beta-TCP-DPI enhanced BMSC adhesion and proliferation compared with unmodified beta-TCP. Results from the present study indicated that functional beta-TCP may be used as an ideal scaffold in tissue engineering and in regenerative medicine. PMID- 30431110 TI - CLCN7 and TCIRG1 mutations in a single family: Evidence for digenic inheritance of osteopetrosis. AB - Osteopetrosis is a monogenic condition with various inheritance patterns, including autosomal dominant, autosomal recessive and X-linked. Several disease causing genes have been identified and three distinguished types of osteopetrosis have been reported. In the present study, a family with osteopetrosis was investigated. Two novel mutations in chloride voltage-gated channel 7 (CLCN7) and T cell immune regulator 1 (TCIRG1) were identified by exome sequencing, Sanger sequencing and microsatellite marker analysis. The CLCN7 mutation occurred in amino acid R286, the same position as previously reported. The TCIRG1 mutation occurred on a splicing site of exon 15, thereby leading to a truncated transcript. These two mutations were undetected in 496 ethnic-matched controls. To the best of our knowledge, this is the first report of human osteopetrosis involving digenic inheritance in a single family, which has important implications for decisions on clinical therapeutic regimen, prognosis evaluation and antenatal diagnosis. PMID- 30431111 TI - Genome-wide DNA methylation analysis of uterosacral ligaments in women with pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is an increasingly serious health problem that impairs quality of life and is caused by multiple additive genetic and environmental factors. As the uterosacral ligaments (ULs) provide primary support for the pelvic organs, it was hypothesized that disruption of these ligaments (as a result of aberrant methylation) may lead to a loss of support and eventually contribute to POP. In the present study, whether there are any aberrant methylations in the ULs of patients with POP compared to those of controls was investigated. Genomic DNA was isolated from the ULs of five women with POP and four women without POP, as controls, undergoing hysterectomy for benign conditions. An Illumina Infinium Methylation EPICBeadChips Infinium Human Methylation 850 K bead array was used to investigate the total methylation in the ULs. There were 3,723 differentially methylated CpG sites (Deltabeta<0.14; P<0.05), including 3,576 hypermethylation and 147 hypomethylation sites in the ULs of patients with POP compared with the normal controls. There were more hypermethylated CpG sites, but a high ratio of hypomethylation between CpG islands and the N-shelf; in the gene structure, there was more hypermethylation than hypomethylation in TSS1500 and the 5' untranslated region. Gene ontology analysis demonstrated that these differentially methylated genes were associated with 'cell morphogenesis', 'extracellular matrix', 'cell junction', 'protein binding' and 'guanosine triphosphatase activity'. Several significant pathways were identified, including 'focal adhesion' and 'extracellular matrix-receptor interaction pathway'. This study provides evidence that there are differences in genome-wide DNA methylation between ULs in menopausal women with and without POP, and that epigenetic mechanisms may partly contribute to POP pathogenesis. PMID- 30431108 TI - Mitochondria-targeted antioxidant therapy for an animal model of PCOS-IR. AB - Polycystic ovary syndrome (PCOS) is a common endocrine disorder with unknown etiology and unsatisfactory clinical treatment. Considering the ethical limitations of studies involving humans, animal models that reflect features of PCOS and insulin resistance (IR) are crucial resources in investigating this syndrome. Our previous study showed that mitochondrial dysfunction resulted from pathogenic mutations of mitochondrial DNA (mtDNA), and that oxidative stress had an active role in the phenotypic manifestation of PCOS-IR. Therefore, it was hypothesized that limiting oxidative stress and mitochondrial damage may be useful and effective for the clinical treatment of PCOS-IR. For this purpose, the present study examined the therapeutic effects of the mitochondria-targeted antioxidant MitoQ10 for PCOS-IR. Furthermore, the histopathology was used to analysis the ovarian morphological changes. The endocrine and reproductive related parameters were analyzed by ELISA approach. A PCOS-IR model was successfully established by subcutaneous injection of rats with testosterone propionate and feeding a high-fat diet. The 30 female Sprague-Dawley rats were then divided into three groups, comprising a control (n=10), animal model (PCOS IR, n=10) and MitoQ10 treatment (n=10) group. It was found that MitoQ10 significantly improved the IR condition and reversed the endocrine and reproductive conditions of PCOS. In addition, the impaired mitochondrial functions were improved following MitoQ10 administration. Notably, western blot results suggested that this antioxidant reduced the expression levels of apoptosis-related proteins cytochrome c and B-cell lymphoma-2 (Bcl-2)-associated X protein, whereas the anti-apoptotic protein Bcl-extra large was increased following MitoQ10 treatment. Taken together, the data indicated that the MitoQ10 may have a beneficial favorable therapeutic effect on animals with PCOS-IR, most likely via the protection of mitochondrial functions and regulation of programmed cell death-related proteins. PMID- 30431112 TI - Expression profile of long non-coding RNAs in cardiomyocytes exposed to acute ischemic hypoxia. AB - Acute myocardial infarction (AMI) is a life-threatening disease and seriously influences patient quality of life. Long non-coding RNAs (lncRNAs), an emerging class of non-coding genes, have attracted attention in research, however, whether lncRNAs serve a function in acute ischemic hypoxia remains to be elucidated. In the present study, an lncRNA microarray was used to analyze differential lncRNA expression in acute ischemic hypoxia. A total of 323 lncRNAs were identified, 168 of which were upregulated and 155 of which were downregulated. Gene Ontology and Pathway analyses were also used to identify the potential functions of dysregulated lncRNAs; it was predicted that these dysregulated lncRNAs may contribute to the initiation of AMI. It was demonstrated that an lncRNA termed sloyfley may influence acute ischemic hypoxia through its neighboring gene Peg3, which has been linked to brain ischemia hypoxia. In summary, the present study identified numerous lncRNAs, which may provide further opportunities for the development of novel therapeutic strategies. PMID- 30431113 TI - miRNA-885-3p inhibits docetaxel chemoresistance in lung adenocarcinoma by downregulating Aurora A. AB - Aurora A is a member of the mitotic serine/threonine kinase family. It is involved in key processes during mitosis and meiosis, and Aurora A upregulation is implicated in malignant transformation. In the present study, we revealed that Aurora A expression was significantly higher in docetaxel-resistant lung adenocarcinoma (LAD) cells than in parental cells. Higher levels of Aurora A expression were significantly correlated with higher chemoresistance and proliferation in LAD cells, while silencing Aurora A promoted caspase-3-dependent cell apoptosis by downregulating NF-kappaB and Bcl-2 and upregulating Bax expression. In addition, an increased proportion of cells in the G2/M phase and a decreased proportion of cells in the S phase were observed due to the suppression of Aurora A. Furthermore, we identified that microRNA-885-3p (miR-885-3p) could target Aurora A directly. There was significantly lower miR-885-3p expression in docetaxel-resistant LAD cells than in parental LAD cells. miR-885-3p could modulate the docetaxel response, cell proliferation and apoptosis in LAD cells in vitro. Moreover, we found that Aurora A overexpression or miR-885-3p inhibition was associated with more aggressive behaviour in LAD cells. Thus, miR-885 3p/Aurora A may be involved in the chemoresistance of LAD cells, and assessing miR-885-3p/Aurora A expression may be a potential method for indicating chemosensitivity to docetaxel-based chemotherapy. PMID- 30431114 TI - Isolation and multipotential differentiation of mesenchymal stromal cell-like progenitor cells from human bladder. AB - Various types of mesenchymal stromal cells (MSCs) have been used in urological tissue engineering but to date the existence of MSCs has not been reported in the human bladder. The present study provided evidence that a small number of MSC like cells exist in the human bladder and designated this class of cells 'human bladder-derived MSC-like cells' (hBSCs). It was demonstrated that hBSCs can be cultured to yield a large population. These hBSCs expressed the surface markers of MSCs and exhibited the capacity for osteogenic, adipogenic and chondrogenic differentiation. On induction with appropriate media in vitro, hBSCs could differentiate into bladder-associated cell types, including urothelial, endothelial and smooth muscle cell-like lineages. In addition, the average telomerase activity of adult hBSCs was higher compared with adult human bone marrow-derived MSCs, but lower than that of human umbilical cord Wharton's jelly derived MSCs. These findings may inspire future studies on the role of hBSCs in urological tissue engineering applications and in other fields. PMID- 30431115 TI - Hypoxia-induced miR-210 contributes to apoptosis of mouse spermatocyte GC-2 cells by targeting Kruppel-like factor 7. AB - The aim of the present study was to investigate the underlying mechanisms of hypoxia-induced microRNA (miR)-210 effects on mouse GC-2spd (GC-2) cells. GC-2 cells were subjected to hypoxia or normoxia for 12, 24, 48 and 72 h. Apoptosis of GC-2 cells was detected using terminal deoxynucleotidyl-transferase-meditated dUTP nick end labeling and flow cytometry. Reverse transcription-quantitative polymerase chain reaction was performed to analyze the expression of miR-210. Hypoxia-inducible factor-1alpha (HIF-1alpha), caspase-3, B-cell lymphoma 2, apoptosis regulator BAX and Kruppel-like factor 7 (KLF7) protein expression levels were detected by western blotting. Luciferase reporter gene assays were used to assess the targeting effects of miR-210 on KLF7. Hypoxia induced GC-2 cell apoptosis and increased the expression of HIF-1alpha and pro-apoptotic proteins; however, decreased anti-apoptotic protein expression levels. Furthermore, hypoxia resulted in the upregulation of miR-210 in GC-2 cells. HIF 1alpha and miR-210 were involved in the apoptosis of GC-2 cells by mediating the expression of apoptosis-associated proteins. Furthermore, KLF7 was directly targeted by miR-210 to influence the apoptosis of GC-2 cells subjected to hypoxia. The results suggested that hypoxia-induced miR-210 stimulated the activation of the apoptosis signaling pathway and contributed to the apoptosis of GC-2 cells by targeting KLF7. PMID- 30431116 TI - Mitochondrial-DNA-associated TLR9 signalling is a potential serological biomarker for non-small cell lung cancer. AB - Mitochondrial (mt) DNA has been long suggested to contribute to carcinogenesis, and a variety of mutations in mtDNA have been confirmed to be related to various early stages of cancers; these data revealed that the detection of mtDNA in clinical samples may be a promising approach for cancer diagnosis. In the present study, the serum mtDNA in healthy donors and groups of patients with cancer was detected. It was revealed that patients with lung cancer without metastasis had more mtDNA in serum compared to patients with metastasis. Moreover, TLR9 associated signalling was activated in vitro after treatment with a synthetic CpG oligodeoxyribonucleotide (ODN) called ODN-M362. In addition, our data revealed that TLR9 and its adaptor protein, MyD88, were induced by ODN-M362 in a dose dependent manner. A human cytokine array to evaluate stimulation of cytokine secretion by ODN-M362 was also used. Our findings may identify the role that TLR9 and mtDNA play in lung cancer progression and metastasis. PMID- 30431117 TI - Knockdown of P120 catenin aggravates endothelial injury under an impinging flow by inducing breakdown of adherens junctions. AB - At present, the mechanisms underlying intracranial aneurysm (IA) development remain unclear; however, hemodynamics is considered a crucial factor in the induction of IA. To elucidate the association between hemodynamics and endothelial cell (EC) functions, a modified T chamber system was designed to simulate the adjustable hemodynamic conditions of an artery bifurcation. Normal human umbilical vein ECs (HUVECs) and HUVECs with P120 catenin (P120ctn) knockdown were cultured on coverslips and placed in the chamber. A flow rate of 250 or 500 ml/min impinged on the cell layer. Subsequently, the expression levels of P120ctn and other proteins, and EC morphological alterations, were examined. In normal HUVECs, after 3 h under a flow rate of 500 ml/min, the expression levels of P120ctn, vascular endothelial (VE)-Cadherin, Kaiso and alpha-catenin were decreased, whereas matrix metalloproteinase-2 (MMP-2) was increased. In HUVECs with P120ctn knockdown, the period during which ECs adhered to the coverslip was reduced to 1 h under a flow rate of 500 ml/min. In addition, the expression levels of VE-Cadherin, Kaiso and alpha-catenin in ECs were decreased, whereas those of MMP-2 were increased after 1 h; more prominent alterations were detected under a 500 ml/min flow rate compared with a 250 ml/min flow rate. Adherens junctions (AJs) are critical to the maintenance of normal morphology and EC functioning in the vascular wall, and P120ctn is an important regulator of AJs. Loss of P120ctn may be induced by hemodynamic alterations. In response to changes in hemodynamic conditions, a loss of P120ctn may aggravate AJs between ECs, thus inducing inflammation in the vascular wall. Clinically, hemodynamic alterations may result in a loss of P120ctn and endothelial injury; therefore, P120ctn may have a critical role in inducing intracranial aneurysms. PMID- 30431118 TI - MicroRNA-663 inhibits the proliferation and invasion of clear cell renal cell carcinoma cells by directly targeting PAK4. AB - Accumulating evidence has demonstrated that microRNAs (miRNAs) are key gene regulators and are abnormally expressed in clear cell renal cell carcinoma (ccRCC). The dysregulation of miRNAs has been implicated in the initiation and progression of ccRCC. Therefore, identification of ccRCC-associated miRNAs may facilitate the determination of promising therapeutic targets for anti-cancer treatment. In the present study, miRNA-663 (miR-663) expression was downregulated in ccRCC tissues and cell lines. Functional experiments suggested that restoration of miR-663 expression inhibited the proliferation and invasion of ccRCC cells. In addition, p21 activated kinase 4 (PAK4) was validated as a direct target of miR-663 in ccRCC cells. PAK4 was upregulated in ccRCC tissues, and the expression level of PAK4 was inversely correlated with the miR-663 expression level. PAK4 restoration partially attenuated the suppressive roles of miR-663 overexpression on the proliferation and invasion of ccRCC cells. The present results provide novel insight into the mechanism underlying the occurrence and development of ccRCC, suggesting that the miR-663/PAK4 axis may be a novel therapeutic target for treatment of patients with ccRCC. PMID- 30431119 TI - Glutathione S-transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer. AB - The roles of glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 2 (GSTM2) and glutathione S-transferase alpha 1 (GSTA1) in cisplatin (DDP) resistance of solid cancer cells (A549/DDP, SKOV3/DDP and SGC7901/DDP) were compared following expression downregulation with small interfering RNAs (siRNAs). DDP cytotoxicity was reflected by its half maximal inhibition concentration (IC50) calculated from data using a Cell Counting Kit-8 assay; cell apoptosis was examined using flow cytometry and Hoechst 33342 staining. Higher activities of GST were detected in the cytosol of DDP-resistant cells, compared with those in the parental DDP-susceptible cells. The silencing efficacy of each positive siRNA was supported by western blot analysis. GSTP1 silencing resulted in a 4-fold sensitization of SGC7901/DDP cells to DDP cytotoxicity, but negligible sensitization of SKOV3/DDP and A549/DDP cells. GSTM2 silencing sensitized SKOV3/DDP and A549/DDP cells to DDP cytotoxicity by ~2-fold, but did not sensitize SGC7901/DDP cells. Notably, GSTA1 silencing enhanced DDP cytotoxicity in SGC7901/DDP cells by 6-fold, in A549/DDP cells by 5-fold and in SKOV3/DDP cells by 2-fold. The combined actions of positive siRNAs and DDP increased the percentages of apoptotic cells in the DDP-resistant solid cancer cells compared with the combined actions of DDP and the negative siRNAs. The present findings indicated that GSTA1 is a predominant GST isozyme associated with DDP resistance of SGC7901/DDP, A549/DDP and SKOV3/DDP cells; GSTA1-specific inhibitors may be general sensitizers of SGC7901/DDP, A549/DDP and SKOV3/DDP cells to DDP cytotoxicity through the promotion of cell apoptosis. PMID- 30431120 TI - TROAP regulates prostate cancer progression via the WNT3/survivin signalling pathways. AB - Prostate cancer (PCa) is one of the most commonly diagnosed malignancies, and 90% of advanced prostate cancer patients relapse after therapy. Trophinin associated protein (TROAP) is essential for centrosome integrity and proper bipolar organisation of spindle assembly during mitosis and plays an essential role in proliferation. We found that TROAP expression correlates with patient survival and speculated that it may be involved in PCa progression. The Oncomine database tool (http://www.oncomine.org) was used to analyse TROAP mRNA expression from microarray data, and patient survival analysis for target genes was performed using the PROGgeneV2 Database (http://watson.compbio.iupui.edu). Gene interference with lentivirus was used to silence TROAP expression in PCa cells and knockdown efficiency was detected by qRT-PCR and western blot analysis. Cell viability, colony formation, cell cycle and apoptosis were then assessed to determine the function of TROAP in PCa cells. Markers of cell cycle and apoptosis were tested by western blotting. The correlation between WNT3 or survivin expression and TROAP transcripts in prostate cancer tissues was analysed using GEPIA (http://gepia.cancer-pku.cn) and validated by western blotting. The in vivo role of TROAP was investigated using xenografts. This protein was overexpressed in PCa, and exhibited relatively higher expression in PCa cell lines, DU145 and 22Rv1. Importantly, analysing human cancer databases available from PROGgeneV2 showed that higher expression of TROAP is associated with shorter overall survival in prostate cancer patients. TROAP knockdown inhibited cell proliferation and led to cell cycle arrest at S phase in 22Rv1 and DU145 cells. Cell cycle arrest resulted in apoptosis in both cell lines via the cyclin A2 cyclin B1-caspase pathway. WNT3 and survivin expression levels were found to correlate with TROAP in PCa, and in vivo xenograft assays revealed that silencing of TROAP inhibited PCa tumour growth. Therefore, TROAP might represent a novel predictive marker to guide therapeutic intervention. PMID- 30431121 TI - [Corrigendum] Netrin-1 induces the proliferation of gastric cancer cells via the ERK/MAPK signaling pathway and FAK activation. AB - During the preparation of the figures in the above article, the authors inadvertently selected images for the shCTL experiments portrayed in Fig. 5I and J (for the MGC803 and SGC7901 cell lines, respectively) that were generated from the same original data source. A corrected version of Fig. 5 is shown opposite, showing the correct data for the shCTL experiment performed in SGC7901 cells (Fig. 5J). This error did not affect the major conclusions reported in the paper. All the authors have agreed to this Corrigendum. The authors regret this error, and apologize for any confusion that it may have caused. [the original article was published in Oncol Rep 40: 2325-2333, 2018; DOI: 10.3892/or.2018.6614]. PMID- 30431122 TI - P4HB knockdown induces human HT29 colon cancer cell apoptosis through the generation of reactive oxygen species and inactivation of STAT3 signaling. AB - Colon cancer is the second most lethal malignancy worldwide. A better understanding of colon cancer at the molecular level may increase overall survival rates. Previous studies have indicated that prolyl 4-hydroxylase, beta polypeptide (P4HB) is associated with tumorigenesis in colon cancer; however, its role and molecular mechanisms in colon cancer remain unclear. In the present study, the cellular responses to P4HB in human colon cancer cell lines were investigated by proliferation and apoptosis assays, western blotting, and immunohistochemistry. The results showed that expression of P4HB was higher in colon cancer tissues compared within adjacent normal tissues. P4HB knockdown increased the apoptosis of human HT29 cells. Furthermore, P4HB knockdown reduced the activation of signal transducer and activator of transcription 3 (STAT3) and promoted accumulation of reactive oxygen species (ROS). Inhibiting the accumulation of ROS abrogated the increased cell apoptosis induced by P4HB knockdown. Notably, decreased ROS levels effectively antagonized the effects of P4HB on STAT3 inactivation. In conclusion, these findings suggested that P4HB knockdown may induce HT29 human colon cancer cell apoptosis through the generation of ROS and inactivation of the STAT3 signaling pathway. PMID- 30431123 TI - CDK5 suppresses the metastasis of gastric cancer cells by interacting with and regulating PP2A. AB - Several previous studies have demonstrated that cyclin-dependent kinase (CDK)-5 expression serves an important role in promoting the development of malignant tumours. We have previously reported that CDK5 suppresses gastric tumourigenesis. The aim of the present study was to investigate the mechanistic basis of CDK5. The results of immunoprecipitation and western blot analysis demonstrated that CDK5 could interact with serine/threonine-protein phosphatase 2A (PP2A). The use of an inhibitor of PP2A in CDK5-overexpressing gastric cancer (GC) cell lines antagonized CDK5-mediated suppression in GC cells. Further analysis revealed that PP2A expression was downregulated in GC and patients with low levels of PP2A had worse survival outcomes than those with high levels of PP2A (P=0.035). Therefore, the present study provided a novel mechanism for CDK5-mediated tumour suppression, suggesting that CDK5 may be an attractive target for future therapeutic strategies for treating GC. In addition, low levels of PP2A may indicate a tendency for poor prognosis in patients with GC. PMID- 30431124 TI - MicroRNA-940 promotes cell proliferation and invasion of glioma by directly targeting Kruppel-like factor 9. AB - MicroRNA-940 (miR-940) has been extensively studied in the pathogenesis of numerous types of human cancer; however, the expression pattern, roles and molecular mechanisms underlying the regulatory actions of miR-940 in glioma remain unknown. The present study aimed to further investigate miR-940 by studying its expression, roles and mechanisms of action in glioma. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect miR-940 expression in glioma tissues and cell lines. The regulatory effects of miR-940 in glioma cell proliferation and invasion were determined using MTT and cell invasion assays. Bioinformatics analyses was performed to identify the potential target of miR-940, which was further confirmed by luciferase reporter assay, RT-qPCR and western blot analysis. In the present study, significantly increased miR-940 expression levels were observed in glioma tissues and cell lines compared with normal brain tissues and normal human astrocytes, respectively. Decreased miR-940 expression levels attenuated glioma cell proliferation and invasion in vitro. Kruppel-like factor 9 (KLF9) was predicted as a potential target of miR-940. Further assays demonstrated that miR-940 negatively regulated KLF9 expression in glioma cells by directly targeting the 3' untranslated regions of KLF9. Additionally, KLF9 expression was downregulated in glioma tissues and was inversely correlated with miR-940. Furthermore, KLF9 knockdown was able to rescue the effects of miR-940 on glioma cell proliferation and invasion. The results of the present study suggest that miR-940 may function as an oncogene in glioma by targeting KLF9 and may be a considered a therapeutic target for the treatment of gliomas. PMID- 30431125 TI - TROP2 promotes the proliferation and metastasis of glioblastoma cells by activating the JAK2/STAT3 signaling pathway. AB - Trophoblast cell surface antigen 2 (TROP2), a single transmembrane domain protein, is often found to be highly expressed in various types of human cancers. However, the biological function and molecular mechanism of TROP2 in glioblastoma have not been fully elucidated, particularly in regards to cell proliferation and metastasis of glioblastoma cells. In the present study, it was demonstrated that TROP2 expression was increased in glioblastoma tissues and glioblastoma cell lines by immunohistochemical analysis and western blot analysis. High TROP2 expression was significantly correlated with the poor survival of glioblastoma patients. MTT assay, BrdU incorporation assay, flow cytometry and Transwell assay were performed to demonstrate that knockdown of TROP2 in glioblastoma cells inhibited cell proliferation and metastasis. We found that the effects of TROP2 knockdown on glioblastoma cells were associated with the inhibition of JAK2 and STAT3 phosphorylation and decreased transcription of STAT3 target genes. In addition, blocking the activation of JAK2/STAT3 signaling by WP1066 negated the effects of TROP2 overexpression. Furthermore, exogenous IL-6, which functions as a potent activator of JAK2/STAT3 signaling, was able to rescue the phosphorylation of JAK2 and STAT3 in TROP2-silenced glioblastoma cells and regulate phenotypic changes in these cells. Therefore, we revealed a novel mechanism by which TROP2 activates the JAK2/STAT3 pathway to promote the growth and metastasis of glioblastoma cells. These data offer insight into the function of TROP2 in glioblastoma and indicate that TROP2 is a promising biomarker and therapeutic target for glioblastoma patients. PMID- 30431126 TI - Integration of high-throughput data of microRNA and mRNA expression profiles reveals novel insights into the mechanism of liver fibrosis. AB - Numerous studies have revealed that microRNAs (miRNAs) are functional non-coding RNAs that serve roles in a variety of biological processes. However, the expression patterns and regulatory networks, as well as the miRNAs involved in liver fibrosis remain to be elucidated. In the present study, a mouse model of liver fibrosis was constructed by CCl4 intraperitoneal injection and the total RNAs were extracted from the liver of the mice. The total RNAs were then sequenced on an Illumina HiSeq 2000 platform and an integrated analysis of miRNA and mRNA expression profiles in CCl4-induced liver fibrosis was performed. Compared with normal liver samples, 56 and 15 miRNAs were found to be upregulated and downregulated in fibrotic livers, respectively. To predict the potential functions of these miRNAs, bioinformatics analysis, including Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, was used to assess target mRNAs. The results indicated that the mitogen-activated protein kinase, phosphoinositide 3 kinase/protein kinase B and focal adhesion signaling pathways were the most significantly enriched. In addition, a regulatory network containing five dysregulated miRNAs and 22 target mRNAs was constructed based on their inverse correlation. Furthermore, the five dysregulated miRNAs were significantly upregulated and the expression of RELB, RAP1A, PPP3CB, MAP2K4, ARRB1, MAP3K4, FGF1 and PRKCB in the network was significantly decreased in LX-2 cells following TGF-beta1 treatment which suggested that they were associated with the activation of human hepatic stellate cells. The miRNA-mRNA regulatory network produced in the present study may provide novel insights into the role of miRNAs in liver fibrosis. PMID- 30431127 TI - Conditioned medium from human palatine tonsil mesenchymal stem cells attenuates acute graft-vs.-host disease in mice. AB - Graft-vs.-host disease (GVHD) is a severe and potentially life-threatening complication of hematopoietic stem cell transplantation. Approximately 50% of patients exhibiting GVHD will not benefit from conventional steroid treatment. Although several second-line treatments are available for these patients, their prognoses remain poor due to the increased risk of infection, immunosuppression mediated toxicity and incomplete GVHD remission, which occurs in the majority of cases. Mesenchymal stem cells (MSCs), a multipotent cell population, possess broad immunosuppressive activity and are a reportedly effective treatment of GVHD. However, the therapeutic effects of conditioned medium from MSCs on GVHD have not been demonstrated. In the present study, the efficacy of conditioned medium from human palatine tonsil-derived MSCs (T-MSC-CM) was validated against GVHD in mice. The suppressive function of T-MSC-CM on immune cell chemotaxis was confirmed in vitro. A systemic infusion of T-MSC-CM in mice with GVHD resulted in prolonged survival, rapid recovery from weight loss and reduced pathological damage in numerous GVHD-targeted organs. Furthermore, lymphocyte gene expression was significantly downregulated in GVHD mice administered T-MSC-CM. These results indicate that T-MSC-CM is a promising cellular agent to prevent or treat transplantation-associated complications such as GVHD. PMID- 30431128 TI - Evironmental pollutant perfluorodecanoic acid upregulates cIAP2 to suppress gastric cell senescence. AB - The role of perfluorodecanoic acid (PFDA) in gastric carcinogenesis and its mechanism remains unknown. Our previous research revealed that PFDA regulated the growth of human gastric cells. However, its core molecules and basic mechanisms are still not clear. In the present study, cDNA microarrays were used to determine mRNA changes in AGS cells after treatment with PFDA. DAVID analysis of the genes with >2-fold increased expression in microarray data revealed five genes which were involved in cancer pathways. The most upregulated gene was cIAP2, whose upregulation in AGS was confirmed by western blot analysis and quantitative PCR (qPCR) analyses. In order to investigate the role of cIAP2 in cell proliferation, cIAP2 siRNA was employed to regulate cIAP2 expression following PFDA treatment. The results revealed that the growth rate of cIAP2 knockdown cells was reduced by about 50% compared to the control. Given that our previous flow cytometric assays revealed no significant change (3.7 vs. 6.4%) in the percentage of apoptotic cells when PFDA was added to the medium and cIAP2 expression was upregulated, we next applied flow cytometry to assess whether cIAP2 would lead to cell cycle variations. The research data revealed that the proportion of cells in the G1, S and G2 phases was not significantly altered with the decrease of cIAP2 expression. Finally, the role of cIAP2 in AGS cell senescence was investigated, and the results indicated that cell senescence was significantly increased in the cIAP2 siRNA group in comparison to the control siRNA group. Since p53 has been identified as a tumor suppressor and its molecular alterations are common in different human tumors, we investigated the relationship of p53 with cIAP2. The experimental results demonstrated that cIAP2 regulated the expression of p53 and thus was likely to be a potential mechanism for PFDA-induced growth promotion. Overall, the results revealed that PFDA may suppress cellular senescence induced by p53 through the regulation of cIAP2 protein expression. PMID- 30431129 TI - Tumor suppressor PLZF regulated by lncRNA ANRIL suppresses proliferation and epithelial mesenchymal transformation of gastric cancer cells. AB - Promyelocytic leukemia zinc finger (PLZF) plays important roles in tumorigenic and developmental processes of various types of cancers. However, the expression of PLZF in gastric cancer (GC) has not been reported. The aim of the present study was to investigate the expression level and potential status of PLZF in GC as well as its possible mechanism. In the present study, we found that PLZF was downregulated in the majority of GC cell lines and tumor tissues and that alteration of PLZF expression was closely correlated with a malignant phenotype, epithelial-mesenchymal transformation and overall survival. Evaluation of in vitro proliferation, colony information, migration and invasion indicated that PLZF gene transduction induced a less malignant phenotype, which was also confirmed through in vivo studies performed in athymic nude mice. Furthermore, we assessed the expression levels of the lncRNA ANRIL in GC and found that it was negatively associated with the level of PLZF and that ANRIL indirectly methylated PLZF to suppress its expression via binding with polycomb repressive complex 2. When GC cells were treated with the methylation inhibitor 5-Aza-2'-deoxycytidine, the expression of PLZF increased, which further confirmed that PLZF was methylated. These results indicated that constitutive ANRIL activation was a possible cause of the lack of PLZF expression in GC cells. Coupled deregulation of PLZF and ANRIL may account for most of the alterations described in GC, and PLZF may become a potential target of GC therapy. PMID- 30431130 TI - Functional analysis of protein disulfide isomerase P5 in glioblastoma cells as a novel anticancer target. AB - P5, which is a member of the protein disulfide isomerase family, possesses isomerase and chaperone activity in vitro; however, the physiological functions of this enzyme in cells remain unclear. To understand the important roles of P5 in cancer cells, the present study examined its expression on the surface of normal and cancer cell lines by flow cytometry using an affinity-purified anti-P5 antibody labeled with 6-(fluorescein-5-carboxamido) hexanoic acid succinimidyl ester. P5 expression was increased on the surface of various cancer cell lines, including leukemia cells, and glioblastoma, breast, colon, ovarian and uterine cervical cancer cells, compared with normal cells. However, P5 was constantly expressed within both normal and cancer cell lysates, and its total expression levels were not significantly different between the cells. P5 knockdown in glioblastoma cells by small interfering RNA affected Bip promoter activation during cancer cell growth, and significantly inhibited cancer cell growth and migration. Immunoprecipitation using an anti-P5 antibody in cancer and normal cells demonstrated that vimentin was bound to P5, predominantly in U251 glioblastoma cells. P5 knockdown in glioblastoma cells did not affect the protein expression levels of vimentin; however, it did affect the expression of numerous epithelial-mesenchymal transition markers, including Snail and Slug. These results suggested that P5 may serve an important role in cancer cell growth, and may be considered an attractive and potent target for the treatment of glioblastoma. PMID- 30431131 TI - Pathway analysis of a genome-wide association study on a long non-coding RNA expression profile in oral squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) have been consistently demonstrated to be involved in oral squamous cell carcinoma (OSCC) as either tumor oncogenes or tumor suppressors. However, the underlying mechanisms of OSCC tumorigenesis and development have not yet been fully elucidated. The expression profiles of mRNAs and lncRNAs in OSCC were analyzed by a microarray assay. To verify the results of the microarray, 10 differentially expressed lncRNAs were randomly selected and measured by quantitative RT-PCR (qRT-PCR). Gene Ontology (GO) and metabolic pathway analyses were performed to analyze gene function and identify enriched pathways. Subsequently, two independent algorithms were used to predict the target genes of the lncRNAs. We identified 2,294 lncRNAs and 1,938 mRNAs that were differentially expressed in all three OSCC tissues by a microarray assay. Through the construction of co-expression networks of differentially expressed genes, 4 critical lncRNAs nodes were identified as potential key factors in the pathogenesis of OSCC. Expression of the 4 critical lncRNA nodes was not associated with age, sex, smoking or tumor location (P>0.05) but was positively correlated with clinical stage, lymphatic metastasis, distant metastasis and survival status (P<0.05). Kaplan-Meier analysis demonstrated that low expression levels of these 4 critical lncRNA nodes contributed to poor median progression free survival (PFS) and overall survival (OS) (P<0.05). GO and pathway analyses indicated that the functions and enriched pathways of many dysregulated genes are associated with cancer. Potential target genes of dysregulated lncRNAs were enriched in 43 metabolic pathways, with cancer pathways being the primary enrichment pathways. In summary, we analyzed the profile of lncRNAs in OSCC and identified the functions and enriched metabolic pathways of both dysregulated mRNAs and the target genes of dysregulated lncRNAs, providing new insights into molecular markers and therapeutic targets for OSCC. PMID- 30431132 TI - UPLC/Q-TOF-MS based plasma metabolomics and clinical characteristics of polycystic ovarian syndrome. AB - The present study aimed to develop novel diagnostic methods for polycystic ovarian syndrome (PCOS) by screening and identifying specific PCOS-associated metabolic markers using plasma metabolomics. Ultra-performance liquid chromatography/quadrapole-time of flight-mass spectrometry was adopted to establish the plasma metabolic fingerprint of 49 patients and 50 normal controls, in order to screen the potential metabolic markers. In addition, these markers were integrated with the clinical indexes, followed by focused analysis to obtain diagnostic markers. The present results demonstrated that not only was the concentration of palmitoyl sphingomyelin in plasma of patients with PCOS significantly increased; however, a statistically significant difference between the two PCOS subgroups was additionally demonstrated. At the same time, the concentrations of cyclic guanosine monophosphate (cGMP) and dehydroepiandrosterone sulphate in the plasma of patients of the subgroup 1 were significantly elevated. These markers were additionally integrated with the clinical index number of follicles in the left ovary and high-density lipoprotein (HDL-C), followed by receiver operating characteristic curve analysis, which demonstrated a diagnostic accuracy of ~90% in the control and the two subgroups. The integrated marker system consisting of palmitoyl sphingomyelin, cGMP and androsterone sulfate, as well as the number of left follicles and HDL-C may be used for the accurate diagnosis and classification of PCOS. These results confirmed that the abnormalities in hormone metabolism and lipid metabolism disorder were primarily involved in the onset of PCOS. PMID- 30431133 TI - Long non-coding RNA Fer-1-like family member 4 suppresses hepatocellular carcinoma cell proliferation by regulating PTEN in vitro and in vivo. AB - The aim of the present study was to investigate the potential role of long non coding RNA Fer-1-like family member 4 (FER1L4) in the proliferation of hepatocellular carcinoma (HCC) through the regulation of phosphatase and tensin homolog (PTEN) expression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression levels of FER1L4 and PTEN mRNA in HCC tissues, and western blotting was performed to measure the protein expression level of PTEN; MTT and colony formation assays were performed to detect the cell proliferative ability. Furthermore, nude mice were injected with transfected HCC cells and the tumor volume and weight were measured. The results indicated that FER1L4 was expressed at a low level in human HCC tissues compared with adjacent normal tissues. Functional studies indicated that FER1L4 may inhibit the proliferative ability of HCC cells. In addition, PTEN was highly expressed in HCC tissues compared with normal adjacent tissues and was positively associated with FER1L4. In addition, it was demonstrated that FER1L4 inhibited the proliferative ability of HCC cells in vitro, and silencing FER1L4 expression by small interfering RNAs promoted the growth of HCC tumors in vivo. Therefore, FER1L4 may be a potent therapeutic target for HCC. PMID- 30431134 TI - Comparative proteomic analysis identifies exosomal Eps8 protein as a potential metastatic biomarker for pancreatic cancer. AB - Exosomes are small vesicles found in extracellular environments including blood, urine, and cell culture medium. Their contents are cell-type specific, and molecules embedded in exosomes can be useful fluid-based clinical biomarkers. To identify proteins with metastatic marker potential, we conducted a comparative exosomal proteome analysis using human pancreatic cancer cell lines derived from metastasis, ascites, and primary tumors. Metastatic potential of cell lines was assessed by migratory and invasive activities. A pancreatic cancer cell line from metastasis (SU.86.86) revealed 23-fold and 20-fold increases in cell migratory and invasive activities, respectively, compared to the MIA PaCa-2 cell line derived from primary tumor cells. Liquid chromatography-mass spectrometry-based proteome analysis and subsequent validation by immunoblot analysis revealed that epidermal growth factor receptor pathway substrate 8 (Eps8) was highly abundant in exosomes from metastasis-derived SU.86.86 cells. Comparison of 12 pancreatic cancer cell lines derived from different stages of malignancy revealed a strong relationship between exosomal Eps8 protein levels and cell motile activities (migration: r=0.85, P=4.2x10-4; invasion: r=0.60, P=3.2x10-2). Conversely, relationships between intracellular Eps8 protein levels and cell motile activities were moderate (migration: r=0.65, P=2.0x10-2; invasion: r=0.51, P=9.2x10-2). It was therefore concluded that exosomal Eps8 protein levels were correlated with the migratory cell potential of human pancreatic cancer cells, indicating that exosomal Eps8 has the potential to be a metastatic biomarker for human pancreatic cancer. PMID- 30431135 TI - In vitro enhancement and functional characterization of neurite outgrowth by undifferentiated adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) can easily be obtained and expanded in vitro for use in autologous cell therapy. Via their production of cytokines and neurotrophic factors, transplanted ASCs provide neuroprotection, neovascularization and induction of axonal sprouting. However, the influencing mechanism of undifferentiated ASCs on nerve regeneration is currently only partially understood. In the present study, undifferentiated ASCs and cutaneous primary afferent dorsal root ganglion (DRG) neurons were co-cultured in order to investigate their interaction. ASCs were isolated from adult rat fat tissue. The presence of characteristic stem cell markers was determined by flow cytometry in three subsequent passages. Adipogenic, osteogenic, chondrogenic and glial differentiation was performed in order to evaluate their differentiation capacity. A direct co-culture system with DRG cells was established to determine the effect of undifferentiated pluripotent ASCs on neurite elongation. Neurite outgrowth, length and number was examined in the co-culture and compared with single-culture cells and cells stimulated with nerve growth factor (NGF). In ASC cultures, NGF expression was assessed by ELISA. The present results demonstrated that the specific mesenchymal stem cell surface markers CD44, CD73 and CD90 were detected in all three subsequent passages of the isolated ASCs. In accordance, ASC differentiation into adipogenic, osteogenic, chondrogenic and Schwann cell phenotype was conducted successfully. Neurite outgrowth of DRG neurons was enhanced following co-culture with ASCs, resulting in increased neurite length after 24 h of cultivation. Furthermore, neurite outgrowth of DRG neurons was directed towards the undifferentiated ASC and direct cell-to-cell contact was observed. In summary, the results of the present study revealed an interaction between the two cell types with guidance of neurite growth towards the undifferentiated ASC. These findings suggest that the use of undifferentiated ASC optimizing tissue-engineered constructs may be promising for peripheral nerve repair. PMID- 30431136 TI - Epigenetic knockdown of Notch1 inhibits hepatitis B virus X protein-induced hepatocarcinogenesis of L02/HBx cells. AB - The present study aimed to investigate the effects of Notch1 on the development of hepatitis B virus X protein (HBx)-induced hepatocarcinogenesis. The L02/HBx cells were transfected with a short hairpin RNA (shRNA) specially targeting Notch1 (Notch1-shRNA). The mRNA and protein expression levels of Notch1 signaling pathway-related molecules (Notch1, Hes1 and NICD) were detected after knockdown of Notch1. The effects of Notch1 knockdown on the proliferation was analyzed by Cell Counting Kit-8 assay, and cell cycle and apoptosis of L02/HBx cells in vitro were investigated by flow cytometry. The in vivo tumor xenograft model was established by subcutaneously injection of mice with Notch1-shRNA or sh-NC transfected cells. The effects of Notch1 knockdown on tumor progression in vivo were then explored by H&E staining and immunohistochemistry. The results showed that knockdown of Notch1 inhibited the activation of the Notch1 signaling pathway. In addition, decreased viability and colony formation ability of L02/HBx cells were detected along with downregulated protein expression levels of Ki-67 and PCNA (proliferating cell nuclear antigen). In addition, knockdown of Notch1 led to L02/HBx cell cycle arrest at G0/G1 phase by decreasing the expression of cyclin D1, CDK4, E2F1 and increasing the expression of p21 and retinoblastoma gene (Rb). Moreover, knockdown of Notch1 promoted the apoptosis of L02/HBx cells by activation of caspase-3 and caspase-9. In vivo experiments demonstrated that knockdown of Notch1 inhibited the tumorigenicity of L02/HBx cells. Our findings revealed that inhibition of the Notch1 signaling pathway may inhibit the development of HBx-induced hepatocellular carcinoma. Notch1 may serve as a promising therapeutic target for HCC. PMID- 30431137 TI - Oncolytic potential of an E4-deficient adenovirus that can recognize the stabilization of AU-rich element containing mRNA in cancer cells. AB - AU-rich elements (AREs) are RNA elements that enhance the rapid decay of mRNA. The fate of ARE-mRNA is controlled by ARE-binding proteins. HuR, a member of the embryonic lethal abnormal vision (ELAV) family of RNA-binding proteins, is involved in the export and stabilization of ARE-mRNA. In the vast majority of cancer cells, HuR constitutively relocates to the cytoplasm, resulting in the stabilization of ARE-mRNA. Previously, we described that the adenovirus gene product, E4orf6, which is necessary for virus replication, participates in ARE mRNA export and stabilization. In the present study, we showed the oncolytic potential of E4orf6-deleted adenovirus dl355, which is expected to be replicated selectively in cancer cells. Virus production and cytolytic activity of dl355 were higher in cancer cells than in normal cells. HuR-depletion downregulated dl355 replication, demonstrating that ARE-mRNA stabilization is required for the production of this virus. Tumor growth was inhibited in nude mice by an intratumoral injection of dl355. Furthermore, dl355 had a stronger oncolytic effect than E1B55k-deleted adenovirus. These results indicate that dl355 has potential as an oncolytic adenovirus for a large number of cancers where ARE-mRNA is stabilized. PMID- 30431138 TI - Functional analysis of the correlation between ABCB11 gene mutation and primary intrahepatic stone. AB - The adenosine 5'-triphosphate binding cassette subfamily B member (ABCB)11 gene is involved in bile transport, and mutations in this gene are associated with cholestasis and cholelithiasis. Therefore, the aim of the present study was to investigate the association between ABCB11 gene mutation and primary intrahepatic stone (PIS)s and to investigate the mechanism through which ABCB11 gene mutations affect the expression of the corresponding protein. Mutations of the ABCB11 gene in 443 PIS patients and 560 healthy participants were detected by exon sequencing. The expression levels of ABCB11 mRNA and bile salt export pump (BSEP) protein in the liver tissues of patients with PISs were measured by quantitative polymerase chain reaction and western blot analysis. The mutant plasmids constructed by site-directed mutagenesis of the human BSEP gene were transfected into human embryonic kidney 293 (293) cells and Madin-Darby canine kidney (MDCK) cells, and the expression and distribution of rs118109635 of BSEP was measured. There were two significant mutations in the ABCB11 gene of the PIS patients compared with the healthy population; a missense mutation, rs118109635 (P=0.025), and a synonymous mutation, rs497692 (P=0.006). The two mutations were associated with the occurrence of preoperative jaundice (P=0.026, and P=0.011, respectively). The expression levels of BSEP in PIS patients with the missense mutation rs118109635 was decreased, whereas its mRNA expression levels remained unchanged. In PIS patients with the synonymous mutation rs497692, the expression levels of ABCB11 were decreased at both the mRNA and protein level. It was also found that mutation A865V reduced the expression levels of BSEP in 293 cells at the cellular level; its distribution in MDCK cell membranes was decreased, whereas its mRNA levels remained unchanged. The mutated loci at rs118109635 and rs497692 of the ABCB11 gene were correlated with PISs, causing a decreased expression of BSEP and reduced distribution of the protein in the cell membrane. Therefore, mutations at rs118109635 and rs497692 of the ABCB11 gene may be risk factors for PISs. PMID- 30431139 TI - Exosomes derived from PM2.5-treated lung cancer cells promote the growth of lung cancer via the Wnt3a/beta-catenin pathway. AB - Fine particulate matter (PM2.5) is associated with an increased lung cancer risk. However, the effect of PM2.5 exposure on lung cancer cells is still largely unknown. The present study revealed that A549 lung cancer cells secreted exosomes containing high levels of Wnt3a after treatment with PM2.5. These exosomes activated beta-catenin signalling in A549 cells. These exosomes exhibited no effects on migration and invasion, but promoted proliferation of A549 cells via the Wnt3a/beta-catenin pathway in vitro. These exosomes promoted A549 tumour progression in a Wnt3a-dependent fashion in vivo. These results demonstrated that PM2.5 has a direct effect on promoting lung tumour development. Inhibition of exosome production by tumour cells or blockade of the Wnt3a/beta-catenin pathway represents a promising strategy to impede PM2.5-mediated lung tumour progression. PMID- 30431140 TI - Reactive oxygen species induced by icaritin promote DNA strand breaks and apoptosis in human cervical cancer cells. AB - Increased production of reactive oxygen species (ROS) is a distinct feature of various types of cancer. ROS drive tumor progression and render cancer cells vulnerable to additional oxidative insult. The various natural herb compounds have been shown to induce additional production of ROS in cancer cells, although the physiological implications of ROS under these conditions are not fully determined. In the present study, icaritin, a natural compound derived from the medicinal plants Epimedium, was demonstrated to potently suppresses the proliferation of human HeLa and SiHa cervical cancer cells, without similar affects on non-cancerous CCD-1095Sk fibroblasts and 293 cells, as measured by MTT and colony formation assays. Icaritin treatment caused a rapid increase in ROS in HeLa and SiHa cells, which was followed by a prominent increase in the number of DNA strand breaks. Consequently, the levels of the pro-apoptotic protein Bax and activated caspase 3 and 9 enzymes were increased, while the levels of the anti apoptotic proteins Bcl-2 and XIAP were downregulated. These protein expression changes were accompanied by marked induction of apoptosis in icaritin-treated cancer cells. The results suggested that the icaritin-induced ROS overload promoted cancer cell death via induction of extensive oxidative DNA damage, which subsequently resulted in large numbers of DNA strand breaks and the activation of the intrinsic apoptotic pathway. PMID- 30431141 TI - Streptolysin O derived from Streptococcus pyogenes inhibits RANKL-induced osteoclastogenesis through the NF-kappaB signaling pathway. AB - Streptococcus pyogenes (GAS) is a clinically significant bacterial strain that causes bacterial arthritis, osteomyelitis and implant infections. Infection complications can lead to serious bone destruction. Osteoclasts, the only type of cell with bone resorption function, participate in this process. Streptolysin O (SLO) is produced by almost all clinical Streptococcus pyogenes isolates. However, the role of SLO in bone infection caused by GAS had not been previously examined. The current study was performed to define the effects of SLO on receptor activator of NF-kappaB ligand-stimulated osteoclast differentiation in vitro. Results demonstrated that SLO decreased the phosphorylation of p65 and NF kappaB inhibitor alpha, suppressed c-FOS and nuclear factor of activated T-cells cytoplasmic 1, and downregulated the expression of osteoclast marker genes. SLO also induced apoptosis of mature osteoclasts. The results suggested that SLO blocked osteoclast activation during GAS infection. These findings may prove useful in the development of novel strategies for treating GAS-associated bone infectious diseases. PMID- 30431142 TI - Hydrogen-rich medium alleviates high glucose-induced oxidative stress and parthanatos in rat Schwann cells in vitro. AB - Diabetic peripheral neuropathy (DPN) is considered to be the most common cause of microvascular diabetic complications, for which no effective therapies currently exist. Previous studies have identified that oxidative stress is the common pathway in all possible hypotheses for the induction of DPN, and poly(ADP-ribose) (PAR) polymerase-1 (PARP-1)-dependent cell death (parthanatos) is key in the pathogenic mechanisms of neurodegenerative disease. The aim of the present study was to investigate the protective effects and corresponding mechanisms of hydrogen-rich medium (HM) on high glucose (HG)-induced oxidative stress and parthanatos in primary rat Schwann cells (RSCs) in vitro. The RSCs were divided into groups and treated for 48 h. Cell counting kit-8 and lactate dehydrogenase assays were used to detect cell viability and cytotoxicity, respectively; intracellular OH- levels were measured using a DCFH-DA assay; concentrations of peroxynitrite (ONOO-) and 8-hydroxy deoxyguanosine (8-OHdG) were evaluated with an enzyme-linked immunosorbent assay; relative expression levels of parthanatos related proteins [PAR, nucleus apoptosis-inducing factor (AIF) and total AIF] were analyzed using western blot analysis, and immunofluorescence was used to determine the nuclear translocation of AIF. After 48 h, HG was shown to induce severe oxidative stress and promote marked levels of parthanatos in the RSCs. Treatment with HM inhibited HG-induced oxidative stress by reducing the production of OH- and ONOO- and suppressed parthanatos by downregulating the levels of 8-OHdG, the expression of PAR and the nuclear translocation of AIF. HM improved cell viability and inhibited cytotoxicity under the HG condition. These results indicate that HM effectively reduces HG-induced oxidative stress in RSCs and protects them against parthanatos. Therefore, HM may be a novel treatment for DPN. PMID- 30431144 TI - Solitary fibrous tumor: an evolving and unifying entity with unsettled issues. AB - Solitary fibrous tumor (SFT) is a distinct fibroblastic neoplasm of intermediate biological potential, prototypically presenting as a pleura-associated tumor characterized by patternless proliferation of generally banal oval to spindle cells with hemangiopericytoma-like staghorn vessels in fibrocollagenous stroma. Over the past decades, the clinicopathological spectrum of SFT has been ever expanding with the incorporation of cases exhibiting myxoid, giant cell containing, and fat-forming histology, as well as those from extrathoracic sites, including the meninx. Atypical, frankly malignant and even dedifferentiated variants have also been recognized in a subset of SFTs. Notably, the recent groundbreaking discovery of the disease-defining NAB2-STAT6 gene fusion, resulting from intrachromosomal inversion involving 12q13.3, has largely unified tumors with the aforementioned variations. The derived immunohistochemical detection of nuclear STAT6 expression has high diagnostic value in distinguishing SFTs from histologic mimics, although some relevant pitfalls have been proposed as a precaution. NAB2-STAT6 fusions yield numerous transcript subtypes associated with the clinicopathological variations. Despite mostly following a favorable course, SFT is notoriously difficult for prognostication because of the propensity for late relapse or even metastases in 10-40% of cases, which prompts several proposed schemes incorporating age, size, mitosis, and/or necrosis as factors for risk stratification. Mitotic figures >4/10 HPFs, TERT promoter and/or TP53 mutations have been considered as variables that are better correlated with aggressiveness. Although radiotherapy and chemotherapy provide unsatisfactory responses, a better understanding of SFT tumorigenesis may pave the way for new treatment modalities. In this review, we comprehensively discuss the recent advances of SFTs in diagnostic and molecular pathology. PMID- 30431143 TI - ERK5-regulated RERG expression promotes cancer progression in prostatic carcinoma. AB - Big mitogen-activated protein kinase 1 [also named extracellular signal-regulated kinase (ERK) 5] is activated by mitogens and oncogenic signals and is strongly implicated in tumorigenesis. Our previous investigation indicated that ERK5 can induce prostatic carcinoma cell proliferation by promoting entry into the S phase of the cell cycle. In the present study, microarray and western blot analysis revealed that ERK5 can inhibit Ras-like oestrogen-regulated growth inhibitor (RERG) protein expression and that the inhibition of RERG expression promotes prostatic carcinoma cell proliferation and migration. In addition, pathological analysis indicated that the RERG expression level was associated with the malignancy of prostatic carcinoma. Furthermore, an apoptotic assay and western blot analysis demonstrated that the downregulation of RERG expression inhibits apoptosis by regulating the protein expression levels of B cell lymphoma-2 and c Myc. Moreover, a luciferase activity assay indicated that the nuclear factor kappaB pathway is associated with RERG-mediated apoptosis in prostatic carcinoma. Therefore, these data suggested that ERK5-regulated RERG expression plays a role in the progression of prostatic carcinoma, indicating that RERG may be a potential biomarker for the prognosis of patients with prostatic carcinoma. PMID- 30431145 TI - The views of consultant dermatologists on creating centralised skin lesion units. AB - The proportion of United Kingdom (UK) specialist dermatology clinical activity related to skin lesions has been estimated at between 40-50%. With skin cancer incidence rising, this is likely to increase even further. In 2014, The King's Fund conducted research to investigate the sustainability of dermatology services, with participants identifying the need for service reconfiguration to improve efficiency. One suggestion was to create consultant-led centralised skin lesion units, receiving all referrals within a region. To the best of our knowledge, there has been no published qualitative research on the organisation of dermatology services, and the views of key stakeholders on service reconfiguration remain unexplored. An independent review following the failed takeover of dermatology services in Nottingham by a private provider concluded that staff must be fully involved in service reconfiguration from the outset. This article is protected by copyright. All rights reserved. PMID- 30431146 TI - Exploring scale validity and measurement invariance of the Toronto Mindfulness Scale across levels of meditation experience and proficiency. AB - OBJECTIVES: The Toronto Mindfulness Scale (TMS) is a widely used instrument of state mindfulness. Research suggests the interpretation and functioning of mindfulness scale items may differ as a function of meditation experience, and thus, establishing invariance across experience levels is essential. METHODS: Five hundred and five meditation practitioners (32.7% male, 33.3% female, and 34.1% unspecified) with an average age of 42.37 years (SD = 12.70) completed the TMS online. RESULTS: Results support at least partial invariance across subgroups based on years of mindfulness meditation experience and self-reported proficiency. Construct validity of the Decentering subscale was also supported; however, the Curiosity subscale did not meet validity expectations, as it required additional model modifications to yield good fit, and means were not sensitive to differences in group experience or proficiency. CONCLUSIONS: Our findings suggest further review of the TMS Curiosity items may be warranted to determine its suitability for use within mindfulness assessment. PMID- 30431147 TI - Unilesional mycosis fungoides is associated with increased expression of microRNA 17~92, and Th1 skewing. AB - BACKGROUND: The molecular basis of unilesional mycosis fungoides (MF), characterized by a solitary lesion which is clinicopathologically indistinguishable from multifocal patch/plaque MF (early MF), is unknown. OBJECTIVES: To investigate the microRNA (miR) profile in unilesional MF distinguishing it from early MF. METHODS: Biopsy samples of unilesional MF and early MF were evaluated with the Affymetrix microRNA array, with further comparison to inflammatory dermatosis, using quantitative polymerase chain reaction. NanoString technology was applied to analyze the gene expression of T helper (Th)1 immune markers and immunohistochemistry was used to evaluate C-X-C motif cytokine receptor 3 (CXCR3) and GATA binding protein 3 (GATA3), markers for Th1 and Th2 cells, respectively. RESULTS: Unilesional MF had a significantly higher level of expression of all members of the miR-17~92 cluster than early MF. Specifically, compared to early MF, unilesional MF was characterized by a higher miR-17 level and inflammatory dermatoses, downregulation of the expression of phosphatase and tensin homolog (Pten) and cAMP response element binding protein 1 (CREB1), known targets of miR 17~92 members, higher gene expressions of interluekin-2 (IL-2), and interferon gamma (IFN-gamma), and statistically lower average percentage of GATA3+ dermal cells (6.7% vs 42.3%, respectively). High immunoreactivity of CXCR3 was noted in both unilesional and early MF. CONCLUSIONS: Unilesional MF exhibits a microRNA profile distinct from conventional early MF, with a higher level of miR-17~92 members along with a Th1 skewing. These findings suggest a robust reactive T-cell immune response in unilesional MF and might account for the localized nature of this disease. This article is protected by copyright. All rights reserved. PMID- 30431148 TI - Cross-sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation. AB - BACKGROUND: Cutaneous viral infections and immune suppression are risk factors for some forms of non-melanoma skin cancer (NMSC), however, their interrelationship is poorly understood. OBJECTIVE: To examine cross-sectional associations between cutaneous viral infections and circulating forkhead-box P3 (FOXP3) expressing T regulatory (Treg) cells, suppressive cells that dampen effective anti-tumour immunity. METHODS: Blood, eyebrow hair (EBH) and skin swab samples (SSW) were collected from 352 skin screening patients 60 years and older without prevalent skin cancer participating in an ongoing prospective cohort study of cutaneous viral infections and skin cancer. DNA corresponding to 98 cutaneous human papillomavirus (HPV) types and five polyomaviruses (HPyV) was assessed in EBH and SSW. Distinct classes of circulating Treg cell subpopulations were defined by flow cytometry including cutaneous lymphocyte antigen (CLA) and CCR4high Treg cells, both previously associated with cutaneous diseases. Age- and gender-adjusted associations between circulating T-cell populations and infection were estimated using logistic regression. RESULTS: Total Treg cell proportion in peripheral blood was not associated with beta HPV or HPyV infection. However, the proportion of circulating CLA+ Treg cells was inversely associated with gamma HPV EB infection (OR= 0.54, 95% CI=0.35-0.84). Interestingly, circulating Treg cells expressing markers indicative of antigen activation (CD27- CD45RA- FOXP3+ CD4+ ) were also inversely associated with gamma HPV infection in SS (OR=0.55, 95% CI=0.30-0.99) and EB (OR=0.56, 95% CI=0.36-0.86). CONCLUSIONS: Inverse associations between circulating Treg cells and gamma HPV infection suggest that localised viral infection may promote immunosuppressive cell migration into skin. This article is protected by copyright. All rights reserved. PMID- 30431149 TI - Reproduction, fear of childbirth and obstetric outcomes in women treated for fear of childbirth in their first pregnancy: A historical cohort. AB - INTRODUCTION: About 8% of the pregnant women in Sweden receive counseling for fear of childbirth (FOC) during pregnancy. Little is known about the long-term reproductive and obstetric outcomes after counseling for FOC: Therefore, the objective of this historical cohort study was to compare the long-term reproductive and obstetric outcomes in women treated for FOC in their first pregnancy to women without FOC. MATERIAL AND METHODS: All nulliparas consecutively referred for treatment of severe FOC between 2001 and 2007 (n = 608) were compared with all other nulliparas giving birth on the same day (n = 431). Women who were not fluent in Swedish, missing a postal address, had moved out of the area, given birth at another hospital or had a late spontaneous abortion were excluded (n = 555). A total of 235 women agreed to participate in the study, 63 (39%) women in the index group and 172 (53%) in the reference group. The women were contacted by letter in 2015, ie 7-14 years after first childbirth, and asked to permit access to their medical charts from pregnancies and childbirths and to fill out a study specific questionnaire. Based on data from the medical charts and questionnaire, the mode of delivery, birth experience, obstetric complications, FOC, counseling for FOC and number of childbirths were compared in the two groups. RESULTS: Women in the index group less often gave birth more than twice compared with the reference group (8.2% vs 22.0%, P = 0.012). We found no significant differences in complications during subsequent pregnancies and deliveries. Women in the index group more often gave birth by CS in their first (P = 0.002) and second childbirth (P = 0.001), more often had a less positive birth experience (index group NRS: median 6.0, interquartile range 6 vs reference group NRS: 7.0, interquartile range 5, P = 0.004) in their first delivery and more often received counseling for FOC (58.7% vs 12.5%, P < 0.001) in subsequent pregnancies. Women in the index group more often experienced FOC (18% vs 5.3%, P = 0.001) 7-14 years after first childbirth. CONCLUSIONS: FOC is not easily treated. Despite treatment and exposure to childbirth many women received treatment in their next pregnancy and still suffered from FOC 7-14 years after the first childbirth. PMID- 30431150 TI - Heterogeneity of PD-L1 Expression in a Case of Merkel Cell Carcinoma Exhibiting Complete Regression After Multiple Metastases. AB - Merkel cell carcinoma (MCC) is a highly malignant skin cancer with a propensity for local recurrence and regional lymph node metastases. Once recurrence occurs, tumour progression becomes hard to be controlled. Overexpression of programmed death-ligand 1 (PD-L1) in MCC correlates with better clinical outcomes, in contrast to other solid carcinomas, e.g., malignant melanoma. The successful results of treatment with the immune checkpoint inhibitor avelumab for metastatic MCC highlight this unusual relationship between MCC and PD-L1 expression. This article is protected by copyright. All rights reserved. PMID- 30431151 TI - The Quality of Reporting Randomised Controlled Trials in the Dermatology Literature in an Era where the CONSORT Statement is a Standard. AB - BACKGROUND: The quality of reporting randomised controlled trials (RCTs) in the dermatology literature has not received much consideration since the late 2000s. OBJECTIVES: We aimed to assess the quality of recently reported RCTs published in dermatology journals, focusing on randomisation processes, blinding, and trial registration. METHODS: We reviewed 2,042 original articles and identified 141 primary reports of RCTs in four dermatology journals (The Journal of the American Academy of Dermatology, JAMA Dermatology, The Journal of Investigative Dermatology, and The British Journal of Dermatology) from January 2015 to December 2017. Details were extracted from articles, supplements, and public trial registries. A multivariable logistic regression analysis was conducted to identify factors associated with optimal reporting quality. RESULTS: Among the 141 RCTs, 99 (70.2%), 82 (58.2%), and 69 (48.9%) RCTs described methods used for randomisation, allocation concealment, and implementation, respectively. Most trials (n = 126, 89.4%) reported blinding status; however, one-third did not state similarity of intervention. Furthermore, 52 (36.9%) RCTs were not registered prospectively. Trials published in The British Journal of Dermatology and using central randomisation were significantly associated with optimal reporting quality after adjusting for covariates. CONCLUSIONS: Several critical items in reporting RCTs, including allocation concealment, similarity of interventions in blinded trials, or prospective trial registration have remained unsatisfactory in the recent dermatology literature. This article is protected by copyright. All rights reserved. PMID- 30431152 TI - Latent profile analysis exploring potential moral injury and posttraumatic stress disorder among military veterans. AB - OBJECTIVES: Theoretical support for the moral injury (MI) construct is mounting, yet empirical support has lagged behind. A conceptual model has been proposed, but studies have not yet explored the constellation of symptoms within treatment seeking Veterans. METHODS: Veterans (N = 212) seeking trauma recovery services completed measures of potential MI symptoms that functioned as indicators in person-centered Latent Profile Analysis. Differences in exposure to potentially morally injurious experiences (pMIEs) were compared across profiles using logistic regression. RESULTS: Three profiles emerged that varied by symptom severity, levels of trauma-related guilt, and levels of dispositional forgiveness. Exposure to pMIEs predicted membership in a class consistent with proposed MI symptomatology. CONCLUSIONS: Person-centered approaches are useful for identifying a distinct group of veterans whose trauma recovery may benefit from specifically targeting moral emotions, consistent with the emerging construct of MI . PMID- 30431153 TI - Prostacyclin: A major prostaglandin in the regulation of adipose tissue development. AB - Prostaglandins (PGs) belong to the group lipid mediators and can act as local hormones. They contain 20 carbon atoms, including a 5-carbon ring, and are biosynthesized from membrane phospholipid derived arachidonic acid through the arachidonate cyclooxygenase (COX) pathway with the help of various terminal synthase enzymes. Prostacyclin (prostaglandin I2 ) is one of the major prostanoids produced with the help of prostacyclin synthase (prostaglandin I2 synthase) enzyme and rapidly hydrolyzed into 6-keto-PGF1alpha in biological fluids. Obesity indicates an excess of body adiposity, which is globally considered as one of the major health disasters responsible for developing complex pathological situations in the human body. Adipose tissues can produce various PGs, and thus, the level and the molecular activity of these endogenously synthesized PGs are considered critical for the development of obesity. In this regard, the involvement of prostacyclin in adipogenesis has been studied in the last few decades. The current review, along with the background of other related PGs, presents the several molecular aspects of endogenous prostaglandin I2 in adipose tissue development. Especially, the regulation of life cycle of adipocytes, impact on terminal differentiation, activity through prostacyclin receptor (IP), autocrine-paracrine manner, thermogenic adipose tissue remodeling and some future experimental aspects of prostacyclin have been focused upon in this study. This discussion might assist to develop new drug molecules acting on the signaling pathways of prostacyclin and devise therapeutic strategies for treating obesity. PMID- 30431154 TI - Blood transfusion following intended vaginal birth after cesarean versus elective repeat cesarean section in women with a prior primary cesarean: A population based record linkage study. AB - INTRODUCTION: There is a lack of evidence around the risk of transfusion following vaginal birth after cesarean (VBAC) compared to elective repeat cesarean section (ERCS); this is important for decision-making about birth options. The aim of this study was to determine transfusion rates and risk of transfusion following intended VBAC and ERCS. MATERIAL AND METHODS: Women with a primary cesarean, who had a subsequent birth at term (>=37 weeks) in New South Wales between 2000 and 2012, were identified from the New South Wales Perinatal Data Collection. Blood transfusions were identified from linked hospital records. Women deemed ineligible for VBAC were excluded. Modified Poisson regression was used to determine transfusion risk associated with intended VBAC compared to ERCS. Intended mode of birth was classified as: 1) intended VBAC and vaginal birth, 2) intended VBAC and cesarean, 3) intended ERCS, and 4) 'intention uncertain'. RESULTS: 90,439 women were eligible for VBAC. Rates of transfusion were: 1.4% for intended VBAC and vaginal birth (n=17,849), 1.2% for intended VBAC and cesarean (n=7,648), 0.3% for intended ERCS (n=60,471), and 1.1% for 'intention uncertain' (n=4,471). After adjusting for maternal and pregnancy characteristics, risk of transfusion was almost four times higher for women classified as intended VBAC compared to intended ERCS (adjusted risk ratio=3.73, 95% CI; 2.90 to 4.78). CONCLUSIONS: Following a prior primary cesarean, there was a higher risk of transfusion associated with attempting VBAC compared to ERCS. Though the absolute risk is small, it is important women considering VBAC choose birthing facilities with ready access to blood products. This article is protected by copyright. All rights reserved. PMID- 30431155 TI - Antihelix/helix violaceous macules in Japanese patients with anti-melanoma differentiation-associated protein 5 (MDA5) antibody-associated dermatomyositis. AB - The diagnosis of clinically amyopathic dermatomyositis (CADM) essentially depends on cutaneous manifestations. The early diagnosis of CADM associated with the anti melanoma differentiation-associated protein-5 (MDA5) antibody is especially important because it includes a subset of patients highly at risk for rapidly progressive interstitial lung disease (RP-ILD) with potentially fatal outcomes. Moreover, the recognition of distinctive rashes for anti-MDA5 antibody-positive DM can greatly aid in distinguishing from other DM subsets since serological anti MDA5 antibody testing is not yet widely accessible. This article is protected by copyright. All rights reserved. PMID- 30431156 TI - Beyond accessing information: Claiming to understand in child social welfare interviews. AB - The present article investigates how people manage understanding of personal experiences in an institutional setting in which shared understanding of one party's experience can become an issue at stake: social welfare interviews with child victims of abuse. New recommendations on how to respond to child interviewees limit interviewers' support to experiences of which they have direct access. Using conversation analysis and discursive psychology to examine cases in which interviewers respond to children's reports of experiences by claiming to understand, the current article shows that interviewers primarily use such claims after interviewees have indicated that the interviewer may not understand. By claiming to understand, interviewers orient to a difference between an interview requirement - not assuming they know the children's specific experiences - and their ability to interpret the children's situations. The study shows how interviewers use claims of understanding to distinguish themselves as understanding persons from their information-eliciting approach as social welfare investigators. Findings contribute to social psychological research on how people manage challenges related to eliciting and recognizing experience in interaction. In particular, the study offers research on interviews with child victims of abuse a new angle on the tension between information elicitation and support. PMID- 30431157 TI - Beyond concept analysis: Uses of mind mapping software for visual representation, management, and analysis of diverse digital data. AB - Mind mapping is a visual-spatial method of representing information using nodes (information segments) to show ideas and connecting lines to define relationships between content. As a critical thinking tool, it is applicable to a range of research activities, including information management, project development, and data analysis. The purposes of this manuscript are to describe the use of mapping for qualitative data analysis, provide step-by-step instructions of how to construct mind maps, and present examples specific to qualitative data analysis. An example from a recent study of patient and provider perceptions of virtual visits demonstrates the use of Xmind in conjunction with Atlas.ti for qualitative content analysis of open-ended survey data. While coding in Atlas.ti, we used Xmind to develop dynamic memos, code networks, and themes. The memo map served to identify common coding patterns and informed subsequent coding stages. After coding in Atlas.ti, the entire code list was imported into a new map in Xmind and iteratively organized to identify conceptual groupings, similarities/differences, and key ideas. Themes were identified through pattern coding and refining code networks within the Xmind map. Map iterations formed part of the analytic trail and facilitated peer-to-peer discussions. The final map served as the model for publication. The use of mind mapping enhanced the rigor, credibility, and transparency of analyses and facilitated peer-to-peer communication. This technique can be used to manage diverse content (documents, audio/video file, image, web links, and personal notes) and thus has great potential to contribute to a variety of data management tasks. PMID- 30431158 TI - Increased alpha2delta-1-NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy-induced neuropathic pain. AB - Painful peripheral neuropathy is a severe and difficult-to-treat neurological complication associated with cancer chemotherapy. Although chemotherapeutic drugs such as paclitaxel are known to cause tonic activation of presynaptic NMDA receptors (NMDARs) to potentiate nociceptive input, the molecular mechanism involved in this effect is unclear. alpha2delta-1, commonly known as a voltage activated calcium channel subunit, is a newly discovered NMDAR-interacting protein and plays a critical role in NMDAR-mediated synaptic plasticity. Here we show that paclitaxel treatment in rats increases the alpha2delta-1 expression level in the dorsal root ganglion and spinal cord and the mRNA levels of GluN1, GluN2A, and GluN2B in the spinal cord. Paclitaxel treatment also potentiates the alpha2delta-1-NMDAR interaction and synaptic trafficking in the spinal cord. Strikingly, inhibiting alpha2delta-1 trafficking with pregabalin, disrupting the alpha2delta-1-NMDAR interaction with an alpha2delta-1 C terminus-interfering peptide, or alpha2delta-1 genetic ablation fully reverses paclitaxel treatment induced presynaptic NMDAR-mediated glutamate release from primary afferent terminals to spinal dorsal horn neurons. In addition, intrathecal injection of pregabalin or alpha2delta-1 C terminus-interfering peptide and alpha2delta-1 knockout in mice markedly attenuate paclitaxel-induced pain hypersensitivity. Our findings indicate that alpha2delta-1 is required for paclitaxel-induced tonic activation of presynaptic NMDARs at the spinal cord level. Targeting alpha2delta 1-bound NMDARs, not the physiological alpha2delta-1-free NMDARs, may be a new strategy for treating chemotherapy-induced neuropathic pain. This article is protected by copyright. All rights reserved. PMID- 30431159 TI - GLUT6 is a lysosomal transporter that is regulated by inflammatory stimuli and modulates glycolysis in macrophages. AB - The solute carrier family is an important protein class governing compound transport across membranes. However, some of its members remain functionally unidentified. We analyzed ChIP-seq data for the NF-kappaB family transcription factor RelA and identified GLUT6 as a functionally uncharacterized transporter that putatively works in inflammatory responses. Inflammatory stimuli increase GLUT6 expression level, although GLUT6-knockout mice exhibit a subtle phenotype to lipopolysaccharide administration. Metabolomics and in vitro analyses show that GLUT6 functions as a glycolysis modulator in inflammatory macrophages. GLUT6 does not mediate glucose uptake and is localized on lysosomal membranes. We conclude that GLUT6 is a lysosomal transporter that is regulated by inflammatory stimuli and modulates inflammatory responses by affecting the metabolic shift in macrophages. PMID- 30431160 TI - Postpartum depression symptoms among Syrian refugee women living in Jordan. AB - Postpartum depression (PPD) is recognized as a common maternal health problem, but few studies have investigated the postpartum mental health of refugee women. In this cross-sectional study, we investigated the prevalence of PPD symptoms and associated factors among Syrian refugee women living in north Jordan. Women (N = 365) were recruited from four health care centers in Ramtha and Jarash, cities in northern Jordan. Participants completed a demographic data form, the Edinburgh Postnatal Depression Scale (EPDS), and the Maternal Social Support Scale at 6-8 weeks postpartum. Half (49.6%; n = 181) of the Syrian refugee women scored >12 on the EPDS. PPD symptoms were significantly associated with low social support, low monthly income, and recent immigration (less than 2 years). There is a high level of PPD symptoms among Syrian refugee women, many of whom are living in poverty and with limited social support. The results highlight the need for immediate action by governments to support childbearing refugee women with early screening for psychosocial risk and respond to women's physical and mental health, and social needs through interservice collaboration. Social support programs would meet an important need for these women, as would ongoing assessment by health professionals and early intervention for women who screen positive for PPD. PMID- 30431162 TI - Irregular complex tachycardia in a 42-year-old man: What is the mechanism? PMID- 30431161 TI - Eomesodermin controls a unique differentiation program in human IL-10 and IFN gamma coproducing regulatory T cells. AB - Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-gamma/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4+ T-cell subsets, including conventional cytotoxic CD4+ T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-gamma and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4+ T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-gamma, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes+ GzmK+ T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4+ Eomes+ T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes+ Tr1-like cells are effector cells of a unique GzmK-expressing CD4+ T-cell subset. PMID- 30431163 TI - Rescue therapy for hypercapnia due to high peep mechanical ventilation in patients with ARDS and renal failure. AB - Extracorporeal removal of carbon dioxide in patients experiencing severe hypercapnia due to lung protective mechanical ventilation was first described over four decades ago. There have been many devices developed and described in the interim, many of which require additional training, resources and staff. This manuscript describes a readily available and relatively simple adjunct that can provide partial lung support in patients with acute respiratory distress syndrome complicated by severe hypercapnia and acute kidney injury requiring dialysis. This article is protected by copyright. All rights reserved. PMID- 30431165 TI - Teaching Images in Headache: Thrombosis of Posterior Communicating Artery Aneurysm. PMID- 30431166 TI - Effects of object-to-detector distance and beam energy on synchrotron radiation phase-contrast imaging of implanted cochleae. AB - OBJECTIVES: To demonstrate that synchrotron radiation phase-contrast imaging (SR PCI) can be used to visualize the intrascalar structures in implanted human cochleae and to find the optimal combination of the parameters object-to-detector distance (ODD) and beam energy (E) for visualization. MATERIALS AND METHODS: Three cadaveric implanted human temporal bones underwent SR-PCI with varying combinations of parameters ODD (3, 2 and 1 m) and E (47, 60 and 72 keV). All images were then reconstructed to a three-dimensional (3D) stack of slices. The acquired 3D images were compared using contrast-to-noise ratios (CNRs) of the basilar membrane ( RESULTS: SR-PCI with computed tomography reconstruction provided good visualization of the anatomical features of the implanted cochleae, specifically the exact location of the electrode with respect to the BM. A single factor ANOVA revealed a significant difference of variance for both CNRE and CNRBM , but failed to show significance for CONCLUSIONS: The results of this study show that SR-PCI is a viable method to visualize implanted human cochleae. SR-PCI is less invasive, less labour intensive and is associated with a much lower acquisition time compared to other methods for postimplantation imaging in humans, such as histological sectioning. We found that the optimal combination of E and ODD parameters was 72 keV and 2 m, respectively. These parameters resulted in high-contrast images of the electrode as well as all internal structures of the cochleae. LAY DESCRIPTION: Cochlear implants (CI) are currently the preferred method of treatment for hearing loss. Cochlear implantation surgery involves placement of a metallic, wire-shaped electrode inside the cochlea, the main organ of the human hearing system. Knowledge of the exact location of the electrode after implantation is beneficial in improving the extent of restored hearing. Common clinical imaging modalities such as computed-tomography (CT) are not ideal for providing such information, due to lack of resolution and streaking caused by the metallic electrode. Recent studies have developed algorithms to extract the electrode location from clinical computed-tomography images and have been validated using histology or micro computed-tomography (micro-CT). Synchrotron radiation phase contrast imaging (SR-PCI) is a high-resolution imaging technique used to visualize small structures in three dimensions. Recently, SR-PCI has been shown to be an alternative to histology or micro-CT for imaging the human cochlea. However, it has not been optimized for imaging implanted human cochleae. The main objective of the present work was to find the optimal organization of imaging parameters (i.e., object-to-detector distance and beam energy) for using SR-PCI to image implanted human cochleae. Three cadaveric human cochleae were imaged using five different combinations of imaging parameters at the Canadian Light Source Inc., Saskatoon, SK, Canada. The resulting images were compared both quantitatively and qualitatively. An optimal combination of parameters was found to produce high-contrast images of the both the CI electrode and all internal structures of the cochlea with minimal streaking. SR-PCI is therefore a viable alternative to histological or micro-CT studies for post-surgical imaging of implanted human cochleae. PMID- 30431168 TI - Why the Submarine Alkaline Vent is the Most Reasonable Explanation for the Emergence of Life. PMID- 30431167 TI - First Bite Syndrome After Trigeminal Radiosurgery: Case Report and Pathophysiology. PMID- 30431169 TI - Community social capital and individual functioning in the post-disaster context. AB - Disasters can have severe and long-lasting consequences for individuals and communities. While scholarly evidence indicates that access to social support can ameliorate their negative impacts, less understood is whether or not neighbourhood social capital can facilitate recovery. This study uses two waves of survey data-collected before and after a significant flood in Brisbane, Australia, in 2011-to examine the relationship between the severity of the event at the individual and neighbourhood level, access to neighbourhood social capital and individual-level social support, and functioning in the post-disaster environment. In line with previous research, the results indicate that the severity of the flood is the most salient predictor of post-disaster functioning. No evidence was unearthed to show that neighbourhood social capital amassed before the flood leads to better functioning subsequently, but the findings do suggest that individual-level social support can moderate the effect of flood severity on functioning. PMID- 30431170 TI - Duration of Postoperative Immobilization Affects MMP Activity at the Healing Graft-Bone Interface: Evaluation in a Mouse ACL Reconstruction Model. AB - Excessive MMP activity may impair tendon-to-bone healing. However, little is known about the effect of joint motion on MMP activity after ACL reconstruction. The aim of this study was to determine the effect of different durations of knee immobilization on MMP activity in a mouse ACL reconstruction model using a fluorescent MMP probe which detects MMP 2,3,9 and 13 and near-infra red in-vivo imaging. Sixty C57BL male mice underwent ACL reconstruction. Post-operatively, the animals were treated with free cage activity (Group 1), or with the use of an external fixator to restrict knee motion and weight bearing for 5 days (Group 2), 14 days (Group 3), and 28 days (Group 4). At days 3, 7, 16, 23 and 30, 5 mice underwent IVIS imaging. At days 3, 7, 16, and 30, histological analysis was also performed. Probe signal intensity in the whole limb peaked at day 7, followed by a decrease at day 16, and maintenance up to day 30. There was no significant difference among groups at any time point based on IVIS, but histologic localization of MMP probe signal showed significantly less activity in Group 2 and Group 3 compared to Group 4 in the bone tunnel at day 30. We demonstrated that short-term immobilization led to less MMP activity around the bone tunnel compared with prolonged immobilization. A short period of immobilization after ACL reconstruction might enhance graft-bone interface healing by mitigating excess MMP expression. These findings have implications for post-operative rehabilitation protocols following ACL reconstruction. This article is protected by copyright. All rights reserved. PMID- 30431171 TI - Assessment of combined fractional CO2 and tranexamic acid in melasma treatment. AB - BACKGROUND: Melasma continues to be a disease that is difficult to treat with no fully satisfactory results. The role of a fractional CO2 laser in its treatment is controversial. The addition of tranexamic acid (TXA) might be helpful. OBJECTIVES: To assess the efficacy of a low-power fractional CO2 laser alone versus its combination with tranexamic acid used either topically or intradermally for melasma treatment. METHODS: A randomized comparative split-face study included a total of thirty female patients with bilateral, symmetrical melasma. The whole face was subjected to treatment via a low-power (12 Watts) fractional ablative CO2 laser. One side was randomly assigned to topical application of tranexamic acid solution after the session immediately or intradermal microinjection of tranexamic acid prior to the laser session. Sessions were conducted every 4-6 weeks for five consecutive sessions. Assessments were done using the melasma area severity index MASI score, melanin index (MI), and erythema index (EI) before sessions and 2 weeks after the final session. RESULTS: After treatment, there was significant reduction in the MASI score on both sides of the face; the side treated with the fractional CO2 laser alone and the side treated with fractional CO2 laser combined with TXA (topically or intradermal injection) (P-values 0.007, <0.001, and 0.016, respectively). MI was significantly lower on the side receiving fractional CO2 laser alone and the side receiving fractional CO2 laser combined with intradermal injection of TXA (P values <0.001 and 0.003, respectively), while the EI showed significant improvement only on the side receiving fractional CO2 laser alone (P-value = 0.023). Although patients reported no differences in improvement on either treated side, the degree of improvement regarding the MASI score was better on the side receiving fractional CO2 laser alone. Regarding MI, the degree of improvement was higher on the side receiving fractional CO2 laser combined with intradermal injection of TXA than on the side receiving fractional CO2 laser alone; however, this improvement did not reach statistical significance. Minimal complications occurred in the form of mild pain. CONCLUSION: A low-power fractional CO2 laser is an effective, safe treatment for melasma. However, the addition of tranexamic acid (either topically or intradermally) to a fractional CO2 laser should be further studied. Lasers Surg. Med. (c) 2018 Wiley Periodicals, Inc. PMID- 30431172 TI - Cardiorespiratory effects of variable pressure thoracic insufflation in cats undergoing video-assisted thoracic surgery. AB - OBJECTIVE: To evaluate the effects of intrathoracic insufflation on cardiorespiratory variables and working space in cats undergoing video-assisted thoracic surgery. STUDY DESIGN: Prospective randomized study. ANIMALS: Six healthy cats. METHODS: Cats were anesthetized using a standardized protocol. A Swan-Ganz catheter was positioned in the pulmonary artery under fluoroscopic guidance for measurement of cardiac output. Intrathoracic pressures (ITP) of 0 (baseline), 3, and 5 mm Hg were induced with CO2 and maintained for 30 minutes. Statistical comparison of cardiorespiratory variables was performed. After the procedures, all cats were recovered from anesthesia. Videos of thoracic working space at each ITP level were scored in a blinded fashion by 3 board-certified surgeons using a numerical scale from 0-10. RESULTS: All cats tolerated insufflation with 3 and 5 mm Hg for 30 minutes without oxygen desaturation, although ventilatory levels had to be increased substantially to maintain eucapnia and oxygenation. Cardiac index was not significantly different from baseline after 30 minutes at 3 mm Hg but was significantly lower after 30 minutes at 5 mm Hg compared with 3 mm Hg. Oxygen delivery was unaffected by 3 or 5 mm Hg compared with baseline. Scores for working space increased between baseline and 3 and 5 mm Hg but were not different between 3 and 5 mm Hg. CONCLUSION: CO2 insufflation to 5 mm Hg seems well tolerated in healthy cats, provided ventilatory settings are substantially increased as ITP increases. CLINICAL SIGNIFICANCE: Thoracic CO2 insufflation of 3 mm Hg in cats during video-assisted thoracic surgery is associated with less hemodynamic perturbation than 5 mm Hg insufflation and may provide the benefit of improved working space compared with baseline. PMID- 30431173 TI - Opioid prescribing practices and medication use following urogynecological surgery. AB - BACKGROUND: Opioid abuse is a growing epidemic in the United States, with opioid overdose becoming a leading cause of death. There is wide variation in prescription practices for post-operative opioids due to absence of guidelines. The purpose of this study is to examine postoperative opioid prescribing patterns after urogynecologic surgery and determine usage and management of opioid pills by patients. MATERIALS AND METHODS: This is an observational, prospective study of female patients (N = 143) who underwent urogynecologic (prolapse or incontinence) surgery from June to December 2017 at a single academic center. Patients were surveyed regarding their pain medication use 30 days postoperatively. Survey questions included preoperative pain medication use, quantity of opioid pills consumed, need for additional opioid prescription, and management of remaining pills. T-test and one-way Anova were used for comparison of continuous variables and chi-squared test used for comparison of categorical variables. RESULTS: Of 143 eligible patients, 99 (69%) responded; 62% of respondent patients underwent vaginal surgery, 22% abdominal surgery with or without vaginal surgery, and 15% underwent other procedures. Postoperatively, 81.8% of patients were prescribed opioids. The average number of tablets prescribed ranged from 12.4 to 17.4 depending on the procedure. 54.3% of patients reported using less than half of their prescribed opioid prescription. Of the patients who had excess opioid tablets, only 8.6% reported discarding their opioids. CONCLUSION: To date, no guidelines exist on prescribing opioids postoperatively. Opioids are overprescribed post-operatively with over half of patients using less than half of the opioids prescribed to them. PMID- 30431174 TI - Soft tissue cutting efficiency by 980 nm laser with carbon-, erbium-, and titanium-doped optothermal fiber converters. AB - OBJECTIVES: The use of near-IR diode lasers for contact soft tissue surgery is attended by a risk of severe thermal damage of surrounding tissues due to the low cutting efficiency of these lasers. To increase the cutting efficiency of a near IR lasers in contact surgery special tips (converters) which transform laser light to heat are used. The present in vivo study evaluated temperature dynamics and soft tissue cutting efficiency of 980 nm diode laser equipped with standard carbon- and novel erbium- and titanium-doped converters. MATERIALS AND METHODS: For in vitro treatment on soft tissue (chicken thigh), 980 nm diode laser was used. The radiation was delivered to the tissue by a quartz fiber with a core diameter of 400 +/- 5 um. The carbon-, erbium-, or titanium-doped converters were mounted at the fiber distal end. The converters temperature was measured by IR sensor integrated into the laser radiation delivery system. The temperature dynamics of each converter during soft tissue treatment was evaluated. The converter was in contact with the soft tissue surface and moved across the surface of soft tissue with a speed of 1, 3, or 6 mm/s. The average power of laser radiation was 0.3, 1.0, or 4.0 W. The collateral thermal damage of treated soft tissues was evaluated using NTBC stain. The width and depth of coagulation and ablation zones of laser wounds was determined. The soft tissue cutting efficiency with different converters was calculated. RESULTS: The cutting efficiency, collateral damage, and converter temperature in contact with soft tissue change depending on the type of converter, the power of laser radiation and the converter movement speed along the tissue surface. Maximal converter temperature (1,980 +/- 154 degrees C), at which a tissue cut takes place, was fixed for Ti-doped converter for laser power of 4.0 W and movement speed of 1 mm/s. Minimal converter temperature (540 +/- 30 degrees C), at which a tissue cut takes place, was fixed for Ti-doped converter for laser power of 1.0 W and movement speed of 6 mm/s. Maximal depth of coagulation (0.72 +/- 0.10 mm) was fixed for Ti-doped converter for laser power of 4.0 W and movement speed of 1 mm/s. Minimal depth of coagulation (0.11 +/- 0.02 mm) was fixed for C-doped converter for laser power of 0.3 W and movement speed of 3 mm/s. Maximal cutting efficiency (0.57 mm3 /W) was fixed for Er-doped converter for laser power of 1.0 W and movement speed of 1 mm/s. Minimal cutting efficiency (0.02 mm3 /W) was fixed for C-doped converter for laser power of 4.0 W and movement speed of 6 mm/s. CONCLUSION: All three studied types of converters can be used for contact surgery of soft tissues by 980 nm diode laser. Er-doped and Ti-doped converters are more resistant to laser heating then C-doped converter, they dissect soft tissue more effectively. This will also expand the potential of everyday routine clinical procedures, making them safer, faster, and easier. These converters can be used in general surgery, plastic surgery, dermatology, angioplasty, dentistry, neurosurgery, etc. Lasers Surg. Med. 9999:1-16, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 30431175 TI - The presbycardia phenotype: Cardiac remodeling and valvular degeneration in nonagenarians. AB - BACKGROUND: Nonagenarians (NON) are a growing segment of the population and have a high prevalence of cardiac disease. Many findings encountered on their echocardiograms are also found in younger individuals with valvular or myocardial disease. Therefore, the purpose of this study was to describe this distinct echocardiographic phenotype. METHODS: We identified our study population by querying our echo database to identify unique septuagenarians (SEPT) and nonagenarians (NON) who underwent a transthoracic echocardiogram (TTE) from January 1, 2010 to December 31, 2014. Exclusion criteria were LVEF < 50%, any akinetic wall segment, aortic stenosis, moderate-severe AR and/or severe MR, coronary revascularization within 60 days of study echo, and prior valve surgery. RESULTS: The mean age of SEPT was 73.0 +/- 2.0 and NON was 92.0 +/- 2.1 (P < 0.001). There was no gender difference between groups. NON had significantly smaller LV end-diastolic diameters than SEPT (41.6 +/- 5.7 mm vs 48.0 +/- 7.0 mm, P < 0.001). NON had a greater relative wall thickness (0.51 +/- 0.10 vs 0.40 +/- 0.08, P < 0.001) and more frequently had concentric remodeling or hypertrophy. NON had higher E/Ea ratios and estimated LA pressures (P < 0.01). 48% of NON had moderate-severe mitral annular calcification compared to 25.0% of SEPT (P < 0.01). CONCLUSIONS: Herein, we provide the first comprehensive echocardiographic description of 'presbycardia'; concentric LVH, asymmetric septal hypertrophy, mitral and aortic valve calcification, and increased epicardial fat thickness. This pattern of findings may be increasingly seen as the population ages. PMID- 30431176 TI - A method to correct background phase offset for phase-contrast MRI in the presence of steady flow and spatial wrap-around artifact. AB - PURPOSE: Background phase offsets in phase-contrast MRI are often corrected using polynomial regression; however, correction performance degrades when temporally invariant outliers such as steady flow or spatial wrap-around artifact are present. We describe and validate an iterative method called automatic rejection of temporally invariant outliers (ARTO), which excludes these outliers from the fitting process. METHODS: The ARTO method iteratively removes pixels with large polynomial regression errors analyzed by a Gaussian mixture model fitting of the residual distribution. A total of 150 trials of a simulated phantom (75 with wrap around artifact) and 125 phase-contrast MRI cines from 22 healthy subjects (48 with wrap-around artifact) were used for validation. Background phase offsets were corrected using second-order weighted regularized least squares (WRLS) with and without ARTO. Flow volumes after WRLS and WRLS+ARTO corrections were compared with the known truth (phantom) and stationary phantom reference (in vivo) using Bland-Altman analysis. The ratio between the pulmonary flow and the systemic flow was also computed in a subset of 6 subjects. RESULTS: In the simulated phantom, compared with WRLS and no correction, correction with WRLS+ARTO produced superior agreement in volumetric flow quantification with the known truth. In vivo, WRLS+ARTO also produced superior agreement with stationary phantom-corrected volumetric flow compared with WRLS and no correction. In data sets with wrap around artifact, WRLS produced significantly larger variance in the pulmonary flow and systemic flow ratio than stationary phantom correction (P = .0008). CONCLUSION: The proposed method provides automatic exclusion of temporally invariant outliers and produces flow quantification results comparable to stationary phantom correction. PMID- 30431177 TI - Challenges to mobilising resources for disaster recovery and reconstruction: perspectives of the Haitian diaspora. AB - Diasporas and diaspora non-governmental organisations (NGOs) are increasingly important as resource lifelines to their home countries, yet the resources that they mobilise, the types of challenges that they face, and their coping mechanisms are not well explored or understood in the context of disaster recovery. To fill this knowledge gap, this study employed an inductive qualitative methodological approach, using interviews to comprehend the role played by Haitian diaspora NGOs after the catastrophic earthquake in 2010. It found that resources take four common forms: event fundraisers; financial and material donations from supporters; remittances; and volunteer labour. Challenges include an overreliance on diaspora donors, competition among NGOs, and what is perceived as inequitable funding practices towards diaspora NGOs. The findings provide insights centred on better coordination among diaspora NGOs, as well as between diaspora NGOs and other local and international NGOs and local governments and international institutions, to ensure more efficient delivery of services to survivors. PMID- 30431178 TI - HPV-related oral dysplasia in a multiple myeloma patient after stem cell transplantation. AB - The development of dysplastic changes in oral epithelial lesions is a potential long-term complication after hematopoietic stem cell transplantation (HSCT). This may be related to mechanisms including radiation and chemotherapy regimens, chronic graft-versus-host disease (cGVHD), inflammation, and prolonged immunosuppression. The current case describes a 54-year-old male with multiple myeloma treated by autologous and allogenic HSCT followed by development of cGVHD (mouth, skin and the eyes) with the complaint of diffuse white lesions on the buccal mucosa, tongue, and palate. A biopsy performed with histopathological analysis revealed moderate to severe epithelial dysplasia with hyperkeratosis, positive for p16INK4A as a surrogate marker for human papillomavirus (HPV). Our finding suggests a possible association of oral dysplasia and HPV in patients after receiving allogenic HSCT with the necessity of more clinical follow-ups for those patients that may be at a higher risk for the development of oral dysplasia associated with HPV. PMID- 30431179 TI - 3D gradient echo snapshot CEST MRI with low power saturation for human studies at 3T. AB - PURPOSE: For clinical implementation, a chemical exchange saturation transfer (CEST) imaging sequence must be fast, with high signal-to-noise ratio (SNR), 3D coverage, and produce robust contrast. However, spectrally selective CEST contrast requires dense sampling of the Z-spectrum, which increases scan duration. This article proposes a compromise: using a 3D snapshot gradient echo (GRE) readout with optimized CEST presaturation, sampling, and postprocessing, highly resolved Z-spectroscopy at 3T is made possible with 3D coverage at almost no extra time cost. METHODS: A 3D snapshot CEST sequence was optimized for low power CEST MRI at 3T. Pulsed saturation was optimized for saturation power and saturation duration. Spectral sampling and postprocessing (B0 correction, denoising) was optimized for spectrally selective Lorentzian CEST effect extraction. Reproducibility was demonstrated in 3 healthy volunteers and feasibility was shown in 1 tumor patient. RESULTS: Low-power saturation was achieved by a train of 80 pulses of duration tp = 20 ms (total saturation time tsat = 3.2 seconds at 50% duty cycle) with B1 = 0.6 MUT at 54 irradiation frequency offsets. With the 3D snapshot CEST sequence, a 180 * 220 * 54 mm field of view was acquired in 7 seconds per offset. Spectrally selective CEST effects at +3.5 and -3.5 ppm were quantified using multi-Lorentzian fitting. Reproducibility was high with an intersubject coefficient of variation below 10% in CEST contrasts. Amide and nuclear overhauser effect CEST effects showed similar correlations in tumor and necrosis as show in previous ultra-high field work. CONCLUSION: A sophisticated CEST tool ready for clinical application was developed and tested for feasibility. PMID- 30431180 TI - Prevalence of dental trauma in individuals with special needs participating in local Special Olympics games. AB - OBJECTIVES: The Special Olympics Special Smiles (SOSS) Program provides oral health screening and data collection for athletes with intellectual disabilities who participate in Special Olympics events. AIM: This study evaluated the prevalence and severity of dental trauma among Special Olympics athletes with intellectual disabilities who participated in the 2016 Israeli Special Olympics games. METHODS: A free voluntary dental examination was offered to all participating athletes. The examination was performed by volunteer dentists who completed a standard SOSS examination form, which included questions on oral health status and evidence of dental trauma in the anterior teeth. The dental traumas were categorized by a modified clinical version of the Ellis classification for dental traumas, and they were combined into three main categories according to their severity. Chi-square analysis was used to find differences between gender and age in regard to the prevalence of dental trauma. RESULTS: The sample consisted of 249 athletes with intellectual disabilities aged 10-65 years (mean 29.2 +/- 11.24). The prevalence of dental trauma was 27.3%, of which 9.64% were categorized as mild and 17.67% as severe. Most of the traumas (94%) involved the maxillary incisors. CONCLUSIONS: The relatively high prevalence of dental trauma in special needs athletes revealed by this study's findings supports the need for using preventive measures, such as mouth guards, during sport activities. PMID- 30431182 TI - Increased expression of PD1 and CD39 on CD3+ CD4+ skin T-cells in the elderly. AB - Normal aging is associated with an impaired systemic immune response contributing to an increased susceptibility to infectious diseases. The aim of this study was to compare the lymphocyte phenotype in human skin from old and young healthy subjects. Skin samples from donors were used for explant cultures before flow cytometry analysis. Our results depicted a higher proportion of CD4+ and a lower proportion of CD8+ among CD3+ T-cells, a decreased proportion of CD45RA+ naive T cells (3.5 +/- 1.9% vs 22.9 +/- 11.1%, p<=0.007) and an upregulation of the expression of CD39 and PD1 on CD3+ CD4+ T-cells (25.1 +/- 8.5% vs 12.5 +/- 8.5%, p<=0.003, 68.8 +/- 11.6% vs 50.0 +/- 11.3%, p<=0.01, respectively) in the skin of old subjects. These findings could explain a reduced generation of long-lived memory T-cells and an impaired antitumoral response in the skin of the elderly. This article is protected by copyright. All rights reserved. PMID- 30431183 TI - A systematic review on reporting outcomes and outcome measures in trials on synthetic mesh procedures for pelvic organ prolapse: Urgent action is needed to improve quality of research. AB - : The use of synthetic mesh in pelvic organ prolapse surgery is being closely scrutinized because of serious concerns regarding life-changing complications such as erosion, pain, infection, bleeding, dyspareunia, organ perforation, and urinary problems. Randomized trials and their syntheses in meta-analysis offer a unique opportunity to assess efficacy and safety. However, outcomes and outcome measures need to be consistently selected, collected, and reported across randomized trials to be effectively combined in systematic reviews. AIMS: We evaluated outcome and outcome measure reporting across randomized controlled trials on surgical interventions using synthetic mesh for pelvic organ prolapse. METHODS: Systematic review of randomized controlled trials using synthetic mesh for the treatment of pelvic organ prolapse. The selected studies were evaluated using Jadad and MOMENT criteria. Outcomes and outcome measures were systematically identified and categorized. RESULTS: Seventy-one randomized trials were included. Twenty-four different types of mesh were identified. Included trials reported 110 different outcomes and 60 outcome measures. Erosion (40 trials, 78%), pain (29 trials, 56%), bleeding (31 trials, 61%), and dyspareunia (25 trials, 49%) were the most frequently reported outcomes. The longest follow up was 74 months. CONCLUSIONS: Most randomized trials evaluating surgical interventions using synthetic mesh for pelvic organ prolapse failed to report on clinically important outcomes and to evaluate efficacy and safety over the medium and long-term. Developing and implementing a minimum data set, known as a core outcome set, in future vaginal prolapse trials could help address these issues. PMID- 30431184 TI - Multidisciplinary rehabilitation of eosinophilic granuloma with bone graft surgery and a modified implant-supported hybrid prosthesis: A case report with a 6-year follow-up. AB - Eosinophilic granuloma is the most common form of Langerhans cell histiocytosis and corresponds with bone lesions characterized by pain, rapid growth, and high tendency of recurrence after inadequate curettage. It is a rare disease that is difficult to diagnose clinically and radiographically because it mimics other odontogenic cysts and tumors. In this report, the reconstruction of an osseous defect with an iliac graft and a modified implant-supported hybrid prosthesis after surgical excision of an eosinophilic granuloma in the mandible of a 27-year old male patient was described. The patient was satisfied with the functional and esthetic results of the implant-supported restoration and a 6-year follow-up showed no sign of recurrence. PMID- 30431185 TI - Immunohistochemistry for small cell carcinoma: a potential diagnostic pitfall. AB - The morphological appearances of small cell lung carcinoma (SCLC) are often characteristic however immunohistochemistry (IHC) is frequently employed to support the diagnosis, especially when there is crush artefact. In general histopathologists look for expression of cytokeratins, CD56 and TTF1 but it is well recognised that SCLC may not show typical staining reactions. While CD56 is usually expressed TTF1 may be negative and cytokeratin staining may be very focal or even absent. We report three cases of mediastinal alveolar rhabdomyosarcoma who presented with radiological features of lung cancer where the morphological and immunohistochemical profile mimicked SCLC. This article is protected by copyright. All rights reserved. PMID- 30431186 TI - Robust visualization of middle cerebral artery main trunk by enhanced acceleration-selective arterial spin labeling (eAccASL) for intracranial MRA. AB - PURPOSE: A new sequence for intracranial MRA is developed, named enhanced acceleration-selective arterial spin labeling (eAccASL), to improve main artery visualization at middle cerebral artery (MCA). The aim of this study is to assess the visualization improvement using eAccASL, compared with the previously developed AccASL. METHODS: eAccASL and AccASL were performed in 8 healthy volunteers and images were compared between the 2 sequences. One patient with Moyamoya disease was evaluated by eAccASL and time of flight. For the volunteer images, vessel visualization was assessed by measuring the contrast-to-noise ratio between MCA M1 to M4 and white matter and by counting the peripheral arteries. Venous artifact level was assessed by measuring the contrast-to-noise ratio between the confluence of the sinuses and white matter and by evaluating cortical vein visualization. For the patient images, qualitative assessment of peripheral and collateral vessel visualization was conducted. RESULTS: In the MCA main trunk, higher arterial signal intensity, with reduced flow void, was observed in eAccASL compared with AccASL. Contrast-to-noise ratios of M1 to M3 for eAccASL were significantly higher than those of AccASL. There was no significant difference between AccASL and eAccASL for venous artifact. CONCLUSION: eAccASL could produce better MCA main trunk visualization compared with AccASL, while maintaining good venous signal suppression. PMID- 30431187 TI - The generative power of metaphor: long-term action research on disaster recovery in a small Japanese village. AB - Disaster recovery is a dynamic process of creating, maintaining, and changing the meaningful context of survivors. It is completed when they redevelop their self reliance and resume managing their social relations with a sense of community. This study employed action research to examine how researchers and survivors collaborated to change disaster recovery through the generative power of metaphor in a small village in Japan that experienced the Niigata-Chuetsu earthquake on 23 October 2004. It outlines long-term collaborative practices as survivors undertook new activities owing to the power of the metaphor of 'school'. Once 'school' was adopted as the metaphor for where survivors learnt new skills and passed on traditional knowledge, they created new metaphors and performed new activities independently, which is critical for recovery as it demonstrates self reliance. The paper assesses the reasons why generative metaphors worked effectively in this case and highlights some academic and practical implications for disaster recovery. PMID- 30431188 TI - YocM a small heat shock protein can protect Bacillus subtilis cells during salt stress. AB - Small heat shock proteins (sHsp) occur in all domains of life. By interacting with misfolded or aggregated proteins these chaperones fulfill a protective role in cellular protein homeostasis. Here, we demonstrate that the sHsp YocM of the Gram-positive model organism Bacillus subtilis is part of the cellular protein quality control system with a specific role in salt stress response. In the absence of YocM the survival of salt shocked cells is impaired, and increased levels of YocM protect B. subtilis exposed to heat or salt. We observed a salt and heat stress-induced localization of YocM to intracellular protein aggregates. Interestingly, purified YocM appears to accelerate protein aggregation of different model substrates in vitro. In addition, the combined presence of YocM and chemical chaperones, which accumulate in salt stressed cells, can facilitate in vitro a synergistic protective effect on protein misfolding. Therefore, the beneficial role of YocM during salt stress could be related to a mutual functional relationship with chemical chaperones and adds a new possible functional aspect to sHsp chaperone activities. PMID- 30431189 TI - Visual and radiographic merged-ICDAS caries progression pattern in 2-6 years old Colombian children: Two-year follow-up. AB - AIM: To describe the two-year clinical and combined with radiographic caries progression pattern in three cohorts of 2-(a), 4-(b), and 6-yr-old children (c). DESIGN: Baseline sample comprised 600 children (each-cohort: n=200). Children's dental surfaces were clinically assessed at schools without air-drying (epi) in terms of: Clinical (C) caries lesions (d/D) with ICDASepi-merged system (C ICDASepi-d/D:Sound/Initial-epi/Moderate/Extensive); fillings (f/F), and missing teeth (m/M). Clinical ICDAS (C) and Radiographic ICDAS (R) indexes were combined (C+R). Caries experience (dmf+DMF) was expressed as: C-dmfs+DMFS (Moderate/Extensive-d/D); C-ICDASepi-dmfs+DMFS (including Initial-epi-d); C+R dmfs+DMFS, and C+R-ICDASepi-dmfs+DMFS. Follow-up caries progression corresponded to a more severe caries score. RESULTS: Two-year follow-up sample was n=352 (58.7%-baseline sample): a: n=81; b: n=131; c: n=140. Around 100% of children presented C+R-ICDASepi-dmf+DMF>=1, with following C+R-ICDASepi-dmfs+DMFS means: a: 7.3+/-14.1; b: 12.2+/-19.5; c: 13.3+/-16.9. Progression was about 60% in all cohorts, mainly corresponding, in cohort b and c, to occlusal and distal surfaces of lower first/second-molar-primary teeth, and in cohort a to buccal surfaces of upper primary-incisor teeth. The addition of radiographs increased caries mean and prevalence in 10% as compared to only visual examination. CONCLUSIONS: Children showed a high C+R caries experience progression rate, mainly related to occlusal and proximal surfaces in lower-molar teeth and buccal in upper-incisor teeth. This article is protected by copyright. All rights reserved. PMID- 30431190 TI - Exploring Preceptorship Programmes: Implications for Future Design. AB - AIMS AND OBJECTIVES: To review and analyse current preceptorship programmes within NHS trusts in the North West of England. To evaluate the pedagogic rigour of the programme and suggest recommendations to inform the future design of preceptorship programmes. BACKGROUND: Enhancing the retention of newly qualified staff is of particular importance given that the journey from a new registrant to a competent healthcare professional poses a number of challenges, for both the individual staff member and organisations. DESIGN: A mixed methods evaluative approach was employed, using online questionnaires and content analysis of preceptorship documentation. METHODS: Forty-one NHS trusts across the North West region employing newly qualified nurses were invited to participate in the completion of an online questionnaire. In addition, preceptorship programme documentation was requested for inclusion in the content analysis. This study utilised the SQUIRE (Standards for Quality Improvement Reporting Excellence) guidelines. RESULTS: The response rate for the questionnaire was 56.1% (n=23). Eighteen trusts (43.9%) forwarded their programme documentation. Findings highlighted the wide variation in preceptorship programmes across the geographical footprint. CONCLUSIONS: There were instances of outstanding preceptorship and preceptorship programmes where there was a clear link between the strategic vision, i.e., trust policy, and its delivery, i.e. preceptorship offering. There was no one framework that would universally meet the needs of all trusts, yet there are key components which should be included in all preceptorship programmes. Therefore, we would encourage innovation and creativity in preceptorship programmes, cognisant of local context. RELEVANCE TO CLINICAL PRACTICE: The significant shortage of nursing staff in England is an ongoing issue. Recruitment and retention are key to ameliorating the shortfall, and formal support mechanisms like preceptorship, can improve the retention of newly qualified staff. Understanding current preceptorship programmes is an important first step in establishing the fundamental building blocks of successful preceptorship programmes and enabling the sharing of exemplary good practice across organisations. This article is protected by copyright. All rights reserved. PMID- 30431191 TI - Complexation and Versatile Reactivity of a Highly Lewis Acidic Cationic Mg Complex with Alkynes and Phosphines. AB - [(BDI)Mg+][B(C6F5)4-] 1 (BDI = CH[C(CH3)N-Dipp]2; Dipp = 2,6-diisopropylphenyl) was prepared by reaction of (BDI)MgnPr with [Ph3C+][B(C6F5)4-]. Addition of 3 hexyne gave [(BDI)Mg+?(EtC=CEt)][B(C6F5)4-]. Single crystal X-ray analysis, NMR investigations, Raman spectra and DFT calculations indicate a significant Mg alkyne interaction. Addition of the terminal alkynes for PhC=CH or Me3SiC=CH led to alkyne deprotonation by the BDI ligand to give [(BDI-H)Mg+(C=CPh)]2 2[B(C6F5)4 ] (2, 70%) and [(BDI-H)Mg+(C=CSi(CH3)3)]2 2[B(C6F5)4-] (3, 63%). Addition of internal alkynes PhC=CPh or PhC=CMe led to a [4+2]-cycloaddition with the BDI ligand to give 4 (53%) and 5 (73%) in which the Mg metal is (N,N,C)-chelated. The (BDI)Mg+ cation can be seen as an intramolecular Frustrated Lewis Pair (FLP) with a Lewis acidic site (Mg) and a Lewis (or Bronsted) basic site (BDI). Reaction of [(BDI)Mg+][B(C6F5)4-] 1 with a range of phosphines varying in bulk and donor strength led to formation of [(BDI)Mg+?PPh3][B(C6F5)4-] (6), [(BDI)Mg+?PCy3][B(C6F5)4-] (7) and [(BDI)Mg+?PtBu3][B(C6F5)4-] (8). The bulkier phosphine PMes3 did not show any interaction. Combinations of [(BDI)Mg+][B(C6F5)4 ] and phosphines did not result in addition to the triple bond in 3-hexyne but during the screening process it was discovered that the cationic magnesium complex catalyses the hydrophosphination of PhC=Ch with HPPh2 which likely proceeds through an FLP-type mechanism. PMID- 30431192 TI - MRI evaluation of vulvar squamous-cell carcinoma in fresh radical local excision specimens for cancer localization and prediction of surgical tumor-free margins. AB - In the surgical treatment of vulvar squamous-cell carcinoma (VSCC), tumor-free margins of 8 mm or more are considered adequate. However, limited perioperative information on the tumor-free margins other than the surgeon's own estimation is available. The purpose of this study was therefore to investigate the feasibility of ex vivo MRI in localizing VSCC and to assess the surgical tumor-free margins in fresh radical local excision (RLE) specimens to guide the surgeon during resections. Nine patients with biopsy-proven VSCC scheduled for RLE were prospectively included. Intact fresh specimens were scanned using a 7 T preclinical MR-scanner. Whole mount H&E-stained slides were obtained every 3 mm and correlated with ex vivo MRI. A pathologist annotated VSCC and minimal tumor free margins (3 o'clock, 9 o'clock, basal) on the digitalized histological slides. An observer with knowledge of histology (the non-blinded annotation) and a radiologist blinded to histology (the blinded annotation) separately performed annotation of the same features on ex vivo MRI. Linear correlation and agreement of the ex vivo MRI measurements with histology were assessed. Diagnostic performance for VSCC localization and identification of margins less than 8 mm was expressed as positive and negative predictive values (PPV, NPV). In 153 matched ex vivo MRI slices, the observer correctly identified 79/91 margins as less than 8 mm (PPV 87%) and 110/124 margins as 8 mm or greater (NPV 89%). The radiologist correctly annotated absence of VSCC in 73/81 (NPV 90%) and presence in 65/72 (PPV 90%) slices. Sixty-four of 90 margins were correctly identified as less than 8 mm (PPV 71%) and 83/102 margins as 8 mm or greater (NPV 81%). Both non-blinded and blinded annotations were linearly correlated and demonstrated good agreement with histology. Accurate localization of VSCC and measurements of the surgical tumor-free margins in fresh RLE specimens using ex vivo MRI seems feasible. High diagnostic performance in VSCC localization and identification of margins less than 8 mm suggest ex vivo MRI to be clinically applicable. PMID- 30431193 TI - Chromosomal inversions associated with environmental adaptation in honeybees. AB - Chromosomal inversions can facilitate local adaptation in the presence of gene flow by suppressing recombination between well-adapted native haplotypes and poorly-adapted migrant haplotypes. East African mountain populations of the honeybee Apis mellifera are highly divergent from neighbouring lowland populations at two extended regions in the genome, despite high similarity in the rest of the genome, suggesting that these genomic regions harbour inversions governing local adaptation. Here we utilize a new highly-contiguous assembly of the honeybee genome to characterize these regions. Using whole-genome sequencing data from 55 highland and lowland bees, we find that the highland haplotypes at both regions are present at high frequencies in three independent highland populations but extremely rare elsewhere. The boundaries of both divergent regions are characterised by regions of high homology with each other positioned in opposite orientations and contain highly repetitive, long inverted repeats with homology to transposable elements. These regions are likely to represent inversion breakpoints that participate in non-allelic homologous recombination. Using long-read data, we confirm that the lowland samples are contiguous across breakpoint regions. We do not find evidence for disruption of functional sequence by these breakpoints, which suggests that the inversions are likely maintained due to their allelic content conferring local adaptation in highland environments. Finally, we identify a third divergent genomic region, which contains highly divergent segregating haplotypes that also may contain inversion variants under selection. The results add to a growing body of evidence indicating the importance of chromosomal inversions in local adaptation. This article is protected by copyright. All rights reserved. PMID- 30431194 TI - Three-dimensional NMR microscopy of zebrafish specimens. AB - While zebrafish embryos in the first five days after fertilization are clear and amenable to optical analysis, older juveniles and adults are not, due to pigmentation development and tissue growth. Thus other imaging methods are needed to image adult specimens. NMR is a versatile tool for studies of biological systems and has been successfully used for in vivo zebrafish microscopy. In this work we use NMR microscopy (MRM) for assessment of zebrafish specimens, which includes imaging of formalin fixed (FF), formalin fixed and paraffin embedded (FFPE), fresh (unfixed), and FF gadolinium doped specimens. To delineate the size and shape of various organs we concentrated on 3D MRM. We have shown that at 7 T a 3D NMR image can be obtained with isotropic resolution of 50 MUm/pxl within 10 min and 25 MUm/pxl within 4 h. Also, we have analyzed sources of contrast and have found that in FF specimens the best contrast is obtained by T1 weighting (3D FLASH, 3D FISP), whereas in FFPE specimens T2 weighting (3D RARE) is the best. We highlight an approach to perform segmentation of the organs in order to study morphological changes associated with mutations. The broader implication of this work is development of NMR methodology for high contrast and high resolution serial imaging and automated analysis of morphology of various zebrafish mutants. PMID- 30431195 TI - Heteromultivalent glycooligomers as mimetics of blood group antigens. AB - Precision glycomacromolecules have proven to be important tools for the investigation of multivalent carbohydrate-lectin interactions by presenting multiple glycan epitopes on a highly-defined synthetic scaffold. Here we present a new strategy for the versatile assembly of heteromultivalent glycomacromolecules presenting different carbohydrate motifs in close proximity within the side chains. A new building block suitable for the solid phase polymer synthesis (SPPoS) of precision glycomacromolecules was developed exhibiting a branching point in the side chain that bears a free alkyne and a TIPS-protected alkyne moiety enabling the subsequent attachment of different carbohydrate motifs by on-resin copper mediated azide alkyne cycloaddition reactions (CuAAC). Applying this synthetic strategy, heteromultivalent glycooligomers presenting fragments of histo-blood group antigens (HBGA) and human milk oligosaccharides (HMO) were synthesized and tested for their binding behavior towards bacterial lectin LecB. PMID- 30431196 TI - Examining consumer purchase intentions of non-prescription medicines in supermarkets and community pharmacies. AB - OBJECTIVE: As supermarkets continue to expand their healthcare categories, consumers now have more choice and access to non-prescription medicines. The aim of this current research is to empirically examine the drivers and barriers of consumer purchase intentions, namely trust and perceived risk, of non prescription medicines in both supermarkets and community pharmacy settings. METHOD: Data were collected using an in-store intercept survey of 402 supermarket shoppers and 310 community pharmacy shoppers. Confirmatory factor analysis including a measurement and structural model tests were employed using AMOS software package to identify variances in the drivers and barriers of purchase intentions between these retail settings. KEY FINDINGS: This study found an association between the purchase intention of non-prescription medicines in community pharmacies with their perceived competence, benevolence and provision accurate information. Other than time risk, no other elements of risk were associated with purchase intentions within this setting. In contrast, the perceived risks associated with the purchase of non-prescription medicines within the supermarkets setting - specifically physical and social risk, were present. Results indicate respondents were more likely to intend to purchase medicines from a supermarket if they perceived that the retailer was competent in providing access to safe non-prescription medicines and had the ability to handle transactions. CONCLUSIONS: This is the first study to examine the psychological drivers and barriers of purchase intentions of non-prescription medicines in supermarkets and community pharmacies, finding very different results across both retail settings. The study presents a comprehensive model of purchase intentions of non-prescription medicines and recommends directions for pharmacy practitioners and supermarkets. PMID- 30431197 TI - Deciphering the multifarious charge transport behaviour of crystalline propeller shaped triphenylamine analogues. AB - A collection of para-substituted propeller-shaped triphenylamine (TPA) derivatives have been computationally investigated for the charge transport characteristics exhibited by the derivatives using the Marcus-Hush formalism. The various substituents chosen in the current work, having features that range from electron withdrawing to electron donating nature, play a key role in defining the reorganization energy and electronic coupling properties of the TPA derivatives. TPA moiety is expected to possess weak electronic coupling on the basis of poor orbital overlap upon aggregation owing to the restriction imposed by the propeller shape of the triphenylamine core. However, the substituent groups attached to the TPA core can significantly dictate the crystal packing motif of the TPA derivatives, wherein the variety of noncovalent intermolecular interactions subsequently generated drive the packing arrangement and influence the electronic coupling between the neighbouring orbitals. The intermolecular interactions in the crystalline architecture of TPA derivatives were probed using Hirshfeld and QTAIM techniques. Furthermore, SAPT analysis of the TPA analogues has revealed that a periodic arrangement of energetically stable dimers having significant electronic coupling is essential in order to contribute a high charge carrier mobility to the overall crystal. PMID- 30431198 TI - Systemic factors trigger vasculature cells to drive Notch signaling and neurogenesis in neural stem cells in the adult brain. AB - It is well documented that adult neural stem cells (NSCs) residing in the subventricular zone (SVZ) and the subgranular zone (SGZ) are induced to proliferate and differentiate into new neurons after injury such as stroke and hypoxia. However, the role of injury-related cues in driving this process and the means by which they communicate with NSCs remains largely unknown. Recently, the coupling of neurogenesis and angiogenesis and the extensive close contact between vascular cells and other niche cells, known as the neurovascular unit (NVU), has attracted interest. Further facilitating communication between blood and NSCs is a permeable blood-brain-barrier (BBB) present in most niches, making vascular cells a potential conduit between systemic signals, such as vascular endothelial growth factor (VEGF), and NSCs in the niche, which could play an important role in regulating neurogenesis. We show that the leaky BBB in stem cell niches of the intact and stroke brain can respond to circulating VEGF165 to drive induction of the notch ligand DLL4 (one of the most important cues in angiogenesis) in Endothelial cells (ECs), pericytes, and further induce significant proliferation and neurogenesis of stem cells. (c) AlphaMed Press 2018. PMID- 30431199 TI - Social decision-making in the brain: Input-state-output modelling reveals patterns of effective connectivity underlying reciprocal choices. AB - During social interactions, decision-making involves mutual reciprocity-each individual's choices are simultaneously a consequence of, and antecedent to those of their interaction partner. Neuroeconomic research has begun to unveil the brain networks underpinning social decision-making, but we know little about the patterns of neural connectivity within them that give rise to reciprocal choices. To investigate this, the present study measured the behaviour and brain function of pairs of individuals (N = 66) whilst they played multiple rounds of economic exchange comprising an iterated ultimatum game. During these exchanges, both players could attempt to maximise their overall monetary gain by reciprocating their opponent's prior behaviour-they could promote generosity by rewarding it, and/or discourage unfair play through retaliation. By adapting a model of reciprocity from experimental economics, we show that players' choices on each exchange are captured accurately by estimating their expected utility (EU) as a reciprocal reaction to their opponent's prior behaviour. We then demonstrate neural responses that map onto these reciprocal choices in two brain regions implicated in social decision-making: right anterior insula (AI) and anterior/anterior-mid cingulate cortex (aMCC). Finally, with behavioural Dynamic Causal Modelling, we identified player-specific patterns of effective connectivity between these brain regions with which we estimated each player's choices with over 70% accuracy; namely, bidirectional connections between AI and aMCC that are modulated differentially by estimates of EU from our reciprocity model. This input-state-output modelling procedure therefore reveals systematic brain-behaviour relationships associated with the reciprocal choices characterising interactive social decision-making. PMID- 30431200 TI - Do fluoride toothpastes have similar preventive effect in permanent and deciduous teeth against erosive tooth wear? AB - BACKGROUND: Little is known about fluoride toothpastes effect on deciduous teeth submitted to erosive tooth wear OBJECTIVES: To evaluate the preventive effect of different toothpastes on surface loss (SL) after severe erosion/abrasion model and to compare this effect between permanent (PT) and deciduous teeth (dt). DESIGN: Enamel samples were randomly divided according toothpastes groups (n=17). G1: placebo; G2: NaF; G3: AmF-NaF-SnCl2 anti-erosion; G4: SnF2 ; and G5: NaF anti erosion for children. Samples were incubated in artificial saliva (1h), submitted to erosive challenge (3min; 1% citric acid; pH3.6; at 25 degrees C) and to toothbrush abrasion (2min slurry immersion; 50 strokes; 200g) during 30 cycles. Surface loss (MUm; mean+/-SD) was quantified by contactless profilometry. The effects of the two covariables "tooth" and "toothpaste" were analyzed by non parametric ANOVA, variables with significant effects were tested by Wilcoxon tests. RESULTS: dt showed significantly higher surface loss than PT in all groups (p<0.001). The mean values of SL of each group were: G1 PT 18.18(+/-3.98), dt 25.65(+/-9.21); G2 PT 14.76(+/-2.82), dt 18.11(+/-3.92); G3 PT 12.62(+/-5.29), dt 15.61(+/-6.70); G4 PT 17.12(+/-2.24), dt 23.41(+/-7.9); G5 PT 13.24(+/-1.29), dt 18.28(+/-8.96) CONCLUSIONS: In permanent teeth G3 showed the best preventive effect. In deciduous teeth G1, G3 and G5 showed similar effect. This article is protected by copyright. All rights reserved. PMID- 30431201 TI - Capillary flow disturbances after experimental subarachnoid hemorrhage: a contributor to delayed cerebral ischemia? AB - BACKGROUND: The high mortality and morbidity after subarachnoid hemorrhage (SAH) is partly due to delayed cerebral ischemia, which is traditionally ascribed to development of angiographic vasospasms. This relation has been challenged, and capillary flow disturbances are proposed as another mechanism contributing to brain damage after SAH. OBJECTIVE: To investigate capillary flow changes four days following experimental SAH. METHODS: SAH was induced by endovascular perforation of circle of Willis. We used two-photon microscopy (TPM) to evaluate blood flow characteristics. Cortical capillary diameters were investigated by both TPM and histology. RESULTS: We found elevated capillary transit-time heterogeneity and mean transit time of blood in SAH mice compared to sham animals. We observed capillaries with stagnant red blood cells, and capillaries with increased red blood cell linear density in the SAH group, suggesting severe blood maldistribution among cortical capillaries. Favoring that these capillary flow changes were primary to upstream vasoconstrictions, TPM showed no significant differences in arteriolar diameter between groups, while histological examination showed reduced capillary diameter in SAH group. CONCLUSION: Our study shows profound subacute hypoperfusion and capillary flow disturbances in a mouse SAH model and suggests that these changes are the result of changes in capillary function, rather than upstream vasospasm. This article is protected by copyright. All rights reserved. PMID- 30431202 TI - High-speed quantitative 3D imaging by dual-illumination holographic microscopy. AB - A new blood flow imaging (BFI) technique using digital holography with double illumination of the sample is proposed. We imaged the moving red blood cells (RBCs) using a two microscope objective lenses setup. The setup consists in a larger angle of separation (90 degrees ) between the two illumination beams, allowing a wider angular rotation at good z resolution. Moreover, the setup geometry allows an easier displacement of the sample in all directions. Results show that this technique is able to perform phase-shifting reconstruction for the two beams at the same time which is more suitable for the future implementation of live 3D holography. Experimental results are carried out for the verification of the effectiveness of the proposed technique on a zebrafish larvae sample. RESEARCH HIGHLIGHTS: Blood flow imaging techniques are often invasive and image analysis is time consuming. To alleviate this issue an imaging technique based on dual illumination in holographic domain is proposed. This method has been validated on zebrafish embryos. PMID- 30431204 TI - Effects of tumor necrosis factor-alpha-induced exosomes on the endothelial cellular behavior, metabolism and bioenergetics. AB - OBJECTIVE: To investigate the effects of TNF-alpha-induced exosomes release on the biological behavior, metabolism, and bioenergetics of HUVECs. METHODS: Exosomes were isolated from conditioned media of HUVECs by ultracentrifugation after treatment with or without TNF-alpha. HUVECs were treated with or without TNF-alpha, or different concentrations of exosomes isolated from conditioned media with or without TNF-alpha induction (TExo and CExo , respectively). RESULTS: The results showed that TNF-alpha significantly inhibited migration, tube formation, and increased apoptosis rate of HUVECs compared with controls. Furthermore, TNF-alpha-induced exosomes (TExo ) rather than CExo , indicated similar effects to inhibit migration, tube formation and promote endothelial apoptosis. Although TNF-alpha treatment did not show a statistical difference, TExo significantly inhibited extracellular OCR compared with controls. TExo could significantly inhibited intracellular OCR in a hypoxia condition. TNF-alpha significantly increased L-ECA compared with control cells, and TExo showed similar stimulative effect on L-ECA. CONCLUSIONS: TNF-alpha-induced exosomes could significantly (a) change migration, tube formation, and apoptosis; (b) inhibit endothelial extracellular OCR and intracellular OCR (hypoxia); (c) increase glycolysis rate of the endothelial cells. These data provide new evidence for exploring endothelial behavior regulation using exosomes and their effects on endothelial metabolism and bioenergetics. PMID- 30431203 TI - Th2 cell differentiation from naive CD4+ T cells is enhanced by autocrine CC chemokines in atopic diseases. AB - BACKGROUND: Chemokines are involved not only in regulating leukocyte recruitment, but also in other activities. However, functions other than cell recruitment remain poorly understood. We have already shown that the production of CC chemokine ligand (CCL)17 and CCL22 by antigen-stimulated naive CD4+ T cells was higher in asthmatic patients than in healthy controls. However, the role of these chemokines in stimulated naive CD4+ T cells remains unclear. OBJECTIVE: To clarify the biological function of CCL17 and CCL22 on naive CD4+ T, we examined effects of these two chemokines on naive CD4+ T cells expressing CC chemokine receptor (CCR)4 (a receptor for CCL17 and CCL22) during differentiation of Th2 cells in asthmatic patients as allergic subjects. METHODS: Naive CD4+ T cells were prepared from healthy controls and patients with asthma. We analyzed effect of CCL17 and CCL22, and blocking their receptor on differentiation of Th2 cells. RESULTS: Production of CCL17 and CCL22 by activated naive CD4+ T cells under Th2 condition was much more in asthmatic patients than in healthy controls. Proliferation and survival of the Th2 differentiating cells and restimulation induced IL-4 production were much greater in asthmatic patients than in healthy controls. These cell biological phenomena were inhibited by blockade of CCR4. The biological effects of exogenous CCL17 and CCL22 were apparently observed in both healthy controls and asthmatic patients. The effectiveness of these chemokines on naive CD4+ T cells from healthy controls was stronger than those from asthmatic patients. We found that thymic stromal lymphopoietin (TSLP), a Th2 promoting chemokine, is involved in the activation of CD4+ naive T cells via production of CCL17 and CCL22. CONCLUSIONS & CLINICAL RELEVANCE: These data suggest that CCL17 and CCL22 produced by TSLP-primed naive CD4+ T cells in asthma might contribute to an increase in Th2 cells via autocrine loops. This article is protected by copyright. All rights reserved. PMID- 30431205 TI - Engineered SH2 domains with tailored specificities and enhanced affinities for phosphoproteome analysis. AB - Protein phosphorylation is the most abundant post-translational modification in cells. Src homology 2 (SH2) domains specifically recognize phosphorylated tyrosine (pTyr) residues to mediate signaling cascades. A conserved pocket in the SH2 domain binds the pTyr side chain and the EF and BG loops determine binding specificity. By using large phage-displayed libraries, we engineered the EF and BG loops of the Fyn SH2 domain to alter specificity. Engineered SH2 variants exhibited distinct specificity profiles and were able to bind pTyr sites on the epidermal growth factor receptor, which were not recognized by the wild-type Fyn SH2 domain. Furthermore, mass spectrometry showed that SH2 variants with additional mutations in the pTyr-binding pocket that enhanced affinity were highly effective for enrichment of diverse pTyr peptides within the human proteome. These results showed that engineering of the EF and BG loops could be used to tailor SH2 domain specificity, and SH2 variants with diverse specificities and high affinities for pTyr residues enabled more comprehensive analysis of the human phosphoproteome. This article is protected by copyright. All rights reserved. PMID- 30431206 TI - An amino acid metabolism-related gene expression-based risk signature can better predict overall survival for glioma. AB - Metabolic reprogramming has been proposed to be a hallmark of cancer. Aside from glycolytic pathway, the metabolic changes of cancer cells primarily involve amino acid metabolism. However, the characteristic of amino acid metabolism-related gene set has not been systematically profiled in glioma. In this study, RNA sequencing expression data from 309 patients in the Chinese Glioma Genome Atlas database were included as training set, while another 550 patients with the Cancer Genome Atlas database were used to validate. Consensus clustering of the 309 samples yielded two robust groups. Compared with Cluster1, Cluster2 correlated with a better clinical outcome. Then, we developed an amino acid metabolism-related risk signature for glioma. Our results showed that patients in the high-risk group had dramatically shorter overall survival than low-risk counterparts in any subgroup, stratified by IDH and 1p/19q status based on the 2016 World Health Organization classification guidelines. The 30-gene signature showed the better prognostic value than the traditional factors "age" and "grade" by analyzing the receiving operator characteristic curve, with areas under curve of 0.966, 0.692, 0.898 and 0.975, 0.677, 0.885 for 3- and 5-year survival, respectively. Moreover, univariate and multivariable analysis shows that the 30 gene signature was an independent prognostic factor for glioma. Furthermore, Gene Ontology analysis and Gene Set Enrichment Analysis illustrated that the tumors with high risk score correlated with various aspects of the malignancy of glioma. In summary, we demonstrated a novel amino acid metabolism-related risk signature for predicting prognosis for glioma. This article is protected by copyright. All rights reserved. PMID- 30431207 TI - 20(S)-ginsenoside-Rg3 reverses temozolomide resistance and restrains epithelial mesenchymal transition progression in glioblastoma. AB - Glioblastoma multiforme (GBM) is one of the most malignant human intracranial tumors. Temozolomide (TMZ) is the primary alkylating agent for GBM patients. However, plenty of GBM patients are resistant to TMZ. Therefore, patients with GBM demand urgently for more effective therapeutic options. 20(S)-ginsenoside-Rg3 (20(S)-Rg3) is a natural chemical with anti-tumor effects, while there is little understanding of its functional mechanism at present. Several research reports have been proved that O6 -methylguanine DNA-methyltransferase (MGMT) repairs damaged DNA and contributes to TMZ-resistance in gliomas. And recent studies showed that MGMT gene expression could be regulated by Wnt/beta-catenin pathway. However, whether 20(S)-Rg3 inhibits MGMT expression and augments chemosensitivity to TMZ in glioma cells remains unclear. In this study, we explored the modulating effects of 20(S)-Rg3 on MGMT. We used glioma cell lines, primary cell strain (including T98G, U118 and GBM-XX, all of them are MGMT-positive glioma cell lines.) and xenograft glioma models to examine whether 20(S)-Rg3 increased the sensitivity to TMZ and to reveal the underlying mechanisms. We found that the MGMT expression was effectively downregulated by 20(S)-Rg3 via the Wnt/beta catenin pathway in glioma cell lines, and TMZ resistance was significantly reversed by 20(S)-Rg3. Meanwhile, 20(S)-Rg3 shows no obvious cytotoxicity at its effective dose and well tolerated in vivo. In addition, we found that 20(S)-Rg3 significantly restrains the epithelial-mesenchymal transition (EMT) progression of glioma cells. Taken together, these results indicate that 20(S)-Rg3 may be a novel agent to use in treatment of GBM, especially in TMZ-resistant GBM with high MGMT expression. This article is protected by copyright. All rights reserved. PMID- 30431208 TI - Quantitative assessment of field strength, total intracranial volume, sex, and age effects on the goodness of harmonization for volumetric analysis on the ADNI database. AB - When analyzing large multicenter databases, the effects of multiple confounding covariates increase the variability in the data and may reduce the ability to detect changes due to the actual effect of interest, for example, changes due to disease. Efficient ways to evaluate the effect of covariates toward the data harmonization are therefore important. In this article, we showcase techniques to assess the "goodness of harmonization" of covariates. We analyze 7,656 MR images in the multisite, multiscanner Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We present a comparison of three methods for estimating total intracranial volume to assess their robustness and correct the brain structure volumes using the residual method and the proportional (normalization by division) method. We then evaluated the distribution of brain structure volumes over the entire ADNI database before and after accounting for multiple covariates such as total intracranial volume, scanner field strength, sex, and age using two techniques: (a) Zscapes, a panoramic visualization technique to analyze the entire database and (b) empirical cumulative distributions functions. The results from this study highlight the importance of assessing the goodness of data harmonization as a necessary preprocessing step when pooling large data set with multiple covariates, prior to further statistical data analysis. PMID- 30431209 TI - Scoping the impact of curriculum and placement on the rural pharmacy workforce. AB - OBJECTIVE: The objective of this review was to scope the impact of university rural curriculum and rural clinical placements on students' intentions to practise rurally and rural pharmacists' choice of rural practice. DESIGN: The scoping review used Arskey and O'Malley's methodological framework, searching the following databases: MEDLINE, CINAHL, Informit and Scopus. This scoping review followed PRISMA for article reporting. SETTING: Studies were selected from those conducted in Australia, USA, Canada and Africa. PARTICIPANTS: Pharmacy undergraduate students, interns, registered and academic pharmacists were included. MAIN OUTCOME MEASURE: The pharmacy curriculum at universities and placements undertaken, specifically in rural and remote settings, were evaluated to determine their influence on intention to practise as a rural pharmacist. RESULTS: The search strategy generated 294 records, 31 of which were included in the scoping review. Key findings were mapped to two domains, which broadly included the impact of rural placements and curriculum on intention to practise rurally. Some universities have attempted to introduce a rural curriculum, but reported resources as a barrier and the lack of resulting evidence of students' intention to practise rurally. Although results indicate rural placements have had a positive influence on students' intention to work rurally, this intention has been measured immediately after exposure to rural practice and might not reflect future intentions. CONCLUSION: This review highlights significant gaps in the impact particularly of a rural curriculum and rural clinical placements in relation to the current rural pharmacist workforce. A greater understanding of this topic may guide recommendations for future strategies to address rural pharmacy workforce maldistribution. PMID- 30431210 TI - Transcriptional profiling identifies critical steps of cell cycle reprogramming necessary for Plasmodiophora brassicae-driven gall formation in Arabidopsis. AB - Plasmodiophora brassicae is a soil-borne biotroph whose life cycle involves reprogramming of host developmental processes leading to the formation of galls on its underground parts. Formation of such structures involves modification of the host cell cycle leading initially to hyperplasia, increasing the number of cells to be invaded, followed by overgrowth of cells colonised by the pathogen. Here we show, that P. brassicae infection stimulates formation of the E2Fa/RBR1 complex and upregulation of MYB3R1, MYB3R4 and A- and B-type cyclin expression. These factors were previously described as important regulators of the G2-M cell cycle checkpoint. As a consequence of this manipulation, a large population of host hypocotyl cells are delayed in cell cycle exit and maintained in the proliferative state. We also report that, during further maturation of galls, enlargement of host cells invaded by the pathogen involves endoreduplication leading to increased ploidy levels. This study characterises two aspects of the cell cycle reprogramming efforts of P. brassicae: systemic, related to the disturbance of host hypocotyl developmental programs by preventing cell cycle exit; and local, related to the stimulation of cell enlargement via increased endocycle activity. This article is protected by copyright. All rights reserved. PMID- 30431211 TI - Weather effects on birds of different size are mediated by long-term climate and vegetation type in endangered temperate woodlands. AB - Species occurrence is influenced by a range of factors including habitat attributes, climate, weather and human landscape modification. These drivers are likely to interact, but their effects are frequently quantified independently. Here we report the results of a 13-year study of temperate woodland birds in south-eastern Australia to quantify how different sized birds respond to the interacting effects of: (1) short-term weather (rainfall and temperature in the 12 months preceding our surveys), (2) long-term climate (average rainfall and maximum and minimum temperatures over the period 1970 to 2014), and (3) broad structural forms of vegetation (old-growth woodland, regrowth woodland, and restoration plantings). We uncovered significant interactions between bird body size, vegetation type, climate and weather. High short-term rainfall was associated with decreased occurrence of large birds in old-growth and regrowth woodland, but not in restoration plantings. Conversely, small bird occurrence peaked in wet years, but this effect was most pronounced in locations with a history of high rainfall, and was actually reversed (peak occurrence in dry years) in restoration plantings in dry climates. The occurrence of small birds was depressed - and large birds elevated - in hot years, except in restoration plantings which supported few large birds under these circumstances. Our investigation suggests that different mechanisms may underpin contrasting responses of small and large birds to the interacting effects of climate, weather and vegetation type. A diversity of vegetation cover is needed across a landscape to promote the occurrence of different sized bird species in agriculture dominated landscapes, particularly under variable weather conditions. Climate change is predicted to lead to widespread drying of our study region and restoration plantings, especially in currently climatically-wet areas may become critically important for conserving bird species, particularly small-bodied taxa. This article is protected by copyright. All rights reserved. PMID- 30431212 TI - Dual Nickel and Bronsted Acid Catalysis for Hydroalkenylation. AB - A highly regioselective hydroalkenylation of imines or aldehydes with styrene derivatives was realized by dual catalysis with Ni(cod)2 /PCy3 and either TsNH2 or PhB(OH)2 . This process provides an atom-, step-, and redox-economic pathway towards synthetically useful allylic amines and alcohols, and opens up a new avenue for the design of more versatile coupling reactions. PMID- 30431213 TI - Emicizumab: Review of the literature and critical appraisal. AB - INTRODUCTION: Emicizumab-kywh (ACE910) is a recombinant, humanized, asymmetric bispecific antibody that functions to bring activated FIX (FIXa) and zymogen FX into an appropriate steric conformation to medicate the activation of FX to FXa thereby mimicking the cofactor function of FVIIIa. AIM: The objective of this manuscript was to review the development and potential role for emicizumab in the treatment of patients with haemophilia A with and without inhibitors. METHODS: A Cochrane Library and PubMed (MEDLINE) search focusing on emicizumab in haemophilia was conducted. RESULTS: In total, 37 citations were retrieved and serve as the database for the literature reviewed herein. Once-weekly subcutaneous injection of emicizumab at three dose levels has been shown to be effective as prophylaxis to prevent bleeding in a majority haemophilia A patients with inhibitors to FVIII. Likewise, prevention of bleeding was also observed in more than two thirds of patients without inhibitors to FVIII. One antidrug antibody to emicizumab has been reported in over 600 treated patients, two have developed thromboembolic events and three thrombotic microangiopathy. These thrombotic complications have occurred in conjunction with FVIII-bypassing agents, and none have been observed following recommendations from the manufacturer regarding concomitant use of bypassing agents. The median annual treated bleeding rates were decreased in patients with as well as those without an inhibitor to FVIII. CONCLUSION: The principal advantage of emicizumab is subcutaneous administration and effectiveness irrespective of the presence of inhibitors. Emicizumab could conceivably represent a new epoch in the treatment of people with haemophilia A. PMID- 30431214 TI - NFKB1 promoter polymorphism: A new predictive marker of cytomegalovirus infection after kidney transplantation. AB - INTRODUCTION: Cytomegalovirus (CMV) infection represents a common cause of morbidity and mortality in kidney transplant recipients (KTR). The NF-kB signaling pathway is highly involved in the pathogenesis of CMV infection. The 94ins/delATTG functional polymorphism in the promoter of NFKB1 has been associated with low intracellular levels of the protein and high incidence of inflammatory and autoimmune disease. In this study, we evaluated the association of this NFKB1 polymorphism with the risk of CMV infection. METHODS: CMV infection was defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. Using Cox regression and survival analysis, we analyzed the association between the polymorphism and CMV infection as well as recurrence in the first 12 months after transplantation. RESULTS: We analyzed the -94ins/delATTG NFKB1 polymorphism of 189 KTRs. The 65% of CMV infections occurred in ins/ins group. Survival free from CMV infection was 54.7% for ins/ins group and 79.4% for deletion carriers one year after transplantation (P < 0.0001). At multivariate regression, deletion carriers showed a lower risk of CMV infection and recurrence with respect to ins/ins KTRs (HR = 0.224 P = 0.0002; HR = 0.307, P = 0.012, respectively). CONCLUSIONS: In conclusion, pretransplantation screening for NFKB1 -94ins/delATTG polymorphism may predict CMV infection and improve the management of patients at higher risk of infection in the post-transplant period. PMID- 30431215 TI - Donor derived HSV hepatitis in a kidney transplant recipient leading to liver fibrosis and portal hypertension. AB - The unexpected transmission of donor-derived infection through organ transplantation is a rare event with current donor screening practices. In this case report we describe a probable donor-derived transmission of Herpes Simplex Virus (HSV)-2 via deceased donor kidney transplantation resulting in HSV hepatitis in the recipient. This manifested as acute liver failure which resolved with appropriate anti-viral therapy. Following recovery from the acute liver insult, the patient developed fibrotic liver morphology and portal hypertension, an unusual departure from the typical course. PMID- 30431217 TI - Vitamin D supplementation and its influence on muscle strength and mobility in community-dwelling older persons: a systematic review and meta-analysis. PMID- 30431216 TI - Diagnostic usefulness of plexus MRI in chronic inflammatory demyelinating polyradiculopathy without electrodiagnostic criteria of demyelination. AB - INTRODUCTION: The usefulness of plexus MRI in the diagnosis of chronic inflammatory demyelinating polyradiculopathy (CIDP) without definite EFNS/PNS electrodiagnostic criteria is currently unclear. METHODS: Data from consecutive patients with clinical manifestations suggesting CIDP, with or without (CIDP-D and CIDP-ND, respectively) definite EFNS/PNS electrodiagnostic criteria, and referred for plexus MRI in our imaging center were retrospectively analyzed. An expert committee of neurologists compared the level of suspicion of CIDP in CIDP ND patients to the blinded/unblinded MRI findings. Plexus MRI were reviewed by a neuroradiologist blinded to the final diagnosis. RESULTS: We assessed 38 patients with suspected CIDP-ND (7/38 [18%], probable; 13/38 [34%], possible; 18/38 [47%], no EFNS/PNS electrodiagnostic criteria), plus 10 with CIDP-D. Thirty-six of the 38 (95%) fulfilled clinical criteria of CIDP variants, including pure sensory neuropathy in 22/36 (61%). Plexus MRI showed abnormalities in 22/38 (58%) patients including increased nerve signal intensity on T2-weighted images in 22/22 (100%), nerve enlargement in 20/22 (91%), and contrast enhancement in 8/22 (36%). Plexus MRI enabled the expert committee's final diagnosis to be adjusted in 7/38 (18%) patients, and in conjunction with nerve conduction studies, was a supportive criterion to classify 7/24 (29%) patients as definite CIDP. MRI abnormalities were more asymmetrical (P=0.03) and less diffuse (P=0.1) in CIDP-ND than in CIDP-D. CONCLUSIONS: Our observations suggest that plexus MRI makes a valuable contribution to the diagnosis of CIDP-ND patients. Further studies are needed to investigate inter-rater reliability of clinical and imaging criteria of CIDP in these patients, and the impact on outcomes. This article is protected by copyright. All rights reserved. PMID- 30431218 TI - Whole exome sequencing in the diagnostic workup of patients with a bleeding diathesis. AB - INTRODUCTION: Bleeding assessment tools and laboratory phenotyping often remain inconclusive in patients with a haemorrhagic diathesis. AIM: To describe the phenotype and genetic profile of patients with a bleeding tendency. METHODS: Whole exome sequencing (WES) was incorporated in the routine diagnostic pathway of patients with thrombocytopenia (n = 17), platelet function disorders (n = 19) and an unexplained bleeding tendency (n = 51). The analysis of a panel of 126 OMIM (Online Mendelian Inheritance in Man) genes involved in thrombosis and haemostasis was conducted, and if negative, further exome-wide analysis was performed if informed consent given. RESULTS: Eighteen variants were detected in 15 patients from a total of 87 patients (17%). Causative variants were observed in MYH9 (two cases), SLFN14, P2RY12 and GP9. In addition, one case was considered solved due to combined carriership of F7 and F13A1 variants and one with combined carriership of F2, F8 and VWF, all variants related to secondary haemostasis protein aberrations. Two variants of uncertain significance (VUS) were found in two primary haemostasis genes: GFI1B and VWF. Eight patients were carriers of autosomal recessive disorders. Exome-wide analysis was performed in 54 cases and identified three variants in candidate genes. CONCLUSION: Based on our findings, we conclude that performing WES at the end of the diagnostic trajectory can be of additive value to explain the complete bleeding phenotype in patients without a definite diagnosis after conventional laboratory tests. Discovery of combinations of (novel) genes that predispose to bleeding will increase the diagnostic yield in patients with an unexplained bleeding diathesis. PMID- 30431219 TI - The Catalytic Enantioselective Ugi Four-Component Reactions. AB - Finally stereoselective: Enantioselective variations have been developed for many multicomponent reactions; however, it has been missing for the Ugi four-component reaction. This has now changed with the discovery of an efficient catalytic enantioselective variant for the four-component reaction of isocyanides, primary amines, aldehydes or ketones, and carboxylic acids. PMID- 30431220 TI - Design, Synthesis and Characterization of Covalent KDM5 Inhibitors. AB - Histone lysine demethylase (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub family. The covalent binding to the targeted proteins was confirmed by MS and time-dependent inhibition. Additional competition assays show that compounds were non 2-OG competitive. Target engagement and ChIP-seq analysis showed that the compounds inhibited the KDM5 members in cells at nano- to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites. PMID- 30431221 TI - Exploration of Interfacial Porphine Coupling Schemes and Hybrid Systems by Bond Resolved Scanning Probe Microscopy. AB - The templated synthesis of porphyrin-based oligomers and heterosystems is of considerable interest for materials with tunable electronic gaps, photovoltaics, or sensing device elements. In this work, temperature-induced dehydrogenative coupling between unsubstituted free-base porphine units and their attachment to graphene nanoribbons on a well-defined Ag(111) support are scrutinized by bond resolved scanning probe microscopy techniques. The detailed inspection of covalently fused porphine dimers obtained by in vacuo on-surface synthesis clearly reveals atomistic details of coupling motifs, whereby also putative reaction intermediates are identified. Moreover, the covalent attachment of porphines at preferred locations of atomically precise armchair-type graphene nanoribbons is demonstrated. PMID- 30431222 TI - Towards evolution of artificial metalloenzymes - A protein engineer's perspective. AB - Incorporating artificial metal-cofactors into protein scaffolds results in a new class of catalysts termed biohybrid catalysts or artificial metalloenzymes. Biohybrid catalysts can be modified chemically at the first coordination sphere of the metal complex as well as at the second coordination sphere provided by the protein scaffold. Protein scaffold reengineering by directed evolution exploits the full power of nature's diversity but requires validated screening and sophisticated metal cofactor conjugation to evolve biohybrid catalysts. In this minireview, we summarize the recent efforts in this field to establish high throughput screening methods for biohybrid catalysts and we show how non-chiral catalysts catalyze reactions enantioselectively by highlighting the first successes in this emerging field. Furthermore, we shed light on the potential and challenges that need to be overcome to advance from biohybrid catalysts to true artificial metalloenzymes. PMID- 30431223 TI - Metathesis at an Implausible Site: A Formal Total Synthesis of Rhizoxin D. AB - The new approach to the anticancer agent rhizoxin D described herein does not cohere with the conventional logic of metathesis, according to which macrocycles are best closed at a disubstituted olefinic site; rather, the trisubstituted C11 C12 alkene flanked by an allylic -OH group served as the pivot point for synthesis. This motif was attained in good yield and excellent selectivity by a sequence of alkyne metathesis, trans-hydrostannation and cross coupling. Because the exact same substructure is prominently featured in numerous other natural products, the underpinning strategy, though unusual, might bear more general relevance. PMID- 30431224 TI - New approaches to characterizing bacteria-phage interactions in microbial communities and microbiomes. PMID- 30431225 TI - From bugs to bioplastics: Total (+)-dihydrocarvide biosynthesis by engineered Escherichia coli. AB - The monoterpenoid lactone derivative (+)-dihydrocarvide ((+)-DHCD) can be polymerised to form shape memory polymers. Synthetic biology routes from simple, inexpensive carbon sources are an attractive, alternative route over chemical synthesis from (R)-carvone. We have demonstrated a 'proof of principle' in vivo approach for the complete biosynthesis of (+)-DHCD from glucose in E. coli (6.6 mg/L). The pathway is based on the Mentha spicata route to (R)-carvone, with the addition of an 'ene'-reductase and Baeyer-Villiger cyclohexanone monooxygenase. Co-expression with a limonene synthesis pathway enables complete biocatalytic production within one microbial chassis. Successful production of (+)-DHCD was achieved by screening multiple homologues of the pathway genes, combined with expression optimisation via selective promoter and/or ribosomal binding site screening. This study demonstrates the potential application of synthetic biology approaches in the development of truly sustainable and renewable bioplastic monomers. PMID- 30431226 TI - The redundancy of positivism as a paradigm for nursing research. AB - New nursing researchers are faced with a smorgasbord of competing methodologies. Sometimes, they are encouraged to adopt the research paradigms beloved of their senior colleagues. This is a problem if those paradigms are no longer of contemporary methodological relevance. The aim of this paper was to provide clarity about current research paradigms. It seeks to interrogate the continuing viability of positivism as a guiding paradigm for nursing research. It does this by critically analysing the methodological literature. Five major paradigms are addressed: the positivist; the interpretivist/constructivist; the transformative; the realist; and the postpositivist. Acceptance of interpretivist, transformative or realist approaches necessarily entails wholesale rejection of positivism, while acceptance of postpositivism involves its partial rejection. Postpositivism has superseded positivism as the guiding paradigm of the scientific method. The incorporation in randomized controlled trials of postpositivist assumptions indicates that even on the methodological territory that it once claimed as its own, positivism has been rendered redundant as an appropriate paradigm for contemporary nursing research. PMID- 30431227 TI - Naringenin inhibited migration and invasion of glioblastoma cells through multiple mechanisms. AB - Glioblastoma (GBM) is the most mortality brain cancer in the world. Due to high invasion and drug resistance cause the poor prognosis of GBM. Naringenin, an ingredient of citrus, exhibits many cellular functions such as antioxidant, anti inflammation, and anticancer. Naringenin inhibits the migration of bladder and lung cancer via modulation of MMP-2 and/or MMP-9 activities, Naringenin inhibits migration and trigger apoptosis in gastric cancer cells through downregulation of AKT pathway. However, the effects of naringenin in GBM still remain to be elucidated. In this study, we reveal the molecular mechanisms of naringenin in the inhibition of migration and invasion in GBM. No overt alternation of cell proliferation was found in of GBM 8901 cells treated with different concentration of naringenin. Slight decreased cell viability was found in GBM 8401 cell treated with 200 and 300 MUM naringenin. Significant reduction of migration and invasion as assayed by Boyden chamber analysis was found in of GBM cells treated with 100, 200, and 300 MUM naringenin. Zymography analysis also revealed that the activities of MMP-2 and MMP-9 of GBM cells were significantly inhibited in response to 100, 200, or 300 MUM naringenin treatment. Proteins of MMP-2 and MMP 9 were downregulated in naringenin treated GBM cells. In addition, naringenin also attenuated the activities of ERK and p38. Naringenin decreased mesenchymal markers (snail and slug) expression as revealed by Western blot analysis. Taken together, our findings indicated that naringenin eliminated the migration and invasion of GBM cells through multiple mechanisms including inhibition of MMPs, ERK, and p38 activities and modulation of EMT markers. Our results also suggested that naringenin may be a potential agent to prevent metastasis of GBM. PMID- 30431229 TI - DNA barcodes identify 99 percent of apoid wasp species (Hymenoptera: Ampulicidae, Crabronidae, Sphecidae) from the Western Palearctic. AB - The apoid wasps have traditionally been regarded as a paraphyletic assemblage of four families (Ampulicidae, Crabronidae, Heterogynaidae and Sphecidae) that are closely related to the bees (Anthophila). The present study covers the three families of apoid wasps known to occur in Europe, i.e., the Ampulicidae, Crabronidae, and Sphecidae. DNA barcode sequences of 3,695 specimens of apoid wasps were analyzed for the present study, including 21 specimens of Ampulicidae, 3,398 Crabronidae, and 276 Sphecidae. The sequences of the dataset represent 661 species of apoid wasps, including two species of Ampulicidae, 613 of Crabronidae, and 46 species of Sphecidae. The dataset includes DNA barcodes of 240 species of German apoid wasps, representing 88% of the German fauna, and, 578 European species, representing 65% of the European apoid wasp fauna. The study demonstrates that virtually all species of the three examined families can be reliably identified by DNA barcodes. The implications of highly congruent results between traditional taxonomy and DNA barcoding for the reliable application of DNA-based identifications are discussed. This article is protected by copyright. All rights reserved. PMID- 30431228 TI - High Seroprevalence of anti-Hepatitis E antibodies in Austrian patients with Autoimmune Hepatitis. AB - BACKGROUND & AIMS: Increasing numbers of autochthonous hepatitis-E-virus (HEV) infections have been reported in Europe. Chronic infections have been shown in immune-compromised patients after solid-organ transplantation. HEV might be a possible trigger for AIH and might cause disease flares or relapses in the further course of disease. Aim of this study was to investigate the presence of HEV antibodies and HEV-RNA and to analyze their impact on immunosuppressive treatment in patients with AIH. METHODS: Sera from 92 autoimmune hepatitis patients (73/79.3% female, age: 42.2+/-16.3 years [mean+/-SD]) were tested. Patients were scored according to the simplified and revised scoring systems of the International Autoimmune Hepatitis Group. The prevalence of anti-HEV (Beijing Wantai Biological Pharmacy Enterprises Co., Ltd.) and HEV-RNA was determined. RESULTS: 19/20.7% AIH-patients tested positive for HEV-IgG, which was higher than in previous reports of healthy Austrian individuals (12.4%, p=0.031); HEV-RNA was not detectable in any patient. Anti-HEV-positive patients were older (49.5+/-9.5 vs. 40.4+/-17.2 years [mean+/-SD], p=0.033) but did not differ in laboratory findings at diagnosis (AST:14.6 [1.3-70.6] vs. 9.5 [0.7-62.7] xULN [median/range]; p=0.387, ALT:18.3 [1.6-62.7] vs. 12.9 [0.8-62.6] xULN; p=0.511; IgG:1.4 [1.0-2.5] vs. 1.3 [0.6-3.8] g/dl x ULN; p=0.278) nor in ALT levels after six months (0.7 [0.5-2.4] vs. 1.0 U/l xULN [0.1-22.4]; p=0.077). CONCLUSIONS: No chronic HEV infection was observed in our cohort of AIH patients. Anti-HEV-IgG positive patients were older and the seroprevalence was nearly twice as high as reported previously in healthy Austrian individuals, suggesting that HEV infection might act as trigger for the development of autoimmune hepatitis. This article is protected by copyright. All rights reserved. PMID- 30431230 TI - Comparison of Risk Factors and Outcomes of Daptomycin-Susceptible and Nonsusceptible Vancomycin-Resistant Enterococcus faecium Infections in Liver Transplant Recipients; A reply to Jorgenson et al. AB - We thank Jorgenson et al. for commenting on our paper. In their letter, the authors provide an analysis of daptomycin non-susceptible vancomycin-resistant Enterococcus (DNS-VRE) infections in liver transplant recipients (LTRs) at their transplant center, comparing 9 episodes of DNS-VRE infection with 61 episodes of daptomycin-susceptible vancomycin-resistant Enterococcus (DS-VRE) infection. This article is protected by copyright. All rights reserved. PMID- 30431231 TI - Novel Application of Aptamer Proteomic Analysis in Cystic Fibrosis Bronchoalveolar Lavage Fluid. AB - PURPOSE: Biomarkers are needed in cystic fibrosis (CF) to understand disease progression, assess response to therapy, and enrich enrollment for clinical trials. Aptamer-based proteomics have proven useful in blood samples. We aimed to evaluate proteins in bronchoalveolar lavage fluid (BALF) in CF children compared to controls and identify endotypes during CF exacerbations. EXPERIMENTAL DESIGN: BALF was collected clinically from 50 patients with CF and 9 disease controls, processed, and stored per protocol. BALF supernatants were analyzed for 1129 proteins by aptamer approach (SOMAscan proteomics platform). Proteins were compared across groups and used for pathway analysis. Endotypes were identified within the CF group. RESULTS: CF BALF had increased concentrations of neutrophil elastase, myeloperoxidase and decreased concentration of protein folding and host defense proteins. Pathways that distinguished CF subjects included interferon gamma signaling, membrane trafficking, and phospholipid metabolism. In the CF group, unbiased analysis of proteins identified two distinct endotypes that differed based on BALF white blood cell and neutrophil counts and detection of CF pathogens. CONCLUSIONS AND CLINICAL RELEVANCE: Proteomic analysis of the CF airway demonstrates a complex environment of proteins and pathways. This work provides evidence that aptamer-based proteomics can differentiate between groups and can determine endotypes within CF. This article is protected by copyright. All rights reserved. PMID- 30431232 TI - The role of Protocadherin 19 (PCDH19) in neurodevelopment and in the pathophysiology of early infantile epileptic encephalopathy-9 (EIEE9). AB - PCDH19 is considered one of the most clinically relevant gene in epilepsy, second only to SCN1A. To date about 150 mutations have been identified as causative for PCDH19-female epilepsy (also known as early infantile epileptic encephalopathy-9, EIEE9), which is characterized by early onset epilepsy, intellectual disabilities and behavioral disturbances. Although little is known about the physiological role of PCDH19 and the pathogenic mechanisms that lead to EIEE9, in this review, we will present latest researches focused on these aspects, underlining protein expression, its known functions and the mechanisms by which the protein acts with particular interest in PCDH19 extracellular and intracellular neuronal roles. This article is protected by copyright. All rights reserved. PMID- 30431233 TI - Dextran-based hydrogel with enhanced mechanical performance via covalent and non covalent cross-linking units carrying adipose derived stem cells towards vascularized bone tissue engineering. AB - Hydrogels for biomedical applications were limited towards bone tissue engineering due to the poor mechanical performance. Tough hydrogels with strong and elastic features have received extensive attention, the application of which, however, was limited by their degradation. The present study introduced an approach to enhance mechanical properties of hydrogel while ensuring its degradation. Carboxyl dextran (Dex) was grafting modified by poly (epsilon caprolactone) (PCL), sequentially followed by being cross-linked through polyethyleneglycol 400 (PEG400) to yield a gel with covalent cross-linking units in DMSO. The gel was underwent solvent displacement in H2 O to induce hydrophobic association of PCL to form non-covalent cross-linking units. The tough Dex-g-PCL hydrogel showed maximum strain of Dex-g-PCL hydrogel was 90% +/- 6%, with the corresponding stress of 2.7+/-0.2 MPa, which was significantly enhanced when comparing to dextran hydrogel (maximum strain 65%+/-5%, with the corresponding stress of 0.225+/-0.06 MPa). Most hydrogel degraded after 12 w in vivo with only a little residues. Adipose derived stem cells (ASCs) proliferated well after being seeded in hydrogel to form micro-mass at 14 days post-seeding. In vitro and in vivo angiogenesis, as well as in vitro osteogenesis illustrated the potential of the Dex-g-PCL hydrogel carrying ASCs towards vascularized bone tissue engineering. This article is protected by copyright. All rights reserved. PMID- 30431234 TI - Investigation of virus retention by size exclusion membranes under different flow regimes. AB - Virus removal by filter membranes is regarded as a robust and efficient unit operation, which is frequently applied in the downstream processing of biopharmaceuticals. The retention of viruses by virus filtration membranes is predominantly based on size exclusion. However, recent results using model membranes and bacteriophage PP7 point to the fact that virus retention can also significantly be influenced by adsorptive interactions between virus, product molecules, and membranes. Furthermore, the impact of flow rate and flow interruptions on virus retention have been studied and responsible mechanisms discussed. The aim of this investigation was to gain a holistic understanding of the underlying mechanisms for virus retention in size exclusion membranes as a function of membrane structure and membrane surface properties, as well as flow and solution conditions. The results of this study contribute to the differentiation between size exclusion and adsorptive effects during virus filtration and broaden the current understanding of mechanisms related to virus breakthroughs after temporary flow interruptions. Within the frame of a Design of Experiments approach it was found that the level of retention of virus filtration membranes was mostly influenced by the membrane structure during typical process related flow conditions. The retention performance after a flow interruption was also significantly influenced by membrane surface properties and solution conditions. While size exclusion was confirmed as main retention mechanism, the analysis of all results suggests that especially after a flow interruption virus retention can be influenced by adsorptive effects between the virus and the membrane surface. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 2018. PMID- 30431235 TI - Fewer teeth are a risk factor for being underweight in community-dwelling Japanese aged 40 years and older: the Yamagata (Takahata) Study. AB - OBJECTIVE: The aim of the present study was to investigate comprehensively the risk factors for underweight in cross-sectional study in the general population of Japan. METHODS: The survey population was the general population of individuals aged >40 years in Takahata town, Japan in 2005. A postal survey in the form of a self-administered questionnaire was distributed, and 6084 individuals were entered into the final statistical analysis. The self administered questionnaire contained items regarding lifestyle, oral health status, socioeconomic status, and dietary intake. To examine the independent relationships between an underweight status and several parameters, a multivariate logistic regression analysis was used to estimate adjusted odds ratios (ORs). RESULTS: The number of teeth, age, alcohol consumption, hypertension, spousal status, smoking habit, appetite, body weight at 20 years of age, habit of going out, and physical activity were independently associated with an underweight status compared with the normal weight group. Individuals with fewer than 10 teeth were especially more likely to be underweight than individuals with more than 20 teeth (OR = 1.956, 95% CI = 1.261-3.035). CONCLUSION: This study showed an independent association between the number of teeth and an underweight status, indicating that fewer teeth can increase the risk of being underweight. This article is protected by copyright. All rights reserved. PMID- 30431236 TI - First detection of novel enterovirus G recombining a torovirus papain-like protease gene associated with diarrhoea in swine in South Korea. AB - Enterovirus species G (EV-G) comprises a highly diversity of 20 genotypes that is prevalent in pig populations, with or without diarrhoea. In the present study, a novel EV-G strain (KOR/KNU-1811/2018) that resulted from cross-order recombination was discovered in diagnostic faecal samples from neonatal pigs with diarrhoea that were negative for swine enteric coronaviruses and rotavirus. The recombinant EV-G genome possessed an exogenous 594-nucleotide (198-amino acid) sequence, flanked by two viral 3Cpro cleavage sites at the 5' and 3' ends in its 2C/3A junction region. This insertion encoded a predicted protease similar to the porcine torovirus papain-like cysteine protease (PLCP), which was recently found in the EV-G1, -G2, and -G17 genomes. The complete KNU-1811 genome shared 73.7% nucleotide identity with a prototype EV-G1 strain, but had 83.9%-86.7% sequence homology with the global EV-G1-PLCP strains. Genetic and phylogenetic analyses demonstrated that the Korean recombinant EV-G's own VP1 and inserted foreign PLCP genes are most closely related independently to contemporary chimeric G1-PLCP and G17-PLCP strains respectively. These results implied that the torovirus-derived PLCP gene might have undergone continuous nucleotide mutations in the respective EV-G genome following its independent acquisition through naturally occurring recombination. Our results advance the understanding of the genetic evolution of EV-G driven by infrequent viral recombination events, by which EV-G populations laterally gain an exotic gene encoding a virulence factor from heterogeneous virus families, thereby causing clinical disease in swine. PMID- 30431237 TI - Analysis of Organelle Positioning Using Patterned Microdevices. AB - The consequences of alterations in the distribution of intracellular organelles, observed in many diseases, are often not clear. Intracellular organelles alter their morphology and positioning to regulate cell homeostasis and function. We outline how organelle positioning can be studied employing a density-based analysis of 3D images applied to cells that show similar cellular geometries. Quantification is facilitated by the use of single cells seeded on micropatterned substrates that provide cues for controlled cell spreading. This minimal system mimics the reproducible distribution of organelles typically observed in tissues, simplifying image analysis and minimizing the number of cells required for the observation of robust phenotypes. Here we provide guidelines for how the majority of organelles can be efficiently analyzed in cells seeded on adhesive micropatterns. We exemplify how alterations in the positioning of different organelles as a result of the perturbation of the cytoskeleton or associated motor proteins can be efficiently quantified. (c) 2018 by John Wiley & Sons, Inc. PMID- 30431238 TI - Connecting Proteomics to Next-Generation Sequencing (NGS): Proteogenomics and its Current Applications in Biology. AB - Understanding the relationship between genotypes and phenotypes is essential to disentangle biological mechanisms and to unravel the molecular basis of diseases. Genes and proteins are closely linked in biological systems. However, genomics and proteomics have developed separately into two distinct disciplines whereby crosstalk among scientists from the two domains has been limited and this constrains the integration of both fields into a single data modality of useful information. The emerging field of proteogenomics attempts to address this by building bridges between the two disciplines. In this review, we briefly discuss how genomics and transcriptomics data in different formats can be utilized to assist proteogenomics application. Subsequently, a much larger part of this review focuses on proteogenomics research that are published in the last five years that answer two important questions. Firstly, we discuss how proteogenomics can be applied to tackle biological problems, covering genome annotation and precision medicine. Secondly, we cover the latest developments in analytical technologies for data acquisition and the bioinformatics tools to interpret and visualize proteogenomics data. This article is protected by copyright. All rights reserved. PMID- 30431239 TI - Up-close-and-personal with the human microbiome. PMID- 30431240 TI - FANCD2 protects genome stability by recruiting RNA processing enzymes to resolve R-loops during mild replication stress. AB - R-loops, which consist of DNA : RNA hybrids and displaced single-strand DNA, are a major threat to genome stability. We have previously reported that a key Fanconi anemia protein, FANCD2, accumulates on large fragile genes during mild replication stress in a manner depending on R-loops. In this study, we found that FANCD2 suppresses R-loop levels. Furthermore, we identified FANCD2 interactions with RNA processing factors, including hnRNP U and DDX47. Our data suggest that FANCD2, which accumulates with R-loops in chromatin, recruits these factors and thereby promotes efficient processing of long RNA transcripts. This may lead to a reduction in transcription-replication collisions, as detected by PLA between PCNA and RNA Polymerase II, and hence, lowered R-loop levels. We propose that this mechanism might contribute to maintenance of genome stability during mild replication stress. PMID- 30431241 TI - [Scorbut, historic disease ?] AB - Scurvy, a disease caused by a deficit in vitamin C, is again described in Europe nowadays. This condition is associated with poverty and malnutrition, as found in developing countries. However, denutrition may also occur with a "western" lifestyle that can lead to nutriment deficiencies. In the following report is described a case of scurvy in a person suffering from alcoholism. PMID- 30431242 TI - [Reappraisal of metformin : less restrictions and more potential indications]. AB - While commercialized since over 60 years, metformin is still the first-line drug recommended for the management of type 2 diabetes and is thus today the first glucose-lowering agent used worldwide. Despite this long experience, metformin retains its mysteries, especially regarding the underlying mechanisms responsible for its antidiabetic activity and other potential beneficial effects. During the last years, some contra-indications of metformin use have been at least partially withdrawn while new indications have been recognized. Furthermore, interesting prospects have been reported in important, although unexpected, medical areas such as cancer and neurodegenerative diseases. However, promising results in animal studies and observational human studies have now to be confirmed in well conducted randomized controlled trials. PMID- 30431243 TI - [Cardiac complications of sickle cell disease in children]. AB - Sickle cell disease (SCD) is a genetic disorder due to an abnormal gene coding for the chain ? of the hemoglobin. The main clinical manifestations related to the major forms of SCD (SS-, SC-, and S-thalassemia) are chronic hemolysis, susceptibility to infections and vasoconstrictive crisis causing micro-emboli and/or infarction responsible for acute or chronic organ lesions. The latest are enhanced by tissue iron overload due to repeated blood transfusions. Cardiac complications are an important part of morbidity and mortality of SCD. They are due to chronic anemia, vaso-occlusive crisis, iron overload, pulmonary, renal and hepatic damage. In children, cardiac complications of SCD are not sufficiently identified. They principally consist in dilated or restrictive cardiomyopathy and pulmonary arterial hypertension. Sudden death and acute cardiac failure due to myocardial infarction or arrhythmias have become exceptional. This review focuses on the pathophysiological aspects of cardiac complications of SCD and on the diagnostic tools allowing their early recognition and improvement of patient care. PMID- 30431244 TI - [Membranous occlusion of the inferior vena cava a rare cause of Budd-Chiari syndrome]. AB - Rarely encountered in the Western countries, membranous occlusion of the inferior vena cava results from a fibrous thickening of the intima and is commonly located at the orifices of the hepatic veins. To date, two etiopathogenic hypotheses have been formulated: the first, dealing with the embryological aspect, the second, arguing for a thrombotic origin. Nevertheless, several studies are still underway to understand the exact physiopathological mechanism of this obstruction. Among these studies, some suspect the predisposing role of anatomical and infectious factors. On average, it takes 6 years between the beginning of the symptoms and the diagnosis. The later the diagnosis is settled, the higher is the risk of encountering a hepatocellular carcinoma. The most relevant additional examinations to visualize the membrane are the abdominal ultrasound and the cavography. Computed tomography allows to highlight the effects of obstruction on the hepatic parenchyma. Concerning the treatment, many studies showed that angioplasty has an excellent immediate and late efficacy. A few surgical techniques also exist but those are less exploited because of the non invasive aspect and lower morbidity-mortality of the endovascular treatment. PMID- 30431245 TI - [Contribution of FreeStyle Libre(r) in the care of diabetic patients : experience at the CHU of Liege]. AB - Since July 2016, diabetic patients included in the INAMI glycemic self-monitoring system in category A in Belgium can benefit from a new system for measuring the concentration of subcutaneous glucose : FreeStyle Libre(r) (FSL) from Abbott company. The main advantage of this technology is that it is less invasive as it does not require finger blood sampling and allows patients to obtain, in addition to the instantaneous value of glucose concentration, retrospective kinetic data, but also prospective trend of its kinetics. In this study, we mainly evaluated the contribution of FSL on the overall equilibration of diabetes and on the time spent in hypoglycaemia. We also asked patients how satisfied they were with this system. Data from 838 diabetic patients (type 1 or total insulin deficiency) were collected between May 2016 and October 2017, 645 patients with FSL system and 193 preferring to continue self-monitoring of capillary blood glucose (SBG). In the FSL group, compared to the SBG group, there was a slight decrease in HbA1c estimated at 0.15 +/- 0.073 % after 15 months. This decrease appears mainly when the starting level is high (HbA1c superior to 7.5 %). Patients perform an average of 8.8 checks per day : the more patients perform daily scans, the greater the number of data comprised within the target, that is, the better the overall glucose control. A higher number of scans is also associated with a decrease in the average duration of hypoglycaemia. Finally, the satisfaction survey shows a high degree of patient satisfaction with the use of FSL. PMID- 30431246 TI - [Exacerbations in asthma and chronic obstructive pulmonary disease (COPD) Survey on the criteria of pescription of systemic corticoids and antibiotics by general practicioners and chest physicians]. AB - Exacerbations in asthma and chronic obstructive pulmonary disease (COPD) are critical events in the evolution of the disease. They are generally defined by the need to be temporarily treated by systemic corticoids and/or antibiotics. Very few studies have examined the criteria on which clinicians including general practitioners (GP) and chest physicians are basing their decision to prescribe. Here we report the results of a survey conducted in GP and chest physicians that looked at the clinical criteria judged as important to initiate a course of systemic corticoids or antibiotics in asthma and COPD. Our finding show discrepancy between GP and chest physicians regarding systemic corticoids but also, more surprisingly, within the same professional group. In contrast, criteria to prescribe antibiotics are more coherent between and within the groups. PMID- 30431247 TI - [Bone disorders and complications of pediatric acute lymphoblastic leukemia : monocentric study and review of the literature]. AB - Bone pain associated with bone marrow infiltration is often present at diagnosis of pediatric acute lymphoblastic leukemia (ALL). It sometimes signs the presence of pathological fracture, lytic lesions, arthritis, or osteitis associated to ALL that can delay the diagnosis. During treatment, bone complications (pain, osteopenia, fracture, avascular necrosis, ...) are also reported. In order to describe bone involvement (BI) of pediatric LLA, we reviewed the records of 104 patients followed in our unit. The overall incidence of BI was 67 %. At diagnosis, 50 % of patients had BI and in 19 %, the diagnosis of ALL was delayed. During and after treatment, respectively 28 % and 37 % of patients presented bone complications (pain, fractures, avascular necrosis, osteopenia). Patients with BI had a lower leukocytosis inferior to 10x109/l (p = 0.005) and an ALL of average risk (p = 0.019). 38 % of patients with BI during treatment were over 10 years old and 55 % were girls (vs. 21 % and 38 % in the entire cohort, respectively). Osteoporosis was more severe at diagnosis than during treatment, suggesting the presence of constitutional promoting factors. In our cohort, the majority of BI was resolved at the end of treatment with no long-term sequelae. PMID- 30431248 TI - [New 2018 European guidelines for the management of hypertension and comparison with the 2017 American guidelines]. AB - New European guidelines for high blood pressure management have just been published in 2018, modifying those published in 2013 and may be seen as a response to those published by the American societies late 2017. The latter proposed a new definition of hypertension (blood pressure equal or higher than 130/80 mmHg), a therapeutic approach based on the evaluation of the cardiovascular risk, and a blood pressure target inferior to130/80 mmHg in all patients, even those older than 80 years still valid. The European guidelines, on the contrary, maintain the definition threshold of hypertension to a blood pressure equal or higher than 140/90 mmHg. This diagnosis remains based on blood pressure determination at the medical office, confirmed if possible by the use of out of the clinic blood pressure measurements such as home blood pressure and/or 24h ambulatory blood pressure measurement. In comparison with 2013, these new guidelines are closer to the American ones for the management, with the need to evaluate the cardiovascular risk before deciding to initiate a drug treatment in addition to lifestyle and diet measures. A medical therapy will be initiated if the risk is very high for blood pressure in the range of high normal blood pressure (130-139/85-89 mmHg). The blood pressure target should be inferior to 130/80 mmHg in people inferior to 65 years. For those older the blood pressure target should be inferior to 140 mmHg but superior to 120 mmHg. The antihypertensive therapy would be, in the majority of the population, a two-drug combination, if possible in a single pill to enhance the medication compliance that should be frequently checked. If the blood pressure lowering remains resistant to three drugs including a diuretic used at high dose, spironolactone would be recommended, at a low dose. In comparison with 2013, the device-based therapies (renal denervation) are no longer recommended. PMID- 30431249 TI - [Exploring focal liver lesions with contrastenhanced ultrasonography]. AB - Noninvasive diagnosis of focal liver lesions is usually based on unenhanced ultrasonography, computed tomography, or magnetic resonance. Contrast-enhanced ultrasonography (CEUS) can be used among the other imaging modalities in evaluating these lesions. The technique requires the intravenous injection of contrast media. Ultrasound contrast agents are very safe and the technique doesn't involve any radiation. A large body of evidence supports and clarifies the role of CEUS in evaluating focal liver lesions. Hemangiomas, focal nodular hyperplasia, focal fatty change will be diagnosed in a majority of cases and CEUS is also helpful in distinguishing malignant from benign lesions. PMID- 30431250 TI - Safe and effective management of analgesics in patients presenting to hospital with acute illness. AB - Chronic pain affects a significant percentage of the population and is defined as pain that lasts beyond the point of healing. People presenting to hospital with acute illness may have underlying chronic pain that can be exacerbated by their presenting condition, even if this chronic pain is not the reason for their admission. While people may tolerate their usual medicine regimen under normal circumstances, small changes in their physical health can rapidly cause issues with their medication such as increased side effects. This article considers how nurses can improve the safety of people experiencing pain who have been admitted to hospital, and outlines when changes in their health might have implications for their prescribed analgesics. PMID- 30431251 TI - Unraveling the Role of Earth-Abundant Fe in the Suppression of Jahn-Teller Distortion of P'2-Type Na2/3MnO2: Experimental and Theoretical Studies. AB - Layered Na2/3MnO2 suffers from capacity loss due to Jahn-Teller (J-T) distortion by Mn3+ ions. Herein, density functional theory calculations suggest Na2/3[Fe xMn1- x]O2 suppresses the J-T effect. The Fe substitution results in a decreased oxygen-metal-oxygen length, leading to decreases in the b and c lattice parameters but an increase in the a lattice constant. As a result, the capacity retention and rate capability are enhanced with an additional redox pair associated with Fe4+/3+. Finally, the thermal properties are improved, with the Fe substitution delaying the exothermic reaction and reducing exothermic heat. PMID- 30431252 TI - Selective De-Cross-Linking of Transformable, Double-Network Hydrogels: Preparation, Structural Conversion, and Controlled Release. AB - This study has demonstrated the design of stimuli-responsive double-network hydrogels that are formed by sequential polymerization and show chemical transformation by selective de-cross-linking without structural failure owing to chemical orthogonality. Each self-immolative and thermoresponsive network established together the double-network structure through a thiol-ene click reaction and radical polymerization. The hydrogel exhibited enhanced mechanical strength but chemically transformed through the selective de-cross-linking of specific network triggered by a molecular stimulus, which significantly alters physical properties of the material such as tunable toughness and lower critical solution temperature behavior. In addition, the material displayed a thermoresponsive, controlled release. Only after treatment with the stimulus did the hydrogel release cargo molecules on demand via de-cross-linking while maintaining the entire structure. PMID- 30431253 TI - Highly Fluoro-Substituted Covalent Organic Framework and Its Application in Lithium-Sulfur Batteries. AB - We report the preparation of a highly fluoro-substituted crystalline covalent organic framework (COF) and its application as a cathode material in lithium sulfur batteries (LSBs) upon sulfur confinement. A sulfur-functionalized COF with high sulfur content (60 wt %) was obtained through physisorption of elemental sulfur and subsequent SNAr reaction of sulfur with aromatic fluorides on the COF backbone. After such physical and chemical confinement of sulfur through a postfunctionalization approach, the COF material still shows some structural order, allowing us to investigate the structure-property relationship of such COF materials in LSB application. We compared the electrochemical performances of the two cathode materials prepared from a crystalline COF and its amorphous counterpart and studied the important factors that affect battery capacity, reaction kinetics, and cycling stability. PMID- 30431254 TI - In Situ Synthesis and Unprecedented Electrochemical Performance of Double Carbon Coated Cross-Linked Co3O4. AB - Improving the structural stability and the electron/ion diffusion rate across whole electrode particles is crucial for transition metal oxides as next generation anodic materials in lithium-ion batteries. Herein, we report a novel structure of double carbon-coated Co3O4 cross-linked composite, where the Co3O4 nanoparticle is in situ covered by nitrogen-doped carbon and further connected by carbon nanotubes (Co3O4 NP@NC@CNTs). This double carbon-coated Co3O4 NP@NC@CNTs framework not only endows a porous structure that can effectively accommodate the volume changes of Co3O4, but also provides multidimensional pathways for electronic/ionic diffusion in and among the Co3O4 NPs. Electrochemical kinetics investigation reveals a decreased energy barrier for electron/ion transport in the Co3O4 NP@NC@CNTs, compared with the single carbon-coated Co3O4 NP@NC. As expected, the Co3O4 NP@NC@CNT electrode exhibits unprecedented lithium storage performance, with a high reversible capacity of 1017 mA h g-1 after 500 cycles at 1 A g-1, and a very good capacity retention of 75%, even after 5000 cycles at 15 A g-1. The lithiation/delithiation process of Co3O4 NP@NC@CNTs is dominated by the pseudocapacitive behavior, resulting in excellent rate performance and durable cycle stability. PMID- 30431255 TI - Control of Molecular Recognition via Modulation of the Nanoenvironment. AB - Many biological processes are driven by the interaction of a host with a guest molecule. We show such interactions can be modulated by carefully defining the local molecular environment to give a specific chemical outcome. Particularly, the selectivity of a host toward two different ions (Ca2+ and Al3+) is defined by it being in solution or the physisorbed state. In solution, the host displays greater selectivity toward Ca2+. When physisorbed, the selectivity profile of the host is reversed with enhanced binding of Al3+. This demonstrates a single host molecule can be tailored to selectively bind multiple guests by altering its nanoenvironment. PMID- 30431256 TI - Phthalocyanine Photoregeneration for Low Power Consumption Chemiresistors. AB - It is well-known that the applicability of phthalocyanine chemiresistors suffers from long recovery time after NO2 exposure. This circumstance enforces the necessity to operate the sensors at elevated temperatures (150-200 degrees C), which shortens the sensor lifetime and increases its power consumption (regardless, a typical measurement period is longer than 15 min). In this paper, we propose a new method for fast and effective recovery by UV-vis illumination at a low temperature (55 degrees C). The method is based on short illumination following short NO2 exposure. To support and optimize the method, we investigated the effects of light in the wavelength and intensity ranges of 375-850 nm and 0.2 0.8 mW/mm2, respectively, on the rate of NO2 desorption from the phthalocyanine sensitive layer during the recovery period. This investigation was carried out for a set of phthalocyanine materials (ZnPc, CuPc, H2Pc, PbPc, and FePc) operating at slightly elevated temperatures (55-100 degrees C) and was further supported by the analysis of UV-vis and FTIR spectral changes. We found out that the light with the wavelength shorter than 550 nm significantly accelerates the NO2 desorption from ZnPc, CuPc, and FePc, and allows bringing the measurement period under 2 min and decreasing the sensor power consumption by 75%. Possible mechanisms of the light-stimulated desorption are discussed. PMID- 30431257 TI - Three-Dimensional and Mesopore-Oriented Graphene Conductive Framework Anchored with Nano-Li4Ti5O12 Particles as an Ultrahigh Rate Anode for Lithium-Ion Batteries. AB - Because of the disadvantages of commercial graphite anodes for high-power lithium ion batteries, a kind of spinel nanolithium titanate (Li4Ti5O12)/graphene microsphere composite [denoted as LTO/reduced graphene oxide (rGO)] is successfully synthesized. The as-prepared composite is made up of curled graphene sheets which are anchored with nano-Li4Ti5O12 particles. These nano-Li4Ti5O12 particles are uniformly decorated on the conductive graphene framework and their sizes range from just 15 to 20 nm. In the as-prepared composite, the curled graphene sheets form a unique mesopore-oriented structure which provides plenty of three-dimensional channels for ion transportation. These structure characters greatly improve both the electron conductivity and Li+ diffusion ability. The ratio of pseudocapacitive capacity dramatically increases in the obtained LTO/rGO composite and generates excellent ultrahigh rate performances. The as-prepared LTO/rGO composite delivers a reversible capacity of 70.3 mA h g-1 at 200 C and a capacity retention of 84.7% after 1000 cycles at 50 C. As the current density varies from 30 to 100 C, the special capacity remains unchanged (about 112 mA h g 1). These results show that the graphene framework-supported nano-Li4Ti5O12 composite has potential application in high-power lithium-ion batteries. PMID- 30431258 TI - Simultaneous and Efficient Capture of Inorganic Nitrogen and Heavy Metals by Polyporous Layered Double Hydroxide and Biochar Composite for Agricultural Nonpoint Pollution Control. AB - Agricultural nonpoint pollution has been recognized as the main source of aquatic contaminants worldwide, such as inorganic nitrogen (ION) and heavy metals (HMs). It is an important challenge to simultaneously and efficiently immobilize soil ION and HMs in farmland. Herein, we present a polyporous Mg/Fe-layered double hydroxide and biochar composite (Mg/Fe-LDH@biochar) with the efficient coadsorption capacity of ION and HMs for the mitigation of agricultural nonpoint pollution toward aquatic systems. The Mg/Fe-LDH@biochar showed strong adsorption toward ION (i.e., NH4+-N and NO3--N) and HMs (i.e., Cu, Zn, Ni, Pb, and Cd), with maximum capacity of 98.53 mg of NH4+-N/g, 27.09 mg of NO3--N/g, 295.80 of mg Cu/g, 141.70 mg of Zn/g, 75.59 mg of Ni/g, 1264.10 mg of Pb/g, and 126.30 mg of Cd/g, respectively. More attractively, by deionized water extraction, the adsorbed ION on the composite was more easily rereleased, with a desorption percentage of about 42.33 +/- 6.87% NO3--N and 1.42 +/- 0.78% NH4+-N, than that of HMs (<1.0%). This difference is primarily related with the strength of bonding forces of ION and HMs when adsorbed on Mg/Fe-LDH@biochar, in the sequence of NO3- N (van der Waals force and electrostatic attraction) < NH4+-N (hydrogen bonding) < HMs (ionic/coordinate bonding). Finally, to examine the performance of Mg/Fe LDH@biochar for practical applications in farmland, column leaching experiments were successfully conducted by stimulated rainfall events. The addition of Mg/Fe LDH@biochar into soils could greatly reduce the leaching of ION and HMs simultaneously, with reduction ratios of >60, >40, and >90% for NH4+-N, NO3--N, and HMs, respectively, at 3.0% addition. Moreover, there was no leaching risk of Fe ions into the water body from Mg/Fe-LDH@biochar-amended soils. PMID- 30431259 TI - Laser-Induced Periodic Surface Structures (LIPSS) on Heavily Boron-Doped Diamond for Electrode Applications. AB - Diamond is known as a promising electrode material in the fields of cell stimulation, energy storage (e.g., supercapacitors), (bio)sensing, catalysis, etc. However, engineering its surface and electrochemical properties often requires costly and complex procedures with addition of foreign material (e.g., carbon nanotube or polymer) scaffolds or cleanroom processing. In this work, we demonstrate a novel approach using laser-induced periodic surface structuring (LIPSS) as a scalable, versatile, and cost-effective technique to nanostructure the surface and tune the electrochemical properties of boron-doped diamond (BDD). We study the effect of LIPSS on heavily doped BDD and investigate its application as electrodes for cell stimulation and energy storage. We show that quasi periodic ripple structures formed on diamond electrodes laser-textured with a laser accumulated fluence of 0.325 kJ/cm2 (800 nm wavelength) displayed a much higher double-layer capacitance of 660 MUF/cm2 than the as-grown BDD (20 MUF/cm2) and that an increased charge-storage capacity of 1.6 mC/cm2 (>6-fold increase after laser texturing) and a low impedance of 2.74 Omega cm2 turn out to be appreciable properties for cell stimulation. Additional morphological and structural characterization revealed that ripple formation on heavily boron-doped diamond (2.8 atom % [B]) occurs at much lower accumulated fluences than the 2 kJ/cm2 typically reported for lower doping levels and that the process involves stronger graphitization of the BDD surface. Finally, we show that the exposed interface between sp2 and sp3 carbon layers (i.e. the laser-ablated diamond surface) revealed faster kinetics than the untreated BDD in both ferrocyanide and RuHex mediators, which can be used for electrochemical (bio)sensing. Overall, our work demonstrates that LIPSS is a powerful single-step tool for the fabrication of surface-engineered diamond electrodes with tunable material, electrochemical, and charge-storage properties. PMID- 30431260 TI - Correlation between Structural Changes and Electrical Transport Properties of Spinel ZnFe2O4 Nanoparticles under High Pressure. AB - The structural phase transition of synthetic ZnFe2O4 nanoparticles (ZFO NPs) is investigated as a function of pressure up to 40.6 GPa at room temperature for the first time, and its associated intriguing electrical transport properties are resolved from in situ impedance spectra and magnetoresistivity measurements. Significant anomalies are observed in the properties of the grain boundary resistance ( Rgb), the relaxation frequency ( fmax), and the relative permittivity (epsilonr) in the ZFO NPs under the pressures around 17.5-21.5 GPa. These anomalies are believed to be correlated with a cubic-to-orthorhombic phase transition of ZnFe2O4 at the pressures between 21.9 and 25.7 GPa, which is found to be partially reversible. The pressure-tuned dielectric properties are measured for the cubic and the orthorhombic phases of ZFO, respectively. Remarkably, Rgb decreases up to 6 orders of magnitude as a function of pressure in the cubic phase. The dielectric polarization is obviously strengthened with increased fmax and decreased epsilonr with pressure in the orthorhombic phase. Furthermore, it is confirmed that the external pressure effectively improves the electrochemical stability of the sample based on the cycled measurements of the impedance spectra at various pressures. The changes in the complex permittivity (epsilon', epsilon") and the dielectric loss tangent (tan delta) with frequency reveal the irreversible increase in the dielectric loss accompanied by phase transition. The MR measurements indicate that ZFO NPs are superparamagnetic under high pressure of up to 40 GPa. The transmission electron microscopy images reflect the decrease in the grain boundary number and some local amorphization of grains after compression, which provides good explanations for the changes in the electrical transport properties as a function of pressure. Herein, the structural and electrical properties of ZnFe2O4 NPs generated are preserved by quenching the high-pressure phase to ambient conditions, thus providing great choices of ferrites materials for a variety of applications. PMID- 30431261 TI - Triple-Modal Imaging-Guided Chemo-Photothermal Synergistic Therapy for Breast Cancer with Magnetically Targeted Phase-Shifted Nanoparticles. AB - Current nanodrug-based cancer therapy is susceptible to the problems of rapid clearance from circulation and limited therapeutic efficacy. Herein, we report a magnetically targeted and photothermal-triggered drug release nanotheranostics system based on superparamagnetic iron oxide (Fe3O4), IR780, doxorubicin (DOX), and perfluoropentane (PFP) entrapped poly-lactide- co-glycolide (PLGA) nanoparticles (IR780/Fe3O4@PLGA/PFP/DOX NPs) for triple-modal imaging-guided synergistic therapy of breast cancer. In this work, IR780 and Fe3O4 convert light into heat, which triggers DOX release from IR780/Fe3O4@PLGA/PFP/DOX NPs and a phase-shift thermoelastic expansion of PFP; this procedure further accelerates the DOX release and tissue extrusion deformation. Fe3O4 NPs also serve as the target moiety by an external magnet directed to the tumor. Specifically, the IR780/Fe3O4@PLGA/PFP/DOX NPs can be used for triple-modal imaging, including near infrared fluorescence, magnetic resonance, and ultrasound. Furthermore, the antitumor therapy studies reveal the extraordinary performance of IR780/Fe3O4@PLGA/PFP/DOX NPs in magnetically targeted synergistic chemo photothermal therapy of cancer. Therefore, the multifunctional IR780/Fe3O4@PLGA/PFP/DOX NPs guided by the magnetic field show a great potential for cancer theranostics. PMID- 30431262 TI - Roles of Small GTPases in Acquired Tamoxifen Resistance in MCF-7 Cells Revealed by Targeted, Quantitative Proteomic Analysis. AB - Development of tamoxifen resistance remains a tremendous challenge for the treatment of estrogen-receptor (ER)-positive breast cancer. Small GTPases of the Ras superfamily play crucial roles in intracellular trafficking and cell signaling, and aberrant small-GTPase signaling is implicated in many types of cancer. In this study, we employed a targeted, quantitative proteomic approach that relies on stable-isotope labeling by amino acids in cell culture (SILAC), gel fractionation, and scheduled multiple-reaction-monitoring (MRM) analysis, to assess the differential expression of small GTPases in MCF-7 and the paired tamoxifen-resistant breast cancer cells. The method displayed superior sensitivity and reproducibility over the shotgun-proteomic approach, and it facilitated the quantification of 96 small GTPases. Among them, 13 and 10 proteins were significantly down- and up-regulated (with >1.5-fold change), respectively, in the tamoxifen-resistant line relative to in the parental line. In particular, we observed a significant down-regulation of RAB31 in tamoxifen resistant cells, which, in combination with bioinformatic analysis and downstream validation experiments, supported a role for RAB31 in tamoxifen resistance in ER positive breast-cancer cells. Together, our results demonstrated that the targeted proteomic method constituted a powerful approach for revealing the role of small GTPases in therapeutic resistance. PMID- 30431263 TI - Dynamic Imaging of Small Molecule Induced Protein-Protein Interactions in Living Cells with a Fluorophore Phase Transition Based Approach. AB - Protein-protein interactions (PPIs) mediate signal transduction in cells. Small molecules that regulate PPIs are important tools for biology and biomedicine. Dynamic imaging of small molecule induced PPIs characterizes and verifies these molecules in living cells. It is thus important to develop cellular assays for dynamic visualization of small molecule induced protein-protein association and dissociation in living cells. Here we have applied a fluorophore phase transition based principle and designed a PPI assay named SPPIER (separation of phases-based protein interaction reporter). SPPIER utilizes the green fluorescent protein (GFP) and is thus genetically encoded. Upon small molecule induced PPI, SPPIER rapidly forms highly fluorescent GFP droplets in living cells. SPPIER detects immunomodulatory drug (IMiD) induced PPI between cereblon and the transcription factor Ikaros. It also detects IMiD analogue (e.g., CC-885) induced PPI between cereblon and GSPT1. Furthermore, SPPIER can visualize bifunctional molecules (e.g. PROTAC)-induced PPI between an E3 ubiquitin ligase and a target protein. Lastly, SPPIER can be modified to image small molecule induced protein-protein dissociation, such as nutlin-induced dissociation between HDM2 and p53. The intense brightness and rapid kinetics of SPPIER enable robust and dynamic visualization of PPIs in living cells. PMID- 30431264 TI - Protein p Ka's from Adaptive Landscape Flattening Instead of Constant-pH Simulations. AB - Protein acid/base constants, or p Ka's are often computed from Monte Carlo or molecular dynamics simulations at a series of constant pH values. Instead, we propose to adaptively flatten the free energy landscape in the space of protonation states. The flattening is achieved by a Wang-Landau Monte Carlo, where a bias potential is constructed adaptively during an initial phase, such that all protonation states achieve comparable probabilities. Biased ensembles of states are then reweighted by subtracting out the bias and adding a pH-dependent free energy term. Titration curves constructed for three test proteins agreed, within the small numerical uncertainty, with those obtained earlier from the constant-pH approach. PMID- 30431265 TI - Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase. AB - We present the results of molecular modeling of conformational changes in the Y231C and F295S mutants of human aspartoacylase (hAsp), which allow us to propose a mechanism of allosteric regulation of enzyme activity of these protein variants. The hAsp enzyme hydrolyzes one of the most abundant amino acid derivatives in the brain, N-acetyl-aspartate. It is important to understand the reasons for diminishing activity of the mutated enzymes, which is crucial for Canavan disease patients bearing the mutated gene. We explore a model which suggests operation of hAsp in the dimer form with two dynamically inequivalent subunits. Large-scale molecular dynamics simulations reveal that the replacements Y231C and F295S at the periphery of the protein shift the equilibrium between hAsp conformations with the open and closed gates to the enzyme active site buried inside the protein. Application of the dynamical network analysis and the Markov state model approach allows us to strengthen this conclusion and provide a detailed description of dynamically induced structural changes of the protein. The decreased availability of the active site for substrate molecules in the mutated enzymes explains their diminishing activity observed in clinical experiments. PMID- 30431266 TI - Urea-Linked Covalent Organic Frameworks. AB - 2D covalent organic frameworks (COFs) with flexible urea linkages have been synthesized by condensation of 1,3,5-triformylphloroglucinol (TFP) with 1,4 phenylenediurea (BDU) or 1,1'-(3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diyl)diurea (DMBDU). The resulting COF-117 and COF-118 undergo reversible structural dynamics within their layers, in response to inclusion and removal of guest molecules, emanating from urea C-N bond rotation and interlayer hydrogen-bonding interactions. These compounds are the first urea-linked COFs, serving to expand the scope of reticular chemistry. PMID- 30431267 TI - Phosphorylation of Serine Induces Lysine pKa Increases in Histone N-terminals and Signaling For Acetylation. Transcription Implications. AB - The mild acetylating agent, methyl acetyl phosphate, is used to estimate the pKa values of some of the amine groups in peptides with sequences corresponding to a segment of the N-terminal tail of histone H4. When Ser-1 is not phosphorylated, the Lys epsilon amines have pKa values in the range of 7.8-8.3, which are much lower than currently assumed. When Ser-1 is phosphorylated, the pKa values of these Lys amines are elevated to the range of 8.8-10.3 thus providing the rationale for reports that they are then better substrates for acetyltransferases. Thus, reversal of suppressed pKa values of Lys epsilon amines by Ser phosphorylation represents the basis for signaling in histone N-terminal tails to promote hyperacetylation, which is a hallmark of transcriptionally active euchromatin. In contrast, a state of hypoacetylation is present in the absence of phosphorylation as in transcriptionally inactive heterochromatin. A novel approach for estimating pKa values based on a linkage between the Henderson Hasselbalch and the Michaelis-Menten equations indicates that the pKa values of the Lys epsilon amines in H3 and H4 N-terminal tails have a highly variable charge gradient dependent on location and proximity to the phosphorylation site. PMID- 30431268 TI - In Situ Selective Measurement of SeIV in Waters and Soils: Diffusive Gradients in Thin-Films with Bi-Functionalized Silica Nanoparticles. AB - The speciation of selenium (Se) controls its fate and behavior, determining both its biological and environmental activities. However, in situ monitoring of SeIV presents a significant challenge due to its sensitivity to redox change. A novel diffusive gradients in thin films (DGT) technique containing mercapto-, amino bifunctionalized SBA15 mesoporous silica nanoparticles was developed and evaluated in a series of laboratory and field deployment tests. The SBA-DGT exhibited a linear accumulation of SeIV ( r2 > 0.997) over a 72 h deployment, with negligible accumulation of SeVI(<5%). Consistent prediction of SeIV occurred within ionic strength and pH ranges of 0.1-200 mmol L-1 and 3.6-8, respectively. Limits of detection of the SBA-DGT were 0.03 MUg SeIV L-1, which is suitable for natural waters. Moreover, the properties of the bifunctionalized SBA15 enable it to be fabricated within ultrathin (0.05 mm) gel layers for use in conjunction with O2 planar optode imaging. This new sandwich sensor technology with SBA-DGT was validated by mapping the two-dimensional distribution of SeIV and oxygen simultaneously in rice rhizospheres. This study shows that SBA-DGT provides a selective measurement of SeIV in situ, demonstrating its potential for both environmental monitoring and as a research tool for improving our understanding of Se biogeochemical processes. PMID- 30431269 TI - Discovery and Lead Optimization of Atropisomer D1 Agonists with Reduced Desensitization. AB - The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines which bring about receptor desensitization and undergo rapid metabolism thus limiting their utility as a therapeutic for chronic illness such as Schizophrenia and Parkinson's disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit, PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. An important structural feature of this series is the locked biaryl ring system resulting in atropisomerism. Disclosed herein is a summary of our hit-to-lead efforts on this series of D1 activators culminating in the discovery of atropisomer 31 (PF-06256142), a potent and selective orthosteric agonist of the D1 receptor that has reduced receptor desensitization relative to dopamine and other catechol-containing agonists. PMID- 30431270 TI - Catalytic Oxidation of Carbon Monoxide on a Curved Pd Crystal: Spatial Variation of Active and Poisoning Phases in Stationary Conditions. AB - Understanding nanoparticle catalysis requires novel approaches in which adjoining crystal orientations can be studied under the same reactive conditions. Here we use a curved palladium crystal and near-ambient pressure X-ray photoemission spectroscopy to characterize chemical species during the catalytic oxidation of CO in a whole set of surfaces vicinal to the (111) direction simultaneously. By stabilizing the reaction at fixed temperatures around the ignition point, we observe a strong variation of the catalytic activity across the curved surface. Such spatial modulation of the reaction stage is straightforwardly mapped through the photoemission signal from active oxygen species and poisoning CO, which are shown to coexist in a transient regime that depends on the vicinal angle. Line shape analysis and direct comparison with ultrahigh vacuum experiments help identifying and quantifying all such surface species, allowing us to reveal the presence of surface oxides during reaction ignition and cooling-off. PMID- 30431271 TI - Accurate and Efficient Calculation of Protein-Protein Binding Free Energy Interaction Entropy with Residue Type-Specific Dielectric Constants. AB - Accurate and efficient computation of protein-protein binding free energy remains a grand challenge. In this study, we develop a new strategy to achieve efficient calculation for total protein-protein binding free energies with improved accuracy. The new method combines the recently developed interaction entropy method for efficient computation of entropic change together with the use of residue type-specific dielectric constants in the framework of MM/GBSA to achieve optimal result for protein-protein binding free energies. The new strategy is shown to be computationally efficient and accurate than that using standard MM/GBSA methods in which the entropic computation is performed by the normal model approach and the protein interior is represented by the standard dielectric constant (typically set to 1), both in terms of accuracy and computational efficiency. Our study using the new strategy on a set of randomly selected 20 protein-protein binding systems produced an optimal dielectric constant of 2.7 for charged residues and 1.1 for noncharged residues. Using this new strategy, the mean absolute error in computed binding free energies for these 20 selected protein-protein systems is significantly reduced by more than 3-fold while the computational cost is reduced by more than 2 orders of magnitude, compared to the result using standard MM/GBSA method with the normal mode approach. A similar improvement in accuracy is confirmed for a test set consisting of 10 protein protein systems. PMID- 30431272 TI - BUMPy: A Model-Independent Tool for Constructing Lipid Bilayers of Varying Curvature and Composition. AB - Molecular dynamics is a powerful tool to investigate atomistic and mesoscopic phenomena in lipid bilayer systems. These studies have progressed with the advent of increased computational power, and efforts are now increasingly being directed toward investigating the role of curvature and bilayer morphology, as these are critical features of biological processes. Computational studies of lipid bilayers benefit from tools that can create starting configurations for molecular dynamics simulations, but the majority of such tools are restricted to generating flat bilayers. Generating curved bilayer configurations comes with practical complications and potential ramifications on physical properties in the simulated system if the bilayer is initiated in a high-strain state. We present a new tool for creating curved lipid bilayers that combines flexibility of shape, force field, model resolution, and bilayer composition. A key aspect of our approach is the use of the monolayer pivotal plane location to accurately estimate interleaflet area differences in a curved bilayer. Our tool is named BUMPy (Building Unique Membranes in Python), is written in Python, is fast, and has a simple command line interface. PMID- 30431273 TI - pi-Extended Corannulene-Based Nanographenes: Selective Formation of Negative Curvature. AB - A geometrically selective bottom-up synthesis of curved nanographenes is described. The synthetic methodology used involves the extension of the pi-system of positively curved corannulene by a [4+2] cycloaddition reaction followed by cyclodehydrogenation (Scholl oxidation). By selecting the conditions for the Scholl oxidation, the formation of a seven-membered ring that also confers negative curvature to the resulting nanographene can be activated, offering two topologically distinct, curved nanographenes from a common precursor. Additionally, the structure-property relationship in these new nanographenes is explored via theoretical, electrochemical, photophysical, Raman, and X-ray crystallographic studies. PMID- 30431274 TI - Rh(III)-Catalyzed One-Pot Synthesis of Benzimidazoquinazolines via C-H Amidation Cyclization of N-LG-2-phenylbenzoimidazoles. AB - An efficient protocol to synthesize substituted benzo[4,5]imidazo[1,2- c]quinazolines starting from N-LG-2-phenylbenzoimidazole and dioxazolones catalyzed by Rh(III) or Ir(III) has been developed. Various substituted benzo[4,5]imidazo[1,2- c]quinazolines could be easily provided in up to 99% yield. A large range of substrates and functional groups are compatible for this transformation. This method features low catalyst loading, acid-free conditions, and low solvent consumption. PMID- 30431275 TI - Copper-Catalyzed Multicomponent Domino Reaction of 2-Bromobenzaldehydes, Aryl Methyl Ketones, and Sodium Azide: Access to 1 H-[1,2,3]Triazolo[4,5- c]quinoline Derivatives. AB - A practical copper-catalyzed multicomponent reaction has been developed for the synthesis of 1 H-[1,2,3]triazolo[4,5- c]quinoline derivatives from commercially available 2-bromobenzaldehydes, aryl methyl ketones, and sodium azide. This protocol integrated consecutive base-promoted condensation, [3 + 2] cycloaddition, copper-catalyzed SNAr, and denitrogenation cyclization sequences. Preliminary mechanistic studies revealed that CuBr2 acted as a multifunctional catalyst to streamline this domino process. The mild catalytic system enabled effective construction of one C-C and four C-N bonds in one operation. PMID- 30431276 TI - One-Pot Synthesis of 7-(Benzimidazol-2-yl)thioxolumazine and -lumazine Derivatives via H2SO4-Catalyzed Rearrangement of Quinoxalinones When Exposed to 5,6-Diamino-2-mercapto- and 2,5,6-Triaminopyrimidin-4-ols. AB - A facile approach to a range of substituted 7-(benzimidazol-2-yl)thioxolumazines [7-(benzimidazol-2-yl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones] and 7 (benzimidazol-2-yl)lumazines [7-(benzimidazol-2-yl)pteridine-2,4(1 H,3 H)-diones] is described. These new biheterocyclic systems are obtained via H2SO4-catalyzed rearrangement of quinoxalin-2-ones in the presence of 5,6-diamino-2-mercapto- and 2,5,6-triaminopyrimidin-4-ols. Thus, benzimidazole and pteridine rings are constructed in one synthetic step. A plausible ANRORC ( addition of nucleophile, ring opening and ring closure)-type reaction mechanism is proposed. Applying the rearrangement to the aza-analogue of 3-benzoylquinoxalin-2(1 H)-one-i.e., 3 benzoylpyrido[2,3- b]pyrazin-2(1 H)-one-with 5,6-diamino-2-mercaptopyrimidin-4-ol makes it possible to synthesize inaccessible 7-(1 H-imidazo[4,5- b]pyridin-2-yl) 6-phenyl-2-thioxo-2,3-dihydropteridin-4(1 H)-one. 7-(Benzimidazol-2-yl)-6-(2 fluorophenyl)-2-thioxo-2,3-dihydropteridin-4(1 H)-ones undergoes intramolecular nucleophilic substitution of fluorine by a nitrogen of the benzimidazole fragment with the formation of benzo[4',5']imidazo[1',2':1,2]quinolino[4,3- g]pteridine 2,4(1 H,3 H)-diones as new heterocyclic systems. PMID- 30431277 TI - Molecular Dynamics Investigations of Dibutyl-phosphoric Acid-Parameterization and Dimerization. AB - A reparameterized molecular dynamics force field for dibutyl-phosphoric acid (HDBP) has been developed. Parameterization was done using the general Amber force field, as a starting point. The density and dipole moment of bulk phase simulations compare well to that of known experimental values, and the heat of vaporization is comparable to an estimated empirical value. All values have been optimized to within 4%. The newly optimized force field was validated against the self-diffusion coefficient, matching experimental data to within 18%, which is a significant improvement compared to the nonoptimized force field. Further, a potential of mean force study was carried out to understand the behavior of hydrogen bonds in HDBP dimers. This required the determination of hydrogen bonding criteria that captures the behavior of the HDBP dimer and is reported in this work as well. PMID- 30431278 TI - Investigation of Local Hydration Structures of Alkanethiol Self-Assembled Monolayers with Different Molecular Structures by FM-AFM. AB - Hydration structures play crucial roles in a wide variety of chemical and biological phenomena. However, the key factors that determine a hydration structure remain an open question. Most recent studies have focused on the electrostatic interactions between the surface charges and dipoles of water molecules, which are determined by the atomic/ionic species of the outermost solid surface, as the dominating factor. The number of studies on the correlation between the hydration structure and the atomic-scale surface corrugation has been limited. In this study, we investigated the hydration structures of alkanethiol self-assembled monolayers terminated with a hydroxyl group using frequency modulated atomic force microscopy. We observed two molecular structures, namely, the (?3 * ?3) R30 degrees structure and the c(4 * 2) superlattice structure, and found that their hydration structures are different mainly because of the slight differences in their molecular arrangements. This result suggests that a slight difference in the molecular/atomic arrangements as well as the atomic/ionic species in the outermost solid surface strongly influences the local hydration structures. PMID- 30431279 TI - Translocation of Human beta Defensin Type 3 through a Neutrally Charged Lipid Membrane: A Free Energy Study. AB - Human beta defensin type 3 (hBD-3) is a cationic (+11 charged) antimicrobial peptide. It has 3 pairs of intramolecular disulfide bonds which can break to form the linear analog of hBD-3 under reducing conditions. hBD-3 can disrupt both gram positive and gram-negative cell membranes, and even mammalian cell membrane at high concentrations. However, the structural basis for the membrane-disrupting function of hBD-3 is still unknown. In order to understand the interaction mechanism of hBD-3 with a neutrally-charged lipid membrane, explicit solvent and lipid umbrella-sampling simulations were performed using NAMD program on the hBD 3 wild-type and the linear analog, in both the monomer and dimer forms. During the insertion and translocation process, most of the protein structure changes take place near the membrane-solvent interface, while the membrane interior appears to stabilize and rigidify the native-like hBD-3 structure. An energy barrier of 20 kcal/mol(domain unit) should be overcome by hBD-3 dimer in wild type to cross the POPC bilayer but only 13 kcal/mol(domain unit) to insert into the bilayer center, and 20 kcal/mol for hBD-3 monomers to insert into the membrane center. Significant reorientation of lipids around hBD-3 inside the membranes was observed, which suggests a toroidal model for the membrane disruption process. PMID- 30431280 TI - Heat Transfer at Hybrid Interfaces: Interfacial Ligand-to-Nanocrystal Heating Monitored with Infrared Pump, Electronic Probe Spectroscopy. AB - The transfer of thermal energy from the ligand passivating layer to the inorganic core of colloidal nanocrystals is observed using infrared-pump, electronic-probe (IPEP) spectroscopy. Inorganic nanocrystals are excellent model systems for organic-inorganic hybrid interfaces as they have much larger surface-to-volume ratios than bulk solids, which facilitate spectroscopic measurements of weak signals. Such interfaces between disparate materials are challenging to probe by traditional methods. Here, resonant excitation of the hydrocarbon ligand vibrational absorptions results in a transient red-shift of the CdSe nanocrystal excitonic features consistent with heating, as demonstrated by steady-state absorption measurements, which provide a calibration of the pump-induced temperature rise. The time constant associated with heating ranges from 10 to 30 ps depending on the sample morphology, static temperature, input fluence, and environment, all of which are studied in this work. Heat transfer speeds up and the magnitude of nanocrystal heating decreases at higher temperatures. Unlike chemical modulation of electrical conductivity, ligand exchange for several common organic ligands does not dramatically change the interfacial conductivity of the nanocrystal-ligand interface. However, changes in the medium (e.g., solvent) do change the rate of heat outcoupling from the nanocrystal-ligand complex. Although applied here to nanocrystals to measure interfacial heat transfer, IPEP spectroscopy is readily applicable for any heterogeneous system in which one component has spectrally isolated molecular vibrations or lattice phonons. PMID- 30431281 TI - Nickel-Catalyzed Cyanation of Unactivated Alkyl Chlorides or Bromides with Zn(CN)2. AB - A nickel-catalyzed cyanation of unactivated secondary alkyl chlorides or bromides using less toxic Zn(CN)2 as the cyanide source has been developed. The reaction features the use of air-stable and inexpensive NiCl2.6H2O or Ni(acac)2 as the precatalysts and offers an efficient synthesis of a broad range of alkyl nitriles. Cyanation of primary alkyl chlorides or bromides was also achieved by reaction with Zn(CN)2 in the presence of n-Bu4NCl without the need of nickel catalyst. PMID- 30431282 TI - Reduced Radiation Damage in Transmission Electron Microscopy of Proteins in Graphene Liquid Cells. AB - Liquid-phase electron microscopy (LPEM) is capable of imaging native (unstained) protein structure in liquid, but the achievable spatial resolution is limited by radiation damage. This damaging effect is more pronounced when targeting small molecular features than for larger structures. The matter is even more complicated because the critical dose that a sample can endure before radiation damage not only varies between proteins but also critically depends on the experimental conditions. Here, we examined the effect of the electron beam on the observed protein structure for optimized conditions using a liquid sample enclosure assembled from graphene sheets. It has been shown that graphene can reduce the damaging effect of electrons on biological materials. We used radiation sensitive microtubule proteins and investigated the radiation damage on these structures as a function of the spatial frequencies of the observed features with transmission electron microscopy (TEM). Microtubule samples were also examined using cryo-electron microscopy (cryo-TEM) for comparison. We used an electron flux of 11 +/- 1-16 +/- 1 e-/A2s and obtained a series of images from the same sample region. Our results show that graphene-encapsulated microtubules can maintain their structural features of spatial frequencies of up to 0.20 nm-1 (5 nm), reflecting protofilaments for electron densities of up to 7.2 +/- 1.4 * 102 e-/A2, an order of magnitude higher than measured for frozen microtubules in amorphous ice. PMID- 30431283 TI - Molecular Oxygen-Promoted General and Site-Specific Alkylation with Organoboronic Acid. AB - A general alkylating method using organoboronic acid under 1 atm of oxygen is developed. It allows a facile access to a wide range of functionalized molecules with privileged scaffolds in drugs and natural products such as oxindoles, quinolinones, chromones, naphthoquinones, coumarins, and quinolones. In contrast to previous alkylation approaches that generally requiring transition-metal catalysis and a stoichiometric chemical oxidant, the present strategy features metal-free, molecular oxygen as the terminal oxidant and site specificity. PMID- 30431284 TI - Tandem Reaction of Allenoate Formation and Cyclization: Divergent Synthesis of Four- to Six-Membered Heterocycles. AB - Tandem reactions of copper-catalyzed cross-coupling of N-substituted prop-2-yn-1 amines with diazoacetates and subsequent cyclization have been developed to prepare several types of four- to six-membered heterocycles. Copper-catalyzed allenoate formation has been proven as the key step for the diverse annulations. Importantly, on the basis of the choice of different N-protecting groups of the alkyne substrates, methods toward 5,6-dihydropiperidin-2-ones, 2 methyleneazetidines, and furan derivatives have been well established. PMID- 30431285 TI - Sialic Acid-Functionalized PEG-PLGA Microspheres Loading Mitochondrial-Targeting Modified Curcumin for Acute Lung Injury Therapy. AB - Acute lung injury (ALI) is a serious illness without resultful therapeutic methods commonly. Recent studies indicate the importance of oxidative stress in the occurrence and development of ALI, and mitochondria targeted antioxidant has become a difficult and hot topic in the research of ALI. Therefore, a sialic acid (SA)-modified lung-targeted microsphere (MS) for ALI therapy are developed, with triphenylphosphonium cation (TPP)-modified curcumin (Cur-TPP) loaded, which could specifically target the mitochondria, increasing the effect of antioxidant. The results manifest that with the increase of microsphere, lung distribution of microsphere is also increased in murine mice, and after SA modification, the microsphere exhibits the ideal lung-targeted characteristic in ALI model mice, due to SA efficiently targeting to E-selectin expressed on inflammatory tissues. Further investigations indicate that SA/Cur-TPP/MS has better antioxidative capacity, decreases intracellular ROS generation, and increases mitochondrial membrane potential, contributing to a lower apoptosis rate in human umbilical vein endothelial cells (HUVECs) compared to H2O2 group. In vivo efficacy of SA/Cur-TPP/MS demonstrates that the inflammation has been alleviated markedly and the oxidative stress is ameliorated efficiently. Significant histological improvements by SA/Cur-TPP/MS are further proved via HE stains. In conclusion, SA/Cur-TPP/MS might act as a promising drug formulation for ALI therapy. PMID- 30431287 TI - Synthesis of Indoles via Electron-Catalyzed Intramolecular C-N Bond Formation. AB - A new protocol for the preparation of N-substituted indole-3-carboxylates has been developed. The key C-N bond formation occurs under transition-metal-free conditions employing a t-BuOK/DMF system without special initiators or additives. Across a number of substrates, indoles were afforded in yields higher or comparable to those obtained under transition-metal-catalyzed conditions. While demonstrating high functional group tolerance, new conditions are particularly attractive for manufacturing halogenated indoles that cannot be made in a pure form using other metal-based catalytic methods. PMID- 30431286 TI - Synthesis, Optoelectronic, and Supramolecular Properties of a Calix[4]arene Cycloparaphenylene Hybrid Host. AB - A novel hybrid host has been obtained by fusion of the calix[4]arene skeleton with a cycloparaphenylene (CPP) ring. The CPP-bridged calix[4]arene 1 combines the optoelectronic and structural properties of the CPP rings with the recognition abilities of the calix[4]arene hosts. Thus, calix-CPP 1 shows an unexpected selectivity for the Li+ cation over Na+, as a result of more favorable cation...pi interactions of Li+ with the CPP bridge and its better size complementarity. PMID- 30431288 TI - A meta-analysis of context integration deficits across the schizotypy spectrum using AX-CPT and DPX tasks. AB - Schizotypy and schizophrenia involve disrupted context integration (CI), the ability to assimilate internal and external information into coherent mental representations. Research has primarily examined patients with schizophrenia, with fewer studies assessing CI in schizotypy-spectrum groups. The literature shows overall CI deficits, but mixed results for specific performance patterns and associations with clinical symptoms. Furthermore, conclusions are limited by small samples and heterogeneity across studies. To examine CI deficits across the schizotypy spectrum using AX-Continuous Performance Task (CPT) and Dot Pattern Expectancy task (DPX) performance. Systematic review involved searching 4 databases and 12 journals, examining key references, and contacting 227 researchers for published and unpublished data. Search terms included AX CPT/DPX/dot pattern expectancy task/CNTRACs/context* integration/context* processing and schizo*/prodromal/high risk/psychosis; context* and ultra high risk. Independent data from studies with diagnostically or psychometrically assessed schizotypy-spectrum groups and AX-CPT/DPX tasks with 10+ trials and 60+% AX trials were included. Articles were independently coded by two authors using predefined coding schemes with good agreement. Meta-analyses pooled outcomes using random-effects models. Forty-one studies met inclusion criteria. CI impairment was present across the schizotypy spectrum. CI deficits in schizophrenia were substantial and associated with disorganized and negative symptoms. Outcomes were comparable between patients with chronic and first episode schizophrenia. At-risk groups demonstrated moderate CI impairment. Results were robust across task parameters and there was no evidence that reporting biases grossly impacted outcomes. Findings lend support to theories suggesting that CI is a stable vulnerability factor for schizophrenia. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431290 TI - Cultural differences in the development of a preference for scarce objects. AB - Adults value scarce objects, such as rare precious stones and limited edition items. This valuation may derive from an understanding of market forces and sociological considerations, but it may also be related to more basic cognitive and motivational processes. The present studies addressed these possibilities by investigating the development and cross-cultural prevalence of a preference for scarce objects. Children (N = 366) from Israel and Taiwan, ranging from 4 to 11 years of age, were given a choice between a scarce and an abundant reward. We found that whereas a preference for the scarce appeared among Israelis by age 7, it never appeared among the Taiwanese. These findings indicate that a scarcity preference emerges already at age 7, but only among children living in a culture that emphasizes self-individuality. These findings are discussed in light of cultural accounts of the development of self-motivations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431289 TI - Probabilistic reinforcement learning abnormalities and their correlates in adolescent bipolar disorders. AB - Theoretical models of bipolar disorders (BD) posit core deficits in reward system function. However, specifying which among the multiple reward system's neurobehavioral processes are abnormal in BD is necessary to develop appropriately targeted interventions. Research on probabilistic-reinforcement learning deficits in BD is limited, particularly during adolescence, a period of significant neurodevelopmental changes in the reward system. The present study investigated probabilistic-reinforcement learning, using a probabilistic selection task (PST), and its correlates, using self-reported reward/threat sensitivities and cognitive tasks, in 104 adolescents with and without BD. Compared with healthy peers, adolescents with BD were less likely to persist with their choices based on prior positive feedback (i.e., lower win-stay rates) in the PST's acquisition phase. Across groups, a greater win-stay rate appeared to be a more efficient learning strategy-associated with fewer acquisition trials and better testing phase performance. Win-stay rates were also related to verbal learning indices, but not self-reported reward/threat sensitivities. Finally, lower win-stay rates had significant incremental validity in predicting a BD diagnosis, after accounting for effects of current symptoms, reward sensitivities, verbal learning, and IQ. The present findings support multiple dysfunctional processes of the reward system in adolescent BD that require additional examinations. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431291 TI - Parent-child-relationship quality predicts offspring dispositional compassion in adulthood: A prospective follow-up study over three decades. AB - Compassion is known to predict prosocial behavior and moral judgments related to harm. Despite the centrality of compassion to social life, factors predicting adulthood compassion are largely unknown. We examined whether qualities of parent child-relationship, namely, emotional warmth and acceptance, predict offspring compassion decades later in adulthood. We used data from the prospective population-based Young Finns Study. Our sample included 2,761 participants (55.5% women). Parent-child-relationship qualities were reported by each participant's parents at baseline in 1980 (T0) when participants were between 3 and 18 years old. Compassion was self-reported 3 times: in 1997 (T1), 2001 (T2), and 2012 (T3) with the Temperament and Character Inventory (Cloninger, Przybeck, Svrakic, & Wetzel, 1994). By using age at the assessment as a time-variant variable, we applied multilevel modeling for repeated measurements to examine developmental trajectories of compassion from the ages of 20 (the age of the youngest cohort at T1) to 50 (the age of the oldest cohort at T3). On average, compassion increased in a curvilinear pattern with age. Higher acceptance (p = .013) and higher emotional warmth (p < .001) were related to higher compassion in adulthood. After adjusting for childhood confounds (i.e., participant gender, birth cohort, externalizing behavior, parental socioeconomic status, and parental mental health problems), only emotional warmth (p < .001) remained a significant predictor of compassion. Quality of the parent-child-relationship has long-term effects on offspring compassion. An emotionally warm and close relationship, in particular, may contribute to higher offspring compassion in adulthood. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431292 TI - False-positive screening events and worry influence decisions about surgery among high-risk women. AB - OBJECTIVE: Studies of cancer screening have found that false positive screening events (FPSE) can affect worry about cancer risk and screening program use, we sought to further explore this. METHOD: In a study of 1,100 women at high risk for ovarian cancer who participated in a previously published randomized controlled trial (RCT), we sought to explore whether worry might also influence the use of risk-reducing surgical procedures by women. Participants included 234 women with BRCA1/2 mutations and 866 women with high-risk pedigrees. We followed the women for up to 6 years. RESULTS: Worry predicted risk reducing prophylactic bilateral salpingo-oophorectomy (pBSO) for both mutation carriers (HR = 1.74; p = .02), and women with high-risk pedigree (HR = 3.41; p < .001). FPSE also predicted subsequent pBSO among women with a high-risk pedigree (HR 2.31; p < .01). While screening may reduce worry among those who never receive a positive result, FPSE increase worry at least temporarily. Worry about ovarian cancer risk predicted use of preventative pBSO among high-risk women including those with BRCA1/2 mutations enrolled in an ovarian cancer-screening program. FPSE also predicted risk-reducing ovarian surgery among high-risk women without a known mutation at the time of screening program enrollment. CONCLUSIONS: Physicians who offer screening should know that false positive results may increase use of pBSO, how this should effect clinical practice is unclear. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431293 TI - Lessons learned while integrating patient-reported outcomes in a psychiatric hospital. AB - In today's world of smart-device monitoring systems, clinicians may be lulled into the assumption that we can download software to monitor our patients' psychological and behavioral functioning with little or no effort or follow-up. This belief is as erroneous as it is tempting; in fact, implementing effective and efficient systems for utilizing patient-reported outcomes (PROs) in daily practice and research takes a virtual village of stakeholders, clinicians, developers, analysts, and clinical researchers. Here, we describe the iterative processes required for designing, implementing, and updating a large-scale inpatient psychiatric quality improvement/research platform that provides real time feedback to clinicians and patients. During the past 10 years, many surprises and counterintuitive discoveries have emerged from this project, not the least of which is how difficult it is to establish and maintain "buy-in" and the utilization of PROs with busy clinicians and administrators. Methods for prioritizing and structuring data for different uses, including examining the effectiveness of treatment programs, identifying moderators of change, and improving treatment planning by developing algorithms to alert clinicians to adverse outcomes, are highlighted. The authors conclude by describing a new venture to integrate biological data and between-visit PROs monitoring to enhance well-being and reduce emergency department and hospital admissions for high-risk patients. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431294 TI - Practice-research integration in the residential treatment of patients with severe eating and comorbid disorders. AB - Residential treatment involves a number of treatment components and modalities, and treatment staff come from diverse training backgrounds. These complexities present unique challenges for the implementation of standardized programming, training, and routine assessment to support practice and research aims. Implementation science highlights the critical role of clinician attitudes in successful adoption and sustainability. This article describes an ongoing real world quality improvement effort to implement transdiagnostic evidence-based interventions for primary eating disorders, as well as routine data collection, in a residential eating disorder treatment center. We specifically focus on clinicians' subjective experience of, and attitudes toward, the implementation of new treatment strategies and data collection. Participating clinicians completed a semistructured interview based on constructs from the Consolidated Framework for Implementation Research, an organizing framework for implementation practice and research. Interviews were analyzed using consensual qualitative research. Results indicate that clinicians had positive overall implementation experiences, with available resources, leadership engagement, patient needs, relative advantage, and self-efficacy emerging as constructs that had the greatest impact on implementation. Clinicians also offered specific critiques and suggestions about the intervention and the implementation process. These results can inform internal sustainability efforts and can be integrated into future evidence-based intervention implementation and data collection efforts. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431295 TI - Personality in captive killer whales (Orcinus orca): A rating approach based on the five-factor model. AB - The comparative study of animal personality has received great interest in recent years. Some studies have analyzed personalities in cetaceans (exclusively in dolphins), but none have analyzed the factorial structure of personality of any species in this order. Our objective was to evaluate a sample of captive killer whales (n = 24) adapting one of the most widely used models of personality in humans and nonhuman animals: the five-factor model. A total of 38 personality descriptive adjectives were rated by 55 raters (mainly trainers and curators). Principal components analysis and regularized exploratory factor analysis revealed four statistically significant factors with acceptable standards of interrater reliability and validity, accounting for 49.85% of the variance. The first factor indicated an Extraversion factor, the second one revealed a combined factor of Conscientiousness and Agreeableness, the third one yielded in a Dominance factor, and the fourth one reflected a Careful factor very close to a combination of Conscientiousness and Agreeableness factor. The results were compared with the results obtained for humans and chimpanzees in prior studies. The similarities could be explained as a result of convergent adaptive traits despite a deep evolutionary divergence, adaptation to physically dissimilar environments, and very different neuroanatomical organization. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431296 TI - Constructed response formats and their effects on minority-majority differences and validity. AB - The inflow of immigrants challenges organizations to consider alternative selection procedures that reduce potential minority (immigrants)-majority (natives) differences, while maintaining valid predictions of performance. To deal with this challenge, this paper proposes response format as a practically and theoretically relevant factor for situational judgment tests (SJTs). We examine a range of response format categories (from traditional multiple-choice formats to more innovative constructed response formats) and conceptually link these response formats to mechanisms underlying minority-majority differences. Two field experiments are conducted with SJTs. Study 1 (274 job seekers) contrasts minority-majority differences in scores on a multiple-choice versus a written constructed response format. Written constructed responses produce much smaller minority-majority differences (d = .28 vs. d = .92). In Study 2 (269 incumbents), scores on a written constructed versus an audiovisual constructed format are compared. The audiovisual format further reduces minority-majority differences (d = .09 vs. d = .41), with validities remaining the same. Results are suggestive of cognitive load as a contributor to the reduction in minority majority differences, as are rater effects: Scores of raters evaluating transcribed audiovisual responses, which anonymized test takers, produce larger differences. In sum, altering response modality via more realistic response formats (i.e., the audiovisual constructed format) leads to significant reductions in minority-majority differences without impairing criterion-related validity. Implications for selection theory and practice are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431297 TI - Practice of therapy acquired regulatory skills and depressive relapse/recurrence prophylaxis following cognitive therapy or mindfulness based cognitive therapy. AB - BACKGROUND: To investigate whether usage of treatment-acquired regulatory skills is associated with prevention of depressive relapse/recurrence. METHOD: Remitted depressed outpatients entered a 24-month clinical follow up after either 8 weekly group sessions of cognitive therapy (CT; N = 84) or mindfulness-based cognitive therapy (MBCT; N = 82). The primary outcome was symptom return meeting the criteria for major depression on Module A of the SCID. RESULTS: Factor analysis identified three latent factors (53% of the variance): decentering (DC), distress tolerance (DT), and residual symptoms (RS), which were equivalent across CT and MBCT. Latent change score modeling of factor slopes over the follow up revealed positive slopes for DC (beta = .177), and for DT (beta = .259), but not for RS (beta = -.017), indicating posttreatment growth in DC and DT, but no change in RS. Cox regression indicated that DC slope was a significant predictor of relapse/recurrence prophylaxis, Hazard Ratio (HR) = .232 90% Confidence Interval (CI) [.067, .806], controlling for past depressive episodes, treatment group, and medication. The practice of therapy-acquired regulatory skills had no direct effect on relapse/recurrence (beta = .028) but predicted relapse/recurrence through an indirect path (beta = -.125), such that greater practice of regulatory skills following treatment promoted increases in DC (beta = .462), which, in turn, predicted a reduced risk of relapse/recurrence over 24 months (beta = .270). CONCLUSIONS: Preventing major depressive disorder relapse/recurrence may depend upon developing DC in addition to managing residual symptoms. Following the acquisition of therapy skills during maintenance psychotherapies, DC is strengthened by continued skill utilization beyond treatment termination. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431298 TI - Cognitive "insomnia" processes in delayed sleep-wake phase disorder: Do they exist and are they responsive to chronobiological treatment? AB - OBJECTIVE: To systematically investigate whether cognitive "insomnia" processes are implicated in adolescent Delayed Sleep-Wake Phase Disorder (DSWPD) and to examine whether these processes are responsive to chronobiological treatment. METHOD: Sixty-three adolescents (M = 15.8 +/- 2.2 years, 63.5% f) diagnosed with DSWPD and 40 good sleeping adolescents (M = 15.9 +/- 2.4 years, 75% f) completed baseline measures of sleep, daytime functioning and cognitive "insomnia" processes (i.e., repetitive negative thinking, physiological hyperarousal, distress, sleep-related attention and monitoring, sleep misperception). Sixty DSWPD adolescents (M = 15.9 +/- 2.2 y, 63% f) entered a treatment trial and received 3 weeks of light therapy. Sleep, daytime functioning, and insomnia were measured again post-treatment and at 3-month follow-up. RESULTS: Adolescents with DSWPD had significantly later sleep timing (d = 0.99-1.50), longer sleep latency (d = 1.14), and shorter total sleep time (d = 0.85) on school nights, compared with the good sleeping adolescents. There was evidence of cognitive "insomnia" symptoms, with the DSWPD group reporting more repetitive negative thinking (d = 0.70-1.02), trait hyperarousal (d = 0.55), distress (d = 2.19), sleep associated monitoring (d = 0.76), and sleep onset misperception (d = 1.29). Across treatment and follow-up, adolescents with DSWPD reported advanced sleep timing (d = 0.54 0.62), reduced sleep latency (d = 0.53), increased total sleep time (d = 0.49), and improved daytime functioning (d = 0.46-1.00). Repetitive negative thinking (d = 0.64-0.96), physiological arousal (d = 0.69), distress (d = 0.87), and sleep onset misperception (d = 0.37) also showed improvement. CONCLUSIONS: Cognitive "insomnia" processes may be implicated in the development and maintenance of DSWPD in adolescents. Many of these processes are amendable to chronobiological treatment; however, residual symptoms may place adolescents at risk of poor treatment outcome or relapse. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431299 TI - PTSD symptom clusters and suicide attempts among high-risk military service members: A three-month prospective investigation. AB - OBJECTIVE: Suicide rates within the U.S. military are elevated, and the assessment and treatment of posttraumatic stress disorder (PTSD) has been identified as one potential conduit for suicide risk reduction. Despite increased interest in examining whether PTSD symptom clusters differentially predict suicide-related outcomes, to our knowledge no study has examined this question utilizing a prospective design for which suicide attempts is the outcome. Thus, the present study assessed whether PTSD symptom clusters differentially predict suicide attempts at 3-month follow-up and examined the moderating role of combat exposure. METHOD: Participants were 758 military service members referred for psychiatric evaluation for suicide-related concerns and who provided both baseline and follow-up data (76.8% male, Mage = 25.20 y [SDage = 6.22 y], 61.6% White/Caucasian, 28.2% combat-exposed). Baseline PTSD symptom clusters scores were derived from an abbreviated version of the PTSD Checklist-Military Version (PCL-M). Suicide attempts occurring from baseline to follow-up were assessed with the Suicide Attempt Self-Injury Interview (SASII). Logistic regression models were utilized, controlling for baseline suicide risk severity (i.e., frequency of suicidal ideation, levels of suicidal intent, past suicide plans and attempts) and sociodemographic characteristics. RESULTS: The hyperarousal symptom cluster was the only significant predictor of subsequent suicide attempts and, moreover, this association was significant for combat-exposed service members but not for non-combat-exposed service members. CONCLUSIONS: PTSD hyperarousal symptoms, characterized in part by overarousal (e.g., agitation), should be considered in military suicide risk assessment and prevention efforts, particularly for combat exposed service members. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431300 TI - Working alliance predicts symptomatic improvement in public hospital-delivered psychotherapy in Nairobi, Kenya. AB - OBJECTIVE: Although patient-therapist collaboration (working alliance) has been studied extensively in Europe and America, it is unknown to what extent the importance of working alliance for psychotherapy outcome generalizes to lower- and middle-income countries. Additionally, there is a need for more studies on the alliance using methods that are robust to confounders of its effect on outcome. METHOD: In this study, 345 outpatients seeking care at the 2 public psychiatric hospitals in Nairobi, Kenya, filled out the Session Alliance Inventory (SAI) and the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) during each session. The effect of alliance on next-session psychological distress was modeled using the random intercept cross-lagged panel model, which estimates a cross-lagged panel model on within- and between-subjects disaggregated data. RESULTS: Changes in the working alliance from session to session significantly predicted change in psychological distress by the next session, with an increase of 1 point of the SAI in a given session resulting in a decrease of 1.27 points on the CORE-OM by the next session (SE = .60, 95% confidence interval [-2.44, -.10]). This finding represents a medium-sized standardized regression coefficient of between .16 and .21. Results were generally robust to sensitivity tests for stationarity, missing data assumptions, and measurement error. CONCLUSION: Results affirm cross-cultural stability of the session-by-session reciprocal effects model of alliance and psychological distress-symptoms as seen in a Kenyan psychiatric outpatient sample, using the latest developments in cross-lagged panel modeling. A limitation of the study is its naturalistic design and lack of control over several variables. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431301 TI - No youth left behind to human trafficking: Exploring profiles of risk. AB - The objective of this study was to analytically identify risk profiles for juvenile human trafficking (JHT) based on adverse childhood experiences (ACEs) and health risk behaviors. First, the study examined which types of ACEs and health risk behaviors were more prevalent among trafficked adolescents using a sample of 913 male and female juvenile-justice-involved adolescents with suspected or verified JHT abuse reports documented between 2009 and 2015 and a comparison group (matched by age, gender, race, ethnicity, and location). Second, latent class analysis was used to identify profiles of risk for JHT. Finally, associations between JHT risk profiles and demographic characteristics provided a more comprehensive depiction of various types of trafficked adolescents. Study findings indicate that adolescents with JHT abuse reports were more likely to report child maltreatment and internalizing health risk behaviors reflective of self-harm and attempts to cope with trauma. Trafficked youth were less likely to report externalizing health risk behaviors related to violence or harming others. Six distinctive profiles of risk for JHT were identified. Three JHT risk profiles were characterized by extensive child maltreatment and health risk behaviors and were differentiated by placement in foster care and substance use. Three JHT risk profiles were characterized by less extensive histories of child maltreatment and were differentiated by drug use. In conclusion, these findings highlight that the current depictions of adolescent victims of human trafficking are too narrow and may lead to critical health care and service provision disparities for many trafficked adolescents. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431303 TI - Decision by sampling implements efficient coding of psychoeconomic functions. AB - The theory of decision by sampling (DbS) proposes that an attribute's subjective value is its rank within a sample of attribute values retrieved from memory. This can account for instances of context dependence beyond the reach of classic theories that assume stable preferences. In this paper, we provide a normative justification for DbS that is based on the principle of efficient coding. The efficient representation of information in a noiseless communication channel is characterized by a uniform response distribution, which the rank transformation implements. However, cognitive limitations imply that decision samples are finite, introducing noise. Efficient coding in a noisy channel requires smoothing of the signal, a principle that leads to a new generalization of DbS. This generalization is closely connected to range-frequency theory, and helps descriptively account for a wider set of behavioral observations, such as how context sensitivity varies with the number of available response categories. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431302 TI - Decision making on spatially continuous scales. AB - A new diffusion model of decision making in continuous space is presented and tested. The model is a sequential sampling model in which both spatially continuously distributed evidence and noise are accumulated up to a decision criterion (a 1 dimensional [1D] line or a 2 dimensional [2D] plane). There are two major advances represented in this research. The first is to use spatially continuously distributed Gaussian noise in the decision process (Gaussian process or Gaussian random field noise) which allows the model to represent truly spatially continuous processes. The second is a series of experiments that collect data from a variety of tasks and response modes to provide the basis for testing the model. The model accounts for the distributions of responses over position and response time distributions for the choices. The model applies to tasks in which the stimulus and the response coincide (moving eyes or fingers to brightened areas in a field of pixels) and ones in which they do not (color, motion, and direction identification). The model also applies to tasks in which the response is made with eye movements, finger movements, or mouse movements. This modeling offers a wide potential scope of applications including application to any device or scale in which responses are made on a 1D continuous scale or in a 2D spatial field. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431304 TI - Measuring collaboration across children's behavioral health and child welfare systems. AB - A commonly emphasized component of trauma-informed care is the practice of building cross-system collaboration (CSC). While existing research on CSC states numerous benefits and barriers associated with increasing collaboration between systems, there is limited empirical understanding on how to define and measure collaboration between county systems of care. The current study presents the psychometric evaluation of scores from the Perceptions of Overarching Cross System Collaboration-Child Welfare and Behavioral Health Systems (POCSC-CW/BH), a 6-item self-report instrument completed by system administrative leadership and direct service providers, administered within child welfare and children's behavioral health systems in 6 California counties. Psychometric analysis demonstrated good support of internal consistency, as well as the factorial, convergent, and discriminant validity of scores produced by the tool. There was also evidence for content validity. System-level analyses showed within-county child welfare, and children's behavioral health system staff reported similar perceptions of CSC in 5 of 6 counties, whereas POCSC-CW/BH scores across counties showed variability. Exploratory results revealed CSC scores varied by staff role in each system. In general, the POCSC-CW/BH is a promising instrument that adds to a limited array of practical empirically supported measurement tools for measuring CSC between child welfare and children's behavior health systems. The study limitations and implications for CSC measurement and trauma-informed practice are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431305 TI - "It's never black and white": Early interventionists' experiences supporting abused children and their families. AB - Early interventionists (EIs) support families of infants and toddlers with delays and disabilities. Children with disabilities are a high risk for abuse and neglect. To understand how or whether trauma-informed practices are utilized in early intervention, 28 EIs participated in focus groups to share their experiences, challenges, and strategies when supporting children with disabilities who have also been abused. A thematic analysis was used to analyze the data. Participants indicated that they experienced challenges related to identifying signs and symptoms of child abuse and neglect, making decisions regarding their role as a mandated reporter and differentiating between family circumstances (i.e., poverty) and abuse and neglect. Participants also indicated that their educational programs did not prepare them to utilize trauma-informed practices or prepare them to work with children who have been abused or neglected. Overall, the EI system supports individuals with disabilities who are more vulnerable to abuse, neglect, and maltreatment. However, this study indicates EIs do not feel prepared or confident to support children who have experienced abuse. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431306 TI - Veterans Affairs and the Department of Defense mental health apps: A systematic literature review. AB - In the present systematic review, we summarize the feasibility, usability, efficacy, and effectiveness of mental health-related apps created by the Veterans Affairs (VA) or the Department of Defense (DoD). Twenty-two articles were identified, reporting on 8 of the 20 VA/DoD mental health self-management and treatment companion apps. Review inclusion criteria were studies that reported original data on the usability, acceptability, feasibility, efficacy, and effectiveness, or attitudes toward the app. We collected data from each article regarding type of study, sample size, participant population, follow-up period, measures/assessments, and summary of findings. The apps have been tested with patients seeking treatment, patients with elevated mental health symptoms, and clinicians. The strongest area of support for the apps is regarding evidence of their feasibility and acceptability. Research support for efficacy and effectiveness of the apps is scarce with exceptions for two apps (PTSD Coach, Virtual Hope Box). Until more evidence accumulates, clinicians should use their judgment and be careful not to overstate the potential benefits of the apps. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431307 TI - Organizational trauma-informed care: Associations with individual and agency factors. AB - In response to the growing awareness of the high rates of potentially traumatic experiences and their potential adverse impacts, health and human service providers have increasingly focused on implementing trauma-informed care (TIC). However, studies focusing on effective implementation have been limited. In this study, we explored the relationship of individual and agency characteristics to the level of organizational TIC. With data collected from a sample of 345 providers from 67 agencies, we used the TICOMETER, a brief measure of organizational TIC with strong psychometric properties, to determine these associations. We found weak relationships between individual factors and TICOMETER scores and stronger associations for agency-level factors. These included agency type, time since last trauma training, and involvement of service users. These findings highlight the importance of robust cultural changes, service user involvement at all levels of the organization, flattening power differentials, and providing ongoing experiential training. This analysis fills an important gap in our knowledge of how best to ensure agency-wide provision of TIC. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431308 TI - Development and preliminary evaluation of a self-guided, internet-based tool for coping with stress and trauma: Life Improvement for Teens (LIFT). AB - Implementation issues often interfere with delivery of evidence-based interventions for students exposed to trauma. To improve uptake of evidence-based techniques for such students, a partnership of interventionist scientists, research and development experts, and students created a self-paced, confidential, online curriculum. This article describes the program and results of an open trial in 5 schools that serve primarily ethnic minority youth in urban settings. Fifty-one middle and high school students completed surveys before and after the program, as well as within the program, to assess emotional and behavioral symptoms (depressive, anxiety, posttraumatic stress disorder [PTSD] symptoms and behavior) and purported mechanisms of action (coping, cognitions, emotional self-efficacy). Results indicated the program was feasible and acceptable, with moderate satisfaction. Despite low power in this study, we observed changes in several hypothesized mechanisms of action. In addition, we observed promising improvements in PTSD symptoms, emotional problems, and total behavioral difficulties. These findings offer the promise of using a self-help web-based tool to augment and enhance usual school support services. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431309 TI - !Aptivate!: A Spanish-language behavioral activation mobile application for delivery via primary care. AB - Treatment for depression is a core health disparity for Latino/as in the United States. U.S. Latino/as are most likely to report depressive symptoms to primary care physicians, who often have limited resources for providing evidence-based psychological depression treatment. This limited treatment accessibility is further compounded by additional treatment barriers, including stigma related to seeking mental health treatment and limited English proficiency. Mobile technologies, including smartphones and mobile applications (apps) delivered via smartphone, are promising for addressing this treatment need. Herein, we discuss the development of a Spanish-language brief behavioral activation mobile application, !Aptivate!, that was developed to disseminate depression-based psychological treatment via primary care to Spanish-speaking Latino/as. This article focuses on the description of (a) rationale for !Aptivate! treatment development, (b) treatment components, and (c) a clinical case example describing potential implementation in primary care. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431310 TI - Integrating play in trauma-informed care: Multidisciplinary pediatric healthcare provider perspectives. AB - Children and their family members may experience potentially traumatic events during medical treatment that can result in pediatric medical traumatic stress reactions. Play is a normative part of childhood that may facilitate engagement in medical care and may be incorporated in trauma-informed care. This qualitative study used semistructured interviews to examine the role of play and its potential use in trauma-informed care. The perspectives of 30 multidisciplinary pediatric healthcare providers representing 5 divisions (Cardiology, Endocrinology, Oncology, Orthopedics, Pulmonology) in 2 children's hospitals were gathered. Constant comparison and directed content analysis were used to analyze the data. Themes and subthemes were derived in 3 areas: (a) aspects of pediatric medical care that are potentially traumatic (specific events; and physical, emotional, and family-level consequences), (b) uses of play in pediatric healthcare settings (general [relieve boredom] and trauma-specific [prevention/alleviation]), and (c) potential barriers to the use of play in trauma-informed care (infection control; lack of provider training). The results document aspects of pediatric medical experiences that providers recognize as potentially traumatic, highlighting the importance of trauma-informed care. They also identify ways to use play to engage with children and families in a trauma informed way. Additional training and development regarding play may increase the viability of using play in trauma-informed pediatric healthcare. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431311 TI - Pathways to increasing the use of psychosocial care with hospitalized children. AB - Trauma-informed care or psychosocial care can prevent or reduce the long-term impacts of hospitalization on children and their families, but few hospital staff members receive formal training in the optimal delivery of this care. This study aimed to (a) identify predictors of staff knowledge, confidence, use, and barriers regarding psychosocial care, and investigate whether these differed by profession; (b) identify pathways to increasing the use of psychosocial care; and (c) understand the association between psychosocial care and staff stress and burnout. Surveys were conducted with staff members (N = 180) within a large pediatric hospital. Questions were based on those used in similar research, and stress and burnout were assessed using the Professional Quality of Life scale. The study found that although all staff members reported using psychosocial care, only 27.2% had received training in these skills. There were no substantial differences in knowledge, confidence, and use of psychosocial care between different professions (medical, nursing, allied health, and administration staff), although nursing staff members reported a higher number of barriers to using psychosocial care. Training was indirectly associated with greater use via greater confidence and greater knowledge. Low confidence and a higher number of barriers were associated with staff burnout, and greater skill use and a higher number of barriers were associated with staff stress. Overall, these findings suggest that training that improves confidence and knowledge may support staff to deliver psychosocial care, with potential benefits for staff well-being. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431312 TI - Attachment anxiety and trauma history uniquely and interactively predict adjustment during and following deployment among military partners. AB - The psychological impact of military deployment on nondeploying partners of service members is only recently gaining attention in the literature, with preliminary findings suggesting that partners of military service members experience significant mental health consequences of deployment, but with little work examining factors that could heighten or attenuate risk for maladjustment in response to deployment. The current study uses attachment theory as a guide to explore the unique and interactive effects of two factors likely to increase risk for maladjustment among nondeploying partners: attachment anxiety and trauma history. Participants (N = 86) completed assessments 2 weeks prior to and 2 weeks following their partners' deployment departure, as well as 2 weeks following their partners' return. Attachment anxiety and trauma history independently contributed to adjustment during and following the deployment, with partners high in either factor at greatest risk for maladjustment and partners high in both exhibiting the most linguistic signs of threat orientation. Further, low attachment anxiety was associated with better adjustment when trauma history was low or moderate, but not high; similarly, low trauma history was associated with better adjustment when attachment anxiety was at low or moderate, but not high. In terms of postdeployment adjustment, partners with less trauma history reported less distress. Somewhat surprisingly, among those with more trauma history, higher attachment anxiety was associated with less risk for maladjustment. We discuss these findings in terms of their implication for theory and prevention. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30431313 TI - Discrimination in healthcare settings among adults with recent HIV diagnoses. AB - The prevalence of discrimination in healthcare settings among HIV patients in the United States is unknown. The Medical Monitoring Project (MMP) is a complex sample survey of adults receiving HIV medical care in the United States. We analyzed nationally representative MMP data collected 2011-2015. We assessed the prevalence of self-reported healthcare discrimination, perceived reasons for discrimination, and factors associated with discrimination among persons with HIV diagnoses <=5 years before interview (n = 3,770). Overall, 14.1% of patients living with HIV (PLWH) experienced discrimination, of whom 82.2% attributed the discrimination to HIV. PLWH reporting poverty, homelessness, or attending a non Ryan White HIV/AIDS Program (RWHAP) facility were more likely to report discrimination compared with other groups. Of patients attending non-RWHAP facilities, discrimination was higher among those in poverty (27.5%) vs. not in poverty (15.1%). Discrimination was associated with homelessness regardless of facility type, and was highest among homeless persons attending non-RWHAP facilities. Healthcare discrimination was commonly reported among PLWH, and was most often attributed to HIV status. Discrimination was higher among those reporting poverty or homelessness, particularly those attending non-RWHAP facilities. Incorporating practices, such as anti-discrimination training, in facilities may reduce healthcare discrimination. PMID- 30431315 TI - Nephrotoxicity of Tripterygium wilfordii Hook. f Preparations: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To evaluate the incidence rate of nephrotoxicity in Tripterygium wilfordii Hook. f (TwHF) preparations approved by the China Food and Drug Administration and the potential risk factors. METHODS: CENTRAL, PubMed, SinoMed, Chinese National Knowledge Infrastructure, VIP, China Important Conference Papers Database, China Dissertation Database, and online clinical trial registry websites were searched for articles that reported on nephrotoxicity of TwHF preparations until November 23, 2017. There was no limitation for study design. RESULTS: A total of 36 articles involving 2,017 participants were included. Results showed that the incidence of nephrotoxicity associated with TwHF preparations was 5.81% (95% confidence interval: 4.43-7.57). Subgroup analysis showed that the disease type, combined medication, duration, and study design were not correlated with the incidence of nephrotoxicity. CONCLUSION: The incidence rate of nephrotoxicity in TwHF preparations was 5.81%. The possible risk factors, such as disease type, the combination with other drugs, medication time, and study design, were not found to be correlated with the incidence of nephrotoxicity. However, due to the limited number of included articles, the limited sample size, and the poor methodology quality, the incidence rate of nephrotoxicity of TwHF preparations might be overestimated, and more prospective articles are needed to explore the potential influence factor. PMID- 30431314 TI - Zusanli (ST36) Acupoint Injection for Diabetic Peripheral Neuropathy: A Systematic Review of Randomized Controlled Trials. AB - BACKGROUND: Acupuncture point (acupoint) injection is a common practice in China. Some trials showed that Chinese herbal extracts and/or conventional medication are injected at the Zusanli (ST36) acupoint for the treatment of diabetic peripheral neuropathy (DPN). The study aimed to assess the effectiveness and safety of acupoint injection for DPN at the ST36 by systematically evaluating the evidence published to date. METHODS: Six databases were searched for randomized controlled trials (RCTs) of ST36 injection for DPN with primary outcome of pain, global symptom improvement, and quality of life. Methodological quality was assessed by the Cochrane risk of bias (ROB) tool. Data were analyzed using RevMan 5.3. RESULTS: Fourteen RCTs involving 1,071 participants with DPN were included. All RCTs were assessed as unclear or high ROB. Few RCTs adequately reported methodology-related items and needling details according to Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) statement. Medications injected at ST36 included conventional medications (11 RCTs) and Chinese herbal extracts (3 RCTs). The authors of this study did not perform any meta-analysis due to the heterogeneity of medications used for injections. Two individual RCTs favored ST36 injection in relieving pain compared with intramuscular injection of the same medication. For global symptom measured by Toronto clinical scoring system, one RCT showed that ST36 injection of Fufang Danggui was more effective than intramuscular injection of vitamin B12, two RCTs demonstrated that ST36 injection of mecobalamin or Danhong with cointervention was superior, while one RCT showed no significant differences between ST36 injection and intramuscular injection of mecobalamin. For improving nerve conduction velocity (NCV), three of four individual RCTs showed that ST36 injection was better than intramuscular or intravenous injection of the same medication, two RCTs favored ST36 injection with cointervention, and one RCT favored ST36 injection without cointervention. Four RCTs reported monitoring adverse events, all of which showed no significant difference between groups. CONCLUSIONS: Limited evidence suggests that ST36 injection appears to be safe, and potentially effective in reducing pain score and improving NCV compared with intramuscular injection of the same medication. However, poor methodological and reporting quality reduced confidence in the findings. Rigorously designed and well-reported RCTs evaluating the effectiveness of ST36 injection for DPN are warranted. PMID- 30431316 TI - Association of Green Tea Consumption and Coronary Arterial Disease Risk in a Chinese Population in Guangzhou. AB - OBJECTIVE: To explore the association between green tea consumption and coronary arterial disease (CAD) in the Chinese population of Guangzhou. Design, Location, Subjects: A retrospective study at the Sun Yat-sen Memorial Hospital in Guangzhou, China. Consecutive patients were enrolled between January 2013 and August 2014. A total of 539 patients were included. Two hundred sixty-seven of them are CAD patients and 272 of them are non-CAD patients. The CAD patients were diagnosed according to international diagnostic criteria. INTERVENTIONS: Using data from the questionnaires and clinical laboratories, we attempted to elucidate the association between green tea and CAD. OUTCOME MEASURES: Baseline characteristics of study population, CAD-related biomarkers, amount, frequency and duration of green tea consumption, and CAD risk analysis. RESULTS: The results showed that among males, those who drank green tea did not have a reduced risk of CAD (odds ratio; OR = 1.58, 95% CI: 0.96-2.59, p > 0.05). However, women in the study who drank green tea had a reduced risk of CAD (OR = 0.13, 95% CI: 0.07-0.23, p < 0.01). The females who consumed <=1 cup/day green tea had lower CAD risk (OR = 0.12, 95% CI: 0.07-0.23, p < 0.01). The frequency of 3-5 days/week (OR = 0.14, 95% CI: 0.07-0.29, p < 0.01) and >5 days/week (OR = 0.24, 95% CI: 0.08-0.69, p < 0.01) were both beneficial in preventing CAD. Those who had been drinking green tea for 0-10 years (OR = 0.11, 95% CI: 0.04-0.30), 10-20 years (OR = 0.22, 95% CI: 0.11-0.46), or >20 years (OR = 0.37, 95% CI: 0.12-0.96) had a reduced risk of CAD. CONCLUSIONS: Through the analysis of green tea consumption and CAD-related biomarkers, we concluded that a small amount of high-frequency green tea consumption was associated with a reduced risk of CAD in female populations in Guangzhou, China, and the association might be partly due to altered CAD-related biomarkers. PMID- 30431317 TI - "What Is 'Enough,' and How Do I Make It?": A Qualitative Examination of Questions Mothers Ask on Social Media About Pumping and Providing an Adequate Amount of Milk for Their Infants. AB - BACKGROUND: Mothers commonly cite an inadequate milk "supply" as a reason for stopping human milk feeding. Further, pumping may affect mothers' understanding of their milk production. We aimed to characterize the questions mothers ask each other online related to the adequacy of the milk they pumped and provided to their infants. MATERIALS AND METHODS: We conducted a secondary analysis of 543 posts containing questions related to pumping on an online discussion forum. These posts were provided by an open cohort of ~25,000 women between 1 month before due date and 4.5 months postpartum. We used thematic analysis with Atlas.ti to analyze the posts. RESULTS: Mothers commonly asked how many ounces they should be pumping and inquired about strategies to increase their pump output. They also wondered how many ounces or bottles of pumped milk they should provide to their infants or store for future use. Finally, mothers reported the inadequacy of the milk they were pumping or providing to their infants as potential reasons for stopping human milk feeding. CONCLUSION: Our findings suggest that mothers may benefit from additional guidance from health care providers on the limitations of using pumps to draw conclusions about their milk production, the current evidence related to the use of herbal galactagogues, and the importance of responsive infant feeding. These findings also highlight the need for future research into how pumping or using herbal galactagogues may affect mothers' actual or perceived milk production and how styles for providing pumped milk compare to styles for feeding directly at the breast. PMID- 30431318 TI - Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis. AB - INTRODUCTION: Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. AIMS AND METHODS: To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several pro-fibrogenic factors related to chronic pancreatitis were evaluated. RESULTS: COX-2 was expressed in the pancreas of the transgenic mice as detected by Western blot. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition and acinar to ductal metaplasia. Quantitative RT-PCR and immunostaining showed that pro-fibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. CONCLUSION: Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. PMID- 30431319 TI - Blended learning in medical physiology improves nursing students' study efficiency. AB - The rapid development of mobile phones and communication networks is profoundly changing the lives of people in China. With the gradual growth of Wi-Fi on college and university campuses, Chinese schools are setting off a wave of teaching reform combining online material with traditional classroom instruction. We adapted a Chinese University massive open online course physiology course into a private university online course, specifically designed for second-semester bachelor's level nursing students at Taishan Medical University. This online course blended with classroom teaching was offered to 108 freshmen from two parallel reform classes. A third class of 55 students was offered the traditional classroom lecture-based course as a control. Impressive teaching effects were achieved in reform classes, as indicated by significant improvement in student performance on the final examination and positive student feedback. The student surveys showed that 68% of students preferred the blended course over traditional classroom courses. The most highly rated advantages of the blended course were flexible learning time (84%) and improvement of independent study skills (75%). As higher education enters the internet era, exploiting the high-quality cyber resources may be the fastest and most economical way to improve teaching efficiency and enhance students' study experience. PMID- 30431320 TI - The self-assessment dilemma: an open-source, ethical method using Matlab to formulate multiple-choice quiz questions for online reinforcement. AB - Student self-assessment using computer-based quizzes has been shown to increase subject memory and engagement. Some types of self-assessment quizzes can be associated with a dilemma between 1) medical students who want the self assessment quiz to be clearly related to upcoming summative assessments or curated by the exam-setters, and 2) university administrators and ethics committees who want clear guarantees that the self-assessment quizzes are not based on the summative assessments or made by instructors familiar with the exam bank of items. An algorithm in Matlab was developed to formulate multiple-choice questions for both ion transport proteins and pharmacology. A resulting question/item subset was uploaded to the Synap online self-quiz web platform, and 48 year 1 medical students engaged with it for 3 wk. Anonymized engagement statistics for students were provided by the Synap platform, and a paper-based exit questionnaire with an 80% response rate ( n = 44) measured satisfaction. Four times as many students accessed the quiz system via laptop compared with phone/tablet. Of 391 questions/items, over 11,749 attempts were made. Greater than 80% of respondents agreed with each of the positive statements (ease of use, enjoyed, engaged more, learned more, and wanted it to be extended to other modules). Despite simplistic questions and rote memorization, the questions developed by this system were engaged with and were received positively. Students strongly supported extending the system. PMID- 30431321 TI - Medical student perceptions about active methodologies in the study of physiology in medical schools in Salvador, Brazil. AB - In the field of medical education, it is possible to consider that the acquisition of professional competences can gain new contours when considering the use of active methodologies. It is important to analyze the perception of the students about the use of them in medical courses, as well as to reflect on their challenges and potentials. In the present study, a semistructured questionnaire of student perception was applied immediately after the execution of different types of active methodologies in the discipline of physiology in two medical courses. The results suggest a highly positive evaluation of the use of active methodologies by the student body of the two institutions. The students evaluated positively the application of the method (94.6%) and the perception about the learning (84.1%). On the other hand, when questioned about the substitution of the traditional expository method by the active methodologies, there was a tendency to the centrality of the answers, with 84.0% of the responses concentrated at positions 2, 3, and 4 on a scale of 1 (minimum) to 5 (maximum) on the Likert scale. There were no statistically significant differences when comparing variables of age, sex, and previous graduation. Although there was no consensus regarding the full replacement of traditional for active methodologies, one can conclude that the students' perception about the introduction of said methodologies in the teaching of physiology in medical courses is positive, regardless of the subgroups evaluated. These results encourage the insertion of these and other methodologies into medical courses. PMID- 30431322 TI - No stress-better results? PMID- 30431323 TI - Win-win: utilizing undergraduate honors college credits in support of sustainable department outreach programs. PMID- 30431324 TI - Student engagement and higher order skill proficiency: a comparison of traditional didactic and renewed integrated active learning curricula. AB - A large, multicampus, public medical school underwent curricular renewal, emphasizing a student-centered approach with 50% of all course contact time devoted to active learning. Determining the impact of active learning on student engagement and higher order skill (HOS) proficiency was the primary aim of this study. Following Institutional Review Board approval, two cohort groups of first year medical students were enrolled. The first cohort ( n = 54) included students before curriculum reform in the legacy curriculum (LC). The second cohort ( n = 73) included students completing studies in the renewed curriculum (RC). Near the end of the first year of medical school, both cohorts completed a validated survey of student engagement, and a proctored problem-based assessment of HOS proficiency [Collegiate Learning Assessment (CLA+)]. Results indicated RC students perceived greater levels of engagement than LC (39.5+5.8 vs. 33.3+5.6), and greater reliance on HOS, including analysis, synthesis, and application. However, there were no significant differences between cohorts in proficiency of HOS when assessed by the CLA+ (LC = 1,878 +/- 161 vs. RC = 1,900 +/- 157). Additionally, poor correlation between engagement and HOS for both LC and RC indicated more engaged students do not necessarily possess greater HOS proficiency. Ceiling effect may explain results as medical students enter medical school as highly skilled learners with potentially little room for improvement. It will be informative to continue to track engagement and HOS of both cohort groups as they continue their medical studies. PMID- 30431326 TI - What makes skeletal muscle striated? Discoveries in the endosarcomeric and exosarcomeric cytoskeleton. AB - One of the most iconic images in biology is the cross-striated appearance of a skeletal muscle fiber. The repeating band pattern shows that all of the sarcomeres are the same length. All of the A bands are the same length and are located in the middle of the sarcomeres. Furthermore, all of the myofibrils are transversely aligned across the muscle fiber. It has been known for 300 yr that skeletal muscle is striated, but only in the last 40 yr has a molecular understanding of the striations emerged. In the 1950s it was discovered that the extraction of myosin from myofibrils abolished the A bands, and the myofibrils were no longer striated. With the further extraction of actin, only the Z disks remained. Strangely, the sarcomere length did not change, and these "ghost" myofibrils still exhibited elastic behavior. The breakthrough came in the 1970s with the discovery of the gigantic protein titin. Titin, an elastic protein ~1 um in length, runs from the Z disk to the middle of the A band and ensures that each sarcomere is the same length. Titin anchors the A band in the middle of the sarcomere and may determine thick-filament length and thus A-band length. In the 1970s it was proposed that the intermediate filament desmin, which surrounds the Z disks, connects adjacent myofibrils, resulting in the striated appearance of a skeletal muscle fiber. PMID- 30431325 TI - Evaluation of a virtual neurophysiology laboratory as a new pedagogical tool for medical undergraduate students in China. AB - This study compared the effect of a virtual laboratory, a living tissue laboratory, and a blended laboratory on student learning about the generation and conduction of neural action potentials and perceptions about life science. Sixty three second-year medical students were randomly assigned to one of three groups (living tissue laboratory, virtual laboratory, and blended group). The students conducted the practical activity, and then they were given a postlaboratory quiz and an attitude survey. The blended group euthanized fewer animals and spent less time to finish the animal experiment than the living tissue group did. In the postlaboratory quiz, students who performed the virtual laboratory alone got significantly lower scores than students in the other two groups, and the blended group did not get better scores than the living tissue group. The attitude surveys showed that the virtual laboratory group had a lower perceived value of the science research and activity in which they participated than the other two groups did. Here, 77.8% of all students chose the blended style as the ideal teaching method for experiments. Our findings led us to believe that isolated use of the virtual laboratory in China is not the best practice: the virtual laboratory serves as an effective preparation tool, and the blended laboratories may become the best laboratory teaching practice, provided that the software design for the virtual laboratory is further improved. PMID- 30431327 TI - Essential oils as natural preservatives for bakery products: Understanding the mechanisms of action, recent findings, and applications. AB - Bakery products, as an important part of a healthy diet, are characterized by their limited shelf-life. Microbiological spoilage of these products not only affects the quality characteristics and result in the economic loss but also threatens consumer's health. Incorporation of chemical preservatives, as one of the most conventional preserving techniques, lost its popularity due to the increasing consumer's health awareness. Therefore, the bakery industry is seeking alternatives to harmful antimicrobial agents that can be accepted by health conscious customers. In this regard, essential oils have been previously used as either a part of product ingredient or a part of the packaging system. Therefore, the antimicrobial aspect of essential oils and their ability in delaying the microbiological spoilage of bakery products have been reviewed. Several types of essential oils, including thyme, cinnamon, oregano, and lemongrass, can inhibit the growth of harmful microorganisms in bakery products, resulting in a product with extended shelf-life and enhanced safety. Research revealed that several bioactive compounds are involved in the antimicrobial activity of essential oils. However, some limitations, such as the possible negative effects of essential oils on sensory parameters, may limit their applications, especially in high concentrations. In this case, they can be used in combination with other preservation techniques such as using appropriate packaging materials. Further research regarding the commercial production of the bakery products formulated with essential oils is required in this area. PMID- 30431329 TI - Organization and Compartmentalization by Lipid Membranes Promote Reactions Related to the Origin of Cellular Life. AB - Liquid crystals have certain physical properties that promote chemical reactions which cannot occur in bulk phase media. These properties are displayed, among other molecules, by amphiphilic compounds which assemble into membrane structures then concentrate and organize biologically relevant monomers within their confined spaces. When mixtures of lipids and nucleotides are cycled multiple times between hydrated and anhydrous conditions, the monomers polymerize in the dry phase into oligonucleotides. Upon rehydration, mixtures of the polymers are encapsulated in lipid-bounded compartments called protocells. Reactions in liquid crystalline organizing matrices represent a promising approach for future research on how primitive cells could emerge on the early Earth and other habitable planets. PMID- 30431328 TI - Intake of vitamin B6, folate, and vitamin B12 and risk of coronary heart disease: a systematic review and dose-response meta-analysis of prospective cohort studies. AB - The objective of this study was to quantify the association of B-vitamins intake with the future risk of coronary heart disease (CHD). A systematic search was performed with the use of PubMed and Scopus from inception to April 30, 2018. Prospective cohort studies evaluating the association of intake of folate, vitamin B6, and vitamin B12 with risk of CHD in the general population were included. A random-effects meta-analysis was performed. Eleven prospective cohort studies (total n = 369,746) with 5133 cases of CHD were included in the analyses. The relative risks were: 0.79 (95%CI: 0.69, 0.89; I2 = 67%) for a 250 ug/d increment in folate intake; 0.87 (95%CI: 0.78, 0.96; I2 = 80%) for a 0.5 mg/d increment in vitamin B6 intake; and 0.97 (95%CI: 0.80, 1.14: I2 = 67%) for a 3 ug/d increment in vitamin B12 intake. The results did not change materially when the analyses were restricted only to dietary vitamins intake. A nonlinear dose response meta-analysis demonstrated a linear inverse association between folate and vitamin B6 intake and risk of CHD. In conclusion, higher intake of folate and vitamin B6 is associated with a lower risk of CHD in the general population. PMID- 30431331 TI - Pulmonary Rehabilitation. PMID- 30431330 TI - Water intake increases mesenteric lymph flow and the total flux of albumin, long chain fatty acids, and IL-22 in rats: New concept of absorption in jejunum. AB - The traditional Japanese health care custom recommends that a suitable volume of water is consumed. However, physiological and immunological mechanisms in support of this practice are unknown. Therefore, we conducted rat and rabbit in vivo experiments to investigate the effects of intragastric administration of distilled water on the jejunal-originated lymph flow, and the concentrations and total flux of cells, albumin, long-chain fatty acids, and innate lymphoid cell 3 (ILC-3)-secreted interleukin-22 (IL-22) through mesenteric lymph vessels. The distribution and activity of ILC-3 in rat small intestine by water intake were evaluated using flowcytometry and RT-PCR. The intragastric administration of distilled water caused significant increases in rat mesenteric lymph flow and in the total flux of cells, albumin, long-chain fatty acids, and IL-22 through the lymph vessels. The intravenously injected Evans blue dye was rapidly transported into rabbit mesenteric lymph vessel and cisterna chyli. The distribution of ILC-3 and the expression of IL-22 mRNA were maximal in the lamina propria cells of the rat jejunum. No significant presence of ILC-3 in the lymph was observed in the control and under water intake conditions. In conclusion, the absorbed water in the jejunum is transported through mesenteric lymph vessels. The higher permeability of albumin in the jejunal microcirculation may play key roles of the transport of consumed water and the reservoir and transporter of long-chain fatty acids. Water intake also accelerates the transfer of IL-22 to the mesenteric lymph, which may contribute, in part, to maintaining and promoting the innate immunity in the body. PMID- 30431332 TI - Determination of Mesalamine levels in Human Milk as a Function of Dose. AB - BACKGROUND: Oral mesalamine (5-amino salicylic acid [5-ASA]) is an anti inflammatory agent commonly used to treat inflammatory bowel disease such as ulcerative colitis and Crohn's disease. The transfer of mesalamine into human milk has to date been poorly described at the current dosages and newer formulations. This study was designed to determine transfer of mesalamine into human milk as a function of maternal dose and time, and dosage form. STUDY DESIGN: Ten breastfeeding mothers (age 28-41 years) suffering from inflammatory bowel disease were recruited who provided milk samples at 0, 1, 2, 4, 8, 12, and 24 hours after a single daily dose of oral mesalamine in pH-dependent gastroresistant coated tablets (1.2, 2.4, 3.6, and 4.8 g). Milk samples were analyzed using liquid chromatography/tandem mass spectrometry. RESULTS: A total of 10 women were enrolled for the study. The calibration curve for mesalamine was linear over a concentration range of 0.32-200 ng/mL. Irrespective of maternal dose, mesalamine levels in milk were exceedingly low. However, a wide range of mesalamine levels were observed among all the participants. The relative infant doses were all lower than 0.1% (range 0.003-0.085%). CONCLUSION: Regardless of dose and high variability, mesalamine levels in human milk were present in exceedingly low levels. The mothers in this study reported no side effects with their infants. These results suggest that the transfer of mesalamine into milk is very low and poses minimal risks to the breastfed infant. PMID- 30431333 TI - A Novel Role for Programmed Cell Death Receptor Ligand 2 (PD-L2) in Sepsis Induced Hepatic Dysfunction. AB - The liver is an organ which, when dysfunctional in a septic patient, is strongly associated with morbidity and mortality. Understanding the pathophysiology of liver failure during sepsis may lead to improved diagnostics and potential therapeutic targets. Historically, Programmed Cell Death Receptor Ligand 1 (PD L1) has been considered the primary ligand for its checkpoint molecule counterpart, Programmed Cell Death Receptor 1 (PD-1), with PD-L2 rarely in the immunopathological spotlight. PD-1 and PD-L1 contribute to liver dysfunction in a murine cecal ligation and puncture (CLP) model of sepsis, but virtually nothing is known about PD-L2's role in sepsis. Therefore, our central hypothesis was that sepsis-induced changes in hepatic PD-L2 expression contributed to worsened liver function and, subsequently, more pronounced morbidity and mortality. We found that, while PD-L1 gene deficiency attenuated the hepatic dysfunction seen in wildtype mice after CLP, the loss of PD-L2 appeared to actually worsen indices of liver function along with a trend towards higher liver tissue vascular permeability. Conversely, some protective effects of PD-L2 gene deletion were noted, such as reduced liver/peritoneal bacterial load and reduced IL-6, IL-10 and MIP-2 levels following CLP. These diverse actions, as well as the unique expression pattern of PD-L2, may explain why no overt survival advantage could be witnessed in the septic PD-L2-/- mice. Taken together, these data suggest that, while PD-L2 has some selective effects on hepatic response seen in the septic mouse, these factors are not sufficient to alter septic mortality in this adult murine model. PMID- 30431334 TI - An Apparent Binary Choice in Biochemistry: Mutual Reactivity Implies Life Chooses Thiols or Nitrogen-Sulfur Bonds, but not Both. AB - A fundamental goal of biology is to understand the rules behind life's use of chemical space. Established work focuses on why life uses the chemistry that it does. Given the enormous scope of possible chemical space, we postulate that it is equally important to ask why life largely avoids certain areas of chemical space. The nitrogen-sulfur bond is a prime example, as it rarely appears in natural molecules, despite the very rich N-S bond chemistry applied in various branches of industry (e.g., industrial materials, agrochemicals, pharmaceuticals). We find that, out of more than 200,000 known, unique compounds made by life, only about 100 contain N-S bonds. Furthermore, the limited number of N-S bond-containing molecules that life produces appears to fall into a few very distinctive structural groups. One may think that industrial processes are unrelated to biochemistry because of a greater possibility of solvents, catalysts, and temperatures available to industry than to the cellular environment. However, the fact that life does rarely make N-S bonds, from the plentiful precursors available, and has evolved the ability to do so independently several times, suggests that the restriction on life's use of N-S chemistry is not in its synthesis. We present a hypothesis to explain life's extremely limited usage of the N-S bond: that the N-S bond chemistry is incompatible with essential segments of biochemistry, specifically with thiols. We support our hypothesis by (1) a quantitative analysis of the occurrence of N-S bond-containing natural products and (2) reactivity experiments between selected N-S compounds and key biological molecules. This work provides an example of a reason why life nearly excludes a distinct region of chemical space. Combined with future examples, this potentially new field of research may provide fresh insight into life's evolution through chemical space and its origin and early evolution. PMID- 30431336 TI - Factors associated with plasma concentrations of polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (p,p'-DDE) in the Canadian population. AB - This study describes blood plasma concentrations of PCBs and p,p'-DDE in the Canadian population aged 20-79 years. PCBs and p,p'-DDE were measured in 1668 participants in the Canadian Health Measures Survey, Cycle 1 (2007-2009). We investigated how concentrations vary by sociodemographic, anthropometric, and lifestyle variables, identified factors associated with exposures, and evaluated concentrations against health-based guidance values. Congeners of PCB most commonly detected were PCB-138, PCB-153, and PCB-180. p,p'-DDE was detectable in > 99% of the samples. Factors associated with ?PCBs were age, region of birth, frequency of fish consumption, and liver intake (R2 = 58.1%). For p,p'-DDE, significant factors were sex, age, region of birth, household education, and ethnic origin (R2 = 47.0%). PCB concentrations in Canadians were similar to those in the United States, and lower than those reported in Europe. A small percentage equalled or exceeded the Human Biomonitoring value of 3.5 ug/L for PCBs. Few exceedances of the p,p'-DDE biomonitoring equivalent were observed. PMID- 30431335 TI - "Vibrant Entanglements": HIV Biomedicine and Serodiscordant Couples in Papua New Guinea. AB - The global ambition to "end AIDS" hinges on the universal uptake of HIV treatment as-prevention and is undergirded by the assumption that biomedical technologies have consistent, predictable effects across highly diverse settings. But as anthropologists argue, such technologies are actively transformed by their local encounters, with various constitutive effects. How priority populations, such as HIV "serodiscordant" couples, negotiate treatment-as-prevention remains relatively unknown. We consider the "vibrant entanglements" that can shape couples' engagement with global biomedical technologies in the local context of Papua New Guinea (PNG)-a relatively uncharted biomedical landscape-and what we hope our current research in this setting will achieve. PMID- 30431337 TI - Social Conformity Effects on Trust in Simulation-Based Human-Robot Interaction. AB - OBJECTIVE:: We investigated the co-acting influences of communication and social conformity on trust in human-robot interaction. BACKGROUND:: Previous work has investigated aspects of the robot, the human, and the environment as influential factors in the human-robot relationship. Little work has examined the conjoint effects of social conformity and communication on this relationship. As social conformity and communication have been shown to affect human-human trust, there are a priori reasons to believe that they will play an influential role in human robot trust also. METHOD:: The experiment examined the influences of social conformity and robot communication on trust. A 2 * 2 (communication * social group) design was implemented with each variable having two levels (communication, no communication; positive social group, negative social group). RESULTS:: We created a communication manipulation which we then demonstrated to mediate the trust level between human and robot. However, this influence on trust was overcome by social information in which the subsequent trust level, attributed to the robot, was dominated by expressed social group attitudes to that robot. CONCLUSION:: The results confirm the importance of human social assessments over direct robot communication in setting human-robot trust levels. When social opinions are expressed, observers appear to conform to the trust displayed by the group than relying on their own judgment. APPLICATION:: In human robot teams, the perceptions of the group may exert a greater impact than even robot communication. This may be especially important when new human members are introduced into such teams. PMID- 30431338 TI - Assembly, Release, and Transport of Airway Mucins in Pigs and Humans. AB - The respiratory system is protected from inhaled particles and microbes by the mucociliary system. This system differs between animal species, where pigs and humans have numerous submucosal glands. The polymer-forming mucin, MUC5B, is packed in a highly organized way in granules of the mucus-secreting cells in the glands. Upon secretion, the packed MUC5B is flushed out by a chloride- and bicarbonate-rich fluid from the cystic fibrosis transmembrane conductance regulator-expressing serosal cells located at the most distal part of the gland. The bicarbonate raises the pH and removes calcium from the N terminus of MUC5B, allowing the mucin to be pulled out into a linear polymer. Thousands of such polymers gather in bundles in the submucosal gland duct, and these bundles appear at the opening of the glands. They are moved by the beating cilia, and sweep over the airway surface and are patchily coated with the MUC5AC mucin from the surface goblet cells. The movement of these bundles is controlled by the MUC5AC mucin attachment/detachment to the goblet cells. Thus, higher animals with submucosal glands and large diameters of the proximal airways are efficiently cleaned by the thick mucus bundles sweeping the airway surface and moving particles and bacteria toward the larynx. PMID- 30431339 TI - Airway Mucin Secretion. AB - Exocytosis of secreted mucins is the final step in their intracellular processing, resulting in their release into the airway lumen to interact with water and ions to form mucus. Mucins are secreted at a low baseline rate and a high stimulated rate, and both rates are regulated by second messengers acting on components of the exocytic machinery. The principal physiologic function of the low baseline rate is to support steady-state mucociliary clearance of inhaled particles and pathogens that enter the airways during normal breathing. Even in the setting of mucin hyperproduction, baseline secretion generally does not induce mucus occlusion. The principal physiologic function of the high stimulated rate of secretion from both submucosal glands and surface goblet cells in proximal airways appears to be to sweep away larger particles, whereas in distal airways it appears to act in concert with mucin hyperproduction to induce mucus occlusion to trap migrating helminths. Pathophysiologically, stimulated mucin secretion in the setting of mucin hyperproduction from allergic or other types of airway inflammation in the absence of helminth infection causes airflow obstruction and infection. Molecular components of the mucin exocytic machinery are increasingly being identified, and surprisingly, many components are not shared between baseline and stimulated machines. The physiologic significance of the presence of two distinct molecular machines is not yet known, such as whether these interact selectively with secretory granules of different sizes or contents. A full understanding of the mechanism and regulation of airway mucin secretion will provide further insight into pathophysiologic processes and may identify therapeutic strategies to alleviate obstructive airway diseases. PMID- 30431340 TI - Airway Epithelial Differentiation and Mucociliary Clearance. AB - The lung is continuously exposed to particles, toxicants, and microbial pathogens that are cleared by a complex mechanical, innate, and acquired immune system. Mucociliary clearance, mediated by the actions of diverse conducting airway and submucosal gland epithelial cells, plays a critical role in a multilayered defense system by secreting fluids, electrolytes, antimicrobial and antiinflammatory proteins, and mucus onto airway surfaces. The mucociliary escalator removes particles and pathogens by the mechanical actions of cilia and cough. Abnormalities in mucociliary clearance, whether related to impaired fluid secretion, ciliary dysfunction, lack of cough, or the disruption of epithelial cells lining the respiratory tract, contribute to the pathogenesis of common chronic pulmonary disorders. Although mucus and other airway epithelial secretions play a critical role in protecting the lung during acute injury, impaired mucus clearance after chronic mucus hyperproduction causes airway obstruction and infection, which contribute to morbidity in common pulmonary disorders, including chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, bronchiectasis, and primary ciliary dyskinesia. In this summary, the molecular and cellular mechanisms mediating airway mucociliary clearance, as well as the role of goblet cell metaplasia and mucus hyperproduction, in the pathogenesis of chronic respiratory diseases are considered. PMID- 30431341 TI - Chair's Summary: Secreted Mucins in Lung Diseases. PMID- 30431342 TI - Purpose of the Conference: The 2018 Transatlantic Conference on Lung Diseases. PMID- 30431343 TI - Emerging Concepts and Therapies for Mucoobstructive Lung Disease. AB - A spectrum of intrapulmonary airway diseases, for example, cigarette smoke induced bronchitis, cystic fibrosis, primary ciliary dyskinesia, and non-cystic fibrosis bronchiectasis, can be categorized as "mucoobstructive" airway diseases. A common theme for these diseases appears to be the failure to properly regulate mucus concentration, producing mucus hyperconcentration that slows mucus transport and, importantly, generates plaque/plug adhesion to airway surfaces. These mucus plaques/plugs generate long diffusion distances for oxygen, producing hypoxic niches within adherent airway mucus and subjacent epithelia. Data suggest that concentrated mucus plaques/plugs are proinflammatory, in part mediated by release of IL-1alpha from hypoxic cells. The infectious component of mucoobstructive diseases may be initiated by anaerobic bacteria that proliferate within the nutrient-rich hypoxic mucus environment. Anaerobes ultimately may condition mucus to provide the environment for a succession to classic airway pathogens, including Staphylococcus aureus, Haemophilus influenzae, and ultimately Pseudomonas aeruginosa. Novel therapies to treat mucoobstructive diseases focus on restoring mucus concentration. Strategies to rehydrate mucus range from the inhalation of osmotically active solutes, designed to draw water into airway surfaces, to strategies designed to manipulate the relative rates of sodium absorption versus chloride secretion to endogenously restore epithelial hydration. Similarly, strategies designed to reduce the mucin burden in the airways, either by reducing mucin production/secretion or by clearing accumulated mucus (e.g., reducing agents), are under development. Thus, the new insights into a unifying process, that is, mucus hyperconcentration, that drives a significant component of the pathogenesis of mucoobstructive diseases promise multiple new therapeutic strategies to aid patients with this syndrome. PMID- 30431344 TI - Idiopathic Pulmonary Fibrosis Is a Genetic Disease Involving Mucus and the Peripheral Airways. AB - Idiopathic pulmonary fibrosis (IPF) is localized to the lung, is characterized by a pattern of heterogeneous, subpleural patches of fibrotic, remodeled lung, and is associated with a median survival of 3-5 years after diagnosis. A common gain of-function MUC5B promoter variant, rs35705950, is the strongest risk factor (genetic and otherwise), accounting for at least 30% of the total risk of developing IPF. The MUC5B promoter variant can be used to identify individuals in the preclinical phase of this progressive disease, and, in the IPF lung, we have found that MUC5B is specifically overexpressed in bronchoalveolar epithelium. Thus, MUC5B represents a key molecule to understand the mechanisms that appear to initiate the fibroproliferative process in the bronchoalveolar epithelium. Moreover, focusing on MUC5B may provide a unique opportunity to define the early molecular events that lead to, and potentially prevent, the development of IPF. PMID- 30431346 TI - Mucociliary Transport in Healthy and Cystic Fibrosis Pig Airways. AB - Cystic fibrosis (CF) lung disease is the major cause of morbidity and mortality in people with CF. Abnormal mucociliary transport has been the leading hypothesis for the underlying pathogenesis of CF airway disease. However, this has been difficult to investigate at very early time points. A porcine CF model, which recapitulates many features of CF disease in humans, enables studies to be performed in non-CF and CF pigs on the day that they are born. In newborn CF pigs, we found that under basal conditions, mucociliary transport rates in non-CF and CF pigs are similar. However, after cholinergic stimulation, which stimulates submucosal gland secretion, particles become stuck in the CF airways owing to a failure of mucus strands to release from submucosal glands. In this review, we summarize these recent discoveries and also discuss the morphology, composition, and function of mucins in the porcine lung. PMID- 30431348 TI - Host and Viral Determinants of Respiratory Syncytial Virus-induced Airway Mucus. AB - Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants worldwide each year. Both host and viral factors host factors predispose a subset of what appear to be healthy infants to severe RSV-induced disease. In this review, we outline many genetic and immunologic factors that contribute to airway obstruction that contributes to the severity of RSV infection. PMID- 30431345 TI - Intracellular Processing of Human Secreted Polymeric Airway Mucins. AB - Mucociliary clearance is a crucial component of innate defense of the lung. In respiratory diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, mucus with abnormal properties contributes to obstruction of the airways. The failure in function of mucus in airway clearance and pathogen protection leads to chronic infection and risk of death. Polymeric mucins (MUC5AC and MUC5B) provide the structural framework of the airway mucus gel. The intracellular synthesis and assembly of these enormous, polymeric O-linked glycoproteins is a complex, multistage process involving intra- and intermolecular disulfide bond formation and extensive addition of O-glycan chains. The fully formed polymers are packaged in a highly organized and condensed form within secretory granules inside specialized secretory cells, and after the appropriate stimulus, mucins are released and expand to form mucus. This short article brings together the current knowledge on the different steps in the production of mucin polymers and the molecular mechanisms that condense them into a packaged form in secretory granules. It is by unraveling the molecular mechanisms that control intracellular mucin supramolecular structure that we might gain new insight into what determines mucus gel properties in health and disease. PMID- 30431347 TI - Fungi in Mucoobstructive Airway Diseases. AB - Asthma, chronic rhinosinusitis, and related incurable allergic afflictions of the upper and lower airways are medically important because of their association with the disabling symptom of dyspnea and, at least for asthma, the potential to cause fatal asphyxiation. Extensive research over the past two decades has uncovered both the physiological basis of airway obstruction in asthma and key governing molecular pathways. Exaggerated airway constriction in response to diverse provocative stimuli, termed airway hyperresponsiveness, is mediated through the cytokines interleukin 4 (IL-4) and IL-13 and the transcription factor signal transducer and activator of transcription 6 (STAT6). Overproduction of mucus has long been known to be an essential second component of airway obstruction and is also mediated in part through the IL-4/IL-13/STAT6 pathway. In this review, we discuss a second major signaling pathway which underlies mucus production that is mediated through proteinase-cleaved fibrinogen signaling through Toll-like receptor 4. Unexpectedly, our analysis of human sputum and paranasal sinus fluid indicates that in most cases of severe allergic airway disease, a unique type of airway fungal infection, termed airway mycosis, is pathogenically linked to these conditions. We further discuss how fungal and endogenous proteinases mediate the fibrinogenolysis that is essential to both Toll-like receptor 4 signaling and fibrin deposition that, together with mucus, contribute to airway obstruction. PMID- 30431349 TI - Functional Anatomic Imaging of the Airway Surface. AB - The airway surface functional microanatomy, including the ciliated airway epithelium and overlying mucus layer, is a critical component of the mucociliary escalator apparatus, an innate immune defense that helps to maintain a clean environment in the respiratory tract. Many genetic and acquired respiratory diseases have underlying pathophysiological mechanisms in which constituents of the airway surface functional microanatomy are defective. For example, in cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator gene, which normally produces a secretory anion channel protein, result in defective anion secretion and consequent dehydrated and acidic mucosal layer overlying the airway epithelium. This thick, viscous mucus results in depressed ciliary beating and delayed mucociliary transport, trapping bacteria and other pathogens, compromising host defenses and ultimately propagating disease progression. Thus, developing tools capable of studying the airway surface microanatomy has been critical to better understanding key pathophysiological mechanisms, and may become useful tools to monitor treatment outcomes. Here, we discuss functional imaging tools to study the airway surface functional microanatomy, and how their application has contributed to an improved understanding of airway disease pathophysiology. PMID- 30431350 TI - Mucociliary Defense: Emerging Cellular, Molecular, and Animal Models. AB - Respiratory tissues are bombarded by billions of particles daily. If allowed to accumulate, these particles can cause injury, inflammation, or infection, and thus may significantly disrupt airflow and gas exchange. Mucociliary defense, a primary mechanism for protecting host tissues, operates through the coordinated functions of mucus and cilia that trap and eliminate inhaled materials. Mucociliary function is also required for the elimination of endogenous cells and debris. Although defense is necessarily robust, it is also tightly regulated to minimize physiologic disruption of the host. Indeed, mucociliary dysfunction contributes to the pathogenesis of many lung diseases-including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and cystic fibrosis-in which airflow limitation, inflammation, persistent tissue injury, and structural remodeling occur. Here, we highlight recent advances in cilia and mucin biology, the importance of well-controlled mucociliary interactions, and the need to better understand how these regulate innate barrier and immune defense. PMID- 30431351 TI - Transgenic Mouse Reporter to Study Muc5b In Vivo. AB - Dysregulation of gel-forming mucins is associated with many airway diseases. Better knowledge of the pathophysiological mechanisms linking mucins and respiratory diseases will advance the understanding of their pathogenesis and should provide opportunities to develop new therapeutic compounds for treatment. MUC5B and MUC5AC are the two main gel-forming mucins in the respiratory tract. The organization in domains and the expression profile of mouse Muc5b are very similar to those in humans, which makes the mouse a relevant model for studies of the translational activities of human mucins. To assess the in vivo biological functions of Muc5b, a mouse reporter tagged in frame with the green fluorescent protein marker has been engineered by homologous recombination. The proof of concept that this reporter model may be informative for translational studies was confirmed by the finding that interleukin-13 administration in living mice upregulated Muc5b production. PMID- 30431352 TI - Autopsy and Imaging Studies of Mucus in Asthma. Lessons Learned about Disease Mechanisms and the Role of Mucus in Airflow Obstruction. AB - Autopsy studies in fatal asthma have clearly documented the central role of airway plugging with pathologic mucus in the pathophysiology of death from asthma, but the role of mucus plugs in chronic severe asthma has been less well understood. Recently, multidetector computerized tomography imaging of the lungs has emerged as a valuable method to visualize mucus plugs in asthma. These multidetector computerized tomography data have revealed mucus plugs as a common occurrence in severe forms of asthma. In addition, an image-based mucus plug scoring system shows that mucus plugs are strongly associated with measures of airflow obstruction and with biomarkers of type 2 cytokine and eosinophilic inflammation. These data provide a rationale for treating airflow obstruction in severe asthma with mucolytics, and they also raise the possibility that treatments that target type 2 inflammation may decrease mucus plugs in asthma. PMID- 30431353 TI - Pediatric and adolescent injury in wilderness and extreme environments. AB - The participation of children and adolescents in wilderness and extreme environment sports is increasing. Engaging in these activities is not without risk of injury, illness, or death. To date, there is limited research investigating pediatric and adolescent injuries in wilderness and extreme environments. With the intent of creating awareness within the sports medicine field, this review begins by examining the growth in popularity of outdoor sports in wilderness and extreme environments and the injury impact they are registering. The review then examines reported pediatric and adolescent injuries in multiple wilderness and extreme environments. Close examination is paid to youth adventuring on global expeditions and entering high altitude environments. Future studies acquiring denominator data to help establish injury rates while keeping pace with the rapidly diversifying outdoor and extreme wilderness sport trends are necessary. PMID- 30431354 TI - Pediatric and adolescent injury in skiing. AB - This review examines risks that accompany child and adolescent participation in downhill skiing. Falls and non-collision events were the most common mechanism of injury, but significant data implicate head injuries, blunt abdominal trauma, and spinal trauma as the leading causes of morbidity and mortality in this population. School-aged children and youth (7-14 years) are more likely to sustain an injury, compared to children (0-6 years) and older teenagers (15-17 years). Knee injuries were the most common injury, reported as 10.3%-47.7% of all lower limb injuries. The literature supports helmet use as protective against injury with a reduced risk of head, neck, or face injury in children under 13 years. Future studies are necessary to evaluate injury and risks in the backcountry given the rapid increase of adolescents traveling outside ski areas. Research examining risk factors and preventive measures in youth skiing is also warranted. PMID- 30431355 TI - Pediatric and adolescent injury in aquatic adventure sports. AB - Drowning is a leading cause of death in children. Each year there are thousands of injuries in children, some fatal, associated with aquatic adventure sports. Personal water craft rapidly accelerate children to high velocities, as does being towed behind boats on skis or tubes, whereupon children have no control of their speed or direction. Canoeing and white-water kayaking particularly stress the upper limbs and shoulder dislocations are a primary concern. Surfing and kite surfing generate more injuries to the head and face than other parts of the body and, in scuba diving, children most frequently injure their ears due to the acute pressure changes experienced. Aquatic injuries cost more in children than in adults and residual functional deficits may last a lifetime. There is a pressing need for research into the prevalence and incidence of aquatic injuries in children, so the effectiveness of preventive interventions can be determined. PMID- 30431356 TI - Pediatric and adolescent injury in mountain biking. AB - Mountain-biking has become a popular competitive and recreational activity but also involves risk of injury. This article provides an overview of what is known about the scope of the injury problem affecting children and adolescent mountain bikers, the risk factors involved and injury prevention strategies. The proportion of injured child and adolescent mountain bikers ranges from 10.6% to 64.0%, but few studies provide separate analysis of youth injuries. Upper extremity injuries appear most common except among adolescents where the risk of head injury and traumatic brain injuries are greater. Concern is raised regarding the reported frequency of spine fractures and spinal cord injuries. Multi faceted, longitudinal injury research focusing on youth mountain bikers is required to provide a reliable basis for testing risk factors and evaluating preventive measures. Reducing mountain biking-related injuries will require multiple strategies that integrate approaches from education, engineering, and evidence-based safety measures and their enforcement. PMID- 30431357 TI - Pediatric and adolescent injury in rodeo. AB - High injury potential in rodeo is well recognized but the injury data for pediatric and adolescent rodeo athletes remain sparse. A systematic review of the literature published between 1990 and 2017 was conducted to assess the incidence and determinants of rodeo-related injuries in this population and to suggest injury prevention measures. Three of the 10 included studies reported event frequency and exposure data while the other seven pertained to particular injuries and/or rodeo events. Although each study documented cases of severe injuries, the limited epidemiological data indicated the majority of pediatric and adolescent athletes sustained minor injuries, such as sprains, strains, and contusions. Most injuries resulted from the impact of a fall or animal contact with the head being the most reported injury site. Owing to an unpredictable nature of this sport, injury prevention is challenging but there is evidence that helmets reduce the incidence and severity of head injuries. PMID- 30431358 TI - Pediatric and adolescent injury in adventure and extreme sports. PMID- 30431359 TI - Children and extreme sports: a parent's perspective. PMID- 30431360 TI - Pediatric and adolescent injury in skateboarding. AB - Skateboarding has become an international action sport attractive to young people. For this reason, skateboarding has been promoted by some researchers as important for encouraging young people to become more physically active. However, skateboarding is also considered to be inherently dangerous by the medical and broader community and as a result skateboarding is banned in many places. This paper reviews scientific literature on the features, outcomes and risk factors related to skateboarding injuries. Findings suggest that while skateboarding injuries can be severe, skateboarding is not as dangerous as it might appear if appropriate risk management steps are taken. Skateboarding should be encouraged as a worthy physical activity and local communities should consider providing specialised, supervised spaces for young people to practice this sport. PMID- 30431362 TI - Pediatric and adolescent injury in snowboarding. AB - To systematically review published literature on pediatric snowboard injuries, a literature search was performed in PubMed for "snowboard*". Studies must 1) have been primary research; 2) included at least 10 snowboarders; 3) included children and/or adolescents 4) reported specific injury outcomes, risk factors, or injury prevention program effectiveness. The overall injury rates ranged from 0.5 per 1,000 runs to 420 per 1,000 snowboarders. The most common injuries types were fractures, sprains and strains. Most injuries occurred to an upper extremity or the head. Falls and collisions were the most common mechanisms. Snowboarders who were younger, female, had less snowboard experience, or had a previous injury were at greater risk for injury. Wearing wrist guards had a protective effect. Injury rates varied by injury denominator and source of data. Injury prevention efforts should evaluate modifiable extrinsic risk factors, such as strategies to increase use of protective equipment. PMID- 30431361 TI - Pediatric and adolescent injury in motocross. AB - Motocross is a competitive outdoor extreme sport in which motorcyclists race across vast courses of jumps, berms and long straightaways of unpredictable terrain. While the sport has gained notoriety in adult popular culture through contests like the X Games, motocross is also increasingly popular among youth in the Unites States and beyond. In the setting of contemporary discussions on traumatic brain injury, this poses an obvious challenge to those advising children and parents on the risks of motocross to the developing brain and spine. The available literature demonstrates that even when practiced with appropriate protective equipment, motocross poses an increased risk for acquiring major trauma to the brain, spine and limbs for which the long-term consequences have been poorly studied. Riders and parents should be counseled about the risks of these injuries prior to participation and in accordance with state laws. Furthermore, formal return-to-play guidelines following concussions should be developed. PMID- 30431363 TI - Injury prevention in kids' adventure and extreme sports: future directions. AB - Youth have very high participation and injury rates across sport and recreational activities, including in adventure and extreme sports. Sport and recreation is the leading cause of injury in youth and may lead to lower levels of physical activity, higher adiposity, and long-term consequences such as overweight/obesity, post-traumatic osteoarthritis, and post-concussion syndrome which can adversely affect future health. Injuries are predictable and preventable in youth sport, including adventure and extreme sport. However, injury prevention strategies can have a significant impact in reducing the number and severity of injuries in many sports. This article provides an evidence informed overview on what is known about injury prevention strategies which have been evaluated in youth adventure and extreme sports. Recommendations to contribute to effective and sustainable injury prevention in youth adventure and extreme sports have been summarized. PMID- 30431364 TI - Pediatric and adolescent injury in rock climbing. AB - Rock climbing is a fast-growing sport performed by athletes in all age groups, especially youths. While epidemiological data are available for injuries in adults, these data are lacking for young climbers. The current literature shows it being a comparably safe activity, mostly in indoor and sport climbing. Age related self-responsibility is necessary under guided supervision by an adult. Injuries are mostly related to a fall (e.g. alpine environment) or overstrain. Epiphyseal stress fractures of the fingers are a major concern, especially during the pubertal growth spurt. A critical evaluation of finger pain in young climbers as well as a neglect of certain training exercises is crucial. Suggestions for injury prevention and further research are provided. PMID- 30431365 TI - Pediatric and adolescent injury in all-terrain vehicles. AB - All-terrain vehicles (ATVs) remain a significant source of death and injury among youth. The purpose of this review is to provide an overview of the scope of the problem, the risk factors involved, crash-related outcomes and costs, and injury prevention strategies. There are currently more than 100 pediatric ATV-related fatalities each year and over 30,000 emergency department visits, with a potential annual cost for deaths and injuries approaching $1 billion. Major risk factors include lack of training, operating adult-size ATVs, riding as or carrying passengers, riding on the road, and not wearing a helmet. Extremity injuries are highly common, and the leading causes of death include brain injuries and multi-organ trauma. The latter increasingly involves being crushed by or pinned under the ATV. Reducing ATV-related deaths and injuries will require multiple strategies that integrate approaches from education, engineering, and evidence-based safety laws and their enforcement. PMID- 30431366 TI - The acute respiratory distress syndrome: pathophysiology, current clinical practice, and emerging therapies. AB - INTRODUCTION: More than fifty years after the first description of acute respiratory distress syndrome (ARDS) by Ashbaugh and colleagues, no specific treatment of the underlying pathophysiological processes is available. The current therapeutic regime is comprised of supportive measures such as lung protective ventilation, restrictive fluid management, paralyzing drugs, and prone positioning. Although vast improvements have been made in ARDS-treatment during the last five decades, mortality among patients with severe ARDS remains at an unacceptable rate of 45%. Areas covered: This article reviews the evolution of the currently used definition, established pathophysiological mechanism, highlights the current best clinical practice to treat ARDS, gives a brief outlook on cutting edge trends in ARDS research and closes with an expert opinion on the subject. Expert commentary: Individualizing the provided measures to specific genotypes is the key challenge in ARDS research today. The ongoing digital revolution will help to individualize ARDS-treatment and will therefore presumably improve survival and quality of life. PMID- 30431367 TI - Incidence of perianaesthetic complications experienced during feline bronchoscopy: a retrospective study. AB - OBJECTIVES: The aim of this study was to report the incidence of anaesthetic complications associated with feline bronchoscopy. METHODS: This was a retrospective analysis of anaesthetic records and electronic case logs of feline bronchoscopies at two university hospitals (centres B and L) between January 2013 and December 2015. A two-tailed Fisher's exact test was used for comparison of variables and outcomes between centres. RESULTS: Seventy-nine cases were included. Desaturation (SpO2 <90%) was the most frequently encountered complication, reported in 24 cats (30.3%); centre B reported significantly less desaturation than centre L (22.4% vs 52.4%; P = 0.014). The use of an endotracheal tube or laryngeal mask airway resulted in lower incidence of desaturation (22.9% vs 22.2%) than the use of a tracheal catheter through which oxygen was insufflated (48.0%). The latter method was associated with increased incidence of desaturation ( P = 0.034). Patients to which terbutaline was administered had a lower incidence of desaturation (27.5%) than those that did not receive it (35.7%), although this was not statistically significant ( P = 0.46). Airway management method and the use of terbutaline differed significantly between centres, as did the profile of complications. Pneumothorax was encountered in two cats (2.5%) and cardiac arrest resulting in the death in one of these cats (1.3%). CONCLUSIONS AND RELEVANCE: Desaturation is a frequently encountered complication during and after bronchoscopy. Airway management method and the use and timing of terbutaline warrant prospective evaluation for their role in decreasing the incidence of desaturation. Bronchoscopy is a high-risk procedure with frequent requirement for post-procedure oxygen supplementation. Pneumothorax and cardiac arrest are potential complications. PMID- 30431368 TI - Exosomes as drug carriers for clinical application. AB - Exosomes are nanoscale vesicles shed from all cell types and play a major role in communication and transportation of materials between cells due to their ability to transfer proteins and nucleic acids from one cell to another. Analogous in size and function to synthetic nanoparticles, exosomes offer many advantages, rendering them the most promising candidates for targeted drug or gene delivery vehicles. Exosomes can also induce chemoresistance or radioresistance of tumor cells. Studies about the related mechanisms help overcome cancer therapy resistance to some extent. In this review, we focus on the application of exosomes as nanocarriers and the current status of the application of exosomes to cancer therapy. PMID- 30431369 TI - Maternity blues: risk factors in Greek population and validity of the Greek version of Kennerley and Gath's blues questionnaire. AB - AIM: To validate the Greek version of Kennerley and Gath's Blues Questionnaire (BQ) and gather further knowledge on maternity blues (MB) associations with certain clinical and sociodemographic factors in Greek population. MATERIAL AND METHODS: 116 postpartum women, who met the inclusion criteria, completed the Blues Questionnaire and the Edinburgh Postnatal Depression Scale on the third day after delivery. Sociodemographic and clinical data were also collected. RESULTS: Fifty women (43.1%) experienced severe MB on the third day postpartum. Lower number of previous births, fewer years of marriage, and husband's occupation were found to be associated with MB occurrence. Of them, years of marriage (odds 0.21, p = .001) and husband's occupation in private sector (odds 1.21, p = .04) were independent predictors of MB in logistic regression analysis. Cronbach's alpha for the total 28-item Greek version of BQ was 0.85. Cluster analysis in our data showed that the optimal number of clusters of BQ items was 4; these four clusters of items presented similarities with the Bartholomew and Horowitz's four-category model of attachment styles (avoidant - dismissing, preoccupied, secure, avoidant fearful). CONCLUSIONS: The Greek version of Blues Questionnaire is a reliable tool for the detection and measurement of MB. Fewer years of marriage and the economic insecurity seem to have strong impact on the occurrence of MB. Further investigation is needed to evaluate whether the phenomenon of MB is associated with parental or mother-to-infant bonding disorders. PMID- 30431370 TI - Pain threshold monitoring during chronic constriction injury of the infraorbital nerve in rats. AB - BACKGROUND: The chronic constriction injury (CCI) of the infraorbital nerve (ION) has been used to establish an animal mode of trigeminal neuralgia (TN), but key parameters of the model have not been quantified until now. OBJECTIVE: The aim of the study was to quantify a standard of pain threshold to evaluate a successful TN model in Sprague-Dawley (SD) rats. METHODS: Forty-eight adult SD rats (200-220 g) underwent chronic constriction injury of the infraorbital nerve. The pain threshold was tested one day preoperatively (baseline) and day 1, 3, 7, 14, 28 postoperatively using the up-down method. At day 28, all the animals were killed by dislocation of the cervical spine and the trigeminal nerve specimens were removed for electron microscopy. RESULTS: The baseline pain threshold was 14.40 +/- 0.87 g. Postoperatively, all the rats presented an initial reduced sensitivity to mechanical stimulation from day 1 (15.63 +/- 1.92 g) through 7 (17.39 +/- 1.43 g) after the surgery. At day 14, 32 (66.7%) began to show significant mechanical allodynia (0.71 +/- 0.43 g) which did not change significantly till day 28 (0.88 +/- 0.54 g). These animals were regarded as successful TN models with a 95% confidence interval of the pain threshold of 0.58 1.27 at Day 14. The electron microscopy demonstrated homogeneously demyelinated changes in those successful TN model animals rather than severe or mild epineurial lesions in those unsuccessful model animals. CONCLUSION: Our study showed that an animal TN model could be established with a two-week chronic constriction injury of the infraorbital nerve. The mechanical allodynia index <1.27 at Day 14 was suggested as a criterion for a successful model. PMID- 30431371 TI - Haemostatic bioactivity of novel Schizonepetae Spica Carbonisata-derived carbon dots via platelet counts elevation. AB - Schizonepetae Spica Carbonisata (SSC) has pronounced haemostatic effects for hundreds of years and has been acknowledged in the 2015 Pharmacopoeia of the People's Republic of China (PPRC) as a haemostatic charcoal drug. However, after years of efforts, the underlying mechanism and the material basis is still less defined. In this research, we developed a novel CDs derived from SSC (SSC-CDs) with an average diameter of 1.29-6.87 nm and a quantum yield of 6.31%. SSC was prepared using a modified pyrolysis method and no further modification and external surface passivation agent is required. With abundant surface groups, SSC CDs showed distinct solubility and bioactivity. In this study, we innovatively used the Deinagkistrodon acutus (D. acutus) venom model as well as the classical haemorrhagic animal model to evaluate the haemostatic bioactivity of SSC-CDs. The results indicated that SSC-CDs had outstanding haemostatic bioactivity and might inhibit the haemorrhagic activity via PLT elevation. According to the results of this study and our previous work, we discovered that CDs derived from different kinds of charcoal drugs presented similarities and differences in the structural feature, physicochemical property and bioactivity. In order to further explore the self-bioactivities, we first named this kind of CDs as "Chinese Medicine charcoal drug nanoparticles" (CMNP). These results may not only provide evidence for further researches of self-bioactivities of CDs but give new insights into potential biomedical and healthcare applications of CDs, therefore, make contributions to future drug discovery. PMID- 30431372 TI - Pregnancy complications and adverse outcomes in placental chorioangioma: a retrospective cohort analysis. AB - OBJECTIVE: To measure the relative risk of pregnancy complications and adverse outcomes in women with placental chorioangioma, and postnatal developmental deficiencies in their offspring. METHODS: We designed a retrospective cohort study using records from 140,387 pregnancies at our hospital between 1 January, 2008 and 1 July, 2017. Follow-up of children in the placental chorioangioma group was conducted by phone interview. RESULTS: Placental chorioangioma was diagnosed in 56 patients (incidence = 0.04%). Fifty-one cases were detected during routine prenatal ultrasound. Placental chorioangioma patients were at increased risk for fetal loss or induced abortion (RR = 9.93, 95% CI [4.66, 21.20]), preterm birth (n = 13, RR = 2.45, 95% CI [1.52, 3.95]), birth by cesarean section (n = 45, RR = 1.62, 95% CI [1.42, 1.84]), and polyhydramnios (n = 9, RR = 9.98, 95% CI [5.48, 18.18]), but not fetal distress (n = 5, RR = 0.49, 95% CI [0.22, 1.15]) or preeclampsia (n = 5, RR = 1.61, 95% CI [0.70, 3.73]), although there was an increased risk for preeclampsia after controlling for preterm birth (n = 3, RR = 3.6, 95% CI [1.33, 9.74]). No developmental complications were reported in offspring. CONCLUSION: Placental chorioangioma increases the risk of fetal demise, pregnancy complications and adverse outcomes. In cases with mild complications or when early cesarean termination of pregnancy is feasible, the prognosis is excellent. PMID- 30431373 TI - Optimization of a dry powder inhaler of ciprofloxacin-loaded polymeric nanomicelles by spray drying process. AB - Ciprofloxacin is a commonly prescribed antibiotic for treatment of pulmonary infections. Nanocarriers such as nanomicelles can increase the drug residence time in the lungs and enhance their antibacterial effects. Dry powder inhalers (DPIs) are the preferred pulmonary drug delivery system and preparation of an optimum nanoaggregate from nanomicelles by means of spray drying would be valuable. The two-level full factorial design was performed in 16 runs. The effects of carrier type, anti-adhesion agent type, carrier to nanoparticle ratio and anti-adhesion agent to carrier ratio on the size of the microparticles, their in vitro pulmonary deposition and redispersibility were investigated. Its antibacterial effects against P. aeruginosa, K. pneumoniae and S. pneumoniae also were investigated. All independent variables were fitted into two factorial interaction models. The optimum nanoaggregate was prepared using mannitol and L phenylalanine with a D0.5 of 1.7 um and 60% fine particles. The process had no negative effect on the stability or drug release profile of the nanomicelles. The antibacterial effects of ciprofloxacin against microorganisms increased significantly. This spray drying process could be used for preparation of an optimum DPI from polymeric nanomicelles. This formulation could increase the efficacy of ciprofloxacin for treatment of pulmonary infections. PMID- 30431374 TI - Pretraining hippocampal stimulation of melatonin type 2 receptors can improve memory acquisition in rats. AB - BACKGROUND: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks. METHODS: IIK7 (0.03, 0.3, and 3 MUg/MUl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task. RESULTS: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task. DISCUSSION: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats. PMID- 30431375 TI - B-type natriuretic peptide plasma level in 5-year breast cancer survivors after radiotherapy. AB - BACKGROUND: Left-sided breast cancer patients treated with radiotherapy (RT) are at risk for late radiation-induced cardiovascular complications. AIM: The aim of this study was to investigate the BNP plasma levels in long-term breast cancer survivors who received only RT as well to assess whether cardiac dose was associated with BNP values . METHODS: Plasma samples for BNP measurement were repeated in 29 patients (63 +/- 11 years) who were alive at 5 years after radiotherapy, free of heart disease and available to provide new blood sample All patients had BNP measurements at baseline. The DeltaBNP was measured to analyze the role of marker variations. No patients received chemotherapy. RESULTS: The mean cardiac and ventricle dose were 2.1 +/- 1.0(range 0.02-4.5) Gy and 3.0 +/- 1.7 (range 0.02-7.6), respectively. Median value of BNP was 47 pg/mL (interquartile ranges, 26-58.2 pg/mL) at baseline, and 34 pg/mL (interquartile ranges, 17.5-54 pg/mL) at 5 years after radiotherapy. There was no not significantly different between two measurements (p=ns). Fifteen (52%) reported an improvement in BNP levels, 1 (3%) no changes and 13 (45%) reported a worsening. There was no correlation between DeltaBNP and age (p=ns). When patients were stratified according to the median value of dose-volume data, DeltaBNP was significantly higher in patients with increased cardiac Dmean (p=0.02) and left ventricle Dmean (p=0.009). CONCLUSION: At 5 years after radiotherapy, median plasma BNP levels remained within the normal range, but the delta-BNP levels are directly related to the heart and ventricular dose received. PMID- 30431376 TI - Relationship of Epidermal Growth Factor Receptor Expression with Clinical Symptoms and Metastasis of Invasive Breast Cancer. AB - This research explores the role of epidermal growth factor receptor (EGFR) in the clinical symptoms and metastasis of patients with invasive breast cancer (IBC). A total of 189 patients with IBC were selected in this research. Immunohistochemical staining and Western blot were performed to detect EGFR in IBC and paratumor breast tissues. The results of statistical analysis showed that the positive expression of EGFR in IBC (140/189 = 74.07%) was significantly higher than that of paratumor breast tissues (23/189 = 12.16%) (P < 0.01). There was no significant correlation between the expression of EGFR and patients' onset age as well as menopausal status (P > 0.05), but it was significantly correlated with the diameter of tumor mass, lymph node metastasis, TNM staging, and histological gradation (P < 0.05). The positive expression of EGFR in estrogen receptor (ER)-negative group (64 tissues, 84.2%) was significantly higher than that in ER-positive group (76 tissues, 67.3%) (P < 0.05). There was no significant difference in the positive expression of EGFR between progesterone receptor (PR)-positive group (73 tissues, 73.0%) and PR-negative group (67 tissues, 75.3%) (P > 0.05). The positive expression of EGFR in human epidermal growth factor receptor 2 (HER2)-positive group (67 tissues, 84.8%) was significantly higher than that in HER2-negative group (73 tissues, 66.4%), with a significant difference (P < 0.05). The high expression of EGFR can be used to predict the severity of IBC, as well as the candidate biomarkers of metastasis, and it may also be associated with poor prognosis of IBC patients. PMID- 30431377 TI - Evaluating the photodynamic therapy efficacy using 5-aminolevulinic acid and folic acid-conjugated bismuth oxide nanoparticles on human nasopharyngeal carcinoma cell line. AB - Selective accumulation of photosensitizers (PSs) into cancerous cells is one of the most important factors affecting photodynamic therapy (PDT) efficacy. 5 Aminolevulinic acid (5-ALA) is precursor of a strong PS, protoporphyrin-IX (Pp IX); but it has poor permeability in lipophilic membrane of the cells due to its hydrophilic property. Therefore, establishment of an improved delivery strategy could highly affect on treatment outcome. Moreover, folate receptors (FRs) are overexpressed on the surface of many tumor cells. In the present work, targeting ligand folic acid (FA) and 5-ALA conjugated bismuth oxide nanoparticles (FA-5ALA Bi2O3 NPs) were synthesized; and used in PDT against human nasopharyngeal carcinoma cells (KB cell line). The KB cells incubated with the synthesized NPs for 2 h; then illuminated using a custom-made red light LED lamp at the light dose of 26 J/cm2. MTT and caspase-3 activity assays were performed to evaluate the efficacy of treatment. Results showed that FR targeting ligand enables selective endocytosis of FA-5-ALA-conjugated NPs into KB cells. Improved internalization of 5-ALA into cells decreased the cell viability to about 50%, 65%, and 85% in the groups receiving FA-5ALA-Bi2O3 NPs, 5ALA-Bi2O3 NPs, free 5 ALA and subsequent PDT, respectively. Therefore, FA-5ALA-Bi2O3 NPs can significantly increase the cell killing effect of PDT. PMID- 30431378 TI - Severe nonalcoholic steatohepatitis and type 2 diabetes: liver histology after weight loss therapy in a randomized clinical trial. AB - OBJECTIVE: To evaluate the effectiveness of the fast weight loss method on liver steatosis, fibrosis, inflammation, glycemic and lipid features and body composition in patients with severe nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). METHODS: A 24 week open prospective randomized controlled clinical trial including 80 adult patients (aged 40-65 years) was performed. The patients after randomization were divided into two groups: the main group followed the fast weight loss method; the control group received conventional drug treatment. The fast weight loss method included calorie restriction, salt intake, walking and sexual self-restraint. The conventional drug therapy included vitamin E, orlistat, pioglitazone hydrochloride, atorvastatin, lisinopril, benzodiazepines and anti-inflammatory agents. Primary endpoints were: ultrasound and histology suggestive of steatohepatitis, hepatic enzymes, weight loss, 2 hour oral glucose tolerance test and glycosylated hemoglobin A1C (HbA1c). Secondary endpoints were: blood pressure and lipids. RESULTS: A total of 83% patients completed the study. In the main group weight lost was 7-16 kg (10-20% from baseline) for 8-10 weeks. In this group weight was lost due to reduction of fat mass only. The main vs. control group showed higher decrease in fat mass from baseline (p < .001). Ultrasound imaging and liver histological scoring system evidenced significant improvement in liver steatosis/fibrosis in the main group (p < .001). In the main vs. control group weight lost at 24 weeks led to positive laboratory changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), 2 hour oral glucose tolerance test (OGTT), HbA1c, Homeostasis Model Assessment insulin resistance indexes (HOMA-IR), blood pressure (BP), cholesterol, triglycerides, bilirubin total and blood hemoglobin (p = .01). The fast weight loss in the patients adequately led to decrease in symptomatic drugs up to complete abolition. CONCLUSIONS: The study showed benefits of the fast weight loss method improving in steatosis/fibrosis and biochemical/metabolic outcomes in patients with severe NASH and T2D. PMID- 30431379 TI - Bioreactor-based advances in plant tissue and cell culture: challenges and prospects. AB - Bioreactors are engineered systems capable of supporting a biologically active situation for conducting aerobic or anaerobic biochemical processes. Stability, operational ease, improved nutrient uptake capacity, time- and cost effectiveness, and large quantities of biomass production, make bioreactors suitable alternatives to conventional plant tissue and cell culture (PTCC) methods. Bioreactors are employed in a wide range of plant research, and have evolved over time. Such technological progress, has led to remarkable achievements in the field of PTCC. Since the classification of bioreactors has been extensively reviewed in numerous reviews, the current article avoids repeating the same material. Alternatively, it aims to highlight the principal advances in the bioreactor hardware s used in PTCC rather than classical categorization. Furthermore, our review summarizes the most significant steps as well as current state-of-the-art of PTCC carried out in various types of bioreactor. PMID- 30431381 TI - Spindle cell oncocytoma of the neurohypophysis with metastasis to the sphenoparietal sinus and immunohistochemical negativity for S100 and epithelial membrane antigen (EMA). AB - We report the case of a 61-year-old male with spindle cell oncocytoma of the hypophysis. On presentation to the Department of Neurosurgery at the German Armed Forces Hospital of Ulm, the patient reported a history of several years of left sixth nerve palsy, right ptosis, increased sensitivity to light, and a bilateral retrobulbar pressure sensation. Pituitary function was normal. A chromophobe non functioning pituitary adenoma was initially suspected. The diagnosis was established on the basis of examination at a histopathology reference laboratory using immunohistochemistry to identify cell surface markers. During two years of follow-up, there were two clinical recurrences requiring surgery. To our knowledge, this is the 35th documented case of spindle cell oncocytoma of the pituitary gland and the first that was immunohistochemically negative for epithelial membrane antigen (EMA) and S100; and the first that displayed haematogenous metastasis to the right sphenoparietal sinus. The three surgical procedures were associated with massive intraoperative bleeding and thus resulted in subtotal tumor resection. Following surgery for the recurrences, the patient underwent radiotherapy. PMID- 30431380 TI - Novel useful markers for follow-up of necrotizing enterocolitis: endocan and interleukin-33. AB - OBJECTIVES: To ascertain the diagnostic value of endocan and interleukin (IL)-33 in infants with necrotizing enterocolitis (NEC) and to compare their effectiveness with C-reactive protein (CRP) and interleukin-6 (IL-6). METHODS: Eighty-four preterm infants including control (n = 42) and NEC (n = 42) were eligible. Blood samples were obtained from infants in the NEC for the assessment of CRP, IL-6, endocan, and IL-33 serum levels at the time of diagnosis (first day), at the third and seventh days of NEC. Endocan, IL-33, CRP, and IL-6 serum levels were measured at the 14th day of life in the control group. RESULTS: Serum levels of endocan, IL-33, CRP, and IL-6 were significantly higher in the NEC group compared to the control group at the first, third, and seventh days (p < .05). IL-33 and endocan levels continued to rise in the consequent days in patients with stage III NEC (p < .05). Serum endocan and IL-33 levels gradually increased in patients who underwent surgery (p < .05). Serum endocan levels were higher in patients with stage III NEC than those in the stage II NEC at the diagnosis. CONCLUSIONS: Serum levels of IL-33 and endocan can be used as markers in the diagnosis and follow-up of NEC. PMID- 30431382 TI - The Influence of TGF-beta3, EGF, and BGN on SOX9 and RUNX2 Expression in Human Chondrogenic Progenitor Cells. AB - Osteoarthritis (OA) is the most common chronic joint disease and leads to the degradation of the extracellular matrix by an imbalance between anabolic and catabolic processes. TGF-beta3 (transforming growth factor beta-3) and epidermal growth factor (EGF) influence the osteochondrogenic potential of chondrocytes. In this study, we compared the expression of mediators and receptors in the TGF beta3 and EGF pathways, as well as biglycan (BGN), in healthy and diseased chondrocytes. Furthermore, we used chondrogenic progenitor cells (CPCs) for in vitro stimulation and knockdown experiments to elucidate the effects of TGF-beta3 and EGF on the chondrogenic potential. Our results demonstrate that the expression of TGF-beta receptor type-1 (TGFBRI) and epidermal growth factor receptor (EGFR) is altered in diseased chondrocytes as well as in CPCs. Moreover, TGF-beta3 and EGF stimulation influenced the expression levels of BGN, SRY (sex determining region Y)-box 9 (SOX9), and Runt-related transcription factor 2 (RUNX2) in CPCs. Therefore, changes in TGFBRI and EGFR expression likely contribute to the degenerative and regenerative effects seen in late stages of OA. PMID- 30431383 TI - Safety and immunogenicity of VAQTA(r) in children 12-to-23 months of age with and without administration of other US pediatric vaccines. AB - Safety and immunogenicity data from 5 clinical trials conducted in the US in children 12-to-23 months old where HAVi was administered alone or concomitantly with other pediatric vaccines (M-M-R(r)II, Varivax(r), TRIPEDIA(r), Prevnar(r), ProQuad(r), PedvaxHIB(r), and INFANRIX(r)) were combined. Among 4,374 participants receiving >= 1 dose of HAVi, 4,222 (97%) had safety follow-up and the proportions reporting adverse events (AE) were comparable when administered alone (69.4%) or concomitantly with other pediatric vaccines (71.1%). The most common solicited injection-site AEs were pain/tenderness (Postdose 1: 25.8%; Postdose 2: 26.1%) and redness (Postdose 1: 13.6%; Postdose 2: 15.1%). The most common vaccine-related systemic AEs were fever (>= 100.4oF, 12.2%) and irritability (8.1%). Serious AEs (SAEs) were observed at a rate of 0.4%; 0.1% were considered vaccine-related. No deaths were reported within 14 days following a dose of HAVi. These integrated analyses also showed that protective antibody concentrations were elicited in 100% of toddlers after two doses and 92% after a single dose, regardless of whether HAVi was given concomitantly with other vaccines or alone. These results demonstrate that HAVi was well-tolerated whether given alone or concomitantly with other vaccines, with a low incidence of vaccine related SAEs. HAVi was immunogenic in this age group regardless of whether administered with or without other pediatric vaccines and whether 1 or 2 doses were administered. HAVi did not impact the immune response to other vaccines. These data continue to support the routine use of HAVi with other pediatric vaccines in children >= 12 months of age. PMID- 30431384 TI - Specific hypertension smartphone app to improve medication adherence in hypertension: a cluster-randomized trial. AB - INTRO: Digital interventions, such as smartphone applications (APP), are becoming an increasingly common way to support medication adherence and self-management in chronic illness. AIM: To evaluate the effectiveness of the intervention in pharmacological therapeutic adherence of the mild-moderate arterial hypertension (AHT), through an APP installed in the mobile phone, as well as the degree of control reached by the patient with this tool. METHODS: Prospective, randomized controlled trial, full-study and multicenter study. Four primary care centers participated. One hundred and fifty-four hypertensive patients under antihypertensive treatment were included. Two groups were established: a control group (CG) with usual intervention (n = 77) and an intervention group (n = 77) (IG), targeting hypertensive people who owned and regularly used a mobile smartphone, specifically using the APP called ALERHTA to promote health education and reminder of appointments. There were 3 visits: initial, 6 and 12 months. Drugs adherence was measured by electronic monitors (MEMS). Primary outcome was average adherence percentage daily between 80 and 100% %, and the AHT control. RESULTS: 148 patients finished the study. Mean age 57.5 +/- 9.9. Were considered adherents of the global sample 77.02% (CI =70.25-83.79) and 74.32% (CI =67.29 81.35%) adherents with the daily dose intake. Adherents once daily were 93.15% and 86.3% in IG and 70.66% and 62.66% in CG after 6 and 12 months respectively (p <0.05). The percentage of uncontrolled patients was 28.3% (CI =21.05-35.55%). The control of high blood pressure at 12 months was 17.8% and 38.6% for IG and CG respectively (p <0.05). The NNT was 4.23 patients. CONCLUSIONS: The intervention with an APP installed in the mobile phone of hypertensive patients favors the pharmacological therapeutic adherence and improves the percentage of hypertensive patient control. TRIAL REGISTRATION: Spanish Agency of Medicine: EPA-SP UN-HTA 2015-01. PMID- 30431385 TI - Societal preferences for fertility treatment in Australia: a stated preference discrete choice experiment. AB - OBJECTIVE: To investigate preferences for fertility treatment from the Australian general population with the aims of calculating the willingness to pay in tax contribution for attributes (characteristics) that make up treatment and for an 'ideal' fertility treatment program. We also assessed whether willingness to pay varies by the relationship status or sexual orientation of the patient. METHODS: A stated preference discrete choice experiment was administered to a panel of 801 individuals representative of the Australian general population. Seven attributes of fertility treatment under three broad categories were included: outcome, process, and cost. Attributes were identified through published literature, focus group discussions, expert knowledge, and a pilot study. A Bayesian fractional experimental design was used, and data analysis was performed using a generalised multinomial logit model. Further analyses included interaction terms and latent class modelling. RESULTS: Six of the seven attributes influenced the choice of a treatment program. Under process attributes, individuals preferred: continuity of care of clinic staff, where patients are seen by the same doctor but different nurses at each visit; 'alternative' treatments being offered to all patients; and onsite clinic counselling and peer-support groups. Personalisation and tailoring of the treatment journey were not important. Among outcome attributes, improved success rate of having a baby per cycle and significant side-effects were considered important. Cost of treatment also influenced the choice of treatment program. Individual preferences for fertility treatment were not associated with patients' relationship status or sexual orientation. Latent class modelling revealed sub-groups with distinct fertility treatment preferences. CONCLUSION: This study provides important insights into the attributes that influence the preferences of fertility treatment in Australia. It also estimates socially inclusive willingness to pay values in tax contributions for an 'ideal' package of treatment. The results can inform economic evaluations of fertility treatment programs. PMID- 30431386 TI - Adipocytokine Involvement in Innate Immune Mechanisms. AB - The innate immune response is defined as an immensely complex and sophisticated process aimed at defending the organism against any disturbance in the body homeostasis, including invading pathogens. It requires a close cooperation of a vast amount of different cell types, recognized as inflammatory migrating cells, as well as stationary cells that form tissues. Moreover, innate immune mechanisms require an efficient functioning of various humoral components that exert a significant impact on physiological and pathological processes. Apart from commonly mentioned humoral factors, this group also includes a family of proteins known as adipocytokines that may act as pro- or anti-inflammatory agents or act both ways. Leptin, predominantly characterized as a proinflammatory adipokine, plays a crucial role in endothelium remodeling and regulation, as well as in cell survival and production of numerous cytokines. Adiponectin, similar to leptin, acts on the endothelial cells and the phagocytic properties of immune cells; however, it exerts an anti-inflammatory impact. Resistin has a documented role in the control of angiogenesis and stimulation of proinflammatory mediator generation and release. Furthermore, there are adipokines, ie, visfatin and chemerin, whose participation in the inflammatory processes is ambiguous. This review focuses on the current knowledge on the extensive role of selected adipokines in innate immune response. PMID- 30431387 TI - Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course in healthy Korean infants: phase III, randomized study. AB - We assessed the immunogenicity and safety of a three-dose primary vaccination schedule with the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Korean infants. In this phase III open-label, multicenter study (NCT01309646), healthy infants aged 42-69 days (randomized 1:1) received three doses of either pentavalent DTPa-IPV/Hib (DTPa-IPV/Hib group) or DTPa-IPV and Hib vaccines administered separately (DTPa-IPV+Hib group) at 2, 4, 6 months of age. The primary objective was to demonstrate non-inferiority of DTPa-IPV/Hib compared to DTPa-IPV+Hib vaccines in terms of immune responses to all vaccine antigens, 1 month post-dose 3. Solicited symptoms (local and general) were recorded during 4 days, and unsolicited adverse events (AEs) during 31 days, after each vaccination. Serious AEs (SAEs) were recorded throughout the study duration. The immunogenicity of the pentavalent DTPa-IPV/Hib vaccine was non-inferior compared to concomitant administration of DTPa-IPV+Hib vaccines. One month post-dose 3, nearly all infants had antibody levels above the seroprotective thresholds for anti-diphtheria toxoid, anti-tetanus toxoid, anti-polyribosyl-ribitol phosphate, and anti-poliovirus type 1, 2 and 3, and had antibody levels above the seropositive thresholds for anti-pertussis toxoid (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibodies. A vaccine response for PT, FHA and PRN was observed in at least 96.7% of study participants. Anti-PRP geometric mean concentrations appeared lower for the DTPa-IPV/Hib group (8.456 ug/mL) than for the DTPa-IPV+Hib group (18.700 ug/mL). In both groups, the most common solicited symptoms were injection site redness and irritability. Fifty seven SAEs were reported throughout the study; none were considered to be vaccination related. PMID- 30431388 TI - Cloning and functional characterization of STAT5a and STAT5b genes in buffalo mammary epithelial cells. AB - Signal transducer and activator 5 (STAT5) plays important roles in regulating mammary glandular cell proliferation and milk-protein gene expression. However, the functions of STAT5a and STAT5b genes in lactation of buffalo remain uninvestigated. In this study, full-length STAT5a (2502 bp) and STAT5b (2515 bp) coding sequences were isolated for the first time. The highest STAT5a gene expression was found in buffalo mammary glands and the highest STAT5b gene expression was found in buffalo brains and mammary glands. H&E staining indicated that STAT5a and STAT5b are mainly expressed in epithelial cells of buffalo mammary glands. Next, we investigated the functions of STAT5 by knocking down and overexpressing STAT5 in buffalo mammary epithelial cells (BuMECs). According to our results, STAT5 knockdown resulted in inhibited G1/S transition of BuMECs and significantly lower expression of milk-protein genes, whereas overexpression of STAT5 resulted in significantly higher expression of milk-protein genes. In summary, our results demonstrate that STAT5 can regulate the cell cycle transition of BuMECs and affect the expression of milk-protein genes. Our research lays a foundation for further study of the role of STAT5 in mammary gland development and lactation. PMID- 30431389 TI - Antimicrobial Susceptibility and Clonal Relationship of Tetracycline Resistance Genes in netF-Positive Clostridium perfringens. AB - NetF-producing type A Clostridium perfringens, a pathotype of C. perfringens, causes necrotizing enteritis in neonatal foals and necrotizing and hemorrhagic enteritis in dogs. Recent core genome multilocus sequence typing study revealed that netF+ C. perfringens strains belong to two distinct clonal populations (clonal complexes I and II). There are no reports on susceptibility to antimicrobial drugs of isolates from this pathotype. The susceptibility to 13 different antimicrobial drugs of 49 netF+ strains recovered from foals or dogs with necrotizing enteritis in Canada, the United States, and Switzerland was assessed using a commercial microdilution panel designed for anaerobic human pathogens. All isolates were highly susceptible to 12 antimicrobial agents, including all beta-lactams tested, such as penicillin G and ampicillin, as well as clindamycin, chloramphenicol, and metronidazole. The isolates consistently presented a reduced susceptibility or resistance to tetracycline, which was associated with previously described tetracycline resistance genes. Clonal complex I isolates (n = 41) possessed the tetA408(P) gene, whereas clonal complex II isolates (n = 8) possessed the tetA(P)-tetB(P) genes and were more likely to be fully resistant. PMID- 30431390 TI - Minimally Invasive Surgery for Rectal Adenocarcinoma Shows Promising Outcomes Compared to Laparotomy, a National Cancer Database Observational Analysis. AB - PURPOSE/BACKGROUND: The surgical approach to adenocarcinoma of the rectum remains a controversial topic. Although current data focus on the noninferiority of minimally invasive surgery (MIS) for rectal cancer compared with laparotomy, conclusions are drawn from smaller sample sizes and may be underpowered. Methods/Interventions: The National Cancer Database (NCDB) from 2010 to 2014 was reviewed for all cases of invasive adenocarcinoma of the rectum (SEER Histology Codes 8140) who underwent surgical resection for malignancy. Groups were separated based on laparotomy or an MIS approach and stratified by NCDB Analytic Stage. Multivariate Cox regression analysis was used to evaluate for survival after diagnosis of adenocarcinoma of the rectum. Results/Outcomes: The inclusion criteria identified 29,199 cases of adenocarcinoma of the rectum managed surgically. After controlling for differences in the cohorts, survival after diagnosis and definitive surgical treatment for adenocarcinoma of the rectum is improved when an MIS approach was used (adjusted hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.77-0.88, P < .001). The protective effect of an MIS approach applied to Stages I, II, III, and IV adenocarcinoma of the rectum. The protective effect of a minimally invasive surgical approach applies to Stages I, II, III, and IV adenocarcinoma of the rectum. The rate of negative circumferential margins (86.2% versus 83.5%, P < .001), proximal and distal margins (94.7% versus 92.1%, P < .001), and lymph node yield >12 (73.2% versus 70.1%, P < .001) was higher in the minimally invasive group compared with laparotomy. The intraoperative conversion rate from MIS to laparotomy was 13.9%. CONCLUSION/DISCUSSION: Minimally invasive resection for adenocarcinoma of the rectum shows promising survival benefit compared with open surgery after adjusting for measured confounds. PMID- 30431391 TI - Comparative Study of the Binding Mode between Cytochrome P450 17A1 and Prostate Cancer Drugs in the Absence of Haem Iron. AB - According to the X-ray crystal structures of CYP17A1 (including its complexes with inhibitors), it is shown that a hydrogen bond exists between CYP17A1 and its inhibitors (such as abiraterone and TOK-001). Previous short MD simulations (50 ns) suggested that the binding of abiraterone to CYP17A1 is stronger than that of TOK-001. In this work, by carrying out long atomistic MD simulations (200 ns) of CYP17A1 and its complexes with abiraterone and TOK-001, we observed a binding mode between CYP17A1 and abiraterone, which is different from the binding mode between CYP17A1 and TOK-001. In the case of abiraterone binding, the unfilled volume in the active site cavity increases the freedom of movement of abiraterone within CYP17A1, leading to the collective motions of the helices G and B' as well as the breaking of hydrogen bond existing between the 3beta-OH group of abiraterone and N202 of CYP17A1. However, the unfilled volume in the active site cavity can be occupied by the benzimidazole ring of TOK-001, restraining the motion of TOK-001. By pulling the two inhibitors (abiraterone and TOK-001) out of the binding pocket in CYP17A1, we discovered that abiraterone and TOK-001 were moved from their binding sites to the surface of protein similarly through the channels formed by the helices G and B'. In addition, based on the free energy calculations, one can see that it is energetically favorable for the two inhibitors (abiraterone and TOK-001) to enter into the binding pocket in CYP17A1. PMID- 30431392 TI - Perspectives on Temperature Management. PMID- 30431393 TI - The Effects of a Theory-Based Patient Portal e-Learning Program for Older Adults with Chronic Illnesses. AB - INTRODUCTION: The high prevalence of chronic illnesses is a serious public health problem in the United States, and more than 70 million older adults have at least one chronic illness. Patient portals (PPs) have an excellent potential to assist older adults in managing chronic illnesses; however, older adults' PP adoption rates have been low. Lack of support for older adults using PPs remains a critical gap in most implementation processes. The main aim of this study was to assess the impact of an older adult friendly Theory-based Patient portal e Learning Program (T-PeP) on PP knowledge, selected health outcomes (health decision-making self-efficacy [SE] and health communication), PP SE and use, and e-health literacy in older adults. MATERIALS AND METHODS: A two-arm randomized controlled trial was conducted with older adults (N = 272) who had chronic conditions. Participants were recruited online, and data were collected at baseline, 3 weeks, and 4 months. The main intervention effects were tested using linear mixed models. RESULTS: The average age of participants was 70.0 +/- 8.5 years, and 78.3% (n = 213) were white. At 3 weeks, the intervention group showed significantly greater improvement than the control group in all outcomes except PP use. At 4 months, the intervention effects decreased, but PP SE remained significant (p = 0.015), and the intervention group showed higher frequency of PP use than the control group (p = 0.029). CONCLUSION: The study findings showed that the T-PeP was effective in improving selected health and PP usage outcomes. Further studies are needed to test the long-term effects of T-PeP using more diverse samples. PMID- 30431395 TI - Pseudo-Source Parameters for Flares: Derivation, Implementation and Comparison. PMID- 30431394 TI - POPs' effect on cardiometabolic and inflammatory profile in a sample of women with obesity and hypertension. AB - Persistent organic pollutants (POPs) are man-made compounds with metabolic disruption impact. We investigated the effect of POP exposure in the cardiometabolic and inflammatory profile in a population of women with obesity and hypertension. In 43 premenopausal women (22 treated vs. 21 nontreated) undergoing bariatric surgery, blood and adipose tissue samples (visceral (vAT) and abdominal subcutaneous (scAT)) were collected. Median concentrations of ?HCH and ?POPs in vAT were significantly higher in treated women. VAT ?HCH and scAT ?HCH and ?POPs concentrations were positively correlated with systolic blood pressure in the non-treated group. Our findings suggest that exposure to POPs and its accumulation in vAT and circulating in plasma may be associated to a higher cardiovascular risk in women with obesity and hypertension, with or without antihypertensive treatment. PMID- 30431396 TI - Luteolin Showed a Resistance Elimination Effect on Gentamicin by Decreasing MATE mRNA Expression in Trueperella pyogenes. AB - Trueperella pyogenes is a common inhabitant of mucosal surfaces in animals and causes a variety of infections, including endometritis, mastitis, and liver abscessation, in dairy cows. Many antimicrobial agents are used for treatment of infections caused by T. pyogenes; however, antibiotic resistance has recently become a serious problem. The objective of this study was to characterize the effect of the efflux pump-encoding multidrug and toxic compound extrusion (MATE) gene on antibiotic resistance in T. pyogenes isolates from cows with signs of endometritis. As a compound from plants, luteolin showed antimicrobial activities in Escherichia coli and Staphylococcus aureus; therefore, we also investigated whether luteolin can eliminate antibiotic resistance. We constructed a MATE deletion mutant in BM-H06-3 to identify the function of MATE in antibiotic resistance. MATE mRNA expression was measured to identify the mechanism of luteolin in gentamicin resistance elimination effect in T. pyogenes. The T. pyogenes isolate BM-H06-3 became susceptible to gentamicin, amikacin, streptomycin, erythromycin, and roxithromycin after MATE deletion. No synergistic effect between luteolin and gentamicin was observed in eight isolates, which were randomly selected from 34 T. pyogenes isolates, but the isolates became susceptible to gentamicin after luteolin treatment at a subinhibitory concentration (1/4 minimum inhibitory concentration [MIC]) for 36 hr. Furthermore, luteolin can decrease MATE mRNA expression after luteolin treatment at a subinhibitory concentration (1/4 MIC). We found that the MATE gene was involved in antibiotic resistance and that luteolin induces a resistance elimination effect in T. pyogenes. Therefore, luteolin may be a potential agent to inhibit efflux pumps in multidrug-resistant T. pyogenes. PMID- 30431397 TI - Simultaneous use of magnetic method in localization of impalpable breast cancer and sentinel lymph nodes detection: initial experience. AB - AIM: In this study we used a new technology for localization of non-palpable breast tumors using a small steel marker in conjunction of sentinel nodes (SLNs) detection through injection of SPIO nanoparticles; both detected through a magnetic probe. Materials & methods: Ten patients with biopsy-proven nonpalpable invasive breast carcinoma or premalignant lesions eligible for SLNs biopsy were enrolled in this study. RESULTS: All tumors were removed with safe surgical margins. The mean nodal detection rate was 3.4 nodes per patient. No interferences in magnetic probe measurements due to the presence of both markers in the same breast were observed. CONCLUSION: Simultaneous use of the magnetic method in localization of impalpable breast tumors and SNs detection makes breast surgery convenient. PMID- 30431398 TI - Omission of carbohydrate-rich breakfast impairs evening 2000-m rowing time trial performance. AB - PURPOSE: The effect of breakfast omission on evening high-intensity exercise performance has not previously been studied. METHODS: In a randomised and counterbalanced cross-over design, 10 competitive rowers (2 male, 8 female; mean +/- SD: age 21 +/- 2 y, height 176 +/- 7 cm, weight 76 +/- 12 kg, body fat 19.7 +/- 6.8%) completed two trials (individualised carbohydrate-rich breakfast (BT; 831 +/- 67 kcal eaten before 09:00) and no-breakfast (NBT; extended overnight fast until 12:00)). Following ad libitum afternoon food intake, participants completed a 2000-m time-trial on a rowing ergometer between 16:30 and 18:00. Appetite and energy intake were measured throughout the day, whilst power output, time, heart rate, blood lactate, blood glucose and RPE were assessed during the time trial. RESULTS: Appetite ratings were higher throughout the morning in NBT compared with BT, but there were no differences in ratings in the afternoon. Energy intake at lunch was greater NBT compared with BT (1236 +/- 594 vs 836 +/- 303 kcal, p < .05), which partly compensated for breakfast omission, although overall energy intake tended to be lower in NBT compared with BT (1236 +/- 594 vs 1589 +/- 225 kcal, p = .08). The time taken to complete the 2000-m time trial was greater in NBT compared with BT (469.2 +/- 43.4 vs 465.7 +/- 43.3 s; p < .05). No differences in heart rate, blood glucose and blood lactate responses were apparent, but overall RPE was higher in NBT compared with BT (17.8 +/- 0.9 vs 16.7 +/- 0.7 au, p < .05). CONCLUSION: The omission of a carbohydrate-rich breakfast impaired evening performance during a 2000-m rowing time trial. This finding has implications for optimising evening high-intensity exercise performance. PMID- 30431399 TI - Development of a Pseudomonas syringae - Arabidopsis suspension cell infection system for investigating host metabolite-dependent regulation of type III secretion and pattern-triggered immunity. AB - The importance of Pattern-Triggered Immunity (PTI) in plant defense has been clearly established through genetic studies of mutants lacking functional pattern recognition receptors (PRRs) and signaling components downstream of PRR activation. Despite extensive knowledge of PRR-mediated signaling responses to Pathogen-Associated Molecular Patterns (PAMPs), little is known about which of these responses, if any, are directly responsible for limiting bacterial growth. In this work we established a protocol for co-culturing the bacterial pathogen Pseudomonas syringae pv tomato DC3000 and Arabidopsis suspensions cells. The system closely mirrors infection processes that occur in leaves, with bacteria relying on the type III secretion system (T3SS) for maximal growth and PAMP induced plant defenses effectively limiting bacterial growth. To demonstrate the utility of this system, we investigated the molecular basis of PAMP-induced growth inhibition and discovered that T3SS-associated genes are inhibited when DC3000 is co-cultured with PAMP-treated plant suspension cells. To determine the underlying mechanism of decreased T3SS gene expression, we performed metabolomics and biochemical analyses of suspension cell exudates and identified fourteen metabolites that significantly increased or decreased following PAMP treatment. Citric acid, a known inducer of T3SS gene expression in DC3000, was among several organic acids decreased in exudates from PAMP-treated plant cells. Exogenous addition of citric acid increased T3SS gene expression and partially recovered growth of DC3000 in the presence of PAMP-treated cells, indicating that a portion of PAMP-induced defense in this system is decreased extracellular release of this metabolite. We envision that the well-defined infection conditions of this co culture system will be valuable for quantitative studies of type III effector delivery by P. syringae. Furthermore, this system provides a unique "top-down" approach to unravel the molecular basis of PTI against P. syringae. PMID- 30431400 TI - A feed-forward subnetwork emerging from integrated TOR- and cAMP/PKA-signaling architecture reinforces Magnaporthe oryzae appressorium morphogenesis. AB - Appressoria are important mediators of plant-microbe interactions. In the devastating rice blast pathogen Magnaporthe oryzae, appressorial morphogenesis from germ tube tips requires activated cAMP/PKA signaling and inactivated TOR signaling (TORoff). TORoff temporarily arrests G2 at a metabolic checkpoint during the single round of mitosis that occurs following germination. G2 arrest induces autophagy and appressorium formation concomitantly, allowing re progression of the cell cycle to G1/G0 quiescence and a single appressorial nucleus. Inappropriate TOR activation abrogates G2 arrest and inhibits cAMP/PKA signaling downstream of cPKA. This results in multiple rounds of germ tube mitosis and the loss of autophagy and appressoria formation. How cAMP/PKA signaling connects to cell cycle progression and autophagy is not known. To address this, we interrogated TOR and cAMP/PKA pathways using signaling mutants, different surface properties and specific cell cycle inhibitors, and discovered a feed-forward subnetwork arising from TOR- and cAMP/PKA-signaling integration. This adenylate cyclase-cAMP-TOR- adenylate cyclase subnetwork reinforces cAMP/PKA dependent appressorium formation under favorable environmental conditions. Under unfavorable conditions, the subnetwork collapses, resulting in reversible cell cycle-mediated germ tube growth regardless of external nutrient status. Collectively, this work provides new molecular insights on germ tube morphogenetic decision-making in response to static and dynamic environmental conditions. PMID- 30431402 TI - Correction. PMID- 30431401 TI - Evaluation of EDTA- and DPA-Based Microdilution Phenotypic Tests for the Detection of MCR-Mediated Colistin Resistance in Enterobacteriaceae. AB - The emergence of the colistin-resistant (COL-R) Enterobacteriaceae represents a worrying health issue. However, only a portion of these strains may carry the plasmid-mediated mcr colistin resistance genes. We evaluated the ability of both ethylenediaminetetraacetic acid (EDTA)-based and dipicolinic acid (DPA)-based broth microdilution (BMD) tests to detect mcr-1 to mcr-5 producers. Of 92 Enterobacteriaceae (85 COL-R), 44 mcr-positive strains (39 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Salmonella spp.) were tested. EDTA (100 MUg/mL) was tested in Mueller-Hinton broth (MHB), whereas the DPA (900 MUg/mL) was used in cation-adjusted MHB. Results were categorized as positive if in presence of chelator strains exhibited >=3 two fold MIC decrease compared to the COL MIC alone. The EDTA-based BMD assay detected 41 mcr-positive strains, but 22 false positive strains (including 12 E. coli and 4 K. pneumoniae) were recorded (sensitivity [SN], 93.2%; specificity [SP], 54.2%). The DPA-based BMD assay detected 37 mcr-positive strains, with 7 false-negative (2 E. coli, 3 K. pneumoniae, 2 Salmonella spp.) strains (SN, 84.1%; SP, 100%). Overall, the EDTA based BMD assay is not accurate to detect mcr producers, whereas the DPA-based BMD test ("colistin-MAC test") demonstrated good accuracy, but only when implemented for E. coli strains (SN, 94.9%; SP, 100%). With the aim to prevent the dissemination of mcr-possessing E. coli strains, the COL-MAC test could be implemented by clinical laboratories that are unable to perform molecular tests. Moreover, this assay could be applied to screen large collections of isolates to reveal the expression of new mcr-like genes not yet targeted by the current molecular assays. PMID- 30431403 TI - Psychosocial Correlates of Frailty Among HIV-Infected and HIV-Uninfected Adults. AB - Frailty is a geriatric condition characterized by increased vulnerability to physical impairments and limitations that may lead to disabilities and mortality. Although studies in the general population suggest that psychosocial factors affect frailty, less is known about whether similar associations exist among people living with HIV (PLWH). The purpose of this study was to examine psychosocial correlates of frailty among PLWH and HIV-uninfected adults. Our sample included 127 adults (51% PLWH) participating in the Multi-Dimensional Successful Aging among HIV-Infected Adults study at the University of California San Diego (average age 51 years, 80% male, 53% White). Frailty was assessed via the Fried Frailty Index. Psychosocial variables significant in bivariate models were included in principal component analysis to generate factor variables summarizing psychosocial correlates. Multivariate logistic regression models were fit to examine the independent effects of factor variables and their interaction terms with HIV status. In bivariate models, frailty was associated with multiple psychosocial variables, for example, grit, optimism, personal mastery, social support, emotional support. Factor analysis revealed that psychosocial variables loaded on two factors-Positive Resources/Outlook and Support by Others. The multivariate model showed significant main effects of Support by Others and HIV status, and interactive effects HIV X Positive Resources/Outlook, such that Positive Resources/Outlook was negatively associated with frailty for PLWH but not for HIV-uninfected individuals. These analyses indicate that psychosocial factors may be associated with frailty among PLWH. Positive resources and outlook may play a role in frailty prevention. Future longitudinal studies are needed to establish causal links. PMID- 30431404 TI - Norovirus GII.17 Virus-Like Particles Bind to Different Histo-Blood Group Antigens and Cross-React with Genogroup II-Specific Mouse Sera. AB - Majority of norovirus (NoV) outbreaks and sporadic infections in the past 20 years have been caused by GII.4 variants. In 2014, NoV GII.17 genotype replaced GII.4 strains in several Asian countries and major outbreaks were reported in other continents. As GII.17 is a recently evolved NoV strain, there is a gap especially in immunogenicity data. In this study, we investigated GII.17 virus like particle (VLP) binding to various cellular ligands, histo-blood group antigens (HBGAs), using human saliva, pig gastric mucin, and synthetic oligosaccharides as HBGA sources. The level of GII.17 immunological cross reactivity was determined in mice immunized with different monovalent and multivalent NoV VLP compositions. Furthermore, healthy adult volunteers with natural NoV exposure history were analyzed for GII.17-specific seroresponses. The results showed that GII.17 Kawasaki VLPs bind to a wide range of HBGAs, even though fewer than GII.4 VLPs. Immunization of mice with a multivalent VLP formulation containing different genogroup II NoV VLPs was required to obtain the highest magnitude of cross-reactive binding antibodies to GII.17. However, coimmunization with different VLP genotypes did not improve potentially neutralizing antibodies to GII.17, which remained very moderate. Low pre-existing cross-reactive antibodies to GII.17 observed in human adults indicate the presence of a large pool of susceptible individuals in this population. These data suggest that GII.17 and alike newly emerging distinct NoV genotypes should be considered as an antigenic component for vaccine formulations, which currently widely rely on GII.4-specific immunity. PMID- 30431405 TI - Graphene oxide coatings prevent Candida albicans biofilm formation with a controlled release of curcumin-loaded nanocomposites. AB - AIM: Fabrication of graphene oxide (GO)-based medical devices coatings that limit adhesion of Candida albicans, a main issue of healthcare-associated infections. METHODS: The GO composites noncovalently functionalized with curcumin (CU), a hydrophobic molecule with active antimicrobial action, polyethylene glycol (PEG) that hinders the absorption of biomolecules or a combination of CU and PEG (GO-CU PEG) were drop-casted on surfaces and antifungal efficacy was assessed. RESULTS: We demonstrate that GO-CU-PEG coatings can reduce fungal adhesion, proliferation and biofilm formation. Furthermore, in an aqueous environment, surfaces release curcumin-PEG nanocomposites that have a minimum inhibitory concentration of 9.25 MUg/ml against C. albicans. CONCLUSION: Prevention of early cell adhesion and creation of a proximal environment unfavorable for growth make these GO-supported biomaterials attractive for innovative medical device manufacturing. [Formula: see text]. PMID- 30431406 TI - A Sensitive Nano Luciferase Immune Complex Assay System for Highly Sensitive and Specific Detection of Antibodies Against Tick-Borne Encephalitis Virus. AB - Tick-borne encephalitis virus (TBEV) can cause fever, headache, neurological disorders, and/or peripheral flaccid paralysis; therefore, it is a major threat to public health. A rapid, sensitive, and simple method for detecting anti-TBEV antibodies is needed urgently to determine infection and for vaccine evaluation. Here, a luciferase-based immunocomplex assay system (Luc-IC) was developed to detect TBEV antibodies. The system is based on a reporter Nano luciferase (NLuc) that is co-expressed as a fusion protein with viral envelope domain III (ED3) in COS7 cells. The cell supernatant was used directly to detect antigen without the need for a purification step. This simple procedure effectively improved the sensitivity of the assay. Sera from 50 patients with an acute tick-borne encephalitis infection were tested to determine the sensitivity of the NLuc-IC assay. Furthermore, 62 sera from individuals infected with Japanese encephalitis virus, West Nile virus, yellow fever virus, dengue virus, or Zika virus were also tested to determine specificity. The results demonstrated that the assay was 100% sensitive and 100% specific for TBEV antibodies. Thus, this very simple NLuc-IC assay is potentially useful for rapid and accurate diagnosis of TBEV infection in both humans and animals. PMID- 30431407 TI - Challenges and value of peer outreach workers in needle and syringe exchange programs: Evidence from an HIV prevention program in Yunnan province, China. AB - We aim to compare the values and challenges of peer outreach workers (POWs) with a history of drug use with non-POWs (NPOWs) in a needle and syringe exchange program (NSEP) in Yunnan, China. Data were abstracted from two independent surveys of 98 outreach workers and 33 program managers in 2014. POWs were more likely than NPOWs to conduct active outreach and to report ease in exchanging needles. Commonly cited concerns from POWs were low wages and frustration with client follow-up. Managers expressed the most concern on high turnover rates and low education levels. POWs seem to be more effective than NPOWs in conducting outreach, though POWs face unique challenges. We call for a recognition of the challenges and needs for more sensitive support for POWs. PMID- 30431408 TI - An Exploration of Coping with Childhood Sexual Abuse in Arab American Women. AB - This research used a descriptive qualitative approach to explore coping with childhood sexual abuse (CSA) and to identify long-term psychological outcomes among Arab American women. Ten Arab American women participated in the study. Data were collected by individual semi-structured interviews and analyzed using content analysis. Five categories emerged for CSA experience among the participants: CSA characteristics, social support, Arabic culture, coping, and long-term psychological outcomes. Most of the women had experienced familial and contact CSA . and had disclosed their CSA and received different reactions from family and friends. Arabic cultural values influenced the women's experience of CSA and their coping strategy, especially regarding the CSA disclosure and seeking mental health services. The women used a spectrum of strategies to cope with their abuse including seeking support, positive reappraisal,,, accepting responsibilities, avoidance and protective coping. All women experienced negative long-term psychological outcomes of CSA such as flashbacks and low self-esteem. Prior to this research, no known studies have explored coping with CSA experience among Arab American women. Thus, this study can be used to inform practice guidelines to minimize the stigma of CSA and to promote help-seeking behavior for Arab American female CSA survivors and their families. PMID- 30431409 TI - Nine novel species of Huntiella from southern China with three distinct mating strategies and variable levels of pathogenicity. AB - The ascomycete genus Huntiella (Microascales) has a cosmopolitan distribution and occurs on a wide range of woody plants. Little is known regarding the identity, diversity, origin, or impact of these fungi in China. Recently, isolates of Huntiella spp. were collected from stumps of freshly felled trees or wounds on plantation-grown Eucalyptus in Guangdong, Guangxi, Fujian, and Hainan provinces of southern China. Additional isolates were obtained from stumps of Acacia confusa near Eucalyptus plantations in Hainan Province. The aim of this study was to identify these Huntiella species and to test their pathogenicity on Eucalyptus seedlings. Morphology and multigene phylogenies of the nuclear rDNA internal transcribed spacer (ITS1-5.8S-ITS2 = ITS) region and partial beta-tubulin (BT1) and translation elongation factor 1alpha (TEF1alpha) genes revealed nine previously unknown Huntiella species, eight from Eucalyptus and one from A. confusa. The mating types of these species were determined, showing that seven are heterothallic, one is homothallic, and one is unisexual (MAT1-2-1 gene). Pathogenicity tests showed that the nine Huntiella species can produce lesions on Eucalyptus seedlings, larger than wounds caused by controls on these plants. This study provides a basic understanding of the distribution, diversity, and pathogenicity of Huntiella species in southern China. PMID- 30431411 TI - Correction. PMID- 30431412 TI - ICTV Virus Taxonomy Profile: Nodaviridae. AB - The family Nodaviridae includes two genera, Alphanodavirus and Betanodavirus. The family name derives from the Japanese village of Nodamura where Nodamura virus was first isolated from Culex tritaeniorhynchus mosquitoes. Virions are non enveloped and spherical in shape with icosahedral symmetry (T=3) and diameters ranging from 25 to 33 nm. The genome consists of two molecules of single-stranded positive-sense RNA: RNA1 and RNA2. The virion capsid consists of 180 protein subunits arranged on a T=3 surface lattice. Alphanodaviruses infect insects, whereas betanodaviruses are pathogens of fish. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Nodaviridae, which is available at www.ictv.global/report/nodaviridae. PMID- 30431413 TI - Simplicispira lacusdiani sp. nov., a novel betaproteobacterium isolated from a freshwater reservoir. AB - A Gram-stain-negative, motile, rod-shaped bacterium, designated CPCC 100842T, was isolated from a freshwater reservoir in south-west China. The 16S rRNA gene sequence comparison of strain CPCC 100842T with the available sequences in the GenBank database showed that the isolate was closely related to members of the family Comamonadaceae, with the highest similarities to Simplicispira metamorpha DSM 1837T (98.05 %), Simplicispira limi KCTC 12608T (97.86 %), Simplicispira psychrophila LMG 5408T (97.04 %) and Simplicispira piscis JCM 19291T (97.0 %). In the phylogenetic tree based on 16S rRNA gene sequences, strain CPCC 100842T formed a distinct phylogenetic subclade within the genus Simplicispira. The major cellular fatty acids were as C16 : 0 and summed feature 3 (C16 : 1 omega7c/C16 : 1omega6c). Q-8 was detected as the only respiratory quinone. Phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid and glycolipid were found in the polar lipid extraction. The genomic DNA G+C content was 67.4 mol%. The average nucleotide identity value was 80.4 % by comparing the draft genome sequences of strain CPCC 100842T and S. metamorpha DSM 1837T. The DNA-DNA hybridization result between strain CPCC 100842T and S. metamorpha DSM 1837T showed 37+/-3 % genomic relatedness. On the basis of the genotypic analysis and phenotypic characteristics, we propose that strain CPCC 100842T represents a novel species of the genus Simplicispira in the family Comamonadaceae with the name Simplicispira lacusdiani sp. nov. Strain CPCC 100842T (=KCTC 52093T=DSM 102231T) is the type strain of the species. PMID- 30431414 TI - Transconjugation of erm(X) conferring high-level resistance of clindamycin for Cutibacterium acnes. AB - Cutibacterium acnes (C. acnes) can become an exacerbating factor in acne vulgaris. Clindamycin has been most frequently used for the treatment of inflammatory acne vulgaris. We studied clindamycin susceptibility and resistance determinants of C. acnes isolated from acne patients in Japan. The isolation rate of clindamycin-resistant C. acnes had significantly increased from 20.3 % in 2009 2010 to 44.1 % in 2016-2017. Strains carrying erm(X), which confers high-level resistance to clindamycin, had significantly increased from 1.4 to 11.8 %. Sequence analysis of the resistance determinant showed that erm(X) was coded on transposon Tn5432. A transconjugation experiment showed that erm(X) can be transferred between C. acnes strains with high frequency and the transconjugants harboured transposon Tn5432 encoding erm(X). Our data show the transconjugation of erm(X) in C. acnes and strongly suggest that the transmission of erm(X) between C. acnes contributes to the increase and spread of clindamycin-resistant C. acnes strains in acne patients. PMID- 30431415 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 68, part 10 of the IJSEM. PMID- 30431417 TI - Moniliella floricola sp. nov., a species of black yeast isolated from flowers. AB - Moniliella yeasts were isolated from flower samples collected in Vietnam using an enrichment medium containing 50 % (w/w) glucose. The yeasts were identified as M. byzovii, M. dehoogii, M. megachiliensis, M. mellis, M. nigrescens and M. spathulata. A group of 20 strains representing a hitherto undescribed species of Moniliella was detected. ITS sequences indicated the presence of four genetic variants differing from each other by 4-14 nt. The strains, however, were identical in the TEF1 sequences and shared 1-2 nt differences in the D1/D2 regions. In the ITS-D1/D2 phylogenetic tree, the strains grouped together and formed a well-supported clade with insect-associated Moniliella species, including M. pollinis, M. megachiliensis and M. oedocephalis. The new group was most closely related to M. pollinis but differed from the latter by 95 nt (58 substitutions, 37 indels) in the ITS, 36 nt (31 substitutions, five indels) in the D1/D2, and 30 nt (30 substitutions) in the TEF1 sequences. Moniliella floricola sp. nov. is proposed to accommodate this group of isolates. The type strain and MycoBank number of M. floricola sp. nov. are TBY 30.1T (=CBS 12758T=NRRL Y-63660T) and MB 825274, respectively. PMID- 30431416 TI - A novel 'Candidatus Phytoplasma asteris' subgroup 16SrI-(E/AI)AI associated with blueberry stunt disease in eastern Canada. AB - Phytoplasmas ('Candidatus Phytoplasma' species) are phytopathogenic bacteria vectored by insects and are associated with crop diseases that cause severe yield losses by affecting reproductive tissue development. Infection of northern highbush blueberry plants (Vaccinium corymbosum; Ericaceae) with phytoplasma leads to yield losses by altering plant development resulting in stunting and subsequent plant death. Samples collected from symptomatic blueberry plants in two important blueberry-producing areas in Canada, in the provinces of Quebec and Nova Scotia, were analysed for the presence of DNA sequences associated with phytoplasma. Analysis of the 16S rRNA gene sequences demonstrated that the plants were infected with a strain of 'Candidatus Phytoplasma asteris', which was previously identified as blueberry stunt phytoplasma (BBS; 16SrI-E). Examination of further bacterial sequences revealed that two distinct 16S rRNA-encoding gene sequences were present in each sample in combination with a single chaperonin-60 (cpn60) sequence and a single rpoperon sequence, suggesting that this strain displays 16S rRNA-encoding gene sequence heterogeneity. Two distinct rrnoperons, rrnE and the newly described rrnAI, were identified in samples analysed from all geographic locations. We propose, based on the sequences obtained, delineating the new subgroup 16SrI-(E/AI)AI, following the nomenclature proposed for heterogeneous subgroups. To our knowledge, this is the first report of a heterogeneous phytoplasma strain affecting blueberry plants and associated with blueberry stunt disease. PMID- 30431418 TI - A genetic screen for mutations affecting temperature sensing in Bacillus subtilis. AB - Two component systems, composed of a receptor histidine kinase and a cytoplasmic response regulator, regulate pivotal cellular processes in microorganisms. Here we describe a new screening procedure for the identification of amino acids that are crucial for the functioning of DesK, a prototypic thermosensor histidine kinase from Bacillus subtilis. This experimental strategy involves random mutagenesis of the membrane sensor domain of the DesK coding sequence, followed by the use of a detection procedure based on changes in the colony morphogenesis that take place during the sporulation programme of B. subtilis. This method permitted us the recovery of mutants defective in DesK temperature sensing. This screening approach could be applied to all histidine kinases of B. subtilis and also to kinases of other bacteria that are functionally expressed in this organism. Moreover, this reporter assay could be expanded to develop reporter assays for a variety of transcriptionally regulated systems. PMID- 30431419 TI - Corrigendum: Performance evaluation of five commercial assays in assessing seroprevalence of HEV antibodies among blood donors. PMID- 30431420 TI - Nitrincola tibetensis sp. nov., isolated from Lake XuguoCo on the Tibetan Plateau. AB - A novel Gram-stain-negative, motile and rod-shaped bacterium, designated xg18T, was isolated from Lake XuguoCo on the Tibetan Plateau. The strain was able to grow optimally at 0-2 % NaCl and tolerate up to 6 % NaCl. Growth occurred at pH 7.0-11.0 (optimum, pH 9.0-10.0) and 15-40 degrees C (optimum, 37 degrees C). Vitamins were not required for growth. The major polar lipids of strain xg18T were phosphatidyl ethanolamine and phosphatidylglycerol. The predominant respiratory quinone was Q-8. The major fatty acids were summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0. The G+C content of genomic DNA was 46.1 mol%. Analysis of 16S rRNA sequences showed that strain xg18T belongs to the genus Nitrincola, with Nitrincola alkalisediminis MEB087T (KC822363, 98.6 %) as its closest neighbour. The DNA-DNA relatedness value of strain xg18T with its closest phylogenetic neighbour, N. alkalisediminis JCM 19317T, was 43.1+/-3.2 %. Strain xg18T was clearly distinguishable from the type strain of the genus Nitrincola through phylogenetic analysis, fatty acid composition data and a range of physiological and biochemical characteristics comparisons. Based on its phenotypic and chemotaxonomic characteristics, strain xg18T could be classified as a representative of a novel species of the genus for which the name Nitrincola tibetensis sp. nov. is proposed. The type strain is xg18T (=CICC 24457T=KCTC 62401T). PMID- 30431421 TI - Fosfomycin: mechanisms and the increasing prevalence of resistance. AB - There are challenges regarding increased global rates of microbial resistance and the emergence of new mechanisms that result in microorganisms becoming resistant to antimicrobial drugs. Fosfomycin is a broad-spectrum bactericidal antibiotic effective against Gram-negative and certain Gram-positive bacteria, such as Staphylococci, that interfere with cell wall synthesis. During the last 40 years, fosfomycin has been evaluated in a wide range of applications and fields. Although numerous studies have been done in this area, there remains limited information regarding the prevalence of resistance. Therefore, in this review, we focus on the available data concerning the mechanisms and increasing resistance regarding fosfomycin. PMID- 30431422 TI - Bacillus salidurans sp. nov., isolated from salt-accumulated pepper rhizospheric soil. AB - A Gram-stain-positive, facultatively anaerobic, motile and rod-shaped bacterium, designated KNUC7312T, was isolated from salt-accumulated rhizospheric soil in a pepper greenhouse in Miryang city, Republic of Korea. Cell growth of strain KNUC7312T occurred at 10-45 degrees C (optimum, 30 degrees C) and pH 7-12 (optimum, pH 7). In addition, this strain was able to tolerate 0-12 % NaCl (w/v) concentration (optimum, 0-1 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain KNUC7312T clustered together with other species of the genus Bacillus and was most closely related to Bacillus humi DSM 16318T (98.0 %). The predominant respiratory quinone was menaquinone-7 (MK-7). The major cellular fatty acids were anteiso C15 : 0, iso-C15 : 0 and iso-C14 : 0. The polar lipid profile contained the major components diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and two unidentified aminolipids. The cell-wall peptidoglycan contained meso-diaminopimelic acid as the major diagnostic diamino acid. Strain KNUC7312T showed a low DNA-DNA relatedness value (47.36 %) with B. humi DSM 16318T, which supported that this strain represents a novel Bacillusspecies. On the basis of phenotypic, chemotaxonomic and phylogenetic evidence, strain KNUC7312T represents a novel species within the genera Bacillus. The name Bacillus salildurans sp. nov. is proposed. The type strain is KNUC7312T (KCTC 33852T=CGMCC 1.13629T). PMID- 30431423 TI - Selective modulation of Wnt-binding receptor tyrosine kinase ROR2 expression by human cytomegalovirus regulates trophoblast migration. AB - Cytomegalovirus (CMV) infection during pregnancy may lead to adverse pregnancy outcomes and permanent neurological disabilities in infants infected in utero. Congenital CMV disease of the foetus and neonate results from both direct viral cytopathic damage and indirect effects through placental dysfunction. Infection specifically alters Wnt signalling, an essential pathway involved in trophoblast migration and placental development. We examined CMV regulation of trophoblast migration. This virus controls expression of Wnt-binding receptor tyrosine kinase ROR2, but not alternate receptor tyrosine kinases ROR1 or RYK. Ectopic expression of ROR2 reduced Wnt5a-induced trophoblast migration, whilst overexpression of ROR1 or RYK did not affect trophoblast migration. CMV infection increased ROR2 protein expression in trophoblasts, with no effect on ROR1 and RYK expression. These data further support the proposal that specific inhibition of this mechanism may be a target for therapeutic intervention to reduce placental damage and consequent foetal disease due to congenital CMV infection. PMID- 30431424 TI - Aeromedical Transfer of Patients with Viral Hemorrhagic Fever. AB - For >40 years, the British Royal Air Force has maintained an aeromedical evacuation facility, the Deployable Air Isolator Team (DAIT), to transport patients with possible or confirmed highly infectious diseases to the United Kingdom. Since 2012, the DAIT, a joint Department of Health and Ministry of Defence asset, has successfully transferred 1 case-patient with Crimean-Congo hemorrhagic fever, 5 case-patients with Ebola virus disease, and 5 case-patients with high-risk Ebola virus exposure. Currently, no UK-published guidelines exist on how to transfer such patients. Here we describe the DAIT procedures from collection at point of illness or exposure to delivery into a dedicated specialist center. We provide illustrations of the challenges faced and, where appropriate, the enhancements made to the process over time. PMID- 30431425 TI - The association between clopidogrel and 2-oxo-clopidogrel plasma levels and the long-term clinical outcome after acute myocardial infarction?. AB - BACKGROUND AND OBJECTIVES: A significant number of ischemic events occur after acute myocardial infarction (MI), even when adhering to dual antiplatelet therapy including aspirin and clopidogrel. The aim of our study was to investigate the association between the concentration of the prodrug clopidogrel and its intermediary metabolite 2-oxo-clopidogrel plasma as well as demographic and clinical factors, and the long-term clinical outcome in patients with their first acute MI, ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction NSTEMI, treated with percutaneous coronary intervention (PCI). MATERIALS AND METHODS: This study included 172 consecutive patients with their first acute MI, 88 STEMI, and 84 NSTEMI, treated with PCI. On the third day of hospitalization, blood samples were collected from each patient to measure the concentration of clopidogrel and its metabolite 2-oxo-clopidogrel using the UHPLC DAD-MS method. The following clinical outcomes were registered during the 28 month follow-up: mortality from cardiovascular causes, nonfatal MI, nonfatal stroke, and hospitalization for urgent myocardial revascularization or heart failure. RESULTS: Lower dose-adjusted clopidogrel concentrations (p < 0.05) were measured in NSTEMI patients with a composite of the hard clinical endpoint events of cardiovascular mortality, non-fatal MI, or a nonfatal stroke. During the follow-up, there was a 3.4 times higher risk of hard clinical endpoint events (p < 0.05) for each unit decrement of the dose-adjusted clopidogrel plasma concentration. Lower dose-adjusted concentrations of clopidogrel in these patients were associated with lower left ventricular ejection fraction (p < 0.001), and fentanyl (p < 0.001) and pantoprazole administration (p < 0.01) during the acute phase of MI. CONCLUSION: In patients with acute MI treated with PCI, lower dose-adjusted clopidogrel and dose-adjusted 2-oxo-clopidogrel plasma concentrations were associated with an increased risk of ischemic events.?. PMID- 30431426 TI - Bioequivalence of fluticasone propionate and salmeterol (FS) given by the FS Spiromax(r) and Seretide Accuhaler(r) systems?. AB - OBJECTIVE: To determine pharmacokinetic (PK) profiles of fluticasone propionate (FP) and salmeterol (SAL) in healthy volunteers following administration as two inhalations from the FS Spiromax 500/50 ug and Seretide Accuhaler 50/500 ug inhalers, without (study 1, n = 79) and with charcoal block (study 2, n = 77). Safety was also assessed. MATERIALS AND METHODS: In two single-center, open label, randomized two-period crossover studies, PK parameters were calculated from plasma drug concentrations obtained pre-dose through 36 hours post-dose. Bioequivalence was established if the 90% confidence intervals for the geometric mean ratios of the area under the plasma drug concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-t) and the maximum observed plasma concentration (Cmax) for the comparison of both FP and SAL were within 0.80 - 1.25. RESULTS: In study 1, in subjects administered FS Spiromax, the mean (standard deviation (SD)) FP AUC0-t and Cmax were 1,622.64 (419.44) pg*h/mL and 151.36 (40.37) pg/mL, respectively, vs. 1,487.52 (341.25) pg*h/mL and 137.57 (33.64) pg/mL with Seretide Accuhaler. Mean (SD) SAL AUC0-t and Cmax with FS Spiromax were 408.42 (155.40) pg*h/mL and 269.48 (105.74) pg/mL, respectively, vs. 401.79 (125.32) pg*h/mL and 265.66 (87.28) pg/mL with Seretide Accuhaler. Comparable data were seen in study 2 with charcoal block. Bioequivalence of FS Spiromax with Seretide Accuhaler was observed both without and with charcoal block for FP and SAL for both AUC0-t and Cmax. Both study treatments were well tolerated, with a similar incidence of adverse events reported with the single use of FS Spiromax (23% study 1, 16% study 2) and Seretide Accuhaler (22%, 15%). CONCLUSION: FS Spiromax 500/50 ug (+/- charcoal block) was bioequivalent to Seretide Accuhaler 50/500ug.?. PMID- 30431427 TI - A simplified percutaneous technique for inserting Tenckhoff peritoneal dialysis?. AB - AIM: Successful catheter implantation is highly essential for delivering effective peritoneal dialysis (PD). The aim of the present study was to describe a newly developed, minimally invasive percutaneous technique for providing safe, timely, and effective peritoneal catheter insertion and assess the long-term outcome. MATERIALS AND METHODS: 100 PD catheters were placed in 100 consecutive patients by a nephrologist using the modified percutaneous technique with a special trocar, from August 1, 2010 to December 31, 2011. The patients were followed up until October 31, 2015. Demographic and clinical features of study subjects, duration of hospital stay, follow-up time, complications, and catheter survival were assessed in all patients. RESULTS: The patient study group included 47 men and 53 women, with a mean age of 55.3 +/- 13.7 years. The mean hospitalization time was 17.1 +/- 8.6 days, and the mean duration of follow-up was 44.7 +/- 15.1 months. 71 patients were still on continuous ambulatory peritoneal dialysis at the time of study completion. Peritonitis was the most common complication observed, with an incidence of 28%. None of the patients experienced surgical complications such as bleeding or incisional hernia. The mean catheter survival time was 57.0 +/- 1.5 months. CONCLUSION: Peritoneal catheter placement using our modified percutaneous technique is simple, safe, minimally invasive, and efficient. It carried less morbidity with respect to bowel perforation, catheter-related infection, and exit-site leak.?. PMID- 30431428 TI - Treatment of recurrent, post-kidney transplant membranoproliferative glomerulonephritis with plasmapheresis and rituximab: A case report and literature review?. AB - Membranoproliferative glomerulonephritis is known to recur after kidney transplantation and may lead to allograft loss. Although an optimal treatment has not been determined, B-cell targeted therapies are now increasingly used as first line agents, based on growing data showing antibodies as key players in the pathogenesis of membranoproliferative glomerulonephritis. Here, we report a case of recurrent immune complex-mediated membranoproliferative glomerulonephritis 3 years after a living-donor kidney transplant. Treatment with plasmapheresis and rituximab resulted in immediate and sustained improvement in allograft function.?. PMID- 30431429 TI - Immunoglobulin G subclass 3 in ISN/RPL lupus nephritis classification?. AB - OBJECTIVES: In lupus nephritis, the immune complex plays a very important role in kidney disease progression, and immunoglobulin G subclass 3 (IgG3) may play an important role in endothelial damage as lupus nephropathy progresses. We evaluated the association between IgG3 positivity and lupus nephritis activity. MATERIALS AND METHODS: We identified 71 biopsies taken from 57 patients who had lupus nephritis with enough tissue to allow light and immunofluorescence microscopy. We compared the intensity of IgG subclass staining (on a scale of 0 - 3+) with IgG subclass dominance among lupus nephritis classes as defined by the ISN/RPS 2003 classification. RESULTS: The proportion of IgG3-positive patients with capillary loop lesion was significantly higher in the class IV group compared with other groups (p < 0.01). Interestingly, in most patients IgG1 was the strongest subclass; in class IV groups, IgG3 was the strongest in 21% of the biopsies. IgG3 deposition in capillary loops was significantly associated with C1q deposition in those loops. According to Kaplan-Meier analysis, renal survival rates in the patients with IgG3 deposition was lower (82.2%) than in patients without IgG3 deposition (93.3%), but the difference was not significant. CONCLUSION: Our results suggest that capillary loop deposition of IgG3 is associated with disease activity in lupus nephritis.?. PMID- 30431430 TI - Chronic systemic capillary leak syndrome treatment with intravenous immune globulin: Case report and review of the literature?. AB - Systemic capillary leak syndrome (SCLS) is a disorder characterized by increased vascular permeability with intermittent acute episodes of profound capillary leak that may result in hypotension or shock. A rarely described chronic form of SCLS (cSCLS) presents as refractory edema, with pleural and/or pericardial effusions and hypoalbuminemia. These entities are differentiated by massive and periodic episodes of capillary leak, which can result in shock in SCLS, and chronic refractory edema in cSCLS. The etiologies of these disorders are poorly understood, but both acute and chronic forms often present with an associated monoclonal gammopathy. Flares of the SCLS have been reduced by treatment with intravenous immune globulin (IVIG). Only six cases of cSCLS have been reported, and previous treatments have included steroids, terbutaline, and theophylline. Based upon the reported responses of SCLS to IVIG, we present the case of a 54 year-old man with cSCLS where ongoing treatment with IVIG resulted in a marked and sustained improvement in the signs and symptoms of the capillary leak syndrome.?. PMID- 30431431 TI - Successful pregnancy in a patient with pulmonary renal syndrome double-positive for anti-GBM antibodies and p-ANCA?. AB - BACKGROUND: Antiglomerular basement membrane (anti-GBM) antibody disease is a rare condition causing pulmonary hemorrhage and necrotizing glomerulonephritis (pulmonary renal syndrome). CASE: We report a 30-year-old woman who presented with life-threatening pulmonary hemorrhage and an active urinary sediment, with normal glomerular filtration rate in the 13th week of pregnancy. Anti-GBM antibodies in serum were negative, but perinuclear antineutrophil cytoplasmatic antibodies (p--ANCA) were detected. A renal biopsy revealed necrotizing glomerulonephritis with linear IgG deposits along the glomerular basement membrane. A diagnosis of pulmonary renal syndrome caused by anti-GBM antibodies and p-ANCA (double-positive) was made. Plasma exchange was started but had to be changed to immunoadsorption because of an allergic reaction to fresh frozen plasma. Oral steroids were introduced. The patient also received one dose of intravenous cyclophosphamide followed by two 1-g doses of rituximab. The patient responded quickly to treatment with resolution of pulmonary hemorrhage and urinary abnormalities. The infant was delivered in the 38th week of pregnancy by caesarian section. It was small for age but otherwise completely healthy with a normal B-cell count. CONCLUSION: To our knowledge, this is the first report of a double-positive pulmonary renal syndrome in pregnancy. Presentation in mid pregnancy allowed for the application of cyclophosphamide without causing malformations and rituximab without B-cell depletion in the infant.?. PMID- 30431432 TI - Peritoneal vasculopathy in the pathophysiology of long-term ultrafiltration failure: A hypothesis based on clinical observations?. AB - Ultrafiltration failure in long-term peritoneal dialysis patients is a well-known and important, but poorly-explained complication of the treatment. Transcapillary ultrafiltration consists mainly of small-pore fluid transport and partly of free water transport. The former is to a large extent dependent on the hydrostatic pressure gradient and on the number of perfused peritoneal microvessels. Free water transport depends mainly on the crystalloid osmotic gradient. A longitudinal analysis of peritoneal transport has shown a dramatic decrease of net ultrafiltration and small-pore fluid transport after 4 years of peritoneal dialysis. It will be argued that in contrast to common belief, a decrease of osmotically induced water transport cannot be the major contributor to long-term ultrafiltration failure. By exclusion of potential alternatives, the presence of vasculopathy in the peritoneal microcirculation is the most likely explanation. The resulting narrowing of vascular lumina will decrease the hydrostatic pressure gradient and thereby small-pore fluid transport and net ultrafiltration. Deposition of advanced glycosylation end products in peritoneal vessels may be important in the development of vasculopathy. This hypothesis is supported by morphological and functional results of dialysis with "biocompatible" solutions.?. PMID- 30431434 TI - Analysis of the adhesion activity of peritoneal macrophages after exposure to radiation from a gas-discharge plasma and mercury lamp. AB - The aim of the work was to study the influence of UV radiation of a spark discharge plasma and a mercury lamp on the state of membrane structures of peritoneal macrophages. The objects of the study were peritoneal macrophages of rats. The total number of cells after exposure and their viability were analyzed. Oxidative modification of proteins was recorded by fluorescence of tryptophan, tyrosine and products of non-enzymatic glycosylation of proteins. The concentration of sialic acids was determined spectrophotometrically, and the intensity of adhesion properties of cells was estimated by the ability to adhere to the plastic. It was shown that the radiation of a spark discharge plasma and UV lamp with the selected exposure regimes affect the structural components of membranes of peritoneal macrophages. The ability to adhere is enhanced by short exposure regimes, and under long-term conditions, adhesion properties decrease. The change in adhesion is probably associated with a decrease in the concentration of sialic acids on the cell surface, as well as with the intensification of oxidative modification of proteins. It has been established that spark plasma and UV lamp radiation promote the oxidation of aromatic amino acids and the accumulation of glycosylation products of proteins. PMID- 30431435 TI - Triiodothyronine improves age-induced glucose intolerance and increases the expression of sirtuin-1 and glucose transporter-4 in skeletal muscle of aged rats. AB - To evaluate the potential beneficial impact and to clarify the underlying mechanisms of triiodothyronine (T3) on glucose intolerance in aged rats. Rats were divided into adult group, aged group, and T3-treated aged group (T3-aged). T3 was administered at a dose of 8 ug/kg body weight for 2 weeks. In comparison to adult group, aged rats presented significant higher levels of fasting insulin and homeostatic model assessment of insulin resistance (HOMA-IR). Glucose area under the curve (AUC), and peak glycemia, estimated from oral glucose tolerance curve, were significantly increased along with decreased mRNA expression of skeletal muscle sirtuin-1, glucose transporter-4 (GLUT-4) and uncoupling protein 3 (UCP-3) in aged versus adult group. T3 administration significantly decreased the serum levels of fasting insulin, HOMA-IR, glucose AUC, and peak glycemia in T3-aged versus aged rats. Skeletal muscle mRNA expression of sirtuin-1 and GLUT-4 were increased, whereas UCP-3 was not changed by T3 administration. T3 administration improved glucose intolerance, and decreased insulin resistance in aged rats. This was associated with upregulation of skeletal muscle sirtuin-1 and GLUT-4 which could mediate such beneficial effect. PMID- 30431436 TI - Relationship of epigenetic variability of miR-124 to extracellular matrix remodelling and age-related MMP-3 expression in rheumatoid arthritis. AB - The aim of study was to examine relation among miR-124 and serum levels of selected cytokines and chemokines, MMP-3, production of auto-antibodies, and factors describing clinical activity (DAS28) and radiographic progression in rheumatoid arthritis (RA). A total of 80 RA patients according to the ACR classification criteria, and 32 control subjects were recruited into study. The measurements of miR-124 and U-6 expression, CRP, anti-CCP, rheumatoid factors (RFs), radiographs of both hands with calculation of total sharp score (TSS), DAS28 and cytokines, chemokines and MMP levels in serum were obtained from all RA patients. miR-124 was down-regulated in RA patients compared to controls (7-fold decrease). The miR-124 expression correlated to MMP-3 levels (p < 0.001), which were in multivariate analysis associated to age of RA onset. Higher levels were detected in younger subjects. No relation of miR-124 expression to measures of RA activity (DAS28 score; TSS), auto-antibodies (anti-CCP, RF, RF IgG, RF IgA, RF IgM), acute inflammatory markers (CRP, IL-6), and other cytokine and chemokines (IL-13, IL-15, IL-8, TNF-alpha, MCP-1, RANTES) was observed. In conclusion, we present a down-regulation of miR-124 in RA patients and its correlation to MMP-3 levels, which associated to age of RA onset. PMID- 30431433 TI - Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. AB - Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth. Moreover BRD9 and SS18-SSX co-localize extensively on the synovial sarcoma genome. Remarkably, synovial sarcoma cells are highly sensitive to a novel small molecule degrader of BRD9, while other sarcoma subtypes are unaffected. Degradation of BRD9 induces downregulation of oncogenic transcriptional programs and inhibits tumour progression in vivo. We demonstrate that BRD9 supports oncogenic mechanisms underlying the SS18-SSX fusion in synovial sarcoma and highlight targeted degradation of BRD9 as a potential therapeutic opportunity in this disease. PMID- 30431437 TI - Inhibition of cytochrome P450 by proadifen diminishes the excitability of brain serotonin neurons in rats. AB - The aim of this study was to investigate the effect an inhibitor of cytochrome P450, proadifen hydrochloride (SKF525), on the excitability of serotonin neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were stereotaxically inserted into the dorsal raphe nucleus (DRN). Serotonin neurons were identified and their firing activity was recorded. It was found that the SKF525 inhibits the excitability of 5-HT neurons. We suggest that corticosterone might play a key role in the SKF525-induced inhibition of 5-HT neurons. PMID- 30431438 TI - Exercise training and dietary restriction affect PINK1/Parkin and Bnip3/Nix mediated cardiac mitophagy in mice. AB - The aim of this study was to investigate the effects of exercise training and dietary restriction on cardiac PINK1/Parkin and Bnip3/Nix pathways involved in mitophagy. C57BL/6 mice were assigned to control (C), exercise training (T), dietary restriction (D) and exercise training + dietary restriction (TD) groups. T group undertook 10 weeks of swimming training. D group was subjected to 40% food reduction. TD group undertook the combination of exercise training and food reduction. Suspectable mitophagy autophagosomes can be observed in T and D groups and more autophagosomes appeared in TD group. In T group, both PINK1 mRNA and protein levels increased significantly (p < 0.01) but Bnip3 and Nix expressions decreased significantly (p < 0.05). Dietary restriction resulted in elevation of Drp1 (p < 0.01) and reduction and Nix (p < 0.05) in D group. The load in TD group resulted in serious mitochondrial abnormalities and myofibrillar damages accompanied by increases in PINK1 and Drp1 levels (p < 0.01) and decreases in Bnip3 and Nix levels (p < 0.05). The increase in PINK1 expression (exercise protocol) or Drp1 expression (diet protocol) contributes to cardiac activation of mitophagy, whereas Bnip3 and Nix are not implicated in this activation. PMID- 30431439 TI - Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2alpha-mediated tumor progression. AB - Macrophages perform key functions in tissue homeostasis that are influenced by the local tissue environment. Within the tumor microenvironment tumor associated macrophages can be altered to acquire properties that enhance tumor growth. Here, we found lactate, a metabolite found in high concentration within the anaerobic tumor environment, activated mTORC1 that subsequently suppressed TFEB-mediated expression of a macrophage-specific vacuolar ATPase subunit ATP6V0d2. Atp6v0d2-/- mice were more susceptible to tumor growth with enhanced HIF-2alpha-mediated VEGF production in macrophages that display a more protumoral phenotype. We found that ATP6V0d2 targeted HIF-2alpha but not HIF-1alpha for lysosome-mediated degradation. Blockade of HIF-2alpha transcriptional activity reversed the susceptibility of Atp6v0d2-/- mice to tumor development. Furthermore, in a cohort of patients with lung adenocarcinoma, expression of ATP6V0d2 and HIF-2alpha was positively and negatively correlated with survival respectively, suggesting a critical role of the macrophage lactate-ATP6V0d2-HIF-2alpha axis in maintaining tumor growth in human patients. Together, our results highlight the ability of tumor cells to modify the function of tumor-infiltrating macrophages to optimize the microenvironment for tumor growth. PMID- 30431440 TI - A Case Report of an Inadvertent Placement of Tracheostomy Tube Into the Pharynx After Emergency Tracheostomy: Management of a Failed Surgical Airway. AB - Inadvertent placement of a tracheostomy tube through the stoma with the distal tip cephalad in the pharynx is an unusual but potentially devastating complication. Previously reported only once in the literature, its occurrence is not well known. There are several causes of ineffective ventilation after an emergency surgical airway, and an incorrectly placed tracheostomy tube is a differential diagnosis to consider. Prompt identification of this rare complication is essential because the consequences can be fatal. We present a case describing the inadvertent insertion of a tracheostomy tube into the pharynx during emergency tracheostomy and its subsequent management. PMID- 30431441 TI - Airway Compression During Transcatheter Aortic Valve Replacement Via Subclavian Artery Approach: A Case Report. AB - Transcatheter aortic valve replacement (TAVR) is an alternative to traditional surgery in patients considered to be at high or intermediate risk for open surgical repair of aortic stenosis. Despite its overall safety and efficacy, TAVR is associated with potentially serious complications including major vascular injury. Tracheal compression resulting from vascular pathology has been previously reported; however, airway compromise secondary to vascular injury during TAVR has not been described. We report a case of airway compression and respiratory compromise resulting from injury to the right subclavian artery during TAVR. PMID- 30431442 TI - Perioperative Hypertensive Urgency After Methylene Blue in a Patient With Undiagnosed Pheochromocytoma: A Case Report. AB - We report the perioperative course of a 75-year-old woman undergoing robotic assisted laparoscopic hysterectomy and tumor debulking. The patient developed severe, persistent hypertension after intraoperative methylene blue administration requiring a Surgical Intensive Care Unit admission with further investigative evaluation revealing a previously undiagnosed pheochromocytoma. Our discussion focuses on the differential diagnoses for her perioperative hypertension. We evaluate whether methylene blue triggered a pheochromocytoma crisis in our patient and emphasize the caution and critical thinking we all should demonstrate while providing anesthetic care. PMID- 30431443 TI - Use of High-Dose Hydroxocobalamin for Septic Shock: A Case Report. AB - In this case report, we describe 2 patients with septic shock requiring high-dose vasopressors for hemodynamic support despite aggressive fluid resuscitation. After the administration of high-dose hydroxocobalamin for presumed septic vasoplegic syndrome, both patients had an immediate response to hydroxocobalamin with a rapid and lasting improvement of blood pressure that significantly reduced the need for vasopressor support. PMID- 30431444 TI - MicroRNA-200c promotes tumor cell proliferation and migration by directly targeting dachshund family transcription factor 1 by the Wnt/beta-catenin signaling pathway in nasopharyngeal carcinoma. AB - The purpose of the present study was to determine the crucial role of microRNAs (miRNAs/miRs) involved in the proliferation and migration of nasopharyngeal carcinoma (NPC) and to investigate their underlying mechanisms. In this study, we focused on the expression and function of miR-200c in NPC. First, we found the expression level of miR-200c in NPC cells and tissues was upregulated, and it was suggested that the high expression of miR-200c accelerated the proliferation and migration of NPC cells in vitro. Notably, a result of the present study was that the cell fate determination factor dachshund family transcription factor 1 (DACH1) was identified as a direct target of miR-200c. Suppression of miR-200c expression in NPC cells increased endogenous DACH1 mRNA and protein levels, which was negatively correlated with miR-200c. Meanwhile, DACH1 was shown to regulate the Wnt/beta-catenin signaling pathway. Accordingly, it was concluded that miR 200c exerted a tumor-promoting role in NPC development by targeting DACH1, which may contribute to the increase in the rates of NPC proliferation and migration. miR-200c may be a potential diagnostic and prognostic biomarker for NPC. PMID- 30431445 TI - Proposal of a new tDCS safety screening tool: TSST (Transcranial direct current stimulation Safety Screening Tool). PMID- 30431446 TI - Nipple-sparing Mastectomy and Immediate Breast Reconstruction After Recurrence From Previous Breast Conservation Therapy. AB - PURPOSE: Breast conservation therapy (BCT) is widely accepted for breast cancer treatment. Nipple-sparing mastectomy has been newly developed to preserve the nipple-areolar complex and enhance aesthetic results. The purpose of this study was to evaluate the oncological safety and results of nipple-sparing mastectomy (NSM) after previous BCT. METHODS: Eighteen patients who received NSM and immediate breast reconstruction for local recurrence after BCT were identified. An additional 127 affected breasts with NSM and immediate breast reconstruction for primary breast cancer were selected as the control group. The patient disease status, reconstructive method, postoperative complications, and oncological outcome were investigated. RESULTS: No apparent significant differences between the 2 groups were found regarding patient demographic data, tumor stage, reconstructive method, surgical complication, or tumor recurrence rate (all P values >0.05), except preoperative radiotherapy was higher in secondary NSM group (0% vs 77.8%, P < 0.001). The further nipple and secondary deep inferior epigastric artery perforator flap reconstruction rate was higher in the secondary NSM group (11.1% vs 0.8%, P = 0.041 and 16.7% vs 2.4%, P = 0.026, respectively). CONCLUSIONS: Prior BCT did not contribute to higher surgical complications in patients who received NSM and immediate reconstruction as a salvage procedure after tumor local recurrence. The oncological safety, general surgical result, and postoperative patient-reported satisfaction remain safe and reliable despite prior ipsilateral surgery and radiation. Care should be taken for possible higher nipple necrosis in the secondary NSM patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30431447 TI - Predicting mortality in patients with disseminated intravascular coagulation after cardiopulmonary bypass surgery by utilizing two scoring systems. AB - : We evaluated clinical and laboratory biomarkers of disseminated intravascular coagulation (DIC) following cardiac surgery in the cardiothoracic surgical ICU (CTICU) to predict mortality. We retrospectively analyzed CTICU patients with suspected DIC identified from the hospital laboratory database, and calculated International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM) DIC scores to predict DIC-related mortality. The predictive accuracy of the JAAM and ISTH DIC scoring system were then assessed by logistic regression analysis and receiver operative characteristics analysis, and compared to other potential predictors of mortality (e.g., Acute Physiology and Chronic Health Evaluation II, systemic inflammatory response syndrome criteria, laboratory variables). Our study showed a 30-day mortality rate of 71% in CTICU patients with DIC. The JAAM DIC score offered the best predictive accuracy [area under the curve (AUC): 0.723, 95% % confidence interval (CI): 0.638-0.947, P = 0.021], when compared with ISTH DIC score (AUC: 0.707, 95% CI: 0.491-0.923, P = 0.066) and Acute Physiology and Chronic Health Evaluation II (AUC: 0.687, 95% CI: 0.483-0.891, P = 0.110). A JAAM DIC score at least 6 was reported in 89% of the nonsurvivors and 46% of survivors (P = 0.010), and predicted mortality [odds ratio: 9.33 (1.50-58.20)] with a 73% sensitivity and a 78% specificity. Our results also show a strong relationship between acid base derangement and mortality. This initial evaluation of DIC-related mortality in the CTICU found the standardized JAAM DIC scoring system in combination with acid-base laboratory values were most useful to predict mortality in postcardiac surgery patients with DIC. Additional prospective studies are needed to further validate our findings. PMID- 30431448 TI - Probable drug-drug interaction between dabigatran and quinidine resulting in thrombin time rebound despite multiple idarucizumab doses. AB - : Dabigatran is a direct thrombin inhibitor that was approved as an alternative to warfarin because it offers the benefit of predictable pharmacokinetic properties, favorable safety profile and ease of administration. Despite the improved safety profile, dabigatran use can lead to bleeding events. The bleeding risk associated with dabigatran is higher in the setting of renal impairment or drug-drug interactions resulting in supratherapeutic serum concentrations. Unfortunately, clinically significant interactions are not always identified by providers, especially in the case of infrequent drug-drug combinations. Dabigatran-related coagulopathy can be effectively reversed by idarucizumab. However, high dabigatran serum concentrations can lead to increased tissue distribution resulting in decreased idarucizumab efficacy and repeat idarucizumab doses may be warranted. This case describes a patient presenting with uncontrolled bleeding due to a significant drug-drug interaction between quinidine and dabigatran resulting in acute kidney injury and persistent coagulopathy despite multiple idarucizumab doses and transfusion measures. PMID- 30431449 TI - Safe childbirth for a type 1 antithrombin-deficient woman with novel mutation in the SERPINC1 gene undergoing antithrombin concentrate therapy. AB - : Inherited antithrombin (AT) deficiency is an autosomal dominant thrombotic disorder. We encountered a case of inherited type I AT deficiency and identified the causative mutation; a novel c.7430A>G missense mutation in the SERPINC1 gene in which tyrosine was substituted for cysteine at the 292nd amino acid. A recombinant AT protein with the 7430A>G mutation was not detected in cell lysates or culture supernatants. And then, our patient without personal or family history of thrombosis was pregnant woman with asymptomatic AT deficiency. Our patient treated with only AT concentrate therapy during pregnancy and she was able to safely give birth naturally and avoid thrombosis. We believe that this therapy for pregnant woman with asymptomatic AT deficiency is effective and safety as anticoagulant therapy during pregnancy. PMID- 30431450 TI - Validation of the short form of the International Crowding Measure in Emergency Departments: an international study. AB - OBJECTIVE: There is little consensus on the best way to measure emergency department (ED) crowding. We have previously developed a consensus-based measure, the International Crowding Measure in Emergency Departments. We aimed to externally validate a short form of the International Crowding Measure in Emergency Department (sICMED) against emergency physician's perceptions of crowding and danger. METHODS: We performed an observational validation study in seven EDs in five different countries. We recorded sICMED observations and the most senior available emergency physician's perceptions of crowding and danger at the same time. We performed a times series regression model. RESULTS: A total of 397 measurements were analysed. The sICMED showed moderate positive correlations with emergency physician's perceptions of crowding, r=0.4110, P<0.05) and safety (r=0.4566, P<0.05). There was considerable variation in the performance of the sICMED between different EDs. The sICMED was only slightly better than measuring occupancy or ED boarding time. CONCLUSION: The sICMED has moderate face validity at predicting clinician's concerns about crowding and safety, but the strength of this validity varies between different EDs and different countries. PMID- 30431451 TI - Encouraging Faculty to Teach Online: Leveraging Rogers' Diffusion of Innovation Theory. PMID- 30431452 TI - A Medical Student Inquiry Behavior Assessment Tool: Development and Validity Evidence. AB - PURPOSE: The University of California, San Francisco (UCSF) School of Medicine's Bridges curriculum is designed to teach inquiry: the process of approaching problems with curiosity, challenging current concepts, and creating new knowledge. The authors aimed to develop and gather validity evidence for a tool to guide development of medical student inquiry behaviors in small groups. METHOD: The authors reviewed the literature to identify inquiry behaviors, verified findings with an expert focus group, and synthesized the results into 40 behaviors. In a modified two-round Delphi survey in 2016, faculty and students rated the behaviors for inclusion in the tool. Feedback from cognitive interviews and a pilot helped refine the tool. In 2016-2017, the authors implemented the final tool for 152 first-year UCSF medical students in inquiry small groups as both a faculty assessment and a student self-assessment each quarter. RESULTS: The two-round response rate was 77% (36/47). Five behaviors were selected for inclusion in the tool: select relevant questions to pursue, justify explanations with evidence, critically evaluate his/her explanation in light of alternative possibilities, allow for the possibility that his/her own knowledge may not be completely correct, and collaborate well with peers. During implementation, faculty and student scores increased on most items, indicating skills development over time. Content, response-process, internal structure, and consequential validity evidence is presented. CONCLUSIONS: The tool's five items are observable, measurable core inquiry behaviors. The tool is ready for use by small group facilitators within inquiry-based curricula to promote student self assessment and guide feedback to students. PMID- 30431453 TI - Computing for Medicine: Can We Prepare Medical Students for the Future? AB - PROBLEM: Technology can transform health care; future physicians need to keep pace to ensure optimal patient care. Because future doctors are poorly prepared in computer literacy, the authors designed a computer programming certificate course. This Innovation Report describes the course and findings from a qualitative study to understand the ways it prepares medical students to use computing science and technology in medicine. APPROACH: The 14-month Computing for Medicine certificate course (C4M, offered beginning in February 2016), University of Toronto, was comprised of hands-on workshops to introduce programming accompanied by homework exercises, seminars by computer science experts on the application of programming to medicine, and coding projects. Using purposive and maximal variation sampling, 17 students who completed the course were interviewed from April-May 2017. Thematic analysis was performed using an iterative constant comparison approach. OUTCOMES: Participants praised the C4M as an opportunity to achieve computer literacy-including language, syntax, and fundamental computational ideas (and their application to medicine)-and acquire or strengthen algorithmic and logical thinking skills for approaching problems. They highlighted that the course illustrated linkages between computer science and medicine. Participants acknowledged a sometimes existent chasm between producers and users of technology in medicine, recommending two-way communication between the disciplines when developing technology for use in medicine. NEXT STEPS: We recommend medical schools consider computer literacy an essential skill to foster future collaborative computing partnerships for improved technology use by physicians and optimal patient care. We encourage further evaluation of future iterations of the C4M and similar courses.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30431454 TI - An Electronic Interview Tracking Tool to Guide Medical Students Through the Match: Improvements in Advising and Match Outcomes. AB - PROBLEM: Medical students are applying to increasing numbers of residency programs to increase their likelihood of success in the Match. However, they have limited data to help them understand their level of competitiveness or identify programs to which they should apply. APPROACH: In 2014-2015 (Match year 2015), the University of Maryland School of Medicine's (UMSOM's) Office of Student Affairs (OSA) implemented an electronic interview tracking tool in which students update their residency application interview status on an ongoing basis. OSA deans can filter and sort data by student, specialty, program, academic metrics, and interview status. The deans use these data to advise students in real time, provide students with examples of programs to consider, and engage clinical faculty to support students at risk of not matching. OUTCOMES: In the Match years 2015, 2016, and 2017, respectively, 86% (n = 135/157), 87% (n = 138/159), and 94% (n = 151/161) of UMSOM students participated actively in this tracking tool, adding over 3,000 data points per year. Following the tool's launch, the average number of applications per student per remained stable. The UMSOM's Match rate and percentages of students self-reporting a match in their top three choices and rating the school's advising as "very useful" all increased, without comparable increases in national data. NEXT STEPS: This tool, which provides students with data-driven examples of programs to which they should consider applying, may be beneficial to students, faculty, and program directors at other institutions-and to the residency application process, if adopted broadly.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30431455 TI - Swimming Against the Tide: Challenges in Pursuing Health Equity Today. AB - The term "health equity" has moved from obscurity to the mainstream, creating new possibilities for those who aspire to a world in which everyone has a fair and just opportunity to be healthy. One can now talk explicitly about health equity. The newfound acceptance, however, carries a risk: loss of meaning. Recognizing the need for a common understanding of the core concepts, the Robert Wood Johnson Foundation has promoted a definition that prioritizes being sufficiently concrete to guide action. Lack of conceptual clarity is, unfortunately, not the only challenge in pursuing health equity. Another challenge is the lack of respect for fundamental ethical and human rights principles-cornerstones of health equity displayed almost daily by those in positions of power, including the president; this lack of commitment to fundamental values has an insidiously toxic effect because many people assume that presidential views must be legitimate. Yet another challenge is lack of imagination. Pursuing health equity inevitably requires swimming against the tide of prevailing forces that exclude, marginalize, or otherwise disadvantage groups of people based on their skin color, wealth, gender, disabilities, sexual orientation, gender identity, religion, or other characteristics tightly linked with social advantage. To persist in swimming against the tide, the end goal and the reason for pursuing it must be very strong and very clear. Academic medicine can play an important role as a powerful force in setting norms and shaping the values and attitudes of medical students, attending physicians, and research faculty. PMID- 30431456 TI - Assuring Integrity in the Residency Match Process. AB - Integrity in medicine is essential. One of the most important competencies a medical student can master is to be honest at all times. Indeed, professionalism is a key competency in the identity formation and development of a medical student. At times, this competency becomes challenged during the resident matching process. The behavior of some students, faculty members, and program directors who participate in the residency program selection process (the Match) often falls short of this ideal when it comes to handling the process that will be most dispositive in directing the future careers of graduating medical students. Violations of both National Resident Matching Program (NRMP) rules and ethical norms have been reported in the literature and experienced by students. In this Invited Commentary, the authors recommend a series of reforms. Substantially more robust enforcement of NRMP rules should be considered, including the creation of an avenue for anonymous reporting by applicants who experience inappropriate pre-Match, post-interview communications. PMID- 30431457 TI - Normalizing cVEMPs: Which Method Is the Most Effective? AB - OBJECTIVES: To determine the most effective method for normalizing cervical vestibular evoked myogenic potentials (cVEMPs). DESIGN: cVEMP data from 20 subjects with normal hearing and vestibular function were normalized using 16 combinations of methods, each using one of the 4 modes of electromyogram (EMG) quantification described below. All methods used the peak to peak value of an averaged cVEMP waveform (VEMPpp) and obtained a normalized cVEMP by dividing VEMPpp by a measure of the EMG amplitude. EMG metrics were obtained from the EMG within short- and long-duration time windows. EMG amplitude was quantified by its root-mean-square (RMS) or average full-wave-rectified (RECT) value. The EMG amplitude was used by (a) dividing each individual trace by the EMG of this specific trace, (b) dividing VEMPpp by the average RMS or RECT of the individual trace EMG, (c) dividing the VEMPpp by an EMG metric obtained from the average cVEMP waveform, or (d) dividing the VEMPpp by an EMG metric obtained from an average cVEMP "noise" waveform. Normalization methods were compared by the normalized cVEMP coefficient of variation across subjects and by the area under the curve from a receiver-operating-characteristic analysis. A separate analysis of the effect of EMG-window duration was done. RESULTS: There were large disparities in the results from different normalization methods. The best methods used EMG metrics from individual-trace EMG measurements, not from part of the average cVEMP waveform. EMG quantification by RMS or RECT produced similar results. For most EMG quantifications, longer window durations were better in producing receiver-operating-characteristic with high areas under the curve. However, even short window durations worked well when the EMG metric was calculated from the average RMS or RECT of the individual-trace EMGs. Calculating the EMG from a long-duration window of a cVEMP "noise" average waveform was almost as good as the individual-trace-EMG methods. CONCLUSIONS: The best cVEMP normalizations use EMG quantification from individual-trace EMGs. To have the normalized cVEMPs accurately reflect the vestibular activation, a good normalization method needs to be used. PMID- 30431458 TI - Comparison of chitinase-3-like protein 1, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 index with shear-wave elastography. AB - BACKGROUND: In the past, there has been an exponential increase in the potential biomarkers that can be used for staging of liver fibrosis. In light of intraobserver and intralobular variations, criticism has been directed at liver biopsy, and its efficacy has been challenged. Shear-wave elastography (SWE) has become a routine method for pre-assessment of liver fibrosis. Serum markers such as chitinase-3-like protein 1 (CHI3L1) also known as YKL-40, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 (Fib-4) index have been researched as potential alternates to detect liver fibrosis. STUDY: A total of 150 enrolled patients with chronic hepatitis underwent serum analysis to estimate CHI3L1 or YKL-40 level, aspartate aminotransferase-to-platelet ratio index, and Fib-4 index. These patients also underwent SWE. RESULTS: The distribution of fibrosis grade according to SWE was F0: 46 patients, F1: 31 patients, F2: 16 patients, F3: four patients, and F4: 53 patients. Receiver operating characteristic curve analysis for F0-F1 versus F2-F3, F0-F1 versus F4, and F2-F3 versus F4 gave area under curve values of 0.56 (P>0.05), 0.76 (P<0.01), and 0.75, respectively (P<0.01) for aspartate aminotransferase-to-platelet ratio index; of 0.65 (P<0.05), 0.78 (P<0.01), and 0.7, respectively (P<0.05) for Fib-4 index; and 0.98, 0.99, and 0.95, respectively (P<0.01 for all) for CHI3L1. CONCLUSION: CHI3L1 could be used as a preliminary tool to assess mild/absent fibrosis from significant fibrosis and cirrhosis. PMID- 30431459 TI - Maori: living and dying with cardiovascular disease in Aotearoa New Zealand. AB - PURPOSE OF REVIEW: This article provides an informed perspective on cardiovascular disease (CVD) and palliative care need among Maori New Zealanders. High Maori CVD risk factors will contribute to a sharp increase in older Maori deaths which has implications for health and palliative care service provision. RECENT FINDINGS: CVD is New Zealand's leading cause of premature deaths and disability among Maori. A projected rise in older Maori deaths within the next 30 years will require increased palliative care. However, accessing palliative care and obtaining and understanding information can be challenging for families who are already often overburdened with high social and economic disadvantages. Meeting the high financial costs associated with end-of-life care make living with CVD challenging. Engaging with the health system's biomedical approach when holistic care is preferable can be a major barrier. SUMMARY: Maori families provide the bulk of care at end-of-life, but they can become fatigued with the challenges that accompany long-term progressive illnesses, such as CVD. They are also burdened by the financial costs associated with end-of-life. It is often difficult for Maori to access palliative care and to obtain and understand information about the illness and treatment. Navigating an unfamiliar and complex health system, low health literacy among Maori and poor relationship building and communication skills of health professionals are significant barriers. Cultural safety training would help to increase health and cardiovascular professionals' cultural understanding of Maori and their holistic end-of-life preferences; this could go some way to strengthen rapport building and communication skills necessary for effective engagement and informational exchanges. Increasing the Maori palliative care workforce and introducing cultural safety training among health professionals could help to bridge the gap. A current study to gather traditional care customs and present these to whanau and the health and palliative care sectors in the form of an online resource could contribute to this decolonizing objective. PMID- 30431460 TI - Dilemmas and challenges in apolipoprotein L1 nephropathy research. AB - PURPOSE OF REVIEW: The purpose of this mini-review is to highlight some unresolved questions and controversies in the evolving story of apolipoprotein L1 (APOL1) nephropathy. RECENT FINDINGS: We highlight studies that introduce complexity in unraveling the mechanisms whereby APOL1 risk variant alleles cause disease. These include studies which support a possible protective role for the APOL1 GO nonrisk ancestral allele, and studies which explore the initiating events that may trigger other downstream pathways mediating APOL1 cellular injury. We also review studies that reconcile the perplexing findings regarding APOL1 anionic or cationic conductance, and pH dependency, and also studies that attempt to characterize the 3-dimensional structure of APOL1 C-terminal in APOL1 variants, as well as that of the serum resistance-associated protein. We also attempt to convey new insights from in-vivo and in-vitro models, including studies that do not support the differential toxicity of APOL1 renal risk variants and recapitulate the clinical variability of individuals at genotypic risk. SUMMARY: Along with major progress that had been achieved in the field of APOL1 nephropathy, controversies and enigmatic issues persist. It remains to be determined which of the pathways which have been demonstrated to mediate cell injury by ectopically expressed APOL1 risk variants in cellular and organismal models are relevant to human disease and can pave the way to potential therapy. PMID- 30431461 TI - Immigration, screening, and cervical cancer incidence: an application of Age Period-Cohort analysis. AB - Cervical cancer (CC) control is based on the implementation of effective screening programs. In the coming years, human papilloma virus vaccination coverage will contribute considerably toward cancer prevention. In Italy, where an organized screening program has been implemented, immigration from low/middle income countries with a high prevalence of human papilloma virus infections has increased steadily over the last decades. To assess the impact of screening efforts in counteracting background changes, we analyzed the incidence trends of cervical intraepithelial neoplasia grade 3 carcinomas in situ (CIS) and invasive CC from 1994 to 2013 through an Age-Period-Cohort model using data of a regional population-based registry. Moreover, using Joinpoint regression, we compared the incidence of cervical lesions in native women with that observed in foreign-born women, highlighting the differences in age and screening status. The results indicate that the CC incidence trend decreased in Italian women (annual percent change =-2.7*%, 95% confidence interval=-4.3; -1.1), but increased (annual percent change=12.2*%, 95% confidence interval=7.6; 17.0) in immigrants. For CIS, incidence rates show a growing trend in both groups, especially in women born abroad. For cancer, no marked changes in period-specific incidence rate ratios were detected until around 2000, when we found a slight decrease, followed by an increase. For CIS, we estimate an important upward trend in cohort-specific risks. The favorable effect of screening in preventing an increase in CC incidence has been counteracted by the progressive increase in immigrants from high-risk countries, where it is of increasing relevance to extend the use of vaccination. PMID- 30431462 TI - Avoiding physician burnout through physical, emotional, and spiritual energy. AB - PURPOSE OF REVIEW: The purpose of this review is to update the physician community on current evidence regarding ways individuals can combat the rise in physician burnout. More than half of US physicians are experiencing at least some degree of burnout and the incidence has increased significantly over the past decade. RECENT FINDINGS: Recent findings suggest practicing physical, mental, and emotional self-care are important factors in avoiding physician burnout. Current evidence demonstrates that physical exercise can improve mood, enhance one's ability to deal with stress, and promote high-quality sleep. New research in the field of nutritional psychiatry supports the association between diet and mental health. A recent study found that the risk of depression is lower in people who eat a diet high in fruits, vegetables, unprocessed grains, and low amounts of animal and dairy products. In addition, there is a growing body of evidence that practicing mindfulness meditation can help reduce the symptoms of physician burnout by reducing stress and improving physical and emotional well-being. SUMMARY: The implications of decreasing physician burnout are improved patient safety, job retention, monetary savings, and better patient care. PMID- 30431463 TI - Mechanisms of leukemic transformation in congenital neutropenia. AB - PURPOSE OF REVIEW: The development of a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia is now the major cause of mortality. Treatment options are limited and there are no effective prevention strategies. This review focuses on mechanisms of leukemic transformation in severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS), the two most common types of congenital neutropenia. RECENT FINDINGS: AML/MDS that develops in the setting of congenital neutropenia has distinct molecular features. Clonal hematopoiesis because of TP53 mutations is seen in nearly 50% of patients with SDS, but is not seen in patients with SCN. Accordingly, there is a very high frequency of TP53 mutations in AML/MDS arising in the setting of SDS but not SCN. The rate of mutation accumulation in hematopoietic stem cells (HSCs) from patients with congenital neutropenia is not increased. SUMMARY: Both HSC cell-intrinsic and noncell-intrinsic changes contribute to the development of clonal hematopoiesis in congenital neutropenia and likely accounts for the high rate of leukemic transformation. In SCN, the persistently high levels of granulocyte colony-stimulating factor drive expansion of HSCs carrying truncation mutations of CSF3R. In SDS, impaired ribosome biogenesis induces p53-mediated growth inhibition and drives expansion of HSCs carrying TP53 mutations. PMID- 30431464 TI - The Impact of Individual and Parental American Indian Boarding School Attendance on Chronic Physical Health of Northern Plains Tribes. AB - This study investigated the relationship of American Indian boarding school attendance and chronic physical health. We hypothesized boarding school attendance would be associated with an increased number of chronic physical health problems. We also examined the relationship between boarding school attendance and the 15 chronic health problems that formed the count of the chronic health conditions. American Indian attendees had a greater count of chronic physical health problems compared with nonattendees. Father's attendance was independently associated with chronic physical health problems. Attendees were more likely to have tuberculosis, arthritis, diabetes, anemia, high cholesterol, gall bladder disease, and cancer than nonattendees. PMID- 30431465 TI - The Role of Collective Efficacy in Reducing Health Disparities: A Systematic Review. AB - Many improvements in health equity are spearheaded by community collaborations working to change policy and social norms. But how can collective efficacy (CE), defined as the willingness and ability of a group to work toward a common good, be increased? Eight articles reporting on interventions aiming to reduce health disparities by improving CE were found for this systematic literature review. All studies showed improvements in CE and most found reduction in disparities, but operationalization of CE varied. Findings support a model of how CE can address health disparities, which can guide standardization of CE interventions and measures. PMID- 30431466 TI - Identifying Food Insecurity in Health Care Settings: A Systematic Scoping Review of the Evidence. AB - This systematic scoping review explores evidence on food insecurity (FI) screening measures, acceptability, and program implementation in health care settings. Validation studies on brief screening tools suggest that instruments exist that adequately measure the construct of FI. Patients and clinicians found FI screening acceptable in a range of clinical settings, though studies are not high quality and rarely reflect substantial patient diversity. Targeted interventions successfully increased screening rates and reduced screening barriers. More research is needed to understand implementation and effectiveness of FI screening in diverse populations to ensure that evolving practices in this area do not widen health inequities. PMID- 30431467 TI - Testing the Efficacy of a Web-Based Parent-Adolescent Sexual Communication Intervention Among Puerto Ricans. AB - This randomized controlled trial tested the efficacy of a Web-based intervention to increase sexual communication between parents and adolescents. Parent/adolescent dyads (n = 660) were recruited from communities in the San Juan area and randomly assigned to the Cuidalos sexual communication or physical activity program. Parent assessments were obtained preintervention and at 3-, 6-, and 12-month follow-up. Parents in the experimental group reported significantly more sexual communication (ie, peer pressure, sexual prevention, protection, risk) over time than parents in the control group. Results support the efficacy of the Cuidalos Web-based format and provide insight into future Web-based sexual health interventions for this population. PMID- 30431468 TI - Social Network Gap Analysis Evaluation: A Case Study of the Southeastern Health Equity Council. AB - Despite the growing emphasis on collaboration in public health, there remains a dearth of literature providing tools for the evaluation of coalitions and councils. This study employed social network gap analysis as an evaluation tool. Survey data collected from the Southeastern Health Equity Council members were used to assess connections among members as a whole, by committee, by state, and by health specialty area. Analysis of how well Southeastern Health Equity Council met the representation outlined in its strategic plan was also conducted. Recommendations for improving the network and opportunities to effectively recruit and advance the work of Southeastern Health Equity Council are discussed. PMID- 30431469 TI - Maternal Social and Economic Factors and Infant Morbidity, Mortality, and Congenital Anomaly: Are There Associations? AB - Experiences during infancy create durable and heritable patterns of social deprivation and illness producing health disparities. This retrospective cohort study of 71 836 infants from Winnipeg, Manitoba, assessed associations between maternal social and economic factors and infant mortality, morbidity, and congenital anomaly. This study found that newborn and postneonatal hospital readmissions are inversely associated with geography. Additionally, social context, including maternal history of child abuse, is associated with infant postneonatal hospital readmissions. Geography and education are associated with infant mortality. Income was not associated with infant mortality or morbidity following adjustment for social support. Interestingly, congenital anomaly rates are 1.2 times more common among 2 parent families and male infants. Understanding associations between infant health and maternal social and economic factors may contribute to interventions and policies to improve health equity. PMID- 30431470 TI - Building and Sustaining Community Capacity to Address Childhood Obesity: A 3-Year Mixed-Methods Case Study of a Community-Academic Advisory Board. AB - Guided by a community-based participatory research and systems-based approach, this 3-year mixed-methods case study describes the experiences and capacity development of a Community-Academic Advisory Board (CAB) formed to adapt, implement, and evaluate an evidence-based childhood obesity treatment program in a medically underserved region. The CAB included community, public health, and clinical (n = 9) and academic partners (n = 9). CAB members completed capacity evaluations at 4 points. Partners identified best practices that attributed to the successful execution and continued advancement of project goals. The methodological framework and findings can inform capacity development and sustainability of emergent community-academic collaborations. PMID- 30431471 TI - Editorial: The future of sarcopenia. PMID- 30431472 TI - Evaluation of Big Bubble Technique for Deep Anterior Lamellar Keratoplasty in Patients With Radial Keratotomy. AB - PURPOSE: To report the outcome of deep anterior lamellar keratoplasty (DALK) and success rates of the big-bubble (BB) technique or manual dissection after a failed use of the BB technique in eyes that underwent prior radial keratotomy (RK). METHODS: A retrospective chart review of patients who underwent DALK after RK at Toronto Western Hospital, Canada, between 1999 and 2017 was performed. Demographic characteristics, success rates of the BB technique and manual dissection, intraoperative and postoperative complications, and best spectacle corrected visual acuity before and after corneal transplant were analyzed. RESULTS: Ten eyes of 9 patients were included in the analysis. The average age was 64 +/- 10 years (range 49-82). The average time between the RK surgery and the corneal transplant was 20 +/- 5 years (range 8-24). Indications for corneal transplant were significant irregular astigmatism in 5 eyes (50%), central scarring or haze in 4 eyes (40%), and progressive hyperopia with visual fluctuation in one eye (10%). BB was successfully achieved in one eye (10%). In 6 eyes (60%), manual dissection was performed, and in 3 eyes (30%), DALK surgery was converted to penetrating keratoplasty. The average best spectacle-corrected visual acuity on the last follow-up visit was 0.26 +/- 0.08 logMAR (Snellen equivalent 20/36). One eye that underwent manual DALK and one eye that underwent penetrating keratoplasty developed a rejection episode 4 and 2 months after keratoplasty, respectively. In both cases, rejection resolved with topical steroids. CONCLUSIONS: In eyes that underwent prior RK, DALK by manual dissection should be considered as a preferable surgical technique. PMID- 30431473 TI - Repeatability of Meibomian Gland Contrast, a Potential Indicator of Meibomian Gland Function. AB - PURPOSE: Meibomian gland contrast may be a potential indicator of gland health, especially among isotretinoin users. We aimed to develop a repeatable and reliable method for measuring Meibomian gland contrast from meibography images. METHODS: Lower lid (LL) and upper lid (UL) meibography were captured with the OCULUS Keratograph 5M (OCULUS, Inc) at 2 visits under the following 4 conditions: face centered with room lights on (C), left-turned face (L), right-turned face (R), and face centered with room lights off (CLO). Contrast was measured with Fiji (v2.0.0-rc-59). Coefficient of repeatability and limits of agreement (LOA) were determined using Bland-Altman plots. RESULTS: A total of 512 meibography images from 16 subjects (age +/- SD = 24.8 +/- 5.2 years; 13 female patients) were collected. Coefficient of repeatability between visits was 10.5 for UL and 14.9 for LL. Lower and upper LOA, respectively, for UL, compared with condition C, were -10.9 [95% confidence interval (CI), -13.5 to -8.3] and 6.2 (95% CI, 3.6 8.8) for L; -11.0 (95% CI, -13.8 to -8.1) and 7.0 (95% CI, 4.2-9.8) for R; and 9.0 (95% CI, -11.6 to -6.5) and 7.2 (95% CI, 4.7-9.8) for CLO. Lower and upper LOA, respectively, for LL, compared with condition C, were -18.1 (95% CI, -22.6 to -13.5) and 11.0 (95% CI, 6.5-15.5) for L; -15.3 (95% CI, -19.2 to -11.3) and 9.9 (95% CI, 6.0-13.9) for R; and -12.0 (95% CI, -15.1 to -8.8) and 8.2 (95% CI, 5.0-11.3) for CLO. CONCLUSIONS: Meibomian gland contrast is a repeatable and reliable measure for changes in Meibomian gland contrast greater than 11 in the UL and 18 in the LL. PMID- 30431474 TI - Anterior Segment Complications Associated With the Live Herpes Zoster Vaccine. PMID- 30431475 TI - Reply. PMID- 30431476 TI - Secondary Union of a Critical Segmental Femoral Defect: A Case Report. AB - CASE: We report the case of a 41-year-old man who sustained an open femoral shaft fracture with 10 cm of segmental bone loss in a motorcycle collision. He underwent serial irrigation and debridement procedures and intramedullary nailing of the fracture. He was lost to follow-up, but presented 9 months after the injury with abundant callus formation; at 11 months, the simple hypertrophic nonunion was treated with exchange nailing. CONCLUSION: Although unusual, secondary union of segmental femoral defects may occur. The mechanism by which this occurs is poorly understood, but is likely related to the biology of the fracture site, the effects of reaming, and the mechanics of the fixation. PMID- 30431477 TI - Late Presentation of Developmental Hip Dislocation: A Case Report. AB - CASE: We describe a patient who was diagnosed with developmental hip dislocation at 21 months of age despite having had normal ultrasonography findings at 5 weeks of age. CONCLUSION: This case report provides evidence that late developmental hip dislocation can occur despite normal clinical and sonographic findings early in life, and that it is difficult to know the cause of developmental hip dislocation when it presents late. PMID- 30431478 TI - Bacterial Arthritis of the Hip Due to Lemierre Syndrome: A Case Report. AB - CASE: A 20-year-old woman presented to the emergency department with a painful left hip. Clinical evaluation and investigation led to the diagnosis of bacterial arthritis of the left hip. After undergoing an irrigation and debridement, the patient became hypoxic and critically ill from sepsis due to Lemierre syndrome. CONCLUSION: Lemierre syndrome is a rare clinical scenario that may present with bacterial arthritis secondary to septic embolization. Patients have anaerobic bacteremia and diffuse septic embolization that may spread to a joint and the lungs. This syndrome has substantial morbidity and mortality. PMID- 30431479 TI - Septic Nonunion Caused by Mycobacterium canariasense: A Case Report. AB - CASE: A 43-year-old former drug user presented with a mycobacterium-caused septic nonunion of the humeral shaft. The patient had undergone 2 previous surgeries for a hematogenous fracture-related infection due to Staphylococcus aureus. The procedures had included debridement, double-plate osteosynthesis, and placement of a gentamicin-loaded bone substitute. Culture specimens produced growth of Mycobacterium canariasense. Because the microbiological diagnosis was obtained after the patient had been discharged, no antibiotic treatment could be prescribed. Nevertheless, solid bone fusion was observed in the most recent outpatient examination. CONCLUSION: This case illustrates the importance of considering atypical pathogens in patients who are immunoincompetent. To the best of our knowledge, this is the first reported case of septic nonunion caused by M. canariasense. PMID- 30431480 TI - Pyoderma Gangrenosum Following Carpal Tunnel Release: A Case Report. AB - CASE: A 51-year-old woman with diabetes developed wound complications consistent with presumed infection 5 days after undergoing a carpal tunnel release. Despite multiple debridements, the wounds continued to necrose and deteriorate. A diagnosis of pyoderma gangrenosum eventually was made, and the condition improved with the administration of systemic corticosteroids. CONCLUSION: Pyoderma gangrenosum, a form of neutrophilic dermatosis that rarely occurs as a complication of surgery, resembles a postoperative infection. Astute awareness of the condition can prevent a delayed diagnosis and unnecessary surgical procedures. PMID- 30431481 TI - Nonvalvular atrial fibrillation in high-hemorrhagic-risk patients: state of the art of percutaneous left atrial appendage occlusion. AB - : Atrial fibrillation is the most common cardiac arrhythmia and its prevalence is constantly increasing. The main complications related to atrial fibrillation are death and major stroke. Oral anticoagulant therapy is the cornerstone of management of atrial fibrillation patients at increased stroke risk. Unfortunately, a significant proportion of patients do not receive adequate anticoagulant therapy due to increased or prohibitive hemorrhagic risk. The observation that most thrombi are generated in the left atrial appendage (LAA) had led to the consideration of surgical or percutaneous occlusion as an alternative. During recent years, the WATCHMAN percutaneous occlusion device has proven to be not inferior to anticoagulant therapy for the prevention of thromboembolic events, with the added benefit of a lower rate of hemorrhagic events. Numerous data showed the same results for the AMPLATZER cardiac plug and Amulet devices. Left atrial appendage occlusion (LAAO) often represents the only therapeutic strategy in this group of patients. We describe the current state of the art of percutaneous LAAO in atrial fibrillation patients with a high hemorrhagic risk. PMID- 30431482 TI - Predictive value of achieved blood pressure for cardiac events in the long-term follow-up of heart transplant recipients. AB - BACKGROUND: A low diastolic blood pressure (DBP) is associated with increased cardiovascular events in patients with coronary artery disease or chronic kidney disease. AIM: The aim of this study was to assess the association of blood pressure with cardiac events during the long-term follow-up of heart transplant recipients. PATIENTS AND METHODS: In this prospective cohort study, we performed ambulatory blood pressure monitoring and home blood pressure monitoring in 76 transplant heart recipients 13.5+/-6.6 years after transplantation. The patients were followed for 54+/-17 months after blood pressure monitoring. RESULTS: Twenty one patients had a cardiac event (cardiac death, acute coronary event, coronary revascularization procedure, and hospitalization for heart failure) during the follow-up. In the Kaplan-Meier survival analysis, we found that a DBP below the median value (<81 mmHg) was associated significantly with cardiac events (log rank: P=0.01). In a multivariate model, plasma creatinine and left ventricular ejection fraction (LVEF), but not DBP, were associated significantly with cardiac events. Low DBP was associated significantly with LVEF less than 55% (P=0.004). CONCLUSION: A DBP below the median value predicts cardiac events during the long term follow-up of heart transplant recipients, but is not an independent predictor. The association between low DBP and low LVEF explains at least in part the predictive value of low DBP. PMID- 30431483 TI - Gabapentin Abuse by Nasal Insufflation: A Case Report. PMID- 30431484 TI - Methotrexate-Induced Vasculitis in a Child with Systemic Onset Juvenile Idiopathic Arthritis. PMID- 30431485 TI - Rheumatoid Arthritis Presenting With Polyserositis and Fever. PMID- 30431486 TI - Serum Interleukin 35 Levels in Systemic Sclerosis and Relationship With Clinical Features. AB - BACKGROUND/OBJECTIVE: Interleukin (IL) 35 is a member of the IL-12 family. Studies show that IL-35 is an important anti-inflammatory cytokine and suppresses effector T-cell activity. In this study, we aimed to evaluate serum IL-35 levels in systemic sclerosis (SSc) patients and its potential relation with clinical findings. METHODS: We conducted a cross-sectional analysis of 70 SSc patients and 29 healthy volunteers in a single center in 5 months' period. Extension of skin fibrosis was evaluated by using modified Rodnan skin score. Disease severity was assessed by Medsger disease severity scores. Serum IL-35 was measured using a commercial enzyme-linked immunosorbent assay (ELISA) kit (Cloud-Clone Corp, Wuhan, China). The relationship between IL-35 levels and clinical and laboratory parameters was investigated. Mann-Whitney U test was used to compare parameters among the groups. Correlation was tested by Spearsman correlation coefficient. RESULTS: Serum IL-35 levels was significantly higher in SSc patients (8.69 [interquartile range, 29.33] pg/mL) than in healthy controls (7.11 [interquartile range 7.53] pg/mL; p < 0.001). There was no significant relationship between serum IL-35 levels and organ involvement. There was a negative correlation between serum IL-35 levels and Medsger disease severity score (Rho, -0.333; p = 0.006), modified Rodnan skin score (Rho, -0.307; p = 0.010), and C-reactive protein (Rho, -0.294; p = 0.015). There was no relationship between IL-35 and disease duration and erythrocyte sedimentation rate. CONCLUSIONS: Our study revealed that IL-35 levels were higher in SSc patients, and in contrast to previous studies, it was the first study that showed that IL-35 levels did not increase in SSc patients with pulmonary fibrosis. PMID- 30431487 TI - Nephrotic Syndrome as a Presenting Feature in a Child With NLRP3 Mutation. PMID- 30431488 TI - Diagnosis and Management of Gastric Antral Vascular Ectasia: Experience in a Large Single Cohort of Patients With Systemic Sclerosis. PMID- 30431489 TI - Digital Ischemia Induced by Fesoterodine. PMID- 30431492 TI - Safety of Percutaneous Dilatational Tracheostomy During Veno-Venous Extracorporeal Membrane Oxygenation Support in Adults With Severe Respiratory Failure. AB - OBJECTIVES: To investigate the safety of percutaneous dilatational tracheostomy in severe respiratory failure patients during veno-venous extracorporeal membrane oxygenation support. DESIGN: A single-center, retrospective, observational cohort study. SETTING: Tertiary referral severe respiratory failure center, university teaching hospital. PATIENTS: Severe respiratory failure patients consecutively admitted and supported with veno-venous extracorporeal membrane oxygenation between January 2010 and December 2015. INTERVENTION: A bronchoscopy-guided percutaneous dilatational tracheostomy was performed in all cases. MEASUREMENTS AND MAIN RESULTS: Sixty-five veno-venous extracorporeal membrane oxygenation patients (median [interquartile range] age, 47 yr [interquartile range, 35-59 yr]; 39 males; Acute Physiology and Chronic Health Evaluation-II score, 18 [interquartile range, 17-22] Sequential Organ Failure Assessment score, 10 [interquartile range, 7-16]) underwent percutaneous dilatational tracheostomy. Ten patients (15%) developed one or more major complications. Of these, seven (11%) had major bleeding, and three of these also required circuit change due to extracorporeal membrane oxygenation circuit dysfunction. Two more patients (3.1%) presented with isolated extracorporeal membrane oxygenation circuit dysfunction requiring circuit change, and one developed bilateral pneumothoraces (1.5%) requiring intercostal drain insertion. Patients who developed complications had significantly lower extracorporeal membrane oxygenation postoxygenator PO2 prior to percutaneous dilatational tracheostomy (45.8 kPa [interquartile range, 36.9 56.5 kPa] vs 57.9 kPa [interquartile range, 45.1-64.2 kPa]; p = 0.019]. On multivariate analysis, including demographic, clinical, biochemical, hematologic variables, and extracorporeal membrane oxygenation circuit functional variables, extracorporeal membrane oxygenation postoxygenator PO2 was the only independent variable associated with major complications following percutaneous dilatational tracheostomy (beta = -0.09; odds ratio, 0.9; 95% CI, 0.84-0.99; p = 0.03). CONCLUSIONS: Percutaneous dilatational tracheostomy is associated with a considerable complication rate in veno-venous extracorporeal membrane oxygenation patients. Preprocedure circuit performance as indicated by extracorporeal membrane oxygenation postoxygenator PO2 is an independent predictor of major complications following percutaneous dilatational tracheostomy. PMID- 30431490 TI - Book Review: Patch Testing by Anton C. de Groot. PMID- 30431494 TI - The Effect of ICU Diaries on Psychological Outcomes and Quality of Life of Survivors of Critical Illness and Their Relatives: A Systematic Review and Meta Analysis. AB - OBJECTIVES: To evaluate the effect of ICU diaries on posttraumatic stress disorder symptoms in ICU survivors and their relatives. Secondary objectives were to determine the effect on anxiety, depression, and health-related quality of life in patients and their relatives. DATA SOURCES: We searched online databases, trial registries, and references of relevant articles. STUDY SELECTION: Studies were included if there was an ICU diary intervention group which was compared with a group without a diary. DATA EXTRACTION: Titles, abstracts, and full-text articles were reviewed independently by two authors. Data was abstracted using a structured template. DATA SYNTHESIS: Our search identified 1,790 articles and retained eight studies for inclusion in the analysis. Pooled results found no significant reduction in patients' posttraumatic stress disorder symptoms with ICU diaries (risk ratio, 0.75 [0.3-1.73]; p = 0.5; n = 3 studies); however, there was a significant improvement in patients' anxiety (risk ratio, 0.32 [0.12, 0.86]; p = 0.02; n = 2 studies) and depression (risk ratio, 0.39 [0.17-0.87]; p = 0.02; n = 2 studies) symptoms. Two studies reported significant improvement in posttraumatic stress disorder symptoms of relatives of ICU survivors; however, these results could not be pooled due to reporting differences. One study reported no significant improvement in either anxiety (risk ratio, 0.94; 95% [0.66-1.33]; p = 0.72) or depression (risk ratio, 0.98; 95% [0.5-1.9]; p = 0.95) in relatives. There was a significant improvement in health-related quality of life of patients with a mean increase in the Short Form-36 general health score by 11.46 (95% CI, 5.87-17.05; p <= 0.0001; n = 2 studies). No studies addressed health-related quality of life of relatives. CONCLUSIONS: ICU diaries decrease anxiety and depression and improve health-related quality of life, but not posttraumatic stress disorder among ICU survivors and may result in less posttraumatic stress disorder among relatives of ICU patients. Multicenter trials with larger sample sizes are necessary to confirm these findings. PMID- 30431493 TI - Variation in Identifying Sepsis and Organ Dysfunction Using Administrative Versus Electronic Clinical Data and Impact on Hospital Outcome Comparisons. AB - OBJECTIVES: Administrative claims data are commonly used for sepsis surveillance, research, and quality improvement. However, variations in diagnosis, documentation, and coding practices for sepsis and organ dysfunction may confound efforts to estimate sepsis rates, compare outcomes, and perform risk adjustment. We evaluated hospital variation in the sensitivity of claims data relative to clinical data from electronic health records and its impact on outcome comparisons. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study of 4.3 million adult encounters at 193 U.S. hospitals in 2013-2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis was defined using electronic health record derived clinical indicators of presumed infection (blood culture draws and antibiotic administrations) and concurrent organ dysfunction (vasopressors, mechanical ventilation, doubling in creatinine, doubling in bilirubin to >= 2.0 mg/dL, decrease in platelets to < 100 cells/uL, or lactate >= 2.0 mmol/L). We compared claims for sepsis prevalence and mortality rates between both methods. All estimates were reliability adjusted to account for random variation using hierarchical logistic regression modeling. The sensitivity of hospitals' claims data was low and variable: median 30% (range, 5-54%) for sepsis, 66% (range, 26 84%) for acute kidney injury, 39% (range, 16-60%) for thrombocytopenia, 36% (range, 29-44%) for hepatic injury, and 66% (range, 29-84%) for shock. Correlation between claims and clinical data was moderate for sepsis prevalence (Pearson coefficient, 0.64) and mortality (0.61). Among hospitals in the lowest sepsis mortality quartile by claims, 46% shifted to higher mortality quartiles using clinical data. Using implicit sepsis criteria based on infection and organ dysfunction codes also yielded major differences versus clinical data. CONCLUSIONS: Variation in the accuracy of claims data for identifying sepsis and organ dysfunction limits their use for comparing hospitals' sepsis rates and outcomes. Using objective clinical data may facilitate more meaningful hospital comparisons. PMID- 30431495 TI - Monoacylglycerol Lipase Inactivation by Using URB602 Mitigates Myocardial Damage in a Rat Model of Cardiac Arrest. AB - OBJECTIVES: Monoacylglycerol lipase participates in organ protection by regulating the hydrolysis of the endocannabinoid 2-arachidonoylglycerol. This study investigated whether blocking monoacylglycerol lipase protects against postresuscitation myocardial injury and improves survival in a rat model of cardiac arrest and cardiopulmonary resuscitation. DESIGN: Prospective randomized laboratory study. SETTING: University research laboratory. SUBJECTS: Male Sprague Dawley rat (n = 96). INTERVENTIONS: Rats underwent 8-minute asphyxia-based cardiac arrest and resuscitation. Surviving rats were randomly divided into cardiopulmonary resuscitation + URB602 group, cardiopulmonary resuscitation group, and sham group. One minute after successful resuscitation, rats in the cardiopulmonary resuscitation + URB602 group received a single dose of URB602 (5 mg/kg), a small-molecule monoacylglycerol lipase inhibitor, whereas rats in the cardiopulmonary resuscitation group received an equivalent volume of vehicle solution. The sham rats underwent all of the procedures performed on rats in the cardiopulmonary resuscitation and cardiopulmonary resuscitation + URB602 groups minus cardiac arrest and asphyxia. MEASUREMENTS AND MAIN RESULTS: Survival was recorded 168 hours after the return of spontaneous circulation (n = 22 in each group). Compared with vehicle treatment (31.8%), URB602 treatment markedly improved survival (63.6%) 168 hours after cardiopulmonary resuscitation. Next, we used additional surviving rats to evaluate myocardial and mitochondrial injury 6 hours after return of spontaneous circulation, and we found that URB602 significantly reduced myocardial injury and prevented myocardial mitochondrial damage. In addition, URB602 attenuated the dysregulation of endocannabinoid and eicosanoid metabolism 6 hours after return of spontaneous circulation and prevented the acceleration of mitochondrial permeability transition 15 minutes after return of spontaneous circulation. CONCLUSIONS: Monoacylglycerol lipase blockade may reduce myocardial and mitochondrial injury and significantly improve the resuscitation effect after cardiac arrest and cardiopulmonary resuscitation. PMID- 30431496 TI - Health Literacy Burden Is Associated with Access to Liver Transplantation. AB - BACKGROUND: Getting listed for liver transplantation is a complex process. Institutional health literacy may influence the ability of patients with limited educational attainment (EA) to list. As an easily accessible indicator of institutional health literacy, we measured the understandability of liver transplant center education websites and assessed whether there was any association with the percentage of low EA patients on their waitlists. METHODS: Patients on the waitlist for liver transplantation 2007-2016 were identified in SRTR. Understandability of patient education websites was assessed using the Clear Communication Index (CCI). The CDC has set itself a goal CCI of 90 as being easy to understand. Low EA was defined as < high school education. We adjusted for center case-mix, DSA characteristics, and EA of the general population. RESULTS: 84 774 patients were listed across 112 liver transplant centers. The median percent of waitlisted patients at each center with low EA was 11.0% (IQR 6.6-16.8). CCI ranged from 53-88 and correlated with the proportion of low EA patients on the waitlist. However, CCI was not associated with the percentage of low EA in the general population. For every 1-point improvement in CCI, low EA patients increase by 0.2% (p<0.05), translating to a 3.6% increase, or additional 3000 patients, if all centers improved their websites to CCI 90. CONCLUSIONS: Educational websites that are easier to understand are associated with increased access to liver transplantation for patients with low EA. Lowering the health literacy burden by transplant centers may improve access to the liver transplant waitlist. PMID- 30431497 TI - More than Words: Health Literacy and Liver Transplant Waitlisting. PMID- 30431498 TI - Relevance of peripheral cholinesterase activity on postoperative delirium in adult surgical patients (CESARO): A prospective observational cohort study. AB - BACKGROUND: The cholinergic system is considered to play a key role in the development of postoperative delirium (POD), which is a common complication after surgery. OBJECTIVES: To determine whether peri-operative acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities are associated with the development of POD in in-hospital surgical patients, and raise hypotheses on cholinergic regulatory mechanisms in POD. DESIGN: A prospective multicentre observational study by the Peripheral Cholinesterase-activity on Neurocognitive Dysfunctions in Surgical Patients (CESARO) study group. SETTING: Nine German hospitals. PATIENTS: Patients of at least 18 years of age scheduled for inpatient elective surgery for a variety of surgical procedures. A total of 650 patients (mean age 61.5 years, 52.8% male) were included. METHODS: Clinical variables, and peripheral AChE and BuChE activities, were assessed throughout the peri-operative period using bedside point-of-care measurements (one pre-operative and two postoperative measurements). POD screening was conducted postoperatively for at least 24 h and up to the third postoperative day using a validated screening tool (nursing delirium screening scale). RESULTS: In all, 179 patients (27.5%) developed POD within the early postoperative phase. There was a lower BuChE activity in patients with delirium compared with patients without delirium pre operatively (Cohen's r = 0.07, P = 0.091), on postoperative day 1 (Cohen's r = 0.12, P = 0.003) and on postoperative day 2 (Cohen's r = 0.12, P = 0.002). In contrast, there was a significantly higher AChE activity in patients with delirium compared with patients without delirium pre-operatively (Cohen's r = 0.10, P = 0.012), on postoperative day 1 (Cohen's r = 0.11, P = 0.004) and on postoperative day 2 (Cohen's r = 0.13, P = 0.002). After adjusting for covariates in multiple logistic regression, a significant association between both BuChE and AChE activities and POD was not found. However, in the multivariable analysis using the Generalized Estimating Equation, cholinesterase activities showed that a decrease of BuChE activity by 100 U L increased the risk of a delirium by approximately 2.1% (95% CI 1.6 to 2.8%) and for each 1 U g of haemoglobin increase in AChE activity, there was a 1.4% (95% CI 0.6 to 2.2%) increased risk of POD. CONCLUSION: Peri-operative peripheral cholinesterase activities may be related to the development of POD, but the clinical implications remain unclear. Further studies, in homogeneous patient groups with a strict protocol for measurement time points, are needed to investigate the relationship between cholinesterase activities and POD. TRIAL REGISTRATION: www.clinicaltrials.gov. Identifier NCT01964274. PMID- 30431499 TI - Goal-directed therapy during transthoracic oesophageal resection does not improve outcome: Randomised controlled trial. AB - BACKGROUND: Goal-directed therapy (GDT) is expected to be of highest benefit in high-risk surgery. Therefore, GDT is recommended during oesophageal resection, which carries a high risk of postoperative complications. OBJECTIVES: The aim of this study was to confirm the hypothesis that GDT during oesophageal resection improves outcome compared with standard care. DESIGN: A randomised controlled study. SETTING: Two Swedish university hospitals, between October 2011 and October 2015. PATIENTS: Sixty-four patients scheduled for elective transthoracic oesophageal resection were randomised. Exclusion criteria included colonic interposition and significant aortic or mitral valve insufficiency. INTERVENTION: A three-step GDT protocol included stroke volume optimisation using colloid boluses as assessed by pulse-contour analysis, dobutamine infusion if cardiac index was below 2.5 l min m and norepinephrine infusion if mean arterial blood pressure was below 65 mmHg. MAIN OUTCOME MEASURE: The incidence of complications per patient at 5 and 30 days postoperatively as assessed using a predefined list. RESULTS: Fifty-nine patients were available for analysis. Patients in the intervention group received more colloid fluid (2190 +/- 875 vs. 1596 +/- 759 ml, P < 0.01) and dobutamine more frequently (27/30 vs. 9/29, P < 0.01). The median [interquartile range, IQR] incidence of complications per patient 5 days after surgery was 2 [0 to 3] in the intervention group and 1 [0 to 2] in the control group (P = 0.10), and after 30 days 4 [2 to 6] in the intervention group and 2 [1 to 4] in the control group (P = 0.10). CONCLUSION: Goal-directed therapy during oesophageal resection did not result in a reduction of the incidence of postoperative complications.Trial registration Clinicaltrials.gov identifier: NCT01416077. PMID- 30431500 TI - Development of a prediction model for postoperative pneumonia: A multicentre prospective observational study. AB - BACKGROUND: Postoperative pneumonia is associated with increased morbidity, mortality and costs. Prediction models of pneumonia that are currently available are based on retrospectively collected data and administrative coding systems. OBJECTIVE: To identify independent variables associated with the occurrence of postoperative pneumonia. DESIGN: A prospective observational study of a multicentre cohort (Prospective Evaluation of a RIsk Score for postoperative pulmonary COmPlications in Europe database). SETTING: Sixty-three hospitals in Europe. PATIENTS: Patients undergoing surgery under general and/or regional anaesthesia during a 7-day recruitment period. MAIN OUTCOME MEASURE: The primary outcome was postoperative pneumonia. DEFINITION: the need for treatment with antibiotics for a respiratory infection and at least one of the following criteria: new or changed sputum; new or changed lung opacities on a clinically indicated chest radiograph; temperature more than 38.3 degrees C; leucocyte count more than 12 000 MUl. RESULTS: Postoperative pneumonia occurred in 120 out of 5094 patients (2.4%). Eighty-two of the 120 (68.3%) patients with pneumonia required ICU admission, compared with 399 of the 4974 (8.0%) without pneumonia (P < 0.001). We identified five variables independently associated with postoperative pneumonia: functional status [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.58 to 3.12], pre-operative SpO2 values while breathing room air (OR 0.83, 95% CI 0.78 to 0.84), intra-operative colloid administration (OR 2.97, 95% CI 1.94 to 3.99), intra-operative blood transfusion (OR 2.19, 95% CI 1.41 to 4.71) and surgical site (open upper abdominal surgery OR 3.98, 95% CI 2.19 to 7.59). The model had good discrimination (c-statistic 0.89) and calibration (Hosmer-Lemeshow P = 0.572). CONCLUSION: We identified five variables independently associated with postoperative pneumonia. The model performed well and after external validation may be used for risk stratification and management of patients at risk of postoperative pneumonia. TRIAL REGISTRATION: NCT 01346709 (ClinicalTrials.gov). PMID- 30431501 TI - Ultrasound-guided vs. palpation-guided techniques for radial arterial catheterisation in infants: A randomised controlled trial. AB - BACKGROUND: The usefulness of ultrasound-guided techniques for radial arterial catheterisation has been well identified; however, its usefulness has not been completely evaluated in infants under 12 months of age, who are generally considered the most difficult group for arterial catheterisation. OBJECTIVE: We evaluated whether ultrasound guidance would improve success rates and reduce the number of attempts at radial arterial catheterisation in infants. DESIGN: A randomised, controlled and patient-blinded study. SETTING: Single-centre trial, study period from June 2016 to February 2017. PATIENTS: Seventy-four infants undergoing elective cardiac surgery. INTERVENTION: Patients were allocated randomly into either ultrasound-guided group (group US) or palpation-guided group (group P) (each n=37) according to the technique applied for radial arterial catheterisation. All arterial catheterisations were performed by one of two experienced anaesthesiologists based on group assignment and were recorded on video. MAIN OUTCOME MEASURES: The primary endpoint was the first-pass success. The number of attempts and total duration of the procedure until successful catheterisation were also analysed. RESULTS: The first-pass success rate was significantly higher in the group US than in the group P (68 vs. 38%, P = 0.019). In addition, fewer attempts were needed for successful catheterisation in the group US than in the group P (median 1 [IQR 1 to 2] vs. 2 [1 to 4], P = 0.023). However, the median [IQR] procedural time (s) until successful catheterisation in the two groups was not significantly different (102 [49 to 394] vs. 218 [73 to 600], P = 0.054). CONCLUSION: The current study demonstrated that the ultrasound guided technique for radial arterial catheterisation in infants effectively improved first-pass success rate and also reduced the number of attempts required. TRIAL REGISTRATION: ClinicalTrials.gov NCT02795468. PMID- 30431502 TI - Biologic Adjuvants for the Management of Osteochondral Lesions of the Talus. AB - Surgical techniques for the management of recalcitrant osteochondral lesions of the talus have improved; however, the poor healing potential of cartilage may impede long-term outcomes. Repair (microfracture) or replacement (osteochondral transplants) is the standard of care. Reparative strategies lead to production of fibrocartilage, which, compared with the native type II articular cartilage, has decreased mechanical and wear properties. The success of osteochondral transplants may be hindered by poor integration between grafts and host that results in peripheral cell death and cyst formation. These challenges have led to the investigation of biologic adjuvants to augment treatment. In vitro and in vivo models have demonstrated promise for cartilage regeneration by decreasing inflammatory damage and increasing the amount of type II articular cartilage. Further research is needed to investigate optimal formulations and time points of administration. In addition, clinical trials are needed to investigate the long term effects of augmentation. PMID- 30431503 TI - Surgical Management of Neuromas of the Hand and Wrist. AB - Neuromas of the hand and wrist are common causes of peripheral nerve pain. Neuromas are formed after the nerve sustains an injury, and they can be debilitating and painful. The diagnosis is made by a thorough history and physical examination. The treatment options are quite varied, but conservative measures tailored to the patient should be initiated first. No surgical treatment has been proven superior to others or to nonsurgical treatment. PMID- 30431504 TI - Necrotizing Soft-tissue Infections: An Orthopaedic Emergency. AB - Necrotizing soft-tissue infections are caused by a variety of bacterial pathogens that may affect patients at any age or health status. This orthopaedic emergency initially presents with nonspecific signs such as erythema and edema. As the disease progresses, classic signs such as bullae, cutaneous anesthesia, ecchymosis, tense edema, and gas can be seen. A high level of suspicion is needed to properly identify and treat in a timely manner. Pain out of proportion to presentation and rapid progression even with appropriate antibiotic treatment should heighten suspicion of a necrotizing soft-tissue infection. The mainstay of management is extensive debridement and decompression of all necrotic tissue and broad-spectrum antibiotics. Debridements are repeated to ensure that disease progression has been halted. Early surgical debridements should take precedent over transfer because of the high rate of limb loss and mortality as a result of surgical delay. PMID- 30431505 TI - Comparing Standard Versus Extended Culture Duration in Acute Hip and Knee Periprosthetic Joint Infection. AB - INTRODUCTION: Periprosthetic joint infection (PJI) is a devastating complication of hip and knee arthroplasties. Surgical cultures are essential for the diagnosis and treatment of PJI. Yet, the ideal culture duration remains unclear. This study compares culture yield, organism profile, and treatment success between standard (5 days) and extended (14 days) cultures in acute hip and knee PJI. METHODS: A retrospective review of medical records was completed between 2006 and 2015. All patients with an acute PJI meeting the modified International Consensus Meeting on PJI criteria of a primary hip or knee arthroplasty were included. All patients underwent irrigation and debridement with exchange of modular bearing surfaces for an acute postoperative or acute hematogenous infection. A standard growth cohort (before February 2012) was compared with an extended growth cohort (after February 2012) to determine if differences existed in culture yield and treatment success using the Delphi consensus criteria. RESULTS: One hundred eighty-nine patients were analyzed, including 102 (54.0%) standard duration and 87 (46.0%) extended duration cohorts. Patient cohorts were closely matched, except more hip PJIs than knee PJIs were included in the standard cohort (69.6% versus 49.4%; P = 0.005). No differences between standard and extended cohorts were observed with regard to overall culture yield, monomicrobial growth, or polymicrobial growth. Propionibacterium acnes was identified more often in the extended cohort (5 versus 0 patients; P = 0.019). However, four of these patients had only one positive P acnes culture and grew additional organisms. Finally, no difference in treatment success between the standard and extended cohorts at the final follow up was found (53% versus 52%; P = 0.282). CONCLUSION: Extended culture duration in acute hip and knee PJIs did not change the rate of culture-negative PJI, identify more patients with polymicrobial PJI, or improve the success of surgical treatment. The only difference was a higher incidence of P acnes growth, but contaminants or indolent chronic PJI cannot be excluded. Although extended culture growth may be indicated in acute shoulder arthroplasty PJI, its utility in hip or knee arthroplasty may be limited. Higher-level studies will be needed to address this in the future. PMID- 30431506 TI - Interventions for Distal Radius Fractures: A Network Meta-analysis of Randomized Trials. AB - INTRODUCTION: The distal radius is the second most commonly fractured bone in the elderly population. Several approaches for management exist including both surgical and nonsurgical treatments. Evidence for alternative approaches remains inconclusive and often conflicting. METHODS: Electronic database searches were conducted to identify randomized trials that (1) enrolled adults with a distal radius fracture; (2) compared external fixation, intramedullary nailing, K-wires, plaster casting (PC), or plate fixation (PF) to one of the other treatments listed; and (3) reported on a functional outcome that categorized patients as "excellent" and "good" or reported fracture healing complication (loss of reduction, malunion, delayed union, nonunion, and refracture). Data were synthesized using a Bayesian network meta-analysis. Odds ratios (ORs) with 95% credible intervals (CrIs) using a random-effects model were calculated. RESULTS: Thirty-eight trials were included. Total sample sizes ranged from 30 to 461 patients. Although no differences were noted between treatments at 3 months, PF was ranked the highest for improving functional outcomes at 6 and 12 months, and it demonstrated a statistically significant difference compared with PC at 12 months (OR = 4.27; 95% CrI, 1.07 to 15.12). For reduction in fracture healing complications, PF was ranked the highest again, showing significantly more favorable results relative to the four other interventions: OR = 0.25 (95% CrI, 0.07 to 0.86) versus external fixation, OR = 0.09 (95% CrI, 0.02 to 0.36) versus K-wire, OR = 0.01 (95% CrI, 0.00 to 0.03) versus PC, and OR = 0.00 (95% CrI, 0.00 to 0.35) versus intramedullary nailing. CONCLUSIONS: A network meta-analysis of randomized trials revealed that open reduction and internal fixation with a plate offers the best results for adult patients with a distal radius fracture, in terms of early and sustained functional recovery and a reduction in fracture healing complications. Determining whether one approach to PF or plate design is superior requires further study. PMID- 30431507 TI - Upper Extremity Immobilization and Driving: Limitations and Liability. AB - Orthopaedic injuries of the upper extremity remain common, often requiring prolonged immobilization after surgical or nonsurgical management. Upper extremity immobilization often has a profound effect on a patient's daily life, including one's ability to safely operate a motor vehicle. Current literature on the safety of driving while immobilized is varied, although above-elbow immobilization of the upper extremity is generally thought to present a particular hazard to safe driving. Unfortunately, as common as this situation is, currently little to no guidance exists for patients, physicians, or lawmakers with regard to deciding whether a patient is safe to return to driving with upper extremity immobilization. Similar discord exists with the issue of patient and physician liability in such cases. In this review, we seek to present both historical precedent and a contemporary update of this complex, though a frequently encountered situation. PMID- 30431508 TI - Cost-effectiveness of a high-intensity rapid access outpatient stroke rehabilitation program. AB - A common strategy to improve cost-effectiveness in healthcare is to offer outpatient care instead of in-hospital care. Toronto Rehabilitation Institute developed an outpatient high-intensity fast-track (FT) stroke rehabilitation program aimed at discharging inpatient stroke rehabilitation patients earlier or bypassing inpatient rehabilitation altogether. This cost-effectiveness analysis compares FT rehabilitation within 1 week of discharge with no FT in a single healthcare payer system. Patient costs and outcomes over a 12-week time horizon were included. Using individual-level FT data from April 2015 to March 2016, incremental cost-effectiveness ratios (ICERs) (with 95% confidence interval) were estimated using regression. Subgroup analysis was completed for patients entering FT directly from inpatient rehabilitation and acute stroke care. Uncertainty was assessed using a cost-effectiveness acceptability curve with a range of willingness-to-pay values ($0-1000 per inpatient day saved). ICER (95% confidence interval) estimate for patients entering FT from inpatient rehabilitation was $404 ($270-620) per inpatient day saved. ICER estimate for direct from acute care admissions was $37 ($20-55) per day saved. At willingness-to-pay of $698 (cost of one alternate level of care day in acute care awaiting rehabilitation), the probability of FT being cost-effective was 99.2 and 100% for patients from inpatient rehabilitation and acute stroke care, respectively. From a single healthcare payer perspective, FT is a cost-effective method of providing appropriate rehabilitation intensity for stroke patients early on, and likely to provide savings to the healthcare system upstream through fewer days awaiting rehabilitation admission. PMID- 30431509 TI - Magnet(r) Nurses Improving Community Health. AB - Keeping a community healthy requires more than hospital care. Magnet(r) nurses go beyond the bedside to promote a culture of health through volunteer work. To mark the season of giving, this month's "Magnet Perspectives" column looks at the ways in which nurses from Magnet-recognized organizations care for their communities. What do they do? Why do they do it? How does the Magnet framework promote and support them? We explore the implications for larger issues, such as population health, and hear from the nurses themselves about why community involvement is important. PMID- 30431510 TI - Technology Myth Busters for Nurse Leaders. AB - Technology is frequently viewed as a barrier to workflow and efficiency rather than as a tool that can be used to improve the quality of our care, increase efficiency, or enhance patient outcomes. However, when technology is applied effectively, nurse leaders can leverage tools such as clinical decision support to avoid errors, inform decision making, and boost provider and patient satisfaction. These topics were discussed at the AONE annual meeting in a preconference session. In this article, AONE session leaders detail ways to ensure that information technology is a valuable tool-and not an obstacle-for effective nursing practice. PMID- 30431512 TI - Conceptualization and Operationalization of Certification in the US and Canadian Nursing Literature: Erratum. PMID- 30431511 TI - Cracks in the Foundation of the Care Environment Undermine Nurse Resilience. AB - To see a meaningful change in nurse burnout, leaders must address the factors in the care environment that undermine nurse resilience. In this article, the authors describe why leaders should focus on the care environment rather than individual resilience building. PMID- 30431513 TI - The Impact of the Doctorate of Nursing Practice Nurse in a Hospital Setting. AB - This article describes the initiatives of doctorate of nursing practice (DNP) prepared nurses in a large healthcare system supporting the DNP competencies as outlined by the American Association of Colleges of Nursing. The goal of this group was to demonstrate the impact of DNP education on the roles for nurse administrators, advanced practice nurses, and educators in a large health system. Exemplars profile nurse administrators, clinical nurse specialists, and a nurse educator. PMID- 30431514 TI - Editorial Thank You. PMID- 30431515 TI - The Nurse Leader's Pivotal Role in Retaining Millennial Nurses. AB - With increasing patient acuity and a significant nursing shortage expected in the near future, understanding and gaining the commitment of the new generation of novice nurses are important for nursing leaders. This article provides a review of recent literature and presents innovative strategies that nurse leaders can use to improve the engagement and commitment of millennials. The benefit of expanding mentoring to 3 years, involvement in department committees, quality initiatives, or unit-based councils and opportunities for lateral movement are also discussed. PMID- 30431516 TI - Implementing a Peer Support Network to Promote Compassion Without Fatigue. AB - OBJECTIVE: The aims of this study were to implement a Peer Support Network (PSN) pilot project including education/training, peer support, and resiliency training and to explore how interventions impact compassion satisfaction (CS) and compassion fatigue (CF) in a community hospital. BACKGROUND: CF has been reported to negatively affect nurse retention. The PSN provides a 3-tiered team approach to enhance CS and support nurses experiencing CF symptoms. METHODS: Twenty nurses participated in PSN training and completed preimplementation and 6-week postimplementation surveys: Professional Quality of Life, Compassion Practice Instrument, and self-care resource utilization. RESULTS: Statistically significant improvements in CS and nonstatistical improvements in CF were found. CONCLUSION: Promoting a PSN may increase CS and potentially prevent work-related physical, emotional, social, and intellectual CF sequelae. PMID- 30431517 TI - The Intergenerational Impact of Management Relations on Nurse Career Satisfaction and Patient Care. AB - OBJECTIVE: This article provides insights into the role of management relations on nurses' career satisfaction across different career stages. BACKGROUND: Managers and positive relations with staff are critical to improving job satisfaction, career development, and retention for new graduates to mid- to late career nurses. METHODS: Using a descriptive qualitative approach, we conducted a thematic analysis of 18 focus groups held in 8 Canadian provinces with 185 student, early-career, and mid- to late-career nurse participants. RESULTS: Student participants expressed the need for a supportive environment to enable successful transition to practice. Early-career nurses expected effective leadership at the unit level, effective communication, and positive working relationships to enable best care outcomes. Mid- to late-career nurses were most dissatisfied with management interactions and relationships. CONCLUSIONS: Management relations are important across all career stages, affecting patient care and job satisfaction. Findings provide insight into how nurse-manager relations can be enhanced from new graduate support to guidance in career development and ongoing recognition and respect for nurses throughout their careers. PMID- 30431519 TI - At the Movies. PMID- 30431518 TI - Associations Among Nurse Fatigue, Individual Nurse Factors, and Aspects of the Nursing Practice Environment. AB - OBJECTIVE: This study examined the relationships among nurse fatigue, individual nurse factors, and the practice environment in the inpatient setting. BACKGROUND: Nurse fatigue affects the quality of care provision on inpatient units. Scant literature exists regarding how aspects of the practice environment relate to nurse fatigue. METHODS: A cross-sectional, correlational design was used in this survey study of 175 neonatal intensive care unit nurses from multiple hospitals. Data were collected using the Checklist Individual Strength questionnaire and the Practice Environment Scale of the Nursing Work Index. Hierarchical regression analysis was performed to examine the relationships. RESULTS: Higher fatigue was significantly associated with more hours worked, fewer hours of sleep, a physical or mental contributor to fatigue, and a recent distressing patient event. Lower fatigue was significantly associated with better nurse manager ability, leadership, and support. CONCLUSIONS: Nurse fatigue may be diminished with organizational and individual strategies. Developing tactics for nurse managers to better support staff members after a recent distressing patient event is indicated. PMID- 30431520 TI - Left dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation reduces the development of long-term muscle pain. AB - The left dorsolateral prefrontal cortex (DLPFC) is involved in the experience and modulation of pain, and may be an important node linking pain and cognition. Repetitive transcranial magnetic stimulation (rTMS) to the left DLPFC can reduce chronic and experimental pain. However, whether left DLPFC rTMS can influence the development of chronic pain is unknown. Using repeated intramuscular injection of nerve growth factor to induce the development of sustained muscle pain (lasting weeks), 30 healthy individuals were randomized to receive 5 consecutive daily treatments of active or sham left DLPFC rTMS, starting before the first nerve growth factor injection on day 0. Muscle soreness and pain severity were collected daily for 14 days and disability on every alternate day. Before the first and 1 day after the last rTMS session, anxiety, depression, affect, pain catastrophizing, and cognitive performance on the attention network test were assessed. Left DLPFC rTMS treatment compared with sham was associated with reduced muscle soreness, pain intensity, and painful area (P < 0.05), and a similar trend was observed for disability. These effects were most evident during the days rTMS was applied lasting up to 3 days after intervention. Depression, anxiety, pain catastrophizing, and affect were unchanged. There was a trend toward improved cognitive function with rTMS compared with sham (P = 0.057). These data indicate that repeated left DLPFC rTMS reduces the pain severity in a model of prolonged muscle pain. The findings may have implications for the development of sustained pain in clinical populations. PMID- 30431521 TI - Adrenal suppression after epidural steroids. PMID- 30431522 TI - Reply. PMID- 30431524 TI - Fatal Carbapenem Resistance Development in Pseudomonas Aeruginosa Under Meropenem Monotherapy, Caused by Mutations in the Oprd Outer Membrane Porin. AB - A 13-year old neutropenic boy succumbed to bacteremia and sepsis with a Pseudomonas aeruginosa strain that rapidly developed resistance to carbapenems during meropenem monotherapy. Whole genome sequencing of the susceptible and resistant blood culture isolates revealed the meropenem-resistant phenotype to be caused by truncation of the oprD gene, which added to a pre-existing inactivated mexR gene. PMID- 30431525 TI - Persistence of High Neutralizing Antibody Titers after Neonatal and Early Infantile Infection with Parechovirus-A3. AB - This 3-year follow-up study evaluated neutralizing antibody titers (NATs) against parechovirus-A3 (PeV-A3) in neonates and young infants who developed PeV-A3 infection. All children had low NATs at disease onset and high NATs after infection during infancy. At age 3 years, all 16 patients tested had high NATs (>= 1:512) against PeV-A3 indicating that specific PeV-A3 NATs persist into childhood. PMID- 30431526 TI - 10 good reasons why adrenal vein sampling is the preferred method for referring primary aldosteronism patients for adrenalectomy. AB - : Nowadays most patients diagnosed with surgically curable primary aldosteronism have small or micro aldosterone-producing adenoma or unilateral micronodular hyperplasia, which are undetectable with available imaging technologies. Therefore, a negative imaging test by no means excludes unilateral primary aldosteronism. Moreover, about 10% of the subjects above the age of 35 years have nonfunctioning adrenal tumors, regardless of being hypertensive or not, with a prevalence that raises with aging. Hence, the finding of an adrenal mass at imaging does not reliably detect the culprit of primary aldosteronism. On the other hand, when primary aldosteronism patients are selected for adrenalectomy on the basis of demonstration of lateralized aldosterone excess at adrenal vein sampling (AVS), close to 100% are biochemically cured from the hyperaldosteronism, about 45% are cured of arterial hypertension and an additional 52% are markedly improved in terms of blood pressure control. By contrast, patients referred for surgery based on imaging alone often fail to reach these successful outcomes, indicating that surgery was unnecessary or, even worse, performed on the wrong side. For these reasons, and because of the lack of accurate and widely available alternative methods, all current guidelines recommend that AVS be offered to all primary aldosteronism patients with only few exceptions, mainly in patients unable or unwilling to undergo surgery and those with germ-line mutations causing familial primary aldosteronism. The main argument against systematic use of AVS entails its suboptimal performance, partly justified by its intrinsic technical difficulty, and its limited availability. This led to propose skipping AVS strategies for predicting surgically curable primary aldosteronism, but success has been inconsistent. The most urgent standing issue is, therefore, not to find loopholes to avoid AVS, but rather to improve its use, which means improving the rate of AVS success, through formal training of interventionists, selection of appropriate cutoffs and exploitation of a standardized procedure. PMID- 30431527 TI - The pressure-dependency of local measures of arterial stiffness. AB - OBJECTIVE: To determine which ultrasound-based, single-point arterial stiffness estimate is least dependent on blood pressure (BP) to improve assessment of local vascular function. METHODS: Ultrasound was used to assess blood flow and diameters at the left brachial artery of 20 healthy adults [55% female, 27.9 years (5.2), 24.2 (2.8) kg/m]. BP of both arms was measured simultaneously. Experimental (left) arm BP was then systematically manipulated by adjusting its position ABOVE (+30 degrees ) and BELOW (-30 degrees ) heart level in a randomized order following measurement at heart level (0 degrees ). The control (right) arm remained at heart level. Six stiffness measurements were calculated: compliance, distensibility, beta-stiffness, and three estimates of pulse wave velocity (PWV) (Bramwell Hill, blood flow, and beta-stiffness). We considered the measurement technique with the least significant change across positions to be the least pressure-dependent. RESULTS: There was a large effect change in mean arterial pressure (np = 0.75, P < 0.001) in the experimental arm when it was ABOVE (Delta-4.4 mmHg) and BELOW (Delta10.4 mmHg) heart level. There was a main effect (P < 0.05) of arm position on all arterial stiffness measures. From least to most pressure-dependent, the arterial stiffness measurements were: PWV (blood flow method), compliance coefficient, beta-stiffness, distensibility coefficient, PWV (Bramwell-Hill method), and PWV (beta-stiffness index method). CONCLUSION: All single-point measures assessed are pressure-dependent. The PWV (blood flow method) may be the least pressure-dependent single-point measure, and may be the most suitable single-point measure to assess local vascular function. PMID- 30431528 TI - Analysis of nicotinamide N-methyltransferase in oral malignant melanoma and potential prognostic significance. AB - Oral malignant melanoma (OMM) is an aggressive tumour, and shows deep tissue invasion at initial presentation. The prognosis is worse than that for cutaneous melanoma (CM), and the overall 5-year survival rate is 10-25%. A study of the molecular mechanisms involved in the development of OMM is necessary to identify new prognostic markers. In this study, we evaluated the possible role of nicotinamide N-methyltransferase (NNMT) in OMM. We carried out immunohistochemical analyses to evaluate the expression of NNMT in 15 OMM and 15 CM, measuring the percentage of positive cells and the value of NNMT expression intensity. Furthermore, we explored the relationship between NNMT levels and the prognostic parameters of patients with OMM. NNMT was significantly more expressed in CM compared with OMM, whereas higher staining intensity for NNMT was observed in OMM cases (P<0.05). In addition, a significant relationship was found between NNMT staining intensity and the presence of ulceration (P<0.05). Furthermore, univariate analysis showed a negative effect of NNMT expression on the disease free survival rate (P<0.05). This study is the first to report the expression of NNMT in OMM and to compare OMM enzyme levels with those detected in CM. Data obtained seem to suggest the presence of potential molecular differences between these two tumours. PMID- 30431529 TI - Association between interleukin-18 (137G/C and 607C/A) gene polymorphisms and risk of ischemic stroke: a meta-analysis. AB - Over the years, numerous researchers have explored the relationship between ischemic stroke (IS) and interleukin-18 (IL-18) gene polymorphisms. However, those studies reported conflicting and ambiguous results. The effects of IL-18 (137G/C and 607C/A) genetic variants on IS were investigated in this article. We performed a systematic search that was comprehensively executed in online databases for studies published up to 30 April 2018. Calculation of pooled odds ratios (ORs) and 95% confidence intervals was applied to assess the intensity of correlation using Stata.12.0. The overall outcome showed that 137G allele increased the risk of IS under the homozygous model (OR=1.36, P=0.027). Nevertheless, on the basis of ethnicity for the subgroup analysis (Asian and Egyptian), it was disclosed that the association was only found in the Egyptian population under the allelic model (OR=2.72, P=0.001) and recessive model (OR=5.04, P=0.000). In the overall analysis, 607C allele increased the risk of IS under all hereditary models (C vs. A: OR=1.26, P=0.002; CC vs. AA: OR=1.67, P=0.002; CA vs. AA: OR=1.30, P=0.001; CC+CA vs. AA: OR=1.41, P=0.000; CC vs. AA+CA: OR=1.48, P=0.000); a similar trend was observed in the Asian population. However, 607C allele was linked to decreased IS risk in the Egyptian population under all genetic models except the heterozygous model (C vs. A: OR=0.48, P=0.006; CC vs. AA: OR=0.19, P=0.007; CA vs. AA: OR=0.47, P=0.078; CC+CA vs. AA: OR=0.39, P=0.020; CC vs. AA+CA:OR=0.30, P=0.030). Although two polymorphisms were associated with IS, the association varied significantly in different countries. Large epidemiological studies will be required to verify these findings in the future. PMID- 30431530 TI - Effect of ACTN3 Polymorphism on Self-reported Running Times. AB - Kreutzer, A, Martinez, CA, Kreutzer, M, Stone, JD, Mitchell, JB, and Oliver, JM. Effect of ACTN3 polymorphism on self-reported running times. J Strength Cond Res XX(X): 000-000, 2018-This investigation examined the effect of ACTN3 genotype on self-reported distance running personal records (PRs). Of 94 (n = 94) recreationally active men and women, 82 (f = 42, m = 40; age: 22.6 +/- 4.5 years; body mass index [BMI]: 23.5 +/- 3.4 kg.m) reported 1-mile running PRs, whereas 57 (f = 33, m = 24; age: 23.4 +/- 5.3 years; BMI: 22.9 +/- 9.3 kg.m) reported 5K running PRs. Subjects were grouped by the presence (ACTN3) or absence (ACTN3) of alpha-actinin-3, as well as by individual genotype (RR, RX, and XX). Among female participants, ACTN3 reported 64.5 seconds faster (p = 0.048) 1-mile PRs compared with their ACTN3 counterparts. No differences were observed when comparing 5K PRs between genotypes. Two one-sided test equivalence testing revealed that none of the effects observed when comparing ACTN3 and ACTN3 were equivalent to zero. Our study confirms a reportedly greater prevalence of XX benefits for endurance performance in females when compared with males but fails to strongly link ACTN3 genotype to endurance performance. Practitioners should continue to be cautious when using genetic information for talent identification and sport selection. PMID- 30431531 TI - Effects of High-Intensity Interval Training on Olympic Combat Sports Athletes' Performance and Physiological Adaptation: A Systematic Review. AB - Franchini, E, Cormack, S, and Takito, MY. Effects of high-intensity interval training on Olympic combat sports athletes' performance and physiological adaptation: A systematic review. J Strength Cond Res XX(X): 000-000, 2018-Combat sports represent around 25% of all Olympic medals disputed, and the success in these sports are determined by technical-tactical excellence and supported by physiological and psychological development. Although the training in combat sports is intermittent training by nature, some researchers have started to focus their attention on the effects of complementary high-intensity interval training (HIIT)-coupled standard combat sports-specific training on morphological, physiological, and performance adaptations. Thus, in this systematic review, we aimed to verify the effects of this type of training on these variables. A total of 117 articles in the electronic databases Pubmed, Scopus, and Web of Science were retrieved, and 9 studies remained in the present systematic review. A total of 228 athletes (138 judo athletes, 40 taekwondo athletes, 18 boxers, 17 karate athletes, and 15 wrestlers) were investigated in these 9 studies (5 with judo athletes, 1 with boxers, 1 with karate athletes, 1 with wrestlers, and 1 with taekwondo athletes). The HIIT protocols investigated did not generate any change in body fat percentage or body mass but generally resulted in increases in V[Combining Dot Above]O2max or V[Combining Dot Above]O2peak, varying from 4.4 to 23.0%. However, the most observed benefit of HIIT protocols was an increase in anaerobic fitness, represented by improvements in anaerobic power and capacity. PMID- 30431532 TI - Ergogenic Effects of beta-Alanine Supplementation on Different Sports Modalities: Strong Evidence or Only Incipient Findings? AB - Brisola, GMP and Zagatto, AM. Ergogenic effects of beta-alanine supplementation on different sports modalities: strong evidence or only incipient findings? J Strength Cond Res XX(X): 000-000, 2018-beta-Alanine supplementation is a popular nutritional ergogenic aid among the sports community. Due to its efficacy, already proven in the literature, to increase the intramuscular carnosine content (beta-alanyl-L-histidine), whose main function is intramuscular buffering, beta alanine supplementation has become a nutritional strategy to improve performance, mainly in high-intensity efforts. However, although many studies present evidence of the efficacy of beta-alanine supplementation in high-intensity efforts, discrepancies in outcomes are still present and the performance enhancing effects seem to be related to the specificities of each sport discipline, making it difficult for athletes/coaches to interpret the efficacy of beta-alanine supplementation. Thus, this study carried out a review of the literature on this topic and summarized, analyzed, and critically discussed the findings with the objective of clarifying the current evidence found in the literature on different types of efforts and sport modalities. The present review revealed that inconsistencies are still found in aerobic parameters determined in incremental tests, except for physical working capacity at the neuromuscular fatigue threshold. Inconsistencies are also found for strength exercises and intermittent high-intensity efforts, whereas in supramaximal continuous mode intermittent exercise, the beneficial evidence is strong. In sports modalities, the evidence should be analyzed separately for each sporting modality. Thus, sports modalities that have strong evidence of the ergogenic effects of beta-alanine supplementation are: cycling race of 4 km, rowing race of 2,000 m, swimming race of 100 and 200 m, combat modalities, and water polo. Finally, there is some evidence of slight additional effects on physical performance from cosupplementation with sodium bicarbonate. PMID- 30431533 TI - Bilateral Quadriceps Strength Asymmetry Is Associated With Previous Knee Injury in Military Special Tactics Operators. AB - Eagle, SR, Keenan, KA, Connaboy, C, Wohleber, M, Simonson, A, and Nindl, BC. Bilateral quadriceps strength asymmetry is associated with previous knee injury in military special tactics operators. J Strength Cond Res XX(X): 000-000, 2018 Bilateral strength asymmetries have been related to lower-limb injury in athletes. Given that military populations often participate in recreational sport, in addition to a physically demanding workload, bilateral strength asymmetries may be related to injury in military populations. The purpose of this study was to determine whether isokinetic strength differs between Operators with/without self-reported knee injury (KI), and to examine the odds of displaying a lower-extremity strength asymmetry based on previous KI history. Operators (n = 150) self-reported injury history and performed isokinetic knee strength testing. Cohorts were separated by those who reported/not reported KI. Mean isokinetic knee strength and odds ratios, with subjects' KI history compared with strength differences: <10, 10-20, and >20%, were calculated. Operators who reported KI demonstrated larger bilateral knee extension (KE) strength differences compared with those who did not report an injury (injured: 13.5 +/- 12.9% vs. noninjured: 8.1 +/- 5.9%, p = 0.01). Operators with <10 or 10-20% KE strength difference had 76-77% reduced odds of previous KI, compared to those with >20% strength difference (p < 0.05). Operators with previous KI demonstrated bilateral differences in KE strength. Those with <10 or 10-20% strength differences had reduced odds of reporting previous KI. Strength and conditioning professionals should consider unilateral, targeted exercises in reducing bilateral asymmetry to rectify more balanced strength between limbs. Targeted exercise programs may improve bilateral strength differences and limit reinjury risk. PMID- 30431534 TI - Effect of Strength on Velocity and Power During Back Squat Exercise in Resistance Trained Men and Women. AB - Askow, AT, Merrigan, JJ, Neddo, JM, Oliver, JM, Stone, JD, Jagim, AR, and Jones, MT. Effect of strength on velocity and power during back squat exercise in resistance-trained men and women. J Strength Cond Res XX(X): 000-000, 2018-The purpose was to examine load-velocity and load-power relationships of back squat in resistance-trained men (n = 20, 21.3 +/- 1.4 years, 183.0 +/- 8.0 cm, 82.6 +/- 8.0 kg, 11.5 +/- 5.0% total body fat) and women (n = 18; 20.0 +/- 1.0 years; 166.5 +/- 6.9 cm; 63.9 +/- 7.9 kg, 20.3 +/- 5.0% body fat). Body composition testing was performed followed by determination of back squat 1 repetition maximum (1RM). After at least 72 hours of recovery, subjects returned to the laboratory and completed 2 repetitions at each of 7 separate loads (30, 40, 50, 60, 70, 80, and 90% 1RM) in a random order. During each repetition, peak and average velocity and power were quantified using a commercially available linear position transducer. Men produced higher absolute peak and average power and velocity at all loads. When power output was normalized for body mass, significant differences remained. However, when normalizing for strength, no significant differences were observed between sexes. Furthermore, when subjects were subdivided into strong and weak groups, those above the median 1RM produced higher peak power, but only at loads greater than 60% 1RM. It was concluded that differences between men and women may be a result of strength rather than biological sex. Furthermore, training for maximal strength may be an appropriate method to augment maximal power output in those athletes who exhibit low levels of strength. PMID- 30431535 TI - In-Season Integrative Neuromuscular Strength Training Improves Performance of Early-Adolescent Soccer Athletes. AB - Panagoulis, C, Chatzinikolaou, A, Avloniti, A, Leontsini, D, Deli, CK, Draganidis, D, Stampoulis, T, Oikonomou, T, Papanikolaou, K, Rafailakis, L, Kambas, A, Jamurtas, AZ, and Fatouros, IG. In-season integrative neuromuscular strength training improves performance of early-adolescent soccer athletes. J Strength Cond Res XX(X): 000-000, 2018-Although forms of integrative neuromuscular training (INT) are used extensively for injury prevention and treatment, no information exists about its effects on performance of adolescent athletes. We investigated the effects of an in-season INT intervention on performance of early-adolescent players using a 2-group, repeated-measures design. Twenty-eight early adolescents were randomly assigned to a control group (CG, participated only in soccer training, N = 14, 11.4 +/- 0.57 years, Tanner stage 2.8 +/- 0.6) or an experimental group (INT was added to conventional soccer training, N = 14, 11.2 +/- 0.5 years, Tanner stage 2.6 +/- 0.5). Integrative neuromuscular training (8 weeks, 3 sessions.wk) aimed to develop core strength, hamstrings eccentric strength, hip/knee musculature, and dynamic stability using body mass exercises, medicine balls, rocker boards, Bosu, stability balls, etc. Ball shooting speed, speed (10, 20-m), change of direction (COD), jumping performance, and strength were measured before and after training. A 2-way repeated-measures ANOVA was used to analyze data. Integrative neuromuscular training improved 10- and 20-m speed (2.52-2.13 and 3.61-3.39 seconds, respectively, p < 0.05), strength (40.1-44.4 kg, p < 0.05), jumping ability (squat jump: 16.3-17.9 cm; countermovement jump: 19.1-20.3 cm, p < 0.05), COD (18.0-17.3 seconds, p < 0.05), and shooting speed (73.8-79.0 km.h, p < 0.05). In the CG, soccer training caused an improvement of smaller magnitude in 10 m and shooting speed (p < 0.05), whereas COD and jumping performance remained unaffected while 20-m speed, COD, and strength deteriorated. These results indicate that an 8-week INT program may induce positive adaptations in performance of early-adolescent soccer players during in-season training, suggesting that INT may be an effective training intervention for this age group. PMID- 30431537 TI - CASES IN REFINING MANAGEMENT OF DIABETIC MACULAR EDEMA. PMID- 30431536 TI - Effects of 8-Week Functional vs. Traditional Training on Athletic Performance and Functional Movement on Prepubertal Tennis Players. AB - Yildiz, S, Pinar, S, and Gelen, E. Effects of 8-week functional vs. traditional training on athletic performance and functional movement on prepubertal tennis players. J Strength Cond Res XX(X): 000-000, 2018-In recent years, studies on functional training (FT) have gained importance among older adults and health care services, but there is a lack of research on the athletic performance of children. Fundamental movement skills are basic skills that need to be improved by the age of 10, and these skills are fundamental to every sport. While developing these basic movement skills, some athletic abilities of children should not be neglected and will be a basis for the future. In this way, children will have the ability to perform their sport-specific movement skills easily when the age of specialization comes. Our hypothesis is that increased functional movement will enhance athletic performance of child tennis players. Question of the study is "will increased functional movement enhance athletic performance of child tennis players?" The purpose of this study is to investigate the effects of the FT model on the athletic performance of young athletes. This study included 28 young tennis players (mean age: 9.6 +/- 0.7, height: 134.1 +/- 6.8, body mass: 31.3 +/- 4.1, and fitness age: 3.1 +/- 1.1) who have an 80% or more dominant side based on the lateralization test and a functional movement screen (FMS) score below 75%. Ten subjects were included in each of the FT group (FTG) and the traditional training group (TTG), 8 subjects were included in the control group (CG). The training program was implemented on 3 nonconsecutive days in a week for 8 weeks. All subjects performed CG exercises; FTG performed additional exercises based on the FT model, and TTG performed additional exercises based on the TT model. Flexibility, vertical jump, acceleration, agility, balance, and FMS tests were conducted before the training program, at the end of the fourth and the eighth week. The Friedman test analysis method bearing intragroup repeated measurements was used to evaluate the effects of the training program on the dependent variables among weeks (beginning the fourth week and the eighth week) since groups display distribution in nonparametric order. The differences between the averages were tested with Wilcoxon post hoc analyses. The Kruskal-Wallis Test analyses method was used to evaluate the effects of the training program on dependent variables among the groups (CG, TTG, and FTG). The differences between the averages were tested with Mann-Whitney U post hoc analyses. Intraclass correlation coefficient (ICC) values were calculated to determine the test-retest reliability of all measurements. According to the data, there was no difference in performance measurements between CG, TTG, and FTG before the exercise program (p > 0.05), but the differences between the groups were significant (p < 0.01) after 4 weeks and 8 weeks. A significant decrease was found in FMS score in CG (p < 0.01), while no difference was found in other parameters (p > 0.05). In TTG, FMS score significantly decreased (p < 0.01), dynamic right balance (p < 0.01) and dynamic left balance (p < 0.05) increased. But, no statistically significant difference was found in other parameters (p > 0.05) in TTG. In FTG, all parameters improved, and differences were statistically significant (p <= 0.001). Based on these results, the FT model seems to be more effective than the TT model in terms of increasing athletic performance. PMID- 30431538 TI - Do postoperative drain volumes correlate with intraoperative blood loss and postoperative transfusion requirements in posterior spinal fusion for adolescent idiopathic scoliosis? AB - Most studies have excluded postoperative drain volumes in analyzing blood loss associated with scoliosis surgery. We sought to analyze patient and surgical factors that influenced postoperative drain outputs. A retrospective review was conducted on 50 consecutive patients who had undergone posterior spinal fusion with pedicle screw instrumentation and subfascial drain placement over a 6-year period at a single institution for adolescent idiopathic scoliosis. Postoperative drain volumes were correlated to patient factors, surgical variables, and change in postoperative hemoglobin values. The association between drain output volumes and the need for allogeneic blood transfusion was also analyzed using univariate and multivariate analysis. Total postoperative drain volume positively correlated with Cell Saver volume (r=0.28, P=0.049), units of packed red blood cells transfused intraoperatively (r=0.31, P=0.03), and a number of Ponte osteotomies (r=0.43, P=0.002). On the basis of multiple linear regression analysis, only the number of osteotomies performed was associated with increasing total drain volume (R=0.25, P=0.003). Total drain output did not correlate with postoperative change in hemoglobin (P=0.85), the need for postoperative blood transfusion (P=0.22), or the total volume of blood transfused perioperatively (P=0.06). Patients with large intraoperative blood loss or multiple osteotomies are more likely to have higher postoperative drain volumes. Drain volume alone, however, should not be used as a trigger for recommending a postoperative blood transfusion. PMID- 30431539 TI - Predictors of Caregiver Burden in Caregivers of Bedridden Patients. AB - BACKGROUND: Caregivers are at risk of experiencing caregiver burden. It is therefore important to determine the caregiver burden of caregivers who provide care to bedridden patients and related factors. PURPOSE: The aim of this study was to determine the caregiver burden of caregivers who provide care to bedridden patients and the factors that impact this burden. METHODS: This cross-sectional study was executed at a state hospital in Istanbul, Turkey, on bedridden patients registered in the home healthcare unit and their caregivers. During study period, the researchers made 312 visits to patients and their caregivers. A sociodemographic questionnaire, the Burden Interview, and the Katz Index of Independence in Activities of Daily Living were used to collect data. Descriptive statistics, an independent sample t test, one-way analysis of variance, and stepwise multiple regression analysis were used for data analysis. RESULTS: The participants reported a moderate level of caregiver burden. Existing caregiver health problems, caregiver employment status, the ability of the caregiver to maintain his or her own good health, type of home, and the degree of patient dependence in terms of activities of daily living were each found to be significant predictors of caregiver burden. CONCLUSIONS/IMPLICATIONS OF PRACTICE: The support provided to caregivers by home healthcare units is important in terms of protecting the physical, mental, and social health conditions of caregivers and preventing the exacerbation of caregiver burden. PMID- 30431540 TI - Pakistan Comprehensive Fistula Classification: A novel Scheme and Algorithm for management of palatal fistula/dehiscence. AB - BACKGROUND: It is not easy to find a management based classification of palatal fistula in the literature. A few attempts have been made to classify the wide variety of fistulae which do not describe the fistula details comprehensively and guide towards its management. We have come across wide variety of fistulae which could not be classified according to any of the prevailing classification systems. The presented classification gives a clear and exact understanding of location and size of fistula/dehiscence. Palatal function has been included as one of the important determinants for devising a management plan. Based on this classification, we have proposed an algorithm which encompasses clear guidelines for surgical treatment of these fistulae. MATERIALS AND METHODS: Over the last 15 years, our team operated upon 2537 palatal fistula patients. The medical records of these patients were reviewed to determine the location, size and velopharyngeal competence. A new classification and algorithm were developed. RESULTS: Out of 2537 patients, 2258 patients had midline fistulae, 208 patients had lateral fistulae and 53 patients had subtotal fistulae. There were 18 patients with dehiscence. Recurrence developed in 181 patients. CONCLUSION: We believe that this classification and algorithm can help follow a practical approach to manage palatal fistulae and dehiscence. PMID- 30431541 TI - Function and Strength after Free Abdominally Based Breast Reconstruction: A 10 year follow-up. AB - BACKGROUND: The long-term impact of abdominally-based free flap breast reconstruction is incompletely understood. The aim of this study is to provide long-term, subjective and objective health data on abdominally based free flap breast reconstruction patients with specific attention to the effects of laterality, flap type and obesity. METHODS: Patients enrolled in this prospective study between 2005 and 2010 and completed preoperative, early (<1 year) and long term(5-10 years) evaluations. Objective examination included an assessment of upper (UA) and lower (LA) abdominal function and a functional independence measure (FIM). Patient-reported outcomes included the Short-Form 36 (SF36) and the Breast-Q abdominal well-being module. Scores were compared by laterality (unilateral vs bilateral), flap type (msfTRAM vs.DIEP), and presence of obesity. RESULTS: Fifty-one patients were included with an average of 8.1 years follow-up. Overall, 78.8% of patients had stable or improved scores across the UA, LA and FIM, and minimal objective differences across flap laterality or types were observed. Post-operative scores improved for SF36 Physical health (p<0.001) and Mental health (p<0.001), and did not differ based on laterality or flap type. Obesity negatively impacted Physical Health (p=0.002) and Mental Health (p=0.006). CONCLUSION: Abdominally based autologous breast reconstruction is associated with significant improvements in long-term quality of life across key domains of physical and mental health with little functional impairments, and no long-term differences across flap type or laterality. Obese patients, however, may be at risk for subjective physical and mental health impairment, perhaps unrelated to the surgery itself. PMID- 30431542 TI - Opioid Use Following Operatively Treated Pediatric Elbow and Femur Fractures. AB - BACKGROUND: Opioids are a commonly utilized component of pain management following pediatric extremity fractures, yet an increasing number of adolescents and children are falling victim to their negative effects. The purpose of this study was to examine opioid use in the pediatric fracture population by determining and comparing the average hospital opioid dosage utilized in the operative pediatric elbow and femur fractures and determining and comparing the average dose prescribed following operative treatment of elbow and femur fractures. METHODS: All elbow and femur fractures treated operatively between January and December 2016 were identified. Patients aged 0 to 17 years with closed injuries who presented to the emergency department (ED) within 24 hours of injury and underwent operative treatment were included. Demographic information, opioid and nonopioid analgesic medication doses administered in the ED and while inpatient, and postdischarge prescription information were recorded. Opioid doses were converted to oral morphine equivalents. RESULTS: In total, 91.9% and 78.1% of patients received opioids during the ED and inpatient periods, respectively. Only 30% of patients in either cohort received a nonopioid analgesic in the ED and only 44% received ibuprofen while inpatient. Average total opioid dose per hour of hospital stay was not significantly different between elbow fracture and femur fracture cohorts, which was unexpected. There was no significant difference between the average opioid dose or number of doses prescribed for postdischarge use between cohorts. CONCLUSIONS: This study provides data on average hospital opioid and nonopioid use following pediatric elbow and femur fractures. The results reveal inconsistent nonopioid analgesic use and similar hospital opioid use in elbow and femur fracture patients. This study provides baseline analgesic use data for future investigations. LEVEL OF EVIDENCE: Level IV. PMID- 30431543 TI - Bayesian Methods Might Solve the Problems with Magnitude-based Inference. PMID- 30431544 TI - Response. PMID- 30431545 TI - Nordic Exercise Should Not Be Used for Predictive Modeling of Hamstring Injuries. PMID- 30431547 TI - Methods to Estimate VO2max upon Acute Hypoxia Exposure-Corrigendum. PMID- 30431546 TI - Response. PMID- 30431548 TI - The one-minute preceptor model: A systematic review. AB - BACKGROUND AND PURPOSE: Teaching models provide a systemic framework for didactic and clinical teaching. The One-Minute Preceptor (OMP) is one teaching model, providing five microskills to organize a learning experience for students in the clinical environment. This review aims to integrate the literature on the OMP model by highlighting potential use for nurse practitioners while identifying directions for future research. METHODS: Electronic databases were searched from December 2017 to January 2018 for articles published in English. The databases included PubMed, CINAHL, and MEDLINE using terms including "preceptor," "clinical teaching," "time-efficient teaching," and "precepting." Of 32 articles in the final search, only 12 experimental quantitative studies were included in the synthesis and 20 descriptive studies in the discussion. CONCLUSIONS: The OMP model is supported by literature for its effectiveness as a teaching model and preference by students and preceptors. It has been shown to increase teaching techniques including feedback and assessment of students' clinical reasoning. IMPLICATIONS FOR PRACTICE: The OMP model has the potential to overcome clinicians' barriers to precepting nurse practitioner students. Future research may evaluate the use of this model specific to nurse practitioner preceptors and students, perceived time benefits in clinical teaching, overall improvement in clinical teaching, and use in interprofessional precepting. PMID- 30431549 TI - Lung cancer screening: Practice guidelines and insurance coverage are not enough. AB - BACKGROUND AND PURPOSE: Low-dose computed tomography (LDCT) is expected to increase early detection of lung cancer and improve survival. The growth in the number of advanced nurse practitioners (NPs) in primary care settings increases the likelihood that an NP will serve as a patient's provider. This study's purpose was to examine knowledge, attitudes, and practices regarding LDCT among NPs who work in primary care settings. METHODS: An explanatory, sequential, mixed method design used a 32-item questionnaire, followed by a semi-structured telephone interview. The development of the survey and interview questions were guided by a conceptual framework representing a temporal sequence for behavior change and potential barriers to guideline adherence. CONCLUSIONS: Nurse practitioners believe that shared decision making with their high-risk patients about LDCT is within their scope of their practice. Working in time-constrained primary care settings, NPs have limited abilities to improve the uptake of LDCT. Substantial patient barriers exist that deter follow through on providers' recommendation. Disseminating guidelines and authorizing health insurance reimbursement is insufficient. IMPLICATIONS FOR PRACTICE: Research is needed that investigates the screening process so that barriers can be closely studied. Culture change is needed where early detection has greater value for insurers, providers, and patients. PMID- 30431551 TI - Can telemedicine improve triage and patient satisfaction in urgent care settings? AB - Urgent care centers (UCCs) frequently experience long wait times, overcrowding, and patient dissatisfaction. According to recent studies in the emergency care setting, utilization of telemedicine during patient triage has demonstrated reduction in patient wait time and improvement in patient satisfaction. Implementation of telemedicine in urgent care settings may make triage faster and more efficient and lead to similar improvements in wait time and patient satisfaction. Finally, there is potential for telemedicine to improve working conditions for providers and staff of UCCs. PMID- 30431550 TI - Delivery of a community-based nutrition education program for minority adults. AB - BACKGROUND AND PURPOSE: Chronic diseases such as heart disease, type 2 diabetes, and obesity disproportionately affect minority adults, including African Americans. Engaging in lifestyle changes such as improving dietary habits and increasing physical activity can decrease the incidence and severity of these chronic diseases. The purpose of this research study is to explore the impact of a nutrition education program on health behaviors, lifestyle barriers, emotional eating, and body mass index (BMI) in a community-based setting with a minority sample. METHODS: A convenience sample of 47 primarily African American adults participated in two similar Full Plate Diet nutrition interventions for 6 weeks (group I) and 8 weeks (group II). Participants completed pre-assessment and post assessment of fruit, vegetable, and fat intake, as well as pre-assessment and post-assessment on physical activity, healthy lifestyle barriers, emotional eating, and BMI. CONCLUSIONS: After intervention, there was a significant increase in intake of fruits and vegetables and decreased fat intake. No significant differences were found in physical activity, healthy lifestyle barriers, emotional eating, or BMI after the intervention. IMPLICATIONS FOR PRACTICE: A structured, community-based nutrition education program may result in improved dietary habits among African Americans. PMID- 30431552 TI - Health Information and the Quality and Safety of Care for People With Disability: An Analysis of Australian Reports of Reviewable Deaths in Residential Care. AB - OBJECTIVE: Many Australians with disability live in residential care and require assistance to manage their health information across hybrid care settings encompassing residential care, primary and tertiary care, and allied health. In this study, we examined case study reports on people with disability living in residential care in New South Wales, Australia to (a) identify threats to the quality of care and safety for this vulnerable patient group in relation to health documentation and information infrastructure and (b) evaluate the applicability of a conceptual health information infrastructure model. METHODS: All 99 case studies were extracted from eight New South Wales Ombudsmen reports of reviewable deaths for a directed content analysis applying a conceptual model of health information infrastructure in residential care. RESULTS: Ninety-one percent of case studies (n = 90) contained information relation to documentation. Forty-seven percent of case studies (n = 47) linked failures in documentation to risk of death, and 12% (n = 12) described best practice use of documentation. Threats to quality of care and safety related to poor "coordination" of information, including information not being implemented, poor "communication" across services, and discrepancies between "policy and practice" in health management. CONCLUSIONS: The conceptual model demonstrated how "coordination" and "communication" of health information relate to tensions between "policy and practice," influencing the safety and quality of care for people with disability in residential care. The model was a good fit to investigate how health information infrastructure may affect the quality of residential care and could inform holistic digital solutions to deliver safer, integrated, and higher quality care for people with disability. PMID- 30431553 TI - Extended Patient Alone Time in Emergency Department Leads to Increased Risk of 30 Day Hospitalization. AB - OBJECTIVES: This study was conducted to describe patients at risk for prolonged time alone in the emergency department (ED) and to determine the relationship between clinical outcomes, specifically 30-day hospitalization, and patient alone time (PAT) in the ED. METHODS: An observational cohort design was used to evaluate PAT and patient characteristics in the ED. The study was conducted in a tertiary academic ED that has both adult and pediatric ED facilities and of patients placed in an acute care room for treatment between May 1 and July 31, 2016, excluding behavioral health patients. Simple linear regression and t tests were used to evaluate the relationship between patient characteristics and PAT. Logistic regression was used to evaluate the relationship between 30-day hospitalization and PAT. RESULTS: Pediatric patients had the shortest total PAT compared with all older age groups (86.4 minutes versus 131 minutes, P < 0.001). Relationships were seen between PAT and patient characteristics, including age, geographic region, and the severity and complexity of the health condition. Controlling for Charlson comorbidity index and other potentially confounding variables, a logistic regression model showed that patients are more likely to be hospitalized within 30 days after their ED visit, with an odds ratio (95% confidence interval) of 1.056 (1.017-1.097) for each additional hour of PAT. CONCLUSIONS: Patient alone time is not equal among all patient groups. Study results indicate that PAT is significantly associated with 30-day hospitalization. This conclusion indicates that PAT may affect patient outcomes and warrants further investigation. PMID- 30431554 TI - The Ambulatory Version of the Safety Attitude Questionnaire: Psychometric Validation and Measurement Properties in Nigerian Clinical Setting. AB - BACKGROUND: Understanding the safety culture of health care providers can help administrators improve patient safety. However, it is difficult to measure complex constructs such as safety culture without valid and reliable tools. This study determined the measurement properties of the ambulatory version of the safety attitude questionnaire (SAQ-AV) in the Nigerian clinical setting. METHODS: A multiphase, iterative research involving clinical staff in primary and tertiary level of care in South-south Nigeria. The phases included face and content validity by subject experts, pretesting with clinical staff and a field validation involving 812 clinical staff. The acceptability, reliability (internal consistency), and validity (face, content, and construct) of the SAQ-AV were determined. All quantitative analysis was conducted using the SPSS Version 22 statistical package with statistical significance set at a P value of less than 0.05. RESULTS: A response rate of 53.7% was obtained during the field validation study. The item nonresponse rates were less than 10%, whereas extremes of the response scale were frequently endorsed. The internal consistency of the scale was good (Cronbach's alpha of 0.91 for entire scale and ranged from 0.62 to 0.76 among the different domains of the tool). Patient safety culture scores from primary and tertiary health care facilities assessed were significantly different. CONCLUSIONS: The SAQ-AV is an acceptable, reliable, and valid tool for use in assessing patient safety culture in ambulatory settings in Nigeria. There is a need to determine its dimensionality and factor structure in future research. PMID- 30431555 TI - Evaluating the Need for Pediatric Procedural Sedation Training in Pediatric Critical Care Medicine Fellowship. AB - OBJECTIVES: Pediatric procedural sedation has been increasingly performed by pediatric intensivists over the past decade. Pediatric Critical Care Medicine fellowship guidelines do not specify how fellows obtain proficiency in pediatric procedural sedation. We sought to survey the state of pediatric procedural sedation training during fellowship and whether fellows thought it was sufficient. DESIGN: A 21-question survey gathered data on pediatric procedural sedation training provided to Pediatric Critical Care Medicine fellows. Surveys were sent to fellowship directors with instructions to distribute to second- and third-year fellows or recent graduates. Over 2 months, up to three e-mail reminders were sent to fellowship directors whose program had not completed at least one survey. SUBJECTS: Senior fellows and graduates of 65 active Accreditation Council for Graduate Medical Education Pediatric Critical Care Medicine fellowship programs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixty-five percent of fellowship programs (42/65) returned at least one response. Ninety senior fellows and 27 recent graduates responded. Of respondents, 38% received pediatric procedural sedation training during the fellowship, and 32% reported mandatory training. Nine percent of programs used simulation. Although 61% who received training felt adequately prepared to perform pediatric procedural sedation, 25% needed additional preceptorship to sedate independently. Nearly one third (31%) reported that completion of a predetermined number of cases was required to sedate independently. Forty-eight percent reported a minimum number of cases was required for hospital credentialing. Nearly 45% were allowed to perform pediatric procedural sedation off the unit after receiving credentials. When asked if inadequate pediatric procedural sedation training would be a deterrent to applying for a position that included pediatric procedural sedation, 8.6% replied yes, 52.6% replied no, and 38.8% replied they were unsure. CONCLUSIONS: Pediatric procedural sedation lacks a clearly defined training pathway. Most fellows find pediatric procedural sedation a valuable skill set. We propose that all Pediatric Critical Care Medicine fellows receive training that includes pediatric procedural sedation critical incident simulation and cases performed outside the PICU to establish proficiency. PMID- 30431556 TI - Mortality of Critically Ill Children Requiring Continuous Renal Replacement Therapy: Effect of Fluid Overload, Underlying Disease, and Timing of Initiation. AB - OBJECTIVE: To identify risk factors associated with mortality in critically ill children requiring continuous renal replacement therapy. DESIGN: Retrospective observational study based on a prospective registry. SETTING: Tertiary and quaternary referral 30-bed PICU. PATIENTS: Critically ill children undergoing continuous renal replacement therapy were included in the study. INTERVENTIONS: Continuous renal replacement therapy. MEASUREMENTS AND MAIN RESULTS: Overall mortality was 36% (n = 58) among the 161 patients treated with continuous renal replacement therapy during the study period and was significantly higher in patients on extracorporeal membrane oxygenation (47.5%, 28 of 59) than in patients not requiring extracorporeal membrane oxygenation (28.4%, 29 of 102; p = 0.022). According to the admission diagnosis, we found the highest mortality in patients with onco-hematologic disease (77.8%) and the lowest in patients with renal disease (5.6%). Based on multivariate logistic regression analysis, the presence of higher severity of illness score at admission (adjusted odds ratio, 1.49; 95% CI, 1.18-1.89; p < 0.001), onco-hematologic disease (odds ratio, 17.10; 95% CI, 4.10-72.17; p < 0.001), fluid overload 10%-20% (odds ratio, 3.83; 95% CI, 1.33-11.07; p = 0.013), greater than 20% (odds ratio, 15.03; 95% CI, 4.03-56.05; p < 0.001), and timing of initiation of continuous renal replacement therapy (odds ratio, 1.01; 95% CI, 1.00-1.01; p = 0.040) were independently associated with mortality. In our population, the odds of dying increases by 1% for every hour of delay in continuous renal replacement therapy initiation from ICU admission. CONCLUSIONS: Mortality in children requiring continuous renal replacement therapy remains high and seems to be related to the underlying disease, the severity of illness, and the degree of fluid overload. In critically ill children at high risk for developing acute kidney injury and fluid overload, earlier initiation of continuous renal replacement therapy might result in decreased mortality. PMID- 30431557 TI - A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children. AB - OBJECTIVES: Limited data exist on the effects of extracorporeal membrane oxygenation on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with extracorporeal membrane oxygenation using population pharmacokinetic modeling. DESIGN: Multicenter, prospective observational study. SETTING: The pediatric and cardiac ICUs of six sites of the Collaborative Pediatric Critical Care Research Network. PATIENTS: Seventeen critically ill children (30 d to < 2 yr old) on extracorporeal membrane oxygenation who received cefepime as standard of care between January 4, 2014, and August 24, 2015, were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A pharmacokinetic model was developed to evaluate cefepime disposition differences due to extracorporeal membrane oxygenation. A two-compartment model with linear elimination, weight effects on clearance, intercompartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg) for a patient weighing 5.8 kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1,170 mL. In the setting of blood transfusions, V1 increased by over two-fold but was reduced with increasing age of the extracorporeal membrane oxygenation circuit oxygenator. CONCLUSIONS: Cefepime clearance was reduced in pediatric patients treated with extracorporeal membrane oxygenation compared with previously reported values in children not receiving extracorporeal membrane oxygenation. The model demonstrated that the age of the extracorporeal membrane oxygenation circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_minimum inhibitory concentration of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on extracorporeal membrane oxygenation might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing. PMID- 30431558 TI - Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males. AB - Painful temporomandibular disorders (TMD) is the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. While many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a GWAS assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified three distinct loci that were significant in combined or sex-segregated analyses. A single nucleotide polymorphism (SNP) on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio [OR]=2.9, 95% CI: 2.02-4.27, P=2.2x10). This association was nominally replicated in a meta-analysis of seven independent orofacial pain cohorts including 160,194 participants (OR=1.16, 95% CI: 1.0-1.35, P = 2.3x10). Functional analysis in human dorsal root ganglia (DRG) and blood indicated this variant is an expression quantitative trait locus (eQTL), with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43x10). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically-determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men.Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a "work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government. PMID- 30431559 TI - Different regimens of penicillin antibiotics given to women routinely for preventing infection after cesarean section: A systematic review and meta analysis. AB - BACKGROUND: Varied regimens of penicillin antibiotics were given to women for preventing infection after cesarean section, but there is no study compares the effectiveness and safety of them. METHODS: We searched MEDLINE, Embase, CENTRAL, CNKI, Wanfang, VIP, and CBM Database, and contacted experts in the field and searched reference lists of retrieved studies. We included randomized controlled trials comparing different regimens of penicillin antibiotics given to women after cesarean section. Two review authors independently assessed the studies for inclusion, assessed risk of bias, and carried out data extraction. RESULTS: A total of 18 randomized controlled trails (involving 3287 pregnant women) were eligible. Compared with after umbilical cord clamping, penicillin antibiotics prophylaxis before skin incision could reduce the risk of endometritis for women undergoing cesarean. Compared with using penicillin antibiotics alone, using antibiotic-inhibitor combination could reduce the risk of endometritis or fever. No statistically significant difference was present between single-dose versus multidose, short term versus long term, intravenous injection versus lavag in the risk of reported outcomes. CONCLUSION: There is insufficient evidence to draw certain conclusions on which regimen of penicillin antibiotics is the best in this review. Further studies should pay attention to the study design, and besides the outcomes of pregnant women, researchers should focus on the outcomes of newborns. PMID- 30431560 TI - Brief topical sodium nitrite and its impact on the quality of life in patients with sickle leg ulcers. AB - Cutaneous ulceration from sickle cell disease negatively impacts quality of life. Topical sodium nitrite has previously been shown to reduce the size of sickle leg ulcers. This study examined how topical sodium nitrite impacted the quality of life scores in patients with sickle leg ulcers.We prospectively collected data in patients enrolled in a leg ulcer study (n = 17) or an allogeneic hematopoietic cell transplant study (nonulcer group, n = 15). Both groups completed a pretreatment Short Form-36 questionnaire; the ulcer group completed a second questionnaire after 4 weeks of topical sodium nitrite applications. Data were analyzed by age, sex, >50% area improvement postintervention, and sickle-related complications (vaso-occlusive crises, pulmonary hypertension, or avascular necrosis). Physical and mental component summary scores were analyzed with Student t test.Physical summary scores were lower than mental summary scores in all groups, indicating leg ulcers among other sickle related complications negatively impacted physical quality of life measures. After sodium nitrite use, physical summary scores improved in the leg ulcer group (34.5 +/- 9.4 to 39 +/- 10.3, P = .03), and mental summary scores improved more in ulcerated patients <=35 years old (40.7 +/- 6.9 to 51.7 +/- 9.7, P = .01).Brief topical sodium nitrite has the potential to improve quality of life, especially in younger individuals. Longer treatment duration and randomized-controlled trials are needed to confirm the efficacy of this topical therapy. PMID- 30431561 TI - Comparison of dipeptidyl peptidase-4 inhibitors and pioglitazone combination therapy versus pioglitazone monotherapy in type 2 diabetes: A system review and meta-analysis. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitor and pioglitazone combination therapy have been widely used for patients with inadequate glycemic control on monotherapy. This meta-analysis assessed the efficacy and safety of this combination therapy in patients with type 2 diabetes mellitus (T2DM). METHODS: We searched the MEDLINE, Embase, and Cochrane databases. Studies were eligible if they were randomized controlled trials (RCTs) on DPP-4 inhibitor and pioglitazone combination therapy in patients with T2DM through the end of February 2016, using the keywords "alogliptin," "dutogliptin, " "linagliptin," "saxagliptin," "sitagliptin," "vildagliptin," "gliptins," "DPP-4 inhibitor," and "pioglitazone." RCTs were selected if they compared DPP-4 inhibitors and pioglitazone as combination therapy; treatment duration was >=12 weeks; and the reported data included hemoglobin A1c (HbA1c) or fasting plasma glucose (FPG) change, total or any other system Adverse Events (AEs). We estimated effect size with random effects or fixed-effects meta-analysis, I statistic was used to estimate heterogeneity of results. RESULTS: Seven RCTs were included. Compared with pioglitazone monotherapy, combination DPP-4 inhibitor and pioglitazone therapy were associated with increased reduction in HbA1c ([MD]-0.64%;-0.73 to -0.55) and FPG ([MD] -0.94; -1.12 to -0.76) levels, more patients in the combination therapy groups versus pioglitazone monotherapy groups had an A1c of < 7% ([OR]2.52; 2.18, 3.17) at the end of the studies, but was not associated with further reduction in higher risk of hypoglycaemia, edema, or any other system AEs. We also noticed that DPP-4 inhibitor and pioglitazone combination therapy were associated with better improvement of pancreatic beta-cell function. CONCLUSIONS: DPP-4 inhibitor and pioglitazone combination therapy provided better glycemic control, both according to HbA1c and FPG levels, than pioglitazone monotherapy. Safety analysis showed well tolerance of combination therapy, even in hypoglycemic and edema AEs. However, additional large-scale, high quality, long-term follow-up clinical trials are necessary to confirm its long-term effectiveness. PMID- 30431562 TI - Efficacy of vitamin D in treatment of inflammatory bowel disease: A meta analysis. AB - BACKGROUND: Vitamin D (VitD) deficiency is prevalent in patient with inflammatory bowel disease (IBD). Recent studies have found that VitD can induce and maintain IBD remission through antibiosis, anti-inflammatory, and repair of intestinal mucosal barriers, thus improving the patient's disease activity and quality-of life. The purpose of this meta-analysis is to evaluate the therapeutic effect and safety of VitD in the treatment of IBD. METHODS: Published randomized controlled trials (RCTs) were included from electronic databases (PubMed, Embase, Cochrane library, Web of Science, and so forth). Cochrane handbook was applied to evaluate the methodological quality. The levels of 25(OH)D3, relapse rate, inflammation index, and adverse events were compared between the experimental group and the control group (placebo group). All statistical analyses were directed by Revman 5.3 software and statistical significance was defined as P < .05. RESULTS: Eighteen RCTs involved 908 patients were included. Meta-analysis showed that VitD improved the 25(OH)D3 levels more significantly than the control group (ng/mL, weighted mean deviation [WMD] = 7.85, 95% CI (5.52, 10.18), P < .000001), and compared with lower doses, there were significant differences increasing 25(OH)D3 levels (WMD = 11.19, 95% CI [4.73, 17.65], P = .0007) in high-dose VitD treatment while there was no significant difference in the adverse events between 2 groups (WMD = 1.56, 95% CI [0.74, 3.29], P = .24). VitD reduced the relapse rate more significantly than the control group, but there were no significant differences between the low-dose and high-dose vitamin D treatment. The erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hsCRP) of the VitD and the control group showed no statistically significant difference (ESR [mm/h]: WMD = -0.22, 95% CI [-5.73, 5.29], P = .94; hsCRP (mg/dL): WMD = -0.53, 95% CI [-1.68, 0.62], P = .37). CONCLUSIONS: The treatment of VitD in patients with IBD can improve the level of 25(OH)D3 and control the relapse rate of the disease, whose clinical curative effect is more accurate. Thus VitD should be recommended for the treatment of IBD, at least as an adjunctive treatment. PMID- 30431563 TI - Comprehensive preoperative regime of selective gut decontamination in combination with probiotics, and smectite for reducing endotoxemia and cytokine activation during cardiopulmonary bypass: A pilot randomized, controlled trial. AB - BACKGROUND: Both selective digestive decontamination (SDD) and probiotics have been reported to reduce endotoxemia. However, the available results are conflicting and few studies have investigated the combined effect of SDD and probiotics. This study aimed to examine the effectiveness of a comprehensive preoperative regimen of SDD in combination with probiotics and smectite on perioperative endotoxemia and cytokine activation in patients who underwent elective cardiac surgery with cardiopulmonary bypass (CPB) in a pilot, prospective, randomized, controlled trial. METHODS: Patients who underwent elective Aortic Valve Replacement or Mitral Valve Replacement surgery from July 2010 to March 2015 were included. In total, 30 eligible patients were randomly assigned to receive either the comprehensive preoperative regimen (n = 15) (a combination of preoperative SDD, probiotics, and smectite) or the control group (n = 15) who did not receive this treatment. The levels of endotoxin, IL-6, and procalcitonin were measured at the time before anesthesia induction, immediately after cardiopulmonary bypass (CPB), 24 hours after CPB, and 48 hours after CPB. The primary outcomes were changes in endotoxin, IL-6, and procalcitonin concentrations after CPB. RESULTS: The mean levels of change in endotoxin levels after CPB in patients receiving the comprehensive preoperative regimen was marginally significantly lower than those in control group (F = 4.0, P = .0552) but was not significantly different for procalcitonin (F = .14, P = .7134). An interaction between group and time for IL-6 was identified (F = 4.35, P = .0231). The increase in IL-6 concentration immediately after CPB in the comprehensive preoperative group was significantly lower than that in the control group (P = .0112). The changes in IL-6 concentration at 24 hours and 48 hours after CPB were not significant between the comprehensive preoperative group and control group. CONCLUSION: The present pilot, prospective, randomized, controlled study in patients undergoing cardiac surgery with CPB demonstrated that 3 days of a comprehensive preoperative regime of SDD in combination with probiotics and smectite may reduce the endotoxin and IL-6 levels after CPB compared with the control group. PMID- 30431564 TI - Unique imaging findings in fibromuscular dysplasia of renal arteries: A case report. AB - RATIONALE: Fibromuscular dysplasia (FMD) is a rare vascular disorder that causes abnormal cell growth in arterial walls. The classic "string of beads" sign has been reported in many cases, whereas the appearance of tubular stenosis and distal tapering of renal arteries with multiple renal infarctions, as well as left kidney atrophy occurring in one patient, has not been precisely described. PATIENT CONCERNS: A 19-year-old woman presented to us with a history of elevated blood pressure without any symptoms for the past 1 month. Routine laboratory tests indicated a moderately impaired renal function, and ultrasound examination demonstrated a small-sized left kidney and seriously decreased blood flow of the left renal artery and its branches. DIAGNOSIS: Subsequent contrast-enhanced computed tomographic angiography (CTA) demonstrated multiple ischemic infarctions in the bilateral kidneys, and FMD was suggested at that time. Thereafter, we performed selective reno-angiography, which confirmed that the all left renal arteries had tubular stenosis and that right renal arterial branches presented distal tapering. INTERVENTION: Antihypertensive drugs were prescribed conservatively, including nifedipine 60 mg/d and prazosin 4 mg/d, to lower the patient's blood pressure. OUTCOMES: The patient had a well-controlled blood pressure and an improved renal function at her 6-month follow-up. LESSONS: We should take the diagnosis of FMD into account if young women develop asymptomatic hypertension. To our knowledge, this is the first case that exhibited renal artery FMD manifesting as tubular stenosis and distal tapering, especially followed by bilateral renal infarctions and significant atrophy of the left kidney. In addition, CTA combined with digital subtraction angiography (DSA) may be more sensitive than other tests with respect to the detection of intrarenal infarctions and arterial variants of FMD. PMID- 30431565 TI - Comparison of dabigatran and warfarin used in patients with non-valvular atrial fibrillation: Meta-analysis of random control trial. AB - BACKGROUND: Dabigatran is a kind of oral anticoagulant and there was little review only about dabigatran and warfarin used in patients with atrial fibrillation. This meta-analysis only assesses the dabigatran and warfarin used in patients with atrial fibrillation. DESIGN: Cochrane Library, PubMed, Clinical Trials.gov, CNKI, and WanFang databases were searched. The primary endpoint was the incidence of stroke and the second endpoints were the incidence of bleeding and embolic events. RESULTS: Six RCTs and 20086 patients were included in our meta-analysis. No significant difference was obtained between 110 mg dabigatran and warfarin on the endpoint of stroke (risk ratio (RR), 0.90; 95% confidence interval [CI], 0.71-1.12; P = .34; I = 0%) and embolic events p (RR, 0.89; 95% CI, 0.71-1.12; P = .32; I = 0%). However, the 110 mg dabigatran associated lower incidence of bleeding (RR, 0.81; 95% CI, 0.69-0.95; P = .01; I = 0%) compare with warfarin. When compared with 150 mg dabigatran, warfarin associated with lower rate of stroke (RR, 0.96; 95% CI, 0.83-1.12; P = .62; I = 0%) and embolic events (RR, 0.67; 95% CI, 0.53-0.86; P = .001; I = 0%) but similar in the incidence of bleeding (RR, 0.67; 95% CI, 0.53-0.86; P = .001; I = 0%). CONCLUSION: No significant difference was obtained between 110 mg dabigatran and warfarin in the incidence of stroke and embolic events. However, the 110 mg dabigatran associated lower incidence of bleeding compare with warfarin. When compared with 150 mg dabigatran, warfarin associated with lower incidence of stroke and embolic events but similar in the incidence of bleeding. PMID- 30431566 TI - The clinical value of using chloroquine or hydroxychloroquine as autophagy inhibitors in the treatment of cancers: A systematic review and meta-analysis. AB - BACKGROUND: Autophagy is a mechanism which relies on lysosomes for clearance and recycling of abnormal proteins or organelles. Many studies have demonstrated that the deregulation of autophagy is associated with the development of various diseases including cancer. The use of autophagy inhibitors is an emerging trend in cancer treatment. However, the value of autophagy inhibitors remains under debate. Thus, a meta-analysis was performed, aiming to evaluate the clinical value of autophagy-inhibitor-based therapy. METHODS: We searched for clinical studies that evaluated autophagy-inhibitor-based therapy in cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR), 6-month progression-free survival (PFS) rate, and 1-year overall survival (OS) rate. RESULTS: Seven clinical trials were identified (n = 293). Treatments included 2 combinations of hydroxychloroquine and gemcitabine, 1 combination of hydroxychloroquine and doxorubicin, 1 combination of chloroquine and radiation, 2 combinations of chloroquine, temozolomide, and radiation, and 1 hydroxychloroquine monotherapy. Autophagy-inhibitor-based therapy showed higher ORR (RR: 1.33, 95% confidence interval [CI]: 0.95-1.86, P = .009), PFS (RR: 1.72, 95% CI: 1.05-2.82, P = .000), OS (RR: 1.39, 95% CI: 1.11-1.75, P = .000) values than the therapy without inhibiting autophagy. CONCLUSION: This meta-analysis showed that autophagy-inhibitor-based therapy has better treatment response compared to chemotherapy or radiation therapy without inhibiting autophagy, which may provide a new strategy for the treatment of cancers. PMID- 30431567 TI - Application of shaft method assisted biological mesh in laparoscopic inguinal hernia repair. AB - To compare the feasibility and advantage of traditional tiling method and shaft method to place biological mesh following laparoscopic repair of inguinal hernia.Sixty cases from January 2013 to January 2014 treated with laparoscopic inguinal hernia neoplasty with biological patches were included. All the cases were randomly divided into control group and observation group. Observation group was treated with shaft method to place biological mesh, while control group was treated with traditional tiling method. The length of the operation, hospital fees, and rate of occurrence of surgical complications were compared.All 60 cases were successfully treated with laparoscope inguinal hernia repair. None were converted to open operations. Total operation times for the observation group and control group were 54 +/- 4.5 and 71 +/- 7.2 minutes, respectively (P < .05). The hospital fees of the observation group and control group were 21,280 +/- 365 RenMinBi Yuan (RMB) and 24,280 +/- 428 RMB, respectively (P < .05). The rates of occurrence of surgical complications were 3.33% (1/30) and 16.7% (5/30), respectively (P < .05).The shaft method can be applied in laparoscopic inguinal hernia repair with biological mesh. Compared with the traditional method, the shaft method has apparent advantages, fewer complications during and after the operation. PMID- 30431568 TI - A methodology to systematically analyze the hospital discharge of terminally ill patients. AB - To provide an appropriate method to systematically analyze the hospital discharge of terminally ill patients especially the cooperation between hospital and community nurses and the quality of the discharge handovers. To evaluate the hospital discharge process of terminally ill patients in an academic hospital in the Netherlands using the proposed method.Data were collected from a prospective cohort of all terminally ill patients discharged from the University Medical Center Groningen, the Netherlands, between June and November 2014. The hospital discharges were assessed using 2 questionnaires: an inventory questionnaire, to determine the required care, and an evaluation questionnaire, to evaluate the care actually organized and the discharge handovers. The inventory questionnaire was completed prior to discharge and the evaluation questionnaire between 3 to 7 days after discharge.Around 130 consecutive patients were included. The discharge took place on the desired date in 86% of cases and the average overall discharge grade on a 10-point scale was 7.4 (range: 3-9.5). In 23% of cases discrepancies between required and provided care were identified and medication queries existed in 29%.This study provides a methodology to analyze the hospital discharge procedure of terminally ill patients that can be utlized in any hospital. Structured analysis of the discharge process is valuable and identifies where improvements can be made. Within the study cohort the home care could be arranged at short notice and was considered sufficient. However, in a significant proportion of patients a discrepancy between required and arranged care and queries about medication were identified. PMID- 30431569 TI - Prognostic value role of radiofrequency lesion size by cardiac magnetic resonance imaging on outcomes of ablation in patients with ischemic scar-related ventricular tachycardia: A single center pilot study. AB - Inadequate ablation lesion formation may be responsible for post-ablation ventricular tachycardia (VT) recurrences.We aimed to evaluate whether visualisation of radiofrequency (RF) lesion size by cardiac magnetic resonance imaging (CMR) has any role in predicting adequacy of lesion and in estimating outcome.Retrospective pilot studyNine consecutive patients (8 male, age 60 +/- 13 years) underwent ablation for sustained VT because of ischemic scar were evaluated for pre- and post-procedure scar tissue by CMR to characterize ablation lesions. Microvascular obstruction (MVO) surrounded by late gadolinium enhancement was defined as irreversible RF lesion. All patients were followed for at least 6 months for recurrences.Five of the patients had previous inferior myocardial infarction (MI), whereas remaining 4 had anterior MI. Acute procedural success, as defined by termination of the arrhythmia without recurrence in 30 minutes, was attained in all patients. Contrast enhancement and wall motion abnormality in presumed infarction area were confirmed by pre-ablation CMR images. MVO was detected at the reported ablation site in 6/9 patients, all arrhythmia- and symptom-free at median 24 months (range 8-38 months) follow-up. In remaining 3 patients who had VT recurrence (clinical VT in 2, sustain VT with a new morphology in 1), MVO was not detected despite achievement of acute procedural success. There was no correlation with pre-ablation scar size and clinical arrhythmia recurrence.CMR is a useful imaging modality to guide ablation procedures by detecting scar tissue. Additionally MVO seen by post-procedural imaging may be related to adequacy of RF ablation lesions and may correlate with clinical outcome. PMID- 30431570 TI - A pilot study of the effect of ezetimibe for postprandial hyperlipidemia. AB - This study aimed to explore the feasible effect of ezetimibe for postprandial hyperlipidemia (PPHP).Sixty participants were included in this study. Of these, 30 subjects in the intervention group received ezetimibe, while the remaining 30 participants in the control group did not undergo ezetimibe. All patients in intervention group were treated for a total of 2 weeks. Primary endpoints consisted of serum levels of total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG). Secondary endpoints included apoB-48, remnant lipoprotein cholesterol (RLP-C), blood glucose, insulin, hemoglobin A1c (HbA1c), and monocyte chemotactic protein (MCP). All outcomes were measured before and after 2-week treatment.After 2-week treatment, participants in the intervention group did not show better outcomes in primary endpoints of Total-C, LDL-C, HDL-C, and TG; and secondary endpoints of apoB-48, RLP-C, blood glucose, insulin, HbA1c, and MCP, compared with subjects in the control group.The results of this study showed that ezetimibe may be not efficacious for participants with PPHP after 2-week treatment. PMID- 30431571 TI - Relapsed subcutaneous panniculitis-like T cell lymphoma evaluated by FDG PET/CT: A clinical case report. AB - RATIONALE: Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is a rare primary cutaneous T cell lymphomas expressing alpha/beta T cell receptors that preferentially involves subcutis, and few reports have investigated the diagnosis of suspicious relapsed SPTCL using F-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT). PATIENT CONCERNS: A 15-year-old woman complaining of a growing painless subcutaneous mass on perinaeum recurred 2 months ago, suggestive of suspicious relapsed SPTCL, underwent FDG PET/CT for diagnosis and treatment follow-up. DIAGNOSIS: Based on the feature of FDG PET/CT images which revealed multiple increased FDG-avid subcutaneous adipose tissue lesions on the left upper arm, the left chest and perinaeum, involvement of bilateral inguinal lymph nodes, and the effective chemotherapy, she was diagnosed with relapsed SPTCL. INTERVENTIONS AND OUTCOMES: Fortunately, the patient's skin lesions subsided gradually after 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) regimen. Besides, complete remission was observed on interim-FDG PET/CT after 3 cycles of CHOP treatment. LESSONS: FDG PET/CT can clarify the diagnosis in suspicious relapsed SPTCL, avoiding performing skin biopsy again. PMID- 30431572 TI - Common atrium and the associated malformations: Evaluation by low-dose dual source computed tomography. AB - Common atrium (CA) is a rare complex congenital heart disease. The studies of CA are mostly case reports, while few have been done regarding its morphological characteristics. We aimed to determine CA characteristics and diagnostic accuracy in assessing associated malformations in these patients with low-dose dual-source computed tomography (DSCT).Twenty-one pediatric and adolescent CA patients underwent low-dose DSCT. Different ventricular types and associated malformations were assessed. The diagnostic accuracy of DSCT and transthoracic echocardiography (TTE) in evaluating associated malformations were assessed. The effective doses of DSCT were calculated.Patients (n = 21) were divided into CA with biventricular physiology (n = 7) and CA with single ventricle (SV) (n = 14). There were 3 types of SV morphology: single left ventricle (n = 5), single right ventricle (n = 6), and undifferentiated ventricle (n = 3). In all, 22 associated malformations were seen in CA and 56 in CA with SV. DSCT was superior to TTE for detecting intracardiac anomalies (sensitivity: DSCT, 92.31% vs TTE, 76.92%), great vessels anomalies (sensitivity: DSCT, 100.00% vs TTE, 77.50%), and of collateral vessels (sensitivity: DSCT, 100% vs TTE, 20.00%). The estimated mean effective dose was 0.95 +/- 0.44 mSv (<1 mSv).This study indicated that low-dose DSCT is an ideal alternative for pediatric and adolescent patients with CA, providing morphological details of CA and associated malformations with high accuracy. PMID- 30431574 TI - WNT6 is an effective marker for osteosarcoma diagnosis and prognosis. AB - Wingless-Type MMTV Integration Site Family, Member 6 (WNT6) is a member of the Wnt family and its expression is abnormal in different human cancer cell lines. The purpose of this study was to investigate the clinical significance of WNT6 in osteosarcoma.The levels of WNT6 mRNA and protein in tissue and serum were detected through quantitative real-time polymorperase chain reaction (qRT-PCR) and Enzyme Lined Immunosorbent Assay (ELISA), respectively. Chi-square test was performed to estimate the association of WNT6 expression with clinical parameters among osteosarcoma patients. Receiver operation characteristic (ROC) curve was plotted to determine diagnostic performance of serum WNT6 in osteosarcoma. Survival analysis was performed using Kaplan-Meier method. Cox regression analysis was adopted to evaluate prognostic significance of WNT6 expression among osteosarcoma patients.Compared with the controls, WNT6 mRNA and protein levels were significantly elevated in patients with osteosarcoma (P > .05 for all). Furthermore, WNT6 upregulation showed positive correlation with patients' age (P < .001), tumor grade (P < .001) and distant metastasis (P = .001). WNT6 might be a diagnostic marker for osteosarcoma with an AUC of 0.854 combining a specificity of 88.4% and a sensitivity of 77.8%. Survival analysis result indicated that high WNT6 expression predicted poor survival (log rank test, P = .001). WNT6 might be a potential prognostic biomarker for osteosarcoma (HR = 2.227, 95%CI = 1.061 10.842, P = .027).WNT6 may be a diagnostic and prognostic marker in osteosarcoma. PMID- 30431573 TI - Cancer antigen-125 levels correlate with pleural effusions and COPD-related complications in people living at high altitude. AB - Chronic obstructive pulmonary disease (COPD) is the most frequently encountered progressive lung disease in clinical practice. This study sought to determine the predictive ability of the tumor biomarker cancer antigen-125 (CA-125) in the identification of COPD in a cohort of 284 patients with COPD living at high altitude (with an average elevation of over 2500 m).Patients were classified by pleural effusion volumes into 4 categories and serum CA-125 concentrations were measured in each category. The analyses revealed that CA-125 concentrations were positively and significantly correlated with pleural effusion volume. CA-125 concentrations were also positively correlated with pulmonary heart disease and acute exacerbations of COPD, and negatively correlated with pulmonary hypertension.The study evidence suggests that serum CA-125 concentrations are positively correlated with the risk of pleural effusions among patients with COPD living in high-altitude areas, and that CA-125 concentrations are also correlated with pulmonary heart disease, acute exacerbations, and pulmonary hypertension. PMID- 30431575 TI - Ambulation capacity and functional outcome in patients undergoing neuromuscular electrical stimulation after cardiac valve surgery: A randomised clinical trial. AB - BACKGROUND: Early mobilization and physical exercise are considered fundamental components in cardiovascular surgery rehabilitation; however, occasionally they are inadequate for inhibiting functional decline. Neuromuscular electrical stimulation (NMES) is a promising tool in cardiovascular rehabilitation; however, to date, no randomized clinical trial has measured the effects of NMES on functional capacity and quality of life in patients who undergo routine cardiac surgery with a short intensive care unit (ICU) stay. Therefore, we aimed to investigate the effects of NMES on walking ability, muscle strength, functional independence, and quality of life in cardiac valve surgery patients in the immediate postoperative period. METHODS: A randomized, parallel, controlled, 2 arm clinical trial with assessor blinding was conducted. Fifty-nine adult patients in the preoperative period after cardiac valve reconstruction and/or replacement were randomly assigned to a control or intervention group. The intervention group underwent NMES in the quadriceps and gastrocnemius, bilaterally, for 60 minutes, for up to 10 sessions. The primary outcome was ambulation ability, assessed through the Six-Minute Walk Test and Walking Speed Test at postoperative day 5 (5PO). Secondary outcomes were muscular strength (assessed through the Medical Research Council scale), functional independence measure (assessed through the Functional Independence Measurement Questionnaire), and quality of life (assessed through the Nottingham Health Profile) at baseline (preoperative) and at postoperative days 3 and 5. RESULTS: The baseline characteristics were similar in both groups, except for body mass index. There was no statistically significant difference, with a small effect size, between both groups regarding the distance walked (95% CI, -64.87 to 65.97) and walking speed (95% CI, -0.55 to 0.57). There was a statistically significant difference in upper-limb muscle strength loss and decline in mobility at postoperative day 3, which had a tendency to recover to initial values at 5PO, in both groups. No significant between-group difference was noted for muscle strength, functional independence, and quality of life. CONCLUSIONS: The use of NMES had no effect on walking ability, strength, quality of life, or functional outcome in the postoperative period for patients that underwent regular valve replacement. PMID- 30431576 TI - The relation of passive smoking with cervical cancer: A systematic review and meta-analysis. AB - BACKGROUND: Published studies about passive smoking and cervical cancer have found inconsistent results. Hence, the present meta-analysis was performed to assess this association. METHODS: A systematical search was performed to identify eligible cohort and case-control studies in PubMed, Scopus, Elsevier ScienceDirect, and Web of Science databases (up to March, 2018). The quality of included studies was assessed by the Newcastle-Ottawa quality scale (NOS). The random effects model (REM) was used to calculate the pooled odds ratio (ORs). Subgroup and sensitivity analyses were performed. Publication bias was assessed by funnel plot, using Begg's test and Egger's test. RESULTS: Around 14 eligible studies were included for analysis, which included a total of 384,995 participants. The pooled ORs of passive smoking with cervical cancer risk was 1.70 (95% CI: 1.40-2.07, I = 64.3%). Subgroups stratified by continent, study design, quality score, and cervical cancer types/phases suggested that the result was robust. For instance, the pooled ORs for the cohort and case-control studies was 1.37 (95% CI: 1.16-1.62, I = 0%) and 2.09 (95% CI: 1.52-2.89, I = 76.6%), respectively. The pooled ORs ranged from 1.61 (95%CI: 1.34-1.92) to 1.77 (95%CI: 1.44-2.16) after one study was removed each time in the sensitivity analyses, indicating that the result was stable. Publication bias was detected by funnel plot and Egger's tests. The recalculated ORs were 1.33 (95% CI: 1.21-1.47). CONCLUSIONS: This meta-analysis provides evidence that passive smoking is associated with an increased risk of cervical cancer. PMID- 30431577 TI - Biliary tract exploration through a common bile duct incision or left hepatic duct stump in laparoscopic left hemihepatectomy for left side hepatolithiasis: which is better?: A single-center retrospective case-control study. AB - Laparoscopic left hemihepatectomy (LLH) followed by biliary tract exploration is used to treat left-sided hepatolithiasis (LSH). The purpose of this study was to compare the efficacy of 2 methods of biliary tract exploration in LLH:biliary tract exploration through a common bile duct (CBD) incision (with T-tube drainage) or through the left hepatic duct (LHD) stump (without T-tube drainage).LSH patients (113 patients) were recruited retrospectively in our hospital from December 2008 to January 2016. To compare different methods of biliary tract exploration during LLH, the patients were divided into 2 groups: 41 patients underwent biliary tract exploration through the LHD stump (LHD group), and 72 patients underwent biliary tract exploration through a CBD incision (CBD group). Baseline characteristics, surgical outcomes, surgery-related complications, postoperative hospital stay (PHS) and long-term results were compared between the 2 groups.There was no unplanned reoperation in the 2 groups. One patient in the CBD group had a residual stone, which was removed by choledochoscopy 2 months postoperation. Two patients in the LHD group and 3 patients in the CBD group had bile leakage and were cured with abdominal drainage. There were no significant differences in the total operation time, incidence of residual stones and bile leakage between the 2 groups (P > .05). The PHS and the incidence of hypokalemia or hyponatremia in the LHD group were significantly lower than those in the CBD group (P < .05). T-tube-related complications occurred in 13.9% (10/72) of the CBD patients. The mean follow-up period was 37.2 +/- 13.8 months. There were no significant differences in the incidence of recurrence stones or cholangitis (P > .05) between the 2 groups.Exploration of the biliary tract through the LHD stump without T-tube drainage is safe with satisfactory short- and long-term results for selected LSH patients. PMID- 30431578 TI - Progressive large pediatric corneal limbal dermoid management with tissue glue assisted monolayer amniotic membrane transplantation: A case report. AB - RATIONALE: Limbal dermoids are choristomas known as congenital benign tumors found in abnormal locations. Despite the benign nature, enlarging limbal dermoids may cause visual abnormalities by cornea infiltration with fat component, visual axis invasion, gradually induced corneal astigmatism, and finally result in anisometropic amblyopia. Here we report a rare case of progressive, large pediatric corneal limbal dermoid in a newborn, managed with tissue glue-assisted monolayer amniotic membrane transplantation. PATIENT CONCERNS: A 1-day-old male baby (gestational age, 36 +/- 6 weeks; birth body weight, 2785 gram) presented to our clinic with a whitish mass on his right eye since birth. DIAGNOSIS: Ocular examination revealed a solid, whitish-yellow, and ovoid mass with central keratinized epithelium over the superior limbus; the lesion covered two-thirds of the cornea with rapid progression in size. The final pathological examination revealed that the lesion is composed of keratotic lining squamous epithelium resembling epidermis, underling dermal fibrotic connective tissue, and mature fat. INTERVENTIONS: The patient underwent deep lamellar excision followed by mitomycin C (MMC) soaking (0.2 mg/mL, 3 minutes) and tissue glue-assisted monolayer amniotic membrane transplantation with the ring conformer at 2 months of age. OUTCOMES: The ring conformer was smoothly removed 2 weeks after the operation. The patient showed a smooth healing process with less pain and rapid corneal re-epithelization. The ocular surface was stable during the follow-up visits, and no complications were detected. Only mild post-operative scarring over the incision wound was observed. LESSONS: Although a combination of excision, lamellar keratoplasty, and multilayer amniotic membrane and limbal stem cell transplantation is advocated for the treatment of grade II and III pediatric corneal limbal dermoids, the procedure used in this study offers an alternative surgical approach. However, because of the large size of the lesion and the young age of the patient, the management of amblyopia with visual rehabilitation and corneal transplantation is still needed in the future. PMID- 30431579 TI - Identification of 11 potentially relevant gene mutations involved in growth retardation, intellectual disability, joint contracture, and hepatopathy. AB - The multisystemic clinical characteristics of growth retardation, intellectual disability, joint contracture, and hepatopathy in humans are rare and there are no clear diagnoses of these conditions. However, previous studies using exome sequencing have suggested that they are caused by gene mutations, and some related pathogenic gene variants have been found.Here, we performed resequencing and genome-wide variation analysis of 3 individuals (an affected proband and unaffected parents) from a consanguineous family using Solexa sequencing technology to identify mutated genes.The following genetic features were identified: 3,586,775 single-nucleotide polymorphisms (SNPs), 583,416 insertion/deletion polymorphisms (InDels), and 8579 structural variations (SVs) in the genome of the father; 3,624,800 SNPs, 608,685 InDels, and 8,827 SVs in the genome of the mother; 3,574,431 SNPs, 571,196 InDels, and 8371 SVs in the genome of the proband. Variations between samples were determined by comparative analysis of authentic collections of SNPs and were functionally annotated. Variations in several important genes, including SEC22B, FLG, ZNF717, MUC4, TRIL, CTAGE4, FOXG1, LOC100287399, KRTAP1-3, and LRRC37A3, were surveyed by alignment analysis.The results present new evidence that mutations in 11 genes may be associated with characteristic clinical growth retardation, intellectual disability, joint contracture, and hepatopathy. PMID- 30431580 TI - Comparison of clinical outcomes between cystotome-assisted prechop phacoemulsification surgery and conventional phacoemulsification surgery for hard nucleus cataracts: A CONSORT-compliant article. AB - BACKGROUND: This study aimed to investigate the safety and efficacy of the cystotome-assisted prechop phacoemulsification surgery (CAPPS) and conventional phacoemulsification surgery (CPS) in patients with IV degree nucleus cataract. METHODS: The prospective, randomized, consecutive, comparative cohort study consecutively recruited Chinese age-related cataract patients, CAPPS and CPS were performed by a seasoned surgeon. Postoperative follow-up was at 1 day, 1 week, 1 month, 3 months, 6 months, and 1 year, and the outcome measures comprised ultrasound power, effective phacoemulsification time (EPT), corrected distance visual acuity (CDVA), endothelial cell density (ECD), corneal endothelium loss rate (ECL), central corneal thickness (CCT), and intraoperative and postoperative complications. RESULTS: Patients in both groups gained a better CDVA postoperatively. The ultrasound power and EPT in the CAPPS group were lower than the CPS group (P < .001). ECD value decreased at each follow-up visit and did not return to the preoperative level; CPS resulted in greater endothelial cell loss than CAPPS did, which was significant. CCT increased immediately after the surgery, and decreased thereafter. The mean CCT values returned to preoperative levels at 3 months after surgery in the CAPPS group while it took 6 months in the CPS group. The differences in cornea edema and anterior chamber flare between the 2 groups were not significant at 1 day postoperatively (P = .070 and .094, respectively), while at the 1-week time point, the differences were statistically significant (P = .002 and .001, respectively). CONCLUSION: CAPPS appears to be an excellent method for treating hard nucleus cataract. PMID- 30431581 TI - Radial artery occlusion with a kaolin-filled pad after transradial cardiac catheterization. AB - Radial artery occlusion (RAO) occurs in 2% to 18% of patients after transradial access (TRA) cardiac catheterization. Using a kaolin-filled pad (QuikClot) reduces compression time during TRA and might reduce RAO. We examined the RAO risk with the kaolin-filled pad after TRA cardiac catheterization.This was a prospective cross-sectional study of 260 patients who underwent TRA cardiac catheterization in a cardiac ward of a Medical Center from 2012 to 2016. Patients were randomly assigned to 1 of 2 groups: the case group (n = 130) was postoperatively treated with a kaolin-filled pad, and the control group (n = 130) was treated with conventional hemostasis. Color duplex ultrasound was used to evaluate the 24-hour and 1-month postoperative radial artery flow velocity, diameter, patency, and RAO risk.RAO risk was not significantly different between the case and control groups after 24 hours (4.6% vs 5.4%, P = .776) or after 1 month (5.4% vs 6.1%, P = .789), regardless of whether it was a first TRA cardiac catheterization (after 24 hours [P = .153] or after 1month [P = .617], respectively) or a repeated TRA cardiac catheterization (after 24 hours [P = .754] or after 1month [P = .753], respectively).Using a kaolin-filled pad after TRA cardiac catheterization did not significantly reduce RAO risk compared with conventional hemostasis. PMID- 30431583 TI - A nonrandomized controlled study of sacral giant cell tumors with preoperative treatment of denosumab. AB - The aim of this nonrandomized controlled study (level 3)was to evaluate whether preoperative denosumab treatment can reduce intraoperative blood loss, facilitate surgical treatment, and improve local control of sacral giant-cell tumor (GCT).Surgical treatment of sacral GCT is very difficult due to extensive bone destruction and complex anatomical structures. The huge intraoperative blood loss may interrupt surgical management and judgment of tumor range. Denosumab can inhibit the differentiation of osteoclast-like giant cells and bone destruction by blocking RANKL-RANK pathway.Study group (preoperative denosumab treatment) and control group (no denosumab treatment) were matched for age, gender, tumor site, staging, and tumor size. In study group, enhanced computed tomography (CT) was performed before and after denosumab treatment. The comparison parameters between 2 groups: CT enhancement rate, intraoperative blood loss, and oncologic outcome.The mean preoperative time of denosumab treatment was 5.2 months in study group. The mean CT enhancement rate of study group was 2.60 before treatment and 1.37 after treatment (P = .012). The posttreatment CT enhancement rate of study group was significantly lower than that of control group (P = .007). The mean intraoperative bleeding of study group and control group was 2166.7 and 5240 mL, respectively (P = .040). The mean operative time of study group and control group was 268.3 and 268.5 minutes, respectively (P = .997). The recurrence rate of study group (66.7%) was significantly higher than that of control group (0%) (P = .046).Preoperative denosumab treatment has the tendency to reduce blood supply and intraoperative bleeding of sacral GCT. But the sclerosis and bony separation can increase the difficulty of tumor curettage and lead to high recurrence rate after denosumab treatment. It is necessary to study the best surgical opportunity after denosumab treatment and precise method to judge tumor range. PMID- 30431582 TI - Phase IV noninferiority controlled randomized trial to evaluate the impact on diagnostic thinking and patient management and the test-retest reproducibility of the Gaxilose test for hypolactasia diagnosis. AB - BACKGROUND: The diagnostic accuracy of the Gaxilose test (GT) for hypolactasia diagnosis has already been proved. The objectives of this clinical trial were to demonstrate the noninferiority of the GT compared to the hydrogen breath test (HBT) on the impact on diagnostic thinking and patient management, to evaluate the GT reproducibility with urine accumulated from 0 to 4 hours and from 0 to 5 hours and to assess test safety. METHODS: We conducted a randomized, parallel, noninferiority clinical trial. Patients with clinical symptoms suggestive of lactose intolerance were screened for inclusion and randomly assigned to the GT arm or the HBT arm of the study. The impact on diagnostic thinking and patient management was analyzed with pretest and posttest questionnaires in which the investigators indicated their estimated probability of hypolactasia diagnosis and the intended management before and after the GT or the HBT (noninferiority margin: -10%). The primary outcome of the study was the impact on diagnostic thinking, expressed as the mean of the absolute values of the differences between the pretest and posttest probabilities of hypolactasia diagnosis. Patients randomized to the GT arm performed also the retest to evaluate the reproducibility of the GT. RESULTS: A total of 147 patients were included in the intend-to-treat (ITT) population. Among them, 74 performed the HBT and 73 performed the GT. The results proved the noninferiority of the GT compared to the HBT on the impact on diagnostic thinking (ImpactGT = 31.74 +/- 23.30%; ImpactHBT = 24.28 +/- 19.87%; DeltaGT-HBT = 7.46%; 95% confidence interval of DeltaGT-HBT: 1.55%, infinite) and on patient management. The test-retest reproducibility was better for the GT with urine accumulated from 0 to 5 h: the intraclass correlation coefficient (ICC) was 0.5761, and the Kappa coefficient was 0.7548, indicative of substantial agreement between both tests. No serious adverse events were reported during the study. CONCLUSIONS: The GT has an impact on diagnostic thinking and patient management noninferior to that of the HBT, is reproducible and well tolerated. These results prove the clinical benefit of its use in the clinical practice (ClinicalTrials.gov identifier: NCT02636413). PMID- 30431584 TI - STROBE-anastomotic leakage after pull-through procedure for Hirschsprung disease. AB - This study was undertaken to explore the causes, diagnosis, and treatment of anastomotic leakage after pull-through (PT) procedure for Hirschsprung disease (HD).A retrospective analysis of patients with anastomotic leakage after a PT procedure in the General Surgery Department of Beijing Children's Hospital from July 2013 to June 2016 was undertaken. The surgical characteristics, diagnosis, and treatment were retrospectively analyzed.Among the 213 patients who underwent PT procedures, 5 patients had a documented anastomotic leakage. The median age of these 5 patients at the time of the PT procedure was 6.8 years old, and this was higher than those without anastomotic leakage (1.7 years old). In all patients, rectal examination in the lithotomy position revealed an anastomotic dehiscence at the 6 o'clock position. The abdominal ultrasonography demonstrated retrorectal pneumatosis with or without an abscess in 4 patients. All patients were treated with ileostomies and anastomotic resuturing. The median delay to management was 4 days (range: 1-29 days). Four patients (4/5, 80%) were cured, and 1 (delay, 29 days) of these 4 patients developed postoperative ileus. The remaining patient (delay, 9 days) was required to undergo a repeat PT procedure. For the 4 cured patients, the median follow-up time was 20 months (range: 15-37 months), and these patients defecated 3 times daily at most without soiling.Older children with HD might be prone to anastomotic leakage. The findings of the rectal examination and ultrasonography were distinctive and useful for the diagnosis. Early ileostomy and resuturing of the anastomosis could be used to treat anastomotic leakage. PMID- 30431585 TI - Invasive ACTH-secreting pituitary macroadenoma in remission after transsphenoidal resection: A case report and literature review. AB - RATIONALE: Knosp grade 4 adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is a rare cause of Cushing disease. After the 1st surgery, the remission rate among these patients is extremely low. PATIENT CONCERNS: We presented a case of a 33-year-old female with classical Cushingoid symptoms. Further investigations revealed ATCH-dependent hypercortisolemia, as well as a Knosp grade 4 pituitary macroadenoma. DIAGNOSIS: Cushing disease, caused by a Knosp grade 4 pituitary macroadenoma. INTERVENTIONS: The patient underwent endoscopic endonasal transsphenoidal surgery with the assistance of intraoperative transsphenoidal Doppler and image-guidance devices. OUTCOMES: Pathologic examinations confirmed that the lesion was an ACTH-secreting pituitary adenoma. The patient was in biochemical remission after surgery. Her postoperative magnetic resonance imaging showed gross-total tumor resection. There was no evidence of recurrence during the 1-year follow-up. LESSONS: With intraoperative Doppler and image-guidance, gross-total resection and biochemical remission can be achieved in Cushing disease when the internal carotid artery is completely encased by the pituitary adenoma. PMID- 30431586 TI - High protein diet is of benefit for patients with type 2 diabetes: An updated meta-analysis. AB - Currently, the prevalence of type 2 diabetes is still increasing worldwide and has become a major public health burden.This meta-analysis was performed to further assess high protein (HP) diet on body weight, glycemic control, and cardiovascular disease risk factors in type 2 diabetes.A literature search was conducted in PubMed and Embase databases up to June 2018. The pooled standard mean difference (SMD) and the corresponding 95% confidence interval (CI) were calculated using RevMan 5.3 software.In total, 18 randomized control trials involving 1099 adults with type 2 diabetes were included. Pooled results indicated that HP diet could not significantly affect blood pressure of patients with type 2 diabetes, compared with low protein (LP) diet. However, the overall analyses showed the significant effect of HP diet on triglycerides reduction (SMD = -0.20, 95% CI = -0.35 to -0.05, P = .01) in patients with type 2 diabetes, compared with LP diet. Subgroup analyses showed that the ratio of energy from fat and carbohydrate in diet could affect the effect of HP diet on weight and triglyceride.HP diet could be indicated to obtain beneficial results in weight loss and lipid metabolism. PMID- 30431587 TI - Prognostic value of pretreatment serum lactate dehydrogenase level in pancreatic cancer patients: A meta-analysis of 18 observational studies. AB - BACKGROUND: Several studies were conducted to investigate the prognostic value of pretreatment serum lactate dehydrogenase (LDH) level in pancreatic cancer (PC), but the results were inconsistent. This study aims to comprehensively assess the prognostic value of pretreatment serum LDH level in PC patients by combining the data of the published literatures on this topic. METHODS: Embase, PubMed, and Web of Science were completely retrieved until June, 2018. The observational studies focusing on the prognostic value of pretreatment serum LDH level in PC patients were eligible. STATA version 12.0 was used to undertake the statistical analysis. RESULTS: Eighteen studies with a total of 3345 patients were included in this meta-analysis. The meta-analysis was conducted to generate pooled hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS). Our analysis results suggested that high serum LDH level predicted worse OS (HR 1.57, 95% CI 1.30-1.90, P < .001) in PC patients. Moreover, for patients with advanced PC, the prognostic relevance of pretreatment serum LDH level not only existed in those receiving palliative chemotherapy (HR 1.72, 95% CI 1.35-2.18, P < .001), but also in those who were precluded from chemotherapy (HR 1.91, 95% CI 1.4219-2.58, P < .001). CONCLUSION: The meta-analysis results demonstrated that pretreatment serum LDH level is closely associated with OS, and it may be a useful biomarker for assessing the prognosis of PC patients. PMID- 30431588 TI - Efficacy and safety of rituximab in childhood-onset, difficult-to-treat nephrotic syndrome: A multicenter open-label trial in Korea. AB - BACKGROUND: The anti-CD20 monoclonal antibody rituximab (RTX) has been proposed as a rescue therapy for difficult-to-treat nephrotic syndrome (NS). We conducted a clinical trial to evaluate the efficacy and safety of RTX in children with difficult-to-treat NS dependent on or resistant to steroids and calcineurin inhibitors (CNIs). METHODS: A multicenter open-label trial was performed at 8 major pediatric nephrology centers in Korea. The investigation consisted of a randomized controlled trial for steroid- and CNI-dependent NS (DDNS; randomization into the RTX group and the control group, at a ratio of 2:1) and a single-arm study of steroid and CNI-resistant NS (DRNS). DDNS patients in the RTX group and DRNS patients received a single dose of intravenous RTX (375 mg/m of body surface area) for B-cell depletion. A second RTX dose was administered at week 2 if the first dose failed to achieve depletion of CD19(+) cells. The primary endpoint was rate of maintaining remission at 6 months after treatment for DDNS and rate of remission achievement for DRNS. RESULTS: Sixty-one children with DDNS were enrolled while in remission and randomized to the control group (21 patients) or the RTX group (40 patients). At 6 months after treatment, the remission rates were 74.3% in the RTX group and 31.3% in the control group (P = .003). The mean duration of remission maintenance was significantly higher in the RTX group than in the control group (9.0 vs 2.9 months, P = .004). Of the 23 patients with DRNS enrolled in the single-arm study and treated with RTX, 9 (39.1%) achieved partial or complete remission within 6 months. Depletion of B cells occurred in all patients with RTX therapy. Thirty patients (50.8% of 59 patients analyzed) experienced mild and transient infusion reaction during RTX administration, and most adverse events were mild. CONCLUSIONS: RTX administration was safe and effective in patients with difficult-to-treat NS. One or 2 doses of RTX may be sufficient to deplete B cells and achieve better control of pediatric NS. PMID- 30431589 TI - Dexmedetomidine combined with local anesthetics in thoracic paravertebral block: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Dexmedetomidine (DEX) improves postoperative pain scores and prolongs the duration of blockage when combined with local anesthetics (LAs) for neuraxial and brachial plexus block; however, there is little information about the effectiveness of DEX as an adjuvant to LAs in paravertebral block (PVB). Therefore, a systematic review and meta-analysis were performed to evaluate the safety and efficacy of DEX combined with LAs in PVB. METHOD: An electronic database search from inception date to February 2018 was performed. Randomized controlled trials (RCTs) comparing DEX as an adjuvant to LAs with LAs alone for PVB in adult patients were included. Postoperative pain scores, duration of analgesia, cumulative perioperative analgesic consumption, and adverse events were analyzed. RESULT: We identified 7 trials enrolling 350 patients and found that DEX reduced pain scores at rest by standardized mean differences (SMD) -0.86 cm (95% confidence interval [CI] [-1.55, -0.17], P = .01) and SMD -0.93 cm (95% CI [-1.41, -0.26], P =.008) at postoperative 12 hours and 24 hours, respectively. DEX reduced pain scores while dynamic by SMD -1.63 cm (95% CI [-2.92, -0.34], P =.01) and SMD -1.78 cm (95% CI [-2.66, -0.90], P =.007) for postoperative 12 hours and 24 hours, respectively. DEX extended the duration of analgesia by weighted mean differences (WMD) 201.53 minutes (95% CI [33.45, 369.61], P =.02); and reduced cumulative postoperative analgesic consumption by WMD -7.71 mg (95% CI [-10.64, -4.78], P <.001) and WMD -45.64 mg (95% CI [-69.76, -21.53], P < .001) for 24 hours morphine and 48 hours tramadol subgroups, respectively. DEX also increased the odds of hypotension by odds ratio (OR) 4.40 (95% CI [1.37, 14.17], P = .01); however, there was no statistically significant difference for intraoperative fentanyl consumption and the incidence of the bradycardia. CONCLUSIONS: DEX combined with LAs in PVB significantly improved postoperative pain scores, prolonged the duration of analgesia, reduced postoperative analgesic consumption, and increased the odds of hypotension. However, we cannot neglect the heterogeneity of the included RCTs. More large-scale prospective studies are needed to further clarify the above conclusions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42018090251. PMID- 30431590 TI - Meta-analysis of clinical trials comparing the efficacy and safety of liposomal cisplatin versus conventional nonliposomal cisplatin in nonsmall cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). AB - BACKGROUND: While liposomal cisplatin has shown enhanced drug tolerability and higher targeting property as compared with the conventional cisplatin, the doubt remains whether lipoplatin could improve its anticancer efficacy. What's more, there is still no systematic evaluation of the safety profiles of lipoplatin comparing with original cisplatin. Thus, we performed a systematic literature search for randomized clinical trials directly comparing efficacy and safety of liposomal cisplatin versus its conventional nonliposomal cisplatin. METHODS: The electronic search was conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov from inception to February 10, 2018. The pooled odds ratio (OR) and 95% confidence intervals (CIs) of progressive disease (PD), partial response (PR), stable disease (SD), and adverse events (AEs) were obtained to assess the efficacy and safety. Heterogeneity was estimated using the I test (I > 50%, significant heterogeneity). RESULTS: The search yielded 5 clinical trials that meet inclusion criteria, with a total of 523 patients. We found that the liposome encapsulated cisplatin was more clinical efficacious than cisplatin as assessed by PD rate (OR, 0.46; 95% CI, 0.28-0.74; P = .002), while subgroup analysis of the only nonsmall cell lung cancer (NSCLC) patients showed higher response rates in PR (OR, 0.46; 95% CI, 0.28-0.74; P = .002) and PD (OR, 0.46; 95% CI, 0.28-0.74; P = .002) simultaneously. In addition, the toxicity meta analysis revealed lipoplatin was much less toxic than the original cisplatin, with respect to grade 3 to 4 neurotoxicity (OR, 0.18; 95% CI, 0.04-0.74; P = .02), grade 3 to 4 leukopenia (OR, 0.47; 95% CI, 0.26-0.85; P = .01), grade 3 to 4 neutropenia (OR, 0.26; 95% CI, 0.09-0.71; P = .009), grade 1 and 2 nausea/vomiting (OR, 0.50; 95% CI, 0.32-0.77; P = .002), and grade 3 and 4 asthenia (OR, 0.11; 95% CI, 0.03-0.42; P = .001). CONCLUSIONS: This meta-analysis revealed that with both NSCLC and squamous cell carcinoma of the head and neck (SCCHN) patients, liposomal cisplatin-based chemotherapy offers significant advantages regarding the PD and reduced toxicities relative to conventional cisplatin. PMID- 30431591 TI - Ureteral inflammatory myofibroblastic tumor: A case report and literature review. AB - RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a rare soft-tissue neoplasm which has been described in a variety of locations. In the urogenital system, IMT predominantly occurs in the bladder and the kidney. IMT arising from the ureter is exceedingly rare and has been sporadically reported before. PATIENT CONCERNS: We reported an extremely exceptional case of IMT arising from the ureteral submucosa in a 54-year-old man. The patient was hospitalized with the main complaint of intermittent and moderate left abdominal pain for 2 months. DIAGNOSES AND INTERVENTIONS: Computed tomography scan revealed a nearly circular mass in the left upper ureter. Ureteroscopy showed that the ureteral lumen mucosa was smooth. However, the upper ureter was compressed and narrow. Renal dynamic imaging was performed and the measured glomerular filtration rate was 46.98 mL/min (right renal) and 9.77 mL/min (left renal), respectively. A retroperitoneoscopic radical nephroureterectomy was performed. The histopathologic examination revealed that the soft-tissue neoplasm was mainly composed of myofibroblastic spindle cells proliferation with mixed inflammatory infiltrate, containing lymphocytes, neutrophils, and eosinophils. On immunohistochemical staining, the tumor was positive for smooth muscle actin and Ki-67 (<1%+), indicating a confirmed diagnosis of ureteral IMT. OUTCOMES: The patient recovered well with no occurrence of complications. At 3-year follow-up, there was no radiologic evidence of tumor recurrence or metastasis and the man was well. LESSONS: Ureteral IMT is extremely rare and often asymptomatic, resulting in delayed diagnosis. Radiologic evidences may be suggestive of the diagnosis of IMT. However, it is necessary to make an accurate diagnosis in terms of histopathologic assessment. Complete lesion excision is the best therapeutic approach with rare recurrences and excellent survival. PMID- 30431592 TI - Rapid-onset hyponatremia and delirium following duloxetine treatment for postherpetic neuralgia: Case report and literature review. AB - RATIONALE: Hyponatremia following duloxetine treatment has been reported in patients with major depressive disorder, fibromyalgia, diabetic neuropathy, or sciatic pain. The manifestations of duloxetine-induced hyponatremia are varying in different individuals. The overall prognosis for this type of hyponatremia is favorable if properly managed. PATIENT CONCERNS AND DIAGNOSES: Herein, we reported rapid-onset hyponatremia and delirium in an older patient after 2 doses of duloxetine, which was used to control his postherpetic neuralgia. Laboratory examinations revealed a rapid decline in serum sodium level and indicated the possibility of syndrome of inappropriate antidiuretic hormone (SIADH). INTERVENTIONS: Discontinuation of duloxetine, restriction of water intake, and intravenous supplement of normal saline were adopted to manage the hyponatremia. OUTCOMES: Serum concentration of sodium gradually normalized following aforementioned strategies. LESSONS: Special attention to the electrolyte abnormality is recommended in old patients undergoing duloxetine treatment. PMID- 30431593 TI - A case report on cystic meningioma in cerebellopontine angle and recommendations for management. AB - RATIONALE: Cystic meningioma located at the cerebellopontine angle (CPA) is an extremely rare occurrence. It is frequently misdiagnosed preoperatively. Little is known about the clinical features and outcome of this rare disease. PATIENT CONCERNS: A 70-year-old male presenting with progressive headache and gait disturbance. DIAGNOSIS: According to the symptoms, signs, and Gd-enhanced magnetic resonance images (MRI), a preoperative diagnosis of hemangioblastoma located in left CPA was made. Finally, the histological examination revealed a meningioma. INTERVENTIONS: A complete resection, including the part of the solid mass together with cyst, was performed. OUTCOMES: The postoperative course of the patient was uneventful, and no residual or recurrent tumor was found during the 24-month follow-up period. LESSONS: Cystic meningioma should be included in the differential diagnosis of a CPA mass with atypical radiologic features, such as a large cyst and enhanced mural nodule. By summarizing the related literature, we found that the most common pathological subtype of CPA cystic meningioma is the clear cell subtype, which belongs to WHO grade II. Gross total resection including the enhanced cyst wall is extremely important. A close follow-up is necessary because of the high recurrence rate in this subset of meningioma. PMID- 30431594 TI - CT diagnosis for metastasis of clear cell renal cell carcinoma to the pancreas: Three case reports. AB - RATIONALE: Clear cell renal cell carcinoma (CCRCC) metastasis to pancreas is clinically rare. Misdiagnosis for these cases is frequently due to the low incidence, lack of specific clinical symptoms, and laboratory results. PATIENT CONCERNS: Three female patients aged 47 years, 69 years, and 76 years, respectively, were admitted to hospital for routine examination after resection of clear cell carcinoma of kidney for 69 months, 57 months, and 123 months, respectively. All 3 cases had no specific clinical symptoms. Routine laboratory tests and common tumor markers including CEA, AFP, CA19-9, and CA125 showed no obvious abnormality. DIAGNOSIS: All 3 cases were finally diagnosed with CCRCC metastasis to pancreas on the basis of CT and pathological findings. On unenhanced CT, foci of the pancreas showed single or multiple nodules or masses with mildly low or equal density and obscure boundary. On enhanced CT, the enhanced mode of foci was similar to CCRCC and showed "fast in fast out." The main body was confined in the pancreas. The peripheral structure was clear relatively. Obstruction of common bile duct, main pancreatic duct, and local infringement of foci cannot be seen. Additional metastases of right adrenal gland can be seen in one case. INTERVENTIONS: All 3 cases underwent CT examination and surgical treatment, with complete removal of metastatic tumors. OUTCOMES: All 3 cases underwent surgical treatment successfully, and recovered successfully after operation. LESSONS: The manifestations of pancreatic metastases from CCRCC on CT show certain characteristics, which may be useful to assess the histological features of pancreatic metastases from CCRCC and facilitate the preoperative diagnosis. PMID- 30431595 TI - Efficacy of tasquinimod in men with metastatic castration-resistant prostate cancer: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Tasquinimod is an oral quinoline-3-carboxamide derivative for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Tasquinimod has antiangiogenic, immunomodulatory, and antimetastatic properties, but it is also associated with toxicities, including skeletal pain, digestive disorders, fatigue, insomnia, and mental disorders. We aimed to perform a meta-analysis to evaluate the efficacy, safety, and long-term survival for tasquinimod in patients with mCRPC. METHODS: Searches were carried out in PubMed, Embase, and the Cochrane Library. Eligible articles included randomized clinical trials (RCTs) comparing systemic or combination therapy (excluding primary or secondary androgen deprivation therapy, bone protective agents, or radionuclides) with placebo in men with mCRPC. RESULTS: Three RCTs were selected for final evaluation. The pooled results from the 3 studies indicated that tasquinimod was associated with good radiologic progression-free survival (rPFS) in mCRPC. For adverse effects (AEs), the results of meta-analysis indicated that patients with mCRPC who received tasquinimod had obvious anemia (risk ratio (RR) 1.35, 95% confidence interval (CI) 1.06-1.73, P = .02), back pain (RR: 1.57, 95% CI: 1.01 2.47, P = .05), pain in the extremities (RR: 1.90, 95% CI: 1.14-3.17, P = .01), insomnia (RR: 1.50, 95% CI: 1.03-2.17, P = .03), vomiting (RR: 1.52, 95% CI: 1.04 2.21, P = .03), and peripheral edema (RR: 1.52, 95% CI: 1.03-2.23, P = .03). CONCLUSIONS: Tasquinimod is associated with better rPFS in mCRPC. The toxicity of tasquinimod requires further investigation, it is not recommended for routine clinical use. PMID- 30431596 TI - Evaluating the optimal radiation dose for definitive chemoradiotherapy for esophageal squamous cell carcinoma: A single institution experience. AB - The optimal radiation dose for definitive chemoradiotherapy in inoperable esophageal squamous cell carcinoma (ESCC) has been long debated. In this study, we evaluated the effect of doses greater than the conventional radiation dose (50.4 Gy) on tumor control, tumor response, overall survival (OS), and disease free survival (DFS).The database of patients diagnosed with inoperable ESCC from 2007 to 2015 was obtained from the cancer registry of Chi-Mei Medical Center. All categorical variables were compared using Chi-squared test. The risk of OS and DFS were estimated using Cox proportional hazards regression, and Kaplan-Meier plots presented the trend of OS and DFS with log-rank tests used to compare differences. All significance levels were set at P < .05.A total of 84 patients were retrospectively analyzed, with 42 (50%) receiving >50.4 Gy and 42 (50%) receiving <=50.4 Gy (50%) concurrently with chemotherapy. Univariate and multivariate analysis revealed no significant differences between higher dose and conventional dose in OS (P = .21) and DFS (P = .26). Further dose analysis of <50, 50 to 50.4, 51 to 60, and >60 Gy showed no significant differences in OS or DFS. Higher doses conveyed no significant benefit on the failure pattern, either local regional failure or distant failure (P = .42). Major prognostic factors associated with better OS on multivariate analysis were stages I and II patients (P = .03) and radiation technique using arc therapy (P = .04). No acute toxicity of grade III or higher was recorded.The results of our study show that providing higher than conventional radiation doses concurrent with chemotherapy for inoperable ESCC does not impact OS or DSF, nor does it improve locoregional failure or distant failure. Although tumor response might be improved by radiation doses >50.4 Gy, the impact on OS and DFS remain to be studied. PMID- 30431597 TI - Perioperative predictors of moderate and severe postoperative pain in idiopathic scoliosis patients following spinal correction and fusion operations. AB - To investigate the predictive factors of pain intensity during the first 48 hours after spinal correction and fusion operations for idiopathic scoliosis patients.A total of 290 scoliosis patients who underwent posterior spinal instrumentation and fusion operations were enrolled in this study. A standard surgical and analgesic method was implemented for all participants and pain intensity was evaluated at fixed times within 48 hours after the operation. Variables including demographics (age, sex, body mass index [BMI], patient sources), surgical variables (procedure, duration of operation), intraoperative variables (total transfusion, autologous transfusion, heterogeneous transfusion, fluid intake, use of preventive analgesia) were investigated.On univariate analysis, BMI, transfusion type and not implementing preventive analgesia were associated with more serious pain after a scoliosis correction operation. Multivariate analysis indicated that receiving heterogeneous transfusion and not implementing preventive analgesia were significant predictive factors for moderate and severe pain after the spinal correction operation.Our research indicated that the type of transfusion and preventive analgesia were significantly associated with the severity of pain. Body mass and patient sources should be considered before surgery. For patients under high risk of moderate and severe pain, the type of transfusion must be taken into consideration. This study explored the influencing factors of postoperative pain from a novel perspective, but some limitations existed in this present study, and future studies are needed. PMID- 30431598 TI - MLL-PTD in a 13-year-old patient with blast phase myeloproliferative neoplasm: A case report. AB - RATIONALE: The risk of leukemic transformation in myeloproliferative neoplasm (MPN) has been increasing with time. Partial Tandem Duplications of the MLL gene (MLL-PTD) has been reported in de novo acute myeloid leukemia (AML), but not in MPN blast phase. The post-MPN AML developed adverse clinical outcomes, which showed no noticeable improvement over the past 15 years. Therefore, the mechanisms and therapeutic approaches of post-MPN AML need to be deeply studied. PATIENT CONCERNS: In this study, we present a JAK2V617F positive MPN patient who experienced fatigue and splenomegaly, transforming into JAK2V617F negative AML. DIAGNOSES: A diagnosis of acute monocytic leukemia was made in MPN blast phase. INTERVENTIONS: The patient received chemotherapy and allogeneic hematopoietic stem cell transplantation (Allo-SCT). OUTCOMES: The patient achieved complete remission twice, but relapsed twice. Relapse-free survival was only 3 months. She died about 24 months after her diagnosis. LESSONS: MLL-PTD occurs in the progression of JAK2V617F positive MPN into JAK2V617F negative AML, which may be a novel mechanism of MPN blast phase and helpful for post-MPN AML diagnosis. Allo SCT may be a good choice for post-MPN AML with MLL-PTD. More therapeutic strategies need to be explored for a better prognosis in these patients. PMID- 30431599 TI - Pneumomediastinum and pneumopericardium as rare complications after retroperitoneal transpsoas lateral lumbar interbody fusion surgery: A case report. AB - RATIONALE: Pneumomediastinum and pneumopericardium refer to conditions in which air exists within the mediastinum and pericardium, respectively. There is the communication between the mediastinum, pericardium, and retroperitoneum. We present the first report of rare complications (pneumomediastinum and pneumopericardium) after retroperitoneal transpsoas lateral lumbar interbody fusion (LLIF) surgery. PATIENT CONCERNS: A 73-year-old female who underwent LLIF using the retroperitoneal approach complained of dysphagia but no other abnormal symptom after surgery. DIAGNOSIS AND INTERVENTIONS: A plain chest radiograph (CXR) taken immediately the following surgery did not show any unusual findings but CXR took on postoperative day (POD) 1 indicated pneumopericardium and pneumomediastinum with abnormal air density along the pericardium and mediastinum with subdiaphragmatic air density. A chest computed tomography revealed bilateral pleural effusion and abnormal air density (pneumopericardium and pneumomediastinum) connected to a large amount of air around the aorta and retroperitoneal space (pneumoretroperitoneum). OUTCOMES: The patient complained of no unusual symptom and the CXR on POD 6 indicated that no air density surrounding the mediastinum and pericardium was found. LESSONS: Pneumomediastinum and pneumopericardium should be considered possible complications of LLIF using retroperitoneal transpsoas approach. Such a condition may progress to fatal conditions without early recognition and rapid management. PMID- 30431600 TI - The drug use to treat community-acquired pneumonia in children: A cross-sectional study in China. AB - To evaluate the rationality of drug use to treat community-acquired pneumonia (CAP) in children of a Chinese hospital using a set of developed indicators.We performed a retrospective cross-sectional study in West China Second University Hospital. Hospitalized children (0-18 years old) diagnosed with CAP from October 2015 to January 2016 were included. A set of developed indicators for assessing rational drug use (RDU) to treat CAP in children were used to evaluate the rationality of drug use. The data of the indicators were compared with the recommendations of the available guidelines, analyzing the situation of drug use in the children diagnosed with CAP.Eight hundred ninety-four children were included, 99.4% of them received antibiotics and 87.4% received more than 1 antibiotic. Antibiotics were administered intravenously in 880 (99.0%) children. About 20 (2.2%) children received antiviral agents and 19 (2.1%) children received antiviral drugs combined with antibiotics. About 208 (23.3%) children received traditional Chinese medicines and the injection of traditional Chinese medicines was given in 20 (2.2%) children.This study illustrated that drug use was partly not consistent with the recommendations of current guidelines, especially antibiotics. The drug use of CAP in children needs to pay more attention to. PMID- 30431601 TI - Complete heart block in systemic sclerosis: A case report and literature review. AB - RATIONALE: Complete heart block (CHB) is a common clinical manifestation. Systemic sclerosis (SSc) is a rare etiology of CHB that has not received enough attention. Whether pacemaker implantation is required remains inconclusive, especially when patients have no symptoms or mild symptoms of CHB. PATIENT CONCERNS: In this study, we report the case of a 48-year-old Chinese male who suffers from SSc and CHB. DIAGNOSE: The patient was previously diagnosed with left anterior hemiblock (LAHB) and right bundle block with normal heart function. CHB was observed on a regular follow-up electrocardiogram (ECG) examination 1 month before his hospitalization. INTERVENTIONS: A permanent dual chamber pacemaker was implanted. OUTCOMES: The patient responded well to pacemaker implantation treatment, and his exertional dyspnea disappeared. LESSONS: The occurrence of heart block associated with SSc often appears concealed. The case highlights the importance of regular follow-up of a patient with SSc. Pacemaker implantation might be unavoidable if CHB is secondary to SSc, even if it is asymptomatic. PMID- 30431602 TI - Musculoskeletal ultrasonography for arthropathy assessment in patients with hemophilia: A single-center cross-sectional study from Shanxi Province, China. AB - Magnetic resonance imaging (MRI) is currently considered the gold standard for assessing hemophilic arthropathy (HA) severity; however, MRI is often costly, time-consuming, and difficult to perform in children. In the present study, we evaluated the joint status of hemophilic patients from Shanxi Province, China, using musculoskeletal ultrasonography (MSKUS) and identified the factors that most strongly correlated with disease severity.The study included 104 patients with hemophilia, who underwent MSKUS examination. A total of 1248 joints (including the shoulder, elbow, wrist, hip, knee, and ankle joints on both sides) from these patients were evaluated. Effusion, hypertrophy, cartilage modification, and bone erosion were assessed. The chi-square test was used to analyze categorical variables, and multivariate logistic regression was used to analyze the relationship between joint disease and risk factors.MSKUS allowed clear visualization of synovial lesions, effusion, cartilage modification, and bone surface damage; however, it was unable to identify changes deep within bones. The distribution of damaged joints was as follows: shoulder, 2 (1.0%); elbow, 80 (38.5%); wrist, 4 (1.9%); hip, 4 (1.9%); knee, 126 (60.6%); and ankle, 90 (43.3%). Damage was more common in the knee, elbow, and ankle joints than in the shoulder, wrist, and hip joints (P < .001). Among the 1248 joints, 306 showed lesions, which included effusion in 102 (8.2%) joints, synovium hypertrophy in 176 (14.1%), cartilage modification in 193 (15.5%), and bone damage in 176 (14.1%). Many joints had multiple lesions at the same time. The chi-square test and multivariate logistic analysis showed that age and hemophilia severity were significantly associated with joint disease, while type of hemophilia and treatment categories were not associated with joint disease.MSKUS is a convenient and cost-effective examination that can play an important role in the diagnosis and long-term monitoring of HA. PMID- 30431603 TI - Feasibility of a single mediastinal drain through the abdominal wall after esophagectomy. AB - This study evaluated the safety and effectiveness of a single mediastinal drainage tube in the thoracic and abdominal cavity after minimally invasive esophagectomy (MIE). This study was undertaken to determine if the procedure could be included in a fast-track surgery program for resectable esophageal carcinoma (EC).From June 17 to November 30, 2015, clinical data for 78 eligible patients who had undergone a fast-track surgery program and MIE were retrospectively analyzed. Twenty-eight patients had a chest tube and mediastinal drainage tube. Thirty-four patients had only a mediastinal drainage tube through the intercostal space. The remaining 30 patients had a single mediastinal drainage tube in the thoracic and abdominal cavity through the abdominal wall. The complication rates and pain scores for each of the groups were compared. The statistical calculations were performed using SPSS 17.0 for Windows (SPSS Inc., Chicago, IL). The quantitative data among the groups were compared using 1-way analysis of variance (ANOVA). The Chi-square, Mann-Whitney U and Fisher exact tests were used for qualitative data analysis.There were no significant differences in the anastomotic leak rates, postoperative days and total complication rates (P = .861). The lowest visual analog scale (VAS) scores of the drainage tubes were observed in the group with a single mediastinal drain through the abdominal wall (P <.001).The results of this study suggested that a single mediastinal drainage tube in the thoracic and abdominal cavity after MIE may be safe and efficient. This clinical practice is a part of our fast-track surgery program. PMID- 30431604 TI - Effect of prophylactic palonosetron and sugammadex on postoperative nausea and vomiting in patients undergoing microvascular decompression under propofol maintained anesthesia: A retrospective observational study. AB - Microvascular decompression (MVD) is associated with a particularly high risk of postoperative nausea and vomiting (PONV) among craniotomy patients. However, there is no information regarding the effect of prophylactic palonosetron and sugammadex on PONV in patients undergoing MVD under propofol-maintained anesthesia.Medical records of 274 adults who had undergone MVD under propofol maintained anesthesia were reviewed. Patients were classified into 4 groups, based on the reversal agent used (sugammadex/pyridostigmine) and whether or not prophylactic palonosetron was used. The PONV incidence and risk factors were analyzed according to the use of these agents.The overall incidence of PONV was 30.7% during the first 24 hours postoperatively. The incidence of PONV was lower in the group using combination of prophylactic palonosetron and sugammadex (19.3%) compared with the group not using both agents (37.2%). The combined use of the prophylactic palonosetron and sugammadex was identified as a factor affecting the occurrence of PONV in both univariable (OR = 0.40, 95% CI: 0.21 0.77, P = .006) and multivariable (OR = 0.38, 95% CI: 0.20-0.75, P = .005) logistic regression analyses. In multivariable logistic regression analysis, female sex was also significant independent risk factor in PONV (OR = 2.62, 95% CI: 1.35-5.08, P = .004).In this retrospective observational study, the combined use of prophylactic palonosetron before anesthetic induction and sugammadex as a reversal of neuromuscular blockade are associated with a reduction in the incidence of PONV in patients undergoing MVD under propofol-maintained anesthesia. PMID- 30431605 TI - Modified quadruple therapy versus bismuth-containing quadruple therapy in first line treatment of Helicobacter pylori infection in Korea; rationale and design of an open-label, multicenter, randomized controlled trial. AB - BACKGROUND: Clarithromycin-containing triple regimen for eradication of Helicobacter pylori is no longer acceptable in Korea due to high clarithromycin resistance. Concomitant therapy or bismuth-containing quadruple therapy is recommended as an alternative regimen. A recent study in Korea has shown that modified quadruple therapy has comparable efficacy and safety to concomitant therapy as a first-line regimen. However, there has been no comparative study of modified quadruple therapy with bismuth-containing quadruple therapy. The aim of this study is to compare the efficacy and safety of modified quadruple therapy with those of bismuth-containing quadruple therapy as a first-line regimen and to present the phenotypic and genotypic antibiotic resistance profile of H pylori. METHODS: This study is an open-label, multicenter, randomized controlled trial. We are recruiting subjects endoscopically diagnosed with H pylori infection from 2 hospitals in Korea. Subjects will be randomly allocated either to modified quadruple therapy (proton-pump inhibitor bid, amoxicillin 1 g bid, metronidazole 500 mg tid, bismuth subcitrate 300 mg qid daily) or bismuth-containing quadruple therapy (proton-pump inhibitor bid, tetracycline 500 mg qid, metronidazole 500 mg tid, bismuth subcitrate 300 mg qid daily) for 14 days. The rate of eradication success and adverse events will be checked at least 4 weeks after the treatment. Antibiotic resistance will be established using both a bacterial culture with agar dilutions and DNA sequencing of the clarithromycin resistance point mutations in the 23S rRNA gene of H pylori. CONCLUSION: The results of this study will provide solid evidence for determining the optimal treatment regimen for first-line H pylori eradication in Korea. PMID- 30431606 TI - Urethral defect due to periurethral abscess treated with a tunica vaginalis flap: A case report. AB - RATIONALE: Periurethral abscess is a life-threatening disease, and the occurrence of a urethral defect with periurethral abscess is a rare finding. In this case, the patient had a lengthy urethral defect from the bulbous urethra to the membranous urethra accompanied by periurethral abscess that developed within a short time. Herein, we report a case of a pedicle-sparing tunica vaginalis flap utilized in urethral reconstruction which degenerated due to fibrotic changes and soft tissue defects in the urethral bed. PATIENT CONCERNS: The patient was a 36 year-old man with fever and lower urinary tract symptoms who had been treated with antibiotics and anti-inflammatory drugs for urinary tract infections 3 days before admission. Purulent necrosis was formed by the urethral abscess, and a long-length urethral defect was formed in the bulbous urethra. DIAGNOSIS: Based on the initial computed tomography and laboratory findings, empirical antibiotics were administered to treat a lower urinary tract infection. On the 7th day of hospitalization, ultrasonography was performed due to the sudden swelling of the scrotum, and the patient was diagnosed with a periurethral abscess that was 10 * 3 cm in size. INTERVENTION: Initial urinary diversion, wide debridement, and a large amount of abscess drainage were performed. Necrosis of the urethral ventral part caused a urethral defect that was 5 cm in size. After treatment with antibiotics, long-term disinfection and intermittent debridement were conducted and urethral reconstruction was performed using a tunica vaginalis flap with preserved vascular structure. OUTCOMES: No complications occurred until 6 months after urethral reconstruction. LESSONS: Urethral reconstruction using a tunica vaginalis flap is a good method for selected patients. Pedicle-sparing tunica vaginalis is an advantageous material for resolving urethral defects, especially when the surrounding circulation conditions are poor. PMID- 30431607 TI - An estrogen receptor-positive locally aggressive smooth muscle neoplasm of the transverse colon: A case report. AB - RATIONALE: Extrauterine leiomyomas (LMs) in women are often positive for the estrogen receptor (ER); however, almost all extrauterine leiomyosarcomas (LMSs) are negative for ER. Invasive smooth muscle neoplasms (SMNs) of the gastrointestinal tract walls are very rare and those ER statuses have not been well studied. PATIENT CONCERNS: A 48-year-old woman presented to our hospital with a 10 years history of recurrent severe abdominal pain and diarrhea lasting about an hour, with frequency of about twice per year. She was clinically diagnosed with a submucosal tumor (SMT) of the transverse colon and underwent a partial transverse colectomy. DIAGNOSIS: A colonoscopy revealed a 30-mm SMT in the transverse colon. A contrast abdominal computed tomography detected a 21-mm mass with significant late phase enhancement in the transverse colon and the lesion was clinically diagnosed as an SMT. Post-operative pathology confirmed a diagnosis of ER-positive locally aggressive SMN. INTERVENTIONS: The patient underwent laparoscopic partial transverse colectomy. OUTCOMES: The patient received no adjuvant therapy postoperatively. The patient has remained disease free without recurrence 13 months after the surgery. LESSONS: This is the first case of an ER-positive invasive SMN in the gastrointestinal tract. It highlights the difficulty in classifying some gastrointestinal SMNs as either LMs or LMSs and the importance of ER status in SMNs. PMID- 30431608 TI - Surgically treated rare intestinal bleeding due to submucosal hematoma in a patient on oral anticoagulant therapy: A case report. AB - RATIONALE: Bleeding in the gastrointestinal tract is a common complication of oral anticoagulant therapy (AT), and it usually appears as mucosal erosion or ulcer; however, intestinal submucosal hematoma (ISH) is an uncommon cause of hemorrhage. PATIENT CONCERNS: This report presents the case of a 70-year-old woman with acute hematochezia induced by AT. She underwent computed tomography and endoscopy. DIAGNOSES: Colon submucosal hematoma. INTERVENTIONS: Conservative treatment had no effect, and the patient underwent emergency surgery. OUTCOMES: Surgical resection showed hemorrhage and necrosis in the left colon, and the patient recovered 24 hours after surgery and continued AT. LESSONS: The present case indicates that the ISH should be kept in mind as a complication of AT. It can be managed conservatively in some stable patients, but emergency surgery may be needed in some serious situations. PMID- 30431609 TI - A prospective evaluation and management of different types of placenta praevia using parallel vertical compression suture to preserve uterus. AB - The rising tendency of cesarean sections will lead invariably to more complications such as placenta praevia. The aim of our study was to evaluate the utility of parallel vertical compression suture to preserve uterus in cases of placenta praevia, and to propose a rational approach of these problematic cases, according to their grade of myometrial invasion.We prospectively included 95 consecutive cases diagnosed with placenta praevia (group1 [Gr1]) where we used parallel compression suture and compared to retrospectively analyzed 100 consecutive cases managed without using this technique (group 2 [Gr2]). We differentiated the types of placenta praevia according to their invasion in myometrium because this parameter appreciates best their degree of severity, so we had 4 Grs: simple praevia (no adherent), accreta, increta, and percreta. All patients underwent ultrasound evaluation before surgery. Cesarean section was planned at 35 to 36 weeks. The main goal was to preserve the uterus whenever was possible. After opening the peritoneal cavity, we first inspected the lower segment and bladder. If no signs of engorged and tortuous vessels we dissected first the bladder and then performed a transverse hysterotomy, removed the placenta and placed 2 parallel vertical sutures on the lower segment below the hysterotomy incision through the entire thickness of both uterine walls. In cases of massively engorged vessels we dissected the bladder after infant delivery and made a transverse uterine incision slightly higher. We measured the amount of blood loss and performed three postoperative ultrasound exams, on day 2, 4 and at 6 to 8 weeks.Using this technique, we were able to preserve the uterus in 98.33% of Gr1 versus 78.47% from Gr2 of simple placenta praevia, in 88.23% in Gr1 compared to 42.86% in Gr2 of placenta accreta, only in 14.28% of increta type and in none (0%) of the 2 cases with placenta percreta.The simplified compression technique for hemostasis and preserving uterus in cases of simple placenta praevia and accreta is easy to perform without special surgical skills and is rapid. There are no short and long-time complications related to the technique. In cases of placenta increta the problem is not that this technique is unsuccessful but getting to that point to place the sutures is difficult. In severe cases of placenta percreta, unfortunately, the hysterectomy remains the treatment of choice. PMID- 30431610 TI - Serum levels of fetuin-A are negatively associated with log transformation levels of thyroid-stimulating hormone in patients with hyperthyroidism or euthyroidism: An observational study at a medical center in Taiwan. AB - Fetuin-A is a protein with various biological functions. It plays a role in insulin resistance and arterial calcium deposition. Thyroid dysfunction may affect energy expenditure, glucose metabolism, and the risk of cardiovascular diseases. In the present study, we compared the serum fetuin-A concentrations in hyperthyroid patients with those in euthyroid patients.We recruited 30 newly diagnosed hyperthyroid patients (the HY group) and treated them with anti-thyroid regimens as clinically indicated. We recruited 30 euthyroid individuals (the EU group) as controls. We compared laboratory parameters at the baseline and at 6 months. We then determined the associations between the levels of fetuin-A and free thyroxine (fT4), thyroid-stimulating hormone (TSH), or log transformation of TSH (logTSH).At the baseline, the HY patients had significantly higher serum fetuin-A levels than the EU patients (median [Q1, Q3]: 735.4 [537.9, 843.4] ng/mL vs 561.1[449.2, 670.5] ng/mL, P = .010). At 6 months, the serum fetuin-A levels of the HY patients decreased but were still higher than those of the EU patients (698.4 [627.6, 924.3] ng/mL vs 616.5 [498.2, 727.7] ng/mL, P = .002). At baseline, the serum levels of fetuin-A were negatively associated with logTSH (beta = -53.79, P = .010). At 6 months, the levels of fetuin-A were positively associated with fT4 (beta = 86.91, P = .039), and negatively associated with logTSH (beta = -104.28, P < .001). Changes to the levels of fetuin-A within 6 months were negatively associated with changes to logTSH (beta = -57.80, P = .019). The negative associations between fetuin-A levels and logTSH at baseline and at 6 months, and the changes during the 6 months remained significant after adjustment for sex and age (beta = -51.72, P = .016; beta = -103.11, P < .001; and beta = -59.36, P = .020, respectively).The patients with hyperthyroidism had higher serum fetuin-A levels than the patients with euthyroidism. In patients with hyperthyroidism, the serum fetuin-A concentrations decreased after the anti thyroid treatment. In the present study, serum fetuin-A concentrations were negatively associated with logTSH. PMID- 30431611 TI - Periodic paralysis with normokalemia in a patient with hyperthyroidism: A case report. AB - RATIONALE: Thyrotoxic periodic paralysis is characterized by a sudden onset of hypokalemia and paralysis. This condition mainly affects the lower extremities and is secondary to thyrotoxicosis. The underlying hyperthyroidism is often subtle without typical symptoms such as palpitations, tremors, anxiety, and weight loss; this causes a difficulty in early diagnosis. Here, we reported a case of periodic paralysis in a patient with hyperthyroidism whose potassium level was within the normal range. PATIENT CONCERNS: A 33-year-old Taiwanese man presented to the emergency department with bilateral limb weakness (more severe in the lower limbs than in the upper limbs). On arrival, the patient's vital status was stable with clear consciousness. He denied experiencing recent trauma, back pain, chest pain, abdominal pain, headache or dizziness, or a fever episode. Physical examination showed no specific findings. Neurological examination showed weakness in the muscles of the bilateral upper and lower limbs. Muscle weakness was more severe in the proximal site than in the distal site. DIAGNOSIS: Blood examination showed normal complete blood count, normal renal and liver function, and normal potassium (3.5 mmol/L, normal range 3.5-5.1 mmol/L), sodium, and calcium levels; however, the examination showed impaired thyroid function (thyroid stimulating hormone: 0.04 uIU/mL, normal range 0.34-5.60 uIU/mL; free T4: 1.96 ng/dL, normal range 0.61-1.12 ng/dL). Brain computed tomography without contrast showed no obvious intra-cranial lesion. INTERVENTIONS: Intravenous potassium infusion (20 mEq/L) with normal saline was prescribed for the patient. OUTCOMES: After treatment, the patient felt a decrease in limb weakness. He was discharged from our emergency department with a scheduled follow-up in the endocrine outpatient department. LESSONS: TPP should be considered as a differential diagnosis in young Asian men presenting with limb paralysis that is more severe in the proximal site and in the lower limbs than in the distal site and in the upper limbs, respectively. It is important for emergency department physicians to consider TPP as a differential diagnosis as it can occur even if the patient's potassium level is within the normal range. PMID- 30431612 TI - Successful conservative treatment of acute traumatic occlusions of the celiac artery and superior mesenteric artery: A case report emphasizing the importance of the visceral collateral circulations. AB - RATIONALE: Blunt injury of major visceral arteries such as celiac artery (CA) and superior mesenteric artery (SMA) are very rare but fatal, therefore, these injuries are challenging to trauma surgeons. The patient with occlusion of CA or SMA is theoretically viable by visceral collateral circulation. However, there are very rare cases in clinics. To date, there have been few reports of both CA and SMA occlusions after blunt trauma. Herein we describe our successful conservative treatment of patients with both CA and SMA occlusions. PATIENT CONCERNS: Fifteen-year-old girl suffering from schizophrenia was transferred to our hospital after a fall from 3-floor-height with a purpose of suicide. DIAGNOSES: An abdominal computed tomography (CT) scan with contrast enhancement showed proximal CA and proximal SMA occlusions with surrounding retroperitoneal hematoma, however, distal parts of occlusion were supplied by the collateral vessels (enlarged marginal artery of left colon from inferior mesenteric artery and pancreaticoduodenal arcade). INTERVENTIONS: She was treated by only supportive care without anticoagulant due to retroperitoneal hematoma. OUTCOMES: The patient was discharged 25 days after admission without complications. LESSONS: We think that our patient could survive because her vascular status was healthy and collateral circulations were plenty according to the young age. We believe that this case can provide a basis for ligation in these forbidding and handless major visceral arterial injuries such as CA or SMA. PMID- 30431613 TI - The associations among Helicobacter pylori infection, white blood cell count and nonalcoholic fatty liver disease in a large Chinese population. AB - Reported relationships among Helicobacter pylori infection, white blood cell (WBC) count and nonalcoholic fatty liver disease (NAFLD) are inconsistent and controversial. We, therefore, conducted a cross-sectional study to investigate the associations among the presence of NAFLD, WBC count and H pylori infection, as diagnosed using the C-urea breath test (UBT).This study included 20,389 subjects enrolled at the International Health Care Center of the Second Affiliated Hospital of the Zhejiang University School of Medicine from January 2015 to December 2015. All participants underwent a C-UBT for the diagnosis of H pylori infection and ultrasonography for NAFLD as well as a blood test to determine WBC count. Multivariate logistic regression was then performed to evaluate the relationship among H pylori infection, WBC count and NAFLD.H pylori infection was detected in 38.49% (7,848/20,389) of the subjects via the UBT, and NAFLD was present in 37.24% (7,592/20,389) of the subjects. The prevalence of H pylori infection was higher in the NAFLD group than in the control group (41.25% vs 36.85%, P <.001). Significant differences were found between various WBC quartiles and H pylori infection, age, gender, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-sensitivity C-reactive protein (HS-CRP), glycosylated hemoglobin (HbA1c), triglyceride (TG), low-density lipoprotein (LDL-C), fasting blood glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), and smoking. Multivariate logistic regression revealed that the combination of H pylori infection and WBC count (odds ratio [OR] = 1.067, 95% confidence interval [CI]: 1.014, 1.093; P = .007; OR = 1.165, 95% CI: 1.023, 1.488; P <.001; OR = 1.183, 95% CI: 1.085, 1.559; P <.001, respectively) was positively associated with NAFLD.H pylori infection and WBC count may contribute to the pathogenesis of NAFLD. PMID- 30431614 TI - Isolated hook of hamate fracture in sports that require a strong grip comprehensive literature review. AB - BACKGROUND: The aim of the study was to report characteristics of isolated hook of hamate fractures related to sports that require a strong grip and to identify factors affecting early diagnosis and recovery period. METHODS: A comprehensive literature search was conducted using MEDLINE, EMBASE, SCOPUS, Web of Science, the Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and the clinical trials registry and database of the US National Institutes of Health (ClinicalTrials.gov). There were no limits on the language or year of publication.This article included case reports and literature reviews for patients with isolated hook of hamate fractures related to sports that require a strong grip from 1977 to 2016.Two experienced reviewers extracted data from each study. The following data were extracted: sample size, patient's characteristics, cause of injury, injury side, time to diagnosis and symptoms, physical examination results, diagnostic work-up, treatment, complications, and recovery period. RESULTS: A total of 21 case reports and literature reviews with 120 patients satisfied our inclusion criteria. There was no significant difference in the time to diagnosis between the group before computed tomography (CT) was widely used and the group after CT was widely used. Recovery period showed a positive relationship with age (coefficient = 0.418, P < .01), time from injury to diagnosis or surgery (coefficient = 0.206, P < .05), and type of athlete (coefficient = 0.270, P < .01). On multiple stepwise regression analysis, recovery period was significantly associated with age (beta = 0.418, P = .00), but not with time from injury to diagnosis or surgery. CONCLUSIONS: Advance in diagnostic techniques does not guarantee early diagnosis of hook of hamate fractures. Strong suspicion of the disease with physical examination and carefully hearing patient's history are important for early diagnosis and management for patients with hook of hamate fractures. PMID- 30431615 TI - Changes in choriocapillaris and retinal morphology after laser photocoagulation by OCT angiography: A case report. AB - RATIONALE: Earlier studies have shown that laser photocoagulation treatments are associated with good long-term visual acuity in most patients with severe nonproliferative diabetic retinopathy (S-NPDR). Histopathologic studies of autopsied eyes have demonstrated defects in the choriocapillaris beneath the retinal laser lesions secondary to photocoagulation for S-NPDR. These lesions have been observed to expand centrifugally over time especially in the posterior pole, and the atrophy of the retinal pigment epithelium (RPE) can be significantly enlarged. There are, however, limited studies detailing the in vivo changes that occur in the RPE and choriocapillaris following laser photocoagulation. PATIENT CONCERNS: A 46-year-old woman presented with visual disturbances in both eyes. DIAGNOSES: Fundus examinations showed many retinal hemorrhages and soft exudates in the four quadrants due to S-NPDR. INTERVENTIONS: Laser photocoagulations with a 532-nm wavelength argon laser with power of 170 to 230 mW and spot size of 200 MUm were performed to treat the S-NPDR. The changes in the choriocapillaris and retinal vasculature were followed by optical coherence tomography (OCT) angiography. OUTCOMES: The choriocapillaris beneath the laser spots was disrupted from 1 hour following the photocoagulation but it was restored at week 2. The choriocapillaris appeared almost normal at some laser spots, but they were still some spots that were altered at 1 year. The outer retina and RPE were disrupted beneath the laser spots at 1 year. On the contrary, there were no visible retinal vascular changes in the superficial and deep plexuses of retinal vasculature determined by OCT angiography with manual and automated segmentation. LESSONS: The choriocapillaris in human eyes can recover after laser photocoagulation although the outer retina and RPE remain disrupted and do not recover. PMID- 30431616 TI - Retroperitoneal extramedullary plasmacytoma: A case report and review of the literature. AB - RATIONALE: The incidence of extramedullary plasmacytoma (EMP) accounts for 3% to 4% of all cases of generalized plasmacytoma. The most common pathogenic sites are the head and the neck. It is noteworthy that the pathogenic site in this case is extraperitoneal, which is uncommon in clinical practice. In this case report, we aim to discuss the clinical features and diagnosis as well as the treatment methods of EMP. PATIENT CONCERNS: A 30-year-old female was admitted to our hospital due to a palpable right upper abdominal mass without symptoms of abdominal pain, diarrhea, constipation, fever, or oliguria. DIAGNOSIS AND INTERVENTIONS: Enhanced CT scan showed a right retroperitoneal mass, which we considered to be isolated fibroma. Multiple myeloma (MM) was excluded through whole-body diffusion weighted imaging (DWI) and bone marrow biopsy. The patient underwent retroperitoneal tumor resection, and the postoperative pathology revealed plasmacytoma. Thereafter, she received only postoperative radiotherapy. OUTCOMES: During the radiotherapy, the patient's condition and appetite were acceptable with I degrees gastrointestinal reaction. The CT examination of the chest and upper abdomen performed 4, 8, and 12 months after the radiotherapy still showed postoperative and postradiotherapy changes after retroperitoneal plasmacytoma resection without obvious abnormal signs. No recurrence and metastasis were detected after a one-year follow-up. LESSONS: Retroperitoneal extramedullary plasmacytoma (EMP) is a rare condition that is frequently a diagnostic challenge, mainly due to its unusual location and nonspecific symptoms, especially in the early stages. The diagnosis of EMP is made through a combination of imaging and pathological examination. Presently, the combinations of radiotherapy and surgery or radiotherapy are the primary treatments, usually leading to an acceptable local control rate. The application of chemotherapy, however, should be carefully considered. PMID- 30431617 TI - Ability of preschoolers to achieve maximal exercise and its correlation with oxygen uptake efficiency slope ~ an observational study by direct cardiopulmonary exercise testing. AB - The oxygen uptake efficiency slope (OUES) is a well-established substitute for maximum oxygen uptake ((Equation is included in full-text article.)O2 max) in submaximal exercise effort among adolescents and adults. Few studies have analyzed the exercise capacity (EC) and OUES of children aged 4 to 6 (preschoolers). Body fat has been proved to negatively affect EC among schoolchildren. The purposes of this study were to assess the capacity of preschoolers in achieving (Equation is included in full-text article.)O2 max and evaluate the correlation of peak metabolic equivalent (peak MET) and peak oxygen consumption (peak O2) with OUES. We also evaluated if body fat affected EC among preschoolers.Forty-three preschoolers under the ramped Bruce protocol of treadmill exercise testing had been retrospectively studied. The criteria for achieving (Equation is included in full-text article.)O2 max included respiratory exchange ratio (RER) >1.1, heart rate (HR) >85% of age-predicted maximum, and HR >200 bpm. OUES was calculated by the 75% (OUES-75) and the entire (OUES-100) duration of the testing and normalized by body surface area. Body fat was measured using vector bioelectrical impedance analysis. The fat mass (FM) index and fat-free mass index (FFMI) were defined as FM or FFM (kg) divided by height squared (m), respectively.The mean age of the participants was 5.70 +/- 0.56. Seventy-nine percent of preschoolers met at least 1 criterion, 36.84% met 2 criteria, and none met all 3 criteria for (Equation is included in full-text article.)O2. OUES-75 was moderately positively correlated with peak MET (P = .034; Spearman's rho = 0.324) and peak O2 (P <.001; Spearman's rho = 0.667). OUES 100 was moderately to highly positively correlated with peak MET (P <.001; Spearman's rho = 0.592) and peak O2 (P <.001; Spearman's rho = 0.825). There were moderate to high positive correlations between FFMI and peak O2 (P <.001; Spearman's rho = 0.668), OUES-75 (P <.001; Spearman's rho = 0.642), and OUES-100 (P < .001; Spearman's rho = 0.670).None of the preschoolers reached all 3 criteria for (Equation is included in full-text article.)O2max. OUES-75 and OUES 100 might be indicators of peak O2 at submaximal effort. Preschoolers with higher FFMI had better EC during treadmill exercise testing. PMID- 30431618 TI - Prognostic and clinical value of Targeting protein for Xenopus kinesin-like protein 2 in patients with gastrointestinal tract cancers: A meta-analysis. AB - BACKGROUND: Accumulating studies have indicated that Targeting protein for Xenopus kinesin-like protein 2 (TPX2) was overexpressed in various types of human cancers. However, the prognostic and clinical value of TPX2 in gastrointestinal (GI) tract cancers was not well-understood. This study was aimed to comprehensively explore the prognostic and clinical significance of TPX2 in GI tract cancers. METHODS: Eligible studies were systematically retrieved in PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang database. The eligible studies were collected to evaluate the association of TPX2 with prognosis and clinicopathological features, with the pooling hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI). RESULT: The meta-analysis suggested that overexpression of TPX2 protein was significantly correlated with poor overall survival (OS) (HR: 2.20, 95% CI: 1.60-2.80, P <.001) in GI tract cancers, the subgroup meta-analysis also confirmed the prognostic value of TPX2 protein. Furthermore, clinical significances of TPX2 protein in gastric cancer were discussed. CONCLUSION: Upregulated TPX2 protein was correlated with poor clinical outcomes, suggesting that TPX2 protein can serve as a promising predictive biomarker in patients with GI tract cancers. PMID- 30431619 TI - Evaluation of prognostic values of inflammation-based makers in patients with HBV related acute-on-chronic liver failure. AB - Systemic inflammatory responses are associated with the development and progression of liver failure. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), prognostic nutritional index (PNI), red cell distribution width (RDW), RDW-to platelet ratio (RPR), mean platelet volume (MPV), and MPV-to platelet ratio (MPR) are markers of systemic inflammation. This study aimed to evaluate the prognostic values of these inflammatory markers in patients with hepatitis B virus-related acute-on chronic liver failure (HBV-ACLF).203 HBV-ACLF patients, 79 cirrhosis patients (LC), 63 chronic hepatitis B (CHB), and 81 healthy subjects (HS) participated in this cohort study. Complete blood counts and biochemical examinations were obtained after overnight fasting. Multivariate analyses of 90-day outcome predictors were analyzed by Cox regression models. Survival probability curves were calculated by the Kaplan-Meier method.The levels of NLR, MLR, RDW, MPV, RPR, and MPR were significantly higher and PNI was lower in patients with liver failure at presentation compared to those in LC, CHB, and HS (P <.001). In acute on-chronic liver failure (ACLF) patients, NLR and MLR were higher in nonsurvivors than in survivors (P <.001), while other inflammatory markers showed no difference. ROC curve analyses showed that NLR combined with MLR had the highest AUC for identified poor outcome, followed by NLR, chronic liver failure sequential organ failure assessment (CLIF-SOFA), MLR, model for end-stage liver disease (MELD), Child-Turcotte-Pugh (CTP) and TBIL. Multivariate analyses showed that TBIL, NLR, CTP, MELD, and CLIF-SOFA were independent predictors for 90-day mortality.Combination of NLR and MLR are more accurate prognostic markers for predicting poor outcome than either marker alone in ACLF patients. And this combination is superior to the CLIF-SOFA, MELD, CTP score, and TBIL in terms of prognostic ability. PMID- 30431621 TI - Effect of LED therapy for the treatment nipple fissures: Study protocol for a randomized controlled trial: Erratum. PMID- 30431620 TI - Prenatal diagnosis and pregnancy outcome analysis of thickened nuchal fold in the second trimester. AB - To summarize the results of prenatal diagnoses and pregnancy outcomes of fetuses with thickened nuchal fold (TNF) in the second trimester.From 2009 to 2016, we studied 72 pregnant women with fetal nuchal fold (NF) measurements over 5 mm at 14 to 19 + 6 weeks or 6 mm at 20 to 28 weeks of gestation who received prenatal diagnosis. Karyotypes were first used to detect common chromosomal diseases, and then chromosome microarray analysis (CMA) was performed if karyotypes were normal. Prognoses were followed up by documentation in the hospital or over the telephone.In total, 12 fetuses with chromosomal defects, including 5 pathogenic copy number variants (CNVs) were detected. The risk of chromosomal defects when a TNF was associated with structural malformations (SMs) (35.5%) was much greater than that of an isolated TNF (3.7%) and a TNF associated with soft markers (0%). The rate of SMs when the NF measured >=10 mm was greater than that NF measured 5 to 7.9 mm or 8 to 9.9 mm. Totally 27 fetuses had adverse pregnancy outcome.A TNF is not only associated with a high risk of trisomy 21 but also with other chromosomal abnormalities, including pathogenic CNVs. The rates of SMs and adverse outcomes increase when the NF thickness increases. PMID- 30431622 TI - Effectiveness of neuromuscular electrical stimulation for wrist rehabilitation after acute ischemic stroke: Erratum. PMID- 30431623 TI - Awareness, incidence and clinical significance of acute kidney injury after non general anesthesia: A retrospective cohort study: Erratum. PMID- 30431624 TI - Corrigendum for: "Oomycete-specific ITS primers for identification and metabarcoding" published in MycoKeys, doi: 10.3897/mycokeys.14.9244. AB - [This corrects the article DOI: 10.3897/mycokeys.14.9244.]. PMID- 30431626 TI - Taming a silyldiium cation and its reactivity towards sodium phosphaethynolate. AB - A dicationic bis(NHC)-stabilised silyldiium complex, [bis(NHC)-SiPh2]2+ (72+) (bis(NHC) = [CH2(NC3H2NDipp)2], Dipp = 2,6-iPr2C6H3), was synthesised for the first time. It reacts with sodium phosphaethynolate (NaOCP) as a source of monoanionic phosphorus to give the P-insertion product [bis(NHC)-PSiPh2]+ (8+). The latter comprises a seven-membered heterocycle containing a Si-P moiety which can easily be desilylated when exposed to dichlorophosphanes as exemplified by the synthesis of the diphosphanide cations [bis(NHC)-PPCy]+ (9+) and [bis(NHC) PPPh]+ (10+). PMID- 30431625 TI - Erratum: The role of visceral adipose tissue on improvement in insulin sensitivity following Roux-en-Y gastric bypass: a study in Chinese diabetic patients with mild and central obesity. AB - [This corrects the article DOI: 10.1093/gastro/goy024.]. PMID- 30431627 TI - Design of softened polystyrene for crack- and contamination-free large-area graphene transfer. AB - The fundamental issues related to the formation of mechanical cracks and the chemical residue during the transfer process of large-area CVD graphene by polymeric carrier-films are addressed in this work. This paper presents a method to design a new polymer carrier-film (using polystyrene (PS) and 4,4' diisopropylbiphenyl (DIPB)) that is free from mechanical cracks and polymer residue during the transfer of large-area graphene from a metal catalyst. This new polymer carrier film shows excellent mechanical flexibility and good solubility in tetrahydrofuran solvent without any residue and it is confirmed that the graphene transfer process is excellent without mechanical destruction even over a large area. Our result gave a technical milestone for the real industrial application of graphene in many application areas (not only graphene but also several two-dimensional materials such as boron nitride, transition metal di-chalcogenide, and black phosphorus). PMID- 30431628 TI - Bidirectional plasmonic coloration with gold nanoparticles by wavelength-switched photoredox reaction. AB - Reversible tuning of localized plasmon resonance that is supported by nanometric sized metal particles holds potentially huge benefits in terms of manipulating light for widespread photonic applications. Although the practice of altering the frequency and the amplitude of plasmon resonance on gold nanoparticles is relatively well established, dynamic tuning by all-optical approaches for coloration has long been hindered due to limited implementation approaches with which gold nanomaterials can be photosynthetically manipulated. Here, we develop a wavelength-switched photoredox approach and demonstrate bidirectional tuning of the plasmonic resonance of crystalline gold nanoparticles for reversible surface plasmon-resonance-based coloration. The reversible plasmonic resonance control is achieved by a combination of photoreduction of gold ions and photooxidation of gold nanorods by switching the illumination between UV and near-UV-Vis light, respectively. As one example, the plasmon resonance peak of gold nanorods is reversibly tuned between 630 and 660 nm by switching the light wavelengths. Utilizing wavelength-switchable photoredox reactions, we demonstrate reversible color patterning by mask illuminating a gold nanorod sample solution. This approach offers not only an easy-to-implement method for realizing non-contact modulating plasmon-resonance based colors, but also new opportunities for reversibly tuning local plasmon resonance by all-optically shaping single nanoparticles. This holds great potential for a wide range of applications, including active-substrate-based surface-enhanced Raman scattering (SERS), erasable optical data storage and dynamic laser color printing, among others. PMID- 30431629 TI - Correction: Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film. AB - Correction for 'Ultrafast dye regeneration in a core-shell NiO-dye-TiO2 mesoporous film' by Lei Tian et al., Phys. Chem. Chem. Phys., 2018, 20, 36-40. PMID- 30431630 TI - Catalytic asymmetric de novo construction of dihydroquinazolinone scaffolds via enantioselective decarboxylative [4+2] cycloadditions. AB - The first de novo construction of enantioenriched dihydroquinazolinones via an intermolecular strategy has been established. This approach also represents the first catalytic asymmetric [4+2] cycloaddition of vinyl benzoxazinanones with sulfonyl isocyanates, which afforded chiral dihydroquinazolinones in high yields and excellent enantioselectivities (up to 98% yield, 99 : 1 er). This reaction not only confronts the great challenge in de novo construction of enantioenriched dihydroquinazolinone skeletons, but also advances the chemistry of decarboxylative cycloadditions involving vinyl benzoxazinanones. PMID- 30431631 TI - A silicon nitride waveguide-integrated chemical vapor deposited graphene photodetector with 38 GHz bandwidth. AB - We demonstrate a high-speed chemical vapor deposited graphene-on-silicon nitride waveguide photodetector. The device is designed with grating-like metal contact to reduce the channel spacing. Benefiting from the narrow channel spacing, a calculated transit-time-limited bandwidth of 111 GHz is derived. The resistance capacitance-limited bandwidth is also improved due to the small relative permittivity of silicon nitride. At a wavelength of 1550 nm, we measured an electro-optic bandwidth of 38 GHz under zero bias and an intrinsic responsivity of 13 mA W-1 at 0.1 V reverse bias with a 6 MUm detection length. PMID- 30431632 TI - Novel non-peptidic small molecule inhibitors of secreted aspartic protease 2 (SAP2) for the treatment of resistant fungal infections. AB - Targeting secreted aspartic protease 2 (SAP2), a kind of virulence factor, represents a new strategy for antifungal drug discovery. In this report, the first-generation of small molecule SAP2 inhibitors was rationally designed and optimized using a structure-based approach. In particular, inhibitor 23h was highly potent and selective and showed good antifungal potency for the treatment of resistant Candida albicans infections. PMID- 30431633 TI - High-depth fluorescence imaging using a two-photon FRET system for mitochondrial pH in live cells and tissues. AB - We developed a fluorescent pH probe (1) capable of two-photon excitation and far visible-emission based on FRET, composed of naphthalimide-piperazine-rhodamine. It exhibited a pH-dependent reversible and fast ratiometric fluorescence change in the rhodamine emission. Probe 1 was applied to image the pH perturbations of mitochondria in living cells and tissues. PMID- 30431634 TI - Hierarchical manganese dioxide nanoflowers enable accurate ratiometric fluorescence enzyme-linked immunosorbent assay. AB - We first developed a green, mild and rapid method for the preparation of hierarchical manganese dioxide nanoflowers (MnO2 NFs) as nanozymes with intrinsic oxidase-like activity using citric acid for the reduction of potassium permanganate. The open structure of MnO2 NFs can lead to a larger specific surface area for improving the antibody loading amount and oxidase mimicking activity. In addition, carboxyl groups from the residual citric acid on the surface of MnO2 NFs afford a good affinity with the antibody through an amidation coupling reaction, which does not need complex surface modification anymore. Then, a reliable ratiometric fluorescence nanozyme-linked immunosorbent assay towards C-reactive protein (CRP) was designed successfully based on the MnO2 NFs. The high sensitivity and clinical feasibility of the presented methodology were demonstrated, which hold great promise in biomedical fields. Moreover, the mild and simple process for the synthesis of MnO2 NFs will make good contributions to many other applications. PMID- 30431635 TI - Correction: Zn2SnO4:Cr,Eu ultra-small nanoparticles as new near infrared-emitting persistent luminescent nanoprobes for cellular and deep tissue imaging at 800 nm. AB - Correction for 'Zn2SnO4:Cr,Eu ultra-small nanoparticles as new near infrared emitting persistent luminescent nanoprobes for cellular and deep tissue imaging at 800 nm' by Hongwu Zhang et al., Nanoscale, 2017, 9, 8631-8638. PMID- 30431636 TI - Role of the Cu substrate in the growth of ultra-flat crack-free highly crystalline single-layer graphene. AB - Producing ultra-flat crack-free single-layer high-quality graphene over large areas has remained the key challenge to fully exploit graphene's potential into next-generation technological applications. In this regard, we show that epitaxial Cu(111) film represents the most promising catalyst for the chemical vapor deposition (CVD) of graphene with superior planarity and physical integrity. We first compare the most widely used Cu catalysts (foils, polycrystalline films and epitaxial films) in order to benchmark the roughness of the Cu surface which serves as a template for graphene growth. We then discuss the correlation between the formation of cracks and wrinkles in as-grown graphene and the surface morphology of these various Cu catalysts. In particular, Cu grain boundary grooves, inherently present in polycrystalline substrates, are found to contribute to the formation of cracks. Finally, we focused on tuning the CVD protocol in order to successfully grow highly crystalline graphene made of millimeter-size domains on every type of catalyst while mitigating Cu surface roughening. Putting into context the challenges and opportunities associated with the most widely used Cu catalysts provides valuable guidelines for high throughput manufacturing of graphene suitable for emerging industrial applications. PMID- 30431637 TI - The role of polymer-solvent interactions in polyvinyl-alcohol dispersions of multi-wall carbon nanotubes: from coagulant to dispersant. AB - Dispersion of carbon nanotubes in solutions of polyvinyl-alcohol is required for solution casting of composite materials with improved interfacial adhesion where chains adsorbed on the nanotubes serve in the dual role of dispersant and compatible "connector" to the polyvinyl-alcohol matrix. Yet polyvinyl-alcohol is known to induce coagulation of nanotubes in aqueous solutions and thus far, it has not been used for dispersing pristine nanotubes. Here, we report that non fully hydrolyzed (80-90%) polyvinyl-alcohol can be used for the preparation of stable, surfactant-free, dispersions of multi-wall carbon nanotubes in ethanol water mixtures (of at least 50 vol% ethanol). Cryo-TEM imaging and rheological measurements of stable, long-lived dispersions reveal the formation of random networks of suspended tubes, with an averaged mesh size of ~500 nm, indicating that the individual tubes do not aggregate or coagulate. We hypothesize that the polyvinyl-acetate sequences found in non-fully hydrolyzed polymers swell in the presence of ethanol, leading to the formation of a long-ranged steric (entropic) repulsion among polymer-decorated nanotubes. The unexpected role of the polyvinyl acetate sequences along with a detailed dispersion mechanism are described. PMID- 30431638 TI - Investigating the effect of supramolecular gel phase crystallization on gel nucleation. AB - Supramolecular gel phase crystallization offers a new strategy for drug polymorph screening and discovery. In this method, the crystallization outcome depends on the interaction between solute and gel fibre. While supramolecular gels have shown success in producing new polymorphs and crystals with novel morphologies, role of the gel and nature of gel-solute interaction remains largely unexplored. The present study aims to provide a comprehensive picture of the structural evolution of a supramolecular gel produced from a bis(urea) based gelator (G) in the presence of a polymorphic drug carbamazepine (CBZ). The structural aspects of the gel have been assessed by single crystal X-ray analysis, X-ray powder diffraction (XRPD) and solid state NMR spectroscopy. Small Angle Neutron Scattering (SANS) has been used to follow the changes in gel structure in the presence of CBZ. Visual evidence from morphological study and structural evolution observed at a macroscopic level from rheological measurements, shows good agreement with the SANS results. The concentration of the gelator and the relative proportion of G to CBZ were found to be crucial factors in determining the competitive nucleation events involving gelation and crystallization. At a critical G to CBZ ratio the effect of CBZ on gel structure was maximum and fiber bundling in the gel was found to be critically affected. This study offers important information about how the interplay of gelator assembly and gel-solute interactions can fine-tune the nucleation events in a supramolecular gel phase crystallization. PMID- 30431639 TI - Phosphine-free engineering toward the synthesis of metal telluride nanocrystals: the role of a Te precursor coordinated at room temperature. AB - A colloidal strategy offers opportunities for the rational design and synthesis of metal telluride nanocrystals (NCs) with the desired crystal structure, uniform geometry, and composition. However, it remains a challenge to use the paradigm to construct metal telluride NCs by a phosphine-free synthesis procedure for promising applications such as luminescence, photovoltaics and thermoelectricity. Here, we developed a new strategy for fabricating metal telluride nanocrystals, e.g. CdTe and PbTe NCs, by using a highly reactive phosphine-free Te precursor. The ability to reduce a TeO2 powder with dodecanethiol (DDT) has been achieved in the presence of oleylamine (OLA) to generate a soluble alkylammonium telluride at room temperature. We provide direct experimental evidence that the OLA-Te complexes were formed in an order of second magnitude kinetic process based on an in situ UV-vis absorption test. In the case of the CdTe NC system, the straightforward measurement of luminescence and the fabrication of LED devices are presented that can semiquantitatively assess the quality of preparation and the reactivity of this air-stable precursor. The proposed strategy highlights several unique features of this solution-based green chemistry that can be useful for synthesizing other metal telluride NCs to develop novel functional materials. PMID- 30431640 TI - Excited state dynamics study of the self-trapped exciton formation in silicon nanosheets. AB - The exciton formation dynamics of several model silicon nanosheets (SiNSs) are investigated using a time-dependent density functional tight binding method. The first excited-state (S1) self-trapped exciton formation in the SiNSs is obtained by observing the frontier orbital localization related to the characteristic size of the electronic excitations. The frontier molecular orbitals are highly localized in the S1 state on the stretched Si-Si bond due to the photo-excited structural relaxation, leading to a significant Stokes shift. A time domain study of the photo-excited emission gap correlated with the frontier orbital localization properties for exciton formation. The stretched Si-Si softer bonds provide a favorable site for exciton localization, resulting in exciton trapping. The exciton formation time was found to be around ~450-850 fs, showing the consistency of the initial exciton formation time with a recent measurement (~500 to ~900 fs). This study reveals that Si-Si bond breaking acts as an optical activity center and provides regulation of the self-trapped exciton formation time by the quantum confinement effect in SiNSs; significant to the Si nanomaterial properties. PMID- 30431641 TI - Rheology and microrheology of deformable droplet suspensions. AB - Dense suspensions of soft colloidal particles display a broad range of physical and rheological properties which are still far from being fully understood. To elucidate the role of deformability on colloidal flow, we employ computer simulations to measure the apparent viscosity of a system of droplets of variable surface tension subjected to a pressure-driven flow. We confirm that our suspension generically undergoes discontinuous shear thinning, and determine the dependence of the onset of the discontinuity on surface tension. We find that the effective viscosity of the suspension is mainly determined by a capillary number. We present active microrheology simulations, where a single droplet is dragged through the suspension. These also show a dynamical phase transition, analogous to the one associated with discontinuous shear thinning in our interpretation. Such a transition is signalled by a discontinuity in the droplet velocity versus applied force. PMID- 30431642 TI - Direct enantio- and diastereoselective Mannich reactions of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine. AB - A highly diastereo- and enantioselective Mannich reaction of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine has been developed. A series of 3-substituted 3-amino-oxindoles containing assembled bicyclic rings linked by a C-C bond were constructed by this protocol in excellent yields (92-99%) with high enantioselectivities (85-99% ee) and diastereoselectivities (up to >99 : 1 dr). PMID- 30431643 TI - Trends in Modern Contraceptive Use among Young Adult Women in sub-Saharan Africa 1990 to 2014. AB - This article provides updated estimates of trends in modern contraceptive use among young adult women (aged 15-24) who have had sex, using Demographic and Health Survey data from 23 sub-Saharan African countries (1990-2014). In East/South Africa, parous women had higher modern contraceptive use than nulliparous women and larger increases in modern contraceptive use over time. In the West/Central region, nulliparous women had higher modern contraceptive use than parous women and larger increases in modern contraceptive use over time. Most of the increase in modern contraceptive use was driven by an increase in short-acting-rather than long-acting-methods across regions and parity groups. Although parous women had higher unmet need for family planning in both regions, nulliparous women had larger increases in unmet need for family planning over time in the East/South region. Decomposition analysis suggests that increases in use of modern contraceptives are largely driven by increases in the rate of contraceptive use rather than changes in the parity composition of women. PMID- 30431644 TI - What prevents doctors from seeking help for stress and burnout? A mixed-methods investigation among metropolitan and regional-based australian doctors. AB - OBJECTIVE: Despite the increased risk of experiencing mental health concerns, particularly related to stress and burnout, psychological help-seeking among medical doctors is typically low. This study examined the barriers to treatment experienced by doctors for stress and burnout-related difficulties. METHODS: A mixed-methods design was adopted. The quantitative sample comprised 274 Australian-based medical doctors. Qualitative interviews were conducted with a subsample of 20 (11 regional and 9 metropolitans) doctors. For triangulation, five stakeholder interviews were also conducted with representatives of the profession. RESULTS: Time was the greatest barrier to treatment. Qualitatively, doctors identified barriers such as stigma and fear of professional consequences, and particularly among regional doctors, access to services and professional culture. CONCLUSIONS: There is a need for tailored strategies to address barriers to psychological treatment among doctors for improving service access and mental health. PMID- 30431645 TI - Classic solutions to a modern problem: exercise training improves metabolic disorders in offspring from fathers on a high fat diet. PMID- 30431646 TI - Pleomorphic adenoma of the head and neck in children: presentation and management. AB - OBJECTIVE: Pleomorphic adenoma is the most common benign salivary gland neoplasm in children. Recurrence and malignant transformation are concerns necessitating proper treatment. The goal of this research was to discuss the presentation, evaluation, and management of pediatric pleomorphic adenoma of the head and neck. METHODS: Retrospective chart review of patients under 20 years of age treated for pleomorphic adenoma of the head and neck between 1998 and 2017. Data assessed included demographics, clinical presentation, imaging, treatment, complications, recurrence, and follow-up. RESULTS: Forty-one patients with pleomorphic adenoma were identified. Major salivary gland lesions were most common (n = 32, 78.0%); 78.1% (25 of 32) arising in the parotid and 21.9% (7 of 32) in the submandibular glands. Minor salivary gland lesions were removed from the palate (5 of 9, 55.6%), buccal mucosa (2 of 9, 22.2%), parapharyngeal space (1 of 9, 11.1%), and upper lip (1 of 9, 11.1%). Preoperative imaging was reviewed in 32 patients and consisted of nine ultrasound exams, 15 computerized tomography (CT) exams, and 23 magnetic resonance imaging (MRI) exams. Multimodality imaging was performed in 14 of 32 patients. Surgical excision was performed in all patients. Postoperative complications included transient facial paresis (n = 9), Frey syndrome (n = 1), and bacterial pharyngitis (n = 1). Average length of follow-up was 25.5 months; confirmed recurrence occurred in two patients (4.9%). CONCLUSION: Evaluation of pleomorphic adenoma in children should include preoperative imaging. The goal of surgery should be complete surgical excision with negative margins. Rate of recurrence is low; however, prolonged monitoring is recommended. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30431647 TI - A qualitative analysis of emotion and emotion regulation in hoarding disorder. AB - OBJECTIVE: The role of emotion regulation (ER) has been receiving increased attention in relation to various forms of psychopathology including hoarding disorder (HD). However, questionnaire designs are limited to finding associations of ER with symptoms or symptom groups, without finding out how such constructs might be involved in the disorder. METHODS: This study was a qualitative investigation of ER in a clinical HD sample (N = 11). RESULTS: Prominent themes provided support for ER difficulties in hoarding. In particular, difficulties with identifying and describing feelings, unhelpful attitudes toward the emotional experience, the use of avoidance-based strategies, and a perceived lack of effective ER strategies were prominent themes. Furthermore, emotional factors were identified as being associated with the onset and/or exacerbation of hoarding behavior, and possessions and acquiring behavior appeared to serve an ER function. CONCLUSION: The current paper provides a nuanced account of the role of ER in hoarding difficulties. PMID- 30431648 TI - Nondestructive adult age at death estimation: Visualizing cementum annulations in a known age historical human assemblage using synchrotron X-ray microtomography. AB - OBJECTIVES: Adult age at death estimation continues to challenge physical anthropologists. One estimation method involves counting tooth cementum annulations (TCA). Non-destructively accessing TCA is a critical step to approaching fossil teeth of unknown age and to verifying life history profiles of human ancestors. This pilot study aims to (a) non-destructively image TCA in teeth from a known age archeological human population by propagation phase contrast X-ray synchrotron MUCT (PPC-SR-MUCT) (b) test the correlation between real and estimated ages, and the accuracy, precision and bias of age estimates. MATERIALS AND METHODS: We examine 20 permanent human canines (aged 20-81 years), from a 18th to 19th century known age collection from St. Luke's Church (London, England). We scanned transverse segments of acellular cementum in the apical portion of the middle root third using PPC-SR-MUCT. We generated virtual transverse sections on which two observers perform two sessions of blind TCA counts. We calculate the estimated ages at death by adding 10 years to the TCA counts. RESULTS: A moderately strong positive linear relationship exists between real and estimated ages (r = 0.76, p < .001), with an average inaccuracy of 16.1 years and an average bias towards underestimation of 15.7 years. This difference is lower in individuals <50 years (6.8 and 6.5 years, respectively, n = 10) compared with those >50 years (24.9 years, n = 10). DISCUSSION: We reliably imaged and identified TCA in individuals <50 years from a known-age archeological sample. Scanning refinement will yield a promising alternative to current destructive methods of TCA analyses and to aid access to life history events in adult fossil hominins. PMID- 30431649 TI - The Alliance and Rupture Observation Scale (AROS): Development and validation of an alliance and rupture measure for repeated observations within psychotherapy sessions. AB - OBJECTIVE: The aim of this study was to test a new observer-rated instrument, the Alliance and Rupture Observation Scale (AROS). It was designed for repeated measurements of the alliance within sessions and to detect alliance ruptures. METHOD: Videotaped therapy sessions with depressed adults were analyzed. Reliability was mainly assessed as inter-rater reliability. Convergent, predictive, and discriminant validity of the AROS was assessed by comparing the instrument with both observer-rated and patient-rated measures. RESULTS: The AROS exhibited excellent inter-rater reliability. Alliance levels measured with the AROS predicted patients' ratings of the alliance in the same session and were highly correlated with another observer-rated alliance measure. Alliance patterns (rupture; repair; and no-rupture) based on AROS scores were significantly correlated with patients' ratings of the alliance. CONCLUSIONS: Preliminary support for convergent and predictive validity was found. It is yet to be determined whether AROS scores are related to psychotherapy outcomes. PMID- 30431650 TI - Engaging with the affiliative system through mindfulness: The impact of the different types of positive affect in psychosis. AB - OBJECTIVES: We aimed to explore associations between positive and negative symptoms, mindfulness, positive affect, and social safeness; and to understand the mediator role of positive emotions in the relationship between mindfulness and social safeness. METHOD: Fifty-six participants with a psychotic disorder were assessed with measures of mindfulness, negative and positive symptoms, positive affect, and social safeness. RESULTS: All variables were associated with each other except for positive symptoms and active affect. Mindfulness predicted social safeness through safe affect, when controlling for positive and negative symptoms. CONCLUSIONS: This study contributes to knowledge of mechanisms behind social safeness adding the role of mindfulness and activation of positive emotions. The continuing study of mindfulness as an important mechanism for social safeness will allow further improvement of interventions for psychosis. PMID- 30431651 TI - Spectroscopy Used as a Tool to Evaluate Hair Damage and Protection. AB - OBJECTIVE: Methods that can be used to analyze hair damage and to support a claim of hair protection are important for the cosmetic industry. There are many approaches available, but they are usually laborious and expensive. The researchers propose a simple fluorescence method that is based upon the emissive properties of damaged hair. METHODS: Hair fluorescence was observed when using both fluorimetry and microscopic procedures. The method was developed by comparing native hair with hair that was damaged by UVA and visible light. RESULTS: Spectroscopic properties (absorption and emission) of hair in the visible range are presented. The changes in the emissive properties of hair during irradiation were characterized and they were correlated with photobleaching, which is due to the generation of singlet oxygen. Emissions were also obtained in the hair shafts that had been previously treated with chamomile extract and this treatment was able to avoid hair bleaching. CONCLUSION: The emissive properties of hair in the visible range can be used as a tool for the evaluation of hair damage and protection. This method can be useful as a tool in order to claim substantiation. This article is protected by copyright. All rights reserved. PMID- 30431652 TI - Construction of direct Z-Scheme photocatalysts for overall water splitting using two-dimensional van der waals heterojunctions of metal dichalcogenides. AB - The direct Z-scheme system constructed by two-dimensional (2D) materials is an efficient route for hydrogen production from photocatalytic water splitting. In the present work, the 2D van der Waals (vdW) heterojunctions of MoSe2 /SnS2 , MoSe2 /SnSe2 , MoSe2 /CrS2 , MoTe2 /SnS2 , MoTe2 /SnSe2 , and MoTe2 /CrS2 are proposed to be promising candidates for direct Z-scheme photocatalysts and verified by first principles calculations. Perpendicular electric field is induced in these 2D vdW heterojunctions, which enhances the efficiency of solar energy utilization. Replacing MoSe2 with MoTe2 not only facilitates the interlayer carrier migration, but also improves the optical absorption properties for these heterojunctions. Excitingly, the 2D vdW MoTe2 /CrS2 heterojunction is demonstrated, for the first time, to be 2D near-infrared-light driven photocatalyst for direct Z-scheme water splitting. (c) 2018 Wiley Periodicals, Inc. PMID- 30431653 TI - Polymorphism in interferon lambda3/interleukin-28B gene and risk to noncirrhotic chronic hepatitis C genotype 3 virus infection and its effect on the response to combined daclatasvir and sofosbuvir therapy. AB - Hepatitis C virus (HCV) infection is a considerable public-health problem and an important cause of liver disease with about 71 million people infected worldwide and more than 399 000 people die every year from hepatitis C-related liver diseases. The present study was, therefore, initiated to investigate the association of polymorphism in interferon lambda3 (IFNL3) also known as interleukin-28B (IL-28B) gene with chronic HCV infection and association of these polymorphic variants with the combination daclatasvir and sofosbuvir HCV therapy response. Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a total of 250 chronic HCV genotype three patients and 500 number of healthy controls. Our data revealed that the TT (minor) genotype of IFNL3 (rs12979860) and GG (minor) genotype of IFNL3 (rs8099917) exhibited a significant association with chronic HCV genotype 3 infection when compared with controls. The results of treatment response showed that CC (major) genotype of IFNL3 (rs12979860) and TT (major) genotype of IFNL3 (rs8099917) are associated with the likelihood of achieving a higher sustained virological response (SVR), to combined daclatasvir and sofosbuvir therapy, in genotype 3-infected HCV patients, whereas the individuals with TT (minor) genotype of IFNL3 (rs12979860) and GG (minor) genotype of IFNL3 (rs8099917) are more susceptible to chronic HCV infection and treatment relapse, suggesting a role of IFNL3 (rs12979860) and (rs8099917) in the treatment outcome of combined daclatasvir and sofosbuvir therapy in chronic HCV genotype 3 infection. PMID- 30431654 TI - Perspectives towards antiviral drug discovery against Ebola virus. AB - Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11500 deaths according to a recent 2018 WHO report. With mortality rates up to 90 %, it is nowadays one of the most deadly infectious diseases. However, no FDA approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination makes Ebola virus a category A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from R&D to clinical trials in the development of small-molecule antiviral drugs, small interference RNA molecules, phosphorodiamidate morpholino oligomers, full-length monoclonal antibodies and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery. This article is protected by copyright. All rights reserved. PMID- 30431655 TI - Sex differences in binge-like and aversion-resistant alcohol drinking in C57BL/6J mice. AB - BACKGROUND: Alcohol use disorder is characterized by compulsive alcohol intake, or drinking despite negative consequences. Previous studies have shown that female rodents have a heightened vulnerability to drug use across different stages of the addictive cycle, but no previous studies have studied females in a model of aversion-resistant alcohol intake. Here, we investigated sex differences in binge-like and aversion-resistant alcohol drinking in C57BL/6J mice using a modified drinking in the dark (DID) paradigm. METHODS: In Experiment 1, 24-h aversion to quinine (0, 100, or 250 MUM) was assessed. In Experiment 2, male and female adult C57BL/6J mice consumed 15% ethanol (EtOH) or water in a 2-bottle limited access DID paradigm for 2 h/day for 15 days. The EtOH was next adulterated with quinine (0, 100, or 250 MUM) over three consecutive drinking sessions to test aversion-resistant intake. In Experiment 3, intake of quinine adulterated (100 MUM) EtOH was assessed across all 15 drinking sessions. RESULTS: Quinine was equally aversive to both sexes in Experiment 1. In Experiment 2, female mice consumed significantly more alcohol than male mice during the final six drinking sessions. Levels of aversion-resistant intake did not differ between the sexes. In Experiment 3, quinine suppressed consumption in all mice, though females drank significantly more on the final two sessions. CONCLUSIONS: The results of this study demonstrate that while female mice escalate and consume more EtOH than males, both sexes exhibit similar levels of aversion-resistant drinking. These results inform our understanding of how sex interacts with vulnerability for addiction and argue for the inclusion of females in more studies of aversion-resistant alcohol drinking. This article is protected by copyright. All rights reserved. PMID- 30431657 TI - In Memoriam: John Anthony 'Tony' Nevin. PMID- 30431656 TI - Contextual influence over deriving another's false beliefs using a relational triangulation perspective taking protocol (RT-PTP-M2). AB - The original relational triangulation perspective taking protocol (RT-PTP-M1; Guinther, ) was extended with a second training and testing module (RT-PTP-M2) showing contextual influence over derivation of another's "false beliefs" during an analog of the Sally-Anne test for Theory of Mind (Baron-Cohen, Leslie, & Frith, ; Wimmer & Perner, ) in verbally competent adults. Under the respective contextual control of experimental stimuli X2 and X3 , participants first learned through direct conditioning procedures that avatars A2 and A3 "behave the same way" towards target stimuli. Participants then made object discriminations under X2 according to the spatial perspective of A2 , who saw an initial target at a particular location but could not see that the target was later swapped with a second target; reporting the identity of the initial target was reinforced for participants. Among participants who had failed baseline testing, this directly trained "false belief attribution" repertoire was then spontaneously emitted by participants relative to the perspective of A3 under X3 during the final test for derivation. Other participants were able to derive false belief under X3 without the X2 attribution training. These results suggest the RT-PTP procedures were successful in causing X3 to acquire context-of-relating functions for exerting control over perspectival relational triangulation. PMID- 30431658 TI - Generalized identity in a successive matching-to-sample procedure in rats: Effects of number of exemplars and a masking stimulus. AB - Two experiments examined the emergence of generalized identity matching in rats using a successive discrimination procedure with olfactory stimuli. Trials consisted of the presentation of two odors separated by a 1-s interstimulus interval. Responses during the second odor presentation were reinforced only if the two odors were identical. In Experiment 1, rats were trained with two odors and then exposed to sessions that included unreinforced probe trials with novel odors. There was evidence of higher response rates on matching probe trials in some rats, but matching did not approach baseline levels. Additional training with four exemplars produced transfer to novel odors that was equivalent to baseline levels. Experiment 2 tested the possibility that detection of stimulus change, rather than generalized identity, was responsible for the transfer seen in Experiment 1. Thus, a masking odor was inserted during the 1-s interstimulus interval so that stimulus change occurred on all trials. Although response rates on probe trials were lower than baseline rates, above chance transfer to novel stimuli was still observed in four of the five animals tested. These findings support the hypothesis that transfer of matching to novel odors in this successive matching-to-sample paradigm is based on a generalized identity relation. PMID- 30431659 TI - Reinforcer magnitude and resurgence. AB - One experiment each was conducted with pigeons and rats to assess the effects of changes in reinforcer magnitude on resurgence. Each experiment involved three phases. In the Training phase, key pecking (Experiment 1) or lever pressing (Experiment 2) on two concurrently available operanda was reinforced according to variable-interval schedules. In the Alternative Reinforcement phase, responding to one operandum was extinguished while that to the other was reinforced with greater duration of food access (Experiment 1), greater number of pellets (Experiment 2a), or a similar number of pellets (Experiment 2b) than occurred in the Training phase. In the Resurgence Test phase, the reinforcer magnitude associated with the Alternative response was either reduced (Experiments 1 & 2a) or increased (Experiment 2b) relative to the preceding condition. Resurgence generally occurred when the reinforcer magnitude maintaining the Alternative response was reduced, but not when it was increased relative to the preceding condition. The results further support the suggestion that resurgence results from an overall "worsening" of reinforcement conditions, but not simply from a change in conditions. PMID- 30431660 TI - The Role of Social Support in Motivating Reductions in Alcohol Use: A Test of Three Models of Social Support in Alcohol-Impaired Drivers. AB - BACKGROUND: Social support has been linked to many therapeutic benefits (e.g., treatment retention, reduced posttreatment relapse) for individuals with alcohol use disorder. However, the positive impacts of social support have not been well understood in the context of alcohol-impaired driving. This article examines the role of social support in motivating those with histories of driving while intoxicated (DWI) arrest to reduce alcohol use by testing 3 major models of social support: the Main-Effects model, the Buffering model, and the Optimal Matching model. METHODS: One hundred and nineteen participants with histories of DWI arrest were recruited from a correctional treatment facility (n = 59) and the local community (n = 60). Participants completed interviews to assess alcohol consumption, psychiatric/physical conditions, and psychosocial factors associated with drinking behavior (e.g., social support, alcohol-related problems, and motivation to change). Hierarchical regression analyses were conducted to test the 3 models. Additionally, the relative magnitude of the effects of general and recovery-specific social support was compared based on the approach of statistical inference of confidence intervals. RESULTS: Overall social support was positively associated with some motivation to change (i.e., importance of change, confidence in change) among alcohol-impaired drivers, supporting the Main Effects model. However, the impact of overall social support on motivation to change was not moderated by alcohol-related problems of individuals arrested for DWI, which did not confirm the Buffering model. Last, recovery-specific social support, rather than general social support, contributed to increasing motivation to reduce alcohol use, which supported the Optimal Matching model. CONCLUSIONS: These findings highlight the benefits of social support (i.e., increased motivation to change alcohol use) for alcohol-impaired drivers. Regardless of the severity of alcohol-related problems of alcohol-impaired drivers, social support had direct positive impacts on motivation to change. In particular, the results underscore that social support can be more effective when it is matched to the recovery effort of individuals, which is consistent with the Optimal Matching model. PMID- 30431661 TI - Hepatitis B virus genotype G and liver fibrosis progression in chronic hepatitis B and human immunodeficiency virus coinfection. AB - INTRODUCTION: Infection with hepatitis B virus (HBV) genotype G has been associated with increased liver fibrosis levels compared with other genotypes in cross-sectional studies, yet its role in fibrosis evolution remains to be established. METHODS: In this prospective cohort study, 158 human immunodeficiency virus (HIV)-HBV coinfected patients had available HBV genotyping at baseline. Liver fibrosis was assessed at baseline and every 6 to 12 months by the FibroTest (BioPredictive, Paris, France). Risk factors for fibrosis regression (F3-F4 to F0-F1-F2) and progression (F0-F1-F2 to F3-F4) between baseline and end of follow-up were evaluated. RESULTS: Most patients were male (88.6%) with a median age of 39 years. HBV genotype A was more prevalent compared with other HBV genotypes (62.7% vs D = 10.8%, E = 10.8%, and G = 15.8%). Patients were followed up for a median of 83 months (IQR = 37-97). In the 43 (27.2%) patients with F3-F4 baseline liver fibrosis, 7 (16.2%) regressed to F0-F1-F2 fibrosis at the last follow-up visit. In the 115 (72.8%) with F0-F1-F2 fibrosis at baseline, 19 (16.5%) progressed to F3-F4 fibrosis at last visit. In multivariable analysis, fibrosis progression was independently associated with older age (P <0.005), baseline CD4+ cell count less than 350/mm 3 ( P <0.01), longer antiretroviral therapy duration ( P <0.03), and HBV genotype G infection (vs non-G, P <0.01). When examining averages over time, the rate of FibroTest increase was faster in genotype G vs non-G-infected patients with baseline F0-F1 F2 fibrosis ( P for interaction = 0.002). CONCLUSION: In HIV-HBV coinfected patients, HBV genotype G is an independent risk factor for liver fibrosis progression as determined by noninvasive markers. HBV genotype G-infected patients with low initial liver fibrosis levels may require more careful monitoring. PMID- 30431662 TI - High performance thermoelectric materials based on metal organic coordination polymers through first-principles band engineering. AB - Metal organic coordination polymers (MOCPs) provide an intriguing platform to design functional thermoelectric materials through modifying metal atoms, organic ligands, etc. Based on density functional theory (DFT) coupled with Boltzmann transport theory, the thermoelectric properties of several MOCPs, which is designed by intercalating organic linkers ranging from benzene to pentacene between two inorganic units, have been investigated. We found that the interplay of d orbital of Ni atom and pi orbitals of the organic linkers play an important role in band engineering and then thermoelectric efficiency. Combining the high conductivity for pi orbitals of organic ligands and high Seebeck coefficient of the d orbital of Ni atom, such intercalated MOCPs provide new way to design high performance thermoelectric materials. (c) 2018 Wiley Periodicals, Inc. PMID- 30431663 TI - Traditional Chinese medicine as targeted treatment for epithelial-mesenchymal transition-induced cancer progression. AB - The epithelial-mesenchymal transition (EMT) program, which loosens cell-cell adhesion complexes, endows cells with enhanced migratory and invasive properties. Furthermore, this process facilitates both the development of drug resistance and immunosuppression by tumor cells, which preclude the successful treatment of cancer. Recent research has demonstrated that many signaling pathways are involved in EMT progression. In addition, cancer stem cells (CSCs), vasculogenic mimicry (VM) and the tumor-related immune microenvironment all play important roles in tumor formation. However, there are few reports on the relationships between EMT and these factors. In addition, in recent years, traditional Chinese medicine (TCM) has developed a unique system for treating cancer. In this review, we summarize the crucial signaling pathways associated with the EMT process in cancer patients and discuss the interconnections between EMT and other molecular factors (such as CSCs, VM, and the tumor-related immune microenvironment). We attempt to identify common regulators that might be potential therapeutic targets to thereby optimize tumor treatment. In addition, we outline recent research on TCM approaches that target EMT and thereby provide a foundation for further research on the exact mechanisms by which TCMs affect EMT in cancer. PMID- 30431664 TI - Umifenovir susceptibility monitoring and characterization of influenza viruses isolated during ARBITR clinical study. AB - Antiviral drugs can play a significant role in the control of influenza. Umifenovir (Arbidol) is licensed and widely used in Russia for the prophylaxis and/or treatment of influenza. We evaluated the susceptibility to umifenovir of reference influenza A and B viruses and influenza A viruses isolated from patients in the ARBITR clinical trial in 2012-2014 seasons. Using an MDCK cell based enzyme-linked immunosorbent assay (ELISA), we showed that the replication of antigenically dominant human influenza A and B viruses was efficiently inhibited by umifenovir. The wild-type A/Perth/265/2009 (H1N1)pdm09, A/Fukui/45/2004 (H3N2), and B/Perth/211/2001 viruses and their oseltamivir resistant counterparts were susceptible to umifenovir among in vitro laboratory assays. All 18 clinical isolates of influenza A viruses obtained before and during therapy were susceptible to umifenovir with 50% effective concentration (EC 50 ) ranging from 8.4 +/- 1.1 to 17.4 +/- 5.4 uM. No molecular markers of umifenovir resistance were identified in influenza viruses isolate d from patients at 3, 5, and 7 days after initiation of therapy. None of the viruses isolated before and during umifenovir therapy displayed reduced susceptibility to neuraminidase (NA) inhibitors. Thus, umifenovir is effective against influenza viruses circulating in 2012-2014 seasons, and therapy did not lead to the emergence of drug-resistant variants. PMID- 30431665 TI - Acute myeloid leukemia with minimal differentiation (AML M0) mimicking acute lymphoblastic leukemia. PMID- 30431666 TI - Venetoclax plus decitabine induced complete remission with molecular response in acute myeloid leukemia relapsed after hematopoietic stem cell transplantation. PMID- 30431667 TI - Biliary papillomatosis. AB - A 74-year-old asymptomatic man was referred to the outpatient clinic by his general practitioner because of abnormal liver enzymes. He had no important medical history. Blood analysis showed mild cholestasis. Abdominal computed tomography showed bile duct dilatation with contrast capturing mural nodules in the common bile duct with protrusion into the dilated lumen (Figure 1a). Magnetic resonance cholangiopancreaticography revealed bile duct dilatation with multiple irregular filling defects (Figure 1b). This article is protected by copyright. All rights reserved. PMID- 30431668 TI - Understanding Gender Differences in Resilience Among Veterans: Trauma History and Social Ecology. AB - A social-ecological framework for resilience underscores the importance of conceptualizing individuals embedded within their context when evaluating a person's vulnerability and adaptation to stress. Despite a high level of trauma exposure, most veterans exhibit psychological resilience following a traumatic event. Interpersonal trauma is associated with poorer psychological outcomes than noninterpersonal trauma and is experienced more frequently across the lifespan by women as compared to men. In the present study, we examined gender differences in trauma exposure, resilience, and protective factors among veterans. Participants included 665 veterans who completed a baseline survey assessing traumatic events; 544 veterans (81.8%) completed a 1-year follow-up survey assessing resilience, combat exposure, deployment social support, deployment preparedness, and military sexual trauma (MST). Principal component analyses revealed the Traumatic Life Events Questionnaire categorized into four meaningful components: sexual abuse, interpersonal violence, stranger violence, and accidents/unexpected trauma. Women reported greater exposure to sexual abuse, d = 0.76; interpersonal violence, d = 0.31; and MST, Cramer's V = 0.54; men reported greater exposure to stranger violence, accidents/unexpected trauma, and combat exposure, ds = 0.24-0.55. Compared to women, men also reported greater social support during deployment, d = 0.46. Hierarchical linear regression indicated that men's resilience scores were higher than women's, beta = .10, p = .032, yet this association was no longer significant once we accounted for trauma type, beta = .07, p = .197. Results indicate that trauma type is central to resilience and suggest one must consider the social-ecological context that can promote or inhibit resilient processes. PMID- 30431669 TI - Implementation of a transition model to adult care may not be enough to improve results: National study of kidney transplant recipients. AB - Adolescents with a kidney transplant (KT) require special attention during the transition of care. Few longitudinal studies have assessed the effect of transition models (TM) on patient outcomes. Between 1986 and 2013, 239 pediatric patients underwent KT in Finland, of whom 132 have been transferred to adult care. In 2005, a TM was developed following international recommendations. We compared patient (PS) and graft survival (GS) rates before and after the introduction of the TM. PS and GS at 10 years were similar before and after the implementation of the TM (PS 85% and 90% respectively, P=0.626; GS 60% and 58%, respectively, P=0.656). GS was lower in patients transplanted at age 10-18 than in patients transplanted at a younger age in the TM cohort (79% vs 95%, P<0.001). During the first five years after transfer, 63% of patients had stable KT function, 13% had deteriorating function and 24% lost their KT. Altogether 32 out of 132 patients lost their kidney allograft within five years after transfer to adult care (13 before and 19 after TM implementation, P= 0.566). The implementation of this TM had no effect on PS or GS. Further measures to improve our TM are in progress. This article is protected by copyright. All rights reserved. PMID- 30431671 TI - Traumatic Stress Among Sexual and Gender Minority Refugees From the Middle East, North Africa, and Asia Who Fled to the European Union. AB - In 2015, more than 600,000 individuals from Syria, Iraq, and Afghanistan fled to Europe in search of protection. Among the most understudied of this population are individuals who identify as lesbian, gay, bisexual, transgender, and queer (LGBTQ). These individuals have not only fled war but also violence due to their sexual and/or gender identities. At the same time, LGBTQ individuals from other parts of the Middle East, Central and South Asia, and North Africa have also fled to Europe to escape persecution. The purpose of this multimethod study was to understand how traumatic stress shaped the experiences of 38 LGBTQ individuals who fled to Austria (n = 19) and the Netherlands (n = 19) from these regions. We assessed participants for posttraumatic stress disorder (PTSD) and conducted qualitative interviews to understand their migration experiences. Of the 37 participants assessed for PTSD, 33 (89.2%) reported that their most distressing event occurred prior to migration. For the 24 (64.9%) participants who met criteria for a provisional diagnosis of PTSD, 15 reported that the precipitating event was related to their sexual and/or gender identities and 9 reported that it was related to another type of event (e.g., war). Grounded theory was used to analyze qualitative data. Themes demonstrated that participants encountered targeted violence and abuse throughout migration and upon their arrival in Austria and the Netherlands. Findings indicate that LGBTQ refugees may be vulnerable to ongoing trauma from other refugees and immigration officials. Recommendations for protecting and supporting LGBTQ refugees during humanitarian emergencies are provided. PMID- 30431670 TI - NMR chiral discrimination of chalcogen containing secondary alcohols. AB - Here, we report the general strategies by which NMR spectroscopy can be used to determine the enantiopurity and absolute configuration of chalcogen containing secondary alcohols, including the evaluation of the use of chiral solvating and chiral derivatizing agents. The BINOL/DMAP ternary complex demonstrated a simple and fast protocol for determining enantiopurity. The drug Naproxen afforded a stable, nonhygroscopic, and readily available chiral derivatizing agent (CDA) for NMR chiral discrimination of chalcogen containing secondary alcohols. The chiral recognition by CDA and chiral solvating agent (CSA) was assessed using 1 H, 77 Se {1H}, and 125 Te-{1H} NMR spectroscopy. A simple model for the assignment of the absolute configuration from NMR data is presented. PMID- 30431672 TI - Tacrolimus overexposure in kidney transplant recipients during the first post operative week: caution is required in older patients. AB - In liver transplantation, tacrolimus trough concentrations (Cmin) above 20 ng/mL during the first days led to worse outcome at 1 year but data in the kidney transplant (KT) era are scarce. The aim of this study was to evaluate the impact of tacrolimus overexposure during the first week post-transplantation on the kidney function (KF) of KT recipients. In this retrospective study, 105 KT recipients were attributed to overexposure group (OG) or normal group according to their Cmin during the first week of treatment. KF was evaluated by comparing the rate of delayed graft function (DGF) and by collecting plasma creatinine from day 1, 2, 3, 4, 5, 6, 7, 14, 21, 28 and at 1 year. Risk factors for developing DGF were also investigated using a multivariate model. DGF was more frequent in OG (43% of patients; P = 0.027) which has higher plasma creatinine on day 7, 14, and 21. OG patients were older with more extended criteria donor's grafts. In the multivariate analysis, only cold ischemia time (CIT) remained associated with DGF (OR = 1.003), while TAC overexposure did not reach significance (P = 0.06; OR = 3.9). In this study, we confirmed the predominant role of CIT as a risk factor for the onset of DGF in kidney transplantation. 43% of KT recipients were overexposed with more DGF, especially older patients. PMID- 30431673 TI - Proline autocatalysis in the origin of biological enantioenriched chirality. AB - Biological enantioenriched chirality is a phenomenon that in living organisms, amino acids and carbohydrates typically have the same absolute configuration. Perhaps one of the earliest attempts to delineate the origins of this phenomenon was a theory known as asymmetric autocatalysis, a reaction in which the structures of the chiral catalyst and the product are the same, and in which the chiral product acts as a chiral catalyst for its own production. In theory, this would mean that small asymmetries in the product will propagate rapidly. However, autocatalysis also relies on the cross-inhibition of chiral states, something that would not likely be possible on primordial Earth. But recently, theories on asymmetric autocatalysis have begun to resurface as more recent findings indicate that other mechanisms exist to stabilize the homochiral states. In this study, I propose an autocatalytic cycle, and using density functional theory, prove that (1) it is plausible on primordial Earth, and (2) it propagates arbitrary asymmetries in proline. Thus, facilitating asymmetry in proline and allowing access to a wide variety of asymmetric proline-catalyzed reactions, including those involved in the synthesis of amino acids and carbohydrates from achiral precursors. PMID- 30431674 TI - Palladium-Catalyzed Three-Component Reaction of Dihydrosilanes and Vinyl Iodides in the Presence of Alcohols: Rapid Assembly of Silyl Ethers of Tertiary Silanes. AB - A one-pot reaction that directly converts dihydrosilanes into silyl ethers of tertiary silanes is reported. Under palladium catalysis, one Si-H bond of the dihydrosilane formally engages in C(sp3 )-Si bond formation with a vinyl iodide while the other Si-H bond is transformed into a silyl iodide that undergoes facile alcoholysis with an alcohol. The C-C double bond is reduced in that process. This three-component reaction provides in a single synthetic operation an access to silyl ethers of functionalized and hindered alcohols. Several of those would otherwise be difficult to make but the intermediacy of a highly reactive silyl iodide even allows for tert-butanol to react at room temperature. PMID- 30431675 TI - GnRH agonist deslorelin implant alters the progesterone release pattern during early pregnancy in gilts. AB - The aim of this study was to investigate the relationship of progesterone (P) and luteinizing hormone (LH) during recognition and establishment of pregnancy in the gilt. Therefore effects of eliminating episodic LH pulses on P patterns were determined during early pregnancy. To this end, a slow-release GnRH implant deslorelin was used for GnRH downregulation. A group of gilts (GnRHa, n=8) was implanted with the GnRH agonist on Day 11 of pregnancy, while a control group (C, n=5) was treated with a non-impregnated placebo implant. Blood was collected via a vena cava caudalis catheter at 10-minute intervals for 8 hours on Day 16 and 21 of pregnancy. As expected, the GnRH implant reduced LH secretion (P<0.01) and abolished LH pulses completely at Day 16 and Day 21 of pregnancy. On Day 16, there was no difference in P levels between the treatments. However, on Day 21, the GnRH agonist treatment led to significantly increased P concentrations (P<0.01) compared with the control gilts. Progesterone was secreted in a pulsatile manner in both treatment groups and no relationship between LH pulsatility and P pulsatility was observed. In conclusion, abolishment of LH pulsatility did not affect the pulsatile pattern of P secretion but led to an unexpected overall increase in P on Day 21 of pregnancy; this effect was delayed and occurred 10 days after commencing treatment with the GnRH depot agonist. The elevation of P on Day 21 of pregnancy in the GnRHa group suggests either a reduced negative feedback effect or an increased autocrine response by the corpora lutea. This article is protected by copyright. All rights reserved. PMID- 30431676 TI - Enhancing Value of MRI: A Call for Action. AB - As national healthcare spending has spiraled out of control, payment reform that moves from volume to value-based payment has been introduced as a practical solution. Under alternative value-based payment models, physicians and clinical teams must deliver the best care possible at a lower cost. Medical imaging has changed the way we diagnose disease, evaluate severity, assess treatment effects, and provide biological insights for the pathophysiology of many diseases. Over the past 50 years, imaging techniques have become increasingly advanced-from X ray to computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and multi-modal imaging. Advanced imaging such as MRI has given clinicians remarkable insights into medical conditions and saved innumerable lives. Under the value proposition, however, we must ask if each imaging study changes treatment decisions, improves patient outcomes, and is cost effective. Imaging research has been focused on developing new technologies and clinical applications to assess diagnostic accuracy. What is needed is the higher level technology assessment. In this article we review why we need to demonstrate the value of MRI, how we define value, what strategies can enhance MR value through partnership with various stakeholders, and how imaging scientists can contribute to healthcare delivery in the future. Level of Evidence: 5 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. PMID- 30431677 TI - Coordinated expression of the VEGF system components in granulosa cells to develop a pro-angiogenic autocrine milieu during ovarian follicle development. AB - In the present study we investigated the temporal relationship between angiogenic and anti-angiogenic vascular endothelial growth factor isoforms (VEGFxxxa and VEGFxxxb respectively), the receptors VEGFR1 and VEGFR2, their soluble forms, and the kinases and the splicing factors regulating the synthesis of VEGF isoforms in healthy and atretic antral follicles. The results show a higher (P<0.05) mRNA expression of VEGF120a, VEGF164a and VEGF120b in healthy than in atretic follicles, but the mRNA expression of VEGF164b was not detected. The mRNA of serine-arginine protein kinase 1 (SRPK1) was higher (P<0.05) in large healthy follicles than in large atretic follicles. In contrast, atretic follicles had higher mRNA expression of soluble form of the receptor 2 of VEGF (sVEGFR2) than healthy follicles (P<0.05). Additionally we observed a positive relationship (P<0.05) between SRPK1 and serine-arginine-rich splicing factor 1 (SRSF1) with the angiogenic isoforms VEGF120a and VEGF164a and between CDC-like kinases-1 (CLK1) and SRSF6 with the antiangiogenic VEGF120b isoform. Principal components analysis (PCA) resulted in two PC explaining 71% of the variation, which were formed by the VEGF isoforms, the kinases and the splicing factor (PC1) and by the VEGF receptors (PC2). When PC analysis was carried out within follicular health status, there were no differences for PC1 between follicular status, whereas PC2 differed between healthy and atretic follicles. In conclusion, the higher mRNA expression for VEGF120a and VEGF164a, the low expression of sVEGFR2 and absent expression of mRNA for VEGF164b provide evidence of a pro-angiogenic autocrine milieu to support granulosa cells during follicle development. This article is protected by copyright. All rights reserved. PMID- 30431678 TI - Greater Early Epinephrine Rise with Head-up Posture: A Marker of Increased Syncope Susceptibility in Vasovagal Fainters. AB - BACKGROUND: Head-up tilt (HUT) is widely used for diagnostic evaluation of patients with suspected vasovagal syncope (VVS), but also offers an opportunity to study VVS pathophysiology. In this regard, it is known that plasma epinephrine (Epi) levels and Epi / norepinephrine (NE) ratio (Epi/NE) are markedly increased from baseline at the time of HUT-induced VVS. However, whether these changes contribute to VVS susceptibility remains uncertain. OBJECTIVE: We hypothesized that if catecholamines contributed to VVS directly, then a greater increase of plasma Epi and Epi/NE ratio early during HUT would be associated with shorter time to syncope. METHODS: The patient population comprised 33 individuals (14 men, 43+/-2 years) with suspected VVS in whom 70 degrees HUT reproduced symptoms. Arterial Epi and NE concentrations were collected at baseline (supine) and 2 minutes (min) of HUT. Linear, exponential, and multiple regression were used to access the association between changing catecholamine levels and time to syncope. RESULTS: Mean (+/-SD) time to positive HUT was 11(7.6) min. Higher plasma Epi levels (pg/ml) both at baseline and at 2 min upright correlated with shorter time to syncope (baseline, R=-0.35, P=0.048; and 2 min, R=-;0.58, P=0.001). Similarly, a greater Epi/NE ratio at 2 min head-up correlated with earlier time to syncope (R=-0.49, P=0.007). These relationships remained significant after adjusting for age and sex (P=0.006 and P=0.02 respectively). CONCLUSION: Greater Epi levels and Epi/NE ratio early during HUT were associated with shorter time to VVS, suggesting a possible contribution to VVS susceptibility. This article is protected by copyright. All rights reserved. PMID- 30431679 TI - Fasciculo-ventricular Pathway Exhibiting Progressive Pre-excitation. AB - A 20-year-old man presented with episodes of rapid palpitations and was diagnosed with Wolff-Parkinson-White syndrome in the Emergency Room based on a 12-lead ECG revealing delta waves (Figure 1). This article is protected by copyright. All rights reserved. PMID- 30431680 TI - Follow-up of patients with negative drug provocation tests to betalactams. AB - Drug allergy work-up in betalactam (BL) allergy is probably the most-developed drug-allergy evaluation at present [1]. During the last few years, the debate on whether one-day or several-day (prolonged) drug provocation test (DPT) should be performed in non-immediate reactions (i.e., occurring >1h after the last administered dose) in order to increase sensitivity has been ongoing and groups working in drug allergy diagnosis have been deploying pro and con arguments and studies in favour of either option [2-5]. The most acceptable way to validate a negative DPT is by studying its negative predictive value (NPV) in patients who are re-challenged to the negatively tested drug, in real-life therapeutic conditions [6,7]. This article is protected by copyright. All rights reserved. PMID- 30431681 TI - "Attenuating Anxieties": A grounded theory study of mental health nurses' responses to clients with suicidal behaviour. AB - AIMS AND OBJECTIVES: To develop a grounded theory to explain mental health nurses' responses to clients with suicidal behaviour. BACKGROUND: Mental health nurses are an integral part of the multi-disciplinary teams supporting people who experience suicidal behaviour, yet limited research is available that explores how nurses respond to the needs of people at risk of suicide and what factors influence their responses and actions. METHODS: Grounded theory was the methodology for this study. Interviews were conducted with 33 mental health nurses working in an urban area in the Republic of Ireland. Data were analysed using the concurrent processes of comparative analysis, theoretical sampling, theoretical sensitivity and memo writing. COREQ 32-item checklist was used. RESULTS: The core category from the data was "Attenuating Anxieties." Participants' main concerns about caring for suicidal clients were related to their feelings of professional and personal vulnerability and the need to protect clients and themselves. This theory "Attenuating Anxieties" highlights the way in which nurses allay their anxieties by utilising historically known risk adverse strategies to care for the suicidal person. Acquisition of further psychotherapeutic training, clinical supervision as well as increased reflexivity protected some participants and enabled them to work creatively and collaboratively while supporting and facilitating therapeutic risk-taking. CONCLUSIONS: The theory of "Attenuating Anxieties" identifies how participants worked within the context of mental health as members of the "risk society," wherein they worried about the possibility and probability of a negative or adverse effect for both the client and self, leaving them to feel constantly vulnerable and unsafe. RELEVANCE TO CLINICAL PRACTICE: This theory highlights the need for a culture of openness that acknowledges nurses' and organisations' anxieties surrounding suicide and promotes a discourse among nurses that moves from a position of risk aversion to a relational and recovery-orientated approach. PMID- 30431682 TI - Life-story work in long-term care facilities for older people: An integrative review. AB - AIM: To systematically review the literature regarding the experience of older people, families and staff using life-story work in residential care facilities for older people. BACKGROUND: Life-story work has been promoted as an approach to enhance care provided and involves collecting memories and moments that are important to the person assisting them to regain their sense of self. DESIGN: An integrative review utilising the PRISMA reporting guidelines where seven databases; Scopus, Embase, CINAHL, MEDLINE, PsychInfo, Psych Articles, Cochrane were searched within the timeframe; 1st January 2006 to 14th March 2016. Data was reviewed using Whittemore & Knalf's (2005) methodological approach for integrative reviews. Analysis was conducted utilising Braun & Clarke's (2006) six phases to identify, analyse and record themes within the data. RESULTS: Thirteen articles were reviewed and the review found that life-story work has been introduced using a range of different approaches, with no common approach. Thematic analysis identified two; maintaining identity and building and maintaining relationships. CONCLUSION: The review extends the current evidence on the experience of using life-story work in long-term aged care facilities for older people. Life-story work has the potential to enhance person centred care in long-term care. However, improving the process of implementation of life story work will require education, time and resources and a commitment from service providers and managers. RELEVANCE TO CLINICAL PRACTICE: Staff who undertake life story work with residents need to be equipped with the skills to recognise and manage the challenges and issues that may potentially arise. Further research into the successful implementation of life-story work and how it can be resourced is required. This article is protected by copyright. All rights reserved. PMID- 30431683 TI - Differential Associations Among PTSD and Complex PTSD Symptoms and Traumatic Experiences and Postmigration Difficulties in a Culturally Diverse Refugee Sample. AB - Forced migration is one of the major challenges currently facing the international community. Many refugees have been affected by traumatic experiences at home and during their flight, putting them at a heightened risk of developing trauma-related disorders. The new version of the International Classification of Diseases (ICD-11) introduced two sibling disorders, posttraumatic stress disorder (PTSD) and complex PTSD (CPTSD). So far, little is known about risk and protective factors in refugees that are specifically associated with the disturbances in self-organization (DSO) characteristic of CPTSD. In this study, we aimed to investigate the association between PTSD and DSO symptoms and traumatic experiences, postmigration difficulties, and social support in a culturally diverse sample of refugees who resettled in Switzerland. A total of 94 refugees (85.1% male; M age = 31.60 years, SD = 10.14, range: 18-61 years) participated in this study. Trained assessors performed either guided questionnaire assessments or structured interviews. In our advice- and help seeking sample, 32.9% of individuals suffered from PTSD and 21.3% from CPTSD. After controlling for potential gender differences, we found positive associations between PTSD symptoms and trauma exposure, beta = .22, as well as between DSO symptoms and postmigration living difficulties, beta = .42, and lack of social support, beta = .22. Our findings support the notion that it is highly important to consider differential associations among PTSD and DSO symptoms and risk and protective factors to gain a deeper understanding of the trauma-related problems refugees face. PMID- 30431684 TI - A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss, and punctate palmoplantar keratoderma. AB - Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2-associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2. PMID- 30431685 TI - Helicobacter pylori infection and prevalence of stroke. AB - BACKGROUND: Helicobacter pylori causes peptic ulcer disease; however, conflicting evidence exists regarding its role in extragastric conditions. We aimed to examine associations of H pylori infection and peptic ulcer disease with stroke. METHODS: A cross-sectional study was undertaken using data of 147 936 individuals aged 25-95 years who underwent the urea breath test during 2002-2012, based on the computerized database of the second largest health maintenance organization in Israel. Logistic regression models were fitted to control for potential confounders. RESULTS: Overall, 1397 (0.9%) patients had stroke and 76 965 (52.0%) had a H pylori positive test. The likelihood of prevalent stroke increased in relation to H pylori infection: adjusted odds ratio (aOR) 1.16 (95% confidence intervals [CI]: 1.04-1.29), gastric ulcer: aOR 1.50 (95% CI: 1.18-1.91), and duodenal ulcer: aOR 1.25 (95% CI: 1.07-1.46). CONCLUSIONS: The results support the premise that stroke may be associated with a history of H pylori infection. PMID- 30431686 TI - Fast free of acrylamide clearing tissue (FACT) for clearing, immunolabelling and three-dimensional imaging of partridge tissues. AB - Fast free of acrylamide clearing tissue (FACT) is a modified sodium dodecyl sulfate-based clearing protocol for the chemical clearing of lipids that completely preserves fluorescent signals in the cleared tissues. The FACT protocol was optimized to image translucent immunostained brain and non-nervous tissues. For this purpose adult male Chukar partridge (Alectoris chukar) was used as a model. After clearing the tissues, 1 or 2 mm-thickness sections of tissues were immunolabeled. The paraventricular nucleus in the hypothalamus (2-mm section) was cleared with FACT, and then was stained with gonadotropin-inhibitory hormone (GnIH) antibody and Hoechst. Simultaneously, immunohistochemical (IHC) staining of cryosectioned brain (30 MUm) was done by GnIH-antibody. The FACT protocol and staining of cell nuclei of nine other tissues were done by a z-stack motorized fluorescent microscope. GnIH-immunoreactive neurons were found by FACT and IHC during the breeding season in male partridges. Deep imaging of the kidney, duodenum, jejunum, lung, pancreas, esophagus, skeletal muscle, trachea, and testis were also done. The FACT protocol can be used for the three dimensional imaging of various tissues and immunostained evaluation of protein markers. RESEARCH HIGHLIGHT: The FACT is a simple and cheap method for whole tissue clearing. The FACT-cleared tissues can be imaged with simple fluorescent microscopes. For the first time, using the FACT, three-dimensional imaging of various tissues was done. PMID- 30431687 TI - Evaluation of the renoprotective effect of nano turmeric against toxic dose of copper sulfate: Role of vascular cell adhesion molecule-1, kidney injury molecule 1, and signal transducer and activator of transcription 3 protein expressions. AB - The aim of this study was to compare the potential renoprotective effects of turmeric (TM) and nano turmeric (NTM) with those of desferrioxamine (DSM) against copper sulfate (CS)-induced toxicity. Rats were administered a toxic dose of CS with TM, NTM, and DSM for 1 week. Next, serum-urea creatinine, uric acid, interleukin (IL)-10, c-reactive protein (CRP), and caspase-3 levels; renal nitric oxide (NO), glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), vascular cell adhesion molecule-1 (VCAM-1), kidney injury molecule (KIM)-1, signal transducer and activator of transcription 3 (STAT-3) protein expression; and nuclear factor (NF)-kappaB and B-cell lymphoma -2 (Bcl-2) messenger RNA expression levels were estimated. Administration of the investigated antioxidants downregulated the marked increase in urea, creatinine, uric acid, CRP, caspase-3, NO, MDA, VCAM-1, kidney injury molecule (KIM-1), STAT-3, NF-kappaB, and DNA fragmentation, and increased Bcl-2, IL-10, GSH, and SOD levels induced by CS. The histopathological examination confirmed the effects of the antioxidants on the investigated biochemical parameters. Interestingly, NTM exhibited a superior renoprotective effect, which was comparable with that of DSM. In conclusion, NTM was shown to be a promising candidate against CS-induced toxicity, and several molecular mechanisms were implicated in the CS-induced renotoxicity as well as the treatment effects of NTM. PMID- 30431688 TI - Salvianolic acid inhibits the effects of high glucose on vascular endothelial dysfunction by modulating the Sirt1-eNOS pathway. AB - Salvianolic acid (SA) is known for improving blood circulation, scavenging hydroxyl radicals, and preventing platelet aggregation. The research explored whether SA can protect against cardiovascular disease induced by high glucose conditions. Our results indicate that SA significantly increases cells viability and nitric oxide levels while decreasing reactive oxygen species generation. SA upregulated the expression levels of Bcl-2 and decreased the levels of Bax, cleaved caspase-3, and cleaved caspase-9. Furthermore, the expression levels of Sirtuin 1 (Sirt1) and p-endothelial nitric oxide synthase (eNOS) were markedly increased in response to SA treatment. Moreover, exposure of human umbilical vein endothelial cells to Ex527 resulted in reducing expression of p-eNOS. However, the beneficial effects of SA were abolished partially when Ex527 was added. These findings suggest that SA can be used as a potential therapeutic to protect against high glucose-induced endothelial injury by modulating Sirt1-eNOS pathway. PMID- 30431689 TI - Overexpression of RYBP inhibits proliferation, invasion, and chemoresistance to cisplatin in anaplastic thyroid cancer cells via the EGFR pathway. AB - Ring1 and YY1 binding protein (RYBP), a new member of the polycomb group protein family, has been reported to play an important role in various biological processes. Recently, more and more studies have demonstrated an implication of RYBP in cancer development. However, the specific role of RYBP in anaplastic thyroid cancer (ATC) remains unknown. In this study, we investigated for the first time the expression pattern and biological functions of RYBP in ATC. We showed that RYBP was lowly expressed in ATC tissues and cell lines. We also found that overexpression of RYBP inhibited ATC cell proliferation, invasion, and cisplatin resistance. Furthermore, we observed that upregulation of RYBP decreased the phosphorylation of EGFR and ERK1/2 in ATC cells. Taken together, our data indicated that RYBP might be considered as a promising therapeutic target for the treatment of ATC. PMID- 30431690 TI - Comparison of the inhibitory potential towards carbonic anhydrase, acetylcholinesterase and butyrylcholinesterase of chalcone and chalcone epoxide. AB - Chalcones and chalcone epoxides are important synthetic intermediates in organic and medicinal chemistry. Chalcones possess a broad spectrum of biological activities; however, 1,3-diphenyl-2-propenone or chalcone has not been given the attention it deserve as its substituted derivatives. In this study, the inhibition effects of chalcone and its epoxidated derivative chalcone epoxide against human carbonic anhydrase isozymes I and II (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were evaluated. The results obtained showed that both compounds exhibited potent inhibitory activity, with IC50 values less than 10 uM. IC 50 values in the submicromolar (hCA I and hCA II) to low micromolar range (AChE and BuChE) were observed for both compounds. The mechanism of inhibition and the inhibitory constants ( K i values) for each compound were also determined. Furthermore, chalcone epoxide was docked within the active sites of hCA I, hCA II, AChE, and BuChE to explore its binding mode with the enzymes. PMID- 30431691 TI - Prevalence of Helicobacter pylori infection among junior high school students in Grudziadz, Poland. AB - BACKGROUND: The purpose of the study was to assess the prevalence of Helicobacter pylori infection among the junior high school students in city Grudziadz, Poland. MATERIALS AND METHODS: A prospective cross-sectional study among second junior high school students was conducted from September 2008 to June 2015 during seven consecutive school years. The studied group was 3241 students 13-17 years old. The 13 C-urea breath test (UBT) was administered to all participants for current H. pylori infection. Clinical, sociodemographic, and hygienic risk factors for H. pylori positivity were analyzed in children with positive and negative UBT. RESULTS: Urea breath test was performed and results were obtained for 3067 of 3241 children, including 723 children (23.6%) with positive result (group 1) and 2344 children (76.4%) with negative result (group 2). The prevalence of H. pylori infection was not different in subsequent seven school years (P = 0.06) and depending on the gender (P = 0.57). In group 1 the cough and in group 2 the epigastric discomfort occurred more frequent (P = 0.04 and P = 0.002, respectively). In multivariate analysis, factors positively associated with prevalence of H. pylori were age >16 years (OR = 2.556; 95%CI 1.293-5.025), living in old town district (OR = 1.374; 95%CI 1.097-1.723), consumption of raw vegetables (OR 1.305; 95%CI 1.038-1.642) or unboiled water (OR = 1.444; 95%CI 1.138-1.832) and using collective catering facilities (OR 1.338; 95%CI 1.039 1.724). Having a cat was protective against H. pylori (OR 0.78; 95%CI 0.614 0.991). CONCLUSIONS: Over the past 10 years, the prevalence of H. pylori infection in Polish adolescents has decreased. H. pylori infection remains problem closely associated with socioeconomic and sanitary conditions. Our results are important to develop prevention strategies for H. pylori-related diseases. PMID- 30431692 TI - Fisetin induces apoptosis in breast cancer MDA-MB-453 cells through degradation of HER2/neu and via the PI3K/Akt pathway. AB - Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in breast cancer. The major snag faced by the human population is the development of chemoresistance to HER2 inhibitors by advanced stage breast cancer cells. Moreover, recent researchers focussed on fisetin as an antiproliferative and chemotherapeutic agent. Therefore, this study was intended to analyze the effects of fisetin on HER2/neu-overexpressing breast cancer cell lines. Our results depicted that fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of phosphatidylinositol 3-kinase/Akt signaling. PMID- 30431693 TI - Impact of Triclosan Adaptation on Membrane Properties, Efflux and Antimicrobial Resistance of Escherichia coli Clinical Isolates. AB - AIM: Analysing the effect of step-wise exposure of Escherichia coli isolates to sub lethal concentrations of triclosan (TCS) that is widely used as antiseptic, preservative and disinfectant. METHODS AND RESULTS: The analysis included the changes in the tolerance to the biocide itself and the cross-resistance to clinically important antibiotics. The involvement of efflux mechanism was studied as well as the possible implication of modifications in cytoplasmic membrane properties including integrity, permeability, potential and depolarization in the resistance mechanisms. Most of E. coli isolates that were adapted to TCS showed increased antimicrobial resistance, lower outer and inner membrane permeability, higher membrane depolarization, more negative membrane potential and enhanced efflux activity using qRT-PCR. Non-significant change in membrane integrity was found in the adapted cells. CONCLUSION: This study suggests that the extensive use of TCS at sub lethal concentrations contributed to the emergence of antibiotic resistance in E. coli clinical isolates, by inducing changes in bacterial membrane properties and enhancing the efflux system. SIGNIFICANCE AND IMPACT OF THE STUDY: The extensive usage of TCS has deleterious effect on the spread of antibiotic resistance, and more studies are needed to investigate the molecular mechanisms underlying the effects of TCS. This article is protected by copyright. All rights reserved. PMID- 30431694 TI - Initial outcomes of local anaesthetic freehand transperineal biopsies in the outpatient setting. AB - INTRODUCTION: Systematic transperineal (TP) and targeted prostate biopsies can be achieved using a freehand access system through perineal punctures, with the potential for reduced morbidity and enabling the procedure under local anesthesia (LA), particularly sepsis. OBJECTIVES: To evaluate the histopathological outcomes, morbidity and tolerability of freehand TP prostate biopsies using the PrecisionPointTM access system under local anaesthetic (LA) in the day surgery and outpatient environments. METHODS: 176 patients underwent freehand TP prostate biopsies from May 2016 to November 2017. The procedure was carried out either under LA alone or with addition of sedation. MRI scans were reported using PIRADS v2. Tolerability was assessed by the Visual Analogue Score for each procedural stage. Histopathological outcomes and complications were recorded RESULTS: Mean age was 65(36-83)years, median PSA 7.9(0.7-1374)ng/ml and mean prostate volume 45(15-157)cc. All cases were carried out under LA alone (160, 90%) or under LA with sedation (16, 9%). The main indication for biopsy was primary diagnosis (88.6%). 91 (52%) patients underwent systematic TP biopsies (mean 24.2cores). Cognitive MRI targeted biopsies alone were performed in 45 (26%) (mean 6.8cores). 40 (23%) patients had standard both systematic and target biopsies (mean 27.9cores). Of the 75 cases who had primary systematic biopsies alone, 46(61%) were positive, 28/46(60.9%) diagnosed clinically significant disease (Gleason >3+4). Pain scores were greatest during LA administration. There were 5 complications (2.8%, Clavien-Dindo I/II). No patients developed urinary sepsis. CONCLUSIONS: Freehand TP biopsies using the PrecisionPoint access system is a safe, tolerable and effective method for systematic and targeted biopsies under LA in the outpatient setting. It has replaced transrectal biopsies in our centre and has potential to transform practice. This article is protected by copyright. All rights reserved. PMID- 30431695 TI - Biological evaluation of some quinoline derivatives with different functional groups as anticancer agents. AB - Due to a great deal of biological activities, quinoline derivatives have drawn attention for synthesis and biological activities in the search for new anticancer drug development. In this work, a variety of substituted (phenyl, nitro, cyano, N-oxide, and methoxy) quinoline derivatives (3-13) were tested in vitro for their biological activity against cancer cell lines, including rat glioblastoma (C6), human cervical cancer cells (HeLa), and human adenocarcinoma (HT29). 6-Bromo-5-nitroquinoline (4), and 6,8-diphenylquinoline (compound 13) showed the greatest antiproliferative activity as compared with the reference drug, 5-fluorouracil (5-FU), while the other compounds showed low antiproliferative activity. 6-Bromo-5-nitroquinoline (4) possesses lower cytotoxic activity than 5-FU in HT29 cell line. Due to its the apoptotic activity 6-Bromo-5-nitroquinoline (4) has the potential to cause cancer cell death. PMID- 30431696 TI - Added diagnostic value of broad-range 16S PCR on periprosthetic tissue and clinical specimens from other normally sterile body sites. AB - AIMS: Evaluation of 16S PCR additional to standard culture to improve the pathogen detection rate in clinical specimens. METHODS AND RESULTS: Microbiological culture and direct 16S PCR was performed on specimens from suspected prosthetic joint infection patients (cohort-1) and on tissues and fluids from other normally sterile body sites (cohort-2). Based on clinical and microbiological data the detection rate for both methods was assessed, assuming no superiority of either 16S PCR or culture. In cohort-1, 469 specimens were obtained. Culture was positive in 170 (36.2%) specimens, 16S PCR detected 70 (41.2%) of those pathogens. Additionally, 16S PCR detected pathogens in 13 of 299 (4.3%) culture-negative specimens. In cohort-2, pathogens were cultured in 52 of 430 (12.1%) specimens and 16S PCR revealed those pathogens in 32 (61.5%) specimens. 16S PCR detected pathogens in 31 of 378 (8.2%) culture-negative specimens. CONCLUSIONS: Overall, the yield with 16S PCR was low. For cohort-1 16S PCR detected pathogens in 4.3% of culture-negative specimens, where this was 8.2% for cohort-2. SIGNIFICANCE AND IMPACT OF STUDY: Although direct 16S PCR cannot replace culture, it may offer a valuable additional diagnostic option for detection of difficult to culture microorganisms in culture negative clinical specimens. This article is protected by copyright. All rights reserved. PMID- 30431697 TI - Evaluation of antioxidant and antiproliferative activities of 1,2-bis (p-amino phenoxy) ethane derivative Schiff bases and metal complexes. AB - In this study, the effects of the two Schiff base derivatives and their metal complexes were tested for MDA concentration, which is an indicator of lipid peroxidation, antioxidant vitamin A, vitamin E, and vitamin C levels in cell culture. A comparison was performed among the groups and it was observed that MDA, vitamin A, vitamin E, and vitamin C concentrations were statistically changed. According to the results, all compounds caused a significant oxidative stress without Zn complexes. Moreover, Mn(II), Cu(II), Zn(II), and Ni(II) complexes of Schiff bases derived from a condensation of 1,2-bis (p-aminophenoxy) ethane with naphthaldehydes and 4-methoxy benzaldehyde were examined in terms of antitumor activity against MCF-7 human breast cancer and L1210 murine leukemia cells. Furthermore, the derivatives were tested for antioxidative and prooxidative effects on MCF-7 breast cancer cells. The compounds which were tested revealed that there was an antitumor activity for MCF-7 and L 1210 cancer cells. Also, some of the compounds induced oxidative harmful. PMID- 30431698 TI - Correlation between SALL4 stemness marker and bone morphogenetic protein signaling genes in esophageal squamous cell carcinoma. AB - SALL4, as a stemness marker, plays a key role in the maintenance of pluripotency and self-renewal of cancer stem cells. To elucidate probable linkage between SALL4 stemness marker and bone morphogenetic protein (BMP) cell signaling pathway, we aimed to analyze the expression levels of the related genes in esophageal squamous cell carcinoma (ESCC) patients. Tumoral and corresponding margin normal tissues from 50 treatment-naive ESCC patients were subjected for expression analysis using relative comparative real-time reverse transcription polymerase chain reaction. There were significant correlations between SALL4 mRNA and BMP signaling target genes expression including SIZN1, VENTX, and DIDO1 (P < 0.01). Tight associations of gene expression were observed in primary stages of tumor progression (stages I/II), and the invaded tumors to the adventitia (T3/T4). Furthermore, significant correlations between the expression of BMP signaling target genes were observed (P < 0.01). SALL4 may play role in tumorigenesis and tumor cell invasiveness of ESCC through correlation with BMP signaling genes. PMID- 30431699 TI - Schinus molle essential oil as a potential source of bioactive compounds: antifungal and antibacterial properties. AB - AIMS: The study was focused on the evaluation of antimicrobial activity in vitro of the essential oil of leaves from S. molle against bacteria and fungi of clinical importance in the search for the discovery of new active compounds. METHODS AND RESULTS: The chemical composition of the S. molle essential oil was determined by gas chromatography/mass spectrometry and its antimicrobial effect was verified by broth microdilution method. The major compounds found were beta pinene (25.23%), epi-alpha-cadinol (21.29%), alpha-pinene (18.72%), myrcene (11.54%) and sabinene (5.02%). The essential oil showed significant antifungal activity against Paracoccidioides brasiliensis (39.06 MUg.mL-1 ), weak action against Cryptococcus neoformans (625 MUg.mL-1 ) and Trichophyton quinckeanum (625 MUg.mL-1 ) and was inactive against Candida spp. In the analysis of the antibacterial action, the microorganisms tested did not show sensitivity. CONCLUSIONS: This study showed a promising result of S. molle volatiles against the fungus P. brasiliensis, which causes paracoccidioidomycosis, a systemic mycosis of great clinical importance in Latin America. SIGNIFICANCE AND IMPACT OF STUDY: The results found here are novel and encourage investigations of the compounds present in this essential oil, which represents a source of molecules with potential use in the treatment of paracoccidioidomycosis. This article is protected by copyright. All rights reserved. PMID- 30431701 TI - Developmental effects of trichloroacetate in Zebrafish embryos: Association with the production of superoxide anion. AB - To assess the developmental toxicity of trichloroacetate (TCA), zebrafish embryos were exposed to 8 to 48 mM of TCA and evaluated for developmental milestones from 8- to 144-hour postfertilization (hpf). All developmental toxicities are reported in this paper. Embryos were found to have developed edema in response to 16 to 48 mM of TCA exposure at 32- to 80-hpf, experienced delay in hatching success in response to 24 to 48 mM at 80-hpf. Lordosis was observed in developing embryos exposed to 40 to 48 mM at 55- to 144-hpf. The observed toxic effects of TCA exposure were found to be concentration and exposure period independent. Effects were found to be associated with increases in superoxide anion production, but these increases were also found to be concentration and time independent. TCA resulted in concentration-dependent increases in embryonic lethality at 144-hpf, with an LC50 determined to be 29.7 mM. PMID- 30431700 TI - The Performance Improvement (Pi) score: an algorithm to objectively score performance improvement during E-BLUS hands on training (HoT) sessions. An ESUT project. AB - INTRODUCTION AND OBJECTIVES: Assessing performance improvement (Pi) is one of the most important roles of a tutor, but is usually based on subjective observation, personal judgement and expertise. Our study is aimed to evaluate the variability of subjective tutor Pi assessment and to compare it to a novel measurement algorithm: 'the Pi-score' MATERIALS AND METHODS: The Pi-score algorithm considers time measurement and number of errors from two different repetitions (first and fifth) of the same training task and compares them to the relative task goals, to produce an objective score. We collected data during 8 courses on the four basic laparoscopic urological skills (E-BLUS) tasks. The same tutor instructed on all courses. Collected data were independently analysed by 14 hands-on-training (HoT) experts for Pi assessment. Their subjective Pi assessments were compared for inter-rater reliability. The average per-participant subjective scores from all 14 proctors were then compared to objective Pi-score algorithm results. Cohen's Kappa Statistics was used for comparison analysis. RESULTS: 50 participants were enrolled. Concordance found between the 14 proctors' scores was the following: Task1=0.42 (moderate); Task2=0.27 (fair); Task3=0.32 (fair); Task4 (Kappa=0.55, moderate). Concordance between Pi-score results and proctor average scores per participant was the following: Task1=0.85 ("almost perfect"); Task2=0.46 ("moderate"); Task3=0.92 ("almost perfect"); Task4=0.65 ("substantial"). CONCLUSION: Our study demonstrated that evaluation of Performance improvement is highly variable, even when formulated by a cohort of experts. Our algorithm successfully provided an objective score that equals the average Pi assessment of a cohort of experts, in relation to a small amount of training attempts. This article is protected by copyright. All rights reserved. PMID- 30431702 TI - Synthesis and anti-HIV activity of guanine modified fluorinated acyclic nucleoside phosphonates derivatives. AB - The preparation of an unprecedented series of nucleobase modified 3-fluoro-2 (phosphonomethoxy)propyl (FPMP) acyclic nucleosides in both their (R) and (S) enantiomerically pure forms is described. The synthesis focuses on a Mitsunobu alkylation reaction to construct the C-N9 bond between a chiral fluorinated side chain residue and 6- or 7-modified guanine analogues. Prodrugs of FPMP-7 deazaguanine were also synthesized by derivatization of the corresponding phosphonic acid functionality with (bis)diamyl aspartate amidate groups, leading to moderate activity against human immunodeficiency virus type 1 (HIV-1). PMID- 30431703 TI - Cytomegalovirus mismatch still negatively affects patient and graft survival in the era of routine prophylactic and preemptive therapy: A paired kidney analysis. AB - The impact of CMV serostatus on kidney transplant outcomes in an era when CMV prophylactic and preemptive strategies are used routinely is not clearly established. Using UNOS/OPTN data, recipients with first deceased donor kidney transplant (>=18 years, 2010-2015) were stratified into 4 groups in the main cohort: D-/R-, D+/R-, D+/R+, and D-/R+. In a paired kidney cohort, we identified 2,899 pairs of D- kidney transplant with discordance of recipient serostatus (D /R- vs D-/R+) and 4,567 pairs of D+ kidney transplant with discordance of recipient serostatus (D+/R- vs D+/R+). In the main cohort, D+/R- was associated with a higher risk of graft failure (HR 1.17, P=0.01), all-cause mortality (HR=1.18, P<0.001) and infection-related mortality (HR=1.38, P=0.03) when compared to D-/R-. In the paired kidney analysis, D+/R- was an independent risk factor for all-cause mortality (HR=1.21, P=0.003) and infection-related mortality (HR=1.47, P=0.04) when compared to D+/R+. No difference in graft loss between D+/R- and D+/R+. CMV mismatch is still an independent risk factor for graft loss and patient mortality. The negative impact of D+/R- serostatus on mortality persists after fully matching for donor factors. This article is protected by copyright. All rights reserved. PMID- 30431704 TI - Geographic disparities in lung transplant rates. AB - In November 2017, an emergency change to the lung allocation policy eliminated the donation service area (DSA) as the first geographic tier of allocation in response to a lawsuit from a New York City lung transplant candidate. The lawsuit claimed that DSA borders are arbitrary and that allocation should be based on medical priority. We investigated whether deceased-donor lung transplant (LT) rates differed substantially between DSAs in the United States prior to the policy change. We estimated LT rates per active person-year using multilevel Poisson regression and empirical Bayes methods. We found that the median incidence rate ratio (MIRR) of transplant rates between DSAs was 2.05, meaning a candidate could be expected to double their LT rate by changing their DSA. This can be directly compared to a 1.54-fold increase in LT rate we found associated with an increase in LAS category from 38-42 to 42-50. Changing a candidate's DSA would have had a greater impact on the candidate's LT rate than changing LAS categories from 38-42 to 42-50. In summary, we found that DSA of listing was a major determinant of LT rate for candidates across the country prior to the emergency lung allocation change. This article is protected by copyright. All rights reserved. PMID- 30431705 TI - Parent, school, and peer factors related to U.S. adolescents' diet and exercise. AB - PURPOSE: Adolescent obesity is a significant public health problem in the United States. Developing interventions to prevent or improve adolescent obesity may positively affect physical and mental health across the lifespan. However, to ensure that interventions are effective, influential factors must first be identified. The purpose of this study was to examine associations among parent-, school-, and peer-related factors and diet and physical activity of the adolescents in the United States. DESIGN AND METHODS: Using logistic regression analyses, cross-sectional data of 5,248 adolescents in grades 5-10 from 184 schools from the World Health Organization's 2009/2010 survey of Health Behavior in School-Aged Children (HBSC) for the United States were analyzed, including variables for parent, peer, and school factors. RESULTS: Parent- and peer-related factors were associated with adolescents' diet and physical activity (PA). Peer factors were associated with time spent on PA, but not a parent or school factors. The type of school lunch program was the only school factor associated with diet; no school factors were associated with exercise. PRACTICE IMPLICATIONS: Results of this secondary analysis extend prior work, which identified associations between parent- and peer factors and adolescents' diet and exercise. Findings will help identify targets for improving adolescents' diet and exercise behaviors. PMID- 30431706 TI - Photorhabdus luminescens Tc toxin is inhibited by the protease inhibitor MG132 and activated by protease cleavage resulting in increased binding to target cells. AB - Photorhabdus luminescens Tc toxins consist of the cell-binding component TcA, the linker component TcB, and the enzyme component TcC. TccC3, a specific isoform of TcC, ADP-ribosylates actin and causes redistribution of the actin cytoskeleton. TccC5, another isoform of TcC, ADP-ribosylates and activates Rho proteins. Here, we report that the proteasome inhibitor MG132 blocks the intoxication of cells by Tc toxin. The inhibitory effect of MG132 was not observed, when the ADP ribosyltransferase domain of the TcC component was introduced into target cells by protective antigen, which is the binding and delivery component of anthrax toxin. Additionally, MG132 affected neither pore formation by TcA in artificial membranes nor binding of the toxin to cells. Furthermore, the in vitro ADP ribosylation of actin by the enzyme domain of TccC3 was not affected by MG132. Similar to MG132, several calpain inhibitors blocked the action of the Tc toxin. Proteolytic cleavage of the binding component TcA induced by P. luminescens protease PrtA1 or by collagenase largely increased the toxicity of the Tc toxin. MG132 exhibited no inhibitory effect on the cleaved TcA component. Moreover, binding of TcA to target cells was largely increased after cleavage. The data indicate that Tc toxin is activated by proteolytic processing of the TcA component, resulting in increased receptor binding. Toxin processing is probably inhibited by MG132. PMID- 30431707 TI - Mitophagy as a new therapeutic target for sarcopenia. PMID- 30431708 TI - Primary posterior perineal hernia: Incidental CT diagnosis of a rare pelvic floor hernia. AB - Perineal hernias are rare, protruding through a defect, congenital or acquired, of the pelvic floor musculature with intraperitoneal or extraperitoneal content. Anatomically they can be classified as anterior and posterior based on the position relative to the superficial transverse perineal muscle. We present a case of a rare primary posterior perineal hernia that was identified incidentally on computed tomography. PMID- 30431709 TI - Bioabsorbable steroid-releasing implants in the frontal sinus ostia: a pooled analysis. AB - BACKGROUND: Bioabsorbable steroid-releasing implants (mometasone furoate, 370 MUg) are effective for improving postsurgical outcomes in the frontal sinus ostia (FSO). In this study we evaluated the effect of these implants on frontal outcomes in various patient subgroups with chronic rhinosinusitis (CRS) using pooled data from 2 randomized, controlled trials (RCTs). METHODS: A total of 160 subjects were enrolled in 2 RCTs. After surgery, subjects were randomized to receive an implant in 1 FSO with the contralateral side as control. Data through day 90 from the 2 studies were pooled and subgroup analyses were performed. RESULTS: At day 30, relative to controls, steroid-releasing implants significantly reduced the need for postoperative interventions by 46.8% (95% confidence interval [CI], -60.7 to -27.9), for surgical interventions by 51.2% (95% CI, -68.2 to -25.2), and for oral steroid interventions by 37.2% (95% CI, 54.6 to -13.1) in the pooled data set. At day 90, statistically significant reductions (p < 0.05) in the need for postoperative interventions (relative reduction [RR], 30.2%), restenosis/occlusion rate (RR, 31.7%), and inflammation score (absolute difference, -6.0), and increase in estimated FSO diameter (absolute difference, 1 mm), favoring the treated side, were observed. Subgroup analyses of the pooled data showed statistically significant improvements (p < 0.05) at day 90 in restenosis/occlusion rate, and estimated FSO diameter, favoring the treated side across subgroups, with no statistically significant subgroup-by-treatment interactions. CONCLUSION: Bioabsorbable steroid-releasing sinus implants improve outcomes of frontal sinus surgery through 90 days, irrespective of asthma status, previous endoscopic sinus surgery, extent of surgery, extent of polyps, or Lund-Mackay computed tomography stage in the FSO. PMID- 30431710 TI - Preoperative management of spontaneous cerebrospinal fluid rhinorrhea with acetazolamide. AB - BACKGROUND: Spontaneous cerebrospinal fluid (CSF) rhinorrhea has been associated with elevated intracranial pressure (ICP). As such, ICP reducing measures are commonly employed to optimize repair. Although postoperative acetazolamide use has been described, no data currently exists on the potential for preoperative use. METHODS: A retrospective review was performed including patients treated for anterior spontaneous CSF leaks by a single surgeon over a 6-year period during which acetazolamide therapy (250 mg twice daily) was employed before considering surgical repair. The primary endpoint was whether the patient went on to require surgical repair. RESULTS: A total of 16 patients were identified who were pretreated with acetazolamide. Leak sites were noted as cribriform (5/16), sphenoid (8/16), ethmoid (1/16), multiple (1/16), and indeterminate (1/16). Five patients had resolution of their rhinorrhea without surgery (31.3%). Mean follow up for these nonsurgical patients was 470 days (range, 64 to 857 days). There were no differences in the patients' age or site of leak between surgical and nonsurgical patients (p = 0.65, p = 0.52, respectively). Nonsurgical patients had a lower body mass index (BMI) than surgical patients (p = 0.04). CONCLUSION: This is the first study to report the use of acetazolamide therapy as a primary treatment option for spontaneous CSF rhinorrhea. This therapy enabled surgery to be avoided in 31.3% of patients. This would indicate that in the absence of other contraindications for delaying repair, a trial of acetazolamide therapy could be considered as an initial option in the management of isolated spontaneous CSF rhinorrhea. PMID- 30431711 TI - In vitro characteristics of an airway barrier-disrupting factor secreted by Staphylococcus aureus. AB - BACKGROUND: Staphylococcus aureus is a major contributor to the pathophysiology of chronic rhinosinusitis (CRS). Previous research has shown that S. aureus secreted products disrupt the airway barrier. METHODS: S. aureus ATCC 13565 and 25923 strains were grown at exponential, postexponential, and stationary phases. Microbial conditioned media (CM) was collected from the cultures and ultrafiltered (UF). Liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) was performed on the UF-CM. UF-CM was subjected to heat and protease treatment, size fractionation, and ultracentrifugation (UC) separation. Human nasal epithelial cells grown at air-liquid interface (HNEC-ALI) cultures were exposed to purified alpha hemolysin (Hla), staphylococcal enterotoxin A (SEA), lipoteichoic acid (LTA), and UF-CM. Barrier function outcomes were measured by transepithelial electrical resistance (TEER) and apparent permeability (Papp). UC fraction exposed cultures were subjected to immunofluorescence microscopy for tight junction (TJ) protein zonula occludens-1 (ZO-1). RESULTS: LC-ESI-MS/MS identified 107 proteins, with Hla being most abundant. Hla, SEA, and LTA did not alter the HNEC-ALI barrier as measured by TEER or Papp. Barrier disruption caused by UF-CM peaked in the postexponential phase, was sensitive to heat and protease treatment, >30-kDa in size, and enriched in the UC fraction. HNEC-ALI exposed to UF-CM and UC demonstrated loss of ZO-1 localization. CONCLUSION: These results suggest that the S. aureus factor responsible for TJ disruption in HNEC-ALI cultures is either a protein macromolecule or a combination of secreted factors. The product is enriched in the UC fraction, suggesting it is associated with large structures such as membrane components or vesicles. PMID- 30431712 TI - A cadaveric model for measuring sinonasal continuous positive airway pressure-a proof-of-concept study. AB - BACKGROUND: Obstructive sleep apnea is a common respiratory disorder that can have negative effects on health and quality of life. Positive pressure therapy (CPAP) is the primary treatment. There is a lack of consensus on the risk of postoperative CPAP after endoscopic sinus or skull base surgery. We present a proof-of-concept cadaver model for measuring sinonasal pressure delivered by CPAP. METHODS: Three fresh cadaver heads were prepared by removing the calvaria and brain. Sphenoidotomies were made and sellar bone was removed. Pressure sensors were placed in the midnasal cavity, sphenoid sinus, and sella. CPAP was applied and the delivered pressure was recorded at increasing levels of positive pressure. Paired t tests and intraclass correlation coefficients were used to analyze results. RESULTS: Increases in positive pressure led to increased pressure recordings for all locations. Nasal cavity pressure was, on average, 81% of delivered CPAP. Pressure was highest in the sphenoid sinus. The effect of middle turbinate medialization on intrasphenoid pressure was not statistically significant in 2 heads. Intrasellar pressure was 80% of delivered CPAP with lateralized turbinates and 84% with medialized turbinates. Pressure recordings demonstrated excellent reliability for all locations. All heads developed non sellar-based cranial base leaks at higher pressures. Cribriform region leaks were successfully sealed with DuraSeal(r). CONCLUSION: Our proof-of-concept cadaver model represents a novel approach to measure pressures delivered to the nasal cavity and anterior skull base by CPAP. With further study, it may have broader clinical application to guide the safe postoperative use of CPAP in this population. PMID- 30431713 TI - Analysis of 24-hour surgical cancellations in an academic rhinology and skull base surgery practice. AB - BACKGROUND: Late cancellations within 24 hours of surgery lead to decreased utilization of operating room time with loss of productivity, decreased access to care, and inconvenience to patients and staff. To date, no studies have analyzed 24-hour cancellations in a tertiary rhinology practice. METHODS: All procedures performed at a tertiary rhinology/skull base practice from January 2016 to December 2017 were reviewed. Twenty-four-hour cancellations were analyzed by procedure type and reason for cancellation. Avoidable cancellations were late cancellations that could have been prevented by review of medical records or communication by hospital staff with the patient before surgery. Univariate analysis was performed to determine predictive factors for cancellations. RESULTS: A total of 39 of 640 surgical cases were cancelled (6.1%) within 24 hours of surgery. Of these, 69.2% were inflammatory and 30.8% were skull base cases. The mean number of operating room minutes lost was 151 (60 of 210) for inflammatory and 263 (102 of 480) for skull base cases. Avoidable cancellations were seen in 25 of 35 (71.4%) cases. Patients undergoing inpatient or skull base surgery were more likely to have medical cancellations than patients undergoing outpatient or inflammatory surgery (91.7% vs 43.5%, p = 0.01; 83.3% vs 47.8%, p = 0.07). CONCLUSION: This is the first study to analyze 24-hour cancellations in tertiary rhinology/skull base surgery. The results suggest that a majority of late cancellations are avoidable and that skull base and inpatient surgeries are more likely to be canceled for medical reasons. Further studies are required to better characterize surgical cancellations in rhinology and identify strategies to try to prevent them. PMID- 30431714 TI - Zygomatic Air Cell Defect - Magnetic Resonance Imaging of the Temporomandibular Joint Compared with Panoramic Radiographs. AB - The aim of the study was to analyze zygomatic air cell defect (ZACD) incidence using magnetic resonance imaging (MRI) and validity of panoramic radiograph as a comparative method of ZACD diagnostics. The connection between ZACD incidence, age, left/right temporomandibular joint (TMJ) and comorbidity with diagnosis of TMJ disorder was analyzed. Panoramic radiographs and MRIs of 140 TMJs of 70 consecutive patients with previously confirmed TMJ diagnosis were compared in the study. A grading system (4-point scale from '0' for absence to '3' for most extended pneumatization) was used to determine low signal on MRIs as pneumatization of temporal bone. ZACD was diagnosed in 22 joints of 15 patients (incidence, 20.4%), with seven patients having bilateral appearance. In the joints of nine patients, ZACD was identified as extensive accord-ing to the grading scale. The validity of ZACD findings on panoramic radiographs compared with MRI findings yielded 0.45 sensitivity and 0.98 specificity. There was no relation (p>0.05) between comorbidity of ZACD and TMJ disorder, either by age or side of the body. More prevalent ZACD in our MRI analysis than in other researches based on panoramic radiographs could be explained by the expected superimposed osseous structures in the area of articular eminence. PMID- 30431715 TI - Measuring Healthcare Quality - Paradigm of Medqual. AB - Medical activity is assumed to be service activity the effects of which can be measured. The SERVQUAL scale was used as a starting point for our research, which resulted in a new, adopted scale called MEDQUAL. The MEDQUAL scale aims to measure the quality of healthcare provided by medical staff of one hospital department instead of the overall quality of hospital services or parts of services on which medical staff in one department has no influence. The study was conducted in a clinical hospital department in Croatia and included 300 respondents (169 patients and 131 medical staff members). The MEDQUAL scale, designed and tested in the study, showed high reliability in all established dimensions, i.e. trust in doctors (Cronbach's Alpha 0.923), nursing professionalism (0.913), medical professionalism (0.938), and departmental organization (0.810). The scale proposed evaluates both patient satisfaction with the quality of healthcare received and medical staff satisfaction with the quality of healthcare provided. The results were comparable to the groups of respondents, departments, and institutions with potential longitudinal studies of this phenomenon. MEDQUAL is a simple, repeatable and cost-effective scale, applicable to almost all departments and used for measuring the quality of healthcare services both provided and received, the aim of which is to contribute to the assessment of healthcare quality and its improvement. PMID- 30431716 TI - Effect of Different Visual Impairment Levels on the Quality of Life in Glaucoma Patients. AB - The aim of this study was to assess the effect of different visual impairment levels on difference in the subjective quality of life estimation. We included 150 patients with glaucoma whose best-corrected visual acuity in the better seeing eye was 0.5 and less. All of them were in advanced stage of the disease, with visual field defect worse than 12 dB in mean defect, when measured with the Octopus Visual Field Analyzer. In order to assess the quality of life, we used the Impact of Vision Impairment questionnaire. Additionally, we used General Information Questionnaire, which was developed for the purpose of this study. The information obtained from the questionnaires was analyzed using the Robust Discriminant Analysis program. Difference analysis was performed for each of the three areas of the questionnaire (reading and accessing information, mobility and inde-pendence, and emotional well-being). Results of this study confirmed the difference between the groups of patients with different levels of visual impairment, varying from total visual loss up to vis-ual acuity 0.5 on the better seeing eye in the effects of visual impairment on the quality of life. All levels of visual impairment had the largest effect in the area of reading and accessing information, slightly less in the area of mobility and independence, and the least effect was in the area of emotional well-being. Based on the results, it is concluded that all levels of visual impairment have negative effect on the quality of life in glaucoma patients. PMID- 30431717 TI - Expression of Nedd9 in Transbronchial Biopsies of Lung Adenocarcinoma. AB - Lung cancer as the major cause of cancer mortality worldwide includes several histologic subtypes evolving from numerous genetic and epigenetic changes emerging in alveolar, bronchiolar and bronchial epithelium. The majority of cases are diagnosed in advanced stage (i.e. stages IIIB and IV), often with scanty amount of tissue in transbronchial biopsies or cytology specimens. The aim of the present study was to investigate the expression of the scaffolding protein neural precursor cell expressed, developmentally downregulated 9 (NEDD9) in small biopsies of lung adenocarcinoma. The expression of NEDD9 was analyzed immunohistochemically in 71 formalin-fixed and paraffin-embedded transbronchial biopsy specimens of primary lung adenocarcinoma. Nuclear and cytoplasmic NEDD9 expression was detected indicating activation of the epithelial-mesenchymal transition process. Direct relationship between the expression of NEDD9 and survival was not demonstrated. PMID- 30431718 TI - Patient, Healthcare System and Total Delay in Tuberculosis Diagnosis and Treatment Among Serbian Population. AB - Currently, topical are studies that examine different reasons for delay of tuberculosis (TB) diagnosis and its impact on disease prognosis. The aim was to examine three time periods associated with treatment delay: patient related, health system related and total delay. This retrospective-prospective study included 100 consecutive patients hospitalized at Department of Pulmonology, Clinical Center of Serbia, in the period from March to December 2015. Study results showed median patient delay to be 92.5 days. Total delay was affected by patient related delay. Median healthcare delay was 18.5 days. Patients that reported excessive alcohol consumption were more likely to have prolonged time to seek medical help. Years of alcohol consumption yielded moderate positive correlation with patient related delay (r=0.362, p <0.001). Correlation between the number of cigarettes and patient delay was moderate, positive and statistically significant (r=0.314, p=0.001). Delay in seeking medical help was more likely in patients with negative family history of TB. There was no difference in the effect of the presence of symptoms on patient related delay (p>0.05). Clinical characteristics such as patient TB category and chest radiograph abnormalities were not associated with prolonged patient related delay (p>0.05). Study results point to the importance of health education and/or health intervention in the population group at a high risk of TB. PMID- 30431719 TI - Differential Expression of TFF Genes and Proteins in Breast Tumors. AB - The objective of this study was to determine differential expression of TFF1, TFF2 and TFF3 genes and proteins in breast tumor subtypes. In addition, we investigated the correlation between TFF genes within tumor subgroups, and TFF genes with clinical and pathologic characteristics of the tumor. Study group included 122 patients with surgically removed breast tumors. Samples were investigated using qRT-PCR and immunohistochemistry. TFF1 and TFF3 genes and proteins were expressed in breast tumors, while the levels of TFF2 gene and protein expression were very low or undetectable. TFF1 was significantly more expressed in benign tumors, while TFF3 was more expressed in malignant tumors. Gene and protein expression of both TFF1 and TFF3 was greater in lymph node negative tumors, hormone positive tumors, tumors with moderate levels of Ki67 expression, and in grade II tumors. A strong positive correlation was found between TFF1 and TFF3 genes, and the expression of both negatively correlated with Ki67 and the level of tumor histologic differentiation. Our results suggest that TFF1 and TFF3, but not TFF2, may have a role in breast tumor pathogenesis and could be used in the assessment of tumor differentiation and malignancy. PMID- 30431720 TI - Cytotoxicity and Genotoxicity of Resin Based Dental Materials in Human Lymphocytes In Vitro. AB - The aim of this in vitro study was to evaluate cytotoxicity and genotoxicity of six different dental nanocomposite materials, three conventional ones and three flowable composite resin materials, in human lymphocytes. The following materials were tested: Tetric EvoCeram, Tetric EvoFlow, Filtek Ultimate, Filtek Ultimate Flow, G-aenial and G-aenial Flo. Cytotoxicity was evaluated for two mass concentrations (0.007 g/mL and 0.013 g/mL) of each material, non-cured and cured, after 4 hours and 24 hours. Genotoxicity was evaluated using micronucleus assay under the same conditions as applied during the investigation of cytotoxicity. Uncured forms of Tetric EvoCeram, Tetric EvoFlow and Filtek Ultimate Flow in higher mass concentration caused genotoxic effect. Uncured G-aenial Flo in higher mass concentration induced apoptosis and necrosis. Uncured Tetric EvoFlow and uncured Filtek Ultimate Flow in higher mass concentration induced early apoptosis after both test periods. None of the conventional composite resin materials tested showed cytotoxicity except for uncured G-aenial, which induced apoptosis in higher mass concentration in both test periods. In conclusion, under the conditions of this in vitro study, cured conventional composites did not show cytotoxic or genotoxic effect, which is important for clinical application of these materials, whereas uncured forms exhibited certain level of cytotoxicity and genotoxicity, mainly because of monomers in their composition. PMID- 30431721 TI - Morphological Characteristics and Frequency of Accessory Right Hepatic Veins - Evaluation with Computed Tomography. AB - In the liver, there are many vascular variants, which are important in liver surgery, the presence of accessory right hepatic veins (aRHVs) in particular. Th eir frequency, number and diameter vary considerably. Detailed imaging diagnostics with computed tomography (CT) should be undertaken before surgery. Th e aim of our study was to examine the characteristics of aRHVs and their demographic correlations. Th e study included data on 188 patients that underwent CT examination of the abdomen with contrast media, 103 men (54.8%) men and 85 (45.2%) women, mean age 63.1+/-14.3 (range, 21-94) years. Th e measurements of hepatic veins were carried out on CT images, which were obtained from the Clinical Institute of Radiology, University Medical Centre of Ljubljana. Forty-fi ve of 142 patients had at least one aRHV: one aRHV in 37 (26.1%) cases, two aRHVs in seven (4.9%) cases, and three aRHVs in one (0.7%) case. Th e incidence of aRHV was between 24% and 39.3% (mean, 31.7%) and of more than one aRHV between 2.3% and 10.3% with 95% confi dence interval (CI). Based on the test of proportions, the proportion of cases with inferior aRHV of at least 7 mm was between 7.2% and 18.1% with 95% CI. Th e mean distance between the aRHV and the main RHV confl uences into the inferior vena cava was 3.73 cm (between 3.32 cm and 4.13 cm, 95% CI). Th e proportion of cases with confl uence distance of at least 4 cm was between 21.6% and 49.5% in cases with at least one aRHV. In cases with more than one aRHV, the distance between the middle aRHV and the main RHV ranged from 1.90 cm to 4.32 cm (95% CI). Th e T-test of independent samples showed no eff ect of age on the incidence of accessory veins (p=0.18), and the test of diff erences of interests showed no impact of sex (p=0.75). Evaluation of the incidence and diameter of aRHVs is of great importance for safe surgical procedure. Th eir presence can change the surgeon's decision in 10%-20% of cases when employing appropriate imaging technique. CT examination, which is easily accessible and minimally invasive for patients, was successful in only 80% cases, when using standard protocol for CT scanning. PMID- 30431723 TI - Flow Changes in Orbital Vessels Detected with Color Doppler Ultrasound in Patients with Early Dysthyroid Optic Neuropathy. AB - Thyroid-associated orbitopathy (TAO) is a common manifestation of Graves' disease. The aim of the study was to assess the six percent of patients with TAO that develop dysthyroid optic neuropathy (DON), which is the most serious complication of TAO. As DON can cause perma-nent damage, it is essential to detect DON early when visual loss is still reversible. Color Doppler ultrasound is a noninvasive diagnostic method, which may be useful in early detection of DON. Thirty-six patients with confirmed Graves' disease and active TAO were included, 21 (58%) of them with early DON (eDON) and 15 (42%) free from any signs of eDON. All study patients underwent Doppler ultrasound examination to determine the blood flow rates in the internal carotid artery, ophthalmic artery, and central retinal artery. Study results showed color Doppler ultrasound examination to have a potential to detect orbital blood flow changes in patients with eDON. Early detection of DON may result in earlier treatment and prevention of permanent optic nerve damage. PMID- 30431722 TI - Albi Score as a Predictor of Survival in Patients with Compensated Cirrhosis Resected for Hepatocellular Carcinoma: Exploratory Evaluation in Relationship to Palbi and Meld Liver Function Scores. AB - The aim of the study was to explore predictive value of the ALBI, PALBI and MELD scores on survival in patients resected for hepatocellular carcinoma with compensated liver cirrhosis and no macrovascular infiltration. In this retrospective study, longitudinal survival analysis was performed. We analyzed patient/tumor characteristics and MELD, ALBI and PALBI scores as liver function tests for predicting survival outcome. Survival was analyzed from the date of liver resection until death, liver transplantation, or end of follow-up. Patients were stratified for age, cirrhosis etiology, presence of esophageal varices, hepatocellular carcinoma stage, microvascular invasion, histologic differentiation, and resection margins. We identified 38 patients (alcoholic cirrhosis in 84.2% of patients) resected over an 8-year period. Median preoperative MELD score was 8, ALBI score -2.63, and PALBI score -2.38. During the follow-up period, 24 patients died. Estimated median survival time was 36 months. Microvascular invasion was observed in 33 patients. Higher ALBI score was associated with 23.1% higher relative risk of death. PALBI score was associated with 12.1% higher relative risk of death, whereas MELD score was not associated with the risk of death. In conclusion, ALBI score demonstrated significant predictive capabilities for survival in patients with compensated cirrhosis resected for hepatocellular carcinoma. PMID- 30431724 TI - Comparison of Different Diagnostic Guidelines for the Diagnosis of Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: Single Centre Experience. AB - Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA), caused by exaggerated but ineffective immune response. The aim of the study was to compare the capacity of the HLH-2004 guidelines with the capacity of the MAS guidelines from 2005, and with the new set of classification criteria from 2016 in diagnosing MAS complicating sJIA. The study included 35 children aged 1-18 diagnosed with sJIA according to ILAR criteria and treated at the Department of Pediatrics, Division of Immunology and Rheu-matology, Zagreb University Hospital Centre, in the period from 2009 to 2015. Out of 35 patients diagnosed with sJIA, there were 12 girls and 23 boys, with the mean age at disease onset (+/-SD) 5.51+/-3.65 years. Eight patients had flare of disease. With the guidelines from 2005, MAS was diag-nosed in six (17.1%) patients with sJIA. With the new set of classification criteria from 2016, MAS was diagnosed in four (11.4%) patients with sJIA. MAS was not diagnosed with the HLH-2004 guidelines. In our study, four out of six patients had MAS at the onset of sJIA, and in the rest two it occurred during relapse. Two patients with MAS developed full-blown clinical picture while another four had incomplete clinical features with minor laboratory alteration. Due to the use of different di-agnostic guidelines, we found difference in the prevalence of MAS. It was slightly higher in comparison to available studies, while other researched features, such as clinical characteristics, were similar. PMID- 30431725 TI - The Efficacy of Low-Level Laser Therapy in Burning Mouth Syndrome - A Pilot Study. AB - The aim of this clinical study was to compare low-level laser therapy (LLLT) switched on and switched off in the treatment of burning mouth syndrome (BMS). BMS is a debilitating condition for patients and highly demanding for physicians, characterized by burning symptoms in the oral cavity. Despite extensive research, so far only cognitive behavioral therapy and clonazepam have been proven successful for its treatment in randomized controlled trials. Forty-four patients with BMS were randomly assigned to the study laser group (LLLT) or the sham laser group. LLLT was performed with the GaAlAs laser (830 nm) used in non-contact mode on the site in the mouth where burning symptoms were present; study patients received 10 sessions (10 days). Each participant filled out the visual analog scale (VAS) and oral health impact on the quality of life scale (OHIP-CRO 14) before and after either therapy protocol. There were no significant differences between the groups before and after LLLT (switched on and off) in the quality of life (OHIP CRO 14 scores) (p>0.05). There was significant decrease in pain symptoms (VAS) in both LLLT switched on and LLLT switched off groups (p <0.05). Both LLLT switched on and switched off decreased pain symptoms (VAS) in patients with BMS; however, neither LLLT switched off or switched on im-proved the OHIP CRO 14 scores. PMID- 30431726 TI - Correlation Between Salivary Biochemical Stress Indicators and Psychological Indicators. AB - Saliva is a complex body fluid that has various functions in the oral cavity. Central nervous system has the most important role in regulating salivation. Saliva as a sample is suitable for simplicity of sampling and because it contains analytes in the free active form. Stress is a condition in which the internal (psychophysical) balance of the body is disturbed. It activates the hypothalamic pituitary axis, so salivary cortisol is a free cortisol indicator that correlates well with its serum value and reflects the free fraction that is biologically active. At the same time, stress conditions stimulate the sympathetic neuronal system causing change in the secretion of salivary alpha-amylase from salivary glands. The hypothesis of this study was that students with daily intensive physical activity are ex-posed to chronic stress compared to other students who have minimal physical activity. The study in-cluded 54 healthy volunteers, students of the University of Zagreb, divided into two groups. One volunteer group consisted of physically active volunteers (n=27) from the Faculty of Kinesiology (FK), and the other group consisted of physically inactive volunteers (n=27) from other faculties (OF). The subjects were first administered a psychological test that consisted of two questionnaires, Quality of Life Questionnaire and Questionnaire of Stressful Styles, and then underwent sampling of saliva. By comparing biochemical and psychological indicators in relation to stress, it was concluded that the two groups of students were equalized and that there was no objective support for either group to be considered exposed to chronic stress. Despite the substantial differences in physical activity, there was no difference between the two student populations. PMID- 30431727 TI - Intravitreal Injection of Perfluoropropane is More Efficacious than Sulfur Hexafluoride In Releasing Vitreomacular Traction. AB - The aim was to compare the efficacy of a single intravitreal injection of perfluoropropane (C3F8) and sulfur hexafluoride (SF6) in releasing vitreomacular traction (VMT). This prospective study included two groups of patients with symptomatic VMT confirmed by spectral-domain optical coherence tomography (SD OCT). Patients from both groups received a single intravitreal injection of expansile gas. One group (29 eyes) received 0.3 mL of 100% C3F8, and the other group (28 eyes) received 0.3 mL of 100% SF6. Eyes without VMT release one month after SF6 injection were secondarily injected with C3F8. The primary outcome was the ratio of eyes in each group with complete VMT release on OCT one month following primary treatment. The secondary outcome was the ratio of reinjected eyes with complete VMT release on OCT one month following second injection. Additional outcome was the ratio of VMT release in eyes with specific clinical characteristics. One month after the application, complete release of VMT on OCT was recorded in 18 out of 29 eyes (62%) in the C3F8 group, in 6 out of 28 eyes (21.4%) in the SF6 group, and in 7 out of 14 (50%) reinjected eyes. There was no statistically significant difference in age, width of vitreomacular attachment (WVMAT), central retinal thickness and presence of additional features between the two groups. In eyes with WVMAT <500 microns, there was no statistically significant difference between the two gases in releasing VMT. In eyes with WVMAT >500 microns, C3F8 was more efficacious (p=0.001). According to the results of our study, intravitreal C3F8 injection seems to be more efficacious in releasing VMT than SF6 in eyes with WVMAT larger than 500 microns. PMID- 30431728 TI - Reliability of Ultrasound Measurement of Muscle Thickness in Patients with Supraspinatus Tendon Pathology. AB - Objectives of the study were to observe supraspinatus muscle thickness in patients with supraspinatus tendon pathology using ultrasound (US) and examining inter- and intra-rater reliability, and to compare muscle thickness with cross sectional area (CSA) and occupation ratio measured by both US and magnetic resonance imaging (MRI). The investigation was designed as a prospective cohort study. Two groups of patients were included in the study: 43 patients with tendon rupture and 44 patients without tendon rupture as a control group. A written consent was obtained from all patients. In both groups, muscle thickness, CSA and occupation ratio were measured with US, and CSA and occupation ratio with MRI. Study results showed statistically significant between-group differences. The mean supraspinatus muscle thickness measured by US was 14.01 mm and 19.83 mm in patients with and without tendon rupture, respectively. CSA and occupation ratio measured by US and MRI also showed statistically significant between-group differences. Pearson correlation coefficient between supraspinatus thickness and occupation ratio and CSA measured by US and MRI showed strong to moderate correlation. US measurements showed moderate to strong intra- and inter-rater reliability. In conclusion, supraspinatus muscle thickness measurement by US is a reliable method for muscle atrophy evaluation and strongly correlates with other acknowledged methods. PMID- 30431729 TI - Differential Diagnosis of Cheilitis - How to Classify Cheilitis? AB - Although cheilitis as a term describing lip inflammation has been identified and recognized for a long time, until now there have been no clear recommendations for its work-up and classification. The disease may appear as an isolated condition or as part of certain systemic diseases/conditions (such as anemia due to vitamin B12 or iron deficiency) or local infections (e.g., herpes and oral candidiasis). Cheilitis can also be a symptom of a contact reaction to an irritant or allergen, or may be provoked by sun exposure (actinic cheilitis) or drug intake, especially retinoids. Generally, the forms most commonly reported in the literature are angular, contact (allergic and irritant), actinic, glandular, granulomatous, exfoliative and plasma cell cheilitis. However, variable nomenclature is used and subtypes are grouped and named differently. According to our experience and clinical practice, we suggest classification based on primary differences in the duration and etiology of individual groups of cheilitis, as follows: 1) mainly reversible (simplex, angular/infective, contact/eczematous, exfoliative, drug-related); 2) mainly irreversible (actinic, granulomatous, glandular, plasma cell); and 3) cheilitis connected to dermatoses and systemic diseases (lupus, lichen planus, pemphi-gus/pemphigoid group, -angioedema, xerostomia, etc.). PMID- 30431730 TI - Multiple Sclerosis: New Aspects of Immunopathogenesis. AB - Multiple sclerosis (MS) is a multicomponent disease characterized by inflammation, neurodegeneration, and cancellation of the central nervous system recovery mechanisms. The cause of MS is still unknown, but it is undeniable that genetic, environmental and immune factors are involved in the etiopathogenesis of this complex and heterogeneous disease. From the aspect of immunopathogenesis, until recently the opinion prevailed that autoreactive T lymphocytes played a major role, the activation of which is a key step in MS. The knowledge of the effector and regulatory roles of B cells supports a new concept of MS immunopathogenesis that is based on the highly com-plex interaction of T and B cells, with B cells actively participating in cellular immunity by directing the intensity and quality of cellular immune response. The mechanisms of B cell activity in MS immunopathogenesis are multiple and include antigen presentation and T cell costimulation, cytokine secretion, antibody synthesis, and formation of ectopic lymphoid B cell aggregates in the intrameningeal spaces. The importance of B cells has been confirmed by modern therapeutic options for the treatment of MS. PMID- 30431731 TI - T-Cell Large Granular Lymphocytic Leukemia - Case Reports. AB - T-cell large granular lymphocytic leukemia (T-LGLL) is an uncommon but probably underdiagnosed disease caused by clonal proliferation of large granular lymphocytes. Diagnosis is typically based on the high number of morphologically characteristic lymphoid cells and finding of an abnormal immunophenotype by flow cytometry. Because of its relatively indolent clinical behavior, observation is often an appropriate therapy. Here we present a case of a 53-year-old male admitted to the hospital because of abdominal pain. Blood examination revealed mild mycrocitic anemia and multiplied lactate dehydrogenase level. Abdominal ultrasound showed splenomegaly of 16 cm, with no lymphadenopathy. Fine needle aspiration of bone marrow revealed hypocellular marrow with 50% of atypical lymphoid cells. There were 81% of atypical medium sized granular lymphocytes with irregularly shaped nuclei in peripheral blood, so the cytologic diagnosis was lymphoproliferative process. Bone marrow biopsy showed nodular and interstitial proliferation of small, partially atypical T lymphocytic cells positive for CD2, CD3, CD5, CD8, granzyme and TIA, and negative for hairy cell markers, CD10, MUM 1, bcl 1, CD4 and CD56. The finding was consistent with T-LGLL. Due to splenomegaly, the patient was treated with cyclosporine and gradually reduced dose of corticosteroids, leading to regression of splenomegaly and normalization of lactate dehydrogenase level. PMID- 30431732 TI - Brachial Plexus Schwannoma - Case Report and Literature Review. AB - Schwannoma as an extracranial nerve sheath tumor rarely affects brachial plexus. Due to the fact that brachial plexus schwannomas are a rare entity and due to the brachial plexus anatomic complexity, schwannomas in this region present a challenge for surgeons. We present a case of a 49-year-old female patient with a slow growing painless mass in the right supraclavicular region that was diagnosed as schwannoma and operated at our department. The case is described to remind that in case of supraclavicular tumors, differential diagnosis should take brachial plexus tumors, i.e. schwannomas, in consideration. Extra caution is also required on fine needle aspiration procedures or biopsies of schwannomas due to the possible iatrogenic injury of the nerve and adjacent structures. On operative treatment of schwannoma, complete tumor resection should be achieved while preserving the nerve. PMID- 30431733 TI - An Unusual Case of Papillary Thyroid Carcinoma Iodine-131 Avid Metastasis to the Adrenal Gland. AB - Papillary thyroid carcinoma (PTC) is considered one of the most favorable tumors, indolent, with rare distant dissemination. Lungs and bones are the most common metastatic sites. Unusual sites of PTC distant metastases are extremely rare. Brain, liver, skin, kidney, pancreas, and adrenal gland PTC metastases have been sporadically reported in the literature. An 86-year-old female patient underwent total thyroidectomy and neck dissection due to PTC. Postoperative whole body iodine-131 scintigraphy with I-131 SPECT/CT of the abdomen revealed radioiodne avid left adrenal gland metastasis together with high postoperative serum thyroglobulin (Tg) value of more than 5000 ug/L and high serum Tg antibodies. Considering the above-mentioned findings, patient's age and multiple comorbidities, radioiodine therapy was applied. PTC metastases to the adrenal gland are extremely rare, and to our knowledge, only nine cases have been reported in the literature. This case report complements rare examples of unusual PTC metastases. PMID- 30431734 TI - Lateral Inverted Osteochondral Fracture of the Talus: Case Reports and Review of the Literature. AB - Lateral inverted osteochondral fracture of the talus (LIFT) is a rare variant of stage IV osteochondral lesion of the talus (OLT), where the fragment is inverted in situ by 180 degrees . The management of LIFT lesion is very challenging and early recognition crucial, given that treatment options depend on the articular cartilage condition and sufficiency of the adjacent bone of the displaced fragment. We describe two LIFT cases referred from other institutions after unsuccessful conservative treatment of OLT. They presented with pain, swelling and tenderness over the anterolateral aspect of the right ankle. We recognized the LIFT lesion on the magnetic resonance imaging scans in patient 2, while in patient 1 the orientation of the fragment was recognized upon direct visualization during operative treatment. Both patients underwent arthroscopic procedure. Due to articular cartilage damage and insufficiency of the adjacent bone of the fragment, both patients were treated with excision fol-lowed by microfracture. Treatment of the LIFT lesion should start arthroscopically to allow clear evaluation of the osteochondral fragment, assessment of the talar defect and identification, as well as treatment of associated disorders. If the articular cartilage appears intact with sufficient subchondral bone, fixation of the fragment is optimal management, otherwise excision and microfracture can be the treatment of choice. PMID- 30431735 TI - Recommendations for Perioperative Management of Patients with Cardiac Implantable Electronic Devices. AB - Four thousand cardiac implantable electronic devices (CIED) are implanted yearly in Croatia with constant increase. General anesthesia and surgery carry some specific risk for the patients with implanted CIEDs. Since most of the surgical procedures are performed in institutions without reprogramming devices available, or in the periods when they are unavailable, these guidelines aim to standardize the protocol for perioperative management of these patients. With this protocol, most of the procedures can be performed easily and, more importantly, safely in the majority of surgical patients. PMID- 30431736 TI - 25(OH)D serum concentration in women with menstrual disorders -risk factors for Vitamin D deficiency. AB - INTRODUCTION: Vitamin D (VD) plays a crucial role in calcium metabolism as well as immunological and endocrine homeostasis. Previous studies revealed strong inverse correlation between VD levels and insulin resistance, parathyroid dysfunctions and autoimmune thyroid disease. Insufficient evidence concerns its dependency of ovarian hormones. Malfunctioning of the ovaries results in menstrual disorders that are one of the most common endocrine impairments in young women of reproductive age. MATERIAL AND METHODS: The study was aimed to evaluate the correlation between 25(OH)D serum concentration and estradiol, testosterone as well as body mass index (BMI) in women with oligomenorrhea. 134 women of reproductive age with oligomenorrhea were eligible for the study. 25 hydroxyvitamin D [25(OH)D], estradiol, testosterone and sex hormone-binding globulin (SHBG) were measured using chemiluminescence immunoassay. Free androgen index (FAI) and body mass index (BMI) were calculated. RESULTS: Critical 25(OH)D deficiency (<10 ng/ml) was found in 13.4% of women, the risk of deficiency (<30 mg/dl) was diagnosed in 69.4%, while sufficient level of VD (>30 mg/ml) in 17.2% of them. Significant negative correlation was detected between 25(OH)D and estradiol serum concentrations (r=-0.2; p=0.049), as well as BMI levels (r=-0.22; p=0.01). However, no significant correlation was found between 25(OH)D and testosterone (r=-017; p=0.055), SHBG (r=0.08; p=0.4) and FAI (r=-0.1; p=0.24). CONCLUSIONS: Thorough assessment of vitamin D deficiency/insufficiency is required among patients with menstrual disorders, especially those overweighed and obese. Early screening and VD supplementation in women with estrogen dependent disorders may become a part of routine management in order to optimize endocrine health. PMID- 30431737 TI - A rare case of ectopic pregnancy - retroperitoneal ectopic pregnancy. AB - Ectopic pregnancy is a condition when fertilized egg implants outside the uterine cavity. The reported incidence is about 0.5-1% of all pregnancies. Retroperitoneal ectopic pregnancies (REP) are extremely rare and early diagnosis and treatment is very difficult. For the adequate management and elimination of risks of maternal morbidity and even mortality, timely diagnosis is of a key importance. A 38-year-old woman was referred to our department for RCUI due to missed abortion/anembryonic pregnancy. Re-RCUI was later indicated due to suspicion of residua post RCUI. Histological examination didn't confirm intrauterine pregnancy, beta-hCG blood levels were flat. Further ultrasonographic examination identified retroperitoneal ectopic pregnancy, most likely in the precaval lymph node. The surgical and subsequently histological examination confirmed this diagnosis. Our case describes successful management of rare retroperitoneal ectopic pregnancy. When common sites of ectopic pregnancy do not have any positive finding, then the presence of REP should be taken into consideration. PMID- 30431738 TI - Cellular brain edema induced by water intoxication in rat experimental model. AB - OBJECTIVES: This paper presents our own rat model of the cellular brain edema, induced by water intoxication (WI). The basic principle of the model is an osmotic imbalance in the cell membrane followed by an intracellular flow of sodium and simultaneous accumulation of water leading to the subsequent increase of BBB permeability. METHODS: The usefulness of the model was tested in precisely specified conditions whose results were clearly expressed. The procedure determined both how WI induces cellular edema as well as the disturbances caused by cellular edema. RESULTS: The evidence of existing cellular edema with increased BBB permeability was proved by intracellular accumulation of intravital dye with a large molecular size; increased brain-water content was confirmed by using the dry/wet weight method and by the decrease in CT density; the elevated intracranial pressure (ICP) due to the expanding volume was determined by continuous monitoring the ICP; the structural lesions were proved by identification of the myelin disintegration; and the impaired nervous functions was demonstrated by the of open field test method. CONCLUSION: Our experimental model can help the future studies of pathophysiology of cellular brain edema and is suitable for testing neuroprotective agents. PMID- 30431739 TI - Clinical effectiveness of parenteral trazodone for the management of psychomotor activation in patients with bipolar disorder. AB - OBJECTIVES: Trazodone is a multifunctional triazolopyridine drug with antidepressant, anxiolytic, sedative, and hypnotic properties. The current retrospective study was designed to investigate the effectiveness of trazodone for reducing acute psychomotor activation (PA) in patients with bipolar disorder (BD). We specifically reasoned that a parenteral route of administration could offer potential advantages in this clinical setting. METHODS: We assessed the effectiveness and safety of parenteral trazodone in a retrospective study conducted in 64 inpatients with BD and acute PA. The effectiveness assessment was the Clinical Global Impression Scale - Severity Of Illness (CGI-S) rated before the administration of parenteral trazodone (baseline) and at the end of treatment. A post-treatment reduction in CGI-S score >= 20% compared with baseline was considered as the primary outcome measure. RESULTS: Administration of parenteral trazodone was associated with significant improvements in CGI-S scores from baseline (5.4 +/- 0.9) to the end of the study (4.2 +/- 1.0; p < 0.001, Wilcoxon matched-pairs signed-ranks test). A total of 34 patients (53.1%) showed a post-treatment reduction in CGI-S score >= 20% compared to baseline. Multivariable binary logistic regression analysis using a forward selection procedure identified treatment duration (in days) as the only independent predictor of post-treatment reduction in CGI-S score >= 20% (odds ratio: 1.28; 95% confidence interval: 1.02-1.60, p <0.05). Adverse effects occurred in 13 (20.3%) patients. CONCLUSIONS: Parenteral trazodone is well-tolerated and effective in 53.1% of patients with BP and acute PA. Treatment duration was identified as an independent predictor of response in our sample. PMID- 30431740 TI - Coexistence of neurofibromatosis type 1 with multiple malignant neoplasia. AB - Neurofibromatosis type 1 (NF1, von Recklinghausen disease) is inherited in autosomal dominant way genetic disorder, with an incidence at birth 1:3000. It is one of the most common congenital disorders. It is characterized by cafe-au-lait spots, neurofibromas, and less common MPTST and gliomas of the optic nerve. It is caused by germline mutations of the NF1 gene, which acts as tumor suppressor. Inactivation of the gene leads to increased activation of the kinase pathways, and in consequence, uncontrolled proliferation of cells. The disease predisposes to the development of both benign and malignant tumors. Malignant tumors, but not related to the nervous system occur in neurofibromatosis quite rare. The aim of the study is a literature review of NF1, with presentation of a patient with NF1 and coexisting numerous tumors: synchronous somatostatinoma and gastrointestinal stromal tumor with metachronous prostate adenocarcinoma and non-small cell lung carcinoma. And attempt to answer the question if there is a common pathway for oncogenesis of these four tumors. PMID- 30431741 TI - Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors' treatment: Spectrum of imaging appearances. AB - OBJECTIVES: Immune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases. MATERIAL AND METHODS: We included 28 patients (19 females, 9 men, mean aged 58+/-13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed. RESULTS: We found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned. CONCLUSION: Secondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations. PMID- 30431742 TI - Neuroendocrine aspects of anorexia nervosa and bulimia nervosa. AB - Endocrine dysfunctions in eating disorders (anorexia nervosa, bulimia nervosa) result from disturbed regulation of hypothalamo-pituitary-gonadal, hypothalamo pituitary-adrenal, hypothalamo-pituitary-thyroid and hypothalamo-pituitary-GH IGF1 axes as well as of altered peripheral endocrine metabolism. Some peptides of hypothalamic origin, as well as those secreted by the adipose tissue and gastrointestinal tract including pancreatic hormones, are involved in the control of appetite and satiety. These peptides play also an important role in the mechanism of hormonal secretion. Altered activity of these biologically active substances may lead to the disturbances in the regulation of energy and hormonal homeostasis. PMID- 30431743 TI - Personality disorder in marriage and partnership - a narrative review. AB - BACKGROUND: Partner conflicts are the most common precipitating factors of decompensation of psychiatric disorders, including personality disorders. Personal characteristics play a fundamental role in both the prediction of marital satisfaction of the individual as well as the satisfaction of the couple as a whole. METHOD: Narrative Review of the articles, books and book chapters within the period 1956 - 2016 using PubMed, Web of Science, and Scopus databases with keywords "personality disorder," "partnership," marital problems," "marital conflicts." Additional references were found using reviews of relevant articles. RESULTS: It is evident that patients with personality disorders can have problems with meeting the criteria that contribute to the marital satisfaction and, on the other hand, easily fulfill the criteria that are related to the causes of the relationship breakups. People with personality disorders have substantial problems with starting and continuing a relationship with a partner. They have an unintentional ability to create and maintain problematic relationships. The association between the dysfunctional marriage and personality problems of the partners may have the basis in the insufficient understanding of the behavior of one or both partners. People with personality disorder experience numerous misunderstandings, misinterpretations, communicate poorly, and they are more alert to verbal and physical aggression in the interpersonal relations. They do not recognize that the basis of experienced struggles has a source in their intrapersonal processes and their relationship with the world. Persons with certain personality disorders tend to seek and create a pathologically stable partnership. To understand the dynamics of such relationships, examining personality traits first should be essential. Understanding the maladaptive personality patterns in the context of the relationship should be beneficial for both partners. PMID- 30431744 TI - Revisiting respiratory muscle strength and pulmonary function in spinal cord injury: The effect of body positions. AB - OBJECTIVES: In the subjects with high cervical spinal cord injury (SCI), The difference of respiratory muscle strength and pulmonary function according to supine and sitting position were investigated whether there are changes in the tendency. METHODS: Twenty-three subjects with high cervical SCI and 23 subjects with low cervical and thoracic SCI were evaluated. The reference neurological level of injury for dividing the groups was fifth cervical vertebrae (C5). SCI severity was classified as motor-complete SCI. The supine and sitting forced vital capacity (FVC), percent of the predicted FVC (FVC%), maximal expiratory pressure (MEP), maximal inspiratory pressure (MIP), MEP / MIP ratio, and peak cough flow (PCF) were compared. RESULTS: The significantly higher FVC, FVC% in the low cervical and thoracic SCI group was identified in the supine position than the sitting position. The same tendency was observed in the high cervical SCI group. In the comparison of respiratory muscle strength, higher values of supine MEP and MIP were found only in the high cervical SCI group. PCF is more positively correlated with MIP than with MEP in all groups. CONCLUSION: We found that the supine position is more advantageous for the strong breathing and larger lung capacity in patients with high cervical SCI. The positive correlation between PCF and MIP in the patients with high cervical SCI was also confirmed. These results may be used to establish a pulmonary rehabilitation strategy for patients with high cervical SCI. PMID- 30431745 TI - The over-expression of GH/GHR in tumour tissues with respect to healthy ones confirms its oncogenic role and the consequent oncosuppressor role of its physiological inhibitor, somatostatin: a review of the literature. AB - The interaction between pituitary hormones, GH - PRL, and Growth Factors, GF, plays a fundamental role in the physiological and neoplastic mechanisms of growth, the latter using these factors to a much greater extent compared to the former, with a direct dose-dependent effect on the speed of local or metastatic expansion. In hormone-dependent tumours, the respective male and female sex hormones interact with GH - PRL - GF to sustain the expansion of the tumour. We carried out a review of the literature on the relationship between the expression of GH and GHR in tumour tissues compared to healthy tissues, and on the correlation between this expression and tumour aggressiveness. An over-expression of GH and GHR in tumours was a constant finding. In more than a thousand cases published in various clinical, observational, retrospective studies investigating cervico-facial tumours, lymphoproliferative diseases, breast cancer, prostate cancer, non-small-cell lung cancer, neuroblastomas, oesophageal cancer, glioblastomas, and sarcomas, we constantly found an improvement in objective response, quality of life and survival, compared to conventional oncological protocols, by inhibiting GH and correlated GF using somatostatin. PMID- 30431751 TI - Cure of Stammering. PMID- 30431752 TI - Remarks on the Medical Topography of the Parish of Neilston. PMID- 30431754 TI - Diseases of the Brain and Spinal Cord. PMID- 30431753 TI - Analecta. PMID- 30431755 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from 1st November, 1827, Till 1st May, 1828. PMID- 30431758 TI - Report of Diseases among the Poor of Glasgow, during February, March, and April, 1828. PMID- 30431757 TI - Case of Lithotomy, Complicated with Obstructed Bowels, from the Pressure of an Osseous Tumour in the Mesentery. PMID- 30431756 TI - Lectures on the Eye, Delivered to the Students Attending the Glasgow Eye Infirmary. PMID- 30431759 TI - Two Cases of Retroversio Uteri, with Remarks. PMID- 30431761 TI - On the Diagnostic Symptoms of the Dislocation of the Femur into the Ischiatic Notch. PMID- 30431760 TI - Cases in Which Lumbrici Were Evacuated by Ulceration, through the Parietes of the Abdomen. PMID- 30431762 TI - Report of Diseases among the Poor of Glasgow during May, June, and July, 1828. PMID- 30431763 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from 1st November 1827, Till 1st May 1828. PMID- 30431764 TI - Mortality of Children. PMID- 30431766 TI - Analecta. PMID- 30431765 TI - On the Utility of Sulphate of Quina in Strumous Ophthalmia; with Cases. PMID- 30431767 TI - Observations on the Utility of the Tartrate of Potash and Magnesia as a Purgative. PMID- 30431768 TI - Case of Spinal Neuralgia. PMID- 30431769 TI - On the Laws of Sympathy. PMID- 30431770 TI - Remarks on the Medical Topography of the Parish of Neilston. PMID- 30431771 TI - Case of Dropsy, Occurring after Scarlet Fever, Treated by Blood-Letting; with Remarks. PMID- 30431773 TI - Analecta. PMID- 30431772 TI - Observations on Polypus of the Uterus. PMID- 30431774 TI - Malaria. PMID- 30431775 TI - Case of Laryngotomy, Performed for the Extraction of a Plum-Stone from the Windpipe. PMID- 30431776 TI - On Irritation of the Spinal Nerves. PMID- 30431777 TI - On the Mineral Waters of Scotland. PMID- 30431779 TI - On the Treatment of Burns. PMID- 30431778 TI - On the Propriety of Introducing a Simplified Anatomical Nomenclature. PMID- 30431780 TI - Case of Ascites, in Which the Abdomen Was Tapped through the Fundus of the Bladder, and an Attempt Made to Establish a Fistulous Communication between the Bladder and Abdomen. PMID- 30431781 TI - Cases in Midwifery. PMID- 30431782 TI - On Defective Hearing Dependant on Deficient Secretion of Wax. PMID- 30431783 TI - Observations on the Use of the Lobelia Inflata, in Asthma and Other Spasmodic Diseases. PMID- 30431784 TI - Report of Diseases among the Poor of Glasgow, during November and December 1827, and January 1828. PMID- 30431785 TI - On the Epidemic Dysentery Which Prevailed in Autumn 1827. PMID- 30431786 TI - Report of the Diseases Which Prevailed among the Poor of Glasgow, during the Autumn of 1827. PMID- 30431787 TI - Analecta. PMID- 30431788 TI - Case of Disease of the Spine, in Which the Ulceration Originated in, and Was Confined to the Bone. PMID- 30431790 TI - On Auscultation and Percussion. PMID- 30431789 TI - Observations on a Particular Species of Ophthalmia, Occurring in Connexion with Porrigo, and Usually Termed Scrofulous Ophthalmia. PMID- 30431791 TI - Anatomico-Chirurgical Remarks on the Different Portions of the Axillary Artery, with a Case in Which This Vessel Was Successfully Tied. PMID- 30431792 TI - On the Mineral Waters of Scotland. PMID- 30431794 TI - Case of Obstructed Respiration. PMID- 30431793 TI - Case of Pulsating Tumour of the Scalp, from Dilatation of the Branches of the External Carotid Artery. PMID- 30431796 TI - Report of Surgical Cases, and Treatment, in the Glasgow Royal Infirmary, for the Summer and Autumn Quarters of 1827. PMID- 30431795 TI - Observations on Putrid Animal Effluvia, and on the Utility of the Chloride of Lime in Destroying Their Foetor. PMID- 30431797 TI - Case of Encysted Dropsy of the Abdomen. PMID- 30431798 TI - On the Epidemic Dysentery Which Prevailed in Glasgow, during the Autumn of 1827. PMID- 30431799 TI - Account of a Singular Distribution of the Venous System. PMID- 30431800 TI - Observations on Spasm or Cramp of the Stomach; with Cases and Dissections. PMID- 30431801 TI - Report of Diseases among the Poor of Glasgow. PMID- 30431802 TI - Lectures on the Eye Delivered to the Students in the Glasgow Eye Infirmary: Lecture II. On Periostitis, Ostitis, Caries, and Necrosis of the Orbit. PMID- 30431803 TI - Intestinal Worms. PMID- 30431804 TI - Report of Surgical Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary. PMID- 30431805 TI - On Digestion. PMID- 30431807 TI - Analecta. PMID- 30431806 TI - Case of Chorea; with Remarks. PMID- 30431808 TI - An Essay on Iritis: Part II. PMID- 30431809 TI - Case of Congenital Occlusion of the Meatus Auditorius Externus, Where Nature Effected a Cure. PMID- 30431810 TI - On the Use of Ergot of Rye in Parturition. PMID- 30431811 TI - Report of Diseases among the Poor of Glasgow, Treated under the Direction of the District Surgeons, during August, September, and October, 1828. PMID- 30431812 TI - Case of Amputation of the Lower Jaw. PMID- 30431813 TI - A Sketch of the Natural Cure of Diseases. PMID- 30431814 TI - An Account of Two Cases of Insensibility of the Eye to Certain of the Rays of Colour. PMID- 30431815 TI - Analecta. PMID- 30431816 TI - An Essay on Iritis: Part I. PMID- 30431817 TI - Case of Extensive Suppuration and Death, Succeeding the Prick of a Pin; with Remarks. PMID- 30431819 TI - Observations on the Management of Fractures of the Thigh Bone. PMID- 30431818 TI - Extirpation of an Enlarged Tonsil. PMID- 30431821 TI - On Spontaneous Perforation of the Stomach. PMID- 30431820 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary. PMID- 30431822 TI - Observations on the Operation of Lithotomy, with Cases. PMID- 30431823 TI - Analecta. PMID- 30431824 TI - Case of Stone Extracted from the Female Bladder. PMID- 30431825 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary. PMID- 30431826 TI - Remarks on the Different Forms of Insanity, and Their Treatment. PMID- 30431827 TI - Practical Observations on the Ophthalmia of New-Born Children; with Cases. PMID- 30431828 TI - Report of Diseases among the Poor of Glasgow, during May, June, and July, 1829. PMID- 30431829 TI - Cases of Asphyxia. PMID- 30431830 TI - Analecta. PMID- 30431832 TI - Cutaneous Diseases. PMID- 30431831 TI - A Practical Essay on the Diseases Which Occur in the Cellular Membrane of the Orbit. PMID- 30431834 TI - Aneurism. PMID- 30431833 TI - Case of Procidentia Uteri, with Remarks. PMID- 30431835 TI - On the Morbid Anatomy of Fever. PMID- 30431836 TI - Report of the Diseases Which Prevailed among the Poor of Glasgow, during February, March, and April, 1829. PMID- 30431837 TI - Remarks on Erysipelas. PMID- 30431838 TI - Report of Surgical Cases Treated in the Glasgow Royal Infirmary, from 1st Nov. 1828, to 1st May, 1829. PMID- 30431840 TI - On the Production of Monstrosities. PMID- 30431839 TI - Case of Congenital Malformation of the Brain; Where the Whole Cerebrum Was Situated without the Cranium. PMID- 30431842 TI - Analecta. PMID- 30431841 TI - Case of Poisoning from Nux Vomica. PMID- 30431843 TI - Remarkable Case of Hysteria. PMID- 30431844 TI - On Glaucoma. PMID- 30431845 TI - Case of Artificial Anus, in Which a Large Portion of the Everted Intestine Was Removed by Ligature. PMID- 30431846 TI - Case of Secondary Haemorrhage in Which the Subclavian Artery Was Tied above the Clavicle; with Clinical Remarks, as Delivered to the Students. PMID- 30431847 TI - Singular Malformation of the Foetus. PMID- 30431848 TI - On the Pharmaceutical Preparation of the Precipitated Carbonate of Iron. PMID- 30431850 TI - Insanity. PMID- 30431849 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary. PMID- 30431851 TI - On the Severe and Fatal Consequences Resulting from Slight Wounds Received in Dissection. PMID- 30431852 TI - Report of Diseases among the Poor of Glasgow, during February, March, and April, 1830. PMID- 30431853 TI - Erratum. AB - [This corrects the article on p. 103 in vol. 3.]. PMID- 30431854 TI - Case of Laceration of the Bladder. PMID- 30431855 TI - Cases of Traumatic Tetanus. PMID- 30431857 TI - Proceedings of the Glasgow Medical Society. PMID- 30431856 TI - On the Medical Service of the Honourable East India Company. PMID- 30431858 TI - Observations on the Evidence of Dr. John Thomson of Edinburgh, in a Trial That Took Place at Glasgow, before the Circuit Justiciary Court, 19th April, 1822, Being an Essay Read before the Glasgow Medical Society, 1st Dec. 1829. PMID- 30431859 TI - Use of Turpentine in Iritis. PMID- 30431860 TI - Analecta. PMID- 30431861 TI - Natural History. PMID- 30431862 TI - Use of Iodine in Bronchocele. PMID- 30431863 TI - Report of Diseases among the Poor of Glasgow, during August, September, and October, 1829. PMID- 30431864 TI - Some Account of Inflammation of the Choroid Coat. PMID- 30431866 TI - Remarks on the Ergot of Rye, and Its Use in Protracted Labours. PMID- 30431865 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from 1st May Till 1st Nov. 1829. PMID- 30431867 TI - Report of the Diseases Which Prevailed among the Poor of Glasgow, during the Summer of 1830. PMID- 30431868 TI - Case of Translation of Disease from the Knee-Joint to the Head. PMID- 30431870 TI - Anomalous Distribution of the Arteries of the Leg. PMID- 30431869 TI - On the Classification and Structure of the Articulations of the Human Body: Part II. PMID- 30431871 TI - On the Uses of the Secale Cornutum, Particularly in Parturition. PMID- 30431872 TI - On Lithoplatomy. PMID- 30431873 TI - Observations on That Peculiar Change of Colour Which Venous Blood Undergoes during Approaching Syncope. PMID- 30431874 TI - Remarks on Hydrophobia, in Connexion with Hysteria, and Other Convulsive Affections. PMID- 30431876 TI - Case of Ossification of the Heart. PMID- 30431875 TI - A Chemical Examination of Singleton's Golden Ointment, with an Improved Formula for Preparing the Red Precipitate Ointment. PMID- 30431877 TI - Remarks on Amaurosis, Illustrated with Cases. PMID- 30431878 TI - Remarks on the Cure of Strangulated Inguinal Hernia by the Taxis, Being the Substance of an Essay Read before the Glasgow Medical Society, on 15th Feb. 1825. PMID- 30431879 TI - Further Observations on the Ophthalmia of New-Born Children. PMID- 30431880 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from 1st November 1829, Till 1st May 1830. PMID- 30431881 TI - Cases Illustrative of the Deleterious Effects of the Fumes of Charcoal. PMID- 30431882 TI - Remarks on Amaurosis, Illustrated with Cases: Part I. PMID- 30431883 TI - Memoranda of a Visit to Buxton, in the Autumn of 1829. PMID- 30431885 TI - On the Production of Worms in the Human Body. PMID- 30431884 TI - Case of Umbilical Hernia Treated by Ligature. PMID- 30431886 TI - Proceedings of the Glasgow Medical Society. PMID- 30431888 TI - Analecta. PMID- 30431887 TI - Report of Diseases among the Poor of Glasgow, during November and December, 1829, and January, 1830. PMID- 30431889 TI - Deficient or Deranged Uterine Action the Chief Cause of the Delays and Difficulties Experienced in Parturition. PMID- 30431890 TI - On the Classification, Nomenclature, and Mechanism of the Articulations of the Human Body: Part I. PMID- 30431891 TI - Cases of Extra-Uterine Pregnancy; with Remarks. PMID- 30431892 TI - Report of a Few of the More Important Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, during the Summer and Autumn of 1829; with Explanatory Remarks, as Delivered to the Students at the Clinical Lectures. PMID- 30431893 TI - On Tetanus; with Cases. PMID- 30431894 TI - Miscellaneous Communications. PMID- 30431896 TI - Lecture Introductory to a Course of Medical Jurisprudence and Police. PMID- 30431895 TI - Report of Diseases Treated at the Ayr Dispensary, from March 1829, Till March 1830. PMID- 30431897 TI - The Rotundo Hospital, Dublin. PMID- 30431898 TI - Comparative Merits of Investigating Sudden Deaths in England and Scotland, and the Defects in the English System. PMID- 30431899 TI - On the Necessity of Appointing Properly Qualified Medical Officers to Conduct Post-Mortem Examinations at Coroners' Inquests. PMID- 30431900 TI - On the Origin of Malaria. PMID- 30431901 TI - Selections from Medical Journals. PMID- 30431903 TI - Medical Intelligence. PMID- 30431902 TI - On the Use of Tartar Emetic in the Treatment of Epilepsy. PMID- 30431904 TI - Case of Ileus with Operation. PMID- 30431905 TI - Medical Intelligence. PMID- 30431906 TI - On Pityriasis Rubra Acuta, a Rare Form of Skin Disease. PMID- 30431907 TI - On Shortening the Duration of Labour. PMID- 30431908 TI - The Medical Pilgrim's Progress: Au Introductory Lecture Delivered at the Grosvenor Place School of Medicine, on October 1, 1857. PMID- 30431909 TI - On the Philosophy of Apparitions. PMID- 30431910 TI - On Aneurism of the Popliteal Artery. PMID- 30431912 TI - Medical Intelligence. PMID- 30431911 TI - Case of Recovery from Compound Fracture of the Skull, under the Care of Wm. Lyon, Esq., in the Glasgow Royal Infirmary. PMID- 30431913 TI - Case of Thoracic Encephaloid Tumour. PMID- 30431914 TI - On the Phenomena and Mechanism of the Focal Adjustment of the Eye to Distinct Vision at Different Distances. PMID- 30431915 TI - On the Escharotic Action of the Sulphate of Zinc. PMID- 30431916 TI - On the Surgical Anatomy of the Brachial Artery. PMID- 30431917 TI - Case of Hypertrophy of the Left Mamma. PMID- 30431919 TI - Biographical Notice of the Late Thomas Thomson, M.D., F.R.SS. L. & E., &c., Regius Professor of Chemistry in the University of Glasgow. PMID- 30431918 TI - On the Physical Climate of Scutari; and on the Nature of the Diseases of the Allied Troops during the Russian War, in 1853, 1854, and 1855. PMID- 30431921 TI - Selections from Medical Journals. PMID- 30431920 TI - Case of Displacement of the Testicle. PMID- 30431922 TI - Case of Vesico-Vaginal Fistula Successfully Treated by Bozeman's Suture. PMID- 30431924 TI - Biographical Notice of the Late Thomas Thomson, M.D., F.R.SS. L. & E., &c., Regius Professor of Chemistry in the University of Glasgow. PMID- 30431923 TI - Case of Catalepsy. PMID- 30431926 TI - Medical Intelligence. PMID- 30431925 TI - Results of Treatment in Seventy-One Cases of Pneumonia Treated in the Glasgow Royal Infirmary; with Some Remarks on Dr. Bennett's Novel Views on This Disease. PMID- 30431927 TI - Medical History of the Late War with Russia-Physical Climate of the Crimea Persistent Pernicious Influence of the Residence in Bulgaria on the Health of the Army in the Crimea. PMID- 30431928 TI - Selections from Medical Journals. PMID- 30431929 TI - On the Treatment of Complicated Gonorrhoea. PMID- 30431930 TI - Clinical Lectures on Typhus and Continued Fever: Lecture III. PMID- 30431931 TI - Case of Mixed Aneurism of Aortic Arch, Simulating Aneurism of Left Carotid, with Remarks. PMID- 30431932 TI - Case of Lithotomy by the Lateral Operation in a Female. PMID- 30431933 TI - Cases of Dislocation and Fracture. PMID- 30431934 TI - On the Effects of Mr. Warburton's Anatomy Bill, and the Facilities for the Study of Practical Anatomy in Glasgow. PMID- 30431935 TI - Remarks on the Medical Statistics of the Glasgow Royal Infirmary, for 1853: Part II.-Surgical. PMID- 30431937 TI - Medical Intelligence. PMID- 30431936 TI - Two Cases in Which Turning Could Not Be Accomplished, in Consequence of the Head of the Child Remaining Firmly Fixed at the Brim of the Pelvis, Preventing the Breech Coming down. PMID- 30431938 TI - On Disease of the Ear Extending to the Brain. PMID- 30431939 TI - Surgical Practice in the British Naval Hospital in the Bosphorus. PMID- 30431940 TI - Case of Premature Labour, Followed by Permanently Retained Placenta. PMID- 30431941 TI - Clinical Lectures on Typhus and Continued Fever. PMID- 30431943 TI - On the Convulsive Affection Which Occasionally Manifests Itself in the Course of Typhus, and Its Probable Connection with Nephritic Disease. PMID- 30431942 TI - Remarks on the Medical Statistics of the Glasgow Royal Infirmary, for 1853: Part I.-Fever. PMID- 30431944 TI - Operation of Opening the Membranous Portion of the Urethra, in Retention of Urine from Enlarged or Diseased Prostate. PMID- 30431946 TI - Medical Intelligence. PMID- 30431945 TI - The Medical Institutions of Paris. PMID- 30431948 TI - Selections from Medical Journals. PMID- 30431947 TI - Report on, and Chemical Analyses of, the Moffat Mineral Wells. PMID- 30431949 TI - Clinical Lectures on Surgery: Injuries of the Head, with Cases. PMID- 30431951 TI - Remarks on the Mode of Treating Cholera with Frequent Doses of Castor Oil. PMID- 30431950 TI - Remarks on the Influence of Fear in Producing Functional Derangements. PMID- 30431953 TI - Selections from Medical Journals. PMID- 30431952 TI - On the Injection of the Cellular Tissue with Water, as Tried in the Year 1848, in the Treatment of Cholera: In a Letter to the Editor. PMID- 30431954 TI - Report on, and Chemical Analyses of, the Moffat Mineral Wells. PMID- 30431955 TI - Clinical Notes. PMID- 30431956 TI - Clinical Lectures on Typhus and Continued Fever: Lecture II. PMID- 30431957 TI - Cases in Clinical Medicine. PMID- 30431958 TI - Medical Intelligence. PMID- 30431959 TI - The Medical School of Glasgow. PMID- 30431961 TI - Medical Intelligence. PMID- 30431960 TI - Observations on the Anatomy and Physiology of the Kidney. PMID- 30431962 TI - On Excision of the Ankle Joint. PMID- 30431963 TI - On the Constitution and Distribution of the Blood in Malignant Cholera, and on Iodine as a Remedy in the Earlier Stages of the Disease. PMID- 30431964 TI - Cases of Concealed Uterine Haemorrhage, with Remarks. PMID- 30431965 TI - Remarks on the Operation for Malignant Disease of the Testicle. PMID- 30431966 TI - Case of Implantation of the Placenta over a Uterine Tumour, Gestation Continuing to the Full Term, with Remarks. PMID- 30431967 TI - Reflections on the History, Pathology, and Treatment of Syphilitic Diseases. PMID- 30431968 TI - On Retinitis from Undue Lactation. PMID- 30431970 TI - Case of Idiopathic Glossitis, with Remarks. PMID- 30431971 TI - Selections from Medical Journals. PMID- 30431969 TI - Case of Congenital Hernia of the Stomach, Spleen, &c., in Which Perforation of the Stomach Supervened. PMID- 30431972 TI - On the Convulsive Affection Which Occasionally Manifests Itself in the Course of Typhus, and Its Probable Connection with Nephritic Disease. PMID- 30431973 TI - Observations on the Present Epidemic of Cholera in Glasgow. PMID- 30431974 TI - On Facial Anaesthesia. PMID- 30431975 TI - On the Utility of a Skeleton Articulated with Caoutchouc, as an Aid in Illustrating the Diagnosis of Dislocations. PMID- 30431976 TI - Remarks on the Propriety and Advantages of Hospitals for the Cure of Syphilitic Diseases. PMID- 30431977 TI - Selections from Medical Journals. PMID- 30431978 TI - Narrative of a Case of Poisoning by Aconite and Belladonna, with Remarks. PMID- 30431979 TI - Case of Diseased Ovarium, in Which Ovariotomy Was Performed by W. Lyon, Esq. PMID- 30431980 TI - Medical Intelligence. PMID- 30431981 TI - Reminiscences of Hernia. PMID- 30431982 TI - Berlin, Its Medical Institutions, Professors, &c. PMID- 30431983 TI - Report of Cases Treated in the Medical Wards of the Glasgow Royal Infirmary. PMID- 30431984 TI - Contributions to Midwifery Statistics and Practice. PMID- 30431985 TI - Notice of the Dissection of a Case of Lateral Transposition of the Viscera of the Thorax and Abdomen in a Man. PMID- 30431986 TI - Case of Pregnancy Complicated with Carcinoma of the Uterus, in Which Gestation Was Prolonged to the Seventeenth Month. PMID- 30431987 TI - Remarks on the Anatomy and Physiology of the Coecum in Man and Animals. PMID- 30431988 TI - Cases of Retention of Urine, with Remarks. PMID- 30431989 TI - Case of Obstructed Labour. PMID- 30431990 TI - Remarks on the Sanatory Arrangements on Board of Passenger Ships. PMID- 30431991 TI - Clinical Notes. PMID- 30431992 TI - Cases in Clinical Medicine. PMID- 30431993 TI - An Instance of Cancerous Disease of the Pituitary Gland. PMID- 30431994 TI - Case of Fracture of the Cervix Femoris. PMID- 30431995 TI - Medical Intelligence. PMID- 30431996 TI - On the Local Use of Veratria, Especially in Scrofulous Affections of Joints. PMID- 30431997 TI - Reminiscences of Hernia. PMID- 30431999 TI - On Fractures Connected with the Hip-Joint. PMID- 30431998 TI - On the Nature and Importance of Clinical Surgery. PMID- 30432000 TI - Report of Diseases among the Poor of Glasgow, during August, September, and October, 1830. PMID- 30432001 TI - Case of Fungus Haematodes of the Thigh, Cured by Amputation. PMID- 30432002 TI - Report of Cases Treated in the Glasgow Royal Infirmary. PMID- 30432003 TI - An Account of the Typhus Icterodes That Prevailed on Board His Majesty's Ship Iphigenia, in 1822. PMID- 30432004 TI - Notices, Statistical and Historical, Respecting the Prevalence of Dysentery in Scotland. PMID- 30432005 TI - On Medical Societies. PMID- 30432007 TI - On Health as Connected with Education. PMID- 30432006 TI - OEsophagotomy in the Horse. PMID- 30432009 TI - Analecta. PMID- 30432008 TI - Case of Colica Constipata Removed by Inflation. PMID- 30432010 TI - Diseases of Infancy. PMID- 30432011 TI - Cases of Idiopathic Glossitis. PMID- 30432012 TI - Diagnostic Indications of the Stethoscope. PMID- 30432013 TI - Case of Attempted Induction of Premature Labour, by Means of the Hot and Cold Water Douche. PMID- 30432014 TI - Observations on the Construction and Ventilation of Hospitals for the Sick. PMID- 30432015 TI - On the Treatment of Oxaluria. PMID- 30432017 TI - Selections from Medical Journals. PMID- 30432016 TI - Case of Diarrhoea Adiposa, with Observations. PMID- 30432018 TI - On the Therapeutical Properties of Some of the More Important Articles of the Materia Medica. PMID- 30432019 TI - Contributions to the Pathology and Treatment of Diseases of the Chest. PMID- 30432020 TI - On Excision of the Shoulder Joint. PMID- 30432021 TI - Medical Intelligence. PMID- 30432022 TI - Case of Difficult Labour Arising from Extensive Contraction of the Vagina and Os Tincae. PMID- 30432023 TI - On the Method of Preserving Vaccine Lymph in Capillary Tubes, and of Rendering Vaccination More General. PMID- 30432024 TI - Clinical Notes. PMID- 30432025 TI - On the Stable Nuisance in Glasgow. PMID- 30432026 TI - Notes on the Transportability of Yellow Fever, or Black Vomit. PMID- 30432027 TI - Analecta. PMID- 30432029 TI - Report of Diseases among the Poor of Glasgow during the Winter Quarter of 1830 31. PMID- 30432028 TI - Report of Diseases Treated at the Ayr Dispensary, from March, 1830, Till March, 1831. PMID- 30432030 TI - On Traumatic Tetanus. PMID- 30432031 TI - On Inflation of the Bowels. PMID- 30432032 TI - On a New Process for Preparing Medicinal Prussic Acid. PMID- 30432033 TI - Case of Monstrosity. PMID- 30432034 TI - Case of Rupture of the Aorta without External Violence. PMID- 30432036 TI - Taliacotian Operation for Restoration of under Lip. PMID- 30432035 TI - Cases of Aneurism. PMID- 30432037 TI - Remarks on Medical Education. PMID- 30432038 TI - Analytical Chemistry. PMID- 30432039 TI - Cases of Spinal Irritation. PMID- 30432040 TI - On Old Dislocations; Being an Essay Read before the Glasgow Medical Society, 1st February, 1831. PMID- 30432041 TI - Erratum in Last No. AB - [This corrects the article on p. 27 in vol. 4.]. PMID- 30432042 TI - Report of a Few of the Surgical Cases, Which Occurred in the Glasgow Royal Infirmary, during the Summer and Autumn of 1830. PMID- 30432043 TI - A Case of Fungus Haematodes of the Spermatic Chord; with Remarks. PMID- 30432045 TI - Cases of Injuries of the Head. PMID- 30432044 TI - Observations on Chronic Pain after Injuries, and Some Corresponding Strictures on the Medical Evidence Given in an Action of Damages for an Assault, Tried in a Jury Court, at Glasgow, 13th April, 1831, before the Right Honourable the Lord President Hope. PMID- 30432046 TI - Chemical and Medical Examination of the Rothsay Sulphuretted Water. PMID- 30432047 TI - Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from Nov. 1830, Till May 1831. PMID- 30432048 TI - Remarks on the Dysentery and Remittent Fever of Hamilton and Its Vicinity. Description of a Remittent Fever That Prevailed in the Parish of Blantyre, in the Autumn of 1830.-Case of the Edinburgh New Town Epidemic. PMID- 30432049 TI - Three Cases of Successful Surgical Operations, Namely, Amputation at the Shoulder Joint, with Portion of Clavicle and Scapula; Removal of Head and Two Inches of Shaft of Humerus; and Amputation of Thigh at Hip-Joint. PMID- 30432051 TI - Remarks on Some of the Physical Effects on the Human System of the Habitual Use of Distilled Spirits. PMID- 30432050 TI - Observations on Dysentery as It Prevailed in Callander, and Its Neighbourhood. PMID- 30432052 TI - Analecta. PMID- 30432053 TI - Medical Opinions on Temperance, Intemperance, Abstinence, and Temperance Societies; Being the Discussion on the Subject of Mr. Ritchie's Essay, at the Glasgow Medical Society. PMID- 30432054 TI - Description of a New and Cheap Herniary Truss. PMID- 30432055 TI - Instructions for the Qualitative Analysis of Mineral Waters. PMID- 30432056 TI - Report of Diseases among the Poor of Glasgow, during February, March, and April, 1831. PMID- 30432057 TI - Case of Severe Injury of the Head. PMID- 30432058 TI - Substance of a Clinical Lecture on Burns and Scalds. PMID- 30432059 TI - On a Peculiar Conformation of the Colon. PMID- 30432060 TI - Observations on the Measles and Small-Pox, That Prevailed Epidemically in Stranraer, in the Autumn of 1829. PMID- 30432061 TI - Case, in Which a Large Needle Was Swallowed, and a Year Afterwards Extracted from the Urinary Bladder, Having Formed the Nucleus of a Stone. PMID- 30432062 TI - On the Cholera Morbus. PMID- 30432063 TI - Die Asiatische Cholera in Russland, in den Jahren, 1830 und 1831, nach Russischen Aktenstucken und Berichten. PMID- 30432064 TI - Case of Severe Injury of the Head, Fungus, and Removal of a Very Large Portion of the Brain, with Remarks. PMID- 30432065 TI - Remarks on Dr. de Vitre's Case of Fungus Haematodes. PMID- 30432066 TI - The New German Doctrine of Dr. Samuel Hahnemann. PMID- 30432067 TI - Analecta. PMID- 30432068 TI - Continuation and Result of the Case of Artificial Anus, Related in the Third Volume of This Journal. PMID- 30432069 TI - Report of Diseases among the Poor of Glasgow, during May, June, and July, 1831. PMID- 30432070 TI - Case of Inflammation of the Heart. PMID- 30432071 TI - On the Use of the Ergot of Rye, as a Means of Preventing the Death of the Child, in Breech and Footling Presentations. PMID- 30432073 TI - Selections from Medical Journals. PMID- 30432072 TI - Report of a Few of the More Interesting Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from 1st November, 1830, Till 1st May, 1831. PMID- 30432074 TI - On Dental Decay. PMID- 30432075 TI - Case of Leucocythemia, with Observations. PMID- 30432076 TI - Report of Cases Treated in the Glasgow Cholera Hospital. PMID- 30432077 TI - Case of Suicide, Attended by Some Singular Circumstances. PMID- 30432078 TI - Case of Vaginal Cystocele, Treated by Mr. J. B. Brown's Operation. PMID- 30432079 TI - Clinical Lectures on Typhus and Continued Fever: Lecture IV. PMID- 30432081 TI - Notes of Clinical Lectures on Medical Cases. PMID- 30432080 TI - Medical Intelligence. PMID- 30432082 TI - Cases of Spontaneous Gangrene, with Remarks. PMID- 30432083 TI - Observations on Some of the Means Recently Proposed for the Prevention of Pitting in Small-Pox. PMID- 30432084 TI - Remarks on the Alterative Treatment of "Continued Fevers." PMID- 30432085 TI - Case of Congenital Malformation. PMID- 30432086 TI - Remarks on Certain Cases of Intestinal Obstruction. PMID- 30432087 TI - Statistical Report of Three Thousand Three Hundred Cases of Obstetricy. PMID- 30432088 TI - Report of Medical Cases Treated in the Glasgow Royal Infirmary, from 1st November, 1854, to 1st May, 1855. PMID- 30432090 TI - Medical Intelligence. PMID- 30432089 TI - Notices of Recent Researches on the Origin of Entozoa, More Especially of Tape Worms. PMID- 30432091 TI - Case of Turning as a Substitute for Craniotomy. PMID- 30432093 TI - By-Gone Cases in Surgery. PMID- 30432092 TI - An Unusual Case of Popliteal Aneurism. PMID- 30432094 TI - On the Therapeutical Properties of Some of the More Important Articles of the Materia Medica: Emetics and Purgatives. PMID- 30432095 TI - On the Developement of Cystic Entozoa in the Human Kidney (with an Illustrative Case). PMID- 30432096 TI - On the Nature and Treatment of Acute Rheumatism, Illustrated by Cases. PMID- 30432097 TI - Report of Obstetric Cases Occurring in Hospital Practice. PMID- 30432098 TI - Medical Intelligence. PMID- 30432099 TI - On Dislocation of the Thumb. PMID- 30432100 TI - Report of Medical Cases Treated in the Glasgow Royal Infirmary, from 1st November, 1854, to 1st May, 1855. PMID- 30432101 TI - The Medical Institutions of Paris. PMID- 30432102 TI - Miscellaneous Communications. PMID- 30432103 TI - By-Gone Cases in Surgery. PMID- 30432104 TI - Notes on the Physiological and Therapeutic Effects of the Chloride of Ammonium. PMID- 30432105 TI - Medical Intelligence. PMID- 30432106 TI - Selections from Medical Journals. PMID- 30432107 TI - Case of Fracture of the Frontal Bone, with Extensive Displacement of the Bones of the Face, and Injury of the Brain. PMID- 30432108 TI - Remarks on the Increase of Small-Pox in Glasgow. PMID- 30432109 TI - Report of Glasgow Lying-In Hospital for the Year 1851-1852, with an Address to the Students. PMID- 30432110 TI - Cases in Clinical Medicine. PMID- 30432112 TI - Medical Intelligence. PMID- 30432111 TI - Case of Bite of a Young Woman by a Large Cobra de Capello. PMID- 30432113 TI - Contributions to the Pathology and Treatment of Diseases of the Chest. PMID- 30432114 TI - Clinical Notes. PMID- 30432115 TI - Case of Excision of the Head of the Femur, with Remarks. PMID- 30432116 TI - Selections from Medical Journals. PMID- 30432117 TI - Case of Cystic Sarcoma of the Mamma. PMID- 30432118 TI - Case of Acute Chorea. PMID- 30432120 TI - Report of the Trial of James Denny Scott, at Glasgow, 4th January, 1853, for an Alleged Murder at Greenock. PMID- 30432119 TI - Contributions to Pathology. PMID- 30432121 TI - Medical Intelligence. PMID- 30432122 TI - Remarks on the Treatment of the Cases of Diabetes Admitted into the Glasgow Royal Infirmary, from November, 1854, Till April, 1856. PMID- 30432123 TI - General Report on the Pathology of the Diseases of the Army in the East. PMID- 30432124 TI - Case of Poisoning by Strychnine, with Experiments on Poisoning by That Substance, and Remarks on Some Parts of the Medical Evidence Given on Palmer's Trial. PMID- 30432126 TI - On the "Expiratory Method" of Performing the Taxis to Effect the Reduction of Hernia. PMID- 30432125 TI - Composition of Fifty-Six East Indian Urinary Calculi. PMID- 30432127 TI - Selections from Medical Journals. PMID- 30432128 TI - Cranial Presentations and Cranial Positions: Suggestions Practical and Critical. PMID- 30432129 TI - Remarks on Dr. Paxton's Case, with Observations on the Structure and Action of the Parts Concerned in the Focal Adjustment of the Eye. PMID- 30432130 TI - Case of Complete Retroversion of the Uterus, Where the Mother Died, Undelivered, in the Tenth Month of Her Pregnancy. PMID- 30432132 TI - Medical Intelligence. PMID- 30432131 TI - On Unusual Mobility of the Iris, His Own Case. PMID- 30432134 TI - Remarkable Cases of Malignant (Encephaloid) Disease, Occurring in Nos. 1 and 2 Medical Wards of the Glasgow Royal Infirmary. PMID- 30432133 TI - Notes from Practice, Public and Private. PMID- 30432135 TI - Medical Intelligence. PMID- 30432136 TI - Mechanism of Vesical Pouches. PMID- 30432137 TI - The Vocation of the Medical Scholar; Being the Eighty-Third Anniversary Oration Delivered before the Medical Society of London. PMID- 30432139 TI - Selections from Medical Journals. PMID- 30432138 TI - Cancrum Oris. PMID- 30432140 TI - Observations on the Treatment of Stricture of the Urethra, with Illustrative Cases. PMID- 30432141 TI - On a Method Recently Introduced into Practice, of Performing Certain Surgical Operations without Haemorrhage. PMID- 30432143 TI - The Hospitals in the East. PMID- 30432142 TI - Notes of Medico-Legal Cases, with Comments. PMID- 30432145 TI - Diabetes Mellitus. PMID- 30432144 TI - Clinical Notes: Two Cases of Deep-Seated Tumour in the Neck. PMID- 30432146 TI - An Account, Showing the Effects on the Genital Organs of Amputation of the Penis. PMID- 30432147 TI - Case of Puerperal Tetanus. PMID- 30432148 TI - On the Treatment of Subcutaneous Naevus, with a Case. PMID- 30432149 TI - Medical Intelligence. PMID- 30432150 TI - Cranial Presentations and Cranial Positions: Suggestions Practical and Critical. PMID- 30432151 TI - Summary of Cases Admitted at the Eye Infirmary of Glasgow, in June, July, and August, 1856. PMID- 30432152 TI - Cases in Surgery, with Remarks. PMID- 30432153 TI - On the Surgical Anatomy of the Subclavian Artery. PMID- 30432154 TI - On Excision of the Ankle-Joint. PMID- 30432156 TI - Cases of Traumatic Tetanus. PMID- 30432155 TI - Description of a Rare Abnormal Condition of the Elbow-Joint and Fore-Arm. PMID- 30432158 TI - Lithotomy. PMID- 30432157 TI - The Pathology and Treatment of Irritable Uterus. PMID- 30432159 TI - Case of Cerebral Affection. PMID- 30432161 TI - Excision of Joints. PMID- 30432160 TI - On Rupture of the Urinary Bladder into the Peritoneum; Being a Refutation of the Objections Urged by Dr. Eben Watson in the "Monthly Medical Journal" for 1849, and Subsequently in the "Glasgow Medical Journal" for 1859, against the Diagnosis of a Case of Recovery from That Lesion. PMID- 30432163 TI - Operations for Hernia. PMID- 30432162 TI - On the Medical Jurisprudence of Rape, with Especial Reference to What Constitutes "Penetration," as Applied to That Crime; Illustrated by Cases. PMID- 30432164 TI - Medical Intelligence. PMID- 30432165 TI - Ligature of Arteries. PMID- 30432166 TI - Excision of Tumours. PMID- 30432168 TI - Amputations. PMID- 30432167 TI - On Lithotomy Instruments. PMID- 30432169 TI - Reasons Why Sanatoria Should Be Established on the Clyde for the Sick Poor of Glasgow. PMID- 30432171 TI - Obstetric Cases. PMID- 30432170 TI - The Medico-Legal Evidence Adduced in a Case of Rape Perpetrated on a Girl under Seven Years of Age; with Remarks. PMID- 30432172 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432173 TI - Erratum. AB - [This corrects the article on p. 269 in vol. 7.]. PMID- 30432174 TI - Excision of Joints. PMID- 30432175 TI - Cases of Traumatic Tetanus. PMID- 30432177 TI - Operations for Hernia. PMID- 30432176 TI - Contributions to the Pathology and Therapeutics of Typhus Fever. PMID- 30432179 TI - Medical Intelligence. PMID- 30432178 TI - AEsophageal Fistula Communicating with the Exterior of the Right Side of the Chest through the Lung and Pleural Cavity. PMID- 30432180 TI - Excision of Tumours. PMID- 30432181 TI - Urethrotomy. PMID- 30432182 TI - Supra-Pubic Puncture of the Bladder. PMID- 30432183 TI - Ligature of Arteries. PMID- 30432184 TI - Plastic Operations. PMID- 30432185 TI - Death Registration-Small-Pox, Vaccination. PMID- 30432186 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432187 TI - Cases of Empyema. PMID- 30432188 TI - Remarks on Some Empirical Medicines and Modes of Treatment. PMID- 30432190 TI - Lithotomy. PMID- 30432191 TI - Obstetric Cases. PMID- 30432189 TI - On Laceration of the Perineum in Labour. PMID- 30432192 TI - On the Treatment of Delirium Tremens. PMID- 30432193 TI - Amputations. PMID- 30432194 TI - Miscellaneous Medical Cases. PMID- 30432196 TI - On the Treatment of Primary Syphilis. PMID- 30432195 TI - Selections from Medical Journals. PMID- 30432197 TI - Case of Idiopathic Tetanus. PMID- 30432198 TI - Observations on Strabismus, with the Description of a New Method of Operating. PMID- 30432199 TI - On Eustachian Catheterism, and the Natural Method of Introducing Medicated Vapours in the Eustachian Tube and Chamber of the Tympanum. PMID- 30432200 TI - Selections from Medical Journals. PMID- 30432201 TI - Case of Obstruction of the Bowels, Continuing during Five Days and a Half, Accompanied by Profuse Stercoraceous Vomiting, and Terminating Favourably; with Remarks. PMID- 30432202 TI - On the Comparative Value of Bloodletting and Purging in the Early Stage of the Acute Hydrocephalus; and on the Extent to Which Each of Them Should Be Carried. PMID- 30432203 TI - Medical Intelligence. PMID- 30432204 TI - Errata. AB - [This corrects the article on p. 342 in vol. 7.]. PMID- 30432205 TI - Statistics of Lithotomy. PMID- 30432206 TI - Notes of Practice-Treatment of Dental Decay. PMID- 30432207 TI - On Rupture of the Urinary Bladder; a Reply to Dr. James D. Gillespie of Edinburgh. PMID- 30432209 TI - Amputations. PMID- 30432208 TI - Selections from Medical Journals. PMID- 30432210 TI - The Case of the Bogota. PMID- 30432211 TI - Lithotomy. PMID- 30432212 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432213 TI - On the Relative Frequency of the Different Positions of the Child's Head at the Commencement of Labour. PMID- 30432214 TI - On Excision of the Knee-Joint. PMID- 30432215 TI - Gleanings from Dispensary Practice. PMID- 30432217 TI - Operations for Hernia. PMID- 30432216 TI - On the Late Accident by Lightning in the West-End Park, Glasgow, on the Afternoon of Sunday, 29th May, 1859. PMID- 30432218 TI - Plastic Operations. PMID- 30432219 TI - Cases of Traumatic Tetanus. PMID- 30432220 TI - Excision of Joints. PMID- 30432221 TI - On the Nature of the Syphilitic Poison, and the Way in Which It Acts. PMID- 30432222 TI - Miscellaneous Medical Cases. PMID- 30432223 TI - Medical Intelligence. PMID- 30432224 TI - Case of "Bright's Disease," in Which Permanent Recovery Took Place, the Results Being Verified by Dissection, the Patient Dying of Obstruction of the Bowels Eight Years Afterwards. PMID- 30432226 TI - Analecta. PMID- 30432225 TI - On the Medical Topography of Some Parts of Peru, Relative to Dysentery and Intermittent Fever. PMID- 30432227 TI - Report of the Albion Street Cholera Hospital. PMID- 30432229 TI - Remarks on Vaccination. PMID- 30432228 TI - On the Origin and Spread of Malignant Cholera in Glasgow and Its Neighbourhood. PMID- 30432230 TI - An Examination into the Etiology of Cholera, Founded on the Phenomena of the Disease, as Exhibited during Its Prevalence in Glasgow and Suburbs. PMID- 30432231 TI - On the Oil Called Palm Oil. PMID- 30432232 TI - Additional Evidence of the Efficacy of the Persesquinitrate of Iron in Curing Diarrhoea, with Cases Illustrating Its Power in Curing the Premonitory Diarrhoea of Cholera. PMID- 30432233 TI - Report of Diseases Treated at the Ayr Dispensary, from March 1831, to March, 1832. PMID- 30432234 TI - Erratum. AB - [This corrects the article on p. 186 in vol. 5.]. PMID- 30432235 TI - Report of the Epidemic Cholera, as It Appeared in the Town's Hospital of Glasgow, in February and March, 1832, with Cases and Observations. PMID- 30432236 TI - Case of Secondary Haemorrhage, in Which the External Iliac, Inguinal, and Femoral Arteries Were Tied; with Clinical Observations, Addressed to the Students Attending the Glasgow Royal Infirmary. PMID- 30432237 TI - Cases of Cholera Asphyxia, in Which the Strychnine Was Employed. PMID- 30432238 TI - Report of Diseases among the Poor of Glasgow, during the Winter Quarter of 1831 2. PMID- 30432239 TI - Address to the Readers of the Glasgow Medical Journal. PMID- 30432240 TI - Report of Diseases among the Poor of Glasgow, during the Months of August, September, and October, 1831. PMID- 30432241 TI - On Fever. PMID- 30432242 TI - The Dyspeptic's Monitor; or the Nature, Causes, and Cure of the Diseases Called Dyspepsia, Indigestion, Liver Complaint, Hypochondriasis, Melancholy, &c. PMID- 30432243 TI - On the Pharmaceutic Preparation and Therapeutic Properties of the Iodurets of Zinc, Lead and Mercury. PMID- 30432244 TI - Inquiry into the Etiology of Fevers, and Laws of the Propagation of Contagions. PMID- 30432245 TI - Reply to Mr. D. Bell's "Remarks on Dr. De Vitre's Case of Fungus Haematodes." PMID- 30432246 TI - Cases of Hydatids of the Uterus, Simulating Pregnancy. PMID- 30432247 TI - Analecta. PMID- 30432248 TI - On the Functions of the Human Kidney, in Relation to Its Principal Secretions. PMID- 30432249 TI - Observations, Pathological and Practical, in Medicine and Surgery; Including Reports of Cases, with Remarks: No. I. PMID- 30432250 TI - Remarks Suggested by the Glasgow Bills of Mortality: On the Mortality of Children in Glasgow. PMID- 30432251 TI - Second Report of the Albion Street Cholera Hospital. PMID- 30432252 TI - Report of Diseases among the Poor of Glasgow, during the Months of Feb., March, and April, 1832. PMID- 30432254 TI - Analecta. PMID- 30432253 TI - Hints Regarding the Utility of Tonic Treatment in Infantile Hydrocephalus. PMID- 30432255 TI - On the Efficacy of the Persesquinitrate of Iron, in Curing Diarrhoea. PMID- 30432256 TI - On the Origin and Spread of Malignant Cholera in Glasgow and Its Neighbourhood. PMID- 30432257 TI - Report of Diseases among the Poor of Glasgow, during the Months of May, June, and July, 1832. PMID- 30432259 TI - Medical Intelligence. PMID- 30432258 TI - Case of Disease of the Trachea, in Which the Operation for Tracheotomy Was Performed. PMID- 30432260 TI - Acute Cerebral Meningitis or Hydrocephalus. PMID- 30432261 TI - Selections from Medical Journals. PMID- 30432262 TI - A Case of Hydatids in the Uterus. PMID- 30432263 TI - Report of Cases Treated in the Medical Wards of the Glasgow Royal Infirmary, from 1st November, 1857, Till 1st May, 1858. PMID- 30432264 TI - General Observations on the Elimination, Catalysis, and Counteraction of Poisons. PMID- 30432265 TI - Case of Partial Facial Anaesthesia. PMID- 30432266 TI - Account of Some Trials Made to Facilitate the Removal of Stones from the Urinary Bladder-Extrusion with the Fingers-Landing-Net. PMID- 30432267 TI - On the Fever Which Prevailed in Malta during 1855-56. PMID- 30432268 TI - Remarks on a Case of Intestinal Concretion, with a Comparative Description and Analysis of Such Bodies in Man and in the Horse. PMID- 30432269 TI - On Sporadic and Epidemic Pemphigus. PMID- 30432270 TI - Case of Dislocation of the Knee Joint. PMID- 30432271 TI - Acute Cerebral Meningitis or Hydrocephalus. PMID- 30432273 TI - Mr. Syme's Title to Be Considered the Inventor of the Operation for Restoring the Lower Lip. PMID- 30432272 TI - Case of Vesico-Vaginal Fistula, Operated on by Dr. Bozeman, with His Button Suture. PMID- 30432274 TI - On the Advantages of Classification in Anatomy. PMID- 30432275 TI - Selections from Medical Journals. PMID- 30432276 TI - General Observations on the Elimination, Catalysis, and Counteraction of Poisons. PMID- 30432277 TI - Report of Cases Treated in the Medical Wards of the Glasgow Royal Infirmary, from 1st November, 1857, Till 1st May, 1858. PMID- 30432278 TI - Medical Intelligence. PMID- 30432279 TI - Selections from Medical Journals. PMID- 30432281 TI - On the Foetus in Utero, as Inoculating the Maternal with the Peculiarities of the Paternal Organism, &c. PMID- 30432280 TI - On Oiled Paper as a Substitute for Oiled Silk and Gutta Percha in Surgical Dressings. PMID- 30432282 TI - Chloroform. PMID- 30432283 TI - Clerical Quackery; Taylor's Specific Liniment. PMID- 30432284 TI - Medical Intelligence. PMID- 30432285 TI - Statistics and Observations on the Liability to Abortion. PMID- 30432286 TI - On a Method for Restoring the Lower Lip, after Complete or Partial Recision. PMID- 30432287 TI - Acute Cerebral Meningitis or Hydrocephalus. PMID- 30432288 TI - Cases of Idiopathic Erysipelas, with Remarks on the Olden and the Modern Treatment of the Disease. PMID- 30432289 TI - Plastic Surgery.-1. Operations for the Formation of a New Nose. PMID- 30432291 TI - Selections from Medical Journals. PMID- 30432290 TI - The French Military Transport Service. PMID- 30432292 TI - Case of Congenital Malformation and Abnormal Presentation. PMID- 30432294 TI - Medical Intelligence. PMID- 30432293 TI - Notice of the Case of Mons. E. Groux, in Which a Congenital Fissure of the Sternum Exposes Partially to Observation Some of the Movements of the Organs of Circulation. PMID- 30432295 TI - Excision of Joints. PMID- 30432296 TI - Lithotomy. PMID- 30432297 TI - Operation for Radical Cure of Hernia. PMID- 30432298 TI - Errata in Former Article. AB - [This corrects the article on p. 142 in vol. 8.]. PMID- 30432299 TI - Excision of Tumours. PMID- 30432300 TI - On Lead Amaurosis. PMID- 30432302 TI - Amputations. PMID- 30432301 TI - The Influence of the Variation of the Size of the Pupil on the Accommodating Power of the Eye. PMID- 30432303 TI - Operation for Rupture of Perineum. PMID- 30432304 TI - Medical Intelligence. PMID- 30432305 TI - Selections from Medical Journals. PMID- 30432306 TI - Operation for Strangulated Hernia. PMID- 30432307 TI - Contributions to the Pathology and Therapeutics of Typhus: No. IV. On the Identity of Typhus and Typhoid Fever. PMID- 30432309 TI - Lithotomy. PMID- 30432308 TI - On the Theory of the Ophthalmoscope. PMID- 30432310 TI - Excision of Joints. PMID- 30432311 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432313 TI - Case of Trephining of Skull. PMID- 30432312 TI - Excision of Tumours. PMID- 30432315 TI - Amputations. PMID- 30432314 TI - Statistics of the Glasgow University Lying-In Hospital, from 1st November, 1852, Till 1st January, 1860. PMID- 30432316 TI - Cases of Traumatic Tetanus. PMID- 30432318 TI - Medical Intelligence. PMID- 30432317 TI - Contributions to the Pathology and Therapeutics of Typhus: No. III. On the Identity of the Typhoid and Typhus Forms of Fever. PMID- 30432320 TI - Miscellaneous Medical and Surgical Cases. PMID- 30432319 TI - On the Value of the Sanguinaria Canadensis as a Remedial Agent. PMID- 30432321 TI - Selections from Medical Journals. PMID- 30432322 TI - On the Theory of the Ophthalmoscope. PMID- 30432323 TI - Excision of Tumours. PMID- 30432324 TI - Operation for Recto-Vaginal Fistula. PMID- 30432325 TI - Chemical Examination of a Urinary Calculus. PMID- 30432327 TI - Amputations. PMID- 30432326 TI - On the Employment of Oiled Paper in Place of Oiled Silk and Gutta Percha in Surgical Dressings. PMID- 30432329 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432328 TI - On the Method of Detecting the Presence and Estimating the Quantity of Sugar in Diabetic Urine, by Means of Concentrated Sulphuric Acid. PMID- 30432330 TI - Lithotomy. PMID- 30432331 TI - Cases of Empyema. PMID- 30432332 TI - Medical Intelligence. PMID- 30432334 TI - Miscellaneous Medical and Surgical Cases. PMID- 30432333 TI - On the Short-Sight (?) of Squinters. PMID- 30432335 TI - Successful Case of Transfusion. PMID- 30432336 TI - Selections from Medical Journals. PMID- 30432337 TI - Excision of Joints. PMID- 30432338 TI - On Lithotomy Considered as a Cause of Death, with Remarks on the Present State of the Operation Usually Called the "Rectangular Operation for Stone;" and on the Best Method of Extending the Ordinary Incisions in That Operation, for the Purpose of Extracting Stones of Unusually Large Size. PMID- 30432339 TI - Facial Neuralgia. PMID- 30432340 TI - Contributions to the Pathology and Therapeutics of Typhus: No. II. Lesions of the Intestinal Mucous Membrane. PMID- 30432341 TI - Notes of Surgical Practice. PMID- 30432342 TI - Excision of Tumours. PMID- 30432343 TI - A Roundabout Paper. PMID- 30432344 TI - Operation for Strangulated Hernia. PMID- 30432345 TI - Miscellaneous Medical and Surgical Cases. PMID- 30432346 TI - Remarks on the Site and Construction of Hospitals, with Reference to the New Surgical Hospital of the Glasgow Royal Infirmary. PMID- 30432347 TI - Selections from Medical Journals. PMID- 30432348 TI - Cases of Operation for Vesico-Vaginal Fistula. PMID- 30432350 TI - Excision of Joints. PMID- 30432349 TI - Contributions to the Pathology and Therapeutics of Typhus: No. V. On the Treatment of the Intestinal Lesions. PMID- 30432351 TI - Miscellaneous Medical and Surgical Cases. PMID- 30432352 TI - Tracheotomy. PMID- 30432353 TI - Cases of Traumatic Tetanus. PMID- 30432354 TI - Operations for Aneurism. PMID- 30432355 TI - Lithotomy. PMID- 30432356 TI - Medical Intelligence. PMID- 30432357 TI - Amputations. PMID- 30432358 TI - Two Cases of Concealed Accidental Haemorrhage at the Full Term of Utero Gestation. PMID- 30432359 TI - The Social Position of the Profession. PMID- 30432360 TI - Medical Intelligence. PMID- 30432361 TI - Illustrations of Puerperal Diseases. PMID- 30432362 TI - On the Treatment of Chronic Swelling of the Bursa Patellae, by Puncture and the Injection of a Solution of Iodine. PMID- 30432363 TI - Case of Renal Injury. PMID- 30432364 TI - Successful Case of Tracheotomy in Croup, and Other Surgical Cases in Private and Hospital Practice. PMID- 30432366 TI - Anomalous Case of Convulsions. PMID- 30432365 TI - Selections from Medical Journals. PMID- 30432367 TI - Cases Illustrative of Diseases of the Ear: No. I. PMID- 30432368 TI - On Infantile Death Rates, in Their Bearing on Sanitary and Social Science. PMID- 30432369 TI - Contributions to the Pathology and Therapeutics of Typhus Fever: No. VI. PMID- 30432370 TI - Cases of Purulent Deposit in the Urine. PMID- 30432372 TI - Selections from Medical Journals. PMID- 30432371 TI - Description of a French Instrument for Effecting Reduction or Reposition of the Umbilical Funis When Prolapsed, with Cases Illustrative of Its Successful Application. PMID- 30432373 TI - Illustrations of Puerperal Diseases. PMID- 30432374 TI - Medical Intelligence. PMID- 30432375 TI - Letter from Dr. Bell to Dr. Murchison. PMID- 30432377 TI - Cases of Induration of the Brain. PMID- 30432376 TI - On Spinal Irritation. PMID- 30432378 TI - On the Laws of the Mutual Interpenetration of Fluids: No. II. PMID- 30432379 TI - Report of a Case of Rupture of the Uterus in the Fourth Month of Utero-Gestation. PMID- 30432380 TI - Cases of Vesico-Uterine Fistula, with an Analysis of a Calculus Found in the Os Uteri. PMID- 30432381 TI - Illustrations of Puerperal Diseases. PMID- 30432382 TI - Selections from Medical Journals. PMID- 30432383 TI - Medical Intelligence. PMID- 30432384 TI - On the Laws of the Mutual Interpenetration of Fluids: No. 1. PMID- 30432385 TI - Cases of Excision of Bursae. PMID- 30432386 TI - Medical Intelligence. PMID- 30432387 TI - Case of Double Renal Abscess. PMID- 30432388 TI - On the Prevention of Pitting in Small Pox, by the Application of the Linamentum Aquae Calcis and Cotton Wool. PMID- 30432389 TI - Observations on Placenta Praevia. PMID- 30432390 TI - Some Observations on the Sensibility of the Eye to Colour. PMID- 30432391 TI - How Is Syphilitic (or Specific) to Be Distinguished from Non-Syphilitic (or Non Specific) Psoriasis? PMID- 30432392 TI - Errata in April Number. AB - [This corrects the article on p. 1 in vol. 9.]. PMID- 30432393 TI - Illustrations of Puerperal Diseases. PMID- 30432394 TI - Report on a Species of Palsy, Prevalent in Part of the District of Allahabad, from the Use of Lathyrus Sativus or Kessaree Dal, as an Article of Food. PMID- 30432395 TI - Selections from Medical Journals. PMID- 30432396 TI - Ovarian Extirpations. The 109th and 110th Cases, and 75th and 76th Successful Operations. PMID- 30432397 TI - Medical Intelligence. PMID- 30432398 TI - Medical Musings. PMID- 30432399 TI - Selections from Medical Journals. PMID- 30432400 TI - Cases Illustrative of Diseases of the Ear: No. IX. Case of Injury to the Internal Ear from the Report of a Cannon, Followed by Paralysis of the Portio Dura Nerve. PMID- 30432401 TI - Observations on Uterine Tumours. PMID- 30432402 TI - On Suicidal Impulse. PMID- 30432403 TI - Notes on Some Forms of Skin Diseases: Psoriasis and Lepra. PMID- 30432404 TI - Extemporaneous Remarks on Surgical Cases in the Royal Infirmary. PMID- 30432405 TI - Case of Spontaneous Inversion of the Uterus. PMID- 30432407 TI - Medical Intelligence. PMID- 30432406 TI - Case of Spontaneous Inversion of the Uterus Occurring Immediately after Delivery. PMID- 30432408 TI - Selections from Medical Journals. PMID- 30432409 TI - On Some Points in the Clinical History of Empyema and Pneumothorax; Including Observations on the Use of Thoracentesis in the Latter Form of Disease. PMID- 30432411 TI - Medical Intelligence. PMID- 30432410 TI - On the Management of the Placenta in Natural Labour. PMID- 30432412 TI - Obstetrical Reports. PMID- 30432413 TI - On the Successful Treatment for Common Tape-Worm (Taenia Solium). PMID- 30432414 TI - Case of Aortic Aneurism with a Spontaneously Curative Tendency, &c., with Remarks. PMID- 30432415 TI - On Two New Specific Remedies for Gonorrhoea. PMID- 30432416 TI - Selections from Medical Journals. PMID- 30432417 TI - On Two Suggestive Cases of Infantile Syphilis. PMID- 30432418 TI - Notes on Some Forms of Skin Diseases: Part II. Psoriasis and Lepra. PMID- 30432420 TI - Selections from Medical Journals. PMID- 30432419 TI - Notes on Some Points in the Treatment Following Severe Labour. PMID- 30432421 TI - Observations in Clinical Medicine.-Two Cases of Aneurism of the Descending Thoracic Aorta. PMID- 30432422 TI - On Tracheotomy in Diphtheria. PMID- 30432423 TI - Notes on Some Forms of Skin Diseases: Psoriasis. PMID- 30432425 TI - Medical Intelligence. PMID- 30432424 TI - Two Months of Fever Duty in the Glasgow Royal Infirmary. PMID- 30432426 TI - Case of Superfoetation. PMID- 30432427 TI - Observations on the Present Epidemic of Typhus. PMID- 30432428 TI - Case of Hernia of the Stomach, into the Left Side of the Thorax. PMID- 30432429 TI - Case of Ovariotomy-Recovery. PMID- 30432430 TI - Case of Tetanus. PMID- 30432431 TI - Tracheotomy in Croup and Diphtheria. PMID- 30432433 TI - Medical Intelligence. PMID- 30432432 TI - A Case of Supposed Embolism, with a Remarkable Succession of Symptoms. PMID- 30432434 TI - Selections from Medical Journals. PMID- 30432436 TI - The Townley Case. PMID- 30432435 TI - Notes of Sixty Cases of Continued Fever Treated in the Temporary Fever Hospital, Bristol, between the Months of January and June, 1865. PMID- 30432437 TI - Selections from Medical Journals. PMID- 30432438 TI - Cases Illustrative of Diseases of the Ear: No. VIII. A Short Sketch of the Principal Forms of Obstruction of the Eustachian Tubes, Including a Description of Politzer's New Method of Treatment. PMID- 30432439 TI - Case of Malignant Fibre-Cellular Tumour Involving the Ileum. PMID- 30432440 TI - Notes on Cases of Injury to the Skull and Its Contents. PMID- 30432441 TI - On the Gastric Juice. PMID- 30432442 TI - Extra-Academical Medical Education. PMID- 30432444 TI - Medical Intelligence. PMID- 30432443 TI - Fifty Aphorisms in Respect of Tissue Metamorphosis, as Illustrating the Production of Tubercle. PMID- 30432445 TI - Statistical Report of Five Thousand Cases of Obstetricy. PMID- 30432446 TI - Two Cases of Uterine Tumour, More or Less Simulating Ovarian Disease; with Remarks on the Diagnosis, and on a Remarkable Action of Ergot of Rye. PMID- 30432447 TI - Case of Epilepsy. PMID- 30432448 TI - Medical Intelligence. PMID- 30432449 TI - A Case of Manioc Poisoning. PMID- 30432450 TI - Successful Case of Ovariotomy. PMID- 30432452 TI - Selections from Medical Journals. PMID- 30432451 TI - Analysis of Three Hundred Cases of Typhus. PMID- 30432453 TI - Case of Excision of Hip Joint in Paisley Infirmary: Under the Care of Dr. M'Kinlay. PMID- 30432454 TI - Notes on Some Forms of Skin Diseases: No. I. Syphilitic Pemphigus in the Adult-Is There Such a Disease? PMID- 30432455 TI - Surgical Notes: On the Restoration to Life of the Apparently Drowned. PMID- 30432456 TI - Selections from Medical Journals. PMID- 30432457 TI - Medical Intelligence. PMID- 30432458 TI - Two Cases of Uterine Hydatids. PMID- 30432459 TI - On Four Cases of Syphilis, with Remarks. PMID- 30432460 TI - Case of Fracture of the Cranium. PMID- 30432461 TI - The Use of the Hypophosphites of Lime, Soda, and Potash, in Remittent Fever, Tabes Mesenterica, and Gastric Irritation of Children, with Illustrative Cases. PMID- 30432462 TI - Cases Illustrative of Diseases of the Ear: No. IX. PMID- 30432463 TI - On the Detection of Aconite by Its Physiological Action: Being Notes of Experiments Made in Connection with the Trial of Dr. E. W. Pritchard. PMID- 30432464 TI - Four Hitherto Unpublished Cases of Inversion of the Uterus Occurring in Consulting Practice of the Late Dr. James Wilson, Glasgow. PMID- 30432465 TI - On the Treatment of Zymotic Diseases by the Alkaline Sulphites. PMID- 30432466 TI - Obstetric Cases and Observations. PMID- 30432467 TI - Report on a Case of Unusual Hernia. PMID- 30432468 TI - Case of Abdominal Tumour. PMID- 30432469 TI - Treatment of Anchylosis of the Elbow-Joint. PMID- 30432471 TI - Selections from Medical Journals. PMID- 30432470 TI - Notes on Fractures. PMID- 30432472 TI - On the Use of So-Called Expectorants in Diseases of the Mucous Membrane of the Lungs, Being Remarks Suggested by Professor Gairdner's Recent Article "on the Action of Expectorant Remedies." PMID- 30432473 TI - The Army Medical Department. PMID- 30432474 TI - Cases Illustrative of Diseases of the Ear: No. VII. Diseases of the Ceruminous Glands. PMID- 30432475 TI - Medical Intelligence. PMID- 30432476 TI - On the Mechanism of Parturition. PMID- 30432477 TI - Case of Ovariotomy. PMID- 30432478 TI - Notes from Practice. PMID- 30432480 TI - Medical Intelligence. PMID- 30432479 TI - Cases Illustrative of Diseases of the Ear: No. VI. Acute and Sub-Acute Suppurative Inflammation of the Cavity of the Tympanum. PMID- 30432481 TI - The Sanitary and Remedial Applications of Bathing, with Remarks on Our Scottish Spas. PMID- 30432482 TI - Notes on Puerperal Convulsions. PMID- 30432483 TI - An Account of the Medical Evidence Connected with the Trial of Jessie M'Lauchlan, at the Glasgow Autumn Circuit, 1862. PMID- 30432484 TI - Selections from Medical Journals. PMID- 30432485 TI - Description of the Dissection of a Case of Right Aortic Arch, with Remarks on This and Allied Malformations. PMID- 30432486 TI - Latent Pleuro-Pneumonia and Sudden Death. PMID- 30432487 TI - Description of Two Tumours Adherent to the Deep Surface of the Dura Mater. PMID- 30432489 TI - Selections from Medical Journals. PMID- 30432488 TI - On the Mechanism of Parturition. PMID- 30432490 TI - Cases of Diphtheria. PMID- 30432491 TI - A Case of Chronic Pemphigus. PMID- 30432492 TI - Mind and Matter. The Influence of Mental Impressions on the Foetus in Utero. PMID- 30432493 TI - On the Action of Expectorant Remedies. PMID- 30432494 TI - Case of Compound Comminuted Fracture of the Skull, with Wound of the Dura Mater and Brain, Followed by Fungus Cerebri; with Ultimate Recovery. PMID- 30432495 TI - Medical Intelligence. PMID- 30432497 TI - Experience and Treatment of Diphtheria in Campbelton and Neighbourhood. PMID- 30432496 TI - On Tracheotomy in Croup and Diphtheria, with Cases. PMID- 30432498 TI - Certain Abuses of Caustics. PMID- 30432500 TI - Report of Two Cases of Inversio Uteri, with Remarks. PMID- 30432499 TI - Cases of Tracheotomy in Croup and Diphtheria. PMID- 30432501 TI - Selections from Medical Journals. PMID- 30432502 TI - Medical Intelligence. PMID- 30432503 TI - Case of Death from Placenta Praevia. PMID- 30432504 TI - On the Mechanism of Parturition. PMID- 30432505 TI - On Loss and Regeneration of Tissue, Particularly Skin. PMID- 30432507 TI - Case of Perforation of the Stomach, with Remarks. PMID- 30432506 TI - Traumatic Femoral Aneurism-Treated by Pressure; Afterwards by Ligature-Cure. PMID- 30432508 TI - Selections from Medical Journals. PMID- 30432509 TI - Cases Illustrative of Diseases of the Ear: No. II. PMID- 30432510 TI - Specialism and Special Hospitals. PMID- 30432511 TI - Practical Remarks on the Diagnosis and Treatment of Rheumatic Pericarditis and Endocarditis. PMID- 30432512 TI - Medical Intelligence. PMID- 30432513 TI - Notes of a Case of Malignant Disease. PMID- 30432515 TI - Practical Remarks on the Diagnosis and Treatment of Rheumatic Pericarditis and Endocarditis. PMID- 30432514 TI - Case of Malignant Disease of the Abdomen. PMID- 30432516 TI - On Diabetes. PMID- 30432517 TI - The Treatment of Varicose Veins by a New and Simple Instrument. PMID- 30432518 TI - Notes on Diphtheria. PMID- 30432519 TI - The Veratrum Viride. PMID- 30432521 TI - Medical Intelligence. PMID- 30432520 TI - Cases Illustrative of Diseases of the Ear: No. III. Foreign Bodies in the Meatus. PMID- 30432522 TI - Case of Puerperal Pyemia. PMID- 30432524 TI - Selections from Medical Journals. PMID- 30432523 TI - On the Use of Aperients after Labour. PMID- 30432525 TI - Medical Intelligence. PMID- 30432526 TI - Case of Separation of the Foetal Head. PMID- 30432527 TI - Analysis of One Thousand Cases of Labour, Occurring in Private Practice. PMID- 30432528 TI - Cases Illustrative of Diseases of the Ear: No. IV. Polypi. PMID- 30432529 TI - Two Cases Illustrating the Advantages of Turning as a Substitute for Craniotomy. PMID- 30432531 TI - Selections from Medical Journals. PMID- 30432530 TI - Surgical Cases. PMID- 30432532 TI - Chronic Diarrhoea. PMID- 30432533 TI - On the Dried Stem of Sea Tangle (Laminaria Digitata) as a Substitute for the Tents in Ordinary Use. PMID- 30432534 TI - On Mechanical Appliances in Fractures of the Lower Extremity, with a Description of a New One. PMID- 30432535 TI - Case of Suppuration of the Pancreas and Liver. PMID- 30432537 TI - Cases of Craniotomy. PMID- 30432536 TI - Views, Ancient and Modern, on the Origin of Species. PMID- 30432538 TI - Selections from Medical Journals. PMID- 30432539 TI - Case of Acute Phthisis, with Remarks. PMID- 30432540 TI - Hare-Lip. PMID- 30432541 TI - Notes of Twenty Cases of Poisoning. PMID- 30432542 TI - Case of Poisoning by Measly Pork. PMID- 30432543 TI - Case of Acute Phthisis, Complicated with Extensive Emphysema. PMID- 30432545 TI - Cases Illustrative of Diseases of the Ear: No. V. Crescentic Opacity of the Membrana Tympani. PMID- 30432544 TI - On Sea-Sickness. PMID- 30432546 TI - Medical Intelligence. PMID- 30432547 TI - A Roundabout Paper. PMID- 30432548 TI - Lithotomy and Lithotrity. PMID- 30432550 TI - Medico-Chirurgical Society. PMID- 30432549 TI - On Diseases of the Eye. PMID- 30432552 TI - Clinical Surgical Report. PMID- 30432551 TI - Errata. AB - [This corrects the article on p. 386 in vol. 1.]. PMID- 30432553 TI - Notes on Acupressure. PMID- 30432554 TI - Transverse Presentation. PMID- 30432555 TI - Medical Intelligence. PMID- 30432556 TI - Diseases Peculiar to Deaf-And-Dumb. PMID- 30432557 TI - Medical Intelligence. PMID- 30432558 TI - On Rupture of Uterus and Vagina. PMID- 30432559 TI - On Retention of the Placenta. PMID- 30432560 TI - On Deaf-Mutism. PMID- 30432561 TI - Clinical Notes. PMID- 30432562 TI - Case of Hydatids of the Uterus. PMID- 30432563 TI - Treatment of Stricture of the Urethra. PMID- 30432564 TI - Development of Generative System. PMID- 30432566 TI - Case of Intus-Susception in an Infant. PMID- 30432565 TI - Case of Villous Excrescence. PMID- 30432567 TI - Glasgow Medico-Chirurgical Society. PMID- 30432569 TI - Medical Intelligence. PMID- 30432568 TI - Cases of Abscess in the Hepatic Region. PMID- 30432571 TI - Case of Abscess of Thoracic Parietes. PMID- 30432570 TI - Development of the Generative System. PMID- 30432572 TI - Glasgow Medico-Chirurgical Society. PMID- 30432573 TI - Case of Adeno-Cystic Tumours of the Axilla. PMID- 30432574 TI - Spontaneous Rupture of the Uterus during Labour. PMID- 30432576 TI - Glasgow Medico-Chirurgical Society. PMID- 30432575 TI - Remarks on the Pathology and Treatment of the Advanced Stage of Croup. PMID- 30432577 TI - On the Normal Temperature of the Body in Infancy and Childhood. PMID- 30432578 TI - Medical Intelligence. PMID- 30432579 TI - Recent Cases of Cholera at Ibrox. PMID- 30432580 TI - On the Harrogate Mineral Waters. PMID- 30432581 TI - Medical Intelligence. PMID- 30432582 TI - Cases of Abscess in the Abdominal Region. PMID- 30432583 TI - Case of Hydatids of Heart and Lungs. PMID- 30432584 TI - Glasgow Medico-Chirurgical Society. PMID- 30432585 TI - Case of Aphasia. PMID- 30432586 TI - On Anthracosis. PMID- 30432587 TI - Case of Strangulated Femoral Hernia. PMID- 30432588 TI - Congenital Goitre. PMID- 30432589 TI - Preventibility of Cholera. PMID- 30432591 TI - Preparations Made against Epidemic Cholera, in Glasgow. PMID- 30432590 TI - On Diabetes Mellitus. PMID- 30432592 TI - Medical Intelligence. PMID- 30432593 TI - Glasgow Medico-Chirurgical Society. PMID- 30432594 TI - On Lithotrity. PMID- 30432595 TI - Instructions on Disinfection in Choleraic Diseases. PMID- 30432596 TI - On Wounds of Joints. PMID- 30432597 TI - Cases of Obstruction of the Bowels. PMID- 30432598 TI - Medical Intelligence. PMID- 30432599 TI - On the Treatment of Acute Rheumatism by Blistering. PMID- 30432600 TI - Suggestions for the Logical Use of Hospital Statistics. PMID- 30432601 TI - Case of Poisoning by External Use of Belladonna. PMID- 30432603 TI - Glasgow Medico-Chirurgical Society. PMID- 30432602 TI - On Prolapse of the Umbilical Cord. PMID- 30432604 TI - Remarks on Alcohol. PMID- 30432606 TI - Clinical Notes. PMID- 30432605 TI - Introductory Address at the Public Opening of the Medical Session, 1866-67. PMID- 30432607 TI - Medical Intelligence. PMID- 30432608 TI - Errata in Last Number. AB - [This corrects the article on p. 111 in vol. 1.]. PMID- 30432609 TI - Glasgow Lying-In Hospital. PMID- 30432610 TI - Case of Rupture of the Liver. PMID- 30432611 TI - Medical Intelligence. PMID- 30432612 TI - Glasgow Medico-Chirurgical Society. PMID- 30432613 TI - Case of Quadruple Birth. PMID- 30432614 TI - Cases of Sciatica. PMID- 30432615 TI - Case of Injury to Left Kidney. PMID- 30432616 TI - Successful Case of Ovariotomy. PMID- 30432617 TI - Observations on Brain Softening, &c. PMID- 30432618 TI - Clinical Surgical Report. PMID- 30432619 TI - Glasgow Medico-Chirurgical Society. PMID- 30432620 TI - Cases of Pericarditis. PMID- 30432622 TI - Army Medical Department. PMID- 30432621 TI - Case of Mercurial Tremor. PMID- 30432623 TI - On Anthracosis. PMID- 30432625 TI - Cases of Typhus Fatal with Rare Complications. PMID- 30432624 TI - Case of Aphasia. PMID- 30432626 TI - Medical Intelligence, &c. PMID- 30432627 TI - Note on Disinfection with Carbolic Acid Vapour. PMID- 30432628 TI - A Visit to Some of the German Spas: Aix-La-Chapelle. PMID- 30432629 TI - Transactions of the Medico-Chirurgical Society. Session 1868-9. PMID- 30432630 TI - Cases of Primary Cancer of the Brain. PMID- 30432631 TI - On Emboli, and Cardiac Coagula. PMID- 30432632 TI - Case of Pyelitis and Pyonephrosis. PMID- 30432633 TI - Case of Thoracic Abscess Treated with Carbolic Acid. PMID- 30432635 TI - On the Excretion of Creatinine and Uric Acid in a Case of Diabetes Mellitus Fatal with Febrile Symptoms. PMID- 30432634 TI - On Stricture of the Internal Os as a Cause of Miscarriage. PMID- 30432636 TI - Two Cases of Tubercular Meningitis in the Adult, with Rather Remarkable Absence of Some of the Symptoms Commonly Regarded as Characteristic. PMID- 30432638 TI - Abstract of Prof. Allen Thomson's Paper on "the Ossification of the First and Other Metacarpal and Metatarsal Bones," in the Journal of Anatomy and Physiology. (Nov. 1868.). PMID- 30432637 TI - Two Cases of Congenital Malformation of the Eye. PMID- 30432639 TI - Encephaloid Tumour of the Lower Jaw. PMID- 30432640 TI - Cases of Intraocular Hemorrhage. PMID- 30432641 TI - On the Normal Temperature in Children. PMID- 30432643 TI - Memoir of Dr William Mackenzie. PMID- 30432642 TI - On the Induction of Premature Labour. PMID- 30432645 TI - The Calabar Bean in Acute Traumatic Tetanus and Strychnia Poisoning. PMID- 30432644 TI - Cases of Excision of the Elbow. PMID- 30432646 TI - Case of Unusually Large Loose Cartilage in the Knee-Joint, Treated on the Antiseptic System. PMID- 30432647 TI - On the Distribution of Enteric Fever in Glasgow. PMID- 30432648 TI - On the Aggravation of Uterine Disease Arising from Fissure of the Anus. PMID- 30432650 TI - Two Cases of Compound Fracture of the Leg, Treated Successfully upon the Antiseptic Principle. PMID- 30432649 TI - An Improvement upon Politzer's Method of Injecting Air into the Eustachian Tubes in Certain Cases of Deafness. PMID- 30432651 TI - Hydrocyanic Acid Physiologically Investigated. PMID- 30432653 TI - Introductory. PMID- 30432652 TI - On the Limits of Alcoholic Stimulation in Acute Disease. PMID- 30432655 TI - Medical Intelligence, &c. PMID- 30432654 TI - Cases of Amputation of the Foot. PMID- 30432657 TI - Transactions of the Medico-Chirurgical Society. Session 1868-9. PMID- 30432656 TI - Case of Poisoning by Arsenic, Externally Applied. PMID- 30432658 TI - Erratum. AB - [This corrects the article on p. 305 in vol. 1.]. PMID- 30432660 TI - A Visit to Some of the German Spas: Carlsbad. PMID- 30432659 TI - Two Cases of Diphtheric Paralysis, with Remarks. PMID- 30432661 TI - Peculiar Case of Haematemesis. PMID- 30432662 TI - Notes of a Visit to Canadian Asylums. PMID- 30432663 TI - On the Excretion of Urea in Typhus, in Relation to the Temperature. PMID- 30432664 TI - Angina Pectoris, Relieved by Nitrite of Amyl. PMID- 30432665 TI - Cases of Ovariotomy. PMID- 30432666 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from November 1st, 1868, to April 30th, 1869. PMID- 30432667 TI - Medical Intelligence, &c. PMID- 30432668 TI - Notes of a Scarlet Fever Epidemic. PMID- 30432669 TI - Case of Typhus, Fatal from Intestinal Haemorrhage. PMID- 30432670 TI - Note on the Curative Tapping of Ovarian Dropsy. PMID- 30432671 TI - Cases of Skin Disease. PMID- 30432672 TI - Alopecia Areata. PMID- 30432673 TI - A Visit to Some of the German Spas: Teplitz. PMID- 30432674 TI - On the Combination of Chloroform with Opiates for the Relief of Pain. PMID- 30432676 TI - Physiological Action of Picrotoxin. PMID- 30432675 TI - Clinical Surgical Report. PMID- 30432677 TI - Cases of Excision of the Wrist and Knee Joints. PMID- 30432679 TI - Medical Intelligence, &c. PMID- 30432678 TI - Calabar Bean in Tetanus. PMID- 30432681 TI - Transactions of the Medico-Chirurgical Society. Session 1868-69. PMID- 30432680 TI - On the Value of the Nitrate of Lead in the Treatment of Sore Nipples. PMID- 30432682 TI - Case of Encephaloid Tumour Attached to the Nates of a Newly-Born Infant. PMID- 30432683 TI - Cases of Nasal Diphtheria. PMID- 30432684 TI - Notes on the Dermatophytae. PMID- 30432686 TI - Vesico-Vaginal Fistula-Two Years Duration-One Operation-Cure. PMID- 30432685 TI - Post-Pharyngeal Abscess-Sloughing, with Rupture of the Internal Carotid. PMID- 30432687 TI - On the Cooling of Dead Bodies as Indicating the Length of Time That Has Elapsed Since Death. PMID- 30432688 TI - Some Remarks on the Diagnosis and Treatment of Syphilitic Waxy Degeneration of the Liver. PMID- 30432690 TI - Clinical Notes on Epithelioma. PMID- 30432689 TI - Remarks on the Treatment of Some Varieties of Inflammation. PMID- 30432692 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary during the Six Months Ending December 31st, 1870. PMID- 30432691 TI - Remarks on Relapsing Fever. PMID- 30432693 TI - Post Febrile Ophthalmia. PMID- 30432694 TI - Medico-Chirurgical Society-Session 1870-71. PMID- 30432695 TI - On Revaccination. PMID- 30432696 TI - Clinical Surgical Report for the Year 1870. PMID- 30432698 TI - Medical Intelligence, &c. PMID- 30432697 TI - Remarks on Skin-Grafting, with Cases. PMID- 30432700 TI - Case of Acute General Tuberculosis of Twenty-Four Days' Duration. PMID- 30432699 TI - Fibro-Cellular Tumour of the Labium Pudendi. PMID- 30432701 TI - Medico-Chirurgical Society-Session 1870-71. PMID- 30432702 TI - On Ulceration of the Fraenum Linguae in Pertussis. PMID- 30432703 TI - Remarkable Lobulated Tumour of Labium. PMID- 30432704 TI - An Insurance Incident. PMID- 30432705 TI - Case of Soft Cancer of Right Kidney, Cancerous Coagula in Heart, Pulmonary Embolism. &c. PMID- 30432706 TI - Note on the Tendency of Sponges to Excite Suppuration in Wounds. PMID- 30432707 TI - On the Medical Treatment of Diphtheria. PMID- 30432708 TI - On Sub-Glottic OEdema of the Larynx and Permanent Stricture, Following Typhus. PMID- 30432709 TI - Contribution on Goitre from the Forest of Dean. PMID- 30432710 TI - Observations on Aphasia, with Cases. PMID- 30432711 TI - An Analysis of 143 Cases of Poisoning with Strychnia, with Remarks on Its Mode of Action, and Detection, and Experiments on an Antidote. PMID- 30432712 TI - Two Cases of Strangulated Hernia Operated on and Treated Antiseptically. PMID- 30432713 TI - Clinical Surgical Report for 1870. PMID- 30432715 TI - Case of Soft Sarcoma of the Cerebellum. PMID- 30432714 TI - Experiments on the Action of Red Bordeaux Wine (Claret) on the Human Body. PMID- 30432716 TI - Anomalous Case of Pyaemia without External Wound. PMID- 30432718 TI - A Case of Lead Colic. PMID- 30432717 TI - On the Treatment of Carbuncle. PMID- 30432719 TI - Two Cases of Vaginismus Relieved by Operation. PMID- 30432720 TI - Case of Extravasation of Urine. Recovery. PMID- 30432721 TI - A Case of Cancer of the Bodies of the Vertebrae Causing Spontaneous Fracture with Resulting Affection of the Spinal Cord. PMID- 30432722 TI - Case of Popliteal Aneurism Cured by Compression. PMID- 30432723 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from Jan. 1st to June 30th, 1870. PMID- 30432724 TI - Case of Poisoning with Oxalic Acid. PMID- 30432725 TI - Vertical Dislocation of the Patella. PMID- 30432726 TI - On Bromal Hydrate. PMID- 30432727 TI - Case of Pyogenic Fever (Jenner). PMID- 30432728 TI - Ovariotomy. PMID- 30432729 TI - Medico-Chirurgical Society-Session 1870-71. PMID- 30432731 TI - Medical Intelligence, &c. PMID- 30432730 TI - Case of Fibrous Polypus of the Uterus. PMID- 30432732 TI - Case of Accidental Poisoning with Carbolic Acid, Causing Double Pneumonia and Death. PMID- 30432733 TI - On an Abscess of the Hip Joint Treated Antiseptically. PMID- 30432734 TI - Note on Dr Barnes' Midwifery Forceps. PMID- 30432735 TI - Medical Intelligence, &c. PMID- 30432736 TI - Case of Pyaemia without External Wound. PMID- 30432737 TI - Case of Strychnia-Poisoning, and Recovery under Treatment with Calabar Bean and Chloroform. PMID- 30432738 TI - Case of Post-Febrile Insanity, Complicated with Hysteria, Cured by Cold Baths. PMID- 30432739 TI - Compound Fractures Treated in the Glasgow Royal Infirmary. PMID- 30432741 TI - Partial Displacement of the Head of the Radius in Children. PMID- 30432740 TI - Remarks on the Pathology of Dr Fraser's Case of Mollities Ossium. PMID- 30432743 TI - Medico-Chirurgical Society-Session 1870-71. PMID- 30432742 TI - On a Case of Addison's Disease. PMID- 30432744 TI - On Two Cases of Poisoning by Aconite. PMID- 30432745 TI - Case of Omental Hernia in an Unusual Situation. PMID- 30432746 TI - Case of Acute Glanders in Man. PMID- 30432747 TI - Suggestion as to the Treatment of Haemorrhagic Small-Pox. PMID- 30432748 TI - On Hospital Gangrene. PMID- 30432749 TI - Tetany. PMID- 30432750 TI - Case of Fibroid Polypus of the Uterus: Removed by Twisting the Pedicle. PMID- 30432752 TI - Case of Mollities Ossium. PMID- 30432751 TI - Clinical Memoranda-No. 1, Case of Aphasia with Right Hemiplegia, Terminating in Recovery. PMID- 30432753 TI - On Certain Risks Attending the Use of Bromide of Potassium. PMID- 30432754 TI - On Putrefiers and Antiseptics. PMID- 30432755 TI - Ligature of the Femoral Artery at the Apex of Scarpa's Triangle, on the "Antiseptic" System, for the Cure of Popliteal Aneurism. PMID- 30432756 TI - Case of Poisoning from Carbolic Acid. PMID- 30432757 TI - Note on the Introduction of the Tube of the Stomach Pump and Nasal Tubes. PMID- 30432758 TI - On the Use of Carbolic Acid as a Counter-Irritant. PMID- 30432759 TI - Clinical Surgical Report for the Year Ending 31st October, 1872. PMID- 30432760 TI - Retrospect of French Medico-Psychological Literature, with Observations on General Paralysis. PMID- 30432761 TI - Notes of Five Weeks' Surgery in the Royal Infirmary, with Remarks on Antiseptic Treatment. PMID- 30432762 TI - Case of Lymphatic Leucocythaemia. PMID- 30432763 TI - Cases from Dr Scott Orr's Clinique. PMID- 30432764 TI - The Southern Medical Society-Session 1872-73. PMID- 30432765 TI - On Conjunctival Transplantation from the Rabbit. PMID- 30432766 TI - On the Treatment of Chronic Exanthemal Katarrh of the Tympanum. PMID- 30432767 TI - Medical Intelligence, &c. PMID- 30432768 TI - Successful Case of Transfusion. PMID- 30432769 TI - Medico-Chirurgical Society-Session 1872-73. PMID- 30432771 TI - Cases from Dr Robert Perry's Clinique. PMID- 30432770 TI - On the Relationship of Abscess of the Liver to Gastro-Intestinal Ulceration. PMID- 30432772 TI - Case of Phosphorus Poisoning. PMID- 30432773 TI - Notes of Four Cases of Tracheotomy. PMID- 30432774 TI - Cases Illustrative of Persistence of the Hymen. PMID- 30432775 TI - On the Dissemination of Zymotic Diseases by Milk. PMID- 30432776 TI - Cases from Indian Practice. Ascites-Use of Drainage-Tube. PMID- 30432777 TI - The Direct Transfusion of Blood. PMID- 30432778 TI - On Pulmonary Disease in Glasgow-Its Prevalence and Distribution. PMID- 30432779 TI - Case of Enteric Fever, in Which the Cold Bath Was Employed. PMID- 30432780 TI - On Colo-Puncture. PMID- 30432782 TI - Medico-Chirurgical Society-Session 1872-73. PMID- 30432781 TI - Clinical Report on Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary during 1872. PMID- 30432784 TI - Clinical Surgical Report for the Year 1872. PMID- 30432783 TI - Medico-Chirurgical Society-Session 1872-73. PMID- 30432785 TI - On Suffocation during a Fit of Epilepsy. PMID- 30432786 TI - On a Case of Prolonged Utero Gestation. PMID- 30432787 TI - A Note on Encysted Placenta. PMID- 30432789 TI - Two Cases of Dislocation of the Hip Reduced by the American Method of Manipulation. PMID- 30432788 TI - Three Interesting Obstetric Cases. PMID- 30432790 TI - Dr Russell's Report on an Outbreak of Enteric Fever Connected with Milk-Supply. PMID- 30432791 TI - Medical Intelligence, &c. PMID- 30432792 TI - Aneurism of the Larger Arteries of the Brain, as a Cause of Cerebral Hemorrhage. PMID- 30432793 TI - Four Cases of Facial Paralysis Successfully Treated with Electricity. PMID- 30432794 TI - Interesting Cases from Dr Gairdner's Clinique, with Remarks. PMID- 30432795 TI - The Effect of Fear on a Boy. PMID- 30432796 TI - Cases of Hydrocephalus Treated with Bromide of Potassium. PMID- 30432797 TI - Clinical Memoranda: No. VI. Case of Aneurism of the Aorta. PMID- 30432798 TI - Two Cases of Injury to the Abdomen Having a Period of Latency, and Thereafter Proving Rapidly Fatal. PMID- 30432799 TI - On Putrefiers and Antiseptics. PMID- 30432800 TI - Compound Fractures Treated in the Glasgow Royal Infirmary. PMID- 30432801 TI - Medical Intelligence, &c. PMID- 30432803 TI - A Study of 972 Cases of Small-Pox, with Reference to the Modifying Influence of Vaccination. PMID- 30432802 TI - Cases of Empyema, Treated Successfully by Pneumatic Aspiration. PMID- 30432804 TI - The "Open Air" Treatment of Hooping-Cough. PMID- 30432805 TI - Cases of Compound Fracture Treated Antiseptically. PMID- 30432806 TI - Case of Wound of the Abdomen and of Protruded Intestine-Recovery, with Remarks. PMID- 30432807 TI - Cases of Intestinal Obstruction, with Remarks on Operative Interference. PMID- 30432809 TI - An Inquiry into the Cause of Pulse Dicrotism. PMID- 30432808 TI - On the Duration of Human Pregnancy. PMID- 30432810 TI - Medico-Chirurgical Society-Session 1873-74. PMID- 30432811 TI - Perforate Foramen Ovale in a Fatal Case of Enteric Fever. PMID- 30432812 TI - On the Solvent Action of Papya Juice on the Nitrogenous Articles of Food. PMID- 30432813 TI - Cases of Diseased Elbow-Joint, Treated by Excision, According to the Antiseptic System. PMID- 30432814 TI - Southern Medical Society-Session 1872-73. PMID- 30432815 TI - Fatal Case of Chronic Muco-Purulent Tympanitis (Vel Otitis Media Purulenta), Inflammation of Mastoid Cells of Both Temporal Bones, Involving Their Osseous Structure. PMID- 30432816 TI - On Some of the Nervous Affections of the Larynx. PMID- 30432817 TI - Ovariotomy: Removal of Both Ovaries. Performed and Treated Antiseptically. PMID- 30432818 TI - Report on Renal Cases, Observed in Professor Gairdner's Clinique during Last Session (1872-73). PMID- 30432819 TI - Medico-Chirurgical Society-Session 1873-74. PMID- 30432820 TI - Notes of Five Cases of Compound Dislocation of, and Compound Fracture into the Ankle Joint. PMID- 30432821 TI - Glasgow Pathological and Clinical Society-Session 1873-74. PMID- 30432822 TI - A Short Account of Work Done in a Summer Course of Practical Physiology. PMID- 30432823 TI - The Treatment of Enteric Fever by Cold Baths. PMID- 30432824 TI - On Congenital Malformations of the Lower Jaw. PMID- 30432825 TI - On the Absorption of Dead Bone. PMID- 30432826 TI - Notes on a Case of Cervical Ribs. PMID- 30432827 TI - Case of Acute Renal Dropsy. PMID- 30432828 TI - Notes of Cases Which Suggest Some Problems in Otology, and Questions in Aural Pathology. PMID- 30432829 TI - Cases Illustrative of the Use of the Pneumatic Aspirator. PMID- 30432830 TI - Glasgow Pathological and Clinical Society-Session 1873-74. PMID- 30432831 TI - The Sacrum-Its Variations, and the Influence by It Exerted on the Soft Parts as Determining Their Variations. PMID- 30432832 TI - Medico-Chirurgical Society-Session 1873-74. PMID- 30432833 TI - Case of Purulent Otitis Followed by Facial Paralysis, and Terminating in Pyaemia and Death. PMID- 30432834 TI - On Parakentesis of the Membrana Tympani: Observations Historical and Clinical. PMID- 30432835 TI - On the Poisonous Agents Found in Coloured Tapers. PMID- 30432837 TI - On the Hours of Maximum Mortality in Acute and Chronic Diseases. PMID- 30432836 TI - Clinical Surgical Report for the Year 1873, with Remarks on the Statistics of Amputation. PMID- 30432838 TI - Some Remarks on Insanity. PMID- 30432839 TI - Albuminuria, a Sequela of Smallpox. PMID- 30432840 TI - Occasional Reports on Local Outbreaks of Epidemic Disease. PMID- 30432842 TI - Glasgow Sanitary Department. PMID- 30432841 TI - Report on a Case of Tetanus Treated with Calabar Bean. PMID- 30432843 TI - Medico-Chirurgical Society-Session 1874-75. PMID- 30432844 TI - On a Peculiar Mode of Death in Diabetes; on Acetonaemia; on the Treatment of Diabetes by Glycerine, and Injection of Diastase into the Blood. PMID- 30432845 TI - Cases of Foreign Body Accidentally Swallowed, with Remarks on Treatment in Such Cases. PMID- 30432846 TI - Notes of Two Cases of Idiopathic Phlebitis. PMID- 30432847 TI - On a Case of Herpes Zoster Treated with Zinc Phosphide. PMID- 30432848 TI - Amputation through Joints without Interfering with the Proximal Bone, and Remarks on the Dressing of Stumps. PMID- 30432849 TI - On the Guaiacum Test in Haematuria. PMID- 30432850 TI - Two Cases in Which the External Application of Belladonna Produced a Scarlet Efflorescence on the Skin, Which Was at First Supposed to Be Due to Scarlatina. PMID- 30432851 TI - Cases of Pathological Interest from the Practice of Glasgow Royal Infirmary. PMID- 30432852 TI - Clinical Surgical Report for the Year 1871. PMID- 30432853 TI - Contribution to Electro-Therapeutics Case of Amblyopia. PMID- 30432854 TI - Clinical Memoranda: No. III. Case of Mediastinal Tumour. PMID- 30432855 TI - Case of Successful Double Amputation at the Knee. PMID- 30432857 TI - Medical Intelligence, &c. PMID- 30432856 TI - On Consanguineous Marriages Viewed in the Light of Comparative Physiology; with Remarks on the Proposed Medical Reform. PMID- 30432858 TI - Case of Successful Ligature of the Femoral Artery. PMID- 30432859 TI - Cancer of OEsophagus Ulcerating into the Right Pleura. PMID- 30432860 TI - Clinical Notes on Epithelioma. PMID- 30432861 TI - On the Perforation of Soil Pipes by Sewer Gas as a Cause of Enteric Fever and Other Diseases. PMID- 30432862 TI - Two Cases of Obstructed Bowel-One Fatal. PMID- 30432863 TI - On the Prevalence of Pulmonary Disease in Glasgow. PMID- 30432864 TI - Transactions of the Medico-Chirurgical Society. Session 1871-72. PMID- 30432865 TI - Hospital Report for the Year 1870-71. PMID- 30432866 TI - Fatal Case of Acute Periostitis and Cellulitis from a Trivial Injury. PMID- 30432867 TI - Notes on Hooping Cough. PMID- 30432868 TI - Interesting Cardiac Cases from Dr Gairdner's Clinique, with Remarks. PMID- 30432869 TI - Remarkable Case of Recovery after Fracture of the Base of the Skull. PMID- 30432871 TI - Two Cases of Calcareous Infiltration of the Muscular Fibre of the Heart. PMID- 30432870 TI - On the Lowenberg-Politzer Method of Eustachian Katheterism. PMID- 30432872 TI - Abstract of the First of a Course of Lectures Delivered during the Summer Session of 1872, in the Glasgow City Parochial Asylum. PMID- 30432874 TI - Medical Intelligence, &c. PMID- 30432873 TI - The Spas of Homburg. PMID- 30432875 TI - Medico-Chirurgical Society-Session 1871-72. PMID- 30432876 TI - The Vomiting of Pregnancy, with a Case Requiring the Induction of Labour. PMID- 30432877 TI - Injection of Ammonia into the Circulation in a Case of Opium Poisoning. PMID- 30432879 TI - Case of Intestinal Occlusion Relieved by Operation for Artificial Anus. PMID- 30432878 TI - Case of Umbilical Anus. PMID- 30432880 TI - On the Treatment of Exanthemal Katarrh of the Tympanum. PMID- 30432881 TI - A Substitute for the Elastic Stocking. PMID- 30432882 TI - The Effect of Fear on a Canary. PMID- 30432883 TI - Clinical Memoranda: No. V. Case of Diffused and Circumscribed Fatty Tumours of the Subcutaneous Cellular Tissue, Complicated with Aneurism. PMID- 30432884 TI - Clinical Notes of Practice. PMID- 30432885 TI - A Suggestion as to the Causes and Treatment of the Haemorrhagic Type of Small Pox. PMID- 30432887 TI - Medico-Chirurgical Society-Session 1871-72. PMID- 30432886 TI - Case of Acute Glanders in Man. PMID- 30432888 TI - A Few Anomalous Cases of Combined Eruptive Disease. PMID- 30432889 TI - Recent Zoo-Chemistry. PMID- 30432890 TI - The Structure of the Myxoma and Sarcoma, with Illustrative Specimens. PMID- 30432891 TI - Sub-Periosteal Excision of the Os Calcis, with Complete Reproduction of Bone. PMID- 30432892 TI - Medical Intelligence, &c. PMID- 30432893 TI - Case of Spina Bifida Treated Antiseptically. PMID- 30432894 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary during the Six Months Ending June 30, 1871. PMID- 30432895 TI - Clinical Memoranda: No. II. Rare Form of Spinal Irritation. PMID- 30432896 TI - A Remarkable Congenital Tumour of the Neck. PMID- 30432897 TI - Successful Extraction of Catheter Broken in Urethra. PMID- 30432898 TI - Favus in the Canary and Scabies in the Cat. PMID- 30432899 TI - On Pseudo-Hypertrophic Muscular Paralysis. PMID- 30432901 TI - Medical Intelligence, &c. PMID- 30432900 TI - Case of Pneumonia with Violent Cerebral Symptoms. PMID- 30432902 TI - Case of Acute Rheumatism: Death. PMID- 30432903 TI - Case of Phthisis Chiefly of the Left Lung-Retraction of the Border of the Lung Visible Pulsation of the Pulmonary Artery-Post-Mortem Examination-Remarks. PMID- 30432904 TI - Case of Bronzed-Skin Chronic Disease of the Membranes of the Brain-Perforation of the Skull-Abscesses of the Scalp-Death. PMID- 30432906 TI - Cases of Ulcerative Stomatitis with Yellow Palms. PMID- 30432907 TI - Medico-Chirurgical Society-Session 1872-73. PMID- 30432905 TI - Large Sarcomatous Tumour in the Abdomen, Probably of Supra-Renal Origin. PMID- 30432908 TI - Clinical Surgical Report for the Year 1871. PMID- 30432909 TI - Case of Imbedded Uterine Fibroid. PMID- 30432910 TI - Notes on the Treatment of Sciatica. PMID- 30432911 TI - Clinical Memoranda: No. IV. Two Cases of Embolism,-One the Result of Aortic Valve Disease, the Other of Hydatid Disease of the Heart. PMID- 30432912 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary during the Six Months Ending December 31, 1871. PMID- 30432913 TI - Interesting Observation with Reference to Skin-Grafting. PMID- 30432914 TI - On the Successful Induction of Premature Labour in a Case of Diseased Placenta. PMID- 30432915 TI - Case of Medullary Cancer of the OEsophagus. PMID- 30432916 TI - Note on Spina Bifida Treated Antiseptically. PMID- 30432917 TI - Two Cases of Rare Congenital Malformation. PMID- 30432918 TI - Notes on the Use of Xylol in Small-Pox, with Remarks on the Fallacies Incidental to the Treatment of Small-Pox. PMID- 30432919 TI - Investigation into the Action of Apomorphin as an Emetic in Its Physiological and Therapeutic Relations. PMID- 30432920 TI - Notes of Five Cases of Poisoning Occurring in Private Practice. PMID- 30432921 TI - Illustrations of Diphtheria and Its Treatment. PMID- 30432922 TI - On Epidemic Scarlet Fever. PMID- 30432923 TI - Medical Intelligence, &c. PMID- 30432924 TI - Syphilisation in Christiania. PMID- 30432925 TI - Case of Spinal Irritation. PMID- 30432926 TI - Case of Chorea Treated by Chloral-Accidental Overdose-Disappearance of the Chorea. PMID- 30432927 TI - Two Cases Presenting Anomalous Nervous Symptoms, Benefited by the Administration of Iron. PMID- 30432929 TI - Transactions of the Medico-Chirurgical Society. Session 1869-70. PMID- 30432928 TI - Notes of Experiments with the Bark, Leaves, Flowers, Young Pods, and Seeds of Cytisus Laburnum. PMID- 30432930 TI - Two Cases of Avulsion of the Scalp. PMID- 30432932 TI - Case of Floating Kidney. PMID- 30432931 TI - Experiments on the Effects of Alcohol (Ethyl Alcohol) on the Human Body. PMID- 30432933 TI - The Forces Which Carry on the Circulation of the Blood: Part III.-The Pneumatic Forces. PMID- 30432934 TI - Case of Protracted Pregnancy. PMID- 30432935 TI - A Case of Fatal Poisoning by Chloride of Zinc (Burnett's Disinfecting Fluid). PMID- 30432936 TI - On Clinical Instruction. PMID- 30432937 TI - Notes of Practice in Samoa. PMID- 30432938 TI - Case of Syphilis Treated by the Subcutaneous Injection of the Perchloride of Mercury. PMID- 30432940 TI - Transactions of the Medico-Chirurgical Society. Session 1869-70. PMID- 30432939 TI - The "Antiseptic" Treatment of Wounds, with Special Reference to Compound Fractures. PMID- 30432941 TI - Remarkable Case of Intussusception in an Infant. PMID- 30432943 TI - Case of Puerperal Convulsions. PMID- 30432942 TI - Case of Complex Presentation. PMID- 30432944 TI - Case of Avulsion of Forefinger, with Deep Flexor Tendon Attached. PMID- 30432945 TI - The Forces Which Carry on the Circulation of the Blood: Part II.-The Vascular Forces. PMID- 30432946 TI - Case of Ovariotomy. PMID- 30432947 TI - Case of Impaction of Damson Stones in the Rectum of a Child. PMID- 30432948 TI - Clinical Notes on Epithelioma. PMID- 30432949 TI - Remarkable Case of Cardiac Polypi, Embolism of Common Iliac, and Gangrene of Foot. PMID- 30432950 TI - On Epidemic Scarlet Fever. PMID- 30432951 TI - Clinical Observations on Hydrate of Chloral as a Hypnotic in Typhus. PMID- 30432952 TI - Hydrocyanic Acid Physiologically Investigated: Part II. PMID- 30432953 TI - On Whisky as an Antiseptic Dressing in Surgery. PMID- 30432954 TI - Medical Intelligence, &c. PMID- 30432955 TI - Report of a Committee of the Medico-Chirurgical Society of Glasgow on the Brain of an Aphasic. PMID- 30432956 TI - Medical Intelligence, &c. PMID- 30432957 TI - On the Temperature of Children in Pleurisy. PMID- 30432958 TI - On Epidemic Scarlet Fever. PMID- 30432959 TI - Hereditary Malformation of Extremities. PMID- 30432960 TI - Case of Recovery after Rupture of the Uterus. PMID- 30432961 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary from May 1st to December 31st, 1869. PMID- 30432962 TI - Case of Puerperal Convulsions Illustrating Great Benefit Derived from Vesication. PMID- 30432963 TI - Liebreich's Theory of the Action of Chloral. PMID- 30432964 TI - Case of Extra-Uterine Pregnancy. PMID- 30432965 TI - Cases of Extraction of Cataract at the Glasgow Eye Infirmary, 1869. PMID- 30432966 TI - Case of Intermittent Fever Treated by Subcutaneous Injection of Sulphate of Quinine. PMID- 30432967 TI - Transactions of the Medico-Chirurgical Society. Session 1869-70. PMID- 30432968 TI - A Case of Secondary Aneurism of the Popliteal Artery, with Remarks. PMID- 30432969 TI - The Forces Which Carry on the Circulation of the Blood: No. III.-The Pneumatic Forces. PMID- 30432970 TI - Cases of Podalic Version by the Combined Method. PMID- 30432971 TI - Notes on the Hydrate of Chloral. PMID- 30432972 TI - Case of Bursal Swelling of the Palm of the Hand and Wrist, Treated Antiseptically. PMID- 30432973 TI - Clinical Report of Cases Treated in the Surgical Wards of the Glasgow Royal Infirmary, from November 1st, 1868, to April 30th, 1869. PMID- 30432974 TI - On the Treatment of Laceration of the Perinaeum, Immediately after Delivery. PMID- 30432975 TI - Cases Illustrative of Paper on Feeding by the Nose in Fever. PMID- 30432976 TI - A Visit to Some of the German Spas: Marienbad. PMID- 30432977 TI - Transactions of the Medico-Chirurgical Society. Session 1868-69. PMID- 30432978 TI - Obstetric Auscultation, with Special Reference to the Diagnosis of Foetal Position. PMID- 30432979 TI - Case of Transfusion. PMID- 30432980 TI - The Forces Which Carry on the Circulation of the Blood: Part I.-The Force of the Heart, Effective and Absolute. PMID- 30432981 TI - Clinical Notes on Extraction of Cataract. PMID- 30432982 TI - Case of Operation for Strangulated Inguinal Hernia. PMID- 30432983 TI - Cases of Puerperal Insanity. PMID- 30432984 TI - Notes on the Surgery of the Upper Extremity. PMID- 30432985 TI - Note on Feeding by the Nose in Fever. PMID- 30432986 TI - Abscess Treated Antiseptically. PMID- 30432988 TI - Abstract of Recent Observations on Relapsing Fever. PMID- 30432987 TI - Medical Intelligence, &c. PMID- 30432989 TI - On the Temperature of Children in Phthisis and Tuberculosis. PMID- 30432990 TI - Nursing: An Account of the Dresden Nursing Association. Albert Verein. PMID- 30432991 TI - Description of a Case of Defective Corpus Callosum. PMID- 30432992 TI - Rare Case of Internal Strangulated Hernia. PMID- 30432993 TI - Lecture on the Course of the Temperature in Defervescence. PMID- 30432994 TI - Glasgow Pathological and Clinical Society-Session 1874-75. PMID- 30432996 TI - Medico-Chirurgical Society-Session 1874-75. PMID- 30432995 TI - Wound of Left Subclavian Artery and Vein; Perforation of Pleura; Death of Patient from Haemorrhage Nearly Three Weeks after Injury. PMID- 30432997 TI - Some Remarks on Insanity: Story of an "Insane" Life. PMID- 30432998 TI - The Results of Amputations Performed in the Glasgow Royal Infirmary during Twenty Five Years, Ending 31st December, 1873. PMID- 30432999 TI - A Study of 200 Cases of Re-Vaccination. PMID- 30433000 TI - Glasgow Pathological and Clinical Society-Session 1874-75. PMID- 30433001 TI - Surgical Practice in the Western Infirmary, from 1st November, 1874, Till 1st May, 1875. PMID- 30433002 TI - A Study of Tubercle. Thesis for Degree of M.D. 1875. PMID- 30433003 TI - Haematoma Auris. PMID- 30433004 TI - On the Prevention of Putrefaction and the Destruction of Contagia. PMID- 30433005 TI - Notes on Pneumonia-Based on Sixty-Four Cases of That Disease Observed in Private Practice. PMID- 30433006 TI - Clinical Surgical Report for the Year 1874. PMID- 30433007 TI - Operation under Chloral Hydrate. PMID- 30433009 TI - Medico-Chirurgical Society-Session 1874-75. PMID- 30433008 TI - A Typhoid Epidemic, Apparently Arising from Infected Milk. PMID- 30433011 TI - The Results of Some Injections of the Kidneys in Bright's Disease, in Relation to Albuminuria and Haematuria. PMID- 30433010 TI - Medical Intelligence. PMID- 30433012 TI - Medico-Chirurgical Society-Session 1875-76. PMID- 30433013 TI - On the Shoulder-Girdle of Birds: Its Morphology and Development. PMID- 30433014 TI - Pathological Record. Fracture of Costal Cartilages-Rupture of Heart-Omental Hernia. PMID- 30433015 TI - Lectures on Clinical Medicine: I. Case of Hysteria. PMID- 30433016 TI - Record of an Epidemic of Chickenpox. PMID- 30433017 TI - Notes of a Case of Poisoning with Oil of Savine. PMID- 30433018 TI - Therapeutical Note. PMID- 30433019 TI - On the Unilateral Phenomena of Mental and Nervous Disorders. PMID- 30433020 TI - Report of Three Cases of Peritonitis Associated with Cardiac and Renal Disease. PMID- 30433022 TI - Glasgow Pathological and Clinical Society-Session 1874-75. PMID- 30433021 TI - Miners' Anthracosis. PMID- 30433023 TI - On Arsenical Wall Papers. PMID- 30433024 TI - Correction. AB - [This corrects the article on p. 554 in vol. 6.]. PMID- 30433025 TI - On Laryngismus Stridulus. PMID- 30433026 TI - Cases Illustrative of Disordered Respiration from Thoracic Aneurism and Other Causes. PMID- 30433027 TI - Case of Abcess of the Brain. PMID- 30433028 TI - On the Treatment of Pleuritic Effusion. PMID- 30433029 TI - Medical Intelligence. PMID- 30433030 TI - Adaptations of the Laryngoscope and Tourniquet. PMID- 30433031 TI - Medico-Chirurgical Society-Session 1874-75. PMID- 30433032 TI - Case of Epileptic Homicidal Impulse. PMID- 30433033 TI - On Penetrating Wounds of Thorax and Abdomen Treated Antiseptically. PMID- 30433034 TI - Case of Enteritis, with Ulceration of the Ileum and Perforation of the Bowel. PMID- 30433035 TI - Myringomycosis Aspergillina and Otitis Parasitica. PMID- 30433036 TI - Clinical Observations on Synovial Bursae; with Special Reference to Those Situated in the Popliteal Space. PMID- 30433037 TI - Notes of Cases of Diabetes Mellitus, Showing the Effects of Diet, and Various Therapeutic Agents on the Amount of Sugar Excreted. PMID- 30433038 TI - Three Cases of Pelvic Haematoma: With Remarks. PMID- 30433039 TI - Glasgow Pathological and Clinical Society-Session 1875-76. PMID- 30433040 TI - New Method of Amputating at the Hip-Joint. PMID- 30433041 TI - Case of Lymphatic Leukaemia, with Tumour in the Mediastinum. PMID- 30433042 TI - Case of Abortion in Enteric Fever. PMID- 30433043 TI - On Defects in Poorhouse Administration, from a Medical Point of View. PMID- 30433044 TI - A Case of a Peculiar Form of Asthma. PMID- 30433045 TI - Improved Pneumatic Aspirator. PMID- 30433046 TI - Glasgow Pathological and Clinical Society-Session 1875-76. PMID- 30433047 TI - Cases of Placenta Praevia. PMID- 30433048 TI - Case of Dermoid Cyst of the Ovary, with Unusual Sympathetic Symptoms. PMID- 30433049 TI - Otological Memoranda: Being Clinical Observations Illustrative of the Diseases and Injuries of the Ear. PMID- 30433050 TI - Lectures on Clinical Medicine: III. Aneurism of the Abdominal Aorta. PMID- 30433051 TI - Case of Intussuception-Slough of a Portion of Bowel-Recovery. PMID- 30433052 TI - Notes of Two Cases of Stricture of the OEsophagus Cured by Dilatation. PMID- 30433054 TI - Glasgow and West of Scotland Medical Association. PMID- 30433053 TI - A Rapid and Simple Method of Staining and Mounting Fresh Brain for Microscopic Examination. PMID- 30433055 TI - Medico-Chirurgical Society-Session 1875-76. PMID- 30433056 TI - Further Information on the Immediate Results of the Operations of the Glasgow Improvement Trust, as Regards the Inhabitants Displaced. Being Portion of the Opening Address of the Sanitary Section of the Philosophical Society of Glasgow. PMID- 30433057 TI - On the AEtiology of Ear Disease in General: A Contribution to the Principles of Aural Surgery. PMID- 30433059 TI - Lectures on Clinical Medicine: II. Case of Mediastinal Tumour. PMID- 30433058 TI - Two Cases of Hydatids of the Liver, Treated by Puncture. PMID- 30433060 TI - Medico-Chirurgical Society-Session 1875-76. PMID- 30433062 TI - Medical Intelligence. PMID- 30433061 TI - Wounds, in Relation to the Instruments Which Produce Them. PMID- 30433063 TI - Short Notes of Three Uterine Cases. PMID- 30433064 TI - Glasgow Pathological and Clinical Society-Session 1875-76. PMID- 30433065 TI - Hepatic Colic from Gallstones, with Recurrent Jaundice. PMID- 30433066 TI - Correction. AB - [This corrects the article on p. 552 in vol. 7.]. PMID- 30433067 TI - Notes of Three Cases of Congenital Obstruction of Gland Ducts. PMID- 30433068 TI - Lectures on Clinical Medicine: III. Aneurism of the Abdominal Aorta (cont.). PMID- 30433070 TI - On a New Form of Parasitic Skin Disease, Prevalent in Fiji. PMID- 30433069 TI - On the Influence of "the Friendly Societies Act, 1875," upon the Proportion of Uncertified Deaths in Glasgow. PMID- 30433071 TI - On a Recent Experience of Puerperal Fever. PMID- 30433072 TI - Typhus Fever Complicated with Intestinal Haemorrhage. PMID- 30433073 TI - A Second Case of Pemphigus Chronicus. PMID- 30433074 TI - Otological Memoranda. II. Injuries of the Membrana Tympani. PMID- 30433076 TI - A Case of Intra-Cranial Tumour. PMID- 30433075 TI - Case of Pernicious Anaemia, with Febrile Symptoms, Proving Fatal Three Months after Delivery. PMID- 30433077 TI - Medico-Chirurgical Society-Session 1875-76. PMID- 30433078 TI - Medical Intelligence, &c. PMID- 30433079 TI - Clinical Surgical Report for the Year Ending 30th April, 1876. PMID- 30433080 TI - The Diagnosis of Alcoholic Coma. PMID- 30433081 TI - On a Case of Intra-Uterine Amputation of Fingers and Toes. PMID- 30433082 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433084 TI - Current Topics. PMID- 30433083 TI - On a Case of Addison's Disease Improving under Treatment, and on the Relationship between Addison's Disease, Vitiligo, and Alopecia Areata. PMID- 30433086 TI - A Series of Cases of Malignant Tumour of the Lungs. PMID- 30433085 TI - Malignant Tumour in the Posterior Mediastinum and Its Differential Diagnosis. PMID- 30433087 TI - Two Cases Illustrative of Chyluria. PMID- 30433088 TI - Glasgow Royal Infirmary. PMID- 30433089 TI - Western Infirmary. PMID- 30433091 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433090 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433092 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433093 TI - On Anderson's College; Its Founder and Its Medical School, Being the Introductory Address at the Commencement of the Session 1878-79. PMID- 30433094 TI - Glasgow Royal Infirmary. PMID- 30433095 TI - A Few Surgical Cases: V. Two Cases of Adenoid Tumour. PMID- 30433096 TI - Case of Ovariotomy, in Which Recovery Took Place after a Long Continuance of Symptoms of Low Peritonitis. PMID- 30433097 TI - Case of Abscess of the Lung. PMID- 30433098 TI - Current Topics. PMID- 30433099 TI - The Use of Esmarch's Bandage in the Removal of Tumours Arising from Elephantiasis Arabum. PMID- 30433101 TI - Western Infirmary. PMID- 30433100 TI - Numerical Anomalies of the Breasts. PMID- 30433102 TI - Current Topics. PMID- 30433103 TI - A Peculiar Cardiac Murmur. PMID- 30433104 TI - A Case of Diphtheria in Which the Primary Local Signs Were Those of Acute Pleurisy. PMID- 30433105 TI - Glasgow Royal Infirmary. PMID- 30433106 TI - On the Arrestment of Bleeding from Internal Organs. PMID- 30433107 TI - Uterine Pressure and the Long Forceps in Tedious Labours; Report of a Case of Unusual Difficulty, in Which the Former Succeeded after the Latter Had Failed. PMID- 30433108 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433109 TI - The Percentage Registration of the Sensitiveness of the Conductive Apparatus of the Ear to Resonant Impulses of Minimum Intensity. PMID- 30433111 TI - Glasgow Southern Medical Society. Session 1878-79. PMID- 30433110 TI - Western Infirmary. PMID- 30433112 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433113 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433114 TI - Current Topics. PMID- 30433116 TI - Western Infirmary. PMID- 30433115 TI - Case of Tubercular Peritonitis, Ending in Recovery, with a Chart Showing the Temperature and Treatment during Its Progress. PMID- 30433117 TI - On an Improved Apparatus for Spray Inhalations. PMID- 30433118 TI - On a Case of Miner's Nystagmus. PMID- 30433120 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433119 TI - Town's Hospital. PMID- 30433121 TI - Glasgow Royal Infirmary. PMID- 30433122 TI - Notes of a Case Illustrating the Simulation of Dislocation by Old Fracture of the Neck of the Humerus. PMID- 30433123 TI - The Causation of Insanity. PMID- 30433124 TI - On Descending Secondary Sclerosis of the Brain and Spinal Cord in a Case of Hemiplegia. PMID- 30433125 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433126 TI - Western Infirmary. PMID- 30433127 TI - Glasgow Royal Infirmary. PMID- 30433128 TI - Notes on a Case of Obstruction of the Bowels with Peritonitis. PMID- 30433129 TI - Current Topics. PMID- 30433130 TI - Case of Recent Inversion of the Uterus-Reduction. PMID- 30433131 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433132 TI - Case of Paroxysmal Haematinuria. PMID- 30433133 TI - Glasgow Royal Infirmary. PMID- 30433134 TI - A Case of Paroxysmal Haematinuria. PMID- 30433135 TI - Some Remarks on the Exciting Causes of Expense in the Antiseptic Treatment of Surgical Cases. PMID- 30433136 TI - Western Infirmary. PMID- 30433137 TI - Note on the Spectroscopic Examination of the Urine, in Two Cases of Paroxysmal Haematinuria. PMID- 30433138 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433140 TI - An Address on Temperance in the Treatment of the Sick. PMID- 30433139 TI - Case of Partial Annular Laceration of Cervix Uteri during Labour. PMID- 30433141 TI - Current Topics. PMID- 30433142 TI - On the Diagnosis of Malignant Abdominal Tumours. PMID- 30433143 TI - A Case of Tetanus Treated by Nerve Stretching. PMID- 30433144 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433145 TI - Western Infirmary. PMID- 30433146 TI - Glasgow Southern Medical Society. Session 1878-79. PMID- 30433147 TI - On a Case of Disseminated Sclerosis of the Brain and Spinal Cord (Multiple Sclerosis). PMID- 30433148 TI - Glasgow Eye Infirmary. PMID- 30433149 TI - One Year's Surgical Operations in the Western Infirmary, Glasgow. PMID- 30433150 TI - Current Topics. PMID- 30433152 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433151 TI - Glasgow Royal Infirmary. PMID- 30433153 TI - Western Infirmary. PMID- 30433154 TI - Glasgow Eye Infirmary. PMID- 30433155 TI - Surgical Experiences and Observations as an Ambulance Surgeon in Bulgaria during the Russo-Turkish War of 1877-78. PMID- 30433156 TI - Salicylate of Iron. PMID- 30433157 TI - Glasgow Royal Infirmary. PMID- 30433158 TI - Probable Case of Aneurism of the Pulmonary Artery and Ductus Arteriosus. PMID- 30433159 TI - A Fatal Case of Rheumatic Fever. PMID- 30433160 TI - On a Case of Melanotic Sarcoma of the Conjunctiva and Cornea. PMID- 30433161 TI - Current Topics. PMID- 30433162 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433163 TI - Private Practice. PMID- 30433164 TI - Glasgow Royal Infirmary. PMID- 30433165 TI - Glasgow Pathological and Clinical Society. Session 1878-79. PMID- 30433166 TI - A New and Improved Waterproof Splint Material. PMID- 30433167 TI - Glasgow Medico-Chirurgical Society. Session 1878-79. PMID- 30433169 TI - Current Topics. PMID- 30433168 TI - Address to the Graduates in Law and Medicine of the University of Glasgow, on 31st July, 1879. PMID- 30433170 TI - Clinical Lecture on the Loss of Speech. PMID- 30433172 TI - Western Infirmary. PMID- 30433171 TI - Short Notes of Rare or Unusual Obstetric Cases. PMID- 30433173 TI - Notes of Two Cases of Dislocation Backwards of the Humerus. PMID- 30433174 TI - Remarks on Zymotic Diseases in Scotland: Being an Address by the President of the Medico-Chirurgical Society, on 3rd October, 1879. PMID- 30433175 TI - Glasgow Royal Infirmary. PMID- 30433176 TI - On the Treatment of Spondylitis and Scoliosis by Partial Suspension to Improve the Position, and the Application of the Plaster of Paris Bandage to Retain It: Being the Account of a Demonstration before the Sixth International Medical Congress at Amsterdam, September, 1879. PMID- 30433177 TI - Case of Acute Delirious Mania: With Remarks on Diagnosis and Treatment. PMID- 30433178 TI - Western Infirmary. PMID- 30433180 TI - Current Topics. PMID- 30433179 TI - On the Treatment of Traumatic Sloughing Ulcer of the Cornea. PMID- 30433181 TI - Current Topics. PMID- 30433182 TI - Clinical Report of Three Cases of Malignant Ear Disease Treated in the Glasgow Dispensary for the Diseases of the Ear. PMID- 30433183 TI - Clinical Surgery Report-Being an Account of the Operations Performed on Patients in Wards III and XI, Western Infirmary, during the Year Ending 1st November 1879. PMID- 30433184 TI - On Some of the Pathological and Physiological Relations of Brain, Mind, and Higher Nerve Function: Being the Address Delivered at the Beginning of the Session of the Pathological and Clinical Society of Glasgow. PMID- 30433185 TI - Some Resemblances Betwixt Plants and Animals in Respect of Their Nutrition, with Some Remarks on the Position of the Natural History Sciences in Medical Education: Being an Address to the Medical Students at the Opening of the Winter Session, University of Glasgow, Tuesday, 28th October, 1879. PMID- 30433186 TI - Western Infirmary. PMID- 30433187 TI - Glasgow Royal Infirmary. PMID- 30433188 TI - Glasgow Royal Infirmary. PMID- 30433189 TI - Glasgow Southern Medical Society. PMID- 30433190 TI - An Historical Sketch of Sanitary Science. PMID- 30433191 TI - Value of the Tuning-Fork in the Diagnosis of Disease of the Auditory Nerve. PMID- 30433192 TI - Current Topics. PMID- 30433193 TI - On the Treatment of Diphtheria. PMID- 30433194 TI - Western Infirmary. PMID- 30433195 TI - Typhus and Enteric Fever Compared Statistically. From Eight Years' Statistics of the Belvidere Fever Hospital. PMID- 30433196 TI - Intestinal Obstruction, Existing for Nine Months, Cured by Colo-Puncture. PMID- 30433197 TI - Medico-Chirurgical Society. PMID- 30433199 TI - Case of Supposed Lymphadenoma Treated with Iodide of Potassium. PMID- 30433198 TI - Pericarditis and Generalised Tubercular Disease, Following Scarlet Fever. PMID- 30433200 TI - Current Topics. PMID- 30433201 TI - Southern Medical Society. PMID- 30433202 TI - Glasgow Eye Infirmary. PMID- 30433203 TI - Glasgow Royal Infirmary. PMID- 30433204 TI - City of Glasgow Fever Hospital, Belvidere-Case of Enteric Fever Treated with Quinine. PMID- 30433205 TI - On Twisting of the Intestine as a Cause of Obstruction. PMID- 30433206 TI - On Influenza: Its Symptoms, Varieties, and Causes, Founded on Six Years' Experience of the Disease. PMID- 30433207 TI - Pathological and Clinical Society. PMID- 30433208 TI - Hooping-Cough, and What It Teaches Us of the Sounds of the Heart. PMID- 30433209 TI - Glasgow Royal Infirmary. PMID- 30433211 TI - Current Topics. PMID- 30433210 TI - University Medico-Chirurgical Society. PMID- 30433212 TI - On the Treatment of Hooping-Cough. PMID- 30433213 TI - On the Treatment of Stricture of the Urethra. PMID- 30433214 TI - Western Infirmary. PMID- 30433216 TI - Southern Medical Society. PMID- 30433215 TI - On the Climatic Treatment of Consumption, with Special Reference to a Visit to Davos Platz. PMID- 30433217 TI - Remarks on the Treatment of Stricture of the Urethra. PMID- 30433218 TI - Medico-Chirurgical Society. PMID- 30433219 TI - Medico-Chirurgical Society. PMID- 30433220 TI - Western Infirmary. PMID- 30433221 TI - Glasgow Royal Infirmary. PMID- 30433222 TI - On the Treatment of Hooping-Cough. PMID- 30433223 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 2. On Boracic Acid, Salicylic Acid, Chloride of Zinc, and Iodoform. PMID- 30433225 TI - Southern Medical Society. PMID- 30433224 TI - Tight Lacing, Venous Congestions, and Atrophy of the Ovaries. PMID- 30433227 TI - The Actual Cautery in Spinal Affections. PMID- 30433226 TI - Current Topics. PMID- 30433228 TI - Observations on the Subcutaneous Method of Administering Medicines, from Cases Treated in Professor M'Call Anderson's Wards in the Western Infirmary of Glasgow: Subcutaneous Injection of Arsenic in Two Cases of Skin Disease. PMID- 30433230 TI - Pathological and Clinical Society. PMID- 30433229 TI - Report of the Aural Work Done in the Glasgow Royal Infirmary, during a Period of Two Years-Viz., from November 1st, 1877, to November 7th, 1879. PMID- 30433231 TI - Glasgow Royal Infirmary. PMID- 30433233 TI - Current Topics. PMID- 30433232 TI - Salicylic Acid in Yellow Fever. PMID- 30433234 TI - Pathological and Clinical Society. PMID- 30433235 TI - Cases of Poisoning with the Seeds of the Castor Oil Plant. PMID- 30433236 TI - Report of the Aural Work Done in the Glasgow Royal Infirmary, during a Period of Two Years-Viz., from November 1st, 1877, to November 7th, 1879. PMID- 30433237 TI - Medico-Chirurgical Society. PMID- 30433238 TI - Periscope of Dermatology: No. I. PMID- 30433239 TI - Western Infirmary. PMID- 30433240 TI - On Influenza: Its Symptoms, Varieties, and Causes, Founded on Six Years' Experience of the Disease. PMID- 30433241 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 4. On the Mackintosh and Protective. PMID- 30433243 TI - Southern Medical Society. PMID- 30433242 TI - Glasgow Royal Infirmary. PMID- 30433244 TI - Pathological and Clinical Society. PMID- 30433245 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 3. On the Antiseptic Gauze. PMID- 30433246 TI - Notes of a Case of Addison's Disease. PMID- 30433247 TI - Glasgow Dispensary for Skin Diseases. PMID- 30433248 TI - Defect of the Cerebellum Occurring in a Brother and Sister. PMID- 30433249 TI - Current Topics. PMID- 30433250 TI - Western Infirmary. PMID- 30433251 TI - The Cavity of the Cervix Uteri in the Last Months of Pregnancy. PMID- 30433252 TI - Report of the Aural Work Done in the Glasgow Royal Infirmary, during a Period of Two Years-Viz., from November 1st, 1877, to November 7th, 1879. PMID- 30433253 TI - Glasgow Royal Infirmary. PMID- 30433255 TI - Southern Medical Society. PMID- 30433254 TI - Western Infirmary. PMID- 30433257 TI - Medico-Chirurgical Society. PMID- 30433256 TI - Woodilee Asylum, Lenzie. PMID- 30433258 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 1. On Carbolic Acid as Used in Lister's Antiseptic System. PMID- 30433259 TI - Pathological and Clinical Society. PMID- 30433260 TI - Medical Education and Qualification: The Introductory Address at the Opening of the Winter Session of the Glasgow Royal Infirmary School of Medicine. Delivered 29th October, 1879. PMID- 30433261 TI - Report of the Aural Work Done in the Glasgow Royal Infirmary, during a Period of Two Years-Viz., from November 1st, 1877, to November 7th, 1879. PMID- 30433262 TI - Current Topics. PMID- 30433263 TI - On the Cure of Artificial Anus. PMID- 30433264 TI - On Puerperal Fever. PMID- 30433265 TI - A Case of Retained Placenta. PMID- 30433266 TI - On an Outbreak of Cholera in Bombay Harbour. PMID- 30433267 TI - A Case of Scrotal Inclusion. PMID- 30433268 TI - Pathological Demonstration on Cerebral Haemorrhage, &c. PMID- 30433269 TI - A Case of Diphtheria. PMID- 30433270 TI - Current Topics. PMID- 30433271 TI - On Numerical Anomalies of the Breasts, with Remarks on the Causes of Deformities. PMID- 30433272 TI - Glasgow Pathological and Clinical Society. PMID- 30433273 TI - Clinical Observations on Two Cases of Renal Disease from Professor Gairdner's Wards, with Remarks. PMID- 30433274 TI - A Case of Recurring Popliteal Aneurism. PMID- 30433275 TI - Glasgow Medico-Chirurgical Society. PMID- 30433276 TI - Current Topics. PMID- 30433277 TI - Medico-Chirurgical Society. PMID- 30433278 TI - A Case of Idiopathic Pericarditis. PMID- 30433279 TI - Pathological Demonstration on Fatty Heart, Cancerous Infection, Hydronephrosis, and Suppurative Nephritis. PMID- 30433280 TI - A Case of Addison's Disease. PMID- 30433281 TI - A Case of Angular Curvature Treated by Sayre's Method. PMID- 30433282 TI - Current Topics. PMID- 30433283 TI - Current Topics. PMID- 30433284 TI - On Teaching the Dumb to Speak. PMID- 30433285 TI - Papers on Various Fractures: III. Transverse Fracture of the Patella. PMID- 30433286 TI - On a Hydatid Tumour of the Liver Opened with Potassa Fusa. PMID- 30433287 TI - Glasgow Medico-Chirurgical Society. PMID- 30433289 TI - Current Topics. PMID- 30433288 TI - Clinical Lecture on "the Radical Cure of Hernia". PMID- 30433290 TI - A Series of Perforating Ulcers of the Stomach and Intestine. PMID- 30433291 TI - A Case of Hydrophobia. PMID- 30433292 TI - Glasgow Pathological and Clinical Society. PMID- 30433294 TI - Glasgow Medico-Chirurgical Society. PMID- 30433293 TI - A New Form of the Long Forceps, and the Treatment of Uterine Haemorrhage. PMID- 30433296 TI - A New Form of Long Forceps. PMID- 30433295 TI - Current Topics. PMID- 30433297 TI - Case of Puerperal Convulsions, with Dislocation of the Humerus. PMID- 30433298 TI - Glasgow Pathological and Clinical Society. PMID- 30433299 TI - Glycogen and Sugar. PMID- 30433301 TI - Current Topics. PMID- 30433300 TI - Papers on Various Fractures: II. On Pott's Fracture. PMID- 30433302 TI - Glasgow Medico-Chirurgical Society. PMID- 30433303 TI - Glasgow Pathological and Clinical Society. PMID- 30433305 TI - Medico Chirurgical Society. PMID- 30433304 TI - On Tubercular Meningitis, with Cases. PMID- 30433306 TI - Southern Medical Society. PMID- 30433307 TI - A Few Surgical Cases: (3) Sub-Mammary Tumour. (4) Some Old Dislocations. PMID- 30433308 TI - On Bromide of Potassium in Epilepsy. PMID- 30433310 TI - Current Topics. PMID- 30433309 TI - The Structure of the Lamina Cribrosa. PMID- 30433311 TI - Pathological and Clinical Society. PMID- 30433312 TI - Stray Thoughts on Phthisis. PMID- 30433313 TI - A Case of Idiopathic Tetanus, Treated by Bromide of Potassium. PMID- 30433314 TI - Glasgow Medico-Chirurgical Society. PMID- 30433315 TI - Cases Illustrative of the Treatment of Abscess. PMID- 30433316 TI - Glasgow Pathological and Clinical Society. PMID- 30433317 TI - Current Topics. PMID- 30433318 TI - Case of Aural Disease with Cerebral Abscess. PMID- 30433319 TI - Healing by Scabbing. PMID- 30433320 TI - Glasgow Medico-Chirurgical Society. PMID- 30433321 TI - Current Topics. PMID- 30433322 TI - On Hydatids. PMID- 30433323 TI - Glasgow Pathological and Clinical Society. PMID- 30433324 TI - Papers on Various Fractures: I. Colles's Fracture of the Radius. PMID- 30433325 TI - A Case of Hydatids of the Liver. PMID- 30433326 TI - Numerical Anomalies of the Breasts. PMID- 30433327 TI - Current Topics. PMID- 30433328 TI - Papers on Various Fractures: IV. Fractures of the Thigh and Arm, Complications and Difficulties. PMID- 30433329 TI - On the Antipyretic Treatment of Specific Fevers, with a Note by Dr Gairdner. PMID- 30433330 TI - On the Administration of Iodine versus Iodide of Potassium. PMID- 30433331 TI - On Moveable Kidney. PMID- 30433332 TI - Medico-Chirurgical Society. PMID- 30433333 TI - A Few Surgical Cases: (1) Tumour of the Hand, and (2) Two Cases of Popliteal Aneurism. PMID- 30433334 TI - Case of Cancer of the Mamma in the Male, Preceded by So-Called Eczema of the Mammary Areola, "Paget's Disease of the Nipple." PMID- 30433335 TI - Glasgow Southern Medical Society. PMID- 30433336 TI - Embolism of the Superior Mesenteric Artery. PMID- 30433338 TI - Current Topics. PMID- 30433337 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 8. On Spray Producers. PMID- 30433339 TI - Western Infirmary. PMID- 30433340 TI - Illustrations of Epileptic Mania and of the Automatic Phenomena of Epilepsy; Likewise of Maniacal Attacks Following, and Also Taking the Place of Uraemic Convulsions. PMID- 30433341 TI - Current Topics. PMID- 30433342 TI - A Case of Imperforate Hymen. PMID- 30433343 TI - Western Infirmary. PMID- 30433344 TI - Periscope of Dermatology: No. II. PMID- 30433345 TI - A Case of Hydrophobia. PMID- 30433346 TI - Diaphragmatic Hernia. PMID- 30433347 TI - An Exaggerated Case of Lupus Exedens. PMID- 30433348 TI - Case of Recovery from Hanging, with Remarks. PMID- 30433349 TI - Glasgow Royal Infirmary. PMID- 30433350 TI - Medico-Chirurgical Society. PMID- 30433351 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 7. On Sponges and Antiseptic Drainage. PMID- 30433352 TI - Current Topics. PMID- 30433353 TI - Western Infirmary. PMID- 30433355 TI - On the Inhalation of Carbolic Acid in Diseases of the Respiratory Organs. PMID- 30433354 TI - On Influenza: Its Symptoms, Varieties, and Causes, Founded on Six Years' Experience of the Disease. PMID- 30433356 TI - Case of Intestinal Perforation in Enteric Fever. PMID- 30433357 TI - Notes of a Case of Ulcerative Endocarditis. PMID- 30433358 TI - Pathological and Clinical Society. PMID- 30433359 TI - Glasgow Royal Infirmary. PMID- 30433361 TI - Resuscitation of a Still Born Child after Stoppage of the Heart's Action. PMID- 30433360 TI - On the Remedial Treatment of the Post-Partum Fevers or Puerperal Fever (so Called). PMID- 30433362 TI - A Case of Retraction of Both Testicles. PMID- 30433364 TI - On the Anatomical Changes Induced at the Elbow by Luxation Backwards of the Head of the Radius in Early Life. PMID- 30433363 TI - Three Cases of Cerebral Abscess Consequent upon Suppurative Disease of the Middle Ear, with Remarks. PMID- 30433366 TI - Medico-Chirurgical Society. PMID- 30433365 TI - Western Infirmary. PMID- 30433367 TI - Glasgow Royal Infirmary. PMID- 30433369 TI - Southern Medical Society. PMID- 30433368 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. 5. On the Carbolised Catgut. PMID- 30433370 TI - Hypertrophy of the Prostate Gland and Its Treatment: Being Summary of a Paper Read before the Medico-Chirurgical Society of Glasgow on 16th April, 1880. PMID- 30433371 TI - Complicated Traumatic Tetanus. PMID- 30433373 TI - Current Topics. PMID- 30433372 TI - Pathological and Clinical Society. PMID- 30433374 TI - On Influenza: Its Symptoms, Varieties, and Causes, Founded on Six Years' Experience of the Disease. PMID- 30433375 TI - On Certain Epidemic Outbreaks of Enteric Fever in April, 1880, Traced to Contamination of Milk, Being a Report Presented to the Police Board of Glasgow. PMID- 30433376 TI - On an Outbreak of Enteric Fever at Possilpark, Being Part of a Report to the Local Authority of the Barony Parish, Glasgow. PMID- 30433377 TI - The Method of Preparing Paraffin Splints. PMID- 30433379 TI - Glasgow Royal Infirmary. PMID- 30433378 TI - Western Infirmary. PMID- 30433380 TI - Medico-Chirurgical Society. PMID- 30433381 TI - Pathological and Clinical Society. PMID- 30433382 TI - Ulceration of the Scalp. PMID- 30433383 TI - Glasgow Royal Infirmary. PMID- 30433384 TI - Western Infirmary. PMID- 30433385 TI - Medico-Chirurgical Society. PMID- 30433386 TI - Renal Epilepsy Occurring in Parturient Women. PMID- 30433387 TI - Practical Papers on the Materials of the Antiseptic Method of Treatment. VI. On Antiseptic Sutures. PMID- 30433388 TI - On the Treatment of Bright's Disease, with Special Reference to the Use of Diuretic Remedies. PMID- 30433389 TI - Cases of Hysteria in the Male. PMID- 30433390 TI - Medico-Chirurgical Society-Session 1877-78. PMID- 30433391 TI - A Year's Experience of Excision of the Hip-Joint in the Wards of the Glasgow Royal Infirmary. PMID- 30433392 TI - On Leprosy in China. PMID- 30433393 TI - Notes on Cardiac Cases, from Clinical Observations. PMID- 30433394 TI - On the Treatment of Rheumatism, Acute and Chronic, by Salicine and Salicylate of Soda. PMID- 30433395 TI - On the Influenza Recently Prevalent. PMID- 30433397 TI - Notes of Cases of Nervous Disease: Retinitis of Bright's Disease and Cerebral Complications. PMID- 30433396 TI - The Treatment of Chronic Pharyngitis. PMID- 30433399 TI - Medico-Chirurgical Society-Session 1876-77. PMID- 30433398 TI - Two Cases of Infantile Poisoning by Opium. PMID- 30433400 TI - Case of Cut-Throat-Vertical-Recovery. PMID- 30433401 TI - Recovery after Pyo-Pneumothorax. PMID- 30433402 TI - Treatment of Small-Pox by Cold Baths. PMID- 30433403 TI - The Diseases of China; Their Causes, Conditions, and Prevalence, Contrasted with Those of Europe. PMID- 30433404 TI - Some Remarks on Uraemia, with Cases of Scarlatinal Dropsy Treated by Bloodletting. PMID- 30433405 TI - Medical Intelligence, &c. PMID- 30433407 TI - Case of Renal Calculus, under the Care of Professor M'Call Anderson, in the Glasgow Western Infirmary. PMID- 30433406 TI - The Glasgow and West of Scotland Medical Association. PMID- 30433408 TI - Case of Alleged Hydrophobia. PMID- 30433410 TI - Glasgow Pathological and Clinical Society-Session 1876-77. PMID- 30433409 TI - Notes of Cases of Diabetes Mellitus, Showing the Effects of Diet, and Various Therapeutic Agents on the Amount of Sugar Excreted. PMID- 30433411 TI - Medico-Chirurgical Society-Session 1876-77. PMID- 30433412 TI - Notes of Cases of Nervous Disease. PMID- 30433413 TI - The Motions of the Brain, with Illustrative Graphic Tracings. PMID- 30433414 TI - Lymphadenoma, or Hodgkin's Disease. PMID- 30433416 TI - Glasgow Pathological and Clinical Society-Session 1876-77. PMID- 30433415 TI - Oxide of Zinc in Infantile Diarrhoea. PMID- 30433417 TI - The Diseases of China; Their Causes, Conditions, and Prevalence, Contrasted with Those of Europe. PMID- 30433418 TI - Case of Encephalocele. PMID- 30433419 TI - Case of Paracentesis Pericardii. PMID- 30433420 TI - Remarks on the Treatment of Chronic Inversion of the Uterus. PMID- 30433421 TI - On Medico-Psychological Evidence and the Plea of Insanity in Courts of Law: Being Portion of an Introductory Lecture to a Course on Mental Diseases, with Clinical Instruction, Delivered in Connection with the Royal Infirmary School of Medicine. PMID- 30433422 TI - Case of Medullary Cancer of the Liver, Stimulating Hydrothorax. PMID- 30433423 TI - Case of Tearing out of the Entire Tendon of the Flexor Longus Pollicis Muscle by a Donkey Bite. PMID- 30433425 TI - Notes on Obstetric Practice. PMID- 30433424 TI - A New Form of Paralytic Disease, Associated with the Presence of a New Species of Liver Parasite. PMID- 30433426 TI - Report of Cases Treated in Professor Macleod's Surgical Wards in the Western Infirmary during the Year Ending 31st October, 1876. PMID- 30433427 TI - Glasgow Pathological and Clinical Society-Session 1875-76. PMID- 30433428 TI - Case of Pemphigus Chronicus. PMID- 30433429 TI - Medico-Chirurgical Society-Session 1876-77. PMID- 30433430 TI - The Pathology of Embolism. Being an Address Delivered to the Glasgow Pathological and Clinical Society at the Opening of Session 1876-77, by the President. PMID- 30433431 TI - Paget's Disease of the Nipple. PMID- 30433432 TI - Gynaecological Notes. PMID- 30433433 TI - Puerperal Eclampsia. PMID- 30433434 TI - Introductory Address Delivered at the Opening of the Winter Session of the Glasgow Royal Infirmary School of Medicine. PMID- 30433435 TI - Western Infirmary. PMID- 30433436 TI - Address at the Opening of the Medico-Chirurgical Society. PMID- 30433437 TI - Current Topics. PMID- 30433438 TI - Glasgow Royal Infirmary. PMID- 30433439 TI - Medico-Chirurgical Society. PMID- 30433440 TI - Current Topics. PMID- 30433441 TI - Scleroderma Adultorum. PMID- 30433442 TI - False Aneurism of the Labium (Commonly Called Thrombus) Following Parturition. PMID- 30433443 TI - On the Rationale of Cold as a Cause of Disease. PMID- 30433444 TI - Glasgow Eye Infirmary. PMID- 30433445 TI - On the Frothing of Urine and Other Organic Liquids. PMID- 30433447 TI - Medico-Chirurgical Society. PMID- 30433446 TI - Glasgow Royal Infirmary. PMID- 30433448 TI - Notes of a Case in Which Chrysophanic Acid Was Administered Internally by Accident. PMID- 30433449 TI - Medico-Chirurgical Society. PMID- 30433450 TI - Traumatic Aneurism of the Temporal-Subcutaneous Compression-Cure. PMID- 30433451 TI - On Epidemics of Dengue Fever: Their Diffusion and Etiology. PMID- 30433452 TI - Western Infirmary. PMID- 30433453 TI - The International Medical Congress of 1881. PMID- 30433454 TI - Current Topics. PMID- 30433455 TI - Necessity for and Location of Contagious and Infectious Hospitals. PMID- 30433456 TI - On the Symptoms and Cure of Croup. PMID- 30433458 TI - Glasgow Royal Infirmary. PMID- 30433457 TI - Cases Illustrative of the Influence of Nitro-Glycerine in Angina Pectoris, and of Casca in Dilatation of the Heart. PMID- 30433459 TI - Current Topics. PMID- 30433460 TI - Pathology and Treatment of Croup. PMID- 30433461 TI - Medico-Chirurgical Society. PMID- 30433462 TI - Four Unusual Obstetric Cases. PMID- 30433463 TI - Periscope of Dermatology: No. III. PMID- 30433464 TI - Historical Note on the Occurrence of Laryngeal and Tracheal Diphtheria in Glasgow at the Beginning of the Nineteenth Century. PMID- 30433465 TI - Accidental Poisoning with Bichromate of Potash. PMID- 30433466 TI - Cases of Ulcerated Sore Throat Terminating in Croup. PMID- 30433467 TI - Glasgow Royal Infirmary. PMID- 30433468 TI - Pathological and Clinical Society. PMID- 30433469 TI - Medico-Chirurgical Society. PMID- 30433470 TI - Western Infirmary. PMID- 30433471 TI - On Insanity in Some of Its Practical Aspects: Being the President's Address at the Annual Meeting of the Glasgow and West of Scotland Branch of the British Medical Association, 24th June, 1881. Delivered at the Glasgow Royal Asylum, Gartnavel. PMID- 30433472 TI - History of a Personal Attack of Typhoid Fever: Being His Thesis for the Degree of M.D. in the University of Glasgow, with Slight Alterations. PMID- 30433473 TI - Cases Illustrating Some Unusual Forms of Necrosis. PMID- 30433474 TI - Foreign Bodies in the Ear. PMID- 30433475 TI - Proportion the Law of Health: Extracted from an Address to the University Medico Chirurgical Society, Delivered in March, 1881. PMID- 30433476 TI - Report of a Case with Funic Souffle. PMID- 30433478 TI - Presidential Remarks. Hunt's Medico-Chirurgical Society, 23rd February, 1881. PMID- 30433477 TI - Pathological and Clinical Society. PMID- 30433479 TI - Western Infirmary: Clinical Surgery Report. PMID- 30433481 TI - Current Topics. PMID- 30433480 TI - The Glasgow Hospital and Dispensary for Diseases of the Ear. PMID- 30433483 TI - Glasgow Royal Infirmary. PMID- 30433482 TI - The Western Medical School: Introductory Address, Session 1881-82. PMID- 30433484 TI - Western Infirmary. PMID- 30433485 TI - Glasgow Royal Infirmary. PMID- 30433486 TI - Some Points in Tracheotomy. PMID- 30433488 TI - Medico-Chirurgical Society. PMID- 30433487 TI - Some Questions on the Pathological Relations of Tubercle, Struma, and Phthisis Pulmonalis. PMID- 30433489 TI - Current Topics. PMID- 30433490 TI - On Some Medical Complications of Surgical Practice: Being His Introductory Address as President of the Pathological and Clinical Society of Glasgow. PMID- 30433491 TI - Removable Axis-Traction Rods for Midwifery Forceps. PMID- 30433492 TI - Glasgow Southern Medical Society. PMID- 30433493 TI - On the Use of Antiseptics in Obstetrics and Gynecology. PMID- 30433494 TI - On Certain Anatomical Relations between Abscess of Brain and Aural Disease. PMID- 30433495 TI - Introductory Lecture to the Clinical Obstetric Course of 1881, in the Glasgow Maternity Hospital, North Portland Street. PMID- 30433496 TI - Current Topics. PMID- 30433497 TI - Western Infirmary. PMID- 30433498 TI - Notes on a Case of Poisoning by Carbolic Acid. PMID- 30433499 TI - On a Case of Phthisis Ab Haemoptoe. PMID- 30433500 TI - On Phthisis Pulmonalis, Especially Its Relation to Tuberculosis. PMID- 30433501 TI - The Differential Diagnosis of a Case of Epileptiform Convulsions: Being a Lecture Delivered in the Extra-Academical School of Medicine, Edinburgh, during the Summer Session, 1880. PMID- 30433502 TI - Western Infirmary. PMID- 30433504 TI - Dr. Borland. PMID- 30433503 TI - Discussion on the Pathology of Phthisis Pulmonalis. PMID- 30433505 TI - Glasgow Royal Infirmary. PMID- 30433506 TI - On the Qualifications and Duties of a Hospital Nurse. PMID- 30433507 TI - On a Case of Enteric Fever, in Which Quinine Was Employed as an Antipyretic. PMID- 30433508 TI - Current Topics. PMID- 30433509 TI - Cases of Congenital Malformation of the Aortic Valve, with Remarks on the Influence of Such Lesions in Producing Disease in after Life. PMID- 30433510 TI - Glasgow Royal Infirmary. PMID- 30433511 TI - Researches on Albumen; with Special Reference to Albuminuria. PMID- 30433513 TI - Medico-Chirurgical Society. PMID- 30433512 TI - Glasgow Southern Medical Society. PMID- 30433514 TI - Case of Chrome Poisoning. PMID- 30433515 TI - Western Infirmary. PMID- 30433516 TI - The Uterine Sound. PMID- 30433517 TI - Dystocia from Hydrocephalus, with Remarks. PMID- 30433518 TI - Western Infirmary. PMID- 30433519 TI - Private Practice. PMID- 30433520 TI - Glasgow Hospital and Dispensary for Diseases of the Ear. PMID- 30433521 TI - On the Pathology of Writer's Cramp, with Illustrative Cases. PMID- 30433523 TI - Pathological and Clinical Society. PMID- 30433522 TI - Medico-Chirurgical Society. PMID- 30433524 TI - On Drainage of the Bladder after Lithotomy, with Particular Reference to Suprapubic Lithotomy. PMID- 30433526 TI - Glasgow Royal Infirmary. PMID- 30433525 TI - The Differential Diagnosis of a Case of Epileptiform Convulsions: Being a Lecture Delivered in the Extra-Academical School of Medicine, Edinburgh, during the Summer Session, 1880. PMID- 30433527 TI - Case of Haematoma of the Pericranium in a Child, Simulating Hydrocephalus and Associated with Constitutional Syphilis. PMID- 30433528 TI - Glasgow Southern Medical Society. PMID- 30433529 TI - Medico-Chirurgical Society. PMID- 30433531 TI - Current Topics. PMID- 30433530 TI - Glasgow Royal Infirmary. PMID- 30433532 TI - The Importance of a Knowledge of Diseases of the Ear to the Student and General Practitioner of Medicine. PMID- 30433533 TI - Diabetes Insipidus, with Great Enlargement of the Bladder: Improvement under Treatment. PMID- 30433534 TI - Western Infirmary. PMID- 30433535 TI - Pathological and Clinical Society. PMID- 30433536 TI - Note on the Treatment of Club Foot. PMID- 30433537 TI - Short Notes on a Rare Obstetric Case, with Specimen of Acephalous Foetus. PMID- 30433538 TI - A Few Surgical Cases. PMID- 30433539 TI - Pathological and Clinical Society. PMID- 30433540 TI - A Case of Spontaneous Lateral Sclerosis of the Spinal Cord and One of Poliomyelitis Anterior. PMID- 30433541 TI - On a Case of Pyelo-Nephritis with Micrococci. PMID- 30433542 TI - Current Topics. PMID- 30433543 TI - Medico-Chirurgical Society. PMID- 30433544 TI - The Glasgow Hospital and Dispensary for Diseases of the Ear. PMID- 30433545 TI - Three Attacks of Scarlet Fever within Two Years in the Same Patient. PMID- 30433546 TI - On the Existence of Typhus with Enteric Fever. PMID- 30433547 TI - Glasgow Royal Infirmary. PMID- 30433549 TI - Western Infirmary. PMID- 30433548 TI - Address to the Medical Students, at the Opening of the Winter Session, 1881-82, in the University of Glasgow. PMID- 30433550 TI - Lithotomy and Lithotrity, with Examples. PMID- 30433551 TI - Case of Aneurism of the Arch of the Aorta, Remarkable for the Almost Total Absence of Direct Physical Signs. PMID- 30433552 TI - Statistical Report of 1,088 Cases of Ear Disease Treated in the Glasgow Western Infirmary, from 6th November 1877, Till 28th May 1881, with Observations. PMID- 30433553 TI - Glasgow Royal Infirmary. PMID- 30433554 TI - Western Infirmary. PMID- 30433555 TI - Current Topics. PMID- 30433556 TI - On the Pathology of Cerebral Haemorrhage. PMID- 30433557 TI - Medico-Chirurgical Society. PMID- 30433558 TI - Students' Medical Societies and the Times We Live in: An Address to the Glasgow University Medico-Chirurgical Society, Delivered in November, 1881. PMID- 30433559 TI - A New Operation for Uterine Displacements. PMID- 30433560 TI - On the Clinical History and Diagnosis of Haematoma of the Dura Mater. PMID- 30433561 TI - On the Pathological Anatomy of Tuberculosis of the Fallopian Tube. PMID- 30433562 TI - Medico-Chirurgical Society. PMID- 30433563 TI - Glasgow Royal Infirmary. PMID- 30433564 TI - A Case of Rheumatic Fever, with Hyperpyretic Temperature. PMID- 30433565 TI - Glasgow Southern Medical Society. PMID- 30433567 TI - Current Topics. PMID- 30433566 TI - One Hundred and Thirty-Eight Cases of Amputation of the Scrotum for Elephantiasis Arabum. PMID- 30433569 TI - Current Topics. PMID- 30433568 TI - Sanitary Legislation and the Duties of the Medical Profession in Relation to the Public Health: Lecture Introductory to a Course on Hygiene and Public Health Delivered 6th May, 1882. PMID- 30433570 TI - On a Case of Triplets. PMID- 30433571 TI - Western Infirmary. PMID- 30433572 TI - Health Resorts at Home and Abroad: No. II. PMID- 30433574 TI - Medico-Chirurgical Society. PMID- 30433573 TI - The Treatment of Certain Intractable Forms of Purulent Discharge from the Ear. PMID- 30433575 TI - Cyst of Fibula (Serous)-Excision of Upper Half of Fibula. PMID- 30433576 TI - Glasgow Royal Infirmary. PMID- 30433577 TI - Glasgow Southern Medical Society. PMID- 30433579 TI - Private Practice: Case of Congenital Closure of Rectum. PMID- 30433578 TI - The Case of Charles H. Warren. PMID- 30433580 TI - Medico-Chirurgical Society. PMID- 30433581 TI - Glasgow Royal Infirmary. PMID- 30433582 TI - Western Infirmary. PMID- 30433584 TI - On Some Points Connected with the Management of Labour. PMID- 30433583 TI - Abdominal Abscess: Following Enteric Fever. PMID- 30433585 TI - Health Resorts at Home and Abroad. PMID- 30433587 TI - Nerve-Stretching in a Case of Locomotor Ataxia, with Good Result. PMID- 30433586 TI - Salicylic Acid: Its History and Uses. PMID- 30433589 TI - Current Topics. PMID- 30433588 TI - The Pathology of Diabetes Mellitus. PMID- 30433590 TI - Pathological and Clinical Society. PMID- 30433591 TI - Case of Lateral and Supra-Pubic Lithotomy. PMID- 30433592 TI - Puerperal Eclampsia. PMID- 30433593 TI - Remarks on the Premonitory Stage of Phthisis and Its Importance in Relation to Treatment. PMID- 30433594 TI - An Experimental Enquiry into the Amount of Heating Which Air Undergoes in the Upper Part of the Air-Passages during Inspiration, with Reference to the After Treatment of Tracheotomy. PMID- 30433595 TI - Medico-Chirurgical Society. PMID- 30433596 TI - On Agaricus in the Treatment of Night Sweating in Phthisis. PMID- 30433597 TI - Pathological and Clinical Society. PMID- 30433598 TI - Western Infirmary. PMID- 30433599 TI - The Double Splint in Affections of the Hip. PMID- 30433600 TI - Current Topics. PMID- 30433601 TI - Glasgow Royal Infirmary. PMID- 30433602 TI - Seven Cases of Amputation. PMID- 30433604 TI - Current Topics. PMID- 30433603 TI - Contributions on Diseases of the Ear : No. II. Furuncular or Circumscribed Inflammation of the External Auditory Canal-Syn.: Otitis Externa Circumscripta Boils in the Ear. PMID- 30433605 TI - Idiopathic Salivation in a Child. PMID- 30433607 TI - On the Lymphatic System of the Abdomen in Relation to the Extension of Inflammation, Tuberculosis, and Cancer. PMID- 30433606 TI - Sanitary Legislation and the Duties of the Medical Profession in Relation to the Public Health: Health Lecture No. 2. PMID- 30433608 TI - On the Unity of Poison in Scarlet, Typhoid, and Puerperal Fevers; Diphtheria, Sore Throats; and Certain Allied Ailments; and Many Other Affections Heretofore Usually Considered to Be Separate and Entirely Distinct Diseases. PMID- 30433610 TI - Western Infirmary. PMID- 30433609 TI - Poisonous Effects Produced by the Topical Use of Iodoform. PMID- 30433611 TI - On a Case of Congenital Absence of the Uterus and Vagina. PMID- 30433612 TI - Note on Paget's Disease of the Nipple. PMID- 30433614 TI - Current Topics. PMID- 30433613 TI - Contributions on Diseases of the Ear : No. IV. Abnormal States of the Ceruminous Secretion. PMID- 30433615 TI - Glasgow Royal Infirmary. PMID- 30433616 TI - Notes of Four Cases of Cerebral and Spinal Tumours. PMID- 30433618 TI - Current Topics. PMID- 30433617 TI - Case of Voluntary Dislocations of the Hip and Jaw. PMID- 30433619 TI - Western Infirmary. PMID- 30433620 TI - A Case of Congenital Malformation of the Heart. PMID- 30433621 TI - Medico-Chirurgical Society. PMID- 30433622 TI - The Indications for the Use of Digitalis. PMID- 30433623 TI - Glasgow Royal Infirmary. PMID- 30433624 TI - An Address on Scottish Medical Teaching, Academic and Extra-Academic, Delivered at the Glasgow Western Medical School, 1st November, 1882. PMID- 30433626 TI - On the Treatment of Scarlet Fever. PMID- 30433625 TI - Statistics of Glasgow Lock Hospital Since Its Foundation in 1805-With Remarks on the Contagious Diseases Acts, and on Syphilis. PMID- 30433627 TI - A Month's Dispensary Work in Glasgow Royal Infirmary. PMID- 30433629 TI - A Case of Lepto-Meningitis Infantum. PMID- 30433628 TI - Abstract of a Clinical Lecture on Two Cases of Hemiplegia-the One the Result of Granular Degeneration of the Kidneys, the Other of Syphilis. PMID- 30433630 TI - Current Topics. PMID- 30433631 TI - Experiment on Brute Animals-Introductory Lecture at the Glasgow Veterinary College. PMID- 30433632 TI - Western Infirmary. PMID- 30433633 TI - Medico-Chirurgical Society. PMID- 30433634 TI - Case of Imperforate Anus. PMID- 30433635 TI - Pathological and Clinical Society. PMID- 30433636 TI - Current Topics. PMID- 30433637 TI - On Contraction of the Uterus and Posture after Completed Delivery. PMID- 30433638 TI - Haemorrhagic Diathesis in Three Generations. PMID- 30433640 TI - Glasgow Southern Medical Society. PMID- 30433639 TI - Pseudo-Hypertrophic Paralysis in Four Brothers. PMID- 30433642 TI - Medico-Chirurgical Society. PMID- 30433641 TI - On the Unity of Poison in Scarlet, Typhoid, and Puerperal Fevers; Diphtheria, Erysipelas, Sore Throats; Certain Forms of Diarrhoea, and Allied Affections; and in Many Other Ailments Heretofore Usually Considered to Be Separate and Entirely Distinct Diseases. PMID- 30433643 TI - Sanitary Legislation and the Duties of the Medical Profession in Relation to the Public Health: Lecture Introductory to a Course on Hygiene and Public Health Delivered 6th May, 1882. PMID- 30433644 TI - Glasgow Royal Infirmary. PMID- 30433645 TI - Two Cases of Ventricular Hydrocephalus: One Due to Pressure on the Sinuses by a Tumour in the Cerebellum, the Other to Thrombosis of Galen's Vein. PMID- 30433646 TI - Paget's Disease of the Nipple. PMID- 30433647 TI - Note on Tertiary-Syphilis of the Pharynx. PMID- 30433648 TI - Glasgow Royal Infirmary. PMID- 30433649 TI - On the Unity of Poison in Scarlet, Typhoid, and Puerperal Fevers; Erysipelas, Diphtheria, Sore Throats, Certain Forms of Diarrhoea, and Allied Affections; Pleurisy, Pneumonia, Pleuro-Pneumonia; and Many Other Ailments Usually Considered to Be Separate and Entirely Distinct Diseases. PMID- 30433650 TI - A Case of Eczema of the Nipple and Areola; with Remarks on the Nature and Diagnosis of That Affection. PMID- 30433651 TI - Private Practice. PMID- 30433653 TI - Current Topics. PMID- 30433652 TI - On the Occurrence of Three Eruptions during One Attack of Measles. PMID- 30433654 TI - The Photography of Microscopic Sections. PMID- 30433655 TI - Obstinate Vomiting in Pregnancy. PMID- 30433656 TI - Western Infirmary. PMID- 30433657 TI - Current Topics. PMID- 30433658 TI - A Defence of the Contagious Diseases Acts and of Government Lock Hospitals. PMID- 30433659 TI - Glasgow Southern Medical Society. PMID- 30433660 TI - Pathological and Clinical Society. PMID- 30433661 TI - The Mercurial and Non-Mercurial Treatment of Syphilis. PMID- 30433662 TI - A Lecture Introductory to a Course on Aural Pathology. PMID- 30433663 TI - Glasgow Royal Infirmary. PMID- 30433665 TI - Pathological and Clinical Society. PMID- 30433664 TI - Western Infirmary. PMID- 30433666 TI - Note on Increased Resistance on Percussion as an Aid to Diagnosis. PMID- 30433667 TI - On a Case of Complicated Malformations. PMID- 30433668 TI - Voluntary Lock Hospitals and the Contagious Diseases Acts. Reply to Dr. Alexander Patterson. PMID- 30433669 TI - On Some of the Advances Which Have Been Made in Surgery during the Last Decade. PMID- 30433670 TI - A Case of Impermeable Stricture of the Urethra, Treated by Perineal Section According to Wheelhouse's Plan. PMID- 30433671 TI - On the Pathological Anatomy of Tuberculosis of the Uterus and Fallopian Tubes. PMID- 30433672 TI - Western Infirmary. PMID- 30433673 TI - Vaccinal Eruptions. PMID- 30433674 TI - On Aural Diagnosis: Lecture Delivered in the Glasgow Hospital and Dispensary for the Diseases of the Ear, February, 1882. PMID- 30433675 TI - Minute Organisms and Their Relation to Disease: Part II. PMID- 30433676 TI - Glasgow Southern Medical Society. PMID- 30433677 TI - Address on the Treatment of Pulmonary Consumption, Delivered at the Glasgow Pathological and Clinical Society, 14th November, 1882. PMID- 30433678 TI - Case of Acute Foetid Empyema, Treated by Incision in Pleural Cavity, with Copious Ablution; Rapid Recovery. PMID- 30433679 TI - Current Topics. PMID- 30433680 TI - Glasgow Royal Infirmary. PMID- 30433681 TI - Western Infirmary. PMID- 30433682 TI - Koch's Researches on Tuberculosis. PMID- 30433683 TI - Medico-Chirurgical Society. PMID- 30433684 TI - Private Practice. PMID- 30433685 TI - An Exposure of the Contagious Diseases Acts, and of Government Lock Hospitals. PMID- 30433686 TI - A New Dressing for Large Ulcers. PMID- 30433687 TI - Minute Organisms and Their Relation to Disease: Part I. PMID- 30433689 TI - Current Topics. PMID- 30433688 TI - The Tubercular Bacillus and Its Relation to Phthisis Pulmonalis: Being a Paper Read to the Glasgow University Medico-Chirurgical Society, 9th February, 1883. PMID- 30433690 TI - Notes of a Case of Enteric Fever Which Had Two Relapses, with an Unusual Prolongation of the Interval between the First and Second Attacks. PMID- 30433691 TI - Western Infirmary. PMID- 30433692 TI - On Bi-Chromate of Potash Poisoning. PMID- 30433693 TI - Tissue Repair, or the Pathology of the Subcutaneous Operation by Injection for the Cure of Hernia: Part II. Permanent Cure of Hernia by Subcutaneous Injection. PMID- 30433694 TI - A Case of Double Uterus in the Living Subject. PMID- 30433695 TI - On Venesection. PMID- 30433696 TI - Western Infirmary. PMID- 30433697 TI - Erratum. AB - [This corrects the article on p. 211 in vol. 19.]. PMID- 30433698 TI - Chlorate of Potash as a Therapeutic Agent. PMID- 30433700 TI - Current Topics. PMID- 30433699 TI - Tissue Repair, or the Pathology of the Subcutaneous Operation by Injection for the Cure of Hernia: Part I. On Inflammation and Its Relation to Tissue Repair. PMID- 30433701 TI - A Lecture Introductory to a Course on Aural Diagnosis. PMID- 30433702 TI - Medico-Chirurgical Society. PMID- 30433703 TI - Notes of Two Cases of Tumour of the Larynx, in One of Which the Tumour Was Successfully Removed by Thyrotomy. PMID- 30433704 TI - Pathological and Clinical Society. PMID- 30433705 TI - Glasgow Eastern Medical Society. PMID- 30433706 TI - Current Topics. PMID- 30433707 TI - The X-Ray Treatment of Ringworm of the Scalp. PMID- 30433708 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433709 TI - The Use of Physical Methods in the Treatment of Chronic Constipation, with Special Reference to Sinusoidal Currents. PMID- 30433710 TI - Case of Associated Cutaneous and Gastro-Intestinal Anthrax. PMID- 30433711 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th May, 1911. PMID- 30433713 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433712 TI - Two Cases of Aneurysm of the Splenic Artery. PMID- 30433715 TI - Medical Education in the United States and Canada. PMID- 30433714 TI - Note on the Treatment of Phthisis Pulmonalis in the Victoria Infirmary. PMID- 30433716 TI - Current Topics. PMID- 30433717 TI - The Protein Requirements of the Body. PMID- 30433718 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 25th March, 1911. PMID- 30433719 TI - Additional Notes on the Treatment of Sciatica by Means of Saline Injections. PMID- 30433720 TI - New Preparations, &c. PMID- 30433721 TI - New Preparations, &c. PMID- 30433722 TI - An Unusual Complication of Measles. PMID- 30433723 TI - The Dr. James Watson Lectures on Recent Advances in Haematology. PMID- 30433724 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th February, 1911. PMID- 30433725 TI - Current Topics. PMID- 30433727 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433726 TI - What Are We Doing to Combat Infant Mortality? PMID- 30433728 TI - New Preparations, &c. PMID- 30433729 TI - Acute Pneumonia: Its Prognosis and Treatment. PMID- 30433730 TI - The X-Rays in Treatment. PMID- 30433731 TI - Current Topics. PMID- 30433732 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433734 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd April, 1911. PMID- 30433733 TI - Enucleation of the Tonsil for Chronic Disease. PMID- 30433735 TI - Partick and District Medical Society. PMID- 30433736 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th December, 1910. PMID- 30433737 TI - New Preparations, &c. PMID- 30433738 TI - The Unfit. PMID- 30433739 TI - The Dr. James Watson Lectures on Recent Advances in Haematology. PMID- 30433740 TI - Scottish Otological and Laryngological Society. PMID- 30433741 TI - Graduated Labour at Bellefield Sanatorium. PMID- 30433742 TI - Current Topics. PMID- 30433743 TI - Current Topics. PMID- 30433744 TI - New Preparations, &c. PMID- 30433745 TI - Glasgow Northern Medical Society. PMID- 30433746 TI - Obstetrical and Gynaecological Society. PMID- 30433747 TI - Haematoporphyrinuria Not Due to Drugs, in a Patient Whose Urine Contained at Times Haemoglobin and at Times Sugar. PMID- 30433748 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 21st January, 1911. PMID- 30433750 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433749 TI - Some Remarks on the Position of Laryngology and Rhinology in Medicine. PMID- 30433751 TI - Adsorption of Proteins on Degradable Magnesium-Which Factors are Relevant? AB - Although the adsorption of proteins on the Mg surface was ascribed to be the main reason for the effect of proteins on magnesium (Mg) degradation, few studies about the adsorption of proteins on the Mg surface were performed due to the labile circumstances during immersion. In the present study, the adsorption of bovine serum albumin (BSA) and fibrinogen (Fib) on the Mg surface during and after immersion was extensively investigated in different media for the first time. The results revealed that BSA and Fib showed a similar adsorption trend on the Mg surface during and after immersion, and they adsorbed more on the Mg surface in Hank's balanced salt solution (HBSS) than in Dulbecco's modified Eagle medium Glutamax-I (DMEM). The possible influence factors for protein adsorption, such as pH, surface roughness, and wettability, were considered to elucidate different adsorption in HBSS and DMEM. It was found that the participation of Ca2+ in the formation of degradation products largely affected the degradation rate of Mg, changed surface roughness, compactness, and surface charge during immersion, which largely suppressed the adsorption of proteins on the Mg surface. PMID- 30433752 TI - Core-Shell Transformation-Imprinted Solder Bumps Enabling Low-Temperature Fluidic Self-Assembly and Self-Alignment of Chips and High Melting Point Interconnects. AB - We demonstrate the realization of core-shell transformation-imprinted solder bumps to enable low-temperature chip assembly, while providing a route to high temperature interconnects through transformation. The reported core-shell solder bump uses a lower melting point BiIn-based shell and a higher melting point Sn core in the initial stage. The bumps enable fluidic self-assembly and self alignment at relatively low temperatures (60-80 degrees C). The bumps use the high surface free energy of the liquid shell during the self-assembly to capture freely suspended Si dies inside a heated (80 degrees C) water bath, leading to well-ordered defect-free chip arrays; the molten liquid shell wets the metal contact (binding site) on the chips and yields self-aligned and electrically connected devices. The solid core provides the anchor point to the substrate. After the completion of the assembly, a short reflow raises the melting point, yielding a solid electrical connection. The low melting point liquid diffuses into the high melting point core. The tuning of the material ratios leads to tailored transformation-imprinted solders with high melting points (160-206 degrees C) in the final structure. PMID- 30433753 TI - Tailoring the Energy Levels and Cavity Structures toward Organic Cocrystal Microlasers. AB - Organic cocrystals with unique energy-level structures are potentially a new class of materials for the development of versatile solid-state lasers. However, till now, the stimulated emission in cocrystal materials remains a big challenge possibly because of the nonradiative charge-transfer (CT) transitions. Here, for the first time, we report organic cocrystal microlasers constructed by simultaneously tailoring the energy levels and cavity structures based on the intermolecular halogen-bonding interactions. The intermolecular interactions triggered different self-assembly processes, resulting in distinct types of high quality resonant microcavities. More importantly, the halogen-bonding interactions alleviated intermolecular CT and thus brought about a favorable four level energy structure for the population inversion and tunable lasing in the cocrystals. PMID- 30433754 TI - Facile Activation of Commercial Carbon Felt as a Low-Cost Free-Standing Electrode for Flexible Supercapacitors. AB - High cost, low capacitance, and complicated synthesis process are still the key limitations for carbon-negative materials to meet their industrial production and application in high-energy-density asymmetric supercapacitors (ASCs). In this work, we demonstrate the facile preparation of ultrahigh-surface-area free standing carbon material from low-cost industrial carbon felt (CF) and its application for flexible supercapacitor electrode with outstanding performance. Through a simple freeze-drying-assisted activation method, the as-prepared activated CF (ACF) was endowed with satisfactory flexibility, ultrahigh specific surface area of 2109 m2 g-1, good electric conductivity (311 S m-1), and excellent wettability to aqueous electrolyte. Owing to these merits, the ACF expressed an ultrahigh areal capacitance of 1441 mF cm-2, a high specific capacitance ( Cs) of 280 F g-1 based on the mass of the whole electrode, and an impressive cycling stability (87% retention after 5000 cycles). When applied as a flexible freestanding electrode for MnO2//ACF ASCs, the ACF-based device provided satisfactory areal energy densities of 0.283 and 0.104 mWh cm-2 in aqueous and quasi-solid electrolytes, respectively. The values outperform many previously reported carbon-based electrochemical devices. The low cost of raw material and the facile fabrication process, together with the high electrochemical performance, make our ACF electrode highly applicable for the mass production of flexible energy-storage devices. PMID- 30433755 TI - Ultra-Sensitive Wearable Pressure Sensor Assembled by Surface Patterned Polyolefin Elastomer Nanofiber Membrane Interpenetrated with Silver Nanowires. AB - Wearable pressure sensors with ultrahigh sensitivity and flexibility have been tremendously concerned due to their abilities to mimic human somatosensory system and percept surrounding pressure distribution. Herein, an ultrasensitive pressure sensor was fabricated with surface patterned nanofibrous membranes (SPNMs) via facile replica method from available plain-weaved nylon textiles. The SPNMs were composed of internal three-dimensional (3-D) interpenetrating polyolefin elastomer (POE) nanofiber and silver nanowires (Ag NWs). The effects of the geometry of surface patterns and the density of Ag NWs network on the sensing performance of the assembled pressure sensor were systematically investigated. The results indicated that the clavate grooves shaped surface patterns improved the sensitivity and the larger groove spacing contributed to higher sensitivities while the denser Ag NWs would reduce the sensing performance. The optimal pressure sensor assembled with SPNMs-45 and Ag NWs fraction of 3.8% showing high sensitivity (19.4 kPa-1) below the pressure of 2.76 kPa, low detection limit (<1.7 Pa), fast response (30 ms and 42ms) as well as excellent durability. These outstanding performances demonstrated its promising potential for wearable electronic applications, like detecting the spatial pressure distribution and monitoring the human muscle motions. PMID- 30433756 TI - Surface Chemistry of Atomically Precise Coinage-Metal Nanoclusters: From Structural Control to Surface Reactivity and Catalysis. AB - A comprehensive understanding of chemical bonding and reactions at the surface of nanomaterials is of great importance in the rational design of their functional properties and applications. With the rapid development in cluster science, it has become clear that atomically precise metal clusters represent ideal models for resolving various important and/or unsolved issues related to surface science. This Account highlights our recent efforts on the fabrication of ligand stabilized coinage nanoclusters with atomic precision from the viewpoint of surface coordination chemistry in particular. The successful synthesis of a large variety of metal clusters in our group has greatly benefitted from the development of an effective amine-assisted NaBH4 reduction method. First discussed in this Account is how the introduction of amines in the synthetic protocol enhances the long-term stability and high-yield production of Ag/Cu based metals in air. Such a method allows the utilization of different organic ligands as surface stabilizing agents to manipulate both the core and surface structures of metal nanoclusters, helping to understand the role of surface ligands in determining the structures of metal nanoclusters. The coordination chemistry of ligands used in the synthesis of metal nanoclusters is crucial in determining their overall shape, metal arrangement, surface ligand binding structure, chirality and also metal exposure. Detailed discussions are given in the following four different systems: (1) The co-use of phosphines and thiolates with rich coordination structures (2 to 4-coordinated) helps to control the formation of a sequence of Ag nanoclusters with a near-perfectly cubic shape; (2) The metal arrangements and surface structures of AuCu clusters highly depend on metal precursors and counter cations used in the synthesis; (3) Metal clusters with intrinsic chirality are readily prepared by introducing chiral ligands or counterions, making it possible to obtain optically active enantiomers and understand the origin of chirality of metal nanoclusters; (4) The variation of metal exposure of the inner metal core of metal nanocluster can be controlled by the surface ligand coordination structure. Such capabilities to manipulate the surface structure of metal nanoclusters allow the creation of model systems for investigating the structure-reactivity relationship of metal nanomaterials. Several important examples are then discussed to highlight the importance of ligand coordination chemistry in tuning the surface reactivity and catalysis of metal nanoclusters. For example, bulky thiolates on Ag are demonstrated to be more labile than small thiolates for making metal nanoclusters with both enhanced ligand exchange capability and catalysis. Alkynyl ligands can be thermally released from metal nanoclusters more easily than thiolates and halides while maintaining the overall structure, thereby serving as ideal systems for understanding the promoting effect of surface stabilizers on catalysis. Finally, we provide a perspective on the principles of surface coordination chemistry of metal nanoclusters and their potential applications with regards to catalysis of protected metal clusters. PMID- 30433757 TI - Correction to On-Demand Drug Release from Gold Nanoturf for a Thermo- and Chemotherapeutic Esophageal Stent. PMID- 30433758 TI - Fabrication and Characterization of Core-Shell Nanofibers Using a Next-Generation Airbrush for Biomedical Applications. AB - The core-shell polymeric nanofiber, owing to its better controlled release of embedded or encapsulated drugs in contrast with the single-compartment nanofibers, has been extensively studied for biomedical applications such as tissue engineering and wound healing. Electrospinning with co-axial needles is the dominant technique to fabricate nanofiber mat, however, associated with potential limitations such as high voltage requirement, costly equipment, slow deposition rate, required trained personal, not suitable in situ fabrication, and direct deposition of core-shell nanofibers on the wound at patient bedside. To address the above limitations, the work aims to introduce a novel co-axial airbrushing method to fabricate core-shell nanofibers using a simple setup and low-cost equipment, yet having a unique ability for fabrication at patient bedside and direct deposition on wound bed. Air-brush with a coaxial needle is designed to flow two different polymers solution with model biomolecules through core [PEO (polyethylene oxide)/poly-dl-lactide/PCL (polycaprolactone)] and shell (PCL/PEO) needle for the fabrication of the model core-shell nanofiber. Various processing parameters such as flow rate, air pressure, working distance, and concentration of polymer solution which affect the morphology of core-shell nanofibers were studied and found to have a prominent effect. The PCL-PEO nanofiber possesses a defined shell and core structure, tunable sustained release behavior of model proteins (bovine serum albumin and basic fibroblast growth factor; bFGF), and improved mechanical strength. In vitro interaction of human bone marrow-derived mesenchymal stem cells with core-shell fibers demonstrated the cytocompatibility and proliferative and differentiative (for bFGF loaded) properties of the core-shell nanofiber mat. Co-axial airbrushing can be used as a superior less-expensive technique for the fabrication of biomolecules/drug encapsulated core-shell fibers scaffold at patient bedside, which can mimic complex in vivo environment and could modulate cells behavior close to their in vivo condition for tissue regeneration and wound healing. PMID- 30433759 TI - High Selectivities among Monovalent Cations in Dialysis through Cation-Exchange Membranes Coated with Polyelectrolyte Multilayers. AB - Cation-exchange membranes allow preferential passage of cations over anions, but they show minimal selectivity among cations, which limits their use in ion separations. Recent studies show that modification of cation-exchange membranes with polyelectrolyte multilayers leads to exceptional monovalent/divalent cation electrodialysis selectivities, but no studies report high selectivity among monovalent ions. This work demonstrates that adsorption of protonated poly(allylamine) (PAH)/poly(4-styrenesulfonate) (PSS) multilayers on Nafion membranes leads to high K+/Li+ selectivities in Donnan dialysis, where K+ and Li+ ions in a source phase pass through the membrane and exchange with Na+ ions in a receiving phase. Addition of 0.01 M HNO3 to a source phase containing 0.01 M KNO3 and 0.01 M LiNO3 increases the K+/Li+ selectivity from 8 to ~60 through (PAH/PSS)5PAH-coated Nafion membranes, primarily because of a >=5-fold increase in K+ flux. These selectivities are much larger than the ratio of 1.9 for the aqueous diffusion coefficients of K+ and Li+, and uncoated Nafion membranes give a K+/Li+ selectivity <3. Bi-ionic transmembrane potential measurements at neutral pH confirm that the membrane is more permeable to K+ than Li+, but this selectivity is less than in Donnan dialysis with acidic solutions. In-situ ellipsometry data indicate that PAH/PSS multilayers (assembled at pH 2.3, 7.5 or 9.3) swell at pH 2.0, and this swelling may open cation-exchange sites that preferentially bind K+ to enable highly selective transport. The coated membranes also exhibit modest selectivity for K+ over H+, suggesting selective transport based on preferential partitioning of K+ into the coatings. Selectivity declines when increasing the source-phase KNO3 concentration to 0.1 M, perhaps because the discriminating transport pathway saturates. Moreover, selectivities are lower in electrodialysis than in Donnan dialysis, presumably because electrodialysis engages other transport mechanisms, such as electroosmosis and strong electromigration. PMID- 30433760 TI - Targeted Quantitative Profiling of GTP-Binding Proteins in Cancer Cells Using Isotope-Coded GTP Probes. AB - GTP-binding proteins play important roles in many essential biological processes, including cell signaling, trafficking, and protein synthesis. To assess quantitatively these proteins at the whole proteome level, we developed a high throughput targeted proteomic method based on the use of isotope-coded GTP probes and multiple-reaction monitoring (MRM) analysis. Targeted proteins were labeled with desthiobiotin-GTP probes, digested with trypsin, and the ensuing desthiobiotin-conjugated peptides were enriched with streptavidin beads for LC MS/MS analysis. We also established a Skyline MRM library based on shotgun proteomic data acquired for 12 different human cell lines. The library contained 605 tryptic peptides derived from 217 GTP-binding proteins, representing approximately 60% of the annotated human GTP-binding proteome. By using this library, in conjunction with isotope-coded GTP probes and scheduled LC-MRM analysis, we investigated the differential expression of GTP-binding proteins in a pair of primary/metastatic colon cancer cell lines (SW480 and SW620). We were able to quantify 97 GTP-binding proteins, and we further validated the differential expression of several GTP-binding proteins by Western blot analysis. Together, we developed a facile targeted quantitative proteomic method for the high-throughput analysis of GTP-binding proteins and applied the method for probing the altered expression of these proteins involved in colon cancer metastasis. PMID- 30433761 TI - Organic Semiconducting Polymer Nanoparticles for Photoacoustic Labeling and Tracking of Stem Cells in the Second Near-Infrared Window. AB - Photoacoustic (PA) imaging and tracking of stem cells plays an important role in the real-time assessment of cell-based therapies. Nevertheless, the limitations of conventional inorganic PA contrast agents and the narrow range of the excitation wavelength in the first near-infrared (NIR-I) window hamper the applications of PA imaging in living subjects. Herein, we report the design and synthesis of a second near-infrared (NIR-II) absorptive organic semiconducting polymer (OSP)-based nanoprobe (OSPN+) for PA imaging and tracking of stem cells. Comparison studies in biological tissue show that NIR-II light excited PA imaging of the OSPN+ has significantly higher signal-to-noise ratio than NIR-I light excited PA imaging, thereby demonstrating the superiority of the OSPN+ for deep tissue imaging. With good biocompatibility, appropriate size, and optimized surface property, the OSPN+ shows enhanced cellular uptake for highly efficient PA labeling of stem cells. In vivo investigations reveal significant NIR-II PA contrast enhancement of the transplanted OSPN+-labeled human mesenchymal stem cells by 40.6- and 21.7-fold in subcutaneous and brain imaging, respectively, compared with unlabeled cases. Our work demonstrates a class of OSP-based nanomaterials for NIR-II PA stem cell imaging to facilitate a better understanding and evaluation of stem cell-based therapies. PMID- 30433762 TI - Defect-Mediated Alloying of Monolayer Transition-Metal Dichalcogenides. AB - Alloying plays a central role in tailoring the material properties of 2D transition-metal dichalcogenides (TMDs). However, despite widespread reports, the details of the alloying mechanism in 2D TMDs have remained largely unknown and are yet to be further explored. Here, we combine a set of systematic experiments with ab initio density functional theory (DFT) calculations to unravel a defect mediated mechanism for the alloying of monolayer TMD crystals. In our alloying approach, a monolayer MoSe2 film serves as a host crystal in which exchanging selenium (Se) atoms with sulfur (S) atoms yields a MoS2 xSe2(1- x) alloy. Our study reveals that the driving force required for the alloying of CVD-grown films with abundant vacancy-type defects is significantly lower than that required for the alloying of exfoliated films with fewer vacancies. Indeed, we show that pre existing Se vacancies in the host MoSe2 lattice mediate the replacement of chalcogen atoms and facilitate the synthesis of MoS2 xSe2(1- x) alloys. Our DFT calculations suggest that S atoms can bind to Se vacancies and then diffuse throughout the host MoSe2 lattice via exchanging the position with Se vacancies, further supporting our proposed defect-mediated alloying mechanism. Beside native vacancy defects, we show that the existence of large-scale defects in CVD-grown MoSe2 films causes the fracture of alloys under the alloying-induced strain, while no such effect is observed in exfoliated MoSe2 films. Our study provides a deep insight into the details of the alloying mechanism and enables the synthesis of 2D alloys with tunable properties. PMID- 30433763 TI - Fast 3D Microscopy Imaging of Contacts Between Surfaces Using a Fluorescent Liquid. AB - A novel method is presented for the rapid direct 3D visualization of the contact between two surfaces by means of fluorescence microscopy using a fluorescent liquid. Distances between the surfaces of up to several hundred nanometers can be determined with subnanometer accuracy in 3D and within seconds of measurement time. The method opens new possibilities for research in the areas of contact mechanics, friction, wear, and lubrication. PMID- 30433764 TI - Sensitive Bacterial Detection via Dielectrophoretic-Enhanced Mass Transport Using Surface-Plasmon-Resonance Biosensors. AB - The performance of surface plasmon resonance (SPR)-based bacterial biosensors is often compromised as a result of diffusion-limited mass transport of bacteria to the sensing surface. In this work, dually functional interdigitated electrodes (IDEs) were developed to sustain SPR and increase bacterial mass transport through external application of dielectrophoresis (DEP). IDEs were defined into 50 nm Au films with fixed electrode gaps ( EG = 5 MUm) and varied electrode widths ( EW = 10, 20, and 100 MUm), referred to as interdigitated SPR (iSPR) chips. The iSPR chips with EW = 100 MUm effectively supported SPR, with comparable sensitivity to those of conventional SPR chips. The surfaces of iSPR chips ( EW = 100 MUm) were modified with mannose to target the FimH adhesin of Escherichia coli and increase cellular adhesion. An LOD of ~3.0 * 102 CFU/mL E. coli was achieved on mannosylated iSPR chips under positive-DEP conditions, which is about a 5 order of magnitude improvement compared with those of mannosylated conventional SPR chips without DEP. Furthermore, secondary antibody amplification enabled selective enhancement of dilute (103 CFU/mL) E. coli suspensions, whereas no amplification was observed for concentrated (108 CFU/mL) nontarget ( Staphylococcus epidermidis) bacterial suspensions. The results presented here indicate the great potential of the incorporation of DEP into SPR biosensors for rapid, sensitive, and specific detection of bacteria with broad applications in areas of biomedical diagnostics, environmental monitoring, food safety, and homeland security. PMID- 30433765 TI - Engineering a Coenzyme A Detour To Expand the Product Scope and Enhance the Selectivity of the Ehrlich Pathway. AB - The Ehrlich pathway is a major route for the renewable production of higher alcohols. However, the product scope of the Ehrlich pathway is restricted, and the product selectivity is suboptimal. Here, we demonstrate that a Coenzyme A (CoA) detour, which involves conversion of the 2-keto acids into acyl-CoAs, expands the biological toolkit of reaction chemistries available in the Ehrlich pathway to include the gamut of CoA-dependent enzymes. As a proof-of-concept, we demonstrated the first biosynthesis of a tertiary branched-alcohol, pivalcohol, at a level of ~10 mg/L from glucose in Escherichia coli, using a pivalyl-CoA mutase from Xanthobacter autotrophicus. Furthermore, engineering an enzyme in the CoA detour, the Lactobacillus brevis CoA-acylating aldehyde dehydrogenase, allowed stringent product selectivity. Targeted production of 3-methyl-1-butanol (3-MB) in E. coli mediated by the CoA detour showed a 3-MB:side-product (isobutanol) ratio of >20, an increase over the ratios previously achieved using the conventional Ehrlich pathway. PMID- 30433766 TI - Blocking-Free and Substrate-Independent Serological Microarray Immunoassays. AB - In bioanalytical applications, many coating strategies have been established for so-called "blocking" of the surfaces. However, most of the procedures developed so far require additional processing steps for surface blocking and small variations in the blocking efficiency result in increased background noise, which lowers the overall sensitivity of an assay. In this study, we demonstrate the preparation of a bioanalytical surface with a thin film of a photo-cross-linkable copolymer that is transformed photochemically into a surface-attached hydrogel network. The presented coating is directly applicable to various plastic substrates that are used for bioassays without the need for any prior surface modification. Such a strategy allows facile one-step immobilization of biomolecules for bioanalysis and protein-repellent properties for avoiding unspecific adsorption of analyte molecules during the assay. The protein adsorption behavior of the hydrogel-coated and blank surfaces is measured by SPR with human serum and physisorption of labeled detection antibodies. We show that the hydrogel surfaces used lower unspecific background signals and background noise and thus increase the sensitivities of the microarray immunoassays. PMID- 30433767 TI - Use of Light-Degradable Aliphatic Polycarbonate Nanoparticles As Drug Carrier for Photosensitizer. AB - Aliphatic poly(carbonate)s (APCs) with rapid and controlled degradation upon specific stimulation have great advantages for a variety of biomedical and pharmaceutical applications. In the present work, we reported a new poly(trimethylene carbonate) (PTMC)-based copolymer containing multiple 4,5 dimethoxy-2-nitrobenzyl photo cleavable groups as pendent chains. The six membered light-responsive cyclic carbonate monomer (LrM) was first prepared from 2-(hydroxymethyl)-2-methylpropane-1,3-diol and 4,5-dimethoxy-2-nitrobenzyl alcohol and then copolymerized with trimethylene carbonate (TMC) by 1,8 diazabicyclo(5.4.0)undec-7-ene (DBU) catalyzed ring-opening polymerization (ROP) to afford the light-responsive polycarbonate (LrPC). The light-triggered decomposition of LrM and LrPC was studied by NMR, UV/vis spectroscopy, and size exclusion chromatography (SEC), as well as ESI-ToF mass spectrometry. Stable monodisperse nanoparticles with hydrodynamic diameter of 100 nm could be formulated from 25% LrPC and 75% poly(lactide- co-glycolide) (PLGA) and applied for the encapsulation of temoporfin. Upon irradiation with UV light these particles displayed a significant decrease of the particle countrate and increased the release rate of temoporfin in comparison to standard PLGA nanoparticles. This work demonstrated that a combination of encapsulation of photosensitizer and light degradation using light-responsive polymers is suitable to enhance photodynamic therapy (PDT). PMID- 30433768 TI - Elements of RNA Design. PMID- 30433769 TI - Concentrations, Trends, and Air-Water Exchange of PCBs and Organochlorine Pesticides Derived from Passive Samplers in Lake Superior in 2011. AB - The largest fresh water body in North America, Lake Superior, has the potential to both accumulate and serve as a secondary source of persistent bioaccumulative toxins, such as polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs). Polyethylene passive samplers (PEs) were thus simultaneously deployed at 19 sites in surface water and near surface atmosphere across Lake Superior to determine air and water concentrations and air-water gradients of 18 PCBs and 24 OCPs. PCBs in the air and water were characterized by penta- and hexachlorobiphenyls with distribution along the coast correlated with proximity to developed areas. Surface water and atmospheric concentrations were dominated by alpha-HCH (average 250 pg L-1 and 4.2 pg m-3, respectively), followed by HCB (average 17 pg L-1 and 89 pg m-3, respectively). Decreases in open lake concentrations of PCBs in water and air from spring to summer were consistent with ongoing volatilization from the surface layer as the main cause. Conversely, alpha-endosulfan was consistently deposited into the surface water of Lake Superior. Results indicated that PCBs were depleted in the surface mixed layer, implying a physical limit on evasive fluxes. This was corroborated with measurements from a vertical profile, displaying greater PCB concentrations at depth. PMID- 30433770 TI - Modification of Poly(ethylene 2,5-furandicarboxylate) with Bio-based 1,5 Pentanediol: Significantly Toughened Copolyesters Retaining High Tensile Strength and O2 Barrier Property. AB - Poly(ethylene 2,5-furandicarboxylate) (PEF) is a bio-based polyester characterized by high gas barrier properties as well as high tensile modulus and strength, but poor toughness. Toughening PEF without sacrificing its modulus, strength and gas barrier performance is a great challenge for PEF modification. In this study, high molecular weight random poly(ethylene-co-1,5-pentylene 2,5 furandicarboxylate)s (PEPeFs) were synthesized via melt copolycondensation of 2,5 furandicarboxylic acid (FDCA), ethylene glycol (EG) and 1,5-pentanediol (PeDO), a cheap, bio-based and commercially available odd-carbon comonomer. The synthesized PEPeFs were characterized and assessed with intrinsic viscosity, ATR-FTIR, 1H NMR, DSC, TGA and tensile, impact and O2 permeation test. Mayo-Lewis equation with "reactivity ratio" of 3.78 for PeDO and 0.75 for EG could be used as an empirical equation to correlate the copolyester composition (?PeF) with monomer composition. PEPeFs proved amorphous copolyesters having excellent thermal stability. Brittle-ductile transition was achieved at ?PeF as low as 9 mol%. Increasing ?PeF led to increase in elongation at break and notch impact strength and decrease in Tg, O2 barrier and tensile modulus and strength. However, in comparison with PEF, PEF-rich PEPeFs (?PeF 9-47%) not only showed greatly improved elongation at break (29-265% vs. 4%) and enhanced impact strength (2.1 3.9 vs. 2.1 kJ/m2), and at the same time retained very high Young's modulus (2.8 3.3 vs. 3.4 GPa) and yielding strength (72-83 vs. 84 MPa). Particularly, when compared with bottle-grade PET, PE82Pe18F possesses equal Tg (ca. 75 oC) and comparable elongation at break (ca. 115%), but greatly improved yielding strength (83 MPa) and O2 gas barrier property (4.8 times). As modified PEF materials possessing superior thermo-mechanical and O2 gas barrier properties, these integrally bio-based copolyesters may find practical applications in eco packaging and other fields. PMID- 30433771 TI - Enhancing Protein Stability with Genetically Encoded Noncanonical Amino Acids. AB - The ability to add noncanonical amino acids to the genetic code may allow one to evolve proteins with new or enhanced properties using a larger set of building blocks. To this end, we have been able to select mutant proteins with enhanced thermal properties from a library of E. coli homoserine O-succinyltransferase ( metA) mutants containing randomly incorporated noncanonical amino acids. Here, we show that substitution of Phe 21 with ( p-benzoylphenyl)alanine (pBzF), increases the melting temperature of E. coli metA by 21 degrees C. This dramatic increase in thermal stability, arising from a single mutation, likely results from a covalent adduct between Cys 90 and the keto group of pBzF that stabilizes the dimeric form of the enzyme. These experiments show that an expanded genetic code can provide unique solutions to the evolution of proteins with enhanced properties. PMID- 30433772 TI - One-Pot 1,1-Dihydrofluoroalkylation of Amines Using Sulfuryl Fluoride. AB - Sulfuryl fluoride, SO2F2, has been known and used as a fumigant for over 50 years but it has only recently gained widespread interest as a reagent for organic synthesis. Herein we report a novel application of sulfuryl fluoride gas in a new 1,1-dihydrofluoroalkylation reaction, which simply involves bubbling SO2F2 through a solution of amine, 1,1-dihydrofluoroalcohol, and diisopropylethylamine. The reaction is successful for a wide range of primary and secondary amines, as well as several 1,1-dihydrofluoroalcohols, to afford the 1,1 dihydrofluoroalkylated amines in 42% to 80% isolated yields. The reaction also displays excellent functional group tolerance. The ease of the one-pot activation and alkylation, combined with the wide substrate scope make this new procedure an attractive alternative to existing 1,1-dihydrofluoroalkylation methodologies. PMID- 30433773 TI - Plasmonic Enhancement of NIR to UV Upconversion by a Nanoengineered Interface Consisting of NaYF4:Yb,Tm Nanoparticles and a Gold Nanotriangle Array for Optical Detection of Vitamin B12 in Serum. AB - A nanoengineered interface fabricated by self-assembly enables the online determination of vitamin B12 via a simple luminescence readout in serum without any pretreatment. The interplay of Tm3+-doped NaYF4 nanoparticles (UCNPs) and a gold nanotriangle array prepared by nanosphere lithography on a glass slide is responsible for an efficient NIR to UV upconversion. Hot spots of the gold assembly generate local electromagnetic-field enhancement, favoring the four photon upconversion process at the low-power excitation of approximately 13 W.cm 2. An improvement by about 6 times of the intensity for the emission peaking at 345 nm is achieved. The nanoengineered interface has been applied in a proof-of concept sensor for vitamin B12 in serum, which is known as a marker for the risk of cancer; Alzheimer disease; or, during pregnancy, neurological abnormalities in newborn babies. Vitamin B12 can be detected in serum down to 3.0 nmol.L-1 by a simple intensity-based optical readout, consuming only 200 MUL of a sample, which qualifies as easy miniaturization for point-of-care diagnostics. Additionally, this label-free approach can be used for long-term monitoring because of the high photostability of the upconversion nanoparticles. PMID- 30433774 TI - Substrate Binding Regulates Redox Signaling in Human DNA Primase. AB - Generation of daughter strands during DNA replication requires the action of DNA primase to synthesize an initial short RNA primer on the single-stranded DNA template. Primase is a heterodimeric enzyme containing two domains whose activity must be coordinated during primer synthesis: an RNA polymerase domain in the small subunit (p48) and a [4Fe4S] cluster-containing C-terminal domain of the large subunit (p58C). Here we examine the redox switching properties of the [4Fe4S] cluster in the full p48/p58 heterodimer using DNA electrochemistry. Unlike with isolated p58C, robust redox signaling in the primase heterodimer requires binding of both DNA and NTPs; NTP binding shifts the p48/p58 cluster redox potential into the physiological range, generating a signal near 160 mV vs NHE. Preloading of primase with NTPs enhances catalytic activity on primed DNA, suggesting that primase configurations promoting activity are more highly populated in the NTP-bound protein. We propose that p48/p58 binding of anionic DNA and NTPs affects the redox properties of the [4Fe4S] cluster; this electrostatic change is likely influenced by the alignment of primase subunits during activity because the configuration affects the [4Fe4S] cluster environment and coupling to DNA bases for redox signaling. Thus, both binding of polyanionic substrates and configurational dynamics appear to influence [4Fe4S] redox signaling properties. These results suggest that these factors should be considered generally in characterizing signaling networks of large, multisubunit DNA-processing [4Fe4S] enzymes. PMID- 30433776 TI - Semi-Empirical Born-Oppenheimer Molecular Dynamics (SEBOMD) within the Amber Biomolecular Package. AB - Semi-empirical quantum methods from the neglect of differential diatomic overlap (NDDO) family such as MNDO, AM1, or PM3 are fast albeit approximate quantum methods. By combining them with linear scaling methods like the divide & conquer (D&C) method, it is possible to quickly evaluate the energy of systems containing hundreds to thousands of atoms. We here present our implementation in the Amber biomolecular package of a SEBOMD module that provides a way to run semi-empirical Born-Oppenheimer molecular dynamics. At each step of a SEBOMD, a fully converged self-consistent field (SCF) calculation is performed to obtain the semiempirical quantum potential energy of a molecular system encaged or not in periodic boundary conditions. We describe the implementation and the features of our SEBOMD implementation. We show the requirements to conserve the total energy in NVE simulations, and how to accelerate SCF convergence through density matrix extrapolation. Specific ways of handling periodic boundary conditions using mechanical embedding or electrostatic embedding through a tailored quantum Ewald summation is developed. The parallel performance of SEBOMD simulations using the D&C scheme are presented for liquid water systems of various sizes, and a comparison between the traditional full diagonalization scheme and the D&C approach for the reproduction of the structure of liquid water illustrates the potentiality of SEBOMD to simulate molecular systems containing several hundreds of atoms for hundreds of picoseconds with a quantum mechanical potential in a reasonable amount of CPU time. PMID- 30433777 TI - Interfacial Engineering in Metal-Organic Framework-Based Mixed Matrix Membranes Using Covalently Grafted Polyimide Brushes. AB - Good interfacial compatibility is the key to realize the full potential of metal organic framework-based mix matrix membranes for gas separation. Here we report a new approach that uses polyimide brushes covalently grafted on the MOF surface to engineer the MOF-polymer interface. Benefiting from the strong brush-brush interaction, polyimide grafted MOF particles can form a stand-alone membrane at 88 wt % MOF loading without the addition of polymeric matrix. Compared to traditional mixed-matrix membranes, the modified membranes exhibit improved ductility up to 472%, reduced interfacial tearing phenomenon under shear force, decreased matrix chain mobility, and improved plasticization resistance against CO2. Most importantly, with increasing MOF loading, only the modified membranes exhibit simultaneous increase of selectivity and permeability for CO2/N2 and CO2/CH4 separation, following the trend predicted by the modified Maxwell model. PMID- 30433778 TI - SimNano: A Trust Region Strategy for Large-Scale Molecular Systems Energy Minimization Based on Exact Second-Order Derivative Information. AB - In this work, a new energy minimization strategy is presented that achieves better convergence properties than the standard algorithms employed in the field (fewer steps and usually a lower minimum) and is also computationally efficient; therefore, it becomes suitable for dealing with large-scale molecular systems. The proposed strategy is integrated into the SimNano energy minimization platform that is also described herein. SimNano relies on the analytical calculation of the molecular systems' gradient vectors and Hessian matrices using the computational modeling framework proposed by the authors ( Chatzieleftheriou , S. ; Adendorff , M. R. ; Lagaros , N. D. Generalized Potential Energy Finite Elements for Modeling Molecular Nanostructures . J. Chem. Inf. Model. 2016 , 56 ( 10 ), 1963 - 1978 ). The basis of the proposed minimization strategy is a trust region algorithm based on exact second-order derivative information. Taking advantage of the Hessian matrices' sparsity, a specialized treatment of the data structure is implemented. The latter is beneficial and often rather necessary, especially in the case of large-scale molecular systems, improving the speed and reducing the memory requirements. In order to demonstrate the efficiency of the proposed energy minimization strategy, several test examples are examined, and the results achieved are compared with those obtained by one of the most popular molecular simulation software packages, i.e., the Large-Scale Atomic/Molecular Massively Parallel Simulator (LAMMPS). The results indicate that the proposed minimization strategy exhibits superior convergence properties compared with the typical algorithms (i.e., nonlinear conjugate gradient algorithm, limited-memory Broyden-Fletcher-Goldfarb-Shanno (LBFGS) algorithm, etc.). The SimNano energy minimization platform can be downloaded from the site http://users.ntua.gr/nlagaros/simnano.html , enabling researchers in the field to build molecular systems and perform energy minimization runs using input files in LAMMPS format. PMID- 30433779 TI - Chemical Profiling of the Endoplasmic Reticulum Proteome Using Designer Labeling Reagents. AB - The endoplasmic reticulum (ER) is an organelle that performs a variety of essential cellular functions via interactions with other organelles. Despite its important role, chemical tools for profiling the composition and dynamics of ER proteins remain very limited because of the labile nature of these proteins. Here, we developed ER-localizable reactive molecules (called ERMs) as tools for ER-focused chemical proteomics. ERMs can spontaneously localize in the ER of living cells and selectively label ER-associated proteins with a combined affinity and imaging tag, enabling tag-mediated ER protein enrichment and identification with liquid chromatography tandem mass spectrometry (LC-MS/MS). Using this method, we performed proteomic analysis of the ER of HeLa cells and newly assigned three proteins, namely, PAICS, TXNL1, and PPIA, as ER-associated proteins. The ERM probes could be used simultaneously with the nucleus- and mitochondria-localizable reactive molecules previously developed by our group, which enabled orthogonal organellar chemoproteomics in a single biological sample. Moreover, quantitative analysis of the dynamic changes in ER-associated proteins in response to tunicamycin-induced ER stress was performed by combining ER-specific labeling with SILAC (stable isotope labeling by amino acids in cell culture)-based quantitative MS technology. Our results demonstrated that ERM based chemical proteomics provides a powerful tool for labeling and profiling ER related proteins in living cells. PMID- 30433780 TI - Mechanistic Insights into a Chiral Phosphoric Acid-Catalyzed Asymmetric Pinacol Rearrangement. AB - The first catalytic enantioselective pinacol rearrangement was reported by Antilla and co-workers in 2010. The reaction was catalyzed by a chiral phosphoric acid and resulted in high levels of enantioselectivity (up to 96% ee). The present study uses density functional theory to investigate the mechanism and origins of stereoselectivity of this important reaction and to explain the difference in selectivity between different catalysts. An OH...O hydrogen bond between the intermediate indolyl alcohol and the phosphate group from the catalyst together with a CH...O hydrogen bond between the indole and the phosphate group were observed in the preferred activation mode for the stereodetermining [1,2]-aryl shift. A stronger CH...O interaction in the major transition state was found to contribute to the high levels of enantioselectivity. A more bulky catalyst (TRIP) was found to impede the formation of the key CH...O interaction, leading to lower levels of enantioselectivity. PMID- 30433781 TI - Discovery of Clinical Candidate 2-(4-(2-((1 H-Benzo[ d]imidazol-2 yl)thio)ethyl)piperazin-1-yl)- N-(6-methyl-2,4-bis(methylthio)pyridin-3 yl)acetamide Hydrochloride [K-604], an Aqueous-Soluble Acyl-CoA:Cholesterol O Acyltransferase-1 Inhibitor. AB - 2-(4-(2-((1 H-Benzo[ d]imidazol-2-yl)thio)ethyl)piperazin-1-yl)- N-(6-methyl-2,4 bis(methylthio)pyridin-3-yl)acetamide hydrochloride (K-604, 2) has been identified as an aqueous-soluble potent inhibitor of human acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also known as SOAT)-1 that exhibits 229 fold selectivity for human ACAT-1 over human ACAT-2. In our molecular design, the insertion of a piperazine unit in place of a 6-methylene chain in the linker between the head (pyridylacetamide) and tail (benzimidazole) moieties led to a marked enhancement of the aqueous solubility (up to 19 mg/mL at pH 1.2) and a significant improvement of the oral absorption (the Cmax of 2 was 1100-fold higher than that of 1 in fasted dogs) compared with those of the previously selected compound, 1. After ensuring the pharmacological effects and safety, we designated 2 as a clinical candidate, named K-604. Considering the therapeutic results of ACAT inhibitors in past clinical trials, we believe that K-604 will be useful for the treatment of incurable diseases involving ACAT-1 overexpression. PMID- 30433782 TI - 4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative Profiles. AB - Human carbonic anhydrases (CA, EC, 4.2.1.1) IX and XII are overexpressed in cancer cells as adaptive response to hypoxia and acidic conditions characteristic of many tumors. In addition, hypoxia facilitates the activity of specific oxido reductases that may be exploited to selectively activate bioreductive prodrugs. Here, new selective CA IX/XII inhibitors, as analogues of the antitumor phase II drug SLC-0111 are described, namely ureido-substituted benzenesulfonamides appended with a nitro-aromatic moiety to yield an antiproliferative action increased by hypoxia. These compounds were screened for the inhibition of the ubiquitous hCA I/II and the target hCA IX/XII. Six X-ray crystallographies with CA II and IX/mimic allowed for the rationalization of the compounds inhibitory activity. The effects of some such compounds on the viability of HT-29, MDA-MB 231, and PC-3 human cancer cell lines in both normoxic and hypoxic conditions were examined, providing the initiation toward the development of hypoxia activated antitumor CAIs. PMID- 30433783 TI - Synthesis and Discovery Novel Anti-Cancer Stem Cells Compounds Derived from the Natural Triterpenoic Acids. AB - Cancer stem cells (CSCs) have been reported to be involved in tumorigenesis, tumor recurrence, cancer invasion, metastasis, and drug-resistance. Therefore, the development of drug molecules targeting CSCs has become an attractive therapeutic approach. However, the molecules which can selectively ablate CSCs are extremely rare. To explore the leading compounds targeting CSCs, 52 analogues of triterpenoic acids were synthesized in this study, whose biological activities were evaluated. On the basis of the results of tumorsphere assay, two compounds 48 and 51, derived from oleanolic acid, exhibited suppressive effect on elimination of different type of CSCs. Meanwhile, compounds 48 and 51 could significantly inhibit the growth of several tumors both in vitro and in vivo. Furthermore, treatment of cancer cells with both of two compounds would dramatically increase the level of ROS, which might eliminate the CSCs. Collectively, the leading compounds 48 and 51 were promising anti-CSCs agents that merited further validation as a novel class of chemotherapeutics. PMID- 30433784 TI - Double Photodetachment of F-.H2O: Experimental and Theoretical Studies of [F.H2O]. AB - Double photodetachment of the cluster F-.H2O in a strong laser field is explored in a combined experimental-theoretical study. Products are observed experimentally by coincidence photofragment imaging following double ionization by intense laser pulses. Theoretically, equation of motion coupled cluster calculations (EOM-CC), suitable for modeling strong correlation effects in the electronic wave function, shed light on the Franck-Condon region, and ab initio molecular dynamics simulations also performed using EOM-CC methods reveal the fragmentation dynamics in time on the lowest-lying singlet and triplet states of [F.H2O]+. The simulations show the formation of H2O+ + F, which is the predominant experimentally observed product channel. Suggestions are proposed for the formation mechanisms of the minor products, for example, the very interesting H2F+, which involves significant geometrical rearrangement. Analysis of the results suggests interesting future directions for the exploration of photodetachment of anionic clusters in an intense laser field. PMID- 30433785 TI - Numerical Investigation of Coalescence-Induced Droplet Jumping from a Hydrophobic Fiber. AB - Coalescence-induced droplet jumping from a round hydrophobic fiber was studied by phase-field-based hybrid lattice-Boltzmann finite-difference simulations in which the interface dynamics is handled by the finite-difference solution of the Cahn Hilliard equation and the hydrodynamics is handled by the lattice-Boltzmann method. It was found that at a small Ohnesorge number of O(0.01), several different outcomes, including normal jumping at a positive velocity, jumping with a negative velocity, jumping after wrapping the fiber, and oscillating on the fiber, may occur after droplet coalescence, depending on the wettability of the fiber and the droplet-to-fiber radius ratio. In accordance with previous reports, normal droplet jumping from the fiber happens only when the radius ratio exceeds some critical value for a given contact angle. The critical radius ratio decreases as the fiber becomes more hydrophobic. For a given contact angle and radius ratio, it was observed that there exists an Ohnesorge number at which the jumping speed achieves a maximum value. PMID- 30433786 TI - Intrinsically Disordered Landscapes for Human CD4 Receptor Peptide. AB - Due to their inherent structural plasticity, intrinsically disordered proteins (IDPs) are generally difficult to characterise, both experimentally and via simulations. In this work, an approach for studying IDPs within the potential energy landscape framework is implemented and tested. Specifically, human CD4 receptor peptide, a disordered region implicated in HIV-1 infection, is characterised via basin-hopping parallel tempering and discrete path sampling. We also investigate the effects of three state-of-the-art AMBER forcefields (ff99SB ILDN, ff14ipq, and ff14SB) on the energy landscape. The results for ff99SB-ILDN exhibit the best agreement with experiment. Metastable states identified on the free energy surface help to unify, and are consistent with, several earlier predictions, and may serve as starting points for probing the reaction interface between CD4 and HIV-1 accessory proteins. PMID- 30433787 TI - Plasmonic nanocomposites based on silver nanocube-polymer blends displaying Nearly Perfect Absorption in the UV region. AB - Plasmonic nanocomposites based on metal nanoparticles embedded in dielectric polymer matrixes combine tunability in plasmonic resonance with simplicity of solution processing. Use of shaped nanoparticles in such nanocomposites is of high interest due to their localized surface plasmon resonances that can lead to novel optical features. Here, we present nanocomposites based on silver nanocubes embedded in poly(vinyl-pyrrolidon) with varying volume fraction of nanocubes. We demonstrate that the dominant absorption of the dipole resonance shows a strong red shift with increasing volume fraction of the silver nanocubes due to plasmonic coupling. Furthermore, a novel resonance absorption peak in the UV is generated by plasmonic coupled silver cubes. Together with the quadripole resonance mode in the UV, which is nearly unaffected by volume fraction, the light absorption in this wavelength range shows nearly perfect light absorption of 98.8% at high silver volume fraction of 8% accompanied by a very weak specular reflection of only 0.28 %. While such perfect absorption is usually only observed when nanocubes are assembled on gold surface, nearly perfect absorption herein is achieved on a large palette of substrates including glass, plastic and cheap metals such as aluminum, making it a promising approach for solution-processed robust and cheap quasi perfect absorption coatings. PMID- 30433788 TI - Adsorption and Interfacial Layer Structure of Unmodified Nanocrystalline Cellulose at Air/Water Interfaces. AB - Nanocrystalline cellulose (NCC) is a promising biological nanoparticle for the stabilization of fluid interfaces. However, the adsorption and interfacial layer structure of NCC are poorly understood as it is currently unknown how to form NCC interfacial layers. Herein, we present parameters for the adsorption of unmodified NCC at the air-water (A/W) interface. Initial NCC adsorption is limited by diffusion, followed by monolayer saturation and decrease in surface tension at the time scale of hours. These results confirm the current hypothesis of a Pickering stabilization. NCC interfacial performance can be modulated by salt-induced charge screening, enhancing adsorption kinetics, surface load, and interfacial viscoelasticity. Adsorbed NCC layers were visualized by atomic force microscopy at planar Langmuir films and curved air bubbles, whereat NCC coverage was higher at curved interfaces. Structural analysis by neutron reflectometry revealed that NCC forms a discontinuous monolayer with crystallites oriented in the interfacial plane at a contact angle < 90 degrees , favoring NCC desorption upon area compression. This provides the fundamental framework on the formation and structure of NCC layers at the A/W interface, paving the way for exploiting NCC interfacial stabilization for tailored colloidal materials. PMID- 30433789 TI - Self-Folding Hybrid Graphene Skin for 3D Biosensing. AB - Biological samples such as cells have complex three-dimensional (3D) spatio molecular profiles and often feature soft and irregular surfaces. Conventional biosensors are based largely on 2D and rigid substrates, which have limited contact area with the entirety of the surface of biological samples making it challenging to obtain 3D spatially resolved spectroscopic information, especially in a label-free manner. Here, we report an ultrathin, flexible skinlike biosensing platform that is capable of conformally wrapping a soft or irregularly shaped 3D biological sample such as a cancer cell or a pollen grain, and therefore enables 3D label-free spatially resolved molecular spectroscopy via surface-enhanced Raman spectroscopy (SERS). Our platform features an ultrathin thermally responsive poly( N-isopropylacrylamide)-graphene-nanoparticle hybrid skin that can be triggered to self-fold and wrap around 3D micro-objects in a conformal manner due to its superior flexibility. We highlight the utility of this 3D biosensing platform by spatially mapping the 3D molecular signatures of a variety of microparticles including silica microspheres, spiky pollen grains, and human breast cancer cells. PMID- 30433790 TI - Single-Crystal Growth and Characterization of the Chalcopyrite Semiconductor CuInTe2 for Photoelectrochemical Solar Fuel Production. AB - Transition-metal chalcogenides are a promising family of materials for applications as photocathodes in photoelectrochemical (PEC) H2 generation. A long standing challenge for chalcopyrite semiconductors is characterizing their electronic structure, both experimentally and theoretically, because of their relatively high-energy band gaps and spin-orbit coupling (SOC), respectively. In this work, we present single crystals of CuInTe2, whose relatively small optically measured band gap of 0.9 +/- 0.03 eV enables electronic structure characterization by angle-resolved photoelectron spectroscopy (ARPES) in conjunction with first-principles calculations incorporating SOC. ARPES measurements reveal bands that are steeply dispersed in energy with a band velocity of 2.5-5.4 * 105 m/s, almost 50% of the extremely conductive material graphene. Additionally, CuInTe2 single crystals are fabricated into electrodes to experimentally determine the valence band edge energy and confirm the thermodynamic suitability of CuInTe2 for water redox chemistry. The electronic structure characterization and band edge position presented in this work provide kinetic and thermodynamic factors that support CuInTe2 as a strong candidate for water reduction. PMID- 30433791 TI - Tandem Cyclopropanation/Vinylogous Cloke-Wilson Rearrangement for the Synthesis of Heterocyclic Scaffolds. AB - Cyclopropanation of 1,3-dienes with ethyl 2-formyldiazoacetate under rhodium catalysis results in either a tandem cyclopropanation/Cloke-Wilson rearrangement or a vinylogous variant, depending on the diene used. These adducts may be subjected to an oxygen to nitrogen substitution with various amines under palladium catalysis. The substrate scope and mechanistic reasoning is presented. PMID- 30433792 TI - Halide Ion-Mediated Synthesis of L10-FePt Nanoparticles with Tunable Magnetic Properties. AB - L10-FePt nanoparticles (NPs) have great potential in areas of advanced magnetic and catalytic applications. Here, we present a facile control route for synthesis of hard magnetic L10-FePt NPs in which halide ions (Cl-, Br-, or I-) were added to the synthetic process to promote the phase transformation. It is confirmed that the strong ionic binding force between halide ions and Fe3+ or Pt2+ ions could facilitate the formation of L10-FePt phase due to favoring growth of FePt NPs in a more thermodynamically stable way, which enables the formation of an ordered structure. L10-FePt NPs with the highest coercivity of 8.64 kOe and saturation magnetization of 64.21 emu/g at room temperature can be directly obtained by controlling the amount of the halide ions. In comparison with conventional solution phase reduction methods, the halide ion-assisted method shows enhanced capability to tune the growth of hard magnetic bimetallic NPs, particularly Pt-based bimetallic NPs. PMID- 30433793 TI - Profile of gynaecology surgeries from Western Province, Solomon Islands. AB - INTRODUCTION: Evidence is lacking on the profile of gynaecological conditions affecting women in the Solomon Islands, including the availability and quality of surgical management. METHODS: Prospective analysis of hospital records was undertaken on all patients who underwent gynaecological surgery at Gizo Hospital, Western Province during a 6-day program led by volunteer Australian surgeons. Patient data on pre-operative history, investigation results, performed surgical procedures and postoperative recovery were collected. RESULTS: Of the 23 patients who presented with gynaecological problems requiring surgery, 20 underwent at least one surgical procedure during the study period. The most common presenting symptoms were pain and abnormal uterine bleeding. Median body mass index was 27, and 70% of patients were overweight or obese. Two surgeries were cancelled due to dengue fever. The surgeries performed were 12 vaginal operations, 8 laparoscopies and 9 laparotomies. Of surgical specimens collected, 61% were sent for histopathology testing. The median duration of postoperative hospital admission was 2 days (interquartile range, 1 day). CONCLUSION: The Solomon Islands presents a unique profile of challenges to surgical practice, including the impact of dengue infection on fitness for surgery, a mobile patient population dispersed across the islands, difficult access to pathology services, and increased length of stay. Despite this, most patients had surgical outcomes equivalent to those in a developed setting. PMID- 30433794 TI - Developing the health visitor concept of family resilience in Wales using Group Concept Mapping. AB - INTRODUCTION: A health visitor's ability to assess and analyse aspects of family resilience in daily practice is essential to enable practitioners to support families and facilitate positive lifestyle choices, and improve child health and developmental outcomes. The purpose of this research was to undertake an in-depth exploration of the concept of family resilience as understood by health visitors in Wales and to develop a concept map. This knowledge has been used to develop the Family Resilience Assessment Instrument Tool (FRAIT). This is a standardised form of assessment, measuring instrument, guidance, training package and community of practice for use in health visitor daily practice. This article presents the first stage of the FRAIT research study, that of identifying the clusters within the concept map of what health visitors perceive as 'family resilience'. METHODS: A structured Group Concept Mapping (GCM) methodology using Concept Systems' Global Max online software was used to gain a consensus of the understanding of the concept of family resilience from 62 invited health visitors practising across Wales. This is an integrated qualitative and quantitative approach to brainstorming, idea synthesis, idea sorting, idea rating and group analysis. GCM has six clear steps, with four steps described in the method: 'preparing for concept mapping', 'generating ideas', 'structuring the statements' and 'concept mapping analysis'. Steps 5 and 6, 'interpreting the maps' and 'utilisation', are considered in the results section. RESULTS: Use of multi dimensional scaling and hierarchical cluster analysis enabled point, cluster, rating and pattern matching maps to be presented to the study group. These were then interpreted, understood and consensus gained on how the concept of family resilience was constructed from both the study group and the health visitor participants. Family resilience understood by health visitors in Wales comprises five clusters: 'family health', 'responsive parenting', 'engagement', 'family support' and 'socioeconomic factors'. Each of the clusters has an identified number of underpinning statements from a total number of 117 statements. CONCLUSION: Family resilience as understood by health visitors is a multidimensional concept. Using online software such as Concept Systems' Global Max enabled health visitors working across Wales to achieve a consensus and generate the data in preparation for building FRAIT for use in their daily practice as required by Welsh Government policy. PMID- 30433795 TI - Changes in heart rate variability in patients with atrial fibrillation after pulmonary vein isolation and ganglionated plexus ablation. AB - Pulmonary vein isolation (PVI) is the cornerstone in the treatment of patients with paroxysmal atrial fibrillation (PAF). Some research has suggested studies have shown that modification of ganglionated plexuses (GP), performed with PVI, could lead to even better outcomes. The aim of this study was to determine the effect of PVI on the autonomic system. Heart rate variability (HRV) was used as a marker of autonomic system activity. Twenty-six PAF patients underwent PVI (PVI group) and twenty patients underwent PVI plus a GP ablation (GP group). In each group, 5 min long ECG signals obtained before and after the electrophysiology EP study were analyzed. Time and frequency domain parameters were evaluated. Vagal responses during ablation were observed in 15 (58 %) patients in the PVI group and in 12 (60 %) patients in the GP group. The change in normalized power in the low frequency (LF) and in the LF/HF ratio, before and after ablation, was statistically significant in both groups (LF/HF 2.6+/-1.6 before vs. 1.4+/-1.7 after ablation in PVI group and LF/HF 3.3+/-2.6 before vs.1.8+/-1.9 after ablation in the GP group). Relative to heart rate variability parameters, there were no differences between PVI and PVI + plus GP ablation. PMID- 30433796 TI - A study on molecular mechanisms of adiposis induced by long-term treatment of high-fat and high-sucrose in C57BL/6J mice. AB - Adiposis is reputed as a twin disease of type 2 diabetes and greatly harmful to human health. In order to understand the molecular mechanisms of adiposis, the changes of physiological, pathological, epigenetic and correlative gene expression were investigated during the adiposis development of C57 BL/6J mice induced by long time (9 months) high-fat and high-sucrose diet (HFSD) sustainably. The results showed that mRNA transcription level of the Leptin, Glut4 and Glut2 genes have been obviously changed, which exhibit a negative correlation with methylation on their promoter DNA. The results also revealed that HFSD induced higher level of DNA methyltransferase 1 (DNMT1) in fat tissue might play important role in regulating the changes of methylation pattern on Glut4 and Leptin genes, and which might be one of the molecular mechanisms for the adiposis development. PMID- 30433797 TI - Differences in serum steroid hormones concentrations in spontaneously hypertensive rats (SHR) - an animal model of attention-deficit/hyperactivity disorder (ADHD). AB - Spontaneously hypertensive rats are the most common animal model used to study attention deficit hyperactivity disorder (ADHD). The present study investigated the levels of steroid hormones in the bloodstream of hypertensive rats and its normotensive control strain, Wistar-Kyoto rats, to check if there are any hormonal differences between both strains at the onset of ADHD. Plasma samples were collected from young (5-week-old) and mature (10-week-old) male hypertensive and normotensive rats to determine the serum level of testosterone, 17beta estradiole, free estriol, progesterone, corticosterone and cortisol using ELISA kits. The results showed statistically significant increases in serum levels of testosterone and free estriol in 10-week-old hypertensive and normotensive rats when compared to 5-week-old animals. Moreover, the concentrations of progesterone, corticosterone and cortisol were significantly elevated in 10-week old hypertensive rats when compared to 5-week-old animals of both strains as well as 10-week-old normotensive rats. Hormonal differences observed between 10-week old hypertensive and normotensive rats were also accompanied by differences in the volumes of lateral ventricles as well as the third ventricle and cerebral aqueduct. In conclusion, elevated contents of progesterone, corticosterone and cortisol in hypertensive rats may be associated not only with ADHD but also with developing hypertension. This question needs further study. PMID- 30433798 TI - Nociceptive behavior induced by chemotherapeutic paclitaxel and beneficial role of antioxidative pathways. AB - Paclitaxel is used for the treatment of several types of cancers. However, one of the significant limiting complications of paclitaxel is painful peripheral neuropathy during its therapy. In this study we examined the engagement of antioxidative signal pathway of the dorsal root ganglion (DRG) in mechanical and thermal hypersensitivity evoked by paclitaxel. Behavioral test was performed to determine mechanical and thermal sensitivity in rats. Western Blot analysis and ELISA were used to examine expression of Nrf2-antioxidant response element (ARE) and superoxide dismutases (SOD); and the levels of products of oxidative stress in the DRG. Our results show that paclitaxel increased mechanical and thermal sensitivity as compared with vehicle control animals. Paclitaxel also impaired Nrf2-ARE and SOD in the DRG and amplified products of oxidative stress, namely 8 isoprostaglandin F2alpha and 8-hydroxy-2'-deoxyguanosine. Systemic administration of SOD mimetic using tempol, antioxidant vitamin C or blocking oxidative pathway using NADPH oxidase inhibitor (GKT137831) attenuated mechanical and thermal hypersensitivity induced by paclitaxel. This inhibitory effect was accompanied with decreases of proinflammatory cytokines (PICs) such as IL-1beta, IL-6 and TNF alpha in the DRG. In conclusion, the data revealed impairment of Nrf2-ARE and heightened oxidative and PIC signals in the DRG of paclitaxel rats, leading to neuropathic pain. Balancing of reactive oxygen species by supplying antioxidants and/or inhibiting NADPH oxidase appears significant to yield beneficial effects in neuropathic pain conditions after chemotherapeutic paclitaxel. PMID- 30433799 TI - Tyrosine kinase Pyk2 is involved in colonic smooth muscle contraction via the RhoA/ROCK Pathway. AB - The contraction of gastrointestinal (GI) smooth muscles is regulated by both Ca2+ dependent and Ca2+ sensitization mechanisms. Proline-rich tyrosine kinase 2 (Pyk2) is involved in the depolarization-induced contraction of vascular smooth muscle via a Ca2+ sensitization pathway. However, the role of Pyk2 in GI smooth muscle contraction is unclear. The spontaneous contraction of colonic smooth muscle was measured by using isometric force transducers. Protein and phosphorylation levels were determined by using western blotting. Pyk2 protein was expressed in colonic tissue, and spontaneous colonic contractions were inhibited by PF-431396, a Pyk2 inhibitor, in the presence of tetrodotoxin (TTX). In cultured colonic smooth muscle cells (CSMCs), PF-431396 decreased the levels of myosin light chain (MLC20) phosphorylated at Ser19 and ROCK2 protein expression, but myosin light chain kinase (MLCK) expression was not altered. However, Y-27632, a Rho kinase inhibitor, increased phosphorylation of Pyk2 at Tyr402 and concomitantly decreased ROCK2 levels; the expression of MLCK in CSMCs did not change. The expression of P(Tyr402)-Pyk2 and ROCK2 was increased when CSMCs were treated with Ach. Pyk2 is involved in the process of colonic smooth muscle contraction through the RhoA/ROCK pathway. These pathways may provide very important targets for investigating GI motility disorders. PMID- 30433800 TI - Coupling activation of pro-apoptotic caspases with autophagy in the Meckel's cartilage. AB - Mammalian Meckel's cartilage is a temporary structure associated with mandible development. Notably, its elimination is not executed by apoptosis, and autophagy was suggested as the major mechanism. Simultaneous reports point to pro-apoptotic caspases as novel participants in autophagic pathways in general. The aim of this research was to find out whether activation of pro-apoptotic caspases (-2, -3, 6, -7, -8 and -9) was associated with autophagy of the Meckel's cartilage chondrocytes. Active caspases were examined in serial histological sections of mouse mandible using immunodetection and were correlated with incidence of autophagy based on Beclin-1 expression. Caspase-2 and caspase-8 were found in Beclin-1 positive regions, whereas caspase-3, -6, -7 and -9 were not present. Caspase-8 was further correlated with Fas/FasL and HIF-1alpha, potential triggers for its activation. Some Fas and FasL positivity was observed in the chondrocytes but caspase-8 activation was found also in FasL deficient cartilage. HIF-1alpha was abundantly present in the hypertrophic chondrocytes. Taken together, caspase 8 activation in the Meckel's cartilage was demonstrated for the first time and along with caspase-2, were the only pro-apoptotic caspases detected in the Beclin 1 positive segment of the cartilage. Activation of caspase-8 appears FasL/Fas independent but may be switched on by HIF-1alpha. PMID- 30433801 TI - Synergistic potential of propolis and vitamin E against sub-acute toxicity of AlCl3 in Albino mice: in vivo study. AB - Current study evaluated the synergistic potential of propolis and Vitamin E against sublethal toxicity of aluminum chloride on different biochemical parameters and liver histology. Swiss albino mice (n=42) were randomly divided into five groups. Group I received 0.2 ml of 0.9 % saline solution, Group II received Propolis (50 mg/kg b.w.), Group III received Vitamin E (150 mg/kg b.w.), Group IV received AlCl3 50 mg/kg b.w., Group V received AlCl3 + Propolis, Group VI received AlCl3 + Vitamin E and Group VI received AlCl3 + propolis + Vitamin E. Blood and tissue samples were collected after 7 and 21 days. The body weight of the animals significantly increased in all groups except group IV. The concentration of serum high density lipoprotein significantly decreased in group IV and increased in group V, VI and VII. The level of aspartate aminotransferase, alanine transferase, alkaline phosphatase, triglycerides, total cholesterol, and low density lipoprotein significantly increased in AlCl3 treated group and increased in group V, VI and VII. Tissue sections were processed and stained by hematoxylin and eosin. Group II showed cellular necrosis. Group V, VI showed decreased number of vacuolization, sinusoidal spacing and macrophage cell infiltration. Group VI showed less degenerative changes in the third week. Vitamin E and propolis in combination with Al provides more protection against AlCl3 induced toxicity. PMID- 30433802 TI - Modification of calcium retention capacity of rat liver mitochondria by phosphate and tert-butyl hydroperoxide. AB - By determining the calcium retention capacity (CRC) of rat liver mitochondria, we confirmed and extended previous observations describing the activation of mitochondrial swelling by phosphate and tert-butyl hydroperoxide (t-BHP). Using CRC measurements, we showed that both phosphate and t-BHP decrease the extent of calcium accumulation required for the full mitochondrial permeability transition pore (MPTP) opening to 35 % of control values and to only 15 % when both phosphate and t-BHP are present in the medium. When changes in fluorescence were evaluated at higher resolution, we observed that in the presence of cyclosporine A fluorescence values return after each Ca2+ addition to basal values obtained before the Ca2+ addition. This indicates that the MPTP remains closed. However, in the absence of cyclosporine A, the basal fluorescence after each Ca2+ addition continuously increased. This increase was potentiated both by phosphate and t-BHP until the moment when the concentration of intramitochondrial calcium required for the full opening of the MPTP was reached. We conclude that in the absence of cyclosporine A, the MPTP is slowly opened after each Ca2+ addition and that this rate of opening can be modified by various factors such as the composition of the media and the experimental protocol used. PMID- 30433803 TI - Strain differences in intraluminal thread model of middle cerebral artery occlusion in rats. AB - Stroke is despite of progressive improvements in treatment and reperfusion strategies one of the most devastating human pathology. However, as quality of acute health care improves and more people survive ischemic attack, healthcare specialists have to solve new challenges to preserve reasonable quality of life to these patients. Thus, novel approaches which prevents comorbidities of stroke and improve quality of life of stroke survivors in general has to be developed and experimentally tested. The aim of the present paper was to establish reliable rat model of middle cerebral occlusion and set of methods allowing selection of animals suitable for long term experiments. We have compared mortality rates, cerebral blood flow and extension of ischemic lesion induced by intraluminal filament in three widely used outbred rat strains. We have additionally used an animal 18F-DG PET scans to verify its reliability in noninvasive detection of ischemic infarct in acute period (24 h after MCAO) for selecting animals eligible for long survival experiments. Our data clearly indicates that high variability between rat strains might negatively influence stroke induction by intraluminal thread occlusion of middle cerebral artery. Most reliable outbred rat strain in our hands was Sprague-Dawley where maximal reduction of cerebral blood flow and extensive ischemic lesion was observed. Contrary, Wistar rats exhibited higher mortality and Long-Evans rats significantly smaller or no ischemic region in comparison to Sprague-Dawley. Additionally, we have confirmed a positron emission tomography with 18F-fluorodeoxyglucose as suitable method to assess extension of ischemic region in acute period after the experimental arterial occlusion in rats. PMID- 30433804 TI - In vivo, in vitro and pharmacologic models of Parkinson's disease. AB - Parkinson's disease (PD), which is the second most common neurodegenerative disorder after Alzheimer's disease, is firstly defined after James Parkinson's report. It carries motor symptoms such as resting tremor, bradykinesia and rigidity of skeletal muscle and freezing of gait. Furthermore, non-motor symptoms such as cognitive and behavioral problems, besides sensory impairments are seen in the patients. However, they may also suffer from sleep disorders or autonomic dysfunction. Although there are some medications in order to symptomatic management, but unfortunately, scientist could not have found exact approaches to cure this disease. Hence, producing a model which can express the most pathophysiologic and behavioral aspects of the disease is a desire. In this paper, we aimed to describe the different models of Parkinson's disease in brief. PMID- 30433805 TI - Repetitive transcranial magnetic stimulation (rTMS) modulates hippocampal structural synaptic plasticity in rats. AB - Repetitive transcranial magnetic stimulation (rTMS) was shown to have therapeutic potential for some neurological and psychiatric disorders. Previous studies reported that low-frequency rTMS (?1 Hz) affected synaptic plasticity in rats, however, there were few investigations to examine the possible effects of rTMS on structural synaptic plasticity changes in rats, which included the effects on synaptic morphology in the hippocampus, synaptic protein markers and Ca2+/calmodulin-dependent protein II (CaMKII). Sprague-Dawley rats were subject to 500 pulses of 0.5 Hz rTMS for 15 days, or sham stimulation. After last stimulation, transmission electron microscope (TEM) and real-time PCR were used to determine the effects of rTMS on synaptic plasticity. Results showed that rTMS could cause the change of structural synaptic plasticity, increase the expression of synaptic protein markers: synaptophysin (SYN) and increase the expression of CaMKII, relative to normal rats. suggesting a modulatory effect of chronic rTMS on synaptic plasticity that may be attributed to the increasedexpression of CaMKII in rats. PMID- 30433806 TI - Downregulation of HCN1 channels in hippocampus and prefrontal cortex in methamphetamine re-exposed mice with enhanced working memory. AB - The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation (HCN) channels play a potential role in the neurological basis underlying drug addiction. However, little is known about the role of HCN channels in methamphetamine (METH) abuse. In the present study, we examined the changes in working memory functions of METH re-exposed mice through Morris water maze test, and investigated the protein expression of HCN1 channels and potential mechanisms underlying the modulation of HCN channels by Western blotting analysis. Mice were injected with METH (1 mg/kg, i.p.) once per day for 6 consecutive days. After 5 days without METH, mice were re-exposed to METH at the same concentration. We found that METH re-exposure caused an enhancement of working memory, and a decrease in the HCN1 channels protein expression in both hippocampus and prefrontal cortex. The phosphorylated extracellular regulated protein kinase 1/2 (p-ERK1/2), an important regulator of HCN channels, was also obviously reduced in hippocampus and prefrontal cortex of mice with METH re-exposure. Meanwhile, acute METH exposure did not affect the working memory function and the protein expressions of HCN1 channels and p-ERK1/2. Overall, our data firstly showed the aberrant protein expression of HCN1 channels in METH re-exposed mice with enhanced working memory, which was probably related to the down-regulation of p ERK1/2 protein expression. PMID- 30433808 TI - Comet assay and its use for evaluating oxidative DNA damage in some pathological states. AB - The comet assay, or single-cell gel electrophoresis (SCGE), is a sensitive, rapid, relatively simple and inexpensive method for detecting DNA strand breaks in individual cells. It is used in a broad variety of applications and as a tool to investigate DNA damage and repair. The sensitivity and specificity of the assay are greatly enhanced if the DNA incubated with an enzyme which recognizes a specific kind of DNA damage. This damage induced by oxidative stress plays a pivotal role in many diseases and in aging. This article is a critical review of the possible application of the comet assay in some pathological states in clinical practice. Most of the studies relate to evaluating the response of an organism to chemotherapy or radiotherapy with statistically significant evidence of DNA damage in patients. Other useful applications have been demonstrated for patients with heart or neurodegenerative diseases. Only a few studies have been published on the use of this method in critically ill patients, although its use would be appropriate. There are also other scenarios where the comet assay could prove to be very useful in the future, such as in predicting the likelihood of certain pathological conditions. PMID- 30433807 TI - Neuronal activity of the medulla oblongata revealed by manganese-enhanced magnetic resonance imaging in a rat model of gastroesophageal reflux-related cough. AB - We investigated neuronal activity of the medulla oblongata during gastroesophageal reflux-related cough (GERC). A rat model of GERC was generated by perfusing HCl into lower esophagus and inducing cough with citric acid. The HCl group rat was received HCl perfusion without citric acid-induced cough. The saline control rat was perfused with saline instead and cough was induced. Citric acid-induced cough rat was only induced by citric acid. Blank group rats were fed normally. Fos expressions were observed in medulla oblongata nuclei using immunohistochemistry. Manganese-enhanced magnetic resonance imaging (MEMRI) was performed to detect the Mn2+ signal following intraperitoneal injection of MnCl2. HCl perfusion and citric acid-induced cough caused Fos expressions in the nucleus of solitary tract (nTS), dorsal motor nucleus of the vagus (DMV), paratrigeminal nucleus (Pa5), and intermediate reticular nucleus (IRt), which was higher than HCl group, saline control group, citric acid-induced cough group, and blank group. A high Mn2+ signal was also observed in most of these nuclei in model rats, compared with blank group animals. The Mn2+ signal was also higher in the HCl, saline and citric acid-induced cough group animals, compared with blank group animals. The study showed medulla oblongata neurons were excited in a HCl perfusion and citric acid-induced cough rat model, and nTS, DMV, Pa5 and IRt neurons maybe involved in the cough process and signal integrate. PMID- 30433809 TI - Cardiovascular regulation and body temperature: evidence from a nap vs. sleep deprivation randomized controlled trial. AB - In this study we set out to understand is sleep fragmentation affects the cardiovascular regulation and circadian variability of core body temperature more or less than sleep deprivation. 50 healthy men (age 29.0+/-3.1 years; BMI 24.3+/ 2.1 kg/m(2)) participated in a 3-day study that included one adaptative night and one experimental night involving randomization to: sleep deprivation (SD) and sleep fragmentation (SF). The evaluation included hemodynamic parameters, measures of the spectral analysis of heart rate and blood pressure variability, and the sensitivity of arterial baroreflex function. Core body temperature (CBT) was measured with a telemetric system. SF affects heart rate (61.9+/-5.6 vs. 56.2+/-7.6, p<0.01) and stroke index (52.7+/-11.1 vs. 59.8+/-12.2, p<0.05) with significant changes in the activity of the ANS (LF-sBP: 6.0+/-5.3 vs. 3.4+/-3.7, p<0.05; HF-sBP: 1.8+/-1.8 vs. 1.0+/-0.7, p<0.05; LF-dBP: 5.9+/-4.7 vs. 3.5+/-3.2, p<0.05) more than SD. Post hoc analysis revealed that after SD mean value of CBT from 21:30 to 06:30 was significantly higher compared to normal night's sleep and SF. In healthy men SF affects the hemodynamic and autonomic changes more than SD. Sympathetic overactivity is the proposed underlying mechanism. PMID- 30433810 TI - Impaired Lung Function, Lung Disease and Risk of Incident Dementia. AB - RATIONALE: Growing evidence suggests that compromised lung health may be linked to dementia and worsening cognitive ability. OBJECTIVES: We tested the hypothesis that impaired lung function or lung disease in midlife would be associated with greater risk of incident dementia and mild cognitive impairment (MCI) later in life. METHODS: A total of 14,184 ARIC study participants who underwent spirometry and were asked about lung health (1987-1989) were followed. Dementia and MCI were defined by a) hospitalization diagnosis codes (1987-2013) in the whole cohort and b) with adjudication among 42% who attended a comprehensive neurocognitive exam (2011-2013). MAIN RESULTS: In analysis using adjudicated outcomes, odds of dementia or MCI were higher among participants with restrictive [multivariable adjusted odds ratio (95% CI): 1.58 (1.15-2.19)] and obstructive lung disease [1.29 (1.05-1.59)], compared to those without disease or respiratory symptoms. Associations were similar in analyses restricted to nonsmokers, and present for both Alzheimer's disease-related dementia and cerebrovascular etiologies. Low forced expiratory volume in 1 second % predicted and forced vital capacity % predicted were also associated with increased dementia risk. CONCLUSIONS: Midlife lung disease and reduced lung function were associated with modestly increased odds of dementia and MCI later in life. Magnitudes of association were more pronounced for restrictive impairment than for obstructive lung disease. These associations were present in both smokers and nonsmokers. If the observed associations are causal, policy and public health efforts to reduce smoking and improve air quality may have the added benefit of preventing the development of dementia and MCI. PMID- 30433811 TI - Severe Necrotizing Staphylococcal Pneumonia with Late Life-Threatening Tracheo Bronchial Involvement in Infant. PMID- 30433812 TI - Eosinophils Express LTA4 Hydrolase and Synthesize LTB4; Important for Asthma Pathogenesis? PMID- 30433813 TI - ICU Telemedicine and the Value of Qualitative Research for Organizational Innovation. PMID- 30433814 TI - Diffusion-weighted imaging in rectal cancer: current applications and future perspectives. AB - This review summarizes current applications and clinical utility of diffusion weighted imaging (DWI) for rectal cancer and in addition provides a brief overview of more recent developments (including intravoxel incoherent motion imaging, diffusion kurtosis imaging, and novel postprocessing tools) that are still in more early stages of research. More than 140 papers have been published in the last decade, during which period the use of DWI have slowly moved from mainly qualitative (visual) image interpretation to increasingly advanced methods of quantitative analysis. So far the largest body of evidence exists for assessment of tumour response to neoadjuvant treatment. In this setting, particularly the benefit of DWI for visual assessment of residual tumour in post radiation fibrosis has been established and is now increasingly adopted in clinics. Quantitative DWI analysis (mainly the apparent diffusion coefficient (ADC)) has potential, both for response prediction as well as for tumour prognostication, but protocols require standardization and results need to be prospectively confirmed on larger scale. The role of DWI for further clinical tumour and nodal staging is less well-defined, although there could be a benefit for DWI to help detect lymph nodes. Novel methods of DWI analysis and post processing are still being developed and optimized; the clinical potential of these tools remains to be established in the upcoming years. This paper provides an overview ofthe various applications of DWI and discusses their potential rolefor rectal cancer imaging. PMID- 30433815 TI - Population-based opportunistic osteoporosis screening: Validation of a fully automated CT tool for assessing longitudinal BMD changes. AB - METHODS:: The automated BMD tool was retrospectively applied to non-contrast abdominal CT scans in 1603 consecutive asymptomatic adults (mean age, 55.9 years; 770 M/833 F) undergoing longitudinal screening (mean interval, 5.7 years; range, 1.0-12.3 years). The spinal column was automatically segmented, with standardized L1 and L2 anterior trabecular ROI placement. Automated and manual L1 HU values were compared, as were automated supine-prone measures. L1-L2 CT attenuation values were converted to BMD values through a linear regression model. BMD values and changes were assessed according to age and gender. RESULTS:: Success rate of the automated BMD tool was 99.8 % (four failed cases). Both automated supine vs prone and manual vs automated L1 attenuation measurements showed good agreement. Overall mean annual rate of bone loss was greater in females than males (-2.0% vs -1.0%), but the age-specific rate declined faster in females from age 50 (-2.1%) to age 65 (-0.3%) compared with males (-0.9% to -0.5%). Mean BMD was higher in females than males at age 50 (143.6 vs 135.1 mg cm-3), but post-menopausal bone loss in females reversed this relationship beyond age 60. By age 70, mean BMD in females and males was 100.8 and 107.7 mg cm-3 , respectively. CONCLUSION:: This robust, fully automated CT BMD tool allows for both individualized and population based assessment. Mean BMD was lower in men than women aged 50-60, but accelerated post-menopausal bone loss in women resulted in lower values beyond age 60. ADVANCES IN KNOWLEDGE:: This fully automated tool can be applied to routine abdominal CT scans for prospective or retrospective opportunistic BMD assessment, including change over time. Mean BMD was lower in men compared with women aged 50-60 years, but accelerated bone loss in women during this early post menopausal period resulted in lower BMD values for women beyond age 60. PMID- 30433816 TI - Recommended Reading from the University of Toronto Sleep Medicine Fellows. PMID- 30433817 TI - Impact of Diet on the Incidence of Cataract Surgery among Diabetic Patients: Findings from the 45 and up Study. AB - OBJECTIVE: To examine the impact of diet on the incidence of cataract surgery among the working-aged diabetic population in Australia. METHODS: This cohort study was conducted among 8,752 participants with diabetes aged 45-65 years who were recruited to the 45 and Up Study from 2006 to 2016. The data was linked to the Medicare Benefits Schedule (MBS) to obtain data on cataract surgery. Diabetes was defined as self-reported on questionnaire or diabetes medication history based on Pharmaceutical Benefits Scheme (PBS). Diet was assessed at baseline, using a self-administered questionnaire and healthy diet scores were calculated based on Australian Dietary Guidelines. Cox regression was used to evaluate the association between diet and the incidence of cataract surgery during the follow up. RESULTS: During a mean follow-up of 8.4 years (73,431 person-years), 914 diabetic participants underwent cataract surgery with a corresponding rate of 12.4 cases per 1,000 person-years. After adjusting for age and gender, the hazard ratios (HR) of cataract surgery for the highest compared to the lowest intake quintile of red meat and poultry were 1.24 (95%CI, 1.00-1.55) and 1.24 (95%CI, 1.02-1.51), respectively. Further adjustment for demographic, lifestyle and dietary factors resulted in no significant difference between cataract surgery risk and healthy diet scores or specific diet groups. In gender-stratified analyses, increasing consumption of red meat (HR for highest versus lowest quintile, 1.39; 95%CI, 1.00-1.93; P for trend = 0.01) and poultry (HR for highest versus lowest quintile, 1.40; 95%CI, 1.05-1.87; P for trend = 0.01) were associated with a higher risk of cataract surgery in women after adjustment of age, gender, income, education level, body mass index, hypertension, cardiovascular disease, family history of diabetes, diabetes duration, insulin use, lifestyle and other dietary factors. CONCLUSION: Higher consumption of red meat and poultry is related to an elevated risk of cataract surgery in the working-aged female population with diabetes. PMID- 30433818 TI - Effect Size Measures for Multilevel Models in Clinical Child and Adolescent Research: New R-Squared Methods and Recommendations. AB - Clinical psychologists studying child and adolescent populations commonly analyze hierarchically structured data via multilevel modeling (MLM). In clinical child and adolescent psychology, and in psychology more broadly, increasing emphasis is being placed on the reporting of effect size, such as R-squared (R2) measures of explained variance. In MLM, however, the literature on R2 had, until recently, suffered from several shortcomings: (a) the relations among existing measures were unknown, (b) methods for quantifying some types of explained variance were unavailable, (c) which (if any) measures should be used for model comparison was unclear, (d) most measures did not generalize to models with more than two levels, and (e) software to compute measures was unavailable. The purpose of this article is to summarize recent methodological developments that resolved these issues and encourage the use of MLM R2 in practice. We provide a nontechnical discussion of how the issues have been resolved and demonstrate how the new measures and methods can be implemented, highlighting their utility with an empirical example. We first consider a two-level MLM for a single hypothesized model in which we examine emotional response to social situations as a predictor of maladaptive self-cognitions, demonstrating the various ways we can quantify explained variance. We then discuss and demonstrate the use of R2 for model comparison, and discuss the extension to models with more than two levels. Last, we discuss new free software that researchers can use to compute measures and produce associated graphics. PMID- 30433819 TI - Urine afamin and afamin-creatinine ratio as biomarkers for kidney injury. AB - AIM: The aim of this study was to evaluate the urine afamin (uAFM) and afamin creatinine ratio (AfCR) levels in patients with glomerulonephritis. PATIENTS & METHODS: We determined uAFM and AfCR of 247 healthy volunteers and 129 biopsy proven glomerulonephritis patients. RESULTS: Analytical evaluation study revealed the assay is a reliable and robust test for measuring uAFM. For reference intervals, uAFM and AfCR values were different significantly between males and females. uAFM and AfCR levels were significantly increased in patients with primary membranous nephropathy, IgA nephropathy and minimal change disease compared with healthy volunteers. uAFM and AfCR were positively correlated with urine albumin and albumin-creatinine ratio, respectively. CONCLUSION: Our study suggested that uAFM and AfCR may be attractive biomarkers for kidney injury. PMID- 30433820 TI - Clinical Practice Guideline: Summary for Clinicians. Diagnosis of Primary Ciliary Dyskinesia. PMID- 30433821 TI - An Evaluation of Techniques for Dose Calculation on Cone Beam Computed Tomography. AB - OBJECTIVE:: To assess the accuracy and efficiency of four different techniques, thus determining the optimum method for recalculating dose on cone beam CT (CBCT) images acquired during radiotherapy treatments. METHODS:: Four established techniques were investigated and their accuracy assessed via dose calculations: (1) applying a standard planning CT (pCT) calibration curve, (2) applying a CBCT site specific calibration curve, (3) performing a density override and (4) using deformable registration. Each technique was applied to 15 patients receiving volumetric modulated arc therapy to one of three treatment sites, head and neck, lung and prostate. Differences between pCT and CBCT recalculations were determined with dose volume histogram metrics and 2.0%/0.1 mm gamma analysis using the pCT dose distribution as a reference. RESULTS:: Dose volume histogram analysis indicated that all techniques yielded differences from expected results between 0.0-2.3% for both target volumes and organs at risk. With volumetric gamma analysis, the dose recalculation on deformed images yielded the highest pass-rates. The median pass-rate ranges at 50% threshold were 99.6-99.9%, 94.6 96.0%, and 94.8.0-96.0% for prostate, head and neck and lung patients, respectively. CONCLUSION:: Deformable registration, HU override and site specific calibration curves were all identified as dosimetrically accurate and efficient methods for dose calculation on CBCT images. ADVANCES IN KNOWLEDGE:: With the increasing adoption of CBCT, this study provides clinical radiotherapy departments with invaluable information regarding the comparison of dose reconstruction methods, enabling a more accurate representation of a patient's treatment. It can also integrate studies in which CBCT is used in image-guided radiation therapy and for adaptive radiotherapy planning processes. PMID- 30433822 TI - Obstetric Violence as Reproductive Governance in the Dominican Republic. AB - A human rights violation, obstetric violence encompasses numerous forms of mistreatment against women giving birth in health care facilities. Based on this framework, we conducted open-ended exit interviews with 43 women who had given birth at either one of the two largest public maternity hospitals in the Dominican Republic. Women's narratives revealed a contrast between scholarly definitions of obstetric violence and their own perceptions of receiving abusive care. Analyzing obstetric violence as a form of reproductive governance and the adaptive preference that ensues helps explain why most women accepted with endurance the poor quality of care that they received. PMID- 30433823 TI - Hospital Resource Utilization and Costs Associated With Warfarin Versus Apixaban Treatment Among Patients Hospitalized for Venous Thromboembolism in the United States. AB - A real-world US database analysis was conducted to evaluate the hospital resource utilization and costs of patients hospitalized for venous thromboembolism (VTE) treated with warfarin versus apixaban. Additionally, 1-month readmissions were evaluated. Of 28 612 patients with VTE identified from the Premier Hospital database (August 2014-May 2016), 91% (N = 26 088) received warfarin and 9% (N = 2524) received apixaban. Outcomes were assessed after controlling for key patient/hospital characteristics. For index hospitalizations, the average length of stay (LOS) was longer (3.8 vs 3.1 days, P < .001; difference: 0.7 days) and mean hospitalization cost higher (US$3224 vs US$2,740, P < .001; difference: US$484) for warfarin versus apixaban-treated patients. During the 1-month follow up period, warfarin treatment was associated with a greater risk of all-cause readmission (odds ratio [OR]: 1.27; 95% confidence interval [CI]: 1.09-1.48, P = .003), major bleeding (MB)-related readmission (OR: 2.10; 95% CI: 1.03-4.27, P = .04), and any bleeding-related readmission (OR: 1.67; 95% CI: 1.09-2.56, P = .02) versus apixaban. The results of this real-world analysis show that compared to warfarin, apixaban treatment was associated with shorter index hospital stays, lower index hospitalization costs, and reduced risk of MB-related readmissions among hospitalized patients with VTE. PMID- 30433824 TI - Hypofractionated radiotherapy with concomitant boost for breast cancer: a dose escalation study. AB - METHODS:: Patients with breast cancer with pathological stage pT1-2 and at least one risk factor for local recurrence such as N1 disease, lymphovascular invasion, extensive intraductal component, close margins, non-hormone sensitive disease, grading G3 were enrolled. Patients were treated with hypofractionated RT to whole breast with a dose of 40.05 Gy in 15 fractions. The dose was escalated to the tumour bed through a daily concomitant boost technique at three dose levels: 48 Gy (3.2 Gy/die), 50.25 Gy(3.35 Gy/die) and 52.5 Gy (3.5 Gy/die). Dose escalation to a higher step was carried out if all patients of the lower dose had completed the treatment without dose limiting toxicity (DLT). Skin toxicity, cosmetic evaluation and quality of life was evaluated at baseline, at treatment end and at 3 and 12 months after RT end. RESULTS:: Three patients for each dose level were enrolled. No DLT occurred. The maximum toxicity collected during RT was G2 skin toxicity in 3 (33.3%) patients, one for each dose level. No G2 toxicity at 3 and 12 months was collected. At median follow up of 21.8 months (range: 13.5 - 40.9 months), no G2 late toxicity was recorded. CONCLUSION:: The 3 week course of post operative RT with dose escalation to the tumour bed to 52.5 Gy has been achieved without dose limiting toxicities and can be tested in Phase II trials. ADVANCES IN KNOWLEDGE:: In our study, we tested the highest dose level to the tumour bed ever reported in studies using accelerated hypofractionation with concomitant boost in high risk patients. PMID- 30433825 TI - Gut microbiota development in mice is affected by hydrogen peroxide produced from amino acid metabolism during lactation. AB - The development of gut microbiota during infancy is an important event that affects the health status of the host; however, the mechanism governing it is not fully understood. l-Amino acid oxidase 1 (LAO1) is a flavoprotein that catalyzes the oxidative deamination of particular l-amino acids and converts them into keto acids, ammonia, and H2O2. Our previous study showed that LAO1 is present in mouse milk and exerts protection against bacteria by its production of H2O2. The data led us to consider whether LAO1, H2O2, or both could impact infant gut microbiota development via mother's milk consumption in mice. Different gut microbiota profiles were observed in the wild-type (WT) and LAO1-knockout mouse pups. The WT pups' microbiota was relatively simple and composed of only a few dominant bacteria, such as Lactobacillus, whereas the lactating knockout pups had high microbiota diversity. Cross-fostering experiments indicated that WT milk (containing LAO1) has the ability to suppress the diversity of microbiota in pups. We observed that the stomach content of pups fed WT milk had LAO1 proteins and the ability to produce H2O2. Moreover, culture experiments showed that Lactobacillus was abundant in the feces of pups fed WT milk and that Lactobacillus was more resistant to H2O2 than Bifidobacterium and Escherichia. Human breast milk produces very little H2O2, which could be the reason for Lactobacillus not being dominant in the feces of breast-fed human infants. In mouse mother's milk, H2O2 is generated from the process of free amino acid metabolism, and H2O2 may be a key player in regulating the initial acquisition and development of gut microbiota, especially growth of Lactobacillus, during infancy.-Shigeno, Y., Zhang, H., Banno, T., Usuda, K., Nochi, T., Inoue, R., Watanabe, G., Jin, W., Benno, Y., Nagaoka, K. Gut microbiota development in mice is affected by hydrogen peroxide produced from amino acid metabolism during lactation. PMID- 30433826 TI - Distinguishing adrenal adenomas from non-adenomas with multidetector CT: evaluation of percentage washout values at a short time delay triphasic enhanced CT. AB - OBJECTIVE:: To retrospectively evaluate the diagnostic values of absolute percentage washout ratio (APW) and relative percentage washout ratio (RPW) obtained from a short time delay triphasic enhanced CT in distinguishing adenomas from non-adenomas. METHODS:: The study population consisted of 116 patients (58 males and 58 females; mean age, 52 years; age range, 23-89 years) with 116 adrenal masses from 2010 to 2016. Absolute attenuation values in each phase of CT were measured, and then the APW and RPW were calculated. The APW and RPW receiver operating characteristic (ROC) analysis was performed to evaluate the strength of the tests. Sensitivity, specificity, and accuracy were calculated for APW and RPW. RESULTS:: Significant differences were observed in APW and RPW values between the adenoma and non-adenoma groups (p < 0.001). Areas under the ROC curve were 0.822 (95% confidence interval: 0.730, 0.914) and 0.913 (95% confidence interval: 0.851, 0.975) for the APW and RPW tests, respectively. The RPW (>=30%) criterion showed the best accuracy (86%), with 85% sensitivity and 90% specificity, followed by the APW (>=32%) criterion, with 81% accuracy, 85% sensitivity, and 69% specificity. CONCLUSION:: The APW and RPW values from a short time delay triphasic enhanced CT were efficient and helpful in differentiating adenomas from non-adenomas, and could provide comparable diagnostic results to the previous reported longer delayed dedicated adrenal CT protocols. ADVANCES IN KNOWLEDGE:: The washout ratio from a short time delay triphasic enhanced CT could help in differentiating adenomas from non-adenomas without the dedicated adrenal CT. PMID- 30433828 TI - Socioeconomic Status and Glaucoma: Associations in High Levels of Income and Education. AB - PURPOSE: Glaucoma affects millions of people globally, and socioeconomic status is known to be associated with glaucoma. This study expands the understanding of the relationship between socioeconomic factors and glaucoma. METHODS: This study used Korean National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2012, with 24,664 persons who did not have missing records on the key variables. The combined relationship between levels of income and education and the prevalence of glaucoma was examined, as well as the occupational difference in the prevalence of glaucoma. Logistic regression models were constructed to generate odds ratios with 95% confidence intervals for predictors of glaucoma. All analyses were adjusted for strata, cluster, and weight. RESULTS: The prevalence of glaucoma generally decreased with increasing levels of education and income, but this trend did not hold at the top two levels of education and income, wherein the prevalence was either the same or somewhat higher. Occupation types were shown to be significantly associated with glaucoma (p < 0.0001), and among all the occupations in the survey, farming/forestry/fishing showed the highest percentage of those with glaucoma (4.9%), and service/retail showed the lowest percentage (1.3%). In the multivariable adjusted model, the odds of glaucoma decreased with increasing income level, and increased at the highest income quartile, though the odds were significant only for the top two quartiles. The odds of glaucoma showed neither a nonlinear relationship nor statistical significance with education level when adjusted for other factors. In contrast, age and gender remained significant even after adjusting for other factors. CONCLUSIONS: There exists a nonlinear relationship between key socioeconomic factors and the prevalence of glaucoma, though the exact nature of the relationship requires further investigation. These findings merit attention in studies that relate disease prevalence to education and income. PMID- 30433827 TI - Longitudinal Analysis of Sleep Duration and Cardiometabolic Risk in Young Children. AB - BACKGROUND: The aim of this study is to determine if sleep duration in early childhood is associated with cardiometabolic risk (CMR) in later childhood as assessed by a CMR cluster score [sum of age- and sex-standardized z-scores of waist circumference (WC), systolic blood pressure, triglycerides, glucose, and (inverse) high-density lipoprotein (HDL)]. Secondary objectives included examining sleep duration and the individual CMR factors and BMI z-score. PATIENTS AND METHODS: A prospective cohort study was conducted using data from the TARGet Kids! practice-based research network in Toronto, Canada. Children (n = 597) with parent-reported 24-hour sleep duration in early childhood (12-36 months) and a follow-up visit (36-96 months) with all five CMR factors were included in the analysis. Multivariable linear regression was used to assess the relationship between early childhood sleep duration and later childhood CMR, adjusting for relevant covariates. RESULTS: Average 24-hour sleep duration in early childhood [mean age: 28.1 (6.6) months] was 11.8 (1.4) hours, with 87% meeting or exceeding total sleep recommendations for their age. Sleep duration in early childhood was not associated with the CMR cluster score in later childhood. Shorter sleep duration was associated with higher HDL concentrations [adjusted beta = -0.028 (95% confidence interval: -0.049 to -0.007), p = 0.009]. CONCLUSIONS: Further research is needed to determine if early childhood sleep duration is associated with HDL in later childhood. Future studies, which investigate sleep quality in addition to sleep duration, may be helpful. PMID- 30433829 TI - New Interpretation of Multimodality Fundus Imaging for Retinal Cavernous Hemangioma. AB - OBJECTIVE: The aim of this study was to investigate the multimodality imaging features of retinal cavernous hemangiomas (RCHs). MATERIALS AND METHODS: The clinical data of three patients with RCH were reviewed and the imaging findings were analyzed. RESULTS: The color photographs of the fundus showed bead-like vesicles in the retina. Some vesicles showed plasma erythrocyte separation - with plasma on the top and erythrocytes at the bottom - which was consistently detected as high spontaneous fluorescence on fundus fluorescence angiography. Other vesicles were surrounded by thick walls and fibrous tissue, showing high spontaneous fluorescence, although they did not show any changes on fluorescence angiography. Optical coherence tomography (OCT) could not discriminate the different characteristics of the vesicles, but could clearly discriminate the appearance of the vesicles and their location on the retina, as well as other structural features. CONCLUSIONS: Fundus color photography, fundus fluorescein angiography, and OCT can aid in acquiring a better understanding of the structural features of cavernous hemangioma and its relationship with retinal vessels. PMID- 30433830 TI - Frailty and Clinical Outcomes in Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Frailty represents an increased vulnerability to adverse health outcomes. The frailty phenotype conceptual model (>=3 patient attributes of wasting, exhaustion, low activity, slowness, and weakness) is associated with increased morbidity and mortality in geriatric populations. OBJECTIVES: Our objective was to describe the risks associated with frailty in chronic obstructive lung disease (COPD) patients. METHODS: Data from the National Emphysema Treatment Trial (NETT) were retrospectively analyzed. The frailty phenotype conceptual model was operationalized as >=3 frailty parameters: body mass index decrease >=5% over 12 months, self-reported exhaustion, low 6-minute walking distance, or physical activity or respiratory muscle strength in the lowest quartile. Frail participants were compared to participants with <=2 frailty parameters. Participants were followed starting 12 months after NETT randomization (to minimize surgical effect) for 24 months. Univariate, multivariate, Kaplan-Meier and Cox proportional hazard analyses were performed, adjusting for treatment arm, age, modified Medical Research Council dyspnea scale, sex, and baseline FEV1. Multiple imputation was used for missing values. RESULTS: Participants (N=902) were predominantly white (94.5%) males (59.5%), with a median age of 67 (IQR 63-70), and a median FEV1 percent predicted of 26 (IQR 20-33). Six percent of participants (95% Confidence Interval [CI] 4.5 to 7.6) were frail. The incidence rate of frailty was 6.4 per 100 person-years. Frail participants reported significantly worse disease-specific and overall quality of life by St. George's Respiratory Questionnaire total score (mean difference of 11.6; 95% CI 7.6 to 15.6; p<0.001), mental composite on Medical Outcomes Survey Short Form-36 (SF-36) (mean difference -6.8; 95% CI -10.0 to 3.6; p<0.001), and physical composite scores on SF-36 (mean difference -16.7; 95% CI -21.3 to -12.1; p=0.001). Frail participants had an increased rate of hospitalization (adjusted hazard ratio (HR) 1.6, 95% CI 1.1-2.5; p=0.02) and an adjusted increase in hospital use of 8.0 days (95% CI 4.4-11.6; p<0.001) compared to non-frail participants. Frail participants had a higher mortality rate (after adjustment HR 1.4, 95% CI 0.97-2.0; p=0.07). CONCLUSIONS: Among adults with COPD, our measure of frailty (modified from the Fried Frailty Phenotype) was associated with incident and longer duration hospitalization and with poor quality of life. PMID- 30433831 TI - The safety of dinutuximab for the treatment of pediatric patients with high-risk neuroblastoma. AB - INTRODUCTION: Dinutuximab, an anti-GD2 antibody, specifically targets the high expression of GD2 on neuroblastoma cells, and its incorporation into maintenance high-risk neuroblastoma therapy has increased event-free survival for this devastating disease. Efficacy of dinutuximab during other phases of therapy or in relapsed and refractory patients remains under investigation. Areas covered: This review looked at available publications (via PubMed search and online abstract catalogs of recent scientific meetings) on pre-clinical safety studies of dinutuximab as well as results and current impressions of pending trials including dinutuximab and other anti-GD2 antibodies. While dinutuximab has become the standard of care for maintenance therapy in many cooperative trials, long term follow-ups as well as ongoing assessment about timing of antibody use and co administration of other pharmacologic or immune-modulatory agents remains under study. Expert opinion: Results of these and ongoing trials demonstrate prolonged time to first relapse and potentially overall survival benefit when dinutuximab is used during maintenance therapy. The role cytokines administered in conjunction with dinutuximab remains unclear and may increase toxicity without additional benefit. Current also investigations demonstrate promising efficacy in relapsed and refractory neuroblastoma. Further study is warranted in order to appropriately incorporate dinutuximab into current treatment strategies. PMID- 30433832 TI - Characterization of autoantibodies in primary membranous nephropathy and their clinical significance. AB - INTRODUCTION: Membranous nephropathy (MN) is the most common cause of a nephrotic syndrome in Caucasian adults. The identification of target antigens in MN in the last decade has had a major impact on the clinical approach to these patients. Areas covered: Since the discoveries in animal models in the 1980s that circulating autoantibodies induce disease upon in situ binding to glomerular podocytes, many attempts have been undertaken to define the human antigens responsible for disease induction. Only in 2009 was Phospholipase A2 Receptor 1 described as the major antigen responsible for MN onset in about 70% of patients. Subsequently, in 2014, Thrombospondin Type-1 Domain-Containing 7A was identified as a second antigen, accounting for 2-3% of patients with MN. The knowledge of the role of these antibodies in MN has improved the diagnosis and management of patients and helped to better define the need for immunosuppressive treatment. Expert commentary: These discoveries over the last 10 years in the discipline of nephrology have clearly shown the improvements a better understanding of disease pathogenesis can bring for patient care. PMID- 30433833 TI - Characterization of Children with Septic Shock Cared for by Emergency Medical Services. AB - OBJECTIVE: To inform the future development of a pediatric prehospital sepsis tool, we sought to 1) describe the characteristics, emergent care, and outcomes for children with septic shock who are transported by emergency medicine services (EMS) and compare them to those self-transported; and 2) determine the EMS capture rate of common sepsis screening parameters and the concordance between the parameters documented in the EMS record and in the emergency department (ED) record. METHODS: This is a retrospective cohort study of children ages 0 through 21 years who presented to a pediatric ED with septic shock between 11/2013 and 06/2016. Data, collected by electronic and manual chart review of EMS and ED records, included demographics, initial vital signs in both records, ED triage level, site of initial ED care, ED disposition, ED therapeutic interventions, outcomes and times associated with processes. Potential screening parameters were dichotomized as normal versus abnormal based on age-dependent normative data. RESULTS: Of the children with septic shock treated in our ED, 19.3% arrived via EMS. These children as compared to those self-transported were more likely (i.e., p < 0.05) to be male, have public insurance, receive initial care in the ED resuscitation suite, be hypotensive on arrival, receive their first ED fluid bolus sooner (33 vs 58 minutes), receive vasoactive agents and be mechanically ventilated in the first 24 hours, and have slightly longer length of hospital stays. Both groups had similar times to antibiotics. While poor outcomes were rare, the 3- and 30- day mortality were similar for both groups. EMS capture rates were highest for heart rate and respiratory rate, and lowest for temperature, glucose and blood pressure. Interrater reliability was highest for heart rate. CONCLUSIONS: Children presenting to the ED with septic shock transported by EMS represent a critically ill subset of modest proportions. Realization of sepsis screening tool for this vulnerable population will require both creation of a tool containing a limited subset of objective parameters along with processes to ensure capture. PMID- 30433834 TI - Neuro protective effect of Naringenin against MPTP induced oxidative stress. AB - BACKGROUND: Parkinson's disease is the most common neurodegenerative disorder, characterized by loss of dopaminergic neurons in substantia nigra and depletion of dopamine in striatum due to excitotoxicity, oxidative stress and many other factors may contribute to MPTP- and PD-related neurodegeneration. The present study deals with the neuroprotective effect of Naringenin (NGN), a bioflavonoid against MPTP induced Parkinson's disease in the mouse model. METHODS: Healthy male C57BL/6J mice (18-22 g b wt) were pretreated with NGN [25, 50,100 mg/kg/b.wt, p.o] once daily for 5 days. Thereafter, 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP) (80 mg/kg b.wt, i.p) was given in two divided doses (2 x 40 mg/kg at 16h interval). The animals were observed for motor functions 48 hours after the first MPTP injection. After completion of behaviour tasks, all animals were euthanized to dissect out the brain and used for biochemical, molecular and histopathological investigations. RESULTS: Pretreatment of NGN significantly reversed the toxic effects of MPTP by reducing LPO levels and increasing the activities of glutathione reductase and catalase along with improved behavioral performance. Interestingly, pre-treatment with NGN down regulated iNOS expression level in MPTP intoxicated mice brain. In addition, the histopathological evaluation revealed that NGN decreased the nuclear pigmentation and cytoplasmic vacuolation in the substantia nigra and striatal regions when compared to MPTP intoxicated mice brain. DISCUSSION: The present study showed that NGN exerts neuroprotection by suppressing oxidative stress via antioxidant mechanisms. The above finding suggests that NGN may act as a potential target in the management of PD. PMID- 30433835 TI - Current strategies for hemostatic control in acute trauma hemorrhage and trauma induced coagulopathy. AB - INTRODUCTION: Despite advances in the treatment of severely injured patients that have resulted in overall improved outcomes, uncontrolled hemorrhage still represents the most common cause of preventable death following major injury. While addressing both endo- and exogenous factors that lead to an acute trauma induced coagulopathy, massive transfusion plays a key role in managing bleeding trauma patients. However, the best practice for hemostatic control including massive transfusion in these patients is still under debate. Areas covered: This review summarizes the current knowledge and clinical practice for hemostatic control including massive transfusion for bleeding trauma patients. The recent literature was reviewed and extended by current guidelines and their underlying evidence was incorporated. Expert commentary: Treatment strategies for bleeding trauma patients are still an area of emerging scientific and clinical interest as advances are likely to translate into improved outcomes including survival. To date, damage control resuscitation principles with ratio-based transfusion of packed red blood cells, plasma and platelets still dominate as "gold standard" of care but goal-directed strategies guided either by conventional coagulation tests or viscoelastic assays may demonstrate a better characterization of the underlying coagulopathy thereby allowing individualized and targeted therapies. PMID- 30433836 TI - Development and evaluation of candidate subunit vaccine against botulinum neurotoxin serotype B. AB - Botulinum neurotoxins (BoNTs) are potential biological weapons because of their high toxicity and mortality. Vaccination is an effective strategy to prevent botulism. The carboxyl-terminus of the heavy chain (Hc domain) is nontoxic and sufficient to generate protective immune responses against natural BoNTs in animals. To produce a vaccine suitable for human use, a recombinant non His tagged isoform of the Hc domain of botulinum neurotoxin serotype B (BHc) was expressed in Escherichia coli and purified by sequential chromatography. The immunogenicity of recombinant E.coli-expressed BHc and the yeast-expressed mBHc antigens was explored and compared in Balb/c mice. BHc provided comparable protective potency but elicited significantly higher antibody titer and neutralization potency against BoNT/B after twice immunization, indicating that the recombinant BHc protein expressed in E.coli have better immunogenicity than the yeast-expressed mBHc. Moreover, a frequency and dose-dependent effect was observed in mice immunized with BHc subunit vaccine and the anti-BHc ELISA antibody titers correlated well with neutralizing antibody titers and protection potency. In summary, the Alhydrogel-formulated BHc subunit vaccine afforded effective protection against BoNT/B challenge. Therefore, the non-His-tagged and homogeneous BHc expressed in E.coli represents a good potential candidate subunit vaccine for human use. PMID- 30433837 TI - Development of a measure to assess vaccine confidence among men who have sex with men. AB - BACKGROUND: Recent serogroup C meningococcal disease outbreaks led to meningococcal vaccine recommendations for Southern California men who have sex with men (MSM). Assessment of vaccine confidence is critical to improving vaccine coverage in the context of disease outbreaks wherein immunization(s) are recommended. METHODS: We surveyed MSM using venue-based sampling and began development of the vaccine confidence index (VCI) with 30 survey items corresponding to trust- and safety-related perceptions. We performed exploratory factor analyses and computed the Cronbach's alpha coefficient to assess internal consistency of the VCI. We created a categorical confidence variable (low, medium, and high confidence) and conducted bivariate and multivariate analyses to evaluate associations with reported confidence and immunization uptake. RESULTS: Ten survey items were included in the final VCI and formed the confidence measure. Participants with low confidence had the lowest levels of reported uptake for both meningococcal vaccines. Confidence differed significantly (p <= 0.05) between MSM who indicated they received vaccines recommended within the context of the outbreak and those who did not. CONCLUSIONS: Our VCI is sensitive to a number of issues that may influence vaccine confidence. It is useful for assessing MSM trust and acceptance of recommended immunizations and may be used to inform intervention development. PMID- 30433838 TI - JAK-inhibitors in dermatology. Current evidence and future applications. AB - The Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathway is a ubiquitous intracellular signaling network. Selective JAK inhibitors have anti-inflammatory properties and have been approved in many countries for the treatment of rheumatoid arthritis (tofacitinib, baricitinib) and myelofibrosis or polycythemia vera (ruxolitinib). The aim of the publication was to summarize and critically analyze the efficacy and safety of JAK-inhibitors in skin diseases, such as psoriasis, alopecia areata, atopic dermatitis and vitiligo. Databases PubMed, Scopus and EBSCO were searched. After exclusions, 17 articles were analyzed (11 randomized clinical trials, 4 case reports, 1 retrospective study of a case series and 1 nonrandomized pilot study). The strongest evidence of JAK-inhibitor efficacy was established for treatment of psoriasis. Additionally, data are available on the potential efficacy of JAK inhibitors in alopecia areata, atopic dermatitis and vitiligo. Mostly, JAK inhibitors are used orally. However, there are studies showing efficacy of topical administration of this group of drugs in psoriasis and vitiligo. Further research is needed, especially the head-to-head comparison studies with JAK inhibitors and current therapeutic methods to verify the superiority of this new group of drugs in these dermatological diseases. PMID- 30433839 TI - Is bronchoscopic treatment of lung cancer possible? PMID- 30433840 TI - Modernizing the Bradford Hill criteria for assessing causal relationships in observational data. AB - Perhaps no other topic in risk analysis is more difficult, more controversial, or more important to risk management policy analysts and decision-makers than how to draw valid, correctly qualified causal conclusions from observational data. Statistical methods can readily quantify associations between observed variables using measures such as relative risk (RR) ratios, odds ratios (OR), slope coefficients for exposure or treatment variables in regression models, and quantities derived from these measures. Textbooks of epidemiology explain how to calculate population attributable fractions, attributable risks, burden-of disease estimates, and probabilities of causation from relative risk (RR) ratios. Despite their suggestive names, these association-based measures have no necessary connection to causation if the associations on which they are based arise from bias, confounding, p-hacking, coincident historical trends, or other noncausal sources. But policy analysts and decision makers need something more: trustworthy predictions - and, later, evaluations - of the changes in outcomes caused by changes in policy variables. This concept of manipulative causation differs from the more familiar concepts of associational and attributive causation most widely used in epidemiology. Drawing on modern literature on causal discovery and inference principles and algorithms for drawing limited but useful causal conclusions from observational data, we propose seven criteria for assessing consistency of data with a manipulative causal exposure-response relationship - mutual information, directed dependence, internal and external consistency, coherent causal explanation of biological plausibility, causal mediation confirmation, and refutation of non-causal explanations - and discuss to what extent it is now possible to automate discovery of manipulative causal dependencies and quantification of causal effects from observational data. We compare our proposed principles for causal discovery and inference to the traditional Bradford Hill considerations from 1965. Understanding how old and new principles are related can clarify and enrich both. PMID- 30433841 TI - Cost of Treating Pediatric Cancer at the Butaro Cancer Center of Excellence in Rwanda. AB - PURPOSE: Improvements in childhood survival rates have been achieved in low- and middle- income countries that have made a commitment to improve access to cancer care. Accurate data on the costs of delivering cancer treatment in these settings will allow ministries of health and donors to accurately assess and plan for expansions of access to care. This study assessed the financial cost of treating two common pediatric cancers, nephroblastoma and Hodgkin lymphoma, at the Butaro Cancer Center of Excellence in rural Rwanda. METHODS: A microcosting approach was used to calculate the per-patient cost for Hodgkin lymphoma and nephroblastoma diagnosis and treatment. Costs were analyzed retrospectively from the provider perspective for the 2014 fiscal year. The cost per patient was determined using an idealized patient receiving a full course of treatment, follow-up, and recommended social support in accordance with the national treatment protocol for each cancer. RESULTS: The cost for a full course of treatment, follow-up, and social support was determined to be between $1,490 and $2,093 for a patient with nephroblastoma and between $1,140 and $1,793 for a pediatric patient with Hodgkin lymphoma. CONCLUSION: Task shifting, reduced labor costs, and locally adapted protocols contributed to significantly lower costs than those seen in middle- or high-income countries. PMID- 30433842 TI - Development of Age-Dependent Dose Modification Factors for Acute Radiation Lethality. AB - PURPOSE: The aim of our work was to develop an approach to account for the impact of age at exposure on acute radiation lethality risk for the purpose of improving casualty estimation tools when applied to a diverse population. MATERIALS & METHODS: Age-dependent radiation lethality data were collected from published animal studies. The 50% lethal dose responses (LD50) were extracted, grouped according to developmental stages in humans, and average LD50 values calculated for select age categories. Dose modification factors (DMFs) were developed by dividing LD50 values of non-young, adult groups to the reference adult category within each study. DMFs were combined across each age group to provide a DMF for each age category. RESULTS: Data from 12 studies with age-dependent LD50 values from 5 species (>21,000 animals) demonstrate increased sensitivity to acute radiation in elderly and young animals compared to young adults. DMFs were developed for infant (0.80), juvenile (0.86), late adult (0.86), and elderly (0.71) populations. CONCLUSIONS: Animal and human data support increased radiosensitivity in infants, juveniles, and aging adults. DMFs provide a mechanism to account for age-dependent variability in health effects models and to determine impact of age on casualty estimates. PMID- 30433843 TI - Adaptation of Oncology Fellowship to Reflect Contemporary Practice. PMID- 30433844 TI - Establishing an Antifungal Program to Reduce Invasive Fungal Infections in Patients With Acute Myeloid Leukemia Receiving Induction and Reinduction Chemotherapy. AB - PURPOSE:: Twenty percent of patients with acute myeloid leukemia (AML) undergoing induction or reinduction chemotherapy at the University of Virginia Health System from May 2011 to August 2014 had a proven or probable invasive fungal infection (IFI). The purpose of our initiative was to reduce the percentage of proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy at the University of Virginia Health System to 10% or less by June 2017, in concordance with national averages. METHODS:: A multidisciplinary team was formed to lead the comprehensive quality improvement (QI) initiative. The team generated both current process state and ideal process state workflow diagrams, a cause-and-effect diagram, and a Pareto diagram to determine the most relevant etiology for proven or probable IFIs in patients with AML undergoing induction or reinduction chemotherapy. RESULTS:: Analysis led to the creation of a program standardizing antifungal prophylaxis in this patient population, along with a suggested work-up for recalcitrant fevers. Through two tests of change (Plan-Do-Study-Act cycles 1 and 2), the QI initiative was able to effectively reduce the proven or probable IFI rate to 0% since program implementation in August 2016, thus surpassing both QI initiative goals and national rates of IFI. Mean length of stay (LOS) decreased by 3.4 days, and median intensive care unit LOS decreased by 2 days. CONCLUSION:: Creation of a standardized antifungal prophylaxis program led to a marked decrease in LOS and the proven or probable IFI rate of patients with AML undergoing induction or reinduction chemotherapy. PMID- 30433845 TI - Examining strategies for improving healthcare providers' communication about adolescent HPV vaccination: evaluation of secondary outcomes in a randomized controlled trial. AB - There is a critical need for campaigns and interventions to increase rates of human papillomavirus (HPV) vaccination among U.S. adolescents. Healthcare providers are key stakeholders in parents' HPV vaccine decision-making. The current study presents the evaluation of secondary outcomes in a multi-component communication-based intervention to improve healthcare providers' communication about HPV vaccination. Evaluation was conducted via surveys of providers participating in a 12-month randomized controlled trial. Findings suggest use of communication components (combined use of the presumptive approach [PA] with all patients, and motivational interviewing and a fact sheet with vaccine hesitant parents) contributed to providers in the intervention group reporting higher perceived levels of parental HPV vaccine acceptance than control providers, as well as increased vaccination rates in the intervention arm in the main RCT. PMID- 30433846 TI - Anarchitectures of health: Futures for the biomedical drone. AB - In recent years, research on the military deployment of unmanned aerial vehicles (UAVs), or drones, has proliferated. However, to date there has been little systematic study of how drones are being used for health surveillance and management, particularly in resource-constrained settings. In this paper, we draw on a number of case studies to explore how the biomedical drone is contributing to a re-spatialization of health and to a process of datafication that is set to fundamentally change the nature and scope of health governance. The promotion of the drone as a solution to global challenges reflects a broader techno-optimism. However, drones and the cybernetworks they rely on are short-circuiting terrestrial systems and driving a strategic, hotspot approach to health. This targeted view of the world, we argue, recapitulates and extends earlier forms of colonial surveillance and intervention premised on security and incipient threat. We develop the notion of 'anarchitecture' to describe the formation of these new inverted health landscapes where state infrastructures are entangled with shifting technological networks. In short, we seek to develop a framework for reflecting on the ways in which global health is being reconfigured through the development of remote-sensing technologies and cyberinfrastructures. PMID- 30433847 TI - Informed Consent and Phase I Trials: Cognitive Failure and Additional Challenges to Informed Decision Making. PMID- 30433848 TI - Validation of Mayo Clinic Staging System for Light Chain Amyloidosis With High Sensitivity Troponin. PMID- 30433850 TI - Personalizing Medicine. PMID- 30433851 TI - Out of the Mouths of Babes: A Physician Discusses Her Cancer Diagnosis With Her Two Young Children. PMID- 30433849 TI - Reply to J. Schildmann et al. PMID- 30433852 TI - Bladder Preservation With Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial. AB - PURPOSE: Fluorouracil plus cisplatin and radiation twice a day (FCT) is an established chemoradiation (CRT) regimen for selective bladder-sparing treatment of muscle-invasive bladder cancer. Gemcitabine and once daily radiation (GD) is a well-supported alternative. The current trial evaluates these regimens. METHODS: Patients with cT2-4a muscle-invasive bladder cancer were randomly assigned to FCT or GD. Patients underwent transurethral resection and induction CRT to 40 Gy. Patients who achieved a complete response (CR) received consolidation CRT to 64 Gy and others underwent cystectomy. We administered adjuvant gemcitabine/cisplatin chemotherapy. The primary end point was the rate of freedom from distant metastasis at 3 years (DMF3). The trial was not statistically powered to compare regimens, but to assess whether either regimen exceeded a DMF3 benchmark of 75%. Toxicity and efficacy end points, including CR and bladder intact distant metastasis free survival at 3 years (BI-DMFS3), were assessed. RESULTS: From December 2008 to April 2014, 70 patients were enrolled, of which 66 were eligible for analysis, 33 per arm. Median follow-up was 5.1 years (range, 0.4 to 7.8 years) for eligible living patients. DMF3 was 78% and 84% for FCT and GD, respectively. BI-DMFS3 was 67% and 72%, respectively. Postinduction CR rates were 88% and 78%, respectively. Of 33 patients in the FCT arm, 21 (64%) experienced treatment-related grade 3 and 4 toxicities during protocol treatment, with 18 (55%), two (6%), and two patients (6%) experiencing grade 3 and 4 hematologic, GI, and genitourinary toxicity, respectively. For the 33 patients in the GD arm, these figures were 18 (55%) overall and 14 (42%), three (9%) and two patients (6%), respectively. CONCLUSION: Both regimens demonstrated DMF3 greater than 75%. There were fewer toxicities observed in the GD arm. Either gemcitabine and once daily radiation or a cisplatin-based regimen could serve as a base for future trials of systemic therapy. PMID- 30433854 TI - Estimation of gestational diabetes mellitus and dose-response association of BMI with the occurrence of diabetes mellitus in pregnant women of the west of Iran. AB - The authors aim to investigate the GDM and the dose-response association of BMI with it in pregnant women in Kermanshah, Iran. During the 2015-2016 year, the 1010 pregnant women were studied. The restricted cubic spline method was used to evaluate the relationship between BMI and GDM. The risk of GDM was 10.1%. The incidence rate ratio for GDM indicates a non-significant protective effect and, then a significant risk for GDM occurrence along with BMI. BMI can be used as a predictive factor. A healthy diet and recommended levels of physical activity are suggested to prevent overweight and obesity and subsequent GDM. PMID- 30433853 TI - Bacterial colonization of healthcare workers' mobile phones in the ICU and effectiveness of sanitization. AB - Extra-European studies report high rates of multi-drug resistant bacteria colonization of healthcare workers' mobile phones in intensive care units. We aimed to assess the prevalence of bacterial colonization of healthcare workers' mobile phones in an intensive care unit in France and the effectiveness of a sanitization product. We designed a prospective, monocentric study in a 15-bed intensive care unit within a 300-bed private hospital. Bacterial colonization was assessed on 56 healthcare workers' mobile phones immediately before and 5 min after sanitization of the phones with bactericidal wipes. The mobile phones of 42 administrative staff acted as controls. All mobile phones in both groups were colonized. Healthcare workers' phones had a higher number of different bacterial species per phone (2.45 +/- 1.34 vs. 1.81 +/- 0.74, p = 0.02). Colonization with pathogens did not differ significantly between healthcare workers' and controls' phones (39.3% vs. 28.6%, p = 0.37). Excluding coagulase negative Staphylococcus, Staphylococcus aureus was the most common pathogen found in both groups (19.6% and 11.9%, p = 0.41). Only one healthcare workers' mobile phone was colonized by methicillin-resistant Staphylococcus aureus, and no other multi-drug resistant bacteria was detected. No covariate was associated with pathogen colonization. After sanitization, 8.9% of mobile phones were sterilized, and colonization with pathogenic bacteria decreased (21.4% vs. 39.3%, p = 0.04) as did the number of CFUs/mL (367 +/- 404 vs. 733 +/- 356, p < 0.001). Colonization of intensive care unit healthcare workers' and administrative staff's mobile phones was similar. Colonization with pathogens was frequent but colonization with multi-drug resistant bacteria was rare. Disinfecting the phones with bactericidal wipes is not completely effective. Specific sanitization protocols and recommendations regarding the management of healthcare workers' mobile phones in intensive care units should be developed. Additionally, good hand hygiene after touching mobile phones should be kept in mind to prevent cross-infections. PMID- 30433855 TI - Stigmasterol promotes neuronal migration via reelin signaling in neurosphere migration assays. AB - Stigmasterol (ST) is a multifunctional phytosterol and is found in diverse food. In our previous transcriptomics study, we found ST upregulated migration-related genes. In the present study, we carried out in vitro neurosphere migration assays to investigate the effects of ST on neuronal migration. For this purpose, neurospheres were produced by culturing rat (Sprague-Dawley) E14 cortical neurons. The addition of ST (75 MUM) to culture medium increased not only the numbers of migratory neurons by 15% but the distance of movement up to 120 MUm from the centers of neurospheres as compared to vehicle cultures. Immunocytochemistry and immunoblotting showed ST upregulated the expressions of Reelin (Reln) and its downstream signaling molecules like phospho-JNK (c-Jun N terminal kinase), doublecortin (DCX) and dynein heavy chain (DHC) in migratory neurons. Furthermore, in silico molecular docking simulation indicated that ST interacts with Relin receptor ApoER2 by forming a hydrogen bond with Lys2467 and other van der Waals interactions. Taken together, our study shows that ST upregulates Reln signaling and promotes neuronal migration and suggests that ST supplementation is considered as a potential means of treating migration-related CNS disorders. PMID- 30433856 TI - Effects of dam and seqA genes on biofilm and pellicle formation in Salmonella. AB - In this study, the effects of dam and seqA genes on the formation of pellicle and biofilm was determined using five different Salmonella serovars S. Group C1 (DMC2 encoded), S. Typhimurium (DMC4 encoded), S. Virchow (DMC11 encoded), S. Enteritidis (DMC22 encoded), and S. Montevideo (DMC89 encoded). dam and seqA mutants in Salmonella serovars were performed by the single step lambda red recombination method. The mutants obtained were examined according to the properties of biofilm on the polystyrene surfaces and the pellicle formation on the liquid medium. As a result of these investigations, it was determined that the biofilm formation properties on polystyrene surfaces decreased significantly (p < 0.05) in all tested dam and seqA mutants, while the pellicle formation properties were lost in the liquid medium. When pBAD24 vector, containing the dam and seqA genes cloned behind the inducible arabinose promoter, transduced into dam and seqA mutant strains, it was determined that the biofilm formation properties on the polystyrene surfaces reached to the natural strains' level in all mutant strains. Also, the pellicle formation ability was regained in the liquid media. All these data demonstrate that dam and seqA genes play an important role in the formation of biofilm and pellicle structures in Salmonella serovars. PMID- 30433857 TI - Positional obstructive sleep apnoea: challenging findings in consecutive patients treated with a vibrating position trainer. AB - OBJECTIVES: Last years, vibrating devices were introduced to treat positional sleep apnoea (POSA). However, few data exist on determinants of effectiveness and adherence in clinical settings. METHODS: The NightBalance Sleep Position Trainer (SPT) analyses the patient's position during the first 2 nights, starts to build up vibrations during the following 7 and is 100% performant from night 10 on; and, reports on %supine, usage time, number of (responses on) vibrations. The device was started for a 28-day try-out period in a clinical cohort of 51 consecutive patients with POSA. SPT-stored data were studied on different time points: first 2 nights without vibrations (baseline), first 2 nights on SPT 100% performance (short term) and 2 later nights after having used the full performant device for 14 days (long term). RESULTS: Only 27 patients used the device throughout the long-term period. The baseline %supine was lower than during polysomnography: 22.9 +/- 16.2 versus 40.7 +/- 20.0% (p = 0.0005). Apnoea hypopnoea index calculation taking into account the %supine on SPT revealed that 2/27 patients would not have obstructive sleep apnoea at home. The baseline %supine dropped (p < 0.0001) on short term without further change on long term. Ten patients could be considered cured and demonstrated higher response on vibrations. Only 29 patients could be considered as adherent, and they demonstrated higher response on vibrations and less side effects; only 13 wanted to purchase the SPT. CONCLUSION: On polysomnography, the %supine is overestimated. The efficacy and low adherence are influenced by differences in response to vibrations. The training effect is already presented on short term. PMID- 30433858 TI - Consumer Preferences and Demand for Annuities: Evidence From Hong Kong. AB - Retirees without annuities in Hong Kong confront longevity and investment risks. Despite these risks, there is very limited uptake of annuities. This study identifies product and consumer characteristics that are associated with the demand for annuities in Hong Kong. We conduct a discrete choice experiment and distribute a consumer survey among two independent representative samples of workers aged between 40 and 64. Results suggest that a fixed monthly income and a 10-year guarantee period are two significant product characteristics, while a bequest motive, being married, and an understanding of the annuity are consumer characteristics that are associated with the demand for annuities. Being presented the optimal hypothetical annuity product, approximately one-third of middle-aged workers choose to annuitize their retirement savings. The findings and methods of this study can be applied for designing annuity products in other contexts. PMID- 30433859 TI - Multiple antibiotic resistances and virulence markers of uropathogenic Escherichia coli from Mexico. AB - Virulence and antibiotic resistance properties related to different Escherichia coli phylogenetic groups have not been studied in detail in Mexico. We aimed to identify patterns of virulence genes and multidrug resistance in phylogenetic groups of uropathogenic strains (UPEC). Strains of E. coli were isolated from outpatients with urinary tract infections (UTIs), who went to unit of the public health sector in the State of Mexico. E. coli virulence markers and phylogenetic groups were identified by PCR. Susceptibility to 12 antimicrobials was determined by Kirby-Bauer. E. coli was identified in 60.4% (n = 194) of the patients with UTIs. Phylogroups B2 51% (n = 99), A 13.4% (n = 26) and B1 10.3% (n = 20) were the most frequent. Resistance to three or up to eleven antibiotics was detected in most phylogroups (n = 188). The genes fimH (n = 146), feoB (n = 179), iutA (n = 178), sitA (n = 121), fyuA (n = 99), and traT (n = 142) were mainly detected in strains of phylogroups B2, A, B1, C, and D. Seventy-two patterns of virulence markers were distributed across eight E. coli phylogenetic groups. A high frequency of virulence markers and the multiple antibiotic resistance phenotypes was observed in the phylogroups. The genes of extended-spectrum beta-lactamases (ESBLs) found with higher frequency among UPEC strains were blaTEM, blaSHV y blaCTX-M group 1, CIT (plasmid-mediated AmpC beta-lactamase), and blaOXA-like. In conclusion, our findings show the importance of surveillance, permanent monitoring, and particularly controlled prescription of antibiotics by physicians in the social security health system to reduce the spread of highly virulent UPEC strains that are resistant to multiple antimicrobial agents. PMID- 30433860 TI - Serum leptin is associated with first-ever ischemic stroke, lesion size and stroke severity in a Chinese cohort. AB - OBJECTIVE: Leptin may be associated with cardiovascular disease. We tested to determine whether leptin is a marker for first-ever acute ischemic stroke (AIS) in a nested case-referent study. METHODS: Consecutive patients with first-ever AIS from May 2017 to December 2017 were included. Referents were matched for sex, age and body mass index. Serum leptin levels and routine tests were examined in both groups. RESULTS: The median serum level of leptin in the stroke patients was 14.3 (interquartile range [IQR], 7.2-21.7) ng/ml, which was significantly higher (P < 0.001) than in the referents (10.7; 5.7-13.6 ng/ml). There was a positive correlation between serum level of leptin and National Institute of Health Stroke Scale score (r[Spearman] = 0.43, P < 0.001). In addition, serum leptin levels paralleled lesion size. Median serum level of leptin in patients with small lesions, medium lesions and large lesions was 7.3 (IQR, 5.3-14.3) ng/ml, 13.9 (IQR, 7.0-21.3) ng/ml, 20.5 (IQR, 12.4-32.7) ng/ml, respectively (analysis of variance: P < 0.001). In the univariate model matching for sex and age, leptin as a continuous variable was associated with AIS, after adjustment for possible confounders (odds ratio [OR] 1.07, 95% confidence interval [CI]: 1.04-1.11; P < 0.001). After adjusting for all other factors, leptin remained an independent stroke predictor with an adjusted OR of 1.03 (95% CI, 1.00-1.10; P = 0.006). Interestingly, the association between AIS and leptin level was more pronounced among men (adjusted OR = 1.05, 95% CI: 1.01-1.12; P < 0.001) when compared with women (adjusted OR = 1.03, 95% CI: 1.10-1.11; P = 0.009). CONCLUSION: Serum leptin is associated with first-ever AIS, lesion size and stroke severity in a Chinese cohort. PMID- 30433861 TI - Reversed ophthalmic artery flow following ischemic stroke: a possible predictor of outcomes following carotid artery stenting. AB - Stroke is the leading cause of death worldwide and stenosis of the carotid artery accounts for more than half of all cases. Carotid duplex is an effective non invasive ultrasound test which identifies stroke patients with moderate to severe carotid stenosis who are candidates for preventative intervention to reduce the risk of recurrence. In patients with moderate to severe carotid stenosis, reversed ophthalmic artery flow (ROAF) is often observed at the time of the carotid duplex scan. In this study, we investigated whether ROAF, denoting exhaustion of cerebral collateral flow in ischemic stroke patients affected mid term functional outcomes following carotid artery stenting (CAS) procedures. In total, 144 consecutive patients with a first episode of ischemic stroke and subsequent CAS procedure conducted between January 2010 and November 2014 at Changhua Christian Hospital, Taiwan were included. Clinical data were obtained by medical record review. Disability was assessed at two time points by utilising the Barthel Index (BI) and modified Rankin Scale (mRS) before CAS and 12 months post-CAS. Among 85 patients presenting without ROAF, 48/85 (56.4%) had improved mRS scores following stenting. The condition remained unchanged (stationary) in 36/85 (43.5%) patients after stenting and one patient exhibited deteriorated condition 1/85(1.1%). In contrast, among the 59 patients presenting with ROAF, 24/59 (40.6%) had improved mRS score following stenting. The condition remained unchanged (stationary) in the remaining 35/59 (59.3%) patients after stenting, and no patient exhibited deteriorated condition 0/59 (0 %). This study provides evidence that CAS is a valid and effective treatment option regardless of whether patients exhibited ROAF or not. Patients without ROAF were significantly more likely to have improved mid-term functional outcomes compared to those with ROAF. In the group without ROAF admission, CRP may play a role in predicting subsequent functional outcomes, whereas admission Barthel Index was a predictor of outcome in the ROAF group. PMID- 30433862 TI - Tetrahydrobiopterin Improves Endothelial Function in Patients with Cystic Fibrosis. AB - : Cystic fibrosis (CF) is a genetic disorder associated with a wide range of systemic complications, including vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus, the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. METHODS: 29 patients with CF (18 +/- 8 yrs old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received either a 5 mg/kg dose of oral BH4 (BH4-5; n=17) or a 20 mg/kg dose of oral BH4 (BH4-20; n=12). On a separate visit, a subset of patients from each group were retested following a placebo (PLC, n=9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function before and 3 h after treatment. RESULTS: Baseline FMD was lower in patients compared to controls. No change in FMD was observed following either PLC or BH4-5 (?FMD: -0.8 +/- 0.0% and -0.5 +/- 2.5%; p=0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in a significant improvement in FMD (?FMD: 1.1 +/- 1.4%) when compared to BH4-5 (p=0.023) and PLC (p=0.017). CONCLUSION: These data suggest that a single oral dose of BH4 at 20 mg/kg can improve vascular endothelial function in patients with CF. These findings support the hypothesis that BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. PMID- 30433863 TI - Voluntary running protects against neuromuscular dysfunction following hindlimb ischemia-reperfusion in mice. AB - Ischemia-reperfusion (IR) due to temporary restriction of blood flow causes tissue/organ damages under various disease conditions, including stroke, myocardial infarction, trauma and orthopedic surgery. In the limbs, IR injury to motor nerves and muscle fibers causes reduced mobility and quality of life. Endurance exercise training has been shown to increase tissue resistance to numerous pathological insults. To elucidate the impact of endurance exercise training on IR injury in skeletal muscle, sedentary and exercise-trained mice (5 weeks of voluntary running) were subjected to ischemia by unilateral application of a rubber band tourniquet above the femur for 1 hour followed by reperfusion. IR caused significant muscle injury and denervation at neuromuscular junction (NMJ) as early as 3 hours after tourniquet release as well as depressed muscle strength and neuromuscular transmission in sedentary mice. Despite similar degree of muscle atrophy and oxidative stress, exercise-trained mice had significantly reduced muscle injury and denervation at NMJ with improved regeneration and functional recovery following IR. Together, these data suggest that endurance exercise training preserves motor nerve and myofiber structure and function from IR injury and promote functional regeneration. PMID- 30433864 TI - Effect of menopause and exercise training on plasma apolipoprotein M and sphingosine-1-phosphate. AB - OBJECTIVE: The axis of apolipoprotein M (apoM) and sphingosine-1-phosphate (S1P) is of importance to plasma lipid levels, endothelial function, and development of atherosclerosis. Menopause is accompanied by dyslipidemia and an increased risk of atherosclerosis, which can be lowered by exercise training. The aim of this study was to explore if effects of menopause and training are paralleled by changes in the apoM/S1P axis. METHODS: Healthy, late premenopausal (n=38, age 49.2+/-2) and recent postmenopausal (n=37, age 53.3+/-3) women from the Copenhagen Women Study participated in a three-month, aerobic high-intensity exercise intervention. RESULTS: Before training, plasma apoM was higher in postmenopausal (1.08+/-0.2 umol/l (mean+/-SD)) compared to premenopausal (0.82+/ 0.2 umol/l) women (p<0.0001). Plasma S1P was similar in the two groups (0.44+/ 0.1 and 0.46+/-0.1 umol/l, respectively). Hence, the pre-training S1P/apoM ratio was 26% lower in postmenopausal than premenopausal women (p<0.0001). After the training program, plasma apoM increased from 0.82+/-0.2 to 0.90+/-0.3 umol/l in premenopausal women and from 1.08+/-0.2 to 1.16+/-0.3 umol/l in postmenopausal women (p<0.05). Plasma S1P increased from 0.44+/-0.1 to 0.47+/-0.1 umol/l in premenopausal women and from 0.46+/-0.1 to 0.48+/-0.1 umol/l in postmenopausal women (p<0.05). CONCLUSIONS: The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations, and that exercise training increases plasma apoM and S1P in healthy middle-aged women irrespective of menopausal status. PMID- 30433865 TI - Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice. AB - Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice (db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 weeks of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. PMID- 30433867 TI - Hang on: It Is Worth the Ride. PMID- 30433866 TI - Neurogenesis in the Adult Hippocampus: History, Regulation, and Prospective Roles. AB - The hippocampus is one of the sites in the mammalian brain that is capable of continuously generating controversy. Adult neurogenesis is a remarkable process, and yet an intensely debatable topic in contemporary neuroscience due to its distinctiveness and conceivable impact on neural activity. The belief that neurogenesis continues through adulthood has provoked remarkable efforts to describe how newborn neurons differentiate and incorporate into the adult brain. It has also encouraged studies that investigate the consequences of inadequate neurogenesis in neuropsychiatric and neurodegenerative diseases, and explore the potential role of neural progenitor cells in brain repair. The adult nervous system is not static; it is subjected to morphological and physiological alterations at various levels. This plastic mechanism guarantees that the behavior regulation of the adult nervous system is adaptable in response to varying environmental stimuli. Two regions of the adult brain, the olfactory bulb and the hippocampal dentate gyrus, contain new-born neurons that exhibit an essential role in the natural functional circuitry of the adult brain. This article explores current advancements in adult hippocampal neurogenesis by presenting its history and evolution, and studying its association with neural plasticity. The article also discusses the prospective roles of adult hippocampal neurogenesis, and describes the intracellular, extracellular, pathological and environmental factors involved in its regulation. PMID- 30433868 TI - Exploring insecticide resistance mechanisms in three major malaria vectors from Bangui in Central African Republic. AB - Malaria remains the main cause of mortality and morbidity in the Central African Republic. However, the main malaria vectors remain poorly characterised, preventing the design of suitable control strategies. Here, we characterised the patterns and mechanisms of insecticide resistance in three important vectors from Bangui. Mosquitoes were collected indoors, using electrical aspirators in July 2016 in two neighborhoods at Bangui. WHO bioassays performed, using F2 An. gambiae sensu lato (s.l.), revealed a high level of resistance to type I (permethrin) and II (deltamethrin) pyrethroids and dichlorodiphenyltrichloroethane (< 3% mortality). Molecular analysis revealed the co-occurrence of Anopheles coluzzii (56.8 %) and An. gambiae s.s. (43.2%) within the An. gambiae complex. Anopheles funestus s.s. was the sole species belonging to An. funestus group. Both kdr-w (40% of homozygotes and 60% of heterozygotes/kdr-w/wild type) and kdr-e (37.5% of heterozygotes) mutations were found in An. gambiae. Contrariwise, only the kdr-w (9.5% homozygotes and 85.7% of heterozygotes) was detected in An. coluzzii. Quantitative RT-PCR showed that CYP6M2 and CYP6P3 are not upregulated in An. coluzzii from Bangui. Analysis of the sodium channel gene revealed a reduced diversity in An. coluzzii and An. gambiae s.s. In An. funestus s.s., the pyrethroid/DDT GSTe2 L119F resistance allele was detected at high frequency (54.7%) whereas a very low frequency for Rdl was observed. Polymorphism analysis of GSTe2 and GABA receptor gene in An. funestus revealed the presence of one resistant haplotype for each gene. This study provides baseline information to help guide current and future malaria vector control interventions in CAR. PMID- 30433869 TI - Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity. AB - Innate immune memory is an emerging area of research. However, innate immune memory at major mucosal sites remains poorly understood. Here, we show that respiratory viral infection induces long-lasting memory alveolar macrophages (AMs). Memory AMs are programed to express high MHC II, a defense-ready gene signature, and increased glycolytic metabolism, and produce, upon re-stimulation, neutrophil chemokines. Using a multitude of approaches, we reveal that the priming, but not maintenance, of memory AMs requires the help from effector CD8 T cells. T cells jump-start this process via IFN-gamma production. We further find that formation and maintenance of memory AMs are independent of monocytes or bone marrow progenitors. Finally, we demonstrate that memory AMs are poised for robust trained immunity against bacterial infection in the lung via rapid induction of chemokines and neutrophilia. Our study thus establishes a new paradigm of immunological memory formation whereby adaptive T-lymphocytes render innate memory of mucosal-associated macrophages. PMID- 30433870 TI - Lack of effect of the SLC47A1 and SLC47A2 gene polymorphisms on the glycemic response to metformin in type 2 diabetes mellitus patients. AB - Background This work aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the SLC47A1 (922-158G>A; rs2289669) and SLC47A2 (-130G>A; rs12943590) genes on the relative change in HbA1c in type 2 diabetes mellitus (T2DM) patients of South India who are taking metformin as monotherapy. It also aims to study the effects of these SNPs on the dose requirement of metformin for glycemic control and the adverse effects of metformin. Methods Diabetes patients on metformin monotherapy were recruited based on the eligibility criteria (n=105). DNA was extracted and genotyping was performed with a real-time PCR system using TaqMan(r) SNP genotyping assay method. The HbA1c levels were measured using Bio-Rad D-10TM Hemoglobin Analyzer. Results After adjusting for multiple comparisons (Bonferroni correction) the difference found in the glycemic response between the "GG" genotype and "AG/AA" genotype groups of the SLC47A2 gene was not significant (p=0.027; which was greater than the critical value of 0.025). Patients with "GG" genotype showed a 5.5% decrease in HbA1c from baseline compared to those with the "AG/AA" genotype (0.1% increase). The SNP in the SLC47A1 gene also did not influence the glycemic response to metformin (p=0.079). The median dose requirements based on the genotypes of the rs12943590 variant (p=0.357) or rs2289669 variant (p=0.580) were not significantly different. Similarly, there was no significant difference in the occurrence of adverse effects across the genotypes in both the SLC47A1 (p=0.615) and SLC47A2 (p=0.309) genes. Conclusions The clinical response to metformin was not associated with the SNPs in the SLC47A1 and SLC47A2 genes coding for the multidrug and toxin extrusion protein (MATE) transporters. Furthermore, the studied SNPs had no influence on the dose requirement or adverse effects of metformin. PMID- 30433872 TI - Insulin resistance linked to subtle myocardial dysfunction in normotensive Turner syndrome young patients without structural heart diseases. AB - Background Turner syndrome (TS) patients have increased cardiovascular risk. This cardiovascular risk is famously attributed to structural abnormalities of the left side of the heart such as aortic stenosis and aortic coarctation. However, due to insulin resistance and subsequent pathogenic mechanisms, normotensive TS patients without structural abnormalities may develop varying degrees of myocardial dysfunction. The aim of this research was to examine the role of speckle tracking echocardiography in early detection of Turner cardiomyopathy and to correlate this myocardial dysfunction with measures of insulin resistance. Methods This cross-sectional case control study included 30 children with TS and 30 age-matched healthy controls. TS patients were excluded if: hypertensive, with major structural abnormalities of the heart or other systemic diseases that may affect myocardial function. Conventional speckle tracking echocardiography and glucose-insulin ratio were performed for all study subjects. Results Routine echocardiographic parameters of left ventricular systolic function were similar in cases and controls while global longitudinal and circumferential strain (GLS and GCS) were lower in patients with TS than controls: (-13.2+/-1.1 vs. -18.3+/ 2.4, p-value<0.000) and (-11.3+/-1.1 vs. -16.3+/-2.1, p-value<0.000), respectively. Fasting glucose:insulin ratio (FGIR) proved to be the best predictor of myocardial dysfunction in TS patients by multivariate analysis. Conclusions This study points towards the potential role of two-dimensional (2D) speckle tracking echocardiography in early detection of subtle systolic myocardial dysfunction in TS patients. It also points towards the implication of insulin resistance in precipitation of the observed dysfunction in TS patients. PMID- 30433871 TI - Arterial stiffness as a measure of cardiovascular risk in obese adolescents and adolescents with diabetes type 1. AB - Background Cardiovascular disease (CVD) is the end result of vascular aging and atherosclerosis, having its origins in childhood. The aim of our study was to compare arterial stiffness (AS) and intima-media thickness (IMT) as markers of an early vascular damage between obese adolescents, adolescents with diabetes type 1 (T1D) and lean control subjects. Methods We analyzed AS and IMT in 68 obese adolescents (13.27+/-2.31 years), 42 adolescents with T1D (14.95+/-2.35 years) lasting over 5 years and 38 controls (15.02+/-1.94 years). AS (measured by pulse wave velocity [PWV], arterial compliance [AC] and beta-stiffness) and IMT were assessed using an e-tracking ultrasound method. Results A significant difference between the groups was found for AC (p=0.022) and PWV (p=0.010), with the lowest compliance and higher velocities in T1D patients. When corrected for age, the difference in AC among the groups did not reach a statistical difference (p=0.059). Correlation analysis in the obese adolescents showed lower AC in females (p=0.041), with higher systolic blood pressure (SBP) (p=0.032). In T1D adolescents, disease duration was the strongest determinant of AS (AC p=0.028, beta p=0.029 and PWV p=0.003), followed by body mass index (BMI; PWV p=0.008; beta p=0.033), SBP (AC p<0.001; PWV p=0.023), diastolic BP (AC p=0.049; PWV p=0.048) and HbA1c (PWV p=0.048). No significant correlations were found for AS measures or IMT with sex, age, BMI, Tanner stage or BP levels in controls. Conclusions Early vascular damage is more pronounced in T1D adolescents than in obese or lean adolescents, which may emphasize the impact of hyperglycemia as a major threat for cardiovascular health. PMID- 30433873 TI - Do parents of children with metabolic diseases benefit from the Triple P - Positive Parenting Program? A pilot study. AB - Background Parents of children with metabolic diseases report more parenting stress, anxiety, depression and dysfunctional parenting styles than parents of children without metabolic diseases. In addition, their children have more behavioral problems. Beside the fact that metabolic diseases are rare, they form a relatively large proportion in the morbidity and mortality of chronically ill children. Methods In this pilot study 14 parents of children with metabolic diseases, aged between 2.5 and 13 years, participated in a quasi-experimental pre post-follow-up study. Results After participating in the Level 4 Group Triple P program there were small effects in decreasing child behavioral problems and large effects in decreasing dysfunctional parenting styles. There was a moderate to large reduction of parental stress and a large reduction of parental anxiety. Only the effects on the behavioral problems and the parenting style 'laxness' were no longer significant at 6 months follow-up. Conclusions In summary it can be said that the existing Triple P-program has good effects, with a great degree of satisfaction, for parents of children with metabolic diseases in reducing dysfunctional parenting styles, parenting stress and behavioral problems of their children. One should not wait for a specialized program to reach these parents, but further research is necessary as a greater effect can be expected when this program is adapted to these parents. PMID- 30433874 TI - Baseline characteristics of gender dysphoric youth. AB - Background Limited information is available regarding baseline characteristics of children and adolescents with gender dysphoria (GD). The purpose of this retrospective study was to describe baseline characteristics of pediatric patients referred for GD. Methods A retrospective chart review of pediatric patients with GD referred to the pediatric endocrine clinic between 2002 and 2017 was conducted. Body mass index (BMI) percentiles and z-scores were calculated based on height and weight at the initial visit. Results Seventy-eight patients aged 14.9+/-2.37 years were identified. Of these, affirmed gender was more often male than female (63% vs. 37%, p=0.024). Although no difference was seen in average BMI z-scores between female to male (FTM) and male to female (MTF) patients, approximately 50% were overweight or obese. A higher incidence of anxiety was present in FTM compared with MTF youth (p=0.05). Fifty-six patients were referred in January 2014 or later, of whom 27% had a history of early expression of GD compared with 55% of those seen prior to 2014 (p=0.061). Conclusions The high prevalence of overweight in TG youth at baseline represents a potential risk for adverse health consequences. There appears to be a change in the age of first manifestation of GD over time. PMID- 30433875 TI - Early higher dosage of alglucosidase alpha in classic Pompe disease. AB - Background With conventional enzyme replacement therapy (ERT), the clinical prognosis of classic Pompe disease is often unsatisfactory. About half the patients treated with ERT at the recommended dosage (20 mg/kg every other week) require ventilatory support within the first years of life. The heterogeneous response to ERT has been related to different factors, including cross-reactive immunologic material (CRIM) status and age at ERT initiation. Early treatment with a standard dosage of ERT improves clinical outcome and avoids mechanical ventilation in CRIM-positive patients detected at newborn screening, not preventing persistent hyperCKemia and muscle weakness. Later treatment with higher dosages of ERT was shown to provide similar benefits in CRIM-positive patients. Here, we report the clinical and biochemical outcomes of six patients with classic Pompe disease treated with different dosages of alglucosidase alpha at different ages. Methods A standard dosage of ERT was employed in five patients, sharing a poor prognosis after transient clinical improvements, even in the case of early treatment (four died at 22.2+/-11.9 months and one survived but required tracheostomy and gastrostomy). Early higher dosage of alglucosidase alpha (40 mg/kg/week from 14 days) was administered to one CRIM-positive patient with fetal persistent bradycardia. Results Early higher dosage of alclucosidase alpha not only achieved normal neuromotor development but also the full correction of biochemical markers of muscle damage until 3 years of age, an unmet target with the standard dosage. Speech delay was not prevented by this approach. Conclusions We suggest that early treatment with a higher dosage of ERT may further improve clinical prognosis in classic Pompe disease. PMID- 30433876 TI - Insulin resistance in children with familial hyperlipidemia. AB - Background The aim of the study was to investigate whether there is insulin resistance in children with familial hyperlipidemia (FHL) and to determine the factors affecting insulin resistance. Methods Hyperlipidemic children aged between 4 and 18 years and followed up with an FHL diagnosis were included in the study. The children of adults followed up with an FHL diagnosis were also recruited after the screening period. The scanned children were divided into two groups as hyperlipidemic and normolipidemic. A total of 77 patients of whom 52 were hyperlipidemic and 25 were normolipidemic were assessed in the study. Insulin resistance was evaluated (homeostatic model assessment of insulin resistance [HOMA-IR]) by performing the oral glucose tolerance test (OGTT). Results Of the patients, 36 were male and 41 were female; the average age was 11.6+/-3.9 years, and the body mass index (BMI) was established to be 20.3+/-4.4. In hyperlipidemic and normolipidemic patients, the following were determined: fasting insulin: 10.6 (+/-0.89) MUU/mL, 4.9 (+/-0.45) MUU/mL (p=0.000); 2-h insulin: 28.7 (+/-12.7) MUU/mL, 18.9 (+/-10.5) MUU/mL (p=0.000); and HOMA-IR: 1.9 (+/-0.17), 0.86 (+/-0.7) (p=0.000). No relationship was identified between lipid profiles and insulin resistance. Nevertheless, there was a positive correlation between insulin resistance and apolipoprotein B (Apo B) levels (0.52), and a negative correlation was determined in carnitine levels (-0.64). Conclusions Insulin resistance was established to be higher in children with FHL compared to normolipidemic children. Insulin resistance was not related to lipid phenotypes, but to Apo B levels and carnitine levels. Insulin resistance should be a routine method of evaluation in the follow-up of children with FHL. PMID- 30433877 TI - Doppler evaluation of the fetal pulmonary artery pressure. AB - Background The Doppler effect has allowed the characterization of several vessels in maternal-fetal circulation that have been used for practical purposes. Our review of the literature showed a paucity of information about fetal pulmonary artery pressure (FMPAP) and its behavior in regard to gestational age (GA). The objectives of the study were to evaluate a formula to calculate the main FMPAP and its correlation with GA. Methods A total of 337 fetuses without obvious pathology were studied prospectively using Doppler evaluation of the FMPAP. Using the fetal main pulmonary artery Doppler acceleration time (FMPAT), we obtained the FMPAP using the following formula: FMPAP=90 - (0.62*FMPAT). Regression analyses, Pearson's bivariate correlation and paired sample t-test were used when appropriate. Results FMPAT increases while FMPAP decreases with GA. Pearson's correlation coefficient for FMPAP and GA was -0.544 (P-value<0.001) and for FMPAT and GA was 0.556 (P-value<0.001). FMPAP and FMPAT were highly correlated (R= 0.972; P<0.001). Conclusions Pulmonary artery pressure in the fetus decreases with GA. PMID- 30433878 TI - Beyond monoisotopic accurate mass spectrometry: ancillary techniques for identifying unknown features in non-targeted discovery analysis. AB - High-resolution mass spectrometry (HR-MS) is an important tool for performing non targeted analysis for investigating complex organic mixtures in human or environmental media. This perspective demonstrates HR-MS compound identification strategies using atom counting, isotope ratios, and fragmentation pattern analysis based on 'exact' or 'accurate' mass, which allows analytical distinction among mass fragments with the same integer mass, but with different atomic constituents of the original molecules. Herein, HR-MS technology is shown to narrow down the identity of unknown compounds for specific examples, and ultimately inform future analyses when these compounds reoccur. Although HR-MS is important for all biological media, this is particularly critical for new methods and instrumentation invoking exhaled breath condensate, particles, and aerosols. In contrast to standard breath gas-phase analyses where 1 mass unit (Da) resolution is generally sufficient, the condensed phase breath media are particularly vulnerable to errors in compound identification because the larger organic non-volatile molecules can form identical integer mass fragments from different atomic constituents which then require high-resolution mass analyses to tell them apart. PMID- 30433879 TI - Hierarchical and Higher-Order Factor Structures in the Rasch Tradition: A Didactic. AB - In this paper, we consider hierarchical and higher-order factor models and the relationship between them, and, in particular, we use Rasch models to focus on the exploration of these models. We present these models, their similarities and/or differences from within the Rasch modeling perspective and discuss their use in various settings. One motivation for this work is that certain well-known similarities and differences between the equivalent models in the two-parameter logistic model (2PL) approach do not apply in the Rasch modeling tradition. Another motivation is that there is some ambiguity as to the potential uses of these models, and we seek to clarify those uses. In recent work in the Item Response Theory (IRT) literature, the estimation of these models has been mostly presented using the Bayesian framework: here we show the use of these models using traditional maximum likelihood methods. We also show how to re-parameterize these models, which in some cases can improve estimation and convergence. These alternative parameterizations are also useful in "translating" suggestions for the 2PL models to the Rasch tradition (since these suggestions involve the interpretation of item discriminations, which are required to be unity in the Rasch tradition). Alternative parameterizations can also be used to clarify the relationship among these models. We discuss the use of these models for modeling multidimensionality and testlet effects and compare the interpretation of the obtained solutions to the interpretation for the multidimenisional Rasch model - a more common approach for accounting multidimensionality in the Rasch tradition. We demonstrate the use of these models using the partial credit model. PMID- 30433880 TI - Factor Structure of the Community Reintegration of Service-Members (CRIS) in Veterans with Blast-Related Mild Traumatic Brain Injury. AB - Veterans with blast-related mild traumatic brain injury (mTBI) report difficulty engaging in life roles, also referred to as participation. Current measures are either global or lack comprehensive coverage of life roles and have not been validated in Veterans with mTBI. The Community Reintegration of Service-members instrument (CRIS) is a promising measure that was specifically developed for Veterans using a well-formulated conceptual framework and Rasch analysis. However, the CRIS has not been validated in Veterans with mTBI. Two data sets were combined for 191 Veterans with blast-related mTBI to conduct a confirmatory factor analysis of the CRIS. High residual and low loading items (33) were removed to improve the model fit. The remaining items demonstrated high correlation (0.87-0.89) between subscales and high test re-test (0.85 to 0.95). Mean scores were better for Veterans without Post Traumatic Stress Disorder (PTSD) or depression compared to Veterans with PTSD or depression. The refined CRIS offers a valid comprehensive measure of participation for Veterans with blast-related mTBI. Future directions include examining aspects of participation that may not be covered by the CRIS for Veterans with mTBI.. PMID- 30433881 TI - Examination of Item Quality in a State-Wide Music Assessment Program using Rasch Methodology. AB - Students' academic performance has been routinely assessed in various subjects, including arts education. The current study uses Rasch methodology to investigate item quality for an annual state-wide arts assessment program administered to 4th grade students. All multiple-choice items were previously analyzed through the true score theory (TST) framework to examine item difficulty, differential item functioning (DIF), and distractor quality. However, these traditional methods are sample-specific, and score interpretations are limited to the particular group being tested. Rasch methodology provides a sample-free framework for item analysis. This approach has the advantage of producing sample-invariant item parameters and using goodness-of-fit criteria to detect problematic items, leading to more accurate item analysis results. Study results suggest that majority of the items performed well and the test was appropriate to its intended audience and evaluation purpose. It also validates the test score interpretation and the use of this assessment program. PMID- 30433882 TI - Validation Instrument to Evaluate Students' Perception of Virtual Manipulatives in Learning Mathematics. AB - The advent of new technologies has replaced physical manipulatives - which are physical models of equivalent representation of concepts by virtual manipulatives which many learners and teachers find useful in the mathematics classroom. The current study investigated students' motivation to engage with virtual manipulatives as a tool in the mathematics education. Activity theory was used to conduct a multicomponential survey of virtual manipulatives in education and administered it to 442 Iranian high school students with the aim of examining students' perception of various aspects of the manipulatives. Using the Rasch Andrich rating scale model (RSM), an item response theory model, psychometric features of the instrument were examined item endorsibility, learners' ability, fit, and unidimensionality. The validated instrument can be used to find the factors that could improve students' perceptions of virtual manipulatives in the mathematics classroom. PMID- 30433883 TI - Psychometric Properties and Convergent Validity of the Chinese Version of the Rosenberg Self-Esteem Scale. AB - The present study used the Rasch rating scale model (RSM) to reassess the psychometric properties of the Chinese version of Rosenberg self-esteem scale (RSES) among 501 Grade 10 students in Taiwan. The reliability, dimensionality, and differential item functioning were examined. The dimensionality assumption was met after excluding item 8 ("I wish I could have more respect for myself."). The successive response categories for item 7 ("I feel that I am a person of worth, at least on an equal plane with others.") were not located in an expected order. After eliminating items 7 and 8 from analysis, the remaining 8-item RSES had acceptable fit statistics, good content coverage and high categorical omega, Rasch person and item reliability. The five response categories performed well; evidence for convergent validity was established through the high correlation between RSES and psychological being scores. Implications and recommendations for instrument users are discussed. PMID- 30433884 TI - Rasch Analysis of the Revised Two-Factor Study Process Questionnaire: A Validation Study. AB - The Revised Two-Factor Study Process Questionnaire (R-SPQ-2F) was developed in 1998 using the true score theory to measure students' deep approaches (DA) and surface approaches (SA) to learning. Using Rasch analyses, this study aimed to 1) validate the R-SPQ-2F's two-factor structure, and 2) explore whether the full scale (FS), after reverse scoring responses to SA items, could measure learning approach as a uni-dimensional construct. University students (N = 327) completed an online version of the R-SPQ-2F. The researchers validated the R-SPQ-2F by showing that items on the three rating scales (DA, SA, and FS) had acceptable fit; both DA and FS, but not SA, showed acceptable targeting function; and all three scales had acceptable reliabilities (0.74 - 0.79). The DA and SA scales, not the FS, satisfied the unidimensionality requirement, supporting the claim that student approaches to learning are represented by DA and SA as separate constructs. PMID- 30433885 TI - A Measurement Model of City-Based Consumer Patriotism in Developing Countries: The Case of Vietnam. AB - This study examined a measurement model for the construct of consumer patriotism in the context of city-based consumers in Vietnam, a developing country, and the linkage of consumer patriotism with consumer ethnocentrism. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted to assess the measurement model. A mediator effect test was utilised to test the hypothesis of the model, using a multiple regression procedure. Two studies were carried out, the first a preliminary study with a convenience sample of 230 people and the second a full study with a probability sample of 300 people. Both studies showed that there was an acceptable fit for the measurement model of consumer patriotism. In addition, consumer patriotism was found to be a mediator in the connection of natural patriotism and ethnocentrism for city-based Vietnamese consumers. PMID- 30433886 TI - Myths and Facts of In-Office Regenerative Procedures for Tendinopathy: Literature Review. AB - Tendinopathy carries a large burden of musculoskeletal disorders seen in both athletes and aging population. Treatment is often challenging, and progression to chronic tendinopathy is common. Physical therapy, NSAIDs, and corticosteroid injections have been the mainstay of treatment but are not optimal given that most tendon disorders appear to involve degenerative changes in addition to inflammation. The field of regenerative medicine has taken the forefront, and various treatments have been developed and explored including prolotherapy, platelet rich plasma (PRP), stem cells, and percutaneous ultrasonic tenotomy. However, high-quality research with standardized protocols and consistent controls for proper evaluation of treatment efficacy is currently needed. This will make it possible to provide recommendations on appropriate treatment options for tendinopathy. PMID- 30433887 TI - LAMM syndrome: two new patients with a novel mutation in FGF3 gene and additional clinical findings. PMID- 30433888 TI - Ten- and 20-year Survivorship of the Hip After Periacetabular Osteotomy for Acetabular Dysplasia. AB - INTRODUCTION: Acetabular dysplasia is a multifactorial condition characterized by a shallow hip socket with predisposition to osteoarthritis of the hip. The Bernese periacetabular osteotomy (PAO), developed by Reinhold Ganz in 1984, reorients the dysplastic hip joint to provide more uniform coverage of the femoral head and to extend the longevity of the native hip. Since 1987, the senior author performed the Bernese PAO on more than 430 patients. We performed a cross-sectional retrospective study on this cohort of patients to determine the 10- and 20-year survivorship after PAO in addition to assessing functional outcomes and radiographic parameters. METHODS: Four hundred thirty-four patients were treated for acetabular dysplasia with PAO by the senior surgeon from 1987 to 2014. Data were obtained for 302 hips in 258 patients in a retrospective fashion from medical records and/or mail-in/phone questionnaires. Functional outcome data consisted of postoperative Hip Osteoarthritis Outcome Score and University of California-Los Angeles Activity Score. Pre- and postoperative radiographs were used to determine lateral center-edge angle, anterior center-edge angle, Tonnis angle/grade, and head-to-ilioischial line distance. Survivorship of the native hip was determined by Kaplan-Meier analysis. RESULTS: Of the 302 hips analyzed, 248 were still surviving native hips and 54 had gone on to a total hip arthroplasty (THA) at the time of data acquisition. The average age of patients in the entire cohort at PAO was 32.7 years (range, 13 to 63 years). Of the 258 patients, 215 were female patients (83.3%) and 43 male patients (16.8%). The average age of patients in the surviving group at PAO was 32.3 years, and the average age of patients in the THA group was 36.6 years (P < 0.01). At the time of data acquisition, follow-up ranged from 2 to 27 years (average, 11.2 years). Hip Osteoarthritis Outcome Score and University of California-Los Angeles Activity Score are reported for the surviving native hips after PAO. Radiographic analyses for surviving and failed hips are described, with pre- and postoperative Tonnis grade being statistically significant predictors for conversion to THA (P < 0.01). Survivorship of the native hip was 86% at 10 years and 60% at 20 years in the surviving cohort. Survivorship stratified by age at the time of PAO demonstrated a 10-year survivorship of 93.3%, 90.1%, 81.6%, and 63.2% at ages 20, 30, 40, and 50 years, respectively. No notable difference exists in survivorship between male and female patients; however, male patients had a trend toward lower survivorship compared with female patients at 15 years. CONCLUSION: The 10- and 20-year survivorship of the native hip after PAO is approximately 86% and 60%, respectively, in our cohort of 302 hips. Older age at the time of PAO and higher Tonnis grade are negative prognostic factors for joint survival after PAO. Surviving hips after PAO have good functional outcomes even up to 20 years after surgery. This survivorship analysis represents one of the largest and longest survival studies of patients after PAO, and our results are consistent with other published studies. LEVEL OF EVIDENCE: Level III. PMID- 30433889 TI - Immediate vs. Delayed Pushing. PMID- 30433890 TI - Nomogram for predicting diabetes mellitus after the first attack of acute pancreatitis. AB - BACKGROUND: Diabetes mellitus can occur after acute pancreatitis (AP), but there are currently no tools for evaluating the risk of developing diabetes after an attack of AP. The aim of the study was to develop a nomogram for prediction of new-onset diabetes mellitus after the first attack of AP. PATIENTS AND METHODS: We enrolled 616 patients with first-attack AP. We collected and statistically analyzed demographic data (age, BMI, and duration of hospitalization) and laboratory data (glucose, low-density lipoprotein cholesterol, triglyceride, and cholesterol). RESULTS: Univariate analysis suggested duration of hospitalization (P=0.0003), BMI (P=0.0059), cholesterol (P=0.0005), triglyceride (P=0.0005), hemoglobin (P=0.0229), and glucose (P<0.001) at admission were significantly associated with newly developed diabetes after the first-attack AP. Multivariate analysis showed that age [odds ratio (OR)=1.01; 95% confidence interval (CI): 1.00-1.03; P=0.045], BMI (OR=1.06; 95% CI: 1.01-1.12; P=0.018), glucose (OR=1.07; 95% CI: 1.02-1.12; P=0.008), triglyceride (OR=1.03; 95% CI: 1.00-1.06; P=0.035), and low-density lipoprotein-cholesterol (OR=1.18; 95% CI: 1.00-1.38; P=0.044) at admission were important predictors. CONCLUSION: The nomogram is a potentially clinically useful tool for predicting new-onset diabetes, which is currently clinically unprecedented. This finding is not confined to the patients with severe AP but is also for patients who have recovered from mild AP. The nomogram must to be validated externally.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 30433891 TI - Robustness and Reproducibility of Radiomics in Magnetic Resonance Imaging: A Phantom Study. AB - OBJECTIVES: The aim of this study was to investigate the robustness and reproducibility of radiomic features in different magnetic resonance imaging sequences. MATERIALS AND METHODS: A phantom was scanned on a clinical 3 T system using fluid-attenuated inversion recovery (FLAIR), T1-weighted (T1w), and T2 weighted (T2w) sequences with low and high matrix size. For retest data, scans were repeated after repositioning of the phantom. Test and retest datasets were segmented using a semiautomated approach. Intraobserver and interobserver comparison was performed. Radiomic features were extracted after standardized preprocessing of images. Test-retest robustness was assessed using concordance correlation coefficients, dynamic range, and Bland-Altman analyses. Reproducibility was assessed by intraclass correlation coefficients. RESULTS: The number of robust features (concordance correlation coefficient and dynamic range >= 0.90) was higher for features calculated from FLAIR than from T1w and T2w images. High-resolution FLAIR images provided the highest percentage of robust features (n = 37/45, 81%). No considerable difference in the number of robust features was observed between low- and high-resolution T1w and T2w images (T1w low: n = 26/45, 56%; T1w high: n = 25/45, 54%; T2 low: n = 21/45, 46%; T2 high: n = 24/45, 52%). A total of 15 (33%) of 45 features showed excellent robustness across all sequences and demonstrated excellent intraobserver and interobserver reproducibility (intraclass correlation coefficient >= 0.75). CONCLUSIONS: FLAIR delivers the most robust substrate for radiomic analyses. Only 15 of 45 features showed excellent robustness and reproducibility across all sequences. Care must be taken in the interpretation of clinical studies using nonrobust features. PMID- 30433892 TI - 7 T Magnetic Resonance Spectroscopic Imaging in Multiple Sclerosis: How Does Spatial Resolution Affect the Detectability of Metabolic Changes in Brain Lesions? AB - OBJECTIVES: The aim of this study was to assess the utility of increased spatial resolution of magnetic resonance spectroscopic imaging (MRSI) at 7 T for the detection of neurochemical changes in multiple sclerosis (MS)-related brain lesions. MATERIALS AND METHODS: This prospective, institutional review board approved study was performed in 20 relapsing-remitting MS patients (9 women/11 men; mean age +/- standard deviation, 30.8 +/- 7.7 years) after receiving written informed consent. Metabolic patterns in MS lesions were compared at 3 different spatial resolutions of free induction decay MRSI with implemented parallel imaging acceleration: 2.2 * 2.2 * 8 mm; 3.4 * 3.4 * 8 mm; and 6.8 * 6.8 * 8 mm voxel volumes, that is, matrix sizes of 100 * 100, 64 * 64, and 32 * 32, respectively. The quality of data was assessed by signal-to-noise ratio and Cramer-Rao lower bounds. Statistical analysis was performed using Wilcoxon signed rank tests with correction for multiple testing. RESULTS: Seventy-seven T2 hyperintense MS lesions were investigated (median volume, 155.7 mm; range, 10.8 747.0 mm). The mean metabolic ratios in lesions differed significantly between the 3 MRSI resolutions (ie, 100 * 100 vs 64 * 64, 100 * 100 vs 32 * 32, and 64 * 64 vs 32 * 32; P < 0.001). With the ultra-high resolution (100 * 100), we obtained 40% to 80% higher mean metabolic ratios and 100% to 150% increase in maximum metabolic ratios in the MS lesions compared with the lowest resolution (32 * 32), while maintaining good spectral quality (signal-to-noise ratio >12, Cramer-Rao lower bounds <20%) and measurement time of 6 minutes. There were 83% of MS lesions that showed increased myo-inositol/N-acetylaspartate with the 100 * 100 resolution, but only 66% were distinguishable with the 64 * 64 resolution and 35% with the 32 * 32 resolution. CONCLUSIONS: Ultra-high-resolution MRSI (~2 * 2 * 8 mm voxel volume) can detect metabolic alterations in MS, which cannot be recognized by conventional MRSI resolutions, within clinically acceptable time.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. PMID- 30433893 TI - Safety and Tolerability of Vacuum Versus Manual Drainage During Thoracentesis: A Randomized Trial. AB - BACKGROUND: Pleural effusions may be aspirated manually or via vacuum during thoracentesis. This study compares the safety, pain level, and time involved in these techniques. METHODS: We randomized 100 patients receiving ultrasound-guided unilateral thoracentesis in an academic medical center from December 2015 through September 2017 to either vacuum or manual drainage. Without using pleural manometry, the effusion was drained completely or until the development of refractory symptoms. Measurements included self-reported pain before and during the procedure (from 0 to 10), time for completion of drainage, and volume removed. Primary outcomes were rates of all-cause complications and of early termination of the procedure with secondary outcomes of change in pain score, drainage time, volume removed, and inverse rate of removal. RESULTS: Patient characteristics in the manual (n=49) and vacuum (n=51) groups were similar. Rate of all-cause complications was higher in the vacuum group (5 vs. 0; P=0.03): pneumothorax (n=3), surgically treated hemothorax with subsequent death (n=1) and reexpansion pulmonary edema causing respiratory failure (n=1), as was rate of early termination (8 vs. 1; P=0.018). The vacuum group exhibited greater pain during drainage (P<0.05), shorter drainage time (P<0.01), no association with volume removed (P>0.05), and lower inverse rate of removal (P<=0.01). CONCLUSION: Despite requiring less time, vacuum aspiration during thoracentesis was associated with higher rates of complication and of early termination of the procedure and greater pain. Although larger studies are needed, this pilot study suggests that manual aspiration provides greater safety and patient comfort. PMID- 30433894 TI - Correlation Between Postoperative Health-Related Quality of Life and Care Needs of Oral Cancer Patients. AB - BACKGROUND: Oral cancer is the fifth most common form of cancer in Taiwan in terms of incidence and death rate and results in at least 2700 deaths each year. OBJECTIVE: The aims of this study were to assess the postoperative health-related quality of life (QOL) and care needs of oral cancer patients comprehensively and to evaluate the correlation between health-related QOL and care needs. INTERVENTIONS/METHODS: This cross-sectional study enrolled 126 oral cancer patients who had received surgical treatment within the previous 2 years and were without cognitive impairment. Each patient completed a demographic questionnaire, the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Quality of Life Scale, and the Short-Form Cancer Needs Questionnaire. RESULTS: Female patients and patients receiving 3 or more chemotherapy treatments were significantly associated with increased Short-Form Cancer Needs Questionnaire scores (higher level of care needs) (beta = 0.177 and 28.49, both P < .05) and patients receiving 3 or more chemotherapy treatments were significantly associated with increased Head and Neck Cancer Quality of Life Scale scores (higher level of symptoms and problems) (beta = 27.77, P = .007). Results of stepwise multiple linear regression analysis indicated that 4 oral cancer-related symptoms and problems, "trouble with social contacts," "swallowing problems," "teeth problems," and "feeling ill," were significantly associated with higher care needs in oral cancer patients (all P <= .05). CONCLUSION: A significant correlation exists between health-related QOL and care needs. IMPLICATIONS FOR PRACTICE: Using a valid health-related QOL scale may help nurses determine their perceived physical and psychological care needs.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. PMID- 30433895 TI - Patients' Evaluation of a Preparatory Online Communication Tool for Older Patients With Cancer Preceding Chemotherapy. AB - BACKGROUND: The online tool PatientVOICE has been developed to enhance older patients' participation during educational nursing encounters preceding chemotherapy and to increase their information recall. OBJECTIVE: The aim of this study was to evaluate perceived usefulness, usability, satisfaction with emotional support, language use, attractiveness, and visit intention of PatientVOICE by older (ex-)patients with cancer. METHODS: Older (ex-)patients with cancer were invited to evaluate the website via an online questionnaire. Perceived usefulness, usability, and satisfaction with emotional support were measured using evaluation statements, the System Usability Scale, and an adapted subscale of the Website Satisfaction Scale, respectively. Questions were also included about language use and attractiveness of the website and patients' intention to visit the website. RESULTS: A total of 44 questionnaires were analyzed. Many patients evaluated the provided information and other integrated techniques (such as the question prompt sheet, video fragments, and the audio facility) positively on aspects as usefulness and helpfulness. The usability was considered good (mean scale score, 74.3). Most patients (84.9%) considered the language use on the website clear, and 63.6% of the patients found the website attractive. Many patients (71.9%) would visit the website if they would like to gather information on the encounter preceding chemotherapy, and 62.5% of the patients would do this for information about chemotherapy. CONCLUSIONS: PatientVOICE is evaluated as a useful and user-friendly tool, enabling patients to prepare themselves for the nursing encounter preceding chemotherapy and to gather information about chemotherapy. IMPLICATIONS FOR PRACTICE: Preparatory online tools, such as PatientVOICE, can be implemented in hospitals to offer patients extra support. PMID- 30433896 TI - The Impact of Hematologic Cancer and Its Treatment on Physical Activity Level and Quality of Life Among Children in Mainland China: A Descriptive Study. AB - BACKGROUND: The effects of hematologic cancer and its treatment on Chinese children's physical activity level and quality of life (QoL) remain unclear despite numerous studies conducted in Western countries and Hong Kong. OBJECTIVE: The aim of this study was to examine the effects of hematologic cancer and its treatment on the physical activity level and QoL among Chinese children. METHODS: A cross-sectional study was conducted. One hundred twenty-five children who were admitted for treatment of hematologic cancer and 243 healthy counterparts of similar age participated in this study. All participants were asked to complete the Chinese University of Hong Kong: Physical Activity Rating for Children and Youth and Pediatric Quality of Life Inventory. The children with hematologic cancer also completed a therapy-related symptom checklist. RESULTS: There were statistically significant differences in the mean physical activity and QoL between children with hematologic cancer and their healthy counterparts. Multiple regression analyses showed that physical activity levels and the adverse effects of hematologic cancer treatment had statistically significant effects on the children's QoL. CONCLUSIONS: Physical activity level and QoL in children with hematologic cancer were both lower than those in their healthy counterparts. IMPLICATIONS FOR PRACTICE: This study provides further evidence that hematologic cancer and the adverse effects of its treatment have negative effects on Chinese children's QoL. Although a lack of physical activity is deeply embedded in Chinese culture, nurses should take a proactive role in effecting change by educating parents about the benefits to their children's physiologic and psychological well-being of physical activity during and after treatment. PMID- 30433897 TI - Cardiotoxicity of Cancer Therapies. AB - Cardiotoxicity is a known complication of many cancer therapies. While the cardiotoxicity of established agents such as anthracyclines, antimetabolites and alkylating agents is well known, it is important to realize that newer anticancer therapies such as tyrosine kinase inhibitors, angiogenesis inhibitors, and checkpoint inhibitors are also associated with significant adverse cardiovascular effects. Echocardiography, magnetic resonance imaging, and radionuclide imaging have been used to identify these complications early and prevent further consequences. We will discuss the different classes of cancer therapeutic agents that cause cardiotoxicity, the mechanisms that lead to these effects, and strategies that can be used to prevent the cardiac morbidity and mortality associated with their use. PMID- 30433898 TI - Fighting the Fire of Burnout in Healthcare. PMID- 30433899 TI - The Science of Motivation Applied to Clinician Burnout: Lessons for Healthcare. AB - The science of motivation can help explain some of the root causes driving clinician burnout, a critical vulnerability in healthcare today. Research finds autonomy, mastery, and purpose to be drivers of intrinsic motivation, and healthcare leaders can use these three principles in program design and communication strategies to make progress toward rediscovering joy and passion in the life-giving work of healthcare. Leaders can achieve a competitive advantage for their organizations by applying these inherent motivators to attract, develop, and retain engaged and purposeful caregivers and by developing participative leadership to nurture a passion for caregiving.In healthcare, we enjoy the privilege of serving with intelligent and caring people who are driven to make a difference on behalf of those they serve. But we also experience the human factors, friction, and uncertainty in a highly complex delivery and reimbursement structure. Each day in our hospitals, clinicians and staff face a marathon of adrenaline, stress, physical fatigue, mental strain, and emotional heights and depths. This reality demands grit and resilience to sustain the high standards of excellence and compassion necessary for delivering personalized care.Before healthcare organizations launch new programs to address these challenges, however, we must align our leadership and communication approaches with the fundamental drivers of motivation that brought us to healthcare in the first place-and in a way that brings out the best in our care teams and builds their creative capacity for any future challenges. PMID- 30433900 TI - Building a Resilient Workforce: Promoting Joy in Clinical Care. AB - At Dignity Health, one of the nation's largest healthcare systems, we believe that all people deserve access to quality medical care regardless of their background, ethnicity, or circumstances. Healing is our calling, and "Hello humankindness" is our brand purpose, which supports our mission to deliver compassionate, high-quality, and affordable patient-centered care with special attention to the poor and underserved. Through teamwork and innovation, faith and compassion, and advocacy and action, we endeavor every day to keep our patients and staff members healthy and fulfilled. This article highlights efforts at Dignity Health to reduce burnout and increase resilience in our employees. Our team is focusing on evidence-based interventions and strategic partnerships to tackle these complicated issues. PMID- 30433902 TI - Empathy at Scale: Burning Bright, Not Burning Out. PMID- 30433901 TI - Preventing Burnout: Successful Initiatives Look Beyond Symptoms. PMID- 30433903 TI - The Impact of Organizational Culture on Leadership Burnout. PMID- 30433904 TI - How Integrated Care Can Serve Rural Needs. PMID- 30433905 TI - Trauma-Informed Care: Responding to the Call for Action. PMID- 30433906 TI - Journal of Forensic Nursing 2017 Articles of the Year. PMID- 30433909 TI - Child Sexual Abuse Perpetrators: What Forensic Nurses Need to Know. AB - Child sexual abuse is a problem of epidemic proportions resulting in lifelong physical and mental health consequences for victims. Most child sexual abuse victims never disclose and do not receive needed treatment. Clearly, pediatric healthcare providers must understand the dynamics of child sexual abuse to better identify and protect potential victims. Forensic nurses are at the forefront of caring for victims of sexual abuse and are strong voices in the education of parents, community members, and other healthcare professionals regarding sexual abuse. Forensic nurses with a deeper understanding of child sexual abuse perpetrators will be better able to educate the public and advocate for children at risk for sexual abuse. In this article, specific types of child sexual abuse perpetration will be explored, and implications for forensic nursing will be discussed. PMID- 30433908 TI - Extreme Control and Instability: Insight Into Head Injury From Intimate Partner Violence. AB - AIM: The aim of this study was to understand the social context of the lives of women who experienced a head injury from intimate partner violence. BACKGROUND: Sixty percent to 92% of survivors of intimate partner violence receive head trauma during the abuse. Little research exists regarding the episodes of abuse when women receive a head injury, or the reasons women might not seek medical care for the head injury or the abuse. METHOD: Twenty-one interviews from nine women who self-reported passing out from being hit in the head were analyzed using thematic analysis. FINDINGS: Themes of extreme control and manipulation from abusers emerged, and women described living with instability from cycles of incarceration, drug and alcohol use, and fear of losing their children. Women did not receive medical care for head injury because the abusers often used forced sex immediately after the head injury to instill fear and authority. IMPLICATIONS FOR FORENSIC NURSING: Hitting women in the head is not only about physical abuse, but also about exerting dominance and creating an environment of extreme control. Forensic nurses are uniquely positioned to screen for head injuries during initial assessments and follow-up visits and connect women with appropriate resources. PMID- 30433910 TI - Evaluating the Introduction of the Safewards Model to a Medium- to Long-Term Forensic Mental Health Ward. AB - Care and treatment in forensic mental health wards can present with challenges when loss of hope and freedom, and aggression are present, which can then influence ward atmosphere and feelings of safety. Safewards is a model designed to address a range of conflict (e.g., aggression and self-harm) and containment (e.g., use of restrictive interventions) events and may provide a suitable approach to delivery of care in a forensic setting, while also addressing aggression, restrictive interventions, and ward atmosphere. The aim of this study was to evaluate the introduction of Safewards to a forensic mental health ward to determine suitability, and to explore if changes to conflict, containment, and ward atmosphere occurred. A mixed methods approach was used involving the collection of incident data related to conflict and containment, an assessment of the degree to which interventions were implemented, and an assessment of the social climate before and after implementation. Results suggested that there were fewer conflict events after Safewards was introduced; however, there did not appear to be any changes in the already low use of restrictive interventions. The Safewards interventions were implemented to a high degree of fidelity, and there was indication of an increase in a positive perception of ward atmosphere, supported by themes of positive change, enhanced safety, and respectful relationships. Safewards may assist in contributing to an improvement in the perception of ward atmosphere. To enhance implementation in a forensic mental health setting, there may be a need to consider additional elements to Safewards, pertinent to this setting. PMID- 30433911 TI - Sexual Misconduct Policies at Institutes of Higher Education: An Integrative Review. AB - Although federal legislation designed to advance sexual misconduct policies at institutes of higher education (IHEs) has been in effect for decades, recent national attention has put more pressure on IHEs to combat sexual violence on their campuses. Thus, the past few years have yielded significant research that examines federal compliance, dissemination, and perception of IHE sexual misconduct policies. This integrative review was conducted to assess sexual misconduct policies in the United States and the potential to prevent and combat sexual violence at IHEs through these policies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and using a quality assessment tool to ensure rigor, eight studies were synthesized. Findings indicate that IHE sexual misconduct policies vary widely and that most IHEs lack transparent, legislation-compliant policies. There remains a need for research examining the association between sexual misconduct policy, campus climate, and students' behavior, so as to better inform future sexual misconduct interventions and IHE policies. Forensic nurses may be key stakeholders in policy development that is currently missing from the literature. PMID- 30433912 TI - Combatting the Opioid Crisis From Prison: Initiating Opioid Agonist Therapy. AB - Presented is a case report of a young man dependent on fentanyl who did not receive opioid agonist therapy (OAT) during incarceration. Highlighted are the barriers to accessing OAT in custody, which exacerbates problems with drug seeking behavior, diversion, and recidivism. Discussed are the implications for correctional healthcare, including the benefits of utilizing telehealth services to maximize accessibility to OAT in correctional institutions that will not only enhance the quality of patient care but also address the growing opioid epidemic across Canada. PMID- 30433913 TI - Child Sexual Abuse Perpetrators: What Forensic Nurses Need to Know. PMID- 30433914 TI - Going With the Flow: Cerebrovascular Disease and Autoregulation. PMID- 30433915 TI - Brain Protection Beyond the OR: Consensus Statement on Perioperative Neurocognitive Disorders (PND). PMID- 30433916 TI - The World Health Organization Surgical Safety Checklist: Happy 10th Birthday! PMID- 30433917 TI - The Hidden Value of Ultrasound? PMID- 30433918 TI - Prevention of Thrombophlebitis in Peripheral Intravenous Catheters: The Butterfly Effect. PMID- 30433919 TI - Pediatric Anesthesia Informed Consent: "That's the Signpost Up Ahead - Your Next Stop, The Twilight Zone!" PMID- 30433920 TI - Clarifying Misconceptions About US Food and Drug Administration Unapproved Drugs Program. PMID- 30433921 TI - An Analysis of Substandard Propofol Detected in Use in Zambian Anesthesia: Erratum. PMID- 30433923 TI - Some Cases Resembling Atrophy of the Optic Nerves Which Recover under Treatment. PMID- 30433922 TI - The case-crossover design for drug-drug interactions: considerations for implementation. AB - BACKGROUND: The case-crossover design may be useful for evaluating the clinical impact of drug-drug interactions in electronic healthcare data; however, experience with the design in this context is limited. METHODS: Using US healthcare claims data (1994-2013), we evaluated two examples of interacting drugs with prior evidence of harm: (1) cytochrome P450 (CYP)3A4-metabolized statins + clarithromycin or erythromycin and rhabdomyolysis; and (2) clopidogrel + fluoxetine or fluvoxamine and ischemic events. We conducted case-crossover analyses with (1) a three-parameter model with a product term and a six-parameter saturated model that distinguished initiation order of the two drugs; and (2) with or without active comparators. RESULTS: In the statin example, the three parameter model produced estimates consistent with prior evidence with the active comparator (product term odds ratio [OR] 2.05, 95% confidence interval [CI] 1.00 4.23) and without (OR 1.99, 95% CI 1.04 - 3.81). In the clopidogrel example, this model produced results opposite of expectation (OR 0.78, 95% 0.68 - 0.89), but closer to what was observed in prior studies when active comparator was used (OR 1.03, 95% CI 0.90 - 1.19). The saturated model revealed heterogeneity of estimates across strata and considerable confounding; strata with concordant clopidogrel exposure likely produced the least biased estimates. CONCLUSION: The three-parameter model assumes a common drug-drug interaction effect, while the saturated model is useful for identifying potential effect heterogeneity or differential confounding across strata. Restriction to certain strata or use of an active comparator may be necessary in the presence of within-person confounding. PMID- 30433924 TI - The Dr. James Watson Lectures on Recent Advances in Haematology. PMID- 30433925 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th May, 1912. PMID- 30433926 TI - Remarks Based on the Analysis of One Hundred Consecutive Cases of Stricture of the Gullet. PMID- 30433927 TI - Glasgow Eastern Medical Society. PMID- 30433928 TI - New Preparations, &c. PMID- 30433929 TI - The Estimation of Sugar in Urine. PMID- 30433931 TI - Current Topics. PMID- 30433930 TI - Notes on the Pathography of the Julian Dynasty. PMID- 30433932 TI - Anti-Typhoid Inoculation. PMID- 30433933 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433934 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433935 TI - Obstetrical and Gynaecological Society. PMID- 30433936 TI - The Plague as a Factor in History. PMID- 30433938 TI - Current Topics. PMID- 30433937 TI - Keratitis as a Cause of Myopia. PMID- 30433939 TI - Concomitant Squint Following Injury to the Head and Eye. PMID- 30433940 TI - Two Cases of Tuberculosis of the Uterus. PMID- 30433941 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd March, 1912. PMID- 30433943 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433942 TI - Remarks Based on the Analysis of One Hundred Consecutive Cases of Stricture of the Gullet. PMID- 30433945 TI - Obstetrical and Gynaecological Society. PMID- 30433944 TI - Current Topics. PMID- 30433946 TI - Syphilis and Deafness. PMID- 30433947 TI - The Problem of the Feeble-Minded. PMID- 30433948 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th April, 1912. PMID- 30433949 TI - Scottish Otological and Laryngological Society. PMID- 30433950 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 16th December, 1911. PMID- 30433951 TI - Obstetrical and Gynaecological Society. PMID- 30433952 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433954 TI - Cancer of the Uterus: Some Practical Aspects of Its Diagnosis and Treatment. PMID- 30433953 TI - Enlargement of the Thymus: A Remarkable Case. PMID- 30433956 TI - Current Topics. PMID- 30433955 TI - Treatment of Pneumonia by a Polyvalent Stock Pneumococcic Vaccine. PMID- 30433957 TI - On the History of Pathology in the Glasgow Royal Infirmary and the Functions of the Pathological Department. PMID- 30433959 TI - New Preparations, &c. PMID- 30433958 TI - The Treatment of Carcinoma of the Rectum and Pelvic Colon. PMID- 30433960 TI - Some Modes of Cardiac Failure. PMID- 30433961 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 20th January, 1912. PMID- 30433962 TI - Current Topics. PMID- 30433963 TI - Medico-Chirurgical Society of Glasgow. PMID- 30433964 TI - Note on the Skull of Dr. Pritchard. PMID- 30433965 TI - The Treatment of Ringworm of the Scalp. PMID- 30433966 TI - Obstetrical and Gynaecological Society. PMID- 30433968 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th February, 1912. PMID- 30433967 TI - The Use of Tuberculin in Phthisis. PMID- 30433969 TI - Splenic Metastasis in a Case of Carcinoma of Tongue, Due Probably to Vascular Dissemination. PMID- 30433971 TI - Current Topics. PMID- 30433970 TI - The Plague as a Factor in History. PMID- 30433972 TI - Erratum. AB - [This corrects the article on p. 126 in vol. 77.]. PMID- 30433973 TI - The Auriculo-Ventricular Node and Bundle in a Case of the Adams-Stokes Syndrome. PMID- 30433974 TI - Western Infirmary. PMID- 30433976 TI - Glasgow Royal Infirmary. PMID- 30433975 TI - On Malpositions of the Kidney: Being His Thesis for the Degree of M.D. in the University of Glasgow. PMID- 30433977 TI - Pathological and Clinical Society. PMID- 30433978 TI - A Case of Acute Fetid Empyema Treated Successfully. PMID- 30433979 TI - Surgical Notes. PMID- 30433980 TI - Reports of Cases of Chronic Exanthemal Catarrh of the Middle Ear. PMID- 30433981 TI - Clinical Remarks on the Treatment of Acute Bronchitis. PMID- 30433982 TI - A Case of Early Recurrence of Measles. PMID- 30433983 TI - Malpositions of the Kidney. PMID- 30433984 TI - On the Influence of Language upon Medical Thought and Practice: Being His Address as President of the Glasgow and West of Scotland Branch of the British Medical Association, on 29th June, 1883. PMID- 30433986 TI - Western Infirmary. PMID- 30433985 TI - Glasgow Eye Infirmary: Two Cases of Hard Chancre of the Eyelid. PMID- 30433987 TI - Medico-Chirurgical Society. PMID- 30433988 TI - Pathological and Clinical Society. PMID- 30433989 TI - Current Topics. PMID- 30433990 TI - Southern Medical Society. PMID- 30433991 TI - A Case of Malignant Growth in the Neck, Implicating the Cervical Spinal Nerves and the Cervical Sympathetic; with Remarks. PMID- 30433992 TI - Medico-Chirurgical Society. PMID- 30433993 TI - On Drugs and Curative Hygiene: Being a Lecture Delivered at the Opening of the Session in the Western Medical School. PMID- 30433994 TI - Western Infirmary. PMID- 30433995 TI - A Case of Severe Cerebral Concussion in Which the Bromide of Potassium in Large Doses Averted Death. PMID- 30433996 TI - Case of Transposition of the Viscera, with Dislocation Downwards of the Liver. PMID- 30433997 TI - On the Immediate Suture of Divided Nerves. PMID- 30433999 TI - Abscess: A Clinical Study. Being an Investigation into the Histories of 100 Cases of Abscess Occurring in Private Family Practice. PMID- 30433998 TI - A Case of Acute Peri-Hepatitis. PMID- 30434001 TI - Medico-Chirurgical Society. PMID- 30434000 TI - Embolism of the Middle Cerebral Artery. PMID- 30434002 TI - Western Infirmary. PMID- 30434004 TI - Current Topics. PMID- 30434003 TI - On Aural Diagnosis: Lecture Delivered in the Glasgow Hospital and Dispensary for the Diseases of the Ear, February, 1882. PMID- 30434005 TI - Pathological and Clinical Society. PMID- 30434006 TI - Glasgow Royal Infirmary. PMID- 30434007 TI - On a Prolonged Case of Enteric Fever; with Remarks Especially with Reference to Aberrant Course of Temperature. PMID- 30434008 TI - Case of Glass Tube Impacted in Bladder and Urethra. PMID- 30434009 TI - Retained Placenta. PMID- 30434010 TI - Glasgow Hospital for Sick Children. PMID- 30434011 TI - Medico-Chirurgical Society. PMID- 30434013 TI - Western Infirmary. PMID- 30434012 TI - A Case of Traumatic Tetanus Treated Unsuccessfully with Calabar Bean. PMID- 30434014 TI - Glasgow Eye Infirmary. PMID- 30434015 TI - A Case of "Movable" Kidney Permanently Cured. PMID- 30434016 TI - On Disinfection by Heat, with Description of a New Disinfecting Chamber. PMID- 30434017 TI - Western Infirmary. PMID- 30434018 TI - Case of Severe Burn, Followed by Intestinal Haemorrhage (Duodenal Ulcer?) with Ultimate Recovery. PMID- 30434019 TI - Current Topics. PMID- 30434020 TI - A Case of Lightning Stroke. PMID- 30434021 TI - Glasgow Royal Infirmary. PMID- 30434022 TI - Private Practice. PMID- 30434023 TI - Glasgow Maternity Hospital. PMID- 30434024 TI - Pathological and Clinical Society: Part 2. PMID- 30434025 TI - Pathological and Clinical Society: Part 1. PMID- 30434027 TI - A Contribution to the Discussion on Albuminuria. PMID- 30434026 TI - Pathological and Clinical Society. PMID- 30434028 TI - Current Topics. PMID- 30434029 TI - Notes of a Curious Instance of Abnormal Development of Adventitious Fingers and Toes, as Illustrating the Influences of Heredity in Five Consecutive Generations. PMID- 30434030 TI - Abdominal Section as Part of the Surgical Treatment of Some Diseases of the Abdominal Organs. PMID- 30434032 TI - Medico-Chirurgical Society. PMID- 30434031 TI - Extraordinary, and Probably Unique, Case of Stone in the Bladder. PMID- 30434034 TI - Pathological and Clinical Society. PMID- 30434033 TI - Current Topics. PMID- 30434035 TI - Pathological and Clinical Society. PMID- 30434036 TI - Current Topics. PMID- 30434037 TI - School Work in Its Relation to Health. PMID- 30434038 TI - Malformations of the Heart in Their Relation to the Pathology of Cyanosis: Illustrated by Specimens from Pathological Museum of the Royal Infirmary. PMID- 30434039 TI - Western Infirmary. PMID- 30434041 TI - Western Infirmary. PMID- 30434040 TI - Idiopathic Pericarditis. PMID- 30434042 TI - Pathological and Clinical Society. PMID- 30434043 TI - Southern Medical Society. PMID- 30434044 TI - Case of Tetanus. PMID- 30434046 TI - Current Topics. PMID- 30434045 TI - A New Effervescing Chalybeate Spring at Strathpeffer Spa, N.B. PMID- 30434047 TI - On Support and Fixation of the Head by Expanding India-Rubber Bags in Disease of the Upper Part of the Spine. PMID- 30434048 TI - Medico-Chirurgical Society. PMID- 30434049 TI - Pathological and Clinical Society. PMID- 30434050 TI - Collective Investigation Committee. British Medical Association-Glasgow Branch. PMID- 30434051 TI - Case of Scarlet Fever, Followed by Coma and Convulsions Treated by Pilocarpine. PMID- 30434052 TI - Private Practice: Case of Tape Worm Treated by Tannate of Pelletierine. PMID- 30434053 TI - Resection in Fracture. PMID- 30434054 TI - Western Infirmary. PMID- 30434055 TI - The Result of Two Years' Experience in Connection with a Provident Dispensary. PMID- 30434056 TI - On a Case of Myxoedema. PMID- 30434057 TI - Abdominal Section as Part of the Surgical Treatment of Some Diseases of the Abdominal Organs. PMID- 30434058 TI - Western Infirmary. PMID- 30434059 TI - The Theory and Practice of the Cure of Phthisis by Hard Mountaineering, as Embraced in What I Know about Consumption. A Memoir. PMID- 30434060 TI - Case of Tubercular Tumour of the Cerebellum. PMID- 30434061 TI - The Proposed Medical Section of the Postal Microscopical Society. PMID- 30434062 TI - Medico-Chirurgical Society. PMID- 30434063 TI - Male Fern and Pomegranate Root Bark Compared, in Their Action on Taenia Solium. PMID- 30434064 TI - New Method of Operating upon Recto-Vaginal and Vesico-Vaginal Fistula. PMID- 30434066 TI - A Visit to the Human Anatomy Section of the Hunterian Museum, Glasgow University. PMID- 30434065 TI - Report of a Slight Outbreak of Epidemic Cerebro-Spinal Meningitis, with Notes of Six Cases. PMID- 30434067 TI - Current Topics. PMID- 30434068 TI - Pathological and Clinical Society. PMID- 30434069 TI - Pathological and Clinical Society. PMID- 30434070 TI - Death from Chloroform, Accompanied with Unusual Symptoms. PMID- 30434071 TI - Medico-Chirurgical Society. PMID- 30434072 TI - Case of Foetid Pyo-Pneumo-Thorax Treated by Means of Two Free Incisions, Continuous Drainage, and Frequent Ablution with Condy's Fluid. Temporary Relief. Death from Suppurative Inflammation in the Other Lung. PMID- 30434073 TI - Current Topics. PMID- 30434074 TI - Western Infirmary. PMID- 30434075 TI - The Alexander-Adams' Operation on the Round Ligaments. PMID- 30434076 TI - On the Case of a Child Affected with Congenital Unilateral Hypertrophy and Patches of Cutaneous Congestion. PMID- 30434077 TI - On Disinfection. PMID- 30434078 TI - Western Infirmary. PMID- 30434079 TI - Case of Hydatid Cyst of the Right Kidney, with Suppuration and Discharge of Secondary Cysts in the Urine. PMID- 30434081 TI - Abdominal Section as Part of the Surgical Treatment of Some Diseases of the Abdominal Organs. PMID- 30434080 TI - Cases of Spontaneous Rupture of the Heart, and Remarks on the Pathology of the Condition, with Special Reference to Fatty Degeneration and Disease of the Coronary Arteries. PMID- 30434083 TI - On the Pathology of Pseudo-Hypertrophic Muscular Paralysis, with Remarks on a So Called Degeneration of the Nervous System: Being His Thesis for the Degree of M.D. in the University of Glasgow. PMID- 30434082 TI - Pathological and Clinical Society. PMID- 30434084 TI - Two Cases of the Alexander-Adams' Operation for Displacements of the Uterus. PMID- 30434086 TI - Southern Medical Society. PMID- 30434085 TI - On a Peculiar Case of Congenital Anti-Flexion of the Right Knee-Joint. PMID- 30434087 TI - Abdominal Section as Part of the Surgical Treatment of Some Diseases of the Abdominal Organs. PMID- 30434088 TI - Medico-Chirurgical Society. PMID- 30434089 TI - Dr. M' Bride's Guide to the Study of Ear Disease. PMID- 30434090 TI - Current Topics. PMID- 30434091 TI - Complete Rupture of the Perineum. PMID- 30434092 TI - Twenty-One Years' Experience of Vaccination. PMID- 30434094 TI - Medico-Chirurgical Society. PMID- 30434093 TI - The Pathology of Suppurative Inflammation of the Kidney: Being His Thesis for the Degree of M.D. in the University of Glasgow. PMID- 30434095 TI - Some Phases of Articular and Muscular Rheumatism. PMID- 30434096 TI - Case of Cancer of the Throat Treated by Radium. PMID- 30434097 TI - The Diagnosis of Chronic Gonococcus Infections. PMID- 30434099 TI - New Preparations, &c. PMID- 30434098 TI - Notes of a Case of Stricture of the OEsophagus. PMID- 30434100 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434101 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st September, 1912. PMID- 30434102 TI - Current Topics. PMID- 30434103 TI - Current Topics. PMID- 30434104 TI - New Preparations, &c. PMID- 30434105 TI - Notes on a Case in Which Certain Symptoms of Syringomyelia Followed Enteric Fever. PMID- 30434106 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th October, 1912. PMID- 30434107 TI - Sanatorium Treatment of Pulmonary Tuberculosis. PMID- 30434108 TI - Three Hundred Consecutive Cases of Appendicitis. PMID- 30434109 TI - Case of Contusional Pneumonia. PMID- 30434110 TI - Current Topics. PMID- 30434111 TI - Note on the Insertion of the Rectus Abdominis Muscle. PMID- 30434112 TI - Obstetrical and Gynaecological Society. PMID- 30434113 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 24th August, 1912. PMID- 30434114 TI - Four Cases of Fracture of the Larynx. PMID- 30434115 TI - Some Aspects of Medical Life in Old Glasgow. PMID- 30434116 TI - Note on a Case of Elephantiasis Occurring in This Country. PMID- 30434117 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434118 TI - Chronic Ovarian Pain as Illustrated in the Record of a Case Finally Treated by Double Oophorectomy. PMID- 30434119 TI - Obstetrical and Gynaecological Society. PMID- 30434120 TI - Primary Carcinoma Arising from the Bronchus in a Tubercular Lung. PMID- 30434121 TI - "Tunnel" Skin-Grafting: A New Method of Covering Raw Surfaces with Epithelium. PMID- 30434123 TI - New Preparations, &c. PMID- 30434122 TI - Successful Removal of Large Retro-Peritoneal Sarcoma, with Notes on the Method and Treatment. PMID- 30434125 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th July, 1912. PMID- 30434124 TI - Current Topics. PMID- 30434126 TI - Case of Doubling of the Great Intestine. PMID- 30434127 TI - Further Contributions to Our Knowledge of the Pernicious Vomiting of Pregnancy. PMID- 30434128 TI - Obstetrical and Gynaecological Society. PMID- 30434129 TI - Necrosis of the Vertebrae Following Scarlet Fever. PMID- 30434130 TI - Current Topics. PMID- 30434131 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 16th November, 1912. PMID- 30434132 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434133 TI - The Effects of Chloroform. PMID- 30434134 TI - Scottish Otological and Laryngological Society. PMID- 30434135 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd June, 1912. PMID- 30434136 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434137 TI - Obstetrical and Gynaecological Society. PMID- 30434138 TI - Note on Two Cases of Glandular Enlargement -(I) Hodgkin's Disease; (II) Endothelioma. PMID- 30434139 TI - The Albumen-Reaction of the Sputum in Pulmonary Tuberculosis. PMID- 30434140 TI - Current Topics. PMID- 30434141 TI - Ether Anaesthesia by Intravenous Infusion. PMID- 30434142 TI - Current Topics. PMID- 30434143 TI - The General Practitioner's Position in Relation to Pulmonary Tuberculosis. PMID- 30434144 TI - Abdominal Incisions and Intestinal Anastomosis in the Treatment of Carcinoma of the Colon. PMID- 30434146 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th May, 1913. PMID- 30434145 TI - The Adulteration of Food Stuffs and Its Influence on Digestion. PMID- 30434147 TI - New Preparations, &c. PMID- 30434148 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434149 TI - Current Topics. PMID- 30434150 TI - Sporadic Congenital Deafness and Deafness from Syphilis. PMID- 30434151 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 15th February, 1913. PMID- 30434153 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434152 TI - Two Unusual Forms of Spina Bifida. PMID- 30434154 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 14th December, 1912. PMID- 30434155 TI - Report of Three Cases of Pancreatitis, with Two Recoveries. PMID- 30434156 TI - Current Topics. PMID- 30434157 TI - The Lesions of Bilharzial Disease. PMID- 30434158 TI - Obstetrical and Gynaecological Society. PMID- 30434159 TI - Glasgow Southern Medical Society. PMID- 30434161 TI - Scottish Otological and Laryngological Society. PMID- 30434160 TI - The Ovum in Relation to Sterility and Abortion. PMID- 30434163 TI - Current Topics. PMID- 30434162 TI - Sporadic Congenital Deafness and Deafness from Syphilis. PMID- 30434164 TI - Obstetrical and Gynaecological Society. PMID- 30434165 TI - New Preparations, &c. PMID- 30434166 TI - On Aseptic, Antiseptic, and Prophylactic Measures in Ophthalmic Surgery: Observations Made in Various British and Continental Hospitals. PMID- 30434167 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 11th January, 1913. PMID- 30434168 TI - Myopia: A Review of Five Hundred Cases, with Special Reference to Etiology. PMID- 30434169 TI - Sclerodermia with Subcutaneous Calcareous Deposits. PMID- 30434171 TI - Notes on Medical History. PMID- 30434170 TI - Sir William T. Gairdner, K.C.B., M.D., F.R.S.: An Appreciation. PMID- 30434172 TI - Current Topics. PMID- 30434173 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd March, 1913. PMID- 30434174 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434175 TI - Obstetrical and Gynaecological Society. PMID- 30434176 TI - New Preparations, &c. PMID- 30434177 TI - Obstetrical and Gynaecological Society. PMID- 30434178 TI - New Preparations, &c. PMID- 30434179 TI - Current Topics. PMID- 30434180 TI - The Passing of Tuberculosis. PMID- 30434182 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th April, 1913. PMID- 30434181 TI - Cases Illustrating Certain Urinary Conditions in Women Associated with Frequent or Painful Micturition. PMID- 30434183 TI - Chloroform Anaesthesia in the Light of Physiological Research. PMID- 30434185 TI - Robert Burns and "Sum Practysis of Medecyne". PMID- 30434184 TI - Chronic Valvular Disease of the Heart: Its Etiology, the Factors Leading to Failure of Compensation, and the Symptoms Produced. PMID- 30434186 TI - Tumours of the Bladder: Three Cases Illustrating Points of Interest in Diagnosis and Treatment. PMID- 30434187 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 13th December, 1913. PMID- 30434188 TI - Obstetrical and Gynaecological Society. PMID- 30434189 TI - New Preparations, &c. PMID- 30434191 TI - Current Topics. PMID- 30434190 TI - Current Topics. PMID- 30434192 TI - The Retraction Ring as an Obstruction in Labour. PMID- 30434193 TI - Partick and District Medical Society. PMID- 30434194 TI - The Drug Treatment of Phthisis Pulmonalis. PMID- 30434195 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434196 TI - Dr. Harry Rainy, Professor of Medical Jurisprudence in the University of Glasgow, 1841-1872, and Surgeon to Glasgow Royal Infirmary. PMID- 30434197 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 21st February, 1914. PMID- 30434198 TI - The History and Prevention of Venereal Disease. PMID- 30434199 TI - The History and Prevention of Venereal Disease. PMID- 30434200 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434201 TI - Scottish Otological and Laryngological Society. PMID- 30434202 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 17th January, 1914. PMID- 30434203 TI - Case of Patent Ductus Arteriosus. PMID- 30434204 TI - New Preparations, &c. PMID- 30434205 TI - Current Topics. PMID- 30434206 TI - Recent Work on the Etiology of Gall-Stones. PMID- 30434207 TI - The Prevention of Malaria. PMID- 30434208 TI - Abdominal Emergencies. PMID- 30434210 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434209 TI - Malingering. PMID- 30434211 TI - On the Dangers of Light Anaesthesia. PMID- 30434213 TI - Current Topics. PMID- 30434212 TI - New Preparations, &c. PMID- 30434214 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st March, 1914. PMID- 30434215 TI - On Myeloid Tumours of Tendon Sheaths, with Report of a Case. PMID- 30434216 TI - Radium: Question of a Supply for Glasgow. Collected Opinions from Workers at Home and Abroad. PMID- 30434217 TI - Glasgow Northern Medical Society. PMID- 30434218 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th April, 1914. PMID- 30434220 TI - Current Topics. PMID- 30434219 TI - Some Observations on the Occurrence of the Wassermann Reaction in the Serum of the Children of the Poorer Classes. PMID- 30434221 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434222 TI - Dr. Andrew Buchanan, Professor of Physiology in the University of Glasgow, 1839 1876, and Surgeon to Glasgow Royal Infirmary, 1835-1862. PMID- 30434223 TI - Auto-Intoxication from the Point of View of a General Practitioner. PMID- 30434224 TI - Surgical Diagnosis in Acute Abdominal Conditions. PMID- 30434225 TI - Current Topics. PMID- 30434226 TI - New Preparations, &c. PMID- 30434227 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 16th May, 1914. PMID- 30434228 TI - Pyorrhoea Alveolaris and Auto-Intoxication. PMID- 30434229 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 24th April, 1915. PMID- 30434230 TI - Chorea. PMID- 30434232 TI - Current Topics. PMID- 30434231 TI - The Preventive and Curative Treatment of Pneumococcal Ulcer of the Cornea. PMID- 30434233 TI - The Prognosis and Treatment of Congenital Syphilis, with a Plea for Notification. PMID- 30434235 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th March, 1915. PMID- 30434234 TI - Case of Carcinoma of the Stomach with Secondary Carcinoma of Bone-Marrow. PMID- 30434236 TI - Chorea. PMID- 30434237 TI - New Preparations, &c. PMID- 30434238 TI - Current Topics. PMID- 30434240 TI - Lacerations of the Maternal Tissues during Labour. PMID- 30434239 TI - Notes on the Agglutinating Power of the Serum of a Person Inoculated against Enteric Fever. PMID- 30434241 TI - New Preparations, &c. PMID- 30434243 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th December, 1914. PMID- 30434242 TI - Leper Houses and Mediaeval Hospitals : Lecture I. PMID- 30434244 TI - Current Topics. PMID- 30434245 TI - The New B.P.: Some Notes for the Use of Prescribers. PMID- 30434246 TI - Rejections among Recruits: Some Statistics. PMID- 30434247 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd May, 1915. PMID- 30434249 TI - Current Topics. PMID- 30434248 TI - Chorea. PMID- 30434250 TI - Simple Peptic Ulcer and Malignant Disease of the Stomach. PMID- 30434252 TI - Current Topics. PMID- 30434251 TI - The Scottish Women's Hospital in Serbia. PMID- 30434254 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th February, 1915. PMID- 30434253 TI - A Case of Polyglandular Syndrome with Adrenal Hypernephroma and Adenoma of the Pituitary Gland-Both of Small Size. PMID- 30434255 TI - The Treatment of Impacted Breech Cases. PMID- 30434256 TI - Head Injuries. PMID- 30434257 TI - Current Topics. PMID- 30434259 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd January, 1915. PMID- 30434258 TI - Types of Bullet Wounds Observed in No. 3 Scottish General Hospital, Stobhill. PMID- 30434260 TI - Case of Gastric Cancer with Bone-Marrow Metastases and Anaemia. PMID- 30434261 TI - Leper Houses and Mediaeval Hospitals: Lecture II. PMID- 30434262 TI - Two Cases of Optic Neuritis of Intracranial Origin. PMID- 30434263 TI - Pathological and Clinical Society. PMID- 30434264 TI - The Treatment of Endometritis. PMID- 30434265 TI - On the Climate of South California and Its Suitability as a Health Resort. PMID- 30434266 TI - A Note on the Treatment of the Cancerous Infiltration of the Cancellated Structure of Bone. PMID- 30434267 TI - A Case of Microcephalus in Which the Operation of Linear Craniotomy (Craniectomy) Was Performed. PMID- 30434268 TI - A Note on the Treatment of Acute Abscess. PMID- 30434269 TI - Medico-Chirurgical Society. PMID- 30434270 TI - Current Topics. PMID- 30434271 TI - The Medical Treatment of Intestinal Obstruction, with a Series of Nine Cases. PMID- 30434272 TI - Current Topics. PMID- 30434273 TI - The Procedure of the Crown as Regards Post-Mortem Examinations in Criminal Cases. PMID- 30434274 TI - Sleeping Accommodation in Relation to Tubercular and Other Diseases. PMID- 30434275 TI - Medico-Chirurgical Society. PMID- 30434277 TI - Two Cases of Leukaemia in Young Children. PMID- 30434276 TI - Epithelioma of Left Vocal Cord Removed by Laryngotomy. PMID- 30434278 TI - Herophilus and Erasistratus: A Bibliographical Demonstration in the Library of the Faculty of Physicians and Surgeons, Glasgow, 16th March, 1893. PMID- 30434279 TI - Analysis of Cases Treated in the Glasgow Royal Infirmary (Wards Nos. 1 and 2) during the Year 1892. PMID- 30434280 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434281 TI - Notes of 1,028 Confinement Cases, Being the Report of Two Years' Work at the West End Branch of the Maternity Hospital. PMID- 30434282 TI - On an Outbreak of Scarlet Fever in Glasgow Connected with an Epidemic Teat Eruption on Milch Cows at Jaapston. PMID- 30434283 TI - A Case in Which a Portion of a Nut Was Impacted in the Right Bronchus and Removed by Operation. PMID- 30434284 TI - Analysis of a Thousand Consecutive Cases of Skin Disease Met with in Private Practice, Including the Sex and Age of the Patients. PMID- 30434285 TI - Medico-Chirurgical Society. PMID- 30434286 TI - Current Topics. PMID- 30434287 TI - Loch Long Sharks (Porbeagle, Lamna Cornubica of Cuvier). PMID- 30434288 TI - Three Cases of Doubtful Sex in One Family. PMID- 30434289 TI - Current Topics. PMID- 30434290 TI - The Examination of the Eye. PMID- 30434291 TI - The Utility of Medical Societies. PMID- 30434292 TI - Clinical Reports from the Glasgow Samaritan Hospital. PMID- 30434293 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434294 TI - Fractures of the Nose, and Their Treatment. PMID- 30434295 TI - A Cystic Glioma of the Cerebellum, with OEdema of the Ventricles. PMID- 30434296 TI - Medico-Chirurgical Society. PMID- 30434297 TI - Case of Spinal Tuberculosis Associated with Abscess. PMID- 30434298 TI - Three Cases from the Wards of the Glasgow Royal Infirmary. PMID- 30434300 TI - Current Topics. PMID- 30434299 TI - On a Case of Multiple Vascular Naevi, with Subsequent Disappearance of Many of Them. PMID- 30434302 TI - Pathological and Clinical Society. PMID- 30434301 TI - On a Case of Diffuse Gangrene of the Left Lung, Due to the Unsuspected Presence in the Bronchus of a Temporary Molar Tooth, Which Had Accidentally Become Dislodged While Patient Was under an Anaesthetic. PMID- 30434303 TI - On the Antipyretic Action of Antipyrin and Antifebrin. PMID- 30434304 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434305 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434306 TI - A Note on Statistics of Enteric Fever. PMID- 30434308 TI - Medico-Chirurgical Society. PMID- 30434307 TI - On a Case of Sensory Aphasia or Word Deafness, with the Clinical and Pathological Record; with a Case of Functional Auditory Amnesia. PMID- 30434309 TI - Pathological and Clinical Society. PMID- 30434310 TI - The Prophylaxis and Treatment of Abortion. PMID- 30434311 TI - Current Topics. PMID- 30434312 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434314 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434313 TI - Medico-Chirurgical Society. PMID- 30434315 TI - Notes on Post-Mortem Examinations in Criminal Cases Conducted by Crown Officials in Glasgow. PMID- 30434317 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th June, 1915. PMID- 30434316 TI - Gynaecology in General Practice. PMID- 30434318 TI - Current Topics. PMID- 30434319 TI - Notes of Cases in General Practice. PMID- 30434320 TI - Simple Peptic Ulcer and Malignant Disease of the Stomach. PMID- 30434321 TI - Vincent's Angina. PMID- 30434322 TI - On a Case of Erythraemia. PMID- 30434324 TI - Current Topics. PMID- 30434323 TI - Further Notes on Cases in General Practice. PMID- 30434325 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd October, 1915. PMID- 30434326 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st August, 1915. PMID- 30434327 TI - Medical Conditions in Glasgow One Hundred Years Ago. PMID- 30434329 TI - Some Observations on the Use of Pituitary Extract in Obstetric Cases. PMID- 30434328 TI - Haematuria, a Symptom: Its Causes and Diagnosis, with a Few Cases Illustrating Some of the Less Common Lesions. PMID- 30434330 TI - Current Topics. PMID- 30434331 TI - A Series of Cases Illustrating Some of the Rarer Blood Diseases. PMID- 30434332 TI - Haematuria, a Symptom: Its Causes and Diagnosis, with a Few Cases Illustrating Some of the Less Common Lesions. PMID- 30434333 TI - Current Topics. PMID- 30434334 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th September, 1915. PMID- 30434335 TI - New Preparations, &c. PMID- 30434336 TI - Extra-Uterine Gestation with Intra-Uterine Pregnancy-Operation-The Uterine Pregnancy Proceeding to Term. PMID- 30434337 TI - Current Topics. PMID- 30434338 TI - A Ganglioneuroma of the Spheno-Maxillary Fossa. PMID- 30434339 TI - Haematuria, a Symptom: Its Causes and Diagnosis, with a Few Cases Illustrating Some of the Less Common Lesions. PMID- 30434340 TI - A Note on Trachoma. PMID- 30434341 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 24th July, 1915. PMID- 30434342 TI - Simple Peptic Ulcer and Malignant Disease of the Stomach. PMID- 30434343 TI - The Cause and Similarity of Origin of Scarlet and Rheumatic Fever. PMID- 30434344 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th November, 1915. PMID- 30434345 TI - Current Topics. PMID- 30434346 TI - The Action of Medicinal Doses of Lead Acetate. PMID- 30434347 TI - Two Famous Lanarkshire Obstetricians. PMID- 30434348 TI - On a Case of Dislocation of the Hip. PMID- 30434350 TI - A Silver Fork Swallowed and Discharged by an Abscess in the Hypogastric Region. Recovery. PMID- 30434349 TI - Lecture on Cardiac Diagnosis: Lecture I.-On the Physical Diagnosis of the Condition of the Organs of Circulation, Apart from Murmurs, and Special States of Valvular Disease. PMID- 30434351 TI - Medico-Chirurgical Society. PMID- 30434352 TI - Case of Idiopathic Myelitis. PMID- 30434353 TI - A Remarkable Case of Penetrating and Lacerated Wound of the Abdomen and Uterus of a Pregnant Woman, with Escape of a Living Child through the Wound. PMID- 30434354 TI - Manipulation as a Means of Reducing Dislocations of the Hip. PMID- 30434355 TI - On a Needle for Fissure Operations. PMID- 30434356 TI - Chloroform Experiences in London. PMID- 30434357 TI - Clinical Notes. PMID- 30434358 TI - On the Coccygeal Body. PMID- 30434359 TI - Temperature in Cholera. PMID- 30434360 TI - Case of Typhus Fever. PMID- 30434361 TI - Lithotrity. PMID- 30434362 TI - Case of Poisoning by Caustic Alkali. PMID- 30434363 TI - Cases of "General Paralysis". PMID- 30434364 TI - Case of Pleurisy. PMID- 30434365 TI - Case of Recovery from Aphasia. PMID- 30434367 TI - Glasgow Medico-Chirurgical Society. PMID- 30434366 TI - Cases of Suicidal Cut-Throat. PMID- 30434368 TI - Lecture on Cardiac Diagnosis, No. II: Lecture II.-The Physiological Diagnosis of Cardiac Valvular Diseases. PMID- 30434370 TI - Case of Faecal Fistula Following Ovariotomy. PMID- 30434369 TI - Case of Fatal Acute Pleurisy. PMID- 30434371 TI - Dislocation into the Ischiatic Notch Reduced by Manipulation. PMID- 30434372 TI - Clinical Study of Stimulation in Typhus. PMID- 30434373 TI - Medico-Chirurgical Society. PMID- 30434374 TI - Rupture of the Uterus during Labour. PMID- 30434375 TI - Case of Rare Disease of Bone. PMID- 30434376 TI - Case of Extraordinary Quintuple Child-Birth. PMID- 30434377 TI - Bromide of Potassium in Puerperal Convulsions. PMID- 30434378 TI - The Use of Acetic Acid in Cancer. PMID- 30434379 TI - Notes of Practice-Facial Neuralgia. PMID- 30434380 TI - Cases of Pneumothorax. PMID- 30434381 TI - Correspondence Regarding Rejected Candidates. PMID- 30434382 TI - Case of Ovariotomy. PMID- 30434383 TI - Case of Enteritis Terminating in Gangrene. PMID- 30434385 TI - Communication upon Coccygeal Body. PMID- 30434384 TI - Case of Erythema Nodosum. PMID- 30434386 TI - Medical Intelligence. PMID- 30434388 TI - Sub-Periosteal Re-Section of Os Calcis. PMID- 30434387 TI - Case of Severe Burn and Bruise. PMID- 30434389 TI - Glasgow Medico-Chirurgical Society. PMID- 30434390 TI - Cases Illustrating Abdominal Intumescence. PMID- 30434391 TI - Acetic Acid Cure for Cancer. PMID- 30434393 TI - Medical Intelligence. PMID- 30434392 TI - Transverse Presentation. PMID- 30434394 TI - Case of Persistent Haemorrhage. PMID- 30434395 TI - Successful Case of Ovariotomy. PMID- 30434396 TI - Excision of the Eyeball. PMID- 30434397 TI - Faculty of Physicians and Surgeons. PMID- 30434398 TI - Cases Illustrative of Diseases of the Ear: No. XI.-Chronic Catarrh of the Middle Ear, in Connection with Secondary Syphilis. PMID- 30434400 TI - Glasgow Medico-Chirurgical Society. PMID- 30434399 TI - A Clinical Study of Stimulation in Typhus. PMID- 30434401 TI - Successful Case of Ovariotomy. PMID- 30434402 TI - Recent Improvements in the Ecraseur. PMID- 30434403 TI - Case of Face Presentation Requiring Craniotomy. PMID- 30434404 TI - On Foecal Fistula. PMID- 30434406 TI - Case of Paraplegia. PMID- 30434405 TI - Syphilis. PMID- 30434407 TI - Case of Disease of the Heart. PMID- 30434409 TI - Glasgow Medico-Chirurgical Society. PMID- 30434408 TI - Case of Albuminuria. PMID- 30434411 TI - Occipito-Atloid Disease. PMID- 30434410 TI - Syphilis. PMID- 30434412 TI - On Medicinal Inhalations. PMID- 30434413 TI - Notes of Cases. PMID- 30434414 TI - Disease of Heart. PMID- 30434415 TI - Ligature of the External Iliac Artery for Aneurism-Secondary Haemorrhage-Cure. PMID- 30434416 TI - Interesting Case. PMID- 30434417 TI - Syphilis. PMID- 30434418 TI - A Clinical Lesson in Diagnosis. PMID- 30434419 TI - Hydronephrosis. PMID- 30434420 TI - Glasgow Medico-Chirurgical Society. PMID- 30434421 TI - Medical Intelligence. PMID- 30434422 TI - Case of Face Presentation Requiring Craniotomy. PMID- 30434424 TI - Glasgow Medico-Chirurgical Society. PMID- 30434423 TI - Syphilis. PMID- 30434425 TI - Successful Case of Ovariotomy. PMID- 30434426 TI - Clinical Surgical Report. PMID- 30434428 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th March, 1917. PMID- 30434427 TI - Case of Pleuro-Pneumonia. PMID- 30434429 TI - Visual Defects: Refractive and Functional. PMID- 30434430 TI - The Effects of Cinematograph Displays upon the Eyes of Children. PMID- 30434432 TI - Current Topics. PMID- 30434431 TI - Inversion of the Uterus: With Notes of Six Cases. PMID- 30434434 TI - Some Frightful Wounds of War. PMID- 30434433 TI - Residual Urine in the Senile Bladder, with Special Reference to the Conduct of the Case so as to Postpone or Avoid the Use of the Catheter. PMID- 30434436 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th February, 1917. PMID- 30434435 TI - Popular Customs and Superstitions in Connection with Puberty and Obstetrics in Central Europe. PMID- 30434437 TI - Current Topics. PMID- 30434438 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th May, 1917. PMID- 30434439 TI - Current Topics. PMID- 30434440 TI - Maternity and Child Welfare Schemes: Responsibility of Local Authorities under the Notification of Births (Extension) Act, 1915. PMID- 30434441 TI - Acute Cystitis: A Word to the Practitioner. PMID- 30434442 TI - New Preparations, &c. PMID- 30434443 TI - Current Topics. PMID- 30434444 TI - The Modern Developments of Radium and X-Ray Therapeutics. PMID- 30434445 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 28th April, 1917. PMID- 30434446 TI - The Causes of Still-Birth. PMID- 30434447 TI - The Action of Pituitrin on the Surviving Human Uterus. PMID- 30434449 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th January, 1917. PMID- 30434448 TI - Residual Urine in the Senile Bladder, with Special Reference to the Conduct of the Case so as to Postpone or Avoid the Use of the Catheter. PMID- 30434450 TI - Current Topics. PMID- 30434451 TI - Case of Mediastinal Tumour with Expansile Pulsation. PMID- 30434452 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd December, 1916. PMID- 30434453 TI - Residual Urine in the Senile Bladder, with Special Reference to the Conduct of the Case so as to Postpone or Avoid the Use of the Catheter. PMID- 30434454 TI - Current Topics. PMID- 30434456 TI - Points in the Operative Treatment of Hare-Lip and Cleft Palate. PMID- 30434455 TI - Achylia Gastrica: Simple or Benign Achylia. PMID- 30434457 TI - A Calculus Weighing 1,400 Grains, Removed by Litholapaxy, and a Calculus Extracted from the Female Bladder by Rapid Dilatation: Specimens Shown at the Glasgow Pathological and Clinical Society, 14th April, 1885. PMID- 30434458 TI - Notes of Two Cases of Disease of the Ear, with Remarks. PMID- 30434459 TI - A Further Note on Measles. PMID- 30434460 TI - Case of Hydatid Cyst of the Right Kidney. PMID- 30434462 TI - Remarks Introductory to a Course of Clinical Instruction in Fever, at Belvidere Hospital. PMID- 30434461 TI - Insanity-Modern Views as to Its Nature and Treatment: Being the Address Delivered at the Close of the Winter Session 1884-85 before the Glasgow University Medico Chirurgical Society, by the Honorary President. PMID- 30434464 TI - Medico-Chirurgical Society. PMID- 30434463 TI - Pathological and Clinical Society. PMID- 30434465 TI - Current Topics. PMID- 30434466 TI - Medico-Chirurgical Society. PMID- 30434467 TI - Glasgow Southern Medical Society. PMID- 30434468 TI - The Oleates. PMID- 30434470 TI - Pathological and Clinical Society. PMID- 30434469 TI - Case of Utero-Ovarian Amputation for Uterine Fibroid, Combined with Pregnancy. PMID- 30434471 TI - Current Topics. PMID- 30434472 TI - The Scientific Basis of Medicine. PMID- 30434473 TI - On the Rearing of Hand Fed Infants: Introductory to a Discussion on the Subject at the Southern Medical Society, 2nd April, 1885. PMID- 30434474 TI - Medico-Chirurgical Society. PMID- 30434475 TI - Pathological and Clinical Society. PMID- 30434476 TI - Notes of a Case of Rupture of the Bladder. PMID- 30434477 TI - Correspondence. PMID- 30434478 TI - Glasgow Southern Medical Society. PMID- 30434480 TI - Current Topics. PMID- 30434479 TI - Calcareous Masses Found in the Pleural Cavity. PMID- 30434481 TI - Cases of Calculus. PMID- 30434482 TI - Notes on a Recent Epidemic of Measles in Guernsey. PMID- 30434483 TI - A Case of Traumatic Tetanus Successfully Treated with Calabar Bean. PMID- 30434485 TI - Pathological and Clinical Society. PMID- 30434484 TI - Western Infirmary. PMID- 30434486 TI - Correspondence. PMID- 30434487 TI - Medico-Chirurgical Society. PMID- 30434488 TI - Current Topics. PMID- 30434489 TI - The Scientific Basis of Medicine. PMID- 30434490 TI - Correction. AB - [This corrects the article on p. 112 in vol. 23.]. PMID- 30434491 TI - On the Treatment of Diseases of the Stomach: In Opening a Discussion on the Subject at the Southern Medical Society, 22nd January, 1885. PMID- 30434492 TI - Erratum: Private Practice. AB - [This corrects the article on p. 57 in vol. 23.]. PMID- 30434494 TI - Pathological and Clinical Society. PMID- 30434493 TI - Case of Eczema Following the Course of the Small Sciatic and Short Saphenous Nerves. PMID- 30434495 TI - Medico-Chirurgical Society. PMID- 30434496 TI - On the Medical Societies of Glasgow, and Recent Advances in Medical and Surgical Treatment: Being His Inaugural Address as President of the Medico-Chirurgical Society of Glasgow. PMID- 30434498 TI - Current Topics. PMID- 30434499 TI - Southern Medical Society. PMID- 30434497 TI - Western Infirmary. PMID- 30434501 TI - Private Practice. PMID- 30434500 TI - Aphasia and Cerebral Haemorrhage Complicating Whooping-Cough. PMID- 30434502 TI - Notes of Cases of Swallowing Foreign Substances. PMID- 30434503 TI - Some Notes on the Use of the Electric Light in Medicine. PMID- 30434504 TI - Pathological and Clinical Society. PMID- 30434505 TI - Cocaine in Ophthalmic Surgery. PMID- 30434506 TI - Current Topics. PMID- 30434508 TI - Case of Purulent Pneumonia Due to the Presence of a Foreign Body (a Piece of the Pith of the Elder) in a Bronchus. PMID- 30434507 TI - On the Administration of Chloroform. PMID- 30434510 TI - Current Topics. PMID- 30434509 TI - Suppuration in the Antrum of Highmore. PMID- 30434511 TI - Tuberculosis as an Infectious Disease. PMID- 30434512 TI - Glasgow Southern Medical Society. PMID- 30434513 TI - The Relations of Ophthalmology to Medicine and Surgery: Being His Thesis for the Degree of M.D. in the University of Glasgow. PMID- 30434514 TI - Medico-Chirurgical Society. PMID- 30434515 TI - Certain Aspects of Corpuscular Action. PMID- 30434516 TI - Medico-Chirurgical Society. PMID- 30434517 TI - Discussion on Acute Intestinal Obstruction, with Special Reference to Treatment, in the Pathological and Clinical Society, 14th and 21st December, 1891. PMID- 30434518 TI - Current Topics. PMID- 30434519 TI - Hippocrates: A Bibliographical Demonstration in the Library of the Faculty of Physicians and Surgeons of Glasgow, 23rd November, 1891. PMID- 30434520 TI - On a Case of Leukaemia, Which Occurred in the Glasgow Royal Infirmary, in 1890; with an Account of Certain Peculiar Bodies Which Were Present in the Interstitial Substance of the Heart-Wall. PMID- 30434521 TI - Current Topics. PMID- 30434522 TI - The Relations of Ophthalmology to Medicine and Surgery. PMID- 30434523 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434524 TI - Glasgow Southern Medical Society. PMID- 30434525 TI - Celsus: Bibliographical Demonstration in the Library of the Faculty of Physicians and Surgeons of Glasgow, 3rd March, 1892. PMID- 30434526 TI - Pathological and Clinical Society. PMID- 30434528 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434527 TI - Infantile Deformities, and Maternal Impressions and Emotions: Being the Presidential Address in the Obstetrical Society of Glasgow, 25th November, 1891. PMID- 30434529 TI - Discussion on "Tuberculosis as an Infectious Disease," in the Medico-Chirurgical Society, 18th December, 1891: The Pathological and Clinical Aspects of Tuberculosis as an Infectious Disease. PMID- 30434530 TI - The Antiseptic Treatment of Burns. PMID- 30434531 TI - Current Topics. PMID- 30434532 TI - Medico-Chirurgical Society. PMID- 30434533 TI - Abstract of a Paper "on a New Form of Epidemic Skin Disease." PMID- 30434534 TI - Current Topics. PMID- 30434535 TI - Medico-Chirurgical Society. PMID- 30434536 TI - Six Cases of Accidental Haemorrhage. PMID- 30434537 TI - The Relations of Ophthalmology to Medicine and Surgery. PMID- 30434538 TI - Note on the Influence of Rest in the Treatment of Diseases of Women. PMID- 30434540 TI - The Significance of Acidity in Relation to the Causation and Cure of Irritative Dyspepsia. PMID- 30434539 TI - A Successful Case of Vaginal Extirpation of the Uterus, with a Comparison of the Relative Merits of the High and Low Operations in Cases of Cancer of the Cervix. PMID- 30434541 TI - Discussion on Acute Intestinal Obstruction, with Special Reference to Treatment, in the Pathological and Clinical Society, 14th December, 1891: On the Pathology of Intestinal Obstruction as Illustrated by Specimens and Post-Mortem Records. PMID- 30434543 TI - Remarks on the Treatment of Varicose Veins and Affections Depending Thereon, by Excision of the Former. PMID- 30434542 TI - The Relations of Ophthalmology to Medicine and Surgery. PMID- 30434544 TI - A Somewhat Unusual Restoration of a Fractured Incisor Tooth. PMID- 30434545 TI - Current Topics. PMID- 30434546 TI - A Side Light on the Question of Anaesthetics. PMID- 30434547 TI - Physiology and Pathology as Illustrated by Menstruation and Gestation. PMID- 30434548 TI - Glasgow Medico-Chirurgical Society. PMID- 30434550 TI - Current Topics. PMID- 30434549 TI - A Case of Myxoedema Successfully Treated with Thyroid Gland; Relapse after Cessation of Treatment, and Death from Tumour of the Mediastinum. PMID- 30434552 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434551 TI - The Glasgow Royal Infirmary: Reminiscences. PMID- 30434553 TI - The Condition of the Bowel in Typhoid after Antiseptic Treatment. PMID- 30434555 TI - Glasgow Medico-Chirurgical Society. PMID- 30434554 TI - The Early Diagnosis of Foetal Hydrocephalus. PMID- 30434556 TI - Disease of Knee-Joint with Distortion Treated Partly by Erasion and Partly by Excision. PMID- 30434557 TI - The Prevention and Treatment of Diphtheria, with Illustrative Cases Having Special Reference to the Removal of the Tonsils. PMID- 30434558 TI - The Malignant Transformation of Benign Laryngeal Tumours as a Consequence of Endolaryngeal Operations-A Rejoinder. PMID- 30434559 TI - Purulent Necrotic Mediastinitis, with Pericarditis and Double Empyema, Resulting from Suppuration of a Submaxillary Gland. PMID- 30434560 TI - Current Topics. PMID- 30434561 TI - Annual Report on Certification of Lunatics, Barony Parish, Glasgow; Together with Some Remarks on the Annual Report of the General Board of Commissioners in Lunacy for Scotland. PMID- 30434562 TI - Glasgow Pathological and Clinical Society. PMID- 30434563 TI - Glasgow Medico-Chirurgical Society. PMID- 30434564 TI - The Period of Incubation in Typhoid, with Notes of Two Cases under Antiseptic Treatment. PMID- 30434565 TI - Lithotomy; Supra-Pubic; Large Calculus. PMID- 30434566 TI - A Case of Haemoptysis and Surgical Emphysema Arising from Fracture of a Necrosed Larynx. PMID- 30434567 TI - Current Topics. PMID- 30434568 TI - The Relation between Chemistry and Medicine. PMID- 30434569 TI - A Case of Mycosis Tonsillaris Benigna. PMID- 30434571 TI - Current Topics. PMID- 30434570 TI - On a Recent Visit to the Central Institute of Gymnastics, Stockholm. PMID- 30434572 TI - Some Remarks on Eye Symptoms in Medical Diagnosis. PMID- 30434573 TI - Excision of the Elbow-Joint, with Thirty Cases in Illustration. PMID- 30434574 TI - Erratum: The Treatment of Diphtheria by Removal of the Tonsils.-A Correction. AB - [This corrects the article on p. 7 in vol. 42.]. PMID- 30434575 TI - Glasgow Medico-Chirurgical Society. PMID- 30434577 TI - Glasgow Royal Infirmary, 1847-51. PMID- 30434576 TI - On the Anatomy of Flat-Foot. PMID- 30434578 TI - A Case Showing Some of the Phenomena Described in Mr. Jonathan Hutchinson's Articles on Acro-Pathology. PMID- 30434580 TI - Glasgow Pathological and Clinical Society. PMID- 30434579 TI - Case of Syphilitic Ulceration of Trachea and Bronchi, with Fibroid Induration and Caseous (Tubercular) Nodules in Basal Parts of Lungs, Enlargement of Lymphatic Glands, and Gummata in Liver. PMID- 30434581 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30434582 TI - Necrosis of the Pancreas with Cyst Formation and Fat Necrosis. PMID- 30434583 TI - Current Topics. PMID- 30434584 TI - Longevity and Heart Disease. PMID- 30434585 TI - Seven Cases of Myxoedema Treated by Thyroid Feeding. PMID- 30434586 TI - A Case of Distension of the Bladder with Retroversion of the Uterus. PMID- 30434587 TI - On the Place of Hygienics in a Medical Journal. PMID- 30434588 TI - Lourdes, by Emile Zola, from a Medical Point of View. PMID- 30434589 TI - A Case of General Bilateral Peripheral Neuritis, with Recovery. PMID- 30434590 TI - Some Considerations Regarding the Etiology and Treatment of Bright's Disease. PMID- 30434591 TI - The Sequel of a Spurious Pregnancy. PMID- 30434592 TI - Glasgow Medico-Chirurgical Society. PMID- 30434593 TI - Current Topics. PMID- 30434594 TI - On Two Cases of Cystitis. PMID- 30434595 TI - Darwin's Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases. PMID- 30434596 TI - Current Topics. PMID- 30434597 TI - Deafness in Bright's Disease. PMID- 30434598 TI - The Additions and Alterations in the New British Pharmacopoeia. PMID- 30434599 TI - Notes from Paris. PMID- 30434601 TI - Notes from Vienna. PMID- 30434600 TI - Case of Labour Attended with Face Presentation, Rupture of the Uterus, and Death of Mother and Child; the Latter Deformed by Spastic (?) Rigidity and Malformation. PMID- 30434602 TI - Current Topics. PMID- 30434603 TI - Lecture on Aphonia, or Loss of Voice Consequent on Laryngeal Disease, with Illustrative Cases. PMID- 30434604 TI - Southern Medical Society. PMID- 30434605 TI - Insanity-Modern Views as to Its Nature and Treatment: Being the Address Delivered at the Close of the Winter Session 1884-85 before the Glasgow University Medico Chirurgical Society, by the Honorary President. PMID- 30434606 TI - Pathological and Clinical Society. PMID- 30434607 TI - Darwin's Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases. PMID- 30434608 TI - On a Case of Multiple Melanotic Sarcoma, with Remarks on the Mode of Growth and Extension of Such Tumours. PMID- 30434609 TI - Lecture on Aphonia, or Loss of Voice Consequent on Laryngeal Disease, with Illustrative Cases. PMID- 30434610 TI - Notes from Vienna. PMID- 30434611 TI - On a Case of Multiple Melanotic Sarcoma. PMID- 30434612 TI - Current Topics. PMID- 30434613 TI - Current Topics. PMID- 30434614 TI - Darwin's Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases. PMID- 30434616 TI - Additional Appendices-Being a Sequel to Professor Gairdner's Address on Insanity. PMID- 30434615 TI - The Treatment of Cancer of the Rectum by Excision, with a Record of Seven Cases. PMID- 30434617 TI - Notes from Vienna. PMID- 30434618 TI - Clinical Observations on Syphilis of the Ear and Throat. PMID- 30434619 TI - Hysterical Ischuria, with Notes of a Case. PMID- 30434620 TI - Some of the Effects of the Winter Climate of the High Alps. PMID- 30434621 TI - Private Practice. PMID- 30434622 TI - Notes from Vienna. PMID- 30434623 TI - Darwin's Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases. Part V. PMID- 30434624 TI - Current Topics. PMID- 30434626 TI - Medico-Chirurgical Society. PMID- 30434625 TI - Lecture on Aphonia, or Loss of Voice Consequent on Laryngeal Disease, with Illustrative Cases. PMID- 30434628 TI - Current Topics. PMID- 30434627 TI - Western Infirmary. PMID- 30434629 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th May, 1916. PMID- 30434630 TI - The Etiology and Treatment of Gastric Ulcer. PMID- 30434631 TI - Rupture of a Pregnant Diverticulum of the Uterus. PMID- 30434632 TI - A Series of 800 Cases with the Vernon Harcourt Chloroform Inhaler. PMID- 30434633 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd January, 1916. PMID- 30434634 TI - The Neurasthenic Element in Disease. PMID- 30434635 TI - Delay in Breech Presentations from Extension of the Legs. PMID- 30434636 TI - Note on the Treatment of Tuberculous Sinuses. PMID- 30434637 TI - Current Topics. PMID- 30434638 TI - The Aural School-Clinique. PMID- 30434639 TI - Gas Gangrene in the Present War. PMID- 30434640 TI - Notes of Several Cases of Complications of Pregnancy Treated in November and December, 1915. PMID- 30434642 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 25th March, 1916. PMID- 30434641 TI - Current Topics. PMID- 30434643 TI - Pyuria, a Symptom: Its Causes and Diagnosis. PMID- 30434644 TI - John Gibson Fleming, M.D., F.R.S.E., Surgeon and Manager, Glasgow Royal Infirmary. PMID- 30434645 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd April, 1916. PMID- 30434646 TI - Current Topics. PMID- 30434647 TI - Subacute Anterior Poliomyelitis. PMID- 30434648 TI - The Prevention and Treatment of Some Obscure Conditions Complicating Convalescence after Gastro-Enterostomy. PMID- 30434649 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th February, 1916. PMID- 30434650 TI - The Treatment of Drug Addiction. PMID- 30434651 TI - Pyuria, a Symptom: Its Causes and Diagnosis. PMID- 30434652 TI - Current Topics. PMID- 30434653 TI - Nasal Affections and Deafness. PMID- 30434654 TI - Hysterical Stomachs. PMID- 30434655 TI - Current Topics. PMID- 30434656 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th December, 1915. PMID- 30434657 TI - Insects in Relation to Disease. PMID- 30434658 TI - Urine-Testing with Esbach's Albuminometer: Source of Error Discussed. PMID- 30434659 TI - Practical Experience of Some Official and Non-Official New Remedies. PMID- 30434660 TI - Notes of Case of Cerebral Abscess, Subsequent to Orbital Periostitis. PMID- 30434661 TI - Glasgow Pathological and Clinical Society. PMID- 30434662 TI - On a Case of Tuberculosis of the Stomach, and One of Acute Miliary Tuberculosis Depending on Tuberculosis of a Pulmonary Vein, with Remarks on the Pathology of These Conditions. PMID- 30434663 TI - Surgical Experiences. PMID- 30434664 TI - Glasgow Southern Medical Society. PMID- 30434665 TI - Current Topics. PMID- 30434666 TI - The Abuse of Our Medical Charities. PMID- 30434668 TI - Glasgow Pathological and Clinical Society. PMID- 30434667 TI - Observations on the Spinal Cord in the Insane. PMID- 30434670 TI - Medico-Chirurgical Society. PMID- 30434669 TI - Glasgow Pathological and Clinical Society. PMID- 30434671 TI - On Decubitus Acutus (Acute Bed-Sore), with an Unusual Case. PMID- 30434672 TI - Current Topics. PMID- 30434673 TI - Observations on the Spinal Cord in the Insane. PMID- 30434674 TI - From the Medical Side of the Out-Patient Department of the Glasgow Royal Infirmary. PMID- 30434676 TI - A Case of Sub-Diaphragmatic Abscess Occupying Part of the Epigastric and Left Hypochondriac Regions, Accompanied with Pleuritic Effusion of the Left Side. PMID- 30434675 TI - Surgical Experiences. PMID- 30434677 TI - Two Lectures on Syphilitic Diseases of the Upper Air Passages: Their Pathology, Symptoms, and Treatment. With Illustrative Cases: Selected from a Course of Lectures Delivered during the Summer Session, 1886, at the Glasgow Royal Infirmary. PMID- 30434678 TI - Glasgow Fever Hospital. PMID- 30434679 TI - Glasgow Southern Medical Society. PMID- 30434680 TI - Current Topics. PMID- 30434681 TI - Notes from Vienna. PMID- 30434682 TI - Western Infirmary, Glasgow. PMID- 30434683 TI - Observations on the Spinal Cord in the Insane. PMID- 30434684 TI - Original Research in Sanitary Science-The Artificial Cultivation of Vaccine Lymph. PMID- 30434685 TI - Surgical Experiences. PMID- 30434686 TI - Glasgow Southern Medical Society. PMID- 30434687 TI - Glasgow Pathological and Clinical Society. PMID- 30434688 TI - On a Case of Double Uterus and Absence of One Kidney. PMID- 30434689 TI - Medico-Legal Risks Encountered by Medical Practitioners in the Practice of Their Profession. PMID- 30434690 TI - Current Topics. PMID- 30434691 TI - Observations on the Spinal Cord in the Insane. PMID- 30434692 TI - Medico-Chirurgical Society. PMID- 30434693 TI - Injury to Head-Recovery. PMID- 30434694 TI - Notes from Vienna. PMID- 30434695 TI - Correspondence. PMID- 30434696 TI - Current Topics. PMID- 30434697 TI - Pathological and Clinical Society. PMID- 30434698 TI - Observations on the Spinal Cord in the Insane. PMID- 30434699 TI - A Case of Acute Tuberculosis of Brain and Lungs, with Tubercles in the Synovial Membranes of the Joints. Clinical Symptoms Those of Acute Rheumatism. PMID- 30434700 TI - OEsophagotomy for the Removal of a Tooth-Plate. PMID- 30434701 TI - Some Manifestations of Congenital Syphilis. PMID- 30434702 TI - New Preparations, &c. PMID- 30434703 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st November, 1914. PMID- 30434704 TI - The Education of the Semi-Blind. PMID- 30434705 TI - Current Topics. PMID- 30434706 TI - The Operative Treatment of Fractures, with Special Reference to Plating. PMID- 30434707 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 13th June, 1914. PMID- 30434708 TI - Acute Suppurative Appendicitis: Some Conclusions from an Analysis of a Series of 100 Consecutive Cases. PMID- 30434709 TI - The Working of the Midwives Act (England, 1902). PMID- 30434710 TI - Current Topics. PMID- 30434711 TI - New Preparations, &c. PMID- 30434712 TI - Practical Points in Abdominal Surgery, Being the "James Watson Lectures" Delivered before the Royal Faculty of Physicians and Surgeons, 11th and 14th March, 1913. PMID- 30434713 TI - Case of Complete Auriculo-Ventricular Heart-Block. PMID- 30434714 TI - Current Topics. PMID- 30434716 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434715 TI - Series of Six Cases of Lumbar Nephrectomy and One Case of Resection for Renal Varix. PMID- 30434718 TI - New Preparations, &c. PMID- 30434717 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 15th August, 1914. PMID- 30434719 TI - New Medical Electrical Department of the Glasgow Royal Infirmary. PMID- 30434720 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 19th September, 1914. PMID- 30434721 TI - Current Topics. PMID- 30434722 TI - Practical Points in Abdominal Surgery, Being the "James Watson Lectures" Delivered before the Royal Faculty of Physicians and Surgeons, 11th and 14th March, 1913. PMID- 30434723 TI - The Use of Neo-Salvarsan in Mental Deficiency. PMID- 30434724 TI - Scottish Otological and Laryngological Society. PMID- 30434725 TI - Current Topics. PMID- 30434726 TI - Malignant Ganglio-Neuroma of Left Suprarenal. PMID- 30434727 TI - Gangrenous Appendicitis with Coprolith, Abscess, Septic Peritonitis, Intestinal Obstruction, Rupture of Intestine, and Fistula-Complete Recovery-And Remarks on Volvulus. PMID- 30434729 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 11th July, 1914. PMID- 30434728 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434730 TI - The Western Medical School, Glasgow. PMID- 30434731 TI - Round-Celled Sarcoma of the Scalp of Two Weeks' Duration, Following an Injury. PMID- 30434732 TI - New Preparations, &c. PMID- 30434733 TI - Six Cases of Disease of the Lower Abdominal Organs, Some of Which Simulated Tumours of the Uterus and Andexa. PMID- 30434734 TI - Two Cases Illustrative of Splenic Anaemia and Splenectomy. PMID- 30434735 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 24th October, 1914. PMID- 30434736 TI - New Preparations, &c. PMID- 30434737 TI - Practical Points in Abdominal Surgery, Being the "James Watson Lectures" Delivered before the Royal Faculty of Physicians and Surgeons, 11th and 14th March, 1913. PMID- 30434738 TI - Current Topics. PMID- 30434739 TI - Current Topics. PMID- 30434740 TI - Glasgow Western Infirmary. PMID- 30434741 TI - Case of Cystic Kidney in Which Nephrectomy Was Performed. PMID- 30434742 TI - Pathological and Clinical Society. PMID- 30434743 TI - Medico-Chirurgical Society. PMID- 30434744 TI - Injuries to the Eyeball. PMID- 30434745 TI - Amputation through the Medio-Tarsal Articulation. PMID- 30434746 TI - Malformations of the Parturient Canal. PMID- 30434747 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434748 TI - Current Topics. PMID- 30434749 TI - The Influence of Hereditary Predisposition in Epilepsy. PMID- 30434750 TI - A Case of Congenital Stenosis of the Pylorus in an Infant. PMID- 30434751 TI - Amputation through the Foot. PMID- 30434752 TI - A Case of Retinitis Albuminurica and a Case of Opaque Nerve Fibres. PMID- 30434753 TI - Pathological and Clinical Society. PMID- 30434754 TI - A Case of Cicatricial Contraction of the Pylorus. PMID- 30434755 TI - Correspondence. PMID- 30434756 TI - Two Cases of Total Loss of Hearing in Both Ears, Consequent upon Mumps, with Observations. PMID- 30434757 TI - Current Topics. PMID- 30434758 TI - Pathological and Clinical Society. PMID- 30434760 TI - Medico-Chirurgical Society. PMID- 30434759 TI - Glasgow Royal Infirmary. PMID- 30434762 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434761 TI - Anomalous Forms of Measles and Scarlet Fever: Being the Introduction to a Discussion in the Medico-Chirurgical Society on 7th December, 1888. PMID- 30434763 TI - Some Fijian Drugs and Methods of Treatment. PMID- 30434764 TI - A Case of Movable Kidney with a Peculiar History. PMID- 30434765 TI - Current Topics. PMID- 30434766 TI - Collation of Recent Authorities on the Infective and the Incubation Period in Contagious Diseases, with Special Reference to the Exclusion of Such Cases from Day Schools. PMID- 30434767 TI - A Lecture on the Duties and Training of the Medical Nurse: Being the First of a Course of Lectures Delivered during the past Winter (1888-89) to the Nurses of the Glasgow Hospital for Sick Children. PMID- 30434768 TI - Pathological and Clinical Society. PMID- 30434770 TI - Medico-Chirurgical Society. PMID- 30434769 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434771 TI - Notes of Surgical Cases. PMID- 30434772 TI - A Case of Retinitis Albuminurica with Pigmentary Changes. PMID- 30434773 TI - Two Cases of Brain Disease. PMID- 30434774 TI - Breakdown of the Present Hospital System-The Freedom of Hospitals Claimed. PMID- 30434775 TI - On the So-Called "Breakdown of the Hospital System." PMID- 30434776 TI - Medico-Chirurgical Society. PMID- 30434777 TI - Current Topics. PMID- 30434778 TI - A Case of Atrophy of the Right Hemisphere in an Epileptic. PMID- 30434779 TI - Case of Dislocation of the Wrist. PMID- 30434780 TI - Are Hospitals a Failure? PMID- 30434781 TI - Case of "Fungus Haematodes." PMID- 30434782 TI - The Breakdown of the Hospital System-Remedies Suggested. PMID- 30434783 TI - Pathological and Clinical Society. PMID- 30434784 TI - On Maloja as a Health Resort for Consumptives and Others. PMID- 30434785 TI - Pathological and Clinical Society. PMID- 30434786 TI - A New Needle Holder. PMID- 30434787 TI - Current Topics. PMID- 30434788 TI - Observations on Some of the Operations Absolutely Necessary for the Prevention of Death: Being the Presidential Address to the Western and Midland Medical Association. PMID- 30434789 TI - Medico-Chirurgical Society. PMID- 30434790 TI - A Case of Cystic Disease of the Kidney Diagnosed during Life. PMID- 30434791 TI - The Etiology of Strabismus. PMID- 30434792 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434793 TI - Observations on Seven Cases of Cancer of the Larynx: These Cases Were Shown at the Glasgow Pathological and Clinical Society. PMID- 30434794 TI - Homoeopathy in America. PMID- 30434795 TI - Medico-Chirurgical Society. PMID- 30434796 TI - Current Topics. PMID- 30434797 TI - Glasgow Southern Medical Society. PMID- 30434798 TI - Pathological and Clinical Society. PMID- 30434799 TI - Paralysis after Delivery. PMID- 30434800 TI - Current Topics. PMID- 30434801 TI - Anderson's College. PMID- 30434803 TI - The Royal Infirmary School of Medicine. PMID- 30434802 TI - Treatment of Third Stage of Labour. PMID- 30434804 TI - Western Medical School. PMID- 30434806 TI - Medico-Chirurgical Society. PMID- 30434805 TI - Faculty of Physicians and Surgeons of Glasgow. PMID- 30434807 TI - Two Cases of Sprue (Psilosis, Dr. Thin). PMID- 30434808 TI - Brief Remarks Introductory to a Course of Clinical Instruction in Infectious Diseases at "City of Glasgow Fever Hospital," Belvidere. PMID- 30434809 TI - The Glasgow Royal Infirmary. PMID- 30434810 TI - Some Noteworthy Cases. PMID- 30434811 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434812 TI - Current Topics. PMID- 30434813 TI - Pathological and Clinical Society. PMID- 30434814 TI - The University of Glasgow. PMID- 30434815 TI - Western Infirmary. PMID- 30434816 TI - Glasgow Southern Medical Society. PMID- 30434817 TI - A Case of Spontaneous Rupture of the Heart; Necropsy and Remarks. PMID- 30434818 TI - Medico-Chirurgical Society. PMID- 30434819 TI - Pathological and Clinical Society. PMID- 30434820 TI - Cerebro-Spinal Fever-Report of Some Additional Cases. PMID- 30434821 TI - Current Topics. PMID- 30434823 TI - Glasgow Southern Medical Society. PMID- 30434822 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434824 TI - Correspondence. PMID- 30434826 TI - Medico-Chirurgical Society. PMID- 30434825 TI - Correspondence. PMID- 30434827 TI - Case of Aphasia with Repeated Localised Convulsions of the Tongue and Right Cheek. PMID- 30434828 TI - On a Case of Syphilitic Disease of the Spinal Cord. PMID- 30434830 TI - Current Topics. PMID- 30434829 TI - Medico-Chirurgical Society. PMID- 30434831 TI - Some Surgical Cases. PMID- 30434832 TI - Pathological and Clinical Society. PMID- 30434833 TI - Saccharine. PMID- 30434834 TI - On the Use of Acetanilid (Antifebrin) in Typhoid Fever. PMID- 30434835 TI - On the Treatment of Scarlet Fever: Being a Paper Introductory to a Discussion in the Southern Medical Society, 23rd February, 1888. PMID- 30434836 TI - Correspondence. PMID- 30434837 TI - Glasgow Southern Medical Society. PMID- 30434838 TI - On the Extraction of Stone from the Bladder, with Seven Successful Cases : Being an Introduction to a Professional Conversation on "Lithoplatomy," at the Southern Medical Society, January, 1888. PMID- 30434839 TI - Current Topics. PMID- 30434840 TI - Our Erect Attitude: An Essay. PMID- 30434841 TI - Medico-Chirurgical Society. PMID- 30434842 TI - Notes of a Case of Acute Inversion of the Uterus. PMID- 30434843 TI - Belvidere Fever Hospital. PMID- 30434844 TI - A Case of Primary Cancer of the Left Kidney, with Secondary Formations in the Pleura and Lungs. With an Account of the Pathology of the Case and Remarks. PMID- 30434845 TI - Clinical Memoranda from the Medical Side of the Glasgow Royal Infirmary: The Specimens from These Cases Were Shown at the Glasgow Pathological and Clinical Society, on the 15th November, 1887. PMID- 30434847 TI - Pathological and Clinical Society. PMID- 30434846 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434848 TI - Glasgow Southern Medical Society. PMID- 30434850 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th October, 1917. PMID- 30434849 TI - On Scrofulous Neck and Its Surgical Treatment, with Illustrative Cases. PMID- 30434851 TI - Current Topics. PMID- 30434852 TI - The Work of a Unit of the Scottish Women's Hospitals in France, Serbia, and Salonica. PMID- 30434853 TI - Uterine Fibroids: Notes on Their Diagnosis, Complications, and Treatment Based on the Observation of 150 Cases. PMID- 30434854 TI - New Preparations, &c. PMID- 30434855 TI - Inguinal Hernia: Some Comments on Present Views. PMID- 30434856 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th August, 1917. PMID- 30434857 TI - A Short Note on Rectal Crises of Non-Tabetic Origin. PMID- 30434858 TI - Current Topics. PMID- 30434860 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd March, 1919. PMID- 30434859 TI - Note on Plastic Meatotomy. PMID- 30434861 TI - Current Topics. PMID- 30434862 TI - The Influence of Respiration on Intra-Abdominal Pressure: A Surgical Note. PMID- 30434863 TI - Diagnostic Mechano-Therapeutics. PMID- 30434864 TI - Cases Simulating Renal Calculus. PMID- 30434865 TI - Current Topics. PMID- 30434866 TI - Two Cases of Friedreich's Ataxia in Adolescents. PMID- 30434867 TI - Two Interesting Cases in Obstetrics. PMID- 30434868 TI - On Dissolving Senile Cataract in the Early Stages. PMID- 30434869 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd September, 1917. PMID- 30434870 TI - Unusual Distribution of Secondary Growths in a Case of Cancer of the Female Mamma. PMID- 30434871 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th November, 1911. PMID- 30434873 TI - Current Topics. PMID- 30434872 TI - On the Development of Acidity in Cow's Milk and Its Relation to Time and Temperature. PMID- 30434874 TI - Proptosis: A Clinical Study. PMID- 30434875 TI - Current Topics. PMID- 30434876 TI - An Inquiry into the Limits of Hearing. PMID- 30434877 TI - Clinical Observations on Epileptic Insanity. PMID- 30434878 TI - Fatal Case of Obstruction of the Bowels. PMID- 30434879 TI - Cholera and Its Fostering Conditions within the Endemic Area. PMID- 30434880 TI - A Case of Remittent Fever in a Child Aged Two Years and Nine Months, with an Idiosyncrasy Towards Quinine. PMID- 30434881 TI - A Review of the Complications of Influenza: With Notes on Their Treatment: Also Notes on Their Bacteriology. PMID- 30434883 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 26th April, 1919. PMID- 30434882 TI - Some Cases of Gunshot Injury to the Head. PMID- 30434884 TI - Current Topics. PMID- 30434885 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th May, 1919. PMID- 30434886 TI - An Investigation into the Phenomena of "Serum Disease": The Relation between Its Various Forms and the Proteins of Horse-Serum. PMID- 30434888 TI - Current Topics. PMID- 30434887 TI - The Treatment of Syphilis. PMID- 30434889 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th November, 1917. PMID- 30434890 TI - Intra-Tracheal Anaesthesia. PMID- 30434891 TI - Current Topics. PMID- 30434893 TI - Current Topics. PMID- 30434892 TI - A Theory of the Etiology of Cancer. PMID- 30434895 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st December, 1918. PMID- 30434894 TI - Remarks on Moro's Percutaneous Inunction Test, and Von Pirquet's Cuti-Reaction Test: With Cases in Which They Were Applied. PMID- 30434896 TI - A Note on the History of Influenza. PMID- 30434898 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd February, 1919. PMID- 30434897 TI - Hernia across the Lesser Sac of the Peritoneum. PMID- 30434900 TI - Current Topics. PMID- 30434899 TI - Rickets: A Historical Note. PMID- 30434901 TI - New Preparations, &c. PMID- 30434903 TI - British Hospital Work in Serbia: Diary of a Member of Dr. Alice Hutchison's Unit. PMID- 30434902 TI - The Induction of Artificial Pneumothorax and Its Value in the Treatment of Pulmonary Tuberculosis. PMID- 30434904 TI - Current Topics. PMID- 30434905 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 28th July, 1917. PMID- 30434906 TI - The Influence of Cerebral Symptoms on the Prognosis in Pneumonia in Childhood. PMID- 30434907 TI - Current Topics. PMID- 30434908 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th January, 1919. PMID- 30434909 TI - The Diagnosis and Treatment of Syphilis. PMID- 30434910 TI - A Study in Self-Revelation. PMID- 30434911 TI - Current Topics. PMID- 30434912 TI - A Short Review of the Public Health Administration in Glasgow. PMID- 30434913 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd September, 1911. PMID- 30434914 TI - Diphtheritic Paralysis. PMID- 30434915 TI - Ulcerating Gummatous Syphilide Treated by "606" in a Congenital Syphilitic. PMID- 30434916 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434917 TI - The Origin and Development of the Glasgow School of Medicine: From Maister Peter Lowe to Sir William T. Gairdner. PMID- 30434918 TI - Current Topics. PMID- 30434919 TI - The Pathological Institute of a General Hospital. PMID- 30434920 TI - Suicide from Cut-Throat and Drowning. PMID- 30434921 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434922 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st October, 1911. PMID- 30434923 TI - New Preparations, &c. PMID- 30434924 TI - British Hospital Work in Serbia: Diary of a Member of Dr. Alice Hutchison's Unit. PMID- 30434925 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd June, 1917. PMID- 30434926 TI - Current Topics. PMID- 30434927 TI - Two Cases of Sub-Dural Haemorrhage Due to Injury without Fracture of the Skull. PMID- 30434928 TI - Acute Cystitis: A Word to the Practitioner. PMID- 30434929 TI - Injury of the Spinal Cord Due to Rupture of an Intervertebral Disc during Muscular Effort. PMID- 30434930 TI - Scottish Otological and Laryngological Society. PMID- 30434931 TI - New Preparations, &c. PMID- 30434932 TI - Glasgow Eastern Medical Society. PMID- 30434933 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 20th June, 1911. PMID- 30434934 TI - Case in Which "Broadbent's Sign" Was Present, Though No Pericardial Adhesions Existed. PMID- 30434935 TI - Current Topics. PMID- 30434936 TI - Case of Acute Pulmonary OEdema: With a Pathological Report. PMID- 30434937 TI - The Treatment of Phthisis by Means of the Intravenous Injection of an Ethereal Solution of Iodoform. PMID- 30434938 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434940 TI - New Preparations, &c. PMID- 30434939 TI - Some Abdominal Emergencies. PMID- 30434941 TI - Carcinoma of the Male Mammary Gland. PMID- 30434942 TI - Current Topics. PMID- 30434943 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 26th August, 1911. PMID- 30434944 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434945 TI - Inflammatory Affections of the Fallopian Tubes and Ovaries. PMID- 30434947 TI - Current Topics. PMID- 30434946 TI - A Case of Aneurism of the Aorta Perforating the Pulmonary Artery. PMID- 30434948 TI - Clinical Memoranda, from the Out-Patient Department of the Glasgow Royal Infirmary. PMID- 30434949 TI - Zulu Witch Doctors and Experiences Amongst the Zulus. PMID- 30434950 TI - Two Cases of Complete Laryngeal Stenosis Produced by Wounds of the Larynx in Attempted Suicides, Treated Successfully by Means of Tupelo Dilators; Also a Case of Syphilitic Stenosis Treated in the Same Way. PMID- 30434951 TI - On Drainage Tubes. PMID- 30434953 TI - Medico-Chirurgical Society of Glasgow. PMID- 30434952 TI - New Preparations, &c. PMID- 30434955 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd July, 1911. PMID- 30434954 TI - Case of Peripheral Neuritis of Obscure Origin, with Secondary Changes in the Spinal Cord. PMID- 30434956 TI - A Short Review of the Public Health Administration in Glasgow. PMID- 30434957 TI - Current Topics. PMID- 30434958 TI - The Treatment of Inoperable Carcinoma of the Female Mamma. PMID- 30434959 TI - Case of Bulbar Paralysis, with Affection of Other Parts of the Nervous System. PMID- 30434961 TI - A Suggestion Towards the Improvement of the Medical Curriculum. PMID- 30434960 TI - A Case of Diffuse, Colloid, Cylinder-Celled Epithelioma of the Stomach, Originating around the Entrance of the OEsophagus, with Secondary Tumours in the Lungs and Other Parts, but Not in the Liver. PMID- 30434962 TI - Breakdown of the Present Hospital System-The Freedom of the Hospital Claimed. PMID- 30434963 TI - A Case of Sclerosis of the Spinal Cord: Case Shown at the Meeting of the Medico Chirurgical Society, on 2nd November, 1888. PMID- 30434964 TI - Pathological and Clinical Society. PMID- 30434965 TI - City of Glasgow Fever Hospital, Belvidere. PMID- 30434966 TI - Medico-Chirurgical Society. PMID- 30434967 TI - The International Otological Congress in Brussels. PMID- 30434968 TI - Raynaud's Disease, or Local Asphyxia and Symmetrical Gangrene of the Extremities. PMID- 30434969 TI - Current Topics. PMID- 30434970 TI - Pathological and Clinical Society. PMID- 30434971 TI - Current Topics. PMID- 30434972 TI - Medico-Chirurgical Society. PMID- 30434973 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30434974 TI - Breakdown of the Present Hospital System-The Freedom of the Hospital Claimed. PMID- 30434975 TI - Current Topics. PMID- 30434976 TI - Notes of Visit to Homburg. PMID- 30434978 TI - Dispensaries. PMID- 30434977 TI - The Glasgow Medical Journal. PMID- 30434979 TI - The Sanitary Journal. PMID- 30434980 TI - Ambulance Association. PMID- 30434981 TI - The Cleansing Department. PMID- 30434982 TI - Convalescent Homes and Homes for Incurables. PMID- 30434983 TI - Pathological and Clinical Society. PMID- 30434985 TI - Institutions for the Training of Nurses. PMID- 30434984 TI - The Sanitary Department. PMID- 30434987 TI - Glasgow Police District Surgeons. PMID- 30434986 TI - Medical Societies. PMID- 30434988 TI - Institutions for the Blind, and the Deaf and Dumb. PMID- 30434989 TI - An Inquiry into the Limits of Hearing. PMID- 30434990 TI - Glasgow Southern Medical Society. PMID- 30434991 TI - Barony Parish Hospital, Barnhill. PMID- 30434992 TI - Govan Poorhouse. PMID- 30434993 TI - The Glasgow Ear Hospital. PMID- 30434994 TI - Glasgow District Asylum: Bothwell. PMID- 30434995 TI - Medico-Chirurgical Society. PMID- 30434996 TI - City Parochial Asylum. PMID- 30434997 TI - Barony Parochial Asylum, Woodilee, Lenzie. PMID- 30434998 TI - Govan Parochial Asylum. PMID- 30435000 TI - Glasgow Ophthalmic Institution for Diseases and Injuries of the Eye. PMID- 30434999 TI - Phenacetine as an Antipyretic. PMID- 30435001 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435003 TI - City of Glasgow Fever and Small-Pox Hospitals, Belvidere. PMID- 30435002 TI - Glasgow Royal Asylum, Gartnavel. PMID- 30435005 TI - The Victoria Infirmary of Glasgow. PMID- 30435004 TI - Joint Hospital, Knightswood. PMID- 30435006 TI - Current Topics. PMID- 30435007 TI - A Case of Congenital Disease of the Heart: Case Shown at the Medico-Chirurgical Society, 4th May, 1888. PMID- 30435008 TI - Glasgow Western Infirmary. PMID- 30435009 TI - The Glasgow Eye Infirmary. PMID- 30435010 TI - Glasgow Hospital for Sick Children. PMID- 30435011 TI - The Town's Hospital or City Poorhouse. PMID- 30435012 TI - The Lock Hospital. PMID- 30435013 TI - Combination Fever Hospital, Govan. PMID- 30435014 TI - The Glasgow Lying-In Hospital. PMID- 30435015 TI - Sores, Analogous to Veld Sores and Barcoo Rot, Appearing among Soldiers Working in Blue Clay and in Chalk. PMID- 30435016 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30435017 TI - With the 1/1st Lowland Field Ambulance in Gallipoli. PMID- 30435018 TI - Current Topics. PMID- 30435019 TI - An Investigation into the Phenomena of "Serum Disease": The Relation between Its Various Forms and the Proteins of Horse-Serum. PMID- 30435020 TI - Current Topics. PMID- 30435022 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30435021 TI - Resection in Sliding Hernia. PMID- 30435024 TI - Spasmodic Stricture of Urethra. PMID- 30435023 TI - Gunshot Wounds, with Deaths and Disabilities Resulting Therefrom, as Seen in a Home Hospital. PMID- 30435025 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30435026 TI - An Investigation into the Phenomena of "Serum Disease": The Relation between Its Various Forms and the Proteins of Horse-Serum. PMID- 30435027 TI - With the 1/1st Lowland Field Ambulance in Gallipoli. PMID- 30435028 TI - Current Topics. PMID- 30435029 TI - Current Topics. PMID- 30435030 TI - With the 1/1st Lowland Field Ambulance in Gallipoli. PMID- 30435031 TI - Syphilis of the Circulatory System. PMID- 30435032 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30435033 TI - The Role of Fat in the Etiology of Infantile Marasmus. PMID- 30435034 TI - With the 1/1st Lowland Field Ambulance in Gallipoli. PMID- 30435036 TI - Current Topics. PMID- 30435037 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30435035 TI - An Investigation into the Phenomena of "Serum Disease": The Relation between Its Various Forms and the Proteins of Horse-Serum. PMID- 30435039 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st June, 1919. PMID- 30435038 TI - The Aftermath of Malaria and Dysentery. PMID- 30435040 TI - With the 1/1st Lowland Field Ambulance in Gallipoli. PMID- 30435041 TI - Note on Certain Relics of William Hunter. PMID- 30435042 TI - Current Topics. PMID- 30435043 TI - Syphilis of the Nervous System and Its Treatment. PMID- 30435044 TI - An Investigation into the Phenomena of "Serum Disease": The Relation between Its Various Forms and the Proteins of Horse-Serum. PMID- 30435045 TI - Current Topics. PMID- 30435046 TI - Cessation of Vertiginous Attacks Following Intra-Nasal Treatment. PMID- 30435047 TI - Aneurysm of the Hepatic Artery-Rupture of Liver-Periarteritis Nodosa. PMID- 30435048 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st October, 1916. PMID- 30435049 TI - Some Eye Symptoms and Their Interpretation. PMID- 30435050 TI - Current Topics. PMID- 30435051 TI - New Preparations, &c. PMID- 30435052 TI - Disease and Domesticity. PMID- 30435054 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd July, 1916. PMID- 30435053 TI - Some Varieties of Congenital Heart Disease-Patent Foramen Ovale-Patent Interventricular Septum-Pulmonic Stenosis-Patent Ductus Arteriosus. PMID- 30435055 TI - Report of a Case of Hernia into the Para-Duodenal Fossa. PMID- 30435057 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th June, 1916. PMID- 30435056 TI - An Experimental Study of Extirpation and Transplantation of the Thymus. PMID- 30435058 TI - Some Varieties of Congenital Heart Disease-Patent Foramen Ovale-Patent Interventricular Septum-Pulmonic Stenosis-Patent Ductus Arteriosus. PMID- 30435059 TI - The Etiology and Treatment of Gastric Ulcer. PMID- 30435060 TI - Current Topics. PMID- 30435061 TI - Some Observations on Advanced Pulmonary Tuberculosis. PMID- 30435063 TI - Current Topics. PMID- 30435062 TI - Outdoor Occupations for Tuberculous Cases. PMID- 30435065 TI - New Preparations, &c. PMID- 30435064 TI - Liver Abscess Amongst Our Soldiers. PMID- 30435066 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 25th November, 1916. PMID- 30435068 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd September, 1916. PMID- 30435067 TI - The Soldier's Heart. PMID- 30435070 TI - Current Topics. PMID- 30435069 TI - The Reduction of Myopia in Children of School Age. PMID- 30435071 TI - Case of Ectopic Pregnancy Which Had Gone beyond Full Time. PMID- 30435073 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 26th August, 1916. PMID- 30435072 TI - Ulceration of the Small Intestine with Formation of Indol Derivatives and Indigo Uria. PMID- 30435074 TI - Some Varieties of Congenital Heart Disease-Patent Foramen Ovale-Patent Interventricular Septum-Pulmonic Stenosis-Patent Ductus Arteriosus. PMID- 30435075 TI - Current Topics. PMID- 30435076 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th December, 1917. PMID- 30435077 TI - An Explanation of Colour and Colour-Vision. PMID- 30435078 TI - A Most Unusual Case of Pathological Fracture -Myeloid Sarcoma and Cystic Disease of Bone. PMID- 30435080 TI - Current Topics. PMID- 30435079 TI - Obstructive Alimentary Toxaemia. PMID- 30435081 TI - Case of Metastatic Cancer of the Bone-Marrow without Erythroblastic Reaction. PMID- 30435082 TI - Current Topics. PMID- 30435083 TI - The Ante-Natal Treatment of Congenital Syphilis with Salvarsan. PMID- 30435085 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th January, 1918. PMID- 30435084 TI - Origin and Progress of the Glasgow and West of Scotland Co-Operation of Trained Nurses. PMID- 30435086 TI - New Preparations, &c. PMID- 30435087 TI - New Preparations, &c. PMID- 30435088 TI - Current Topics. PMID- 30435090 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd February, 1918. PMID- 30435089 TI - A General Survey of Five Years' Work in a Sanatorium. PMID- 30435091 TI - The Causes of Infantile Mortality. PMID- 30435092 TI - Rickets in Its Relationship to Housing. PMID- 30435093 TI - Current Topics. PMID- 30435094 TI - An Unusual Case of Haematemesis and Hyperpyrexia, Probably of Hysterical Origin. PMID- 30435095 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 27th April, 1918. PMID- 30435096 TI - Uterine Fibroids, or Myomata of the Uterus Complicating Pregnancy, Labour, and the Puerperium. PMID- 30435099 TI - Current Topics. PMID- 30435098 TI - New Preparations, &c. PMID- 30435097 TI - Case of Partial Hereditary Anonychia. PMID- 30435100 TI - Sympathetic Ophthalmia: Some Observations on Its Etiology. PMID- 30435101 TI - Anaesthesia in General Practice. PMID- 30435102 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 30th March, 1918. PMID- 30435103 TI - Soamin in the Treatment of Bronchial Asthma. PMID- 30435105 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th May, 1918. PMID- 30435104 TI - Post-Malarial Severe Anaemia. PMID- 30435106 TI - Current Topics. PMID- 30435107 TI - Private Practice. PMID- 30435108 TI - Current Topics. PMID- 30435109 TI - Some Less Common Causes of Menorrhagia, with Illustrative Cases. PMID- 30435110 TI - On Hydrophobia, and a Visit to the Pasteur Institute, Paris. PMID- 30435112 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435111 TI - August Martin and Ovariotomy. PMID- 30435113 TI - Madura Foot in Its Initial Stage: Case No. II. PMID- 30435115 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435114 TI - Correspondence. PMID- 30435117 TI - On the Pathology of Acute and Chronic Bronchitis and Bronchial Asthma. PMID- 30435116 TI - Two Cases of Athetosis. PMID- 30435118 TI - Clinical Lecture upon Cough and Disturbance of Respiration, as Indications of Disease of the Upper Air Passages, with a Few Illustrative Cases. PMID- 30435119 TI - On a Case of Occipito-Atloid Disease. PMID- 30435120 TI - Current Topics. PMID- 30435122 TI - Current Topics. PMID- 30435121 TI - Is It Influenza? A Brief Reference to Twenty Suspicious Cases. PMID- 30435123 TI - The Action of Solutions of Bichloride of Mercury upon Different Metals, with a View to Testing the Relative Value of Waste Pipes Used for Drains, &c., in Hospitals and Other Such Institutions. PMID- 30435124 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435125 TI - Framboesia or "Coko." PMID- 30435126 TI - Glasgow Southern Medical Society. PMID- 30435127 TI - The Examination of the Eye. PMID- 30435128 TI - Private Practice. PMID- 30435129 TI - A Case of Fissure of the Abdomen, Ectopia of the Viscera, and Extroversion of the Bladder. PMID- 30435130 TI - Influenza. PMID- 30435131 TI - Notes on Influenza. PMID- 30435133 TI - Inoculation, with Suggestions for Its Further Application in Medicine, Especially in Mitigating the Severity of Measles. PMID- 30435132 TI - The Examination of the Eye. PMID- 30435134 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435135 TI - On Influenza in Jersey. PMID- 30435136 TI - Current Topics. PMID- 30435138 TI - Glasgow Pathological and Clinical Society. PMID- 30435137 TI - The Influenza Epidemic of 1890 at H.M. Convict Prison, Borstal, Rochester. PMID- 30435139 TI - Notes on Skin Diseases. PMID- 30435140 TI - Influenza in Guernsey, 1890. PMID- 30435141 TI - Current Topics. PMID- 30435142 TI - Some Remarks upon Stricture of the Urethra. PMID- 30435143 TI - Medico-Chirurgical Society. PMID- 30435144 TI - Account of a MS. Volume, by William Clift, Relating to John Hunter's Household and Estate; and to Sir Everard Home's Publications: In the Library of the Faculty of Physicians and Surgeons, Glasgow. PMID- 30435145 TI - Glasgow Southern Medical Society. PMID- 30435146 TI - The Examination of the Eye. PMID- 30435147 TI - On the Pathology of Acute and Chronic Bronchitis and Bronchial Asthma. PMID- 30435148 TI - The Bacillus of Tetanus. PMID- 30435149 TI - Pathological and Clinical Society. PMID- 30435150 TI - An Inflammatory Lesion in the Kidneys of a Ram, with Streptococci in the Glomeruli and Tubules. PMID- 30435152 TI - Medico-Chirurgical Society. PMID- 30435151 TI - On Congenital Dislocation of the Hips. PMID- 30435153 TI - The Russian Epidemic. PMID- 30435154 TI - Glasgow Southern Medical Society. PMID- 30435155 TI - Some Obscure Causes of Sudden Death Revealed by Post-Mortem Examinations in Medico Legal Investigations and in Private Practice. PMID- 30435156 TI - Current Topics. PMID- 30435157 TI - On the Pathology of Acute and Chronic Bronchitis and Bronchial Asthma. PMID- 30435159 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 24th January, 1920. PMID- 30435158 TI - The Royal Medico-Chirurgical Society of Glasgow: Centenary Celebration. PMID- 30435160 TI - Current Topics. PMID- 30435162 TI - Sores, Analogous to Veld Sores and Barcoo Rot, Appearing among Soldiers Working in Blue Clay and in Chalk. PMID- 30435161 TI - Is Fat Starvation a Causal Factor in the Production of Rickets? PMID- 30435163 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th December, 1919. PMID- 30435164 TI - Prenatal Tuberculosis. PMID- 30435166 TI - Current Topics. PMID- 30435165 TI - New Preparations, &c. PMID- 30435167 TI - The Repair, by Bone Graft, of Gaps in the Skull Due to Congenital Deficiency, Injury, or Operation. PMID- 30435168 TI - "Rhumatisme Tuberculeux," or Tubercular Rheumatism. PMID- 30435169 TI - Two Cases of Embolic Aneurysm of Peripheral Arteries Complicating Ulcerative Endocarditis. PMID- 30435170 TI - Some Septic Cases. PMID- 30435171 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th May, 1920. PMID- 30435172 TI - Post-Graduate Medical Teaching: The Position in Glasgow. PMID- 30435174 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th April, 1920. PMID- 30435173 TI - Current Topics. PMID- 30435175 TI - Penetrating Gunshot Wounds of the Chest. PMID- 30435176 TI - The Fatality of Peptic Ulcer, and the Importance of Early Diagnosis. PMID- 30435177 TI - Personal Experiences of the Ocular Sequelae of Malaria. PMID- 30435178 TI - Current Topics. PMID- 30435179 TI - The Practical Significance of Attention to Detail in Abdominal Operations. PMID- 30435180 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st February, 1920. PMID- 30435181 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435182 TI - Chiefly Concerning Dr. Dover of Powder Fame. PMID- 30435183 TI - Current Topics. PMID- 30435184 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th March, 1920. PMID- 30435185 TI - Report on the Work of the Ophthalmic Department of 3rd Scottish General Hospital, Glasgow, during the Period from 27th May, 1915, to 1st February, 1919. PMID- 30435187 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435186 TI - Note on a Case of Diffuse Symmetrical Scleroderma. PMID- 30435189 TI - War Pensions. PMID- 30435188 TI - On "Concentrating" and "Centrifugal" Vibrations. PMID- 30435190 TI - A Method for Test-Meals. PMID- 30435191 TI - The Digestion and Absorption of Fats in a Case of Congenital Atresia of the Bile Ducts. PMID- 30435192 TI - Psychotherapy in General Practice. PMID- 30435194 TI - Current Topics. PMID- 30435193 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 31st July, 1920. PMID- 30435195 TI - Current Topics. PMID- 30435197 TI - Lethargic Encephalitis: A Clinical Lecture. PMID- 30435196 TI - Infectivity in Acquired Syphilis, with Special Reference to the Wassermann Reaction: The Bearing on Administrative Control of Treatment. PMID- 30435199 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th June, 1920. PMID- 30435198 TI - The Surgical Service of the Salonika Army. PMID- 30435200 TI - Preventive Mastoidotomy. PMID- 30435203 TI - Current Topics. PMID- 30435201 TI - Correspondence. PMID- 30435202 TI - Physiology: The Institutes of Medicine. PMID- 30435204 TI - Correspondence. PMID- 30435205 TI - Scurvy among Adults in Glasgow. PMID- 30435206 TI - A Few Diagnostic Hints. PMID- 30435207 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th November, 1920. PMID- 30435208 TI - The Tonsil and Its Function. PMID- 30435209 TI - Current Topics. PMID- 30435210 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 28th August, 1920. PMID- 30435212 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435211 TI - Medicine in Scotland in the Early Part of the Eighteenth Century. PMID- 30435213 TI - Practical Points in the Diagnosis of Pulmonary Tuberculosis, with Special Reference to Inspection. PMID- 30435214 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435215 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd October, 1920. PMID- 30435217 TI - Current Topics. PMID- 30435216 TI - The Defects of Medical Practice, Education, and Research. PMID- 30435218 TI - The Basal Ganglia: Their Functions and Diseases. PMID- 30435219 TI - Note on Recent Work on Auricular Flutter and Auricular Fibrillation. PMID- 30435220 TI - The Bergonie Chair: An Apparatus for Producing a Painless, Alternating, Interrupted Electrical Current. PMID- 30435221 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435223 TI - Current Topics. PMID- 30435222 TI - An Undescribed Condition of Infancy and Its Treatment. PMID- 30435225 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th September, 1920. PMID- 30435224 TI - A Plea for the Early Recognition of Syphilis. PMID- 30435226 TI - Case of Ischaemic Contracture of Fore-Arm, Occurring after Fracture of Both Bones of the Left Fore-Arm; Treated by Manipulation and Splinting. PMID- 30435227 TI - Abnormal Enlargement of Foetal Abdomen, with Absent Rectum and Anus, and Enlarged Distended Bladder. PMID- 30435228 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435229 TI - Case of Large Uterine Myomata Characterised by Profuse Menorrhagia Ceasing at the Menopause-Death Subsequently from an Intra-Thoracic Cancerous Tumour. PMID- 30435230 TI - A Case of Hodgkin's Disease Associated with Amyloid Disease, and Showing Absorption of Amyloid Substance in the Spleen. PMID- 30435232 TI - Current Topics. PMID- 30435231 TI - Clinical Memoranda, from the Out-Patient Room of the Glasgow Royal Infirmary. PMID- 30435233 TI - A Case of Gastrostomy for Malignant Stricture of OEsophagus. PMID- 30435235 TI - City of Glasgow Fever Hospital, Belvidere. PMID- 30435237 TI - Current Topics. PMID- 30435236 TI - Notes from the Annual Meeting of the British Medical Association at Leeds, August, 1889. PMID- 30435234 TI - On Two Cases of Diabetes Associated with Lipaemia. PMID- 30435238 TI - Some Causes of Preventible Disease. PMID- 30435239 TI - Notes of Six Cases of Malignant Disease of the Alimentary Canal, under the Care of Professor M'Call Anderson, with Some Statistics of Similar Cases in the Western Infirmary, Glasgow. PMID- 30435240 TI - On a Case of Unilocular Ovarian Cyst. PMID- 30435242 TI - Pathological and Clinical Society. PMID- 30435241 TI - Two Cases of Healed Tubercular Peritonitis, One of Them Resulting in Fatal Obstruction of the Intestine. PMID- 30435243 TI - Medico-Chirurgical Society. PMID- 30435244 TI - Current Topics. PMID- 30435245 TI - Case of Madura Foot in Its Initial Stage. PMID- 30435247 TI - On the Relief and Cure of Some Medical Affections by Surgical Operations, Being an Address at the Opening of the Medical Session in Glasgow University. PMID- 30435246 TI - The Study of Pathology. PMID- 30435248 TI - Medico-Chirurgical Society. PMID- 30435249 TI - Current Topics. PMID- 30435250 TI - The Abortive Treatment of Specific Febrile Disorders. PMID- 30435251 TI - Tubercular Disease of the Spinal Column. PMID- 30435252 TI - Parting Words Addressed to the Students Attending the Belvidere Clinique in the Summer of 1889. PMID- 30435253 TI - Case of Obstinate Intestinal Obstruction-Recovery. PMID- 30435255 TI - A Case of Primary Cancer of the Pleura. PMID- 30435256 TI - Medical Report on the Clyde Volunteer Brigade Camp at Gailes, Irvine. PMID- 30435257 TI - Case of Old Standing Fixation of the Jaw-Cured by Operation. PMID- 30435254 TI - On Hyaline or Vitreous (Zenker's) Degeneration of Striped Muscle Fibre in the Neighbourhood of Tumours. PMID- 30435258 TI - Note on a Case of Poisoning by Salt of Sorrell. PMID- 30435260 TI - Notes from the Annual Meeting of the British Medical Association at Leeds, August, 1889. PMID- 30435259 TI - Valedictory Address Delivered at the Close of the Graduation Ceremony, 25th July, 1889. PMID- 30435261 TI - Current Topics. PMID- 30435262 TI - A Case of Mal Perforant du Pied. PMID- 30435263 TI - Pathological and Clinical Society. PMID- 30435264 TI - On Brides-Les-Bains as a Health-Resort. PMID- 30435265 TI - Case of Mediastinal Tumour, Presenting Certain of the Features of Hodgkin's Disease, in a Patient Who Had Suffered from Genuine Rheumatic Attacks. PMID- 30435267 TI - Medico-Chirurgical Society. PMID- 30435266 TI - Two Cases of Fracture of the Femur Treated by Wiring. PMID- 30435268 TI - Current Topics. PMID- 30435270 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435269 TI - Experimental Research as to the General Comparative Action of the Natural and Artificial Salicyclic Acids and Their Salts of Sodium. PMID- 30435272 TI - On Various Anaesthetics, with Special Reference to Methylene. PMID- 30435271 TI - Remarks on Intra-Laryngeal Injections in the Treatment of Pulmonary Affections. PMID- 30435273 TI - Anaesthetics in Relation to Midwifery. PMID- 30435274 TI - On Various Anaesthetics, with Special Reference to Methylene. PMID- 30435275 TI - Nitrous Oxide, Cocaine, and Other Anaesthetics. PMID- 30435277 TI - Causes of Death under Chloroform. PMID- 30435276 TI - A Short Resume of Some of the Work Accomplished in the Male Surgical Ward of the New Victoria Infirmary Since Its Opening Nine Months Ago. PMID- 30435278 TI - Anaesthetics in Dental Practice. PMID- 30435279 TI - Current Topics. PMID- 30435280 TI - Professor Liebreich on Koch's Treatment. PMID- 30435281 TI - Thirty-Five Years' Experience of Anaesthetics. PMID- 30435282 TI - On Various Anaesthetics, with Special Reference to Methylene. PMID- 30435284 TI - On the Relative Value of the Various Anaesthetics. PMID- 30435283 TI - Current Topics. PMID- 30435285 TI - On Primary Chloroform Syncope. PMID- 30435286 TI - Haemoptysis in Apparently Healthy Persons. PMID- 30435287 TI - The Action of Anaesthetics on the Respiration and Cardiac Action, and on the Risks Incident to This Action. PMID- 30435288 TI - On the Clinical Demonstration of Diseases of the Throat and Nose. PMID- 30435289 TI - Guernsey as a Health Resort. PMID- 30435290 TI - Ether as an Anaesthetic. PMID- 30435291 TI - Large Naso-Pharyngeal Polypus. PMID- 30435292 TI - Influenza in Rothesay. PMID- 30435293 TI - Current Topics. PMID- 30435294 TI - Glasgow Pathological and Clinical Society. PMID- 30435295 TI - The Examination of the Eye. PMID- 30435297 TI - An Epidemic of Sore-Throat and Erysipelas Referred to Infection by Milk. PMID- 30435296 TI - Notes of a Case of Mania, Followed by Hyperaesthesia and Osteomalacia-Singular Family Tendency to Excessive Constipation and Self-Mutilation. PMID- 30435298 TI - The International Medical Congress at Berlin. PMID- 30435299 TI - An Epidemic of Dengue Fever in Fiji during the Year 1885. PMID- 30435300 TI - Current Topics. PMID- 30435301 TI - Glasgow Pathological and Clinical Society. PMID- 30435302 TI - Correspondence. PMID- 30435303 TI - On a Case of Cancer of the OEsophagus Involving the Recurrent Laryngeal Nerve and the Body of the Last Dorsal Vertebra. PMID- 30435304 TI - The Influenza Epidemic in Rural Bengal. PMID- 30435306 TI - Unusually Large Nasal Polypi, with Remarks on the Methods Employed in Their Removal. PMID- 30435305 TI - An Anencephalous Foetus (Cranioschisis) with Open Spina Bifida (Rachischisis). PMID- 30435307 TI - Rupture of the Pelvic Floor: Its Causes, Prevention, Cure: The Pelvic Floor. PMID- 30435309 TI - Glasgow Southern Medical Society. PMID- 30435308 TI - Case of Phthisis Pulmonalis Complicated during the Last Week of the Illness with Extensive Subcutaneous Emphysema. PMID- 30435310 TI - On the Pathology of Acute and Chronic Bronchitis and Bronchial Asthma. PMID- 30435311 TI - A Case of Central Lipoma of a Rib Associated with Three Other Forms of Tumour, One Being an Ovarian Cystoma in Process of Transplantation. PMID- 30435312 TI - Correspondence. PMID- 30435314 TI - Current Topics. PMID- 30435313 TI - Note on the Employment of Impure Lanolin (Oesypus) as an External Application in Classical Times. PMID- 30435316 TI - Current Topics. PMID- 30435315 TI - Cancer of Terminal Part of Common Bile Duct-Rupture of Gall Bladder and Biliary Peritonitis. PMID- 30435317 TI - Medico-Chirurgical Society. PMID- 30435319 TI - Errors in the Diagnosis of Infectious Diseases. PMID- 30435318 TI - Photography in Medicine and Allied Sciences. PMID- 30435321 TI - Glasgow Southern Medical Society. PMID- 30435320 TI - On Two Cases of Severe Vomiting in the Later Months of Pregnancy, Associated with (So-Called) Hemi-Albumosuria, and, in One, Diaceturia; with Remarks on Similar States of the Urine in Other Diseases. PMID- 30435322 TI - The Pyrexia of the Specific Fevers, with Special Reference to the Daily Fluctuations of Temperature. PMID- 30435323 TI - The Treatment of Uterine Cancer. PMID- 30435324 TI - Illustrations of Syphilitic Disease in the Nervous System. PMID- 30435325 TI - Medico-Chirurgical Society. PMID- 30435326 TI - A Short Paper on the Use of the More Common Anaesthetics. PMID- 30435327 TI - Three Cases of Brain and Ear Disease, Considered with Reference to Diagnosis, and Also to Questions of Brain Surgery. PMID- 30435329 TI - Pathological and Clinical Society. PMID- 30435328 TI - Case of Pulsating Exophthalmos. PMID- 30435330 TI - Glasgow Southern Medical Society. PMID- 30435331 TI - Notes on the Traditions and Customs of the Natives of Fiji in Relation to Conception, Pregnancy, and Parturition. PMID- 30435332 TI - Case of Cerebral Abscess Due to Ear Disease; Long Course and Remarkable Intermission of Symptoms. PMID- 30435333 TI - Medico-Chirurgical Society. PMID- 30435334 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435335 TI - Observations on Thirty Cases of Abdominal Section for Ovarian and Other Cystic Tumours. PMID- 30435336 TI - Current Topics. PMID- 30435337 TI - Medico-Chirurgical Society. PMID- 30435338 TI - Glasgow Southern Medical Society. PMID- 30435339 TI - On Haemorrhages from the Unimpregnated Uterus: Being His Introductory Address as President of the Obstetrical Section of the Glasgow Medico-Chirurgical Society. PMID- 30435340 TI - Pathological and Clinical Society. PMID- 30435341 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435342 TI - Chronic Lead-Poisoning, with Special Reference to Its Prevention. PMID- 30435343 TI - Current Topics. PMID- 30435344 TI - Lectures on the Diseases Classified as Tabes Mesenterica. Lecture IV.-Practical Considerations; Prevention and Cure. PMID- 30435345 TI - On the Relation of the Air We Breathe to Our Common Diseases. PMID- 30435346 TI - Pathological and Clinical Society. PMID- 30435348 TI - Medico-Chirurgical Society. PMID- 30435347 TI - Case of Opium Poisoning. PMID- 30435349 TI - The Treatment of the Inflammatory Affections of Joints. PMID- 30435350 TI - On the Relation of the Air We Breathe to Our Common Diseases. PMID- 30435352 TI - Glasgow Southern Medical Society. PMID- 30435351 TI - Correspondence. PMID- 30435353 TI - Current Topics. PMID- 30435354 TI - Current Topics. PMID- 30435355 TI - Lectures on the Diseases Classified as Tabes Mesenterica. PMID- 30435356 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435357 TI - A Method of Securing and Suturing the Bladder in Supra-Pubic Cystotomy. PMID- 30435358 TI - Pathological and Clinical Society. PMID- 30435359 TI - Case of Myxoedema. PMID- 30435360 TI - Medico-Chirurgical Society. PMID- 30435362 TI - Puerperal Septicaemia: Its Causes, and the Means to Be Adopted for Its Prevention. PMID- 30435361 TI - Observations on the Study of Disease: Being the Retiring Address as Honorary President of the Royal Infirmary Medical Society, Session 1886-87. PMID- 30435364 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435363 TI - On the Relation of the Air We Breathe to Our Common Diseases. PMID- 30435365 TI - Epidemic Pneumonia. PMID- 30435367 TI - Current Topics. PMID- 30435366 TI - Lectures on the Diseases Classified as Tabes Mesenterica. PMID- 30435368 TI - On the Treatment of Spinal Disease by Continuous Extension in the Horizontal Position. PMID- 30435369 TI - Glasgow Pathological and Clinical Society. PMID- 30435370 TI - Exophthalmic Goitre: A Clinical Study. PMID- 30435372 TI - Current Topics. PMID- 30435371 TI - The Treatment of Diphtheria by the Injection of the Erysipelas Albumose. PMID- 30435373 TI - The Pathology of Mediastinal Tumours, with Special Reference to Clinical Diagnosis. PMID- 30435374 TI - Current Topics. PMID- 30435376 TI - From the Pathological Department of the Glasgow Royal Infirmary. PMID- 30435375 TI - Glasgow Pathological and Clinical Society. PMID- 30435378 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435377 TI - The Pathology of Mediastinal Tumours, with Special Reference to Clinical Diagnosis. PMID- 30435379 TI - The Treatment of Abortion. PMID- 30435380 TI - Current Topics. PMID- 30435381 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435383 TI - Glasgow Pathological and Clinical Society. PMID- 30435382 TI - A Case of Punctured Wound of the Right Auricle of the Heart-Survival for Nine Days: Shown at the Pathological and Clinical Society, 9th November, 1891. PMID- 30435384 TI - A Case of Multiple Sarcoma of Bone: Shown in the Pathological and Clinical Society of Glasgow, 2nd November, 1891. PMID- 30435385 TI - Inaugural Address to the Physiology Class in Anderson's College, Session 1891-92. PMID- 30435386 TI - The Treatment of Chronic Ulcers by Massage. PMID- 30435387 TI - The Pathology of Mediastinal Tumours, with Special Reference to Clinical Diagnosis. PMID- 30435389 TI - Glasgow Pathological and Clinical Society. PMID- 30435388 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435390 TI - Severe Effects Resulting from Contact with a Jelly-Fish. PMID- 30435391 TI - Mechanics of the Pelvis and Its Contents. PMID- 30435392 TI - Current Topics. PMID- 30435393 TI - The Examination of the Eye. PMID- 30435394 TI - A Case of Tetanus in Which the Infection Was Traced to a Chronic Ulcer. PMID- 30435396 TI - Exophthalmic Goitre: A Clinical Study. PMID- 30435395 TI - The Examination of the Eye. PMID- 30435397 TI - The Pathology of Mediastinal Tumours, with Special Reference to Clinical Diagnosis. PMID- 30435398 TI - Current Topics. PMID- 30435399 TI - "The Supposed Curative Effect of Operations per se". PMID- 30435400 TI - The Examination of the Eye. PMID- 30435401 TI - Case of Complete Obstruction of the Left Bronchus by a Soluble Foreign Body; Slow but Complete Recovery after Five Days. PMID- 30435402 TI - Aneurysm of the Innominate Artery: Macewen's Operation; Formation of a Stratified Thrombus. PMID- 30435404 TI - Congenital Talipes: Some Cases Bearing on Its Etiology. PMID- 30435403 TI - Current Topics. PMID- 30435405 TI - On a Case of Fatty Tumour of the Thigh Simulating Sarcoma. PMID- 30435407 TI - Scottish Otological and Laryngological Society. PMID- 30435406 TI - A Case of Chloral Rash Simulating Measles. PMID- 30435408 TI - Current Topics. PMID- 30435409 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 14th June, 1913. PMID- 30435410 TI - Things Ophthalmic New and Old. PMID- 30435412 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 15th November, 1913. PMID- 30435411 TI - Congenital Occlusions of the OEsophagus and Lesser Bowel. PMID- 30435414 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435413 TI - Note on a Case of Carcinoma of the Vermiform Appendix in a Girl, Aged 20 Years. PMID- 30435415 TI - Medical Life and Work: An Address to Students, Introductory to a Course of Lectures on Practice of Medicine. PMID- 30435417 TI - Current Topics. PMID- 30435416 TI - Byzantine Medicine: The Finlayson Memorial Lecture. PMID- 30435418 TI - Intestinal Toxaemia in Its Relationship to Obstetrical and Gynaecological Affections. PMID- 30435420 TI - New Preparations, &c. PMID- 30435419 TI - The Operation for Acute Appendicitis-Primary Closure of the Abdominal Wound. PMID- 30435421 TI - X-Rays in Malignant Disease. PMID- 30435422 TI - On the Differential Diagnosis of Manic-Depressive Insanity and Dementia Precox. PMID- 30435423 TI - Miners' Nystagmus: The Stage Prior to Nystagmus. PMID- 30435424 TI - Current Topics. PMID- 30435425 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd August, 1913. PMID- 30435426 TI - On the Treatment of Haemoptysis in Pulmonary Tuberculosis. PMID- 30435428 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th October, 1913. PMID- 30435427 TI - Dilatation of the Stomach : With X-Ray Photographs Illustrative of the Subject. PMID- 30435429 TI - New Preparations, &c. PMID- 30435430 TI - Byzantine Medicine: The Finlayson Memorial Lecture. PMID- 30435431 TI - Current Topics. PMID- 30435432 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435434 TI - Current Topics. PMID- 30435433 TI - Notes on the Serum Treatment of Cerebro-Spinal Meningitis. PMID- 30435435 TI - Tuberculosis: Renal and Vesical Cystoscopic Appearances in the Early Stages Demonstrated by the Projectoscope. PMID- 30435438 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th September, 1913. PMID- 30435437 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435436 TI - Obstruction of the Pulmonary Artery Due to Carcinoma. PMID- 30435440 TI - New Preparations, &c. PMID- 30435439 TI - Notes on a Glasgow Physician. PMID- 30435442 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435441 TI - The Avoidance of Unsightly Scar Deformities in the Operative Treatment of Cervical Lymphadenitis. PMID- 30435443 TI - Current Topics. PMID- 30435444 TI - Vaccine-Therapy in the Treatment of Gonococcal Vulvo-Vaginitis. PMID- 30435445 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 12th July, 1913. PMID- 30435447 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435446 TI - Congenital Occlusions of the OEsophagus and Lesser Bowel. PMID- 30435449 TI - Glasgow Pathological and Clinical Society. PMID- 30435448 TI - The Pharmacy Act Amendment Bill. PMID- 30435451 TI - Current Topics. PMID- 30435450 TI - Successful Thyrotomy for Epithelioma of the Larynx. PMID- 30435452 TI - Case of Epithelioma of the Upper Portion of the OEsophagus Successfully Treated by Gastrostomy and Tracheotomy. PMID- 30435453 TI - On a Case Characterised by Subcutaneous Emphysema of the Neck and Thorax, of Peculiar Origin. PMID- 30435454 TI - The Pathology of Mediastinal Tumours, with Special Reference to Clinical Diagnosis. PMID- 30435455 TI - Glasgow Southern Medical Society. PMID- 30435456 TI - The Histology, Development, and Physiological Action of the Fallopian Tube. PMID- 30435457 TI - Rupture of the Uterus in a Case of Twin Pregnancy. PMID- 30435458 TI - Three Cases of Stricture of the OEsophagus Treated by Gastrostomy. PMID- 30435459 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435460 TI - On a Case of Pulsus Bigeminus or Cardiac Couple-Beat, Complicated by a Quadruple Aortic Murmur. PMID- 30435462 TI - Notes of a Case of Pulmonary Embolism Occurring before Delivery. PMID- 30435461 TI - On the Training of a Medical Man: Being the Introductory Address Delivered at the Opening of the Winter Session of St. Mungo's College, Glasgow, 22nd October, 1890. PMID- 30435464 TI - Current Topics. PMID- 30435463 TI - Two Cases in Which Dyspnoea and Dysphagia Were Marked Symptoms-One a Case of Aneurism, Simulating Stricture of the OEsophagus, the Other an Epithelioma of the OEsophagus, Simulating Aortic Aneurism. PMID- 30435465 TI - Cases Treated by Koch's Method in the Victoria Infirmary, Glasgow. PMID- 30435466 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435467 TI - Current Topics. PMID- 30435468 TI - The Chloroform Question. PMID- 30435469 TI - Rheumatism and Chorea as Complications of Scarlet Fever. PMID- 30435470 TI - Case of Osteomyelitis of the Shaft of the Femur. PMID- 30435471 TI - Cases of Hydronephrosis of Unusual Origin. PMID- 30435472 TI - Bacteriology: A General Review of Its Progress and Its Prospects. PMID- 30435473 TI - Glasgow Pathological and Clinical Society. PMID- 30435474 TI - Medico-Chirurgical Society of Glasgow. PMID- 30435475 TI - Further Observations on Chronic Inflammatory Lesions of the Bronchi and on Bronchiectasis. PMID- 30435476 TI - On the Digital Measurement of the True Conjugate in Flat Pelves during Labour. PMID- 30435477 TI - Notes of a Case of Nephrectomy for Pyonephrosis. PMID- 30435478 TI - Current Topics. PMID- 30435479 TI - On a Method of Examining the Sputum for Tubercle Bacilli: Employed in the Pathological Department of the Glasgow Royal Infirmary. PMID- 30435480 TI - Notes of a Case of Trephining of the Spine for Fracture, with Dislocation of Dorsal Vertebrae. PMID- 30435481 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435482 TI - A Case of Extirpation of the Uterus for Fibroids. PMID- 30435483 TI - Syphilis and Marriage, with Special Reference to the Effect Produced on Procreation. PMID- 30435484 TI - On the Place of the Debating Society in the Education of the Medical Student: Being an Introductory Address Delivered in the St. Mungo's College Medical Society, on the 15th November, 1890. PMID- 30435485 TI - Scheme for a Pathological Index. PMID- 30435486 TI - On a Case of Pulsus Bigeminus or Cardiac Couple-Beat, Complicated by a Quadruple Aortic Murmur. PMID- 30435487 TI - A Specimen of the Prismatic Variety of the Taenia Saginata (Mediocanellata). PMID- 30435488 TI - Current Topics. PMID- 30435489 TI - Pathological and Clinical Society. PMID- 30435490 TI - Experimental Observations and Inferences Relating to the Physiological Action of an Overdose of an Anaesthetic-Influence of Respiratory Movements on the Systemic and Pulmonic Circulations-Changes in the Lung and Cardiac Impulses-Indications of Danger in Chloroform Narcosis. PMID- 30435491 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435492 TI - Pathological and Clinical Society. PMID- 30435494 TI - Anaesthetics in Obstetric Practice. PMID- 30435493 TI - Anaesthetics in Disease of the Heart. PMID- 30435495 TI - The Clinical Aspects of Anaesthetics. PMID- 30435496 TI - The Administrations and Dangers of Anaesthetics. PMID- 30435497 TI - Experimental Observations and Inferences Relating to the Physiological Action of an Overdose of an Anaesthetic-Influence of Respiratory Movements on the Systemic and Pulmonic Circulations-Changes in the Lung and Cardiac Impulses-Indications of Danger in Chloroform Narcosis. PMID- 30435499 TI - Anaesthetics in Obstetric Practice. PMID- 30435498 TI - Anaesthetics in Obstetric Practice. PMID- 30435500 TI - Anaesthetics in Practice. PMID- 30435501 TI - Anaesthetics in Obstetric Practice. PMID- 30435502 TI - Current Topics. PMID- 30435503 TI - The President's Concluding Remarks on Anaesthetics, with Special Reference to Chloroform and Ether-Their Physiological Action, Their Relative Value, Their Dangers, and Their Mode of Administration. PMID- 30435504 TI - Anaesthetics in Obstetric Practice. PMID- 30435505 TI - Special Remarks on Ether. PMID- 30435506 TI - Anaesthetics in Obstetric Practice. PMID- 30435508 TI - Anaesthetics in Obstetric Practice. PMID- 30435507 TI - Anaesthetics at the Children's Hospital. PMID- 30435509 TI - Current Topics. PMID- 30435510 TI - Obstetrical and Gynaecological Society. PMID- 30435511 TI - Wound of the Thoracic Duct in the Removal of Tuberculous Cervical Glands. PMID- 30435512 TI - Ophthalmology in Modern Medical Practice. PMID- 30435513 TI - The Examination of the Blood in Cases of Cancer of the Breast in Regard to Operation and Prognosis. PMID- 30435514 TI - Glasgow Northern Medical Society. PMID- 30435515 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st May, 1921. PMID- 30435517 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd April, 1921. PMID- 30435516 TI - The Examination of the Blood in Cases of Cancer of the Breast in Regard to Operation and Prognosis. PMID- 30435518 TI - Obstetrical and Gynaecological Society. PMID- 30435519 TI - Cookery and Digestion. PMID- 30435520 TI - Current Topics. PMID- 30435521 TI - Defects in Cardiac Rhythm in Relation to Cardiac Failure. PMID- 30435522 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435524 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th March, 1921. PMID- 30435523 TI - Notes on Some Sequels of Influenza. PMID- 30435525 TI - Typhoid and Paratyphoid Fevers. PMID- 30435526 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435528 TI - Current Topics. PMID- 30435527 TI - Glasgow Southern Medical Society. PMID- 30435529 TI - A Preliminary Study of the Etiology of Osteomalacia in the City of Bombay. PMID- 30435531 TI - Current Topics. PMID- 30435530 TI - Some Comments on Medical Education, Legislation, and Practice in the United States. PMID- 30435533 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd January, 1921. PMID- 30435532 TI - Notes on Case of Acute Myoclonic Encephalitis Presenting Some Unusual Features. PMID- 30435534 TI - Enteric Fevers in the British Expeditionary Force, 1914-1918. PMID- 30435535 TI - Glasgow Southern Medical Society. PMID- 30435536 TI - Effects of the Factors Producing Shell Shock. PMID- 30435538 TI - Current Topics. PMID- 30435537 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 25th December, 1920. PMID- 30435539 TI - Note on Recent Work in Tropical Ophthalmology. PMID- 30435540 TI - Epidemic Encephalitis (Encephalitis Lethargica) in Childhood: With Special Reference to the Changes in the Cerebro-Spinal Fluid. PMID- 30435541 TI - Some Comments on Medical Education, Legislation, and Practice in the United States. PMID- 30435543 TI - The Psychology of Vision. PMID- 30435542 TI - Current Topics. PMID- 30435544 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th February, 1921. PMID- 30435545 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435546 TI - 1840 versus 1920. PMID- 30435547 TI - Appetite Juice. PMID- 30435548 TI - Change of Type in Disease. PMID- 30435549 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd June, 1918. PMID- 30435550 TI - Current Topics. PMID- 30435551 TI - Gastro-Intestinal Toxaemia as a Cause of Nephritis. PMID- 30435552 TI - On Trinitrotoluene Poisoning, with Records of Five Cases. PMID- 30435553 TI - Vitiligo: With Notes of Four Cases. PMID- 30435554 TI - Current Topics. PMID- 30435555 TI - On Some Unusual Forms of Nervous Disease. PMID- 30435556 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th July, 1918. PMID- 30435557 TI - Current Topics. PMID- 30435558 TI - The Surgical Importance of the Cerebellar Amygdalae. PMID- 30435559 TI - How Pelmanism Helps Medical Men. PMID- 30435560 TI - Erratum. AB - [This corrects the article on p. 91 in vol. 90.]. PMID- 30435561 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st September, 1918. PMID- 30435562 TI - Lethargic Encephalitis. PMID- 30435563 TI - Treatment and Prognosis of Nephritis. PMID- 30435565 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 30th November, 1918. PMID- 30435564 TI - Some Medicines of Our Ancestors. PMID- 30435566 TI - Current Topics. PMID- 30435568 TI - Current Topics. PMID- 30435567 TI - Remarks on Moro's Percutaneous Inunction Test, and Von Pirquet's Cuti-Reaction Test: with Cases in Which They Were Applied. PMID- 30435570 TI - New Preparations, &c. PMID- 30435569 TI - An Amateur Evolutionist. PMID- 30435571 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th August, 1918. PMID- 30435572 TI - Catarrhal Pancreatitis. PMID- 30435573 TI - New Preparations, &c. PMID- 30435574 TI - A Note on the New Antisepsis in Surgery. PMID- 30435575 TI - The Treatment of Acute Gonorrhoeal Epididymitis by Normal Horse Serum. PMID- 30435577 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 26th October, 1918. PMID- 30435576 TI - Current Topics. PMID- 30435579 TI - Index: Part 1. PMID- 30435578 TI - The Treatment of Mal-Positions and Mal-Presentations. PMID- 30435580 TI - Index: Part 2. PMID- 30435581 TI - Prefatory Note and Explanations. PMID- 30435582 TI - Index: Part 3. PMID- 30435584 TI - Stovain Anaesthesia. PMID- 30435583 TI - War Psychoses-The Infective-Exhaustive Group. PMID- 30435586 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th November, 1921. PMID- 30435585 TI - Current Topics. PMID- 30435587 TI - The Practical Application of the Determination of the Respiratory Exchange in Health and Disease. PMID- 30435589 TI - Current Topics. PMID- 30435588 TI - Correction. AB - [This corrects the article on p. 241 in vol. 96.]. PMID- 30435591 TI - The Ravages of Congenital Syphilis-How to Combat Them: A Plea for Notification. PMID- 30435590 TI - Ante-Natal Treatment of Congenital Syphilis. PMID- 30435592 TI - Syphilis as Seen by a Hospital Physician. PMID- 30435593 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd October, 1921. PMID- 30435594 TI - Sulfarsenol in Congenital Syphilis. PMID- 30435595 TI - The Antisyphilitic Action and Other Effects of Arsenical Compounds in Relation to Their Constitution. PMID- 30435596 TI - The Post-Natal Treatment of Congenital Syphilis. PMID- 30435597 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435598 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd July, 1921. PMID- 30435599 TI - The Radical Cure of Femoral Hernia in Children. PMID- 30435600 TI - Current Topics. PMID- 30435601 TI - Post-War Surgical Disabilities. PMID- 30435603 TI - Medical and Food Preparations. PMID- 30435602 TI - Prolapse of the Female Genitalia. PMID- 30435605 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435604 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th June, 1921. PMID- 30435606 TI - Lethargic Encephalitis. PMID- 30435608 TI - Current Topics. PMID- 30435607 TI - Ophthalmology in Modern Medical Practice. PMID- 30435610 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th August, 1921. PMID- 30435611 TI - A Modern School of Medicine in China. PMID- 30435609 TI - Case of Frohlich's Syndrome Following Injury to the Sella Turcica. PMID- 30435613 TI - Current Topics. PMID- 30435612 TI - The Surgical Treatment of Uterine Prolapse. PMID- 30435615 TI - Current Topics. PMID- 30435614 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435616 TI - Case of Acute Pellagra in Childhood. PMID- 30435617 TI - Two Unusual Malformations of the Hind End of the Body. PMID- 30435618 TI - The Present-Day Conditions-Social, Medical, and Political-In Vienna. PMID- 30435619 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th September, 1921. PMID- 30435620 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 28th October, 1922. PMID- 30435621 TI - Current Topics. PMID- 30435623 TI - The Clinical Significance of Failing Sight. PMID- 30435622 TI - Some Links between Natural History and Medicine. PMID- 30435625 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd September, 1922. PMID- 30435624 TI - The Cause of Increased Electrical Excitability. PMID- 30435626 TI - The Report of the Medical Officer of Health, City of Glasgow, 1921. PMID- 30435627 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435628 TI - Two Cases of Syphilis of the Liver with Symptoms of Abscess Formation. PMID- 30435630 TI - Current Topics. PMID- 30435629 TI - Influenza: A Suggested Explanation of Certain Associated Phenomena and Its Relationship to Control and Cure. PMID- 30435632 TI - Minor Displacements of the Coccyx. PMID- 30435631 TI - A Short Sketch of the History of Early Medicine. PMID- 30435633 TI - Current Topics. PMID- 30435634 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th July, 1922. PMID- 30435635 TI - Notes on Splenomegaly and Splenectomy. PMID- 30435637 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435636 TI - Treatment of Amoebic Dysentery by Alcresta and Emetin. PMID- 30435638 TI - A Study of the Diets and Economic Conditions of Labouring-Class Families in Glasgow in June, 1922. PMID- 30435639 TI - A Rare Case of Polydactylism of the Foot. PMID- 30435640 TI - An Outbreak of Food Poisoning by Milk, Caused by B. AErtrycke. PMID- 30435641 TI - A Review of Service Patients in a Mental Hospital. PMID- 30435643 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th November, 1922. PMID- 30435642 TI - Current Topics. PMID- 30435644 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th August, 1922. PMID- 30435645 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435646 TI - Current Topics. PMID- 30435647 TI - Mortality-Rates in Glasgow Families: An Analysis of the Various Kinds of Wastage of Child-Life in Well-To-Do and in Poor Families of Varying Size. PMID- 30435648 TI - A Short Sketch of the History of Early Medicine. PMID- 30435649 TI - Pneumonias in Glasgow and Their Pneumococcal Types. PMID- 30435650 TI - A Surgeon Invents the First Electric Telegraph. PMID- 30435651 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435652 TI - Current Topics. PMID- 30435653 TI - Scottish Society of Anaesthetists. PMID- 30435654 TI - Note on Some Medical Mss. and Books in the Hunterian Library. PMID- 30435655 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th June, 1922. PMID- 30435656 TI - Note on Some Interesting Possessions of the Royal Faculty of Physicians and Surgeons. PMID- 30435657 TI - The Middle Age. PMID- 30435658 TI - A Consideration of Some of the Claims of the "New Nancy School". PMID- 30435659 TI - Early Reminiscences. PMID- 30435661 TI - Current Topics. PMID- 30435660 TI - The "Discovrse" of Maister Peter Lowe: Extracts and Comments. PMID- 30435662 TI - Chronic Suppurative Disease of the Middle Ear. PMID- 30435664 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th July, 1902. PMID- 30435663 TI - Glasgow Medico-Chirurgical Society. PMID- 30435666 TI - Obstetrical and Gynaecological Society. PMID- 30435665 TI - Recent Electro-Therapeutic Work in Medicine and Surgery. PMID- 30435667 TI - New Preparations, &c. PMID- 30435668 TI - Obstetrical and Gynaecological Society. PMID- 30435669 TI - Current Topics. PMID- 30435671 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st June, 1902. PMID- 30435670 TI - Puerperal Eclampsia. PMID- 30435673 TI - Glasgow Eastern Medical Society. PMID- 30435672 TI - Chronic Suppurative Disease of the Middle Ear. PMID- 30435674 TI - Glasgow Southern Medical Society. PMID- 30435675 TI - Spina Bifida: Its Operative Treatment Amongst Out-Patients. PMID- 30435676 TI - Glasgow Pathological and Clinical Society. PMID- 30435677 TI - Glasgow Medico-Chirurgical Society. PMID- 30435678 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th September, 1902. PMID- 30435679 TI - Current Topics. PMID- 30435680 TI - Canceroderms. PMID- 30435681 TI - On Removal of the Superior Row of Carpal Bones in Acute Septic Disease of the Wrist-Joint. PMID- 30435682 TI - A Clinical Study of Diplopia. PMID- 30435683 TI - Case of Double Empyema Following on Double Pneumonia. PMID- 30435685 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th October, 1902. PMID- 30435684 TI - Ethyl Chloride as a General Anaesthetic. PMID- 30435686 TI - Current Topics. PMID- 30435687 TI - A Case of Chylous Urine and a Case of Blue Urine. PMID- 30435688 TI - Recent Electro-Therapeutic Work in Medicine and Surgery. PMID- 30435689 TI - Glasgow Eastern Medical Society. PMID- 30435690 TI - Note on an Operation to Correct Undue Prominence of the Ears. PMID- 30435691 TI - Case of Pericardio-Mediastinitis, Associated with Tubercular Peritonitis and Ascites. PMID- 30435693 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd November, 1902. PMID- 30435692 TI - The Value of Rest as Effected by Operation in the Treatment of Certain Diseases of the Alimentary Canal. PMID- 30435694 TI - New Preparations, &c. PMID- 30435695 TI - Current Topics. PMID- 30435696 TI - The Vision in Various Affections of the Eye. PMID- 30435697 TI - Notes on a Few Cases of Lupus Treated in the Electrical Department of the Western Infirmary. PMID- 30435698 TI - Dimness of Vision in Diseases of the Kidney Characterised by Albuminuria. PMID- 30435699 TI - Current Topics. PMID- 30435701 TI - Glasgow Pathological and Clinical Society. PMID- 30435700 TI - The New Electrical Pavilion of the Glasgow Royal Infirmary. PMID- 30435702 TI - Glasgow Medico-Chirurgical Society. PMID- 30435703 TI - Symphysiotomy: Report of a Case of Contracted Pelvis and Pregnancy, Terminated at Full Time by Symphysiotomy. PMID- 30435704 TI - New Preparations, &c. PMID- 30435705 TI - Gastroschisis in a Twin. PMID- 30435707 TI - Obstetrical and Gynaecological Society. PMID- 30435706 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd August, 1902. PMID- 30435708 TI - Notes of a Case of Cerebro-Spinal Meningitis. PMID- 30435710 TI - Current Topics. PMID- 30435709 TI - A Case of Tubal Pregnancy. PMID- 30435711 TI - Medico-Chirurgical Society. PMID- 30435712 TI - Atheromatous Disease of Arteries: Its Nature, Etiology, and Diagnosis: An Original Research Carried out in the Pathological Department of the Glasgow Royal Infirmary in 1890, at the Suggestion of John Lindsay Steven, M.D., Pathologist and Curator of the Museum. PMID- 30435714 TI - Pathological and Clinical Society. PMID- 30435713 TI - A Case of Addison's Disease in Which the Tubercular Nature of the Lesions in the Supra-Renal Bodies Was Demonstrated. PMID- 30435715 TI - Current Topics. PMID- 30435716 TI - Sleep, Dreams, and Delirium: With an Account of His Experiences in the Delirium of Typhus Fever. PMID- 30435717 TI - Contribution to the Inquiry into the Causes of the Increase of Pauper Lunacy in Scotland. PMID- 30435718 TI - Medico-Chirurgical Society. PMID- 30435719 TI - The Epidemic of Cholera in Paris. PMID- 30435720 TI - Current Topics. PMID- 30435721 TI - A Case of Puerperal Fever Illustrating the Mode of Infection and the Infective Agent. PMID- 30435722 TI - Notes of a Case of Gastro-Enterostomy for Dilatation of the Stomach-Recovery. PMID- 30435723 TI - Medico-Chirurgical Society. PMID- 30435724 TI - Specimens of Lobulated Adult Human Kidneys. PMID- 30435725 TI - Tuberculosis of the Peritoneum and Uterine Appendages in a Child. PMID- 30435726 TI - Pathological and Clinical Society. PMID- 30435728 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435727 TI - On the Staining of the Medullary Sheath of Nerve Fibres. PMID- 30435729 TI - Pathological and Clinical Society. PMID- 30435730 TI - Foreign Body in the Air Passages for Five Months. PMID- 30435731 TI - Ununited Intracapsular Fracture of the Neck of the Femur. PMID- 30435732 TI - Notes of a Very Protracted Case of Broncho-Pneumonia in a Woman Aged 81. PMID- 30435733 TI - Medico-Chirurgical Society. PMID- 30435735 TI - Current Topics. PMID- 30435734 TI - Statistics of Surgical Operations from 1883 to 1892. PMID- 30435736 TI - A Note on Infantile Spasmodic Paraplegia (Little's Paralysis). PMID- 30435737 TI - Metchnikoff on the Comparative Pathology of Inflammation. PMID- 30435739 TI - Pathological and Clinical Society. PMID- 30435738 TI - Notes of a Case of Myxoedema Treated by Means of Subcutaneous Injections of an Extract of Sheep's Thyroid. PMID- 30435740 TI - Two Cases of Sarcoma of the Choroid. PMID- 30435741 TI - Medico-Chirurgical Society. PMID- 30435742 TI - Case of Sarcoma of the Choroid of Long Duration, and Characterised by the Unusually Small Size of the Primary Growth. PMID- 30435744 TI - Current Topics. PMID- 30435743 TI - Recent Advances in the Surgery of the Urinary Organs. PMID- 30435745 TI - Atheromatous Disease of Arteries: Its Nature, Etiology, and Diagnosis: An Original Research Carried out in the Pathological Department of the Glasgow Royal Infirmary in 1890, at the Suggestion of John Lindsay Steven, M.D., Pathologist and Curator of the Museum. PMID- 30435746 TI - Brains Prepared for Use as Dry Specimens. PMID- 30435747 TI - On Two Illustrative Cases of Cerebral Haemorrhage. PMID- 30435748 TI - Notes of a Fatal Case of Opium Poisoning. PMID- 30435749 TI - Current Topics. PMID- 30435750 TI - A Specimen of a Traumatic Aneurysm of the Radial Artery, Removed by Extirpation. PMID- 30435751 TI - A Case of Myxoedema with Microscopic Examination of the Thyroid Gland. PMID- 30435752 TI - Address in Commencing His Course of Surgery in Glasgow University. PMID- 30435754 TI - Pathological and Clinical Society. PMID- 30435753 TI - Medico-Chirurgical Society. PMID- 30435756 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 28th July, 1923. PMID- 30435755 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435757 TI - Current Topics. PMID- 30435758 TI - The Treatment of Traumatic Defects of the Skull. PMID- 30435759 TI - The Career of Alexander Maxwell Adams, M.D. (Erlangen), Poor-Law Reformer and Agitator: Arranged, from Material Left by Him. PMID- 30435760 TI - Current Topics. PMID- 30435761 TI - Some Results of Clinical Laboratory Tests in the Diagnosis of Various Types of Jaundice. PMID- 30435762 TI - Tuberculin. PMID- 30435764 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd September, 1923. PMID- 30435763 TI - Local Medical Diathermy. PMID- 30435766 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th August, 1923. PMID- 30435765 TI - Protein Therapy: Its Use in Chronic Infectious Arthritis. PMID- 30435767 TI - Staple and Holder Used in the Radical Cure of Femoral Hernia in Children. PMID- 30435768 TI - Current Topics. PMID- 30435769 TI - The Problem of Pyogenic Disease in Bone. PMID- 30435770 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 23rd June, 1923. PMID- 30435771 TI - Health Visitors in Scotland. PMID- 30435772 TI - Notes of a Case of Diverticulum of the Bladder. PMID- 30435773 TI - The Etiology of Sarcoma. PMID- 30435774 TI - Current Topics. PMID- 30435775 TI - An Hitherto Unpublished Letter by Dr. Robert Knox, the Anatomist, 1791-1862. PMID- 30435776 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30435777 TI - Current Topics. PMID- 30435778 TI - Moliere and the Doctors. PMID- 30435779 TI - The Clinical Manifestations of Cerebral Tumours. PMID- 30435780 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th October, 1923. PMID- 30435781 TI - The Management of Medical Research. PMID- 30435782 TI - Observations on Certain Aspects of the Experimental Transmission of Disseminated Sclerosis. PMID- 30435784 TI - The Relationship of Jejunal Ulcer to the Use of Unabsorbable Sutures. PMID- 30435785 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th November, 1923. PMID- 30435783 TI - Current Topics. PMID- 30435786 TI - Diabetes Mellitus: Its Modern Treatment, with Special Reference to Insulin. PMID- 30435787 TI - Introduction to a Discussion on Disseminated Sclerosis, Its Symptomatology, Pathology, and Treatment. PMID- 30435788 TI - The Early Ocular Manifestations of Disseminated Sclerosis. PMID- 30435789 TI - Glasgow Pathological and Clinical Society. PMID- 30435791 TI - Glasgow Medico-Chirurgical Society. PMID- 30435790 TI - Current Topics. PMID- 30435792 TI - Glasgow Eastern Medical Society. PMID- 30435793 TI - Lectures on Clinical Medicine. Delivered in the Glasgow Royal Infirmary: XI. On Three Fatal Cases of Mitral Stenosis Illustrating Various Complications of the Disease, and Especially Its Relation to the Occurrence of Pregnancy. PMID- 30435794 TI - The Heart from a Case of Morbus Caeruleus. PMID- 30435795 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th May, 1899. PMID- 30435797 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th February, 1899. PMID- 30435796 TI - Vaginal Coeliotomy. PMID- 30435798 TI - Current Topics. PMID- 30435799 TI - Treatment, in the Early Stages, of Acute Appendicitis by Saline Aperients. PMID- 30435800 TI - One Hundred and Thirty-Eight Consecutive Cases of Abdominal Surgery. PMID- 30435801 TI - Glasgow Medico-Chirurgical Society. PMID- 30435802 TI - Intercellular Saline Injections in Cases of Haemorrhage and Eclampsia. PMID- 30435803 TI - Glasgow Pathological and Clinical Society. PMID- 30435804 TI - Obstetrical and Gynaecological Society. PMID- 30435805 TI - An Unusual Case of Traumatic Separation of Epiphyses. PMID- 30435806 TI - Endemic Goitre and Its Occurrence in Lanarkshire, with Some Observations on the Pathology of the Disease. PMID- 30435807 TI - Lectures on Clinical Medicine. Delivered in the Glasgow Royal Infirmary: X. On Profuse Haematemesis Due to "Pore-Like" Erosion of the Gastric Arteries - No Round Ulcer-Exulceratio Simplex of Dieulafoy. PMID- 30435808 TI - On Movable Kidney. PMID- 30435809 TI - The Forfarshire Medical Association. PMID- 30435811 TI - A Case of Dermoid Cyst of the Penis, of Tubular Form. PMID- 30435810 TI - Current Topics. PMID- 30435812 TI - Report on the Bacteriological Examination of Paisley Water in Connection with the Recent Epidemic of Enteric Fever in That Town. PMID- 30435813 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th December, 1898. PMID- 30435814 TI - Summary of the Work of the Plague Hospital, Poona, India, in Its Clinical Relations. PMID- 30435815 TI - Glasgow Pathological and Clinical Society. PMID- 30435816 TI - Glasgow Medico-Chirurgical Society. PMID- 30435817 TI - Nerve Suturing-Two Cases. PMID- 30435818 TI - Current Topics. PMID- 30435819 TI - Glasgow Pathological and Clinical Society. PMID- 30435820 TI - Case of Congenital Malformation of the Heart. PMID- 30435822 TI - The Forfarshire Medical Association. PMID- 30435821 TI - Some Observations on the Tuberculin Treatment. PMID- 30435824 TI - Obstetrical and Gynaecological Society. PMID- 30435823 TI - Notes on the Lymphatic Constitution. PMID- 30435825 TI - Frontal Sinusitis, with Several Illustrative Cases. PMID- 30435826 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd April, 1899. PMID- 30435827 TI - The Fevers of West Africa: Their Nature, Treatment, and Prevention. PMID- 30435829 TI - Current Topics. PMID- 30435828 TI - Glasgow Medico-Chirurgical Society. PMID- 30435830 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st January, 1899. PMID- 30435831 TI - Some Results of Gastric Analysis in Stomach Disease, with Illustrative Cases. PMID- 30435832 TI - A Case Illustrative of the Early Occurrence of Eye Symptoms in Exophthalmic Goitre, with Remarks. PMID- 30435834 TI - Two Cases Illustrating the Duration of General Peritonitis after the Rupture of a Perforating Ulcer of the Stomach and of the Duodenum Respectively. PMID- 30435833 TI - A Clinical Case of Transvaal Malaria. PMID- 30435835 TI - Glasgow Pathological and Clinical Society. PMID- 30435837 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th March, 1899. PMID- 30435836 TI - A Case of Cirrhosis of the Liver in a Child Six Years Old. PMID- 30435838 TI - The Forfarshire Medical Association. PMID- 30435839 TI - List of the Principal Writings of the Late Professor Joseph Coats, M.D. PMID- 30435840 TI - Glasgow Medico-Chirurgical Society. PMID- 30435841 TI - Demonstration of Cases. PMID- 30435843 TI - Obstetrical and Gynaecological Society. PMID- 30435842 TI - Amputations. PMID- 30435844 TI - Glasgow Pathological and Clinical Society. PMID- 30435846 TI - Current Topics. PMID- 30435845 TI - A Case of Defective Development of the Limbs. PMID- 30435847 TI - Glasgow Eastern Medical Society. PMID- 30435848 TI - Notes on Tubal Cases. PMID- 30435850 TI - Current Topics. PMID- 30435849 TI - The Alleged Increase of Insanity: And the Hospital Treatment of Mental Diseases. PMID- 30435851 TI - Some Cases of Spina Bifida with Other Deformities. PMID- 30435852 TI - On Enteric Fever and Some Diseases Which Simulate It. PMID- 30435853 TI - Personal Reminiscences of M. Charcot. PMID- 30435854 TI - Death Certification and Registration in Scotland: Its Present Defects and a Proposed Remedy. PMID- 30435855 TI - Congenital Deafness. PMID- 30435856 TI - The True Position of Oxygen as a Restorative in Carbonic Acid Poisoning. PMID- 30435857 TI - Case of Diphtheritic Paralysis without Any Preceding History of Throat Affection. PMID- 30435858 TI - On Medical Education. PMID- 30435859 TI - Glasgow Medico-Chirurgical Society. PMID- 30435860 TI - Glasgow Pathological and Clinical Society. PMID- 30435861 TI - Case of Traumatic Aneurysm of the Common Femoral Cured by Ligature. PMID- 30435862 TI - Current Topics. PMID- 30435863 TI - Varioloid or Varicella? PMID- 30435864 TI - Clinical Reports from the Glasgow Samaritan Hospital: II.-Miscellaneous Cases. PMID- 30435865 TI - A Foetus with Various Deformities, Apparently Due to Adherent Amnion. PMID- 30435866 TI - Glasgow Pathological and Clinical Society. PMID- 30435867 TI - A Retrospect. PMID- 30435868 TI - Two Cases of Atrophy of Muscles of Traumatic Origin: Being Extended Notes of Cases Shown at a Meeting of the Pathological and Clinical Society, 8th May, 1893. PMID- 30435869 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30435871 TI - Glasgow Medico-Chirurgical Society. PMID- 30435870 TI - Unusual Varieties of Ectopic Gestation. PMID- 30435873 TI - The True Position of Oxygen as a Restorative in Carbonic Acid Poisoning. PMID- 30435872 TI - A Case of Myxoedema, with Insanity, Treated by Thyroid Feeding and Thyroid Extract. PMID- 30435874 TI - Luke, the Christian Physician of Antioch. PMID- 30435875 TI - Current Topics. PMID- 30435876 TI - The Present Position of the Cystoscope in Surgical Practice. PMID- 30435877 TI - Glasgow Medico-Chirurgical Society. PMID- 30435878 TI - Then and Now; or, the Progress of Surgery during the Present Century. PMID- 30435879 TI - Case of Marked Improvement in General Paralysis, with Remarks on Treatment. PMID- 30435880 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30435881 TI - The Prevention of Preventable Disease. PMID- 30435883 TI - Glasgow Pathological and Clinical Society. PMID- 30435882 TI - Notes of a Case of Congenital Diaphragmatic Hernia. PMID- 30435884 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435885 TI - Current Topics. PMID- 30435886 TI - Glasgow Medico-Chirurgical Society. PMID- 30435887 TI - On Caisson Disease, with Some Speculations as to Its Causation. PMID- 30435888 TI - Case in Which a Tumour Was Removed by Operation from the Cerebellum of a Child Who Suffered from Hydrocephalus. PMID- 30435889 TI - Current Topics. PMID- 30435890 TI - Small-Pox and Its Prevention. PMID- 30435891 TI - Brief Personal Sketch of the Medical Quadrennium, 1857 to 1861. PMID- 30435893 TI - Glasgow Medico-Chirurgical Society. PMID- 30435894 TI - A Few Investigations and Researches on Diphtheria, Extending from 1874 to 1893. PMID- 30435892 TI - A Case of Pyaemia without External Wound (Malignant Periostitis). PMID- 30435895 TI - Two Cases of Myxoedema Treated by Thyroid Feeding. PMID- 30435896 TI - Friedreich's Ataxia. PMID- 30435897 TI - Current Topics. PMID- 30435898 TI - Remarks on a Case of Eclampsia during Pregnancy. PMID- 30435899 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435900 TI - A Marked Case of Acromegaly with Joint Affections. PMID- 30435901 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30435902 TI - The Malignant Transformation of Benign Laryngeal Tumours as a Consequence of Endolaryngeal Operations-A Correction. PMID- 30435904 TI - Glasgow Medico-Chirurgical Society. PMID- 30435903 TI - Acute Atrophic Spinal Paralysis in an Adult. PMID- 30435906 TI - Glasgow Pathological and Clinical Society. PMID- 30435905 TI - Glasgow Pathological and Clinical Society. PMID- 30435907 TI - Intestinal Haemorrhage in Enteric Fever. PMID- 30435908 TI - Case of Amputation at the Hip-Joint for Necrosis of Femur-Recovery. PMID- 30435909 TI - Food-Preservatives in Relation to the Provisions of the Food and Drugs Acts. PMID- 30435911 TI - On the Severer Forms of Scarlet Fever, with Special Reference to Antipyretic Methods of Treatment. PMID- 30435910 TI - Scarlatina and Scarlatinal Sore Throat-A Record of Milk Infection. PMID- 30435912 TI - Current Topics. PMID- 30435913 TI - Case of Suspected Gonorrhoea in a Young Boy, with Peculiar Source of Infection-A Caution. PMID- 30435914 TI - Glasgow Pathological and Clinical Society. PMID- 30435915 TI - Notes on a Case of Hydrophobia. PMID- 30435916 TI - Traumatic Rupture of Stomach. PMID- 30435918 TI - Current Topics. PMID- 30435917 TI - The Haematozoa of Malaria. PMID- 30435919 TI - The True Position of Oxygen as a Restorative in Carbonic Acid Poisoning. PMID- 30435920 TI - On the Severer Forms of Scarlet Fever, with Special Reference to Antipyretic Methods of Treatment: Being the Substance of His Thesis for the Degree of M.D. in the University of Glasgow. PMID- 30435921 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435923 TI - Glasgow Medico-Chirurgical Society. PMID- 30435922 TI - Two Cases of Depressed Compound Fracture of Skull. PMID- 30435924 TI - Current Topics. PMID- 30435925 TI - A Case of Excision of Portion of the Rectum for Carcinoma by the Sacral Method (Kraske); Recovery : Extract from the Report of the Case Taken by the Resident Assistant, Dr. Symington. PMID- 30435926 TI - Notes and Observations on Certain Forms of Epistaxis. PMID- 30435927 TI - Glasgow Pathological and Clinical Society. PMID- 30435928 TI - Three Cases of Faecal Tumour, in One of Which Death Occurred from Faecal Poisoning. PMID- 30435929 TI - Abstract of a Year's (1893) Medical Work in Wards 1, 2, and 9 of the Glasgow Royal Infirmary, with a Few Details of Some Rarer Cases, and Remarks on Treatment. PMID- 30435930 TI - Current Topics. PMID- 30435931 TI - Memorandum on a Case of Bishe or Malignant African Dysentery-Result, Death. PMID- 30435932 TI - Case of Marked Tricuspid Stenosis with Great Dilatation of the Right Auricle, Complicated with Mitral and Aortic Stenosis. PMID- 30435933 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30435935 TI - Septicaemia during Scarlet Fever, Implicating Several Joints and Causing Necrosis of Clavicle. PMID- 30435934 TI - Certain Points in the Basis of the Diagnosis of Syphilis: A Critical Review. PMID- 30435936 TI - Glasgow Medico-Chirurgical Society. PMID- 30435937 TI - Glasgow Pathological and Clinical Society. PMID- 30435938 TI - On a Complicated Case of Raynaud's Disease: Local Asphyxia with Gangrene, Occurring at a Very Early Age-Congenital Disturbance of General Cutaneous Circulation-Congenital Hydrocephalus-Tracheocele. PMID- 30435939 TI - Extraction of the Lens for High Degrees of Myopia. PMID- 30435940 TI - Report of Last Year's Work at the West-End Branch of the Maternity Hospital. PMID- 30435941 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30435943 TI - Note on a Specimen of Horse-Shoe Kidney. PMID- 30435942 TI - A Remarkable Case of Unilateral Hypertrophy in a Child. PMID- 30435945 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30435944 TI - Case of Hydrophobia. PMID- 30435946 TI - Glasgow Medico-Chirurgical Society. PMID- 30435947 TI - Hydronephrosis Simulating an Ovarian Cyst-Abdominal Section-Recovery. PMID- 30435948 TI - Current Topics. PMID- 30435950 TI - Glasgow Medico-Chirurgical Society. PMID- 30435949 TI - Three Years' Inductions of Premature Labour for Contracted Pelvis in the Glasgow Maternity Hospital. PMID- 30435951 TI - Current Topics. PMID- 30435952 TI - Gynaecology One Hundred and Fifty Years Ago. PMID- 30435953 TI - Case of Intestinal Obstruction-Volvulus and Internal Hernia-Successfully Operated on. PMID- 30435954 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd July, 1899. PMID- 30435955 TI - Gynaecologica. PMID- 30435956 TI - Uncorrected Errors of Refraction and Their Results. PMID- 30435958 TI - Current Topics. PMID- 30435957 TI - On the Position of the Gravid Uterus at the Onset of Labour with Regard to Lateroflexion and Rotation. PMID- 30435959 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th June, 1899. PMID- 30435960 TI - Demonstration of Cases. PMID- 30435961 TI - Notes upon a Case in Which Psychical Influence Appeared to Affect the Development of Organic Disease in the Presence of Heredity and Environment. PMID- 30435962 TI - Cases of Pregnancy Admitted to the Ward for Diseases of Women. PMID- 30435963 TI - William Hunter, Anatomist: A Lecture with Demonstration of Preparations from the Obstetrical Series of the Hunterian Museum. PMID- 30435964 TI - Glasgow Eastern Medical Society. PMID- 30435965 TI - Remarks upon the Operative Treatment of Infective Thrombosis of the Sigmoid Sinus Following Chronic Purulent Otitis Media: Record of a Case Successfully Treated. PMID- 30435967 TI - Current Topics. PMID- 30435966 TI - Cremation. PMID- 30435968 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd September, 1899. PMID- 30435969 TI - A Rare Medical Book, and Its Author. PMID- 30435970 TI - On the Value of Perchloride of Mercury as a Disinfectant for Floors. PMID- 30435971 TI - Clinical Gynaecology. PMID- 30435972 TI - The Treatment of Neurasthenia. PMID- 30435973 TI - Glasgow Pathological and Clinical Society. PMID- 30435975 TI - Clinical Gynaecology: Two Cases of Elongatio Colli of Different Causation and Requiring Different Treatment. PMID- 30435974 TI - On Loss of the Knee-Jerks in Gross Lesions of the Praefrontal Region of the Brain. PMID- 30435976 TI - Glasgow Eastern Medical Society. PMID- 30435977 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st October, 1899. PMID- 30435978 TI - On the Changes in Surgical Theory and Treatment in the past Twenty-Five Years. PMID- 30435980 TI - A Note on the Minute-Book of an Early Glasgow Medico-Chirurgical Society. PMID- 30435979 TI - Current Topics. PMID- 30435981 TI - Glasgow Medico-Chirurgical Society. PMID- 30435982 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th August, 1899. PMID- 30435984 TI - Missed Labour. PMID- 30435983 TI - Appendicitis. PMID- 30435985 TI - Glasgow Medico-Chirurgical Society. PMID- 30435986 TI - Obstetrical and Gynaecological Society. PMID- 30435987 TI - The Bacillus Coli Communis in Puerperal Septicaemia. PMID- 30435988 TI - Current Topics. PMID- 30435989 TI - Six Cases of Rash after Enemata. PMID- 30435990 TI - On the State of the Knee-Jerk in Cases of Cerebellar Tumour. PMID- 30435991 TI - Glasgow Pathological and Clinical Society. PMID- 30435992 TI - Current Topics. PMID- 30435993 TI - Recurrent Insanity: An Analysis of Relapsed Cases. PMID- 30435994 TI - Remarks on Tuberculosis. PMID- 30435996 TI - The Forfarshire Medical Association. PMID- 30435995 TI - Sarcoma Ovarii. PMID- 30435997 TI - Post-Epileptic Hemiplegia of Short Duration. PMID- 30435998 TI - Glasgow Eastern Medical Society. PMID- 30435999 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th November, 1899. PMID- 30436000 TI - Glasgow Southern Medical Society. PMID- 30436001 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st August, 1897. PMID- 30436002 TI - A Series of Cases of Ectopic Pregnancy, with Remarks on Diagnosis and Treatment. PMID- 30436003 TI - Clinical Essays on Insanity: V. On Certifying Lunatic Patients and the General Principles of Treatment. PMID- 30436004 TI - Two Comparatively Rare Cases of Accident. PMID- 30436005 TI - Current Topics. PMID- 30436006 TI - Cases of Cystic Disease of the Kidney, with Special Reference to Their Pathology, Diagnosis, and Surgical Treatment. PMID- 30436007 TI - Obstetrical and Gynaecological Society. PMID- 30436009 TI - Glasgow Medico-Chirurgical Society. PMID- 30436008 TI - Notes on the Routine Examination of the Normal and the Strictured Urethra, with Details of the Treatment of "Dilatable" Stricture: Based on the Practice at Prof. Guyon's Clinique, Necker Hospital, Paris. PMID- 30436010 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th July, 1897. PMID- 30436011 TI - Glasgow Pathological and Clinical Society. PMID- 30436012 TI - Current Topics. PMID- 30436013 TI - A Series of Intestinal Preparations. PMID- 30436014 TI - Sequel to a Case of Large Faecal Tumour. PMID- 30436015 TI - Obstetrical and Gynaecological Society. PMID- 30436016 TI - Case of Myxoedema Complicated with Cardiac Disease, with an Account of the Post Mortem Examination. PMID- 30436017 TI - Glasgow Medico-Chirurgical Society. PMID- 30436018 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th November, 1897. PMID- 30436019 TI - Glasgow Pathological and Clinical Society. PMID- 30436020 TI - On the Functions of a Medical Society. PMID- 30436021 TI - Hysteria as a Psychosis. PMID- 30436023 TI - Current Topics. PMID- 30436022 TI - Scarlatinal Albuminuria. PMID- 30436024 TI - A Year's Work at the Glasgow Maternity Hospital, with Notes of Cases. PMID- 30436025 TI - Our Motto-"'UpsilonPiHPETAI PhiUpsilonSigmaEOmegaSigma." PMID- 30436026 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd October, 1897. PMID- 30436027 TI - Current Topics. PMID- 30436028 TI - The History of Pathology. PMID- 30436029 TI - Obstetrical and Gynaecological Society. PMID- 30436030 TI - Some Observations on the Difficulties of Diagnosis in Abdominal Disease, with Brief Accounts of Illustrative Cases. PMID- 30436031 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 26th June, 1897. PMID- 30436033 TI - The Nature and Purpose of the British Pharmacopoeia. PMID- 30436034 TI - Glasgow Medico-Chirurgical Society. PMID- 30436032 TI - On Some Diseases of the Eye, the Result of Syphilis. PMID- 30436035 TI - Remarks Preceding a Demonstration in the Glasgow Royal Infirmary, 14th May, 1897. PMID- 30436036 TI - Current Topics. PMID- 30436037 TI - Cases of Cystic Disease of the Kidney, with Special Reference to Their Pathology, Diagnosis, and Surgical Treatment. PMID- 30436038 TI - Lectures on Clinical Medicine. Delivered in the Glasgow Royal Infirmary: VIII. A Case of the So-Called Hypertrophic Pulmonary Osteo-Arthropathy of Marie, without Pulmonary Disease. PMID- 30436039 TI - An Unusual Case of Zona. PMID- 30436041 TI - The Administration of Chloroform. PMID- 30436040 TI - Current Topics. PMID- 30436042 TI - Surgical Treatment of Acute Rheumatic Arthritis. PMID- 30436043 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th September, 1897. PMID- 30436044 TI - A Series of Cases of Ectopic Pregnancy, with Remarks on Diagnosis and Treatment. PMID- 30436045 TI - The History of the Circulation. PMID- 30436047 TI - Current Topics. PMID- 30436046 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436048 TI - A Case of Ureteritis Cystica. PMID- 30436049 TI - Leptospiral Jaundice. A Report of Two Cases with Special Reference to Clinical Investigation. PMID- 30436050 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436052 TI - Current Topics. PMID- 30436051 TI - Traumatic Asphyxia: With Illustrative Cases. PMID- 30436053 TI - New Preparations, Appliances, &c. PMID- 30436054 TI - Educational Supplement. PMID- 30436055 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436057 TI - Current Topics. PMID- 30436056 TI - The Non-Surgical Treatment of Cataract. PMID- 30436058 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436059 TI - Echinococcus Disease: Hydatid Cysts in Lung and in Liver: A Report on Two Cases, with Illustrations. PMID- 30436060 TI - Sulphanilamide in the Treatment of Gonorrhoea: With Special Reference to a Review of One Hundred Early Acute Cases. PMID- 30436061 TI - Para-Aminobenzine Sulphonamide in the Treatment of Pyelitis of Pregnancy. PMID- 30436062 TI - Current Topics. PMID- 30436063 TI - New Preparations, Appliances, &c. PMID- 30436064 TI - Some Cardiac Accidents Associated with Cardiazol Convulsion Therapy. PMID- 30436066 TI - Current Topics. PMID- 30436065 TI - Reports of a Few Cases of Tetanus Treated with Antitetanic Serum and Magnesium Sulphate. PMID- 30436067 TI - A Case of Tetanus Treated by Subcutaneous Injections of Magnesium Sulphate. PMID- 30436068 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436069 TI - Abdominal Symptoms in Degenerative Cardiac Disease. PMID- 30436071 TI - Acute Phlegmonous Gastritis: A Report of Seven Cases. PMID- 30436070 TI - Nomogram of Standard Body Weight in Men: A Note on McKinlay's Formula. PMID- 30436072 TI - Glasgow Northern Medical Society. PMID- 30436073 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436074 TI - Recent Work Concerning the AEtiology of Essential Hypertension. PMID- 30436075 TI - Glasgow Southern Medical Society. PMID- 30436076 TI - Current Topics. PMID- 30436078 TI - Current Topics. PMID- 30436077 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436079 TI - The Surgery of the Eye in Hungary. PMID- 30436080 TI - Educational Supplement. PMID- 30436081 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436082 TI - Current Topics. PMID- 30436083 TI - A Case of Torsion of the Gall-Bladder. PMID- 30436084 TI - Glasgow Northern Medical Society. PMID- 30436085 TI - Nomograms for Haematologists. PMID- 30436086 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436088 TI - Current Topics. PMID- 30436089 TI - Current Topics. PMID- 30436087 TI - Chemotherapy of Pneumonia by M. & B. 693 in Practice. PMID- 30436090 TI - Eye Casualties on the Home Front. PMID- 30436092 TI - Spontaneous Hyperaemic Dislocation of the Atlas. PMID- 30436091 TI - Eye Casualties at the Front. PMID- 30436093 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436094 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436095 TI - Current Topics. PMID- 30436096 TI - Inflammatory Stricture of the Rectum. PMID- 30436097 TI - The Diagnosis and Treatment of Sprue. PMID- 30436098 TI - Herpes and Varicella: Simultaneously in the Same Patient. PMID- 30436099 TI - Personal Experiences in Vascular Surgery. PMID- 30436100 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436101 TI - Two Cases of Haemochromatosis. PMID- 30436102 TI - Current Topics. PMID- 30436103 TI - Darwin's Doctrine of Evolution in Explanation of the Coming into Being of Some Diseases. Section VI. PMID- 30436104 TI - Current Topics. PMID- 30436105 TI - Glasgow Royal Infirmary. PMID- 30436106 TI - Notes from Vienna. PMID- 30436107 TI - Case of Hermaphrodite. PMID- 30436108 TI - The Treatment of Cancer of the Rectum by Excision, with a Record of Seven Cases. PMID- 30436110 TI - Notes from Berlin. PMID- 30436109 TI - On Recent Methods of Treatment of the Asphyxia of New-Born Children, with a Description and Illustration of That of Professor B. S. Schultze, of Jena: Being an Address at the Inaugural Meeting of the Glasgow Obstetrical and Gynoecological Society, 14th October, 1885, by the President of the Society. PMID- 30436111 TI - On the Vis Medicatrix Naturae: Being the Introductory Address at the Opening of the Session in the Royal Infirmary School of Medicine, 27th Oct., 1885. PMID- 30436112 TI - A Case of Puerperal Mania with Remarks. PMID- 30436113 TI - Chordoma: Report of a Case. PMID- 30436114 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436115 TI - New Preparations, Appliances, &c. PMID- 30436116 TI - Glasgow Southern Medical Society. PMID- 30436117 TI - A Critical Review of the Steinach II. Operation as a Method of Treating Prostatic Obstruction. PMID- 30436118 TI - Undulant Fever: A Review with a Report of a Case. PMID- 30436119 TI - Current Topics. PMID- 30436120 TI - Current Topics. PMID- 30436121 TI - Anaesthesia and Analgesia in Obstetrics. PMID- 30436122 TI - The Influence of Acid-Feeding on the Utilization of the Mineral Elements. PMID- 30436123 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436125 TI - Glasgow Northern Medical Society. PMID- 30436124 TI - Complete Atrophy of the Penis. PMID- 30436126 TI - Glasgow Southern Medical Society. PMID- 30436127 TI - Current Topics. PMID- 30436128 TI - Pulmonary Carcinoma: A Pathological Study of a Series of Cases with Special Reference to the Route of Spread and to the Factors That Determine the Mode of Spread. PMID- 30436130 TI - New Preparations, Appliances, &c. PMID- 30436129 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436131 TI - A Survey of the Results of Fractures of the Long Bones of the Lower Limb. PMID- 30436132 TI - Benign Lymphocytic Meningitis. PMID- 30436133 TI - Current Topics. PMID- 30436135 TI - A Case of Verruca Necrogenica. PMID- 30436134 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436136 TI - Glasgow Southern Medical Society. PMID- 30436137 TI - New Preparations, Appliances, &c. PMID- 30436138 TI - Recent Theories of the Nature of Glaucoma. PMID- 30436139 TI - Glasgow Northern Medical Society. PMID- 30436140 TI - The Glasgow and West of Scotland Medical Association. PMID- 30436141 TI - Current Topics. PMID- 30436142 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436143 TI - Glasgow Southern Medical Society. PMID- 30436144 TI - Carcinoma of the Pancreas. PMID- 30436146 TI - New Preparations, Appliances, &c. PMID- 30436145 TI - Glasgow Northern Medical Society. PMID- 30436147 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436149 TI - Case of Diabetes Mellitus, Associated with Lesions of the Pituitary Body. PMID- 30436148 TI - A Method of Treating Fractures of the Spine, with Eight Case Records. PMID- 30436150 TI - Glasgow Southern Medical Society. PMID- 30436152 TI - Current Topics. PMID- 30436151 TI - Visual Perception. PMID- 30436153 TI - Eye Symptoms in Diseases of the Nervous System. PMID- 30436154 TI - On General Paralysis of the Insane, with Notes of an Unusual Case. PMID- 30436155 TI - Current Topics. PMID- 30436156 TI - Glasgow Medico-Chirurgical Society. PMID- 30436157 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd May, 1897. PMID- 30436158 TI - Shoulder Presentations in Midwifery Practice. PMID- 30436159 TI - Case of Extensive Burns of the Face, Eyes, and Scalp, Caused by Molten Brass. PMID- 30436160 TI - Glasgow Pathological and Clinical Society. PMID- 30436161 TI - Clinical Essays on Insanity: IV. General Paralysis of the Insane. PMID- 30436162 TI - Obstetrical and Gynaecological Society. PMID- 30436163 TI - Current Topics. PMID- 30436164 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd January, 1897. PMID- 30436166 TI - Glasgow Medico-Chirurgical Society. PMID- 30436165 TI - Cases from the Glasgow Royal Infirmary Dispensary. PMID- 30436167 TI - Glasgow Pathological and Clinical Society. PMID- 30436168 TI - Peritonitis in Enteric Fever with Regard to Surgical Interference: Being a Study of Forty-Seven Cases from the Records of Belvidere Fever Hospital. PMID- 30436169 TI - Notes on a Case of Hypertrophic Pulmonary Osteo-Arthropathy. PMID- 30436171 TI - Some Cases of Hepatic Surgery. PMID- 30436170 TI - Outbreak of Enteric Fever at Possilpark, Glasgow. PMID- 30436173 TI - On the Numbers of the Medical Practitioners in Glasgow in the Years 1885 and 1897 Respectively. PMID- 30436172 TI - Current Topics. PMID- 30436174 TI - Glasgow Medico-Chirurgical Society. PMID- 30436176 TI - Glasgow Eastern Medical Society. PMID- 30436175 TI - Cases of Cystic Disease of the Kidney, with Special Reference to Their Pathology, Diagnosis, and Surgical Treatment. PMID- 30436177 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th April, 1897. PMID- 30436178 TI - Glasgow Pathological and Clinical Society. PMID- 30436180 TI - Glasgow Medico-Chirurgical Society. PMID- 30436179 TI - Intubation and Tracheotomy in Diphtheria. PMID- 30436181 TI - Current Topics. PMID- 30436183 TI - Case of Chronic Purulent Inflammation of the Middle Ear on Both Sides, Proving Fatal by Extension on the Left Side, through the Labyrinth and Auditory and Facial Nerves to the Interior of the Cranium-With Observations. PMID- 30436182 TI - A Case of Successful Removal of a Large Sarcoma of the Brain. PMID- 30436184 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th March, 1897. PMID- 30436185 TI - Glasgow Pathological and Clinical Society. PMID- 30436186 TI - Clinical Essays on Insanity: III. Epileptic Insanity (the Demonstrative Manner of Epileptics) and Puerperal Insanity. PMID- 30436187 TI - Obstetrical and Gynaecological Society. PMID- 30436188 TI - Clinical Essays on Insanity: II. Insanity of the Different Periods of Life Evolutional and Involutional Types. PMID- 30436189 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th February, 1897. PMID- 30436190 TI - Glasgow Medico-Chirurgical Society. PMID- 30436191 TI - Glasgow Eastern Medical Society. PMID- 30436193 TI - Glasgow Pathological and Clinical Society. PMID- 30436192 TI - Notes on the Occurrence of a Number of Cases of Epidemic Roseola or Rotheln in the City of Glasgow Fever Hospital, Kennedy Street. PMID- 30436194 TI - Case of Spastic Hemiplegia of Gradual Onset, Following a Severe Attack of Enteric Fever, and Terminating in Insanity. PMID- 30436196 TI - Lectures on Clinical Medicine. Delivered in the Glasgow Royal Infirmary: V. On the Jaundice of Early Infancy, with a Case of Congenital Obliteration of the Bile Ducts. PMID- 30436195 TI - The Jubilee of Anaesthetic Midwifery: An Inaugural Address to the Glasgow Obstetrical and Gynaecological Society, on Tuesday, 19th January, 1897, by the Honorary President. PMID- 30436197 TI - Current Topics. PMID- 30436198 TI - Glasgow Eastern Medical Society. PMID- 30436199 TI - Glasgow Pathological and Clinical Society. PMID- 30436200 TI - The Birth and Death of Pain. PMID- 30436201 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th December, 1896. PMID- 30436203 TI - Glasgow Medico-Chirurgical Society. PMID- 30436204 TI - Glasgow Southern Medical Society. PMID- 30436202 TI - Clinical Essays on Insanity: I. Melancholic, Maniacal, and Demented States. PMID- 30436205 TI - Obstetrical and Gynaecological Society. PMID- 30436206 TI - Landolt on Squint. PMID- 30436207 TI - Recurrent Sarcomatous Growths after Amputation of Scapula. PMID- 30436208 TI - Current Topics. PMID- 30436209 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436210 TI - Renal Tuberculosis and Excretory Bacilluria. PMID- 30436211 TI - New Preparations, Appliances, &c. PMID- 30436212 TI - Glasgow Southern Medical Society. PMID- 30436213 TI - Case of Colic-Ovarian Fistula. PMID- 30436214 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436215 TI - Weil's Disease: A New Occupational Disease in Fish Workers. PMID- 30436216 TI - New Preparations, Appliances, &c. PMID- 30436218 TI - Glasgow Southern Medical Society. PMID- 30436217 TI - The Glasgow and West of Scotland Medical Association. PMID- 30436219 TI - Current Topics. PMID- 30436221 TI - New Preparations, Appliances, &c. PMID- 30436220 TI - Massive Ischaemic Gangrene with Thrombosis of Veins and Patent Arteries. PMID- 30436222 TI - Current Topics. PMID- 30436223 TI - Paget's Disease of Bone: Its Frequency, Diagnosis and Complications. PMID- 30436224 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436226 TI - Glasgow Southern Medical Society. PMID- 30436225 TI - Otitic Hydrocephalus with Contralateral Sixth Nerve Palsy. PMID- 30436228 TI - Current Topics. PMID- 30436227 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436230 TI - Glasgow Southern Medical Society. PMID- 30436229 TI - A Survey of Virus Infections. PMID- 30436231 TI - Glasgow Southern Medical Society. PMID- 30436232 TI - Current Topics. PMID- 30436233 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436235 TI - Glasgow Northern Medical Society. PMID- 30436234 TI - Observations on the Diagnostic and Prognostic Significance of Electrocardiograms Showing Anomalous Forms of QRS in Lead III, Based on an Analysis and Follow up of a Series of Cases. PMID- 30436236 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436237 TI - Treatment of Mental Disorders by Cardiazol. PMID- 30436238 TI - Carcinoma of the Ileo-Caecal Valve: A Report of Three Cases and Statistical Survey. PMID- 30436239 TI - Glasgow Northern Medical Society. PMID- 30436241 TI - Current Topics. PMID- 30436240 TI - Recurrence by Anastomotic Circulation of an Arteriovenous Aneurysm of the Axillary Artery and Vein. PMID- 30436242 TI - The Superior Mediastinum in Its Clinical Aspects: With Special Reference to Signs of Aneurysm of the Transverse Aorta: A Record of 110 Cases. PMID- 30436243 TI - Vital Statistics, &c. PMID- 30436244 TI - Is There a Gastro-Intestinal Ataxia? PMID- 30436245 TI - Current Topics. PMID- 30436246 TI - Problems of Vision in Aviation. PMID- 30436247 TI - Congenital Absence of Tears. PMID- 30436248 TI - Current Topics. PMID- 30436249 TI - Vital Statistics, &c. PMID- 30436250 TI - The Prognosis in Diabetes in Childhood: A Review of Seventy Cases. PMID- 30436251 TI - Vital Statistics, &c. PMID- 30436252 TI - Current Topics. PMID- 30436253 TI - Thrombosis of the Abdominal Aorta: With Report of a Case. PMID- 30436254 TI - The Newer Insulins. PMID- 30436255 TI - Current Topics. PMID- 30436256 TI - Vital Statistics, &c. PMID- 30436257 TI - Thomas Johnson (1597? - 1644): Botanist and Barber Surgeon. PMID- 30436258 TI - Vital Statistics, &c. PMID- 30436259 TI - Current Topics. PMID- 30436260 TI - The Radiological Examination of the Normal and Adolescent Kyphotic Spines. PMID- 30436262 TI - An Analogy between the Intrinsic Muscles of the Eye and the Muscle of the Heart. PMID- 30436261 TI - Vital Statistics, &c. PMID- 30436263 TI - Codeine in Chronic Bronchitis. PMID- 30436264 TI - Vital Statistics, &c. PMID- 30436266 TI - Current Topics. PMID- 30436265 TI - Observations on Non-Industrial Lead Poisoning. PMID- 30436268 TI - Current Topics. PMID- 30436267 TI - Vital Statistics, &c. PMID- 30436269 TI - Some Relations between the Diseases of the Central Nervous System and the Eye. PMID- 30436270 TI - Clinical Notes: S.U.P. 36 in General Practice. PMID- 30436272 TI - Educational Supplement. PMID- 30436271 TI - Carcinoma of the Bronchus: An Investigation into the Incidence and Pathological Features of 131 Cases from Glasgow Royal Infirmary. PMID- 30436273 TI - Asthma Associated with Haemoglobinuria. PMID- 30436275 TI - Current Topics. PMID- 30436274 TI - Vital Statistics, &c. PMID- 30436276 TI - Current Topics. PMID- 30436277 TI - Vital Statistics, &c. PMID- 30436278 TI - Cyclopropane Anaesthesia: With Notes on 200 Cases. PMID- 30436280 TI - Fatal Agranulocytosis after Sulphapyridine (M. & B. 693) Therapy. PMID- 30436279 TI - Vital Statistics, &c. PMID- 30436281 TI - Current Topics. PMID- 30436283 TI - Calcium Gluconate in Cardiac Failure: Clinical Pharmacology and Therapeutics. PMID- 30436282 TI - A Contrast in Methods of Vaccination: By Intradermal Injection and by Linear Scratch. PMID- 30436284 TI - Vital Statistics, &c. PMID- 30436286 TI - Glasgow Southern Medical Society. PMID- 30436285 TI - Perimetry and the Visual Pathway. PMID- 30436287 TI - Current Topics. PMID- 30436288 TI - Observations on Some of the Newer Remedies in the Treatment of Diseases of the Eye. PMID- 30436289 TI - Current Topics. PMID- 30436290 TI - Glasgow Eastern Medical Society. PMID- 30436291 TI - Obstetrical and Gynaecological Society. PMID- 30436292 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st May, 1904. PMID- 30436293 TI - Contract Practice. PMID- 30436294 TI - Movable Displacements of the Kidney. PMID- 30436295 TI - Notes of a Case in Which There Were Attacks of Acute Pulmonary OEdema. PMID- 30436296 TI - Case of Sudden Death from Embolism of the Left Cardiac Coronary Artery (Death Occurring within a Minute of the Seizure). PMID- 30436297 TI - Rib Fractured by Coughing. PMID- 30436298 TI - The External and Internal Use of Normal Saline. PMID- 30436299 TI - Glasgow Eastern Medical Society. PMID- 30436300 TI - Notes on American Hospitals. PMID- 30436302 TI - Glasgow Northern Medical Society. PMID- 30436301 TI - Tubercular Iritis. PMID- 30436303 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd January, 1904. PMID- 30436304 TI - Glasgow Pathological and Clinical Society. PMID- 30436305 TI - New Preparations, &c. PMID- 30436306 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th February, 1904. PMID- 30436307 TI - Current Topics. PMID- 30436308 TI - Accouchement Force by Modern Methods, with Special Reference to the Use of Bossi's and Frommer's Dilators, and Duhrssen's Incisions of the Cervix. PMID- 30436309 TI - Two Cases in Cerebral Surgery. PMID- 30436311 TI - Glasgow Northern Medical Society. PMID- 30436310 TI - Description of a Porencephalic Brain. PMID- 30436312 TI - Glasgow Southern Medical Society. PMID- 30436313 TI - Obstetrical and Gynaecological Society. PMID- 30436315 TI - New Preparations, &c. PMID- 30436314 TI - Glasgow Medico-Chirurgical Society. PMID- 30436317 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd April, 1904. PMID- 30436316 TI - Glasgow Northern Medical Society. PMID- 30436318 TI - Current Topics. PMID- 30436319 TI - Movable Displacements of the Kidney. PMID- 30436320 TI - Glasgow Medico-Chirurgical Society. PMID- 30436322 TI - New Preparations, &c. PMID- 30436321 TI - Case of "Hysteroid" Disease in the Male. PMID- 30436323 TI - Glasgow Pathological and Clinical Society. PMID- 30436324 TI - Glasgow Eastern Medical Society. PMID- 30436325 TI - Ulceration of the Duodenum, with General Peritonitis and Severe Haemorrhage: Recovery. PMID- 30436327 TI - Obstetrical and Gynaecological Society. PMID- 30436326 TI - On the Use of Alcohol as a Medicine. PMID- 30436329 TI - Glasgow Eastern Medical Society. PMID- 30436328 TI - Three Cases of Ocular Paralysis. PMID- 30436331 TI - Movable Displacements of the Kidney. PMID- 30436330 TI - Glasgow Medico-Chirurgical Society. PMID- 30436333 TI - Current Topics. PMID- 30436332 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th March, 1904. PMID- 30436334 TI - Abdominal Surgery, Retrospective and Prospective: Based on Fourteen Years' Personal Experience in the Wards of the Victoria Infirmary, Glasgow. PMID- 30436335 TI - New Preparations, &c. PMID- 30436336 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th December, 1903. PMID- 30436337 TI - Poisoning Produced by Thirty Grains of Salicylate of Sodium. PMID- 30436338 TI - High-Frequency Currents in Medical Practice. PMID- 30436339 TI - Some Observations on Ocular and Other Forms of Chronic Headache. PMID- 30436341 TI - Glasgow Southern Medical Society. PMID- 30436340 TI - Hodgkin's Disease (Lymphadenoma) or Lymphosarcoma? A Clinical Study of a Case. PMID- 30436343 TI - Glasgow Eastern Medical Society. PMID- 30436342 TI - Current Topics. PMID- 30436345 TI - New Preparations, &c. PMID- 30436344 TI - Glasgow Pathological and Clinical Society. PMID- 30436346 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd June, 1901. PMID- 30436347 TI - Obstetrical and Gynaecological Society. PMID- 30436348 TI - Current Topics. PMID- 30436349 TI - Glasgow Medico-Chirurgical Society. PMID- 30436350 TI - Furunculosis of the External Auditory Canal. PMID- 30436351 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436352 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th October, 1901. PMID- 30436353 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436354 TI - On Blood-Letting in the Treatment of Disease. PMID- 30436355 TI - Vis Medicatrix Naturae. PMID- 30436356 TI - Observations on Perforated Gastric Ulcer. PMID- 30436357 TI - Current Topics. PMID- 30436358 TI - Freedom in Teaching. PMID- 30436359 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th August, 1901. PMID- 30436360 TI - Sarcoma of the Prevertebral Lymphatic Glands, Involving the Solar and Coeliac Plexuses-Sudden Death from Haemorrhagic Pancreatitis. PMID- 30436361 TI - Glasgow Pathological and Clinical Society. PMID- 30436362 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436364 TI - Glasgow Medico-Chirurgical Society. PMID- 30436363 TI - Case of Diabetes in Which Threatened Coma Was Averted under Treatment by Intravenous Saline Injections. PMID- 30436366 TI - Patency of Pericardium: Solitary Kidney: Septum in Urinary Bladder. PMID- 30436365 TI - Current Topics. PMID- 30436367 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th July, 1901. PMID- 30436368 TI - Notes on a Case of Symphysiotomy. PMID- 30436369 TI - Current Topics. PMID- 30436370 TI - Three and a Half Years' Experience of Faradisation of the Head, on Scientific Principles, in the Treatment of Chronic Insomnia and Associated Neuroses, Comprising a Series of Forty-Six Cases. PMID- 30436372 TI - Glasgow Pathological and Clinical Society. PMID- 30436371 TI - Tonsillar Calculi Occurring in Both Tonsils. PMID- 30436374 TI - Glasgow Medico-Chirurgical Society. PMID- 30436373 TI - Cases in Clinical Surgery. PMID- 30436375 TI - Obstetrical and Gynaecological Society. PMID- 30436376 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436377 TI - Current Topics. PMID- 30436378 TI - Obstetrical and Gynaecological Society. PMID- 30436379 TI - Glasgow Pathological and Clinical Society. PMID- 30436381 TI - Purpura Haemorrhagica in a Case of Vomiting of Pregnancy. PMID- 30436380 TI - Dr. Finsen's Lupus Treatment. PMID- 30436383 TI - The Communicability of Scarlet Fever by Discharge from the Ear. PMID- 30436382 TI - Glasgow Medico-Chirurgical Society. PMID- 30436384 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd November, 1901. PMID- 30436385 TI - Case of Peripheral Thrombosis and Cardiopulmonary Embolism Treated by Large Doses of Ammonia. PMID- 30436386 TI - Membranous Sore Throat and Perforation of the Faucial Pillars Resulting from Infection by the Pneumococcus. PMID- 30436387 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436389 TI - Glasgow Medico-Chirurgical Society. PMID- 30436388 TI - Notes on Irideremia, with Remarks upon the Histological Examination of Cases. PMID- 30436390 TI - Note on a Case of Unilateral Acute Retrobulbar Optic Neuritis. PMID- 30436391 TI - Two Cases of Tubercular Peritonitis. PMID- 30436392 TI - Changes in the Peripheral Nerves in a Case of Diabetes Mellitus. PMID- 30436393 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st September, 1901. PMID- 30436394 TI - Current Topics. PMID- 30436395 TI - Glasgow Eastern Medical Society. PMID- 30436396 TI - Case of Diphtheria Complicated by Acute Endocarditis of the Mitral Valve. PMID- 30436397 TI - Obstetrical and Gynaecological Society. PMID- 30436399 TI - Faculty of Physicians and Surgeons, Glasgow: Presentation to the Faculty of the Portrait of the Secretary and Librarian, Alexander Duncan, B.A., LL.D. PMID- 30436398 TI - A Retrospect and Prospect in Obstetrics and Gynaecology. PMID- 30436400 TI - Current Topics. PMID- 30436401 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th December, 1902. PMID- 30436402 TI - An Old Stethoscope. PMID- 30436403 TI - A Consideration of Labour among Primitive People. PMID- 30436404 TI - Glasgow Pathological and Clinical Society. PMID- 30436405 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd May, 1903. PMID- 30436406 TI - Volkmann's Contracture. PMID- 30436408 TI - Obstetrical and Gynaecological Society. PMID- 30436407 TI - Glasgow Northern Medical Society. PMID- 30436409 TI - Current Topics. PMID- 30436410 TI - The Histological Appearances of the Nervous System in Krait and Cobra Poisoning. PMID- 30436412 TI - Obstetrical and Gynaecological Society. PMID- 30436411 TI - Glasgow Medico-Chirurgical Society. PMID- 30436413 TI - Snake Venoms: Their Physiological Action and Antidote. PMID- 30436414 TI - New Preparations, &c. PMID- 30436415 TI - Amblyopia from Non-Use. PMID- 30436416 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th January, 1903. PMID- 30436417 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th April, 1903. PMID- 30436419 TI - Glasgow Eastern Medical Society. PMID- 30436418 TI - Some Questions Bearing on Infant-Feeding Dealt with in the Light of Recent Observations. PMID- 30436420 TI - Notes of a Case of Inoperable Carcinoma of the Pregnant Uterus in Which the Porro Caesarean Operation Was Successfully Performed. PMID- 30436421 TI - New Preparations, &c. PMID- 30436422 TI - The Consumptive Poor-What to Do with Them: A Plea for Notification. PMID- 30436423 TI - Current Topics. PMID- 30436424 TI - Glasgow Medico-Chirurgical Society. PMID- 30436426 TI - Current Topics. PMID- 30436425 TI - Case of Puerperal Eclampsia Complicated by Hemiplegia. PMID- 30436428 TI - New Preparations, &c. PMID- 30436427 TI - Unaware of Pregnancy Till Baby Was Born. PMID- 30436429 TI - Glasgow Pathological and Clinical Society. PMID- 30436430 TI - Can Anything Special Be Done by the Medical Practitioner to Diminish the Frequency and Lessen the Mortality of Cancer of the Uterus? PMID- 30436431 TI - Glasgow Medico-Chirurgical Society. PMID- 30436432 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st March, 1903. PMID- 30436433 TI - Glasgow Eastern Medical Society. PMID- 30436434 TI - Glasgow Northern Medical Society. PMID- 30436435 TI - Case of Marked Dilatation of the Superficial Abdominal and Thoracic Veins without Evident Cause. PMID- 30436436 TI - Three Cases of Different Forms of Congenital Syphilitic Disease of the Eye Occurring in the Same Family, with Remarks Thereon. PMID- 30436437 TI - Clinical Cases. PMID- 30436439 TI - Glasgow Eastern Medical Society. PMID- 30436438 TI - Obstetrical and Gynaecological Society. PMID- 30436440 TI - Glasgow Pathological and Clinical Society. PMID- 30436442 TI - The Significance of Pain in the Ear. PMID- 30436441 TI - On Obscure Pyaemia: With the Description of a Case Which Originated in a Gonorrhoeal Urethritis. PMID- 30436443 TI - Current Topics. PMID- 30436444 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st February, 1903. PMID- 30436445 TI - Obstetrical and Gynaecological Society. PMID- 30436446 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd July, 1904. PMID- 30436448 TI - Glasgow Medico-Chirurgical Society. PMID- 30436447 TI - New Preparations, &c. PMID- 30436449 TI - Intraperitoneal Haemorrhage and Haematocele Arising from Tubal Abortion or Rupture, with Records of Illustrative Cases. PMID- 30436451 TI - Glasgow Pathological and Clinical Society. PMID- 30436450 TI - Glasgow Northern Medical Society. PMID- 30436453 TI - Current Topics. PMID- 30436452 TI - Case of Chronic Lymphatic Leukaemia. PMID- 30436454 TI - Glasgow Eastern Medical Society. PMID- 30436455 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th August, 1904. PMID- 30436456 TI - Movable Displacements of the Kidney. PMID- 30436457 TI - A Case of General Amnesia? PMID- 30436458 TI - The Operative Treatment of Appendicitis: A Six Months' Record. PMID- 30436459 TI - Glasgow Medico-Chirurgical Society. PMID- 30436460 TI - Current Topics. PMID- 30436462 TI - The Causes of Infantile Mortality: Discussion at the Glasgow Medico-Chirurgical Society on 4th March, 1904. PMID- 30436461 TI - New Preparations, &c. PMID- 30436464 TI - A Contribution to the Pathology of the Antrum of Highmore. PMID- 30436463 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th September, 1904. PMID- 30436465 TI - New Apparatus for the Production of X-Rays and High-Frequency Currents. PMID- 30436467 TI - Obstetrical and Gynaecological Society. PMID- 30436466 TI - New Preparations, &c. PMID- 30436468 TI - Current Topics. PMID- 30436469 TI - Some Notes on the Treatment of Tuberculous Glands in the Neck by Excision. PMID- 30436470 TI - A Contribution to the Pathology of the Antrum of Highmore. PMID- 30436471 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd October, 1904. PMID- 30436472 TI - Current Topics. PMID- 30436473 TI - Glasgow Eastern Medical Society. PMID- 30436474 TI - Movable Displacements of the Kidney. PMID- 30436475 TI - Glasgow Medico-Chirurgical Society. PMID- 30436476 TI - Obstetrical and Gynaecological Society. PMID- 30436477 TI - Mycoses, with Special Reference to Mycosis of the Eyeball. PMID- 30436478 TI - Eye-Strain and Its Consequences. PMID- 30436479 TI - Case of Traumatic Exophthalmus Pulsans-Ligature of Common Carotid-Cure. PMID- 30436481 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th November, 1904. PMID- 30436480 TI - Glasgow Medico-Chirurgical Society. PMID- 30436483 TI - Glasgow Medico-Chirurgical Society. PMID- 30436482 TI - Current Topics. PMID- 30436484 TI - Movable Displacements of the Kidney. PMID- 30436486 TI - Current Topics. PMID- 30436485 TI - Glasgow Pathological and Clinical Society. PMID- 30436487 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th June, 1904. PMID- 30436488 TI - Case of Severe Concussion Injury to the Eye. PMID- 30436489 TI - Glasgow Northern Medical Society. PMID- 30436490 TI - Obstetrical and Gynaecological Society. PMID- 30436491 TI - New Preparations, &c. PMID- 30436492 TI - Glasgow Eastern Medical Society. PMID- 30436493 TI - Surgical or Traumatic Rheumatism, with a Note on the Use of Corrigan's Button. PMID- 30436494 TI - Note on Two Cases of Parotitis as a Complication of Influenza and Pneumonia. PMID- 30436495 TI - The Causes of the Neglect of Suppurative Ear-Disease. PMID- 30436496 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30436497 TI - Popular Therapeutics at the Beginning of the Eighteenth Century. PMID- 30436498 TI - Glasgow Medico-Chirurgical Society. PMID- 30436499 TI - Notes of a Case of Missed Labour. PMID- 30436500 TI - On Secondary Parotitis, with Notes of Four Cases. PMID- 30436501 TI - Case of a Doctor Affected with Diphtheria, Wherein Behring's Antitoxin Was Employed. PMID- 30436502 TI - A Visit to Garches with Dr. Roux. PMID- 30436503 TI - Cases of Functional Paralysis; Treatment by Hypnotism, Myelin, &c.; Recovery. PMID- 30436504 TI - Twenty-Six Cases of Puerperal Fever Observed in Belvidere Hospital. PMID- 30436505 TI - Current Topics. PMID- 30436506 TI - Glasgow Pathological and Clinical Society. PMID- 30436507 TI - Clinical Cases from General Practice. PMID- 30436508 TI - Glasgow Medico-Chirurgical Society. PMID- 30436509 TI - A History of the Chronic Degenerative Diseases of the Central Nervous System. PMID- 30436510 TI - The Board of Trade and Seamen's Eyesight. PMID- 30436511 TI - Glasgow Pathological and Clinical Society. PMID- 30436512 TI - On Ludwig and Pasteur; and on Vivisection. PMID- 30436514 TI - Current Topics. PMID- 30436513 TI - American Notes-Medical and Hygienic. PMID- 30436516 TI - A History of the Chronic Degenerative Diseases of the Central Nervous System. PMID- 30436515 TI - Glasgow Medico-Chirurgical Society. PMID- 30436517 TI - Idiopathic Enlargement of the Spleen, with Recurrent Attacks of Purpura. PMID- 30436519 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436518 TI - Ludwig and Physiology. PMID- 30436520 TI - Observations on Epidemics of Cholera in India, with Special Reference to Their Immediate Connection with Pilgrimages. PMID- 30436521 TI - Current Topics. PMID- 30436522 TI - A History of the Chronic Degenerative Diseases of the Central Nervous System. PMID- 30436523 TI - A Contribution to the Meteorology of Sporadic Pneumonia. PMID- 30436524 TI - Eponymic Structures in Human Anatomy. PMID- 30436525 TI - Ceylon as a Winter Resort. PMID- 30436526 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436527 TI - Case of Marked Muscular Atrophy of Hands and Fore-Arms-Progressive Muscular Atrophy(?). PMID- 30436528 TI - Glasgow Medico-Chirurgical Society. PMID- 30436529 TI - Current Topics. PMID- 30436530 TI - Strangulated Femoral Hernia on Right Side-Gangrene; Rupture; Resection of the Bowel; Cure. PMID- 30436532 TI - Glasgow Pathological and Clinical Society. PMID- 30436531 TI - A Case of Missed Abortion-Retention of Ovum for Eighty-Six Days after Death of Foetus. PMID- 30436533 TI - A Case of Transposition of the Thoracic and Abdominal Viscera. PMID- 30436534 TI - Case of Diphtheria in Which the Serum Was Used-Tracheotomy-Recovery. PMID- 30436535 TI - Insured Lives as Affected by Gout. PMID- 30436536 TI - The Climate of the Isles of Scilly, with Special Reference to Their Suitability as a Health Resort. PMID- 30436537 TI - Necrosis of the Labyrinth, with Report of a Case. PMID- 30436538 TI - Current Topics. PMID- 30436539 TI - Glasgow Medico-Chirurgical Society. PMID- 30436540 TI - New Preparations, &c. PMID- 30436541 TI - Perforative Peritonitis in Enteric Fever. PMID- 30436542 TI - On a Case of Acute Lymphatic Leukaemia with Numerous Subcutaneous Lymphocytic Nodules-Chloroma. PMID- 30436543 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th June, 1903. PMID- 30436544 TI - Current Topics. PMID- 30436545 TI - Glasgow Pathological and Clinical Society. PMID- 30436546 TI - Glasgow Medico-Chirurgical Society. PMID- 30436547 TI - Case of Diffuse Symmetrical Scleroderma Characterised by Involvement Principally, and at First Only, of the Lower Limbs. PMID- 30436549 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st November, 1903. PMID- 30436548 TI - Glasgow Medico-Chirurgical Society. PMID- 30436550 TI - Glasgow Eastern Medical Society. PMID- 30436551 TI - New Preparations, &c. PMID- 30436553 TI - Current Topics. PMID- 30436552 TI - Report on Continental Maternity Hospitals Submitted to the Directors of the Glasgow Maternity Hospital. PMID- 30436554 TI - Obstetrical and Gynaecological Society. PMID- 30436555 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th September, 1903. PMID- 30436556 TI - Evidences of Rheumatism in Childhood. PMID- 30436557 TI - Glasgow Pathological and Clincal Society. PMID- 30436558 TI - The Selection of Methods in Abdominal Hysterectomy. PMID- 30436559 TI - Current Topics. PMID- 30436560 TI - New Preparations, &c. PMID- 30436561 TI - Intussusception, with Special Reference to Relapse. PMID- 30436562 TI - Glasgow Pathological and Clinical Society. PMID- 30436563 TI - Glasgow Eastern Medical Society. PMID- 30436564 TI - Obstetrical and Gynaecological Society. PMID- 30436565 TI - Current Topic. PMID- 30436566 TI - Case of Acute Poisoning after the Instillation of a Small Dose of Atropine into the Eye. PMID- 30436567 TI - The Early History of Appendicitis in Great Britain. PMID- 30436568 TI - Distortion and Displacement of the Uterus Due to a Myoma. PMID- 30436569 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th July, 1903. PMID- 30436571 TI - New Preparations, &c. PMID- 30436570 TI - Glasgow Eastern Medical Society. PMID- 30436572 TI - Exanthematous Jaw-Necrosis after Typhoid Fever. PMID- 30436573 TI - Deformities of the Hands and Feet. PMID- 30436574 TI - Current Topics. PMID- 30436575 TI - Glasgow Pathological and Clinical Society. PMID- 30436576 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd August, 1903. PMID- 30436578 TI - Glasgow Medico-Chirurgical Society. PMID- 30436577 TI - Obstetrical and Gynaecological Society. PMID- 30436580 TI - Glasgow Southern Medical Society. PMID- 30436579 TI - Coagulation of Infantile Blood. PMID- 30436581 TI - Glasgow Medico-Chirurgical Society. PMID- 30436582 TI - Three Cases of Ectopic Pregnancy Recently Operated upon. PMID- 30436583 TI - Sarcoma of the Nose. PMID- 30436584 TI - Glasgow Eastern Medical Society. PMID- 30436585 TI - Lunatic Asylums as Hospitals, and the Relation of the General Practitioner to the Treatment of Insanity. PMID- 30436586 TI - Hammer-Finger, with Notes of Seven Cases Occurring in One Family. PMID- 30436588 TI - New Preparations, &c. PMID- 30436587 TI - Current Topics. PMID- 30436590 TI - Glasgow Medico-Chirurgical Society. PMID- 30436589 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th October, 1903. PMID- 30436592 TI - The Forfarshire Medical Association. PMID- 30436591 TI - Isolation of the Proteus Vulgaris from Faeces from a Case of Acute Gastro Enteritis. PMID- 30436593 TI - Current Topics. PMID- 30436594 TI - The Use of Modern Chemical Methods in the Diagnosis of Gastric Disorders. PMID- 30436596 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th November, 1898. PMID- 30436595 TI - On Movable Kidney. PMID- 30436597 TI - Glasgow Eastern Medical Society. PMID- 30436599 TI - Aseptic Midwifery. PMID- 30436598 TI - Lectures on Clinical Medicine. Delivered in the Glasgow Royal Infirmary: IX. Case of Scleroderma with Pronounced Hemiatrophy of the Face, Body, and Extremities Death from Ovarian Tumour-Account of the Post-Mortem Examination: A Sequel. PMID- 30436601 TI - Obstetrical and Gynaecological Society. PMID- 30436600 TI - Current Topics. PMID- 30436602 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 29th June, 1898. PMID- 30436603 TI - Notes on Alginic Acid and Some of Its Compounds as Therapeutic Agents. PMID- 30436604 TI - Case of Acute Maniacal Excitement Complicating Bright's Disease. PMID- 30436605 TI - Glasgow Eastern Medical Society. PMID- 30436606 TI - Sympathetic Pains: Their Nature and Diagnostic Value. PMID- 30436607 TI - Glasgow Medico-Chirurgical Society. PMID- 30436609 TI - Early Symptoms of Pressure upon the Vagus and Recurrent Laryngeal Nerves. PMID- 30436608 TI - Specimens Illustrating Fractures of the Upper Extremity; Also Specimen of Abnormally Thick Ribs from a Case of Chronic Empyema. PMID- 30436610 TI - Case of Acromegaly-Autopsy-Round-Celled Sarcoma of Pituitary Body. PMID- 30436612 TI - Glasgow Medico-Chirurgical Society. PMID- 30436611 TI - A Year's Work at the Glasgow Maternity Hospital. PMID- 30436613 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd July, 1898. PMID- 30436615 TI - Current Topics. PMID- 30436616 TI - Glasgow Pathological and Clinical Society. PMID- 30436614 TI - Dentigerous Cysts. PMID- 30436617 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th August, 1898. PMID- 30436619 TI - Is There Room for Improvement in Our Present Mode of Clinical Instruction in Midwifery? PMID- 30436618 TI - Obstetrical and Gynaecological Society. PMID- 30436620 TI - Cysts of the Broad Ligament: Their Diagnosis and Treatment. PMID- 30436622 TI - Glasgow Medico-Chirurgical Society. PMID- 30436621 TI - Surgical Treatment of Acute Rheumatism. PMID- 30436623 TI - On the Treatment of Strabismus, with Special Reference to the Adoption of Advancements for Convergent Squint. PMID- 30436624 TI - A Case of Ruptured Ectopic Gestation about the Fifth Week: A Contribution to the Etiology and Pathological Anatomy of Early Tubal Pregnancy. PMID- 30436625 TI - A Case of Intracranial Suppuration Complicated by Cerebral Haemorrhage in a Child of Eleven Years. PMID- 30436627 TI - Current Topics. PMID- 30436626 TI - A Statistical Investigation of the Difficulties in the Diagnosis of Enteric Fever from Clinical Symptoms Alone. PMID- 30436628 TI - A Case of Congenital Absence of the Left Radius and of the Left Thumb, Malformation of the Left Ulna, Spinal Curvature, and Complete Displacement of the Heart to the Right. PMID- 30436629 TI - Complete Excision of the Pylorus, with Notes of a Second Case. PMID- 30436630 TI - Case of Myxoedema with Dulness of Hearing and Tinnitus in a Man. PMID- 30436631 TI - The Last Will and Testament, with the Inventory of the Estate, of Maister Peter Lowe, Founder of the Faculty of Physicians and Surgeons, Glasgow. PMID- 30436632 TI - Glasgow Medico-Chirurgical Society. PMID- 30436633 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th September, 1898. PMID- 30436634 TI - Current Topics. PMID- 30436635 TI - A Case of Hemiplegia Associated with Diphtheritic Paralysis. PMID- 30436636 TI - Poisoning by Gaseous Ammonia, with Clinical and Pathological Reports on Two Cases Treated in the Glasgow Royal Infirmary. PMID- 30436637 TI - Glasgow Medico-Chirurgical Society. PMID- 30436638 TI - Case of Ovarian Tumour with Twisted Pedicle. PMID- 30436639 TI - On Movable Kidney. PMID- 30436640 TI - Two Cases of Chronic Cardiac Disease Treated by the Schott Method. PMID- 30436641 TI - Glasgow Pathological and Clinical Society. PMID- 30436642 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd October, 1898. PMID- 30436643 TI - Case of Recovery from Tubercular Meningitis in a Child. PMID- 30436644 TI - Demonstration of Cases. PMID- 30436645 TI - Current Topics. PMID- 30436646 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th December, 1904. PMID- 30436648 TI - The Action of Poisoned Arrows Obtained from the Aros District of Nigeria. PMID- 30436649 TI - Extra-Uterine Pregnancy. PMID- 30436647 TI - The Defensive Powers of the Body in Disease. PMID- 30436650 TI - New Preparations, &c. PMID- 30436651 TI - Glasgow Medico-Chirurgical Society. PMID- 30436652 TI - Glasgow Southern Medical Society. PMID- 30436653 TI - Glasgow Pathological and Clinical Society. PMID- 30436654 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th March, 1905. PMID- 30436655 TI - Some Cases of Uterine Myoma, with Remarks on the Indications for Operation. PMID- 30436657 TI - Current Topics. PMID- 30436656 TI - Obstetrical and Gynaecological Society. PMID- 30436658 TI - Perityphlitis in Relation to Carcinoma and Foreign Bodies. PMID- 30436659 TI - Movable Displacements of the Kidney. PMID- 30436660 TI - Glasgow Pathological and Clinical Society. PMID- 30436661 TI - Current Topics. PMID- 30436662 TI - Movable Displacements of the Kidney. PMID- 30436663 TI - Epileptiform Attacks Complicating Double Ovarian Tumour: Removal of Growths, Followed by Cessation of Attacks. PMID- 30436665 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st January, 1905. PMID- 30436664 TI - Notes on a Case of Uterus Didelphys with Septate Vagina. PMID- 30436667 TI - Obstetrical and Gynaecological Society. PMID- 30436666 TI - Vulcanite Ring Pessary Worn for Fifteen Years and Causing Symptoms Simulating Malignancy in a Woman, Aged 60. PMID- 30436668 TI - Glasgow Medico-Chirurgical Society. PMID- 30436669 TI - New Out-Patient Department at the Western Infirmary. PMID- 30436670 TI - Glasgow Pathological and Clinical Society. PMID- 30436672 TI - Glasgow Pathological and Clinical Society. PMID- 30436671 TI - On the Amylolytic Action of Urine. PMID- 30436674 TI - Glasgow Northern Medical Society. PMID- 30436673 TI - A Note on Appendicitis in Children. PMID- 30436676 TI - Report and Description of Specimens of Five Cases of Uterine Myoma and Three Cases of Ovarian Dermoid Tumour. PMID- 30436675 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th May, 1905. PMID- 30436677 TI - Obstetrical and Gynaecological Society. PMID- 30436678 TI - Current Topics. PMID- 30436679 TI - Glasgow Medico-Chirurgical Society. PMID- 30436680 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th February, 1905. PMID- 30436681 TI - Glasgow Eastern Medical Society. PMID- 30436682 TI - The Increase of Lunacy. PMID- 30436683 TI - Obstetrical and Gynaecological Society. PMID- 30436685 TI - Glasgow Southern Medical Society. PMID- 30436684 TI - New Preparations, &c. PMID- 30436687 TI - Current Topics. PMID- 30436686 TI - Perforated Enteric Ulcer in a Child of 7-Operation Twenty-Three Hours Later Pneumonia-Recovery. PMID- 30436688 TI - Glasgow Northern Medical Society. PMID- 30436689 TI - Case of Vagitus Uterinus. PMID- 30436690 TI - The Presence of Connective Tissue Cellular Elements (Glia?) in Epithelium. PMID- 30436692 TI - Case of Cerebro-Spinal Meningitis Following Scarlet Fever. PMID- 30436691 TI - Case of Traumatic Stretching of the Lower Cervical Nerve Roots, with Remarks on Some Allied Conditions, Including the Mechanism of Their Production. PMID- 30436693 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd April, 1905. PMID- 30436694 TI - New Preparations, &c. PMID- 30436695 TI - Thickening of the Ribs in Chronic Empyema. PMID- 30436696 TI - Glasgow Eastern Medical Society. PMID- 30436697 TI - Glasgow Medico-Chirurgical Society. PMID- 30436698 TI - Glasgow Northern Medical Society. PMID- 30436699 TI - Current Topics. PMID- 30436701 TI - Glasgow Pathological and Clinical Society. PMID- 30436700 TI - Acute Fatal Pneumococcic Pleurisy, Resembling Clinically Acute Lobar Pneumonia, with Remarks upon the Relationship of Pneumonia to the Pneumococcus. PMID- 30436702 TI - State Provision for the Care of the Destitute Sick. PMID- 30436703 TI - Notes on Extraction of Senile Cataract. PMID- 30436704 TI - Dr. Charles Badham: Professor of the Practice of Medicine in the University of Glasgow-1827-1841. PMID- 30436705 TI - Current Topics. PMID- 30436706 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st April, 1900. PMID- 30436708 TI - Clinical Gynaecology. PMID- 30436707 TI - Lectureships on Trade Diseases. PMID- 30436709 TI - Glasgow Pathological and Clinical Society. PMID- 30436710 TI - Glasgow Eastern Medical Society. PMID- 30436711 TI - Clinical Gynaecology. PMID- 30436712 TI - Current Topics. PMID- 30436713 TI - Some Topics in Gynaecology and Obstetrics. PMID- 30436714 TI - Glasgow Pathological and Clinical Society. PMID- 30436715 TI - A Case of Mastoid Abscess, Followed by Cerebellar Abscess, the Results of Otitis Media: Death. PMID- 30436716 TI - The Forfarshire Medical Association. PMID- 30436718 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd December, 1899. PMID- 30436717 TI - Clinical Notes on Cancer. PMID- 30436720 TI - Glasgow Eastern Medical Society. PMID- 30436719 TI - Three English Medical MSS., 1550-1660. PMID- 30436722 TI - Measurement of Involution of the Uterus, with Nine Charts. PMID- 30436721 TI - A Means of Practising the Use of the Ophthalmoscope. PMID- 30436723 TI - Notes on Clinical Surgery. PMID- 30436724 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th March, 1900. PMID- 30436725 TI - Glasgow Southern Medical Society. PMID- 30436727 TI - Current Topics. PMID- 30436726 TI - On Thorax Resection for Empyema and the Resulting Deformities. PMID- 30436728 TI - Obstetrical and Gynaecological Society. PMID- 30436729 TI - Notes of a Case of Uncontrollable Vomiting of Pregnancy. PMID- 30436730 TI - Notes on Cases Simulating Extra-Uterine Pregnancy. PMID- 30436731 TI - Current Topics. PMID- 30436732 TI - The Developments of Intra-Cranial Surgery in Relation to Purulent Diseases of the Ear, Accompanied by a Demonstration of Cases. PMID- 30436733 TI - Some Observations on the Sterilisation of Milk in Infant Feeding. PMID- 30436735 TI - Glasgow Southern Medical Society. PMID- 30436734 TI - Glasgow Pathological and Clinical Society. PMID- 30436737 TI - Obstetrical and Gynaecological Society. PMID- 30436736 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th May, 1900. PMID- 30436738 TI - Glasgow Southern Medical Society. PMID- 30436739 TI - Clinical Gynaecology. PMID- 30436740 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th January, 1900. PMID- 30436741 TI - Fibrous Epulis of the Upper Jaw. PMID- 30436742 TI - Glasgow Eastern Medical Society. PMID- 30436743 TI - Current Topics. PMID- 30436744 TI - Glasgow Pathological and Clinical Society. PMID- 30436745 TI - The Treatment of Cutaneous Ulcers. PMID- 30436746 TI - Aneurysm at the Bifurcation of the Abdominal Aorta. PMID- 30436747 TI - The Forfarshire Medical Association. PMID- 30436748 TI - Two Cases of Gastric Ulcer in Which Symptoms Arose Suggesting Perforation of the Stomach. PMID- 30436749 TI - Obstetrical and Gynaecological Society. PMID- 30436751 TI - Glasgow Eastern Medical Society. PMID- 30436750 TI - Epithelioma of the Penis: Removal of the Entire Penis, Scrotum, and Testicles. PMID- 30436752 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th February, 1900. PMID- 30436753 TI - Isolation Hospitals for Consumption in the Insane. PMID- 30436755 TI - Obstetrical and Gynaecological Society. PMID- 30436754 TI - Glasgow Southern Medical Society. PMID- 30436756 TI - Current Topics. PMID- 30436757 TI - Clinical Gynaecology. PMID- 30436758 TI - Glasgow Pathological and Clinical Society. PMID- 30436760 TI - Auscultation in the Management of Labour. PMID- 30436759 TI - The Treatment of Brow Presentation, with Notes of Two Cases. PMID- 30436761 TI - Current Topics. PMID- 30436762 TI - Tendon-Lengthening in a Case of Volkmann's Ischaemic Paralysis. PMID- 30436763 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th October, 1900. PMID- 30436764 TI - Glasgow Medico-Chirurgical Society. PMID- 30436765 TI - Introduction to the Course of Lectures on the Practice of Medicine. PMID- 30436766 TI - Three Cases Cured by Surgical Operation in Johnstone District Hospital. PMID- 30436767 TI - Ocular Headache. PMID- 30436768 TI - Glasgow Medico-Chirurgical Society. PMID- 30436769 TI - Current Topics. PMID- 30436770 TI - Glasgow Royal Infirmary: The Birthplace of Aseptic Surgery: A Kirkyard Eclogue. PMID- 30436771 TI - The Hygiene of the Mouth from the Individual and Public Health Aspects. PMID- 30436772 TI - Case of Epithelioma of the OEsophagus Involving the Pneumogastric Nerve with Its Recurrent Branch on the Right Side, and Where the Symptoms Closely Pointed to Aneurysm of the Arch of the Aorta. PMID- 30436773 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd June, 1900. PMID- 30436774 TI - Case of Myoclonus Multiplex. PMID- 30436775 TI - Notes on Clinical Gynaecology. PMID- 30436776 TI - Glasgow Pathological and Clinical Society. PMID- 30436778 TI - Glasgow Eastern Medical Society. PMID- 30436777 TI - The Clinical Examination of the Blood and Its Bearing on the Diagnosis and Prognosis of Disease. PMID- 30436779 TI - Glasgow Southern Medical Society. PMID- 30436780 TI - Glasgow Medico-Chirurgical Society. PMID- 30436781 TI - Current Topics. PMID- 30436782 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 24th November, 1900. PMID- 30436784 TI - The Evolution of the Mastoid Operation. PMID- 30436783 TI - Case of Total Aphasia and Right Hemiplegia in a Patient Who Had Previously Lost His Left Arm by Accident. PMID- 30436785 TI - Glasgow Pathological and Clinical Society. PMID- 30436787 TI - Current Topics. PMID- 30436786 TI - Case of Anaemia in a Young Girl, Associated with Enlargement of the Spleen. PMID- 30436789 TI - Glasgow Southern Medical Society. PMID- 30436788 TI - Evolution and Natural Selection: Their Aspects and Prospects. PMID- 30436790 TI - Notes of Eight Labours Complicated by Tumours. PMID- 30436791 TI - Glasgow Pathological and Clinical Society. PMID- 30436792 TI - Obstetrical and Gynaecological Society. PMID- 30436794 TI - Case of Superficial Emphysema Occurring during Labour. PMID- 30436793 TI - Two Cases Bearing on Menstruation. PMID- 30436795 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st July, 1900. PMID- 30436796 TI - Melanotic Sarcoma of the Choroid. PMID- 30436797 TI - Glasgow Medico-Chirurgical Society. PMID- 30436798 TI - Notes on a Case of Double Uterus (Uterus Septus) and Double Vagina. PMID- 30436799 TI - Cured Spina Bifida, or Sacral Teratoma? PMID- 30436800 TI - Glasgow Southern Medical Society. PMID- 30436801 TI - Glasgow Medico-Chirurgical Society. PMID- 30436802 TI - Case of Profound Aphasia and Mental Confusion Cured by Trephining and Evacuation of a Large Haemorrhagic Cerebral Cyst. PMID- 30436804 TI - Obstetrical and Gynaecological Society. PMID- 30436803 TI - On Some of the Difficulties Met with in the Surgical Treatment of Gall-Stones, Illustrated by Two Cases. PMID- 30436805 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th August, 1900. PMID- 30436806 TI - Report on Relapsing Fever and Other Ailments in H.M. Common Prison, Bombay, for the Year 1899. PMID- 30436807 TI - Current Topics. PMID- 30436808 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd September, 1900. PMID- 30436809 TI - Obstetrical and Gynaecological Society. PMID- 30436810 TI - Glasgow Pathological and Clinical Society. PMID- 30436811 TI - Case of Probable Addison's Disease Associated with Leucodermia and Tuberculosis. PMID- 30436812 TI - Note on the Minute-Book (Vol. II) of an Early Glasgow Medico-Chirurgical Society. PMID- 30436814 TI - Current Topics. PMID- 30436813 TI - On the Clinical Examination of the Blood, Specially by Means of Dried and Stained Films. PMID- 30436815 TI - Glasgow Medico-Chirurgical Society. PMID- 30436816 TI - Two Examples in Men of Severe and Prolonged Attacks of Asthma, Associated with, and Apparently Dependent upon, the Presence of Nasal Polypi, Extirpation of Which Resulted in Complete Immunity from Asthmatic Symptoms. PMID- 30436817 TI - Notes of Six Cases of Puerperal Eclampsia Treated by Saline Infusions. PMID- 30436819 TI - Obstetrical and Gynaecological Society. PMID- 30436818 TI - Case of Cancer of the Body of the Uterus. PMID- 30436820 TI - Glasgow Medico-Chirurgical Society. PMID- 30436821 TI - The Glasgow Maternity Hospitals: Past and Present. PMID- 30436822 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd December, 1900. PMID- 30436823 TI - My Experiences in South Africa. PMID- 30436824 TI - A Clinical Demonstration Given to the Class in Gynaecology, St. Mungo's College, 1st December, 1900. PMID- 30436826 TI - Glasgow Eastern Medical Society. PMID- 30436825 TI - Current Topics. PMID- 30436827 TI - Glasgow Pathological and Clinical Society. PMID- 30436828 TI - Glasgow Medico-Chirurgical Society. PMID- 30436829 TI - The Story of a Resurrectionist. PMID- 30436831 TI - Current Topics. PMID- 30436830 TI - Surgical Diseases of the Kidney: Their General Symtomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436832 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th January, 1901. PMID- 30436833 TI - Glasgow Southern Medical Society. PMID- 30436834 TI - Current Topics. PMID- 30436835 TI - Some Points in the Formation of the Connective Tissue of the Liver, with Special Reference to Hepatic Cirrhosis. PMID- 30436836 TI - Case of Irregular Movements of the Right Hand and Leg in a Patient of Middle Age, Apparently Referable to Slight Hemiplegia. PMID- 30436837 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th April, 1901. PMID- 30436838 TI - Obstetrical and Gynaecological Society. PMID- 30436839 TI - Ehrlich's Eyepiece for the Differential Count of Red and White Corpuscles in Stained Films. PMID- 30436840 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436841 TI - New Preparations, &c. PMID- 30436842 TI - Glasgow Medico-Chirurgical Society. PMID- 30436844 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 25th May, 1901. PMID- 30436843 TI - Some Points in the Formation of the Connective Tissue of the Liver, with Special Reference to Hepatic Cirrhosis. PMID- 30436845 TI - Foetal Abnormality Obstructing Labour. PMID- 30436847 TI - Glasgow Eastern Medical Society. PMID- 30436846 TI - Case of Anus Vulvalis. PMID- 30436848 TI - The Ninth Jubilee of the University of Glasgow. PMID- 30436849 TI - Obstetrical and Gynaecological Society. PMID- 30436850 TI - Glasgow Pathological and Clinical Society. PMID- 30436852 TI - Current Topics. PMID- 30436851 TI - Daily Cerebral Vomiting of Six Months' Duration Due to a Columnar-Celled Adenoma of the Cerebellum Involving the Fourth Ventricle. PMID- 30436853 TI - Glasgow Eastern Medical Society. PMID- 30436854 TI - Glasgow Medico-Chirurgical Society. PMID- 30436856 TI - Glasgow Pathological and Clinical Society. PMID- 30436855 TI - A Chapter of Field-Hospital Experiences in the Eastern Transvaal. PMID- 30436857 TI - New Preparations, &c. PMID- 30436858 TI - The Forfarshire Medical Association. PMID- 30436859 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 16th February, 1901. PMID- 30436860 TI - Obstetrical and Gynaecological Society. PMID- 30436861 TI - Two Cases of Paralysis in Enteric Fever. PMID- 30436862 TI - Notes of Surgical Cases in the Western Infirmary. PMID- 30436863 TI - Current Topics. PMID- 30436864 TI - Eye-Strain in Young Children. PMID- 30436865 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30436866 TI - Current Topics. PMID- 30436867 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd March, 1901. PMID- 30436868 TI - New Preparations, &c. PMID- 30436869 TI - Obstetrical and Gynaecological Society. PMID- 30436870 TI - On the Usefulness of the Term, Functional Inertia of Protoplasm. PMID- 30436871 TI - Glasgow Medico-Chirurgical Society. PMID- 30436872 TI - Glasgow Eastern Medical Society. PMID- 30436873 TI - Glasgow Pathological and Clinical Society. PMID- 30436874 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st May, 1898. PMID- 30436876 TI - Extra-Uterine Pregnancy. PMID- 30436875 TI - On Cysts of the Prepuce and Raphe, with an Illustrative Case. PMID- 30436877 TI - Twenty-Two Consecutive Arthrotomies of the Knee. PMID- 30436878 TI - On a Case of Intracranial Disease Treated by Trephining-Death-Post-Mortem Examination. PMID- 30436880 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd April, 1898. PMID- 30436879 TI - Some Remarkable Cases from the Medical Literature of the Past Fifty Years. PMID- 30436882 TI - The Forfarshire Medical Association. PMID- 30436881 TI - Case of Gall-Stones-Cholecystotomy-Hour Glass Contraction of the Gall-Bladder. PMID- 30436883 TI - Glasgow Pathological and Clinical Society. PMID- 30436884 TI - Glasgow Medico-Chirurgical Society. PMID- 30436885 TI - On White Blood Corpuscles. PMID- 30436887 TI - Case of Spastic Paraplegia in a Boy with a Peculiar Gait, and Probably Due to a Progressive Myopathy. PMID- 30436886 TI - Case of Chloroform Poisoning, in Which Five Ounces of Chloroform Were Swallowed Recovery. PMID- 30436888 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 26th March, 1898. PMID- 30436889 TI - The Pathology of Ante-Natal Life. PMID- 30436890 TI - Glasgow Pathological and Clinical Society. PMID- 30436891 TI - Glasgow Medico-Chirurgical Society. PMID- 30436893 TI - The Forfarshire Medical Association. PMID- 30436892 TI - Current Topics. PMID- 30436894 TI - Obstetrical and Gynaecological Society. PMID- 30436895 TI - A Case of Cephalic, Dysphagic, or Hydrophobic Tetanus. PMID- 30436896 TI - Glasgow Medico-Chirurgical Society. PMID- 30436897 TI - Glasgow Pathological and Clinical Society. PMID- 30436898 TI - Obstetrical and Gynaecological Society. PMID- 30436900 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th February, 1898. PMID- 30436899 TI - Current Topics. PMID- 30436901 TI - On the Formation of Gastric Diverticula. PMID- 30436902 TI - On the Presystolic Murmur. PMID- 30436903 TI - Obstetrical and Gynaecological Society. PMID- 30436904 TI - Glasgow Southern Medical Society. PMID- 30436905 TI - Remarks Preceding a Demonstration in the Glasgow Royal Infirmary, 19th Nov., 1897. PMID- 30436906 TI - Glasgow Medico-Chirurgical Society. PMID- 30436907 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th December, 1897. PMID- 30436908 TI - Current Topics. PMID- 30436909 TI - Large Pulsating Vessels in the Pharynx. PMID- 30436911 TI - Glasgow Eastern Medical Society. PMID- 30436910 TI - Ante-Partum Haemorrhage, with a Table of Fifty-One Cases of Placenta Praevia. PMID- 30436912 TI - Acquired Oblique Inguinal Hernia-A New Operation. PMID- 30436913 TI - A Series of Specimens Illustrative of Certain Congenital Affections of the Urinary Apparatus. PMID- 30436915 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd January, 1898. PMID- 30436914 TI - Glasgow Pathological and Clinical Society. PMID- 30436917 TI - Current Topics. PMID- 30436916 TI - Glasgow Eastern Medical Society. PMID- 30436918 TI - Cases from the Glasgow Royal Infirmary Dispensary. PMID- 30436919 TI - On a Case of Primary Cancer of Bone. PMID- 30436920 TI - Case of Simultaneous Ulceration of the Lymphatic Tissues of the Throat and Intestines, with Suppuration of the Corresponding Glands in the Neck and Mesentery. PMID- 30436921 TI - Abstract of Diseases Treated in Wards Nos. 1, 2, and 9 of the Glasgow Royal Infirmary during the Year 1894, with Details of Some Severe Cases, &c. PMID- 30436922 TI - John Reid, Surgeon, Glasgow: A Biographical Sketch of the Surgeon in Whose Memory Was Founded "the John Reid Prize," Open to All Medical Students of Glasgow. PMID- 30436923 TI - A Case of Perforation of the Bowel by a Fish Bone Which Was Removed from an Intra Abdominal Abscess. PMID- 30436924 TI - Glasgow Pathological and Clinical Society. PMID- 30436925 TI - Further Notes on Cases of Diphtheria Treated with Antitoxin. PMID- 30436926 TI - Current Topics. PMID- 30436927 TI - A New Life Table for Glasgow. PMID- 30436928 TI - Diphtheria and Other Acute Inflammations of the Nose and Throat, with Special Reference to Recent Methods of Diagnosis and Treatment. PMID- 30436929 TI - The Relation between Chemical Constitution and Physiological Action. PMID- 30436930 TI - Haematoporphyrinuria Following the Administration of Sulphonal-Notes of a Case, with Remarks. PMID- 30436931 TI - A Case of Acute Osteitis and Separation of Coracoid Process; Abscess in Axillary and Pectoral Regions; Pleuro-Pneumonia; Death. PMID- 30436933 TI - Glasgow Pathological and Clinical Society. PMID- 30436932 TI - A Contribution to the Study of Injuries of the Eye. PMID- 30436934 TI - Correspondence. PMID- 30436935 TI - Report of Last Year's Work at the West End Branch of the Glasgow Maternity Hospital. PMID- 30436936 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30436937 TI - Current Topics. PMID- 30436938 TI - The Therapeutics of Sydenham. PMID- 30436939 TI - Glasgow Medico-Chirurgical Society. PMID- 30436940 TI - The Diagnosis and Treatment of Glaucoma. PMID- 30436941 TI - A Case of Diphtheria Treated with Antitoxin. PMID- 30436942 TI - Glasgow Pathological and Clinical Society. PMID- 30436943 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436945 TI - Glasgow Medico-Chirurgical Society. PMID- 30436944 TI - Foreign Body in Air-Passages; Tracheotomy; Pneumothorax; Recovery. PMID- 30436946 TI - A Case of Syphilitic Chancre of the Eyelid. PMID- 30436948 TI - Current Topics. PMID- 30436947 TI - The Diagnosis and Treatment of Glaucoma. PMID- 30436950 TI - Local Massage in the Treatment of Certain Gynaecological Conditions. PMID- 30436949 TI - Notes on Cases of Diphtheria Treated with Antitoxin. PMID- 30436951 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30436953 TI - Primary Malignant Disease of Liver (?). PMID- 30436952 TI - The Successful Preventive Treatment of the Scourge of St. Kilda (Tetanus Neonatorum), with Some Considerations Regarding the Management of the Cord in the New-Born Infant. PMID- 30436955 TI - Current Topics. PMID- 30436954 TI - Discharge of Tympanic Ossicles in Suppurative Middle-Ear Disease. PMID- 30436956 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436957 TI - Investigations into the Connection of the Paisley Water Supply with the Epidemic of Enteric Fever in the Autumn of 1893. PMID- 30436958 TI - Why Does the Foetus Present by the Cephalic Extremity? PMID- 30436959 TI - Glasgow Medico-Chirurgical Society. PMID- 30436960 TI - Current Topics. PMID- 30436961 TI - A Chemical Antidote for Chloral Poisoning. PMID- 30436963 TI - Glasgow Pathological and Clinical Society. PMID- 30436962 TI - Case of Tubercular Pericarditis with Double Pleurisy and Large Effusion-Pulsus Paradoxus. PMID- 30436964 TI - Glasgow Medico-Chirurgical Society. PMID- 30436965 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30436967 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436966 TI - An Unusual Case of Lithotomy. PMID- 30436968 TI - On a Case in Which Half of a Vulcanite Dental Plate Impacted in the OEsophagus Was Removed by a Coin-Catcher. PMID- 30436969 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436970 TI - Mycosis Pharyngis Leptothricia and Keratosis Pharyngis. PMID- 30436972 TI - Glasgow Pathological and Clinical Society. PMID- 30436971 TI - Rotheln (German Measles) as a Specific Disease, with Notes of Cases. PMID- 30436973 TI - Glasgow Medico-Chirurgical Society. PMID- 30436974 TI - Current Topics. PMID- 30436975 TI - Glasgow Medico-Chirurgical Society. PMID- 30436977 TI - Notes on a Case of Scarlatinal Nephritis in Which a Grave Cerebral Lesion Was Found Post-Mortem. PMID- 30436976 TI - A Plea for the Re-Use of Tuberculin. PMID- 30436979 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436978 TI - Notes on the Eucalyptus Oils Presently Used in Medicine, with a Short History of the Oils Used during the Last Ten Years. PMID- 30436980 TI - Inauguration of a New Pathological Institute in Connection with the Western Infirmary and the University. PMID- 30436981 TI - Phlegmasia Alba Dolens, with Notes of Two Cases. PMID- 30436982 TI - Landolt on the Treatment of Squint. PMID- 30436983 TI - Current Topics. PMID- 30436984 TI - Epithelioma of the OEsophagus at the Level of the Third Dorsal Vertebra; Ulceration and Rupture into the Aorta, a Month after Gastrostomy Was Performed. PMID- 30436985 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30436986 TI - Western Infirmary: Notes of Cases in Professor Buchanan's Wards. PMID- 30436987 TI - Vaginal Versus Abdominal Surgery. PMID- 30436988 TI - A Case of Paroxysmal Haemoglobinuria. PMID- 30436989 TI - Abdominal Examination in Pregnancy and Labour: A Critical Estimate of Its Value. PMID- 30436990 TI - Some Notes on 1,400 Cases of Anaesthesia. PMID- 30436991 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30436992 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30436993 TI - Traumatic Haemarthrosis of Knee-Joint. PMID- 30436994 TI - Case of Haematoma of the Dura Mater. PMID- 30436996 TI - Glasgow Medico-Chirurgical Society. PMID- 30436995 TI - Current Topics. PMID- 30436997 TI - The History, Forms, and Theories of the Vaginal Speculum. PMID- 30436999 TI - Glasgow Pathological and Clinical Society. PMID- 30436998 TI - Mycosis Pharyngis Leptothricia and Keratosis Pharyngis. PMID- 30437000 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437001 TI - Two Cases of Brain Tumour in Which Recovery Took Place. PMID- 30437002 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30437003 TI - Glasgow Medico-Chirurgical Society. PMID- 30437004 TI - Glasgow Medico-Chirurgical Society. PMID- 30437005 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30437006 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437007 TI - A Case of Missed Labour. PMID- 30437008 TI - On Badly-Fitting Spectacles and on the Decentration of Lenses. PMID- 30437009 TI - Current Topics. PMID- 30437010 TI - Glasgow Pathological and Clinical Society. PMID- 30437011 TI - Three Renal Cases, a Case of Cyst of Urachus, and a Case of Strangulated Hernia. PMID- 30437012 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437013 TI - Glasgow Pathological and Clinical Society. PMID- 30437014 TI - Lectures on Clinical Medicine, Delivered in the Glasgow Royal Infirmary: On a Series of Cases Illustrating the Influence of Syphilis in the Sudden Production of Alarming Disorders of the Nervous System. PMID- 30437015 TI - Addison's Disease with Phthisis Pulmonalis and Atypical Pigmentation of the Skin; Melanoderma with Symmetrical Patches of Leucoderma. PMID- 30437017 TI - Glasgow Medico-Chirurgical Society. PMID- 30437016 TI - Mycosis Pharyngis Leptothricia and Keratosis Pharyngis. PMID- 30437018 TI - An Account of Eight Consecutive Cases of Thyrotomy (Crico-Thyrotomy), with One Death, for Removal of Intra-Laryngeal Growths, &c. PMID- 30437019 TI - Amputation of the Scapula for Sarcoma, with Preservation of a Useful Limb. PMID- 30437021 TI - Aprosexia, Convulsions and Adenitis, Dependent on Pathological Changes in the Faucial, Lingual, and Pharyngeal Tonsils. PMID- 30437020 TI - The AEtiology and Treatment of Chronic Enlargements of Lymphatic Glands, with Special Reference to Those of the Neck. PMID- 30437022 TI - Lectures on Clinical Medicine, Delivered in the Glasgow Royal Infirmary: I. Landry's Paralysis. PMID- 30437023 TI - Glasgow Medico-Chirurgical Society. PMID- 30437024 TI - Glasgow Eastern Medical Society-Meeting II. PMID- 30437025 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30437027 TI - Glasgow Pathological and Clinical Society. PMID- 30437026 TI - Current Topics. PMID- 30437028 TI - Observations on Epidemics of Cholera in India, with Special Reference to Their Immediate Connection with Pilgrimages. PMID- 30437029 TI - Cases of Primary Cancer of the Kidneys. PMID- 30437030 TI - The Diagnostic Value of Sudden and Acute Pain as a Symptom in Abdominal Disease. PMID- 30437032 TI - Current Topics. PMID- 30437031 TI - Anchylostomiasis. PMID- 30437033 TI - Account of a Few Cases of Beri-Beri Treated in the Glasgow Western Infirmary. PMID- 30437034 TI - Glasgow Pathological and Clinical Society. PMID- 30437035 TI - Lectures on Clinical Medicine, Delivered in the Glasgow Royal Infirmary: III: On the Nauheim (Schott) Methods of Treatment as Applied to Cases of Cardic Valve Disease of Rheumatic Origin. PMID- 30437036 TI - Diphtheria Treated with Antitoxin: Statistical Statement of Results Obtained in City of Glasgow Fever Hospital, Belvidere. PMID- 30437038 TI - Current Topics. PMID- 30437037 TI - Bacteria in Oysters. PMID- 30437039 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437040 TI - Glasgow Pathological and Clinical Society. PMID- 30437042 TI - Glasgow Medico-Chirurgical Society. PMID- 30437041 TI - On a Simple Method of Making Diagrams for Lecture or Demonstration Purposes. PMID- 30437043 TI - Lectures on Clinical Medicine, Delivered in the Glasgow Royal Infirmary: II. A Case of Mediastinal Tumour Involving the Root of the Left Lung. PMID- 30437044 TI - Current Topics. PMID- 30437045 TI - Malignant Mediastinal Tumour, with Secondary Growth in the Liver, Having Unusual Features. PMID- 30437046 TI - Glasgow Southern Medical Society. PMID- 30437048 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437047 TI - On Recent Views as to the Part the Nucleus Plays in Development. PMID- 30437049 TI - Glasgow Medico-Chirurgical Society. PMID- 30437050 TI - A Case of Movable Kidney, with Dilatation of the Stomach. PMID- 30437051 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30437052 TI - Case of Multiple Polypi in the Stomach. PMID- 30437053 TI - Current Topics. PMID- 30437055 TI - Intestinal Perforation in Enteric Fever. PMID- 30437054 TI - Notes of Five Cases of "Endometritis" in Private Practice (Illustrating the Relation between the Local Disease and the Constitutional Condition of the Patients). PMID- 30437057 TI - Demonstration on the Rontgen Rays. PMID- 30437056 TI - Historical Sketch of Gynaecology during the Last Fifty Years. PMID- 30437058 TI - Current Topics. PMID- 30437059 TI - Correspondence. PMID- 30437060 TI - On the Relation of Our Hospitals to the Medical Profession. PMID- 30437062 TI - Glasgow Medico-Chirurgical Society. PMID- 30437061 TI - Clinical Memoranda, Being Selected Cases from the Wards of Dr. M'Call Anderson. PMID- 30437063 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437064 TI - Two Cases of Tubercular Laryngitis, in Which Complete Recovery Took Place; Also, Two Cases of Malignant Disease of the Tonsil Treated by Operation, and Well More Than Four Years Thereafter. PMID- 30437065 TI - Phases in Foetal Life. PMID- 30437066 TI - Current Topics. PMID- 30437067 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437068 TI - Current Topics. PMID- 30437069 TI - Neurological Complications of Organic Arsenical Injections. PMID- 30437070 TI - Blast Injuries. PMID- 30437072 TI - Current Topics. PMID- 30437071 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437073 TI - On Testing Dark Adaptation. PMID- 30437074 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437075 TI - Gastric Injury: Two Unusual Cases. PMID- 30437076 TI - Peripheral Nerve Injuries. PMID- 30437077 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437078 TI - An Interesting Congenital Deformity. PMID- 30437079 TI - Current Topics. PMID- 30437080 TI - Fractures and Dislocations of the Clavicle. PMID- 30437081 TI - Gastric Cancer: An Experimental Approach to the Problem of Causation. PMID- 30437083 TI - Current Topics. PMID- 30437082 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437084 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437085 TI - Traumatic Dislocation at the Hip Joint. An Experimental Study on the Cadaver. PMID- 30437086 TI - Anaemia in Gastric Carcinoma. PMID- 30437087 TI - Current Topics. PMID- 30437088 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437089 TI - The Role of the Capillaries in the Causation of Disease with Special Reference to the Pathogenesis of Acute Primary Glaucoma. PMID- 30437090 TI - Current Topics. PMID- 30437091 TI - Primary Thrombosis of the Axillary Vein: A Report of Three Cases. PMID- 30437092 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437094 TI - Current Topics. PMID- 30437093 TI - Knee Injuries in the Army. PMID- 30437095 TI - The Genesis of the Human Voice. PMID- 30437097 TI - Current Topics. PMID- 30437096 TI - Infectious Mononucleosis: Preliminary Investigation of a Series of Cases. PMID- 30437098 TI - Bile Peritonitis: Report of a Case. PMID- 30437099 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437100 TI - Tremor in Hyperthyroidism. Its Value in the Diagnosis and Assessment of the Condition. PMID- 30437102 TI - Educational Supplement. PMID- 30437101 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437104 TI - Current Topics. PMID- 30437103 TI - Ischaemic Paralysis Anomalous Sensori-Motor and Trophic Reactions Following Injury to a Limb. PMID- 30437105 TI - Current Topics. PMID- 30437107 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437106 TI - Ischaemic Paralysis Anomalous Sensori-Motor and Trophic Reactions Following Injury to a Limb. PMID- 30437108 TI - Current Topics. PMID- 30437111 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437109 TI - Pellagra Following Gastro-Enterostomy. PMID- 30437110 TI - Various Hypotheses on the Causes of Diabetes Mellitus. PMID- 30437112 TI - Salol in the Treatment of Small-Pox. PMID- 30437113 TI - New Preparations, &c. PMID- 30437114 TI - Current Topics. PMID- 30437115 TI - Ruptured Perineum-The Mechanism of Its Causation: Its Prevention and Treatment. PMID- 30437116 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th May, 1902. PMID- 30437117 TI - Obstetrical and Gynaecological Society. PMID- 30437118 TI - Glasgow Southern Medical Society. PMID- 30437119 TI - Caesarean Section-With Notes of a Series of Nine Successful Cases. PMID- 30437120 TI - Glasgow Medico-Chirurgical Society. PMID- 30437122 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th April, 1902. PMID- 30437121 TI - Discussion on Pneumonia. PMID- 30437124 TI - Eucalyptus in the Treatment of Diabetes. PMID- 30437123 TI - Glasgow Southern Medical Society. PMID- 30437125 TI - Current Topics. PMID- 30437126 TI - Glasgow Pathological and Clinical Society. PMID- 30437127 TI - The Treatment of Endometritis. PMID- 30437128 TI - New Preparations, &c. PMID- 30437129 TI - The Use of the Reception-House in Infectious Diseases. PMID- 30437130 TI - Glasgow Pathological and Clinical Society. PMID- 30437131 TI - On Obstruction of the Coronary Arteries. PMID- 30437132 TI - Glasgow Southern Medical Society. PMID- 30437133 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30437134 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd March, 1902. PMID- 30437135 TI - Current Topics. PMID- 30437136 TI - The Antitoxin Treatment of Diphtheria in the City of Glasgow Fever Hospital, Belvidere, during Six and a Half Years. PMID- 30437137 TI - Discussion on Pneumonia. PMID- 30437138 TI - Some Cases from the Rothesay Cottage Hospital. PMID- 30437139 TI - New Preparations, &c. PMID- 30437140 TI - Myopia and Its Treatment. PMID- 30437141 TI - Case of Lupus Vulgaris of Ten Years' Duration Successfully Treated by the Finsen Lamp. PMID- 30437142 TI - Glasgow Pathological and Clinical Society. PMID- 30437143 TI - Glasgow Southern Medical Society. PMID- 30437144 TI - Current Topics. PMID- 30437145 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th January, 1902. PMID- 30437146 TI - On Some Practical Details of Sanatorium Treatment. PMID- 30437147 TI - Glasgow Medico-Chirurgical Society. PMID- 30437148 TI - Glasgow Southern Medical Society. PMID- 30437149 TI - Glasgow Pathological and Clinical Society. PMID- 30437150 TI - Current Topics. PMID- 30437151 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st December, 1901. PMID- 30437152 TI - The Influence of a Medical Society on the Position of the General Medical Practitioner. PMID- 30437153 TI - The Nitro-Propiol Test for Sugar in Urine, Based on Two Hundred Observations. PMID- 30437154 TI - Obstetrical and Gynaecological Society. PMID- 30437155 TI - Surgical Diseases of the Kidney: Their General Symptomatology and Physical Diagnosis-With Illustrative Cases. PMID- 30437156 TI - Glasgow Medico-Chirurgical Society. PMID- 30437157 TI - Current Topics. PMID- 30437158 TI - Case of Obturator Hernia of the Ovary. PMID- 30437160 TI - New Preparations, &c. PMID- 30437159 TI - The Treatment of Uterine Fibro-Myoma. PMID- 30437161 TI - Obstetrical and Gynaecological Society. PMID- 30437162 TI - Glasgow Medico-Chirurgical Society. PMID- 30437164 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd February, 1902. PMID- 30437163 TI - Some Statistics Bearing on the Increasing Prevalence and Mortality of Pneumonia. PMID- 30437165 TI - The Abdominal Surgery of "Total War." PMID- 30437167 TI - Current Topics. PMID- 30437166 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437168 TI - Recent Work on Vascular Disease and Its Significance in Medical Ophthalmology. PMID- 30437169 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437171 TI - Current Topics. PMID- 30437170 TI - Current Topics. PMID- 30437172 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437173 TI - Epiphyseolysis: A Report of Two Familial Cases. PMID- 30437175 TI - Current Topics. PMID- 30437174 TI - Some Observations on Epanutin Therapy in Epilepsy: From the Orphan Homes of Scotland, the Sanatorium, and the Colony for Epileptics, Bridge of Weir. PMID- 30437176 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437178 TI - Current Topics. PMID- 30437177 TI - Non-Articular Rheumatism in the Army-Symptomatology, AEtiology Treatment. PMID- 30437180 TI - Current Topics. PMID- 30437179 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437181 TI - Disturbances in the Coagulation of the Blood. PMID- 30437182 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437183 TI - Current Topics. PMID- 30437184 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437185 TI - The Vitreous Route for Retinal Toxins. PMID- 30437186 TI - The Fuller Development of the Fever Hospital. PMID- 30437187 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437188 TI - Nesidioblastoma. Islet Cell Tumour of Pancreas. PMID- 30437189 TI - Current Topics. PMID- 30437190 TI - A Case of Chloroma. PMID- 30437191 TI - Recent Work on Vascular Disease and Its Significance in Medical Ophthalmology. PMID- 30437192 TI - Educational Supplement. PMID- 30437193 TI - The Acute Head Injury as a Neurological Problem. PMID- 30437195 TI - Current Topics. PMID- 30437194 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437196 TI - Current Topics. PMID- 30437197 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437198 TI - Prematurity and the High Scottish Infant Death Rate. PMID- 30437199 TI - New Preparations, Appliances, &c. PMID- 30437200 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437201 TI - War-Time Problems of a Cardiologist. PMID- 30437202 TI - Current Topics. PMID- 30437203 TI - Some Statistical Notes on Vaccination. PMID- 30437204 TI - Current Topics. PMID- 30437206 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437205 TI - Tests of Hepatic Efficiency. A Review. PMID- 30437208 TI - Current Topics. PMID- 30437207 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437210 TI - New Preparations, Appliances, &c. PMID- 30437209 TI - Anaemia in the Poor of Glasgow. PMID- 30437211 TI - The Interior of the Living Eye Considered as a Biochemical Laboratory. PMID- 30437213 TI - Current Topics. PMID- 30437212 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437214 TI - An Unusual Case of Staphylococcal Pyaemia. PMID- 30437216 TI - Current Topics. PMID- 30437215 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437218 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437217 TI - The Present Position of Chemotherapy. PMID- 30437219 TI - Current Topics. PMID- 30437221 TI - Current Topics. PMID- 30437220 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437222 TI - Glycosuria in Recruits. PMID- 30437223 TI - Macular Burning and Ring Scotoma. PMID- 30437224 TI - Current Topics. PMID- 30437225 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437226 TI - The Royal Faculty of Physicians and Surgeons and Its Contributions to Medicine. PMID- 30437227 TI - One Hundred Consecutive Cases of Acute Lobar Pneumonia Treated with Sulphapyridine. PMID- 30437228 TI - Current Topics. PMID- 30437229 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437230 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437231 TI - Neurosurgery in 1940. PMID- 30437232 TI - Current Topics. PMID- 30437233 TI - The Persistence of the Chronic Peptic Ulcer. PMID- 30437234 TI - Current Topics. PMID- 30437235 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437236 TI - A Plea for a Co-Ordinated Hospital Service. PMID- 30437238 TI - Current Topics. PMID- 30437237 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437239 TI - Erratum. AB - [This corrects the article on p. 103 in vol. 136.]. PMID- 30437240 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437241 TI - The Postgraduate Study of Ophthalmology. PMID- 30437243 TI - Educational Supplement. PMID- 30437242 TI - Current Topics. PMID- 30437244 TI - The Effort Syndrome. PMID- 30437245 TI - Current Topics. PMID- 30437246 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437247 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437248 TI - The Present-Day Treatment of Fractures. PMID- 30437249 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 27th January, 1923. PMID- 30437250 TI - Current Topics. PMID- 30437251 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th February, 1923. PMID- 30437252 TI - X-Rays in the Treatment of Uterine Fibroids. PMID- 30437253 TI - The Glasgow Eye Infirmary: Story of Its Beginning. PMID- 30437254 TI - Current Topics. PMID- 30437255 TI - Some Points in the Etiology of Eczema. PMID- 30437256 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437257 TI - The Surgical Treatment of Uterine Fibroids. PMID- 30437258 TI - Tendon Transplantations for Musculo-Spiral Paralysis. PMID- 30437260 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 31st March, 1923. PMID- 30437259 TI - Surgical Diathermy in the Treatment of Malignant Disease of the Throat. PMID- 30437261 TI - The Influence of Local Anaesthesia on the Mortality-Rate of Laryngectomy. PMID- 30437262 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437263 TI - High Blood-Pressure and Its Treatment. PMID- 30437264 TI - Appendicitis: Its Diagnosis and Treatment. PMID- 30437265 TI - Current Topics. PMID- 30437266 TI - Current Topics. PMID- 30437268 TI - The Heart and the Circulation: An Historical Sketch. PMID- 30437267 TI - A Method for the Quantitative Estimation of Blood in Urine. PMID- 30437270 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 28th April, 1923. PMID- 30437269 TI - Spongy Exostosis of the Long Bones. PMID- 30437272 TI - New Instruments. PMID- 30437271 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th May, 1923. PMID- 30437273 TI - Case of Advanced Chronic Interstitial Nephritis in a Girl of Ten Years. PMID- 30437274 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437275 TI - Mental Hygiene. PMID- 30437276 TI - The Use of Blood-Sugar Estimations in the Investigation of Glycosuria. PMID- 30437277 TI - Current Topics. PMID- 30437278 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437280 TI - Current Topics. PMID- 30437279 TI - The Treatment of Early Opacities in the Senile Lens, with Demonstration of Six Cases. PMID- 30437281 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 30th December, 1922. PMID- 30437282 TI - Cases of Perforation of Bowel and Rupture of Heart. PMID- 30437283 TI - Dr. John Borland, First Surgeon to the Kilmarnock Infirmary: His Life and Work. PMID- 30437284 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th December, 1908. PMID- 30437285 TI - Some Problems Connected with Diseases of the Prostate. PMID- 30437286 TI - Pasteur. PMID- 30437287 TI - Some Considerations on the Pathology of Extra-Uterine Pregnancy, with a Note on Treatment. PMID- 30437288 TI - Current Topics. PMID- 30437289 TI - Obstetrical and Gynaecological Society. PMID- 30437290 TI - Glasgow Medico-Chirurgical Society. PMID- 30437291 TI - Glasgow Northern Medical Society. PMID- 30437292 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 27th March, 1909. PMID- 30437293 TI - Current Topics. PMID- 30437295 TI - Obstetrical and Gynaecological Society. PMID- 30437294 TI - Cerebral Physiology and the Education of Abnormal Children. PMID- 30437296 TI - Glasgow Medico-Chirurgical Society. PMID- 30437297 TI - Glasgow Eastern Medical Society. PMID- 30437298 TI - A Consideration of Some of the More Recent Researches on Immunity, Especially in Relation to Diagnosis and Treatment. PMID- 30437299 TI - New Preparations, &c. PMID- 30437300 TI - Radium in Dermatology. PMID- 30437301 TI - Current Topics. PMID- 30437302 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd May, 1909. PMID- 30437304 TI - Glasgow Medico-Chirurgical Society. PMID- 30437303 TI - New Preparations, &c. PMID- 30437305 TI - Case of Possible Incipient Addison's Disease. PMID- 30437307 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th April, 1909. PMID- 30437306 TI - Report on the State of Education in British and Irish Schools for the Deaf. PMID- 30437308 TI - Current Topics. PMID- 30437309 TI - A Case of Dermatitis Repens. PMID- 30437310 TI - Short Notes on "Puna" or "Soroche." PMID- 30437311 TI - Macrostoma, Associated with Cleft of Soft Palate. PMID- 30437312 TI - Glasgow Northern Medical Society. PMID- 30437313 TI - Glasgow Medico-Chirurgical Society. PMID- 30437314 TI - Rheumatoid Arthritis Illustrated. PMID- 30437315 TI - The Treatment of Phthisis by the Intravenous Injection of Iodoform. PMID- 30437316 TI - Partick and District Medical Society. PMID- 30437317 TI - Three Somewhat Remarkable Cases Illustrating Some of the Difficulties Connected with the Diagnosis of Abdominal Disease. PMID- 30437319 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 27th February, 1909. PMID- 30437318 TI - Recent Methods of Examination of the Nose and Throat. PMID- 30437320 TI - A Case of Hodgkin's Disease. PMID- 30437321 TI - Treatment of Hypertrichosis by X-Rays. PMID- 30437322 TI - Current Topics. PMID- 30437323 TI - The History of Botany in Glasgow University and Some Personal Reminiscences. PMID- 30437324 TI - Obstetrical and Gynaecological Society. PMID- 30437325 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd January, 1909. PMID- 30437327 TI - Cerebral Physiology and the Education of Abnormal Children. PMID- 30437326 TI - A Case of Peripheral Neuritis, in Which the Diaphragm Was Paralysed for Three Months. PMID- 30437328 TI - A Case of Landry's Paralysis. PMID- 30437329 TI - Correspondence. PMID- 30437330 TI - Intestinal Obstruction in the Newborn: Strangulation through a Hole in the Mesentery. PMID- 30437331 TI - Glasgow Medico-Chirurgical Society. PMID- 30437332 TI - Current Topics. PMID- 30437334 TI - Current Topics. PMID- 30437333 TI - A Short Note on "Verruga Peruana." PMID- 30437335 TI - Remarks on Pyogenic Infection of the Urinary Tract in Infancy and Childhood. PMID- 30437336 TI - Septic (Non-Venereal) Infections of Bladder and Kidney in General Practice. PMID- 30437337 TI - The Diagnosis and Treatment of Non-Venereal Pyogenic Infections of the Urinary Tract, with Special Reference to Urinary Antiseptics. PMID- 30437338 TI - On the Health of Munition Workers in a Shell-Filling Factory. PMID- 30437339 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th December, 1921. PMID- 30437340 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th March, 1922. PMID- 30437341 TI - A Form of Industrial Dermatitis. PMID- 30437343 TI - The Structure of the Vertebrate Head. PMID- 30437342 TI - Clinical Note on Facial Paralysis Complicating Acute Otitis Media. PMID- 30437345 TI - Current Topics. PMID- 30437344 TI - Tay-Sachs' Disease: A Study of the Symptomatology and Pathology of Three Atypical Cases. PMID- 30437346 TI - Tay-Sachs' Disease: A Study of the Symptomatology and Pathology of Three Atypical Cases. PMID- 30437347 TI - Herpes and Varicella. PMID- 30437348 TI - An Unusual Case of Extra-Peritoneal Abdominal Pregnancy. PMID- 30437350 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd April, 1922. PMID- 30437349 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437351 TI - Lacerations of Cervix Involving Lower Uterine Segment and Fornix, with Illustrative Cases. PMID- 30437352 TI - Current Topics. PMID- 30437353 TI - Fibroids Complicating Pregnancy, Labour, and the Puerperium, with Illustrative Cases. PMID- 30437354 TI - Bacillus Coli Infection of Urinary Tract in Infants. PMID- 30437355 TI - Surgical Kidney. PMID- 30437356 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 21st January, 1922. PMID- 30437358 TI - Current Topics. PMID- 30437357 TI - On the Health of Munition Workers in a Shell-Filling Factory. PMID- 30437360 TI - Current Topics. PMID- 30437359 TI - Fundamental Points in the Diagnosis of Pulmonary Tuberculosis. PMID- 30437361 TI - What Is Heterophoria? PMID- 30437363 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437362 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 27th May, 1922. PMID- 30437364 TI - Tay-Sachs' Disease: A Study of the Symptomatology and Pathology of Three Atypical Cases. PMID- 30437365 TI - Case of Cerebral Injury and Cranioplasty. PMID- 30437366 TI - Rickets: The Part Played by Unhygienic Social Conditions in Predisposing to the Disease. PMID- 30437367 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th February, 1922. PMID- 30437368 TI - Current Topics. PMID- 30437369 TI - Rickets in India. PMID- 30437370 TI - The Erect Dislocation of the Humerus, with Notes of a Case. PMID- 30437371 TI - Glycosuria and Jaundice Caused by Obstruction of Common Duct. PMID- 30437372 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th April, 1925. PMID- 30437373 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437374 TI - Some Preventive Aspects of Psychiatric Work. PMID- 30437376 TI - Some Aspects of Otitis Media Suppurativa. PMID- 30437375 TI - Current Topics. PMID- 30437377 TI - Tetany: An Historical Note. PMID- 30437378 TI - Tetany: The Blood Chemistry. PMID- 30437379 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 28th February, 1925. PMID- 30437380 TI - The Treatment of Infantile Tetany. PMID- 30437381 TI - The Causation and Origin of Hernia: A Reply to Sir Arthur Keith's Address. PMID- 30437382 TI - Current Topics. PMID- 30437383 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th January, 1925. PMID- 30437384 TI - The Surgical Aspects of Rheumatoid Arthritis. PMID- 30437385 TI - Rheumatoid Arthritis. PMID- 30437387 TI - Non-Specific Therapy in Rheumatoid Arthritis. PMID- 30437386 TI - Case of Hodgkin's Disease with Paraplegia. PMID- 30437388 TI - Current Topics. PMID- 30437389 TI - Pathological Evidence Bearing on Disease Incidence in Calcutta. PMID- 30437390 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 30th May, 1925. PMID- 30437391 TI - The Acute Abdomen. PMID- 30437392 TI - The Acute Abdomen. PMID- 30437393 TI - Current Topics. PMID- 30437394 TI - Dental Focal Infection and Its Diagnosis by X-Rays. PMID- 30437395 TI - The Lymphatics of the Heart: A Hunterian Memorandum. PMID- 30437396 TI - Undescended Caecum. PMID- 30437397 TI - Pathological Evidence Bearing on Disease Incidence in Calcutta. PMID- 30437398 TI - Embolism of the Spinal Cord. PMID- 30437400 TI - A Case of Myositis Ossificans Traumatica Occurring in the Region of the Patella. PMID- 30437399 TI - Student Life at Glasgow University about Ninety Years Ago. PMID- 30437401 TI - R.A.M.C. (Glasgow Territorials) War Memorial. PMID- 30437402 TI - Glasgow Eastern Medical Society. PMID- 30437403 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 27th December, 1924. PMID- 30437404 TI - Current Topics. PMID- 30437405 TI - Current Topics. PMID- 30437406 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 28th March, 1925. PMID- 30437407 TI - On the Growth of Glasgow from 1841 to 1921. PMID- 30437408 TI - Hepatic Cirrhosis Following Phosgene Poisoning. PMID- 30437409 TI - Zoology and the Medical Curriculum. PMID- 30437410 TI - Ocular Disturbances in Functional Inefficiency of the Kidney. PMID- 30437411 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437412 TI - Current Topics. PMID- 30437413 TI - Vital Statistics, &c. PMID- 30437414 TI - Plasma Phosphatase and Bone Disease. PMID- 30437415 TI - A Case of Intersexuality: Pseudohermaphroditism. PMID- 30437416 TI - Vital Statistics, &c. PMID- 30437418 TI - Vital Statistics, &c. PMID- 30437417 TI - Antenatal Diet and Its Influence on Still-Births and Prematurity. PMID- 30437419 TI - Current Topics. PMID- 30437420 TI - Transplantation of the Ureters into the Bowel. PMID- 30437421 TI - Recovery in a Case of Staphylococcal Meningitis Treated by Chemotherapy. PMID- 30437423 TI - Educational Supplement. PMID- 30437422 TI - A Study of Vitamin C Saturation in Hospital Children. PMID- 30437424 TI - Current Topics. PMID- 30437425 TI - Medicine under Vichy. PMID- 30437426 TI - Vital Statistics, &c. PMID- 30437427 TI - The Tuberculin Patch Test. PMID- 30437428 TI - Vital Statistics, &c. PMID- 30437429 TI - Systemic Changes in Blood Vessels and Connective Tissues and Acute Necrosis of the Pancreas. PMID- 30437431 TI - Current Topics. PMID- 30437430 TI - Peptic Ulcer: A Study of the Number of Cases Treated in the Western Infirmary of Glasgow during 46 Years (1897 to 1942). PMID- 30437433 TI - The Significance of the Rh Factor in Medicine and Obstetrics. PMID- 30437432 TI - Vital Statistics, &c. PMID- 30437434 TI - Current Topics. PMID- 30437436 TI - Current Topics. PMID- 30437435 TI - A Case of Accessory Pancreas in an Unusual Position Complicated by Acute Necrosis. PMID- 30437437 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437438 TI - Surgical Relief of Pain. PMID- 30437439 TI - The Transfusion of Cell Concentrates. PMID- 30437441 TI - Current Topics. PMID- 30437440 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437442 TI - Current Topics. PMID- 30437443 TI - Some Aspects of Aviation Medicine. PMID- 30437444 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437446 TI - Current Topics. PMID- 30437445 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437447 TI - Simple Polypoid Tumour of the Bronchus: Report of a Case. PMID- 30437448 TI - Problems of Infection: A Lecture Commemorating the Hundredth Anniversary of the Birth of Sir Hector Cameron. PMID- 30437449 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437450 TI - On Growing up: Some Observations, Scientific and Otherwise on the Surgery of Childhood. PMID- 30437451 TI - Current Topics. PMID- 30437452 TI - A Method of Treating Mammary Abscess. PMID- 30437453 TI - Herpes Corneae and Virus Infection. PMID- 30437454 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437455 TI - A National Plan of Treatment for the Chronic Rheumatic Diseases. PMID- 30437456 TI - Current Topics. PMID- 30437457 TI - New Preparations, &c. PMID- 30437458 TI - Glasgow Medico-Chirurgical Society. PMID- 30437459 TI - Medical Practice in Pondoland, South Africa. PMID- 30437460 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st November, 1908. PMID- 30437461 TI - Current Topics. PMID- 30437462 TI - Obstetrical and Gynaecological Society. PMID- 30437463 TI - Gastrotomy for Foreign Body. PMID- 30437464 TI - Traumatic Rupture of Small Intestine. PMID- 30437465 TI - New Preparations, &c. PMID- 30437466 TI - Obstetrical and Gynaecological Society. PMID- 30437467 TI - Glasgow Medico-Chirurgical Society. PMID- 30437468 TI - An Experimental Investigation into the Function of the Thymus Gland. PMID- 30437469 TI - Case of Chorion-Epithelioma. PMID- 30437471 TI - Current Topics. PMID- 30437470 TI - Gangrene of the Extremities after Pneumonia, with Notes of Two Illustrative Cases. PMID- 30437472 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th July, 1908. PMID- 30437473 TI - Case of Rare Pelvic Tumour in a Child of Four Years. PMID- 30437474 TI - A Case of Facial Paralysis, with Remarks on Surgical Treatment of This Affection. PMID- 30437476 TI - Obstetrical and Gynaecological Society. PMID- 30437475 TI - Multiple Telangiectases: Three Cases in One Family. PMID- 30437477 TI - The Choice of a General Anaesthetic. PMID- 30437478 TI - Current Topics. PMID- 30437479 TI - An Obstetric Diary of William Hunter, 1762-1765. PMID- 30437480 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 19th September, 1908. PMID- 30437481 TI - New Preparations, &c. PMID- 30437482 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th October, 1908. PMID- 30437483 TI - The Vaccine Treatment of Infectious Diseases-(a) Chronic Acne Vulgaris; (b) Infection of the Urinary Tract; (c) Tuberculosis (with Opsonic Charts in the Vaccine Treatment of Tuberculous Disease). PMID- 30437485 TI - Current Topics. PMID- 30437484 TI - An Obstetric Diary of William Hunter, 1762-1765. PMID- 30437487 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 15th August, 1908. PMID- 30437486 TI - Headache and Ocular Treatment. PMID- 30437488 TI - Infantile Mortality. PMID- 30437489 TI - An Obstetric Diary of William Hunter, 1762-1765. PMID- 30437490 TI - The Vascular System and the Fibromyomata. PMID- 30437491 TI - Chauffeur's Fracture. PMID- 30437492 TI - Agglutination Reactions. PMID- 30437493 TI - A Review of the Serum Treatment of Infectious Diseases in the Practice of the City of Glasgow Fever and Small-Pox Hospitals, Belvidere. PMID- 30437494 TI - Current Topics. PMID- 30437495 TI - Glasgow Southern Medical Society. PMID- 30437496 TI - New Preparations, &c. PMID- 30437497 TI - Note on the Course of the Cerebello-Olivary Fibres, as Demonstrated in a Case of Tuberculosis of the Spinal Cord and Medulla. PMID- 30437498 TI - Current Topics. PMID- 30437500 TI - Glasgow Medico-Chirurgical Society. PMID- 30437499 TI - Case of Intracystic Papilloma of an Accessory Thyroid. PMID- 30437501 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 20th June, 1908. PMID- 30437502 TI - A Case of Hypertrophic Stenosis of the Pylorus in an Infant 8 Weeks Old. PMID- 30437503 TI - An Unusual Form of Mediastinal Tumour. PMID- 30437504 TI - A Procedure to Fill in a Medium-Sized Gap in the Nostril. PMID- 30437506 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 28th November, 1925. PMID- 30437505 TI - Wry Neck or Torticollis. PMID- 30437507 TI - The Plus-Potentially Sick of the Race. PMID- 30437508 TI - The Significance of Guanidins in the Animal Body. PMID- 30437509 TI - Current Topics. PMID- 30437511 TI - Inventory of the Surgical Instruments of the Glasgow Royal Infirmary a Hundred Years Ago. PMID- 30437510 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 25th July, 1925. PMID- 30437513 TI - Current Topics. PMID- 30437512 TI - A Case of Delirium Associated with Physical Signs of Exophthalmic Goitre Recovery. PMID- 30437514 TI - Notes from a Doctor's Diary of His Voyages. PMID- 30437515 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437516 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 31st October, 1925. PMID- 30437517 TI - The Symptomatology of Disturbances of the Visual Function. PMID- 30437518 TI - Some Old Tendencies in Medicine. PMID- 30437519 TI - Fatal Anaemia at an Unusually Early Age. PMID- 30437520 TI - Current Topics. PMID- 30437521 TI - Current Topics. PMID- 30437522 TI - The Epidemic Diseases of the Central Nervous System. PMID- 30437523 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th September, 1925. PMID- 30437525 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437524 TI - Ringbodies in Anaemia. PMID- 30437526 TI - Current Topics. PMID- 30437527 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th August, 1925. PMID- 30437528 TI - Early Diagnosis of Pulmonary Tubercle. PMID- 30437529 TI - The Epidemic Diseases of the Central Nervous System. PMID- 30437530 TI - Current Topics. PMID- 30437531 TI - Chronic Catarrhal Colitis: A Clinical Study. PMID- 30437532 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 27th June, 1925. PMID- 30437533 TI - Two Cases of Haemopneumothorax without Traumatism. PMID- 30437535 TI - The Hunter Memorial at the University. PMID- 30437534 TI - The End-Results of Pleurisy with Effusion in Children. PMID- 30437536 TI - On the Examination and Treatment of a Case of Talipes. PMID- 30437537 TI - The Princess Louise Scottish Hospital for Limbless and Disabled Sailors and Soldiers: Memorial to Sir William Macewen. PMID- 30437538 TI - Pyelography. PMID- 30437540 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th December, 1923. PMID- 30437539 TI - The Pel-Ebstein Pyrexia, with Involvement of the Central Nervous System: Notes of a Case. PMID- 30437541 TI - A Study of the Diets and Economic Conditions of Artisan Families in Glasgow in May, 1923. PMID- 30437542 TI - Current Topics. PMID- 30437543 TI - Some Practical Points in the Administration of Ether. PMID- 30437545 TI - The Pathology of Nephritis. PMID- 30437544 TI - Renal Efficiency Tests in Nephritis in Children. PMID- 30437546 TI - A Note on the Clinical Application of Certain Bio-Chemical Methods of Examination in Renal Disease. PMID- 30437547 TI - The Clinical Varieties of Nephritis. PMID- 30437548 TI - Current Topics. PMID- 30437549 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th January, 1924. PMID- 30437550 TI - The Practice of Psycho-Analysis. PMID- 30437551 TI - The Problem of Fitness. PMID- 30437552 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 29th March, 1924. PMID- 30437553 TI - A Combination of Abdominal Difficulties. PMID- 30437554 TI - Current Topics. PMID- 30437555 TI - Medical Aspects of Samuel Johnson. PMID- 30437556 TI - A Case of Alkaptonuria. PMID- 30437558 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 24th May, 1924. PMID- 30437557 TI - Anaesthesia: Its Present Position. PMID- 30437560 TI - Stone in the Urethra for Twenty-Three Years. PMID- 30437559 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437561 TI - The Treatment of Syphilis. PMID- 30437563 TI - Current Topics. PMID- 30437562 TI - A Case of Ulcerative Endocarditis Terminating in the Appearance of Widespread Embolic Phenomena. PMID- 30437565 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 1st March, 1924. PMID- 30437564 TI - Chinese Foot-Binding. PMID- 30437566 TI - Current Topics. PMID- 30437567 TI - Extreme Voluntary Hyperextensibility of Fingers. PMID- 30437568 TI - Human Blood-Grouping: A Review of Its Present Position and Applications. PMID- 30437569 TI - The X-Ray Examination of the Alimentary Tract. PMID- 30437570 TI - Recent Leprosy Research and Its Bearing on the Tuberculosis Problem. PMID- 30437571 TI - A Surgical Reminiscence of Lister. PMID- 30437573 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437572 TI - Double Penis and Double Vulva. PMID- 30437574 TI - Medical Education. PMID- 30437575 TI - Current Topics. PMID- 30437576 TI - The Treatment of Ununited Fractures and Other Bone Defects by Bone Grafts and Bone Comminution. PMID- 30437578 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th April, 1924. PMID- 30437577 TI - Case of Lymphadenoma, with Relapsing Pyrexia of the Pel-Ebstein Type. PMID- 30437580 TI - Obstetrical and Gynaecological Society. PMID- 30437579 TI - Case of "Spider's Lick." PMID- 30437581 TI - A Case of Ankylosis of the Spine. PMID- 30437582 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd February, 1907. PMID- 30437583 TI - On the Value of the Tuberculo-Opsonic Index in Diagnosis. PMID- 30437584 TI - Current Topics. PMID- 30437585 TI - Glasgow Medico-Chirurgical Society. PMID- 30437586 TI - New Preparations, &c. PMID- 30437587 TI - Note on Fracture of a Rib by Sneezing. PMID- 30437588 TI - Glasgow Northern Medical Society. PMID- 30437590 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 26th January, 1907. PMID- 30437589 TI - Throat Department, Glasgow Royal Infirmary. PMID- 30437591 TI - Note on a Case Where the Radical Mastoid Operation Was Performed for Purulent Otitis Media (When Seen for the First Time, the Patient Had a Primary Diphtheria of the External Auditory Canal). PMID- 30437592 TI - Obstetrical and Gynaecological Society. PMID- 30437593 TI - Current Topics. PMID- 30437594 TI - New Preparations, &c. PMID- 30437595 TI - Glasgow Eastern Medical Society. PMID- 30437597 TI - Glasgow Medico-Chirurgical Society. PMID- 30437596 TI - A Plea for the Study of the Deaf Child and for the Teaching of Speech to the Semi Deaf and Semi-Mute. PMID- 30437598 TI - On the Need for a Progressive Study of Industrial Diseases. PMID- 30437599 TI - The Treatment of Conjunctivitis. PMID- 30437600 TI - The Treatment of Neurasthenia. PMID- 30437601 TI - Our Motto-"'UpsilonPiHPETAI PhiYSigmaEOmegaSigma." PMID- 30437602 TI - A Plea for the Study of the Deaf Child and for the Teaching of Speech to the Semi Deaf and Semi-Mute. PMID- 30437603 TI - Glasgow Medico-Chirurgical Society. PMID- 30437604 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 22nd December, 1906. PMID- 30437605 TI - Current Topics. PMID- 30437606 TI - Some Curious Bodies Found in the Female Bladder. PMID- 30437607 TI - Congenital Dislocation of the Patella. PMID- 30437608 TI - Glasgow Pathological and Clinical Society. PMID- 30437609 TI - Operations for Deviation of the Nasal Septum, with Special Reference to Submucous Resection. PMID- 30437610 TI - Glasgow Northern Medical Society. PMID- 30437612 TI - Blue Pigmentation of the Tympanic Membrane. PMID- 30437611 TI - Two Cases of Eye Injury Caused by Burning: Result of Operative and Other Treatment. PMID- 30437613 TI - Current Topics. PMID- 30437614 TI - Glasgow Southern Medical Society. PMID- 30437615 TI - Glasgow Medico-Chirurgical Society. PMID- 30437616 TI - Two Cases of Strangulated Ovarian Tumour, with Symptoms Suggestive of Other Conditions. PMID- 30437617 TI - On the Value of the Tuberculo-Opsonic Index in Diagnosis. PMID- 30437619 TI - Glasgow Pathological and Clinical Society. PMID- 30437618 TI - The Histological Diagnosis of the Endotheliomata. PMID- 30437621 TI - The Auld Hoose. PMID- 30437620 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 23rd March, 1907. PMID- 30437622 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th May, 1907. PMID- 30437623 TI - Glasgow Southern Medical Society. PMID- 30437625 TI - Current Topics. PMID- 30437624 TI - Obstetrical and Gynaecological Society. PMID- 30437627 TI - Glasgow Pathological and Clinical Society. PMID- 30437626 TI - Case of Perforation of Jejunal Ulcer Seven Years after Gastro-Jejunostomy. PMID- 30437628 TI - Glasgow Medico-Chirurgical Society. PMID- 30437630 TI - New Preparations, &c. PMID- 30437629 TI - Fluid of Milky Appearance Removed from Tunica Vaginalis. PMID- 30437632 TI - Obstetrical and Gynaecological Society. PMID- 30437631 TI - Scottish Medicine before the Union. PMID- 30437633 TI - Glasgow Medico-Chirurgical Society. PMID- 30437634 TI - The Treatment of Sciatica by Means of Saline Injections. PMID- 30437635 TI - Glasgow Southern Medical Society. PMID- 30437637 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th April, 1907. PMID- 30437636 TI - Case of Sarcoma of the Right Pleura and Lung, with Involvement of the Mediastinal Glands and Extension through the Diaphragm to the Liver. PMID- 30437638 TI - Current Topics. PMID- 30437639 TI - New Preparations, &c. PMID- 30437641 TI - Glasgow Pathological and Clinical Society. PMID- 30437642 TI - Clinical Haemoglobinometry. PMID- 30437640 TI - The West Australian Aborigines: Their Marriage Laws and Some Peculiar Customs. PMID- 30437643 TI - The Photoelectric Estimation of Haemoglobin. PMID- 30437644 TI - Vital Statistics, &c. PMID- 30437645 TI - The Royal Medical Corporations. PMID- 30437647 TI - Educational Supplement. PMID- 30437646 TI - Current Topics. PMID- 30437648 TI - Current Topics. PMID- 30437649 TI - The Surgical Uses of ZIPP. PMID- 30437651 TI - Indolic Intoxication. PMID- 30437650 TI - Vital Statistics, &c. PMID- 30437652 TI - Anaesthetic Convulsions. PMID- 30437653 TI - A Case of Mediterranean Kala-Azar in a British Soldier. PMID- 30437654 TI - Vital Statistics, &c. PMID- 30437655 TI - The Effect of Venous Stasis of Short Duration on Haemoglobin and Haematocrit Levels. PMID- 30437656 TI - Current Topics. PMID- 30437657 TI - Report of a Case of Amoebic Abscess of Liver, Lung, and Brain. PMID- 30437658 TI - Vital Statistics, &c. PMID- 30437659 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437660 TI - Glasgow Southern Medical Society. PMID- 30437661 TI - New Preparations, Appliances, &c. PMID- 30437662 TI - The Surgical Uses of ZIPP. PMID- 30437663 TI - Current Topics. PMID- 30437664 TI - Observations on the Incidence of Neuroses in R.A.F. Ground Personel. PMID- 30437665 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437667 TI - New Preparation. PMID- 30437666 TI - Haematemesis: A Critical Survey. PMID- 30437668 TI - Current Topics. PMID- 30437669 TI - Vital Statistics, &c. PMID- 30437670 TI - Current Topics. PMID- 30437671 TI - Vital Statistics, &c. PMID- 30437672 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437673 TI - Obstetrical and Gynaecological Society. PMID- 30437675 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd November, 1907. PMID- 30437674 TI - Current Topics. PMID- 30437676 TI - Breisky's Kraurosis Vulvae: Four Cases, Three of Them Complicated with Epithelioma. PMID- 30437678 TI - Glasgow Medico-Chirurgical Society. PMID- 30437677 TI - The Physio-Psychology of Hallucinations. PMID- 30437680 TI - New Preparations, &c. PMID- 30437679 TI - Note on a Danger in Urine-Testing. PMID- 30437681 TI - Ovarian Tumours Complicating Pregnancy, Labour, and the Puerperium. PMID- 30437682 TI - Four Cases of Acute Empyema of the Mastoid Cells, in Three of Which the Cavities Made by the Operation Were Treated by the Iodoform Wax Bone-Plugging Method of Mosetig-Moorhof. PMID- 30437684 TI - Glasgow Eastern Medical Society. PMID- 30437683 TI - Demonstration of a Series of Cases of Diseases of the Bladder, and a Method of Draining the Kidney and Bladder. PMID- 30437685 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th August, 1907. PMID- 30437686 TI - Glasgow Pathological and Clinical Society. PMID- 30437687 TI - Obstetrical and Gynaecological Society. PMID- 30437688 TI - Glasgow Medico-Chirurgical Society. PMID- 30437689 TI - Current Topics. PMID- 30437690 TI - Notes of Two Cases of Ludwig's Angina : With Pathological Report on One of the Cases. PMID- 30437691 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th July, 1907. PMID- 30437692 TI - New Preparations, &c. PMID- 30437693 TI - Glasgow Pathological and Clinical Society. PMID- 30437695 TI - Sarcoma of the Nose. PMID- 30437694 TI - The Really Useful in Electrotherapeutics. PMID- 30437696 TI - Glasgow Medico-Chirurgical Society. PMID- 30437697 TI - Notes on Some Tumours of the Caecal Region. PMID- 30437698 TI - Current Topics. PMID- 30437699 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd June, 1907. PMID- 30437700 TI - Current Topics. PMID- 30437701 TI - Obstetrical and Gynaecological Society. PMID- 30437702 TI - Notes on Interesting Cases. PMID- 30437703 TI - The Resuscitation of the Apparently Stillborn. PMID- 30437704 TI - The Evolution of the Medical Curriculum in the United Kingdom. PMID- 30437705 TI - Glasgow Pathological and Clinical Society. PMID- 30437706 TI - Case of Septicaemia Secondary to Small Abscess in Intestinal Wall. PMID- 30437707 TI - Obstetrical and Gynaecological Society. PMID- 30437708 TI - Current Topics. PMID- 30437709 TI - Skingrafting by a Modification of the Wolfe-Krause (Whole Thickness of the Skin) Method. PMID- 30437711 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 14th September, 1907. PMID- 30437710 TI - Infantile Mortality and Morbidity from the Obstetric Standpoint. PMID- 30437712 TI - Glasgow Medico-Chirurgical Society. PMID- 30437713 TI - Normal Plasma in Abnormal Lactation. PMID- 30437714 TI - The Medico-Chirurgical Society of Glasgow, 1814-1907. PMID- 30437715 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 19th October, 1907. PMID- 30437716 TI - On Some of the Difficulties Connected with the Diagnosis of Gastric Derangements. PMID- 30437718 TI - Current Topics. PMID- 30437717 TI - Glasgow Medico-Chirurgical Society. PMID- 30437719 TI - On the Treatment of Chronic Middle-Ear Suppuration in the Light of the Pathological Findings in Fifty Cases. PMID- 30437721 TI - Current Topics. PMID- 30437720 TI - Obstetrical and Gynaecological Society. PMID- 30437722 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437723 TI - Regional Enteritis. PMID- 30437724 TI - An Analogy Between Eye Strain (Asthenopia) and Heart Strain (Angina): To Illustrate the Essential Unity of Physiological and Pathological Processes. PMID- 30437726 TI - Current Topics. PMID- 30437725 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437727 TI - Congenital Short OEsophagus Complicated by Vitamin B. Deficiency. PMID- 30437728 TI - Diphtheritic Paralysis. PMID- 30437729 TI - Serum Neuritis. PMID- 30437730 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437731 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437732 TI - The Progress of Resolution in Patients Treated with Sulphonamides. PMID- 30437734 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437733 TI - Chemotherapy in Pneumonia. PMID- 30437735 TI - The Blood Concentration of the Sulphonamides, and Its Relation to Effective Dosage. PMID- 30437736 TI - Current Topics. PMID- 30437737 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437738 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437739 TI - Current Topics. PMID- 30437740 TI - The Treatment of Toxic Goitre with Thiouracil. PMID- 30437741 TI - Gastric Excretion of Neutral Red. PMID- 30437742 TI - Current Topics. PMID- 30437743 TI - Endometriosis of the Inguinal Region: Report of Two Cases. PMID- 30437744 TI - Corrigendum. AB - [This corrects the article on p. 156 in vol. 142.]. PMID- 30437745 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437746 TI - Some Aspects of Human Infertility. PMID- 30437747 TI - New Preparations, Appliances, &c. PMID- 30437748 TI - Some Aspects of Male Infertility. PMID- 30437749 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30437750 TI - Extrinsic and Intrinsic Conditions Affecting School Children: A Study of Some Schools and School Children in Glasgow. PMID- 30437751 TI - The Pathology and Treatment of Atrophic Rhinitis. PMID- 30437752 TI - Shakspere's Doctors. PMID- 30437753 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th June, 1909. PMID- 30437754 TI - New Preparations, &c. PMID- 30437755 TI - Medico-Chirurgical Society of Glasgow. PMID- 30437756 TI - Current Topics. PMID- 30437757 TI - Obstetrical and Gynaecological Society. PMID- 30437758 TI - Medico-Chirurgical Society of Glasgow. PMID- 30437760 TI - New Preparations, &c. PMID- 30437759 TI - The "Bruit De Roger." PMID- 30437762 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th November, 1909. PMID- 30437761 TI - The Subcutaneous Treatment of Hernia in Children. PMID- 30437763 TI - An Ophthalmic Retrospect. PMID- 30437764 TI - Current Topics. PMID- 30437765 TI - Glasgow Northern Medical Society. PMID- 30437766 TI - Reflexes in Cardiac Disease, Illustrated by a Case of Paroxysmal Tachycardia in Which an Unusual Reflex Occurred. PMID- 30437767 TI - The Schools for the Deaf in England. PMID- 30437768 TI - Medico-Chirurgical Society of Glasgow. PMID- 30437769 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th July, 1909. PMID- 30437770 TI - Royal Infirmary Reconstruction. PMID- 30437772 TI - Current Topics. PMID- 30437771 TI - Address on the Presentation of a Memorial of Lord Lister at the Opening of the New Glasgow Royal Infirmary, 23rd June, 1909. PMID- 30437773 TI - Extrinsic and Intrinsic Conditions Affecting School Children: A Study of Some Schools and School Children in Glasgow. PMID- 30437774 TI - Current Topics. PMID- 30437775 TI - A Retrospect: Some Glasgow Physicians and Surgeons of the Earlier Years of Last Century. PMID- 30437777 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 18th September, 1909. PMID- 30437776 TI - Modern Moods and Movements in Medicine. PMID- 30437778 TI - New Preparations, &c. PMID- 30437779 TI - Glasgow Eastern Medical Society. PMID- 30437780 TI - The Schools for the Deaf in Scotland and Ireland. PMID- 30437781 TI - Semmelweis. PMID- 30437783 TI - Notes on the Treatment of Quinsy, with an Illustrative Case. PMID- 30437782 TI - The Condition of the Eyes in the Deaf: Appendix to Dr. Kerr Love's Paper. PMID- 30437784 TI - Extrinsic and Intrinsic Conditions Affecting School Children: A Study of Some Schools and School Children in Glasgow. PMID- 30437785 TI - Case of Tabes Dorsalis in a Female in Which Laryngeal Crisis, Ocular Paralysis, & Vasomotor Phenomena Were Early Symptoms. PMID- 30437786 TI - Current Topics. PMID- 30437787 TI - Medico-Chirurgical Society of Glasgow. PMID- 30437788 TI - New Preparations, &c. PMID- 30437789 TI - The Schools for the Deaf in Scotland and Ireland. PMID- 30437791 TI - Current Topics. PMID- 30437790 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 14th August, 1909. PMID- 30437792 TI - The Doctrine of Inflammation. PMID- 30437794 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd October, 1909. PMID- 30437793 TI - Some Cases of Pregnancy with Kidney Complications. PMID- 30437795 TI - Obstetrical and Gynaecological Society. PMID- 30437796 TI - Glasgow Northern Medical Society. PMID- 30437797 TI - New Preparations, &c. PMID- 30437798 TI - Pyelitis Complicating Pregnancy and the Puerperium. PMID- 30437799 TI - Glasgow Southern Medical Society. PMID- 30437800 TI - Obstetrical and Gynaecological Society. PMID- 30437801 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th November, 1905. PMID- 30437803 TI - Glasgow Medico-Chirurgical Society. PMID- 30437802 TI - The Ophthalmoscope in General Medicine. PMID- 30437804 TI - New Preparations, &c. PMID- 30437805 TI - On the Mode of Spread of Breast Cancer in Relation to Its Operative Treatment. PMID- 30437806 TI - Current Topics. PMID- 30437807 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd July, 1905. PMID- 30437808 TI - Glasgow Pathological and Clinical Society. PMID- 30437809 TI - Movable Displacements of the Kidney. PMID- 30437810 TI - Notes on Eight Interesting Obstetrical Cases. PMID- 30437812 TI - Obstetrical and Gynaecological Society. PMID- 30437811 TI - Case of Endocarditis in Typhoid Fever, with Infarctions of the Spleen and Kidney. PMID- 30437813 TI - Glasgow Eastern Medical Society. PMID- 30437814 TI - New Preparations, &c. PMID- 30437815 TI - Current Topics. PMID- 30437816 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 17th June, 1905. PMID- 30437817 TI - Glasgow Northern Medical Society. PMID- 30437818 TI - Current Topics. PMID- 30437820 TI - Glasgow Eastern Medical Society. PMID- 30437819 TI - On the Secondary Operation for Complete Rupture of the Perineum. PMID- 30437821 TI - A Note on the Treatment of Endometritis. PMID- 30437822 TI - Glasgow Pathological and Clinical Society. PMID- 30437823 TI - Movable Displacements of the Kidney. PMID- 30437824 TI - Case of Enlargement of the Spleen and Liver in a Child, the Second Case in the Same Family: Splenic Anaemia or Banti's Disease? PMID- 30437825 TI - Glasgow Medico-Chirurgical Society. PMID- 30437827 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 21st October, 1905. PMID- 30437826 TI - Current Topics. PMID- 30437828 TI - Glasgow Pathological and Clinical Society. PMID- 30437829 TI - Morgagni to Virchow: An Epoch in the History of Medicine. PMID- 30437830 TI - The Treatment of Small-Pox by Ichthyol. PMID- 30437832 TI - Glasgow Eastern Medical Society. PMID- 30437831 TI - Case of Precocious Development. PMID- 30437833 TI - Case of Perforation of an Ulcer of the Duodenum, with Remarks on the Diagnosis and Treatment of This Affection. PMID- 30437834 TI - Glasgow Medico-Chirurgical Society. PMID- 30437835 TI - Old Glasgow Hospitals. PMID- 30437837 TI - Current Topics. PMID- 30437836 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th August, 1905. PMID- 30437838 TI - Glasgow Eastern Medical Society. PMID- 30437839 TI - On Leucocythaemia, Lymphadenoma, and Allied Diseases. PMID- 30437840 TI - New Preparations, &c. PMID- 30437841 TI - Case Operated on for Radical Cure of Inguinal Hernia. PMID- 30437842 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 16th September, 1905. PMID- 30437843 TI - Enteric Fever: Discussion at the Glasgow Medico-Chirurgical Society on 3rd February, 1905. PMID- 30437844 TI - Glasgow Pathological and Clinical Society. PMID- 30437845 TI - Current Topics. PMID- 30437846 TI - Glasgow Medico-Chirurgical Society. PMID- 30437847 TI - Glasgow Eastern Medical Society. PMID- 30437848 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437849 TI - Current Topics. PMID- 30437850 TI - Pulmonary Tuberculosis in the Eastern District of Glasgow, and Its Early Recognition. PMID- 30437851 TI - Cases of Cancer of Stomach of Prolonged Duration. PMID- 30437852 TI - Observations on the Symptomatology and Treatment of Albuminuria and Eclampsia. PMID- 30437853 TI - Some Chemical Aspects of the Toxaemias of Pregnancy. PMID- 30437854 TI - Vital Statistics, &c., for Four Weeks Ended 25th June, 1927. PMID- 30437855 TI - Vital Statistics, &c., for Four Weeks Ended 27th August, 1927. PMID- 30437856 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437857 TI - Syphilis of the Stomach. PMID- 30437858 TI - Status Lymphaticus and Sudden Death. PMID- 30437859 TI - Three Types of Cases of Thyroid Enlargement, and Their Treatment. PMID- 30437860 TI - Current Topics. PMID- 30437861 TI - Acute Endocarditis: A Clinical Study. PMID- 30437862 TI - Current Topics. PMID- 30437863 TI - Case of Congenital Transposition of Viscera with Certain Cardiac Peculiarities. PMID- 30437864 TI - Professional Secrecy and Professional Privilege. PMID- 30437865 TI - Vital Statistics, &c., for Four Weeks Ended 26th November, 1927. PMID- 30437866 TI - Diverticulum of the Common Bile Duct. PMID- 30437867 TI - Case of Auricular Flutter with Full Heart Block. PMID- 30437868 TI - Diathesis, or the Influence of Soil in the Causation and Treatment of Disease. PMID- 30437869 TI - On the Effect of Chronic Absorption of Bacterial Toxins on the Capillary Vessels. PMID- 30437870 TI - Current Topics. PMID- 30437871 TI - The Diagnosis of Renal Neoplasm by Pyelography. PMID- 30437872 TI - Sympathetic Ophthalmia. PMID- 30437873 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437874 TI - Vital Statistics, &c., for Five Weeks Ended 30th July, 1927. PMID- 30437875 TI - Acute Endocarditis: A Clinical Study. PMID- 30437877 TI - Current Topics. PMID- 30437876 TI - Acute Endocarditis in Pregnancy and the Puerperium: Notes on Eleven Autopsies. PMID- 30437878 TI - Injuries of the Urinary Bladder. PMID- 30437879 TI - Vital Statistics, &c., for Five Weeks Ended 29th October, 1927. PMID- 30437880 TI - The Treatment of Aneurysm of the Common Carotid Artery: With Notes of a Case. PMID- 30437881 TI - Case of "Hodgkin's Disease," with Paraplegia and Other Somewhat Rare Complications. PMID- 30437882 TI - Current Topics. PMID- 30437883 TI - Two Cases of Pseudochylous Effusion. PMID- 30437884 TI - Case of Chocolate-Coloured, Cholesterol-Containing Pleural Effusion. PMID- 30437885 TI - Note on the Balance of Calcium, Magnesium, Phosphorus, and Sulphur in a Case of Osteitis Deformans. PMID- 30437886 TI - Vital Statistics, &c., for Four Weeks Ended 24th September, 1927. PMID- 30437887 TI - Cystic Changes in External Semilunar Cartilage of Knee. PMID- 30437888 TI - Observations on Prostatic Cancer with Metastases in Bone. PMID- 30437889 TI - Pyelography in the Erect Position. PMID- 30437890 TI - Glasgow Eastern Medical Society. PMID- 30437891 TI - Gastric Analysis in Cases of Diabetes and Glycosuria. PMID- 30437892 TI - Case of Patency of the Spinous Processes Simulating Appendicitis. PMID- 30437893 TI - Current Topics. PMID- 30437894 TI - Vital Statistics, &c., for Four Weeks Ended 28th May, 1927. PMID- 30437895 TI - Vital Statistics, &c., for Four Weeks Ended 25th December, 1926. PMID- 30437896 TI - Difficulties in the Clinical Diagnosis and Prognosis in the Various Forms of Chronic Bright's Disease. PMID- 30437897 TI - Professional Education. PMID- 30437898 TI - Glasgow Eastern Medical Society. PMID- 30437899 TI - Current Topics. PMID- 30437900 TI - Case of Bence-Jones Proteinuria, with a Note on the Urinary Excretion of the Mineral Elements. PMID- 30437901 TI - Case of the Charcot-Marie-Tooth Type of Muscular Atrophy, with a Note on the Condition of the Bones. PMID- 30437902 TI - Vital Statistics, &c., for Five Weeks Ended 30th April, 1927. PMID- 30437903 TI - Lister Centenary Celebrations. PMID- 30437904 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437905 TI - Current Topics. PMID- 30437906 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437907 TI - Current Topics. PMID- 30437908 TI - On Osteomyelitis in Childhood. PMID- 30437909 TI - Gonorrhoea. PMID- 30437910 TI - Vital Statistics, &c., for Four Weeks Ended 26th March, 1927. PMID- 30437912 TI - Modern Aspects of Syphilis in Special and General Practice. PMID- 30437911 TI - Syphilis of the Eye. PMID- 30437913 TI - Current Topics. PMID- 30437914 TI - Vital Statistics, &c., for Four Weeks Ended 26th February, 1927. PMID- 30437915 TI - Some Social Aspects of Psychiatry. PMID- 30437917 TI - Current Topics. PMID- 30437916 TI - Tachycardia. PMID- 30437918 TI - A Case of Pyrexia of Unknown Origin Associated with a Cutaneous Eruption. PMID- 30437920 TI - Case of Paroxysmal Auricular Flutter, with 1-1 Ventricular Response: Effects of Digitalis and Quinidine. PMID- 30437919 TI - Vital Statistics, &c., for Five Weeks Ended 29th January, 1927. PMID- 30437921 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437922 TI - Massage. PMID- 30437923 TI - Current Topics. PMID- 30437924 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437925 TI - General Discussion on Insanity from the Point of View of the General Practitioner. PMID- 30437927 TI - Vital Statistics, &c., for Four Weeks Ended 27th March, 1926. PMID- 30437926 TI - Disorders of the Capillary Vessels as a Factor in Disease. PMID- 30437928 TI - Exophthalmic Goitre. PMID- 30437929 TI - Vital Statistics, &c., for Four Weeks Ended 24th April, 1926. PMID- 30437930 TI - To Illustrate a Nail in the Hip for Fourteen Years. PMID- 30437932 TI - Current Topics. PMID- 30437931 TI - The Scientific Basis of Public Health Administration. PMID- 30437933 TI - Gastric Carcinoma without Gastric Symptoms: Notes on Two Cases. PMID- 30437934 TI - Medicine as a Career. PMID- 30437935 TI - Corrigendum. AB - [This corrects the article on p. 298 in vol. 105.]. PMID- 30437936 TI - Current Topics. PMID- 30437937 TI - Present-Day Methods in the Treatment of Tuberculosis. PMID- 30437938 TI - Hospitals in Relation to the Public and the Profession. PMID- 30437939 TI - Vital Statistics, &c., for Five Weeks Ended 29th May, 1926. PMID- 30437940 TI - Case of Paroxysmal Tachycardia of Ventricular Origin with Stokes-Adams Syndrome, Exhibiting Retrograde Conduction with Partial Heart-Block. PMID- 30437941 TI - A Method of Supporting the Bulging Brain in Extensive Decompressive Trephining. PMID- 30437942 TI - Current Topics. PMID- 30437944 TI - A Reconsideration of the Sense of Smell. PMID- 30437943 TI - A Suggested Cardio-Pulmonary Syndrome in Early Rheumatism. PMID- 30437945 TI - Miners' Nystagmus. PMID- 30437946 TI - Vital Statistics. &c., for Four Weeks Ended 27th February, 1926. PMID- 30437947 TI - Variation in the Mortality from Cancer Amongst Persons in the Different Districts of Glasgow and Its Relationship to Social Status. PMID- 30437948 TI - Lingual Goitre: Removal Followed by Myxoedema. PMID- 30437950 TI - The Clinical Aspects of Ischaemic Necrosis of the Heart Muscle. PMID- 30437949 TI - The Diseased Gall-Bladder. PMID- 30437952 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437951 TI - Vital Statistics. &c., for Four Weeks Ended 26th December, 1925. PMID- 30437953 TI - The Electrocardiographic Evidence of Myocardial Disease. PMID- 30437954 TI - Current Topics. PMID- 30437955 TI - The Psychological Factor in Physical Disease. PMID- 30437956 TI - Pharmaceutical Specialities, &c. PMID- 30437957 TI - Some Observations on the Suprarenal Gland. PMID- 30437958 TI - The Effects of Rheumatism in Children. PMID- 30437959 TI - The Diagnosis and Treatment of Chronic Intestinal Obstruction, with Three Illustrative Cases. PMID- 30437960 TI - Two Cases of Congenital Diaphragmatic Hernia. PMID- 30437961 TI - Glasgow Eastern Medical Society. PMID- 30437962 TI - Current Topics. PMID- 30437964 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437963 TI - Vital Statistics. &c., for Five Weeks Ended 30th January, 1926. PMID- 30437965 TI - Case of Unilateral Mydriasis. PMID- 30437967 TI - Glasgow Eastern Medical Society. PMID- 30437966 TI - A Study in the Symptomatology of Headache. PMID- 30437968 TI - Vital Statistics, &c., for Five Weeks Ended 30th October, 1926. PMID- 30437969 TI - Endoscopy and the Removal of Foreign Bodies from the Air Passages and Upper Food Passages. PMID- 30437970 TI - Current Topics. PMID- 30437972 TI - Cholecystography: The X-Ray Visualisation of the Gall-Bladder by Means of Sodium Tetraiodophenolphthalein (Graham's Method). PMID- 30437971 TI - A Commentary on a Seventeenth Century Review of the Arts and Sciences, Including Medicine. PMID- 30437973 TI - Vital Statistics, &c., for Four Weeks Ended 28th August, 1926. PMID- 30437974 TI - Current Topics. PMID- 30437975 TI - New Preparations, &c. PMID- 30437976 TI - Case of Stokes-Adams Syndrome: Treatment by Adrenalin. PMID- 30437978 TI - Ileo-Caecal Intussusception Followed by Ileo-Ileal Intussusception. PMID- 30437977 TI - Vital Statistics, &c., for Four Weeks Ended 25th September, 1926. PMID- 30437979 TI - Some Further Observations on the Capillary Vessels in Disease. PMID- 30437980 TI - The Etiology of Psychasthenia. PMID- 30437981 TI - Haemoptysis Due to Rubber Tube Retained in the Pleural Cavity. PMID- 30437983 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437982 TI - Arterio-Venous Aneurysm of the Popliteal Vessels. PMID- 30437985 TI - Current Topics. PMID- 30437984 TI - Leptothricosis. PMID- 30437986 TI - Current Topics. PMID- 30437987 TI - On Hare-Lip and Other Developmental Lesions of the Face. PMID- 30437988 TI - The Muscle of the Heart, the Intestinal Tract, the Iris, and the Ciliary Body: An Analogy and a Contrast. PMID- 30437989 TI - Vital Statistics, &c., for Four Weeks Ended 27th November, 1926. PMID- 30437990 TI - The Provision of an Anaesthetic Service. PMID- 30437991 TI - Water: Its Physiological Significance. PMID- 30437992 TI - Current Topics. PMID- 30437993 TI - Vital Statistics, &c., for Four Weeks Ended 26th June, 1926. PMID- 30437994 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437995 TI - Neuralgias of the Head, with Special Reference to Trigeminal Neuralgia and Its Operative Treatment. PMID- 30437996 TI - Case of Sacro-Coccygeal Chordoma. PMID- 30437997 TI - A Method of Alcohol Injection in Trigeminal Neuralgia. PMID- 30437998 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30437999 TI - Glasgow Eastern Medical Society. PMID- 30438000 TI - A Commentary on a Seventeenth Century Review of the Arts and Sciences, Including Medicine. PMID- 30438001 TI - Vital Statistics, &c., for Five Weeks Ended 31st July, 1926. PMID- 30438002 TI - Current Topics. PMID- 30438003 TI - Acute Perforating Peptic Ulcer: An Analysis of 387 Cases. PMID- 30438004 TI - Three Specimens Illustrative of Gangrenous Hernia. PMID- 30438006 TI - Puerperal Eclampsia. PMID- 30438005 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 22nd January, 1910. PMID- 30438007 TI - Sugars. PMID- 30438008 TI - The Natural and Unnatural Feeding of the Infant. PMID- 30438009 TI - Current Topics. PMID- 30438010 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th March, 1910. PMID- 30438011 TI - Four Cases of Gonorrhoeal Arthritis Treated by Vaccine Therapy. PMID- 30438012 TI - Current Topics. PMID- 30438013 TI - Case of Carcinoma of the Stomach with Metastases in the Bone-Marrow, and a Blood Picture Suggestive of Pernicious Anaemia. PMID- 30438014 TI - Gynaecology and Abdominal Surgery. PMID- 30438015 TI - Note on a Case of Merycism. PMID- 30438016 TI - Glasgow Northern Medical Society. PMID- 30438017 TI - Partick and District Medical Society. PMID- 30438018 TI - Cases Treated by Injections of Bacterial Vaccines. PMID- 30438019 TI - Medico-Chirurgical Society of Glasgow. PMID- 30438020 TI - Glasgow Southern Medical Society. PMID- 30438021 TI - Current Topics. PMID- 30438022 TI - Myxo-Sarcoma of Upper End of Tibia-Osteomyelitis of Lower End of Tibia. PMID- 30438023 TI - New Preparations, &c. PMID- 30438024 TI - Epilepsy in Some of Its Gynaecological Aspects. PMID- 30438025 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 21st May, 1910. PMID- 30438027 TI - Medico-Chirurgical Society of Glasgow. PMID- 30438026 TI - Colour Perception and Other Visual Functions in Their Practical Aspects. PMID- 30438028 TI - New Preparations, &c. PMID- 30438029 TI - Acute Pneumonia and Its Treatment: An Experience of 460 Cases Treated in the Wards of the Victoria Infirmary, Glasgow. PMID- 30438030 TI - Gynaecology and Abdominal Surgery. PMID- 30438031 TI - Obstetrical and Gynaecological Society. PMID- 30438032 TI - Medico-Chirurgical Society of Glasgow. PMID- 30438034 TI - Current Topics. PMID- 30438033 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th February, 1910. PMID- 30438035 TI - Case of Addison's Disease. PMID- 30438036 TI - Significance of Certain Changes in the Composition of the Urine. PMID- 30438037 TI - The Formation and Early Days of the St. Andrew's Ambulance Association. PMID- 30438038 TI - Glasgow-Meteorological and Vital Statistics for the Five Weeks Ended 25th December, 1909. PMID- 30438039 TI - The Symptoms and Diagnosis of Duodenal Ulcer. PMID- 30438040 TI - Malt Extracts and Disinfectants. PMID- 30438041 TI - Case of Acute Haemorrhagic Leukaemia. PMID- 30438042 TI - Glasgow Southern Medical Society. PMID- 30438043 TI - Medico-Chirurgical Society of Glasgow. PMID- 30438044 TI - Current Topics. PMID- 30438045 TI - New Preparations, &c. PMID- 30438046 TI - Two Cases of Rupture of the Vessels of the Neck into the Pharynx in Scarlet Fever. PMID- 30438048 TI - Medico-Chirurgical Society of Glasgow. PMID- 30438049 TI - Case of Symmetrical Keratodermia of the Extremities. PMID- 30438047 TI - Advances in Gynaecology in Recent Years. PMID- 30438051 TI - Current Topics. PMID- 30438050 TI - Case of Aplastic Anaemia. PMID- 30438052 TI - Introduction to a Discussion of the Effects of Moderate Doses of Alcohol. PMID- 30438053 TI - Glasgow Eastern Medical Society. PMID- 30438054 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd April, 1910. PMID- 30438055 TI - The Etiology of 320 Consecutive Cases of Failing Heart. PMID- 30438056 TI - An Appendix Causing Acute Peritonitis and Acute Intestinal Obstruction. PMID- 30438057 TI - Current Topics. PMID- 30438058 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438059 TI - A Case of Hydronephrosis with Double Ureters. PMID- 30438060 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 26th July, 1924. PMID- 30438061 TI - Lord Lister. PMID- 30438062 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 27th September, 1924. PMID- 30438063 TI - A Study of the Urea Concentration Test in Sixty-Two Cases of Disease. PMID- 30438064 TI - Current Topics. PMID- 30438066 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438065 TI - Contraluesin: A Note on Its Use in the Treatment of Syphilis. PMID- 30438067 TI - Current Topics. PMID- 30438068 TI - The Diagnosis of Obscure Pyrexias. PMID- 30438070 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 30th August, 1924. PMID- 30438069 TI - An Unusual Case of Pulmonary Syphilis. PMID- 30438071 TI - A Study of the Urea Concentration Test in Sixty-Two Cases of Disease. PMID- 30438072 TI - Current Topics. PMID- 30438073 TI - Scottish Society of Anaesthetists. PMID- 30438074 TI - Flattening or Reduction of the Inner Canthus Following Extirpation of the Lacrymal Sac. PMID- 30438075 TI - Case of Complete Lateral Sinus Thrombosis in a School Child, without Any of the Usual Signs or Symptoms. PMID- 30438076 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 28th June, 1924. PMID- 30438077 TI - A Clinical and Pathological Study of Simple and Malignant Tumours of the Breast, with Reference to the Presence of Mastitis and Pre-Cancerous Changes. PMID- 30438078 TI - The Place of the Emotion of Fear in the Etiology of the Neuroses. PMID- 30438079 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 29th November, 1924. PMID- 30438080 TI - The Problem of the Tuberculous Child. PMID- 30438081 TI - Four Cases of Bone Transplantation. PMID- 30438083 TI - Current Topics. PMID- 30438082 TI - Vistas and Visions: Some Aspects of the Colonial Medical Services. PMID- 30438084 TI - A Cerebral Case. PMID- 30438085 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438086 TI - Ileo-Colic Intussusception Due to a Fibro-Lipoma of the Ileum. PMID- 30438087 TI - Current Topics. PMID- 30438088 TI - The General Practitioner and the Tonsils. PMID- 30438089 TI - The Limitations of Surgery, Past and Present. PMID- 30438090 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438091 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438093 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438092 TI - Summary of Health Statistics for 1947. PMID- 30438095 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438094 TI - The Royal College of Surgeons of Edinburgh. PMID- 30438096 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438097 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438099 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438098 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438100 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438101 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438102 TI - University of Glasgow-Department of Ophthalmology: Spring, 1948. PMID- 30438103 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438105 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438104 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438106 TI - Royal College of Surgeons of Edinburgh. PMID- 30438107 TI - Sir William Macewen, 1848-1948. PMID- 30438108 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438109 TI - Royal College of Surgeons of Edinburgh. PMID- 30438110 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438111 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438112 TI - University of Glasgow. PMID- 30438113 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438115 TI - Glasgow Obstetrical Society. PMID- 30438114 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438117 TI - Royal College of Surgeons of Edinburgh. PMID- 30438116 TI - The Doctor's Essayist: Michel De Montaigne. PMID- 30438118 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438119 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438120 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438121 TI - University of Glasgow-Department of Ophthalmology: Autumn, 1948. PMID- 30438122 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438123 TI - Our Provision for Treating the Sick. PMID- 30438124 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438126 TI - Fissure in Ano. PMID- 30438125 TI - Primary Intrathoracic Growths: A Clinical and Pathological Study of Cases Occurring in the Victoria Infirmary, Glasgow. PMID- 30438127 TI - Diabetes in Childhood: I. AEtiology, Diagnosis and Prognosis. PMID- 30438128 TI - Cervical Ribs. PMID- 30438129 TI - Diabetes in Childhood: III. Coma. PMID- 30438131 TI - Current Topics. PMID- 30438130 TI - Diabetes in Childhood: II. Treatment. PMID- 30438132 TI - Vital Statistics, &c., for Five Weeks Ended 29th October, 1932. PMID- 30438133 TI - Diabetes in Childhood: IV. The Significance of the Blood-Sugar Curve in Ketosis. PMID- 30438134 TI - Case of Double Endophthalmitis Complicating Pneumonia. PMID- 30438135 TI - Vital Statistics, &c., for Four Weeks Ended 24th September, 1932. PMID- 30438136 TI - Spinal Anaesthesia with Percaine. PMID- 30438137 TI - The Use of Regional Anaesthesia. PMID- 30438138 TI - Tuberculosis in Infancy and Childhood. PMID- 30438139 TI - Notes on Tropical Diseases Sometimes Seen in Home Practice. PMID- 30438140 TI - Current Topics. PMID- 30438141 TI - Spinal Anaesthesia in Obstetrics and Gynaecology. PMID- 30438143 TI - New Preparations, Appliances, &c. PMID- 30438142 TI - A Series of Lesions in the Vicinity of the Optic Chiasma: Seven Cases Verified by Operation. PMID- 30438144 TI - The X-Ray Diagnosis and Treatment of Tumours in the Region of the Sella. PMID- 30438145 TI - Remarks on the Diagnosis of Chiasmal Lesions from an Ophthalmological Aspect. PMID- 30438147 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438146 TI - Current Topics. PMID- 30438148 TI - Case of Cerebral Syphilis with Unusual Clinical Features and Death from Pulmonary Haemorrhage. PMID- 30438149 TI - Vital Statistics, &c., for Four Weeks Ended 27th August, 1932. PMID- 30438150 TI - The Work of a Neurosurgical Clinic. PMID- 30438151 TI - Vital Statistics, &c., for Four Weeks Ended 24th February, 1934. PMID- 30438152 TI - The More Recent Relationship of Ophthalmology to General Medicine. PMID- 30438153 TI - Epivan-Sodium Intravenous Anaesthesia in Gynaecology: A Note on 137 Cases. PMID- 30438154 TI - Current Topics. PMID- 30438155 TI - New Preparations, Appliances, &c. PMID- 30438156 TI - Current Topics. PMID- 30438157 TI - Traumatic Rupture of the Intestine without External Sign of Injury. PMID- 30438158 TI - Sodium Citrate as a Haemostatic. PMID- 30438159 TI - Medical Education. PMID- 30438160 TI - Vital Statistics, &c., for Four Weeks Ended 28th April, 1934. PMID- 30438161 TI - The Bearing of the Experimental Induction of Cancer on Our Conceptions of Its Nature and Causation. PMID- 30438162 TI - Current Topics. PMID- 30438163 TI - Vital Statistics, &c., for Five Weeks Ended 30th December, 1933. PMID- 30438164 TI - New Preparations, Appliances, &c. PMID- 30438166 TI - Supersensitiveness: An Outline of the Chief Facts and Views as to Its Nature. PMID- 30438165 TI - Cholelithiasis: A Summary. PMID- 30438168 TI - Streptococcal Septicaemia: A Case Successfully Treated with Streptococcal (Scarlatinal) Antitoxin. PMID- 30438167 TI - Current Topics. PMID- 30438169 TI - A Note on Chronic Lymphatic OEdema and Its Treatment by the Kondoleon Operation. PMID- 30438170 TI - Vital Statistics, &c., for Four Weeks Ended 26th May, 1934. PMID- 30438171 TI - Certain Aspects of the Metabolic Response to Injury. PMID- 30438173 TI - Current Topics. PMID- 30438172 TI - Corrigendum. AB - [This corrects the article on p. 24 in vol. 121.]. PMID- 30438174 TI - Intestino-Vesical Fistula. PMID- 30438175 TI - Vital Statistics, &c., for Four Weeks Ended 27th January, 1934. PMID- 30438176 TI - Vital Statistics, &c., for Five Weeks Ended 31st March, 1934. PMID- 30438177 TI - Oxygen and Carbon Dioxide Therapy: Some Physiological Considerations. PMID- 30438178 TI - Current Topics. PMID- 30438179 TI - Pulmonary Tuberculosis and Pregnancy, with Special Reference to the Effect of Compression. PMID- 30438181 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438180 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438182 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438183 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438184 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438185 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438186 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438187 TI - Royal College of Surgeons of Edinburgh. PMID- 30438188 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438189 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438190 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438191 TI - Royal College of Surgeons of Edinburgh. PMID- 30438192 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438193 TI - Higher Dental Diplomates. PMID- 30438194 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438195 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438196 TI - Correspondence. PMID- 30438197 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438198 TI - The Royal Medico-Chirurgical Society. PMID- 30438199 TI - The Glasgow Southern Medical Society. PMID- 30438200 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438201 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438202 TI - Royal Faculty of Physicians and Surgeons. PMID- 30438203 TI - Royal College of Surgeons of Edinburgh. PMID- 30438204 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438205 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438206 TI - Glasgow Ear, Nose and Throat Hospital. PMID- 30438207 TI - The Western Infirmary. PMID- 30438208 TI - University of Glasgow-Department of Ophthalmology: Autumn, 1947. PMID- 30438209 TI - The Victoria Infirmary. PMID- 30438210 TI - Stobhill Hospital. PMID- 30438211 TI - Royal Hospital for Sick Children. PMID- 30438212 TI - Glasgow Eye Infirmary. PMID- 30438213 TI - The Royal Infirmary. PMID- 30438214 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438216 TI - Royal College of Surgeons of Edinburgh. PMID- 30438215 TI - Glasgow Royal Cancer Hospital and the Glasgow and West of Scotland Radium Institute. PMID- 30438217 TI - Royal Samaritan Hospital for Women. PMID- 30438218 TI - Southern General Hospital. PMID- 30438219 TI - Glasgow Royal Maternity and Women's Hospital. PMID- 30438220 TI - A Case of Infective Endocarditis Due to Bacillus Coli. PMID- 30438221 TI - Vital Statistics, &c., for Five Weeks Ended 30th June, 1934. PMID- 30438222 TI - Current Topics. PMID- 30438223 TI - Madness in Literature and Life. PMID- 30438224 TI - Current Topics. PMID- 30438225 TI - Vital Statistics, &c., for Four Weeks Ended 27th October, 1934. PMID- 30438226 TI - Diabetes Mellitus: A Broader Basis of Interpretation. PMID- 30438228 TI - Current Topics. PMID- 30438227 TI - Unrevealed Primary Carcinoma of the Gall-Bladder: Report of a Case with Unusual Metastases and Review of the Literature. PMID- 30438229 TI - Vital Statistics, &c., for Four Weeks Ended 28th July, 1934. PMID- 30438230 TI - Madness in Literature and Life. PMID- 30438231 TI - The Place of Neurotic Symptoms in Physical Disease. PMID- 30438233 TI - Current Topics and Educational Supplement. PMID- 30438232 TI - William Mackenzie, M.D., Founder of the Glasgow Eye Infirmary, and the First Lecturer on Diseases of the Eye in the University of Glasgow. PMID- 30438234 TI - Correction. AB - [This corrects the article on p. 187 in vol. 121.]. PMID- 30438235 TI - Vital Statistics, &c., for Four Weeks Ended 25th August, 1934. PMID- 30438236 TI - Aneurysm of the Popliteal Artery. PMID- 30438237 TI - Vital Statistics, &c., for Five Weeks Ended 29th September, 1934. PMID- 30438239 TI - New Preparations, Appliances, &c. PMID- 30438238 TI - Extrapleural Thoracoplasty in Tuberculosis. PMID- 30438240 TI - On the Occurrence of the So-Called "Coronary T Wave" in Electrocardiograms from Cases of Pericarditis. PMID- 30438241 TI - Glycosuria Following X-Ray Therapy: A Case of Lymphadenoma. PMID- 30438242 TI - Current Topics. PMID- 30438243 TI - Corrigendum. AB - [This corrects the article on p. 102 in vol. 122.]. PMID- 30438244 TI - A Vertical Writer. PMID- 30438245 TI - Review of the Burn Cases Treated in the Glasgow Royal Infirmary during the past Hundred Years (1833-1933), with Some Observations on the Present-Day Treatment. PMID- 30438246 TI - Letter and Word Blindness. PMID- 30438247 TI - Rabelais: Physician and Humanist. PMID- 30438248 TI - Vital Statistics, &c., for Four Weeks Ended 24th November, 1934. PMID- 30438249 TI - Glasgow Northern Medical Society. PMID- 30438251 TI - New Preparations, Appliances, &c. PMID- 30438250 TI - Current Topics. PMID- 30438253 TI - Glasgow Northern Medical Society. PMID- 30438252 TI - Vital Statistics, &c., for Five Weeks Ended 29th December, 1928. PMID- 30438254 TI - Current Topics. PMID- 30438255 TI - The School of Salerno. PMID- 30438256 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438257 TI - An Unusual Case of Tubo-Ovarian Inguinal Hernia. PMID- 30438258 TI - Vital Statistics, &c., for Four Weeks Ended 26th January, 1929. PMID- 30438260 TI - The School of Salerno. PMID- 30438259 TI - Current Topics. PMID- 30438261 TI - Splenomegaly in Britain: Investigations into Etiology, Pathology, and Relative Frequency; with a Tentative Classification. PMID- 30438263 TI - Current Topics. PMID- 30438262 TI - Vital Statistics, &c., for Four Weeks Ended 23rd February, 1929. PMID- 30438264 TI - Trans-Urethral Diathermy in the Diagnosis and Treatment of Tumours of the Bladder. PMID- 30438266 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438265 TI - Cancer of the Rectum: A Plea for Earlier Diagnosis. PMID- 30438267 TI - The General Practitioner of To-Day. PMID- 30438268 TI - An Unusual Case of Intestinal Obstruction. PMID- 30438269 TI - New Apparatus. PMID- 30438270 TI - The Recent Outbreak of Smallpox, Introduced from India by the S.S. "Tuscania". PMID- 30438271 TI - Horae Subsecivae and Dr. John Brown. PMID- 30438272 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438273 TI - Vital Statistics, &c., for Four Weeks Ended 25th May, 1929. PMID- 30438274 TI - Current Topics. PMID- 30438276 TI - The Northern Medical Society. PMID- 30438277 TI - Current Topics. PMID- 30438275 TI - Vital Statistics, &c., for Five Weeks Ended 30th March, 1929. PMID- 30438278 TI - Splenomegaly in Britain. PMID- 30438280 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438279 TI - Case of Diaphragmatic Hernia. PMID- 30438281 TI - Benign Papilloma of the Renal Pelvis. PMID- 30438282 TI - Vital Statistics, &c., for Four Weeks Ended 27th April, 1929. PMID- 30438283 TI - Splenomegaly in Britain. PMID- 30438285 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438284 TI - Cystic Pneumatosis of the Bowel. PMID- 30438286 TI - Current Topics. PMID- 30438287 TI - A Simple Method of Obtaining Permanently Stained Preparations to Show Reticulocytes in the Blood. PMID- 30438289 TI - A Demonstration of the X-Ray Diagnosis of the Gastro-Intestinal Tract. PMID- 30438288 TI - Note on a Case of Carcinoma of the Small Intestine. PMID- 30438290 TI - The Dick Test and Immunity to Scarlet Fever. PMID- 30438291 TI - The Influence of Variations of Vagal Tone on a Case of Partial Heart-Block. PMID- 30438292 TI - Leukaemia in Childhood, with Notes of Twenty-Two Cases. PMID- 30438293 TI - Current Topics. PMID- 30438295 TI - Current Topics. PMID- 30438294 TI - Vital Statistics, &c., for Five Weeks Ended 31st December, 1927. PMID- 30438296 TI - Case of Surgical Emphysema. PMID- 30438297 TI - Vital Statistics, &c., for Four Weeks Ended 25th February, 1928. PMID- 30438298 TI - The Regulation of the Acid-Base Balance of the Body. PMID- 30438299 TI - Diagnosis, Prognosis, and Treatment of Acute Toxic Iritis. PMID- 30438301 TI - Vital Statistics, &c., for Four Weeks Ended 26th May, 1928. PMID- 30438300 TI - The Evolution, Development, and Application of Modern Medico-Legal Methods. PMID- 30438303 TI - Current Topics. PMID- 30438302 TI - The Use of Fascial Sutures in the Operative Treatment of Hernia. PMID- 30438305 TI - Current Topics. PMID- 30438304 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438306 TI - Some Points in the Early Diagnosis of Diseases of the Central Nervous System in General Practice. PMID- 30438307 TI - A Statistical Analysis of a Series of Cases Showing Extrasystoles. PMID- 30438308 TI - Vital Statistics, &c., for Four Weeks Ended 28th April, 1928. PMID- 30438309 TI - Erratum. AB - [This corrects the article on p. 322 in vol. 109.]. PMID- 30438311 TI - A Case of Tic. PMID- 30438310 TI - The Debt of Modern Medicine to the Seventeenth and Eighteenth Centuries. PMID- 30438313 TI - Current Topics. PMID- 30438312 TI - Primary Repair of the Perineum: A Modified Technique and After-Treatment. PMID- 30438314 TI - Modern Views Regarding Diagnosis of Surgical Diseases of the Kidney. PMID- 30438315 TI - Mineral Metabolism in Coeliac Disease. PMID- 30438316 TI - Vital Statistics, &c., for Five Weeks Ended 31st March, 1928. PMID- 30438317 TI - Problems of Medical Administration in the Early Nineteenth Century and Later. PMID- 30438318 TI - Labuntur Anni. PMID- 30438319 TI - Medicina Curiosa: An Early Medical Journal. PMID- 30438320 TI - Some Notes on Medical Journalism. PMID- 30438321 TI - Medical Journalism. PMID- 30438322 TI - Recollections of Glasgow and Its University. PMID- 30438324 TI - The "Glasgow Medical Journal" and Its Editors. PMID- 30438323 TI - Note on the Medical School of Glasgow University, 1828-1928. PMID- 30438326 TI - The Position of Extra-Mural Teaching in Glasgow in 1828 and Its Progress during the Century. PMID- 30438325 TI - Progress of Therapeutics in the Past Hundred Years. PMID- 30438327 TI - The Evolution of Bacteriology in Relation to Medical and Surgical Practice and Preventive Medicine. PMID- 30438328 TI - Surgery in 1828. PMID- 30438329 TI - The Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438330 TI - The Glasgow Hospitals of a Century Ago. PMID- 30438332 TI - Current Topics. PMID- 30438331 TI - Vital Statistics, &c., for Four Weeks Ended 28th January, 1928. PMID- 30438334 TI - New Preparations, Appliances, &c. PMID- 30438333 TI - Vital Statistics, &c., for Five Weeks Ended 29th December, 1934. PMID- 30438335 TI - Surgical Shock. PMID- 30438337 TI - Rabelais: Physician and Humanist. PMID- 30438336 TI - The Effect of Continued Unemployment on the Health of School Children in a Depressed Area. PMID- 30438338 TI - Glasgow Northern Medical Society. PMID- 30438339 TI - Current Topics. PMID- 30438340 TI - The Basis of Standard Tables of Body Weight. PMID- 30438341 TI - Vital Statistics, &c., for Four Weeks Ended 26th January, 1935. PMID- 30438342 TI - Some Pages from the History of the Prevention of Malaria. PMID- 30438343 TI - Iodism. PMID- 30438344 TI - Conjunctivitis: A Clinical and Bacteriological Investigation. PMID- 30438345 TI - Some Pages from the History of the Prevention of Malaria. PMID- 30438346 TI - Current Topics. PMID- 30438347 TI - New Preparations, Appliances, &c. PMID- 30438349 TI - The Western Infirmary of Glasgow, Pathological Institute: Opening of the Margaret Macgregor Extension. PMID- 30438348 TI - Vital Statistics, &c., for Five Weeks Ended 30th March, 1935. PMID- 30438350 TI - New Preparations, Appliances, &c. PMID- 30438351 TI - Some Pages from the History of the Prevention of Malaria. PMID- 30438352 TI - Current Topics. PMID- 30438354 TI - Asthma and Angio-Neurotic OEdema. PMID- 30438353 TI - Prognosis in Intracranial Tumours. PMID- 30438355 TI - Intussusception of the Stump of the Appendix. PMID- 30438356 TI - Vital Statistics, &c., for Four Weeks Ended 23rd February, 1935. PMID- 30438357 TI - Vital Statistics, &c., for Four Weeks Ended 25th May, 1935. PMID- 30438358 TI - Current Topics. PMID- 30438359 TI - Some Observations on Physicotherapy in the Treatment of Fibrositis and Other Rheumatic Conditions. PMID- 30438360 TI - The Common Cold: A Survey of Recent Work. PMID- 30438362 TI - New Preparations, Appliances, &c. PMID- 30438361 TI - Fracture or Epiphyseal Diastasis of Innominate Bone Followed by Pyaemia and Death. PMID- 30438363 TI - The Incidence of Positive Wassermann Reactions in General Medicine. PMID- 30438365 TI - Glasgow Northern Medical Society. PMID- 30438364 TI - The Parathyroid Glands: A Review of the Anatomy, Physiology and Pathology of the Parathyroid Glands, with Observations on Three New Cases of Generalized Osteitis Fibrosa Cystica. PMID- 30438366 TI - New Preparations, Appliances, &c. PMID- 30438367 TI - Carbohydrates in the Treatment of Diabetes Mellitus. PMID- 30438368 TI - Current Topics. PMID- 30438369 TI - Vital Statistics, &c., for Four Weeks Ended 27th April, 1935. PMID- 30438371 TI - Vital Statistics, &c., for Four Weeks Ended 26th September, 1931. PMID- 30438370 TI - Certain Preliminary Observations on the Treatment of Anaemia by Tryptophan and Histidine. PMID- 30438372 TI - Current Topics. PMID- 30438373 TI - The State of the Capillaries in Certain Pathological Lesions and Their Condition in Cases of Sudden Death. PMID- 30438374 TI - Cancer of the Caecum with Protracted Course in a Young Subject. PMID- 30438375 TI - Current Topics. PMID- 30438376 TI - The Constancy of the Cultural Reactions of the Streptococci on Holman's Carbohydrate and Blood Agar Media: A Contribution to the Classification of Streptococci. PMID- 30438378 TI - Vital Statistics, &c., for Five Weeks Ended 29th August, 1931. PMID- 30438377 TI - New Preparations, Appliances, &c. PMID- 30438379 TI - What Surgery Offers in Cancer of the Stomach. PMID- 30438380 TI - Vital Statistics, &c., for Four Weeks Ended 28th November, 1931. PMID- 30438382 TI - New Preparations, Appliances, &c. PMID- 30438381 TI - The Treatment of Pernicious Anaemia by Injections of Liver Extract. PMID- 30438384 TI - Current Topics. PMID- 30438383 TI - The AEtiological Factor of Injury in Disease. PMID- 30438385 TI - Vital Statistics, &c., for Five Weeks Ended 30th January, 1932. PMID- 30438386 TI - Observations on the Retroverted Uterus. PMID- 30438387 TI - Observations on Retroflexion of the Uterus. PMID- 30438388 TI - The Present Methods of Treating Tumours of the Urinary Bladder. PMID- 30438390 TI - Current Topics. PMID- 30438389 TI - Recurring Subconjunctival Haemorrhage in Elderly People. PMID- 30438391 TI - Outbreak of Chickenpox in Residential School for the Deaf Due to a Case of Herpes Zoster. PMID- 30438392 TI - Report on Asthma Research at Stobhill Hospital, Glasgow. PMID- 30438393 TI - Current Topics. PMID- 30438394 TI - Vital Statistics, &c., for Four Weeks Ended 25th July, 1931. PMID- 30438395 TI - The Mass Experiment in the Treatment of Syphilis. PMID- 30438396 TI - Significance and Interpretation of Pain. PMID- 30438397 TI - Current Topics. PMID- 30438398 TI - Coronary Atheroma with Aneurysm of the Left Ventricle Simulating Gas Poisoning in a Coal Miner. PMID- 30438400 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438399 TI - Vital Statistics, &c., for Four Weeks Ended 26th December, 1931. PMID- 30438401 TI - New Preparations, Appliances, &c. PMID- 30438402 TI - An Investigation into the Value of the Bendien Chemical Test. PMID- 30438403 TI - Northern Medical Society. PMID- 30438404 TI - Vital Statistics, &c., for Five Weeks Ended 31st October, 1931. PMID- 30438405 TI - New Preparations, Appliances, &c. PMID- 30438406 TI - Northern Medical Society. PMID- 30438407 TI - Rickets: Osteotomy and Caesarean Section in Glasgow, 1877-1930. PMID- 30438409 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438408 TI - Some Aspects of Mental Hygiene. PMID- 30438411 TI - Current Topics. PMID- 30438410 TI - The Incidence of Anaemia in Infancy. PMID- 30438412 TI - Vital Statistics, &c., for Four Weeks Ended 27th June, 1931. PMID- 30438414 TI - A Case of Thallium Poisoning. PMID- 30438413 TI - The Place of Peri-Arterial Sympathectomy and of Ganglionectomy and Sympathetic Trunk Resection in the Treatment of Certain Vascular Diseases and Other Conditions. PMID- 30438416 TI - Royal Medico-Chirurgical Society of Glasgow. PMID- 30438415 TI - Current Topics. PMID- 30438418 TI - Current Topics. PMID- 30438417 TI - Vital Statistics, &c., for Four Weeks Ended 28th May, 1932. PMID- 30438419 TI - Some Ocular Manifestations of High Blood Pressure: A Plea for the Routine Use of the Ophthalmoscope in Clinical Medicine. PMID- 30438421 TI - Correction. AB - [This corrects the article on p. 43 in vol. 117.]. PMID- 30438420 TI - Primary Intrathoracic Growths: A Clinical and Pathological Study of Cases Occurring in the Victoria Infirmary, Glasgow. PMID- 30438422 TI - New Preparations, Appliances, &c. PMID- 30438423 TI - The Surgical Treatment of Pulmonary Tuberculosis. PMID- 30438424 TI - The Treatment of Pulmonary Tuberculosis by Collapse Therapy. PMID- 30438426 TI - Annotations. PMID- 30438425 TI - Bibliography of John Brownlee, M.D., D.Sc., F.R.F.P.S., 1867-1927. PMID- 30438428 TI - Current Topics. PMID- 30438427 TI - Vital Statistics, &c., for Four Weeks Ended 26th March, 1932. PMID- 30438429 TI - Observations on a Case of Retroperitoneal Sarcoma. PMID- 30438431 TI - Convulsions in Infancy : Part II. PMID- 30438430 TI - Vital Statistics, &c., for Four Weeks Ended 27th February, 1932. PMID- 30438432 TI - Convulsions in Infancy : Part III. PMID- 30438434 TI - Current Topics. PMID- 30438435 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438433 TI - Convulsions in Infancy : Part I. PMID- 30438436 TI - Disseminated Encephalomyelitis: Preliminary Communication. PMID- 30438437 TI - Plastic Replacement of Upper Lip in a Case of Epitheliomatous Ulcer Resulting from X-Ray Treatment of Sycosis Barbae. PMID- 30438439 TI - Current Topics. PMID- 30438438 TI - Sir Walter Scott and Medicine. PMID- 30438441 TI - Glasgow Northern Medical Society. PMID- 30438440 TI - Vital Statistics, &c., for Five Weeks Ended 30th April, 1932. PMID- 30438442 TI - Endocrine Relationship to Epilepsy. PMID- 30438443 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438444 TI - Clinical Pathological Meetings-1950, Western Infirmary. PMID- 30438445 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438446 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438447 TI - Royal College of Physicians and Surgeons of Edinburgh. PMID- 30438449 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438448 TI - Summary of Health Statistics for First Six Months of 1950. PMID- 30438450 TI - The Glasgow Southern Medical Society. PMID- 30438451 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438452 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438453 TI - University of Glasgow, Department of Ophthalmology: Autumn Term, 1950. PMID- 30438454 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438456 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438455 TI - Errata. AB - [This corrects the article on p. 255 in vol. 149.]. PMID- 30438457 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438458 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438459 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438460 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438461 TI - The Haematological Effects of Nitrogen Mustard Therapy with Special Reference to the Cytology of the Sternal Bone Marrow. PMID- 30438463 TI - The Glasgow Southern Medical Society. PMID- 30438462 TI - Megaloblastic Erythropoiesis in a Case of Myeloid Leukaemia during Treatment. PMID- 30438465 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438464 TI - A Comparison of the Effects of Diuretic and Antidiuretic Substances in Man. PMID- 30438466 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438467 TI - Submucous Lipomata of the Large Intestine. PMID- 30438468 TI - University of Glasgow. Department of Ophthalmology: Spring Term, 1950. PMID- 30438469 TI - The Importance of the Tongue as an Index of Disease. PMID- 30438470 TI - Extreme Leucocytosis Occurring in a Case of Empyema. PMID- 30438471 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438472 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438474 TI - The Glasgow Southern Medical Society. PMID- 30438473 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438476 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438475 TI - Plasma Lipoid Phosphorus in Toxaemias of Pregnancy. PMID- 30438477 TI - Summary of Health Statistics for 1949. PMID- 30438478 TI - The Treacher Collins Prize Essay. PMID- 30438479 TI - The Scottish Society of the History of Medicine. PMID- 30438480 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438481 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438483 TI - Sir Thomas Browne and His Books. PMID- 30438482 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438484 TI - Royal Society of Edinburgh: David Anderson-Berry Prize (1950). PMID- 30438485 TI - Scottish Fever Group. PMID- 30438486 TI - Royal College of Physicians of Edinburgh. PMID- 30438487 TI - Royal College of Surgeons of Edinburgh. PMID- 30438488 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438489 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438490 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438491 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438492 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438493 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438494 TI - Current Topics. PMID- 30438495 TI - Diuretics. PMID- 30438496 TI - A Note on the Serum Treatment of Ulcerative Colitis. PMID- 30438497 TI - Some Aspects of Bright's Disease. PMID- 30438498 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438499 TI - Spontaneous Subarachnoid Haemorrhage. PMID- 30438500 TI - Current Topics. PMID- 30438501 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438502 TI - Purulent Meningitis with Recovery: A Case Presenting Certain Resemblances to the Meningitic Form of Poliomyelitis. PMID- 30438503 TI - Case of Food-Poisoning with Unusual Features. PMID- 30438504 TI - A Case of Crossed Renal Dystopia. PMID- 30438505 TI - Current Topics. PMID- 30438506 TI - New Preparations, Appliances, &c. PMID- 30438507 TI - Glasgow Northern Medical Society. PMID- 30438508 TI - Current Topics. PMID- 30438509 TI - Chronic Hyperplastic Peritonitis with Chylous Ascites in a Case of Rheumatic Carditis, with Auricular Fibrillation of over Fifteen Years' Duration. PMID- 30438511 TI - The Effect of Massage on Metabolism: A Survey. PMID- 30438510 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438512 TI - New Preparations, Appliances, &c. PMID- 30438513 TI - Treatment of Empyema: A Review of Recent Methods. PMID- 30438514 TI - New Preparations, Appliances, &c. PMID- 30438515 TI - Surgical Diseases of the Biliary Tracts : An Analysis of 200 Cases. PMID- 30438516 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438517 TI - Current Topics. PMID- 30438518 TI - Current Topics and Educational Supplement. PMID- 30438519 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438520 TI - A Localized Outbreak of Enteritis Due to B. Dysenteriae (Sonne). PMID- 30438521 TI - A Year's Work in Intracranial Surgery. PMID- 30438523 TI - Current Topics. PMID- 30438522 TI - Vital Statistics, &c., for Five Weeks Ended 31st August, 1929. PMID- 30438524 TI - The Early Stages of Oral Cancer. PMID- 30438526 TI - Erratum. AB - [This corrects the article on p. 110 in vol. 112.]. PMID- 30438527 TI - Defective Intestinal Rotation. PMID- 30438525 TI - The Cerebro-Spinal Circulation: With Particular Reference to the Role of Increased Cerebro-Spinal Pressure, in the Pathology and Symptomatology of Tumours and Certain Other Conditions of the Brain and Spinal Cord: Also a Description of Certain Special Methods of Investigation. PMID- 30438528 TI - Vital Statistics, &c., for Four Weeks Ended 28th September, 1929. PMID- 30438529 TI - Recent Advances in the Treatment of Asphyxia Neonatorum and Allied Conditions. PMID- 30438530 TI - Current Topics. PMID- 30438532 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438531 TI - The Cerebro-Spinal Circulation: With Particular Reference to the Role of Increased Cerebro-Spinal Pressure, in the Pathology and Symptomatology of Tumours and Certain Other Conditions of the Brain and Spinal Cord: Also a Description of Certain Special Methods of Investigation. PMID- 30438533 TI - Problems of Old Age. PMID- 30438534 TI - Current Topics. PMID- 30438535 TI - Observations on Puerperal Sepsis from the Epidemiological Standpoint. PMID- 30438536 TI - Vital Statistics, &c., for Four Weeks Ended 26th October, 1929. PMID- 30438537 TI - An Unusual Degree of Recovery in Abdominal Aneurysm. PMID- 30438538 TI - Glasgow Northern Medical Society. PMID- 30438539 TI - New Preparations, Appliances, &c. PMID- 30438540 TI - Current Topics. PMID- 30438541 TI - The Radiological Factor in the Diagnosis of Gastric and Duodenal Disease. PMID- 30438542 TI - Chronic Nephritis with Hypertension and Retinitis of More Than Nineteen Years' Duration but without Azotaemia or Gross Cardiac Hypertrophy. PMID- 30438544 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438543 TI - The Tannic Acid Treatment of Burns. PMID- 30438545 TI - Vital Statistics, &c., for Five Weeks Ended 29th June, 1929. PMID- 30438546 TI - The Influence of Sepsis and Endocrine Disturbance on Carbohydrate Metabolism. PMID- 30438547 TI - The Origin of the Surgeon's Aspirator. PMID- 30438548 TI - Vital Statistics, &c., for Four Weeks Ended 27th July, 1929. PMID- 30438550 TI - Discussion on Anaesthesia in Relation to Operation Risk. PMID- 30438549 TI - A Note on the Treatment of Gonococcal Epididymitis. PMID- 30438551 TI - The General Practitioner and the Neuroses. PMID- 30438552 TI - Preparations and Appliances. PMID- 30438553 TI - Current Topics. PMID- 30438554 TI - Vital Statistics, &c., for Five Weeks Ended 30th November, 1929. PMID- 30438555 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438556 TI - Preparations and Appliances, &c. PMID- 30438557 TI - Current Topics. PMID- 30438558 TI - Hedonal: A Study in Experimental Physiology, with Suggestions for Its Safer Use in the Clinic. PMID- 30438559 TI - Transient Inversion of the "T" Wave in Electrocardiograms in Cases of Acute Rheumatism with Cardiac Complications. PMID- 30438561 TI - Royal College of Surgeons of Edinburgh. PMID- 30438560 TI - Glasgow Northern Medical Society. PMID- 30438562 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438563 TI - The Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438565 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438564 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438566 TI - The Glasgow Southern Medical Society. PMID- 30438567 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438568 TI - Errata. AB - [This corrects the article on p. 271 in vol. 148.]. PMID- 30438569 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438570 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438571 TI - University of Glasgow, Department of Ophthalmology: Autumn Term, 1949. PMID- 30438572 TI - Errata. AB - [This corrects the article on p. 283 in vol. 148.]. PMID- 30438573 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438574 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438575 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438577 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438576 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438579 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438578 TI - Summary of Health Statistics for 1948. PMID- 30438580 TI - Royal College of Surgeons of Edinburgh. PMID- 30438581 TI - The Glasgow Southern Medical Society. PMID- 30438582 TI - Royal College of Surgeons of Edinburgh. PMID- 30438583 TI - The Royal Faculty of Physicians and Surgeons of Glasgow: 1599 - 1949. PMID- 30438584 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438585 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438586 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438587 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438588 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438589 TI - University of Glasgow, Department of Ophthalmology: Whitsun Term, 1949. PMID- 30438591 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438590 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438592 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438593 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438594 TI - Royal College of Surgeons of Edinburgh. PMID- 30438595 TI - Royal Society of Edinburgh: Notice. PMID- 30438596 TI - The History of the Royal Faculty of Physicians and Surgeons. PMID- 30438597 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438598 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438600 TI - Royal Society of Arts: Award of Swiney Prize for Medical Jurisprudence. PMID- 30438599 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438602 TI - The Glasgow Southern Medical Society. PMID- 30438601 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438604 TI - Annotations. PMID- 30438603 TI - Royal College of Surgeons. PMID- 30438605 TI - New Preparations, Appliances, &c. PMID- 30438606 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438608 TI - Current Topics. PMID- 30438607 TI - Some Recollections on Asthma, with a Few Suggestions as to Its Treatment in Childhood. PMID- 30438609 TI - New Preparations, Appliances, &c. PMID- 30438610 TI - Glasgow Northern Medical Society. PMID- 30438611 TI - Annotations. PMID- 30438612 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438613 TI - Recent Views on the Female Sex Hormones. PMID- 30438614 TI - Current Topics. PMID- 30438615 TI - New Preparations, Appliances, &c. PMID- 30438616 TI - The Zondek-Ascheim Reaction in Diagnosis. PMID- 30438617 TI - Some Bone and Joint Conditions in Children. PMID- 30438618 TI - The Present Position of Compression Therapy in the Treatment of Diseases of the Lungs. PMID- 30438620 TI - Current Topics. PMID- 30438619 TI - Atheroma of the Pulmonary Artery. PMID- 30438621 TI - Vital Statistics, &c., for Five Weeks Ended 29th June, 1935. PMID- 30438622 TI - Alveolar and Diffuse Carcinoma of the Prostate Gland Simulating Carcino-Sarcoma. PMID- 30438623 TI - Vital Statistics, &c., for Four Weeks Ended 28th September, 1935. PMID- 30438624 TI - Diabetes Mellitus Following Mumps. PMID- 30438625 TI - Prognosis in Nephritis. PMID- 30438627 TI - Current Topics. PMID- 30438626 TI - Certain Observations on the Treatment of Cervical Metastases in Cancer of the Mouth. PMID- 30438629 TI - Current Topics. PMID- 30438628 TI - Two Cases of Thrombo-Phlebitis Migrans. PMID- 30438630 TI - New Preparations, Appliances, &c. PMID- 30438631 TI - Developmental Defects of the Lens and Their Embryology. PMID- 30438633 TI - Current Topics and Educational Supplement. PMID- 30438632 TI - Vital Statistics, &c., for Four Weeks Ended 27th July, 1935. PMID- 30438634 TI - Developmental Defects of the Lens and Their Embryology. PMID- 30438635 TI - New Preparations, Appliances, &c. PMID- 30438636 TI - The Chemical Constitution of Sex Hormones. PMID- 30438638 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438637 TI - Vital Statistics, &c., for Five Weeks Ended 31st August, 1935. PMID- 30438640 TI - The Glasgow Obstetrical and Gynaecological Society. PMID- 30438639 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438641 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438642 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438643 TI - Infections Diseases and Epidemiological Notes. PMID- 30438644 TI - University of Glasgow, Department of Ophthalmology: Martinmas Term, 1951. PMID- 30438645 TI - Royal College of Surgeons of Edinburgh. PMID- 30438646 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438647 TI - Royal College of Physicians of Edinburgh. PMID- 30438648 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438649 TI - University of Glasgow, Department of Ophthalmology: Spring Term, 1951. PMID- 30438650 TI - Summary of Health Statistics for First Six Months of 1951. PMID- 30438651 TI - Royal College of Surgeons of Edinburgh. PMID- 30438652 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438653 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438654 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438655 TI - Royal College of Physicians of Edinburgh. PMID- 30438656 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438657 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438658 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438659 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438660 TI - The Association of Physicians. PMID- 30438662 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438661 TI - Royal College of Physicians of Edinburgh. PMID- 30438663 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438664 TI - Errata. AB - [This corrects the article on p. 442 in vol. 149.]. PMID- 30438666 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438665 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438667 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438668 TI - Royal College of Surgeons of Edinburgh. PMID- 30438669 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438670 TI - University of Glasgow-1451-1951. PMID- 30438671 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438672 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438673 TI - Clinical Pathological Meetings-Western Infirmary. PMID- 30438674 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438675 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438676 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438678 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438677 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438679 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438680 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438681 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438682 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438683 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438684 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438685 TI - Summary of Health Statistics for First Six Months of 1954. PMID- 30438687 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438686 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438688 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438689 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438691 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438690 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438693 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438692 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438695 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438694 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438696 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438697 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438699 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438698 TI - Spontaneous Delivery of an Intra-Ocular Foreign Body: Report of a Case. PMID- 30438700 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438701 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438702 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438703 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438704 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438705 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438706 TI - Current Topics. PMID- 30438707 TI - Observations on Renal Function Tests in Childhood. PMID- 30438708 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438709 TI - The Clinical Incidence of Laryngeal Vertigo. PMID- 30438710 TI - The Early Stages of Tobacco Amblyopia. PMID- 30438711 TI - New Preparations, Appliances, &c. PMID- 30438712 TI - Erratum. AB - [This corrects the article on p. 124 in vol. 125.]. PMID- 30438713 TI - Annotations. PMID- 30438714 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438715 TI - Puerperal Jaundice. PMID- 30438717 TI - Current Topics. PMID- 30438716 TI - Nutritional Anaemia in Infancy and Childhood. PMID- 30438718 TI - Current Topics. PMID- 30438719 TI - Glasgow Northern Medical Society. PMID- 30438720 TI - Spirochaetal Jaundice. PMID- 30438722 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438721 TI - "Secondary" Pellagra. PMID- 30438723 TI - Glasgow Northern Medical Society. PMID- 30438724 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438725 TI - The Therapeutic Outlook in Organic Nervous Diseases. PMID- 30438726 TI - Rupture of the Uterus at the Twenty-Fifth Week of Pregnancy. PMID- 30438727 TI - Current Topics. PMID- 30438728 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438729 TI - Current Topics. PMID- 30438730 TI - The Later Results of Operations on the Stomach and Duodenum. PMID- 30438731 TI - Glasgow Northern Medical Society. PMID- 30438732 TI - Otosclerosis, Hereditary Congenital Deafness and Senile Deafness, with Special Reference to Their Pathological Differentiation. PMID- 30438734 TI - Annotations. PMID- 30438733 TI - New Preparations, Appliances, &c. PMID- 30438735 TI - Current Topics. PMID- 30438736 TI - The Tennent Memorial Building, Western Infirmary, Glasgow. PMID- 30438737 TI - Glasgow Northern Medical Society. PMID- 30438738 TI - Blood Viscosity in Congestive Heart Failure. PMID- 30438739 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438740 TI - Ophthalmology and General Medicine. PMID- 30438741 TI - Vital Statistics, &c., for Four Weeks Ended 26th April, 1930. PMID- 30438742 TI - Mineral Metabolism in Infancy: Part I. PMID- 30438744 TI - Current Topics. PMID- 30438743 TI - Doctors in Court. PMID- 30438745 TI - Chronic Infections of the Paranasal Sinuses and General Toxaemic Conditions. PMID- 30438746 TI - The Etiology of Conversion Hysteria. PMID- 30438747 TI - Vital Statistics, &c., for Four Weeks Ended 22nd February, 1930. PMID- 30438748 TI - A Note on the Mortality from Pernicious Anaemia in Scotland, with Special Reference to the Influence of Liver Treatment. PMID- 30438750 TI - Current Topics. PMID- 30438749 TI - Bright's Disease, Hyperpiesis, and Hyperpiesia. PMID- 30438752 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438751 TI - Palliative Treatment for Oral Administration in Cases of Inoperable Malignant Disease. PMID- 30438753 TI - Vital Statistics, &c., for Five Weeks Ended 31st May, 1930. PMID- 30438754 TI - Case of Healed Tuberculoma of the Brain: Operative Removal: with Pathological Report. PMID- 30438755 TI - A Note on Psychotherapy in Alcoholism. PMID- 30438756 TI - Accidental Inoculation with Bacillus Tuberculosis in a Child. PMID- 30438757 TI - Current Topics. PMID- 30438758 TI - Fatal Epidemic Enteritis Due to B. Dysenteriae Sonne: A Preliminary Report. PMID- 30438759 TI - The Surgical Treatment of Exophthalmic Goitre. PMID- 30438760 TI - Vital Statistics, &c., for Four Weeks Ended 28th December, 1929. PMID- 30438761 TI - Current Topics. PMID- 30438762 TI - Some Medical Aspects of Exophthalmic Goitre. PMID- 30438763 TI - The Changes in the Thyroid Gland Following the Administration of Iodine to Cases of Exophthalmic Goitre. PMID- 30438764 TI - Gastric, Duodenal, and Secondary Peptic Ulcers. PMID- 30438765 TI - Vital Statistics, &c., for Five Weeks Ended 29th March, 1930. PMID- 30438767 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438766 TI - Current Topics. PMID- 30438768 TI - Rapidly Fatal Pneumonia in Childhood: Two Cases with an Unusual Degree of Lymphatic Hyperplasia. PMID- 30438769 TI - Narcolepsy. PMID- 30438770 TI - Principles and Facts in the Development of Radium Therapy, Especially in Relation to Malignant Disease. PMID- 30438772 TI - The Diagnosis and Infectivity of Influenza. PMID- 30438771 TI - Current Topics. PMID- 30438774 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438773 TI - Case of Tabes Dorsalis with Unusual Symptomatology. PMID- 30438775 TI - A Clinical Account of an Outbreak in Glasgow of Bacillary Dysentery. PMID- 30438777 TI - Pneumonia in Relation to Influenza. PMID- 30438776 TI - The Etiology of Influenza. PMID- 30438778 TI - Vital Statistics, &c., for Four Weeks Ended 25th January, 1930. PMID- 30438779 TI - Corrigendum. AB - [This corrects the article on p. 29 in vol. 113.]. PMID- 30438780 TI - The History of Angina Pectoris. PMID- 30438782 TI - Current Topics. PMID- 30438781 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438783 TI - Current Topics. PMID- 30438784 TI - Glasgow Northern Medical Society. PMID- 30438785 TI - Erratum. AB - [This corrects the article on p. 342 in vol. 126.]. PMID- 30438786 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438787 TI - Therapeutics in Medical Practice. PMID- 30438788 TI - Thomas Reid, LL.D., M.D.: An Appreciation. PMID- 30438789 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438790 TI - The Modern Treatment of Squint. PMID- 30438791 TI - The Deafened Man and Hearing Aids. PMID- 30438792 TI - Experimental Carcinogenesis. PMID- 30438793 TI - Current Topics. PMID- 30438795 TI - New Preparations, Appliances, &c. PMID- 30438794 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438796 TI - A Plea for a Planned and a Fuller Medical Specialism. With an Addendum on the Necessity for the Re-Integration of the Medical Profession. PMID- 30438797 TI - Convulsions in Acute Nephritis in Childhood. PMID- 30438798 TI - Current Topics. PMID- 30438800 TI - The Pituitary: Its Relation to the Endocrine System. PMID- 30438799 TI - Current Topics. PMID- 30438801 TI - The Later Results of Treatment of Peptic Ulceration of the Duodenum. PMID- 30438803 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438802 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438804 TI - Glasgow Northern Medical Society. PMID- 30438805 TI - Post-Traumatic Painful Osteoporosis. (Sudeck's Atrophy). PMID- 30438806 TI - Obstructive Anuria. PMID- 30438807 TI - New Preparations, Appliances, &c. PMID- 30438808 TI - The Influenzal "Acute Ear". PMID- 30438810 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438809 TI - Current Topics. PMID- 30438811 TI - Notifiable Infectious Diseases. PMID- 30438812 TI - Notifiable Infectious Diseases. PMID- 30438813 TI - The Glasgow Obstetrical and Gynaecological Society. PMID- 30438814 TI - Teaching and Learning. PMID- 30438815 TI - The Glasgow Obstetrical and Gynaecological Society. PMID- 30438816 TI - Notifiable Infectious Diseases. PMID- 30438817 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438818 TI - The Royal Society of Edinburgh. PMID- 30438819 TI - Notifiable Infectious Diseases. PMID- 30438820 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438821 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438822 TI - Notifiable Infectious Diseases. PMID- 30438824 TI - Notifiable Infectious Diseases. PMID- 30438823 TI - The Glasgow Obstetrical and Gynaecological Society. PMID- 30438826 TI - Editorial. PMID- 30438825 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438827 TI - The Southern Medical Society. PMID- 30438828 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438829 TI - Notifiable Infectious Diseases. PMID- 30438830 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438831 TI - Notifiable Infectious Diseases. PMID- 30438832 TI - Notifiable Infectious Diseases. PMID- 30438833 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438834 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438835 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438836 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438838 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438837 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438839 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438840 TI - Current Topics. PMID- 30438841 TI - Hodgkin's Disease: An Unusual Case. PMID- 30438843 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438842 TI - Cardiac Infarction: A Study of 148 Cases. PMID- 30438844 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438845 TI - Maister Peter Lowe. PMID- 30438846 TI - Notes on Tropical Diseases Sometimes Seen in Home Practice. Part II. PMID- 30438847 TI - New Preparations, Appliances, &c. PMID- 30438848 TI - Current Topics. PMID- 30438849 TI - Some Observations upon General Anaesthesia. PMID- 30438850 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438851 TI - Preventive Medicine and Public Health. PMID- 30438853 TI - Current Topics. PMID- 30438852 TI - Enterogenous Cyst: Record of a Case. PMID- 30438855 TI - A Rare Disease of the Conjunctiva, with Spontaneous Cure. PMID- 30438854 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438856 TI - Current Topics. PMID- 30438858 TI - New Preparations, Appliances, &c. PMID- 30438857 TI - Antitoxin in the Treatment of Scarlatina, with Special Reference to the Prevention of Complications. PMID- 30438859 TI - Eczema: A Survey of the Position. PMID- 30438860 TI - On the Complaints of Patients with Senile Cataract. PMID- 30438861 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438862 TI - Current Topics. PMID- 30438863 TI - Antidromic Phenomena. PMID- 30438864 TI - Observations on Tattooing. PMID- 30438865 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30438866 TI - Multiple Myeloma. PMID- 30438868 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd December, 1905. PMID- 30438867 TI - Current Topics. PMID- 30438869 TI - Sleeping Sickness in Uganda. AB - An address on sleeping sickness in Uganda was delivered by Captain Greig, I.M.S., to the Southern Medical Society of Glasgow on 16th November, 1905. The address, which was illustrated by numerous lantern slides, was listened to with interest by the large number of members present; and at the conclusion of his remarks the lecturer was awarded a hearty vote of thanks. The following abstract has been made from Report No. VI of the Sleeping Sickness Commission of the Royal Society, of which Commission Captain Greig was a member. PMID- 30438871 TI - Glasgow Eastern Medical Society. PMID- 30438870 TI - Case of Acute Exudative Choroiditis, Complete Amaurosis of Two Weeks' Duration: Iodopin by Injection: Recovery. PMID- 30438872 TI - The Treatment of Purulent Otitis Media and Its Complications. PMID- 30438873 TI - Glasgow Northern Medical Society. PMID- 30438874 TI - Glasgow Pathological and Clinical Society. PMID- 30438875 TI - Case of Chronic Inversion of the Uterus, Resulting from Carcinoma. PMID- 30438876 TI - To the Glasgow Eastern Medical Society on the Occasion of Its Annual Symposium, 5th December, 1905. PMID- 30438877 TI - Gummatous Synovitis of Many Joints, Closely Simulating Rheumatoid Arthritis, in a Congenitally Syphilitic Child. PMID- 30438878 TI - Current Topics. PMID- 30438879 TI - New Preparations, &c. PMID- 30438881 TI - Progress in Otology. PMID- 30438880 TI - Glasgow Medico-Chirurgical Society. PMID- 30438883 TI - Current Topics. PMID- 30438882 TI - Address to the Southern Medical Society. PMID- 30438884 TI - Glasgow Eastern Medical Society. PMID- 30438885 TI - New Preparations, &c. PMID- 30438886 TI - Broncho-Pneumonia and Abscess of Lung. PMID- 30438887 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th March, 1906. PMID- 30438888 TI - Remarks on Syphilis of the Upper Respiratory Passages. PMID- 30438889 TI - Several Patients from a Further Series of Cases of Congenital Obstruction of the Pylorus Treated by Operation. PMID- 30438890 TI - Case of Typhoidal Cholecystitis, in Which the Usual Symptoms of Typhoid Were Absent, and in Which the Bacillus Typhosus Was Isolated during Life from the Cystic and Intestinal Contents. PMID- 30438892 TI - Current Topics. PMID- 30438891 TI - Case of Round-Cell Sarcoma of the Brain Situated in the Frontal Lobes, and Beginning with Mental Symptoms. PMID- 30438894 TI - Glasgow Medico-Chirurgical Society. PMID- 30438893 TI - Heredity and Disease. PMID- 30438895 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th February, 1906. PMID- 30438896 TI - Glasgow Eastern Medical Society. PMID- 30438897 TI - Glasgow Northern Medical Society. PMID- 30438898 TI - Medico-Legal. PMID- 30438899 TI - New Preparations, &c. PMID- 30438900 TI - Obstetrical and Gynaecological Society. PMID- 30438901 TI - Current Topics. PMID- 30438902 TI - "Double Lip" (Hypertrophy of Labial Glands). PMID- 30438903 TI - The Roentgen Rays in the Diagnosis of Urinary Calculus. PMID- 30438905 TI - Glasgow Northern Medical Society. PMID- 30438904 TI - Case of Exophthalmic Goitre in a Man Treated Successfully. PMID- 30438906 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 27th January, 1906. PMID- 30438907 TI - Glasgow Medico-Chirurgical Society. PMID- 30438909 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 23rd June, 1906. PMID- 30438908 TI - Glasgow Eastern Medical Society. PMID- 30438910 TI - Death by Lightning. PMID- 30438912 TI - Glasgow Eastern Medical Society. PMID- 30438911 TI - The Surgical Aspect of Anuria. PMID- 30438914 TI - Obstetrical and Gynaecological Society. PMID- 30438913 TI - Current Topics. PMID- 30438916 TI - Glasgow Northern Medical Society. PMID- 30438915 TI - Post-Graduate Demonstration in Ward I, Glasgow Royal Infirmary, 3rd May, 1906. PMID- 30438917 TI - New Preparations, &c. PMID- 30438918 TI - Glasgow Pathological and Clinical Society. PMID- 30438919 TI - Current Topics. PMID- 30438920 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 19th May, 1906. PMID- 30438922 TI - Sterility in the Female: Its Causes and Treatment. PMID- 30438921 TI - Multiple Telangiectases of the Skin and Mucous Membranes of the Nose and Mouth. PMID- 30438923 TI - Glasgow Medico-Chirurgical Society. PMID- 30438924 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th August, 1906. PMID- 30438925 TI - Current Topics. PMID- 30438927 TI - Glasgow Pathological and Clinical Society. PMID- 30438926 TI - Unusual Case of Ruptured Tendo Achillis. PMID- 30438928 TI - The Clinical and Pathological Aspects of a Fulminating Case of Epidemic Cerebro Spinal Meningitis of the "Convulsive Comatose Type" of Tourdes. PMID- 30438930 TI - Post-Graduate Demonstration in Ward 2, Glasgow Royal Infirmary, 17th May, 1906. PMID- 30438929 TI - Case of Marked Paroxysmal Dyspnoea, Occurring in a Patient with Double Aortic Disease, and Wherein, after Death, Were Disclosed Striking Appearances of Chronic Mediastinitis. PMID- 30438931 TI - Glasgow Medico-Chirurgical Society. PMID- 30438932 TI - Glasgow Eastern Medical Society. PMID- 30438934 TI - New Preparations, &c. PMID- 30438933 TI - Current Topics. PMID- 30438935 TI - The Diffuse Hyperplastic Laryngitis and Pharyngitis of Congenital Syphilis. PMID- 30438937 TI - Glasgow Medico-Chirurgical Society. PMID- 30438936 TI - Notes on Some Ophthalmic Cases. PMID- 30438939 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 20th October, 1906. PMID- 30438938 TI - Arterio-Venous Aneurysm of the Neck Caused by Gunshot Wounds: Reports of Two Cases, Illustrating the Tendency to Spontaneous Cure. PMID- 30438940 TI - A Plea for the Study of the Deaf Child and for the Teaching of Speech to the Semi Deaf and Semi-Mute. PMID- 30438941 TI - Glasgow Pathological and Clinical Society. PMID- 30438942 TI - Current Topics. PMID- 30438943 TI - On Certain Clinical Aspects of Arterial Disease. PMID- 30438944 TI - The Influence of the Acute Infections upon the Arteries. PMID- 30438945 TI - Case of Otitic Extra-Dural Abscess, Associated with Paralysis of Sixth Cranial Nerve and Double Optic Neuritis-With Remarks. PMID- 30438947 TI - Choroido-Retinitis of Obscure Etiology. PMID- 30438946 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st July, 1906. PMID- 30438948 TI - The Physiological and Therapeutic Actions of High-Frequency Currents, with Illustrative Cases. PMID- 30438949 TI - Glasgow Medico-Chirurgical Society. PMID- 30438950 TI - New Preparations, &c. PMID- 30438952 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd September, 1906. PMID- 30438951 TI - Nasal Headache. PMID- 30438953 TI - Glasgow Medico-Chirurgical Society. PMID- 30438954 TI - Current Topics. PMID- 30438955 TI - Case of Mixed-Celled Leukaemia. PMID- 30438956 TI - Case of Anastomosis between the Femoral Veins Subsequent to Thrombosis of the Left External Iliac Vein during Typhoid Fever. PMID- 30438957 TI - Two Cases of Syringomyelia : With Report on the Anatomy of the Spinal Cord in One Case. PMID- 30438959 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 24th November, 1906. PMID- 30438958 TI - New Preparations, &c. PMID- 30438960 TI - Case of Supplementary Lobe of the Liver Causing Symptoms of Pyloric Obstruction. PMID- 30438962 TI - Glasgow Pathological and Clinical Society. PMID- 30438961 TI - Notes of a Case of Enteric Fever in Which the Action of the Typhoid Virus Was Directed Mainly to the Kidney (Nephro-Typhoid). PMID- 30438963 TI - Current Topics. PMID- 30438964 TI - Glasgow Northern Medical Society. PMID- 30438965 TI - Typhoid Spine. PMID- 30438966 TI - Glasgow Medico-Chirurgical Society. PMID- 30438967 TI - An Account of Five Cases of Pyelitis in Enteric Fever : With a Description of the Post-Mortem Appearances in One Case. PMID- 30438968 TI - Glasgow Eastern Medical Society. PMID- 30438969 TI - Glasgow Medico-Chirurgical Society. PMID- 30438970 TI - Three Cases of (So-Called) Double Uterus, with a Table of One Hundred Collected Cases. PMID- 30438971 TI - Current Topics. PMID- 30438972 TI - Glasgow Pathological and Clinical Society. PMID- 30438973 TI - Several of the Most Recent Cystoscopes, with Special Reference to Inspection of the Ureteral Orifices. PMID- 30438974 TI - Glasgow Northern Medical Society. PMID- 30438975 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st April, 1906. PMID- 30438976 TI - The Mechanism, Diagnosis, and Treatment of Persistent Occipito-Posterior Presentations. PMID- 30438977 TI - Laparotomy in Tubercular Peritonitis. PMID- 30438978 TI - New Preparations, &c. PMID- 30438979 TI - University of Glasgow-Department of Ophthalmology: Martinmas Term, 1952. PMID- 30438981 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438980 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438982 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438983 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438984 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438985 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438986 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438987 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438988 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438989 TI - University of Glasgow: Department of Ophthalmology: Whitsun Term, 1952. PMID- 30438990 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30438991 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30438992 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438993 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438994 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30438995 TI - Royal College of Surgeons of Edinburgh. PMID- 30438996 TI - Royal College of Physicians of Edinburgh. PMID- 30438997 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30438999 TI - Infectious Diseases and Epidemiological Notes. PMID- 30438998 TI - Royal College of Surgeons of Edinburgh. PMID- 30439000 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439001 TI - A Case of Advanced Rheumatoid Arthritis Treated with Oral and Parenteral Cortisone. PMID- 30439003 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439002 TI - Summary of Health Statistics for 1951. PMID- 30439004 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439005 TI - Royal College of Physicians of Edinburgh. PMID- 30439006 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439007 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30439009 TI - Royal College of Surgeons of Edinburgh. PMID- 30439008 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439010 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439011 TI - Royal College of Surgeons of Edinburgh. PMID- 30439012 TI - The Suprerenal Cortex. PMID- 30439013 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30439014 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439015 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439016 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439017 TI - The Importance of Nasal Sinusitis in General Practice. PMID- 30439018 TI - A Simple Operation for the Treatment of Varicose Veins. PMID- 30439019 TI - Current Topics. PMID- 30439021 TI - Current Topics. PMID- 30439020 TI - Smooth Muscle Tumours of the Kidney: Report of a Case and Review of the Literature. PMID- 30439022 TI - Glasgow Northern Medical Society. PMID- 30439023 TI - A Case of Traumatic Aneurysm of the Palm. PMID- 30439024 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439025 TI - A Note on the Physique of Young Adult Males during Unemployment. PMID- 30439026 TI - The Ammonia Coefficient of the Urine in Treated Cases of Diabetes Mellitus.-The Effect of Diet. PMID- 30439027 TI - New Preparations, Appliances, &c. PMID- 30439028 TI - The Spastic Colon. PMID- 30439029 TI - Current Topics. PMID- 30439030 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439032 TI - Glasgow Northern Medical Society. PMID- 30439031 TI - Respiration - Cystorespiration - Viscerorespiration. PMID- 30439033 TI - Teak-Wood Dermatitis. PMID- 30439034 TI - Note on a Case of Fracture of the Patella. PMID- 30439035 TI - Smooth Muscle Tumours of the Prostate: Report of Three Cases with Mention of Similar Growths of the Bladder and Epididymis. PMID- 30439036 TI - Trigeminal Neuralgia: A Review. PMID- 30439037 TI - New Preparations, Appliances, &c. PMID- 30439038 TI - The Urea Clearance Test of Van Slyke. PMID- 30439040 TI - Current Topics. PMID- 30439039 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439041 TI - Review of One Hundred Consecutive Cases of Disease of the Antrum of Highmore Operated on by the Caldwell Luc Radical Operation. PMID- 30439042 TI - The Diagnosis and Treatment of Bone Sarcoma. PMID- 30439043 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439044 TI - Current Topics. PMID- 30439046 TI - Current Topics and Educational Supplement. PMID- 30439045 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439047 TI - The Diagnosis and Treatment of Bone Sarcoma. PMID- 30439048 TI - Dr. William B. Coley-Postscriptum. PMID- 30439049 TI - The Doctor's Back Garden. PMID- 30439050 TI - The Dr. James Watson Lectures on Recent Advances in Haematology : Lecture I. PMID- 30439051 TI - Prophylaxis in Obstetrics. PMID- 30439053 TI - Current Topics. PMID- 30439052 TI - The Education of the Very Young Deaf Child. PMID- 30439055 TI - Glasgow Southern Medical Society. PMID- 30439054 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 19th November, 1910. PMID- 30439056 TI - Medico-Chirurgical Society of Glasgow. PMID- 30439057 TI - Case of Congenital Occlusion of the Duodenum (Accompanying a Deficiency of the Hindgut), with a Note on the Etiology. PMID- 30439058 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 23rd July, 1910. PMID- 30439059 TI - New Preparations, &c. PMID- 30439060 TI - The Embryological Significance of Certain Lesions of the Prepuce and Neighbourhood. PMID- 30439061 TI - Latent and Chronic Infections with the Typhoid Bacillus. PMID- 30439062 TI - Current Topics. PMID- 30439063 TI - Medico-Chirurgical Society of Glasgow. PMID- 30439065 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 20th August, 1910. PMID- 30439064 TI - Notes of Some Cystoscopic Cases. PMID- 30439066 TI - Current Topics. PMID- 30439067 TI - Glasgow Southern Medical Society. PMID- 30439068 TI - New Preparations, &c. PMID- 30439069 TI - The Action of Thiosinamine. PMID- 30439070 TI - The Treatment of Operable and Inoperable Carcinoma of the Mamma. PMID- 30439072 TI - Current Topics. PMID- 30439071 TI - Notes on Some Old Glasgow Institutions with Medical Associations. PMID- 30439073 TI - New Preparations, &c. PMID- 30439074 TI - An Experience in Treatment of the Insane without the Use of Sedatives. PMID- 30439075 TI - Three Modern Poisons. PMID- 30439076 TI - Syphilis and "606." PMID- 30439077 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ended 22nd October, 1910. PMID- 30439078 TI - Joint Communication on Syphilis: Recent Methods of Diagnosis and Treatment-The Wassermann Serum-Reaction and Ehrlich's "No. 606." PMID- 30439079 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 17th September, 1910. PMID- 30439080 TI - A Case of Strangulated Femoral Hernia (Richter's Variety)-Enterectomy-Lateral Anastomosis-Recovery. PMID- 30439082 TI - New Preparations, &c. PMID- 30439081 TI - Advice to Patients in Bellefield Sanatorium, Lanark. PMID- 30439083 TI - Double Central Blindness Following upon Injury to the Head by a Fall. PMID- 30439084 TI - Two Cases of Acute Leukaemia. PMID- 30439085 TI - Notes on Some Old Glasgow Institutions with Medical Associations. PMID- 30439087 TI - Current Topics. PMID- 30439086 TI - Some Problems in Infant Feeding. PMID- 30439088 TI - Arterial Spasm in the Brain, Associated with Transient and Permanent Paralysis : With Report on the Pathological Conditions Found in a Fatal Case. PMID- 30439089 TI - Current Topics. PMID- 30439090 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ended 18th June, 1910. PMID- 30439091 TI - Medico-Chirurgical Society of Glasgow. PMID- 30439092 TI - The Deaf Child from the Viewpoint of the Physician and of the Teacher. PMID- 30439093 TI - Study and Teaching of Industrial Diseases. PMID- 30439094 TI - Glasgow Eastern Medical Society. PMID- 30439095 TI - Note on a Case of Congenital Enchondroma of the Right Hand. PMID- 30439096 TI - Cases of Disease of the Caecum and Sigmoid Which Simulated Affections of the Uterus and Adnexa. PMID- 30439098 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439097 TI - Myasthenia Gravis: Its Treatment by a Combination of Prostigmin and Glycine Ephedrine Therapy. PMID- 30439100 TI - Current Topics. PMID- 30439099 TI - Diphtheria Immunization in the Nursing Staff of Ruchill Fever Hospital. PMID- 30439101 TI - Note on a Case of Fracture-Dislocation of the Elbow Joint. PMID- 30439102 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439103 TI - Current Topics. PMID- 30439105 TI - Educational Supplement. PMID- 30439104 TI - Immune Globulin (Human) Lederle in the Prevention of Measles. PMID- 30439106 TI - New Preparations, Appliances, &c. PMID- 30439107 TI - Ectopic Kidney. PMID- 30439108 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439109 TI - Current Topics. PMID- 30439110 TI - Wassermann Reaction in Maternity Work. PMID- 30439111 TI - Current Topics. PMID- 30439112 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439113 TI - Glasgow Southern Medical Society. PMID- 30439115 TI - New Preparations, Appliances, &c. PMID- 30439114 TI - The Chemistry of Bacterial Action in Relation to Enzyme Activity and Human Pathogenicity. PMID- 30439117 TI - Annotations. PMID- 30439116 TI - The Mechanism of Headache. PMID- 30439118 TI - Prolegomena to the Study of Therapeutics. PMID- 30439120 TI - Current Topics. PMID- 30439119 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439121 TI - Glasgow Northern Medical Society. PMID- 30439122 TI - Optic Neuritis (Retrobulbar and Papillary). PMID- 30439124 TI - Glasgow Southern Medical Society. PMID- 30439123 TI - Glasgow: Meteorological and Vital Statistics. PMID- 30439125 TI - Current Topics. PMID- 30439126 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439128 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439127 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439129 TI - Summary of Health Statistics for 1952. PMID- 30439130 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439132 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439131 TI - Royal College of Physicians of Edinburgh. PMID- 30439133 TI - Royal College of Surgeons of Edinburgh. PMID- 30439134 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30439135 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30439136 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439137 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439138 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30439140 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439139 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439141 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30439142 TI - Storage and Preservation of Blood. PMID- 30439143 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439144 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439145 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30439146 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30439147 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439148 TI - Royal Faculty of Physicians and Surgeons of Glasgow. PMID- 30439149 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439150 TI - Infectious Diseases and Epidemiological Notes. PMID- 30439151 TI - Glasgow Obstetrical and Gynaecological Society. PMID- 30439152 TI - Glasgow and West of Scotland Society of Anaesthetists. PMID- 30439153 TI - Glasgow Medico-Chirurgical Society. PMID- 30439154 TI - Consumptive Sanatoria: Are They Worth While? PMID- 30439155 TI - Case of Injury to the Motor Area of the Brain. PMID- 30439157 TI - Obstetrical and Gynaecological Society. PMID- 30439156 TI - Operative Procedures in Relation to Disease of the Frontal and Sphenoidal Sinuses. PMID- 30439158 TI - Case of Multiple Exostoses in a Rachitic Subject. PMID- 30439159 TI - Current Topics. PMID- 30439160 TI - Preliminary Note on Quinine Sulphate as a Factor in the Causation of Black-Water Fever. PMID- 30439161 TI - Glasgow.-Meteorological and Vital Statistics for the Five Weeks Ending 22nd February, 1908. PMID- 30439162 TI - New Preparations, &c. PMID- 30439163 TI - Case of Cirrhosis of the Liver in a Boy 9 Years Old. PMID- 30439164 TI - Degeneration of the Spinal Cord Associated with Severe Anaemia in a Case of Chronic Gastric Ulcer : With an Account of the Anatomical Condition. PMID- 30439165 TI - Albuminuric Retinitis with Vascular Changes: Aneurysms on Retinal Arteries. PMID- 30439166 TI - Glasgow Northern Medical Society. PMID- 30439168 TI - Glasgow Southern Medical Society. PMID- 30439167 TI - Three Cases of Severe Injury at the Ankle-Joint. PMID- 30439169 TI - Glasgow Medico-Chirurgical Society. PMID- 30439170 TI - Mediastinal Cancer, Occurring Ten Years after Removal of the Breast, with Secondary Nodulation Well Distributed over the Head and Trunk. PMID- 30439171 TI - Current Topics. PMID- 30439172 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th January, 1908. PMID- 30439173 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 18th April, 1908. PMID- 30439175 TI - Glasgow Southern Medical Society. PMID- 30439176 TI - Glasgow Medico-Chirurgical Society. PMID- 30439174 TI - The Record of a Year's Work in the Royal Samaritan Hospital for Women, Glasgow. PMID- 30439177 TI - Aneurysm of the Hepatic Artery: Clinical and Pathological Notes of a Case, with a Review of the Previously Recorded Cases. PMID- 30439179 TI - Current Topics. PMID- 30439178 TI - On the Causation and Treatment of Diabetes. PMID- 30439180 TI - Current Topics. PMID- 30439181 TI - Diagnosis and Treatment of Diseases of the Tear Passages. PMID- 30439182 TI - Calmette's "Ophthalmo-Reaction" for Tuberculosis: A Suggestion of Caution in Its Use. PMID- 30439183 TI - The Diagnosis and Treatment of Appendicitis. PMID- 30439184 TI - On the Symptomatology of Acute Abdominal Diseases. PMID- 30439185 TI - On the Development, Growth, and Reproduction of the Short-Lived Hairs. PMID- 30439187 TI - Glasgow Eastern Medical Society. PMID- 30439186 TI - Glasgow Medico-Chirurgical Society. PMID- 30439188 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st December, 1907. PMID- 30439189 TI - OEsophagoscopy. PMID- 30439190 TI - Glasgow Medico-Chirurgical Society. PMID- 30439191 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 16th May, 1908. PMID- 30439192 TI - Report of a Case of Cerebral Abscess: Rupture into the Lateral Ventricle: Post Mortem. PMID- 30439193 TI - Errata. AB - [This corrects the article on p. 277 in vol. 69.]. PMID- 30439194 TI - A Means of Observing and Recording the Efficiency of Urinary Discharge per Urethram, with Diagrams of Illustrative Cases. PMID- 30439195 TI - New Preparations, &c. PMID- 30439196 TI - Current Topics. PMID- 30439197 TI - The Serum Disease in Man after Single and Repeated Doses. PMID- 30439198 TI - Current Topics. PMID- 30439199 TI - Glasgow.-Meteorological and Vital Statistics for the Four Weeks Ending 21st March, 1908. PMID- 30439201 TI - Glasgow Eastern Medical Society. PMID- 30439200 TI - The Schola Salernitana: Its History and the Date of Its Introduction into the British Isles: Being the Finlayson Memorial Lecture. PMID- 30439202 TI - Glasgow Northern Medical Society. PMID- 30439203 TI - Glasgow Medico-Chirurgical Society. PMID- 30439204 TI - Note on a Case of Purulent Otitis Media with Involvement of the Sigmoid Sinus Operation-Ligation of the Internal Jugular Vein-Septic Abscess of the Lung Recovery. PMID- 30439205 TI - Lachrymation: Its Causes and Treatment. PMID- 30439206 TI - Glasgow Southern Medical Society. PMID- 30439207 TI - Case of Primary Sarcoma of the Spleen. PMID- 30439209 TI - Current Topics. PMID- 30439208 TI - Mineral Metabolism in Infancy: Part II. PMID- 30439211 TI - An Investigation into Pyuria in Infancy and Childhood. PMID- 30439210 TI - Vital Statistics, &c., for Four Weeks Ended 28th June, 1930. PMID- 30439212 TI - New Preparations, &c. PMID- 30439214 TI - The Present Position of Psychotherapy. PMID- 30439213 TI - Complications Arising from Nasal Sinusitis. PMID- 30439215 TI - A Short Study of Nephritis in Children. PMID- 30439216 TI - Vital Statistics, &c., for Four Weeks Ended 26th July, 1930. PMID- 30439217 TI - Infective Diarrhoea of Children, Glasgow, 1929. PMID- 30439218 TI - Current Topics. PMID- 30439219 TI - Current Topics. PMID- 30439220 TI - The Treatment of Circulatory Failure. PMID- 30439221 TI - Observations on Cancer of the Breast in the Light of Experimental Cancer Research. PMID- 30439222 TI - New Preparations, Appliances, &c. PMID- 30439223 TI - Vital Statistics, &c., for Four Weeks Ended 28th March, 1931. PMID- 30439224 TI - Rupture of the Chordae Tendineae Following Scarlet Fever. PMID- 30439225 TI - Mineral Metabolism in Infancy: Part III. PMID- 30439226 TI - Vital Statistics, &c., for Five Weeks Ended 29th November, 1930. PMID- 30439227 TI - The Occurrence of "White Bile" in Gall-Stone Obstruction: Note of a Case: With Histological Note. PMID- 30439228 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439229 TI - Current Topics. PMID- 30439231 TI - Current Topics. PMID- 30439230 TI - The Epidemiology of Poliomyelitis. PMID- 30439232 TI - The Pathology of Poliomyelitis. PMID- 30439233 TI - Vital Statistics, &c., for Four Weeks Ended 28th February, 1931. PMID- 30439234 TI - The Early Symptoms, Diagnosis and Treatment of Acute Anterior Poliomyelitis. PMID- 30439235 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439236 TI - Vital Statistics, &c., for Four Weeks Ended 27th December, 1930. PMID- 30439237 TI - Ureteral Prolapse and Ureterocele in Occlusion of the Lower End of the Ureter. PMID- 30439238 TI - Excretion Urography: An Experimental Investigation of the Properties of "Uroselectan". PMID- 30439240 TI - Current Topics. PMID- 30439239 TI - Intravenous Pyelography. PMID- 30439241 TI - Vital Statistics, &c., for Five Weeks Ended 31st January, 1931. PMID- 30439242 TI - The Treatment of Lobar Pneumonia by Felton Serum: The Serological Typing of Pneumonia. PMID- 30439243 TI - Current Topics. PMID- 30439244 TI - The Administration of Felton's Serum. PMID- 30439245 TI - The Treatment of Lobar Pneumonia with Felton's Serum. PMID- 30439246 TI - Glasgow Northern Medical Society. PMID- 30439247 TI - Certain Biochemical Aspects of Lobar Pneumonia. PMID- 30439248 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439249 TI - Current Topics. PMID- 30439250 TI - Vital Statistics, &c., for Five Weeks Ended 30th May, 1931. PMID- 30439251 TI - The Treatment of Certain Sequelae of Head Injuries by the Intraspinal Injection of Air. PMID- 30439253 TI - A Note on Two Recent Cases of Typhus Fever in Glasgow. PMID- 30439252 TI - The Place of Peri-Arterial Sympathectomy and of Ganglionectomy and Sympathetic Trunk Resection in the Treatment of Certain Vascular Diseases and Other Conditions. PMID- 30439254 TI - Current Topics. PMID- 30439255 TI - Fahraeus's Test for the Suspension Stability of the Erythrocytes in Tuberculosis Practice. PMID- 30439256 TI - The Teaching of the Clinical Subjects in the Final Year, with Special Reference to Obstetrics. PMID- 30439257 TI - Vital Statistics, &c., for Five Weeks Ended 30th August, 1930. PMID- 30439258 TI - Septic Coronary Thrombosis with Myocardial Infarction, Embolic Infarction of a Complete Kidney, and Death from Uraemia. PMID- 30439259 TI - Current Topics. PMID- 30439261 TI - Vital Statistics, &c., for Four Weeks Ended 27th September, 1930. PMID- 30439260 TI - Asthma. PMID- 30439262 TI - Current Topics. PMID- 30439263 TI - Intravenous Pyelography. PMID- 30439264 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439265 TI - Correction. AB - [This corrects the article on p. 199 in vol. 114.]. PMID- 30439266 TI - The Reticulo-Endothelial System in the Light of Vital Staining: The Application of the Methods to Problems in Pathology. PMID- 30439268 TI - Some Sixteenth Century Scientists. PMID- 30439267 TI - Vital Statistics, &c., for Four Weeks Ended 25th October, 1930. PMID- 30439270 TI - British Congress of Obstetrics and Gynaecology. PMID- 30439269 TI - Current Topics. PMID- 30439271 TI - Vital Statistics, &c., for Four Weeks Ended 25th April, 1931. PMID- 30439272 TI - Glasgow Northern Medical Society. PMID- 30439273 TI - Cholelithiasis: Some Pathological Observations. PMID- 30439275 TI - New Preparations, Appliances, &c. PMID- 30439274 TI - Marked Spondylitis without Incapacity. PMID- 30439276 TI - The Royal Medico-Chirurgical Society of Glasgow. PMID- 30439277 TI - Correspondence. PMID- 30439278 TI - Radial-Artery Grafts for Coronary-Artery Bypass Surgery. PMID- 30439279 TI - Radial-Artery Grafts for Coronary-Artery Bypass Surgery. PMID- 30439280 TI - Radial-Artery Grafts for Coronary-Artery Bypass Surgery. PMID- 30439281 TI - Dengue Serostatus and Dengue Vaccine Safety and Efficacy. PMID- 30439283 TI - Closed-Loop Insulin for Glycemic Control in Noncritical Care. PMID- 30439284 TI - Closed-Loop Insulin for Glycemic Control in Noncritical Care. PMID- 30439285 TI - Procalcitonin-Guided Antibiotic Use. PMID- 30439287 TI - Friction and adhesion of different structural defects of graphene. AB - Graphene structural defects, namely edges, step-edges and wrinkles are susceptible to severe mechanical deformation and stresses under frictional operations. Applied forces cause deformation by folding, buckling, bending and tearing the defective sites of graphene, which lead to a remarkable decline in normal load and friction bearing capacity. In this work, we experimentally quantified the maximal normal and friction forces corresponding to the damage thresholds of the different investigated defects as well as their pull-out (adhesion) forces. Horizontal wrinkles (with respect to the basal plane, i.e. folded) sustained the highest normal load, up to 317 nN, during sliding, whereas for vertical (i.e. standing collapsed) wrinkles, step-edges and edges, the load bearing capacities are up to 113 nN, 74 nN and 63+/-5 nN, respectively. The related deformation mechanisms were also experimentally investigated by varying the normal load up to the initiation of the damage from the investigated defects and extended with the numerical results from Molecular Dynamics and Finite Element Method simulations. PMID- 30439286 TI - Procalcitonin-Guided Antibiotic Use. PMID- 30439289 TI - Nanoparticle albumin bound-paclitaxel for treatment of advanced non-small cell lung cancer: an evaluation of the clinical evidence. AB - INTRODUCTION: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), a microtubule inhibitor, has demonstrated clinical efficacy in the treatment of advanced non-small cell lung cancer (NSCLC) either as monotherapy or in combination. Nab-paclitaxel was developed to reduce the toxicities associated with solvent-bound paclitaxel (sb-paclitaxel). Areas covered: This review first focuses on the clinical trials evaluating the efficacy and tolerability of nab paclitaxel in NSCLC at different settings. The approval of nab-paclitaxel in combination with carboplatin at the front-line setting for advanced NSCLC was based on the key phase III study, which showed that nab-paclitaxel/carboplatin was associated with superior overall response rate and favorable toxicity profile compared to sb-paclitaxel/carboplatin. The review also addresses the nab paclitaxel pharmacology, other combinations (e.g. immunotherapy with PD-1/PD-L1 inhibitors), potential biomarkers (e.g. caveolin-1), and special subgroups (e.g. the elderly, squamous histology). Expert opinion: Existing data has established the role of nab-paclitaxel in the management of advanced NSCLC. Emerging evidence, such as preliminary results from Keynote-407 and IMpower 131 studies, indicates that novel combinations of nab-paclitaxel/carboplatin and PD-1/PD-L1 inhibitors could further improve clinical benefits with manageable toxicity. Nevertheless, in order to better position nab-paclitaxel and to improve patient selection, future studies are warranted to further understand its mechanism of action, predictive biomarkers, and potential synergism with other agents. PMID- 30439290 TI - Current therapeutical strategies for allergic rhinitis. AB - INTRODUCTION: Allergic rhinitis is a common condition with increasing prevalence and is associated with several comorbid disorders such as bronchial asthma and atopic dermatitis. If allergen avoidance is not possible, allergen-specific immunotherapy is the only causal treatment option. Areas covered: This review focuses on current treatments and the future outlook for allergic rhinitis. Pharmacotherapy includes mast cell stabilizers, antihistamines, glucocorticosteroids (GCSs), leukotriene receptor antagonists, and nasal decongestants. Nasal GCSs are currently regarded as the most effective treatment and are considered first-line therapy together with non-sedating antihistamines. The new formulation MP29-02 combines the nasal GCS fluticasone propionate with azelastine in one single spray and has achieved greater improvements than those under monotherapy with modern GCSs or antihistamines. Furthermore, this review discusses allergen immunotherapy alone and in combination with modern monoclonal antibodies. Expert opinion: Despite the variety of medications for allergic rhinitis, ranging from general symptomatic agents like GCSs or decongestants, to more specific ones like histamine receptor or leukotriene blockers, to causal therapy like immunotherapy, many patients still experience treatment failures or unsatisfactory results. The ultimate goal may be to endotype every downstream pathway separately in order to offer patients individualized, targeted therapy with specific antibodies against the respective pathway. PMID- 30439288 TI - L-DOPA-Induced Motor Impairment and Overexpression of Corticostriatal Synaptic Components Are Improved by the mGluR5 Antagonist MPEP in 6-OHDA-Lesioned Rats. AB - Levodopa (L-DOPA) is still the most effective drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often triggers L-DOPA induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its inhibition is thought to modulate postsynaptic excitatory synaptic transmission and glutamate hyperactivity in PD and LID. In this report, we examined the effects of mGluR5-specific antagonist 2 methyl-6-(phenylethynyl)pyridine (MPEP) on LID and synaptic components in the PD model rat. We found the selective mGluR5 antagonist MPEP attenuated abnormal involuntary movements, prolonged the duration of rotational response, reversed the decrease of left forepaw adjusting steps, and reduced overexpression of striatal mGluR5 in the LID rats. Moreover, our results showed much thicker postsynaptic densities, narrower synapse cleft, as well as the increased ratio of perforated synapses induced by L-DOPA treatment, while coadministration of L-DOPA and MPEP reversed these postsynaptic effects. Finally, MPEP reduced overexpression of the two postsynaptic proteins (PSD-95 and SAP102) induced by L DOPA treatment. Hence, these results provide evidence that aberrant neural plasticity at corticostriatal synapses in the striatum is closely correlated with the occurrence of LID, and targeted inhibition of mGluR5 by MPEP alleviates LID in the PD rat model. PMID- 30439291 TI - PRODUCTION OF A PIECE OF CUSTOM-MADE ABUTMENT SCREWDRIVER: TECHNIQUE AND CASE REPORT. AB - Crown fractures, framework fractures, and abutment screw loosening or screw fracture are examples of mechanical implant failures. Abutment screw loosening is a serious problem that can result in abutment screw fractures. This clinical report describes the production method for a custom-made abutment screwdriver piece for a patient with abutment screw loosening. PMID- 30439292 TI - Implications of the GC-HARMS Fishermen's Citizen Science Network: Issues Raised, Lessons Learned, and Next Steps for the Network and Citizen Science. AB - This paper is intended to complement our extended documentation and analysis of the activities of the Gulf Coast Health Alliance: Health Risks related to the Macondo Spill project Community Outreach and Dissemination Core entitled, "Building and maintaining a citizen science network with fishermen and fishing communities after the Deepwater Horizon oil disaster using a Community-Based Participatory Research (CBPR) approach." We discuss nuances of CBPR practice, including trust-building, clarification of stakeholder expectations, balancing timelines and agendas, cultural fluency, and the importance of regional history political-economic context, regulatory practices, and cultural life-ways-in creating social dynamics that overarch and underpin the entire process. We examine the unique role of knowledge-making hybrid structures like the project's Fishermen's citizen science network and compare/contrast this structure with other models of participatory science or deliberation. Finally, we reiterate the importance of environmental health literacy efforts, summarize project outcomes, and offer thoughts on the future roles of collaborative efforts among communities and institutional science in environmental public health. PMID- 30439293 TI - Three More Voices Papers for This Special Issue of New Solutions-Environmental Justice in the U.S. Gulf Coast Region. AB - The U.S. states along the northern shores of the Gulf of Mexico have often been described as America's Energy Colony. This region is festooned with polluting industries, storage and waste disposal sites for toxic products, and a history of generally lax approaches to environmental public health and enforcement of regulations. This issue of New Solutions includes three interviews of groups and individuals who work for Environmental Justice in the Gulf Coast region. The interviewees provide key insights into the diverse cultural texture and social fabric of the Gulf. Their range of gulf locales and population groups embody different styles of engagement and different relationships to organizing, disseminating health and environmental risk information, and advocating for social and environmental justice. Similarities among their communities in terms of health and economic disparities, climate risks, and vulnerabilities lend credence to the idea of the Gulf as a regional Environmental Justice community. PMID- 30439294 TI - Better science for safer medicines: the human imperative. PMID- 30439295 TI - Understanding the Relation between Establishment Food Safety Management and Risk Factor Violations Cited during Routine Inspections. AB - Certified Food Manager (CFM) training can help ensure proper food safety practices for decreasing risk factor violations associated with foodborne illness. However, the effectiveness of food safety management also depends on the authority of the person in charge (PIC) and the added value of third-party inspectors auditing food safety policies and practices. To examine the effect of food safety management characteristics on risk factor violations cited on routine inspections, we evaluated results of 546 routine inspections in the cities of Bloomington and Richfield, MN, between 2016 and 2017. Food establishment management was characterized by the presence of a CFM of record for the establishment, whether the PIC was certified, and whether the establishment used a third-party inspector to audit food safety policies and practices. For each of these food safety management characteristics, the establishment had fewer risk factor observations that were out of compliance during routine inspections. The relationship between the establishment's food safety management characteristics and either the percentage of observations out of compliance or the inspections with observations out of compliance differed by risk factor category. For preventing contamination by hands, the lowest rates were found for inspections in which the CFM of record was the PIC. However, for potentially hazardous food time and temperature violations, establishments that used third-party inspectors had lower percentages of both observations and inspections out of compliance across all categories of management characteristics. The results of our study support the recommendations of the U.S. Food and Drug Administration regarding CFMs. However, our findings also suggest greater complexity in the characteristics of food safety management, which include the role of third-party inspectors and whether a CFM is acting in the role of the CFM of record. PMID- 30439296 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section III: Evaluation of Atopic Dermatitis Patients for Comorbidities. AB - Atopic dermatitis (AD) is often associated with other atopic diseases, including asthma, allergic rhinitis, atopy-associated eye disorders, and eosinophilic esophagitis. Depression and anxiety are also comorbidities to AD that significantly affect quality of life and should be screened for in patients with AD. Links to other comorbidities such as cardiovascular disease and malignancy are considered inconclusive, but patient counselling and screening may be appropriate in some patients. This article highlights practical recommendations for the recognition and management of atopic and nonatopic comorbidities commonly associated with AD. PMID- 30439297 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section II: Tools for Assessing the Severity of Atopic Dermatitis. AB - Clinicians rely on clinical measures to define the severity of atopic dermatitis and assess outcomes of therapy. These measures can be objective (ie, physician assessments of disease severity) or subjective (ie, patient-reported symptoms and quality of life outcomes). In this review, the most commonly used tools for assessing atopic dermatitis severity in adult patients are presented and compared. These include Eczema Area and Severity Index (EASI); SCORing Atopic Dermatitis (SCORAD); Physician Global Assessment (PGA); body surface area (BSA); Atopic Dermatitis Severity Index (ADSI); Six Area, Six Sign Atopic Dermatitis (SASSAD); Patient Oriented Eczema Measure (POEM); Dermatology Life Quality Index (DLQI); and pruritus Numerical Rating Scale (NRS). Available severity strata for the tools are summarized, although the use of severity strata in clinical practice is not recommended. Since both objective and subjective assessments of disease severity are important to assess, consideration of clinical characteristics such as disease recurrence or persistence, as well as location of the affected areas, should be considered in the overall judgement of disease severity and consideration of therapy choice. PMID- 30439299 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section I: Pathophysiology of Atopic Dermatitis and Implications for Systemic Therapy. AB - Atopic dermatitis (AD) is a chronic, relapsing, and remitting inflammatory skin disease whose onset typically occurs early in life. AD pathophysiology includes genetic, immune, and environmental factors contributing to chronic inflammation. A rapidly evolving understanding of the pathogenesis of AD has led to the development of several treatment options for AD in adults, including topicals, phototherapy, and systemic therapies. Here, we provide a concise summary of AD pathophysiology with a focus on implications for systemic therapy. PMID- 30439298 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. AB - BACKGROUND:: Atopic dermatitis (AD) is a chronic, relapsing, and remitting inflammatory skin disease with complex pathophysiology, primarily driven by type 2 inflammation. Existing guidelines often do not reflect all current therapeutic options and guidance on the practical management of patients with AD is lacking. OBJECTIVES:: To develop practical, up-to-date guidance on the assessment and management of adult patients with AD. METHODS:: An expert panel of 17 Canadian experts, including 16 dermatologists and 1 allergist, with extensive clinical experience managing moderate-to-severe AD reviewed the available literature from the past 5 years using a defined list of key search terms. This literature, along with clinical expertise and opinion, was used to draft concise, clinically relevant reviews of the current literature. Based on these reviews, experts developed and voted on recommendations and statements to reflect the practical management of adult patients with AD as a guide for health care providers in Canada and across the globe, using a prespecified agreement cutoff of 75%. RESULTS:: Eleven consensus statements were approved by the expert panel and reflected 4 key domains: pathophysiology, assessment, comorbidities, and treatment. CONCLUSIONS:: These statements aim to provide a framework for the assessment and management of adult patients with AD and to guide health care providers in practically relevant aspects of patient management. PMID- 30439301 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section IV: Treatment Options for the Management of Atopic Dermatitis. AB - The objectives of therapy for atopic dermatitis (AD) are to reduce skin inflammation and pruritus, restore skin barrier function, and improve quality of life (QoL). Treatments can be classified as moisturizing and basic care, topical therapy, phototherapy, and systemic therapy. In this review, we summarize the treatments for AD and recommendations for their use. PMID- 30439300 TI - Approach to the Assessment and Management of Adult Patients With Atopic Dermatitis: A Consensus Document. Section V: Consensus Statements on the Assessment and Management of Adult Patients With Moderate-to-Severe Atopic Dermatitis. AB - This document is a concise, current, and practical guide for dermatologists and other health care providers managing adult patients with moderate-to-severe atopic dermatitis (AD). The recommendations made here are based on a consensus of specialists with extensive experience managing patients with AD. Topics reviewed in this publication include AD pathophysiology, assessment, comorbidities, and treatment options. PMID- 30439302 TI - Elisabeth Kubler-Ross and the "Five Stages" Model in a Sampling of Recent American Textbooks. AB - This article examines some aspects of the enduring influence of the work of Dr. Elisabeth Kubler-Ross and especially of her "five stages" model through a sampling of recent textbooks published in the United States in selected academic disciplines and professional fields. The following are the questions to be asked: 1. Does the "five stages" model appear without significant change in the textbooks described here? 2. Is the "five stages" model applied in these textbooks to issues involving loss, grief, and bereavement, as well as to those involving terminal illness and dying? 3. Is the "five stages" model criticized in some or all of these textbooks? 4. If so, is the criticism sufficient to argue that, while the "five stages" model might be presented as an important historical framework, it should no longer be regarded as a sound theory to guide contemporary education and practice? PMID- 30439303 TI - Identifying Psychological Strains in Suicide Notes. AB - The Strain Theory of Suicide and mental disorders proposes that psychological strains precede suicidal behaviors and psychiatric disorders. This study was designed to test the theory with a large sample of suicide notes collected from Tasmania, Australia. The content of 261 suicide notes was analyzed for the presence of four psychological strains. It was found that 39.6% of the 261 suicide notes had at least one of the four psychological strains, with aspiration and coping strains being the most prevalent. We then compared the ratings of psychological strains with ratings of thwarted belonging and perceived burdensomeness and found that the presence of aspiration strain and coping strain was associated with thwarted belonging, while aspiration and deprivation strains were associated with perceived burdensomeness. PMID- 30439304 TI - Avoidance Behavior Prevents Modification of Fear Memory During Reconsolidation. AB - Several studies have revealed that fear recovery is prevented when extinction training is conducted after retrieval of a fear memory. Postretrieval extinction training is related to modification of memory during reconsolidation. Providing new information during reconsolidation can modify the original memory. We propose that avoidance behavior is a relevant factor that prevents subjects from obtaining new safety information during reconsolidation. Postretrieval extinction training without avoidance behavior reduced the fear response to conditioned stimulus and prevented spontaneous recovery in the current study, which corresponded with previous studies. Under the condition of postretrieval extinction training with avoidance behavior, the fear response was not reduced as much as it was in the condition without avoidance. It is possible that avoidance behavior prevents receiving new safety information during postretrieval extinction training. PMID- 30439305 TI - Making Sense of Chinese Employees' Suicidal Ideation: A Psychological Strain-Life Meaning Model. AB - Using the strain theory of suicide, this study examines how psychological strains influence suicide ideation via the mediating mechanism of the meaning in life. To check the hypothesized model, data were drawn from professional employees ( n=687) across six organizations of various business types to increase the variability of respondent perception and the generalizability of the study findings. The results showed significant correlations among psychological strains, meaning in life, and suicide ideation. Furthermore, this study provides evidence for the mediation effect of meaning in life in the relationship between psychological strain and suicide ideation. Implications and future directions are discussed. PMID- 30439306 TI - Erratum. PMID- 30439307 TI - [Effects of different administration methods of hydrocortisone on blood glucose in patients with septic shock: a Meta-analysis]. AB - OBJECTIVE: To systematically evaluate the effect of different administration methods of hydrocortisone on blood glucose in patients with septic shock. METHODS: The Cochrane Library, PubMed, Web of Science, Embase, CNKI, CBM, Wanfang, and VIP databases were searched from foundation to December 31st, 2017 for the randomized controlled trials (RCTs) about hydrocortisone on blood glucose of different drug-deliver ways in patients with septic shock. In addition, the citation retrievals were performed by the literature references. Then the quality evaluation and data extraction was conducted by two researchers independently according to the Cochrane systematic review methods. RevMan 5.3 software was utilized to perform meta-analysis on the influences of the two different administration methods of the continuously pumping hydrocortisone group (experimental group) vs. the intermittently dripping hydrocortisone group (control group) on the mean blood glucose (MBG), largest amplitude of glycemic excursion (LAGE), glucose variability (GV), hyperglycemia time window in patients with septic shock. RESULTS: 1 203 relevant articles were preliminarily searched. Then the duplications were removed, reviews, and non-RCTs and articles evidently not accordant with the inclusion criteria were excluded by titles and abstracts. Eventually a total of 5 well-designed RCTs (404 cases) were incorporated, including 201 cases in the experimental group and 203 cases in the control group. The results of meta-analysis showed that compared with the control group, MBG was significantly decreased in the experimental group [mean difference (MD) = -0.99, 95% confidence interval (95%CI) = -1.53 to -0.45, P < 0.05], LAGE was decreased (MD = -5.66, 95%CI = -6.92 to -4.41, P < 0.05), GV was reduced (MD = -0.67, 95%CI = -0.82 to -0.53, P < 0.05), and hyperglycemia time window was shortened (MD = 7.68, 95%CI = -9.03 to -6.33, P < 0.05). The funnel chart revealed that there was publication bias in the MBG, hyperglycemia time window of the articles, and the publication bias was lower in the LAGE and GV. CONCLUSIONS: Compared with intermittent administration method, the continuous pumping hydrocortisone method can stabilize the blood glucose of septic shock patients, shorten the duration of hyperglycemia and reduce the peak value of blood glucose. PMID- 30439308 TI - [The difference between hematocrit and plasma albumin in the course of systemic capillary leak syndrome: a systematic review]. AB - OBJECTIVE: To investigate the changes of the difference between hematocrit (Hct) and plasma albumin (Alb) in the course of patients with systemic capillary leak syndrome (SCLS). METHODS: 281 case reports on human vascular leaking from the PubMed database from January 1st, 1996 to September 30th, 2015 were screened by systematic review method. Studies related to intracranial vascular leakage or intraocular vascular leakage were excluded. 213 articles related to SCLS were identified (164 in English, 16 in French, 8 in Japanese, 7 in German, 7 in Spanish, 4 in Italian, 2 in Chinese, 2 in Danish, 2 in Dutch, and 1 in Swedish). Due to the unavailable full text, 40 articles were excluded. A total of 173 articles related to SCLS were screened, of which 84 patients were enrolled. The data of Alb, Hct, age, gender, weight change, the length of hospital stay and 24 hour fluid infusion volume in SCLS patients were recorded, and the difference between Hct and plasma Alb (Hct-Alb) was calculated. According to the time when accurate Hct and Alb data were collected, they were divided into three groups: basic value group before onset, value group at onset and value group at recovery/discharge after onset. The levels of Hct and Alb and Hct-Alb at different time points in the course of the disease were compared. Pearson test was used to analyze the correlation between Hct-Alb and 24-hour fluid infusion volume. RESULTS: (1) A total of 12 cases with both exact values of Alb and Hct [or hemoglobin (Hb)] at the time of onset and recovery after treatment were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that after treatment (26.33+/-16.36 vs. 0.55+/-8.81, P < 0.001). (2) A total of 17 cases with both the pre-onset baseline value and the exact values of Alb and Hct (or Hb) at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb at the time of onset was significantly higher than that of the pre-onset basic value (15.83+/ 11.37 vs. 1.82+/-7.97, P < 0.001). (3) A total of 14 cases with both exact values of Alb, Hct and 24-hour fluid infusion volume at the time of onset were selected from 84 cases of SCLS. It was shown that the Hct-Alb was 35.45+/-19.58 at the time of onset. The average 24-hour fluid infusion volume was (9.82+/-4.95) L, and the maximum volume of fluid infusion was 20 L. Pearson correlation analysis showed that the Hct-Alb at the time of onset was significantly positively correlated with 24-hour fluid infusion volume (r = 0.578, P < 0.05). CONCLUSIONS: In the analysis of SCLS cases published with adequate data available from 1996 to 2015, it was revealed that: (1) the difference in Hct-Alb levels at the onset of SCLS was 32.06+/-17.41. (2) The greater the difference between Hct and plasma Alb, the more amount of fluid required to maintain normal blood pressure. PMID- 30439309 TI - [Predictive value of plasma cell-free DNA for prognosis of sepsis]. AB - OBJECTIVE: To explore the predictive value of plasma cell-free DNA (cf-DNA) for prognosis in patients with sepsis. METHODS: 105 patients with sepsis admitted to department of emergency of the First Hospital of Quanzhou Affiliated to Fujian Medical University from June 2015 to June 2017 were enrolled. Patients were divided into sepsis group (n = 50) and severe sepsis group (n = 55). At the same time, 50 cases of physical examination center in our hospital were randomly selected as the healthy control group. The differences of cf-DNA, procalcitonin (PCT) and acute physiology and chronic health evaluation II (APACHE II) score among the three groups were compared. The correlation between cf-DNA and PCT or APACHE II were analyzed by Bivarite method. Logistic regression was used to analyze the independent predictors of sepsis. The receiver operating characteristic curve (ROC) was made to evaluate cf-DNA, PCT, APACHE II alone or combined ability to predict the prognosis of sepsis. RESULTS: The PCT, APACHE II and cf-DNA in the sepsis group and severe sepsis group were significantly higher than those in the healthy control group [PCT (MUg/L): 5.80 (3.28, 8.85), 17.53 (8.40, 29.61) vs. 0.02 (0.01, 0.03); APACHE II: 13.04+/-3.03, 23.29+/-8.02 vs. 2.10+/-1.05; cf-DNA (MUg/L): 1 438.0 (1 154.0, 1 576.0), 2 595.0 (2 162.0, 5 198.0) vs. 17.0 (13.0, 20.5); all P < 0.05], and the indicators in the severe sepsis group were further higher than the sepsis group (all P < 0.05). Correlation analysis showed that cf-DNA was significantly positive correlated with PCT [r = 0.675, 95% confidence interval (95%CI) = 0.575-0.766, P < 0.001] and APACHE II (r = 0.911, 95%CI = 0.874-0.939, P < 0.001). ROC curve analysis showed that the areas under ROC curve (AUC) of PCT, APACHE II, cf-DNA, PCT+APACHE II, cf-DNA+PCT, cf-DNA+APACHE II, cf-DNA+PCT+APACHE II to predict the prognosis of sepsis patients were 0.898, 0.905, 0.961, 0.941, 0.974, 0.976 and 0.982, respectively. It was shown that when predicted alone with PCT, APACHE II and cf DNA, the AUC of cf-DNA was the largest (0.961), the sensitivity was 100%, and the specificity was 81.43%; the combined prediction of cf-DNA with PCT or APACHE II could further increase AUC, and the combined prediction of cf-DNA, PCT and APACHE II had the highest AUC (0.982), the sensitivity was 94.29%, the specificity was 98.57%. CONCLUSIONS: cf-DNA, PCT and APACHE II have certain predictive value for the prognosis of sepsis. The value of cf-DNA was the highest when predicted alone, but the predictive ability of cf-DNA combined with PCT and APACHE II was the best. PMID- 30439310 TI - [Clinical characteristics and predictors of mortality in patients with candidemia in intensive care unit]. AB - OBJECTIVE: To investigate the clinical characteristics and predictors of mortality in patients with candidemia in intensive care unit (ICU). METHODS: The patients with candidemia admitted to ICU of Peking University People's Hospital from January 2010 to December 2017 were enrolled. The general clinical data, indicators related to Candidia infection and prognosis were collected, and the clinical characteristics, infection characteristics and prognosis of patients with candidiasis were analyzed. Patients were divided into death group and survival group according to hospital survival status. The differences of each index were compared between two groups. The independent risk factors of mortality in patients with candidemia were analyzed by multivariate Logistic regression analysis. RESULTS: A total of 95 patients (55 males) with candidemia were included, with an average age of (69.3+/-16.5) years, acute physiology and chronic health evaluation II (APACHE II) was 24.7+/-3.6, sequential organ failure assessment (SOFA) was 6.6+/-2.7. Candida albicans accounted for the largest proportion of Candida infections (n = 56, 58.9%). Thirty-two (33.7%) patients received inadequate antifungal therapy and 38 (40.0%) patients received inadequate source control. Fifty-five (57.9%) patients were died in hospital. Compared with the survival group, patients in the death group was older (years: 72.5+/-14.6 vs. 64.9+/-18.0, P < 0.05), had higher APACHE II and SOFA scores (26.6+/-2.2 vs. 22.1+/-3.6, 7.9+/-2.0 vs. 4.7+/-2.4, both P < 0.01), higher rate of glucocorticoid treatment (18.2% vs. 10.0%, P < 0.05), and higher proportion of Candida albicans and Candida glabrata (69.1% vs. 45.0%, 10.9% vs. 7.5%, both P < 0.05), the rate of multi-site Candida infection also significantly increased (47.3% vs. 17.5%, P < 0.05). Intra-abdominal infection was the primary infection site and more common in death group (49.1% vs. 35.0%, P < 0.05). The rates of sepsis (87.3% vs. 62.5%), inadequate antifungal therapy (49.1% vs. 10.0%), inadequate source control (60.0% vs. 12.5%) in death group were all higher than those in survival group (all P < 0.01). It was shown by multivariate Logistic regression analysis that APACHE II [odds ratio (OR) = 1.605, P = 0.002, beta = 0.473], SOFA (OR = 1.501, P = 0.029, beta = 0.406), inadequate antifungal therapy (OR = 12.084, P = 0.006, beta = 2.492) and inadequate source control (OR = 7.332, P = 0.024, beta = 1.992) were independent risk factors for mortality in ICU patients with candidemia. CONCLUSIONS: Candidemia patients were severe and had poor prognosis. APACHE II, SOFA, inadequate antifungal therapy and inadequate source control were independent risk factors of mortality. PMID- 30439311 TI - [Risk factors and etiological analysis of ventilator-associated pneumonia: three year's cases analysis of intensive care unit in county hospital]. AB - OBJECTIVE: To investigate the risk factors of ventilator-associated pneumonia (VAP) and the distribution and drug resistance of pathogens in intensive care unit (ICU) of county hospital. METHODS: 234 patients on mechanical ventilation for more than 48 hours admitted to ICU of Shexian People's Hospital of Huangshan City from January 2016 to June 2018 were enrolled. The clinical data of all patients including gender, age, past medical history, exposure to antibiotics, medication, the duration of mechanical ventilation, the length of ICU stay, serum albumin, tracheotomy, re-intubation, prognosis, and pathogenic bacteria and drug sensitivity test of VAP patients were collected. The patients were divided into VAP group and non-VAP group according to the occurrence of VAP. The differences of each index between the two groups were compared. The risk factors of VAP were analyzed by multivariate Logistic regression. The distribution and drug resistance of pathogenic bacteria in sputum culture of lower respiratory tract of VAP patients were analyzed. RESULTS: Among the 234 patients on mechanical ventilation, 95 patients had VAP, and the incidence of VAP was 40.60%. (1) Risk factors of VAP: it was shown by univariate analysis that there were significant differences between VAP patients and non-VAP patients in past history, the duration of mechanical ventilation, the length of ICU stay, albumin < 28 g/L, antibiotic exposure and tracheotomy, but there were no significant differences in gender, age, glucocorticoid, sedative, gastric motility and coma between the two groups. It was shown by multivariate Logistic regression analysis that brain injury and cerebrovascular accident, the duration of mechanical ventilation > 7 days, albumin < 28 g/L and tracheotomy were independent risk factors for VAP occurrence [brain injury: odds ratio (OR) = 41.40, 95% confidence interval (95%CI) = 2.14-799.60, P = 0.014; cerebrovascular accident: OR = 36.07, 95%CI = 1.86-699.64, P = 0.018; the duration of mechanical ventilation > 7 days: OR = 1.23, 95%CI = 1.11-1.36, P < 0.001; albumin < 28 g/L: OR = 2.27, 95%CI = 1.03 5.01, P = 0.042; tracheotomy: OR = 3.33, 95%CI = 1.30-8.56, P = 0.012]. (2) Distribution and drug resistance of VAP pathogens: a total of 108 strains of pathogens were isolated from sputum samples of 95 patients with VAP. Gram negative (G-) bacteria accounted for 86.11% (93/108). The isolation rate of Klebsiella pneumoniae was the highest, reaching 31.48% (34/108); the isolation rates of Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Acinetobacter baumannii were 22.22% (24/108), 8.33% (9/108) and 9.26% (10/108), respectively. Gram-positive (G+) bacteria accounted for 6.48% (7/108), of which Staphylococcus aureus was 4.63% (5/108); and fungi was 7.41% (8/108). Drug resistance analysis showed that Klebsiella pneumoniae was 100% sensitive to amikacin (AMK), meropenem (MEM) and polymyxin (POL), and were suggested as the preferred drug. Pseudomonas aeruginosa was 100% sensitive to AMK, tobramycin (TOB) and POL, but 100% resistant to compound trimethoprim (PCST). Stenotrophomonas maltophilia was 100% sensitive to PCST and 100% resistant to AMK, piperacillin (PIP), piperacillin tazobactam (TZP) and TOB. Acinetobacter baumannii was 100% sensitive to cefoxitin (FOX), cefuroxime (CXM) and POT. Staphylococcus aureus was 100% sensitive to gentamicin (GEN), furantoin (NIT), rifampicin (RIF), vancomycin (VAN) and teicoplanin (TEC), while the drug resistance to clindamycin (CLI) and penicillin (PEN) was high (both 80.00%). Most pathogens were multidrug-resistant. The mortality of patients with multidrug resistant bacteria infection was significantly higher than that of non-multidrug resistant bacteria infection [51.85% (28/52) vs. 30.56% (11/36), chi 2 = 4.240, P = 0.046]. CONCLUSIONS: VAP was associated with brain injury and cerebrovascular accident, duration of mechanical ventilation < 7 days, albumin > 28 g/L and tracheotomy. VAP patients were infected mainly with G- bacteria and showed multiple drug resistance. PMID- 30439312 TI - [Comparison of the effect of CPAP+PPS mode and CPAP+ASB mode in weaning on acute exacerbation of chronic obstructive pulmonary disease patients]. AB - OBJECTIVE: To investigate the effect of different appropriate modes of weaning from mechanical ventilation (MV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Patients with AECOPD and mechanically ventilated by orotracheal intubation, suitable for continuous positive airway pressure+proportional pressure support (CPAP+PPS) and CPAP+assisted spontaneous breath (ASB) ventilation mode for weaning from MV, admitted to intensive care unit (ICU) of Tianjin Third Central Hospital form January 1st, 2016 to December 31st, 2017 were enrolled. When the patients recovered to spontaneous respiration and down regulation of ventilator support frequency to 10 bpm, they were taken ventilator weaning in CPAP+PPS and CPAP+ASB mode according to the random number table method, respectively. Basic characteristics, ventilator parameters, the incidence of high man-machine confrontation (man-machine confrontation index > 10%) and clinical outcomes (ventilator weaning time, which was defined as the time from randomization to successful weaning from MV, ventilator weaning failure times, the duration of MV, the length of ICU stay and the length of hospital stay) were compared between the two groups. RESULTS: Eighty-seven AECOPD patients were selected, 44 in CPAP+ASB group and 43 in CPAP+PPS group. There was no significant difference in gender, age, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure score (SOFA), Glasgow coma score (GCS), Charsen index and the highest arterial blood carbon dioxide partial pressure (PaCO2), the lowest arterial oxygen partial pressure (PaO2) and tidal volume (VT) at the time of onset between the two groups. Compared with CPAP+ASB group, incidence of high man machine confrontation was significantly decreased in CPAP+PPS group [9.30% (4/43) vs. 27.27% (12/44), P = 0.027], and the airway occlusion pressure (P0.1) was significantly decreased [cmH2O (1 cmH2O = 0.098 kPa): 2.21+/-0.83 vs. 2.63+/ 0.94, P = 0.032], and the failure rate of the first spontaneous breathing trial (SBT) was significantly decreased [6.98% (3/43) vs. 22.73% (10/44), P = 0.039], ventilator weaning time, the length of ICU stay and the length of hospital stay were significantly shortened [ventilator weaning time (hours): 12.73+/-14.23 vs. 50.64+/-38.11, the length of ICU stay (hours): 254.53+/-108.06 vs. 344.93+/ 124.95, the length of hospital stay (days): 18.53+/-7.59 vs. 26.64+/-11.22, all P < 0.05]. However, there was no significant difference in PaCO2, duration of MV, ICU mortality and hospital mortality between the two groups. CONCLUSIONS: Compared with CPAP+ASB ventilation mode, CPAP+PPS ventilation mode can reduce respiratory muscle load, promote respiratory function recovery, and reduce the occurrence of man-machine confrontation, which is beneficial to AECOPD patients taking ventilator weaning, and can significantly shorten the ventilator weaning time of patients and further shorten the hospitalization time. PMID- 30439313 TI - [Application of Venturi combined with MR850 in ventilator offline patients with tracheotomy]. AB - OBJECTIVE: To investigate the effect of oxygen therapy with Venturi combined with MR850 heating humidifier on patients without mechanical ventilation after tracheotomy. METHODS: Eighty patients (>= 18 years old) who had undergone tracheotomy and without mechanical ventilation admitted to Fenyang Hospital of Shanxi Province from June 2016 to December 2017 were enrolled, and they were divided into control group and observation group according to random number table method, with 40 patients in each group. The observation group was given Venturi (removed the mask) combined with MR850 device active warm and humid oxygen therapy; the control group was given one-off ordinary flow device and warm and humid exchanger (artificial nose, HME) passive humid oxygen therapy. Body temperature increased by 1 centigrade above basal body temperature, white blood cell count (WBC) increased 2*109/L than the base value, oxygenation index (PaO2/FiO2) < 300 mmHg (1 mmHg = 0.133 kPa), airway mucosal hemorrhage, pulmonary infection and sputum viscosity were observed in the two groups for 5 days after oxygen therapy. RESULTS: Among the 80 patients, there were 46 males and 34 females, with an average age of (67.7+/-12.2) years. Compared with the control group, the incidence of increased body temperature (5.0% vs. 20.0%), the incidence of increased WBC (7.5% vs. 35.0%), the incidence of low PaO2/FiO2 (2.5% vs. 7.5%), the incidence of airway mucosal bleeding (5.0 % vs. 15.0%) and the incidence of pulmonary infection (2.5% vs. 10.0%) were significantly decreased in the observation group (all P < 0.01), and the proportion of sputum viscosity I degree of patients was significantly increased (57.5% vs. 12.5%, P < 0.01). CONCLUSIONS: Venturi combined with MR850 device can effectively control airway temperature and humidity, promote sputum dilution and conducive to drainage, reduce pulmonary infection in adults patients without mechanical ventilation after tracheotomy, thereby reducing postoperative complications of tracheotomy. PMID- 30439314 TI - [Consistency study of indirect calorimetry and HB equation for measuring energy expenditure of patients with multiple injury receiving mechanical ventilation]. AB - OBJECTIVE: To evaluate the difference and correlation of 24-hour energy expenditure in patients with multiple trauma receiving mechanical ventilation predicted by indirect calorimetry (IC) and HB formula. METHODS: 140 patients with multiple trauma receiving mechanical ventilation admitted to intensive care unit (ICU) of the General Hospital of Ningxia Medical University from December 1st, 2016 to August 31st, 2017 were enrolled. The 24-hour energy expenditure of patients was repeatedly measured at 1, 3, 5, and 7 days after ICU admission by IC method, and the 24-hour energy expenditure measured by IC method was used as the "gold standard" to calculate the 24-hour kilogram body weight energy expenditure. The 24-hour energy expenditure value measured by IC method was compared with the 24-hour energy expenditure predicted value calculated by HB formula method, the consistency of the two measurement methods was detected by Bland-Altman method, and the correlation between the two measurement methods was analyzed by Pearson method and the linear equation was fitted. RESULTS: The 24-hour energy expenditure of patients at 1, 3, 5 and 7 days after ICU was repeatedly measured by IC method for 501 times, and there was no significant difference in 24-hour energy expenditure (kJ/d: 8 163.1+/-1 599.4, 8 221.1+/-1 694.7, 8 445.8+/-1 756.4, 8 707.0+/-1 820.7, respectively, F = 2.451, P = 0.063) and 24-hour kilogram body weight energy expenditure (kJ*kg-1*d-1: 120.5+/-18.9, 121.4+/-19.7, 122.7+/-19.3, 121.4+/-19.3, respectively, F = 0.252, P = 0.860) at each time point, indicating that the first week of multi-injury patients had no significant changes in energy metabolism. The consistency between the 24-hour energy expenditure measured by IC method on the first day [(8 163.1+/-1 599.4) kJ/d] and that predicted by HB formula method [(6 568.8+/-782.0) kJ/d] was analyzed. The results showed that there was significant bias between the two methods, with an average bias of -(1 591.8+/-121.4) kJ/d, but the correlation analysis showed that there was a linear correlation between them (r = 0.439, P = 0.000), using one-way regression, the fitted linear equation was Y = 2 270.5+0.897X (X was 24-hour energy expenditure predicted by the HB formula). CONCLUSIONS: The energy metabolism of patients with multiple trauma receiving mechanical ventilation is not obvious within 1 week. The HB formula method underestimates the 24-hour energy expenditure of patients. The prediction formula can be used to correct the HB formula and further to improve the accuracy of predicting the 24-hour energy consumption of patients. PMID- 30439315 TI - [Comparison of two schemes of daily arousal and comfort analgesia and sedation in patients on mechanical ventilation in intensive care unit]. AB - OBJECTIVE: To explore the efficacy of comfort analgesia and sedation in patients with mechanical ventilation in intensive care unit (ICU). METHODS: Eighty patients with mechanical ventilation admitted to ICU of Pingxiang People's Hospital from June 2017 to May 2018 were enrolled, and they were randomly divided into control group and observation group by random number table method, with 40 patients in each group. The control group was given a daily analgesic and sedation regimen with critical-care pain observation tool (CPOT) 0-3 and Richmond agitation-sedation scale (RASS) maintained at -3 to -4. The observation group was given comfort analgesic sedative scheme with immediate analgesia and sedation score, CPOT 0-1 and RASS -1-0. Under these circumstances, patients could be waken up at any time, feel comfortable and cooperate with treatment. The duration of mechanical ventilation, the length of ICU stay, ventilator associated pneumonia (VAP) rate, delirium rate and sedatives drugs usage were compared between the two groups. RESULTS: There were no significant differences in baseline data such as gender [male (cases): 25 vs. 28], age (years old: 55.2+/-8.3 vs. 56.1+/-7.9), acute physiology and chronic health evaluation II (APACHE II: 19.4+/-3.0 vs. 19.8+/-3.2) and etiology [sepsis (cases): 13 vs. 16, chronic obstructive pulmonary disease (cases): 12 vs. 10, acute lung injury (cases): 8 vs. 9, hemorrhagic shock (cases): 5 vs. 4, cardiogenic shock (cases): 2 vs. 1] between the observation group and the control group (all P > 0.05). Compared with control group, the duration of mechanical ventilation and the length of ICU stay were significantly decreased in observation group (days: 5.6+/-1.9 vs. 7.8+/-2.7, 6.6+/-2.1 vs. 9.8+/-2.5, both P < 0.01), the VAP rate and delirium rate were significantly decreased (17.5% vs. 40.0%, 25.0% vs. 47.5%, both P < 0.05), the average dose and total dose of sedative drugs were significantly reduced [propofol average dose (mg): 200.3+/-94.2 vs. 455.7+/-143.1, propofol total dose (mg): 1 266.4+/-419.7 vs. 2 682.6+/-734.1; dexmedetomidine average dose (g): 726.6+/-241.1 vs. 1 312.7+/-841.6, dexmedetomidine total dose (g): 5 647.3+/-2 215.2 vs. 9 864.5+/-4 268.0; all P < 0.01]. CONCLUSIONS: The therapy of comfort analgesia and sedatives on ICU patients with mechanical ventilation, can decrease the treatment time, lower the risk of adverse events, and reduce the dosage of sedatives drugs. PMID- 30439316 TI - [Effect of progressive early bed exercise on blood flow in lower limb of patients on mechanical ventilation in intensive care unit]. AB - OBJECTIVE: To investigate the effect of progressive early bed physical activity on blood flow in lower limb of patients on mechanical ventilation in intensive care unit (ICU). METHODS: Adult patients with mechanical ventilation >= 72 hours admitted to ICU of the Affiliated Hospital of Zunyi Medical University from February 22nd to November 30th, 2016 were enrolled. The patients were randomly divided into experimental group and control group by random number table method. Patients in the two groups were given the same basic treatment, including antibiotics, analgesia and sedation, mechanical ventilation, nutritional support, and routine ICU activities such as maintaining functional position of limbs and raising of bed head. On the basis of those, the experimental group was given early bed physical activity with gradual enhancement of grades I-III according to the nerve, circulation and respiration situations, such as passive/active exercise of the bicycle, straight leg lifting exercise, etc. The exercise intensity was evaluated with target heart rate, and the exercise was performed for 15-30 minutes at a time, twice a day. The control group was given intermittent pneumatic compression (IPC), 30 minutes in each time, twice a day. Mean blood flow and blood volume were measured before and immediately, 5, 10 and 15 minutes after intervention on the 3rd day. Heart rate and blood pressure were measured at 5 minutes before intervention, during 5 minutes, and 5, 10, 15, 30 minutes after intervention on the 3rd day. RESULTS: 214 adult patients were selected, after excluding the patients who died during the intervention or gave up treatment, 160 patients were included in the data analysis, with 81 in the experimental group and 79 in the control group. The mean blood flow velocity and blood volume were increased in both groups, and the mean blood flow velocity and blood flow volume in the experimental group were significantly increased and lasted longer than those in the control group [mean blood flow velocity (mm/s) of the experimental group were 11.92+/-1.06, 18.19+/-0.17, 17.24+/-0.14, 15.48+/ 0.12, 12.68+/-0.16, and that of the control group were 12.01+/-1.41, 15.65+/ 0.18, 12.91+/-0.14, 12.13+/-0.12, 11.59+/-0.16, respectively, the time effect was F = 1 043.101, P = 0.000, the intervention effect was F = 151.001, P = 0.000, and the interaction effect between intervention and time was F = 224.830, P = 0.001; the blood volume (mL/min) of the experimental group were 3.39+/-0.96, 5.59+/ 0.11, 5.16+/-0.12, 4.19+/-0.10. 3.35+/-0.09, and that of the control group were 3.28+/-0.82, 4.04+/-0.11, 3.40+/-0.12, 3.02+/-0.10, 3.00+/-0.10, respectively, the time effect was F = 680.405, P = 0.000, the intervention effect was F = 125.359, P = 0.000, and the interaction effect between intervention and time was F = 79.631, P = 0.012]. The heart rate and blood pressure of the two groups of patients in the course of intervention were increased first, then decreased and then slowly recovered to the change trend before intervention, but the index of the experimental group fluctuated greatly [heart rate (bpm) of the experimental group were 97.64+/-1.50, 113.91+/-1.36, 105.96+/-1.34, 98.52+/-1.48, 97.84+/ 1.46, 97.54+/-1.48, and that of the control group were 97.03+/-1.57, 105.39+/ 1.38, 96.76+/-1.35, 96.54+/-1.50, 97.22+/-1.48, 96.53+/-1.49, respectively, the time effect was F = 235.030, P = 0.000, the intervention effect was F = 39.473, P = 0.000, and the interaction effect between intervention and time was F = 3.494, P = 0.063; the systolic blood pressure (mmHg, 1 mmHg = 0.133 kPa) of the experimental group were 118.57+/-1.06, 133.05+/-1.01, 120.44+/-1.10, 117.78+/ 1.07, 117.65+/-1.01, 118.14+/-1.00, and that of the control group were 118.10+/ 1.08, 126.68+/-1.02, 118.23+/-1.11, 117.48+/-1.08, 118.04+/-1.03, 118.90+/-1.10, respectively, the time effect was F = 336.604, P = 0.000, the intervention effect was F = 26.350, P = 0.000, and the interaction effect between intervention and time was F = 0.948, P = 0.332; the diastolic blood pressure (mmHg) of the experimental group were 68.07+/-0.72, 72.79+/-0.73, 70.68+/-0.74, 69.30+/-0.72, 68.73+/-0.74, 67.80+/-0.73, and that of the control group were 68.51+/-0.73, 72.03+/-0.74, 70.05+/-0.75, 69.10+/-0.73, 68.41+/-0.75, 67.85+/-0.74, respectively, the time effect was F = 286.390, P = 0.000, the intervention effect was F = 4.812, P = 0.000, and the interactive effect between intervention and time was F = 0.055, P = 0.815]. CONCLUSIONS: The effects of progressive early bed physical activity on the mean blood flow velocity and blood volume of lower limbs in ICU patients with mechanical ventilation are better than those of IPC. Although the fluctuation of heart rate and blood pressure is large, it does not cause any harm to the patients. PMID- 30439317 TI - [Correlation between shock index and diastolic blood pressure in patients with postpartum hemorrhage and early warning of postpartum hemorrhage risk: an analysis of numerous cases in 4 years]. AB - OBJECTIVE: To observe the changes of shock index (SI) and diastolic blood pressure (DBP) in postpartum hemorrhage patients, and the explore their relationship with postpartum hemorrhage and the clinical significance of early warning of hemorrhage risk. METHODS: 402 patients with postpartum hemorrhage (within 24 hours after delivery, the amount of bleeding in vaginal delivery >= 500 mL, and the amount of bleeding in caesarean delivery >= 1 000 mL) admitted to the obstetrics ward of Affiliated Hospital of Hangzhou Normal University from January 2014 to December 2017 were selected as the objective group and 416 without complications during delivery were selected as the control group in the same hospital at the same period. Clinical data in the two groups before and after childbirth was collected, including age, pregnancy week, 24-hour blood loss, and hemoglobin (Hb), whole blood cell parameters, heart rate (HR), systolic blood pressure (SBP), DBP, SI, blood urea nitrogen (BUN), serum creatinine (SCr) within 24 hours before and after delivery, and postpartum 24 hours and prenatal DBP difference (DeltaDBP). The differences of indicators were compared between the two groups. Pearson method was used to analyze the correlation between the postpartum DBP and SI in the objective group. Ordinal regression model was used to analyze the early warning risk factors of each index to postpartum hemorrhage. RESULTS: Compared with the control group, older age (years: 29.29+/-5.01 vs. 28.05+/-4.46), more pregnancies (times: 2.68+/-1.42 vs. 2.33+/-1.28), shorter gestation weeks (weeks: 38.33+/-3.57 vs. 39.05+/-1.40), more 24-hour blood loss (mL: 726.57+/-467.66 vs. 244.49+/-50.25) in the objective group were significant differences (all P < 0.01). Postpartum hemorrhage patients were successfully hemostatic, no maternal and perinatal death was found in the two groups. Compared with the control group, DBP was significantly decreased at 24 hours after delivery in the objective group [mmHg (1 mmHg = 0.133 kPa): 71.19+/-12.55 vs. 75.68+/-8.96, P < 0.05], and DeltaDBP was significantly increased (mmHg: 5.39+/ 3.93 vs. 0.67+/-0.33, P < 0.01). In addition, compared with the control group, SI and HR were significantly increased in the objective group [SI: 0.80+/-0.15 vs. 0.72+/-0.11, HR (bpm): 91.56+/-13.37 vs. 82.96+/-11.76, both P < 0.05], Hb, red blood cell count (RBC), platelet count (PLT) and SBP were significantly decreased [Hb (g/L): 91.30+/-13.41 vs. 112.30+/-13.41, RBC (*1012/L): 3.74+/-0.38 vs. 4.59+/-0.45, PLT (*109/L): 173.02+/-59.08 vs. 182.09+/-54.76, SBP (mmHg): 115.13+/-9.27 vs. 117.94+/-11.66, all P<0.05]. Correlation analysis showed that postpartum DBP was negatively correlated with SI, 24-hour blood loss, DeltaDBP, BUN and SCr (r value was -0.419, -0.268, -0.490, -0.108, -0.163, respectively, all P < 0.05), and positively correlated with SBP, Hb and RBC (r value was 0.739, 0.125, 0.096, respectively, all P < 0.05). It was shown by Ordinal regression analysis that the risk of postpartum hemorrhage was significantly increased when DeltaDBP >= 9.32 mmHg [relative risk (RR) = 2.64, 95% confidence interval (95%CI) = 1.94-3.34, P = 0.000], SI >= 0.95 (RR = 1.78, 95%CI = 1.01-2.55, P = 0.000), DBP <= 59.64 mmHg (RR = 0.86, 95%CI = 0.31-1.41, P = 0.000), SBP <= 105.86 mmHg (RR = 0.63, 95%CI = 0.18-1.07, P = 0.000), Hb <= 77.89 g/L (RR = 1.68, 95%CI = 0.99-2.38, P = 0.000), and DeltaDBP >= 9.32 mmHg was the most effective early warning effect. CONCLUSIONS: Combined with clinical manifestations of patients with postpartum hemorrhage, SI and DBP can be used as an important reference indicator for the observation of postpartum hemorrhage conditions. DeltaDBP >= 9.32 mmHg can be used as the risk factors of the patient with postpartum hemorrhage. PMID- 30439318 TI - [Analysis of treatment with 167 critically ill pregnant women in intensive care unit]. AB - OBJECTIVE: To analyze the pathogenic factors, clinical features and treatment measures of critically ill pregnant women so as to provide experience for improving the success rate of treatment. METHODS: The clinical data of 167 cases of critically ill pregnant women who admitted to intensive care unit (ICU) of the Affiliated Hospital of Guizhou Medical University from January 2013 to December 2017 were collected, and the disease distribution of patients, the causes of postpartum hemorrhage, the treatment situation and the results. Patients were divided into obstetrical complications group, pregnancy complicated with basic diseases group and other complicated diseases group according to disease types, and the treatment status of each group was analyzed. RESULTS: Among 167 critically ill pregnant women, 118 cases (70.6%) were in the obstetric complications group, 26 cases (15.6%) were in the pregnancy complicated with basic diseases group, and 23 cases (13.8%) were in the other complicated diseases group. Nine cases died in 167 critically ill pregnant women, with a mortality rate of 5.4%. Postpartum hemorrhage was the major obstetric complication (35.3%), and the coagulation function of 59 patients with postpartum hemorrhage was significantly improved 48 hours after active hemostasis and reasonable blood transfusion [compared to entering the ICU, prothrombin time (PT, s): 14.49+/-4.66 vs. 23.39+/-8.11, activated partial thromboplastin time (APTT, s): 52.94+/-36.36 vs. 87.35+/-74.69, fibrinogen (Fib, g/L): 2.91+/-1.03 vs. 1.03+/-0.65, platelet count (PLT, *109/L): 94.85+/-30.09 vs. 43.15+/-24.07, all P < 0.01]. Compared with pregnancy complicated basic diseases group and other complicated diseases group, the acute physiology and chronic health evaluation II (APACHE II) scores was reduced significantly in obstetrical complications group (10.41+/-4.85 vs. 16.46+/-13.87, 16.90+/-8.82, both P < 0.05), the length of ICU stay was significantly reduced (hours: 57.83+/-34.67 vs. 79.64+/-36.01, 278.30+/-83.72, both P < 0.05). Compared with other complicated diseases group, the mechanical ventilation time [hours :14 (6, 38) vs. 43 (12, 396)] and mortality (0.8% vs. 13.0%) were significantly decreased in obstetrical complications group (both P < 0.05). CONCLUSIONS: Observe the changes of the condition closely, necessary hemodynamic treatment, respiratory support, and organ function support with critically ill pregnant women can improve the rescue success rate and prognosis. PMID- 30439319 TI - [Etiology and prognosis of thrombocytopenia in children: a case analysis in 683 children within 10 years of pediatric intensive care unit]. AB - OBJECTIVE: To analyze the etiology and prognosis of children with thrombocytopenia (TP) in pediatric intensive care unit (PICU). METHODS: The data of children with TP (exclusion of congenital and unknown TP) admitted to PICU of Anhui Provincial Children's Hospital from January 2008 to December 2017 was analyzed retrospectively. According to the age of onset, the children were divided into infantile group (29 days to less than 1 year), early childhood group (1 to less than 3 years), preschool group (3 to less than 6 years), school age group (6 to less than 10 years) and puberty group (more than 10 years). Moreover, according to the lowest platelet count (PLT), the children were divided into PLT <= 20*109/L group, PLT (21-50)*109/L group and PLT > (50-100) *109/L group. The distribution and mortality of TP were analyzed, and the relationship between age, PLT decrease and prognosis were analyzed by Pearson method. RESULTS: Among 6 725 children admitted to PICU in our hospital from January 2008 to December 2017, there were 683 children with TP, with the incidence of 10.2%. Among 683 children with TP, there were 387 males and 296 females, with the median age of 2.72 (0.61, 3.08) years, and 92 children died, with a total mortality of 13.5%. Analysis of primary disease showed that TP caused by non-hematological malignant tumor disease accounted for 73.9%, with the mortality of 11.1% (56/505). TP induced by hematological malignant tumor disease accounted for 21.4%, with the mortality of 24.7% (36/146). Pseudothrombocytopenia accounted for 0.6%, with the mortality of 0% (0/4). Other children who gave up treatment accounted for 4.1%. It was shown by further analysis that multiple organ dysfunction syndrome (MODS) caused by TP associated with non-hematological malignant tumor disease accounted for 26.9%, with the mortality of 15.4% (21/136). Sepsis, severe trauma, pneumonia, central nervous system infection and disseminated intravascular coagulation (DIC) accounted for 17.4%, 16.6%, 12.7%, 11.7% and 11.5%; with the mortality of 8.0% (7/88), 2.4% (2/84), 0% (0/64), 20.3% (12/59) and 24.1% (14/58), respectively. The main causes of TP associated with hematological malignant tumor disease were hemophagocytic syndrome [accounting for 27.4%, with the mortality of 32.5% (13/40)] and bone marrow inhibition [accounting for 21.2%, with the mortality of 25.8% (8/31)]. The younger were the children with TP, the higher would be the mortality. The mortality of infantile group was significantly higher than that of early childhood group, preschool group, school age group and puberty group [18.8% (53/282) vs. 14.0% (28/200), 6.7% (7/104), 4.3% (4/92), 0% (0/5), all P < 0.01]. The lower was the PLT, the higher would be the mortality. The mortality of PLT <= 20*109/L group was significantly higher than that of PLT (21-50)*109/L group and PLT > (50-100)*109/L group [18.1% (39/215) vs. 13.0% (32/247), 9.5% (21/221), both P < 0.05]. It was shown by correlation analysis that there was no association between age and 28-day death time in children with TP (r = -0.037, P = 0.727), but PLT was positively correlated with 28-day death time in children with TP (r = 0.844, P = 0.010). CONCLUSIONS: MODS, infection, sepsis, severe trauma and DIC are the common causes of TP in PICU. The younger are the children with TP, the lower is the PLT, and the worse would be the prognosis. PMID- 30439320 TI - [Study on the application of classification tree model in screening the risk factors of ischemic stroke]. AB - OBJECTIVE: To construct a prediction model for the risk of ischemic stroke (IS) by classification tree model, and evaluate its application value. METHODS: By cluster sampling, 858 IS patients with perfect clinical data from January to December 2017 in the Affiliated Hospital of Guilin Medical College (IS group) were enrolled, and 844 health checkups matched with the gender and age of IS patients in the same period were enrolled as controls (healthy control group). The metabolic characteristics of the two groups were compared and analyzed. The classification tree model was used to construct the prediction model of the risk of IS, and the gain diagram, index chart, risk value of misclassification probability and receiver operating characteristic curve (ROC) were used to evaluate the application value of the model. RESULTS: Compared with the healthy control group, body mass index (BMI), fasting blood glucose (FPG), triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) in IS group were significantly increased [BMI (kg/m2): 25.34+/-3.70 vs. 24.24+/-3.10, FPG (mmol/L): 6.79+/-2.89 vs. 5.73+/-1.17, TG (mmol/L): 1.62+/-1.06 vs. 1.44+/ 1.06, TC (mmol/L): 4.70+/-2.73 vs. 4.35+/-0.79, LDL-C (mmol/L): 3.18+/-0.94 vs. 2.73+/-0.73, all P < 0.01], high density lipoprotein cholesterol (HDL-C) was significantly decreased (mmol/L: 1.12+/-0.33 vs. 1.35+/-0.36, P < 0.01), and the proportion of hypertension, smoking and drinking were significantly increased (69.0% vs. 41.9%, 23.1% vs. 16.8%, 19.2% vs. 13.4%, all P < 0.01). By assigning values to each factor [IS: No = 0,Yes = 1; BMI: < 24.0 kg/m2 = 0, >= 24.0 kg/m2 = 1; FPG: < 7.0 mmol/L = 0, >= 7.0 mmol/L = 1; TG: < 2.26 mmol/L = 0, >= 2.26 mmol/L = 1; TC: < 6.22 mmol/L = 0, >= 6.22 mmol/L = 1; LDL-C: < 4.14 mmol/L = 0, >= 4.14 mmol/L = 1; HDL-C: < 1.04 mmol/L = 0, >= 1.04 mmol/L = 1; hypertension: No = 0,Yes = 1; smoking: No = 0,Yes = 1; drinking: No = 0,Yes = 1], a classification tree model was established to analyze the risk factors of IS. The classification tree model consisted of 4 layers and 17 nodes: the first layer was hypertension, the second layer was FPG and HDL-C, the third layer was HDL-C and FPG, and the fourth layer was LDL-C and smoking. There were five explanatory variables screened out in the model, including hypertension, FPG, HDL-C, LDL-C and smoking. The first layer of the tree showed that the incidence of IS in hypertensive population (62.6%) was significantly higher than that in non hypertensive population (35.2%). The second layer of the tree showed that the incidence of IS in people with hypertension with HDL-C >= 1.04 mmol/L (53.6%) was lower than that in people with HDL-C < 1.04 mmol/L (78.5%). However, in the population without hypertension, the probability of IS occurrence in the population with FPG >= 7.0 mmol/L (71.1%) was significantly higher than that in the population with FPG < 7.0 mmol/L (28.3%). The third layer of the tree showed that the IS incidence of HDL-C >= 1.04 mmol/L (21.8%) was lower than that of HDL C < 1.04 mmol/L (48.7%) in the population without hypertension and FPG < 7.0 mmol/L. However, in the population with hypertension and HDL-C >= 1.04 mmol/L, the probability of IS occurrence in the population with FPG >= 7.0 mmol/L (78.6%) was significantly higher than that in the population with FPG < 7.0 mmol/L (46.7%). The fourth layer of the tree showed that the IS incidence of people with LDL-C >= 4.14 mmol/L (53.8%) was higher than that of people with LDL-C < 4.14 mmol/L (19.0%) in the population without hypertension, FPG < 7.0 mmol/L and HDL-C >= 1.04 mmol/L. In the population without hypertension, the incidence of IS in smokers (76.9%) was higher than that in non-smokers (39.1%) of people with FPG < 7.0 mmol/L and HDL-C < 1.04 mmol/L. In the population with hypertension, the probability of IS occurrence in the population with LDL-C >= 4.14 mmol/L (72.5%) was higher than that in the population with LDL-C < 4.14 mmol/L (44.4 %) of people with HDL-C >= 1.04 mmol/L and FPG < 7.0 mmol/L. The gain diagram of IS classification tree model shown that the gain value increased rapidly from 0% to 100% and then tended to be stable. The index chart shown that the index value kept stable in the moving direction from above 100% and then dropped rapidly to 100%, indicating the model was very well. The risk value of misclassification probability of the classification tree model was 0.291, and the correct rate of risk factor for IS patients was 70.90%. The area under ROC curve (AUC) was 78.0% [95% confidence interval (95%CI) = 75.9%-79.9%, P < 0.001], the sensitivity was 62.5% (95%CI = 59.1%-65.7%) and the specificity was 79.4% (95%CI = 76.5%-82.1%). CONCLUSIONS: Classification tree model can properly predict the risk factor of IS, and the most important risk factors are hypertension, hyperglycemia, high LDL C and smoking. PMID- 30439321 TI - [Risk factors analysis of acute respiratory distress syndrome in intensive care unit traumatic patients]. AB - OBJECTIVE: To investigate the risk factors of acute respiratory distress syndrome (ARDS) occurrence in intensive care unit (ICU) traumatic patients. METHODS: Clinical data of traumatic patients in ICU of the People's Hospital of Liangping in Chongqing from January 1st, 2012 to June 30th, 2018 were retrospectively analyzed. According to the outcomes, the patients were divided into ARDS group and non-ARDS group. The differences of demographic indexes (gender, age), time of admission, type of injury, atrial fibrillation, trachea cannula, multiple injury, open injury, shock, surgery, blood transfusion, central venous indwelling catheter, infection, and blood routine indexes [white blood cell count (WBC), red blood cell count (RBC), platelet count (PLT), plateletcytocrit (PCT), hematocrit (Hct)], biochemical indexes [total bilirubin (TBil), albumin (Alb), serum creatinine (SCr), blood sodium, blood calcium, blood potassium, blood glucose], arterial blood gas analysis indexes [partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), oxygenation index (PaO2/FiO2), blood pH], coagulation indicators [activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), international normalized ratio (INR), fibrinogen (Fib)], injury severity score (ISS), new injury severity score (NISS), acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), Glasgow coma scale (GCS) within 24 hours of admission, and the length of ICU stay between the two groups were analyzed, and the possible influencing factors were screened out. Logistic regression model was used to analyze the risk factors of ARDS in patients with severe trauma, and receiver operating characteristic curve (ROC) was drawn to evaluate its predictive value. RESULTS: A total of 303 patients with severe trauma, including 223 males and 80 females, were enrolled. The average age was (52.98+/-17.03) years old. ARDS occurred in 149 cases (49.17%), including 114 males and 35 females. Compared with the non-ARDS group, the ARDS group had older age, higher rates of traffic injuries, endotracheal intubation and infection, higher blood sugar, PaO2/FiO2, TT, ISS, NISS and SOFA, lower GCS and longer the length of ICU stay. Logistic regression analysis showed that hyperglycemia, PaO2/FiO2 anomalies and increased SOFA score were independent risk factors for ARDS in ICU trauma patients [blood glucose > 6.10 mmol/L: odds ratios (OR) = 2.72, 95% confidence interval (95%CI) = 1.20-6.19, P = 0.017; PaO2/FiO2 < 400 mmHg (1 mmHg = 0.133 kPa): OR = 7.40, 95%CI = 1.59-34.37, P = 0.011; SOFA > 5: OR = 2.92, 95%CI = 1.63-5.21, P < 0.001]. ROC curve analysis showed that blood glucose, SOFA and PaO2/FiO2 could predict ARDS in ICU trauma patients, with the area under ROC curve (AUC) were 0.65, 0.70 and 0.75, respectively (all P < 0.01). The predictive value of PaO2/FiO2 was better, when the cut-off value was 275 mmHg, the sensitivity was 85.89% and specificity was 70.29%. CONCLUSIONS: The traumatic patients on admission with hyperglycemia, abnormal PaO2/FiO2 and increased SOFA score are more susceptible to ARDS occurrence. PMID- 30439322 TI - [Effect of Xuebijing injection on postoperative inflammatory response in patients after hepatobiliary and pancreatic surgeries: a retrospective cohort study]. AB - OBJECTIVE: To analyze the effect of Xuebijing injection on inflammatory response in patients after hepatobiliary and pancreatic surgeries, and to evaluate its safety and clinical value. METHODS: A retrospective cohort study was conducted. 708 patients received hepatobiliary and pancreatic surgeries of Nanfang Hospital, Southern Medical University from January 2015 to September 2017 were enrolled and divided into Xuebijing treatment group and conventional treatment group according to whether they were treated with Xuebijing injection or not. The inflammatory response indexes included white blood cell count (WBC), neutrophil (NE), C reactive protein (CRP), body temperature, which were compared between the two groups at 1, 3, and 5 days after operation. The incidence of adverse reactions, the length of postoperative hospital stays and hospitalization costs were compared. RESULTS: A total of 209 patients were prescribed with Xuebijing injection, and 499 patients were allocated into conventional treatment group. The two groups were stratified by liver, biliary and pancreatic surgery types, and further 1:1 propensity score matching was performed. After propensity score match, 189 patients were included in each group, with 101, 46, and 42 patients undergoing liver, biliary, and pancreas surgery, respectively. There were no significant differences in baseline data such as gender, age and inflammatory response indexes before surgery between the two groups. In both groups, the WBC and NE showed a gradual decline after operation, CRP were increased gradually and then decreased after 3 days. Compared with the conventional treatment group, Xuebijing treatment group showed obvious anti-inflammatory effect from 3 days after operation [WBC (*109/L): 10.1+/-4.0 vs. 11.0+/-3.5, NE: 0.71+/-0.10 vs. 0.76+/-0.12, CRP (mg/L): 73.1+/-38.7 vs. 82.2+/-41.8, all P < 0.05]. On the 5th day, it still showed a strong anti-inflammatory trend [WBC (*109/L): 7.0+/-2.8 vs. 7.9+/-2.6, NE: 0.62+/-0.10 vs. 0.68+/-0.12, CRP (mg/L): 43.4+/-31.0 vs. 50.9+/-25.3, all P < 0.05]. The cases of postoperative fever in the Xuebijing treatment group were significantly less than that in the conventional treatment group (cases: 98 vs. 119, chi2 = 4.711, P = 0.029). There was no significant different in the total incidence of adverse drug reactions such as rash, nausea and vomiting (5.0% vs. 3.2%), the length of postoperative hospital stays [days: 9.3 (6.1, 13.5) vs. 9.1 (5.5, 13.3)] and hospitalization costs [wanyuan: 5.8 (3.6, 9.5) vs. 5.7 (3.5, 9.8)] between Xuebijing treatment group and conventional treatment group (all P > 0.05). CONCLUSIONS: Xuebijing injection has a good anti inflammatory effect on patients undergoing hepatobiliary and pancreatic surgeries. Xuebijing injection has good safety and can be applied to the prevention and treatment of excessive inflammatory reaction after hepatobiliary and pancreatic surgeries. PMID- 30439323 TI - [Epidemiological analysis and disease spectrum characteristics of emergency patients with critical illness: 3 176 emergency cases in 2017 in a hospital in Beijing were analyzed]. AB - OBJECTIVE: To investigate the epidemiological characteristics of emergency critical illness and disease spectrum in emergency department of a hospital in Beijing. METHODS: A retrospective study was conducted. The data of 3 176 critically ill patients aged >= 14 years old admitted to the emergency room of Xuanwu Hospital Capital Medical University from January 1st to December 31st in 2017 were analyzed, including gender, age, clinical time, discharge diagnosis, outcomes, etc. To analyze the epidemiological characteristics and disease spectrum distribution of emergency critically ill patients, annual and daily 24 hour emergency visits in 2017 were analyzed. RESULTS: Among the 3 176 cases of acute critical illness, there were more males than females (1 824 vs. 1 352, 1.35:1); the age ranged from 14 to 100 years old, with an average of (66.52+/ 17.18) years old; the highest incidence age was 75-89 years old (35.2%, 516 males and 603 females), followed by 60-70 years old (30.0%, 572 males and 381 females). The top four prevalence diseases in the emergency critical disease spectrum were cardiovascular diseases [41.8%, 716 males and 610 females, age (70.25+/-15.08) years old], nervous system diseases [26.7%, 502 males and 346 females, age (60.28+/-17.57) years old], respiratory disease [12.3%, 226 males and 166 females, age (72.96+/-16.23) years old] and digestive system diseases [5.6%, 119 males and 60 females, age (65.40+/-17.96) years old], accounting for 86.4% of the total. There were more males than females (all P < 0.05), and the age difference was statistically significant (F = 84.094, P < 0.001). Arrhythmia was the most common cardiovascular disease (16.7%), followed by acute coronary syndrome (12.0%) and heart failure (9.1%); the main nervous system diseases were stroke (20.9%); respiratory diseases mainly included severe pneumonia (8.3%); digestive system diseases were mainly with digestive tract bleeding (4.4%). The high incidence of acute critical illness in the emergency department occurred in winter (287 cases in December and 277 cases in January) and the early stage of spring (282 cases in March). The daily peak period was midday and at night, especially from 18:00 to 23:00 (163 cases at 18:00, 173 cases at 19:00, 172 cases at 20:00, 186 cases at 21:00, 167 cases at 22:00, 169 cases at 23:00). The average treatment time of critically ill patients in emergency room was 1.5 days (the longest was 23.0 days, the shortest was 6 minutes), among them, 85.6% of the patients could be discharged from the emergency within 3 days, and 1.9% of the patients stayed in the emergency for more than 7 days. There were 305 deaths (9.6%), mainly among the elderly, with an average age of (71.10+/-16.08) years old. CONCLUSIONS: Cardiovascular and cerebrovascular diseases, respiratory and digestive diseases are the main causes of acute critical diseases in department of emergency of Xuanwu Hospital Capital Medical University in 2017. Male and elderly patients are more common; different types of acute and severe patients tend to attack at different ages. PMID- 30439325 TI - [Study on the protective effect of ligustrazine on the transporting function of hepatocellular mitochondria membrane in the septic rats]. AB - OBJECTIVE: To investigate the protective effect of ligustrazine on the transporting function of hepatocellular mitochondria membrane in the rats with sepsis-induced acute liver injury (SALI). METHODS: The Sprague-Dawley (SD) rats were randomly divided into sham operation group, SALI group [established by cecal ligation and puncture (CLP)], ligustrazine treatment group (injection of ligustrazine 60 mg/kg through tail vein after CLP) and ligustrazine preventive group (7 days before CLP, ligustrazine was injected daily through tail vein for 60 mg/kg), and there were 12 rats in each group. Abdominal aorta blood and liver were harvested at 10 hours after operation. The content of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and mitochondrial aspartate aminotransferase (m-AST) were determined by enzyme coupling rate method. The content of ATP was detected by colorimetric and chemical fluorescein method. The activity of mitochondrial ATPase was detected by phosphorus quantification. The expressions of mitochondrial membrane aquaporin 8 (AQP8) and carnitine palmitoyl transferase (CPT) were detected by Western Blot. RESULTS: Compared with sham operation group, the levels of serum ALT, AST and m-AST were significantly increased in SALI group, ligustrazine treatment group and ligustrazine preventive group, and the content of ATP was reduced, the activity of mitochondrial membrane ATPase, the expressions of AQP8 and CPT-1A were significantly decreased. Compared with SALI group, the levels of serum ALT, AST and m-AST were significantly decreased in ligustrazine treatment and ligustrazine preventive groups [ALT (U/L): 123.8+/-32.8, 105.0+/-44.5 vs. 233.0+/-110.1; AST (U/L): 427.0+/-117.9, 303.9+/-110.3 vs. 742.6+/-441.4; m-AST (U/L): 239.6+/-64.9, 168.2+/-60.0 vs. 412.8+/-252.6; all P < 0.01], the content of ATP were significantly increased (nmol/mg: 29.5+/-10.3, 34.6+/-11.2 vs. 19.3+/-8.8, both P < 0.01), the activity of ATPase in hepatocellular mitochondrial membrane were significantly increased [Na+-K+-ATPase (U/mg): 3.91+/-0.30, 3.97+/-0.35 vs. 2.87+/-0.82; Mg2+-ATPase (U/mg): 3.75+/-0.38, 3.88+/-0.35 vs. 2.64+/-1.06; Ca2+ ATPase (U/mg): 3.15+/-0.58, 2.98+/-0.31 vs. 1.75+/-1.25; Ca2+-Mg2+-ATPase (U/mg): 3.82+/-0.31, 3.91+/-0.42 vs. 2.57+/-1.01, all P < 0.01], the expressions of AQP8 and CPT-1A were significantly increased [percentage increase from sham operation group (100%), AQP8/COX-IV: (79.12+/-7.79)%, (88.40+/-9.22)% vs. (62.08+/-11.91)%; CPT-1A/COX-IV: (87.92+/-10.06)%, (84.91+/-17.48)% vs. (72.11+/-7.82)%, all P < 0.01]. The levels of serum AST and m-AST in ligustrazine preventive group were significant lower than those in ligustrazine treatment group [AST (U/L): 303.9+/ 110.3 vs. 427.0+/-117.9; m-AST (U/L): 168.2+/-60.0 vs. 239.6+/-64.9, both P < 0.05]. There was no significant difference in the expression of CPT-2 in mitochondrial membrane between the four groups. CONCLUSIONS: Ligustrazine could play a protective role on the mitochondrial membrane function of transporting water, ion and fat in the rats with SALI. The preventive function of ligustrazine is better than the treatment effect of the rats with sepsis. PMID- 30439324 TI - [Research on the intervention of Yishen Huoxue prescription to renal fibrosis through the signal regulation by microRNA-126 to VEGF-Notch]. AB - OBJECTIVE: To explore the molecular mechanism of Yishen Huoxue prescription in delaying the development of renal fibrosis by regulating the microRNA 126/vascular endothelial growth factor-Notch (miR-126/VEGF-Notch) signaling pathway. METHODS: Ninety male Sprague-Dawley (SD) rats were randomly divided into sham operation group (sham group), unilateral ureteral obstruction (UUO) model group, losartan group (50 mg*kg-1*d-1) and high, medium and low doses Yishen Huoxue prescription group (25.2, 12.6, 6.3 mL/kg). Each treatment group began to administer drugs by gavage on the day when UUO modeling was finished until the end of the experiment. Left renal tissues of rats were harvested after 7, 14 and 21 days postoperatively. The pathological changes of renal tissue were observed after hematoxylin and eosin (HE) and Masson staining under the microscope, and the renal fibrosis score was calculated. The mRNA expressions of renal tissues miR-126, VEGFA, vascular endothelial growth factor receptor-2 (VEGFR-2), Notch1 were detected by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: (1) Pathology results: the kidney tissue of sham group was normal. In UUO model group, renal tubules expanded and inflammatory cells in renal interstitium increased; renal tubulointerstitial fibrosis could be seen 7 days after operation, and the degree of fibrosis was gradually increased with time. The renal fibrosis score at each time point after operation in UUO model group was significantly higher than that in sham group. Compared with UUO model group, each treatment group were improved the degree of renal swelling and atrophy of renal parenchyma; the score of renal fibrosis were significantly decreased in the middle and high doses Yishen Huoxue prescription group and losartan group at the 7th day after operation (1.00+/-1.00, 0.91+/-0.58, 1.01+/-0.58 vs. 2.00+/-0.00, all P < 0.01); but there was no significant difference between low dose Yishen Huoxue prescription group and UUO model group. (2) RT-PCR results: Compared with sham group, the mRNA expressions of miR-126, VEGFA, VEGFR-2 and Notch1 in renal tissues were significantly increased at each time point after operation in UUO model group. Compared with the UUO model group, the mRNA expressions of miR-126, VEGFA, VEGFR-2 and Notch1 in renal tissue of 7 days postoperatively in the middle and high doses Yishen Huoxue prescription group and the losartan group were significantly increased [miR-126 (2-DeltaDeltaCt): 0.465+/-0.067, 0.639+/-0.092, 0.404+/-0.069 vs. 0.132+/-0.021; VEGFA (2-DeltaDeltaCt): 0.024+/-0.005, 0.027+/ 0.007, 0.023+/-0.006 vs. 0.014+/-0.006; VEGFR-2 (2-DeltaDeltaCt): 0.021+/-0.007, 0.023+/-0.008, 0.019+/-0.007 vs. 0.012+/-0.004; Notch1 (2-DeltaDeltaCt): 0.017+/ 0.004, 0.020+/-0.005, 0.018+/-0.005 vs. 0.007+/-0.004; all P < 0.05]; compared with the losartan group, the mRNA expressions of each index in the middle and high doses Yishen Huoxue prescription group were increased at all the time points, but there was no significant difference between them (all P > 0.05). There was no significant difference in mRNA expression of each index between low dose Yishen Huoxue prescription group and UUO model group. CONCLUSIONS: The medium and high doses of Yishen Huoxue prescription can effectively antagonize renal fibrosis. Yishen Huoxue prescription may use up-regulation the signaling pathways of miR-126/VEGF-Notch to mediate renal microvascular newly born, eventually to improve renal microvascular damage and delay the development of renal fibrosis progression. PMID- 30439326 TI - [Effect of heme oxygenase-1 on the apoptosis of type II alveolar epithelial cells in rats with hyperoxia-induced acute lung injury]. AB - OBJECTIVE: To investigate the effect of heme oxygenase-1 (HO-1) on the apoptosis of type II alveolar epithelial cells (AEC-II) in rats with hyperoxia-induced acute lung injury (HALI). METHODS: Twenty-four healthy male Sprague-Dawley (SD) rats were randomly divided into 4 groups (n = 6): control group, HALI group, HO-1 group, and HO-1 inhibition group. The control group was fed in the room air; the HALI group was fed in the hyperoxia box (the oxygen concentration was more than 90%, the temperature was kept at 25-27 centigrade, the humidity was maintained at 50%-70%, and the CO2 concentration was less than 0.5%); the HO-1 group was fed in the hyperoxia box after HO-1 (0.2 MUmol/L) treatment; and the HO-1 inhibition group was fed in the hyperoxia box after treatment with zinc protoporphyrin IX (20 MUmol/L). After 48 hours of hyperoxia treatment, rats were sacrificed, left upper lung tissue was stained with hematoxylin-eosin (HE) and the pathological changes of lung tissue were observed under light microscope. The ratio of wet/dry weight (W/D) was measured in the lower left lung. AEC II was extracted from the right lung tissue, the apoptosis rate was detected by flow cytometry, and the expressions of apoptosis-related proteins Bcl-2 and caspase-3 were detected by Western Blot. RESULTS: (1) It was shown by light microscopy that the lung tissue structure of the control group was clear. In HALI group and HO-1 inhibitor group, the lung tissue structure was disordered, alveolar wall was broken and fused into pulmonary alveoli, alveolar septum was obviously swollen and widened, a large number of inflammatory cells infiltrated, and edema fluid and inflammatory cells appeared in alveolar cavity. The pathological changes of lung tissue in HO-1 group were significantly less than those in HALI group. (2) Compared with the control group, the lung W/D ratio, the apoptosis rate of AEC II and the expression of Bcl-2 protein in the HALI group and the HO-1 inhibitor group were significantly increased, and the expression of caspase-3 was significantly decreased [lung W/D ratio: 4.61+/-0.41 vs. 3.68+/-0.45, apoptosis rate of AEC II: (42.44+/-0.93)% vs. (24.74+/-0.64)%, Bcl-2 (integral absorbance): 0.72+/-0.18 vs. 0.41+/-0.12, caspase-3 (integral absorbance): 1.32+/-0.32 vs. 1.81+/-0.69, all P < 0.05]. Compared with the HALI group, the lung W/D ratio, the apoptosis rate of AEC II, the expression of Bcl-2 protein in HO-1 group were significantly decreased, and the expression of caspase-3 was significantly increased [lung W/D ratio: 3.82+/-0.28 vs. 4.61+/-0.41, apoptosis rate of AEC II: (26.67+/-1.58)% vs. (42.44+/-0.93)%, Bcl-2 (integral absorbance): 0.39+/-0.08 vs. 0.72+/-0.18, caspase-3 (integral absorbance): 1.78+/-0.46 vs. 1.32+/-0.32, all P < 0.05]. There was no significant difference between HO-1 inhibitor group and HALI group. CONCLUSIONS: HO-1 can reduce the apoptosis rate of AEC II in rats with HALI, which may be related to the expressions of apoptosis related proteins Bcl-2 and caspase-3. PMID- 30439327 TI - [Advances in pre-hospital recognition and cooling treatment of exertional heat stroke]. AB - OBJECTIVE: Heat stroke (HS) is a life-threatening illness characterized by an altered level of consciousness with an elevated core body temperature 40 centigrade, which may be further classified as exertional heat stroke (EHS) or classical heat stroke (CHS) according to the etiology of the condition. In recent years, the morbidity of EHS increases year by year. The severity and clinical outcome for an EHS casualty have a strong correlation with the area under the time and temperature curve for heat exposure. The early recognition and rapid cooling body core temperature <= 38.9 centigrade within 30 minutes of EHS results in the best clinical outcome and minimize severe multiple organ dysfunction and death for patients. Cold water immersion (CWI) is considered as an optimum cooling method for the reversal of hyperthermia in EHS. Some alternative modalities have also shown acceptable cooling rate, for example, the subjects immersed in a circulated water bath controlled below 20 centigrade, tarp-assisted cooling with oscillation, body cooling unit, undressed, air-conditioned room, the whole body and large vessels placed ice packs, massaging the extremities; cold intravenous saline applied to dehydrated one. It is necessary to monitor body core temperature for hypothermia and/or recurrent hyperthermia, and to provide physical care for shivering, agitation, or concerns with the potential discomfort combativeness that may occur during cooling process. In this paper, pre-hospital recognition, care, monitoring and rapid cooling treatment measures of EHS have been reviewed to provide references for early identification of EHS and scientific, reasonable and effective cooling treatment. PMID- 30439328 TI - Corrigendum to "Cannabinoid Receptor Agonists Reduce the Short-Term Mitochondrial Dysfunction and Oxidative Stress Linked to Excitotoxicity in the Rat Brain" [Neuroscience 285C (2015) 97-106]. PMID- 30439329 TI - Ankylosis of the Coronoid Process to the Zygomatic Bone: A Case Report and Review of the Literature. AB - PURPOSE: Extra-articular temporomandibular bony ankylosis between the zygomatic bone and coronoid process is a rare condition. Currently, there are fewer than 40 cases reported in the English-language literature. The aim of this study was to report a case of zygomatico-coronoid ankylosis with surgical intervention and a literature review. MATERIALS AND METHODS: Through a PubMed search from 1946 to February 2018, using the terms ("extra-capsular" OR "zygomatico-coronoid" OR "extra-articular") AND ("ankylosis"), 61 articles were initially identified. After screening, manual reviewing, and including additional articles through reviews of the reference lists, 26 reports (33 patients) were included in the analysis. RESULTS: Patients' age ranged from 12 to 71 years (mean, 36.62 yr; standard deviation, 16.24 yr). The gender composition of patients was male (n = 20; 60.6%), female (n = 12; 36.4%), and unknown (n = 1; 0.3%), with a clear male predominance. The etiologies were trauma (n = 25; 75.8%), infection (n = 3; 9.1%), surgical complication (n = 4; 12.1%), and radiotherapy for maxillary cancer (squamous cell carcinoma; n = 1; 3.0%). The treatment options were surgical intervention through an intraoral approach (n = 19; 57.6%), an extraoral approach (n = 10; 30.3%), and intraoral and extraoral approaches (n = 2; 6.1%) and nonsurgical intervention (n = 2; 6.1%). CONCLUSION: Zygomatico-coronoid ankylosis is a possible cause of mouth-opening limitation, particularly in relation to facial trauma. However, it can be easily overlooked because of the rarity of zygomatico-coronoid ankylosis and the attention focused on the joint. Surgical intervention is regarded as a good treatment to improve mouth-opening limitation. PMID- 30439330 TI - Three-Dimensional Analysis of Transverse Width of Hard Tissue and Soft Tissue After Mandibular Setback Surgery Using Intraoral Vertical Ramus Osteotomy: A Retrospective Study. AB - PURPOSE: Some clinicians are concerned that if an intraoral vertical ramus osteotomy (IVRO) is used to position the mandible posteriorly, the proximal segments should be positioned laterally to the distal segment, which could increase the transverse mandibular width, leading to esthetically unfavorable results. This study investigated short- and long-term postoperative transverse mandibular width changes in the soft and hard tissue after IVRO for mandibular prognathism. MATERIALS AND METHODS: The study comprised 44 patients who were treated with mandibular setback surgery using an IVRO. They were categorized into either the facial symmetry group or facial asymmetry group based on their preoperative levels of chin top deviation. Three-dimensional cone-beam computed tomography images were obtained at the preoperative, 1-month postoperative, and 12-month postoperative stages, designated as T1, T2, and T3, respectively. We set hard tissue width 1 (HW1) and hard tissue width 2 (HW2) as the sum of the distance at the bilateral ends of the angle and ramus, respectively, and set soft tissue width 1 (SW1) and soft tissue width 2 (SW2) as the sum of the distance at the bilateral ends of the soft tissue angle and ramus, respectively. RESULTS: Compared with the value at T1, the HW1 value increased by 8.16% (P < .05) and HW2 increased by 4.39% (P > .05) at T2; HW1 increased by 4.35% (P < .05) and HW2 increased by 2.95% (P > .05) at T3. Compared with the value at T1, the SW1 value increased by 2.49% and SW2 increased by 2.50% at T2; however, SW1 decreased by 0.85% and SW2 increased by 0.37% at T3. The soft tissue variations between T1 and T2, as well as between T2 and T3, were statistically significant. However, no significant difference was found between T1 and T3 (P > .05). No difference between the facially symmetrical and asymmetrical groups was found over time for soft and hard tissues (P > .05). CONCLUSIONS: Notably, IVRO does not seem to impact the transverse facial profile and enables reliable prediction of the esthetic results of surgery. PMID- 30439331 TI - Long-Term Stability of Condylectomy and Costochondral Graft Reconstruction for Treatment of Idiopathic Condylar Resorption. AB - PURPOSE: To assess and update long-term outcomes of endoscopic condylectomy and costochondral graft (CCG) reconstruction for treatment of active idiopathic condylar resorption (ICR). PATIENTS AND METHODS: This study is a continuation of a retrospective cohort study of patients with active ICR who underwent bilateral condylectomies and CCG reconstruction from 1999 to 2016. Predictor variables were demographic and operative factors. The primary outcome variable was occlusal stability, as defined by normal overbite (1 to 4 mm) at latest follow-up. Overbite; overjet; the angle formed by the sella, nasion, and B point (SNB); mandibular plane angle; and ramus-and-condyle unit height were measured. Time points were preoperative (T0) and immediate (T1), 1 year (T2), 2 years (T3), 3 to 5 years (T4), and at least 5 years (T5) postoperative. Descriptive and bivariate statistics were computed. A Firth logistic regression model was used to identify variables associated with occlusal instability. RESULTS: Twenty-six patients (25 female; mean age, 23.1 yr) who underwent bilateral endoscopic condylectomies and CCG reconstruction were included: 14 from the original cohort and 12 additional patients for the present analysis. Median follow-up was 3.65 years (range, 1.11 to 17.1 yr). Preoperatively, all patients had a Class II malocclusion with a mean overjet of 6.89 mm (range, 1.2 to 17.1 mm) and a mean anterior open bite of -2.12 mm (range, -0.4 to -7.9 mm). Normal overbite (1 to 4 mm) and overjet (2 to 4 mm) were achieved postoperatively in all patients. There were no significant changes in overjet, overbite, SNB, mandibular plane angle, and ramus-and-condyle unit height from T1 to T4. At latest follow-up, 88.5% of patients had a normal overbite. Three patients developed an anterior open bite postoperatively: 1 at 2 years (0.1 mm; preoperative, -3.4), 1 at 9 years (-0.8 mm; preoperative -7.9), and 1 at 11 years (-1.3 mm; preoperative -1.1). Subjects at T5 (n = 9 of 26) had mean overjet and overbite of 3.48 and 1.56 mm, respectively. Non-white race and follow-up time were significant predictors of occlusal instability in the regression model. CONCLUSIONS: Stable and predictable long-term outcomes can be achieved using endoscopic condylectomy and CCG reconstruction for treatment of active ICR. PMID- 30439332 TI - Retinal signs and risk of incident dementia in the Atherosclerosis Risk in Communities study. AB - INTRODUCTION: The easily-imaged retinal microvasculature may reflect the brain microvasculature and therefore be related to dementia. METHODS: In a population based study of 12,482 adults aged 50-73 years (22% African American), we estimated the relationship of retinal characteristics from fundus photography (1993-1995) with incident all-cause dementia (1993-1995 to 2011-2013) and with etiologic subtype of dementia/mild cognitive impairment (2011-13). RESULTS: A total of 1259 (10%) participants developed dementia over a mean 15.6 years. Moderate/severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% confidence interval [CI]: 1.36-2.55) and central retinal arteriolar equivalent (narrowest quartile vs. widest three quartiles; HR, 1.26; 95% CI: 1.09-1.45) were associated with all-cause dementia. Results were qualitatively stronger (but not statistically significantly different) in participants with diabetes. Retinopathy was associated with a joint outcome of cerebrovascular-related, but not Alzheimer's disease-related, dementia/mild cognitive impairment (HR, 2.29; 95% CI: 1.24-4.23). DISCUSSION: Exploration of measures in the eye may provide surrogate indices of microvascular lesions relevant to dementia. PMID- 30439334 TI - Extracellular Electron Transfer Transcends Microbe-Mineral Interactions. AB - Extracellular electron transfer (EET) allows microbes to drive their metabolism through interactions with minerals or electrodes. In recent work, Light et al. (2018) discover a specialized EET pathway in Listeria monocytogenes with homologs in pathogens and gut commensals, suggesting that EET plays important roles in diverse environments. PMID- 30439333 TI - A signature pattern of cortical atrophy in dementia with Lewy bodies: A study on 333 patients from the European DLB consortium. AB - INTRODUCTION: We explored regional brain atrophy patterns and their clinical correlates in dementia with Lewy bodies (DLB). METHODS: In this multicentre study, we included a total of 333 patients with DLB, 352 patients with Alzheimer's disease (AD), and 233 normal controls and used medial temporal lobe atrophy, posterior atrophy, and frontal atrophy (GCA-F) visual rating scales. Patients were classified according to four atrophy patterns. RESULTS: Patients with DLB had higher scores on all the three atrophy scales than healthy controls but had less medial temporal lobe atrophy than those with AD (all P-values < .001). A signature hippocampal-sparing pattern of regional atrophy was observed in DLB. The magnetic resonance imaging measures showed 65% ability to discriminate between DLB and AD and marginally contributed to the discrimination over and above the core clinical features. DISCUSSION: The most common pattern of atrophy of DLB was hippocampal-sparing. Future studies should explore whether comorbid AD pathology underlies the atrophy patterns seen in DLB. PMID- 30439335 TI - Sex Bias in Sepsis. AB - Though critical for preventing fatal sepsis, the mechanisms mediating the capture of bloodstream bacteria are incompletely understood. New work by Zeng et al. (2018) demonstrates that estrogen-regulated innate antibodies protect females and newborns from death following bloodstream infection with enteropathogenic Eschericia coli. PMID- 30439336 TI - MDVs: Spare the SOD and Spoil the Bug. AB - Mitochondrial reactive oxygen species are important anti-microbial weapons utilized by phagocytes of the innate immune system. In this issue of Cell Host and Microbe, Abuaita et al. (2018) show that in macrophages, mitochondrial derived vesicles deliver the superoxide dismutase Sod2 to bacteria-containing phagosomes to produce hydrogen peroxide and kill invading bacteria. PMID- 30439337 TI - A pLOT of Viral Persistence. AB - In this issue of Cell Host & Microbe, Bouziat et al. (2018) and Van Winkle et al. (2018) find that the capsid gene of murine norovirus (MNV) functions as a trigger of host inflammation. These studies specifically describe how MNV-induced inflammation promotes loss of oral tolerance and persistent viral infection, respectively. PMID- 30439338 TI - Hepatitis C Virus Neutralizing Antibodies: Is a Vaccine Still Possible? AB - Many hurdles have plagued the development of an effective vaccine for hepatitis C virus. In this issue of Cell Host & Microbe, Kinchen et al. (2018) and Flyak et al. (2018) report on the characterization of neutralizing antibodies from individuals that spontaneously cleared infection, providing insights that promise to propel vaccine design forward. PMID- 30439339 TI - Cross-Reactive Flavivirus Antibody: Friend and Foe? AB - The introduction of Zika virus (ZIKV) into the Americas sparked interest in the influence of heterologous antibodies on sequential ZIKV and dengue virus (DENV) infections. In this issue of Cell Host & Microbe, Fowler et al. (2018) demonstrate in mice that maternally acquired anti-ZIKV antibodies exacerbate disease following DENV challenge. PMID- 30439340 TI - HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design. AB - Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74 like germline precursors may represent candidate vaccine immunogens. PMID- 30439341 TI - Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection. AB - The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains. Acquisition of resistance to bNAbs by some autologous strains was accompanied by progressive loss of E2 protein function, and temporally associated with HCV clearance. These data demonstrate that bNAbs can mediate clearance of human HCV infection by neutralizing infecting strains and driving escaped viruses to an unfit state. These immunopathologic events distinguish HCV from HIV-1 and suggest that development of an HCV vaccine may be achievable. PMID- 30439342 TI - Cross-Reactive Dengue Virus Antibodies Augment Zika Virus Infection of Human Placental Macrophages. AB - Zika virus (ZIKV), which emerged in regions endemic to dengue virus (DENV), is vertically transmitted and results in adverse pregnancy outcomes. Antibodies to DENV can cross-react with ZIKV, but whether these antibodies influence ZIKV vertical transmission remains unclear. Here, we find that DENV antibodies increase ZIKV infection of placental macrophages (Hofbauer cells [HCs]) from 10% to over 80% and enhance infection of human placental explants. ZIKV-anti-DENV antibody complexes increase viral binding and entry into HCs but also result in blunted type I interferon, pro-inflammatory cytokine, and antiviral responses. Additionally, ZIKV infection of HCs and human placental explants is enhanced in an immunoglobulin G subclass-dependent manner, and targeting FcRn reduces ZIKV replication in human placental explants. Collectively, these findings support a role for pre-existing DENV antibodies in enhancement of ZIKV infection of select placental cell types and indicate that pre-existing immunity to DENV should be considered when addressing ZIKV vertical transmission. PMID- 30439344 TI - Diversity and biting patterns of Anopheles species in a malaria endemic area, Umphang Valley, Tak Province, western Thailand. AB - Malaria is highly endemic in Umphang Valley, a district in the western edge of Tak Province, along the boundary with Kayin State of Myanmar. Although there are high indigenous malaria cases in this area every year, nothing about malaria vectors and their transmission role have been investigated before this study. The objective of this work is to characterize the Anopheles species diversity and trophic behavior of malaria vectors in the transmission area of Umphang Valley. Females of Anopheles mosquitoes were collected every two months during a two-year period. Mosquito collections were using standard collection technique, indoor and outdoor human landing collections and outdoor cattle bait collection. Anopheles mosquitoes were identified using morphological characters and multiplex AS-PCR assay for the identification of sibling species within groups and complexes present. From a total of 16,468 Anopheles females, 2723 specimens (16.54%) were collected from humans and 13,745 specimens (83.46%) were captured from cattle. From human landing collections, 2447 specimens (89.86%) of Anopheles minimus were obtained, followed by 119 Anopheles peditaeniatus (4.37%), 62 Anopheles maculatus (2.28%), 17 Anopheles dirus (0.6%), 15 Anopheles aconitus (0.5%) and 6 Anopheles sawadwongporni (0.2%) respectively. Seven putative malaria vectors, including An. minimus, An. dirus, An. baimaii, An. sawadwongporni, An. maculatus, An. pseudowillmori and An. aconitus were documented from this study and trophic behavior of each respective species were observed. Such information is definitely crucial for defining the vector capacity of each single species and for designing appropriate vector prevention and control strategies against target vector species. PMID- 30439343 TI - Maternally Acquired Zika Antibodies Enhance Dengue Disease Severity in Mice. AB - Antibody (Ab)-dependent enhancement can exacerbate dengue virus (DENV) infection due to cross-reactive Abs from an initial DENV infection, facilitating replication of a second DENV. Zika virus (ZIKV) emerged in DENV-endemic areas, raising questions about whether existing immunity could affect these related flaviviruses. We show that mice born with circulating maternal Abs against ZIKV develop severe disease upon DENV infection. Compared with pups of naive mothers, those born to ZIKV-immune mice lacking type I interferon receptor in myeloid cells (LysMCre+Ifnar1fl/fl) exhibit heightened disease and viremia upon DENV infection. Passive transfer of IgG isolated from mice born to ZIKV-immune mothers resulted in increased viremia in naive recipient mice. Treatment with Abs blocking inflammatory cytokine tumor necrosis factor linked to DENV disease or Abs blocking DENV entry improved survival of DENV-infected mice born to ZIKV immune mothers. Thus, the maternal Ab response to ZIKV infection or vaccination might predispose to severe dengue disease in infants. PMID- 30439345 TI - Comparing vector competence of Mepraia gajardoi and Triatoma infestans by genotyping Trypanosoma cruzi discrete typing units present in naturally infected Octodon degus. AB - Chagas disease is a vector-borne disease caused by the parasite Trypanosoma cruzi, and transmitted by triatomine insects to several mammal species. In Chile, the wild triatomine species are the endemic Mepraia species, and the only domestic vector of Chagas disease is Triatoma infestans. The aim of this study was to determine the competence of M. gajardoi compared to T. infestans as a T. cruzi vector using the naturally infected rodent Octodon degus. M. gajardoi amplified T. cruzi present in all O. degus studied while T. infestans only in half of the infected rodents. Both triatomine species excrete metacyclic trypomastigotes and amplified the same three T. cruzi DTUs, however, M. gajardoi showed differences in their ability to amplify TcI. TcV and TcVI had the same probability to be amplified by both triatomine species. Both species amplified mixed infections, with TcI-TcVI as the most represented. This study reports the higher vector competence of M. gajardoi in comparison to T. infestans. PMID- 30439346 TI - Natural Trypanosoma (Trypanozoon) evansi (Steel, 1885) infection among mammals from Brazilian Amazon. AB - Trypanosoma evansi (Kinetoplastea Trypanosomatidae) is the Trypanosoma species that infects the greatest variety of mammals worldwide. In 2014, a dog from Rio Branco/AC, in the Brazilian Amazon region, presented flagellates without evident kinetoplasts in blood and symptoms of T. evansi infection. Our aim was to investigate the occurrence of T. evansi in dogs, bats and capybaras from Rio Branco. Blood was collected from 78 dogs from residential areas near the Zoobotanical Park (PZ). The serological diagnosis by IFAT detected the presence of anti-T. evansi antibodies in 21.9% of the evaluated dogs. T. evansi DNA was detected in one dog using a higly specific target of a repeated monomer of the satellite DNA of Trypanosoma (Trypanozoon) sp. Molecular diagnosis was also performed on 182 bat spleen samples collected inside PZ, and one Carollia perspicillata was positive. The DNA sequences obtained from these two samples showed similarities with T. brucei satellite DNA. Anti-T. evansi IFAT was carried out in 46 capybaras from rural and urban areas and the infection detected in 17.4% of them. We confirmed for the first time the presence of T. evansi in Acre State and describe three putative host species involved in the parasite transmission in that Amazon region. Moreover, this is the first study that confirms the infection by T. evansi through DNA sequence analysis in the Brazilian Amazon Region. PMID- 30439347 TI - Virulence of Trypanosoma cruzi from vector and reservoir in in natura acai pulp resulting in food-borne acute Chagas disease at Para State, Brazil. AB - BACKGROUND: In recent decades some outbreaks of food-borne acute Chagas disease (ACD) in humans were identified by clinical and epidemiological characterization after association through the ingestion of acai pulp probably contaminated with Trypanosoma cruzi. Whereas Belem and Abaetetuba stood out as important risk regions for disease transmission, the importance of Rhodnius pictipes, and Philander opossum for the biological cycle of T. cruzi, and data from agribusiness market of acai, to study T. cruzi from vector and reservoir of the Brazilian Amazon region is critical for this context. Thus, the purpose of this study was to verify the infective capacity and the virulence of T. cruzi in acai pulp from vector and reservoir at Para State experimentally. METHODS: 105T. cruzi I in in natura acai pulp from Belem at Para State, at room temperature, after forced sieving, by intraperitoneal, gavage or oral route of inoculation in B6.129S7Rag1-/-tmMom/J Unib allowed food-borne ACD analysis using common light microscopy. PRINCIPAL FINDINGS: T. cruzi in in natura acai pulp from R. pictipes (Val-De-Cans Forest, Belem, and Ajuai River, Abaetetuba, Para), and P. opossum (Combu Island, Belem, Para) caused ACD and death between 17 and 52 days after experimental infections in murine immunodeficient hosts. CONCLUSIONS: T. cruzi from different sources and locations at Para State in in natura acai pulp retained its infective capacity and virulence, and can cause new outbreaks of ACD by oral transmission. Additionally, quality basic education will facilitate efficient hygiene practices throughout the acai productive chain can eradicate food-borne ACD in the coming decades. PMID- 30439348 TI - STAT3 signaling maintains homeostasis through a barrier function and cell survival in corneal endothelial cells. AB - The cornea protects the eye from inflammation, which is one of the leading causes of blindness. Severe inflammation in the anterior chamber disrupts the barrier function of corneal endothelial cells (CECs) leading to severe visual loss. However, the mechanism by which such inflammation affects CEC function and survival is unknown. Activation of STAT3 signaling regulates various intracellular responses through inflammation and generally mediates expression of the barrier function marker zonula occludens-1 (ZO-1). In this study, we investigated the relationship between the corneal endothelial barrier function and activation of STAT3 signaling through a variety of cytokines in human CECs. Phosphorylated STAT3 (pSTAT3) was expressed in human and mouse CECs. Inhibition of pSTAT3 remarkably decreased the expression of the ZO-1 protein, reduced the trans-endothelial electric resistance, and induced cell apoptosis. The expression level of ZO-1 mRNA was correlated with that of STAT3 mRNA in the human corneal endothelium. pSTAT3 was increased with the addition of LIF, IL-6, and IFN-gamma. LIF expressed in CECs suppressed pSTAT3 activation as observed experimentally using an anti-LIF antibody. Promoter regions of ZO-1 and SOCS3 were directly regulated by transcriptional activation of STAT3. These findings suggest that regulation of the STAT3 pathway is essential for corneal endothelial homeostasis via barrier function and may protect from various inflammatory factors. PMID- 30439349 TI - MEK/ERK/1/2 sensitive vascular changes coincide with retinal functional deficit, following transient ophthalmic artery occlusion. AB - Retinal ischemia remains a major cause of blindness in the world with few acute treatments available. Recent emphasis on retinal vasculature and the ophthalmic artery's vascular properties after ischemia has shown an increase in vasoconstrictive functionality, as previously observed in cerebral arteries following stroke. Specifically, endothelin-1 (ET-1) receptor-mediated vasoconstriction regulated by the MEK/ERK1/2 pathway. In this study, the ophthalmic artery of rats was occluded for 2 h with the middle cerebral artery occlusion model. MEK/ERK1/2 inhibitor U0126 was administered at 0, 6, and 24 h following reperfusion and the functional properties of the ophthalmic artery were evaluated at 48 h post reperfusion. Additionally, retinal function was evaluated at day 1, 4, and 7 after reperfusion. Occlusion of the ophthalmic artery led to a significant increase of endothelin-1 mediated vasoconstriction which can be attenuated by U0126 treatment, most evident at higher ET-1 concentrations of 10-7 M (Emax151.0 +/- 22.0% of 60 mM K+), vs non-treated ischemic arteries Emax 212.1 +/- 14.7% of 60 mM K+). Retinal function also deteriorated following ischemia and was improved with treatment with a-wave amplitudes of 725 +/- 36 MUV in control, 560 +/- 21 MUV in non-treated, and 668 +/- 73 MUV in U0126 treated at 2 log cd*s/m2 luminance in the acute stages (1 days post-ischemia). Full spontaneous retinal recovery was observed at day 7 regardless of treatment. In conclusion, this is the first study to show a beneficial in vivo effect of U0126 on vascular contractility following ischemia in the ophthalmic artery. Coupled with the knowledge obtained from cerebral vasculature, these results point towards a novel therapeutic approach following ischemia-related injuries to the eye. PMID- 30439350 TI - TKS5-positive invadopodia-like structures in human tumor surgical specimens. AB - Invadopodia, cancer cell protrusions with proteolytic activity, are functionally associated with active remodeling of the extracellular matrix. Here, we show that the invadopodia-related protein TKS5 is expressed in human pancreatic adenocarcinoma lines, and demonstrate that pancreatic cancer cells depend on TKS5 for invadopodia formation and function. Immunofluorescence staining of human pancreatic cancer cells reveals that TKS5 is a marker of mature and immature invadopodia. We also analyze the co-staining patterns of TKS5 and the commonly used invadopodia marker Cortactin, and find only partial co-localization of these two proteins at invadopodia, with a large fraction of TKS5-positive invadopodia lacking detectable levels of Cortactin. Whereas compelling evidence exist on the role of invadopodia as mediators of invasive migration in cultured cells and in animal models of cancer, these structures have never been detected inside human tumors. Here, using antibodies against TKS5 and Cortactin, we describe for the first time structures strongly resembling invadopodia in various paraffin embedded human tumor surgical specimens from pancreas and other organs. Our results strongly suggest that invadopodia are present inside human tumors, and warrants further investigation on their regulation and occurrence in surgical specimens, and on the value of TKS5 antibodies as pathological research and diagnostic tools. PMID- 30439351 TI - Effects of speech rate, preview time of visual context, and participant instructions reveal strong limits on prediction in language processing. AB - There is a consensus among language researchers that people can predict upcoming language. But do people always predict when comprehending language? Notions that "brains ... are essentially prediction machines" certainly suggest so. In three eye-tracking experiments we tested this view. Participants listened to simple Dutch sentences ('Look at the displayed bicycle') while viewing four objects (a target, e.g. a bicycle, and three unrelated distractors). We used the identical visual stimuli and the same spoken sentences but varied speech rates, preview time, and participant instructions. Target nouns were preceded by definite gender marked determiners, which allowed participants to predict the target object because only the targets but not the distractors agreed in gender with the determiner. In Experiment 1, participants had four seconds preview and sentences were presented either in a slow or a normal speech rate. Participants predicted the targets as soon as they heard the determiner in both conditions. Experiment 2 was identical except that participants were given only a one second preview. Participants predicted the targets only in the slow speech condition. Experiment 3 was identical to Experiment 2 except that participants were explicitly told to predict. This led only to a small prediction effect in the normal speech condition. Thus, a normal speech rate only afforded prediction if participants had an extensive preview. Even the explicit instruction to predict the target resulted in only a small anticipation effect with a normal speech rate and a short preview. These findings are problematic for theoretical proposals that assume that prediction pervades cognition. PMID- 30439352 TI - Activity-dependent development of GABAergic synapses. AB - In the brain, dendrites of pyramidal neurons contain intermingled excitatory and inhibitory synapses. Synaptic connections dynamically change during development and throughout our lifetime, yet the brain can properly maintain an optimal ratio of synaptic excitation to inhibition. Despite recent advances in our understanding of the formation and refinement of excitatory glutamatergic synapses, little is known about signals that regulate inhibitory GABAergic synapse development. In this review, we discuss previous and recent insights in the cellular and molecular mechanisms that underlie GABAergic synapse formation and plasticity, with a specific focus on the key roles of synaptic activity and postsynaptic membrane molecules. PMID- 30439353 TI - Frank Beach award winner: Neuroendocrinology of group living. AB - Why do members of some species live in groups while others are solitary? Group living (sociality) has often been studied from an evolutionary perspective, but less is known about the neurobiology of affiliation outside the realms of mating and parenting. Colonial species offer a valuable opportunity to study nonsexual affiliative behavior between adult peers. Meadow voles (Microtus pennsylvanicus) display environmentally induced variation in social behavior, maintaining exclusive territories in summer months, but living in social groups in winter. Research on peer relationships in female meadow voles demonstrates that these selective preferences are mediated differently than mate relationships in socially monogamous prairie voles, but are also impacted by oxytocin and HPA axis signaling. This review addresses day-length dependent variation in physiology and behavior, and presents the current understanding of the mechanisms supporting selective social relationships in meadow voles, with connections to lessons from other species. PMID- 30439354 TI - The right blood collection tube for therapeutic drug monitoring and toxicology screening procedures: Standard tubes, gel or mechanical separator? AB - Stability data of toxics or drugs in gel-based or mechanical separation blood collection tubes are lacking, especially for therapeutic drug monitoring and clinical toxicology procedures. According to ISO 15189 accreditation standard, laboratories need to master the entire preanalytical process including the stability of analytes in a specific tube. Here we explored the impact of BD PSTTM II and BarricorTM separator tubes on the stability of 167 therapeutic compounds and common drugs of abuse in plasma samples using LC-MS/MS. Forty drugs were significantly affected by the use of PSTTM II tubes, including antidepressants (11/26), neuroleptics (9/13), cardiovascular drugs (5/26), anxiolytics and hypnotics (4/25) and some drugs of abuse (5/26). Six compounds exhibited significant reduction by the mechanical BarricorTM tubes. Ten drugs exhibited low (<85%) but non-significant recoveries due to inter-assay variability. Besides, a logP > 3.3 was determined as a cut-off value to predict a potential lack of stability in PSTTM II gel tubes with an 86.4% sensitivity and a 61.4% specificity. As a consequence, determination of drugs with a logP > 3.3 should be carried out with caution in plasma samples withdrawn on PSTTM II. The study showed the BarricorTM and non-gel tubes cause less drug interference and are recommended for the drugs studied. PMID- 30439355 TI - Direct blood PCR: TaqMan-probe based detection of the venous thromboembolism associated mutations factor V Leiden and prothrombin c.20210G>A without DNA extraction. AB - BACKGROUND: Practically, the initial step of genetic analysis is the extraction of DNA from blood or other cells, which is often time consuming and cost intensive. We aimed at establishing a real-time PCR protocol for the detection of the venous thromboembolism associated mutations factor V Leiden (F5 c.1691G>A; p.R506Q) and prothrombin (F2) c.20210G>A from whole blood, without DNA extraction. METHODS: F5 c.1691G>A (p.R506Q) and F2 c.20210G>A mutations were determined in 205 EDTA anti-coagulated whole blood samples from patients who underwent routine clinical genotyping using the DirectBlood Genotyping PCR Kit (myPOLS Biotec, Konstanz, Germany) together with in-house developed TaqMan primer probe assays. RESULTS: Validity score values of genotype calls using whole blood were similar and did not significantly differ compared to those using genomic DNA as substrate in PCR. Mutation analysis of 205 whole blood samples showed a negligible PCR dropout rate (one in 410 reactions) and were in 100% concordance with results obtained by conventional genotyping. CONCLUSION: We successfully established a robust and valid real-time PCR protocol for the detection of the venous thromboembolism associated mutations F5 c.1691G>A (p.R506Q) and F2 c.20210G>A directly from whole blood. PMID- 30439356 TI - Essential role of mouse Dead end1 in the maintenance of spermatogonia. AB - Dead end is a vertebrate-specific RNA-binding protein implicated in germ cell development. We have previously shown that mouse Dead end1 (DND1) is expressed in male embryonic germ cells and directly interacts with NANOS2 to cooperatively promote sexual differentiation of fetal germ cells. In addition, we have also reported that NANOS2 is expressed in self-renewing spermatogonial stem cells and is required for the maintenance of the stem cell state. However, it remains to be determined whether DND1 works with NANOS2 in the spermatogonia. Here, we show that DND1 is expressed in a subpopulation of differentiating spermatogonia and undifferentiated spermatogonia, including NANOS2-positive spermatogonia. Conditional disruption of DND1 depleted both differentiating and undifferentiated spermatogonia; however, the numbers of Asingle and Apaired spermatogonia were preferentially decreased as compared with those of Aaligned spermatogonia. Finally, we found that postnatal DND1 associates with NANOS2 in vivo, independently of RNA, and interacts with some of NANOS2-target mRNAs. These data not only suggest that DND1 is a partner of NANOS2 in undifferentiated spermatogonia as well as in male embryonic germ cells, but also show that DND1 plays an essential role in the survival of differentiating spermatogonia. PMID- 30439357 TI - A novel cry52Ca1 gene from an Indian Bacillus thuringiensis isolate is toxic to Helicoverpa armigera (cotton boll worm). AB - The novel cry52Ca1 gene from an Indian Bacillus thuringiensis (Bt) isolate was cloned in an expression vector (pET301/CT-DEST, 6xHis). The gene expressed as a ~77.2 kDa protein in E. coli BL21-CodonPlus (DE3)-RIPL cells upon induction with isopropyl-thio-galactoside (IPTG) for 18 h at 28 degrees C. Cry52Ca1 protein was toxic to Helicoverpa armigera (cotton bollworm) neonate larvae (LC50 36.66 ug per ml and MIC50 3.051 ug per ml) in diet-based laboratory assays. This gene has potential for deployment in insect-resistant transgenic crops. PMID- 30439358 TI - Continuation of self-injected v. provider-administered contraception in Senegal: a non-randomized, prospective cohort study. AB - OBJECTIVES: The primary objective of this study was to compare the 12-month continuation rate for women who self-injected DMPA-SC (subcutaneous depot medroxyprogesterone acetate) with that for women receiving DMPA-IM (intramuscular depot-medroxyprogesterone acetate) from a provider. This research contributes to the broader goal of identifying solutions to support women to use contraception for their full desired duration. STUDY DESIGN: Participants were clients from 13 clinics in the Dakar and Thies regions of Senegal who had decided to use injectable contraception prior to enrollment. They chose self-injection of DMPA SC or provider-administration of DMPA-IM. Self-injectors were trained and given three units of DMPA-SC. The provider-injected group received DMPA-IM and returned to the clinics for future injections. We interviewed participants at baseline and after the second, third, and fourth injections (the equivalent of 12months of contraceptive coverage). We employed Kaplan-Meier methods to estimate continuation probabilities, with a log rank test to compare differences between groups. A multivariate Cox regression identified factors correlated with discontinuation. RESULTS: The 12-month continuation rate for 650 women self injecting DMPA-SC was 80.2%, while that for 649 women receiving DMPA-IM from a provider was 70.4% (p<.01). The difference in continuation between self-injectors and those receiving DMPA from a provider remained significant in a multivariate Cox regression model. The primary reason for discontinuation in both groups (44.7% self-injected; 44.5% provider-injected) was forgetting to reinject or reinjecting late. Fewer women reported side effects in the self-injection group than in the provider-administered group. CONCLUSIONS: The higher 12-month continuation rate for women self-injecting DMPA-SC relative to provider administered DMPA-IM suggests self-injection may help prevent pregnancy more consistently and continuously. IMPLICATIONS: Discontinuation of injectable contraception among women wishing to avoid pregnancy may increase unmet need in Francophone West Africa. This study showed higher 12-month continuation rates for women who self-injected DMPA-SC, suggesting that this delivery method may improve injectable continuation. PMID- 30439359 TI - A phase 2b multicenter, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of vaginal rings containing nomegestrol acetate or etonogestrel and 17beta-estradiol in the treatment of women with primary dysmenorrhea. AB - OBJECTIVE: To evaluate the effect of investigational vaginal rings containing nomegestrol acetate (NOMAC) plus 17beta-estradiol (E2) or etonogestrel (ENG) plus E2 in women with moderate to severe primary dysmenorrhea. STUDY DESIGN: This was a Phase 2b randomized, placebo-controlled, multicenter, double-blind study. We randomized participants to one of five treatment groups: four hormonal rings and one placebo ring. The investigational vaginal rings released 300MUg of E2 daily along with 700MUg or 900MUg of NOMAC or 100MUg or 125MUg of ENG. Each participant received 2 identical rings and was to insert each for 21days followed by a 7-day ring-free period. The primary endpoint, as assessed by a daily electronic diary (e-Diary), was the change in menstrual pain score from baseline to the second in treatment withdrawal bleeding episode (Cycle 2). The pain score was the mean of the three highest scores for menstrual cramping pain (0-4 point scale) recorded from the day before menses to the third day of bleeding. The primary hypothesis was that at least one investigational vaginal ring would demonstrate a statistically significant larger reduction from baseline in pain score compared to placebo. Secondary endpoints included total mean impact score (which assessed the negative impact on work/school, physical activities, leisure/social activities) and the amount and days of rescue medication (ibuprofen) used. RESULTS: We randomized 439 participants. The mean pain score decreased from baseline to Cycle 2 in all groups; the decrease in all four treatment groups compared to placebo was statistically significant (p-values<=0.002). All treatment groups had greater reductions than placebo in ibuprofen intake and greater improvement in impact scores; these differences were statistically significant for both endpoints for the ENG-E2 100/300MUg/day group, while the other groups were not statistically significant for one or both endpoints. CONCLUSION: All four investigational rings produced a statistically significantly larger reduction from baseline in mean menstrual pain score compared to placebo while pain medication use decreased. IMPLICATIONS: This placebo-controlled study provides evidence that vaginal contraceptive rings containing NOMAC-E2 or ENG-E2 improve moderate to severe dysmenorrhea, across all of doses studied. This adds to the evidence that hormonal contraceptives are effective treatments for dysmenorrhea. PMID- 30439360 TI - Woodchuck VEGF (wVEGF) characteristics: Model for angiogenesis and human hepatocellular carcinoma directed therapies. AB - Vascular endothelial growth factor (VEGF) stimulates angiogenesis. Human hepatocellular carcinoma (HCC) is a VEGF-driven tumor often associated with chronic hepatitis B or C virus infection. The woodchuck is a well-characterized model of hepatitis B virus related HCC and a valuable tool for translational studies of novel VEGF targeted agents. We cloned the cDNA encoding woodchuck VEGF (wVEGF), transiently expressed it in COS cells and functionally characterized the recombinant protein. The open reading frame of wVEGF contained 645 nucleotides encoding a protein of 214 amino acids. Two protein bands (17 and 25 kDa) were detected in conditioned media of wVEGF expressing COS-1 cells and a single band of 25 kDa was identified in cell lysates. Addition of recombinant wVEGF to COS cells enhanced cell proliferation and stimulated VEGFR2, Akt, ERK1/2, and FAK phosphorylation. Sunitinib, a tyrosine kinase inhibitor, inhibited wVEGF- induced VEGFR2 phosphorylation in a dose-dependent manner. Finally, development of HCC in woodchucks was accompanied by increased laminin and PECAM1 expressing vessels, VEGFR2 expression, increased ligation of VEGF to VEGFR2, and a decrease in collagen IV-positive blood vessels. Our results suggest that woodchuck model can be used further to study angiogenesis and the effect of VEGF directed therapies in human HCC. PMID- 30439361 TI - Interplay of N acetyl cysteine and melatonin in regulating oxidative stress induced cardiac hypertrophic factors and microRNAs. AB - Early and specific diagnosis of oxidative stress linked diseases as cardiac heart diseases remains a major dilemma for researchers and clinicians. MicroRNAs may serve as a better tool for specific early diagnostics and propose their utilization in future molecular medicines. We aimed to measure the microRNAs expressions in oxidative stress linked cardiac hypertrophic condition induced through stimulants as Endothelin and Isoproterenol. Cardiac hypertrophic animal models were confirmed by BNP, GATA4 expression, histological assays, and increased cell surface area. High oxidative stress (ROS level) and decreased antioxidant activities were assessed in hypertrophied groups. Enhanced expression of miR-152, miR-212/132 while decreased miR-142-3p expression was observed in hypertrophic condition. Similar pattern of these microRNAs was detected in HL-1 cells treated with H2O2. Upon administration of antioxidants, the miRNAs expression pattern altered from that of the cardiac hypertrophied model. Present investigation suggests that oxidative stress generated during the cardiac pathology may directly or indirectly regulate anti-hypertrophy pathway elements through microRNAs including antioxidant enzymes, which need further investigation. The down-regulation of free radical scavengers make it easier for the oxidative stress to play a key role in disease progression. PMID- 30439362 TI - Mitochondrial breakdown in skeletal muscle and the emerging role of the lysosomes. AB - Skeletal muscle mitochondria are essential in providing the energy required for locomotion. In response to contractile activity, the production of mitochondria is upregulated to meet the energy demands placed upon muscle cells. In a coordinated fashion, exercise also promotes the breakdown of dysfunctional mitochondria via mitophagy. Mitophagy is characterized by the selection of poorly functioning organelles, engulfment in an autophagosome and transport to lysosomes for degradation. In addition to the activation of mitophagy, exercise also elevates lysosome biogenesis. This coordinated increase in mitophagy targeting and lysosomal biogenesis serves to enhance the capacity for autophagosomal degradation, thereby aiding in the maintenance of mitochondrial quality. Lysosome dysfunction, as observed in lysosomal storage disorders (LSDs), negatively impacts mitochondrial function likely through the suppression of mitophagy. Since exercise is capable of activating mitophagy and lysosome biogenesis, researchers have begun to investigate physical activity as an effective therapy for LSDs. This review summarizes the current understanding of how mitophagy and lysosomal biogenesis are regulated in exercising skeletal, with potential therapeutic implications. PMID- 30439363 TI - Sialidase activity in human pathologies. AB - Sialic acid residues are frequently located at the terminal positions of glycoconjugate chains of cellular glycocalyx. Sialidases, or neuraminidases, catalyse removal of these residues thereby modulating various normal and pathological cellular activities. Recent studies have revealed the involvement of sialidases in a wide range of human disorders, including neurodegenerative disorders, cancers, infectious diseases and cardiovascular diseases. The accumulating data make sialidases an interesting potential therapeutic target. Modulating the activity of these enzymes may have beneficial effects in several pathologies. Four types of mammalian sialidases have been described: NEU1, NEU2, NEU3 and NEU4. They are encoded by different genes and characterized by different subcellular localization. In this review, we will summarize the current knowledge on the roles of different sialidases in pathological conditions. PMID- 30439365 TI - Raw cow's milk consumption and allergic diseases - The potential role of bioactive whey proteins. AB - The prevalence of allergic diseases has increased significantly in Western countries in the last decades. This increase is often explained by the loss of rural living conditions and associated changes in diet and lifestyle. In line with this 'hygiene hypothesis', several epidemiological studies have shown that growing up on a farm lowers the risk of developing allergic diseases. The consumption of raw, unprocessed, cow's milk seems to be one of the factors contributing to this protective effect. Recent evidence indeed shows an inverse relation between raw cow's milk consumption and the development of asthma and allergies. However, the consumption of raw milk is not recommended due to the possible contamination with pathogens. Cow's milk used for commercial purposes is therefore processed, but this milk processing is shown to abolish the allergy protective effects of raw milk. This emphasizes the importance of understanding the components and mechanisms underlying the allergy-protective capacity of raw cow's milk. Only then, ways to produce a safe and protective milk can be developed. Since mainly heat treatment is shown to abolish the allergy-protective effects of raw cow's milk, the heat-sensitive whey protein fraction of raw milk is an often-mentioned source of the protective components. In this review, several of these whey proteins, their potential contribution to the allergy protective effects of raw cow's milk and the consequences of heat treatment will be discussed. A better understanding of these bioactive whey proteins might eventually contribute to the development of new nutritional approaches for allergy management. PMID- 30439364 TI - Coiled-coil domain-containing 80 accelerates atherosclerosis development through decreasing lipoprotein lipase expression via ERK1/2 phosphorylation and TET2 expression. AB - Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2 regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis. PMID- 30439366 TI - Impairment of Valpha24-Jalpha18+Vbeta11+ natural killer T cells in adult acute lymphoblastic leukemia patients. AB - Type I natural killer T (NKT) cells are attractive candidates for cancer immunotherapy. In this study, we examined the characteristics of type I NKT cells in patients with adult B-cell acute lymphoblastic leukemia (ALL). We first identified type I NKT cells as Valpha24-Jalpha18 and Vbeta11 double-positive CD3+ lymphocytes. Using this method, we found that the adult B-cell ALL patients presented significantly lower level of type I NKT cells than the age- and sex matching control subjects. The expression of IL-21 by type I NKT cells was then examined using intracellular flow cytometry, which showed that with alpha-GalCer stimulation, the adult B-cell ALL patients presented significantly lower level of IL-21+ type I NKT cells than control subjects. By both flow cytometry and ELISA, we found that the vast majority of IL-21-expressing type I NKT cells expressed IL 21R, which was also reduced in adult B-cell ALL patients. Using an in vitro co culture system, we demonstrated that IL-21R+, but not IL-21R-, type I NKT cells could promote the IFN-gamma, granzyme B, and perforin expression by CD8 T cells in an IL-21-dependent fashion. This type I NKT cell-mediated stimulatory effect was reduced in adult B-cell ALL patients than in control subjects. In addition, we observed a positive correlation between the frequency of IL-21R+ type I NKT cells and the frequencies of IFN-gamma-, granzyme B-, and perforin-expressing circulating CD8 T cells in adult B-cell ALL patients directly ex vivo. Overall, this study identified an IL-21-related impairment in type I NKT cells from adult B-cell ALL patients. PMID- 30439367 TI - A fluorescent probe for hypochlorite with colorimetric and fluorometric characteristics and imaging in living cells. AB - An excellent fluorescent probe with "turn on" phenomenon for sensitive monitoring hypochlorite (ClO-) was prepared using the mild condensation reaction between coumarin and hydroxylamine (NH2OH). The probe possessed potent selectivity to ClO with obvious color changes from yellow to light yellow and green to blue fluorescence emission, which could be noticed by the naked eye. Moreover, the probe has been succeeded in imaging ClO- in living A549 cells and thus has the potential prospect in the visual detection of intracellular ClO-. PMID- 30439368 TI - Electrochemiluminescent immunosensor for prostate specific antigen based upon luminol functionalized platinum nanoparticles loaded on graphene. AB - A novel label-free electrochemiluminescent (ECL) immunosensor based upon luminol functionalized platinum nanoparticles loaded on graphene sheets (Lu-Pt@GS) as sensing platform was fabricated for highly sensitive and selective determination of prostate specific antigen (PSA). In this work, for the first time luminol was employed as both ECL luminescence reagent and reductants to in-situ reduce H2PtCl6 forming Pt NPs on surface of GS. A great deal of luminol could be attached onto the surface of Pt NPs within the reduction process, which can generate strong ECL emission. Pt NPs not only could enhance ECL signals of luminol but supply active sites for the immobilization of PSA antibodies with micro friendly environment. For preventing the consecutive reaction among luminol and H2O2, single-step cycle pulse was adopted, resulting in stable and strong ECL signals. Under optimized experimental conditions, the proposed ECL immunosensor acquired a wide linear range of 1 pg/mL to 10 ng/mL with a relatively low detection limit of 0.3 pg/mL for PSA. Furthermore, due to high sensitivity, simplicity and cost-effectiveness, the designed immunosensor provides a new method for detecting other important biomarkers in clinical analysis. PMID- 30439369 TI - Enzyme kinetics in crowded solutions from isothermal titration calorimetry. AB - Isothermal titration calorimetry (ITC) is a universal technique that directly measures the heat absorbed or released in a process. ITC is typically used to determine thermodynamic parameters of association of molecules without the need to label them. However, ITC is still rarely applied to study chemical reactions catalyzed by enzymes. In addition, these few studies of enzyme kinetic measurements that have been performed were in diluted solutions. Yet, to estimate realistic kinetic parameters, we have to account for the fact that enzymatic reactions in cells occur in a crowded environment because cells contain 200-400 g/L of macromolecular crowders such as proteins, ribosomes and lipids. Thus we expanded the ITC application for solutions mimicking the cellular environment by adding various macromolecular crowders. We investigated how these crowders affect the kinetics of trypsin-catalyzed reactions and determined the Michaelis-Menten parameters for hydrolysis of two trypsin substrates: Nalpha-benzoyl-l-arginine ethyl ester (BAEE) and Nalpha-benzoyl-dl-arginine beta-naphthylamide (BANA). Since ITC enables investigations of complex and turbid solutions with label-free reagents, it seems a perfect technique for kinetic analyses in crowded solutions. ITC also offers the opportunity to control enzyme-crowder and substrate-crowder interactions. PMID- 30439370 TI - Staging of colorectal cancers based on elastic Lamina invasion. AB - Peritoneal involvement in colorectal cancer (CRC) has prognostic significance and is an important parameter in pathologic tumor staging. Restaging of tumors based on peritoneal elastic lamina invasion (ELI) has prognostic significance in CRCs classified as pathologic stage 3 tumors without regional lymph node metastasis (pT3N0). However, limited data are available on the significance of ELI in patients with node-positive disease. We applied elastic stain to one block per case for 141 consecutive patients with pT3N1M0 CRCs. The elastic lamina (EL) was identified in only 62 cases (44%), of which 39 (27.6%) displayed ELI. The ELI+ group was associated with a significantly worse (P<.001) 5-year disease-free survival (5-year DFS=48.7%) and 5-year overall survival (5-year OS=61.4%) compared to the ELI- (5-year DFS=73.9%, OS=95.7%) and no EL (5-year DFS=79.5%, OS=85.7%) groups. Comparison of outcomes in cases with pT3N1M0 with peritoneal ELI and pT4aN1M0 tumors (based on the original pathologic assessment without the use of elastic staining), showed no significant differences in the 5-year DFS (P=.47) and OS (P=.65). These findings suggest that ELI is a significant prognostic marker and elastic staining should be considered for routine use in pT3 CRCs in a node-positive setting. Upstaging of pT3 tumors with ELI should be considered in the future iterations of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor node metastasis (TNM) staging system for CRC. PMID- 30439371 TI - Identification and functional characterization of a g-type lysozyme gene of Labeo rohita, an Indian major carp species. AB - Lysozyme, an important secretory innate immune component, possesses antimicrobial activity against broad spectrum of bacteria and viruses. In the present study, complete CDs (558 bps) of g-type lysozyme of rohu (Labeo rohita) was amplified and translated for a putative protein of 185 amino acids. The domain architecture and tertiary structure was also predicted for the protein. Its expression profile was studied in three infection models (bacteria: Aeromonas hydrophila, poly I:C, a dsRNA viral analogue and an ectoparasite: Argulus siamensis) in liver and kidney tissues of rohu. An up-regulation of 630-fold and 420-fold of the gene was observed at 48 h in liver and anterior kidney tissues respectively, after A. hydrophila infection. Significant increase in transcript level was noticed in both liver (0.8-fold) and kidney (480-fold) after 1 h and 12 h of poly I:C induction, respectively. Similarly, expression of lysozyme g transcripts was increased 6000-fold after 7 d of A. siamensis infection in liver tissue. The recombinant protein of g-type lysozyme of rohu (rLr-lysG) of 20.19 kDa was produced in Escherichia coli system and the lysozyme activity of rLr-lysG was found to be most active at pH 6.0 and temperature 35 degrees C. The potential lytic activity was found to be against A. hydrophila (UL = 0.53) followed by for E. tarda (UL = 0.45) whereas the lytic activity was the least against S. aureus (UL = 0.35) and M. lysodeikticus (UL = 0.34), at pH 6.0 and temperature 35 degrees C. The normal serum level of protein was estimated using indirect ELISA and was found to be very low (0.12-0.15 MUg/ml). These results suggested that g type lysozyme of rohu might be a potent immunostimulant against microbial infections, with a major role in innate immunity. PMID- 30439372 TI - Depression caused by long-term stress regulates premature aging and is possibly associated with disruption of circadian rhythms in mice. AB - Depression has been associated with circadian disruption and premature aging. Nevertheless, mechanisms underlying the link between long-term stress with premature aging and possible associations with circadian rhythms remain elusive. Here, mice were exposed to chronic mild stress for 16 weeks to induce depression like symptoms, which were confirmed with the open field test, tail suspension test, and sucrose preference test. Then, the circadian rhythms of age-related indexes were compared between control and stressed mice. Long-term stress resulted in decreased body weight gain and locomotor activities, accompanied by losses of subcutaneous backside fat, decreased amounts of thigh muscle fibers, and shortened telomere length in hepatocytes. Stressed mice showed increased oxidative damage, causing impaired mitochondrial function and inflammatory responses, which may be mediated by the sirtuin 3 (SIRT3)-superoxide dismutase 2 (SOD2) signaling pathway. These changes may be associated with partial disruption of circadian rhythms or shifting phase values of some age-related indicators induced by long-term stress. These findings suggest that long-term exposure to stress may increase the risk of depression and regulate age-related phenotypes through associations with circadian rhythms. PMID- 30439373 TI - Neuroimaging of chronic MDMA ("ecstasy") effects: A meta-analysis. AB - In this meta-analysis, we aimed to assess the evidence from neuroimaging studies for chronic alterations in the brains of MDMA users. The databases PubMed, Embase, and Web of Science were searched for studies published from inception to August 24, 2018, without any language restriction. Sixteen independent studies comprising 356 MDMA users and 311 controls were included. Of these, five studies investigated frontal and occipital N-acetylaspartate/creatine and myo inositol/creatine ratios, three studies assessed basal ganglia blood flow and ten studies investigated serotonin transporter (SERT) density in various regions. We found significantly decreased SERT density in eight of 13 investigated regions. Meta-regression indicated a positive association with abstinence, but none with lifetime episodes of use. Therefore, other variables (such as doses taken per occasion) might be more important determinants. Positive associations between time of abstinence and SERT density might indicate that these alterations are reversible to some extent. Furthermore, there were no significant differences between user and control groups in terms of neurochemical ratios in the frontal and occipital lobes and blood flow in the basal ganglia. Overall, MDMA user groups showed heavy use patterns and study quality was poor. PMID- 30439374 TI - Retinopathy of prematurity status during screening: invisible with binocular indirect ophthalmoscopy but established with Optos ultra-wide-field retinal imaging. PMID- 30439375 TI - Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch. AB - The p53 protein, a tumour suppressor, is a key player in the DNA damage response. The activation of apoptosis by p53 involves the intrinsic apoptotic pathway to eliminate stressed cells that contain DNA lesions. Recent experiments have found that apoptosis happen in an all-or-none switch like manner (Albeck et al., 2008; Rehm et al., 2002). We focus on modelling the mechanism of p53 activation of apoptosis in response to sustained high DNA double-strand breaks. The aim of the research is to investigate the design principles behind the regulation of p53 activation of apoptotic switch. Building on previous models (Chong et al., 2015; Zhang et al., 2009a), we developed a mathematical model that incorporated the molecular interactions in the core regulation of p53 and the apoptosis initiation module involving Puma, Bcl2 and Bax. Activation of Bax was assumed to be an indicator of apoptosis initiation. Chen et al. (2013) suggested that one of the components in the p53 pathway may control a threshold activation of apoptosis. We hypothesized that ATM auto-activation is the component that controls p53 threshold activation of apoptosis with ATM's multi-site autophosphorylation depending on damage intensity. The constructed model demonstrated how molecular interactions and stress signalling molecule ATM's auto-activation of the p53 network dictate cell fate decisions. Our simulation results are qualitatively consistent with the experimental findings of all-or-none activation of apoptosis and predicted overexpression of Bcl2 as a factor in causing malfunction of the apoptotic switch. We present a simplified yet plausible model of molecular mechanism that controls p53 activation of apoptotic switch. PMID- 30439376 TI - FTY720P inhibits the Na+/K+ ATPase in Caco-2 cells via S1PR2: PGE2 and NO are along the signaling pathway. AB - AIMS: Sphingosine-1-phosphate (S1P) has been implicated lately in inflammatory bowel disease which has diarrhea as one of its symptoms. Diarrhea is due to altered water movements as a result of altered electrolyte transport, and in particular sodium. Sodium movements are geared by the sodium gradient established by the Na+/K+ ATPase. The aim of this work was to investigate if S1P can modulate the activity of the ATPase, using Caco-2 cells as a model and the S1P analogue, FTY720P. MATERIALS AND METHODS: The activity of the ATPase was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of ouabain. Protein expression of the various S1P receptors was studied by western blot analysis. KEY FINDINGS: Caco-2 cells were found to express mainly S1PR2 and S1PR3. FTY720P (7.5 nM) reduced significantly the activity of the Na+/K+ ATPase when applied for 15 min. This inhibitory effect disappeared in presence of JTE 013, a specific blocker of S1PR2, and indomethacin, an inhibitor of cyclooxygenase enzymes, and was mimicked by CYM5520, a S1PR2 agonist and by exogenous PGE2. The inhibitory effect of PGE2 did not appear when EP3 receptors were blocked or when a nitric oxide scavenger was added. RpcAMP, a PKA inhibitor, reduced the activity of the Na+/K+ ATPase, while dbcAMP, a PKA activator was without any effect and when added, abrogated the effect of PGE2. SIGNIFICANCE: It was concluded that FTY720P inhibits the Na+/K+ ATPase via activation of S1PR2 and generation of PGE2 nitric oxide. PMID- 30439377 TI - Induction of functional erythropoietin and erythropoietin receptor gene expression by gamma-aminobutyric acid and piperine in kidney epithelial cells. AB - AIMS: The aim of this study was to evaluate gamma-aminobutyric acid (GABA)- and piperine-induced erythropoietin (EPO) and EPO-receptor expression. MATERIALS AND METHODS: The effect of GABA and piperine on cell viability was examined using kidney epithelial cells. Expression levels of EPO and EPO-R mRNA and protein were evaluated in response to GABA and piperine treatments. GABA- and piperine mediated activation of the mitogen-activated protein kinase (MAPK) signaling pathway was investigated. Additionally, EPO function was evaluated using conditioned media containing EPO. The GABA receptor type involved in this process was identified. KEY FINDINGS: Messenger RNA and protein expression levels of EPO and EPO-R significantly increased in response to treatment with GABA, piperine, or the combination of both, compared with control. GABA plus piperine synergistically enhanced EPO and EPO-R expression through p38 and c-Jun N terminal kinase (JNK) MAPK signaling pathways, but not through the extracellular signal-regulated kinase (ERK) MAPK pathway. SB203580 and SP600125 (p38 and JNK pathway inhibitors, respectively) attenuated GABA plus piperine-induced EPO and EPO-R expression. Treatment of macrophages with EPO-containing conditioned media induced mRNA expression of interleukin (IL)-10 and nuclear factor (NF)-kappaB due to the interaction between EPO and EPO-R. Interestingly, GABA-induced EPO and EPO R expression was mediated through GABAA, not GABAB, receptor activation. SIGNIFICANCE: These findings demonstrate that GABA plus piperine-mediated p38 and JNK MAPK activation increases EPO and EPO-R expression, resulting in up regulation of IL-10 and NF-kappaB. PMID- 30439378 TI - Protein kinase C inhibitor chelerythrine attenuates partial unilateral ureteral obstruction induced kidney injury in neonatal rats. AB - The present study aimed to evaluate the renoprotective effects of chelerythrine (CHE), a protein kinase C inhibitor, on neonatal rats after partial unilateral ureteral obstruction (UUO) surgery. New born Sprague Dawley rats were subjected to partial UUO 48 h after birth and received a daily intraperitoneal injection of 5 mg/kg CHE. At 21-day age, the rats were scarified and the kidneys were collected for analysis. Results showed that CHE treatment significantly increased kidney weight and restored renal function in the obstructed kidney. Histological examination demonstrated that CHE attenuated renal injury by reducing renal parenchymal loss and preventing glomerular and tubular degeneration. In addition, CHE inhibited partial UUO-induced upregulated kidney injury molecule-1 expression and apoptosis and renal fibrosis. Moreover, as a PKC inhibitor, CHE significantly inhibited PKCalpha and PKCbeta membrane translocation. This action may be associated with its effects of anti-apoptosis and anti-fibrosis and contribute to the renoprotection. This short-term study suggests that CHE is beneficial for obstructive nephropathy in neonatal rats and provides foundation for further studies to reveal the long-term effects of CHE on obstructive nephropathy in children and infants. PMID- 30439379 TI - Cannabinoid-like effects of five novel carboxamide synthetic cannabinoids. AB - A new generation of novel cannabinoid compounds have been developed as marijuana substitutes to avoid drug control laws and cannabinoid blood tests. 5F-MDMB PINACA (also known as 5F-ADB, 5F-ADB-PINACA), MDMB-CHIMICA, MDMB-FUBINACA, ADB FUBINACA, and AMB-FUBINACA (also known as FUB-AMB, MMB-FUBINACA) were tested for in vivo cannabinoid-like effects to assess their abuse liability. Locomotor activity in mice was tested to screen for locomotor depressant effects and to identify behaviorally-active dose ranges and times of peak effect. Discriminative stimulus effects were tested in rats trained to discriminate Delta9 tetrahydrocannabinol (3 mg/kg, 30-min pretreatment). 5F-MDMB-PINACA (ED50 = 1.1 mg/kg) and MDMB-CHIMICA (ED50 = 0.024 mg/kg) produced short-acting (30 min) depression of locomotor activity. ADB-FUBINACA (ED50 = 0.19 mg/kg), and AMB- FUBINACA (ED50 = 0.19 mg/kg) depressed locomotor activity for 60-90 min; whereas MDMB-FUBINACA (ED50 = 0.04 mg/kg) depressed locomotor activity for 150 min. AMB FUBINACA produced tremors at the highest dose tested. 5F-MDMB-PINACA (ED50 = 0.07), MDMB-CHIMICA (ED50 = 0.01 mg/kg), MDMB-FUBINACA (ED50 = 0.051 mg/kg), ADB FUBINACA (ED50 = 0.075 mg/kg) and AMB-FUBINACA (ED50 = 0.029) fully substituted for the discriminative stimulus effects of Delta9-THC following 15-min pretreatment. All 5 compounds decreased locomotor activity and produced discriminative stimulus effects similar to those of Delta9-THC, which suggests they may have abuse liability similar to that of Delta9-THC. AMB-FUBINACA may have an increased risk of toxicities in recreational users. PMID- 30439380 TI - Fluoroquinolone Use and Associated Adverse Drug Events in England. PMID- 30439381 TI - Exploring the consumption of ultra-processed foods and its association with food addiction in overweight children. AB - The present study explored the consumption of ultra-processed foods and its association with food addiction in overweight children. The prevalence of food addiction was investigated using the Yale Food Addiction Scale for Children in overweight 9-11 year-old children (BMI/age >=1 Z score) of both sexes from two schools (n = 139). Food intake was estimated by a food frequency questionnaire and the food items were classified into 4 categories: minimally processed, culinary ingredients, processed foods and ultra-processed foods (UPF), based on their degree of processing. Among the children, 95% showed at least one of the seven symptoms of food addiction and 24% presented with a diagnosis of food addiction. In analysis of covariance adjusted for age and sex, a tendency of higher consumption of added sugar (refined sugar, honey, corn syrup) and UPF was found among those diagnosed with food addiction. Multiple logistic regression adjusted for sugar, sodium and fat ingestion showed that consumption of cookies/biscuits (OR = 4.19, p = 0.015) and sausages (OR = 11.77, p = 0.029) were independently associated with food addiction. The identification of foods that may be associated with addictive behavior is very important for correctly treating and preventing childhood obesity, which continues to be one of the greatest health problems in the world. PMID- 30439383 TI - CORRECTION. PMID- 30439382 TI - PASylated interferon alpha efficiently suppresses hepatitis B virus and induces anti-HBs seroconversion in HBV-transgenic mice. AB - Interferon alpha (IFNalpha) so far is the only therapeutic option for chronic hepatitis B virus (HBV) infection that can lead to virus clearance. Unfortunately, its application is limited by side effects and response rates are low. The aim of this study was to generate a novel long-acting IFNalpha with the help of PASylation technology that adds a polypeptide comprising Proline, Alanine and Serine (PAS) to increase protein half-life. Following evaluation of four selected recombinant murine IFNalpha (mIFNalpha) subtypes in cell culture, the most active subtype mIFNalpha11 was fused with a 600 amino acid PAS-residue. The activity of PAS-mIFNalpha was assessed by interferon bioassay and further evaluated for induction of interferon-stimulated genes (ISG) and antiviral efficacy in cell culture and HBV-transgenic mice. PAS-mIFNalpha induced expression of ISG comparable to unmodified mIFNalpha and, likewise, evoked dose dependent reduction of HBV replication in vitro. In vivo, PAS-mIFNalpha led to pronounced suppression of HBV replication without detectable liver damage whereas conventional mIFNalpha treatment only had a modest antiviral effect. Importantly, all PAS-mIFNalpha treated mice showed an anti-HBs antibody response, lost HBsAg and achieved seroconversion after three weeks. PASylated IFNalpha showed a profoundly increased antiviral effect in vivo compared to the non-modified version without toxicity, providing proof-of-concept that an improved IFNalpha can achieve higher rates of HBV antiviral and immune control. PMID- 30439384 TI - An overview of the neuroprotective potential of rosmarinic acid and its association with nanotechnology-based delivery systems: A novel approach to treating neurodegenerative disorders. AB - Neurodegenerative disorders (ND) are characterized by slow and progressive neuronal dysfunction induced by the degeneration of neuronal cells in the central nervous system (CNS). Recently, the neuroprotective effects of natural compounds with anti-inflammatory and antioxidant activities has been clearly demonstrated. This appears to be an attractive therapeutic approach for ND, particularly regarding the use of polyphenols. In this review, we present an overview of the neuroprotective potential of rosmarinic acid (RA) and discuss the use of nanotechnology as a novel approach to treating ND. RA presents a variety of biological important activities, i.e. the modulation of pro-inflammatory cytokine expression, prevention of neurodegeneration and damage reduction. However, its poor bioavailability represents a limitation in terms of pharmacodynamics. In this sense, nanotechnology-based carriers could allow for the administration of higher but still safe amounts of RA, aiming for CNS delivery. Nasal administration could be a pleasant route for delivery to the CNS, as this represents a direct route to the CNS. With these advantages, RA-loaded nanotechnology-based therapy through the nasal route could be promising approach for the treatment of ND. PMID- 30439385 TI - Trends in childhood type 1 diabetes incidence in France, 2010 - 2015. AB - AIMS: To estimate type 1 diabetes incidence in children in France and its evolution between 2010 and 2015, based on comprehensive medico-administrative databases. METHODS: The algorithm built to identify new cases of type 1 diabetes selected children aged between 6 months and 14 years who had at least one hospital stay for diabetes, followed by their first insulin treatment, excluding children suffering from another form of diabetes. Age and sex specific annual incidence rates were estimated and time trend was analyzed using Poisson regression. RESULTS: A total of 12 067 children were identified as newly diagnosed with type 1 diabetes and the annual incidence rates increased between 2010 and 2015 (from 15.4 [95% Confidence Interval: 14.7;16.1] to 19.1 [18.3;19.9] per 100 000 person-years), among boys and girls, and in each age group (4 and under, 5 - 9, 10 - 14 year olds). The annual rate of increase was 4.0% [3.4;4.6]. This trend was not significantly different between each gender, and each age group. CONCLUSIONS: Valid database information on disease incidence is essential for healthcare planning and provides a valuable resource for health research. An increase of the incidence rate of type 1 diabetes in children was highlighted in both sexes and in all age groups. PMID- 30439386 TI - Characterization and application of chemical-resistant polyurethane-based enzyme and whole cell compartments. AB - This study presents the preparation and physical-chemical characterization of chemical resistant polyurethane-based compartments for biocatalytic application. The artificial compartments were prepared from an emulsion of polymer precursor and an aqueous phase that includes a biocatalytic reaction system. After curing, highly dispersed aqueous domains were obtained, which still contain the entire biocatalytic reaction system and remain fixed in the solid polymer preparation. The tensile and compression behavior of the prepared polymeric material is not significantly affected by the incorporation and facilitates excellent stability against various organic solvents and acid solutions. Thereby, the compartments can be used not only for enantioselective alcohol-dehydrogenase catalyzed reduction but also for a whole cell catalyzed hydrolysis of esters. Moreover, the compartmented whole-cell system was considerably stable to allow multiple reuses without a noticeable loss of catalytic activity of the incorporated whole cell catalytic reaction system. PMID- 30439387 TI - A defined approach for predicting skin sensitisation hazard and potency based on the guided integration of in silico, in chemico and in vitro data using exclusion criteria. AB - A decision tree-based defined approach (DA) has been designed using exclusion criteria based on applicability domain knowledge of in chemico/in vitro information sources covering key events 1-3 in the skin sensitisation adverse outcome pathway and an in silico tool predicting the adverse outcome (Derek Nexus). The hypothesis is that using exclusion criteria to de-prioritise less applicable assays and/or in silico outcomes produces a rational, transparent, and reliable DA for the prediction of skin sensitisation potential. Five exclusion criteria have been established: Derek Nexus reasoning level, Derek Nexus negative prediction, metabolism, lipophilicity, and lysine-reactivity. These are used to prioritise the most suitable information sources for a given chemical and results from which are used in a '2 out of 3' approach to provide a prediction of hazard. A potency category (and corresponding GHS classification) is then assigned using a k-Nearest Neighbours model containing human and LLNA data. The DA correctly identified the hazard (sensitiser/non-sensitiser) for 85% and 86% of a dataset with reference LLNA and human data. The correct potency category was identified for 59% and 68% of chemicals, and the GHS classification accurately predicted for 73% and 76% with reference LLNA and human data, respectively. PMID- 30439388 TI - Application of the in vivo Pig-a gene mutation assay to test the potential genotoxicity of p-phenylenediamine. AB - Currently, it remains controversial whether p-phenylenediamine (PPD) is genotoxic. In this study, we evaluated the potential genotoxicity of PPD using the newly-developed Pig-a gene mutation assay. The results of three classical genetic toxicity tests (bacterial reverse mutation assay, mammalian cell chromosomal aberration test, and mammalian erythrocyte micronucleus test) are all positive, suggesting that PPD is potentially genotoxic. In Pig-a assay, Sprague Dawley rats are orally administered with PPD for 28 consecutive days at three doses (12.5, 25, and 50 mg/kg/day). Our result shows that PPD (25 and 50 mg/kg/day) dose-dependently increases RETCD59- value over controls on Day 8. RETCD59- keeps increasing to the maximum on Day 15 and then decreases until Day 29. PPD also dose-dependently increase RBCCD59- value on Day 15, which keeps elevating until Day 29. The time-course of RETCD59- and RBCCD59- induced by PPD are similar with that induced by N-ethyl-N-nitrosourea (ENU) treatment for 3 days. Our data suggests that PPD has potential genotoxic effects, and the Pig-a assay is sensitive to assess mutagenicity. However, further investigation of the changes of RETCD59- and RBCCD59- induced by hair dyes containing PPD should be detected by Pig-a assay in occupational exposure population to confirm the safety of PPD usage. PMID- 30439390 TI - In vivo cell type-specific CRISPR gene editing for sleep research. AB - Sleep is an innate behavior conserved in all animals and, in vertebrates, is regulated by neuronal circuits in the brain. The conventional techniques of forward and reverse genetics have enabled researchers to investigate the molecular mechanisms that regulate sleep and arousal. However, functional interrogation of genes in specific cell subtypes in the brain remains a challenge. Here, we review the background of newly developed gene-editing technologies using engineered CRISPR/Cas9 system and describe the application to interrogate gene functions within genetically-defined brain cell populations in sleep research. PMID- 30439389 TI - Assessing recurrent interactions in cortical networks: Modeling EEG response to transcranial magnetic stimulation. AB - BACKGROUND: The basic mechanisms underlying the electroencephalograpy (EEG) response to transcranial magnetic stimulation (TMS) of the human cortex are not well understood. NEW METHOD: A state-space modeling methodology is developed to gain insight into the network nature of the TMS/EEG response. Cortical activity is modeled using a multivariariate autoregressive model with exogenous stimulation parameters representing the effect of TMS. An observation equation models EEG measurement of cortical activity. An expectation-maximization algorithm is developed to estimate the model parameters. RESULTS: The methodology is used to assess two different hypotheses for the mechanisms underlying TMS/EEG in wakefulness and sleep. The integrated model hypothesizes that recurrent interactions between cortical regions are the source of TMS/EEG, while the segregated model hypothesizes that the TMS/EEG results from excitation of independent cortical oscillators. The results show that the relatively simple EEG response to TMS recorded during non-rapid-eye-movement sleep is described equally well by either the integrated or segregated model. However, the integrated model fits the more complex TMS/EEG of wakefulness much better than the segregated model. COMPARISON WITH EXISTING METHOD(S): Existing methods are limited to small numbers of cortical regions of interest or do not represent the effect of TMS. Our results are consistent with previous studies contrasting the complexity of TMS/EEG in wakefulness and sleep. CONCLUSION: The new method strongly suggests that effective feedback connections between cortical regions are required to produce the TMS/EEG in wakefulness. PMID- 30439391 TI - Reply to: "Sofosbuvir/velpatasvir for patients with chronic genotype 3 HCV infection with compensated cirrhosis: Response to EASL recommendations on treatment of Hepatitis C 2018": EASL Recommendations on Treatment of Hepatitis C 2018: Precision on the treatment of patients with genotype 3a infection and compensated cirrhosis. PMID- 30439393 TI - Characterization of an endonuclease in rice stripe tenuivirus Pc1in vitro. AB - Rice stripe tenuivirus (RSV) initiates its mRNA transcription by using the cap snatching mechanism during which an endonuclease activity is required for the cleavage of host mRNA. In this study, we aim to characterize the endonuclease in RSV. Sequence alignment revealed the presence of a cap-snatching endonuclease domain in RSV Pc1. Expression and in vitro enzymatic activity assay demonstrated that this domain indeed had a manganese-dependent endonuclease activity. The enzyme could efficiently degrade ssRNA with preference for unstructured ssRNA, but not DNA. Mutations in the endonuclease domain allowed the identification of four key residues (D547, D567, E585 and K604). The endonuclease of RSV was similar but not identical to other known viral endonucleases, suggesting that RSV endonuclease may have some distinct catalytic characteristics. PMID- 30439392 TI - Functional and immunogenic characterization of diverse HCV glycoprotein E2 variants. AB - BACKGROUND AND AIMS: Induction of cross-reactive antibodies targeting conserved epitopes of the envelope proteins E1E2 is a key requirement for an HCV vaccine. Conserved epitopes like the viral CD81-binding site are targeted by rare broadly neutralizing antibodies. However, these viral segments are occluded by variable regions and glycans. We aimed to identify antigens exposing conserved epitopes and to characterize their immunogenicity. METHODS: We created HCV variants with mutated glycosylation sites and/or hypervariable region 1 (HVR1). Exposure of the CD81 binding site and conserved epitopes was quantified by soluble CD81 and antibody interaction and neutralization assays. E2 or E1-E2 heterodimers with mutations causing epitope exposure were used to immunize mice. Vaccine-induced antibodies were examined and compared with patient-derived antibodies. RESULTS: Mutant viruses bound soluble CD81 and antibodies targeting the CD81 binding site with enhanced efficacy. Mice immunized with E2 or E1E2 heterodimers incorporating these modifications mounted strong, cross-binding, and non-interfering antibodies. E2-induced antibodies neutralized the autologous virus but they were not cross-neutralizing. CONCLUSIONS: Viruses lacking the HVR1 and selected glycosylation sites expose the CD81 binding site and cross-neutralization antibody epitopes. Recombinant E2 proteins carrying these modifications induce strong cross-binding but not cross-neutralizing antibodies. LAY SUMMARY: Conserved viral epitopes can be made considerably more accessible for binding of potently neutralizing antibodies by deletion of HVR1 and selected glycosylation sites. Recombinant E2 proteins carrying these mutations are unable to elicit cross-neutralizing antibodies suggesting that exposure of conserved epitopes is not sufficient to focus antibody responses on production of cross-neutralizing antibodies. PMID- 30439394 TI - SilentMutations (SIM): a tool for analyzing long-range RNA-RNA interactions in viral genomes and structured RNAs. AB - A single nucleotide change in the coding region can alter the amino acid sequence of a protein. In consequence, natural or artificial sequence changes in viral RNAs may have various effects not only on protein stability, function and structure but also on viral replication. In recent decades, several tools have been developed to predict the effect of mutations in structured RNAs such as viral genomes or non-coding RNAs. Some tools use multiple point mutations and also take coding regions into account. However, none of these tools was designed to specifically simulate the effect of mutations on viral long-range interactions. Here, we developed SilentMutations (SIM), an easy-to-use tool to analyze the effect of multiple point mutations on the secondary structures of two interacting viral RNAs. The tool can simulate disruptive and compensatory mutants of two interacting single-stranded RNAs. This allows a fast and accurate assessment of key regions potentially involved in functional long-range RNA-RNA interactions and will eventually help virologists and RNA-experts to design appropriate experiments. SIM only requires two interacting single-stranded RNA regions as input. The output is a plain text file containing the most promising mutants and a graphical representation of all interactions. We applied our tool on two experimentally validated influenza A virus and hepatitis C virus interactions and we were able to predict potential double mutants for in vitro validation experiments. The source code and documentation of SIM are freely available at github.com/desiro/silentMutations. PMID- 30439395 TI - Association between carotid artery plaque inflammation and brain MRI. AB - PURPOSE: To explore the association between presence of inflammatory cells in the carotid plaques surgically treated and brain MRI findings. MATERIAL AND METHODS: Forty consecutive patients were prospectively analyzed. Brain MRI was performed with a 1.5 Tesla scanner and infacts (lacuna and non-lacunar) pertinence of the anterior circulation were recorded. All patients underwent carotid endarterectomy "en bloc"; carotid plaques histological sections were prepared and immuno cytochemical analysis was performed to characterize and quantify the presence of inflammatory cells. ROC curve analysis, Pearson Rho correlation and Mann-Whitney test were applied. RESULTS: The immuno-cytochemical analysis demonstrated that plaques of symptomatic patients (stroke?TIA; n = 25) had more inflammatory cells, mainly macrophages (CD68) compared with plaques of patients without symptoms (Mann-Whitney = P < 0.001, ROC curve area = 0.901). Correlation analysis showed a statistically significant association between the number of brain non-lacunar infarcts and the entity of macrophages (P < 0.001); whereas no association with lacunar infarcts (P = 0.1934) was found. CONCLUSION: Results of this preliminary study suggest that the presence and amount of inflammatory cells within carotid artery plaque is associated with cerebrovascular events and with the number of MRI brain detectable infarct. PMID- 30439396 TI - Differentiation between glioblastoma and solitary brain metastasis using neurite orientation dispersion and density imaging. AB - BACKGROUND AND PURPOSE: Neurite orientation dispersion and density imaging (NODDI) is a new technique that applies a three-diffusion-compartment biophysical model. We assessed the usefulness of NODDI for the differentiation of glioblastoma from solitary brain metastasis. METHODS: NODDI data were prospectively obtained on a 3T magnetic resonance imaging (MRI) scanner from patients with previously untreated, histopathologically confirmed glioblastoma (n = 9) or solitary brain metastasis (n = 6). Using the NODDI Matlab Toolbox, we generated maps of the intra-cellular, extra-cellular, and isotropic volume (VIC, VEC, VISO) fraction. Apparent diffusion coefficient - and fraction anisotropy maps were created from the diffusion data. On each map we manually drew a region of interest around the peritumoral signal-change (PSC) - and the enhancing solid area of the lesion. Differences between glioblastoma and metastatic lesions were assessed and the area under the receiver operating characteristic curve (AUC) was determined. RESULTS: On VEC maps the mean value of the PSC area was significantly higher for glioblastoma than metastasis (P < 0.05); on VISO maps it tended to be higher for metastasis than glioblastoma. There was no significant difference on the other maps. Among the 5 parameters, the VEC fraction in the PSC area showed the highest diagnostic performance. The VEC threshold value of >= 0.48 yielded 100% sensitivity, 83.3% specificity, and an AUC of 0.87 for differentiating between the two tumor types. CONCLUSIONS: NODDI compartment maps of the PSC area may help to differentiate between glioblastoma and solitary brain metastasis. PMID- 30439397 TI - Altered baseline activity and connectivity associated with cognitive impairment following acute cerebellar infarction: A resting-state fMRI study. AB - The aims of this study were to investigated the changes of brain function and cognitive function in patients with acute posterior cerebellar infarction using the functional magnetic resonance imaging (fMRI) tecniques: fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC). Forty acute cerebellar infarction patients and 40 healthy controls were included. The differences of fALFF were compared. The regions showed significant differences were set as regions of interest (ROIs), and then the FC values between ROIs and the whole brain were analysed. Pearson correlation analysis was used to understand the correlation between FC values and cognitive function scores. The results showed significant group differences in fALFF values in the four brain regions, including the right frontal lobe, left hippocampus, right cingulate gyrus and cerebellum posterior lobe. Pearson correlation analysis suggested that abnormal alterations in the left hippocampus and right cingulate gyrus may play a core role in the cognitive impairment associated with cerebellar infarction. The changes of fALFF and FC values in related brain area from cerebellar stroke complement and enrich our understanding of cerebellar involvement in cognition involved in cognitive performance. PMID- 30439398 TI - Effects of lentivirus-mediated CYP17A1 gene silencing on the biological activity of glioma. AB - Gliomas are the most common malignant primary brain tumors with poor prognosis. We attempted to explore the role of CYP17A1 in glioma progression. We demonstrated that the expression of CYP17A1 was significantly higher in the glioma tissues than the normal brain tissues, especially in malignant glioma. Moreover, the expression of CYP17A1 gene was positively correlative with glioma pathological grades. In vitro, CYP17A1 gene silence inhibited the proliferation and invasion of glioma cells and promoted the apoptosis in glioma cells. Also, the subcutaneously transplanted tumour in BALB/C-nu showed that CYP17A1 gene silence inhibited glioma growth. These results reveal that CYP17A1 plays a major role in the progress of glioma. PMID- 30439399 TI - Dorsal root ganglion explants derived from chemotherapy-treated mice have reduced neurite outgrowth in culture. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and debilitating adverse effect of cancer therapy that results from treatment with neurotoxic agents. Although chemotherapy treatment has been shown to inhibit neurite outgrowth from dorsal root ganglion (DRG) neurons in vitro, evidence for this effect in vivo is lacking. In this study, we investigated whether chemotherapy treatment in mice alters the capacity for axonal outgrowth from ex vivo cultured DRG explants. Using a neurite outgrowth assay, we demonstrated that DRG explants isolated at day 30 from mice treated with 6 cycles of paclitaxel, or 12 cycles of oxaliplatin showed a significant reduction in neurite outgrowth as compared to DRG explants from control vehicle-treated mice. DRGs that were isolated at day 90 showed recovery of the neurite outgrowth, and no significant differences were detected in comparison to vehicle controls. These results are corroborated with an in vitro model, whereby direct application of oxaliplatin and paclitaxel dose dependently reduced neurite outgrowth of DRG explants. In conclusion, our results show that the effect of paclitaxel and oxaliplatin on the structural plasticity of DRG is retained ex vivo (for at least 30 days) and suggest the use of DRG explants derived from chemotherapy-treated mice as an efficient method to investigate the mechanisms underlying CIPN and test for possible therapeutic targets. PMID- 30439400 TI - Antibacterial and anti-biofilm activities of cinnamaldehyde against S. epidermidis. AB - The search for new antimicrobial drugs has been necessary due to the increased bacterial resistance to antibiotics currently in use, and natural products play an important role in this field. The aim of this study was to evaluate the in vitro effect of cinnamaldehyde on S. epidermidis strains, biofilm set-up prevention, as well as its effect on pre-established biofilms. The minimum inhibitory concentration (MIC) ranged from 300 to 500 MUg/mL, and the minimum bactericidal concentration (MBC) from 400 to 600 MUg/mL. The biofilm inhibitory concentration and biofilm eradication concentration values were four-fold (clinical isolate) and eight-fold (ATCC strain) greater than the concentration required to inhibit planktonic growth. Sub-inhibitory concentrations of cinnamaldehyde attenuated biofilm formation of S. epidermidis strains on polystyrene microtiter plates. The combination of cinnamaldehyde and linezolid was able to inhibit S. epidermidis with a bactericidal effect. Further investigation of the mechanism of action of cinnamaldehyde revealed its effect on the cell membrane permeability, and confocal laser scanning microscopy (CLSM) images illustrated the impact of cinnamaldehyde in the detachment and killing of existing biofilms. Thereby, our data confirmed the ability of cinnamaldehyde to reduce bacterial planktonic growth of S. epidermidis, inhibiting biofilm formation and eradicating pre-formed biofilm. PMID- 30439401 TI - Involvement of the phosphoryl transfer network on cardiac energetic metabolism during Staphylococcus aureus infection and its association to disease pathophysiology. AB - Evidences have suggested that the phosphoryl transfer network by the enzymatic activities of creatine kinase (CK), adenylate kinase (AK), pyruvate kinase (PK), and lactate dehydrogenase (LDH), shows new perspectives to understand some disturbances in the energy metabolism during bacterial infections. Thus, the aim of this study was to evaluate whether Staphylococcus aureus infection in mice could alter serum and cardiac activities of these enzymes and their association to disease pathophysiology. For that, we measured total leukocytes, lymphocytes and neutrophils (just 48 h of infection) that were lower in infected animals after 48 and 72 h in infected mice compared with negative control, while total protein and globulin plasma levels were higher after 72 h of infection. The serum CK activity was higher in infected animals 48 and 72 h post-infection compared to the control group, as well as observed for mitochondrial cardiac CK activity. The serum PK activity was higher in infected animals after 72 h of infection compared to the control group, and lower in the cardiac tissue. The cardiac AK activity was lower in infected animals 48 h and 72 h post-infection compared to the control group, while serum and cardiac LDH activities were higher. Based on these evidences, it is possible to conclude that the stimulation of CK activity exerts a key role as an attempt to maintain the bioenergetic homeostasis by the production of phosphocreatine to avoid a rapid fall on the concentrations of total adenosine triphosphate. In summary, the phosphoryl transfer network can be considered a pathway involved in the improvement on tissue and cellular energy homeostasis of S. aureus-infected mice. PMID- 30439402 TI - Traditional Oriental Medicine for Sensorineural Hearing Loss: Can ethnopharmacology contribute to potential drug discovery? AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Traditional Oriental Medicine (TOM), the development of hearing pathologies is related to an inadequate nourishment of the ears by the kidney and other organs involved in regulation of bodily fluids and nutrients. Several herbal species have historically been prescribed for promoting the production of bodily fluids or as antiaging agents to treat deficiencies in hearing. AIM OF REVIEW: The prevalence of hearing loss has been increasing in the last decade and is projected to grow considerably in the coming years. Recently, several herbal-derived products prescribed in TOM have demonstrated a therapeutic potential for acquired sensorineural hearing loss and tinnitus. Therefore, the aims of this review are to provide a comprehensive overview of the current known efficacy of the herbs used in TOM for preventing different forms of acquired sensorineural hearing loss and tinnitus, and associate the traditional principle with the demonstrated pharmacological mechanisms to establish a solid foundation for directing future research. METHODS: The present review collected the literature related to herbs used in TOM or related compounds on hearing from Chinese, Korean, and Japanese herbal classics; library catalogs; and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct). RESULTS: This review shows that approximately 25 herbal species and 40 active compounds prescribed in TOM for hearing loss and tinnitus have shown in vitro or in vivo beneficial effects for acquired sensorineural hearing loss produced by noise, aging, ototoxic drugs or diabetes. The inner ear is highly vulnerable to ischemia and oxidative damage, where several TOM agents have revealed a direct effect on the auditory system by normalizing the blood supply to the cochlea and increasing the antioxidant defense in sensory hair cells. These strategies have shown a positive impact on maintaining the inner ear potential, sustaining the production of endolymph, reducing the accumulation of toxic and inflammatory substances, preventing sensory cell death and preserving sensory transmission. There are still several herbal species with demonstrated therapeutic efficacy whose mechanisms have not been deeply studied and others that have been traditionally used in hearing loss but have not been tested experimentally. In clinical studies, Ginkgo biloba, Panax ginseng, and Astragalus propinquus have demonstrated to improve hearing thresholds in patients with sensorineural hearing loss and alleviated the symptoms of tinnitus. However, some of these clinical studies have been limited by small sample sizes, lack of an adequate control group or contradictory results. CONCLUSIONS: Current therapeutic strategies have proven that the goal of the traditional oriental medicine principle of increasing bodily fluids is a relevant approach for reducing the development of hearing loss by improving microcirculation in the blood-labyrinth barrier and increasing cochlear blood flow. The potential benefits of TOM agents expand to a multi target approach on different auditory structures of the inner ear related to increased cochlear blood flow, antioxidant, anti-inflammatory, anti-apoptotic and neuroprotective activities. TOM is proposed as an important source of drug discovery and well-controlled, double-blind clinical trials are required to determine the efficacy and possible side effects of the main active compounds in the herbal species traditionally prescribed for hearing loss. PMID- 30439404 TI - CD3+CD4-CD8- mucosal T cells are associated with uncontrolled chronic rhinosinusitis with nasal polyps. AB - Increased mucosal double-negative (DN) CD3+CD4-CD8- T cells were found for the first time in CRS and were much more abundant in uncontrolled CRSwNP than in well controlled CRSwNP. PMID- 30439403 TI - Mast Cell CRF2 Suppresses Mast Cell Degranulation and Limits the Severity of Anaphylaxis and Stress-Induced Intestinal Permeability. AB - BACKGROUND: Psychological stress and heightened MC activation are linked with important immunological disorders including allergy, anaphylaxis, asthma, and functional bowel diseases, but the mechanisms remain poorly defined. We have previously demonstrated that activation of the corticotropin releasing factor (CRF) system potentiates MC degranulation responses during IgE-mediated anaphylaxis and psychological stress, via CRF receptor subtype 1 (CRF1) expressed on MCs. OBJECTIVE: In this study, we investigated the role of CRF receptor subtype 2 (CRF2) as a modulator of stress-induced MC degranulation and associated disease pathophysiology. METHODS: In vitro MC degranulation assays were performed with bone marrow derived MCs (BMMCs) derived from WT and CRF2-deficient (CRF2-/-) mice and RBL-2H3 MCs transfected with CRF2-overexpressing plasmid or CRF2-siRNA. In vivo MC responses and associated pathophysiology in IgE-mediated passive systemic anaphylaxis (PSA) and acute psychological restraint stress were measured in WT, CRF2-/-, and MC-deficient KitW-sh/W-sh knock-in mice. RESULTS: Compared with WT mice, CRF2-/- exhibited heightened serum histamine levels and exacerbated PSA-induced anaphylactic responses and colonic permeability. In addition, CRF2-/- mice exhibited increased serum histamine and colonic permeability following acute restraint stress. Experiments with BMMCs and RBL-2H3 MCs demonstrated that CRF2 expressed on MCs suppresses store-operated Ca2+ entry (SOCE) signaling and MC degranulation induced by diverse MC stimuli. Experiments with MC-deficient KitW sh/W-sh mice systemically engrafted with WT and CRF2-/- BMMCs demonstrated the functional importance of MC-CRF2 in modulating stress-induced pathophysiology. CONCLUSIONS: MC CRF2 is a negative, global modulator of stimuli-induced MC degranulation and limits the severity of IgE-mediated anaphylaxis and stress related disease pathogenesis. PMID- 30439405 TI - Th9 immunodeficiency in Hyper IgE syndrome patients. PMID- 30439407 TI - Message from the Editor. PMID- 30439406 TI - Loss of an IgG plasma cell checkpoint in lupus. AB - BACKGROUND: IgG anti-nuclear antibodies (ANA) are a feature of several autoimmune diseases. These antibodies arise through defects in central or peripheral tolerance checkpoints. The specific checkpoints breached in autoimmune disease are not fully understood. OBJECTIVES: To study whether autoreactive plasma cells in lupus models and SLE patients arise as a consequence of defective antigen specific selection or a global enhancement of IgG PC differentiation. METHODS AND RESULTS: We optimized and validated a novel technique to detect naturally occurring ANA+ B cells and PC. We observed a major checkpoint for generation of ANA+ IgG+ PC in both non-autoimmune mice and healthy human subjects. Interestingly, we observed increased numbers of ANA+ IgG+ PC despite normal tolerance checkpoints in immature and naive B cells in lupus-prone MRL/lpr and NZB/W mice as well as patients with systemic lupus erythematosus (SLE). This increase was due to increased numbers of total IgG+ PC rather than lack of selection against ANA+ PC. CONCLUSION: Using a method that permits quick and accurate quantification of autoreactive B cells and PC in vivo within a native B cell repertoire in mice and humans, we demonstrate the importance of a checkpoint that restricts the generation of IgG plasma cells and protects against IgG ANA. Our observations suggest a fundamentally revised understanding of SLE: that it is a disease of aberrant B cell differentiation rather than a defect in antigen specific B cell tolerance. CLINICAL IMPLICATION: Therapies for SLE might need to be targeted at IgG plasma cell differentiation rather than antigen-specific tolerance. PMID- 30439408 TI - Neotuberostemonine inhibits osteoclastogenesis via blockade of NF-kappaB pathway. AB - Osteoporosis has been attributed to low bone mass arising from cellular communications between bone formation and bone resorption. Osteoclastogenesis is induced by M-CSF and RANKL in hematopoietic lineage cells. Once RANK/RANKL complex is formed, TRAF6 is recruited and triggers the activation of NF-kappaB pathway and the expression of osteoclast-related genes including NFATc1. Neotuberostemonine (NTS) is an active compound isolated from Stemona tuberosa Lour. Pharmacologically, NTS has been known to possess antitussive, anti-fibrotic and anti-inflammatory activities through regulation of macrophage. However, the influence of NTS to osteoclastogenesis has not been reported. The purpose of this study is to investigate whether NTS can modulate the osteoclastogenesis induced by RANKL or cancer cells. We found that NTS inhibits RANKL- or cancer cell mediated osteoclastogenesis via blockade of TRAF6 and NF-kappaB activation. NTS also impairs the formation of F-actin ring structure, an important feature of osteoclast differentiation and function. These results indicate that NTS can be a preventive and therapeutic candidate for bone-related disease and that NTS provides insights underlying molecular mechanisms that influence osteoclastogenesis. PMID- 30439409 TI - Study of the metabolomic relationship between lung cancer and chronic obstructive pulmonary disease based on direct infusion mass spectrometry. AB - The high prevalence of lung cancer (LC) has triggered the search of biomarkers for early diagnosis of this disease. For this purpose the study of metabolic changes related to the development of lung cancer could provide interesting information about its early diagnosis. In this sense, chronic obstructive pulmonary disease (COPD), a disease associated with tumor development, is a comorbidity that increases the risk of onset and progression of lung neoplasia and has also to be considered in the study of pathology related to lung cancer. This work develop a metabolomic approach based on direct infusion mass spectrometry using a hybrid triple quadrupole-time of flight mass spectrometer (DI-ESI-QqQ-TOF-MS) in order to identify altered metabolites from serum of LC and COPD patients and evaluate its relationship and implication in the progression of LC. This methodology has been applied to 30 serum samples from LC, 30 healthy patients used as controls (HC) and 30 serum samples from COPD to found altered metabolites from both LC and COPD diseases. In addition, some metabolic differences and similarities were found in Pulmonary Emphysema and Chronic Bronchitis patients. On the other hand, altered metabolites were studied in different stages of LC (II, III and IV) to evaluate the perturbation of them throughout the progression of disease. The sample treatment consisted of the extraction of polar and non-polar metabolites from serum that was later infused into the mass spectrometer using an electrospray ionization source in positive and negative mode. Partial least squares discriminant analysis (PLS-DA) allowed a classification between LC, HC and COPD groups in all acquisition modes. A total of 35 altered and common metabolites between LC and COPD, including amino acids, fatty acids, lysophospholipids, phospholipids and triacylglycerides were identified, being alanine, aspartate and glutamate metabolism the most altered. Finally, ROC curves were applied to the dataset and metabolites with AUC value higher than 0.70 were considered as relevant in the progression of LC. PMID- 30439410 TI - Intra-axonal Ca2+ mobilization contributes to triphenyltin-induced facilitation in glycinergic transmission of rat spinal neurons. AB - Triphenyltin (TPT) is an organotin compound causing environmental hazard to many wild creatures. Our previous findings show that TPT increases of the frequency of spontaneous glycinergic inhibitory postsynaptic currents (sIPSCs) in rat spinal neurons without changing the amplitude and 1/e decay time. In our study, the effects of 2-aminoethoxydiphenyl borate (2-APB), dantrolene sodium, and thapsigargin on sIPSC frequency were examined to reveal the contribution of intra axonal Ca2+ mobilization by adding TPT. 2-APB considerably attenuated the TPT induced facilitation of sIPSC frequency while dantrolene almost completely masked the TPT effects, suggesting that the TPT-induced synaptic facilitation results from the activation of both IP3 and ryanodine receptors on endoplasmic reticulum (ER) membrane, though inositol triphosphate (IP3) receptor is less sensitive to TPT. Thapsigargin itself significantly increased the sIPSC frequency without affecting the current amplitude and decay time. Successive addition of TPT could not further increase the sIPSC frequency in the presence of thapsigargin, indicating that thapsigargin completely masked the facilitatory action of TPT. Results suggest that TPT activates the IP3 and ryanodine receptors while TPT inhibits the Ca2+-pump of ER membranes, resulting in the elevation of intra axonal Ca2+ levels, leading to the increase of spontaneous glycine release from synaptic vesicles. PMID- 30439411 TI - Response to: Letter to the editor "Some thoughts about the possibility of diet derived exogenous small RNAs". PMID- 30439412 TI - 5 Maneuvers to Facilitate Faster Robotic Mitral Valve Repair. AB - Robotically-assisted mitral valve reconstruction has become a cornerstone in the management of degenerative mitral valve regurgitation. High-volume centers report exceptional outcomes with minimal morbidity and mortality in select patient populations. As compared to conventional sternotomy, robotically-assisted surgery has yielded comparable efficacy and safety, with potential benefits of improved cosmesis and a faster recovery period. Despite the potential benefits of a robotic approach, there has been a reluctance in widespread adoption due to concerns over increased operative and cross-clamp times as compared to conventional sternotomy approaches. In light of this specific concern, we have identified opportunities to improve the efficiency of robotic mitral valve repair by application of five innovations and surgical strategies. PMID- 30439413 TI - Cyclo(His-Pro) inhibits NLRP3 inflammasome cascade in ALS microglial cells. AB - Neuroinflammation, i.e. self-propelling progressive cycle of microglial activation and neuron damage, as well as improper protein folding, are recognized as major culprits of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). Mutations in several proteins have been linked to ALS pathogenesis, including the G93A mutation in the superoxide dismutase 1 (SOD1) enzyme. SOD1(G93A) mutant is prone to aggregate thus inducing both oxidative stress and neuroinflammation. In this study we used hSOD1(G93A) microglial cells to investigate the effects of the antioxidant and anti-inflammatory cyclic dipeptide (His-Pro) on LPS-induced inflammasome activation. We found that cyclo(His-Pro) inhibits NLRP3 inflammasome activation by reducing protein nitration via reduction in NO and ROS levels, indicative of lower peroxynitrite generation by LPS. Low levels in peroxynitrite are related to NF-kappaB inhibition responsible for iNOS down-regulation and NO dampening. On the other hand, cyclo(His-Pro)-mediated ROS attenuation, not linked to Nrf2 activation in this cellular model, is ascribed to increased soluble SOD1 activity due to the up regulation of Hsp70 and Hsp27 expression. Conclusively, our results, besides corroborating the anti-inflammatory properties of cyclo(His-Pro), highlight a novel role of the cyclic dipeptide as a proteostasis regulator, and therefore a good candidate for the treatment of ALS and other misfolding diseases. PMID- 30439414 TI - Critical review: Cardiac telocytes vs cardiac lymphatic endothelial cells. AB - The study of cardiac interstitial Cajal-like cells (ICLCs) began in 2005 and continued until 2010, when these cells were renamed as telocytes (TCs). Since then, numerous papers on cardiac ICLCs and TCs have been published. However, in the initial descriptions upon which further research was based, lymphatic endothelial cells (LECs) and initial lymphatics were not considered. No specific antibodies for LECs (such as podoplanin or LYVE-1) were used in cardiac TC studies, although ultrastructurally, LECs and TCs have similar morphological traits, including the lack of a basal lamina. When tissues are longitudinally cut, migrating LECs involved in adult lymphangiogenesis have an ICLC or TC morphology, both in light and transmission electron microscopy. In this paper, we present evidence that at least some cardiac TCs are actually LECs. Therefore, a clear-cut distinction should be made between TCs and LECs, at both the molecular and the ultrastructural levels, in order to avoid obtaining invalid data. PMID- 30439415 TI - Effects of anti-estrogens on cell invasion and survival in pituitary adenoma cells: A systematic study. AB - Although the molecular mechanisms underlying the formation of pituitary adenomas are largely unknown, it is clear that estrogen plays a key role in the pathogenesis of pituitary adenomas. Though this is exemplified by an investigation of fulvestrant in the pituitary adenoma cell line GH3, no systematic studies on the effects of selective estrogen receptor modulators (SERMs) on functional properties of pituitary adenoma cell lines to modulate cell migration, cell invasion, and cell survival are available. Here we analyzed the effects of fulvestrant and three SERMs, bazedoxifene, clomifene, and raloxifene, on pituitary adenomas cell lines AtT20, TtT/GF, and GH3. In cell survival assays, clomifene was shown to be the most potent compound in all three cell lines with IC50 values ranging between 2, 6, and 10 MUM, respectively, depending on the cell type. Raloxifene and bazedoxifene were also effective but to a lower extent. Also, all SERMs affected migratory and invasive behavior of pituitary adenoma cells. Mechanistically, treatment of cells with SERMs caused cell apoptosis, as demonstrated by Caspase 3/7 activity and western blot assays. In addition, western blots demonstrate activation of p53 in TtT/GF cells and loss of ERK1/2 activation in AtT20 cells. In contrast, fulvestrant was only effective in GH3 cells. Thus, the general applicability of SERMs for pituitary adenoma cells might be promising in clinical applications for the treatment of pituitary adenomas. PMID- 30439416 TI - Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid. AB - Folic acid (FA)-induced acute kidney injury (AKI) is a widely used model for studies of the renal damage and its progression to chronic state. However, the molecular mechanisms by which FA induces AKI remain poorly understood. Since renal function depends on mitochondrial homeostasis, it has been suggested that mitochondrial alterations contribute to AKI development. Additionally, N-acetyl cysteine (NAC) can be a protective agent to prevent mitochondrial and renal dysfunction in this model, given its ability to increase mitochondrial glutathione (GSH) and to control the S-glutathionylation levels, a reversible post-translational modification that has emerged as a mechanism able to link mitochondrial energy metabolism and redox homeostasis. However, this hypothesis has not been explored. The present study demonstrates for the first time that, at 24 h, FA induced mitochondrial bioenergetics, redox state, dynamics and mitophagy alterations, which are involved in the mechanisms responsible for the AKI development. On the other hand, NAC preadministration was able to prevent mitochondrial bioenergetics, redox state and dynamics alterations as well as renal damage. The protective effects of NAC on mitochondria and renal function could be related to its observed capacity to preserve the S-glutathionylation process and GSH levels in mitochondria. Taken together, our results support the idea that these mitochondrial processes can be targets for the prevention of the renal damage and its progression in FA-induced AKI model. PMID- 30439417 TI - Transcranial direct current stimulation induces hippocampal metaplasticity mediated by brain-derived neurotrophic factor. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate neuronal excitability via externally applied electric fields. Despite the positive effects of tDCS in a wide range of neurological disorders in humans, its mechanism of action remains poorly understood. Here we investigated cellular and molecular mechanisms underlying the aftereffects of anodal tDCS on the induction of long-term potentiation (LTP), a cellular correlate of learning and memory, at Schaffer collateral-CA1 synapses. We found that hippocampal CA1 LTP was enhanced in slices from rats subjected to anodal tDCS with no significant changes in basal synaptic function. The enhancing effect of tDCS on LTP was still maintained 12 h after stimulation. Treatment of ex vivo hippocampal slices from tDCS-treated rats with tropomyosin receptor kinase B (TrkB) inhibitor ANA-12, but not D1 receptor antagonist SKF-83566 or beta2-adrenergic receptor antagonist propranolol, efficiently prevented tDCS induced enhancement of LTP. The tDCS-treated rats exhibited higher levels of brain derived neurotrophic factor (BDNF) in the hippocampal CA1 region compared to sham-treated rats. Anodal tDCS also enhances memory performance in hippocampal dependent passive avoidance learning task, and this enhancement can be blocked by ANA-12 pretreatment. Altogether, our results underscore the importance of BDNF/TrkB-mediated metaplastic effect of anodal tDCS on the induction of hippocampal CA1 LTP. PMID- 30439418 TI - Inhibition of N-acylethanolamine acid amidase reduces nicotine-induced dopamine activation and reward. AB - Tobacco smoke is the leading preventable cause of death in the world and treatments aimed to increase success rate in smoking cessation by reducing nicotine dependence are sought. Activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) by synthetic or endogenous agonists was shown to suppress nicotine-induced activation of mesolimbic dopamine system, one of the major neurobiological substrates of nicotine dependence, and nicotine-seeking behavior in rats and monkeys. An alternative indirect way to activate PPARalpha is inhibition of N-acylethanolamine acid amidase (NAAA), one of the major hydrolyzing enzyme for its endogenous agonists palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). We synthetized a novel specific brain permeable NAAA inhibitor, AM11095. We administered AM11095 to rats and carried out brain lipid analysis, a functional observational battery (FOB) to assess toxicity, in vivo electrophysiological recording from dopamine cells in the ventral tegmental area, brain microdialysis in the nucleus accumbens shell and behavioral experiments to assess its effect on nicotine -induced conditioned place preference (CPP). AM11095 (5 and 25 mg/kg, i.p.) was devoid of neurotoxic and behavioral effects and did not affect motor behavior and coordination. This NAAA inhibitor (5 mg/kg i.p.) increased OEA and PEA levels in the hippocampus and cortex, prevented nicotine-induced activation of mesolimbic dopamine neurons in the ventral tegmental area, nicotine-induced elevation of dopamine levels in the nucleus accumbens shell and decreased the expression of nicotine CPP. Our results indicate that NAAA inhibitors represent a new class of pharmacological tools to modulate brain PEA/PPARalpha signalling and show potential in the treatment of nicotine dependence. PMID- 30439419 TI - Concomitant THC and stress adolescent exposure induces impaired fear extinction and related neurobiological changes in adulthood. AB - Delta9-tetrahydrocannabinol (THC) consumption during adolescence is reported to be a risk factor for the appearance of psychiatric disorders later in life. The interaction between genetic or environmental events and cannabinoid exposure in the adolescent period can also contribute to exacerbate behavioural deficits in adulthood. Here we investigate the effects of THC treatment as well as the consequences of concomitant THC and stress exposure during adolescence in the extinction of fear memory in adult mice. Adolescent mice treated with THC and exposed to stress exhibit impaired cued fear extinction in adulthood. However, no effect was observed in animals exposed to these two factors separately. Notably, resistance to fear extinction was associated with decreased neuronal activity in the basolateral amygdala (BLA) and the infralimbic prefrontal cortex, suggesting a long-term dysregulation of the fear circuit. These changes in neuronal activation were paralleled with structural plasticity alterations. Indeed, an increase of immature dendritic spines in pyramidal neurons of the BLA was revealed in mice simultaneously exposed to THC and stress. Corticosterone levels were also enhanced after the cued fear conditioning session in the same experimental group. These results show that an interaction between cannabis exposure and stress during adolescence may lead to long-term anxiety disorders characterized by the presence of pathological fear. PMID- 30439420 TI - Synthesis of acryloylated starch-g-poly acrylates crosslinked polymer functionalized by emulsified vinyltrimethylsilane derivative as a novel EOR agent for severe polymer flooding strategy. AB - Starch is a natural polysaccharide with reasonable biodegradable properties, which grafted with vinyl monomers through different initiators to be applied in enhanced oil recovery (EOR) techniques. Several authors stated about starch modification through copolymerization and grafting of different monomers, however, these derivatives have some drawbacks related to bacterial biodegradation, ionic and thermal aging under severe reservoir conditions. The present study reported the preparation of grafted acryloylated starch with acrylamide/acrylic acid monomers and vinyltrimethylsilane through initiation copolymerization with the aid of quaternary ammonium-based surfmer. The chemical analysis generated by various spectroscopic analysis comprising IR, NMR, meanwhile particles distribution estimated through DLS. The embedded silica through a polymer matrix photographed by TEM, SEM and EDX elementary analysis, and the thermal effect determined by thermal gravimetric analysis. The rheological analysis estimated relative to shear degradation, ionic strength, and thermal aging at imitated reservoir environment. Flooding runs performed on linear non-consolidated sandstone model at nearly practical field conditions, where the displaced oil by polymer effect was recorded through the volumetric collector. The flooding tests designate that the synthesized starch-g-copolymer is prospering for chemical flooding applications under severe reservoir conditions, and achieve a recovery factor of 46% Sor. PMID- 30439421 TI - Antibacterial activity and cytotoxicity of l-phenylalanine-oxidized starch coordinated zinc (II). AB - Zn (II) coordination compounds have aroused growing attentions as antibacterial entities. In the present work, we fabricated a new antibacterial complex of l phenylalanine-oxidized starch-coordinated zinc (II) (l-Phe-OSt -> Zn (II)) by successive reactions of oxidization, Maillard and coordination. Maillard reaction occurred between l-Phe and OSt to form l-Phe-OSt, which was then coordinated with Zn (II) by carboxyl groups for l-Phe-OSt -> Zn (II). The complex showed good antibacterial activity and the antibacterial activity against E. coli was slightly poorer than B. subtilis. The presence of complex favored the generation of reactive oxygen species (ROS) in bacteria and the ROS level in B. subtilis was higher than that in E. coli. Furthermore, the toxicity of l-Phe-OSt -> Zn (II) towards HT-29 cells was very low. The characteristics of better antibacterial activity and less cytotoxicity endow l-Phe-OSt -> Zn (II) a great potential of application as a food additive. PMID- 30439423 TI - Three-phase partitioning for the direct extraction and separation of bioactive exopolysaccharides from the cultured broth of Phellinus baumii. AB - In this study, three-phase partitioning (TPP) was used to directly extract and separate bioactive exopolysaccharides (EPSs) from a cultured broth of Phellinus baumii. The maximum extraction yield of EPS was 52.09% under the following optimal conditions: 20% (w/v) ammonium sulfate concentration, 1.0:1.5 (v/v) ratio of cultured broth to t-butanol, 30 min, and 35 degrees C. A multifrequency power ultrasound in a sequential mode coupled with TPP resulted in ~9.12% increment in extraction yield and ~80% reduction in extraction time compared with those of traditional TPP. The carbohydrate (88.21%) and uronic acid (3.37%) contents of partially purified EPS were higher than those of EPS-C obtained through conventional ethanol precipitation and separation methods. EPS and EPS-C exhibited similar preliminary structural characteristics and different monosaccharide compositions and molecular weights. The radical-scavenging abilities, antioxidant capacities, alpha-amylase and alpha-glycosidase inhibitory activities, and macrophage stimulation activities of EPS were also higher than those of EPS-C. Therefore, it could be concluded that TPP as a simple and green separation technique could be used to directly extract and separate bioactive EPS from the fermentation broths of mushrooms and other fungi. PMID- 30439422 TI - Polysaccharide from Phellinus Igniarius activates TLR4-mediated signaling pathways in macrophages and shows immune adjuvant activity in mice. AB - Polysaccharide from Phellinus igniarius (PPI) is known for its immune-regulating effect with low toxicity. Toll like receptor 4 (TLR4) is important in both innate and adaptive immune responses and considered to be a promising target for new immune adjuvants. In this study, PPI was investigated for its effect on activating TLR4 in RAW264.7 and peritoneal macrophages. The adjuvant potential of PPI was evaluated in OVA-immunized mice. The results showed PPI treatment significantly increased the secretion and the mRNA expression of both MyD88 dependent and TRIF dependent cytokines. IRAK-1, a key molecule on the downstream of MyD88, was polyubiquitinated while IRF-3, another key molecule on the downstream of TRIF, was phosphorylated obviously after the treatment of PPI. The phosphorylation of molecules involved in both NF-kappaB pathway and MAPK pathway were significantly up-regulated after PPI treatment. In addition, the effects of PPI on the macrophages almost completely disappeared after treating the cells with the TLR4 antagonist TAK-242. Further in vivo results showed PPI significantly increased the serum OVA-specific antibody and the OVA-specific spleen cell proliferation. Taken together, PPI can specifically stimulate TLR4 and activate both MyD88 and TRIF pathways. PPI has immune adjuvant activity and may become a new potential immune adjuvant. PMID- 30439424 TI - Crown ether modification of starch for adsorption of heavy metals from synthetic wastewater. AB - The adsorbent resin was prepared by grafting copolymerization of dibenzo-18-crown 6 onto corn starch under microwave irradiation and was used to adsorb Cd2+, Zn2+, Ni2+ and Cu2+ from aqueous solution. Microwave assisted synthesis method, which uses only microwave radiation to generate free radical in the polymer backbone, is fast, and reliable. It can produce high-quality product as compared to the conventional method. The resultant microwave produced modified starch was characterized by FTIR, UV-Vis, XRD and SEM devices. Adsorption of heavy metal ions on adsorbent could be well fitted by the pseudo-second-order and Freundlich equations. The influences of pH, contact time, adsorbent dose, temperature and metal ion concentration were studied in batch method experiments. Grafted corn starch could be reused by HNO3 as eluting agent. All the results show that St:DB18C6 is a good adsorbent for the removal of heavy metal ions from wastewater. PMID- 30439425 TI - Cationic polysaccharide spermine-pullulan drives tumor associated macrophage towards M1 phenotype to inhibit tumor progression. AB - Macrophages are predominant immune cells in the tumor microenvironment where they display an immunosuppressive M2 phenotype to support tumor growth. Reprogramming M2-like tumor-associated macrophages (TAMs) to antitumor M1 phenotype represents as a promising strategy in cancer immunotherapy. In this work we reported that one cationic polysaccharide spermine modified pullulan (PS) could act as an effective immunological stimulator to modulating either naive (M0) or M2 macrophages towards M1 phenotype. We showed that PS upregulated the expression of TLR1/3/4 and promoted the phosphorylation of Akt, Erk, JNK, following the activation of NF-kappaB, which led to the polarization towards M1. In a murine breast cancer model of tumor cell 4T1 inoculation, subcutaneous injection of PS induced effective antitumor effect through reprogramming M2 macrophages in the tumor microenvironment to M1, increased CD4+ and CD8+ T cells, and decreased the expression of CD31 in the tumor mass, which together inhibited the tumor progression and the metastasis in lung and liver, leading to the prolong of the mice survival. In conclusion, PS could effectively stimulate the immunological function of macrophages. Therefore, PS may provide a novel immunological stimulator to cancer immune therapies. PMID- 30439426 TI - Trigonella foenum graecum seed polysaccharide coupled nano hydroxyapatite chitosan: A ternary nanocomposite for bone tissue engineering. AB - Biomimetic nanocomposites containing hydroxyapatite and natural polymers are promising candidates for bone grafting. In this work, a tricomponent bioactive nanocomposite (nHA-CH-TFSP) assembling nano-hydroxyapatite (nHA), Chitosan (CH) and Trigonella foenum graecum seed polysaccharide (TFSP) was developed using co precipitation method and investigated against bicomponent nHA-CH nanocomposite for bone tissue engineering. In contrast to nHA-CH nanocomposite, nHA-CH-TFSP nanocomposite exhibited rough and interconnected porous structure as revealed by SEM with the porosity (60.3 +/- 0.17) lying in the range of cancellous bone. The incorporation of TFSP in nHA-CH substantially enhanced the in vitro water absorption capacity and protein adsorption ability along with appropriate biodegradation rate. Additionally, the nHA-CH-TFSP nanocomposite exhibited superior antibacterial activity. The nHA-CH-TFSP evinced a compressive strength of 6.7 +/- 0.24 MPa and a compressive modulus of 100 +/- 1.4 MPa, which fulfill the strength requisite of cancellous bone and could provide strong support for the growth of osteoblasts cells. Furthermore, the in vitro bioactivity study demonstrated its excellent biomineralization capacity in comparison to nHA-CH. The synthesized nHA-CH-TFSP nanocomposite exhibited better cytocompatibility towards the MG-63 cells along with its haemocompatible nature. Taken together the results of the present study indicate that nHA-CH-TFSP could serve as a prospective analogue for bone tissue engineering. PMID- 30439427 TI - Impedimetric mechanism study of horseradish peroxidase at low and high concentrations of hydrogen peroxide based on graphene/sol-gel/horseradish peroxidase. AB - A novel electrochemical modified electrode for the impedimetric mechanism study of horseradish peroxidase and hydrogen peroxide was proposed based on immobilizing horseradish peroxidase/3-(trimethoxysilyl) propylamine/graphene on glassy carbon electrode (HRP/TMSPA/Gr/GCE). Cyclic voltammetry and SEM were utilized to corroborate the successful stepwise assemblage procedure of the electrode. The electrochemical impedance spectroscopy measurements revealed that the charge transfer resistance increases at low concentrations and significantly decreases at high concentrations after enzymatic reaction with hydrogen peroxide. The mechanism study of the horseradish peroxidase and hydrogen peroxide were also investigated by electrochemical impedance spectroscopy. PMID- 30439428 TI - Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo. AB - Human serum albumin (HSA) is an opulent, non-glycosylated, most versatile carrier protein in plasma possessing multiple functions. HSA has the ability to interact with a variety of ligands, including exogenous pharmacological drugs. HSA has multiple binding sites located in different subdomains and which are responsible for binding of ligands. While antecedent research has discovered various functional and structural properties of HSA, the objective of this review paper is to shed light on some of the important properties of HSA and how binding pattern of different ligands can sustain the development of new drugs. Some significant properties include transportation, ligand-binding, distribution and metabolism of a compound. The HSA molecule can undergo various structural changes modifying its conformation and finally affects the ligand binding properties and redox state. Another important feature is an esterase-like activity possessed by HSA, which is also crucial in converting the prodrugs into active therapeutics. Therefore, HSA is one of the most suitable molecules for future research in drug discovery in pharmaceutical industry because of its numerous features and binding pattern that also governs the metabolism and drug dosage. PMID- 30439429 TI - Molecular interaction between human SUMO-I and histone like DNA binding protein of Helicobacter pylori (Hup) investigated by NMR and other biophysical tools. AB - The proteins secreted by bacteria contribute to immune mediated gastric inflammation and epithelial damage; thus aid bacterial invasion in host tissue, and may also interact with host proteins, conspirating a mechanism against host immune system. The Histone-like DNA binding protein is one of the most abundant nucleoid-associated proteins in Helicobacter pylori (H. pylori). The protein referred here as Hup- is also secreted in vitro by H. pylori, thus it may have its role in disease pathogenesis. This is possible only if Hup interact with some human proteins including Small-Ubiquitin-like-Modifier (SUMO) proteins. Studies have established that SUMO-proteins participate in various innate-immune pathways and thus promote an efficient immune response to combat pathogenic infections. Sequence analysis revealed the presence of two SUMO interacting motifs (SIMs) and several positively charged lysine residues on the protein surface of Hup. Additionally, SUMO-proteins epitomize negatively charged surface which confers them the ability to bind to DNA/RNA binding proteins. Based on the presence of SIMs as well as charge complementarity between the proteins, it is legitimate to consider that Hup protein would bind to SUMO-proteins. The present study has been undertaken to establish this interaction for the first time using NMR in combination with ITC and other biophysical techniques. PMID- 30439430 TI - Controlled fragmentation of starch into nanoparticles using a dry heating treatment under mildly acidic conditions. AB - Normal corn starch was treated with acidic ethanol solution with various concentrations of ethanol (0, 10, 30, 50 and 95%) and acid (0.0026, 0.0053 and 0.0079 M) and then subjected to a dry heating treatment for 1, 2 and 4 h at 130 degrees C to prepare starch nanoparticles. Size of nanoparticles was determined using DLS (dynamic light scattering). FT-IR (Fourier-transform infrared spectroscopy), XRD (X-ray diffraction) and TEM (transmission electron microscopy) were used to determine the structure and morphology of starch nanoparticles. As the ethanol concentration decreased, the starch granule readily fragmented into smaller particles when simply dispersed in water, and this was possibly by the preferential hydrolysis of the starch chains in the amorphous region. A higher ethanol concentration (50 and 95%) did not produce homogenous nanoparticles, however 30% ethanol concentration produced uniform nanoparticles with a mean diameter of 46.4 nm. The treatment condition (30% ethanol) partially broke the long-range crystalline order but left the short range order of the spherical nanoparticles intact. However, lower ethanol (<30%) concentrations induced severe damages in the both crystalline structures (long and short range) of starch granule. PMID- 30439431 TI - Impact of heat treatments and some technological processing on immunoglobulins of Egyptian buffalo's milk. AB - The effects of heat treatments, ultrafiltration and manufacture of soft cheese on the gross composition and immunoglobulins (Igs) of Egyptian buffalos were investigated. Four Igs (IgG1, IgG2, IgM and IgA) were identified and determined by single radial immunodiffusion (SRID). High concentrations of Igs were found in colostrum which decreased rapidly within the first 72 h postpartum parallel to the transition from colostrum to normal milk. IgG (IgG1, IgG2) and IgM were not completely denatured by pasteurization temperature up to 80 degrees C/15 s, while IgA was completely denatured under these conditions. Ultrafiltration of milk resulted in retentate of high values for total IgG (IgG1, IgG2), but low in IgM and IgA content and permeate was free of Igs. Domiati cheese made from UF milk retentate contained similar levels of Igs to the used retentate. PMID- 30439432 TI - Protective effects of a polysaccharide BLE0 isolated from barley leaf on bone loss in ovariectomized mice. AB - Potent anti-osteoporotic drugs have been developed over the past decades; however, the substantial need for treatments that can effectively and safely manage osteoporosis remains unmet. Barley leaf-derived products are one of best functional foods that can be used as nutritional supplements and detoxifiers in humans and are beneficial in improving bone disease. However, little information is available regarding the anti-osteoporotic effects of polysaccharides as the main component of barley leaf. This study aimed to clarify the beneficial effects of barley leaf (BLE0) polysaccharides on bone loss in ovariectomized mice and osteoclast differentiation in bone marrow-derived macrophages. BLE0 remarkably inhibited receptor activator of the nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in a dose-dependent manner. It also blocked RANKL induced activation of osteoclastogenic signals including ERK and p38 and the expression of nuclear factor of activated T cells cytoplasmic 1, as a master regulator of osteoclast differentiation, leading to decreased expression of osteoclast-specific marker genes such as Atp6v0d2, DC-STAMP and cathepsin K. Micro-computed tomography revealed that a seven-week oral administration of BLE0 dramatically improved ovariectomy-induced trabecular bone loss. Anti-osteoporotic effects were confirmed using morphometric analysis. Taken together, BLE0 is a bioactive polysaccharide; it mitigates estrogen deficiency-induced bone loss by directly inhibiting osteoclast differentiation. PMID- 30439433 TI - Production, purification and biochemical characterization of a thermoactive, alkaline lipase from a newly isolated Serratia sp. W3 Tunisian strain. AB - A newly isolated Serratia sp. W3 strain was shown to secrete a non-induced lipase in the culture medium. Lipolytic activity was optimized using the response surface methodology (RSM) and the extracellular lipase from Serratia sp. W3 (SmL) was purified to homogeneity with a total yield of 10% and its molecular mass was estimated of about 67 kDa by SDS-PAGE. The amino acid sequence of the first 7 N terminal residues of SmL revealed a high degree of homology with other Serratia lipase sequences. The purified SmL can be considered as thermoactive lipase, its maximal specific activity measured at pH 9 and 55 degrees C was shown to be 625 U/mg and 300 U/mg using tributyrin and olive oil emulsion as substrate, respectively. In contrast to other described Serratia lipases, SmL was found to be stable at a large scale of pH between pH 5 and pH 12. SmL was also able to hydrolyze its substrate in presence of various oxidizing agents as well as in presence of surfactants and some commercial detergents. Then, considering the overall biochemical properties of SmL, it can be considered as a potential candidate for industrial and biotechnological applications, such as synthesis of biodiesel and in the detergent industry. PMID- 30439434 TI - Fungal chitosan from Agaricus bisporus (Lange) Sing. Chaidam increased the stability and antioxidant activity of liposomes modified with biosurfactants and loading betulinic acid. AB - Agaricus bisporus (Lange) Sing. Chaidam, a special brown mushroom with thick body indigenous in Chaidam basin, was used for fungal chitosan extraction. FTIR, XRD and DSC spectra showed that fungal chitosan was similar to commercial chitosan from aquatic sources. Fungal chitosan and commercial chitosan were used to coat on betulinic acid-loaded liposomes modified with biosurfactants mannosylerythritol lipid A (MEL-A), respectively. After chitosan coating, the mean size, zeta potential and encapsulation efficiency of both liposomes increased. The liposomes coated with fungal chitosan were discovered to have smaller size and higher zeta potential. Furthermore, the wall material MEL-A and coating material chitosan endue liposomes with increased antioxidant capacity. Fungal chitosan coated liposomes also have stronger antioxidant effects than commercial chitosan. The findings implied that the fungal chitosan coated liposomes modified with MEL-A can be considered as a promising delivery system with enhanced antioxidant effects for bioactive compounds. PMID- 30439435 TI - Simultaneous fermentation and hydrolysis to extract chitin from crayfish shell waste. AB - Chitin is the second-most abundant bioresource and widely used in the food, agricultural, textile, biomedical, and pharmaceutical industries. However, an efficient, environmentally friendly, and economically feasible process for chitin extraction from shellfish waste remains to be explored. This study aimed to extract chitin from crayfish shell waste powder (CSP) by removing Ca2+ and protein, using Bacillus coagulans LA204 and proteinase K. A simultaneous enzymatic hydrolysis and fermentation process was conducted at 50 degrees C with 5% (w/v) CSP, 5% (w/v) glucose, 1000 U proteinase k g-1 CSP, and 10% inoculation of B. coagulans LA204 in a 5-L bioreactor under non-sterile conditions. After 48 h of fermentation, the deproteinization efficiency, demineralization efficiency, and chitin recovery reached 93%, 91%, and 94%, respectively. 1 mol additional glucose efficiently removed 0.91 mol calcium carbonate and 93% of the removed protein was hydrolyzed to acid-soluble protein. Simultaneous enzymatic hydrolysis and fermentation was a new strategy and a competitive biological method for chitin extraction. PMID- 30439436 TI - Physical properties and structural characterization of starch/polyvinyl alcohol/graphene oxide composite films. AB - The starch/polyvinyl alcohol/graphene oxide composite film was prepared by casting method by adding GO to starch/PVA matrix. The effects of GO with different concentrations on the performance of the composite film were studied. With the increase of GO concentration, the thickness increased, the tensile strength increased first and then decreased. When the concentration of GO reached 2 mg/ml, the tensile strength was 25.28 MPa reaching the maximum. The increase of GO concentration caused the enhancement of film's moisture resistance. Through FTIR, SEM and TGA analysis, it was found that the addition of GO did not change the composition of the film, but it could change the phenomenon of matrix agglomeration and improve the thermal stability of the film. The preparation of composite films by adding GO could improve the properties, expand the application of nanomaterials in the food packaging field, and expand the research of biodegradable composite films. PMID- 30439437 TI - Preparation, characterization and evaluation of glycerol plasticized chitosan/PVA blends for burn wounds. AB - Chitosan like natural polymers have been widely used in burn wound management. Novel low molecular weight chitosan-PVA soft membranes have been studied for antibacterial and wound healing properties. The effectiveness of antibacterial activity was carried against bacterial pathogens while wound healing nature of chitosan was conducted in second degree burns on rabbits as model animal. Rabbits were divided into three groups; control untreated, treated with commercial Fusidic acid (Fu-A) cream and chitosan-PVA membranes. Low molecular weight chitosan showed significant antibacterial property towards bacterial pathogens. Wound healing experiments on second degree burn exhibited chitosan as significant wound healing agent for wound dressings. In morphological studies, normal growth of epidermis was observed and chitosan exhibited more effective for wound healing. Morphological studies also showed that chitosan wound dressings accelerated the granule and fibrous connective tissues formation. Physical characteristics of chitosan-PVA membranes were evaluated by water uptake capacity, SEM analysis, mechanical and water barrier studies. PMID- 30439438 TI - Complex coacervation of carboxymethyl konjac glucomannan and chitosan and coacervate characterization. AB - Carboxymethyl konjac glucomannan (CMKGM) shows potential in the construction of colon-targeted delivery systems through electrostatic interaction-based techniques. Its coacervation with chitosan (CHI) was investigated as a function of degree of substitution (DS). CMKGMs displayed the same optimum coacervation conditions of pH 6.5 and mass ratio 1:1 with CHI, but the coacervate yield was positively related to their DS. The coacervation was weakened by the presence of NaCl, but was not affected in temperatures 25-75 degrees C and total biopolymer concentrations 0.05-0.15% (w/v). Both electrostatic interaction and hydrogen bonding were involved in the coacervation and a higher DS contributed a denser network structure, a smaller particle size, and greater elasticity. The coacervates maintained their structures in simulated gastrointestinal fluids, but could be degraded by the beta-mannanase in simulated colonic fluid. Hence, CMKGMs could be used in colon-targeted and enzyme-triggered delivery systems and the delivery performance could be tailored by varying their DS. PMID- 30439439 TI - Extraction and antioxidant activities of polysaccharides from roots of Arctium lappa L. AB - Polysaccharides were extracted from the roots of Arctium lappa L. (ALPs) using response surface methodology with ultrasonication. A central composition design was used to optimize extraction parameters by maximizing the polysaccharide extraction yield. The modified optimal conditions were as follows: water to raw material ratio of 31 mL/g, ultrasonic power of 158 W, extraction time of 83 min, and extraction temperature of 50 degrees C. Furthermore, fractions of ALP40-1, ALP60-1, and ALP80-1 were obtained for chemical and antioxidant activity analyses after purification. Results indicated that the three fractions had a molecular weight of 218, 178, and 60 kDa, respectively, and were composed of mannose, glucose, fructose, and galactose. ALP60-1 exhibited strong scavenging activities on 1,1-diphenyl-2-picryhydrazyl, hydroxyl, and superoxide radicals. These results demonstrate that ultrasonic-assisted extraction is a very effective method for extracting ALPs, and ALP60-1 is a potential novel natural antioxidant. However, further structure elucidation and in vivo experiments are required. PMID- 30439440 TI - Tetrodotoxin and its analogues profile in nemertean species from the sea of Japan. AB - For the first time search for tetrodotoxin (TTX) and its analogues in the extracts of nemerteans using HPLC-MS/MS was performed. TTX analogues were detected in two nemertean species in addition to TTX: 7 analogues were detected in the extract of Cephalothrix simula, 3 analogues - in the extract 11-norTTX of Kulikovia manchenkoi. Presence of 5-deoxyTTX, 11-deoxyTTX, 5,6,11-trideoxyTTX and -6(R)-ol in nemerteans was shown for the first time. PMID- 30439441 TI - Assessment of endophyte-derived tremorgenic compounds in Ipomoea asarifolia using mouse models. AB - Ipomoea asarifolia has been associated with a tremorgenic syndrome in livestock. Recently indole diterpene compounds were identified in I. asarifolia, some of which have been shown to cause a tremorgenic syndrome. In this study, the tremorgenic nature of I. asarifolia was assessed using a mouse model. Adult mice were fed rodent chow containing 10, 15, 20 and 25% endophyte infected (E+), or 25% endophyte free (E-), I. asarifolia for 14 days. The mice fed E+ chow developed a tremorgenic syndrome as characterized by visually observed muscle tremors and an inability to traverse a balance beam, whereas the mice fed E- chow did not develop tremors and had similar muscle coordination to control mice. A lactating mouse model was also used to determine if the compounds can be transferred to nursing pups via the milk. Nursing pups were exposed via their mother's milk for 21 days, from post-natal day 0-21. The pups from dams exposed to E+ chow developed a similar tremorgenic syndrome. Data presented in this study demonstrate that the tremorgenic compounds in I. asarifolia are endophyte derived. Additionally, both adult mice and nursing pups are good models for studying the tremorgenic nature of I. asarifolia and related plants. PMID- 30439442 TI - Mushroom poisoning: A proposed new clinical classification. AB - Mushroom poisoning is a significant and increasing form of toxin-induced-disease. Existing classifications of mushroom poisoning do not include more recently described new syndromes of mushroom poisoning and this can impede the diagnostic process. We reviewed the literature on mushroom poisoning, concentrating on the period since the current major classification published in 1994, to identify all new syndromes of poisoning and organise them into a new integrated classification, supported by a new diagnostic algorithm. New syndromes were eligible for inclusion if there was sufficient detail about both causation and clinical descriptions. Criteria included: identity of mushrooms, clinical profile, epidemiology, and the distinctive features of poisoning in comparison with previously documented syndromes. We propose 6 major groups based on key clinical features relevant in distinguishing between poisoning syndromes. Some clinical features, notably gastrointestinal symptoms, are common to many mushroom poisoning syndromes. Group 1 - Cytotoxic mushroom poisoning. Syndromes with specific major internal organ pathology: (Subgroup 1.1; Primary hepatotoxicity); 1A, primary hepatotoxicity (amatoxins); (Subgroup 1.2; Primary nephrotoxicity); 1B, early primary nephrotoxicity (amino hexadienoic acid; AHDA); 1C, delayed primary nephrotoxicity (orellanines). Group 2 - Neurotoxic mushroom poisoning. Syndromes with primary neurotoxicity: 2A, hallucinogenic mushrooms (psilocybins and related toxins); 2B, autonomic-toxicity mushrooms (muscarines); 2C, CNS toxicity mushrooms (ibotenic acid/muscimol); 2D, morel neurologic syndrome (Morchella spp.). Group 3 - Myotoxic mushroom poisoning. Syndromes with rhabdomyolysis as the primary feature: 3A, rapid onset (Russula spp.); 3B, delayed onset (Tricholoma spp.). Group 4 - Metabolic, endocrine and related toxicity mushroom poisoning. Syndromes with a variety of clinical presentations affecting metabolic and/or endocrine processes: 4A, GABA-blocking mushroom poisoning (gyromitrins); 4B, disulfiram-like (coprines); 4C, polyporic mushroom poisoning (polyporic acid); 4D, trichothecene mushroom poisoning (Podostroma spp.); 4E, hypoglycaemic mushroom poisoning (Trogia venenata); 4F, hyperprocalcitoninemia mushroom poisoning (Boletus satanas); 4G, pancytopenic mushroom poisoning (Ganoderma neojaponicum). Group 5 - Gastrointestinal irritant mushroom poisoning. This group includes a wide variety of mushrooms that cause gastrointestinal effects without causing other clinically significant effects. Group 6 - Miscellaneous adverse reactions to mushrooms. Syndromes which do not fit within the previous 5 groups: 6A, Shiitake mushroom dermatitis; 6B, erythromelagic mushrooms (Clitocybe acromelagia); 6C, Paxillus syndrome (Paxillus involutus); 6D, encephalopathy syndrome (Pleurocybella porrigens). PMID- 30439443 TI - Intracranial atherosclerotic disease. AB - Intracranial atherosclerosis (ICAS) is a progressive pathological process that causes progressive stenosis and cerebral hypoperfusion and is a major cause of stroke occurrence and recurrence around the world. Multiple factors contribute to the development of ICAS. Angiography imaging techniques can improve the diagnosis of and the selection of appropriate treatment regimens for ICAS. Neither aggressive medication nor endovascular interventions can eradicate stroke recurrence in patients with ICAS. Non-pharmacological therapies such as remote ischemic conditioning and hypothermia are emerging. Comprehensive therapy with medication in combination with endovascular intervention and/or non pharmacological treatment may be a potential strategy for ICAS treatment in the future. We summarized the epidemiology, pathophysiological mechanisms, risk factors, biomarkers, imaging and management of ICAS. PMID- 30439444 TI - Calcium activated nucleotidase 1 (CANT1) is critical for glycosaminoglycan biosynthesis in cartilage and endochondral ossification. AB - Desbuquois dysplasia type 1 (DBQD1) is a chondrodysplasia caused by mutations in CANT1 gene encoding an ER/Golgi calcium activated nucleotidase 1 that hydrolyses UDP. Here, using Cant1 knock-in and knock-out mice recapitulating DBQD1 phenotype, we report that CANT1 plays a crucial role in cartilage proteoglycan synthesis and in endochondral ossification. Specifically, the glycosaminoglycan synthesis was decreased in chondrocytes from Cant1 knock-out mice and their hydrodynamic size was reduced, whilst the sulfation was increased and the overall proteoglycan secretion was delayed. Interestingly, knock-out chondrocytes had dilated ER cisternae suggesting delayed protein secretion and cellular stress; however, no canonical ER stress response was detected using microarray analysis, Xbp1 splicing and protein levels of BiP and ATF4. The observed proteoglycan defects caused deregulated chondrocyte proliferation and maturation in the growth plate resulting in the reduced skeletal growth. In conclusion, the pathogenic mechanism of DBQD1 comprises deregulated chondrocyte performance due to defective intracellular proteoglycan synthesis and altered proteoglycan properties in the extracellular matrix. PMID- 30439445 TI - A sesquiterpenoid tropolone and 1,2,3,4-tetrahydronaphthalene derivatives from Olax imbricata roots. AB - The methanol extract of Olax imbricata roots afforded one new sesquiterpenoid tropolone and three new 1,2,3,4-tetrahydronaphthalene derivatives, olaximbrisides A-D (1-4). Their structures were determined by 1D and 2D NMR experiments in combination of HRESIMS. The relative configurations were assigned by the NOESY experiments. The absolute configurations were established by a combination of X ray diffraction analysis and electronic circular dichroism (ECD) experiments. All isolated compounds were evaluated for their cytotoxic effects against some cancer cell lines. Among them, compound 1 exhibited the cytotoxicities against MCF-7, HepG2 and LU cell lines with IC50 values of 16.3, 34.3 and 8.0 MUM, respectively. PMID- 30439446 TI - Role of Trichoderma arundinaceum tri10 in regulation of terpene biosynthetic genes and in control of metabolic flux. AB - Production of trichothecene toxins occurs in phylogenetically diverse fungi with different lifestyles. In these fungi, most homologs of the trichothecene biosynthetic gene cluster include the transcription factor genes tri6 and tri10. Analyses of phytopathogenic species of Fusarium indicate that the TRI6 and TRI10 proteins positively regulate genes required for synthesis of trichothecenes as well as farnesyl diphosphate (FPP), a precursor of the trichothecene and other terpenoids (e.g., ergosterol). However, the apparent absence of tri6 and tri10 in some trichothecene-producing fungi, and the presence of multiple paralogs of the genes in others suggest considerable variability in genetic regulation of trichothecene biosynthesis. To begin to investigate this variability, we functionally characterized tri10 in the saprotrophic fungus Trichoderma arundinaceum. We found that TRI10 is required for wild-type expression of tri genes and trichothecene production during the first 12 h of growth of T. arundinaceum. Comparison of the effect of tri10 deletion in T. arundinaceum and Fusarium species has provided evidence for similarities in the genetic regulation of trichothecene biosynthesis in these two fungi with different lifestyles. In contrast to trichothecenes, tri10 deletion increased production of ergosterol and the polyketide-derived metabolites aspinolides, which is more likely caused by an increase in the intracellular pool of FPP resulting from loss of trichothecene production. Furthermore, although it is unclear how TRI10 affects polyketide production, one possibility is that it does so by rechanneling terpene precursors. PMID- 30439447 TI - Role of MIF and D-DT in immune-inflammatory, autoimmune, and chronic respiratory diseases: from pathogenic factors to therapeutic targets. AB - Macrophage migration inhibitory factor (MIF) is a protein that acts as a cytokine , enzyme-, endocrine- and chaperon-like molecule. It binds to the cell-surface receptor CD74 in association with CD44, which activates the downstream signal transduction pathway. In addition, MIF acts also as a noncognate ligand for C-X-C chemokine receptor type 2 (CXCR2), type 4 (CXCR4), and type 7 (CXCR7). Recently, D-dopachrome tautomerase (D-DT), a second member of the MIF superfamily, was identified. From a pharmacological and clinical point of view, the nonredundant biological properties of MIF and D-DT anticipate potential synergisms from their simultaneous inhibition. Here, we focus on the role of MIF and D-DT in human immune-inflammatory, autoimmune, and chronic respiratory diseases, providing an update on the progress made in the identification of specific small-molecule inhibitors of these proteins. PMID- 30439448 TI - Toward improving drug delivery research in Egypt: Cancer Nanotechnology Research Laboratory (CNRL) as a role model. PMID- 30439449 TI - The essentiality of drug targets: an analysis of current literature and genomic databases. AB - Essential genes encode proteins thought to be crucial for the survival of an organism. However, the role of essential genes in human disease and their suitability as drug targets is less clear. Here, we use a recent catalog of nearly 9000 known essential and nonessential genes to evaluate their involvement as therapeutic targets in human diseases. We find that essential genes are more likely than nonessential genes to play a part in specific therapeutic areas such as cardiovascular diseases and neoplasms. We also find significant differences between essential and nonessential genes among protein classes relevant to drug discovery. Taken together, our analyses suggest that the essentiality status of a potential new target is an important consideration in drug discovery. PMID- 30439450 TI - Biomechanics of the human lens and accommodative system: Functional relevance to physiological states. AB - The ability of the human lens to accommodate is mediated by the ciliary muscle and zonule; the manifest optical power changes depend on the shape and material properties of the lens. The latter are difficult to measure with accuracy and, given the dynamic aspects of accommodation and the ageing of cells and tissues, the biomechanics of the lens is neither fixed nor constant. A range of techniques have been developed to measure both ageing trends and spatial variations in the mechanical properties and these have yielded a diverse array of findings and respective conclusions. The majority of quasi-static measurements, where the observation time is in minutes or hours, indicate that the stiffness of the lens increases with age at a faster rate in the lens centre than in the periphery. Dynamic measurements show that lens material properties are dependent on the loading frequency. Recent in vivo analyses suggest that, along the optic axis, profiles of elastic moduli are very similar to profiles of refractive index. This review assesses the advantages and limitations of different measurement techniques and consequent variations in elastic moduli that have been found. Consideration is given to the role of computational modelling and the various modelling methods that have been applied. The changes in mechanical properties of the lens associated with ageing and pathology and future implications for implant design are discussed. PMID- 30439451 TI - Sexual interaction is essential for the transformation of non-copulating rats into sexually active animals by the endocannabinoid anandamide. AB - The endocannabinoid anandamide (AEA) transforms half of the population of previously non-copulating (NC) rats into sexually active animals in a long lasting manner. The aim of this work was to explore the nature of this transformation. We identified the dose range in which AEA induces mating behavior in previously NC rats, which evidenced a dose-based, biphasic profile for AEA to induce the transformation of NC rats. We demonstrate that the sexual interaction with a receptive female, involving at least an intromission, is essential for AEA to induce the transformation of NC rats. This AEA-induced conversion is centrally mediated and involves the activation of CB1 receptors. Results indicate that the sexual impairment of this population of NC rats relies on their incapacity to initiate sexual activity and that an unidentified brain inhibitory influence on sexual behavior expression is removed by AEA treatment, allowing previously NC rats to show copulatory behavior in a long-lasting manner. The inhibitory influence is not removed by AEA treatment when animals are not allowed to have sexual contact with the female immediately after AEA injection. The same result was found for the opioid receptor antagonist naloxone, the other treatment reported to induce copulation in rats classified as NC. These data suggest that sexual behavior expression could depend on two different neural mechanisms at two different moments: one involved in the display of the first copulatory response and another responsible for maintaining subsequent sexual behavior responding. PMID- 30439452 TI - The influence of reward sensitivity, heart rate dynamics and EEG-delta activity on placebo analgesia. AB - Personality traits have been shown to interact with environmental cues to modulate biological responses including treatment responses, and potentially having a role in the formation of placebo effects. Here we used the Reinforcement Sensitivity Theory Personality Questionnaire (RST-PQ) to identify personality traits that predict placebo analgesic responding. Cardiac inter-beat (RR) time series and electroencephalographic (EEG) band oscillations were recorded from healthy women in a cold-pain (Pain) and placebo analgesia (PA) condition. The measures of Hypnotizability, and self-reported ratings of Hypnotic Depth, Motivation, Pain Expectation, Involuntariness in PA responding, Pain and Distress intensity were obtained. Separate principal components factor analyses with varimax rotation were performed on summarized heart rate variability (HRV) measures of time, frequency, nonlinear Complexity, and EEG-band activity. Both analyses yielded a similar three-factor solution including Frequency HRV (factor 1), Complexity HRV dynamics (factor-2), and time HRV & EEG-delta activity (factor 3). Reward Interest sub-trait of the Behavioral Approach System (BAS-RI), Pain Expectation, Involuntariness in PA responding, and Hypnotic Depth were positively associated, whereas negative changes in time-HRV & EEG-delta scores were associated with Pain Reduction. Multiple mediation analyses disclosed that BAS RI, potentially served by the dopaminergic system, through Involuntariness in PA responding can alter placebo responding to laboratory pain. Our results also show that a linear compound of HR slowing and higher EEG delta activity during PA explains a substantial proportion of the variance in placebo analgesic responses. Future studies should examine the potential role that these individual difference measures may play in patient responsiveness to treatments for clinical pain. PMID- 30439453 TI - Identification of schizophrenia related biological pathways across eight brain regions. AB - Schizophrenia is a severe mental disorder with high heritability. GWAS had identified multiple susceptible regions associated with schizophrenia. However, a number of variants remained to be explored due to their location in non-coding regions. Enhancers were important DNA elements that positively regulated the expression of target genes. We applied a novel method to conduct pathway enrichment analysis in schizophrenia across 8 brain regions. GWAS summary data and enhancer-target networks of the 8 regions were integrated in this approach. Finally, we identified several genes involving in neurodevelopmental processes across the 8 regions. It is remarkable germinal matrix showed strongest relationship with schizophrenia, which is mainly involved in cells migrate out during brain development. Substantia nigra, dorsolateral prefrontal cortex, inferior temporal lobe and hippocampus middle also showed stronger signals. We also found that schizophrenia was mainly associated with "Immune Diseases", "Gene Expression", "Cell Cycle", "Cellular Component" and "Biological Process" across specific brain regions. Our study supported the argument that schizophrenia is a severe mental disorder with early brain dysplasia or impairment of cognitive and memory related areas, which provided novel insight to the pathophysiology of schizophrenia. PMID- 30439454 TI - Neuropeptide receptors as potential pharmacological targets for obesity. AB - Obesity is a chronic multifactorial disease, characterized by an excessive accumulation of adipose tissue. It is usually the result of excessive food intake and/or low energy expenditure. Obesity can be triggered by lifestyle, nutritional, genetic, environmental, hormonal and psychological factors. Several strategies are used to treat obesity, including dietary reeducation, with balanced food intake, increased physical exercise, in order to promote energy expenditure and to overcome the insufficiency in weight reduction by other strategies, and the administration of drugs to treat obesity. However, these medications are associated to undesirable side effects, resulting in a high withdrawal rate. Several studies have been focused on the development of compounds that act in the hypothalamic region where the center of the regulation of hunger and satiety is located. Some of them target the activity of endogenous peptide, such as ghrelin pancreatic polypeptide, peptide YY and neuropeptide Y, as well as their receptors. This review addresses the importance of understanding the neuropeptide/peptide hormones and their receptors for the development of novel anti-obesity compounds that may aid in weight reduction as a promising alternative for the treatment of obesity. PMID- 30439455 TI - Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics. AB - Atherosclerosis, the principal cause of cardiovascular death worldwide, is a pathological disease characterized by fibro-proliferation, chronic inflammation, lipid accumulation, and immune disorder in the vessel wall. As the atheromatous plaques develop into advanced stage, the vulnerable plaques are prone to rupture, which causes acute cardiovascular events, including ischemic stroke and myocardial infarction. Emerging evidence has suggested that atherosclerosis is also an epigenetic disease with the interplay of multiple epigenetic mechanisms. The epigenetic basis of atherosclerosis has transformed our knowledge of epigenetics from an important biological phenomenon to a burgeoning field in cardiovascular research. Here, we provide a systematic and up-to-date overview of the current knowledge of three distinct but interrelated epigenetic processes (including DNA methylation, histone methylation/acetylation, and non-coding RNAs), in atherosclerotic plaque development and instability. Mechanistic and conceptual advances in understanding the biological roles of various epigenetic modifiers in regulating gene expression and functions of endothelial cells (vascular homeostasis, leukocyte adhesion, endothelial-mesenchymal transition, angiogenesis, and mechanotransduction), smooth muscle cells (proliferation, migration, inflammation, hypertrophy, and phenotypic switch), and macrophages (differentiation, inflammation, foam cell formation, and polarization) are discussed. The inherently dynamic nature and reversibility of epigenetic regulation, enables the possibility of epigenetic therapy by targeting epigenetic "writers", "readers", and "erasers". Several Food Drug Administration-approved small-molecule epigenetic drugs show promise in pre-clinical studies for the treatment of atherosclerosis. Finally, we discuss potential therapeutic implications and challenges for future research involving cardiovascular epigenetics, with an aim to provide a translational perspective for identifying novel biomarkers of atherosclerosis, and transforming precision cardiovascular research and disease therapy in modern era of epigenetics. PMID- 30439456 TI - Altered cancer metabolism in mechanisms of immunotherapy resistance. AB - Many metabolic alterations, including the Warburg effect, occur in cancer cells that influence the tumor microenvironment, including switching to glycolysis from oxidative phosphorylation, using opportunistic modes of nutrient acquisition, and increasing lipid biosynthesis. The altered metabolic landscape of the tumor microenvironment can suppress the infiltration of immune cells and other functions of antitumor immunity through the production of immune-suppressive metabolites. Metabolic dysregulation in cancer cells further affects the expression of cell surface markers, which interferes with immune surveillance. Immune checkpoint therapies have revolutionized the standard of care for some patients with cancer, but disease in many others is resistant to immunotherapy. Specific metabolic pathways involved in immunotherapy resistance include PI3K-Akt mTOR, hypoxia-inducible factor (HIF), adenosine, JAK/STAT, and Wnt/Beta-catenin. Depletion of essential amino acids such as glutamine and tryptophan and production of metabolites like kynurenine in the tumor microenvironment also blunt immune cell function. Targeted therapies against metabolic checkpoints could work in synergy with immune checkpoint therapy. This combined strategy could be refined by profiling patients' mutation status before treatment and identifying the optimal sequencing of therapies. This personalized combinatorial approach, which has yet to be explored, may well pave the way for overcoming resistance to immunotherapy. PMID- 30439457 TI - Gut-brain axis and addictive disorders: A review with focus on alcohol and drugs of abuse. AB - Due to the limited efficacy of existing medications for addictive disorders including alcohol use disorder (AUD), the need for additional medications is substantial. Potential new medications for addiction can be identified through investigation of the neurochemical substrates mediating the ability of drugs of abuse such as alcohol to activate the mesolimbic dopamine system. Interestingly, recent studies implicate neuropeptides of the gut-brain axis as modulators of reward and addiction processes. The present review therefore summarizes the current studies investigating the ability of the gut-brain peptides ghrelin, glucagon-like peptide-1 (GLP-1), amylin and neuromedin U (NMU) to modulate alcohol- and drug-related behaviors in rodents and humans. Extensive literature demonstrates that ghrelin, the only known orexigenic neuropeptide to date, enhances reward as well as the intake of alcohol, and other drugs of abuse, while ghrelin receptor antagonism has the opposite effects. On the other hand, the anorexigenic peptides GLP-1, amylin and NMU independently inhibits reward from alcohol and drugs of abuse in rodents. Collectively, these rodent and human studies imply that central ghrelin, GLP-1, amylin and NMU signaling may contribute to addiction processes. Therefore, the need for randomized clinical trials investigating the effects of agents targeting these aforementioned systems on drug/alcohol use is substantial. PMID- 30439458 TI - Synaptic dysfunction in Alzheimer's disease: Mechanisms and therapeutic strategies. AB - Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly population, is characterized by progressive cognitive decline and pathological hallmarks of amyloid plaques and neurofibrillary tangles. However, its pathophysiological mechanisms are poorly understood, and diagnostic tools and interventions are limited. Here, we review recent research on the amyloid hypothesis and beta-amyloid-induced dysfunction of neuronal synapses through distinct cell surface receptors. We also review how tau protein leads to synaptotoxicity through pathological modification, localization, and propagation. Finally, we discuss experimental therapeutics for AD and propose potential applications of disease-modifying strategies targeting synaptic failure for improved treatment of AD. PMID- 30439459 TI - Enabling an HCV Treatment Revolution and the Frontiers of Solid Solution Formulation. PMID- 30439460 TI - Bioequivalence comparison of pediatric Dasatinib formulations and elucidation of absorption mechanisms through integrated PBPK modeling. AB - Sprycel(r) (Dasatinib) is a BCS II weakly basic drug that exhibits strong pH dependent solubility. Dasatinib is currently presented in two drug product formulations as an adult immediate release tablet and a pediatric powder for oral suspension (PFOS). A bioequivalence study comparing the formulations in adult healthy subjects found overall exposure (AUC0-24) from suspension treatments was ~9-13% lower, Cmax was similar, and median Tmax from PFOS was ~30 minutes earlier. To understand the mechanism contributing to this behavior a combination of biorelevant dissolution studies and physiologically based pharmacokinetic (PBPK) modeling was used to simulate in vivo performance. In-vitro biorelevant dissolution confirmed the rate and extent of release was similar between tablet and suspension formulations (>90% release within first 15 minutes). PBPK parameter sensitivity analysis demonstrated particular sensitivity to dosage form gastric residence time. A 12% higher AUC0-24 was simulated for tablet dosage forms with 10-15 minutes longer gastric transit relative to solutions or suspensions of small particulates (rapid gastric emptying). The corresponding narrow simulated Cmax range also agreed with observed tablet and suspension bioequivalence data. The unique physicochemical properties, absorption characteristics, and inherent differences in dosage form transit behavior are attributed to influence the dasatinib bioequivalence. PMID- 30439461 TI - Numerical investigation of analytical models of drug flux through microporated skin. AB - In this work drug flux through microporated skin was modeled using detailed numerical solution of the diffusion equation. The results of the modelling were compared to previously published simplified and easy to use analytical equations. Limitations and accuracy of these equations were investigated. Appropriate modifications of the equations were identified to expand them to wider practical applications when pores shape is not circular. Numerical simulations have shown a good accuracy of the new simple equations when these are used within their limits of application. PMID- 30439462 TI - Preparation of Curcuma longa L. Extract Nanoparticles Using Supercritical Solution Expansion. AB - Nanoparticles of Curcuma longa Linn (turmeric) rhizome extract were prepared using supercritical carbon dioxide (SC-CO2). The SC-CO2 was used for sample pretreatment, including lipophilic compounds removal and extraction as well as particle production. The particle formation process was based on the expansion of supercritical solution (ESS) of plant extract into a secondary chamber. In the course of the ESS process, the herbal extract changed from dissolved mode at higher pressures to precipitated mode at lower pressures, as long as the pressures were higher than critical pressure. The particle growth via coagulation was limited by a large number of unsuccessful collisions between CO2 molecules and primary nuclei due to the presence of pressurized CO2 molecules where the particle formation occurs. The presence of curcumin derivatives in nanoparticles was confirmed by Liquid Chromatography-Mass Spectrometry (LC-MS) results. Irregular to quasi-spherical particles with average diameter of 47 +/- 20 nm (n = 300) were prepared at a pre-expansion pressure of 35 MPa, pressure drop of 24 MPa, temperature of 50 degrees C, equilibration time of 30 min, collection time of 60 min, extract volume of 30 MUL, and feeding solution concentration of 2 mg mL-1. PMID- 30439463 TI - Rapid detection of colistin-resistant Klebsiella pneumoniae using MALDI-TOF MS peak-based assay. AB - Carbapenemase-producing Klebsiella pneumoniae has become a worldwide recognized cause of nosocomial infections and requires urgent public health attention. The main reason of this concern is the increasing resistance to all the last-resort antibiotics, including colistin. The ideal methodology for colistin susceptibility testing still remains undefined. However, the emergence of colistin as one of the last-option treatments requires a reliable method to determine the susceptibility profile of resistant isolates. The aim of the present study was to evaluate the impact of detecting colistin resistance in Klebsiella pneumoniae isolates using MALDI-TOF MS in clinical routine practice. For this reason, 139 isolates of K. pneumoniae were collected during 2015-2017 from patients hospitalized at Pisa University Hospital. Colonies suspected to be colistin resistant were identified using MALDI-TOF MS (Bruker Daltonik GmbH, Bremen, Germany) following a protein extraction protocol. Strains were previously wholly genome sequenced. To create a customized database entry and to generate classifying algorithm models, 1.112 mass spectra were collected. In relation to their mass signals and intensities, a two dimensional peak distribution was created. The recognition capability of the algorithm based on two manually selected mass peaks was 91,8%, while cross validation was 87,6%. The proportion of correctly classified colistin-resistant K. pneumoniae was 91% and colistin susceptible was 73%. The emergence of colistin-resistant Gram-negative organisms has a dramatic impact on patient outcomes. Our study, based on MALDI-TOF MS technology, offers rapid preliminary results on colistin resistance profile coupled with bacteria identification. PMID- 30439464 TI - Colorimetric assay for active biomass quantification of Fusarium fujikuroi. AB - A colorimetric assay has been developed for quantitative analysis of active biomass of Fusarium fujikuroi, based on the reduction of the tetrazolium salt 2,3 Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT) when menadione was present as an electron coupling agent. The optimum assay-conditions were set as 200 MUg/ml XTT, 5 MUM menadione and one-hour reaction time. Under these settings, the produced formazan displayed a linear relationship with F. fujikuroi biomass. This method was subsequently applied to evaluate the cell growth behavior, which showed a positive correlation with the carbon source consumption and gibberellin biosynthesis under the industrial fermentation conditions. Our results showed that the XTT-menadione assay is a valuable tool in analyzing the industrial fermentation process of F. fujikuroi, especially when the medium contains insoluble and complex components. PMID- 30439465 TI - Applying simple linear combination, multiple logistic and factor analysis methods for candidate fecal bacteria as novel biomarkers for early detection of adenomatous polyps and colon cancer. AB - BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer, and presents a considerable disease burden, worldwide. Recently, the gut microbiota has been proposed as a potential risk factor for CRC, and even adenomatous polyps (AP). Here, the aim of this study was to investigate the role of selected gut bacteria as fecal bacterial biomarkers, in early detection of CRC and AP. MATERIAL AND METHODS: Fecal samples (n = 93) were collected from Taleghani Hospital, Tehran, Iran, between 2015 and 2017, from normal controls (NC), AP cases and CRC stage I patients, who were undergoing screening for colonoscopy. Absolute quantitative real time PCR (qPCR) assays were established for the quantification of bacterial marker candidates, in all cases and control groups. In order to evaluate the diagnostic value of bacterial candidates in distinguishing CRC from a polyp, receiver operating characteristic curve (ROC) was performed. Multiple logistic regressions were used to find the best combinations of the bacterial candidates, then, combinations were analyzed based on three methods, including linear combination, multiple logistic and factor analysis models. RESULTS: According to the logistic model, combination of Fusobacterium nucleatum, Enterococcus feacalis, Streptococcus bovis, Enterotoxigenic Bacteroides fragilis (ETBF) and Porphyromonas spp. showed improved diagnostic performance, compared to each bacterium alone, as area under the receiver operating characteristic (AUROC) increases to 0.97, with 95% confidence interval. It was found that a simple linear combination was an appropriate model for discriminating AP and CRC cases, compared to the NC, with a sensitivity of 91.4% and specificity of 93.5%. CONCLUSION: Our results indicated that based on fecal bacterial candidates, statistical simple linear combination model and ROC curve analysis, early detection of AP and CRC might be possible. PMID- 30439466 TI - Establishment of a suspension array for Pseudomonas aeruginosa O-antigen serotyping. AB - Pseudomonas aeruginosa (P. aeruginosa) is widespread in the environment. It readily infects hospital and immunocompromised patients. Traditional biochemical and immunological diagnoses of P. aeruginosa infection cannot meet clinical demands. The variability of O-antigens is the primary basis for the serotyping schemes of many gram-negative bacteria, which is the most widely used method for pathogenic epidemiological purposes. In this study, we developed a suspension array that can accurately diagnose and identify 19 different P. aeruginosa O antigen serotypes except O15, whose O-antigen gene cluster has not been characterized. In this assay, wzx/wzy genes were selected as the sero-specific gene for 18 serotypes other than O6, for which the glycosyltransferase gene wbpP was utilized. Meanwhile, the wzybeta gene was added to separate O2/16 from O5/18/20, and the insertion sequence (IS) in wzx was used to separate O17 from O11. Eighty-two clinical isolates were screened to test our assay. A total of 65 isolates (79.3%) could be serotyped, and the result were confirmed to be correct by sequencing. Sensitivity analysis indicated that at least 5 ng DNA or 103 CFU cells could be detected using our suspension array. To our knowledge, this is the first report on serotyping P. aeruginosa by suspension array and may be of great value in the clinical diagnostics of P. aeruginosa infection. PMID- 30439467 TI - The effect of delayed and early diagnosis in siblings, and importance of newborn screening for SCID. PMID- 30439468 TI - An ounce of caution: Superparamagnetic iron oxide nanoparticle based magnetic resonance imaging contrast-associated anaphylaxis. PMID- 30439469 TI - Food OIT is Superior to Food Avoidance. PMID- 30439470 TI - The first reported case of pelvic inflammatory disease caused by Actinobaculum massiliense. AB - We report the first case of pelvic inflammatory disease (PID) caused by Actinobaculum massiliense. A 53-year-old woman attended the emergency department with symptoms compatible with a PID episode, finally resolved by intramuscular antibiotic treatment. Actinobaculum sp. was isolated by culture, and A. massiliense was confirmed by matrix assisted laser desorption time-of-flight mass spectrometry and 16S rRNA gene sequencing. Only a few cases of A. massiliense infections have been reported, and the pathogenesis of infections by these bacteria is poorly understood. The introduction of new diagnostic methods into hospital routines will improve the detection of new and little-studied pathogens. PMID- 30439471 TI - A new subfamily, Pseudohaploporinae subfam. n. (Digenea: Haploporidae), with morphometric and molecular analyses of two new species: Pseudohaploporus vietnamensis n. g., sp. n. and Pseudohaploporus planilizum n. g., sp. n. from Vietnamese mullet. AB - Adult specimens representing Pseudohaploporus vietnamensis n. g., sp. n., Pseudohaploporus planilizum n. g., sp. n., and Pseudohaploporus sp. were collected from the intestines of Osteomugil engeli (Bleeker, 1858), Moolgarda seheli (Forsskal, 1775), and Planiliza subviridis (Valenciennes, 1836) from Vietnam. The new genus Pseudohaploporus n. g. is similar to the genus Haploporus Looss, 1902 in morphology and host-specificity. Species of Pseudohaploporus and Haploporus both possess an elongated body, a long oesophagus, an intestinal bifurcation behind the ventral sucker, a large hermaphroditic bursa, vitellarium consisting of two compact accumulations, concretions in the excretory vesicle, and numerous small eggs that contain miracidia with a pigment eye, and both infect mullet. In contrast to Haploporus, both species of the genus Pseudohaploporus possess two testes. These species differ from each other morphometrically. Pseudohaploporus planilizum sp. n., in comparison with P. vietnamensis sp. n., possess a larger maximum and mean size for the body length, oral and ventral suckers, pharynx, oesophagus length, hermaphrodite bursa, and egg width. Molecular data (ITS and 28S rDNA sequences) support the validity of the new genus and the two new species and indicate the presence of another representative of this genus, Pseudohaploporus sp. Phylogenetic reconstructions show that Pseudohaploporus formed a well-supported clade within a large clade that represents the Haploporidae Nicoll, 1914. Based on morphological and molecular data for P. vietnamensis sp. n. and P. planilizum sp. n., we erected a new subfamily, Pseudohaploporinae subfam. n., which appears to be a sister taxon to Haploporinae Nicoll, 1914. Molecular data show that Pseudohaploporus differ from other haploporids at a level similar to that between other subfamilies. PMID- 30439472 TI - High sensitivity proteomics of prostate cancer tissue microarrays to discriminate between healthy and cancerous tissue. AB - Biopsies, in the form of tissue microarrays (TMAs) were studied to identify anomalies indicative of prostate cancer at the proteome level. TMAs offer a valuable source of well-characterized biological material. However, because of the small tissue sample size method development was essential to provide the sensitivity and reliability necessary for the analysis. Surface digestion of TMA cores was followed by peptide extraction and shotgun proteomics analysis. About 5 times better sensitivity was achieved by the optimized surface digestion compared to bulk digestion of the same TMA spot and it allowed the identification of over 500 proteins from individual prostate TMA cores. Label-free quantitation showed that biological variability among all samples was about 3 times larger than the technical reproducibility. We have identified 189 proteins which showed statistically significant changes (t-test p-value <.05) in abundance between healthy and cancerous tissue samples. The proteomic profile changed according to cancer grade, but did not show a correlation with cancer stage. Results of this pilot study were further evaluated using bioinformatics tools, identifying various protein pathways affected by prostate cancer progression indicating the usefulness of studying TMA cores to identify quantitative changes in tissue proteomics. SIGNIFICANCE: Detailed proteomics analysis of TMAs presents a good alternative for tissue analysis. Here we present a novel method, based on tissue surface digestion and nano-LC-MS measurements, which is capable of identifying and quantifying over 500 proteins from a 1.5 mm diameter tissue section. We compared healthy and cancerous prostate tissue samples, and tissues with various grades and stages of cancer. Tissue proteomics clearly distinguished healthy and cancerous samples, furthermore the results correlated well with cancer grade, but not with cancer stage. Over 100 proteins showed statistically significant abundance changes (t-test p-value <.05) between various groups. This was sufficient for a meaningful bioinformatics evaluation; showing e.g. increased abundance of proteins in cancer in the KEGG ribosome pathway, GO mRNA splicing via spliceosome, and chromatin assembly biological processes. The results highlight the feasibility of the developed method for future large-scale tissue proteomics studies using commercially available TMAs. PMID- 30439474 TI - The tapeworm Ligula intestinalis alters the behavior of the fish intermediate host Engraulicypris sardella, but only after it has become infective to the final host. AB - Ligula intestinalis is a tapeworm using copepods and cyprinid fish as intermediate hosts and fish-eating birds as final hosts. Since some parasites can increase their own fitness by manipulating the behavior of the intermediate host, we explored if this parasite affected predator avoidance, swimming activity and depth preference of the fish intermediate host, Engraulicypris sardella. We found that when L. intestinalis had reached a developmental stage that is able to establish in the bird host, it had a significant impact on E. sardella behavior, while the tapeworm that was not fully developed had little effect and fish hosts showed a behavior more similar to uninfected fish. These results are discussed with respect to two different processes: the manipulation hypothesis and the energy drain hypothesis. PMID- 30439473 TI - A novel murine model for contact lens wear reveals clandestine IL-1R dependent corneal parainflammation and susceptibility to microbial keratitis upon inoculation with Pseudomonas aeruginosa. AB - PURPOSE: Contact lens wear carries a risk of complications, including corneal infection. Solving these complications has been hindered by limitations of existing animal models. Here, we report development of a new murine model of contact lens wear. METHODS: C57BL/6 mice were fitted with custom-made silicone hydrogel contact lenses with or without prior inoculation with Pseudomonas aeruginosa (PAO1-GFP). Contralateral eyes served as controls. Corneas were monitored for pathology, and examined ex vivo using high-magnification, time lapse imaging. Fluorescent reporter mice allowed visualization of host cell membranes and immune cells. Lens-colonizing bacteria were detected by viable counts and FISH. Direct-colony PCR was used for bacterial identification. RESULTS: Without deliberate inoculation, lens-wearing corneas remained free of visible pathology, and retained a clarity similar to non-lens wearing controls. CD11c-YFP reporter mice revealed altered numbers, and distribution, of CD11c positive cells in lens-wearing corneas after 24 h. Worn lenses showed bacterial colonization, primarily by known conjunctival or skin commensals. Corneal epithelial cells showed vacuolization during lens wear, and after 5 days, cells with phagocyte morphology appeared in the stroma that actively migrated over resident keratocytes that showed altered morphology. Immunofluorescence confirmed stromal Ly6G-positive cells after 5 days of lens wear, but not in MyD88 or IL-1R gene-knockout mice. P. aeruginosa-contaminated lenses caused infectious pathology in most mice from 1 to 13 days. CONCLUSIONS: This murine model of contact lens wear appears to faithfully mimic events occurring during human lens wear, and could be valuable for experiments, not possible in humans, that help solve the pathogenesis of lens-related complications. PMID- 30439475 TI - The effects of anthropogenic noise on feeding behaviour in black-capped chickadees (Poecile atricapillus). AB - Anthropogenic noise has been shown to impact animal behaviour. Most studies investigating anthropogenic noise, and the detrimental effect it has on behaviour, have been conducted in the field, where a myriad of covariates can make interpretation challenging. In this experiment, we studied the effects of an approximation of anthropogenic noise, simulated with brown noise, on the feeding behaviour of wild-caught black-capped chickadees in a laboratory setting. We measured the amount of time spent eating while subjects heard either conspecific calls, brown noise, or a combination of calls and brown noise. We found that subjects fed more in the silence following playback than during the playback itself for all types of stimuli, suggesting that chickadees may shift their feeding behaviour to avoid feeding during periods of noise. The ability to adapt to changing environments (e.g., varying noise levels) may allow species to thrive in the presence of anthropogenic noise. Our findings outline a laboratory-based method that could be adopted and adapted to examine a variety avian species and of types anthropogenic noise. PMID- 30439476 TI - Pigeons spontaneously form three-dimensional shape categories. AB - We explored the pigeon's representation of the shape of simple three-dimensional objects (geons) rotated in depth (four views each of four geons). Pigeons assigned to the Categorization group had to respond differentially to images of four different geons-termed arch, barrel, brick, and wedge-based on their 3D shape, regardless of the orientation of the object. Pigeons assigned to the Pseudocategorization group had to respond differentially to the same objects based on groupings that did not correspond to object identity, which required the learning of local orientation-dependent features (e.g., a concave curve on top, or the position of an illumination hotspot). The Categorization group, which could employ object-identity representations, quickly achieved highly accurate responding. The Pseudocategorization group, however, failed to achieve reliable above-chance responding. In addition, the reaction times for the Categorization group were significantly shorter than for the Pseudocategorization group. These results indicate that pigeons show a strong, spontaneous tendency to categorize the shapes of different orientations in depth of the same 3D object as similar, if not equivalent; they do so despite the vast differences in image characteristics caused by the variations in orientations, even when such categorization is contrary to the reinforcement contingencies. PMID- 30439477 TI - Cross-talk between signal transduction and metabolism in B cells. AB - Mounting evidence demonstrates that specific metabolic adaptations are needed to support B cell development and differentiation and to enable B cells to thrive in different environments. Mitogen induced activation of intracellular signaling pathways triggers nutrient uptake and metabolic remodeling to meet the cells' current needs. Reciprocally, changes in the metabolic composition of the environment, or in intracellular metabolite levels, can modulate signal transduction and thus shape cell fate and function. In summary, signal transduction and metabolic pathways operate within an integrated network to cooperatively define cellular outcomes. PMID- 30439478 TI - Extracellular nucleotides and nucleosides as signalling molecules. AB - Extracellular nucleotides, mainly ATP, but also ADP, UTP, UDP and UDP-sugars, adenosine, and adenine base participate in the "purinergic signalling" pathway, an ubiquitous system of cell-to-cell communication. Fundamental pathophysiological processes such as tissue homeostasis, wound healing, neurodegeneration, immunity, inflammation and cancer are modulated by purinergic signalling. Nucleotides can be released from cells via unspecific or specific mechanisms. A non-regulated nucleotide release can occur from damaged or dying cells, whereas exocytotic granules, plasma membrane-derived microvesicles, membrane channels (connexins, pannexins, calcium homeostasis modulator (CALHM) channels and P2X7 receptor) or specific ATP binding cassette (ABC) transporters are involved in the controlled release. Four families of specific receptors, i.e. nucleotide P2X and P2Y receptors, adenosine P1 receptors, and the adenine selective P0 receptor, and several ecto- nucleotidases are essential components of the "purinergic signalling" pathway. Thanks to the activity of ecto nucleotidases, ATP (and possibly other nucleotides) are degraded into additional messenger molecules with specific action. The final biological effects depend on the type and amount of released nucleotides, their modification by ecto nucleotidases, and their possible cellular re-uptake. Overall, these processes confer a remarkable level of selectivity and plasticity to purinergic signalling that makes this network one of the most relevant extracellular messenger systems in higher organisms. PMID- 30439480 TI - Genome classification improvements based on k-mer intervals in sequences. AB - Given the vast amount of genomic data, alignment-free sequence comparison methods are required due to their low computational complexity. k-mer based methods can improve comparison accuracy by extracting an effective feature of the genome sequences. The aim of this paper is to extract k-mer intervals of a sequence as a feature of a genome for high comparison accuracy. In the proposed method, we calculated the distance between genome sequences by comparing the distribution of k-mer intervals. Then, we identified the classification results using phylogenetic trees. We used viral, mitochondrial (MT), microbial and mammalian genome sequences to perform classification for various genome sets. We confirmed that the proposed method provides a better classification result than other k-mer based methods. Furthermore, the proposed method could efficiently be applied to long sequences such as human and mouse genomes. PMID- 30439479 TI - Human natural killer cells and other innate lymphoid cells in cancer: Friends or foes? AB - Innate lymphoid cells (ILC) including NK cells (cytotoxic) and the recently identified "helper" ILC1, ILC2 and ILC3, play an important role in innate defenses against pathogens. Notably, they mirror analogous T cell subsets, regarding the pattern of cytokine produced, while the timing of their intervention is few hours vs days required for T cell-mediated adaptive responses. On the other hand, the effectiveness of ILC in anti-tumor defenses is controversial. The relevance of NK cells in the control of tumor growth and metastasis has been well documented and they have been exploited in the therapy of high risk leukemia in the haploidentical hematopoietic stem cell transplantation setting. In contrast, the actual involvement of helper ILCs remains contradictory. Thus, while certain functional capabilities of ILC1 and ILC3 may favor anti-tumor responses, other functions could rather favor tumor growth, neo-angiogenesis, epithelial-mesenchymal transition and metastasis. In addition, ILC2, by secreting type-2 cytokines, are thought to induce a prevalent pro-tumorigenic effect. Finally, the function of both NK cells and helper ILCs may be inhibited by the tumor microenvironment, thus adding further complexity to the interplay between ILC and tumors. PMID- 30439481 TI - SNPs associated with body weight and backfat thickness in two pig breeds identified by a genome-wide association study. AB - Growth and fat deposition are important economic traits due to the influence on production in pigs. In this study, a dataset of 1200 pigs with 345,570 SNPs genotyped by sequencing (GBS) was used to conduct a GWAS with single-marker regression method to identify SNPs associated with body weight and backfat thickness (BFT) and to search for candidate genes in Landrace and Yorkshire pigs. A total of 27 and 13 significant SNPs were associated with body weight and BFT, respectively. In the region of 149.85-149.89 Mb on SSC6, the SNP (SSC6: 149876737) for body weight and the SNP (SSC6: 149876507) for BFT were in the same locus region (a gap of 230 bp). Two SNPs were located in the DOCK7 gene, which is a protein-coding gene that plays an important role in pigmentation. Two SNPs located on SSC8: 54567459 and SSC11: 33043081 were found to overlap weight and BFT; however, no candidate gene was found in these regions. In addition, based on other significant SNPs, two positional candidate genes, NSRP1 and CADPS, were proposed to influence weight. In conclusion, this is the first study report using GBS data to identify the significant SNPs for weight and BFT. A total of four particularly interesting SNPs and one potential candidate genes (DOCK7) were found for these traits in domestic pigs. This study improves our knowledge to better understand the complex genetic architecture of weight and BFT, but further validation studies of these candidate loci and genes are recommended in pigs. PMID- 30439482 TI - Distinct signaling programs associated with progression of FGFR1 driven leukemia in a mouse model of stem cell leukemia lymphoma syndrome. AB - Constitutive activation of FGFR1 as a result of chromosome translocations is responsible for the development of a hematopoietic stem cell disorder that progresses to AML. We have developed a syngeneic mouse model of BCR-FGFR1 driven AML and used RNASeq to define gene expression signatures associated with disease progression. The development of the leukemic stem cells (LSC) is associated with a profound downregulation of specific transcription factors that normally maintain stem cell quiescence as well as cell adhesion and motility gene sets related to confinement to the stem cell niche. A prominent feature of the LSCs is the upregulation of genes involved in T-cell function, activation, migration and development. Despite this apparent T-cell priming in the LSCs, however, the majority of these genes are subsequently inactivated in the leukemic blast cells that derive from them. These studies provide insights into the molecular etiology of development and progression of FGFR1 driven AML. PMID- 30439483 TI - A comparative transcriptomic study on developmental gonads provides novel insights into sex change in the protandrous black porgy (Acanthopagrus schlegelii). AB - Protandrous black porgy (Acanthopagrus schlegelii) is a popular and valuable commercial marine fish in China and East Asian countries. Controlling and managing its breeding has been an imperative step towards obtaining a sustainable supply of this fish in aquaculture production systems. Therefore, study on the molecular mechanisms of sex change in black porgy has both scientific and commercial importance. Previously, we identified some candidate genes related to sex determination and differentiation from a high-quality genome assembly of the black porgy. In the present study, transcriptome sequencing of developmental gonads (including testis, ovotestis and ovary) of black porgy was performed to further investigate the sex-change mechanisms. Our results showed that the highly expressed male-related genes (dmrt1, piwi1, piwi2, sox9, sox30 and amh) at the male phase were significantly down-regulated to a substantial degree at the intersexual stage, and the female-related genes (jnk1, vasa, wnt4, figla and foxl2) were distinctly up-regulated when the fish grows into a female adult, suggesting the potential roles of these genes in sex change of the black porgy. These data also support a previous hypothesis that the femaleness will be switched on when the testis is entering the degenerated stage through the diminished dmrt1 expression. Our transcriptome data provide a very useful genomic resource for future studies on sex change and practical aquaculture in the black porgy. PMID- 30439484 TI - Endothelial nitric oxide synthase protein distribution and nitric oxide production in endothelial cells along the coronary vascular tree. AB - OBJECTIVE: Freshly isolated endothelial cells from both conduit arteries and microvasculature were used to test the hypothesis that eNOS protein content and nitric oxide production in coronary endothelial cells increases with vessel radius. METHODS: Porcine hearts were obtained from a local abattoir. Large and small arteries as well as arterioles were dissected free of myocardium and homogenized as whole vessels. Additionally, endothelial cells were isolated from both conduit arteries and left ventricular myocardium by tissue digestion with collagenase, followed by endothelial cell isolation using biotinylated-anti-CD31 and streptavidin-coated paramagnetic beads. Purity of isolated endothelial cells was confirmed by immunofluorescence and immunoblot. RESULTS: In whole vessel lysate, immunoblot analysis revealed that protein content for eNOS was greater in arterioles compared to small and large arteries. Nitric oxide metabolites (nitrite plus nitrate; NOx) levels measured from whole vessel lysate decreased as vessel size increased, with both arterioles and small arteries displaying significantly greater NOx content than conduit. Consistent with our hypothesis, both eNOS protein level and NOx were significantly greater in endothelial cells isolated from conduit arteries compared with those from coronary microvasculature. Furthermore, confocal microscopy revealed that eNOS protein was present in all conduit and microvascular endothelial cells, although eNOS staining was less intense in microvascular cells than those of conduit artery. CONCLUSIONS: These findings demonstrate increased eNOS protein and NOx content in endothelial cells of conduit arteries compared with the microcirculation and underscore the importance of comparing endothelial-specific molecules in freshly isolated endothelial cells, rather than whole lysate of different sized vessels. PMID- 30439486 TI - Medical Malpractice Analysis in Radiation Oncology: a Decade of Results from a National Comparative Benchmarking System. AB - BACKGROUND: Medical errors in radiation oncology (RO) practice have received significant national attention over the last decade. Medical errors can lead to malpractice cases. Better characterizing these events can educate providers with the goal of improving patient care. METHODS: The REMOVED FOR BLINDING Comparative Benchmarking System (CBS) represents approximately 30% of all closed US malpractice cases and includes the experience of over 30 academic hospitals. Registered nurses trained as clinical taxonomy specialists code each case and individual case-level detail is available. Practicing ROs extracted all closed RO cases from years 2005 to 2014 and sub-grouped them by patient allegation category, clinical injury severity, care setting and academic affiliation, disease site and natural history, treatment modality, and contributing factor. Chi-square tests were used within categories to test for the variables' association with an indemnity payment. RESULTS: RO was the primary service in 102 closed cases (0.2% of all cases in the CBS), accounting for $13,323,578 in indemnity payments (0.1% of all payments in the CBS). The median indemnity payment was $100,000. Head and neck and central nervous system tumors accounted for 23.9% and 10.9% of all RO cases, respectively, and 41.3% and 31.4% of all indemnity payments, respectively. Benign diseases and brachytherapy were involved in 12.0% and 15.2% of cases, respectively. Cases involving benign disease (p=0.009), treatment of the wrong site (p=0.001), or treatment using the wrong dose (p<0.001) were all associated with indemnity payments. The top 5 most expensive cases accounted for nearly 80% of all indemnity payments, and all involved head and neck, central nervous system, benign, or brachytherapy cases. CONCLUSION: We found that while closed malpractice cases involving radiation oncology are rare events, certain populations may be overrepresented in closed claims. These data can help inform providers and systems with the goal of ultimately improving patient safety. PMID- 30439485 TI - Internal mammary node irradiation (IMNI) improves survival outcome for patients with clinical stage II-III breast cancer after preoperative systemic therapy. AB - BACKGROUND: The indication for internal mammary node irradiation (IMNI) after preoperative systemic therapy in breast cancer remains vague. This study was designed to evaluate the effect of IMNI in clinical stage II-III breast cancer patients after preoperative systemic therapy and surgery. METHODS: Between August 2005 and December 2013, 497 patients with clinical stage II-III breast cancer underwent anthracycline- or taxane-based preoperative systemic therapy, surgery and postoperative radiotherapy. A median dose of 50Gy (range, 46-60Gy) in 25 fractions was delivered to the chest wall/breast with (n=236) or without IMNI (n=261). Disease-free survival (DFS) and overall survival (OS) rates with or without IMNI were evaluated using Kaplan-Meier method and compared with log-rank test. Propensity score matching (PSM) was performed to adjust for the unbalanced characteristics between the two groups. Prognostic factors associated with survival were evaluated by univariate and multivariate analysis. RESULTS: The median follow-up time was 64 months. Patients with IMNI presented with more advanced clinical T stage, pathological N stage, positive lymph-vascular invasion and medically/centrally located disease (p<0.05). The 5-year DFS and OS rates were 73.7% and 86.3% in the IMNI group, and 71.5% and 86.7% in the non-IMNI group, respectively (P>0.05). Multivariate analysis demonstrated that IMNI was an independent prognostic factor for DFS (P=0.018) and resulted in a borderline improvement in OS (P=0.067). After PSM, characteristics were well balanced. The 5 year DFS rates of IMNI and non-IMNI group were 76.8% and 63.4%, respectively (P=0.030), and the 5-year OS rate was 88.9% and 84.1%, respectively (P=0.083). IMNI was independently prognostic for DFS (P=0.014) and OS (P=0.047) in matched patients. CONCLUSION: IMNI improves survival outcomes in clinical stage II-III breast cancer patients after preoperative systemic therapy. Further prospective studies are warranted to identify the role of IMNI in the preoperative systemic therapy setting. PMID- 30439488 TI - Throwing Down the Gauntlet Regarding Lowering the Elective Nodal Irradiation Dose in HPV-Associated Oropharyngeal Cancer. PMID- 30439487 TI - Is it necessary to Test Oropharyngeal Cancer for both p16 and HPV? PMID- 30439489 TI - Polyion complexes of a cationic antimicrobial peptide as a potential systemically administered antibiotic. AB - Antimicrobial peptides (AMPs) are regarded as next-generation antibiotics to replace conventional antibiotics due to their rapid and broad-spectrum antimicrobial properties and far less sensitivity to the development of pathogen resistance. However, they are susceptible to proteolysis in vivo by endogenous or bacterial proteases as well as induce the lysis of red blood cells, which prevent their intravenous applications. In this work, polyion complex (PIC) micelles of the cationic AMP MSI-78 and the anionic copolymer methoxy poly(ethylene glycol)-b poly(alpha-glutamic acid) (mPEG-b-PGlu) were prepared to develop novel antimicrobial agents for potential application in vivo. With an increase in molar ratio of mPEG-b-PGlu to MSI-78, the complexation ability of the PIC micelles increased. FITC-labeled MSI-78 showed a sustained release from the PIC micelles. More importantly, these PIC micelles greatly decreased the hemolytic toxicity of MSI-78 to human red blood cells, without influencing its antimicrobial activity. Thus, this approach could be used as a suitable in vivo delivery method of AMPs in the future. PMID- 30439490 TI - smartPearls - Novel physically stable amorphous delivery system for poorly soluble dermal actives. AB - Dermally applied poorly soluble actives whether in cosmetics or pharmaceuticals show insufficient skin penetration. Especially actives being insoluble in both phases of dermal vehicles, i.e. water and oil have no or less real effect. An approach to overcome this obstacle is the use of amorphous actives instead of the crystalline ones. The higher saturation solubility creates an increased concentration gradient between the formulation and skin. Thus, the diffusive flux into the skin is improved. However, the amorphous state of actives is highly labile, and the durability of such formulations would be too short for a marketable product. smartPearls is a novel technology efficiently long-term stabilize the amorphous state. They consist of um sized particles with mesopores (e.g. silica: SYLOID(r), AEROPERL(r), Neusilin(r)), in which the active can be loaded and preserved in amorphous state. Due to the tightness of the pores, not enough space is given for re-crystallization. In this work, the skin penetration of poorly soluble actives loaded in smartPearls is compared to the present "gold standards" in dermal delivery, e.g. amorphous microparticles, amorphous nanoparticles and nanocrystals. The performance was at least similar or even better than the gold standards, explainable by the increased saturation solubility of active due to a) amorphous state and b) nanostructure inside the um sized particles. Sedimentation investigations showed, that the physical stabilization of very dense smartPearls in semi-solid vehicles is possible by viscoelastic repulsion. Also, the technical, regulatory and marketing aspects for the use of smartPearls technology in products are discussed, e.g. status of excipients used, and advantages of not being a nanoparticle, but being as efficient as them. Overall, smartPearls proved to be a promising dermal delivery technology for poorly soluble actives with a high market potential. PMID- 30439491 TI - Extrudability analysis of drug loaded pastes for 3D printing of modified release tablets. AB - The rheological characteristics of pastes for 3D printing of tablets may not be described fully by the traditional rheological tests generally used for other pastes. In the present study, extrudability testing of carbopol based 3D printing pastes was performed to establish a constitutive rheological model for micro extrusion. This model was developed for pastes that exhibit a non-linear plasto viscoelastic behavior and follow the generalized Herschel-Bulkley flow rule. An analytical model was applied to extrudability data obtained by micro-extrusion through nozzles of 0.4 and 0.6 mm diameters. For this purpose, nineteen pastes were prepared per a fractional factorial design using various concentrations of the active ingredient and soluble and insoluble excipients. Critical material parameters (sigma0, k and n) of the pastes were then calculated by analyzing extrudability data using a constitutive equation relating flow rate, nozzle and cartridge diameters, printing pressure and slip-flow angle. The accuracy of the constitutive model to predict paste yield stress, consistency and flow indices was evident by low RMSE values of 0.0691 bar, 0.034 and 6.3 bar/sn, respectively. Yield stress, flow and consistency parameters of the pastes were significantly affected by percentages of soluble and swellable excipients. The nozzle diameter had significant effect on flow index (n) but not on the consistency index (k). Hence, this study provides a mechanistic model to characterize the complex rheological behavior of pastes for 3D printing of tablets by a micro-extrusion process. PMID- 30439492 TI - Biocompatibility studies of intravenously administered ionic-crosslinked chitosan BSA nanoparticles as vehicles for antitumour drugs. AB - In this study, a new alternative of ionic crosslinked nanoparticles (NPs) based on chitosan (C) and bovine serum albumin (A; BSA) was evaluated as drug delivery system for antitumour compounds (doxorubicin hydrochloride as a model). The different responses to the pH of the medium were determined by the electrostatic interactions induced by each polymeric combination (C50/A50; C80/A20; C20/A80). NPs revealed a nanoscale size (167-392 nm) and a positive net charge (12-26 mV), modulated by doxorubicin (DOX) loading. Drug loading capacity was higher than 5.2 +/- 1.8 MUgDOX/mgNP (Encapsulation efficiency = 34%), and an initial burst release was followed by a sustained delivery. Cellular uptake assays confirmed the entry of NPs in three human tumor cells (MCF7, T47D and Hela), triggering antioxidant responses (superoxide dismutase, catalase, glutathione reductase and total glutathione content) in those cells. This was also consistent with the decreased in IC50 values observed after the incubation of these cells with C20/A80-DOX and C50/A50-DOX NPs (1.90-3.48 MUg/mL) compared with free DOX (2.36 6.025 MUg/mL). In vivo results suggested that the selected proportions of chitosan-BSA created nonhemolytic and biocompatible stable NPs at the selected dose of 20 mg/kg. Despite the different formulations, this study demonstrated that these NPs could serve as safe drug carriers in further in vivo investigations. PMID- 30439493 TI - Rethinking carbamazepine oral delivery using polymer-lipid hybrid nanoparticles. AB - Epilepsy is the most common chronic brain disorder and affects millions of people worldwide. Carbamazepine (CBZ) is one of the first-line pharmacological therapy instituted to patients due to its wide spectrum of action. Although marketed for more than 30 years, CBZ efficacy is strongly limited by its lateral effects, and variable and slow intestinal absorption. This reality leads to resistance drug development, which compromises the patients' quality of life. Rethinking about CBZ oral delivery is required to achieve a more effective strategy for the treatment of epilepsy. This work aimed at developing polymer-lipid hybrid nanoparticles, using chitosan as the polymer coating, as a surrogate nanosystem for oral administration of CBZ. The hybrid nanoparticles were produced by high pressure homogenization, and a systematic evaluation was carried out in terms of particle size, zeta potential, loading properties, mucoadhesion, stability and in vitro - in vivo performance assessment, including release, intestinal permeability, and biodistribution studies. Subsequently, nanoparticles were spray dried and tableted to provide a differentiated solid dosage form. Chitosan coating improved lipid nanoparticle stability under gastric environment, presenting a size of ca. 150 nm and a polydispersity index smaller than 0.150, and increasing up to two orders of magnitude the drug intestinal permeability. The in vivo studies herein performed evidenced that hybrid nanoparticles prompted a similar brain disposition of CBZ to that of an oral suspension, after the administration of a lower dose. These findings are consistent with a controlled and reproducible release pattern, suggesting that the therapeutic effect is ensured with lower adverse effects. The present work may provide a proof-of concept for further preclinical studies in the treatment of epilepsy. PMID- 30439494 TI - Predicting the metabolic capabilities of Synechococcus elongatus PCC 7942 adapted to different light regimes. AB - There is great interest in engineering photoautotrophic metabolism to generate bioproducts of societal importance. Despite the success in employing genome-scale modeling coupled with flux balance analysis to engineer heterotrophic metabolism, the lack of proper constraints necessary to generate biologically realistic predictions has hindered broad application of this methodology to phototrophic metabolism. Here we describe a methodology for constraining genome-scale models of photoautotrophy in the cyanobacteria Synechococcus elongatus PCC 7942. Experimental photophysiology parameters coupled to genome-scale flux balance analysis resulted in accurate predictions of growth rates and metabolic reaction fluxes at low and high light conditions. Additionally, by constraining photon uptake fluxes, we characterized the metabolic cost of excess excitation energy. The predicted energy fluxes were consistent with known light-adapted phenotypes in cyanobacteria. Finally, we leveraged the modeling framework to characterize existing photoautotrophic and photomixtotrophic engineering strategies for 2,3 butanediol production in S. elongatus. This methodology, applicable to genome scale modeling of all phototrophic microorganisms, can facilitate the use of flux balance analysis in the engineering of light-driven metabolism. PMID- 30439495 TI - Visualization of the penetration modifying mechanism of laurocapram by Mass Spectrometry Imaging in buccal drug delivery. AB - The aim of the study was to visualize the penetration modifying effect of laurocapram on the delivery of diazepam and codeine across buccal mucosa by MALDI Mass Spectrometry Imaging (MALDI-MSI). A qualitative ex vivo study was carried out by mounting porcine buccal mucosa in Ussing chamber sliders and applying a pre-treatment of phosphate buffered saline (PBS) or a 50% (v/v) laurocapram:ethanol solution apically before incubation for 1 or 3 h with a 0.1 M diazepam or 0.1 M codeine solution. MALDI-MSI analysis was performed on vertical cryo-sections of porcine buccal mucosa. The analysis provided detailed images of the localisation of the drugs, laurocapram and endogenous lipids in the epithelium and connective tissue. While diazepam in the absence of laurocapram was distributed with a steady concentration gradient through the connective tissue, indicating passive diffusion, pre-treatment with laurocapram fundamentally altered the penetration of diazepam through the buccal mucosa. In the presence of laurocapram, the distribution of diazepam was restricted to areas where laurocapram itself was present, in particular in the outer epithelial cell layers and in certain islands in the connective tissue. In contrast, the penetration of codeine was unaffected by the presence of laurocapram in similar experiments. The co-localization of laurocapram and diazepam indicates a reservoir effect, which has previously been found in diffusion experiments in Ussing chambers. The major difference in the penetration of codeine and diazepam through the buccal mucosa in presence of laurocapram was explained by the physicochemical properties of the drugs. Codeine is characterized by being more hydrophilic than diazepam and was partly charged under the given experimental conditions. PMID- 30439496 TI - Characterization of gene expression profiles and functional analysis of peptidoglycan recognition protein 2 from rock bream (Oplegnathus fasciatus). AB - Peptidoglycan recognition protein 2 (PGRP2) is a Zn2+-dependent peptidase that plays important roles in binding to microbial components of the cell membrane, inducing phagocytosis and antimicrobial activity. Rock bream (Oplegnathus fasciatus) PGRP2 (RbPGRP2) was identified in the intestine by next generation sequencing (NGS) analysis. The open reading frame (ORF) the RbPGRP2 cDNA (470 amino acid residues) contains a peptidoglycan recognition protein domain (residues 300 to 446). Alignment analysis revealed that RbPGRP2 shares 37.6-53.5% overall sequence identity with the PGRP2s of other species. Phylogenetic analysis revealed that RbPGRP2 clustered together with PGRP2s from teleosts. In healthy rock bream, RbPGRP2 was found to be ubiquitously expressed in all of the examined tissues, especially in the liver. RbPGRP2 expression was significantly upregulated in all of the examined tissues of rock bream after infection with Edwardsiella piscicida, Streptococcus iniae and red sea bream iridovirus (RSIV) compared with the control. Purified rRbPGRP2 interactions with bacteria and inhibited the growth of bacteria in the presence of Zn2+. These results indicate that RbPGRP2 plays an important role in the innate immune response against bacterial infection. PMID- 30439497 TI - Cloning of six serpin genes and their responses to GCRV infection in grass carp (Ctenopharyngodon idella). AB - Grass carp, an economically important aquaculture fish, is very sensitive to Grass Carp Reovirus (GCRV). Haemorrhagic disease caused by GCRV infection can cause large-scale death of first-year grass carp, thereby severely restricting the intensive culture. Serpins (serine protease inhibitors) belong to the protease inhibitor gene family and are involved in numerous physiological and pathological processes, particularly coagulation and anticoagulation. Reports on grass carp serpins are scarce. Thus, we cloned six grass carp serpin genes (serpinb1, serpinc1, serpind1, serpinf1, serpinf2b and serping1) in this study. Molecular evolution showed that serpins between grass carp and zebrafish or carp are the closest relatives. SERPIN domains in these 6 serpins and reactive centre loop (RCL) along with their cleavage sites of 5 serpins (serpinb1, serpinc1, serpind1, serpinf2b and serping1) were predicted. Real-time quantitative PCR (RT qPCR) showed that these serpins displayed tissue significance. Among them, serpinc1, serpind1, serpinf2b and serping1 had the highest expression levels in the liver. After GCRV infection, RT-qPCR showed that the liver-enriched serpins were significantly changed. Key procoagulant factor genes (kng-1, f2, f3a, f3b and f7) and anticoagulant genes (tpa, plg, thbd, proc and pros) also showed significant changes on the mRNA level. Comprehensive comparative analysis showed that the up-regulated expression of key clotting factor genes was more prominent than that of main anti-coagulation factor genes. Thus, the function of coagulation may be more dominant in grass carp during the GCRV infection, which may cause overproduction of thrombi. The serpins were involved in GCRV infection and liver-enriched serpins participate in the interaction between coagulation and anticoagulation. This study provided new insights into further research on the biological functions of grass carp serpins and clarifying the molecular mechanism of GCRV affecting the homeostasis of grass carp blood environment. PMID- 30439498 TI - The amphioxus ERK2 gene is involved in innate immune response to LPS stimulation. AB - The ERK2 gene is a member of the MAPK family, which plays very important roles in responses to external environmental pressures. However, the ERK2 has yet not been identified in amphioxus to date. To further illuminate the function and evolutionary mechanism of the ERK2 gene, in this present study, we have cloned the full length of the ERK2 gene of Branchiostoma belcheri (designed as AmphiERK2), which is highly homologous to these vertebrate ERK2 genes. The AmphiERK2 protein contains the conserved S_TKc domain and the TEY motif, and its 3D structure is also highly similar to human ERK2 protein. Taken together, our results indicate that the AmphiERK2 gene belongs to a member of the ERK2 gene family. We further use qRT-PCR technology to detect an ubiquitous expression of AmphiERK2 gene in all five investigated tissues (muscle, notochord, gill, hepatic caecum and intestine), and the expression level of AmphiERK2 in both notochord and muscle is significantly higher than the other three tissues. Meanwhile our results also demonstrate that LPS stimulation can induce the up-regulation expression of AmphiERK2 gene and significantly increase the phosphorylation level of AmphiERK2 protein, which seems to imply that the AmphiERK2 may be involved in amphioxus innate immune responses. Overall, our findings provide an important insight into amphioxus innate immune function and evolution of the ERK2 gene family. PMID- 30439499 TI - Litopenaeus vannamei stylicins are constitutively produced by hemocytes and intestinal cells and are differentially modulated upon infections. AB - Stylicins are anionic antimicrobial host defense peptides (AAMPs) composed of a proline-rich N-terminal region and a C-terminal portion containing 13 conserved cysteine residues. Here, we have increased our knowledge about these unexplored crustacean AAMPs by the characterization of novel stylicin members in the most cultivated penaeid shrimp, Litopenaeus vannamei. We showed that the L. vannamei stylicin family is composed of two members (Lvan-Stylicin1 and Lvan-Stylicin2) encoded by different loci which vary in gene copy number. Unlike the other three gene-encoded antimicrobial peptide families from penaeid shrimp, the expression of Lvan-Stylicins is not restricted to hemocytes. Indeed, they are also produced by the columnar epithelial cells lining the midgut and its anterior caecum. Interestingly, Lvan-Stylicins are simultaneously transcribed at different transcriptional levels in a single shrimp and are differentially modulated in hemocytes after infections. While the expression of both genes showed to be responsive to damage-associated molecular patterns, only Lvan-Stylicin2 was induced after a Vibrio infection. Besides, Lvan-Stylicins also showed a distinct pattern of gene expression in the three portions of the midgut (anterior, middle and posterior) and during shrimp development. We provide here the first evidence of the diversity of the stylicin antimicrobial peptide family in terms of sequence and gene expression distribution and regulation. PMID- 30439500 TI - Efficacy of synbiotic Jerusalem artichoke and Lactobacillus rhamnosus GG supplemented diets on growth performance, serum biochemical parameters, intestinal morphology, immune parameters and protection against Aeromonas veronii in juvenile red tilapia (Oreochromis spp.). AB - Synbiotics, a synergistic combination of probiotics and prebiotics, are currently regarded as one of the most practical nutritional supplements in tilapia farms. In this study, the effect of supplementing the diet of red tilapia (Oreochromis spp.) with Jerusalem artichoke (Helianthus tuberosus) and Lactobacillus rhamnosus GG (LGG) was evaluated. Growth performance, serum biochemical parameters, intestinal morphology, goblet cell counts, immune parameters and protection against Aeromonas veronii challenge were determined. The results showed that fish fed with synbiotic-supplemented diets had a significantly higher (P < 0.05) feed conversion ratio (FCR), specific growth rate (SGR), and average daily gain (ADG) than fish fed with a control diet. The synbiotic-supplemented diet increased glucose, total protein and the total cholesterol levels. The absorptive area of the proximal and distal intestine of fish fed on the synbiotic diet was significantly higher (P < 0.05) than in those fed with probiotics (LGG), prebiotic-supplemented diets (JA), and the control diet. Goblet cell counts revealed that the numbers of acid mucous cells, neutral mucous cells and double staining mucous cells of fish fed the synbiotic-supplemented diet (JA + LGG) were significantly higher (P < 0.05) in the proximal and distal intestine. Fish fed the synbiotic-supplemented diets also exhibited significantly higher (P < 0.05) lysozyme activity. The cumulative mortalities of fish fed with a synbiotic supplemented diet were significantly lower than those of fish fed other diets. The results suggested the beneficial effect of JA and LGG synbiotic diet on growth performance and health status of red tilapia. Direct administration of JA and LGG in fish feed can be used as a practical nutritional supplement in red tilapia. PMID- 30439501 TI - Local regulation of immune genes in rainbow trout (Oncorhynchus mykiss) naturally infected with Flavobacterium psychrophilum. AB - Flavobacterium psychrophilum is the etiological agent of bacterial cold water disease (BCWD), also referred to as rainbow trout fry syndrome (RTFS), a disease with great economic impact in salmonid aquaculture. Despite this, to date, not many studies have analyzed in depth how the immune system is regulated during the course of the disease. In the current study, we have studied the transcription of several immune genes related to T and B cell activity in the skin of rainbow trout (Oncorhynchus mykiss) naturally infected with F. psychrophilum in a farm located in Lake Titicaca (Peru). The levels of expression of these genes were tested and compared to those obtained in asymptomatic and apparently healthy rainbow trout. In the case of symptomatic fish, skin samples containing characteristic ulcerative lesions were taken, as well as skin samples with no lesions. Our results pointed to a significant local up-regulation of IgD, CD4, CD8, perforin and IFNgamma within the ulcerative lesions. On the other hand, no differences between the levels of expression of these genes were visible in the spleen. To confirm these results, the distribution of IgD+ and CD3+ cells was studied through immunohistochemical techniques in the ulcerative lesions. Our results demonstrate a strong local response to F. psychrophilum in rainbow trout in which IgD and T cells seem to play a major role. PMID- 30439502 TI - Neuroprotective effects of overexpressed microRNA-200a on activation of glaucoma related retinal glial cells and apoptosis of ganglion cells via downregulating FGF7-mediated MAPK signaling pathway. AB - Glaucoma is a progressive optic neuropathy and is one of the leading causes of blindness in the industrialized countries. The involvement of microRNAs (miRs) has been implicated in regulating the complex biological responses to changes in intraocular pressure. However, the therapeutic role of miR-200a on glaucoma has not been well studied yet. In this study, we confirmed the role of miR-200a in glaucoma progression and identified the related mechanism. Microarray expression profiles were used to screen the glaucoma-related genes. The relationship between miR-200a and FGF7 was validated by bioinformatics analysis and dual-luciferase reporter gene assay. Glaucoma-related parameters including the expression of CD11b and iNOS, activation of Muller cells, and apoptosis of retinal ganglion cells (RGCs) in the mouse model were measured by immunohistochemistry, MTT assay and TUNEL assay, respectively. miR-200a was reduced in glaucoma, whereas FGF7 was robustly induced. Thereby, we speculated that FGF7 was negatively regulated by miR-200a. Downregulated miR-200a could activate the MAPK signaling pathway following elevations in ERK, JNK, p38 and Bax expression and reduction in Bcl-2 expression. In the mouse model, downregulated miR-200a increased the expression of CD11b and iNOS and the apoptosis of RGCs, but stimulated the inactivation of Muller cells. However, the above-mentioned alternations induced by downregulated miR-200a were reversed after FGF7 repression. miR-200a can inhibit the FGF7 mediated MAPK signaling pathway and play a protective role on improving the glaucoma-induced optical nerve injury. PMID- 30439503 TI - Tri-ortho-cresyl phosphate (TOCP) induced ovarian failure in mice is related to the Hippo signaling pathway disruption. AB - As a plasticizer widely used in society, tri-ortho-cresyl phosphate (TOCP) is reported to inhibit spermatogenesis and growth of spermatogonial stem cells. However, its effects on female reproductive system are virtually unknown. The present study investigated the effects of TOCP on ovarian follicle development by using mouse model of chronic TOCP exposure, and examined the expression of the core components of the Hippo pathway, which had been proven to be crucial for ovarian follicle development. Furthermore, through up-regulation of Hippo-yes associated protein 1 (Yap1) in ovaries, the potential protective effects of Yap1 over-expression on TOCP-induced ovarian dysfunction were observed. The results showed that TOCP impaired ovarian function in a dose-dependent manner, and the expression of the Hippo pathway changed significantly in TOCP-exposed ovaries. Further, YAP1 over-expression partially reversed the TOCP-induced ovarian impairment. Collectively, these data indicate that the Hippo pathway is involved in the mechanism by which TOCP elicits ovarian function impairment. PMID- 30439504 TI - On-demand manufacturing of immediate release levetiracetam tablets using pressure assisted microsyringe printing. AB - Fast and accurate manufacturing of individually tailored solid dosage forms is one of the main challenges for personalized medicine. The use of 3D printers has recently been studied to determine their suitability for personalized drug manufacturing. In the current work, formulations free of organic solvents were developed for a pressure-assisted microsyringe printing method (PAM). The water soluble polymer polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG) was used as matrix, while levetiracetam (LEV) was used as model drug. Furthermore, the influence of a second polymer, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-PVAc) on the properties of the printed tablets was investigated. Tablets were printed using a 3D-Bioplotter. The printed formulations were analyzed regarding mass variation, friability and thickness. Furthermore, the disintegration behavior and dissolution profile were analyzed. Investigations of the dissolution profiles of printed tablets show that an immediate release of the API could be achieved. For tablets with PVA-PEG the drug is released completely within 10 min while the additional use of PVP-PVAc leads to a slightly delay with a complete release within 20 min. The same trend is observed regarding the disintegration time of printed tablets. Tablets with PVA PEG disintegrated within 95 +/- 10 s while tablets with additional PVP-PVAc disintegrated witin 130 +/- 20 s. Friability of < 0.5 % indicate that the used PAM printing method provides tablets without loss of structural integrity during handling. Furthermore, it could be shown that the production of tablets with a good content uniformity using a 3D Bioplotter is suitable. PMID- 30439505 TI - The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management. AB - Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed. PMID- 30439507 TI - Acinetobacter baumannii outer membrane protein 34 elicits NLRP3 inflammasome activation via mitochondria-derived reactive oxygen species in RAW264.7 macrophages. AB - Acinetobacter baumannii (A. baumannii) is a Gram-negative bacterium, which acts as an opportunistic pathogen and causes hospital-acquired pneumonia and bacteremia by infecting the alveoli of epithelial cells and macrophages. Evidence reveals that A. baumannii outer membrane protein 34 (Omp34) elicits cellular immune responses and inflammation. The innate immunity NOD-like receptor 3 (NLRP3) inflammasome exerts critical function against pneumonia caused by A. baumannii infection, however, the role of Omp34 in the activation of the NLRP3 inflammasome and its corresponding regulatory mechanism are not clearly elucidated. The present study aimed to investigate whether Omp34 elicited NLRP3 inflammasome activation through the mitochondria-derived reactive oxygen species (ROS). Our results showed that Omp34 triggered cell pyroptosis by up-regulating the expression of NLRP3 inflammasome-associated proteins and IL-1beta release in a time- and dose-dependent manner. Omp34 induced the expression of caspase-1-p10 and IL-1beta, which was significantly attenuated by NLRP3 gene silencing in RAW264.7 mouse macrophage cells. Additionally, Omp34 stimulated RAW264.7 mitochondria to generate ROS, while the ROS scavenger Mito-TEMPO inhibited the Omp34-triggered expression of NLRP3 inflammasome-associated proteins and IL-1beta synthesis. The above findings indicate that mitochondria-derived ROS play an important role in the process of NLRP3 inflammasome activation. In summary, our study demonstrates that the A. baumannii pathogen pattern recognition receptor Omp34 activates NLRP3 inflammasome via mitochondria-derived ROS in RAW264.7 cells. Accordingly, down-regulating the mitochondria-derived ROS prevents the severe infection consequences caused by A. baumannii-induced NLRP3 inflammasome hyper-activation. PMID- 30439506 TI - Associations between sleep duration and sleep debt with insulin sensitivity and insulin secretion in the EGIR-RISC Study. AB - AIM: Extremes in sleep duration play an important role in the development of type 2 diabetes. We examined the associations between sleep duration and sleep debt with estimates of insulin sensitivity and insulin secretion. METHODS: Data were derived from the European multi-centre EGIR-RISC study. Sleep duration and sleep debt were derived from a sleep questionnaire asking about sleeping time during the week and during the weekend. Insulin sensitivity and insulin secretion were estimated from a 2-hour Oral Glucose Tolerance Test, with samples every 30 minutes. Associations between sleep duration and sleep debt with insulin sensitivity and insulin secretion, were analysed by multiple linear regression models corrected for possible confounders. RESULTS: Sleep data were available in 1002 participants, 46% men, mean age 48 +/- 8 years, who had an average sleep duration of 7 +/- 1 hours [range 3-14] and an average sleep debt (absolute difference hours sleep weekend days minus weekdays) of 1 +/- 1 hour [range 0-8]. With regard to insulin sensitivity, we observed an inverted U-shaped association between sleep duration and the Stumvoll MCR in (mL/kg/min), with a corrected beta (95% CI) of 2.05 (0.8; 3.3) and for the quadratic term -0.2 (-0.3; -0.1). Similarly, a U-shaped association between sleep duration and log HOMA-IR in (uU/mL), with a corrected betas of -0.83 (-1.4; -0.24) and 0.06 (0.02; 0.10) for the quadratic term. Confounders showed an attenuating effect on the associations, while BMI mediated 60 to 91% of the association between sleep duration and insulin sensitivity. No significant associations were observed between sleep duration with insulin secretion or between sleep debt with either insulin sensitivity or insulin secretion. CONCLUSIONS: Short and long sleep duration are associated with a lower insulin sensitivity, suggesting that sleep plays an important role in insulin resistance and may provide the link with development of type 2 diabetes. PMID- 30439508 TI - Acyl-ghrelin mediated lipid retention and inflammation in obesity-related Type 2 diabetes. AB - Acyl-ghrelin has various peripheral effects including the potential role in mediating cellular lipid removal and macrophage polarization. Previous reports are contradictory as to how glycaemia and acyl-ghrelin mediates lipid retention and inflammation within individuals with Type 2 diabetes (T2D). Our aim was to explore acyl-ghrelin levels and ghrelin expression in relation to lipid and inflammatory markers within an ex vivo human model, biopsied visceral adipose tissue. Results indicated that acyl-ghrelin was associated with a decline in key lipid homeostasis genes ABCG1 and LXRbeta expression. Within T2D there was also a down regulation of these genes which was independent of acyl-ghrelin levels. Circulatory pro-inflammatory markers (IL-6 and TNFalpha) had no association with ghrelin expression nor circulating acyl-ghrelin levels. Anti-inflammatory marker (IL-10) and total antioxidant status (TAOS%) were positively associated with ghrelin expression across samples from all groups combined (total sample cohort) and specifically within the obesity sample cohorts. Data supported the hypothesis that hyperglycaemia and acyl-ghrelin have a regulatory role in lipid retention. Furthermore, that both acyl- and desacyl-ghrelin is responsible for a protective inflammatory response; however this response is diminished in T2D. PMID- 30439509 TI - Differentiating guilt and shame in an interpersonal context with univariate activation and multivariate pattern analyses. AB - Guilt and shame are usually evoked during interpersonal interactions. However, no study has compared guilt and shame processing under such circumstances. In the present study, we investigated guilt and shame in an interpersonal context using functional magnetic resonance imaging (fMRI). Behaviorally, participants reported more "guilt" when their wrong advice caused a confederate's economic loss, whereas they reported more "shame" when their wrong advice were correctly refused by the confederate. The fMRI results showed that both guilt and shame activated regions related to the integration of theory of mind and self-referential information (dorsal medial prefrontal cortex, dmPFC) and to the emotional processing (anterior insula). Guilt relative to shame activated regions linked with theory of mind (supramarginal gyrus and temporo-parietal junction) and cognitive control (orbitofrontal cortex/ventrolateral prefrontal cortex and dorsolateral prefrontal cortex). Shame relative to guilt revealed no significant results. Using multivariate pattern analysis, we demonstrated that in addition to the regions found in the univariate activation analysis, the ventral anterior cingulate cortex and dmPFC could also distinguish guilt and shame. These results do not only echo previous studies of guilt and shame using recall and imagination paradigms but also provide new insights into the psychological and neural mechanisms of guilt and shame. PMID- 30439510 TI - Spoken language coding neurons in the Visual Word Form Area: Evidence from a TMS adaptation paradigm. AB - While part of the left ventral occipito-temporal cortex (left-vOT), known as the Visual Word Form Area, plays a central role in reading, the area also responds to speech. This cross-modal activation has been explained by three competing hypotheses. Firstly, speech is converted to orthographic representations that activate, in a top-down manner, written language coding neurons in the left-vOT. Secondly, the area contains multimodal neurons that respond to both language modalities. Thirdly, the area comprises functionally segregated neuronal populations that selectively encode different language modalities. A transcranial magnetic stimulation (TMS)-adaptation protocol was used to disentangle these hypotheses. During adaptation, participants were exposed to spoken or written words in order to tune the initial state of left-vOT neurons to one of the language modalities. After adaptation, they performed lexical decisions on spoken and written targets with TMS applied to the left-vOT. TMS showed selective facilitatory effects. It accelerated lexical decisions only when the adaptors and the targets shared the same modality, i.e., when left-vOT neurons had initially been adapted to the modality of the target stimuli. Since this within-modal adaptation was observed for both input modalities and no evidence for cross-modal adaptation was found, our findings suggest that the left-vOT contains neurons that selectively encode written and spoken language rather than purely written language coding neurons or multimodal neurons encoding language regardless of modality. PMID- 30439511 TI - Age-related changes in brain deactivation but not in activation after motor learning. AB - It is poorly understood how healthy aging affects neural mechanisms underlying motor learning. We used blood-oxygen-level dependent (BOLD) contrasts to examine age-related changes in brain activation after acquisition and consolidation (24 h) of a visuomotor tracking skill. Additionally, structural magnetic resonance imaging and diffusion tensor imaging were used to examine age-related structural changes in the brain. Older adults had reduced gray matter volume (628 +/- 57 ml) and mean white matter anisotropy (0.18 +/- 0.03) compared with young adults (741 +/- 59 ml and 0.22 +/- 0.02, respectively). Although motor performance was 53% lower in older (n = 15, mean age 63.1 years) compared with young adults (n = 15, mean age 25.5 years), motor practice improved motor performance similarly in both age groups. While executing the task, older adults showed in general greater brain activation compared with young adults. BOLD activation decreased in parietal and occipital areas after skill acquisition but activation increased in these areas after consolidation in both age groups, indicating more efficient visuospatial processing immediately after skill acquisition. Changes in deactivation in specific areas were age-dependent after consolidating the motor skill into motor memory. Young adults showed greater deactivations from post-test to retention in parietal, occipital and temporal cortices, whereas older adults showed smaller deactivation in the frontal cortex. Since learning rate was similar between age groups, age-related changes in activation patterns may be interpreted as a compensatory mechanism for age-related structural decline. PMID- 30439512 TI - Assessment of metallic patient support devices and other items at 7-Tesla: Findings applied to 46 additional devices. AB - OBJECTIVE: Recently, the first 7-Tesla MR system was approved for clinical use in Europe and the United States. Unfortunately, few metallic objects have undergone testing in association with this high-field-strength scanner, including essential equipment such as patient support devices and other items. Therefore, the objective of this investigation was to assess metallic patient support devices and other items for translational attraction at 7-Tesla. METHODS: Thirteen different metallic items (e.g., gurney, Mayo stand, step stool, utility table, wheelchair, etc.) underwent testing for translational attraction using a previously described methodology in association with a clinical 7-T MR system. The findings were categorized as pass (no translational attraction) or fail (the item was attracted by the scanner). RESULTS: Every metallic item tested exhibited a lack of magnetism while in a worst-case use position and, thus, passed the test for translational attraction in associated with the 7-Tesla MR system. CONCLUSIONS: The different thirteen different metallic patient support devices and other items can be designated as MR Conditional at 7-T or less. Furthermore, because each item represented a worst-case with respect to its mass and the type of metallic material used for its fabrication, the results can be applied to 46 additional smaller items made from the same material or material with a lower magnetic susceptibility. This expanded list of essential patient support devices and other items will facilitate the clinical use of a comparable 7-Tesla scanner, or another UHF scanner with similar fringe field characteristics. PMID- 30439513 TI - Rigid motion correction for magnetic resonance fingerprinting with sliding-window reconstruction and image registration. AB - Magnetic resonance fingerprinting (MRF) can be used to simultaneously obtain multiple parameter maps from a single pulse sequence. However, patient motion during MRF acquisition may result in blurring and artifacts in estimated parameter maps. In this work, a novel motion correction method was proposed to correct for rigid motion in MRF. The proposed method involved sliding-window reconstruction to obtain intermediate images followed by image registration to estimate rigid motion information between these images. Finally, the motion corrupted k-space data were corrected with the estimated motion parameters and then reconstructed to obtain the parameter maps via the conventional MRF processing pipeline. The proposed method was evaluated using both simulations and in vivo MRF experiments with intently different types of motion. For motion corrupted data, the proposed method yielded brain T1, T2 and proton density maps with obviously reduced blurring and artifacts and lower normalized root-mean square error, compared to MRF without motion correction. In conclusion, motion corrected MRF using the proposed method has the potential to produce accurate parameter maps in the presence of in-plane rigid motion. PMID- 30439514 TI - Characterizing contrast origins and noise contribution in spin-echo EPI BOLD at 3 T. AB - In this work, we characterize contrast origins and noise contributions of spin echo (SE) EPI BOLD signal at 3 T. SE BOLD is a fMRI method of choice for imaging brain regions affected by susceptibility artifacts at lower fields, but its sensitivity remains a limiting factor for whole-brain imaging. To resolve this, the signal and noise contributions as well as TE dependence of SE EPI are characterized in this study. By integrating a two-compartment BOLD model with a physiological-thermal noise model, a new SE-BOLD signal model was introduced. The new SE-BOLD model was fit into SE-EPI fMRI data acquired during hypercapnic manipulations at various TEs, using typical fMRI voxel dimensions (3.4 * 3.4 * 5 mm3). Our model predicts intra- and extravascular signal and noise contributions consistent with our understanding of the SE-EPI contrast mechanism. The intravascular BOLD contribution is shown to dominate at TEs lower than tissue T2, but the physiological noise contributions in SE-EPI signal is also shown to be lower than that of gradient-echo (GE). Furthermore, SE-EPI contrast-to-noise ratio (CNR) is not maximized at tissue T2 as is typically assumed. To summarize, a new SE-BOLD model was proposed to characterize SE-BOLD contrast and physiological noise contribution at 3 T. Results suggests that SE-BOLD sensitivity can be improved by using shorter TEs, making it a more attractive choice for fMRI, especially in regions with susceptibility artifacts. Such optimizations could also help extend the application of SE BOLD to WM fMRI studies. PMID- 30439515 TI - Linking spherical mean diffusion weighted signal with intra-axonal volume fraction. AB - Diffusion MRI has been widely used to assess brain tissue microstructure. However, the conventional diffusion tensor imaging (DTI) is inadequate for characterizing fiber direction or fiber density in voxels with crossing fibers in brain white matter. The constrained spherical deconvolution (CSD) technique has been proposed to measure the complex fiber orientation distribution (FOD) using a single high b-value (b >= 3000 s/mm2) to derive the intra-axonal volume fraction (Vin) from the calculated FOD. Recently, the spherical mean technique (SMT) was developed to fit Vin directly from a multi-compartment model with multi-shell b values. Although different numbers of b-values are needed in the two techniques, both methods have been suggested to be related to the spherical mean diffusion weighted signal (S-). The current study compared the two techniques on the same high-quality Human Connectome Project diffusion data and investigated the relation between S- and Vin systematically. At high b-values (b >= 3000 s/mm2), S is linearly related to Vin, and S- provides similar contrast with Vin in white matter. At low b-values (b ~ 1000 s/mm2), the linear relation between S- and Vin is sensitive to the variations of intrinsic diffusivity. These results demonstrate that S- measured with the typical b-value of 1000 s/mm2 is not an indicator of Vin, and previous DTI studies acquired with b = 1000 s/mm2 cannot be re-analyzed to provide Vin-weighted contrast. PMID- 30439516 TI - Gadoxetic acid-enhanced dynamic magnetic resonance imaging using optimized integrated combination of compressed sensing and parallel imaging technique. AB - PURPOSE: To evaluate the feasibility of optimized integrated combination of compressed sensing and parallel imaging technique (prototype Compressed SENSE) in gadoxetic acid-enhanced dynamic magnetic resonance (MR) imaging. MATERIALS AND METHODS: Sixty-one patients underwent gadoxetic acid-enhanced dynamic imaging using enhanced T1 high-resolution isotropic volume excitation (eTHRIVE) with the Compressed SENSE (CS-eTHRIVE; C SENSE factor, 3.4; acquisition time, 10 s). Results were compared with 61 propensity score-matched patients who underwent conventional eTHRIVE (eTHRIVE; acquisition time, 20 s). For quantitative image analyses, signal intensity ratio (SIR) and signal-to-noise ratio (SNR), coefficient of variation (CV) of liver parenchyma were calculated in each dynamic phase. For qualitative image analyses, two radiologists rated the homogeneity of liver parenchyma, sharpness of liver edge and left external lobe, motion artifacts, and overall image quality in each dynamic phase using a five-point scale. RESULTS: SIRs of liver parenchyma with CS-eTHRIVE were significantly higher than with eTHRIVE in the hepatic arterial phase (HAP) (1.70 vs. 1.52) and transitional phase (TP) (2.18 vs. 2.06) (P <= 0.030). SNR of liver parenchyma were comparable between the two sequences in all phases. CV of liver parenchyma in HAP with eTHRIVE (0.079) was significantly higher than with CS-eTHRIVE (0.065) (P < 0.001). Motion artifacts were significantly reduced with CS-eTHRIVE compared with eTHRIVE in all phases (P <= 0.005). The appearance ratio of extensive motion artifacts in HAP with CS-eTHRIVE (0/61; 0%) were significantly reduced compared with eTHRIVE (4/61; 6.6%) (P = 0.042). Overall image quality with CS-eTHRIVE was significantly better than with eTHRIVE in all phases (P <= 0.039). CONCLUSION: CS eTHRIVE compared with eTHRIVE effectively reduced the acquisition time and extensive motion artifacts without degradation of image quality. PMID- 30439517 TI - Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. METHODS: The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. RESULTS: The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. CONCLUSIONS: The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316 hepatocellular-carcinoma-early-detection-strategy. PMID- 30439518 TI - Luteal phase stimulation, the future of fertility preservation? Retrospective cohort study of luteal phase versus follicular phase stimulation. AB - RESEARCH QUESTION: Is luteal phase stimulation capable of improving fertility preservation? MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive ovarian stimulations, during July 2012 and September 2018 at Strasbourg University Teaching Hospital in France. Enrollment criteria were patients aged below 40 who had been referred to our center following a diagnosis of cancer or requiring gonadotoxic treatment. All patients enrolled had regular menstrual cycles and normal ovulation. Non-enrollment criteria were an expected low ovarian response (defined by an anti-Mullerian hormone (AMH) level <0.75MUg/L and/or an antral follicle count inferior (AFC) inferior than 5), polycystic ovarian syndrome, amenorrhea, prior history of infertility or gonadotoxic treatment. The primary endpoint is the number of mature oocytes (metaphase II) obtained. Secondary outcomes were oocyte yields obtained, stimulation duration, initial gonadotropin dose and total gonadotropin dose. RESULTS: A total of 100 patients were included: 20 in luteal phase and 80 in follicular phase. A larger number of mature oocytes was obtained in luteal phase versus follicular phase (13.1+/8.0 versus 9.2+/-5.8 with p=0.01). A greater amount of total (mature and immature) oocytes was obtained in luteal phase versus follicular phase with a significant difference (16.8+/-9.3 versus 11.8+/-7.3 with p=0.01). No difference was found for the initial and total doses of gonadotropin. CONCLUSIONS: Luteal phase stimulation has the advantage of a better flexibility with positives results as to the number of oocytes obtained in fertility preservation. PMID- 30439519 TI - Multiple clones of metallo-beta-lactamase-producing Acinetobacter ursingii in a children hospital from Argentina. AB - Acinetobacter spp. are opportunistic pathogens being A. baumannii the most frequently identified in nosocomial settings. A. ursingii was mainly described as causing bacteremia and outbreaks in neonatal intensive care units. Ten A. ursingii isolates were recovered from rectal swab screening for carbapenemase producing bacteria between June 2013 and December 2015 from a children hospital in Argentina. All ten isolates were metallo-beta-lactamase-producing, nine were positive for blaIMP-1 and one for blaNDM-1. IMP-positive isolates were also positive for blaOXA-58 gene. All isolates were susceptible to ciprofloxacin, colistin and minocycline, and nine were susceptible to ampicillin-sulbactam and gentamicin. Two A. ursingii displayed high level of resistance to aztreonam associated with blaCTX-M-15 in one isolate, and blaVEB-1 in the other. Eight SmaI PFGE patterns were recognized. We evaluated the usefulness of Acinetobacter MLST Pasteur scheme, to analyse A. ursingii isolates, however the rpoB gene was not amplified. A new set of primers were designed for specific amplification and sequencing, allowing the analysis of rpoB gene for this species. New alleles and the sequence types 748, 749, 750, 751, 993, 1186, 1187, and 1189 were included at the Acinetobacter MLST-Pasteur database. Those isolates showing related PFGE patterns were assigned to the same ST. To the best of our knowledge, this is the first report of MBL-producing A. ursingii in Argentina. The inclusion of A. ursingii species to the Acinetobacter MLST-Pasteur scheme allows deeper molecular characterization and a better understanding about the epidemiology of this germen. PMID- 30439520 TI - Real-Time Single-Molecule Kinetic Analyses of AIP1-Enhanced Actin Filament Severing in the Presence of Cofilin. AB - Rearrangement of actin filaments by polymerization, depolymerization, and severing is important for cell locomotion, membrane trafficking, and many other cellular functions. Cofilin and actin-interacting protein 1 (AIP1; also known as WDR1) are evolutionally conserved proteins that cooperatively sever actin filaments. However, little is known about the biophysical basis of the actin filament severing by these proteins. Here, we performed single-molecule kinetic analyses of fluorescently labeled AIP1 during the severing process of cofilin decorated actin filaments. Results demonstrated that binding of a single AIP molecule was sufficient to enhance filament severing. After AIP1 binding to a filament, severing occurred with a delay of 0.7 s. Kinetics of binding and dissociation of a single AIP1 molecule to/from actin filaments followed a second order and a first-order kinetics scheme, respectively. AIP1 binding and severing were detected preferentially at the boundary between the cofilin-decorated and bare regions on actin filaments. Based on the kinetic parameters explored in this study, we propose a possible mechanism behind the enhanced severing by AIP1. PMID- 30439521 TI - Hemorrhagic Complications of External Ventriculostomy in the Aspirin and P2Y12 Response Assay Era. AB - OBJECTIVE: Hemorrhagic complications reported from EVD placement range from 10 44%. There remains limited literature investigating incidence, risk factors, and mechanisms to prevent its occurrence, especially in the setting of anti-platelet agent use. We investigated EVD related hemorrhagic complications after the implementation of VerifyNow platelet inhibition assays at our institution. METHODS: Medical records from 445 patients requiring EVD placement during a 2 year period in which our institution utilized the assays were reviewed. 345 patients were included, and 208 of them received assay testing. Indications for EVD included complications of cerebrovascular disease (n=215), traumatic brain injury (TBI) (n=74), primary hydrocephalus (n=23), and tumor (n=33). Hemorrhage was defined as any new area of hyperdensity adjacent to or immediately along the catheter trajectory on CT. RESULTS: There was no significant decrease in CIH between patients who received the VerifyNow assay and those who did not. Platelet transfusion did not significantly decrease CIH risk. CIH occurred in 17.7% of patients, significantly decreased when compared to our previously published incidence of 33% prior to platelet inhibition assay use (p<0.05). Patients with cerebrovascular disease complications exhibited significant decrease in CIH, 20% versus 39% before assay use (p<0.01). CONCLUSIONS: The incidence of hemorrhage is lower in our new cohort when compared to that of our previously published cohort. Despite the overall decreased rate of hemorrhage, there was no significant difference in hemorrhage rates between patients who did or did not receive the assay. Platelet transfusion did not decrease the incidence of hemorrhage in patients with inhibited platelet function. PMID- 30439522 TI - Continuous activity tracking using a wrist-mounted device in adult spinal deformity: A proof of concept study. AB - BACKGROUND: Sagittal imbalance in adult spinal deformity (ASD) likely influences balance and ambulatory capacity due to muscular demand, pain, and disability. Disability measures for ASD rely heavily on ambulatory function, yet current metrics may fail to fully capture its contribution. We sought to determine (1) the utility of continuous remote step-count monitoring and activity tracking in ASD using a consumer-friendly accelerometer, and (2) investigate trends and patterns both before and after surgical intervention. CASE DESCRIPTION: One patient with progressive ASD was enrolled. Daily step count (SC), distance travelled (DT), and levels of activity were measured using a wrist-mounted device (FitBit) for 17 months. Spinopelvic parameters were measured from standing radiographs. The patient underwent T4-ilium long segment fusion for correction of progressive deformity (CC: 8; SVA: 4cm; CVA: 2cm); recovery was uneventful. The device was worn 216/520 (41%) of recorded days during waking hours, with an average SC of 5254+/-2696 per day. SC (p<0.001), DT (p<0.001), and minutes of LA (light activity) (p<0.001) declined over the 9-month preoperative course, while SA increased (p<0.001). Following surgery, SC, DT, and LA decreased in the early postoperative period, with a significant increase at 7-8 months compared to the preoperative period (p<0.001). CONCLUSIONS: Wrist-mounted devices are a non invasive and effective measure to track daily activity and ambulatory capacity of spinal deformity patients. In a single case, progressive deformity correlated with worsening activity levels, while deformity correction improved step count and activity level. These results support remote activity monitoring as an exploratory outcome for future studies. PMID- 30439523 TI - An Emergency placement of a Flow Diverter Stent for a Iatrogenic Internal Carotid Artery Injury During Endoscopic Pituitary Surgery - Case Report. PMID- 30439525 TI - Application of microanastomosis techniques in vascular neurosurgery training and innovation of future surgical strategies for giant aneurysms. PMID- 30439524 TI - Tetraventricular Atypical Central Neurocytoma - Case Report. AB - BACKGROUND: Central neurocytomas are benign tumors accounting for < 0.5% of all intracranial tumours. They are usually intraventricular, the commonest site being the lateral ventricles and are associated with good prognosis if they are completely resected surgically. CASE AND DESCRIPTION: We report a case of middle aged lady who was evaluated for recent onset headache and Magnetic resonance imaging (MRI) brain was suggestive of solid-cystic intraventricular mass spanning all the ventricles. Patient underwent subtotal excision of the mass with intraoperative neuromonitoring. Histopathology was suggestive of atypical neurocytoma. Patient had complete neurological recovery in spite of immediate post-operative deficts. CONCLUSION: Gross total resection should be the goal in all patients with central neurocytoma but it may be limited due to proximity to eloquent areas especially in large tumours. Intra-operative neuro-monitoring plays pivotal role in maximal safe resection of such large tumours. Tetraventricular atypical central neurocytoma is a very rare entity and this could be, to the best of our knowledge only the second reported case. PMID- 30439526 TI - Radiographic and Clinical Outcomes of Surgical Correction of Poliomyelitis Related Spinal Deformities: A Comparison Among Three Types of Pelvic Instrumentations. AB - BACKGROUND: We compared the clinical and radiographic outcomes of corrective surgery in patients with poliomyelitis-related spinal deformity (PSD) using 3 types of pelvic fixation and investigated the incidence and risk factors for complications. METHODS: We reviewed the data from 42 patients with PSD who had undergone spinopelvic reconstruction at a single institution from 2000 to 2016. Of the 42 patients, 15 had been treated with the Galveston technique, 13 with iliac screw fixation, and 14 with S2-alar-iliac (S2AI) screw fixation. Demographic data, radiographic parameters, and complications were analyzed. Health-related quality of life was determined using Scoliosis Research Society (SRS) 22-item questionnaires and the Oswestry Disability Index scores. RESULTS: After surgery, the correction rate of the main curve was 51.7%, 57.8%, and 52.1% in the 3 groups, with significant improvement in regional kyphosis, coronal balance, and pelvic obliquity (PO) (P < 0.05). The correction of PO was similar among the 3 types of pelvic fixation; however, the patients treated with S2AI fixation required significantly less operative time (P < 0.05) and blood loss (P < 0.006). The overall complication rate was 40.5%, with a major complication rate of 23.8%. Age at surgery (P = 0.006) and grade >2 SRS-Schwab osteotomy (P = 0.036) were significant risk factors for complications. Significant improvement was found in the SRS-22 and Oswestry Disability Index scores at the final follow up examination in the 3 groups. CONCLUSIONS: The present study showed satisfactory correction of spinopelvic deformity for 42 patients with PSD. Compared with the Galveston technique and iliac screw fixation, the use of S2AI significantly decrease the operative time and estimated blood loss and obtained similar correction of PO. Patient age at surgery and grade >2 SRS-Schwab osteotomy were significant risk factors for complications. PMID- 30439527 TI - Mdivi1 prevents early-stage induction of mitophagy and accelerated cell death in a rat model of moderate controlled cortical impact brain injury. AB - BACKGROUND: Growing evidences have implicated dysfunctional mitochondria in the pathophysiology of neurodegenerative disorders. Selective degradation of dysfunctional mitochondria is termed mitophagy and constitutes a pivotal component of mitochondrial quality control to maintain cellular homeostasis. Mitochondrial fission plays prominent roles in controlling mitochondrial shape and function. However, it is unclear whether mitochondrial fission in the context of eliminating damaged mitochondria is involved in traumatic brain injury (TBI). The objective of this study was to examine the role of mitochondrial division inhibitor 1 (Mdivi1), a small-molecule inhibitor of dynamin-related protein (Drp1), in general autophagy and mitophagy after controlled cortical impact (CCI). METHODS: Mitophagy and the role of Drp1 in this process after CCI were examined using western blotting, electron microscopy, double immunofluorescence staining, neurological severity scores (NSS), and hematoxylin and eosin (HE) staining. Statistical analysis was performed using one-way ANOVA followed by the least significant difference (LSD) test or the Games-Howell test. RESULTS: Animals exposed to CCI exhibited induction of mitophagy and fragmentation of mitochondria. When fission was blocked with Mdivi1, the mitochondria became excessively long and interconnected. Inhibition of Drp1 blocked the induction of mitophagy specifically, which aggravated neurological manifestations and neuronal apoptosis. Mdivi1 activated caspase-3 and caspase-9, implying that selective degradation of damaged mitochondria by autophagy markedly decreased cell apoptosis induced by TBI and thus promoted cell survival. CONCLUSIONS: This study supports the hypothesis that Drp1-dependent mitochondrial fission contributes to mitophagy in TBI, and further understanding the regulatory mechanisms of Drp1 will provide opportunities to develop novel strategies against TBI. PMID- 30439528 TI - Efficiency of dual siRNA-mediated gene therapy for intervertebral disc degeneration (IVDD). AB - BACKGROUND CONTEXT: One of the common causes of low back pain is intervertebral disc degeneration. The pathophysiology of disc degeneration involves apoptosis of nucleus pulposes cells and degradation of extra cellular matrix (ECM). Caspase 3 plays a central role in apoptosis and the ADAMTS5 (A Disintegrin and Metalloproteinase with Thrombospondin motifs 5) gene plays a critical role in ECM degradation. Hence, we hypothesized that if one can silence these two genes, both apoptosis and ECM degradation can be prevented, thereby preventing the progression and even reverse disc degeneration. PURPOSE: The purpose of this study is to demonstrate the regenerative potential of small interfering RNA (siRNA) designed against Caspase 3 and ADAMTS5 genes in an in vitro and animal model of disc degeneration. STUDY DESIGN: In vitro study followed by in vivo study in a rabbit model. METHODS: In vitro studies were done using the human hepatocellular carcinoma (Hep G2) cell line for validating the efficacy of liposomal siRNA in controlling the expression of genes (Caspase 3 and ADAMTS5). Later, siRNA's validation was done in a rabbit annular punctured model by administering siRNA's individually (Caspase 3 and ADAMTS5) and in combination Caspase3-ADAMTS5) for assessing their synergistic effect in down regulating the gene expression in the degenerative discs. Annular punctured intervertebral discs of the rabbit were injected with siRNA formulations (single and dual) and phosphate buffer saline, one week after initial puncture. Magnetic resonance imaging (MRI) scans were done before and after siRNA treatment (1, 4 and 8 weeks) for assessing the progression of disc degeneration. The histopathology and real time polymerase chain reaction (RT-PCR) studies were done for evaluating their efficacy. We did not receive any funding for conducting the study, and we do not have a conflict of interest with any researchers or scientific groups. RESULTS: The observations made from both in vitro and in vivo studies indicate the beneficial effects of siRNA formulation in down regulating the expression of Caspase 3 and ADAMTS5 genes. The MRI and histopathological evaluation showed that the disc degeneration was progressive in phosphate buffer saline and AT5-siRNA injected discs but the discs that received Caspase 3-siRNA and dual siRNA (Cas3 AT5-siRNA) formulation showed signs of recovery and regeneration 4 and 8 weeks after injection. The efficacy of siRNA designed against Cas3 and AT5 was also assessed in both in vitro and in vivo experiments by using RT-PCR analysis and the results showed downregulation of Caspase 3 gene in Caspase 3-siRNA group, but there was no significant downregulation of ADAMTS5 gene in ADAMTS5-siRNA group (ie, indicated by fold change). Synergistic effect was observed in the group that received dual siRNA (Cas3-AT5 siRNA) formulation. CONCLUSIONS: This experiment suggests that intervention by siRNA treatment significantly reduced the extent of apoptosis in the discs. CLINICAL SIGNIFICANCE: Delivery of siRNA directly into spinal discs has a potential in treating disc degeneration nonsurgically. PMID- 30439529 TI - Combined effects of intermittent hyperoxia and intermittent hypercapnic hypoxia on respiratory control in neonatal rats. AB - Chronic exposure to intermittent hyperoxia causes abnormal carotid body development and attenuates the hypoxic ventilatory response (HVR) in neonatal rats. We hypothesized that concurrent exposure to intermittent hypercapnic hypoxia would influence this plasticity. Newborn rats were exposed to alternating bouts of hypercapnic hypoxia (10% O2/6% CO2) and hyperoxia (30-40% O2) (5 cycles h-1, 24 h d-1) through 13-14 days of age; the experiment was run twice, once in a background of 21% O2 and once in a background of 30% O2 (i.e., "relative hyperoxia"). Hyperoxia had only small effects on carotid body development when combined with intermittent hypercapnic hypoxia: the carotid chemoafferent response to hypoxia was reduced, but this did not affect the HVR. In contrast, sustained exposure to 30% O2 reduced carotid chemoafferent activity and carotid body size which resulted in a blunted HVR. When given alone, chronic intermittent hypercapnic hypoxia increased carotid body size and reduced the hypercapnic ventilatory response but did not affect the HVR. Overall, it appears that intermittent hypercapnic hypoxia counteracted the effects of hyperoxia on the carotid body and prevented developmental plasticity of the HVR. PMID- 30439530 TI - Manual dexterity and dental biofilm accumulation in independent older adults without hand disabilities: a cross-sectional study. AB - BACKGROUND: This study investigated the relationship between manual dexterity and dental biofilm accumulation in independent older Koreans using Quantitative Light Induced Fluorescence-Digital (QLF-D). METHODS: This cross-sectional study included 44 participants recruited from senior welfare facilities in South Korea and aged >= 65 years. Participants were surveyed using face-to-face structured interviews; manual dexterity was assessed using the Box and Blocks Test. To evaluate dental biofilm accumulation, the 528 surfaces of six index teeth were imaged using QLF-D and then quantified into Simple Plaque Scores (SPS) and DeltaR20 values. The t-test and one-way analysis of variance were used to analyze differences in SPS and DeltaR20 according to general characteristics and manual dexterity. RESULTS: Those who brushed their teeth <= 2 times per day had higher SPS and DeltaR20 values on the lingual surface of tooth #24 than those who brushed >= 3 times per day (p < 0.05). The low manual dexterity group had higher SPS on lingual surfaces of teeth #12, #24, and #32, as well as higher DeltaR20 values on the lingual surfaces of teeth #12, #24, #32, and #44 (p < 0.05) than the normal group. CONCLUSIONS: The low manual dexterity group had more dental biofilm-particularly on the lingual surfaces of teeth-and more mature biofilm than the normal group. These findings indicate that reduced manual dexterity could be a predictor of poor oral hygiene in independent older adults without hand disabilities. Therefore, we suggest manual dexterity be assessed in advance of dental biofilm assessment and tooth brushing instruction. PMID- 30439531 TI - Antimicrobial efficacy of methylene blue-mediated photodynamic therapy on titanium alloy surfaces in vitro. AB - Bacterial elimination using antimicrobial photodynamic therapy (aPDT) has been considered an alternative therapeutic modality in peri-implantitis treatment. The present in vitro study was to evaluate the dose-dependent and pH-dependent bactericidal effects of methylene blue (MB)-mediated aPDT at eliminating Gram negative (P. gingivalis and A. actinomycetemcomitans) and Gram-positive (S. mutans) bacteria on sandblasting, large-grit and acid-etching (SLA)-pretreated titanium alloy. The effects of different MB concentrations (50, 100, and 200 MUg/mL), the pH of the MB (4, 7, and 10), and irradiation time (0, 30, and 60 sec) on the bacterial viability and residual lipopolysaccharide (LPS) levels were examined. The variations in the pH of the MB solution after aPDT for 60 sec on the uncontaminated and contaminated specimens were also detected. The experimental results indicated that MB-mediated PDT could effectively kill the majority of bacteria on the titanium alloy surfaces of biofilm-contaminated implants compared with the MB alone. Of note, aPDT exhibited better antibacterial efficacy with increase in the MB concentration and irradiation time. While treated in an acidic solution on the biofilm-contaminated specimens, aPDT caused the pH to increase. By contrast, the initially high alkaline pH decreased to a value of about pH 8.5 after aPDT. Intriguingly, the neutral pH had minor changes, independent of the MB concentration and bacterial species. As expected, aPDT with higher MB concentration at higher pH environment significantly lowered the LPS concentration of A. actinomycetemcomitans and P. gingivalis. On the basis of the data, the aPDT with 200 MUg/mL MB at pH 10 for 60 sec of irradiation time might be an effectively treatment to eliminate bacteria and LPS adherent to titanium surface, however, the use of the multispecies biofilm model and the evaluation of in vitro osteogenesis needed to be further evaluated. PMID- 30439532 TI - A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death. AB - RRM2B encodes the crucial p53-inducible ribonucleotide reductase small subunit 2 homolog (p53R2), which is required for DNA synthesis throughout the cell cycle. Mutations in this gene have been associated with a lethal mitochondrial depletion syndrome. Here we present the case of an infant with a novel homozygous p.Asn221Ser mutation in RRM2B who developed hypotonia, failure to thrive, sensorineural hearing loss, and severe metabolic lactic acidosis, ultimately progressing to death at 3 months of age. Through molecular modeling using the X ray crystal structure of p53R2, we demonstrate that this mutation likely causes disruption of a highly conserved helix region of the protein by altering intramolecular interactions. This report expands our knowledge of potential pathogenic RRM2B mutations as well as our understanding of the molecular function of p53R2 and its role in the pathogenesis of mitochondrial DNA depletion. PMID- 30439533 TI - A de novo variant in MMP13 identified in a patient with dominant metaphyseal anadysplasia. AB - Metaphyseal anadysplasia 1 (MIM# 602111) belongs to a heterogeneous group of skeletal diseases characterized by an autosomal dominant form of growth defects due to metaphyseal changes with epiphyseal involvement similar to other metaphyseal disorders. Matrix metalloproteinase 13 encoded by MMP13 presumably plays important roles in bone formation and growth, and pathogenic variants in MMP13 have been identified to cause metaphyseal anadysplasia 1. Only six pathogenic variants in MMP13 have been previously reported worldwide. The genotype-phenotype correlation of MMP13-related disorders has not been fully understood. Here we reported the identification of a previously unreported pathogenic heterozygous de novo variant NM_002427.3:c.212T > C/p.Met71Thr in MMP13 in a Chinese male pediatric patient with metaphyseal anadysplasia 1 and additional phenotypes, including mild rickets-like changes observed on upper long bone metaphyses and patchy bone defects on the spine vertebrae particularly resolved by childhood. Our findings not only expand genotype and phenotype spectrums of MMP13-related disorders but also offer further information for precise diagnosis and classification of metaphyseal anadysplasia disorders. PMID- 30439534 TI - Australians' perspectives on support around use of personal genomic testing: Findings from the Genioz study. AB - Personal genomic testing using direct-to-consumer and consumer-directed models, with or without involvement of healthcare providers, is increasing internationally, including in Australia. This study forms a sub-set of the Genioz study - Genomics: National Insights of Australians. We aimed to explore Australians' experiences with these types of tests, especially online DNA tests, and their views regarding whom they would seek support from around understanding test results. The study used a mixed methods approach, employing an exploratory quantitative online survey and follow-up qualitative semi-structured interviews. Between May 2016 and May 2017, 2841 Australians responded to the survey. Interviews were conducted with 63 purposively sampled respondents, including 45 who had a genetic test and 18 who had not. Of 571 respondents who had any type of genetic test, 322 had a personal genomic test using criteria defined by the researchers. Testing for ancestry/genealogy was the most common, reported by 267 participants, reflecting the increased advertising of these tests in Australia. Some respondents described downloading their raw data for further interpretation through third party websites for genealogical as well as health related information. Carrier testing, testing for serious and preventable conditions and nutrition and/or wellness were the most common health related tests reported by respondents. Participants generally preferred to seek support from general practitioners (GPs), medical specialists with relevant expertise and independent genetics specialists, although another important preference for non-health information was online forums and networks. There was less preference for seeking support from employees associated with the testing companies. Generally, of those who had a health related PGT, the most common actions were seeking medical advice or doing nothing with the information, while more of those who had a personal genomic test for nutrition and/or wellness sought advice from complementary/alternative health practitioners (eg naturopaths) and integrative GPs, and 60% reported they had changed their diet. As awareness of personal genomic testing increases, publicly funded clinical genetics services may be less inclined to discuss results from personal genomic testing. Genetic counsellors could play an important role in providing this support, both pre-test and post test, through opportunities for private practice but independent from testing companies. PMID- 30439535 TI - Comparison of suture button fixation and syndesmotic screw fixation in the treatment of distal tibiofibular syndesmosis injury: A systematic review and meta analysis. AB - PURPOSE: This systematic review and meta-analysis was performed to investigate the outcomes of syndesmotic screw fixation versus suture button fixation in the treatment of distal tibiofibular syndesmosis injury from the current literature. METHODS: The electronic literature database of PubMed, Embase, and Cochrane library were searched in August 2018. The data on medial clear space, tibiofibular clear space, tibiofibular overlap, American Orthopaedic Foot and Ankle Society (AOFAS) scores and complications (including wound infection, local irritation or discomfort, screw loosening and screw breakage) were extracted. Stata 14.0 software was used for our meta-analysis. RESULTS: A total of 11 studies including 5 randomized controlled trials (RCTs) and 6 cohort studies met our inclusion criteria. This meta-analysis showed that there was no significant difference between the two groups regarding medial clear space (P = 0.54), tibiofibular clear space (P = 0.23) and tibiofibular overlap (P = 0.88) postoperatively. However, the present meta-analysis demonstrated that the suture button fixation group had significantly higher AOFAS scores than the syndesmotic screw fixation group at 3rd, 6th, 12th and 24th months postoperatively (P = 0.001, P = 0.006, P = 0.000 and P = 0.049 respectively). Besides, the time to full weight bearing in the suture button fixation group was significantly earlier than that in the syndesmotic screw fixation group (P = 0.000). As for the complications, the suture button fixation group had a lower rate of post operative complication (screw loosening and screw breakage) compared with the syndesmotic screw fixation group (P = 0.048 and P = 0.000 respectively). CONCLUSION: Our meta-analysis suggested that suture button fixation could achieve significant higher AOFAS scores with a lower rate of postoperative complications and earlier time to full weight bearing in distal tibiofibular syndesmosis injury. More RCTs are required for further research. PMID- 30439536 TI - Safe laparoscopic cholecystectomy: A systematic review of bile duct injury prevention. AB - BACKGROUND: Since the introduction of laparoscopic cholecystectomy (LC), a substantial increase in bile duct injury (BDI) incidence was noted. Multiple methods to prevent this complication have been developed and investigated. The most suitable method however is subject to debate. In this systematic review, the different modalities to aid in the safe performance of LC and prevent BDI are delineated. MATERIALS AND METHODS: A systematic search for articles describing methods for the prevention of BDI in LC was conducted using EMBASE, Medline, Web of science, Cochrane CENTRAL and Google scholar databases from inception to 11 June 2018. RESULTS: 90 studies were included in this systematic review. Overall, BDI preventive techniques can be categorized as dedicated surgical approaches (Critical View of Safety (CVS), fundus first, partial laparoscopic cholecystectomy), supporting imaging techniques (intraoperative radiologic cholangiography, intraoperative ultrasonography, fluorescence imaging) and others. Dedicated surgical approaches demonstrate promising results, yet limited research is provided. Intraoperative radiologic cholangiography and ultrasonography demonstrate beneficial effects in BDI prevention, however the available evidence is low. Fluorescence imaging is in its infancy, yet this technique is demonstrated to be feasible and larger trials are in preparation. CONCLUSION: Given the low sample sizes and suboptimal study designs of the studies available, it is not possible to recommend a preferred method to prevent BDI. Surgeons should primarily focus on proper dissection techniques, of which CVS is most suitable. Additionally, recognition of hazardous circumstances and knowledge of alternative techniques is critical to complete surgery with minimal risk of injury to the patient. PMID- 30439537 TI - Clinical utility of radioactive seed localization in nonpalpable breast cancer: A retrospective single institutional cohort study. AB - BACKGROUND: With advances in mammographic screening techniques, it has become easier to detect nonpalpable breast lesions at an early stage. Pre-surgical localization of lesions by radioactive seed localization (RSL) has several benefits over conventional wire localization (WL) in guiding breast conserving surgery. In this study, we compared WL and RSL, focusing on the relationship between the techniques and in-breast recurrence or margin positivity. METHODS: This study included 1083 patients with nonpalpable breast lesions who underwent breast conserving surgery between 2010 and 2015. The patients were classified into WL and RSL groups. RESULTS: Margin positivity and in-breast recurrence rates did not differ significantly between the WL and RSL groups (P = 0.368 and P = 0.167, respectively). Multivariate analysis showed that tumor grade (OR: 5.016; 95% CI: 1.53-23.059) was significantly associated with margin positivity in patients undergoing RSL. Tumor size was significantly associated with in-breast recurrence in both the WL group (OR: 2.299; 95% CI: 1.561-3.411) and RSL group (OR: 2.998; 95% CI: 1.128-8.043). CONCLUSION: As the method of tumor localization did not influence margin positivity or in-breast recurrence, either WL or RSL appear to be appropriate for breast conserving surgery. Given the advantages of RSL, including the ability to perform this technique days to weeks before surgery, we propose that high-volume breast centers consider adopting this localization method. PMID- 30439538 TI - Fluoxetine Modulates Spontaneous and Conditioned Behaviors to Carbon Dioxide (CO2) Inhalation and Alters Forebrain-Midbrain Neuronal Activation. AB - Panic disorder (PD), a prevalent anxiety disorder, is characterized by unexpected panic attacks, persistent anxiety and avoidance of panic contexts. Selective serotonin reuptake inhibitors (SSRIs) are effective in treating PD; however, the mechanisms underlying SSRI efficacy are poorly understood. Using CO2-inhalation, a PD-relevant translational paradigm, we examined the effect of chronic SSRI (fluoxetine) treatment on unconditioned and context-conditioned defensive behaviors, as well as respiratory responses, in mice. In addition, cFos expression was evaluated as a measure of the functional activity and interregional correlation matrices were used to explore the neurocircuitry recruited in CO2-conditioned behavior and SSRI treatment response. Chronic fluoxetine attenuated CO2-induced passive (freezing) behavior during inhalation and active (rearing) behavior on re-exposure to context, in addition to reducing CO2-evoked respiratory responses. Brain mapping in CO2-context-conditioned mice revealed altered regional neuronal activation within and correlations across midbrain regions subserving defensive behaviors (periaqueductal gray (PAG) and raphe nuclei) and forebrain emotional and contextual processing loci (medial prefrontal cortex, insular cortex and hippocampus). Importantly, fluoxetine treatment normalized these alterations. Collectively, our results provide novel information on fluoxetine modulation of panic-relevant defensive behaviors and neurocircuitry, facilitating increased understanding of panic neurobiology in the context of treatment response. PMID- 30439539 TI - Pigment epithelium-derived factor inhibits lung cancer migration and invasion by upregulating exosomal thrombospondin 1. AB - Exosomes are implicated in cancer cell development, migration and invasion. Pigment epithelium-derived factor (PEDF) is a secreted anticancer protein that can regulate lung cancer progression; however, the role of PEDF in non-small cell lung cancer (NSCLC), including metastasis and cancer cell-derived exosome secretion, is unclear. In this study, we analyzed the effects of PEDF on exosome mediated migration, invasion, and tumorigenicity of cultured NSCLC cells. The results showed that PEDF overexpression significantly reduced NSCLC invasion and migration, while inducing cell aggregation, whereas PEDF knockdown had the opposite effects. Exosomes from NSCLC cells treated with recombinant PEDF had a significantly reduced ability to promote cancer cell motility, migration, and invasion compared to exosomes from untreated cells. Exosomes from PEDF-treated cells contained thrombospondin 1 (THBS1), which inhibited cytoskeletal remodeling and exosome-induced lung cancer cell motility, migration, and invasion. Furthermore, PEDF-overexpressing NSCLC cells formed smaller xenograft tumors with higher THBS1 expression compared to control tumors. Our findings indicate that PEDF decreases the metastatic potential of NSCLC cells through regulation of THBS1 release in cancer cell-derived exosomes, thus uncovering a new mechanism of lung cancer progression. PMID- 30439540 TI - ZNF32 induces anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling in hepatocellular carcinoma. AB - Tumor cells need to attain anoikis resistance to survive prior to metastasis making it a vital trait of malignancy. The molecular mechanism by which hepatocellular carcinoma (HCC) cells resist anoikis remains not fully understood. Here, we report that ZNF32 expression is markedly upregulated in HCC cells upon detachment. Enforced ZNF32 expression significantly promotes the anchorage independent growth capability of HepG2 and Huh7 cells, whereas knockdown of ZNF32 results in increased apoptosis of HCC cells after detachment. Mechanistically, we demonstrate that ZNF32 overexpression suppresses the reactive oxygen species (ROS) accumulation and maintains mitochondrial membrane potential, leading to ATP, GSH and NADPH elevation and promoting HCC cell survival in response to suspension. Moreover, ZNF32 enhances the phosphorylation and activation of Src/FAK signaling. Src and FAK inhibitors effectively reverse ZNF32-induced anoikis resistance in HCC cells. Collectively, our findings not only reveal a novel and important mechanism by which ZNF32 contributes to anoikis resistance through maintaining redox homeostasis and activating Src/FAK signaling, but also suggest the potential therapeutic value of ZNF32 in HCC patients. PMID- 30439541 TI - Intratumoral injection of gels containing losartan microspheres and (PLG-g-mPEG) cisplatin nanoparticles improves drug penetration, retention and anti-tumor activity. AB - Intratumoral injection of chemotherapy agents may be employed in the treatment of cancers. However, its anti-tumor efficacy is significantly impeded by collagen fibers in the tumor which decrease drug penetration into the tumor tissues. To improve the penetration, collagen inhibiting drug exposure is required. In this study, microspheres were fabricated by the modified double emulsion-solvent evaporation method as the drug delivery system of losartan potassium (LP MSs), with 5% gelatin as the inner phase. The collagen inhibiting experiment analyzed by Sirius Red stains demonstrated that LP MSs may effectively inhibit collagen I synthesis in B16 tumors. In addition, 15% F127 was used as the solvent to fix the formulations at the injection site, with poly (alpha-l-glutamate) grafted polyethylene glycol mono methyl ether (PLG-g-mPEG)-cisplatin loaded nanoparticles (CDDP NPs) as the model drug. The in vivo live imaging system showed that formulations dissolved in 15% F127 had 54.91% CDDP NPs retained in tumors at the end of 10 days, in comparison with 19.72% for those solved in water, suggesting strong intratumoral retention property of the in situ gel. In addition, confocal laser scanning microscope (CLSM) and Energy-Dispersive Analysis of X-ray spectroscopy combined with scanning electron microscope (SEM-EDAX) tests showed that LP MSs can effectively enhance the distribution and penetration of CDDP NPs within tumors. Furthermore, tumors i.t. treated with LP MSs/CDDP NPs gel could be significantly halted, or even reduced to 200 mm3, comparing with a volume of about 12000 mm3 incontrol group at the end of the anti-tumor effect experiment. These results provided important guiding principles for prolonged and localized drug delivery system of intratumoral collagen inhibitor. The improvements of intratumoral penetration method made in this study provided practical significance for the treatment of cancer, especially for mass tumors. PMID- 30439542 TI - NMR study of microscopic mechanism of water molecules diffusion in natrolite. AB - The mineral natrolite is a good object for studying the features of the molecular mobility of water molecules in spatially restricted structures by NMR techniques. The microscopic mechanisms of water molecule mobility in channels of monocrystal natural zeolite natrolite (Na16Al16Si24O80.16H2O) have been investigated by broad line (CW) NMR method. The CW NMR method, which accurately reproduces the shape of a Pake doublets of water molecules, has made it possible to trace diffusion of individual water molecules between specific positions in the crystal lattice as a function of temperature, which is important in understanding diffusion mechanisms in narrow channels of natrolite, where a diameter of the channel is smaller than the diameter of the water molecule. It has been shown that at temperatures higher than 250 K the regular diffusion of water molecules along the Schottky defects located along channels parallel to the c-crystal axis is a main kind of water molecules mobility. At temperature higher than 350 K the diffusion of water molecules in transversal channels of natrolite was observed also. Using the structural data the possible pathways of water molecules diffusion in natrolite channels have been discussed. The relationship between diffusion of water molecules and the dynamics of the zeolite framework and sodium cations is discussed on the basis of the assumption non-Markovian characte of diffusion in natrolite. PMID- 30439543 TI - Microbes and Their Metabolites Correlate with Hematopoietic Stem Cell Transplantation Outcomes? PMID- 30439544 TI - Randomised trials involving surgery did not routinely report considerations of learning and clustering effects. AB - OBJECTIVE: To establish current practice of the management of learning and clustering effects, by treating centre and surgeon, in the design and analysis of randomised surgical trials. STUDY DESIGN AND SETTING: The need for more surgical randomised trials is well recognised, and in recent years conduct has grown. Rigorous design, conduct and analyses of such studies is important. Two methodological challenges are clustering effects, by centre or surgeon, and surgical learning on trial outcomes.Sixteen leading journals were searched for randomised trials published within a two year period. Data were extracted on considerations for learning and clustering effects. RESULTS: 247 eligible studies were identified. Trials accounted for learning with 2% using an expertise-based design and 39% accounting for expertise by pre-defining surgeon credentials. One study analysed learning. Clustering, by site and surgeon, was commonly managed by stratifying randomisation, although one-third of centre and 40% of surgeon stratified trials did not also adjust analysis. CONCLUSION: Considerations for surgical learning and clustering effects are often unclear. Methods are varied and demonstrate poor adherence to established reporting guidelines. It is recommended that researchers consider these issues on a trial-by-trial basis, and report methods or justify where not needed to inform interpretation of results. PMID- 30439545 TI - The TRIP database showed most Acute Respiratory Infections questions were already addressed by Cochrane reviews. AB - OBJECTIVE: Cochrane systematic reviews require more methodological support from Cochrane Review Groups (CRGs) than is customary in journals, CRGs must prioritise reviews to conserve resources. The TRIP database provided a dataset of questions to guide prioritization for the Acute Respiratory Infections (ARI) CRG. STUDY DESIGN AND SETTING: We extracted the ARI searches from the TRIP database (2010 to 2017) that contained at least one disease and one clinical management term, (defined as a 'search'), and tabulated these by frequency. RESULTS: There were 314,346 ARI searches from which we inferred 45,497 clinical questions, covering 365 topics. In two thirds (30,541) these addressed only 20 clinical questions, of which treatment were the most frequent; followed by diagnosis, mortality and prognosis. The 5 most frequent clinical questions were "Influenza + Vaccination" 4,989 (12.1%), "acute otitis media + antibiotics" 3578 (8.7%), "common cold + vitamin C" 3528 (8.6%), "meningitis + corticosteroids" 1,910 (4.6%), "pneumonia + general treatment" 1765 (4.3%). The 20 most frequent clinical questions were addressed by Cochrane reviews or protocols. CONCLUSION: ARI questions are common and repeated often. Most may have been addressed by Cochrane reviews. The remainder form the basis of a priority list to assign resources for future Cochrane topics. PMID- 30439546 TI - Applications of 3D printing on craniofacial bone repair: A systematic review. AB - OBJECTIVES: Three-dimensional (3D) bioprinting, a method derived from additive manufacturing technology, is a recent and ongoing trend for the construction of 3D volumetric structures. The purpose of this systematic review is to summarize evidence from existing human and animal studies assessing the application of 3D printing on bone repair and regeneration in the craniofacial region. DATA & SOURCES: A rigorous search of all relevant clinical trials and case series was performed, based on specific inclusion and exclusion criteria. The search was conducted in all available electronic databases and sources, supplemented by a manual search, in December 2017. STUDY SELECTION: 43 articles (6 human and 37 animal studies) fulfilled the criteria. The human studies included totally 81 patients with craniofacial bone defects. Titanium or hydroxylapatite scaffolds were most commonly implanted. The follow-up period ranged between 6 and 24 months. Bone repair was reported successful in nearly every case, with minimal complications. Also, animal intervention studies used biomaterials and cells in various combination, offering insights into the techniques, through histological, biochemical, histomorphometric and microcomputed tomographic findings. The results in both humans and animals, though promising, are yet to be verified for clinical impact. CONCLUSIONS: Future research should be focused on well-designed clinical trials to confirm the short- and long- term efficacy of 3D printing strategies for craniofacial bone repair. CLINICAL SIGNIFICANCE: Emerging 3D printing technology opens a new era for tissue engineering. Humans and animals on application of 3D printing for craniofacial bone repair showed promising results which will lead clinicians to investigate more thoroughly alternative therapeutic methods for craniofacial bone defects. PMID- 30439547 TI - Gold-catalyzed synthesis of alpha-D-glucosides using an o-ethynylphenyl beta-D-1 thioglucoside donor. AB - A gold-catalyzed glucosylation method using an o-ethynylphenyl beta-D-1 thioglucoside as donor is described. The reaction proceeds in a mostly SN2 pathway. A series of alpha-D-glucosides are obtained in good yields and with up to 19:1 alpha-selectivity. PMID- 30439548 TI - Traumatic atlanto-axial rotatory subluxation after surgical correction of prominent ears: Case report and review of the literature. AB - Corrective surgery of prominent ears may be justified for social or aesthetic reasons during childhood or adulthood. Post-operative complications occur in approximately 0 to 8.4% of cases. This case describes a rare atlanto-axoid rotatory subluxation after bilateral surgical correction of prominent ears under general anesthesia. Orthopedic treatment was done after two months of medical roaming outside of our center. The one-year post-operative clinic consultation and radiological exam were normal. Only the psychological impact of the episode remained. Traumatic atlanto-axial rotatory subluxation is a rare complication but should be considered after post-operative torticollis in order to aid with diagnosis and allow doctors to implement the appropriate course of treatment. PMID- 30439549 TI - About a pediatric facial trauma. AB - Less-lethal weapon are more and more used in law enforcement to neutralize combative individuals and to disperse riot crowds. Even if this type of weapon has been created to be less damaging than classical firearms, it has been incriminated many times in cases of facial injuries with functional consequences, even death. In many countries, these guns can be possessed by average citizens. They could be extremely harmful when handled by inexperienced users and cannot be considered solely as defense weapons. Interestingly, little literature is available concerning facial injuries caused by the less-lethal weapons. We report the case of a ballistic wound on a 3-year-old child. PMID- 30439550 TI - Small cell carcinoma of the floor of mouth: Difficulties of a therapeutic choice. AB - INTRODUCTION: With only 14 cases and as many different therapeutic strategies reported in the literature, small cell carcinoma of the oral cavity remains a real challenge with diagnostic and therapeutic pitfalls. CLINICAL CASE SUMMARY: A 65-year-old patient with an active smoking habit consulted for a painful oral pelvic mass. The staging confirmed the diagnosis of small cell carcinoma of the anterior floor of mouth, classified as cT3N0M0. By analogy with pulmonary locations, medical management combining chemotherapy specific for small bronchial cell carcinoma (carboplatin-etoposide) and radiotherapy (tumor bed and cervical lymph nodes) was preferred. We found no recurrence of the disease 12 months after treatment. DISCUSSION: Local invasiveness and metastatic potential of small cell carcinoma of the oral cavity require harmonization of therapeutic strategies. We suggest initiating chemotherapy associated with radiotherapy as quickly as possible, a treatment to which these tumors are known to have histological sensitivity. PMID- 30439551 TI - R-spondins: Multi-mode WNT signaling regulators in adult stem cells. AB - R-spondins (RSPOs) are secreted cysteine-rich glycoproteins that belong to a superfamily of thrombospondin type 1 repeat-containing proteins. RSPOs together with WNT proteins potentiate canonical WNT/beta-catenin signaling activity. Over the last several years, the understanding of the regulatory mechanisms and functional roles of RSPOs in many biological contexts has increased. Particularly, because a leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), a stem cell marker originally identified as a marker for intestinal stem cells, and two closely related proteins, LGR4 and LGR6, were identified as cognate receptors for RSPOs, significant research progress has been made in understanding the functional roles of RSPO/LGR signaling in stem cell biology. Given the crucial roles of canonical WNT signaling in self-renewal and differentiation of various types of stem cells, examination of RSPO function and underlying mechanism in these stem cells has provided new insight into the regulatory roles of WNT signaling in stem cell behavior. In this review, we summarize and discuss recent advances in the understanding of the signaling mechanism and roles of RSPOs in different stem cell contexts. PMID- 30439552 TI - Leading interagency planning and collaboration in mass gatherings: public health and safety in the 2012 London Olympics. AB - OBJECTIVES: Planning and implementing public health initiatives in mass gatherings such as the Olympic Games pose unique challenges for interorganizational collaboration, which involves interaction among multiple and diverse agencies. Nonetheless, there is limited empirical evidence to support interagency collaboration and public health planning decisions in mass gatherings and how leadership can shape such interactions. We empirically explored these topics in the 2012 London Olympics to identify lessons to inform planning for future mass gatherings. STUDY DESIGN: This is a qualitative case study. METHODS: Data comprised 39 semistructured interviews with key informants conducted before, during, and after the games; in addition, direct observations of field exercises and documentary analysis were also used. Open coding and thematic analysis was used to analyze the data. RESULTS: We identified two main leadership challenges that influenced interagency collaboration: organizational public health leadership and coordinating collaborative decision-making. Two facilitative conditions helped overcome the previous challenges: nurturing interorganizational linkages and creating shared understanding by activating codified frameworks at the organizational level. CONCLUSIONS: Our study highlights leadership issues in interagency collaboration in mass gatherings. Practical implications arising from this study may inform the ways the organizers of mass gatherings, public health and safety agencies, and professionals can engage in effective partnerships and joint working. PMID- 30439553 TI - Lack of health insurance among juvenile offenders: a predictor of inappropriate healthcare use and reincarceration? AB - OBJECTIVES: Relationships between the health insurance status and healthcare use among justice-involved youths transitioning into adulthood is an underexplored topic, even if transition to adulthood is a crucial time period for healthcare outcomes. To fill in these knowledge gaps, this study had two aims: (1) to examine trajectories of health insurance coverage and healthcare use among serious juvenile offenders transitioning into adulthood; and (2) to explore associations between the lack of health insurance, healthcare use and reincarceration. STUDY DESIGN: We conducted a secondary analysis on the data of the US longitudinal Pathways to Desistance study between ages 20 and 23 years (2000-2010). METHODS: Participant data on health insurance coverage, healthcare use, reincarceration and sociodemographic variables (n = 1215) were extracted and analysed using descriptive statistics, generalized linear regressions and cross lagged panel models. RESULTS: About half of the young offenders had no health insurance coverage or intermittent coverage between the age of 20 and 23 years. Emergency services were used (>=17.4%), notably more by insured participants and were increasingly used over time. Being uninsured at the age of 20 years was associated with reincarceration at the age of 23 years (b = -0.052, p = 0.014, odd-ratio = 0.95), but incarceration at the age of 20 years did not predict the insurance status at the age of 23 years (b = 0.009, p = 0.792). CONCLUSIONS: Serious juvenile offenders, especially if uninsured, faced major barriers to accessing health care and often reported an inappropriate healthcare use. This likely led to reincarceration. The lack of continuity of care and of access to health care may, therefore, increase health disparities, and efforts are needed to mitigate detrimental outcomes, by effective in and out of detention coordination of health insurance coverage and among health services. PMID- 30439554 TI - Discordance in latent tuberculosis (TB) test results in patients with end-stage renal disease. AB - OBJECTIVES: This natural experiment was designed to assess the impact of exposure to an active case of tuberculosis (TB) on a group of immunosuppressed individuals, with end-stage renal disease over an extended follow-up. STUDY DESIGN: Close contacts of people with sputum smear-positive Mycobacterium tuberculosis are at high risk of infection, particularly immunosuppressed individuals. An infectious TB healthcare worker worked in a renal dialysis unit for a month before diagnosis, with 104 renal dialysis patients, was exposed for >=8 h. METHODS: Patients were informed and invited for screening 8-10 weeks postexposure. They either underwent standard two-step assessment with tuberculin skin test (TST) and QuantiFERON(r)-TB Gold (Cellestis GmbH; QFN) interferon-gamma release assay (IGRA) or after consent, enrolled in a study where these two tests were performed simultaneously with T-SPOT(r)-TB (Oxford Immunotec Ltd; TSPOT). Patients within the study were followed up for 2 years from exposure, with QFN and TSPOT repeated at months 3 and 6 from the first testing. RESULTS: Of 104 exposed individuals, 75 enrolled in the study. There was a high degree of discordance among QFN, TSPOT and TST. This was seen at both the first time point and also over time in subjects who were retested. No patients had active TB at the baseline testing. None received treatment for latent TB infection. Over the following 2 years, no one developed TB disease. CONCLUSION: This study suggests that there is a low risk of progression to active TB in low-incidence countries even in high-risk groups. This plus the degree of the test result discordance emphasises the complexities of managing TB in such settings as it is unclear which of these tests, if any, provides the best diagnostic accuracy. PMID- 30439555 TI - Multi-modal plasma focused ion beam serial section tomography of an organic paint coating. AB - Pigment distributions have a critical role in the corrosion protection properties of organic paint coatings, but they are difficult to image in 3D over statistically significant volumes and at sufficiently high spatial resolutions required for detailed analysis. Here we report, for the first time, large volume analytical serial sectioning tomography of an organic composite coating using a xenon Plasma Focused Ion Beam (PFIB) combined with secondary electron imaging, energy dispersive X-ray (EDX) spectrum imaging (SI) and electron backscattered diffraction (EBSD). Together these techniques provide a comprehensive quantitative description of the physical orientation and distribution of the pigments within a model marine ballast tank coating, as well as their crystallographic and elemental characterisation. Polymers and organic materials are challenging because of their propensity for ion beam damage and possible beam heating effects. Our novel, optimised block preparation technique permits automated data acquisition with minimal operator intervention, and can have significant applications for the structural and chemical characterisation of a wide range of organic materials. Our results revealed that the paint contained 7.5 vol% aluminium flakes and 25 vol% quartz particles. The aluminium flakes were oriented parallel to the substrate surface, which is beneficial in terms of the corrosion protection capability of the coating. PMID- 30439556 TI - Butyrate interacts with benzo[a]pyrene to alter expression and activities of xenobiotic metabolizing enzymes involved in metabolism of carcinogens within colon epithelial cell models. AB - Butyrate helps to maintain colon homeostasis and exhibits chemopreventive effects in colon epithelium. We examined the interactive effects of butyrate and benzo[a]pyrene (BaP), dietary carcinogen, in regulation of expression of a panel of phase I and II xenobiotic metabolizing enzymes (XMEs) in human colon cells. In human colon carcinoma HCT-116 and HT-29 cell lines, butyrate alone increased mRNA levels of some enzymes, such as N-acetyltransferases (in particular NAT2). In combination with BaP, butyrate potentiated induction of cytochrome P450 family 1 enzymes (CYP1A1), aldo-keto reductases (AKR1C1) or UDP-glucuronosyltransferases (UGT1A1). There were some notable differences between cell lines, as butyrate potentiated induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) and UGT1A4 only in HCT-116 cells, and it even repressed AKR1C3 induction in HT-29 cells. Butyrate also promoted induction of CYP1, NQO1, NAT2, UGT1A1 or UGT1A4 in human colon Caco 2 cells, in a differentiation-dependent manner. Differentiated Caco-2 cells exhibited a higher inducibility of selected XME genes than undifferentiated cells. Butyrate increased induction of enzymatic activities of NATs, NQO1 and UGTs by BaP in HCT-116 and HT29 cells, whereas in differentiated Caco-2 cells it helped to increase only enzymatic activity of NQO1 and UGTs. Together, the present data suggest that butyrate may modulate expression/activities of several enzymes involved in metabolism of carcinogens in colon. In some cases (NAT2, UGT1 A1), this was linked to inhibition of histone deacetylases (HDAC), as confirmed by using HDAC inhibitor trichostatin A. These results may have implications for our understanding of the role of butyrate in regulation of XMEs and carcinogen metabolism in colon. PMID- 30439557 TI - Vascular disrupting effect of combretastatin A-4 phosphate with inhibition of vascular endothelial cadherin in canine osteosarcoma-xenografted mice. AB - Combretastatin A-4 phosphate (CA4P) induces tumor necrosis by selectively inhibiting tumor blood flow. However, the detailed mechanisms by which CA4P selectively disrupts tumor blood vessels are not well understood. Our previous study indicated that the selective blocking effect of CA4P might be related to a vascular endothelial cadherin (VE-cadherin) dysfunction in the tumor vasculature. In this study, we evaluated the vascular disrupting effect of CA4P on canine osteosarcomas xenografted into mice, focusing on VE-cadherin. Even though 30 mg/kg CA4P only partially inhibited blood flow in the xenografted tumor, a combination of an anti-VE-cadherin neutralizing antibody and 30 mg/kg CA4P inhibited most of the tumor blood flow. In addition, the combination of antibody and drug significantly inhibited tumor growth compared to the control. These results strongly suggested a relationship between the expression of VE-cadherin in tumor blood vessels and the selective blocking mechanisms of CA4P. PMID- 30439558 TI - The use of photoperiods to provide year round spawning in lumpfish Cyclopterus lumpus. AB - In order to provide year round spawning broodstock, lumpfish (initial size 746 g and 24.9 cm) were reared under four different photoperiod regimes from January 2017 to July 2018. One group was reared under simulated natural photoperiod (LDN, control group) for Tromso (70 degrees N). The second group was transferred to continuous light (LD240) on 30 January 2017 and reared at LD24:0 throughout the trial period. Two compressed and phase advanced photoperiods were also established. Both groups were moved from LDN to LD24:0 on 30 January 2017, and after that reared at compressed natural photoperiods where the annual photoperiod was compressed down to six months (L6) or nine months (L9) for the duration of the study. Spawning time was shifted in both compressed groups during both years of the study. Spawning activity in the second year of the study was higher and followed more closely the expected spawning period in the compressed and the LDN groups. Spawning in the LD240 group was spread out over the experimental period with no distinct peak in spawning. A seasonal and pronounced drop in condition factor was found for females in the L9, L6 and the LDN groups. This post-spawning loss in condition was closely related to the spawning activity of each group. The current findings suggest that photoperiod has a strong influence on the timing of lumpfish maturation and can be used as an efficient and inexpensive tool to secure lumpfish reproduction operations i.e. year-round supply of egg and milt and/or timing with optimal temperature regimes. PMID- 30439559 TI - The effect of algal turbidity on larval performance and the ontogeny of digestive enzymes in the grey mullet (Mugil cephalus). AB - A study comprised of two trials determined the effects of water turbidity produced by live microalgae and inert clay particles on the larval rearing of grey mullet (Mugil cephalus). Trial 1 evaluated the effect of microalgae produced water turbidity on grey mullet larval performance and digestive tract (DT) enzyme ontogeny. Two microalgae (Nannochloropsis oculata and Isochrysis galbana) water turbidity levels (0.76 and 1.20 NTU, respectively) and a non-microalgae control (0.26 NTU) were investigated on 2 to 23 dph grey mullet larvae. The higher turbidity (1.2 NTU) larvae (5 dph) consumed markedly (P < .05) more rotifers than other treatment fish, independently of the microalgae type. There was no clear effect of the turbidity treatments on DT enzyme ontogeny. However, in all treatments lipase and alkaline proteases appeared to be modulated by the diet. Alkaline phosphatase activity was ca. 8 times higher and alpha-amylase activity increased 5.3 times in 79 dph fish compared to 40 dph individuals. The ratio of alkaline phosphatase and leucine-alanine aminopeptidase indicated gut maturation occurred around 61 dph. Trial 2 compared the most effective N.occulata produced turbidity level (1.2 NTU) with the identical water turbidity produced by inert clay on larval performance. M. cephalus larvae exposed to high algal turbidity demonstrated superior performance (P < .05), in terms of rotifer ingestion, dry weight gain and survival, compared to cohorts reared under the clay treatment and the lower microalgae produced turbidity. These findings suggested that water algal turbidity is not the dominant factor determining improved grey mullet larval performance. PMID- 30439560 TI - The effects of active social media engagement with peers on body image in young women. AB - This experimental study examined the effects of engaging on social media with attractive female peers on young adult women's body image. Participants were 118 female undergraduate students randomly assigned to one of two experimental conditions. Participants first completed a visual analogue scale measure of state body image and then either browsed and left a comment on the social media site of an attractive female peer (n = 56) or did the same with a family member (n = 62) and then completed a post-manipulation visual analogue scale measure of state body image. A 2 * 2 mixed analysis of variance showed a significant interaction between condition and time. Follow-up t-tests revealed that young adult women who engaged with an attractive peer on social media subsequently experienced an increase in negative body image (dependence-corrected d = 0.13), whereas those who engaged with a family member did not (dependence-corrected d = 0.02). The findings suggest that upward appearance comparisons on social media may promote increased body image concerns in young adult women. PMID- 30439561 TI - Nitric oxide regulates intussusceptive-like angiogenesis in wound repair in chicken embryo and transgenic zebrafish models. AB - Angiogenesis is the formation of new blood vessels that occurs by two distinct processes following sprouting angiogenesis (SA) and intussusceptive angiogenesis (IA). Nitric oxide (NO) is known for its pro-angiogenic functions. However, no clear mechanisms are delineated on its role in promoting angiogenesis in reparative wound healing. We propose that NO regulates SA to IA transition and vice versa in wound milieu. We have used three models which include a new chick embryo extra-vasculature (CEV) burn wound model, adult Tie2-GFP transgenic Zebrafish caudal fin regeneration model and Zebrafish skin wound model to study the mechanisms underlying behind the role of NO in wound healing. Wounds created in CEV were treated with NO donor (Spermine NONOate (SPNO)), NOS inhibitor (L nitro-l-arginine-methyl ester (l-NAME)), NaNO2, NaNO3, and beetroot juice, a nitrite-rich juice respectively and the pattern of wound healing was assessed. Morphological and histological techniques tracked the wound healing at the cellular level, and the molecular changes were investigated by using real-time RT PCR gene expression analysis. The result concludes that NO donor promotes wound healing by activating SA at an early phase of healing while NOS inhibitor induces wound healing via IA. At the later phase of wound healing NO donor followed IA while NOS inhibitor failed to promote wound repair. The current work underpinned a differential regulation of NO on angiogenesis in wound milieu and this study would provide new insights in designing therapeutics for promoting wound repair. PMID- 30439562 TI - Calcium signalling and breast cancer. AB - The past two decades have seen the identification of important roles for calcium signalling in many of the hallmarks of cancer. One of the cancer types that has been a particular focus of such studies is breast cancer. The breast is intrinsically linked to the calcium ion due to the importance of milk calcium in neonatal growth and development. Indeed, some of the calcium channels and pumps involved in transporting calcium ions into milk also have altered expression in some breast cancers. However, altered expression is not confined to channels and pumps important in lactation, other calcium channels and pumps may also be modulated and may even be specific to breast cancer molecular subtypes. This review considers calcium signalling in the context of breast cancer and provides an overview of the roles that have been attributed to specific regulators of cellular calcium levels in processes relevant to breast cancer progression. Emerging areas in the study of calcium signalling in breast cancer are considered, such as the intersection between calcium signalling, the tumour microenvironment and breast cancer. PMID- 30439563 TI - Dynamics and development in number-to-space mapping. AB - Young children's estimates of numerical magnitude increase approximately logarithmically with actual magnitude. The conventional interpretation of this finding is that children's estimates reflect an innate logarithmic encoding of number. A recent set of findings, however, suggests that logarithmic number-line estimates emerge via a dynamic encoding mechanism that is sensitive to previously encountered stimuli. Here we examine trial-to-trial changes in logarithmicity of numerosity estimates to test an alternative dynamic model (D-MLLM) with both a strong logarithmic component and a weak response to previous stimuli. In support of D-MLLM, first-trial numerosity estimates in both adults (Study 1, 2, 3, and 4) and children (Study 4) were strongly logarithmic, despite zero previous stimuli. Additionally, although numerosity of a previous trial affected adults' estimates, the influence of previous numbers always accompanied the logarithmic-to-linear shift predicted by D-MLLM. We conclude that a dynamic encoding mechanism is not necessary for compressive mapping, but sequential effects on response scaling are a possible source of linearity in adults' numerosity estimation. PMID- 30439564 TI - Exploiting novel tailored immunotherapies of type 1 diabetes: Short interfering RNA delivered by cationic liposomes enables efficient down-regulation of variant PTPN22 gene in T lymphocytes. AB - In autoimmune diseases as Type 1 diabetes, the actual treatment that provides the missing hormones is not able, however, to interrupt the underlining immunological mechanism. Importantly, novel immunotherapies are exploited to protect and rescue the remaining hormone producing cells. Among probable targets of immunotherapy, the C1858T mutation in the PTPN22 gene, which encodes for the lymphoid tyrosine phosphatase (Lyp) variant R620W, reveals an autoimmunity related pathophysiological role. Our scope was to establish new C1858T PTPN22 siRNA duplexes delivered by liposomal carriers (lipoplexes) to patients' PBMC. Following lipoplexes treatment, CD3+ and CD3- immunotypes were efficiently transfected; cell integrity and viability were preserved. Specific target mRNA down-modulation was observed. After T cell receptor stimulation, in lipoplexes treated PBMC Lyp function was restored by increased release of IL-2 in cultures. Results set-up the stage for ultimate trials in the treatment of autoimmunity based on the specific inhibitory targeting of C1858T PTPN22 by lipoplexes. PMID- 30439565 TI - Memory systems 2018 - towards a new paradigm. AB - The multiple memory systems theory (MMS) postulates that the brain stores information based on the independent and parallel activity of a number of modules, each with distinct properties, dynamics, and neural basis. Much of the evidence for this theory comes from dissociation studies indicating that damage to restricted brain areas cause selective types of memory deficits. MMS has been the prevalent paradigm in memory research for more than thirty years, even as it has been adjusted several times to accommodate new data. However, recent empirical results indicating that the memory systems are not always dissociable constitute a challenge to fundamental tenets of the current theory because they suggest that representations formed by individual memory systems can contribute to more than one type of memory-driven behavioral strategy. This problem can be addressed by applying a dynamic network perspective to memory architecture. According to this view, memory networks can reconfigure or transiently couple in response to environmental demands. Within this context, the neural network underlying a specific memory system can act as an independent unit or as an integrated component of a higher order meta-network. This dynamic network model proposes a way in which empirical evidence that challenges the idea of distinct memory systems can be incorporated within a modular memory architecture. The model also provides a framework to account for the complex interactions among memory systems demonstrated at the behavioral level. Advances in the study of dynamic networks can generate new ideas to experimentally manipulate and control memory in basic or clinical research. PMID- 30439566 TI - Lower Extremity Function as a Marker of Frailty and Outcomes of Heart Failure with Preserved Ejection Fraction in Older Adults. PMID- 30439568 TI - A peroxidized omega-3-enriched polyunsaturated diet leads to adipose and metabolic dysfunction. AB - Consumption of diets that differ in fat type and amount, and sequestration of various fatty acids to tissues and organs likely have effects on overall physiology and metabolic health. However, the contributions of dietary lipids to brain-adipose communication and adipose tissue function are poorly understood. We designed six custom diets that differed only in amount and type of dietary fat, with high or low levels of saturated fatty acids (SFA), omega-6 polyunsaturated fatty acids (n-6 PUFA) or omega-3 (n-3) PUFA. Mice fed the n-3 PUFA diet for 16 weeks displayed a striking reduction in weight gain accompanied by smaller adipose depots and improved glucose sensitivity. Reduced body weight occurred despite lowered energy expenditure and no difference in food intake. Despite the apparent beneficial effects to whole body physiology, we have demonstrated for the first time that a peroxidized n-3-enriched diet led to lipotoxicity of white adipose tissue, as evidenced by increased fibrosis, lipofuscin, reduced anti inflammatory markers and loss of proper nerve supply. While healthful, n-3 fats are prone to peroxidation, and we observed peroxidated lipid metabolites in the adipose tissue of mice on these diets. Furthermore, using a lipidomics approach, we have observed that brain, white adipose tissue and brown adipose tissue accumulate lipid metabolites differently. The brain remained mostly shielded from changes in dietary fat type and amount, but differences in adipose lipid metabolites across these six diets may have affected metabolic function and brain adipose communication, as observed in this study. PMID- 30439567 TI - Thymineless Death by the Fluoropyrimidine Polymer F10 Involves Replication Fork Collapse and Is Enhanced by Chk1 Inhibition. AB - We are developing the fluoropyrimidine polymer F10 to overcome limitations of 5 fluorouracil (5-FU) that result from inefficient metabolism to 5-fluoro-2' deoxyuridine-5'-mono- and tri-phosphate, the deoxyribonucleotide metabolites that are responsible for 5-FU's anticancer activity. F10 is much more cytotoxic than 5 FU to colorectal cancer (CRC) cells; however, the mechanism of enhanced F10 cytotoxicity remains incompletely characterized. Using DNA fiber analysis, we establish that F10 decreases replication fork velocity and causes replication fork collapse, while 1000-fold excess of 5-FU is required to achieve similar endpoints. Treatment of HCT-116 cells with F10 results in Chk1 phosphorylation and activation of intra-S-phase checkpoint. Combining F10 with pharmacological inhibition of Chk1 with either PF-477736 or prexasertib in CRC cells enhanced DNA damage relative to single-agent treatment as assessed by gammaH2AX intensity and COMET assay. PF-477736 or prexasertib co-treatment also inhibited upregulation of Rad51 levels in response to F10, resulting in reduced homologous repair. siRNA knockdown of Chk1 also increased F10-induced DNA damage assessed and sensitized CRC cells to F10. However, Chk1 knockdown did not inhibit Rad51 upregulation by F10, indicating that the scaffolding activity of Chk1 imparts activity in DNA repair distinct from Chk1 enzymatic activity. Our results indicate that F10 is cytotoxic to CRC cells in part through DNA damage subsequent to replication fork collapse. F10 is ~1000-fold more potent than 5-FU at inducing replication mediated DNA damage which correlates with the increased overall potency of F10 relative to 5-FU. F10 efficacy can be enhanced by pharmacological inhibition of Chk1. PMID- 30439569 TI - Liver-type of tissue non-specific alkaline phosphatase is induced during mouse bone and tooth cell differentiation. AB - BACKGROUND AND OBJECTIVE: Tissue non-specific alkaline phosphatase (TNSALP) contains two types-bone- and liver-type-which are produced from the same gene due to differences in splicing. These two differ in their promoter, but the amino acid sequences of the mature proteins are identical. In this study, we examined the relationship between the two types of TNSALP expression and osteoblast differentiation. DESIGN: Gene expression of the two types of TNSALP was observed by reverse transcription-polymerase chain reaction. MC3T3-NM4 was sub-cloned from an established mouse osteoblastic cell line in which osteoblast characters do not appear without dexamethasone. The C2C12 mouse myoblastic cell line, which can be induced to osteoblasts with bone morphogenic protein 2, and organ-cultured tooth germs were also used in this work. RESULTS: The gene expression of liver-type TNSALP was observed in only MC3T3-NM4 activated by dexamethasone. For C2C12, the gene expression of bone-type TNSALP was observed even in non-induced conditions where myotubes were formed, whereas the liver-type TNSALP mRNA was only expressed when C2C12 differentiated into osteoblasts by bone morphogenic protein 2. Furthermore, in the organ-cultured tooth germs, the liver-type TNSALP mRNA was expressed according to differentiation of tooth germs. CONCLUSION: These results suggest that the liver-type TNSALP mRNA is induced according to differentiation of bone and tooth. PMID- 30439570 TI - The effect of presentation level on spectrotemporal modulation detection. AB - The understanding of speech in noise relies (at least partially) on spectrotemporal modulation sensitivity. This sensitivity can be measured by spectral ripple tests, which can be administered at different presentation levels. However, it is not known how presentation level affects spectrotemporal modulation thresholds. In this work, we present behavioral data for normal hearing adults which show that at higher ripple densities (2 and 4 ripples/oct), increasing presentation level led to worse discrimination thresholds. Results of a computational model suggested that the higher thresholds could be explained by a worsening of the spectrotemporal representation in the auditory nerve due to broadening of cochlear filters and neural activity saturation. Our results demonstrate the importance of taking presentation level into account when administering spectrotemporal modulation detection tests. PMID- 30439571 TI - Improved interaural timing of acoustic nerve stimulation affects sound localization in single-sided deaf cochlear implant users. AB - The main impairment associated with single-sided deafness (SSD) is the loss of binaural hearing. Currently, the most effective treatment to compensate for this deficit is to supply patients suffering from SSD with a cochlear implant (CI) in the deaf ear. With this approach binaural hearing abilities can be restored to a certain extent, which is expressed in an improvement in such patients with regard to sound source localization and speech comprehension in noise after receipt of a CI. However, binaural performance of these listeners does not reach the level of normal-hearing listeners. One of the reasons for this might be that the electrical stimulation via CI and the physiological stimulation via the intact ear are not synchronized: the CI transmits the information to the auditory nerve with different timing than does the intact inner ear. As a result, there is a timing mismatch of the information transfer between the left and the right side, which may account for the limited binaural performance. The effective mismatch in timing depends on the CI system because of different stimulation strategies implemented in devices from different manufacturers. For the particular CI device used in this study (MED-EL Mi1000/Mi1200) electrical stimulation led to faster activation of the auditory nerve than natural for a wide frequency range. In particular, electrical stimulation was about 1 to up to 2 ms ahead of time for frequencies above 1.5 kHz. Hence, it was hypothesized that information transfer between the left and the right ear can be tuned by delaying the CI signal. The goal of the present study was to investigate whether such a delay in the CI signal affects binaural performance of CI users with SSD. For this purpose, sound source localization and speech perception in noise were tested in a sample of 12 CI users with SSD (mean age 51 +/- 12 years). The tests were performed for four different delay times of the CI signal applied spontaneously (0.5, 1, 2 and 4 ms) and for the base line condition "no delay" in the CI signal (i.e. everyday use). It was found that delaying the signal had a significant impact on sound source localization. Speech perception in noise was affected, but less pronounced than was sound localization. Regarding sound source localization, a signal delay of 1 ms applied to this particular CI device produced the best performance in our patients. It is concluded that improving the synchronisation between the CI transferred signal and the naturally transferred signal could increase binaural hearing performance in CI users with SSD. PMID- 30439572 TI - Innervation of the tibial epiphysis through the intercondylar foramen. AB - The periosteum and mineralized bone are innervated by nerves that sense pain. These include both myelinated and unmyelinated neurons with either free nerve endings or bearing nociceptors. Parasympathetic and sympathetic autonomic nerves also innervate bone. However, little is known about the route sensory nerves take leaving the epiphyses of long bones at the adult knee joint. Here, we used transgenic mice that express fluorescent Venus protein in Schwann cells (Sox10 Venus mice) to visualize myelinated and unmyelinated nerves in the tibial epiphysis. Immunofluorescence to detect a pan-neuronal marker and the sensory neuron markers calcitonin gene-related peptide (CGRP) and tropomyosin receptor kinase A (TrkA) also revealed Schwann cell-associated sensory neurons. Foramina in the intercondylar area of the tibia were conserved between rodents and primates. Venus-labeled fibers were detected within bone marrow of the proximal epiphysis, exited through foramina along with blood vessels in the intercondylar area of the tibia, and joined Venus-labeled fibers of the synovial membrane and meniscus. These data suggest that innervation of the subchondral plate and trabecular bone within the tibial epiphysis carries pain signals from the knee joint to the brain through intercondylar foramina. PMID- 30439573 TI - M cell targeting engineered biomaterials for effective vaccination. AB - Vaccines are one of the greatest medical interventions of all time and have been successful in controlling and eliminating a myriad of diseases over the past two centuries. Among several vaccination strategies, mucosal vaccines have wide clinical applications and attract considerable interest in research, showing potential as innovative and novel therapeutics. In mucosal vaccination, targeting (microfold) M cells is a frontline prerequisite for inducing effective antigen specific immunostimulatory effects. In this review, we primarily focus on materials engineered for use as vaccine delivery platforms to target M cells. We also describe potential M cell targeting areas, methods to overcome current challenges and limitations of the field. Furthermore, we present the potential of biomaterials engineering as well as various natural and synthetic delivery technologies to overcome the challenges of M cell targeting, all of which are absent in current literature. Finally, we briefly discuss manufacturing and regulatory processes to bring a robust perspective on the feasibility and potential of this next-generation vaccine technology. PMID- 30439574 TI - Better together: Coexistence of for-profit and nonprofit firms with an application to the U.S. hospice industry. AB - Many markets maintain a nontrivial mix of both nonprofit and for-profit firms, particularly in health care industries such as hospice, nursing homes, and home health. What are the effects of coexistence vs. dominance of one ownership type? We show how the presence of both ownership types can lead to greater diversity in consumer types served, even if both firms merely profit-maximize. This is the case where firms serve consumers for multiple consumption durations, but where donations are part of a nonprofit firm objective function and happen after services have been provided. This finding is strengthened if the good or service has value beyond immediate consumption or the direct consumer. We show these predictions empirically in the hospice industry, using data containing over 90 percent of freestanding U.S. hospices, 2000-2008. Nonprofit and for-profit providers split the patient market according to length of stay, leading to a wider range of patients being served than in the absence of this coexistence. PMID- 30439575 TI - Heterogeneity in long term health outcomes of migrants within Italy. AB - This article examines the long term physical and mental health effects of internal migration focusing on a relatively unique migration experience concentrated over a short period between 1950 and 1970 from the South to the North of Italy. We find a positive and statistically significant association between migration, its timing and physical health for migrant females, which we show are likely to represent rural females in both the early and the late cohort. We find less defined evidence of migration-health association for mental health. We link our findings to the economic transition and labor market transformation that Italy witnessed in that era. Male migrants were likely to be positively selected to migration, but harsh working conditions were likely to downplay this differential. On the contrary, women migrants, by and large, would not engage in the formal labor market avoiding the ill effects of working environments, at the same time benefiting from better living conditions and health care in the destination regions. PMID- 30439576 TI - Aerobic and anaerobic formation and biodegradation of guanyl urea and other transformation products of metformin. AB - The aim of the study was to investigate the biodegradability of guanyl urea (GU) and the behavior of other transformation products (TPs) of Metformin (MF). Most biodegradation studies of MF with activated sludge of waste water treatment plants (WWTPs) showed GU as the only bacterial dead-end metabolite without further degradation. In this study, batch experiments with activated sludge revealed biodegradability of GU. GU degradation was much faster under anaerobic than under aerobic conditions. Degradation kinetics for MF was much slower under anaerobic conditions. Adsorptive removal of up to 20% was an additional elimination process of MF and GU. The batch experiments were conducted with sludge of 2 WWTPs, WWTP 1 showed decreasing concentrations of GU from influent to effluent and the other increasing concentrations. This indicates a different adaption of the sludge to GU and may explain the better GU degradation capability of the sludge from WWTP 1. Furthermore, the biodegradation potential of MF was confirmed and in addition, occurrence of the TPs methylbiguanide (MBG), 2-amino-4 methylamino-1,3,5-triazine (2,4-AMT) and the secondary TP 2,4-diamino-1,3,5 triazine (2,4-DAT) was observed in batch experiments with activated sludge of WWTP 1. After fast formation, degradation in turn was slower, especially for 2,4 AMT. In general, TPs played a minor role in MF and GU degradation. PMID- 30439577 TI - Enhanced mineralization of atrazine by surface induced hydroxyl radicals over light-weight granular mixed-quartz sands with ozone. AB - A light-weight granular mixed-quartz sand (denoted as L-GQS) combined with stirring-assisted bubble column reactor was firstly applied in catalytic ozonation of atrazine. The L-GQS, with a density of 2.36 g cm-3 and average diameter of ca. of 4 mm, was readily churned up and uniformly distributed within the solution in the reactor. The introduction of L-GQS was found to exhibit enhanced catalytic ozonation of atrazine, with the increase in degradation rate and the dissolved organic carbon (DOC) removal being more than 2-fold for the catalytic process (L-GQS dosage = 5 g L-1, [atrazine]0 = 50 MUM, [O3] = 25 mg L 1, gas flow = 0.2 L min-1, at pH 7.0 and 293 K). The L-GQS settled at the bottom of the reactor after experimentation, allowing its easy separation from the solution. A complete characterization of the material (XRD, XPS, FTIR, FE SEM/EDS, BET and pHpzc) revealed that L-GQS consisted of alpha-quartz, beta cristobalite, anorthoclase and small amount of iron oxy-hydroxides. Hydroxyl groups, Bronsted acid sites and Lewis acid sites on the surface of L-GQS all contributed to the atrazine adsorption, ozone decomposition and .OH generation. The L-GQS catalyzed ozonation exhibited superior atrazine degradation and mineralization rates in a wide range of pH (3.0-9.0) and reaction temperatures (278 K-293 K). Also, an enhancement of DOC abatement was observed both in presence of natural organic matter isolates and natural water matrices (river water) when L-GQS was used. Finally, the degradation mechanism was proposed, based on the intermediates and by-products formation analyzed by LC-QTOF-MS/MS and ionic chromatography. Our results indicate that the L-GQS combined with stirring-assisted bubble column reactor could be utilized as an enhancement of ozone-based advanced oxidation processes. PMID- 30439578 TI - Bromate reduction and reaction-enhanced perchlorate adsorption by FeCl3 impregnated granular activated carbon. AB - This work studied simultaneous bromate (BrO3-) reduction and adsorption of perchlorate (ClO4-) by FeCl3-impregnated granular activated carbon (Fe-GAC) and the mutual co-solute effects. We report that BrO3- reduction by Fe-GAC was coupled with enhanced adsorption of ClO4- by the material. The Langmuir maximum adsorption capacity for ClO4- by Fe-GAC was increased from 0.179 mmol g-1 (without BrO3-) to 0.256 mmol g-1 in the presence of 0.2 mmol L-1 of BrO3- (a 43% increase) at pH 6.0. While the activated carbon alone was able simultaneously remove both BrO3- and ClO4-, Fe-GAC offered much greater removal efficacy and synergistic effect, likely because the immobilized Fe3+ acted as a catalyst and provided a local acidic environment, both being in favor of accelerated BrO3- reduction. Mechanistic analyses revealed that BrO3- removal was through a two step process: ion exchange with OH- and Cl- on Fe-GAC, and then Fe-catalyzed reduction of BrO3- to Br- by carbon. The carbon-BrO3- redox reaction generated more Fe-O and C-O groups on the material surface, which can bind with ClO4- by surface complexation and electrostatic interactions. To our knowledge, this is the first report that metal modified activated carbon may facilitate synergistic removal of both BrO3- and ClO4-, which are common co-solutes in contaminated waters. PMID- 30439579 TI - Enhanced aerobic granulation by applying the low-intensity direct current electric field via reactive iron anode. AB - A novel granulation strategy by applying the low-intensity direct current (DC) electric field via reactive iron anode into the aerobic granular sludge (AGS) system was systematically investigated in this study. Three identical sequencing batch reactors (SBRs, namely R1, R2, and R3) were operated for 100 days. Comparatively, the R1 and R3 were continuously subjected to the 1.0 V DC electric field via a reactive Fe anode and an inert Ti-Ir/Rh anode, respectively, while the R2 without DC exposure. The results showed that the sludge granulation processes were accelerated in order as follows: R2 debris (17 +/- 4%) > organelles (12 +/- 2%) > heat-stable peptides (HSP) (~2%) > heat-denaturable proteins (HDP) (< 1%), indicating that the majority of intracellular Al was detoxified and stored in inorganic forms. The subcellular distribution of Al in the diatom is different from that of Al in freshwater green algae, in which most of the internalized Al is partitioned to organelles. We also evaluated an artificial seawater-based EDTA rinse solution to remove Al adsorbed on the diatom cell surface. Overall, our study provides new information to understand the mechanisms of uptake of Al by marine diatoms, and the mechanisms responsible for the biological effects (both toxic and beneficial) of Al on the growth of marine phytoplankton, especially diatoms. PMID- 30439584 TI - Metal and metalloid exposure and oxidative status in free-living individuals of Myotis daubentonii. AB - Metal elements, ubiquitous in the environment, can cause negative effects in long lived organisms even after low but prolonged exposure. Insectivorous bats living near metal emission sources can be vulnerable to such contaminants. Although it is known that bats can bioaccumulate metals, little information exists on the effects of metal elements on their physiological status. For example, oxidative status markers are known to vary after detoxification processes and immune reactions. Here, for two consecutive summers, we sampled individuals from a natural population of the insectivorous bat, Myotis daubentonii, inhabiting a site close to a metal emission source. We quantified metals and metalloids (As, Ca, Cd, Co, Cu, Mn, Ni, Pb, Se, Zn) from individual fecal pellets. We measured enzymatic antioxidants (GP, CAT, SOD), total glutathione (tGSH) and ratio between reduced and oxidized glutathione (GSH:GSSG) from their red blood cells together with biometrics, hematocrit and parasite prevalence. In general, metal concentrations in feces of M. daubentonii reflected the exposure to ambient contamination. This was especially evident in the higher concentrations of Cd, Co, Cu and Ni close to a smelter compared to a site with less contaminant exposure. Annual differences were also observed for most elements quantified. Sex specific differences were observed for calcium and zinc excretion. SOD and CAT enzymatic activities were associated with metal levels (principal components of six metal elements), suggesting early signs of chronic stress in bats. The study also shows promise for the use of non-invasive sampling to assess the metal exposure on an individual basis and metal contamination in the environment. PMID- 30439585 TI - Conformational preferences and phase behavior of intrinsically disordered low complexity sequences: insights from multiscale simulations. AB - While many proteins and protein regions utilize a complex repertoire of amino acids to achieve their biological function, a subset of protein sequences are enriched in a reduced set of amino acids. These so-called low complexity (LC) sequences, specifically intrinsically disordered variants of LC sequences, have been the focus of recent investigations owing to their roles in a range of biological functions, specifically phase separation. Computational studies of LC sequences have provided rich insights into their behavior both as individual proteins in dilute solutions and as the drivers and modulators of higher-order assemblies. Here, we review how simulations performed across distinct resolutions have provided different types of insights into the biological role of LC sequences. PMID- 30439586 TI - Developments in integrative modeling with dynamical interfaces. AB - Proteins are dynamic, and this holds especially for their surfaces. They display ensembles of conformations, which allows them to interact with diverse partners, often via the same patch of surface, and execute their distinct functions. Binding a specific partner can stimulate - or suppress - a distinct signaling pathway. This diversity poses a challenge: how to reliably model a specific protein-protein interaction (PPI)? This problem is compounded in protein assemblies, which are typically large, involving multiple protein-protein interfaces. Integrative modeling (IM), which combines diverse data, has emerged as the most promising strategy; however, modeling dynamical interfaces, often at the detailed level, which are at the heart of reliable predictions of assemblies, still poses a challenge. Here we review hurdles and advances in integrative modeling of dynamical interfaces; while some could have been predicted or expected, others transformed modeling in unanticipated ways. We further comment on what we believe could be possible future advances. PMID- 30439587 TI - On the perturbation nature of allostery: sites, mutations, and signal modulation. AB - Regardless of the diversity of systems, allosteic signalling is found to be always caused by perturbations. This recurring trait of allostery serves as a foundation for developing different experimental efforts and theoretical models for the studies of allosteric mechanisms. Among computational approaches considered here particular emphasis is given to the structure-based statistical mechanical model of allostery (SBSMMA), which allows one to study the causality and energetics of allosteric communication. We argue that the reverse allosteric signaling on the basis of SBSMMA can be used for predicting latent allosteric sites and inducing a tunable allosteric response. Per-residue allosteric effects of mutations can also be explored and 'latent drivers' expanding the cancer mutational landscape can be predicted using SBSMMA. Most recent and important implementations of computational models in web-resources along with a brief outlook on future research directions are also discussed. PMID- 30439588 TI - Multi-phase 3D arterial spin labeling brain MRI in assessing cerebral blood perfusion and arterial transit times in children at 3T. AB - BACKGROUND: 3D pseudocontinuous arterial spin labeling (pCASL) with a single post labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT). PURPOSE: To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines. MATERIAL & METHODS: Forty patients (average age: 8.6 y, 5 d-22.4 y) referred for routine brain MRI underwent additional 5-7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients. RESULTS: All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97-0.99 across the measured regions (p < 0.05). Correlation coefficients for ATT ranged from 0.87-0.96 (p < 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients. CONCLUSION: Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients. PMID- 30439590 TI - Efficient and accurate determination of 13C T1 and T1rho relaxation time constants of high-mobility polymers from limited-resolution spectra with optimized pulse sequences and data fitting. AB - The pulse sequences for the measurement of 13C T1 and T1rho relaxation time constants in soft organic solids were modified to include steady-state nuclear Overhauser enhancement with direct polarization (ssNOE/DP). The increased signal intensities with ssNOE are particularly well-suited for highly mobile and structurally heterogeneous polymers and proteins like elastin. The phase cycling of these experiments was modified to yield datasets that require less time, with more accurate results. The "3D-fitting process" was developed and then optimized for natural-abundance 13C spectra of elastin, with its characteristic and significant overlap. A comparison of 3D-fitting with the similarly purposed SPORT (Geppi and Forte, 1999) illustrates that the former is more robust, with smaller uncertainty values and higher precision. PMID- 30439589 TI - Viral resistance in HCV infection. AB - The introduction of new multi-genotypic direct acting antivirals (DAA) in clinical practice has revolutionized HCV treatment, permitting the achievement of >95% rates of sustained virological response in many patients. However, virological failures can occur particularly if the treatments are sub optimal and/or with too short duration. Failure is often associated with development of resistance. The wide genetic variability in terms of different genotypes and subtypes, together with the natural presence and/or easy development of resistance during treatment, are intrinsic characteristics of HCV that may affect the treatment outcome and the chances of achieving a virological cure. This review explores in detail the aspects of HCV innate and treatment-induced resistance to new interferon-free DAA regimens. PMID- 30439591 TI - Bisphenol S, a Bisphenol A alternative, impairs swine ovarian and adipose cell functions. AB - The high-volume-produced plastic monomer Bisphenol A (BPA) has been in the spotlight in the last years because of its endocrine disruptor (ED) behavior, leading to disclosure of the association between the widespread human and wildlife exposure to BPA and reproductive, metabolic, and developmental disorders and hormone-dependent cancer onset. These evidences caused restrictions and prohibitions of BPA industrial uses and prompted investigation of harmless alternative compounds. Above all, several countries have substituted the parental analogue with Bisphenol S (BPS) in baby care product manufacturing, even if its structural homology to BPA suggests similar ED properties not yet completely ruled out. In light of this consideration, the aim of this in vitro study was to investigate the effect of BPS exposure (0.1, 1, and 10 MUM for 48 h) on granulosa cells that are considered the prime ovarian targets of BPA as a "reproductive toxicant". Our data document that BPS inhibited E2 production, cell proliferation, and scavenging nonenzymatic activity (P < 0.05) while it significantly (P < 0.05) stimulated cell viability, superoxide (O2-) and nitric oxide (NO) production in cultured swine granulosa cells, a previously validated endocrine cell model for BPA. Evidence also exists that BPA and its analogues, as environmental lipophilic pollutants, are involved in the disruption of adipose tissue (AT) endocrine function, resulting in metabolic effects and thus in potential reproductive disorders. On this basis, our second purpose was the assessment of BPS effects on mesenchymal stromal cells (MSCs) isolated from porcine AT, taking into account MSCs viability and adipogenic differentiation, a process actually demonstrated to be largely affected by EDs. Our results show that BPS decreased (P < 0.001) cell viability of proliferating adipose stromal cells. Taken as a whole, our data demonstrate an effective BPS ED activity at MUM concentrations, suggesting that further studies are needed before considering its use in industrial application as an alternative to BPA. PMID- 30439592 TI - The potential role of tubeimosides in cancer prevention and treatment. AB - Natural compounds are important sources of anticancer drugs. Rhizoma Bolbostemmatis (Chinese name "Tu Bei Mu") is the dry tuber of Bolbostemma paniculatum (Maxim.) Franquet (Cucurbitaceae). It has long been widely used for treating various ailments including cancer in traditional Chinese medicine. Its major pharmacologically active components are the triterpenoid saponins tubeimosides (TBMs) including tubeimoside (TBM) I, II and III. Extensive researches have provided evidences of the anticancer activities of TBMs in different stages of carcinogenesis both in vitro and in vivo model. TBMs could inhibit cell growth and proliferation, induce cell differentiation, apoptosis, autophagy and, inhibit inflammation, and suppress angiogenesis, invasion and metastasis via various signaling pathways. They are effective in combination therapies, particularly at targeting drug-resistant cancer cells. This mini review aims to summarize and analyze the current knowledge on the pre-clinical studies of anti-tumor effects, the underlying molecular mechanisms and discuss the prospects of the application of TBMs in cancer prevention and treatment. The potential of TBMs as pertinent candidates could be appropriately developed and designed into an efficacious anticancer drug. PMID- 30439593 TI - Procalcitonin-Guided Antibiotic Use. PMID- 30439594 TI - Phenotypic and functional differences between senescent and aged murine microglia. AB - Microglia, the key innate immune cells in the brain, have been reported to drive brain aging and neurodegenerative disorders; however, few studies have analyzed microglial senescence and the impact of aging on the properties of microglia. In the present study, we characterized senescence- and aging-associated phenotypes of murine brain microglia using well-accepted markers, including telomere length, telomerase activity, expression of p16INK4a, p21, p53, senescence-associated beta galactosidase, and a senescence-associated secretory phenotype. Quantitative real time polymerase chain reaction analysis and a Telomeric Repeat Amplification Protocol assay indicated shortened telomeres and increased telomerase activity in senescent microglia, whereas telomeres remained unaltered and telomerase activity was reduced in aged microglia. Senescent microglia upregulated p16INK4a, p21, and p53, whereas acutely isolated microglia from the aged brain only exhibited a modest upregulation of p16INK4a. Senescent microglia showed decreased proliferation, while it was unchanged in aged microglia. Furthermore, microglia at late passages strongly upregulated expression of the senescent marker senescence-associated beta-galactosidase. Senescent and aged microglia exhibited differential activation profiles and altered responses to stimulation. We conclude that microglia from the aged mouse brain do not show typical senescent changes because their phenotype and functional response strongly differ from those of senescent microglia in vitro. PMID- 30439595 TI - A cross-brain regions study of ANK1 DNA methylation in different neurodegenerative diseases. AB - Recent epigenome-wide association studies in Alzheimer's disease have highlighted consistent robust neuropathology-associated DNA hypermethylation of the ankyrin 1 (ANK1) gene in the cortex. The extent to which altered ANK1 DNA methylation is also associated with other neurodegenerative diseases is not currently known. In the present study, we used bisulfite pyrosequencing to quantify DNA methylation across 8 CpG sites within a 118 bp region of the ANK1 gene across multiple brain regions in Alzheimer's disease, Vascular dementia, Dementia with Lewy bodies, Huntington's disease, and Parkinson's disease. We demonstrate disease-associated ANK1 hypermethylation in the entorhinal cortex in Alzheimer's disease, Huntington's disease, and Parkinson's disease, whereas in donors with Vascular dementia and Dementia with Lewy bodies, we observed elevated ANK1 DNA methylation only in individuals with coexisting Alzheimer's disease pathology. We did not observe any disease-associated differential ANK1 DNA methylation in the striatum in Huntington's disease or the substantia nigra in Parkinson's disease. Our data suggest that ANK1 is characterized by region and disease-specific differential DNA methylation in multiple neurodegenerative diseases. PMID- 30439596 TI - Image-guided phenotyping of ovariectomized mice: altered functional connectivity, cognition, myelination, and dopaminergic functionality. AB - A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice. This effect coincided with cognitive deficits and an underlying pathological molecular phenotype involving an imbalance of neurodevelopmental/neurodegenerative signaling. Furthermore, this quantitative mass spectrometry proteomics-based analysis of molecular signaling patterns further identified a strong involvement of altered dopaminergic functionality (e.g., DAT and predicted upstream regulators DRD3, NR4A2), reproductive signaling (e.g., Srd5a2), rotatin expression (rttn), cellular aging (e.g., Rxfp3, Git2), myelination, and axogenesis (e.g., Nefl, Mag). With this, we have provided an improved understanding of the impact of hypothalamus-pituitary-gonadal dysfunction and highlighted the potential of using a highly translational magnetic resonance imaging technique for monitoring these effects on the brain. PMID- 30439597 TI - Older adults fail to form stable task representations during model-based reversal inference. AB - Older adults struggle in dealing with changeable and uncertain environments across several cognitive domains. This has been attributed to difficulties in forming adequate task representations that help navigate uncertain environments. Here, we investigate how, in older adults, inadequate task representations impact on model-based reversal learning. We combined computational modeling and pupillometry during a novel model-based reversal learning task, which allowed us to isolate the relevance of task representations at feedback evaluation. We find that older adults overestimate the changeability of task states and consequently are less able to converge on unequivocal task representations through learning. Pupillometric measures and behavioral data show that these unreliable task representations in older adults manifest as a reduced ability to focus on feedback that is relevant for updating task representations, and as a reduced metacognitive awareness in the accuracy of their actions. Instead, the data suggested older adults' choice behavior was more consistent with a guidance by uninformative feedback properties such as outcome valence. Our study highlights that an inability to form adequate task representations may be a crucial factor underlying older adults' impaired model-based inference. PMID- 30439598 TI - Efficient automated detection of mitotic cells from breast histological images using deep convolution neutral network with wavelet decomposed patches. AB - In medical practice, the mitotic cell count from histological images acts as a proliferative marker for cancer diagnosis. Therefore, an accurate method for detecting mitotic cells in histological images is essential for cancer screening. Manual evaluation of clinically relevant image features that might reflect mitotic cells in histological images is time-consuming and error prone, due to the heterogeneous physical characteristics of mitotic cells. Computer-assisted automated detection of mitotic cells could overcome these limitations of manual analysis and act as a useful tool for pathologists to make cancer diagnoses efficiently and accurately. Here, we propose a new approach for mitotic cell detection in breast histological images that uses a deep convolution neural network (CNN) with wavelet decomposed image patches. In this approach, raw image patches of 81 * 81 pixels are decomposed to patches of 21 * 21 pixels using Haar wavelet and subsequently used in developing a deep CNN model for automated detection of mitotic cells. The decomposition step reduces convolution time for mitotic cell detection relative to the use of raw image patches in conventional CNN models. The proposed deep network was tested using the MITOS (ICPR2012) and MITOS-ATYPIA-14 breast cancer histological datasets and shown to outperform existing algorithms for mitotic cell detection. Overall, our method improves the performance and reduces the computational burden of conventional deep CNN approaches for mitotic cell detection. PMID- 30439599 TI - Characterization and classification of asthmatic wheeze sounds according to severity level using spectral integrated features. AB - OBJECTIVE: This study aimed to investigate and classify wheeze sounds of asthmatic patients according to their severity level (mild, moderate and severe) using spectral integrated (SI) features. METHOD: Segmented and validated wheeze sounds were obtained from auscultation recordings of the trachea and lower lung base of 55 asthmatic patients during tidal breathing manoeuvres. The segments were multi-labelled into 9 groups based on the auscultation location and/or breath phases. Bandwidths were selected based on the physiology, and a corresponding SI feature was computed for each segment. Univariate and multivariate statistical analyses were then performed to investigate the discriminatory behaviour of the features with respect to the severity levels in the various groups. The asthmatic severity levels in the groups were then classified using the ensemble (ENS), support vector machine (SVM) and k-nearest neighbour (KNN) methods. RESULTS AND CONCLUSION: All statistical comparisons exhibited a significant difference (p < 0.05) among the severity levels with few exceptions. In the classification experiments, the ensemble classifier exhibited better performance in terms of sensitivity, specificity and positive predictive value (PPV). The trachea inspiratory group showed the highest classification performance compared with all the other groups. Overall, the best PPV for the mild, moderate and severe samples were 95% (ENS), 88% (ENS) and 90% (SVM), respectively. With respect to location, the tracheal related wheeze sounds were most sensitive and specific predictors of asthma severity levels. In addition, the classification performances of the inspiratory and expiratory related groups were comparable, suggesting that the samples from these locations are equally informative. PMID- 30439600 TI - Exudate detection in fundus images using deeply-learnable features. AB - Presence of exudates on a retina is an early sign of diabetic retinopathy, and automatic detection of these can improve the diagnosis of the disease. Convolutional Neural Networks (CNNs) have been used for automatic exudate detection, but with poor performance. This study has investigated different deep learning techniques to maximize the sensitivity and specificity. We have compared multiple deep learning methods, and both supervised and unsupervised classifiers for improving the performance of automatic exudate detection, i.e., CNNs, pre trained Residual Networks (ResNet-50) and Discriminative Restricted Boltzmann Machines. The experiments were conducted on two publicly available databases: (i) DIARETDB1 and (ii) e-Ophtha. The results show that ResNet-50 with Support Vector Machines outperformed other networks with an accuracy and sensitivity of 98% and 0.99, respectively. This shows that ResNet-50 can be used for the analysis of the fundus images to detect exudates. PMID- 30439601 TI - Supravital expression of heat-shock proteins. AB - Heat-shock proteins (HSPs) are expressed during cellular stress, especially thermal stress, to support protein homeostasis. Extensive investigations have revealed that HSP27 is rapidly and intensively expressed in the pulmonary and renal tissues of most cases of death due to fire, contrary to cases without premortem thermal influences, which are negative for HSP expression. As such, HSP27 can be used as a marker of vitality in the investigation of fire-related deaths. Without positive HSP27 expression or only slight expression, one can conclude that the deceased was not alive at the time of heat stress. This is presented in two case reports of men who were shot and later burned. HSP espression could not be found in these cases. In the very early supravital period, particularly the latency and supravital periods, metabolic processes can continue after irreversible cardiac arrest. Extensive cellular stress can lead to an immunohistochemically detectable expression of HSP in this portmortem period. This is shown in the case report of a 49-year-old man who immediately died and burned following the massive detonation of an air mine. Immunohistochemical studies of recovered renal tissues have revealed HSP27 expression in the vessel walls as well as renal tubules, as presented in a third case report. This HSP expression can be considered as a phenomenon of supravitality. Heat stress induces massive cellular stress and the expression of HSP under global ischemic conditions. When vitality is to be determined in cases of suspected fire deaths, the possibility of supravital expression has to be considered. PMID- 30439603 TI - Robustness of individual and marginal model-based estimates: A sensitivity analysis of flexible parametric models. AB - BACKGROUND: Flexible parametric survival models (FPMs) are commonly used in epidemiology. These are preferred as a wide range of hazard shapes can be captured using splines to model the log-cumulative hazard function and can include time-dependent effects for more flexibility. An important issue is the number of knots used for splines. The reliability of estimates are assessed using English data for 10 cancer types and the use of online interactive graphs to enable a more comprehensive sensitivity analysis at the control of the user is demonstrated. METHODS: Sixty FPMs were fitted to each cancer type with varying degrees of freedom to model the baseline excess hazard and the main and time dependent effect of age. For each model, we obtained age-specific, age-group and internally age-standardised relative survival estimates. The Akaike Information Criterion and Bayesian Information Criterion were also calculated and comparative estimates were obtained using the Ederer II and Pohar Perme methods. Web-based interactive graphs were developed to present results. RESULTS: Age-standardised estimates were very insensitive to the exact number of knots for the splines. Age group survival is also stable with negligible differences between models. Age specific estimates are less stable especially for the youngest and oldest patients, of whom there are very few, but for most scenarios perform well. CONCLUSION: Although estimates do not depend heavily on the number of knots, too few knots should be avoided, as they can result in a poor fit. Interactive graphs engage researchers in assessing model sensitivity to a wide range of scenarios and their use is highly encouraged. PMID- 30439602 TI - Association of anal symptoms with anal high grade squamous intraepithelial lesions (HSIL) among men who have sex with men: Baseline data from the study of the prevention of anal cancer (SPANC). AB - BACKGROUND: The association between anal high-grade squamous intraepithelial lesion (HSIL) and anal symptoms has not been systematically investigated. METHODS: The Study of Prevention of Anal Cancer is a prospective cohort study of men who have sex with men (MSM) >= 35 years old in Sydney, Australia. Self reported symptoms were collected. Anal cytology and high-resolution anoscopy were undertaken. Using baseline visit data, men negative for squamous intra-epithelial lesion (SIL) were compared with men diagnosed with composite-HSIL (cytology and/or histology). Logistic regression analyses were performed to assess the association of symptoms with HSIL. RESULTS: Among 414 MSM included (composite HSIL (n = 231); negative for SIL (n = 183)), 306 (73.9%) reported symptom(s) within the last 6 months. There was no association between any symptom and composite-HSIL. A significant association between anal lump and a larger burden of HSIL (at least 2 intra-anal octants) (anal lump within last month: p = 0.014; anal lump within last 6 months: p = 0.010) became non-significant after adjusting for HIV-status and recent anal warts (anal lump within last month: p = 0.057; anal lump within last 6 months: p = 0.182). CONCLUSIONS: Among MSM age 35 years and older, most anal symptoms are not a useful marker of anal HSIL. PMID- 30439604 TI - Celastrol antagonizes high glucose-evoked podocyte injury, inflammation and insulin resistance by restoring the HO-1-mediated autophagy pathway. AB - Diabetic nephropathy (DN) contributes to end-stage renal disease and kidney dysfunction with a proverbial feature of podocyte injury. Inflammation and insulin resistance is recently implicated in the pathogenesis of diabetic kidney injury. Celastrol exerts critical roles in inflammatory diseases and injury progression. However, its function and mechanism in DN remains elusive. Here, celastrol dose-dependently restored podocyte viability under high glucose (HG) conditions, but with little cytotoxicity in podocyte. Preconditioning with celastrol counteracted HG-evoked cell apoptosis, LDH release, ROS production and podocyte depletion. Additionally, HG-elevated high transcripts and secretions of pro-inflammatory cytokines were reversed following celastrol treatment, including IL-1beta, TNF-alpha, IL-6. Simultaneously, the inhibitory effects of HG on insulin-triggered glucose uptake and nephrin expression were overturned after celastrol exposure. Intriguingly, celastrol restored HG-induced deficiency of autophagy pathway. Nevertheless, blocking the autophagy signaling by its antagonist 3-MA muted celastrol-protected against HG-evoked cell injury, inflammation and insulin resistance. Importantly, celastrol enhanced heme oxygenase-1 (HO-1) expression in HG-stimulated podocytes. Notably, HO-1 cessation depressed autophagy pathway activation and subsequently blunted beneficial effects of celastrol on HG-exposed podocytes. These finding suggest that celastrol may protect against HG-induced podocyte injury, inflammation and insulin resistance by restoring HO-1-mediated autophagy pathway, implying a promising therapeutic strategy against DN. PMID- 30439605 TI - Thermoelectric stack sample cooling modification of a commercial atomic force microscopy. AB - Enabling temperature dependent experiments in Atomic Force Microscopy is of great interest to study materials and surface properties at the nanoscale. By studying Curie temperature of multiferroic materials, temperature dependent phase transitions on crystalline structures or resistive switching phenomena are only a few examples of applications. We present an equipment capable of cooling samples using a thermoelectric cooling stage down to -61.4 degrees C in a 15 * 15 mm2 sample plate. The equipment uses a four-unit thermoelectric stack to achieve maximum temperature range, with low electrical and mechanical noise. The equipment is installed into a Keysight 5500LS Atomic Force Microscopy maintaining its compatibility with all Electrical and Mechanical modes of operation. We study the contribution of the liquid cooling pump vibration into the cantilever static deflection noise and the temperature dependence of the cantilever deflection. A La0.7Sr0.3MnO3-y thin film sample is used to demonstrate the performance of the equipment and its usability by analyzing the resistive switching phenomena associated with this oxide perovskite. PMID- 30439606 TI - Quantitative EMCD by use of a double aperture for simultaneous acquisition of EELS. AB - The weak signal strength in electron magnetic circular dichroism (EMCD) measurements remains one of the main challenges in the quantification of EMCD related EELS spectra. As a consequence, small variations in peak intensity caused by changes of background intervals, choice of method for extraction of signal intensity and equally differences in sample quality can cause strong changes in the EMCD signal. When aiming for high resolution quantitative EMCD, an additional difficulty consists in the fact that the two angular resolved EELS spectra needed to obtain the EMCD signal are taken at two different instances and it cannot be guaranteed that the acquisition conditions for these two spectra are identical. Here, we present an experimental setup where we use a double hole aperture in the transmission electron microscope to obtain the EMCD signal in a single acquisition. This geometry allows for the parallel acquisition of the two electron energy loss spectra (EELS) under exactly the same conditions. We also compare the double aperture acquisition mode with the qE acquisition mode which has been previously used for parallel acquisition of EMCD. We show that the double aperture mode not only offers better signal to noise ratio as compared to qE mode but also allows for much higher acquisition times to significantly improve the signal quality which is crucial for quantitative analysis of the magnetic moments. PMID- 30439607 TI - The effect of hydromorphone as an adjuvant to ropivacaine in brachial plexus block. PMID- 30439608 TI - Incidental hepatomegaly during quadratus lumborum block in pediatric patient. PMID- 30439609 TI - The relationship between smoking cessation and binge drinking, depression, and anxiety symptoms among smokers with serious mental illness. AB - INTRODUCTION: Concerns about the adverse effects of smoking cessation on alcohol use and mental health are a barrier to cessation for smokers with serious mental illness (SMI). The purpose of this study is to examine how incident smoking cessation affects binge drinking and symptoms of depression and anxiety among smokers with SMI. METHODS: The present study is a secondary analysis of the OPTIN trial, which demonstrated the effectiveness of proactive outreach for smoking cessation among Minnesota Health Care Programs enrollees. Participants with ICD-9 codes indicating schizophrenia spectrum disorders, psychotic disorders, bipolar disorders, or severe/recurrent major depressive disorder were categorized as having SMI (n = 939); remaining smokers were categorized as non-SMI (n = 1382). Multivariable regressions modeled the association between incident smoking cessation and binge drinking, PHQ-2 depression scores, and PROMIS anxiety scores in the two groups. RESULTS: Quitting smoking was not associated with binge drinking among those with SMI, but was associated with less binge drinking among those without SMI (p = 0.033). Quitting smoking was not associated with PHQ-2 depression scores among those with or without SMI. However, quitting smoking was associated with lower mean PROMIS anxiety scores for those with SMI (p = 0.031), but not those without SMI. CONCLUSION: Quitting smoking was not associated with heightened binge drinking or symptoms of depression and anxiety among smokers with SMI. These findings suggest that quitting smoking is not detrimental for these patients, and provide evidential support for facilitating access to cessation resources for patients with serious mental illness who smoke. PMID- 30439610 TI - Conditional probabilities of substance use disorders and associated risk factors: Progression from first use to use disorder on alcohol, cannabis, stimulants, sedatives and opioids. AB - BACKGROUND: Relatively little is known about factors that may lead to the development of a substance use disorder (SUD), across a range of drug classes. This study aimed to identify factors that predict the likelihood of transition from use to SUD and the speed with which this may occur at the population level, with a focus on the impact of pre-existing mental disorders. METHODS: Data were collected as part of the 2007 Australian National Survey of Mental Health and Wellbeing, a nationally representative survey of 8841 Australian adults. A series of discrete time survival analyses were undertaken on data pertaining to the age of onset of use and symptoms of use disorder, for alcohol, cannabis, sedatives, stimulants, and opioids, as well as the impact of pre-existing mood and anxiety disorders on the likelihood of developing a SUD. RESULTS: Lifetime cumulative probability estimates indicated that 50.4% of stimulant, 46.6% of opioid, 39% of sedative, 37.5% of alcohol, and 34.1% of cannabis users would develop a SUD on those substances, within an estimated 14, 12, 8, 30, and 23 years after onset respectively. Pre-existing mental disorders were significantly associated with increased risk of developing a SUD for alcohol, cannabis and stimulant use disorder. CONCLUSION: The relative speed associated with the transition from use to SUD emphasizes the narrow window of time available to intervene, underscoring the urgency of early identification of mental health conditions and the timely provision of appropriate evidence-based interventions, which could potentially prevent the development of secondary SUDs. PMID- 30439611 TI - Patterns and history of prescription drug use among opioid-related drug overdose cases in British Columbia, Canada, 2015-2016. AB - BACKGROUND: British Columbia is the epicenter of the current fentanyl-related overdose crisis in Canada. Our study characterizes prescribing histories of people who had an opioid-related overdose compared to matched controls. METHODS: We examined linked administrative data for individuals who overdosed between January 1, 2015 and November 30, 2016. Past prescriptions over five years were assessed for opioids for pain, opioid agonist therapy, benzodiazepines/z-drugs, antidepressants, antipsychotics, gabapentinoids, mood stabilizers and anti epileptics, muscle relaxants, and other sedating medications. Prescribing history of 9964 cases was compared with that of 49,820 matched controls. RESULTS: Overdose cases were more likely to be prescribed opioids for pain and to have used prescription opioids on a long-term basis in the previous five years compared to controls. However, at the time of overdose, 92% of men and 86% of women did not have an active opioid for pain prescription, and approximately half had not filled one in the past five years. Those who overdosed tended to have more prescriptions for psychotropic substances than controls. Fewer than 10% of cases had an active prescription for opioid agonist therapy and most were not on treatment in the past. CONCLUSIONS: Low prevalence of active prescriptions for opioids for pain at the time of overdose suggests that opioid prescribing plays a limited short-term impact in the current fentanyl-related crisis of overdoses. While liberal opioid prescribing practices may have contributed to the development of the current overdose crisis, regulation and enforcement of clinicians' prescribing practices will likely have limited impact in reducing overdoses. PMID- 30439612 TI - Synthesis and characterization of bacteriochlorin loaded magnetic nanoparticles (MNP) for personalized MRI guided photosensitizers delivery to tumor. AB - HYPOTHESIS: Hydrophobic bacteriochlorin based photosensitizer (PS) can be effectively immobilized on MNP covered by human serum albumin (HSA). PS loading into MNP protein shell allows solubilizing PS in water solution without altering its photodynamic activity. MNP@PS can serve as diagnostic tool for tracking PS delivery to tumor tissues by MRI. EXPERIMENTS: Immobilization on MNP-HSA-PEG was performed by adding PS solution in organic solvents with further purification. MNP@PS were characterized by DLS, HAADF STEM and AFM. Absorbance and fluorescence measurements were used to assess PS photophysical properties before and after immobilization. MNP@PS internalization into CT26 cells was investigated by confocal microscopy in vitro and MRI/IVIS were used for tracking MNP@PS delivery to tumors in vivo. FINDINGS: MNP@PS complexes were stable in water solution and retained PS photophysical activity. The length of side chain affected MNP@PS size, loading capacity and cell internalization. In vitro testing demonstrated MNP@PS delivery to cancer cells followed by photoinduced toxicity. In vivo studies confirmed that as-synthetized complexes can be used for MRI tracking over drug accumulation in tumors. PMID- 30439613 TI - Ultrathin manganese oxide nanosheets uniformly coating on carbon nanocoils as high-performance asymmetric supercapacitor electrodes. AB - Two key limitations affecting supercapacitor application of manganese oxide (MO) are the poor electric conductivity and low accessible surface area. In this work, we reported an effective method to fabricate lamellar MO coating on carbon nanocoil (CNC) and investigated its supercapacitive properties. The elegant MO/CNC core shell structure enabled synergistic effects from both MO nanosheets and CNC by using nanosheets to provide a large interaction area for ion transport and CNC to improve the electric conductivity of composites. The investigation of electrochemistry showed that the specific capacitance of MO could reach 435 F g-1 at current density of 1 A g-1. Moreover, the composites presented an excellent rate capability and cycling performance with 92.7% capacitance retention at current density of 2 A g-1 after 5000 cycles. In addition, the asymmetric supercapacitor fabricated with MO/CNC as the positive electrode and CNC as the negative electrode demonstrated excellent energy density of 21.58 Wh kg-1 at a power density of 100 W kg-1. And the asymmetric supercapacitor exhibited an excellent electrochemical cycling stability with 96.3% initial capacitance remained after 1000 cycles. PMID- 30439614 TI - Solid-state speciation of interlayer anions in layered double hydroxides. AB - Layered double hydroxides (LDH) have been proposed for phosphate (PO4) recovery and recycling from waste streams due to their high anion exchange capacity, good stability and high affinity towards PO4. The high affinity towards PO4 strongly relates to the electrostatic interaction with PO4, and thus the charge of PO4. However, the anion speciation of intercalated PO4, i.e. either H2PO4-, HPO42- or PO43- is often overlooked. This study was set up to measure solid phase PO4 speciation through ion exchange stoichiometry, X-ray diffraction (XRD), attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) and modelling. Six phase pure Mg/Al LDH materials were synthesized using co precipitation of metal nitrate (NO3-) solutions with varying M2+/M3+ ratio at pH 12 and pH 10. The LDHs synthetized at pH 12 contained larger equivalent fractions of intercalated OH-, smaller fractions of NO3- and smaller interlayer distance than those prepared at pH 10, likely because of the higher OH- concentration in the more alkaline synthesis solutions. Two high charge LDHs prepared at pH 12 or 10 were selected, exchanged with PO4 (0-20 mM initial PO4, 24 h) at one starting pH (7.20); desorption was subsequently performed with carbonate (3 mM, initial pH 8.4) during 480 h. The resulting solution concentrations of NO3, PO4 and CO3 and the pH allowed the identification of the anion exchange stoichiometry. The LDH synthesized at pH 12, which had a large fraction of exchangeable OH-, adsorbed PO4 as HPO42-/PO43-, in exchange for both NO3- and OH- anions. The material synthesized at pH 10 containing a lower fraction of exchangeable OH-, therefore, adsorbed mainly HPO42- in exchange for NO3- anions. The carbonate exchange was consistent with adsorption of divalent CO32-. The pH dependent speciation modelling showed that the exchanged PO4 ions have higher charge compared to those in the contacting solution. This study suggests that the highest P content of LDH is obtained in high charge materials holding divalent PO4 anions, i.e. materials synthesized at lower pH and/or exchanged in solutions with low alkalinity. PMID- 30439615 TI - Membrane targeting cationic antimicrobial peptides. AB - Many short cationic peptides are amphiphilic and are often termed antimicrobial peptides (AMPs) as they can kill various microorganisms. These AMPs have largely been discovered from nature, but over the past two decades many biomimetic and de novo designed AMPs have been reported, offering a huge variety of attractive properties for further exploitation. Under the current global endeavour of fighting against antimicrobial resistance, it is useful to introduce AMPs to the biointerface research community and compare their modes of action with conventional antibiotics. Because natural AMPs often have long sequences and other biological functions implicated, they can't be used as antimicrobial agents. However, rational AMP design helps eliminate their shortcomings and more importantly, optimise their structure-function relationship. This review will first introduce the key approaches recently utilised in structural design of AMPs and then introduce the main lipid membrane models such as spread lipid monolayers and vesicles together with the characterisation techniques adopted in early AMP design and development. These studies are crucial towards understanding key factors affecting their efficacy and toxicity. Thus, various interfacial measurements facilitated by different forms of lipid monolayers and bilayers provide valuable support to the selective responses of AMPs to different cell types used in bactericidal assays and cytotoxicity tests, emphasising the link between molecular models and cell models. A number of clinical trials of AMPs have been either under way or completed, demonstrating the huge potential of AMPs in a range of applications. PMID- 30439616 TI - Synergetic enhancement of mechanical and fire-resistance performance of waterborne polyurethane by introducing two kinds of phosphorus-nitrogen flame retardant. AB - In this work, a novel hydroxyl-terminated monomer containing phosphorus and nitrogen, tri(N, N-bis-(2-hydroxy-ethyl) acyloxoethyl) phosphate (TNAP), was synthesized successfully with phosphorus oxychloride, hydroxyethyl acrylate, and diethanolamine as raw materials, and then incorporated into flame-retarded waterborne polyurethanes to improve their flame retardancy, thermal behavior, and mechanical properties. Their structures were confirmed by nuclear magnetic resonance (NMR) and fourier transform infrared spectroscopy (FTIR). Besides, the thermal performance and combustion behaviors of crosslinked flame-retarded waterborne polyurethane (CFRWPU) films were evaluated through thermogravimetric analysis (TGA), thermogravimetry-FTIR, limiting oxygen index (LOI) tests, and microscale combustion calorimeter tests (MCC). Additionally, the mechanical properties were investigated by tensile stress-strain tests. These results revealed that the monomer TNAP exhibited remarkable residual char formation ability of 34.98 wt% and that TNAP-embedded FRWPU films attained an LOI value of 25.5% at a TNAP content of 4 wt%. Moreover, there was significant enhancement in tensile strength (15.81 MPa) obtained with the combined incorporation of TNAP into FRWPU. Also, scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS) provided the morphologies and the element distributions of char residues of CFRWPU after LOI tests. Finally, the thermal mechanical properties of CFRWPU were assessed by dynamic mechanical analysis (DMA). PMID- 30439617 TI - Characterization and ecotoxicological investigation of biochar produced via slow pyrolysis: Effect of feedstock composition and pyrolysis conditions. AB - This study systematically investigated the biochar toxicity from the in vitro tests involving the use of human liver and lung cell lines, as well as in vivo tests using Drosophila melanogaster (fruit fly). Biochars used in this study were produced from vegetable waste, pine cone and their mixture (1:1 by weight) at two representative temperatures (200 and 500 degrees C). Two common toxicant groups in biochar, heavy metals (HM) and polycyclic aromatic hydrocarbons (PAHs) contents, were detected for clarification of the relationship between their toxicity behaviors and biochar bulk characteristics. The results showed that (1) no HMs can be found in the biochar if HMs are absence in their feedstock (2) PAHs were formed during the pyrolysis no matter what type of biomss used, but the concentration is low that can be acceptable for soil legislative criteria (3) biochars had limited impact to the viability of flies, but inhibited the growth of the cells (4) the low leaching potential of HMs and PAHs (total 16 USEPA) in the studied biochars may not be the major reason which put the harm to the cell, more effort on the identification need to be done. This work can provide a new picture to the biochar researchers for better understanding of the two faces of biochar. PMID- 30439618 TI - Evaluation of floor-wise pollution status and deposition behavior of potentially toxic elements and nanoparticles in air conditioner dust during urbanistic development. AB - The study was undertaken to investigate deposition behaviors of various size segregated particles and indoor air quality using dust accumulated on the air conditioner filter acting as a sink for PTEs and nanoparticles that can pose a significant health risk. However, the particulate matter size and chemical composition in AC dust and its relationship with PTEs remains uncertain. Current study aims to investigate the PTEs and nanoparticles composition of AC dust using different analytical approaches including ICP-MS, XRD, XPS, SEM/TEM along with EDS and Laser Diffraction particle size analyzer. The mean concentration of PTEs like Al, As, Cd, Cu, Li, Pb, Sb, Se, Sn, Ti, V and Zn exceeded the corresponding background value. Pb, As, Sn, Sb, Cd were categorizing under geo-accumulation index class IV. Most of the particles were found to be > 100 MUm and it decreased significantly with increase in floor altitude. A significantly negative correlation was found between particles size and PTEs concentration showing a significant increase in PTEs content with decrease in particles size. The XPS results showed dominant peaks for TiO2, Ti-O-N, As2O3, Fe+3, Fe+2, Al-OH and Al203. Additionally, As, Pb, Si and Fe were dominant metallic nanoparticles identified using SEM/TEM along with EDS. PMID- 30439619 TI - Efficiently capturing tobacco specific nitrosamines with Hbeta zeolite in solution. AB - The high-efficiency capture of Tobacco Specific Nitrosamines by Hbeta zeolite in solution is reported for the first time, along with the adsorption of 4 methylnitrosamino-1-3-pyridyl-1-butanone in aqueous solution. Different from other zeolites such as NaZSM-5, the specific pore size of Hbeta exerted a crucial function endowing the zeolite a higher removal of TSNA and selectivity of NNK. The adsorption thermodynamics of NNK by Hbeta in aqueous adsorption was fitted to Temkin adsorption model with a linearly decreasing isosteric heat of adsorption. In addition, the adsorptive capacity of Hbeta zeolite for NNK reached over 70 mg g-1, offering a powerful sorbent of TSNA to protect environment. PMID- 30439620 TI - Uptake and modification of umbelliferone by various seedlings. AB - Inspired by the recently discovered phenomenon of "horizontal natural product transfer" we investigated the putative uptake of phenolic specialized metabolites. Umbelliferone was chosen for this case study, since this coumarin as well as its derivatives can easily be determined by HPLC analyses. Barley (Hordeum vulgare L.), radish (Raphanus sativus L.), pea (Pisum sativum L.), flax (Linum usitatissimum L.), and garden cress (Lepidium sativum L.) were cultivated in hydroponic media, to which the coumarin was applied. Uptake of umbelliferone was verified by corresponding HPLC analyses of extracts obtained from the aerial parts of the seedlings. In all cases, a tremendous uptake of umbelliferone was observed. In plants that genuinely contain coumarins, the umbelliferone taken up was modified: in garden cress, it was hydroxylated and glucosylated to yield esculin, while in barley seedlings, the imported umbelliferone was modified by methoxylation to yield scopoletin. Corresponding reactions are known from modifications of xenobiotics to be catalyzed by cytochrome P450 enzymes. Accordingly, in an additional approach, umbelliferone was applied together with naproxen, which is reported to reduce enzyme activity of P450 enzymes. As predicted, the conversion of umbelliferone to scopoletin in barley as well as the modification to esculin in garden cress was strongly reduced by the addition of naproxen. These data for the first time demonstrate that - in addition to alkaloids - also phenolic compounds are taken up by various acceptor plants. Apart from the leaching of rotting plants, coumarins are known to be exuded by many plants. Accordingly, these compounds are frequently present in soils and will be taken up. These coherences imply that the horizontal natural product transfer might represent a more general phenomenon in plant ecology. Moreover, this study outlines that - in analogy to the modification of xenobiotics - also natural products taken up are modified in the acceptor plants. PMID- 30439621 TI - Lotuslactone, a non-canonical strigolactone from Lotus japonicus. AB - Root exudates from Lotus japonicus were found to contain at least three different hyphal branching-inducing compounds for the arbuscular mycorrhizal (AM) fungus Gigaspora margarita, one of which had been previously identified as (+)-5 deoxystrigol (5DS), a canonical strigolactone (SL). One of the two remaining unknown hyphal branching inducers was purified and named lotuslactone. Its structure was determined as methyl (E)-2-(3-acetoxy-2-hydroxy-7-methyl-1-oxo 1,2,3,4,5,6-hexahydroazulen-2-yl)-3-(((R)-4-methyl-5-oxo-2,5-dihydrofuran-2 yl)oxy)acrylate, by 1D and 2D NMR spectroscopy, and HR-ESI- and EI-MS. Although lotuslactone, a non-canonical SL, contains the AB-ring and the enol ether-bridged D-ring, it lacks the C-ring and has a seven-membered cycloheptadiene in the A ring part as in medicaol, a major SL of Medicago truncatula. Lotuslactone was much less active than 5DS, but showed comparable activity to methyl carlactonoate (MeCLA) in inducing hyphal branching of G. margarita. Other natural non-canonical SLs including avenaol, heliolactone, and zealactone (methyl zealactonoate) were also found to be moderate to weak inducers of hyphal branching in the AM fungus. Lotuslactone strongly elicited seed germination in Phelipanche ramosa and Orobanche minor, but Striga hermonthica seeds were 100-fold less sensitive to this stimulant. PMID- 30439622 TI - WINDOW consortium: A path towards increased therapy efficacy against glioblastoma. AB - Glioblastoma is the most common and malignant form of brain cancer, for which the standard treatment is maximal surgical resection, radiotherapy and chemotherapy. Despite these interventions, mean overall survival remains less than 15 months, during which extensive tumor infiltration throughout the brain occurs. The resulting metastasized cells in the brain are characterized by chemotherapy resistance and extensive intratumoral heterogeneity. An orthogonal approach attacking both intracellular resistance mechanisms as well as intercellular heterogeneity is necessary to halt tumor progression. For this reason, we established the WINDOW Consortium (Window for Improvement for Newly Diagnosed patients by Overcoming disease Worsening), in which we are establishing a strategy for rational selection and development of effective therapies against glioblastoma. Here, we overview the many challenges posed in treating glioblastoma, including selection of drug combinations that prevent therapy resistance, the need for drugs that have improved blood brain barrier penetration and strategies to counter heterogeneous cell populations within patients. Together, this forms the backbone of our strategy to attack glioblastoma. PMID- 30439623 TI - CuS as co-reaction accelerator in PTCA-K2S2O8 system for enhancing electrochemiluminescence behavior of PTCA and its application in detection of amyloid-beta protein. AB - In this work, 3,4,9,10-perylenetetracar-boxylic acid (PTCA) as luminophor was grafted on the surface of graphene oxide (PTCA-GO) directly. GO exhibited large specific surface area and excellent electrical conductivity which can immobilize large amounts of PTCA to improve the electrochemiluminescence (ECL) efficiency. Moreover, gold nanoparticles (Au NPs) were anchored on the surface of PTCA-GO to immobilize primary antibodies (Ab1) via Au-NH2 bond and enhance the electron transport of PTCA-GO. CuS was used as a novel co-reaction accelerator in PTCA K2S2O8 system to label secondary antibodies (Ab2), which can react with the coreactant (K2S2O8) to produce more SO4*-. SiO2 nanospheres with large specific surface area were used to load a mass of CuS and Au NPs, which can directly combine with Ab2 and accelerate the ECL emission remarkably. Therefore, a novel sandwich-type ECL immunosensor was fabricated successfully for amyloid-beta protein (Abeta) detection. Under the optimal condition, a wide detection range from 50 fg/mL to 25 ng/mL and a low detection limit of 18 fg/mL (S/N = 3) were obtained. Featuring favorable specificity, stability and reproducibility, the strategy can be a powerful analytical tool in sensitive trace detection of biomolecules in clinical analysis. PMID- 30439624 TI - Electrochemical immunosensor for CDH22 biomarker based on benzaldehyde substituted poly(phosphazene) modified disposable ITO electrode: A new fabrication strategy for biosensors. AB - A novel label-free impedimetric immunosensor was fabricated for rapid, selective and sensitive detection and quantification of Cadherin-like protein 22 (CDH22), a cancer marker, in human serum by using easy and quickly prepared disposable ITO immunoelectrode. cancer marker, in human serum by using easy and quickly prepared disposable ITO immunoelectrode. The biosensing approach implied the use of ITO electrode coated with poly(phosphazene) polymer including benzaldehyde groups attached with CDH22 antibody and CDH22 antigens. Benzaldehyde side groups containing poly(phosphazene) film coated disposable ITO electrode were utilized as an immunosensing platform and anti-CDH22 antibodies bound to aldehyde groups of benzaldehyde substituted poly(phosphazene) (P-PHP) covalently. The immunosensor modification steps and affinity interaction between anti-CDH22 antibodies and CDH22 antigens were observed by EIS and CV in the presence of the redox couple. Furthermore, antibody immobilization was followed via FTIR and Raman spectroscopy. The morphological analyses of the suggested immunosensor during the fabrication steps were carried out with SEM and AFM monitoring. All the experimental parameters affecting the construction of the immunoelectrodes were optimized. The fabricated immunosensor exhibited an excellent working performance with a wide detection linear range (0.015-2.9 pg/mL) and low limit of detection (4.4 fg/mL). Moreover, the proposed immunosensor had great reproducibility, repeatability and long-term stability. Additionally, the fabricated immunosensor was successfully used in the quantification of CDH22 in human serum without any pretreatment. PMID- 30439625 TI - Co-Expression of VEGF and IL-6 Family Cytokines is Associated with Decreased Survival in HER2 Negative Breast Cancer Patients: Subtype-Specific IL-6 Family Cytokine-Mediated VEGF Secretion. AB - Breast cancer cell-response to inflammatory cytokines such as interleukin-6 (IL 6) and oncostatin M (OSM) may affect the course of clinical disease in a cancer subtype-dependent manner. Furthermore, vascular endothelial growth factor A (VEGF) secretion induced by IL-6 and OSM may also be subtype-dependent. Utilizing datasets from Oncomine, we show that poor survival of invasive ductal carcinoma (IDC) breast cancer patients is correlated with both high VEGF expression and high cytokine or cytokine receptor expression in tumors. Importantly, epidermal growth factor receptor-negative (HER2-), but not HER2-positive (HER2+), patient survival is significantly lower with high tumor co-expression of VEGF and OSM, OSMRbeta, IL-6, or IL-6Ralpha compared to low co-expression. Furthermore, assessment of HER2- breast cancer cells in vitro identified unique signaling differences regulating cytokine-induced VEGF secretion. The levels of VEGF secretion were analyzed by ELISA with siRNAs for hypoxia inducible factor 1 alpha (HIF1alpha) and signal transducer and activator of transcription 3 (STAT3). Specifically, we found that estrogen receptor-negative (ER-) MDA-MB-231 cells respond only to OSM through STAT3 signaling, while ER+ T47D cells respond to both OSM and IL-6, though to IL-6 to a lesser extent. Additionally, in the ER+ T47D cells, OSM signals through both STAT3 and HIF1alpha. These results highlight that the survival of breast cancer patients with high co-expression of VEGF and IL-6 family cytokines is dependent on breast cancer subtype. Thus, the heterogeneity of human breast cancer in relation to IL-6 family cytokines and VEGF may have important implications in clinical treatment options, disease progression, and ultimately patient prognosis. PMID- 30439627 TI - Opioid responsiveness of nociceptive versus mixed pain in clinical cancer patients. AB - OBJECTIVE: To investigate whether clinical cancer patients with mixed nociceptive neuropathic pain are less responsive to opioids than patients with nociceptive pain. BACKGROUND: Pain is common in advanced cancer patients. Pain driven by neuropathic mechanisms is considered to be resistant to opioids. This hypothesis is mainly based on animal studies and single-dose opioid studies in humans but has not been confirmed in clinical practice. METHODS: Data were prospectively collected from 240 clinical cancer pain patients using opioids. Multiple linear regression was used for assessing the associations between the logarithm of the morphine equivalent dose (MED) at three days after admission (T = 3d) relative to admission (T = 0d) (logRMED) and type of pain (nociceptive versus mixed pain), corrected for gender, age, primary cancer site and use of non-opioid and adjuvant analgesics. As secondary outcome measures, associations between logMED and logPFent (fentanyl plasma level) at T = 3d and type of pain were assessed. RESULTS: Pain intensity between T = 0d and T = 3d was significantly and evenly reduced in patients with nociceptive pain (n = 173) and mixed pain (n = 67). Median (interquartile range) MED was 20 (10-52) and 20 (20-80) mg (T = 0d), 40 (10-67) and 40 (20-100) mg (T = 3d), median PFent (T = 3d) was 1.59 (0.58-3.19) and 1.38 (0.54-4.39) ng/ml, none of them significantly different, in patients with nociceptive and mixed pain, respectively. Neither logRMED, logMED (T = 3d), or logPFent (T = 3d) was significantly associated with type of pain, after correction for confounding factors. CONCLUSIONS: We conclude that, at least in clinical cancer patients, mixed pain is as responsive to opioids as nociceptive pain. PMID- 30439626 TI - High Keratin 8/18 Ratio Predicts Aggressive Hepatocellular Cancer Phenotype. AB - BACKGROUND & AIMS: Steatohepatitis (SH) and SH-associated hepatocellular carcinoma (HCC) are of considerable clinical significance. SH is morphologically characterized by steatosis, liver cell ballooning, cytoplasmic aggregates termed Mallory-Denk bodies (MDBs), inflammation, and fibrosis at late stage. Disturbance of the keratin cytoskeleton and aggregation of keratins (KRTs) are essential for MDB formation. METHODS: We analyzed livers of aged Krt18-/- mice that spontaneously developed in the majority of cases SH-associated HCC independent of sex. Interestingly, the hepatic lipid profile in Krt18-/- mice, which accumulate KRT8, closely resembles human SH lipid profiles and shows that the excess of KRT8 over KRT18 determines the likelihood to develop SH-associated HCC linked with enhanced lipogenesis. RESULTS: Our analysis of the genetic profile of Krt18-/- mice with 26 human hepatoma cell lines and with data sets of >300 patients with HCC, where Krt18-/- gene signatures matched human HCC. Interestingly, a high KRT8/18 ratio is associated with an aggressive HCC phenotype. CONCLUSIONS: We can prove that intermediate filaments and their binding partners are tightly linked to hepatic lipid metabolism and to hepatocarcinogenesis. We suggest KRT8/18 ratio as a novel HCC biomarker for HCC. PMID- 30439629 TI - Use of biomarkers in the prediction of culture-proven infection in the surgical intensive care unit. AB - PURPOSE: The purpose of this study was to prospectively analyze the predictive role of classic predictors for suspected infection (temperature, WBC and derivatives) with two biomarkers, procalcitonin and lactate, on the incidence of culture-proven infection in the surgical intensive care unit (SICU). MATERIALS AND METHODS: One hundred forty-six consecutive patients admitted for suspected infection had admission and 12-h procalcitonin values, admission and every 6-h lactate values for 24 h, and admission temperature, leukocyte count, lymphocyte count and percentage measured and analyzed in this study. RESULTS: Peak (highest measured value <=24-h of admission) procalcitonin values were not predictive for culture-proven infection. However, a culture-negative subset was identified when peak procalcitonin values were < 2.9 ng/mL and when peak lactate values were < 1.3 mmol/L with a probability of 98.3% (P < .001). No other admission predictor was statistically associated with culture-proven infection. Following boosted tree partitioning, a C-index of 0.85 was calculated with a misclassification rate of 23.3%. CONCLUSIONS: The ability to utilize procalcitonin values in the diagnosis of culture-proven infection was not realized in this study. However, the association of admission peak procalcitonin values with admission peak lactate values identified a group of patients who were culture-negative for suspected infection. No other admission predictor was associated with culture proven infection. PMID- 30439630 TI - "What if she was your mother?" Toward better responses. AB - Critical care physicians may hear a surrogate decision-maker ask, "What would you do if she was your mother?" or "What if your father was this sick?" These kinds of questions ask more of the critical care physician than the surrogate might realize. There are deep-seated ethical, professional, and personal complexities that can challenge critical care physicians to answer these questions with honesty. This essay offers practical guidance for critical care physicians who aim to respond to such queries with honesty and beneficence. We discuss a variety of motivations that can accompany this unique kind of question from a surrogate. The surrogate may be seeking moral guidance-the true question being, "What should I do?" We offer a number of questions that the critical care physician might ask of the surrogate in order to attend to both the surrogate's moral dilemma and the patient's values and preferences for medical interventions. We also offer a number of questions to promote contemplation of these issues by the critical care physician herself. We argue that until the critical care physician: discovers the surrogate's motivation, connects this motivation to patient preferences, and asks herself important questions regarding death and dying, the physician's responses will not adequately attend to the issues prompted by such questions. PMID- 30439631 TI - Differential effects of muscle fatigue on dynamic spine stability: Implications for injury risk. AB - This study was designed to assess the utility of using a measure of dynamic spine stability in an unfatigued, rested state as a predictor of dynamic spine stability in a challenged, fatigued state. Participants completed three trials (Day 1: Rested, Fatigued; Day 2: Recovery) during which the dynamic stability of the spine was assessed over 30 repeated flexion/extension motions using maximum finite-cycle Lyapunov exponents. Multiple sets of dynamic trunk extensions were performed to fatigue the trunk extensor muscles. Across the sample population, an increase in dynamic spine stability when fatigued was observed, as well as a moderate correlation between the level of dynamic stability when rested and a stabilizing response when fatigued. Further analysis of the data on a person-by person basis revealed three distinct responses in which participants either stabilized, destabilized or had no change in dynamic spine stability when fatigued. Therefore, the mean response of the sample population did not adequately represent the true, meaningful response of individuals within the population. These results illustrate the importance of considering individualized responses when examining dynamic stability measures, and provide preliminary evidence that suggests that individual injury risk cannot be completely captured by measures taken in an unchallenged, rested state. PMID- 30439628 TI - Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti tumour response: A case series. AB - IMPORTANCE: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. OBJECTIVE: The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. METHODS: Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. RESULTS: This multicenter case series describes 36 cancer patients who had rheumatic disease before anti PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. CONCLUSIONS: Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes. PMID- 30439632 TI - Drug Utilization Studies in Latin America: A Scoping Review and Survey of Ethical Requirements. AB - BACKGROUND: Drug utilization studies (DUSs) are increasingly being conducted in Latin America, especially in countries with a universal healthcare coverage, to inform policies and decision making. The need for an ethical framework specific to DUSs in Latin America has been recognized. OBJECTIVES: To describe the ethical and/or legal requirements applicable to DUSs in Latin American countries with universal healthcare coverage. METHODS: We conducted a nonsystematic scoping review on DUSs in this region, covering the period from January 1, 2012, to July 1, 2017, and reviewed legislations and data protection requirements in each country. We also surveyed 45 ethics committees and 22 key informants to determine specific ethical requirements for various types of DUSs differing in data collection methods, study populations, and settings. RESULTS: Local legislations on DUSs are highly heterogeneous across Latin America. In Chile and Guatemala, authorization from the national health authority must be obtained for accessing clinical records, whereas in Argentina, no authorization is required for the secondary use of existing data. In Argentina, Brazil, Costa Rica, Guatemala, and Peru, a national ethics committee approval is required in addition to a site specific approval. Requirements for patient informed consent also vary across countries and depend on the type of DUS and study population. CONCLUSIONS: The lack of consensus in the legislative and ethical frameworks applicable to DUSs across Latin America leads to operational challenges for the implementation of multinational studies. In many countries, absence of a framework leads to precautionary stringent requirements, which restricts the feasibility of DUSs. PMID- 30439633 TI - Catalytic fast pyrolysis of biomass: Selective deoxygenation to balance the quality and yield of bio-oil. AB - Firstly, the operating conditions were screened for biomass pyrolysis in a fixed bed with respect to higher oil yield. A temperature of 600 degrees C with an N2 flow of 80 ml/min exhibited the highest bio-oil yield. Then, the catalytic pyrolysis of biomass with various catalysts (Al2O3, CaO, MgO, CuO, Fe2O3, NiO, ZnO, ZrO2, TiO2, HZSM-5 and MCM-41) was studied to identify the selective deoxygenation method with respect to improve bio-oil quality with smaller drop in bio-oil yield. With the addition of CaO, the oxygen was mainly removed in the form of CO2, while, in other cases, more oxygen was removed in the form of H2O. Furthermore, more decarboxylation or less dehydration is better for the balance between yield and deoxygenation amount, and the preferred decarboxylation would lead to a higher pH and lower moisture content of bio-oil. PMID- 30439634 TI - Co-gasification of high ash biomass and high ash coal in downdraft gasifier. AB - The present work studies gasification of high ash biomass (20-25% w/w), high ash coal (30-35% w/w), and their co-gasification in a downdraft gasifier developed in our earlier study (Siddiqui et al., 2018). TGA studies were performed to examine the change in performance due to the catalytic effect of inorganic content. The effect of biomass ratio (BR) was examined. Higher percentage of biomass increased the conversion to gas on carbon basis, and decreased the conversions to char and tar. The presence of coal enhanced the temperature and hence the rates of the reactions to certain extent. The respective cold gas and thermal efficiencies for BR0 are 33.06% and 49.38%, and for BR1 are 52.22% and 64.15%. BR0.75 gave the best performance with CGE of 57.5% and thermal efficiency of 72.63%. Finally, the clinker formation issue and the preliminary atmospheric emissions measurements are reported for gasifier. PMID- 30439635 TI - Removal of fine particulate matter (PM2.5) via atmospheric humidity caused by evapotranspiration. AB - Reduction of particulate matter (PM) has emerged as one of the most significant challenges in public health and environment protection worldwide. To address PM related problems and effectively remove fine particulate matter (PM2.5), environmentalists proposed tree planting and afforestation as eco-friendly strategies. However, the PM removal effect of plants and its primary mechanism remains uncertain. In this study, we experimentally investigated the PM removal performance of five plant species in a closed chamber and the effects of relative humidity (RH) caused by plant evapotranspiration, as a governing parameter. On the basis of the PM removal test for various plant species, we selected Epipremnum aureum (Scindapsus) as a representative plant to identify the PM removal efficiency depending on evapotranspiration and particle type. Results showed that Scindapsus yielded a high PM removal efficiency for smoke type PM2.5 under active transpiration. We examined the correlation of PM removal and relative humidity (RH) and evaluated the increased effect of RH on PM2.5 removal by using a plant-inspired in vitro model. Based on the present results, the increase of RH due to evapotranspiration is crucial to the reduction of PM2.5 using plants. PMID- 30439636 TI - Potential reductions in premature mortality attributable to PM2.5 by reducing indoor pollution: A model analysis for Beijing-Tianjin-Hebei of China. AB - BACKGROUND: China has one of the highest PM2.5 (particulate matter with an aerodynamic diameter smaller than 2.5 MUm) pollution levels in the world. It might still be long before air quality reaches the National Class II standard of 35 MUg/m3. OBJECTIVE: We aim to estimate the potential reduction in premature mortality by reducing indoor PM2.5 levels in the Beijing-Tianjin-Hebei (BTH) region and compare it with reducing outdoor levels. METHODS: We combined PM2.5 transport model and the Global Burden of Disease (2016) methodology to estimate potential reductions in premature mortality attributable to PM2.5 by reducing indoor PM2.5 to National Class I standard of 15 MUg/m3, and compared with reducing outdoor PM2.5 to Government 2020 Interim target of 64 MUg/m3 or National Class II standard of 35 MUg/m3. RESULTS: A total of 74,000 (95% confidence interval (CI): 43,000-111,000) premature deaths were attributable to PM2.5 exposure in 2013. Thirty percent, or 22,000 (95% CI: 17,000-32,000) deaths, would have been averted if indoor PM2.5 had reached the National Class I standard. The benefit is greater than that from reaching the Government 2020 Interim target for outdoor PM2.5 [22%, or 16,000 (95% CI: 12,000-23,000), deaths], although still smaller than that from reaching the National Class II standard [42%, or 31,000 (95% CI: 24,000-45,000), deaths]. CONCLUSIONS: Reaching the National Class I level of indoor PM2.5 at current outdoor pollution levels could bring considerable health benefits, which are comparable to those from reaching the Government 2020 Interim target for outdoor PM2.5. MAIN FINDINGS: The avertable premature deaths gained from cleaning indoor PM2.5 to National Class I standard level would be greater than reducing outdoor PM2.5 to Government 2020 Interim target. PMID- 30439637 TI - Biological effects of the benzotriazole ultraviolet stabilizers UV-234 and UV-320 in early-staged zebrafish (Danio rerio). AB - Among the benzotriazole ultraviolet stabilizers (BUVSs), UV-234 and UV-320 are frequently detected in aquatic ecosystem. Despite the fact that these chemicals are present in low ng/L levels in surface water, they show high bio-accumulation potential and pose exposure risks to aquatic organisms. However, there are limited toxicological data available in fish. In this study, zebrafish embryos were exposed to 0.01, 0.1 and 1 MUM UV-234 or UV-320 for up to 6 days. Developmental toxicity as well as effects on mitochondrial bioenergetics, immune system responses, and locomotor activity in zebrafish were measured. After UV-234 treatment (0.1-1 MUM), hatching time of embryos was increased compared to controls. There was also a ~20-40% reduction in non-mitochondrial respiration and oligomycin-dependent mitochondrial respiration in embryos treated with 1 MUM UV 234 for 24 and 48 h respectively; conversely basal respiration and non mitochondrial respiration were increased ~20-30% in embryos treated with 1 MUM UV 320 at 48 h. Transcript levels of sod1 were down-regulated with BUVSs while sod2 mRNA was highly up-regulated with both UV-234 and UV-320, suggesting an oxidative damage response. Considering that mitochondrial signaling regulates innate immune pathways, we measured the expression of immune related transcripts (tlr5a, tlr5b, mmp9, il8, tnfa, cxcl-C1c, nfkb1, and ifng). Of these, only il8 and cxcl-C1c mRNA were decreased in response to 0.1 MUM UV-320. To associate early molecular events with behavior, locomotor activity was assessed. UV-234 reduced larval activity in a dark photokinesis assay by ~15%, however behavioral responses at environmentally-relevant concentrations of BUVSs were not consistent across experiments nor BUVSs. These data suggest that BUVSs can perturb mitochondrial bioenergetics, embryonic development, and locomotor activity of zebrafish, but these responses appear to be dose-, time- and BUVSs dependent, suggesting these chemicals may have unique modes of action. PMID- 30439638 TI - Influence of hybrid polymeric nanoparticle/thermosensitive hydrogels systems on formulation tracking and in vitro artificial membrane permeation: A promising system for skin drug-delivery. AB - In recent years, the development of hybrid drug delivery systems, such as hydrogels and nanoparticles, has gained considerable attention as new formulations for skin-delivery. Meanwhile, transdermal diffusion synthetic membranes have been used to assess skin permeability to these systems, providing key insights into the relationships between drug and nanoformulations. In this study, benzocaine-loaded poly-epsilon-caprolactone nanoparticles (BZC:NPs) were synthesized, characterized and incorporated into Poloxamer 407-based hydrogel (PL407). Benzocaine (BZC) was used as a drug model since has been commonly applied as a topical pain reliever in the last years. Hence, we developed a hybrid polymeric nanoparticle/thermosensitive hydrogels system and evaluated the in vitro permeation of the BZC, as well as nanoformulation tracking in an artificial membrane. In vitro permeation study was conducted in a vertical diffusion cell system using a Strat-M(r) membrane model. BZC:NPs were prepared by coprecipitation method and their physicochemical stability measured before incorporating into the thermosensitive hydrogel. Also, viscosity measurements and sol-gel transition temperature were performed by rheological analysis. Different techniques, including microscopy, were used to tracking the nanoparticles on both receptor medium and synthetic membranes. Results showed high BZC encapsulation efficiency into NPs (93%) and good physicochemical stability before and after hydrogel incorporation. BZC in vitro permeation kinetics from NPs-loaded Poloxamer 407-based hydrogel presented slower permeation profile compared with the BZC: Poloxamer 407-based hydrogel. Also, NPs were observed into the diffusion cells receptor compartment after the in vitro permeation study. These results contribute to a better understanding the interaction between hydrogels, nanoparticles and synthetic membrane, as well as open perspectives for the development of new drug delivery systems for skin. PMID- 30439639 TI - Zeta potential changes of Saccharomyces cerevisiae during fermentative and respiratory cycles. AB - Saccharomyces cerevisiae is a type of yeast, widely used in diverse biotechnological food-beverage processes. Although the performance of an industrial fermentation process depends largely on the number of cells, it is necessary to consider the physiological state of the cultures. In this context, the aim of this study was to determine in a yeast culture how factors such as growth conditions affect surface properties at the different growth stages. Our results show that, S. cerevisiae spp. exhibits different zeta potential mean values along the exponential, post-diauxic and stationary growth phases. In addition, there were differences depending on whether they are in aerobic or anaerobic conditions. When the effect of pH on the media was studied, a different dependence of zeta potential at each stage reveals that in the living cells the surface potential depends on the interaction between secreted acids and the constituents of the surfaces, according to the growth conditions. In order to have a view at the cellular level, the zeta potential on individual cells by optical microscopy has been determined at different stages of culture in aerobic and anaerobic conditions. This single-cell method allows for the identification and following of the development of different cell subpopulations during each growth stage. Furthermore, the behavior of the dead cells provided evidence to relate the large negatively charged population with cell wall damage. Overall, the results obtained in the present work represent an important milestone for a novel application of zeta potential technique on yeast. PMID- 30439640 TI - Magnetic bioinspired micro/nanostructured composite scaffold for bone regeneration. AB - Magnetic-responsive materials are promising for applications in various biomedical fields. Especially, superparamagnetic nanoparticles are widely used in magnetic system for bone tissue engineering owing to superior biocompatibility and long term stability. Based on the idea of in situ bionics, we successfully incorporate the nano-hydroxyapatite (nHAP) and Fe3O4 nanoparticles which were prepared by in situ crystallization and freeze-drying technique into the chitosan/collagen (CS/Col) organic matrix to achieve the uniform dispersion of inorganic substrate with nanometer-scale. The in vitro results of the physicochemical and biocompatibility tests showed that CS/Col/Fe3O4/nHAP magnetic scaffold possessed superior structural and mechanical performance for cell adhesion and proliferation, as well as the osteogenic differentiation. Mineralization experiments showed better bioactive and good ability of in situ biomimetic mineralization. Moreover, from the in vivo model of SD rats' skull defects proved that the CS/Col/Fe3O4/nHAP hybrid scaffold had a better tissue compatibility and higher bone regeneration ability when implanted into the skull defects comparing to control group. Herein, the magnetic hybrid micro/nanostructured scaffold showed a potential application for bone defect repair. PMID- 30439641 TI - A novel optical sensor based on carbon dots embedded molecularly imprinted silica for selective acetamiprid detection. AB - A molecularly imprinted polymer (MIP) on silane-doped carbon dots (Si-CDs) has been synthesized as a novel optical sensor for selective detection of acetamiprid (ACT). Highly fluorescence Si-CDs have been first prepared by hydrothermal method. Subsequently, MIP has been formed on the surface of Si-CDs (MIP@Si-CDs) by a sol-gel process. The properties and structure of the Si-CDs and MIP@Si-CD nanocomposites have been characterized by fluorescence spectroscopy, UV-Vis absorption spectroscopy, transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectroscopy, and X-ray diffraction techniques. Various parameters, which affect the optical signal, have been optimized. The fluorescence signal of MIP@Si-CDs showed linear response with ACT concentration in the 7-107 nM range with a detection limit of 2 nM and a precision of 2.7% and 3.3% for five replicate detections of 17 and 33 nM ACT under optimal conditions. In addition, the sensor has been satisfactorily utilized for the detection of ACT content in real samples. PMID- 30439642 TI - Limbal epithelial stem cell activity and corneal epithelial cell cycle parameters in adult and aging mice. AB - Limbal epithelial stem cells (LESCs) are believed to be responsible for corneal epithelial maintenance and repair after injury, but their activity has never been properly quantified in aging or wounded eyes. In this study, labelling with thymidine analogues, 5-iodo-2'-deoxyuridine (IdU), 5-chloro-2'-deoxyuridine (CldU) and 5-ethynyl-2'-deoxyuridine (EdU), was used to estimate cell-cycle time of the corneal and limbal epithelia in wild-type eyes, comparing aging (12 months) and young adult (8 week) mice. In C57BL/6 mice, cells cycled significantly faster in the central corneal epithelium of aging eyes (3.24 +/- 0.2 days) compared to 10 week old mice (4.97 +/- 0.5 days). Long-term labelling with IdU was used to detect slow-cycling stem cells, followed by CldU or EdU labelling to quantify the proliferative dynamics of LESCs during corneal wound healing. In unwounded eyes, 4.52 +/- 1.4% of LESCs were shown to enter S phase in a 24 h period and were estimated to divide every 2-3 weeks. Within 24 h of corneal injury this rose significantly to 32.8 +/- 10.0% of stem cells indicating a seven-fold increase in activation. In contrast, no comparable increase in LESC activation was observed in aging mice after wounding. In the 24-48 h period after wounding in young adults, LESC activation continued to increase (86.5 +/- 8.2% of label-retaining cells in wounded eye were in S-phase) but surprisingly, 46.0 +/- 9.4% of LESCs were observed to reenter S-phase in the contralateral unwounded eye. These data imply an unsuspected systemic effect of corneal wounding on LESC activation suggesting that injury to one eye elicits a regenerative response in both. PMID- 30439643 TI - Extracellular matrix affects different aspects of cell behaviour potentially involved in response to aminolevulinic acid-based photoinactivation. AB - Two-dimensional cell cultures do not seem to be reliable models for anticancer drug discovery and validation. Numerous in vitro tumour models of different complexity have been evaluated with the aim to enhance anticancer drug development, but whether all these models could be considered as physiologically relevant is a question. Even type of the extracellular matrix may markedly influence experimental results and supposedly also clinical treatment outcome. By using three human oesophageal cell lines and three-dimensional cultures based on collagen type I, abundant component of stromal tissue, and Matrigel, a surrogate of basement membrane, we tested the impact of extracellular matrix on different aspects of cell behaviour. We applied live cell fluorescence confocal microscopy in combination with image analysis and supplemented it with immunohistochemical analysis of differentiation markers in fixed samples. We found that cell morphogenesis, differentiation, extracellular vesicle formation, protoporphyrin IX production from aminolevulinic acid and response to subsequent photodynamic intervention induced by red light may be affected by the type of extracellular matrix and these modifications occur in a cell-type dependent manner. Our results demonstrate that the choice of the correct extracellular matrix for in vitro tumour models is crucial for gathering clinically relevant information from in vitro experimental studies. PMID- 30439644 TI - Development of culturally sensitive Pain Neuroscience Education for first generation Turkish patients with chronic pain: A modified Delphi study. AB - BACKGROUND: Pain Neuroscience Education (PNE) has been recognized as an efficacious approach for chronic pain, but evidence for these findings have mainly been gathered in Caucasian patient populations. In recent years, it has been proposed that the treatment of pain and patient information materials should be culturally sensitive for different ethnic populations and cultures since cultural variations in pain beliefs and cognitions. OBJECTIVES: To culturally adapt PNE material for first-generation Turkish patients with chronic pain. DESIGN: A modified Delphi study with three consecutive rounds. METHOD: A total of 10 participants (8 experts and 2 first-generation Turkish patients with chronic pain) were recruited for this study. Three online questionnaire rounds were conducted to synthesize the perspectives and to reach agreement on the suggested PNE materials. RESULTS: Results on multiple-choice questions from the first round revealed that the compatibility of the visual information and the clarity of the message obtained lower scores. Examples, visual information (illustrations, pictures), and metaphors in the teaching materials and the home education leaflet were revised based on suggestions in Rounds 1 and 2. In Round 3, respondents reached an acceptable agreement level for the clinical usefulness of the PNE teaching materials and the home education material. CONCLUSIONS: Culturally sensitive PNE materials were produced for first-generation Turkish patients. Since the results of the present study only reveal perspectives of the experts, further validation of education materials may be required before they are recommended for Turkish patients in clinical practices. PMID- 30439645 TI - Novel Human miRNA-Disease Association Inference Based on Random Forest. AB - Since the first microRNA (miRNA) was discovered, a lot of studies have confirmed the associations between miRNAs and human complex diseases. Besides, obtaining and taking advantage of association information between miRNAs and diseases play an increasingly important role in improving the treatment level for complex diseases. However, due to the high cost of traditional experimental methods, many researchers have proposed different computational methods to predict potential associations between miRNAs and diseases. In this work, we developed a computational model of Random Forest for miRNA-disease association (RFMDA) prediction based on machine learning. The training sample set for RFMDA was constructed according to the human microRNA disease database (HMDD) version (v.)2.0, and the feature vectors to represent miRNA-disease samples were defined by integrating miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity. The Random Forest algorithm was first employed to infer miRNA-disease associations. In addition, a filter-based method was implemented to select robust features from the miRNA-disease feature set, which could efficiently distinguish related miRNA-disease pairs from unrelated miRNA-disease pairs. RFMDA achieved areas under the curve (AUCs) of 0.8891, 0.8323, and 0.8818 +/- 0.0014 under global leave-one-out cross validation, local leave-one-out cross-validation, and 5-fold cross-validation, respectively, which were higher than many previous computational models. To further evaluate the accuracy of RFMDA, we carried out three types of case studies for four human complex diseases. As a result, 43 (esophageal neoplasms), 46 (lymphoma), 47 (lung neoplasms), and 48 (breast neoplasms) of the top 50 predicted disease-related miRNAs were verified by experiments in different kinds of case studies. The results of cross-validation and case studies indicated that RFMDA is a reliable model for predicting miRNA-disease associations. PMID- 30439646 TI - Role of Long Noncoding RNA 799 in the Metastasis of Cervical Cancer through Upregulation of TBL1XR1 Expression. AB - Long noncoding RNAs (lncRNAs) are closely associated with the molecular mechanisms underlying cancer development, and it would be highly useful to study their expression and mechanisms in cervical cancer too. The current study investigated lncRNA799 expression in cervical cancer in order to determine its clinical importance in the progression of cervical cancer. lncRNA799 expression was studied in 218 cervical cancer samples. Expression of lncRNA799 was significantly higher in the cervical cancer tissue than in the adjacent normal tissue. Overexpression of lncRNA799 was found to have a significant correlation with FIGO stage, SCC-Ag level, and lymphatic metastasis, and it was also associated with poor survival. Ectopic expression of lncRNA799 promoted the metastasis of SiHa cells, whereas lncRNA799 knockdown had an inhibitory effect on metastasis. Western blot analysis demonstrated that lncRNA799 promotes the expression of transducing beta-like protein 1-related protein (TBL1XR1), and that lncRNA799 and TBL1XR1 expression show strong correlation in cervical cancer. Moreover, lncRNA799 modulated the expression of TBL1XR1 by acting as a competitive endogenous RNA (ceRNA) for miR-454-3P. The results indicate that lncRNA799 could be used as a novel marker of cervical cancer prognosis. Thus, targeting the ceRNA network involving lncRNA799 could be a potential treatment strategy against cervical cancer. PMID- 30439649 TI - The social anatomy of adverse childhood experiences and aggression in a representative sample of young adults in the U.S. AB - Objective The current study assesses the effect of adverse childhood experiences on later aggression and violence across young adult relationships contexts, including intimate partners, friends, or strangers. Method Surveys were conducted with a nationally representative sample of young adults ages 18-32, drawn from the AmeriSpeak panel, a probability-based panel with coverage of 97% of U.S. households. The weighted study sample is 2284 young adult respondents, of whom 1561 reported being in an intimate partnership. Results Rates of verbal aggression perpetrated by young adults declined with the intimacy of the relationship, such that aggression against a partner (72%) exceeded aggression directed at friends (43%) and strangers (34%). Similar rates of physical violence (about 9%) were reportedly perpetrated against partners, friends, and strangers. Adjusting for a range of personal characteristics, both adverse childhood experiences and recent stressors in these young adult lives exhibited direct associations with verbal and physically aggressive outcomes. Conclusions In models of verbal and physical aggression across relationship contexts, childhood adversity exhibits lasting effects unaccounted for by important proximal life circumstances, including recent life stressors, mental health, and substance use behaviors. These results provide empirical insights for clinical treatment of young adults prone to aggressive conflicts as well as input to positive youth development programming to foster healthy approaches to conflict. PMID- 30439648 TI - Identification of Novel Antisense-Mediated Exon Skipping Targets in DYSF for Therapeutic Treatment of Dysferlinopathy. AB - Dysferlinopathy is a progressive myopathy caused by mutations in the dysferlin (DYSF) gene. Dysferlin protein plays a major role in plasma-membrane resealing. Some patients with DYSF deletion mutations exhibit mild symptoms, suggesting some regions of DYSF can be removed without significantly impacting protein function. Antisense-mediated exon-skipping therapy uses synthetic molecules called antisense oligonucleotides to modulate splicing, allowing exons harboring or near genetic mutations to be removed and the open reading frame corrected. Previous studies have focused on DYSF exon 32 skipping as a potential therapeutic approach, based on the association of a mild phenotype with the in-frame deletion of exon 32. To date, no other DYSF exon-skipping targets have been identified, and the relationship between DYSF exon deletion pattern and protein function remains largely uncharacterized. In this study, we utilized a membrane-wounding assay to evaluate the ability of plasmid constructs carrying mutant DYSF, as well as antisense oligonucleotides, to rescue membrane resealing in patient cells. We report that multi-exon skipping of DYSF exons 26-27 and 28-29 rescues plasma membrane resealing. Successful translation of these findings into the development of clinical antisense drugs would establish new therapeutic approaches that would be applicable to ~5%-7% (exons 26-27 skipping) and ~8% (exons 28-29 skipping) of dysferlinopathy patients worldwide. PMID- 30439647 TI - Epistatic Association of CD14 and NOTCH2 Genetic Polymorphisms with Biliary Atresia in a Southern Chinese Population. AB - Biliary atresia (BA) is the most common cause of endstage liver disease in infants with poor prognosis and high mortality. The etiology of BA is still unknown, but the genetic factors have been considered as an important player in BA. We investigated the association of two cis-regulated variants in CD14 (rs2569190) and NOTCH2 (rs835576) with BA susceptibility, using the largest case control cohort, totaling 506 BA patients and 1,473 healthy controls in a Southern Chinese population. Significant epistatic interaction between the two variants in our samples was observed (p = 8.1E-03; OR = 2.78; 95% CI: 1.32-5.88). The expression of CD14 and NOTCH2 in the BA group was consistently lower than that in the control (CC) group (0.31 +/- 0.02 versus 1.00 +/- 0.14; p < 0.001), which might be related to the genetic susceptibility of the genes awaiting further validation. PMID- 30439651 TI - Factors influencing the difficulty of laparoscopic myomectomy: the development of a surgical rating tool. AB - Objective To obtain expert consensus on the patient and fibroid characteristics that affect the complexity of laparoscopic myomectomy (LM) and to use these factors to create a grading tool for objective evaluation of LM procedures. Study design Modified Delphi Methodology Study (Canadian Task Force III). Setting included a series of online surveys via SurveyMonkey (SurveyMonkey Inc., San Mateo, California, USA). Participants were Canadian minimally invasive gynecologic surgeons (MIGS) who perform LM. A list consisting of patient, uterine and procedural characteristics was disseminated to Canadian MIGS. Opportunity to include additional factors was provided. Consensus was predefined as Cronbach's alpha of >=0.80. A second Delphi survey was then done to assign weight value for each item in the grading tool. Results Twenty-seven surgeons from across Canada participated. Most (23/27, 85%) were MIGS fellowship trained, and performed more than 6 LM per year (18/27, 66.7%). Consensus was achieved in the first round of the survey (Cronbach's alpha = 0.93). Sixteen of 27 factors met the criteria for inclusion (>80% respondents agreed or strongly agreed) and were included in the final rating tool. Factors that met the criteria for inclusion were grouped as patient factors (including body mass index), uterine factors (including number of fibroids, size of largest fibroid), and surgical factors (including ease of developing the cleavage plane). Conclusions Using the Delphi methodology to obtain expert consensus on the factors influencing the difficulty of LM, we have developed an objective grading tool to evaluate the degree of technical complexity of LM. PMID- 30439650 TI - Is perivitelline space morphology of the oocyte associated with pregnancy outcome in intracytoplasmic sperm injection cycles? AB - OBJECTIVE(S): To investigate the effect of perivitelline space (PVS) abnormalities on the outcomes of intracytoplasmic sperm injection (ICSI) cycles in which the entire cohort was affected. STUDY DESIGN: Data from 9752 oocytes obtained from 1151 ICSI cycles performed from June/2010 to August/2016 in a private university-affiliated IVF centre. Cycles were divided into four groups according to the presence or absence of PVS abnormalities: PVS-L group (cycles with the entire oocyte cohort affected by large PVS, n = 265), PVS-G group (cycles with the entire oocyte cohort affected by PVS granularity, n = 280), PVS L + PVS-G group (cycles with the entire oocyte cohort affected by PVS-L and PVS G, n = 204), and control group (cycles with the entire oocyte cohort free of PVS abnormalities, n = 402). The effect of PVS abnormalities on ICSI outcomes was assessed by GLM adjusted for potential confounders. RESULTS: Groups with PVS abnormalities presented substantially higher FSH/follicle (p < 0.001) and FSH/oocyte (p < 0.001) ratios, and lower numbers of follicles (p < 0.001), oocytes (p < 0.001) and embryos (p = 0.002) compared to the control group. PVS-L + PVS-G implantation (p = 0.044) and pregnancy (p = 0.004) rates were significantly lower than in cycles with isolated PVS abnormalities and controls. CONCLUSION(S): Cycles in which the entire oocyte cohort is affected by both large PVS and PVS granularity have compromised implantation and pregnancy rates. PMID- 30439652 TI - Pre-pregnancy or first-trimester risk scoring to identify women at high risk of preterm birth. AB - Objective To develop a pre-pregnancy or first-trimester risk score to identify women at high risk of preterm birth. Study design In this retrospective cohort analysis, the sample was drawn from California singleton livebirths from 2007 to 2012 with linked birth certificate and hospital discharge records. The dataset was divided into a training (2/3 of sample) and a testing (1/3 of sample) set for discovery and validation. Predictive models for preterm birth using pre-pregnancy or first-trimester maternal factors were developed using backward stepwise logistic regression on a training dataset. A risk score for preterm birth was created for each pregnancy using beta-coefficients for each maternal factor remaining in the final multivariable model. Risk score utility was replicated in a testing dataset and by race/ethnicity and payer for prenatal care. Results The sample included 2,339,696 pregnancies divided into training and testing datasets. Twenty-three maternal risk factors were identified including several that were associated with a two or more increased odds of preterm birth (preexisting diabetes, preexisting hypertension, sickle cell anemia, and previous preterm birth). Approximately 40% of women with a risk score >= 3.0 in the training and testing samples delivered preterm (40.6% and 40.8%, respectively) compared to 3.1 3.3% of women with a risk score of 0.0 [odds ratio (OR) 13.0, 95% confidence interval (CI) 10.7-15.8, training; OR 12.2, 95% CI 9.4-15.9, testing). Additionally, over 18% of women with a risk score >= 3.0 had an adverse outcome other than preterm birth. Conclusion Maternal factors that are identifiable prior to pregnancy or during the first-trimester can be used create a cumulative risk score to identify women at the lowest and highest risk for preterm birth regardless of race/ethnicity or socioeconomic status. Further, we found that this cumulative risk score could also identify women at risk for other adverse outcomes who did not have a preterm birth. The risk score is not an effective screening test, but does identify women at very high risk of a preterm birth. PMID- 30439653 TI - Risk assessment for preterm preeclampsia in first trimester: Comparison of three calculation algorithms. AB - OBJECTIVE: To better adjust the risk for preeclampsia, multifactorial models in first trimester of pregnancy have found the way in clinical practice. This study compares the available test algorithms. STUDY DESIGN: In a cross-sectional study between November 2013 and April 2016 we compared the tests results of three first trimester testing algorithms for preeclampsia in 413 women. Risk for preterm preeclampsia was calculated with three different algorithms: Preeclampsia PredictorTM Software by PerkinElmer (PERK), ViewPoint(r) Software by GE Healthcare (VP) and the online calculator of the Fetal Medicine Foundation (FMF).We analyzed the data descriptively and determined Cohen's Kappa to assess the agreement among the algorithms. RESULTS: VP classified 89(21.5%) women, PERK 43(10.4%) women and FMF 90 (21.8%) women as having high risk for preterm preeclampsia (<34 weeks of gestation for VP and PERK and <37 weeks of gestation for FMF). Agreement between tests ranged from moderate to substantial (PERK/VP: kappa = 0.56, PERK/ FMF: kappa = 0.50, and VP/ FMF: kappa = 0.72). CONCLUSION: The three algorithms are similar but not equal. This may depend on chosen cut off, but also on test properties. This study cannot decide which algorithm is the best, but differences in results and cut offs should be taken into account. PMID- 30439654 TI - Transformation of bisphenol AF and bisphenol S by permanganate in the absence/presence of iodide: Kinetics and products. AB - Recent studies have reported that permanganate (Mn(VII)) shows a good performance in treatment of phenolic compounds, and the presence of iodide (I-) may display a great impact on Mn(VII) oxidation with the formation of toxic iodinated aromatic products. In this work, transformation of bisphenol AF (BPAF) and bisphenol S (BPS) by Mn(VII) in the absence or presence of I- was studied. Mn(VII) showed considerable reactivity towards BPAF with apparent second-order rate constants (0.09-1.65 M-1s-1) higher than those of Mn(VII) with BPS (0.02-0.12 M-1s-1) reported in literature over the pH range of 5-9. The presence of I- apparently accelerated the transformation rates of BPAF and BPS by Mn(VII), and these results could be explained by the contribution of hypoiodous acid (HOI) in situ formed from Mn(VII) oxidation of I-. A kinetic model involving the competitive reactions (i.e., Mn(VII) with I- and bisphenols, HOI with Mn(VII) and bisphenols) well simulated BPAF/BPS transformation by Mn(VII) in the presence of I- under various conditions. Hydroxylated, bond-cleavage, and polymeric products were identified from BPAF/BPS oxidation by Mn(VII), and iodinated aromatic products (e.g., mono- and multi-iodinated BPAF/BPS) were additionally detected in the presence of I-. Reaction pathways involving Mn(VII) one-electron oxidation as well as HOI substitution of BPAF/BPS were proposed. Eco-toxicity analysis by ECOSAR showed that the toxicity of these products generally followed the order of polymeric and iodinated aromatic products > parent BPAF/BPS > hydroxylated products > bond-cleavage products. PMID- 30439655 TI - Amido Black 10B a widely used azo dye causes DNA damage in pro- and eukaryotic indicator cells. AB - Acid Black 10B (AB10B) is widely used for the production of textiles, leather and prints. It is a representative of azo dyes and it is well documented that some of these compounds are mutagenic per se, and that cleavage products (in particular aromatic amines) may cause damage of the genetic material and cancer. Since no toxicological data on AB10B have been published, we evaluated its mutagenic activity in Salmonella/microsome assays and studied its acute toxic and genotoxic properties in a human derived liver cell line (HepG2) which retained the activities of drug metabolizing enzymes. The compound did not cause cytotoxicity (MTT assay), but clear genotoxic effects were detected in pro- and eukaryotic indicator cells. Dose dependent induction of his+ revertants was seen in strain TA98 which detects frameshift mutations without metabolic activation; a more pronounced effect was seen in its derivative YG1024 which overexpresses N acetyltransferase. Induction of single/double strand breaks by Comet assay was detected with concentrations > 0.125 mg/mL in liver derived cells; as well as increased rates for micronucleus (reflecting structural and numeric chromosomal aberrations) and nuclear buds which are a consequence of gene amplifications were seen with a higher dose (2.0 mg/mL) (p < 0.05; Tukey's test). The mutational pattern which was observed in the bacterial tests indicates that the cleavage product p-nitroaniline may cause the genotoxic effects of the dye. Our findings indicate that exposure of humans and the release of the compound into the environment may lead to adverse effects due to its DNA damaging activity. PMID- 30439657 TI - Optimization of heavy metal biosorption onto freshwater algae (Chlorella coloniales) using response surface methodology (RSM). AB - In this study, the interaction of the initial metal concentration, time of reaction and Chlorella coloniales algae dose were taken for the biosorption of Cr, Cd, Co, Fe and As from aqueous solutions using the Box-Behnken design. The regression equation coefficients were calculated and the data confirmed the validity of second-order polynomial equation for the removal of Cr, Cd, Co, Fe and As with Chlorella coloniales algae. Analysis of variance (ANOVA) showed a high coefficient of determination value (R2) for Cr, Cd, Co, Fe, and As, being respectively 0.998, 0.998, 0.995, 0.998 and 0.994. Heavy metal biosorption increased with the increase in time of reaction from 30 h to 100 h then smoothly steadily decreased. The biosorption capacity of Chlorella coloniales increased when initial Cd concentration was increased from 5 to 12 mg/L, and then no change was seen with further increasing in initial Cd concentration. At low concentrations of heavy metal, Chlorella coloniales showed its effectiveness for Cr, Co, Fe and As bioaccumulation, but at high concentrations of heavy metal bioaccumulation efficiency decreased Under optimal value of process parameters, maximum efficiencies for the removal of Cr, Cd, Co, Fe, and As were 97.8, 97.05, 95.15, 98.6 and 96.5% respectively. The results of the present study suggest that use of C. Coloniales algae can be a good alternative to the current expensive methods of removing heavy metals from aqueous solution. PMID- 30439656 TI - Occurrence, distribution and seasonal variation of five neonicotinoid insecticides in surface water and sediment of the Pearl Rivers, South China. AB - Occurrence and distribution of five neonicotinoids (NEOs) in surface water and sediment were studied in the Pearl Rivers, including three trunk streams, Dongjiang, Beijiang, Xijiang River (DR, BR and XR), South China. At least one neonicotinoid was detected in surface water and sediment of the Pearl Rivers, with imidacloprid (IMI) and thiamethoxam (THM) being the frequently detected NEOs. Total amount of NEOs (?5neonics) in surface water and sediment ranged from 24.0 to 322 ng/L, and from 0.11 to 11.6 ng/g dw, respectively. Moreover, the order of contamination level of NEOs in the Pearl Rivers was as follows: XR > DR > BR for surface water, and BR > DR > XR for sediment. Local agricultural activities and effluents of wastewater treatment plants (WWTPs) could be major sources of NEOs in the Pearl Rivers. Solubilization and dilution of NEOs between surface water and sediment during different seasons (spring and summer) could be attributed to rainfall intensities or climate of the Pearl River Delta. An ecological risk assessment of the exposure to current environmental concentration of imidacloprid and ?5NEOs suggests a threat to sensitive non-target invertebrates, including aquatic invertebrates. Results would provide a better understanding of NEOs contamination in the Pearl Rivers, as well as being a reliable dataset for decision-making in contamination control and environmental protection. PMID- 30439658 TI - Monitoring of methylated naphthalenes in sludge-derived pyrogenic carbonaceous materials. AB - Methylated analogues of polycyclic aromatic hydrocarbons (PAHs) represent important environmental contaminants produced often at process of feedstock thermochemical conversion. In the present study, we determined and compared levels of 1-methylnaphtalene and 2-methylnaphtalene in municipal sewage sludge (MSS), sludge-derived pyrogenic carbonaceous materials produced at 350 degrees C (PCM350) and 500 degrees C (PCM500) in process of slow pyrolysis. The highest extraction efficiency of both aromatic structures from MSS, PCM350 and PCM500 for toluene as extraction agent and 36 h of extraction time was revealed. The total concentrations of 1-methylnaphtalene reached values 8.7 mg/kg for MSS, 14.6 mg/kg for PCM350 and 18.1 mg/kg for PCM500.2-methylnaphtalene was quantified in concentrations 12.5 mg/kg for MSS, 19.3 mg/kg for PCM350 and 23 mg/kg for PCM500. Available levels of 1-methylnaphtalene and 2-methylnaphtalene determined by Tenax resin desorption test during 36 days showed decreasing trend in order PCM500 > PCM350 > MSS. In summary, pyrolysis treatment of sewage sludge can increase total amount of methylated PAHs in produced carbonaceous materials but decrease their available forms. This fact can contribute to global ecotoxicological assessment of organic pollutants in biochars and pyrogenic carbonaceous materials applied in agronomy as soil amendments. PMID- 30439659 TI - Mineralization of pentachlorophenol by ferrioxalate-assisted solar photo-Fenton process at mild pH. AB - This work reports the use of ferrioxalate complexes to assist solar photo-Fenton treatment of pentachlorophenol (PCP) in aqueous medium at mild pH, which inhibits the precipitation of iron hydroxides and allows working at a low iron dosage. The experimental parameters were optimized by assessing the effect of initial concentrations of H2O2 (0-2.5 mM) and Fe(II) (2-10 mg/L), pH (3.0-9.0) and iron/oxalic acid molar ratios (1:0-1:13.5) on total organic carbon (TOC) removal. Ferrioxalate-assisted solar photo-Fenton achieved 97.5% mineralization in 120 min, clearly outperforming conventional Fenton and solar photo-Fenton. The presence of photosensitive ferrioxalate complexes accounted for the enhancement, as a result of Fe(II) regeneration that accelerated the hydroxyl radical (OH) production. The time course of H2O2 and Fe(II) concentrations was evaluated under different iron/oxalic acid ratios. The five carboxylic acids determined by ion exclusion HPLC and the eight aromatic by-products identified by GC-MS allowed the proposal of a degradation pathway that included hydroxylation, dechlorination and dimerization steps. Complete chloride ion release was achieved after 90 min of treatment. PMID- 30439660 TI - Ultrafast removal of arsenic using solid solution of aero-gel based Ce1-XTixO2-Y oxide nanoparticles. AB - An aero-gel based solid solution of titanium and cerium oxide nanoparticles have been used for the first time for ultra fast and trace level removal of arsenic from water. The interconnected long range ordered mesoporous structure was observed from TEM analysis which has been verified as an essential facet for the fast removal of arsenic in this study. The HR-XRD spectra indicated the face centred cubic structure with Fm3-m space group. Le-Bail refinement and Raman spectroscopy confirmed the formation of single phase solid solution of Ce1-XTixO2 Y oxide nanoparticles. The HR-XPS and FT-IR study indicated the surface complexation and partial oxidation of As(III) to As(V) via electron transfer mechanism by reduction of Ce(IV) to Ce(III) and Ti(IV) to Ti(III) simultaneously during adsorption process. The kinetics study demonstrated 99% removal of As(III) within 10 min of initiating the adsorption process. The effect of pH and interfering ions confirmed the wide range of applicability for solid solution of titania and cerium oxide nanoparticles over the different environmental conditions for the removal of arsenic. The adsorption capacity for our best adsorbent (Ce0.8Ti0.2O2-y) was found to be 2 * 105 mg kg-1 while the lowest concentration of water body system was 7 MUg L-1 which is the minimum concentration of arsenic achieved by any metal oxide based adsorbent. PMID- 30439661 TI - Mercury sequestration and transformation in chemically enhanced treatment wetlands. AB - Mercury (Hg) pollution is a concern to human and wildlife health worldwide, and management strategies that reduce Hg inputs to aquatic systems are of broad interest. Using a replicated field-scale study in California's Sacramento-San Joaquin Delta, we tested the effectiveness of chemically enhanced treatment wetlands (CETWs) under two coagulation treatments, polyaluminum chloride (Al treatment) and ferric sulfate (Fe treatment), in their initial removal and longer term sequestration of Hg compared to untreated control wetlands. The primary mechanism for Hg removal by CETWs was the transfer of Hg from filtered forms to insoluble particulate forms and enhanced settling of particles. CETWs resulted in total Hg annual load removals of 63 ng m-2 yr-1 (71%) and 54 ng m-2 yr-1 (54%) for the Al and Fe treatments, respectively. Control wetlands removed significantly less at 13 ng m-2 yr-1 (14%). Load removals indicate that Fe treatment wetlands more effectively reduced filtered and total methylmercury (MeHg) exports, while Al treatment wetlands more effectively reduced particulate MeHg and total Hg exports. These differences in Hg species load reductions possibly indicate different mechanisms of Hg sequestration; current data suggest more effective floc formation and particle settling was likely responsible for the Al treatment behavior, while either preferential MeHg sequestration or methylation suppression was potentially responsible for Fe treatment behavior. Differences in Hg sequestration behavior post-coagulation between the flocs formed by different coagulants indicate the importance of in-situ studies and the need for careful selection of coagulant treatment depending on the Hg species requiring remediation. PMID- 30439662 TI - Chemical and bioactivity screening of subcritical water extracts of chokeberry (Aronia melanocarpa) stems. AB - Subcritical water extracts of chokeberry (Aronia melanocarpa) stems were chemically and biologically characterised. Chemical profile was defined by GC-MS analysis whereas anti-oxidant, anti-diabetic and tyrosinase-inhibitory activities of the extracts were investigated by in vitro assays. Antioxidant activity assays revealed strong activity against DPPH radical (IC50 = 0.1 mg/mL) and reducing power (IC50 = 0.25 mg/mL). The extracts demonstrated remarkable amylase (0.59 mmol ACAE/g) and glucosidase (7.50 mmol ACAE/g) inhibitory effects. Anti tyrosinase activity of aronia stem extracts obtained by subcritical water was calculated to be 15.87 mg KAE/g extract. GC-MS analysis of chokeberry stem subcritical water extracts revealed the presence of different chemical classes. The compounds present in the highest concentrations were polyols arabitol (13.7%), xylitol (3.5%), and glycerol (1.96%), as well as sugars such as fructose (3.04%), ribose (1.99%) and xylulose (1.18%). PMID- 30439663 TI - Tracking of the degradation process of chlorhexidine digluconate and ethylenediaminetetraacetic acid in the presence of hyper-pure chlorine dioxide in endodontic disinfection. AB - Accurate knowledge of the safety of the combined use of hyper-pure chlorine dioxide (ClO2, Solumium) with different endodontic agents is not known. The objective was to investigate the possible interactions between hyper-pure ClO2 and Chlorhexidine digluconate (CHX) as well as hyper-pure ClO2 and ethylenediaminetetraacetic acid (EDTA) in vitro. High-performance liquid chromatography (HPLC) was used to analyse the reaction between ClO2 and CHX for studying the possible increase of para-chloroaniline (PCA). Nuclear magnetic resonance (NMR) method was applied to investigate if the oxidising property of ClO2 inactivates EDTA. CHX itself may contain PCA; however, its amount did not increase after the mixing up with ClO2. While ClO2 did not oxidise PCA, on the other hand, it oxidised EDTA into numerous degradation products, but this reaction was slow. Hyper-pure ClO2 of excellent antimicrobial properties should be considered as a safe alternative endodontic disinfectant agent in combinations or as a final rinse. The lack of chemical interaction between ClO2 and CHX confirms their safe application in combination. PMID- 30439664 TI - Characterization, anti-oxidative effect of grape seed powder and in silico affinity profiling of polyphenolic and extra-phenolic compounds for calpain inhibition. AB - Vitis vinifera grape is a highly cultivated crop and solid wastes generated by the wine industry are largely under exploited. Plentiful studies have intended analyzing the polyphenolic content of grape seeds but characterization of non phenolic compounds is rather scarce. The present study aimed at the selective extraction of lipid, phenolic and aqueous phases from grape seed powder (GSP) in order to establish their intimate composition, as well as their antioxidant and chelating properties underlying partly their biological effects. Major non phenolic compounds identified in the lipid phase were glyceryl-monostearate and 2 monostearin whereas fructofuranose and sucrose were the most abundant in the aqueous phase. Among the most abundant compounds detected in the various phases, the polyphenol quercetin exhibited the best affinity and free binding energy towards the active site of the calcium-dependent protease calpain. Polyphenols likely constitute the bioactive part of GSP that should be exploited as safe modulators of intracellular signaling which is likely at the basis of their health beneficial effects. Nevertheless other compounds as lipids or sugars should be valorized along with polyphenols to improve their bioavailability into highly protected organs as brain or eye. PMID- 30439665 TI - Reliable and easy-to-use LC-MS/MS-method for simultaneous determination of the antihypertensives metoprolol, amlodipine, canrenone and hydrochlorothiazide in patients with therapy-refractory arterial hypertension. AB - BACKGROUND: Therapy-refractory arterial hypertension is defined as a blood pressure (BP) in a subset of patients who fail to achieve BP control despite a three-drug regimen (including a diuretic). Various factors have impact on loss of therapy response. Drug-drug-interactions (DDIs) may cause altered pharmacokinetics (PK) of antihypertensive drugs. Upregulation of activity and expression of cytochrome P450 (CYP) enzymes can result in decreased plasma drug levels. Besides these PK considerations a significant problem could be nonadherence to drug therapy. In this regard Therapeutic Drug Monitoring (TDM) is a useful tool for detecting nonadherence. Therefore a LC-MS/MS-method for determination of Metoprolol (MET), Amlodipine (AML), Canrenone (CAN) and Hydrochlorothiazide (HCT) was developed. METHODS: An UHPLC-MS/MS method was developed and validated for simultaneous determination of MET, AML, CAN and HCT in plasma matrix. Extraction of serum samples consisted of simple protein precipitation using acetonitrile. Stable isotope labeled analogues for each antihypertensive were obtained for internal standardization and quantitative analysis ([2H7]-MET, ([13C6]-AML, [2H4]-CAN, [13C6]-HCT). Calibrators and quality controls were prepared in plasma matrix of normal individuals. Sample preparation: protein precipitation with acetonitrile and addition of internal standard-mix. RESULTS: All analytes were eluted within a runtime of 2.5 min. Linearity experiments were demonstrated in plasma over following concentration ranges: MET: 5-750 MUg/l, AML: 1-50 MUg/l, CAN: 10-500 MUg/l, HCT: 5-500 MUg/l (R2 > 0.993). Chromatographic separation was achieved using a C18 column (50 * 2.1 mm, 1.9 MUm particle size) and an isocratic elution. LC-MS/MS analyses were performed on a triple quadrupole mass spectrometer using positive and negative electrospray ionization in selected reaction monitoring (SRM) mode. Ion transitions monitored for quantitation were m/z 268.2 -> 74.1 for MET, m/z 409.1 > 238.0 for AML, m/z 341.2 -> 91.0 for CAN and m/z 296.0 -> 205.1 for HCT. For all analytes, inter- and intra-day precision (CV, %) varied between 1.7 and 14.0 and inter- and intra-day accuracy values ranged from -2.5 to 7.1%. The lower limits of detection and quantification were: 0.08 and 0.23; 0.05 and 0.15; 2.82 and 8.54; and 0.02 and 0.05 MUg/l for MET, AML, CAN and HCT, respectively. Results of stability experiments were within the required range of +/- 15%. CONCLUSIONS: Although the level of recommendation of TDM of antihypertensive drugs in patients with refractory hypertension is not yet established, the present LC-MS/MS-method can serve as an effective tool for detection of PK alterations/nonadherence and may help to monitor antihypertensive pharmacotherapy. PMID- 30439666 TI - Computer-assisted UHPLC-MS method development and optimization for the determination of 24 antineoplastic drugs used in hospital pharmacy. AB - This study reports the use of retention modeling software for the successful method development of 24 injectable antineoplastic agents. Firstly, a generic screening of several stationary and mobile phases (using various organic modifiers and pH) was achieved. Then, an optimization procedure of mobile phase temperature, gradient profile and mobile phase binary composition was conducted through only 28 real experiments using retention modeling software for data treatment. Finally, the optimized separation was achieved with a mobile phase consisting in 10 mM acetic acid at pH 5.1 (A) and acetonitrile (B). A Waters CORTECS(r) T3 column (100 * 2.1 mm, 1.6 MUm) operated at 25 degrees C with a gradient time of 17.5 min (0-51%B) at a flow rate of 0.4 mL/min was used. The prediction offered by the retention model was found to be highly reliable, with an average error lower than 1%. A robustness testing step was also assessed from a virtual experimental design. Success rate and regression coefficient were evaluated without the need to perform any real experiment. The developed LC-MS method was successfully applied to the analysis of pharmaceutical formulations and wiping samples from working environment. PMID- 30439667 TI - Development and optimization of confirmatory liquid chromatography-Orbitrap mass spectrometry method for the determination of 17 anticoccidials in poultry and eggs. AB - A new sensitive and selective multi-residue method based on liquid chromatography - Orbitrap high resolution mass spectrometry (LC-Orbitrap-HRMS) was developed and validated for the determination of 17 anticoccidials in poultry and eggs. Instrumental parameters were optimized by the means of statistical experimental designs to improve the sensitivity, precision, and repeatability of the method. Further optimization of auto-tuned MS parameters led to an increase of signal intensity by 10% to 99% for 16 out of 17 analytes. The sample preparation procedure included extraction from muscle tissue and egg samples with acetonitrile, followed by preconcentration, reconstitution, and filtration. Validation was performed according to the Commission Decision 2002/657/EC. The occurrence of anticoccidials in eggs and poultry was assessed by using the developed analytical procedure within the Latvian national monitoring program, revealing quantifiable residues for 6 analytes (marker residue of nicarbazin - 4,4'-dinitrocarbanilide (DNC), salinomycin, narasin, toltrazuril, and its two metabolites). PMID- 30439668 TI - Investigation of dextrin-based synergistic system with chiral ionic liquids as additives for enantiomeric separation in capillary electrophoresis. AB - In this paper, two spiral structure CILs, 1-butyl-3-methylimidazolium(T-4) bis[(2S)-2-(hydroxy-kappaO)-3-methyl-butanoato-kappaO]borate(BMIm+BLHvB-) and 1 butyl-3-methylimidazolium (T-4)-bis[(alphaS)-alpha-(hydroxy-kappaO)-4-methyl benzeneacetato-kappaO]borate (BMIm+BSMB-)were applied to evaluate their potential synergistic effect with dextrin for CE enantiomeric separation. The established dextrin-based synergistic system with CILs as additives showed good separation performance towards four tested drugs, including duloxetine, ketoconazole, sulconazole and citalopram. It was also observed that significantly improved separation and selectivity for tested analytes were achieved in CILs/dextrin synergistic system compared to single dextrin system. Primary parameters, such as the concentration of CIL, dextrin concentration, buffer pH and applied voltage, were systematically investigated to optimize the enantiomeric separation with BMIm+BLHvB-/dextrin as model system. Finally, the method of Statistical Product and Service Solutions (SPSS) was exploited to further elucidate the influence of experimental parameters on the synergistic effect. PMID- 30439669 TI - Yield of trihalomethane, haloacetic acid and chloral upon chlorinating algae after coagulation-filtration: Is pre-oxidation necessarily negative for disinfection by-product control? AB - Effect of pre-chlorination and pre-ozonation on Microcystis aeruginosa (MA) and Coccomyxa subellipsoidea (CS) as disinfection by-products (DBPs) precursors was investigated after coagulation-filtration. Pre-chlorination considerably decreased the autofluorescence of algae cells but barely influenced cell granularity. In comparison, after pre-ozonation more algae cells were associated with decreased cell size; yet less reduction in the autofluorescence was observed. In MA case, pre-chlorination increased the residual algae density after coagulation-filtration by 132%-146% while pre-ozonation enhanced the algae removal by 26%-28%. In CS case, algae removal was improved by pre-chlorination (32%-45%) and pre-ozonation (7%-45%). Pre-chlorination enhanced the removal of algogenic organic matters (AOM) by coagulation-filtration, especially for tryptophan-like and soluble microbial products. Effect of pre-ozonation on the fluorescence intensity of AOM after coauglation-filtration depended on AOM species and the ratio of [ozone dose]:[algae density]. In both MA and CS cases, chlorine increased the yields of trihalomethane (THM, 25%-78% and 51%-103%), haloacetic acid (HAA, 140%-360% and 167%-233%) and chloral (50%-161% and 68% 108%), respectively. Pre-ozonation decreased the total DBPs yields. For MA-added suspensions, ozone decreased the production of THM, HAA and chloral by 15%-37%, 28%-39% and 60%, respectively. In CS case, chloral yield was decreased by 12%-31% while THM formation was largely unchanged. HAA production varied by +/- 1.5 MUg/L. PMID- 30439670 TI - Effects of conjugation metabolism on radical scavenging and transport properties of quercetin - In silico study. AB - Quercetin (Q) is a natural polyphenol with high radical scavenging capacity, but low in vivo bioavailability. It is extensively transformed by host phase II metabolism and microbiota. Herein, effects of major in vitro and in vivo conjugation transformations of Q on its radical scavenging capacity and human serum albumin (HSA) binding were studied by using appropriate computational approaches, DFT (U)B3LYP/6-31 + G(d,p) and molecular docking, respectively. With regard to radical scavenging capacity of Q, conjugation transformations generally reduce its antioxidant capacity including regeneration efficiency through disproportionation of an intermediate radical species since these structural modifications occur mainly at its radical scavenging -OH groups. They were also found to alter dominant radical scavenging mechanism in a specific way dependent upon conjugation type and site. Concerning distribution by HSA, binding to this main plasma transporter protein may not be dominant transport mechanism for Q and its metabolites in vivo. Like Q aglycon, most of its metabolites are bound non specifically at multiple binding sites of HSA, with relatively weak affinities. Only sulfo-conjugates including plasma abundant isomer Q-3'-O-SO3-, were predicted to bind specifically in warfarin-like manner, but also with relatively low binding affinity. PMID- 30439671 TI - Angiographic embolization followed by piecemeal resection of giant posterior mediastinal schwannoma: Case report and concise review. AB - INTRODUCTION: Posterior mediastinal masses present unique diagnostic and therapeutic challenges, particularly when large highly vascularized tumors extend toward or emanate from the spinal cord. The rare nature of these tumors precludes the development of standardized management algorithms, underscoring the importance of case reports. PRESENTATION OF CASE: A 57 year old female presented with exertional dyspnea and right chest pressure. Chest radiography followed by computed tomography (CT) scan demonstrated a 13 cm posterior mediastinal mass involving the T7 vertebral body. CT-guided percutaneous biopsy confirmed benign schwannoma. During open exploration, the tumor bled easily with contact. Angiography with intercostal arterial embolization decreased tumor vascularity while preserving spinal cord perfusion. Subsequent piecemeal resection facilitated exposure of the tumor base and complete resection. Postoperative recovery was uneventful. DISCUSSION: Neurogenic tumors are most commonly located in the posterior mediastinum. When untreated, schwannomas continue to grow, and will inevitably cause compressive symptoms if given sufficient time. Therefore, resection is recommended. This may be performed thoracoscopically in select patients with small tumors, avoiding the morbidity of a thoracotomy incision. CONCLUSION: Large posterior mediastinal schwannomas require posterolateral thoracotomy and resection. Preoperative angiography helps identify arteries shared by the tumor and the spinal cord, and embolization may reduce tumor vascularity and operative blood loss thereby permitting safer resection. PMID- 30439672 TI - Ibrutinib and Rituximab in Waldenstrom's Macroglobulinemia. PMID- 30439673 TI - Harnessing lignin evolution for biotechnological applications. AB - Lignin evolved concomitantly with the rise of vascular plants on planet earth ~450 million years ago. Several iterations of exploiting ancestral phenylpropanoid metabolism for biopolymers occurred prior to lignin that facilitated early plants' adaptation to terrestrial environments. The first true lignin was constructed via oxidative coupling of a number of simple phenylpropanoid alcohols to form a sturdy polymer that supports long-distance water transport. This invention has directly contributed to the dominance of vascular plants in the Earth's flora, and has had a profound impact on the establishment of the rich terrestrial ecosystems as we know them today. Within vascular plants, new lignin traits continued to emerge with expanded biological functions pertinent to host fitness under complex environmental niches. Understanding the chemical and biochemical basis for lignin's evolution in diverse plants therefore offers new opportunities and tools for engineering desirable lignin traits in crops with economic significance. PMID- 30439674 TI - Recovery of 3D rib motion from dynamic chest radiography and CT data using local contrast normalization and articular motion model. AB - Dynamic chest radiography (2D x-ray video) is a low-dose and cost-effective functional imaging method with high temporal resolution. While the analysis of rib-cage motion has been shown to be effective for evaluating respiratory function, it has been limited to 2D. We aim at 3D rib-motion analysis for high temporal resolution while keeping the radiation dose at a level comparable to conventional examination. To achieve this, we developed a method for automatically recovering 3D rib motion based on 2D-3D registration of x-ray video and single-time-phase computed tomography. We introduce the following two novel components into the conventional intensity-based 2D-3D registration pipeline: (1) a rib-motion model based on a uniaxial joint to constrain the search space and (2) local contrast normalization (LCN) as a pre-process of x-ray video to improve the cost function of the optimization parameters, which is often called the landscape. The effects of each component on the registration results were quantitatively evaluated through experiments using simulated images and real patients' x-ray videos obtained in a clinical setting. The rotation-angle error of the rib and the mean projection contour distance (mPCD) were used as the error metrics. The simulation experiments indicate that the proposed uniaxial joint model improved registration accuracy. By searching the rotation axis along with the rotation angle of the ribs, the rotation-angle error and mPCD significantly decreased from 2.246 +/- 1.839 degrees and 1.148 +/- 0.743 mm to 1.495 +/- 0.993 degrees and 0.742 +/- 0.281 mm, compared to simply applying De Troyer's model. The real-image experiments with eight patients demonstrated that LCN improved the cost function space; thus, robustness in optimization resulting in an average mPCD of 1.255 +/- 0.615 mm. We demonstrated that an anatomical-knowledge based constraint and an intensity normalization, LCN, significantly improved robustness and accuracy in rib-motion reconstruction using chest x-ray video. PMID- 30439675 TI - Positivity-approach training for depressive symptoms: A randomized controlled trial. AB - OBJECTIVE: Depression is highly comorbid and depressive symptoms are very common. Symptom severity adversely affects treatment outcome and later health status. Established interventions for depression leave ample room for improvement. Short interventions that target specific vulnerabilities emerge as plausible augmentation strategies. In this study, we tested the efficacy of a computerized general positivity-approach training and its effect on depressive symptoms. METHODS: Patients (N = 240) with various diagnoses of mental disorders who received treatment-as-usual in an inpatient setting were randomly assigned to also receive either 4 sessions of a positivity-approach training or 4 sessions of sham training. Depression severity was assessed at baseline and post-treatment. Training data were analyzed for a subset of 111 patients. RESULTS: Depressive symptoms were reduced more after positivity-approach training than after sham training. Initial depression symptom severity moderated the intervention effects, such that approach tendencies and depression symptoms were only affected positively among patients with higher levels of initial depression symptom severity. CONCLUSIONS: The findings provide preliminary support for positivity approach training as an add-on treatment option for depressive symptoms. PMID- 30439676 TI - Tachyphylaxis in major depressive disorder: A review of the current state of research. AB - BACKGROUND: Patients with major depressive disorder (MDD) often experience a re emergence or worsening of symptoms despite ongoing treatment with previously effective antidepressant pharmacotherapy. This lost or reduced antidepressant response during maintenance, referred to as tachyphylaxis, negatively impacts treatment outcomes and quality of life for patients with MDD. This review assesses the prevalence of antidepressant tachyphylaxis as well as the evidence for interventions to manage it. METHODS: We searched PubMed/Medline for the relevant clinical trials and meta-analyses on antidepressant tachyphylaxis up to January 2017. Search terms included "depression" paired with "treatment" (n = 186,674), "tachyphylaxis" paired with "depression" (n = 112), "tachyphylaxis" paired with "major depressive disorder" (n = 21), and "antidepressant" paired with "tachyphylaxis" (n = 68). Studies were included if they reported on a clinical trial or meta-analysis exploring tachyphylaxis in MDD and were excluded if the sample population did not have a primary DSM diagnosis of MDD. RESULTS: Rates of tachyphylaxis varied from 9% to 57% depending on the patient population and duration of follow-up. Limited evidence suggests potentially beneficial strategies for managing tachyphylaxis, including change in antidepressant dosing, switch of class of antidepressant medication, augmentation or combination pharmacotherapy, and psychotherapy. LIMITATIONS: Studies of antidepressant tachyphylaxis are largely heterogeneous in nature and employ strict inclusion/exclusion criteria; thus, these findings may not be generalizable to all depressed populations. CONCLUSION: Few established treatment strategies exist to manage antidepressant tachyphylaxis. Further interventional research is needed to provide symptomatic relief for patients with tachyphylaxis in MDD. PMID- 30439677 TI - Prevalence of depressive symptoms among adolescents in secondary school in mainland China: A systematic review and meta-analysis. AB - BACKGROUND: The objective of the study reported here is to systematically estimate the prevalence of depressive symptoms among adolescents in secondary schools in mainland China. METHOD: Literature searches were conducted in both English and Chinese databases from database inception to January 2018. This meta analysis used a random-effects model to estimate the prevalence of depressive symptoms. RESULTS: Fifty-one eligible studies (n = 144,060) using probability sampling were identified. The results revealed a pooled prevalence of depressive symptoms of 24.3% (95% CI, 21.3%-27.6%), with high between-studies heterogeneity (Q = 9909, I2 = 99.5%, p < 0.001). The prevalence estimates reported by the individual studies ranged from 6.2% to 64.8%. There was an increased prevalence with increasing grades from year 1 in junior secondary school (24.5%; 95% CI, 17.8%-32.8%) to year 3 in senior secondary school (40.1%; 95% CI, 29.4%-51.9%) (Q = 7.1, p < 0.01). Potential sources of high heterogeneity of prevalence among studies can be accounted for by screening instruments with different cutoffs. Further analysis stratified by gender, grade, household registration (hukou) and number of children in the household were performed. LIMITATIONS: Limitations include the high level of heterogeneity between studies (mainly from the heterogeneity of measurement tools) and stringent inclusion and exclusion criteria. CONCLUSIONS: This study suggests that depressive symptoms are common among Chinese secondary school students. Further research is needed to identify the risk factors and effective strategies for preventing and treating depression among adolescents in secondary schools. PMID- 30439678 TI - Validation of the University of California San Diego Performance-based Skills Assessment (UPSA) in major depressive disorder: Replication and extension of initial findings. AB - BACKGROUND: The University of California San Diego Performance-based Skills Assessment (UPSA) has been validated as a functional measure in patients with major depressive disorder (MDD). The study herein aims to both replicate and extend the initial validation incorporating data sets from two additional studies. METHODS: NCT02279966 and NCT02272517 were multinational, double-blind, placebo-controlled studies in adult outpatients with moderate-to-severe MDD and a current major depressive episode of >=3 months and less than 1 year, respectively. Subjects were randomized to vortioxetine (10 or 20 mg), placebo or active reference drug (paroxetine [20 mg], or escitalopram [10 or 20 mg]) for 8 weeks. Pearson correlation coefficients were estimated for baseline UPSA-Brief (UPSA-B), demographic/disease characteristics, Montgomery-Asberg Depression Rating Scale (MADRS), Perceived Deficit Questionnaire-20 items (PDQ-20), and Digit Symbol Substitution Test (DSST), to examine construct validity. Distribution- and anchor-based methods examined clinically important difference (CID) threshold. A pooled analysis with data from NCT01564862 (initial validation study) was performed to increase the statistical power of the estimations. RESULTS: In pooled analysis of the two new studies, UPSA-B score correlated with the DSST (r = 0.32, P < 0.0001), but not the MADRS (r = -0.07, p = 0.302) or the PDQ-20 (r = -0.10, p = 0.109), replicating initial validation results. Estimated CID range was 7.1-11.2 and 5.5-6.1 points for anchor- and distribution-based methods, respectively. In pooled analyses of all three studies, the CID was 7.0 and 6.4 for anchor- and distribution-based methods, respectively. CONCLUSIONS: These results confirm the construct validity of UPSA for assessing functional capacity in patients with MDD. Estimated CID using UPSA is approximately 6-7 points. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01564862; NCT02272517; NCT02279966. PMID- 30439679 TI - Longitudinal decreases in suicidal ideation are associated with increases in salience network coherence in depressed adolescents. AB - BACKGROUND: Suicidal ideation (SI) is an important predictor of suicide attempt, yet SI is difficult to predict. Given that SI begins in adolescence when brain networks are maturing, it is important to understand associations between network functioning and changes in severity of SI. METHODS: Thirty-three depressed adolescents were administered the Columbia-Suicide Severity Rating Scale to assess SI and completed resting-state fMRI at baseline (T1) and 6 months later (T2). We computed coherence in the executive control (ECN), default mode (DMN), salience (SN), and non-relevant noise networks and then examined the association between changes in brain network coherence and changes in SI severity from T1 to T2. RESULTS: A greater reduction in severity of SI was associated with a stronger increase in SN coherence from T1 to T2. There were no associations between the other networks and SI. LIMITATIONS: We cannot generalize our findings to more psychiatrically diverse samples. More time-points are necessary to understand the trajectory of SI and SN coherence change. CONCLUSIONS: Our finding that reductions in SI are associated with increases in SN coherence extends previous cross-sectional results documenting a negative association between SI severity and SN coherence. The SN is involved in coordinating activation of ECN and DMN in response to salient information. Given this regulatory role of the SN, the association between SN coherence and SI suggests that adolescents with reduced SN coherence might more easily engage in harmful thoughts. Thus, the SN may be particularly relevant as a target for treatment applications in depressed adolescents. PMID- 30439680 TI - Age and sex differences in the effects of peer victimization on depressive symptoms: Exploring sleep problems as a mediator. AB - BACKGROUND: Peer victimization contributes to an elevated risk of adolescent depression. Although theoretical evidence has noted that peer victimization may disrupt sleep and subsequently increase levels of depressive symptoms, this pathway has never been tested. This study explores a novel mechanism leading from peer victimization to depressive symptoms through sleep problems and considers whether the direct and indirect pathways vary by age and sex of adolescents. METHODS: Data were from 4072 adolescents (2042 males, 2030 females; age range 14 19 years) residing in northern Taiwan. Mediation analyses were first conducted to understand the mediating role of sleep problems in the association between peer victimization and depressive symptoms for males and females, respectively. Moderated mediation analyses were then applied to test age differences in the direct and indirect pathways from peer victimization to depressive symptoms. RESULTS: Sleep problems mediated the association between peer victimization and depressive symptoms in adolescent females but not in males. Age further moderated the indirect pathway from peer victimization to depressive symptoms through sleep problems, such that the mediating effects of sleep problems increased with age and were only significant in older females. No age differences were observed for the direct effects of peer victimization on depressive symptoms in either males or females. LIMITATIONS: Study was not designed to infer causality and all variables were assessed by self-report measures. CONCLUSIONS: Our analyses revealed age and sex differences in the link from peer victimization to depressive symptoms through sleep problems. Efforts to reduce depressive symptoms in adolescent females who have experienced peer victimization may be made more effective by targeting sleep problems, especially in older female adolescents. PMID- 30439681 TI - The relationship of anxious and depressive symptoms in Parkinson's disease with voxel-based neuroanatomical and functional connectivity measures. AB - BACKGROUND: Anxiety and depression are two frequent comorbidities of Parkinson's disease (PD). However, the underlying neural mechanism is still unclear and the studies on their neural correlates were insufficient. METHODS: Using voxel-based neuroanatomical and functional connectivity (FC) measures, i.e. grey matter volume, fractional anisotropy, and weighted degree centrality (WD), we examined their correlations with the severity levels of anxious and depressive symptoms in 36 PD patients. RESULTS: Positive correlations were shown between anxiety and the WDs in the left amygdala, and between depression and short-ranged WDs in the left parahippocampal gyrus. Using these two regions as the seeds, we found that the severity levels of anxiety and depression were positively correlated with the FCs between the two seeds and the areas in the default mode network (DMN), while negatively correlated with the FCs between the two seeds and the prefrontal and superior temporal cortices. Anxiety was also positively correlated with the FC between the amygdala and the superior parietal lobule. LIMITATIONS: The severity levels of anxious and depressive symptoms of our participants is relatively mild than some previous studies. The cross-sectional design of this study cannot clarify the etiological relationship between PD and two comorbidities. CONCLUSIONS: Our results were in line with the key roles of the amygdala and parahippocampal gyrus in anxiety and depression, and reflected the distinct effects of the DMN, prefrontal and superior temporal cortices, and sensory-motor regions on emotional regulation. The identification of these neural substrates might assist clinical monitoring mood disturbances in PD. PMID- 30439682 TI - A preliminary framework to guide implementation of The Flipped Classroom Method in nursing education. AB - Healthcare environments have increased in complexity over the last 30 years. However, educational methods to prepare nurses have remained virtually unchanged. To prepare nurses to practice in today's complex practice environment, there are calls for change and transformation in how nursing education is implemented. This transformation requires nurse educators to shift their epistemic beliefs about teaching and learning by considering theories that promote effective learning. An innovative method being used in nursing education is the Flipped Classroom Method (FCM). The FCM is a teaching strategy that encourages critical thinking and application of knowledge obtained outside of the classroom to real-world situations and problems within the classroom. This paper presents a preliminary framework synthesized from multiple theories including andragogy, constructivism, self-efficacy, and diffusion of innovations. The purpose of this preliminary framework is to support the nurse educator's reflections about the learner, their abilities to implement the FCM and to synthesize theoretical constructs to implement the FCM. PMID- 30439683 TI - Influence of biological maturity on static and dynamic postural control among male youth soccer players. AB - BACKGROUND: Peak height velocity has been reported to be associated with the phenomenon of adolescent awkwardness, a temporary disruption in motor skills, and an increase in injuries in some adolescents. To date, it is not entirely clear which motor abilities are deficient during the phase of rapid growth. RESEARCH QUESTION: We hypothesized that static as well as dynamic postural control is influenced by biological maturation. METHODS: The study was conducted in a prospective, cross-sectional design. Maturity offset, a somatic indicator for biological maturation was captured for n = 99 male soccer players (13.7 +/- 0.5 years). Static and dynamic balance were assessed by the Balance Error Scoring System (BESS) and the Y-Balance Test (YBT), respectively. Influences of biological maturation on balance performances have been analyzed by linear mixed models. RESULTS: Linear mixed model analyses revealed that biological maturation is significantly associated with the total BESS score (p = 0.022, b = 2.195) as well as the YBT anterior (right leg: p = 0.023, b = -0.022; left leg: p = 0.015, b = -0.024) and posteromedial reach directions (left leg: p = 0.02, b = -0.029). No significant associations were found for the other YBT distances. SIGNIFICANCE: Based on our results, maturation seems to have a considerable influence on postural control. It might be that deficits in balance performance contribute to the phenomenon of adolescent awkwardness and therefore lead to an increased injury risk during the adolescent growth spurt. To possibly prevent injuries in youth soccer, biological maturation should be taken into consideration in youth sport coaching. PMID- 30439684 TI - Effects of upper body strength, hand placement and foot placement on ladder fall severity. AB - BACKGROUND: A plurality of fatal falls to lower levels involve ladders. After a slip/misstep on a ladder, climbers use their upper and lower limbs to reestablish contact with the ladder. RESEARCH QUESTION: This study investigates the impact of upper body strength, hand placement and foot placement on fall severity after a ladder climbing perturbation. METHODS: Participants performed upper body strength tests (breakaway and grip strength) and climbed a vertical, fixed ladder while a misstep perturbation was applied under the foot. After the perturbation, three hand placement and two foot placement responses were generally observed. Common hand placement responses included the hand moving two rungs, one rung, or did not move to a different rung. Foot placement responses included at least one foot or no feet reestablished contact with the ladder rung(s). Fall severity was quantified by the peak harness force observed after the perturbation. RESULTS: Increased strength, reestablishing at least one foot on the ladder, and ascending (compared with descending) the ladder was associated with a reduction in fall severity. An interaction effect indicated that the impact of hand placement was altered by climbing direction. Moving the hand one rung during ascent and moving the hand two rungs during descent was associated with an increased fall severity. Cases where the hand decoupled from the ladder was associated with higher fall severity. Upper body strength assessed using a portable grip dynamometer was sufficient to predict fall severity. DISCUSSION: This study confirms the multifactor role of upper body strength, hand placement and foot placement in preventing falls from ladders. Furthermore, a portable dynamometer shows potential to screen for high-risk individuals. Results of this investigation may guide targeted interventions to prevent falls from ladders. PMID- 30439685 TI - Colonization of the mammalian intestinal tract by enterococci. AB - Enterococci are colonizers of the mammalian gastrointestinal tract (GIT) and normally live in healthy association with their human host. However, enterococci are also major causes of healthcare-acquired infections, prompting the US Centers for Disease Control and Prevention to declare vancomycin-resistant enterococci (VRE) a serious threat to public health. Because of both intrinsic and acquired antibiotic resistance, enterococci proliferate in the GIT during antibiotic therapy, leading to dissemination and disease. The recognition that colonization of the GIT is a pre-requisite for enterococcal infections has prompted research to study mechanisms used by enterococci to colonize this niche. This review discusses major findings of recent research to understand GIT colonization by enterococci using diverse experimental models, each of which exhibits unique strengths. This work has revealed enterococcal transcriptional reprogramming in the GIT, contributions of specific enterococcal genes encoded by the core genome to GIT colonization, the impact of genome plasticity, and roles for intra-species and inter-species interactions in modulation of GIT colonization. PMID- 30439687 TI - Recycling rainwater by submerged gravity-driven membrane (GDM) reactors: Effect of hydraulic retention time and periodic backwash. AB - Rainwater recycling has been considered as an alternative cost-effective decentralized water supply. The low cost and effective gravity-driven membrane (GDM) filtration technology has been introduced to treat the rainwater prior use. In this study, we investigated the effects of hydraulic retention time (HRT; 27 h, 51 h, and 156 h) and periodic backwash durations (2 min, 5 min, 10 min, and 30 min per 2-3 days' filtration) on the permeate quality, flux and fouling mechanism in lab-scale submerged GDM reactors. Compared to the performance at HRT of 51 h (40% of DOC removal and ~2.9 L/m2 h), better permeate quality and higher membrane flux were achieved at HRT of 27 h (51% of DOC removal and ~4.2 L/m2 h) and 156 h (48% of DOC removal and ~5.0 L/m2 h). Although the hydraulically reversible resistance was predominant (up to 90% of the total fouling resistance), the permeate flux could not be fully recovered by periodic backwash, regardless of the backwash durations. After several filtration-backwash cycles, the stabilized flux of GDM reactor with backwash was even worse than those without backwash. However, no correlation can be established between the stabilized flux (i.e., cake layer resistance) and the soluble organics and microbial cells in the cake layer of the GDM system during rainwater treatment. PMID- 30439686 TI - Enhanced mitochondrial pyruvate transport elicits a robust ROS production to sensitize the antitumor efficacy of interferon-gamma in colon cancer. AB - Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-gamma (IFNgamma) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFNgamma by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFNgamma in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-gamma against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFNgamma mediated antitumor immunity that have implications for targeting a unique aspect of this disease. PMID- 30439688 TI - The role of hardpan formation on the reactivity of sulfidic mine tailings: A case study at Joutel mine (Quebec). AB - The former Eagle and Telbel mine site (hereafter referred to as Joutel mine), located near the town of Joutel in the Nord-du-Quebec (Canada) houses a tailings storage facility (TSF) that has been inactive since 1996. Fresh, unweathered tailings (beneath 10-30 cm of oxidized horizon) are characterized by an average sulfide content of 6-7 wt% and an average Fe-Mn-carbonate content of 20-40 wt%. The oxidation of Joutel's tailings under atmospheric conditions resulted in the precipitation of secondary phases such as ferric oxyhydroxides and gypsum. Accumulation of these secondary phases throughout the TSF caused cementation and agglomeration of grains, which decreased the porosity of the material in a horizon below the surface. This horizon, which is referred to as hardpan, is frequently encountered within fine, reactive tailings. Characterizations showed that hardpans have a highly compact texture. The formation of hardpans limits vertical water infiltration and oxygen diffusion and these layers greatly affect the global geochemical behavior of underlying tailings in the Joutel TSF by protecting the unweathered material from oxidation. As a result, the water quality of the TSF is largely controlled by the reactivity of the upper oxidized tailings horizon. Joutel's oxidized tailings showed an acidic behavior early during laboratory kinetic leaching tests despite the near absence of sulfides and neutralizing minerals. However, when unweathered tailings were added under oxidized tailings, the water became neutral and metal leaching rates were reduced. After over a year of laboratory leaching tests, hardpans formed within the columns and the natural phenomenon was reproduced under laboratory conditions. PMID- 30439689 TI - Aquatic ecotoxicity of an antidepressant, sertraline hydrochloride, on microbial communities. AB - Sertraline hydrochloride (Ser-HCl), a widely used antidepressant, becomes an aquatic contaminant via metabolic excretion and improper disposal; however, it is unknown how Ser-HCl affects aquatic microbial communities. The present study investigated the effects of Ser on the structures of aquatic microbial communities via high-throughput sequencing analyses. Ser-HCl treatment inhibited the growth of two model algae (the green alga, Chlorella vulgaris, and the cyanobacterium, Microcystis aeruginosa) and decreased the chlorophyll a (Chl-a) concentration in the microcosm to reduce the photosynthetic efficiency. High throughput sequencing analyses showed that exposure to Ser-HCl disturbed the balance of cyanobacteria species by stimulating the growth of specific cyanobacteria. Among eukaryotes, the richness as well as the diversity indices were significantly enhanced after 5 days of Ser-HCl treatment but sharply decreased with exposure time. Nucleariida occupied an absolute majority (97.83%) within the eukaryotes, implicating that Ser-HCl disturbed the ecological equilibrium in microcosms. Ser-HCl will continue to be an environmental contaminant due to its wide usage and production. Our current study clarified the potential ecological risk of Ser-HCl to aquatic microorganisms. These findings suggest that more attention should be given to the negative effects of these bioactive pollutants on aquatic environments. PMID- 30439690 TI - A national case-crossover study on ambient ozone pollution and first-ever stroke among Chinese adults: Interpreting a weak association via differential susceptibility. AB - Evidence suggesting an association between ozone exposure and stroke risk remains inconsistent; variations in the distributions of susceptibilities of the study populations may explain some of it. We examined the hypothesis in a general Chinese population. During 2013-2015, 1356 first-ever stroke events were selected from a large representative sample, the China National Stroke Screening Survey (CNSSS) database; daily maximal 8-hour ozone concentrations were obtained from spatiotemporally interpolated estimates of in-situ observations over China. We conducted a time-stratified case-crossover design to assess associations between stroke risk and ambient ozone exposure. Next, potential effect modifiers were identified using interaction analyses. Final, a well-established approach was applied to estimate individual-level susceptibility (i.e., the individual specific effect given a certain combination of multiple effect-modifiers) and its probability distribution among all the CNSSS participants (n = 1,292,010). With adjustments for temperature, relative humidity and ambient fine particulate matter exposure, a 10-MUg/m3 increment in mean ozone levels 2-3 day prior to symptom onset was associated with a 3.0% change in stroke risk (95% confidence interval: -1.2%, 7.3%). This association was statistically significantly enhanced by male gender, rural residence and low vegetable and fruit consumption. The subgroup results suggested that a fraction of the population might be considerably affected by ozone, regardless of the insignificant association in average level. The analysis of susceptibility distribution further indicated that the ozone-stroke association was statistically significantly positive in 14% of the general population. Susceptibility to ozone-related stroke significantly varied among Chinese adults. Characterizing individual-level susceptibility reveals the complexity underlying the weak average effect of ozone, and supports to plan subpopulation-specific interventions to mitigate the stroke risk. PMID- 30439691 TI - Predictive models for adsorption of organic compounds by Graphene nanosheets: comparison with carbon nanotubes. AB - The Linear Solvation Energy Relationships (LSER) technique was applied in the present study for predicting models of organic compounds (OCs) adsorption by Graphene and Graphene oxide (GO), and the results were compared with those of multi-walled carbon nanotube (MWCNT) and single-walled carbon nanotube (SWCNT). Adsorption database of 38 OCs (28 aromatic and 10 aliphatic) for Graphene and 69 OCs (59 aromatic and 10 aliphatic) for GO were collected from the literature and our laboratory. The r2 of the LSER models on the adsorption of aromatic OCs by Graphene and GO at three different equilibrium concentrations gradually increased up to OC molecular weight of 400 g/mol, after which a declining trend was observed for GO, while there was no visible change for Graphene. Among descriptors for all LSER models, V (molecular volume) and B (hydrogen bond accepting) for Graphene nanosheets (GNS) and carbon nanotubes (CNT) were the most significant descriptors (p values <= 0.05). B term had high value and was negatively correlated with adsorption of all OCs by Graphene (-1.24 to -9.45), GO (-0.55 to -9.31), SWCNT (-0.10 to -5.38) and MWCNT (-1.24 to -1.85). LSER successfully trained models for adsorption of OCs by GNS, and model coefficients were dependent on adsorbent type and OC properties. PMID- 30439692 TI - Nickel speciation of spent electroless nickel plating effluent along the typical sequential treatment scheme. AB - The electroless nickel (EN) industry has suffered from the reduction in Ni concentration to lower than 0.1 mg/L. Hence, Ni speciation along a typical sequential treatment scheme has important implications to optimize the design of advanced treatment. For the first time, we revealed the Ni speciation in segmented EN outfall effluents by virtue of multiple analytical methods. After ensuring all the Ni-bearing complexes were completely dissolved by size fractioned ultrafiltration trials, customized mass spectra analysis was conducted. In a series of ICP-MS assays, the potential polyatomic interfering species was primarily excluded. The chromatography hyphenated IC-ICP-MS and SEC ICP-MS results demonstrated that the dominant Ni species in the EN effluents was similar to EDTA-Ni but with a smaller size. The LC-MS experiment further distinguished several typical Ni-bearing complexes. Although Ni concentration declined continuously along the treatment scheme, the number of detected Ni bearing complexes gradually increased but with lower molecular weights. Most of the detected mononuclear complexes had higher indexes of hydrogen deficiency (IHD) than EDTA-Ni, whereas it was believed that the similar stereo ring shape was widespread in the EN effluent. Considering the efficient Ni decrease after the Fenton unit, further post-treatment approaches featuring higher active radical yields were suggested. PMID- 30439693 TI - The background context matters: Local-scale socioeconomic conditions and the spatial distribution of wildfires in Italy. AB - Wildfires, a key socio-environmental challenge in Mediterranean regions, are influenced by anthropogenic factors shaping land-use and socioeconomic spatial structures. By assuming that the dominant socioeconomic structure of local districts exerts a variable impact on wildfire spatial regimes, the present study investigates 174 indicators on a municipal scale in Italy, identifying a multidimensional relationship between wildfire characteristics and socioeconomic contexts. An exploratory statistical approach was adopted to identify linear and non-linear relationships among variables assessing socioeconomic contexts and wildfire patterns. Empirical results demonstrate that characteristic wildfire attributes (frequency, intensity and severity) are systematically higher in socioeconomic contexts characterized by rural poverty, unemployment and deregulated urban expansion, especially in southern Italy. A higher fire frequency was typically observed in (i) peri-urban districts with a dynamic socio demographic profile and (ii) in rural districts with intensive cropping systems. Joint information on socioeconomic structure/dynamics and environmental change, is crucial for a better understanding of local-scale spatial patterns of wildfires in the Mediterranean region. Integrated socio-environmental information provides a better understanding of the local communities' role in the management of wildfire-prone land, contributing to implement more effective strategies aimed at minimizing wildfire impact on land resources. PMID- 30439694 TI - The future of European water management: Demonstration of a new WFD compliant framework to support sustainable management under multiple stress. AB - The Water Framework Directive (WFD), which is the most comprehensive instrument of EU water policy, is more relevant than ever. Sixty percent of Europe's surface water bodies still fail to achieve good ecological status and a multitude of new stressors continue to emerge. A sustained and wholehearted water management effort is therefore of highest priority. Here, we present a new biological assessment approach specifically designed to safeguard sustainable water management under multiple stress. The framework contains three independent elements: 1) an ecological assessment system based on community abundance and composition to quantify ecological status; 2) a diagnostic tool to identify cause(s) of ecological degradation; 3) a management platform to guide the choice of relevant mitigation measures for improvement of the ecological status. The proposed framework is fully compliant with the WFD and currently applied in the assessment of aquatic plant communities in Danish streams. Importantly, the approach presented is not restricted to specific taxonomic groups or ecosystem types but is an example of how a simple approach can bring the conceptual idea of the WFD - that community characteristics in unimpacted, type-specific water bodies should be the backbone in ecological assessments - into practice. PMID- 30439695 TI - Thiamethoxam: Long-term effects following honey bee colony-level exposure and implications for risk assessment. AB - Neonicotinoid insecticides have been used in a wide range of crops through seed treatment, soil and foliar applications and a large database exists on both their lethal and sub-lethal effects on honey bees under controlled laboratory conditions. However, colony-level studies on the effects of neonicotinoids in field studies are limited, primarily due to their complexity and the resources required. This paper reports the combined results of two large-scale colony feeding studies, each with 6 weeks of continuous dosing of 12 colonies per treatment (24 control) to 12.5, 25, 37.5, 50 or 100 ng thiamethoxam/g sucrose solution. Exposure continued beyond dosing with residues present in stored nectar and bee-bread. The studies were conducted in an area with limited alternative forage and colonies were required to forage for pollen and additional nectar The studies provide colony-level endpoints: significant effects (reductions in bees, brood) were observed after exposure to the two highest dose rates, colony loss occurred at the highest dose rate, but colonies were able to recover (2-3 brood cycles after the end of dosing) after dosing with 50 ng thiamethoxam/g sucrose. No significant colony-level effects were observed at lower dose rates. The data reported here support the conclusions of previous colony-level crop-based field studies with thiamethoxam, in which residues in pollen and nectar were an order of magnitude below the colony-level NOEC of 37.5 ng thiamethoxam/g sucrose. The feeding study data are also compared to the outcomes of regulatory Tier 1 risk assessments conducted using guidance provided by the USA, Canada, Brazil and the EU regulatory authorities. We propose an adaptation of the European chronic adult bee risk assessment that takes into account the full dataset generated in laboratory studies while still providing an order of magnitude of safety compared with the colony feeding study NOEC. PMID- 30439696 TI - Joint optimization of water allocation and water quality management in Haihe River basin. AB - A hydroeconomic optimization modelling framework for joint water allocation and water quality management is presented in this study. Water resources planning is often limited to water quantity, even though water quantity and quality are interdependent. Including water quality in a hydroeconomic optimization model increases complexity and uncertainty. In this study, the problem is addressed with a multi-reservoir, multi-temporal, multi-objective linear optimization model with fixed but spatially variable water quality. Model complexity is kept at a manageable level, leading to limited demand for computational resources, despite a high spatial resolution and representation of both surface water and groundwater resources. The model is applied to Haihe River basin, a water-scarce and highly polluted river basin in China. Economic trade-offs between limiting groundwater overdraft and sub-basin specific costs as well as maps of water availability shadow prices are presented. Adding water quality to the model framework impacts water availability shadow prices, which can influence model based decision support. If groundwater abstractions are limited to sustainable levels, Haihe River basin will benefit from increasing inter-basins transfers and groundwater recharge to the shallow plain area aquifer. A scenario analysis showed that managed aquifer recharge in the plain area is also a feasible adaptation strategy. PMID- 30439698 TI - Allogenic Stem Cell Transplantation and the Subsequent Paraproteinemia: A Benign Altered B-Cell Homeostasis? PMID- 30439697 TI - Spatial modeling of litter and soil carbon stocks on forest land in the conterminous United States. AB - Forest ecosystems contribute substantially to carbon (C) storage. The dynamics of litter decomposition, translocation and stabilization into soil layers are essential processes in the functioning of forest ecosystems, as these processes control the cycling of soil organic matter and the accumulation and release of C to the atmosphere. Therefore, the spatial distribution of litter and soil C stocks are important in greenhouse gas estimation and reporting and inform land management decisions, policy, and climate change mitigation strategies. Here we explored the effects of spatial aggregation of climatic, biotic, topographic and soil variables on national estimates of litter and soil C stocks and characterized the spatial distribution of litter and soil C stocks in the conterminous United States (CONUS). Litter and soil variables were measured on permanent sample plots (n = 3303) from the National Forest Inventory (NFI) within the United States from 2000 to 2011. These data were used with vegetation phenology data estimated from LANDSAT imagery (30 m) and raster data describing environmental variables for the entire CONUS to predict litter and soil C stocks. The total estimated litter C stock was 2.07 +/- 0.97 Pg with an average density of 10.45 +/- 2.38 Mg ha-1, and the soil C stock at 0-20 cm depth was 14.68 +/- 3.50 Pg with an average density of 62.68 +/- 8.98 Mg ha-1. This study extends NFI data from points to pixels providing spatially explicit and continuous predictions of litter and soil C stocks on forest land in the CONUS. The approaches described illustrate the utility of harmonizing field measurements with remotely sensed data to facilitate modeling and prediction across spatial scales in support of inventory, monitoring, and reporting activities, particularly in countries with ready access to remotely sensed data but with limited observations of litter and soil variables. PMID- 30439699 TI - Inhibition of MicroRNA-124 Reduces Cardiomyocyte Apoptosis Following Myocardial Infarction via Targeting STAT3. AB - BACKGROUND/AIMS: MicroRNAs play an important role in regulating myocardial infarction (MI)-induced cardiac injury. MicroRNA-124 (miR-124) plays a vital role in regulating cellular proliferation, differentiation and apoptosis. Although the alteration of miR-124 was confirmed in peripheral blood of MI patients, little is known regarding the biological functions of miR-124 in cardiomyocytes. This study was designed to explore the role of miR-124 in MI and its underlying mechanisms. METHODS: Real-time PCR was used to quantify the microRNAs levels. TUNEL and Flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect expression of Bcl-2, Bax, Caspase-3 and STAT3 proteins. RESULTS: We revealed that miR-124 was significantly up-regulated in a mice model of MI and in neonatal rat ventricular myocytes (NRVMs) with H2O2 treatment. H2O2 treatment induced cardiomyocyte injury with reduced cell viability and enhanced apoptotic cell death, whereas silencing expression of miR-124 by AMO-124 (antisense inhibitor oligodeoxyribonucleotides) alleviated these deleterious changes. AMO-124 decreased the expression of Bax and cleaved-caspase-3 and upregulated the expression of Bcl-2 in H2O2-treated NRVMs. Besides, AMO-124 improved mitochondrial dysfunction of NRVMs induced by H2O2 treatment. Moreover, antagomir-124 markedly decreased the infarct area and apoptotic cardiomyocytes and improved cardiac function in MI mice. Furthermore, we identified STAT3 as a direct target of miR-124, and downregulation of miR-124 ameliorated the diminished levels of STAT3 and p-STAT3 (Tyr705) in response to H2O2 or MI. STAT3 inhibitor, stattic, was shown to attenuate the elevation of p-STAT3 in NRVMs with AMO-124 transfection. Inhibiting of STAT3 activity by stattic abrogated protective effects of AMO-124 on H2O2-induced cardiomyocytes apoptosis. CONCLUSION: Taken together, our data demonstrate that downregulation of miR-124 inhibits MI-induced apoptosis through upregulating STAT3, which suggests the therapeutic potential of miR-124 for myocardial infarction. PMID- 30439700 TI - Modern Information Technology for Cancer Research: What's in IT for Me? An Overview of Technologies and Approaches. AB - Information technology (IT) can enhance or change many scenarios in cancer research for the better. In this paper, we introduce several examples, starting with clinical data reuse and collaboration including data sharing in research networks. Key challenges are semantic interoperability and data access (including data privacy). We deal with gathering and analyzing genomic information, where cloud computing, uncertainties and reproducibility challenge researchers. Also, new sources for additional phenotypical data are shown in patient-reported outcome and machine learning in imaging. Last, we focus on therapy assistance, introducing tools used in molecular tumor boards and techniques for computer assisted surgery. We discuss the need for metadata to aggregate and analyze data sets reliably. We conclude with an outlook towards a learning health care system in oncology, which connects bench and bedside by employing modern IT solutions. PMID- 30439701 TI - A Novel and Cytogenetically Cryptic t(7;21)(q36.1;q22) Disrupting RUNX1 in Acute Myeloid Leukemia. AB - Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report here a novel RUNX1 partner gene, KMT2C (MLL3), in a patient with de novo acute myeloid leukemia, having a novel and cytogenetically cryptic t(7;21)(q36.1;q22) leading to disruption of RUNX1 and KMT2C. This is the third cryptic RUNX1 rearrangement in myeloid and the fourth in hematologic malignancies. PMID- 30439702 TI - Long Non-Coding RNA MALAT1 Protects Human Osteoblasts from Dexamethasone-Induced Injury via Activation of PPM1E-AMPK Signaling. AB - BACKGROUND/AIMS: Dexamethasone (Dex) induces injuries to human osteoblasts. In this study, we tested the potential role of the long non-coding RNA metastasis associated lung adenocarcinoma transcript 1 (Lnc-MALAT1) in this process. MATERIALS: Two established human osteoblastic cell lines (OB-6 and hFOB1.19) and primary human osteoblasts were treated with Dex. Lnc-MALAT1 expression was analyzed by quantitative real-time polymerase chain reaction assay. Cell viability, apoptosis, and death were tested by the MTT assay, histone-DNA assay, and trypan blue staining assay, respectively. AMP-activated protein kinase (AMPK) signaling was evaluated by western blotting and AMPK activity assay. RESULTS: Lnc MALAT1 expression was downregulated by Dex treatment in the established osteoblastic cell lines (OB-6 and hFOB1.19) and primary human osteoblasts. The level of Lnc-MALAT1 was decreased in the necrotic femoral head tissues of Dex administered patients. In osteoblastic cells and primary human osteoblasts, forced overexpression of Lnc-MALAT1 using a lentiviral vector (LV-MALAT1) inhibited Dex-induced cell viability reduction, cell death, and apoptosis. Conversely, transfection with Lnc-MALAT1 small interfering RNA aggravated Dex induced cytotoxicity. Transfection with LV-MALAT1 downregulated Ppm1e (protein phosphatase, Mg2+/ Mn2+-dependent 1e) expression to activate AMPK signaling. Treatment of osteoblasts with AMPKalpha1 short hairpin RNA or dominant negative mutation (T172A) abolished LV-MALAT1-induced protection against Dex-induced cytotoxicity. Furthermore, LV-MALAT1 induced an increase in nicotinamide adenine dinucleotide phosphate activity and activation of Nrf2 signaling. Dex-induced reactive oxygen species production was significantly attenuated by LV-MALAT1 transfection in osteoblastic cells and primary osteoblasts. CONCLUSION: Lnc MALAT1 protects human osteoblasts from Dex-induced injuries, possibly via activation of Ppm1e-AMPK signaling. PMID- 30439704 TI - Multiple Congenital Anomalies and Global Developmental Delay in a Patient with Interstitial 6q25.2q26 Deletion: A Diagnostic Odyssey. AB - Interstitial deletions involving 6q25 are rare chromosomal abnormalities associated with distinctive phenotypic features. We describe a 9-year-old boy who was followed from his infancy due to his multiple congenital anomalies and complex medical history. Over the years, a number of diagnoses were considered including Cornelia de Lange syndrome, Rubinstein-Taybi syndrome, as well as "a novel genetic disorder." Various genetic tests, including a BAC-based array-CGH analysis, were reported as normal. Recently, a SNP-based microarray analysis was performed and showed an 11.1-Mb deletion from 6q25.2 to 6q26, including ARID1B and ZDHHC14. Recent literature suggests that the 6q25 deletion syndrome is a recognizable entity characterized by growth delay, developmental disabilities, microcephaly, hearing loss, and variable other malformations including cleft palate. These features overlap with those of Coffin-Siris syndrome, which is caused by deletions and loss-of-function mutations of ARID1B. Retrospectively, this patient has features resembling both Coffin-Siris and 6q25 microdeletion syndromes. PMID- 30439703 TI - Calcium Supplementation Enhanced Adipogenesis and Improved Glucose Homeostasis Through Activation of Camkii and PI3K/Akt Signaling Pathway in Porcine Bone Marrow Mesenchymal Stem Cells (pBMSCs) and Mice Fed High Fat Diet (HFD). AB - BACKGROUND/AIMS: It has been implicated that calcium supplementation is involved in reducing body weight/fat and improving glucose homeostasis. However, the underlying mechanisms are still not fully understood. Here, we investigated the effects of calcium supplementation on adipogenesis and glucose homeostasis in porcine bone marrow mesenchymal stem cells (pBMSCs) and high fat diet (HFD)-fed mice and explored the involved signaling pathways. METHODS: In vitro, pBMSCs were treated with 4 mM extracellular calcium ([Ca2+]o) and/or 1 MUM nifedipine, 0.1 MUM BAPTA-AM, 1 MUM KN-93, 50 nM wortmannin for 10 days. The intracellular calcium ([Ca2+]i) levels were measured using Fluo 3-AM by flow cytometry. The adipogenic differentiation of pBMSCs was determined by Oil Red-O staining and triglyceride assay. The expression of marker genes involved in adipogenesis (peroxisome proliferator activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein alpha (C/EBPalpha)) and glucose uptake (glucose transporter 4 (GLUT4)), as well as the activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and PI3K/Akt-FoxO1/AS160 signaling pathways were determined by Western blotting. Glucose uptake and utilization were examined using 2-NBDG assay and glucose content assay, respectively. In vivo, C57BL/6J male mice were fed a HFD (containing 1.2% calcium) without or with 0.6% (w/w) calcium chloride in drinking water for 13 weeks. The adipogenesis, glucose homeostasis and the involvement of CaMKII and PI3K/Akt signaling pathway were also assessed. RESULTS: In vitro, [Ca2+]o stimulated pBMSCs adipogenesis by increasing [Ca2+]i level and activating CaMKII and PI3K/Akt-FoxO1 pathways. In addition, [Ca2+]o promoted glucose uptake/utilization by enhancing AS160 phosphorylation, GLUT4 expression and translocation. However, the stimulating effects of [Ca2+]o on pBMSCs adipogenesis and glucose uptake/utilization were abolished by L-VGCC blocker Nifedipine, [Ca2+]i chelator BAPTA-AM, CaMKII inhibitor KN-93, or PI3K inhibitor Wortmannin. In vivo, calcium supplementation decreased body weight and fat content, increased adipocyte number, and improved glucose homeostasis, with elevated PPARgamma and GLUT4 expression and PI3K/Akt activation in iWAT. CONCLUSION: calcium supplementation enhanced adipogenesis and glucose uptake in pBMSCs, which was coincident with the increased adipocyte number and improved glucose homeostasis in HFD-fed mice, and was associated with activation of CaMKII and PI3K/Akt-FoxO1/AS160 pathways. These data provided a broader understanding of the mechanisms underlying calcium-induced body weight/fat loss and glycemic control. PMID- 30439705 TI - Novel Protective Effects of Cistanche Tubulosa Extract Against Low-Luminance Blue Light-Induced Degenerative Retinopathy. AB - BACKGROUND/AIMS: Blue light-emitting diode light (BLL)-induced phototoxicity plays an important role in ocular diseases and causes retinal degeneration and apoptosis in human retinal pigment epithelial (RPE) cells. Cistanche tubulosa extract (CTE) is a traditional Chinese medicine with many beneficial protective properties; however, few studies have examined the ocular protective roles of CTE. In this study, we investigated the mechanisms underlying the effects of CTE on BLL-induced apoptosis in vitro and in vivo. METHODS: RPE cells were applied in the current in vitro study and cell viability was determined by an 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis-related protein expression was determined by western blot analysis and immunofluorescence staining. Brown Norway rats were used to examine exposure to commercially available BLL in vivo. Hematoxylin and eosin staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and western blot assays were used to examine retinal morphological deformation. RESULTS: CTE significantly inhibited hydrogen peroxide-, tert-butyl hydroperoxide-, sodium azide-, and BLL-induced RPE damage. Further, CTE reduced the expression of apoptotic markers such as cleaved caspase-3 and TUNEL staining after BLL exposure by inactivating apoptotic pathways, as shown via immunofluorescent staining. In addition, CTE inhibited the BLL-induced phosphorylation of c-Jun N-terminal kinase, extra signal-related kinases 1/2, and p38 in RPE cells. In vivo, the oral administration of CTE rescued 60-day periodic BLL exposure-induced decrements in retinal thickness and reduced the number of TUNEL-positive cells in the brown Norway rat model. CONCLUSION: CTE is a potential prophylactic agent against BLL-induced phototoxicity. PMID- 30439706 TI - The State of Nutrigenomic Education in Poland. AB - BACKGROUND: In Poland, 45 higher education institutions offer degrees in dietetics. However, only 20 of these offer nutrigenomics or nutrigenetics courses. OBJECTIVES: The purpose of this study was to assess the current state of nutri-genomic education in Poland and to evaluate the level of nutrigenomic knowledge held by dieticians. METHODS: A cross-sectional survey was performed to examine the self-reported attitudes of 193 dietetics students and dietetics professionals who graduated from 33 Polish higher-level institutions. RESULTS: The great majority of respondents were familiar with nutrigenomics and had a positive attitude to it, and this attitude was independent of whether they participated in nutrigenomics courses. Sixty-six percent of the respondents had received training in nutrigenomics, but nutrigenomic education did not meet the expectations of 57% of dieticians. Dieticians possess low levels of self-reported knowledge of nutrigenomics, and only about 15% of respondents know how to effectively communicate information on genetic risk to patients and understand the effect of nutrients on molecular mechanisms. Despite this lack of knowledge, 59% of respondents had a positive attitude to nutri-genomics, and 63% of them had a great interest in broadening their knowledge. Subjects who had participated in nutrigenomics courses exhibited a better understanding of several areas of nutrigenomics. They were especially interested in practical aspects of nutrigenomics, such as the essence of personalized diets and the practical application of nutrigenomics. CONCLUSIONS: In conclusion, Polish dieticians have a positive attitude to nutrigenomics but do not perceive themselves as well educated in this field, which is partly due to systemic problems. The study shows the need for improvements in nutrigenomic education in Poland. PMID- 30439707 TI - Recovery of miR-139-5p in Ovarian Cancer Reverses Cisplatin Resistance by Targeting C-Jun. AB - BACKGROUND/AIMS: In platinum-based chemotherapy for ovarian cancer, acquired drug resistance is a frequent occurrence. Because recent studies have demonstrated that dysregulation of microRNAs (miRNAs) is partly responsible for the induction of acquired drug resistance in cancers, we hypothesized that correcting the dysregulation of key miRNAs would reverse the acquired resistance to platinum based drugs in ovarian cancer. METHODS: Cisplatin-resistant SKOV3 and A2780 ovarian cancer cell lines (SKOV3-R and A2780-R, respectively) were established by long-term exposure to cisplatin. MTT assays were performed to evaluate the viability of SKOV3, SKOV3-R, A2780, and A2780-R cells. Quantitative PCR was used to examine the expression of miR-139-5p in these cell lines. The regulatory mechanism was confirmed by western blot analysis and luciferase reporter assays. After treatment with miR-139-5p and cisplatin, mitochondrial membrane potential and apoptosis were measured by using flow cytometry. Interaction with c-Jun and activating transcription factor 2 (ATF2) was evaluated by co-immunoprecipitation. Expression of B-cell lymphoma-extra large (Bcl-xl) and activation of caspase-9 and caspase-3 were detected by western blotting. RESULTS: Expression of miR-139 5p was decreased in SKOV3-R and A2780-R cells. Recovery of miR-139-5p increased the sensitivity of SKOV3-R and A2780-R cells to cisplatin treatment, inhibited the interaction of c-Jun and ATF2, and decreased Bcl-xl expression in SKOV3-R and A2780-R cells. Expression of miR-139-5p promoted cisplatin-induced mitochondrial apoptosis through binding the 3' untranslated region of c-Jun mRNA. CONCLUSION: Recovery of miR-139-5p suppressed the expression of c-Jun and thus reversed cisplatin-resistance in ovarian cancer. PMID- 30439708 TI - Working Memory Function in Children with Single Side Deafness Using a Bone Anchored Hearing Implant: A Case-Control Study. AB - The importance of a good hearing function to preserve memory and cognitive abilities has been shown in the adult population, but studies on the pediatric population are currently lacking. This study aims at evaluating the effects of a bone-anchored hearing implant (BAHI) on speech perception, speech processing, and memory abilities in children with single side deafness (SSD). We enrolled n = 25 children with SSD and assessed them prior to BAHI implantation, and at 1-month and 3-month follow-ups after BAHI implantation using tests of perception in silence and perception in phonemic confusion, dictation in silence and noise, and working memory and short-term memory function in conditions of silence and noise. We also enrolled and evaluated n = 15 children with normal hearing. We found a statistically significant difference in performance between healthy children and children with SSD before BAHI implantation in the scores of all tests. After 3 months from BAHI implantation, the per-formance of children with SSD was comparable to that of healthy subjects as assessed by tests of speech perception, working memory, and short-term memory function in silence condition, while differences persisted in the scores of the dictation test (both in silence and noise conditions) and of the working memory function test in noise condition. Our data suggest that in children with SSD BAHI improves speech perception and memory. Speech rehabilitation may be necessary to further improve speech processing. PMID- 30439709 TI - The Onset of Monoclonal and Oligoclonal Gammopathies Is a Good Prognostic Factor after Allogeneic Stem Cell Transplantation. PMID- 30439710 TI - Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease. AB - Neurologic complications of allogeneic hematopoietic cell transplantation (allo HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient's condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD. PMID- 30439711 TI - Increased KIF15 Expression Predicts a Poor Prognosis in Patients with Lung Adenocarcinoma. AB - BACKGROUND/AIMS: Lung cancer is the leading cause of cancer-related deaths worldwide. The outcome of patients with non-small cell lung cancer remains poor; the 5-year survival rate for stage IV non-small cell lung cancer is only 1.0%. KIF15 is a tetrameric kinesin spindle motor that has been investigated for its regulation of mitosis. While the roles of kinesin motor proteins in the regulation of mitosis and their potentials as therapeutic targets in pancreatic cancer have been described previously, the role of KIF15 in lung cancer development remains unknown. METHODS: Paired lung carcinoma specimens and matched adjacent normal tissues were used for protein analysis. Clinical data were obtained from medical records. We first examined KIF15 messenger RNA expression in The Cancer Genome Atlas database, and then determined KIF15 protein levels using immunohistochemistry and western blotting. Differences between the groups were analyzed using repeated measures analysis of variance. Overall survival was analyzed using the Kaplan-Meier method. Cell-cycle and proliferation assays were conducted using A549, NCI-H1299, and NCI-H226 cells. RESULTS: KIF15 was significantly upregulated at both the messenger RNA and protein levels in human lung tumor tissues. In patients with lung adenocarcinoma, KIF15 expression was positively associated with disease stages; high KIF15 expression predicted a poor prognosis. KIF15 knockdown using short hairpin RNA in two human lung adenocarcinoma cell lines induced G1/S phase cell cycle arrest and inhibited cell growth, but there was no effect in human lung squamous cell carcinoma. CONCLUSION: Our findings show that KIF15 is involved in lung cancer carcinogenesis. KIF15 could therefore serve as a specific prognostic marker for patients with lung adenocarcinoma. PMID- 30439712 TI - Visual Analogue Scales as a Tool for Initial Assessment of Tinnitus Severity: Psychometric Evaluation in a Clinical Population. AB - The aim of this study was to evaluate the psychometric properties of patient reported visual analogue scale (VAS) ratings. All of the participants (100 Polish speaking adults) completed a Tinnitus Functional Index (TFI) once and a 4 component VAS twice over a period of 3 days. Spearman's correlation coefficients between the VAS score and global TFI ranged from rho = 0.52 for VAS-coping (VAS C) to rho = 0.81 for VAS-annoyance (VAS-A). Using the Bland-Altman method, the agreement ranged from 93% for VAS-A to 96% for VAS-distress (VAS-D). Interclass correlation coefficients ranged from 0.67 for VAS-C to 0.90 for VAS-A. The VAS cutoff points representing significant tinnitus severity ranged from 45 points for VAS-C to 66 points for VAS-D. VAS scales are a valid and reliable brief screening tool for obtaining quick information about tinnitus. PMID- 30439713 TI - MicroRNA-24-3p Attenuates Myocardial Ischemia/Reperfusion Injury by Suppressing RIPK1 Expression in Mice. AB - BACKGROUND/AIMS: This study was developed to investigate a potential therapeutic method for myocardial ischemia/reperfusion injury involving the promotion of miR 24-3p expression. METHODS: Microarray analysis was used to screen differentially expressed genes in a myocardial ischemia/reperfusion (I/R) injury mouse model. Gene set enrichment analysis was utilized to determine vital signaling pathways. Targeting verification was conducted with a luciferase reporter assay. Myocardial I/R injury was developed in mice, and the expression levels of RIPK1 and miR-24 3p were investigated by qRT-PCR and Western blot. Hemodynamic parameters and the activity of serum myocardial enzymes were measured to evaluate cardiac function. Infarct area was observed through HE and TTC staining. Myocardial cell apoptosis was examined by TUNEL staining and caspase-3 activity analysis. RESULTS: RIPK1 was an upregulated mRNA found by microarray analysis and a verified target of the downregulated miRNA miR-24-3p. The upregulation of RIPK1 (1.8-fold) and the downregulation of miR-24-3p (0.3-fold) were confirmed in I/R mice. RIPK1 led to impaired cardiac function indexes, increased infarct area and cell apoptosis, while miR-24-3p could reverse the injury by regulating RIPK1. The TNF signaling pathway was proven to be involved in myocardial I/R injury through the detection of the dysregulation of related proteins. CONCLUSION: In conclusion, RIPK1 was upregulated and miR-24-3p was downregulated in a myocardial I/R injury mouse model. RIPK1 could aggravate myocardial I/R injury via the TNF signaling pathway, while miR-24-3p could suppress RIPK1 and therefore exert cardioprotective effects in myocardial I/R injury. PMID- 30439714 TI - Type III Interferons in Viral Infection and Antiviral Immunity. AB - Interferons (IFNs) can serve as the first line of immune defense against viral infection. The identification of IFN-lambdas 1, 2, 3 & 4 (termed as type III IFNs) has revealed that the antiviral immune response to viruses contains more components than the type I IFNs that have been known for more than 50 years. IFN lambdas are IFN-lambda1 (IL-29), IFN-lambda2 (IL-28a), IFN-lambda3 (IL-28b) and IFN-lambda4, which resembles IFN-lambda3. IFN-lambdas have type I-IFN-like immune responses and biological activities, but our knowledge of these novel players in the antiviral response is not well established. In this review, we try to describe the current information on the expression and function of IFN-lambdas in the innate antiviral immune defense and IFN-lambda2's role in regulating and shaping the adaptive immune response. We suggest that IFN-lambdas are key antiviral cytokines, directly performing an antiviral immune response at epithelial surfaces in the early stages of viral infection, and that these cytokines also skew the balance of Th1 and Th2 cells to Th1 phenotype. In addition, genetic polymorphisms in IFN-lambda genes can impair antiviral immune responses in clinical treatment. PMID- 30439715 TI - Coincidence and Management of Non-Motor Stroke-Associated Risks (Dysphagia - Swallowing Deficits - Visual Neglect). PMID- 30439716 TI - Spontaneous Regression of Hodgkin Lymphoma: Case Report and Review of the Literature. AB - Spontaneous regression of Hodgkin lymphoma (HL) is a rare event. We describe a 32 year-old woman with spontaneous regression of HL and review the literature. The patient presented with cervical lymphadenopathy and was diagnosed with stage IIA classical HL. The patient refused to receive any treatment for her disease. Positron emission tomography/computed tomography carried out 2 years later showed complete regression of the lymphadenopathy, without pathological uptake of fluorodeoxyglucose. At the last follow-up, 3.5 years after the initial presentation, the patient is with no evidence of disease. During workup for the HL, concomitant papillary thyroid carcinoma was diagnosed, for which the patient refused treatment as well. The thyroid malignancy has remained stable throughout the follow-up. PMID- 30439717 TI - Protective Role of NMDAR for Microwave-Induced Synaptic Plasticity Injuries in Primary Hippocampal Neurons. AB - BACKGROUND/AIMS: The N-methyl-D-aspartic acid receptor (NMDAR) has been extensively studied for its important roles in synaptic plasticity and learning and memory. However, the effects of microwave radiation on the subunit composition and activity of NMDARs and the relationship between NMDARs and microwave-induced synaptic plasticity have not been thoroughly elucidated to date. MATERIALS: In our study, primary hippocampal neurons were used to evaluate the effects of microwave radiation on synaptic plasticity. Structural changes were observed by diolistic (Dil) labeling and scanning electron microscopy (SEM) observation. Functional synaptic plasticity was reflected by the NMDAR currents, which were detected by whole cell patch clamp. We also detected the expression of NMDAR subunits by real-time PCR and Western blot analysis. To clarify the effects of microwave radiation on NMDAR-induced synaptic plasticity, suitable agonists or inhibitors were added to confirm the role of NMDARs on microwave-induced synaptic plasticity. Dil labeling, SEM observation, whole cell patch clamp, real-time PCR and Western blot analysis were used to evaluate changes in synaptic plasticity after treatment with agonists or inhibitors. RESULTS: Our results found that microwave exposure impaired neurite development and decreased mRNA and protein levels and the current density of NMDARs. Due to the decreased expression of NMDAR subunits after microwave exposure, the selective agonist NMDA was added to identify the role of NMDARs on microwave-induced synaptic plasticity injuries. After adding the agonist, the expression of NMDAR subunits recovered to the normal levels. In addition, the microwave-induced structural and functional synaptic plasticity injuries recovered, including the number and length of neurites, the connections between neurons, and the NMDAR current. CONCLUSION: Microwave radiation caused neuronal synaptic plasticity injuries in primary hippocampal neurons, and NMDARs played protective roles on the damage process. PMID- 30439718 TI - Knockdown of Long Non-Coding RNA XIST Inhibited Doxorubicin Resistance in Colorectal Cancer by Upregulation of miR-124 and Downregulation of SGK1. AB - BACKGROUND/AIMS: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. METHODS: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-pi (GST-pi) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. RESULTS: XIST expression was upregulated and miR-124 expression was downregulated in DOX resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST pi levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR 124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. CONCLUSION: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients. PMID- 30439719 TI - Impact of Dry Eye on Prolonged Reading. AB - SIGNIFICANCE: Patients with dry eye frequently report difficulty with reading. However, the impact of dry eye on reading has not been studied in detail. This study shows the unfavorable effect of dry eye on reading speed and offers mechanisms that may be responsible. PURPOSE: The purpose of this study was to evaluate the impact of dry eye signs as well as symptoms on both short-duration out-loud and prolonged silent reading. METHODS: This study included 116 patients with clinically significant dry eye, 39 patients with dry eye symptoms only, and 31 controls, 50 years or older. After the Ocular Surface Disease Index (OSDI) questionnaire, objective testing of dry eye (tear film stability studies, Schirmer's test, and ocular surface staining) was performed. Total OSDI score and two subscores (vision related and discomfort related) were calculated. A short duration out-loud reading test and a 30-minute sustained silent reading test were performed. Reading speed for each test was calculated as words per minute (wpm) and compared across the three groups. RESULTS: Patients with clinically significant dry eye read slower than controls measured with sustained silent reading test (240 vs. 272 wpm, P = .04), but not with short-duration out-loud reading test (146 vs. 153 wpm, P = .47). Patients with dry eye symptoms only did not have slower reading speed measured using either reading test as compared with controls. However, vision-related OSDI subscore independently was associated with slower reading speed (P = .02). Multivariable regression models demonstrated that each 1-point (between 0 and 6) increase in corneal staining score led to a 10-wpm decrease in sustained silent reading speed (P = .01). CONCLUSIONS: This study demonstrates a significant negative impact of dry eye (particularly presence of corneal staining) on prolonged reading. Prolonged reading task may serve as an objective clinically relevant test to measure the impact of dry eye on vision related quality of life. PMID- 30439720 TI - Functional brain activity during motor control and pain processing in chronic jaw pain. AB - Changes in brain function in chronic pain have been studied using paradigms that deliver acute pain-eliciting stimuli or assess the brain at rest. Although motor disability accompanies many chronic pain conditions, few studies have directly assessed brain activity during motor function in individuals with chronic pain. Using chronic jaw pain as a model, we assessed brain activity during a precisely controlled grip force task and during a precisely controlled pain-eliciting stimulus on the forearm. We used multivariate analyses to identify regions across the brain whose activity together best separated the groups. We report 2 novel findings. First, although the parameters of grip force production were similar between the groups, the functional activity in regions including the prefrontal cortex, insula, and thalamus best separated the groups. Second, although stimulus intensity and pain perception were similar between the groups, functional activity in brain regions including the dorsal lateral prefrontal cortex, rostral ventral premotor cortex, and inferior parietal lobule best separated the groups. Our observations suggest that chronic jaw pain is associated with changes in how the brain processes motor and pain-related information even when the effector producing the force or experiencing the pain-eliciting stimulus is distant from the jaw. We also demonstrate that motor tasks and multivariate analyses offer alternative approaches for studying brain function in chronic jaw pain. PMID- 30439721 TI - Opioid Prescribing Patterns Among American Society of Ophthalmic Plastic and Reconstructive Surgery Members in the Medicare Part D Database. AB - PURPOSE: To assess opioid prescribing patterns among American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) members. METHODS: An observational, retrospective, cohort study of ASOPRS members' prescribing patterns in the 2013-2016 Medicare Part D Prescriber database. These prescribers were stratified by years in practice, sex, and geography. The ASOPRS member cohort was compared with all ophthalmologists, as a group, and other surgeons. RESULTS: The authors identified 617 surgeons in the 2017 ASOPRS directory. Members wrote an average of 45 opioid prescriptions/year. Almost half (45%) wrote <10 prescriptions. Those with >10 prescriptions averaged 78 annually. A minority wrote >100 prescriptions per year (14.8%). Overall, opioids comprised 16.5% of all prescriptions written by ASOPRS members. Despite seeing a similar number of beneficiaries (p = 0.20), male members prescribed a greater number (p < 0.05) and a higher rate (p < 0.05) of opioids than female members. Older members had a lower opioid prescription rate (p < 0.0001). Many heavy opioid prescribers practiced in states with high opioid overdose deaths. CONCLUSIONS: American Society of Ophthalmic Plastic and Reconstructive Surgery members prescribe moderate amounts of opioids at a rate (16.5%) higher than all of ophthalmology (4%), above the national mean (6.8%), but lower than other surgical services (36.5%). Male gender, younger age, and practice in states with high opioid related deaths were correlated to number of prescriptions. Prescribing patterns may naturally relate to the type of surgical intervention and population. Further research is warranted to understand opioid prescriptions and their role in the opioid epidemic. PMID- 30439722 TI - Histopathological Study on the Proposed Pathogenesis of Intratarsal Keratinous Cysts. AB - PURPOSE: Intratarsal keratinous cysts (IKCs) are a recently described entity that is frequently misdiagnosed clinically as chalazia and mislabeled in the literature as "intratarsal epidermal inclusion cysts" or "epidermoid cysts." It is important to accurately diagnose IKCs and distinguish them from chalazia because IKCs require a complete surgical excision and can exhibit multiple recurrences following curettage. The authors performed a retrospective case series to further elucidate the pathogenesis of IKCs and to determine the diagnostically optimal panel of stains for diagnosis. METHODS: A study group of 8 specimens of IKCs and control specimens of epidermal inclusion cysts were obtained from their pathology laboratories. The authors compared the histological and immunohistochemical profile of IKCs and epidermal inclusion cysts by staining sections from each specimen with hematoxylin and eosin, periodic acid-Schiff, Masson trichrome, cytokeratin 5, cytokeratin 17, carcinoembryonic antigen, and epithelial membrane antigen. The immunoreactivity data were then analyzed using a 2-tailed Mann-Whitney test, assuming a nonparametric population (p < 0.05 is significant). RESULTS: Histopathologically, IKCs are embedded in the tarsus lined by stratified squamous epithelium with an inner undulating cuticle filled with a compact keratinous-appearing material. The authors demonstrate that IKCs develop progressively from dilated meibomian ducts to the formation of complete cysts with their markers. The most valuable immunochemical stains to diagnose IKC were cytokeratin 17, carcinoembryonic antigen, and epithelial membrane antigen (p < 0.05 with each). CONCLUSIONS: These findings provide a better understanding of the pathogenesis and the immunohistochemical findings of this relatively new entity allowing for more appropriate diagnosis of IKCs aiming to reduce future complications from their management. PMID- 30439723 TI - Absorbable Implant Foreign Body Reaction Masquerading as Orbital Cellulitis. AB - Poly-DL-lactide polymer implants absorb over a period of 6 to 12 months and have been used with increasing frequency for repair of orbital fractures. The authors describe the case of a 7-year-old boy who presented with orbital inflammation 10 months following repair of a white-eyed blowout fracture with a poly-DL-lactide implant. Rapid improvement in symptoms followed initiation of oral steroids, with excellent long-term result. Clinical presentation and treatment response implicated a foreign body inflammatory reaction as the underlying etiology of symptoms. Ophthalmologists and orbital surgeons should be aware that absorbable implants can demonstrate this late idiosyncratic complication. PMID- 30439724 TI - Mini-Open Surgical Fasciotomy for Chronic Exertional Compartment Syndrome of the Forearm in Professional Motorcycling Adolescents. AB - OBJECTIVE: Evaluate treatment and outcome of mini-open fasciotomy (MOF) in a population of adolescent motorcycling racers affected by forearm chronic exertional compartment syndrome (CECS). DESIGN: Prospective case series. SETTING: University hospital/private practice. PATIENTS: Nine professional motorcycling adolescents were diagnosed with forearm CECS. All were treated with MOF between 2007 and 2012 and followed for a minimum of 5 years (range 5-10 years). Age, sex, body mass index, laterality, and profession were recorded. INTERVENTIONS: A MOF to obtain decompression of all compartments was performed in all patients. MAIN OUTCOME MEASURES: Visual analog scale; a subjective scale to measure strength; and Quick-DASH functional scores. Time to resume full riding capacities as the short-term evaluation. RESULTS: A significant decrease in visual analog scale (P < 0.001) and Quick-DASH (P < 0.001) scores was observed in the first 3 months, stabilizing during follow-up (P = 0.521; P = 0.217). Average time to return to sport was 2.8 +/- 1 week. No symptom recurrence was reported, but one patient suffered a minor complication. There were no cases of infection, hematoma, or peripheral nerve injury. CONCLUSIONS: We assess that MOF can be a valid alternative for the treatment of forearm CECS in adolescent competitive motorcycling racers, as demonstrated by the good success rate and minimal incidence of complications during follow-up. LEVEL OF EVIDENCE: IV, case series. PMID- 30439725 TI - Can Exercise Targeting Mid-Thoracic Spine Segmental Movement Reduce Back Pain and Improve Sensory Perception in Cross-Country Skiers? AB - OBJECTIVE: To assess the role of exercise targeting proper trunk stabilization and segmental spinal movement in back pain and sensory perception among cross country skiers. DESIGN: Randomized, controlled trial with blinded outcome assessors. SETTING: University Hospital, Department of Rehabilitation and Sports Medicine. PARTICIPANTS: Twenty elite cross-country skiers aged 17 to 27 years. INTERVENTIONS: Ten cross-country skiers integrated 3 types of exercise targeting segmental motion in mid-thoracic spine into their routine training practice for 2 months. The 10 controls performed routine athletic training. MAIN OUTCOME MEASURES: The Young Spine Questionnaire to measure intensity and frequency of back pain was completed at the start and end of study. Tactile sensory perception using 10-g Semmes-Weinstein monofilament, thermic perception using TIP THERM device, graphesthesia assessed by a touch monitor pencil, 2-point discrimination assessed by a digital caliper, and vibration perception assessed by a 128-Hz tuning fork measured in mid-thoracic spine 5 times. RESULTS: No significant group differences in pain and sensory perception were identified at baseline. Over the 2-month study interval, repeated-measures analysis of variance revealed that the experimental group improved significantly relative to the control group on pain intensity (P = 0.005 for cervical, P = 0.004 for thoracic, and P = 0.014 for lumbar) and frequency of pain in the thoracic area only (P = 0.011). Improvements were also observed in the experimental relative to control group on graphesthesia (P < 0.001), vibration perception (P = 0.002), and 2-point discrimination (P < 0.001). CONCLUSIONS: Exercise targeting the mid-thoracic spine may decrease back pain and improve sensory perception in cross-country skiers. LEVEL OF EVIDENCE: Original research, level I. PMID- 30439726 TI - Graded Exercise Testing Predicts Recovery Trajectory of Concussion in Children and Adolescents. AB - OBJECTIVE: To determine whether graded exercise testing can predict recovery trajectory of concussion in children and adolescents. DESIGN: Prospective study. SETTING: Children's Hospital, Westmead, Australia. PARTICIPANTS: One hundred thirty-nine children aged 12 to 16 years at 5 to 7 days after an acute concussive injury. INTERVENTION: Graded exercise testing on a treadmill at the subacute phase to assess symptom provocation and determine clinical recovery indicating readiness to commence a return to activity (RTA) protocol. Exercise time to symptom exacerbation and clinical recovery were measured. MAIN OUTCOME MEASURES: Standard concussion assessment and clinical testing (neurocognitive, vestibular/ocular, and balance) were conducted to determine major clinical drivers/indicators. RESULTS: Participants (mean age 12.4 +/- 2.8 years, 73% male) had a confirmed sport-related concussion. The main clinical drivers identified on exercise testing were headache, balance, and vestibular dysfunction. Participants fell into 1 of 2 groups, exercise-tolerant (54%) and exercise-intolerant (46%). Exercise-tolerant patients showed mild clinical indicators, no symptom exacerbation during 10.3 +/- 3.3 minutes of exercise, were safely transitioned to a RTA protocol, and recovered within 10 days. Exercise-intolerant patients had high clinical indicators, significant symptom exacerbation at 4.2 +/- 1.6 minutes of exercise, and prolonged recovery of 45.6 days. No adverse effects from exercise were reported in either group. Combined use of provocative exercise and clinical testing was 93% predictive of outcome. CONCLUSIONS: Exercise testing during the subacute phase after a concussion can predict longer recovery. Exercise testing can identify a unique window where patients can be safely transitioned to activity, enabling clinicians to better inform patients and families, allocate resources and streamline care. PMID- 30439727 TI - Performance Outcomes and Return-to-Sport Rate of National Hockey League Athletes Vary After Common Orthopedic Surgical Procedures. AB - OBJECTIVE: Evaluate performance-based outcomes and return-to-sport rate in National Hockey League (NHL) athletes. DESIGN: Retrospective cohort study. SETTING: Public records. No direct patient care was provided. PARTICIPANTS: National Hockey League athletes who underwent different orthopedic procedures were identified using public records. Three hundred thirty-seven athletes met inclusion criteria. INDEPENDENT VARIABLES: Common orthopedic surgical procedures in NHL athletes. MAIN OUTCOME MEASURES: Return-to-play and preoperative and postoperative performance measures were collected to calculate a position specific performance score. Short-term and medium-term outcomes were defined as 1 and 2 to 3 seasons after surgery, respectively. RESULTS: Three hundred seven athletes (92.6%) successfully returned to play. The number of games played during the first season after surgery compared with baseline was significantly decreased for hip arthroscopy (HA), noninstability shoulder arthroscopy (ie, shoulder arthroscopy procedure to address pathology other than shoulder instability), knee arthroscopy, and sports hernia repair (P = 0.002, 0.009, 0.03, and 0.01, respectively). The number of games played for seasons 2 and 3 after surgery was significantly decreased for both HA and noninstability shoulder arthroscopy (P = 0.01 and 0.001, respectively). Short-term postoperative performance scores were significantly decreased for HA, noninstability shoulder arthroscopy, and anterior cruciate ligament reconstruction (P = 0.00004, 0.02, and 0.02, respectively) while medium-term scores were significantly decreased for HA only (P = 0.009). CONCLUSIONS: National Hockey League athletes return to play at a high rate after common orthopedic surgeries. However, certain procedures portend poorer performance scores and game participation than others. In particular, HA and noninstability shoulder arthroscopy have the greatest negative effect on NHL careers after surgery. PMID- 30439728 TI - Heterotrophic Ossification in Patient With Prosthetic Leg. AB - Heterotrophic ossification (HO) is a well-described phenomenon in patients with spinal cord injury, head injury, burns, hip replacement, and general trauma. However, it has also been described through a relative paucity of case reports that repeated microtrauma from the use of weight-bearing leg prostheses is an additional possible cause of HO. In our case, we examine a patient who developed an extreme case of HO after he began an exercise regimen with assistance from a running limb. This abnormal formation was actually advantageous because it created a more snug fit of the prosthetic device and improved the patient's ability to run. PMID- 30439729 TI - Textbooks in Plastic Surgery: Paper or Digital? PMID- 30439730 TI - Review of "The Surgeon Volume-Outcome Relationship: Not Yet Ready for Policy" by Modrall JG, Minter RM, Minhajuddin A, Eslava-Schmalbach J, Joshi GP, Patel S, Rosero EB in Ann Surg 267:863-867, 2018. PMID- 30439732 TI - Review of "Artificial Intelligence in Surgery: Promises and Perils" by Hashimoto DA, Rosman G, Rus D, Meireles OR in Ann Surg 268:70-76, 2018. PMID- 30439731 TI - Analysis of Cranial Morphology of Healthy Infants Using Homologous Modeling. AB - OBJECTIVE: Data on cranial morphology of healthy individuals can be used as the guide in the treatment of cranial deformity. There are many reports analyzing the cranial morphology of healthy children in the past. But most of them focus on 2 dimensional values, and there are only a few reports, which analyzed the cranial morphology of Japanese healthy infants. We report a novel method that enables the comprehensive analysis of cranial morphology of Japanese healthy infants in 3D. METHODS: Craniofacial CT data of 20 healthy infants (9 males, 11 females) ranging in age from 1 to 11 months were collected. Based on the CT data, we created 20 homologous models of cranium using software specifically designed to support homologous modeling. We averaged vertex coordinates of the homologous models to create average model. We further performed principal component analysis, and created virtual models based on each principal component. The contribution rate was calculated, and the features described by each principal component were interpreted. RESULTS: We created the average cranial model of Japanese healthy infants. Seven principal components (cumulative contribution rate: 89.218%) were interpreted as to which part of the cranial shape each component was related to. The elements were extracted that may characterize the cranial morphology of some of the clinical conditions such as dolico/brachycephaly and deformational plagiocephaly. Some of these elements have not been mentioned in the past literature. CONCLUSION: Homologous modeling was considered to be valid and strong tool for comprehensive analysis of cranial morphology. PMID- 30439733 TI - Personal Computer-Based Cephalometric Landmark Detection With Deep Learning, Using Cephalograms on the Internet. AB - BACKGROUND: Cephalometric analysis has long been, and still is one of the most important tools in evaluating craniomaxillofacial skeletal profile. To perform this, manual tracing of x-ray film and plotting landmarks have been required. This procedure is time-consuming and demands expertise. In these days, computerized cephalometric systems have been introduced; however, tracing and plotting still have to be done on the monitor display. Artificial intelligence is developing rapidly. Deep learning is one of the most evolving areas in artificial intelligence. The authors made an automated landmark predicting system, based on a deep learning neural network. METHODS: On a personal desktop computer, a convolutional network was built for regression analysis of cephalometric landmarks' coordinate values. Lateral cephalogram images were gathered through the internet and 219 images were obtained. Ten skeletal cephalometric landmarks were manually plotted and coordinate values of them were listed. The images were randomly divided into 153 training images and 66 testing images. Training images were expanded 51 folds. The network was trained with the expanded training images. With the testing images, landmarks were predicted by the network. Prediction errors from manually plotted points were evaluated. RESULTS: Average and median prediction errors were 17.02 and 16.22 pixels. Angles and lengths in cephalometric analysis, predicted by the neural network, were not statistically different from those calculated from manually plotted points. CONCLUSION: Despite the variety of image quality, using cephalogram images on the internet is a feasible approach for landmark prediction. PMID- 30439734 TI - Approaches for Excision of Intramasseteric Nodules. AB - Developmental lesions, including benign or malignant tumors, rarely arise in the masseteric region. This retrospective study was performed to evaluate the adequacy of different surgical approaches in a series of patients with lesions in the masseteric region. The surgical methods, postoperative complications, pathological diagnosis, and aesthetic outcome were compared in 4 patients who underwent excision of intramasseteric mass lesions. A flap was elevated in 3 patients and direct incisional resection was performed in 1 patient. Two patients underwent incisional biopsy to exclude malignancy before the total excision was performed. The final diagnosis was hemangioma in 3 patients and schwannoma in 1 patient. All patients were satisfied with the aesthetic results and there were no major complications. In conclusion, surgery with skin flap elevation was concluded to be the best approach based on overall assessment of technical considerations, complications, and the cosmetic outcome. However, the surgeon should not hesitate to perform direct incisional biopsy when malignancy needs to be excluded. PMID- 30439735 TI - Telementoring Demonstration in Craniofacial Surgery with HoloLens, Skype, and Three-Layer Facial Models. AB - BACKGROUND: Telementoring is the technology for providing surgical instruction from a remote place via a network. To demonstrate the use of telementoring in craniofacial surgery, Skype and a mixed reality device HoloLens were adopted, and 3-layer facial models had been developed. METHODS: A resident in hospital A used the model surgery under remote guidance by a mentor surgeon in hospital B 4 times on different dates. The straight-line between hospitals A and B is 250 km. The mentor gave the resident guidance via Skype and HoloLens, communicating by voice, and video of the surgical field, and providing reference data. RESULTS: There was no delay in voice communication and a delay of <0.5 seconds in the video. The resident was able to confirm the main landmarks of the surgical field and to grasp the situation without problems. The mentor could send appropriate instructions by voice, could point out a specific part by telestration function, and could draw lines on the 2-dimentional images pasted on the operator's field of vision. DISCUSSION: With the use of HoloLens, Skype, and the 3-layer models, it was possible to demonstrate telementoring. The risk of personal information leakage due to data interception seems to be very low because its data communication is encrypted with advanced encryption standard. CONCLUSION: This telementoring system has various advantages and many improvable aspects in the field of craniofacial surgery. PMID- 30439736 TI - The Effect Evaluation of Functional Appliance Used for Class II Patients With Temporomandibular Joint Anterior Disc Displacement. AB - Orthopedic functional appliances are usually used to correct patients with retrognathic mandible. However, a part of cases have a trend of relapse after splint treatment. The aim of this study was to explore the role of temporomandibular joint disc position in functional appliance treatment. This study included 8 patients who had 1 joint anterior disc displacement with reduction (ADDWR) and the other joint anterior disc displacement without reduction (ADDWoR) confirmed by magnetic resonance imaging (MRI). Only the ADDWR joint could return to its normal position after wearing the anterior repositioning appliances (ARAs). Condylar morphology, condylar height, and disc length were evaluated 6 months after ARA treatment. The MRI showed that new bone appeared on 7 joints with ADDWR and on 1 joint with ADDWoR. The condylar height has increased 1.4 mm in the ADDWR group, while 0.1 mm shorter in the ADDWoR group. Disc length has increased from 8.5 to 8.7 mm in the ADDWR group and 0.4 mm shorter in the ADDWoR group after wearing the ARA. Our results suggested that it is noneffective of functional appliance used for class II malocclusion adolescents with ADDWoR and only a normal disc-condyle relationship benefits condyle growth by functional appliance. Thus it is important to reposition the disc as soon as possible. PMID- 30439737 TI - Dural Reconstruction With Autologous Rectus Fascia: A New Technique for Addressing Large-Sized Defects During Cranioplasty. AB - INTRODUCTION: Patients requiring cranioplasty reconstruction with customized cranial implants may unexpectedly present with cerebrospinal fluid (CSF) leaks and durotomies following previous neurosurgical procedures. As such, multiple factors influence the type of dural reconstruction chosen at this time, which are essential for achieving long-term success. Overall, the most common material used for duraplasty is currently an "off-the-shelf" xenograft construct. However, some believe that they are not suitable for large-sized defects and accompany a higher incident of complications. Therefore, based on our success and experience with scalp augmentation using rectus fascia grafts, the authors herein present our preliminary experience with duraplasty using autologous rectus fascia grafts (ARFGs). METHODS: A retrospective review of our database, consisting of 437 cranial reconstructions from 2012 to 2017, was performed under institutional review board approval. Selection criteria included all adult patients (n = 6) requiring dural reconstruction (duraplasty) with ARF grafting for an active CFS leak with concomitant skull defect. Cadaver study and patient illustrations are also presented to demonstrate clinical applicability. All outcomes, including complications, were reviewed and are presented here. RESULTS: A total of 6 patients underwent autologous duraplasty with either unilateral or bilateral ARFGs. All patients (6/6) of large-sized (>3 cm) defect repair with ARFGs were indicated for repair of secondary CSF leaks following previous craniotomy by neurosurgery. To date, none have demonstrated recurrent leaking and/or dura related complications. At this time, all 6 patients were reconstructed using customized cranial implants with a mean follow-up of 10 months. CONCLUSION: Based on our preliminary experience presented here, the use of rectus fascia grafts for autologous dural reconstruction appears to be both safe and reliable. This new technique adds another tool to the neurosurgical armamentarium by reducing the additional risk of "off-the-shelf" dural substitutes. PMID- 30439738 TI - Anterior Maxillary Segmental Distraction Osteogenesis for Treatment of Maxillary Hypoplasia in Patients With Repaired Cleft Palate: Retraction. PMID- 30439739 TI - Onabotulinum Toxin A Injections Into the Salivary Glands for Spinal Muscle Atrophy Type I: A Prospective Case Series of 4 Patients. AB - OBJECTIVE: The aim of the study was to investigate the safety and efficacy of onabotulinum toxin A injection to the salivary glands under ultrasound guidance for the treatment of sialorrhea in patients with spinal muscular atrophy type I. DESIGN: Prospective case series with four patients with spinal muscular atrophy type I who received onabotulinum toxin A injection to parotid and submandibular glands for sialorrhea as part of clinical care. All four patients received validated surveys for measuring drooling, including objective measures of number of bib changes, and number of mouth wipes before injection and 4-6 wks after injection. Research was limited to survey completion. Scales included the Drooling Severity and Frequency Scale and the Drooling Impact Scale as well as a new scale used in our clinic, the Posterior Drooling Scales looking at coughing/choking and number of aspiration pneumonias. RESULTS: There were no adverse events. All four patients showed clinically significant improvements. The improvement in drooling using the Drooling Impact Scale was statistically significant (paired t test, t = 3.243, P = 0.048). All patients improved with number of mouth wipes. CONCLUSION: Ultrasound-guided onabotulinum toxin A injections to the salivary glands may be a safe and effective method of decreasing drooling in patients with spinal muscular atrophy type I. PMID- 30439740 TI - Physical Medicine and Rehabilitation Role on Notalgia Paresthetica: Case Report and Treatment Review. AB - Notalgia paresthetica is a rarely reported T2-T6 sensory neuropathy whose etiology and treatment are not fully established. Although it is believed to be common in dermatological practice, it remains underrecognized, underdiagnosed, and therefore underreported. This case-report provides a physical medicine and rehabilitation perspective on notalgia paresthetica diagnosis and treatment. This article presents a case report of a 39-yr-old woman with pain, pruritus, and a hyperpigmented area in the right dorsal infra scapular region. The diagnosis of notalgia paresthetica was established. She was successfully treated with topical anesthetics, postural corrective exercises, scapular muscle strengthening, and pectoral muscle stretching. In this context, different treatment options were reviewed. A small set of pharmacological and nonpharmacological techniques were identified. Several of these modalities belong to the physical medicine and rehabilitation field of action. PMID- 30439741 TI - Mental health of first time fathers - it's time to put evidence into practice. PMID- 30439742 TI - Effectiveness of coffee for postoperative ileus in patients following abdominal surgery: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The purpose of this systematic review is to critically appraise, synthesize and present the best available evidence concerning the effects of coffee on postoperative ileus following abdominal surgery. The review will consider the effect of coffee and decaffeinated coffee on recovering gastrointestinal function, time to first bowel movement, time to first flatus, time to tolerance of solid food, postoperative complications and length of hospital stay. PMID- 30439743 TI - Health professionals' experiences of grief associated with the death of pediatric patients: a qualitative systematic review protocol. AB - REVIEW QUESTION: What are health professionals' experiences of grief associated with the death of pediatric patients in acute or community healthcare settings? PMID- 30439744 TI - Use of GRADE in Australian clinical practice guidelines: a methodological review protocol. AB - RESEARCH QUESTION/OBJECTIVE: The purpose of this methodological review is to determine whether and to what extent GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology has been and is currently being used in Australian clinical practice guidelines. PMID- 30439745 TI - Women's experiences of induced abortion resulting from unplanned pregnancy: a qualitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize qualitative evidence on the experiences of women undergoing an induced abortion resulting from an unplanned pregnancy.More specifically, the review question is: how do women experience induced abortions resulting from an unplanned pregnancy? PMID- 30439746 TI - Effectiveness of flavonoid rich fruits for hypertension in adults: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what is the effectiveness of flavonoid rich fruits for blood pressure in adults with hypertension? PMID- 30439747 TI - Effectiveness of Silexan oral lavender essential oil compared to inhaled lavender essential oil aromatherapy for sleep in adults: a systematic review. AB - OBJECTIVE: The objective of the review was to identify the effectiveness of Silexan oral lavender essential oil compared to inhaled lavender essential oil aromatherapy for sleep latency, sleep duration, sleep quality, disturbed sleep and anxiety in adult patients. INTRODUCTION: Insomnia is a common problem, with 10-20% of the global population using sleep aids. Benzodiazepine and non benzodiazepine sleep aids have the potential to cause side effects which may result in falls or other injuries. Lavender oil has anxiolytic properties that may improve sleep and reduce anxiety without the potential for adverse reaction. Silexan, an oral pill produced from lavender essential oil, has limited availability. This review sought to determine if lavender essential oil aromatherapy was as effective as Silexan to enable promotion of the use of essential oil aromatherapy in markets where Silexan is not available. INCLUSION CRITERIA: This review considered both experimental and epidemiological studies that included participants 18 years and over utilizing Silexan therapy of any dose or duration compared to inhaled lavender essential oil aromatherapy. The outcomes of interest were sleep latency, sleep duration, sleep quality, disturbed sleep and anxiety. METHODS: A comprehensive search strategy aimed to find relevant published and unpublished quantitative English language studies from 2010 through to February 16, 2018. Databases searched included: PubMed, CINAHL, Cochrane Central Register of Controlled Trials and Embase. A search of gray literature was also performed. RESULTS: No studies were identified that met the inclusion criteria. CONCLUSIONS: A comprehensive search of the literature uncovered no evidence related to the effectiveness of Silexan compared to inhaled lavender essential oil aromatherapy for sleep latency, sleep duration, sleep quality, disturbed sleep or anxiety in adult patients. Research is needed to determine if lavender essential oil aromatherapy, which is readily available worldwide, can be proven to be as effective as Silexan for improving sleep and anxiety in adult patients. PMID- 30439748 TI - Indicators to measure prehospital care quality: a scoping review. AB - OBJECTIVE: The purpose of this scoping review was to locate, examine and describe the literature on indicators used to measure prehospital care quality. INTRODUCTION: The performance of ambulance services and quality of prehospital care has traditionally been measured using simple indicators, such as response time intervals, based on low-level evidence. The discipline of paramedicine has evolved significantly over the last few decades. Consequently, the validity of utilizing such measures as holistic prehospital care quality indicators (QIs) has been challenged. There is growing interest in finding new and more significant ways to measure prehospital care quality. INCLUSION CRITERIA: This scoping review examined the concepts of prehospital care quality and QIs developed for ambulance services. This review considered primary and secondary research in any paradigm and utilizing any methods, as well as text and opinion research. METHODS: Joanna Briggs Institute methodology for conducting scoping reviews was employed. Separate searches were conducted for two review questions; review question 1 addressed the definition of prehospital care quality and review question 2 addressed characteristics of QIs in the context of prehospital care. The following databases were searched: PubMed, CINAHL, Embase, Scopus, Cochrane Library and Web of Science. The searches were limited to publications from January 1, 2000 to the day of the search (April 16, 2017). Non-English articles were excluded. To supplement the above, searches for gray literature were performed, experts in the field of study were consulted and applicable websites were perused. RESULTS: Review question 1: Nine articles were included. These originated mostly from England (n = 3, 33.3%) and the USA (n = 3, 33.3%). Only one study specifically aimed at defining prehospital care quality. Five articles (55.5%) described attributes specific to prehospital care quality and four (44.4%) articles considered generic healthcare quality attributes to be applicable to the prehospital context. A total of 17 attributes were identified. The most common attributes were Clinical effectiveness (n = 17, 100%), Efficiency (n = 7, 77.8%), Equitability (n = 7, 77.8%) and Safety (n = 6, 66.7%). Timeliness and Accessibility were referred to by four and three (44.4% and 33.3%) articles, respectively.Review question 2: Thirty articles were included. The predominant source of articles was research literature (n = 23; 76.7%) originating mostly from the USA (n = 13; 43.3%). The most frequently applied QI development method was a form of consensus process (n = 15; 50%). A total of 526 QIs were identified. Of these, 283 (53.8%) were categorized as Clinical and 243 (46.2%) as System/Organizational QIs. Within these categories respectively, QIs related to Out-of-hospital cardiac arrest (n = 57; 10.8%) and Time intervals (n = 75; 14.3%) contributed the most. The most commonly addressed prehospital care quality attributes were Appropriateness (n = 250, 47.5%), Clinical effectiveness (n = 174, 33.1%) and Accessibility (n = 124, 23.6%). Most QIs were process indicators (n = 386, 73.4%). CONCLUSION: Whilst there is paucity in research aiming to specifically define prehospital care quality, the attributes of generic healthcare quality definitions appear to be accepted and applicable to the prehospital context. There is growing interest in developing prehospital care QIs. However, there is a need for validation of existing QIs and de novo development addressing broader aspects of prehospital care. PMID- 30439749 TI - Use of test weights for breastfeeding infants with congenital heart disease in a cardiac transitional care unit: a best practice implementation project. AB - OBJECTIVES: The goal of this project was to promote breastfeeding among infants with congenital heart disease in a quaternary care academic children's hospital. We aimed to increase the total number of breastfeeding episodes among all patients in the Pediatric Cardiac Transitional Care Unit with implementation of pre- and post-breastfeeding (test) weights. INTRODUCTION: Infants with congenital heart disease are able to breastfeed, but are often not encouraged to do so by healthcare providers. Fears and concerns relating to the inability to account for exact intake volumes through breastfeeding often prevent providers from supporting breastfeeding in these patients. METHODS: This project used Joanna Briggs Institute's Practical Application of Clinical Evidence System (JBI PACES) and Getting Research into Practice (GRiP) audit tool for promoting health practice change. A baseline medical record audit was conducted, followed by staff nurse education on breastfeeding test weights and the development of a parent education program. One follow-up audit measured compliance with best practice criteria for using breastfeeding test weights in infants with congenital heart disease. RESULTS: Compliance rates for use of breastfeeding test weights and provision of parent education, with baseline rates of 7% and 0%, respectively, rose to 90%. Identification of maternal intent to breastfeed upon admission to the unit increased to 78% compliance from 0%. Eighty-four percent of healthcare staff were educated on breastfeeding test weights. CONCLUSIONS: The safety of breastfeeding very ill infants was established. Breastfeeding episodes of all patients in the unit significantly increased after implementation of breastfeeding test weights and mothers of the sample patients expressed more confidence in breastfeeding their sick infants. Although barriers to breastfeeding for patients with congenital heart disease still persisted, this project had a positive impact on the culture of breastfeeding within the project unit. Increased healthcare provider education on breastfeeding will be essential to sustaining outcomes of this implementation. PMID- 30439751 TI - Poor Sleep Quality in Patients With Amyotrophic Lateral Sclerosis at the Time of Diagnosis. AB - OBJECTIVES: Patients with amyotrophic lateral sclerosis (ALS) have poor sleep quality, but little is known about which factors affect sleep at time of diagnosis. METHODS: Patients with newly diagnosed ALS were administered the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, Beck Depression Inventory-Revised, and ALS Functional Rating Scale and were compared with controls. RESULTS: Forty-three patients, age 63.8 +/- 11.5 years, ALS Functional Rating Scale 30.7 +/- 5.0. Poor sleep quality was frequent: 27 (63%) patients had PSQI >5 compared with 16 (37%) controls (P = 0.031); with higher PSQI (7.1 +/- 4.1 vs. 4.7 +/- 2.8, P = 0.003). PSQI correlated with Beck Depression Inventory Revised (r = 0.344, P = 0.024) and inability to turn in bed (r = -0.335, P = 0.033). CONCLUSIONS: Patients with newly diagnosed ALS have poor sleep quality, which is associated with depression and difficulty turning in bed. Longitudinal studies to examine the evolution of sleep quality and the effectiveness of individualized interventions are needed in patients with ALS. PMID- 30439750 TI - Satisfactory Response With Achieving Maintenance Low-Dose Prednisone in Generalized Myasthenia Gravis. AB - OBJECTIVES: To estimate the satisfactory response rate (SR%) with achieving maintenance, low-dose prednisone in acetylcholine receptor antibody-positive generalized myasthenia gravis. METHODS: In this retrospective study, we estimate the SR% as defined by (remission/minimal manifestations status for at least 6 months using 7.5 mg or less of prednisone daily, for maintenance treatment at 2, 4, and 6 years after symptoms onset) for patients who were not taking steroid sparing immunosuppressant (SSI) as a primary outcome and for patients taking an SSI as a secondary outcome. RESULTS: Forty-five patients were not taking an SSI at 2 years, 34 patients at 4 years, and 17 patients at 6 years; SR% was 44.4%, 64.7%, and 58.8%, respectively. Thirty-six patients were taking an SSI at 2 years, 22 patients at 4 years, and 15 patients at 6 years; the SR% was 50.0%, 45.4%, and 66.7%, respectively. CONCLUSIONS: Nearly half of the generalized myasthenia gravis patients who were not taking an SSI achieved an SR. PMID- 30439752 TI - Gender Differences in Skin Biopsy Findings in Small Fiber Neuropathy: A Retrospective Chart Review. AB - OBJECTIVES: To determine whether there are gender differences in the clinical presentation or skin biopsy measures of nerve fiber density in patients with small fiber neuropathy (SFN). METHODS: Retrospective chart review of subjects with suspected SFN. RESULTS: Of 218 cases (137 women and 81 men) with suspected SFN, 96 (44%), including 63% of the men and 33% of the women (P < 0.05), had low epidermal nerve fiber density (ENFD) or sweat gland nerve fiber density (SGNFD). There were no differences in the clinical presentation between men and women. In those with abnormal findings, low ENFD alone was more frequent in women than men (51.1% vs. 7.8%, P < 0.05), whereas abnormal SGNFD alone was more frequent in men than women (68.6% vs. 11.1%, P < 0.05). Both SGNFD and ENFD were low in 23.5% of men and 33.3% of women. Skin biopsy findings were independent of clinical presentation or etiology. CONCLUSIONS: The clinical presentation of SFN is similar in men and women. In skin biopsy studies, low ENFD is more common in women and low SGNFD in men. PMID- 30439753 TI - What is in the Neuromuscular Junction Literature? AB - This update begins with myasthenia gravis and the roles of anti-agrin and cortactin antibodies. Regarding diagnosis, a report on repeated ice pack testing is highlighted as are several reports on the close correlation of electrodiagnostic testing with clinical features and the response to treatment. The incidence of head drop and associated clinical and ventilatory features are gleaned from a retrospective study. We also discuss a study that assessed the predominantly symmetric and conjugate ocular findings in MuSK-myasthenia gravis. Other topics that are covered include quality of life and preoperative risk. We then summarize the positive treatment trials of subcutaneous immunoglobulin and eculizumab. Turning to Lambert-Eaton Myasthenic Syndrome, we report on an epidemiologic study performed on the veteran affairs population, the results of the DAPPER study of 3, 4 diaminopyridine, and look to the future for other treatment options involving calcium gating modifiers. PMID- 30439754 TI - Current Cardiac Imaging Approaches in Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular condition caused by mutations in the dystrophin gene leading to skeletal muscle weakness and dilated cardiomyopathy. The prevalence of DMD-related cardiomyopathy increases with age and is almost universal by the third decade of life. Myocardial fibrosis and progressive left ventricular dysfunction lead to the development of heart failure and premature death. With modern advances in medical and surgical management for patients with DMD increasing their life expectancy, cardiac dysfunction represents an increasing cause of morbidity and mortality in these patients. Early diagnosis of dilated cardiomyopathy before symptom development enables the initiation of potentially disease-modifying therapies, but requires regular dedicated imaging surveillance with sufficient sensitivity to detect subclinical changes in cardiac structure and function. Currently, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) are commonly used and have complementary roles. TTE is rapid and readily available, whereas CMR is the gold standard for the quantification of ventricular structure and function and can detect the presence and extent of myocardial fibrosis, an increasingly appreciated marker for early disease. This review describes the clinical applications, advantages, and disadvantages of cardiac imaging screening and surveillance for the myocardial manifestations of DMD, with a particular focus on TTE and CMR. PMID- 30439755 TI - Toxic Myopathy due to Antidopaminergic Medication Without Neuroleptic Malignant Syndrome. AB - Severe recurrent proximal muscle weakness without neuroleptic malignant syndrome secondary to antidopaminergic medication has rarely been reported. We report a 29 year-old man with history of obsessive compulsive disorder and Tourette syndrome who presented with 2 months of worsening dyspnea 3 weeks after starting ziprasidone 40 mg daily that required mechanical ventilation. A year before, after an increased risperidone dose from 0.5 to 1 mg daily, he had developed proximal muscle weakness that spontaneously improved 2 months after discontinuation of risperidone. On this admission, his creatine kinase (CK) was 3318 units/L, and ziprasidone was discontinued. He fully recovered 2 months after discontinuation of ziprasidone, and his CK was 62 units/L. Genetic testing for limb-girdle muscular dystrophy was negative. This case highlights the importance of evaluating CK level in patients taking antidopaminergic medication with any suggestion of muscle weakness to prevent potentially life-threatening complication. PMID- 30439756 TI - Immune Checkpoint Inhibitors and Myasthenic Syndromes: A Case Report of a Metastatic Renal Cell Carcinoma Patient Treated With Nivolumab. PMID- 30439757 TI - Acute Flaccid Myelitis With Early, Severe Compound Muscle Action Potential Amplitude Reduction: A 3-Year Follow-up of a Child Patient. PMID- 30439758 TI - Evaluation of Baseline Impedance During Water-perfused High Resolution Impedance Manometry in Patients With Symptomatic GERD. AB - GOALS: We aimed to investigate the hypothesis whether baseline impedance measured during water-perfused high resolution impedance manometry (HRIM) can help discriminate patients with reflux symptoms from the controls and predict the response to the proton pump inhibitors (PPIs). BACKGROUND/AIM: Baseline impedance measured during solid-state HRIM can reliably discriminate patients with gastroesophageal reflux disease (GERD) from controls. STUDY: We enrolled consecutive patients with typical reflux symptoms and healthy controls for the measurement of baseline impedance during the landmark period of HRIM. All patients were given PPIs and PPI response was assessed after 8 weeks of the treatment. RESULTS: Baseline mucosa impedance measured during HRIM was lower in GERD patients than the controls (1861+/-183 vs. 3371+/-250 Omega; P<0.001). Baseline impedance during water-perfused HRIM had moderate diagnostic accuracy for differentiating symptomatic GERD with an area under the curve of 0.853 on receiver operating characteristics analysis. A threshold of 2530 Omega for baseline impedance had a sensitivity of 88.3% and specificity of 82.4% for GERD with a positive predictive value of 83.4% and negative predictive value of 87.6%. Among symptomatic GERD patients, poor PPI responders had higher baseline impedance than those without it (2340+/-260 vs. 1479+/-189 Omega; P=0.02). BMI negatively correlated to base impedance in either controls (r=-0.59; P=0.012) or GERD patients (r=-0.47; P=0.047). CONCLUSIONS: Baseline impedance measurement during water-perfused HRIM helps differentiate patients with typical reflux symptoms from controls and also serves as a potential utility in predicting PPI response. PMID- 30439759 TI - Variations in Insurances Policies Regarding Adherence to the AGA Guideline for Therapeutic Drug Monitoring in IBD. AB - BACKGROUND: The American Gastroenterological Association (AGA) published guidelines on therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) in August 2017 recommending use of reactive TDM to guide treatment changes in patients with active IBD who are being treated with anti-tumor necrosis factor (anti-TNF) agents or thiopurines. We sought to determine if changes in national clinical practice guidelines result in changes in health care insurance policies within 6 months of publication. METHODS: Using the National Association of Insurance Commissioners Market Share Reports of the top 125 insurance companies by market share in 2016, we reviewed the largest 50 companies for their publicly available online policies regarding TDM of anti-TNF and thiopurine in IBD. For those with available policies, we looked for whether proactive and/or reactive TDM was covered. Policies were also looked for genetic or enzymatic activity of thiopurine methyltransferase (TPMT) testing before use of thiopurine. All these policies were reviewed within the week of publication of the AGA guideline. They were reviewed again 1, 3, and 6 months later for evaluation of any policy changes after the published AGA guidelines. RESULTS: Fifty of the largest insurance company policies were included. With regards to TDM policy for anti-TNF, we did not find a difference between baseline and 6 months values (P=0.38). With regards to TDM policy for thiopurine, we did not find a difference between baseline and 6 months values (P=1.00). About half of the companies did not have a policy regarding TPMT testing for thiopurine use. Of those with available policies for TPMT testing, there was no difference between baseline and 6 months values (P=0.13). CONCLUSIONS: Even after publication of national guidelines, a large number of the largest health insurance companies do not have a policy regarding reactive TDM for anti-TNF and/or thiopurines. Majority of those with a policy, fail to meet the current standards set forth by the practice guidelines. A significant gap remains between the insurance policies and AGA guidelines. Further studies are needed to determine how to effectuate change to improve insurance company adherence to clinical practice guidelines. PMID- 30439760 TI - Probiotic Yogurt for the Prevention of Antibiotic-associated Diarrhea in Adults: A Randomized Double-blind Placebo-controlled Trial. AB - GOAL: To evaluate the effect of yogurt supplemented with probiotic bacteria on the prevention of antibiotic-associated diarrhea (AAD) in hospitalized patients. BACKGROUND: Diarrhea following antibiotic administration is a frequent clinical problem. The usefulness of probiotics for the prevention of AAD in the hospitalized adult population remains unclear. STUDY: A randomized, double-blind, placebo-controlled clinical trial was conducted in hospitalized patients who started antibiotic treatment. Patients were randomized (2:2:1) to receive a daily amount of 200 mL of placebo-yogurt (Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus), 200 mL of probiotic yogurt (previous plus Lactobacillus acidophilus La-5, Bifidobacterium animalis subsp. lactis Bb-12 and Lactobacillus casei subsp. casei Lc-01 or no yogurt (unblinded control) within 48 hours of beginning the antibiotic therapy and up to 5 days after stopping the antibiotic. Patients were followed up with for 1 month to determine occurrence of diarrhea. RESULTS: We included 314 patients, mean age 76 years. The rate of diarrhea was 23.0% in the probiotic group versus 17.6% in the placebo group, absolute risk reduction -5.35% (95% confidence interval, -15.4% to 4.7%; P=0.30). Rate of diarrhea was similar in the unblinded external control and in the blinded study groups combined (20.9% vs. 20.2% respectively; P=0.91). There was no difference in the duration of diarrhea, maximum number of bowel movements or prolonged admission because of diarrhea among the groups. All-cause mortality did not differ between groups. CONCLUSIONS: The combined probiotic strains LA-5, BB 12, and LC-01 do not have an effect in the prevention of AAD in hospitalized patients. PMID- 30439761 TI - Clinical Predictors for Poor Quality of Life in Patients With Covert Hepatic Encephalopathy. AB - BACKGROUND: Current EASL/AASLD guidelines recommend treatment of covert hepatic encephalopathy (HE) only in symptomatic patients, for example, in those with impaired quality of life or with affected driving abilities. GOALS: Because testing for impaired quality of life is time consuming, the aim of the present study was to identify simple clinical predictors for poor quality of life in patients with covert HE (CHE). STUDY: In total, 139 cirrhotic in- and outpatients without a history of overt hepatic encephalopathy were enrolled. Diagnosis of HE grade 1 (HE1) was diagnosed clinically according to the West-Haven Criteria. Critical flicker frequency and the Psychometric Hepatic Encephalopathy Score were used to detect minimal HE (MHE). Chronic Liver Disease Questionnaire was used to assess health-related quality of life (HrQoL). RESULTS: CHE was detected in 51 (36.7%) patients. Multivariate analysis identified a history of falls in the previous year (P=0.003) and female gender (P=0.030) as independent predictors of reduced HRQoL in patients with CHE. Comparison of patients with and without a history of falls revealed relevant differences in the subdomains-abdominal symptoms, fatigue, systemic symptoms, emotional functions and worries. CONCLUSIONS: A history of falls and female gender are associated with impaired HRQoL in patients with CHE. These data indicate that a history of falls should be considered as a treatment indication in patients with CHE to improve HRQoL and ultimately prognosis. PMID- 30439762 TI - A Theory-based Educational Pamphlet With Low-residue Diet Improves Colonoscopy Attendance and Bowel Preparation Quality. AB - GOALS/BACKGROUND: Patients who "no-show" for colonoscopy or present with poor bowel preparation waste endoscopic resources and do not receive adequate examinations for colorectal cancer (CRC) screening. Using the Health Belief Model, we modified an existing patient education pamphlet and evaluated its effect on nonattendance rates and bowel preparation quality. STUDY: We implemented a color patient education pamphlet to target individual perceptions about CRC and changed bowel preparation instructions to include a low-residue diet instead of the previous clear liquid diet. We compared the nonattendance rate over a 2-month period before and after the introduction of the pamphlet, allowing for a washout period during which pamphlet use was inconsistent. We compared the Boston Bowel Preparation Scale (BBPS) in 100 consecutive patients who underwent colonoscopy during each of the 2 periods. RESULTS: Baseline characteristics between the 2 groups were similar, although patients who received the pamphlet were younger (P=0.03). The nonattendance rate was significantly lower in patients who received the pamphlet (13% vs. 21%, P=0.01). The percentage of patients with adequate bowel preparation increased from 82% to 86% after introduction of the pamphlet, although this was not statistically significant (P=0.44). The proportion of patients with a BBPS score of 9 was significantly higher in the pamphlet group (41% vs. 27%, P=0.03). There was no difference in adenoma and sessile serrated adenoma detection rates before and after pamphlet implementation. CONCLUSIONS: After implementing a theory-based patient education intervention with a low-residue diet, our absolute rate for colonoscopy nonattendance decreased by 8% and the proportion of patients with a BBPS score of 9 increased by 14%. The Health Belief Model appears to be a useful construct for CRC screening interventions. PMID- 30439763 TI - The Model to Estimate Survival in Ambulatory Hepatocellular Carcinoma Patients Aids in the Decision for TACE Retreatment. AB - BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a major therapeutic modality for patients with unresectable hepatocellular carcinoma, which needs repeated treatments. Model to Estimate Survival in Ambulatory Hepatocellular carcinoma patients (MESIAH) was recently developed as a model for predicting survival. We aimed to develop a novel index for TACE retreatment using MESIAH scores. PATIENTS AND METHODS: From 2005 to 2008, 783 patients with hepatocellular carcinoma who had undergone 1 previous TACE procedure were enrolled. We calculated their pre-TACE and post-TACE-MESIAH and calculated the MESIAH ratio by dividing the post-TACE by pre-TACE score. The discriminatory abilities of the MESIAH ratio and post-TACE-MESIAH were compared with ART and ABCR scores. RESULTS: Among 783 patients, 355 (45.3%) received a second TACE (test set), and 195 (24.9%) patients received a third TACE treatment (validation set). In the test set, patients with a MESIAH ratio <0.9 obtained longer overall survival than patients with a MESIAH ratio >=0.9 [26.0 vs. 9.0 mo, respectively; hazard ratio 1.66 (1.29-2.14)], and patients with a post-TACE-MESIAH<4.5 showed longer overall survival than patients with a post-TACE-MESIAH>=4.5 [38.0 vs. 7.0 mo, respectively; hazard ratio, 3.17 (2.45-4.09)]. The post-TACE-MESIAH [C-index 0.663 (0.628-0.697)] was better than the ART [C-index 0.596 (0.554-0.638)] and ABCR scores [C-index 0.576 (0.536-0.617)] at estimating prognosis. Our results were confirmed by the validation set. CONCLUSIONS: A MESIAH score >=4.5 after TACE identifies patients with a poor prognosis. Randomized studies are needed to establish whether additional TACE may affect survival. PMID- 30439764 TI - Insufficient Evidence to Diagnose Intrauterine Transmission of Hepatitis B Virus. PMID- 30439765 TI - A Systematic Review of the Reported Proportions of Diagnoses for Dizziness and Vertigo. AB - OBJECTIVES: To determine the typical proportions of diagnoses for patients presenting with dizziness or vertigo based on clinical speciality and to assess the change in proportions of diagnoses over time. DATA SOURCES: Following PRISMA guidelines, systematic searches of PubMed and CINAHL databases and follow-up reference searches were performed for articles published in English up to October 2016. STUDY SELECTION: Analysis of searches yielded 42 studies meeting the criteria of case series of adult patients with dizziness and/or vertigo presenting to general practice, emergency departments or specialist outpatient clinics. DATA EXTRACTION: Data comprising demographics, diagnostic cases, and the total number of cases were recorded and independently tested, followed by a risk of bias analysis. DATA SYNTHESIS: Sample size weighted proportions expressed as percentages with confidence intervals were calculated and compared using chi analysis and a reference proportion formed by the combination of Ear Nose and Throat and Neurotology case series published between 2010 and 2016. Analysis of diagnostic trends over time used Poisson regression with consideration for overdispersion. CONCLUSIONS: This systematic review of case series demonstrated significant differences in the proportions of diagnoses for patients presenting with dizziness or vertigo, depending on the specialty making the diagnosis. ENT proportions were dominated by BPPV, Psychogenic and Meniere's disease diagnostic categories, whereas emergency proportions were dominated by Other, Cardiac, and Neurological categories. Analysis of case series proportions over time revealed increases in diagnoses such as Benign Paroxysmal Positional Vertigo and Vestibular Migraine, and a corresponding decrease in the diagnoses of Meniere's disease. PMID- 30439766 TI - Post-transcriptional, post-translational and pharmacological regulation of tissue factor pathway inhibitor. AB - : Tissue factor (TF) pathway inhibitor (TFPI) is an endogenous natural anticoagulant that readily inhibits the extrinsic coagulation initiation complex (TF-FVIIa-Xa) and prothrombinase (FXa, FVa and calcium ions). Alternatively, spliced TFPI isoforms (alpha, beta and delta) are expressed by vascular and extravascular cells and regulate thrombosis and haemostasis, as well as cell signalling functions of TF complexes via protease-activated receptors (PARs). Proteolysis of TFPI plays an important role in regulating physiological roles of the TF pathway in host defense and possibly haemostasis. Elimination of TFPI inhibition has therefore been proposed as an approach to improve haemostasis in haemophilia patients. In this review, we focus on posttranscription and translational modification of TFPI and its function in thrombosis and how pharmacological inhibitors and endogenous proteases interfere with TFPI and alter haemostasis. PMID- 30439767 TI - Prediction of bleeding by thromboelastography in ICU patients with haematological malignancy and severe sepsis. AB - : ICU patients with haematological malignancy have an increased risk of bleeding. Recently, global haemostatic methods such as thromboelastography (TEG) have gained impact in evaluating coagulation. The aim of this study was to observe whether TEG could predict bleeding in haematological ICU patients with severe sepsis. Post-hoc single-centre analysis of patients with haematological malignancy included in the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial. Clinical characteristics, TEG measurements and details regarding bleeding complications were retrieved from the 6S database. The association between TEG and bleeding were analysed by Cox regression and receiver operating characteristic curves. A total of 202 patients with severe sepsis were admitted to the ICU of Rigshospitalet, Copenhagen and included in the 6S trial. Forty-one had haematological malignancy and were analysed in the current study. During ICU stay, 20 patients (49%) had bleeding complications and 13 (32%) patients bled within the first 5 ICU days. We observed no associations between TEG and subsequent bleeding in Cox regression models. TEG variables at baseline had low predictive value for bleeding. Baseline TEG variables did not add value in identifying patients with high risk of bleeding in ICU patients with haematological malignancy and severe sepsis. PMID- 30439768 TI - Prevalence of factor VIII inhibitors among Afghan patients with hemophilia A: a first report. AB - : Prevalence of inhibitors in Afghan hemophilia patients has not been reported previously. Our aim was to determine the prevalence of factor VIII inhibitors among hemophilia A patients from the Kabul province of Afghanistan to identify and characterize the pattern of inhibitor formation. Clinical information and blood samples were collected from three hemophilia centers in Kabul, Afghanistan. Plasma samples were obtained from 62 patients with severe (80.5%) and 15 patients with moderate hemophilia A (19.5%) in this cross-sectional study design. All the patients were receiving on-demand treatment. The Nijmegen modification of the Bethesda assay was used to detect inhibitors. Multiplex PCR, inverse-PCR, Multiplex ligation-dependent probe amplification and direct sequencing were performed for genotyping. Inhibitor activity was detected in one out of 15 (6.7%) patients with moderate hemophilia and in six out of 62 (9.7%) with severe disease. Apart from the intron 22 inversion, five different mutations including one missense, two large and two small deletions were detected. This is the first report showing that the prevalence of inhibitors in Afghan hemophilia A patients is much lower than in other populations. PMID- 30439769 TI - Protein C deficiency (a novel mutation: ala291Thr) with systemic lupus erythematosus leads to the deep vein thrombosis. AB - : The current study aims to explore the phenotype and genotype of a mutation Ala291Thr, which responsible for type I protein C (PC) deficiency in a Chinese woman. The PROC antigen was tested with chromogenic substrate method. PROC gene were amplified by PCR with direct sequencing. Bioinformatics and model analysis were used to study the harm of the mutation. PC activity (PC: A) levels of three members were reduced to 39, 57 and 56%, respectively, PC: antigen was decreased parallelly same as PC: A. Sequencing analysis showed proband with a novel heterozygous c.997G>A point mutation in exon 9 of PROC gene resulting in Ala291Thr. The Ala291Thr mutation is responsible for the decrease of PC: A, which is cross-reacting material negative deficiency and the first reported in the world. This mutation alone may not have significant clinical symptoms, whereas it will cause deep vein thrombosis when combined with systemic lupus erythematosus. PMID- 30439771 TI - Adverse childhood experiences and implementing trauma-informed primary care. PMID- 30439770 TI - ICH NP/APNN 2018 conference advances the NP role globally. PMID- 30439772 TI - Drug updates and approvals: 2018 in review. PMID- 30439773 TI - Prediabetes: Early identification and management. AB - Prediabetes continues to be a national and worldwide health concern, affecting 84 million adults in the US. Early identification and intervention have been successful in delaying and/or preventing the progression to type 2 diabetes mellitus (T2DM). Nonpharmacologic treatment of prediabetes is paramount, although pharmacologic treatment is appropriate in high-risk patients. In an attempt to curb the increasing prevalence of T2DM, recognizing the importance of identifying and managing prediabetes should remain in the national healthcare forefront. PMID- 30439774 TI - Israeli staff nurse knowledge and perception of the nurse practitioner role. AB - This study assessed Israeli nurses' knowledge of the emerging role of master's prepared NPs. Based on an integrated review of the literature, a study-specific survey was developed, including dichotomous knowledge items, Likert scored perception items, and self-disclosed demographic data. Analyses of the 146 responses revealed that exposure to NPs was limited. Knowledge specific to the role or clinical competency was lacking, yet the assessment capabilities and overall perception of NPs were positive. Data demonstrate a willingness to include NPs in the care model and an awareness that doing so would positively contribute to the overall health of patients. PMID- 30439775 TI - NCNP Fall 2018 recap. AB - The National Conference for Nurse Practitioners (NCNP) Fall 2018 meeting took place in sunny Anaheim, California, September 19 to 22 at the Anaheim Marriott Hotel. PMID- 30439777 TI - Neurocognitive and Metacognitive Profiles of Intact Social Cognition in Prolonged Schizophrenia. AB - Social cognition (SC) appears to contribute to long-term outcomes in schizophrenia; however, little is known about whether different forms of SC are supported by the same cognitive processes. Accordingly, we examined the relationship of two domains of SC: emotion recognition (ER), using the Bell Lysaker Emotion Recognition Test, and social inference (SI), using the Social Attribution Task-Multiple Choice, to measures of neurocognition, metacognition, theory of mind (ToM), and symptoms. Participants were 72 adults with schizophrenia in a nonacute phase. Multivariate analysis of variance and univariate analysis of variance revealed participants with intact ER had better neurocognition (MATRICS Consensus Cognitive Battery [MCCB]), metacognition (Metacognition Assessment Scale-Abbreviated), ToM (The Hinting Task), and higher emotional discomfort symptoms than participants with impaired scores. Participants with intact SI had higher MCCB visual and verbal learning and SC scores. Stepwise regressions revealed neurocognition and metacognition uniquely contribute to ER performance. Results suggest ER and SI are differentially related to cognitive processes. PMID- 30439778 TI - Therapy Adherence and Emotional Awareness and Regulation in Persons With Human Immunodeficiency Virus. AB - Adherence to antiretroviral therapy (ART) is a key issue for people with human immunodeficiency virus. Optimal adherence leads to benefits in terms of survival and quality of life, which do not occur with incomplete adherence. One factor that may influence adherence to ART is emotional unawareness deficits. To explore this possibility, we assessed emotional deficits and measured adherence in 100 adults using both self-report and viral load testing. Results showed that people classified as adherent in both measurements were more likely to have a greater awareness of their own emotions. Participants classified as nonadherent were more likely to have a reduced ability to recognize the emotions of others. Difficulty in recognizing one's own emotions, otherwise known as alexithymia, and impairment of the ability to recognize other's emotions may contribute to nonadherence to ART. Consequently, after repeated studies to confirm the findings, it can be considered a target for psychological therapies aimed at increasing adherence. PMID- 30439779 TI - Characteristics of Parents With High Expressed Emotion and Related Factors: A Study of Parents of Adults With Schizophrenia. AB - This study aimed to clarify characteristics of parents with high expressed emotion (EE) and related factors among parents of adults with schizophrenia. In total, 73 (25.3%) of the 289 parents had high EE (Family Attitude Scale [FAS] score >=60), and 216 (74.7%) had low EE (FAS score <60). A multiple logistic regression analysis showed that high EE parents were more distressed (odds ratio [OR] = 1.27; 95% confidence interval [CI] = 1.16-1.39) and experienced more physical violence from their adult children with schizophrenia (OR = 2.86; 95% CI = 1.28-6.43); the children with schizophrenia had been hospitalized at time of survey (OR = 6.54; 95% CI = 1.10-38.89) and were less likely to attend rehabilitation services (OR = 2.56; 95% CI = 1.06-6.17). Practitioners need to provide crisis intervention, home-visiting services, and support services for parents during hospitalization of their children with schizophrenia. PMID- 30439780 TI - The Effect of Psychoeducation on Anxiety in Women Undergoing Their Initial Breast Cancer Screening Mammography. AB - We conducted a prospective, randomized, single-blinded study to determine whether a psychoeducational intervention for patients undergoing screening mammography could influence the level of anxiety related to the procedure. Fifty women undergoing mammography for the first time were included in the study and randomized to two groups. In the study group, patients received a psychoeducational session before mammography. In the control group, psychoeducation was not applied. To evaluate the level of anxiety, we used the State-Trait Anxiety Inventory. State Anxiety Scale (S-Anxiety) score and Trait Anxiety Scale (T-Anxiety) scores were assessed before and after mammography in both groups. After evaluating the S-Anxiety score in the study group before mammography and after the procedure, a statistically significant difference (p = 0.043) was observed. In contrast, no statistically significant changes were noticed in the control group (p = 0.886). Our study showed that psychoeducation reduced state anxiety among the participants of a breast cancer screening. PMID- 30439781 TI - Investigating the Link Between Pathological Narcissism and Somatization. AB - Although the self-image distortions and sensitivities of pathological narcissism have been theorized to contribute to somatization, limited empirical research has been devoted to this issue. The present study was developed to test the hypothesis that pathological narcissism contributes to somatic symptoms through increased hypervigiliance to physical sensations. A community sample of 248 adults completed measures of pathological narcissism, somatosensory amplification, somatic symptoms, and depression. Mediation analysis was conducted, controlling for depression, using 99% bootstrapped confidence intervals to examine the indirect effect of pathological narcissism on somatic symptoms via somatosensory amplification. Although pathological narcissism was not directly related to somatic symptoms, a significant indirect effect was observed for pathological narcissism on somatic symptoms via somatosensory amplification. This finding suggests that pathological narcissism contributes to physical hypersensitivity, in turn influencing perceptions of somatic distress. The role of narcissistic dysfunction in somatization indicates the importance of further research and potential clinical consideration. PMID- 30439782 TI - Prospective Patterns of Help-Seeking Behavior Among Military Veterans With Probable Posttraumatic Stress Disorder and Major Depressive Disorder. AB - This study examined help-seeking behavior from professional, informal, and religious sources in veterans with a probable need for treatment. In total, 93 veterans who screened positive for posttraumatic stress disorder/major depressive disorder completed assessments of help-seeking at two time points spaced apart by 6 months. Less than half (40%) reached out to a mental health professional or physician; only 1 in 10 engaged with providers who specialize in evidence-based therapies to a minimally adequate degree. Although roughly two thirds pursued help from informal sources, less than 10% similarly sought help nine or more times. Veterans with high willingness to seek help from specific sources at baseline were more likely to report sustained engagement in help-seeking behavior along these same lines at follow-up. Assessing veterans' help-seeking intentions may add prognostic value in predicting engagement in services. Veterans may also benefit from tailoring service delivery models according to preferred sources of help in their families and communities. PMID- 30439783 TI - How Music Impacts Visual Attention Training in Schizophrenia: A Pilot Study. AB - Music has been demonstrated to improve cognitive test performance in neuropsychiatric populations. However, the impact of music on cognitive training effects, and the importance of music preference, has yet to be studied. This is an essential oversight because many cognitive training programs play music in the background. We sought to determine if participant-preferred or random music would increase the efficacy of computer-based attention training (AT). Forty-eight patients with schizophrenia were randomly assigned to 2 weeks of either: 1) AT with participants' choice of background music, 2) AT with random background music, 3) AT without music, or 4) a no training or music control-watching videos without AT or music. All groups except the no training/no music control group demonstrated improvement in reaction time and response accuracy after training, with those participating in AT with their choice of music exhibiting greater gains than either of the other two AT groups. These findings suggest that complimenting AT with music, and allowing participants to choose the music, may increase the efficacy of AT. PMID- 30439784 TI - Multimodal Imaging of Spontaneous Suprachoroidal Hemorrhage Associated With Pathologic Myopia. PMID- 30439785 TI - Physiological and Perceived Exertion Responses during Exercise: Effect of beta blockade. AB - PURPOSE: This study investigated the effect of beta-blockade on physiological and perceived exertion (RPE) responses during incremental treadmill exercise. METHODS: Sixteen healthy participants (n=8 men; age 25.3+/-4.6 y) performed a maximal treadmill exercise test following ingestion of 100 mg Metoprolol or placebo, with a double-blind, randomised and counter-balanced design. Heart rate (HR), ventilatory and gas exchange variables were measured continuously, and participants reported RPE at the end of each minute. Physiological and RPE responses during each condition were compared at the ventilatory threshold (VT), respiratory compensation point (RCP) and at maximal exercise using repeated measures ANOVA. Linear regression modelled relationships between perceived exertion and physiological variables. RESULTS: The HR and V[Combining Dot Above]O2 at the VT, RCP and maximal exercise were all significantly lower following beta-blockade (p<.05). However, when standardised to within condition peak values, differences were no longer significant. The RPE associated with VT was higher following beta-blockade (12.9+/-1.0 vs 12.3+/-1.2, p<.05), but lower at maximal exercise (19.1+/-0.6 vs. 19.4+/-0.5, p<.05). Increases in RPE relative to HR were greater following beta-blockade and remained significant when expressed relative to peak HR. There was no difference in the growth of the relationship between RPE and V[Combining Dot Above]O2 across conditions, though the origin of the relationship was higher with beta-blockade. CONCLUSIONS: Although beta-blockade resulted in a significant reduction in exercising HR and V[Combining Dot Above]O2, the RPE for a given relative intensity remained unchanged. The relationship between RPE and V[Combining Dot Above]O2 was not affected by beta-blockade. The results provide evidence that RPE is a useful and reliable measure for exercise testing and prescription in patients prescribed beta-blockade therapy. PMID- 30439786 TI - Two-Day Residence at 2500 m to 4300 m Does Not Affect Subsequent Exercise Performance at 4300 m. AB - PURPOSE: To determine the efficacy residing for two days at various altitudes while sedentary (S) or active (A; ~90 min hiking 2*day) on exercise performance at 4300m. METHODS: SL resident men (n=45) and women (n=21) (mean+/-SD; 23+/-5 yr; 173+/-9 cm; 73+/-12 kg; VO2peak= 49+/-7 ml*kg*min) were randomly assigned to a residence group and, S or A within each group: 2500m (n=11S, 8A); 3000m (n=6S, 12A); 3500m (n=6S, 8A); or 4300m (n=7S, 8A). Exercise assessments occurred at SL and 4300 m after 2 days residence and consisted of 20 min of steady-state (SS) treadmill walking (45+/-3% SL VO2peak) and a 5-mile, self-paced running time trial (TT). Arterial oxygen saturation (SpO2) and heart rate (HR) were recorded throughout exercise. Resting SpO2 was recorded at SL, at 4 and 46 hrs of residence, and at 4300 m prior to exercise assessment. To determine if 2-day altitude residence improved 4300 m TT performance, results were compared to estimated performances using a validated prediction model. RESULTS: For all groups, resting SpO2 was reduced (P<0.01) after 4 hrs of residence relative to SL inversely to the elevation and did not improve after 46 hrs. Resting SpO2 (~83%) did not differ among groups at 4300 m. While SL and 4300 m SS exercise SpO2 (97+/ 2 to 74+/-4%), HR (123+/-10 to 140+/-12 b*min) and TT duration (51+/-9 to 73+/-16 min) were different (P<0.01), responses at 4300 m were similar among all groups, as was actual and predicted 4300 m TT performances (74+/-12 min). CONCLUSIONS: Residing for two days at 2500m to 4300m, with or without daily activity, did not improve resting SpO2, SS exercise responses, or TT performance at 4300m. PMID- 30439787 TI - Anticipated Task Difficulty Provokes Pace Conservation and Slower Running Performance. AB - PURPOSE: Models of self-paced endurance performance suggest that accurate knowledge of the exercise end-point influences pace-related decision-making. No studies have examined the effects of anticipated task difficulty during equidistant endurance activities. Accordingly, the purpose of this study was to investigate the effects of anticipated task difficulty on pacing, psychological, and physiological responses during running time-trials. METHODS: Twenty-eight trained runners completed three self-paced 3000 m time-trials. The first was a baseline (BL) time-trial completed on a 0% treadmill gradient. Time-trials 2 and 3 were counterbalanced. Before a known incline (KI) time-trial, anticipated to be more difficult, subjects were accurately informed that the gradient would increase to 7% for the final 800 m. Before an equivalent, unknown incline (UI) time-trial subjects were deceptively informed that the gradient would remain at 0% throughout. RESULTS: Expressed relative to BL, running speed was 2.44% slower (d = -0.47) over the first 2200 m during KI than UI. Effort perception, affective valence, heart rate, and blood lactate did not differ between time-trials. Initial running speed during KI was related to pre-trial motivation, pre-trial vigor, perceived effort, and affective valence (all r >= .382). No such relationships existed during UI. More subjects also reported a conscious focus on pacing during KI. CONCLUSION: An anticipated increase in task difficulty provoked pace conservation during 3000 m running time-trials. The reduced pace may have resulted from greater task uncertainty and consciously aware, effort- and affect based decisions to conserve energy and maintain hedonic state during KI. The findings add to theoretical understandings of factors that influence pacing during endurance activity. Consequently, recommendations to minimize the potentially deleterious effects of anticipated increases in task difficulty are provided. PMID- 30439788 TI - Single versus Split Dose of Iron Optimizes Haemoglobin Mass Gains at 2106 m Altitude. AB - PURPOSE: To determine if a single versus a split equivalent daily dose of elemental iron was superior for haemoglobin mass (Hbmass) gains at altitude, while minimizing gastrointestinal (GI) discomfort. METHODS: Twenty-four elite runners attended a 3.1 +/- 0.3 week training camp (Flagstaff, AZ; 2106 m). A two group design, randomized and stratified to baseline Hbmass, sex and ferritin (>30 MU/L), was implemented daily as: 1) single dose of 1 x 200 mg (PM only, SINGLE) vs; 2) split dose of 2 x 100 mg (AM & PM; SPLIT) elemental iron (ferrous fumarate). Hbmass and venipuncture assessments were completed upon arrival and departure (+/- 2 days) from camp for ferritin, hepcidin and erythroferrone (ERFE) concentrations. Validated food frequency (FFQ), GI-distress, menstrual blood loss (MBL) and training questionnaires were implemented throughout. Univariate analysis was used to compare Hbmass; with baseline ferritin, dietary iron intake, MBL and training volume used as covariates. RESULTS: Both conditions increased Hbmass from baseline (p<0.05), with SINGLE (867.3 +/- 47.9 g) significantly higher than SPLIT (828.9 +/- 48.9 g) (p=0.048). GI-scores were worse in SINGLE for weeks 1 & 2 combined (SINGLE: 18.0 +/- 6.7 points, SPLIT: 11.3 +/- 6.9 points, p=0.025), however, GI-scores improved by week 3, resulting in no between group differences (p=0.335). Hepcidin significantly decreased over time (p=0.043) in SINGLE, with a non-significant decrease evident in SPLIT (~22%). ERFE significantly decreased in both groups (~28.5%; p<0.05). No between group differences existed for ERFE, hepcidin, FFQ, MBL or daily training outcomes (p>0.05). CONCLUSION: A single nightly 200 mg dose of elemental iron was superior to a split dose for optimizing Hbmass changes at altitude in runners over a ~3 week training camp. PMID- 30439789 TI - Discrimination of Anti-drug Antibodies With Neutralizing Capacity in Infliximab- and Adalimumab-Treated Patients: Comparison of the Homogeneous Mobility Shift Assay and the Affinity Capture and Elution Assay. AB - BACKGROUND: The measurement of anti-drug antibody (ADA) levels in adalimumab (ADAL)-treated and infliximab (IFX)-treated patients is critical for guiding therapeutic strategies. The homogeneous mobility shift assay (HMSA) and affinity capture elution (ACE) assay provide effective, drug-tolerant formats for measuring total ADA levels. However, their ability to discriminate between ADA from samples with or without neutralizing capacity is unclear and therefore was analyzed in this study. METHODS: Sera from ADAL and IFX patients with low drug levels (<1 mcg/mL) were analyzed by ACE, HMSA, and bridging assay. Neutralizing capacity was determined by competitive ligand-binding assay. RESULTS: HMSA and ACE detected high ADA levels in all ADAL (19/42) and IFX (27/64) samples with neutralizing capacity. ADA was also detected in most of the samples without neutralizing capacity, but levels were significantly lower (P < 0.0001). Receiver operator characteristic curve analysis demonstrated that for both assays, ADA levels were a strong discriminatory marker of neutralizing ADA (area under the curve > 0.9, P < 0.0001). Using a signal >8* background as a cut-point, neutralizing ADA could be identified with high specificity (HMSA > 95%, ACE > 85%) and sensitivity (HMSA > 70%, ACE > 80%). The detection of multimeric drug ADA complexes after HMSA was also a highly specific marker (specificity > 95%) of neutralizing ADA in both ADAL and IFX patients. Results using ACE and HMSA were highly correlated. CONCLUSIONS: Results obtained after HMSA and ACE analysis are strongly correlated, and in both assays, high ADA levels are a specific marker of neutralizing capacity. The detection of multimeric complexes by HMSA also selectively identifies sera with neutralizing capacity. These data support the use of these assays as quantitative rather than simple qualitative measures of ADA. PMID- 30439790 TI - Evaluation of Infliximab and Anti-infliximab LISA-TRACKER Immunoassays for the Therapeutic Drug Monitoring of SB2 Infliximab Biosimilar. AB - BACKGROUND: SB2, an infliximab (IFX) biosimilar to the reference infliximab (R.I.) product (Remicade), received approval in the European Union for all IFX indications. Many decision algorithms based on the measurement of IFX trough levels and antibodies to infliximab are being increasingly used to optimize IFX treatment. The aim of our study was to evaluate whether the biosimilar SB2 could be efficiently monitored using the LISA-TRACKER IFX and anti-IFX assays developed by Theradiag (Croissy Beaubourg, France). METHODS: Standard curves of R.I. and SB2 were compared, and then accuracy of the LISA-TRACKER IFX assay in detecting the spiked concentration of SB2 was measured. Levels of IFX from SB2 spiked samples and R.I. clinical samples were calculated. Intra-run and inter-run imprecision were also measured with SB2 spiked samples. The ability of polyclonal antibodies directed against R.I. to block the detection of SB2 using the LISA TRACKER IFX assay and the capacity of SB2 to block the detection of anti-R.I. antibodies using the LISA-TRACKER anti-IFX assay were tested. RESULTS: Twelve patients treated with SB2 including 2 patients with SB2-specific antibodies were measured with the LISA-TRACKER anti-IFX assay. We demonstrated that the LISA TRACKER assay is suitable for the quantification of SB2 in human serum samples. The percentage of recovery was between 82% and 113%. High intra-run and inter-run imprecisions were obtained with the LISA-TRACKER infliximab assay for the quantification of SB2 (SD ranged from 3.3% to 17.9%). The SB2-blocking capacity of R.I. polyclonal antibodies in spiked samples was demonstrated with inhibition between 80% and 97%. SB2 trough levels and anti-SB2 antibodies have also been confirmed in SB2-treated patients. CONCLUSIONS: LISA-TRACKER IFX and anti-IFX assays are suitable for the monitoring of patients treated with SB2. PMID- 30439791 TI - Care Coordination and Population Health Management Strategies and Challenges in a Behavioral Health Home Model. AB - OBJECTIVES: Behavioral health home (BHH) models have been developed to integrate physical and mental health care and address medical comorbidities for individuals with serious mental illnesses. Previous studies identified population health management capacity and coordination with primary care providers as key barriers to BHH implementation. This study examines the BHH leaders' perceptions of and organizational capacity to conduct these functions within the community mental health programs implementing BHHs in Maryland. METHODS: Interviews and surveys were conducted with 72 implementation leaders and 627 front-line staff from 46 of 48 Maryland BHH programs. In-depth coding of the population health management and primary care coordination themes identified subthemes related to these topics. RESULTS: BHH staff described cultures supportive of evidence-based practices, but limited ability to effectively perform population health management or primary care coordination. Tension between population health management and direct, clinical care, lack of experience, and state regulations for service delivery were identified as key challenges for population health management. Engaging primary care providers was the primary barrier to care coordination. Health information technology and staffing were barriers to both functions. CONCLUSIONS: BHHs face a number of barriers to effective implementation of core program elements. To improve programs' ability to conduct effective population health management and care coordination and meaningfully impact health outcomes for individuals with serious mental illness, multiple strategies are needed, including formalized protocols, training for staff, changes to financing mechanisms, and health information technology improvements. PMID- 30439792 TI - The Effects of the Patient Protection and Affordable Care Act on Children's Health Coverage. AB - BACKGROUND: Prior research of the impacts of the Patient Protection and Affordable Care Act (PPACA) on children's health coverage has been largely descriptive and focused on the Medicaid expansions. OBJECTIVE: This study examined the causal impacts of the PPACA Medicaid expansions and of the PPACA as a whole on children's health coverage through 2016. RESEARCH DESIGN: We utilized quasiexperimental difference in differences designs to estimate the Medicaid expansion and overall PPACA effects. The first model compared coverage changes between Medicaid expanding and nonexpanding states by household income level. The second model identified the overall PPACA effects by estimating coverage changes across differences in pre-PPACA area-level uninsured rates in expanding states for which the identifying assumptions were valid. We used data from the American Community Survey for years 2011 through 2016 for 3,630,988 children aged 0-18 years living in the 50 states and District of Columbia. RESULTS: The PPACA Medicaid expansions led to gains in public coverage for children at <=405% federal poverty line especially in 2015-2016. Gains were largest for children at 138%-255% federal poverty line (~4 percentage-point increase in 2016). These gains however were mostly due to switching from private to public coverage (ie, crowd-out effects). As a whole however, the PPACA reduced children's uninsured rate in Medicaid-expanding states by about 3 percentage-points in 2016. CONCLUSIONS: The PPACA resulted in a meaningful decline in children's uninsured rate in Medicaid-expanding states. PPACA provisions targeting private coverage take-up offset crowd-out effects of the Medicaid expansions resulting in lower children's uninsured rates. PMID- 30439793 TI - Lasso Regression for the Prediction of Intermediate Outcomes Related to Cardiovascular Disease Prevention Using the TRANSIT Quality Indicators. AB - BACKGROUND: Cardiovascular disease morbidity and mortality are largely influenced by poor control of hypertension, dyslipidemia, and diabetes. Process indicators are essential to monitor the effectiveness of quality improvement strategies. However, process indicators should be validated by demonstrating their ability to predict desirable outcomes. The objective of this study is to identify an effective method for building prediction models and to assess the predictive validity of the TRANSIT indicators. METHODS: On the basis of blood pressure readings and laboratory test results at baseline, the TRANSIT study population was divided into 3 overlapping subpopulations: uncontrolled hypertension, uncontrolled dyslipidemia, and uncontrolled diabetes. A classic statistical method, a sparse machine learning technique, and a hybrid method combining both were used to build prediction models for whether a patient reached therapeutic targets for hypertension, dyslipidemia, and diabetes. The final models' performance for predicting these intermediate outcomes was established using cross-validated area under the curves (cvAUC). RESULTS: At baseline, 320, 247, and 303 patients were uncontrolled for hypertension, dyslipidemia, and diabetes, respectively. Among the 3 techniques used to predict reaching therapeutic targets, the hybrid method had a better discriminative capacity (cvAUCs=0.73 for hypertension, 0.64 for dyslipidemia, and 0.79 for diabetes) and succeeded in identifying indicators with a better capacity for predicting intermediate outcomes related to cardiovascular disease prevention. CONCLUSIONS: Even though this study was conducted in a complex population of patients, a set of 5 process indicators were found to have good predictive validity based on the hybrid method. PMID- 30439794 TI - A Comparison of Methods for Classifying and Modeling Respondents Who Endorse Multiple Racial/Ethnic Categories: A Health Care Experience Application. AB - BACKGROUND: Race/ethnicity information is vital for measuring disparities across groups, and self-report is the gold standard. Many surveys assign simplified race/ethnicity based on responses to separate questions about Hispanic ethnicity and race and instruct respondents to "check all that apply." When multiple races are endorsed, standard classification methods either create a single heterogenous multiracial group, or attempt to impute the single choice that would have been selected had only one choice been allowed. OBJECTIVES: To compare 3 options for classifying race/ethnicity: (a) hierarchical, classifying Hispanics as such regardless of racial identification, and grouping together all non-Hispanic multiracial individuals; (b) a newly proposed additive model, retaining all original endorsements plus a multiracial indicator; (c) an all-combinations approach, separately categorizing every observed combination of endorsements. RESEARCH DESIGN: Cross-sectional comparison of racial/ethnic distributions of patient experience scores; using weighted linear regression, we model patient experience by race/ethnicity using 3 classification systems. SUBJECTS: In total, 259,763 Medicare beneficiaries age 65+ who responded to the 2017 Medicare Consumer Assessments of Healthcare Providers and Systems Survey and reported race/ethnicity. MEASURES: Self-reported race/ethnicity, 4 patient experience measures. RESULTS: Additive and hierarchical models produce similar classifications for non-Hispanic single-race respondents, but differ for Hispanic and multiracial respondents. Relative to the gold standard of the all combinations model, the additive model better captures ratings of health care experiences and response tendencies that differ by race/ethnicity than does the hierarchical model. Differences between models are smaller with more specific measures. CONCLUSIONS: Additive models of race/ethnicity may afford more useful measures of disparities in health care and other domains. Our results have particular relevance for populations with a higher prevalence of multiracial identification. PMID- 30439795 TI - Do Hospital and Physician Volume Thresholds for the Volume-Outcome Relationship in Heart Failure Exist? AB - BACKGROUND: Although volume-outcome relationships have been explored for various procedures and interventions, limited information is available concerning the effect of hospital and physician volume on heart failure mortality. Most importantly, little is known about whether there are optimal hospital and physician volume thresholds to reduce heart failure mortality. OBJECTIVES: We used nationwide population-based data to identify the optimal hospital and physician volume thresholds to achieve optimum mortality and to examine the relative and combined effects of the volume thresholds on heart failure mortality. METHODS: We analyzed all 20,178 heart failure patients admitted in 2012 through Taiwan's National Health Insurance Research Database. Restricted cubic splines and multilevel logistic regression were used to identify whether there are optimal hospital and physician volume thresholds and to assess the relative and combined relationships of the volume thresholds to 30-day mortality, adjusted for patient, physician, and hospital characteristics. RESULTS: Hospital and physician volume thresholds of 40 cases and 15 cases a year, respectively, were identified, under which there was an increased risk of 30-day mortality. Patients treated by physicians with previous annual volumes <15 cases had higher 30-day mortality compared with those with previous annual volumes >=15 cases, and the relationship was stronger in hospitals with previous annual volumes <40 cases. CONCLUSIONS: This is the first study to identify both the hospital and physician volume thresholds that lead to decreases in heart failure mortality. Identifying the hospital and physician volume thresholds could be applied to quality improvement and physician training. PMID- 30439796 TI - Empathy, Sense of Coherence and Resilience: Bridging Personal, Public and Global Mental Health and Conceptual Synthesis. AB - Different ways of thinking about policy-making for public and global mental health are constantly emerging. Turning patients into consumers and mental health into commodity may open the door for dystopic future of mental health care. Research has indicated that practicing love, kindness, and compassion for ourselves and others builds our confidence and sense of coherence, helps us create meaningful, caring relationships, increases individual and community resilience and well-being, promotes human rights, physical and mental health. Public and global mental health promotion may be predicated on the theory of salutogenesis and three key inter-related terms: empathy, coherence and resilience. The WHO Mental Health Action Plan 2013-20120 is based on the vision of a world in which mental health is valued, promoted and protected, and has four objectives: to improve leadership and governance, health and social care, promotion and prevention, and information and research. Practicing public and global actions that promote and educate empathy, coherence and resilience may significantly help achieving equality for mental health in the 21st century and improving public and global mental health. PMID- 30439797 TI - Forbidden insanity: the systematic denial of mental health issues from a state run psychiatry. AB - The authors discuss the issue of psychiatric care and patients during the second half of XX century in Albania, when the country was under an absolute regime of communism. Completely isolated from the rest of the world, the territory remained a prohibited area for scholars, and local authors due to censorship or self censorship, offered very scarce information. The general feeling of the public was that of a denial of psychic disorders in total, combined with the fear that this kind of disorders has ever since provoked. Nevertheless, insanity defence was a formulation encountered with a certain frequency in Albanian judicial procedures, although forensic psychiatry was a peripheral part of an already neglected medical specialty. The entire system of psychiatric care was mainly hospital based, and shock therapies (electroconvulsive therapy, pyretotherapy, insulin coma) were normal part of the therapeutic armamentarium along with antipsychotics and social isolation. Some recently unclassified documents and some archival papers, whose exhaustive consultation needs further study, might shed light to the problems of a psychiatry, that are not substantially different from the ones encountered in the Eastern communist Europe of the same period of time. PMID- 30439798 TI - Job Stressors and Slow Medicine in Health Care: A Scoping Review. AB - This paper provides a framework for addressing the stressors in modern medical health care, especially those that relate to psychology and psychiatry. Despite its advances, organized medicine is beset with inefficiencies and imperfections. The extent of burnout and stress for health professionals is documented in this scoping review. The impact on mental health is described and an approach based on a slower medicine is advocated. PMID- 30439799 TI - Big Data in Adolescent Psychiatry: Do Patients Share Their Psychiatric Symptoms on Social Networking Sites? AB - BACKGROUND: Fascinating developments in big data technologies and unprecedented diffusion of social networking sites (SNSs) generate unseen opportunities for scientific fields, including psychiatry. This study focuses on the use of SNSs by adolescent psychiatric patients and the potential use of SNS-generated data to help medical practitioners diagnose and treat patients' mental health. Our objective is to understand and measure the psychiatric and individual conditions in which symptom-sharing occurs on SNSs and the frequency of these conditions. Based on literature, we hypothesized that the perceived value of social network sites positively affects adolescents' sharing of symptoms on these sites. SUBJECTS AND METHODS: An empirical test of this hypothesis was conducted with a survey of 224 adolescents admitted to a psychiatry clinic in Turkey. The hypothesis was tested using a hierarchical multiple regression analysis. RESULTS: The perceived value of SNSs explained an additional 37.8% of variation in symptom sharing on SNSs above and beyond the control variables, which are gender, age, type of disorder, and amount of internet and SNS use. The findings suggested that adolescents share symptoms on SNSs only if they attribute value to the SNSs that they use. We also found that 72% of adolescents in our sample shared their symptoms on SNSs. CONCLUSIONS: There is an attractive opportunity for information technology companies to develop, together with health professionals; data analytics that are able to detect symptoms to support psychiatric diagnoses and pave the way for big-data enabled personalized medicine. PMID- 30439800 TI - Internet searches for "suicide", its association with epidemiological data and insights for prevention programs. AB - BACKGROUND: Literature demonstrates that analysis of internet search data is a useful tool in predicting the occurrence of illnesses and health-related behaviors. The aim of the study was to quantitatively present the trends in Google searches for the keyword "suicide" and to analyze its correlation with the number of suicides in Poland. SUBJECTS AND METHODS: We used the Google Trends tool to compile data for years 2004-2016. Statistical analysis was performed for annual, monthly, daily and hourly data. Official data on suicide in Poland were obtained from the Central Statistical Office and the General Police Headquarters of Poland. RESULTS: A gradual decrease in Google Relative Search Volume of the keyword "suicide" was observed in years 2004-2014, despite the significant increase of suicide rate in Poland (R=-0.24). Reverse correlation was also found between regional suicide coefficients and search volume (R=-0.22). The highest search volumes were recorded in winter months, first days of the week and at night hours (p<0.001). CONCLUSIONS: Presented results may contribute to more effective suicide prevention programs. By specifying the time intervals in which searching suicide information is the highest, it will become easier get to individuals at risk. PMID- 30439801 TI - Non-Suicidal Self-Injury among University Students in Turkey: The Effect of Gender and Childhood Abuse. AB - BACKGROUND: The purpose of this study was to explore the effect of gender and childhood abuse on non-suicidal self-injurious (NSSI) behaviors among university students in Turkey. SUBJECTS AND METHODS: In this study convenience sampling technique was used, the sample consisted of 1000 young adults who were from the eight universities in two big cities; Istanbul and Ankara. Besides with demographic questionnaire, Inventory of Statements about Self-Injury and Childhood Trauma Questionnaire were used. RESULTS: The prevalence of NSSI was 28.5% and the most prevalent three self-injurious behaviors were wound picking, banging/hitting and pinching self. There was not a gender difference in NSSI behavior frequency but in the type of behavior; males had significantly higher percentages of hitting and burning behavior. Examining the intrapsychic and interpersonal functions of NSSI, "affect regulation" and "toughness" functions were the most used ones among the participants. In terms of gender differences, "revenge" function was used by females more than males. Self-injurers had higher childhood abuse scores on sexual, physical, and emotional abuse and neglect subscales than non self-injurers, and males were significantly more abused than females. CONCLUSIONS: Accepting childhood abuse as an important predictor of NSSI behavior, screening and assessment of abused children and adolescents can help to prevent the onset of the behavior. PMID- 30439802 TI - Health Status, Lifestyle, Use of Health Services, Social Capital and Life Satisfaction As Predictors of Mental Health - Comparative Analysis of Women that Receive and Do not Receive Public Assistance in Croatia. AB - BACKGROUND: The connection between socio-economic status and health is documented, yet not fully understood. The goal of this research was to analyze the relationship between socio-economic status, lifestyle and health status, availability of health-care, social capital, and satisfaction with life. SUBJECTS AND METHODS: Subjects were 1117 women aged 25-65 years divided in two groups. Group 1 consisted of women who receive public assistance (N1=591), while Group 2 consisted of women who do not (N2=526). The sample was stratified by random choice into multiple stages based on six regions of Croatia, residential area size, and the age of respondents. Visiting nurses surveyed the deprived population, while in Group 2 self-interviewing was conducted. A questionnaire entitled "Inequalities in health" was used. The respondents participated in this research voluntarily and anonymously. RESULTS: Socially deprived women consume spirits and wine more often (p<0.001). There is no difference between groups regarding tobacco consummation. Working women perform significantly less strenuous physical tasks (p<0.001). Deprived women are significantly less engaged in physical activities (p<0.001). Health conditions in deprived women more commonly limit their physical activity (p<0.001). There is a significant difference in utilization of health-care among groups (p<0.001). Younger women who are married, with a higher number of household members, a larger income, and with higher education are generally more satisfied with life (p<0.001). Although deprived women are significantly less satisfied with their lives, feel less free, are less physically active, and less likely to consume spirits or beer, they are significantly happier than working women (p<0.001). CONCLUSIONS: Personal health status and lifestyle, access to health-care services, and life satisfaction have a high importance as predictors and protective factors of mental health in women recipients of state-provided financial welfare. PMID- 30439803 TI - Level of mother-baby bonding and influencing factors during pregnancy and postpartum period. AB - BACKGROUND: Bonding is the process of an emotional relationship between mothers and babies. Pregnancy and postpartum periods are most important of developing a mother-child bonding. Here we aimed to determine the level of mother-baby bonding and identify the influencing factors during pregnancy and the postpartum period and to examine the relationship between bonding level during pregnancy and the postpartum period. SUBJECTS AND METHODS: This cross-sectional descriptive study included twelve districts across a range of socioeconomic structures. Every district was selected by a simple random sampling method. Data were collected with Prenatal Attachment Inventory, Mother-to-Infant Bonding Scale, Center for Epidemiologic Studies' Depression Scale and Beck Anxiety Inventory. The study included two home visits. The first visit at gestational age >=35 weeks and second visit on the seventh or eighth day of the postpartum period. The study was conducted with 227 pregnant women. RESULTS: We found that, 50.7% pregnant women had prenatal depression and 36.6% pregnant women had postpartum depression. We detected a negative association between depression level during pregnancy and the postpartum period with mother-baby bonding in the postpartum period (r=0.174, p=0.009; and r=0.221, p=0.001, respectively). A negative correlation was detected between anxiety level and mother-baby bonding level in the postpartum period (r=0.151, p=0.023). It was found that when the prenatal attachment level increases, the level of postpartum bonding is also increases (r=0.297, p=0.000). CONCLUSIONS: Depression and anxiety levels were higher during pregnancy than the postpartum period. Depression level during pregnancy and postpartum period depression and anxiety level negatively affected mother-baby bonding in the postpartum period. We found that as prenatal attachment level increases, the level of postpartum bonding also increases. PMID- 30439804 TI - Quality of close relationships and emotional regulation regarding social anxiety. AB - BACKGROUND: The aim of this research is to propose new models in understanding the relationship between social anxiety and experiencing positive and negative emotions and satisfaction with life in general. Its main focus is to explore the roles of different types of close relationships in these models. SUBJECTS AND METHODS: The sample consisted of 521 female students attending University of Rijeka and University of Pula (average age 21.21 years). The participants completed The Big Five Inventory, Beck Depression Inventory-II, Social Interaction Anxiety Scale, Social Phobia Scale, Emotion Regulation Questionnaire, Attitudes Towards Emotional Expression Questionnaire, Positive and Negative Affect Schedule - Expanded Form, Satisfaction with Life Scale, Quality of Relationship Inventory and Friendship Quality Questionnaire. The results were processed using the program LISREL 8. RESULTS: Two models have been tested. The first model includes the relationship between both types of social fears, beliefs about expressing emotions, emotional suppression, romantic relationship quality and the frequency of experiencing positive and negative emotions and life satisfaction. The second one included friendship quality, instead of romantic relationship quality. Both models are acceptable and draw out the powerful role of cognition in the aforementioned relations. This is achieved as a result of beliefs about the expression of emotions on other variables, and also confirms the mediatory role such beliefs have on social anxiety and emotional suppression. The models tested show the importance of the type of close relations we are following. CONCLUSIONS: The contribution of this research lies in the point that it offers a more detailed insight into the complex relation between social anxiety and the experiencing of emotions, as well as the quality of life in general. This is achieved in the way that structural modeling has captured a part of the mediator mechanisms that have a role in this relation. PMID- 30439805 TI - Prevalence and Correlation of Depressive Symptoms with Functional Scores, Therapy and Disease Activity among Croatian Patients with Rheumatoid Arthritis: A Preliminary Study. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic, autoimmune and disabling disease that significantly affects the quality of life. Additionally, significant number of patients with RA suffer from depressive disorders, which are commonly underrecognised and undertreated. We aimed to estimate the prevalence of depressive symptoms in Croatian RA patients and to assess the relationship between them and clinical correlates. SUBJECTS AND METHODS: Fifty-four RA patients treated at the Clinic for Rheumatic Diseases and Rehabilitation at the University Hospital Centre Zagreb were prospectively enrolled in the study and evaluated for functional status using the Disease Activity Score 28 (DAS-28), Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Visual Analogue Scale (VAS) for pain and health related quality of life (HRQL) measurement. The depressive symptoms were assessed using the Beck Depression Inventory-II (BDI-II) questionnaire. RESULTS: Thirty RA patients (55.6%) had some sort of mood disorder, with 10 (18.5%) patients accounting as depressed. Positive correlation was found between depressive symptoms, higher disease activity and disablity during daily activities (taub=0.385, p=0.001 and taub=0.282, p=0.024 respectively). We found no significant association between depression and disease activity in the whole sample of RA patients, but for postmenopausal patients, the disease activity correlated with postmenopausal patients accounting as depressed (BDI-II score moderate or severe; taub=0.363, p=0.021). The use of biologic therapy correlated negatively with the disease acitivity, pain intensity and worse health related quality of life score (taub=-0.360, p=0.06; taub=-0.310, p=0.07; taub=-0.380, p=0.01 respectively). CONCLUSION: Considering the high prevalence of depressive sympoms in RA patients and the effect on functional disability and quality of life, we wanted to emphasize the importance of recognizing and optimizing depression treatment through multidisciplinary approach in RA patients. PMID- 30439806 TI - Influencing Factors of the Diabetes Distress among Chinese Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND: Patients with Diabetes Mellitus (DM) are required to have long-term treatment regimen and strict self-management, which thus might lead to the Diabetes Distress (DD). Patients' DD varies in different regions with different levels of medical conditions. For improving the treatment effect of the patients with the Type-2-Diabetes-Mellitus (T2DM), this study explores the influencing factors of the patients' DD in the regions where the medical treatment are at low level. SUBJECTS AND METHODS: In this study, 167 adult patients with T2DM were selected from the People's Hospital of Jinhua city, an A-grade hospital of a small-mid-sized city in Eastern China. Based on these samples, the Diabetes Distress Scale with 17 items (DDS17) was adopted to measure the degree of patients' DD, and then regression analyses were carried out to investigate the influencing factors for their DD. RESULTS: The T2DM patients with moderate and high levels of DD take up 54.5% of the samples investigated in this study. According to the Spearman correlation analysis, sleep time, physical exercise, diet control, treatment regimen, TG and HbA1c significantly affect the patients' DD. Through the multivariate linear regression analysis, this study shows that (1) sleep time significantly influences the T2DM patients' DD (beta=-0.213, P=0.034); (2) sleep time also impacts emotional burden (beta=-0.379, P=0.027); (3) physical exercise (beta=-0.195, P=0.002), treatment regimen (beta=0.158, P=0.026) and diet control (beta=0.158, P=0.026) are the three major influencing factors for regimen-related distress. CONCLUSION: In the small-mid-sized city where the treatment regimen is not highly advanced, to alleviate the T2DM patients' DD, the medical staff should suggest the patients to improve sleep quality and exercise more, help them positively understand the insulin infusion therapy and take proper diet control. PMID- 30439807 TI - Anxiety and Depression Scores in Patients with Burning Mouth Syndrome. AB - BACKGROUND: Burning mouth syndrome is a condition of unknown etiology, characterized by burning symptoms on the otherwise clinically healthy oral mucosa. Central and/or peripheral neuropathy is one of the proposed causes for this condition. Psychological component in these patients is also very present, as it is known that BMS patients exhibit high levels of pain, anxiety, and depression. The aim of this study was to evaluate anxiety and depression among patients with burning mouth syndrome and a control group. We also further review and discuss the literature available on this subject. SUBJECTS AND METHODS: A total of 93 subjects, divided into two groups, participated in this study. The group of patients with BMS included 43 participants, while the control group consisted of 50 participants. Self-reported STAI (State anxiety and Trait anxiety) and BDI questionnaires were used to evaluate anxiety and depression in subjects in both groups. RESULTS: BMS group had higher average total scores of state anxiety, trait anxiety and depression. The difference between the BMS group and control group was statistically significant for state anxiety scores and BDI scores. CONCLUSION: We might conclude that BMS patients are more anxious (state) and depressed when compared with the control group. However, they do not differ from the control group regarding anxiety as a trait. Thus we might conclude that feeling of anxiety in general starts after the BMS symptoms first occur and last for a longer period of time. PMID- 30439808 TI - Quality of Life and Depression Level in Patients with Watery Eye. AB - BACKGROUND: The aim of this study was to assess subjective, human aspect of the medical condition, evaluate the quality of life (QOL) and level of depressive symptoms in patients with watery eye and compare it with patients with two most common causes of visual deterioration: cataract and macular region pathology. The results of this study may serve to raise awareness of watery eye impact on a large number of patients and subsequently promote their treatment in order to restore full visual and life quality necessary for normal human functioning. SUBJECTS AND METHODS: In this prospective, randomised, questionnaire-based study, we have surveyed three groups of patients with a total of 210 patients: group with the watery eye of different etiology (n=69), group with one pseudophakic eye and one cataract eye (n=73) and group with the unilateral pathology of the macular region (n=68). All three groups underwent a complete ophthalmologic examination. To examine the overall quality of life we have used a modified vision-related quality of life questionnaire (VR-QOL) and to evaluate depression level "Beck Depression Inventory - 2". The results were analyzed with statistical program STATISTICA 13. RESULTS: Compared to group with unilateral cataract eye and to group with unilateral pathology of the macular region, the results of this study show that patients with watery eye have significantly decreased quality of life in all daily activities, particularly in outdoor activities (F=125.80, df=2/143, p<0.01), during sports (F=36.67, df=2/143, p<0.01) and interpersonal relations (F=18.73, df=2/143, p<0.01). Results between three groups showed that group with watering eye expressed highest depression level and group with one pseudophakic eye and the other cataract eye the lowest (F=25.86, df=2/207, p<0.01). CONCLUSION: Watery eye has a significant impact on vision-related quality of life. Our research showed that patients with watery eye had expressed more depressive symptoms than other groups, but still without statistically significant value. Since it affects a large and heterogenic group of patients it is important to be recognized on time and treated etiologically in attempt to restore full function and life quality. The results of this study may serve to raise awareness of watery eye impact on a large number of patients and subsequently promote their treatment in order to restore full visual and life quality necessary for normal functioning. PMID- 30439809 TI - [Anxiety disorders - clinical and neurobiological aspects]. AB - Anxiety disorders are considered among the most common psychiatric disorders in general population. They may be characterized by prominent subjective suffering, frequent chronic courses of illness, increased rates of comorbid other psychiatric disorders and somatic diseases, a distressing amount of psychosocial disabilities, in all, a challenging high burden of disease. Anxiety disorders have principally to be conceptualized within a multifactorial biopsychosocial model. Various psychological and psychosocial approaches have contributed to a multi-layered understanding of various major predisposing, eliciting, and maintaining factors in the course of illness. Modern neurobiological research has significantly broadened and deepened the aetiopathogenetic complexity of anxiety disorders. The main focus of this short review is on neural fear- and anxiety circuits, neurotransmitter systems, neuroendocrine and inflammatory stress systems, genetics and epigenetics that characterize the general basis of fear and anxiety regulation and their dysregulation in anxiety disorders. Anxiety disorders may be effectively treated both by psychotherapeutic and pharmacological approaches. Basic principles and general guidelines in the treatment of anxiety disorders are being presented. PMID- 30439810 TI - [Why we fear the wrong things?] AB - Deadly shark attacks, cancer from meat, toxic beer: Our health seems to be threatened seriousely all the time. But do we fear the real dangers? And how can we identify the big risks? How to deal with numbers and statistics. PMID- 30439811 TI - How understanding the temperaments can help clinicians to make a correct diagnosis of bipolar mood disorders: 10 case reports. AB - The temperament is a key factor when assessing a patient within the bipolar spectrum. The temperaments are conditions in their own right within the bipolar spectrum, since they are 'soft' forms of bipolar condition within the spectrum: they can develop over time into a more clear bipolar condition, and hence are important in early diagnosis. Bipolar disorders are very often diagnosed late (approximately 25 year late, on average, from the beginning of the illness), in part because the temperaments of the patients have not been identified early. PMID- 30439812 TI - Depression and physical health, the therapeutic alliance and antidepressants. AB - BACKGROUND: In a two-year study we compared the efficacy of noradrenergic (duloxetine D) and serotonergic (escitalopram E) antidepressants with and without the addition of 100 mg acetylsalicylic acid (ASA) in subjects suffering from a major depressive episode (MDE). The results showed that the D + ASA (DASA) group improved more rapidly than the E + placebo (EP) subgroup. In particular, Hamilton Depression Scale (HDS) scores improved as early as two months, Clinical Global Impression (CGI) scores improved at five months, and remission rates were better. In the course of this study, we also investigated the role of the therapeutic relationship (alliance) on both the progress of the MDE, and patients' mental and physical health. SUBJECTS AND METHODS: 40 people suffering from an MDE were randomly assigned to treatment groups. At the beginning of the study sociodemographic data were collected, and the Helping Alliance Questionnaire (HAQ) was completed. During the study, patients were regularly assessed using the HDS, CGI and the Short Form Health Survey (SF-12). RESULTS: Subgroup comparisons revealed that HAQ scores are not correlated with HAD scores, but a correlation was found with remission rates (r=0.316*). Similarly, at all times, HAQ scores were correlated with physical health (p<0.05), which is in turn correlated with HDS and CGI scores. CONCLUSION: Physical health is linked to the level of depression. While the alliance with the patient is not directly correlated with the intensity of depression, is it correlated with their physical condition and its improvement. For patients, improving their physical health appears to be more important than improving their mental health. These observations must be confirmed. PMID- 30439813 TI - Relationship between Cognitive Remediation and Evaluation Tools in Clinical Routine. AB - Many clinicians do not have adequate knowledge and interest in assessing cognitive deficits in psychiatric patients. However, these deficits are crucial and key symptoms, which can lead to impairment of quality of life, worsening of symptoms of disorders and difficulties in social, family and work relationships. Another limitation to the assessment of cognitive deficits is the poor maneuverability and practicality of the main cognitive assessment tools. Because there are no appropriate pharmacological approaches, new techniques have been developed to improve cognitive abilities in these patients. The most important techniques concern cognitive remediation (CR). In this article we summarize the main techniques of cognitive remediation. PMID- 30439814 TI - How should psychiatrists and general physician communicate to increase patients' perception of continuity of care after their hospitalization for alcohol withdrawal? AB - BACKGROUND: There are medico-psycho-social indications to apprehend the alcohol use disorder (AUD) as a chronic problem for which a continuous care is necessary. The perception of continuity of care is also associated with positive outcomes on the patient's health. Communication between caregivers is essential to maintain a good continual care. In order to put patients back into the center of care, we asked them the question: "why should the psychiatric department (PD) and general physicians (GP) should communicate about AUD patients"? SUBJECTS AND METHODS: After a week of hospitalization for alcoholic withdrawal, we used a qualitative approach with 4 open questions to explore AUD patients' point of view (N=17) about the best way of communication between psychiatrists and GP to improve care continuity. The data collection was carried out in the psychiatric department of the University Hospital of Mont-Godinne, Belgium. RESULTS: AUD patients consider that the GP is the first line actor that will be consulted after hospitalization and have a privileged relationship with him. These arguments justify him being informed. Concerning these patients, communication is useful to have a continuous treatment and project care, for purposes of symptoms' evolution follow-up and so as to help the GP to understand them better to follow the evolution of symptoms and to help the GP to understand them better. CONCLUSION: From AUD patients' point of view, communication between psychiatric department and the GP is useful for a perspective of continuity of care at discharge from the hospital. This communication seems to be at the service of the GP and his patient rather than for the psychiatrist himself. Mainly because of the GP's role as a privileged first-line care, but also thanks to the specific relationship relating him to his patient. PMID- 30439815 TI - Incidence and prevention of deep vein thrombosis in restrained psychiatric patients. AB - BACKGROUND: Although physical restraint is still used in psychiatric inpatient settings, it sometimes causes serious side effects, including deep vein thrombosis (DVT) and resulting pulmonary embolism. The aim of this study was to review the literature investigating the incidence of the DVT in restrained psychiatric patients, to identify the risk factors of this condition and the effectiveness of routine prophylaxis. SUBJECTS AND METHODS: Studies investigating associations between deep vein thrombosis and restrained psychiatric patients were searched in the Pubmed database. More than 700 articles were sorted independently by two of the authors using predefined criteria. Only research articles, reviews and meta-analyses were selected for this review. RESULTS: 5 articles published between 2010 and 2016 were selected. Although antipsychotics and restrain are known to be thrombogenenic, in all retrospective studies, with anticoagulant prophylaxis for those restrained for more than 12 or 24 h, incidence of DVT in restrained psychiatric patients was almost not existent. Controversially, in a comparative study by Ishida, although deep sedation and physical comorbidities were associated with the occurrence of DVT, not using of anticoagulants was not associated with any increased incidence of DVT. DVT may be overlooked because psychiatric patients are often unaware of leg symptoms because of their psychiatric disease and induced sedation. Furthermore most DVT, in particular distal DVT are asymptomatic. When screened and assessed with more appropriate methods such as plasma D Dimer and ultrasound scanning the incidence of DVT reaches 11.6%. CONCLUSION: The incidence of DVT in restrained psychiatric patients was not low in spite of prophylaxis. These findings emphasize the importance of regular screening of and thorough assessments of DVT, especially in restrained psychiatric patients. PMID- 30439816 TI - Neuroleptic malignant syndrome in a patient treated with clotiapine. AB - BACKGROUND: Neuroleptic malignant syndrome (NMS), which is linked to the use of antipsychotic medication, is a potentially lethal neurological emergency. The interest of our study is that NMS induced by the use of clotiapine has never previously been described. SUBJECTS AND METHODS: We present the case of a 61-year old man whose sleep disorders were treated with clotiapine 40 mg/day. After 7 days of taking 40 mg clotiapine, the patient presented with a deterioration of his general health which had gradually taken hold, with altered consciousness accompanied by generalised muscle rigidity and hypersalivation. Laboratory blood tests revealed elevated levels of Creatine Phosphokinase (CPK) at 812 U/l. The patient was diagnosed with NMS and treated accordingly. RESULTS: The mechanism that underlies the appearance of NMS remains largely unknown. Clotiapine is a second-generation antipsychotic, first released onto the market in the 1970s, and is available in a few countries, including Belgium. NMS is treated as a medical emergency due to the possibility of morbidity and death. The first step in the treatment of NMS consists in withholding the agent suspected of provoking the symptoms. CONCLUSIONS: NMS is difficult to diagnose due to a great variability in clinical presentations and the absence of specific tests and laboratory results. The use of clotiapine in treating sleep disorders can provoke NMS as a life threatening side-effect. To our knowledge, this is the first time a case of clotiapine-induced NMS has been published. PMID- 30439817 TI - Partial denial of pregnancy at 32 weeks in a diabetic and suicidal patient: A case report. What Are the Treatment Recommendations? AB - BACKGROUND: Denial of pregnancy is an issue that is often discovered a posteriori with sometimes dramatic complications. Denial of pregnancy is considered partial when the woman becomes aware of the pregnancy after the fifth month before delivery. The populations studied were heterogeneous, which made it impossible to establish a standard algorithm of the treatment and support of a discovery of partial denial of pregnancy. SUBJECTS AND METHODS: Based on a literature review and a discussion of partial denial of pregnancy case and the consequential treatment with a five-year follow-up, the global management recommendations need consideration in the case of partial denial of pregnancy. RESULTS: The reported case confirmed the significance of the trauma caused by the discovery of pregnancy in a patient in denial, but also showed that this trauma can extend to caregivers concerned by the treatment. CONCLUSION: Continuous training of all caregivers for denial of pregnancy is essential even if the issue may be considered infrequent. Contraception, prevention of sexually transmitted diseases and the importance of gynecological follow-up must be systematically addressed in a medical consultation. A standard algorithm for the treatment of partial denial is difficult to establish, but the rapid mobilization of a multidisciplinary team or hospitalization is recommended for the announcement of the diagnosis as well as personalized support during ultrasounds. The establishment of a relationship of trust remains the major issue. PMID- 30439818 TI - Triage of children with mental health difficulties presenting in a&e in a general hospital. AB - In Wexford and Waterford, an "out of hours" child psychiatric service has been developed, in order to provide help when the regular Child Psychiatry services (CAMHS) are not accessible. Providing a service for under 18 years old patients with mental health issues presenting in the Emergency Department (ED) of a General hospital, it functions with extremely limited resources (a consultant psychiatrist and a doctor in psychiatric training), and therefore needs an efficient triage procedure. The purpose of this article is to review the literature about existing triage tools, and especially the 2016 Irish Children's Triage System (ICTS) and to discuss how to optimise triaging our specific patients in this new 'out of hours' CAMHS cover for Waterford /Wexford area. CONCLUSION: A post triage tool and some clinical changes could improve the service. PMID- 30439819 TI - Stressful childhood events: a retrospective journey into the life of adults with depression; a report of 5 cases. The Importance of Maternal Love. AB - The importance of maternal care for a harmonious development of the child has been at the center of the interest of child psychology since the second half of the twentieth century. Great scholars such as Lorenz, Harlow, Spitz and Bowlby have asserted that love for mum does not have its roots in satisfying the need for food, but in the need for protection and if there is a lack of care the consequences are extremely negatives. Nowadays, epigenetics is finding the biological basis of the effects of maternal care, if they are present and affectionate, and even if they are lacking or absent. A report of 5 cases helps to understand the importance of maternal love. PMID- 30439820 TI - Ecosustainibility and Mental Health: female aspects. AB - The relationship with the environment is one of determinants of the health status of the human population. Many aspects of today's society negatively affect the environment and, consequently, human health. In particular there seems to be a prevalence of diseases, linked to environmental pollution, which affects the female gender, almost to assume a role of gender pathogenicity. But the female gender is also the promoter of changes; in fact, women are more sensitive to environmental health and adopt more appropriate behavior to prevent environmental damage. It is precisely in the balance between these two aspects that we can see a factor promoting behaviors to combat the effects of environmental pollution on the mental health of Man. PMID- 30439821 TI - The Precision Psychiatry. An Individualized Approach to the Diseases. AB - The Precision Psychiatry is a new emergent topic in Psychiatry, and is "an approach for treatment and prevention that takes into account each person's variability in genes, environment, and lifestyle". It promises to be even more transformative than in other fields of medicine, because the psychiatry has not yet benefited from the advanced diagnostic and therapeutic technologies that now form an integral part of other clinical specialties. It may be an epistemological change in the field of psychiatry. This paper briefly highlights the story, the features, and the future of the Precision Psychiatry. Indeed, this approach is becoming a reality with the availability of massive data (derived from physiological recordings, brain imaging, 'omics' biomarkers, environmental exposures, self-reported experience). PMID- 30439822 TI - Effects of financial precariousness on mental health. AB - BACKGROUND: The physical and mental health of a population is based, in particular, on its quality of life and its access to health care. Given these determinants, Greece's population has greatly suffered due to the sharp cuts in the budget for social benefits and health care (some measurable evidence is the recent increase in the suicide rate). Starting January, the 1st of 2015, unemployment benefits in Belgium have been eliminated for all recipients who do not have a full-time year of work over the last three years. Therefore, we must ask whether there will be similar psycho-medical consequences for Belgium's population. SUBJECTS AND METHODS: Open study over a year (01/07/14 - 30/06/15) of emergencies admitted to the University Hospital Center of Mont-Godinne including a psychopathological motif. In addition to general socio-demographic data, psychic disorders are measured, as well as different types of crises (familial, professional or couple crisis), familial support and its dynamic (FACES III of Olson) and finally social integration (social isolation scale from the National Social Life, Health, and Aging Project (NSHAP)). These patients are compared with those admitted during the six months preceding the Act modifying the unemployment benefits. RESULTS: Between July the 1st of 2014 and June the 30th of 2015, we saw an increase in the number of admissions to the psychiatric emergency department by 2.5% in six months, despite a decrease in the number of admissions to all cause emergencies. Our study also shows a degradation of social network quality characterized by a more pronounced social isolation of our patients. At last, an alteration of cohesion in the patient's origin family was highlighted. CONCLUSION: Although we cannot establish a direct causal link between this law and the results of this study, these may suggest a weakening of the population mental health due to difficult socio-economic context. As a result, we are faced not only with a public health problem but also with one concerning health care organization. PMID- 30439823 TI - A transient personality disorder induced by football matches. AB - BACKGROUND: Personality disorders are a class of mental diseases characterized by inflexible and maladaptive patterns of behavior, cognition, and inner experience, involving several areas of functioning, such as affectivity, impulse control, ways of perceiving and thinking and reaction to stress factors. In the literature, personality disorders have always been described as stable patterns of long duration, and their onset can be found during adolescence or early adulthood. These patterns are associated with significant distress or impairment in a patient's life in which a main element affects every aspect of living, and in which no biological or other pathologies exist to assist in its identification. Therefore, they often lead to comorbidities such as dysfunctional anxiety, drug abuse, major depression and suicide. SUBJECTS AND METHODS: We present a case of a 37-year-old man, who came to the outpatient department needing support to quit smoking. During the follow up, he described some transitory changes in his personality while watching football (soccer) games. These episodes were characterized by inappropriate anger crises, rapid and dramatic shifts in emotional tone, dysphoria and superstitious and magical beliefs with paranoid elements; connecting himself, his family and friends to players in the match and to the unfolding of the game. Every manifestation was induced by the football match, and there were no signs of difficulty in handling impulses and in managing relationships, or any superstitious beliefs, outside of it. RESULTS: The combination of all the symptoms led us to think about a diagnosis of the borderline personality disorder. There was a lack of managing impulsivity, intense uncontrollable emotional reactions, and episodes of psychotic decompensation with unreal and paranoid connections made between the patient's entourage and the results of the match. CONCLUSIONS: With this case, we propose to consider the personality disorder, not just as a stable and inflexible pattern, but also as a transitory dysfunction induced by stress factors, as in this case, a football match, introducing therefore a new entity: transient personality disorder. PMID- 30439824 TI - Immunity and psychiatric disorders: variabilities of immunity biomarkers are they specific? AB - BACKGROUND: In previous studies we showed the interaction between depression and immunity. We observed that psychological stress seems to be important in this association. In this review we try to understand if psychological stress and immunity have similar or specific impact on the other psychiatric disorders. More generally we review literature to understand if specific immune alterations exist between the main psychiatric diagnoses. METHOD: We studied the literature in search of variabilities between the different psychiatric disorders in terms of immunity especially inflammation. We search on Pubmed, PsycINFO, PsycARTICLES and Sciencedirect articles with the keywords immunity or inflammation and depression, anxious disorders and schizophrenia. RESULTS: Prevalence of inflammation in psychiatric disorders seems to be between 21 to 42%. Psychiatric disorders are correlated with elevated levels of CRP, pro-inflammatory cytokines (IL-6, IL 1beta and TNFalpha) and anti-inflammatory factors (TGF beta, IL-10, sIL-2, IL 1RA). IL-6 in childhood were associated with subsequent risk of depression or psychotic disorders in early adulthood and in a dose dependent manner. DISCUSSIONS: We found similar immune processes through the different disorders. Variations in cytokines levels seem paralleling various stages of the illness and treatment. Inflammatory markers are linked with severity and resistance to treatment and with subsequent risk of disorders. CONCLUSIONS: Some inflammatory parameters could be considered as risk factor, severity, resistance, trait or state markers of a psychiatric disorder. Other studies are necessary to a better understanding of clinical implications of this heterogeneity. PMID- 30439825 TI - Sleep Disorders: Are They a Genetic Question? AB - Sleep disorders are commonly studied from the psychiatric and neurological point of view, leaving aside other aspects such as genetic component. Despite the limited literature regarding this field, different genetic variants have been proposed to be associated with sleep disorders. In this review, we summerize the experimental research that has brought to light the pivotal genetic influence in the development of these pathologies. PMID- 30439826 TI - Rewriting neural pathways to stop depressive distress in a suspended space away from everyday life. AB - An increasing number of human behavior scholars are redirecting their professional curiosity towards studies carried out with innovative research and intervention methods, far from the obsolete and reductive systems of analysis of the past. As part of these studies, aimed at the individual's bio-psycho-social betterment, the fascinating perspective of using the opportunities offered by a trip as a catalyst for important changes, has an important place. A sort of 'Journey' in the Journey, in which the suspended space-time of a travel can be the frame for innovative and interesting situations of parallel discovery of one's inner world. According to Hippocrates, therapy was not just a question of medicine and diet, in fact the cure he gave to his patients included also a trip to an island in order to temporarily move away from their environment, and therefore from the context that, somehow, had contributed to the emergence of the disease. Furthermore, the journey in itself, produces extraordinary beneficial effects. According with another study, for example, conducted by the Global Commission on Aging and Transamerica Center for Retirement Studies, in partnership with the U.S. Travel Association, women who vacationed every 6 years, or less, had a significantly higher risk of developing a heart attack or a coronary death, compared to women who vacationed at least twice a year. Similarly, another study showed that men who did not take an annual vacation had a 20 percent higher risk of death and 30 percent greater risk of death from heart disease. (www.globalcoalitiononaging.com, 2013) As regards the therapeutic value, the idea of facing a fascinating "Journey" in a Journey, could prepare the individual to enter in a sort of a suspended space, in which, according to many authors, the travel can induce both psychophysical and psychosomatic beneficial changes. For this reason, Body and Mind project, prepared by the Genius Academy Research and Psychological Studies Center, started in 2015, thanks to a protocol of intervention which includes associated psycho-physical inductions, with the aim of demonstrating the increase in the level of well-being (from the 30% to the 60% ). The research, continued in 2016/17 with the objective of raising the level of well-being perceived and measured, has shown a further health improvement. This improvement was evaluated and compared to data expressed by measurement of heart rate, blood pressure, hours of night time sleep, headache, sense of anxiety recorded an increase in well-being of 67% by stimulating the organisms affected by a specific suffering such as depression in the oncological patient. As the results of three years of study have been so encouraging, it was decided to continue the research by making the necessary changes to contextualize the Body and Mind project within a travel situation. The project a "Journey" in the Journey, which for the last five years optimizes the opportunities offered by a trip to promote the psychological growth of individuals through prescriptions, work shops, seminars, drinking and talking, social dreams, has therefore widened the research space, also bonding the objectives of the Body and Mind project. A "Journey" in the Journey in the places of Body and Mind, develops along two main directions: 1) the places of Body and Mind; 2) the Body and Mind project. But the red thread that binds and unites the study and research initiatives we have talked about is always the same: the innovative strategic approach where the individual is at the center of the scene, in contexts where life is live and where it is always the person to have the role of leading actor. PMID- 30439827 TI - Ethical and Organisational considerations in screening for dementia. AB - The United Kingdom National Screening Committee (UKNSC) defines screening as "the process of identifying individuals who may be at higher risk of a disease or condition amongst large populations of healthy people". Building on foundations laid by Wilson and Jungner in the landmark paper in 1968, the UKNSC states that "Once identified, those individuals can consider further tests, and healthcare providers can offer them interventions of benefit. A screening programme needs to offer more benefit than harm, at a reasonable cost to the NHS" (gov.uk 2014). We will consider the ethical issues surrounding some of the UK's screening programmes and other methods used to assess and communicate patients' risk of disease. We will discuss the appropriateness of candidate dementia biomarkers in order to inform research into developing such a biomarker or series of biomarkers. PMID- 30439828 TI - Dementia risk assessment and risk reduction using cardiovascular risk factors. AB - Given the poor efficacy of disease modifying treatments and evidence that Alzheimer's Disease (AD) pathophysiology begins in middle-age, efforts to reduce the substantial disease burden have shifted towards preventative intervention in midlife. Up to a third of all AD (the commonest cause of dementia) is attributable to modifiable cardiovascular risk factors. A tool for predicting risk of future dementia using only cardiovascular risk factors has been validated and the effect of lifestyle modification on future cognitive decline is under investigation. In the UK, the QRISK3 risk calculator is used to quantify 10-year risk of cardiovascular disease. Lifestyle changes and lipid modifying therapy are recommended to patients based on their risk score. We will compare the emerging evidence for dementia risk assessment and risk reduction using cardiovascular risk factors with the evidence used to support the implementation of QRISK3 for cardiovascular disease risk assessment and intervention. This will guide future research to determine whether cardiovascular risk assessment can also be used to inform patients of risk of future dementia and advise on risk reduction strategies, in a primary care setting. PMID- 30439829 TI - Correlations between event-related potentials and NK cells, B and T lymphocytes. AB - BACKGROUND: The links between psychiatry and immune dysfunctions are well known. By contrast, there are few studies that evaluate the link between neuroelectrophysiology and immune system disturbances. SUBJECTS AND METHODS: We retrospectively included 31 patients hospitalized between 2011 and 2012. They completed a sociodemographic questionnaire and were assessed using DSM IV TR on Axis 1. Event-related potentials were performed. Lymphocyte subtypes were quantified using flow cytometry. RESULTS: In terms of P300 latency, there are correlations with the absolute value of leukocytes: for P3a component, we find a correlation in frontal derivation Fz (r=0.405*), in central derivation Cz (r=0.438*), in parietal derivation Pz (r=0.403*) and for P3b component, there is a correlation in Fz (r=0.414*), in Cz (r=0.402*) and in Pz (r=0.425*). In terms of P300 amplitude, for P3b component, there are correlations with CD3 lymphocytes percentage in all derivations (Fz (r=-0.621**); Cz (r=-0.567**); Pz (r=-0.499**)) and with CD19 lymphocytes percentage in all derivations (Fz (r=0.469*); Cz (r=0.466*); Pz (r=0.430*)). For P3a, it is correlated with CD3 percentage (in Fz (r=-0.539**); Cz (r=-0.406*)) and with CD19 percentage (Fz (r=0.364*); Pz (r=0.357*)). With respect to the relationship between mismatch negativity (MMN) amplitude and natural killer (NK) cells percentage, there are correlations in left temporal derivation T3 (r=-0.426*), in Cz (r=-0.401*) and in right temporal derivation T4 (r=-0.427*). A correlation is found between the contingent negative variation (CNV) amplitude and the lymphocytes percentage in Fz (r=-0.471**). CONCLUSIONS: There is a link between lymphocyte-related immunity and electrophysiological disturbances in psychiatric patients. Further studies would be needed to evaluate this relationship more specifically, particularly prospectively and by pathology. PMID- 30439830 TI - Mental Illness and Prejudices in Psychiatric Professionals. Data from the Social Stigma Questionnaire for Psychiatric Professionals: A Multicentre Study. AB - The prejudices about mental illness and the related social stigma are still present in the population. People suffer from both the disease and the marginalization behaviors implemented by the "so-called healthy" towards them and their relatives. Even psychiatric professionals can get sick and suffer for the same reason. The authors of this multicentric study have focused their attention on the presence or absence of groups of psychiatric pathologies among the "insiders". The most frequent pathologies encountered were the mood and anxiety disorders, in a percentage similar to that of the general population. To continue the research on the stigma begun in a previous study, the authors asked themselves if there could be prejudices and/or stigma among psychiatric professionals towards sick colleagues, how they relate in the workplace and how they react to the behavior of colleagues. The stigma questionnaire has been used on psychiatric professionals, and 130 Italian colleagues were tested in the provinces of Avellino, Brindisi and Trento. The data were compared with those of the research on the stigma "Thinking of Psychiatric Disorders as" Normal "Illness" (Tavormina et al. 2016) and it emerged that among the attending professionals there are no statistically significant behaviors of marginalization, exclusion or stigma against sick colleagues, even if there is a certain discomfort in working together. Above all, it emerged that 80% of the interviewees, who have had work experience with sick colleagues, have replied that the latter can treat those who are also sick of their own disease, thus showing esteem and confidence in their work, in analogy with the Jungian thesis of the "wounded Healer" in the myth of the centaur Chiron. PMID- 30439831 TI - Tailoring treatment for Major Depressive Episode: Lessons learned from the inpatient unit. AB - Major depressive disorder (MDD) represents one of the main diagnosis of admission to the inpatient psychiatric unit, because of the frequent comorbid suicidal behavior. It is a clinically heterogeneous diagnostic category comprising a various array of symptoms presentation. This clinical heterogeneity can represent a challenge for treatment, and patients are often discharged with substantial residual symptomatology that still impacts functioning1. Characterizing subtypes of major depressive disorder ad admission could possibly help tailoring treatment and improving outcomes. The aim of the study was to detected clinical signs at admission for tailoring treatment (that includes pharmacotherapy, cognitive behavioral therapy, individual psychoeducation) in order to prevent suicide, improve quality of life and reduce re-hospitalization. Tailored treatment was routinely implemented in a sample of patient with a major depressive episode consecutively admitted to an inpatient psychiatric unit from 1st april 2018 to 31st august 2018. Results showed that, at 5 months follow up, it was associated to symptoms reduction, improved quality of life and reduction of hospitalization. The limited sample size, the absence of a control group and the naturalistic structure of the study, limit the generalizability of those results. However, those preliminary findings could provide a blueprint for a larger study and a longer follow up. PMID- 30439833 TI - Mobility in Psychiatry, an Alternative to Forced Hospitalization? AB - BACKGROUND: The number of forced hospitalizations has increased across Europe. One way to reduce these is to set up mobile crisis teams. A reform of psychiatry in Belgium allowed the creation of these mobile teams. These offer an alternative to forced hospitalization. SUBJECTS AND METHODS: 196 situations were referred to the mobile crisis team located east of Brussels in 2017. We examined the orientation of these requests according to the applicants and the reasons for them. RESULTS: It appears that the health sector has the best indications for using the mobile crisis team. CONCLUSION: Access to psychiatric care is of major importance in Western societies. The creation of mobile teams increases this accessibility and should reduce the need for forced hospitalizations. These observations must be confirmed. PMID- 30439832 TI - Involuntary hospitalization and violent behaviors: medical act or social control? A 3-Year Retrospective Analysis. AB - BACKGROUND: The present retrospective study is aimed at assessing the clinical and psychopathological correlates of violent behaviors in a sample of acute involuntary committed inpatients. SUBJECTS AND METHODS: Involuntary inpatients were retrospectively assessed for the presence of violent behaviors. Patients with and without overt hetero-aggressive behaviors were compared according to socio-demographic, clinical and psychopathological features. A stepwise backward logistic regression was performed in order to assess the variables most associated with the perpetration of violent acts. The sample of violent patients was then divided in two subgroups on the basis of the presence/absence of a serious mental illness (SMI). Bivariate analyses were performed between SMI and non-SMI violent patients. RESULTS: In the present sample of 160 inpatients, 88 (55%) perpetrated violent acts. Subjects who performed violence presented a higher rate of mood stabilizers prescription (p=0.038). The PANSS-excited component was positively associated with violent behaviors (p=0.027, Odds Ratio (OR)=1.14, Confidence Interval (CI) 1.01-1.28), whilst the PANSS depressed/anxiety factor displayed a negative association (p=0.015, OR=0.78, CI 0.64-0.95). Violent inpatients diagnosed with SMI presented higher rehospitalization rate (p=0.009), longer length of stay (p=0.005), more frequent long-acting injectable antipsychotics prescription (p<0.001) and a higher positive symptoms severity as measured by the PANSS-positive factor (p=0.049). CONCLUSIONS: The clinical population of acute psychiatric inpatients performing violent behavior represents a specific and heterogeneous subgroup of patients for which prevention and treatment strategies should be addressed. PMID- 30439834 TI - "Please admire me!" When healthcare providers' positive stereotypes of asylum seeker patients contribute to better continuity of care. AB - BACKGROUND: Among asylum seekers (AS), mental health conditions are highly prevalent. However this population group has poor access to adequate services and frequently incurs discontinuity of mental healthcare. Many factors explain discontinuity of mental healthcare for asylum seekers. The aim of this study is to evaluate if facilitation of care for AS decreases healthcare provider stereotypes of this population and improves their continuity of care. SUBJECTS AND METHODS: General practitioners (GPs) and mental health professionals (MHPs) were invited to participate in a vignette study, presenting an AS patient manifesting post-traumatic stress symptoms. We randomly manipulated the context of the clinical vignette to create two experimental conditions: facilitated care versus non-facilitated care. In each condition, we measured participants' stereotypes and continuity of care. RESULTS: There was a significant effect of participant's type of stereotypes on continuity of care (F=2.87, p=0.035). However, we found no effect of condition (facilitated vs. non facilitated care) on stereotypes (F=0.11, p=0.95), nor on continuity of care (F=0.35, p=0.55). Furthermore, there was a significant effect of profession (GPs vs MHPs) on continuity of care (F=11.43, p=0.001). Participants' number of consultations per week (F=10.33, p=0.002) and their gender (F=3.69, p=0.030) both have a significant effect on continuity of care. CONCLUSION: Among healthcare providers, we found that "admiration" stereotypes were associated more with continuity of care. Paradoxically, continuity of mental healthcare was better among GPs compared to MHPs. Thus, improvement of continuity of mental healthcare for AS among MHPs should be investigated in further studies. PMID- 30439835 TI - Is Electroconvulsive Therapy any More Effective than Simulated Electroconvulsive Therapy in Treatment-Resistant Depression? AB - BACKGROUND: Electroconvulsive therapy (ECT) fell out of favour towards the end of the 20th century with the advent of effective and well-tolerated antidepressants. It is now experiencing somewhat of a 'renaissance' in England, with an 11 percent increase in the number of ECT treatments carried out in 2015-16 compared with 2012-13, which represents approximately 2,000 additional treatments. AIMS: This paper seeks to examine clinical trials comparing the efficacy of real ECT with simulated ECT in treatment-resistant depression (TRD) to determine whether the resurgence of ECT in recent years is justified. METHODS: A PubMed search was performed to identify clinical trials comparing real ECT with simulated ECT. 6 trials met the inclusion criteria. These were then analysed, and their methodology assessed. RESULTS: 5 out of the 6 trials found real ECT to have a greater antidepressant effect than simulated ECT. The trial that showed no significant difference used a unilateral electrode placement. Analysis revealed significant weaknesses in the trials. CONCLUSIONS: There is clear evidence that real ECT has a greater antidepressant effect than simulated ECT when a bilateral electrode placement is used, despite the weaknesses identified in the trials. Continued use of ECT to treat TRD in England and other countries should be encouraged. Further research is needed to better understand its mechanism of action and refine the techniques used. PMID- 30439836 TI - A Post-Traumatic Stress Disorder review: the prevalence of underreporting and the role of stigma in the Military. AB - Exposure to traumatic events has been a part of human existence since the beginning of time; however modern lifestyles and developments mean that the majority of the population are spared the affliction of extreme trauma. The military, however, are one subgroup of individuals who are actively and repeatedly exposed to terrifying events on a regular basis, putting them at risk of developing "Post-Traumatic Stress Disorder" (PTSD). Despite this, the prevalence of PTSD reports in the UK military remains lower than its international allies, suggesting this value may be an underestimation of the true prevalence. Wider investigation of the potential causes of this has highlighted the stigmatization of mental illness in the military as the key barrier to the help-seeking behaviours. However, the effect of national de-stigmatization programs on PTSD help seeking is unclear. This review aims to determine the prevalence of PTSD within the UK military in the context of other international powers and examine how stigmatization of mental illness in military may contribute to this. The international value of de-stigmatization programs will be debated and future directions for research suggested. PMID- 30439837 TI - The Role of the Social Networks, between a Utility and a New Addiction. AB - The reality of social networks in recent years has taken on new and enriching scenarios, to learn more about the problems and complex dynamics of life that surround the generations of preadolescents and adolescents. This work has matured over several years, interacting with schools in the Campania region (southern Italy), meeting and talking with teachers, parents and students, observing the reality that surrounds them. The territory of Naples and its province was the one in which the activity was mainly carried out. It has been found that the new frontiers of youth language find their maximum form of exposure in sharing, exhibition, media "exposure", through the channel of the narration of their daily life "live" (most of the time), often it implies a high probability of incurring dangers and dangers that are difficult to manage, as "children" of an age in which to exhibit is in conformity with the historical moment. The definition given by the experts is "Digital Natives", "Digital Immigrants" are adults, who have a different and less fluid approach compared to the reality of youth. Dangers, pitfalls and others are amplified through the simple sharing of one's own experiences. This work benefited from the help of various professional figures, which made sure that some difficult aspects and contexts could emerge. Some problems of this reality linked to social networks are distinguished in a more specific and authentic way. PMID- 30439838 TI - Overcoming Depression with Dance Movement Therapy: A Case Report. AB - In our society that sets high standards of perfection to be ok and wins, the depressed is commonly considered as an outsider, a marginalized person unable to be in line with standards and rhythms fast and competitive of the time we live. So the social stigma against people who suffer from mood disorders is a very powerful factor that negatively affects the healing of patient. He is often isolated from the others for the fear of being judged "fool, crazy or dangerous" or discriminated and emarginated for his mental health problem. For this reason, a cornerstone of depression rehabilitation is the bringing out of the patient from his isolation, the reintegration of user in the social context with the increase and the improvement in the quality of interpersonal relationships in the family and in the external context. So in this way is possible an increase in the tone of mood and a reduction of the symptoms of depression. The method used in our project is the dance movement therapy. In particular, dancing the "Bachata" and later more spontaneous dance becomes a rehabilitation tool to express emotions through the body and to open to the world, on the territory, overcoming the fear of being judged by others, the prejudice and the social stigma about mental illness. This work presents the results of a case report of a depressed patient treated with dance movement therapy. PMID- 30439839 TI - The Suffering Body: Manipulation and Discomfort in Eating Disorders. AB - What is the meaning of piercing and tattoo in sixteen years old? What are the deep reasons, affective and relational, that explain the explosion of this "fashion" among teenagers? The recent spread of these practices among young people and very young people offered the opportunity to reflect on the value attributed to the body manipulation in teenager growth context. Inked bodies, pierced, and other similar manipulations, express a communicative intention, whose strength is proved by the violence of these practices. The sense of the message, however, risks remaining obscure to adults, who lack the tools to decode it. Self-injury begins as a general expression of a lack of integration between oneself and the alienation of one's own body, resulting in conflicting and split feelings. Many manifest a behavior of disrespect, disapproval, devaluation of the bodily ego, whose self-injurious gesture would represent a particularly dramatic expression. The variability that characterizes the manifestations of self-injury prevents one from applying to a universal definition, valid under any circumstances. Instead it reveals the conceptual flexibility of self-injury that appears itself as a peculiar product in the current historical time. In a society that increasingly accepts various forms of transformative intervention on the physicality of each, where piercing and tattoos, once considered barbaric practices, now these become ordinary practices, a distinction between ornaments and self-injuries becomes necessarily confused (Levenkron 1998). The ego leak is unnecessarily buffered, occluded, braked trough any means (food, alcohol, substances, self-injury, shopping, kleptomania) because the bets are not really the shape of the body but the possibility to escape the dissolution of the Self. Self-injury and eating disorder have many common factors: impulsive, ritualistic, hidden behavior characterized by shame and guilt. These are experiences that use the body to resolve psychological conflicts and feelings of tension, anger, loneliness and emptiness. The two syndromes report a distorted image and a deep disdain of their body, lived as an enemy to fight, punish and anesthetize. The body that gets sick is very often of a teenager. The food and the obsession with the shape of the body have a primary value because they validate the identity structure, precarious, shaky, of personality in progress. The adhesion to the symptom is understandable only from this point of view, this self-destructive research, carried out to the bitter end, would not otherwise be explained if underneath there was not the fear of the disagreement of the ego. The body becomes the refuge, the theater where you can experience the emotions that you cannot tolerate in life. The problem that revolves around the emotional life is just that: we feel that we cannot control our emotions, and unable to support them from within, we try an external control. All teenagers experience pubertal transformations in a problematic way, as accepting them requires the cognitive integration of one's body into a positive image. PMID- 30439840 TI - How Artworks can gather unspoken yet deeply felt experiences. Using narrative lab in daily psychiatric center. AB - In this paper I'm going to illustrate my experience related to the six month narrative laboratory with the psychiatric patients of the Daily Psychiatric Center located in Rutigliano. This project originated from my own way of conceiving the concept of Psychiatric and Psychosocial Rehabilitation in terms of Therapeia, that is in my view the regaining "sense and meaning" as the essence of rehabilitation therapy. My goal was to awaken thoughts, words, gestures, emotions in order to reconnect an interrupted dialogue with themselves and start an initial storytelling experience. By telling this new story the relationship between the Self, the Story and the Character is recreated so that freedom and life planning are generated again. In order to "gather unspoken yet deeply felt experiences" I used artworks extracted from the catalogue "tutti uguali, tutti diversi"; catalogue created during the awareness campaign and the fight against social stigma and social exclusion by Art, that the Center of Mental Health 3 - CSM 3 - in Troia (Puglia, Italy) held in 2007 in synergy with the School of Fine Art and with the Monuments and Fine Art Department. PMID- 30439841 TI - Management of adult patients with anorexia nervosa: a literature review. AB - BACKGROUND: Anorexia is a frequent pathology; not only does it cause major changes in patients' quality of life, but also the mortality rate is high. This mortality mainly affects young people. However, care remains controversial. The aim of this literature review is, therefore, to review current guidelines. SUBJECTS AND METHODS: A review of the literature published between 2006 and 2017, from articles contained in the Cochrane, PubMed, Scopus and PsychINFO databases. Keywords were 'anorexia nervosa', 'adults' and 'management'. RESULTS: Patient management must be multidisciplinary and prioritise weight gain. For this to happen, outpatient monitoring must include a gradual normalisation of eating habits. This always involves psychotherapy and sometimes prescription medication. However, no specific therapy or psychotropic drug has demonstrated statistical superiority in the management of anorexic patients. Cognitive behavioural therapy remains the most effective therapy in preventing relapse, and family therapies for the treatment of young patients who are still living with their families of origin. Hospitalization is sometimes necessary and must then include gradual and closely monitored refeeding to avoid the potentially fatal refeeding syndrome. CONCLUSIONS: The management of anorexic patients is complex but always involves reaching a normal weight. The best prognosis is found in young patients with the least chronic disease. PMID- 30439842 TI - Why do cyberbullied adolescents stay in contact with their harasser? A Literature Review and Reflection on Cyberbullied Adolescents' Coping Strategies. AB - BACKGROUND: Many young patients who are cyberbullied maintain communication with their harasser, despite the fact that this behaviour perpetuates the harassment. Numerous studies describe coping strategies adopted by cyberbullied adolescents. None describe what motivates adolescents to continue to communicate with their harassers. METHODS: We conducted a literature review of cyberbullying, taking into account the challenges of adolescence. We used several search engines (Scopus, PsycINFO, Cairn and PubMed), using the following keywords: cyberbullying, teens, behaviour, coping strategies, social network, Facebook, counterpart. Our search returned 526 results, which were subsequently sorted as a function of their relevance. We also consulted reference books on adolescent psychology. RESULTS: The adolescent, whose identity is being rebuilt, seeks a peer group, but also a relationship with a counterpart. This search is replayed on social networks and can lead adolescents to meet a counterpart harasser. Studies show that adolescents who suffer from cyberbullying are more likely than others to be in search of new friendships, and use social networks to make up for a lack or absence of fulfilling social relationships. They have fewer friends, have more difficulty maintaining social ties, and have fewer communication skills. In addition, cyberbullied adolescents have poorer relationships with their parents and teachers than their peers. CONCLUSIONS: Narcissistically fragile adolescents are at greater risk of being unable to stop communicating with their cyberbully. If the adolescent has no other relationships that enable him or her to develop their identity, they will be unable to put an end to this harmful counterpart relationship. It would be interesting to supplement this review with an experimental study, and to consider the development of new, secondary prevention strategies in the adolescent population. PMID- 30439843 TI - Neuroscience and Visual Art; Moving through empathy to the Ineffable. AB - In this article we wish to discuss recent work on neurobiology and visual arts, with impact on human pleasure, wellbeing and improved mental health. We wish to discuss briefly our model of the Human Person and apply it to Visual Art, and we wish to discuss our view of how empathy has been suggested as an important factor in how visual art can impact the human person, with its links with neuroscience and anthropology, and thus how Visual Art can put Human Beings in touch with their deepest feelings and even with the ineffable. PMID- 30439844 TI - The effect of music therapy sessions on the interactions between children and their parents and how to measure it, with reference to attachment theory. AB - Music therapy and attachment is an expanding field and the number of studies addressing the theoretical work is slowly growing. There are both qualitative and quantitative approaches to studying the effect of regular music therapy sessions on parent-child interactions and these cover a range of patient populations including: children at risk of neglect, parents with a trauma history, children coping with bereavement and a large number addressing the disability population, including autism spectrum disorder. These studies suggest that music therapy benefits the parent-child relationship through the improvement communication, especially non-verbal communication, and so increased the feeling of closeness and understanding. Following a review of the available literature, a pilot study is described using transcripts of video recordings of music therapy sessions, and subsequent colour coding and conversion of the data into pie charts provides a potential method of analysis that produces an "interaction profile" of each parent-child dyad. Preliminary results of this method of analysis suggest that music therapy sessions might be able to improve interactions through therapists addressing the power dynamics within a relationship. The new method developed in this pilot study to visualise and study the parent-child relationship in music therapy sessions was effective and could be used and developed by music therapy researchers in the future. PMID- 30439845 TI - What is Beauty? Should Doctors point out Beauty to their patients during therapy? AB - It has been argued that aesthetics, or the appreciation of beauty, can be used in therapy. We explore this concept from the point of view of new findings in neurobiology which give us an understanding of the mechanisms by which we experience beauty and creativity. We argue from anthropological perspectives that the experience of beauty is common to all cultures, and leads to the experiencing of important abstract concepts which enhance our lives, but which may be described differently in different cultures. We are beginning to understand how these abstract concepts are perceived, but this does not mean that the concepts themselves do not exist. Indeed, a Thomistic view of the human person will predict that there will be a mechanism within the body to express every bodily function. Based on this we argue that doctors should encourage their patients to appreciate beauty itself, as they understand it, because experiencing it can be therapeutic. PMID- 30439846 TI - Does Schizoaffective Disorder explain the mental illnesses of Robert Schumann and Vincent Van Gogh? AB - The geniuses Robert Schumann and Vincent Van Gogh show striking similarities both in the longitudinal nature of the progression of their illnesses, and the symptoms they experienced. There have been physiological explanations posed for both men, including Meniere's disease, tertiary syphilis, acute intermittent porphyria, terpenoid and lead poisoning, intracranial masses, temporal lobe epilepsy and dementia caused by vascular hypertension. The evidence for these physiological explanations is assessed. Schizophrenia and Bipolar disorder have also both been postulated to explain the symptoms of the two men, but neither man perfectly fits the diagnostic criteria for either. Schizoaffective disorder is a term used to describe patients who experience symptoms from both the psychosis of Schizophrenia and the mood disorders of Bipolar disorder. This paper aims to explain why Schizoaffective disorder explains the symptomology of these men better than either Schizophrenia or Bipolar disorder does alone. Schizoaffective disorder, however, did not exist as a diagnosis when Van Gogh and Schumann were alive, and so was not considered by their physicians. PMID- 30439847 TI - Tertiary Syphilis (General Paralysis of the Insane) and Bipolar Disorder; the role of these two disorders in the life of famous composers. AB - Syphilis is a complex disease, which can lead to General Paralysis of the Insane if left untreated. Before antibiotics this was the natural progression of the disease, with many people being admitted to mental asylums with the diagnosis of GPI, and going on to die there. Diagnoses however, were difficult, as it was difficult to distinguish between GPI and other mental conditions such as bipolar disorder. We can use the works of the classical composers Beethoven, Schubert, Schumann and Smetana, who all suffered from mental illness, to gain an insight into what it is like to live with these conditions. All these are potential cases of GPI, highlighting how a sexually transmitted disease can end the life of such talented and influential people. With antibiotic resistance becoming a growing concern, it is key that we continue to recognise and treat syphilis in an appropriate manner, so as to limit the future of this disease. PMID- 30439849 TI - Genius and Madness between Normality and Pathology. AB - It is reasonable to affirm that madness is inborn with the human spirit and that only in lunacy it is possible to be creative, being the intellect a system of rules that make possible to live with the least conflict possible, as masterfully said by Umberto Galimberti. To understand madness we must glean our lunacy and put aside the reason which relates to the non contradiction principle thus being not capable to comprehend madness that does not respond to the rational principles, whereas as Schopenhauer says, is the essence and the strength of the will to live. PMID- 30439848 TI - Mozart's music and multidrug-resistant epilepsy: a potential EEG index of therapeutic effectiveness. AB - Multidrug-resistant epilepsy is a pathological condition that affects approximately one-third of patients with epilepsy, especially those with associated intellectual disabilities. Several non-pharmacological interventions have been proposed to improve quality of life of these patients. In particular, Mozart's sonata for two pianos in D major, K448, has been shown to decrease interictal electroencephalography (EEG) discharges and recurrence of clinical seizures in these patients. In a previous study we observed that in institutionalized subjects with severe/profound intellectual disability and drug resistant epilepsy, a systematic music listening protocol reduced the frequency of seizures in about 50% of cases. This study aims to assess electroencephalography as a quantitative (qEEG) predictive biomarker of effectiveness of listening to music on the frequency of epileptic discharges and on background rhythm frequency (BRF). PMID- 30439850 TI - The persisting sadness, an inclination to become emotional: the case of inspector Ricciardi gifted with the capacity to feel pain. AB - Through the analysis of "Luigi Alfredo Ricciardi" the main character of detective series by Maurizio De Giovanni, the structuring of a normal melancholic constitution, which we term the depression-prone style of personality, is reconstructed. PMID- 30439851 TI - Depression as a "Comorbidity" of a Disorder not Recognized in Adolescence. AB - Depression is one of the most frequent mood disorders. The spectrum of its meanings is very complex. Symptoms of depression can be felt at every stage of life. Depressed mood states can, as for intensity, show the clinical picture that varies from mood changes to psychotic states. In this presentation, it is described a case of the patient who since early childhood showed the symptoms of ADHD that was showing as a comorbidity feelings of depression, which have significantly hindered the emotional maturation of the person. This etiological clarification has led to effective treatment, including the psychopharmacological and psychotherapeutic approach. PMID- 30439852 TI - Dysphoria as a psychiatric syndrome: a preliminary study for a new transnosographic dimensional approach. AB - BACKGROUND: We currently define dysphoria as a complex and disorganized emotional state with proteiform phenomenology, characterized by a multitude of symptoms. Among them prevail irritability, discontent, interpersonal resentment and surrender. Dysphoria, in line with the most recent Interpersonal Dysphoria Model, could represent a "psychopathological organizer" of the Borderline Personality Disorder. We would like to extend this theoretical concept to other psychiatric disorders in order to consider dysphoria as a possible psychopathological nucleus, a syndrome on its own. This syndromic vision may open up the possibility of new paths both in the differential diagnosis and in the therapeutic approach to the various disorders. AIMS: The goal of this paper is to understand if the dimensional spectrum that composes dysphoria differs from the different psychiatric disorders. Specifically, we would like to assess if the phenomenological expression of dysphoria differs in patients with Borderline Personality Disorder (BPD), Mixed State Bipolar Disorder (BDM) and Major Depressive Disorder (MDD) through an observational comparative study. SUBJECTS AND METHODS: In this study, 30 adult patients, males and females between the ages of 18 and 65, were enrolled from the Psychiatric Service of the Santa Maria della Misericordia Hospital in Perugia (PG), Italy, from January 1st to June 30th, 2018. The aim was to form 3 groups each one composed of 10 individuals affected respectively with Borderline Personality Disorder (BPD), with Bipolar Disorder, Mixed State (BPM) and Major Depression Disorder (MDD). After a preliminary assessment to exclude organic and psychiatric comorbidity, we administered them the Neapen Dysphoria Scale - Italian Version (NDS-I), a specific dimensional test for dysphoria. Starting from the dataset, with the aid of the statistical program SPSS 20, we have obtained graphs showing the comparison between disorders groups selected and NDS-I total score and subscales (irritability, discontent, interpersonal resentment, surrender). Finally, a comparison was made, taking two groups at a time, between the means of single groups for total scores and for single subscales considered into the NDS-I test. We made it using the Mann Whitney U test, a nonparametric test with 2 independent samples, by setting a significance level alpha=0.05. CONCLUSIONS: This study, through a transnosographic-dimensional approach, allowed us to explore dysphoria and its expressions in different psychopathological groups, despite analyzing a small sample. Differences between means of values obtained through NDS-I subscales were statistically significant in patients with BPD, BDM and MDD (p<0.05). Among the latter, the group of BPD patients has greater pervasiveness and severity of dysphoria symptoms. PMID- 30439853 TI - The neuroscience of music; a review and summary. AB - Present knowledge about the neurobiology of music is discussed and summarised. Music playing, reading and listening are all complex processes requiring co ordination of various parts of the brain in hierarchically structured sequences. The involvement of the right hemisphere of the brain in musical functions is well established, however in fact both hemispheres are involved. Plasticity is heavily involved in all functions of the brain related to music. The role of mirror neuron systems of the brain appears to be of great importance and parallels exist in the development and functioning of language and music. PMID- 30439854 TI - The use of Music Therapy in the treatment of Mental Illness and the enhancement of Societal Wellbeing. AB - Music Therapy can be broadly described as the use of Music in a therapeutic context in order to help improve mental health. Music Therapy does not simply imply the playing of music to patients, relaxing though this may be, but in fact it does involve more active involvement of the patient, so as to use the power of music in order to help improve the mental health of patients and in order to treat mental health conditions. We review the evidence for the effect of Music Therapy on Depression, Anxiety, Schizophrenia, Sleep Disorders, and Dementia. Encouraging singing appears to be a good adjunct to treating all of these conditions, and it also seems to help bonding between mothers and children within families. Music appears to be beneficial to both the individual, and also to the improvement of social cohesion. The reasons for this must reside in the nature of music itself as an art form which supports human interactions within society. PMID- 30439855 TI - Aesthetic experience: when emotions become a care. AB - Visual arts enable the artist to present to the viewer their internal subconscious thoughts. There is a connection between the artist and the viewer. This is so with famous artists, but also with patients who create artworks. This link between artist and viewer can be used in therapy to explore the artist/patient's interior self. This understanding between artist and viewer can , in therapy, become an expression of caring. PMID- 30439856 TI - Dignity Therapy: Prevention of Suicidal Risk in the Penitentiary Area. AB - Dignity therapy was administered to ten prisoners in a detention center. The Beck Depression Inventory was administered before and after the intervention. The results obtained from the Beck Depression Inventory have highlighted dimensional changes in all the prisoners. There was a significant improvement in relational abilities and the disappearance of self-harming thoughts. PMID- 30439857 TI - Selective Serotonin Re-uptake Inhibitors: An overview. AB - Selective serotonin re-uptake inhibitors (SSRIs) are front-line pharmacotherapies in the treatment of major depressive disorder (MDD), a disorder characterized by a persistent low mood, anhedonia and feelings of worthlessness. Since their formulation over 40 years ago, there have been several conflicting studies exploring the efficacy of these highly prevalent drugs. The nature of their therapeutic effect has also remained elusive, with several hypothesises pertaining to neurotransmitter and endocrine modulation proposed. While the medications are better tolerated than their predecessors, the tricyclic antidepressant family (TCAs), the side effect profile of SSRIs is not insubstantial and novel cases have highlighted adverse effects enduring past the cessation of drug treatment. Data gathered from clinical practice also highlights that the prevalence of these side effects is often underestimated, leading to patient frustration and non-compliance. This report will seek to outline the rise of SSRI usage in the last half century while exploring possible avenues of pharmacotherapeutic action, with a particular focus on the side effect profile of these drugs. PMID- 30439858 TI - Self Harm and Suicidality: an audit of follow-up in primary care. AB - Deliberate self harm is the strongest predictor of completed suicide. Primary care is often the entry point for those presenting with self harm and suicidality and so the primary care follow-up of such patients should include risk assessment for repeated self harm and completed suicide. This is of particular importance in patients at high risk for suicide, such as those with Bipolar Affective Disorder. This audit makes recommendations for the average UK GP Teaching Practice based on standards from the NICE guidelines relating to the prevalence, timing and content of follow-up in primary care of those patients who present with self harm or suicidality in the practice population. PMID- 30439859 TI - Innovative approaches to improving the image of psychiatrists and psychiatry amongst medical students and doctors in the UK. AB - In this paper we identify some of the critical factors that contribute to the ongoing shortage of psychiatrists in the UK. We discuss initiatives that have been launched to try and encourage more medical students and trainee doctors to choose psychiatry as a career. We describe the innovative anti-stigma Wounded Healer programme that was pioneered in the UK with the aim of improving the image of psychiatry and psychiatrists and that was subsequently scaled up and rolled out to over 65,000 medical students and doctors in 14 countries in five continents worldwide. We conclude, with some suggestions that we believe will help recruitment efforts into psychiatry. PMID- 30439860 TI - Rescue of the Appropriative "Thought-Action-Mood" Space: Anatomy and Mast Cells Generate "Mixable" Dimensions in Language and Statistics. AB - BACKGROUND: The orthogonal axes of Thought (T), Action (A), and Mood (M) span a phase space which corresponds e.g. to the three medial thalamic areas related to three resonating cortico-subcortico-thalamo-cortical loops. The above three of several loops constitute an "appropriative engine", since within that space, as hinted to via Fig. 228 by Emil Kraepelin to illustrate bipolar mixed states, circular waves of appropriative functioning - from need via action to e.g. satisfaction - reflect a spectrum of temperamental to anxio-affective signatures of sequential appropriation waves. This neo-classical "dyn4TAM"-model also posits that a prime (thalamic) motivating system of Uncertainty-orientation (R. M. Sorrentino) regulates the temperamental balance between only 4-dimensional (D) "Thought" (G. Halford) about effort-sparing models and high-D-"Action" (G. Rizzolatti) meaningfully related to movement. In fact the exchange across this "complexity divide" - between "grasping" action-related high-D-modules and "calculating" 4D-modules of brains - even concerns the grounding of symbolic relational "concepts. " It thus expands on the Franco-Kraepelinian "TAM"-System (FKS) which suffered a distortion by Kraepelin and the eliminative eugenicist Wilhelm Weygandt, unfortunately carried on in the "bipolar spectrum" current. Because the above loops are independently segregated they generate true dimensions. Furthermore the phenomena they jointly create become patterns, i.e. independently filled slots. Now these are irremediably destroyed at acquisition by Galtonian statistics which is detrimental to conceiving dimensional topics. HYPOTHESIS: Here we posit that preponderantly "uncertainty-oriented", calculating academics unless depressed, are attracted by 4D-Thought and repulsed by intuition. They thus avoid bio-psychologically the " comprehension" of patterns. METHOD & RESULT: New research initiated by dyn4TAM confirmed, that the homologous rodent sign-tracking depends on mast cells modulating the ACC-loop for "Action." CONCLUSION: The "complexity divide" warrants more attention in clinical and pure cognitive sciences and should include a "psychology of statistics". PMID- 30439861 TI - Poor Compliance as a sign of Depression. Why Might an Elderly Man Stop His Medication? AB - With only half of individuals prescribed medication actually taking it, the reasons behind non-compliance warrant a thorough understanding. This paper reviews the factors behind medication non-adherence with a special interest in the link between depression and non-compliance. Whilst this link has been evidenced, we propose that non-compliance could be a presenting sign of underlying depression. Implications of the role of depression as a cause of non compliance - in particular, why a patient might suddenly stop taking their medication - are discussed; further, early intervention to circumvent a major depressive episode could be implemented if recognition of sudden non-compliance is used by clinicians as a diagnostic tool to alert them to screen the patient for depression. PMID- 30439862 TI - The Psychology of Scars: A Mini-Review. AB - Scars can result from a range of causes: accidents, surgery, and even acne. The resultant change in appearance can negatively affect body image and self confidence. Scarring is stigmatised in society because of the premium placed on beauty - disfigurement or unsightly features are still used to portray evil in horror films, comic strips, and fairy tales. Patients describe scars as living with the trauma and sufferers can feel devalued by society. Scars are inflexible and cause functional impairment which may prompt a change in career and have financial repercussions. Those with scars undergo a remodelling of their emotional state and are more prone to the development of depression and anxiety; feelings of shame and aggression can follow. This creates strain in social interactions, resulting in stunted communication, reduced intimacy, and avoidant behaviours. There is limited treatment available to address the psychological burden in this subset of patients. Additionally, doctors often lack training in recognition and management of psychosocial issues. Steps must be taken to relieve the physical, emotional, and psychological marks caused by scars. PMID- 30439863 TI - The Importance of Anxiety in Understanding how Decision Making is Affected in Autism Spectrum Disorder. AB - Autobiographical and clinical accounts of individuals with autism spectrum disorder (ASD) have highlighted that these individuals experience several difficulties during the decision making process. A review of the experimental based studies assessing performance in decision making tasks compared to controls emphasizes key differences including altered risk preferences, decreased sensitivity to social rewards, increased deliberative reasoning and atypical integration of emotional cues. Despite several attempts to devise cognitive theories to explain these differences, none so far can account for all the differences seen. However, one key observation, consistent with clinical accounts, is elevated levels of anxiety in populations with ASD. Whilst this has traditionally been considered a bi-product of the decision making process, I argue that increased anxiety may directly influence decision making in individuals with ASD, through 2 main routes. Firstly, elevated anxiety overwhelms Type 1 (intuitive) fast processes (within the Dual Process Model), leading to a decision making style biased by Type 2 (deliberative) processes. In addition, heightened anxiety decreases cognitive flexibility, leading to a more logic based, deliberative decision making style. This is superimposed on pre-existing cognitive impairments which altogether may account for the differences seen. Therefore, anxiety must be considered as a key variable in cognitive models of decision making in ASD. Specific recommendations for future research exploring the role of anxiety are discussed. PMID- 30439864 TI - Effectiveness of serotonergic drugs in the management of problem behaviors in patients with neurodevelopmental disorders. AB - Neurodevelopmental disorders often result in disabilities associated with auto- and / or hetero-aggressive behaviors, that can be defined as "problem behaviors" (Lacy 2007). Therapeutic interventions are mainly directed towards the use of neuroleptic drugs or benzodiazepines, to ensure a rapid and significant sedation in most of cases. These pharmacological devices exposes the patient to clinical risks and/or long-term management difficulties. The main problem of the chronic use of benzodiazepines is the development of tolerance and dependence; furthermore benzodiazepine withdrawal or their abrupt reduction may lead to rebound effect. Regarding the long-term effects of neuroleptics, it is necessary to focus on extrapyramidal effects, motor restlessness and akathisia, anticholinergic effects, as well as endocrine and metabolic alterations. Several studies have shown that the reduction of serotonergic receptor activity is associated with the appearance of aggressive behavior (Farnam et al. 2017), especially impulsive behaviors (Manchia et al. 2017, Takahashi et al. 2012). The dynamics that subtend these data are still not fully clarified, however there are evidences that the use of selective serotonin reuptake inhibitors (SSRI) is helpful in the treatment of aggressive behavior in mental disabilities (Sterke et al. 2012, Janowsky et al. 2015). In this study we observe the behavioral response to sertraline, for minors, and to vortioxetine, for adults, considering that the literature shows significant evidence of modulation of synaptic neuroplasticity (Waller et al. 2017). To support the observation we used behavioural scales to collect the data, before the administration of the drug, during the course of treatment, at 3 months from the start of the administration. We detected the improve of behavioral disorders with the less use neuroleptic drugs and benzodiazepines. PMID- 30439865 TI - Can writing poems and taking photos help the psychiatrist to improve his humanity and the mental health of his patients? AB - The relationship between the art forms of photography and poetry and mental wellbeing is described, both for the psychiatrist and for the patient. These, as well as other art forms, improve the experience of human persons interior life. It is suggested that these art forms, as well as music and dance, can be helpful in the treatment of Depression. PMID- 30439866 TI - Evaluation of Intravenous Parecoxib Infusion Pump of Patient-Controlled Analgesia Compared to Fentanyl for Postoperative Pain Management in Laparoscopic Liver Resection. AB - BACKGROUND As laparoscopic liver resection is becoming a commonly used method for hepatic surgery, postoperative pain management is emerging as one of the trickiest problems after surgery. The ideal method of pain management is controversial and the optimal strategy for postoperative pain management after surgery remains unclear. The present study evaluated the postoperative analgesic efficacy of parecoxib and fentanyl, and the benefit of a new intravenous parecoxib infusion pump with patient-controlled analgesia after laparoscopic liver resection. MATERIAL AND METHODS This controlled, prospective, randomized, double-blind trial compared VAS scores among 3 groups of patients: a fentanyl group (FEN group) using a fentanyl citrate pump, an intravenous parecoxib group (IVPA group) receiving intravenous parecoxib, and a parecoxib pump group (PUPA group) receiving parecoxib sodium by analgesia pump. We enrolled 124 patients planned for laparoscopic liver resection. The primary outcome was VAS score at rest and with movement. Secondary outcomes were adverse effects (including nausea), sedation, pruritus, and quality of life. RESULTS For all time intervals, the VAS scores were significantly lower in the PUPA group. VAS scores at rest and with movement in the PUPA group were the lowest among the 3 groups, while the scores in the FEN group were the highest. More adverse effects were detected in the FEN group, and no significant differences in adverse effects were found between the intravenous group and the parecoxib pump group. CONCLUSIONS Use of the intravenous infusion parecoxib pump for patient-controlled analgesia provides superior analgesic efficacy and fewer adverse effects for patients after laparoscopic liver resection. PMID- 30439867 TI - Increase in Acute Flaccid Myelitis - United States, 2018. AB - In August 2018, CDC noted an increased number of reports of patients having symptoms clinically compatible with acute flaccid myelitis (AFM), a rare condition characterized by rapid onset of flaccid weakness in one or more limbs and spinal cord gray matter lesions, compared with August 2017. Since 2014, CDC has conducted surveillance for AFM using a standardized case definition (1,2). An Epi-X* notice was issued on August 23, 2018, to increase clinician awareness and provide guidance for case reporting. PMID- 30439869 TI - Suicide Rates by Major Occupational Group - 17 States, 2012 and 2015. AB - During 2000-2016, the suicide rate among the U.S. working age population (persons aged 16-64 years) increased 34%, from 12.9 per 100,000 population to 17.3 (https://www.cdc.gov/injury/wisqars). To better understand suicide among different occupational groups and inform suicide prevention efforts, CDC analyzed suicide deaths by Standard Occupational Classification (SOC) major groups for decedents aged 16-64 years from the 17 states participating in both the 2012 and 2015 National Violent Death Reporting System (NVDRS) (https://www.cdc.gov/violenceprevention/nvdrs). The occupational group with the highest male suicide rate in 2012 and 2015 was Construction and Extraction (43.6 and 53.2 per 100,000 civilian noninstitutionalized working persons, respectively), whereas the group with the highest female suicide rate was Arts, Design, Entertainment, Sports, and Media (11.7 [2012] and 15.6 [2015]). The largest suicide rate increase among males from 2012 to 2015 (47%) occurred in the Arts, Design, Entertainment, Sports, and Media occupational group (26.9 to 39.7) and among females, in the Food Preparation and Serving Related group, from 6.1 to 9.4 (54%). CDC's technical package of strategies to prevent suicide is a resource for communities, including workplace settings (1). PMID- 30439870 TI - Erratum: Vol. 67, No. SS-6. PMID- 30439868 TI - Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. AB - PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2012. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence and characteristics of ASD among children aged 8 years whose parents or guardians reside in 11 ADDM Network sites in the United States (Arkansas, Arizona, Colorado, Georgia, Maryland, Missouri, New Jersey, North Carolina, South Carolina, Utah, and Wisconsin). Surveillance to determine ASD case status is conducted in two phases. The first phase consists of screening and abstracting comprehensive evaluations performed by professional service providers in the community. Data sources identified for record review are categorized as either 1) education source type, including developmental evaluations to determine eligibility for special education services or 2) health care source type, including diagnostic and developmental evaluations. The second phase involves the review of all abstracted evaluations by trained clinicians to determine ASD surveillance case status. A child meets the surveillance case definition for ASD if one or more comprehensive evaluations of that child completed by a qualified professional describes behaviors that are consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnostic criteria for any of the following conditions: autistic disorder, pervasive developmental disorder-not otherwise specified (including atypical autism), or Asperger disorder. This report provides ASD prevalence estimates for children aged 8 years living in catchment areas of the ADDM Network sites in 2012, overall and stratified by sex, race/ethnicity, and the type of source records (education and health records versus health records only). In addition, this report describes the proportion of children with ASD with a score consistent with intellectual disability on a standardized intellectual ability test, the age at which the earliest known comprehensive evaluation was performed, the proportion of children with a previous ASD diagnosis, the specific type of ASD diagnosis, and any special education eligibility classification. RESULTS: For 2012, the combined estimated prevalence of ASD among the 11 ADDM Network sites was 14.5 per 1,000 (one in 69) children aged 8 years. Estimated prevalence was significantly higher among boys aged 8 years (23.4 per 1,000) than among girls aged 8 years (5.2 per 1,000). Estimated ASD prevalence was significantly higher among non Hispanic white children aged 8 years (15.3 per 1,000) compared with non-Hispanic black children (13.1 per 1,000), and Hispanic (10.2 per 1,000) children aged 8 years. Estimated prevalence varied widely among the 11 ADDM Network sites, ranging from 8.2 per 1,000 children aged 8 years (in the area of the Maryland site where only health care records were reviewed) to 24.6 per 1,000 children aged 8 years (in New Jersey, where both education and health care records were reviewed). Estimated prevalence was higher in surveillance sites where education records and health records were reviewed compared with sites where health records only were reviewed (17.1 per 1,000 and 10.4 per 1,000 children aged 8 years, respectively; p<0.05). Among children identified with ASD by the ADDM Network, 82% had a previous ASD diagnosis or educational classification; this did not vary by sex or between non-Hispanic white and non-Hispanic black children. A lower percentage of Hispanic children (78%) had a previous ASD diagnosis or classification compared with non-Hispanic white children (82%) and with non Hispanic black children (84%). The median age at earliest known comprehensive evaluation was 40 months, and 43% of children had received an earliest known comprehensive evaluation by age 36 months. The percentage of children with an earliest known comprehensive evaluation by age 36 months was similar for boys and girls, but was higher for non-Hispanic white children (45%) compared with non Hispanic black children (40%) and Hispanic children (39%). INTERPRETATION: Overall estimated ASD prevalence was 14.5 per 1,000 children aged 8 years in the ADDM Network sites in 2012. The higher estimated prevalence among sites that reviewed both education and health records suggests the role of special education systems in providing comprehensive evaluations and services to children with developmental disabilities. Disparities by race/ethnicity in estimated ASD prevalence, particularly for Hispanic children, as well as disparities in the age of earliest comprehensive evaluation and presence of a previous ASD diagnosis or classification, suggest that access to treatment and services might be lacking or delayed for some children. PUBLIC HEALTH ACTION: The ADDM Network will continue to monitor the prevalence and characteristics of ASD among children aged 8 years living in selected sites across the United States. Recommendations from the ADDM Network include enhancing strategies to 1) lower the age of first evaluation of ASD by community providers in accordance with the Healthy People 2020 goal that children with ASD are evaluated by age 36 months and begin receiving community based support and services by age 48 months; 2) reduce disparities by race/ethnicity in identified ASD prevalence, the age of first comprehensive evaluation, and presence of a previous ASD diagnosis or classification; and 3) assess the effect on ASD prevalence of the revised ASD diagnostic criteria published in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. PMID- 30439871 TI - Retraction Notice: Suicide Rates by Occupational Group - 17 States, 2012. AB - On July 1, 2016, MMWR published "Suicide Rates by Occupational Group - 17 States, 2012" (1). On June 14, 2018, the authors informed MMWR about their concerns regarding the validity of some of the findings in the report, and on June 29, 2018, MMWR published "Notice to Readers: Ongoing Analysis of Suicide Rates Data by Occupational Group from Results Reported in MMWR" (2). The analysis is complete, and because the corrections change the conclusions, the original report is retracted. PMID- 30439872 TI - Correction and Republication: Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012. AB - On April 1, 2016, MMWR Surveillance Summaries published "Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years-Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2012" (1). On June 5, 2018, the authors informed MMWR about a number of inadvertent errors throughout the report that resulted from reporting of autism spectrum disorder cases among persons who did not live in the geographic surveillance area. Corrections of these errors do not change the interpretation or the conclusions of the original report. In accordance with December 2017 guidance from the International Committee of Medical Journal Editors (2), MMWR has corrected and republished the report (3). The republished report includes the original report with clearly marked corrections in supplementary materials. PMID- 30439873 TI - Global Routine Vaccination Coverage - 2017. AB - Endorsed by the World Health Assembly in 2012, the Global Vaccine Action Plan 2011-2020 (GVAP) (1) calls on all countries to reach >=90% national coverage with all vaccines in the country's national immunization schedule by 2020. This report updates previous reports (2,3) and presents global, regional, and national vaccination coverage estimates and trends as of 2017. It also describes the number of infants surviving to age 1 year (surviving infants) who did not receive the third dose of diphtheria and tetanus toxoids and pertussis-containing vaccine (DTP3), a key indicator of immunization program performance (4,5), with a focus on the countries with the highest number of children who did not receive DTP3 in 2017. Based on the World Health Organization (WHO) and United Nations Children's Fund (UNICEF) estimates, global DTP3 coverage increased from 79% in 2007 to 84% in 2010, and has remained stable from 2010 to 2017 (84% to 85%). In 2017, among the 19.9 million children who did not receive DTP3 in the first year of life, 62% (12.4 million) lived in 10 countries. From 2007 to 2017, the number of children who had not received DTP3 decreased in five of these 10 countries and remained stable or increased in the other five. Similar to DTP3 coverage, global coverage with the first measles-containing vaccine dose (MCV1) increased from 80% in 2007 to 84% in 2010, and has remained stable from 2010 to 2017 (84% to 85%). Coverage with the third dose of polio vaccine (Pol3) has remained stable at 84%-85% since 2010. From 2007 to 2017, estimated global coverage with the second MCV dose (MCV2) increased from 33% to 67%, as did coverage with the completed series of rotavirus (2% to 28%), pneumococcal conjugate (PCV) (4% to 44%), rubella (26% to 52%), Haemophilus influenzae type b (Hib) (25% to 72%) and hepatitis B (HepB) (birth dose: 24% to 43%; 3-dose series: 63% to 84%) vaccines. Targeted, context specific strategies are needed to reach and sustain high vaccination coverage, particularly in countries with the highest number of unvaccinated children. PMID- 30439874 TI - Progress Toward Global Eradication of Dracunculiasis - January 2017-June 2018. AB - Dracunculiasis (Guinea worm disease), caused by the parasite Dracunculus medinensis, is acquired by drinking water containing copepods (water fleas) infected with its larvae. The worm typically emerges through the skin on a lower limb approximately 1 year after infection, causing pain and disability (1). The worldwide eradication campaign began at CDC in 1980. In 1986, the World Health Assembly called for dracunculiasis elimination, and the global Guinea Worm Eradication Program (GWEP), led by the Carter Center in partnership with the World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and others, began assisting ministries of health in countries with dracunculiasis. There is no vaccine or medicine to treat the disease; the GWEP relies on case containment* to prevent water contamination and other interventions to prevent infection, including health education, water filtration, chemical treatment of water, and provision of safe drinking water (1,2). In 1986, an estimated 3.5 million cases? occurred each year in 20S African and Asian countries (3,4). This report, based on updated health ministry data (3), describes progress during January 2017-June 2018 and updates previous reports (1,4). In 2017, 30 cases were reported from Chad and Ethiopia, and 855 infected animals (mostly dogs) were reported from Chad, Ethiopia, and Mali, compared with 25 cases and 1,049 animal infections reported in 2016. During January-June 2018, the number of cases declined to three cases each in Chad and South Sudan and one in Angola, with 709 infected animals reported, compared with eight cases and 547 animal infections during the same period of 2017. With only five affected countries, the eradication goal is near, but is challenged by civil unrest, insecurity, and lingering epidemiologic and zoologic questions. PMID- 30439875 TI - Notes from the Field: Use of Electronic Cigarettes and Any Tobacco Product Among Middle and High School Students - United States, 2011-2018. PMID- 30439876 TI - QuickStats: Birth Rates* by Urbanization Level? and Age Group of Mother - National Vital Statistics System, United States, 2017. PMID- 30439878 TI - Diode-pumped Q-switched Alexandrite laser in single longitudinal mode operation with Watt-level output power. AB - We present significantly improved performance data of a diode-pumped Q-switched Alexandrite laser in single longitudinal mode operation developed as a beam source for resonance lidar systems. The average output power of the laser operating at the potassium resonance at 770 nm with a linewidth below 10 MHz could be increased by a factor of five to the Watt-level by means of an optimized resonator design and pump scheme. The pulse energy is 1.7 mJ with a beam quality of M2<=1.1 in both spatial directions at a repetition rate of 500 Hz. PMID- 30439879 TI - Brillouin optical time-domain analysis via compressed sensing. AB - A compressed-sensing-technique-based Brillouin optical time-domain analysis is proposed. The Brillouin spectrum has a sparse representation in its discrete cosine transform domain, which can be successfully recovered from far fewer measurements with high probability through an orthogonal matching-pursuit algorithm. This work shows both empirically and experimentally that the amount of frequency acquisitions needed is only 30% of those required by a conventional distributed Brillouin fiber-optic sensing system with 1 MHz frequency increment in the acquisition process to obtain Brillouin spectra along an optical fiber; therefore, the number of acquisitions and the amount of data storage/transfer are greatly reduced. Moreover, the proposed method does not need any hardware modification in an existing sensing system and can also be adopted by Brillouin optical time-domain reflectometry. PMID- 30439877 TI - Updated Framework for Development of Evidence-Based Recommendations by the Advisory Committee on Immunization Practices. AB - The Advisory Committee on Immunization Practices (ACIP)* is a federal advisory committee that provides expert advice to the Director of CDC and the Secretary of the U.S. Department of Health and Human Services in the form of recommendations on the use of vaccines and related agents for control of vaccine-preventable diseases in the U.S. civilian population (1,2). Work groups that gather, analyze, and prepare scientific information assist in the recommendation formulation process and present options for recommendations based on the scientific evidence they have assessed. Recommendations that are approved by a majority of ACIP's voting members are then reviewed by the Director of CDC and published in MMWR if approved by the director. This report briefly summarizes an update to the ACIP process for developing evidence-based recommendations that ACIP adopted at its February 2018 meeting. PMID- 30439880 TI - Thermal coupling impact on an MMW carrier generated using two free-running DFB lasers on glass. AB - In this Letter, the impact of thermal coupling between two glass laser cavities on a heterodyned signal for millimeter-wave frequency generation is presented. In addition to a narrow heterodyne linewidth estimated to be lower than 1 kHz, the frequency drift is reduced to +/-16.5 ppm/7 s. The signal quality is also evaluated by performing data transmission, respecting communication standards at 60 GHz using complex modulation formats. PMID- 30439882 TI - Polarization determination based on the longitudinal field of a converging terahertz wave. AB - Based on coherently measuring the longitudinal field of a converging terahertz (THz) wave, a polarization determination method to the THz radiation is proposed. By utilizing the method, the arbitrary uniform polarization state of a THz field can be effectively identified in a single measurement. By using the vector diffraction integral, the principle of the method is theoretically discussed in detail. The feasibility of the method is validated experimentally by measuring a THz wire grating polarizer and a THz quarter-wave plate. The method offers a powerful technical support for developing the THz polarization spectroscopy. PMID- 30439881 TI - Dispersion engineering and thermo-optic tuning in mid-infrared photonic crystal slow light waveguides on silicon-on-insulator. AB - In this Letter, the design, fabrication, and characterization of slow light devices using photonic crystal waveguides (PhCWs) in the mid-infrared wavelength range of 3.9-3.98 MUm are demonstrated. The PhCWs are built on the silicon-on insulator platform without undercut to leverage its well-developed fabrication process and strong mechanical robustness. Lattice shifting and thermo-optic tuning methods are utilized to manipulate the slow light region for potential spectroscopy sensing applications. Up to 20 nm wavelength shift of the slow light band edge is demonstrated. Normalized delay-bandwidth products of 0.084-0.112 are obtained as a result of dispersion engineering. From the thermo-optic characterization results, the slow light enhancement effect of thermo-optic tuning efficiency is verified by the proportional relationship between the phase shift and the group index. This work serves as a proof of concept that the slow light effect can strengthen light-matter interaction and thereby improve device performance in sensing and nonlinearity applications. PMID- 30439883 TI - Whispering-gallery-mode excitation in a microsphere by use of an etched cavity on a multimode fiber end. AB - In this Letter, we demonstrate a whispering-gallery-mode (WGM) microsphere resonator. The device is fabricated by fusion splicing a section of no-core fiber with multimode fiber (MMF) and single-mode fiber at its two ends. The open end of the MMF is etched to create an arc-shaped cavity, with a microsphere glued at its bottom. When the arc of the cavity bottom and microsphere surface are tangent, part of the incident light is coupled into the microsphere and travels exactly one circle before being directed back to the MMF core along the tangent line and exciting the WGM. The device has a Q-factor of 1.21*104, and is robust in structure and low in cost. PMID- 30439884 TI - Dielectric metamaterials with electric response. AB - Dielectric metamaterials are usually studied as low-loss media with magnetic response. However, control over the electric response is more promising for applications in photonics. Here we report an all-dielectric metamaterial with electric response. The structure consists of high-index dielectric rods arranged in a square lattice. We present a phase diagram that includes regions of metamaterials with magnetic and electric response. A metamaterial behavior is demonstrated for homogeneous epsilon-near zero modes, which are observed regardless of a lattice orientation and a structure boundary. The epsilon-near zero modes make it possible to enhance electric field intensity by two orders of magnitude, which can be used for applications exploiting light-matter interactions. PMID- 30439885 TI - Electrical conductance of near-infrared femtosecond air filaments in the multi filament regime. AB - Electrical conductive properties of femtosecond laser filaments are of significant interest for applications such as remote arc suppression and discharge guiding. We transmitted electrical current through a DC-biased air plasma channel formed in the wake of an energetic femtosecond laser pulse and observed an increased rate of change of the charge transmitted through the ionized channel with laser energy when crossing from the single- to multi filament regimes. This behavior is attributed to the confluent effects of greater electron density and an increased cross-sectional area of the multi-filament plasma structures. As the laser energy is increased, the formation of additional conductive channels in the multi-filamentation regime becomes a significant contributor to the rapid increase of conductivity. These observations suggest a potential path to attractive applications such as efficient energy transfer in air mediated by femtosecond laser-produced filaments. PMID- 30439886 TI - Highly flexible organic-inorganic hybrid perovskite light-emitting devices based on an ultrathin Au electrode. AB - Organic-inorganic hybrid perovskite materials have received much attention in light-emitting applications during the past several years. The commonly used indium tin oxide (ITO) electrodes in perovskite light-emitting devices (PeLEDs) have unavoidable drawbacks of increasing cost and incompatibility with flexible devices, which limit the development of PeLEDs. Here, high-performance and ITO free flexible PeLEDs utilizing ultrathin Au electrodes have been achieved and exhibited high brightness (>10,000 cdm-2). By introducing a MoO3/SU-8 modification layer, the ultrathin Au film with a thickness of 7 nm exhibits excellent surface morphology with a root-mean-square roughness value of 0.307 nm. Meanwhile, the ultrathin Au film demonstrates an outstanding optical property with transparency of 83% at the wavelength of 550 nm. Simultaneously, favorable conductivity with a sheet resistance of 13 Omega sq-1 has been achieved. High mechanical robustness and flexibility have been obtained for the flexible PeLEDs by surviving 1000 bending cycles. The flexible PeLEDs reported here exhibit tremendous potential for commercial applications. PMID- 30439887 TI - Depth-resolved speckle-correlations imaging through scattering layers via coherence gating. AB - Recently, novel imaging techniques based on the "memory-effect" speckle correlations have enabled diffraction-limited imaging through scattering layers and around corners. These techniques, however, are currently limited to imaging only small planar objects contained within the angular and axial range of the memory effect. In addition, they do not provide depth information or depth sectioning capability. Here, we extend speckle-correlation imaging to include high-resolution depth-sectioning capability in the reflection mode, by combining it with coherence gating via low-coherence holography. We demonstrate depth measurements of reflective targets through a scattering layer, and speckle correlation imaging using coherence-gated scattered light. PMID- 30439888 TI - Enhanced absorption by coherent control in a photonic crystal resonator coupled with a microfiber. AB - We demonstrate enhanced absorption in a photonic crystal resonator (PCR) coupled with an optical microfiber. Enhanced absorption is based on coherent perfect absorption (CPA) that is time-reversed lasing. The PCR is fabricated on a silicon membrane with optimized parameters obtained from a numerical simulation. In an experiment, we observed 72% of absorption for the PCR with the optimized parameters. We also verified numerically that the absorption required for CPA can be tuned by changing the distance between the PCR and the optical microfiber. PMID- 30439889 TI - Static and dynamic mode coupling in a double-pass rod-type fiber amplifier. AB - This Letter describes an experimental realization of a double-pass amplifier using rod-type fiber. In this device, the gain reaches 26 dB amplifying a 300 mW, 20 ps, 20 MHz seed up to 120 W, with an optical-to-optical efficiency of 50% and excellent beam quality. In addition, by design the output of the amplifier has a polarization extinction ratio of 33 dB. Besides these good performances, we report a marginal degradation of mode quality and degree of polarization followed by the so-called transverse mode instability which occurs at 120 W signal power. The first degradation is static, and by analyzing its two polarizations, we conclude it is caused by a coupling between modes due to the formation of a static thermal long-period grating, which in turn initiates the dynamic instability. PMID- 30439890 TI - All-optical non-volatile tuning of an AMZI-coupled ring resonator with GST phase change material. AB - We present a Ge2Sb2Te5 (GST)-integrated ring resonator with the tuning enabled by an all-optical phase change of GST using a sequence of optical pulses. The tuning is non-volatile and repeatable, with no static power consumption due to the "self holding" feature of the GST phase-change material. The 2 MUm long GST can be partially crystallized by controlling the number of pulses, increasing the tuning freedom. The coupling between the ring resonator and the bus waveguide is based on an asymmetric Mach-Zehnder interferometer. The coupling strength is wavelength dependent, so that an optimal wavelength can be selected for the probe light to get more than 20 dB transmission contrast between the amorphous and crystalline GST states. PMID- 30439891 TI - Flipping interferometry with doubled imaging area. AB - We present a new external off-axis holographic module that doubles the acquired complex wavefront field of view, based on using both holographic flipping and multiplexing. In contrast to previous designs, this design does not require spatial filtering (no pinhole or lenses) to create the reference beam externally. In addition, the overlap area between the fields of view, as well as the off-axis angle between the sample and reference beams, can be fully controlled. As we demonstrate experimentally, this approach is useful for quantitative phase microscopy of extended stationary and dynamic samples, such as cancer cells during rapid flow and beating cardiomyocytes. PMID- 30439892 TI - Photoluminescence spectra of the Mn2+d-d multiplets transitions of zinc-blende MnTe epitaxial films: laser and deuterium lamp excitation study. AB - The luminescences of zinc-blende MnTe epitaxial films are respectively excited by a laser and deuterium lamp to study Mn2+d-d multiplets transitions. Besides the inclusion of the band gap, all other excited states related to Mn2+d-d transitions including T14(G4), T24(G4), A14[E4(G4)], T24(D4), E4(D4), and T22(I2) are observed. The shift and broadening of the T14(G4) and T24(G4) lines with increasing temperature are described by the electron-phonon coupling. Step-like energy and intensity shifts for the A14[E4(G4)], T24(D4), E4(D4), and T22(I2) transitions occur in the vicinity of the Neel point, which can be ascribed to the different spin-ordering-induced energy relaxation in ground and excited states of Mn2+d-d multiplets, and these transitions show temperature independence and weak quenching. PMID- 30439893 TI - All-optical generation of magnetization with arbitrary three-dimensional orientations. AB - In this Letter, all-optical generation of magnetization with arbitrary three dimensional (3D) orientations is numerically demonstrated through the inverse Faraday effect (IFE) by using a reversing calculation method. The IFE-induced magnetization with an expected 3D orientation is initially conceived by coherently configuring two orthogonally arranged electric dipoles with a phase difference of pi/2 in the focal region of a to-be-determined incident light field. Based on the dipole antenna theory, this required incident light field can be deduced analytically according to the orientations of the electric dipoles. By utilizing this field as illumination and reversing the field propagation, magnetization with the expected orientation can be obtained in the focal region through the IFE. Moreover, this method showcases a high magnetization orientation purity (greater than 93%) within the focal volume defined by the full width at half maximum when the numerical aperture of the focal lens is 0.95. This result demonstrates extended flexibility of magnetization manipulations in an all optical fashion and possesses great potential in spintronics and all-optical magnetic recording. PMID- 30439894 TI - Slice-illuminated optical projection tomography. AB - To improve the imaging performance of optical projection tomography (OPT) in live samples, we have explored a parallelized implementation of semi-confocal line illumination and detection to discriminate against scattered photons. Slice illuminated OPT (sl-OPT) improves reconstruction quality in scattering samples by reducing interpixel crosstalk at the cost of increased acquisition time. For in vivo imaging, this can be ameliorated through the use of compressed sensing on angularly undersampled OPT data sets. Here, we demonstrate sl-OPT applied to 3D imaging of bead phantoms and live adult zebrafish. PMID- 30439895 TI - Long-distance distribution of the telecom band intensity difference squeezing generated in a fiber optical parametric amplifier. AB - Using an all-fiber source of pulsed twin beams, with the record intensity difference squeezing of 6.1+/-0.15 dB for fiber optical parametric amplifiers, we experimentally distribute the pulsed continuous variable (CV) quantum state over a long distance. After separating the signal and idler twin beams by 26 km single-mode fibers, the measured intensity difference noise is still below the shot noise limit by 2 dB. The result shows that the distribution process is only affected by the vacuum noise originated from the fiber transmission loss. The extra noise contributed by the acoustic wave Brillouin scattering and Raman scattering in 26 km transmission fibers has not been observed. The investigation is beneficial for studying long-distance CV quantum communication. PMID- 30439896 TI - Scalable and reconfigurable optical tapped-delay-line for multichannel equalization and correlation using nonlinear wave mixing and a Kerr frequency comb. AB - We experimentally demonstrate a scalable and reconfigurable optical tapped-delay line (TDL) for multichannel equalization and correlation of 20-Gbaud quadrature phase-shift-keyed (QPSK) signals using nonlinear wave mixing and a microresonator Kerr frequency comb. The optical TDL mainly consists of two stages: one being a multicasting of the original signals in a periodically poled lithium niobate (PPLN) waveguide with Kerr comb lines functioning as mutually coherent pumps, while the other is a coherent multiplexing of the delayed and weighted signal replicas in a second PPLN. A two- or three-tap optical TDL is demonstrated to simultaneously equalize a distorted QPSK data signal, reducing the error vector magnitude (EVM) from 22.5% to either 19.9% or 18.2%, and search two- or three symbol patterns on another QPSK signal. PMID- 30439897 TI - High-order harmonic generation from a solid-surface plasma by relativistic intensity sub-100-fs mid-infrared pulses. AB - High-order harmonic generation (HHG) in plasmas induced by ultrashort, relativistic-intensity laser pulses on solid surfaces can provide an efficient source of attosecond pulses and opens routes toward new regimes of laser-matter interactions, x-ray generation, laser particle acceleration, and relativistic nonlinear optics. However, field intensities in the range of Irel~1019 W/cm2 are typically needed to achieve the relativistic regime of HHG in experiments with near-infrared laser pulses. Here, we show that, in the mid-infrared range, due to the lambda-2 scaling of Irel with the driver wavelength lambda, relativistic HHG can be observed at much lower levels of laser field intensities. High-peak-power 80-fs, 3.9-MUm pulses are focused in our experiments on a solid surface to provide field intensities in the range of 1017 W/cm2. Remarkably, this level of field intensities, considered as low by the standards of relativistic optics in the near infrared, is shown to be sufficient for generation of high-order harmonics with signature properties of relativistic HHG-beam directionality, spectra with extended plateaus, and a high HHG yield sustained for both p- and s polarized driver fields. PMID- 30439898 TI - Phase-shifting radial-shearing digital holography with Greek-ladder zone plates. AB - Holography has been widely applied in fields of imaging and measurement, but the optical setup of traditional phase-shifting holography is complicated. Here, a kind of phase-shifting radial-shearing holography with Greek-ladder zone plates is presented, which largely simplifies the optical configuration for holographic recording and enhances the stability of system. A 1951 U.S. Air Force resolution test target is measured by experiment to verify the validity of our proposed method. Benefiting from amplitude-only diffractive lenses and high stability of the common path, the phase-shifting radial-shearing interference with Greek ladder zone plates has great potential in biological imaging and x-ray holography for the next generation of synchrotron light sources. PMID- 30439899 TI - Generation of 3.9-cycle pulses from the coherent synthesis of two continuous-wave injection seeded optical parametric amplifiers at 53 MHz. AB - A high repetition-rate, few-cycle light pulse is of great importance due to its potential for a variety of applications, including two-dimensional infrared spectroscopy and time-resolved imaging of molecular structures, which benefit from its ultrabroadband spectrum and ultrashort pulse duration. The generation of an ultrabroadband coherent spectrum is one of the frontiers of ultrafast optics, and accessing such few-cycle pulses is presently under active exploration. Here, we demonstrate a simple yet effective pulse synthesizer. It is based on two continuous-wave (cw) injection-seeded high-repetition-rate optical parametric amplification systems and the following self-phase-modulation dominated spectra broadening processes. The combined spectrum spans from 1250 to 1670 nm, and a near Fourier-transform-limited 3.9-cycle (19.2 fs) synthesized pulse with a central wavelength of 1470 nm is obtained accordingly. PMID- 30439900 TI - NDR-effect vertical-illumination-type Ge-on-Si avalanche photodetector. AB - We present the enhanced performances of a vertical-illumination-type Ge-on-Si avalanche photodetector based on internal RF-gain effects operating up to 50 Gb/s. A fabricated Ge-on-Si avalanche photodetector (APD) exhibits three operational voltage regions associated with different aspects of the current (DC) gain and bandwidth characteristics. The measured current-voltage (I-V) curve of a Ge-on-Si APD exhibits a negative photoconductance (negative differential resistance [NDR]) in a high bias region beyond the avalanche breakdown voltage (V br ), where a device shows good eye openings up to 50 Gb/s (non-return-to-zero [NRZ] signal) with further improved signal-to-noise ratios and signal amplitudes. A ROSA packaged module, wherein a fabricated Ge-on-Si APD is wire-bonded to a commercial TIA with a ~75% optical alignment for lambda~1310 nm and biased at a lower voltage than the V br , exhibits the sensitivities of -18.9 and -15.3 dBm for 30 and 35 Gb/s, respectively, and -13.9 dBm for 40 Gb/s at a 10-12 bit error rate. The experimental results indicate that considerable improvement in a module performance can be expected by utilizing the Ge-on-Si APD operated in the NDR region with a properly customized TIA. PMID- 30439901 TI - Thickness dependent surface plasmon of silver film detected by nitrogen vacancy centers in diamond. AB - Precise detection of surface plasmons is crucial for the research of nanophotonics and quantum optics. In this Letter, we used a single nitrogen vacancy center in diamond as a probe to detect the surface plasmon that was tuned by the thickness of a metallic film. The fluorescence intensity and lifetime of the nitrogen vacancy (NV) center were measured to obtain the information of local light-matter interaction. A nonlinear thickness dependent change of the surface plasmon was observed, with the maximum at the thickness of approximately 30 nm. With optimized thickness of silver film, the fluorescence intensity of a single NV center was enhanced 2.6 times, and the lifetime was reduced by a factor of 3, without affecting the coherence time of the NV spin state. The results proved that this system can quantitatively detect the light-matter interaction at nanoscale, and it provides an approach to enhance the fluorescence intensity of a quantum emitter. PMID- 30439902 TI - InGaN/GaN microdisks enabled by nanoporous GaN cladding. AB - The fabrication of nanoporous (NP) GaN is proposed as a generic technique to create out-of-plane index guiding for nitride microcavities. Compared to the conventional undercut technique, the proposed technique forms uniformly a low index NP-GaN layer beneath the entire microcavity. Therefore, it supports all cavity modes (with different cavity geometries), while the undercut technique only supports the modes that reside at the circumference of a circular microcavity. As a proof of concept, GaN microdisk cavities were fabricated with the NP-GaN as the bottom low-index medium. A cold cavity with Q>2,000 was reported under continuous-wave pumping. Lasing was demonstrated with threshold optical pumping power Pth~60 kW/cm2 for the r=10 MUm microdisk and Pth~7 kW/cm2 for the r=50 MUm microdisk. A rate equation analysis was performed to estimate the spontaneous coupling factor beta~1E-3, which was one order of magnitude higher than the previous report of a nitride microdisk laser with an InGaN quantum well active region. Therefore, NP GaN was proven to be a suitable replacement of the undercut technique for future nitride microcavities applications. PMID- 30439903 TI - Ray-wave duality in classical optics: crossing the Feynman bridge. AB - Classical ray and wave optics share a common structure with quantum mechanics. Much of this results from the representations given to abstract operators. It is possible to build a mathematical bridge that allows one to transform back and forth between the ray and wave picture. This is given by the Feynman path integral representation. The map between the ray and wave description is given in terms of a sum over histories integration. In particular, it allows for the computation of wave phenomena by the summation of multiple ray paths of a phase function connected to the classical optical path length. PMID- 30439904 TI - Discrimination of incoherent vortex states of light. AB - Coherence vortex (CV) states provide a new way for optical manipulation and communication. As a promising option for increasing the data-transmission capacity, CV multiplexing warrants investigation. However, few studies have focused on discriminating and sorting CV states with different topological charges. In this work, we examine the cross-spectral density (CSD) of a CV state embedded in an incoherent light field and so-called incoherent vortex (ICV). Given a multiplexed ICV, we propose a method to recognize the constituting single ICVs therein. Our analytical results, which are derived according to the coherence theory and the paraxial propagation law and are given in analytical forms, show that the CSD can reveal the topological charge spectrum of a multiplexed incoherent Laguerre-Gaussian mode. This proposal can be used for free space communication and remote sensing where light fields with low coherence are preferable to completely coherent beams. PMID- 30439905 TI - High-power 266 nm laser generation with a NaSr3Be3B3O9F4 crystal. AB - We demonstrate a 266 nm ultraviolet (UV) picosecond laser by fourth-harmonic generation of a Nd:YAG laser with a 5.4 mm thick NaSr3Be3B3O9F4 (NSBBF) crystal. A maximum output power exceeding 1 W at 266 nm was obtained (the highest output power being 1.6 W), corresponding to a conversion efficiency of 10.3%. The stability measurements on the NSBBF crystal with a fluctuation of 3.34% at 200 mW within 1 h indicate that it is a promising UV nonlinear optical material for practical applications. In addition, for the first time, to the best of our knowledge, we measured the effective nonlinear coefficient of NSBBF crystal at 266 nm and compared it with that of beta-BaB2O4 crystal. PMID- 30439906 TI - Pulse coding linearization for Brillouin optical time-domain analysis sensors. AB - We introduce a simple method to extend the performance of pulse coding techniques in their application to Brillouin optical time-domain analysis sensors (BOTDA). It is based on applying a simple logarithmic processing on the detected probe wave that compensates the deviation from linearity of the sensor response for long code lengths. The technique ensures that the accumulated effect of a sequence of pulses is equal to the linear addition of the effects of the individual components, which is the essential condition to ensure a correct decoding of the probe gain measurement. We experimentally demonstrate the compensation of the Brillouin frequency shift error induced by the accumulated gain nonlinearity. Furthermore, a proof-of-concept 80 km sensing link within a total 200 km fiber loop demonstrated a better than 2 MHz precision with 2 m spatial resolution. PMID- 30439907 TI - Hybrid multi-wavelength nonlinear photoacoustic sensing and imaging. AB - Multi-wavelength photoacoustic (PA) imaging has been studied extensively to explore the spectroscopic absorption contrast of biological tissues. To generate strong PA signals, a high-power wavelength tunable pulsed laser source has to be employed, which is bulky and quite expensive. In this Letter, we propose a hybrid multi-wavelength PA imaging (hPAI) method based on the combination of a single wavelength pulsed laser source and multi-wavelength continuous-wave (CW) laser sources. By carefully controlling the laser illumination sequence (pulse-CW pulse) and extracting the PA signal difference before and after the heating of CW lasers, the optical absorption property of multi-wavelength light illumination could be obtained. Compared with conventional PA imaging, the proposed hPAI shows a much lower system cost due to the usage of single-wavelength pulsed lasers and multiple inexpensive CW lasers. As the preliminary results show in this Letter, hPAI imaging has the potential to provide another pathway for high spectroscopic optical absorption contrast in PA imaging. PMID- 30439908 TI - Supercritical focusing coherent anti-Stokes Raman scattering microscopy for high resolution vibrational imaging. AB - We report the development of, to the best of our knowledge, a novel supercritical focusing coherent anti-Stokes Raman scattering (SCF-CARS) microscopy for high resolution vibrational imaging. Two optimized phase patterns with a combination of concentric rings with an alternative 0 and pi phase are generated by using a spatial light modulator and applied to the pump beam for minimizing its focal spot size. One of the phase patterns is for both the lateral and axial resolution enhancement, and the other can further improve the lateral resolution, but it sacrifices the axial resolution to some extent. We demonstrate this high resolution SCF-CARS microscopy technique by imaging the polymethyl methacrylate (PMMA) nano-cylinder on a microscope slide and glass-air interface, as well as biomedical samples, for example, tooth. PMID- 30439909 TI - Far-field radiative thermal rectifier based on nanostructures with vanadium dioxide. AB - Radiative thermal rectifiers capable of realizing asymmetric heat flux transfer have attracted a lot of research interests recently, mainly focusing on the engineering of the emissivity spectra. In this Letter, we propose a far-field radiative thermal rectifier utilizing the phase change material vanadium dioxide (VO2). The thermal rectifier consists of a metamaterial infrared absorber and a two-layer thin-film structure acting as the active and the passive components, respectively. Numerical optimization has been carried out to control the emissivity spectra of both parts and maximize the overall rectification effect. A large thermal rectification factor of 3.5 is predicted at a temperature bias of DeltaT=100 K. PMID- 30439910 TI - Time-reversal symmetry in temporal coupled-mode theory and nonreciprocal device applications. AB - We present a fundamental result on the role of time-reversal symmetry in the temporal coupled-mode theory (TCMT). The TCMT is a phenomenological theory that describes resonant wave scattering in photonics, acoustics, and other fields. Modifications to the canonical formulation of the TCMT are required for nonreciprocal devices where time-reversal symmetry is usually absent. We discover that previous results on reciprocity for the TCMT are incomplete, and we provide a mathematical proof to clarify the roles of time-reversal symmetry and reciprocity in the TCMT. The new result leads to a general treatment of nonreciprocity in the TCMT. The theoretical result has many practical applications, including the design of nonreciprocal devices such as optical circulators and isolators. PMID- 30439911 TI - Laser speckle contrast imaging of blood flow in the deep brain using microendoscopy. AB - Poor blood flow circulation can occur in the subcortical regions of the brain in many brain diseases. However, the limitations of light penetration imaging techniques hinder the detection of blood flow in deep brain tissues in vivo. Hence, in this Letter, we present a gradient index lens-based laser speckle contrast imaging system for time-lapse blood flow detection in subcortical regions of the brain. We monitored the hemodynamic changes in the thalamus of mouse models of acute hypoxia and transient middle cerebral artery occlusion as a proof of concept for practical applications. PMID- 30439912 TI - Further emission efficiency improvement of a commercial-quality light-emitting diode through surface plasmon coupling. AB - It is usually believed that surface plasmon (SP) coupling is practically useful only for improving the performance of a light-emitting diode (LED) with a low intrinsic internal quantum efficiency (IQE). In this Letter, we demonstrate that the performance of a commercial-quality blue LED with a high IQE (>80%) can still be significantly improved through SP coupling based on a surface Ag nanoparticle (NP) structure. The performance improvement of such an LED is achieved by increasing the Mg doping concentration in its p-AlGaN electron blocking layer to enhance the hole injection efficiency such that the p-GaN layer thickness can be significantly reduced without sacrificing its electrical property. In this situation, the distance between surface Ag NPs and quantum wells is decreased and hence SP coupling strength is increased. By reducing the distance between the surface Ag NPs and the top quantum well to 66 nm, the IQE can be increased to almost 90% (an ~11% enhancement) and the electroluminescence intensity can be enhanced by ~24%. PMID- 30439913 TI - Measurement of the vortex spectrum in a vortex-beam array without cuts and gluing of the wavefront. AB - We present a new technique for measuring the squares of the amplitudes and phases of partial vortex-beams in a complex beam array in real time. The technique is based on measuring the high-order intensity moments and analyzing the solutions of a system of linear equations. Calibration measurements have shown that the measurement error at least for a beam array of 10-15 beams does not exceed 4%. PMID- 30439914 TI - Demonstration of a 10 Mbit/s quantum communication link by encoding data on two Laguerre-Gaussian modes with different radial indices. AB - We experimentally demonstrate a 10 Mbit/s free-space quantum communication link using data encoding on orthogonal Laguerre-Gaussian (LG) modes with the same azimuthal index but different radial indices. Data encoding on two LGlp modes (i.e., for l=0, we encode ["0", "1"] as [p=0, p=1], and for l=1, we encode ["0", "1"] as [p=0, p=1]) is demonstrated by employing directly modulated laser diodes and helical phase holograms. The quantum symbol error rate (QSER) of <5% is achieved at an encoding rate of 10 Mbit/s. Moreover, the influence of the circle radius (R) of the receiver phase pattern on registered photon rates and QSERs is investigated. Our results show that a receiver phase pattern whose R does not match the beam size of the LG modes would induce higher cross talk between the two encoded quantum branches. PMID- 30439916 TI - Effects of photonic crystal structures on the imaging properties of a ZnO:Ga image converter. AB - We investigate the effects of photonic crystal structures on radiation imaging properties of a ZnO:Ga image converter. The results show that photonic crystal structures can regulate luminescence distribution and spatial resolving power, which is caused by the light extraction and the defect scattering of photonic crystal structures. The present investigation confirms that photonic crystals can improve the imaging properties of existing image converters and proposes a new coupling mode between the photonic crystal image converter and back-end optical devices, which is beneficial to the application of photonic crystals in the field of radiation imaging. PMID- 30439915 TI - Self-compression in a multipass cell. AB - We demonstrate self-compression of short-wavelength infrared pulses in a multipass cell (MPC) containing a plate of silica. Nonlinear propagation in the cell in the anomalous dispersion regime results in the generation of 14 MUJ 22 fs pulses at 125 kHz repetition rate and 1550 nm wavelength. Periodic focusing inside the cell allows us to circumvent catastrophic self-focusing, despite an output peak power of 440 MW well beyond the critical power in silica of 10 MW. This technique allows straightforward energy scaling of self-compression setups and control over the spatial manifestation of Kerr nonlinearity. More generally, MPCs can be used to perform, at higher energy levels, temporal manipulations of pulses that have been previously demonstrated in waveguides. PMID- 30439917 TI - Polarization-multiplexed multiplane display. AB - We demonstrate a polarization-multiplexed multiplane display system for near-eye applications. A polarization-sensitive Pancharatnam-Berry phase lens is implemented to generate two focal depths simultaneously. A spatial polarization modulator is utilized to direct the two images to designated focal planes. Based on this design, a dual-focal-plane display system is constructed without space- or time-multiplexing operations, to suppress the vergence-accommodation conflict successfully. PMID- 30439918 TI - Cascaded downconversion interface to convert single-photon-level signals at 650 nm to the telecom band. AB - We present a device designed for two-step downconversion of single-photon-level signals at 650 nm to the 1.5-MUm band with low excess noise and low required pump power as a quantum interface between matter-qubit-based nodes and low-loss photonic channels for quantum communication networks. The required pump power for this interface is around 60% of that for a comparable conventional single-pass device, which reduces the demand on the pump laser and yields a corresponding reduction in dark counts due to inelastic pump scattering. The single-photon level signal at 649.7 nm is downconverted to the telecom band using a fiber coupled reverse proton exchange periodically poled lithium niobate waveguide and a 2.19-MUm pump laser. By testing the device in the linear regime with a classical input, we achieved 99% depletion efficiency for each stage, corresponding to an internal quantum efficiency of 63% at the optimum pump power for the complete cascaded process. PMID- 30439919 TI - Vector beam generation from vertical cavity surface emitting lasers. AB - Radially and azimuthally polarized beams in a single transverse mode are generated from a commercially available vertical cavity surface emitting laser (VCSEL) in an external cavity with a birefringent rutile lens, of which the c axis is parallel to the optical axis of the cavity, to select favorable polarization. Additionally, a vector Bessel-Gaussian beam is generated from a VCSEL, which is fabricated to oscillate with a linear polarization in a fixed direction in free running, in the same way. These results clearly show the potential ability of VCSELs to generate vector beams, which will be essential to space-division multiplexing in the future optical communication. PMID- 30439920 TI - Color image identification and reconstruction using artificial neural networks on multimode fiber images: towards an all-optical design. AB - The rapid growth of applications that rely on artificial neural network (ANN) concepts gives rise to a staggering increase in the demand for hardware implementations of neural networks. New types of hardware that can support the requirements of high-speed associative computing while maintaining low power consumption are sought, and optical artificial neural networks fit the task well. Inherently, optical artificial neural networks can be faster, support larger bandwidth, and produce less heat than their electronic counterparts. Here we propose the design of an optical ANN-based imaging system that has the ability to self-study image signals from an incoherent light source in different colors. Our design consists of a combination of a multimode fiber and a multi-core optical fiber realizing a neural network. We show that the signals, transmitted through the multimode fiber, can be used for image identification purposes and can also be reconstructed using ANNs with a low number of nodes. An all-optical solution can then be achieved by realizing these networks with the multi-core optical neural network fiber. PMID- 30439921 TI - Localized chaos of elliptically polarized cavity solitons in broad-area VCSEL with a saturable absorber. AB - We introduce a spin-flip model for a broad-area vertical-cavity surface-emitting laser (VCSEL) with a saturable absorber. We demonstrate simultaneous existence of orthogonally linearly polarized and elliptically polarized cavity solitons. We show that polarization degree of freedom leads to a period-doubling route to spatially localized chaos of the elliptically polarized cavity solitons. PMID- 30439922 TI - Off-axis quartz-enhanced photoacoustic spectroscopy using a pulsed nanosecond mid infrared optical parametric oscillator: publisher's note. AB - This publisher's note corrects an affiliation error in Opt. Lett.41, 4118 (2016)OPLEDP0146-959210.1364/OL.41.004118. PMID- 30439923 TI - Ultra-broadband tunable continuous phase masks using optical aberrations: publisher's note. AB - This publisher's note corrects errors in Eq. (2) of Opt. Lett.43, 5480 (2018)OPLEDP0146-959210.1364/OL.43.005480. PMID- 30439924 TI - Deep learning model for ultrafast multifrequency optical property extractions for spatial frequency domain imaging. AB - Spatial frequency domain imaging (SFDI) is emerging as an important new method in biomedical imaging due to its ability to provide label-free, wide-field tissue optical property maps. Most prior SFDI studies have utilized two spatial frequencies (2-fx) for optical property extractions. The use of more than two frequencies (multi-fx) can vastly improve the accuracy and reduce uncertainties in optical property estimates for some tissue types, but it has been limited in practice due to the slow speed of available inversion algorithms. We present a deep learning solution that eliminates this bottleneck by solving the multi-fx inverse problem 300* to 100,000* faster, with equivalent or improved accuracy compared to competing methods. The proposed deep learning inverse model will help to enable real-time and highly accurate tissue measurements with SFDI. PMID- 30439925 TI - Sensitivity-enhanced ultrafast optical tomography by parametric- and Raman amplified temporal imaging. AB - To overcome the speed limitation of conventional optical tomography, a temporal imaging technique has been integrated with optical time-domain reflectometry to realize ultrafast temporally magnified (TM) tomography. In this Letter, the sensitivity of TM tomography has been further enhanced using optical parametric amplification and distributed Raman amplification, and this technique is named temporally encoded amplified and magnified (TEAM) tomography. As a result, a 78 dB sensitivity has been realized, comparable to ultrafast optical coherence tomography systems. In addition, an 86.7-MUm axial resolution can be realized across a 67.5-mm imaging range. To demonstrate the significance of sensitivity improvement, tomographic imaging of a centimeter-thick phantom is provided at an A-scan rate of 44 MHz. PMID- 30439926 TI - Orbit-induced localized spin angular momentum in the tight focusing of linearly polarized vortex beams. AB - Optical spin-orbit interaction has gained much interest recently due to its universality and importance in modern photonics. In this Letter, we theoretically demonstrate that orbit-induced localized spin angular momentum (SAM) conversion can occur in the tight focusing of spin-free linearly polarized vortex beams (LPVBs). By analysis of the polarization states that are associated with the SAM density, we attribute the occurrence of such a conversion to the helical-phase induced change of local polarization states in the focused field. In the local SAM, density can be further regulated by altering the sign and value of the orbital angular momentum in the incident LPVBs, as well as their polarization orientations. This Letter is expected to advance our understanding of optical spin-orbit coupling and benefit applications of optical microscopy and trapping. PMID- 30439927 TI - 339 J high-energy Ti:sapphire chirped-pulse amplifier for 10 PW laser facility. AB - We report on the laser pulse output of 339 J centered at 800 nm from a chirped pulse amplification (CPA) Ti:sapphire laser system at the Shanghai Superintense Ultrafast Laser Facility. The experimental results demonstrated that the parasitic lasing as well as the transverse amplified spontaneous emission of the homemade 235-mm-diameter Ti:sapphire final amplifier were suppressed successfully via the temporal dual-pulse pumped scheme and the index-matching liquid cladding technique. The maximum pump-to-signal conversion efficiency of 32.1% was measured for the final amplifier. With a compressor transmission efficiency of 64% and a compressed pulse duration of 21 fs obtained for the sample light at a lower energy level, this laser system could potentially generate a compressed laser pulse with a peak power of 10.3 PW. The experimental results represent significant progress with respect to the CPA laser. PMID- 30439928 TI - Microwave photonic multiband filter with independently tunable passband spectral properties. AB - Multiband RF filters with independently controllable passbands are an essential component in dynamic multiband RF communications. Unfortunately, even a fixed multiband RF filter without the capability to adjust the passband properties individually is very difficult to achieve using either RF electronics or microwave photonic technologies. In microwave photonic approaches, the critical limitation is the close relationship between passbands-the tuning of one passband leads to a change in another, hindering the ability to independently control each passband. In this Letter, a programmable microwave photonic multiband filter with full control of amplitude, frequency, bandwidth, group delay slope, and the spectral shape of each passband has been experimentally demonstrated. A multiband filter design algorithm has also been developed that considers each RF passband as an individual, then uses inverse Fourier transform and filter design rule to determine the corresponding optical parameters and combines a series of shaped cosine functions to achieve the desired RF properties. PMID- 30439929 TI - Dual-mode phase and fluorescence imaging with a confocal laser scanning microscope. AB - We present dual-mode phase and fluorescence imaging in a confocal laser scanning microscopy (CLSM) system. For phase imaging, the depth of field of the CLSM system is extended by fast axial scanning with a tunable acoustic gradient index of refraction lens. Under transillumination, intensity images of the sample are recorded at a few different defocusing distances. The phase image is reconstructed from these intensity images by using the transport-of-intensity equation. The 3D fluorescence image is obtained by confocal scanning. The dual mode images with pixel-to-pixel correspondence yield complementary quantitative structural and functional information. Combination of the two imaging modalities enables standalone determination of the refractive index of live cells. PMID- 30439930 TI - Free-beam spectral self-compression at supercritical peak powers. AB - We demonstrate free-beam spectral self-compression of ~100-GW femtosecond laser pulses due to self-phase modulation (SPM) in a transparent dielectric. While all the earlier studies of SPM-induced spectral narrowing have been performed using optical fibers, experiments and simulations presented in this Letter show that this type of spectral transformation can be implemented as a part of a full three dimensional field-waveform dynamics and can be extended to peak powers ~105 times higher than the critical power of self-focusing. With a properly chosen initial chirp, spectral self-compression is accompanied by pulse compression, providing spectral-temporal mode self-compression as a whole. PMID- 30439931 TI - Molecular mechanisms of polymyxin resistance and detection of mcr genes. AB - Antibiotic resistance is an ever-increasing global problem. Major commercial antibiotics often fail to fight common bacteria, and some pathogens have become multi-resistant. Polymyxins are potent bactericidal antibiotics against gram negative bacteria. Known resistance to polymyxin includes intrinsic, mutational and adaptive mechanisms, with the recently described horizontally acquired resistance mechanisms. In this review, we present several strategies for bacteria to develop enhanced resistance to polymyxins, focusing on changes in the outer membrane, efflux and other resistance determinants. Better understanding of the genes involved in polymyxin resistance may pave the way for the development of new and effective antimicrobial agents. We also report novel in silico tested primers for PCR assay that may be able distinguish colistin-resistant isolates carrying the plasmid-encoded mcr genes and will assist in combating the spread of colistin resistance in bacteria. PMID- 30439932 TI - Mesenchymal stem cells as the near future of cardiology medicine - truth or wish? AB - Cardiac damage is one of major cause of worldwide morbidity and mortality. Despite the development in pharmacotherapy, cardiosurgery and interventional cardiology, many patients remain at increased risk of developing adverse cardiac remodeling. An alternative treatment approach is the application of stem cells. Mesenchymal stem cells are among the most promising cell types usable for cardiac regeneration. Their homing to the damaged area, differentiation into cardiomyocytes, paracrine and/or immunomodulatory effect on cardiac tissue was investigated extensively. Despite promising preclinical reports, clinical trials on human patients are not convincing. Meta-analyses of these trials open many questions and show that routine clinical application of mesenchymal stem cells as a cardiac treatment may be not as helpful as expected. This review summarizes contemporary knowledge about mesenchymal stem cells role in cardiac tissue repair and discusses the problems and perspectives of this experimental therapeutical approach. PMID- 30439933 TI - Various surgical techniques for the repair of injured vas deferens in rat experiments. AB - OBJECTIVE: The aim of this study was to evaluate whether the different vasovasostomy techniques can be performed using only the operating loupe in a rat model. The secondary aims were to evaluate the patency rate and inflammation of the vas deferens (VD) after contusion and the different vasovasostomy repair techniques. METHODS: A total of 40 male rats were divided into 4 groups based on the type of surgery: 1. contusion of the VD; 2. cutting of the VD and vasovasostomy with absorbable sutures; 3. cutting and joining of the VD using absorbable sutures with an intraluminally situated lead fibre; and 4. cutting and joining of the VD using non-absorbable sutures with an intraluminally situated lead fibre. Ninety days after the surgery the VD was resected, patency and histopathological signs of inflammation in the VD were evaluated. RESULTS: All vasovasostomy techniques were successfully performed in all animals using only the operating loupe. The patency rate was 100% in the subgroup with contusion. Differences in the patency rates were found among the subgroups with vasovasostomy (P=0.007). The patency rate was higher in the subgroup that underwent group 3. Compared with vasovasostomies, contusion was associated with lower rates of inflammation (P=0.02) and severe inflammation (P=0.003). No differences were found among the subgroups of vasovasostomy techniques. CONCLUSION: Contusion of the VD was not related to impairment in terms of patency. Vasovasostomy with an intraluminally situated lead fibre resulted in the highest patency rate among the standard vasovasostomy techniques. PMID- 30439934 TI - Cytoplasmic flows in starfish oocytes are fully determined by cortical contractions. AB - Cytoplasmic flows are an ubiquitous feature of biological systems, in particular in large cells, such as oocytes and eggs in early animal development. Here we show that cytoplasmic flows in starfish oocytes, which can be imaged well with transmission light microscopy, are fully determined by the cortical dynamics during surface contraction waves. We first show that the dynamics of the oocyte surface is highly symmetric around the animal-vegetal axis. We then mathematically solve the Stokes equation for flows inside a deforming sphere using the measured surface displacements as boundary conditions. Our theoretical predictions agree very well with the intracellular flows quantified by particle image velocimetry, proving that during this stage the starfish cytoplasm behaves as a simple Newtonian fluid on the micrometer scale. We calculate the pressure field inside the oocyte and find that its gradient is too small as to explain polar body extrusion, in contrast to earlier suggestions. Myosin II inhibition by blebbistatin confirms this conclusion, because it diminishes cell shape changes and hydrodynamic flow, but does not abolish polar body formation. PMID- 30439936 TI - Heterologous Hsp90 promotes phenotypic diversity through network evolution. AB - Biological processes in living cells are often carried out by gene networks in which signals and reactions are integrated through network hubs. Despite their functional importance, it remains unclear to what extent network hubs are evolvable and how alterations impact long-term evolution. We investigated these issues using heat shock protein 90 (Hsp90), a central hub of proteostasis networks. When native Hsp90 in Saccharomyces cerevisiae cells was replaced by the ortholog from hypersaline-tolerant Yarrowia lipolytica that diverged from S. cerevisiae about 270 million years ago, the cells exhibited improved growth in hypersaline environments but compromised growth in others, indicating functional divergence in Hsp90 between the two yeasts. Laboratory evolution shows that evolved Y. lipolytica-HSP90-carrying S. cerevisiae cells exhibit a wider range of phenotypic variation than cells carrying native Hsp90. Identified beneficial mutations are involved in multiple pathways and are often pleiotropic. Our results show that cells adapt to a heterologous Hsp90 by modifying different subnetworks, facilitating the evolution of phenotypic diversity inaccessible to wild-type cells. PMID- 30439935 TI - Ten simple rules for delivering live distance training in bioinformatics across the globe using webinars. PMID- 30439938 TI - Ten simple rules for collaboratively writing a multi-authored paper. PMID- 30439937 TI - Gut microbiome transition across a lifestyle gradient in Himalaya. AB - The composition of the gut microbiome in industrialized populations differs from those living traditional lifestyles. However, it has been difficult to separate the contributions of human genetic and geographic factors from lifestyle. Whether shifts away from the foraging lifestyle that characterize much of humanity's past influence the gut microbiome, and to what degree, remains unclear. Here, we characterize the stool bacterial composition of four Himalayan populations to investigate how the gut community changes in response to shifts in traditional human lifestyles. These groups led seminomadic hunting-gathering lifestyles until transitioning to varying levels of agricultural dependence upon farming. The Tharu began farming 250-300 years ago, the Raute and Raji transitioned 30-40 years ago, and the Chepang retain many aspects of a foraging lifestyle. We assess the contributions of dietary and environmental factors on their gut-associated microbes and find that differences in the lifestyles of Himalayan foragers and farmers are strongly correlated with microbial community variation. Furthermore, the gut microbiomes of all four traditional Himalayan populations are distinct from that of the Americans, indicating that industrialization may further exacerbate differences in the gut community. The Chepang foragers harbor an elevated abundance of taxa associated with foragers around the world. Conversely, the gut microbiomes of the populations that have transitioned to farming are more similar to those of Americans, with agricultural dependence and several associated lifestyle and environmental factors correlating with the extent of microbiome divergence from the foraging population. The gut microbiomes of Raute and Raji reveal an intermediate state between the Chepang and Tharu, indicating that divergence from a stereotypical foraging microbiome can occur within a single generation. Our results also show that environmental factors such as drinking water source and solid cooking fuel are significantly associated with the gut microbiome. Despite the pronounced differences in gut bacterial composition across populations, we found little differences in alpha diversity across lifestyles. These findings in genetically similar populations living in the same geographical region establish the key role of lifestyle in determining human gut microbiome composition and point to the next challenging steps of determining how large-scale gut microbiome reconfiguration impacts human biology. PMID- 30439940 TI - Creative use of the priority review voucher by public and not-for-profit actors delivers the first new FDA-approved treatment for river blindness in 20 years. PMID- 30439941 TI - Internal consistency of a synthetic population construction method for chronic disease micro-simulation models. AB - BACKGROUND: Micro-simulation models of risk-factors and chronic diseases are built increasingly often, and each model starts with an initial population. Constructing such populations when no survey data covering all variables are available is no trivial task, often requiring complex methods based on several (untested) assumptions. In this paper, we propose a method for evaluating the merits of construction methods, and apply this to one specific method: the construction method used in the DYNAMO-HIA model. METHODS: The initial population constructed using the DYNAMO-HIA method is compared to another population constructed by starting a simulation with only newborns and simulating the course taken by one risk-factor and several diseases. In this simulation, the age- and sex-specific prevalence of the risk-factor is kept constant over time. RESULTS: Our simulations show that, in general, the DYNAMO-HIA method clearly outperforms a method that assumes independence of the risk-factor and the prevalence of diseases and independence between all diseases. In many situations the DYNAMO-HIA method performs reasonably well, but in some the proportion with the risk-factor for those with a disease is under- or overestimated by as much as 10 percentage points. For determining comorbidity between diseases linked by a common causal disease or a common risk-factor it also performs reasonably well. However, the current method performs poorly for determining the comorbidity between one disease caused by the other. CONCLUSION: The DYNAMO-HIA methods perform reasonably well; they outperform a baseline assumption of independence between the risk-factor and diseases in the initial population. The method for determining the comorbidity between diseases that are causally linked needs improvement. Given the existing discrepancies for situations with high relative risks, however, developing more elaborate methods based on running simulation models to generate an initial population would be worthwhile. PMID- 30439939 TI - Selfish genetic elements. AB - Selfish genetic elements (historically also referred to as selfish genes, ultra selfish genes, selfish DNA, parasitic DNA, genomic outlaws) are genetic segments that can enhance their own transmission at the expense of other genes in the genome, even if this has no or a negative effect on organismal fitness. [1-6] Genomes have traditionally been viewed as cohesive units, with genes acting together to improve the fitness of the organism. However, when genes have some control over their own transmission, the rules can change, and so just like all social groups, genomes are vulnerable to selfish behaviour by their parts. Early observations of selfish genetic elements were made almost a century ago, but the topic did not get widespread attention until several decades later. Inspired by the gene-centred views of evolution popularized by George Williams[7] and Richard Dawkins,[8] two papers were published back-to-back in Nature in 1980-by Leslie Orgel and Francis Crick[9] and Ford Doolittle and Carmen Sapienza[10] respectively-introducing the concept of selfish genetic elements (at the time called "selfish DNA") to the wider scientific community. Both papers emphasized that genes can spread in a population regardless of their effect on organismal fitness as long as they have a transmission advantage. Selfish genetic elements have now been described in most groups of organisms, and they demonstrate a remarkable diversity in the ways by which they promote their own transmission.[11] Though long dismissed as genetic curiosities, with little relevance for evolution, they are now recognized to affect a wide swath of biological processes, ranging from genome size and architecture to speciation.[12]. PMID- 30439942 TI - Geostatistical mapping of the seasonal spread of under-reported dengue cases in Bangladesh. AB - Geographical mapping of dengue in resource-limited settings is crucial for targeting control interventions but is challenging due to the problem of zero inflation because many cases are not reported. We developed a negative binomial generalised linear mixed effect model accounting for zero-inflation, spatial, and temporal random effects to investigate the spatial variation in monthly dengue cases in Bangladesh. The model was fitted to the district-level (64 districts) monthly reported dengue cases aggregated over the period 2000 to 2009 and Bayesian inference was performed using the integrated nested Laplace approximation. We found that mean monthly temperature and its interaction with mean monthly diurnal temperature range, lagged by two months were significantly associated with dengue incidence. Mean monthly rainfall at two months lag was positively associated with dengue incidence. Densely populated districts and districts bordering India or Myanmar had higher incidence than others. The model estimated that 92% of the annual dengue cases occurred between August and September. Cases were identified across the country with 94% in the capital Dhaka (located almost in the middle of the country). Less than half of the affected districts reported cases as observed from the surveillance data. The proportion reported varied by month with a higher proportion reported in high-incidence districts, but dropped towards the end of high transmission season. PMID- 30439943 TI - Correction: Anticoagulation Knowledge Tool (AKT): Further evidence of validity in the Italian population. AB - [This corrects the article DOI: 10.1371/journal.pone.0201476.]. PMID- 30439944 TI - Prevalence and distribution of Taenia solium cysticercosis in naturally infected pigs in Punjab, India. AB - BACKGROUND: Taenia solium (T. solium) cysticercosis remains a neglected zoonotic disease in India. The current study was planned to estimate the prevalence of T. solium porcine cysticercosis in the Punjab state of India, to compare this prevalence with the disease prevalence in pigs reared outside Punjab and to assess the distribution of the parasite in pig carcasses. METHODS: Two slaughter shops were selected in each of the 22 districts of Punjab. Pigs slaughtered on the day/s of inspection were post-mortem inspected to identify the presence of T. solium cysts. Estimated true prevalence was estimated by taking into account the diagnostic sensitivity (38%) and specificity (100%) of post-mortem inspection using the Rogan-Gladen estimator. Positive carcasses were purchased and brought to the laboratory to assess the tissue distribution of T. solium cysts and to conduct PCR targeting large subunit rRNA gene, internal transcribed spacer 1 gene, ITS1 gene and Cytochrome oxidase I gene. The selected PCR products were submitted for sequencing and phylogenetic analyses were performed. FINDINGS: We contacted 71 shop owners to achieve a sample of 44 shops for the study. We inspected 642 pigs reared in Punjab and 450 imported from other states at these slaughter shops. In addition, we sampled 40 pigs from an abattoir located in the state capital. Of the 642 pigs reared in Punjab, 9 had T. solium cysts with an apparent prevalence of 1.40% (95% CI: 0.74%, 2.64%) and the estimated true prevalence of 3.69% (95% CI: 1.95%, 6.95%). Pigs imported from outside the state had a significantly higher prevalence (odds ratio: 2.58; 95% CI: 1.12, 5.98; p value: 0.026) as 15 of the 450 imported pigs were positive (apparent prevalence: 3.33%; 95% CI: 2.03%, 5.43%; estimated true prevalence: 8.77%; 95% CI: 5.34%, 14.28%). None of samples was positive from the pigs sampled at the abattoir in the state capital. The PCR confirmed T. solium cysts from all the 24 positive samples. We counted a median of 897 (range 526-1964) cysts per infected pig from the 19 infected pig carcasses inspected. The phylogenetic tree based on the alignment of partial cytochrome oxidase 1 sequences indicated all positive samples to be clustered with the T. solium Asian genotype. The analysis did not indicate the presence of T. asiatica in the slaughter pigs. CONCLUSIONS: Despite the underestimation of the prevalence due to missing mildly-infected carcasses, low participation and lack of representative sampling, the presence of heavily infected carcasses containing viable cysts, particularly those imported from outside the state, indicates that T. solium cysticercosis is an important food safety concern for pork consumers in Punjab, India. Measures should be taken to reduce the disease prevalence in pigs to reduce the disease burden in the public. PMID- 30439945 TI - Accuracy of the WHO praziquantel dose pole for large-scale community treatment of urogenital schistosomiasis in northern Mozambique: Is it time for an update? AB - BACKGROUND: A pioneering strategy developed by the World Health Organization (WHO) for the control of schistosomiasis was the concept of a height-based dose pole to determine praziquantel (PZQ) dosing in large-scale treatment campaigns. However, some recent studies have shown variable accuracy for the dose pole in terms of predicting correct mg/Kg dosing, particularly for treatment of adults. According to the WHO, 91 million adults in 52 countries are targeted to be treated by 2020. METHODS/PRINCIPAL FINDINGS: The present study aimed to test the accuracy of the dose pole in determining PZQ dosage by comparing the number of tablets determined by the dose pole with the number of tablets determined according to total body weight. The analysis included height-for-weight data from 9,827 school-aged children (SAC) and adults from 42 villages in the province of Cabo Delgado in Mozambique. The results revealed that of the 7,596 SAC, 91.8% has received an appropriate dose (30-60mg/Kg), 6% received an insufficient dose (<30mg/Kg) and 2% an excessive dose (> 60mg/Kg). On the other hand, 13.7% out of 2,231 adults were treated inaccurately with 13.5% receiving an insufficient dose and 0.2% an excessive dose. When the percentage of insufficient dosing was disaggregated by gender, the frequency of adult females who were underdosed reached 18.3% versus 10.8% of adult males. Of note, Adult females aged 21-55 years were found to have an underdose frequency of 21.3%, compared to 11.8% of adult males in the same age range. The performance of a proposed modified dose pole was compared using the same dataset of adult Mozambicans. The results showed that the modified dose pole reduced the underdose frequency among adults from 13.5% to 10.4%, and subsequently increased the percentage of optimal dosing from 33.7% to 45.3%. CONCLUSIONS: Our findings highlight the need to update the WHO dose pole to avoid administration of insufficient PZQ doses to adults and therefore minimize the potential emergence of PZQ-resistant strains. TRIAL REGISTRATION: International Standard Randomized Controlled Trial registry under ISRTC number 14117624. PMID- 30439946 TI - Diagnostic accuracy of computed tomography for differentiating diffuse thyroid disease from normal thyroid parenchyma: A multicenter study. AB - This study aimed to assess the diagnostic performance of computed tomography (CT) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma (NTP) using multicenter data. Between January 2016 and June 2016, 229 patients underwent preoperative neck CT and subsequent thyroid surgery at five participating institutions. The neck CT images of each patient were retrospectively reviewed and classified into the following four categories: no DTD, indeterminate, suspicious for DTD, and DTD. The results of the CT image evaluations were compared with the histopathological results to determine the diagnostic accuracy of CT at each institution. According to the histopathological results, there were NTP (n = 151), Hashimoto thyroiditis (n = 24), non-Hashimoto lymphocytic thyroiditis (n = 47), and diffuse hyperplasia (n = 7). The CT categories of the 229 patients were "no DTD" in 89 patients, "indeterminate" in 40 patients, "suspicious for DTD" in 42 patients, and "DTD" in 58 patients. The presence of two or more CT features of DTD, which was classified as "suspicious for DTD" by all radiologists, had the largest area under the receiver-operating characteristic curve (Az = 0.820; 95% confidence interval: 0.764, 0.868), with sensitivity of 85.9% and specificity of 78.2%. However, no statistical significance between readers' experience and their diagnostic accuracy was found. In conclusion, evaluations of CT images are helpful for differentiating DTD from NTP. PMID- 30439947 TI - Observational study of characteristics and clinical outcomes of Dutch patients with tuberous sclerosis complex and renal angiomyolipoma treated with everolimus. AB - OBJECTIVE: To compare kidney size (used as proxy for total renal angiomyolipoma [rAML] size) and kidney function outcomes between patients with tuberous sclerosis complex (TSC) and rAML treated and not treated with everolimus. METHODS: Medical charts of adults with TSC-associated rAML followed at a specialty medical center in the Netherlands (1990-2015). Included patients treated with everolimus (n = 33, of which 27 were included in the kidney size analyses and 27 in the kidney function analyses [21 patients in both]; index date = everolimus initiation) and non-treated patients (n = 39, of which 29 were included in the kidney size analyses and 33 in the kidney function analyses [23 patients in both]; index date = one date among all dates with outcome measurement).Percent change in kidney size and kidney function from the index date to the best measurement in the two years post-index date (best response) compared between patients treated and not treated with everolimus. RESULTS: Compared with non-treated patients, significantly more everolimus-treated patients experienced a reduction in the size of their largest kidney in the two years post-index date (85.2% vs. 37.9%, p < 0.01). Also, there was a tendency towards more improvement in the estimated glomerular filtration rate (eGFR) among the everolimus-treated patients (55.6% vs. 33.3%, p = 0.08). CONCLUSIONS: The study results suggest that everolimus is effective in controlling and even reversing the growth of the kidneys, used as a proxy for rAML size, as well as preserving or improving kidney function in patients with TSC and rAML treated in a real-world, observational setting. PMID- 30439948 TI - Knockdown of the translocon protein EXP2 in Plasmodium falciparum reduces growth and protein export. AB - Malaria parasites remodel their host erythrocytes to gain nutrients and avoid the immune system. Host erythrocytes are modified by hundreds of effector proteins exported from the parasite into the host cell. Protein export is mediated by the PTEX translocon comprising five core components of which EXP2 is considered to form the putative pore that spans the vacuole membrane enveloping the parasite within its erythrocyte. To explore the function and importance of EXP2 for parasite survival in the asexual blood stage of Plasmodium falciparum we inducibly knocked down the expression of EXP2. Reduction in EXP2 expression strongly reduced parasite growth proportional to the degree of protein knockdown and tended to stall development about half way through the asexual cell cycle. Once the knockdown inducer was removed and EXP2 expression restored, parasite growth recovered dependent upon the length and degree of knockdown. To establish EXP2 function and hence the basis for growth reduction, the trafficking of an exported protein was monitored following EXP2 knockdown. This resulted in severe attenuation of protein export and is consistent with EXP2, and PTEX in general, being the conduit for export of proteins into the host compartment. PMID- 30439949 TI - Mitochondrial genome of the garfish Hyporhamphus quoyi (Beloniformes: Hemiramphidae) and phylogenetic relationships within Beloniformes based on whole mitogenomes. AB - Mitochondrial DNA (mtDNA) can provide genome-level information (e.g. mitochondrial genome structure, phylogenetic relationships and codon usage) for analyzing molecular phylogeny and evolution of teleostean species. The species in the order Beloniformes have commercial importance in recreational fisheries. In order to further clarify the phylogenetic relationship of these important species, we determined the complete mitochondrial genome (mitogenome) of garfish Hyporhamphus quoyi of Hemiramphidae within Beloniformes. The mitogenome was 16,524 bp long and was typical of other teleosts mitogenomes in size and content. Thirteen PCGs started with the typical ATG codon (with exception of the cytochrome coxidase subunit 1 (cox1) gene with GTG). All tRNA sequences could be folded into expected cloverleaf secondary structures except for tRNASer (AGN) which lost a dihydrouracil (DHU) stem. The control region was 866 bp in length, which contained some conserved sequence blocks (CSBs) common to Beloniformes. The phylogenetic relationship between 26 fish Beloniformes species was analyzed based on the complete nucleotide and amino acid sequences of 13 PCGs by two different inference methods (Maximum Likelihood and Bayesian Inference). Phylogenetic analyses revealed Hemiramphidae as the sister group to Exocoetidae and it is a paraphyletic grouping. Our results may provide useful information on mitogenome evolution of teleostean species. PMID- 30439950 TI - Similar image retrieval in large-scale trademark databases based on regional and boundary fusion feature. AB - In order to retrieve similar trademarks from large-scale trademark databases, combining the characteristics of trademark images, this paper presents a trademark image retrieval method based on regional and border feature fusion. Based on the target image extraction, the proposed approach describes the target region and border features. The region feature description is mainly based on the concept of partition block statistics. The region is divided into equal-area unit using concentric circles, and feature extraction is performed in each small block unit. For the border feature description, this study first detect corners, and then construct a Delaunay graph and extract features by combining the corner detected and the Delaunay triangulation reconstruction. In the search process, the method also incorporates information such as the trademark's color characteristics, trademark classification, and trademark keywords. The present study carried out image retrieval experiment on CE-SHAPE-1 database containing 1400 MPEG-7 core experimental shape, a classification trademark database containing 2000 images, and a national trademark database containing approximately 4.89 million images. The experimental results show that the proposed approach combines the advantages of region and border feature description, and can choose the best among various local optimizations, which makes the retrieval result more effective, more in line with human visual perception, and improves the retrieval accuracy. PMID- 30439954 TI - Patterning the insect eye: From stochastic to deterministic mechanisms. AB - While most processes in biology are highly deterministic, stochastic mechanisms are sometimes used to increase cellular diversity. In human and Drosophila eyes, photoreceptors sensitive to different wavelengths of light are distributed in stochastic patterns, and one such patterning system has been analyzed in detail in the Drosophila retina. Interestingly, some species in the dipteran family Dolichopodidae (the "long legged" flies, or "Doli") instead exhibit highly orderly deterministic eye patterns. In these species, alternating columns of ommatidia (unit eyes) produce corneal lenses of different colors. Occasional perturbations in some individuals disrupt the regular columns in a way that suggests that patterning occurs via a posterior-to-anterior signaling relay during development, and that specification follows a local, cellular-automaton like rule. We hypothesize that the regulatory mechanisms that pattern the eye are largely conserved among flies and that the difference between unordered Drosophila and ordered dolichopodid eyes can be explained in terms of relative strengths of signaling interactions rather than a rewiring of the regulatory network itself. We present a simple stochastic model that is capable of explaining both the stochastic Drosophila eye and the striped pattern of Dolichopodidae eyes and thereby characterize the least number of underlying developmental rules necessary to produce both stochastic and deterministic patterns. We show that only small changes to model parameters are needed to also reproduce intermediate, semi-random patterns observed in another Doli species, and quantification of ommatidial distributions in these eyes suggests that their patterning follows similar rules. PMID- 30439952 TI - Knee sensorimotor control following anterior cruciate ligament reconstruction: A comparison between reconstruction techniques. AB - The sensorimotor system helps to maintain functional joint stability during movement. After anterior cruciate ligament (ACL) injury and reconstruction, several sensorimotor deficits may arise, including altered proprioception and changes in neuromuscular control. It is still unknown whether the type of autograft used in the reconstruction may influence knee sensorimotor impairments. The aim of this study was to comparatively assess the effects of the hamstring tendon (HT) and bone-patellar tendon-bone (BPTB) ACL reconstruction techniques on knee sensorimotor control 6-12 months post-operation. A total of 83 male subjects participated in this study: 27 healthy participants, 30 BPTB-operated patients and 26 HT-operated patients. Active joint position sense in 3 ranges of motion (90-60 degrees , 60-30 degrees , and 30-0 degrees of knee flexion), isometric steadiness, and onset of muscle activation were used to compare sensorimotor system function between groups. Both operated groups had a small (< 5 degrees ) but significant joint position sense error in the 30-0 degrees range when compared to the healthy group. No significant differences were found between the operated and the control groups for isometric steadiness or onset of muscle activation. The results of this study suggest that operated patients present knee proprioceptive deficits independently of surgical technique. Nevertheless, the clinical implications of this impairment are still unknown. It seems that selected surgical approach for ACL reconstruction do not affect functioning of the sensorimotor system to a large degree. PMID- 30439953 TI - Validation of SYBR green I based closed tube loop mediated isothermal amplification (LAMP) assay and simplified direct-blood-lysis (DBL)-LAMP assay for diagnosis of visceral leishmaniasis (VL). AB - BACKGROUND: The World Health Organization has targeted elimination of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) by 2020. Despite distinctive decline seen in the number of VL cases in ISC, there is still a quest for development of a diagnostic test which has the utility for detection of active infection and relapse cases and as a test of cure. The present study validated the sensitivity and specificity of SYBR Green I based closed tube LAMP assay reported by us for diagnosis of VL. METHODOLOGY: The validation study was carried out at two endemic sites in India, located at Rajendra Memorial Research Institute of Medical Sciences (RMRIMS), Patna and Institute of Medical Sciences (IMS), Banaras Hindu University (BHU), Varanasi. Standard operating protocols were provided at the two sites for applying LAMP assay on confirmed VL cases. The diagnostic accuracy of LAMP assay was evaluated by Receiver operator curve (ROC) analysis. Furthermore, a simplified LAMP assay based on direct blood lysis, DBL LAMP, was developed and verified for its diagnostic accuracy. PRINCIPAL FINDINGS: A total of 267 eligible participants were included in the study which comprised of 179 VL cases and 88 controls. Sensitivity and specificity of the LAMP assay were 98.32% (95% C.I- 95.2-99.7%) and 96.59% (95% C.I.-90.4-99.3%), respectively. ROC curve analysis depicted no significant difference between area under curve (AUCROC) for LAMP assay and rK39 RDT, indicative of LAMP as an excellent diagnostic test. DBL-LAMP assay, performed on 67 VL and 100 control samples, yielded a sensitivity of 93.05% (95% C.I- 84.75-97%) and specificity of 100% (95% C.I.- 96.30-100%). CONCLUSIONS/SIGNIFICANCE: The validated closed tube LAMP for diagnosis of VL will provide impetus to the ongoing VL elimination programme in ISC. The assay based on direct blood lysis promotes its scope for application in field settings by further reducing time and cost. PMID- 30439955 TI - Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends. AB - Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question-do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications-activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)-at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer. PMID- 30439956 TI - A single class of ARF GTPase activated by several pathway-specific ARF-GEFs regulates essential membrane traffic in Arabidopsis. AB - In eukaryotes, GTP-bound ARF GTPases promote intracellular membrane traffic by mediating the recruitment of coat proteins, which in turn sort cargo proteins into the forming membrane vesicles. Mammals employ several classes of ARF GTPases which are activated by different ARF guanine-nucleotide exchange factors (ARF GEFs). In contrast, flowering plants only encode evolutionarily conserved ARF1 GTPases (class I) but not the other classes II and III known from mammals, as suggested by phylogenetic analysis of ARF family members across the five major clades of eukaryotes. Instead, flowering plants express plant-specific putative ARF GTPases such as ARFA and ARFB, in addition to evolutionarily conserved ARF LIKE (ARL) proteins. Here we show that all eight ARF-GEFs of Arabidopsis interact with the same ARF1 GTPase, whereas only a subset of post-Golgi ARF-GEFs also interacts with ARFA, as assayed by immunoprecipitation. Both ARF1 and ARFA were detected at the Golgi stacks and the trans-Golgi network (TGN) by both live imaging with the confocal microscope and nano-gold labeling followed by EM analysis. ARFB representing another plant-specific putative ARF GTPase was detected at both the plasma membrane and the TGN. The activation-impaired form (T31N) of ARF1, but neither ARFA nor ARFB, interfered with development, although ARFA-T31N interfered, like ARF1-T31N, with the GDP-GTP exchange. Mutant plants lacking both ARFA and ARFB transcripts were viable, suggesting that ARF1 is sufficient for all essential trafficking pathways under laboratory conditions. Detailed imaging of molecular markers revealed that ARF1 mediated all known trafficking pathways whereas ARFA was not essential to any major pathway. In contrast, the hydrolysis-impaired form (Q71L) of both ARF1 and ARFA, but not ARFB, had deleterious effects on development and various trafficking pathways. However, the deleterious effects of ARFA-Q71L were abolished by ARFA-T31N inhibiting cognate ARF-GEFs, both in cis (ARFA-T31N,Q71L) and in trans (ARFA-T31N + ARFA-Q71L), suggesting indirect effects of ARFA-Q71L on ARF1-mediated trafficking. The deleterious effects of ARFA-Q71L were also suppressed by strong over-expression of ARF1, which was consistent with a subset of BIG1-4 ARF-GEFs interacting with both ARF1 and ARFA. Indeed, the SEC7 domain of BIG5 activated both ARF1 and ARFA whereas the SEC7 domain of BIG3 only activated ARF1. Furthermore, ARFA-T31N impaired root growth if ARF1-specific BIG3 was knocked out and only ARF1- and ARFA-activating BIG4 was functional. Activated ARF1 recruits different coat proteins to different endomembrane compartments, depending on its activation by different ARF-GEFs. Unlike ARF GTPases, ARF-GEFs not only localize at distinct compartments but also regulate specific trafficking pathways, suggesting that ARF-GEFs might play specific roles in traffic regulation beyond the activation of ARF1 by GDP-GTP exchange. PMID- 30439951 TI - Competition among Aedes aegypti larvae. AB - Adult Aedes aegypti mosquitoes are important vectors of human disease. The size of the adult female affects her success, fitness, and ability to transmit diseases. The size of the adults is determined during the aquatic larval stage. Competition among larvae for food influences the size of the pupa and thus the adult. In these experiments, the food level (mg/larva) and the density (larvae/vial) both affect intraspecific competition, which shows up as the interaction of the two factors. Furthermore, the total food per vial affects the nature of competition among the larvae, also apparent in the interaction of food and density. Male larvae are affected by the percent of males in the vial, but females are not. Seven biologically significant dependent variables were examined, and the data analyzed by multivariate analysis of variance to gain insight into the relationships among the variables and the effects of these factors on the larvae as they grew in small containers. Male and female larvae compete differently from one another for the particulate yeast cells in this experiment; female larvae outcompete males through larger size and by retaining cells within their gut at low total food levels. Under conditions of more intense competition, the pupal masses of both males and females are smaller, so the effect of competition is a reduced apparent food level. The age at pupation is also affected by food and density. Across the twenty treatment combinations of food/larva and larvae/vial, female larvae grew as though there were six different ecological environments while male larvae grew as though there were only four different environments. No interference competition was observed. Eradication efforts aimed at adult populations of this mosquito may inadvertently increase the size and robustness of the next generation of larvae, resulting in a subsequent adult population increase in the second generation. PMID- 30439957 TI - Glucose variability during delirium in diabetic and non-diabetic intensive care unit patients: A prospective cohort study. AB - PURPOSE: To determine whether glucose variability is altered during delirium days compared to non-delirious days in critically ill patients with and without diabetes in the intensive care unit (ICU). MATERIALS AND METHODS: Critically ill patients with delirious and non-delirious days during ICU stay were included from a prospective cohort study which was conducted from January 2011- June 2013. Glucose variability was measured each observation day using various definitions (change in mean glucose, standard deviation, mean absolute glucose, daily delta and occurrence of hypo- and hyperglycemia). Mixed-effects models and generalized mixed-effects models with logit link function were performed to study the association between delirium and glucose variability, adjusting for potential confounders. RESULTS: With the exception of the risk of hypoglycemia, delirium was not linked to higher glucose variability using the various definitions of this estimate. For hypoglycemia, we did find an association with delirium in diabetic patients (OR adj.: 2.78; 95% CI: 1.71-6.32, p = 0.005), but not in non diabetic patients (OR adj.: 1.16; 95% CI: 0.58-2.28, p = 0.689). CONCLUSIONS: Despite the positive association between delirium and hypoglycemia in critically ill patients with diabetes, delirium was not associated with more pronounced glucose variability. Our findings suggest that glucose levels should be monitored more closely in diabetic patients during delirium at the ICU to prevent hypoglycemia. PMID- 30439958 TI - The #chatsafe project. Developing guidelines to help young people communicate safely about suicide on social media: A Delphi study. AB - INTRODUCTION: Many countries have developed guidelines advocating for responsible reporting of suicidal behaviour in traditional media. However, the increasing popularity of social media, particularly among young people, means that complementary guidelines designed to facilitate safe peer-peer communication are required. The aim of this study was to develop a set of evidence informed guidelines to assist young people to communicate about suicide via social media with the input of young people as active participants of the study. METHODS: Systematic searches of the peer-reviewed and grey literature were conducted resulting in a 284-item questionnaire identifying strategies for safe communication about suicide online. The questionnaire was delivered over two rounds to two panels consisting of Australian youth advocates; and international suicide prevention researchers and media and communications specialists. Items were rerated if they were endorsed by 70-79.5% of both panels, or if 80% or more of one panel rated the item as essential or important. All items that were endorsed as essential or important by at least 80% of both panels were included in the final guidelines. RESULTS: A total of 173 items were included in the final guidelines. These items were organised into the following five sections: 1) Before you post anything online about suicide; 2) Sharing your own thoughts, feelings, or experience with suicidal behaviour online; 3) Communicating about someone you know who is affected by suicidal thoughts, feelings or behaviours; 4) Responding to someone who may be suicidal; 5) Memorial websites, pages and closed groups to honour the deceased. DISCUSSION: This is the first study to develop a set of evidence-informed guidelines to support young people to talk safely about suicide on social media. It is hoped that they will be a useful resource for young people and those who support them (e.g., parents, teachers, community workers and health professionals). PMID- 30439959 TI - Stable isotopes reveal opportunistic foraging in a spatiotemporally heterogeneous environment: Bird assemblages in mangrove forests. AB - Environmental heterogeneity can foster opportunistic foraging by mobile species, resulting in generalized resource and habitat use. Determining species' food web roles is important to fully understand how ecosystems function, and stable isotopes can provide insight into the foraging ecology of bird assemblages. We investigated flexibility of food choice in mangrove bird assemblages of northeast Australia by determining whether species' carbon and nitrogen isotopic values corresponded to foraging group classification described in the literature, such as groups of species that are omnivorous or insectivorous. Subsequently, we evaluated foraging group isotopic niche size, overlap, degree of individual specialisation, and the probable proportions of coastal resources that contribute to their collective diets. We found that mangrove birds are more opportunistic when foraging than expected from previous diet studies. Importantly, relationships between the dietary diversity of species within a foraging group and isotopic niche size are spatially inconsistent, making inferences regarding foraging strategies difficult. However, quantifying individual specialisation and determining the probable relative contributions of coastal resources to the collective diet of isotope-based foraging groups can help to differentiate between specialised and generalised foraging strategies. We suggest that flexibility in mangrove bird foraging strategy occurs in response to environmental heterogeneity. A complementary approach that combines isotopic analysis with other dietary information (collated from previous diet studies using visual observation or gut content analyses) has provided useful insight to how bird assemblages partition resources in spatiotemporally heterogeneous environments. PMID- 30439960 TI - Demographic analysis of fenpyroximate and thiacloprid exposed predatory mite Amblyseius swirskii (Acari: Phytoseiidae). AB - Knowledge of the impact of pesticides on predators is crucial for developing integrated pest management (IPM) programs. Amblyseius swirskii (Acari: Phytoseiidae) is a predatory mite used to control several species of pest including Tetranychus urticae (Acari: Tetranychidae) and arthropods. T. urticae is a major pest of multiple greenhouse-grown and field crops including apples in Iran. Lethal and sublethal effects of fenpyroximate and thiacloprid were investigated on A. swirskii, using these chemicals separately at recommended rates or in combination at reduced rates. Recommended tested rates of both pesticides negatively influenced the biological parameters of A. swirskii such as the net reproductive rate (R0) and the intrinsic rate of increase (r). However, the combined treatment of the two pesticides at their reduced rates was less hazardous to A. swirskii. Our findings indicate that the combined use of these chemicals may be compatible with IPM programs utilizing A. swirskii as biological control tool against phytophagous mites and other pests. However, semifield and field studies to investigate the effects of reduced rate treatments of fenpyroximate and thiacloprid alone and in combination on T. urticae and A. swirskii are required for developing IPM programs. PMID- 30439962 TI - Risk factors for self-reported diabetes among Bhutanese adults: A nationally representative survey data analysis. AB - BACKGROUND: Bhutan, a small land-locked country in the eastern Himalayas has been undergoing an epidemiological and nutritional transition in the last two decades. The objective of this paper was to determine the prevalence and explore the risk factors of self-reported diabetes among Bhutanese adults. METHODS: We conducted a secondary data analysis among adults 18 years and older Bhutanese using the data from the National Health Survey 2012 (NHS, 2012) of Bhutan. The self-reported information on risk factors was obtained using standard protocols of the WHO STEPwise approach to Surveillance. The outcome of interest was self-reported diabetes on medication. Adjusted and unadjusted logistic regression analyses were performed to identify the risk factor of diabetes. RESULTS: A total of 31,066 participants aged 18 years and older were included for the analysis. The prevalence of self-reported hypertension was 1.8% (491). Risk factors for diabetes were: age groups: 35-44 years adjusted odds ratio (AOR) = 2.82 (95% CI, 1.07, 7.41), 45-54 years AOR = 6.02 (95% CI, 2.29, 15.83), 55-64 year AOR = 15.7 (95% CI 5.93, 41.55) and >65 years AOR = 19.60 (95% CI, 6.93, 55.71); high school and diploma/certificate education AOR = 2.57, (95% CI 1.62, 4.07) and AOR = 3.92 (95% CI 1.70, 9.07); and urban dwellers AOR = 2.37, (95% 1.58, 3.57); hypertension AOR = 3.3, (95% CI 2.47, 4.41); and fruit servings of 1-3 per week AOR = 1.63 (95% CI 1.15, 2.31). CONCLUSION: The number of Bhutanese adults with diabetes and co-morbidities associated with it is likely to increase with the ageing of the population, nutrition transition, and high rural-urban migration in the near future. This calls for an urgent need to implement strategies to prevent diabetes in the Bhutanese population targeting risk factors including healthy lifestyle with increased physical activities and reduced smoking. At the same time treating other chronic morbidities including hypertension. PMID- 30439963 TI - Land-use/cover conversion affects soil organic-carbon stocks: A case study along the main channel of the Tarim River, China. AB - Soil organic carbon (SOC) constitutes a large pool within the global carbon cycle. Changes in land-use/cover strongly drive variation of SOC stocks. We analyzed the changes in four types of land use/cover and their influence on SOC content, density, and regional stocks along the main channel of the Tarim River in China for 2000-2010 obtained from remotely sensed images and field surveys. The areas and structures of the land uses/covers changed greatly during this period. Specifically, the areas of cultivated, industrial and residential, and shrub land increased, particularly cultivated and shrub land. The areas of forestland, grassland, water bodies, and unused land decreased. SOC stocks in forestland, grassland and unused land decreased between 2000 and 2010. The total SOC stock for the forestland shrub land grassland and unused land was lower in 2010 than 2000. Land-use/cover conversion thus affected SOC stocks. Specifically, conversions from forestland to shrub land, forestland to grassland, forestland to unused land, grassland to shrub land, grassland to unused land, and shrub land to unused land decreased the SOC stocks. This study provides a scientific basis for eco-environmental protection in arid areas. PMID- 30439961 TI - Global fingerprint of humans on the distribution of Bartonella bacteria in mammals. AB - As humans move and alter habitats, they change the disease risk for themselves, their commensal animals and wildlife. Bartonella bacteria are prevalent in mammals and cause numerous human infections. Understanding how this genus has evolved and switched hosts in the past can reveal how current patterns were established and identify potential mechanisms for future cross-species transmission. We analyzed patterns of Bartonella transmission and likely sources of spillover using the largest collection of Bartonella gltA genotypes assembled, including 67 new genotypes. This pathogenic genus likely originated as an environmental bacterium and insect commensal before infecting mammals. Rodents and domestic animals serve as the reservoirs or at least key proximate host for most Bartonella genotypes in humans. We also find evidence of exchange of Bartonella between phylogenetically distant domestic animals and wildlife, likely due to increased contact. Care should be taken to avoid contact between humans, domestic animals and wildlife to protect the health of all. PMID- 30439964 TI - Hyperacute changes in blood mRNA expression profiles of rats after middle cerebral artery occlusion: Towards a stroke time signature. AB - Stroke evolution is a highly dynamic but variable disease which makes clinical decision making difficult. Biomarker discovery programs intended to aid clinical decision making have however largely ignored the rapidity of stroke evolution. We have used gene array technology to determine blood mRNA expression changes over the first day after stroke in rats. Blood samples were collected from 8 male spontaneously hypertensive rats at 0, 1, 2, 3, 6 and 24h post stroke induction by middle cerebral artery occlusion. RNA was extracted from whole blood stabilized in PAXgene tubes and mRNA expression was detected by oligonucleotide Affymetrix microarray. Using a pairwise comparison model, 1932 genes were identified to vary significantly over time (p<=0.5x10-7) within 24h after stroke. Some of the top20 most changed genes are already known to be relevant to the ischemic stroke physiopathology (e.g. Il-1R, Nos2, Prok2). Cluster analysis showed multiple stereotyped and time dependent profiles of gene expression. Direction and rate of change of expression for some profiles varied dramatically during these 24h. Profiles with potential clinical utility including hyper acute or acute transient upregulation (with expression peaking from 2 to 6h after stroke and normalisation by 24h) were identified. We found that blood gene expression varies rapidly and stereotypically after stroke in rats. Previous researchers have often missed the optimum time for biomarker measurement. Temporally overlapping profiles have the potential to provide a biological "stroke clock" able to tell the clinician how far an individual stroke has evolved. PMID- 30439965 TI - Endobiliary radiofrequency ablation for distal extrahepatic cholangiocarcinoma: A clinicopathological study. AB - BACKGROUND: Most patients with distal extrahepatic cholangiocarcinoma have developed jaundice or cholangitis at the time of initial diagnosis, which can delay surgery. We aim to evaluate the actual EB-RFA ablation volume and validated the clinical feasibility of preoperative endobiliary radiofrequency ablation (EB RFA) for resectable distal extrahepatic cholangiocarcinoma. METHODS: The medical records of patients who underwent EB-RFA from July 2016 to June 2017 at a single tertiary academic medical center were reviewed. Inclusion criteria were patients with resectable distal extrahepatic cholangiocarcinoma who required preoperative biliary decompression. Clinical outcomes of EB-RFA were reviewed retrospectively and the surgical specimens were reevaluated. RESULTS: Of the eight patients who required a delayed operation, preoperative EB-RFA was successfully performed without serious complications including peritonitis, hemobilia, or perforation. Although curative resection was attempted in all patients, one patient underwent open and closure due to hepatic metastasis. Seven patients underwent curative surgical resection and the histology revealed that median maximal ablation depth was 4.0 mm (range, 1-6) and median effective ablation length (histological ablation length/fluorosocopic ablation length) was 72.0% (range, 42.1-95.3). CONCLUSIONS: EB-RFA partially ablated human cancer tissue and preoperative EB-RFA might be a safe and feasible in patients with distal extrahepatic cholangiocarcinoma who require a delayed operation. Ablation of the target lesion longer than the estimated length by fluoroscopy may improve the efficacy of EB RFA. PMID- 30439966 TI - Development, characterization and comparisons of targeted and non-targeted metabolomics methods. AB - The potential of a metabolomics method to detect statistically significant perturbations in the metabolome of an organism is enhanced by excellent analytical precision, unequivocal identification, and broad metabolomic coverage. While the former two metrics are usually associated with targeted metabolomics and the latter with non-targeted metabolomics, a systematic comparison of the performance of both approaches has not yet been carried out. The present work reports on the development and performance evaluation of separate targeted and non-targeted metabolomics methods. The targeted approach facilitated determination of 181 metabolites (quantitative analysis of 18 amino acids, 11 biogenic amines, 5 neurotransmitters, 5 nucleobases and semi-quantitative analysis of 50 carnitines, 83 phosphatidylcholines, and 9 sphingomyelins) using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and flow injection-tandem mass spectrometry (FI-MS/MS). Method accuracy and/or precision were assessed using replicate samples of NIST SRM1950 as well as fish liver and brain tissue from Gilthead Bream (Sparus aurata). The non-target approach involved UPLC-high resolution (Orbitrap) mass spectrometry (UPLC-HRMS). Testing of ionization mode and stationary phase revealed that a combination of positive electrospray ionization and HILIC chromatography produced the largest number of chromatographic features during non-target analysis. Furthermore, an evaluation of 4 different sequence drift correction algorithms, and combinations thereof, revealed that batchCorr produced the best precision in almost every test. However, even following correction of non-target data for signal drift, the precision of targeted data was better, confirming our existing assumptions about the strengths of targeted metabolomics. Finally, the accuracy of the online MS2 library mzCloud was evaluated using reference standards for 38 different metabolites. This is among the few studies that have systematically evaluated the performance of targeted and non-targeted metabolomics and provides new insight into the advantages and disadvantages of each approach. PMID- 30439967 TI - Above- and below-ground biomass relationships of Leucaena leucocephala (Lam.) de Wit in different plant stands. AB - The above and below-ground biomass (AGB and BGB) relationship is often used to assess the impact of biotic and abiotic effects on the growth and development of individual plants. The AGB and BGB relationship of the same tree species in different habitats can change significantly because of environmental stress. To investigate how the tree size, the biomass allocation and BGB/AGB ratio of Leucaena leucocephala (Lam.) de Wit varied according to spacing and mixed plant patterns in a valley-type savanna of southwest China, we examined the growth of L. leucocephala, and sampled 23 individuals for biomass measurement in each of four treatments (close/wide spacing of Leucaena leucocephala monocultures, mixed plantation of Leucaena leucocephala and Eucalyptus camaldulensis, and mixed plantation of Leucaena leucocephala and Eucalyptus citriodora), and then determined the regression relationships between AGB and BGB of L. leucocephala in different plant stands. Our results indicated that mixed planting significantly reduced all growth metrics for the tree sizes of L. leucocephala and increased the value of BGB/AGB. Changing plant spacing in monocultures had a significant impact on AGB and TB (Total Biomass) of L. leucocephala, but it had no significant effect on the other metrics. Within mixed plant schemes, L. leucocephala significantly reduced the biomass allocation to leaves and small roots and increased the allocation to coarse root biomass. There were no significant differences in tree size and biomass allocation of L. leucocephala between different spacing regimes in monocultures or between different mixtures in mixed plant stands. The correlation between BGB and AGB of L. leucocephala in all plant stands was consistent with the model of allometric growth, and AGB can be used to accurately estimate BGB. Interestingly, the correlations were not exactly the same. BGB and AGB in monoculture showed isometric growth, and their values in mixed plant stands showed allometric growth. BGB also increased faster than AGB. The findings indicated that L. leucocephala allocated more biomass to the root system when it was planted with Eucalyptus. PMID- 30439969 TI - Expression of CMIP in podocytes is restricted to specific classes of lupus nephritis. AB - Lupus glomerulopathies are classified into various histological patterns, which probably result from different pathophysiological origins. Podocyte injury can be demonstrated in lupus nephritis but its clinical relevance is far little appreciated and is often masked by proliferative lesions and inflammatory cell infiltrations. Two patterns of podocyte lesions may be considered, either occurring in the context of renal inflammation or reflecting podocyte dysfunction in non-proliferative and non-inflammatory glomerulopathies. This distinction remains elusive since no reliable biomarker discriminates between both entities. CMIP was recently found induced in some glomerular disease but its expression in different lupus nephritis classes has not been investigated. Twenty-four adult patients with lupus nephritis, including non-proliferative (n = 11) and proliferative (n = 13) glomerulopathies were analyzed. Clinical, biological and immunological data were compared with immunomorphological findings. We analyzed by quantitative and qualitative methods the expression of CMIP in different histological classes. We found CMIP abundance selectively increased in podocytes in class II and class V glomerulopathies, while in proliferative forms (class III and class IV), CMIP was rarely detected. CMIP was not expressed in cellular crescents, endothelial cells or mesangial cells. CMIP colocalized with some subsets of B and T cells within glomerular or interstitial mononuclear cell infiltrates but never with macrophages. Hematuria is rarely present in lupus glomerulopathies expressing CMIP. There was no correlation between classical immunological markers and CMIP expression. Thus, CMIP induction in lupus nephritis seems restricted to non-proliferative glomerulopathies and may define a specific pattern of podocyte injury. PMID- 30439970 TI - Interpersonal problem behavior and low back pain. AB - OBJECTIVE: The theory of interpersonal problem behaviour (IPB) provides a more fundamental framework for understanding the psychosocial aspects of pain. The present study focused on the IPB, based on the Interpersonal Problem Circumplex (IPC), in persons with low back pain and its association with pain, psychological characteristics, and health care utilisation. METHODS: In a cross-sectional design, individuals with back pain (N = 88) and healthy control persons who matched by age, gender, and educational level (N = 88) were compared with regard to IPB. Furthermore, back pain patients classified by their IPB (N = 24 low, N = 48 moderate, N = 16 high) were compared regarding pain, depression, catastrophising, and health care utilisation. RESULTS: In comparison to the healthy reference sample, a significant difference in the interpersonal problems of the low back pain group, with a tendency towards being overly 'introverted', 'exploitable', and 'subassertive', was revealed. In the back pain group, participants with elevated IPB showed significantly higher levels of pain intensity, functional disability, depression, catastrophising, and health care utilisation than participants with IPB in the normal range. CONCLUSION: Application of the Interpersonal Circumplex Model can help to characterize a subgroup of persons with low back pain. Increased general interpersonal problems are associated with elevated burden in pain-related, psychological, and health care-related variables. Future research should focus on the treatment opportunities for this subgroup, as well as on the influence of interpersonal problems during the course of back pain. PMID- 30439968 TI - The impact of vitamin D supplementation on musculoskeletal health outcomes in children, adolescents, and young adults living with HIV: A systematic review. AB - OBJECTIVE: HIV-positive children, adolescents, and young adults are at increased risk poor musculoskeletal outcomes. Increased incidence of vitamin D deficiency in youth living with HIV may further adversely affect musculoskeletal health. We investigated the impact of vitamin D supplementation on a range of musculoskeletal outcomes among individuals aged 0-25 years living with HIV. METHODS: A systematic review was conducted using databases: PubMed/Medline, CINAHL, Web of Knowledge, and EMBASE. Interventional randomised control trials, quasi-experimental trials, and previous systematic reviews/meta-analyses were included. Outcomes included: BMD, BMC, fracture incidence, muscle strength, linear growth (height-for-age Z-score [HAZ]), and biochemical/endocrine biomarkers including bone turnover markers. RESULTS: Of 497 records, 20 studies met inclusion criteria. Thirteen studies were conducted in North America, one in Asia, two in Europe, and four in Sub-Saharan Africa. High-dose vitamin D supplementation regimens (1,000-7,000 IU/day) were successful in achieving serum 25-hydroxyvitamin-D (25OHD) concentrations above study-defined thresholds. No improvements were observed in BMD, BMC, or in muscle power, force and strength; however, improvements in neuromuscular motor skills were demonstrated. HAZ was unaffected by low-dose (200-400 IU/day) supplementation. A single study found positive effects on HAZ with high-dose supplementation (7,000 vs 4,000IU/day). CONCLUSIONS: Measured bone outcomes were unaffected by high-dose vitamin D supplementation, even when target 25OHD measurements were achieved. This may be due to: insufficient sample size, follow-up, intermittent dosing, non standardised definitions of vitamin D deficiency, or heterogeneity of enrolment criteria pertaining to baseline vitamin D concentration. High-dose vitamin D may improve HAZ and neuromuscular motor skills. Adequately powered trials are needed in settings where HIV burden is greatest. PROSPERO Number: CRD42016042938. PMID- 30439971 TI - Experiences of case managers in providing person-centered and integrated care based on the Chronic Care Model: A qualitative study on embrace. AB - BACKGROUND: Due to the rise in the number of older adults within the population, healthcare demands are changing drastically, all while healthcare expenditure continues to grow. Person-centered and integrated-care models are used to support the redesigning the provision of care and support. Little is known, however, about how redesigning healthcare delivery affects the professionals involved. OBJECTIVES: To explore how district nurses and social workers experience their new professional roles as case managers within Embrace, a person-centered and integrated-care service for community-living older adults. METHODS: We performed a qualitative study consisting of in-depth interviews with case managers (district nurses, n = 6; social workers, n = 5), using a topic-based interview guide. Audiotaped interviews were transcribed verbatim and analyzed using qualitative content analysis. RESULTS: The experiences of the case managers involved four major themes: 1) the changing relationship with older adults, 2) establishing the case-manager role, 3) the case manager's toolkit, and 4) the benefits of case management. Within these four themes, subthemes addressed the shift to a person-centered approach, building a relationship of trust, the process of case management, knowledge and experience, competencies of and requirements for case managers, and the differences in professional background. DISCUSSION: We found that this major change in role was experienced as a learning process, one that provided opportunities for personal and professional growth. Case managers felt that they were able to make a difference, and found their new roles satisfying and challenging, although stressful at times. Ongoing training and support were found to be a prerequisite in helping to shift the focus towards person-centered and integrated care. PMID- 30439972 TI - Irregular work schedule and sleep disturbance in occupational drivers-A nationwide cross-sectional study. AB - BACKGROUND: The objective of this study was to investigate the relationship between irregular work schedules and sleep disturbance and compare the impacts of work schedule on sleep disturbance between occupational drivers and office workers. METHODS: Using data from the 3rd and 4th Korean Working Conditions Survey, 3,070 occupational drivers and 9,898 office workers were included in this study. The subjects' days of night work, evening work, and subjective complaints of sleep disturbance were investigated along with other covariates. RESULTS: In the multivariate logistic regression analyses, occupational drivers (odds ratio [OR], 95% confidence interval [CI]: 1.51, 1.11-2.05), workers who were engaged in more night work (2.49, 1.84-3.38 for 1-15 days, and 3.80, 2.67-5.41 for 16-30 days) and evening work (2.22, 1.66-2.97 for 1-15 days, and 1.76, 1.26-2.45) were more likely to report sleep disturbance. Moreover, occupational driving showed significant interaction effects with both night and evening work on sleep disturbance, and therefore, showed higher ORs for sleep disturbance in the 16-30 days night (5.38, 3.40-8.52) and evening (3.13, 1.97-4.98) compared to no night and evening working office workers. CONCLUSIONS: Occupational drivers who are exposed to night work and evening work are at higher risks for sleep disturbance. Therefore, for the public and drivers' safety, optimal work schedules for minimising sleep disturbance should be developed. PMID- 30439973 TI - Graph measures in task-based fMRI: Functional integration during read-out of visual and auditory information. AB - This study investigated how attending to auditory and visual information systematically changes graph theoretical measures of integration and functional connectivity between three network modules: auditory, visual, and a joint task core. Functional MRI BOLD activity was recorded while healthy volunteers attended to colour and/or pitch information presented within an audiovisual stimulus sequence. Network nodes and modules were based on peak voxels of BOLD contrasts, including colour and pitch sensitive brain regions as well as the dorsal attention network. Network edges represented correlations between nodes' activity and were computed separately for each condition. Connection strength was increased between the task and the visual module when participants attended to colour, and between the task and the auditory module when they attended to pitch. Moreover, several nodal graph measures showed consistent changes to attentional modulation in form of stronger integration of sensory regions in response to attention. Together, these findings corroborate dynamical adjustments of both modality-specific and modality-independent functional brain networks in response to task demands and their representation in graph theoretical measures. PMID- 30439974 TI - Critically ill healthcare workers with the middle east respiratory syndrome (MERS): A multicenter study. AB - BACKGROUND: Middle East Respiratory Syndrome Coronavirus (MERS-CoV) leads to healthcare-associated transmission to patients and healthcare workers with potentially fatal outcomes. AIM: We aimed to describe the clinical course and functional outcomes of critically ill healthcare workers (HCWs) with MERS. METHODS: Data on HCWs was extracted from a multi-center retrospective cohort study on 330 critically ill patients with MERS admitted between (9/2012-9/2015). Baseline demographics, interventions and outcomes were recorded and compared between survivors and non-survivors. Survivors were approached with questionnaires to elucidate their functional outcomes using Karnofsky Performance Status Scale. FINDINGS: Thirty-Two HCWs met the inclusion criteria. Comorbidities were recorded in 34% (11/32) HCW. Death resulted in 8/32 (25%) HCWs including all 5 HCWs with chronic renal impairment at baseline. Non-surviving HCW had lower PaO2/FiO2 ratios 63.5 (57, 116.2) vs 148 (84, 194.3), p = 0.043, and received more ECMO therapy compared to survivors, 9/32 (28%) vs 4/24 (16.7%) respectively (p = 0.02).Thirteen of the surviving (13/24) HCWs responded to the questionnaire. Two HCWs confirmed functional limitations. Median number of days from hospital discharge until the questionnaires were filled was 580 (95% CI 568, 723.5) days. CONCLUSION: Approximately 10% of critically ill patients with MERS were HCWs. Hospital mortality rate was substantial (25%). Patients with chronic renal impairment represented a particularly high-risk group that should receive extra caution during suspected or confirmed MERS cases clinical care assignment and during outbreaks. Long-term repercussions of critical illness due to MERS on HCWs in particular, and patients in general, remain unknown and should be investigated in larger studies. PMID- 30439975 TI - Zoster vaccination inequalities: A population based cohort study using linked data from the UK Clinical Practice Research Datalink. AB - OBJECTIVE: To quantify inequalities in zoster vaccine uptake by determining its association with socio-demographic factors: age, gender, ethnicity, immigration status, deprivation (at Lower-layer Super Output Area-level), care home residence and living arrangements. METHOD: This population-based cohort study utilised anonymised primary care electronic health records from England (Clinical Practice Research Datalink) linked to deprivation and hospitalisation data. Data from 35,333 individuals from 277 general practices in England and eligible for zoster vaccination during the two-year period (2013-2015) after vaccine introduction were analysed. Logistic regression was used to obtain adjusted odds ratios (aOR) for the association of socio-demographic factors with zoster vaccine uptake for adults aged 70 years (main target group) and adults aged 79 years (catch-up group). RESULTS: Amongst those eligible for vaccination, 52.4% (n = 18,499) received the vaccine. Socio-demographic factors independently associated with lower zoster vaccine uptake in multivariable analyses were: being older (catch-up group: aged 79 years) aOR = 0.89 (95% confidence interval (CI):0.85-0.93), care home residence (aOR = 0.64 (95%CI: 0.57-0.73)) and living alone (aOR = 0.85 (95%CI: 0.81-0.90)). Uptake decreased with increasing levels of deprivation (p value for trend<0.0001; aOR most deprived versus least deprived areas = 0.69 (95%CI: 0.64-0.75)). Uptake was also lower amongst those of non-White ethnicities (for example, Black versus White ethnicity: aOR = 0.61 (95%CI: 0.49-0.75)) but was not lower among immigrants after adjusting for ethnicity. Lower uptake was also seen amongst females compared to men in the catch-up group. CONCLUSIONS: Inequalities in zoster vaccine uptake exist in England; with lower uptake among those of non-White ethnicities, and among those living alone, in a care home and in more deprived areas. Tailored interventions to increase uptake in these social groups should assist in realising the aim of mitigating vaccination inequalities. As care home residents are also at higher risk of zoster, improving the uptake of zoster vaccination in this group will also mitigate inequalities in zoster burden. PMID- 30439976 TI - Paternal portrait of populations of the middle Magdalena River region (Tolima and Huila, Colombia): New insights on the peopling of Central America and northernmost South America. AB - The valley of the Magdalena River is one of the main population pathways in Colombia. The gene pool and spatial configuration of human groups in this territory have been outlined throughout three historical stages: the Native pre Hispanic world, Spanish colonization, and XIX century migrations. This research was designed with the goal of characterizing the diversity and distribution pattern of Y-chromosome lineages that are currently present in the Tolima and Huila departments (middle Magdalena River region). Historic cartography was used to identify the main geographic sites where the paternal lineages belonging to this area have gathered. Twelve municipalities were chosen, and a survey that included genealogical information was administered. Samples collected from 83 male volunteers were analyzed for 48 Y-SNPs and 17 Y-STRs. The results showed a highly diverse region characterized by the presence of 16 sublineages within the major clades R, Q, J, G, T and E and revealed that 93% (n = 77) of haplotypes were different. Among these haplogroups, European-specific R1b-M269 lineages were the most representative (57.83%), with six different subhaplogroups and 43 unique haplotypes. Native American paternal ancestry was also detected based on the presence of the Q1a2-M3*(xM19, M194, M199) and Q1a2-M346*(xM3) lineages. Interestingly, all Q1a2-M346*(xM3) samples (n = 7, with five different haplotypes) carried allele six at the DYS391 locus. This allele has a worldwide frequency of 0.169% and was recently associated with a new Native subhaplogroup. An in-depth phylogenetic analysis of these samples suggests the Tolima and Huila region to be the principal area in all Central and South America where this particular Native lineage is found. This lineage has been present in the region for at least 1,809 (+/- 0,5345) years. PMID- 30439977 TI - Influence of long and short arms of X chromosome on maxillary molar crown morphology. AB - Although genes on the human X chromosome reportedly influence tooth crown morphology, little is known about X chromosome activation or inactivation systems relevant to morphological variations. We assessed the relationships between tooth crown size and crown morphological traits in females with Turner syndrome, the variants of which include complete absence of one X chromosome, lack of the short arm (Xp), or duplication of the long arms (Xq), and then estimated the functions of Xp and Xq in the process of unilateral X chromosome inactivation during tooth crown development. The mesiodistal and buccolingual diameters in the maxillary first (M1) and second (M2) permanent molars were compared among X chromosome karyotypes by multiple regression analyses, and their relationships with the development of Carabelli's cusp and the distolingual cusp were analyzed using logistic regression analysis. The crown sizes increased in the order of the 46,X,i(Xq) karyotype, 45,X and 45,X/46,XX karyotypes, and control group. A lower frequency of Carabelli's cusp and higher frequency of a reduced distolingual cusp in M1 were characteristics of Turner syndrome. The overall M1 and M2 crown sizes differed among the X chromosome karyotypes, whereas a smaller crown size was associated with a reduced distolingual cusp but not with Carabelli's cusp. Considering the differences in chromosome arrangement among females with Turner syndrome and the process of unilateral X chromosome inactivation, the observed results can be considered in terms of quantity or number of promoters/inhibitors during tooth crown development. The X chromosome karyotypes have a strong influence on the overall crown sizes of the M1 and M2 molars because those karyotypes with variable numbers of active gene regions directly influence tooth germ development in an early stage of human odontogenesis. The later forming cusps, such as the distolingual cusp and Carabelli's cusp, may be affected by this developmental prerequisite. PMID- 30439978 TI - Fine mapping of the male-sterile genes (MS1, MS2, MS3, and MS4) and development of SNP markers for marker-assisted selection in Japanese cedar (Cryptomeria japonica D. Don). AB - Pollinosis caused by Japanese cedar (Cryptomeria japonica) is a widespread social problem in Japan. To date, 23 male-sterile C. japonica trees have been selected in Japan to address pollinosis, from which four male-sterility loci (MS1, MS2, MS3, and MS4) have been identified from test crossing results. For efficient breeding of male-sterile C. japonica trees, more male-sterile individuals and individuals heterozygous for male-sterile genes are required. Therefore, we aimed to develop DNA markers for marker-assisted selection of four types of male sterile genes from populations without a family structure. First, for four families exhibiting segregation of each male-sterile locus (MS1, MS2, MS3, and MS4), genome-wide single-nucleotide polymorphism and insertion/deletion (indel) genotyping was performed using the Axiom myDesign Targeted Genotyping Array method. Four high-density linkage maps for mapping the MS1, MS2, MS3, and MS4 families were constructed, which included 4923, 1722, 1896, and 2247 markers, respectively. In these maps, 15, 4, 2, and 2 markers were located 0.0, 3.3, 1.1, and 0.0 cM from the MS1, MS2, MS3, and MS4 loci, respectively. Second, for the markers located 0.0 cM from a male-sterile locus (i.e., MS1 and MS4), to clarify the most tightly linked markers, we calculated the prediction rate of male sterile gene genotypes from marker genotypes for 78 trees. The markers with the highest prediction rates were AX-174127446 (0.95) for MS1 and AX-174121522 (1.00) for MS4. The AX-174121522 marker was considered to be suitable for selecting trees homozygous or heterozygous for the MS4 gene from plus-trees without a pollination test, which requires a large amount of time and effort. The nearest markers to the male-sterile loci found in this study may facilitate the isolation of male-sterile genes in C. japonica via combination with the draft genomic sequence that is currently being collated. PMID- 30439979 TI - Thromboelastographic analysis of novel polyethylene glycol based low volume resuscitation solutions. AB - BACKGROUND: Low volume resuscitation (LVR) in shock prevents deleterious effects of crystalloid loading in pre-hospital settings. Polyethylene glycol 20,000 (PEG 20k) based LVR solutions are 20-fold more effective at maintaining perfusion and survival in shock compared to conventional crystalloids. The aim of this study was to determine coagulation and platelet function of whole blood treated with 10% PEG-20k. METHODS: Citrated blood from volunteers (n = 25) or early admission severely injured trauma patients (n = 9) were diluted 10% with various LVR solutions in a matched design with a paired volume control (saline), and studied using thromboelastography (TEG). FINDINGS: In healthy volunteers and patients, 10% PEG-20k significantly increased clot amplification time (k), decreased propagation (angle), maximal clot size and strength (MA), and the overall coagulation index (CI), but not clot initiation (R) or fibrinolysis (Ly30), relative to paired saline dilutional controls. Clinically, K, angle, and MA were just outside of the normal limits in volunteers but not in patients. No statistical differences existed between PEG-20k and Hextend (HES) in either patient population. In a dose response series using volunteer blood, all effects of 10% PEG-20k on TEG were reversed and normalized by lower concentrations (7.5% and 5%). Furthermore, 7.5% PEG-20k produced similar resuscitation effects as 10% PEG in rodent hemorrhagic shock models (n = 5). CONCLUSIONS: In conclusion, PEG 20k based LVR solutions produced a dose-dependent minor hypocoagulative state, possibly associated with changes in clot propagation and platelet function, which can be reversed by dose reduction in concentration while providing superior LVR, microvascular rescue, and lactate clearance compared to saline or starch. PMID- 30439980 TI - Uniparental and transgressive expression of alpha-zeins in maize endosperm of o2 hybrid lines. AB - The alpha-zein gene family encodes the most abundant storage proteins of maize (Zea mays) endosperm. Members of this family are expressed in a parent-of-origin manner. To characterize this phenomenon further, we investigated the expression of a subset of alpha-zein polypeptides in reciprocal crosses between o2 lines that were characterized by a simplified alpha-zein pattern. Maize lines that suppressed the expression of alpha-zeins when used as female parents were identified. The suppression was cross-specific, occurring only when specific genetic backgrounds were combined. Four alpha-zein sequences that were sensitive to uniparental expression were isolated. Molecular characterization of these alpha-zeins confirmed that their expression or suppression depended on the genetic proprieties of the endosperm tissue instead of their parental origin. DNA methylation analysis of both maternally and paternally expressed alpha-zeins revealed no clear correlation between this epigenetic marker and parent-of-origin allelic expression, suggesting that an additional factor(s) is involved in this process. Genetic analyses revealed that the ability of certain lines to suppress alpha-zein expression was unstable after one round of heterozygosity with non suppressing lines. Interestingly, alpha-zeins also showed a transgressive expression pattern because unexpressed isoforms were reactivated in both F2 and backcross plants. Collectively, our results suggest that parent-of-origin expression of specific alpha-zein alleles depends on a complex interaction between genotypes in a manner that is reminiscent of paramutation-like phenomena. PMID- 30439981 TI - Percutaneous closure of perimembranous ventricular septal defect using patent ductus arteriosus occluders. AB - OBJECTIVES: To assess the safety and efficacy of percutaneous closure of perimembranous ventricular septal defect (PmVSD) using patent ductus arteriosus (PDA) occluders. BACKGROUND: Widespread use of conventional PmVSD closure devices has been limited by unacceptable high rate of complete heart block (CHB). The elegant design of PDA occluders is supposed to ease implantation, increase closure rate and minimize damage to adjacent structures. Thus, PDA occluders may reduce complications, especially the CHB, and offer a good alternative for PmVSD closure. METHOD: From September 2008 to October 2015, patients who underwent attempted percutaneous VSD closure using PDA occluders were included in the study. Patient demographics, echocardiography measurements, procedure details and follow-up data until October 2017 were collected. RESULTS: In total, 321 patients with a mean age of 15.5+/-12.6 years and mean a weight of 33.3+/-20.5 kg were included in this study. The mean defect size was 4.8+/-2.1 mm. Implantation was successful in 307 (95.6%) patients. The median follow-up time was 63 months (24 to 108 months). The closure rates were 89.5%, 91.5%, and 99.3% after the procedure 24 hours, 6 months and 2 years, respectively. Major complications occurred in 5 (1.7%) patients during the procedure and follow-up, including persistent CHB in 2 (0.7%) patients and device embolization in 3 (1.0%) patients. No death, disability, or other major complication was detected. CONCLUSION: Percutaneous closure of PmVSD using PDA occluders is feasible, safe and efficacious in selected patients. PMID- 30439983 TI - Influenza B viruses circulated during last 5 years in Mongolia. AB - Influenza B virus-caused illness has recently been considered as an urgent public health problem due to substantial morbidity, mortality and life-threatening medical complications. In this study, we have reported the main characteristics of influenza B virus in Mongolia, including prevalence, lineages, suitability with vaccine strains and drug susceptibility against the virus. 15768 specimens were tested by qPCR for detecting influenza viruses. From positive specimens for influenza B virus, the clinical isolates were isolated using MDCK cells. Sequencing analysis, hemagglutination inhibition assay and Neuraminidase inhibitor (NAI) drug susceptibility testing were performed for the clinical isolates. Influenza B virus was around in 3.46% of the samples in Mongolia, and B/Victoria clade-1A and B/Yamagata clade-3 lineages were predominant. Importantly, it was confirmed that the lineages corresponded to the vaccine strains. Moreover, drug susceptibility tests revealed that some Mongolian clinical isolates showed reduced susceptibility to antiviral agents. Interestingly, G104R was identified as a novel mutation, which might have a significant role in drug resistance of the virus. These results describe the characteristics of influenza B viruses that have caused respiratory illness in the population of Mongolia between 2013 and 2017. PMID- 30439982 TI - Evaluation of the capacities of mouse TCR profiling from short read RNA-seq data. AB - Profiling T cell receptor (TCR) repertoire via short read transcriptome sequencing (RNA-Seq) has a unique advantage of probing simultaneously TCRs and the genome-wide RNA expression of other genes. However, compared to targeted amplicon approaches, the shorter read length is more prone to mapping error. In addition, only a small percentage of the genome-wide reads may cover the TCR loci and thus the repertoire could be significantly under-sampled. Although this approach has been applied in a few studies, the utility of transcriptome sequencing in probing TCR repertoires has not been evaluated extensively. Here we present a systematic assessment of RNA-Seq in TCR profiling. We evaluate the power of both Fluidigm C1 full-length single cell RNA-Seq and bulk RNA-Seq in characterizing the repertoires of different diversities under either naive conditions or after immunogenic challenges. Standard read length and sequencing coverage were employed so that the evaluation was conducted in accord with the current RNA-Seq practices. Despite high sequencing depth in bulk RNA-Seq, we encountered difficulty quantifying TCRs with low transcript abundance (<1%). Nevertheless, top enriched TCRs with an abundance of 1-3% or higher can be faithfully detected and quantified. When top TCR sequences are of interest and transcriptome sequencing is available, it is worthwhile to conduct a TCR profiling using the RNA-Seq data. PMID- 30439984 TI - Bioactivity of selected materials for coffee substitute. AB - Epidemiological studies have suggested that coffee consumption is negatively correlated with the incidence of Parkinson's disease. Coffee contains relatively high levels of beta-carbolines, which have been ascribed neuroactive effects in humans however the positive or negative effect has not been confirmed yet. Two ingredients with applications as coffee substitutes-chicory, which is traditionally used in this way, and artichoke-were considered in this study both from the neuroactive point of view but also in relation to the other bioactive compounds that result from their thermal processing. These thermal products are of concern because of their possible toxic properties. The estimated concentration of beta-carbolines was high in both materials (1.8 MUg/g and 2.5 MUg/g harman and 2.9 MUg/g and 3.1 MUg/g norharman in chicory and artichoke, respectively). Artichoke had more beta-carbolines than chicory, and also more all the toxic compounds examined here-acrylamide, carboxymethyllysine, and furans, which were detected in significantly higher concentrations in artichoke, particularly acrylamide. Chicory and artichoke also contain phenolic compounds that possess high antioxidant activity, on a similar level. Artichoke, a new proposed ingredient in coffee substitutes, appears to be a richer source of beta carbolines than the traditionally chicory. Both materials contained high level of undesirable components, such as furan and its derivatives, carboxymethyllysine and particularly acrylamide, much higher in artichoke. PMID- 30439985 TI - Additive effects of obesity and loneliness on C-reactive protein. AB - Obesity and loneliness are associated with C-reactive protein (CRP), a predictor of cardiovascular disease. It is unknown whether the co-presence of obesity and loneliness is associated with additional risk for clinically elevated CRP. The present study thus examines their independent and combined effects on elevated CRP in older adults. Data come from 10,912 respondents who completed the 2008 and 2010 waves of the Health and Retirement Study. Loneliness was measured using an 11-item Loneliness Scale and body mass index was calculated from technician measured height and weight. Our primary outcome is high sensitivity CRP (hsCRP). Survey-weighted logistic regression models were used to test whether loneliness and BMI category are independent predictors of CRP after adjusting for demographics and other inflammatory-related covariates. In the fully adjusted model for men, obesity (OR = 2.36, p < .0001) was associated with increased odds of hsCRP >3.0. Among females, being overweight (OR = 1.75, p < .0001) or obese (OR = 4.01, p < .0001) were associated increased odds of hsCRP>3.0. Among both men and women, results from fully adjusted models indicated that loneliness was not associated with clinically elevated hsCRP (OR = 1.34, p = .0535; OR = 0.97, p = 0.6776, respectively). PMID- 30439986 TI - Refractive errors in an elderly rural Japanese population: The Kumejima study. AB - The prevalence of refractive errors, which closely relates to visual function difficulties, several ocular disorders, and decreased quality of life, varies among countries and populations. One of the highest prevalence of myopia (spherical equivalent [SE] < -0.5 diopters [D], 41.8%) has been reported in an urban city (Tajimi) in central Japan. Here, we assess refractive conditions in a rural southwestern island (Kumejima) of Japan, where a high prevalence of glaucoma, especially angle-closure glaucoma, has been found. In Kumejima, the prevalence of myopia (SE < -0.5 D), high myopia (SE < -5 D), hyperopia (SE > +0.5 D), refractive astigmatism (cylinder > 0.5 D), and anisometropia (difference in SE between eyes > 1.0 D) were 29.5%, 1.9%, 34.1%, 38.8%, and 15.5%, respectively. Myopia decreased with age up to 70 years old but increased slightly thereafter, whereas hyperopia increased up to 70 years old and was unchanged thereafter. The prevalence of astigmatism and anisometropia was higher in older subjects. The prevalence of myopia and high myopia was higher than most of white, Hispanic, and other Asian populations, while was considerably lower than in the urban city of Japan. The high prevalence of hyperopia should be associated with high prevalence of angle closure glaucoma in this island. PMID- 30439988 TI - Reaching substantive female representation among decision-makers: A qualitative research study of gender-related experiences from the health sector in Mozambique. AB - BACKGROUND: Achieving significant female representation in government at decision making levels has been identified as a key step towards achieving gender equality. In 2015, women held 39.6% of parliamentary seats in Mozambique, which is above the benchmark of 30% that has been suggested as the turning point for minority representation to move from token status to having a sizable impact. We undertook a study to identify gender-related barriers and facilitators to improving women-centered policies in the health sector. METHODS: We conducted in depth interviews with 39 individuals (32 women, 7 men) involved at a senior level in policy making or implementation of woman-centric policies within the Mozambique Ministry of Health and affiliated institutions. We used a semi structured interview guide that included questions on difficulties and facilitating factors encountered in the policy making process, and the perceived role of gender in this process. We used both deductive and inductive analysis approaches, starting with a set of pre-identified themes and expanding this to include themes that emerged during coding. RESULTS: Our data suggest two main findings: (1) the women who participated in our study generally do not report feeling discrimination in the workplace and (2) senior health sector perceive women to be more personally attuned to women-centric issues than men. Within our specific sample, we found little to suggest that gender discrimination is a problem professionally for female decision-makers in Mozambique. However, these findings should be contextualized using an intersectional lens with recognition of the important difference between descriptive versus substantive female representation, and whether "percentage of women" is truly the best metric for gaging commitment to gender equality at the policy making level. CONCLUSIONS: Mozambique's longstanding significant representation of women may have led to creating an environment that leads to positive experiences for female decision makers in the government. However, while the current level of female representation should be celebrated, it does not negate the need for continued focus on female representation in decision-making positions. PMID- 30439987 TI - Respiratory syncytial virus hospitalization in children in northern Spain. AB - OBJECTIVES: Understanding respiratory syncytial virus (RSV) morbidity may help to plan health care and future vaccine recommendations. We aim to describe the characteristics and temporal distribution of children diagnosed with RSV admitted in a Spanish hospital. METHODS: Descriptive study for which the hospital discharges of children < 5 years of age with RSV infection were analyzed. The information was extracted from the hospital discharge database of a reference pediatric hospital in northern Spain for the 2010-2011 to 2014-2015 RSV seasons. RESULTS: Six hundred and forty-seven hospitalizations of children with RSV infection were analyzed, 94% of which occurred between the second week of November and the last week of March. Most children (72%) were under one year of age and 95% were previously healthy infants. Infants born from October to December had the highest risk of hospitalization in the first year of life. The median length of hospital stay of children with and without comorbidities was six and three days, respectively. 6.5% of the hospitalized cases were admitted to the pediatric intensive care unit; this percentage was higher among children < 2 months (adjusted odds ratio 4.15; 95% confidence interval: 1.37-12.61) or with comorbidities (adjusted odds ratio 4.15; 95% confidence interval: 1.53-11.28). The case lethality was 0.3%. CONCLUSIONS: The risk of hospitalizations for RSV is high during the first year of life and increases among infants born in the fall. Being under two months of age and presenting comorbidities are the main risk factors associated to pediatric intensive care unit admission. PMID- 30439989 TI - Maternal stress and placental function, a study using questionnaires and biomarkers at birth. AB - BACKGROUND: Prenatal stress affects the health of the pregnant woman and the fetus. Cortisol blood levels are elevated in pregnancy, and fetal exposure to cortisol is regulated by the placenta enzyme 11beta-HSD2. A decrease in enzyme activity allows more maternal cortisol to pass through the placental barrier. Combining the fetal and maternal cortisol to cortisone ratio into the adjusted fetal cortisol exposure (AFCE) represents the activity of the enzyme 11beta-HSD2 in the placenta. AIM: To investigate the effect of prenatal maternal stress on the ratio of cortisol and cortisone in maternal and fetal blood at birth in a normal population. METHOD: Maternal self-reported stress was assessed at one time point, as late in the pregnancy as convenient for the participant, using the Depression Anxiety Stress Scales (DASS-42), Pregnancy Related Anxiety (PRA), and Major Life Events during pregnancy. The study included 273 participants from Copenhagen University Hospital. Maternal and umbilical cord blood was sampled directly after birth and cortisol and cortisone concentrations were quantified using UPLC chromatography. Data were analyzed in a five-step regression model with addition of possible confounders. The primary outcome was AFCE, and plasma concentrations of maternal and fetal cortisol and cortisone were secondary outcomes. RESULTS: Significant associations were seen for the primary outcome AFCE and the plasma concentrations of maternal cortisol and fetal cortisone with exposure to Pregnancy Related Anxiety (PRA), though the associations were reduced when adjusting for birth related variables, especially delivery mode. The weight of the placenta affected the associations of exposures on AFCE, but not plasma concentrations of cortisol and cortisone in mother and fetus. Moreover, the study demonstrated the importance of delivery mode and birth strain on cortisol levels right after delivery. CONCLUSION: Our main finding was associations between PRA and AFCE, which shows the effect of maternal stress on placental cortisol metabolism. PMID- 30439990 TI - Periodontal regenerative effect of enamel matrix derivative in diabetes. AB - The present study aimed to investigate the periodontal regenerative effect of enamel matrix derivative (EMD) in diabetes. Thirty-six rats were assigned to streptozotocin-induced diabetes or control (non-diabetic) groups. Three-wall intrabony defects were surgically generated in the bilateral maxilla molar, followed by application of EMD or saline. Primary wound closure and defect fill were evaluated via histomorphological analysis and micro-computed tomography. mRNA expression levels of inflammatory and angiogenic factors in the defects were quantified via real-time polymerase chain reaction. Gingival fibroblasts were isolated from control animals and cultured in high-glucose (HG) or control medium. The effects of EMD on insulin resistance and PI3K/Akt/VEGF signaling were evaluated. The achievement rate of primary closure and the parameters of defect fill were significantly higher at EMD-treated site than at EMD-untreated sites in both diabetic and non-diabetic rats, although defect fill in the diabetic groups was significantly lower in the control groups on two-way repeated-measures analysis of variance (for both, p<0.05). Newly formed bone and cementum were significantly increased at EMD-treated sites in diabetic rats than at EMD untreated sites in control rats (for both, p<0.05). Vegf was significantly upregulated at EMD-treated sites in both diabetic and non-diabetic rats (for both, p<0.05). In vitro, insulin or EMD-induced Akt phosphorylation was significantly lower in cells cultured in HG medium (p<0.05). EMD-mediated Vegf upregulation was suppressed by the Akt inhibitor wortmannin, although the effect was significantly lower in HG medium (p<0.01). In conclusion, EMD might promote periodontal tissue regeneration via Akt/VEGF signaling, even in a diabetic condition. PMID- 30439991 TI - The nutritional content of Tana River yellow baboon (Papio cynocephalus) foods in a partially forested habitat. AB - Here we report the first dietary macronutrient and mineral content information for a little-studied yellow baboon group (i.e., the Mchelelo troop) at the Tana River Primate National Reserve, Kenya. We compare forest to savanna samples for this troop found in a partially forested habitat. Observations conducted between 1988 and 1992 determined our list of foods. Subsequently, flora samples, representing 56 species, were collected between April 2008 and March 2009 with nutrient content determined via standard procedures for fiber, gross energy, ash/minerals, crude protein, and crude fat/lipids. Concentrations of specific minerals (calcium, iron, magnesium, manganese, phosphorus, potassium, zinc) were also measured. We predicted forest items would be higher in gross energy and lipids and savanna items higher in crude protein, fiber, and minerals. Our analyses support only the predicted difference in crude protein for savanna items for the overall dataset. In our examination of the top 15 foods, savanna items had significantly higher crude protein, ash, magnesium, and manganese while forest items had higher gross energy. Right-angled mixture triangles show some clustering by location but with substantial overlap in values. Our data provide further indication of the particularity and purposefulness of dietary choices made by primates. They also contribute to the broader discussions of primate nutritional ecology and are a first step towards an examination of macronutrient balancing for this group. Finally, we discuss the impact heavy reliance upon forest products by a "savanna species" may have upon competitors and forest composition. Ultimately, we show that there is still much to be learned about baboon nutrition. PMID- 30439992 TI - Academic coaching and decision analysis: Ways of deciding whether to pursue an academic career. AB - We analyzed and compared the decision-making processes underlying two approaches that academics might use to decide whether to pursue a professorship or an alternative career: academic coaching (a paid service that supports academics with career-related issues) and decision analysis (a method for applying decision theory to real-world decision problems). To this end, we conducted in-depth expert interviews with seven out of 11 academic coaches known to work in Berlin to examine empirically the career decision-making process that they use. Moreover, we demonstrate theoretically how decision analysis can be applied to an academic's hypothetical career choice problem. A comparison of the two approaches showed that they both advise (i) structuring the decision problem by dividing it into smaller components, (ii) using the academic's objectives to generate career alternatives, and (iii) quantifying the uncertainty of decision outcomes using subjective probabilities. Moreover, the observed differences in the way the two approaches structure the decision problem suggest ways in which they could inform each other: (i) they could make use of each other's techniques to help academics define their objectives and generate career alternatives; (ii) academic coaching could, in addition, use decision trees (a hallmark of decision analysis) to represent the structure of the career decision problem, and use simple measurement scales to quantify how much the career options contribute to the academic's objectives. PMID- 30439993 TI - Solid peripheral tumor leads to systemic inflammation, astrocyte activation and signs of behavioral despair in mice. AB - Prevalence of depression is higher in patients with cancer than in the general population. Sustained systemic inflammation has been associated with depressive behavior and it has been reported that depressed patients commonly display alterations in their immune system. We previously showed that cancer in mice induces a systemic environment that promotes neutrophil activation and leukocytosis. We thus hypothesized that the peripheral systemic response to a solid tumor leads to endothelial activation, which may promote inflammatory changes in the brain with behavioral consequences. Using the Lewis lung carcinoma (LLC) model, we show that tumor growth induces a progressive increase in peripheral inflammation as observed by elevated interleukin-6 (IL-6). In behavioral studies, tumor-bearing mice showed no sign of motor, coordination or short term working memory deficits as assessed by rotarod, balance-beam, and novel object recognition tests. However, there was an impairment in the grip strength test and interestingly, an anxious and despair-like phenotype in the elevated plus-maze, and tail suspension tests, respectively. Immunostaining of perfused brains revealed fibrin accumulation in the vasculature with some leakage into the parenchyma, a process known to activate endothelial cells. Taken together, our results suggest that the inflamed and prothrombotic systemic environment created by the growth of a peripherally-located solid tumor induces endothelial activation, accumulation of fibrin in the brain and astrocyte activation, perhaps leading to depressive-like behavior. PMID- 30439994 TI - In vitro effects of commercial mouthwashes on several virulence traits of Candida albicans, viridans streptococci and Enterococcus faecalis colonizing the oral cavity. AB - Oral microbiota consists of hundreds of different species of bacteria, fungi, protozoa and archaea, important for oral health. Oral mycoses, mostly affecting mucosae, are mainly caused by the opportunistic pathogen Candida albicans. They become relevant in denture-wearers elderly people, in diabetic patients, and in immunocompromised individuals. Differently, bacteria are responsible for other pathologies, such as dental caries, gingivitis and periodontitis, which affect even immune-competent individuals. An appropriate oral hygiene can avoid (or at least ameliorate) such pathologies: the regular and correct use of toothbrush, toothpaste and mouthwash helps prevent oral infections. Interestingly, little or no information is available on the effects (if any) of mouthwashes on the composition of oral microbiota in healthy individuals. Therefore, by means of in vitro models, we assessed the effects of alcohol-free commercial mouthwashes, with different composition (4 with chlorhexidine digluconate, 1 with fluoride, 1 with essential oils, 1 with cetylpyridinium chloride and 1 with triclosan), on several virulence traits of C. albicans, and a group of viridans streptococci, commonly colonizing the oral cavity. For the study here described, a reference strain of C. albicans and of streptococci isolates from pharyngeal swabs were used. Chlorhexidine digluconate- and cetylpyridinium chloride-containing mouthwashes were the most effective in impairing C. albicans capacity to adhere to both abiotic and biotic surfaces, to elicit proinflammatory cytokine secretion by oral epithelial cells and to escape intracellular killing by phagocytes. In addition, these same mouthwashes were effective in impairing biofilm formation by a group of viridans streptococci that, notoriously, cooperate with the cariogenic S. mutans, facilitating the establishment of biofilm by the latter. Differently, these mouthwashes were ineffective against other viridans streptococci that are natural competitors of S. mutans. Finally, by an in vitro model of mixed biofilm, we showed that mouthwashes-treated S. salivarius overall failed to impair C. albicans capacity to form a biofilm. In conclusion, the results described here suggest that chlorhexidine- and cetylpyridinium-containing mouthwashes may be effective in regulating microbial homeostasis of the oral cavity, by providing a positive balance for oral health. On the other side, chlorhexidine has several side effects that must be considered when prescribing mouthwashes containing this molecule. PMID- 30439995 TI - Efficacy of concomitant acromioplasty in the treatment of rotator cuff tears: A systematic review and meta-analysis. AB - BACKGROUND: Scientific evidence is not clear regarding the routine use of acromioplasty in the treatment of rotator cuff repair. The aim of this study was to compare clinical outcomes between patients undergoing arthroscopic rotator cuff repair with and without concomitant acromioplasty. METHODS: Medline, Cochrane Library, and EMBASE databases were searched to identify eligible studies focused on arthroscopic rotator cuff repair with and without acromioplasty from January 2000 to February 2018. Postoperative functional outcomes, visual analog scale (VAS) for pain and reoperation rate were extracted for systemic analysis. RESULTS: Six randomized controlled trials (RCTs) and one cohort study (CS), including 651 patients, fulfilled our selection criteria. The results showed a significant difference in American Shoulder and Elbow Surgeons (ASES) score, but not in the Constant score, University of California-Los Angeles (UCLA) score, or Simple Shoulder Test (SST) score, in the treatment of rotator cuff tear with or without concomitant acromioplasty at the final follow-up. In the subgroup analysis, the results showed no significant differences between the two treatments in reoperation rate at the final follow-up or VAS score at 6 months postoperatively and final follow-up, but there was a significant difference in VAS score at 12 months postoperatively in favor of acromioplasty treatment. The evidence quality for each outcome evaluated by the GRADE system was low. CONCLUSIONS: In summary, our present study demonstrated that acromioplasty treatment is significantly superior to nonacromioplasty in shoulder pain relief at 12 months postoperatively and in ASES score improvement at the final follow-up in conjunction with rotator cuff repair. However, these significant differences were not clinically relevant. Thus, there were no differences in shoulder function or pain scores for patients undergoing rotator cuff repair with and without acromioplasty. Further high-quality studies with larger sample sizes and long-term follow-ups are needed to clarify this issue. PMID- 30439996 TI - Occupational health disparities among U.S. long-haul truck drivers: the influence of work organization and sleep on cardiovascular and metabolic disease risk. AB - OBJECTIVE: The organization of work has undergone vast transformations over the past four decades in the United States and has had profound impacts on worker health and wellbeing. The profession of commercial truck driving is one of the best examples. Particularly for long-haul truck drivers, changes in work organization have led to disproportionately poor physiological, psychological, and sleep health outcomes. METHODS: The present study examined disparities in cardiometabolic disease risk among long-haul truck drivers and the general population, and the influence of work organization and sleep in generating these outcomes. Researchers collected survey data from 260 drivers, and blood assay samples from 115 of those drivers, at a large highway truck stop in North Carolina. Comparisons were made for cardiovascular and metabolic risk against the 2011-2012 National Health and Nutrition Examination Survey (NHANES). In addition, logistic regression was used to explore predictive relationships between work organization and sleep and risk for cardiovascular and metabolic disease. RESULTS: There were statistically significant mean differences between the long haul truck driver sample and the NHANES sample for both cardiovascular (3.71 vs. 3.10; p <0.001) and metabolic (4.31 vs. 3.09; p <0.001) disease risk. The truck driver sample was less physically active and had lower HDL cholesterol along with greater levels of smoking, BMI, and metabolic syndrome diagnosis. More years of driving experience and poor sleep quality were statistically significant predictors for both cardiovascular and metabolic disease risk. CONCLUSIONS: Study findings implicate elements of the occupational milieu experienced by long-haul truck drivers that induce disproportionate cardiometabolic disease risk. Sleep quality, largely compromised by poor work conditions and workplace environments, plays a significant role in increased risks for cardiometabolic disease. There is an urgent need for longitudinal studies of this critical occupational sector as well as intervention research centered on policy and systems level change. PMID- 30439997 TI - Serum sphingolipid levels associate with upcoming virologic events and HBV genotype D in a cohort of patients with HBeAg-negative HBV infection. AB - OBJECTIVES: Sphingolipids (SLs) have been implicated as potent regulators of the hepatitis B virus (HBV) life cycle. We investigated the SL biomarker potential regarding virologic endpoints in a prospective subgroup of patients with HBeAg negative chronic HBV infection. METHODS: From 2009-2016 98 patients with HBeAg negative HBV infection were prospectively followed over four years. Clinical, laboratory and imaging data were evaluated annually. SLs were assessed in available serum probes via liquid chromatography coupled to tandem mass spectrometry. RESULTS: Of those 98 patients, 10 (10.2%) showed HBV reactivation, 13 (13.2%) lost HBsAg and 9 (9.1%) gained status of HBsAg-/HBsAb-coexistence, whereas 66 (67.3%) had no events. Within the four-year analysis sphingosine (p = 0.020), sphinganine (p<0.001), dhS1P (p<0.001), C16DHC (p<0.01) and C20Cer (p<0.001) showed a significant upregulation in patients without virologic events, C18Cer significantly decreased (p<0.001). At baseline decreased S1P-, dhS1P- and C16Cer-levels were observed in patients with upcoming status of HBsAg-/HBsAb coexistence. S1P and dhS1P levels were elevated HBV genotype D infected patients. CONCLUSIONS: In a prospective cohort of patients with a HBeAg-negative HBV infection, serum SLs associated with the virologic course and HBV genotype D. Further studies are required to elucidate SLs as potential novel predictors of the course of HBeAg-negative HBV infection. PMID- 30439998 TI - Feasibility assessment of an ergonomic baby wrap for kangaroo mother care: A mixed methods study from Nepal. AB - BACKGROUND: Kangaroo mother care, an evidence based practice and a national policy for management of low birth weight newborns in Nepal, is not widely practiced. This implementation research study aimed to explore the consumer preference and acceptability of the traditional and a new ergonomic wrap on the continuation of kangaroo mother care in the facility and community following discharge. METHODS: A mixed method feasibility study was done from May to October 2015. Ninety-six families of stable low birth weight newborns weighing 1800 to 2499 grams were counseled and taught to practice kangaroo mother care using both wraps. They were randomized into two groups of 48 with one group trying out the traditional wrap for the first six hours and the new wrap for the next six, and vice versa. Mothers were allowed to choose between the wraps for continuation of kangaroo mother care at the facility and post discharge. They were followed up telephonically weekly over 28 days postpartum to ascertain practice of kangaroo mother care. In-depth interviews with mothers (n = 12) and focus group discussions with health workers (n = 16) further evaluated the intervention. Descriptive statistics are presented for the quantitative part of the study. RESULTS: Mothers in the two groups chose the new wrap with no significant difference (81.3% vs 89.6%, p = 0.24). Of the 96 randomized mothers, 85% chose the new wrap. During the hospital stay, six mothers dropped out and remaining 90 mothers who were discharged with the intention of continuing Kangaroo Mother Care, 78 and 12 mothers did so with the new and traditional wrap respectively. New wrap users (429.1 hours, 95% confidence interval [CI]: 351.7-470.3) performed skin-to-skin contact for an extra 77.4 hours overall than traditional wrap (351.7 hours, 95%CI: 259.3-444) users from first day to 28 day postpartum. Health workers and mothers reported positive experience with the new wrap as it was easy to wear without assistance, secure and flexible to move around in kangaroo mother care position. CONCLUSIONS: Involvement of mothers and families with provision of ergonomic wraps showed improvement in kangaroo mother care practice during hospital stay and at home. PMID- 30439999 TI - Can repeated in vivo micro-CT irradiation during adolescence alter bone microstructure, histomorphometry and longitudinal growth in a rodent model? AB - In vivo micro-computed tomography (micro-CT) can monitor longitudinal changes in bone mass and microstructure in small rodents but imposing high doses of radiation can damage the bone tissue. However, the effect of weekly micro-CT scanning during the adolescence on bone growth and architecture is still unknown. The right proximal tibia of male Sprague-Dawley rats randomized into three dose groups of 0.83, 1.65 and 2.47 Gy (n = 11/group) were CT scanned at weekly intervals from 4th to 12th week of age. The left tibia was used as a control and scanned only at the last time point. Bone marrow cells were investigated, bone growth rates and histomorphometric analyses were performed, and bone structural parameters were determined for both left and right tibiae. Radiation doses of 1.65 and 2.47 Gy affected bone marrow cells, heights of the proliferative and hypertrophic zones, and bone growth rates in the irradiated tibiae. For the 1.65 Gy group, irradiated tibiae resulted in lower BMD, Tb.Th, Tb.N and a higher Tb.Sp compared with the control tibiae. A decrease in BMD, BV/TV, Tb.Th, Tb.N and an increase in Tb.Sp were observed between the irradiated and control tibiae for the 2.47 Gy group. For cortical bone parameters, no effects were noticed for 1.65 and 0.83 Gy groups, but a lower Ct.Th was observed for 2.47 Gy group. Tibial bone development was adversely impacted and trabecular bone, together with bone marrow cells, were negatively affected by the 1.65 and 2.47 Gy radiation doses. Cortical bone microstructure was affected for 2.47 Gy group. However, bone development and morphometry were not affected for 0.83 Gy group. These findings can be used as a proof of concept for using the reasonable high-quality image acquisition under 0.83 Gy radiation doses during the adolescent period of rats without interfering with the bone development process. PMID- 30440000 TI - HIV cascade of care in Greece: Useful insights from additional stages. AB - BACKGROUND: Aiming to eliminate HIV infection, UNAIDS has set a global "90-90-90" target by 2020. We sought to construct a 6-stages HIV Cascade of Care (CoC) in Greece, overall and by risk group, to assess risk-group and stage-specific progress in achieving the UNAIDS target. PATIENTS AND METHODS: Combining data from the HIV/AIDS surveillance system and a population-based HIV cohort study, the CoC included: i) number of people living with HIV (PLHIV) by end of 2013; ii) proportion of PLHIV ever diagnosed; iii) proportion of diagnosed linked-to-care iv) proportion of linked-to-care ever initiating antiretroviral therapy (ART); v) proportion of treated who retained-in-care vi) proportion of those retained-in care who were virally suppressed (<=200 copies/mL) at their last visit (01/07/2012-31/12/2013). RESULTS: In 2013, 14147 PLHIV were in Greece. Overall, proportions of each stage in the cascade were: 78.4% diagnosed; 86% linked-to care; 78.5% initiated ART; 86.4% retained-in-care, and 87.1% virally suppressed. Totally, 42.6% of all PLHIV were virally suppressed. The percentage diagnosed was lower among heterosexual men and women (heterosexuals) than in MSM (men who have sex with men) or PWID (people who inject drugs). Most MSM were linked to care (97.2% of diagnosed) while a substantial proportion of PWID were not (80.8% of diagnosed). Once treated, PWID remained in care in similar proportions to MSM. Unlike PWID, a high proportion of the retained in care MSM and heterosexuals achieved viral suppression. CONCLUSIONS: At the end of 2013, we identified gaps in the HIV CoC in Greece, which differed across risk groups. Targeted interventions are critical in optimizing early diagnosis and timely linkage. A 6 stage CoC, stratified by risk group, can inform strategic public health planning in improving HIV treatment outcomes. PMID- 30440001 TI - Yeast XRS2 and human NBN gene: Experimental evidence for homology using codon optimized cDNA. AB - The genes, XRS2 in Saccharomyces cerevisiae and NBN in mammals, have little sequence identity at the amino acid level. Nevertheless, they are both found together with MRE11 and RAD50 in a highly conserved protein complex which functions in the repair of DNA double-strand breaks. Here, we have examined the evolutionary and functional relationship of these two genes by cross complementation experiments. These experiments necessitated sequence correction for specific codon usage before they could be successfully conducted. We present evidence that despite extreme sequence divergence nibrin can, at least partially, replace Xrs2 in the cellular DNA damage response, and Xrs2 is able to promote nuclear localization of MRE11 in NBS cells. We discuss that the extreme sequence divergence reflects a unique adaptive pressure during evolution related to the specific eukaryotic role for both Xrs2 and nibrin in the subcellular localisation of the DNA repair complex. This, we suggest, is of particular relevance when cells are infected by viruses. The conflict hypothesis of co-evolution of DNA repair genes and DNA viruses may thus explain the very low sequence identity of these two homologous genes. PMID- 30440002 TI - Feasibility of CT radiomics to predict treatment response of individual liver metastases in esophagogastric cancer patients. AB - In this study we investigate a CT radiomics approach to predict response to chemotherapy of individual liver metastases in patients with esophagogastric cancer (EGC). In eighteen patients with metastatic EGC treated with chemotherapy, all liver metastases were manually delineated in 3D on the pre-treatment and evaluation CT. From the pre-treatment CT scans 370 radiomics features were extracted per lesion. Random forest (RF) models were generated to discriminate partial responding (PR, >65% volume decrease, including 100% volume decrease), and complete remission (CR, only 100% volume decrease) lesions from other lesions. RF-models were build using a leave one out strategy where all lesions of a single patient were removed from the dataset and used as validation set for a model trained on the lesions of the remaining patients. This process was repeated for all patients, resulting in 18 trained models and one validation set for both the PR and CR datasets. Model performance was evaluated by receiver operating characteristics with corresponding area under the curve (AUC). In total 196 liver metastases were delineated on the pre-treatment CT, of which 99 (51%) lesions showed a decrease in size of more than 65% (PR). From the PR set a total of 47 (47% of RL, 24% of initial) lesions were no longer detected in CT scan 2 (CR). The RF-model for PR lesions showed an average training AUC of 0.79 (range: 0.74 0.83) and 0.65 (95% ci: 0.57-0.73) for the combined validation set. The RF-model for CR lesions had an average training AUC of 0.87 (range: 0.83-0.90) and 0.79 (95% ci 0.72-0.87) for the validation set. Our findings show that individual response of liver metastases varies greatly within and between patients. A CT radiomics approach shows potential in discriminating responding from non responding liver metastases based on the pre-treatment CT scan, although further validation in an independent patient cohort is needed to validate these findings. PMID- 30440003 TI - Karyotype heterogeneity in Philodendron s.l. (Araceae) revealed by chromosome mapping of rDNA loci. AB - Philodendron s.l. (Araceae) has been recently focus of taxonomic and phylogenetic studies, but karyotypic data are limited to chromosome numbers and a few published genome sizes. In this work, karyotypes of 34 species of Philodendron s.l. (29 species of Philodendron and five of Thaumatophyllum), ranging from 2n = 28 to 36 chromosomes, were analyzed by fluorescence in situ hybridization (FISH) with rDNA and telomeric probes, aiming to understand the evolution of the karyotype diversity of the group. Philodendron presented a high number variation of 35S rDNA, ranging from two to 16 sites, which were mostly in the terminal region of the short arms, with nine species presenting heteromorphisms. In the case of Thaumatophyllum species, we observed a considerably lower variation, which ranged from two to four terminal sites. The distribution of the 5S rDNA clusters was more conserved, with two sites for most species, being preferably located interstitially in the long chromosome arms. For the telomeric probe, while exclusively terminal sites were observed for P. giganteum (2n = 30) chromosomes, P. callosum (2n = 28) presented an interstitial distribution associated with satellite DNA. rDNA sites of the analyzed species of Philodendron s.l. species were randomly distributed considering the phylogenetic context, probably due to rapid evolution and great diversity of these genomes. The observed heteromorphisms suggest the accumulation of repetitive DNA in the genomes of some species and the occurrence of chromosomal rearrangements along the karyotype evolution of the group. PMID- 30440004 TI - How does it work? Factors involved in telemedicine home-interventions effectiveness: A review of reviews. AB - INTRODUCTION: Definitive evidence of the effectiveness and cost-effectiveness of telemedicine home-interventions for the management of chronic diseases is still lacking. This study examines whether and how published reviews consider and discuss the influence on outcomes of different factors, including: setting, target, and intensity of intervention; patient engagement; the perspective of patients, caregivers and health professionals; the organizational model; patient education and support. Included reviews were also assessed in terms of economic and ethical issues. METHODS: Two search algorithms were developed to scan PubMed for reviews published between 2000 and 2015, about ICT-based interventions for the management of hypertension, diabetes, heart failure, asthma, chronic obstructive pulmonary disease, or for the care of elderly patients. Based on our inclusion criteria, 25 reviews were selected for analysis. RESULTS: None of the included reviews covered all the above-mentioned factors. They mostly considered target (44%) and intervention intensity (24%). Setting, ethical issues, patient engagement, and caregiver perspective were the most neglected factors (considered in 0-4% of the reviews). Only 4 reviews (16%) considered at least 4 of the 11 factors, the maximum number of factors considered in a review is 5. CONCLUSIONS: Factors that may be involved in ICT-based interventions, affecting their effectiveness or cost-effectiveness, are not enough studied in the literature. This research suggests to consider mostly the role of each one, comparing not only disease-related outcomes, but also patients and healthcare organizations outcomes, and patient engagement, in order to understand how interventions work. PMID- 30440005 TI - The value of magnetic resonance spectroscopy as a supplement to MRI of the brain in a clinical setting. AB - BACKGROUND: There are different opinions of the clinical value of MRS of the brain. In selected materials MRS has demonstrated good results for characterisation of both neoplastic and non-neoplastic lesions. The aim of this study was to evaluate the supplemental value of MR spectroscopy (MRS) in a clinical setting. MATERIAL AND METHODS: MRI and MRS were re-evaluated in 208 cases with a clinically indicated MRS (cases with uncertain or insufficient information on MRI) and a confirmed diagnosis. Both single voxel spectroscopy (SVS) and chemical shift imaging (CSI) were performed in 105 cases, only SVS or CSI in 54 and 49 cases, respectively. Diagnoses were grouped into categories: non neoplastic disease, low-grade tumour, and high-grade tumour. The clinical value of MRS was considered very beneficial if it provided the correct category or location when MRI did not, beneficial if it ruled out suspected diseases or was more specific than MRI, inconsequential if it provided the same level of information, or misleading if it provided less or incorrect information. RESULTS: There were 70 non-neoplastic lesions, 43 low-grade tumours, and 95 high-grade tumours. For MRI, the category was correct in 130 cases (62%), indeterminate in 39 cases (19%), and incorrect in 39 cases (19%). Supplemented with MRS, 134 cases (64%) were correct, 23 cases (11%) indeterminate, and 51 (25%) incorrect. Additional information from MRS was beneficial or very beneficial in 31 cases (15%) and misleading in 36 cases (17%). CONCLUSION: In most cases MRS did not add to the diagnostic value of MRI. In selected cases, MRS may be a valuable supplement to MRI. PMID- 30440006 TI - A systematic review of historical and contemporary evidence of trachoma endemicity in the Pacific Islands. AB - INTRODUCTION: Trachoma is endemic in several Pacific Island countries. The aims of this study were to (a) identify future trachoma mapping needs in the Pacific and (b) to examine whether any temporal trends in trachoma prevalence could be ascertained from the historical literature on trachoma in the Pacific Islands. METHODS: Human studies of trachoma and eye care in the Pacific Islands were identified from a systematic search of PubMed, EMbase, Scopus and Web of Science databases. A published quality assessment system for disease prevalence studies was modified to assess studies for quality and transparency. RESULTS: Few general ophthalmic studies in the Pacific mention trachoma. In targeted studies of trachoma, cases have consistently been identified throughout the Pacific since the early twentieth century. The largest number of studies come from Papua New Guinea and Fiji, whereas some countries have no published data on trachoma. The majority of studies identified were published before the Alliance for the Global Elimination of Trachoma 2020 was convened, so lack the standardisation of population-based mapping which has been implemented in the past decade. CONCLUSIONS: Population-based trachoma prevalence estimates have been recently generated in Papua New Guinea, Solomon Islands, Vanuatu, Kiribati and Fiji. There is insufficient evidence to assess whether there has been temporal change in trachoma prevalence in these countries over the past century. Cases of trachoma have been identified in some countries (for example, Nauru and Samoa) which have no recent population-based mapping data, but may be at risk of trachoma endemcitiy. Deployment of appropriate mapping strategies is warranted to identify whether interventions are required. PMID- 30440009 TI - Prevalence of infectious diseases and its associated factors among the blood donors of the Honduran Red Cross - Northern Region between 2014 and 2016. AB - INTRODUCTION: A number of parenteral infections in third-world countries are caused by blood transfusions. Our objective was to determine the prevalence of and factors associated with infected blood obtained by the Honduran Red Cross through blood donations, to ensure the safety of the donated blood. MATERIALS AND METHODS: This study used a cross-sectional analytical design based on the secondary analysis of data. Information on blood donors from San Pedro Sula, Honduras, between 2014 and 2016 were obtained from the database of the Honduran Red Cross. Data analysis was performed in two phases. The first phase described the variables, with the values presented as frequencies and percentages for categorical variables. The second phase involved a statistical analysis using generalized linear models. RESULTS: The proportions of donors who tested positive for syphilis, core hepatitis, hepatitis B, human T-cell lymphotropic virus, human immunodeficiency virus, and hepatitis C infections were 45% (n = 447), 35% (348), 11% (105), 10% (97), 6% (59), and 3% (24), respectively. The results of multivariate analysis demonstrated that the number of women positive for HIV infection was lower than that of men (p = 0.006). Older participants were more likely to be positive for core hepatitis (p = 0.029) and syphilis (p<0.001) infection but less likely to be positive for hepatitis B (p<0.001), hepatitis C (p = 0.027), human immunodeficiency virus (p<0.001), and human T-cell lymphotropic virus (p<0.001) infection compared to younger participants. Replacement donors had an increased likelihood of positivity for core hepatitis (p = 0.003) infections but a decreased likelihood of positivity for human T-cell lymphotropic virus infection (p = 0.001). DISCUSSION: The high prevalence of infectious diseases in Honduras warrants the need for monitoring donated blood to prevent infected blood from being provided for transfusions. Furthermore, education efforts through the creation of prevention programs are necessary to educate the Honduran population, especially younger individuals, about transfusion-transmissible infections. PMID- 30440007 TI - Second malignant neoplasms after childhood cancer: A nationwide population-based study in Korea. AB - BACKGROUND: Second malignant neoplasm is one of the most devastating late effects of childhood cancers. This study aimed to evaluate the incidence and survival outcomes of patients developing second malignant neoplasms (SMNs) after surviving childhood cancer in Korea. METHODS: Medical data of childhood cancer patients diagnosed between 1993 and 2012 were obtained from the Korea Central Cancer Registry. The risk of developing SMNs was calculated using standardized incidence ratio (SIR), excess absolute risk (EAR), and cumulative risk. Kaplan-Meier survival curves were estimated, stratified by SMN status. RESULTS: A total of 28,405 childhood cancer patients were diagnosed in the study period, and 337 (1.2%) developed SMN. The total follow-up period was 197,359 person-years at risk (PYR), with a median follow-up duration of 5.6 years. Overall SIR was 20.0, which was 23.2 in women, and 17.6 in men. The overall EAR was 16.4 per 10,000 PYR. The most common types of SMNs, in order of incidence, were other malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. The cumulative incidence of developing SMNs was 0.7% at 5 years, 1.2% at 10 years, and 2% at 15 years. After primary cancer diagnosis, the 10-year overall survival rate of patients with SMNs was 65.1%, which was lower than the 73.4% in patients without SMN. After SMN diagnosis, the 10-year overall survival rate was 55.8%. CONCLUSION: Through this registry-based study of 5.6 years of follow up, childhood cancer survivors were found to be at 20-fold higher risk of developing a malignant neoplasm compared to the general population. The majority of malignant neoplasms are malignant epithelial neoplasms, leukemia, and soft tissue sarcomas. Continued surveillance for assessing long-term risks, and guidance for appropriate long-term follow up of childhood cancer survivors, are needed. PMID- 30440008 TI - Long-term effects of smallpox vaccination on expression of the HIV-1 co-receptor CCR5 in women. AB - BACKGROUND: Smallpox vaccinations were stopped globally in 1980. Recent studies have shown that in women, being smallpox vaccinated was associated with a reduced risk of HIV infection compared with not being smallpox vaccinated. At the initial infection, HIV-1 most often uses CCR5 as a co-receptor to infect the T lymphocytes. We therefore investigated whether smallpox vaccination is associated with a down-regulation of CCR5 on the surface of peripheral T-lymphocytes in healthy women in Guinea-Bissau. METHODS: We included HIV seronegative women from Bissau, Guinea-Bissau, born before 1974, with and without a smallpox vaccination scar. Blood samples were stabilised in a TransFix buffer solution and stained for flow cytometry according to a T-cell maturation profile. RESULTS: Ninety-seven women were included in the study; 52 with a smallpox vaccination scar and 45 without a scar. No association between smallpox vaccination scar and CCR5 expression was found in any T-lymphocyte subtype. CONCLUSION: Among HIV seronegative women, being smallpox vaccinated more than 40 years ago was not associated with a down-regulation of CCR5 receptors on the surface of peripheral T-lymphocytes. PMID- 30440010 TI - Psychophysiological characterization of different capoeira performances in experienced individuals: A randomized controlled trial. AB - The aim of this study was to characterize the psychophysiological demand in different capoeira performances. Eleven experienced capoeira practitioners underwent the following procedures in different days: 1) anamnesis and anthropometric measurements; 2) aerobic performance assessment; 3 to 5) performances of 90 seconds in three capoeira styles (Angola, Benguela and Sao Bento), which were performed in randomized controlled cross-over design. The psychophysiological demand was assessed through the heart rate (HR), R-R interval (RRi), blood pressure (BP), blood lactate ([Lac]), blood glucose ([Gluc]), rating perceived effort (RPE), feeling scale (FS) and perceived activation (PA). Descriptive statistics with mean and standard deviation was performed. A two-way repeated measures ANOVA with Bonferroni post-hoc test was used. The Angola demand was between 56-71% maximal HR with [Lac]PEAK: 6.9+/-2.9 mM, RPEPEAK: 10.0+/-2.2 pts and FS: 2.7+/-1.7 pts, while in the Benguela participants reached 64-85% maximal HR with [Lac]PEAK: 9.5+/-3.0 mM, RPEPEAK: 11.0+/-2.8 pts and FS: 2.1+/ 1.6 pts and for Sao Bento between 69-102% maximal HR with [Lac]PEAK: 15.7+/-2.6 mM, RPEPEAK: 15.5+/-4.1 pts and FS: -0.8+/-3.0 pts. Interaction time*performance occurred to [Lac] (F = 42.157; p<0.001), HR (F = 12.154; p<0.001), RRi (F = 4.774; p<0.001), parasympathetic modulation-rMSSD (F = 3.189; p<0.01), [Gluc] (F = 2.152; p<0.05), RPE (F = 5.855; p<0.01), FS (F = 2.448; p<0.05) and PA (F = 3.893; p<0.05). We concluded that Sao Bento rhythm resulted in a greater physiological demand according to the HR, [Lac] and cardiac autonomic indicators, with the Benguela rhythm being intermediate while the Angola rhythm presented a reduced demand. The [Gluc] increased after the Sao Bento rhythm when compared to the other rhythms. The perceptual demand presented increased in terms of RPE and PA variables and decreased in terms of FS when the Sao Bento performance was analyzed in comparison to the Angola and/or Benguela in capoeira. PMID- 30440011 TI - Generation of an inducible RPE-specific Cre transgenic-mouse line. AB - The retinal pigment epithelium (RPE) is an epithelial monolayer in the back of the vertebrate eye. RPE dysfunction is associated with retinal degeneration and blindness. In order to fully understand how dysregulation affects visual function, RPE-specific gene knockouts are indispensable. Since the currently available RPE-specific Cre recombinases show lack of specificity or poor recombination, we sought to generate an alternative. We generated a tamoxifen inducible RPE-specific Cre transgenic mouse line under transcriptional control of an RPE-specific Tyrosinase enhancer. We characterized the Cre-mediated recombinant expression by crossing our RPE-Tyrosinase-CreErT2 mouse line with the tdTomato reporter line, Ai14. Detected fluorescence was quantified via high content image analysis. Recombination was predominantly observed in the RPE and adjacent ciliary body. RPE flatmount preparations revealed a high level of recombination in adult mice (47.25-69.48%). Regional analysis of dorsal, ventral, nasal and temporal areas did not show significant changes in recombination. However, recombination was higher in the central RPE compared to the periphery. Higher levels of Cre-mediated recombinant expression was observed in embryonic RPE (~83%). Compared to other RPE-specific Cre transgenic mouse lines, this newly generated RPE-Tyrosinase-CreErT2 line shows a more uniform and higher level of recombination with the advantage to initiate recombination in both, prenatal and postnatal animals. This line can serve as a valuable tool for researches exploring the role of individual gene functions, in both developing and differentiated RPE. PMID- 30440012 TI - Very long intergenic non-coding RNA transcripts and expression profiles are associated to specific childhood acute lymphoblastic leukemia subtypes. AB - Very long intergenic non-coding RNAs (vlincRNAs) are a novel class of long transcripts (~50 kb to 1 Mb) with cell type- or cancer-specific expression. We report the discovery and characterization of 256 vlincRNAs from a cohort of 64 primary childhood pre-B and pre-T acute lymphoblastic leukemia (cALL) samples, of which 61% are novel and specifically expressed in cALL. Validation was performed in 35 pre-B and pre-T cALL primary samples. We show that their expression is cALL immunophenotype and molecular subtype-specific and correlated with epigenetic modifications on their promoters, much like protein-coding genes. While the biological functions of these vlincRNAs are still unknown, our results suggest they could play a role in cALL etiology or progression. PMID- 30440013 TI - Broad-complex Z3 contributes to the ecdysone-mediated transcriptional regulation of the vitellogenin gene in Bombus lantschouensis. AB - During reproduction, vitellogenin (Vg), as an egg yolk precursor, is critical in sexually mature females of oviparous species including some insects. The transcription of Vg is usually mediated by hormones such as juvenile hormone (JH), ecdysteroids and some neuropeptides. In this study, the structure of the Vg gene from the bumblebee Bombus lantschouensis, (BlVg) was determined by sequencing and assembly. BlVg was found to be expressed at higher levels in reproductive queens than in virgins by quantitative real-time PCR analysis. Tissue-specific expression analysis showed that BlVg was expressed at the highest levels in the fat bodies of both virgin and reproductive queens. Prediction of the BlVg promoter revealed the presence of ecdysteroid-responsive cis-regulatory elements (CREs) containing one Broad-Complex zinc-finger isoform 3 (BR-C Z3), and one ecdysone-induced protein 74A (E74A). In addition, luciferase reporter expression, driven by the 5' -regulatory region of the BlVg gene, from -1517 bp to +895 bp downstream of the start codon, was induced by treatment with 20 hydroxyecdysone (20-E). Moreover, the luciferase activity of the BlVg promoter was elevated by only BlBrC-Z3 when Sf9 cells were cotransfected with four BlBrC isoforms respectively. BlVg promoter-mediated luciferase activation was significantly reduced when the putative BrC-Z3 CRE in the promoter was mutated. In summary, this report describes the first study of vitellogenin gene regulation at the transcriptional level in bumblebees and demonstrates that the ecdysone induced transcription of the BlVg gene is mediated by the binding of BlBrC-Z3 to the BrC-Z3 CRE in the BlVg promoter in bumblebees. PMID- 30440014 TI - De novo biosynthesis of myricetin, kaempferol and quercetin in Streptomyces albus and Streptomyces coelicolor. AB - Flavonols are a flavonoid subfamily widely distributed in plants, including several ones of great importance in human and animal diet (apple, tomato, broccoli, onion, beans, tea). These polyphenolic nutraceuticals exert potent antimicrobial (membrane potential disruptors), antioxidant (free-radical scavengers), pharmacokinetic (CYP450 modulators), anti-inflammatory (lipoxygenase inhibitors), antiangiogenic (VEGF inhibitors) and antitumor (cyclin inhibitors) activities. Biotechnological production of these nutraceuticals, for example via heterologous biosynthesis in industrial actinomycetes, is favored since in plants these polyphenols appear as inactive glycosylated derivatives, in low concentrations or as part of complex mixtures with other polyphenolic compounds. In this work, we describe the de novo biosynthesis of three important flavonols, myricetin, kaempferol and quercetin, in the industrially relevant actinomycetes Streptomyces coelicolor and S. albus. De novo biosynthesis of kaempferol, myricetin and quercetin in actinomycetes has not been described before. PMID- 30440015 TI - A stochastic algorithm for accurately predicting path persistence of cells migrating in 3D matrix environments. AB - Cell mobility plays a critical role in immune response, wound healing, and the rate of cancer metastasis and tumor progression. Mobility within a three dimensional (3D) matrix environment can be characterized by the average velocity of cell migration and the persistence length of the path it follows. Computational models that aim to predict cell migration within such 3D environments need to be able predict both of these properties as a function of the various cellular and extra-cellular factors that influence the migration process. A large number of models have been developed to predict the velocity of cell migration driven by cellular protrusions in 3D environments. However, prediction of the persistence of a cell's path is a more tedious matter, as it requires simulating cells for a long time while they migrate through the model extra-cellular matrix (ECM). This can be a computationally expensive process, and only recently have there been attempts to quantify cell persistence as a function of key cellular or matrix properties. Here, we propose a new stochastic algorithm that can simulate and analyze 3D cell migration occurring over days with a computation time of minutes, opening new possibilities of testing and predicting long-term cell migration behavior as a function of a large variety of cell and matrix properties. In this model, the matrix elements are generated as needed and stochastically based on the biophysical and biochemical properties of the ECM the cell migrates through. This approach significantly reduces the computational resources required to track and calculate cell matrix interactions. Using this algorithm, we predict the effect of various cellular and matrix properties such as cell polarity, cell mechanoactivity, matrix fiber density, matrix stiffness, fiber alignment, and fiber binding site density on path persistence of cellular migration and the mean squared displacement of cells over long periods of time. PMID- 30440016 TI - The deletion of the ORF1 and ORF71 genes reduces virulence of the neuropathogenic EHV-1 strain Ab4 without compromising host immunity in horses. AB - The equine herpesvirus type 1 (EHV-1) ORF1 and ORF71 genes have immune modulatory effects in vitro. Experimental infection of horses using virus mutants with multiple deletions including ORF1 and ORF71 showed promise as vaccine candidates against EHV-1. Here, the combined effects of ORF1 and ORF71 deletions from the neuropathogenic EHV-1 strain Ab4 on clinical disease and host immune response were further explored. Three groups of EHV-1 naive horses were experimentally infected with the ORF1/71 gene deletion mutant (Ab4DeltaORF1/71), the parent Ab4 strain, or remained uninfected. In comparison to Ab4, horses infected with Ab4DeltaORF1/71 did not show the initial high fever peak characteristic of EHV-1 infection. Ab4DeltaORF1/71 infection had reduced nasal shedding (1/5 vs. 5/5) and, simultaneously, decreased intranasal interferon (IFN)-alpha, interleukin (IL)-10 and soluble CD14 secretion. However, Ab4 and Ab4DeltaORF1/71 infection resulted in comparable viremia, suggesting these genes do not regulate the infection of the mononuclear cells and subsequent viremia. Intranasal and serum anti-EHV-1 antibodies to Ab4DeltaORF1/71 developed slightly slower than those to Ab4. However, beyond day 12 post infection (d12pi) serum antibodies in both virus infected groups were similar and remained increased until the end of the study (d114pi). EHV-1 immunoglobulin (Ig) G isotype responses were dominated by short lasting IgG1 and long-lasting IgG4/7 antibodies. The IgG4/7 response closely resembled the total EHV-1 specific antibody response. Ex vivo re-stimulation of PBMC with Ab4 resulted in IFN-gamma and IL-10 secretion by cells from both infected groups within two weeks pi. Flow cytometric analysis showed that IFN gamma producing EHV-1-specific T-cells were mainly CD8+/IFN-gamma+ and detectable from d32pi on. Peripheral blood IFN-gamma+ T-cell percentages were similar in both infected groups, albeit at low frequency (~0.1%). In summary, the Ab4DeltaORF1/71 gene deletion mutant is less virulent but induced antibody responses and cellular immunity similar to the parent Ab4 strain. PMID- 30440018 TI - Association of gastric and duodenal ulcers with anthropometry and nutrients: Korean National Health and Nutrition Examination Survey (KNHANES II-IV) 2001 2009. AB - OBJECTIVES: The objective of this study was to examine the association of peptic ulcer disease (PUD), including gastric ulcer and duodenal ulcer, with obesity related indices, nutrients, and blood parameters in Korean adults. METHODS: Data were obtained from the Second-Fourth Korean National Health and Nutrition Examination Survey (KNHANES II-IV). Binary logistic regression was carried out to analyze the association between PUD and all variables in the crude analysis; in a subsequent analysis, adjustments were made for age, region, house type, number of snacks per day, and number of household members. RESULTS: PUD exhibited the highest association with age in both men and women among all variables used in this study. In men, only body mass index was associated with PUD in both the crude and adjusted analyses. PUD was associated with weight, height, and fat in the crude analysis, but these associations disappeared after adjustment for confounders. Vitamin B2, hemoglobin, and glucose were related to PUD, but these associations became nonsignificant in the adjusted analysis. Water, vitamin C, and potassium were not associated with PUD in the crude analysis but were associated with PUD after adjustment for confounders. In women, systolic blood pressure and height were associated with PUD. PUD was also related to waist circumference, the waist-to-height ratio, fat, and cholesterol, but these associations became nonsignificant after adjustment for confounders. Vitamin C, protein, niacin, sodium, energy, vitamin B2, vitamin B1, and aspartate aminotransferases were associated with PUD in only the crude analysis. PUD was not associated with diastolic blood pressure, water, vitamin A, or glucose, but these factors were associated with the disease in the adjusted analysis. CONCLUSION: Older age was a risk factor for PUD in Korean adults, and the association of PUD with most nutrients and anthropometric indices may differ according to gender. PMID- 30440017 TI - Sex-based differences in speed, sub-technique selection, and kinematic patterns during low- and high-intensity training for classical cross-country skiing. AB - OBJECTIVES: We investigated sex-based differences in speed, sub-technique selection, and kinematic patterns during low- (LIT) and high-intensity training (HIT) for classical cross-country (XC) skiing across varying terrain. METHODS: Six male and six female elite XC skiers with an approximately 15% differences in VO2max (men: 68.9+/-2.9 mL.min-1.kg-1, women: 60.1+/-3.3 mL.min-1.kg-1) were monitored using a multi-sensor system to collect time-synchronised data of heart rate, speed, and multiple tri-axial inertial measurements units while XC skiing on a 5-km competition track. RESULTS: Men skied 21% faster than women during HIT (5.9+/-0.3 m.s-1 vs. 4.9+/-0.2 m.s-1, P < .001), with the greatest difference (26%) while skiing on flat terrain, whereas skiing speed did not significantly differ between men and women during LIT. At similar instructed intensity and rating of perceived effort, women exhibited significantly higher relative heart rate (85+/-2% vs. 71+/-3% of maximum) and blood lactate levels (4.0+/-1.3 vs. 1.2+/-0.2 mmol/L) during LIT (all P < .001) than men, whereas physiological responses did generally not differ between the sexes during HIT. During both intensities and among both sexes, double poling (DP) was the sub-technique most used relative to distance, followed by miscellaneous sub-techniques (MISC), diagonal stride (DIA), kick double poling (DK) and herringbone (HRB). In relation to distance women used DIA more than men during LIT (22% vs. 17%, P = .009) and HIT (23% vs. 12%, P = .001), whereas men used MISC, including tucking and turning, more than women during LIT (39% vs. 25%, P = .017) and HIT (41% vs. 30%, P = .064). In particular, men used DP more than women while skiing the uphill sections during both LIT (24% vs. 11%, P = .015) and HIT (39% vs. 13%, P = .002). CONCLUSIONS: Our findings provide novel insights into sex-based differences in speed, sub-technique selection, and kinematic patterns during LIT and HIT for classical skiing. PMID- 30440019 TI - Gentamicin delivery to the inner ear: Does endolymphatic hydrops matter? AB - INTRODUCTION: Middle ear application of gentamicin is a common medical treatment for uncontrolled Meniere's disease. The objective of the study was to evaluate the impact of endolymphatic hydrops on inner ear delivery. METHODS: Perilymph gentamicin concentrations and correlation with endolymphatic hydrops in an animal model were assessed. A group of 24 guinea pigs was submitted to surgical obstruction of the endolymphatic sac and duct of the right ear. Gentamicin was applied either to the right ear's round window niche or through a transtympanic injection. Perilymph specimens were collected at different times. Histologic morphometry was used to evaluate both turn-specific and overall hydrops degree. RESULTS: In animals with endolymphatic hydrops, lower concentrations of gentamicin were observed after 20 or 120 minutes of exposure and in both types of administration, when compared to controls. This difference reached statistical significance in the round window niche application group (Mann-Whitney, p = 0,007). A negative correlation between perilymphatic gentamicin concentration and hydrops degree could be observed in both groups, after 120 minutes of exposure (Spearman correlation, round window niche p<0,001; TT p = 0,005). CONCLUSIONS: The study indicates that the endolymphatic hydrops degree has a negative interference on the delivery of gentamicin into the inner ear following middle ear application. PMID- 30440020 TI - Comorbidity and diagnosis distribution in transdiagnostic treatments for emotional disorders: A systematic review of randomized controlled trials. AB - The advantages of transdiagnostic protocols for emotional disorders (ED) (anxiety and depression) include the ability to treat multiple psychological disorders using the same treatment protocol, and the capacity to better address comorbidity. Comorbidity in ED has been associated with higher rates of severity, functional impairment, and chronicity. However, no attempts have been made in the literature to systematically review whether these studies include assessments to evaluate the treatment response in comorbid diagnoses, in addition to the principal diagnosis. Moreover, transdiagnostic treatments have been developed for a range of ED, but to date no study has analyzed the real distribution of diagnoses in these studies. The current study aimed to analyze: a) whether treatment response in comorbidity is evaluated in transdiagnostic treatments for ED; b) what diagnoses are targeted in transdiagnostic treatments for ED; and c) the real distribution of the diagnoses at baseline in these studies. A systematic search of the literature was conducted in PsycINFO, PubMed, EMBASE, and the Cochrane Library. Fifty-two randomized controlled trials were identified, with a total of 7007 adult participants. The results showed that, although most of the studies reported data on comorbidity at baseline, only 40% of them examined the effects of the intervention on the comorbid disorders. The most commonly targeted diagnoses in transdiagnostic protocols were panic/agoraphobia, generalized anxiety, social anxiety, and depression. Other disorders, such as obsessive compulsive disorder, posttraumatic stress disorder, and anxiety/depression not otherwise specified, were marginally included in these studies. Regarding the distribution of diagnoses at baseline, generalized anxiety, panic/agoraphobia, social anxiety, and depression were the most frequently observed, whereas depression not otherwise specified was the least represented. The results highlight the importance of assessing comorbidity in addition to the principal diagnoses in transdiagnostic treatments, in order to draw conclusions about the true potential of these interventions to improve comorbid symptoms. Implications of the current study and directions for future research are discussed. PMID- 30440022 TI - Tuberculosis among correctional facility workers: A systematic review and meta analysis. AB - INTRODUCTION: Prison inmates can transmit tuberculosis, including drug-resistant strains, to correctional facility workers and the community. In this systematic literature review, we investigated the magnitude of active and latent tuberculosis infection (LTBI) and associated risk factors among correctional facility workers. METHODS: We searched MEDLINE, EMBASE, LILACS, Cochrane CENTRAL, ISI Web of Science, CINAHL, and SCOPUS databases (January 1, 1989-December 31, 2017) for studies with the MeSH terms "prison" (and similar) AND "tuberculosis", without language restriction. We searched for gray literature in Google Scholar and conference proceedings. Stratified analyses according to tuberculosis burden were performed. RESULTS: Of the 974 titles identified, 15 (nine good, six fair quality) fulfilled the inclusion criteria (110,393 correctional facility workers; six countries; 82,668 active tuberculosis; 110,192 LTBI). Pooled LTBI prevalence and incidence rates were 26% (12-42, I2 = 99.0%) and 2% (1-3, I2 = 98.6%), respectively. LTBI prevalence reached 44% (12-79, I2 = 99.0%) in high-burden countries. Active tuberculosis was reported only in low-burden countries (incidence range, 0.61-450/10,000 correctional facility workers/year). LTBI associated risk factors included job duration, older age, country of birth, current tobacco smoking, reported contact with prisoners, and BCG vaccination. CONCLUSION: Despite the risk of bias and high heterogeneity, LTBI was found to be prevalent in correctional facility workers, mainly in high-burden countries. LTBI risk factors suggest both occupational and community exposure. Active tuberculosis occurrence in low-burden countries suggests higher vulnerability from recent infection among correctional facility workers in these countries. Systematic surveillance and infection control measures are necessary to protect these highly vulnerable workers. PMID- 30440023 TI - Changes in chemical and ultrastructural composition of ameroid constrictors following in vitro expansion. AB - OBJECTIVE: To (1) characterise the chemical and ultra-structural composition of ameroid constrictors, at a native state and during in vitro expansion and (2) determine the presence of irritant compounds at the surface or within the bulk of the constrictor. METHODS: Twelve sterile, commercially packaged ameroid constrictors (3 repeats of 3.5 mm, 5 mm, 6 mm and 7 mm internal diameter) were analysed by time-of-flight secondary ion mass spectrometry, Raman spectroscopy, attenuated total reflectance Fourier transform infrared spectroscopy and scanning electron microscopy. RESULTS: Ameroid constrictors have a composition commensurate with casein with little-to-no intra- or inter- constrictor variation. Microscopic analysis indicated that the topographical features of the constrictor surfaces were consistent between all constrictors. Following in vitro expansion there was a reproducible decrease in Ca+ ion content, little-to-no variation in secondary protein structure and morphological changes including the presence of surface aggregates present only at the inner surface of the ameroid constrictor. The potential irritant polydimethylsiloxane was found on the constrictor surface. A trace quantity of an ion fragment assigned as formaldehyde was detected; however, the extremely low level is thought highly unlikely to play a role as an inflammatory trigger clinically. DISCUSSION: There is a high degree of inter- and intra-constrictor homogeneity from different batches, and reproducible ultrastructural changes following in vitro expansion. Variations occur in both the surface chemistry and topography of the device during closure, which can potentially affect the biomaterial-host interface. Ameroid constrictor closure mechanism is likely involving calcium-mediated inter-protein interactions rather than the imbibition of water only. PMID- 30440024 TI - New perspectives in the study of the Earth's magnetic field and climate connection: The use of transfer entropy. AB - The debated question on the possible relation between the Earth's magnetic field and climate has been usually focused on direct correlations between different time series representing both systems. However, the physical mechanism able to potentially explain this connection is still an open issue. Finding hints about how this connection could work would suppose an important advance in the search of an adequate physical mechanism. Here, we propose an innovative information theoretic tool, i.e. the transfer entropy, as a good candidate for this scope because is able to determine, not simply the possible existence of a connection, but even the direction in which the link is produced. We have applied this new methodology to two real time series, the South Atlantic Anomaly (SAA) area extent at the Earth's surface (representing the geomagnetic field system) and the Global Sea Level (GSL) rise (for the climate system) for the last 300 years, to measure the possible information flow and sense between them. This connection was previously suggested considering only the long-term trend while now we study this possibility also in shorter scales. The new results seem to support this hypothesis, with more information transferred from the SAA to the GSL time series, with about 90% of confidence level. This result provides new clues on the existence of a link between the geomagnetic field and the Earth's climate in the past and on the physical mechanism involved because, thanks to the application of the transfer entropy, we have determined that the sense of the connection seems to go from the system that produces geomagnetic field to the climate system. Of course, the connection does not mean that the geomagnetic field is fully responsible for the climate changes, rather that it is an important driving component to the variations of the climate. PMID- 30440021 TI - Discovering proteins for chemoprevention and chemotherapy by curcumin in liver fluke infection-induced bile duct cancer. AB - Modulation or prevention of protein changes during the cholangiocarcinoma (CCA) process induced by Opisthorchis viverrini (Ov) infection may become a key strategy for prevention and treatment of CCA. Monitoring of such changes could lead to discovery of protein targets for CCA treatment. Curcumin exerts anti inflammatory and anti-CCA activities partly through its protein-modulatory ability. To support the potential use of curcumin and to discover novel target molecules for CCA treatment, we used a quantitative proteomic approach to investigate the effects of curcumin on protein changes in an Ov-induced CCA harboring hamster model. Isobaric labelling and tandem mass spectrometry were used to compare the protein expression profiles of liver tissues from CCA hamsters with or without curcumin dietary supplementation. Among the dysregulated proteins, five were upregulated in liver tissues of CCA hamsters but markedly downregulated in the CCA hamsters supplemented with curcumin: S100A6, lumican, plastin-2, 14-3-3 zeta/delta and vimentin. Western blot and immunohistochemical analyses also showed similar expression patterns of these proteins in liver tissues of hamsters in the CCA and CCA + curcumin groups. Proteins such as clusterin and S100A10, involved in the NF-kappaB signaling pathway, an important signaling cascade involved in CCA genesis, were also upregulated in CCA hamsters and were then suppressed by curcumin treatment. Taken together, our results demonstrate the important changes in the proteome during the genesis of O. viverrini-induced CCA and provide an insight into the possible protein targets for prevention and treatment of this cancer. PMID- 30440025 TI - Origins of truncated supplementary capsid proteins in rAAV8 vectors produced with the baculovirus system. AB - The ability to produce large quantities of recombinant Adeno-Associated Virus (rAAV) vectors is an important factor for the development of gene therapy-based medicine. The baculovirus/insect cell expression system is one of the major systems for large scale rAAV production. So far, most technological developments concerned the optimization of the AAV rep and cap genes in order to be expressed correctly in a heterologous system. However, the effect of the baculovirus infection on the production of rAAV has not been examined in detail. In this study we show that the baculoviral cathepsin (v-CATH) protease is active on several (but not all) rAAV serotypes, leading to a partial degradation of VP1/VP2 proteins. Subsequently, we identified the principal v-CATH cleavage site in the rAAV8 capsid proteins and demonstrated that the cleavage is highly specific. The proteolytic degradation of VP1/VP2 AAV capsid proteins reduces the infectivity of rAAV vectors but can be prevented by the use of a baculovirus vector with a deletion of the chiA/v-cath locus or by addition of the E64 protease inhibitor during production. Moreover, the codon optimization of AAV cap performed for several serotypes and originally aimed at the removal of potential alternative initiation codons, resulted in incorporation of additional forms of truncated VP1 into the rAAV capsids. PMID- 30440026 TI - Prevalence of gastrointestinal parasites in bonnet macaque and possible consequences of their unmanaged relocations. AB - Relocation is one of the mitigating measures taken by either local people or related officers to reduce the human-bonnet macaque Macaca radiata conflict in India. The review on relocations of primates in India indicates that monkeys are unscreened for diseases or gastrointestinal parasites (henceforth endoparasites) before relocation. We collected 161 spatial samples from 20 groups of bonnet macaque across their distribution range in south India and 205 temporal samples from a group in Chiksuli in the central Western Ghats. The isolation of endoparasite eggs/cysts from the fecal samples was by the centrifugation flotation and sedimentation method. All the sampled groups, except one, had an infection of at least one endoparasite taxa, and a total of 21 endoparasite taxon were recorded. The number of helminth taxon (16) were more than protozoan (5), further, among helminths, nematodes (11) were more common than cestodes (5). Although the prevalence of Ascaris sp. (26.0%), Strongyloides sp. (13.0%), and Coccidia sp. (13.0%) were greater, the load of Entamoeba coli, Giardia sp., Dipylidium caninum and Diphyllobothrium sp. were very high. Distant groups had more similarity in composition of endoparasites taxon than closely located groups. Among all the variables, the degree of provisioning was the topmost determinant factor for the endoparasite taxon richness and their load. Temporal sampling indicates that the endoparasite infection remains continuous throughout the year. Monthly rainfall and average maximum temperature in the month did not influence the endoparasite richness. A total of 17 taxon of helminths and four taxon of protozoan were recorded. The prevalence of Oesophagostomum sp., and Strongyloides sp., and mean egg load of Spirurids and Trichuris sp. was higher than other endoparasite taxon. The overall endoparasite load and helminth load was higher in immatures than adults, where, adult females had the highest protozoan load in the monsoon. The findings indicate that relocation of commensal bonnet macaque to wild habitat can possible to lead transmission of novel endoparasites that can affect their population. Thus, we suggest avoidance of such relocations, however, if inevitable the captured animals need to be screened and treated for diseases and endoparasites before relocations. PMID- 30440027 TI - Correction: Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis. AB - [This corrects the article DOI: 10.1371/journal.pone.0205928.]. PMID- 30440028 TI - Correction: Meta-analysis of postoperative adjuvant therapy for small bowel adenocarcinoma. AB - [This corrects the article DOI: 10.1371/journal.pone.0200204.]. PMID- 30440030 TI - Correction: Wild-Type Mouse Models to Screen Antisense Oligonucleotides for Exon Skipping Efficacy in Duchenne Muscular Dystrophy. AB - [This corrects the article DOI: 10.1371/journal.pone.0111079.]. PMID- 30440031 TI - The pathways between female garment workers' experience of violence and development of depressive symptoms. AB - BACKGROUND: The prevalence of intimate partner violence (IPV) is high (54%) in Bangladesh. Moreover, female garment workers report higher rates of IPV and are also vulnerable to workplace violence (WPV). Experience of violence puts women at increased risk of developing depressive symptoms, which are related with low self esteem, lower life satisfaction and lower productivity. To our knowledge, there has been no previous research on depression among female garment workers and its connections to IPV and WPV in Bangladesh. This paper aims to address this gap by studying the relationship of IPV, WPV and depression among female garment workers. METHODS: The data for this paper comes from a cross-sectional survey of female garment workers (n = 800) conducted as baseline survey of a quasi experimental study known as HERrespect. Survey data were collected during September-December, 2016 among randomly selected female garment workers from eight garment factories in and around Dhaka city. Structural equation modelling was conducted to explore the relationship among IPV, WPV and depression. RESULTS: The findings show high rates of any IPV (69%); WPV (73%, experienced or witnessed) and depressive symptomatology (40%) among female garment workers. The analysis of pathways shows that IPV impacts a woman's experience of WPV and work related stress leading to the development of depression; while WPV had direct and mediated pathways to depression. Experience of controlling by their husband leads to WPV and increased work related stress, and thus leads to depression. It also reveals that a worker's ability to mobilize resources in emergency, however, increased self-esteem and reduced work related stress. CONCLUSION: This study shows the pathways through which experience of IPV and WPV lead to development of depressive symptoms among female garment workers. The link between women's ability to mobilize resources with self-esteem and work related stress indicates the need for socio-economic empowerment of women and may suggest that combined intervention to address IPV and women's empowerment could be successful in dealing with WPV and mental health. PMID- 30440032 TI - Infection of anopheline mosquitoes with Wolbachia: Implications for malaria control. PMID- 30440029 TI - Evaluation of mechanisms that may generate DNA lesions triggering antigenic variation in African trypanosomes. AB - Antigenic variation by variant surface glycoprotein (VSG) coat switching in African trypanosomes is one of the most elaborate immune evasion strategies found among pathogens. Changes in the identity of the transcribed VSG gene, which is always flanked by 70-bp and telomeric repeats, can be achieved either by transcriptional or DNA recombination mechanisms. The major route of VSG switching is DNA recombination, which occurs in the bloodstream VSG expression site (ES), a multigenic site transcribed by RNA polymerase I. Recombinogenic VSG switching is frequently catalyzed by homologous recombination (HR), a reaction normally triggered by DNA breaks. However, a clear understanding of how such breaks arise including whether there is a dedicated and ES-focused mechanism-is lacking. Here, we synthesize data emerging from recent studies that have proposed a range of mechanisms that could generate these breaks: action of a nuclease or nucleases; repetitive DNA, most notably the 70-bp repeats, providing an intra-ES source of instability; DNA breaks derived from the VSG-adjacent telomere; DNA breaks arising from high transcription levels at the active ES; and DNA lesions arising from replication-transcription conflicts in the ES. We discuss the evidence that underpins these switch-initiation models and consider what features and mechanisms might be shared or might allow the models to be tested further. Evaluation of all these models highlights that we still have much to learn about the earliest acting step in VSG switching, which may have the greatest potential for therapeutic intervention in order to undermine the key reaction used by trypanosomes for their survival and propagation in the mammalian host. PMID- 30440033 TI - A scoring strategy for progression risk and rates of treatment completion in subjects with latent tuberculosis. AB - It is unknown whether patients with LTBI at high vs. low risk of developing active TB are currently adequately identified and treated in the US. In this study our objective was 1) To retrospectively apply the online calculator (tstin3d.com) to determine the probability of having LTBI and assign cumulative risk of progression. 2) Measure treatment outcomes in subjects with Low: 0-<10%, Intermediate: 10-<50% and High: 50-100% cumulative risk. We performed medical record review of tuberculin skin test and/or Interferon-gamma release assay (IGRAs) positive patients with LTBI seen from 2010-2015. Of 125 subjects included, 51(41%), 46 (37%) and 28 (22%) subjects were in Low, Intermediate and High risk groups respectively. Tstin3d.com was useful in determining the probability of LTBI in tuberculin skin test positive US-born subjects. Overall treatment completion rate was 61% in 114 subjects with complete treatment information and similar completion rates were seen in the three groups (Low-60%, Intermediate-63% and High-57%). Provider assessment of important clinical risk factors was often incomplete. Logistic regression analysis showed no association of assessment of important risk factors with treatment completion. The major limitations of the calculator are the lack of an updated data on country-specific prevalence of TB disease as the global burden of TB continues to decrease as well as falsely high positive predictive values that due to "transiently" positive IGRA results in subjects from countries with low prevalence. Nonetheless, our findings suggest that tstin3d.com could be utilized in the US setting for improving providing awareness of risk stratification of patients with LTBI for short course treatment regimens based on risk. PMID- 30440035 TI - Correction: The cost-effectiveness of systematic screening for age-related macular degeneration in South Korea. AB - [This corrects the article DOI: 10.1371/journal.pone.0206690.]. PMID- 30440034 TI - Clathrin adaptor GGA1 modulates myogenesis of C2C12 myoblasts. AB - During myogenesis, myogenic stem cells undergo several sequential events, including cell division, migration, and cell-cell fusion, leading to the formation of multinuclear myotubes, which are the precursors of myofibers. To understand the molecular mechanisms underlying these complex processes, an RNA interference-based gene depletion approach was used. Golgi associated, gamma adaptin ear containing, ARF binding protein 1 (GGA1), a Golgi-resident monomeric clathrin adaptor, was found to be required for the process of myotube formation in C2C12 cells, a cultured murine myoblast cell line. Gga1 mRNA expression was upregulated during myogenesis, and Gga1 depletion prevented the formation of large multi-nucleated myotubes. Moreover, inhibition of lysosomal proteases in Gga1 knockdown myoblasts increased the amount of insulin receptor, suggesting that GGA1 is involved in the cell surface expression and sorting of the insulin receptor. These results suggested that GGA1 plays a significant role in the formation and maturation of myotubes by targeting the insulin receptor to the cell surface to establish functionally mature myofibers. PMID- 30440037 TI - Biocontrol of Sirex noctilio by the parasitic nematode Deladenus siricidicola: A five season field study in southern Chile. AB - In 2001, the woodwasp Sirex noctilio was detected in Pinus radiata plantations in the Biobio region of southern Chile. Subsequently, an intense biological control program using the female sterilizing nematode Deladenus siricidicola was implemented in 2010. During five seasons between 2012 and 2017, we studied the parasitism of D. siricidicola nematode and its effect on woodwasp populations and infestation of P. radiata in different locations within the Biobio region. Parasitism was assessed by dissecting adult females of S. noctilio obtained from infested P. radiata logs. The total population of S. noctilio was determined by the emergence of individuals from the same logs. The level of damage caused by the S. noctilio pest was determined by establishing plots in stands of P. radiata at an intensity of 1 plot every 5 ha-1. During the study period, parasitism of S. noctilio by the nematode D. siricidicola increased from 29.6% in 2012 to 93.1% in 2016, while pest population decreased 3.4% in the same time period. Infestation increased from 0.3 to 11,6% of trees between 2012 and 2015, but subsequently decreased to 5.9% by 2017. We confirmed establishment of the nematode in the region under study and its natural dispersion to non-inoculated areas. Finally, we determined that the effect of inoculation age (antiquity) on parasitism levels reached 90% after three years of inoculation. PMID- 30440036 TI - Cytokine-induced cysteine- serine-rich nuclear protein-1 (CSRNP1) selectively contributes to MMP1 expression in human chondrocytes. AB - Irreversible cartilage collagen breakdown by the collagenolytic matrix metalloproteinases (MMPs)-1 and MMP-13 represents a key event in pathologies associated with tissue destruction such as arthritis. Inflammation is closely associated with such pathology and occurs in both rheumatoid and osteoarthritis making it highly relevant to the prevailing tissue damage that characterises these diseases. The inflammation-induced activating protein-1 (AP-1) transcription factor is an important regulator of both MMP1 and MMP13 genes with interplay between signalling pathways contributing to their expression. Here, we have examined the regulation of MMP1 expression, and using in vivo chromatin immunoprecipitation analyses we have demonstrated that cFos bound to the AP-1 cis element within the proximal MMP1 promoter only when the gene was transcriptionally silent as previously observed for MMP13. Subsequent small interfering RNA-mediated silencing confirmed however, that cFos significantly contributes to MMP1 expression. In contrast, silencing of ATF3 (a prime MMP13 modulator) did not affect MMP1 expression whilst silencing of the Wnt-associated regulator cysteine- serine-rich nuclear protein-1 (CSRNP1) resulted in substantial repression of MMP1 but not MMP13. Furthermore, following an early transient peak in expression of CSRNP1 at the mRNA and protein levels similar to that seen for cFOS, CSRNP1 expression subsequently persisted unlike cFOS. Finally, DNA binding assays indicated that the binding of CSRNP1 to the AP-1 consensus-like sequences within the proximal promoter regions of MMP1 and MMP13 was preferentially selective for MMP1 whilst activating transcription factor 3 (ATF3) binding was exclusive to MMP13. These data further extend our understanding of the previously reported differential regulation of these MMP genes, and strongly indicate that although cFos modulates the expression of MMP1/13, downstream factors such as CSRNP1 and ATF3 ultimately serve as transcriptional regulators in the context of an inflammatory stimulus for these potent collagenolytic MMPs. PMID- 30440038 TI - Age-related changes in the sense of body ownership: New insights from the rubber hand illusion. AB - How do age-related changes affect the sense of body ownership? This study tackles this issue by means of the rubber hand illusion (RHI), a widely used experimental tool for investigating the sense of body ownership. There is ample literature on the RHI in young populations, but research on age-related changes in the RHI is still scarce. Here we extend the use of the RHI to examine the changes in the sense of body ownership related to healthy aging. Subjective reports (i.e., questionnaire) and proprioceptive drift were compared among young (n = 22, age range 20-22 years), middle-aged (n = 22, age range 44-55 years), and older adults (n = 22, age range 60-72 years). A stronger subjective experience of illusion was observed in the young and older adults as compared to the middle-aged. No differences in proprioceptive drift were found between the three groups. These findings are discussed in relation to: 1) different stages of development of perceptual and cognitive components of the sense of body ownership, and 2) compensatory mechanisms. PMID- 30440039 TI - Genome-wide analysis of the soybean CRK-family and transcriptional regulation by biotic stress signals triggering plant immunity. AB - Cysteine-rich receptor-like kinases (CRKs) are transmembrane proteins that exhibit ectodomains containing the domain of unknown function 26 (DUF26). The CRKs form a large subfamily of receptor-like kinases in plants, and their possible functions remain to be elucidated. Several lines of evidence suggest that CRKs play important roles in plant defense responses to environmental stress, including plant immunity. We performed a genome-wide analysis of CRK encoding genes in soybean (Glycine max). We found 91 GmCRKs distributed in 16 chromosomes, and identified several tandem and segmental duplications, which influenced the expansion of this gene family. According to our phylogenetic analysis, GmCRKs are grouped in four clades. Furthermore, 12% of the members exhibited GmCRKs with a duplicated bi-modular organization of the ectodomains, containing four DUF26 domains. Expression analysis of GmCRKs was performed by exploring publicly available databases, and by RT-qPCR analysis of selected genes in soybean leaves responding to biotic stress signals. GmCRKs exhibited diverse expression patterns in leaves, stems, roots, and other tissues. Some of them were highly expressed in only one type of tissue, suggesting predominant roles in specific tissues. Furthermore, several GmCRKs were induced with PAMPs, DAMPs and the pathogens Phakopsora pachyrhizi and Phytophthora sojae. Expression profiles of several GmCRKs encoding highly similar proteins exhibited antagonist modes of regulation. The results suggest a fine-tuning control of GmCRKs transcriptional regulation in response to external stimuli, including PAMPs and DAMPs. This study offers a comprehensive view of the GmCRKs family in soybean, and provides a foundation for evolutionary and functional analysis of this family of plant proteins involved in the perception of pathogens and activation of plant immunity. PMID- 30440040 TI - Living a burdensome and demanding life: A qualitative systematic review of the patients experiences of peripheral arterial disease. AB - BACKGROUND: Peripheral arterial disease (PAD) has a significant negative impact on the quality of life of individuals. Understanding the experiences of people living with PAD will be useful in developing comprehensive patient-centred secondary prevention therapies for this population. AIM: The aim of this study is to identify first-hand accounts of patients' experiences of living with PAD. METHODS: Six databases (CINALH, PsyclNFO, MEDLINE, AMED, EMBASE, Social citation index/Science citation index via Web of Science (WOS)) and reference lists of identified studies were searched until September 2017 (updated February 2018). Qualitative studies reporting patients' account of living with PAD were eligible for inclusion. A framework thematic synthesis was implemented. RESULTS: Fourteen studies with 360 participants were included. Pain and walking limitation were recurrent among the varied symptom descriptions. Patients' ignorance and trivialisation of symptoms contributed to delays in diagnosis. Inadequate engagement in disease understanding and treatment decisions meant patients had poor attitudes towards walking treatments and unrealistic expectations about surgery. Depending on symptom progression, patients battle with walking impairment, powerlessness, and loss of independence which were a source of burden to them. Lack of disease understanding is central through patients' journey with PAD and, although they subsequently began adaptation to long term living with PAD, many worried about their future. CONCLUSIONS: Disease understanding is vital across the illness trajectory in patients with PAD. Although certain experiences are common throughout patient journey, some might be unique to a particular stage (e.g. unrealistic expectation about surgery, or rationale of walking in spite of pain in a supervised exercise program). Given that PAD is an overarching construct ranging from the mildest form of intermittent claudication to severe critical limb ischemia with ulceration and gangrene, consideration of important patient constructs specific to each stage of the disease may enhance treatment success. Systematic review registration CRD42017070417. PMID- 30440041 TI - Genetic diversity of symbiotic bacteria nodulating common bean (Phaseolus vulgaris) in western Kenya. AB - Biological nitrogen fixation (BNF) in legumes plays a critical role in improving soil fertility. Despite this vital role, there is limited information on the genetic diversity and BNF of bacteria nodulating common bean (Phaseolus vulgaris L.). This study evaluated the genetic diversity and symbiotic nitrogen fixation of bacteria nodulating common bean in soils of Western Kenya. The genetic diversity was determined using 16S rRNA gene partial sequences while BNF was estimated in a greenhouse experiment. The sequences of the native isolates were closely affiliated with members from the genera Pantoea, Klebsiella, Rhizobium, Enterobacter and Bacillus. These results show that apart from rhizobia, there are non-rhizobial strains in the nodules of common bean. The symbiotic efficiency (SE) of native isolates varied and exhibited comparable or superior BNF compared to the local commercial inoculants (CIAT 899 and Strain 446). Isolates (MMUST 003 [KP027691], MMUST 004 [KP027687], MMUST 005 [KP027688], KSM 001 [KP027682], KSM 002 [KP027680], KSM 003 [KP027683] and KSM 005 [KP027685]) recorded equal or significantly higher SE (p < 0.05) compared to N supplemented treatments. The results demonstrate the presence of genetic diversity of native bacteria nodulating bean that are effective in N fixation. These elite bacterial strains should be exploited as candidates for the development of Phaseolus vulgaris inoculants. PMID- 30440042 TI - Motor system recruitment during action observation: No correlation between mu rhythm desynchronization and corticospinal excitability. AB - Observing others' actions desynchronizes electroencephalographic (EEG) rhythms and modulates corticospinal excitability as assessed by transcranial magnetic stimulation (TMS). However, it remains unclear if these measures reflect similar neurofunctional mechanisms at the individual level. In the present study, a within-subject experiment was designed to assess these two neurophysiological indexes and to quantify their mutual correlation. Participants observed reach-to grasp actions directed towards a small (precision grip) or a large object (power grip). We focused on two specific time points for both EEG and TMS. The first time point (t1) coincided with the maximum hand aperture, i.e. the moment at which a significant modulation of corticospinal excitability is expected. The second (t2), coincided with the EEG resynchronization occurring at the end of the action, i.e. the moment at which a hypothetic minimum for action observation effect is expected. Results showed a Mu rhythm bilateral desynchronization at t1 with differential resynchronization at t2 in the two hemispheres. Beta rhythm was more desynchronized in the left hemisphere at both time points. These EEG differences, however, were not influenced by grip type. Conversely, motor potentials evoked by TMS in an intrinsic hand muscle revealed an interaction effect of grip and time. No significant correlations between Mu/Beta rhythms and motor evoked potentials were found. These findings are discussed considering the spatial and temporal resolution of the two investigated techniques and argue over two alternative explanations: i. each technique provides different measures of the same process or ii. they describe complementary features of the action observation network in humans. PMID- 30440044 TI - Correction: Summer habitat use and activity patterns of wild boar Sus scrofa in rangelands of central Argentina. AB - [This corrects the article DOI: 10.1371/journal.pone.0206513.]. PMID- 30440045 TI - Correction: Prognosis for ocular toxocariasis according to granuloma location. AB - [This corrects the article DOI: 10.1371/journal.pone.0202904.]. PMID- 30440043 TI - Gut and blood differ in constitutive blocks to HIV transcription, suggesting tissue-specific differences in the mechanisms that govern HIV latency. AB - Latently-infected CD4+ T cells are widely considered to be the major barrier to a cure for HIV. Much of our understanding of HIV latency comes from latency models and blood cells, but most HIV-infected cells reside in lymphoid tissues such as the gut. We hypothesized that tissue-specific environments may impact the mechanisms that govern HIV expression. To assess the degree to which different mechanisms inhibit HIV transcription in the gut and blood, we quantified HIV transcripts suggestive of transcriptional interference (U3-U5; "Read-through"), initiation (TAR), 5' elongation (R-U5-pre-Gag; "Long LTR"), distal transcription (Nef), completion (U3-polyA; "PolyA"), and multiple splicing (Tat-Rev) in matched peripheral blood mononuclear cells (PBMCs) and rectal biopsies, and matched FACS sorted CD4+ T cells from blood and rectum, from two cohorts of ART-suppressed individuals. Like the PBMCs, rectal biopsies showed low levels of read-through transcripts (median = 23 copies/106 cells) and a gradient of total (679)>elongated(75)>Nef(16)>polyadenylated (11)>multiply-spliced HIV RNAs(<1) [p<0.05 for all], demonstrating blocks to HIV transcriptional elongation, completion, and splicing. Rectal CD4+ T cells showed a similar gradient of total>polyadenylated>multiply-spliced transcripts, but the ratio of total to elongated transcripts was 6-fold lower than in blood CD4+ T cells (P = 0.016), suggesting less of a block to HIV transcriptional elongation in rectal CD4+ T cells. Levels of total transcripts per provirus were significantly lower in rectal biopsies compared to PBMCs (median 3.5 vs. 15.4; P = 0.008) and in sorted CD4+ T cells from rectum compared to blood (median 2.7 vs. 31.8; P = 0.016). The lower levels of HIV transcriptional initiation and of most HIV transcripts per provirus in the rectum suggest that this site may be enriched for latently infected cells, cells in which latency is maintained by different mechanisms, or cells in a "deeper" state of latency. These are important considerations for designing therapies that aim to disrupt HIV latency in all tissue compartments. PMID- 30440046 TI - An aromatic amino acid and associated helix in the C-terminus of the potato leafroll virus minor capsid protein regulate systemic infection and symptom expression. AB - The C-terminal region of the minor structural protein of potato leafroll virus (PLRV), known as the readthrough protein (RTP), is involved in efficient virus movement, tissue tropism and symptom development. Analysis of numerous C-terminal deletions identified a five-amino acid motif that is required for RTP function. A PLRV mutant expressing RTP with these five amino acids deleted (Delta5aa-RTP) was compromised in systemic infection and symptom expression. Although the Delta5aa RTP mutant was able to move long distance, limited infection foci were observed in systemically infected leaves suggesting that these five amino acids regulate virus phloem loading in the inoculated leaves and/or unloading into the systemically infected tissues. The 5aa deletion did not alter the efficiency of RTP translation, nor impair RTP self-interaction or its interaction with P17, the virus movement protein. However, the deletion did alter the subcellular localization of RTP. When co-expressed with a PLRV infectious clone, a GFP tagged wild-type RTP was localized to discontinuous punctate spots along the cell periphery and was associated with plasmodesmata, although localization was dependent upon the developmental stage of the plant tissue. In contrast, the Delta5aa-RTP-GFP aggregated in the cytoplasm. Structural modeling indicated that the 5aa deletion would be expected to perturb an alpha-helix motif. Two of 30 plants infected with Delta5aa-RTP developed a wild-type virus infection phenotype ten weeks post-inoculation. Analysis of the virus population in these plants by deep sequencing identified a duplication of sequences adjacent to the deletion that were predicted to restore the alpha-helix motif. The subcellular distribution of the RTP is regulated by the 5-aa motif which is under strong selection pressure and in turn contributes to the efficient long distance movement of the virus and the induction of systemic symptoms. PMID- 30440047 TI - A stochastic simulation model to study respondent-driven recruitment. AB - Respondent-driven detection is a chain recruitment method used to sample contact persons of infected persons in order to enhance case finding. It starts with initial individuals, so-called seeds, who are invited for participation. Afterwards, seeds receive a fixed number of coupons to invite individuals with whom they had contact during a specific time period. Recruitees are then asked to do the same, resulting in successive waves of contact persons who are connected in one recruitment tree. However, often the majority of participants fail to invite others, or invitees do not accept an invitation, and recruitment stops after several waves. A mathematical model can help to analyse how various factors influence peer recruitment and to understand under which circumstances sustainable recruitment is possible. We implemented a stochastic simulation model, where parameters were suggested by empirical data from an online survey, to determine the thresholds for obtaining large recruitment trees and the number of waves needed to reach a steady state in the sample composition for individual characteristics. We also examined the relationship between mean and variance of the number of invitations sent out by participants and the probability of obtaining a large recruitment tree. Our main finding is that a situation where participants send out any number of coupons between one and the maximum number is more effective in reaching large recruitment trees, compared to a situation where the majority of participants does not send out any invitations and a smaller group sends out the maximum number of invitations. The presented model is a helpful tool that can assist public health professionals in preparing research and contact tracing using online respondent-driven detection. In particular, it can provide information on the required minimum number of successfully sent invitations to reach large recruitment trees, a certain sample composition or certain number of waves. PMID- 30440048 TI - Impact of meropenem on Klebsiella pneumoniae metabolism. AB - The aim of this study was to analyze the metabolome of several Klebsiella pneumoniae strains characterized by different resistance patterns. A total of 59 bacterial strains (27 carbapenemase-negative and 32 carbapenemase-positive) were included and their metabolic features were assessed in basal conditions. Moreover, 8 isolates (4 wild-type and 4 KPC-producers) were randomly selected to evaluate the impact of sub-lethal concentrations of meropenem on bacterial metabolism. The metabolomic analysis was performed by 1H-NMR spectroscopy both on filtered supernatants and cell lysates. A total of 40 and 20 molecules were quantified in the intracellular and the extracellular metabolome, respectively. While in basal conditions only five metabolites showed significant differences between carbapenemase-positive and negative strains, the use of meropenem had a profound impact on the whole bacterial metabolism. In the intracellular compartment, a reduction of different overflow metabolites and organic acids (e.g. formate, acetate, isobutyrate) was noticed, whereas, in the extracellular metabolome, the levels of several organic acids (e.g. succinate, acetate, formate, lactate) and amino acids (aspartate, threonine, lysine, alanine) were modified by meropenem stimulation. Interestingly, carbapenemase-positive and negative strains reacted differently to meropenem in terms of number and type of perturbed metabolites. In wild-type strains, meropenem had great impact on the metabolic pathways related to methane metabolism and alanine, aspartate and glutamate metabolism, whereas in KPC-producers the effect was predominant on pyruvate metabolism. The knowledge about the bacterial metabolic profiles could help to set up innovative diagnostic methods and new antimicrobial strategies to fight the global crisis against carbapenemase-positive K. pneumoniae. PMID- 30440049 TI - Ibrutinib and Rituximab in Waldenstrom's Macroglobulinemia. PMID- 30440050 TI - Topographic distribution of choriocapillaris flow deficits in healthy eyes. AB - PURPOSE: To evaluate the topographic distribution of the choriocapillaris (CC) flow deficits in a population of healthy subjects. METHODS: Using a swept-source optical-coherence tomography angiography (SS-OCTA) device, two repeated volume 6 x 6 mm and 3 x 3 mm scans were acquired in healthy subjects at the Doheny-UCLA Eye Centers. The en-face CC angiogram was binarized and analyzed for percentage of flow deficits (FD%) using a grid of progressive, concentric rings covering a circular area with a diameter of 2.5 mm (in the 3 x 3 mm scans) and 5 mm (in the 6 x 6 mm scans). The FD% for each ring was plotted against the distance from the fovea. The linear trendline of the resulting curve was analyzed and the slope (m) and intercept (q) were computed. RESULTS: Seventy-five eyes of 75 subjects were enrolled and divided into three subgroups based on age (year ranges: 21-40, 41-60 and 61-80). For the entire cohort and within each subgroup, there was a significant association between distance from the fovea and FD% in both 3X3 mm and 6X6 mm scans, with flow deficits increasing with closer proximity to the foveal center. Age was a significant predictor for both m and q for both scan patterns, with older subjects showing a steeper slope. CONCLUSIONS: In SS-OCTA images, the topographic distribution of CC flow deficits varies with distance from the fovea and age. In particular, the FD% tends to decrease from the fovea towards the periphery, with a steeper decline with advancing age. These normal trends may need to be accounted for in future studies of the CC in disease. PMID- 30440051 TI - CRB3 and the FERM protein EPB41L4B regulate proliferation of mammary epithelial cells through the release of amphiregulin. AB - Numerous observations have suggested a connection between the maintenance of cell polarity and control of cell proliferation; however, the mechanisms underlying these connections remain poorly understood. Here we found that ectopic expression of CRB3, which was previously shown to restore tight junctions and membrane polarity in MCF-10A cells, induced a hyperproliferative phenotype, with significantly enlarged acini in basement membrane culture, similar to structures induced by expression of proliferative oncogenes such as cyclinD1. We found that CRB3-induced proliferation is epidermal growth factor (EGF)-independent and occurs through a mechanism that involves secretion of the EGF-family ligand, amphiregulin (AREG). The increase in AREG secretion is associated with an increase in the number and size of both early and late endosomes. Both the proliferative and endocytic phenotypes associated with CRB3 expression require the FERM-binding domain (FBD) but not the PDZ-binding domain of CRB3, arguing that this proliferative phenotype is independent of the PDZ-dependent polarity signaling by CRB3. We identified the FBD-containing protein, EPB41L4B, as an essential mediator of CRB3-driven proliferation and observed that the CRB3 dependent changes in endocytic trafficking were also dependent on EPB41L4B. Taken together, these data reveal a previously uncharacterized role for CRB3 in regulating proliferation in mammalian cells that is associated with changes in the endocytic trafficking machinery. PMID- 30440052 TI - Clinical decisions and stigmatizing attitudes towards mental health problems in primary care physicians from Latin American countries. AB - OBJECTIVE: The aim of this paper is to investigate how doctors working in primary health care in Latin American address patients with common mental disorders and to investigate how stigma can affect their clinical decisions. METHODS: Using a cross-sectional design, we applied an online self-administered questionnaire to a sample of 550 Primary Care Physicians (PCPs) from Bolivia, Brazil, Cuba and Chile. The questionnaire collected information about sociodemographic variables, training and experience with mental health care. Clinicians' stigmatizing attitudes towards mental health were measured using the Mental Illness Clinicians' Attitudes Scale (MICA v4). The clinical decisions of PCPs were assessed through three clinical vignettes representing typical cases of depression, anxiety and somatization. RESULTS: A total of 387 professionals completed the questionnaires (70.3% response rate). The 63.7% of the PCPs felt qualified to diagnose and treat people with common mental disorders. More than 90% of the PCPs from Bolivia, Cuba and Chile agreed to treat the patients presented in the three vignettes. We did not find significant differences between the four countries in the scores of the MICA v4 stigma levels, with a mean = 36.3 and SD = 8.3 for all four countries. Gender (p = .672), age (p = .171), training (p = .673) and years of experience (p = .28) were unrelated to stigma. In the two multivariate regression models, PCPs with high levels of stigma were more likely to refer them to a psychiatrist the patients with depression (OR = 1.03, 95% CI, 0.99 to 1.07 p<0.05) and somatoform symptoms somatoform (OR = 1.03, 95% CI, 1.00 to 1.07, p<0.05) to a psychiatrist. DISCUSSION: The majority of PCPs in the four countries were inclined to treat patients with depression, anxiety and somatoform symptoms. PCPs with more levels of stigma were more likely to refer the patients with depression and somatoform symptoms to a psychiatrist. Stigmatizing attitudes towards mental disorders by PCPs might be important barriers for people with mental health problems to receive the treatment they need in primary care. PMID- 30440053 TI - Controlling fluid flow to improve cell seeding uniformity. AB - Standard methods for seeding monolayer cell cultures in a multiwell plate or dish do not uniformly distribute cells on the surface. With traditional methods, users find aggregation around the circumference, in the centre, or a combination of the two. This variation is introduced due to the macro scale flow of the cell seeding suspension, and movement of the dish before cells can settle and attach to the surface. Reproducibility between labs, users, and experiments is hampered by this variability in cell seeding. We present a simple method for uniform and user independent the cell seeding using an easily produced uniform cell seeder (UCS) device. This allows precise control of cell density in a reproducible manner. By containing the cell seeding suspension in a defined volume above the culture surface with the UCS, fluctuations in cell density are minimised. Seeding accuracy, as defined by the actual cell density versus the target seeding density is improved dramatically across users with various levels of expertise. We go on to demonstrate the impact of local variation in cell density on the lineage commitment of human embryonic stem cells (hESCs) towards pancreatic endoderm (PE). Variations in the differentiation profile of cells across a culture well closely mirror variations in cell density introduced by seeding method-with the UCS correcting variations in differentiation efficiency. The UCS device provides a simple and reproducible method for uniform seeding across multiple culture systems. PMID- 30440054 TI - A neuraminidase activity-based microneutralization assay for evaluating antibody responses to influenza H5 and H7 vaccines. AB - Outbreaks of the highly pathogenic avian influenza H5N1 and H7N9 viruses have spurred an unprecedented research effort to develop antivirals and vaccines against influenza. Standardized methods for vaccine evaluation are critical for facilitating vaccine development. Compared with hemagglutination inhibition assays, mounting evidence suggest that microneutralization tests (MNTs) is a better choice for the evaluation of candidate pandemic influenza vaccines because they measure neutralizing antibody activity in cell cultures and are more sensitive in detecting H5 and H7. Here, we report a MNT measuring neuraminidase activity as the read-out (NA-MNT) for quantitative analysis of neutralizing antibodies against avian influenza viruses. Compared to the conventional microneutralization assay (ELISA-MNT), the NA-MNT is faster with lower intra- and inter-assay variations, while no difference in geometric mean titers was found between these two assays for the evaluation of H5N1 and H7N9 vaccines. These results suggest that NA-MNT is a reliable and high throughput method which could facilitate the development of candidate pandemic influenza vaccine. PMID- 30440055 TI - Significance of NF-kappaB signaling and PARP1 activity in the TNF-induced inhibition of PHEX gene expression in human osteoblasts. AB - Although loss of bone mineral density is a common symptom of chronic inflammatory diseases, its mechanisms are still poorly understood. The PHEX gene encodes a Zn endopeptidase expressed in osteoblasts and contributes to bone mineralization. Data derived from rodents has indicated co-repression of the PHEX gene by the NF kappaB pathway and poly(ADP-ribose) polymerase 1 (PARP1). The aim of this study was to determine the molecular mechanism involved in TNF-mediated downregulation of PHEX expression in human osteoblasts and human osteosarcoma cell line. We observed that activation of the NF-kappaB pathway by TNF was manifested as a nuclear increase in RELA and NFKB1 heterodimer. We found that TNF reduced PHEX expression and the proteasome inhibitor reversed this effect in osteosarcoma cell line. Contrary to the effects seen in rodents, inhibition of PARP1 enzymatic activity did not significantly reverse the effect of TNF on the human PHEX gene expression. EMSA studies showed that the number of adenines in the PHEX proximal promoter is crucial for the transcription factors' interactions within that region. The obtained results support the hypothesis indicating the existence of a molecular mechanism of gene repression that involves a poly adenine-rich region of the proximal gene promoters and PARP1 transcriptional activity. PMID- 30440064 TI - The Duke minor criterion "predisposing heart condition" in native valve infective endocarditis - a systematic review. AB - BACKGROUNDThe term "predisposition" is used as an indication of antimicrobial prophylaxis to prevent infective endocarditis and as a criterion for diagnosing infective endocarditis according to the modified Duke criteria. The criterion for diagnosing infective endocarditis in native valves is not well defined.OBJECTIVESTo identify conditions that increase the risk for infective endocarditis in native valves, for the diagnosis of infective endocarditis according to the modified Duke criteria. In parallel, we compared the results with the year of patient inclusion for each study and echocardiographic techniques.RESULTSOur systematic review included 207 studies published from January 1970 to August 2015. Studies that focused on mitral valve prolapse (112 studies), prior infective endocarditis (96) and bicuspid aortic valve (78) provided the most data. However, only six (5.3%), three (3.1%) and one (1.3%) of these studies, respectively, used analytical statistical methods. Three (2.7%), two (2.1%) and one (1.3%), respectively, were graded as good quality studies. Odds ratios (ORs) for developing infective endocarditis were 3.5-8.2 for mitral valve prolapse, and 2.2 and 2.8 for prior infective endocarditis. The hazard ratio for developing infective endocarditis was 6.3 for bicuspid aortic valve. The mean prevalence proportion of infective endocarditis in patients with these three heart conditions were 8.5% (mitral valve prolapse), 8.3% (prior infective endocarditis) and 8.8% (bicuspid aortic valve). The proportions of publications prior to the publication of the modified Duke criteria were 81.8, 75.6 and 74%, respectively. Evolution of the imaging method and echocardiographic technique was estimated to be considerable for mitral valve prolapse. The literature review on aortic valve stenosis (46 studies), mitral valve insufficiency (41) and aortic valve insufficiency (39) provided two analytical studies for aortic stenosis. One study was graded as good quality and reported a hazard ratio 4.9. The mean prevalence of these heart conditions in patients with infective endocarditis were 7.3, 19.9 and 10.2%, respectively. The proportions of publications prior to the publication of the modified Duke criteria were 78, 75.6 and 79.5%, respectively. The evolution of both the echocardiographic technique and the categorisation of valve disease severity was considerable for all three entities.CONCLUSIONSThe evidence for native valve heart conditions predisposing to infective endocarditis is mainly based on studies with only descriptive statistics published prior to the release of the modified Duke criteria. Mitral valve prolapse, prior infective endocarditis and bicuspid aortic valve are frequently cited as predisposing heart conditions for infective endocarditis. The evolution in echocardiographic techniques over the past decades and its influence on diagnosis was considerable for mitral valve prolapse, aortic stenosis, mitral insufficiency and aortic insufficiency. PMID- 30440065 TI - Basic patient characteristics predict antimicrobial resistance in E. coli from urinary tract specimens: a retrospective cohort analysis of 5246 urine samples. AB - BACKGROUND: Antimicrobial resistance data from surveillance networks are frequently do not accurately predict resistance patterns of urinary tract infections at the bedside. OJECTIVE: To determine simple patient- and institution related risk factors affecting antimicrobial resistance patterns of Escherichia coli urine isolates. METHODS: From January 2012 to May 2015 all consecutive urine samples with significant growth of E. coli (>=103 CFU/ml) obtained from a tertiary care hospital were analysed for antimicrobial susceptibility and related to basic clinical data such a patient age, ward, sample type (catheter vs non catheter urine). RESULTS: Antimicrobial susceptibility testing was available for 5246 E. coli urine isolates from 4870 patients. E. coli was most commonly resistant to amoxicillin (43.1%), cotrimoxazole (24.5%) and ciprofloxacin (17.4%). Resistance rates were low for meropenem (0.0%), fosfomycin (0.9%) and nitrofurantoin (1.5%). Significantly higher rates of resistance to ciprofloxacin (32.8 vs 15.8%) and cotrimoxazole (30.6 vs 23.9%) were found in urological patients compared with patients on other wards (p <0.01). In multivariable analysis, predictors for E. coli resistance against ciprofloxacin and cotrimoxazole were: treatment in the urological unit (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.63-2.54; p <0.001 and OR 1.33, 95% CI 1.07-1.64; p = 0.010, respectively), male sex (OR 1.93, 95% CI 1.630-2.29; p <0.001 and OR 1.22, 95% CI 1.22-1.04; p = 0.015), and only to a lesser extent urine samples obtained from indwelling catheters (OR 1.30, 95% CI 1.05-1.61; p = 0.014 and OR 1.26, 95% CI 1.04-1.53; p = 0.020). Age >=65 years was associated with higher resistance to ciprofloxacin (OR 1.42, 95% CI 1.21-1.67; p <0.001), but lower resistance to cotrimoxazole (OR 0.76, 95% CI 0.67-0.86; p <0.001). CONCLUSIONS: Simple bedside patient data such as age, sex and treating hospital unit help to predict antimicrobial resistance and can improve the empirical treatment of urinary tract infections. PMID- 30440066 TI - TachoSil Dural Reconstruction in Extracranial-Intracranial Bypass Surgeries. AB - BACKGROUND: Superficial temporal artery to middle cerebral artery (STA-MCA) bypass is a treatment option for hemodynamic insufficiency in the anterior cerebral circulation. Complications associated with extracranial-intracranial bypass surgeries are ischemic strokes caused by bypass failure, wound-healing disorders, and further issues from cerebrospinal fluid (CSF) leakage. CSF leakage can provide pathways for infection. It is well known in general neurosurgery that watertight closure of the dura mater is necessary to prevent such complications. OBJECTIVE: To provide a technical description of TachoSil dural reconstruction in standard STA-MCA bypasses and their follow-up analyses. METHODS: In this technical report with observational follow-up, the dura mater was closed partially by adaptive sutures, and the perforation site of the donor vessel was sealed with TachoSil. TachoSil is a collagen sponge covered with clotting factors that provides hemostatic and sealing effects. RESULTS: Our study included eight cases of standard STA-MCA bypasses that had been operated between July 2015 and September 2016. Follow-up examinations were completed for all patients at 1 month and 6 months after surgery. Duplex and Doppler ultrasound demonstrated regular bypass patency in all patients without increased flow velocity at the perforation sites, which is a possible sign of stenosis. No wound-healing disorders or CSF leakage occurred. No cerebrovascular stroke events were observed. CONCLUSION: Duraplasty with TachoSil enables the elastic reconstruction of the dura perforation gap in standard extracranial-intracranial bypass surgeries. PMID- 30440067 TI - [Development and Results of Transcatheter and Surgical Aortic Valve Replacement in Germany 2014 and 2015]. AB - INTRODUCTION: Treatment of aortic valve stenosis has been changing since the introduction of transcatheter aortic valve replacement (TAVR). The present study investigates the treatment of aortic valve stenosis in a real-world population 2014 and 2015 in Germany. METHODS: Patient characteristics and in-hospital outcomes of all 38 414 isolated surgical aortic valve replacements (SAVR) or TAVR were analyzed. RESULTS: Since 2014 more TAVR than SAVR were performed in Germany. Overall interventions on the aortic valve increases: from 10 858 in 2009 to 19 929 in 2015. In 2015 patients > 75 were mainly treated with transfemoral (TF) TAVR. SAVR was performed in 474 patients over 80 years (for comparison: TF TAVR: 7519; transapical (TA) TAVR: 1192). Patients treated with TAVR were older, more often female, and had more co-morbidities. Consequently, they were at higher operative risk. Overall in-hospital mortality was 2 % after SAVR, 3 % after TF TAVR, and 6 % after TA-TAVR. Stroke rates were similar. Relevant bleeding events occurred after SAVR and TA-TAVR in 9 % and 8 % respectively and 3 % after TF TAVR. 66 % of patients after TF-TAVR and 40 % after SAVR were discharged home. DISCUSSION: TF-TAVR has become the most often performed therapy for patients > 75. Despite a higher operative risk, patients can be treated safely with TF-TAVR. PMID- 30440068 TI - [Examination of the Skin - an Important Skill in General Medical Practice]. PMID- 30440069 TI - ? PMID- 30440070 TI - [17-Year-Old Pupil with Cervical Lymphe Node Masses]. PMID- 30440071 TI - [Frequent Skin Findings in Daily Routine of the General Practitioner]. AB - Diseases of the skin are the cause of approximately one fifth of outpatient visits to general practitioners (GPs) in Germany. GPs are expected to be competent in both knowledge and skills required to manage dermatological diseases, but making the correct diagnosis can be challenging facing the broad clinical spectrum of dermatological disorders. Knowledge of morphological characteristics is essential in the accurate diagnosis of a dermatological condition and to ensure optimal patient care. The objective of this dossier is to provide an overview of common dermatological diseases in daily routine, with a focus on acute and chronic-inflammatory dermatoses. The most important dermatological diseases were sorted by three anatomic regions (face, trunk and lower leg), and an overview on the respective differential diagnoses is provided. PMID- 30440072 TI - [Pitfalls of Differential Diagnosis in Dermatologic Surgery]. AB - Evaluation of skin diseases can be challenging for non-dermatologists. Even obvious well-characterized skin pathologies might be misleading and thus treatment can fail. Particularly the differentiation of surgical treated entities is important, for example the management of a wound healing disturbance profoundly differs from that of a pyoderma gangrenosum. This article outlines several easily mistaken pairs of dermatologic entities on one hand and surgical on the other. For example, a livedo vasculopathy can be confused with a leg ulcer, a nail melanoma with a simple hematoma and finally a hidradenitis suppurativa with an axillary abscess. Typical clinical signs and anamnestic data may often lead to the right diagnosis also assisted by the simple fact to "keep it in mind". PMID- 30440073 TI - [Dermal Clues to Systemic Diseases]. AB - Many systemic diseases go along with dermal involvement. Only a few of systemic diseases show characteristic skin derangements directly leading to the diagnosis of the underlying disease. Ten of these entities are described within this article. Some of these are autoimmune diseases, such as systemic lupus erythematodes, dermatomyositis or the anti-synthetase-syndrome. Others are genetic diseases with benign or malignant neoplasias (Peutz-Jeghers-syndrome, neurofibromatosis, tuberous sclerosis, Birt-Hogg-Dube-syndrome, Cowden-syndrome). Other genetically based diseases with typical skin manifestations are characterised by vascular malformations (Pseudoxanthoma elasticum and Osler-Weber Rendu syndrome) or metabolic and structural organ defects (Morbus Fabry, cystic fibrosis). Being familiar with the typical skin-appearance of these diseases will allow physicians and general practitioners to make a timely diagnosis. PMID- 30440074 TI - [Acute Renal Failure in a Healthy Young Woman]. AB - HISTORY: A healthy young woman comes to admission because of an acute renal failure with hypercalcemia. FINDINGS AND DIAGNOSIS: An infective and a non infective inflammation could be disclosed, as well as a granulomatosis and a myeloma. Drug history was essential for diagnosis. THERAPY AND COURSE: By forced diuresis the patient recovered completely from hypercalcemia and kidney function improved. CONCLUSION: For acute renal failure potentially nephrotoxic drugs are to be considered, including dietary supplements. PMID- 30440076 TI - A Very Rare Etiology of Hypotonia and Seizures: Congenital Glutamine Synthetase Deficiency. AB - Mutations in the human GLUL gene, which encodes the enzyme glutamine synthetase (GS), may cause congenital glutamine synthetase deficiency. The disease was first described in 2005 and only three patients have been reported to date. We report a fourth patient suffering from congenital GS deficiency who was found to have some distinctive clinical findings. The patient was a 30-month-old girl who was referred to us due to developmental delay and seizures which began at 5 months of age. She was seizure free for 5 months with valproic acid and vigabatrin. At presentation, she was found to have microcephaly and hypotonia. Her plasma glutamine concentration was near normal and she had mild hyperammonemia. Cranial magnetic resonance imaging (MRI) showed mild changes. Whole exome sequencing (WES) revealed a homozygous c.121C > T (p.R41C) (p.Arg41Cys) pathogenic variant of the GLUL gene. The diagnosis of this patient underlines the importance of careful evaluation of patients with borderline low glutamine levels. Treatment was begun with L-glutamine and nicotinamide and biochemical improvements have been observed at 6 months of follow-up. The outcome of this patient may provide important data about the effectiveness of glutamine and nicotinamide treatment in patients with congenital GS deficiency. PMID- 30440075 TI - [Mosquitoes and Ticks: The Influence of Global Warming in the Transmission of Infectious Diseases in Germany]. AB - During the last 135 years, the average temperature in Germany has increased by 1.4 degrees C. By 2050, a further rise by 1.5 degrees C is expected. This is associated with an increase of precipitation during the winter months. This climate change probably will improve both the growth conditions for mosquitoes and ticks, as well as their ability to transmit infectious diseases. Today, vectors that have not yet been present are invading into Germany. Among them is Aedes albopictus, which transmits Chikungunya, Zika, and Dengue Fever. Also, spreading of autochthonous malaria and West Nile Fever appear possible in Germany. Because of the increased presence of Phlebotomus species, leishmaniasis should be considered as a potential differential diagnosis in unclear hematologic diseases. Among the tick-borne diseases, climate change has already led to increased case numbers of Borreliosis and Tick Borne Encephalitis (TBE), and Crimean Congo Virus is spreading from the Balkan region towards Central Europe. This requires physicians to consider additional differential diagnoses in febrile illnesses. PMID- 30440077 TI - Are Grapes Able to Mitigate the Noxious Effects Induced by Cadmium Exposure in Different Tissues and/or Organs? A Mini Review. AB - Grapes are fruits that grow in clusters and can be crimson, black, dark blue, yellow, green, orange, and pink. Cadmium is a non-essential metal toxic to living organisms and the environment. Recently, health professionals, food scientists, and consumers have paid much attention to grapes for their health-promoting effects. To the best of our knowledge, there are no reviews describing the ability of grapes to mitigate the toxic effects induced by cadmium exposure in different tissues and/or organs. Herein, the aim of this review is to present the effects of grapes following cadmium exposure on the number of papers published in the scientific literature. The results showed that grapes are able to mitigate the harmful activities induced by exposure to cadmium in several tissues and organs. The main actions are closely related to tissue regeneration as a result of the reestablishment of morphology and antioxidant activity. However, further studies are welcomed in order to elucidate new biological pathways regarding the outcomes promoted by grapes in this context, specially related to inflammation, tissue regeneration and cellular death. PMID- 30440079 TI - A quick glance at noteworthy articles in this month's issue. PMID- 30440078 TI - Piper nigrum Oil - Determination of Selected Terpenes for Quality Evaluation. AB - The growing demand and commercial value of black pepper (Piper nigrum) has resulted in considerable interest in developing suitable and cost-effective methods for chemical characterization and quality evaluation purposes. In the current study, an extensive set of oil samples (n = 23) that were extracted by steam distillation from black pepper seeds was investigated to compare the chemical profiles of samples originating from nine major producing countries, as well as to identify potential chemical markers for quality evaluation. The twenty two most abundant volatile compounds, mainly terpenes, in these oils were determined by conventional GC/MS analysis. Principal component analysis with this set of data revealed distinct clusters for samples that originated from China and Malaysia. Relatively low concentrations of sabinene (< 0.2%) and high concentrations of 3-carene (10.9 - 21.1%) were observed in these samples, respectively, compared to oil samples from other countries. The enantiomeric distributions of key terpene markers, viz., beta-pinene, sabinene, limonene, and terpinen-4-ol, were determined by chiral GC/MS analysis. Interestingly, for these four monoterpenes, levo-isomers were found to be predominant, emphasizing the highly conserved enzymatic processes occurring in P. nigrum. Moreover, consistent enantiomeric ratios (+/- isomers) of 92.2 +/- 3.0% for beta-pinene, 94.8 +/- 2.8% for sabinene, 60.7 +/- 1.1% for limonene, and 78.3 +/- 1.3% for terpinen-4-ol were observed, independent of geographical location. These results demonstrate the potential of using stereospecific compositions as chiral signatures for establishing the authenticity and quality of black pepper oil. PMID- 30440080 TI - Rethinking Risk Assessment for Public Utility Safety Regulation. AB - To aid in their safety oversight of large-scale, potentially dangerous energy and water infrastructure and transportation systems, public utility regulatory agencies increasingly seek to use formal risk assessment models. Yet some of the approaches to risk assessment used by utilities and their regulators may be less useful for this purpose than is supposed. These approaches often do not reflect the current state of the art in risk assessment strategy and methodology. This essay explores why utilities and regulatory agencies might embrace risk assessment techniques that do not sufficiently assess organizational and managerial factors as drivers of risk, nor that adequately represent important uncertainties surrounding risk calculations. Further, it describes why, in the special legal, political, and administrative world of the typical public utility regulator, strategies to identify and mitigate formally specified risks might actually diverge from the regulatory promotion of "safety." Some improvements are suggested that can be made in risk assessment approaches to support more fully the safety oversight objectives of public regulatory agencies, with examples from "high-reliability organizations" (HROs) that have successfully merged the management of safety with the management of risk. Finally, given the limitations of their current risk assessments and the lessons from HROs, four specific assurances are suggested that regulatory agencies should seek for themselves and the public as objectives in their safety oversight of public utilities. PMID- 30440081 TI - BDNF provides many routes toward STN DBS-mediated disease modification. AB - The concept that subthalamic nucleus deep brain stimulation (STN DBS) may be disease modifying in Parkinson's disease (PD) is controversial. Several clinical trials that enrolled subjects with late-stage PD have come to disparate conclusions on this matter. In contrast, some clinical studies in early- to midstage subjects have suggested a disease-modifying effect. Dopaminergic innervation of the putamen is essentially absent in PD subjects within 4 years after diagnosis, indicating that any neuroprotective therapy, including STN DBS, will require intervention within the immediate postdiagnosis interval. Preclinical prevention and early intervention paradigms support a neuroprotective effect of STN DBS on the nigrostriatal system via increased brain-derived neurotrophic factor (BDNF). STN DBS-induced increases in BDNF provide a multitude of mechanisms capable of ameliorating dysfunction and degeneration in the parkinsonian brain. A biomarker for measuring brain-derived neurotrophic factor trkB signaling, though, is not available for clinical research. If a prospective clinical trial were to examine whether STN DBS is disease modifying, we contend the strongest rationale is not dependent on a preclinical neuroprotective effect per se, but on the myriad potential mechanisms whereby STN DBS-elicited brain derived neurotrophic factor-trkB signaling could provide disease modification. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 30440082 TI - Caries prevalence and associations with medications and medical comorbidities. AB - OBJECTIVES: To use extensive electronic dental, medical, and pharmacy databases to estimate the prevalence of dental caries in a cohort of new patients during a 5-year period (FY2010-FY2015) and determine whether medication use and medical comorbidities are associated with caries prevalence. METHODS: This was a retrospective analysis of existing data from the Department of Veterans Affairs (VA). The number of teeth treated due to a caries-related diagnosis was determined and outcomes were presented as number of teeth/person and proportion of patients receiving caries-related treatment. Logistic and negative binomial regression modeled teeth/person with caries-related treatment; covariates included age, gender, race, ethnicity, physical and mental comorbidities, and use of prescription medications and prescription drugs with strong anticholinergic properties. RESULTS: The study population included 95,850 dentate dental patients: 92.1 percent were male, mean age of 58.7 +/- 12.6 years, 73.2 percent were White/Caucasian, and 21.3 percent were Black/African American. They were taking a mean of 10.6 +/- 5.9 VA prescription drug classes, 0.6 +/- 0.4 drugs with strong anticholinergic properties, and had 3.6 +/- 2.2 physical and 1.4 +/- 1.2 mental comorbidities. On average, 2.2 teeth/person received caries-related treatment and 58 percent of the study population received any caries-related treatment. An increase in the rate of caries-related treatment in Veterans was statistically significantly associated with increased prescription medication use; one or more drugs with strong anticholinergic properties and with 1+ mental comorbidities. Increased physical comorbidity was not statistically significantly associated with caries-related treatment. CONCLUSIONS: This study demonstrates a high prevalence of caries among Veteran dental patients, with an increased prevalence in those taking higher numbers of prescription medications. PMID- 30440083 TI - Development of a Sulfite-Based Oxygen Scavenger and its Application in Kimchi Packaging to Prevent Oxygen-mediated Deterioration of Kimchi Quality. AB - A sulfite-based oxygen scavenger (SOS) was developed with sodium metabisulfite and applied to kimchi packaging in an attempt to prevent oxygen-mediated kimchi quality degradation. The results of the oxygen- scavenging capacity test showed that the SOS had a competitive oxygen- scavenging performance in comparison with commercial oxygen scavengers. The kimchi was packaged with and without the SOS and stored over 12 weeks at 0 and 10 degrees C for an SOS application test. The kimchi treated with the SOS showed a significantly lower (P < 0.05) headspace oxygen and carbon dioxide concentration and pressure inside the packages than the control. The pH and titratable acidity values indicated that the SOS did not retard the kimchi fermentation process. The Hunter L, a, and b values in the kimchi packaged with the SOS were significantly higher (P < 0.05) than those in the control. After 12 weeks of storage, the total aerobic bacteria counts were reduced by 1.32 and 2.97 log CFU/g, lactic acid bacteria counts were reduced by 2.22 and 4.42 log CFU/g, and total yeasts and molds counts were reduced by 1.76 and 3.04 log CFU/g at 0 and 10 degrees C, respectively, by the SOS compared to those in the control. These results demonstrated that the developed SOS inhibited oxygen-mediated deterioration of the kimchi, but did not affect the kimchi fermentation. Therefore, our SOS can be used as an active food-packaging technology for kimchi quality preservation. PRACTICAL APPLICATION: A newly designed sulfite-based oxygen scavenger was applied in kimchi packaging, and it showed remarkable preventive effects on the kimchi quality deterioration caused by oxygen. Accordingly, it can be used as an active food-packaging technology to maintain kimchi quality during the storage period. Moreover, it can also be effectively utilized in the packaging of other high-moisture foods such as meat, fish, fruits, vegetables, and dairy products. PMID- 30440084 TI - The Effect of Pretreatment (Spray Drying) on the Yield and Selected Nutritional Components of Whole Camel Milk Powder. AB - The effect of spray drying on the composition of camel milk powder was evaluated. A full factorial experimental design was used to see the effects of inlet temperature (160 degrees C, 140 degrees C, and 120 degrees C), atomization pressure (800, 600, and 400 bar) and feed flow rate (5, 4, and 3 rev/s) on cyclone and vitamin C recoveries. Principal components analysis (PCA) was used to check classification of spray dried whole camel milk powders based on their processing conditions and multiple correspondence analysis (MCA) on the fatty acid profiles. The average proximate composition of the camel milk viz., fat, protein, lactose, and total solid were 3.0%, 3.21%, 3.01%, and 10.29% respectively. The powder yield (cyclone recovery) increased with increasing inlet temperature and decreasing feed flow rate. High outlet temperature and pressure decreased vitamin C recovery. As a result of PCA of the camel milk powders, they were classified into high heat treated and low heat treated milk powders while the MCA of the fatty acid profiles of camel milk powders were classified into high pressure and low pressure treated powders and it was concluded that higher atomization pressure caused increase in the content of fatty acids. PRACTICAL APPLICATION: Drying of camel milk (using spray drying) can extend its shelf life. The spray drying process must be optimized in order to retain the nutritional properties of the milk and the techno-functional characteristics of the powder. Here, the effect of the spray drying conditions on the yield and selected nutritional components of the milk powder was studied using a bench top spray dryer. However, there is need to translate these findings to an industrial volume dryer. These findings will play a big role in future spray drying operations since retention of important nutritional components is an important part of food processing. PMID- 30440085 TI - Geographical traceability of wheat and its products using multielement light stable Isotopes coupled with chemometrics. AB - The present study was aimed to investigate the variation of stable isotopic ratios of carbon, nitrogen, hydrogen, and oxygen in wheat kernel along with different processed fractions from three geographical origins across five years using isotope ratio mass spectrometry (IRMS). Multiway ANOVA revealed significant differences among region, harvest year, processing and their interactions for all isotopes. The region contributed the major variability in the delta13 C 0/00, delta2 H 0/00, delta15 N 0/00, and delta18 O0/00 values of wheat. Variation of delta13 C 0/00, delta15 N 0/00, delta18 O0/00 between wheat whole kernel and its products (break, reduction, noodles, and cooked noodles) were ? 0.70/00 and no significant difference was observed, suggesting the reliability of these isotope fingerprints in geographical traceability of wheat processed fractions and foods. A significant influence of wheat processing was observed for delta2 H values. By applying linear discriminant analysis (LDA) to the whole dataset, the generated model correctly classified over 91% of the samples according to the geographical origin. The application of these parameters will assist in the development of an analytical control procedure that can be utilized to control the mislabeling regarding geographical origin of wheat kernel and its products. PMID- 30440086 TI - Pharmacological modulation of mitochondrial ion channels. AB - The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria-specific channels. However, many ion channels have multiple localization within the cell hampering a clear-cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels with special focus on the channels that have received much attention in recent years, namely the voltage-dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane-located potassium channels. In addition, possible strategies to overcome difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interaction partners. Altogether, these promising tools along with large-scale chemical screenings set up to identify new, specific channel modulators will hopefully allow to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischemic damage and cancer. PMID- 30440087 TI - The Effects of Added Water and Grinding Temperature on Stability and Degradation Kinetics of Antioxidant Activity, Phenolic Compounds, and Ascorbic Acid in Ground Apples. AB - The effects of added water (1:0 up to 1:4 apple:water w/v) and grinding temperature on browning and antioxidant capacity of apples were investigated. Grinding apple with addition of water decreased browning and loss of antioxidant activity when ground with water up to 1:3 ratio. Browning, antioxidant capacity, major phenolic compounds (chlorogenic acid, epicatechin, and procyanidin B2), and ascorbic acid in ground apple with water (1:1) were evaluated at grinding temperatures from 5 degrees C to 45 degrees C. The degradation of antioxidant activity, phenolic compounds, and ascorbic acid followed first-order kinetics. The temperature-dependent degradation was adequately modeled using the Arrhenius equation, and kinetic parameters such as k, t1/2 , Q10 , and Ea indicated that the grinding temperature was a key factor affecting retention of antioxidant activity, phenolics, and ascorbic acid contents in apple. PRACTICAL APPLICATION: The phenolic compounds and antioxidant activity of fruits and vegetables can be altered by processing such as thermal treatments and grinding. Therefore, it is important to evaluate and predict the quality characteristics of the fruits as affected by processing conditions. In this study, we found grinding conditions retard the changes in color and loss in phenolic compounds and antioxidant activity of ground apples. This new finding can be helpful for engineers and scientists to control and optimize the grinding system by retaining the high nutritional values of apple products. PMID- 30440088 TI - Chemical and Chemometric Methods for Halal Authentication of Gelatin: An Overview. AB - The issue of food authenticity has become a concern among religious adherents, particularly Muslims, due to the possible presence of nonhalal ingredients in foods as well as other commercial products. One of the nonhalal ingredients that commonly found in food and pharmaceutical products is gelatin which extracted from porcine source. Bovine and fish gelatin are also becoming the main commercial sources of gelatin. However, unclear information and labeling regarding the actual sources of gelatin in food and pharmaceutical products have become the main concern in halal authenticity issue since porcine consumption is prohibited for Muslims. Hence, numerous analytical methods involving chemical and chemometric analysis have been developed to identify the sources of gelatin. Chemical analysis techniques such as biochemical, chromatography, electrophoretic, and spectroscopic are usually combined with chemometric and mathematical methods such as principal component analysis, cluster, discriminant, and Fourier transform analysis for the gelatin classification. A sample result from Fourier transform infrared spectroscopy analysis, which combines Fourier transform and spectroscopic technique, is included in this paper. This paper presents an overview of chemical and chemometric methods involved in identification of different types of gelatin, which is important for halal authentication purposes. PMID- 30440089 TI - Progressively Disrupted Somatodendritic Morphology in Dopamine Neurons in a Mouse Parkinson's Model. AB - BACKGROUND: Parkinson's disease is characterized by the progressive loss of dopamine neurons in the substantia nigra, leading to severe motor deficits. Although the disease likely begins to develop years before observable motor symptoms, the specific morphological and functional alterations involved are poorly understood. OBJECTIVES: MitoPark mice lack the gene coding for mitochondrial transcription factor A specifically in dopamine neurons, which over time produces a progressive decline of neuronal function and related behavior that phenotypically mirrors human parkinsonism. Our previous work identified a progressive decrease in cell capacitance in dopamine neurons from MitoPark mice, possibly suggesting reduced membrane surface area. We therefore sought to identify and quantify somatodendritic parameters in this model across age. METHODS: We used whole-cell patch clamp and fluorescent labeling to quantify somatodendritic morphology of single, neurobiotin-filled dopamine neurons in acutely isolated brain slices from MitoPark mice. RESULTS: We found that MitoPark mice exhibit an adult-onset, age-dependent reduction of neuritic branching and soma size in dopamine neurons. This decline proceeds similarly in MitoPark mice of both sexes, but does not begin until after the age that early decrements in ion channel physiology and behavior have previously been observed. CONCLUSIONS: A progressive and severe decline in somatodendritic morphology occurs prior to cell death, but is not responsible for the subtle decrements observable in the earliest stages of neurodegeneration. This work could help identify the ideal time window for specific treatments to halt disease progression and avert debilitating motor deficits in Parkinson's patients. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30440090 TI - alpha-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. AB - BACKGROUND: The objective of this study was to investigate the discriminating value of a range of CSF alpha-synuclein species for dementia with Lewy bodies compared with Alzheimer's disease, PD, and cognitively normal controls. METHODS: We applied our recently published enzyme-linked immunosorbent assays to measure the CSF levels of total alpha-synuclein, oligomeric alpha-synuclein, and phosphorylated alpha-synuclein in dementia with Lewy bodies (n = 42), Alzheimer's disease (n = 39), PD (n = 46), and controls (n = 78). General linear models corrected for age and sex were performed to assess differences in alpha-synuclein levels between groups. We used backward-elimination logistic regression analysis to investigate the combined discriminating value of the different CSF alpha synuclein species and Alzheimer's disease biomarkers. RESULTS: CSF levels of total alpha-synuclein were lower in dementia with Lewy bodies and PD compared with Alzheimer's disease as well as controls (P < 0.001). In contrast, CSF levels of oligomeric alpha-synuclein were higher in dementia with Lewy bodies and PD compared with Alzheimer's disease (P < 0.05) and controls (P < 0.001). No group differences were found for phosphorylated alpha-synuclein. In dementia with Lewy bodies and PD, CSF total alpha-synuclein levels positively correlated with tau and phosphorylated tau (both r > 0.40, P < 0.01), but not with amyloid-beta1-42 . The optimal combination to differentiate dementia with Lewy bodies from controls consisted of amyloid-beta1-42 , tau, total alpha-synuclein, oligomeric alpha synuclein, age, and sex (AUC, 0.90). To differentiate dementia with Lewy bodies from Alzheimer's disease, the combination of tau and oligomeric alpha-synuclein resulted in an AUC of 0.83. CSF alpha-synuclein species do not contribute to the differentiation of dementia with Lewy bodies from PD. CONCLUSIONS: CSF alpha synuclein species could be useful as part of a biomarker panel for dementia with Lewy bodies. Evaluating both oligomeric alpha-synuclein and total alpha-synuclein in CSF helps in the diagnosis of dementia with Lewy bodies. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 30440091 TI - Comparative Evaluation on the Quality and Shelf life of Atlantic Salmon (Salmo salar L.) Filets Using Microwave and Conventional Pasteurization in Combination with Novel Packaging Methods. AB - A comparative evaluation on the effect of carbon dioxide (CO2 ) on quality and shelf life of Atlantic salmon loins pasteurized with microwave and conventional technology was conducted. The experimental design allowed CO2 to enter the salmon muscle before (soluble gas stabilization [SGS] + vacuum) or after pasteurization (CO2 emitter + vacuum), whereas the control samples (vacuum only) were not presented for CO2 . This setup resulted in six different groups; three heated with microwaves and three with conventional pasteurization. The core temperature of microwave samples was 58.8 +/- 2.2 degrees C, whereas the surface temperature was equal to the oven temperature (62 degrees C) during conventional pasteurization and close to the core temperature during microwave pasteurization (57.6 +/- 1.4 degrees C). Microwave-heated samples showed higher microbial growth; decreased shelf life; and darker (lower L* -value), more reddish (higher a* -value), and yellowish (higher b* -value) colors compared to conventional heated salmon. Lowest liquid loss (LL) was observed in salmon packaged with the CO2 emitter, whereas a SGS step prior to pasteurization did not affect the LL negatively as compared to samples packaged in vacuum only. Treatment with CO2 , independent of the prestep using SGS or an emitter, resulted in increased shelf life. Protein denaturation, microbial growth, product color, product shelf life, and sensory properties of the salmon loin were significantly affected by the applied pasteurization method (microwave- or conventional pasteurization). However, the heat load was probably too high to detect differences resulting from the pretreatment using SGS or packaging with CO2 emitter. PRACTICAL APPLICATION: Recent developments with increased time pressure from both work and past time activities have led to a tremendous increase in the demand for convenient, tasty ready-to-use food options. Furthermore, contemporary trends for consumption of fresh or lightly processed seafood stress the need to develop processing methods that allow a fulfillment of these demands, while still offering a reasonable shelf life. Carbon dioxide in combination with either microwave or conventional pasteurization is innovative processing technology that can meet consumer's demand of such products. PMID- 30440092 TI - Effect of Different Storage Conditions on Analytical and Sensory Quality of Thermally Processed, Milk-Based Germinated Foxtail Millet Porridge. AB - Foxtail millet porridge was prepared using germinated grains and milk and was evaluated for its storage stability after thermal processing at ultra-high temperatures (UHT) of 142 degrees C for 5 s and retort processing temperatures of 121.5 degrees C for 15 min. Various physical, chemical, and microbial changes of the porridge were studied for a storage period of 180 days at 25 +/- 1 degrees C. Using consumer perception and survival analysis, the predicted shelf life of the UHT treated and retort processed foxtail millet porridge samples stored at 25 +/- 1 degrees C was found to be 186 +/- 9 days and 245 +/- 15 days, respectively. Also, data from consumer liking, profiling, physical, chemical, and microbial parameters showed significant changes (P < 0.05) in the thermally treated packaged porridge samples over time. As the consumer overall acceptability decreased, the detection of positive attributes (thick and uniformly colored texture and appearance; grainy mouth texture; caramel taste and aroma) in the porridge decreased, while the detection of negative attributes (uneven, decolored, and curdled texture and appearance; sticky mouth texture; cooked, sour and off smell; cooked, sour and off taste) increased. The present study could establish a significant difference (P < 0.05) in the storage induced properties of UHT and retort processed porridge samples. The analytical evaluation of foxtail millet porridge found that UHT treated porridge was better in quality, but consumers preferred retort processed porridge. PRACTICAL APPLICATION: The quality and sensory attributes, evaluated for UHT treated and retort processed porridge samples during the storage period of 180 days, were found to be contradictory. Based on the results of CATA sensory analysis, the shelf life of UHT treated and retort processed porridge samples was predicted to be more than 6 months. Therefore, both UHT treatment and retort processing can be effectively applied to prepare a ready to eat milk based porridge using germinated foxtail millet grains. PMID- 30440093 TI - Evaluation of gastric microbiome and metagenomic function in patients with intestinal metaplasia using 16S rRNA gene sequencing. AB - BACKGROUND: Despite recent advances in studies on the gastric microbiome, the role of the non-Helicobacter pylori gastric microbiome in gastric carcinogenesis remains unclear. We evaluated the characteristics of the gastric microbiome and metagenomic functions in patients with IM. METHODS: Participants were classified into six groups according to disease status (chronic superficial gastritis [CSG], intestinal metaplasia [IM], and cancer) and H. pylori- infection status (H. pylori-positive and H. pylori-negative). The gastric microbiome was analyzed in mucosal tissues at the gastric antrum by 16S rRNA gene sequencing. Moreover, we assessed the metagenome including the type IV secretion system (T4SS) gene, as T4SS proteins are essential for transferring CagA from H. pylori- into the human gastric epithelium. RESULTS: Among the 138 included patients, 48, 9, 23, 14, 12, and 32 were classified into the H. pylori-negative CSG, H. pylori-negative IM, H. pylori-negative cancer, H. pylori-positive CSG, H. pylori-positive IM, and H. pylori-positive cancer groups, respectively. Cyanobacteria were predominant in the H. pylori-negative CSG group compared to in the H. pylori-negative IM and H. pylori-negative cancer groups (H. pylori-negative CSG vs H. pylori-negative IM vs H. pylori-negative cancer: 14.0% vs 4.2% vs 0.04%, P < 0.001). In contrast, Rhizobiales were commonly observed in the H. pylori-negative IM group (H. pylori negative CSG vs H. pylori-negative IM vs H. pylori-negative cancer: 1.9% vs 15.4% vs 2.8%, P < 0.001). The relative abundance of Rhizobiales increased as H. pylori infected stomachs progressed from gastritis to IM. In the H. pylori-negative IM group, genes encoding T4SS were prevalent among the metagenome. Additionally, after H. pylori- eradication therapy, the gastric microbiome was similar to the microbiome observed after spontaneous clearance of H. pylori-. CONCLUSIONS: The relative abundance of Rhizobiales was higher in patients with H. pylori-negative IM than in those with H. pylori-negative CSG or cancer. Additionally, T4SS genes were highly observed in the metagenome of patients with IM. Highly abundant T4SS proteins in these patients may promote gastric carcinogenesis. PMID- 30440094 TI - A Supramolecular Coordination Polymer Derived Electrocatalyst for Oxygen Evolution Reaction. AB - An iron oxide decorated nickel iron alloy nanoparticle/porous graphene hybrid exhibits high electrocatalytic activity and excellent durability toward oxygen evolution reaction (OER). It displays a low overpotential of 274 mV at 10 mA/cm2, and low Tafel slope of 37 mV/dec, showing a superior performance to the state-of the-art RuO2 OER electrocatalyst. PMID- 30440095 TI - Study of the mainstream cigarette smoke aerosols by Fourier transform ion cyclotron resonance mass spectrometry coupled to laser/desorption and electrospray ionization - Additional insights on the heteroaromatic components. AB - RATIONALE: The chemical composition of particulate phase of cigarette smoke inhaled by the active smoker is still poorly known in spite of its importance on a health point of view. A non-targeted approach is applied on cigarette smoke particles collected on a quartz filter to obtain an as complete as possible description of this complex mixture. METHODS: A home-made smoking machine including devices for volatile organic compounds (VOCs) and particles sampling was used. The validation of the cigarette smoking and cigarette smoke collection procedures was conducted by the quantification of some compounds by GC/MS. The particles were investigated by Fourier transform ion cyclotron resonance mass spectrometry (FT ICR-MS) directly after their collection on quartz filter by laser/desorption ionization (LDI) or after extraction with CH2 Cl2 by electrospray ionization (ESI). RESULTS: The determination of the benzene, toluene, ethyl-benzene and xylenes (from 2 to 35 MUg/cigarette) and nicotine (0.68 +/- 0.05 mg/cigarette) validated the used sampling method. The complementarity of the LDI and ESI for the cigarette smoke analysis was established. The ESI analyses evidenced polar compounds and components with a pyridine group and, LDI ensured the detection of poly-condensed hetero-aromatic species. Finally, this methodology was employed to characterize particles from cigarettes with or without flavoring additives. CONCLUSIONS: Some insights of the composition of cigarette smoke inhaled by active smoker have been obtained. The ~1750 observed features revealed the huge complexity of cigarette smoke particles and the diversity of the possible associated health issues. Both hetero-aromatic and highly oxygenated compounds produced by combustion and pyrolysis have been highlighted. PMID- 30440096 TI - Pallidal beta bursts in Parkinson's disease and dystonia. AB - BACKGROUND: Exaggerated beta power has been discussed as a disease-specific biomarker for Parkinson's disease (PD) and has recently been suggested to rely on prolonged bursts of subthalamic beta synchronization. OBJECTIVE: In this study, we test whether prolonged bursts are disease specific for beta activity in PD by comparison to oscillatory activity in dystonia. METHODS: Pallidal local field potentials were recorded from 5 PD patients ON and OFF dopaminergic medication and 5 dystonia patients. Synchronization of beta and low-frequency oscillations in bursts was compared between groups with respect to their duration, amplitude, and rate. RESULTS: Pallidal beta bursts were longer in PD-OFF than PD-ON or dystonia (P < .05). PD-ON and dystonia displayed similar beta burst dynamics. Low frequency burst features showed no differences across groups. CONCLUSIONS: Prolonged burst duration appears as a disease-specific feature for beta activity in PD across the basal ganglia. With dopaminergic medication, beta bursts in PD resemble those in dystonia, which supports the notion of short beta bursts as a physiological pattern. PMID- 30440097 TI - Relative potency of proton-pump inhibitors, Helicobacter pylori therapy cure rates, and meaning of double-dose PPI. AB - BACKGROUND: Helicobacter pylori treatment recommendations often recommend use of double-dose PPI or greater. This is confusing because PPIs very markedly in relative potency such that a double dose of one may not even be equivalent to the single dose of another. OBJECTIVE: To relate the concept of double-dose to specific amounts of the different PPIs METHODS: We used data standardizing PPI potency in terms of the duration of intragastric pH >4/24 hours (pH4-time) to rank PPIs. Relative potency varies from 4.5 mg omeprazole equivalents (20 mg pantoprazole) to 72 mg omeprazole equivalents (40 mg rabeprazole). RESULTS: We defined PPI dosing for H. pylori therapy as low dose (eg, approximately 20 mg omeprazole equivalents, b.i.d.), high or double dose as approximately 40 mg omeprazole equivalents, b.i.d.) and high dose as approximately 60 mg omeprazole equivalents, b.i.d.). For example, standard double dose PPI would thus be 40 mg of omeprazole, 20 mg of esomeprazole or rabeprazole, 45 mg of lansoprazole, or 120 mg of pantoprazole each given b.i.d. CONCLUSIONS: Simply doubling the dose of any PPI achieves markedly different effects on pH4-time. However, PPIs can be used interchangeably and cost effectively based on their omeprazole equivalency. PMID- 30440098 TI - Thermo-modulated Hela cell release from an elastic and biocompatible hydrogel. AB - Cell growth and release from the hydrogel scaffolds are critical steps in cell culture and cell therapies. Herein a double network hydrogel with one thermosensitive P(AEtMA-Cl-DEAEA) network and the other polyacrylamide network is reported. The diad hydrogel is elastic and maintains its structural integrity under large deformation. BSA is adsorbed onto the hydrogel at body temperature and subsequently released from the hydrogel at lower temperature. Hela cells proliferate on the hydrogel scaffolds at 37 degrees C. When the scaffold is incubated at low temperature (20 degrees C), 32.6% +/- 6.4% of its population are detached from the scaffolds. The detached cells remain active in cell culture. This hydrogel with excellent mechanical properties and unique biological function has promising biomedical applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: 00B: 1-6, 2018. PMID- 30440099 TI - Use of platelet-rich plasma to facilitate wound healing. AB - Platelet-rich plasma (PRP) is widely used nowadays in different fields of medicine, affecting physiological processes including tissue regeneration. The use of PRP in maxillofacial surgical interventions and its efficiency in the improvement of postoperative wound healing were analysed. Patients undergoing plastic and reconstructive surgeries in the maxillofacial region were recruited: 50 patients were enrolled into a control group (received no PPRP injection) and 50 patients were enrolled into a treatment group, where PRP was applied during the surgical procedure. Evaluation of treatment outcomes was carried out by determination of IL-1beta, TNFalpha, and IL-6 cytokines levels in the wound-drain fluid. The stages of wound healing were assessed by cytological analyses and ultrasound within a month period. The use of the PRP has substantially positive effects, contributing to the improvement of the healing process. In the treatment group, fibroblasts, macrophages, and collagen fibres appeared and their quantities increased earlier than when compared with control group patients. The concentration of IL-1beta and TNFalpha in wound fluid on day 1 and day 5 after operation was higher for the treatment group as opposed to the control group, which was linked to the influence of PRP on inflammatory and granulation phases of the healing process. An ultrasound examination showed less oedema and infiltration in the tissues around the wound of the treatment group. PMID- 30440100 TI - Halitosis: Helicobacter pylori or oral factors. AB - INTRODUCTION: Halitosis is a common complaint among people which has various socioeconomic effects. The prevalence of halitosis includes a variety of 22% up to 50% in different societies. According to studies, there have been reports of remarkable improvements in halitosis after Helicobacter pylori eradication treatment. In studies on the relationship between H. Pylori and halitosis, the role of oral factors as the most important cause of halitosis has been neglected. This study was conducted with the aim of investigating the effect of oral factors on halitosis in patients with H. Pylori. MATERIALS AND METHODS: A total of 100 dyspeptic patients who had H. pylori-positive serologic test were examined by an organoleptic method for the presence of halitosis. DMFT index was used in order to record the dental status. Oral hygiene was evaluated using the simplified oral hygiene index (OHI-S). RESULTS: The mean DMFT index was 9.09 +/- 3.97. The score of simplified oral hygiene index was 1.79 +/- 0.949. There was a direct and significant relationship between halitosis with DMFT, OHI-S (P < 0.01). There was no significant relationship between halitosis and coated tongue (P > 0.01). CONCLUSIONS: According to the results of this study, there is a relation between oral factors and halitosis in patients with positive H. pylori test. Due to the lower level of all these indices in patients with halitosis, we cannot attribute halitosis in patients with H. pylori infection to the presence of this microorganism with certainty. PMID- 30440101 TI - Review of antimicrobial peptides with anti-Helicobacter pylori activity. AB - BACKGROUND: The emergence of antibiotic-resistant Helicobacter pylori strains in recent years has increased the need for finding an alternative in the post antibiotic era. One of the fields being considered for this purpose is antimicrobial peptides. The aim of this review was to provide an obvious scheme from the studied anti-H. pylori peptides and to investigate their common features. METHOD: First, all of the antimicrobial peptides with their anti-H. pylori effects have been proved up to September 2018 were selected and their information including structure, mechanism of action, and function was reviewed. To achieve this, three databases of PubMed, Scopus, and Web of science were used. RESULTS: A total of 9 groups containing 22 antimicrobial peptides were found with demonstrated anti-H. pylori effects. The nine groups included pexiganan, tilapia piscidins, epinecidin-1, cathelicidins, defensins, bicarinalin, odorranain-HP, PGLa-AM1, and bacteriocins. Most of the antimicrobial peptides, not all, had common features such as the ability to kill antibiotic-resistant strains, having alpha-helical structure, being cationic, with high positive charge and isoelectric point. CONCLUSION: Antimicrobial peptides with anti-H. pylori effects have the potential to replace the antibiotics, especially in the post-antibiotic era, if a rapid and low-cost production method would be found. PMID- 30440102 TI - Control of Metal-Organic Framework Crystallization by Metastable Intermediate Pre equilibrium Species. AB - There is an increasingly large amount of interest in metal-organic frameworks (MOFs) for a variety of applications, from gas sensing and separations to electronics and catalysis. Their exciting properties arise from their modular architectures, which self-assemble from different combinations of metal-based and organic building units. However, the exact mechanisms by which they crystallize remain poorly understood, thus limiting any realisation of real "structure by design". We report important new insight into MOF formation, gained using in situ X-ray diffraction, pH and turbidity measurements to uncover for the first time the evolution of metastable intermediate species in the canonical zeolitic imidazolate framework system, ZIF-8. We reveal that the intermediate species exist in a dynamic pre-equilibrium prior to network assembly and, depending on the reactant concentrations and the progress of reaction, the pre-equilibrium can be made to favour under- or over-coordinated Zn-imidazolate species, thus accelerating or inhibiting crystallization, respectively. We thereby find that concentration can be effectively used as a synthetic handle to directly control particle size, with great implications for industrial scale-up and gas sorption applications. These finding enables us to rationalise the apparent contradictions between previous studies of ZIF-8 and, importantly, opens up new opportunities for the control of crystallization in network solids more generally, from the design of local structure to assembly of particles with precise dimensions. PMID- 30440103 TI - DNA Surface Technology: From Gene Sensors to Integrated Systems for Life and Materials Sciences. AB - The evolution of DNA microarray technology has led to sophisticated DNA chips that are being used as routine tools for fundamental and applied genome research such as genotyping and expression profiling. Owing to their capability for highly parallel, site-directed immobilization of complementary nucleic acids through canonical Watson-Crick base-pairing, however, DNA-modified surfaces can also be used for the assembly of complex surface architectures comprised of non-nucleic acid compounds, such as proteins or colloidal materials. Furthermore, implementation of functional DNA devices and structural DNA nanotechnology can unlock the full potential of DNA surfaces. Based on case studies from diagnostics, sensing, proteome research, cell adhesion, and cell signaling, we show how classical gene sensors have developed into modern integrated systems and platforms for various applications in life sciences and materials research. PMID- 30440104 TI - Management of sacrococcygeal pilonidal sinus disease. AB - The ideal treatment for patients who suffer from pilonidal sinus disease should lead to a cure with a rapid recovery period allowing a return to normal daily activities, with a low level of associated morbidity. A variety of different surgical techniques have been described for the primary treatment of pilonidal sinus disease and current practice remains variable and contentious. Whilst some management options have improved outcomes for some patients, the complications of surgery, particularly related to wound healing, often remain worse than the primary disease. This clinical review aims to provide an update on the management options to guide clinicians involved in the care of patients who suffer from sacrococcygeal pilonidal sinus disease. PMID- 30440105 TI - Nutritional management of older hospitalised patients with pressure injuries. AB - This cross-sectional, multicentre study was conducted in hospitals to investigate nutritional interventions conducted in patients aged 70 years or older with (risk of) pressure injuries. A total of 1412 patients from 33 hospitals with 208 wards participated in the study. A standardised questionnaire was used to collect demographic data and data on care dependency, malnutrition risk, risk for/prevalence of pressure injuries, and nutritional interventions. Data analyses were conducted by using descriptive statistics, chi-square tests, or independent t-tests. According to the Braden Scale, 678 (48.0%) of the patients were at risk of developing pressure injuries, and 71 patients (5.0%) had at least one pressure injury (assessed by skin inspection). The most frequently conducted nutritional interventions in patients with pressure injuries were providing support during mealtimes (50.7%), food specifically desired by the patient (40.8%), and conducting a malnutrition screening (39.4%). One quarter of the patients with pressure injuries were referred to a dietitian. The provision of an energy enriched/protein-enriched diet (18.3%), energy-enriched/protein-enriched snacks (12.7%), or oral nutritional supplements (8.5%) was rare. Nutritional care in older patients with risk of pressure injuries is suboptimal. Health care professionals need to raise awareness regarding the importance of nutrition in the management of patients with pressure injuries. PMID- 30440106 TI - Comparative study on the donor site aesthetic outcome between epidermal graft and split-thickness skin graft. AB - Donor site aesthetic outcomes of epidermal graft (EG) vs split-thickness skin graft (SSG) have yet to be objectively compared. Here, we evaluate donor site healing using a validated scar assessment tool and digital colorimetric technique, which compares colour in a consistent and objective manner. Ten patients (SSG (n = 5) and EG (n = 5)) were included. Donor site scarring was evaluated using the Vancouver Scar Scale (VSS) at Week 6 and Month 3. Colorimetric measurement was performed at Weeks 3 and 6 and Month 3. The mean donor site healing time for EG was significantly shorter (EG: 4.6 days (95% c.i. 3.8-5.3), SSG: 16.8 days (95% c.i. 13.3-20.1) (P = 0.003)). The VSS scores of the EG donor site were lower at Week 6 and Month 3(P < 0.001). The colour match between the donor site and surrounding skin for EG was better compared with SSG at all time points and was almost identical to their surrounding healthy skin at Month 3. This study is the first to objectively measure the clinical appearance of the EG donor site against SSG. EG donor site has faster healing with excellent scarring and good colour match with its surrounding normal skin at all time points compared with SSG. PMID- 30440107 TI - "Pikachu-shaped" flap for extramammary Paget's disease. PMID- 30440108 TI - Lumpers versus splitters: What to do with suspected idiopathic pulmonary fibrosis? PMID- 30440109 TI - Bayesian sample size determination for phase IIA clinical trials using historical data and semi-parametric prior's elicitation. AB - The Simon's two-stage design is the most commonly applied among multi-stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre-trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two-stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B-splines. The motivating example is the planning of the phase IIA two-stage trial on anti-HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated. PMID- 30440110 TI - The clinical dynamic changes of macrophage phenotype and function in different stages of human wound healing and hypertrophic scar formation. AB - The pathogenesis of hypertrophic scar (HS) is still poorly understood. Macrophages, especially the polarisation of that to M1 or M2, play a pivotal role in control of the degree of scar formation. Profiling of macrophage phenotypes in human specimens during long-term period of wound healing and HS formation may provide valuable clinical evidence for understanding the pathology of human scars. Human wound and HS specimens were collected, the macrophage phenotype was identified by immunofluorescence, and biomarkers and cytokines associated with M1 and M2 macrophages were detected by RT-PCR. The correlation between the macrophage phenotype and HS characteristics was analysed by linear regression analyses. We found excessive and persistent infiltration by M1 macrophages around the blood vessels in the superficial layer of the dermis at early wound tissues, whereas M2 macrophages predominated in later wound tissues and the proliferative phase of HS and were scattered throughout the dermis. The density of M1 macrophages was positively correlated with mRNA expression levels of tumour necrosis factor-alpha (TNF-alpha) and IL-6. The density of M2 macrophages was positively correlated with ARG1 and negatively correlated with the duration of HS. The sequential infiltration by M1 macrophage and M2 macrophages in human wound and HS tissues was confirmed. PMID- 30440111 TI - Optimization of flow splitting and make-up flow conditions in liquid chromatography - electrospray ionization - mass spectrometry. AB - RATIONALE: In LC/MS the LC flow is often split prior to the MS, for instance when collecting fractions of the separated sample for other purposes or when less sensitive parallel detection is applied. The aim of this study is to optimize the actual split ratio and make-up flow composition. METHODS: Different types of splitters were evaluated in combination with a make-up flow. A home-made 1/10 T piece splitter and commercial 1/10, 1/100 and 1/250 splitters were evaluated by continuous and accurate measurements of the actual split ratio throughout the LC gradient. The make-up flow composition was optimized for maximum ESI-MS sensitivity in the positive mode using ESI ionization efficiency measurements. RESULTS: Altogether 22 different solvent conditions were tested on 20 pharmaceutical compounds with a wide variety of functional groups and physicochemical properties (molecular weight, logP, and pKa ). Methanol/10 mM formic acid in water (90/10) provided on average the best results. CONCLUSIONS: Methanol/10 mM formic acid in water (90/10) showed to be the best make-up flow composition in relation to the average sensitivity obtained. Stronger acidic conditions using oxalic acid or higher formic acid concentrations had a clear positive effect on the sensitivity of compounds with low ionization efficiency. The tested split ratios were relatively stable over the main part of the gradient but showed some variation at very low and very high organic conditions. Differences were larger with methanol compared to acetonitrile containing solvent compositions and when applied without a column or with very long connecting tubing. PMID- 30440112 TI - New challenges in psycho-oncology: Economic evaluation of psychosocial services in cancer: Challenges and best practice recommendations. PMID- 30440114 TI - Clinical Course and Management of Hypertrophic Cardiomyopathy. PMID- 30440113 TI - Repeated exposure to temperature variation exacerbates airway inflammation through TRPA1 in a mouse model of asthma. AB - BACKGROUND AND OBJECTIVE: Studies from epidemiology suggest that ambient temperature is one of the underlying triggers and potential causes of asthma. The aim of this study was to examine the impact and the molecular mechanism of temperature-invoked airway inflammation using an experimental model of asthma in BALB/c mice. METHODS: Mice were exposed to different temperature conditions (steady 26 degrees C, 26 degrees C/18 degrees C cycle, 26 degrees C/10 degrees C cycle) and received sensitization and challenge of ovalbumin (OVA) during a 21 day period. HC030031, a selective transient receptor potential A1 (TRPA1) channel blocker, was used to investigate the underlying mechanism of TRPA1 in 'asthmatic' airways. After the final OVA challenge, in vivo lung function was measured, and bronchoalveolar lavage fluid (BALF) and pulmonary inflammation were assessed. RESULTS: The temperature variations, especially the largest temperature difference (16 degrees C), exacerbated airway inflammation in OVA-induced mice, increasing the levels of serum total-IgE (immunoglobulin E) and IgG1, inflammatory cells and cytokines in BALF. Analysis of histopathological changes and lung function verified that repeated exposure to very cold and changed temperatures aggravated airway hyperresponsiveness (AHR). Significant upregulation of TRPA1 expression was revealed by immunohistochemistry in the presence of the largest temperature variation (26 degrees C/10 degrees C cycle), while administration of HC030031 successfully inhibited TRPA1 expression, thus attenuating the asthma-like pathological features. CONCLUSION: Repeated exposure to temperature variation exacerbated experimental 'asthma' and TRPA1 mediated this temperature-dependent inflammatory effect. PMID- 30440116 TI - [Misunderstanding in the diagnosis and treatment of Guillain Barre syndrome]. PMID- 30440115 TI - Clinical Course and Management of Hypertrophic Cardiomyopathy. PMID- 30440117 TI - [The clinical expert consensus should be comprehened and practised with critical thinking]. PMID- 30440118 TI - [Robot assisted sacroiliac screw placement with a modified method of screw path planning]. AB - Objective: To introduce a robot-assisted modified method of sacroiliac screw path planning in order to reduce the incidence of screw misplacement. Methods: The study involved 13 patients suffering from posterior pelvic injuries treated by percutaneous sacroiliac screw in Yantai Shan Hospital from August 2016 to May 2018. The patients included 9 males and 4 females, aged from 18 to 70 years (mean age 46.2 years). Causes of injury were traffic accidents (n=7), crushing injury (n=4) and fall from height (n=2). According to AO classification, 8 cases were classified with type B fractures (3 with type B1 and 5 with type B2), and 5 cases with type C fractures (2 with type C1, 1 with type C2, 2 with type C3). All the patients were treated by robot-assisted percutaneous sacroiliac screws (AO cannulated screws with a diameter of 7.3 mm) with an improved method of screw path planning. The screw placement time, blood loss, postoperative neurological, vascular and visceral function etc were observed. X-ray and CT were checked in the follow-up after the operation. Visual analogue scale (VAS) score was used to assess the pain degree of patients one week after the surgery. Results: All the sacroiliac screws were successfully implanted once with the robot-assisted improved method of screw path planning. The mean placement time of single screw was 15.9 min and the mean blood loss for single screw placement was less than 1 ml. No clinical manifestations of injuries of blood vessels, internal organs and lumbosacral nerve was found after the operation. The postoperative X-ray films and CT showed that none of the sacroiliac screws wore out the sacral body or the sacral wing's frontal cortex. Also, it was found that none of the sacroiliac screws strayed into the sacral canal and the intervertebral space. The mean VAS score decreased from preoperative 6.9 (4-10) to postoperative 1.8(0-3). Conclusion: The robot-assisted improved method of screw path planning contributes to safe and accurate sacroiliac screw placement. PMID- 30440120 TI - [Relationship between sonographic markers and fetal chromosome abnormality during 16-18 weeks of pregnancy]. AB - Objective: To analysis of fetal ultrasound soft index positive cases during 16-18 weeks of pregnancy, and to explore the relationship with chromosomal abnormalities in order to increase the positive rate of invasive prenatal diagnosis and reduce the rate of missed diagnosis. Methods: A total of 569 cases which were diagnosed with positive soft markers in the department of gynecology and obstetrics of the Second Hospital of Jilin University from Jan.2016 to Jan.2017 were studied by ultrasonography. Twenty-five cases were lost in follow up and finally 544 cases were included as group A. Those fetuses who combined with other malformations were induced labor. Non-invasive DNA examination was recommended for continued pregnant women, and those pregnant women whose results were high risk underwent the amniotic cavity puncture. When the fetal aneuploidy was confirmed, they chose induced labor. We followed the rest of those patients until postnatal half year. Randomly selected 544 cases during 16-18 weeks of pregnancy without obvious abnormalities into group B, followed up to half a year after birth. Results: In group A, 7 of the 544 cases were combined with other severe malformation in the beginning, among the remaining 537 patients, 273 of them received non-invasive DNA examination. Ten cases were high risk results, all of them underwent the amniotic cavity puncture with the result of chromosome abnormality, and they chose induced labor. Six cases were found other malformation in the second trimester who chose induced labor, and the rest 521 cases followed until the fetuses was born after half year had a favorable prognosis. In group B, 1 cases of severe deformities and 1 cases of haploid fetuses were found in 544 fetuses. The incidence of haploid fetus in group A and group B were 1.8% and 0.2%, respectively, with statistically significant (P<0.05). The incidence of severe malformation in group A and group B were 2.3% and 0.2%, respectively, with statistically significant (P<0.05). Conclusions: During 16-18 weeks of pregnancy, sonographic markers may indicate an increased risk in fetal chromosomal abnormalities. The risk of serious malformation was increased in the fetuses with ultrasonic soft marker positive, but there was no specificity. PMID- 30440119 TI - [Value of thumb ossification composite index for predicting peripubertal growth potential in girls with adolescent idiopathic scoliosis]. AB - Objective: To evaluate the predictive value of thumb ossification composite index (TOCI) for growth potential in female adolescent idiopathic scoliosis (AIS) patients and to analyze its correlation with several other indicators of growth potential. Methods: A retrospective review was conducted on 45 girls with AIS who underwent standard bracing treatment between October 2006 and August 2013 in Nanjing Drum Tower Hospital. All patients were regularly followed up with an interval of 3-6 months until brace weaning. At each visit, the following data were collected and recorded: chronologic age, stage of menses, standing height, Cobb angle of main curve, TOCI score, digital skeletal age (DSA) score and radius, ulna and small bones (RUS) score. The height velocity (HV) at each visit were calculated. The correlations analysis between TOCI and other indicators including DSA scores and RUS scores were studied. Results: The average age at initial visit was (10.9+/-1.3) years. The mean age of menarche was (12.6+/-1.3) years. The mean peak height velocity (PHV) was (7.5+/-1.5) cm/year and the mean age of PHV was (12.0+/-0.9) years. A total of 71.8% AIS girls attained their PHV at TOCI 5. The Spearman correlation analysis showed that TOCI was highly correlated with the DSA and RUS scores (r=0.95 and 0.96, both P<0.001). Chi square test showed that TOCI 5 accurately predicted the occurrence of PHV (Cramer V=0.531, P=0.007). Conclusion: The TOCI 5 indicates high HV and high growth potential in AIS patients with bracing treatment. TOCI can thus serve as a good indicator for growth potential in braced AIS girls. PMID- 30440121 TI - [Presenilin 1 p. F105L mutation was associated with a Chinese pedigree with early onset familial Alzheimer's disease]. AB - Objective: To investigate the clinical manifestations of an early-onset Alzheimer's family and the novel mutation sites of PSEN1 gene. Methods: Clinical data was collected from 30 members of a family with early onset Alzheimer's disease from Neurology Department of Henan Province People's Hospital in 2016, and high-throughput sequencing and sanger sequencing were used to detect and further validate the PSEN1 gene mutation. At the same time, 100 unrelated healthy people were selected as controls. Results: A total of 3 members of the family carried PSEN1 (p.F105L mutation). The clinical symptoms or imaging of the three people were consistent with the diagnosis of Alzheimer's disease. Conclusion: The p. F105L mutation of the PSEN1 gene has been found in the Chinese population, which may be involved in the pathogenesis of this familial Alzheimer's disease. PMID- 30440122 TI - [Comparative study on the display ability of CBCT and MSCT in vestibular aqueduct]. AB - Objective: To compare the ability and visibility of cone-beam CT and MSCT in showing vestibular aqueduct. Methods: An experimental anatomical study which from June 2017 to August 2017 was performed on 76 temporal bones from 38 human cadavers with unknown clinical history. They all underwent CBCT and MSCT and all images were unified and standardized. The standard position was oblique sagital reconstruction.The length of the vestibular aqueduct, the midpoint and the external aperture width were measured on the standard position. The internal aperture, isthmus and proximal portion of the vestibular aqueduct on the images of the two kinds of equipment were evaluated. The measurement results of the two devices and image quality of the vestibular aqueduct were compared. Results: There was no significant statistical difference between the results of the measurement of CBCT and MSCT(P>0.05). In CBCT images, the total display rate of internal aperture was 77.6%(59/76), and the clearly display rate was 81.4%(48/59). The total display rate of the proximal portion of vestibular aqueduct was 57.0%(45/79), and the clearly display rate was 60.0%(27/45). The total display rate of isthmus of vestibular aqueduct was 59.2%(45/76), and the clearly display rate was 60.0%(27/45). In MSCT images, the total display rate of was 46.1%(35/76), and the clearly display rate was 60.0%(21/35). The total display rate of 5 of the proximal portion of vestibular aqueduct was 56.6%(43/76), the clearly display rate was 46.5%(20/43). The total display rate of isthmus of vestibular aqueduct was 68.4%(52/76), and the clear display rate 36.5%(19/52). There was significant statistical difference between the CBCT and the MSCT (P<0.05) in displaying of internal aperture of vestibular aqueduct. Conclusion: Compared with MSCT, the image of vestibular aqueduct obtained by CBCT can meet the diagnostic requirements and CBCT have better visibility in showing some subtle structures of vestibular aqueduct than MSCT. PMID- 30440123 TI - [The correlation between the cell density of local advanced lung cancer tumor and the ADC value of 3.0 T MRI diffusion weighted imaging]. AB - Objective: To investigate the correlation between tumorous cellular density (TCD) and apparent diffusion coefficient (ADC) of 3.0 T magnetic resonance diffusion weighted imaging (DWI) in local advanced lung cancer. Methods: From January 2015 to December 2017, a total of 59 patients with locally advanced lung cancer confirmed by pathology in Shaoxing People's Hospital who underwent DWI by 3.0 T magnetic resonance imaging were included.The ADC and TCD values of tumor were measured. The difference and correlation between ADC value and TCD in lung cancer were analyzed. Results: Among 59 lung cancer cases who were examined with DWI, 45 cases of TCD were obtained. Statistical analysis showed that the ADC value of small cell lung cancer (SCLC) was significantly higher than that of squamous cell carcinoma (P=0.011)and adenocarcinoma (P=0.004). TCD of small cell carcinoma was significantly higher than that of squamous cell carcinoma (P=0.007) and adenocarcinoma (P<0.01). There was no statistical difference in ADC value and TCD between squamous cell carcinoma and adenocarcinoma (all P>0.05). There was negative correlation between the ADC value and TCD in lung cancer (P=0.001, r= 0.534). Conclusions: DWI is not only beneficial to distinguish SCLC from squamous cell carcinoma and adenocarcinoma, but also can indirectly reflect the tumorous cellular density.It can provide a basis for monitoring the therapeutic effect of clinical lung cancer. PMID- 30440124 TI - [The effect of pre-operation (125)I seed activity measuring on dose accuracy]. AB - Objective: To measure the activity of (125)I seed and compare the dose difference of ten patients treated with seed implantation in pre-plan with actual seed activity and calibrate activity. Method: The activity of 100 seeds from company A and B was measured with a well-type ionization chamber 1 day before operation and named group A and B. The activity of two groups was compared and the error between actual and calibrate activity (22.2 MBq, group C) was calculated. Ten patients implanted with (125)I seeds from November 1 st to 30 th, 2017, solstice 30 were selected in Hebei General Hospital. Firstly, pre-plans were designed with 22.2 MBq, prescribed dose were 100-140 Gy. The dose parameters of 90% volume absorbed dose (D(90)), 150% volume fraction (V(150)) and 100% volume fraction (V(100)) were calculated. Then changed 22.2 MBq to actual activity of group A and B, calculated the dose parameters above again. Then dose parameters of D(90), V(150), V(100) in group C were compared with those in group A and B respectively. Result: The actual activity 1 day before the operation was(22.6+/-0.7)and(23.9+/ 0.9)MBq in group A and B respectively. Compared with 22.2 MBq, the difference was statistically significant(t=5.7, P<0.05 and t=19.2, P<0.05), and the activity error of group B was greater than 5%. The D(90) of group A, B and C were (124.3+/ 9.7) , (131.2+/-10.2) and (121.9+/-9.5) Gy respectively.The V(150) were 58.4%+/ 9.4%, 63.7%+/-8.9% and 56.5%+/-9.2% respectively. The V(100) were 88.9%+/-5.0%, 92.0%+/-4.1%, 88.1%+/-5.2% respectively.The difference of D(90) between calibrate activity(group C) and actual activity(group A and B) were statistically significant (t=40.2, P<0.05 and t=40.3, P<0.05). The difference of V(150) between group C and group A and B were statistically significant (t=7.5, P<0.05 and t=24.7, P<0.05). The difference of V(100) between group C and group A and B were statistically significant (t=6.6, P<0.05 and t=7.3, P<0.05). Conclusion: There is difference between the actual activity and calibration activity. The difference affects the dose parameters in pre-plan.The seed activity should be measured before operation strictly and the pre-plan should be designed with the actual activity. PMID- 30440125 TI - [Relevant molecular characteristics analysis on malignant transformation of interstitial cells induced by tumor stem cells in glioma microenvironment]. AB - Objective: A variety of interstitial cells in tumor microenvironment (TME) based on glioma stem cells(GSC) have the function to promote malignant progression of tumors, but whether these interstitial cells have already undergone malignant transformation and their related molecular characteristics are still poorly understood. Methods: Human SU3-RFP glioma stem cells (GSC) stably transfected with red fluorescent protein (RFP) and interstitial cells from enhanced green fluorescent protein (EGFP) transgenic nude mice were co-cultured in vitro. SU3 RFP cells were also inoculated in different tissues of EGFP-Balb/c nude mice. Immortal EGFP(+) cells were monocloned either from co-culture cells in vitro, or from their xenografts in vivo. These immortal EGFP(+) cells were confirmed to bear characteristics of tumor cell via chromosomal analysis and tumorigenicity assay. Related molecular phenotypes of these cells were further detected through RT-PCR, flow cytometry and immunochemistry(IHC) techniques. Results: (1) Two EGFP(+) cell lines were obtained in vitro, and 5 EGFP(+) cell lines were obtained in vivo tumorigenic experiments. Seven EGFP(+) cell lines all have characteristics of self-renewal, heteroploid of chromosomes and 100% tumorigenicity. (2) Cell surface marker analysis showed cell origin of these cell lines were macrophages (tMPhi1 and tMPhi2 ), dendritic cells (tDC1 and tDC2), fibroblasts (tFB), oligodendrocytes (tOG) and BMSC cells (tBMSC), respectively. (3)All of these seven cell lines co-expressed Sca-1 and c-myc, and have Sox-2 or Nanog expression also, which suggest that they may bear molecular characteristics of mesenchymal stem cells or pluripotent stem cells. Conclusions: (1) Tumor stromal cells in TME have undergone malignant transformation, which is related to the tissue remodeling of TME by GSCs, and not limit to the specific type of their parasitic tissues. (2) Tumor cells originated from GSC and tumor interstitial cells, respectively, are two major types of tumor cells with different origins in glioma parenchyma, can not be simply regarded as tumor heterogeneity, transformed interstitial cells of TME may have the potential to serve as new targets for target diagnosis and therapy. PMID- 30440126 TI - [Effects of calcineurin gene silencing on the remodeling of transient outward potassium current ionic channel in hypertrophic ventricular myocytes from neonatal rats]. AB - Objective: To investigate the effects of calcineurin gene silencing on the remodeling of transient outward potassium current (Ito) ionic channel and action potential duration (APD) in phenylephrine (PE)-induced hypertrophic ventricular myocytes from neonatal rats. Methods: The ventricular myocytes of 1-day-old Sprague-Dawley rats were isolated and cultured for 48 h. RNA interference mediated by adenovirus carrying short hairpin RNA was used to knock down the gene which encodes the beta subtype of calcineurin A subunit (CnAbeta) and the cells were divided into 4 groups as Ad-null group, Ad-null+ PE group, Ad CnAbetashRNA1(A1) group and A1+ PE group, and then cultured for 48 h. The gene expression of Kv4.2 was assayed by real-time reverse transcriptase-polymerase chain reaction. The protein expressions of CnAbeta and Kv4.2 were assayed by Western blot test. Whole cell patch clamp technique was used to record Ito and action potential. Results: Treatment of the neonatal rat ventricular myocytes with PE induced the cell hypertrophy, up-regulated the protein expression of CnAbeta, attenuated the gene and protein expressions of Kv4.2 and the Ito current density, and prolonged APD. Silencing of CnAbeta in the neonatal rat ventricular myocytes using Ad-CnAbetashRNA1 inhibited the aforementioned ability of PE significantly. Conclusion: CnAbeta gene silencing inhibits the remodeling of transient outward potassium current ionic channel and change of APD in PE-induced hypertrophic ventricular myocytes from neonatal rats. PMID- 30440127 TI - [Brachytherapy treatment planning calculation (125)I particle esophageal stent dosimetric study]. AB - Objective: To investigate the dosimetric distribution characteristics of (125)I seed stents with different seed spacing, diameter and length, as well as different (125)I seed activity. The dosimetry table of (125)I seed esophageal stent was derived to provide dosimetry for its clinical application. Methods: The self-expanding coated esophagus stent was designed to carry radioactive (125)I seeds with different length, diameter and seed spacing. A cylindrical organic glass model (Thickness 0.8 cm, diameter 20 cm, height 20 cm) was fixed vertically to a cylindrical organic glass containing a solid paraffin (analytical pure) solution. After paraffin cooling and solidification, CT scan was used to transmit image information to TPS. With the center of the bracket as a dot, the cumulative dose at a distance of 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0 and 8.0 cm away from the dot was simulated respectively in 0 degrees and 9 degrees direction. Results: The radial cumulative dose with the seed spacing which was 1.0 and 1.5 cm were different by 4.8%, 5.8%, 7.2%, 8.0%, 8.6% and 13.3% respectively under the exposure of 18.5, 22.2, 25.9, 29.6, 33.3 and 37.0 MBq. When the seed spacing was the same as the length of the stent, the radial cumulative dose with the stent which diameter was 1.3, 2.0, 2.4 cm were different by 4.9% vs 3.4%, 4.7% vs 3.8%, 5.4% vs 6.6%, 4.5% vs 5.3%, 4.7% vs 4.8%, 4.8% vs 5.4% respectively under the exposure of 18.5, 22.2, 25.9, 29.6, 33.3 and 37.0 MBq. When the seed spacing was the same as the diameter of the stent, the radial cumulative dose with the stent which length was 8, 12, 16 cm were different by 1.9% vs 1.2%, 1.7% vs 0.8%, 1.6% vs 1.3%, 1.9% vs 1.5%, 1.7% vs 1.8%, 1.6% vs 1.3% respectively under the exposure of 18.5, 22.2, 25.9, 29.6, 33.3 and 37.0 MBq. Conclusions: The radial cumulative dose of the (125)I seed stent is positively correlated with the activity of the radioactive seeds, Which means the dose rate of a certain point of the (125)I seed stent increase with the increase of the activity of the radioactive seeds. The stent of the (125)I radioactive seeds is negatively correlated with the distance, the dose rate of the (125)I seed stents decrease rapidly with the increase of distance. PMID- 30440128 TI - [Role of signaling pathway of long non-coding RNA growth arrest-specific transcript 5/microRNA-200c-3p/angiotensin converting enzyme 2 in the apoptosis of human lung epithelial cell A549 in acute respiratory distress syndrome]. AB - Objective: To investigate whether long non-coding RNA (lncRNA) growth arrest specific transcript 5 (GAS5)/microRNA-200c-3p/angiotensin converting enzyme 2(ACE2) involved in the regulation of the apoptosis of human lung epithelial cell A549 in acute respiratory distress syndrome (ARDS). Methods: ARDS rat models were established and were divided into control, ARDS, ARDS+ pcDNA and ARDS+ pcDNA-GAS5 groups. Six hours after the establishment of ARDS rat model, arterial blood and lung tissues of the rats from the four groups were collected. The changes of partial pressure of oxygen (PO(2)) and partial pressure of CO(2) (PCO(2)) were analyzed and the expression of GAS5 in lung tissue was observed in these groups. Then, A549 cells were divided into control, lipopolysaccharide (LPS), LPS+ pcDNA, LPS+ pcDNA-GAS5, LPS+ pcDNA-GAS5+ pre-NC, LPS+ pcDNA-GAS5+ miR-200c-3p mimic groups. Quantitative real-time PCR (qRT-PCR) was conducted to measure lncRNA GAS5, ACE2 and miR-200c-3p levels. RNA immunoprecipitation and RNA pull-down assay were used to detect the combination between GAS5 and miR-200c-3p. Western blotting was used to detect the protein level of ACE2. Flow cytometry was used to observe the apoptosis of A549 cells in those groups. The data between groups were compared by t test. Results: In ARDS rat model, PO(2) value was significantly increased in ARDS+ pcDNA-GAS5 group than that in ARDS+ pcDNA group[(81.5+/-3.3) vs (57.5+/-5.1) mmHg, t=4.850, P<0.05], and PCO(2) value was significantly decreased in ARDS+ pcDNA-GAS5 group than that in ARDS+ pcDNA group[(50.6+/-1.9) vs (64.0+/-1.9) mmHg, t=5.940, P<0.05]. LncRNA GAS5 level in A549 cells of LPS group decreased significantly than that in control group (0.43+/-0.01 vs 1.01+/ 0.01, t=0.242, P<0.05). Compared with LPS+ pcDNA group, ACE2 expression increased significantly in LPS+ pcDNA-GAS5 group (0.85+/-0.04 vs 0.34+/-0.02, t=1.800, P<0.05). Compared with LPS+ pcDNA-GAS5+ pre-NC group, ACE2 expression decreased significantly in LPS+ pcDNA-GAS5+ miR-200c-3p mimic group (0.62+/-0.01 vs 0.84+/ 0.02, t=9.440, P<0.05). Compared with control group, the percentage of A549 cell apoptosis promoted significantly in LPS group (25.90+/-0.61 vs 7.90+/-0.22, t=0.257, P<0.05). Compared with LPS+ pcDNA group, the percentage of A549 cell apoptosis suppressed significantly in LPS+ pcDNA-GAS5 group (10.50+/-0.37 vs 26.37+/-0.45, t=1.760, P<0.05). Compared with LPS+ pcDNA-GAS5+ pre-NC group, the percentage of A549 apoptosis promoted significantly in LPS+ pcDNA-GAS5+ miR-200c 3p mimic group (19.07+/-0.56 vs 10.87+/-0.26, t=0.643, P<0.05). Conclusion: In ARDS, down-regulation of lncRNA GAS5 decreases ACE2 expression through increasing miR-200c-3p to promote the apoptosis of A549 cells, thus to promote the progression of ARDS. PMID- 30440129 TI - [HIV epidemic among pregnant women in China, 2016: trend and spatial analysis]. AB - Objective: To describe the spatial distribution characteristics of the HIV prevalence among pregnant women in mainland China in 2016, providing scientific evidence for the prevention of mother-to-child transmission of HIV. Methods: Data on pregnant women and those living with HIV in 2016 for all counties in mainland China is from the National Maternal & Child Health Statistics dataset. To obtain robust estimates, 2 964 counties were merged into 344 cities. Spatial autocorrelation analysis and trend analysis were performed based on the city level dataset to detailedly describe the characteristics of the spatial distribution. Results: A total of 14 879 082 pregnant women were included in the analysis, among whom 5 051 were diagnosed to be infected with HIV, giving an overall prevalence of 34.0 per 100 000 pregnant women. The prevalence was higher in the south than in the north, and decreased from the west (93.5/100 000) to the east(8.6/100 000 ), more specifically, the prevalence in the West region was 11 times as high as that in the East region(chi(trend)(2)=68.61, P<0.01). Stratified analysis by provinces showed that there were 6 provinces whose prevalence was >50.0 per 100 000, and they (Yunnan, Xinjiang, Sichuan, Guangxi, Guizhou and Chongqing) were all located in the West Region; pregnant women in these provinces accounted for 21% of all pregnant women, but the HIV cases accounted for 76% of all cases diagnosed in mainland China. Stratified analysis by cities showed that there were 30 cities whose prevalence was >100.0 per 100 000, and 28 of these cities were also located in the western provinces above. Furthermore, the global Moran's I (0.5, P<0.01) indeed indicated a strong clustered distribution across mainland China; 2 hot spots were observed in the Midwest of Xinjiang, and Yunnan and its bordering areas (Sichuan, Guizhou, Guangxi and Chongqing), while 1 cold spot in the central and east China. The HIV prevalence in the hot spots (183.6/100 000) was 23 times as much as that in the cold spot (8.1/100 000). Conclusion: The overall HIV prevalence for pregnant women who lived in mainland China in 2016 (34.0/100 000) ranked at low-level worldwide, but varied markedly across the whole country with 2 high-prevalence-clustered areas: the Midwest of Xinjiang Uygur Autonomous Region, and Yunnan province along with its bordering areas, indicating comprehensive intervention strategies especially targeted to the areas with high HIV prevalence should be developed. PMID- 30440130 TI - [Relationship between UGT1A4 142T>G polymorphism and serum concentration of lamotrigine in Chinese epileptic patients: a meta-analysis]. AB - Objective: To investigate the relationship between the polymorphism of Uridine diphosphate glucuronosyltransferases (UGT)1A4 142T>G (*3, L48V, rs 2011425)and serum concentration of lamotrigine(LTG) in Chinese epileptic patients. Methods: Databases including Cochrane Library, PubMed, Embase, CNKI, VIP and Wanfang were searched for the studies on the relationship of the polymorphisms of UGT1A4 142T>G with concentration of LTG (from the establishment a database to December 1, 2017). Meta-analysis was performed by RevMan 5.3. Results: We pooled data from 6 literatures, including 903 Chinese epileptic patients. Meta-analysis: In terms of the effect of UGT1A4 142T>G polymorphism on the serum concentration/dose ratio(CDR)of LTG, there was no significant difference between the wild-type(TT genotype)group and mutant-type (TG+ GG genotype) group (MD=-0.08, 95% CI (-0.40 0.23)). Further subgroup analysis was performed on LTG monotherapy or valproic acid(VPA)co-administration. For patients treated with LTG as monotherapy, difference was not statistically significant between the 2 groups(MD=0.16, 95% CI(-0.25-0.57)). But in children treated with VPA co-administration, difference was statistically significant between the 2 groups (MD=-0.50, 95% CI(-0.75- 0.26)). Conclusion: UGT1A4 142T>G polymorphism has an effect on LTG concentration only with VPA co-administration in Chinese epileptic pediatric patients and those children with wild-type (TT genotype) have a tendency to have a lower serum concentration of lamotrigine. PMID- 30440131 TI - [Effects of interaction between fructose and intestinal microflora on chronic kidney disease progression]. PMID- 30440132 TI - [Evaluation of protein-energy wasting in maintenance hemodialysis patients]. PMID- 30440133 TI - [Association of low serum parathyroid hormone with protein-energy wasting in maintenance hemodialysis patients]. AB - Objective: To examine the relationship between low serum parathyroid hormone (PTH) and protein-energy wasting (PEW) in patients who underwent maintenance hemodialysis (MHD) treatment. Methods: A cross-sectional study was conducted in MHD patients between June 2015 and August 2017 in 11 MHD centers from Guizhou province. Body composition and physical parameters were measured, clinical data and other related laboratory values were collected according to the medical record system. Participants were assigned to low serum PTH group (PTH<150 ng/L), target PTH group (150 ng/L<= PTH <=300 ng/L) and high serum PTH group (PTH>300 ng/L). Multivariate logistic regression analysis was used to analyze the relationship between low serum PTH and risk of PEW, which was diagnosed according to the diagnostic criteria recommened by the International Society of Renal Nutrition and Metabolism (ISRNM). Results: A total of 873 MHD patients (488 males and 385 females) were included in the final analysis, with a mean age of 55.0 (44.0, 67.0) years and a mean hemodialysis duration of 31.0(17.0, 54.0) months. In unadjusted model, low serum PTH group was associated with PEW (OR=2.12, 95% CI: 1.26-3.54, P=0.004), when compared with high serum PTH group. After adjustment for age and sex, low serum PTH group was still significantly associated with PEW (OR=2.09, 95% CI: 1.23-3.52, P=0.006). Further adjustment for diabetes and hypertension, the correlation between low serum PTH group and PEW was still significant (OR=2.02, 95% CI: 1.04-3.90, P=0.037). However, the correlation was not observed in target PTH group and high serum PTH group. Conclusion: Low serum PTH was associated with risk of PEW, regardless of age, sex, history of diabetes and hypertension, and thus it might be a promising indicator of PEW in MHD patients. PMID- 30440134 TI - [Effect of hyperphosphatemia on patency rate of arteriovenous fistula of patients with late fistula dysfunction/failure after reoperation]. AB - Objective: To investigate the effect of hyperphosphatemia on long-term patency of arteriovenous fistula (AVF) of patients with late fistula dysfunction/failure after reoperation. Methods: The study was carried out in the Department of Nephrology of the First Affiliated Hospital of Tsinghua University between March 2012 and March 2013. A total of 136 maintenance hemodialysis patients[73 males, 63 females, with an average age of (57.7+/-16.1) years]with late AVF dysfunction/faliure who received AVF reoperation were enrolled in the study. After follow-up for 3 years, 118 patients were left and divided into two groups: fistula dysfunction group (n=38), fistula patency group (n=80). Patients were aslo divided into two groups according to the blood phosphorus level: the blood phosphorus >1.78 mmol/L group (n=53) and the blood phosphorus <=1.78 mmol/L group (n=65). t test was used to compare the serum phosphorus levels of patients with dysfunction group and fistula patency group. Patency rate was calculated by survival analysis method and log-rank test was used to compare secondary patency rate between groups of blood phosphorus >1.78 mmol/L and blood phosphorus <=1.78 mmol/L. Multivariate Cox regression was used to analyze the influencing factors. Results: The average blood phosphorus level was significantly higher in dysfunction group[(1.87+/-0.42) mmol/L vs (1.65+/-0.39) mmol/L, P=0.008], and patency rate was significantly lower in patients of blood phosphorus>1.78 mmol/L group than that in patients of blood phosphorus <=1.78 mmol/L (42.2% vs 60.4%, P=0.009). Blood phosphorus>1.78 mmol/L (RR=2.527, 95% CI: 1.272-5.023, P=0.008), diabetes (RR=2.667, 95% CI: 1.339-5.313, P=0.005) and C-reactive protein (CRP)>5 mg/L (RR=2.749, 95% CI: 1.324-5.710, P=0.007) were risk factors affecting secondary patency rate of internal fistua. Conclusion: Hyperphosphatemia is an independent risk factors for the patency rate of AVF after reoperation in hemodialysis patients. PMID- 30440135 TI - [Relationship between visceral obesity and atherosclerosis in hemodialysis patients]. AB - Objective: To evaluate the relationship between surrogate markers of visceral obesity[hypertriglyceridemic waist (HW) phenotype, visceral adiposity index (VAL), lipid accumulation product (LAP)]and atherosclerosis in hemodialysis patients. Methods: A multi-center cross-sectional study was carried out. A total of 961 maintenance hemodialysis (MHD) patients from 11 hemodialysis centers of Guizhou province between July 2016 and September 2017 were enrolled in the study. Anthropometric measures were performed in all subjects. Laboratory parameters including triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein-cholesterol were extracted from the medical records by researchers. Pearson correlation analysis was used to investigate the correlation between HW phenotype, VAI, LAP and plasma atherosclerotic index (AIP). Multivariate linear regression analysis was used to evaluate factors affecting AIP. Results: Totally, 585 men and 376 women aged 18-90 years, with a mean age of (56.08+/-15.42) years were recruited in the study. Pearson correlation analysis showed that VAI (men: r=0.82, women: r=0.84), LAP (men: r=0.73, women: r=0.74) and having HW phenotype (men: r=0.62, women: r=0.63) correlated positively with AIP (all P<0.001). Multivariate linear regression analysis showed that VAI (men: beta=0.77, women: beta=0.82) and LAP (men: beta=0.73, women: beta=0.73) were independent associated factors of AIP after adjustment of BMI, age, smoking and history of diabetes and hypertension (all P<0.001). Conclusions: Surrogate markers of visceral obesity such as having HW phenotype, VAI, LAP correlated positively with AIP. VAI, LAP has positive impacts on AIP independent of BMI, age, smoking and other traditional atherosclerosis risk factors. PMID- 30440136 TI - [Value of RNA oxidation product 8-oxo-Gsn in evaluating renal function in patients with chronic kidney disease]. AB - Objective: To investigate the relationship of DNA oxidative product 8-oxo-dGsn and RNA oxidative product 8-oxo-Gsn with chronic kidney disease (CKD). Methods: Between January 2015 and December 2016, 146 cases of CKD (30, 30, 31, 30 and 25 cases of CKD stage 1-5, respectively) were collected in the Department of Nephrology in Beijing Hospital. Among them, 70 cases were male, accounting for 47.95%. The age distribution ranged from 21 to 88 years, with an average age of (56.43+/-16.79) years. Their fasting blood and morning urine were collected. The levels of 8-oxo-dGsn and 8-oxo-Gsn in plasma and urine were quantified by isotope diluted liquid chromatography mass spectrometry (MS)/MS (ID-LC-MS/MS). Results: The urine 8-oxo-Gsn/Cr in patients with CKD stage 1-5 was (3.07+/-1.07) MUmol/mol, (3.42+/-1.34) MUmol/mol, (3.72+/-1.47) MUmol/mol, (3.90+/-1.93) MUmol/mol and (3.75+/-2.26) MUmol/mol, respectively. The urinary 8-oxo-Gsn content in CKD stage 4 patients was significantly higher than those of other 4 stages (P<0.05). The serum/urine ratio of 8-oxo-Gsn was 0.02+/-0.02, 0.03+/-0.02, 0.06+/-0.04, 0.10+/-0.05 and 0.34+/-0.03, respectively, and in CKD stage 4 and 5 patients, it increased significantly, especially in CKD stage 5 cases (P<0.05). Expression of 8-oxo-Gsn had a good correlation with renal function[the Spearman 's correlation coefficient: serum 8-oxo-Gsn and serum creatinine was 0.629 (P<0.001); urine/serum 8-oxo-Gsn and eGFR was 0.799 (P<0.001); serum/urine 8-oxo Gsn and serum/urine creatinine was 0.888 (P<0.001)]. With age increasing, CKD patients showed increased RNA oxidation, and 8-oxo-Gsn increased significantly in patients over 60 years (P<0.05). After multiple linear regression analysis, 8-oxo Gsn was only associated with serum creatinine (beta=0.656, t=8.275, P<0.001). Conclusions: Our finding indicates that the RNA oxidation occurs in patients with renal disease, and its oxidation increased as the disease progressing. The significant increase in the ratio of plasma and urinary 8-oxo-Gsn is of great importance on evaluating renal function. PMID- 30440137 TI - [Clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy and the corresponding pharmacogenomics analysis]. AB - Objective: To investigate the association between Thymidine phosphorylase(TYMP)genetic variation and clinical outcomes of postoperative gastric cancer (GC) patients received capecitabine based regimens. Methods: A total of 198 GC patients underwent surgical treatment and received capecitabine based adjuvant chemotherapy were included in this retrospective study. Peripheral blood and the postoperative tissue specimen of the GC patients were collected for the genotyping of polymorphism and TYMP mRNA expression, respectively. The correlation between polymorphism and clinical outcomes and safety of postoperative GC patients were analysed. Results: Located in the upstream, rs11479 was of clinical significance. The prevalence of rs11479 in TYMP among the GC patients were as follows: CC genotype 125 cases (63.13%), CT genotype 65 cases (32.83%), TT genotype 8 cases (4.04%), minor allele frequency of rs11479 is 0.20. The distribution of three genotypes were in accordance with Hardy-Weinberg Equilibrium (P=0.901). The analysis results of patients with different genotypes found that the 3-year disease free survival rate of the patients with CT/TT genotype and CC genotype were 73.97% and 65.60%, respectively, which was statistically significant (P=0.003). In terms of overall survival, the 3-year overall survival rate of the two genotypes were 83.56% and 72.80% (P=0.012), respectively. Adjusted in multivariate Cox regression analysis, CT/TT genotype was an independent favorable factor for disease free survival (OR=0.55, P=0.011). Safety analysis indicated that there was no significant association between genotypes and grade 2 adverse reaction. Additionally, of the 79 postoperative tissue specimens, the results showed that the expression of TYMP in cancer tissues of the patients with CT/TT genotypes were significantly higher than those of the wild type CC genotype patients (P<0.001). Conclusion: The polymorphism rs11479 of TYMP have favorable influence on the clinical outcomes of gastric cancer patients received capecitabine based adjuvant chemotherapy treatment through changing the mRNA expression of TYMP. PMID- 30440138 TI - [Study of de novo point mutations in known genes among patients with unexplained intellectual disability or developmental delay]. AB - Objective: To analyze the de novo point mutations in known genes among patients with unexplained intellectual disability (ID) or developmental retardation (DD). Methods: A total of 120 outpatients with ID or DD were recruited in the Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics between September 2015 and April 2017. Target gene sequencing was used to screen the candidate gene. The sequencing data were analyzed by a variety of bioinformatics software. Combining with the phenotypes of the patients, the candidate genetic/genomic variants were identified from next-generation sequencing data. The final pathogenicity of the genetic/genomic variants were interpreted according to the guideline of the American College of Medical Genetics and Genomics (ACMG) for variants after segregation analysis in the parents and necessary family members by Sanger sequencing. The comprehensive physiological function and signaling pathways of 20 disease genes with de novo point mutation discovery was also studied. Results: Among the 120 patients, 23 patients were found to carry clear pathological changes, and the incidence of de novo point variation was 19.2%. The patients included 12 males and 11 females, with an age of 2 months to 6-year-6-month. Five patients were diagnosed with early onset of epileptic encephalopathy. Seven had mental retardation type 5, 6, 8, 19, 20, 22, 39, respectively. Weill-Marchesani syndrome type 2 was found in one case, Wiedemann-Steiner syndrome in one case, Coffin-Siris syndrome in two cases, Rubinstein-Taybi syndrome in one case, GLUT1 deficiency syndrome in one case, Rett syndrome in one case, cardio-facio-cutaneous syndrome 3 in one case, neurodegeneration with brain iron accumulation in one case, corpus callosum local dysplasia in one case, and congenital fibrosis of the extra-ocular muscles in one case. A total of 20 novel mutations were reported in this study. No somatic mutation was found in the samples of 6 patients with mutation and their parents' peripheral blood DNA samples by amplicon-based deep sequencing. This study found that the main disease genes were involved in chromatin remodeling, transcriptional regulation, autophagy body assembly, MAPK signal pathway, DNA methylation, potassium, sodium ion transport, cell skeleton assembly and skeletal muscle development. These genes were significantly enriched in the following biological processes: Ras signaling pathways, transcription factor binding and cancer related signaling pathway. Conclusions: The etiology of children affected with intellectual disability or developmental delay is complex. Harmful de novo point mutation plays an important role in these diseases. Targeted exome/genome sequencing based on the core family is helpful for the molecular diagnosis of patients and the discovery of more genes. PMID- 30440139 TI - [The technique and efficacy of complete resection of mesogastrium above the pancreas by the right approach in laparoscopic assisted distal gastrectomy for radical gastrectomy]. AB - Objective: To explore the safety and efficacy of mesogastrium excision above the pancreas by the right approach in radical distal gastrectomy for cancer. Methods: A total of 154 distal gastric cancer patients in the Department of Gastrointestinal Surgery of the first affiliated Hospital of Chongqing Medical University, from October 2013 to October 2014, were included in this random controlled study. These patients were divided into the study group (n=78), who received mesogastrium excision above the pancreas by the right approach, and the control group (n=76), who received mesogastrium excision above the pancreas when by the left approach. Results: No significant differences were observed between the two groups in terms of the number of lymph node, postoperative recover, complications and 3-year survival rate(P>0.05), while significant differences were observed between the two groups in terms of operation time and surgical bleeding(P<0.05). Conclusions: In radical distal gastrectomy for cancer, the safety and efficacy for mesogastrium excision above the pancreas were the same by the right approach, compared to by the left approach, however, the group by the right approach had the advantage on the operation time and surgical bleeding. PMID- 30440140 TI - [Correlation between serum CD147 and carotid intraplaque hemorrhage]. AB - Objective: Intraplaque hemorrhage (IPH) is one of the most important causes of ischemic stroke. The purpose of this study was to explore the association between carotid IPH and CD147, which may be the serum marker related to IPH. Methods: Serum samples were collected from 68 patients with carotid artery stenosis from April to September 2004. 3.0T MRI with the 8 channel surface coil was used to scan carotid artery. Images was processed by MRI-PlaqueView. The integrity of lipid, IPH, calcified components and fibrous cap in the plaque was analysed qualitatively and quantitatively. The correlation and difference analysis among serum CD147 and plaque components were carried out. Results: Serum CD147 level in IPH positive was higher than that in IPH negative, 5 510.1 vs 4 648.0 (P=0.04). There was no significant correlation among serum CD147 and the quantitative parameters of lipid, IPH and calcification in carotid plaque and fibrous cap rupture. Serum CD147 in patients using statins was lower than that in patients not using statins, 4 914.0 vs 5 926.7 (P<0.01). Serum total cholesterol and LDL were positively correlated with serum CD147. In patients without statin, serum CD147 had a better diagnostic value for carotid IPH (AUC=0.81, P=0.04, 95% CI 0.62-0.99). Conclusion: Serum CD147 would probably be one biomarker of IPH and shows good diagnostic value of carotid IPH in the specific population. PMID- 30440141 TI - [Clinical analysis of IgG4-related lung disease]. AB - Objective: To improve the understanding and treatment of IgG4-related lung disease (IgG4-RLD) by analyzing the clinical characteristics of patients. Methods: A total of 13 patients with IgG4-related lung disease (IgG4-RLD) diagnosed by pathology at Zhongshan Hospital affiliated to Fudan University during December 2007 to December 2017 were included. The clinical characteristics, chest CT, pathological features, serum IgG4 levels, therapy and prognosis of these 13 patients were analyzed. Results: The 13 patients with IgG4 RLD included 8 men and 5 women, with an average age of (51.1+/-14.8) years. The clinical manifestations were varied, 10 patients showed respiratory symptoms, mainly including cough (n=9), expectoration (n=6), hemoptysis (n=6), chest tightness (n=2) and breathless (n=2). Multiple organs were involved in 12 cases. Chest CT showed solid lung nodules (n=9), ground glass shadows (n=1), alveolar interstitial infiltration (n=3), bronchovascular lesions (n=3), and the solid lung nodules was predominant. Enlargement of lymph nodes in the mediastinal and bilateral hilum of the lung were present in 10 cases. Serum IgG4 levels were elevated in all the 13 cases, with an average concentration of (7.92 +/ 13.98)g/L. Quite amount of lymphocytes, plasma cell infiltration and fibrosis were common pathologic findings. Immunohistochemical staining showed a large number of IgG4 positive plasma cells infiltration with IgG4 positive plasma cells count 10-320/HP in 13 cases. The ratio of IgG4 positive plasma cells to IgG positive plasma cells was higher than 40%. Eight patients received glucocorticoid therapy alone, five received glucocorticoids with immunosuppressant therapy. After treatment, 10 patients were with remission, and disease progressed in 3 patients, but no death. Conclusions: The clinical manifestations and imaging features of IgG4-RLD are diverse, and lesions can often involve multiple organs. The diagnosis could be made based on pathological features and IgG4 serum levels. Glucocorticoid can be used as the first choice for the treatment of IgG4-RLD. PMID- 30440142 TI - [Mechanism of miR-221 contributes to gefitinib resistance in PC-9 cells]. AB - Objective: To investigate the effect of microRNA-221 (miR-221) overexpression on gefitinib resistance in PC-9 cells and study its underlying mechanisms. Methods: PC-9 cells were transfected with LV-NC and LV-miR-221 to establish cell stabilizing strains (PC-9/NC and PC-9/miR-221), then they were used to detect the relative expression of miR-221 and apoptotic protease activating factor-1 (APAF 1) mRNA by real-time fluorescence quantitative PCR (qRT-PCR). The effects of gefitinib (0-4 MUmol/L) on the growth and proliferation of cell stabilizing strains were detected by CCK-8 Assay. After gefitinib treatment, cell apoptosis was detected by Flow Cytometry Assays. The expression of epidermal growth factor receptor (EGFR), phosphorylated epidermal growth factor receptor (p-EGFR), APAF-1 and cleaved cysteinyl aspartate specific proteinase-3 (Cleaved-caspase-3) were detected by Western blot. Dual-Luciferase Reporter Assay was used to evaluate the relationship between APAF-1 and miR-221. Results: The relative expression of miR 221 in PC-9/NC cells was significantly lower than that in PC-9/miR-221 cells[(1.00+/-0.082) vs (40.24+/-0.017)](P<0.01). The half maximal inhibitory concentration (IC(50)) in PC-9/NC cells was significantly lower than that in PC 9/miR-221 cells[(IC(50)=0.1 MUmol/L) vs (IC(50)>4 MUmol/L)](P<0.05). Apoptosis rate of PC-9/NC cell was significantly higher than PC-9/miR-221[(33.42+/-4.28)% vs (10.27+/-1.12)%](P<0.05); APAF-1 mRNA expression was significantly higher in PC-9/NC cells than PC-9/miR-221[(1.000+ 0.069) vs (0.701+/-0.072)](P<0.05), and the expression of APAF-1 protein in PC-9/NC cells was significantly higher than that of PC-9/miR-221 cells. The dual luciferase reporter gene results showed that miR-221a inhibited luciferase activity significantly stronger than transfected miRNA negative control group after co-transfection of luciferase plasmids pmir REPORT-APAF-1-wt and miR-221a mimics (P<0.01). p-EGFR was down-regulated in both PC-9/NC and PC-9/miR-221 cells after treatment with gefitinib. APAF-1 and Cleaved caspase-3 proteins were significantly down-regulated in PC-9/miR-221 cells compared with PC-9/NC cells, while APAF-1 and Cleaved-caspase-3 proteins were up regulated in PC-9/NC cells treated with gefitinib compared with PC-9/miR-221 cells (P<0.05). Conclusion: miR-221 induces resistance to gefitinib in PC-9 cells by downregulating APAF-1 expression. PMID- 30440143 TI - [Chinese burn referral criteria (2018 version)]. AB - There is no national referral criteria for burns in China till now, which brings inconvenience and confusion. Based on the oversea experiences and the actual situation in China, many famous experts on burns discussed and developed this Chinese burn referral criteria (2018 version). We hope these referral criteria will be helpful in clinical practice in burn field and can be improved continuously during application. PMID- 30440144 TI - [National experts consensus on application of silver-containing dressings in wound therapy (2018 version)]. AB - New silver-containing dressings developed in recent years have brought new and powerful means for the prevention and treatment of wound infection, which promote development and progress of wound therapy. There are many kinds of silver containing dressings, however, misunderstanding and even misapplication exist in how to choose and use these dressings. Based on literature evidence, we propose this national expert consensus on clinical application of silver-containing dressings, particularly in terms of kinds and mechanisms, indications, contraindications, rational selections in different wounds, and cautions in the clinical application of silver-containing dressings. This consensus would be helpful for medical and nursing personnels to use silver-containing dressings in wound repair field in clinic correctly and professionally. PMID- 30440145 TI - [National experts consensus on clinical application of collagen-based wound biomaterials (2018 version)]. AB - Collagen, as the main structural protein in human body, plays an important role in the wound healing process. Due to their inherent hemostatic characteristics, good biocompatibility, low immunogenicity, as well as controllable biodegradability, collagen-based materials have attracted much attention. In this article, we mainly introduce the characteristics of collagen-based wound biomaterials and the application mechanism as scaffold and wound dressing. And the standard and unified experts' consensus formed on the clinical indications, recommended applications, contraindications, and matters needing attention. The consensus wound help clinicians and patients to recognize collagen-based wound biomaterials correctly and use them rationally. PMID- 30440146 TI - [National experts consensus on clinical diagnosis and treatment of inhalation injury (2018 version)]. AB - Inhalation injury is caused by inhalation of heat, toxic or irritating gases which lead to respiratory and pulmonary parenchyma damage. At present, the clinical understanding about it is still limited and lack of effective diagnosis and treatment standard. Based on the experience of diagnosis and treatment of domestic inhalation injury, combined with reports of international researches, criteria (expert consensus) for inhalation injury were systematically discussed from pathological and pathophysiological changes, clinical diagnosis and evaluation, and clinical treatment, which provides reference for clinical diagnosis and treatment of patients inflicted with inhalation injury. PMID- 30440147 TI - [National experts consensus on application of pulse contour cardiac output monitoring technique in severe burn treatment (2018 version)]. AB - As a newly developed technique for hemodynamic monitoring, pulse contour cardiac output (PiCCO) monitoring takes great advantages in guiding shock resuscitation and fluid administration. PiCCO has been used more and more in burn patients in recent years, however there is no clinic consensus on how to apply PiCCO monitoring, understand the significance of PiCCO monitored parameters, and guide the treatment using PiCCO monitored parameters in patients with severe burns. Based on the current literatures and the experts' clinical experience, national experts consensus on application of pulse contour cardiac output monitoring technique in severe burn treatment (2018 version) is now issued by the Burn and Trauma Branch of Chinese Geriatrics Society, aiming to provide practical guidance for its usage in clinic. PMID- 30440148 TI - [National experts consensus on tracheotomy and intubation for burn patients (2018 version)]. AB - Airway edema, stenosis, obstruction and even asphyxia are easy to occur in patients with extensive burn, deep burn of head, face, and neck area, inhalation injuries, etc., which threaten life. Timely tracheotomy and intubation is an important treatment measure, but lack of knowledge and improper handling in some hospitals resulted in airway obstruction. The technique of percutaneous tracheotomy and intubation provides convenience for emergency treatment of critical burns and mass burn. The Chinese Geriatrics Society organized some experts in China to discuss the indications, timing, methods, extubation, and precautions of tracheotomy and intubation for burn patients. The national experts consensus on tracheotomy and intubation for burn patients (2018 version) was written to provide a reference standard for clinical treatment. PMID- 30440149 TI - [Rational application of optical coherence tomography in examining glaucomatous optic neuropathy]. AB - Glaucoma-related retinal imaging using frequency domain optical coherence tomography (OCT) has become an important but not the only basis for the diagnosis and follow-up of glaucoma. The circumpapillary retinal nerve fiber layer thickness and the macular ganglion cell thickness are two commonly used structural parameters in glaucoma. Their diagnostic efficacy is similar, but each has different influencing factors. Clinically, these two parameters should be analyzed together to improve the specificity and sensitivity for detecting glaucomatous optic nerve damage. Recently, there have been quite a few clinical studies on new OCT technologies and concepts related to glaucoma, but it is still necessary to further confirm the application value. Ophthalmologists should master the principle of glaucoma-related OCT retinal imaging, combining with other clinical evaluation methods, to improve early diagnosis and timely detection of glaucomatous progression.(Chin J Ophthalmol, 2018, 54: 801-805). PMID- 30440150 TI - [Which is better for anti-glaucoma surgery, filtering bleb dependence or non dependence]. AB - The filtration bleb dependent surgeries, such as trabeculectomy, are the main methods for glaucoma treatment in China. However, the filtration bleb scarring after the surgery has always been a challenge to long-term results. In recent years, with the application of anti-glaucoma non-filtering bleb dependent surgery, the surgery complications of filter bubble dependence have been avoided, such as shallow anterior chamber and leakage of filtering bleb. Researches are still needed on the indications, long-term effects and health economics evaluations. It also takes time to widely popularize its application in China. This article focuses on comparing the filtration bleb dependent surgeries with non-filtering bleb dependent surgeries to deeply state the characteristics, advantages and disadvantages of the two methods. (Chin J Ophthalmol, 2018, 54: 806-810). PMID- 30440151 TI - [The function-structure impairment pattern of optic nerves in primary open-angle glaucoma and normal-tension glaucoma]. AB - Objective: To investigate the characteristics of impairment of the visual field (VF) and retinal nerve fiber layer (RNFL) and the differences of progression pattern of early, middle and late stages of primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG) , and to analyze the correspondence of structure and function. Methods: Cross-sectional study. POAG patients, NTG patients and healthy volunteers who were enrolled from February 2008 to May 2017 at Department of Ophthalmology, Eye & ENT Hospital of Fudan University, underwent basic ophthalmic examination, Humphrey central 24-2 threshold test and optical coherence tomography. Patients were divided into early, middle and late stages according to the mean defect (MD) index of the VF test. According to the RNFL distributional characteristics, the pattern deviation map and RNFL were divided into 6 sectors. The differences of each sector's MD and RNFL thickness in the healthy group and groups of patients at 3 stages were analyzed using the Kruskal Wallis test, and the correlation of MD and RNFL thickness of each sector was analyzed using the Pearson coefficient. Results: In the POAG group, there were 84 cases (84 eyes) including 35 eyes of early stage, 20 eyes of middle stage and 29 eyes of late stage, with a male/female ratio of 43?41, aged (45+/-15) years. In the NTG group, 69 cases (69 eyes) included 30 eyes of early stage, 20 eyes of middle stage and 19 eyes of late stage, with a male/female ratio of 33?36, aged (49+/-13) years. The control group had 23 cases (23 eyes), with a male/female ratio of 16?17 and an age of (44+/-10) years. There was no significant difference in male/female ratio, age or best corrected visual acuity among the three groups. (1) In the middle stage of POAG, the VF defects of inferior hemi-fields were more severe than the superior (t=21.62, P=0.000), which was opposite to the late stage of POAG (t=-3.28, P=0.003). In each stage of NTG, there was no significant difference between two hemi-fields. In the control group, the MD values(antilog) of VF in the superior peripheral arch (PEA), superior paracentral arch (PAA), inferior PEA and PAA, temporal and central regions were 0.87 (0.63-1.11)/L, 0.74 (0.61-0.83)/L, 0.72 (0.55-0.97)/L, 0.65 (0.51-0.87)/L, 0.69 (0.57-0.97)/L, and 0.82 (0.54-0.93)/L, respectively. The sectoral MD values in the VF sectors of POAG were significant compared with the control group (P<0.05): superior PAA for early stage [0.61 (0.18-0.92)/L, H=21.58], superior PEA and PAA for middle stage [0.61 (0.15-0.87)/L, 0.21 (0.00-0.78)/L, H=25.99, 34.91], superior PEA and PAA, inferior PEA and PAA for late stage [0.01 (0.00-1.13)/L, 0.00 (0.00-0.76)/L, 0.41 (0.00-1.07)/L, 0.21 (0.00-0.95)/L, H=46.27, 54.19, 25.64, 28.10]. With the aggravation of POAG, superior PAA had the largest reduction percentage of sectoral MD. The sectoral MD values in the VF sectors of NTG were significant compared with the control group (P<0.05): superior PAA for early stage [0.54 (0.19-0.80)/L, H=20.93], superior PAA for middle stage [0.60 (0.02-1.01)/L, H=22.13], superior PEA and PAA, inferior PEA and PAA for late stage [0.33 (0.00 0.90)/L, 0.05 (0.00-0.92)/L, 0.16 (0.01-0.87)/L, 0.64 (0.02-1.10)/L, H=37.66, 42.78, 35.15, 37.15]. With the aggravation of NTG, the largest reduction percentage of sectoral MD was found in superior PAA at the beginning but in inferior PAA at last. (2) The RNFL thickness of the control group in Region 1NI, 2TI, 3NS, 4TS, 5N, and 6T was 112.76 (63.54-150.99) MUm, 134.89 (89.44-198.55) MUm, 96.52 (57.32-158.79) MUm, 120.96 (69.25-148.48) MUm, 71.85 (65.03-95.47) MUm, and 66.24 (55.44-90.97) MUm, respectively. The sectoral thickness in the RNFL sectors of POAG were significant compared with the control group (P<0.05): 2TI for early stage [109.17 (43.77-173.86) MUm, H=31.50], 1NI, 2TI and 4TS for middle stage [71.54 (49.92-94.98) MUm, 62.92 (42.33-102.73) MUm, 84.20 (45.98 120.13) MUm, H=38.91, 49.89, 30.60], 1NI, 2TI, 3NS, 4TS, 5N and 6T for late stage [61.76 (39.32-97.99) MUm, 59.59 (42.80-108.69) MUm, 67.28 (42.56-117.96) MUm, 65.16 (41.96-138.02) MUm, 59.45 (21.04-78.48) MUm, 53.74 (27.88-92.71) MUm, H=52.76, 55.06, 35.76, 41.72, 41.32, 29.93]. With the aggravation of POAG, at the beginning 2TI had the largest reduction percentage of RNFL thickness but 4TS had it at last. The sectoral thickness in the RNFL sectors of NTG were significantly different from the control group (P<0.05): 2TI for early stage [78.97 (47.77 131.45) MUm, H=28.86], 1NI, 2TI, 3NS and 4TS for middle stage [61.46 (49.69 97.38) MUm, 74.51 (40.25-135.16) MUm, 86.36 (42.70-105.06) MUm, 83.60 (54.75 117.35) MUm, H=38.76, 35.64, 22.47, 24.14], 1NI, 2TI, 3NS, 4TS and 6T for late stage [61.45 (49.09-92.64) MUm, 54.35 (37.40-102.62) MUm, 63.72 (28.68-105.55) MUm, 61.00 (44.92-108.49) MUm, 50.33 (35.62-82.09) MUm, H=42.56, 51.50, 36.11, 47.44, 25.50]. With the aggravation of NTG, the sector with the largest reduction percentage of thickness changed from 2TI to NI and 4TS. (3) The VF superior PAA RNFL 2TI had the highest Pearson correlation coefficient in POAG (r=0.630, P<0.001), while it was the inferior PAA-4TS in NTG (r=0.645, P<0.001). Conclusions: The impairment patterns of VF and RNFL in each stage of POAG and NTG are distinctly different from certain rules of aggravation. The sector with the strongest correlation of function-structure is the VF superior PAA-RNFL inferior temporal sector in POAG and inferior PAA-superior temporal sector in NTG. (Chin J Ophthalmol, 2018, 54: 811-819). PMID- 30440152 TI - [Differences in anterior segment structure between Chinese Han people and American Caucasians]. AB - Objective: To compare the difference of anterior segment structure between Chinese Han people and American Caucasians, and to explore the confounding factors of anterior chamber angle. Methods: Cross-sectional study. The study was designed to include two healthy groups of Chinese Han people (enrolled from Department of Ophthalmology, Peking University Third Hospital) and American Caucasians (enrolled from Department of Ophthalmology, University of California, San Francisco) from May 2008 to December 2010, each with approximately 120 participants, including 15 persons of each gender in each decade between 40 and 80 years of age. The parameters of the anterior segment were measured by the automatic refractive test, A-ultrasound and ultrasound biomicroscopy. Differences between the two groups were compared with the independent-sample t test or Wilcoxon two-sample test for continuous variable data and the chi(2) test for classified variable data. Multiple linear regression models were performed to analyze the associated factors of anterior chamber angle. Results: There were 118 subjects (118 eyes) and 117 subjects (117 eyes) enrolled in the Chinese and American Caucasians groups, respectively. Compared to Caucasians, Chinese had smaller A-ultrasound measured anterior chamber depth [(3.03+/-0.34) mm vs. (3.38+/-0.36) mm, t=-5.791, P<0.001], smaller relative lens position [0.227 (0.198, 0.256) vs. 0.235 (0.191, 0.262), Z=-3.063, P=0.002], smaller axial length [23.3 (20.9,28.3) mm vs. 24.2 (20.8,28.5) mm, Z=-5.510, P<0.001], smaller iris root distance [0.111 (0.000, 0.401) mm vs. 0.142 (0.000, 0.451) mm, Z=-3.188, P=0.001], smaller ciliary body thickness at 1 mm posterior to the scleral spur [0.661 (0.424, 0.892) mm vs. 0.716 (0.467, 0.942) mm, Z=-3.456, P=0.001], smaller trabecular ciliary process distance [0.780 (0.410, 1.400) mm vs. 0.930 (0.420, 1.470) mm, Z=-3.191, P=0.001], smaller trabecular ciliary process angle [73.4 degrees (36.3 degrees , 115.3 degrees ) vs. 81.1 degrees (47.9 degrees , 147.9 degrees ), Z=-3.407, P=0.001], smaller angle opening distance at 500 MUm (AOD500) [0.181 (0.000, 0.703) mm vs. 0.264 (0.000, 0.806) mm, Z=-3.444, P=0.001], smaller angle recess area (ARA) [0.118 (0.011, 0.457) mm(2) vs. 0.179 (0.000, 0.626) mm(2), Z=-3.814, P<0.001], larger spherical equivalent [0.40 (-5.80, 4.00) D vs. 0.70 (-8.00, 4.00) D, Z=-5.454, P<0.001], larger lens thickness [(4.62+/-0.40) mm vs. (4.52+/-0.40) mm, t=2.077, P=0.039] and larger iris thickness [0.430 (0.280, 0.600) mm vs. 0.410 (0.240, 0.580) mm, Z=-2.263, P=0.024]. On average, with each decade of the increased age, Chinese had a greater decrease in the AOD500 than Caucasians (0.040 mm in Chinese vs. 0.030 mm in Caucasians), while the angle recess area decreased at the same rate (0.020 mm(2) in both groups). After adjusted for age, gender, spherical equivalent, axial length and other parameters of the anterior segment, the trabecular ciliary process angle [for AOD500, standardized regression coefficient (SRC)=0.487, R(2)=0.549, P<0.001; for ARA, SRC=0.372, R(2)=0.502, P<0.001] and anterior chamber depth (for AOD500, SRC=0.413, R(2)=0.476, P<0.001; for ARA, SRC=0.331, R(2)=0.403, P<0.001) were the main factors of anterior chamber angle parameters for Chinese and Caucasians, respectively. Conclusions: Compared with age and gender matched American Caucasians, Chinese Han people have more crowded anterior chambers and narrower anterior chamber angles. The more anteriorly positioned ciliary processes and shallower anterior chambers are the main factors that contributed to more crowded anterior chambers in Chinese Han people and American Caucasians, respectively. (Chin J Ophthalmol, 2018, 54: 820-826). PMID- 30440153 TI - [Preliminary study on the measurement of optic nerve subarachnoid space in patients with normal tension glaucoma]. AB - Objective: To investigate the ultrasonographic measurements of the optic nerve subarachnoid space (ONSAS) in patients with normal tension glaucoma (NTG). Methods: Cross-sectional study. Patients with NTG or primary open-angle glaucoma (POAG) but without any anti-glaucoma treatment and the control group were collected from June 2016 to March 2017 at Beijing Tongren Hospital affiliated to Capital Medical University. Measurements of 24-h intraocular pressure, central corneal thickness, mean visual field damage, visual axis, blood pressure and body mass index and ocular ultrasound scans were performed. The differences in the ONSAS of the two-dimensional ultrasound images of the three groups of subjects and their correlation with various clinical variables were evaluated. Qualitative data were analyzed by the chi-square test for comparison between groups; quantitative data were analyzed by the one-way ANOVA for comparison between groups, and the LSD-t test was used for comparison between groups; the Pearson correlation analysis was used for correlation analysis of measurement data. The intra-group correlation coefficient was used to evaluate the reproducibility and repeatability of two measurements by different measurers or the same measurer. Results: A total of 35 patients (35 eyes) with NTG were enrolled in the NTG group, including 14 males and 21 females, aged (50+/-8) years; 32 patients (32 eyes) with POAG were enrolled in the POAG group, including 14 males and 18 females, aged (52+/-10) years; 37 healthy people (37 eyes) were enrolled in the control group, including 20 males and 17 females, aged (49+/-9) years. The ONSAS was (5.07+/-0.83) mm(2) in the retrobulbar 3- to 7-mm range in the NTG group, significantly smaller than the control group (6.57+/-1.43) mm(2) and the POAG group (6.19+/-0.90) mm(2) (t=1.17, 1.29; P=0.03, 0.01). There was no significant difference in the statistical results between the control group and the POAG group (t=1.31, P=0.75). Between the ONSAS and mean intraocular pressure and maximum intraocular pressure, there was a statistically positive correlation in the NTG group (r=0.66, 0.48; both P<0.01), but there was no linear correlation; there was no statistical correlation in the control group or the POAG group (all P>0.05). There was no statistically significant association between the ONSAS and age, mean arterial pressure, body mass index, central corneal thickness, visual axis length, and mean visual field loss in any group (all P>0.05). Conclusion: Compared with the POAG group and the control group, the ONSAS is smaller in the NTG group, indicating lower retrobulbar cerebrospinal fluid pressure, and it is positively correlated with the mean intraocular pressure and the highest intraocular pressure. (Chin J Ophthalmol, 2018, 54: 827-832). PMID- 30440154 TI - [Effect of 2% ganciclovir eye drops on cytomegalovirus positive Posner-Schlossman syndrome]. AB - Objective: To observe the effect of 2% ganciclovir eye drops on Posner-Schlossman syndrome (PSS) patients with positive cytomegalovirus (CMV) in aqueous humor. Methods: Prospective study. The cases clinically diagnosed as PSS with positive CMV were enrolled from August 2017 to January 2018 at Department of Ophthalmology, Eye & ENT Hospital of Fudan University. All patients underwent aqueous and serum analysis for CMV by the enzyme linked immunosorbent assay and polymerase chain reaction. The history and clinical signs were noted, 2% ganciclovir eye drops were prescribed for topical use (4 times per day), and the patients were followed up. The Pearson Chi-square test was used for the comparison of factors including keratic precipitates (KPs), and the Tyndall, and paired t test or Wilcoxon rank sum test was used for factors like intraocular pressure (IOP), corticoid dosage, and IOP lowering medication dosage. Results: Fifty cases (31 males and 19 females) clinically diagnosed as PSS with positive CMV had an average age of (38+/-13) years. Some characteristics could help to identify CMV-positive PSS: iris depigmentation (96%, 48/50), coin-shaped KPs, loss of corneal endothelium (an average loss rate of 10.8%+/-5.5%), and high IOP during attack[(47.8+/-9.9)mmHg,1 mmHg=0.133 kPa]. After topical antivirus therapy with the mean time of (5.4+/-2.7) weeks, the clinical manifestations of CMV positive PSS cases improved. The granulomatous or middle-sized KPs decreased from 94%(47/50) to 52%(26/50), the coin-shaped KPs almost disappeared [from 22%(11/50) to 2%(1/50)], and the Tyndall reaction disappeared [from 12%(6/50) to 0]. The mean IOP value decreased from (26.2+/-10.9) mmHg to (15.5+/-3.6) mmHg. Furthermore, corticoid use decreased (from 3 times per day to 0 time per day, by median value), the number of cases that did not use corticoids increased from 6% (3 cases) to 60% (30 cases), and 17 (65%) out of those 26 corticoid dependent patients could withdraw corticoids. The number of IOP lowering eye drops used also decreased (from 2 to 0, by median value), and the proportion of cases without IOP lowering medication increased from 24% (12 cases) to 58% (29 cases). There were statistical differences between post-treatment and pre-treameat (all P<0.05).Thirteen cases that accepted CMV re-test of aqueous humor were all CMV DNA negative after treatment. Conclusion: Topical treatment with 2% ganciclovir eye drops has a good short-term effect on CMV-positive PSS patients by contributing to inflammation and IOP control. (Chin J Ophthalmol, 2018, 54: 833 838). PMID- 30440155 TI - [Clinical features of glucocorticoid eye drops induced ocular hypertension in pediatric and adult uveitic eyes]. AB - Objective: To investigate the clinical features of glucocorticoid eye drops induced ocular hypertension in pediatric and adult uveitic eyes. Methods: Retrospective survey of consecutive uveitic patients attending referral service at Peking Union Medical College Hospital from March 2013 to August 2017. Incidences of glucocorticoid eye drops induced ocular hypertension were compared between the pediatric and adult uveitic groups. The clinical patterns of 1% prednisolone acetate eye drops induced ocular hypertension in pediatric and adult uveitic eyes were also investigated. Data were analyzed using the Mann-Whitney test and the chi(2) test. Results: The clinical data of 1 138 uveitic eyes [677 patients; 331 males and 346 females; mean age (31+/-16) years]receiving corticosteroid eye drops were reviewed, among which 246 eyes (143 patients) had pediatric uveitis and 892 eyes (534 patients) had adult uveitis. The incidence of glucocorticoid eye drops induced ocular hypertension was higher in pediatric eyes (39.8%, 98/246) as compared to adults (29.1%, 260/892) (chi(2)=9.880, P=0.002). One hundred and thirty eyes (75 patients) with 1% prednisolone acetate induced ocular hypertension were included in the clinical pattern analysis, including 49 [28 patients; 15 males and 13 females; mean age (11+/-3) years] pediatric and 81 [47 patients; 22 males and 25 females;mean age (34+/-12) years] adult uveitic eyes. No differences were found in daily doses of 1% prednisolone acetate between the pediatric group [4.60 (3.46, 5.36) drops/day] and the adult group [4.00 (3.30, 4.88) drops/day; Z=-1.675, P=0.094]. But the duration of medication in pediatric eyes [4.71 (2.79, 6.36) weeks] was significantly shorter as compared to the adults [6.00 (4.86, 9.00) weeks; Z=-3.446, P<0.001]. The intraocular pressure (IOP) was 26.00 (24.00, 31.00) mmHg (1 mmHg=0.133 kPa) in pediatric uveitic eyes and 26.00 (23.30, 31.15) mmHg in the adults, which showed no statistical significance (Z=-0.231,P=0.818). To achieve effective IOP control, 79.6% (39/49) of pediatric and 54.3% (44/81) of adult eyes received IOP-lowering drug therapy (chi(2)=8.447,P=0.004). And during the follow-up, the withdrawal rate of IOP lowering drugs was much lower in pediatric eyes (48.7%, 19/39) as compared to the adult group (72.7%, 32/44) (chi(2)=5.031, P=0.025). Conclusion: Compared with adult patients with uveitis, children with uveitis are more prone to IOP elevation, which is more difficult to control after the use of glucocorticoid eye drops. (Chin J Ophthalmol, 2018, 54: 839-842). PMID- 30440156 TI - [Ultrasound diagnosis and differential diagnosis of medium and small choroidal melanomas]. AB - Objective: To analyze the ultrasound diagnosis and differential diagnosis of medium and small choroidal melanomas. Methods: It was a retrospective case series study. Thirty-six cases (36 eyes) with medium or small choroidal melanoma were collected between January 2016 and January 2017 in Beijing Tongren Hospital, including 16 males and 20 females aged (50+/-12) years old. All tumors' apical heights were within 5 mm and the largest basal diameter was within 15 mm. Sixty nine cases (69 eyes) with choroidal hemangioma, including 45 males and 24 females aged (45+/-11) years old, and 16 cases (19 eyes) with choroidal metastasis, including 4 males and 12 females aged (50+/-11) years old, of equal size were also analyzed as differential diagnosis. Univariate (Chi-square test, Fisher's exact test, and analysis of variance) and multivariate analyses (Logistic regression) were used for statistical analysis. Results: There were significant differences in morphology, height, base-height ratio, internal echo, choroidal excavation and secondary retinal detachment among the three types of tumors(all P<0.05). Approximately 91.7% (33/36) of choroidal melanomas and 94.2% (65/69) of hemangiomas were flat or dome, while 63.2% (12/19) of metastatic tumors showed a polygonal shape and an irregular surface contour. The average height was (4.02+/ 0.70) mm for choroidal melanoma, (3.10+/-1.08) mm for metastasis and (2.75+/ 0.87) mm for hemangioma. The base-height ratio of choroidal melanoma, metastasis, and hemangioma was 2.62+/-0.48, 4.09+/-1.18 and 3.16+/-0.58, respectively. About 86.1% (31/36) of choroidal melanomas and 84.2% (16/19) of metastases showed lower echo than adjacent orbital tissue, while 92.8% (64/69) of hemangiomas had similar or higher echo. About 16.7% (6/36) of choroidal melanomas showed choroidal excavation, but no such signs were found in other tumors. Approximately 80.6% (29/36) of choroidal melanomas, 78.9% (15/19) of metastases and 52.2% (36/69) of hemangiomas showed secondary retinal detachment. The internal echo, height and base-height ratio were taken as significant independent influencing factors into the Logistic regression model. The low internal echo and large height were risk factors of choroidal melanoma (OR=0.016, 0.199, both P<0.05), while the low echo and large base-height ratio were risk factors of choroidal metastasis (OR=0.011, 0.073, both P<0.05). Conclusion: Ultrasonography plays an important role in the diagnosis of medium and small choroidal melanomas, and the echo, height, and base height ratio of the lesion can be helpful for the diagnosis and differential diagnosis. (Chin J Ophthalmol, 2018, 54: 843-848). PMID- 30440157 TI - [Clinical characteristics and treatment of congenital fibrovascular pupillary membranes]. AB - Objective: To investigate the clinical characteristics, surgical approaches and postoperative effects associated with congenital fibrovascular pupillary membranes. Methods: A retrospective study design was used. Thirteen children (13 eyes) with congenital fibrovascular pupillary membranes, treated in Beijing Children's Hospital from January 2014 to December 2017 were included. The morphology of the membrane and the anterior chamber was evaluated using a digital wide-area fundus imaging system. The ophthalmic signs, examination results, operation methods, intraocular pressure and ocular position were analyzed. Results: There were 13 children (13 eyes) were enrolled, including 9 males and 4 females. The age at surgery ranged from 2.0 months to 34.5 months, with an median of 5.1 months. According to the degree of obstruction of the pupil and the intraocular pressure, the eyes were divided into three groups. In the 5 eyes of group A, the pupil membrane did not completely cover the pupil, and the depth of the anterior chamber was normal. Among them, 4 eyes had normal intraocular pressure (9-12 mmHg) (1 mmHg=0.133kPa), and 1 eye had elevated intraocular pressure (18 mmHg). In the 5 eyes of group B, the pupillary membrane completely covered the pupil into a pinhole, the anterior chamber was normal or slightly shallow, and the intraocular pressure was normal (6-16 mmHg). In the 3 eyes of group C, the pupillary membrane completely covered the pupil, the anterior chamber was shallow or disappeared, and the intraocular pressure was high (24-45 mmHg). Membranectomy and pupilloplasty were performed in group A, and trabeculectomy was combined when there was glaucoma; postoperative intraocular pressure was normal (4-10 mmHg). Membranectomy, pupilloplasty and iridectomy were performed in group B; postoperative intraocular pressure was normal (7-13 mmHg). Membranectomy, pupilloplasty, iridectomy and goniosychialysis were performed in group C; after surgery, intraocular pressure was normal in 2 eyes (10 mmHg and 13 mmHg) and 25 mmHg in 1 eye. All eyes were orthophoric before and after operation in group A. In group B, 1 eye was esotropic, 2 eyes were exotropic (worse after surgery in 1 eye), and 2 eyes were orthophoric before surgery. In group C, one eye was esotropic, one eye was exotropic, and one eye was orthophoric before surgery, and all eyes were exotropic after operation. Conclusions: Congenital fibrovascular pupillary membranes are unilaterally a continuation of the iris covering the pupil at different degrees, with or without glaucoma. Surgical treatment should be performed promptly when there is obscuring of the visual axis or incorporating of glaucoma. The main surgical procedures are membranectomy and pupilloplasty and iridectomy. Postoperative intraocular pressure can be well controlled, and strabismus has no improvement. (Chin J Ophthalmol, 2018, 54:849 854). PMID- 30440158 TI - [The heritability of phenotypes related to primary angle closure glaucoma]. AB - Glaucoma is the leading cause of irreversible blindness throughout the world. Primary angle closure glaucoma (PACG) is one of the common types of this disease. Research indicates that its prevalence is always associated with many factors, including ocular anatomical characteristics and the genetic susceptibility. According to many studies, phenotypes related to PACG, such as anterior chamber depth, relative lens position and thickness, chamber angle state, and axial length, are heritable. Heritability is an important indicator to quantify this genetic tendency. Therefore, the study of heritability plays an important role in explaining the genetic susceptibility and understanding the mechanism of these diseases. This article reviews the heritability of the phenotypes that relate to PACG. (Chin J Ophthalmol, 2018, 54:864-867). PMID- 30440159 TI - [Electrophysiology and early glaucoma diagnosis]. AB - Glaucoma can lead to irreversible visual impairment. The pathogenesis of glaucoma is complicated and it is difficult to diagnose early. As an objective and functional examination tool, visual electrophysiology has its own advantages to detect early glaucomatous damage. It can indicate early functional degeneration of retinal ganglion cells and can direct doctors to diagnose and give treatment to glaucoma patients. It has been proved that the pattern electroretinogram, photopic negative response and multifocal electroretinogram can provide most of the information in the early diagnosis of glaucoma. This article overviews the latest application progress of these three visual electrophysiological techniques.(Chin J Ophthalmol, 2018, 54:868-872). PMID- 30440160 TI - [The genetic factors of non-response to anti-vascular endothelial growth factor therapy]. AB - The response to anti-vascular endothelial growth factor (VEGF) treatment is variable. It is generally measured in terms of changes in correlated functional and/or anatomical outcomes, and patients are then classified as optimal response, poor response and non-response. The precise cause of non-response remains undetermined. A variety of factors could account for poor or non-response to anti VEGF therapy, such as age, baseline vision, disease course, lesion characteristics and genomic polymorphism. At the present time, many studies on the genetic factors of non-response or poor response to anti-VEGF treatment mainly focus on VEGF genes (VEGF-A, VEGFR-2), complement factor H (CFH), age related maculopathy susceptibility 2 (LOC387715/ARMS2), high temperature factor A 1 (HTRA1), interleukin-related gene (IL-8 rs4073) and so forth. It is still worthy of further investigations that how to assess genetic reasons for non response or poor response, so that we can provide individualized treatment sequences and predict the response to anti-VEGF therapy. (Chin J Ophthalmol, 2018, 54:873-878). PMID- 30440162 TI - Psychological debriefing for acute trauma - a welcome demise? PMID- 30440161 TI - Percutaneous laser ablation for benign and malignant thyroid diseases. AB - Minimally invasive image-guided thermal ablation is becoming increasingly common as an alternative to surgery for the treatment of benign thyroid nodules. Among the various techniques for thermal ablation, laser ablation (LA) is the least invasive, using the smallest applicators available on the market and enabling extremely precise energy deposition. However, in some cases, multiple laser fibers must be used simultaneously for the treatment of large nodules. In this review, the LA technique is described, and its main clinical applications and results are discussed and illustrated. PMID- 30440163 TI - Psychiatric disorders amongst adults with learning disabilities - prevalence and relationship to ability level. AB - OBJECTIVES: To determine the prevalence of psychiatric disorders in adults with learning disabilities, and the relationship with severity of learning disabilities. METHOD: The study is population-based. Detailed psychiatric assessments on 207 adults with learning disabilities living in Leicestershire, UK. were conducted by a learning disabilities psychiatrist, using the Present Psychiatric State - Learning Disabilities; and Disability Assessment Schedule. Diagnostic criteria are clearly defined. Developmental assessments were undertaken using the Vineland Scale (survey form). RESULTS: Psychiatric disorders were found in 49.2%, and rates for most individual disorders were higher than those found in the general population. Comparison with the two previous population-based studies shows the ascertained rates were broadly similar to those reported by Corbett but higher than those reported by Lund. Adults with more severe learning disabilities had higher rates of additional psychiatric disorders. CONCLUSIONS: The results may be explained by a combination of the genetic, physical, psychological and social factors associated with learning disabilities also being aetiological to psychiatric disorders. The high prevalence rates of psychiatric disorders demonstrate the importance of health service provision for adults with learning disabilities. PMID- 30440164 TI - Factors affecting GUM clinic attenders decisions and intentions to seek HIV testing. AB - OBJECTIVES: To evaluate factors that predict HIV testing using the model of health care utilisation as its conceptual framework and to analyse some of the factors that encourage or inhibit seeking an HIV test in this population. METHOD: A cross sectional questionnaire study in two Genito-Urinary Medicine (GUM) clinics in central Scotland. A final sample of 195 represented a 91% response rate. Participants were categorised by their HIV testing status (already tested, planning to be tested, no intention to seek testing). RESULTS: The 'already tested' and 'planning to be tested' groups were combined as there were no significant differences on reported risk behaviours. Analysis therefore compared two groups those 'testing' (n = 66) and 'not testing' (n = 129). 67% of those not tested for HIV reported at least one HIV risk factor. Perceived risk was the strongest predictor of HIV testing using our model. Perception of risk and actual risk were not correlated. Those not seeking testing endorsed less benefits of testing and more denial of the need to be tested. Same day testing and testing without an appointment were endorsed as factors to promote testing. CONCLUSION: To encourage people who have high risk factors to access HIV testing, programmes should: (1) highlight the benefits of testing which would be lost if people do not test, eg. effective drug treatments (2) increase the range of HIV testing services available (eg. same day testing). Furthermore, studies to determine the main predictors of perceived risk are needed if we are to increase testing in relevant populations. PMID- 30440165 TI - Psychological problems of early school leavers. AB - OBJECTIVES: To establish the prevalence of psychological problems in early school leavers, who attend training schemes. METHOD: The Youth self report inventory was completed by teenagers as part of a group setting. Percentages of those scoring above clinical threshold were calculated and gender differences examined. RESULTS: 78 teenagers participated in the study, 40 males and 38 females. 24% were classified as being in the clinical range of total problem score. Girls reported more total, internalising and externalising problems than boys. 13% of girls frequently thought of suicide and 7% had frequent thoughts of self harm, this contrasts with none of the boys admitting suicidal ideation and 2.5% reporting thoughts of self harm. CONCLUSIONS: 24% of this group experienced problems which placed them within the clinical range. Girls experienced greater problems than boys and appear to be at greater risk of self harm. This group appear to be representative of those who attend training programmes, however it is not possible to determine whether they are representative of all early school leavers. This highlights the vulnerability of older adolescents, and in particular those who leave school early. More detailed examination of issues facing this group are needed and should be a priority along with greater service provision from the educational and health sectors. PMID- 30440166 TI - Responses of football fans to relegation of their team from the English Premier League: PTS? AB - OBJECTIVES: To measure the level of psychological distress caused to supporters of a football team by relegation from the English Premier League. The relationship between age, sex and psychological distress are examined. METHOD: Opportunity sample cross-sectional survey. Participants were approached through networks of fans and through e-mail networks. Participants were supporters (n = 65) of two relegated premiership football teams. Participants completed the Impact of Event Scale. RESULTS: Mean total Impact of Event Scale scores indicated a clinically significant degree of psychological distress for the majority of respondents. Age or sex of the participants did not predict Impact of Event Scale scores. CONCLUSIONS: The results are discussed in terms of the magnitude of Impact of Event Scale scores in relation to other stressors. It is concluded that the impact of such sporting events is psychologically significant. The psychological literature has considered traumatic stress responses to a number of stressors such as threats to life, threats to psychological well-being, threats to physical/ psychological well-being of others, witnessing traumatic events and involvement in a human or natural disaster. PMID- 30440167 TI - What it says in the papers: an audit. AB - OBJECTIVES: There have been concerns in the international literature that the manner in which psychiatry and psychiatric patients is portrayed in the print media is negative and sensational. If correct this has serious implications for the stigma and prejudice that our patients will suffer. This study was designed to evaluate the content and tone of articles relating to psychiatry. It was compared with a broadly similar study published in 1995 and will form the base from which to measure changes in psychiatric coverage over time. METHOD: All the daily broadsheets, one daily tabloid and three Sunday broadsheets were examined for a six month period in 1999 and all articles, letters or headlines incorporating psychiatry-related material were examined. Using specific definitions, articles and headlines were examined for tone and content as well as for the contribution of mental health professionals. RESULTS: Overall 0.65 articles per newspaper per day were found. News items and feature predominated, with forensic issues receiving the greatest attention. The tone of the articles was either neutral or positive and the improvement in the tone of articles in the tabloids was particularly noticeable when compared with an earlier study. This is very different from the findings of international studies. However, the headlines were more sensational in tone than the contents of the articles themselves. Increasingly the opinion of health professionals was sought but contributions from psychiatrists remained low, writing just two articles and constituting 15% of health professionals whose opinions were sought. Nine per cent of items constituted misuse of terms. CONCLUSIONS: The Irish print media are not hostile to psychiatry and there has been an improvement in tone and type of article in the past five years. Greater involvement of psychiatrists in the media and particularly more direct engagement with editors is required if there is to be a shift from coverage of forensic matters in favour of informative articles as well as improvement in the headline tone. PMID- 30440168 TI - Childhood 'risk characteristics' and the schizophrenia spectrum prodrome. AB - This review identifies similarities between behavioural indicators of children with future schizophrenia-spectrum disorders and prodromal symptoms in the first episode of schizophrenia. An alternative concept of prodrome is described with implications for early recognition, monitoring and intervention of individuals at risk of future schizophrenia spectrum disorders. PMID- 30440169 TI - Screening for dementia in primary care - a viable proposition? AB - Health policy documents recommend screening for cognitive impairment, although in practice this is not implemented. This article looks at the issues which require consideration in implementing a screening programme. These include factors pertinent to the disease under consideration, resources, both personnel and time, lack of experience of cognitive screening at a primary care level, use of screening instruments and uncertainty about management of positive cases. Only by identifying the practical difficulties involved in screening, can steps can be taken to overcome them and to implement screening programmes which are acceptable to the population under consideration and their primary care physicians. PMID- 30440170 TI - Transcranial magnetic stimulation: an alternative physical treatment in depression. PMID- 30440171 TI - Suicidal thoughts and acts in Irish adolescents. AB - OBJECTIVES: To determine the frequency of reported suicidal thoughts and acts in (a) a school-based sample of Irish adolescents, (b) adolescents attending a community child and family mental health service. METHOD: The study population consisted of: (a) 195 adolescents aged 13-15 years attending ten secondary schools throughout Ireland. The schools were selected to represent a wide social and cultural spread: and (b) 66 adolescents aged 13-15 years attending a community child mental health service. The measures used were the Child Behaviour Checklist completed by the parents of the adolescents and the Youth Self Report completed by the adolescents. RESULTS: Within the school sample, the parents of 3% of adolescents reported that their child had talked of harming him/herself, but none reported acts of self-harm. Fifteen percent of the adolescents themselves reported that they had thoughts of harming or killing themselves, and 8% reported that they had tried to harm or kill themselves. Within the mental health clinic attenders sample, the parents of 33% of the adolescents reported that their child had talked of harming him/herself, and the parents of 27% reported that their child had tried to harm or kill themselves. Twenty-one percent of the adolescents themselves reported that they had thoughts of harming or killing themselves, and 21% percent reported that they had tried to do so. In both groups, adolescents with higher total problem, internalising and externalising scores on the questionnaires, indicating greater disturbance, were more likely to report thoughts and acts of self harm. CONCLUSIONS: Thoughts of suicide and acts of self harm are common in Irish adolescents and are not limited to those attending mental health services. Parents are frequently unaware of these thoughts. Further studies involving interviews with adolescents at risk are indicated to determine the significance of these thoughts and how adolescents deal with them. PMID- 30440172 TI - Suicide rates in Irish counties: 10 years later. AB - OBJECTIVES: This exploratory study was designed to explore the social correlates of suicides rates of Irish counties. METHOD: Suicide rates were calculated for Irish counties and subdivisions for the period 1988-1994 and correlated with social data for these regions obtained from the 1991 Census. RESULTS: The suicide rates showed a low level of reliability for the periods 1978-1984 and 1988-1994, and the social correlates of suicide rates changed between the two periods. Whereas age structure was associated with suicide rates in 1978-1984, urbanisation was associated with suicide rates in 1988-1994. CONCLUSIONS: It is important to check the reliability of results of ecological studies of Irish suicide rates. Furthermore, the impact on suicide rates of the changing role of women in Ireland needs to be explored in time-series studies of the Irish suicide rate. PMID- 30440173 TI - Psychopharmacological treatment of adolescent and adult attention deficit hyperactivity disorder. AB - Adult ADHD is becoming a rather 'firm' diagnosis in adult psychiatry practice. Nevertheless it is a diagnosis that is often missed which leads to unnecessary distress to patients. This paper sets out the treatment possibilities. PMID- 30440174 TI - Fact or fantasy? A review of recovered memories of childhood sexual abuse. AB - More than a century ago Freud provoked a bitter controversy concerning alleged recollections of childhood sexual abuse: Were they fact or fiction? This debate is still ongoing, with some professionals stubbornly holding on to deeply entrenched and polarised positions. On the one side there are those who continue to deny the veracity of all 'recovered memories', and thus also of the implicated psychological defenses of repression and dissociation. At the other extreme are those therapists who simplistically assume that particular symptoms invariably imply sexual abuse. Over the decades there is a growing corpus of anecdotal, clinical and, more recently, research evidence supporting the contention that childhood sexual abuse, like all other trauma, can be forgotten for days, and even for many years, before being recalled. However, the reconstruction of these memories is a complex and, at times, a rather fallible process. PMID- 30440175 TI - Low birth weight - a predictor for psychiatric problems? PMID- 30440176 TI - Immigration: new challenges for psychiatry and mental health services in Ireland. PMID- 30440177 TI - Characteristics and treatment of asylum seekers reviewed by psychiatrists in an Irish inner city area. AB - OBJECTIVES: To assess social and educational status, trauma experienced, diagnosis and treatment of asylum seekers, who presented to psychiatrists in St James's hospital Dublin over a two-year period. METHOD: All files of asylum seekers assessed by psychiatrists in St James's hospital over a two-year period were scrutinised. Using a pro-forma, data was obtained about social and educational status, language skills, trauma suffered, diagnosis, treatment and follow-up. Demographic data was obtained from the Department of Justice, the Irish refugee centre and various social welfare offices. RESULTS: Over a two-year period 31 asylum seekers were in contact with this service. Most originated from Africa. Overall subjects were well educated but socially isolated with poor language skills. Many had been imprisoned or tortured, or had relatives or friends tortured or killed prior to migration. Almost one third met criteria for PTSD and greater than a third met criteria for major depression. The majority of subjects received pharmacological treatment, but few were offered psychological treatments. Most had no prior psychiatric diagnosis and dropped out of treatment at an early stage. CONCLUSIONS: Large numbers of asylum seekers are currently residing in Dublin and may need specialised psychological support and treatment. They have been exposed to significant levels of pre-migratory trauma, often have poor language skills and drop out of treatment quickly which may indicate dissatisfaction with existing treatment approaches. There is an urgent need for increased funding for the psychological needs of this vulnerable group, for the provision of trained interpreters, specialised psychotherapy and assessment of their needs. PMID- 30440178 TI - Infanticide and child murder - admissions to the Central Mental Hospital 1850 2000. AB - Infanticide and child murders have been known to all civilisations throughout time. This study looks at the problem from an Irish perspective, particularly with regard to the forensic psychiatry service. The case notes and legal files of 64 women admitted to the Central Mental Hospital (CMH), Dublin, between May 1850 and 2000 were examined. This group represents a complete sample of female inpatients charged with these offenses over the 150 year history of the institution. Sociodemographic and clinical data were analysed to provide psychiatric and social backgrounds to the cases. There has been a considerable decrease in the number of women admitted to the CMH on charges or conviction for infanticide and child murder in recent years. It appears that the attitude of the judiciary to these women has altered. The cases are discussed in the context of the prevailing attitudes of the era. PMID- 30440179 TI - Psychiatric and medical co-morbidity in mitral valve prolapse. AB - OBJECTIVE: Significant controversy continues to exist in the empirical literature regarding the diagnosis and treatment of mitral valve prolapse (MVP). In addition, there is also inconsistency in the correlation of anxiety disorders as co-existing with MVP, as well as cause and effect issues in terms of the role of the autonomic nervous system, MVP and panic attacks. Recent studies suggest that the co-morbidity of an anxiety disorder and clinical depression appears to increase the likelihood of MVP in predisposed patients. The objective of this review was to examine, clarify, and further define the medical and psychiatric aspects of MVP. METHODS: A literature review was conducted on empirical studies and reviews examining MVP. RESULTS: It was found that although MVP is highly correlated with psychiatric disorders, the lack of adequate control groups and clear criteria for a diagnosis of MVP in most empirical studies examining these associations make it difficult to determine the relationship between MVP and psychiatric disorders. CONCLUSIONS: Suggestions for further research in the areas of depression and personality characteristics are offered. It is also suggested that the use of control groups from populations with cardiac disorders and a better definition of MVP will clarify many of the problems in empirical studies aiming to determine the relationship between MVP and psychiatric disorders. PMID- 30440180 TI - Psychiatric services in Ireland: North and South. AB - This overview of mental illness services in Ireland, North and South, over recent decades, is a descriptive account. It refers to policies, development and operation of the services, with certain figures relating to hospital admissions, human resources and costs in Northern Ireland and the Republic of Ireland. The paper points to the need for more detailed comparisons, which would require more rigorous, systematic health services research. PMID- 30440181 TI - James Joyce and a North Dublin asylum. AB - It is perhaps surprising that mental illness has such a limited role in the various works of James Joyce. When one considers the volume of material in his books relating to Dublin, topographical and biographical, there appears to be a studious avoidance of psychiatric institutions. The then huge Grangegorman complex (now St Brendan's Hospital) must have had an ominous presence in the city: the size of its population (between 1,500 and 2,000 patients) indicating that few families of whatever class could have escaped contact with it. Indeed, as an institution it probably had economic power comparable to Guinness's brewery or the British Army, which had five barracks in the city, each about the same size as Grange-gorman. PMID- 30440182 TI - Mental illness in migrants: diagnostic and therapeutic challenges. AB - We describe the case of a 30 year old Chinese woman who presented to an Irish psychiatric service with a five-month history of somatic delusions, auditory hallucinations and denial of lineage. We utilise this case to illustrate the significant cultural influences on psychopathology. We discuss the increasingly frequent diagnostic and therapeutic challenges presented by migrants with mental illness. PMID- 30440183 TI - A delusion of immortality - the dilemma of the Struldbruggs. AB - We describe a lady with a history of recurrent psychotic depression, together with a persistent delusion of immortality, which appears to be independent of the depressive illness. It is of interest that this woman is a patient of the hospital founded by Dean Jonathan Swift, who described a people stricken with a similar dilemma of unhappy immortality over 200 years ago. PMID- 30440184 TI - Debriefing and post traumatic stress disorder. PMID- 30440185 TI - A case for transcranial magnetic stimulation. PMID- 30440186 TI - Mental health and human rights: challenges for a new millennium. PMID- 30440187 TI - Assessment following deliberate self-harm: who are we seeing and are we following the guidelines? AB - OBJECTIVES: To determine whether assessments of patients admitted to a general hospital following deliberate self-harm (DSH) were in line with the Royal College of Psychiatrists guidelines. To examine the profile of cases and presentations and to make recommendations for improvements to the service. METHOD: Clinical and demographic data recorded on 70 admissions after DSH during 1997-98 were analysed retrospectively. A checklist was also developed, using factors shown by previous research to be associated with future risk of suicide, to determine the quality of assessments. RESULTS: The majority (70%) of assessments took place within 24 hours of admission thereby meeting College recommendations. Medical personnel performed all adult assessments. Circumstances of the overdose, recent stresses, psychiatric diagnosis, immediate risk and follow-up arrangements were documented in the majority of cases. Family psychiatric history, past suicidal behaviour, alcohol and drug abuse history, and previous violence, were frequently not documented. A copy of a discharge summary to the GP was found in 41% of charts. Overdoses accounted for 93% of cases of DSH. The most frequently recorded problem (37.5%) was adjustment disorder. CONCLUSIONS: Despite evidence showing that non psychiatric medical staff are competent in assessing DSH and guidelines encouraging multidisciplinary involvement, DSH assessments remain the preserve of the medical psychiatric team. Closer attention should be paid to all the risk factors associated with suicide by assessors; a checklist could prove helpful. There is room for improved communication between psychiatric services and GPs following DSH. The setting up of a self-harm service planning group could improve the co-ordination and efficiency of delivery of general hospital services to this patient group. PMID- 30440188 TI - The attitudes of Irish trainees to their training and its supervision: a five year follow up study. AB - OBJECTIVES: To assess the current attitudes of Irish psychiatric trainees to their training and to determine whether problems identified five years ago have improved. METHOD: A postal questionnaire was circulated to all identified psychiatric trainees in the eastern region of Ireland over a six-month period in 2000. RESULTS: 153 (62%) trainees responded to the study, and 81% described their training as 'adequate' or better. Significant demographic changes over the last five years are recorded. Satisfactory induction, regular supervision and access to tutors are all associated with higher overall satisfaction with training. Sixty-seven per cent report receiving an induction course, but just 40% describe this as satisfactory, and only 49% of trainees receive regular supervision. Specific difficulties in training are reported less frequently than in 1995, but 35% of non-EU doctors report racial discrimination in training and only 59% of trainees received a practical demonstration prior to administering electroconvulsive therapy (ECT). CONCLUSIONS: Trainees continue to express high levels of satisfaction with their training. Improvements have been made in a number of key areas, although difficulties remain. For example, regular supervision, which was associated with a positive outlook on training, are unavailable to a majority of trainees. PMID- 30440189 TI - Outcome of alcoholism in old age. AB - OBJECTIVE: This retrospective study describes the follow-up of a birth cohort of alcohol dependent patients as they enter old age. The aim is to define the global outcome of survivors by combining a measure of current drinking behaviour with ratings for depression and dementia. METHODS: A series of 100 referrals to a regional unit for alcohol misuse in Bristol, England, were followed up at a mean of 13 years after first referral for treatment. Survivors were traced when they were aged between 67 and 77 years. At follow-up interview, subjects were screened for current alcohol problems, depression and dementia. RESULTS: The mortality rate in the cohort was raised significantly. Almost one third of survivors had depressive symptoms at follow-up and rates of global dementia were higher than expected in an aged-matched sample of the general population. However, the majority of survivors were classified as having an intermediate global outcome with less than 10% having a poor outcome. CONCLUSIONS: The high rates of mortality and psychiatric morbidity observed in this cohort illustrate the importance of detecting alcohol problems in the elderly. Further prospective studies are necessary to validate these findings in a community sample of older people. PMID- 30440190 TI - An audit of admissions to an acute psychiatric unit. AB - OBJECTIVES: In an era of cost containment in the health services, it is important to endeavour to manage existing resources in the optimum way. This study examines admissions to an acute psychiatric unit in a general hospital in order to identify factors that characterise these admissions, which in turn may suggest appropriate interventions. METHODS: This was a retrospective casenote review of 105 consecutive admissions. Demographic information and clinical data concerning this admission and service contact in the preceding year was collected. Chi squared tests were used to compare patients who were admitted during normal working hours with those admitted after 5pm and at weekends. Patients whose length of stay exceeded four weeks were compared with those who had a shorter admission. RESULTS: Eventually 101 patients were included in the study; of these 46.5% of admissions occurred during normal working hours. Admissions outside this time were more likely to be under 45 years (chi2 = 4.05, df = 1, p 4 weeks duration was more likely in single patients (chi2 = 9.68, df = 2, p <0.01), those living outside the more urban areas (chi2 = 4.04, df = 1, p <0.05) and those who had a diagnosis of a depressive illness or schizophrenia/psychosis (chi2 = 13.43, df = 3, p <0.01). Patients with a diagnosis of alcohol or substance abuse were spending significantly shorter periods in hospital. CONCLUSIONS: Further development of day hospitals is necessary to provide alternatives to inpatient treatment and facilitate earlier discharge for patients living throughout the catchment area. Alternative methods of service delivery such as outreach programmes should be considered for subgroups of patients who are unable or unwilling to access traditional services. Introducing outpatient detoxification programmes would have a substantial impact on admission patterns in the unit. PMID- 30440191 TI - Trichotillomania. AB - Trichotillomania is a relatively uncommon condition that classically occurs in young females. It can result in trichobezoar formation, which is usually managed successfully by surgical intervention, although rarely it can be fatal. This article presents a brief review of trichotillomania. A literature search was performed for 'trichotillomania' using the PubMed database, and relevant papers and their references were researched. This review commences by defining the condition and considering its presentation and its prevalence. Diagnostic dilemmas including differential diagnosis and the uncertainty about structural abnormalities in the brain as indicated by magnetic resonance imaging findings are then reviewed. Finally we examine the current treatment options of this interesting condition. PMID- 30440192 TI - Rehabilitation psychiatry. AB - Rehabilitation services are changing across Britain. The focus of service developments appears to be in relation to community teams and assertive outreach. This leaves the question of which direction rehabilitation services are heading. As patients move into the community from long stay wards as part of the process of bed closures and resource transfer, rehabilitation services are left with changing patient characteristics. In addition, patient characteristics in rehabilitation vary between Trusts. This article explores and expands on these themes. PMID- 30440193 TI - The limitations of critical incident stress debriefing. PMID- 30440195 TI - Promoting potential in all our children. PMID- 30440194 TI - Diagnostic criteria used to assess ADHD/hyperkinetic disorder. PMID- 30440196 TI - Recovered memories of sexual abuse. PMID- 30440197 TI - Movement disorders: what the psychiatrist needs to know. PMID- 30440198 TI - A 15-year follow-up of schizophrenia in Ireland. AB - OBJECTIVES: Psychiatric hospitalisation rates in Ireland have been high. Recent studies indicate that this is not a consequence of raised incidence. This study explored the possibility that poor outcome may have been responsible for this high hospitalisation prevalence. METHOD: Through participation in the WHO Study, Determinants of Outcome of Severe Mental Disorders (DOSMeD), we followed up a cohort of 67 first-onset schizophrenic patients over 15 years to determine symptomatic and functional outcomes and to compare these with outcomes of the cohorts recruited to the International Study of Schizophrenia (ISoS). RESULTS: Thirty-seven (55%) of the original 67 were successfully followed up over 15 years and, of these, 43% were continuously psychotic for most of the period; a similar proportion had recurrent episodes of illness; two-thirds of subjects had moderate to severe symptoms for most of the time; and, in terms of functional outcome, over four-fifths were unemployed at follow-up. CONCLUSIONS: Outcome for the majority of followed-up patients was poor in symptomatic and functional terms. While this outcome was one of the poorest among the DOSMeD groups the question whether functional psychotic illness outcome is inherently poorer in Ireland than elsewhere remains unanswered. The high rate of attrition (45%) from the group during the follow-up period vitiated interpretation of outcome overall. The high number of suicides among the group was noteworthy. PMID- 30440199 TI - Down's syndrome, dementia and macrocytosis. AB - OBJECTIVE: No definitive peripheral biological marker has yet been found to correlate with Alzheimer's disease (AD). This study investigated the role of macrocytosis as a marker which could significantly improve our understanding of AD in the Down's syndrome (DS) population. METHODS: This study investigated the possible association between raised mean corpuscular volume (MCV) and AD in 150 adults with DS over a five year study period. RESULTS: A raised MCV is common in the DS population. A statistically significant association between a further elevated MCV and clinically diagnosed AD in adults with DS was found. CONCLUSIONS: The findings suggest that further research into the association between macrocytosis and DS could improve our understanding of the underlying biological mechanisms of AD. The measurement of MCV should be undertaken in all DS individuals with a diagnosis of possible or definite dementia. A significant raised MCV (above 97fl for males and 99fl for females) may further improve the clinical diagnosis. A single MCV measurement, however, cannot be recommended as a diagnostic test for AD in adults with DS. PMID- 30440200 TI - Dealing with violent and aggressive patients: at what cost to nurses? AB - OBJECTIVES: To determine the attitudes and experiences of nursing staff in relation to violent and aggressive patients. METHOD: A self-administered questionnaire booklet was distributed to 289 nursing staff working in 'high-risk' units within two NHS Trusts. In addition to assessing the frequency of violent incidents, the degree of burnout and post-traumatic symptoms experienced were assessed by the inclusion of two standardised measures in the survey, viz, the Maslach Burnout Inventory and the Impact of Event Scale-Revised respectively. RESULTS: One hundred and fifty six (54%) nurses responded to this survey. Over two-thirds of nurses (72%) had been physically assaulted during the previous two years. The longterm psychological impact of these incidents was not related to whether or not a physical injury was sustained. A positive correlation between burnout and exposure to verbal abuse, threatened assault and violence was demonstrated. CONCLUSIONS: Nurses in these Trusts are exposed to an unacceptable level of violence or aggression from patients, potential implications of which include post-traumatic reactions and burnout. However, nurses are reluctant to report incidents of verbal abuse or threats formally, and they rely upon the support of their colleagues following 'distressing' incidents. To protect the wellbeing of their staff, hospital management needs to consider preventative measures, such as training and personal alarms, and improved reporting systems to ensure all incidents are accurately recorded. PMID- 30440201 TI - What is the profile of post-traumatic reactions within medical literature? A survey of eight journals. AB - OBJECTIVES: The importance of traumatic events is recognised by the public but the profile of psychological sequelae such as Post-traumatic Stress Disorder (PTSD) within psychiatry and medicine is unclear. We aimed to establish the profile of PTSD within high impact medical journals and within psychiatric journals based in America and the United Kingdom, since the initial classification of PTSD in DSM-III in 1980 and, before and after classification of PTSD in ICD-10 in 1992. METHOD: A survey of all articles on post-traumatic reactions published in eight journals between 1980 and 2000. RESULTS: The proportion of articles on PTSD was less in UK based psychiatric journals than their counterparts based in America. The proportion of articles published after the classification of PTSD in ICD-10 has increased in both psychiatric and medical journals. CONCLUSIONS: In UK based journals, there is an under representation of articles on PTSD compared with disorders of similar prevalence. PMID- 30440202 TI - Saints-protectors from headache - historical hints of suggestive therapy? AB - A short overview of several saints, venerated in Christian tradition as protectors from headache, is offered as an introduction to a more substantial debate on the possibility and value of analysing historical literary and iconographic sources and their interpretation. Headache of possible psychosomatic origin allows (auto) suggestive therapy obtained by the invocation of saints to have had considerable success. This possibility favours the opinion that historical material can be useful not only for cultural-anthropological, but also for modern medical considerations as well. PMID- 30440203 TI - Koro: a case in an Eastern European asylum seeker in Ireland. AB - Koro is characterised as a perception that one's genital organs are shrinking and will eventually recede into the abdomen. It was initially described in South East Asia as a culture bound syndrome but this syndrome has recently been recognised in a non-culture bound context A case is described of a depressed Eastern European asylum seeker with koro like symptoms. All symptoms resolved completely with fluoxetine treatment The relevant literature to the case is reviewed, in relation to onset, symptoms and treatment of this rare syndrome. In addition comparison is made with previous reports of the non-culture bound variant. PMID- 30440204 TI - The Geriatric Depression Scale: feasibility of cardbased-administration. PMID- 30440205 TI - Equity and the multidisciplinary team: four developments for clinical psychology. PMID- 30440206 TI - Psychotherapy and learning disability. PMID- 30440207 TI - Costing the hospital-based process of resettling people with learning disability in the community. AB - OBJECTIVES: Much has been written about the costs and cost-effectiveness of community care for people with learning disabilities resettled from long stay hospital care. However, comparatively little has been published about the cost of hospital services relating to the preparatory process before eventual resettlement and the disengagement of formal, sustained input from hospital staff. This study describes and costs the input provided by a hospital based multi-disciplinary team into the resettlement of adults with learning disabilities from long stay wards in Muckamore Abbey Hospital in Northern Ireland between 1996 and 1999 (n = 71). METHOD: The study employs a retrospective survey design. Information about the nature and frequency of the input of each member of hospital multi-disciplinary team was collected for each former client. According to the level of professional resources expended during the resettlement process, each former client was then categorised into one of three categories. One case was then selected at random to represent each category. A summary of clinical information, a description of the resettlement process and an estimate of the cost of the process was provided for each case. RESULTS: Approximately 55% of people resettled in the community during the study period did so with a modest degree of input from hospital staff. For 18% resettlement proved to be a demanding and prolonged process, requiring intensive input from hospital staff. Financial costs of the resettlement process ranged from approximately stgL1,500 to stgL8,000, with an average of stgL3,400 for each person. CONCLUSION: This study provides evidence of the input by hospital staff into the process of community resettlement of long stay hospital clients and the associated costs. These costs must be included in service budgets if quality care and appropriate service provision is to be maintained in resettlement practice. PMID- 30440209 TI - The use of HoNOSCA in a child and adolescent mental health service. AB - OBJECTIVES: To assess the health and social functioning of patients attending a Child and Adolescent Mental Health Service (CAMHS) and to measure the impact of attendance using the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). METHOD: HoNOSCA was completed on 73 consecutive patients attending for initial assessment with a review assessment being completed after six months or at discharge from the clinic if this occurred sooner on 53 of these. The impact of attendance at the clinics was determined by comparing initial and review mean HoNOSCA Scores. RESULTS: Of the 53, 66% were male and 34% female. Boys were more highly rated with regard to aggressive behaviour, performance in peer relationships and family life relationships whilst girls were rated as having more nonorganic and emotional symptoms. Older children showed the highest rates of poor school attendance, non accidental (self) injury and emotional problems while younger children showed the greatest aggressive behaviour and language skill problems. An improvement in the total HoNOSCA score from initial assessment to review was seen in 92%. There was an improvement in the HoNOSCA mean score from initial assessment to review. CONCLUSIONS: Age, sex and symptom profiles of patients attending the service were similar to other CAMHS. Attendance at CAMHS produces improvements in patient outcomes over a six month period as measured using HoNOSCA, which proved to be a useful if somewhat time consuming tool. PMID- 30440208 TI - Meeting the needs of people with schizophrenia living in the community: a report from a European collaboration. AB - OBJECTIVES: This study was carried out as part of a collaborative European study, with the aim of assessing needs in a population with chronic schizophrenia in the context of a community service, and also to measure service use in this population. METHOD: This is the first part of a 12 month follow-up study of a sample of persons with schizophrenia who were in contact with the psychiatric services. Seventy eight patients who matched the inclusion criteria were randomly selected and 64 (82%) were interviewed using the Schedules for Clinical Assessment in Neuro-Psychiatry (SCAN) and the Needs for Care Assessment Schedule (NCAS). Service use data for a 12 month period were collected prospectively using the Mannheim Service Recording Sheet (MSRS). RESULTS: The levels of clinical and social need were quite low at 2.1 and 2.6 respectively. Most needs were met; unmet need was 0.11 for clinical problems and 0.4 for social. Service use was high, with a total of 6,969 contacts with community services, a mean of 109 per patient per year. Total service use (including inpatient and hostel) was partly predictive of met need (R2 23.6). The levels of met and unmet need in Dublin compare favourably with that reported in Mannheim and Granada. Service use was similar to that in Mannheim, although there was a higher level of service provision in Mannheim. CONCLUSIONS: This study has shown that there is a low level of clinical and social need in this sample of patients with schizophrenia living in the community, and a relatively high level of service use. There is good evidence that services are meeting the needs of this sample of patients. PMID- 30440210 TI - Secular trends in the mental health of primary school children. AB - Over the recent past, reports have argued that there has been a decline in the mental health of children and young people in Western societies. This is said to have occurred gradually over the second half of the last century and possibly longer. This view is based on evidence of a progressively declining peak age for adult type depressive disorders, and an apparent increase in adolescent disturbance such as substance abuse, attempted and completed suicide, perhaps eating disorders, and behaviour disorders. These phenomena have been attributed to the major changes in social values and behaviour, with their impact on child rearing and family life that gathered pace over the course of the last century. PMID- 30440211 TI - An audit of psychotropic prescribing practice of general adult psychiatrists in elderly demented patients. AB - OBJECTIVES: In Ireland elderly patients with behavioural and psychological symptoms of dementia (BPSD) are frequently prescribed anti-psychotic and other psychotropic agents. Elderly patients with dementia are more sensitive to adverse effects of medications. Despite this, little is known of the psychotropic prescribing practice of psychiatrists who treat this population. General adult psychiatrists in the Republic of Ireland continue to treat elderly patients with BPSD. The aim of this audit was to identify the prescribing practice of general adult psychiatrists in elderly patients with BPSD. We compare this practice to that of old age psychiatrists in the UK and that recommended by the American Psychiatric Association in 1997. METHODS: We devised a structured anonymous questionnaire, which was forwarded to all general adult psychiatrists in the Republic of Ireland. RESULTS: Atypical anti-psychotics are frequently prescribed by general adult psychiatrists to manage BPSD in elderly patients. The anti psychotic agent of first preference chosen to treat psychotic symptoms in dementia is risperidone. Overall, sedative typical anti-psychotics are still the most frequently chosen anti-psychotic agents, chosen to manage behavioural symptoms in dementia. Benzodiazepines and trazadone are the most frequently prescribed other psychotropic agents chosen to manage agitated behaviour. In general the median doses of antipsychotics and other psychotropic medication used are in keeping with both the APA guidelines and practice of old age psychiatrists in the UK. A minority of practitioners (10%) specified at least one dosage regime that was grossly outside recommended ranges. CONCLUSIONS: Overall, prescribing practice in terms of choice of treatment and dosage regime, of general adult psychiatrists in BPSD is in keeping with the best practice guidelines. However, sedating typical anti-psychotics and on occasion extraordinarily high doses of anti-psychotics are still prescribed. PMID- 30440212 TI - Liaison psychiatry in rural general practice. AB - The recent government health strategy document described the integration between primary and secondary care in Ireland as often poor and outlined plans to redress this deficit. In mental health care, the gradual shift away from institutions over the past four decades has resulted in the GP becoming the most frequent professional contact for people with mental disorders. However, access to specialist opinion is usually available only for the fraction of psychiatric presentations which are formally referred to the psychiatric service. On-site psychiatric liaison to primary care is commonly practised in other countries but not in Ireland. Research in the area suggests possible advantages for approaches which aim to enhance GPs' psychiatric skills while selectively encouraging referral of more serious disorders. This model has been adopted by GPs and psychiatrists in east Cavan and may be relevant to other similar settings, especially in the context of forthcoming changes in the organisation of primary care services. PMID- 30440214 TI - Regulatory disorders and Asperger's syndrome: diagnosis in the first two year of life. PMID- 30440213 TI - Treatment of early onset bipolar disorder, NOS with low dose Carbamazepine. AB - This report describes the presentation, monitoring and successful treatment of an eight year old girl with bipolar disorder, NOS (not otherwise specified), with low dose carbamazepine. The difficulties of diagnosing and managing bipolar disorder in prepubertal children are discussed. PMID- 30440215 TI - Sectorised versus subspecialist care: what does the patient deserve? PMID- 30440216 TI - Hyperactivity and conduct disorder: exploring origins. AB - OBJECTIVES: This paper explores the relationship of hyperactivity (HA), conduct disorder (CD) and combined hyperactivity and conduct disorder (HACD) with certain environmental and biological stresses and vulnerabilities. METHOD: It is based upon a large epidemiological database from the North of England. RESULTS: The findings suggest that CD is uncommon and strongly related to environmental stresses. This is true to a lesser extent of HACD. While both CD and HACD were related to family adversity and adverse styles of parental discipline, subtly different patterns of associations are also evident. In particular, CD is linked with poverty, parental violence and contact with child care social agencies. These findings are consistent with the hypothesis that HA contributes to a pattern of confrontation and punishment associated, in some cases, with the emergence of a more complex combination disturbance. However, CD occurs against a background of family conflict and poor child-care. CONCLUSIONS: Most apparent cases of conduct disorder are in fact hybrid conditions including symptoms of HA and CD. True CD should be diagnosed not only by positive symptomatology but also by the absence of hyperactivity symptoms. PMID- 30440217 TI - Interaction of forensic and general psychiatric services in Ireland: learning the lessons or repeating the mistakes? AB - OBJECTIVE: General psychiatric bed numbers in Ireland have reduced markedly in recent decades. In other jurisdictions such reductions have been accompanied by increases in the prevalence rates of severe mental illness among prisoners. We examined variations in per capita provision of local psychiatric beds and community residential places in Ireland for associations with forensic psychiatric service utilisation. METHOD: All admissions via the courts and prisons to the national forensic psychiatry service during the years 1997-1999 were assigned to the appropriate health board. Forensic admission and bed utilisation rates were compared with measures of general psychiatric service provision. RESULTS: There were 476 admissions via the criminal justice system during the study period (0.74% of all psychiatric admissions in Ireland). A disproportionate number came from the most urbanised area. There were fivefold differences in overall bed and hostel place allocation between Irish health boards. Combined general psychiatric beds were inversely correlated with forensic bed utilisation (Spearman r = -0.75, p = 0.013). These differences showed a strong inverse correlation with forensic service utilisation. CONCLUSIONS: General psychiatric services are relatively under-resourced in areas of greatest predicted need in Ireland. This is associated with increased use of forensic psychiatric services and may reflect accumulation of the mentally ill in Irish prisons. PMID- 30440219 TI - Atypical antipsychotics and diabetes. PMID- 30440218 TI - Differences in the quality of life of two groups of drug users. AB - OBJECTIVES: The aim of this study was to compare aspects of the quality of life of drug users on a methadone maintenance programme to drug users on a harm minimisation programme. METHOD: Thirty-six clients attending the harm minimisation programme in the National Drug Treatment Centre, Dublin, were matched for age and sex to 36 clients on the methadone maintenance programme. All were interviewed with the SF-36 Health Survey Questionnaire to measure health related quality of life and with the Hospital Anxiety and Depression Scale (HADs) to measure psychological morbidity. RESULTS: More clients from the harm minimisation programme had previous psychiatric problems than clients on the methadone maintenance programme, with an odds ratio of 4.3 CI(1.2,15.2). On the HADs, clients on the methadone maintenance programme had significantly lower depression scores than clients on the harm minimisation programme. In addition more clients on the harm minimisation programme were severely depressed than clients on the methadone maintenance programme. On the UK SF-36 Scale, clients on the harm minimisation programme perceived a significantly greater deterioration in 'change in health' over the previous year than clients on the methadone maintenance programme. CONCLUSIONS: Although clients on a methadone maintenance programme had an improved perception of their quality of life in relation to psychological and overall health function from the previous year, compared to clients on a harm minimisation programme, there still existed varying degrees of psychopathology in both groups which need to be considered when providing future services for drug users. PMID- 30440220 TI - Mental health legislation in child and adolescent psychiatry in England and Wales. AB - As colleagues in Ireland and England and Wales are bracing themselves for revisions of their respective mental health legislations, I would like to share some of the joys and tribulations of working within the legal framework of mental health of young people in England and Wales as it stands. (This is the first major reform of UK Mental Health legislation since the 1983 Mental Health Act, which was based on a full review of mental health legislation from the 1950s.) On first approach, the complexities of this framework can be daunting. However the underlying principles are similar to Ireland's. Ideally, health professionals, parents and children are working together in a co-operative therapeutic alliance. In reality, factors such as time, communication, resources, differences in professional judgements regarding thresholds for concern and action, interagency and interprofessional rivalries impact greatly on our day-to-day practice. PMID- 30440221 TI - 'Fright of mothers' and the aetiology of deaf-dumbness. PMID- 30440222 TI - Electroconvulsive therapy and cognitive function. PMID- 30440223 TI - Debriefing and post traumatic stress disorder. PMID- 30440224 TI - Managing sex offenders: is there a role for psychiatry? PMID- 30440225 TI - Eye movements and neurocognitive function in treatment resistant schizophrenia: a pilot study. AB - OBJECTIVES: It is increasingly important to develop predictors of treatment response and outcome in schizophrenia. Neuropsychological impairments, particularly those reflecting frontal lobe function, appear to predict poor outcome. Eye movement abnormalities probably also reflect frontal lobe deficits. We wished to see if these two aspects of schizophrenia were correlated and whether they could distinguish a treatment resistant from a treatment responsive group. METHODS: Ten treatment resistant schizophrenic patients were compared with ten treatment responsive patients on three eye movement paradigms (reflexive saccades, antisaccades and smooth pursuit), clinical psychopathology (BPRS, SANS and CGI) and a neuropsychological test battery designed to detect frontal lobe dysfunction. Ten aged-matched controls also carried out the eye movement tasks. RESULTS: Both treatment responsive (p = 0.038) and treatment resistant (p = 0.007) patients differed significantly from controls on the antisaccade task. The treatment resistant group had a higher error rate than the treatment responsive group, but the difference was not statistically significant. Similar poor neuropsychological test performance was found in both groups. CONCLUSIONS: To demonstrate the biological differences characteristic of treatment resistance, larger sample sizes and wider differences in outcome between the two groups are necessary. PMID- 30440226 TI - Home-based treatment in Monaghan: the first two years. AB - OBJECTIVES: To describe a home-based treatment (HBT) service. To profile the patient population using HBT. To determine why HBT was used and to record disposal. METHOD: All patients treated by HBT during the first two years of this new service were identified from the HBT logbook. A checklist recording demographic, diagnostic, presenting complaint data and details of HBT contact was used to analyse the patients' charts. A statistical package JMP was used to analyse the data. RESULTS: Two hundred and six patients (275 episodes) were treated using HBT. These were 101 (49.1 %) males and 105 (50.9%) females. Of these, 89 (43.2%) were single. Forty-eight (19.4%) lived alone and 53 (25.7%) were unemployed. The most common presenting complaint was severe depression (39.3%). A depressive disorder was the most frequent diagnosis (28.7%). Twenty six (13%) episodes of HBT ended in admission. One hundred and eighty five (67.3%) were referred to outpatients and 26 (9.5%) were discharged to the GP. CONCLUSIONS: Home-based treatment is feasible for a wide range of patients with an array of presenting complaints. This model of service delivery is viable in a rural setting. Admission will still be required for some patients. Further work is needed to examine its sustainability and its generalisability to other Irish settings. PMID- 30440227 TI - Self-poisoning patients in the general hospital: the frequency and nature of their consultations with the general practitioner. AB - OBJECTIVES: To update the 20 year-old maxim that the majority of patients who undertake self-poisoning have recently seen their general practitioner, and to determine the patients' expressed reasons for consulting the doctor. METHODS: Two stage cross-sectional survey: first, to find out from all self-poisoning patients whether they had recently attended their general practitioner; second, to determine, in a sub-sample of those who had attended, why they made their most recent consultation. The subjects were consecutive adult patients who were admitted to the general hospital in the City of Bradford as a consequence of self poisoning. RESULTS: Overall 125/237 (53%) patients reported a consultation with their general practitioner in the previous month, and 61 of the 237 (26%) were within the last week. Patients recounted that their main expectations when consulting were to do with prescriptions, sick-notes and physical check-ups. CONCLUSIONS: Although many of those who undertake self-poisoning consult their general practitioner shortly beforehand, a preponderance of physical complaints may render anticipation of the self-poisoning a difficult task. PMID- 30440228 TI - Pharmacological management of treatment resistant depression: a clinical review. AB - OBJECTIVES: Treatment resistant depression (TRD), commonly encountered in clinical practice, leads to socioeconomic disability and therapeutic pessimism. This paper reviews evidence for pharmacological approaches used in TRD. METHOD: Electronic literature searches were performed using Medline and Psychlit using broad search terms relating to TRD. RESULTS: Agents that potentiate both serotonin and noradrenaline may allow more patients to achieve full remission. Attention must be paid to dose titration and length of treatment courses in TRD. Augmentation with lithium and switching within antidepressant class or between classes can often improve symptoms but efficacy of other augmentation approaches remains uncertain. Antidepressant combinations and addition of atypical antipsychotics can be useful but combinations of predominantly serotonergic antidepressants should be avoided. Electroconvulsive therapy retains an important role in TRD but pharmacological treatments need to be continued concomitantly. CONCLUSIONS: Good improvement is seen in TRD after vigorous antidepressant treatment but most patients continue to have lower grade symptomatology. PMID- 30440229 TI - Antipsychotic drugs: atypical advantages and typical disadvantages. AB - Atypical antipsychotic drugs are recommended for the first line treatment of all patients with schizophrenia. This is because it has been demonstrated that atypical antipsychotic drugs are more effective across a broader range of symptoms of schizophrenia than typical antipsychotic drugs and because they are dramatically less likely to cause the extrapyramidal and endocrine side effects that greatly impair quality of life for patients and reduce their willingness to adhere to maintenance treatment. Atypical antipsychotic drugs are not perfect but they are the most effective and the safest treatment for schizophrenia presently available. The atypical antipsychotic drugs currently marketed in Ireland for the first line treatment of schizophrenia include amisulpride, olanzapine, quetiapine, risperidone and ziprasidone. These agents differ somewhat in chemical class, indications, daily dose range, need for titration, daily dosing regimen and available formulations (see Table 1). Clozapine is marketed for patients unresponsive to, or intolerant of, other antipsychotic drugs and must thus be regarded as a second line treatment for schizophrenia. Zotepine is not yet available in Ireland while the marketing of sertindole has been suspended following reports of arrhythmias and sudden cardiac deaths. PMID- 30440230 TI - Did Alan Turing have Asperger's syndrome? AB - Alan Turing was born in Paddington, London on June 23, 1912 . His family were middle-class and well-off. He was fascinated with science from an early age and showed precocious talent, especially in the areas of chemistry and mathematics. He attended Sherbourne Public School and then King's College, Cambridge where he studied mathematics. His areas of interest at Cambridge were probability theory and mathematical logic. It was at Cambridge that he first conceptualised the Universal Turing Machine, an idea that was to evolve into the modern theory of computing. He has been referred to as the father of the computer. He worked on a cipher machine at Princeton University between 1936 and 1938. He worked for the British Government during World War II with the Government Code and Cipher School at Bletchley Park. He was ultimately the key player in deciphering the German 'Enigma' code used by its submarines during the war. After the war he took up a post in Manchester University where he continued to work on ideas of artificial intelligence. He was arrested and charged for homosexual activity in 1952 and underwent a course of oestrogen therapy. He committed suicide in 1954. He was regarded as being socially aloof and eccentric by colleagues and friends. He was interested in mathematics, chemistry and logic from an early age, to the exclusion of other activities. This paper attempts to establish whether he fulfilled the criteria for Asperger's syndrome. PMID- 30440231 TI - Deterioration in renal function following commencement of citalopram. AB - We report the case of an 85 year old woman, admitted to hospital with a two month history of a depressive illness. Within one week of commencing treatment with citalopram 20mg daily, she had developed a widespread rash, bilateral ankle oedema and a range of biochemical and haematological abnormalities, including marked elevations of plasma urea and creatinine and increased neutrophil and eosinophil counts. Following withdrawal of citalopram, her physical state returned to normal within two weeks. The episode is suggestive of acute interstitial nephritis triggered by citalopram, a phenomenon not previously reported in association with the selective serotonin reuptake inhibitors. PMID- 30440232 TI - Catastrophic reaction following the separation of adult twins. AB - We describe a case of adult twins presenting simultaneously with profound psychological disturbance following sudden separation. Formulation is made of a catastrophic adjustment reaction manifesting as depression in one sibling and anxiety in the other. An alternative possibility of acute onset psychosis in one or both of the twins is discussed. PMID- 30440233 TI - Complex partial seizures presenting as frontotemporal dementia: a case report. AB - Both epilepsy and dementia are common after the age of 65. Epilepsy, originating in the temporal lobes, can present clinically in a variety of ways and can be difficult to diagnose. Loss of consciousness may not be evident. Reported here is a unique case of a 65 year old man who presented with clinical features of frontotemporal dementia but was subsequently diagnosed as suffering from complex partial seizures. He made a full recovery with antiepileptic treatment. PMID- 30440234 TI - Our parents' keepers? - Making more of ethics in old age psychiatry. PMID- 30440235 TI - Irish Travellers and forensic mental health. AB - OBJECTIVES: To determine whether Irish Travellers are over-represented amongst transfers from prison to psychiatric hospital. If so, to determine whether this represents an excess over the proportion of Irish Travellers committed to prison. METHOD: Irish Travellers admitted to the National Forensic Psychiatry service were identified from a case register over three years 1997-1999. New prison committals were sampled and interviewed as part of the routine committal screening to identify ethnicity. RESULTS: Irish Travellers accounted for 3.4% of forensic psychiatric admissions compared to 0.38% of the adult population. Travellers transferred from prison to psychiatric hospital had more learning disability and less severe mental illness than other groups, while black and other ethnic minorities had a higher proportion of severe mental illness. Travellers accounted for 6% (95% CI 3-11) of 154 male committals and 4% (95% CI 2 12) of 70 female committals. The estimated annualised prison committal rate was 2.8% (95% CI 2.4-3.3) of all adult male Travellers in Ireland and 1% for female Travellers (95% CI 0.8-1.3). Male Travellers had a relative risk of imprisonment compared to the settled community of 17.4 (95% CI 2.3-131.4), the relative risk for female Travellers was 12.9 (95% CI 1.7-96.7). Imprisoned Travellers had greater rates of drugs and alcohol problems than other prisoners (Relative risk 1.46, 95% C11.11-1.90). CONCLUSION: There is gross over-representation of Travellers in forensic psychiatric admissions. This reflects the excess of Travellers amongst prison committals. PMID- 30440236 TI - Buprenorphine detoxification treatment for heroin dependence: a preliminary experience in an outpatient setting. AB - OBJECTIVES: The aim of the study was to evaluate buprenorphine as a detoxification agent for heroin dependence in an outpatient setting. Specifically we sought to establish the rate of completion of detoxification and retention in treatment, the duration of successful detoxification and dose requirements. METHODS: The study was an open prospective evaluation of routinely collected clinical data on the first 60 consecutive heroin dependent patients who underwent buprenorphine detoxification. A flexible dosing regime was adopted with the dose of buprenorphine being adjusted daily against the previous day's withdrawal symptoms. RESULTS: The majority of patients (40 (67%)) completed detoxification. The median duration of treatment for completers was 17 days (range 9-30 days) with 90% of detoxification episodes completed within 21 days. Patients were commenced on initial median dose of 4mg buprenorphine (range 2mg-6mg) and the median stabilisation dose for the sample was 10mg daily (range 6mg-14mg). The median final dosage of buprenorphine required by patients retained in treatment was 1.2mg (range 0.4mg-2mg). We found older patient age to be a significant predictor of treatment completion. CONCLUSIONS: Buprenorphine was an acceptable and a feasible outpatient detoxification treatment option for heroin dependent patients. Based on the study findings we propose a standard 21-day fixed-dose detoxification schedule. PMID- 30440237 TI - Adult ADHD: a controversial diagnosis? AB - Attention deficit hyperactivity disorder (ADHD) is characterised by inattention, hyperactivity and impulsivity with onset in children before the age of seven years. ADHD is the most common disorder presenting to child guidance clinics and has been shown to be a well-validated diagnosis. Current estimates of prevalence range from 1%5%. The concept of adult ADHD as a clinical entity is an emerging but controversial area in psychiatry. While childhood ADHD is accepted as a reliable and valid diagnosis, the validity of adult ADHD as a disorder is unclear. This paper reviews the likely presenting features of adult ADHD and common comorbid disorders. Guidelines for assessment and management are discussed and the evidence for validity of the diagnosis is critically examined. PMID- 30440238 TI - Cognitive psychotherapy: what happens when the therapeutic relationship breaks down? AB - Behavioural and interpersonal difficulties arising during the course of cognitive psychotherapy are common and they provide unique opportunities to assess and modify patients' beliefs and assumptions. A breakdown in the therapeutic relationship may be on a continuum from a simple misunderstanding to a more chronic and complex problem. It may act as a potent vehicle for change in the patient, but may also precipitate change in the therapist who is also part of that relationship which can influence treatment outcome. PMID- 30440239 TI - Disintegrative syndrome in young adults. PMID- 30440240 TI - Louis Wain and Asperger's syndrome. PMID- 30440241 TI - The Geriatric Depression Scale: feasibility of cardbased-administration. PMID- 30440242 TI - A Bayesian parametric model for quantifying brain maturation from sleep-EEG in the vulnerable newborn baby. AB - Newborn babies, particularly preterms, can exhibit early deviations in sleep maturation as seen by Electroencephalogram (EEG) recordings. This may be indicative of cognitive problems by school-age. The current 'clinically-driven' approach uses separate algorithms to first extract sleep states and then predict EEG 'brain-age'. Maturational deviations are identified when the brain-age no longer matches the Postmenstrual Age (PMA, the age since the last menstrual cycle of the mother). However, the PMA range where existing sleep staging algorithms perform optimally, is limited, which subsequently limits the PMA range for brain age prediction. We introduce a Bayesian Parametric Model (BPM) as a single end-to end solution to directly estimate brain-age, modelling for sleep state maturation without requiring a separately optimized sleep staging algorithm. Comparison of this model with a traditional multi-stage approach, yields a similar Krippendorff's $?alpha = 0.92$ (a performance measure ranging from 0 (chance agreement) to 1 (perfect agreement)) with the BPM performing better at younger ages <30 weeks PMA. The BPM's potential to detect maturational deviations is also explored on a few preterm babies who were abnormal at 9 months follow-up. PMID- 30440243 TI - Approximating Cellular Densities from High-Resolution Neuroanatomical Imaging Data. AB - Characterizing the cellular architecture (cytoar-chitecture) of tissues in the nervous system is critical for modeling disease progression, defining boundaries between brain regions, and informing models of neural information processing. Extracting this information from anatomical data requires the expertise of trained neuroanatomists, and is a challenging task for inexperienced analysts. To address this need, we present an unbiased, automated method to estimate cellular density of retinal and neocortical datasets. Our approach leverages the fact that within retinal and neurocortical datasets, cells are organized into "layers" of constant density to approximate cytoarchitecture with a small number of known basis elements. We introduce methods for patch extraction, cell detection, and sparse approximation of inhomogeneous Poisson processes to differentiate changes in cellular densities and detect layers. Our results demonstrate the feasibility of using automation to reveal the cytoarchitecture of large-scale biological samples. PMID- 30440244 TI - Optimal Insulin Bolus Dosing in Type 1 Diabetes Management: Neural Network Approach Exploiting CGM Sensor Information. AB - Type 1 diabetes (TID) therapy is based on multiple daily injections of exogenous insulin. The so-called insulin bolus calculators facilitate insulin dose calculation to the patients by implementing a standard formula SF which, besides some patient-related parameters, also considers the current value of blood glucose concentration (BG), normally measured by the patient through a fingerprick device. The recent approval by the U.S. Food and Drug Administration to use the measurements collected by wearable continuous glucose monitoring (CGM) sensors for insulin dosing of fers new perspectives. Indeed, CGM sensors provide real-time information on both glucose concentration and rate of change, currently not considered in the SF. The purpose of this work is to preliminary investigate the possibility of using neural networks (NN)s for the calculation of meal insulin bolus dose exploiting CGM-based information. Using the UVa/Padova TID Simulator, we generated data of 100 subjects in 9-h, single-meal, noise-free scenarios. In particular, for each subject we analyzed different meal conditions in terms of carbohydrate intakes, preprandial BG and glucose rate-of -change. Then, a fully-connected feedforward NN was trained, with the aim of estimating the insulin bolus needed to obtain the best glycemic outcomes according to the blood glucose risk index (BGRI). Preliminary results show that by using the NN to calculate insulin doses lower BGRI values are obtained, on average, compared to the SF. These results encourage further development of the approach and its assessment in more challenging scenarios. PMID- 30440245 TI - Classification of propofol-induced sedation states using brain connectivity analysis. AB - connectivity measurements can provide key information about ongoing brain processes. In this paper, we propose to investigate the performance of the binary classification of Propofol-induced sedation states using partial granger causality analysis. Based on the brain connectivity measurements obtained from EEG signals in a database that contains four sedation states: baseline, mild, moderate, and recovery, we consider eight sensors and evaluate the area under the ROC curve with five classifiers: the k-nearest neighbor (density method), support vector machine, linear discriminant analysis, Bayesian discriminant analysis, and a model based on extreme learning machine. The results support the conclusion that the different Propofol-induced sedation states can be identified with an AUC of around 0.75, by considering signal segments of only 4 second. These results highlight the discriminant power that can be obtained from scalp level connectivity measures for online brain monitoring. PMID- 30440246 TI - Fall Risk Estimation for Inpatients on Beds Using 3D Vision Sensor. AB - Fall accidents at medical centers are one of the most serious problems, and many accidents happen at the bedside. In order to deal with this problem, this paper proposes a method for estimating an inpatient's fall risk using only depth data from Kinect. In this method, the obtained depth data are modified as if Kinect were above the center of the bed to estimate fall risks accurately. Then, these corrected data are divided into multiple cells, and human location is detected using gravity coordinates obtained from the data in each cell. Finally, the fall risks are estimated using the human location and predefined fall risk weights. Through verification using hospitalized subjects, the authors confirmed that the proposed method can estimate appropriate fall risks. PMID- 30440247 TI - Nonlinear System Identification Based on Convolutional Neural Networks for Multiple Drug Interactions. AB - In heart failure patients, hemodynamics can be regulated by therapeutic drugs. Although the cardiovascular responses to these drugs usually include nonlinearity and drug interactions, it is difficult to identify the characteristics of the dynamics under such conditions. This study, therefore, was aimed at evaluating the technique used for nonlinear system identification based on convolutional neural networks (CNN). As an image i.e., pixel values corresponding to time course data), CNN can be used to treat the complicated relation between previous inputs (i.e., drug infusions) and outputs i.e., hemodynamics). To compare the accuracy of CNN, traditional methods based on the standard neural networks (NN) and fast Fourier transformation FFT were applied to nonlinear system identification with drug interactions. The cardiac output and arterial blood pressure under heart failure were modulated by the drug infusions of an inotropic agent and a vasodilator. CNN accurately predicted the dynamic system responses regardless of the inclusion of nonlinearity and drug interactions. Based on the findings of this study, CNN to carry out nonlinear system identification could clarify complicated pharmacodynamics, and thus could be useful for in appropriate cardiac treatment with multiple therapeutic agents. PMID- 30440248 TI - A stringent fiber distance measure for dMRI tractography clustering and segmentation. AB - Most analysis and segmentation methods for diffusion MRI tractography datasets require a fiber distance measure able to determine the similarity between a pair of fibers. We present a stringent fiber distance measure able to perform a good discrimination between fiber shapes and lengths. It uses three terms: (i) a fiber maximum Euclidean distance, (ii) a fiber shape distance, and (iii) a fiber length distance. The distance was evaluated applying a hierarchical clustering of fibers connecting the pre-and post-central gyri of a subject. Results where compared with other known fiber distance measures. A better sensitivity to differences in fiber shape and length was found for the proposed distance. This will be very useful for the detailed study and description of white matter bundles. Known bundles will be better decomposed into sub-bundles, with more precision on the bundle shape and on the regions connected by the fibers. For short association bundles, this distance will be a real improvement, as even the most stringent distance used until now shows some limitations when evaluating the similarity of these fibers. PMID- 30440249 TI - Multiple neutrophils tracking in vitro array using high-order temporal information. AB - It is crucial to dynamically analyze the movement of neutrophils (a type of white cell) during the process of inflammation. However, manually tracking and analyzing the cells is a time-consuming task due to the large volume of cells and similar appearance. To facilitate neutrophils analysis and address the issues mentioned above, we propose to leverage high-order temporal information as a cue to track neutrophils. A tensor-based approach is introduced to encode the high order motion pattern and appearance variation for multi-frame multicell association. To evaluate the proposed method, we collected 354 sequences of cells from 200 frames of microscopic images. We conduct a systematic study on the collected data and show significant performance improvement over other solutions. PMID- 30440250 TI - Spread Spectrum Steganographic Capacity Improvement for Medical Image Security in Teleradiology. AB - this paper presents a capacity-improved Spread Spectrum (SS) watermarking method for data hiding and security for medical image and Electronic Medical Record (EMR) transmission in Teleradiology. SS watermarking is more secure than other watermarking methods but currently has low data carrying capacity due to the spreading of a single bit in larger cover sample in order to achieve higher robustness and security. In this work, a new method in spatial domain is proposed in order to improve on the current hiding capacity of just one bit per sample to up to 6 bits per sample (8*8 pixel block). This new watermark compression encoding method is suitably adapted for blind SS watermarking for hiding patient data securely in medical images of high pixel depth. The new method was successfully implemented and evaluated using Magnetic Resonance Image (MRI) scans. PMID- 30440251 TI - Super-Resolution in Optical Coherence Tomography. AB - Optical coherence tomography (OCT) is an essential medical imaging tool for retinal disease diagnosis. Nevertheless, as with all optical imaging techniques, image degradation is a very common phenomenon, affecting the quality of the images. In this paper, we address issues related to the resolution of OCT images and propose solutions based on solving inverse problems. A cost function for deconvolution and super-resolution is formulated and the alternating direction method of multiplier (ADMM) and forward-backward splitting (FBS) algorithms are then employed for its minimisation. On the one hand, the standard Ll norm regularisation with soft thresholding is compared with a total variation (TV) regularisation within an ADMM scheme. On the other hand, nonconvex regularisation is also considered via a multivariate generalisation of the minimax-concave scheme in FBS. In the latter case, the regularisation function is judiciously chosen in order to preserve the overall convexity of the cost function. To be able to evaluate our algorithms qualitatively, a number of standard images are initially used. Then, we also assess our algorithms subjectively by applying them to real OCT images of the human eye. Given that the point spread function (PSF) of OCT images is generally unknown, we also propose ways of estimating it in the deconvolution component of our methods. Our results show that the ADMM scheme with soft thresholding achieves the best performance in terms of enhancing the overall quality of OCT images. PMID- 30440252 TI - Co-Sparse Analysis Model Based Image Registration to Compensate Brain Shift by Using Intra-Operative Ultrasound Imaging. AB - Notwithstanding the widespread use of image guided neurosurgery systems in recent years, the accuracy of these systems is strongly limited by the intra-operative deformation of the brain tissue, the so-called brain shift. Intra-operative ultrasound (iUS) imaging as an effective solution to compensate complex brain shift phenomena update patients coordinate during surgery by registration of the intra-operative ultrasound and the pre-operative MRI data that is a challenging problem.In this work a non-rigid multimodal image registration technique based on co-sparse analysis model is proposed. This model captures the interdependency of two image modalities; MRI as an intensity image and iUS as a depth image. Based on this model, the transformation between the two modalities is minimized by using a bimodal pair of analysis operators which are learned by optimizing a joint co-sparsity function using a conjugate gradient.Experimental validation of our algorithm confirms that our registration approach outperforms several of other state-of-the-art registration methods quantitatively. The evaluation was performed using seven patient dataset with the mean registration error of only 1.83 mm. Our intensity-based co-sparse analysis model has improved the accuracy of non-rigid multimodal medical image registration by 15.37% compared to the curvelet based residual complexity as a powerful registration method, in a computational time compatible with clinical use. PMID- 30440253 TI - Sample Entropy of High Frequency Oscillations for Epileptogenic Zone Localization. AB - For epileptic patients whose seizures are poorly controlled with medication, removing the brain region responsible for seizure onset is a treatment option. This requires the epileptogenic zone (EZ) to be accurately delineated. In this paper, a two-stage approach for EZ delineation is proposed. The algorithm starts by detecting events of high-frequency oscillations (HFOs) directly from the multi channel intracranial electroencephalograms (iEEGs). The sample entropy is then computed for each of their channels that will be used for determining the channels correlated with the EZ. The performance of our proposed method is evaluated using the receiver operating characteristic curve analysis, and the results indicate that our proposed approach can provide an accurate estimation of the EZ. PMID- 30440254 TI - Development of Software for Obtaining Image Attributes for Evaluation of the Wound Healing Process. AB - The biological process of wound healing is one of the most complex occurrences during our lives turning a serious public health problem. The rate of healing chronic wounds in humans is relatively uniform, regardless of etiologies, and is estimated to be 0.63-0.65 mm/week for diabetics and non- diabetics [1], respectively, being visually unnoticeable throughout the daily care of a wound. A ruler designed for this purpose using a decal for setting the wound limits, however an area with a lot of irregularity requires a tool that carries out this measurement autonomously through image recognition, making the process feasible for the medical teams responsible for the treatment. The digitized images undergo morphological processes sing on the polygonal line that delimits the wound region. With the region delimited by the polygonal, the area and the perimeter are determined. A comparison with analytical methods demonstrates that this tool has the potential to become gold standard for estimating to estimate the area and the perimeter of wounds in the healing process. PMID- 30440255 TI - Seasonal Variation In An At-Home Telemonitoring Trial. AB - This paper aims to present findings on seasonal variation in a recently completed Commonwealth Scientific and Industrial Research Organization (CSIRO) national trial of home telemonitoring of patients with chronic conditions, carried out at five locations along the east coast of Australia. Patients in this trial were selected from a list of eligible patients living with a range of chronic conditions. Each test patient was case matched with at least one control patient. A total of 114 test patients and 173 control patients were available in this trial. However, of the 287 patients, we only considered subjects who had one or more admissions in the years 2010-2012. Three different groups were analyzed because of substantially different climates, i.e., Queensland (QLD), Australian Capital Territory & Victoria (ACT + VIC), and Tasmania (TAS). Time series data were analyzed using linear regression for a period of 3 years before the intervention in order to obtain an average seasonal variation pattern. PMID- 30440257 TI - Tracking Kinematic and Kinetic Measures of Sit to Stand using an Instrumented Spine Orthosis. AB - Age related spinal deformity is becoming an increasingly prevalent problem, resulting in decreased quality of life. While spinal deformity can be corrected via surgical intervention, a large number of people with spinal fusions require follow-up surgery due to further degeneration. The identification of changes to a subjects kinematics and kinetics post-surgery are limited by a lack of methods to collect patient specific motion data over the course of surgical recovery. This paper introduces an Instrumented Spine Orthosis (ISO) that can capture the motions of the subjects torso without requiring the use of a control computer or other dedicated motion capture equipment. This system is used to collect the peak torso angles and velocities for a single subject performing sit-to-stand actions. The accuracy of the ISO is evaluated using motion capture, during different sit to-stand protocols designed to highlight motion changes that have been seen in subjects with reduced mobility. This system was found to provide reliable measurements of these kinematic and kinetic torso measures across all tested motions, demonstrating the potential for the use of Instrumented Spine Orthotics to provide quantitative measures during the surgical recovery process. PMID- 30440256 TI - SSVEP Transient Feature Extraction and Rapid Recognition Method Based on Bistable Stochastic Resonance. AB - Steady-state Visual Evoked Potential, SSVEP), as the most commonly used communication paradigm for non-implantable Brain-Computer Interface (BCI), boasts the advantages of unnecessity of training, noise immunity and periodicity. The traditional SSVEP extraction methods can effectively identify the target frequency contained in original EEG, however, the required data length usually lasts a few seconds. In this paper, bistable stochastic resonance (BSR) is applied to SSVEP extraction. BSR is very sensitive to amplitude mutation and frequency fluctuation of the input signal, making the output difference can be used for the detection of the target frequency. The processing results illustrate that the proposed method not only has a high recognition accuracy, but also effectively shortens the recognition time, thus improving the calculating speed. Therefore, SSVEP extraction based on BSR has a higher information transmission rate (ITR), which is more suitable for the real-time BCI system. PMID- 30440258 TI - Gated Recurrent Neural Networks for EMG-Based Hand Gesture Classification. A Comparative Study. AB - Electromyographic activities (EMG) generated during contraction of upper limb muscles can be mapped to distinct hand gestures and movements, posing them as a promising modality for prosthetic and cybernetic applications. This paper presents a comparative analysis between different recurrent neural network (RNN) configurations for EMG-based hand gesture classification. In particular, RNNs with recurrent units of long short-term memory (LSTM) and gated recurrent unit (GRU) are evaluated. Furthermore, the effects of an attention mechanism and varying learning rates are evaluated. Results show a classifier 1) with a bidirectional recurrent layer composed of LSTM units, 2) that applies the attention mechanism, and 3) trained with step-wise learning rate outperforms all other tested RNN classifiers. PMID- 30440259 TI - Improved Sparse Adaptive Algorithms for Accurate Non-contact Heartbeat Detection Using Time-Window-Variation Technique. AB - Recently, a sparse adaptive algorithm termed zero-attracting sign least-mean square (ZA-SLMS), has been clarified to be able to reconstruct robustly heartbeat spectrum by Doppler radar signal. However, since the strengths of noise evidently differ under different body motions, the sparse heartbeat spectra cannot be always acquired accurately by the constant regularization parameter (REPA) that balances the gradient correction and the sparse penalty, applying in the ZA-SLMS algorithm. In this paper, an improved ZA-SLMS algorithm is proposed by introducing adaptive REPA (AREPA), where the proportion of sparse penalty is adjusted based on the standard deviation of radar data. Moreover, to enhance the stability of heartbeat detection, a time-window-variation (TWV) technique is further introduced in the improved ZA-SLMS algorithm, considering the fact that the position of spectral peak associated with the heart rate (HR) is stable when the length of time window changes within a short period. Experimental results measured against five subjects validated that our proposal reliably improves the error of HR estimation than the standard ZA-SLMS algorithm. PMID- 30440260 TI - A Spinal Motion Measurement Protocol Utilizing Inertial Sensors Without Magnetometers. AB - This study presents an approach for instrumenting a spinal motion measurement protocol using two inertial measurement units (IMU)s affixed at the posterior pelvis and superior trunk. The accuracy of the inertial motion measurement instrumentation in tracking the relative orientation of the trunk with respect to the pelvis in three spinal motions (flexionextension, side bending, and rotation) is compared to that of a concurrent optical motion capture (mocap) system. Six healthy adults $(31.5 ?pm 11.2$; 2 females) were recruited to perform the spinal motions. The results show minimal deviations of the IMU measurements from those of the mocap system (RMSE $?lt 2 ?deg $, $?mathrm {r}?gt 0.84$ in all cases) and demonstrate the efficacy of the proposed instrumentation approach for spinal motion measurement. PMID- 30440261 TI - Imaging of IR700DX Labeled Mouse Breast Tumor Using a Custom Angle-Selective Fluorescence Contact Imaging System. AB - Cancer treatment faces the challenge of identifying small clusters of residual tumor cells in the resection cavity after the gross section of tumor is surgically removed. Despite the introduction of targeted fluorescent probes to guide cancer surgeries, large, bulky, optical components restrict the ability of fluorescence imaging devices to detect small clusters of tumor cells in the complex surgical cavity. We have developed a small size-scale contact fluorescence image sensor that incorporates angle-selective gratings and a thin 15 m amorphous silicon optical wavelength filter for detecting residual cancer tissue in vivo. Using a custom fluorescent probe combining a fluorescent dye, IR700DX, with a targeted antibody, Trastuzumab, we label and visualize breast tissue in in vivo mouse models of breast cancer. When imaging tumorbearing mice injected with the probe, HER2+ breast cancer tissue intensity is 3.80.8 times brighter than other tissue. Excised cancer tumors and residual cancer attached to healthy tissue are imaged using the custom image sensor. Residual cancer tissue can be detected in real-time and is imaged with a high SNR of 45 dB using an integration time of only 40 ms. PMID- 30440262 TI - Multifractal Analysis of Speech Imagery of IPA Vowels. AB - In Brain Computer Interfacing (BCI), speech imagery is still at nascent stage of development. There are few studies reported considering mostly vowels or monosyllabic words. However, language specific vowels or words made it harder to standardise the whole analysis of electroencephalography (EEG) while distinguishing between them. Through this study, we have explored significance of multifractal parameters for different imagined vowels chosen from International Phonetic Alphabets (IPA). The vowels were categorised into two categories, namely, soft vowels and diphthongs. Multifractal analysis at EEG subband levels were evaluated. We have also reported significant contrasts between spatiotemporal distributions with fractal analysis for activation of different brain regions in imagining vowels. PMID- 30440263 TI - A functional method for generating individualized spine models from motion capture data. AB - A representative model is necessary for the analysis of spine kinematics and dynamics during motion. Existing models, based on stationary imaging or cadaveric data, may not be accurate through the full range of spinal motion or for clinical populations. In this paper, we propose a functional method for estimating subject specific spinal joint centers, generating a one-joint or two-joint kinematic model of the spine. These models are driven by the motion of the thorax and pelvis as observed by eight surface landmarks. We apply this method to experimental data from ten subjects performing flexion/extension and sit-to-stand motions. The recovered functional models are assessed against an allometric model though the analysis of marker residuals. We found that the functional models provide lower residuals than the allometric methods. Between the functional models, the two-joint model provided lower residuals with less sensitivity to the training action, while the one-joint model should be trained on the motion of interest. PMID- 30440264 TI - A Biomechatronic EPP upper-limb prosthesis teleoperation system implementation using Bluetooth Low Energy. AB - In this paper a real time, stand-alone wireless Biomechatronic Extended Physiological Proprioception (EPP) teleoperation system was implemented using two Bluetooth Low Energy (BLE) wireless Systems on Chip (SoCs). This system is designed to achieve kinesthetic coupling between the amputee and prosthetic arm without the use of the classic EPP mechanical linkage, but with the use of a wireless implementation of a Master/Slave teleoperation topology. The experimental real-time implementation achieved a high level of transparency with minuscule time delays. PMID- 30440265 TI - Ensemble Convoluted Feature Extraction for Affective Auditory P300 Brain-Computer Interfaces. AB - Since most of P300 brain-computer interface (BCI) methods have assumed visual events, they are not always suitable for the BCI with auditory events, and feature extraction methods appropriate for auditory P300 BCI are required. This study proposed ensemble convoluted feature extraction for affective auditory P300 BCI, which took advantage of auditory responses elicited by different affective sounds. The proposed method was compared to feature extraction method that uses the canonical correlation analysis in addition to the traditional method. Those methods were evaluated on the dataset recorded from the improved affective auditory P300 BCI system. The mean online classification accuracy was 84.1% when using the traditional feature. The offline analysis showed that the proposed ensemble convolution feature extraction achieved significantly higher accuracy (86.75%) than the traditional method. The propose feature extraction may effective for the multi-channel time-series BCI that is featured by different stimuli. PMID- 30440266 TI - Increasing the learning Capacity of BCI Systems via CNN-HMM models. AB - Despite all the work in the Brain Computer Interface (BCI) community, one of the main issues that prevents it from becoming pervasive is the limitation on the number of commands with a satisfactory accuracy of detection. In this paper, we propose a solution to increase the number of commands while maintaining a satisfactory accuracy performance via a hybrid Convolutional Neural Network (CNN) Hidden Markov Model (HMM). The setup makes use of a classifier (a CNN) that works over a small alphabet of established mental tasks like the motor imagery task and detects sequences comprised of these tasks using HMMs. To optimize the learning capacity, we select a subset of sequences by measuring the distance between HMM models. This system, based on the experiments we have conducted, shows a 14% gain in accuracy over the non-sequenced classifier. Alternatively, it can be used to increase the command set size by 4 times when using all the channels or by 1.5 times when using only 1/3 of the EEG channels and have the same performance as a non-sequenced classifier that uses all available channels. This shows that the CNN-HMM hybrid model is a viable approach to increase the capacity of learning in BCI. PMID- 30440267 TI - Improved Heart Rate Tracking Using Multiple Wrist-type Photoplethysmography during Physical Activities. AB - Photoplethysmography (PPG) signals collected from wearable sensing devices during physical exercise are easily corrupted by motion artifact (MA), which poses great challenge on heart rate (HR) estimation. This paper proposes a new framework to accurately estimate HR using two leads of PPG signals in combination with accelerometer (ACC) data in the presence of MA. A moving time window is first used to segment PPG signals and ACC signals. Then, MA is attenuated by joint sparse spectrum reconstruction in each time window, where maximum spectrum frequencies of ACC are subtracted from the spectrum frequency of PPG signals. Further, HR for each cleansed PPG is estimated from the frequency with maximum amplitude in the sparse spectrum. The actual HR is determined using spectral band powers calculated from each reconstructed PPG signals. The proposed method was validated using the 2015 IEEE Signal Processing Cup dataset. The average absolute error is 1.15 beats per minutes (BPM) (standard deviation: 2.00 BPM), and the average absolute error percentage is 0.95% (standard deviation: 1.86%). The proposed method outperforms the previously reported work in terms of accuracy. PMID- 30440268 TI - Parametric Modeling of Electrocardiograms using Particle Swarm optimization. AB - The electrocardiogram (ECG) is commonly used to monitor or diagnose adverse heart conditions. While general ECG recordings are widely available, parametric ECG models have been proposed to generate ECG-like signals. Such ECG generators can create extended segments of specific beat morphology or cardiac rhythm, especially in disease states, which can be used to validate cardiac devices or evaluate ECG processing algorithms. Furthermore, ifthe parameters can be fit to a variety of ECGs, these models are valuable tools in ECG compression and modeling. In this paper we propose a framework to fit parameter values of an ECG generator such that the generated signal is similar to a reference signal. We first design a parametric ECG generator with relatively minimal assumptions of single beat waveform morphology. We then use Particle Swarm optimization to find ideal values for parameters of our ECG generator which minimize the percent root mean square difference (PRD) between the reference and generated signals. We were able to capture waveform morphologies of normal, idioventricular, and ventricular flutter rhythms with Pearson correlation coefficients above 0.9 between generated and pre recorded signals from the MIT-BIH database. PMID- 30440269 TI - Detection of Diabetes by Macrovascular Tortuosity of Superior Bulbar Conjunctiva. AB - More than 8% of world population have diabetes which causes long term complications such as retinopathy, neuropathy, nephropathy and foot ulcers. Growing patient numbers has prompted large scale screening methods to detect early symptoms of diabetes (rather than elevated blood glucose levels which is a late symptom). Vascular tortuosity (twisted and curved nature of blood vessels) in retinal fundus images has proven to reflect the effect of diabetes on macrovasculature. However, large scale patient screening using retinal fundus images has limitations due to the requirement of a retinal camera. Therefore, we hypothesize that the vasculature of superior bulbar conjunctiva which could be captured using a regular camera could be used to measure tortuosity instead of retinal fundus images enabling mass screening.To test this hypothesis, a total of 168 scleral images were acquired from 50 healthy subjects and 34 diabetic patients using a digital camera. The sclera region was segmented using Chan-Vese algorithm and macrovasculature of superior bulbar conjunctiva was segmented using B-COSFIRE filters. Results revealed that the superior bulbar conjunctival macrovascular tortuosity of diabetic patients was significantly less than that of non-diabetic group (p-value =0.015). A similar result was yielded (p-value =0.049) from a group of participants who were less than 40 years old which excluded the age related variation of tortuosity. PMID- 30440270 TI - Real-Time ECG Delineation with Randomly Selected Wavelet Transform Feature and Random Walk Estimation. AB - Detection of Electrocardiogram (ECG) characteristic points can provide critical diagnostic information about heart diseases. We propose a novel feature extraction and machine learning scheme for ECG delineation. A new feature, termed as randomly selected wavelet transform (RSWT), is proposed to effectively represent ECG morphology. With the RSWT feature pool, a regression tree is trained to estimate the probability distribution to the direction toward the target point, relative to the current position. The continual random walk through 1D space will eventually produce a reliable region from which the final position of the target point is derived. The evaluation results on QT database show better detection accuracy compared with other studies while providing real-time processing capability. PMID- 30440271 TI - Cycling-enhanced Knee Exoskeleton Using Planar Spiral Spring. AB - Reported in our previous study on passive cycling support, the energy cost of knee extension can be reduced using the energy stored from knee flexion by torsion spring. In the current study, the planar spiral spring is applied to attain the compact design of the cycling augmented knee exoskeleton (CAKE-2). The surface electromyography (EMG) results over the rectus femoris muscles of three healthy male participants performing constant power cycling on a trainer at 200 W and 225 W are analyzed in time-frequency via the continuous wavelet transform. In all cycling tests with and without the exoskeletons worn on both legs, no sign of peripheral muscle fatigue or significant change in the EMG median power spectral frequency (MDF) appears throughout the two-minute cycling trials. At the same cycling speed and leg cadence, the average of EMG-MDF increases with the exercise intensity. At the same cycling power, less quadriceps activity can be observed from all the participants when the spring support was used during cycling. The capability to modify the unbalanced effort required from the quadriceps and the hamstring during cycling without requiring an external energy source is applicable for cycling enhancement and rehabilitation applications. PMID- 30440272 TI - Transfer Learning Over Time and Position in Wearable Myoelectric Control Systems. AB - Wearable sensors for upper limbs enable the use of myoelectric control systems in real environments. An important issue in the practical use of myoelectric control is how to deal with the variations of electromyograms (EMGs); the distribution of EMGs changes over days and device (electrode) positions. The amount of training data is usually limited, as the data are collected at the beginning of the system use. To compensate for the difference of EMGs over time and device placement with limited-amount training data, transfer learning can be employed. However, it was unclear how transfer learning improve the motion recognition accuracy over long term use with varying device positions. In this paper, we evaluated transfer learning algorithms on one-month long data with three different device positions. We found that transfer learning was able to compensate for the variations over long period and also over different electrode placements, suggesting the practical efficacy of transfer learning. But there were some cases when transfer learning did not recover the original accuracy, in particular when electrodes were placed at "out-of-muscle" positions. These findings would motivate further investigations into the design of myoelectric control systems, e.g., denser electrode configurations or lifetime-long recordings. PMID- 30440273 TI - Analysis of uterine electromyography signals in preterm condition using multifractal algorithm. AB - In this work, an attempt has been made to analyze the preterm (gestation period $?leq 37$ weeks) condition using uterine electromyography (EMG) signals and multifractal detrended fluctuation analysis (MFDFA). The signals recorded from the electrodes placed on the surface of abdomen are used for this study and these are obtained from a publically available online database. These signals are preprocessed using 4-pole digital Butterworth filter. The preprocessed signals are subjected to MFDFA to extract multifractal features namely maximum singularity exponent, peak singularity exponent, strength of multifractality and exponent index. Generalized Hurst exponent extracted from the signals indicate that uterine EMG signals show multifractal behavior in preterm condition. Among the extracted features the coefficient of variation is found to be lower for peak singularity exponent. This indicates that this feature have lower inter-subject variability. Hence, it appears that the multifractal features can help in the assessment of uterine EMG signals for preterm detection. PMID- 30440274 TI - Applying machine learning to the flagellar motor for biosensing. AB - Escherichia coli detects and follows chemical gradients in its environment in a process known as chemotaxis. The performance of chemotaxis approaches fundamental biosensor speed and sensitivity limits, but there have been relatively few attempts to incorporate the response into a functional biosensor. Toward that end, we have developed software to process digital microscope images of a large number of tethered E. coli responding to different chemical perturbations. Upwards of fifty cells can be recorded in one experiment, allowing for rapid labeling of the chemotactic responses of multiple cells. After we collected hundreds of wild-type chemotactic E. coli motor responses to dilutions of aspartate and leucine, we trained a support vector classifier (SVC) to estimate the order of magnitude of aspartate concentration between 0M, 100nM, and 1MUM with a single cell classification subset accuracy of 69%. We trained another SVC to differentiate between aspartate and leucine with a single cell classification subset accuracy of 83%. Using a majority-vote method on a bacterial population of size N, estimates have 95% confidence for N = 27 bacteria for concentration detection and N = 9 bacteria for chemical differentiation. These methods are a step towards adaptable chemotaxis-based biosensing. PMID- 30440275 TI - Intracranial Pressure Sensor and Valve to Control Hydrocephalus. AB - Hydrocephalus is a neurological condition that can result from trauma, hemorrhage, cancer, and infection. To control the intracranial pressure (ICP) a shunt is implanted to drain the cerebro-spinal fluid (CSF). We are working to develop an implantable pressure sensor. When the ICP is too high it will open a valve to relieve the ICP. When the ICP is too low, it will close the valve. PMID- 30440276 TI - Visually Impaired Users can Locate and Grasp Objects Under the Guidance of Computer Vision and Non-Visual Feedback. AB - The purpose of this study was to assess the ability of blind individuals to reach and grasp for objects, under the guidance of auditory (verbal) or vibrotactile cues controlled by real time computer vision algorithms. For these experiments, we created the Object Localization and Tracking System (OLTS). The OLTS utilized a head mounted wide-angle (diagonal 92 degrees degrees) monocular camera, a central processing unit and two types of physical feedback: auditory bone conduction headphones or cranially positioned vibration motors. A computer vision algorithm, the Context Tracker, processed live video to track objects in front of the visually impaired subject. Physical feedback was then generated based on the object position. The feedback guided the user to move the camera until the desired object was in the central region of the camera, defined by an angle of the camera field of view. The central region was varied between 3.9 and 39.6 degrees. Experiments consisted of localizing and grasping for an object based on feedback provided. On average, subjects were able to locate the correct object within 20 seconds. For auditory feedback, using a central angle of 7.8 degrees led to poor performance compared to the other angles. Performance using vibrotactile feedback worsened when using a central angle of 3.9 degrees . No consistent performance trends were evident based on age of blindness onset. PMID- 30440277 TI - A Molecular Imaging "Skin A Time-resolving Intraoperative Imager for Microscopic Residual Cancer Detection Using Enhanced Upconverting Nanoparticles. AB - Optimal cancer therapy requires targeted and individualized treatment of all tumor cells, including both gross and microscopic disease. Intraoperatively hard to visualize and often left behind, microscopic foci of residual cancer cells significantly increase the risk of cancer recurrence and treatment failure rates. Fluorescently-tagged targeted molecular labels are employed to guide surgery, but conventional fluorescent intraoperative imagers suffer from lack of sensitivity and maneuverability, limiting practicality in small tumor cavities owing to their cumbersome sizes driven by optics. This work does away with conventional lenses and filters and introduces an optics-free molecular imaging "skin" consisting of only a $25?mu ?mathrm{m}$ thin CMOS contact imager that synergistically integrates the long emission lifetimes of upconverting nanoparticles (UCNP) combined with upconversion to use a time domain approach to acquire the image coupled with infrared illumination allowing deep tissue penetration and elimination of autofluorescence. Using this strategy, we are able to visualize UCNPs at fluences (W/cm2) compatible with intraoperative use, opening the door to visualize targeted areas with microscopic sensitivity and facilitate residual microscopic disease detection during surgery, and laying the groundwork for precision post-operative radiation. PMID- 30440278 TI - Temperature Compensated Fibre Bragg Grating Pressure Sensor for Ventricular Assist Devices. AB - Rotary blood pumps may be used as ventricular assist devices (VADs) to support patients with end-stage heart failure-'rotary VADs'. Clinically, rotary VADs are operated at a constant speed which is set manually. Due to inadequate haemodynamic monitoring equipment outside of the hospital setting, device speed remains the same for weeks or months at a time, leaving clinicians in the dark, and patients vulnerable to harmful over- or under-pumping events. Therefore, it would be beneficial to have an implantable sensor which can measure blood pressure at the rotary VAD inlet or outlet and detect the onset of adverse events. In this study, a temperature compensated fibre Bragg grating (FBG) based strain sensor which can be incorporated into a VAD and used for continuous, real time blood pressure monitoring is investigated. Error in the pressure reading between the developed and reference sensor occurred due to changes in temperature. A generalised linear model was used to compensate for temperature related error between 35-39o. Without temperature compensation, the mean error in the pressure reading over the desired range of -25 to 150 mmHg was approximately +/-5 mmHg. The temperature compensated mean error over the same range was less than +/-2 mmHg. The compensation technique was effective over a wide range of temperatures and pressures, demonstrating the potential of the sensor for continuous real-time blood pressure monitoring. PMID- 30440279 TI - A Fiducial Scaffold for ECG Compression in Low-Powered Devices. AB - Large volumes of physiological data can now be routinely collected using wearable devices, though a key challenge that remains is the conversion of raw data into clinically relevant and actionable information. While power constraints prevent continuous wireless streaming of large amounts of raw data for offline processing, on-board microprocessors have become sufficiently powerful for data reduction to be performed in real time on the wearable device itself, so that only aggregate, clinically interpretable measures need to be transmitted wirelessly. Here, we use the curve-length transform to extract key beat-by-beat information from the raw ECG waveform, and to identify clinically relevant timing and amplitude information. Each beat is parameterized by 12 morphological features that serve as fiducial markers, sufficient to directly reconstruct a scaffold representation of the ECG waveform. At a nominal heart rate of 70 beats/min and a sampling rate of 250 Hz, typical for wearable monitors, this represents approximately an 18-fold compression. Using difference encoding, the compression ratio improves to 21. Our algorithm computes a running exponentially weighted average of each identified morphological feature. When any feature deviates significantly from its running average, the algorithm retains the raw waveform for five beats preceding and following the anomaly, enabling future review of the raw data. The algorithm automatically located 93.8% of the 3,615 expert-annotated QRS onsets and offsets in the PhysioNet QT-Database to within 20 ms. Similarly, it located 83.5% of all 3,194 P-wave onset and offset annotations to within 32 ms, and 89.0% of all 3,542 T-wave offset annotations within 72 ms. PMID- 30440280 TI - Automating Event-detection of Brain Neuron Synaptic Activity and Action Potential Firing in vivo using a Random-access Multiphoton Laser Scanning Microscope for Real-time Analysis. AB - Determining how a neuron computes requires an understanding of the complex spatiotemporal relationship between its input (e.g. synaptic input as a result of external stimuli) and action potential output. Recent advances in in vivo, laser scanning multiphoton technology, known as random-access microscopy (RAM), can capture this relationship by imaging fluorescent light, emitted from calcium sensitive biosensors responding to synaptic and action potential firing in a neuron's full dendritic arbor and cell body. Ideally, a continuous output of fluorescent intensities from the neuron would be converted to a binary output ('event', 'or no-event'). These binary events can be used to correlate temporal and spatial associations between the input and output. However, neurons contain hundreds-to-thousands of synapses on the dendritic arbors generating an enormous quantity of data composed of physiological signals, which vary greatly in shape and size. Thus, automating data-processing tasks is essential to support high throughput analysis for real-time/post-processing operations and to improve operators' comprehension of the data used to decipher neuron computations. Here, we describe an automated software algorithm to detect brain neuron events in real time using an acousto-optic, multiphoton, laser scanning RAM developed in our laboratory. The fluorescent light intensities, from a genetically encoded, calcium biosensor (GCAMP 6m), are measured by our RAM system and are input to our 'event-detector', which converts them to a binary output meant for real-time applications. We evaluate three algorithms for this purpose: exponentially weighted moving average, cumulative sum, and template matching; present each algorithm's performance; and discuss user-feasibility of each. We validated our system in vivo, using the visual circuit of the Xenopus laevis. PMID- 30440281 TI - Velocity Selective Recording: A Demonstration of Effectiveness on the Vagus Nerve in Pig. AB - Neural interfaces that can both stimulate and record from the peripheral nervous system are an important component of future bioelectronic devices. However, despite a long history of neurostimulation, there has been relatively little success in the design of a chronically implantable device for recording from peripheral nerves. This fundamental road block must be overcome if the design of advanced implantable devices is to continue. In this paper, we demonstrate the effectiveness of one method: velocity selective recording, a method that has been proposed as a tool for online neural recording that does not require training. We present results and analysis from invivo recordings made on the right vagus nerve of pig using a multiple-electrode cuff as a chronically implantable recording array. PMID- 30440282 TI - Abnormal Spontaneous Neuronal Discharge and Local Field Potential both in Cortex and Striatum of a Non- human Primate of Parkinson's Disease using Implantable Microelectrode Arrays. AB - Parkinson's disease (PD) is a neurodegenerative disease with the loss of dopaminergic neurons in substantia nigra. This study described abnormal spontaneous neuronal information both in cortex and striatum of a non-human primate of PD using implantable microelectrode arrays. In cortex of PD monkey, Neurons discharged from single-spike mode to burst-firing mode compared to normal monkey; Mean amplitude was $197 ?mu ?mathrm{V}$ that was twice of mean amplitude of normal monkey, and mean firing rate was 82Hz; burst-firing activity showed distinctive, stereotypic periods of oscillatory lasted for $20 ?pm 5?mathrm{s}$ occurring ever 30-40 seconds, which was consistent with local field potential (LFP) oscillating at 4.79Hz related to PD tremor; neuronal discharge were approximately synchronous from four channels, that were consistent with local field potential fluctuating greatly with a correlation coefficient of 0.99997, and the main frequency of local field potential had a good respond to firing rate of spike with a correlation coefficient of 0.9891. In striatum of PD monkey, two types of neurons were detected with mean amplitude of $102 ?mu ?mathrm{V}$ and $296 ?mu ?mathrm{V}$ respectively; the mean firing rate was 62 Hz significantly higher than that in normal monkey; as for one representative type of neurons, with respect to local field potential oscillating at a period in cortex, local field potential continuously oscillated in striatum at low frequency at the range of 4-7Hz which was constituent with neuronal burst firing rate, while single neuron discharged at the range of 10-32Hz, almost at beta frequencies. Abnormal neural information detection by microelectrode arrays with ifferent signals in different position will play an important role in target location in brain of PD patients, especially for treatment. PMID- 30440283 TI - Virtual reality for activities of daily living training in neurorehabilitation: a usability and feasibility study in healthy participants. AB - After severe injury or neurodegenerative disorders patients often experience long term functional deficits, resulting in a reduction o performance in activities of daily living (ADL). Given their direct relevance to everyday functioning and quality of life, neurorehabilitative programs using simulated ADL's have seen increased interest recently. One of the core elements in simulated ADL's is the interface between the user and the virtual environment, which has a high impact on the therapeutic outcome. The aim of this study was to nalyze the feasibility of a simple virtual ADL (tea preparation task) using two different input devices. The tea preparation task setup consisted of a computer rendering the virtual environment, a head-mounted display (HMD) to visually present the ADL, and two input devices (mouse and handheld controller) to guide virtual hands in the virtual environment. A total of 24 healthyyoung adults performed the tea preparation task after which workload, usability, immersion and presence was rated. The handheld controller was rated significantly lower workload and higher usability than the mouse input device. Also, the sense of being there (immersion) and spatial presence ratings for the task and setup were close to the maximum score of 5. Thus, the handheld controller outperformed the mouse, suggesting that user interaction in the virtual environment with the handheld controller is similar to the real world and intuitive to use. Overall, the simulated ADL implemented with VR technology is feasible for diagnostic and rehabilitative purposes in patients experiencing long-term functional deficits. PMID- 30440284 TI - Sleep Posture Classification using a Convolutional Neural Network. AB - Sleep is a process of rest and renewal that is vital for humans. However, there are several sleep disorders such as rapid eye movement (REM) sleep behaviour disorder (RBD), sleep apnea, and restless leg syndrome (RLS) that can have an impact on a significant portion of the population. These disorders are known to be associated with particular behaviours such as specific body positions and movements. Clinical diagnosis requires patients to undergo polysomnography (PSG) in a sleep unit as a gold standard assessment. This involves attaching multiple electrodes to the head and body. In this experiment, we seek to develop non contact approach to measure sleep disorders related to body postures and movement. An Infrared (IR) camera is used to monitor body position unaided by other sensors. Twelve participants were asked to adopt and then move through a set of 12 pre-defined sleep positions. We then adopted convolutional neural networks (CNNs) for automatic feature generation from IR data for classifying different sleep postures. The results show that the proposed method has an accuracy of between 0.76 & 0.91 across the participants and 12 sleepposes with, and without a blanket cover, respectively. The results suggest that this approach is a promising method to detect common sleep postures and potentially characterise sleep disorder behaviours. PMID- 30440285 TI - Objective Liver Fibrosis Estimation from Shear Wave Elastography. AB - Diffuse liver disease is common, primarily driven by high prevalence of non alcoholic fatty liver disease (NAFLD). It is currently assessed by liver biopsy to determine fibrosis, often staged as F0 (normal) - F4 (cirrhosis). A noninvasive assessment method will allow a broader population to be monitored longitudinally, facilitating risk stratification and treatment efficacy assessment. Ultrasound shear wave elastography (SWE) is a promising noninvasive technique for measuring tissue stiffness that has been shown to correlate with fibrosis stage. However, this approach has been limited by variability in stiffness measurements. In this work, we developed and evaluated an automated framework, called SWE-Assist, that checks SWE image quality, selects a region of interest (ROI), and classifies the ROI to determine whether the fibrosis stage is at or exceeds F2, which is important for clinical decisionmaking. Our database consists of 3,392 images from 328 cases. Several classifiers, including random forest, support vector machine, and convolutional neural network (CNN)) were evaluated. The best approach utilized a CNN and yielded an area under the receiver operating curve (AUROC) of 0.89, compared to the conventional stiffness only based AUROC of 0.74. Moreover, the new method is based on single image per decision, vs. 10 images per decision for the baseline. A larger dataset is needed to further validate this approach, which has the potential to improve the accuracy and efficiency of non-invasive liver fibrosis staging. PMID- 30440287 TI - Poincare Analysis based on Short-term Heart Rate Variability Data for Stress Evaluation. AB - Dynamic changes in autonomic stress responses may provide details on autonomic nervous system functions. Time-varying evaluation can be achieved with a sliding window, however, in order to learn dynamic changes, an evaluation method needs to not only conduct calculation with a short sliding step but also derive evaluation indices with a narrow window. Stress analysis using HRV data shorter than one minute is still a challenge in this field. This paper investigates a Poincar plot analysis method for stress evaluation based on short term heart rate variability (HRV) data. First a sliding window, with no overlap, is used to segment data in order to form Poincare plots. Then a simple index, which corresponds to mean distance between two adjacent points in the plot, is calculated on each evaluation window. The window length is defined with time duration and four lengths are examined in this paper, namely, 15, 30, 45, and 60 s. Two mental stress induction experiments, mental arithmetic and Stroop color-word tests, are utilized to validate the proposed method. PMID- 30440286 TI - Bleeding Detection in Wireless Capsule Endoscopy Image Video Using Superpixel Color Histogram and a Subspace KNN Classifier. AB - Wireless Capsule Endoscopy (WCE) has become increasingly popular in clinical gastrointestinal (GI) disease diagnosis, benefiting from its painless and noninvasive examination. However, reviewing a large number of images is time consuming for doctors, thus a computer-aided diagnosis (CAD) system is in high demand. In this paper, we present an automatic bleeding detection algorithm that consists of three stages. The first stage is the preprocessing, including key frame extraction and edge removal. In the second stage, we discriminate the bleeding frames using a novel superpixelcolor histogram (SPCH) feature based on the principle color spectrum, and then the decision is made by a subspace KNN classifier. Thirdly, we further segment the bleeding regions by extracting a 9-D color feature vector from the multiple color spaces at the superpixel level. Experimental results with an accuracy of 0.9922 illustrate that our proposed method outperforms the state-of-the-art methods in GI bleeding detection with low computational costs. PMID- 30440288 TI - A Row-Column (RC) Addressed 2D Capacitive Micromachined Ultrasonic Transducer (CMUT) Array on a Glass Substrate: Preliminary Results. AB - In this work, we present preliminary characterization results from a 32 x 32 row column (RC) addressed 2D capacitive micromachined ultrasonic transducer (CMUT) array. The device was fabricated using anodic bonding on a borosilicate glass substrate, which eliminates the substrate - bottom electrode coupling previously observed in traditional CMUT RC arrays fabricated on silicon substrates. The characterization results were compared for the top and bottom electrodes and include impedance measurements, pulseecho impulse responses, and 2D scans of the pressure field using a calibrated hydrophone. The results showed that the array elements behave similarly when ground and hot electrodes were switched between the top and bottom electrodes for all of the measured parameters including device capacitance, center frequency, and pulse-echo response amplitude. The pressure scans verified the highly customizable nature of RC arrays by showing multiple active element configurations. A sample cross-sectional image of a metal target was also demonstrated. PMID- 30440289 TI - Power Spectral Analysis of Short-Term Blood Pressure Recordings for Assessing Daily Variations of Blood Pressure in Human. AB - Although daily variations of blood pressure (BP) predict cardiovascular event risk, their assessment requires ambulatory BP monitoring which hinders the clinical application of this approach. Since the baroreflex is a major determinant of BP variations, especially in the frequency range of 0.01-0.1 Hz (baro-frequency), we hypothesized that the power spectral density (PSD) of short term BP recordings in the baro-frequency range may predict daily variations of BP. In nine-week-old Wister-Kyoto male rats (N =5) with or without baroreflex dysfunction, we telemetrically recorded continuous BP for 24 hours and estimated PSD using Welch's periodogram for the recordings during the 12-hour light period. We compared the reference PSD of 12-hour recording with the PSDs obtained from shorter data lengths ranging from 5 to 240 minutes. The 30-minute BP recordings reproduced PSD of 12-hour recordingswell, and PSD in the baro-frequency range paralleled the standard deviation of 12-hour BP. Thus, the PSD of 30-minute BP reflects the daily BP variability in rats. In human subjects, we estimated PSD from 30-minute noninvasive continuous BP recordings. The rat and human PSDs shared remarkably similar characteristics. Furthermore, comparison of PSD between elderly and young subjects suggested that the baro-frequency range in humans overlapped with that in rats. In conclusion, PSD derived from 30-minute BP recordings is capable of predicting daily BP variations. Our proposed method may serve as a simple, noninvasive and practical tool for predicting cardiovascular events in the clinical setting. PMID- 30440290 TI - Coupling Analysis of Fetal and Maternal Heart Rates via Transfer Entropy Using Magnetocardiography. AB - Recent studies have shown that occasional short term coupling between fetal and maternal cardiac systems occurs. Fetal magnetocardiography (fMCG) is a non invasive technique that records the magnetic fields associated with the electrical activity of the fetal heart through sensors placed over the maternal abdomen. The fMCG allows accurate estimation of fetal heart rates (fHR) due to its high signal-to-noise ratio (SNR) and temporal resolution. In this study, we analyzed couplingbetween fHR and maternal heart rates (mHR) using Transfer Entropy (TE). TE determines coupling between two variables by quantifying the information transferred between them in both directions. In this work, we used 74 fMCG recordings to compute TE in both directions over 1-minute disjoint time windows (TW). We examined the effect of fetal movement (FM) as a factor of influence on the TE analysis. We identified 21 subjects with FM during the recording and separated them into two gestational age (GA) groups (GA1<32 and GA2>=32 weeks). Next, TE values were compared between TWs containing non- FM with TWs containing FM using Wilcoxon Signed-Rank test. In addition, we compared TE calculations for non-FM segments obtained from the 74 subjects using Rank-Sum test in the two GA groups. Our results showed that TE values from TWs containing FM are not significantly different than those computed for TWs of non-FM. In both directions, we found that TE values obtained from the 74 subjects did not show any significant difference between GA1 and GA2 which is consistent with previous studies. Our study suggests that FM does not affect the TE computations. PMID- 30440291 TI - The Calibration Method for Blood Pressure Pulse Wave Measurement Based on Arterial Tonometry Method. AB - In this study, we report a method to accurately calibrate the forces measured by a wearable device for measuring blood pressure pulse waves by the arterial tonometry method to obtain blood pressure measurements. A device based on the arterial tonometry method and a commercially available manometer was used for this research. The force and the blood pressure were simultaneously measured at three measurement heights using the arterial tonometry device and the manometer. The proposed calibration was found to reduce the influence of the inclination of the lower arm. As a result, the average coefficient of determination of the regression equations between the force and the blood pressure was 0.96. Thus, it was concluded that the proposed method can be used to accurately calibrate the measured forces to obtain blood pressure measurements with a high coefficient of determination. PMID- 30440292 TI - A Super-Capacitive Pressure Sensor for a Urethral Catheter. AB - Urinary incontinence can be due to neuromuscular or structural problems in either the bladder or the urethra. Urodynamics is often used to analyze the patientspecific cause of urinary incontinence. In urodynamics, a challenging part of the studies involves measurement of the urethral (contact) pressure profile. Here we present an instrumented urethral catheter that is equipped with a novel super-capacitive pressure transducer that is highly sensitive to the applied pressure. A solid ionic electrolyte is used to create a high capacitance device. Through an innovative design the solid electrolyte is made and bounded to a 3d printed soft balloon and then assembled on a 6 Fr urethral catheter. In this paper the design, fabrication and evaluation of the highly-sensitive instrumented catheter's performance are discussed. PMID- 30440293 TI - Natural gait event-based level walking assistance with a robotic hip exoskeleton. AB - In this paper, we present an assistance strategy for level walking by using a robotic hip exoskeleton. Our strategy utilizes a foot contact event estimated by an inertial measurement unit (IMU) on the pelvis. The gait cycle is composed of three phases. The transitions between the phases are established upon natural gait events that are inevitable and perceived reliably by sensors attached to our exoskeleton. The presented strategy provides a systematic way of adjusting the quantity of assistance that corresponds to the wearer's preference and needs, and also provides explicit principles for the initiation and termination of assistance. When a step begins, the maximum torque and duration of assistance are decided, and the torque profile for the entire step is designed in advance. We conduct experiments in order to investigate the effect on metabolic cost when walking on a motorized treadmill. PMID- 30440294 TI - Personalized Markerless Upper-Body Tracking with a Depth Camera and Wrist-Worn Inertial Measurement Units. AB - A markerless motion capture technique is proposed based on a fusion between a depth camera (Kinect V2) and a pair of wrist-worn inertial measurement units (IMU). The method creates a personalized articulated human mesh model from one depth image frame and uses that model to improve the accuracy of the upper-body joint tracking. The IMUs are useful as an additional clue for the arm tracking, especially during an occlusion. An evaluation of the method against a marker based system as a gold standard using data from 6 subjects is done. The result shows over 20% reduction in upper-limb joint position errors when compared to Kinect's skeleton tracking. All the collected data are calibrated, synchronized, and made publicly available for research purposes. PMID- 30440295 TI - Predicting Lymph Node Metastasis in Head and Neck Cancer by Combining Many objective Radiomics and 3-dimensioal Convolutional Neural Network through Evidential Reasoning. AB - Lymph node metastasis (LNM) is a significant prognostic factor in patients with head and neck cancer, and the ability to predict it accurately is essential for treatment optimization. PET and CT imaging are routinely used for LNM identification. However, uncertainties of LNM always exist especially for small size or reactive nodes. Radiomics and deep learning are the two preferred imaging based strategies for node malignancy prediction. Radiomics models are built based on handcrafted features, and deep learning can learn the features automatically. We proposed a hybrid predictive model that combines many-objective radiomics (MO radiomics) and 3-dimensional convolutional neural network (3D-CNN) through evidential reasoning (ER) approach. To build a more reliable model, we proposed a new many-objective radiomics model. Meanwhile, we designed a 3D-CNN that fully utilizes spatial contextual information. Finally, the outputs were fused through the ER approach. To study the predictability of the two modalities, three models were built for PET, CT, and PET& CT. The results showed that the model performed best when the two modalities were combined. Moreover, we showed that the quantitative results obtained from the hybrid model were better than those obtained from MO-radiomics and 3D-CNN. PMID- 30440296 TI - Deep residual networks for automatic sleep stage classification of raw polysomnographic waveforms. AB - We have developed an automatic sleep stage classification algorithm based on deep residual neural networks and raw polysomnogram signals. Briefly, the raw data is passed through 50 convolutional layers before subsequent classification into one of five sleep stages. Three model configurations were trained on 1850 polysomnogram recordings and subsequently tested on 230 independent recordings. Our best performing model yielded an accuracy of 84.1% and a Cohen's kappa of 0.746, improving on previous reported results by other groups also using only raw polysomnogram data. Most errors were made on non-REM stage 1 and 3 decisions, errors likely resulting from the definition of these stages. Further testing on independent cohorts is needed to verify performance for clinical use. PMID- 30440297 TI - Effect of Epoch Length on Compressed Sensing of EEG. AB - Aging populations are stretching existing healthcare systems to their limits in both developing and developed countries. Telemedicine is a promising solution to this challenging problem. Under the conventional data compression paradigm, long time recording of electroencephalography (EEG) signals still generates excessive amount of data, which requires large data storage and long transmission time. While promoting mobile telemedicine with compressed sensing (CS) as a key system for EEG monitoring, this paper investigates the effect of epoch length on CS to compress EEG signals. Experimental results show that a longer epoch length leads to better signal compression at the expense of larger signal reconstruction time. At a sampling frequency of 256 Hz, a 4-s epoch length is suitable when using a general desktop computer to perform signal reconstruction. PMID- 30440298 TI - Electromagnetic Field Analysis of Low-Magnitude High-Frequency Vibrator with Multiple Plungers. AB - Low-magnitude high-frequency (LMHF) of vibrational stimulation has been accepted as an effective method to enhance bone remolding. However, the electromagnetic field (EMF) generated by the vibrator could also be an influence factor in the vibrational experiments. This phenomenon underlies the bone remodeling effect caused by vibrational stimulation is disrupted to be investigated. This paper presents a design of LMHF vibrator with multiple plungers to generate vibrational stimulation with ultra low magnetic flux density to minimize the biological effect caused by the EMF. The EMF is analyzed in finite element method (FEM) using COMSOL. PMID- 30440299 TI - Obstructive Sleep Apnea Detection Using Difference in Feature and Modified Minimum Distance Classifier. AB - The current gold standard of Obstructive Sleep Apnea (OSA) diagnosis involves the use of a Polysomnography (PSG) system which requires the patient to stay in the hospital for overnight recording. The process is uncomfortable for the patient and it disturbs the patient's sleep pattern. On the other hand, it is well known that some acoustic features of the snoring sounds are good indicators of the presence of OSA, and a variety of acoustic OSA detection algorithms have been reported in the literature. Typically, these algorithms use multiple features and a relatively complex classifier, which are not ideal for handling the huge over night data. In this paper, we propose an algorithm that uses a single feature and a relatively simple classifier. The proposed feature is the difference between two carefully selected Mel-frequency cepstral coefficients (MFCCs) of the snoring sound samples. The proposed classifier is derived based on a modified minimum distance criterion. The proposed algorithm has been tested with patient data. The results show that the proposed algorithm outperforms existing algorithms and is able to achieve up to 97.1% detection accuracy. PMID- 30440300 TI - Design and evaluation of a portable smart-phone based peripheral neuropathy test platform. AB - In this paper, we describe a novel portable test platform that can be used to test peripheral neuropathy either within a clinic or at home. The system, called the PeriVib, is comprised of (1) a small, custom vibration motor designed to apply a vibration stimulus to the toe with constant pressure to test sensation threshold, and (2) a custom smart-phone app that enables a patient to run a series of functional gait and balance tests. Vibration is applied by PeriVib in two separate modes. The first mode, ramp-up, starts at zero amplitude and increases to a maximum level while the patient indicates when they start feeling the pressure by lifting their finger off the touch-screen on the phone. The second mode, ramp-down, starts at a maximal intensity and decreases in intensity; the patient indicates when they stop feeling the vibration. The smart-phone app determines the patient's threshold by recording the vibration amplitude when they indicate the onset or loss of vibratory sensation, depending on the mode. In both modes, the measurement is repeated five times. In addition to controlling the vibration motor during the vibration test, the smart phone app also enables collection of gait and sway metrics through the use of the accelerometer and gyroscope sensors on the smartphone. The entire set of tests requires approximately 5 minutes to complete and can be done by a patient with minimal instructions from a clinician. In a cohort of 28 subjects with a history of chemotherapy-induced peripheral neuropathy, we compared the PeriVib performance with two established threshold sensing systems: (1) a Biothesiometer device and (2) a tuning fork. We found that the sensation threshold estimated by PeriVib correlated well with the Biothesiometer ($?mathrm{R}^{2}$ of 0.68) but less well with the tuning fork ($?mathrm{R}^{2}$ of 0.15). Functional gait and balance metrics did not correlate with peripheral neuropathy severity. PMID- 30440301 TI - Human activity recognition from inertial sensor time-series using batch normalized deep LSTM recurrent networks. AB - In recent years machine learning methods for human activity recognition have been found very effective. These classify discriminative features generated from raw input sequences acquired from body-worn inertial sensors. However, it involves an explicit feature extraction stage from the raw data, and although human movements are encoded in a sequence of successive samples in time most state-of-the-art machine learning methods do not exploit the temporal correlations between input data samples. In this paper we present a Long-Short Term Memory (LSTM) deep recurrent neural network for the classification of six daily life activities from accelerometer and gyroscope data. Results show that our LSTM can processes featureless raw input signals, and achieves 92 % average accuracy in a multi class-scenario. Further, we show that this accuracy can be achieved with almost four times fewer training epochs by using a batch normalization approach. PMID- 30440302 TI - Invasive Optical Pacing in Perfused, Optogenetically Modified Mouse Heart Using Stiff Multi-LED Optical Probes. AB - We present the first invasive use of a stiff, multiLED optical probe for intramural optical stimulation of cardiac tissue. We demonstrate that optical pacing is possible with high spatial and temporal resolution in transgenic mice expressing channelrhodopsin-2. The technical implementation of this study builds on optical probes recently developed and tested ex vivo in cerebral tissue of mice. The probes comprise LEDs integrated on flexible substrates stiffened by silicon-based MEMS structures enabling the successful penetration into the cardiac tissue. The probe technology is extended to allow dual-sided illumination for directional tissue stimulation. Implantation trials affirm the ability to optically pace the isolated perfused heart at stimulation frequencies between 4Hz and 12Hz with experimentally determined emittance levels of 10mW mm-2 Rapid activation of two distant LEDs could reliably be used to induce short runs of ventricular fibrillation, while simultaneous activation of all LEDs allowed termination of re-entrant rhythm disturbances (optical defibrillation). Thus, spatially-resolved intramural pacing and rhythm control of the isolated heart is possible using stiff, multi-LED optical probes. PMID- 30440303 TI - Classifying Treated vs. Untreated MDD Adolescents from Anatomical Connectivity using Nonlinear SVM. AB - Identification of the treatment-related responders for adolescent Major Depressive Disorder (MDD) is urgently needed to develop effective treatments. In this paper, machine learning based classifiers are used to reveal anatomical features as responders for distinguishing MDD patients who have received treatment from those who never received any treatment. The features are drawn from two sets of measurements: 1) anatomical connectivity defined by diffusion tensor imaging measurements between a pair of brain regions, and 2) topological measurements from anatomical networks. Feature selection was performed based on p value and minimum redundancy maximum relevance (mRMR) method to achieve improved classification accuracy. The classification performance is evaluated with a leave one-out cross-validation method using 37 treated and 15 untreated subjects. The proposed methodology achieves 73% accuracy, 100% specificity, and 100% precision for 52 subjects. The most distinguishing features are the strength of the right hippocampus of the mean diffusivity (MD) network at 18% density and of the track count (TR) network, the participation coefficient of the left middle temporal gyrus of the radial diffusivity (RD) network at 20% density, the axial diffusivity (AD) connectivity between right middle temporal gyrus and right supramarginal gyrus, the betweenness centrality of the right hippocampus of the TR network at 11% density, the apparent diffusion coefficient (ADC) connectivity between the left pars opercularis and the left rostral anterior cingulate cortex, the clustering coefficient of the middle anterior corpus callosum of the TR network at 11% density, and the AD connectivity between the left pars opercularis and the left rostral anterior cingulate cortex. PMID- 30440304 TI - Brain Monitoring of Sedation in the Intensive Care Unit Using a Recurrent Neural Network. AB - Over and under-sedation are common in critically ill patients admitted to the Intensive Care Unit. Clinical assessments provide limited time resolution and are based on behavior rather than the brain itself. Existing brain monitors have been developed primarily for non-ICU settings. Here, we use a clinical dataset from 154 ICU patients in whom the Richmond Agitation-Sedation Score is assessed about every 2 hours. We develop a recurrent neural network (RNN) model to discriminate between deep vs. no sedation, trained end-to-end from raw EEG spectrograms without any feature extraction. We obtain an average area under the ROC of 0.8 on 10-fold cross validation across patients. Our RNN is able to provide reliable estimates of sedation levels consistently better compared to a feed-forward model with simple smoothing. Decomposing the prediction error in terms of sedatives reveals that patient-specific calibration for sedatives is expected to further improve sedation monitoring. PMID- 30440305 TI - The Accuracy of Atrial Fibrillation Detection from Wrist Photoplethysmography. A Study on Post-Operative Patients. AB - Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. Although not life-threatening itself, AF significantly increases the risk of stroke and myocardial infarction. Current tools available for screening and monitoring of AF are inadequate and an unobtrusive alternative, suitable for long-term use, is needed. This paper evaluates an atrial fibrillation detection algorithm based on wrist photoplethysmographic (PPG) signals. 29 patients recovering from surgery in the post-anesthesia care unit were monitored. 15 patients had sinus rhythm (SR, 67.5+/- 10.7 years old, 7 female) and 14 patients had AF (74.8+/- 8.3 years old, 8 female) during the recordings. Inter-beat intervals (IBI) were estimated from PPG signals. As IBI estimation is highly sensitive to motion or other types of noise, acceleration signals and PPG waveforms were used to automatically detect and discard unreliable IBI. AF was detected from windows of 20 consecutive IBI with 98.45+/-6.89% sensitivity and 99.13+/-1.79% specificity for 76.34+/-19.54% of the time. For the remaining time, no decision was taken due to the lack of reliable IBI. The results show that wrist PPG is suitable for long term monitoring and AF screening. In addition, this technique provides a more comfortable alternative to ECG devices. PMID- 30440306 TI - Feasibility of Noninvasive Blood Pressure Measurement using a Chest-worn Patch Sensor. AB - Pulse arrival time (PAT) and pulse transit time (PTT) derived from the finger have been widely investigated for noninvasive blood pressure (BP) measurement. The study investigates the feasibility of BP measurement using a chestworn patch sensor derived systolic timing intervals and pulse timing measurements. Healthy volunteers (N=14, 38 +/- 13 years) carried out a protocol including deep breathing test, sustained hand grip test and modified Valsalva test with continuous physiological measurements from a patch sensor attached on left chest and intermittent BP measurements from an automated oscillometric monitor as a reference. The efficacy of chest derived PAT and PTT for univariate BP prediction is assessed using correlation and regression slope. The cross validation performance of predicting BP using multivariate regression model with chest derived systolic timing intervals and pulse timing features were also evaluated. The results suggest that the chest derived PAT and PTT had modest correlations ( 0.52 and -0.31) and regression slopes (-0.21 and -0.14) with automated oscillometric systolic and diastolic BP references, respectively. On the other hand, a multivariate regression approach for prediction of mean blood pressure (MBP) using patch sensor measurements showed a correlation of 0.72, mean error of 0.1 mmHg and RMSE error of 5.1 mmHg compared to the oscillometric MBP values. The study demonstrated the feasibility of BP measurement using a wearable chest-worn patch sensor in healthy control subjects. PMID- 30440307 TI - Convolutional Neural Networks for Pathological Voice Detection. AB - Acoustic analysis using signal processing tools can be used to extract voice features to distinguish whether a voice is pathological or healthy. The proposed work uses spectrogram of voice recordings from a voice database as the input to a Convolutional Neural Network (CNN) for automatic feature extraction and classification of disordered and normal voice. The novel classifier achieved 88.5%, 66.2% and 77.0% accuracy on training, validation and testing data set respectively on 482 normal and 482 organic dysphonia speech files. It reveals that the proposed novel algorithm on the Saarbruecken Voice Database can effectively been used for screening pathological voice recordings. PMID- 30440308 TI - Temperature Profiling of ex-vivo Organs during Ferromagnetic Nanoparticles Enhanced Radiofrequency Ablation by Fiber Bragg Grating Arrays. AB - In this paper, we present real-time profiles of temperature during a ferromagnetic nanoparticles (NPs)enhanced radiofrequency ablation (RFA). A minimally invasive RFA setup has been prepared and applied ex vivo on a liver phantom; NPs (with concentration of 5 mg/mL) have been synthetized and injected within the tissue prior to perform the ablation, in order to facilitate the heat distribution to the peripheral sides of the ablated tissue. Temperature detection has been realized in situ with a network of 15 fiber Bragg grating (FBG) sensors in order to highlight the impact of the NPs on the RFA mechanism. Obtained temperature profiles and thermal maps confirm that nanoparticles injection ensures better heat penetration than in case of pristine RFA procedure. The results show that adding NPs solution leads to extending the successfully ablated area achieving a double-sized lesion. PMID- 30440309 TI - Carbon Nanotube-Cellulose Pellicle for Glucose Biofuel Cell. AB - Carbon nanotube (CNT)-cellulose pellicle was developed to create a conductive CNT network on 20 MUm nanostructured cellulose film. The flexible and electrically conductive film was prepared by the modification of bacterial nanocellulose pellicle with multi-walled carbon nanotubes (MWCNTs). The composite film was further modified with redox enzymes including pyroquinoline quinone glucose dehydrogenase (PQQ-GDH) and bilirubin oxidase (BODx) functioning as the anodic and cathodic catalyst, respectively with glucose as the biofuel source. The enzyme functionalized MWCNT-cellulose based glucose/O2 biofuel cell system harnessed the biochemical energy of glucose via the oxidation of glucose and reduction of molecular oxygen to generate electrical power in the microwatt range. The biofuel cell system exhibited an open circuit voltage and power density of 470 mV and 46.25 MUW/cm2, respectively, with a current density of 381 MUA/cm2 in the presence of 25 mM glucose. At physiological glucose concentration, the biofuel cell exhibited an open circuit voltage and power density of 418 mV and 24.975 MUW/cm2 respectively, with a current density of 293.75MUA/cm2. As a result, we expect that this facile strategy to prepare flexible conductive bioelectrodes for the development of glucose biofuel cell system using synthesized bacterial nanocellulose crosslinked with MWCNTs and enzyme can be readily extended to diverse applications in enzymatic biofuel cell and biosensor technology. PMID- 30440310 TI - Eigen Posture Based Fall Risk Assessment System Using Kinect. AB - Postural Instability (PI) is a major reason for fall in geriatric population as well as for people with diseases or disorders like Parkinson's, stroke etc. Conventional stability indicators like Berg Balance Scale (BBS) require clinical settings with skilled personnel's interventions to detect PI and finally classify the person into low, mid or high fall risk categories. Moreover these tests demand a number of functional tasks to be performed by the patient for proper assessment. In this paper a machine learning based approach is developed to determine fall risk with minimal human intervention using only Single Limb Stance exercise. The analysis is done based on the spatiotemporal dynamics of skeleton joint positions obtained from Kinect sensor. A novel posture modeling method has been applied for feature extraction along with some traditional time domain and metadata features to successfully predict the fall risk category. The proposed unobstrusive, affordable system is tested over 224 subjects and is able to achieve 75% mean accuracy on the geriatric and patient population. PMID- 30440312 TI - Personalized Prediction of Asthma Severity and Asthma Attack for a Personalized Treatment Regimen. AB - Control of asthma is critical for disease management and quality of life. Asthma treatment depends on the patient demographic information (e.g., age), and disease severity, which is determined by: (1) how symptoms affect a patient's daily life, (2) measured lung function, and (3) estimated risk of having an asthma attack. In this paper, we will present the Tensorflow Text Classification (TC) method to classify a patient's asthma severity level. We will also propose a Qlearning method to train an agent through trials and errors to improve the prediction accuracy and create a personalized treatment regimen for asthma patients. PMID- 30440311 TI - A Low-cost, Smartphone-only Pulse Transit Time Measurement System Using Cardio mechanical Signals and Optical Sensors. AB - This paper presents a smartphone-only solution for measuring pulse transit time (PTT). An application based on an Android smartphone is developed to collect seismocardiogram (SCG), gyrocardiogram (GCG), and photoplethysmography (PPG) recordings. The system does not need any other external system for measurements, so the total cost and system complexity are minimized. PTT metrics are calculated as the time difference between the aortic valve opening points in the SCG or GCG signals recorded by the accelerometer or gyroscope of a smartphone respectively, and the fiducial points in the PPG signal recorded by a modified optical sensor connected to the audio input. A digital signal processing (DSP) system is developed in a post-processing environment and experimentally validated on ten healthy subjects at rest. Our results indicate that a smartphone-only PTT measurement system is feasible and comparable with stand-alone sensor node systems. PMID- 30440313 TI - Computer Aided Clinical Trials for Implantaule Cardiac Devices. AB - In this paper we aim to answer the question, "How can modeling and simulation of physiological systems be used to evaluate life-critical implantable medical devices?" Clinical trials for medical devices are becoming increasingly inefficient as they take several years to conduct, at very high cost and suffer from high rates of failure. For example, the Rhythm ID Goes Head-to-head Trial (RIGHT) sought to evaluate the performance of two arrhythmia discriminator algorithms for implantable cardioverter defibrillators, Vitality 2 vs. Medtronic, in terms of time-to-first inappropriate therapy, but concluded with results contrary to the initial hypothesis- after 5 years, 2,000+ patients and at considerble ethical and monetary cost. In this paper, we describe the design and performance of a Computer-aided Clinical Trial (CACT) for Implantable Cardiac Devices where previous trial information, real patient data and closed-loop device models are effectively used to evaluate the trial with high confidence. We formulate the CACT in the context of RIGHT using a Bayesian statistical framework. We define a hierarchical model of the virtual cohort generated from a physiological model which captures the uncertainty in the parameters and allow for the systematic incorporation of information available at the design of the trial. With this formulation, the estimates the inappropriate therapy rate of Vitality 2 compared to Medtronic as 33.22% vs 15.62% $(?mathrm{p}?lt 0.001)$, which is comparable to the original trial. Finally, we relate the outcomes of the computer- aided clinical trial to the primary endpoint of RIGHT. PMID- 30440314 TI - Doubling the Signal Quality of Smartphone Camera Pulse Oximetry Using the Display Screen as a Controllable Selective Light Source. AB - Recent smartphones have the potential to bring camera oximetry to everyone using their powerful sensors and the capability to process measurements in real-time, potentially augmenting people's lives through always-available oximetry monitoring everywhere. The challenge of camera oximetry on smartphones is the low contrast between reflections from oxyhemoglobin and deoxyhemoglobin. In this paper, we show that this is the result of using the camera flash for illumination, which illuminates evenly across bands than thus leads to the diminished contrast in reflections. Instead, we propose capturing pulse using the front-facing camera and illuminating with the phone's display, a selective illuminant in the red, green, and blue band. We evaluate the spectral characteristics of the phone display using a spectroradiometer in a controlled experiment, convolve them with the sensitivity curves of the phone's camera, and show that the screen's narrow-band display illumination increases the contrast between the reflections in the desired bands by a factor of two compared to flash illumination. Our preliminary evaluation showed further support for our approach and findings. PMID- 30440315 TI - Exploration of Metrics for Leg Length Discrepancy Using a Wearable Gait Analysis System. AB - : The purpose of this study was to explore effective metrics for differentiating levels ofleg length discrepancy (LLD) using a wearable device. DESIGN: A wearable device for measuring ground reaction forces and kinetic features was developed in this study. PARTICIPANTS: Eight volunteers without previously diagnosed LLD walked along a 120.0 m walkway with a 2.5 cm and 3 cm foot spacer to simulate LLD. MAIN OUTCOME MEASURES: The p-values of thirteen kinetic and kinematic metrics between normal and LLD walking. RESULTS: Difference in stance time duration, difference in heel reposition time, and ratio difference of loading effect showed statistical difference between normal walking and simulated LLD walking. CONCLUSION: The metrics with statistical difference may serve as effective indicators oflow levels ofLLD and be implemented into a point-of-care system for gait analysis. PMID- 30440316 TI - Continuous Blood Pressure Monitoring Algorithm using Laser Doppler Flowmetry. AB - A novel machine learning algorithm is introduced to estimate continuous blood pressure monitoring using Laser Doppler Flowmetry (LDF). LDF provides instantaneous, continuous, and noninvasive measurements of blood flow in a small tissue sample. The proposed algorithm segments the continuous blood flow profile based on heartbeat cycles to subsequently extract multiple features. The beat-to beat blood pressure was estimated from a multi-layer neural network algorithm using the extracted features. The algorithm was also validated with clinically proven cuff based continuous blood pressure sensors. Mean average error values of 4.54 ?sim5.37 mmHg were observed, which conform to a Grade B/C category per the IEEE standard 1708-2014 for cuffless blood pressure measuring devices. PMID- 30440317 TI - Evaluation of a Force-Sensing Handheld Robot for Assisted Retinal Vein Cannulation. AB - Approximately 16.4 million people are affected by retinal vein occlusion (RVO) resulting from hypercoagulability, low blood flow or thrombosis in the central or the branched retinal veins. Most common current treatments for RVO aim to limit the damage. In recent years, an experimental procedure, retinal vein cannulation (RVC) has been studied in animal models as well as human eye models. RVC is a procedure for targeted delivery of a therapeutic agent into the occluded retinal vein for dissolving the thrombi. Although effective treatment has been demonstrated via RVC, performing this procedure manually still remains at the limits of human skills. RVC requires to precisely insert a thin cannula into a delicate thin retinal vein, and to maintain it inside the vein throughout the infusion. The needle-vein interaction forces are too small to sense even by an expert surgeon. In this work, we present an evaluation study of a handheld robotic assistant with a force-sensing microneedle for RVC. The system actively cancels hand tremor, detects venous puncture based on detected tool-tissue forces, and stabilizes the needle after venous puncture for reduced trauma and prolonged infusion. Experiments are performed cannulating the vasculature in fertilized chicken eggs. Results show 100% success in venous puncture detection and significantly reduced cannula position drift via the stabilization aid of the robotic system. PMID- 30440318 TI - Deep Learning for Medication Assessment of Individuals with Parkinson's Disease Using Wearable Sensors. AB - Motor fluctuations between "OFF" state (with no benefit from medication) and " ON" state (with optimum benefit from medication) are a major focus of clinical managements in individuals with mid-stage and advance Parkinson's disease (PD). In this work, an automated algorithm based on Long Short-Term Memory (LSTM) as a deep learning method is developed to identify motor fluctuations in individuals with PD using wearable sensors during a variety of daily living activities. This network was evaluated on two datasets i.e., Dataset 1 and Dataset 2) that included recordings of 19 individuals with PD using subject-based leave-one-out cross-validation. The designed LSTM network yielded promising results using only one ankle sensor with an average classification rate of 73% and 77% for Dataset 1 and Dataset 2, respectively. PMID- 30440319 TI - Diagnosis of prostate cancer in a Chinese population by using machine learning methods. AB - An early diagnosis of prostate cancer (PC) is key for the successful treatment. Although invasive prostate biopsies can provide a definitive diagnosis, the number of biopsies should be reduced to avoid side effects and risks especially for the men with the low risk of cancer. Therefore, an accurate model is in need to predict PC with the aim of reducing unnecessary biopsies. In this study, we developed predictive models using four machine learning methods including Support Vector Machine (SVM), Least Squares Support Vector Machine (LS-SVM), Artificial Neural Network (ANN) and Random Forest (RF) to detect PC cases using available prebiopsy information. The models were constructed and evaluated on a cohort of 1625 Chinese men with prostate biopsies from Hong Kong hospital. All the models have the excellent performances in detecting significant PC cases, with ANN achieving the highest accuracy of 0.9527 and the AUC value of 0.9755. RF outperformed the other three methods in classifying benign, significant and insignificant PC cases, with an accuracy of 0.9741 and a F1 score of 0.8290. PMID- 30440320 TI - Ionic Conduction in Biological Nanopores Created by Ultrashort9 High-Intensity Pulses. AB - Ultrashort, high-intensity electric pulses open nanopores in biological cell membranes. Ion transport in nanopore is analyzed using a numerical method that couples the Nernst-Planck equations for ionic concentrations, the Poisson equation for the electric potential, and Navier-Stokes equations for the fluid flow. Roles of the applied bias, pore size, as well as the surface charge lining the membrane are comprehensively examined through I-V characteristics, conductance variations of the pore. Our results show that the surface charge distribution has an impact on the ionic conduction due to mutual electrostatic force interference. In addition, a larger pore would conduct a larger ionic current thus being more conductive on the condition of the same bias applied, which would suggest a bias-dependent expansion of pores. PMID- 30440321 TI - Design and Fabrication of Graphene-based Phototransistor for Drinking Water Monitoring System using Vibrio Fischeri. AB - Drinking Water safety is critical for human's daily life. Real-time monitoring and early warning systems of harmful substances in drinking water is crucial to ensure the safety of tap water. This paper reports the fabrication of a graphene based phototransistor, oriented towards an integrated system for high accuracy measure of the bioluminescent bacteria. Aliivibrio fischeri is a bioluminescence bacterium (light emission at 490nm), that has a significant light reduction in the presence of harmful contaminants. Each step of the phototransistor was designed and fabricated, including the mask used for the Oxygen Plasma Etching of Graphene and Electron Beam deposition of the gold pads and Spin coating of the polymer. All the fabrication process including experimental conditions were controlled to achieve a high phototransistor performance. Experimental tests were realized to evaluate the performance of the photodetector to the measurement of Vibrio Fischeri light emission The graphene-based phototransistor shows good sensitivity to detect the change of light intensity, for Aliivibrio fischeri. Compared with the traditional design method, this new design and fabrication can not only be more distinct and visualized, but also greatly reduce the cost and difficulty. PMID- 30440322 TI - Low-noise Transimpedance Amplifier Design using Chopper-stabilized Technique for Nanopore Applications. AB - This paper presents a low-noise transimpedance amplifier (TIA) employing chopper stabilized technique for nanopore applications. The TIA, which is used as a headstage for the monitoring system, must achieve low-noise performance to accurately measure a minute ionic current signal generated from the nanopore. In this work, we analyze detailed input- referred noise current of the capacitive feedback TIA and propose a core amplifier adopting the chopper-stabilized technique to effectively reduce flicker noise in a bandwidth of interest for nanopore applications. This proposed circuit schematic is designed by harnessing 0.35 $?mu ?mathrm{m}$ CMOS process and is verified using elaborate simulation results. PMID- 30440323 TI - Head-motion Robust Video-based Heart Rate Estimation Using Facial Feature Point Fluctuations. AB - Interest in measuring heart rates (HRs) without physical contact has increased in the area of stress checking and health care. In this paper, we propose head motion robust video-based heart rate estimation using facial feature point fluctuations. The proposed method adaptively estimates and removes such rigid noise components as noise stemming from horizontal head motion and extracts relatively small heart signals. Rigid-noise components can be accurately estimated and removed by using changes in facial feature points which are not dominant over heart signals and are more dominant over noise signals than are such luminance signals as RGB. In evaluation experiments on a benchmark dataset, our method achieved the highest accuracy among state-of-the-art methods. PMID- 30440324 TI - In-vivo Measurements of Tissue Impeditivity by Electrical Impedance Spectroscopy. AB - The electrical properties of biological tissues differ depending on their structural characteristics. In literature, a lot of study have been carried out with the intent of taking advantage of bioimpedance analysis. Unfortunately, many apparatuses used during these evaluations were not always designed for measurements on living tissues. As a consequence, data could be affected by electrode polarization. In 2016, we presented a new impedance meter, developed for measurements on living tissues. Initially, it was tested only on ex-vivo rabbit's tissues with promising results. As a continuation, this device has been tested on in-vivo samples by placing a needle-probe into 3 tissues (liver, spleen, ovary) of 2 female dogs. Furthermore, was evaluated also the bioimpedance signal of the ovary explanted, comparing it with the in-vivo data. Bioimpedance was analyzed in terms of modulus and phase along a broad spectrum of frequencies (10Hz - 10kHz).Data obtained confirm the possibility of discriminating among the 3 tested tissues, at high frequencies for modulus and at low for phase. Confirmation that values on in-vivo and exvivo tissues are comparable if detected within few minutes after the explant, is also reported. We conclude that this clinical evaluation confirmed, also in-vivo, the good performance of the device previously tested on ex-vivo tissues, and provide more information about the tissue properties and characteristics. PMID- 30440325 TI - Onset Detection of Epileptic Seizures From Accelerometry Signal. AB - Epileptic seizures are the result of any abnormal asynchronous firing of cortical neurons. Seizures are abrupt and pose a risk of injury and fatal harm to the patient. Epilepsy affects patients quality of life (QOL) and imposes financial, social, and physical burden on the patient. The unpredictability associated with seizures further adds to the reduced QOL and increases dependence on caregivers and family members. A seizure triggered alarm system can reduce the risk of seizure-related injuries and aid in improving patient's QOL. This study presents real-time onset detection of seizures from accelerometry signal. An automated approach based on statistical machine learning is employed to learn the onset of seizures. To search for the optimal parameter that simultaneously maximizes detection sensitivity (sens) while minimizing false alarm rate (FAR) and latency, the epoch length is varied from $t=?{1,~10s?}$. Linear and non-linear time varying dynamical patterns were extracted from every epoch using Poincare plot analysis. The correlation patterns were learned using a kernalized support vector data descriptor. The preliminary analysis on accelerometry data collected from 8 epileptic patients with 9 generalized tonicclonic seizures (GTCS) shows promising results. The proposed algorithm detected all GTCS events (sens: 100%, FAR: 1. 09/24h) at 8s from onset. The proposed algorithm can lead to a sensitive, specific, and a relatively short-latency detection system for real-time remote monitoring of epileptic patients. PMID- 30440327 TI - Multiple Brain Activities During Sequential Memory Encoding - MEG Study Of Modulation Of Alpha-Band Rhythm. AB - It is known that alpha-band rhythm during memory maintenance is enhanced by increasing memory load. This enhancement is generally thought to be caused by active inhibition of task-irrelevant visual inputs. During sequential memory processing, we previously found that alpha-band activity increases from beginning to midterm during memory encoding, and conversely decreases from midterm to ending. In the present study, we conducted two experiments to determine the spatial and functional role of alpha-band rhythm during sequential memory processing. The first experiment showed that alpha-band rhythm increased in the occipital brain region, suggesting that active inhibition of task-irrelevant visual inputs continues from midterm to ending of memory encoding. The second experiment, in which subjects could not anticipate the ending of the sequential presentation of memory items, demonstrated that alpha-band rhythm is suppressed in correspondence with preparation for memory recall. These results indicate that alpha-band rhythm is simultaneously modulated by multiple brain processes in sequential memory encoding. PMID- 30440328 TI - Relationships Between Behavioral And Single-Trial Target Detection Performance With Magnetoencephalography. AB - Target detection during serial visual presentation tasks is an active research topic in the brain-computer interface (BCI) community as this type of paradigm allows to take advantage of event-related potentials (ERPs) through electroencephalography (EEG) recordings to enhance the accuracy of target detection. The detection of brain evoked responses at the single-trial level remains a challenging task and can be exploited in various applications. Typical non-invasive BCIs based on event-related brain responses use EEG. In clinical settings, brain signals recorded with magnetoencephalography (MEG) can be advantageously used thanks to their high spatial and temporal resolution. In this study, we address the problem of the relationships between behavioral performance and single-trial detection by considering a task with different levels of difficulty. We consider images of faces with six different facial expressions (anger, disgust, fear, neutrality, sadness, and happiness). We consider MEG signals recorded on ten healthy participants in six sessions where targets were one of the six types of facial expressions in each session. The results support the conclusion that a high performance can be obtained at the single-trial level $( {AUC }= 0 . 903 ?pm 0 .045)$, and that the performance is correlated with the behavioral performance (reaction time and hit rate). PMID- 30440326 TI - A Fully-Papertronic Biosensing Array for High-Throughput Characterization of Microbial Electrogenicity. AB - For the first time, we report a low-cost, disposable fully-papertronic screening platform for rapid screening and identification of electroactive microorganisms. This novel papertronic device is capable of simultaneous characterizing the electrogenicity of 10' s of the newly discovered, genetically engineered, bacteria. This work explored an exciting range of possibilities with the goal of fusing microbial fuel cell technology with 'papertronics,' the emerging field of paper-based electronics. Spatially distinct 64 sensing units of the array were constructed by patterning hydrophilic anodic reservoirs in paper with hydrophobic wax boundaries and utilizing 3-D multi-laminate paper structures. Full integration of a high-performance microbial sensor on paper can be achieved by improving the microbial electron exchange with the electrodes in an engineered conductive paper reservoir and reducing cathodic overpotential by using a solid electron acceptor on paper. Furthermore, the intrinsic capillary force of the paper and the increased capacity from the engineered reservoir allowed for rapid adsorption of the bacterial sample and promote immediate microbial cell attachment to the electrode, leading to instant power generation with even a small amount of the liquid. PMID- 30440329 TI - Non-Invasive, Cost-Effective, Early Diagnosis of Mild Cognitive Impairment in an Outpatient Setting: Pilot Study. AB - Mild cognitive impairment (MCI) and Alzheimer's Disease (AD) affect millions worldwide, yet no curative treatments for these neuro-degenerative disorders have been developed to date. The current study aims to propose a noninvasive, cost effective, early diagnostic protocol for individuals suffering with MCI in an outpatient setting. Elderly participants (n=11) were screened for MCI utilizing the Montreal Cognitive Assessment (MoCA) questionnaire preceding a visual stimuli task. Participants were presented with facial stimuli to elicit event related potentials (ERP) while their cortical activity was recorded utilizing electroencephalogram (EEG). Combining regional neurophysiological biomarkers into a multidimensional feature space allowed for differentiation between healthy and MCI participants based on their respective MoCA scores. This study illustrates the feasibility of recording reliable EEG in an outpatient setting while presenting a novel method for diagnosing MCI in elderly (age >60) populations. PMID- 30440330 TI - Functional Connectivity Analysis on Mild Alzheimer's Disease, Mild Cognitive Impairment and Normal Aging using fNIRS. AB - This paper reports a functional connectivity analysis at prefrontal cortex (PFC) during semantic verbal fluency task (SVFT) for three groups of elderly people, i.e., normal aging (NA), mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Functional Near Infrared Spectroscopy (fNIRS) was used to measure neuronal activities. A new software algorithm was developed to process fNIRS signals and to derive the parameters of functional connectivity. The synchronization of oxygenated hemoglobin signals from paired channels was evaluated using their temporal correlation. Results from 61 subjects of experiment show that a general decline in functional connectivity from NA (edge count $=$ 307) to AD (edge count $=$170), and the laterality between left and right PFC became insignificant $( ?mathrm {p}>0.01)$ at AD stage. Moreover, the NA group demonstrated a significantly higher clustering coefficient than the AD group $( ?mathrm {p}< 0.01)$, indicating the NA has higher regularity in brain network. Using semantic verbal fluency task, this work demonstrated fNIRS as a feasible measuring instrument to differentiate AD from NA based on functional connectivity, with clustering coefficient and laterality as suitable biomarkers. PMID- 30440331 TI - Cortical functional reorganization in response to intact forelimb stimulation from acute to chronic stage in rodent amputation model. AB - Brain plasticity after amputation is related to the short-term unmasking of latent synapses as well as the long-term reorganization due to the sprouting new synaptic connections. The cortical functional reorganization has been reported along the intact somatosensory pathway after unilateral deafferentation. Cerebral blood flow (CBF) change serves as an important biomarker of the functional reorganization of brain. Using laser speckle contrast imaging (LSCI) technology, we performed a longitudinal study to unveil the cortical functional reorganization after forelimb amputation in rodent model, particularly along the intact somatosensory pathway. Our results showed that the CBF response to electrical stimulation of the intact forepaw increased significantly at 9 hours after amputation in acute stage. While in chronic stage (>14 days), the CBF response showed a pattern similar to the control group. The results showed the dynamic brain functional response along the intact somatosensory pathway at different stages after amputation and indicated that cortical functional reorganization occurred within the acute stage. Our work provided additional insights in understanding the inter-hemispheric functional changes from acute to chronic stages of amputation. PMID- 30440332 TI - Real-Time Decoding of Auditory Attention from EEG via Bayesian Filtering. AB - In a complex auditory scene comprising multiple sound sources, humans are able to target and track a single speaker. Recent studies have provided promising algorithms to decode the attentional state of a listener in a competing-speaker environment from non-invasive brain recordings sun exhibit poor performance at temporal resolutions suitable for real-time implementation, which hinders their utilization in emerging applications such as smart hearich as electroencephalography (EEG). These algorithms require substantial training datasets and ofteng aids. In this work, we propose a real-time attention decoding framework by integrating techniques from Bayesian filtering, $?ell_{1}$ regularization, state-space modeling, and Expectation Maximization, which is capable of producing robust and statistically interpretable measures of auditory attention at high temporal resolution. Application of our proposed algorithm to synthetic and real EEG data yields a performance close to the state-of-the-art offline methods, while operating in near real-time with a minimal amount of training data. PMID- 30440333 TI - Bayesian Model Selection Framework to Improve Calibration of Continuous Glucose Monitoring Sensors for Diabetes Management. AB - Minimally-invasive continuous glucose monitoring (CGM) sensors have revolutionized perspectives in the treatment of type 1 diabetes (T1D). Their accuracy relies on an internal calibration function that transforms the raw, physically measured, electrical data into blood glucose concentration values. Usually, a unique, pre-determined, calibration functional is adopted, with parameters periodically updated in individual patients by using "gold standard" references suitably collected by finger prick devices. However, retrospective analysis of CGM data suggests that variability of sensor-subject characteristics is often inefficiently coped with. In the present study, we propose a conceptual Bayesian model- selection framework aimed at guaranteeing wide margins of flexibility for both the determination of the most appropriate calibration functional and the numerical values of its unknown parameters. The calibration model is determined among a finite specified set of candidates, each one depending on a set of unknown model parameters, for which a priori statistical expectations are available. Model selection is based on predictive distributions carrying out asymptotic calculations through Monte Carlo integration methods. Performance of the proposed approach is assessed on synthetic data generated by a well-established T1D simulation model. PMID- 30440334 TI - A Smoother State Space Multitaper Spectrogram. AB - A recent work (Kim et al. 2018) has reported a novel statistical modeling framework, the State-Space Multitaper (SSMT) method, to estimate time-varying spectral representation of non-stationary time series data. It combines the strengths of the multitaper spectral (MT) analysis paradigm with that of state space (SS) models. In this current work, we explore a variant of the original SSMT framework by imposing a smoothness promoting SS model to generate smoother estimates of power spectral densities for non-stationary data. Specifically, we assume that the continuous processes giving rise to observations in the frequencies of interest follow multiple independent Integrated Wiener Processes (IWP). We use both synthetic data and electroencephalography (EEG) data collected from a human subject under anesthesia to compare the IWP- SSMT with the SSMT method and demonstrate the former's utility in yielding smoother descriptions of underlying processes. The original SSMT and IWP-SSMT can co-exist as a part of a model selection toolkit for nonstationary time series data. PMID- 30440335 TI - A Point Process Characterization Of Electrodermal Activity. AB - Electrodermal activity (EDA) is a measure of sympathetic activity using skin conductance that has applications in research and in clinical medicine. However, current EDA analysis does not have physiologically-based statistical models that use stochastic structure to provide nuanced insight into autonomic dynamics. Therefore, in this study, we analyzed the data of two healthy volunteers under controlled propofol sedation. We identified a novel statistical model for EDA and used a point process framework to track instantaneous dynamics. Our results demonstrate for the first time that point process models rooted in physiology and built upon inherent statistical structure of EDA pulses have the potential to accurately track instantaneous dynamics in sympathetic tone. PMID- 30440336 TI - Bayesian Transfer Learning for the Prediction of Self-reported Well-being Scores. AB - Predicting the severity and onset of depressive symptoms is of great importance. User-specific models have better performance than a general model but require significant amounts of training data from each individual, which is often impractical to obtain. Even when this is possible, there is a significant lag between the beginning of the data-collection phase and when the system is completely trained and thus able to start making useful predictions. In this study, we propose a transfer learning Bayesian modelling method based on a Markov Chain Monte Carlo (MCMC) sampler and Bayesian model averaging for dealing with the challenge of building user-specific predictive models able to make predictions of self-reported well-being scores with limited sparse training data. The evaluation of our method using real-world data collected within the NEVERMIND project showed a better predictive performance for the transfer learning model compared to conventional learning with no transfer. PMID- 30440337 TI - Bayesian Online Changepoint Detection Of Physiological Transitions. AB - Transition dynamics between two states can help elucidate the behavior of sequential events in physiological signals. By detecting transitions between healthy and pathological states within individual patients, we can help clinicians focus attention on critical transitions, to either preemptively treat adverse events or to detect changes resulting from treatments. We introduce a novel application of singlepoint Bayesian online changepoint detection to predict clinical state transitions, and apply this framework to detecting pathological transitions in preterm infants with episodes of apnea and bradycardia. Bayesian analysis of sequential physiological events provides insights on how to objectively classify clinically important state transitions that can be triggered by external or intrinsic mechanisms. PMID- 30440338 TI - Segmentation of the uterine wall by an ensemble of fully convolutional neural networks. AB - In the past decades, the number of in vitro fertilization (IVF) procedures for the conception of a child has been rising continuously, however, the success rate of artificial insemination remained low. According to current statistics, large portion of unsuccessful IVF relates to some women' factors. As the directly related female organ, the proper investigation of the uterus has primary importance. Namely, visible markers may indicate inflammations or other negative effects that jeopardize successful implantation. The purpose of this study is to support the observability of the uterus from this aspect by providing computer aided tools for the extraction of its wall from video hysteroscopy. As for methodology, fully convolutional neural networks (FCNNs) are used for the automatic segmentation of the video frames to determine the region of interest. We provide the necessary steps for the applicability of the general deep learning framework for this specific task. Moreover, we increase segmentation accuracy with applying ensemble-based approaches at two levels. First, the predictions of a given FCNN are aggregated for the overlapping regions of subimages, which are derived from the splitting of the original images. Next, the segmentation results of different FCNNs are fused via a weighted combination model; optimization for adjusting the weights are also provided. Based on our experimental results, we have achieved 91.56% segmentation accuracy regarding the recognition of the uterus wall. PMID- 30440339 TI - Fully Automated Spleen Localization And Segmentation Using Machine Learning And 3D Active Contours. AB - Automated segmentation of the spleen in CT volumes is difficult due to variations in size, shape, and position of the spleen within the abdominal cavity as well as similarity of intensity values among organs in the abdominal cavity. In this paper we present a method for automated localization and segmentation of the spleen within axial abdominal CT volumes using trained classification models, active contours, anatomical information, and adaptive features. The results show an average Dice score of 0.873 on patients experiencing various chest, abdominal, and pelvic traumas taken at different contrast phases. PMID- 30440340 TI - Alzheimer'S Disease Classification Using Bag-Of-Words Based On Visual Pattern Of Diffusion Anisotropy For DTI Imaging. AB - Diffusion tensor imaging (DTI) has recently been added to the large scale of studies for Alzheimer's Disease (AD) to investigate the White Matter (WM) defects that are not detectable using structural MRI. In this paper, we extracted Speeded Up Robust Features (SURF) and Scale Invariant Feature Transform (SIFT) features, based on the visual diffusion patterns of Fractional Anisotropy (FA), and Mean Diffusivity (MD) maps, to build bag-of-words AD-signature for the hippocampal area. The experiments were accomplished with a subset of participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset formed of AD patients (n = 35), Early Mild Cognitive Impairment (EMCI) (n=6), Late Mild Cognitive Impairment (LMCI) (n=24) and cognitively healthy elderly Normal Controls (NC) (n=31). The preliminary studied experiments give promising results that would consider the proposed system as an accurate and useful tool to capture the AD leanness with accuracy of 87% and 89% for FA and MD maps respectively. PMID- 30440341 TI - Multiple Kernel Learning Based Classification of Parkinson's Disease With Multi Modal Transcranial Sonography. AB - Parkinson's Disease (PD) is the most common motor neurodegenerative disease in elderly population. Transcranial sonography (TCS) has become a popular imaging tool for diagnosis of PD in clinical practice. Moreover, several pioneering work have developed the computer-aided diagnosis (CAD) for PD with the transcranial B mode sonography (TBS). It is worth noting that TCS not only has the TBS modality, but also can image the blood flow of major cerebral arteries, which is named transcranial Doppler sonography (TDS). TDS also has been applied to evaluate PD patients with orthostatic hypotension. However, the TDS-based CAD for PD has not been investigated. Since TBS and TDS provide the complementary structural and functional information about brain, it is feasible to develop a multi-modal TCS based CAD for PD by combining both TBS and TDS. Therefore, in this work, we propose a multiple kernel learning (MKL) based CAD for PD with multi-modal TCS imaging. Particularly, the statistical and texture features are extracted from the midbrain region from TBS images, and the features about blood flow are calculated from the spectrum curves in TDS. The multi-modal features are then fed to a MKL classifier for classification of PD. The experimental results show that the multi-modal TCS-based method outperforms both the single-modal TBS- and TDS based algorithm, which suggests the feasibility and effectiveness of combining TBS and TDS for diagnosis of PD. PMID- 30440342 TI - Classification of Informative Frames in Colonoscopy Videos Using Convolutional Neural Networks with Binarized Weights. AB - Colorectal cancer is one of the common cancers in the United States. Polyps are one of the major causes of colonic cancer, and early detection of polyps will increase the chance of cancer treatments. In this paper, we propose a novel classification of informative frames based on a convolutional neural network with binarized weights. The proposed CNN is trained with colonoscopy frames along with the labels of the frames as input data. We also used binarized weights and kernels to reduce the size of CNN and make it suitable for implementation in medical hardware. We evaluate our proposed method using Asu Mayo Test clinic database, which contains colonoscopy videos of different patients. Our proposed method reaches a dice score of 71.20% and accuracy of more than 90% using the mentioned dataset. PMID- 30440343 TI - Polyp Segmentation in Colonoscopy Images Using Fully Convolutional Network. AB - Colorectal cancer is one of the highest causes of cancer-related death, especially in men. Polyps are one of the main causes of colorectal cancer, and early diagnosis of polyps by colonoscopy could result in successful treatment. Diagnosis of polyps in colonoscopy videos is a challenging task due to variations in the size and shape of polyps. In this paper, we proposed a polyp segmentation method based on the convolutional neural network. Two strategies enhance the performance of the method. First, we perform a novel image patch selection method in the training phase of the network. Second, in the test phase, we perform effective post-processing on the probability map that is produced by the network. Evaluation of the proposed method using the CVC-ColonDB database shows that our proposed method achieves more accurate results in comparison with previous colonoscopy video-segmentation methods. PMID- 30440344 TI - Near Perfect Neural Critic from Motor Cortical Activity Toward an Autonomously Updating Brain Machine Interface. AB - We are developing an autonomously updating brain machine interface (BMI) utilizing reinforcement learning principles. One aspect of this system is a neural critic that determines reward expectations from neural activity. This critic is then used to update a BMI decoder toward an improved performance from the user's perspective. Here we demonstrate the ability of a neural critic to classify trial reward value given activity from the primary motor cortex (M1), using neural features from single/multi units (SU/MU), and local field potentials (LFPs) with prediction accuracies up to 97% correct. A nonhuman primate subject conducted a cued center out reaching task, either manually, or observationally. The cue indicated the reward value of a trial. Features such as power spectral density (PSD) of the LFPs and spike-field coherence (SFC) between SU/MU and corresponding LFPs were calculated and used as inputs to several classifiers. We conclude that hybrid features of PSD and SFC show higher classification performance than PSD or SFC alone (accuracy was 92% for manual tasks, and 97% for observational). In the future, we will employ these hybrid features toward our autonomously updating BMI. PMID- 30440345 TI - The effect of miniaturization and galvanic separation of EEG sensor devices in an auditory attention detection task. AB - Recent technological advances in the design of concealable miniature electroencephalography (mini-EEG) devices are paving the way towards 24/7 neuromonitoring applications in daily life. However, such mini-EEG devices only cover a small area and record EEG over much shorter inter- electrode distances than in traditional EEG headsets. These drawbacks can potentially be compensated for by deploying a multitude of such mini-EEG devices and then jointly processing their recorded EEG signals. In this study, we simulate and investigate the effect of using such multi-node EEG recordings in which the nodes are galvanically separated from each other, and only use their internal electrodes to make short- distance EEG recordings. We focus on a use-case in auditory attention detection (AAD), and we demonstrate that the AAD performance using galvanically separated short-distance EEG measurements is comparable to using an equal number of long- distance EEG measurements if in both cases the electrodes are optimally placed on the scalp. To this end, we use a channel selection method based on a modified version of the least absolute shrinkage and selection operator (LASSO) technique, viz. the group-LASSO, in order to find these optimal locations. PMID- 30440346 TI - Virtual Reality, Visual Cliffs, and Movement Disorders. AB - We outline an experimental setup designed to dynamically understand neural responses to visual cliffs while walking. The goal of our work is understanding and mitigating fear of falling, particularly among the elderly. In our setup, an EEG cap monitors a subject's neural activity while the subject is immersed in a virtual world and walking on an instrumented treadmill. The subject's response to visual stimuli is measured by both the EEG cap and by speed and pressure data from the treadmill. Based on this data, we can dynamically alter the landscape in the virtual world. We hope that our setup may be useful in helping subjects develop mechanisms to compensate for significant fear of falling while walking. PMID- 30440347 TI - Detection of Mental Task Related Activity in NIRS-BCI systems Using Dirichlet Energy over Graphs. AB - Near Infrared Spectroscopy (NIRS)-based Brain Computer Interfaces (NIRS-BCI) rely mainly on the mean concentration changes and slope of the hemodynamic responses in separate recording channels to detect the mental-task related brain activity. Nevertheless, spatial patterns across the measurement channels are also present and should be taken into account for reliable evaluation of the aforementioned detection. In this work the Dirichlet Energy of NIRS signals over a graph is considered for the definition of a measure that would take into account the spatial NIRS features and would integrate the activity of multiple NIRS channels for robust mental task related activity detection. The application of the proposed measure on a real NIRS dataset demonstrates the efficiency of the proposed measure. PMID- 30440348 TI - Transferring Shared Responses Across Electrode Montages for Facilitating Calibration in High-Speed Brain Spellers. AB - Recent studies have shown that using the user's average steady-state visual evoked responses (SSVEPs) as the template to template-matching methods could significantly improve the accuracy and speed of the SSVEP-based brain- computer interface (BCI). However, collecting the pilot data for each individual can be time-consuming. To resolve this practical issue, this study aims to explore the feasibility of leveraging pre- recorded datasets from the same users by transferring common electroencephalogram (EEG) responses across different sessions with the same or different electrode montages. The proposed method employs spatial filtering techniques including response averaging, canonical correlation analysis (CCA), and task- related component analysis (TRCA) to project scalp EEG recordings onto a shared response domain. The transferability was evaluated by using 40-class SSVEPs recorded from eight subjects with nine electrodes on two different days. Three subsets of electrode montages were selected to simulate different scenarios such as identical, partly overlapped, and non-overlapped electrode placements across two sessions. The target identification accuracy of the proposed methods with transferred training data significantly outperformed a conventional training-free algorithm. The result suggests training data required in the BCI speller could be transferred from different EEG montages and/or headsets. PMID- 30440349 TI - Decoding Speech from Intracortical Multielectrode Arrays in Dorsal "Arm/Hand Areas" of Human Motor Cortex. AB - Neural prostheses are being developed to restore speech to people with neurological injury or disease. A key design consideration is where and how to access neural correlates of intended speech. Most prior work has examined cortical field potentials at a coarse resolution using electroencephalography (EEG) or medium resolution using electrocorticography (ECoG). The few studies of speech with single-neuron resolution recorded from ventral areas known to be part of the speech network. Here, we recorded from two 96- electrode arrays chronically implanted into the 'hand knob' area of motor cortex while a person with tetraplegia spoke. Despite being located in an area previously demonstrated to modulate during attempted arm movements, many electrodes' neuronal firing rates responded to speech production. In offline analyses, we could classify which of 9 phonemes (plus silence) was spoken with 81% single-trial accuracy using a combination of spike rate and local field potential (LFP) power. This suggests that high-fidelity speech prostheses may be possible using large-scale intracortical recordings in motor cortical areas involved in controlling speech articulators. PMID- 30440350 TI - Single-Channel Real-Time Drowsiness Detection Based on Electroencephalography. AB - The need of a reliable drowsiness detection system is arising today, as drowsiness is considered as a major cause for accidents as much as alcohol. In this paper, we propose a real-time drowsiness detection algorithm based on a single-channel electroencephalography (EEG) for wearable devices without demanding computing and power resources. The proposed algorithm adopts a cumulative counter to extract important features from 8 different frequency bands: delta (1-3 Hz), theta ($?not?subset-7$ Hz), low-alpha (8-9 Hz), high-alpha (10-12 Hz), low-beta (13-17 Hz), high-beta (18-30 Hz), low-gamma (31-40 Hz), and high-gamma (41-50 Hz). These features are then processed by a support vector machine (SVM) to distinguish between drowsy and awake states. Our preliminary results demonstrate that the proposed algorithm is capable of detecting drowsiness with superior accuracy (83.36%) over the conventional method (70.62%). PMID- 30440351 TI - Performance Improvement of Driving Fatigue Identification Based on Power Spectra and Connectivity Using Feature Level and Decision Level Fusions. AB - Power and connectivity features extracted from EEG signals have been previously utilized to detect mental fatigue during driving. Although each of the feature categories has the discriminative power to differentiate alert and fatigue states, they might represent different aspects of information relevant to fatigue identification. Two fusion methods, feature level and decision level fusions, were proposed in this study to combine individual channel information (i.e., power features) and between-channel information (i.e., connectivity features). According to the results of the study, the average accuracies of the fusion methods were higher than the accuracies of the individual feature categories (feature level fusion: 84.70%, decision level fusion: 87.13%, power features: 80.82%, connectivity features: 79.36%). The statistical analysis demonstrated that the two fusion methods significantly improved the classification performance of driving fatigue. The fusion methods proposed in this study can be embedded into a driving fatigue detection system for a practical use in a vehicle. PMID- 30440352 TI - Online Automatic Artifact Rejection using the Real-time EEG Source-mapping Toolbox (REST). AB - Non-brain contributions to electroencephalographic (EEG) signals, often referred to as artifacts, can hamper the analysis of scalp EEG recordings. This is especially true when artifacts have large amplitudes (e.g., movement artifacts), or occur continuously (like eye-movement artifacts). Offline automated pipelines can detect and reduce artifact in EEG data, but no good solution exists for online processing of EEG data in near real time. Here, we propose the combined use of online artifact subspace reconstruction (ASR) to remove large amplitude transients, and online recursive independent component analysis (ORICA) combined with an independent component (IC) classifier to compute, classify, and remove artifact ICs. We demonstrate the efficacy of the proposed pipeline using 2 EEG recordings containing series of (1) movement and muscle artifacts, and (2) cued blinks and saccades. This pipeline is freely available in the Real-time EEG Sourcemapping Toolbox (REST) for MATLAB (The Mathworks, Inc.). PMID- 30440353 TI - Towards the development of physiological models for emotions evaluation. AB - In the last decades numerous researches have revealed a strong link between emotions and several physiological responses. However, the automatic recognition of emotions still remains a challenge. In this work we describe a novel approach to estimate valence, arousal and dominance values from various biological parameters (derived from electrodermal activity, heart rate variability signal and electroencephalography), by means of multiple linear regression models. The models training was performed by using a set of pictures pre-evaluated in terms of valence, arousal and dominance, selected from the International Affective Picture System (IAPS) database. By using the step-wise regression method, all the possible combinations of considered biological parameters were tested as input variables for the models. The three multiple linear regression models that could provide the best fit for IAPS pictures valence, arousal and dominance values were selected. The features included in the optimal models were the average of the inter-beat duration (mean RR), the EEG spectral power computed in alpha, beta and theta frequency bands (Alpha, Beta and Theta power) and the average value of EDA signal (mean EDA). The obtained models show an overall good performance in predicting valence, arousal and dominance values. PMID- 30440354 TI - A Parametric EEG Signal Model for BCIs with Rapid-Trial Sequences. AB - Electroencephalogram (EEG) signals have been shown very effective for inferring user intents in brain-computer interface (BCI) applications. However, existing EEG-based BCIs, in many cases, lack sufficient performance due to utilizing classifiers that operate on EEG signals induced by individual trials. While many factors influence the classification performance, an important aspect that is often ignored is the temporal dependency of these trial-EEG signals, in some cases impacted by interference of brain responses to consecutive target and non target trials. In this study, the EEG signals are analyzed in a parametric sequence-based fashion, which considers all trials that induce brain responses in a rapid-sequence fashion, including a mixture of consecutive target and non target trials. EEG signals are described as a linear combination of time-shifted cortical source activities plus measurement noise. Using a superposition of time invariant with an auto-regressive (AR) process, EEG signals are treated as a linear combination of a stationary Gaussian process and time-locked impulse responses to the stimulus (input events) onsets. The model performance is assessed in the framework of a rapid serial visualization presentation (RSVP) based typing task for three healthy subjects across two sessions. Signal modeling in this fashion yields promising performance outcomes considering a single EEG channel to estimate the user intent. PMID- 30440355 TI - Brain Morphometry Analysis with Surface Foliation Theory. AB - Brain morphometry study plays a fundamental role in neuroimaging research. In this work, we propose a novel method for brain surface morphometry analysis based on surface foliation theory. Given brain cortical surfaces with automatically extracted landmark curves, we first construct finite foliations on surfaces. A set of admissible curves and a height parameter for each loop are provided by users. The admissible curves cut the surface into a set of pairs of pants. A pants decomposition graph is then constructed. Strebel differential is obtained by computing a unique harmonic map from surface to pants decomposition graph. The critical trajectories of Strebel differential decompose the surface into topological cylinders. After conformally mapping those topological cylinders to standard cylinders, parameters of standard cylinders (height, circumference) are intrinsic geometric features of the original cortical surfaces and thus can be used for morphometry analysis purpose. In this work, we propose a set of novel surface features rooted in surface foliation theory. To the best of our knowledge, this is the first work to make use of surface foliation theory for brain morphometry analysis. The features we computed are intrinsic and informative. The proposed method is rigorous, geometric, and automatic. Experimental results on classifying brain cortical surfaces between patients with Alzheimer's disease and healthy control subjects demonstrate the efficiency and efficacy of our method. PMID- 30440356 TI - Radiomics features as predictors to distinguish fast and slow progression of Mild Cognitive Impairment to Alzheimer's disease. AB - Prediction of Alzheimer's disease (AD) from Mild Cognitive Impairment (MCI) by analyzing Magnetic Resonance Imaging (MRI) image features has become popular in recent years. However, defining effective predictive biomarkers is still challengeable. The 'radiomics' is an established method to identify advanced and high order quantitative imaging features for computer-aided diagnosis and has been applied into oncology study. However, it has not been applied into brain disorder disease study. Therefore, the purpose of this study is to identify whether the features from radiomics could be the predictors of the conversion from MCI to AD. We analyzed 197 samples with MRI scans from the ADNI database, which contained 32 healthy subjects and 165 MCI patients. Firstly, we extracted 215 radiomics features from hippocampus. Then we used Cronbach's alpha coefficient, the intra-class correlation coefficient, Kaplan-Meier model and cox regression to select 44 radiomics features as effective features. Finally, we used SVM classification to validate these features. The results showed that the classification accuracy using linear, polynomial and sigmoid kernel could achieve 80.0%, 93.3% and 86.6% to distinguish MCI-to-AD fast and slow converter. As a result, this study indicated that the radiomics features are potential to be applied into predicting AD from MCI. PMID- 30440357 TI - Automatic Midline Shift Detection in Traumatic Brain Injury. AB - Fast and accurate midline shift (MLS) estimation has a significant impact on diagnosis and treatment of patients with Traumatic Brain Injury (TBI). In this paper, we propose an automated method to calculate the amount of shift in the midline structure of TBI patients. The MLS values were annotated by a neuroradiologist. We first select a number of slices among all the slices in a CT scan based on metadata as well as information extracted from the images. After the slice selection, we propose an efficient segmentation technique to detect the ventricles. We use the ventricular geometric patterns to calculate the actual midline and also anatomical information to detect the ideal midline. The distance between these two lines is used as an estimate of MLS. The proposed methods are applied on a TBI dataset where they show a significant improvement of the the proposed method upon existing approach. PMID- 30440358 TI - A Novel MRI-Based Radiomics Model for Predicting Recurrence in Chordoma. AB - Chordoma is a rare primary malignant tumor. For evaluating the related factors of postoperative recurrence probability of chordoma before surgery, we retrospective collected 80 patients to analyze by using a novel radiomics method. A total of 620 3D imaging features used for radiomics analysis were extracted, and 5 features were selected from T2-weighted (T2-w) magnetic resonance imaging (MRI) that were most strongly associated with 4-year recurrence probability to build a radiomics signature. Verification by logistic regression classification model, the area under the receiver operating characteristic curve and accuracy was 0.8600 (95% CI: 0.7226-0.9824) and 85.00% in the training cohort, respectively, while in the validation cohort was 0.8568 (95% CI: 0.7327-0.9758) and 85.00%. Experimental results show that T2-w MRI-based radiomics signature is closely associated with the recurrence of chordoma. It is possible to prejudge the recurrence of chordoma before surgery. PMID- 30440359 TI - Tracing and analysis of the whole mouse brain vasculature with systematic cleaning to remove and consolidate erroneous images. AB - Whole mouse brain microvascular images at submicrometer scale can be obtained by Knife-Edge Scanning Microscopy (KESM). However, due to the large size of the image dataset and the noise from the serial sectioning process of the KESM, whole mouse brain vascular reconstruction and analysis with submicrometer resolution have not been achieved yet, while several previous studies demonstrated manually selected small noise-free portion of the KESM dataset. In addition to the KESM dataset, there have been studies for vessel reconstruction and analysis of the whole mouse brain at lower resolution or of partial brain regions at submicrometer resolution. However, to the best of our knowledge, there has been no study for vessel reconstruction and analysis of the whole mouse brain at submicrometer resolution. In this paper, we propose a framework for the 3D reconstruction and analysis of the whole KESM mouse brain vasculature dataset with rich vasculature information extracted at submicrometer resolution. The framework consists of two methods. The propose methods provide the systematic cleaning to remove and consolidate erroneous images automatically, which enables the full tracing and analysis of the whole KESM mouse brain dataset with richer vasculature information. PMID- 30440360 TI - Parameter Optimization Of Injectable Polycaprolactone Microspheres Containing Curcumin Using Response Surface Methodology. AB - The achievement of desirable pharmacokinetic parameters from particulate drug delivery systems are dependent on the physical characteristics of the systems namely, particle dimension, loading of therapeutic agent, encapsulation efficiency, in vitro release kinetics. This study aimed to evaluate the main and interaction effects of the formulation variables on those physical characteristics and also to optimize the best combination of the variables to formulate small size particles with high encapsulation efficiency. The results showed that all the process variables (amount of polycaprolactone and stirring speed) except the amount of surfactant contributed significantly to the parameters previously mentioned. The best optimized formulation was experimentally validated for the closeness to the theoretical estimates. PMID- 30440361 TI - Spiral Folded Adhesive Plaster Optimization for Laparoscopic Surgery. AB - Laparoscopic surgery has the advantage of the minimally invasive for patients. However, the surgery is technically difficult for surgeon because high dexterity is required for suturing in the narrow patient's body. This paper presents a sealing method to locate the adhesive plaster at the incision instead of suturing. The objective is to optimize the plaster material and structure. We made the plaster with the thermally cross-linked gelatin film in a spiral fold because thermally cross-linked gelatin film has the high biocompatibility and tackiness, and a spiral fold has great storage efficiency. In 3 experiments, we measured expansion rate, expansion tension, peeling force, and sealing pressure in a variety of gelatin volume and concentration, and the films diameter. From these experimental results, we optimized the films using response surface method. As a result, the plaster is optimal at gelatin volume 10 mL, gelatin concentration 4 wt %, and films diameters 75 mm. We concluded that the optimized spiral folded adhesive plaster is sufficient in terms of the expansion, tackiness, and sealing properties. PMID- 30440362 TI - The inhibition of acetylcholinesterase by a brain-targeting polylysine-ApoE peptide: biochemical and structural characterizations. AB - The in-trans delivery of protein therapeutics across the blood-brain barrier by K16ApoE peptide carrier has been demonstrated to improve the neurological symptoms and increase the life-span of late-infantile neuronal ceroid lipofuscinosis (LINCL) mice. However, acute toxicity of K16ApoE was observed in LINCL mice resulting in a narrow therapeutic index, limiting the potential of translating the K16ApoE into a viable drug delivery system. This study aims to unravel the toxic mechanism of action. We hypothesized that the toxic response towards the peptide was induced by inhibition of acetylcholinesterase (AChE) activity at neuro-muscular junction. Here, results from the dose-response study suggested that AChE activity was inhibited by K16ApoE at either low or high doses but not at the mid-dose where a significant increase in AChE activity was observed. Meanwhile, molecular docking simulations showed that the N-terminus of K16ApoE is capable of binding to the active site gorge of AChE. In addition to a favorable spatial orientation, this docking pose also revealed strong surface charge interactions which may account for the observed inhibitory effect. While statistical analysis of the dose response and survival ratio suggested that AChE is not the primary mechanism of action for the acute toxicity of K16ApoE, both biochemical evidence and structural analysis have assigned indirect but critical roles for AChE in the overall toxicity mechanism of this peptide carrier. PMID- 30440363 TI - A Model of Acetaminophen Pharmacokinetics and its Effect on Continuous Glucose Monitoring Sensor Measurements. AB - Some of commercial continuous glucose monitoring (CGM) devices, i.e., minimally invasive sensors able to measure almost continuously glucose concentration in the subcutaneous tissue, recently received the regulatory approval to be used for making therapeutic decisions in diabetes management. A fundamental requirement for its safe and effective use is represented by the accuracy of CGM measurements. However, despite recent advances in sensors accuracy and reliability, CGM still suffers from inaccuracy problems in presence of pharmacologic interferences, e.g., the common orally administered acetaminophen (APAP), which artificially raises CGM glucose readings for several hours. A model of the artifact induced by APAP on CGM measurements would be useful to design algorithms to compensate such a distortion. The aim of this work is to exploit the data published by previous literature studies to design a model of oral APAP pharmacokinetics and its effect on glucose concentration measured by CGM sensors. Specifically, the developed model was identified on average data of both plasma APAP concentration and the APAP effect on CGM profiles after an oral administration of 1000 mg of APAP. The APAP effect on CGM readings was estimated from the difference observed, in the same study, between the glucose profile measured by a Dexcom G4 Platinum sensor and the plasma glucose concentration. The model was validated by comparing the simulated effect of mealtime APAP administration in CGM measurements of 100 virtual subjects generated by the UVA/Padova Type 1 Diabetes (TID) Simulator vs. the effect observed in a clinical study by Maahs et al. (Diabetes Care, 2015) in 40 TID subjects taking APAP at breakfast. Results suggest that the proposed model is able to reliably describe the mean APAP effect on CGM measurements. PMID- 30440364 TI - Probabilistic Data-Driven Method for Limb Movement Detection during Sleep. AB - Periodic limb movement disorder (PLMD) is a sleep disorder characterized by repetitive limb movements (LM) during night. The gold standard for LM detection consists of visual analysis of tibialis left (TIBL) and right (TIBR) electromyographic (EMG) signals. Such analysis is subjective and time-consuming. We here propose a semi-supervised and data-driven approach for LM detection during sleep that was trained and tested on 27 healthy controls (C) and 36 PLMD patients. After preprocessing of the EMG signals, discrete wavelet transform (Daubechies 4 mother wavelet and down to 4th decomposition level) was applied. EMG was reconstructed for each set of detail coefficients, thus obtaining four signals (DI-D4). The pre-processed EMG and DI-D4 signals were divided in 3-s mini epochs of which traditional EMG features were calculated. Based on the assumption of lack of movements in healthy controls during rapid eye movement (REM) sleep, we used the features during REM of a subgroup of C to build a non-parametric probabilistic model defining the resting EMG distribution. This model was then used to classify the remaining mini-epochs as either resting EMG or LM. The percentages of 3-s mini-epochs with LMs were calculated for each subject and used to distinguish the remaining C and PLMD with a support vector machine and 5-fold cross validation scheme. Results showed that C can be distinguished by PLMD with accuracy higher than 82% in the preprocessed EMG and DI-D3 signals. PMID- 30440365 TI - Multichannel Sleep Stage Classification and Transfer Learning using Convolutional Neural Networks. AB - Current sleep medicine relies on the supervised analysis of polysomnographic measurements, comprising amongst others electroencephalogram (EEG), electromyogram (EMG), and electrooculogram (EOG) signals. Convolutional neural networks (CNN) provide an interesting framework to automated classification of sleep based on these raw waveforms. In this study, we compare existing CNN approaches to four databases of pathological and physiological subjects. The best performing model resulted in Cohen's Kappa of $?kappa = 0 .75$ on healthy subjects and $?kappa = 0 .64$ on patients suffering from a variety of sleep disorders. Further, we show the advantages of additional sensor data (i.e., EOG and EMG). Deep learning approaches require a lot of data which is scarce for less prevalent diseases. For this, we propose a transfer learning procedure by pretraining a model on large public data and fine-tune this on each subject from a smaller dataset. This procedure is demonstrated using a private REM Behaviour Disorder database, improving sleep classification by 24.4%. PMID- 30440366 TI - Bispectral Analysis to Enhance Oximetry as a Simplified Alternative for Pediatric Sleep Apnea Diagnosis. AB - This study aims at assessing the bispectral analysis of blood oxygen saturation (SpO2) from nocturnal oximetry to help in pediatric sleep apnea-hypopnea syndrome (SAHS) diagnosis. Recent studies have found excessive redundancy in the SAHS related information usually extracted from SpO2, while proposing only two features as a reduced set to be used. On the other hand, it has been suggested that SpO2 bispectral analysis is able to provide complementary information to common anthropometric, spectral, and clinical variables. We address these novel findings to assess whether bispectrum provides new non-redundant information to help in SAHS diagnosis. Thus, we use 981 pediatric SpO2 recordings to extract both the reduced set of features recently proposed as well as 9 bispectral features. Then, a feature selection method based on the fast correlationbased filter and bootstrapping is used to assess redundancy among all the features. Finally, the non-redundant ones are used to train a Bayesian multi-layer perceptron neural network (BYMLP) that estimate the apnea-hypopnea index (AHI), which is the diagnostic reference variable. Bispectral phase entropy was found complementary to the two previously recommended features and a BY-MLP model trained with the three of them reached high agreement with actual AHI (intra class correlation coefficient = 0.889). Estimated AHI also showed high diagnostic ability, reaching 82.1%, 81.9%, and 90.3% accuracies and 0.814, 0.880, and 0.922 area under the receiver-operating characteristics curve for three common AHI thresholds: 1 e/h, 5 e/h, and 10 e/h, respectively. These results suggest that the information extracted from the bispectrum of SpO2 can improve the diagnostic performance of the oximetry test. PMID- 30440367 TI - Night to night pulse oximetry variability in children with suspected sleep apnea. AB - Obstructive Sleep Apnea (OSA) is the most common form of sleep-disordered breathing in children. The gold standard to screen for OSA, polysomnography (PSG), requires an overnight stay in the hospital and is resource intensive. The Phone Oximeter is a non-invasive smartphone-based tool to record pulse oximetry. This portable device is able to measure patients over multiple nights while at home, causing less sleep disturbance than PSG and is able to measure night to night variability in sleep. This study analyzed the Screen My Sleep children (SMS) dataset, in which 74 children were monitored over multiple nights with the Phone Oximeter, including one night simultaneously with PSG in the hospital and two nights at home. In this study, we aim to investigate the night to night variability and assess the accuracy of the oxygen desaturation index (ODI) screening for children with significant OSA. In order to assess the performance of the ODI calculation in children, we implemented different ODIs at different desaturation levels and time durations. The variability was studied using a one way ANOVA, and ODI's performance screening for OSA using the area under the ROC curve (AUC). The implemented ODIs provide similar OSA screening results, using different apnea/hypopnea index (AHI) thresholds, as the ODI recommended for adults by the American academy of sleep medicine (AASM). The ODI provides an AUC of around 0.77, 0.76, 0.94 and 0.97 classifying children with an AHI > 1, AHI > 5 AHI > 10 and AHI > 15, respectively. The SMS dataset shows no significant night to night variability between the two nights at home. However, when comparing with the night at the hospital, both nights at home show a decrease in the lowest SpO2 value as well as overall SpO2 signal quality percentage. This study shows that there is variability in SpO2 signal between at-home versus in hospital settings. PMID- 30440368 TI - Interactive Sleep Stage Labelling Tool For Diagnosing Sleep Disorder Using Deep Learning. AB - Traditional manual scoring of the entire sleep for diagnosis of sleep disorders is highly time-consuming and dependent to experts experience. Thus, automatic methods based on electrooculography (EOG) analysis have been increasingly attracted attentions to lower the cost of scoring. Such computeraided diagnosis of sleep disorders are usually based on the 6 scores, wake (W), sleep status (S1 S4) and REM by labelling every 30-second long EOG records. This paper presents an automatic scoring method of sleep stages by using the recent advancements in deep learning. We also suggest an interactive scoring scheme to enable the doctors of practitioners to give feedback by correcting errors and improve the accuracy of scoring as well as diagnosis of sleep disorders. PMID- 30440369 TI - Analysis of the effects of medication for the treatment of epilepsy by ensemble Iterative Extended Kalman filtering. AB - This paper proposes an objective methodology for the analysis of epileptic seizure count time series by developing a non-linear state space model. An iterative extended Kalman filter (IEKF) is employed for the estimation of the states of the non-linear state space model. In order to improve convergence of the IEKF, the recently proposed Levenberg-Marquardt variant of the IEKF is explored. As external inputs time-dependent dosages of several simultaneously administered anticonvulsants are included. The aim of the analysis is to decide whether each anticonvulsant decreases or increases the number of seizures per day. The performance of the analysis is analyzed for simulated data, as well as for real data from a patient suffering from myoclonic-astatic epilepsy. PMID- 30440370 TI - Knowledge-driven dictionaries for sparse representation of continuous glucose monitoring signals. AB - Continuous glucose monitoring (CGM) of patients with diabetes allows the effective management of the disease and reduces the risk of hypoglycemic or hyperglycemic episodes. Towards this goal, the development of reliable CGM models is essential for representing the corresponding signals and interpreting them with respect to factors and outcomes of interest. We propose a sparse decomposition model to approximate CGM time-series as a linear combination of a small set of exemplar atoms, appropriately designed through parametric functions to capture the main fluctuations of the CGM signal. Sparse decomposition is performed through the orthogonal matching pursuit (OMP). Results indicate that the proposed model provides 0.1 relative reconstruction error with 0.8 compression rate on a publicly available dataset containing 25 patients diagnosed with Type 1 diabetes. The atoms selected from the OMP procedure can be further interpreted in relation to the clinically meaningful components of the CGM signal (e.g. glucose spikes, hypoglycemic episodes, etc. PMID- 30440371 TI - Tracking the Time Varying Neural Tuning via Adam on Point Process Observations. AB - Brain machine interfaces(BMIs) translate the neural activity into the control of movement by understanding how the neural activity responds to the movement intension. However, the neural tuning property, where the modulation depth and preferred direction describe how a neuron responses to stimuli, is time varying gradually and abruptly during the interaction with environment. There has been some research to address such an issue considering either one of the cases, but never address them in a general framework. We propose a novel optimization algorithm based on the point process observations to capture these two changes at the same time. At each time index, the tuning parameter is updated stochastically according to the gradient based Adam searching method, which maximizes the likelihood of point process. Our algorithm is compared with the Adaptive Point Process Estimation (APPE), where the abrupt change is addressed by sampling all the possibilities globally, on synthetic neural data. The results show that our algorithm leads to a better prediction of tuning parameters as well as kinematics over 16.8% and 20% respectively. PMID- 30440372 TI - Pipeline for Forward Modeling and Source Imaging of Magnetocardiographic Recordings via Spatiotemporal Kalman Filtering. AB - the aim of this proof-of-concept work was to apply the spatiotemporal Kalman filter (STKF) algorithm to magnetocardiographic (MCG) recordings of the heart. Due to the lack of standardized software and pipelines for MCG source imaging, we needed to construct a pipeline for MCG forward modeling before we could apply the STKF method. In the forward module, the finite element method (FEM) solvers in SimBio software are used to solve the MCG forward problem. In the inverse module, STKF and Low Resolution Brain Electromagnetic Tomography (LORETA) algorithms are applied. The work was conducted using two simulated datasets contaminated with different levels of additive white Gaussian noise (AWGN). Then the inverse problem was solved using both LORETA and STKF. The results indicate that STKF outperformed LORETA for MCG datasets with low signal-to-noise ratio (SNR). In the future clinical MCG recordings and more sophisticated simulations will be used to evaluate the accuracy of MCG source imaging via STKF. PMID- 30440373 TI - Comparison of different EEG signal analysis techniques for an offline lower limb motor imagery brain-computer interface. AB - The use of motion assistance devices improves the rehabilitation process of patients that have motor disabilities. In the case these devices are controlled by brain-machine interfaces, the rehabilitation process can be improved due to neuroplasticity. However, in the case of lower limb rehabilitation, the limited accuracy of the control algorithms is a serious difficulty to overcome. In this research, different EEG signal's processing techniques, based on motor imagery, are tested for a brain-computer interface in an offline scenario, in order to detect the limitations of the models previous to its realtime implementation. The results reveal that motor imagery is very dependent on the subject and that Stockwell Transform provides the best accuracy among the models tested. PMID- 30440374 TI - Sparse Kernel Machines for motor imagery EEG classification. AB - Brain-computer interfaces (BCIs) make humancomputer interaction more natural, especially for people with neuro-muscular disabilities. Among various data acquisition modalities the electroencephalograms (EEG) occupy the most prominent place due to their non-invasiveness. In this work, a method based on sparse kernel machines is proposed for the classification of motor imagery (MI) EEG data. More specifically, a new sparse prior is proposed for the selection of the most important information and the estimation of model parameters is performed using the bayesian framework. The experimental results obtained on a benchmarking EEG dataset for MI, have shown that the proposed method compares favorably with state of the art approaches in BCI literature. PMID- 30440375 TI - Analysis and Classification for EEG Patterns of Force Motor Imagery Using Movement Related Cortical Potentials. AB - Motor imagery-based BCIs are the most natural human-computer interaction paradigms. In recent years, researchers have tried to decode the kinetic information of motor imagery. In this paper, we analyzed and discriminated the EEG patterns of different force levels motor imagery using MRCPs. In the experiment, nine healthy subjects were required to perform the hand force motor imagery tasks (30% MVC and 10% MVC). From the view of MRCPs, the most significant discrimination between the two levels of mental tasks was the manifestation of motor planning. The average classification accuracy for features involving both MRCP and CSP was 78.3%, which was 8.5% higher than the CSP-based features (p!0.001) and 2% higher than the MRCP-based features. The results demonstrated the feasibility of using MRCPs for hand force motor imagery classification. PMID- 30440376 TI - FBCSP-based Multi-class Motor Imagery Classification using BP and TDP features. AB - Use of Motor Imagery in EEG signals is gaining importance to develop Brain Computer Interface (BCI) applications in various fields ranging from bio-medical to entertainment. Filter Bank Common Spatial Pattern (FBCSP) algorithm is a promising feature extraction technique to deal with subject-specific behavior in Motor Imagery classification. Using FBCSP on EEG we have developed an accurate but less computationally expensive approach by making use of Time Domain Parameters (TDP) and Band Power (BP) features to form a combined feature set. The novelty of our approach is also the use of optimal time segmentation to overcome non-stationary state behavior of Event-Related Desynchronization (ERD) and Event Related Synchronization (ERS) over time. We analyzed the impact of parameter variations on classification accuracy and achieved 0.59 mean kappa value for Dataset 2a BCI competition IV, the highest reported for FBCSP approaches, along with the lowest inter-subject variation. PMID- 30440377 TI - DeepMI: Deep Learning for Multiclass Motor Imagery Classification. AB - In Brain-Computer Interface (BCI) Research,Electroencephalography (EEG) has obtained great attention for biomedical applications. In BCI system, feature representation and classification are important tasks as the accuracy of classification highly depends on these stages. In this paper, we propose a model in which Common Spatial Pattern (CSP) is used to discriminate inter-class data using co-variance maximization and Fast Fourier Transform Energy Map (FFTEM) is used for feature selection and mapping of 1D data into 2D data (energy maps). Convolutional Neural Network is used for classification of multi-class Motor Imagery (MI) signals. Further, this paper investigates near-optimal parameter selection for feature mapping, frequency bands selection, and temporal segmentation. It is shown that our proposed method outperformed the reported methods by achieving 0.61 mean kappa value. PMID- 30440378 TI - Emotion Recognition for Brain Machine Interface: Non-linear Spectral Analysis of EEG Signals Using Empirical Mode Decomposition. AB - Emotions are a fundamental part of the human experience but currently there are no methods that can objectively detect and categorize them. This study utilizes the empirical mode decomposition (EMD) method to categorize emotions from encephalography (EEG) recordings. In the past, EMD has proven to be a very useful signal analysis tool because of its ability to decompose nonstationary signals, like those from an EEG, into component signals with varying frequency content called intrinsic mode functions (IMFs). The method in this paper utilizes three features extracted from the IMFs-the first difference of time, the first difference of phase, and the normalized energy-for data categorization using support vector machine (SVM) classifiers. Two classifiers were trained for each subject, one for valence and another for arousal. The mean accuracies yielded for valence and arousal were 75.86% and 75.31%, respectively. The results of this study verify previous findings by other researchers that these three features are useful in emotion recognition when applied to previously recorded EEG data, though we add the caveat that subject-specific classifiers are needed instead of generalized, global classifiers. PMID- 30440379 TI - Unsupervised Phase Learning and Extraction from Repetitive Movements. AB - Phase extraction from repetitive movements is one crucial part in various applications such as interactive robotics, physical rehabilitation, or gait analysis. However, pre-existing automatic phase extraction techniques are specific to a target movement due to some handcrafted-features. To make it more universal, a novel unsupervised-learning-based phase extraction technique is proposed. A neural network architecture and a cost function are designed to learn the concept of phase from records of a repetitive movement without any given phase label. The method is tested on a rat's gait cycle and a human's upper limb movement. The phases are successfully extracted at the sample level despite the variations in movement speed, trajectory, or subject's anthropometric features. PMID- 30440380 TI - EEG Processing to Discriminate Transitive-Intransitive Motor Imagery Tasks: Preliminary Evidences using Support Vector Machines. AB - It is known that brain dynamics significantly changes during motor imagery tasks of upper limb involving different kind of interactions with an object. Nevertheless, an automatic discrimination of transitive (i.e., actions involving an object) and intransitive (i.e., meaningful gestures that do not include the use of objects) imaginary actions using EEG dynamics has not been performed yet. In this study we exploit measures of EEG spectra to automatically discern between imaginary transitive and intransitive movements of the upper limb. To this end, nonlinear support vector machine algorithms are used to properly combine EEG derived features, while a recursive feature elimination procedure highlights the most discriminant cortical regions and associated EEG frequency oscillations. Results show the significance of $?gamma ( 30 -45$ Hz) oscillations over the fronto-occipital and ipsilateral-parietal areas for the automatic classification of transitive-intransitive imaginary upper limb movements with a satisfactory accuracy of 70.97%. PMID- 30440381 TI - Evaluation of Different Signal Processing Methods in Time and Frequency Domain for Brain-Computer Interface Applications. AB - Brain-computer interface (BCI) has been widely introduced in many medical applications. One of the main challenges in BCI is to run the signal processing algorithms in real-time which is challenging and usually comes with high processing unit costs. BCIs based on motor imagery task are introduced for severe neurological diseases especially locked-in patients. A common concept is to detect one's movement intention and use it to control external devices such as wheelchair or rehabilitation devices. In real-time BCI, running the signal processing algorithms might not always be possible due to the complexity of the algorithms. Moreover, the speed of the affordable computational units is not usually enough for those applications. This study evaluated a range of feature extraction methods which are commonly used for such real-time BCI applications. Electroencephalogram (EEG) and Electrooculogram (EOG) data available through IEEE Brain Initiative repository was used to investigate the performance of different feature extraction methods including template matching, statistical moments, selective bandpower, and fast Fourier transform (FFT) power spectrum. The support vector machine (SVM) was used for classification. The result indicates that there is not a significant difference when utilizing different feature extraction methods in terms of movement prediction although there is a vast difference in the computational time needed to extract these features. The results suggest that computational time could be considered as the primary parameter when choosing the feature extraction methods as there is no significant difference between the results when different features extraction methods are used. PMID- 30440382 TI - Real-Time Human Physical Activity Recognition with Low Latency Prediction Feedback Using Raw IMU Data. AB - In the realm of Human Activity Recognition (HAR), supervised machine learning and deep learning are commonly used. Their training is done using time and frequency features extracted from raw data (inertial and gyroscopic). Nevertheless, raw data are seldom employed. In this paper, a dataset of able-bodied participants is recorded using 3 custom wireless motion sensors providing embedded IMU and sEMG detection and processing and a base station (a Raspberry Pi 3) running a classification algorithm. A Support Vector Machine with Radius Basis Function Kernel (RBF-SVM) is augmented using Spherical Normalization to achieve a motion classification accuracy of 97.35% between 8 body motions. The proposed classifier allows for real-time prediction callback with low latency output. PMID- 30440383 TI - EEG Based Network Connectivity Classification in 7 and 9 Years- Old Children. AB - Investigating the brain neural pathways requires extensive knowledge of childrens' cognitive development. Significant variations in the cognitive process of a child, across ages, were assessed through the success in recognizing various stimuli. Longitudinal EEG data were gathered from 45 healthy children at the ages of seven and nine years. During the EEG data acquisition, children were asked to respond to the Flanker stimuli for investigating the development of the response conflict process. In each age group, the coherence and imaginary component of coherency were used to assess the network connectivity of each child. The congruent and incongruent stimuli were tried within delta, theta, alpha and beta bands. Following that, efficacies of various classification algorithms were tested in discriminating the coherency data of the two age groups. It was observed that brain connectivity was more helpful in distinguishing between two age groups using the incongruent Flanker stimuli. For the incongruent condition, the imaginary part of the coherency provides better features for classification. Using the features derived from the theta, alpha and beta bands, a classification accuracy of more than 94.31% could be achieved using the naive Bayes classifier. PMID- 30440384 TI - Low Gamma Band Cortico-muscular Coherence Inter-Hemisphere Difference following Chronic Stroke. AB - Brain oscillation and motor control process would change due to chronic stroke. Inter-hemisphere brain activation patterns may relate to motor related recovery. This study employed cortico-muscular coherence to explore cortical motor control process during wrist isometric contraction experiments of both affected and unaffected hands from chronic stroke subjects. Eleven chronic stroke subjects with moderate hand function involved in the experiments and each subject took three visits. Multitaper coherence estimation with bias-correction was performed to acquire cortico-muscular coherence, neuronal coherence source Localization was conducted to determine typical scalp motivation area during isometric contraction. Non-parametric permutation based multiple frequency bin statistics was utilized to compare the difference between two sides. The results demonstrated significant typical low gamma band inter-hemisphere disparity in cortico-muscular coherence between two sides after chronic stroke. The spatial topographical pattern and source Localization outcomes also supported these findings. PMID- 30440385 TI - Preliminary Evaluation of Fetal Congenital Heart Defects Changes on Fetal Maternal Heart Rate Coupling Strength. AB - Monitoring fetal heart rate in an important aspect in evaluating fetal well being. Maternal-fetal interaction has shown evolution during fetal maturation. In this work, we studied maternal-fetal heart rate synchronization in early and late gestation fetuses. We also evaluated variations in the synchronization due to congenital heart defect (CHD). Maternal-fetal heart rate synchronization for 22 early gestation (Age < 32 weeks), $late gestation (Age >32 weeks) and 7 CHD fetuses (5 of them with gestational age < 32 weeks). The synchronization ratio between the mother and the fetus was more localized at certain fetus heart rate in the early gestation group while it was spreading over more fetal heart rate for the late group. For example, for maternal primary cycle of 3 beat- to-beat (m=3), the synchronization ratio of 5 fetus beats (n=5) contributed 60+/-30% of the whole coupling ratios for the early group while it contributed 30 degrees 30% for the late group (p< 0.01). On the other hand, the coupling ratio of m:n=3:7 contributed 4+/-17% of the early group and 13+/-24% for the late group (p< 0.05). The standard deviation of the phase coherence index $(?lambda_{ ?mathrm{S}?mathrm{D}})$ for both the late and the CHD groups were significantly higher than the early group at different values. For example, $?lambda ?mathrm{S}?mathrm{D} was 0.006?pm 0.004$ for the early group while it was 0.009+/ 0.008 for the late group (p< 0.01) and 0.01+/- 0.002 for the CHD group (p< 0.01) for m=3. The variation between the early and late normal groups might indicate a healthy development of the autonomic nervous system while the higher variation in the CHD group could be a good marker for impairment of the cardiac autonomic activity. Further coupling analysis with more abnormal cases is needed to verify these findings. PMID- 30440386 TI - Complex Modulation Method for Measuring Cross-Frequency Coupling of Neural Oscillations. AB - There is growing evidence from human intracranial electrocorticography (ECoG) studies that interactions between cortical frequencies are important for sensory perception, cognition and inter-regional neuronal communication. Recent studies have focused mainly on the strength of phase-amplitude coupling in cross frequency interactions. Here, we introduce a complex modulation method based on measures of coherence to investigate cross-frequency coupling in the neural time series. This novel approach uses complex demodulation transform and coherence measures from the transformed signals. We used this method to quantify power coupling between two cortical frequency bands: theta (47 Hz) and high gamma (70 150 Hz) in ECoG signals recorded during an auditory task. We compared complex modulation results with traditional phase-amplitude coupling measures (PAC) derived from the same ECoG dataset. Our results suggest that cross-frequency coupling may involve changes in both phase-amplitude and power relationships between frequencies, reflecting the complexity of neuronal oscillatory interactions. PMID- 30440388 TI - Assessment of EEG Connectivity Patterns in Mild Cognitive Impairment Using Phase Slope Index. AB - Mild cognitive impairment (MCI) is a pathology characterized by an abnormal cognitive state. MCI patients are considered to be at high risk for developing dementia. The aim of this study is to characterize the changes that MCI causes in the patterns of brain information flow. For this purpose, spontaneous EEG activity from 41 MCI patients and 37 healthy controls was analyzed by means of an effective connectivity measure: the phase slope index (PSl). Our results showed statistically significant decreases in PSI values mainly at delta and alpha frequency bands for MCI patients, compared to the control group. These abnormal patterns may be due to the structural changes in the brain suffered by patients: decreased hippocampal volume, atrophy of the medial temporal lobe, or loss of gray matter volume. This study suggests the usefulness of PSI to provide further insights into the underlying brain dynamics associated with MCI. PMID- 30440387 TI - Modulation of Low-Frequency Pulsed Magnetic Field on Hippocampal Neural Oscillation in Depression Rats. AB - Transcranial magnetic stimulation (TMS), as a non-invasive brain stimulation technique, has been approved for some medication-resistant depression by the United States Food and Drug Administration. However, the majority of these studies have focused on the effects of high-frequency TMS, and little is known about low-frequency TMS in depression treatment. Furthermore, the potential electroneurophysiology mechanisms of TMS on the improvement of and function of the brain remain poorly understood. In the present study, a depression rat model was established by chronic unpredictable stress (CUS). Rats were exposed to low frequency pulsed magnetic field (LFPMF) (1Hz, 20mT) for 14 days, one hour per day, then elevated plus-maze test was assessed and local field potentials (LFPs) in hippocampus were recorded. In order to analyze LFPs, sample entropy was calculated to make complexity analysis, while phase locked value and phase amplitude coupling modulation index were used to figure out the correlation of oscillations. Our data showed that LFPMF significantly relieved CUS-induced depression-behaviors and improved the undesirable changes of the identical frequency synchronization and theta-gamma phase-amplitude coupling in CUS rats. These findings indicated that the antidepressive-like effects of LFPMF might be associated with the LFPMF-induced improvement in neural oscillation. PMID- 30440389 TI - Nonlinear Interaction Analysis of Cardiovascular-Respiratory Data by Means of Convergent Cross Mapping. AB - Appropriate analyses of directed complex interactions within the cardiovascular respiratory system are of growing interest for a better understanding of physiological regulatory mechanisms in healthy subjects and diseased persons. There are various concepts to analyze such interactions. Convergent Cross Mapping (CCM) provides the possibility to define directed interactions in terms of nonlinear stability. A proof-of-principle approach is introduced to apply CCM to cardiovascular-respiratory data of healthy subjects during resting state period. Showing group results of time-invariant as well as single subject results of interval-based CCM, the introduced approach was able to quantify correct directionality and strength of interactions within the cardiovascular-respiratory system and to provide statistical thresholds for significant interactions. These results may serve as a methodological base to compare healthy subjects and diseased persons. PMID- 30440390 TI - Functional brain network analysis reveals time-on-task related performance decline. AB - Because of the undesired consequences, particularly seen in deteriorated performance in real-word workspace, continuous efforts have been made to understand time-on-task (TOT) related mental fatigue. However, our understanding of the underlying neural mechanism of TOT is still rudimentary. In this study, EEG signals were recorded from 26 subjects undergoing a 20-min mentally-demanding psychomotor vigilance test. Instead of a mere two-point comparison (i.e., fatigue vs. vigilant), behaviour and EEG data were divided into 4 quartiles for better revealing the progression of TOT effect. We then employed advanced graph theoretical approach to quantify TOT effect in terms of global and local reorganisation of EEG functional connectivity within the lower alpha (8-10 Hz) band. Interestingly, we found a development trend towards disintegrated network topology with the TOT effect, as seen in significantly increased characteristic path length and reduced small-worldness. Moreover, we found TOT-related reduced local property of interconnectivity in left frontal and central areas with an increased local property in right parietal areas. These findings augment our understanding of how the brain reorganises following the accumulation of prolonged task and demonstrate the feasibility of using network metrics as neural biomarkers for mental fatigue assessment. PMID- 30440391 TI - Biophysically interpretable recurrent neural network for functional magnetic resonance imaging analysis and sparsity based causal architecture discovery. AB - Recent efforts use state-of-the-art Recurrent Neural Networks (RNN) to gain insight into neuroscience. A limitation of these works is that the used generic RNNs lack biophysical meaning, making the interpretation of the results in a neuroscience context difficult. In this paper, we propose a biophysically interpretable RNN built on the Dynamic Causal Modelling (DCM). DCM is an advanced nonlinear generative model typically used to test hypotheses of brain causal architectures and associated effective connectivities. We show that DCM can be cast faithfully as a special form of a new generalized RNN. In the resulting DCM RNN, the hidden states are neural activity, blood flow, blood volume, and deoxyhemoglobin content and the parameters are biological quantities such as effective connectivity, oxygen extraction fraction and vessel wall elasticity. DCM-RNN is a versatile tool for neuroscience with great potential especially when combined with deep learning networks. In this study, we explore sparsity- based causal architecture discovery with DCM-RNN. In the experiments, we demonstrate that DCM-RNN equipped with $l_{1}$ connectivity regulation is more robust to noise and more powerful at discovering sparse architectures than classic DCM with $l_{2}$ connectivity regulation. PMID- 30440392 TI - Adaptive Multi-task Elastic Net based feature selection from Pharmacogenomics Databases. AB - Integrating multiple databases of similar tasks is a significant problem in biological data analysis. In this paper, we consider whether feature selection in a single database can benefit from incorporating similar databases. We report that by using adaptive multi-task elastic net for feature selection and Random Forest for prediction, the prediction performance can be improved for pharmacogenomics databases. We also present a simulation study to explain the robust feature selection benefit of adaptive multi task elastic net while dealing with noisy features. PMID- 30440393 TI - An Approximate Nearest Neighbour System For Neonatal EEG Recall. AB - Clinical neurophysiologists often find it difficult to recall rare EEG patterns despite the fact that this information could be diagnostic and help with treatment intervention. Traditional search methods may take time to retrieve the archived EEGs that could provide the meaning or cause of the specific pattern which is not acceptable as time can be critical for sick neonates. If neurophysiologists had the ability to quickly recall similar patterns, the prior occurrence of the pattern may help make an earlier diagnosis. This paper presents a system that may be used to assist a clinical neurophysiologist in the recall of neonatal EEG patterns. The proposed system consists of an alignment technique followed by an approximate nearest neighbour search algorithm called locality sensitive hashing. The system was tested on six different neonatal EEG pattern types with 430 events in total and the results are presented in this paper. PMID- 30440394 TI - Analysis of Features Extracted from EEG Epochs by Discrete Wavelet Decomposition and Hilbert Transform for Sleep Apnea Detection. AB - Sleep apnea (SA) is one of the most common disorders manifesting during sleep and the electroencephalo-gram (EEG) belongs to these biomedical signals that change during apnea and hypopnea episodes. In recent years, a few publications reported approaches to the automatic classification of sleep apnea episodes based only on the EEG. The purpose of this work was to analyze statistical features extracted from the EEG epochs by combined discrete wavelet transform (DWT) and Hilbert transform (HT). Additionally, the selected most discriminative 30 features were then used in the automatic classification of normal breathing and obstructive (OSA) and central (CSA) apnea by a feedforward neural network with 17+7 neurons in two hidden layers. This classifier returned the accuracy of 73.9% for the training and 77.3% for the testing set. The analysis of features extracted from EEG epochs revealed the importance of theta, beta and gamma brain waves. PMID- 30440395 TI - Multi-modal Approach for Affective Computing. AB - Throughout the past decade, many studies have classified human emotions using only a single sensing modality such as face video, electroencephalogram (EEG), electrocardiogram (ECG), galvanic skin response (GSR), etc. The results of these studies are constrained by the limitations of these modalities such as the absence of physiological biomarkers in the face-video analysis, poor spatial resolution in EEG, poor temporal resolution of the GSR etc. Scant research has been conducted to compare the merits of these modalities and understand how to best use them individually and jointly. Using multi-modal AMIGOS dataset, this study compares the performance of human emotion classification using multiple computational approaches applied to face videos and various bio-sensing modalities. Using a novel method for compensating physiological baseline we show an increase in the classification accuracy of various approaches that we use. Finally, we present a multi-modal emotion-classification approach in the domain of affective computing research. PMID- 30440396 TI - Classifying the mental representation of word meaning in children with Multivariate Pattern Analysis of fNIRS. AB - This study presents the implementation of a within-subject neural decoder, based on Support Vector Machines, and its application for the classification of distributed patterns of hemodynamic activation, measured with Functional Near Infrared Spectroscopy (fNIRS) on children, in response to meaningful and meaningless auditory stimuli. Classification accuracy nominally exceeds chance level for the majority of the participants, but fails to reach statistical significance. Future work should investigate whether individual differences in classification accuracy may relate to other characteristics of the children, such as their cognitive, speech or reading abilities. PMID- 30440397 TI - Automating Interictal Spike Detection: Revisiting A Simple Threshold Rule. AB - Interictal spikes (IIS) are bursts of neuronal depolarization observed electrographically between periods of seizure activity in epilepsy patients. However, IISs are difficult to characterize morphologically and their effects on neurophysiology and cognitive function are poorly understood. Currently, IIS detection requires laborious manual assessment and marking of electroencephalography (EEG/iEEG) data. This practice is also subjective as the clinician has to select the mental threshold that EEG activity must exceed in order to be considered a spike. The work presented here details the development and implementation of a simple automated IIS detection algorithm. This preliminary study utilized intracranial EEG recordings collected from 7 epilepsy patients, and IISs were marked by a single physician for a total of 1339 IISs across 68 active electrodes. The proposed algorithm implements a simple threshold rule that scans through iEEG data and identifies IISs using various normalization techniques that eliminate the need for a more complex detector. The efficacy of the algorithm was determined by evaluating the sensitivity and specificity of the detector across a range of thresholds, and an approximate optimal threshold was determined using these results. With an average true positive rate of over 98% and a false positive rate of below 2%, the accuracy of this algorithm speaks to its use as a reliable diagnostic tool to detect IISs, which has direct applications in localizing where seizures start, detecting when seizures start, and in understanding cognitive impairment due to IISs. Furthermore, due to its speed and simplicity, this algorithm can be used for real-time detection of IIS that will ultimately allow physicians to study their clinical implications with high temporal resolution and individual adaptation. PMID- 30440398 TI - Bioinformatics Identification of Drug Gene Modules: Application to Clear Cell Carcinoma of the Ovary. AB - Targeted therapy is a treatment that targets the cancer's specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. Identification of therapeutics targets is a very challenging problem in bioinformatics. An integrative and iterative approach for the identification of drug-gene modules (i.e., groups of genes and drugs such that genes in the same module may regulate each other and are targets of some of the drugs in the same module) is developed. Application to clear cell carcinoma of the ovary data reveals several drug-gene modules and a target network that may play important roles in treating this disease. PMID- 30440399 TI - An Evaluation of EEG-based Metrics for Engagement Assessment of Distance Learners. AB - Maintaining students' cognitive engagement in educational settings is crucial to their performance, though quantifying this mental state in real-time for distance learners has not been studied extensively in natural distance learning environments. We record electroencephalographic (EEG) data of students watching online lecture videos and use it to predict engagement rated by human annotators. An evaluation of prior EEG-based engagement metrics that utilize power spectral density (PSD) features is presented. We examine the predictive power of various supervised machine learning approaches with both subject-independent and individualized models when using simple PSD feature functions. Our results show that engagement metrics with few power band variables, including those proposed in prior research, do not produce predictions consistent with human observations. We quantify the performance disparity between cross-subject and per-subject models and demonstrate that individual differences in EEG patterns necessitate a more complex metric for educational engagement assessment in natural distance learning environments. PMID- 30440400 TI - Spectrum and Phase Adaptive CCA for SSVEP-based Brain Computer Interface. AB - Among various brain activity patterns, Steady State Visual Evoked Potential (SSVEP) based Brain Computer Inter-face (BCI) requires the least training time while carrying the fastest information transfer rate, making it highly suitable for deploying efficient self-paced BCI systems. In this study, we propose a Spectrum and Phase Adaptive CCA (SPACCA) for subject-and device-specific SSVEP based BCI. Cross subject heterogeneity of spectrum distribution is taken into consideration to improve the prediction accuracy. We design a library of phase shifting reference signals to accommodate subjective and device-related response time lag. With the flexible reference signal generating approach, the system can be optimized for any specific flickering source, include LED, computer screen and mobile devices. We evaluated the performance of SPACCA using three sets of data that use LED, computer screen and mobile device (tablet) as stimuli sources respectively. The first two data sets are publicly available whereas the third data set is collected in our BCI lab. Across different data sets, SPACCA consistently performs better than the baseline, i.e. standard CCA approach. Statistical test to compare the overall results across three data sets yield a p value of 1.66e-6, implying the improvement is significant. PMID- 30440401 TI - On the Interaction between Gaze Behavior and Physiological Responses when Viewing Garden Scenes. AB - Recent research has shown that design principles inherent in a Japanese style garden can reduce measures of stress in both healthy and dementia patients. However, it was not clear how subjects' visual interaction with the scene affected their physiological responses. To address that, we developed a novel non invasive system to collect synchronized measurements of eye gaze and physiological indicators of sympathetic neural activity: the electrocardiogram, the blood volume pulse and the galvanic skin response, as subjects view a garden environment. We characterized the visual engagement of subjects using the average fixation duration, the saccade amplitude and the gaze transition entropy. We find a statistically significant positive correlation between gaze transition entropy and mean heart rate change. Our results suggest that the visual engagement of subjects with their environment may influence their physiological responses to it: more engagement may lead to more relaxation. Our results also highlight the importance of taking into account the detailed spatio-temporal characteristics of the gaze trajectory. PMID- 30440402 TI - A Feature Selection Method Based on Shapley Value to False Alarm Reduction in ICUs A Genetic-Algorithm Approach. AB - High false alarm rate in intensive care units (ICUs) has been identified as one of the most critical medical challenges in recent years. This often results in overwhelming the clinical staff by numerous false or unurgent alarms and decreasing the quality of care through enhancing the probability of missing true alarms as well as causing delirium, stress, sleep deprivation and depressed immune systems for patients. One major cause of false alarms in clinical practice is that the collected signals from different devices are processed individually to trigger an alarm, while there exists a considerable chance that the signal collected from one device is corrupted by noise or motion artifacts. In this paper, we propose a low-computational complexity yet accurate game-theoretic feature selection method which is based on a genetic algorithm that identifies the most informative biomarkers across the signals collected from various monitoring devices and can considerably reduce the rate of false alarms 1. PMID- 30440403 TI - A Comparison of 1-D and 2-D Deep Convolutional Neural Networks in ECG Classification. AB - Effective detection of arrhythmia is an important task in the remote monitoring of electrocardiogram (ECG). The traditional ECG recognition depends on the judgment of the clinicians' experience, but the results suffer from the probability of human error due to the fatigue. To solve this problem, an ECG signal classification method based on the images is presented to classify ECG signals into normal and abnormal beats by using two-dimensional convolutional neural networks (2D-CNNs). First, we compare the accuracy and robustness between one-dimensional ECG signal input method and two-dimensional image input method in AIexNet network. Then, in order to alleviate the overfitting problem in two dimensional network, we initialize AIexNet-like network with weights trained on ImageNet, to fit the training ECG images and fine-tune the model, and to further improve the accuracy and robustness of ECG classification. The performance evaluated on the MIT-BIH arrhythmia database demonstrates that the proposed method can achieve the accuracy of 98% and maintain high accuracy within SNR range from 20 dB to 35 dB. The experiment shows that the 2D-CNNs initialized with AIexNet weights performs better than one-dimensional signal method without a large-scale dataset. PMID- 30440404 TI - Recurrent Neural Network for Classification of Snoring and Non-Snoring Sound Events. AB - Obstructive sleep apnea (OSA) is a disorder that affects up to 38% of the western population. It is characterized by repetitive episodes of partial or complete collapse of the upper airway during sleep. These episodes are almost always accompanied by loud snoring. Questionnaires such as STOP-BANG exploit snoring to screen for OSA. However, they are not quantitative and thus do not exploit its full potential. A method for automatic detection of snoring in whole-night recordings is required to enable its quantitative evaluation. In this study, we propose such a method. The centerpiece of the proposed method is a recurrent neural network for modeling of sequential data with variable length. Mel frequency cepstral coefficients, which were extracted from snoring and non snoring sound events, were used as inputs to the proposed network. A total of 20 subjects referred to clinical sleep recording were also recorded by a microphone that was placed 70 cm from the top end of the bed. These recordings were used to assess the performance of the proposed method. When it comes to the detection of snoring events, our results show that the proposed method has an accuracy of 95%, sensitivity of 92%, and specificity of 98%. In conclusion, our results suggest that the proposed method may improve the process of snoring detection and with that the process of OSA screening. Follow-up clinical studies are required to confirm this potential. PMID- 30440405 TI - Deep Classification of Epileptic Signals. AB - Electrophysiological observation plays a major role in epilepsy evaluation. However, human interpretation of brain signals is subjective and prone to misdiagnosis. Automating this process, especially seizure detection relying on scalpbased Electroencephalography (EEG) and intracranial EEG, has been the focus of research over recent decades. Nevertheless, its numerous challenges have inhibited a definitive solution. Inspired by recent advances in deep learning, here we describe a new classification approach for EEG time series based on Recurrent Neural Networks (RNNs) via the use of Long- Short Term Memory (LSTM) networks. The proposed deep network effectively learns and models discriminative temporal patterns from EEG sequential data. Especially, the features are automatically discovered from the raw EEG data without any pre-processing step, eliminating humans from laborious feature design task. Our light-weight system has a low computational complexity and reduced memory requirement for large training datasets. On a public dataset, a multi-fold cross-validation scheme of the proposed architecture exhibited an average validation accuracy of 95.54% and an average AUC of 0.9582 of the ROC curve among all sets defined in the experiment. This work reinforces the benefits of deep learning to be further attended in clinical applications and neuroscientific research. PMID- 30440406 TI - Finger ECG based Two-phase Authentication Using 1D Convolutional Neural Networks. AB - This paper presents a study using 1D convolutional neural networks (CNNs) for ECG based authentication. A simple CNN structure is used to both learn the features and do the classification automatically. Two types of CNNs are used in classification as a two-phase process. The "general" CNN is constructed based on global data and used as the preliminary screening, while "person-specific" CNN is constructed using single individual's data and applied as the fine-grained identification. The two-phase identification enables efficient recognition while guarantees a high specificity. Finger ECG signals are collected in different sessions using a mobile device. The proposed algorithm is tested on both within and across session data sets, and on different sample sizes. Results show that the proposed method achieves promising performance in authentication, with a 2.0% EER over 12000 beats. Due to its simple nature, the proposed system is highly applicable for practical application. PMID- 30440407 TI - Arrhythmia Classification from Single Lead ECG by Multi-Scale Convolutional Neural Networks. AB - Arrhythmia refers to any abnormal change from the normal electrical impulses of the heart. Some arrhythmias are manifested as abnormal heartbeat. Effective heartbeat classification is helpful for computer aided diagnosis. Conventional heartbeat classification methods work on information of multiple leads, and need heuristic or hand-crafted feature extraction. In this paper, we propose a new heartbeat classification approach based on a recent deep learning architecture called multi-scale convolutional neural networks (MCNN). A unique feature of our work is that we take single lead ECG as input, rhythm information is not taken into consideration. Such a single-lead setting, although more challenging than multi-lead cases, is often faced in medical practice due to advancements in mobile ECG devices and hence much needed. We exploit the power of convolutional neural networks for find discriminative features in heartbeat time series. The algorithm was tested on public datasets. The overall accuracy is 0.8866, the accuracy on supraventricular ectopic beat is 0.9600, and accuracy on ventricular ectopic beat is 0.9250. The performance is comparable with conventional method using features hand crafted by human experts. PMID- 30440408 TI - Machine Learning of Spatiotemporal Bursting Behavior in Developing Neural Networks. AB - As with other modern sciences (and their computational counterparts), neuroscience experiments can now produce data that, in terms of both quantity and complexity, challenge our interpretative abilities. It is relatively common to be faced with datasets containing many millions of neural spikes collected from tens of thousands of neurons. Traditional data analysis methods can, in a relatively straightforward manner, identify large-scale features in such data (e.g., on the scale of entire networks). What these approaches often cannot do is to connect macroscopic activity to the relevant small-scale behaviors of individual cells, especially in the face of ongoing background activity that is not relevant. This communication presents an application of machine learning techniques to bridge the gap between microscopic and macroscopic behaviors and identify the small scale activity that leads to large-scale behavior, reducing data complexity to a level that can be amenable to further analysis. A small number of spatiotemporal spikes (among many millions) were found to provide reliable information about if and where a burst will occur. PMID- 30440409 TI - Detection of Early Stage Alzheimer's Disease using EEG Relative Power with Deep Neural Network. AB - Electroencephalogram (EEG) signal based early diagnosis of Alzheimer's Disease (AD), especially a discrimination between healthy control (HC) and mild cognitive impairment (MCI) has received remarkable attentions to complement conventional diagnosing methods in clinical fields. A relative power (RP) metric which quantifies the abnormal EEG pattern 'slowing' has widely been used as a major feature to distinguish HC and MCI, however, the optimal spectral ranges of the RP are influenced by the given dataset. In this study, we proposed the deep neural network based classifier using the RP to fully exploit and recombine the features through its own learning structure. The DNN enhanced the diagnosis results compared to shallow neural network, and enabled to interpret the results as we used the wellknown RP features as the domain knowledge. We investigated and explored the potentials of DNN based detection of the earlystage AD. PMID- 30440410 TI - Crackle and Breathing Phase Detection in Lung Sounds with Deep Bidirectional Gated Recurrent Neural Networks. AB - In this paper, we present a method for event detection in single-channel lung sound recordings. This includes the detection of crackles and breathing phase events (inspiration/expiration). Therefore, we propose an event detection approach with spectral features and bidirectional gated recurrent neural networks (BiGRNNs). In our experiments, we use multichannel lung sound recordings from lung-healthy subjects and patients diagnosed with idiopathic pulmonary fibrosis, collected within a clinical trial. We achieve an event-based F-score of F1 ~ 86% for breathing phase events and F1 ~ 72% for crackles. The proposed method shows robustness regarding the contamination of the lung sound recordings with noise, bowel and heart sounds. PMID- 30440411 TI - Enhanced Error Decoding from Error-Related Potentials using Convolutional Neural Networks. AB - Error-related potentials are considered an important neuro-correlate for monitoring human intentionality in decision-making, human-human, or human-machine interaction scenarios. Multiple methods have been proposed in order to improve the recognition of human intentions. Moreover, current brain-computer interfaces are limited in the identification of human errors by manual tuning of parameters (e.g., feature/channel selection), thus selecting fronto-central channels as discriminative features within-subject. In this paper, we propose the inclusion of error-related potential activity as a generalized two-dimensional feature set and a Convolutional Neural Network for classification of EEG-based human error detection. We evaluate this pipeline using the BNCI2020 - Monitoring Error Related Potential dataset obtaining a maximum error detection accuracy of 79.8% in a within-session 10-fold cross-validation modality, and outperforming current state of the art. PMID- 30440412 TI - Biosignal Data Augmentation Based on Generative Adversarial Networks. AB - In this paper, we propose a synthetic generationmethod for time-series data based on generative adversarial networks (GANs) and apply it to data augmentation for biosinal classification. GANs are a recently proposed framework for learning a generative model, where two neural networks, one generating synthetic data and the other discriminating synthetic and real data, are trained while competing with each other. In the proposed method, each neural network in GANs is developed based on a recurrent neural network using long short-term memories, thereby allowing the adaptation of the GANs framework to time-series data generation. In the experiments, we confirmed the capability of the proposed method for generating synthetic biosignals using the electrocardiogram and electroencephalogram datasets. We also showed the effectiveness of the proposed method for data augmentation in the biosignal classification problem. PMID- 30440413 TI - Automated Pain Assessment using Electrodermal Activity Data and Machine Learning. AB - Objective pain assessment is required for appropriate pain management in the clinical setting. However, clinical gold standard pain assessment is based on subjective methods. Automated pain detection from physiological data may provide important objective information to better standardize pain assessment. Specifically, electrodermal activity (EDA) can identify features of stress and anxiety induced by varying pain levels. However, notable variability in EDA measurement exists and research to date has demonstrated sensitivity but lack of specificity in pain assessment. In this paper, we use timescale decomposition (TSD) to extract salient features from EDA signals to identify an accurate and automated EDA pain detection algorithm to sensitively and specifically distinguish pain from no-pain conditions. PMID- 30440414 TI - Convolutional Feature Vectors and Support Vector Machine for Animal Sound Classification. AB - Pattern classification based on deep network outperforms conventional methods in many tasks. However, if the database for training exhibits internal representation that lacks substantial discernibility for different classes, the network is considered that learning is essentially failed. Such failure is evident when the accuracy drops sharply in the experiments performing classification task where the animal sounds are observed similar. To address and remedy the learning problem, this paper proposes a novel approach composed of a combination of multiple CNNs each separately pre-trained for generating midlevel features according to each class and then merged into a combined CNN unit with SVM for overall classification. For experiment, animal sound database that include 3 classes with 102 species is firstly established. From the experimental results using the database, the proposed method is shown to outperform over prominent conventional methods. PMID- 30440415 TI - Enhanced Frequency Difference of Tumor inside Vibrated Tissue by a Compression Cylinder. AB - Breast cancer diagnosis has been mostly accomplished by imaging technologies. These methods have the great advantages of detecting the presence and location of breast cancer. However, it's difficult to distinguish between a benign and malignant tumor in a deep position because both tumor types look similar. In this paper, we vibrated the tissue including tumor from skin with a compression cylinder to analyze the frequency difference for distinguishing the tissue type. Before distinguishing a benign and malignant tumor, it's necessary to validate to distinguish between normal tissue and tumor. The objective is to validate the feasibility of using a compression cylinder that emphasizes the differences in frequency between normal tissue and tumor. In two experiments, we measured the displacement on the surface of a breast phantom vibrated by an impulse hammer. We compared the frequency difference with and without a cylinder. We also studied the frequency changes in the relationship between tumor and cylinder position. We found a 5.0 Hz difference in compliance between normal tissue and the simulated tumor using a compression cylinder. The difference in frequency correlated negatively with distance from the simulated tumor to a compression cylinder. We concluded that a compression cylinder would enhance the frequency difference between normal tissue and a simulated tumor with appropriate configuration. PMID- 30440416 TI - Normalization factor for the assessment of elbow spasticity with passive stretch measurement: maximum torque VS. body weight. AB - Spasticity of the elbow was generally assessed by repeated passive stretch movement, including the modified Ashworth Scale (MAS) from physiotherapist, and biomechanics analysis of the movement. The MAS-based method depends on the subjective evaluations and the performance of biomechanics analysis assessment is affected by the individual difference. Therefore, the normalization to reduce the individual difference for the assessment of spasticity is very important. In this study, the elbow spasticity was assessed with MAS by one skillful physiotherapist and biomechanics measurements during repetitive passive isokinetic movements at velocity of 60 degree$/$second. 20 post-stroke patients with elbow spasticity caused by hemorrhagic cerebral damage were divided into three groups according to the MAS grades (MAS $=1, 1+$, 2). The torque and position were recorded when the patients extension their elbows passively. The mean stiffness and the mean torque features of the passive isokinetic were calculated. Two normalization factors for biomechanics analysis assessment were investigated: body weight normalization factor and maximum isometrics volunteer contraction normalization factor. Spearman correlation analysis was used to investigate the relationship between the features and spasticity grades. The results showed that the correlation between MAS and two biomechanics features (mean stiffness, mean torque) were significant improved. For mean stiffness feature, the correlation coefficients were $-0.313, -0.563$ and -0.603 individually for non-normalization, body weight normalization and maximum isometrics volunteer contraction normalization. For mean torque feature, the correlation coefficients were $-0.260, -0.523$ and 0.691, respectively. These results suggest that the normalization methods would be helpful for the assessment of spasticity in biomechanics and will be a necessary way of spasticity estimation in clinical methods. PMID- 30440417 TI - A Multiclass Arousal Recognition using HRV Nonlinear Analysis and Affective Images. AB - This paper reports on a multiclass arousal recognition system based on autonomic nervous system linear and nonlinear dynamics during affective visual elicitation. We propose a new hybrid method based on Lagged Poincare Plot (LPP) and symbolic analysis, hereinafter called LPPsymb. This tool uses symbolic analysis to evaluate the irregularity of the trends of Lagged Poincare Plot (LPP) quantifiers over the lags, and is here applied to investigate complex Heart Rate Variability (HRV) changes during emotion stimuli. In the experimental protocol 22 healthy subjects were elicited through a passive visualization of affective images gathered from the international affective picture system. LPPsymb and standard HRV analysis (defined in time and frequency domains) were applied to HRV series of one minute length. Then, an ad-hoc pattern recognition algorithm based on quadratic discriminant classifier was implemented and validated through a leave onesubject-out procedure. The best performance of the proposed classification algorithm for recognizing the four classes of arousal was obtained using nine features comprising heartbeat complex dynamics, achieving an accuracy of 71.59%. PMID- 30440418 TI - A Stimulus-Response Processing Framework for Pupil Dynamics Assessment during Iso Luminant Stimuli. AB - Pupil size is governed by the synergic action of the Autonomic Nervous System. Pupil Diameter (PD) is primarily influenced by the light level and it is responsive to variations of global luminance level. However, recent studies have shown that there is also a high-level interpretation which could modulate this physiological response. In this paper, we develop an ad-hoc protocol based on iso luminant stimuli and validate its effectiveness for the analysis of high-level modulation of pupil response. A visual illusion was reproduced from literature and adapted in two different colors. Prior to the response analysis, a reconstruction of the missing data due to blinks and other artifacts were reconstructed by using a recently developed signal reconstruction algorithm (Iterative - Single Spectrum Analysis: I-SSA); then both time and frequency domain parameters were extracted from the PD signal. Results indicate that there are peculiarly different responses to iso-luminant stimuli with different image structures and dominating colors, thus indicating a possible high-level processing mechanism. Our results pave the way for future evaluation of comatose or generic unconscious state based on non-contact pupil dynamics assessment. PMID- 30440419 TI - Improving the performance of hearing aids in noisy environments based on deep learning technology. AB - The performance of a deep-learning-based speech enhancement (SE) technology for hearing aid users, called a deep denoising autoencoder (DDAE), was investigated. The hearing-aid speech perception index (HASPI) and the hearing- aid sound quality index (HASQI), which are two well-known evaluation metrics for speech intelligibility and quality, were used to evaluate the performance of the DDAE SE approach in two typical high-frequency hearing loss (HFHL) audiograms. Our experimental results show that the DDAE SE approach yields higher intelligibility and quality scores than two classical SE approaches. These results suggest that a deep-learning-based SE method could be used to improve speech intelligibility and quality for hearing aid users in noisy environments. PMID- 30440420 TI - Fundamental Heart Sound Classification using the Continuous Wavelet Transform and Convolutional Neural Networks. AB - Correct identification of the fundamental heart sounds is an important step in identifying the heart cycle stages. Heart valve pathologies can cause abnormal heart sounds or extra sounds, and an important distinguishing feature between different pathologies is the timing of these extra sounds in the heart cycle. In the design of an understandable heart sound analysis system, heart sound segmentation is an indispensable step. In this study classification of the fundamental heart sounds using continuous wavelet transform (CWT) scalograms and convolutional neural networks (CNN) is investigated. Classification between the first and second heart sound of scalograms produced by the Morse analytic wavelet was compared for CNN, support vector machine (SVM), and knearest neighbours (kNN) classifiers. Samples of the first and second heart sound were extracted from a publicly available dataset of normal and abnormal heart sound recordings, and magnitude scalograms were calculated for each sample. These scalograms were used to train and test CNNs. Classification using features extracted from a fully connected layer of the network was compared with linear binary pattern features. The CNN achieved an average classification accuracy of 86% when distinguishing between the first and second heart sound. Features extracted from the CNN and classified using a SVM achieved similar results (85.9%). Classification of the CNN features outperformed LBP features using both SVM and kNN classifiers. The results indicate that there is significant potential for the use of CWT and CNN in the analysis of heart sounds. PMID- 30440421 TI - Low Level Texture Features for Snore Sound Discrimination. AB - Snoring is often associated with serious health risks such as obstructive sleep apnea and heart disease and may require targeted surgical interventions. In this regard, research into automatically and unobtrusively analysing the site of blockages that cause snore sounds is growing in popularity. Herein, we investigate the use of low level image texture features in classification of four specific types of snore sounds. Specifically, we explore histogram of local binary patterns (LBP) in dense grid of rectangular regions and histogram of oriented gradients (HOG) extracted from colour spectrograms for snore sound characterisation. Support vector machines with homogeneous mapping are used in the classification stage of the proposed method. Various experimental works are carried out with both LBP and HOG descriptors on the INTERSPEECH ComParE 2017 snoring sub-challenge dataset. Results presented indicate that LBP descriptors are better than the HOG descriptors in snore type detection and fusion of the LBP and HOG descriptors produces stronger results than either individual descriptor. Further, when compared to the challenge baseline and state-of-the-art deep spectrum features, our approach achieved relative percentage increases in unweighted average recall of 23.1% and 8.3% respectively. PMID- 30440422 TI - Influence of MVDR beamformer on a Speech Enhancement based Smartphone application for Hearing Aids. AB - This paper presents the minimum variance distortionless response (MVDR) beamformer combined with a Speech Enhancement (SE) gain function as a real-time application running on smartphones that work as an assistive device to Hearing Aids. It has been shown that beamforming techniques improve the Signal to Noise Ratio (SNR) in noisy conditions. In the proposed algorithm, MVDR beamformer is used as an SNR booster for the SE method. The proposed SE gain is based on the Log-Spectral Amplitude estimator to improve the speech quality in the presence of different background noises. Objective evaluation and intelligibility measures support the theoretical analysis and show significant improvements of the proposed method in comparison with existing methods. Subjective test results show the effectiveness of the application in real-world noisy conditions at SNR levels of -5 dB, 0 dB, and 5 dB. PMID- 30440423 TI - Tracheal Sounds Features Changes in Different Sleep Stages Based on Complex Wavelet Analysis. AB - Breathing sounds analysis during sleep is an informative method to study the upper airway. Different sleep stages may affect the breathing sound features. In this study, the tracheal breathing sounds were recorded from 5 individuals and the complex Gaussian wavelet of the deceleration phase of about 3000 successive breath cycles were calculated. The segmented portions were divided into 30 seconds episodes and the appropriate sleep stage of each segment were labeled. The results showed that the Mahalanobis distance between the real parts of the complex Gaussian wavelet coefficients and the reference distribution of each stage is changing consistently in different sleep stages. PMID- 30440424 TI - Quantitative Assessment of Syllabic Timing Deficits in Ataxic Dysarthria. AB - Parametric analysis of Cerebellar Dysarthria (CD) may be valuable and more informative compared to its clinical assessment. A quantifiable estimation of the timing deficits in repeated syllabic utterance is described in the current study. Thirty-five individuals were diagnosed with cerebellar ataxia to varying degrees and twenty-six age-matched healthy controls were recruited. To automatically detect the local maxima of each syllable in the recorded speech files, a topographic prominence incorporated concept is designed. Subsequently, four acoustic features and eight corresponding parametric measurements are extracted to identify articulatory deficits in ataxic dysarthria. A comparative study on the behaviour of these measures for dysarthric and non-dysarthric subjects is presented in this paper. The results are further explored using a dimensionreduction tool (Principal Component Analysis) to emphasize variation and bring out the strongest discriminating patterns in our feature dataset. PMID- 30440426 TI - Design of Compensated Multi-Channel Dynamic-Range Compressor for Hearing Aid Devices using Polyphase Implementation. AB - Dynamic-range compression (DRC) is widely used in hearing aid devices (HADs) to reduce the wide dynamic range of input speech signal to match the residual dynamic range of people with hearing loss. Most compression systems use multi channel compression to provide more effective and accurate solutions to match input signal with hearing-impaired people's audiogram. However, multi-channel compression introduces distortion to the system, and increases computational complexity. It limits the sampling rate and results in systems latency, hence, introduces difficulty realizing it in real-time. In this paper, a compensation filter is proposed to reduce the distortion, and polyphase implementation is applied to reduce the computational complexity. Objective and subjective tests are conducted to evaluate the quality and intelligibility of the output audio (speech) signal under different noise types and signal to noise ratios (SNRs). PMID- 30440427 TI - Real-time Smartphone application for improving spatial awareness of Hearing Assistive Devices. AB - In this paper, we present an improved version of a Speech source Iocalization method for Direction of Arrival (DOA) estimation using only two microphones. We also present a real-time Android application on a latest smartphone to help improve the spatial awareness of hearing impaired users. Unlike earlier methods, the proposed method is computationally more efficient and fully adaptive to dynamically changing background noise. We compare the performance of proposed method with similar earlier methods and demonstrate significantly lower DOA estimation errors as well as lower computation times. People who find it difficult to localize speech sources during group conversations or social activities can use the 'easy-to-use' Android application. The proposed implementation does not need any additional hardware or external microphone attachments, and can run on any dual-microphone device, such as a smartphone or tablet. PMID- 30440428 TI - Prediction of Physiological Response over Varying Forecast Lengths with a Wearable Health Monitoring Platform. AB - The goal of this study is to characterize the accuracy of prediction of physiological responses for varying forecast lengths using multi-modal data streams from wearable health monitoring platforms. We specifically focus on predicting breathing rate due to its significance in medical and exercise physiology research. We implement a nonlinear support vector machine regression model for accurate prediction of future values of these physiological signals with forecast windows of up to one minute long. We explore the effects of heart rate and various other sensing modalities in prediction of breathing rate. Results reveal that including other physiological responses and activity information captured by inertial measurements in the regression model improves the breathing rate prediction accuracy. We carried out experiments by collecting and analyzing physiological and activity data outside the lab using a wearable platform composed of various off-the-shelf sensors. PMID- 30440429 TI - A new physiological signal acquisition patch designed with advanced respiration monitoring algorithm based on 3-axis accelerator and gyroscope. AB - In a gradually aging society, families and hospitals have a growing demand for reliable and unobtrusive physiological signal monitoring for elderly people. However, the existing respiration rate monitoring methods and algorithms are still unsatisfactory. In this work, we introduce a physiological signal acquisition patch which integrates 3-axis accelerator and 3-axis gyroscope to estimate respiration rate, as well as ECG(electrocardiogram) sensor and surface temperature sensor. A complete set of respiration rate estimation algorithms is embedded in our patch, which can be used to identify whether the patch is worn or not, and to recognize, segment, de-noise and reconstruct the respiration signal. In-situ experiments have been conducted to prove the validity of the algorithms described in this paper and the possibilities of estimating respiration rate using a physiological signal acquisition patch. The mean absolute error (MAE) is 0.11(about +/-0.7 times in a minute), which is the least among similar studies that acquire respiratory rate from 3-axis accelerators or electrocardiogram. PMID- 30440425 TI - Isometry Invariant Shape Descriptors for Abnormality Detection on Brain Surfaces Affected by Alzheimer's Disease. AB - Alzheimer's disease (AD), a progressive brain disorder, is the most common neurodegenerative disease in older adults. There is a need for brain structural magnetic resonance imaging (MRI) biomarkers to help assess AD progression and intervention effects. Prior research showed that surface based brain imaging features hold great promise as efficient AD biomarkers. However, the complex geometry of cortical surfaces poses a major challenge to defining such a feature that is sensitive in qualification, robust in analysis, and intuitive in visualization. Here we propose a novel isometry invariant shape descriptor for brain morphometry analysis. First, we calculate a global area-preserving mapping from cortical surface to the unit sphere. Based on the mapping, the Beltrami coefficient shape descriptor is calculated. An analysis of average shape descriptors reveals that our detected features are consistent with some previous AD studies where medial temporal lobe volume was identified as an important AD imaging biomarker. We further apply a novel patch-based spherical sparse coding scheme for feature dimension reduction. Later, a support vector machine (SVM) classifier is applied to discriminate 135 amyloid-beta positive persons with the clinical diagnosis of Mild Cognitive Impairment (MCI) from 248 amyloid-beta negative normal control subjects. The 5-folder cross-validation accuracy is about 81.82?% on the dataset, outperforming some traditional, Freesurfer based, brain surface features. The results show that our shape descriptor is effective in distinguishing dementia due to AD from age-matched normal aging individuals. Our isometry invariant shape descriptors may provide a unique and intuitive way to inspect cortical surface and its morphometry changes. PMID- 30440430 TI - Smartphone Based Human Breath Analysis from Respiratory Sounds. AB - Human breath analysis plays important role for diagnosis and management of pulmonary diseases to guarantee normal health. The critical task is to distinguish normal and abnormal lung sounds. This research work presents a scheme for breath analysis used to detect irregular patterns occurred in respiratory cycles due to respiratory diseases. After de-noising breath segments using wavelet de-noising method, intrinsic mode functions are extracted with complete ensemble empirical mode decomposition (CEEMD). Instantaneous frequency (IF) and instantaneous envelope are extracted to get robust features for classification. The study contains breath samples captured using smartphone under natural setting. The data set contains 255 breath cycles. For cycle classification, Bag of-word was applied to group segments based features. The support vector machine (SVM) was applied on randomly partitioned data samples. Experiments resulted with performance accuracy of (75.21%+/-2) for asthmatic inspiratory cycles and (75.5%+/-3%) for complete Respiratory Sounds (RS) cycle with diagnostic odds ratio (DOR) of 20.61% and 13.S7% respectively. PMID- 30440431 TI - Systematic Comparison of Respiratory Signals for the Automated Detection of Sleep Apnea. AB - Sleep apnea is one of the most common sleep disorders. It is characterized by the cessation of breathing during sleep due to airway blockages (obstructive sleep apnea) or disturbances in the signals from the brain (central sleep apnea). The gold standard for diagnosing sleep apnea is performing an overnight polysomnography recording which contains, among others, a wide array of respiratory signals. Respiration information can also be extracted from other physiological signals such as an electrocardiogram or from a bio-impedance measurement on the chest. Studies have shown that algorithms can be developed for automated sleep apnea detection using one of these many respiratory signals. In this work, the predictive power of these different respiratory signals is analyzed and compared. The results provide useful insights into the comparative predictive power of the different respiratory signals in a realistic setting for automated sleep apnea detection and provide a basis for the development of less obtrusive measurement techniques. PMID- 30440432 TI - DNN Filter Bank Improves 1-Max Pooling CNN for Single-Channel EEG Automatic Sleep Stage Classification. AB - We present in this paper an efficient convolutional neural network (CNN) running on time-frequency image features for automatic sleep stage classification. Opposing to deep architectures which have been used for the task, the proposed CNN is much simpler However, the CNN's convolutional layer is able to support convolutional kernels with different sizes, and therefore, capable of learning features at multiple temporal resolutions. In addition, the 1-max pooling strategy is employed at the pooling layer to better capture the shift-invariance property of EEG signals. We further propose a method to discriminatively learn a frequency-domain filter bank with a deep neural network (DNN) to preprocess the time-frequency image features. Our experiments show that the proposed 1-max pooling CNN performs comparably with the very deep CNNs in the literature on the Sleep- EDF dataset. Preprocessing the time-frequency image features with the learned filter bank before presenting them to the CNN leads to significant improvements on the classification accuracy, setting the state- of-the-art performance on the dataset. PMID- 30440433 TI - Mobile Apnea Screening System for at-home Recording and Analysis of Sleep Apnea Severity. AB - Obstructive Sleep Apnea (OSA) is a common sleep disorder affecting $>10?%$ of the middle-aged population. The gold standard diagnostic procedure is the Polysomnography (PSG), which is both costly and time consuming. A simple and non expensive screening therefore would be of great value. This study presents a novel at-home screening method for OSA using a smartphone, a microphone and a modified armband, to measure continuous biological signals during a whole night sleep. A signal-processing algorithm was used to classify the subjects, into classes according to severity of the disorder. The system was validated by conducting a routine sleep study parallel to the data acquisition on a total of 23 subjects. Both binary and 4-class classification problems were tested. The binary classifications showed the best results with sensitiv- ities between 92.3 % and 100 %, and accuracies between 78.3 % and 91.3 %. The 4-class classification was not as successful with a sensitivity of 75 %, and accuracies of 56.5 % and 60 %. We conclude that mobile smartphone technology has a potential for OSA ambulatory screening. PMID- 30440434 TI - Sleep Posture Classification Using Bed Sensor Data and Neural Networks. AB - Sleep posture has been shown to be important in monitoring health conditions such as congestive heart failure (CHF), sleep apnea, pressure ulcers, and even blood pressure abnormalities. In this paper, we investigate the use of four hydraulic bed transducers placed underneath the mattress to classify different sleep postures. For classification, we employed a simple neural network. Different combinations of parameters were studied to determine the best configuration. Data were collected on four major postures from 58 subjects. We report the results of classification for different combinations of these four postures. Both 10-Fold and Leave-One-Subject-Out (LOSO) Cross-validations (CV) were used to evaluate the accuracy of our predictions. Our results show that there are multiple configuration settings that make classification accuracy as high as 100% using k Fold CV for all postures. Maximum classification accuracy after applying LOSO is 93% for a two-class classification of separating Left vs. Right lateral positions. The second-best classification accuracy with LOSO is 92% for the classification of lateral versus non-lateral. PMID- 30440435 TI - A Two Stage Approach for the Automatic Detection of Insomnia. AB - Chronic insomnia can significantly impair an individual's quality of life leading to a high societal cost. Unfortunately, limited automated tools exist that can assist clinicians in the timely detection of insomnia. In this paper, we propose a two stage approach to automatically detect insomnia from an overnight EEG recording. In the first stage we trained a sleep stage scoring model and an epoch level insomnia detection model. Both models are deep neural network (DNN)- based which are fed by a set of temporal and spectral features derived from 2 EEG channels. In the second stage we computed two subject-level feature sets. One is computed using the output of the sleep stage scoring model and consists of the sleep stage ratios, the stage pair ratios and the stage transition ratios. The second feature set is derived from the output of the epoch-level insomnia detection model and represents the ratio of detected insomniac epochs in each stage and their average posterior probability. These features are then used to train a final binary classifier to classify each subject as control, i.e., with no sleep complaints, or insomniac. We compared 5 different binary classifiers, namely the linear discriminant analysis (LDA), the classification and regression trees (CART) and the support vector machine (SVM) with linear, Gaussian and sigmoid kernels. The system was evaluated against data collected from 115 participants, 61 control and 54 with insomnia, and achieved $F1$ score, sensitivity and specificity of 0.88, 84% and 91% respectively. PMID- 30440436 TI - The Neurophysiological Effect of Acoustic Stimulation with Real-time Sleep Spindle Detection. AB - Sleep spindle is a salient brain activity found in the sigma frequency range (11 16 Hz) during sleep stage 2. It has been demonstrated that sleep spindle is related to memory consolidation, neurodegenerative disease, and mental disorders. Slow wave activity (0.5-4 Hz) is the most prominent EEG activity during sleep and appears as a large, spontaneous synchronization of cortical neurons. The role of slow wave activity has been proposed to regulate synaptic strength and memory consolidation. Many studies have investigated the effect of acoustic stimuli during the sleep slow wave. However, there have been few studies which investigated an effect of acoustic stimulation during sleep spindle activity. In this study, we examined the neurophysiological effect of acoustic stimulation during sleep spindle activity. We delivered pink noise after the detection of sleep spindle, and surmised that acoustic stimulation after sleep spindle detection may preserve delta activity during ongoing sleep. Further, we observed suppression of the sleep spindle activity around the times of acoustic stimulation and evoked slow wave activity and theta band activity immediately after tone onset. PMID- 30440437 TI - Automatic Identification and Classification of Fetal Heart-Rate Decelerations from Cardiotocographic Recordings. AB - Cardiotocography (CTG) consists in the simultaneous recording of two distinct traces, the fetal heart rate (FHR; bpm) and the maternal uterine contractions (UCs; mmHg). CTG analysis consists in the evaluation of specific features of traces, among which fetal decelerations (DECs) are considered the "center-stage" since possibly related to fetal distress. DECs are classified based on their duration and occurrence in relation to UCs as prolonged, early, late and variable; each class associates to a specific status of the fetus health. Typically, CTG traces are visually interpreted; however, computerized CTG analysis may overcome subjectivity in CTG interpretation. Thus, this study proposes a new automatic algorithm for computerized identification and classification of DECs. The algorithm was tested on the 552 CTG recordings constituting the "CTU-CHB intra-partum CTG database" of Physionet. Of these, 470 (85.15%) were found suitable for automatic DECs identification and classification. Overall, 5888 DECs were identified, of which 3255 (55.28%) were classified while the other 2633 (44.72%) remained unclassified due to very strict preliminary classification criteria (now required for avoiding misclassifications). Among the classified DECs, 468 (14.38%) were classified as prolonged, 1498 (46.02%) as early, 32 (0.98%) as late, 1257 (38.62%) as variable. Thus, among the classified DECs, the most common are the early and the variable ones (overall 84.64%), the occurrence of which ranged from 0 to 14 DECs per recording. These findings are in agreement with what reported in literature. In conclusion, the proposed algorithm for automatic DECs identification and classification represents a useful tool for computerized CTG analysis. PMID- 30440438 TI - A Simple and Robust Method for Determining the Quality of Cardiovascular Signals Using the Signal Similarity. AB - This paper proposes a novel signal quality assessment method for quasi-periodic cardiovascular signals, chiefly focus on the photoplethysmogram (PPG). The proposed method utilizes the fact that most cardiovascular signals are slowly time varying and thus morphological aspects of the two adjacent beats are almost identical. In order to implement this idea, the method first identifies pulse onset to divide the signal into several segments each of which contains one period of the signal. The segmented pulse signals having different pulse durations are then temporarily normalized by resampling them at a specific rate. Finally, the quality of the signals is evaluated as the signal similarity between the two adjacent segments. Optimal thresholds for the classification between high and low-quality PPG signals are determined using the equal training sensitivity and specificity criterion. The proposed method is evaluated using a database where PPG signals are collected during a variety of activities such as cycling exercise. It attains a sensitivity of 97.9%, a specificity of 85.3%, and an accuracy of 93.8%, compared to manually annotated results. The promising results indicate that the proposed method is affordable to simply determine the quality of quasi-periodic cardiovascular signals, particularly PPG signals. In addition, based on the quasi-periodic characteristics of cardiovascular signals, the proposed method can also be used to indicate the reliability and the availability of the collected signals. PMID- 30440439 TI - Pattern Analysis in Physiological Pulsatile Signals: An Aid to Personalized Healthcare. AB - We present a system to analyze patterns inside pulsatile signals and discover repetitions inside signals. We measure dominance of the repetitions using morphology and discrete nature of the signals by exploiting machine learning and information theoretic concepts. Patterns are represented as combinations of the basic features and derived features. Consistency of discovered patterns identifies state of physiological stability which varies from one individual to another. Hence it has immense impact on deriving the accurate physiological parameters for personalized health analytics. Proposed mechanism discovers the regular and irregular patterns by performing extensive analysis on several real life cardiac data sets. We have achieved more than 90% accuracy in identifying irregular patterns using our proposed method. PMID- 30440440 TI - Classification of Cardiovascular Disease via A New SoftMax Model. AB - Cardiovascular disease clinical diagnosis is an essentially problem of pattern recognition. In the traditional intelligent diagnosis, the evaluation of classification algorithm is based on the final accuracy of the disease diagnosis. In this paper, a new classification method called Softmax regression model is proposed and it uses the known state data of two-layer neural network structure of the Softmax regression model for training and learning, and then calculate the probability of reclassification data belonging to each category. These categories are corresponding to the maximum probability and the classification result of the data to be classified. It provides a new method for classification of disease with higher speed and higher accuracy. Experiment is designed to compare with the K-nearest neighbours and BP neural networks, and also verify the classification accuracy of Softmax regression model. ECG data from MIT-BIH open database is considered for the experiment. The correct classification rate of the diagnosis reaches 94.44% which outperforms than K- nearest neighbor method (77.78%) and BP neural network (72.27%) in regards to the detection of the Cardiovascular disease. PMID- 30440441 TI - Spatio-temporal Analysis of Multichannel Atrial Electrograms Based on a Concept of Active Areas. AB - Atrial tachycardia and atrial flutter are frequent arrhythmia that occur spontaneously and after ablation of atrial fibrillation. Depolarization waves that differ significantly from sinus rhythm propagate across the atria with high frequency (typically 140 to 220 beats per minute). A detailed and personalized analysis of the spread of depolarization is imperative for a successful ablation therapy. Thus, catheters with several electrodes are employed to measure multichannel electrograms inside the atria. Here we propose a new concept for spatio-temporal analysis of multichannel electrograms during atrial tachycardia and atrial flutter. It is based on the calculation of simultaneously active areas. The method allows to identify atrial tachycardia and to automatically distinguish between subtypes of focal activity, micro-reentry and macro-reentry. PMID- 30440442 TI - Robust Heart Rate Estimation During Physical Exercise Using Photoplethysmographic Signals. AB - A method for estimating heart rate (HR) from photoplethysmographic (PPG) signal, during physical exercise, is presented in this paper. Accurate and reliable estimation of HR from PPG during intensive physical activity is challenging because intense motion artifacts can easily mask the true HR. If PPG signal is contaminated by intense motion artifacts, the highest peak of PPG spectrum is shifted from true HR due to motion artifacts. The proposed method employs a simple technique using spectral estimation and median filtering for HR estimation from intensely motion artifacts corrupted PPG signal. Experimental result for a database of 12 subjects recorded during fast running showed that the average absolute estimation error was 1.31 beats/minute. PMID- 30440443 TI - Real-time Evaluation of ECG Acquisition Systems through Signal Quality Assessment in Horses during Submaximal Treadmill Test. AB - This paper reports on a novel real time index designed to assess the quality of electrocardiographic (ECG) traces recorded in a group of five horses during a submaximal treadmill test procedure. During the experimental protocol two ECG monitoring systems were simultaneously applied to the animals. The first system was equipped with textile electrodes while the second one with standard red-dot electrodes. The procedure comprised four phases with an increased treadmill velocity, specifically, Walk 1, Trot 1, Trot 2 and Gallop. Three signal quality levels have been fixed according to the amount of noise present in the ECG trace: good (G), acceptable (A), and unacceptable (U). Moreover, a statistical comparison between textile and red-dot electrodes has been performed in terms of percentage of signal belonging to each class. Even if preliminary, results showed that in each experimental phase textile electrodes are more robust to movement artifacts with respect to the reddot showing a significant evidence of their better performance. These results enable to design robust wearable monitoring systems suitable to improve the quality of collected ECG, reducing the great amount of motion artifacts due to red-dot electrode application and leading to a more accurate diagnosis of high speed arrhythmias. PMID- 30440444 TI - Performance Evaluation of Processing Methods for Ballistocardiogram Peak Detection. AB - Several methods are proposed in the literature to detect ballistocardiogram (BCG) peaks. There is a need to narrow these methods down in terms of their performance under similar conditions. This study reports early results from a systematic performance evaluation. To date, we have replicated three methods from the literature and compared their performance using data from five volunteers. A basic cross-correlation approach was also included as a baseline level of performance. The best-performing method had an average peak-detection success rate of 95.0{%, associated with 0.1090 average false alarms per second and 0.0078 s mean standard deviation between real and detected peaks. PMID- 30440445 TI - Closed-loop administration of analgesic drugs based on heart rate variability analysis. AB - General anesthesia is based on the use of hypnotic, muscle relaxant and analgesic drugs in order to render the patient unresponsive to the surgical procedure. The difficulty for anesthesiologists is then to determinate the minimum efficient dose to avoid any risk of under or over dosing. For several years, monitoring systems were developed in order to measure depth of hypnosis, myorelaxation and analgesia. As soon as all these monitoring systems became available, several teams worked on the closed-loop administration of anesthetic agents. We have developed a closed-loop system allowing the automatic administration of analgesic drugs. This system is based on the analysis of a heart rate variability based index: the ANI (Analgesia Nociception Index). In this paper, we describe this device and demonstrate its efficiency, repeatability and safety in a simulation environment. PMID- 30440446 TI - Insights on Spectral Measures for HRV Based on a Novel Approach for Data Acquisition. AB - In this paper, we present new insights on classical spectral measures for heart rate variability (HRV), based on a novel method for HRV acquisition. A dynamic breathing task, where the test participants are asked to breathe following a metronome with slowly increasing frequency, allows for the acquisition of respiratory-related HRV-data covering the frequency range in which adults breathe in different everyday situations. We discuss how the use of a time-frequency representation, e.g. the spectrogram or the Wigner-Ville distribution, should be preferred to the traditional use of the periodogram, due to the non-stationarity of the data. We argue that this approach can highlight the correlation of spectral measures such as low-frequency and high-frequency HRV with relevant factors as age, gender and Body-Mass-Index, thanks to the improved quality of the spectral measures. PMID- 30440447 TI - CHF Detection with LSTM Neural Network. AB - Heart rate variability has been proven to be an effective prediction of risk of heart failure. The tradition method required manual feature extraction, thus may lead to potential error. In order to improve the robustness, a deep learning method based on long short-term memory has been presented in this paper. Three RR interval length (N) for detection are used. Without pre-processing, this method obtain 82.47%, 85.13% and 84.91% accuracy for N=50 (average time length is 37. 8s), N=100 (average time length is 73. 9s), N=500 (average time length is 369. 5s), respectively. This method makes it possible to detect CHF through intelligent hardware or mobile application. PMID- 30440448 TI - Model-Based Classification of Heart Rate Variability. AB - Several Heart Rate Variability (HRV) based novel methodologies for describing heart rate dynamics have been proposed in the literature with the aim of risk assessment. One such methodology is ARFIMA-EGARCH modeling which allows the quantification of long range dependence and time-varying volatility with the aim of describing non-linear and complex characteristics of HRV. This study applies the ARFIMA-EGARCH modeling of HRV recordings from 30 patients of the Noltisalis database to investigate the discrimination power of a set of features comprising currently used linear HRV features (low and high frequency components) and new measures obtained from the modeling such as, long memory in the mean, and persistence and asymmetry in volatility. A subset of the multidimensional HRV features is selected in a two-step procedure using Principal Components Analysis (PCA). Additionally, supervised classification by quadratic discriminant analysis achieves 93.3% of discrimination accuracy between the groups using the new feature set created by PCA. PMID- 30440449 TI - A Case for the Interspecies Transfer of Emotions: A Preliminary Investigation on How Humans Odors Modify Reactions of the Autonomic Nervous System in Horses. AB - We examined the Autonomic Nervous System (ANS) activity of horses in response to human body odors (BOs) produced under happy and fear states. The ANS response of horses was analyzed in terms of Heart Rate Variability (HRV) features extracted in the frequency domain. Our results revealed that human BOs induce sympathetic and parasympathetic changes and stimulate horses emotionally, suggesting interspecies transfer of emotions via BOs. These preliminary findings open the way to measure changes in horse's ANS dynamics in response to human internal states via human BOs, and allow us to better understand unexpected animal behavior that could compromise human-horse interaction. Moreover, it becomes possible to design more effective strategies to manage animals across a range of situations in which a strict humananimal interaction is required, such as the well known Animal Assisted Therapy (AAT). PMID- 30440450 TI - Comparative Study on Heart Rate Variability Analysis for Atrial Fibrillation Detection in Short Single-Lead ECG Recordings. AB - Detection of atrial fibrillation (AFib) using wearable ECG monitors has recently gained popularity. The signal quality of such recordings is often much lower than that of traditional monitoring systems such as Holter monitors. Larger noise contamination can lead to reduced accuracy of the QRS detection which is the basis of the heart rate variability (HRV) analysis. Hence, it is crucial to accurately classify short ECG recording segments for AFib monitoring. A comparative study was conducted to investigate the applicability and performance of a variety of HRV feature extraction methods applied to short single lead ECG recordings to detect AFib. The data employed in this study is the publicly available dataset of the 2017 PhysioNet challenge. In particular, detection of AFib against non-AFib instances, including normal sinus rhythm, other types of arrhythmias and noisy signals, is investigated in this study. The HRV features can be divided into the categories of statistical, geometrical, frequency, entropy, Poincare plotand Lorentz plot-based. For feature selection, stepwise forward selection approach was employed and support vector machines with linear and radial basis function kernels were used for classification. The results indicate that a combination of features from all the categories leads to the highest accuracy levels. The feasibility of using different HRV features for short signals is discussed as well. In conclusion, AFib can be detected with high accuracy using short single-lead ECG signals using HRV features. PMID- 30440451 TI - Emotion Recognition from EEG and Facial Expressions: a Multimodal Approach. AB - The understanding of a psychological phenomena such as emotion is of paramount importance for psychologists, since it allows to recognize a pathology and to prescribe a due treatment for a patient. While approaching this problem, mathematicians and computational science engineers have proposed different unimodal techniques for emotion recognition from voice, electroencephalography, facial expression, and physiological data. It is also well known that identifying emotions is a multimodal process. The main goal in this work is to train a computer to do so. In this paper we will present our first approach to a multimodal emotion recognition via data fusion of Electroencephalography and facial expressions. The selected strategy was a feature-level fusion of both Electroencephalography and facial microexpressions, and the classification schemes used were a neural network model and a random forest classifier. Experimental set up was out with the balanced multimodal database MAHNOB-HCI. Results are promising compared to results from other authors with a 97% of accuracy. The feature-level fusion approach used in this work improves our unimodal techniques up to 12% per emotion. Therefore, we may conclude that our simple but effective approach improves the overall results of accuracy. PMID- 30440452 TI - Eigendecomposition-based Interference Suppression for Ultra-Wideband Impulse Radio Life Detection. AB - Life detection using ultra-wideband impulse radar is susceptible to various kinds of interference, including dominant background clutter, radio frequency interference (RFI), disturbance caused by the radar hardware, thermal noise, etc. An interference suppression algorithm based on eigendecomposition is proposed. In the fast-time domain, the proposed algorithm has the ability to remove the interferences in the radar operating band. In the slow-time domain, the proposed algorithm can suppress the interferences in the respiratory signal frequency band, 0.17 to 2HZ. Experimental results demonstrate that the proposed algorithm further improves SNR without respiratory signal suppression. PMID- 30440453 TI - Quantitative Characteristics of Hypsarrhythmia in Infantile Spasms. AB - Infantile spasms is a type of epilepsy characterized by clinical seizures termed "spasms" and often an electroencephalographic (EEG) pattern known as hypsarrhythmia. Multiple studies have shown that the interrater reliability for human visual recognition of hypsarrhythmia is poor. Quantitative measurements of this EEG pattern would provide objective basis for identification; however, the basic temporal and spectral characteristics of hypsarrhythmia have never been assessed. Thus, we measured EEG amplitude and power spectra in 21 infantile spasms patients before and after treatment, as well as 21 control subjects. The hypsarrhythmia EEG pattern was associated with (1) high broadband amplitude, especially in frontal and central brain regions, (2) high median power in the delta and alpha frequency bands, and (3) low spectral edge frequency. Our results indicate that hypsarrhythmia can be quantitatively distinguished from data without hypsarrhythmia. Introduction of these quantitative measures into clinical practice may increase diagnostic accuracy, expediting proper treatment and improving outcomes. PMID- 30440454 TI - Dengue Fever Detecting System Using Peak-detection of Data from Contactless Doppler Radar. AB - Infectious diseases, such as dengue fever and Middle East respiratory syndrome, have become prevalent worldwide in recent times. To conduct highly accurate and effective infection screening, we are working on the development of a contactless infection screening system using Doppler radar and thermography. In our previous work, three parameters (face temperature, heartbeat rate, and respiration rate) were used to judge whether a subject was infected. However, facial temperature measurements may be vastly different from temperatures measured at the axilla owing to influence from the immediate environment. In this study, heartbeat rate (HR), respiration rate (RR), and standard deviation of heartbeat interval (SDHI) were used to quantify the infection screening system without using facial temperature as a parameter. We found that respiratory sinus arrhythmia (RSA) diminished in patients who had dengue fever. We gathered data from 47 patients with dengue fever using a 10-GHz Doppler radar system at the National Hospital of Tropical Diseases (NHTD) in Hanoi, Vietnam. To evaluate the accuracy, the data of these patients were compared to that of 23 unaffected subjects. We observed that a linear discriminant analysis (LDA) was effective at detecting the dengue fever conditions, and the detection accuracy was approximately 97.6%. PMID- 30440455 TI - Brain-to-brain synchronization of the expectation of cooperation behavior: A fNIRS hyperscanning study. AB - Expectation of cooperation (hereafter EOC) plays an important role in social dilemmas. In the present study, participant dyads performed an improved prisoner's dilemma game, with their prefrontal cortex and inferior frontal gyrus recorded via the functional near-infrared spectroscopy (fNIRS) hyperscanning technique. Inter brain results indicated significant inter-brain neural synchronization (INS) across participant pairs' inferior frontal gyrus (IFG) in high-powered incentives and defective expectation. Furthermore, the agreeableness proved to be a predictor of cooperative expectation in the inter brain frame. These results may revealed the inter-brain underlying substrate of EOC in social dilemmas and indicated the involvement of the mentalizing network and human mirror neuron system network in social dilemmas. PMID- 30440456 TI - Brain tumor segmentation on Multimodal MRI scans using EMAP Algorithm. AB - The utilization of digital images is becoming popular in multiple areas such as clinical applications. There are multiple diagnostic and machine vision-based applications, where image processing plays a vital role in analyzing, interpreting, and solving the problem. Digital image processing techniques are used to increase the quality of images for human interpretation and machine perception. Tumor segmentation in brain magnetic resonance (MRI) volumes is considered as a complex task because of tumor shape, location, and texture. Manual segmentation is a time-consuming task that can be inaccurate due to an increasing volume of MR scanning performed. The goal of this research is to propose an automated method that can identify the whole tumor in each slice in volumetric MRI brain images, and find out the sub-tumor (core tumor, enhancing and non-enhancing) regions. The proposed algorithm is fully automated to segment out both high-grade glioma (HGG) and low-grade glioma (LGG), using the information provided by a sequence of MRI volumes. The designed algorithm does not require any training database and estimates the tumor regions independently using image processing techniques based on expectation maximization and K-mean clustering. The method is evaluated on BRATS 2015 dataset of LGG and HGG MR volumes. The average DICE score achieved by using the proposed technique is 0.92 and is comparable to state-of-the-art techniques which rely on computationally expensive algorithms. PMID- 30440457 TI - Heritability of nested hierarchical structural brain network. AB - When a brain network is constructed by an existing parcellation method, the topological structure of the network changes depending on the scale of the parcellation. To avoid the scale dependency, we propose to construct a nested hierarchical structural brain network by subdividing the existing parcellation hierarchically. The method is applied in diffusion tensor imaging study of 111 twins in characterizing the topology of the brain network. The genetic contribution of the whole brain structural connectivity is determined and shown to be robustly present over different network scales. PMID- 30440458 TI - Abnormal Dynamic Functional Network Connectivity and Graph Theoretical Analysis in Major Depressive Disorder. AB - Major depressive disorder (MDD) is a complex mood disorder characterized by persistent and overwhelming depression. Previous studies have identified abnormalities in large scale functional brain networks in MDD, yet most of them were based on static functional connectivity. By contrast, here we explored disrupted topological organization of dynamic functional network connectivity (dFNC) in MDD based on graph theory. 182 MDD patients and 218 healthy controls were included in this study, all Chinese Han people. By applying group information guided independent component analysis (GIG-ICA) on resting-state fMRI data, the dFNCs of each subject were estimated using a sliding window method and k-means clustering. Five dynamic functional states were identified, three of which demonstrated significant group difference on the percentage of state occurrence. Interestingly, MDD patients spent much more time in a weakly connected state 2, which is associated with self-focused thinking, a representative feature of depression. In addition, the abnormal FNCs in MDD were observed connecting different networks, especially among prefrontal, sensorimotor and cerebellum networks. As to network properties, MDD patients exhibited increased node efficiency in prefrontal and cerebellum. Moreover, three dFNCs with disrupted node properties were commonly identified in different states, which are also correlated with depressive symptom severity and cognitive performance. This study is the first attempt to investigate the dynamic functional abnormalities in Chinese MDD using a relatively large sample size, which provides new evidence on aberrant time-varying brain activity and its network disruptions in MDD, which might underscore the impaired cognitive functions in this mental disorder. PMID- 30440459 TI - Tracing Tubular Structures from Teravoxel-Sized Microscope Images. AB - Tracing vasculature and neurites from teravoxel sized light-microscopy data-sets is a challenge impeding the availability of processed data to the research community. This is because (1) Holding terabytes of data during run-time is not easy for a regular PC. (2) Processing all the data at once would be slow and inefficient. In this paper, we propose a way to mitigate this challenge by Divide Conquer and Combine (DCC) method. We first split the volume into many smaller and manageable sub-volumes before tracing. These sub-volumes can then be traced individually in parallel (or otherwise). We propose an algorithm to stitch together the traced data from these sub-volumes. This algorithm is robust and handles challenging scenarios like (1) sub-optimal tracing at edges (2) densely packed structures and (3) different depths of trace termination. We validate our results using whole mouse brain vasculature data-set obtained from the Knife-Edge Scanning Microscopy (KESM) based automated tissue scanner. PMID- 30440460 TI - Performance of Registration Tools on High-Resolution 3D Brain Images. AB - Recent progress in tissue clearing allows the imaging of entire organs at single cell resolution. A necessary step in analysing these images is registration across samples. Existing methods of registration were developed for lower resolution image modalities (e.g., MRI) and it is unclear whether their performance and accuracy is satisfactory at this larger scale (several gigabytes for a whole mouse brain). In this study, we evaluated five freely available image registration tools. We used several performance metrics to assess accuracy, and completion time as a measure of efficiency. The results of this evaluation suggest that ANTS provides the best registration accuracy, while Elastix has the highest computational efficiency among the methods with an acceptable accuracy. The results also highlight the need to develop new registration methods optimised for these high-resolution 3D images. PMID- 30440461 TI - Towards An Open-Source Framework For The Analysis Of Cerebrovasculature Structure. AB - The use of graphs to analyze cerebrovascular networks is quite common in studies of the microcirculation. While we have learned a lot from studies utilizing graphs as a tool for the analysis of microvessels, most methodologies for these procedures have only been described in brief and most are not publicly accessible. In this work, we introduce the foundation for an anticipated open source framework that we hope will streamline the analysis of cerebrovascular structure. We believe that a standardized and accessible framework for the analysis vascular filaments is not only needed, but is necessary, for studies charting the microcirculation on image volumes spanning several grains of tissue. We set forth the foundations for a comprehensive and complete framework in our current work. PMID- 30440462 TI - Transcranial Sonography Based Diagnosis Of Parkinson's Disease Via Cascaded Kernel RVFL. AB - The transcranial sonography (TCS) based computer-aided diagnosis (CAD) for Parkinson's disease (PD) has attracted considerable attention. The learning using privileged information (LUPI) is a new learning paradigm, in which, the privileged information (PI) is only available for model training, but unavailable in the testing stage. The Random vector functional link network plus (RVFL+) algorithm is a newly proposed LUPI algorithm, which has shown its effectiveness for classification task. Moreover, the kernel-based RVFL+ (KRVFL+) has been proposed to overcome the randomness in RVFL+. In this work, we propose a cascaded KRVFL+ (cKRVFL+) algorithm for the single-modal TCS-based PD diagnosis. The predicted value of the former KRVFL+ classifier is adopted as the PI for the current KRVFL+, and only the KRVFL+ in the last layer is finally used as classifiers during the testing stage. This cascaded structure progressively promotes the discrimination performance of KRVFL+ classifier. The experimental results show the effectiveness of the cascaded LUPI classifier framework for single-modality TCS based diagnosis of PD, and the proposed cKRVFL+ algorithm achieves the best performance. PMID- 30440464 TI - Detecting Intracranial Hemorrhage with Deep Learning. AB - Initial results are reported on automated detection of intracranial hemorrhage from CT, which would be valuable in a computer-aided diagnosis system to help the radiologist detect subtle hemorrhages. Previous work has taken a classic approach involving multiple steps of alignment, image processing, image corrections, handcrafted feature extraction, and classification. Our current work instead uses a deep convolutional neural network to simultaneously learn features and classification, eliminating the multiple hand-tuned steps. Performance is improved by computing the mean output for rotations of the input image. Postprocessing is additionally applied to the CNN output to significantly improve specificity. The database consists of 134 CT cases (4,300 images), divided into 60, 5, and 69 cases for training, validation, and test. Each case typically includes multiple hemorrhages. Performance on the test set was 81% sensitivity per lesion (34/42 lesions) and 98% specificity per case (45/46 cases). The sensitivity is comparable to previous results (on different datasets), but with a significantly higher specificity. In addition, insights are shared to improve performance as the database is expanded. PMID- 30440463 TI - Cold Water Pressor Test Differentially Modulates Functional Network Connectivity in Fibromyalgia Patients Compared with Healthy Controls. AB - Fibromyalgia is a multifaceted chronic pain condition of unknown etiology. Conditioned pain modulation (CPM) such as cold water pressor test of the foot, is widely documented as being disrupted in patients with fibromyalgia. To date, the mechanisms underlying such dysregulation of the descending control of pain in fibromyalgia remain poorly understood. In this study, we used ICA-based network analysis to comprehensively compare differences in functional network connectivity among relevant (nonartifactual) intrinsic connectivity brain networks during the resting state before and after cold pressor test in patients with fibromyalgia and healthy controls. The results revealed significant differences in functional connectivity between the two groups that included the networks that integrate cognitive control and attention systems with memory, emotion and brainstem regions. Specifically, functional connectivity involving central executive network was absent in patients with fibromyalgia compared with controls. Patients showed significant functional connectivity changes involving subcortical and brainstem networks with the sensorimotor and dorsal attention networks. Accordingly, aberrant CPM in patients with fibromyalgia may be due to the differences in functional connectivity involving the subcortical/brainstem regions, and is facilitated by the recruitment of the dorsal attention network in lieu of the central executive network. Future research replicating the present findings with larger sample size can shed more light on neurobiology of endogenous pain modulation in fibromyalgia. PMID- 30440465 TI - Structural connectome of the human vestibular, pre-motor, and navigation network. AB - The aim of this study is to characterize modules and hubs within the multimodal vestibular system and, particularly, to test the centrality of posterior peri sylvian regions. Structural connectivity matrices from 50 unrelated healthy right handed subjects from the Human Connectome Project (HCP) database were analyzed using multishell diffusion-weighted data, probabilistic tractography (constrained spherical-deconvolution informed filtering of tractograms) in combination with subject-specific grey matter parcellations. Network nodes included parcellated regions within the vestibular, pre-motor and navigation system. Module calculation produced two and three modules in the right and left hemisphere, respectively. On the right, regions were grouped into a vestibular and pre-motor module, and into a visual-navigation module. On the left this last module was split into an inferior and superior component. In the thalamus, a region comprising the mediodorsal and anterior complex, and lateral and inferior pulvinar, was included in the ipsilateral navigation module, while the remaining thalamus was clustered with the ipsilateral vestibular pre-motor module. Hubs were located bilaterally in regions encompassing the inferior parietal cortex and the precuneus. This analysis revealed a dorso-lateral path within the multi-modal vestibular system related to vestibular / motor control, and a ventro-medial path related to spatial orientation / navigation. Posterior peri-sylvian regions may represent the main hubs of the whole modular network. PMID- 30440467 TI - An Iterative Diffeomorphic Algorithm for Registration of Subdivision Surfaces: Application to Congenital Heart Disease. AB - In this paper, we present a new diffeomorphic registration algorithm for the registration of 3D models to 3D points. A biventricular template is iteratively fitted to the data by a series of implicitly constrained diffeomorphic linear least squares fits with decreasing regularization weights before performing an explicitly constrained diffeomorphic fit. The algorithm has been tested on a set of manual contours from 20 patients with a variety of congenital heart disease. Registration accuracy was assessed by calculating the mean point-to-point distance and the Dice overlap metric. Results showed that the method was able to accurately fit the biventricular model to 3D points and that the deformable model was able to fit all the pathologies while being diffeomorphic. The algorithm took approximately 5 minutes to fit each case, with an average of 52,580 points per case. PMID- 30440466 TI - Mechanical Activation Computation from Fluoroscopy for Guided Cardiac Resynchronization Therapy. AB - Congestive heart failure is associated with significant morbidity and mortality, as first line treatments are not always effective in improving symptoms and quality of life. Furthermore, 30-50% of patients who are treated with cardiac resynchronization therapy (CRT), a minimally invasive intervention, do not respond when assessed by objective criteria such as cardiac remodeling. Positioning of the left ventricular lead in the latest activating myocardial region is associated with the best outcome. Cardiac magnetic resonance (CMR) imaging can detect scar tissue and interventricular dyssynchrony; improving the outcome of CRT. However, MR is currently not standard modality for CRT due to its cost and limited availability. This paper explores a novel method to exploit interventional X-ray fluoroscopy set up in CRT procedures to gain information on mechanical activation of the myocardium by tracking the movement of vessels overlying to left ventricular myocardium. Fluoroscopic images were labelled, to track branch movement and determine the motion along the main principal component associated with cardiac motion, to optimize lead placement in CRT. A comparison between MR- and fluoroscopy-derived mechanical activation was performed on 9 datasets, showing more than 66% agreement in 8 cases. PMID- 30440468 TI - Lumen Segmentation in Optical Coherence Tomography Images using Convolutional Neural Network. AB - Lumen segmentation in Optical Coherence Tomography (OCT) images is a very important step to analyze points of interest that may help on atherosclerosis diagnostic and treatment. Past studies use many different methods to segment the lumen in IVOCT images, like level set, morphological reconstruction, Markov random fields, and Otsu binarization. Despite Convolutional Neural Networks (CNN) have shown promising results in the image processing area, we did not identify, in the literature, works applying CNN in IVOCT images. In this paper, we present the lumen segmentation using CNN. We evaluated three different CNN architectures. The CNNs were evaluated using three versions from the image dataset, differing from each other by image size (768x768 pixels and 192x192 pixels), and by coordinate system representation (Cartesian and polar). The best results, Accuracy, Dice index and Jaccard index of over 99%, 98% and 97%, respectively, were obtained with the smallest size images represented by polar coordinate system. PMID- 30440469 TI - Corner Detection Based Automatic Segmentation of Bioresorbable Vascular Scaffold Struts in IVOCT Images. AB - Bioresorbable Vascular scaffold (BVS) is a promising type of stent in percutaneous coronary intervention. Struts apposition assessment is important to ensure the safety of implanted BVS. Currently, BVS struts apposition analysis in IVOCT images still depends on manual delineation of struts, which is labor intensive and time consuming. Automatic struts segmentation is highly desired to simplify and speed up quantitative analysis. However, it is difficult to segment struts accurately based on the contour, due to the influence of fractures inside strut and blood artifacts around strut. In this paper, a novel framework of automatic struts segmentation based on four corners is introduced, in which priori knowledge is utilized that struts have obvious feature of box-shape. Firstly, a cascaded AdaBoost classifier based on enriched haar-like features is trained to detect struts corners. Then, segmentation result can be obtained based on the four detected corners of each strut. Tested on five pullbacks consisting of 483 images with strut, our novel method achieved an average Dice's coefficient of 0.82 for strut segmentation areas. It concludes that our method can segment struts accurately and robustly. Furthermore, automatic struts malapposition analysis in clinical practice is feasible based on the segmentation results. PMID- 30440470 TI - Coronary Artery Segmentation by Deep Learning Neural Networks on Computed Tomographic Coronary Angiographic Images. AB - Coronary artery lumen delineation, to localize and grade stenosis, is an important but tedious and challenging task for coronary heart disease evaluation. Deep learning has recently been successful applied to many applications, including medical imaging. However for small imaged objects such as coronary arteries and their segmentation, it remains a challenge. This paper investigates coronary artery lumen segmentation using 3D U-net convolutional neural networks, and tests its utility with multiple datasets on two settings. We adapted the computed tomography coronary angiography (CTCA) volumes into small patches for the networks and tuned the kernels, layers and the batch size for machine learning. Our experiment involves additional efforts to select and test various data transform, so as to reduce the problem of overfitting. Compared with traditional normalization of data, we showed that subject-specific normalization of dataset was superior to patch based normalization. The results also showed that the proposed deep learning approach outperformed other methods, evaluated by the Dice coefficients. PMID- 30440471 TI - CardioXNet: Automated Detection for Cardiomegaly Based on Deep Learning. AB - In this paper, we present an automated procedure to determine the presence of cardiomegaly on chest X-ray image based on deep learning. The proposed algorithm CardioXNet uses deep learning methods U-NET and cardiothoracic ratio for diagnosis of cardiomegaly from chest X-rays. U-NET learns the segmentation task from the ground truth data. OpenCV is used to denoise and maintain the precision of region of interest once minor errors occur. Therefore, Cardiothoracic ratio (CTR) is calculated as a criterion to determine cardiomegaly from U-net segmentations. End-to-end Dense-Net neural network is used as baseline. This study has shown that the feasibility of combing deep learning segmentation and medical criterion to automatically recognize heart disease in medical images with high accuracy and agreement with the clinical results. PMID- 30440472 TI - Quantitative descriptions of extended volume cardiac tissue architecture from multiple large hearts. AB - The arrangement of cardiac cells into strand and sheet-like structures within the heart wall, confers important electrical properties onto heart tissue. Unraveling cardiomyocyte architecture in both healthy and diseased hearts is fundamental to understanding the mechanisms generating normal rhythm and arrhythmia. We analyzed five extended volume serial image stacks of normal pig left ventricular tissue. Analysis included: (1) reconstruction of original tissue volume and shape with non-linear correction maps; (2) segmentation and higher-order descriptions, areas and orientations of laminar structures through the heart wall; (3)computation of fiber directions; (4) computation of tissue connectivity using a shell filter. These measures contributed to a deeper and more objective understanding of cardiac tissue structures and their spatial variation than previously possible. PMID- 30440473 TI - Deep Learning Models Differentiate Tumor Grades from H&E Stained Histology Sections. AB - Aberration in tissue architecture is an essential index for cancer diagnosis and tumor grading. Therefore, extracting features of aberrant phenotypes and classification of the histology tissue can provide a model for computer-aided pathology (CAP). As a case study, we investigate the application of convolutional neural networks (CNN)s for tumor grading and decomposing tumor architecture from hematoxylin and eosin (H&E) stained histology sections of kidney. The former and latter contribute to CAP and the role of the tumor architecture on the outcome (e.g., survival), respectively. A training set is constructed and sample images are classified into six categories of normal, fat, blood, stroma, low-grade granular tumor, and high-grade clear cell carcinoma. We have compared the performances of a deep versus shallow networks, and shown that the deeper model outperforms the shallow network. PMID- 30440474 TI - Temporal Detection of Changes in the Vascularity and Concentration of Pigment Structures of a Skin Lesion. AB - Changes in morphology of a skin Iesion is indicative of melanoma, a deadly type of skin cancer. This paper proposes a temporal analysis approach to monitor the vascular appearance, the pigment structure, and growth of a skin Iesion. A set of digital images of a patients- skin Iesion acquired during follow-up imaging sessions serves as an input to our proposed system. The vascularity of the Iesion is modelled as the Kullback-Leibler (KL) divergence of the skin images- red channel information. The Iesion-s melanin pigment structures are quantified in terms of the textural energy and the ratio of its coverage to the total Iesion area. An optical flow field and related divergence field are implemented to indicate the direction of growth in a Iesion during follow-up image scans. An auto-regressive (AR) model predicts the change in the growth with time. Our results show the capability of the system proposed for real-time as well as off line skin Iesion image analysis. PMID- 30440475 TI - Automatic Detection and Segmentation of Mitochondria from SEM Images using Deep Neural Network. AB - Investigating the link between mitochondrial function and its physical structure is a hot topic in neurobiology research. With the rapid development of Scanning Electron Microscope (SEM), we can look closely into the fine mitochondrial structure with high resolution. Consequently, many meaningful researches have focused on how to detect and segment the mitochondria from EM images. Due to the complex background, hand-crafted features designed by traditional algorithms cannot provide satisfying results. In this paper, we propose an effective deep neural network improved from Mask R-CNN to produce the detection and segmentation results. On this base, we use the morphological processing and mitochondrial context information to rectify the local misleading results. The valuation was performed on two widely used datasets (FIB-SEM and ATUMSEM), and the results demonstrate that the proposed method has comparable performance than state-of-the art methods. PMID- 30440476 TI - Cell Classification in ER-Stained Whole Slide Breast Cancer Images Using Convolutional Neural Network. AB - Hormone receptor status in breast carcinoma is determined primarily to identify patients who may benefit from hormonal therapy. Estrogen receptor (ER) is one of the hormone receptor positive factors which have been recognized as a marker for which women with breast cancer would respond to hormone treatment. We propose a system to classify cells in ER-stained whole slide breast carcinoma images according to their staining strength using convolutional neural network (CNN). The proposed CNN multiclass classifier was tested on a region of 1200 cells, and achieved very promising results, with overall accuracy of 88.8% and AUC score of 97.5%. The proposed system is useful for use in hormone receptor testing, where the outcomes are used to decide whether the cancer is likely to respond to hormonal therapy or other treatments. PMID- 30440477 TI - A Framework for Automatic Recognition of Cell Damage on Microscopic Images using Artificial Neural Networks. AB - Despite several technological advances in the past years, the vast majority of microscopy examinations continue to be performed in a very laborious, time consuming manner, requiring highly experienced personnel to spend several hours to visually examine each microscope slide. Due to recent improvements in modern Digital Image Processing, professionals that work on microscopic exams could benefit from new tools that can apply image processing possibilities to their specific field. We propose a framework consisting of an image segmentation stage, feature extraction, and then a Shallow Neural Network related to human perception. The framework is used to classify among 5 types of animal cell damage analyzed in a case study. The case study used applies the Single Cell Gel Electrophoresis assay (SCGE, also known as comet assay) to the cells of land mollusk Helix aspersa in order to measure the DNA damage caused by mutagenic agents. To train and analyze the performance of our approach, we used a dataset manually segmented by a biologist and comprised of 130 slide samples with labeled cells. Our framework proved to be robust, achieving an average accuracy of 88.3%. PMID- 30440478 TI - Colorization of H&E stained tissue using Deep Learning. AB - Histopathology is a critical tool in the diagnosis and stratification of cancer. Digital Pathology involves the scanning of stained and fixed tissue samples to produce highresolution images that can be used for computer-aided diagnosis and research. A common challenge in digital pathology related to the quality and characteristics of staining, which can vary widely from center to center and also within the same institution depending on the age of the stain and other human factors. In this paper we examine the use of deep learning models for colorizing H&E stained tissue images and compare the results with traditional image processing/statistical approaches that have been developed for standardizing or normalizing histopathology images. We adapt existing deep learning models that have been developed for colorizing natural images and compare the results with models developed specifically for digital pathology. Our results show that deep learning approaches can standardize the colorization of H&E images. The performance as measured by the chi-square statistic shows that the deep learning approach can be nearly as good as current state-of-the art normalization methods. PMID- 30440479 TI - Patch-level Tumor Classification in Digital Histopathology Images with Domain Adapted Deep Learning. AB - Tumor histopathology is a crucial step in cancer diagnosis which involves visual inspection of imaging data to detect the presence of tumor cells among healthy tissues. This manual process can be time-consuming, error-prone, and influenced by the expertise of the pathologist. Recent deep learning methods for image classification and detection using convolutional neural networks (CNNs) have demonstrated marked improvements in the accuracy of a variety of medical imaging analysis tasks. However, most well-established deep learning methods require large annotated training datasets that are specific to the particular problem domain; such datasets are difficult to acquire for histopathology data where visual characteristics differ between different tissue types, in addition to the need for precise annotations. In this study, we overcome the lack of annotated training dataset in histopathology images of a particular domain by adapting annotated histopathology images from different domains (tissue types). The data from other tissue types are used to pre-train CNNs into a shared histopathology domain (e.g., stains, cellular structures) such that it can be further tuned/optimized for a specific tissue type. We evaluated our classification method on publically available datasets of histopathology images; the accuracy and area under the receiver operating characteristic curve (AUC) of our method was higher than CNNs trained from scratch on limited data (accuracy: 84.3% vs. 78.3%; AUC: 0.918 vs. 0.867), suggesting that domain adaptation can be a valuable approach to histopathological images classification. PMID- 30440480 TI - Assessment of disease severity in a Canine Model of Duchenne Muscular Dystrophy: Classification of Quantitative MRI. AB - Duchenne muscular dystrophy (DMD) is a fatal Xlinked muscle disorder caused by mutations in the dystrophin gene with a consequence of progressive degeneration of skeletal and cardiac muscle. Golden retriever muscular dystrophy (GRMD) is a spontaneous X-linked canine model of DMD with similar effects. Due to high soft tissue contrast images, MRI is preferred as a non-invasive method to extract information corresponding to biological characteristics. We propose and evaluate non-invasive MRI-based imaging biomarkers to assess the severity of golden retriever muscular dystrophy (GRMD) using 3T and 4.7T MRI data of nine animals. These imaging biomarkers use first order statistics and texture (assessed by wavelets) in quantitative MRI (qMRI). In a leave-one-sampleout cross-validation framework, we use SVM to differentiate between young and old GRMD animals. The preliminary results show good differentiation between young and old animals for different qMRI sequences and based on a different selection of features. PMID- 30440481 TI - A Comparative Study of Automatic Approaches for Preclinical MRI-based Brain Segmentation in the Developing Rat. AB - Accurate pre-clinical study reporting requires validated processing tools to increase data reproducibility within and between laboratories. Segmentation of rodent brain from non-brain tissue is an important first step in preclinical imaging pipelines for which well validated tools are still under development. The current study aims to clarify the best approach to automatic brain extraction for studies in the immature rat. Skull stripping modules from AFNI, PCNN-3D, and RATS software packages were assessed for their ability to accurately segment brain from non-brain by comparison to manual segmentation. Comparison was performed using Dice coefficient of similarity. Results showed that the RATS package outperformed the others by including a lower percentage of false positive, non brain voxels in the brain mask. However, AFNI resulted in a lower percentage of false negative voxels. Although the automatic approaches for brain segmentation significantly facilitate the data stream process, the current study findings suggest that the task of rodent brain segmentation from T2 weighted MRI needs to be accompanied by a supervised quality control step when developmental brain imaging studies were targeted. PMID- 30440482 TI - Fully Convolutional Mandible Segmentation on a valid Ground- Truth Dataset. AB - This contribution presents the automatic segmentation of the lower jawbone (mandible) in humans' computed tomography (CT) images with the support of trained deep learning networks. CT acquisitions from the mandible frequently include radiological artifacts e.g., from metal dental restorations, ostheosynthesis materials or include trauma related free pieces of bones with missing bone contour anatomy. As a result, manual outlining these slices to generate the ground truth for evaluating segmentation algorithms lead to massive uncertainties and results in significant interphysician disagreement. Simply excluding these slices is also not the option of choice, regarding the treatment outcome. Hence, we defined strict inclusion and exclusion criteria for our datasets to avoid subjectivity or occurring bias in the groundtruth creation. Amongst others, datasets must display a complete physiological mandible without teeth. According to these data selection criteria such images are difficult to find since they originate from the clinical routine and therefore need a medical indication (such as trauma or pathologic lesions) to be provided as CT data. Furthermore, to prove the adequateness of our ground-truth, clinical experts segmented all cases twice manually, showing the great qualitative and quantitative agreement between them. Our dataset collection and the corresponding ground truth is an absolute novelty and the first serious evaluation of segmentation algorithms for the mandible. PMID- 30440483 TI - Fully Convolutional DenseNets for Segmentation of Microvessels in Two-photon Microscopy. AB - Segmentation of microvessels measured using two-photon microscopy has been studied in the literature with limited success due to uneven intensities associated with optical imaging and shadowing effects. In this work, we address this problem using a customized version of a recently developed fully convolutional neural network, namely, FC-DensNets. To train and validate the network, manual annotations of 8 angiograms from two-photon microscopy was used. Segmentation results are then compared with that of a state-of-the-art scheme that was developed for the same purpose and also based on deep learning. Experimental results show improved performance of used FC-DenseNet in providing accurate and yet end-to-end segmentation of microvessels in two-photon microscopy. PMID- 30440484 TI - An mRMR-SVM Approach for Opto-Fluidic Microorganism Classification. AB - The detection of microorganisms is important in numerous applications such as water quality monitoring, blood analysis, and food testing. The conventional detection methods are tedious and labour-intensive. Establish methods involve culturing, counting and identification of the pathogen by an experienced technician which typically can take several days. The use of opto-fluidic technology to capture microorganism images offers 0 route to reduce the overall assay time. However, the detection still requires a trained technician. This paper proposes an image processing method that can be used to classify microorganism images captured by an opto-fluidic set up in an automatic manner. The proposed algorithm incorporates some of the features used in other microorganism image detection methods and proposes two new features-Entropy of Histogram of Oriented Gradients (HOG) and the filtered intensities. In addition, we propose to apply the minimal-Redundancy-Maximal-Relevance (mRMR) criterion to select and rank these features. The probability and joint probability distribution functions of the mRMR are estimated using a Gaussian model and the Kernel Density Estimation model. The performance of the proposed method was validated using SVM and data collected from an experimental setup. The results show that our proposed method outperforms existing methods and is capable of achieving a classification accuracy up to 95.8%. PMID- 30440485 TI - Fusing Results of Several Deep Learning Architectures for Automatic Classification of Normal and Diabetic Macular Edema in Optical Coherence Tomography. AB - Diabetic Macular Edema (DME) is a severe eye disease that can lead to irreversible blindness if it is left untreated. DME diagnosis still relies on manual evaluation from opthalmologists, thus the process is time consuming and diagnosis may be subjective. This paper presents two novel DME detection frameworks: (1) combining features from three pre-trained Convolutional Neural Networks: AlexNet, VggNet and GoogleNet and performing feature space reduction using Principal Component Analysis and (2) a majority voting scheme based on a plurality rule between classifications from AlexNet, VggNet and GoogleNet. Experiments were conducted using Optical Coherence Tomography datasets retrieved from the Singapore Eye Research Institute and the Chinese University Hong Kong. The results are evaluated using a Leave-Two-Patients-Out Cross Validation at the volume level. This method improves DME classification with an accuracy of 93.75%, which is similar to the best algorithms so far on the same data sets. PMID- 30440486 TI - Automated Assessment of Bone Age Using Deep Learning and Gaussian Process Regression. AB - Bone age is an essential measure of skeletal maturity in children with growth disorders. It is typically assessed by a trained physician using radiographs of the hand and a reference model. However, it has been described that the reference models leave room for interpretation leading to a large inter-observer and intra observer variation. In this work, we explore a novel method for automated bone age assessment to assist physicians with their estimation. It consists of a powerful combination of deep learning and Gaussian process regression. Using this combination, sensitivity of the deep learning model to rotations and flips of the input images can be exploited to increase overall predictive performance compared to only using the deep learning network. We validate our approach retrospectively on a set of 12611 radiographs of patients between 0 and 19 years of age. PMID- 30440487 TI - A 3D Convolutional Neural Network Framework for Polyp Candidates Detection on the Limited Dataset of CT Colonography. AB - Proper training of convolutional neural networks (CNNs) requires annotated training datasets oflarge size, which are not currently available in CT colonography (CTC). In this paper, we propose a well-designed framework to address the challenging problem of data shortage in the training of 3D CNN for the detection of polyp candidates, which is the first and crucial part of the computer-aided diagnosis (CAD) of CTC. Our scheme relies on the following two aspects to reduce overfitting: 1) mass data augmentation, and 2) a flat 3D residual fully convolutional network (FCN). In the first aspect, we utilize extensive rotation, translation, and scaling with continuous value to provide numerous data samples. In the second aspect, we adapt the well-known V-Net to a flat residual FCN to resolve the problem of detection other than segmentation. Our proposed framework does not rely on accurate colon segmentation nor any electrical cleansing of tagged fluid, and experimental results show that it can still achieve high sensitivity with much fewer false positives. Code has been made available at: http://github.com/chenyzstju/ctc_screening_cnn. PMID- 30440488 TI - Analysis of DCE-MRI for Early Prediction of Breast Cancer Therapy Response. AB - Positive response to neoadjuvant chemotherapy (NACT) has been correlated to better long-term outcomes in breast cancer treatment. Early prediction of response to NACT can help modify the regimen for non-responding patients, sparing them of potential toxicities of ineffective therapies. It has been observed that tumor functions such as vascularization and vascular permeability change even before noticeable changes occur in the tumor size in response to the treatment. Therefore, it is essential to have reliable imaging based features to measure these changes. Texture analysis on parametric maps from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has shown to be a good predictor of breast cancer response to NACT at an early stage. But hand crafted texture features might not be able to capture the rich spatio-temporal information in the parametric maps. In this work, we studied the ability of convolutional neural networks in predicting the response to NACT at an early stage. PMID- 30440489 TI - Using Multi-level Convolutional Neural Network for Classification of Lung Nodules on CT images. AB - Lung cancer is one of the four major cancers in the world. Accurate diagnosing of lung cancer in the early stage plays an important role to increase the survival rate. Computed Tomography (CT)is an effective method to help the doctor to detect the lung cancer. In this paper, we developed a multi-level convolutional neural network (ML-CNN)to investigate the problem of lung nodule malignancy classification. ML-CNN consists of three CNNs for extracting multi-scale features in lung nodule CT images. Furthermore, we flatten the output of the last pooling layer into a one-dimensional vector for every level and then concatenate them. This strategy can help to improve the performance of our model. The ML-CNN is applied to ternary classification of lung nodules (benign, indeterminate and malignant lung nodules). The experimental results show that our ML-CNN achieves 84.81?% accuracy without any additional hand-craft preprocessing algorithm. It is also indicated that our model achieves the best result in ternary classification. PMID- 30440490 TI - Osteosarcoma Patients Classification Using Plain X-Rays and Metabolomic Data. AB - Osteosarcoma is the most common type of bone cancer. The primary means of osteosarcoma diagnosis is through evaluating plain x-rays. Using image analysis techniques, features that clinicians use to diagnose osteosarcoma can be quantified and studied using computer algorithms. In this paper, we classify benign tumor patients and osteosarcoma patients using both image features and metabolomic data. These two types of feature sets are processed with feature selection algorithms - recursive feature elimination and information gain. The selected features are then assessed by two classification models - random forest and support vector machine (SVM). The performances of the two models are evaluated and compared using receiver operating characteristic curves. The random forest classifier outperformed the SVM, with a sensitivity of .92 and a specificity of .78. PMID- 30440491 TI - Performance Evaluation of Age Estimation from T1-Weighted Images Using Brain Local Features and CNN. AB - The age of a subject can be estimated from the brain MR image by evaluating morphological changes in healthy aging. We consider using two-types of local features to estimate the age from T1-weighted images: handcrafted and automatically extracted features in this paper. The handcrafted brain local features are defined by volumes of brain tissues parcellated into 90 or 1,024 local regions defined by the automated anatomical labeling atlas. The automatically extracted features are obtained by using the convolutional neural network (CNN). This paper explores the difference between the handcrafted features and the automatically extracted features. Through a set of experiments using 1,099 T1-weighted images from a Japanese MR image database, we demonstrate the effectiveness of the proposed methods, analyze the effectiveness of each local region for age estimation and discuss its medical implication. PMID- 30440492 TI - Mahalanobis Outier Removal for Improving the Non-Viable Detection on Human Injuries. AB - Machine learning techniques have been recently applied for discriminating between Viable and Non-Viable tissues in animal wounds, to help surgeons to identify areas that need to be excised in the process of burn debridement. However, the presence of outliers in the training data set can degrade the performance of that discrimination. This paper presents an outlier removal technique based on the Mahalanobis distance to improve the accuracy detection of Non-Viable skin in human injuries. The iteratively application of this technique improves the accuracy results of the Non-Viable skin in a 13.6% when applying K-fold cross validation. PMID- 30440493 TI - A New and Improved Method for Automated Screening of Age-Related Macular Degeneration Using Ensemble Deep Neural Networks. AB - In this paper, we provide a new framework on deep learning based automated screening method for finding individuals at risk of developing Age-related Macular Degeneration (AMD). We studied the appropriateness of using the transfer learning to screen AMD by using color fundus images. We make use of the Age Related Eye Disease Study (AREDS) dataset with nearly 150,000 images, which also provided qualitative grading information by expert graders and ophthalmologists. We use ensemble learning technique with two deep neural networks, namely, Inception-ResNet-V2 and Xception with a custom fine-tuning approach. For our study, we have identified two experiments that are most useful in the screening of AMD. First, we have categorized the images into two classes based on the clinical significance: None or early AMD and Intermediate or Advanced AMD. Second, we have categorized the images into four classes: No AMD, early AMD, Intermediate AMD and Advanced AMD. On AREDS dataset, we have achieved an accuracy of over 95.3% for two-class experiment with our ensemble method. With accuracies ranging from 86% (for four-class) to 95.3% (for two-class), we have demonstrated that the training of a deep neural network with the transfer of learned features with a sufficient number of images fares very well and is comparable to human grading. PMID- 30440494 TI - Automated Classification Using End-to-End Deep Learning. AB - According to a study [1] by the Ministry of Health in Singapore, since 2009, cancer, ischaemic heart disease and pneumonia together accounted for approximately 60% of the total causes of death. It has been 9 years, and Pneumonia and other Acute Upper Respiratory Infections still is one of the top 10 conditions of hospitalization. In cases of respiratory diseases such as Chronic Obstructive Pulmonary Disease (COPD), it has been found that close to 55% of cases are misdiagnosed. This is shocking as, an early diagnosis of respiratory diseases can lead to an earlier treatment intervention, ultimately lessening symptoms, slowing the progression, and improving overall quality of life. With the advent of Deep Neural Network architectures which have shown phenomenal results in the field of Computer Assisted Diagnosis (CAD), we hope to implement a Lung Classification Model using End-to-End Deep learning to classify Chest X-Ray images into one of 14 primary classes of lung diseases. Using our implementation of the Densely Connected Convolutional Neural Network model architecture, we aim to increase existing model accuracy in Lung Disease classification by iteratively reducing the search space and region of interest for different. We shall experiment on a 14-class classification model and compare the results with a binary classifier as well, to understand the performance of DenseNets on Chest X Ray (CXR) Data with a reduced search space. PMID- 30440495 TI - Semi-Supervised Multi-Task Learning for Lung Cancer Diagnosis. AB - Early detection of lung nodules is of great importance in lung cancer screening. Existing research recognizes the critical role played by CAD systems in early detection and diagnosis of lung nodules. However, many CAD systems, which are used as cancer detection tools, produce a lot of false positives (FP) and require a further FP reduction step. Furthermore, guidelines for early diagnosis and treatment of lung cancer are consist of different shape and volume measurements of abnormalities. Segmentation is at the heart of our understanding of nodules morphology making it a major area of interest within the field of computer aided diagnosis systems. This study set out to test the hypothesis that joint learning of false positive (FP) nodule reduction and nodule segmentation can improve the computer aided diagnosis (CAD) systems' performance on both tasks. To support this hypothesis we propose a 3D deep multi-task CNN to tackle these two problems jointly. We tested our system on LUNA16 dataset and achieved an average dice similarity coefficient (DSC) of 91% as segmentation accuracy and a score of nearly 92% for FP reduction. As a proof of our hypothesis, we showed improvements of segmentation and FP reduction tasks over two baselines. Our results support that joint training of these two tasks through a multi-task learning approach improves system performance on both. We also showed that a semi-supervised approach can be used to overcome the limitation of lack of labeled data for the 3D segmentation task. PMID- 30440496 TI - Human-level Performance On Automatic Head Biometrics In Fetal Ultrasound Using Fully Convolutional Neural Networks. AB - Measurement of head biometrics from fetal ultrasonography images is of key importance in monitoring the healthy development of fetuses. However, the accurate measurement of relevant anatomical structures is subject to large inter observer variability in the clinic. To address this issue, an automated method utilizing Fully Convolutional Networks (FCN) is proposed to determine measurements of fetal head circumference (HC) and biparietal diameter (BPD). An FCN was trained on approximately 2000 2D ultrasound images of the head with annotations provided by 45 different sonographers during routine screening examinations to perform semantic segmentation of the head. An ellipse is fitted to the resulting segmentation contours to mimic the annotation typically produced by a sonographer. The model's performance was compared with inter-observer variability, where two experts manually annotated 100 test images. Mean absolute model-expert error was slightly better than inter-observer error for HC (1.99mm vs 2.16mm), and comparable for BPD (0.61mm vs 0.59mm), as well as Dice coefficient (0.980 vs 0.980). Our results demonstrate that the model performs at a level similar to a human expert, and learns to produce accurate predictions from a large dataset annotated by many sonographers. Additionally, measurements are generated in near real-time at 15fps on a GPU, which could speed up clinical workflow for both skilled and trainee sonographers. PMID- 30440497 TI - A novel stacked generalization of models for improved TB detection in chest radiographs. AB - Chest x-ray (CXR) analysis is a common part of the protocol for confirming active pulmonary Tuberculosis (TB). However, many TB endemic regions are severely resource constrained in radiological services impairing timely detection and treatment. Computer-aided diagnosis (CADx) tools can supplement decision-making while simultaneously addressing the gap in expert radiological interpretation during mobile field screening. These tools use hand-engineered and/or convolutional neural networks (CNN) computed image features. CNN, a class of deep learning (DL) models, has gained research prominence in visual recognition. It has been shown that Ensemble learning has an inherent advantage of constructing non-linear decision making functions and improve visual recognition. We create a stacking of classifiers with hand-engineered and CNN features toward improving TB detection in CXRs. The results obtained are highly promising and superior to the state-of-the-art. PMID- 30440498 TI - Ischemic stroke clinical outcome prediction based on image signature selection from multimodality data. AB - Quantitative models are essential in precision medicine that can be used to predict health status and prevent disease and disability. Current radiomics models for clinical outcome prediction often depend on huge amount of image features and may include redundant information and ignore individual feature importance. In this work, we propose a prognostic discrimination ranking strategy to select the most relevant image features for image assisted clinical outcome prediction. Firstly, a redundancy and prognostic discrimination evaluation method is proposed to evaluate and rank a large number of features extracted from images. Secondly, forward sequential feature selection is performed to select the top ranked relevant features in each discriminate quantization. Finally, representative vectors are generated by the fusion of pivotal clinical parameters and selected image signatures to be fed into a classification model. The proposed model was trained and tested over 70 patient studies with six MR sequences and four clinical parameters from ISLES challenges. The evaluations using ROC curves demonstrated the improved performance over five other feature selection models where the proposed model achieved AUCs of 0.821, 0.968, 0.983, 0.896 and 1 when predicting five clinical outcome scores respectively. PMID- 30440499 TI - Merging of Classifiers for Enhancing Viable vs Non-Viable Tissue Discrimination on Human Injuries. AB - Non-invasive optical imaging techniques have been recently proposed for distinguishing between different types of tissue in burns generated in porcine models. These techniques are designed to assist surgeons during the process of burn debridement, to identify regions requiring excision and their appropriate excision depth. This paper presents a machine learning tool for discriminating between Viable and Non- Viable tissues in human injuries. This tool merges a supervised (QDA) with an unsupervised (k-means clustering) classification algorithms. This combination improves the Non-Viable tissue detection in 23.7% with respect to a simple QDA classifier. PMID- 30440500 TI - Automated Assessment of Loss of Consciousness Using Whisker And Paw Movements During Anesthetic Dosing in Head-Fixed Rodents. AB - The precise identification of loss of consciousness (LOC) is key to studying the effects of anesthetic drugs in neural systems. The standard behavioral assay for identifying LOC in rodents is the Loss of Righting Reflex (LORR), assessed by placing the animal in the supine position every minute until it fails to right itself. However, this assay cannot be used when the rodents are head-fixed, which limits the use of powerful techniques such as multi-electrode recordings, in vivo patch clamp, and neuronal imaging. In these situations, an alternative way to assess LOC is needed. We propose that loss of movement (LOM) in whiskers and paws of head-fixed animals can be used as an alternative behavioral assay in head fixed animals. Unlike LORR, LOM in whiskers and paws is much harder to detect by visual inspection. Therefore, we developed a method to automatically assess for LOM of whiskers and paws in head fixed rodents during in vivo patch clamp recordings. Our method uses an algorithm based on optical flow and point-process filtering which can be run on images acquired on regular cameras at low frame rates. We show that the algorithm can achieve at least comparable accuracy in detecting LOC when compared with consensus among human observers, as well as improved precision when compared with individual observers. In the future, we aim to to expand the method to detect more behavioral end-points during anesthesia such as paradoxical excitation. Eventually, we hope to enable multi-modal anesthesia studies, which incorporates behavioral and neurophysiological data. PMID- 30440501 TI - Robotic Path Planning Using A* Algorithm for Automatic Navigation in Magnetic Resonance Angiography. AB - Magnetic resonance navigation (MRN) is an emerging research technique in recent years. The micro/nano robots existing in vessels can be driven by magnetic gradients given by MR scanner. As a non-invasive vascular imaging technique, Magnetic resonance angiography (MRA) is able to provide a vascular network of an anatomy without injection of contrast agent. In order to automatically guide and drive micro/nano robots to target in vascular network, a navigation strategy is desired. In this paper, a novel path planning algorithm based on A* search is proposed. The MRA image is preliminarily processed to extract major vessels. Then, pixel-based A* search algorithm identifies the shortest path between start point and target without human supervision. Experimental results on both of simulation image and MRA image demonstrate that the proposed method is able to accomplish path planning automatically in MRA image. That path can guide the injected micro/nano robots to navigate in the blood vessels. PMID- 30440502 TI - Decision Supporting Model for One-year Conversion Probability from MCI to AD using CNN and SVM. AB - Prediction of Alzheimer's disease (AD) from Mild Cognitive Impairment (MCI) has become popular in recent years. Especially, deep learning technique has been used to extract high-quality features and for classification in this topic. Whether the patient would converse from MCI into AD is a particular evaluation criteria in clinics. However, there is no such a conversion prediction model in literature. Therefore, the purpose of this study is to propose a decision supporting model based on deep learning and machine learning to predict the conversion probability from MCI into AD within one year. We analyzed 165 samples with MRI scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) database, in which all MCI patients were converted into AD in different time span for conversion. In this model, we first extracted image features based on convolutional neural network (CNN) method, and then we used support vector machine (SVM) classifier to classify these features. The results showed that the classification accuracy using linear, polynomial and RBF kernel could achieve 91.0%, 90.0% and 92.3%. As a result, this study indicated that the decision supporting model is potential to be applied into predicting the conversion probability from MCI into AD within one year. PMID- 30440503 TI - Symmetry determined superpixels for efficient lesion segmentation of ischemic stroke from MRI. AB - Non-invasive, quantitative and robust identification of ischemic stroke and estimation of injury extent is essential for assisting neuroradiologists. Manual Iesion delineation techniques are susceptible to subjective errors and therefore computer aided preliminary screening of necrosis is warranted. Superpixel based segmentation has gained importance in the recent past by reducing the computational complexity and preserving the characteristics of a group of pixels with similar properties. Axial and coronal MR images of brain exhibit the important feature of symmetry which was integrated with superpixels for segmenting ischemic Iesion. This method was evaluated on a challenging 10 patient data set along with MICCAI challenge data of 28 patients yielding promising results. Proposed symmetry determined superpixel based method demonstrated accuracy close to manual Iesion demarcation with high performance indices with average sensitivity of 82.32%, specificity of 93.7% and Dice similarity score of81.14%. PMID- 30440504 TI - Breast Region Segmentation being Convolutional Neural Network in Dynamic Contrast Enhanced MRI. AB - Breast density and background parenchymal enhancement (BPE) are suggested to be related to the risk of breast cancer. The first step to quantitative analysis of breast density and BPE is segmenting the breast from body. Nowadays, convolutional neural networks (CNNs) are widely used in image segmentation and work well in semantic segmentation, however, CNNs have been rarely used in breast region segmentation. In this paper, the CNN was employed to segment the breast region in transverse fat-suppressed breast dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). Image normalization was initially performed. Subsequently, the dataset was divided into three sets randomly: train set validation set and test set. The 2-D U-Net was trained by train set and the optimum model was chosen by validation set. Finally, segmentation results of test set obtained by U-Net were adjusted in the postprocessing. In this step, two largest volumes were computed to determine whether the smaller volume is the scar after mastectomy. With the limitation of small dataset, 5-fold cross-validation and data augmentation were used in this study. Final results on the test set were evaluated by volume-based and boundary-based metrics with manual segmentation results. By using this method, the mean dice similarity coefficient (DSC), dice difference coefficient (DDC), and root-mean-square distance reached 97.44%, 5.11%, and 1.25 pixels, respectively. PMID- 30440505 TI - A Novel Multimodal MRI Analysis for Alzheimer's Disease Based on Convolutional Neural Network. AB - Recent years, Alzheimer's disease (AD) has become a significant threat to human health while the accurate screening and diagnosis of AD remain a tough problem. Multimodal Magnetic resonance imaging (MRI) can help to identify the variation of brain function and structure in a non-invasive way. Deep learning, especially the convolutional neural networks (CNN), can be utilized to automatically detect appropriate features for classification, which is well adapted for computer-aided AD screening and identification. This paper proposed a multimodal MRI analytical method based on CNN, which is also suitable for single type MRI data analysis. First, the human brain network connectivity matrix were extracted from multimodal MRI data, used as the input data for CNN. Then a novel CNN framework was proposed to process the network matrix and classify AD, amnestic mild cognitive impairment (aMCI) patients and normal controls (NC). The advantage of this method lies in that we combined multimodal MRI information through CNN convolution kernel, and achieved a higher classification accuracy. In our experiments, the comprehensive classification accuracy of AD, aMCI patients and NC was as high as 92.06% when using multimodal MRI data as input, which is effective enough to provide a reference for multimodal MRI data analysis. PMID- 30440506 TI - A Coupled Modified Reaction Diffusion and Biomechanical Models for Cerebral Tumor Growth Modeling in Presence of Treatment. AB - Tumor growth modeling at macroscopic level from multimodal images can help in predicting the future evolution of tumor and the treatment planning. This can be achieved using mathematical models where multi time-point images are available. In this paper, we propose a coupled modified reaction diffusion model that measures tumor invasion and infiltration with biomechanical model to consider tumor mass effect. In addition, our model considers treatment effects from radiotherapy and/or chemotherapy if any. The chemotherapy effect is included via a modified log-kill method to consider tissue heterogeneity while radiotherapy effect is considered using the linear quadratic model. We test the proposed model on both synthetic and 6 real datasets of low grade glioma cases with and without treatments. Experimental results of the proposed model on the clinical magnetic resonance images show that our model can simulate the tumor growth with good accuracy and effectively include the treatment effects. PMID- 30440507 TI - Effects of non-linear correlation measures on brain functional connectivity in Parkinson's disease. AB - Parkinson's disease (PD) is one of the most prevalent and growing disorders. The most reason for this disease is the abnormalities in brain functional organization of PD patients. Functional magnetic resonance imaging in the resting state (rs-fMRI) is a useful technique to assess brain dysfunctions in patients. The objective of our research is to generate the closest model of complex brain network by different approaches. Hence we constructed the brain graphs employing one linear and three non-linear correlation metrics in order to investigate complicated relations among signals. The local and global metrics of the produced correlation matrices were extracted utilizing graph theory. Evaluating centralization, a global metric, exhibited a decrease in PD patients compared with healthy controls. In addition, we investigated significant changes of nodal degree in patients. The achieved results on graph measures implied alterations of brain functional connectivity. To conclude, we disclosed new findings in brain functional networks of PD patients by non-linear correlation measures. PMID- 30440508 TI - Exudates Segmentation using Fully Convolutional Neural Network and Auxiliary Codebook. AB - Diabetic retinopathy (DR) is an asymptotic complication of diabetes and the leading cause of preventable blindness in the working-age population. Early detection and treatment of DR is critical to avoid vision loss. Exudates are one of the earliest and most prevalent signs of DR. In this work, we propose a novel two-stage method for the detection and segmentation of exudates in fundus photographs. In the first stage, a fully convolutional neural network architecture is trained to segment exudates using small image patches. Next, an auxilary codebook is built from network's intermediate layer output using incremental principal component analysis. Finally, outputs of both systems are combined to produce final result. Compared to other methods, the proposed algorithm does not require computation of candidate regions or removal of other anatomical structures. Furthermore, a transfer learning approach was applied to improve the performance of the system. The proposed method was evaluated using publicly available E-Ophtha datasets. It achieved better results than the state of-the-art methods in terms of sensitivity and specificity metrics. The proposed method accomplished better results using a diseased//not diseased evaluation scenario which indicates its applicability for screening purposes. Simplicity, performance, efficiency and robustness of the proposed method demonstrate its suitability for diabetic retinopathy screening applications. PMID- 30440509 TI - Automatic Vessel Detection Technique in Laparoscopic Surgical Imaging Including Surgical Instruments. AB - In this paper, we propose a new technique to recognize vessels in robot-assisted laparoscopic surgery images by using surgical instruments. The proposed method does not require additional hardware or parameter adjustment because it detects blood vessels by using only the color information of the image. The concept of a hessian matrix is used in the HSV color space of the image to detect the edges of the blood vessels. In addition, the histogram equalization technique, clustering technique, and region growing are used to remove the surgical tools. Images of actual robot-assisted laparoscopic surgery videos were used. The processing speed was approximately 0.3 s per frame at 640p and approximately 0.8 s per frame at 1280p. The average recall was 92.67%. PMID- 30440510 TI - Pose-Invariant Face Detection by Replacing Deep Neurons with Capsules for Thermal Imagery in Telemedicine. AB - The aim of this work was to examine the potential of thermal imaging as a cost effective tool for convenient, nonintrusive remote monitoring of elderly people in different possible head orientations, without imposing specific behavior on users, e.g., looking toward the camera. Illumination and pose invariant head tracking is important for many medical applications as it can provide information, e.g., about vital signs, sensory experiences, injuries, wellbeing. In the performed experiments, we investigated the influence of different modifications of images (rotation, displacement of facial features, and displacement of facial quarters) on the prediction accuracy. Specifically, two models were tested on the set of collected low-resolution thermal images: Inception V3 Convolutional Neural Network (CNN) and Hinton's Capsule Network. The preliminary results confirm that the prediction ability of the model based on capsules can deal with different head orientations much better than CNN (for the 45 degrees head rotation Capsule Network achieved ~% accuracy while CNN only 9.5%). PMID- 30440511 TI - Use of apparent diffusion coefficient images to predict response to induction chemotherapy in sinonasal cancer. AB - The purpose of this study is to identify a set of radiomic features extracted from apparent diffusion coefficient (ADC) maps, obtained using baseline diffusion weighted magnetic resonance imaging (DW-MRI), which are able to predict the outcome of induction chemotherapy (IC) in sinonasal cancers. Such prediction could help the clinician defining the better treatment for a particular patient. Eighty-eight radiomic features were extracted from the ADC maps of 15 patients that underwent IC. A preliminary filtering of the features was made by assessing their stability to geometrical transformations of the region of interest (ROI). Mann-Whitney tests corrected for control of false discoveries were performed to identify the features that could discriminate between responsive and nonresponsive patients (4 and 11 respectively). Twenty features were found to be able to discriminate the two groups and they can potentially be used for prediction of response to treatment. PMID- 30440512 TI - Mathematical Model for Body Fat Percentage in Military using Thermal Imaging and Circumferences. AB - The prevalence of overweight and obesity has gradually increased throughout the world. In this sense, body composition evaluation' methods have gained special attention in some research areas. The aim of this study was to propose a mathematical model to estimate body fat percentage (BF%) of men from thermal imaging and body circumferences variables and using as gold standard values obtained by Dual-Energy XRay Absorptiometry (DXA). This was a cross-sectional study. A Sample of 47 men aged from 18 to 20 years was involved in the study. They were selected among soldiers from Brazilian Army. Data collection was carried out in just one day, in the following sequence: thermal imaging, body fat percentage assessed by DXA and anthropometric measures. It was performed the identification of the skin temperature strongest correlated with BF% in each body segment (trunk, upper and lower limbs). The same procedure was done with anthropometrics variables. After that, these variables were tested in the linear regression model. Waist, abdomen and hip circumferences, as expected, showed strong positive correlations with BF% (r = 0.826, 0.873, and 0.853, respectively). Since the skin temperature values tended to negative correlation with BF%, the best results were found for mean skin temperature of the anterior face of the trunk (r = -0 753) and posterior face (r = -0723). The best model reaches an R square of 0.800 using just one anthropometric and one skin temperature variable (BF% =32.34 + (0.6 x AC) - (1.87 x ATSkTMean)), where AC means abdominal circumference and ATSkTMean means the mean skin temperature from the anterior face of the trunk. The proposed model can be used by Brazilian Army to estimate BF% of soldiers and male military personal aged from 18 to 20 years. PMID- 30440513 TI - Reversible Image Watermarking for Health Informatics Systems Using Distortion Compensation in Wavelet Domain. AB - Reversible image watermarking guaranties restoration of both original cover and watermark logo from the watermarked image. Capacity and distortion of the image under reversible watermarking are two important parameters. In this study, a reversible watermarking is investigated by focusing on increasing the embedding capacity and reducing the distortion in medical images. We use integer wavelet transform for embedding one bit of watermark in a transform coefficient. We devise a novel approach that when a coefficient is modified in one iteration, the produced distortion is compensated in the next iteration. This distortion compensation method would result in low distortion rate. The proposed method is tested on four types of medical images including MRI of the brain, cardiac MRI, MRI of breast and intestinal polyp images. The maximum capacity of 1.5 BPP is obtained by using a one-level wavelet transform. Experimental results demonstrate that the proposed method is superior to the stateof-the-art works in terms of capacity and distortion. PMID- 30440514 TI - MRI Based Brain-Specific 3D-Printed Model Aligned to Stereotactic Space for Registering Histology to MRI. AB - Studies that seek to predict the brain microstructure based on MRI require precise alignment of processed brain histology slices to the corresponding 3D MRI data. However, achieving such alignment is a challenging problem, due to tissue distortions and the different contrasts seen in MRI and the processed tissue. Here we present a pipeline for aligning a histology volume to the MRI data of the tissue and to a stereotaxic brain atlas. To this end, we segment the volume of the brain from ex-vivo MRI data, align the MRI data obtained in the native space to an MRI stereotaxic template and create a 3D printed model (a mold or cradle) that precisely fits the brain. The pipeline then makes it possible to create grooves in the 3D model, for guiding blades for cutting slabs of tissue. Placing the brain in the brain-specific 3D printed model aligns the tissue to the MRI data by default. Aligning the MRI data to an MRI stereotaxic template makes it possible to section histology slices parallel to the standard stereotaxic axes of the atlas. This facilitates comparisons to other MRI contrasts and to images of processed tissue aligned to the standard space, while maintaining the high resolution of the tissue images along the standard stereotaxic plane. Guiding the positioning of the grooves according to species-specific anatomical information from the co-registered atlas facilitates region-specific histology. The pipeline we introduce can be used to create brain-specific sectioning models for a variety of species, including humans, primates, and rodents. To demonstrate the generalizability of the pipeline across species, we show models generated for macaques and rats. PMID- 30440515 TI - Background Modeling Method to Identify Interactions Between Circulating Tumor Cells and Dendritic Cells. AB - Interactions between dendritic cells (DCs) and circulating tumor cells (CTCs) have attracted wide attention in tumor immunity research, especially on specifically targeted tumors. However, feature extraction and noninvasive tracking of DCs and CTCs are challenges that have long existed in biomedicine. In this study, we developed an automatic algorithm for identifying, counting, tracking, and segmenting fluorescently-labeled CTCs and DCs from the blood vessels of mouse ears. For fluorescence imaging, we constructed an in vivo image flow cytometry system to capture dual-channel (green and red) fluorescence image sequence simultaneously. To achieve real-time functions for the CTCs and DCs, we developed a motion detection method based on codebook which first performs background modeling and then cone-shaped area search procedures for postprocessing. We validated this novel algorithm through in vivo image sequencing, through which we observed the interaction of CTCs and DCs. Moreover, we used quantitative colocalization to determine the relationship between CTCs and DCs. The quantitative results illustrated the interactions between CTCs and DCs, as did image sequences which are promising for driving research on cancer immunotherapy in the future. PMID- 30440516 TI - Segmentation of Overlapped Steatosis in Whole-Slide Liver Histopathology Microscopy Images. AB - An accurate steatosis quantification with pathology tissue samples is of high clinical importance. However, such pathology measurement is manually made in most clinical practices, subject to severe reader variability due to large sampling bias and poor reproducibility. Although some computerized automated methods are developed to quantity the steatosis regions, they present limited analysis capacity for high resolution whole-slide microscopy images and accurate overlapped steatosis division. In this paper, we propose a method that extracts an individual whole tissue piece at high resolution with minimum background area by estimating tissue bounding box and rotation angle. This is followed by the segmentation and segregation of steatosis regions with high curvature point detection and an ellipse fitting quality assessment method. We validate our method with isolated and overlapped steatosis regions in liver tissue images of 11 patients. The experimental results suggest that our method is promising for enhanced support of steatosis quantization during the pathology review for liver disease treatment. PMID- 30440517 TI - Tracking Gene Expression via Light Sheet Microscopy and Computer Vision in Living Organisms. AB - Automated tracking of spatiotemporal gene expression using in vivo microscopy images have given great insight into understanding developmental processes in multicellular organisms. Many existing analysis tools rely on the fluorescent tagging of cell wall or cell nuclei localized proteins to assess position, orientation, and overall shape of an organism; information necessary for determining locations of gene expression activity. Particularly in plants, organism lines that have fluorescent tags can take months to develop, which can be time consuming and costly. We propose an automated solution for analyzing spatial characteristics of gene expression without the necessity of fluorescent tagged cell walls or cell nuclei. Our solution indicates, segments, and tracks gene expression using a fluorescent imaging channel of a light sheet microscope while determining gene expression location within an organism from a Brightfield (non-fluorescent) imaging channel. We use the images obtained from the Arabidopsis thaliana root as a proof of concept for our solution by studying the effects of heat shock stress on CYCLIN B1 protein production. PMID- 30440518 TI - Confocal imaging of cytosolic Ca2+ and fuzzy clustering reveal the circuit topology details underlying synchronization in hippocampal neurons. AB - Neuronal synchronization contributes to various cognitive functions and disruption in synchronicity may lead to various diseased conditions. However, measurement of synchronicity at a higher spatial resolution remains challenging. Specifically, investigation on understanding the role of network topology in tuning the network activity and synchronicity remains sparse. In this context, we propose imaging of intracellular Ca2+ in primary cultures of hippocampal neurons using Fluo-4 as the fluorescent indicator using the confocal microscope. In order to identify the synchronous response from a set of heterogeneous Ca2+ spiking, we present fuzzy clustering of the oscillatory responses. Further, the synchronicity was measured through evaluation of the correlation between Ca2+ spiking trends. Confocal imaging and analysis show that neuronal connectivity and topology play an essential role in tuning the synchronicity of the neuronal network. PMID- 30440519 TI - Enhanced Image Sensor Module for Head-Mounted Microscopes. AB - Several research groups have developed head-mounted fluorescence microscopes as a modality for recording neural activity in freely behaving mice. The current designs have shown exciting results from in vivo imaging of the bright dynamics of genetically encoded calcium indicators (GECI). However, despite their potential, head-mounted microscopes are not in use with genetically encoded voltage indicators (GEVI) or bioluminescence indicators. Due to its ability to match the temporal resolution of neuron spiking, GEVIs offer great benefits to experiments designed to provide feedback after real-time detection of specific neural activity such as the less than 250ms replay events that can occur in the hippocampus. Orthogonally, the emerging bioluminescence activity reporters have the potential to eliminate autofluorescence and photobleaching that can occur in fluorescence imaging. There are two important properties of the head-mounted microscope's image sensor affecting the ability to image GEVIs and bioluminescence indicators. First, the low signal to noise ratio (SNR) characteristics of GEVIs and bioluminescent indicators make signal detection difficult. Second, in order to take advantage of the GEVIs faster fluorescence kinetics, the image sensor must be capable of matching frame rates. Here, we present the design of a new imaging module for head-mounted microscopes incorporating the latest CMOS sensor technology aimed at increasing image sensor sensitivity and frame rates for use in real-time detection experiments. The design builds off an existing open-source project and can integrate into the existing data acquisition hardware and microscope housing. PMID- 30440520 TI - Detecting murine Inflammatory Bowel Disease using Optical Coherence Elastography. AB - Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes regions of ulceration within the interior of the colon. UC is estimated to afflict hundreds of thousands of people in the United States alone. Ultrasonic techniques can detect colitis, but have limited spatial resolution, which frequently results in underdiagnoses. Nevertheless, clinical diagnosis of colitis is still generally performed via colonoscopy. Optical techniques such as confocal microscopy and optical coherence tomography (OCT) have been proposed as higher resolution alternative imaging modalities to detect colitis. Additionally, IBD can potentially alter tissue biomechanical properties, which cannot be quantified from structural imaging alone. Elastography is a potential method to assess colon biomechanical properties to provide additional contrast for distinguishing healthy and diseased colon tissue. In this work, we induced elastic waves in ex vivo mouse colon tissue using a focused air-pulse. The elastic waves were detected using a phase-stabilized swept source optical coherence elastography system, and the wave velocity was translated into stiffness. Measurements were taken at six random positions for each sample in order to assess regional sample elasticity. The results show distinct differences ($p ?lt 0.05$) in the stiffness between healthy and IBD-diseased samples, with a Young's Modulus of $10.2 ?pm 3.7$ kPa and $4.9 ?pm 0.3$ kPa, respectively. Dispersion analysis presents another parameter to distinguish tissue health. The high frequency components of the phase velocity dispersion curve indicate a variation between healthy and IBD colonic tissue. Our results show that OCE may be useful for detecting IBD noninvasively. PMID- 30440521 TI - Vulnerable Plaque Recognition Based on Attention Model with Deep Convolutional Neural Network. AB - Previous studies have proved that the vulnerable plaque is a major factor leading to the onset of acute coronary syndrome (ACS). Recognizing vulnerable plaques is essential for cardiologists to treat illnesses, early. However, this task often comes with the challenge of insufficient annotated data sets and subtle differences between lesion regions and normal regions. In this paper, we apply the visual attention model with deep neural network to improve the performance of recognizing vulnerable plaques. There are two key ideas about our method: 1) using a top-down attention model to extract salient regions (blood vessels) according to the doctor's prior knowledge, and 2) employing a multi-task neural network to complete the recognition task. The first branch, a typical classification task, is to distinguish whether the image contains vulnerable plaques. The other branch uses a column-wise segmentation to locate vulnerable plaques. We have verified the effectiveness of our proposed method on the data set provided by 2017 CCCV-IVOCT Challenge. The proposed method obtains good performance. PMID- 30440522 TI - Comparing Immunofluorescent versus H&E Glandular Architecture Features in Prognostic Models from Prostate Biopsies. AB - Determining the best treatment for prostate cancer patients with a newly diagnosed positive biopsy can be challenging. Multivariate prognostic models are often employed to stratify patients into risk populations. Many models leverage quantitative features derived from morphological analysis of the tumor architecture in the biopsy specimen. The vast majority of these features are derived from analyzing standard hematoxylin and eosin (H&E) images. Immunofluorescence (IF) image analysis of tissue pathology has also recently been proven to be robust. In this work, we constructed multivariate models for prostate cancer prognosis comparing the usage of previously published IF vs H&E features. In images from 304 patients, the IF features prognostically outperform the H&E features. The IF feature model also exhibits consistent training vs validation performance, an important consideration when developing models subject to regulatory oversight. This paper presents the first evaluation of comparing previously published H&E and IF morphological features head-to-head in prognostic models from prostate biopsies. PMID- 30440523 TI - Cell Counting and Segmentation of Immunohistochemical Images in the Spinal Cord: Comparing Deep Learning and Traditional Approaches. AB - Estimation of cell nuclei in images stained for the c-fos protein using immunohistochemistry (IHC) is infeasible in large image sets. Use of multiple human raters to increase throughput often creates variance in the data analysis. Machine learning techniques for biomedical image analysis have been explored for cell-counting in pathology, but their performance on IHC staining, especially to label activated cells in the spinal cord is unknown. In this study, we evaluate different machine learning techniques to segment and count spinal cord neurons that have been active during stepping. We present a qualitative as well as quantitative comparison of algorithmic performance versus two human raters. Quantitative ratings are presented with cell-count statistics and Dice (DSI) scores. We also show the degree of variability between multiple human raters' segmentations and observe that there is a higher degree of variability in segmentations produced by classic machine learning techniques (SVM and Random forest) as compared to the newer deep learning techniques. The work presented here, represents the first steps towards addressing the analysis time bottleneck of large image data sets generated by c-fos IHC staining techniques, a task that would be impossible to do manually. PMID- 30440524 TI - Non-Contact Remote Measurement of Heart Rate Variability using Near-Infrared Photoplethysmography Imaging. AB - Heart rate variability (HRV) is an important clinical parameter associated with the autonomous nervous system (ANS), age, as well as many diseases such as myocardial infarction, diabetes or renal failure. Gold standard for measurement of HRV is a high-resolution electrocardiogram (ECG). With the current trend towards non-contact and unobtrusive monitoring of vital signs, HRV has also become an interesting and important parameter for non-contact monitoring. In this paper, we present an approach towards non-contact and unobtrusive monitoring of heart rate variability using the camera-based technology of photoplethysmography imaging (PPGI). We investigated the suitability of invisible near-infrared illumination for PPGI, which would enable measurement of HRV in darkness. We compared results obtained using infrared illumination with those obtained using visible light as PPGI illumination and calculated both time-domain as well as frequency-domain HRV parameters. The results achieved with infrared illumination were on par with those using conventional illumination in the visible spectrum. We concluded that infrared illumination enables unobtrusive and non-contact remote HRV measurement in both darkness as well as regular daylight conditions using PPGI. PMID- 30440525 TI - Dynamic analysis of mental sweating of the sweat glands and peripheral vessels by optical coherence tomography. AB - The sweat gland and peripheral vessels underneath skin are a typical minute organ governed by the sympathetic nerve, and have important physiology functions to control of body temperature and maintenance. In this paper, we demonstrated the dynamic analysis of the mental sweating of the eccrine sweat glands and the dynamics of the small artery of human finger by optical coherence tomography (OCT). In the experiment of mental sweating, not only time variation of the amount of excess sweat can be evaluated simultaneously a few tens of sweat glands eccrine sweat glands but also the dynamics of peripheral vessels of a human finger were analyzed. PMID- 30440526 TI - Diffuse Speckle Contrast Analysis Assisted Intraoperative Blood Flow Monitoring in the Rat Model of Femoral Arterial Occlusion. AB - The rodent model has been largely used for understanding specific disease pathophysiology, with low cost and the large spectrum from genetic strains. Here, we present a diffuse speckle contrast analysis (DSCA) system to measure blood flow changes non-invasively in rat's thigh and paw during femoral arterial occlusion (FAO) surgery which is the procedure for inducing peripheral arterial disease. The blood flow index in rat's paw showed significant decrease according to arterial occlusion. Moreover, we analyzed cross-correlation between two measurement positions. The results showed the affinity with hemodynamic response. In conclusion, the DSCA system secured the intraoperative blood flow monitoring during FAO surgery in a rat model. PMID- 30440527 TI - Optic Disc and Cup Segmentation with Blood Vessel Removal from Fundus Images for Glaucoma Detection. AB - Glaucoma is one of the major causes of blindness. Researchers keep looking for better ways to detect glaucoma in its early stage before it gets worse and cannot be cured. Among existing methods, the vertical cup to disc ratio (CDR) has been found to be effective for glaucoma measurement, which is calculated from the diameters of the optic cup and disc regions. Therefore, in order to achieve a more accurate CDR, a good segmentation of the optic disc and cup regions is quite important. Noting that the shape of the disc and cup regions can be assumed to be an ellipse, in this work we propose to find the minimal bounding boxes for the two regions based on the recent advances of deep learning. Also, considering blood vessels, passing through the disc area in a fundus image, can affect the detection of the bounding boxes, we further propose to remove the blood vessels beforehand in order to further boost the overall performance. Comprehensive experiments show that our proposed method achieves state-of-the-art performance on ORIGA-650 for optic disc and cup segmentation. PMID- 30440528 TI - High resolution volumetric imaging of primary and secondary tumor spheroids using multi-angle Light Sheet Fluorescence Microscopy (LSFM). AB - Breast cancer and Glioblastoma brain cancer are severe malignancies with poor prognosis. In this study, primary Glioblastoma and secondary breast cancer spheroids are formed and treated with the well-known Temozolomide and Doxorubicin chemotherapeutics, respectively. High resolution imaging of both primary and secondary cancer cell spheroids is possible using a custom multi-angle Light Sheet Fluorescence Microscope. Such a technique is successful in realizing preclinical drug screening, while enables the discrimination among physiologic tumor parameters. PMID- 30440529 TI - Retinal Artery and Vein Classification for Automatic Vessel Caliber Grading. AB - Automated retinal artery and vein identification is a necessity to measure their caliber automatically and to achieve high efficiency and repeatability for a large number of images. In this paper, a novel framework for retinal artery and vein classification is provided. The proposed method utilizes the vessel crossover and color intensity profile which are the most significant features for artery and vein classification. The method first extracts retinal vascular network and then identify individual blood vessels for further classification as artery or vein. We apply deep learning algorithm based segmentation method to extract the retinal vascular network. We then identify each blood vessels to measure caliber that will be used for computing the Central Retinal Artery Equivalent (CRAE) and Central Retinal Vein Equivalent (CRVE). We map the vessel network and use the individual vessel crossover information, vessel color and intensity profile to identify individual vessel segment as artery and vein. We compared automatically classified artery and vein results with a human grader which showed an accuracy of 95%. We compare our results of caliber grading against an established semi-automated caliber grading system and protocol which showed a very high correlation of 0.85 and 0.92, for CRAE and CRVE respectively. PMID- 30440530 TI - Speckle Suppression of Ultrasonography Using Maximum Likelihood Estimation and Weighted Nuclear Norm Minimization. AB - Speckle noise corrupts medical ultrasound images and suppression of speckle noise is valuable for image interpretation. This paper presents a new method for speckle suppression named the maximum likelihood based weighted nuclear norm minimization (MLWNNM) filtering by integrating the maximum likelihood estimation (MLE) with the weighted nuclear norm minimization (WNNM). The MLE is first used to get an initially filtered image with reduced Rayleigh distributed noise, and then the WNNM is applied to further improve the denoising effect by preserving and enhancing tissue details. Simulation work shows that when the noise variance is as high as 0.14, the MLWNNM improves the Pratt's figure of merit, peak signal to noise ratio, and mean structural similarity by 123.51%, 0.84%, and 6.13%, respectively, in contrast to the best values of other six methods. Experimental results on clinical ultrasound images suggest that the MLWNNM outperforms other six methods in noise reduction and detail preservation. PMID- 30440531 TI - Fast And Simple Automatic 3D Ultrasound Probe Calibration Based On 3D Printed Phantom And An Untracked Marker. AB - Tracking the pose of an ultrasound (US) probe is essential for an intraoperative US-based navigation system. The tracking requires mounting a marker on the US probe and calibrating the probe. The goal of the US probe calibration is to determine the rigid transformation between the coordinate system (CS) of the image and the CS of the marker mounted on the probe. We present a fast and automatic calibration method based on a 3D printed phantom and an untracked marker for three-dimensional (3D) US probe calibration. To simplify the conventional calibration procedures using and tracking at least two markers, we used only one marker and did not track it in the whole calibration process. Our automatic calibration method is fast, simple and does not require any experience from the user. The performance of our calibration method was evaluated by point reconstruction tests. The root mean square (RMS) of the point reconstruction errors was 1.39 mm. PMID- 30440532 TI - A visual probe positioning tool for 4D ultrasound-guided radiotherapy. AB - Ultrasound (US) guidance is a rapidly growing area in image-guided radiotherapy. For motion compensation, the therapy target needs to be visualized with the US probe to continuously determine its position and adapt for shifts. While US has obvious benefits such as real-time capability and proven safety, one of the main drawbacks to date is its user dependency - high quality results require long years of clinical experience. To provide positioning assistance for the setup of US equipment by non-experts, we developed a visual guidance tool combining real time US volume and CT visualization in a geometrically calibrated setup. By using a 4D US station with real-time data access and an optical tracking system, we achieved a calibration accuracy of 1.2 mm and a mean 2D contour distance of 1.7 mm between organ boundaries identified in US and CT. With this low calibration error as well as the good visual alignment of the structures, the developed probe positioning tool could be a valuable aid for ultrasound-guided radiotherapy and other interventions by guiding the user to a suitable acoustic window while potentially improving setup reproducibility. PMID- 30440533 TI - Fetal Skull Reconstruction via Deep Convolutional Autoencoders. AB - Ultrasound (US) imaging is arguably the most commonly used modality for fetal screening. Recently, 3DUS has been progressively adopted in modern obstetric practice, showing promising diagnosis capabilities, and alleviating many of the inherent limitations of traditional 2DUS, such as subjectivity and operator dependence. However, the involuntary movements of the fetus, and the difficulty for the operator to inspect the entire volume in real-time can hinder the acquisition of the entire region of interest. In this paper, we present two deep convolutional architectures for the reconstruction of the fetal skull in partially occluded 3DUS volumes: a TL deep convolutional network (TL-Net), and a conditional variational autoencoder (CVAE). The performance of the two networks was evaluated for occlusion rates up to 50%, both showing accurate results even when only 60% of the skull is included in the US volume (Dice coeff. $0.84?pm 0.04$ for CVAE and $0.83?pm 0.03$ for TL-Net). The reconstruction networks proposed here have the potential to optimize image acquisition protocols in obstetric sonography, reducing the acquisition time and providing comprehensive anatomical information even from partially occluded images. PMID- 30440534 TI - Improved Real-Time Capability for Nonlinear Seperable Harmonic Filtering of Ultrasound Images Using a Damped Regularization Method With In-Vivo Results. AB - During the early stage of the disease, idiopathic Parkinson's Disease can be very difficult to differentiate from atypical parkinsonian syndromes. Hyperechogenicity in the substantia nigra is one marker that has been shown to help make this differential diagnosis, and Transcranial Ultrasound Imaging is the preferred method for detecting SN hyperechogenicity. Hyperechogenicity is defined as an echogenic area larger than 0.2cm2. However, B-mode imaging often contains enough noise that the boundary may not be clear, thus making this diagnosis much more difficult. Harmonic imaging using a Third- Order Volterra filter is one solution that has been shown to be successful in filtering out the noise in these images. In this paper we show that regularization methods such as the Truncated Singular Value Decomposi- tion and Damped Singular Value Decomposition can be used to solve for the Volterra Filter's coefficients much more quickly than adaptive Least Mean Squared methods without sacrifice in image quality. These findings have significant implications for the viability of using the Volterra Filter in real-time applications. PMID- 30440535 TI - Using Filter Factors for Regularization in Ultrasound Tomography. AB - The motivation for ultrasound tomography is the location and identification of malignant human breast tissues for the purpose of detecting breast cancer. Although mammography is widely used for breast cancer detection, it has a high false positive rate and does not always accurately separate malignant tissue from benign tissue. Ultrasound tomography is used to compensate for these shortcomings. The computational model for ultrasound tomography is based upon solving an inverse scattering problem by finding the approximate total field and unknown scattering function using an iterative method. The principal computational problem involved is the solution of an ill-conditioned linear system, $Xy?approx b$, arising from an ill-posed problem written as an integral equation. In this paper, we explore the DSVD and the DGSVD regularization methods to solve the inverse scattering problem. The DGSVD algorithm gives better results than the DSVD algorithm when we introduce noise in either one or both sides of the linear system $Xy?approx b$. PMID- 30440536 TI - Comparison of 3D reconstruction methods based on different cardiovascular imaging: a study of multimodality reconstruction method. AB - Coronary arterial imaging and the assessment of the severity of arterial stenoses can be achieved with several modalities classified mainly according to their invasive or noninvasive nature. These modalities can be further utilized for the 3-dimensional (3D) reconstruction of the arterial geometry. This study aims to determine the prediction performance of atherosclerotic disease progression using reconstructed arteries from three reconstruction methodologies: Quantitative Coronary Analysis (QCA), Virtual Histology Intravascular Ultrasound (VH)-IVUS Angiography fusion method and Coronary Computed Tomography Angiography (CCTA). The accuracy of the reconstruction methods is assessed using several metrics such as Minimum lumen diameter (MLD), Reference vessel diameter (RVD), Lesion length (LL), Diameter stenosis (DS%) and the Mean wall shear stress (WSS). Five patients in a retrospective study who underwent X-ray angiography, VH-IVUS and CCTA are used for the method evaluation. PMID- 30440537 TI - Multiview Three-Dimensional Echocardiography Image Fusion Using a Passive Measurement Arm. AB - Three-dimensional (3D) echocardiography offers a fast and efficient way to scan and assess the structures and function of the heart. However, due to limitations inherent to 3D echocardiography such as limited field-of-view and low signal-to noise ratio, 3D assessment of the heart is performed only in a minority of patients who undergo transthoracic echocardiography. One approach for improving the field-of-view and image quality is to scan the heart from multiple locations by moving the transducer and fusing the resulting images into a single volume, which requires 3D alignment of individual volumetric echocardiography scans. Previous approaches relied on optical or electromagnetic trackers for transducer tracking. This study proposes a passive measurement arm system for tracking the position of the ultrasound transducer and thereby aligning multiple echocardiography scans. The proposed system does not suffer from line-of-sight limitation as in the case of an optical tracking based fusion system. Additionally, in contrast to an electromagnetic based tracking system, measurement arm measurements are not affected by other ferromagnetic materials in the vicinity. The proposed approach was tested by scanning a heart phantom and fusing nine echocardiography volumes acquired from different locations. The fusion of all nine scans yielded a percentage field-of-view improvement of 98.5%. PMID- 30440539 TI - Phase-Shift Depth Migration for Plane-Wave Ultrasound Imaging. AB - Plane-wave ultrasound imaging is an important modality that enables very high frame rates, which is necessary for adequate characterization of blood flow and tissue motion properties. This work describes a novel Fourier-domain method for plane-wave ultrasound image reconstruction that can be used in situations where the speed of sound varies with depth in a layered propagation medium. Our approach is based on geophysical phase-shift migration technique that has been modified to handle plane-wave ultrasound data processing. Our simulation results show that the proposed method is capable of accurately imaging point targets in a three-layer medium, mimicking tissue-bone-tissue ultrasound propagation. PMID- 30440538 TI - Coherence Plane-Wave Compounding with Angle Coherence Factor for Ultrafast Ultrasound Imaging. AB - Ultrafast ultrasound imaging with plane wave transmission has been a promising technique to image moving objects, however, implies compromises among resolution, contrast and sensitivity. Coherence plane-wave compounding (CPWC) can balance the image quality and frame rate. The image quality, especiallyin terms of the suppression of artifacts stemmed from side lobes, is greatly comprised by reducing the number of the tilted plane-waves. However, in some special scenarios, such as tracking shear wave propagation inside soft tissue, and imaging the complex blood flow, it's better to keep a very high frame rate. How to realize a B-mode image of equivalent quality to the standard focused approach at a very high frame rate? Here we proposed a new imaging framework by combining CPWC with angle coherence factor. The B-mode images from simulation, experimental phantoms demonstrated that our proposed methodology greatly suppressed the side lobes artifacts by around 20 dB compared with CPWC imaging, while the image quality, especially lateral resolution and contrast kept equivalent. PMID- 30440540 TI - Automatic Recognition of Complete Atrioventricular Activity in Fetal Pulsed-Wave Doppler Signals. AB - Echocardiography is the gold standard for antenatal cardiological assessment. However, the adoption of this technique is challenging, since it is intrinsically operator-dependent and because of the different confounding factors related to the fetal heart size, the fetal movements and the ultrasound artifacts. Among the different options, fetal echocardiography is widely used, concurring to an early diagnosis of several cardiac pathologies. In this work, a neural network-based algorithm targeted at the identification of the most important features of Doppler fetal echocardiography videos is presented and evaluated on real signals. Compared to other approaches, the proposed algorithm works on a couple of ID signals, representing the pulse-wave Doppler envelope extracted from the video, thus preserving a Iightweight approach. For the validation, a small dataset was created, including recordings from five voluntary pregnant women 21st to 27th gestational week), for a total of 20 records, 10 seconds each. The dataset was annotated by an expert cardiologist in order to identify the epochs of the signal where a complete readable cardiac cycle could be identified. The performance of the method was evaluated through a 5-fold cross-validation. An average accuracy up to 88% was obtained, confirming the validity of the proposed approach and paving the way to future improvements of the technique. PMID- 30440541 TI - Compact and Programmable Ultrasound Front-End Processing Module for Research Activities. AB - Ultrasound signal processing involves diversified requirements in terms of processing, power, hardware etc. Ultrasound signal processing is continuously evolving area, and hence researchers who need to evaluate the novel algorithms in real time need to have the complete hardware setup. Commercially available ultrasound scanners are based on Application Specific Integrated Circuit (ASIC) and hence it does not have any provision to test the novel algorithms. In this paper, we propose a compact and programmable module, equipped with required hardware support for implementing complete front-end processing. The board is supported with an external interface that can be connected to other computing platforms like Field-Programmable Gate Arrays (FPGA's), and Digital Signal Processors (DSP's), etc, for implementing the mid-end and back-end algorithms. Provision is provided for acquiring the raw RF data, which will be beneficial for developing computer-aided diagnostics, and also to develop signal processing algorithms in offline. The proposed front-end hardware module will be very beneficial for rapid testing of the novel ultrasound signal processing algorithms. PMID- 30440542 TI - Development of a Load-Cell Based Palpation Sensor Suitable for Ophthalmic Anesthesia Training. AB - Palpation is the process of using one's hand to perform a physical examination. Ophthalmic anaesthetists palpate the orbital bone around the eye, to locate anatomical markers to help them guide the needle safely for regional needle block into the orbital cavity. The anaesthetists are provided very little training on palpation procedure due to the lack of a suitable training system. Inadvisable palpation can cause damage to the soft tissue if the applied force is more than required. There is a necessity to provide ophthalmic anaesthetists with the relevant knowledge about palpation and the force exerted during this procedure. In this paper, a load cell based palpation sensor which can be integrated with recently developed ophthalmic anaesthesia training systems with a virtual instrument environment that is capable of mimicking the skin reaction to applied palpation with the variable warning threshold is proposed. PMID- 30440543 TI - Instrumentation of Surgical Tools To Measure Load and Position During Incision, Tissue Retraction, and Suturing. AB - The characterization of soft tissue interaction with surgical tools is critical for authentic surgical simulations and accurate robotic-assisted surgery. Virtual and augmented reality are often used to simulate surgical procedures with haptic feedback to increase the sense of reality. Haptic simulations require models with parameters based on real tissue data. The accuracy of haptic feedback can be increased when the mechanics of the interaction between tool and tissue is better understood. Several foundational surgical tools were instrumented to acquire such data for a variety of applications. Presented here are a set of modular tools and software built to expand the scope of surgical procedures for which comprehensive training data for surgical simulators are desired. In a demonstration, the system measured loads in 6 degrees-of-freedom and position and orientation in relation to a cadaver leg. Additionally, the tools were designed with modularity to accommodate adaptation for additional tools not used in this study. PMID- 30440544 TI - Preliminary Assessment of a Microwave System to Detect Contrast Enhancing Agents. AB - This paper presents a preliminary study of the impact of potential contrast enhancing agents on a 2-port microwave imaging system. To this end, we have conducted microwave measurements inside a dual cylindrical tank, comprised of an outer and inner cylinder filled with high and low loss liquids, respectively. A third smaller cylinder inside the low loss filled tank represents a target. The target materials consisted of safflower oil, water, PEGylated zinc oxide nanoparticles dispersed in water, and saline with varying concentrations of salt. To benchmark our experimental results, we have also performed accurate numerical simulations of the system under three target scenarios: safflower oil, water, and PEGylated zinc oxide suspension. Our results show that the difference in received signal strength in scenarios with and without PEGylated zinc oxide nanoparticles in our 2-port system was comparable to measurement error. However, with the use of varying concentrations of saline solutions as a target, we have observed a significant difference in received signal strength. PMID- 30440545 TI - Innovation in Medical Technology Driven by Advances in Aerospace. AB - : The International Space Medicine Summit II sought to identify mature data with significant clinical implications for Terrestrial populations. This work aims at identifying space medical technology which has been translated for use by private costumers, those in remote locations on Earth and areas affected by natural disasters. METHODS: Following PRISMA Guidelines, we sought to review the published literature and NASA technical resources (from 2012 to 2017). Search terms used included "Medical AND Technology AND Diagnosis AND Monitor". RESULTS: 23 applications were identified of medical technology arisen from the Space industry. Of these, 5 were treatment based; 6 diagnostic; 10 medical measurement devices. DISCUSSION: The Aerospace industry has provided a significant transfer in knowledge and technology which can improve our management of patients on Earth. SIGNIFICANCE: Highlighting the use and benefits of Aerospace medical research for terrestrial medical care. PMID- 30440546 TI - Enhanced Control to Improve Navigation and Manipulation of Power Wheelchairs. AB - Our team developed a mobile wheelchair control kit designed to allow power wheelchair users the ability to maneuver their wheelchair without the need to manipulate a joystick with their hands. A smartphone and its internal accelerometer sensor was used to detect the vector of gravity, and thus detecting the pitch and roll. The wheelchair control system was tested with the phone attached in three mounting positions: hand held, hat and arm band and compared to the manipulation using the wheelchair joystick. To determine the viability of the commercialization of this kit as well as which features to further develop, a customer discovery was completed. Over a hundred interviews of power wheelchairs users, therapists, care takers, manufacturers, dealers, and assistive technology professionals were conducted at clinics, tradeshows, disabilities support groups, and rehabilitation organizations. After discovering the needs of the customers, collision avoidance was implemented into the control kit and back up cameras were added into the smart phone app to allow for the camera view to be seen without additional screens attached to the wheelchair. Future work will test these new design features and will concentrate on removing excess weight from the control kit. Improving the ease of installation of the kit to any power wheelchair will also be a focus. PMID- 30440547 TI - The Development of a Benchtop Breast Reconstruction Surgical Simulator. AB - A modified Delphi technique was used to survey plastics surgeons with an expertise in breast reconstruction from 6 university centers with plastic surgery residency programs across Canada. A list of the most challenging steps in teaching alloplastic breast reconstruction was obtained. From the survey results, a benchtop post-mastectomy breast reconstruction simulator was created using various silicon materials. The simulator was designed to be completely reusable with no disposable components necessary for each use. Senior plastic surgeons (n= 6) with an expertise in breast reconstruction were recruited and asked to perform a sub-pectoral, implant-based breast reconstruction on the simulator. Following the procedure, participants were asked to complete a survey and grade the simulator on its physical attributes, realism of experience, realism of material and overall experience.Preliminary face and content validation results based on the evaluations performed by those expert plastic surgeons showed excellent results among parameters evaluated, with an overall mean score of 4.7 on 5 (94.0%). Evaluators considered the six relevant anatomical components that were successfully included in the simulator. PMID- 30440548 TI - Determination of Saccade Latency Distributions using Video Recordings from Consumer-grade Devices. AB - Quantitative and accurate tracking of neurocognitive decline remains an ongoing challenge. We seek to address this need by focusing on robust and unobtrusive measurement of saccade latency - the time between the presentation of a visual stimulus and the initiation of an eye movement towards the stimulus - which has been shown to be altered in patients with neurocognitive decline or neurodegenerative diseases. Here, we present a novel, deep convolutional neuralnetwork-based method to measure saccade latency outside of the clinical environment using a smartphone camera without the need for supplemental or special-purpose illumination. We also describe a model-based approach to estimate saccade latency that is less sensitive to noise compared to conventional methods. With this flexible and robust system, we collected over 11,000 saccade-latency measurements from 21 healthy individuals and found distinctive saccade-latency distributions across subjects. When analyzing intra-subject variability across time, we observed noticeable variations in the mean saccade latency and associated standard deviation. We also observed a potential learning effect that should be further characterized and potentially accounted for when interpreting saccade latency measurements. PMID- 30440549 TI - Lung Consolidation Detection through Analysis of Vocal Resonance Signals. AB - Consolidation of the lung is a common pathology which is sometimes life threatening. One of the primary causes is the infection of lung tissue (pneumonia). Vocal resonance and vocal fremitus are part of the routine clinical examination of the respiratory system by physicians, which although time consuming, helps in the diagnosis of consolidation of the lung. In this paper, we suggest a possible automatic lung consolidation detection system that can be used by health workers with basic training. Analysis is performed on the vocal resonance sound signals recorded using an electronic stethoscope from the chest walls of normal subjects and patients. We show that for the detection system, use of signal loudness, which is generally considered by physicians, would be infeasible and propose that signal power spectral density computed using our system be considered. Certain frequency regions in the power spectral density (periodogram) are proved to be significant indicators of lung consolidation using t-tests. These findings are then applied to design the detection system using Gaussian naive Bayes classifiers. PMID- 30440550 TI - Design and Evaluation of Haptic Constraints for Laparoscopic Instrument Handling. AB - Learning and mastering laparoscopic skills is an involved and complicated process, especially in the case of pediatric surgery due to extremely fragile tissues and small spaces. Given these constraints, precise, controlled, and gentle laparoscopic tool motions are essential. Proper handling and ergonomics of laparoscopic tool handling are often overlooked when training novice surgeons. Novice surgeons tend to overgrip the tool, which may lead to applying excessive amounts of force and potential surgical complications. We have developed two constraint mechanisms to enable proper tool handling: one mechanism is a passive kinematic constraint which physically prevents the user from over-gripping the tool. The second mechanism operates under dynamic resistive control. An elastic silicone membrane, secured by a hard plastic clip to the finger loop of the laparoscopic tool, actively resists the user's overgrip. These constraint devices were tested in a series of human subject studies with novice learners. The resulting data shows a both a significant reduction in over-grip and overall task completion time when using the passive constraint. The left index, right middle, and right ring fingers are shown to have the least amount of over-grip, as well as the lowest time of non-contact with the tool, indicating the importance of these fingers for laparoscopic tool control. PMID- 30440551 TI - Feasibility Study of a Syringe Angulation Measurement System Suitable for Ophthalmic Regional Anesthesia Training. AB - Regional anaesthesia for the eye requires a needle that is inserted in a specific way into the eye orbit. Angulation of the needle is a concern for the ophthalmic anaesthetists. Inappropriate angulation can place the needle in an unsafe location or result in the unsafe release of the anaesthetic. Recently developed mannequin based ophthalmic training systems had a visual angulation warning; however, an automated quantifiable warning and the ability to provide a preemptive warning to the trainee would provide useful knowledge. In this paper, an angulation measurement methodology which uses two external cameras, in the mannequin system, which can accurately sense angulation in both the vertical and the horizontal axis of the syringe with customizable angle warning system, is presented. Details of the system developed, test results and the outcome are discussed. PMID- 30440552 TI - Volume Manipulation Based on 3D Reconstructed Surfaces for Joint Function Evaluation and Surgery Simulation. AB - In joint surgery, evaluation of the relative positions and angles among joint structures (bones, ligaments, muscle, and cartilages, etc.) in range of motion, lifting and weight bearing of the joint is required. However, current volume visualization techniques provide only static 3D images of anatomic structures in volume data. We propose a method to manipulate (reposition, resize and bend) the joint structures in a volume, by which surgeons can visualize and evaluate the critical positions or angles of the joint structures, and thus plan surgery to correct the morphologic pathology of the joint structures. We also propose a system with a real-time cutting simulation function together with the proposed structure manipulation functions by which surgeons can rehearse and verify joint surgery. PMID- 30440553 TI - Space Medicine Requirements open to Innovation in Biomedical Engineering. AB - : The International Space Medicine Summit II sought to identify mature data with significant clinical implications for Terrestrial populations. This work aims at identifying innovation in biomedical engineering (BE), involving space medicine and translation. METHODS: Following PRISMA Guidelines, we sought to review the published literature and NASA technical resources (from 2012 to 2017) to identify space medical technology which has been translated for use by private costumers. RESULTS: The analysis focuses on technical and medical requirements, human health and Terrestrial implication. DISCUSSION: Innovation in BE arises from matching space medical requirements for developing autonomous medical systems. SIGNIFICANCE: Highlighting the use and benefits of aerospace medical research for Terrestrial medical care. PMID- 30440554 TI - Single-Trial Detection of Semantic Anomalies From EEG During Listening to Spoken Sentences. AB - We propose a method for the automatic detection of mismatched feelings that occur in communication. As our first step, we examined the semantically anomalous feelings from EEGs when participants listened to spoken sentences. Previous studies have shown that the event-related potentials (ERP) of an electroencephalogram (EEG) are evoked in the auditory and visual modalities where a semantic anomaly occurs. We expand this knowledge and detect it from a single trial ERP using machine learning techniques. We recorded the brain activity of eight participants as they listened to sentences that contained semantic anomalies and found that a combination of feature selection using linear discriminant analysis and linear kernel support vector machines achieved the highest accuracy that exceeded 60%. By applying this technique, we plan to detect other types of anomalies in practical situations. PMID- 30440555 TI - Single Neuron Firing Rate Statistics in Motor Cortex During Execution and Observation of Movement. AB - Mirror neurons, which fire during both the execution and observation of movement, are believed to play an important role in motor processing and learning. However, much work still remains to understand the similarities and differences in how these neurons compute in the motor cortex during movement execution and observation. Here, we performed experiments where a monkey both executes and observes a center-out-and-back task within the same experimental session. By recording from putatively the same neural population, we were able to analyze and compare single neuron statistics between movement execution and observation. We found that a majority of neurons in the primary motor cortex (M1) and dorsal premotor cortex (PMd) have statistically different firing rate statistics between movement execution and observation. As a result of this difference, we then wondered if neurons during movement observation exhibited a similar characteristic to those during movement execution: changing of preferred directions as a function of movement speed. Interestingly, we found that while observed movement speed is encoded in the neural population, it only alters a small proportion of the neuron's firing rate statistics. These results suggest that neural populations in Ml and PMd process information related to movement differently between execution and observation. PMID- 30440557 TI - Effect of Vigilance Changes on the Incidence of High Frequency Oscillations in the Epileptic Brain. AB - Recent studies show that the rate of cortical high frequency oscillations (HFOs) differentiates epileptogenic tissue in individuals with epilepsy. However, HFO occurrence can vary widely with vigilance state. In this study we attempt to characterize this variation, which has implications for the choice of a suitable diagnostic baseline for spatiotemporal analysis of HFO activity. We analyzed simultaneous recordings of the scalp electroencephalogram (EEG) and the electrocorticogram (ECoG) to examine the correlation of HFO activity with vigilance state. We detected HFOs (80-500 Hz) from all bipolar ECoG derivations using the well-known Staba algorithm in ten seizure-free overnight recordings from five patients being evaluated for surgery. In addition, we classified EEG features using a linkage tree into four vigilance states representing gradations in sleep depth from wakefulness to slow wave sleep. Finally, we examined the correlation between vigilance state and HFO occurrence in the five channels with the most HFOs in each recording. The proportion of 30-s epochs containing HFOs was found to increase significantly with sleep depth (p<0.01). Further analysis is necessary to examine the effects of epoch length and sample size in the choice of diagnostic baseline. PMID- 30440556 TI - Individual Classification of Single Trial EEG Traces to Discriminate Brain responses to Speech with Different Signal-to-Noise Ratios. AB - To gain knowledge of listening effort in adverse situations, it is important to know how the brain processes speech with different signal-to-noise ratios (SNR). To investigate this, we conducted a study with 33 hearing impaired individuals, whose electroencephalographic (EEG) signals were recorded while listening to sentences presented in high and low levels of background noise. To discriminate between these two conditions, features from the 64-channel EEG recordings were extracted using the power spectrum obtained by a Fast Fourier Transform. Features vectors were selected on an individual basis by using the statistical R2 approach. The selected features were then classified by a Support Vector Machine with a nonlinear kernel, and the classification results were validated using a leave-one-out strategy, and presented an average classification accuracy over all 33 subjects of 83% (SD=6.4%). The most discriminative features were selected in the high-beta (19-30 Hz) and gamma (30-45 Hz) bands. These results suggest that specific brain oscillations are involved in addressing background noise during speech stimuli, which may reflect differences in cognitive load between the conditions of low and high background noise. PMID- 30440558 TI - Investigation of Propagating Cortical Waves and Spirals Recorded by High Density Porous Graphene Arrays. AB - Propagating waves along the cortical surface have recently attracted significant attention by the neuroscience community. However, whether these propagating waves imply network connectivity changes for the neural circuits is not known. In this work, we employ a high density porous graphene microelectrode array and perform in vivo experiments with rodents to investigate network connectivity during cortical propagating waves. The spatial-temporal analysis of the cortical recordings reveals various types of propagating waves across the recording area. Network analysis results show that these propagating waves are consistent with the functional connectivity changes in the neural circuits, suggesting that the underlying network states are reflected by the cortical potential propagation patterns. PMID- 30440559 TI - A Deep Learning Approach for the Classification of Neuronal Cell Types. AB - Classification of neurons from extracellular recordings is mainly limited to putatively excitatory or inhibitory units based on the spike shape and firing patterns. Narrow waveforms are considered to be fast spiking inhibitory neurons and broad waveforms excitatory neurons. The aim of this work is twofold. First, we intend to use the rich spatial information from high-density Multi-Electrode Arrays (MEAs) to make classification more robust; second, we hope to be able to classify sub-types of excitatory and inhibitory neurons. We first built, in simulation, a large dataset of action potentials from detailed neural models. Then, we extracted spike features from the simulated recordings on a high-density Multi-Electrode Array model. Finally, we used a Convolutional Neural Networks (CNN), to classify the different cell types. Compared with the ground truth data from the simulated dataset, the results show that this forward modelling/machine learning approach is very robust in recognizing excitatory and inhibitory spikes (accuracy $?ge 92.15$%). Additionally, the approach can, to a certain extent, correctly classify different cell sub-types. As the detail and fidelity of neural models increase and high-density recordings become available, this approach could become a viable and robust alternative for classification of neural cell types from in-vivo extracellular recordings. PMID- 30440560 TI - Tracking of dynamic functional connectivity from MEG data with Kalman filtering. AB - Owing to their millisecond-scale temporal resolution, magnetoencephalography (MEG) and electroencephalography (EEG) are well-suited tools to study dynamic functional connectivity between regions in the human brain. However, current techniques to estimate functional connectivity from MEG/EEG are based on a two step approach; first, the MEG/EEG inverse problem is solved to estimate the source activity, and second, connectivity is estimated between the sources. In this work, we propose a method for simultaneous estimation of source activities and their dynamic functional connectivity using a Kalman filter. Based on simulations, our approach can reliably estimate source activities and resolve their time-varying interactions even at low SNR (< 1). When applied on empirical MEG responses to simple visual stimuli, our approach could capture the dynamic patterns of the underlying functional connectivity changes between the lower (pericalcarine) and higher (fusiform and parahippocampal) visual areas. In conclusion, we demonstrate that our approach is capable of tracking changes in functional connectivity at the millisecond resolution of MEG/EEG and thus making it suitable for real-time tracking of functional connectivity, which none of the current techniques are capable of. PMID- 30440561 TI - Does independent component analysis influence EEG connectivity analyses? AB - Analysis of electroencephalographic (EEG) data requires cautious consideration of interfering artefacts such as ocular, muscular or cardiac noise. Independent component analysis (ICA) has proven to be a powerful tool for the detection and separation out of these contaminating components from brain activity. Yet thus far thorough investigation is lacking into how this pre-processing step might affect or even distort the information on brain connectivity inherent in the raw signals. The aim of this work is to address this question by systematically investigating and comparing three different strategies: first, analysis of all network nodes without eliminating contamination; second, removing the node which is contaminated by artefacts; third, using the ICA artefact removal method as an initial step prior to the analysis. Multivariate, time-variant autoregressive models are used to approximate the recorded data; the assessment of information flow within the modelled networks is carried out by means partial directed coherence, offering a frequency-selective estimation of connectivity. PMID- 30440562 TI - Increased Randomness of Functional Network Connectivity in Nicotine and Alcohol Consumers. AB - Alcohol and nicotine are substances that alter the functional connectivity of the brain. These changes have been observed after pinpointing particular brain areas as well as studying the overall brain wiring structure. One property of this wiring structure is the level of randomness. Evidence strongly agrees that brain connectivity is not random, but that chemical substances can affect the connectivity structure. This work aims at studying changes in resting state functional connectivity randomness in relation to the consumption of nicotine and alcohol. Results suggest that randomness in whole brain connectivity is not affected by used substance. However, connectivity among particular brain areas does show changed randomness linked to substance use. Abnormal randomness was found between salience and default mode functional domains. This dysfunction is in line with some postulates of the network model of addiction. The study provides new information on the effects of substance use on the brain. PMID- 30440563 TI - EEG Hyperconnectivity Study on Saxophone Quartet Playing in Ensemble. AB - A professional quartet of saxophonists playing in ensemble provides a perfect scenario to study the eventual occurrence of synchronous oscillatory brain activity across subjects. Here, we applied hyperscanning methodologies for simultaneously recordings of electroencephalographic (EEG) signals from four professional saxophonists while they observ an audiovideo recording of their own previous musical performance. An ad-hoc musical composition was written for the study. At debriefing, the subjects were asked to answer two questionnaires to assess their empathy trait and the musical leadership. In order to estimate the hyperconnectivity of each musician we proposed a measure which combines phase synchronization index of brain oscillations and graph theory framework. The inter connectivity level of each musician was statistically compared. Statistical results revealed a significant lower hyperconnectivity in the left Brodmann area 44 for the Soprano with respect to the other three members. Recent theories attributed this brain region (Broca's area) to music generation, empathy processes and communication. We hypothesize a relationship between brain-to-brain connectivity level and the musical role within the quartet. PMID- 30440564 TI - Investigation Of Interaction Between Physiological Signals And fMRI Dynamic Functional Connectivity Using Independent Component Analysis. AB - The blood oxygen level dependent (BOLD) fMRI signal is influenced not only by neuronal activity but also by fluctuations in physiological signals, including respiration, arterial CO2 and heart rate/ heart rate variability (HR/HRV). Even spontaneous physiological signal fluctuations have been shown to influence the BOLD fMRI signal in a regionally specific manner. Consequently, estimates of functional connectivity between different brain regions, performed when the subject is at rest, may be confounded by the effects of physiological signal fluctuations. In addition, resting functional connectivity has been shown to vary with respect to time (dynamic functional connectivity - DFC), with the sources of this variation not fully elucidated. The effect of physiological factors on dynamic (time-varying) resting-state functional connectivity has not been studied extensively, to our knowledge. In our previous study, we investigated the effect of heart rate (HR) and end-tidal CO2 (PETCO2) on the time-varying network degree of three well-described RSNs (DMN, SMN and Visual Network) using mask-based and seed-based analysis, and we identified brain-heart interactions which were more pronounced in specific frequency bands. Here, we extend this work, by estimating DFC and its corresponding network degree for the RSNs, employing a data-driven approach to extract the RSNs (low-and high-dimensional Independent Component Analysis (ICA)), which we subsequently correlate with the characteristics of simultaneously collected physiological signals. The results confirm that physiological signals have a modulatory effect on resting-state, fMRI-based DFC. PMID- 30440565 TI - Identification of Time-Varying Cortico-cortical and Cortico-Muscular Coherence during Motor Tasks with Multivariate Autoregressive Models. AB - Neural populations coordinate at fast subsecond time-scales during rest and task execution. As a result, functional brain connectivity assessed with different neuroimaging modalities (EEG, MEG, fMRI) may also change over different time scales. In addition to the more commonly used sliding window techniques, the General Linear Kalman Filter (GLFK) approach has been proposed to estimate time varying brain connectivity. In the present work, we propose a modification of the GLFK approach to model timevarying connectivity. We also propose a systematic method to select the hyper-parameters of the model. We evaluate the performance of the method using MEG and EMG data collected from 12 young subjects performing two motor tasks (unimanual and bimanual hand grips), by quantifying time-varying cortico-cortical and corticomuscular coherence (CCC and CMC). The CMC results revealed patterns in accordance with earlier findings, as well as an improvement in both time and frequency resolution compared to sliding window approaches. These results suggest that the proposed methodology is able to unveil accurate time-varying connectivity patterns with an excellent time resolution. PMID- 30440566 TI - Test-retest Reliability of Functional Connectivity and Graph Metrics in the Resting Brain Network. AB - The combination of graph theoretical approaches and neuroimaging data provides a powerful way to explore the characteristics of brain network. Recently, the temporal variability of spontaneous brain activity and functional connectivity has attracted wide attention. Thus, it is essential to evaluate the reliability of functional network connectivity and properties from the dynamic perspective. However, previous test-retest (TRT) studies have explored this reliability with a static point of view. In this study, using a large rs-fMRI dataset from Human Connectome Project (HCP), we investigated TRT reliability of functional connectivity and graph metrics derived from the most commonly used method- sliding window at three time intervals (short: 72 seconds, middle: 15 minutes and long: >24 hours). The results revealed that reliable connectivities and related brain regions are mainly distributed in primary cortex, such as visual area and sensorimotor area and default mode network. Notably, connectivity strength and global efficiency have better reliability than other metrics. Finally, short scan time interval and long scan duration can increase the TRT reliability of metrics. Findings of present study provide important guidance for searching reliable network markers in future research. PMID- 30440567 TI - Implementation of High-Performance Correlation and Mapping Engine for Rapid Generation of Brain Connectivity Networks from Big fMRI Data. AB - With the emergence of the dynamic functional connectivity analysis, and the studies relying on real-time neurological feedback, the need for rapid processing methods becomes even more critical. Seed-based Correlation Analysis (SCA) of fMRI data has been used to create brain connectivity networks. With close to a million voxels in a fMRI dataset, the number of calculations involved in SCA becomes high. This work aims to demonstrate a new approach which produces high-resolution brain connectivity maps rapidly. The results show that HPCME with four FPGAs can improve the SCA processing speed by a factor of 40 or more over that of a PC workstation with a multicore CPU. PMID- 30440568 TI - Dynamic Influence of Ongoing Brain Stimulation on Resting State fMRI Connectivity: A Concurrent tDCS-fMRI Study. AB - Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that serves as treatment tool to neurological disorders. However, the mechanism of how the stimulation modulates ongoing brain activity and connectivity is still not fully understood. Simultaneous acquisition of neuroimaging data together with brain stimulation could allow a noninvasive examination of the brain dynamic changes during the process. In this pilot study, concurrent tDCS and fMRI was conducted in a healthy subject. Dynamic functional connectivity and effective connectivity were used to reveal the information flow. The results demonstrated that tDCS duration has important effects on the brain connectivity and the causal relationships among the brain regions. These results might reflect the fundamental mechanism of brain processing under the external stimulation. PMID- 30440569 TI - Characterizing the Effects of MR Image Quality Metrics on Intrinsic Connectivity Brain Networks: A Multivariate Approach. AB - Motion-induced artifact detection has become a fixture in the assessment of functional magnetic resonance imaging (fMRI) quality control. However, the effects of other MR image quality (IQ) metrics on intrinsic connectivity brain networks are largely unexplored. Accordingly, we report herein the initial assessment of the effects of a comprehensive list of IQ metrics on resting state networks using a multivariate analysis of covariance (MANCOVA) approach based on high-order spatial independent component analysis (ICA). Three categories of MR IQ metrics were considered: (1) metrics for artifacts including the AFNI outlier ratio and quality index, framewise displacement, and ghost to signal ratio, (2) metrics for the temporal quality of MRI data including the temporal framewise change in global BOLD signals (DVARS), global correlation of time-series, and temporal signal to noise ratio, (3) metrics for the structural quality of MRI data including the entropy focus criterion, foreground-background energy ratio, full-width half maximum smoothness, and static signal to noise ratio. After FDR correction for multiple comparisons, results showed significant effects of the static and temporal signal to noise ratios on the spatial map intensities of the basal ganglia, default-mode and cerebellar networks. AFNI outlier ratio, framewise displacement and DVARS exhibited significant effects on the BOLD power spectra of sensorimotor networks. The global correlation of time-series displayed wide-spread modulation of the spectral power in most networks. Further investigations of the effect of IQ metrics on the characteristics of intrinsic connectivity brain networks allow more accurate interpretation of the fMRI results. PMID- 30440570 TI - Measuring the Influence of Physiological Noise Corrections on ICA Derived Intrinsic Connectivity Brain Networks in Rest and Task fMRI. AB - Physiological noise corrections using RETROICOR algorithm has been shown to increase signal sensitivity in resting state networks such as the default-mode network. However, independent component analysis (ICA)-based network approach may suffer from such corrections especially if there is any overlap between two sources in the decomposition domain. To address the extent the physiological noise corrections may impact ICA derived intrinsic connectivity brain networks, we measured network features including functional network connectivity (FNC), power spectra, and network spatial maps in the resting state and task functional magnetic resonance imaging (fMRI) data that were acquired in the same visit from a group of healthy volunteers. Statistical analysis showed functional connectivity between several networks were significantly changed after RETROICOR corrections in both rest and task fMRI. Significant FNC alterations were found in the subcortical, basal ganglia, salience, and default-mode networks. Power spectra analysis showed a trend toward lower power spectra in the subcortical and salience networks at [0.20 and 0.24] Hz after RETROICOR corrections in both rest and task fMRI. Furthermore, physiological noise corrections led to volumetric decrease in the resting state networks that included the subcortical, basal ganglia, salience, and default-mode networks, and volumetric enlargement in the sensorimotor and cerebellar networks. In task fMRI data, physiological noise corrections generally resulted in the expansion of networks except for task activated networks including the anterior salience, central executive, dorsal attention, and cerebellar networks. If confirmed with larger sample sizes, these results suggest that physiological noise corrections alter some network features, and that such alterations are different between resting state and task fMRI data. PMID- 30440571 TI - Differential Amplitude of Low-Frequency Fluctuations in brain networks after BCI Training with and without tDCS in Stroke. AB - Mapping the brain alterations post stroke and post intervention is important for rehabilitation therapy development. Previous work has shown changes in functional connectivity based on resting-state fMRI, structural connectivity derived from diffusion MRI and perfusion as a result of brain-computer interface-assisted motor imagery (MI-BCI) and transcranial direct current stimulation (tDCS) in upper-limb stroke rehabilitation. Besides functional connectivity, regional amplitude of local low-frequency fluctuations (ALFF) may provide complementary information on the underlying neural mechanism in disease. Yet, findings on spontaneous brain activity during resting-state in stroke patients after intervention are limited and inconsistent. Here, we sought to investigate the different brain alteration patterns induced by tDCS compared to MI-BCI for upper limb rehabilitation in chronic stroke patients using resting-state fMRI-based ALFF method. Our results suggested that stroke patients have lower ALFF in the ipsilesional somatomotor network compared to controls at baseline. Increased ALFF at contralesional somatomotor network and alterations in higher-level cognitive networks such as the default mode network (DMN) and salience networks accompany motor recovery after intervention; though the MI-BCI alone group and MI-BCI combined with tDCS group exhibit differential patterns. PMID- 30440572 TI - Spectral Estimation Methods for Evaluating iPPG Pulse Rate Variability. AB - Non-contact measurement of physiological parameters, like pulse rate variability (PRV), has numerous applications in medicine and affective computing. PRV is an informative measure of autonomic nervous system activity. Spectral estimation from unevenly sampled, non-stationary data is integral to pulse rate variability frequency-domain analysis. We present the first comparison of results of PRV computation using the Lomb-Scargle method and Bayesian Spectral Estimation. The Lomb-Scargle method performs well, even in the presence of missing beats. However, the Bayesian Spectral Estimation method has advantages when tracking changes in amplitude and frequency. We illustrate these characteristics with results from synthetic data and real non-contact imaging photoplethysmography measurements. PMID- 30440573 TI - Electroencephalography Classification in Brain-Computer Interface with Manifold Constraints Transfer. AB - Insufficient training data is a serious problem in all domains related to bioinformatics. Transfer learning is a promising tool to solve this problem, which relaxes the hypothesis that training data must be independent and identically distributed with the test data. We construct a sophisticated electroencephalography (EEG) signal representation and obtain an efficient EEG feature extractor through manifold constraints-based joint adversarial training with training data from other domains. EEG signal is more easily distinguished in the feature space mapped by the feature extractor. Negative transfer is one of the most challenging problems in transfer learning. In our approach, we apply manifold constraints to overcome this problem, which can avoid the geometric manifolds in the target domain being destroyed. The experiments demonstrate that our approach has many advantages when applied to EEG classification tasks. PMID- 30440574 TI - Development of a Cognitive Brain-Machine Interface Based on a Visual Imagery Method. AB - In the field of brain-machine interface (BMI) research, the development of cognitive BMI is a hot topic because it may lead to more intuitive and goal directed findings than existing BMI technology. In this study, we devised a "visual-imagery method," which enables visual imaging of the operation of a target. We also investigated an "inner-speech method," which comprised internal pronunciation of words without emitting sounds, and an "inner-speech + visual imagery method," which combined the two methods. When only the high $?gamma$ band (60-120 Hz) power in the prefrontal cortex was used, the average accuracy of the 15 participants, with 20-fold crossvalidation, was 81.3% in inner speech, 84.6% in visual imagery, and 83.2% in inner speech + visual imagery. This study also found that the frontal pole was the most useful region in the prefrontal cortex. PMID- 30440575 TI - Spatiotemporal Characteristics of Cortical Activities Associated with Articulation of Speech Perception. AB - Recently, brain computer interface (BCI) technologies that control external devices with human brain signals have been developed. However, most of the BCI systems, such as P300-speller, can only discriminate among options that have been given in advance. Therefore, the ability to decode the state of a person's perception and recognition, as well as that person's fundamental intention and emotions, from cortical activity is needed to develop a more general-use BCI system. In this study, two experiments were conducted. First, articulations were measured for Japanese monosyllabic utterances masked by several levels of noise. Second, auditory brain magnetic fields evoked by the monosyllable stimuli used in the first experiment were recorded, and neuronal current sources were localized in regions associated with speech perception and recognition - the auditory cortex (BA41), the Wernicke's area (posterior part of BA22), Broca's area (BA22), motor (BA4), and premotor (BA6) areas. Although the source intensity did not systematically change with SNR, the peak latency changed along SNR in the posterior superior temporal gyrus in the right hemisphere. The results suggest that the information associated with articulation is processed in this area. PMID- 30440576 TI - FPGA implementation of deep-learning recurrent neural networks with sub millisecond real-time latency for BCI-decoding of large-scale neural sensors (104 nodes). AB - Advances in neurotechnology are expected to provide access to thousands of neural channel recordings including neuronal spiking, multiunit activity and local field potentials. In addition, recent studies have shown that deep learning, in particular recurrent neural networks (RNNs), provide promising approaches for decoding of large-scale neural data. These approaches involve computationally intensive algorithms with millions of parameters. In this context, an important challenge in the application of neural decoding to next generation brain-computer interfaces for complex human tasks is the development of low-latency real-time implementations. We demonstrate a Field-Programmable Gate Array (FPGA) implementation of Long Short-Term Memory (LSTM) RNNs for decoding 10,000 channels of neural data on a mobile lowpower embedded system platform called "NeuroCoder". We provide a proof of concept in the context of decoding 20dimensional spectrotemporal representation of spoken words from simulated 10,000 neural channels. In this particular case, the LSTM model included 4,042,420 parameters. In addition to providing multiple communication interfaces for the BCI system, the NeuroCoder platform can achieve sub-millisecond real-time latencies. PMID- 30440577 TI - Effect of Implant Duration, Anatomical Location and Electrode Orientation on Bandwidth Recorded with a Chronically Implanted Endovascular Stent-Electrode Array. AB - Access to the brain to implant recording electrodes has conventionally required a craniotomy. To mitigate risks of open brain surgery, we previously developed a stent-electrode array that can be delivered to the cortex via cerebral vessels. Following implantation of a stent-electrode array (Stentrode) in a large animal model, we investigated the longevity of highquality signals, by measuring bandwidth in animals implanted for up to six months; no signal degradation was observed. We also investigated whether bandwidth was influenced by implant location with respect to the superior sagittal sinus and branching cortical veins; it was not. Finally, we assessed whether electrode orientation had an impact on recording quality. There was no significant difference in bandwidths from electrodes facing different orientations. Interestingly, electrodes facing the skull (180 degrees ) were still able to record neural information with high fidelity. Consequently, a minimally invasive surgical approach combined with a stent-electrode array is a safe and efficacious technique to acquire neural signals over a chronic duration. PMID- 30440578 TI - Increased Theta Oscillations During Motor Imagery in a Subject with Late-stage ALS. AB - Non-invasive brain computer interface (BCI) has been successfully used to control cursors, helicopters and robotic arms. However, this technology is not widely adopted by people with late-stage amyotrophic lateral sclerosis (ALS) due to poor effectiveness. In this study, we attempt to assess the cognitive state of a completely locked-in ALS subject, and her ability to use motor imagery-based BCI for control. The subject achieves above chance level accuracies for both open loop (62.2%) and closed-loop (68.7%) 2-class movement vs. idle decoding. We also observe a prominent theta oscillation with peak frequency at 4.5 Hz during the experiments. Quantification shows that the theta oscillatory power increases during motor imagery tasks compared to idle tasks for both open-loop as well as closed-loop BCI tasks. Furthermore, for closed-loop sessions, theta oscillation power correlates positively with feedback accuracy during movement tasks, and negatively with feedback accuracy during idle tasks. Our study demonstrates the feasibility of motor imagery-based BCI for late-stage ALS subjects, and highlights the importance of feedback during BCI implementation. PMID- 30440579 TI - A Multi-feature Fuzzy Index to Assess Stress Level from Bio-signals. AB - A mono-feature fuzzy index that evaluates the stress level from one feature extracted from ECG or GSR is presented. It is build using several measures of the feature recorded when the subject is at rest. The mono-feature fuzzy index can be merged in a multi-feature stress index without any tuning. It can be used to select relevant features and to detect stress. The performance of the stress index is analyzed on a data set made of 160 time periods of time when 20 subjects had to perform stressful tasks and corresponding control tasks. The stress was induced by 4 different tasks. The performances reached are 72% of correctly classified time periods in stress and no stress situations. Interesting conclusions could also be made on the tasks ability to induce stress. PMID- 30440580 TI - Automatic Detection of Hot Flash Occurrence and Timing from Skin Conductance Activity. AB - Hot flashes (HF) are intense, transient feelings of heat usually accompanied with flushed skin and sweating that are experienced by women around the time of menopause. HFs are associated with poor quality of life and increased cardiovascular risk. Automatic detection of HF occurrence and precise timing of HF onset could provide unique insight into the physiology of the HF and its effect on the cardiovascular system. A novel automatic algorithm is proposed for the detection of HFs occurrence and timing from the sternal skin conductance signal that is robust to noise and artifacts. The method is based on the gold standard rule (2MUS rise in skin conductance within 30 s) and considers several conditions based on the skin conductance level and its derivative to reject unwanted events. ECG-derived heart rate pattern variations are studied prior to the detected HF onset. The algorithm is validated against expert detected HFs over 200 hours of sleep data collected from 12 perimenopausal women. It achieved a total accuracy of 93% and a total error of 3% in HF detection. It was observed that heart rate increased before the onset of 80% of the HFs occurring in undisturbed sleep. Application of this algorithm along with fusion of other simultaneously recorded physiological measures has the potential to advance understanding of the HF. PMID- 30440581 TI - Quantitative Assessment of Cerebellar Ataxia With Kinematic Sensing During Rhythmic Tapping. AB - The aim of this study is to investigate the validity of an entropy-based objective assessment of cerebellar ataxia patients performing rhythmic tapping. Previous research conducted, particularly in time and frequency domains, tested the adherence of patients to more stringent experimental requirements. These requirements may inadvertently cause higher level brain functions to influence the performance and possibly obscure the cerebella related disabilities in the data stream. In this study, a multiscale entropy-based learning process that overcomes this practical limitation was considered. In particular, assessment techniques with less restrictions on the tapping duration were considered. Thirty three patients were engaged in the test, with three levels of severity 0 (normal), 1 (moderate) and 2 (severe) ranked by specialist clinicians. The performance of each model was evaluated using leave-oneout cross validation. Results from both time-frequency features and entropy features extracted and characterized the cerebellar condition captured during the finger and foot tapping tests (with over 80% accuracy). Strong correlations with clinical assessment-based scoring were observed with the entropy based approach for both tests, although the correlation with timefrequency features were less convincing. PMID- 30440582 TI - Study of Compressed Sensing and Predictor Techniques for the Compression of Neural Signals under the Influence of Noise. AB - In this paper an analysis of compression schemes based on compressed sensing (CS) and predictor techniques for neural signals is presented. The focus is on how much a compression algorithm can reduce data while not affecting the subsequent signal processing. Since neural signals are processed by means of spike sorting algorithms the evaluation is not trivial and not well defined, since there exists in fact many different ways to detect and cluster the spikes. Evaluating how much a compression scheme affects the result of spike sorting programs is a crucial step before implementing such compression technique. In the analysis two use cases are evaluated: in the first, spikes are detected and extracted and only thereafter compressed. In the second case, no information on the spikes is available and the whole raw signal is compressed. When dealing only with spike frames CS offers great compression at almost no loss, in the case of the whole recording its performances are greatly impaired and delta compression outperforms it in terms of data reduction and spike sorting results. In this case the reduction rates are modest but significant, ~3 - 4 times data reduction and the whole signal is preserved avoiding big permanent losses of information. PMID- 30440583 TI - Motion Tracking for Beating Heart Based on Sparse Statistic Pose Modeling. AB - A novel region-based method to track beating heart is proposed. Sparse statistical pose modeling is used to reconstruct the region of interest (ROI) on beating heart surface. Firstly, a high-complexity thin plate spline is employed to pre-reconstructed the ROI of a series of frames. The 3D pose data of the ROI from the pre-reconstructed results are extracted to train a low-complexity model based on the sparse statistical analysis. The new trained low-complexity model is robust and efficient for ROI reconstruction of the following frames. The proposed model significantly reduces the redundant degrees of freedom to fit the surface of the heart. A constraint item is added to the objective function which describes the 3D tracking problem to avoid erroneous convergence of the efficient second-order minimization (ESM) optimization algorithm. The new proposed method is evaluated on the phantom heart video and the in vivo video obtained by the da Vinci surgical system. PMID- 30440584 TI - Image Data Analysis for Quantifying Scar Transmurality in MRI phantoms for Cardiac Resynchronisation Therapy. AB - The use of implantable cardiac devices has increased in the last 30 years. Cardiac resynchronisation therapy (CRT) is a procedure which involves implanting a coin sized pacemaker for reversing heart failure. The pacemaker electrode leads are implanted into cardiac myocardial tissue. The optimal site for implantation is highly patient-specific. Most implanters use empirical placement of the lead. One region identified to have a poor response rate are myocardial tissue with transmural scar. Studies that precisely measure transmurality of scar tissue in the left ventricle (LV) are few. Most studies lack proper validation of their transmurality measurement technique. This study presents an image analysis technique for computing scar transmurality from late-gadolinium enhancement MRI. The technique is validated using phantoms under a CRT image guidance system. The study concludes that scar transmurality can be accurately measured in certain situations and validation with phantoms is important. PMID- 30440585 TI - Comparison of Image Acquisition Techniques in Four-Dimensional Flow Cardiovascular MR on 3 Tesla in Volunteers and Tetralogy of Fallot Patients. AB - Four-dimensional phase-contrast (PC) velocity-encoded flow magnetic resonance imaging (4D flow MRI) is a potentially valuable tool for studying cardiovascular hemodynamics for disease monitoring and/or treatment planning. In this study we compared the performance of two 4D flow MRI pulse sequences - echo-planar imaging (EPI) and segmented gradient-echo (turbo-field-echo or TFE on vendor's platform) on a clinical 3T system in 6 human subjects including 3 patients with Tetralogy of Fallot (TOF). For aortic flow rate, the coefficients of variation (COV) between 2D and 4D EPI were 7.0% and 7.7% for controls and patients respectively. The corresponding COV between 2D and 4D TFE were 19.0% and 18.3% for controls and patients respectively. The COV between 4D TFE and 4D EPI were larger than 18.7% in kinetic energy analysis. 4D EPI demonstrated acceptable accuracy of intra cardiac flow quantification, which was also shown in the ex-vivo phantom measurements. PMID- 30440586 TI - A Novel 4D Semi-Automated Algorithm for Volumetric Segmentation in Echocardiography. AB - Segmentation of the left ventricle (LV) in temporal 3D echocardiography sequences poses a challenge. However, it is an essential component in generating quantitative clinical measurements for the diagnosis and treatment of various cardiac diseases. Identifying the endocardial borders of the left ventricle can be difficult due to the inherent properties of ultrasound. This study proposes a 4D segmentation algorithm that segments over temporal 3D volumes that has minimal user interaction and is based on a diffeomorphic registration approach. In contrast to several existing algorithms, the proposed method does not depend on training data or make any geometrical assumptions. The algorithm was evaluated on seven patients obtained from the Mazankowski Alberta Heart Institute, Edmonton, Canada in comparison to expert manual segmentation. The proposed approach yielded Dice scores of 0.94 (0.01), 0.91 (0.03) and 0.92 (0.02) at end diastole, at end systole and over the entire cardiac cycle, respectively. The corresponding Hausdorff distance values were 4.49 (1.01) mm, 4.94 (1.41) mm, and 5.05 (0.85) mm, respectively. These results demonstrate that the proposed 4D segmentation approach for the left ventricle is robust and can potentially be used in clinical practice. PMID- 30440587 TI - Multiview Sequential Learning and Dilated Residual Learning for a Fully Automatic Delineation of the Left Atrium and Pulmonary Veins from Late Gadolinium-Enhanced Cardiac MRI Images. AB - Accurate delineation of heart substructures is a prerequisite for abnormality detection, for making quantitative and functional measurements, and for computer aided diagnosis and treatment planning. Late Gadolinium-Enhanced Cardiac MRI (LGE CMRI) is an emerging imaging technology for myocardial infarction or scar detection based on the differences in the volume of residual gadolinium distribution between scar and healthy tissues. While LGE-CMRI is a well established non-invasive tool for detecting myocardial scar tissues in the ventricles, its application to left atrium (LA) imaging is more challenging due to its very thin wall of the LA and poor quality images, which may be produced because of motion artefacts and low signal-to-noise ratio. As the LGE-CMRI scan is designed to highlight scar tissues by altering the gadolinium kinetics, the anatomy among different heart substructures has less distinguishable boundaries. An accurate, robust and reproducible method for LA segmentation is highly in demand because it can not only provide valuable information of the heart function but also be helpful for the further delineation of scar tissue and measuring the scar percentage. In this study, we proposed a novel deep learning framework working on LGE-CMRI images directly by combining sequential learning and dilated residual learning to delineate LA and pulmonary veins fully automatically. The achieved results showed accurate segmentation results compared to the state-of the-art methods. The proposed framework leads to an automatic generation of a patient-specific model that can potentially enable an objective atrial scarring assessment for the atrial fibrillation patients. PMID- 30440588 TI - Improving Visual Detection of Wall Motion Abnormality with Echocardiographic Image Enhancing Methods. AB - Analysis of wall motion abnormality using echocardiography is an established method for detecting myocardial ischemia. We describe a hybrid approach of enhancing 2D+T echo datasets with border detection and Eulerian motion magnification to improve the visual assessment of wall motion. We implemented a local phase-based approach using the monogenic signal and its derived features, either feature asymmetry (FA) or oriented feature symmetry (OFS), to detect boundaries of the heart structure. We enhanced the 2D+T datasets using either an intensity-based or phase-based Eulerian Motion Magnification (EMM) video processing technique, and identified among eight different types of enhancements the best performing method as OFS with an accuracy of 78% versus the original B Mode with an accuracy of 71%. PMID- 30440589 TI - The Correlation Analysis Between DTI Network Parameters and AVLT Scale Scores of Alzheimer's Disease. AB - Neuroimaging and neuropsychology are employed to investigate the pathological features and clinical characteristics of Alzheimer's disease (AD) in order to find a method for the precise treatment. Diffusion tensor imaging (DTI) provides a non-intrusive examination of cranial nerve diseases which can help us observe the microstructure of neuron fibers. Building the brain network provides a chance to reveal the significance of specific brain region and the relevance among different regions. In this study, we propose a completely novel method to analyze AD. First whole brain network is built on the basis of a novel segmentation atlas, and global graph theoretical parameters are calculated to evaluate the characteristic of whole brain. Then graph theoretical parameters of specific brain regions are extracted based on whole brain network. Finally neuropsychology scale are employed and we analyze the correlation between graph theoretical parameters of specific regions and scale scores. Our results illustrate the connection between neuroimaging data and neuropsychological scores, and provide a reasonable explanation for the potential connection between clinical performance and physiological brain lesions of AD patients. PMID- 30440590 TI - Left fimbria atrophy is associated with hippocampal metabolism in female major depressive disorder patients. AB - Despite the high incidence of major depressive disorder (MDD) in females, the detailed neurobiology mechanism remains not fully understood. Increasing evidence showed that MDD was associated with hippocampal volumetric abnormality with different subfields demonstrating various alteration features. However, the linkage between hippocampal atrophy with its biochemical information remains unclear. In this study, we aim to investigate the relationship between bilateral hippocampal subfields volumetric and metabolic information in female MDD patients, using a combined T1weighted magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (H-MRS) technology. There are 15 female MDD patients and 12 matched healthy controls involved in the study. We found a significant decrease in left fimbria volume in MDD group, which was negatively correlated with left hippocampal choline level. In addition, the left hippocampal creatine concentration in patients was negatively correlated with left fimbria volume. Moreover, the NAA level in left hippocampus was negatively correlated with MDD clinical symptomology including anxiety and depression scores. Our findings suggest that the altered coupling between hippocampal structural and metabolic features might contribute to the etiology of female MDD patients. PMID- 30440591 TI - Multivariate Analysis of White Matter Structural Networks of Alzheimer's Disease. AB - The connectome-wide association studies exploring association between brain connectome and disease phenotypes have suffered from massive number of comparisons. In this paper, we propose to apply a multivariate distance-based analytic framework on brain white matter (WM) structural networks invaded by Alzheimer's disease (AD). Eighty-three subjects including patients with AD, amnestic mild cognitive impairment (aMCI) and healthy subjects were scanned with dMRI. By constructing WM structural network for each individual, we used both multivariate and traditional univariate statistical models to complimentarily analyze network pattern and fiber strength changes due to AD. WM connections linked with several brain structures were found significantly changed between AD group and normal controls. No significant findings were observed between aMCI group and normal controls. Our results demonstrate the sensitivity of the combined connectome-based analytic framework in detecting abnormalities of structural brain network. PMID- 30440592 TI - Altered Fractional Amplitude of Low Frequency Fluctuations in Unmedicated Female Patients with Obsessive-Compulsive Disorder. AB - A number of resting-state functional magnetic resonance imaging (rs-fMRI) studies indicate dysfunction of large-scale brain networks underlying the pathophysiology of obsessive-compulsive disorder (OCD). Recent epidemiology studies show that the prevalence of female OCD patients is higher than that of males. However, the underlying neurobiology mechanism for female OCD patients remains not fully understood. In this study, we are aimed to explore the spontaneous brain neuronal activity in unmedicated female OCD patients using rs-fMRI methodology and fractional amplitude of low frequency fluctuations (fALFF) analysis. Additionally, we examine the relationship between fALFF changes and female OCD symptomatology. Increased fALFF values in right brainstem, right rectus, left middle temporal gyrus and right angular were found in OCD females. And decreased fALFF values in right cerebellum, left middle occipital gyrus, left insula, postcentral gyrus and left precentral gyrus were shown in female OCD patients. Moreover, the fALFF values in left precentral gyrus and left middle temporal gyrus were positively associated with patients YBOCS-Obsessions scores and HAMD scores, respectively. Our findings bring additional insights in understanding the pathophysiology of female OCD patients. PMID- 30440593 TI - Diagnostic Classification of Autism using Resting-State fMRI Data and Conditional Random Forest. AB - Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is associated with atypical connectivity within and between brain regions. In this study, we attempted to classify functional Magnetic Resonance Images (fMRI) of Typically Developing (TD) and ASD participants using conditional random forest and random forest. Restingstate fMRI images of TD and ASD participants (N=320 for training and N=80 for validation) were obtained from the Autism Imaging Data Exchange; ABIDE-I, ABIDE-II. Images were preprocessed using a standard pipeline. A Functional Connectivity (FC) matrix was calculated using 237 cortical, subcortical, and cerebellar Regions of Interest (ROIs). The dimensionality of the FC matrix was reduced using conditional random forests and at each dimension classification accuracy was tested using random forests. Results suggest that in the current dataset, the random forest is able to classify the TD and ASD with a peak accuracy of 65% using 143 features. Remarkably, the Cingulo-Opercular Task Control (COTC) region contributed the highest number of features linked to more accurate classification, and connectivity between COTC and the dorsal attention network distinguished ASD and TD participants. PMID- 30440594 TI - Effects of Consecutive Moderately Cold Days on Cardiovascular Disease Mortality in Shenzhen, China: A Preliminary Study. AB - Despite traditional risk factors such as aging and hyperlipemia for cardiovascular disease (CVD) mortality, many studies have also confirmed that both hot and cold ambient temperatures are associated with CVD mortality. This paper aims to explore the effects of consecutive moderately cold days on CVD mortality in the warm city Shenzhen during relatively cold months from 2011 to 2015. In this study, totally there were 4589 CVD death cases among the residents during a total of 24 relatively cold months. Effects of consecutive cold days on CVD mortality was evaluated by the daily percent increase of CVD mortality. Three temperature thresholds were selected, which were 15 degrees , 14 degrees , and 13 degrees , respectively. The results showed that when the cold weather lasted 5 days and onwards, CVD mortality showed a continuous increment. When the temperature thresholds were 15 degrees , 14 degrees , or 13 degrees , percent increase of CVD mortality at the consecutive 6th cold day reached 22%, 21%, and 24% respectively, and 26%, 38%, 33% at the consecutive 10th cold day, respectively. Thus, the consecutive moderately cold days in warm regions had continuous and accumulative negative effects on CVD mortality. The study may help local government to take timely prevention measures for moderately cold temperatures and thus to protect the wellbeing for the public. PMID- 30440595 TI - Biomarkers for Adolescent MDD from Anatomical Connectivity and Network Topology Using Diffusion MRI. AB - Due to the high resistance (35%) to the current treatment methods in adolescent Major Depressive Disorder (MDD) and its tragic outcomes, the discovery of treatmentrelated responders is critical to developing effective treatments. In this paper, the permutation test is performed to identify statistically significant changes in anatomical characteristics during pairwise comparisons among the control group (n=27), treated MDD group (n=37), and untreated MDD group (n=15). The anatomical characteristics include: 1) anatomical connectivity defined using DTI metrics between a pair of brain regions, and 2) topological measurements of anatomical networks. With the Bonferroni correction for multiple comparison, significant alterations in community structure and local topology were identified as the p-value < 5%, which include: 1) a reduced nodal centrality (degree and strength) on right hippocampus for treated compared to untreated group, 2) an elevated clustering coefficient and local efficiency on right lateral orbitofrontal cortex for untreated compared to the combination of control and treated groups, 3) an increased participation coefficient for untreated patients on left insula cortex in the meandiffusivity network compared to the combination of control and treated groups, and 4) a degraded module degree z score on right caudate nucleus for all the patients compared to the control group. Two connections, hippocampus-insula in the right hemisphere and parahippocampal-insula in the left hemisphere, were found significantly altered in TR, AD, and FA due to MDD. PMID- 30440596 TI - Investigation of Key Variables Impacting ICM Sensing Using Computer Simulations. AB - The insertable cardiac monitors (ICMs) used for diagnosing and managing abnormal heart activities can falsely detect heart rhythms due to respiration, device rotation/orientation, device position, device flipping, and body mass that alter the amplitudes and morphologies. The objective of this paper is to investigate the effects of these key variables on ICM sensing by using computer simulations and virtual human family. We observed in these simulations that sensing amplitudes can vary greatly depending on device flipping, orientation/rotation, and migration; change significantly due to respiration effect; and are most sensitive to it when body mass is large. Those findings support identification of the key variables impacting clinical false detections. PMID- 30440597 TI - Monitoring Lung Mechanics during Mechanical Ventilation using Machine Learning Algorithms. AB - Evaluation of lung mechanics is the primary component for designing lung protective optimal ventilation strategies. This paper presents a machine learning approach for bedside assessment of respiratory resistance (R) and compliance (C). We develop machine learning algorithms to track flow rate and airway pressure and estimate R and C continuously and in real-time. An experimental study is conducted, by connecting a pressure control ventilator to a test lung that simulates various R and C values, to gather sensor data for validation of the devised algorithms. We develop supervised learning algorithms based on decision tree, decision table, and Support Vector Machine (SVM) techniques to predict R and C values. Our experimental results demonstrate that the proposed algorithms achieve 90.3%, 93.1%, and 63.9% accuracy in assessing respiratory R and C using decision table, decision tree, and SVM, respectively. These results along with our ability to estimate R and C with 99.4% accuracy using a linear regression model demonstrate the potential of the proposed approach for constructing a new generation of ventilation technologies that leverage novel computational models to control their underlying parameters for personalized healthcare and context aware interventions. PMID- 30440598 TI - Synthetic Sensor Data Generation for Health Applications: A Supervised Deep Learning Approach. AB - Recent advancements in mobile devices, data analysis, and wearable sensors render the capability of in-place health monitoring. Supervised machine learning algorithms, the core intelligence of these systems, learn from labeled training data. However, labeling vast amount of data is time-consuming and expensive. Moreover, sensor data often contains personal information that a user may not be comfortable sharing. Therefore, there is a strong need to develop methods for generating realistic labeled sensor data. In this paper, we propose a supervised generative adversarial network architecture that learns from feedback from both a discriminator and a classifier in order to create synthetic sensor data. We demonstrate the effectiveness of the architecture on a publicly available human activity dataset. We show that our generator learns to output diverse samples that are similar but not identical to the training data. PMID- 30440599 TI - Comparisons of Oscillometric Blood Pressure Measurements at Different Sites of the Upper Limb. AB - The importance of home blood pressure (BP) monitoring has been emphasized for achieving effective hypertension management. Currently, the most popular non invasive BP monitors for home use are the upper-arm cuff-style oscillometric devices which determine BP from the cuff pressure oscillations during the cuff inflation/deflation induced by the pulsatile blood flow in the compressed arteries. However, the large size of the upper-arm cuff is not favorable for attachment in daily life for ambulatory BP monitoring. Therefore, the miniaturization of home BP monitors is in demand to improve their portability for frequent measurements. This work examined the oscillometric measurement of mean blood pressure(MBP) at upper arm (UA), middle forearm (MA), wrist (WR), finger proximal phalanx (FP) and finger distal phalanx (FD) on 14 young adults. The experimental results showed that the mean and standard deviation of the differences between the oscillometric MBP at UA and the other sites are 8.86+/ 6.28 mm Hg at MA, 14.43+/-5.52 mm Hg at WR, 9.80+/-6.57 mm Hg at FP and -0.77+/ 6.37 mm Hg at FD, respectively. Based on hand checking and literature data, the order of the ratios of the bone volume to the surrounding tissue volume from large to small is WR>MA~FP>FD~UA. Together with the experimental results, we infer that a larger bone-tissue volume ratio could result in a larger oscillometric MBP reading. Since the applied cuff pressure are supposed to be less effectively absorbed by the soft-tissue surrounding a larger rigid bone, it is more difficult to occlude the arteries buried in the pressure-absorbing tissue at a bonier site by the inflatable cuffs, which leads to a higher measured MBP than the real MBP. In conclusion, it is promising to develop the finger oscillometric BP monitors to be worn on the finger distal phalanx which have a compact size and provide consistent measurement results with the UA measurements. PMID- 30440600 TI - Vomit Comet Physiology: Autonomic Changes in Novice Flyers. AB - This exploratory study examined the effects of varying g-forces, including feelings of weightlessness, on an individual's physiology during parabolic flight. Specifically, we collected heart rate, accelerometer, and skin conductance measurements from 16 flyers aboard a parabolic flight using wearable, wireless sensors. The biosignals were then correlated to participant reports of nausea, anxiety, and excitement during periods of altered g-forces. Using linear mixed-effects models, we found that (1) heart rate was positively correlated to individuals' self-reported highest/lowest periods of both anxiety and excitement, and (2) bilateral skin conductance asymmetry was positively correlated to individuals' self-reported highest/lowest periods of nausea. PMID- 30440601 TI - A Novel Synthetic Simulation Platform for Validation of Breathing Rate Measurement. AB - Validation of biosensor algorithms is paramount for regulated medical devices applied to patient monitoring. We present validation of breathing rate (BR) measurement using a patch medical device via a novel synthetic simulation platform, in-hospital data collection and controlled laboratory study. Single lead ECG and triaxial body acceleration signals with variability and noise are synthetically generated and quantized for a constellation according to the input parameters of heart rate (HR) as a fundamental frequency $( f_{c})$ of ECG and reference BR as a modulating frequency $( f_{r})$. Synthetic signals are input to the BR algorithms and the performance of output BRs are evaluated for a region-of interest of the constellation $( f_{c}/ f_{r}?,?ge 3$ & $f_{c}/ f_{r}?,?le 8)$ accounting the Nyquist and physiological varability. The performances of patch sensor's BR are also evaluated in 13 post-operative patients with reference to a clinical bedside monitor and in 57 subjects carrying out a controlled laboratory protocol with reference to capnography. The synthetic simulations revealed mean absolute error (MAE) of 0.8+/-0.6 brpm and standard deviation of absolute error of 0.3+/-0.2 brpm for the BR algorithms of patch sensor. The controlled laboratory testing revealed MAE of 1.7+/-0.7 brpm (n=57) for stationary conditions. The proposed simulation platform can be useful for developmental refinement or validation of BR measurement prior to testing in humans at clinical or laboratory conditions and applicable for testing other patient monitoring devices with modular modifications. PMID- 30440602 TI - Efficient Design of Real Time Bio-Signal Preprocessing for Wearable Devices. AB - Wearable devices for body-status monitoring require various signal processing such as ambient noise filtering and signal quality evaluation. While wearable devices are very limited in resource, conventional noise filtering and signal quality evaluating methods consume considerable amount of processing power. Moreover, these conventional methods are not suitable for processing bio-signals in terms of its performance. In this paper, we propose a novel method of preprocessing bio-signals. This preprocessing method includes distortionless noise filtering and signal quality estimation, where both parts are basically based on a simple combination of multiple low pass IIR filters. PMID- 30440603 TI - Optimizing Energy Harvesting for Foot Based Wearable Sensors. AB - Wearable devices have the potential to improve healthcare, but suffer from significant barriers to adoption, including the need for constant recharging. Harvesting energy from the ambient environment to top-up batteries can overcome this, but the actual energy available is very small, and hence it is critical that the whole system is highly optimized. This paper presents an investigation into the optimization of inertial energy harvesters for placement at the human foot. Lower body locations have previously been shown to be very energy dense, however previous energy harvester modeling has focused on the lower leg rather than the foot itself for ease of device placement. We show that the typical energy density can be almost double at the foot compared with lower leg positions, with substantially more energy concentrated in a smaller bandwidth. There is thus a dual benefit of placing a harvester at the foot: there is more energy due to the larger movement of the foot, and more efficient (higher Q) harvesters can be used to increase the collected energy. We place these results in context by analyzing the power demands of a typical wearable, and identify that with appropriate harvester tuning the peak current requirements of the electronics can be fitted into the energy peaks generated from each footstep. PMID- 30440604 TI - Personalized Human Activity Recognition using Wearables: A Manifold Learning based Knowledge Transfer. AB - Human activity recognition (HAR) is an important component in health-care systems. For example, it can enable context-aware applications such as elderly care and patient monitoring. Relying on a set of training data, supervised machine learning algorithms form the core intelligence of most existing HAR systems. Meanwhile, the accuracy of an HAR model highly depends on the similarity between the training and the operating context. Therefore, there is a need for developing machine learning algorithms that can easily adapt to the operating context at hand. In this paper, we propose a cross-subject transfer learning algorithm that links source and target subjects by constructing manifolds from feature-level representation of the source subject(s). Our algorithm assigns labels to the unlabeled data in the current context using the manifold learned from the source subject(s). The newly labeled data is used to develop a personalized HAR model for the current context (i.e., target subject). We demonstrate the efficacy of the algorithm using a publicly available dataset on HAR. We show that the proposed framework improves the accuracy of activity recognition by up to 24%. PMID- 30440605 TI - A machine learning approach to targeted balance rehabilitation in people with Parkinson's disease using a sparse sensor set. AB - Clinical Balance Assessments Often Rely On Functional Tasks As A Proxy For Balance (E.G., Timed Up And Go). In Contrast, Analyses Of Balance In Research Settings Incorporate Quantitative Biomechanical Measurements (E.G., Whole-Body Angular Momentum, H) Using Motion Capture Techniques. Fully Instrumenting Patients In The Clinic Is Not Feasible, And Thus It Is Desirable To Estimate Biomechanical Quantities Related To Balance From Measurements Taken From A Subset Of The Body Segments. Machine Learning Algorithms Are Well-Suited For This Type Of Low- To High-Dimensional Mapping. Thus, Our Objective Was To Develop And Validate An Artificial Neural Network For Estimating Contributions To H From 12 Body Segments Using Only Five Inertial Measurement Units. The Network Was Trained, Tested And Validated On Data From Five Able-Bodied Individuals Performing Forty Trials Each Of A Circuit Involving Complex Walking Tasks, Including Stairs, Ramp, And Direction Changes. The Network Was Also Separately Tested On Four Trials Of An Individual With Parkinson'S Disease Walking On The Circuit. The Output Of The Network Was Strongly Correlated With The Segment Contributions To H In Both Able-Bodied (R= 0.997) And Parkinson'S Disease (R= (0.998) Subjects. The Estimated Values Also Had Low Error Relative To The Signal Magnitude, With The Largest Mean +/- SD Rootmean-Squared Errors Of 8.04 +/- 1.76% Peak Signal Magnitude In Able-Bodied Individuals And 7.96 +/- 0.91% In The Individual With Parkinson'S Disease. These Promising Results Establish The Feasibility Of Using A Sparse Set Of Inertial Measurement Units To Provide Quantitative Data To Clinicians For Targeted Balance Rehabilitation Across Different Patients. PMID- 30440606 TI - An Investigation of the Effect of AGC Gain on the Output Signal to Noise Ratio in Cochlear Implant Sound Processing. AB - Measurement of speech intelligibility of cochlear implant (CI) recipients is typically carried out with a speech-innoise test procedure. Metrics which predict speech intelligibility can pre-screen new sound processing strategies prior to comprehensive testing with human subjects.The Output Signal to Noise Ratio (OSNR) metric calculates the Signal to Noise Ratio (SNR) which is present at the CI sound processor output. Watkins et al. (2018) found OSNR was an accurate predictor of speech intelligibility that could predict intelligibility in scenarios where other predictors could not.The current study investigated the effect of the sound processor automatic gain control (AGC) on OSNR and a simplified metric, Separate gain SNR (SSNR), which calculated the SNR at the CI output, assuming no interaction between the signal and noise in the sound processor. Prediction accuracy of OSNR was compared to that of Input SNR and SSNR.It was found that AGC-induced distortion and SNR degradation in speech gaps worsened OSNR. For scenarios with significant non-linear, time-varying processing, OSNR was the most accurate prediction metric. SSNR was found to be an inaccurate predictor. PMID- 30440607 TI - Noise-Induced Hearing Loss in Mice: Effects of High and Low Levels of Noise Trauma in CBA Mice. AB - Acoustic trauma can induce temporary or permanent noise-induced hearing loss (NIHL). Noise exposed animal models allow us to study the effects of various noise trauma insults on the cochlea and auditory pathways. Here we studied the short-term and long-term functional changes occurring in the auditory system following exposure to two different noise traumas. Several measures of hearing function known to change following noise exposure were examined: Temporary (TTS) and permanent (PTS) threshold shifts were measured using auditory brainstem responses (ABR), outer hair cell function was examined using distortion product otoacoustic emissions (DPOAEs), and auditory temporal processing was assessed using a gap-in-noise (GIN) ABR paradigm. Physiological measures were made before and after the exposure (24 hours, 2 weeks, 4 weeks, and 1 year). The animals were perfused and their brain, and cochlea were collected for future biomarker studies. Young adult mice were exposed to 110 dB and 116 dB octave-band noise levels for 45 minutes, and both groups demonstrated significant threshold shifts 1 day post-noise exposure across all frequencies. However 2 weeks postexposure, PTS within the 110 dB group was significantly reduced compared to 1 day post trauma, this improvement in thresholds was not as great in the 116 dB exposure group. At 2 weeks post-trauma, differences between the measured PTS in the two groups was significant for 4 of the 7 measured frequencies. At this 1 year time point after exposure, mice in the 110 dB group showed very minor PTS, but the 116 dB group showed a large PTS comparable to their 2 and 4 week PTS. At this time point, PTS variation between the two groups was significant across all frequencies. DPOAE amplitudes measured 2 weeks post exposure showed recovery for all frequencies within 10 dB (average) of the baseline in the 110 dB group, however for the 116 dB exposure DP amplitudes were elevated by about 30 dB. The differences in DPOAE amplitudes between the 110 dB and 116 dB groups were significant at 2 weeks, 4 weeks, and 1 year post-trauma in the mid frequency range. At 2 weeks, 4 weeks, and 1 year, DPOAE thresholds returned to within 10 dB of the baseline for the 110 dB group in the low and mid frequency range, whereas the 116 dB group still showed shifts of 30 dB for all frequency ranges. For Gap ABRs, there was a significant decrease in both noise burst 1 (NB1) and noise burst 2 (NB2) amplitudes for peaks 1 and 4 in the 116 dB group relative to the 110 dB group when measured at 1 year post trauma. These results indicate that a 6 dB increase in noise exposure intensity results in a significant increased ototrauma in both the peripheral and central auditory systems. PMID- 30440608 TI - Recovery of the Response of Sensory Fibers to the Second of a Pair of Peripheral Nerve Stimuli. AB - Neural interfaces that stimulate the peripheral nerves have the potential to provide sensory feedback from artificial hands. Many neural interfaces are now being developed that allow for multi-channel stimulation of nerves. It is widely accepted that the electric fields generated by two or more contacts on a neural interface can interact. However, this has previously not been examined in the context of sensory feedback prostheses. Here, we aimed to investigate these interactions and the recovery dynamics of the sensory fibers. A multi-channel cuff electrode was implanted on the sciatic nerve of a rat. It comprised four rings (1 mm apart), each containing four circumferentially arranged electrodes. Temporally-patterned pairs of electrical stimuli were delivered through all 120 combinations of electrode pairs. Compound action potentials, elicited by stimulation of the sciatic nerve, were measured with two pairs of hook electrodes placed on the L4 dorsal root. We find that regardless of the relative position of the two electrodes on the cuff, at an interval of 0 ms, the CAP response is facilitated. At all other intervals, an inter-stimulus interval of even 5 ms was not enough for the response to the second stimulus to fully recover. This observation suggests that overlapping regions of nerve were stimulated. Examining only the intervals where the CAP did not fully recover, we noticed that if the electrodes lay longitudinally, that is, along the nerve, the CAP recovery was significantly impaired, compared to when the electrodes were in any other relative position. The observed space- and time-dependent interactions advocate for further controlled neuroscience studies in parallel to translational work on closed-loop prosthesis control. PMID- 30440609 TI - Normalized Transfer Entropy as a Tool to Identify Multisource Functional Epileptic Networks. AB - Epilepsy is a major health problem worldwide. A significant proportion of patients develop medication-refractory epilepsy (MRE); they are of ten evaluated for possible surgery where the focus of epileptogenic zones (EZ) are removed from the brain. Hence, prior to epilepsy surgery, insertion of depth electrodes into the brain is necessary to identify the EZs. These depth electrodes have multiple contacts that monitor the neuronal activity in multiple locations within the brain along each electrode trajectory. In the present study, we show that normalized transfer entropy measurements demonstrate functional connectivity across multiple sites within the brain of an MRE patient who did not demonstrate a clear EZ using conventional EEG criteria. Interestingly, linear measures of functional connectivity were not predictive of such an epileptic network. Our results suggest that routine evaluation of both linear and non-linear functional connectivity including normalized transfer entropy from depth electrode recordings may be useful to identify multisource epileptogenic networks in MRE patients. Identification of networks that contribute to epilepsy in such patients could potentially allow the clinician to avoid resective surgery and adopt alternate therapies such as vagal nerve stimulation or other emergent alternatives. PMID- 30440610 TI - Electrical Field Shaping Techniques in a Feline Model of Retinal Degeneration. AB - The majority of preclinical studies investigating multi-electrode field shaping stimulation strategies for retinal prostheses, have been conducted in normally sighted animals. This study aimed to reassess the effectiveness of two electrical field shaping techniques that have been shown to work in healthy retinae, in a more clinically relevant animal model of photoreceptor degeneration. Four cats were unilaterally blinded via intravitreal injections of adenosine triphosphate. Cortical responses to traditional monopolar (MP) stimulation, focused multipolar (FMP) stimulation and two-dimensional current steering were recorded. Contrary to our previous work, we found no significant difference between the spread of cortical activation elicited by FMP and MP stimulation, and we were not able to reproduce cortical responses to singleelectrode retinal stimulation using two dimensional current steering. These findings suggest that while shown to be effective in normally-sighted animals, these techniques may not be readily translatable to patients with retinal degeneration and require further optimization. PMID- 30440611 TI - Optic nerve and retinal electrostimulation in rats: direct activation of the retinal ganglion cells. AB - Visual prosthesis is competing with biological approaches to restore vision to the blind. Understanding and developing the ability to replicate the neural code of the retina are key factors that can bring bionic vision significant advantage. Here, electrically evoked potentials were recorded in anesthetized rats from the dorsal surface of the superior colliculus. Electrical stimuli of different amplitudes were delivered at the retina and the optic nerve. An evoked potential appeared in both cases within the first 5 ms post-stimulus suggesting that this component of the response was initiated by direct activation of the retinal ganglion cells. However, in the case of retinal neurostimulation, a second evoked potential occurred $9.0 ?pm 3.4$ ms after the stimulus delivery. Because this component was not present in the case of optic nerve electrostimulation, it is expected to be originated by the activation of other cells in the retinal network. PMID- 30440612 TI - Supervised Bayesian Source Separation of Nonlinear Mixtures for Quantitative Analysis of Gas Mixtures. AB - In medical applications, quantitative analysis of breath may open new prospects for diagnosis or for patient monitoring. To detect acetone, a breath biomarker for diabetes, we use a single metal-oxide (MOX) gas sensor working in a dual temperature mode. We propose a linear-quadratic model to describe the mixing model mapping gas concentrations to MOX sensor responses. In this purpose, it is necessary to inverse the nonlinear problem in order to quantify the component of the gas mixture. As a proof of concept, we study a mixture of two gases, acetone and ethanol diluted in air buffer. In order to estimate the concentration of each gas, we introduce a supervised Bayesian source separation method. Based on MCMC stochastic sampling methods to estimate the mean of the posterior distribution, this Bayesian approach is robust to noise for solving this ill-posed non-linear inversion problem. We analyze the performance on a set of samples associated with a set of gas concentration covering the range suitable for exhaled breath. We use a cross-validation approach, calibrating the mixing parameters with some samples and validating the source estimation with others. Our new supervised method applied on a linear-quadratic model allows to estimate acetone and ethanol concentration with a precision of around 2 ppm. PMID- 30440613 TI - Separation of Respiratory Signatures for Multiple Subjects Using Independent Component Analysis with the JADE Algorithm. AB - Respiration monitoring using microwave Doppler radar has attracted significant interest over the last four decades due to its non-invasive and non-contact form of measurement. However, this technology is still not at the level of practical implementations in healthcare due to motion artifacts and interference from multiple subjects within the range of the Doppler radar sensor. Most reported results in literature focus only on single subject measurements because when multiple subjects are present there are interfering respiration signals which are difficult to separate as individual respiration signals. This paper investigates the feasibility of separating respiratory signatures from the multiple subjects. We employed a new approach using Independent Component Analysis (ICA) with the Joint Approximate Diagonalization of Eignematrices (JADE) algorithm to achieve this for closely spaced subjects, and the system is also capable of estimating Direction of Arrival (DOA) for well-spaced subjects. Experimental results demonstrated that the ICA-JADE method can separate respiratory signatures from two subjects one meter apart from each other at a distance from the radar of 2.89 meters. The separated respiratory pattern closely correlates with reference chest belt respiration patterns, and the mean square error is approximately 11.58%. Concisely, this paper clearly demonstrates that by integrating ICA with the JADE algorithm in a Doppler radar physiological monitoring system, multiple subjects can be monitored simultaneously. PMID- 30440614 TI - Removal of Electrocardiogram Interference from Diaphragmatic Electromyogram Signals using Sliding Singular Spectrum Analysis. AB - Over recent years, Singular Spectrum Analysis (SSA) has gained popularity as an effective means to denoise biologically sourced single channel signals, especially Electromyogram (EMG) and Electrocardiogram (ECG) signals amongst others. There are numerous applications whereby the signal acquisition process results in the mixing of both types of signals along with body motion artifacts and the inevitable electromagnetic interference. Both ECG and EMG signals are very useful to physicians, though preferably in isolation, though they rarely present themselves in this manner. Simple filtering techniques are ineffective in their separation as both signal spectra overlap in the frequency domain. In this paper, we propose a technique based on a sliding SSA algorithm which proves to be more successful in separating real mixed EMG and ECG signals than traditional block based approaches on single channel data. SSA is a non-parametric technique that decomposes the original time series into a number of additive components, each of which can then be readily identified based on statistical analysis as belonging to EMG or ECG signals. This approach could be applied equally to other signal types using different statistical methods as required, moreover, this technique is relatively straight-forward to implement and does not require any reference signals or training. PMID- 30440615 TI - Evaluation of Artifact Subspace Reconstruction for Automatic EEG Artifact Removal. AB - One of the greatest challenges that hinder the decoding and application of electroencephalography (EEG) is that EEG recordings almost always contain artifacts - non-brain signals. Among existing automatic artifact-removal methods, artifact subspace reconstruction (ASR) is an online and realtime capable, component-based method that can effectively remove transient or large-amplitude artifacts. However, the effectiveness of ASR and the optimal choice of its parameter have not been evaluated and reported, especially on real EEG data. This study systematically validates ASR on ten EEG recordings in a simulated driving experiment. Independent component analysis (ICA) is applied to separate artifacts from brain signals to allow a quantitative assessment of ASR's effectiveness in removing various types of artifacts and preserving brain activities. Empirical results show that the optimal ASR parameter is between 10 and 100, which is small enough to remove activities from artifacts and eye-related components and large enough to retain signals from brain-related components. With the appropriate choice of the parameter, ASR can be a powerful and automatic artifact removal approach for offline data analysis or online real-time EEG applications such as clinical monitoring and brain-computer interfaces. PMID- 30440616 TI - Dimensionality Reduction based Transfer Learning applied to Pharmacogenomics Databases. AB - Recent years have observed a number of Pharmacogenomics databases being published that enable testing of various predictive modeling techniques for personalized therapy applications. However, the consistencies between the databases are usually limited in spite of having significant number of common cell lines and drugs. In this article, we consider the problem of whether we can use the model learned from one secondary database to improve the prediction for the other target database. We illustrate using two pharmacogenomics databases that representing the databases using common basis vectors can improve prediction performance as compared to the naive application of a model trained on one database to another. We also elucidate the robustness of using PCA based basis vectors for scenarios with low correlated input features. PMID- 30440617 TI - Introducing a Combination of ICA-EMD to Suppress Muscle and Ocular Artifacts in EEG Signals. AB - This paper presents a combination of Independent Component Analysis (ICA) with Empirical Mode Decomposition (EMD) to suppress muscle and ocular artifacts in electroencephalographic (EEG) signals: By means of ICA, the EEG signals are decomposed into independent components. To avoid the suppression of artifactual components still containing physiological information, EMD is applied to decompose the components in Intrinsic Mode Functions (IMFs). The IMFs with mainly muscle artifacts are removed, and a new data set of independent components without muscle artifacts is generated. From this set, the components containing ocular artifacts are suppressed and clean data are reconstructed. In this way, the muscle and ocular artifacts are better suppressed than using pure ICA, or pure EMD. The performance of the proposed combination is applied to a semi simulated data set, and three real EEG data sets from healthy subjects contaminated with both artifacts. PMID- 30440618 TI - Join and Deep Ensemble Regression of Clinical Scores for Alzheimer's Disease Using Longitudinal and Incomplete Data. AB - Alzheimer's disease (AD) is a neurodegenerative disease with an irreversible and progressive process. Close monitoring of AD is essential for making adjustments in the treatment plan. Since clinical scores can indicate the disease status effectively, the prediction of the scores based on the magnetic resonance imaging (MRI data is highly desirable. Different from previous studies at a single time point, we propose to build a model to explore the relationship between MRI data and scores, thereby predicting longitudinal scores at future time points from the corresponding MRI data. The model incorporates three parts, correntropy regularized joint learning-based feature selection, deep polynomial network based feature encoding, and finally, support vector regression. The regression process is carried out for two scenarios. One is to use baseline data for predictions at future time points, and the other is to combine all the previous data for the prediction at the next time point. Meanwhile, the missing scores are filled in the second scenario to address the incompleteness presented in the data. The simulation results demonstrate that the proposed model accurately describes the relationship between MRI data and scores, and thus it can be effective in predicting longitudinal scores. PMID- 30440619 TI - Filter-Pruned 3D Convolutional Neural Network for Drowsiness Detection. AB - Human drowsiness while operating motor vehicles or heavy machinery can have potentially lethal consequences for the operator and others in their immediate vicinity. In this study, we developed a visual-based drowsiness detection system that can analyze videos and make predictions on attention status. A 3D convolutional neural network (CNN) was built for spatio-temporal feature extraction in consecutive frames, and temporal smoothing was used to remove noisy predictions. As a part of an assistance system, a real-time, lightweight and computationally-efficient system is preferable. Thus, we proposed a Scale Module that can be easily integrated into the convolutional layer and estimate the importance of filters. Our results show that scale values calculated from the Scale Module are good indicators for filter pruning, and that filters with small scale values can be removed with negligible loss in the model's performance. PMID- 30440620 TI - Skin Lesion Analysis By Multi-Target Deep Neural Networks. AB - Automatic skin lesion analysis involves two critical steps: lesion segmentation and lesion classification. In this work, we propose a novel multi-target deep convolutional neural network (DCNN) to simultaneously tackle the problem of segmentation and classification. Based on U-Net and GoogleNet, a single model is constructed with three different targets of both lesion segmentation and two independent binary lesion classifications (i.e., melanoma detection and seborrheic keratosis identification), aiming to explore the differences and commonalities over different target models. We conduct experiments on dermoscopic images from the International Skin Imaging Collaboration (ISIC) 2017 Challenge. Results of our multi-target DCNN model demonstrates superiority over single model with one target only (such as U-net or GoogleNet), indicating its learning efficiency and potential for application in automatic skin lesion diagnosis. To the best of our knowledge, this work is the first demonstration for a single end to-end deep neural network model that simultaneously handle both segmentation and classification in the field of skin lesion analysis. PMID- 30440621 TI - A Deep Unsupervised Learning Approach Toward MTBI Identification Using Diffusion MRI. AB - Mild traumatic brain injury is a growing public health problem with an estimated incidence of over 1.7 million people annually in US. Diagnosis is based on clinical history and symptoms, and accurate, concrete measures of injury are lacking. This work aims to directly use diffusion MR images obtained within one month of trauma to detect injury, by incorporating deep learning techniques. To overcome the challenge due to limited training data, we describe each brain region using the bag of word representation, which specifies the distribution of representative patch patterns. We apply a convolutional auto-encoder to learn the patch-level features, from overlapping image patches extracted from the MR images, to learn features from diffusion MR images of brain using an unsupervised approach. Our experimental results show that the bag of word representation using patch level features learnt by the auto encoder provides similar performance as that using the raw patch patterns, both significantly outperform earlier work relying on the mean values of MR metrics in selected brain regions. PMID- 30440622 TI - A Multi-modal Convolutional Neural Network Framework for the Prediction of Alzheimer's Disease. AB - This paper presents a multi-modal Alzheimer's disease (AD) classification framework based on a convolutional neural network (CNN) architecture. The devised model takes structural MRI, and clinical assessment and genetic (APOe4) measures as inputs. Our CNN structure is designed to be efficient in its use of parameters which reduces overfitting, computational complexity, memory requirements and speed of prototyping. This is achieved by factorising the convolutional layers in parallel streams which also enables the simultaneous extraction of high and low level feature representations. Our method consistently achieves high classification results in discriminating between AD and control subjects with an average of 99% accuracy, 98% sensitivity, 100% specificity and an AUC of 1 across all test folds. Our study confirms that careful tuning of CNN characteristics can result in a framework which delivers extremely accurate predictions in a clinical problem despite data paucity, opening new avenues for application to prediction tasks which regard patient stratification, prediction of clinical evolution and eventually personalised medicine applications. PMID- 30440624 TI - Simple, Fast And Highly Sensitive Detection Of Gram-Negative Bacteria By A Novel Electrical Biosensor. AB - This work presents a rapid, low-cost, highly sensitive and specific capacitive sensor for detection of Gram negative bacteria in a field setting. Recognition of Gramnegative bacteria is based on specific detection of lipopolysaccharides (LPS) by LPS-specific aptamer probe immobilized on electrode sensors. An inhomogeneous AC electric field is applied on sensor electrodes and induces positive dielectrophoresis that attracts LPS particles to the sensor electrodes for rapid detection. The same AC signal is also used to detect the binding reactions occurred on the sensor surface. The AC signal was optimized, and the binding between LPS and the specific aptamer was demonstrated. The detection limit reaches as low as 4.9 fg/mL for free LPS molecules and 53 #/mL of bacteria within a 30s' response time, meeting the needs of onsite bacteria detection. PMID- 30440623 TI - Left Ventricle Segmentation in Cardiac MR Images Using Fully Convolutional Network. AB - Medical image analysis, especially segmenting a specific organ, has an important role in developing clinical decision support systems. In cardiac magnetic resonance (MR) imaging, segmenting the left and right ventricles helps physicians diagnose different heart abnormalities. There are challenges for this task, including the intensity and shape similarity between the left ventricle and other organs, inaccurate boundaries, and presence of noise in most of the images. In this paper, we propose an automated method for segmenting the left ventricle in cardiac MR images. We first automatically extract the region of interest and then employ it as an input of a fully convolutional network. We train the network accurately despite the small number of left ventricle pixels in comparison with the whole image. Thresholding on the output map of the fully convolutional network and selection of regions based on their roundness are performed in our proposed post-processing phase. The Dice score of our method reaches 87.24% by applying this algorithm on the York dataset of heart images. PMID- 30440625 TI - An Exploration of Behind-the-Ear ECG Signals From a Single Ear Using Inkjet Printed Conformal Tattoo Electrodes. AB - Wearable sensors placed behind-the-ear are emerging as being very promising for unobtrusive long term monitoring. Factors such as gait, electroencephalography (EEG), and ballistocardiography (BCG) can all be measured from behind-the-ear in a socially acceptable hearing aid based form factor. Previous works have investigated the recording of electrocardiography (ECG) from the ear, but generally with one electrode placed some distance away from the ear itself. This paper uses recently introduced tattoo electrodes to investigate whether ECG components can indeed be measured from behind a single ear. Compared to a reference photophelsmography (PPG) device we show that the fundamental heart beat frequency is present in behind-the-ear ECG only in half of the cases considered. In contrast the second harmonic is present in all records and could allow the extraction of heart rate to within a few beats-per-minute accuracy. Further signal processing work is required to allow the automated extraction of this, particularly when working with short time windows of data, but our results characterize the signal and demonstrate the principle of behind-the-ear ECG collected from a single ear. PMID- 30440627 TI - Increased Conductivity and Reduced Settling Time of Carbon-Based Electrodes By Addition of Sea Salt for Wearable Application. AB - A carbon-based dry electrode is designed to measure bio-potential from skin surface without hydrogel. Consequently, unlike Ag/AgCl electrodes, the carbon based electrodes require some settling time before a high-fidelity signal is obtained due to the process for impedance matching among skin surface, electrode and amplifiers in biometric system. Besides, especially, when electrocardiogram (ECG) is measured at some distance away from the chest using carbon-based electrodes for wearable application, the settling time could be a critical concern for immediate data collection due to the smaller bio-potential and bigger motion artifact noises. The settling time was defined as the time it takes for the carbon-based electrodes to have the same impedance as that of Ag/AgCl electrodes at a particular frequency (< 1 kHz) for bio-signals. In this study, we investigated the characteristics of the skin contact impedance as a function of time using carbon-based electrodes with and without sea salt and different thickness. Specifically, sea salt was added to the carbon black (SCB)/polydimethlysiloxane (PDMS) electrode to examine the level of enhanced conductivity and reduction of settling time. We used SCB/PDMS and CB/PDMS electrodes with thickness of 1.0 mm and 1.5 mm, examined their electrode and skin contact impedance values and compared them to Ag/AgCl electrodes. We collected impedance data from seven subjects using both SCB and CB/PDMS electrodes every 10 minutes for 50 minutes. A SCB/PDMS electrode showed lower impedance than a CB/PDMS electrode, and for both types of electrodes, higher thickness resulted in lower impedance. The same results were found for skin contact impedance. The settling times of the SCB/PDMS electrodes were found to be $20 ?pm 10$ minutes and $40 ?pm 10$ minutes for widths of 1.0 mm and 1.5 mm, respectively. The settling time for CB/PDMS without sea salt resulted in significantly higher settling time (> 50 minutes) when compared to SCB/PDMS electrodes. In summary, when carbon-based electrodes are used to measure bio-signals from skin surface for wearable application, its settling time can be partially offset by adding sea salt to CB/PDMS electrode and by making it thinner. PMID- 30440626 TI - Low-Cost Carbon Fiber-Based Conductive Silicone Sponge EEG Electrodes. AB - We propose a novel carbon fiber-based conductive silicone sponge for low electrode-skin impedance EEG recordings. When this sponge is used with water or saline solution, no gel is required, lowering the setup time drastically compared to classical wet electrodes. Moreover, the wet conductive carbon fiber silicone sponges achieve an electrode-skin impedance as low as $2.5?mathrm {k} ?Omega $ at 1kHz when wet, making them better than state of the art gel electrodes. Additionally, even as the sponge dries out, it continues to remain conductive and performs as a reliable dry electrode. We demonstrate through experiments that these conductive carbon fiber silicone sponge electrodes, wet or dry, are able to measure alpha wave activity. Our carbon fiber conductive sponge electrodes are low-cost and are highly suitable for designs of portable high density EEG measurement systems. PMID- 30440628 TI - Design of High-Density Electrodes For EEG Acquisition. AB - In a 256-channel electrode cap for electroencephalogram (EEG) acquisition, the inter-space between adjacent electrodes is around 20mm. Theoretical and experimental evidence predict that improving the density of electrode can get more information from the added electrodes. 10mm or less center distance, corresponding to 1000 electrodes on a full head EEG cap, might be a more proper density to current EEG analysis methods. To develop high-density electrode array with center distance equal or less than 10mm, one must make sure that the adjacent electrodes are electrical isolated. It is difficult to avoid short circuit when common wet electrodes are used to build high-density electrode array. The contact area (about 28mm2 with diameter of 6mm) and gelling method make short circuit easily happen. To provide more isolation space between adjacent electrodes, the contact area of the proposed electrode should be less than 8mm2. To restrict the diffusion of the electrolyte, a customized hydrogel is used to replace the conventional gel. Compared with common wet electrode and gel, preliminary tests indicate that the high-density hydrogel-Ag/AgCl electrodes perform well at the impedance, isolation, as well as data quality in EEG acquisition. PMID- 30440629 TI - A Multichannel EEG Acquisition System With Novel Ag NWs/PDMS Flexible Dry Electrodes. AB - In this paper, a multichannel reconfigurable EEG acquisition system with novel flexible dry electrodes is proposed. The novel electrode is designed to overcome the limitations of conventional wet electrodes such as skin irritation, skin preparation, and conductive gel requirements. It is based on the conductive and stretchable Ag NWs/PDMS composite material and produced by 3D printing technology. Meanwhile, a portable reconfigurable 8-channel EEG acquisition system based on the analog front end ADS1299 is proposed to overcome the drawbacks of traditional EEG acquisition system such as, large in size, difficult to configure, and complicated to use. It can be reconfigured by adjusting the gain of system and sampling rate. To verify the performance of proposed electrodes, a comprehensive test including electrode characterization and signal quality measurement is performed in comparison with Ag/AgCl electrode and Gold Cup electrode. Experiments reveal that proposed electrode achieves favorably results with wet electrodes. Furthermore, the proposed EEG acquisition system with novel dry electrodes is evaluated and compared with the commercial product. The evoked EEG signals (the steady-state visual evoked potentials, SSVEP) acquisition tasks of the proposed system are also conducted. Experimental results exhibit that proposed system satisfies the requirements of multi-channel EEG acquisition and provides a portable and comfortable way for EEG acquisition. With the high quality sensing ability of the novel electrodes and the programmable gain amplifier of the proposed system, it can be expected to acquire the physiological signals like the electrocardiogram (ECG) and electromyogram (EMG) in the future. PMID- 30440630 TI - Datalog Extensions for Bioinformatic Data Analysis. AB - Recent growth in public bioinformatic databases has facilitated the analysis of genomic and proteomic data. However, the large size of the datasets makes it hard for nonexpert programmers to perform the analysis. In this paper we present B Log, a high-level query language for bioinformatic data analysis. Based on Datalog, B-Log can simply express graph analysis algorithms; it is extended with nested tables, recursive aggregations, and foreign functions, which helps quick exploratory analyses. We implemented several analysis algorithms in B-Log; we also implemented a prototype system to explore TCGA dataset. We find B-Log to be useful for exploratory analysis and quick prototyping. PMID- 30440631 TI - Assessing The Predictive Value Of Regulatory Molecules For Patient Outcome In Pancreatic Cancer: A Computational Approach. AB - Pancreatic Cancer (PC) can be characterized as one of the most lethal cancers considering its poor diagnosis and symptoms in early stages. To assess the predictive value of regulatory molecules in terms of differentially expressed genes, we first performed a thorough search of gene expression profiling studies in pancreatic cohorts. We obtained the genes that have been identified and validated experimentally to be associated with patient outcome and also differentially expressed in tumors compared with adjacent non-tumor tissues. A two-step upstream analysis on the derived set of the genes under study was performed. The subsequent promoter and pathway analysis unveiled candidate transcription factors and regulatory molecules that potentially have regulated the detected differentially expressed genes. Predictive analysis was applied in the identified regulators and classification algorithms were implemented to model accurately patient outcome. In view of our findings, Gaussian Naive Bayes model exhibited the highest classification accuracy and f-score concerning the predictive value of regulatory molecules in PC (accuracy =0.85, f-score =0.84). PMID- 30440633 TI - Unsupervised fuzzy binning of metagenomic sequence fragments on three-dimensional Barnes-Hut t-Stochastic Neighbor Embeddings. AB - Shotgun metagenomic studies attempt to reconstruct population genome sequences from complex microbial communities. In some traditional genome demarcation approaches, high-dimensional sequence data are embedded into two-dimensional spaces and subsequently binned into candidate genomic populations. One such approach uses a combination of the Barnes-Hut approximation and the $t $Stochastic Neighbor Embedding (BH-SNE) algorithm for dimensionality reduction of DNA sequence data pentamer profiles; and demarcation of groups based on Gaussian mixture models within humanimposed boundaries. We found that genome demarcation from three-dimensional BH-SNE embeddings consistently results in more accurate binnings than 2-D embeddings. We further addressed the lack of a priori population number information by developing an unsupervised binning approach based on the Subtractive and Fuzzy c-means (FCM) clustering algorithms combined with internal clustering validity indices. Lastly, we addressed the subject of shared membership of individual data objects in a mixed community by assigning a degree of membership to individual objects using the FCM algorithm, and discriminated between confidently binned and uncertain sequence data objects from the community for subsequent biological interpretation. The binning of metagenome sequence fragments according to thresholds in the degree of membership opens the door for the identification of horizontally transferred elements and other genomic regions of uncertain assignment in which biologically meaningful information resides. The reported approach improves the unsupervised genome demarcation of populations within complex communities, increases the confidence in the coherence of the binned elements, and enables the identification of evolutionary processes ignored in hard-binning approaches in shotgun metagenomic studies. PMID- 30440632 TI - Structural Variant Prediction in Extended Pedigrees Through Sparse Negative Binomial Genome Signal Recovery. AB - Structural variants (SVs) are rearrangements, such as deletions, insertions, duplications, inversions, and translocations, in an individual's genome relative to a reference. SV detection is often marred by high false positive rates due to errors in sequencing and mapping. In previous work, we proposed a maximum likelihood approach to SV prediction that incorporated low-coverage sequencing data and coverage distribution. In particular, we developed a negative binomial framework to reflect a more realistic representation DNA fragment distributions sampled from an individual's genome. In this paper, we leverage relationships between an off spring and both parents, in addition to the negative binomial framework, to improve SV identification accuracy. We present numerical results on both simulated genomes as well as two sequenced parent-child trios from the 1000 Genomes Project. PMID- 30440634 TI - Identification of Primary and Metastatic Melanoma based on Copy Number Variation. AB - The development of new sequencing technology has stimulated the cancer-related genome analysis. Copy number variation is one of the most important features that represents the structural variation. In this paper, we suggest the metastasis identification method of melanoma using copy number variations. The identification marker is defined in consideration of the presence and the type of copy number variations in primary and metastatic tumors. The optimization of marker is also provided and classification performances of developed markers are compared using the linear classifier. PMID- 30440635 TI - Micro-Inversions In Human Cancer Genomes. AB - During the past few years, although scientists and researchers have studied variations in the cancer genomes, our current knowledge about the function of Micro-inversions (MIs) in cancer are still limited. MIs are generally defined as small inversions in DNA segments shorter than 100 bp. To expand our knowledge of their roles in cancer, we analyzed the MIs of 209 samples from four types of cancer, including hepatocellular carcinoma, lung cancer, pancreatic cancer, and bladder cancer. Within all the 209 samples, we identified 2,925 MIs, of which 1,519 (51.93%) are in gene regions. Of the 1,519 MIs in the gene regions, 106 (6.98%) are in the exon regions. We also analyzed 209 healthy samples as the control samples. We further analyzed the distribution of MIs in the four types of cancer among 24 chromosomes. Besides the chromosome preference, different cancers also have different preference for various genes. The MIs preference for different genes among four types of cancer may provide a guidance for the treatment and diagnosis on the four types of cancer. Medical doctors should concentrate more on chromosomes and the genes that MIs prefer to locate on. We also calculated the average count of MIs per individual among each cancer. From this result, we found that the bladder cancer has the most average count of MIs per individual, which means MIs may be more likely to exist in bladder cancer. According to our analysis, MIs play an important role in cancer and should be considered for further analysis. PMID- 30440636 TI - 3DRA Reconstruction of Intracranial Aneurysms - How does Voxel Size Influences Morphologic and Hemodynamic Parameters. AB - Three-dimensional shape analysis and imagebased hemodynamic simulations are widely used to assess the individual rupture risk of intracranial aneurysms. However, the quality of those results highly depends on pre-simulative working steps including image reconstruction and segmentation. Within this study, three patient-specific aneurysms were reconstructed using three different voxel sizes (0.1 mm, 0.3 mm, 0.5 mm). Afterwards, 3D segmentations and time-dependent blood flow simulations were carried out to evaluate the impact of the reconstruction size. The results indicate that overall all voxel sizes lead to a qualitatively good agreement with respect to the aneurysm surfaces. However, deviations occur regarding the neck representation as well as the consideration of perforating arteries. Further, morphological differences lead to clear hemodynamic variations, especially for shear force predictions. The findings indicate that depending on the desired analysis, careful reconstruction parameter selection is required. Particularly, for quantitative morphology and blood flow studies, the early step of reconstruction can have a crucial effect on subsequent results. PMID- 30440638 TI - Comparison of hemodynamic parameters that can predict an aneurysmal rupture: 20 patient-specific models experiment. AB - Hemodynamic analysis of cerebral aneurysms is widely performed to understand the mechanism of aneurysmal rupture. Computational fluid dynamics (CFD) studies have suggested that several hemodynamic parameters are associated with such ruptures. However, a number of factors remain to be addressed to correlate these parameters with aneurysmal ruptures, especially under analytical conditions. Specifically, CFD analysis is often performed with rigid wall models due to computational cost limitations. Here, to evaluate the effects of the deformation of the aneurysmal wall, experimental flow measurement with elastic models under pulsating conditions was conducted using three-dimensional particle image velocimetry (3D PIV). By analyzing 20 patient-specific, elastic, silicone aneurysm models, the hemodynamic parameters of ruptured and unruptured aneurysms were statistically compared to identify the variables that can effectively predict an aneurysmal rupture. Our analyses yielded three parameters (average wall shear stress ratio, in-phase deviation ratio, and pressure difference) which could effectively predict an aneurysmal rupture. These results suggested that measurement of wall shear stress (WSS) at both the aneurysm dome and parent artery is important and that pressure difference can also be a potential indicator of aneurysmal rupture. PMID- 30440637 TI - Blood Flow Analysis in Coil Embolized Aneurysms: Difference between Porous Media and Real Coil Geometry Model. AB - To clarify the mechanism of aneurysmal recanalization, it is necessary to understand the characteristics of the blood flow inside the aneurysm in particular the flow resistance generated by the coil. In studies using computational fluid dynamics (CFD), mainly two approaches have been used to model the coil embolized aneurysm; modeling the coils as porous media or by real coil geometries. In this study, we calculated the pressure drop along a vessel through a coiled region modeled as porous media or by real coil geometry and compared the pressure drop generated by the two coil models. The porous media model was described by Darcy's law and Ergun's equation, while the real coil geometry was generated using finite element method (FEM) structural analysis. We calculated the pressure drop for inlet velocities from 0.1 m/s to 1.0 m/s in steps of 0.1 m/s. Our results indicated that the porous media model may produce larger pressure drops than the real coil geometry model under low packing density. The value of the pressure drop was also changed due to the difference of coil distribution even if the packing density was the same. PMID- 30440639 TI - Multivariate Analysis For Predicting Internal Carotid (IC) And Middle Cerebral (MC) Aneurysmal Rupture By Hemodynamic Parameters. AB - Currently, aneurysmal rupture can hardly be predicted and the search for an objective and precise indicator is ongoing. The objective of this study was to find a rupture prediction indicator (RPI) based on hemodynamic parameters of unruptured aneurysms focusing on the internal carotid (IC) and middle cerebral (MC) arteries. Computational fluid dynamics simulations were performed and hemodynamic parameters were calculated using three-dimensional C-arm computed tomography (3D C-arm CT) images of a total of 137 unruptured aneurysms (69 IC and 68 MC artery aneurysms) with known outcomes of rupture or unrupture. Multivariate analysis was applied to build an RPI model. The final RPI models contained the pressure-loss coefficient at the time maximum (TMAXPLc). Ruptured aneurysms were found to have lower TMAXPLc than unruptured aneurysms. The mean values were 1.002 (95%CI 0.827 to 1.177) and 1.466 (95%CI 1.352 to 1.579), respectively (P=0.002). TMAXPLc may thus be a useful parameter for rupture prediction of IC and MC artery aneurysms. PMID- 30440640 TI - Hemodynamic Change In A Cerebral Aneurysm Treated By Double Stenting Technique. AB - Rupture of cerebral aneurysms often causes subarachnoid hemorrhage which is a life-threatening condition with high mortality rates. Larger aneurysms are believed to be more likely to rupture and should therefore be treated. Recently, flow diverters (FDs) are widely used to treat large or wide neck aneurysms. However, it can be difficult to treat them by deployment of a single FD because of its insufficient flow disturbance. To overcome this problem, double stenting technique is sometimes applied with the aim to improve the effect of blood velocity reduction. In this study, we used computational fluid dynamics (CFD) to investigate the hemodynamic changes in an aneurysm when deploying virtual FDs. The results showed that the characteristics of the blood flow field inside the aneurysm did not changed much after the deployment of a single FD but underwent a large change after the deployment of two FDs. Furthermore, the velocity reduction in the aneurysm sac at a plane away from the parent artery increased from 25.9% to 92.8% when two FDs were deployed instead of one compared to no stenting. Double stenting was effective to decrease blood velocity in large or wide neck aneurysms. PMID- 30440641 TI - Relationship between hemodynamic parameters and cerebral aneurysm initiation. AB - Research on the relationship between cerebralaneurysm initiation and hemodynamic parameters, but several open questions remain on initiation and growth mechanisms of cerebral aneurysms. If factors contributing to initiation were identified, it would be possible to predict the initiation of aneurysms. The purpose of this study is to investigate the relationship between cerebral aneurysm initiation and hemodynamic factors. Blood flow simulations in aneurysms of three patients were performed using computational fluid dynamics (CFD) based on the cerebral blood vessel geometry before aneurysm initiation. We evaluated pressure, wall shear stress (WSS), wall shear stress gradient (WSSG), oscillatory shear index (OSI) and gradient oscillatory number (GON) since these factors are known to be associated with aneurysmal initiation. We also focused on the wall shear stress divergence (WSSD) in particular on the direction of WSS. Our results indicated that only high WSSD regions corresponded to the initiation regions, and the value of WSSD was remarkably high. Stretching force to the vessel wall may be related to the initiation of cerebral aneurysms. PMID- 30440642 TI - Super Slice Interpolation For Generating Thin-Slice Images From Multichannel Multislice MRI Data. AB - This study aims to develop a super slice interpolation (SSI) method that generates thin-slice images from multichannel multislice images by exploiting the intra-slice coil sensitivity variations. SSI first calculates the thin-slice sensitivity maps by through-plane interpolation of the sensitivity maps computed from the acquired multislice images. It then reconstructs multiple thin-slice images from each acquired image using a through-plane regularized sensitivity encoding (SENSE) like procedure that consists of an initial SENSE reconstruction and denoising to set the prior information image, and subsequent regularized SENSE reconstruction. We evaluated SSI using multislice brain and abdominal images with typical slice thickness. SSI successfully separated each acquired image into two thinner ones without magnitude bias. Compared with the original thick-slice images, SSI revealed more anatomical details that were consistent with those in the separately acquired thin-slice images. SSI presents a novel slice interpolation approach to obtain thin-slice images from the multichannel thick-slice images. PMID- 30440643 TI - A Surface Electromyography-Driven Magnetic Resonance Sequence Controller for Real Time Myoelectric Triggered Imaging. AB - Combination of surface electromyography (EMG) with diffusion-weighted magnetic resonance imaging (DW-MRI) enables improved studies of spontaneous mechanical contractions in resting human musculature (SMAM). Mechanical muscular activities follow characteristic electrical neuromuscular activities after a delay of several tens of milliseconds. A low-cost standalone system for simultaneous surface EMG measurements during DW-MRI with a real-time model-based surface EMG activity detection is demonstrated which controls the MR sequence. Therefore, a multilayer perceptron (MLP) with sequential forward selection (SFS) was investigated. MLP achieved an area under curve (AUC) of 0.933 in the detection of small surface EMG activities based on five time-domain features. Integration on a microcontroller system enabled fast real-time surface EMG activity detection with highly flexible trigger time settings. Small deviations with only 7.2+/-1.7 ms time delay between decision of MLP activity detection and onset of MR sequence were measured. PMID- 30440645 TI - Double-Tuned Cable Traps For Multinuclear MRI And MRS. AB - Using the method of pole-insertion, double-tuned cable traps were constructed and studied. The effectiveness of the method was examined for four different magnetic field strengths. The double-tuned cable trap design was able to effectively block shield currents at two frequencies simultaneously for all field strengths attempted. The effectiveness of the design seemed to increase at higher field strengths, eventually outperforming even the single-tuned cable traps at the highest frequencies examined. The double-tuning method demonstrated here could be a useful cable trap design for multinuclear studies and is considerably more spaceefficient than using two single-tuned cable traps mounted in series. This design should be particularly useful in cases where space is limited, such as when using high channel-count array coils. PMID- 30440644 TI - Effect Of Incident Field Magnitude And Phase Distribution On Rfinduced Heating Due To Hip Implants. AB - We investigated how the distribution of magnitude and phase of incident electric field affects RFinduced heating near a hip implant. The results showed that varying the incident electric field, for example due to different phantom shape or different landmark position, for two-or three-dimensional implants can result in up to 50% variation of estimated RF-induced temperature rise. To avoid systematic errors in predicting the RF-induced heating, varied distributions of the incident electric field should be applied. PMID- 30440646 TI - Flexible RF Filtering Front-End For Simultaneous Multinuclear MR Spectroscopy. AB - Simultaneously interrogation of multiple nuclei has been of interest since the very earliest days of MRI [1]-[3]. Our group and several others are revisiting this topic [4]-[6]. Very fast broadband electronics make it possible to digitize a wide spectrum, including multiple nuclei, but this places great demands on data throughput. Another issue is that there can be great variance between RF preamplifier gain required for the different nuclei. To overcome the data problem, it is desirable to use undersampling, but this requires passband filtering around the resonant frequency of each nuclei. Here we present a frequency agile front end that provides separate data paths for each nucleus, either from a single coil or from multiple ports, allows independent gain, filters each using very flexible transmission line filtering, and then combines them back for undersampling. PMID- 30440647 TI - 4D Dual-Venc Spiral Flow. AB - Dual-Venc flow acquisition sequences perform flow imaging with differing Vencs. The technique can be used to improve velocity to noise ratio and image quality for diastolic flow velocities as part of a single scan. In this paper, Dual-Venc was used in conjunction with spiral read-out trajectories, offering a faster coverage of k-space. The results illustrate that 4D Dual Venc Spiral Flow behaves similarly to 4D Dual-Venc Cartesian Flow but with the benefit of faster acquisition time and lower echo time (TE). PMID- 30440648 TI - Auditory Steady-State Responses Across Chirp Repetition Rates For Ear-EEG And Scalp EEG. AB - Measurement of auditory steady-state responses (ASSR) using ear-EEG potentially enables objective audiometry out of the clinic in the everyday life of hearing aid users. As ear-EEG are measured from electrodes placed within the ear, electrode distances are inherently small and consequently the potential differences, and thereby signal amplitudes, are also small. Because the detection of the ASSR is based on the signalto-noise ratio (SNR), it is of fundamental interest to know the inherent SNR of the ASSR as a function of the stimulus repetition rate. In this study, ASSRs were recorded using both scalp and ear-EEG in response to broadband chirp stimuli with repetition rates from 20 to 95 Hz. The results showed that in general ear-EEG and scalp EEG SNR was on par across repetition rates; an exception to this was at rates around 40 Hz where the SNR was significantly lower for ear-EEG as compared to scalp EEG. For ear-EEG, the ASSR was relatively constant across repetition rates, whereas the noise showed a 1/f characteristic. In consequence, there was a tendency to increased SNR as a function of repetition rate. This suggests that use of relatively high repetition rates may be beneficial in earEEG applications. PMID- 30440650 TI - Decoding Movement States in Stepping Cycles Based on Subthalamic LFPs in Parkinsonian Patients. AB - Gait disturbances are a prominent feature of Parkinson's disease (PD), often refractory to medication or continuous deep brain stimulation (DBS) on basal ganglia targets such as the subthalamic nucleus (STN). Here we sought to identify movement states during stepping cycles, such as left leg stance and right leg stance. To this end we analyzed local field potential (LFP) activity in STN using a combination of the multivariate autoregressive (MAR) model and the Hidden Markov model (HMM). Our results confirm that information is present in the STN related to movement states in stepping cycles, and that it is feasible to decode movement states based on STN LFPs recorded from DBS electrodes. This information can be used to implement temporally flexible stimulation strategies in order to facilitate patterns of neural modulation associated with better gait performance. PMID- 30440651 TI - A Closed-Loop Multi-Channel Asynchronous Neurostimulator to Mimic Neural Code for Cognitive Prosthesis. AB - We describe a novel hardware and embedded system design of a closed loop neurostimulator for generating precise neural code-like, multi-channel, asynchronous electrical stimulation pulses. Such stimulator will be used as the output unit of the cortical prosthesis that aims to restore cognitive functions by reinstating the neural signal transmission. PMID- 30440649 TI - Graph-Based Models of Cortical Axons for the Prediction of Neuronal Response to Extracellular Electrical Stimulation. AB - Over the past decade, many important insights to brain function have been obtained through clever application of detailed compartmental model neurons. New computing capabilities brought opportunities to study large networks of model neurons. Certain applications for these models, such as extracellular electrical stimulation, demand a very high degree of biological realism. While dendrites and somatic morphology may be obtained from explicit reconstructions, this approach is less useful for axonal structures, which are more difficult to characterize across a neuronal population. The purpose of this paper is to extend neuronal morphology generative models to highly branched axon terminal arbors as well as to present a clear use-case for such models in the study of cortical tissue response to externally applied electric fields. The results of this work are (i) presentation and quantitative/qualitative description of generated fibers and (ii) an extracellular electrical stimulation strength-duration study. PMID- 30440652 TI - Sleep Depth Enhancement Through Ambient Temperature Manipulation in Mice. AB - The restorative properties of deep sleep and its central role in learning and memory are well-recognized but still in the process of being elucidated with the help of animal models. Currently available approaches for deep sleep enhancement are mainly pharmacological and may have undesirable side effects on physiology and behavior. Here, we propose a simple strategy for sleep depth enhancement that involves manipulation of ambient temperature (Ta) using a closed-loop control system. Even mild shifts in Ta are known to evoke thermoregulatory responses that alter sleep-wake dynamics. In our experiments, mice evinced greater proportions of deep NREM sleep as well as REM sleep under the dynamic sleep depth modulation protocol compared to a reference baseline in which Ta was left unchanged. The active manipulation approach taken in this study could be used as a more natural means for enhancing deep sleep in patients with disorders like epilepsy, Alzheimer's disease and Parkinson's, in which poor quality sleep is common and associated with adverse outcomes. PMID- 30440653 TI - Cholinergic Modulation of CA1 Pyramidal Cells via M1 Muscarinic Receptor Activation: A Computational Study at Physiological and Supraphysiological Levels. AB - The hippocampus receives extensive cholinergic modulation from the basal forebrain, which has been shown to have a prominent role in attention, learning, and synaptic plasticity. Disruptions of this modulation have been linked to a variety of neural disorders including Alzheimer's Disease. Pyramidal cells of the CA1 region of the hippocampus express several cholinergic receptor types in different locations throughout the cells' morphology. Developing a computational model of these cells and their modulation provides a unique opportunity to explore how each receptor type alters the overall computational role of the cell. To this end we implemented a kinetic model of the most widely distributed receptor type, the M1 muscarinic receptor and examined its role on excitation of a compartmental model of a CA1 pyramidal cell. We demonstrate that the proposed model replicates the increased pyramidal cell excitability seen in experimental results. We then used the model to replicate the effect of organophosphates, a class of pesticides and chemical weapons, whose effects consist in inhibiting the hydrolysis of acetylcholine; we demonstrated the effect of increasing concentrations of acetylcholine on the pyramidal cell's excitability. The cell model we implemented and its associated modulation constitute a basis for exploring the effects of cholinergic modulation in a large scale network model of the hippocampus both under physiological and supraphysiological levels. PMID- 30440654 TI - Comparison of Cough, Wheeze and Sustained Phonations for Automatic Classification Between Healthy Subjects and Asthmatic Patients. AB - In this work, we consider the task of automatic classification of asthmatic patients and healthy subjects using voice stimuli. Cough and wheeze have been used as voice stimuli for this classification task in the past. In this work, we focus on sustained phonations, namely /a?/, /i?/, /u?/, /ei/, /o?/ and compare their classification performances with the cough and wheeze. Classification experiments using 35 asthmatic patients and 36 healthy subjects show that sustained vowel /i?/ achieves the highest classification accuracy of 80.79% among five vowels considered. However, it is found to be higher and lower than the classification accuracies of 78.72% and 90.25% obtained using cough and wheeze respectively. This suggests that for speech-based asthma classification, /i?/ would be a better choice compared to other vowels considered in this work. However, when non-speech sounds are included for classification, wheeze is a better choice than sustained /i?/. PMID- 30440655 TI - Study of the Automatic Detection of Parkison's Disease Based on Speaker Recognition Technologies and Allophonic Distillation. AB - The use of new tools to detect Parkinson's Disease (PD) from speech articulatory movements can have a considerable impact in the diagnosis of patients. In this study, a novel approach involving speaker recognition techniques with allophonic distillation is proposed and tested separately in four parkinsonian speech databases (205 patients and 186 controls in total). This new scheme provides values between 72% and 94% of accuracy in the automatic detection of PD, depending on the database, and improvements up to 9% respect to baseline techniques. Results not only point towards the importance of the segmentation of the speech for the differentiation of parkinsonian and control speakers but confirm previous findings about the relevance of plosives and fricatives in the detection of parkinsonian dysarthria. PMID- 30440656 TI - Learning Front-end Filter-bank Parameters using Convolutional Neural Networks for Abnormal Heart Sound Detection. AB - Automatic heart sound abnormality detection can play a vital role in the early diagnosis of heart diseases, particularly in low-resource settings. The state-of the-art algorithms for this task utilize a set of Finite Impulse Response (FIR) band-pass filters as a front-end followed by a Convolutional Neural Network (CNN) model. In this work, we propound a novel CNN architecture that integrates the front-end band-pass filters within the network using time-convolution (tConv) layers, which enables the FIR filter-bank parameters to become learnable. Different initialization strategies for the learnable filters, including random parameters and a set of predefined FIR filter-bank coefficients, are examined. Using the proposed tConv layers, we add constraints to the learnable FIR filters to ensure linear and zero phase responses. Experimental evaluations are performed on a balanced 4-fold cross-validation task prepared using the PhysioNet/CinC 2016 dataset. Results demonstrate that the proposed models yield superior performance compared to the state-of-the-art system, while the linear phase FIR filter-bank method provides an absolute improvement of 9.54% over the baseline in terms of an overall accuracy metric. PMID- 30440657 TI - Bruit-enhancing phonoangiogram filter using sub-band autoregressive linear predictive coding. AB - Subjective analysis of bruits has long been an element of vascular access physical exams. Digital recordings of blood flow bruits-phonoangiograms (PAGs) may provide an objective, non-imaging measure of vascular access stenosis. We have analyzed the long-term stability in PAGs from typical dialysis patients with arteriovenous fistulas and grafts and found that typical patients have correlated PAG spectra. PAGs can be analyzed using nonlinear, sub-band frequency-domain linear prediction to produce both bruit-enhanced recordings and a bruit-enhanced power envelope. This approach is novel over prior methods because it adaptively predicts signal envelopes based on physiologic properties of blood flow determined from chronic dialysis recipients. Our results indicate that a generalized bruit-enhancing filter can be developed for dialysis vascular access. Outputs from this filter may be analyzed to determine vascular physiology, including re-stenosis risk. PMID- 30440658 TI - Classification of Parkinson's disease Using Pitch Synchronous Speech Analysis. AB - Human speech production is a complex task that demands synchronized cognitive and muscular functioning. Assessment of a Parkinson's disease (PD) patient's speech using computational methods is a growing field of research. Existing methodologies aim at extraction and usage of features from speech to capture perturbations due to PD. In this paper, we propose a novel methodology for feature extraction and analysis. Features are extracted from each pitch cycle of the speech and variances of the features are used for analysis making this a pitch synchronous methodology. Dimensionality problem is addressed by feature selection, which is followed by an unsupervised k-means clustering to perform classification. A dataset containing 40 participants, 22 (7 female and 15 male) PD and 18 (12 female and 6 male) healthy controls (HC) is used for evaluation. The promising results yielded from this study provides support for our hypothesis that pitch synchronous speech analysis can be useful in PD analysis. PMID- 30440660 TI - Flexibility of Finger Activation Patterns Elicited through Non-invasive Multi Electrode Nerve Stimulation. AB - The inability to effectively activate and control skeletal muscles is a common impairment following a variety of neurological conditions or injuries. One common approach to restoring or augmenting this impairment is the use of external electrical stimulation of the muscles, called functional electrical stimulation (FES). Typically targeted directly at the anatomical muscle belly, existing methodologies often involve high current amplitudes, limited superficial muscle activation, and early onset of muscle fatigue. We have recently explored the capabilities of a non-invasive peripheral nerve stimulation method for the dexterous control of finger and hand muscles. Further development of our stimulation system has enabled us to manually search across a variety of stimulation locations with increased consistency and efficiency. This study examined the preliminary results in two subjects of an automated stimulation system which can rapidly characterize a large combination of stimulation electrodes. Our preliminary findings suggested that the stimulation grid was able to produce a number of clustered EMG activities and finger forces. This robust ability to flexibly generate different grasp patterns demonstrates the promise of the methodology in future applications for FES and rehabilitation. PMID- 30440659 TI - Selective Recruitment of Arm Motoneurons in Nonhuman Primates Using Epidural Electrical Stimulation of the Cervical Spinal Cord. AB - Recovery of reaching and grasping ability is the priority for people with cervical spinal cord injury (SCI). Epidural electrical stimulation (EES) has shown promising results in improving motor control after SCI in various animal models and in humans. Notably, the application of stimulation bursts with spatiotemporal sequences that reproduce the natural activation of motoneurons restored skilled leg movements in rodent and nonhuman primate models of SCI. Here, we studied whether this conceptual framework could be transferred to the design of cervical EES protocols for the recovery of reaching and grasping in nonhuman primates. We recorded muscle activity during a reaching and grasping task in a macaque monkey and found that this task involves a stereotypical spatiotemporal map of motoneuron activation. We then characterized the specificity of a spinal implant for the delivery of EES to cervical spinal segments in the same animal. Finally, we combined these results to design a simple stimulation protocol that may reproduce natural motoneuron activation and thus facilitate upper limb movements after injury. PMID- 30440661 TI - Long-term functionality of a soft electrode array for epidural spinal cord stimulation in a minipig model. AB - Long-term biointegration of man-made neural interfaces is influenced by the mechanical properties of the implant materials. Substantial experimental work currently aims at replacing conventional hard implant materials with soft alternatives that can favour a lower immune response. Here we assess the performance of a soft electrode array implanted in the spinal epidural space of a minipig model for a period of 6 months. The electrode array includes platinum silicone electrode contacts and elastic thin-film gold interconnects embedded in silicone. textbfIn-vivo electrode impedance and voltage transients were monitored over time. Following implantation, epidural stimulation produced muscle-specific evoked potentials and visible muscle contractions. Over time, postoperative and stimulation induced changes in electrode impedance were observed. Such trends provide a basis for future technological improvements aiming at ensuring the stability of soft implantable electrodes for neural interfacing. PMID- 30440662 TI - A Novel EMG-driven Functional Electrical Stimulator for Post- Stroke Individuals to Practice Activities of Daily Living. AB - Prior research has demonstrated that hand function can be recovered in individuals with mild stroke through an intervention that is both 'intense' and 'functional'. However, in individuals with moderate to severe post stroke hand paresis, current evidence for an effective intervention to regain hand function is almost absent. A possible contributor to such poor recovery in these individuals may be the inability to intensively practice with the paretic hand during activities of daily living (ADLs). Many ADLs require use of the paretic arm and hand. Due to post-stroke abnormal muscle synergies, functional arm movements, such as lifting or reaching, often result in unwanted activity in the wrist/finger flexors. This makes voluntary hand opening more difficult. A possible solution to enable these individuals to practice with their paretic hand in a functional context is using devices to assist hand opening. Unfortunately, most of currently available hand rehabilitation devices do not sufficiently address hand opening with the appearance of abnormal muscle synergies. We, therefore, developed a synergy resistant, electromyographic (EMG)-driven electrical stimulation device that allows for $?mathbf {Re}$liable and $?mathbf {In}$tuitive control of the hand (ReIn-Hand) opening while using the paretic arm during lifting and reaching. PMID- 30440663 TI - Applying Multichannel Optogenetic System for Epidural Spinal Cord Stimulation in Rats. AB - This study reports on the technique of applying multichannel optogenetic system to spinal cord stimulation in rats. Epidural spinal cord stimulation has been shown to reactivate spinalized hind limb motion; however, the stimulating parameters and detailed mechanism remain unclear. In order to utilize the high spatial resolution and cell type selectivity of optogenetics for studying the mechanism behind epidural spinal cord stimulation, a multichannel optical fiber bundle was designed, composed of 720 optical fibers of 200 $?mu $m diameter arranged in a 48$?times $ textbf15 matrix cover the vertebral columns of rats from level T13 to L2. The stimulating location was controlled by changing the direction of projection of a laser diode, and the appropriate projecting angle to obtain the maximum optical power output of each fiber was determined by a hill climbing algorithm. A spinal cord window was developed to fit the head of the optical fiber bundle onto the dorsal part of rat spinal cord. Preliminary test in a rat revealed different stimulating area distribution of the optogenetically induced tibialis anterior (TA) and medial gastrocnemius (MG) muscle reactions and demonstrated the capability of the system for in-vivo study. PMID- 30440664 TI - Feature Selection for the Detection of Sleep Apnea using Multi-Bio Signals from Overnight Polysomnography. AB - Patients with sleep apnea (SA) are at increased risk of stroke and cardiovascular disease. Diagnosis of sleep apnea depends on the standard overnight polysomnography (PSG). In this study, the DREAM Apnea Database was used to evaluate the importance of the various features proposed in the literature for the analysis of sleep apnea. Various timeand frequency- domain features that include wavelet and power spectral density were extracted from ECG, EMG, EEG, airflow, SaO2, abdominal and thoracic recordings. Evaluation measures of one-way analysis of variance (ANOVA) and Rank-Sum test were used to test the performance of different features. The selected feature subset indicated that frequency domain features outperform time-domain ones. This study will help in enhancing the detection accuracy of sleep apnea for the various polysomnography signals. PMID- 30440665 TI - Autonomic cardiac activity in adults with short and long sleep onset latency. AB - Autonomic cardiac activity during sleep has been widely studied. Research has mostly focused on cardiac activity between different sleep stages and wakefulness as well as between normal and pathological sleep. This work investigates autonomic activity changes during sleep onset in healthy subjects with long and short sleep onset latency (SOL). Polysomnography (PSG) and electrocardiography (ECG) were simultaneously recorded in 186 healthy subjects during a single night. Autonomic activity was assessed based on frequency domain analysis of RR intervals and results show that the analysis of RR intervals differs significantly between the short SOL and the long SOL groups. We found that the spectral power in the low frequency band (LF) was significantly higher in the long SOL group compared to the short SOL group in the first 10 minutes in bed intended to sleep. There was no significant difference for LF and the spectral power in the high frequency band (HF) 10 minutes before and after sleep onset between the two groups. Only in the short SOL group there was a significant increase in HF from the first 10 minutes in bed intended to sleep to 10 minutes before SO, while LF decreased significantly in both groups. The effect of time (5.5-min bin) on the heart rate variability (HRV) features around sleep onset showed that both LF and HF differed significantly during the period surrounding sleep onset only in the short SOL group. PMID- 30440666 TI - Automatic Sleep Stage Classification Using Single-Channel EEG: Learning Sequential Features with Attention-Based Recurrent Neural Networks. AB - We propose in this work a feature learning approach using deep bidirectional recurrent neural networks (RNNs) with attention mechanism for single-channel automatic sleep stage classification. We firstly decompose an EEG epoch into multiple small frames and subsequently transform them into a sequence of frame wise feature vectors. Given the training sequences, the attention-based RNN is trained in a sequence-to-label fashion for sleep stage classification. Due to discriminative training, the network is expected to encode information of an input sequence into a high-level feature vector after the attention layer. We, therefore, treat the trained network as a feature extractor and extract these feature vectors for classification which is accomplished by a linear SVM classifier. We also propose a discriminative method to learn a filter bank with a DNN for preprocessing purpose. Filtering the frame-wise feature vectors with the learned filter bank beforehand leads to further improvement on the classification performance. The proposed approach demonstrates good performance on the Sleep-EDF dataset. PMID- 30440667 TI - Characteristics of EEG power spectrum during sleep spindle events in ADHD children. AB - The attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder that interferes with the typical development and both learning and motor functioning in a child's life. Most of the children with ADHD present also sleep problems like difficulties in falling asleep and maintaining sleep. Sleep spindles are characteristic waves of sleep stage 2 in humans and are characterized by a fusiform morphology. In the last years, the empirical evidence indicates that spindles are associated with cognitive faculties and intelligence as well as with several disease states. On the other hand, power spectral analysis of EEG represents a powerful noninvasive tool for examining cerebral behavior. The aim of this study is to evaluate the differences between ADHD and healthy children of the power spectral values in delta, theta, alpha, beta and gamma bands, before, during and after sleep spindles. Our results show significant differences concentrated in the period immediately after spindle epochs, in the left hemisphere of the brain, in almost all bands, with greater values in control than in ADHD children. PMID- 30440668 TI - Automating the Detection of REM Sleep Behaviour Disorder. AB - This study aims to develop automated diagnostic tools to aid in the identification of rapid-eye-movement (REM) sleep behaviour disorder (RBD). Those diagnosed with RBD enact their dreams and therefore present an abnormal characteristic of movement during REM sleep. Several methods have been proposed for RBD detection that use electromyogram (EMG) recordings and manually annotated sleep stages to objectively quantify abnormal REM movement. In this work we further develop these proven techniques with additional features that incorporate the relationship of muscle movement between sleep stages and general sleep architecture. Performance is evaluated using polysomnography (PSG) recordings from 43 aged-matched healthy controls and subjects diagnosed with RBD obtained from multiple institutions and publicly available resources. Using a random forest classifier with established and additional features, the performance of RBD detection was shown to improve upon established metrics (achieving 88% accuracy, 91% sensitivity, and 86% specificity). PMID- 30440669 TI - Quantitative Analysis of a Marked Point Process based Sleep Spindle Detector (MPP SSD). AB - Sleep spindles result from interactions between the thalamic and cortical neurons during the NREM2 stage. Studies show that these waxing and waning episodes of field potentials may have an implied role in memory consolidation, cellular plasticity and neuronal development besides serving as important markers in several neuronal pathologies. For these reasons, accurate spindle scoring of polysomnographic signals is important and has garnered interest in automating the tedious process of scoring via visual inspection. In this paper, we employ a transient model for automatic sleep spindle detection designed as a Marked Point Process (MPP). Further, in order to simplify the model development, the determination of the atoms was done independently for each of the EEG bands. However, this brings the problem of quantifying the effect of the required bandpass filtering, which was not done in previous work. Here we change the Q- factor of the filters and evaluate the effect on the detections provided by the model, when compared with two sleep experts. Several statistics are utilized, and we conclude that the design of the bandpass filters affects the performance. Low Q filters were thought necessary, but the results show that the optimal Q - factor is around 2. PMID- 30440670 TI - In vivo relationship between joint stiffness, joint-based estimates of muscle stiffness, and shear-wave velocity. AB - Shear-wave (SW) ultrasound elastography is both a clinical and research tool that is increasingly being used to quantify the material properties of muscle. However, how SW velocity relates to stiffness changes on the joint- and musclelevels is poorly understood. Therefore, the purpose of this work was to develop a biomechanical model to estimate plantar flexor muscle stiffness, and measure joint stiffness, joint-based estimates of muscle stiffness, and medial gastrocnemius (MG) SW velocity under different activations (0, 20, and 40%) to quantify the relationships between 1) joint stiffness and jointbased estimates of muscle stiffness; 2) joint stiffness and MG SW velocity; and 3) joint-based estimates of muscle stiffness and MG SW velocity. Our main findings include strong relationships between 1) joint stiffness and joint-based estimates of muscle stiffness $( R^{2}?,= 0 .70)$ and 2) joint stiffness and MG SW velocity $( R^{2}?,= 0 .66)$, and a weak relationship between joint-based estimates of muscle stiffness and MG SW velocity $( R^{2}?,= 0 .24)$. These findings further our understanding of SW velocity measures in muscle and provide a biomechanical model to decompose muscle stiffness from joint stiffness. PMID- 30440671 TI - Elbow Joint Angle Estimation with Surface Electromyography Using Autoregressive Models. AB - This paper presents a method to estimate the elbow joint angle from surface electromyography (sEMG) measurements of biceps, triceps and brachioradialis. This estimation is of major importance for the design of human robot interfaces based on sEMG. It is also relevant to model the muscular system and to design biomimetic mechanisms. However, the processing and interpretation of electromyographic signals is challenging due to nonlinearities, unmodeled muscle dynamics, noise and interferences. In order to determine an estimation model and a calibration procedure for the model parameters, a set of experiments were carried out with six subjects. The experiments consisted of series of continuous (cyclical) and discrete elbow flexo-extensions with three different loads (i.e. 0 kg, 1.5kg and 3 kg). The sEMG data from the biceps brachii, triceps brachii and brachioradialis and the joint angle were recorded. Four different modeling techniques were evaluated: State Space (SS), Autoregressive with Exogenous Input (ARX), Autoregressive Moving-Average with Exogenous Input (ARMAX), Autoregressive Integrated Moving-Average with Exogenous Input (ARIMAX). After the model was selected, a second experiment was performed in order to validate the estimation procedure. The results show a procedure to estimate the EMG-to-angle relation with high correlation and low meansquare- root errors with respect to the measured angle data. PMID- 30440672 TI - A New Algorithm to Estimate Glenohumeral Joint Location Based on Scapula Rhythm. AB - This work analyzes the human shoulder complex workspace by introducing a new method to estimate the intraarticulation location of the glenohumeral (GH) joint. The proposed algorithm is based on the hypothesis of the GH joint remaining fixed during the first 30 degrees of shoulder elevation. This part of any vertical movement is considered to estimate the center of spherical motions CoS) where the humeral head is located.For the experimental results, six subjects performed 5 cycles of 12 different movements in different planes. The data are collected using motion capture, for various landmarks of the shoulder girdle. With the proposed method, estimating the location of GH is possible for any motion of the shoulder girdle complex. In order to complete the kinematic model of the shoulder complex, PCA is used to identify a relation between the shoulder joints. This technique indicates that the shoulder complex can be modeled using two degrees of freedom (DOFs) to locate the spherical GH joint. The overall shoulder model can generate any possible vertical motion of the human shoulder. PMID- 30440673 TI - Shoulder Glenohumeral Elevation Estimation based on Upper Arm Orientation. AB - In this paper, the shoulder glenohumeral displacement during the movement of the upper arm is studied. Four modeling approaches were examined and compared to estimate the humeral head elevation (vertical displacement) and translation (horizontal displacement). A biomechanics-inspired method was used firstly to model the glenohumeral displacement in which a least squares method was implemented for parameter identification. Then, three Gaussian process regression models were used in which the following variable sets were employed: i) shoulder adduction/abduction angle, ii) combination of shoulder adduction/abduction and flexion/extension angles, iii) overall upper arm orientation in the form of quaternions. In order to test the respective performances of these four models, we collected motion capture data and compared the models' representative capabilities. As a result, Gaussian process regression that considered the overall upper arm orientation outperformed the other modeling approaches; however, it should be noted that the other methods also provided accuracy levels that may be sufficient depending on task requirements. PMID- 30440674 TI - Generalized Lower Limb Joint Angular Phase Space Analysis of Subject Specific Normal and Modified Gait. AB - This study presents and applies generalized angular phase space analysis to lower limb joint angles of specific subject during normal and modified gait for discrimination of gait and joint angular movements. Case study of an adult healthy male in-vivo and noninvasive kinematic assessment of skin surface adhesive markers at lower limb was performed at human movement lab during normal gait, stiff knee gait and slow running. Musculoskeletal modeling was performed using AnyGait v.0.92 morphing Twente Lower Extremity Model (TLEM) to match the size and joint morphology of the stick-figure model. Inverse kinematics was performed obtaining hip, knee and ankle joint flexion-extension angular displacements, velocities and accelerations. Generalized phase space analysis was applied to lower limb joint angular displacements, velocities and accelerations. Directional statistics was applied to generalized phase planes with mean direction, resultant length and circular standard deviation assessment. Rayleigh test was employed for directional concentration and coordination assessment, and Watson's $?mathrm{U^{2$ goodness of fit test applied to the von Mises distribution. Results point for the importance of subject specific study, generalized joint angular phase space analysis, comparing results with other normalization methods and validation of applied methods with qualitative clinical analysis. PMID- 30440675 TI - A Guide-Wired Helical Microrobot for Mechanical Thrombectomy: A Feasibility Study. AB - In this paper, we present a novel guide-wired helical microrobot for mechanical thrombectomy in cardiovascular system, especially for calcified thrombus therapeutics. We designed and fabricated a prototype of the helical shape microrobot equipped with a freely rotatable spherical joint connected to a catheter guidewire, that enables drilling capability to remove calcified objects in vascular. The guidewire helps supporting and maneuvering the microrobot against blood flow during thrombus removal procedure. In addition to the microrobot, an enhanced electromagnetic navigation system (ENS) is implemented to utilize high frequency operation based on resonant effect, which enables powerful drilling force of the microrobot. The in-vitro experimental results illustrate that the suggested method could successfully enhance the locomotion and the drilling force of the helical microrobot that would be sufficient for future mechanical thrombectomy application in cardiovascular therapeutics. PMID- 30440676 TI - Preliminary Study of Palatal Implant for Sleep Apnea Control. AB - A fully-implantable device for treating obstructive sleep apnea (OSA) is conceptually suggested using soft palate stimulation. In this research, two in vivo studies were conducted to demonstrate electrical and physical feasibilities of the suggested device. First, electrical stimulation was delivered to the soft palate of a rabbit using a stimulator ASIC. The stimulation frequencies were swept from 20 Hz to 200 Hz to find out the appropriate parameter. Also, threshold level of the current pulse was evaluated to be 1.10 mA with an observance of a C arm fluoroscopy. Second, a mock-up was fabricated with liquid crystal polymer (LCP), reflecting dimensions of the suggested device. The mock-up was inserted toward the soft palate of a rabbit by incising the hard palate in a lateral direction. After the mock-up was inserted, protrusion of the device was not detected and the subject stayed alive for at least a month at the time of this writing. Finally, several discussions on the palatal implant fabrication with LCP are presented. PMID- 30440677 TI - Performance Assessment of a Dedicated Reflectance Pulse Oximeter in a Neonatal Intensive Care Unit. AB - The measurement of peripheral oxygen saturation (SpO2) in neonatal intensive care units (NICUs) poses a significant challenge. Motion artifacts due to the patient's limb motion induce many false alarms, which in turn cause an additional workload for the medical staff and anxiety for the parents. We developed a reflectance pulse oximeter dedicated to be placed at the patient's forehead, which is less prone to such artifacts. We trained our algorithms for SpO2 estimation on 8 adult healthy volunteers participating in a controlled desaturation study. We then validated our SpO2 monitoring system on 25 newborn patients monitored in an NICU. We further evaluated the versatility and resilience to low signal-tonoise ratios (SNR) of our solution by testing it on signals acquired in a low-perfusion region (upper right part of the chest) of our adult volunteers. We obtained an SpO2 estimation accuracy ($A _{?mathbf {rms}}$) of 1.9 % and 3.1 % at the forehead and the chest in our adult volunteers, respectively. These performances were obtained after automatic rejection of 0.1 % and 30.0 %, respectively, of low-SNR signals by our dedicated quality index. In the dataset recorded on newborn patients in the NICU, we obtained an accuracy of 3.9 % after automatic rejection of 11.7 % of low-SNR signals by our quality index. These analyses were carried out following the procedures suggested by the ISO 80601-2-61:2011 standard, which specifies a target $A _{?mathbf {rms}} ?le $ 4 % for SpO2 monitoring applications. These promising results suggest that reflectance pulse oximeters can achieve clinically acceptable accuracy, while being placed at locations less sensitive to limb motion artifacts - such as the forehead - thereby reducing the amount of SpO2-related false alarms in NICUs. PMID- 30440678 TI - Basic Performance Tests of the MILL Intravascular CO2 Removal Catheter. AB - Currently available treatment methods for acute lung failure show high rates of complications. There is an urgent need for alternative treatment methods. A catheter device which can be minimal invasively inserted into the vena cava for intracorporeal gas exchange was developed. Main components of the device are a drive unit and a membrane module. In this study, the flow behavior in a vena cava model with inserted catheter prototype was investigated in experiments and basic computational fluid dynamic (CFD) simulations. Main findings are that the miniature blood pump has suitable characteristics and generates sufficient power to overcome the pressure drop induced in the membrane module, and that the design of the membrane outlet might be critical to avoid additional pressure losses. Parts manufactured with a high resolution 3D printer have proven to be suitable for the prototyping process. PMID- 30440679 TI - Design, Development, and Characterization of BreathForce: A Respiratory Training System for Patients with Spinal Cord Injuries. AB - In this effort, we report the development of a portable inspiratory-expiratory training device for use in rehabilitation of participants with cardiovascular and respiratory motor deficits. The device uses existing airway restriction components to establish a manually adjustable respiratory training apparatus and includes an integrated pressure sensor with custom software to direct and track therapy sessions. The battery-powered system promotes proven rehabilitation methodologies performed at the clinic in a platform to be translated to the home for participants with spinal cord injuries. PMID- 30440680 TI - Feasibility of a Post-Auricle Wireless Power System for Pediatric Mechanical Circulatory Support Pumps. AB - Heart failure (HF) affects approximately 12,000-35,000 children each year in the United States. The development of blood pumps has provided circulatory support for many adults suffering with HF until they receive a heart transplant. However, while the development of blood pumps for adults has led to fullyimplantable continuous flow devices, blood pump technology for children has lagged significantly behind. One area for improving blood pump implantability in children is the use of wireless powering transfer systems (WPTS). These systems eliminate the power cord connecting the implanted blood pump to the external power supply. In adults, WPTS have decreased the number of power cord-related infections and have improved patient outcomes after pump implantation. Unfortunately, the components of these wireless systems are too large for children. In this paper we describe the preliminary work to develop a fully implantable WPTS specifically designed to power the Jarvik 2000 Child. Specifically, we design planar coils 36 um in thickness to be implanted in behind the-ear fashion. An amplifier and rectifier circuit were also built to provide 15.7V and 0.5A of voltage and current to the pump. PMID- 30440681 TI - Estimating Mini Mental State Examination Scores using Game-Specific Performance Values: A Preliminary Study. AB - Individuals with permanent cognitive impairment need to be evaluated and monitored. There exists a number of clinically validated cognitive assessment tools, but they often need to be administered by trained therapists in clinical settings. This serves as a major barrier for frequent, longitudinal monitoring of cognitive function. In this work, we introduce Neuro-World, a collection of innovative 3D mobile games, that allows one to self-administer the assessment of his/her cognitive function. The game performance is analyzed and converted into a clinically-accepted measure of cognitive function, specifically the Mini Mental State Examination (MMSE) score, improving the translational impact of the system in real-world clinical settings. To validate the feasibility of our approach, we collected game-specific performance data from 12 post-stroke patients, which was used to train a supervised machine learning model to estimate the corresponding MMSE score. Our experiment results showed a normalized root mean square error of 5.3% between the actual and estimated MMSE scores. This study enables new clinical and research opportunities for accurate longitudinal assessment of cognitive function via an interactive means of playing mobile games. PMID- 30440682 TI - Optimizing Mental Workload by Functional Near-Infrared Spectroscopy Based Dynamic Difficulty Adjustment. AB - Gains of cognitive training may be eliminated due to mental fatigue. This paper reports the design and implementation of a functional near-infrared spectroscopy (fNIRS) - dynamic difficulty adjustment (DDA) system. A total of 25 healthy volunteers underwent two training sessions - one with fixed difficulty level of training (FDT) and one with neurofeedback training (NFT) using our fNIRS-DDA system. The workload in each training session was assessed using the National Aeronautics and Space Administration Task Load Index (NASA-TLX). Whilst sustaining mental task performance, the drop in oxygenation level observed in NFT subjects might indicate mental fatigue as they received higher NASA-TLX scores, especially in both mental demand and frustration subscales. In contrast, the oxygenation levels remained almost constant by NFT subjects throughout the experiment. This suggests that the proposed fNIRS-DDA system aided the participants in avoiding mental fatigue. Future studies will investigate if the system may prevent the progression of Alzheimer's disease. PMID- 30440683 TI - Automated Measurement and Subtask Analysis of the Timed Upand- Go Test in the Field of Geriatrics. AB - Multimorbidity and age-physiological functional restrictions can lead to frailty and a loss of a self-determined life in elderly patients. The Timed Up-and-Go test (TUG) is a sensitive and specific measure of frailty and has also many other areas of application, for example in chronic diseases. Besides the measurement of the complete TUG time, the analysis of subtasks may also reveal important information about particular aspects of the health status of test subjects. We developed an ultrasonic-based device for performing the TUG automatically, which can be attached to the backrest of a chair. This device provides the total TUG time as well as the displacement-time data for all included subtasks. To prepare for its use in clinical studies, we performed a field test at a geriatric center. The goal was to confirm feasibility, i.e., to assess its application in real patients. Despite some improvement potential revealed by the field test, the concept turned out to be an appropriate method for monitoring the TUG time and its subtasks. PMID- 30440684 TI - Mobile Fall Risk Assessment Solution for Daily-Life Settings. AB - Prevention of falls requires accurate means for fall risk assessment in order to identify persons at risk. This paper introduces a novel mobile fall risk assessment solution for daily-life settings. The solution contains an Android application that uses acceleration sensor data received via Bluetooth LE connection. The application guides through a simple walk test, analyzes the acceleration data measured from the acceleration sensor attached to the lower back and gives feedback about the fall risk for the user. Preliminary user tests with 12 healthy subjects were conducted to evaluate the feasibility of the solution. Each test subject performed three walks demonstrating normal, dragging and slow gait. The results showed that the acceleration features calculated by the application distinguish normal gait from dragging and slow gaits. Further collection of comprehensive data set with older adults is needed to adjust the application parameters appropriately for the target group. PMID- 30440685 TI - A new smart balance rehabilitation system technology platform: Development and preliminary assessment of the Smarter Balance System for home-based balance rehabilitation for individuals with Parkinson's disease. AB - Physical and balance rehabilitation programs have been shown to improve postural stability and balance performance and to be more effective than dopaminergic medication and surgical treatments for individuals with Parkinson's disease (PD). This paper describes the development and assessment of a new Smarter Balance System (SBS) intended for home-based use by individuals with PD. We report the initial results of a long-term study currently underway that quantifies the clinical impacts of using the SBS during a 6-week, home-based rehabilitation program. Preliminary results indicate that individuals with PD improved their balance and postural stability, and maintained the improvements for 1 month after completing the 6-week, homebased rehabilitation program with the SBS. PMID- 30440686 TI - Functional near infrared spectroscopy in the noninvasive assessment of brain death. AB - Brain death, whose assessment is of great significance, is the irreversible loss of all the functions of the brain and brainstem. The traditional diagnostic methods mainly relies on complex, harmful or unstable test, including apnea test,textbf evoked potential test, etc. Functional near infrared spectroscopy (fNIRS) utilize the good scattering properties of blood corpuscle to NIR, has the ability to monitor cerebral hemodynamics noninvasively. To objectively evaluate the brain death diagnosis with fNIRS, we use our portable fNIRS oximeter to measure the physiological data of fifteen brain death patients and twenty-two patients under natural state. The varied fractional concentration of inspired oxygen (FIO2) were provided in different phase. We found that the ratio ofthe concentration changes in oxy-hemoglobin to deoxy hemoglobin(Delta[HbO2]/Delta[Hb])in normal patients is significantly lower than brain death patients, and its restore oxygen change process in low-high-low paradigm is more remarkable. This resulting promotion indicates potential of fNIRS-measured hemodynamic index in diagnosing brain death. PMID- 30440687 TI - Non-invasive method to monitor molecular changes in human stratum corneum during acute barrier disruption using reflectance NIR spectroscopy. AB - Stratum corneum is the outer most part of skin for barrier function. Disorder in stratum corneum is related with many skin diseases including acne, atopic dermatitis and psoriasis. In developed countries, about 20% of the population has disorder in the barrier function of stratum corneum. Adhesive tape stripping is a method to disrupt skin barrier function in studying disorder in stratum corneum. In this study, we obtained NIR (Near-Infrared) spectrum of human skin after tape stripping. Changes in skin spectra after barrier disruption were investigated through principal component analysis (PCA) of spectrum. PCA analysis revealed that peaks for -NH stretching and -CH vibration mainly contributed to the spectral variation caused by barrier disruption. Furthermore, second derivative of spectrum revealed that acute barrier disruption contributes to spectral changes in the region related with secondary structure of protein, lipid and water associated with lipid in stratum corneum. We demonstrated that acute barrier disruption affected features in NIR spectrum. These spectral changes revealed that acute barrier disruption affected keratin protein and ceramide in human stratum corneum. These results suggest that NIR spectroscopy can be used to monitor changes in filamentous network and lamellar structure in stratum corneum. NIR spectroscopy can provide non-invasive method to investigate skin disease related with barrier disruption by monitoring disturbance in protein and lipid structure in stratum corneum. PMID- 30440688 TI - On the Fly Reporting of Human Body Movement based on Kinect v2. AB - Human gait analysis is of utmost importance in understanding several aspects of human movement. In clinical practice, characterizing movement in order to obtain accurate and reliable information is a major challenge, and physicians usually rely on direct observation in order to evaluate a patient's motor abilities. In this contribution, a system that can objectively analyze the patients gait and generate an on the fly, targeted and optimized gait analysis report is presented. It is an extension to an existing system that could be used without interfering with the healthcare environment, which did not provide any on the fly feedback to physicians. Patient data are acquired using Kinect v2, followed by data processing, gait specific feature extraction, ending with the generation of a quantitative on the fly report. To the best of our knowledge, the complete system fills the gap as a proper gait analysis system, i.e., a low-cost tool that can be applied without interfering with the healthcare environment, provide quantitative gait information and on the fly feedback to physicians through a motion quantification report that can be useful in multiple areas. PMID- 30440689 TI - Physiological Responses of the Youth Viewing a Japanese Garden. AB - Previous studies have demonstrated that exposure to a Japanese garden is a non pharmacological measure to improve the behavioral symptoms of elderly people with dementia, and that Japanese gardens are significantly more effective than other environments. However, it is not clear whether Japanese gardens have similar effects in the young. To address this open question, we measured the physiological responses of university students when viewing a Japanese garden, and compared them to the same students' responses when viewing a control space. We measured three physiological indicators of autonomous nervous system (ANS) activity: the electrocardiograph (ECG), the blood volume pulse (BVP) and the galvanic skin response (GSR). Our results suggest that the Japanese garden does not have as calming an effect on younger subjects as observed previously in elderly subjects. However, students did respond more positively to the Japanese garden than to an unstructured space. Ambient temperature was found to be a critical factor affecting heart rate and heart rate variability, but not other measures. PMID- 30440690 TI - Knee extensor muscular activity estimation during different walking patterns: flat normal and brisk walking, stair climbing. AB - Preserving mobility, the ability to keep a correct posture and dynamic balance in order to walk properly, is fundamental to maintain autonomy in daily life. Based on the correlation between muscle groups and autonomy, previous research has suggested that maintaining muscular tone in knee extensors is critical. Continuous training of knee extensors during aging is therefore essential to maintain independence. In this work, it is hypothesized that it is possible to estimate knee extensor activity only from IMU data based on a simple lower limbs model. The accuracy of the knee extensor activity estimation algorithm has been tested using sEMG measurements as control data on three different walking patterns: normal walk, fast walk and stair climbing. Estimated knee torque area and measured muscular activity for each step were compared confirming a high estimation accuracy with a correlation efficient R=0.80. Moreover, muscular activity can be divided based on intensity in three groups of statistically significant difference confirmed by the Steel-Dwass method. Future works should test the usability of the algorithm for different walking patterns, and use the collected data and the refined algorithm to implement a smart resistive device to increase knee extensor exertion during each walking pattern to the level necessary for sufficient extensor training. PMID- 30440691 TI - Long Distance Vital Signs Monitoring with Person Identification for Smart Home Solutions. AB - Imaging photoplethysmography has already been proved to be successful in short distance (below 1m). However, most of the real-life use cases of measuring vital signs require the system to work at longer distances, to be both more reliable and convenient for the user. The possible scenarios that system designers must have in mind include monitoring of the vital signs of residents in nursing homes, disabled people, who can't move, constant support for people regardless of the performed activity (e.g., during sleeping), infants, etc. In this work we verified the possibility of remote pulse estimation at a distance above 5m. Additionally, we integrated the deep learning algorithm for person tracking and identification, even when facial features are not visible. In this way, we enabled the collection of user specific measurements to create personalized vital signs patterns and we provided the support for monitoring of multiple people using one video stream. The preliminary results showed that it is possible to accurately (RMSE $< 2.8$ beats per minute) extract pulse from visible light sequences acquired with a webcam at a distance of 6m after applying a proper image pre-processing algorithm. PMID- 30440692 TI - Elevation Measurement of Laryngeal Prominence from Depth Images for Evaluating Swallowing Function. AB - A system which easily evaluates swallowing function is needed for the early diagnosis of deglutition disorder and the support for daily exercise for the purpose of its maintenance and recovery. We propose a method to measure laryngeal movement in a non-contact and non-invasive way with reasonable accuracy. To evaluate laryngeal elevation quantitatively, laryngeal prominence is detected from depth data by area extraction based on the classifier obtained by using a decision tree and optimum solution selection using species-based PSO. The elevation time and amount is calculated by tracking the laryngeal prominence. The laryngeal movement could be observed in persons with laryngeal prominence during water swallowing test. PMID- 30440693 TI - Co-Saliency-Enhanced Deep Recurrent Convolutional Networks for Human Fall Detection in E-Healthcare. AB - This paper addresses the issue of fall detection from videos for e-healthcare and assisted-living. Instead of using conventional hand-crafted features from videos, we propose a fall detection scheme based on co-saliency-enhanced recurrent convolutional network (RCN) architecture for fall detection from videos. In the proposed scheme, a deep learning method RCN is realized by a set of Convolutional Neural Networks (CNNs) in segment-levels followed by a Recurrent Neural Network (RNN), Long Short-Term Memory (LSTM), to handle the time-dependent video frames. The co-saliency-based method enhances salient human activity regions hence further improves the deep learning performance. The main contributions of the paper include: (a) propose a recurrent convolutional network (RCN) architecture that is dedicated to the tasks of human fall detection in videos; (b) integrate a co-saliency enhancement to the deep learning scheme for further improving the deep learning performance; (c) extensive empirical tests for performance analysis and evaluation under different network settings and data partitioning. Experiments using the proposed scheme were conducted on an open dataset containing multicamera videos from different view angles, results have shown very good performance (test accuracy 98.96%). Comparisons with two existing methods have provided further support to the proposed scheme. PMID- 30440694 TI - Teenagers' Usage of a Mobile-Wearable-Cloud Platform to Promote Healthy Lifestyles: the PEGASO Experience. AB - In contemporary society, non-communicable diseases linked to unhealthy lifestyles, such as obesity, are on the rise with a major impact on global deaths. Prevention is the new frontier, promising to increase life expectancy and quality, while reducing costs related to healthcare. The PEGASO project developed a mobile ecosystem where the digital Companion aims at empowering teenagers in the adoption of healthy lifestyles. The pilot study conducted in three European countries (Spain, UK and Italy) shows a good acceptance of the system and that teenagers are keen to use mobile technology to improve their lifestyle, although wearable devices did not engage the young users. PMID- 30440695 TI - Increasing Health Care Adherence Through Gamification, Video Feedback, and Real World Rewards. AB - Treatment non-adherence poses a sizeable and persistent challenge to health professionals. In the US alone, it is estimated that at least $100 billion per year is spent on avoidable health care costs with an additional $230 billion per year forfeited due to lost productivity. Efforts to increase adherence have yielded mixed results. We present an adaptable, theoretical framework that uses established gamification methods coupled with a means of motivating patients using real-world rewards. The framework presented herein is implemented via user interface modifications to a clinically validated health tracking app, as well as a means of delivering video feedback for viewing a variety of potential reward outcomes. PMID- 30440696 TI - A Conductance-Based Sensor to Estimate Bladder Volume in Felines. AB - New research tools are essential to help understand the neural control of the lower urinary tract (LUT). A more nuanced understanding of the neuroanatomy of bladder function could enable new treatment options or neuroprosthesis to eliminate incontinence. Here we describe the design, prototyping and validation of a sensing mechanism for a catheter-free fluid volume estimating system for chronic neurophysiological studies of the lower urinary tract and ambulatory urodynamics. The system consists of two stimulation electrodes, one sensing anode, and a microcontroller for control and recording. The packaged device is small enough to be surgically implanted within the bladder lumen, where it does not inhibit bladder function nor inflict trauma. Benchtop evaluation of the conductance-sensing system in simulated bladder-like conditions has demonstrated that the system can predict intra-vesical fluid volume with $< 5$ mL mean error below 40mL and worst-case mean error of 13mL near full-scale volume. These results indicate that conductance-based volume sensing of the urinary bladder is a feasible method for real-time measurement. PMID- 30440697 TI - Towards an Untethered Ultrasound Beamforming System for Brain Stimulation in Behaving Animals. AB - In this paper, we present a wireless ultrasound transmit (TX) beamforming system, potentially enabling wearable brain stimulation for small awake/behaving animals. The system is comprised of a 16-element capacitive micromachined transducer (CMUT) array, driven by a custom phased-array integrated circuit (IC), which is capable of generating high-voltage (13.5 V) excitation signals with sixteen phase delays and four amplitude levels. In addition, a Bluetooth low-energy module and a power management unit were integrated into the system, which realizes a battery operated self-contained unit. We validated the functionality of the system by demonstrating beamforming and steering with a hydrophone measurement setup. We achieved an acoustic pressure output of 554 kPapp at the depth of 5 mm, which corresponds to a spatial-peak pulse-average intensity (ISPPA) of 2.9 W/cm2. The measured 6-dB beamwidth (0.4 mm) is promising in that it can stimulate a specific region of the brain, especially for small animals such as mice. Further smart partitioning of the system will enable a truly wearable device for small animals. PMID- 30440698 TI - Evaluation of Bone Conduction Vibration System Using Photoacoustic Effect. AB - This article proposes a novel bone conduction vibrator based on an interesting phenomenon where audible sound can be perceived when a vibration is produced using a laser beam that is synchronized to the sound and this vibration is transmitted to an auricular cartilage. To study this phenomenon, we measured the effect using a rubber sheet with similar properties to those of soft tissue, together with an acceleration sensor, and found that audible sound was produced in the sample. We also calculated the force level based on the mechanical impedance and the acceleration in the proposed system. It is expected that a force level equal to the reference equivalent threshold force level can be achieved at a light intensity below the safety limit for human skin exposure by choosing an irradiation wavelength at which a larger degree of optical absorption occurs. This novel application of the photoacoustic effect is promising for bone conduction hearing aids. PMID- 30440699 TI - Unobtrusive Heartbeat Detection from Mice Using Sensors Embedded in the Nest. AB - Unobtrusive monitoring of physio-behavioral variables from animals can minimize variability in preclinical research and thereby maximize the potential for clinical translation. In this paper, we present the design, implementation, and validation of an instrumented nest providing continuous recordings of seismocardiogram (SCG) signals and skin temperature. SCG represents the chest wall vibrations associated with the heartbeat, and can potentially provide a measure by which individual heartbeats can be detected without the need for electrodes or implantable devices. A non-contact electric field sensor placed in proximity to the animal in the nest was also used to detect respiratory dynamics. The setup was tested with a total of six anesthetized mice. To understand the effects of mouse positioning within the nest on signal quality, the error in heartbeat detection at different positions of the sensor on the body was quantified, with a simultaneously-obtained electrocardiogram (ECG) as the reference standard. At the optimal placement determined with this approach, multiple perturbations were performed such as pinching, changing ambient temperature, and norepinephrine injection to modulate physiology and assess measurement capability. Heartbeat intervals obtained from the ECG and SCG during the perturbations were correlated (R2=0.82) and were in agreement according to Bland-Altman methods (bias: 0.006ms, 95% confidence interval: [-3.79, 3.78]ms) suggesting that SCG can be reliably used for unobtrusive heartbeat detection. Accordingly, the setup can provide a means by which individual heartbeats - and thereby heart rate and heart rate variability indices - can be quantified without the need for any sensors to be attached to the body of the animal. PMID- 30440700 TI - A Wireless Optoelectronic Neuroscience Platform for Chronic Fluorescence Sensing in Freely Behaving Rodents. AB - We present a new head mountable wireless fiber biophotometry microsystem conceived to detect fluorescent signal fluctuations correlated with neuronal activity. The proposed system incorporates all aspects of a conventional tethered fiber-based biophotometry system encompassed into a wireless microsystem. The interface includes an LED as excitation light source, a custom designed CMOS biosensor, a multimode fiber, a microcontroller (MCU), and a wireless data transceiver enclosed within a 3D-printed, small and light weight, plastic housing. Precisely, the system incorporates a new optoelectronic biosensor merging two individual building blocks, namely a low-noise sensing front-end and $?mathrm {a}2 ^{nd}$ order continuous-time $?Sigma ?Delta $ modulator (CTSDM), into a single module for enabling high-sensitivity and high energy-efficiency photo-sensing. The proposed CMOS biosensor is implemented in $?mathrm {a}0 .18- ?mu m$ CMOS technology, consuming $41 ?mu W$ from $?mathrm {a}1 .8- V$ supply voltage, while achieving a peak dynamic range of $86 dB$ over a $50- Hz$ input bandwidth at a 20-kS/s sampling rate. This new interface opens new avenues for conducting in-vivo experiments with live animals. PMID- 30440701 TI - A Novel Environment-Invariant Core Body Temperature Estimation for High Sensitivity and Specificity Fever Screening. AB - We propose a novel concept for core body temperature estimation to improve sensitivity and specificity of a fever screening system under different environmental conditions based on an infrared thermal camera. The conventional approach of setting low temperature thresholds to determine presence of fever to increase sensitivity has led to highly-degraded specificity due to the low accuracy in core body temperature estimation. Two main causes are the moderate correlation between core body temperature and surface temperature data used to determine it, and the estimation algorithm that does not consider changes in the environment. Hence, in our novel concept, we eliminate the environmental effects by using direct and correcting temperature data, and thus improve the accuracy in estimating core body temperature. The direct data contain rich information about core body temperature through maximum temperatures obtained from the mouth, ear, around the eye and forehead, while the correcting data contain information related to the surroundings such as the cheek and nose temperatures to compensate for the environmental effect on the former. Since direct data can be easily affected by the environment and noise, multiple direct data are taken to minimize this problem. Through improved accuracy, both sensitivity and specificity will be automatically increased and the trade-off between them when adjusting the threshold values will be greatly relaxed. Analysis of the results shows improvement in both sensitivity and specificity from78.9% and 87.0%, respectively, in the conventional approach, to 84.2% and 91.3% in the proposed method when 37.5$^{o}?text{C}$ was set as the threshold. Data in the present study was obtained from a wide spectrum of ages (between 22 and 58 years), ethnicities (seven) and core body temperatures (36.0$^{o}?text{C}$ to 39.5$^{o}?text{C}$). Data were also collected at variable room temperatures ranging from 20.2$^{o}?text{C}$ to 30.8$^{o}?text{C}$. PMID- 30440703 TI - Detection of Respiratory Crackle Sounds via an Android Smartphone-based System. AB - Pulmonary auscultation with traditional stethoscope, although useful, has limitations for detecting discontinuous adventitious respiratory sounds (crackles) that commonly occur in respiratory diseases. In this work, we present the development of a mobile health system for the automated detection of crackle sounds, comprised by an acoustical sensor, a smart phone device, and a mobile application (app) implemented in Android. The app allows the physician to record, store, reproduce, and analyze respiratory sounds directly on the smart phone. The algorithm for crackle detection was based on a time-varying autoregressive modeling. Performance of the automated detector was analyzed using synthetic fine and coarse crackle sounds randomly added to the basal respiratory sounds acquired from healthy subjects with different signal to noise ratios. Accuracy and sensitivity were found to range from 90.7% to 94.0% and from 91.2% to 94.2%, respectively. Application of the proposed mobile system to real acquired data from a patient with pulmonary fibrosis is also exemplified. PMID- 30440702 TI - Polymer-coated fiber optic probe for the monitoring of breathing pattern and respiratory rate. AB - In recent years, no-invasive and small size systems are meeting the demand of the new healthcare system, in which the vital signs monitoring is gaining in importance. In this context, Fiber Bragg grating (FBG) sensors are becoming very popular and FBG-based systems could be used for monitoring vital signs. At the same time, FBG could be able to sense chemical parameters by the polymer functionalization. The aim of our study was investigating the ability of a polymer-coated FBG-based probe for monitoring breathing patterns and respiratory rates. We tested the proposed FBG-based probe on 9 healthy volunteers during spirometry, the most common pulmonary function test. Results showed the high accuracy of the proposed probe to detect respiratory rate. The comparison between the respiratory rates estimated by the probe with the ones by the spirometer showed the absolute value of the percentage errors lower than 2.07% (in the 78% of cases <.91%). Lastly, a Bland Altman analysis was performed to compare the instantaneous respiratory rate values gathered by the spirometer and the FBG probe showing the feasibility of breath-by-breath monitoring by the proposed probe. Results showed a bias of 0.06+/- 2.90 $?mathrm{breaths}?square {?mathrm {min}}^{-1}$. Additionally, our system was able to follow the breathing activities and monitoring the breathing patterns. PMID- 30440704 TI - A 3D-Printed, Adjustable-Stiffness Knee Brace with Embedded Magnetic Angle Sensor. AB - In this work, we detail the design and verification of a novel, 3D-printed, flexible knee brace with an embedded magnetic angle sensor for monitoring joint kinematics. The brace's torsional stiffness can be selectively modified by applying elastic bands of varying thickness. Through benchtop tests and finite element analysis simulations, we characterize the mechanical behavior of the knee brace and determine estimates of torsional stiffness across a range of band thicknesses. To demonstrate the ability to modulate knee joint loading in a real world scenario, we report results of a pilot study in which able-bodied subjects wear the device during treadmill walking and seated flexion-extension tasks. PMID- 30440705 TI - Clinical Validation of a Wearable Respiratory Rate Device for Neonatal Monitoring. AB - Respiratory rate monitoring is of paramount importance in neonatal care. Manual counting of expansions and contractions of the abdomen or diaphragm of the neonate is still the widely accepted measure of respiratory rate in most clinical settings. A practical, affordable, easy-to-use technology to continuously measure respiratory rate in neonates is essential to recognize the signs and symptoms of respiratory disorders. Clinical validation of a system for continuous and long term respiratory rate monitoring of neonates, in a wearable form factor with the capability of remote monitoring is presented in this paper. The respiratory rate monitor was validated in clinical settings on 10 premature babies with various disease conditions and respiratory rates varying from 25 to 90 breaths per minute. Results show a high degree of correlation between the respiratory rate measured by the device and reference measurements. An intelligent algorithm which can remove motion corruption from the accelerometer data and provide reliable results is essential for large-scale adoption of the technology for both clinical as well as home monitoring. The technical details of implementation, results and analysis of the clinical study and observations made during clinical study regarding the feasibility of integrating the device in neonatal care are covered in this paper. PMID- 30440706 TI - Fully Disposable Wireless Patch Sensor for Continuous Remote Patient Monitoring. AB - Continuous remote monitoring with convenient wireless sensors is attractive for early detection of patient deterioration, preventing adverse events and leading to better patient care. This article presents an innovative sensor design of VitalPatch, a fully disposable wireless biosensor, for remote continuous monitoring, and details the performance assessments from bench testing and laboratory validation in 57 subjects. The bench testing results reveal that VitalPatch's QRS detection had a positive predictive value of $> 99$% from testing with ECG databases. The accuracies of HR, BR and skin temp (in mean absolute error, MAE) from bench testing were $< 5$ bpm, $< 1$ brpm, $< 1 ^{ ?circ}C$ respectively. The laboratory testing in 57 subjects revealed the accuracy of HR and BR to be $2.2 ?pm 1.5$ bpm and $1.7 ?pm 0.7$ brpm respectively for stationary periods. The absolute percent error in detecting steps was $4.7 ?pm 4.6$%, and the accuracy in detecting posture was $96.4 ?pm 3.1$%. Meanwhile, the specificity and sensitivity of fall detection $( ?mathrm {n}=20)$ was found to be 100% and 93.8%, respectively. In conclusion, VitalPatch biosensor demonstrated clinically acceptable accuracies for its vital signs and actigraphy metrics applicable for continuous unobtrusive patient monitoring. PMID- 30440707 TI - Designing a Hybrid Engineering Course combining Case-Based and Lecture-Based Teaching. AB - Traditional engineering and business school courses have different pedagogical emphases. Engineering courses are perceived as technical, dense and require students to provide definitive answers to problems. On the other hand, business school courses aim to increase students' knowledge by confronting them with real world cases and by encouraging both in- and out-of-the-classroom teamwork, thinking in groups and problem solving. In business school courses, the teaching is directed towards the thought process rather than the final answer itself. These two approaches to learning are both valuable and give the opportunity to develop complementary skills. Combining both approaches in a single course is however challenging. We tackled this challenge by designing the semester-long "Introduction to Nanobiotechnology and Nanobioscience" course for senior undergraduate and first year graduate students as a hybrid class. Our objective was to design an engineering course of standard length, which incorporates key elements of the business schools' case study approach to learning while retaining essential elements of the traditional engineering education. PMID- 30440708 TI - Engineering, Physical Therapy and the Community: A Service Learning Course. AB - The School of Engineering and the Physical Therapy program at the University of North Florida developed a novel, community-based course where undergraduate engineering students are partnered with physical therapy students. In this course students participate in hands-on, team-based design projects focused on low-tech and high-tech rehabilitation technology for children with disabilities. The impact of this interprofessional education experience on the students has been evaluated using the Public Service Motivation Scale for three years and its impact on the students is presented. PMID- 30440709 TI - Proposal for a New Training Exercise for Single Port Laparoscopic Cholecystectomy. AB - This paper presents the design and implementation of a new training exercise to improve technical textbfskills in the surgeons who performtextbf Single Port Laparoscopic Cholecystectomy (SPLC), a technique that requires active improvements to overcome the lack of triangulation and collision of instruments both within and outside the abdominal cavity. The proposed mechanisms were developed based on peg transfer tests, performed by an expert surgeon in SPLC, with straight forceps and SILS$^{?mathbf {TM}}$ access in a pelvictrainer afterwards an unstructured interview was showed to the surgeon. These methodological tools provided the characteristics of the type of movement required by the peg transfer test at the time of performing the training task, which was taken as a reference to propose a new protocol to be implemented. The mentioned structure was tested by an expert surgeon, who performed 5 tasks, within an average running time of 170 seconds. At the end of the tests, a semi structured interview was carried out again to the surgeon, where the improvement of the technique was tested. PMID- 30440711 TI - How to Invent New Medical Devices. AB - Further develop strong engineering skills, supplement with knowledge of medicine and biology. Acquire clinical problems requiring solutions from medical and biological professionals. Form design teams to solve those problems: review the literature, confer with experts, brainstorm all the possibilities, select the most promising solution, build it in the lab, test it, iterate, publish. PMID- 30440710 TI - Activities to Invigorate a Student Chapter of the IEEE Engineering in Medicine and Biology Society. AB - An IEEE Engineering in Medicine and Biology Society (EMBS) student chapter can play an important service role for collegiate biomedical curricula, supporting (a) faculty and administrators as they offer biomedical programs and work to strengthen industry/community relationships, and (b) students as they engage in engineering skill development and seek industry employment, graduate school opportunities, or medical school placement. This paper summarizes recent projects and activities sponsored by the Kansas State University (KSU) Student Chapter of the IEEE EMBS - efforts intended to maintain interest in the student chapter while supporting its service role. Such a role will become more important in upcoming years in light of the increasing demand for biomedical engineers, especially in the Midwest United States, a reality which motivated the inception of a new KSU undergraduate degree in Biomedical Engineering starting in Fall 2018. The KSU IEEE EMBS student chapter can play a large role in the overall success of this new curriculum, and the projects and activities summarized in this paper are offered as examples to programs that may wish to benefit from an IEEE EMBS student chapter in a similar and meaningful way. PMID- 30440712 TI - Integrated Information Rich Engineering Course Design. AB - This study applies several high impact practices in an integrated fourth-year biomedical engineering course. The engineering design project is mapped to six deliverables using an adaptation of the Information Rich Engineering Design (IRED) model. This pedagogy facilitates regular student interactions with the instructor, the teaching assistant, the librarian and peers. Periodic information audits provide students with opportunities to reflect, integrate their learning, and share diverse experiences with the instructor. The term project is a real world application which allows students to discover the relevance of theoretically learned concepts to hands-on problem solving. Students demonstrate competence in skills related to information seeking, writing and critical thinking through the completion of an IEEEstyle conference paper. PMID- 30440713 TI - The Influence of Mechanical Rubbing on the Dissolution of Blood Clots. AB - Mechanical rubbing of blood clots is a potential minimally-invasive method for clearing clogged blood vessels. In this work, we investigate the influence of the interaction of the tip of a helical robot with blood clots. This interaction enables the dissolution of the blood clot and the release of the entrapped red blood cells and platelets from its three-dimensional fibrin fiber network. We analyze the pre- and post-conditions of the blood clots following 40 minutes of mechanical rubbing, under the influence of a rotating magnetic field in the frequency range of 20 Hz to 45 Hz. Our measurements show that the weight of the blood clots is decreased by 22.5 +/- 11.1% at frequency of 25 Hz. We also validate the influence of mechanical rubbing using cell count and spectrophotometric analysis on phosphate buffered saline samples past the robot and the clot. The maximum cell count is measured as 654 +/- 108 * 104 cells/m1 and 54 +/- 12 * 104 cells/m1, whereas the absorbance is measured as 4. 35 * 10-6 mol and 1. 05 * 10-6 mol under the influence of mechanical rubbing and without mechanical rubbing, respectively. PMID- 30440714 TI - Prediction of Minimum Toe Clearance with a Radial Basis Function Network at the Start of the Swing Phase. AB - Prediction of minimum toe clearance (MTC) during walking can decrease the risk of tripping. In this paper, we proposed a novel MTC prediction method using a radial basis function network. Input data were the angles, angular velocities, and angular accelerations of the hip, knee, and ankle joints in the sagittal plane at the start of the swing phase. In experiments, five subjects walked on a treadmill for 360 s. The radial basis function network was trained with 60 s of gait data and tested with the remaining 300 s of gait data. The root mean square error between the true and predicted MTC values was lower than 2.79 mm in all subjects. PMID- 30440715 TI - F3Hand: A Five-Fingered Prosthetic Hand Driven with Curved Pneumatic Artificial Muscles. AB - Recently, many five-fingered prosthetic hands have been commercialized. However, most five-fingered prosthetic hands have heavyweight problems. In addition, their fingers with high rigidity are difficult to fit the object to be grasped. This paper reports a five-fingered prosthetic hand driven with curved pneumatic artificial muscles. By using the curved pneumatic artificial muscles as a skeleton and an actuator of the finger, flexible grasps and natural motions are achieved. Its weight of 255 g is less than one-third of the conventional fivefingered prosthetic hand. An evaluation using SHAP demonstrated that an amputee was able to operate various abstract objects. PMID- 30440716 TI - On Muscle Selection for EMG Based Decoding of Dexterous, In-Hand Manipulation Motions. AB - The field of Brain Machine Interfaces (BMI) has attracted an increased interest due to its multiple applications in the health and entertainment domains. A BMI enables a direct interface between the brain and machines and is capable of translating neuronal information into meaningful actions (e.g., Electromyography based control of a prosthetic hand). One of the biggest challenges in developing a surface Electromyography (sEMG) based interface is the selection of the right muscles for the execution of a desired task. In this work, we investigate optimal muscle selections for sEMG based decoding of dexterous in-hand manipulation motions. To do that, we use EMG signals derived from 14 muscle sites of interest (7 on the hand and 7 on the forearm) and an optical motion capture system that records the object motion. The regression problem is formulated using the Random Forests methodology that is based on decision trees. Regarding features selection, we use the following time-domain features: root mean square, waveform length and zero crossings. A 5-fold cross validation procedure is used for model assessment purposes and the importance values are calculated for each feature. This pilot study shows that the muscles of the hand contribute more than the muscles of the forearm to the execution of inhand manipulation tasks and that the myoelectric activations of the hand muscles provide better estimation accuracies for the decoding of manipulation motions. These outcomes suggest that the loss of the hand muscles in certain amputations limits the amputees' ability to perform a dexterous, EMG based control of a prosthesis in manipulation tasks. The results discussed can also be used for improving the efficiency and intuitiveness of EMG based interfaces for healthy subjects. PMID- 30440717 TI - Empirical Based Modeling for the Assessment of Dynamic Knee Stability: Implications for Anterior Cruciate Ligament Injury Risk. AB - Anterior cruciate ligament (ACL) injuries are common sports injuries, costing the U.S. roughly $1 billion annually. To better understand the underlying injury mechanism, Nyquist and Bode stability criteria were applied to assess frontal plane dynamic knee stability among male Australian Football players during the weight-acceptance phase of single-leg jump landing. Out of 30 landings, 19 were classified as stable and 11 as unstable. Medial and lateral vasti, hamstring and gastrocnemii muscle activation waveforms were analyzed in parallel to determine if individuals with stable and unstable frontal plane joint biomechanics possessed different lower limb neuromuscular strategies. The total quadriceps muscle activation during the stable landings were significantly higher (p=0.02) than during the unstable landings. Additionally, the vasti exhibited a medial dominance during the stable landings compared to the unstable (p=0.06). These results suggest that individuals with unstable frontal plane knee landing mechanics may have reduced recruitment of the muscles crossing the knee; specifically, the medial muscles, which could limit their ability to compress and support the joint. The stability criteria were able to classify stable and unstable knee mechanics. And the differences in muscle activation during these stable and unstable landings provided new insights towards the ACL injury mechanism and possible injury prevention countermeasures. PMID- 30440718 TI - A sEMG Classification Framework with Less Training Data. AB - Supervised machine learning algorithms, such as Artificial Neural Network (ANN), have been applied to surface electromyograph (sEMG) to classify user's muscular states. This paper introduces a novel framework to design a binary sEMG classifier to distinguish if the user performs a repetitive motion with a dumbbell. This framework enables to reduce the number of tasks required for collecting training data as it utilizes prior knowledge of sEMG. The performance of the proposed classifier is validated experimentally. Experimental results show that the proposed framework enables the design of a classifier which distinguishes the user's state with a 95.7% success rate. This accuracy is comparable to an accuracy of ANN classifier (99.6%), but with less training data. Under the identical training conditions, the accuracy of the proposed framework outperforms the ANN classifier whose accuracy drops to 65.6%. PMID- 30440719 TI - Blowfly yaw control via electrical stimulation of the H1 lobula plate tangential cell. AB - Eliciting predictable flight responses in insects via exogenous stimulation of the nervous system is an area of both scientific and engineering interest. Blowflies in particular possess an excellent biological flight control system, making them an ideal system for characterising responses to stimulation. Here we demonstrate a means of electrically controlling Calliphoridae-Protophormia terranovae wing behaviour, generating a repeatable yaw response via biphasic electrical stimulation of the H1 lobula plate tangential cell (LPTC). We found that a 10 mA current pulse at a frequency of 30-270 Hz produces a yaw response in the preferred direction of H1 in a tethered blowfly preparation, and the magnitude of the yaw response is proportional to the frequency of the stimulus. This result suggests that these LPTCs, which encode optic flow, may be a viable interface for controlling fly flight behaviour. This platform could find application not only for micro air vehicles (MAVs), but also in developing flight models or for studying neurological control of fly flight behaviour. PMID- 30440720 TI - Development of an Integrated Actuated Hand Orthosis and Virtual Reality System for Home-Based Rehabilitation. AB - Stroke survivors often require a lengthy and costly rehabilitation regimen to regain some of the hand function lost due to stroke. Financial, travel, and scheduling issues can limit access to clinical therapy, thereby depriving individuals of care. Interventions are needed which can extend from the clinic into the home. Home-based rehabilitation strategies, however, must promote sensorimotor learning while maintaining user engagement. Virtual reality, in combination with actuated orthoses, has the potential to provide solutions to these issues. The orthosis can facilitate appropriate therapy while the virtual reality can provide a conduit for maintaining human interaction and engagement in the home environment. In this paper, we describe the development of such an integrated system for hand and upper extremity rehabilitation. PMID- 30440721 TI - Evidence of a "Clock" Determining Human Locomotion. AB - The motor control of human locomotion is still an open issue, and it may be the leading cause of the low effectiveness of lower limbs rehabilitation therapies. Locomotion motor control has proved to be fundamentally different from the upper limbs reaching task strategies, which have been used for the development of current motor control computational models used to define rehabilitation protocols. The main difference between these two tasks is the relevance of the environmental dynamics in task planning and execution. Reaching movements are dominated by the intrinsic impedance of the human body. On the other hand, locomotion is determined by the interaction between the human body and Earth's gravity. The dynamic primitives have been recently proposed to explain how humans account for the environmental dynamics during motor control; however, it is not yet possible to explain how the nervous system combines the information. This paper proposes and validates with human data that the brain controls locomotion to have the centre of mass moving between the two legs as a harmonic oscillator. This finding has enabled us to propose a control architecture that can explain how the motor primitives can be described as a special type of dynamics primitives. PMID- 30440722 TI - Comparing Physical Human-Robot Interaction with Spring-and Elastomer-Based Series Elastic Actuators. AB - Physical human-robot interaction (pHRI) is an important consideration in the design of rehabilitation exoskeletons. Series Elastic Actuators (SEAs) are seen as a promising method of introducing compliance and comfort to robotic exoskeletons. Recently, authors have proposed the use of elastomers in SEAs, rather than springs, but there is a dearth of literature comparing how the two compliant elements are perceived by humans. In this paper, we quantitatively and qualitatively compare human interaction with an elastomer and a spring in terms of comfort and motion smoothness, with the aim of informing future SEA design. Two mechanisms were designed to compare human interaction with a spring and elastomer, and a cross-over experimental design was used to help eliminate any learning effects. Overall, the elastomer appeared to be slightly more comfortable and allow slightly smoother motion than the spring, holding promise for the use of elastomers as a means of improving pHRI in exoskeletons actuated by SEAs. PMID- 30440723 TI - Asymmetric Dual Arm Approach For Post Stroke Recovery Of Motor Functions Utilizing The EXO-UL8 Exoskeleton System: A Pilot Study. AB - In a dual arm therapeutic regime aiming to rehabilitate motor functions post stroke, both the affected arm (paretic) and the unaffected (non-paretic) arm are involved. In this context, the leading idea is that motor functions of the affected arm during a reaching task may be improved if the unaffected arm has already reached the target. As part of this pilot study, one chronic post-stroke patient with weakness and spasticity on his right arm conducted reaching tasks to virtual targets arranged in a $5?times 3$ matrix located parallel to his frontal plane, in two different configurations: (1) affected arm only (without assistance from the exoskeleton); (2) unaffected arm first followed by the affected arm (2a) without, and (2b) with assistance. A force field attracting the wrist of the affected arm to the target was used in the assistive mode. The data post processing and analysis included task completion time, reachable task space, joint range of motion, human-robot interaction force/torque and power exchange at multiple sensors along the arm - visualized in a series of interaction maps. The data validated the robotic system's basic functionality in facilitating post stroke unilateral and asymmetric bilateral training. Future work would be expanded to clinical trials with more subjects to be recruited and additional features to be implemented. PMID- 30440725 TI - Functional Tasks Performed by People with Severe Muscular Atrophy Using an sEMG Controlled Robotic Manipulator. AB - For paralyzed people activities of daily living like eating or drinking are impossible without external assistance. Robotic assistance systems can give these people a part of their independence back. Especially if the operation with a joystick is not possible anymore due to a missing hand function, people need innovative interfaces to control assistive robots in 3D. Besides brain computer interfaces an approach based on surface electromyography (sEMG) can present an opportunity for people with a strong muscular atrophy. In this work we show that two people with proceeded spinal muscular atrophy can perform functional tasks using an sEMG controlled robotic manipulator. The interface provides a continuous control of three degrees of freedom of the endeffector of the robot. The performance was assessed with two clinical measures of upper limb functionality: the Box and Blocks Test and the Action Research Arm Test. Additionally, the participant could show that they can drink by themselves with the provided system. PMID- 30440724 TI - Observations And Experiments For The Definition Of A New Robotic Device Dedicated To CT, CBCT And MRI-Guided Percutaneous Procedures. AB - In this paper, we present the work achieved to define the robotic functionalities of interest for percutaneous procedures as performed in interventional radiology. Our contributions are twofold. First, a detailed task analysis is performed with workflow analysis of biopsies, one of the most frequent tasks, under three imaging modalities, namely CT, CBCT and MRI. Second, the functionalities of a robotic assistant are identified, and we analyze whether a single device can bring an added value during procedures in the three modalities while keeping the robotized workflow close to manual tasks, to minimize learning time and difficulty of use. Experimental analysis on CBCT is notably used to confirm the interest of the determined robotic functionalities. PMID- 30440726 TI - Modified Computed Torque Control of a Robotic Orthosis for Gait Rehabilitation. AB - Rehabilitation robots may help the patient improve their recovery by supporting them to perform repetitive, systematic training sessions. Safety and comfortable feeling of the patients who training with robots is an important issue in not only the steady state but also the transient process. In this research, the trajectory tracking control problems of a two-degrees of freedom (2-DOF) robotic orthosis is discussed. The robotic orthosis is powered by pneumatic artificial muscles (PAMs) in an antagonistic configuration. based on a mathematical model, a modified computed torque control scheme is employed to enhance the tracking performance. The effectiveness of the proposed control strategy is verified by the experiments with the participation of different subjects. PMID- 30440727 TI - Autonomous Positioning of Eye Surgical Robot Using the Tool Shadow and Kalman Filtering. AB - Vitreoretinal surgery is one of the most difficult surgical operations, even for experienced surgeons. Thus, a master-slave eye surgical robot has been developed to assist the surgeon in safely performing vitreoretinal surgeries; however, in the master-slave control, the robotic positioning accuracy depends on the surgeon's coordination skills. This paper proposes a new method of autonomous robotic positioning using the shadow of the surgical instrument. First, the microscope image is segmented into three regions-namely, a micropipette, its shadow, and the eye ground-using a Gaussian mixture model (GMM). The tips of the micropipette and its shadow are then extracted from the contour lines of the segmented regions. The micropipette is then autonomously moved down to the simulated eye ground until the distance between the tips of micropipette and its shadow in the microscopic image reaches a predefined threshold. To handle possible occlusions, the tip of the shadow is estimated using a Kalman filter. Experiments to evaluate the robotic positioning accuracy in the vertical direction were performed. The results show that the autonomous positioning using the Kalman filter enhanced the accuracy of robotic positioning. PMID- 30440728 TI - Reference Trajectory Adaptation to Improve Human-Robot Interaction: A Database Driven Approach. AB - Many robotic devices that are used for therapy or as assistive devices rely on pre-defined reference trajectories to assist the user's movements. Fixed pre defined trajectories force the user to adapt to unnatural movement patterns which may be detrimental to rehabilitation outcomes. We propose a database-driven approach to adapt the reference trajectory of robotic training devices that rely on cyclic motion such as walking. Dynamic time warping is used to compare the measured pattern with a database of pre-approved safe trajectories; the best matching pattern is selected from the database and used for the next movement sequence. The proposed approach was evaluated in computer simulations and a bioinspired robotic test bench. Our proposed method reduced the RMS error between individual user trajectories and the supplied reference, even in the presence of measurement noise. PMID- 30440729 TI - Design and Pilot Evaluation of a Reconfigurable Spinal Exoskeleton. AB - Low back pain is a leading cause of disability, and there is a tremendous need for nonsurgical, nonpharmaceutical interventions to manage it. Versatile spinal exoskeletons have been proposed as a method of supporting or augmenting the wearer, but experimental data from human subjects are limited, and the effects of such exoskeletons remain poorly understood. We thus present a prototype of a reconfigurable spinal exoskeleton that features easily adjustable resistance and compression at multiple spinal levels, allowing us to study the effect of different exoskeleton configurations on the body. In a pilot evaluation with a single subject, both thoracic and abdominal compression were found to affect trunk angle, low back moment and the electromyogram of the erector spinae, though different exoskeleton configurations had different effects during different tasks. This supports the premise that intelligent mechanical adjustments of a spinal exoskeleton are necessary for optimal support or augmentation of the wearer, though the results need to be examined in a larger, varied sample of subjects. PMID- 30440730 TI - Musculoskeletal Simulation for Determining Influences of the Magnitude of Sensory Noise and Stiffness on the Selection of Hip or Ankle Movement Strategies. AB - While standing, the elderly exhibit different move- ment behaviors compared to young people. However, the causes of these differences remain clear. The purpose of this study was to verify a hypothesis that only the magnitude of sensory noise and stiffness can reproducibly determine trends in the hip or ankle movement strategies. Simulations of postural control of a musculoskeletal model for three noise conditions and three stiffness conditions were performed. Variations in the angles of the hip and ankle suggested that the sensory noise amplitude had no influence on the selection. However, the ankle strategy tended to be selected with the increase of stiffness. Strategy shifts of elderly may be derived from other components; muscle weakness, increase of neurological time delay, or learning based on other evaluation index. PMID- 30440731 TI - An Investigation of the Sensing Capabilities of Magnetotactic Bacteria. AB - We investigate the sensing capabilities of magnetotactic bacteria (Magnetospirillum gryphiswaldense strain MSR1) to MCF-7 breast cancer cells. Cancer cells are allowed to grow inside a capillary tube with depth of 200 $?mu ?mathrm {m}$ and motion of magnetotactic bacteria is investigated under the influence of oxygen gradient and geomagnetic field. The influence of cancer cells is modeled to predict the oxygen gradient within the capillary tube in three dimensional space. Our experimental motion analysis and count of motile magnetotactic bacteria indicate that they migrate towards less-oxygenated regions within the vicinity of cancer cells. Bands of magnetotactic bacteria with average concentration of 18.8+/-2.0% are observed in close proximity to MCF-7 cells $(h = 20~ ?mu ?mathrm {m})$, whereas the concentration at proximity of $190~ ?mu ?mathrm {m}$ is 5.0 +/- 6.8%. PMID- 30440732 TI - Load exposure of osseointegrated implants for transfemoral limb prosthesis during running. AB - Direct skeletal attachment of lower limb prostheses ensures direct load transfer between the prosthetic leg and the skeleton. Knowledge of the load characteristics at the boneimplant interface during high-loading activities is needed to understand the limitations of current implant systems, as well as to inform their future development. The present study estimates the load scenario at the bone-implant interface of a transfemoral amputee while running with kinematic symmetry between the prosthetic and the intact limbs corresponding to that of an ablebodied subject. Kinematic symmetry was used as this represents the ultimate aim of advanced bionic legs. Kinematic data and ground reaction forces from a running trial of an able-bodied subject were matched to a musculoskeletal model of a transfemoral amputee. The joint reaction forces at the boneimplant interface were calculated using inverse dynamics. The normalized peak forces and moments during a single gait cycle were calculated to 153 % BW (body weight) / -14.8 % BWm, 186 % BW / 16.2 % BWm and 56.8 % BW / -18.7 % BWm for the x- (anterior), y- (longitudinal), and z-axis (lateral-medial), respectively. These findings can potentially be used as design input for future implant systems and external safety devices. PMID- 30440733 TI - The Effects of Hind Limb Suspension and Cast Mediated Immobilization on Bone Strength Properties. AB - Astronauts and patients on bedrest are subject to a combination of bone strength losses and muscle atrophy due to microgravity and unloading. In this study, mice were subject to both hind limb suspension and cast mediated immobilization. Pre treatment and post-treatment microCT scans were utilized to create finite element models. Both pre-treatment and posttreatment scans were then cropped, rotated and threedimensional image registration was performed to eliminate inconsistency in alignment. A hexahedral finite element mesh was then generated from this 3D data. Finite element analysis was conducted to perform simulated physiological loading of the femoral neck to assess bone strength through bone structural morphology. Hind limb suspension combined with Cast Mediated Immobilization caused a 7.9% decrease in bone FEA stiffness compared to the in-vivo pre-treatment control. No differences were found in bone volume or structural efficiency. PMID- 30440734 TI - Estimation of the Operating Force From the Human Motion. AB - In this research, we propose a new method to estimate the operating force exerted when moving an object with the hands by observing the human motion only. The required force for moving the object can be estimated without equipping any sensors on the object or on the human body. From the measured joint angles, we calculate the center of mass and the hand's position using a human model. Then, the operating forces of the hands can be estimated by considering the balance of forces and moments using a dynamic model. In the experiments, we estimated the operating force of the hands for three representative movements of operating a box: pushing, pulling and lifting. By comparing the estimated and measured operating force, we verified the effectiveness of the proposed method with human subjects. PMID- 30440735 TI - A Biomechatronic EPP upper-limb prosthesis controller and its performance comparison to other topologies. AB - Historically, Classic Extended Physiological Proprioception (EPP) as an upper limb prosthesis control topology has been outperforming functionally all other topologies of the past. A novel Biomechatronic EPP controller has been designed to overcome shortcomings of the classic EPP control topology, and has been hypothesized to be functionally equivalent to the classic EPP topology. Using the dSpace realtime hardware platform and other mechanical and electronic components, the following were developed in the lab: (a) A Biomechatronic EPP controller, (b) a classic EPP controller, (c) an "unconnected" controller and (d) an EMG controller. All four topologies were tested in the lab using the target experiments methodology. Initial results of one subject show that performance of (a) is superior or comparable to (b) and superior to (c) and (d). PMID- 30440736 TI - Modeling Space Radiation Induced Bone Changes in Rat Femurs through Finite Element Analysis. AB - As the duration of manned missions outside of the Earth's protective shielding increase, astronauts are at risk for exposure to space radiation. Various organ systems may be damaged due to exposure. This study investigates the bone strength changes using finite element modeling of Long Evans rats (n=85) subjected to graded, head-only proton (0, 10, 25, and 100 cGy, 150 MeV/n) and 28silicon (0, 10, 25, and 50 cGy, 300 MeV/n) radiation. The strength of the femoral neck will be examined due its clinical relevance to hip fractures. It has been shown in previous studies that bone mineral density was not reduced at the site of fracture. These findings question whether measurements of bone mineral density may be used to assess risk of hip fracture. The mechanisms leading to the irregular relationship between bone density and strength are still uncertain within literature and investigated to greater extent in clinical applications. Finite element analysis within this study simulated physiological loading of the femoral neck. No significant changes in femoral neck strength were found across doses of proton or 28silicon head-only radiation. Future work includes performing mechanical testing of the bone samples. Moving from mouse to larger animal models may also provide the increased lifespan for assessing the long-term outcomes of radiation exposure. PMID- 30440737 TI - Model-Free Control of Movement in a Tendon-Driven Limb via a Modified Genetic Algorithm. AB - Tendon-driven systems have many benefits over other actuation strategies such as torque-driven systems; however, their over-determined nature and posture dependent actuation presents strong constraints on their control. Also, parameters or even exact structure of the model in these systems, especially in the biological ones, are normally not clear to the controller. Here, we propose a modified Genetic Algorithm that provides the tendon excursion values for the limb to follow a desired trajectory. Our results show that the proposed algorithm was able to accurately follow the desired trajectory without the model of the system being exposed to it. We believe that this method can enable biologically inspired tendon-driven mechanisms with variable mechanical structures to autonomously control their movements. PMID- 30440738 TI - A Neuromorphic Quadratic, Integrate, and Fire Silicon Neuron with Adaptive Gain. AB - An integrated circuit implementation of a silicon neuron was designed, manufactured, and tested. The circuit was designed using the Quadratic, Integrate, and Fire (QIF) neuron model in $0.5 ?mu ?mathrm {m}$ silicon technology. The neuron implementation was optimized for low current consumption, drawing only 1.56 mA per QIF circuit and utilized hysteretic reset, non-inverting integrator, and voltage-squarer circuits. The final area of each circuit in silicon was $268 ?mu ?mathrm {m}$ height $?times 400 ?mu ?mathrm {m}$ width. This design is the first IC of its kind for this neuron model and is successfully able to output true spiking that follows the behaviors of bistability, monotonic, and excitability spiking. The normal QIF design also features an easy way to change the time constant (which nominally operates in the millisecond range) of the spiking via a single, external capacitor (the only off-chip component in this design); the adaptive gain variation of the QIF circuit adds a second parameter that adjusts the time constant via an external resistor. The design also allows for an adjustable reset threshold and operates on $?mathrm {a}?pm 5?mathrm {V}$ power supply. PMID- 30440739 TI - Design And Experiment Of A Passive Sit-To-Stand And Walking (STSW) Assistance Device For The Elderly. AB - Most elderly people complain about the discomfort of movements such as a sit-to stand (STS) motion through losing their muscular strength of lower extremity over aging. This paper presents a novel passive sit-to-stand and walking (STSW) assistance device to aid in physical support for indoor daily life of the elderly. The STSW assistance device is actuated by a pneumatic cylinder and a gas spring. The standing motion is driven by extension of actuators and the sitting motion is driven naturally with gravitational force of user's weight that reloads actuators. The effect of physical support by using this device was evaluated by experiment with measuring electromyograph signals of subjects during STS motion. As a result, the reduction rate of average maximal voluntary isometric contraction with assistance by the STSW device is about 51.2%. This means that users with the assistive device can stand up by using only about half of muscular activation in the case of natural standing up. PMID- 30440740 TI - Footwear Affects Biomechanical Work And Knee Adduction Moment During Stance Phase In Medial Knee Osteoarthritic Male Pakistani Adults. AB - OBJECTIVE: The objective of this study was to explore the effects of commonly used footwear in urban Pakistan on knee adduction moment (KAM), knee adduction angular impulse (KAAI) and biomechanical work at lower limb joints (both individually and collectively). METHODOLOGY: Cinematographic gait analysis of 20 medial knee osteoarthritis patients (Kellgren-Lawrence Grade I and II, age: 55.48 +/- 5.78 years; weight: 68.92 +/- 9.61 kg, height: 1.62 +/- 0.15m) was done, walking barefoot, with casual shoes, party shoes and traditional Pakistani sandals, at a walking speed of 1.2m/sec. RESULTS: Repeated measures ANOVA with Tukey corrections showed that all the shoes were found to be increasing first & second peaks external KAM and decreasing net joint work and total limb work significantly, at p < 0.05. CONCLUSION: Effects of footwear were found to be majorly favouring knee osteoarthritis progression. This might be one of the risk factors of increased kOA rate in urban Pakistan. PMID- 30440741 TI - A Pilot Study On The Novel Non-Invasive Nerve-Holder With Negative-Pressure Suctions. AB - In performing neurosurgical operation on peripheral nervous system, the most important first step is to robustly hold the target nerve, since the nerve holding stability and reliability significantly affect the result of surgical operation. However it is not straightforward to robustly hold peripheral nerve during the surgical operation, because the peripheral nerve is too flexible and slippery. In this study, we design a novel peripheral nerve-holder that can be used for the neurosurgical operation. Considering the anatomical characteristics of the peripheral nerve that small bundles of nerve fibers (i.e., fascicles) are structured inside the outermost layer of the nerve bundle (i.e., epineurium), we aim to develop a non-clamping and non-invasive type nerve-holder to protect the nerve fibers. For the aim, the negative-pressure suction method is applied to the proposed holder. And, in order to hold the nerve more robustly, micro-bump structure is fabricated on the suction surface contacting with the nerve. This paper introduces the concept, working principle, characteristics, and in-vitro experimental results on feasibility evaluation of the proposed holder. PMID- 30440742 TI - SATR-DL: Improving Surgical Skill Assessment And Task Recognition In Robot Assisted Surgery With Deep Neural Networks. AB - PURPOSE: This paper focuses on an automated analysis of surgical motion profiles for objective skill assessment and task recognition in robot-assisted surgery. Existing techniques heavily rely on conventional statistic measures or shallow modelings based on hand-engineered features and gesture segmentation. Such developments require significant expert knowledge, are prone to errors, and are less efficient in online adaptive training systems. METHODS: In this work, we present an efficient analytic framework with a parallel deep learning architecture, SATR-DL, to assess trainee expertise and recognize surgical training activity. Through an end-to-end learning technique, abstract information of spatial representations and temporal dynamics is jointly obtained directly from raw motion sequences. RESULTS: By leveraging a shared highlevel representation learning, the resulting model is successful in the recognition of trainee skills and surgical tasks, suturing, needle-passing, and knot-tying. Meanwhile, we explore the use of ensemble in classification at the trial level, where the SATR-DL outperforms state-of-the-art performance by achieving accuracies of 0.960 and 1.000 in skill assessment and task recognition, respectively. CONCLUSION: This study highlights the potential of SATR-DL to provide improvements for an efficient data-driven assessment in intelligent robotic surgery. PMID- 30440743 TI - Development of 6-Axis Orthodontic Force and Moment Sensing Device for Decreasing Accident of Orthodontic Treatment. AB - The purpose of this study is to develop the sensing device which measures three axis force and three-axis moment for reducing the number of accident in orthodontic treatment. The device is necessary for adequate quantitative evaluation of orthodontic forces during orthodontics. The developed sensing device is composed of six-axis force sensors, tooth models, and arms for connecting sensors and tooth models. The developed device simulates rows of teeth in orthodontic operation and measures $14 ?times 6$ axes force and moment from tooth models simultaneously. The averages of the difference of force and moment to theoretical values in each direction are 1.78 % (0.043 N) and 2.72 % (0.60 Nmm) respectively. The average moment applying couple forces is 17.1 % (0.81 Nmm). Then the device is able to measure more accurately as the value of the moment was larger. Therefore using our proposed device, we can conduct the orthodontic treatment which dentition moves large for attaching the rail of wire to the teeth. PMID- 30440744 TI - An Assistive Robotic Arm For People With Physical Disabilities Of The Extremities: HOG Based Food Detection. AB - An assistive robotic arm for helping feed people with physical disabilities of the extremities is presented in this paper. In order to detect foods on a plate, HOG based food detectors were created and implemented in our robotic arm system. The system consists of a 6-axis robotic arm, Web camera, laptop computer, and microcontroller. Using the robotic arm system, we performed two experiments: (1) eating chicken nuggets task and (2) eating shao mais task. It was found from the experimental results that the proposed assistive robotic arm system could stably transfer chicken nuggets and shao mais to the user's mouth. PMID- 30440745 TI - Impedance Model of the Interaction Between Environment and Human Body and Its Modification Design. AB - This paper presents a model of environment-human body interaction, which is critical for us to perform balanced motions such as locomotion and activities of daily living while standing. Specifically, movement smoothness and stiffness are quantitatively represented by an impedance between environment and body (ENV-BODY impedance) based on the concept of mechanical impedance, which is commonly used in robotics. The ENV-BODY impedance model considers a spring and a damper to represent the behavior of the center of pressure with respect to the ground reaction force. The model parameters are obtained from experimentally measured motion data. In addition, real-time feedback is applied for intervening the ENV BODY impedance model by either attenuating (in-phase mode) or amplifying (anti phase mode) the displacement of the center of pressure. Experimental results show that the proposed ENV-BODY impedance model suitably reflects the relationship between ground reaction force and center of pressure during static standing, and reconstructs the center-of-pressure acceleration with average error of 4.1E-0l mm/s2 Furthermore, the stiffness is smaller at the in-phase than at the anti phase mode, thus being consistent with the expected mechanical stability. This model could be applied to training programs for evaluating movement smoothness and roughness using real-time motion measurement/analysis and environment control technology. PMID- 30440746 TI - Bone Drilling Breakthrough Detection via Energy-Based Signal. AB - In this paper, a novel energy-based signal, the removal energy density $e_{b}$, is proposed as the detecting signal to determine the breakthrough instances in bone drilling based on the energy approach during the process. The proposed signal is derived from the energy conversion and conservation in drilling process. And the relationship between the signal and the drilling parameter, e.g., drilling speed, feed rate and drill bit radius, is derived. Recursive least square with time forgetting factor is used to estimate $e_{b}$ from the drilling parameters and drilling torque information. Unlike the traditional force profile, this proposed signal profile is similar under different drilling parameters including drilling speed and feed rate, hence reducing the difficulty in setting a threshold for the detection. Experiment on porcine bone is performed. The results show that the proposed signal profile is more consistent than the commonly used force profile, verifying the effectiveness of the proposed method. PMID- 30440747 TI - Gaze-controlled Laser Pointer Platform for People with Severe Motor Impairments: Preliminary Test in Telepresence. AB - This paper describes the implementation and the preliminary evaluation of a novel interaction solution for people with severe motor impairments, and particularly for those affected by Amyotrophic Laterals Sclerosis (ALS) in Locked-In State (LIS): patients able to control only the ocular muscles. The proposed communication approach allows the person to control a laser beam and interact with the environment or interlocutors in an intuitive way by pointing at objects through their gaze. For this, a tip-tilt laser control device was developed and mounted on a small robot equipped with a high definition video camera. In addition, a gaze-tracking user interface was developed to control of both systems, i.e., laser and robot. This new platform was then preliminary assessed through trials with 14 subjects without disabilities, who performed tasks of robot navigation and pointing at objects along its path. User experience was evaluated with encouraging results, indicating the proposed technology has real potential to assist communication and interaction acts of people with ALS. PMID- 30440749 TI - Preliminary Analysis Of Positive Knee Energy Injection In A Transfemoral Amputee Walking With A Powered Prosthesis. AB - Individuals with lower limb amputations show higher metabolic costs during ambulation than able-bodied individuals. This high metabolic cost may be explained by the inability of available passive prostheses to replicate the biomechanics of intact legs during walking. Powered prostheses promise to address this issue by imitating the power generation of intact legs. Several studies have investigated the effect of power generation and energy injection at the ankle joint in transtibial amputees. In contrast, no study has directly addressed knee power generation in transfemoral amputees. This study investigates the effect of knee power generation in late stance in one transfemoral amputee subject using a lightweight powered prosthesis. Experimental results suggest that injecting positive energy into the gait cycle at the knee level may improve gait ability by reducing effort. PMID- 30440750 TI - Assessment of Robot Interventions in a Task-based Rehabilitation: a case study. AB - This study is aimed at assessing of a robot intervention in a task-based upper arm rehabilitation procedure. Robotic devices have significantly been useful to help therapists do the training procedure. However, due to the lack of quantifiable feedback regarding the level of intervention, effectiveness of various parameters, such as timing, intensity, etc., the training and its efficacy varies remarkably between institution and therapists. In this study, Universal Robot 5 (UR5) has been utilized to move an arm of healthy subjects over a circular path while the muscle activities are recorded through surface electromyography (sEMG); at the same time, all components of the forces applied to the robot have also been measured using Robotiq force sensors (FT300 sensor). System identification (SI) is performed to relate the amount of force in the UR5 to the level of muscle activity in the upper-arm through model. This model has been identified through the data obtained from four healthy subjects, and has been tested and verified with data from a fifth subject. In order to visualize the robot intervention and its efficacy, muscle activities have also been recorded while the subjects perform the task with no robot assistance. The data from this test setting have shown a good agreement in terms of signal profile which suggests robot has not introduced any complications in terms of force or stiffness to the subjects. This preliminary study provides an insight for data driven intervention procedure while robots are used in facilitating the muscle recruitment to complete the desired rehabilitation task, as some patients may not complete the task properly due to muscle weakness in a certain direction and location. PMID- 30440748 TI - Visual Terrain Identification and Surface Inclination Estimation for Improving Human Locomotion with a Lower-Limb Prosthetic. AB - Lower-limb robotic prosthetics can benefit from context awareness to provide comfort and safety to the amputee. In this work, we developed a terrain identification and surface inclination estimation system for a prosthetic leg using visual and inertial sensors. We built a dataset from which images with high sharpness are selected using the IMU signal. The images are used for terrain identification and inclination is also computed simultaneously. With such information, the control of a robotized prosthetic leg can be adapted to changes in its surrounding. PMID- 30440751 TI - Automatic Surgical Skill Rating Using Stylistic Behavior Components. AB - A gold standard in surgical skill rating and evaluation is direct observation, which a group of experts rate trainees based on a likert scale, by observing their performance during a surgical task. This method is time and resource intensive. To alleviate this burden, many studies have focused on automatic surgical skill assessment; however, the metrics suggested by the literature for automatic evaluation do not capture the stylistic behavior of the user. In addition very few studies focus on automatic rating of surgical skills based on available likert scales. In a previous study we presented a stylistic behavior lexicon for surgical skill. In this study we evaluate the lexicon's ability to automatically rate robotic surgical skill, based on the 6 domains in the Global Evaluative Assessment of Robotic Skills (GEARS). 14 subjects of different skill levels performed two surgical tasks on da Vinci surgical simulator. Different measurements were acquired as subjects performed the tasks, including limb (hand and arm) kinematics and joint (shoulder, elbow, wrist) positions. Posture videos of the subjects performing the task, as well as videos of the task being performed were viewed and rated by faculty experts based on the 6 domains in GEARS. The paired videos were also rated via crowd-sourcing based on our stylistic behavior lexicon. Two separate regression learner models, one using the sensor measurements and the other using crowd ratings for our proposed lexicon, were trained for each domain in GEARS. The results indicate that the scores predicted from both prediction models are in agreement with the gold standard faculty ratings. PMID- 30440752 TI - A Postural Model for Tracking the Base of Support. AB - Mobility impairment is a major challenge for the healthcare systems of developed countries. Balance deterio-ration is a physiological consequence of the ageing process, which makes it an endemic problem in ageing societies. Despite the importance of this issue, the development of appropriate therapies and protocols is challenging due to our limited understanding of human locomotion and equilibrium. This paper presents a technique that can track the BoS geometry from the feet' posture and its validation with healthy subjects. The proposed model uses a posture dependent reference frame called Saddle Space, which is aligned to the principal direction of the potential energy surface. The target application for the model described in this paper is the development of sensors for the evaluation of balance during activity of daily living. However, the proposed methodology can also be applied to bipedal robots, and the saddle space can also be employed to describe other posture dependent variables. PMID- 30440753 TI - Biosensing by Learning: Cancer Detection as Iterative optimization. AB - We propose a novel cancer detection procedure (CDP) based on an iterative optimization method. The global minimum of a tumor-induced biological cost function indicates the tumor location, the domain of the cost function is the tissue region at high risk of malignancy, and the time-variant guess input is a swarm of externally controllable and trackable nanorobots for tumor sensing. We consider the spatial distrib-ution of fibrin as the cost function; the fibrin is formed during the coagulation cascade activated by tumor-targeted signalling modules (nanoparticles) and recruits clot-targeted receiving modules (nanorobots) towards the site of disease. Subsequently, the CDP can be interpreted from the iterative optimization perspective: the guess input (i.e., a swarm of nanorobots) is continuously updated according to the gradient of the cost function in order to find the optimum (i.e., cancer) by moving through the domain (i.e., tissue under screening). Along this line of thought, we consider the gradient descent (GD) iterative method, and propose the GD-inspired CDP, which takes into account the realistic in vivo propagation scenario of nanorobots. Finally, we present numerical examples to demonstrate the features of the GD-inspired CDP. PMID- 30440754 TI - Design of a Handheld Trocar Insertion Device for Laparoscopic Surgery to Avoid Overshooting. AB - Overshooting trocar insertion in Iaparoscopic surgery has been extensively cited as a major cause of surgical injury. The complexity and extensive insertion force required of the current handheld insertion method increases the risk of overshooting and is difficult for novice and female operators. Hence, we developed a trocar insertion device to make the procedure easier and safer. The device is designed so it is easy to handle and assemble. It used negative pressure and pneumatic cylinders to lift the abdominal wall and two motors to drive the trocar insertion. In addition, we interpreted the characteristics of the insertion force and developed an algorithm to detect whether the trocar is properly inserted. By monitoring changes in the insertion force with this device, the trocar insertion can be stopped automatically and immediately. The development of this device has realized the automation of trocar insertion. It reduces the demand on operators and improves the safety of the procedure. PMID- 30440755 TI - Assessment and comparison of target registration accuracy in surgical instrument tracking technologies. AB - Image guided surgery systems aim to support surgeons by providing reliable pre operative and intra-operative imaging of the patient combined with the corresponding tracked instrument location. The image guidance is based on a combination of medical images, such as Magnetic Resonance Imaging (MRI), Computed Tomography (CT) and Ultrasonography (US), and surgical instrument tracking. For this reason, tracking systems are of great importance as they determine location and orientation of the equipment used by surgeons. Assessment of the accuracy of these tracking systems is hence of the utmost importance to determine how much error is introduced in image guided surgery only due to tracking inaccuracy. Thus, this study aimed to compare in a surgical Operating Room (OR) accuracy of the two most used tracking systems, Optical Tracking (OT) and Electromagnetic Tracking (EMT), in terms of Target Registration Error (TRE) assessment at multiple distances from the target position. Results of the experiments show that optical tracking performs more accurately in tracking the instrument tip than electromagnetic tracking in the experimental conditions. This was tested using a phantom designed for accuracy measurement in a wide variety of positions and orientations. Nevertheless, EMT remains a viable option for flexible instruments, due to its reliability in tracking without the need for line of sight. PMID- 30440756 TI - Consistent Manufacturing Device for Coiled Polymer Actuators. AB - Coiled polymer actuators are fabricated by heating a twisted nylon fishing filament. This paper provides a detailed review of their manufacturing process and proposes a method to manufacture these actuators consistently to improve the predictability of their behavior. Two devices are presented: a device that prepares consistent filament sections, and another that twists and coils the filament. Seven successful actuators are produced using the proposed method. The behavior of the manufactured actuators is characterized using a tensile test on an Instron universal testing machine. Fluctuations in the observed force are believed to be due to inconsistencies in resistance wire lengths. PMID- 30440757 TI - Testing of Coiled Nylon Actuators for Use in Spastic Hand Exoskeletons. AB - Natural muscles have many favorable characteristics including their high power-to weight ratio, efficient energy conversion and fast actuation times. These factors become important criteria for judging artificial actuation methods. Unfortunately, traditional systems such as pneumatic and electromagnetic motors have yet to attain similar characteristics. In recent years, a new category of actuators has been developed from highly twisted and coiled low-cost nylon fibers. These muscles are capable of providing a powerful stroke per cycle with a reversible contraction. In this paper, twisted and coiled polymer (TCP) actuators with two different commercially available nylon fibers: Shieldex conductive yarn 117/17 and 235/34 are fabricated and tested, then implemented into a low profile, hand exoskeleton. Maintaining quality control on muscle fabrication proved to be challenging and the use of nylon as muscle actuators for exoskeletons would require much more research and better measurements of critical parameters before providing a consistent solution. PMID- 30440758 TI - Assessing the Role of Teleoperated Robotic Systems in Biomanipulations - A Case Study on Blastocyst Microinjection. AB - Blastocyst microinjections, like many other biomanipulation tasks, involve delicate and precise manual control of micropipettes under a microscope. The operations are carried out by highly trained operators who spend hours peering through the binoculars of microscopes. As a result, the skills of the operator and the taxing working conditions have a significant impact on the results of biomanipulations. This has led to the development of robotic systems to automate the operations, which have been shown to significantly improve their consistency and efficiency. However, the flexibility of direct operator control is often desired, especially in research environments developing or testing new protocols. In such cases, robotics can still play a significant role to improve biomanipulations when used in connection with an intuitive teleoperation interface. This is shown here for the case of blastocyst microinjection, for which we have developed a new teleoperation system offering improved ergonomics and easy and precise control over the biomanipulation equipment. Here, the performance of expert and naive operators with this system is assessed and compared with results from traditional manual microinjections conducted by experts. The results show that the robotic system allows even naive operators to outperform experts and achieve very high success rates (greater than 80%). Furthermore, the quality of the microinjections tends to improve with the teleoperated robotic system, as birth rate data demonstrates. These results offer evidence that robotics and teleoperation have the potential to significantly improve biomanipulation efficiency while maintaining the flexibility of the operations and eliminating the need for extensive training of microinjection personnel. PMID- 30440759 TI - Surgical Robot with Environment Reconstruction and Force Feedback. AB - We present a new surgical robot hardware-in-the-loop simulator, with 3D surgical field reconstruction in RGB-D sensor range, which allows tool-tissue interactions to be presented as haptic feedback and thus provides the situation awareness of unwanted collision. First, the point cloud of the complete surgical environment is constructed from multiple frames of sensor data to avoid the occlusion issue. Then the user selects a region of interest where the robot's tool must avoid (also called forbidden region). The real-time haptic force rendering algorithm computes the interaction force which is then communicated to a haptic device at 1 kHz, to assist the surgeon to perform safe actions. The robot used is a RAVEN II system, RGB-D sensor is used to scan the environment, and two Omni haptic devices provide the 3-DoF haptic force. A registration pipeline is presented to complete the surgical environment point cloud mapping in preoperative surgery planning phase, which improves quality of haptic rendering in the presence of occlusion. Furthermore, we propose a feasible and fast algorithm which extends the existing work on the proxy-based method for haptic rendering between a Haptic Interaction Point (HIP) and a point cloud. The proposed methodology has the potential of improving the safety of surgical robots. PMID- 30440760 TI - A Soft Wearable Robotic Suit for Ankle and Hip Assistance: a Preliminary Study. AB - As a walking assistive device, one of major goals should be reduce wearer's metabolic cost as much as possible. Toward this goal, this paper presents the preliminary study on a new soft wearable robotic suit for ankle and hip assistance for daily life activities. The presented robotic suit is lightweight, and it almost does not restrict the lower limb motion range. In addition, its structure is simple, and thus wearers can easily take the device on and off by themselves. Experimental results on two young subjects show that the robotic suit reduced metabolic cost with averaged reductions of 10.2 % and 6.8 %, respectively, by not drastically disrupting the normal walking biomechanics of the subjects. PMID- 30440761 TI - Locomotion Control of Pigeons using Polymer-based Deep Brain Electrodes. AB - This paper describes the electrical modulation of locomotion in pigeons using deep brain electrodes. Polymer-based depth electrodes with four channels were fabricated. Based on the location of the nucleus intercollicularis (ICo), the shanks of the depth electrodes were designed to be a length of 11 mm. After the implantation of the depth electrode into the ICo region of the brain, it was connected by wires to a custom-made stimulator, and biphasic current pulses were delivered. Current pulses with an amplitude of 0.5 mA, a rate of 58.0 Hz, and a duration of $320?mu ?mathrm{s} $s were applied for 0.5 s. When the ICo region was electrically stimulated, taking-off behavior was successfully induced for 0.4 s. Induction of taking-off behavior by electrical stimulation, when coupled to control of turning and running forward locomotions, may contribute to the development of remote flight-control system of freely moving pigeon. PMID- 30440762 TI - A force augmenting exoskeleton for the human hand designed for pinching and grasping. AB - Almost 1 million Americans suffer from debilitative disorders or injuries to the hand, which result in decreased grip strength and/or impaired ability to hold objects. The objective of this study was to design and test the functioning of a fivedigit exoskeleton for the human hand that augments pinching and grasping efforts. The exoskeleton digits and the wrist and forearm structure was computer designed and 3-D printed using ABS plastic, while the housing for the control system, motors, and batteries was constructed from laser-cut acrylic. The user's finger movement efforts were monitored with force sensing resistors (FSR) located within the fingertips of the exoskeleton. A microcomputer-based control system monitored the FSRs and commanded linear actuators that augmented the wearer's force production. The exoskeleton device was tested on six healthy individuals. Using the device for grasping efforts significantly decreased the muscle activity necessary to maintain a constant force $( ?mathrm {p}<0.001)$; however, no significant benefit was identified during pinching efforts. In conclusion, a novel 5-digit exoskeleton was designed, and functional testing identified a significant benefit of using the device during grasping efforts. PMID- 30440763 TI - High-performance polymer dry adhesives based on ethylene vinyl acetate copolymer and high-adhesion mechanism. AB - We have proposed a new soft replication fabrication method to fabricate mushroom shaped dry adhesives with excellent high adhesion, and analyzed its performance and mechanism by taking into consideration the microstructure deformation. The large Young's modulus of ethylene-vinyl acetate (EVA) copolymer (48.0 MPa) together with rational structure design contribute to easy demolding as well as strong adhesion. The fabricated EVA dry adhesives exhibited strong normal adhesion up to 70 N/cm $^{?mathbf {2}}$, which is one of the best records reported for polymer-based dry adhesives by far. Flexible and transparent EVA dry adhesive films were readily microfabricated through our soft replication method in an inexpensive and high-throughput manner, which enables low-cost adhesive coatings for various substrates and shapes.. In addition, the non-wetting characteristics to repel water and oil makes it promising for robust self cleaning and reusability. These results may shed new lights for the mass production of dry adhesives, and to understand the reversible adhesion/detachment mechanism. PMID- 30440764 TI - Residual Limb Revision Surgery Alters Velocity-Curvature Coupling During Stepping and Turning of a Transfemoral Amputee. AB - Two-Thirds Power Law is a frequently observed relationship in human movement, relating velocity and curvature of movement trajectory. These movements span handwriting, larvae crawling, and human-robot interaction. Despite vast acceptance as a common principle of biology, it is unknown if the power law applies to interaction between amputees and prostheses, and if interventions to augment the physical connection between amputees and prostheses influence this speed-curvature coupling during demanding forms of human locomotion. The purpose of this study was to determine if individuals with transfemoral amputation exhibit a biologically-appropriate power law relationship during non-steady-state locomotion, and if a surgical intervention to reduce residual limb soft tissue would influence the observed coupling. We hypothesized that a power regression would well characterize amputee locomotion, and that limb revision surgery would result in a non-linear power coupling close to one-third and overall increased speed (i.e., higher linear coupling) in each non-steady-state movement. The subject performed repeated trials of left and right 90 degrees turns during walking, as well as Foursquare Step Test (FSST), while whole-body kinematics were captured. After fitting center-of-mass velocity and curvature to the power law, the power coupling in FSST was similar to the Two-Thirds Power Law, while turning was not. Finally, the intervention was shown to increase linear coupling suggesting an overall improvement in movement tempo characterized by modest changes in velocity, enabling tasks to be achieved more quickly. PMID- 30440765 TI - Virtual-reality Cataract Surgery Simulator Using Haptic Sensory Substitution in Continuous Circular Capsulorhexis. AB - Cataract is one of the most common geriatric diseases, and surgery is known to be the best treatment. Despite the increasing demand for cataract surgery, the opportunity for novice residents to practice cataract surgery is gradually diminishing as the patient and animal ethics become strict. Therefore, there have been many attempts to overcome the lack of experience by using virtual reality training system. So far, most of the surgical training simulation devices so far focused on visual training, and when they have a haptic sense, they are tethered to a fixed station, which is different from the feeling of moving the actual surgical tool. In this study, we have developed a haptic surgical training tool with sensory substitution and virtual-reality-based cataract surgery simulator. To assess and reproduce the tactile senses during surgery, we prepared viscoelastic lens dummies and measured vibrations in contact and motion required during Continuous Circular Capsulorhexis (CCC). Based on measurement we designed vibration models for haptic sensory substitution and applied them to virtual reality simulator. With complete virtual reality training system, the contact vibration was successfully implemented for virtual contacts to reproduced realistic haptic senses. PMID- 30440767 TI - Verification of Computed Muscle Control and Static Optimization for Isokinetic, Isometric and Isotonic Exercise of Upper Limb. AB - To measure muscle activity during motion is a significant topic in biomechanics. Even though EMG (electromyography) is utilized for this, musculoskeletal simulations are potential alternatives. In this paper, the accuracy of muscle activity calculation of two different algorithms are verified by comparing with EMG during three types of muscle contractions (isokinetic, isotonic and isometric). PMID- 30440766 TI - Evaluation of Compensatory Movement by Shoulder Joint Torque during Gain Adjustment of a Powered Prosthetic Wrist Joint. AB - Powered prostheses with low degree of freedom (DoF) have been developed for people with disabilities to assist daily tasks. These prostheses neglect the user's compensatory movements caused by the low degree of freedom. We assume that the movements can be reduced by well-designed controller of the devices. This paper explores an optimal control gain of the powered prosthesis to prevent the user from compensatory movements through experiments. In the experiments, we developed 1-DoF hand prosthesis with a position-controlled servo, which includes the constant gain as a feed-forward term. The compensatory movements are regarded as a joint torque at a shoulder (abduction/adduction). 4 intact subjects performed a pick-and-place task, using the prosthesis with several control gains. The empirical results show that there was the optimal gain for each subject, which reduces their compensatory movement. PMID- 30440768 TI - Disrupted network topology in patients with Lewy bodies dementia compared to Alzheimer's disease, Parkinson disease dementia and Health Control. AB - The clinical manifestation of Lewy body dementia (DLB) is distinct from Alzheimer's disease (AD), but overlap with Parkinson's disease dementia (PDD). However, little is known about different topology properties of abnormal brain networks associated with these neurodegenerative diseases. In order to study the difference of brain networks in various dementia subtypes, we used $^{?mathbf {18}}?text{F}$-Fluorodeoxyglucose positron emission tomography ($^{?mathbf {18}}?text{F}$-FDG PET) images and graph theory methods to investigate altered whole-brain intrinsic glucose metabolic functional networks in three Chinese dementia groups compared to healthy control (HC) group, including 22 AD patients, 18 PDD patients, 22 DLB patients and 22 HC subjects from Huashan Hospital, Shanghai, China. The experimental results disclosed that in the three dementia groups, compared to HC group, the small-world characteristics were lost. Additionally, compared with HC group, the clustering coefficients of three dementia groups were higher; the characteristic path lengths were longer. In terms of local efficiency and global efficiency, it was at the lowest level in DLB group. We also found differences about distributions of hub regions amongst the four groups. This finding could further help physicians to understand pathological mechanisms of different dementia. PMID- 30440769 TI - Improving EEG-Based Motor Imagery Classification via Spatial and Temporal Recurrent Neural Networks. AB - Motor imagery (MI) based Brain-Computer Interface (BCI) is an important active BCI paradigm for recognizing movement intention of severely disabled persons. There are extensive studies about MI-based intention recognition, most of which heavily rely on staged handcrafted EEG feature extraction and classifier design. For end-to-end deep learning methods, researchers encode spatial information with convolution neural networks (CNNs) from raw EEG data. Compared with CNNs, recurrent neural networks (RNNs) allow for long-range lateral interactions between features. In this paper, we proposed a pure RNNs-based parallel method for encoding spatial and temporal sequential raw data with bidirectional Long Short- Term Memory (bi-LSTM) and standard LSTM, respectively. Firstly, we rearranged the index of EEG electrodes considering their spatial location relationship. Secondly, we applied sliding window method over raw EEG data to obtain more samples and split them into training and testing sets according to their original trial index. Thirdly, we utilized the samples and their transposed matrix as input to the proposed pure RNNs- based parallel method, which encodes spatial and temporal information simultaneously. Finally, the proposed method was evaluated in the public MI-based eegmmidb dataset and compared with the other three methods (CSP+LDA, FBCSP+LDA, and CNN-RNN method). The experiment results demonstrated the superior performance of our proposed pure RNNs-based parallel method. In the multi-class trial-wise movement intention classification scenario, our approach obtained an average accuracy of 68.20% and significantly outperformed other three methods with an 8.25% improvement of relative accuracy on average, which proves the feasibility of our approach for the real-world BCI system. PMID- 30440770 TI - Effect of Emotion States on the Updating Function of Working Memory. AB - In recent years, the interaction between emotion and working memory has been investigated with mixed results. Yet, few neurophysiological studies systematically investigated the effect of emotion states on the updating function of working memory that is a core part of executive functioning. Executive functioning has also been identified as cognitive function, which plays an important role in everyday life and even be a predictor of higher-level cognitive function. Here, we studied the effect of emotions on the updating function of working memory. 16 subjects were recruited to participate in verbal working memory task, and 14 in spatial working memory task. Pictures from International Affective Picture System(IAPS) were employed to evoke positive, negative and neutral states, and 4 digits or 4 spatial positions instructions created verbal or spatial working memory tasks. Combining event-related potentials(ERPs) and repeated measures ANOVA methods, the results showed that the updating time significantly increased in the positive state, and P3 amplitude was significantly lower than that of the neutral state in verbal working memory task; while in spatial working memory task, the updating time significantly increased in the negative state, but there was no significant difference in ERP components. These findings suggest that the updating function of verbal working memory may be affected by the positive state, while that of the spatial working memory may be affected by the negative state. PMID- 30440771 TI - Relationship Between Kinesthetic/Visual Motor Imagery Difficulty and Event Related Desynchronization/Synchronization. AB - Motor imagery (MI) is divided into two types: kinesthetic (KMI) and visual (VMI). To estimate the MI that an examinee performs, event-related desynchronization (ERD) or event-related synchronization (ERS) is used to characterize KMI or VMI via electroencephalogram (EEG). However, no definitive method using ERD/ERS via EEG has been established yet to estimate the type of MI performed. This is because the MI performed by the examinee is not always the same as that instructed by the examiner. One of the reasons for this mismatch is the difficulty of MI, especially KMI. However, almost no reported studies have considered MI difficulty to estimate MI type. Therefore, in this study, we examined the relationship between MI difficulty and the ERD/ERS pattern corresponding to the type of MI in the case of single flexion of the right index finger (SFRIF). The results showed that for a subject who felt MI was less difficult, the alpha-band ERD value (alphaERD) at the electrode of the occipital area (O1 or O2 site) of the KMI instruction was significantly smaller than that of the VMI instruction. On the contrary, for a subject who felt MI was very difficult, alphaERD at the O1 or O2 site on the KMI instruction was similar to that of the VMI instruction. In addition, for the subject who felt MI was easy, the alphaERDs at the O1 or O2 site on the KMI and VMI instructions were similar to those on the movement execution (ME) and movement observation (MO) instructions, respectively. Therefore, in the case of SFRIF, it was suggested that MI difficulty could be estimated by ERD/ERS patterns in the occipital area. This was supported by referring to the ME and MO ERD/ERS patterns in the occipital area. PMID- 30440772 TI - Resting-state Gamma-band EEG Abnormalities in Autism. AB - Gamma-band rhythmic abnormalities have been of significant interests in autism spectrum disorders (ASD). Most studies used magnetoencephalography (MEG) due to its advantage in measuring weak gamma signals as compared to electroencephalography (EEG). However, EEG is more accessible, portable, and importantly, more sensitive to cortical sources located at the crowns of gyri, than MEG. Therefore, it is extremely valuable if EEG can be used to detect gamma band abnormalities in ASD, which could provide complementary insights on pathology of ASD. One challenge in detecting gamma-band neural activities is to remove muscular artifacts, which share the same frequency band. In the present study, we used a previously developed time-frequency independent component analysis (ICA)approach to probe EEG gamma-band abnormalities in ASD. We examined functional connectivity (FC) patterns on intrinsic connectivity networks (ICNs), i.e., the ICs representing distributed neural activities obtained from ICA, using the metrics of spectral power of individual ICNs and coherence between different ICNs. Seven ICNs that reassembled ICNs obtained from EEG data in the band of 2-30 Hz, were successfully identified in the gamma-band (31-50 Hz) data by the approach. Local over-connectivity in the bilateral frontal and left parietal ICNs, as well as long-range under-connectivity between left and right motor ICNs, were observed in ASD. In addition, the age-related effect was identified in the left motor and left parietal ICNs in healthy control, but not in ASD. These findings demonstrated a mixed pattern of gamma-band FC changes in ASD. It further indicated that the developed approach is promising in reconstructing gamma-band patterns from resting-state EEG signals. PMID- 30440773 TI - Single-Trial EEG Classification of Similar Errors. AB - When humans recognise errors, either committed by themselves or observed, error related potentials (ErrP) are produced in the brain. Recently, a few studies have shown that it is possible to differentiate between the ErrPs generated for errors of different direction, severity, or type (e.g., response errors, interaction errors). However, in real-world scenarios, errors cannot always be delineated by these metrics. As such, it is important to consider whether errors that are similar in all of the aforementioned aspects can be classified against each other on a single-trial basis. In this paper, for the first time, we consider two different response errors, which are of equal severity and have no associated direction. This study used electroencephalogram (EEG) data from a sustainedattention based time-critical reaction task, where time pressure caused subjects to commit two different errors. Using data from 16 subjects, we applied time domain EEG features and an ensemble of linear classifiers to separate these two error conditions on a single-trial basis. We achieved a mean balanced accuracy of 63.23% and, for most of these subjects, achieved statistically significant (p ! 0.05) separation of the two error conditions. The ability to classify similar error conditions, such as these, increases the scope of possible applications for EEG error detection, and has the potential to improve brain machine interaction. PMID- 30440774 TI - On the Spatiotemporal Characteristics of Class-Discriminating Functional Networks. AB - We target the problem of identifying brain's functional networks that are discriminatory across classes of tasks, using data obtained through electroencephalography (EEG). A three-step framework is presented. First, the EEG data is segmented to identify the intervals during which cortical functional networks remain quasi-stationary. Second, these functional networks are spatially localized in the cortex. Finally, by employing the proposed discriminative Boolean matrix factorization (DBMF) algorithm, functional networks that are most recurrent in one class of tasks, but are least recurrent in the other are identified. The DBMF algorithm is capable of providing the spatial maps of the discriminative functional networks as well as information about their dynamic occurrence over time. The framework is applied to experimental EEG data, recorded during a motor task. The results show that the proposed framework identifies several parietal/motor functional networks as being the most discriminatory for motor execution trials from non-execution trials. PMID- 30440775 TI - Frequency Band Variations Predict EEG Single-Trial Classification Performance in Disorder of Consciousness Patients. AB - Single-trial classification of EEG data from Disorder of Consciousness patients (DoC) has proved particularly challenging. We present an approach that establishes a measure to relate the performance of single-trial classification of DoC patient EEG data with relational frequency bands and thus with their mental state. We evaluate our approach on 31 patient data sets from two studies, showing that our measure indicates for different data sets a particular likelihood for misclassifying either target or non-target class samples. PMID- 30440776 TI - Effect of Body Positions on EEG signals in Mal de Debarquement Syndrome. AB - Multimodal neuroimaging, such as combined electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), are being increasingly used to investigate the human brain in healthy and diseased conditions. However, certain neuroimaging data are typically acquired in different body positions, e.g., supine fMRI and upright EEG, overlooking the effect of body position on signal characteristics. In the current study we examined EEG signals in three different positions, i.e., supine, standing and sitting, in patients with a balance disorder called mal de debarquement syndrome (MdDS). Individuals with MdDS experience a chronic illusion of self-motion triggered by prolonged exposure to passive motion, such as from sea or air travel. The degree of perception of rocking dizziness is modulated by body position, suggesting a physiological effect related to body positions. In the present study, EEG features were quantified as peak frequency, peak amplitude, and average amplitude of the alpha band due to its strongest signal characteristics compared to other frequencies. The effect of body position was examined in EEG features from data acquired before and after the individuals received treatment with repetitive transcranial magnetic stimulation. Our results indicate a significant effect of body positions on the EEG signals in MdDS. PMID- 30440777 TI - Does A Subject Independent Dynamic Stopping Model for P300 Speller Work on Different Flash Durations and Inter Stimulus Intervals? AB - Event-related potential (ERP)-based brain- computer interfacing (BCI) is an effective communication method. However, calibration itself can be unintuitive and tedious for users. The no-calibration Subject Independent Brain Computer Interface (SIBCI) is a popular solution to the lengthy calibration. Researches have proved the subject independent model is efficient in some P300 spellers, but it is still need to be explored whether the subject independent model works when the flash durations (FDs) and the inter stimulus intervals (ISIs) are changed in a P300 speller. This study introduces a subject independent dynamical stopping model (SIDSM), which based on a subject independent model to dynamically stop the data collection process. The performance of the SIDSM is studied by modifying the FDs and ISIs in online experiments for 8 subjects. Results showed the SIDSM has an average accuracy of 92.45% for different settings. This research proved that the SIDSM is very robust to different stimulus parameters as good performance is observed across all experimental sessions. PMID- 30440778 TI - Different Feedback Methods For An SSVEP-Based BCI. AB - In this paper we examined different ways to inform the user of the classification progress in our online SSVEPbased BCI speller. Different user feedback was given based on the distance from the classification threshold, separately calculated for each stimulus. We focused on the comparison of the accuracies and spelling times associated with each different feedback type. We tested eight different methods, one without feedback for comparison, and the two paradigms each (an increase and a decrease), for three varying parameters, during an online spelling task. The eighth method was a combination of the best performing feedback modalities. A 28 target speller was used for spelling the same word with different feedback methods. The level of comfort was assessed by the seven healthy participants, using a questionnaire. We found substantial decreases in spelling times; they were reduced to 12-77% of the no-feedback condition spelling times, for each of our subjects, with at least one of the parameters. However, this parameter, as expected, was different for each user. According to the personal fastest feedback methods, a combination of them was also used for spelling. These combined feedback methods usually resulted in a slower spelling than the individual best feedback, but still faster than without any feedback. Overall, the average spelling times with the different feedback methods were: no feedback, 95.09 s, increasing size, 62.94 s, decreasing size, 87.73 s, increasing contrast, 77.80 s, decreasing contrast, 124.37 s, increasing duty-cycle, 134.70 s, and decreasing dutycycle, 103.77 s. PMID- 30440779 TI - Decoding hindlimb kinematics from primate motor cortex using long short-term memory recurrent neural networks. AB - Recent machine learning techniques have become a powerful tool in a variety of tasks, including neural decoding. Deep neural networks, particularly recurrent models, leverage the temporal evolution of neural ensemble activity to decode complex movement and sensory signals. Using single-unit recordings from microelectrode arrays implanted in the leg area of primary motor cortex in non human primates, we decode the positions and angles of hindlimb joints during a locomotion task using a long short-term memory (LSTM) network. The LSTM decoder improved decoding over traditional filtering methods, such as Wiener and Kalman filters. However, dramatic improvements over other machine learning (e.g. XGBoost) and latent state-space methods were not observed. PMID- 30440780 TI - Discriminating Between Imagined Speech and Non-Speech Tasks Using EEG. AB - People who are severely disabled (e.g Locked-in patients) need a communication tool translating their thoughts using their brain signals. This technology should be intuitive and easy to use. To this line, this study investigates the possibility of discriminating between imagined speech and two types of non-speech tasks related to either a visual stimulus or relaxation. In comparison to previous studies, this work examines a variety of different words with only single imagination in each trial. Moreover, EEG data are recorded from a small number of electrodes using a low-cost portable EEG device. Thus, our experiment is closer to what we want to achieve in the future as communication tool for locked-in patients. However, this design makes the EEG classification more challenging due to a higher level of noise and variations in EEG signals. Spectral and temporal features, with and without common spatial filtering, were used for classifying every imagined word (and for a group of words) against the non-speech tasks. The results show the potential for discriminating between each imagined word and non-speech tasks. Importantly, the results are different between subjects using different features showing the need for having subject specific features. PMID- 30440781 TI - Using Robust Principal Component Analysis to Reduce EEG Intra-Trial Variability. AB - Practical brain-computer interfaces need to overcome several challenges, including tolerance to signal variability within- and across sessions. We introduce Robust Principal Component Analysis (RPCA) as a potential approach to tackle intra-trial variability. Assuming that subjects undergo the same cognitive process or perform the same task in a short period (e.g., a few seconds), as a result, the signal of interest should be represented by only a few components. We verified this approach on a workload detection task, where subjects needed to pilot a simulated drone. We used RPCA as a processing step to decrease trial variability and assessed its impact on classification accuracy. Our results showed that RPCA significantly increased performance in both at group and subject level analysis. On average, class-balanced accuracy when simulating RPCA online increased from 63.9% up to 70.6% $(p~ 0 . 001)$. PMID- 30440783 TI - Hierarchical Graphical Models for Context-Aware Hybrid Brain-Machine Interfaces. AB - We present a novel hierarchical graphical model based context-aware hybrid brain machine interface (hBMI) using probabilistic fusion of electroencephalographic (EEG) and electromyographic (EMG) activities. Based on experimental data collected during stationary executions and subsequent imageries of five different hand gestures with both limbs, we demonstrate feasibility of the proposed hBMI system through within session and online across sessions classification analyses. Furthermore, we investigate the context-aware extent of the model by a simulated probabilistic approach and highlight potential implications of our work in the field of neurophysiologically-driven robotic hand prosthetics. PMID- 30440782 TI - Motor Imagery based Brain Computer Interface Paradigm for Upper Limb Stroke Rehabilitation. AB - Motor Imagery (MI) based Brain Computer Interface (BCI) systems have shown potential to serve as a tool for neurorehabilitation for post stroke patients to complement the standard therapy. The aim of this study was to develop an MI based BCI system that could potentially be used in neurorehabilitation of hand motor function in stroke patients. Two co-adaptive, three-class MI based BCI systems for realtime processing were developed and compared using the publicly available data from the BCI Competition III Dataset V as well as our own data. The first algorithm utilizes the Filterbank Common Spatial Pattern (FBCSP) for feature extraction, and the other utilizes the Separable Common Spatio-Spectral Pattern (SCSSP) - both combined with a Multi-layer Perceptron (MLP) for classification. The proposed system proved successful when using the competition data showing an average accuracy of 64.71 % for the SCSSP compared to 60.48% for the FBCSP. This proved superior to a related study using the same feature extraction methods, but with other classification methods. The proposed system, however did show results around chance level for the 3-class MI experimental data that we have collected in our laboratory. Further studies needs to be conducted to improve the performance as well as to realize such a system to put in use. PMID- 30440784 TI - Improvement in Classification of Tactile Event-Related Potentials using Random Interval Tasks*. AB - The classification accuracy of an event-related potential (ERP) induced by a tactile stimulus is investigated to create a brain-computer interface (BCI). Mechanical tactile stimuli were applied to the left and right index fingers using two piezo actuator probes that were used as a Braille display for the visually impaired. In an experiment, two-class classification was investigated using three kinds of tactile stimulus pattern. The subjects were instructed to pay attention to unusual target stimuli while avoiding other frequent nontarget stimuli. The extracted features were classified using stepwise linear discriminant analysis. As a result, high accuracy was obtained by the task of random intervals compared with the task of constant intervals. It was suggested that the accuracy of the BCI using tactile stimuli is influenced by the concentration on the task. PMID- 30440785 TI - Evaluating the Performance of Non-Hair SSVEP-Based BCIs Featuring Template-Based Decoding Methods. AB - Our previous study has demonstrated the feasibility of employing non-hair-bearing electrodes to build a Steadystate Visual Evoked Potential (SSVEP)-based Brain Computer Interface (BCI) system, relaxing technical barriers in preparation time and offering an ease-of-use apparatus. The signal quality of the SSVEPs and the resultant performance of the non-hair BCI, however, did not close upon those reported in the state-of-the-art BCI studies based on the electroencephalogram (EEG) measured from the occipital regions. Recently, advanced decoding algorithms such as task-related component analysis have made a breakthrough in enhancing the signal quality of the occipital SSVEPs and the performance of SSVEP-based BCIs in a well-controlled laboratory environment. However, it remains unclear if the advanced decoding algorithms can extract highfidelity SSVEPs from the non-hair EEG and enhance the practicality of non-hair BCIs in real-world environments. This study aims to quantitatively evaluate whether, and if so, to what extent the non-hair BCIs can leverage the state-of-art decoding algorithms. Eleven healthy individuals participated in a 5-target SSVEP BCI experiment. A high-density EEG cap recorded SSVEPs from both hair-covered and non-hair-bearing regions. By evaluating and demonstrating the accessibility of nonhair-bearing behind-ear signals, our assessment characterized constraints on data length, trial numbers, channels, and their relationships with the decoding algorithms, providing practical guidelines to optimize SSVEP-based BCI systems in real-life applications. PMID- 30440786 TI - P300 Latency Estimation Using Least Mean Squares Filter. AB - Event-related potentials (ERPs) are the brain response directly related to specific events or stimuli. The P300 ERP is a positive deflection nominally 300ms post-stimulus that is related to mental decision making processes and also used in P300-based speller systems. Single-trial estimation of P300 responses will help to understand the underlying cognitive process more precisely and also to improve the speed of speller brain-computer interfaces (BCIs). This paper aims to develop a single-trial estimation of the P300 amplitudes and latencies by using the least mean squares (LMS) adaptive filtering method. Results for real data from people with amyotrophic lateral sclerosis (ALS) have shown that the LMS filter can be effectively used to estimate P300 latencies. PMID- 30440787 TI - Mental Fatigue Estimation Using EEG in a Vigilance Task and Resting States. AB - Mental fatigue induced by long time mental work can cause deterioration in task performance and increase the risk of accidents. Recently, electroencephalogram (EEG)-based monitoring of mental fatigue has received increasing attention in the field of brain-computer interfaces (BCI). This study aims to employ EEG signals to measure the mental fatigue level by estimating reaction time (RT) in a psychomotor vigilance task (PVT). In a 36-hour sleep deprivation experiment, EEG data from 18 subjects were recorded every four hours in nine blocks, each consisting of three tasks: a 6-minute PVT task and two 3-minute resting states (eyes closed and eyes open). The mean RT in the PVT task showed a generally increasing trend during the 36-hour awake period, reflecting the increase of fatigue over time. For each task, multiple EEG features were extracted and selected to better estimate RT using a multiple linear regression (MLR) method. The correlation between predicted RT and actual RT was evaluated using a leave one-subject-out (LOSO) validation strategy. After parameter optimization, EEG data from the PVT task obtained a mean correlation coefficient of $0.81 ?pm 0.16$ across all subjects. Resting-state EEG data showed lower correlations (eyes closed: $0.65 ?pm 0.20$, eyes-open: $0.50 ?pm 0.30)$ partially due to the involvement of shorter data lengths. These results demonstrate the feasibility and robustness of the EEG-based fatigue monitoring method, which could be potential for applications in operational environments. PMID- 30440788 TI - EEG-based discrimination of different cognitive workload levels from mental arithmetic. AB - Cognitive workload, which is the level of mental effort required for a cognitive task, can be assessed by monitoring the changes in neurophysiological measures such as electroencephalogram (EEG). This study investigates the performance of an EEG-based Brain-Computer Interface (BCI) to discriminate different difficulty levels in performing a mental arithmetic task. EEG data from 10 subjects were collected while performing mental addition with 3 difficulty levels (easy, medium and hard). EEG features were then extracted using band power and Common Spatial Pattern features and subsequently features were selected using Fisher Ratio to train a Linear Discriminant Classifier. The results from 10-fold cross-validation yielded averaged accuracy of 90% for 2 classes (easy versus hard tasks) and 66% for 3 classes (easy versus medium versus hard tasks). Hence the results showed the feasibility of using EEG-based BCI to measure cognitive workload in performing mental arithmetic. PMID- 30440790 TI - Robust Local Field Potential-based Neural Decoding by Actively Selecting Discriminative Channels. AB - Local field potentials (LFPs) have been proposed as a neural decoding signal to compensate for spike signal deterioration in invasive brain-machine interface applications. However, the presence of redundancy among LFP signals at different frequency bands across multiple channels may affect the decoding performance. In order to remove redundant LFP channels, we proposed a novel Fisher-distance ratio based method to actively batch select discriminative channels to maximize the separation between classes. Experimental evaluation was conducted on 5 non consecutive days of data from a non-human primate. For data from each day, the first experimental session was used to generate the training model, which was then used to perform 4-class decoding of signals from other sessions. Decoding achieved an average accuracy of 79.55%, 79.02% and 79.40% using selected LFP channels for beta, low gamma and high gamma frequency bands, respectively. Compared with decoding using full LFP channels, decoding using selected LFP channels in high gamma band resulted in an increase of 8.67% in accuracy, even if this accuracy was still 7.26% lower than that of spike-based decoding. These results demonstrate the effectiveness of the proposed method in selecting discriminative LFP channels for neural decoding. PMID- 30440789 TI - Modeling EEG-based Motor Imagery with Session to Session Online Adaptation. AB - Subject-specific calibration plays an important role in electroencephalography (EEG)-based Brain-Computer Interface (BCI) for Motor Imagery (MI) detection. A calibration session is often introduced to build a subject specific model, which then can be deployed into BCI system for MI detection in the following rehabilitation sessions. The model is termed as a fixed calibration model. Progressive adaptive models can also be built by using data not only from calibration session, but also from available rehabilitation sessions. It was reported that the progressive adaptive model yielded significant improved MI detection compared to the fixed model in a retrospective clinical study. In this work, we deploy the progressive adaptation model in a BCI-based stroke rehabilitation system and bring it online. We dub this system nBETTER (Neurostyle Brain Exercise Therapy Towards Enhanced Recovery). A clinical trial using the nBETTER system was conducted to evaluate the performance of 11 stroke patients who underwent a calibration session followed by 18 rehabilitation sessions over 6 weeks. We conduct retrospective analysis to compare the performance of various modeling strategies: the fixed calibration model, the online progressive adaptation model and a light-weight adaptation model, where the second one is generated online by nBETTER system and the other two models are obtained retrospectively. The mean accuracy of the three models across 11 subjects are 68.17%, 74.04% and 74.53% respectively. Statistical test conducted on the three groups using ANOVA yields a p-value of 9.83-e06. The test result shows that the two adaptation models both have significant different mean from fixed mode. Hence our study confirmed the effectiveness of using the progressive adaptive model for EEGbased BCI to detect MI in an online setting. PMID- 30440791 TI - EEG Channel Selection Based on Correlation Coefficient for Motor Imagery Classification: A Study on Healthy Subjects and ALS Patient. AB - Brain-Computer Interface (BCI) provides an alternate channel of interaction for people with severe motor disabilities. The Common Spatial Pattern (CSP) algorithm is effective in extracting discriminative features from EEG data for motor imagery-based Brain-Computer Interface (BCI). CSP yields signal from various locations for better performance. In this study, we selected a subset of EEG channels using correlation coefficient of spectral entropy and compared the classification performance using the Filter Bank Common Spatial Pattern (FBCSP) algorithm. We conducted experiments on 4 healthy subjects and one Amyotrophic Lateral Sclerosis (ALS) patient. The results showed that the proposed channel selection method increased classification accuracy of all subjects from 1.25% to 8.22%. Optimal performance was obtained using between 13 to 24 channels, and channels located over the motor cortex zone possess higher probabilities of being selected. Comparing with the channels manually selected to over the motor cortex area, the correlation coefficient method is able to identify the optimal channel combination and improve the motor imagery decoding accuracy of Healthy and ALS subjects. PMID- 30440792 TI - A hybrid EEG-EMG BMI improves the detection of movement intention in cortical stroke patients with complete hand paralysis. AB - Motor rehabilitation based on brain-machine interfaces (BMI) has been shown as a feasible option for stroke patients with complete paralysis. However, the pathologic EEG activity after a stroke makes the detection of movement intentions in these patients challenging, especially in those with damages involving the motor cortex. Residual electromyographic activity in those patients has been shown to be decodable, even in cases when the movement is not possible. Hybrid BMIs combining EEG and EMG activity have been recently proposed, although there is little evidence about how they work for completely paralyzed stroke patients. In this study we propose a neural interface, relying on EEG, EMG or EEG+EMG features, to detect movement attempts. Twenty patients with a chronic stroke affecting their motor cortex were recruited, and asked to open and close their paralyzed hand while their electrophysiological signals were recorded. We show how EEG and EMG activities provide complementary information for detecting the movement intentions, being the accuracy of the hybrid BMI significantly higher than the EEG-based system. The obtained results encourage the integration of hybrid BMI systems for motor rehabilitation of patients with paralysis due to stroke. PMID- 30440793 TI - Data Space Adaptation for Multiclass Motor Imagery-based BCI. AB - Various adaptation techniques have been proposed to address the non-stationarity issue faced by electroencephalogram (EEG)-based brain-computer interfaces (BCIs). However, most of these adaptation techniques are only suitable for binary-class BCIs. This paper proposes a supervised multiclass data space adaptation technique (MDSA) to transform the test data using a linear transformation such that the distribution difference between the multiclass train and test data is minimized. The results of using the proposed MDSA on BCI Competition IV dataset 2a improved the classification accuracy by an average of 4.3% when 20 trials per class were used from the test session to estimate adaptation transformation. The results also showed that the proposed MDSA algorithm outperformed the multi pooled mean linear discrimination (MPMLDA) technique with as few as 10 trials per class used for calculating the transformation matrix. Hence the results showed the effectiveness of the proposed MDSA algorithm in addressing non-stationarity issue for multiclass EEG-based BCI. PMID- 30440794 TI - Convolutional Neural Network for Target Face Detection using Single-trial EEG Signal. AB - Face recognition plays an import role in our daily lives. However, computer face recognition performance degrades dramatically with the presence of variations in illumination, head pose and occlusion. In contrast, the human brain can recognize target faces over a much wider range of conditions. In this paper, we investigate target face detection through electroencephalography (EEG). We address the problem of single-trial target-face detection in a rapid serial visual presentation (RSVP) paradigm. Whereas most previous approaches used support vector machines (SVMs), we use a convolutional neural network (CNN) to classify EEG signals when subjects view target and non-target face stimuli. The CNN outperforms the SVM algorithm, which is commonly used for event-related-potential (ERP) detection. We also compare the difference in performance when using animal stimuli. The proposed system can be potentially used in rapid face recognition system. PMID- 30440795 TI - Decoding Spike Trains from Neurons with Spatio-Temporal Receptive Fields. AB - The point-process filter (PPF) is a real-time recursive algorithm that computes the minimum mean-squared error estimate of a behavioral state, given neural spiking observations. When used with stimulus-sensitive neurons that represent behavioral states transiently, the PPF needs to know the times at which stimuli will occur. However, these times will not be known a-priori. In this work, we develop a matched-filter point process filter (MF-PPF) that can decode behavioral states that are encoded transiently in neural activity when stimulus times are unknown. A linear filter matched to each neuron's temporal receptive field is used to estimate stimulus onset times, which are then fed into the PPF to decode the behavioral state. As an example, we use the MF-PPF to decode visual saliency from simulated superior colliculus spiking activity. This new decoder has the potential to decode behavioral states from brain regions with transient representations and temporal receptive fields. PMID- 30440796 TI - Non-contact Wearable EEG Sensors for SSVEP-based Brain Computer Interface Applications. AB - Electroencephalography (EEG) based brain computer interfaces (BCI) introduces promising communication pathway between the brain and external devices, not only for the motor-impaired but also the healthy users. However, the current EEG-based interface device is not convenient enough for daily uses. In this study, we developed an EEG acquisition system that records brain signals without contacting scalp. The proposed system consists of a small sized ($5.5?,?times 3?,?mathrm{cm}^{2}$ acquisition hardware and four stainless steel electrodes integrated in a regular sport hat. To demonstrate the concept, we used an in house developed steady-state visual evoked potentials (SSVEP) paradigm and recorded EEG signals using the proposed system. The EEG signals were compared with three different brain states - Eye Closed, Eye Open, and Visual Stimulation. The results show that the BCI system can record SSVEP from the brain without any professional setups or expensive dry-electrodes. PMID- 30440797 TI - Covert Speech vs. Motor Imagery: a comparative study of class separability in identical environments. AB - In this study a single experimental protocol and analysis pipeline is used: once for MI tasks, and once for covert speech tasks. The goal of this study is not to maximizing classification accuracy; rather the main objective is to provide an identical environment for both paradigms, while identifying the most important activities related to the most class dependent features. Four volunteers participated in this experiment. With four classes, the average classification accuracy for covert speech tasks is 82.5%, and for motor imagery is 77.2%. The average performance is significantly higher than chance level for both paradigms, suggesting that the results are meaningful, despite being imperfect. For motor imagery tasks the most important activities are the execution of imagined movements, and goal driven executive control for suppression of overt movements, which also occur for covert speech tasks. However, the most important activity for covert speech tasks is the linguistic processing stages of word production prior to articulation, which does not occur in motor imagery. These high-Gamma linguistic processes are extremely class dependent, which contribute to the higher performance of covert speech tasks, compared to motor imagery in an otherwise identical environment. PMID- 30440798 TI - Upper Limb Prosthesis Control: A Hybrid EEG-EMG Scheme for Motion Estimation in Transhumeral Subjects. AB - This study described the use of Kernel Least Square Tracker based estimation for 3-dimensional shoulder, elbow motion kinematics from surface Electromyogram (EMG) and a two-stage multiclass Support Vector Machine based classification of different wrist, grip and finger motions from Electroencephalogram (EEG). The advantage of employing hybrid EEG-EMG strategy for upper limb motion estimation was demonstrated for a transhumeral subject. The method utilized EMG from upper arm muscles for elbow motion (and shoulder motion in case of higher degree amputation scenario) and used EEG for discerning basic wrist, grip and finger motions. The results showed that the hybrid scheme could estimate shoulder, elbow motion with more than 90% accuracy and wrist, grip and finger motion with 65%-70% accuracy. This strategy of using hybrid EEG-EMG motion estimation, thus, could be employed in developing a more intuitive upper limb prosthesis controller with multiple degrees of freedom. PMID- 30440799 TI - Brain Computer Interface Using Modulation of Auditory Steady-State Response with Help of Stochastic Resonance. AB - This paper proposes an eye-movement independent brain computer interface based on the modulations of auditory steady-state response (ASSR-BCI) to amplitude modulated (AM) tones elicited by paying selective attention to one of the two AM tones. Moreover, the proposed ASSR-BCI exploits a stochastic resonance effect to improve the signal separation and attained the mean classification accuracy of 77 % across nine normal subjects under a noise-added condition with sound pressures 60 dB for the two tones and 30 dB for the noise added to the two AM tones. Results from information transfer rate and its inter-individual difference suggest that it may be adequate to set an inter-trial interval at 2?3 s for a trial time length. It is consequently feasible to develop a practical eye movement-independent BCI available in eyes-closed state by optimizing the parameters such as the trial time length and electrode sites each user. PMID- 30440800 TI - Implication of N400 and P600 waves in the Linguistic Code Change in Monolinguals and Bilinguals. AB - There is evidence of the importance of N400 and P600 waves in linguistic processes, theses brain waves are related to syntax. This work proposes to evaluate learning process through the analysis of responses generated when formulation of word is requested, an artificial grammar test (AGT) is developed and N400 and P600 peaks are taken as indicators of performance; and two different groups of subjects took the AGT, 5 monolinguals and 5 bilinguals.The AGT is composed by 30 hybrids, each hybrid defines rules to formulate words; then if this word accomplished the rules, it is considered as grammatical. The N400 and P600 waves are computed by each word letter, and the mean for all 30 hybrids is compared between both two groups by electrode.Greater amplitudes for N400 and P600 peaks was found for monolinguals in comparison with bilinguals. PMID- 30440801 TI - Module differences of glucose metabolic brain network among Alzheimer's disease, Parkinson's disease dementia, Lewy body dementia and health control. AB - Dementia has become a serious disease in elderly population. Graph theory based brain network analysis method is considered as a popular and universal technique in the field of the neurosciences. It can help neuroscientists to investigate the neuropathology of dementia, especially to understand dementia subtypes. However, brain network analysis for various dementia subtypes at the same time is still limited. The aim at this study is to investigate the similarities and differences in brain network modular parameters of three dementia subtypes: Alzheimer's disease (AD), Parkinson's disease dementia (PDD), Lewy body dementia (DLB). Health control has also been compared. All subjects of health control(HC), AD, PDD and DLB groups were from Huashan Hospital. Using topological analysis algorithms, we found that HC brain was divided into 4 modules; AD brain was divided into 4 modules; PDD brain was divided into 6 modules; and DLB brain was divided into 10 modules, which demonstrated differences in these dementia subtypes. We also found that right thalamus area was scattered in all dementia subtypes. After using the seed point correlation analysis, it can be seen that the connections between right thalamus and subcortical, frontal gyrus were enhanced and the connections with the occipital gyrus was attenuated in dementia subtypes. As a result, findings in this paper are expected to be useful for neuroscientists to further understand the pathology of AD, PDD and DLB. PMID- 30440802 TI - EEG Neural Correlates of Self-Paced Left- and Right-Hand Movement Intention during a Reaching Task. AB - The study of neural correlates of self-paced movement intention helps develop a more natural and practical brain computer interface. In this paper, we studied EEG neural correlates of self-paced left- and right-hand movement intention during a reaching task. A slow decreased movement related cortical potential (MRCP) related to movement intention was found before both the left- and right hand movements. The temporal start point and decrement of MRCP before the left- and right-hand reaching movements showed differently. Moreover, alpha band power increase/decrease was observed before the onset of both left- and right-hand movements. Alpha band powers increase before both movement conditions in the frontal-central area. In the central area, alpha band powers decrease consistently at electrodes C3, Cz and C4 before the right-hand reaching movement. While alpha band powers increase at electrodes C3 and Cz before the left-hand reaching movement. PMID- 30440803 TI - Neuro-Glial Network Model Of Postictal Generalized EEG Suppression (PGES). AB - Over the past couple of decades, glial cells have been highlighted as active agents in hyperexcitability of neuronal networks, specifically playing key roles in seizure onset and termination. In particular, microglia have been suggested to have both neuroprotective and neurotoxic effects on the brain. Investigation into seizure termination is of particular interest, as it is sometimes followed by a postictal generalized EEG suppression (PGES) - a low activity state that is potentially associated with sudden unexpected death in epilepsy. In this study, we attempt to link glial effects - synaptic pruning and astrocytic potassium clearance - to the duration of spontaneous epileptiform discharges (SEDs) as well as interSED intervals (iSEDs). We build upon an earlier model of a neuroglial network by translating it into the cortical paradigm and including microglial units. Preliminary findings of our model demonstrated that the duration of SEDs is largely determined by the astrocytic potassium clearance, whereas iSEDs significantly increased with microglial-driven synaptic pruning. In our model, astrocytic potassium clearance itself did not bring a PGES-like state, whereas microglial effects did, which suggests a potential biomarker for PGES phenomena. PMID- 30440804 TI - Transfer Functions of a Spinal Cord Stimulation System in Mixed Media and Homogeneous Media for Estimation of RF Heating during MRI Scans. AB - There is a risk for patients with spinal cord stimulation (SCS) implants that MRI RF induced heating may cause harm to spinal cord (SC) or spinal nerves. The ISO/TS 10974 Clause 8, Tier 3 based evaluation of RF heating has been commonly used for active implantable manufactures through regulatory body world-wide. Generating TFs for the lead and SCS system is an essential component in Tier 3. The objective of this paper is to investigate the effects of media on transfer functions (TFs) and dissipated power near the distal electrode along clinical pathways of SCS implants. The simulation results indicate that SCS TF measurement and validation should be performed in HCM (0.47 S/m) since it has the closest match with SC mixed media. With the SC mixed media model, the compound tissue effect from tissues around the system was seen and TF follows that of the HCM TFs closely. These trends were confirmed through power calculation of TF equation by integrals of electrical fields along clinical SCS implant pathways in an adult male model, with a 2%-4% underestimation from HCM while LCM overestimates by 72%- 74%. This study indicates appropriate section of media for deriving TFs could lead to more clinically relevant RF heating predictions during MRI scans. PMID- 30440805 TI - Muscle Synergy for Hand Motions Based on Electromyography Analysis. AB - This study aimed to investigate the muscle synergy for hand motions of both the left and right hands based on surface electromyography (sEMG) signals. Six hand motions, including hand grasp (HG), four fingers flexion (FFF), index finger extension (IFE), thumb internal rotation (TIR), thumb opposition (TO), key pinch (KP), were examined in the experiment. The sEMG signals were recorded from brachioradialis (BRA), flexor carpi ulnaris (FCU), flexor carpi radialis (FCR), extensor digitorum communis (EDC), flexor digitorum superficialis (FDS), abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM) of both the left and right hands. A co-contraction index (CI) followed by a correlation coefficients (CC) was applied to quantify the muscle synergy during the hand motions and to compare the synergistic patterns across hands. Results shown that the left and right hands had similar muscle synergy (CC (CC>0.9) for any of the motions. For both hands, there were strong correlations between the synergistic matrix of different motions (CC (CC>0.85), including the correlations between HG and FFF, between FFF and IFE, and between TO and KP. By contrast, weak correlations between the synergistic matrix for IFE and that for TIR (CC (CC<0.1), suggesting a low similarity of the muscle synergy for the two motions. This study shed light on how the muscles of the left and right hands are involved and co-contracted for the dexterous hand motions. PMID- 30440806 TI - Estimation of compressive tibiofemoral force using over resistance of ankle-foot orthosis on gait. AB - The purpose of this study was to investigate the effect of changing the plantar flexion resistance (PFR) of an ankle-foot orthosis (AFO) on the compressive tibiofemoral force, knee muscle forces, and knee joint angle. We measured and estimated knee flexion angle, knee muscle force, and the compressive tibiofemoral force in healthy adult males. The results showed that the first peak compressive tibiofemoral force, peak knee flexion angle, and peak quadriceps muscle force increased in the strong PFR condition compared with the no-AFO condition. These results suggest that over-PFR caused various knee troubles. PMID- 30440807 TI - Neuromechanical Simulation of Hand Pronation and Supination Task in Parkinson's disease. AB - Parkinson's disease is a prevalent and debilitating neurological disorder, where the severity of motor symptoms are frequently monitored using clinical tests that include a hand pronation and supination task. Objective quantification of motor symptoms in persons with Parkinson's disease and detection of dopamine-induced dyskinesias during treatment is important for the management of the most common symptoms in persons with Parkinson's disease. Thus, the development of a neuromechanical model of rhythmic hand pronation and supination may further our understanding of the mechanisms underlying motor symptoms during rhythmic upper extremity tasks in persons with Parkinson's disease. The aim of this study was to create a model for a rhythmic hand pronation and supination task. This was done to create a simulation of a popular diagnostic task used in determining the severity of motor impairments in persons with Parkinson's disease. It is imperative to understand the neural dynamics as well as the physiological constraints placed on a system such as this in both the creation of a usable model as well as understanding the neuromechanical interactions occurring during this diagnostic task. This model of either normal or slowed, clinical behavior, can then serve as a springboard for the creation of models that characterize disordered motor movement and perhaps even the creation of models that could be incorporated into the diagnostic process. PMID- 30440808 TI - Control with Adjusted Pulse Frequency and Amplitude in Functional Electrical Stimulation. AB - In this paper, we describe the control of a body using functional electrical stimulation (FES) by adjusting pulse amplitude and frequency. FES is a technique used in the rehabilitation of spinal injury patients and application development for healthy people. However, control using the FES involves a delay time, resulting a high-frequency vibration (called chattering). In this paper, we propose that the control performance can be improved by adjusting the frequency in addition to the conventional pulse amplitude adjustment. In experiments, target values were controlled using subjects, and the performance of the proposed method was verified. Results confirmed that chattering is suppressed by the proposed method. PMID- 30440809 TI - An Analytical Approach to Posture-Dependent Muscle Force and Muscle Activation Patterns. AB - Personalized training by taking into account individual anatomy to improve performance is a research frontier. In this paper, we first introduce an analytical method to study the pattern of changes in muscle forces as a function of posture. Our method is also able to analyze variation of maximal muscle force and muscle activation values (in various postures) as a result of posture dependent changes in moment arms. This method also helps us evaluate the utility of person specific training. It also provides us with model based approximations for activation and muscle force patterns during different motions without a need for subject recordings, which enables athletes to have a better understanding of how each muscle contributes during each posture, in a fast and efficient way. Second, we analyze the results of this method for a simple squat move. Our results show that both maximal muscle force and muscle activation values have variable sensitivity to the moment arm values for different postures and muscles. It suggests that individually modified training plans could likely improve performance for some sets of movements. PMID- 30440810 TI - Motion Sequence Alignment for A Kinect-Based In-Home Exercise System for Lymphatic Health and Lymphedema Intervention. AB - Using Kinect sensors to monitor and provide feedback to patients performing intervention or rehabilitation exercises is an upcoming trend in healthcare. However, the users' motion sequences differ significantly even when doing the same exercise and are not temporally aligned, making the evaluation of the correctness of their movement challenging. We have developed a method to divide the long motion sequence for each exercise into multiple subsequences, each corresponding to the transition of one key pose to another. We also developed a subsequence-based dynamic time warping algorithm that can automatically detect the endpoint of each subsequence with minimum delay, while simultaneously aligning the detected subsequence to the reference subsequence for the exercise. These methods have been integrated into a prototype system for guiding patients at risks for breast-cancer related lymphedema to perform a set of lymphatic exercises in order to promote lymphatic health and reduce the risk of lymphedema. The system can provide relevant feedback to the patient performing an exercise in real time. PMID- 30440811 TI - Comparison of Accelerometry-Based Features for Fall Risk Assessment Measured From Two Sensor Locations. AB - Falls are an unfortunate problem for older adults, their relatives and societies. Continuous gait monitoring for fall risk assessment during daily lives would allow early interventions to prevent injurious falls. Continuous gait monitoring is possible using technological solutions such as inertial sensors; for example accelerometers. Current solutions require attaching the sensor to a certain location on the body and many of them to the lower back, which is not convenient for the user. The objective of this study was to find out whether gait variables calculated from the acceleration signal measured during walk from two different locations on waist area differ from each other. Forty two older adult subjects were measured during walk test with a triaxial acceleration sensor worn on an elastic belt at the lower back and frontal hip area. Most of the analyzed gait features from the two locations have a strong correlation, indicating that these features are not sensitive to sensor location around waist level. A subsequent study is needed to confirm other locations for the sensors to allow analyzing gait during everyday lives. PMID- 30440812 TI - Eye Movements of Patients with MCI against Wrong-Way Driving Countermeasures. AB - Wrong-way driving on highways is an important issue in many countries as it can potentially put the lives of many at risk. In Japan, approximately 200 instances of wrong-way driving occur annually, and preventative countermeasures, such as road arrows, have been implemented. However, the incidence of wrong-way driving has not decreased since the introduction of these countermeasures, and stronger countermeasures are therefore necessary. More than 70% of wrong-way drivers are elderly individuals, and, in Japan, over 30% of elderly individuals have diseases leading to cognitive decline. In this paper, we focus on the reduction of visual cognitive function due to mild cognitive impairment (MCI), and the effects of visual countermeasures on patients with MCI, as determined using a computer graphics movie and an infrared eye tracker to investigate gaze movements. We analyzed differences in fixation points and the quantity of saccades between patients with MCI and healthy individuals. Patients with MCI were found to have delayed identification of wrong-way driving. This suggests that deficits in visual attention and deterioration of visual cognitive function in dynamic environments may be factors underlying wrong-way driving in patients with MCI. PMID- 30440813 TI - Objective and Subjective Assessment of Amplified Parkinsonian Speech Quality. AB - Hypophonia is a common speech impairment associated with Parkinson's disease (PD). Voice amplifiers are typically used to increase voice loudness, but little is known about their impact on perceived speech quality. In this paper, speech recordings were obtained from 11 PD subjects with and without the use of seven different amplification devices, and in the absence or presence of background noise. The recorded speech samples were rated for their sound quality by 10 naive listeners. The same speech recordings were analyzed objectively, where in linear prediction, mel-frequency cepstral coefficients (MFCCs), and gammatone cepstral coefficients (GFCCs) were extracted and mapped to predicted quality scores using linear regression and Support Vector Regression (SVR). Results showed that amplification devices differentially affect the perceived quality of PD speech, that objective and subjective quality scores correlated well, and that a reduced set of GFCC features mapped with SVR produced the best correlation with the subjective scores. PMID- 30440814 TI - Latency and amplitude changes in cognitive event related potentials due to hemodialysis. AB - Chronic kidney disease impacts the cognitive abilities of patients, and yet few works have analyzed functional electroencephalographic changes on event-related potentials before and after an hemodialysis session. This work shows that, as a consequence of hemodialysis, cognitive potential waveforms suffer changes, occurring with reduced latency $( ?sim 50$ ms) and with larger amplitude $( ?sim 0.128?mathrm {a}$.u.) after the treatment session. While only a limited sample of five patients is reported herein, the observed changes immediately after hemodialysis could be a sign of central nervous system alterations that are not clinically evaluated. Signs like these could entail an early indicator of possible evolution into some neuropathology. PMID- 30440815 TI - Instance-Based Genre-Specific Music Emotion Prediction with An EEG Setup. AB - This paper explores a novel direction in music-induced emotion (music emotion) analysis - the effects of different genres on the prediction of music emotion. We aim to compare the performance of various classifiers in the prediction of the emotion induced by music, as well as to investigate the adaptation of advanced features (such as asymmetries) in improving classification accuracy. The study is supported by real-world experiments where 10 subjects listened to 20 musical pieces from 5 genres- classical, heavy metal, electronic dance music, pop and rap, during which electroencephalogram (EEG) data were collected. A maximum 10 fold cross-validation accuracy of 98.4% for subject-independent and 99.0% for subject-dependent data were obtained for the classification of short instances of each song. The emotion of popular music was shown to have been most accurately predicted, with a classification accuracy of 99.6%. Further examination was conducted to investigate the effect of music emotion on the relaxation of subjects while listening. PMID- 30440816 TI - Impact of nurse-assisted patient turning at different sleep stages on the quality of subsequent sleep. AB - BACKGROUND: Nursing care performed during sleep, including nurse-assisted patient turning, is one of the factors that deteriorates sleep quality but is necessary for pressure ulcer prevention. Thus, it is important to determine when nurseassisted patient turning has the least impact on sleep quality. AIM: The aim of this study was to clarify the impact of nurseassisted patient turning at different sleep stages and to determine the optimal timing of this aspect during sleep. METHODS: The experiment, which consisted of healthy men in their 20s and 30s, was performed over four successive nights per subject. The first night was dedicated to environment adaptation, and the 2nd to the 4th nights were randomly assigned for shallow sleep intervention, deep sleep intervention, and non intervention. On the intervention day, nurse-assisted patient turning was conducted twice. Overnight sleep conditions were measured by polysomnography (PSG). The PSG waveform transmitted to a tablet was analyzed in real time to determine the stage of sleep. The patient was turned when he entered the planned stage of sleep. RESULTS: The study analyzed fourteen (14) subjects. Shallow sleep time, deep sleep time, and sleep resumption time after nurse-assisted patient turning were compared among the three groups of non-intervention day, shallow sleep intervention day and deep sleep intervention day. There was no significant difference in the shallow and deep sleep time among the three groups. However, sleep resumption time after nurse-assisted patient turning was significantly shorter on the deep sleep intervention day than on the shallow sleep intervention day (p = textbf 0.033). CONCLUSIONS: This study has novelty in examining the impact of nurse-assisted patient turning performed at different sleep stages on subsequent sleep using objective indicators. The study suggested that a deep sleep state is the optimal timing of nurseassisted patient turning due to the short time to sleep resumption. PMID- 30440817 TI - Postural Balance Performance of Children with ADHD, with and without Medication: A Quantitative Approach. AB - tAtention Deficit Hyperactivity Disorder (ADHD) significantly impairs the performance of students during their early school years. However, the extent of the difference in postural stability between children with ADHD and Typically Developed (TD) children, are still not fully understood. Also, it is clinically important to investigate possible effects of medication on their performances. We recruited 38 children between the ages 6 to 12 with ADHD (15 medically naive, 23 with current treatment history) and 25 age-matched as TD. Postural stability performance was assessed in four conditions: 1-eyes open, 2-eyes closed, 3-eyes open on foam and 4-eyes closed on foam. A cost-effective mobile force platform was used to evaluate postural performance quantitatively. Results revealed a lower stability performance in the medically-naive participants especially in trials with eyes open on foam. No significant difference in performance was seen between children with medical treatment history and the TD group. Results suggest that using medication can effectively enhance postural stability for children with ADHD. We found portable balance assessment tools helpful in identifying changes in motor performances among children with ADHD. Our results indicate that further research is needed to understand the exact implications of ADHD on postural stability under different sensory stimuli. PMID- 30440818 TI - A Reliable Multi-User EMG Interface Based on A Generic-Musculoskeletal Model against Loading Weight Changes. AB - The reliability of myoelectric control is important to ensure the performance of prostheses during daily use. Recently, we proposed a multi-user neural-machine interface based on a generic musculoskeletal model to simultaneously and continuously estimate flexion/extension movements at the metacarpophalangeal (MCP) and wrist joints from surface electromyography (EMG) signals. Our previous results demonstrated that the multi-user EMG interface was reliable against upper limb posture changes. However, the reliability of the interface against different loading weights, which is an important factor that would decrease the performance of myoelectric control and be tested during the occupational therapy for myoelectric prosthesis users, is still unclear. In this study, we aimed to evaluate the reliability of the generic model over different loading weights. Four able-bodied subjects were tested in this study. Subjects performed a virtual hand/wrist posture matching task with three different loading weights (no weight, 1.25 Lbs, and 2.5 Lbs). All subjects accomplished all the assigned virtual tasks. The on-line experimental results showed that performance with different loading weights was very close. The results demonstrated that the multi-user EMG interface was reliable against the different loading weights, indicating it has potential to promote the myoelectric control into clinical applications. PMID- 30440819 TI - Spatio-Temporal Inertial Measurements Feature Extraction Improves Hand Movement Pattern Recognition without Electromyography. AB - Recent studies indicate the limited clinical acceptance of myoelectric prostheses, as upper extremity amputees need improved functionality and more intuitive, effective, and coordinated control of their artificial limbs. Rather than exclusively classifying the electromyogram (EMG) signals, it has been shown that inertial measurements (IMs) can form an excellent complementary signal to the EMG signals to improve the prosthetic control robustness. We present an investigation into the possibility of replacing, rather than complementing, the EMG signals with IMs. We hypothesize that the enhancements achieved by the combined use of the EMG and IM signals may not be significantly different from that achieved by the use of Magnetometer (MAG) or Accelerometer (ACC) signals only, when the temporal and spatial information aspects are considered. A large dataset comprising recordings with 20 ablebodied and two amputee participants, executing 40 movements, was collected. A systematic performance comparison across a number of feature extraction methods was carried out to test our hypothesis. Results suggest that, individually, each of the ACC and MMG signals can form an excellent and potentially independent source of control signal for upper-limb prostheses, with an average classification accuracy of $?approx 93$% across all subjects. This study suggests the feasibility of moving from surface EMG to IM signals as a main source for upper-limb prosthetic control in real-life applications. PMID- 30440820 TI - Abstract Decoding using Bayesian Muscle Activation Estimators. AB - Two recursive Bayesian muscle activation estimators were compared against standard linear filtering during use of a myoelectric abstract decoder. The decoder was controlled by intrinsic muscles of the hand. In both experiments the linear filter outperformed the Bayesian methods in terms of general score. The Bayesian muscle decoders were faster to respond to changes in muscle activity and show promise for significantly enhancing overall decoder communication rate. PMID- 30440821 TI - CMOS Magnetic Sensors for Wearable Magnetomyography. AB - Magnetomyography utilizes magnetic sensors to record small magnetic fields produced by the electrical activity of muscles, which also gives rise to the electromyogram (EMG) signal typically recorded with surface electrodes. Detection and recording of these small fields requires sensitive magnetic sensors possibly equipped with a CMOS readout system. This paper presents a highly sensitive Hall sensor fabricated in a standard $0.18~?mu ?mathrm {m}$ CMOS technology for future low-field MMG applications. Compared with previous works, our experimental results show that the proposed Hall sensor achieves a higher current mode sensitivity of approximately 2400 V/A/mT. Further refinement is required to enable measurement of MMG signals from muscles. PMID- 30440822 TI - Flexo-glove: A 3D Printed Soft Exoskeleton Robotic Glove for Impaired Hand Rehabilitation and Assistance. AB - This paper presents a compact and streamlined design of a soft exoskeleton glove for assistance in activities of daily livings and also rehabilitation purposes of patients with hand function impairment. Most of the existing hand exoskeletons have focused on either providing a customizable and modular design or making it portable to be used outside the hospital environment. We have developed a design of an exoskeleton glove that combines both of these features in one compact design. This was achieved by using a parameterised CAD design of glove, 3D printing of soft (i.e., compliant) materials, design a bidirectional cable driven spooling system and integrating them together in a modular fashion. The overall weight of the Flexo-glove is 330g including battery and is able to provide 22N pinch force, 48N power grasp force and object grasp size of up to 81mm in diameter. The device has two control modes: intention-sensing via wireless sEMG for assistive mode and externally-directed via an accompanying smartphone application for rehabilitation (repetitive exercise) programs, both managed through Bluetooth communication. The effectiveness of the proposed design is evaluated in performing cylindrical, hook, and pinch grasps on various objects. PMID- 30440823 TI - Crosstalk Reduction in Epimysial EMG Recordings from Transhumeral Amputees with Principal Component Analysis. AB - Electromyographic (EMG) recordings of muscle activity using monopolar electrodes suffer from poor spatial resolution due to the crosstalk from neighbouring muscles. This effect has mainly been studied on surface EMG recordings. Here, we use Principal Component Analysis (PCA) to reduce the crosstalk in recordings from unipolar epimysial electrodes implanted in three transhumeral amputees. We show that the PCA-transformed signals have, on average, a better signal-tonoise ratio than the original unipolar recordings. Preliminary investigations show that this transformation is stable over long periods of time. If the latter is confirmed, our results show that the combination of PCA with unipolar electrodes allows for a higher number of muscles to be targeted in an implant (compared with bipolar electrodes), thus facilitating 1-to-1 proportional control of prosthetic hands. PMID- 30440824 TI - Coordination of Voluntary Residual Muscle Contractions in Transtibial Amputees: a Pilot Study. AB - Recently there has been considerable interest in the use of electromyography (EMG) for the control of powered, lower-limb prostheses. However, little is understood regarding amputee residual muscle, specifically the ability for lower limb amputees to coordinate previously antagonist residual muscles for different control tasks. In this study, we aimed to investigate the capability of transtibial amputees in coordinating residual gastrocnemius and tibialis anterior for performing a high-level task. Specifically, we examined how three transtibial amputees and one ablebodied subject used residual and intact ankle muscles to balance a virtual inverted pendulum. Subjects controlled the pendulum by modulating stiffness of the base joint proportional to the level of EMG signal exerted. We conducted ten trials for each subject and quantified success of task performance by area of overall sway and number of falls (termed failure). Amputees successfully reduced number of failures, though not to the extent of able-bodied subjects. Interestingly, while able-bodied subjects reduced overall pendulum sway, amputees did not. EMG coordination patterns that preceded failure for amputees were different than that of able-bodied subjects. These results suggest that amputees have altered ability to coordinate muscle post-amputation; however, all subjects can improve the task performance and learn to reduce EMG coordination patterns that led to task failure. Further study is required to investigate the limit of amputees in learning of coordination between antagonist residual muscles in order to inform future neural control of prosthetic legs. PMID- 30440825 TI - Comparing the Effects of Signal Noise on Pattern Recognition and Linear Regression-Based Myoelectric Controllers. AB - Myoelectric pattern recognition using linear discriminant analysis (LDA) classifiers has been a wellestablished control method for upper limb prostheses for many years. More recently, linear regression (LR) controllers have been proposed as an alternative solution due to their ability to control multiple degrees of freedom (DOF) simultaneously. The aim of this experiment was to compare the online performance of LDA and LR control systems under three electromyographic (EMG) signal conditions: baseline, noise in all channels, and noise in a single channel. To simulate the last two conditions, different levels of Gaussian noise were added to the EMG signals. Completion rate, path efficiency, dwelling time, and completion time were computed after virtual Fitts' Law tasks. While both controllers were significantly affected by the lowest noise levels, we found no significant differences between the controllers under the baseline and all-channel noise conditions. However, the LDA controller outperformed the LR controller in the single-channel noise condition. Therefore, while both controllers are comparable in most cases, the added complexity of simultaneous control affects an LR controller's performance under certain noise conditions. Based on these results, neither control system should be dismissed in future developments. PMID- 30440826 TI - An sEMG-based Interface to give People with Severe Muscular Atrophy control over Assistive Devices. AB - Injuries, accidents, strokes, and other diseases can significantly degrade the capabilities to perform even the most simple activities in daily life. While assistive technology becomes more and more available to the people affected, there is still a big need for user interfaces suitable for people without functional hand movement. A large share of these cases involves neuromuscular diseases, which lead to severely reduced muscle function. However, even though affected people are no longer able to functionally move their limbs, residual muscle function can still be existent. Previous work has shown that this residual muscular activity can suffice, to create an EMG-based user interface, and e.g., allow for control of assistive devices. In this paper, we enhance this user interface with additional EMG-features and an improved training paradigm in order to increase information extraction from recordings of strongly atrophic muscles. The interface was tested and validated by subjects with severe spinal muscular atrophy. Results show that the used methods improve the decoding and thereby allow for a considerable increase in performance when controlling a robotic manipulator in a 3D reaching task. PMID- 30440828 TI - Wrist Kinematics and Kinetics during Wheelchair Propulsion with a Novel Handle based Propulsion Mechanism. AB - Wheelchairs are important for daily mobility and recreation of the elderly and physically challenged individuals. The non-ergonomical propulsion design of wheelchairs frequently causes injuries to the upper extremities, especially in the wrist region. In this study, the joint kinematics and kinetics of the wrist joint was analyzed on subjects propelling a novel handle based wheelchair propulsion unit at 1.2m/s speed (20W and 40W respectively). The joint kinematics and the joint moments of the wrist were determined using a 3D musculoskeletal model. The mean values of joint ranges and torques during propulsion at the mentioned speeds were lower when compared to standard wheelchair propulsion with the push-rim, making the novel propulsion mechanism with its compact design an interesting alternative for wheelchair users that might help to avoid or reduce joint injuries. PMID- 30440827 TI - A Variable-Impedance Tactile Sensor With Online Performance Tuning for Tissue Hardness Palpation in Robot-Assisted Minimally Invasive Surgery. AB - This paper presents a novel tactile sensor whose sensing performance (sensitivity, range, etc.) can be tuned online by varying its mechanical impedance with a double-cantilever structure. Therefore, it can solve the problems of narrow sensing range and non-optimal sensitivity faced by existing dynamic tactile sensors. The sensor is driven by a piezoelectric patch which acts simultaneously as both the actuator to generate vibration and the sensor to detect resonance from its electrical impedance. Its basic working principle and the variable-impedance method for performance tuning are explained mathematically and verified by numerical simulations and experimental studies. The proposed variable-impedance methodology can inspire the designs of a new class of tactile sensors for applications in robotics, biomedical engineering, aerospace, etc. PMID- 30440829 TI - Eye-Hand Coordination Assessment Metrics Using a Multi-Platform Haptic System with Eye-Tracking and Motion Capture Feedback. AB - In this paper, we discuss the possibility to determine assessment metrics for eye hand coordination, using a mapping between a robotic haptic device to a virtual environment, and correlating it with the eye-gaze and upper arm movements. Our goal is to develop, implement and refine a system that will assess and improve eye-hand coordination in individuals with disabilities. A detailed analysis of patterns was conducted by therapists in order to select various levels of difficulty that could be included in the system, and which would yield the greatest benefit in terms of assessment of coordination as well as in training. Participants were instructed to use a haptic device (Omni) to follow the trajectories. This was completed while video data were collected using a Vicon motion capture system. Readings of traced trajectories, time, and upper limb motions were recorded for further analysis. One of the patterns was chosen to develop a multi-platform haptic system to be virtually rendered with any haptic device and a Graphic User Interface (GUI) with options to guide the user along the chosen pattern using a haptic tunnel calculated by using B-splines. Two types of haptic tunnels are presented and evaluated: one that follows the mid path of the pattern, and one that takes the smoothest path through the pattern. Finally, the Pearson coefficient was chosen as a metric to correlate the haptic device and the eye-gaze coordinates recorded simultaneously while the user traces a path. PMID- 30440830 TI - Granular Jamming Based Controllable Organ Design for Abdominal Palpation. AB - Medical manikins play an essential role in the training process of physicians. Currently, most available simulators for abdominal palpation training do not contain controllable organs for dynamic simulations. In this paper, we present a soft robotics controllable liver that can simulate various liver diseases and symptoms for effective and realistic palpation training. The tumors in the liver model are designed based on granular jamming with positive pressure, which converts the fluid-like impalpable particles to a solid-like tumor state by applying low positive pressure on the membrane. Through inflation, the tumor size, liver stiffness, and liver size can be controlled from normal liver state to various abnormalities including enlarged liver, cirrhotic liver, and multiple cancerous and malignant tumors. Mechanical tests have been conducted in the study to evaluate the liver design and the role of positive pressure granular jamming in tumor simulations. PMID- 30440831 TI - The Helping Hand: An Assistive Manipulation Framework Using Augmented Reality and Tongue-Drive Interfaces. AB - A human-in-the-loop system is proposed to enable collaborative manipulation tasks for person with physical disabilities. Studies show that the cognitive burden of subject reduces with increased autonomy of assistive system. Our framework obtains high-level intent from the user to specify manipulation tasks. The system processes sensor input to interpret the user's environment. Augmented reality glasses provide ego-centric visual feedback of the interpretation and summarize robot affordances on a menu. A tongue drive system serves as the input modality for triggering a robotic arm to execute the tasks. Assistance experiments compare the system to Cartesian control and to state-of-the-art approaches. Our system achieves competitive results with faster completion time by simplifying manipulation tasks. PMID- 30440832 TI - Design and Evaluation of a Performance-based Adaptive Curriculum for Robotic Surgical Training: a Pilot Study. AB - Training with simulation systems has become a primary alternative for learning the fundamental skills of robotic surgery. However, there exists no consensus regarding a standard training curriculum: sessions defined a priori by expert trainers or self-directed by the trainees feature lack of consistency. This study proposes an adaptive approach that structures the curriculum on the basis of an objective assessment of the trainee's performance. The work comprised an experimental session with 12 participants performing training on virtual reality tasks with the da Vinci Research Kit surgical console. Half of the subjects self managed their training session, while the others underwent the adaptive training. The final performance of the latter trainees was found to be higher compared to the former (p=0.002), showing how outcome-based, dynamic designs could constitute a promising advance in robotic surgical training. PMID- 30440833 TI - Investigation of the Stimulation Capabilities of a High-Resolution Neurorecording Probe for the Application of Closed-Loop Deep Brain Stimulation. AB - Deep brain stimulation is an established surgical treatment for several neurological and movement disorders, such as Parkinson's disease, in which electrostimulation is applied to targeted deep nuclei in the basal ganglia through implanted electrode leads. Recent technological improvements in the field have focused on the theoretical advantage of current steering and adaptive (closed-loop) deep brain stimulation. Current steering between several active electrodes would allow for improved accuracy when targeting the desired brain structures. This has the additional benefit of avoiding undesired stimulation of neural tracts that are related to side effects, e.g., internal capsule fibres of passage in subthalamic nucleus deep brain stimulation. Closed-loop deep brain stimulation is based on the premise of continuous recording of a proxy for pathological neural activity (such as beta-band power of measured local field potentials in patients with Parkinson's disease) and accordingly adapting the used stimulus parameters. In this study, we investigate the suitability of an existing highresolution neurorecording probe for high-precision neurostimulation. If a subset of the probe's recording electrodes can be used for stimulation, then the probe would be a suitable candidate for closed-loop deep brain stimulation. A finiteelement model is used to calculate the electric potential, induced by current injection through the high-resolution probe, for different sets of active electrodes. Volumes of activated tissue are calculated and a comparison is made between the highresolution probe and a conventional stimulation lead. We investigate the capability of the probe to shift the volume of activated tissue by steering currents to different sets of active electrodes. Finally, safety limits for the injected current are used to determine the size of the volume in which neurons can be activated with the relatively small electrodes patches on the highresolution probe. PMID- 30440834 TI - Novel tDCS montage favors lower limb motor imagery detection. AB - This work studies a novel transcranial direct current stimulation (tDCS) montage to improve a brain-machine interface (BMI) lower limb motor imagery detection. The tDCS montage is composed by two anodes and one cathode. One anode is located over the motor cortex and the other one over the cerebellum. Ten healthy subjects participated in this experiment. They were randomly separated into two groups: sham, which received a fake stimulation, and active tDCS, which received a real stimulation. Each subject was experimented on five consecutive days. Results pointed out that there was a significant difference $(p < 0 .05)$ in the classification accuracy between the sham and the active tDCS group. On each of the five days of the experiment the active tDCS group achieved better accuracy results than the sham group: 4%, 10%, 10%, 9% and 7% higher respectively. PMID- 30440835 TI - Simulation Study on Coil Design for Transcranial Magnetic Stimulation. AB - The purpose of this study is to optimize the coil for transcranial magnetic stimulation (TMS). A novel multi-circle tangent coil (MTC) was designed, which consisted of five inner circular coils and one outer circular coil. These six circular coils were tangent to each other. The induced electric field and target area of MTC were investigated with both homogeneous phantom model and realistic human head model by numerical simulation. The results showed that MTC induced low electric field along its 4 surrounding inner coils thus weakened the stimulus effect on non-target areas. MTC not only takes the advantages of figure-8 coils with high focality, but also enables deep stimulation and multi-point stimulation at the same time. MTC is expected to have great potential in clinical application. PMID- 30440836 TI - Synchronous Responses of Population Neurons to the Changes of Inter-Pulse Intervals during Stimulations of Afferent Fibers. AB - Deep brain stimulation (DBS) has been used to treat many brain disorders. Studies have shown that in DBS therapies, high frequency stimulation (HFS) with a constant pulse frequency over ~90 Hz can obtain better efficacy than stimulations with irregular inter-pulse-interval (IPI). The reasons are not clear yet. We hypothesized that irregular IPI might cause synchronous firing in target neurons thereby weakening the DBS efficacy. To test this hypothesis, stimulation trains of orthodromic-HFS (O-HFS) with different IPI were applied on the Schaffer collaterals, i.e., the afferent fiber tracts of the hippocampal CA1 region in anaesthetized rats. The amplitude of evoked population spikes (PS) in the downstream region was used as an electrophysiological index to evaluate the synchronicity of neuronal firing. The results showed that 100 Hz O-HFS with constant IPI induced de-synchronized firing of downstream neurons without PS events, whereas O-HFS with sparse prolonged IPI (20 or 100 ms) or with irregular IPI (1.7 - 50 ms) generated large PS events. Presumably, the longer IPI in O-HFS trains might provide adequate time to allow axons to recover from HFS-induced block and to respond the next coming pulse, synchronously. Therefore, following longer IPI, the population neurons in the target region could receive synchronous impulses from a lot of axonal fibers thereby generating action potentials synchronously. These findings are important for revealing new underlying mechanisms of DBS and for advancing the application of DBS. PMID- 30440837 TI - Frequency-Dependent Inhibition Induced by Stimulations in Rat Hippocampus. AB - Deep brain stimulation (DBS) has a good prospect in treating brain diseases such as epilepsy. However, its therapeutic mechanism is undetermined yet. To investigate the inhibitory effects of DBS acting on the downstream neurons in target region, 1-min pulse trains of orthodromic stimulations with various frequencies (10 - 100 Hz) were applied to the Schaffer collaterals of hippocampal CA1 region in anaesthetized rats. Unit spikes of downstream interneurons and pyramidal cells were detected and analyzed. Interneurons activated by the stimulation through mono-synaptic connections were recognized based on short latencies. Their firing was used as an index of stimulation-induced inhibition. Results showed that during stimulations with pulse frequency of 20 Hz, the mean firing rate of mono-synaptically-activated interneurons was significantly higher than the value during 10 Hz stimulations. Afterward, even if the pulse frequency increased to 100 Hz, the mean firing rate of the interneurons did not change significantly. However, only during stimulations with lower frequencies (10, 20 Hz), the firing of pyramidal cells was suppressed by the stimulation-activated interneurons. The inhibitory effects of interneurons were weakened during stimulations with higher frequencies (50 and 100 Hz). De-synchronous firing of interneurons induced by high-frequency stimulation might cause the loss of effective inhibition on the principal neurons. These findings provide new information for advancing the application of DBS. PMID- 30440838 TI - Merged Haptic Sensation in the Hand during Concurrent Non-Invasive Proximal Nerve Stimulation. AB - When individuals interact with the environment, sensory feedback is a critical aspect of the experience. Individuals using prosthesis often have difficulty controlling their device, partly due to a lack of sensory information. Transcutaneous nerve stimulation has the potential to elicit focal haptic sensation when controlled electrical current was delivered to a pair of electrodes in proximity to the nerve. The objective of this preliminary study was to evaluate how different elicited focal haptic sensation were altered, when multiple concurrent electrical stimuli were delivered to different portions of the median and ulnar nerve bundles. The delay between the individual stimulation during concurrent stimuli was also varied to identify if this parameter could alter the resulting sensation region. Lastly, the stability/repeatability of the perceived sensation during concurrent stimuli was determined. Our preliminary results showed that the spatial distribution of the haptic sensation was largely a direct summation/merge of the sensation regions from the individual nerve stimulation when comparing the regions to that of the concurrent double stimulation. Our results also showed that merged sensation region was not sensitive to different time delays the two concurrent stimuli. Lastly, the sensation regions remained stable and showed repeatable sensation in the hand even with 20-60 minutes between repeated stimulations. PMID- 30440839 TI - On the need for adaptive learning in on-demand Deep Brain Stimulation for Movement Disorders. AB - The results presented in this paper indicate that future on-demand Deep Brain Stimulation (DBS) systems for chronic use in patients with movement disorders should continuously and adaptively "learn" in order to maintain high symptom control efficacy. In this work, two machine learning algorithms-Decision Tree and LArge Memory STorage And Retrieval (LAMSTAR) neural network, both with surface Electromyography and accelerometry as control signals-are used to predict onset of tremor after DBS has been switched off in two patients, one suffering from Parkinson's disease and the other from essential tremor. The novelty of this work is that training and testing are done by using different data recorded during sessions at least one week apart. The question is whether the applied algorithms are robust to long-term operation (as patient's control signal may change over time due to disease progression, displacement of the wearable sensor, etc.). Various metrics are used to compare the performance of the proposed approach to those available in the literature, where training and testing are done on data from the same recording session. It is shown that a 100% sensitivity is achieved for training and testing over the same session; however, the sensitivity reduces when tested over a different session. The ratio of predicted stimulation-off time to observed stimulation-off time value is also found to be lower when training and testing on data from separate sessions. These results point to the need of adaptive learning in on-demand DBS systems. PMID- 30440840 TI - Delayed Feedback Frequency Adjustment for Deep Brain Stimulation of Subthalamic Nucleus Oscillations. AB - Neural oscillations within the Basal Ganglia (BG) circuitry are associated with Parkinson's Disease (PD) and are observable through the Local Field Potential (LFP) of the Subthalamic Nucleus (STN) or Globus Pallidus externa (GPe) neurons. LFP amplitude modulation in a delayed feedback protocol for Deep Brain Stimulation (DBS) is shown to destabilize the complex intermittent synchronous states. However, traditional High Frequency Stimulations (HFS) often intensify the synchronization of highly fluctuating neurons, are less efficient in activating all neurons in large scale networks and consume more battery of the DBS device. Here, we investigate the partially synchronous dynamics of a STN-GPe coupling network to examine the effect of frequency adjustment in the stimulation signal. The frequency of the stimulation signal is adjusted according to the nonlinear delayed feedback LFP of the STN population. Frequency adjustment protocol with a fixed stimulation amplitude is shown to increase the desynchronization efficiency and neuronal activation by 25% and 16.2%, respectively, while reducing the energy consumption by 31.5% compared to amplitude modulation methods for stimulation of large networks (1000 neurons). PMID- 30440841 TI - Assessments of basic properties of distal-presented bone-conducted ultrasonic hearing. AB - Bone-conducted ultrasound (BCU) is perceived even by the profoundly sensorineural deaf and a novel hearing aid using the perception of amplitude-modulated BCU (BCU hearing aid) has been developed. In the BCU hearing aid, the vibrator is pressed onto a part of the cranial bone behind the ear (mastoid process). However, BCU can be heard on distal parts of the body; i. e., the muscle of the neck, the clavicle, and the upper limb. In this study, to assess basic properties of such distal-presented BCU hearing, hearing thresholds were measured when 30-kHz tone bursts were presented to the neck and the upper and lower arms in normal hearing participants. Further, to assess the basic capability of transferring information by the distal-presented BCU hearing, temporal modulation transfer functions (TMTFs), that reflect the temporal resolution of the hearing, were estimated for 30-kHz carrier. The results showed that BCUs presented to the distal parts, including the lower arm, can be perceived at least in the normal hearing, whereas threshold increased depending on the distance from the head. Also, the temporal resolutions of the distal-presented BCU hearing at the neck, and the upper and lower arms were comparable to that of the mastoid process of the temporal bone. These results provide useful information not only for the improvement of the existing BCU hearing aid, but also for the development of novel distal-presented BCU devices that can provide sound information selectively to the specific person who touches the device by the arms or so. PMID- 30440842 TI - PEDOT as a high charge injection material for low-frequency stimulation. AB - Alternating current stimulation (ACS) provides a versatile tool for modulating brain activity and presents a promising strategy for the treatment of neurological disorders like Parkinson's disease or epilepsy. Stimulation of neural tissue at low-frequency however poses new challenges on conventional electrode materials which support limited charge transfer in the desired frequency range, from less than 0.1 Hz to several tens of Hz. In our study we address this challenge by investigating the charge transfer properties of PEDOT/PSS coatings for low-frequency applications, focusing on the impact of the polymer bulk. PEDOT films of various thicknesses were exposed to low-frequency as well as DC stimulation textbfin vitro and compared to Pt and IrOx electrodes as controls. The charge injection performance of the metallic substrates could be substantially improved already by a thin PEDOT coating. Additionally a linear dependency between charge injection and polymer thickness suggests that PEDOT coatings are promising as materials for future ACS applications. PMID- 30440843 TI - Closed Loop Microfabricated Facial Reanimation Device Coupling EMG-Driven Facial Nerve Stimulation with a Chronically Implanted Multichannel Cuff Electrode. AB - Permanent facial paralysis and paresis (FP) results from damage to the facial nerve (FN), and is a debilitating condition with substantial functional and psychological consequences for the patient. Unfortunately, surgeons have few tools with which they can satisfactorily reanimate the face. Current strategies employ static (e.g., implantation of nonmuscular material in the face to aid in function/cosmesis) and dynamic options (e.g., gracilis myoneurovascular free tissue transfer) to partially restore volitional facial function and cosmesis. Here, we propose a novel neuroprosthetic approach for facial reanimation that utilizes electromyographic (EMG) input coupled to a chronically implanted multichannel cuff electrode (MCE) to restore instantaneous, volitional, and selective hemifacial movement in a feline model. To accomplish this goal, we developed a single-channel EMG-drive current source coupled with a chronically implanted MCE via a portable microprocessor board. Our results demonstrated a successful feasibility trial in which human EMG input resulted in FN stimulation with subsequent concentric contraction of discrete regions of a feline face. PMID- 30440844 TI - Electrophysiological Activity Evoked by Direct Electrical Stimulation of the Human Brain: Interest of the P0 Component. AB - Direct electrical stimulation (DES) at 60 Hz is used clinically to perform real time functional mapping of the brain and guide tumor resection during wide-awake neurosurgery. The electrophysiological effects of DES remain by far unknown, both locally and remotely. In this study, by lowering the DES frequency to 9 Hz and by using differential recording of electro-corticographic signals to improve the focality, we were able to observe that the amplitude of the initial P0 component of the direct cortical response increased when the inter-electrode distance was increased and the pulse width was decreased. This result strongly suggests that larger neural elements, including somas and axons of pyramidal neurons buried in deeper layers of the cortical column, are activated. Their activation produce the observed P0 component, which results from the synchronized summation of action potentials triggered by DES. Interestingly, the early P0 component was not observed during the usual 60 Hz DES. The study of the P0 component and subsequent evoked potentials may help decipher the effects of DES on the stimulated cortical column and identify the activation of underlying white matter fibers. This is crucial to better understand the electrophysiological diffusion of DES, especially at higher frequencies (e.g., 60 Hz). PMID- 30440845 TI - The Crucial Role of Nerve Depolarisation in High Frequency Conduction Block in Mammalian Nerves: Simulation Study. AB - Neurostimulations which use High Frequency Alternating Current (HFAC) block show great promise for neuromodulatory therapies. Treatments have been developed for various health conditions including obesity and obesity related health risks, and now even stomach cancer treatments are being considered. However the mechanism of the block is still not completely clear, as well as how various neural and electrode parameters affect it. In order to study conduction block during HF stimulation in mammalian axons, we describe a detailed computational model and perform comprehensive simulations. We establish relationships between the blocking frequency and amplitude versus fibre diameter and the distance between the electrode and fibre. We found that only a certain level of depolarisation will universally create a block irrespective of the fibre size, and it is in the range 24-30mV depending on the stimulus frequency. Our study crucially improves our knowledge about this important technique which is rapidly emerging as a commercially available therapy. PMID- 30440846 TI - Therapeutic Effects of repetitive Transcranial Magnetic Stimulation on Corticospinal Tract Activities and Neuromuscular Properties in Children with Cerebral Palsy. AB - The objective of this research was to study the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) on corticospinal tract (CST) activities, reflex hyper-excitability, muscle stiffness, and the clinical status of children with spastic hemiplegic cerebral palsy (CP). Three children participated in this study. The treatment lasted for 6 weeks. Two of the patients, the experimental group, received rTMS therapy 4 days a week during the first 3 weeks, and then received typical occupational therapy (OT) after each rTMS session during the second 3 weeks. One patient, the control group, received the same treatment except that a sham coil was used. Each rTMS session lasted for 20 minutes and each OT session lasted for 45 minutes. We evaluated CST activities by transcranial magnetic stimulation (TMS), reflex hyperexcitability by H-reflex response, and muscle stiffness by sonoelastography images. The tests were taken before and after the treatment. Major TMS parameters (i.e., motor evoked potential (MEP) latency, MEP p-p amplitude, cortical silent period (cSP), and intensity of pulse) for experimental patients were improved in comparison with the control patient. H response latency and max H response on max M-wave (H/M) were improved for the experimental group compared to the control group. Two parameters of texture analysis of the sonoelastography images (i.e., entropy and contrast) were improved for the experimental group. Clinical evaluations such as 10 meter walk test (10MWT), timed up and go (TUG), and 6 minute walk test (6MWT) were performed before and after the course of treatment and were improved for the experimental group compared to the control group. These results indicated that rTMS therapy can improve CST activities, reflexes, muscle stiffness, and walking capacity of spastic hemiplegic CP. Therefore, it can be considered as an effective therapeutic tool for enhancing neuromuscular abnormalities resulting from CP. PMID- 30440847 TI - Analysis of adverse effects of stimulation during DBS surgery by patient-specific FEM simulations. AB - Deep brain stimulation (DBS) represents today a well-established treatment for movement disorders. Nevertheless the exact mechanism of action of DBS remains incompletely known. During surgery, numerous stimulation tests are frequently performed in order to evaluate therapeutic and adverse effects before choosing the optimal implantation site for the DBS lead. Anatomical structures responsible for the induced adverse effects have been investigated previously, but only based on stimulation data obtained with the implanted DBS lead. The present study introduces a methodology to identify these anatomical structures during intraoperative stimulation tests based on patient-specific electric field simulations and visualization on the patient specific anatomy. The application to 4 patients undergoing DBS surgery and presenting dysarthria, paresthesia or pyramidal effects shows the different anatomical structures, which might be responsible for the adverse effects. Several of the identified structures have been previously described in the literature. To draw any statistically significant conclusions, the methodology has to be applied to further patients. Together with the visualization of the therapeutic effects, this new approach could assist the neurosurgeons in the future in choosing the optimal implant position. PMID- 30440848 TI - Optimizing stimulus waveforms for suppressing epileptic activity reveals a counterbalancing mechanism. AB - Electrical stimulation is used to treat drug- resistant epilepsy, and excessive stimulation can lead to adverse effects for patients. In this article, we use an extrema featured stochastic search algorithm to find energy-efficient stimulus waveforms that suppress seizure activity in two different computational models of epilepsy. We infer general principles that may provide insight into future design of energy efficient stimulus for epilepsy treatments. PMID- 30440849 TI - Micro-solenoid inductors with magnetic core for neural stimulation. AB - Magnetic stimulation using micro-coils has shown to be an effective method for brain neural modulation [1]. These micro-coils could arguably be superior to commonly used micro-electrodes in terms of long-term functionality. This is because, unlike electrode based devices, magnetic coils do not need to have direct contact with brain tissues and thus their efficiency and stimulation capability do not degrade overtime. In this study, we compare three different micro-coils and show that the use of magnetic-core in the inductors could substantially improve the coil's performance and help to generate more than 13 times stronger electric field and electric field gradient. PMID- 30440850 TI - Electrical Weapon Charge Delivery With Arcing. AB - INTRODUCTION: Human electronic control with the Conducted Electrical Weapon (CEW) has gained widespread acceptance as the preferred law enforcement force option technology due to its dramatic injury and fatal shooting reduction. However, with bulky or baggy clothing, a CEW probe may fail to make direct skin contact and thus arcing is critical to complete the circuit. The goal of the study was to evaluate the ability of modern CEWs to deliver their pulse charges across typical required arcing distances. METHODS: Popular TASER(r) CEW models X26E (openloop output), and the X2 and X26P (with closed-loop outputs) were activated using a cartridge connected to a custom polymer air-gap fixture. For each model 5 units were tested. The raw and normalized charge delivery were evaluated according to ANSI-CPLSO-17. RESULTS: All 5 units of each model satisfied ANSICPLSO-17 even at maximum arcing length. The X26P CEW had the greatest arcing gap capability. CONCLUSIONS: The stabilized closed-loop charge output feedback of modern electrical weapons (X2 and X26P CEWs) provides a significantly improved output consistency under arcing conditions. With arc lengths of 10-20 mm per probe, the X2 CEW normalized output charge exceeds that of some units of the older higher output X26E CEW model. PMID- 30440851 TI - Neuromuscular Electrical Stimulation with Kilohertz Frequency Alternating Current to Enhance Sensorimotor Cortical Excitability. AB - Enhancement of cortical excitability has been demonstrated to be beneficial for neural recovery of motor dysfunction, such as stroke and spinal cord injury. Neuromuscular electrical stimulation (NMES) has been widely used to evoke limb movements, resulting in the increasing cortical excitability. Due to the advantages of low skin impedance and less discomfort, an alternative NMES of kilohertz frequency alternating current (KFAC) has been proposed, and the effects of current parameters on evoked torque has been studied. However, few studies concerned cortical excitability effects during KFAC-evoked limb movement. In this paper, we utilized the event-related spectral estimation (ERSP) to calculate the beta ERD values to investigate the effects of KFAC-evoked elbow flexion movement on cortical excitability and compared them with that of passive movement. Firstly, averaged ERSP values were extracted in beta band during elbow flexion movements by sliding a 2Hz wide window for all trails of each subject. And then the minimal value was chosen as the representative value of beta ERD. Finally, the absolute ERD values and the descending slopes of all subjects were both calculated for statistical analysis by one-way repeated measures ANOVA. The results showed KFAC can increase cortical excitability, especially with long pulse duration. Moreover, beta cortical activities during KFAC500-evoked movement are significantly activated than those during passive movement. Therefore, our study may provide a new NMES rehabilitation method to enhance cortical excitability for motor dysfunction patients. PMID- 30440852 TI - Estimating Voluntary Activation Of The Elbow And Wrist Muscles In Chronic Hemiparetic Stroke Using Twitch Interpolation Methodology. AB - One of the cardinal motor deficits that occurs after stroke is paresis, a decrease in the voluntary activation of muscles. Paresis leads to a decrease in voluntary joint strength, impacting stroke survivors' ability to perform activities of daily living (ADLs). Quantifying this decrease in voluntary activation is important when designing rehabilitation interventions to address movement impairments and restore the ability to perform ADLs. Twitch interpolation is an experimental technique developed to quantify muscle voluntary activation [1]. This method has been used widely across pathologies but often limited to assessment of the voluntary activation of the plantar flexors, given the ease of activating these muscles through stimulation of the tibial nerve [2]. The complex innervation of elbow and wrist musculature imposes practical difficulties when applying the twitch interpolation technique to these joints [1]. Therefore, only a few studies have used this technique to examine the pathological [3]-[5] upper extremity, with little quantitative data documenting the degree of paresis present in the upper limb after stroke. The goal of this study is to evaluate the feasibility of applying twitch interpolation to quantify voluntary activation of the elbow and wrist flexors and extensors in chronic stroke survivors. PMID- 30440853 TI - Computational Models And Tools For Developing Sophisticated Stimulation Strategies For Retinal Neuroprostheses. AB - Improvements to the efficacy of retinal neuroprostheses can be achieved by developing more sophisticated neural stimulation strategies to enable selective or preferential activation of specific retinal ganglion cells (RGCs). Computational models are particularly well suited for these investigations. The electric field can be accurately described by mathematical formalisms, and the population-based neural responses to the electrical stimulation can be investigated at resolutions well beyond those achievable by current state-of-the art biological techniques. In this study, we used a biophysically-and morphologically-detailed RGC model to explore the ability of high frequency electrical stimulation (HFS) to preferentially activate ON and OFF RGC subtypes, the two major information pathways of the retina. The performance of a wide range of electrical stimulation amplitudes (0 - $100~?mu ?mathbf {A}$) and frequencies (1 - 10 kHz) on functionally-distinct RGC responses were evaluated. We found that ON RGCs could be preferentially activated at relatively higher stimulation amplitudes $( > 50 {?mu } ?mathrm {A})$ and frequencies $( >2$ kHz) while OFF RGCs were activated by lower stimulation amplitudes (10 to $50 {?mu } ?mathrm {A})$ across all tested frequencies. These stimuli also show great promise in eliciting RGC responses that parallel RGC encoding: one RGC type exhibited an increase in spiking activity during electrical stimulation whilst another exhibited decreased spiking activity, given the same stimulation parameters. PMID- 30440854 TI - Electric Fields Induced By Transcutaneous And Intracranial Current Injections In The Rat Brain. AB - As a non-invasive brain stimulation technique, transcranial electrical stimulation (TES) and specifically the transcranial direct current stimulation (tDCS) has gained popularity in recent years for treatment of a wide variety of cognitive and neurological disorders. Recent studies have shown that TES can alter the motor cortex excitability. Animal studies to demonstrate the underlying mechanisms of TES are clearly lacking in literature. Clinical studies have agreed on the critical role of the current intensity and the montage of the electrodes for the treatment to be effective. In this study, we used a rat model for in vivo investigation of the vertical electrical (E) field distribution due to electrodes placed over the skin and through a craniotomy hole. A mono-phasic current pulse was used as a substitute for DC currents by taking advantage of primarily resistive properties of the brain tissue at low frequencies. The electrical potentials induced by the current pulses were recorded with penetrations at 0mm, 2mm, and 4mm away from the stimulation electrode. The results showed that the E field was maximum immediately under the anodic electrode and decreased both in the vertical and horizontal directions rapidly by distance. The magnitude of the electric field varied from tens of mV/mm to a fraction of mV/mm by distance for a 100 MU A stimulus amplitude. The results also show that the E-field amplitudes and distribution strongly depend on whether the stimulus electrode is placed over the skin or into a craniotomy hole. PMID- 30440855 TI - Congestive Heart Failure Detection Via Short-Time Electrocardiographic Monitoring For Fast Reference Advice In Urgent Medical Conditions. AB - This study proposed a detection approach for the congestive heart failure (CHF) by short-time electrocardiographic monitoring. Recent literature only reported that RR intervals and Heart Rate Variability (HRV) indicated key hidden information to discriminate CHF groups from healthy controls. However whether it was possible to find certain short-time electrocardiographic monitoring duration for CHF clinical diagnoses, has not been well addressed. In the study, databases of 54 normal subjects and 15 CHF patients from PhysioNet were introduced. Signals were classified into variable assessment lengths. Based on R-R intervals in the assessment length, raw R-R intervals, mean and standard deviation (STD) of R-R intervals, and clinically standard features of shortterm (5-min) Heart Rate Variability (HRV), were comparatively analyzed, while combining with classifiers of Recurrent Neural Network (RNN), Random Forest (RF), and Support Vector Machine (SVM). The Leave-one-out Cross-Validation (LOOCV) was adopted for performance verification, by which the model extracted from certain assessment length was utilized to test measured data of a subject with the same length. Results showed that based on testing databases, a specific 30-minute duration can be achieved by choosing HRV features in full with sensitivity of 88.55% and specificity of 94.81%. It was believed that a short-time electrocardiographic monitoring for the CHF detection could be feasible if standard HRV features together with the classifier of RF or RNN are adopted. It implied that a short-time electrocardiographic monitoring can be applied for fast reference advice of CHF in urgent medical conditions. PMID- 30440856 TI - Experimental Study on Nerve Signals Block for Spasticity Based on Antimissile Strategy. AB - A method of blocking neural signal for spasticity which is based on the antimissile strategy was proposed. When the pathological nerve action potential signal is detected at the proximal end of the nerve, such a potential signal that is opposite to the signal of the primary neural activity is applied at the distal end of the nerve at a proper delay so as to block the pathological nerve signal. Preliminary tests were performed on toad sciatic nerve-gastrocnemius specimens. Firstly, the effect of the distance between blocking electrodes on the blocking pulse voltage threshold was studied based on the electrical tension induced by the nerve signal on the controlled muscle. Then, the effective parameters of the blocking waveform were studied. Finally, the delay range of the blocking pulse compared to the pathogen action potential was studied. The results showed that in the sciatic nerve-gastrocnemius specimens, the most effective distance between the blocking electrode pairs was 5 mm and the anodic block required an inverted triangle waveform. The voltage threshold of an effective anodic blocking pulse was 1 V and the minimum pulse width was 90 ms. Under the condition of voltage threshold and minimum pulse width, the time shifting value of blocking pulse was greater than 1ms. It is concluded from the study that the spastic action potential caused by the disease can be effectively blocked, and limb muscle spasms can be eliminated under the action of appropriate electrode configuration and blocking signal waveforms. PMID- 30440857 TI - Using Interictal HFOs to Improve the Identification of Epileptogenic Zones in Preparation for Epilepsy Surgery. AB - For the more than 15 million patients who have drug-resistant epilepsy, surgical resection of the region where seizure arise is often the only alternative therapy. However, the identification of this epileptogenic zone (EZ) is often imprecise. Generally, insufficient EZ identification and resection may cause seizures to continue and too much resection may lead to unnecessary neurological deficits. In this paper, an automatic high frequency oscillations (HFOs) detection method based on noise-assisted multivariate EMD (NA-MEMD) is proposed to improve the localization of the EZ for epilepsy patients. In this method, different detected HFO types such as fast-ripple (FR), ripple (R), and fast ripple concurrent with ripple (FRandR) are utilized to investigate their clinical relevance in identifying EZ. The proposed method may significantly improve the precision by which pathological brain tissue can be identified. PMID- 30440858 TI - Hardware Implementation of a Performance and Energy-optimized Convolutional Neural Network for Seizure Detection. AB - We present for the first time a MUW-power convolutional neural network for seizure detection running on a low-power microcontroller. On a dataset of 22 patients a median sensitivity of 100% is achieved. With a false positive rate of 20.7 fp/h and a short detection delay of 3.4 s it is suitable for the application in an implantable closed-loop device. PMID- 30440859 TI - Neural Modulation By Repetitive Transcranial Magnetic Stimulation (rTMS) for BCI Enhancement in Stroke Patients. AB - Brain-computer interface (BCI) is a novel method for stroke rehabilitation. However, lacking of sufficient motor-related cortical activity greatly decreases the BCI performance in stroke patients. Interestingly, high-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to increase the cortical excitability of lesioned hemisphere in stroke patients. This stimulation effect may have benefits on the enhancement of BCI decoding. This study recruited 16 stroke patients to evaluate the stimulation effect on BCI accuracy, with 8 patients were assigned to the TMS-group and the other 8 patients were assigned to the Control-group. Patients in the TMS-group underwent 12 sessions of 10-Hz TMS interventions in four consecutive weeks, whereas no stimulation was applied during this period in the Control-group. Meanwhile, three BCI evaluation sessions were carried out in one day before, one day after, and three days after the TMS intervention, separately. The results showed that the TMS intervention significantly improved the BCI accuracy from 63.5% to 74.3% in motor imagery (MI) tasks, and from 81.9% to 91.1% in motor execution (ME) tasks. This finding provides a novel method for the cure of BCI-inefficiency problem, and may facilitate the clinical application of BCI-based stroke rehabilitation. PMID- 30440860 TI - Ultra Broad Band Neural Activity Portends Seizure Onset in a Rat Model of Epilepsy. AB - Epilepsy affects over 70 million people worldwide and 30% of patients' seizures cannot be controlled with medications, motivating the development of alternative therapies such as electrical stimulation. Current stimulation strategies attempt to stop seizures after they start, but none aim to prevent seizures altogether. Preventing seizures requires knowing when the brain is entering a preictal state (i.e., approaching seizure onset). Here we show that such preictal activity can be detected by an informative neural signal that progressively and monotonically changes as the brain approaches a seizure event. Specifically, we use local field potentials (LFP) from a rat model of epilepsy to develop an innovative measure of signal novelty relative to nonseizure activity, that shows the presence of progressive neural dynamics in an ultra broad band (4 Hz - 5 kHz). The measure is extracted from functional connectivity features computed from the LFPs which are used as an input to a one-class Support Vector Machine (SVM). The SVM outputs a scalar signal which quantifies how novel the current activity looks relative to baseline (non-seizure) activity and shows a progression towards seizure onset minutes ahead of time. The use of ultra broad band multivariate features into the SVM results in a novelty signal that has a significantly higher slope in the progression to seizure onset when compared to using power in conventional frequency bands (4 - 500 Hz) on individual channels as input features to the SVM. Functional connectivity in conjunction with the SVM is a strategy that generates a new measurement of novelty that can be used by closed-loop systems for seizure forecasting and prevention. PMID- 30440861 TI - Development of a Method to Quantify Abnormal Kinetic and Kinematic Coupling Patterns during Functional Movements in the Paretic Arm and Hand of Individuals with Pediatric Hemiplegia. AB - A main focus of clinical interventions for adults after a stroke and children with hemiplegia is upper limb motor impairments. Robotic and motion capture technologies have been used to quantify the presence of abnormal joint coupling patterns in the arm and hand in adults who have had a stroke. Similar impairments have been observed clinically in children with hemiplegia, however, quantitative measurement tools tailored for this population are lacking. Here, we describe the integration of haptic robotics, pressure recording, and motion capture designed specifically for use with pediatric participants. Preliminary results demonstrate that these measurement techniques are effective in quantifying deficits in reaching abilities in this population. PMID- 30440862 TI - Challenges of Stride Segmentation and Their Implementation for Impaired Gait. AB - Stride segmentation represents important but challenging part of the gait analysis. Different methods and sensor systems have been proposed for detection of markers for segmentation of gait sequences. This task is often performed with wearable sensors comprising force sensors and/or inertial sensors. In this paper, we have compared four different methods for stride segmentation based on signals collected from force sensing resistors, accelerometers and gyro sensors. The results were evaluated on 15 healthy and 15 patients with Parkinson's disease, and expressed in terms of number of imprecisely, missed or wrongly detected gait events, as well as temporal absolute error. It was established that the methods using the inertial data, provide results with up to 12% higher error rate comparing to detection from force sensing resistors. PMID- 30440863 TI - Temporal Pattern of Ripple Events in Temporal Lobe Epilepsy: Towards a Pattern based Localization of the Seizure Onset Zone. AB - Ripples (80-250 Hz) are brief high-frequency oscillations that are often detected in intracranial EEG (iEEG) and are currently investigated as a potential biomarker to facilitate the Iocalization of the seizure onset zone (SOZ) in patients with drug-resistant epilepsy. While the rate and shape of these oscillations have been positively correlated with the SOZ, the temporal pattern of these oscillations in the epileptic brain still requires investigation. In this study, we investigate the temporal pattern of ripple events in five patients with temporal lobe epilepsy (TLE), which is one of the most common forms of epilepsy. The rate of ripple events is positively correlated with the SOZ in TLE but its diagnostic utility in localizing the SOZ remains unclear, which suggests that additional ripple-related features should be investigated. By combining point process modeling and cluster analysis, we show that a recurrent, non stationary bursting pattern characterizes the SOZ channels consistently across patients, while the non-SOZ channels have poor between-channel similarity and no consistent pattern over time nor across patients. Furthermore, the degree of separation between SOZ and non-SOZ model parameter vectors is significantly higher (ANOVA test, ${P}$-value $P?lt 0.01$) than the degree of separation between the ripple rates, which suggests that the temporal pattern more than the rate may contribute to the pre- surgical Iocalization of the SOZ. PMID- 30440864 TI - Frequency Dependence of Shear Wave Velocity in Stroke-Affected Muscles During Isometric Contraction- Preliminary Data. AB - In addition to changes in the central nervous system, many changes can occur in the composition and structure of skeletal muscles after a hemispheric stroke. The mechanical behavior of skeletal muscles is linked to the density and structural arrangement of key constituents. Yet, little is known about changes in post stroke muscle mechanical properties such as viscoelasticity. The aim of this study was to explore the frequency-dependent changes in shear wave (SW) velocity as a potentially informative feature accompanying changes in muscle viscoelastic properties under passive and active conditions in hemiplegic stroke. We used the ultrasound SuperSonic Imaging technique to induce and measure SW propagation in the biceps brachii muscle for both the paretic and contralateral limbs in three hemiplegic stroke survivors during passive and submaximal voluntary muscle contractions. We found that for all subjects, the muscles on both the paretic and non-paretic sides demonstrated large dispersion (i.e., a change in SW phase velocities as a function of frequency within each contraction level) under both passive and active conditions, although muscles on the paretic side displayed larger dispersion. In addition, for a range of frequencies from 108-756 Hz, the SW phase velocity was higher in active nonparetic muscles compared to those of paretic side with an increase of 42% at 756 Hz. This is in contrast with the muscle response under passive condition where the SW phase velocity exhibited a 97 % increase at 765Hz on the paretic side compared to the non-paretic side. These results suggest the mechanical properties are altered for stroke-affected muscles, which may be a result of changes in the muscle extracellular matrix composition. Further, this study provides evidence that there are changes in tissue mechanical properties and that may consequently influence muscle function. PMID- 30440865 TI - Neural Correlation between Evoked Tactile Sensation and Central Activities in the Somatosensory Cortex. AB - Evoked tactile sensation (ETS) is induced with stimulation of areas in the projected finger map (PFM) in the stump skin of forearm amputees. The aim of the present study is to further explore the neural correlation of the ETS with central activities in the somatosensory cortex (SI). Two forearm amputees were recruited to participate in this study. The neuroimaging technique of Magnetoencephalography (MEG) was employed to reveal the activities in the somatosensory cortex (SI), while the thumb and little finger areas in the PFM and the thumb and little finger of the contralateral hand were stimulated with a bi phasic current pulse train. In one subject, local anesthesia was applied to the skin areas of the thumb and little finger of the PFM to examine the effects of blocking peripheral nerve transmission on the central activities in SI. Results obtained in the two subjects indicated that stimulation of the thumb and little finger areas in the PFM of amputated side produced the similar neural activities in the somatosensory cortex as those of stimulating the thumb and little finger of the contralateral hand, both of which were consistent with the homunculus organization of the SI cortex. The intensity of SI cortical activities was proportional to the intensity of the amplitude of peripheral stimulation. In particular, local anesthesia reduced the intensity of central activities in SI as revealed by the MEG response, as well as the sensitivity of ETS as reported by the subject. This neural correlation appears to suggest that the finger areas in the PFM in the stump skin are neuroanatomically connected to the finger areas of the somatosensory cortex. Thus, electrical stimulation of the PFM can induce natural sensation as that of normal fingers. This establishes the neural basis of natural sensory feedback from the prosthetic hand to the forearm amputee with finger-to-finger specificity. PMID- 30440866 TI - Gait Symmetry Can Reduce Dependence on the Intact Limb during Walking with Constraint of Unilateral Metatarsophalangeal Joints. AB - Our previous research showed that healthy subjects exhibited asymmetrical walking gait when their unilateral metatarsophalangeal (MTP) joints were constrained. They relied more on their intact limb for the compensation of missing functions of their constrained limb, which may result in poor balance, increased metabolic cost, and higher risks of falls. We examined how subjects would respond if gait asymmetry in stance time was improved using a split-belt treadmill. Twelve healthy subjects were instructed to walk on a split-belt treadmill at comfortable and fast speeds with their unilateral MTP joints constrained. The walking trials were performed in two conditions, i.e., tied-belt walking (TBW, both belts moved at the same speed), and split-belt walking (SBW, the speed of the belt on the constrained leg was appropriately slower than that of the contralateral leg). The ground reaction forces (GRF) and electromyography (EMG) data during walking were collected. Results showed that the GRF and impulses on the constrained foot at fast speed SBW significantly increased, compared with TBW, and the activation of medial gastrocnemius and soleus of the intact lower limb decreased significantly, which suggest that improved symmetry in stance time may reduce dependence on the intact limb for humans with the constraint of unilateral MTP joints. PMID- 30440867 TI - Towards Enhancement of Patients' Engagement: Online Modification of Rehabilitation Training Modes Using Facial Expression and Muscle Fatigue. AB - Rehabilitation training combined with human psychological and physiological information can enhance patients' neural engagement. For this purpose, a racial expression and muscle fatigue based rehabilitation training method is proposed in this paper. Signals from major zygomaticus and corrugator supercilii muscles are used for racial expression recognition, and signals from rectus femoris and biceps femoris muscles are used for fatigue level analysis. Facial expressions (positive, neutral, and negative) are recognized by a classifier which is constructed by wavelet packet features and neural network, and median frequency (MF) is applied to analyze fatigue level. A passive training mode and five-level active training modes are included. Different training modes have different damping levels. When the patient is with positive expression and without fatigue, the damping will be raised automatically in order to increase exercise difficulties and enhance the patient's engagement; when with negative expression and mild fatigue, damping will be decreased properly to reduce exercise difficulties and ease user's burden to obtain more efficient training. Moreover, when patient is severe fatigue, passive training is selected to avoid overfatigue and muscle injury. Feasibility of the proposed method is validated by the experiment conducted on the platform of a damping adjustable treadwheel. PMID- 30440868 TI - Prediction Method of Walking Speed at Swing Phase using Soleus Electromyogram Signal at Previous Stance Phase. AB - A recent research has proposed a prediction method of walking speed with soleus electromyogram (EMG) signal activation level at push-off phase. However, the prediction of walking speed at low speed is inaccurate and the coefficients of determination (R2 values) of the used linear regression model is low. In this study, we propose a new method for predicting walking speed during swing phase with soleus EMG signal activation levels at pre-load and push-off phases, and square root value is used as a feature. The proposed method is verified by walking experiment with 5 nondisabled subjects. (R2 values) of the new method is improved by 10.3 % than that of the method used in the previous study. And the proposed method improves accuracy mainly at low speed and precision at high speed to predict a correct walking speed throughout walking speed range. Thus, the proposed method enhances the performance of the prediction model of walking speed without being biased in the range of high or low speed. The proposed method has potential to be used to control the gait speed of a lower-limb exoskeleton according to wearer's gait intention. PMID- 30440869 TI - Application of an LDA Classifier for Determining User-Intent in Multi-DOF Quasi Static Shoulder Tasks in Individuals with Chronic Stroke: Preliminary Analysis. AB - Abnormal synergies commonly present after stroke, limiting function and accomplishment of ADL's. They cause co-activation of sets of muscles spanning multiple joints across the affected upper-extremity. These synergies present proportionally to the amount of shoulder effort, thus the effects of the synergy reduce with reduced effort of shoulder muscles. A promising solution may be the application of a wearable exoskeletal robotic device to support the paretic shoulder in hopes to maximize function. To date, control strategies for such a device remain unknown. This work examines the feasibility of using two different linear discriminant analysis classifiers to control shoulder abduction and adduction as well as external and internal rotation simultaneously, two primary degrees of freedom that have gone largely unstudied in hemiparetic stroke. Forces, moments, and muscle activity were recorded during single and dual-tasks involving these degrees of freedom. A classifier that classified all tasks was able to determine user-intent in 14 of the 15 tasks above 90% accuracy. A classifier using force and moment data provided an average 94.3% accuracy, EMG 79%, and data sets combined, 94.9% accuracy. Parallel classifiers identifying user-intent in either abduction and adduction or internal and external rotation were 95.4%, 92.6%, and 97.3% accurate for the respective data sets. These preliminary results indicate that it seems possible to classify user-intent of the paretic shoulder in these degrees of freedom to an adequate accuracy using load cell data or load cell and EMG data combined that would enable control of a powered exoskeletal device. PMID- 30440870 TI - Designing Feedback Controllers for Human-Prosthetic Systems Using Hinfinity Model Matching. AB - Prosthetic hands are important tools for improving the lives of upper limb amputees, yet most devices lack the ability to provide a sense of touch back to the user. Recent improvements have been made in electromyography (EMG) prosthesis control as well as in biologically relevant tactile sensors to provide sensory feedback to amputees through nerve stimulation. However, sensory feedback has been designed heuristically, which can lead to either unnatural sensations or to excessive feedback that bothers the user. In this study, we apply optimal control techniques to synthesize sensory feedback to the user, and to synthesize the conversion from EMG to an actuation command to the prosthesis. Specifically, we construct a feedback control system architecture and solve the $H_{?infty }$ model matching problem to make the closed-loop user-prosthetic system to behave like a pre-specified ideal system in response to elemental inputs (e.g. impulse, step, etc). We design feedback controllers assuming that human and prosthetic components behave in a linear fashion as a proof-of-concept, and the closed-loop system is able to match ideal systems that are slow, fast and that have both slow and fast dynamics (like healthy humans). PMID- 30440872 TI - Identifying Noisy Electrodes in High Density Surface Electromyography Recordings Through Analysis of Spatial Similarities. AB - In this study we developed a technique for identifying noisy electrodes in high density surface electromyography (HD-sEMG). The technique finds the spatial similarity of each electrode in the electrode array by counting the number of interactions the electrode has. Using this information the technique identifies noisy electrodes by finding electrodes that are significantly dissimilar to the other electrodes. The HD-sEMG recordings used in this study were taken from three participants who performed two isometric contractions of their biceps at 40% and 80% of their maximum voluntary contraction (MVC) force. White Gaussian noisy was added to a varying number of recorded signals before being digital filtering to generate a variety of recordings to test the technique with. In the recordings, groups of 2, 4, 8, and 16 electrodes had noise added such that the signal to noise ratios (SNR) were 0, 5, 10, 15, and 20dB. The results show that the technique can reliably identify groups of 2, 4, and 8 noisy electrodes with SNRs of 0, 5, and 10dB. PMID- 30440871 TI - Parkinsonian Tremor Detection from Subthalamic Nucleus Local Field Potentials for Closed-Loop Deep Brain Stimulation. AB - Deep Brain Stimulation (DBS) is a widely used therapy to ameliorate symptoms experienced by patients with Parkinson's Disease (PD). Conventional DBS is continuously ON even though PD symptoms fluctuate over time leading to undesirable side-effects and high energy requirements. This study investigates the use of a Iogistic regression-based classifier to identify periods when PD patients have rest tremor exploiting Local Field Potentials (LFPs) recorded with DBS electrodes implanted in the Subthalamic Nucleus in 7 PD patients (8 hemispheres). Analyzing 36.1 minutes of data with a 512 milliseconds non overlapping window, the classification accuracy was well above chance-level for all patients, with Area Under the Curve (AUC) ranging from 0.67 to 0.93. The features with the most discriminative ability were, in descending order, power in the 31-45 Hz, 5-7 Hz, 21-30 Hz, 46-55 Hz, and 56-95 Hz frequency bands. These results suggest that using a machine learning-based classifier, such as the one proposed in this study, can form the basis for on-demand DBS therapy for PD tremor, with the potential to reduce side-effects and lower battery consumption. PMID- 30440873 TI - Interference of Visual Conditions and Stance Postures on Center of Pressure Sway in Patients with Schizophrenia with History of Fall. AB - This study examines the interaction effects among incidences of falls, visual conditions, and stance postures on the magnitude of center of pressure sway (MCOPS) in patients with schizophrenia. The coordinates of COP in ten postural control demands were measured in subjects with at least one or without any falls in the previous year. MCOPS was calculated by the default program in Balance 3.78 software. Cognitive functions were also measured. The findings include: (1) the MCOPS increased as the postural control demands increase in subjects who have fallen; (2) MCOPS in subjects without falls was the largest for the lowest postural control demands; (3) MCOPS increased when the eyes were closed in subjects without a history of falls but decreased in subjects with a history of falls; (4) cognition function in subjects who have fallen was inferior to that in those without falls. The interference visual condition and stance postures on MCOPS tended to be different in schizophrenia with or without incidences of falls indicating the possible association between psychomotor dysfunction and falls in the subjects. PMID- 30440874 TI - Combined Visual Feedback with Pelvic Assistance Force Improves Step Length during treadmill walking in Individuals with Post-Stroke Hemiparesis. AB - Altered spatiotemporal gait characteristics are common impairments after stroke. Visual feedback has been used to improve spatiotemporal gait characteristics. In addition, pelvic assistance force applied in the mediolateral direction to the paretic side can improve walking pattern. Potentially, combined visual feedback and pelvic assistance force can have better rehabilitation outcomes on walking patterns. The purpose of this study was compare the effects of combined visual feedback with pelvic assistance force and visual feedback only during treadmill walking in individuals with post-stroke hemiparesis. Fifteen subjects with hemiparesis due to chronic (>6 months) stroke participated. A computer monitor placed in front of the treadmill was used to provide visual feedback on subjects' weight bearing on the paretic leg. A customized cabledriven robotic system was used to apply pelvic assistance force. The magnitude of pelvic assistance force was 9% of body weight. The session consisted of 5 sections: 1-min baseline, 7-min treadmill training (visual feedback only or combined visual feedback and pelvic assistance force), 1-min post-training (no visual feedback or pelvic assistance force), 1-min standing break, and 5-min treadmill training. The order of the visual feedback only and combined visual feedback and pelvic assistance force sessions was randomized across subjects. Spatiotemporal gait variables within the session, including stance time, single leg support time and step length, were computed. Combined visual feedback with pelvic assistance force resulted in a better improvement in step length of the paretic leg when compared to visual feedback only (p=0.03). Walking patterns after stroke could potentially be improved by applying visual feedback regrading paretic leg weight bearing and pelvic assistance force. Future study is needed to confirm the effectiveness of visual feedback for treadmill training after stroke. PMID- 30440875 TI - Design of Functional Electrical Stimulation Cycling System for Lower-Limb Rehabilitation of Stroke Patients. AB - The active participation of the stroke survivor during Functional Electrical Stimulation (FES) cycling system is an interesting question that we would like to investigate, since active rehabilitation can promote a better motor function recovery than passive training. In this pilot study, a smart FES cycling system which can assess the participants cycling effort was proposed to record real-time Electromyography (EMG) and torque during lower limb training for chronic stroke survivors. The rehabilitation goals were to increase the lower-limb muscle strength and enhance the muscle coordination. Chronic stroke patients (n=6) with gait impairment and moderate motor disability were recruited to evaluate the functionality of the system. The system was composed of a modified station bike with an adjustable chair, a programmable functional electrical stimulator, a step motor, a torque sensor, and a surface electromyography (EMG) amplifier. Four channel FES and EMG electrodes were placed at quadriceps (QC), hamstrings (HS), tibialis anterior (TA) and gastrocnemius (GL) to exert stimulation. We adopted two measurements, clinical assessment scores and symmetric index (SI), to evaluate the training effects. The experimental results showed the proposed cycling system could improve the participants walking ability (p=.046) and enhance balance of the muscle coordination (p=.042) after training. PMID- 30440876 TI - Exploration of the Effect of Race on Cortical Current Flow Due to Transcranial Direct Current Stimulation: Comparison across Caucasian, Chinese, and Indian Standard Brains. AB - It is well known that genetic and environmental factors amongst others make different ethnic populations dissimilar reflected by the difference in overall skull and brain volume, shape, and size. We sought to investigate in this study the effects of race related morphological changes by comparing across standard Caucasian, Chinese and Indian templates on brain current flow due to transcranial Direct Current Stimulation. Findings indicate up to 1.4 fold variation in induced electrical field magnitude in both target and non-target regions across the electrode montage and average heads considered. The observed variation is similar to the variation observed in adults of Caucasian race indicating that variation observed due to race are not significantly more than within race variation. PMID- 30440877 TI - Development and Evaluation of a Kinect-based Rapid Movement Therapy Training Platform for Balance Rehabilitation. AB - With the growing aging and overall population, the demand for healthcare professionals and their burden increases by time. Effective balance recovery reaction is required to prevent falls. The aim of this project is to provide low cost portable balance training system that trains the two important components of effective balance recovery reaction: faster movement completion time (MT) and larger range of motion (ROM). This is done by a Kinect-based interactive rapid movement therapy training platform for reaching and stepping actions. The platform provides real-time feedback to the patient, generates a report for healthcare professionals to monitor the patient's progress, and can be utilized in patient's home or community centers. A pilot study to test the platform was conducted on seventeen stroke patients and it has shown significant improvement in both MT (faster) and ROM (larger). PMID- 30440878 TI - Studying The Sensitivity Of Coronary Blood Flow Using Nondimensional Analysis. AB - Nondimensional analysis was used to develop a novel model of coronary blood flow. In addition to general hemodynamics, the model was used to study the sensitivity of the arterial flow to variations in characteristic lumped parameters. Experimental hemodynamic data obtained from four normal healthy pigs were used in the current study. The results suggest that the mean coronary arterial flow is primarily sensitive to the flow and elasticity parameters of the coronary vasculature. Other flow features were also studied, and it was shown that the sensitivities of the general flow waveforms are influenced to different extents by the perturbations of these parameters. More specifically, the flow coefficient affects the systolic inflow more than the diastolic portion; conversely, the elasticity coefficient has more impact on the diastolic period. PMID- 30440879 TI - Modelling of fasting glucose-insulin dynamics from sparse data. AB - With the fast growth of diabetes prevalence, the disease is now considered an epidemic. Diabetes is characterized by elevated glucose levels, that may be treated with insulin. Tight control of glucose is essential for prevention of complications and patients' well-being. In this paper we model the fasting glucose-insulin dynamics in type 2 diabetes, aiming at controlling the glucose level. Relevant clinical data are typically sparse and have a sampling period much greater than the fast dynamics in the glucose-insulin dynamics in humans. We adapt a physiological model such that important slow non-linear dynamics are identifiable and test the resulting model on deterministic simulated data and sparse, slow sampled clinical data. PMID- 30440880 TI - An Application of Conditional Robust Calibration (CRC) to The Lotka-Volterra Predator-Prey model in computational systems biology: a comparison of two sampling strategies. AB - Mathematical modeling is a widely used technique for describing the temporal behavior of biological systems. One of the most challenging topics in computational systems biology is the calibration of nonlinear models, i.e. the estimation of their unknown parameters. The state of the art methods in this field are the frequentist and Bayesian approaches. For both of them, the performances and accuracy of results highly depend on the sampling technique employed. Here, we test a novel Bayesian procedure for parameter estimation, called Conditional Robust Calibration (CRC), comparing two different sampling techniques: uniform and logarithmic Latin Hypercube Sampling (LHS). CRC is an iterative algorithm based on parameter space sampling and on the estimation of parameter density functions. We apply CRC with both sampling strategies to the Lotka-Volterra model and we obtain a more precise and reliable solution through logarithmically spaced samples. PMID- 30440881 TI - Parameter Estimation in Synaptic Coupling Model Using a Point Process Modeling Framework. AB - Biophysical models are widely used to characterize temporal dynamics of the brain networks on different topological and spatial scales. In parallel, the state space modeling framework with point process observations has been successfully applied in characterizing spiking activity of neuronal ensembles in response to different dynamical covariates. Parameter estimation in biophysical models is generally done heuristically, which hampers their applicability and interpretability. Heuristic parameter estimation becomes an intractable problem when the number of model parameters grows. Here, we propose an algorithm for estimating biophysical model parameters using point-process models and a state space framework. The framework provides methods for parameter estimation as well as model validation. We demonstrate the application of this methodology to the problem of estimating the parameters of a dynamic synapse model. We generate simulation data for the dynamic synapse across a range of parameters values and assess the estimation accuracy of our method using a combination of goodness-of fit measures. The proposed methodology can be applied broadly to parameter estimation problems across a broad range of biophysical models, including Hodgkin Huxley models and network models. PMID- 30440882 TI - A Mean Field Model of Acute Hepatic Encephalopathy. AB - Acute hepatic encephalopathy (AHE) is a common form of delirium, a state of confusion, impaired attention, and decreased arousal due to acute liver failure. However, the neurophysiological mechanisms underlying AHE are poorly understood. In order to develop hypotheses for mechanisms of AHE, our work builds on an existing neural mean field model for similar EEG patterns in cerebral anoxia, the bursting Liley model. The model proposes that generalized periodic discharges, similar to the triphasic waves (TPWs) seen in severe AHE, arise through three types of processes a) increased neuronal excitability; b) defective brain energy metabolism leading to impaired synaptic transmission; c) and enhanced postsynaptic inhibition mediated by increased GABA-ergic and glycinergic transmission. We relate the model parameters to human EEG data using a particle filter based optimization method that matches the TPW inter-event-interval distribution of the model with that observed in patients EEGs. In this way our model relates microscopic mechanisms to EEG patterns. Our model represents a starting point for exploring the underlying mechanisms of brain dynamics in delirium. PMID- 30440883 TI - A Novel Bi-Level Framework for Fitting the Parameters in Cardiac Cellular Models. AB - Cardiac models constructed from sets of differential equations provide invaluable information about heart mechanism and disorder of both human and animals. As tuning the parameters is a profoundly important step of modeling, this paper presents a novel parametrization technique based on a bilevel framework that benefits from two solution approaches, namely mixed integer genetic algorithm (MIGA) and linear least squares (LLS). In the upper-level optimization step, the action potential (AP) of the model is fitted to the reference AP using MIGA. In the lower-level optimization step, the mismatch between the total current of the model and reference is minimized via a clamp concept-based linearization and LLS solution approach. Notably, the clamp concept can diminish the nonlinearity of the parameter fitting problem. The issue of dependency on initial parameters in the lower-level problem, as well as the sensitivity of model parameters to linearization, are circumvented by MIGA in the upper-level optimization. For evaluation of MIGA-LLS performance, two complex human ventricular models are employed. The results demonstrate that in comparison to the genetic algorithm (GA)-based approach, the proposed framework significantly reduces the average and variation of normalized root-mean-squared error (NRMSE) in terms of the AP and total current in different trials. Variability in the resulting parameter values is considerably decreased as well. PMID- 30440885 TI - Single-Cell Transcriptomics Reveals Heterogeneity and Drug Response of Human Colorectal Cancer Organoids. AB - Organoids are three-dimensional cell cultures that mimic organ functions and structures. The organoid model has been developed as a versatile in vitro platform for stem cell biology and diseases modeling. Tumor organoids are shown to share ~ 90% of genetic mutations with biopsies from same patients. However, it's not clear whether tumor organoids recapitulate the cellular heterogeneity observed in patient tumors. Here, we used single-cell RNA-Seq to investigate the transcriptomics of tumor organoids derived from human colorectal tumors, and applied machine learning methods to unbiasedly cluster subtypes in tumor organoids. Computational analysis reveals cancer heterogeneity sustained in tumor organoids, and the subtypes in organoids displayed high diversity. Furthermore, we treated the tumor organoids with a first-line cancer drug, Oxaliplatin, and investigated drug response in single-cell scale. Diversity of tumor cell populations in organoids were significantly perturbed by drug treatment. Single cell analysis detected the depletion of chemosensitive subgroups and emergence of new drug tolerant subgroups after drug treatment. Our study suggests that the organoid model is capable of recapitulating clinical heterogeneity and its evolution in response to chemotherapy. PMID- 30440884 TI - Microbiota of Inflammatory Bowel Disease Models. AB - Gut microbiome plays an important role in inflammatory bowel disease (IBD), a group of intestinal chronic inflammation conditions that affect a large population. The animal models of IBD have long been established on basis of pathological features, but their ability to recapitulate patient gut microbiota is unknown. We investigated and compared the composition and biodiversity of bacterial population in the fecal samples from rat models of the two IBD subtypes, and compared them with patient samples. Our analyses revealed that inflammation reduces overall microbiome diversity and increased variation between individuals. We identified specific microbial signatures associated with the two IBD subtypes that were consistent between the animal models and human IBD patients, suggesting that the animal models can partially recapitulate the microbiota in human diseases. Furthermore, metagenome prediction analysis suggested microbial functions that were likely altered by host-microbiota interactions in IBD models. PMID- 30440886 TI - In Silico Model of Vitamin D3 Dependent NADPH Oxidase Complex Activation During Mycobacterium Infection. AB - Mycobacterium tuberculosis (Mtb) is a highly infectious aerosolizable bacterium, which causes upward of 1.5 million deaths per year. Alveolar macrophages, the primary defense cell of the lung, are the preferred host cell of this intracellular bacterium. Vitamin D3 is a known transcription factor, modulating the transcription of pro- and anti-inflammatory cytokines and immunologically relevant proteins. In a vitamin D3 deficient host, the immune systems response to infection is greatly impaired. We used a quantitative systems biology approach to model the impact of long-term vitamin D3 deficiency on macrophage effector response. We then compared our simulation output to our in vitro model of mycobacterium infection of macrophages from vitamin D3 supplemented hosts. Our in silico model results agreed with in vitro levels of hydrogen peroxide (H2O2) production, an antimicrobial effector molecule produced by the host's macrophage, known to be modulated indirectly by vitamin D3. The current model will provide a foundation for further studies into the effects of micronutrient deficiency on immune response. PMID- 30440887 TI - Modeling HPV Late Promoter Regulation. AB - High risk HPV can induce cervical and oropharyngeal Iesions. HPV productive infection is strictly linked by differentiation-dependent control of the late promoter. This latter produces HPV transcripts at different epithelial layers through a complex post-transcriptional control. The aim of this study is to develop a novel mathematical model of the late promoter condensing the biological knowledge present in literature. The model describes the interaction among primary transcript, spliced transcripts and their proteins and includes the major splicing mechanisms. When used as an in silico tool it shows the crucial role of splicing regulation to explain the HPV gene expression. Novel testing hypothesis are then formulated to uncover this still elusive but pivotal promoter. PMID- 30440888 TI - Spatiotemporal Analysis of Mycobacterium-Dependent Macrophage Response. AB - There are three main outcomes of Mycobacterium tuberculosis infection: clearance, dissemination, and containment - in which the immune system physically isolates the invading microbes in lesions called granulomas. These structures are a hallmark of the disease and play an important role in the progression of infection. However, current in vitro and in vivo methods are ill adapted for spatial and temporal quantification of host-pathogen dynamics, which are necessary for the development of granulomas. We have developed an integrated 3D in vitro and computational platform with longterm time-lapse confocal imaging to provide a semi-automatic analysis of host-pathogen interaction data. Through exploratory data analysis, we conduct a preliminary investigation of how the intracellular bacterial load of macrophages can impact cellular spatiotemporal dynamics during Mycobacterium infection. PMID- 30440889 TI - Deep-2'-O-Me: Predicting 2'-O-methylation sites by Convolutional Neural Networks. AB - 2'-O-methylation (2'-O-me) of ribose moiety is one of the significant and ubiquitous post-transcriptional RNA modifications which is vital for metabolism and functions of RNA. Although recent development of new technology (Nmseq) enabled biologists to find precise location of 2'-O-me in RNA sequences, there is still a lack of computational tools that can also provide high resolution prediction of this RNA modification. In this paper, we propose a deep learning based method that takes advantage of an embedding method to learn complex feature representation of pre-mRNA sequences and employs a Convolutional Neural Network to fine-tune the features required for accurate prediction of such alteration. Specifically, we adopted dna2vec, a biological sequence embedding method originally inspired by the word2vec model of text analysis, to yield embedded representation of sequences that may or may not contain 2-O-me sites before feeding those features into CNN for classification. Our model was trained using the data collected from Nm-seq experiment. The proposed method achieved AUC and auPRC scores of 90% outperforming existing state-of-the-art algorithms by a significant margin in both balanced and unbalanced class testing scenarios. PMID- 30440890 TI - Offline Lower-Limb Kinematic Decodification by Segments of EEG Signals. AB - In this work, hip and knee angles were decoded from low frequency EEG components recorded during the execution of two tasks. In order to compare their performance, three decoders based on multiple linear regression (MLR) models were applied under different conditions; which consisted in considering the processed data as a whole or divided into segments. Results suggest that, when the segments are related to specific tasks, the segmentation provides a better performance than applying the decoding method to unsegmented data. PMID- 30440891 TI - Eigen Decomposition of Cardiac Synchronous EEGs for Investigation of Neural Effects of Tempo and Cognition of Songs. AB - There is growing evidence of palliative effects of listening to songs on neural and cardiovascular function. It is also known that listening to songs can entrain cardiac variability. These results suggest that the neural changes in response to listening to songs in turn affect cardiac rhythm. How these effects come about is less clearly known. Therefore, investigation of the changes in neural rhythms that are synchronous with cardiac rhythm is likely to shed further light on the mechanisms via which songs produce these effects. Towards this aim, we conducted eigen decomposition of cardiac-synchronized EEGs to investigate the effects of tempo and cognition by auditory stimuli (listening to songs). For evaluating the effects of tempo, songs of slow and fast tempo were used, and for cognition, each subjects' favorite song was used. ECG and six EEGs (F3, F4, T3, T4, P3, P4) were recorded as subjects listened to songs. For cardiac synchronization, R waves from the ECG were localized and the EEGs during 300-millisecond segments ending at each R wave were extracted. Eigen decomposition of the covariance matrix of these EEG segments was performed. Results from 14 subject showed that, compared with other locations, P3 appears to have the ability to discriminate between songs. All songs lowered the second and the third largest eigenvalues compared to control, among these, the slow tempo song induced more significant decreases in T3, T4 and P3. During the slow song, 80% of the variance in all six EEGs could be represented with less eigenvalue/vectors while during the favorite song this number was larger. These results show that eigen decomposition of cardiac synchronized EEGs has the potential to investigate effects of music on neural and cardiovascular systems. PMID- 30440893 TI - Cross-Recurrence Quantification Analysis for Inter-Muscular Coordination during Power Grip at Different Force Levels. AB - This study aimed to examine the dynamical coordination across muscles during power grip at different force levels. Twenty-four healthy volunteers (12 males, 12 females) participated in this experiment. Subjects were instructed to grip a hydraulic hand dynamometer and produce forces at 30%, 50%, 70% Maximal Voluntary Contractions (MVC) for at least 10s, respectively. Surface electromyography (sEMG) signals were simultaneously recorded from eight muscles, including brachioradialis (BR), flexor carpi ulnaris (FCU), flexor carpi radialis (FCR), extensor digitorum communis (EDC), flexor digitorum superficialis (FDS), abductor pollicis brevis (APB), first dorsal interosseous (FDI) and abductor digiti minimi (ADM). A cross-recurrence quantification analysis (CRQA) was applied to analyze the sEMG signals by both visualization and quantifications. Results showed that percentage of determinism (%DET) and percentage of entropy (%ENT) of the extrinsic muscle pairs were augmented with increased force levels and had a weak but positive correlation. For intrinsic muscle pairs, the %DET and %ENT increased with force levels but the difference is not or less statistically significant. These results showed that the intermuscular coordination would be alter with force output increased. For the right-handers, the values of intrinsic muscles couplings in right hand were lower than left hand, because less coupled intrinsic muscles contribute to finger dexterity; the reason why the values of extrinsic muscles couplings in right hand were greater than left hand was stronger couplings of extrinsic muscles produced higher synergistic force. PMID- 30440892 TI - EMD-Based, Mean-Phase Coherence Analysis to Assess Instantaneous Phase-Synchrony Dynamics in Epilepsy Patients. AB - In this paper, an adaptive, non-linear, analytical methodology is proposed in order to quantitatively evaluate the instantaneous phase-synchrony dynamics in epilepsy patients. A group of finite neuronal oscillators is extracted from a multichannel electrocorticographic (ECoG) data, using the empirical mode decomposition (EMD). The instantaneous phases of the extracted oscillators are measured using the Hilbert transform in order to be utilized in the mean-phase coherence analysis. Finally, the dynamical evolution of phase-synchrony among the extracted neuronal oscillators within 1-600 Hz frequency range is assessed using eigenvalue decomposition. A different phasesynchrony dynamics was observed in two patients with frontal vs. temporal lobe epilepsy, as their seizures evolve. However, experimental results demonstrated a hypersynchrony level at seizure offset for both types of epilepsy during the ictal periods. This result suggests that hypersynchronization of the epileptic network may be a crucial, self regulatory mechanism by which the brain terminate seizures. PMID- 30440894 TI - Weighted Network Density Predicts Range of Latent Variable Model Accuracy. AB - Current experimental techniques impose spatial limits on the number of neuronal units that can be recorded invivo. To model the neuronal dynamics utilizing these sampled data, Latent Variable Models (LVMs) have been proposed to study the common unobserved processes within the system that drives neuronal activities, through an implicit network with hidden states. Yet, relationships between these latent variable models and widely-studied network connectivity measures have remained unclear. In this paper, a biologically plausible latent variable model was fit to neuronal activity recorded via 2-photon microscopic calcium imaging in the murine primary visual cortex. Graph theoretic measures were then applied to quantify network properties in the recorded sub-regions. Comparison of weighted network measures with LVM prediction accuracy shows some network measures having a strong relationship with LVM prediction accuracy, while other measures do not have a robust relationship with LVM prediction accuracy. Results show LVM will achieve high accuracy in dense networks. PMID- 30440895 TI - Short-Time Fourier Transform Based Spike Detection of Spontaneous Peripheral Nerve Activity. AB - Peripheral nerve interfaces are designed to record neural activity from residual nerves in amputees. Reliable detection of neural events from these recordings dictate the performance of neuroprosthetic device control. Extraction of neural events from peripheral nerve recordings is challenging because of low signal to noise ratio (SNR), sparse spiking pattern and the presence of electromyographic signal contamination from the surrounding muscles. In this study, we developed a spike detection algorithm based on Short-time Fourier Transform (STFT) and compared its performance to simple thresholding technique using synthesized nerve recordings. To mimic peripheral nerve recordings and produce ground-truth for validation, a quasi-simulation framework is proposed to incrementally synthesize signals from physiological recordings. A detection threshold was optimized on the spectral features of simulated signals and performance evaluation was done using an independent simulated data set. Results show that the STFT based technique, compared to the simple thresholding, reduces the false detection rate even in recordings with moderately low SNR. PMID- 30440896 TI - Noninvasive seizure prediction using autonomic measurements in patients with refractory epilepsy. AB - There is resurgent interest in the role played by autonomic dysfunction in seizure generation. Advances in wearable sensors make it convenient to track many autonomic variables in patient populations. This study assesses peri-ictal changes in surrogate measures of autonomic activity for their predictive value in epilepsy patients. We simultaneously recorded fronto-central surface EEG and submental EMG to score vigilance state, intracranial EEG (iEEG) to compute several electrophysiological variables (EV), and measurements (heart rate, blood volume pulse, skin impedance, and skin temperature) relevant to autonomic function (AV) using a wrist-worn sensor from three patients. A naive Bayes classifier was trained on these features and tested using five-fold cross- validation to determine whether preictal and interictal sleep (or wake) epochs could be distinguished from each other using either AV or EV features. Of 16 EV features, beta power, gamma power (30-45 Hz and 47-75 Hz), line length, and Teager energy showed significant differences for preictal versus interictal sleep (or wake) state in each patient (t test: $p<0.001$). At least one AV was significantly different in each patient for interictal and preictal sleep (or wake) segments ($p<0.001$). Using AV features, the classifier labeled preictal sleep epochs with 84% sensitivity, 79% specificity, and 64% kappa; and 78%, 80% and 55% respectively for preictal wake epochs. Using EV, the classifier labeled preictal sleep epochs with 69% sensitivity, 64% specificity, and 33% kappa; and 15%, 93% and 10% respectively for preictal wake epochs. PMID- 30440897 TI - Subspace-Based Suppression of Cortical Stimulation Artifacts. AB - Bi-directional brain-computer interfaces for the restoration of movement and sensation must simultaneously record neural signals and deliver cortical stimulation. This poses a challenge since stimulation artifacts can be orders of magnitude stronger than neural signals. In this article, we propose a novel subspace-based method for the removal of cortical electrical stimulation artifacts. We demonstrate the practical application of our approach on experimentally recorded electroencephalogram data, where artifacts were suppressed by as much as $30-40?mathrm {d}?mathrm {B}$. Our method is computationally simple, yet it achieves superior results to the state-of-the art methods. PMID- 30440898 TI - Positioning the Nerve Cuff Distally on the Sciatic Nerve Improves the Classification of Ankle-Movement Proprioceptive ENG Signals. AB - Recording of neural signals from intact peripheral nerves in patients with spinal cord injury or stroke survivors offers the possibility for the development of closed-loop sensorimotor prostheses. However, questions remain over the positioning of neural interfaces such that the separability of neural data recorded from the peripheral nerves is improved. Afferent electroneurographic signals were recorded with nerve cuffs placed on the sciatic nerve of rats in response to various mechanical stimuli to the hindpaw. The mean absolute value of the signal was extracted and fed into classifiers. The performance of the classifier was evaluated when information was available from a single cuff placed either distally or proximally on the sciatic nerve. Results confirmed earlier findings that proprioceptive ENG signals, elicited by the movement of the ankle, can be identified and separated in neural recordings made with a cuff electrode. In addition, classification scores improved when the nerve cuff was placed distally on the nerve rather than proximally, taking advantage of the nerve's underlying anatomy. PMID- 30440899 TI - Visual and electric spiking responses of seven types of rabbit retinal ganglion cells. AB - Electric stimulation of the retina via retinal implants is currently the only commercially available method to restore vision in patients suffering from a wide range of outer retinal degenerations. To improve the quality of retinal implants, it is desirable to better understand how different retinal cell classes and types respond to electric stimuli so that more effective stimulation strategies can be developed. Here, we measured the response of seven major types of retinal ganglion cells to electric stimulation. A simple series of light stimuli were used to classify cells into known types. Electric stimulation produced unique responses in almost all ganglion cell types and the electric responses typically matched elements of the corresponding light responses. PMID- 30440900 TI - Evaluation of Time-Domain Features of Sensory ENG Signals. AB - In the development of closed-loop prostheses that record from the patient's own nerves to provide sensory feedback, it is first necessary to determine the features of sensory signals that may help to identify different sensations. The aim of this work was to investigate different time-domain features for separation of sensory electroneurographic signals. To do this, sensory signals were elicited in response to mechanical stimulation of the rat hindpaw and these signals were recorded from a cuff electrode array placed on the sciatic nerve. Thirteen features were extracted, including: mean absolute value, variance, waveform length and ten time-domain descriptors that were recently proposed for classification of electromyographic signals. These features were individually fed into a linear discriminant analysis classifier. The results showed that the best overall performing features were the mean absolute value and waveform length. Additionally, six of the ten time-domain descriptors showed a comparable performance to these two features. This indicates that these features could be used as a tool to aid our understanding of the sensory neural signals recorded and further improve classification results. Enhanced classification of electroneurographic signals will provide the opportunity to develop more efficacious sensory-motor prostheses in the future. PMID- 30440901 TI - An ERP Study on the Combined-stimulation Advantage in Vocoder Simulations. AB - Electric hearing is presently the only treatment solution for patients with profound-to-severe hearing loss. For those patients also preserving low-frequency residual hearing on the ipsilateral ear, combined electric-and-acoustic stimulation (EAS) could notably improve their speech understanding abilities relative to those aided with electric-only (E-only) hearing. Early behavioral studies have consistently shown the advantage of combined stimulation. The aim of this work was to objectively examine the advantage of combined stimulation over electric-only hearing using an oddballparadigm based event-related potential (ERP) experiment. The vowel stimulus was processed by vocoding processes simulating the E-only and EAS conditions, and the generated stimuli were presented to normal-hearing listeners in the ERP experiment. Experiment results showed that the mismatch negativity (MMN) response elicited in the combined stimulation condition featured a smaller peak amplitude and a more delayed peak latency than that in the E-only condition. The MMN results in this work demonstrated that compared with the ERP response elicited in the E-only condition, the response in the combinedstimulation condition was much closer to that elicited by the full-spectrum stimulus, yielding neurophysiological evidence on the combined-stimulation advantage. PMID- 30440902 TI - Congruent Visual Stimulation Facilitates Auditory Frequency Change Detection: An ERP Study. AB - Exploring effective methods to improve the ability of frequency change detection for normal-hearing listeners and hearing-impaired patients is important to enhance their auditory perception, particularly in noise. This work studied the effect of congruent visual stimulation on facilitating auditory frequency change detection. Specially, an event-related potential (ERP) experiment was designed to investigate the functional mechanism underlying the audiovisual integration ability. Subjects were stimulated in three types of modalities, i.e., auditory only, visual-only, and audiovisual. ERP components (e.g., N1 and P2) were compared among the three modalities. Results showed that the congruent visual stimulation significantly improved the perceptual ability of auditory frequency change detection. Compared with the other two unimodal modalities, the audiovisual modality yielded larger amplitudes in N1 and P2 components. This work provided neurophysiological evidence supporting that the ability of frequency change detection could be facilitated by the congruent visual stimulation. PMID- 30440903 TI - Neural Representation Of Harmonic Single Sideband Encoder In Inferior Colliculus Of Guinea Pigs. AB - The supplement of harmonics and temporal fine structure (TFS) information has been verified to increase the tone recognition of cochlear implants (CIs) users. However, the limited resolution of spectral and temporal in electric hearing hindered the delivery of TFS information. Harmonic single sideband encoder (HSSE) can explicitly track the harmonics of complex sounds and linearly transform harmonics into modulators conveying both amplitude modulation (AM) and TFS information to electrodes. However, it keeps urgent to develop fast, objective and quantitative methods to evaluate the TFS representation in higher level centers of auditory pathway to HSSE strategy. The study built an IC mathematical model based on spectro-temporal receptive field (STRF) by recording the vivo neural responses of inferior colliculus (IC) to a couple of original Chinese Mandarin speech and analyzing the FS representation on IC. Finally the study predicted neural response to HSSE coded speech. The results showed that the IC neuronal response evoked by HSSE coded speech contained FS information. PMID- 30440904 TI - Using Muscle Synergy to Evaluate the Neck Muscular Activities during Normal Swallowing. AB - Swallowing is an extremely complex motion controlled by multiple muscles on the front neck region. Normal swallowing is dependent on orderly activation and co coordination of the associated neck muscles, known as muscle synergy. However, evidence for muscle synergy during normal swallowing is rarely investigated. In this study, we studied the muscle synergy associated with swallowing saliva based on high-density (HD) surface electromyography (sEMG) signals acquired from four healthy subjects. The non-negative matrix factorization algorithm was applied to reconstruct the muscle activation patterns, and the values of variance accounted for (VAF) coefficients were computed to determine the number of muscle synergies. The results showed that the VAF values raised with the increase in the number of synergies on both the left and right sides of the neck. And the variation tendency of the VAF values was almost similar between the left and right area with a significant correlation ($?text{r}=0.9902 ?pm 0.0046$, $?mathrm {p}<0.05)$. Furthermore, it was observed that an average of 5 muscle synergies was the minimum number required to sufficiently reconstruct the spatial characteristics of the synergism between both sides of the neck. These results suggest that the muscle synergy approach could serve as a promising candidate to evaluate the muscular co-contractions during swallowing, and it might be a useful method for dysphagia monitoring and diagnoses. PMID- 30440905 TI - Comparison of responses of visual cortical neurons in the mouse to intraocular and extraocular electric stimulation of the retina. AB - Retinal implants offered the promise of restoring functional vision to the blind via the delivery of electrical stimulation to the retina. To enhance the efficacy of these devices, stimulation should elicit neural responses that are similar to the responses that occur naturally in the retina as these have the best chance of carrying a robust signal to visual cortex. A corollary of this is that the responses that arise in visual cortical neurons can be used to compare the effectiveness of different stimulation strategies in the retina. Here, we studied how visual cortical neurons in the mouse respond to monophasic cathodal and anodal electric stimulation delivered via a wire electrode positioned on the outer surface of the eye (extraocular) or within the vitreous cavity of the eye (intraocular). Responses of visual cortical neurons were recorded from primary visual cortex on the side contralateral to the stimulatated eye. For both stimulation modalities, response patterns consisted of a brief burst of spikes followed by a 400-500 ms period of inhibition. Both modalities also elicited stronger responses to cathodal stimuli (vs. anodal). The preferential sensitivity to cathodal stimuli is similar to that of epiretinal stimulation (anodal stimuli are more effective with sub-retinal stimulation) suggest the extraocular approach mirrors epiretinal stimulation. Extraocular stimulation also showed some response characteristics that were different from those observed in the retina, e.g., at very strong amplitudes, cathodal and anodal stimulation produced similar responses. PMID- 30440906 TI - Computational Simulation of Array-based Electroporation in the Cochlea. AB - We present a computational model for predicting electric field distributions following array-based closed-loop electroporation in the cochlea. The model geometry was reconstructed from magnetic resonance images of the guinea pig cochlea and an eight-channel electrode array embedded within this geometry. The model's electrode voltage output waveform was obtained from electric potential mapping conducted in physiological solution following constant-current stimulation using the electrode array. Our simulations predict that a tandem electrode configuration with four ganged cathodes and four ganged anodes produces a larger area in target tissue where the electric field is within the range for successful gene transfer compared to an alternate paired anode-cathode electrode configuration. These findings corroborate published in vivo evidence comparing the two configurations and support the utility of the developed model as a tool to optimize the efficacy of electroporation electrodes. PMID- 30440907 TI - Effectiveness of the RAPAEL Smart Board for Upper Limb Therapy in Stroke Survivors: A Pilot Controlled Trial. AB - We aim to assess the effectiveness of using the RAPAEL Smart Board as an assistive tool for therapists in clinical rehabilitation therapy settings and to investigate if it can be used to improve the motor recovery rate of stroke survivors. The RAPAEL Smart Board is a therapy tool where therapists actively engage patients, giving necessary verbal and physical interventions as in traditional treatment sessions. We conducted a randomized controlled study with 17 stroke survivors. An experimental group received therapy using the RAPAEL Smart Board for 30 minutes a day, 5 days per week, for 4 weeks in addition to their traditional treatments (i.e., 30 minutes of functional arm movement therapy). A control group received two 30-minute sessions of traditional treatment 5 days per week, for 4 weeks. The upper-extremity function was measured using the Wolf Motor Function Test before and after the 4-week interventions. Our results demonstrate that using the RAPAEL Smart Board, in combination with traditional treatment, significantly improves motor recovery when compared to traditional treatments alone. PMID- 30440908 TI - Effect Of Arm Deweighting Using End-Effector Based Robotic Devices On Muscle Activity. AB - Deweighting of the limb is commonly performed for patients with a neurological injury, such as stroke, as it allows these patients with limited muscle activity to perform movements. Deweighting has been implemented in exoskeletons and other multi-contact devices, but not on an end-effector based device with single contact point between the assisting robot and the human limb being assisted. This study inves-tigates the effects of deweighting using an end-effector based device on healthy subjects. The muscle activity of five subjects was measured in both static postures and dynamic movements. The results indicate a decrease in the activity of muscles which typically act against gravity - such as the anterior deltoid and the biceps brachii - but also suggest an increase in activity in muscles which act with gravity - such as the posterior deltoid and the lateral triceps. This can be explained by both the change in required muscle-generated torques and a conscious change in approach by the participants. These observations have implications for neurorehabilitation, particularly with respect to the muscle activation patterns which are trained through rehabilitation exercises. PMID- 30440909 TI - Effect of Pelvic Movement on Healthy Subjects During Gait Training Using a Gait Rehabilitation System. AB - Rapidly aging society faces with increases in neurological disorders including stroke. Hemiplegia, which is one of the common sequelae due to stroke, causes difficulties in activities of daily living. As the number of stroke patients grows, demands for gait training increases, where robotic gait training systems are necessary. A robotic gait training system, called "COWALK-I," is designed to provide pelvic motion on the transverse plane as well as leg motions in the sagittal plane during gait training sessions. The pelvic motion allows weight shifting as well as more natural gait patterns during gait training. In this research, effect of the pelvic motion during waking in the COWALK-I system is studied. Interaction force between the healthy subjects and the COWALK-I and electromyography(EMG) sensor data are measured. The average interaction forces did not show significant difference while each subject exhibited diverse patterns. The EMG signals shows that more activation of rectus femoris and less activation of gastrocnemius and gluteus medius. PMID- 30440910 TI - The effect of myoelectric computer interface training on arm kinematics and function after stroke. AB - Abnormal co-activation patterns of arm muscles is a substantial cause of impaired arm function after stroke. We designed a myoelectric computer interface (MCI) training paradigm to help stroke survivors reduce this abnormal coactivation. Here, we evaluated the effects of MCI training on function and arm kinematics in 32 chronic stroke survivors. We compared the effects of training duration and isometric vs. movement-based training conditions in 3 different groups. All groups reduced abnormal co-activation in targeted muscles, and showed reduced arm impairment after 6 weeks of training. They also showed improvements in arm kinematics as well as functional scores. Moreover, the gains persisted, though most were reduced, at one month after training stopped. These results suggest that MCI training holds promise to improve arm function after stroke. PMID- 30440911 TI - Speaking Ability while Using an Inductive Tongue-Computer Interface for Individuals with Tetraplegia: Talking and Driving a Powered Wheelchair - a Case Study. AB - This paper assesses the ability of speaking while using an inductive tongue computer interface. Lately, tongue- computer interfaces have been proposed for computer/robotic interfacing for individuals with tetraplegia. To be useful in home settings these interfaces should be aesthetic and interfere as little as possible with the limited preserved functionality of individuals with tetraplegia. As tongue interfaces from an aesthetical point of view are preferred to be entirely intra-oral it is relevant to address their effect on speech. Here we show that reading more than 566 words while using an inductive tongue-computer interface results in a maximum sensor activation time of less than 0.6 s, which means that false activations can be avoided by a sensor dwell time of 0.6 s. Furthermore, we show that it is possible to speak while controlling a powered wheelchair with the inductive tongue computer interface. PMID- 30440912 TI - The Effects of Lower Body Positive Pressure Treadmill Training on Dynamic Balance of Children with Cerebral Palsy. AB - We aimed to characterize the therapeutic effects of Anti-gravity (AlterG) body weight supported treadmill training on the impaired balance of children with cerebral palsy (CP). Four spastic CP children participated; two received AlterG training 3 times a week for 8 weeks and the other two received typical occupational therapy accordingly. Their dynamic balance was evaluated before the start of the treatment and 2 months after it. Features related to the center of pressure (COP) and the center of mass (COM) were considered as dynamic balance parameters. Our results showed that the maximum velocity and acceleration of the COP and COM, the average variability (RMS) and peak to peak of the COM-COP separation, and RMS of velocity and acceleration of the COM and COP were all improved for both AlterG training patients (15-90%), though there was a limited improvement of 0.2-24% in some features of the control patients. Our results demonstrate that intensive sessions of the AlterG training program could have the potential to be used as a therapeutic tool that can produce dynamic balance improvements in CP children compared to that of typical occupational therapy. PMID- 30440913 TI - The Effects of Low Frequency Repetitive Transcranial Magnetic Stimulation on White Matter Structural Connectivity in Children with Cerebral Palsy. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive treatment technique for recovery of movement disorders by altering cortical plasticity. In this research, we studied the effects of low-frequency rTMS on white matter (WM) structural connectivity and clinical parameters in children with cerebral palsy (CP).,Four spastic hemiplegic CP children were randomly divided into experimental and control groups. In the experimental group, at first, 1Hz rTMS treatment was performed 4 days/week for 3 weeks on two hemiplegia patients over a contralesional primary motor cortex (M1). Then, 1Hz rTMS treatment was performed 4 days/week for 3 weeks followed by a 30min occupational therapy (OT). In the control group, two CP children received sham rTMS for 3 weeks and then sham rTMS combined with OT for 3 weeks in the same schedule as the experimental group. Evaluations performed using diffusion tensor imaging (DTI), and clinical measurements of gait performance before and after the treatment. Graph theoretical analysis was used to characterize topological changes of structural connectivity. Our findings demonstrate the 1Hz rTMS is effective in improving motor activity in spastic hemiplegic CP children, and is more effective when combined with OT. PMID- 30440914 TI - Assessment of neuroplasticity of corticospinal tract induced by antigravity treadmill (AlterG) in cerebral palsy children. AB - The aim of this study was to assess neuroplasticity that occurred in the corticospinal tract (CST) following antigravity treadmill (AlterG) training. AlterG can facilitate walking by having up to an 80% reduction of weight-bearing in patients. Systematic and intensive gait training for sufficient periods of time may lead to neuroplasticity and walking capacity improvement. AlterG gait training was done for eight weeks, 3 sessions per week, and 45 minutes each session. Three cerebral palsy (CP) children participated in this study. The function and structure of CST on the brain's more affected side were evaluated using Transcranial Magnetic Stimulation (TMS) and Diffusion Tensor Imaging (DTI). Also, some common clinical tests were performed to evaluate walking capacity and endurance. DTI features such as fractional anisotropy (FA) and mean diffusivity (MD) as well as some TMS features were extracted to estimate structural changes of the CST. The evaluations were performed before and after 8week AlterG training. The results showed an improvement in the DTI metrics of the CST following AlterG training. Also, TMS parameters were improved and these changes in CST function and structure were concurrent with changes in walking capacity. These results suggest that AlterG training can be used as a therapeutic tool to provide an effective and persistent gait improvement in CP children. PMID- 30440915 TI - The impact of AlterG training on balance and structure of vestibulospinal tract in cerebral palsy children. AB - We aimed to investigate the effects of an antigravity treadmill (AlterG) on the balance and structure of the vestibulospinal tract. The AlterG can reduce the weightbearing of patients and hence can facilitate their locomotion. Three children with cerebral palsy (CP) received AlterG training three days per week for eight weeks with each session lasting 45 minutes. The balance of children was evaluated using the Berg balance test and the Timed Up and Go (TUG) test. The diffusion tensor imaging (DTI) method was employed to quantify changes of the structure of the vestibulospinal tract. Evaluations were performed before and after the 8-week training. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were measured to evaluate the vestibulospinal tract structure. The results showed that the mean FA of the vestibulospinal tract increased and other metrics decreased for all subjects. Our findings indicated that the balance and structure of the vestibulospinal tract were improved up to 30% for all children following the 8 week AlterG training. This indicates that the balance improvement of the CP children following the AlterG training was accompanied with persistent neuroplasticity in their brain. The clinical implication is that the AlterG training has a potential to be used as an effective therapeutic tool for the treatment of balance impairment in CP children. PMID- 30440916 TI - Relative Efficacy of Sensor Modalities for Estimating Post-Stroke Motor Impairment. AB - Wearable inertial sensing has been beneficial in the development of measures of motor impairment after stroke. While most early work focused on the use of accelerometry, recent work has increasingly shown that rate gyroscopes may provide complementary information. Differences in performance of accelerometers and gyroscopes in activity recognition may be due to the nature of the impairment. The current approach seeks to investigate the relative sensitivity of these sensor modalities to impairment by evaluating their classification accuracy for tasks adapted from the Fugl-Meyer Assessment. Our findings indicated that, for upper-extremity motion, classifiers trained using a combination of accelerometer and rate gyroscope data performed the best (accuracy of 73.1%). Classifiers trained using accelerometer data alone and rate gyroscope data alone performed slightly worse than the combined data classifier (70.2% and 65.7%, respectively). PMID- 30440917 TI - Energetics during robot-assisted training predicts recovery in stroke. AB - Clinical investigators have asserted patients should be active participants in the therapy process in stroke rehabilitation. While robotics introduces new tools for measurement and treatment of motor impairments, it also presents challenges for evaluating how much a patient contributes to observed movements during training. Our approach employs established methods of inverse dynamics combined with measurements of human motion and interaction forces between the human and robot. Here, we investigated whether measures of patient active involvement predict the level of upper limb recovery due to robot-assisted therapy. Stroke survivors (n=11) completed "exploration" training with customizable forces that increased their velocities (i.e., negative damping). While our results showed a mild trend between mechanical work during training and expanded velocity capability (Pearson r = 0.57), we found significant correlations with the amount of positive work (i.e., propulsion; r = 0.77), but not negative work (i.e., braking; r = 0.41). This work supports robotic tools that encourage more positive work. PMID- 30440918 TI - Feature Learning in Assistive Rehabilitation Robotic Systems. AB - Feature learning plays a crucial role in data analysis when the measured data is in a high dimensional space. This paper applied the feature learning technique in data set collected from human movement experiments in an upper limb rehabilitation robotic device. The results showed that the proposed feature learning technique can identify key features to characterize the upper limb movements of humans, even though human variations exist. Four representative features were obtained out of 72 statistic features with very good prediction performance. In future, this feature learning technique can be used in building the link between the movement quality measured from robotic device to the well known clinic measurements. PMID- 30440919 TI - Real-time Electromyography-driven Functional Electrical Stimulation Cycling System for Chronic Stroke Rehabilitation. AB - Stroke-induced lower extremity dysfunction has become a severe medical problem nowadays and effective rehabilitation methods are in great demand. In this work, a new real-time Electromyography-driven Functional Electrical Stimulation (FES) cycling system was developed to help chronic stroke patients with lower limb rehabilitation training. To evaluate the feasibility and effectiveness of this system, 3 chronic stroke subjects were recruited and each received 20 training sessions where real-time Electromyography (EMG) was used to interact with the cycling system. During the training, two typical metrics, averaged Area Under Torque (AUT) and maximal EMG amplitude, were adopted to measure the muscle strength changes of hamstring (HS). The training results showed that the two measurements of HS both significantly increased, especially the maximal EMG amplitude in the last trial was twice as much as that in the first trial, indicating paretic limb strength increment and functional recovery, which suggested that our system is effective and helpful in the stroke rehabilitation. PMID- 30440920 TI - Directly Measuring the Rate of Slacking as Stroke Survivors produced Isometric Forces during a Tracking Task. AB - Slacking limits the rehabilitative effectiveness of certain exercises following stroke. When patients receive assistance during an exercise, they exhibit a persistent tendency to reduce their own contribution to that exercise. This phenomenon was first coined 'slacking' in the context of robot-mediated therapy, where controller design continues to involve prediction and mitigation of slacking. In this pilot study, 14 individuals in the chronic stage of stroke participated in a visuomotor tracking task during which they produced isometric grip forces. Visual feedback displayed on a monitor helped participants track eight distinct forces ranging effort level from 4 to 30% maximum voluntary contraction (MVC). A specialized method of toggling between veridical and nonveridical visual feedback isolated each participant's realtime slacking rate at each of the eight effort levels, with both their contralesional and ipsilesional hand. Below 10-15% MVC, participants did not slack. At higher effort levels, participants slacked, and their slacking rate increased non-linearly with effort. Slacking took the form of smooth reductions in grip force. On average, across participants, slacking rates were remarkably similar between hands, just marginally faster with the contralesional hand. However, individualized slacking rates varied from almost zero to approximately double the acrossparticipant average. The paradigm for measuring slacking rate, used here, might be incorporated into robot-mediated therapy to maintain an accurate, individualized estimate of a patient's slacking rate at various force levels and ensure the robot provides assistance only as needed. PMID- 30440921 TI - The Impact of Repetitive Transcranial Magnetic Stimulation on Affected and Unaffected Sides of a Child with Hemiplegic Cerebral Palsy. AB - The purpose of this study was to investigate the therapeutic effects of neuro navigated repetitive transcranial magnetic stimulation (rTMS) combined with occupational therapy (OT) on gait impairment of a child (male, age: 13.2) with spastic hemiplegic cerebral palsy (CP). The treatment included 4 days a week of rTMS sessions for 3 weeks and 4 days of rTMS and OT sessions per week for 3 weeks. Transcranial magnetic stimulation (TMS) was used to evaluate corticospinal tract (CST) activities and H-reflex test was used to assess reflex hyper excitability. Common clinical tests demonstrate the clinical status of the patient. Evaluations were performed in 4 time steps: baseline, 3 weeks after the beginning of the treatment, at the end of the treatment, and 1 month after the end of the treatment. The patient did not receive any specific treatment after the end of the treatment up to the follow up evaluations. The tests' results were compared between the affected and unaffected legs of the patient. Four parameters of the TMS test were calculated (motor evoked potential (MEP) latency, MEP peak to-peak amplitude, cortical silent period (cSP), and stimulation intensity). These parameters were all improved for the affected side and cSP improved for the unaffected side, but MEP p-p amplitude and intensity got worse slightly for the unaffected side. Recruitment curves of H response and M-wave of the H-reflex test for both sides were obtained. Improvements could be seen after the treatment for both sides. Max H response on max M-wave (H/M) and H response latency got better after the treatment for both sides. Walking speed for self and fast velocity, timed up and go, and walking endurance improved during and after the treatment. All the improvements persisted after one month of the end of the treatment in the follow up evaluations. These findings indicate that rTMS combined with OT can have effective and long-lasting impact on neuromuscular impairments in spastic CP children. PMID- 30440922 TI - Enhancement of cortical activation for motor imagery during BCI-FES training. AB - Brain-computer Interfaces (BCIs) provide a direct pathway between the brain and the outward environment. Specifically, motor imagery (MI)-based BCI controlling functional electric stimulation (FES) is a promising approach for disabled patients with intact mind to restore or rehabilitate their motor functions. This study probed for the improvement of cortical activation for motor imagery during the closed-loop BCI-FES training. We used electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to inspect the cortical activation for four different training strategies, i.e. MI-BCI-FES, MI-FES, MI and FES. Compared with the other three training conditions, the MI-BCI-FES could achieve stronger cortical activation viewing from the event-related desynchronization (ERD) and the blood oxygen response. The results demonstrate that the closed-loop MI training using BCI-FES can prospectively increase the cortical activation of motor cortical areas. PMID- 30440923 TI - Enhancing Detection of SSVEPs with Intermodulation Frequencies Using Individual Calibration Data. AB - Steady-state visual evoked potential (SSVEP)-based brain-computer interfaces (BCIs) have potential to realize high-speed communication between human brain and external devices. Recently, we proposed an intermodulation frequency-based stimulation approach to increase the number of visual stimuli that can be presented on a computer monitor. Although our recent studies have demonstrated that this approach can encode more visual stimuli by only one flickering frequency, the performance of the intermodulation frequency-based SSVEP BCI remains poor and needs further improvement. This study aims to incorporate filter bank analysis and individual SSVEP calibration data into canonical correlation analysis (CCA) to improve the detection of SSVEPs with intermodulation frequencies. Results on classification accuracy and information transfer rate (ITR) suggest that the employment of individual calibration data can significantly improve the performance of the intermodulation frequency-based SSVEP BCI. PMID- 30440924 TI - EEG Data Augmentation for Emotion Recognition Using a Conditional Wasserstein GAN. AB - Due to the lack of electroencephalography (EEG) data, it is hard to build an emotion recognition model with high accuracy from EEG signals using machine learning approach. Inspired by generative adversarial networks (GANs), we introduce a Conditional Wasserstein GAN (CWGAN) framework for EEG data augmentation to enhance EEG-based emotion recognition. A Wasserstein GAN with gradient penalty is adopted to generate realistic-like EEG data in differential entropy (DE) form. Three indicators are used to judge the qualities of the generated high-dimensional EEG data, and only high quality data are appended to supplement the data manifold, which leads to better classification of different emotions. We evaluate the proposed CWGAN framework on two public EEG datasets for emotion recognition, namely SEED and DEAP. The experimental results demonstrate that using the EEG data generated by CWGAN significantly improves the accuracies of emotion recognition models. PMID- 30440925 TI - Neural Decoding Forelimb Trajectory Using Evolutionary Neural Networks with Feedback-Error-Learning Schemes. AB - Changes in the functional mapping between neural activities and kinematic parameters over time poses a challenge to current neural decoder of brain machine interfaces (BMIs). Traditional decoders robust to changes in functional mappings required many day's training data. The decoder may not be robust when it was trained by data from only few days. Therefore, a decoder should be trained to handle a variety of neural-to-kinematic mappings using limited training data. We proposed an evolutionary neural network with error feedback, ECPNN-EF, as a neural decoder, that considered the previous error as an input to the decoder in order to improve the robustness. The decoder was validated to reconstruct rat's forelimb movement in a water-reward lever-pressing task. Two days of data were only used to train the decoder while ten days of data were used to test the decoder. The results showed that the performance of ECPNN-EF was significantly higher than that of standard recurrent neural network without error feedback, which was commonly used in BMI. This suggested that ECPNN-EF trained with few days of training data can be robust to changes in functional mappings. PMID- 30440926 TI - Analyzing P300 Distractors for Target Reconstruction. AB - P300-based brain-computer interfaces (BCIs) are often trained per-user and per application space. Training such models requires ground truth knowledge of target and nontarget stimulus categories during model training, which imparts bias into the model. Additionally, not all non-targets are created equal; some may contain visual features that resemble targets or may otherwise be visually salient. Current research has indicated that non-target distractors may elicit attenuated P300 responses based on the perceptual similarity of these distractors to the target category. To minimize this bias, and enable a more nuanced analysis, we use a generalized BCI approach that is fit to neither user nor task. We do not seek to improve the overall accuracy of the BCI with our generalized approach; we instead demonstrate the utility of our approach for identifying targetrelated image features. When combined with other intelligent agents, such as computer vision systems, the performance of the generalized model equals that of the user specific models, without any user specific data. PMID- 30440927 TI - Spike Rate Estimation Using Bayesian Adaptive Kernel Smoother (BAKS) and Its Application to Brain Machine Interfaces. AB - Brain Machine Interfaces (BMIs) mostly utilise spike rate as an input feature for decoding a desired motor output as it conveys a useful measure to the underlying neuronal activity. The spike rate is typically estimated by a using non-overlap binning method that yields a coarse estimate. There exist several methods that can produce a smooth estimate which could potentially improve the decoding performance. However, these methods are relatively computationally heavy for real time BMIs. To address this issue, we propose a new method for estimating spike rate that is able to yield a smooth estimate and also amenable to real-time BMIs. The proposed method, referred to as Bayesian adaptive kernel smoother (BAKS), employs kernel smoothing technique that considers the bandwidth as a random variable with prior distribution which is adaptively updated through a Bayesian framework. With appropriate selection of prior distribution and kernel function, an analytical expression can be achieved for the kernel bandwidth. We apply BAKS and evaluate its impact on offline BMI decoding performance using Kalman filter. The results reveal that BAKS can improve the decoding performance compared to the binning method. This suggests the feasibility and the potential use of BAKS for real-time BMIs. PMID- 30440928 TI - Premature Ventricular Contraction Detection from Ambulatory ECG Using Recurrent Neural Networks. AB - Premature ventricular contraction (PVC) is usually considered to as benign arrhythmia in the absence of structural heart diseases. However, frequent premature beats may significantly increase the risk of heart failure and even death by an arrhythmia-induced cardiomyopathy. Therefore, high PVC counts have been considered as an approach to predict the risk of severe arrhythmias. Progress of wearable devices provides a convenient tool for the detection of premature contraction in casual life. Considering the huge quantities of data recorded by wearable devices, reliable and low-cost data analysis programs should be developed for real time PVC detection. In this research, we use recurrent neural networks with, long short-term memory to detect PVC. Through validating with MIT-BIH arrhythmia database, the detection accuracy of this method is 96% 99%. PMID- 30440929 TI - Bidirectional Recurrent Neural Network And Convolutional Neural Network (BiRCNN) For ECG Beat Classification. AB - We propose a novel electrocardiogram (ECG) beat classification algorithm using a combination of Bidirectional Recurrent Neural Network (BiRNN) and Convolutional Neural Network (CNN) named as BiRCNN. Our model is an end-to-end model. The morphological features of each ECG beat is extracted by CNN. Then the features of each beat are considered in the context via BiRNN. The assessment on MIT-BIH Arrhythmia Database (MITDB) resulted in a sensitivity of 98.7% and a positive predictivity of 96.4% on average for the VEB class. For the SVEB class, the sensitivity was 92.8%, which was an over 6% promotion compared with the state-of the-art method, and the positive predictivity was 81.9% on average. The results demonstrate the superior classification performance of our method. PMID- 30440930 TI - Region Aggregation Network: Improving Convolutional Neural Network for ECG Characteristic Detection. AB - Detection of ECG characteristic points serves as the first step in automated ECG analysis techniques. We propose a novel end-to-end deep learning scheme called Region Aggregation Network (RAN) for ECG characteristic points de- tection. A 1D Convolutional Neural Network (CNN) is adopted to automatically process ECG signals. A novel strategy of Region Aggregation is proposed to replace the conventional fully connected layer as regressor. Our work provides robust and accurate detection performance on public ECG database. The evaluation results of our method on QT database show comparable detection accuracy compared with state of-the-art works. PMID- 30440931 TI - A Novel Deep Learning based Neural Network for Heartbeat Detection in Ballistocardiograph. AB - Ballistocardiography (BCG) is a revamped technology for cardiac function monitoring. Detecting individual heart beats in BCG remains a challenging task due to various artifacts and low signal-to-noise ratio, which are not well addressed by conventional approaches based on intuitive observations of BCG waveforms. In this paper, we propose to employ deep learning networks to capture the characteristics of the variations of BCG waveforms within and across individual subjects. Particularly, we design a neural network that combines Convolutional-Neural-Network (CNN) and Extreme Learning Machine (ELM). We test the new learning method on a real BCG data set and show better detection result compared with a state-of-the-art method. We demonstrate how the advanced machine learning technology can learn and detect BCG waveforms robustly. PMID- 30440932 TI - Real-Time Cardiac Arrhythmia Classification Using Memristor Neuromorphic Computing System. AB - Cardiac arrhythmia is known to be one of the most common causes of death worldwide. Therefore, development of efficient arrhythmia detection techniques is essential to save patients' lives. In this paper, we introduce a new real-time cardiac arrhythmia classification using memristor neuromorphic computing system for classification of 5 different beat types. Neuromorphic computing systems utilize new emerging devices, such as memristors, as a basic building block. Hence, these systems provide excellent trade-off between real-time processing, power consumption, and overall accuracy. Experimental results showed that the proposed system outperforms most of the methods in comparison in terms of accuracy and testing time, since it achieved 96.17% average accuracy and 34 ms average testing time per beat. PMID- 30440933 TI - A Generative Modeling Approach to Limited Channel ECG Classification. AB - Processing temporal sequences is central to a variety of applications in health care, and in particular multichannel Electrocardiogram (ECG) is a highly prevalent diagnostic modality that relies on robust sequence modeling. While Recurrent Neural Networks (RNNs) have led to significant advances in automated diagnosis with time-series data, they perform poorly when models are trained using a limited set of channels. A crucial limitation of existing solutions is that they rely solely on discriminative models, which tend to generalize poorly in such scenarios. In order to combat this limitation, we develop a generative modeling approach to limited channel ECG classification. This approach first uses a Seq2Seq model to implicitly generate the missing channel information, and then uses the latent representation to perform the actual supervisory task. This decoupling enables the use of unsupervised data and also provides highly robust metric spaces for subsequent discriminative learning. Our experiments with the Physionet dataset clearly evidence the effectiveness of our approach over standard RNNs in disease prediction. PMID- 30440934 TI - Classification Of Skin Lesions Using An Ensemble Of Deep Neural Networks. AB - Skin cancer is among the deadliest variants of cancer if not recognized and treated in time. This work focuses on the identification of this disease using an ensemble of state-of-the-art deep learning approaches. More specifically, we propose the aggregation of robust convolutional neural networks (CNNs) into one neural net architecture, where the final classification is achieved based on the weighted output of the member CNNs. Since our framework is realized within a single neural net architecture, all the parameters of the member CNNs and the weights applied in the fusion can be determined by backpropagation routinely applied for such tasks. The presented ensemble consists of the CNNs AlexNet, VGGNet, GoogLeNet, all of which have been won in subsequent years the most prominent worldwide image classification challenge ImageNet. For an objective evaluation of our approach, we have tested its performance on the official test database of the IEEE International Symposium on Biomedical Imaging (ISBI) 2017 challenge on Skin Lesion Analysis Towards Melanoma Detection dedicated to skin cancer recognition. Our experimental studies show that the proposed approach is competitive in this field. Moreover, the ensemble-based approach outperformed all of its member CNNs. PMID- 30440935 TI - Using Octuplet Siamese Network For Osteoporosis Analysis On Dental Panoramic Radiographs. AB - Dental Panoramic radiography (DPR) image provides a potentially inexpensive source to evaluate bone density change through visual clue analysis on trabecular bone structure. However, dense overlapping of bone structures in DPR image and scarcity of labeled samples make learning of accurate mapping from DPR patches to osteoporosis condition challenging. In this paper, we propose a deep Octuplet Siamese Network (OSN) to learn and fuse discriminative features for osteoporosis condition prediction using multiple DRP patches. By exploring common features, OSN uses patches of eight locations together to train the shared feature extractor. Feature fusion for different location adopts both accumulation and concatenation with fully considering of patches' spatial symmetry. In our dedicated two-stage fine-tuning scheme, an augmented texture analysis dataset is employed to prevent overfitting in transferring weights learned on ImageNet to DPR dataset when using merely 108 samples. Leave-one-out test shows that our proposed OSN outperforms all other state of the art methods in osteoporosis category classification task. PMID- 30440936 TI - Unsupervised Deep Learning Features for Lung Cancer Overall Survival Analysis. AB - Lung cancer overall survival analysis using computed tomography (CT) images plays an important role in treatment planning. Most current analysis methods involve hand-crafted image features for survival time prediction. However, hand-crafted features require domain knowledge and may lack specificity to lung cancer. Advanced self-learning models such as deep learning have showed superior performance in many medical image tasks, but they require large amount of data which is difficult to collect for survival analysis because of the long follow-up time. Although data with survival time is difficult to acquire, it is relatively easy to collect lung cancer patients without survival time. In this paper, we proposed an unsupervised deep learning method to take advantage of the unlabeled data for survival analysis, and demonstrated better performance than using hand crafted features. We proposed a residual convolutional auto encoder and trained the model using images from 274 patients without survival time. Afterwards, we extracted deep learning features through the encoder model, and constructed a Cox proportional hazards model on 129 patients with survival time. The experiment results showed that our unsupervised deep learning feature gained better performance (C-Index = 0.70) than using hand-crafted features (C-Index = 0.62). Furthermore, we divided the patients into two groups according to their Cox hazard value. Kaplan-Meier analysis indicated that our model can divide patients into high and low risk groups and the survival time of these two groups had significant difference (p < 0.01). PMID- 30440937 TI - Transfer Representation Learning using Inception-V3 for the Detection of Masses in Mammography. AB - Breast cancer is the most prevalent cancer among women. The most common method to detect breast cancer is mammography. However, interpreting mammography is a challenging task that requires high skills and is timeconsuming. In this work, we propose a computer-aided diagnosis (CAD) scheme for mammography based on transfer representation learning using the Inception-V3 architecture. We evaluate the performance of the proposed scheme using the INBreast database, where the features are extracted from different layers of the architecture. In order to cope with the small dataset size limitation, we expand the training dataset by generating artificial mammograms and employing different augmentation techniques. The proposed scheme shows great potential with a maximal area under the receiver operating characteristics curve of 0.91. PMID- 30440938 TI - Controlled Synthesis of Dermoscopic Images via a New Color Labeled Generative Style Transfer Network to Enhance Melanoma Segmentation. AB - Dermoscopic imaging is an established technique to detect, track, and diagnose malignant melanoma, and one of the ways to improve this technique is via computer aided image segmentation. Image segmentation is an important step towards building computerized detection and classification systems by delineating the area of interest, in our case, the skin lesion, from the background. However, current segmentation techniques are hard pressed to account for color artifacts within dermoscopic images that are often incorrectly detected as part of the lesion. Often there are few annotated examples of these artifacts, which limits training segmentation methods like the fully convolutional network (FCN) due to the skewed dataset. We propose to improve FCN training by augmenting the dataset with synthetic images created in a controlled manner using a generative adversarial network (GAN). Our novelty lies in the use of a color label (CL) to specify the different characteristics (approximate size, location, and shape) of the different regions (skin, lesion, artifacts) in the synthetic images. Our GAN is trained to perform style transfer of real melanoma image characteristics (e.g. texture) onto these color labels, allowing us to generate specific types of images containing artifacts. Our experimental results demonstrate that the synthetic images generated by our technique have a lower mean average error when compared to synthetic images generated using traditional binary labels. As a consequence, we demonstrated improvements in melanoma image segmentation when using synthetic images generated by our technique. PMID- 30440939 TI - Heart Rate Estimation using Hermite Transform Video Magnification and Deep Learning. AB - Monitoring of heart rate can be used in many medical and sports applications. Lack of portability and connection problems make traditional monitoring methods difficult to use outside of clinical environments. The computer vision techniques have been shown that some physiological variables as heart rate can be measured without contact. Video magnification is one of these approach used for the detection of the pulse signal. In this paper we propose a new strategy to magnify motion in a video sequence using the Hermite transform. In addition a deep learning technique is implemented to estimate the beat by beat pulse signal. We trained the system and validated our results using an electronic pulse monitoring device. Our approach is compared with the classical video magnification using a Gaussian pyramid. The results show a better enhancement of spectral information from the colour changes allowing an accurate estimation of the instantaneous beat by beat pulse than the Gaussian approach. PMID- 30440940 TI - Fetal MRI Synthesis via Balanced Auto-Encoder Based Generative Adversarial Networks. AB - Machine learning approaches for image analysis require large amounts of training imaging data. As an alternative, the use of realistic synthetic data reduces the high cost associated to medical image acquisition, as well as avoiding confidentiality and privacy issues, and consequently allows the creation of public data repositories for scientific purposes. Within the context of fetal imaging, we adopt an auto-encoder based Generative Adversarial Network for synthetic fetal MRI generation. The proposed architecture features a balanced power of the discriminator against the generator during training, provides an approximate convergence measure, and enables fast and robust training to generate high-quality fetal MRI in axial, sagittal and coronal planes. We demonstrate the feasibility of the proposed approach quantitatively and qualitatively by segmenting relevant fetal structures to assess the anatomical fidelity of the simulation, and performing a clinical verisimilitude study distinguishing the simulated data from the real images. The results obtained so far are promising, which makes further investigation on this new topic worthwhile. PMID- 30440941 TI - A Two-Level Food Classification System For People With Diabetes Mellitus Using Convolutional Neural Networks. AB - Accurate estimation of food's macronutrient content for people with Diabetes Mellitus (DM) is of great importance, as it determines postprandial insulin dosage. This paper introduces a classification system for food images that is adjusted to the nutritional needs of people with DM. A two-level image classification scheme, exploiting Convolutional Neural Networks (CNNs), is proposed, in order to classify an image in one of eight broad food categories with similar macronutrient content and then assign it to a specific food within that category. To this end, a visual dataset, namely NTUA-Food 2017, has been designed, consisting of 3248 images organized in eight broad food categories of totally 82 different foods. Moreover, a novel evaluation metric is proposed, which penalizes classification errors proportionally to the discrepancy in postprandial blood sugar levels between the actual and predicted class. The proposed system achieves 84.18% and 85.94% classification accuracy at the first and second level of classification, respectively, on the NTUA-Food 2017 dataset. The algorithm developed for the first level of classification on the NTUA-Food 2017 dataset improves classification accuracy on the benchmark Food Image Dataset (FID) to 97.08% outperforming previous approaches. The algorithm's mean error in terms of carbohydrate content estimation on the NTUA-Food 2017 dataset is less than 2 g per food serving. PMID- 30440942 TI - The Analysis of Temperature Changes of the Saliva Traces Left on the Fur During Laboratory Rats Soial Contacts. AB - Automatic analysis of complex rodent social behavior, especially aggressive ones, is of important scientific interest. In this paper we analyze the properties of the data created as a result of aggressive rodent social behavior. Detection of specific aggressive behaviors is based on the event of leaving traces of saliva on the fur of the attacked individual, which are clearly visible in the thermal imaging. The traces change temperature in time in a specific way. After bite, saliva is cooled and then heated to the body temperature. Usage of this method in social behavior analysis ensures detection and tracking aggressive behaviors even if the event itself is invisible. PMID- 30440944 TI - A Convolutional Neural Network Based Auto-Positioning Method For Dental Arch In Rotational Panoramic Radiography. AB - Dental panoramic radiography (DPR), a widely used medical examination method, has its intrinsic weakness in high requirement to the positioning of patient. Although positioning devices like chin support can provide a relatively stable and guaranteed environment for exposure, problems including morphological differences of jaw between patients and their improper standing postures still put the reconstructed image at high risk of getting blurred, especially in the anterior segment of dental arch. This paper proposes a novel method based on convolutional neural network (CNN) to estimate the positioning error of patient's dental arch, and thereby reconstruct the panoramic image with the corrected dental curvature, so that the blur gets reduced. Experiment results demonstrate the method's effectiveness in providing reconstructed images of stable quality for further diagnosis. PMID- 30440943 TI - MARBLES - Metal Artifact Based Landmark Enhanced Susceptibility Weighted Imaging For Interventional Device Localization In MRI. AB - Susceptibility Weighted Imaging (SWI) is a method extensively studied for its application to improve contrast in MR imaging modality. The method enhances the visualization of magnetically susceptible content such as iron, calcium and zinc in the tissues by using the susceptibility differences in tissues to generate a unique image contrast. In this study, we propose an SWI based approach to improve the visualization of interventional devices in MRI data. Results obtained from two datasets (biopsy needle and brachytherapy seeds), indicate SWI to be suitable for visualization of the interventional devices, while also being computationally faster when compared with quantitative susceptibility mapping (QSM). PMID- 30440945 TI - Estimation of Neural Inputs and Detection of Saccades and Smooth Pursuit Eye Movements by Sparse Bayesian Learning. AB - Eye movements reveal a great wealth of information about the visual system and the brain. Therefore, eye movements can serve as diagnostic markers for various neurological disorders. For an objective analysis, it is crucial to have an automatic and robust procedure to extract relevant eye movement parameters. An essential step towards this goal is to detect and separate different types of eye movements such as fixations, saccades and smooth pursuit. We have developed a model-based approach to perform signal detection and separation on eye movement recordings, using source separation techniques from sparse Bayesian learning. The key idea is to model the oculomotor system with a state space model and to perform signal separation in the neural domain by estimating sparse inputs which trigger saccades. The algorithm was evaluated on synthetic data, neural recordings from rhesus monkeys and on manually annotated human eye movement recordings with different smooth pursuit paradigms. The developed approach shows a high noise-robustness, provides saccade and smooth pursuit parameters, as well as estimates of the position, velocity and acceleration profiles. In addition, by estimating the input to the oculomotor system, we obtain an estimate of the neural inputs to the oculomotor muscles. PMID- 30440946 TI - Extraction of Muscle Synergies in Spinal Cord Injured Patients. AB - Muscle synergies encode motor activity as a linear superposition of multiple motor units composed of a temporal command exciting a specific network of muscles. This study examines muscle synergies derived from simple standing studies of a complete spinal cord injury (SCI) patient under epidural spinal stimulation. A popular technique for extracting these synergies from EMG data is non-negative matrix factorization (NNMF). However, standard NNMF algorithms do not allow for physiological delays for a neural signal to reach different muscles. These delays are prevalent in SCI patients under spinal stimulation, and so we propose a new algorithm (regularized ShiftNMF) to extract muscle synergies which account for signal delays. We find muscle synergies extracted by the regularized ShiftNMF algorithm are significantly better at reconstructing EMG activity, and the resulting features are physiologically consistent and more useful in describing patient behavior. PMID- 30440947 TI - Independent Component Analysis for Fully Automated Multi-Electrode Array Spike Sorting. AB - In neural electrophysiology, spike sorting allows to separate different neurons from extracellularly measured recordings. It is an essential processing step in order to understand neural activity and it is an unsupervised problem in nature, since no ground truth information is available. There are several available spike sorting packages, but many of them require a manual intervention to curate the results, which makes the process time consuming and hard to reproduce. Here, we focus on high-density Multi-Electrode Array (MEA) recordings and we present a fully automated pipeline based on Independent Component Analysis (ICA). While ICA has been previously investigated for spike sorting, it has never been compared with fully automated state-of-the-art algorithms. We use realistic simulated datasets to compare the spike sorting performance in terms of complexity, signal to-noise ratio, and recording duration. We show that an ICA-based fully automated spike sorting approach can be a viable alternative approach due to its precision and robustness, but it needs to be optimized for time constraints and requires sufficient density of electrodes to cover active neurons in the proximity of the MEA. PMID- 30440948 TI - An Information-Theoretic Measure of Multiscale Causality for Spike-Field Activity. AB - Simultaneous recordings of spikes and fields could enable analyses of functional connectivity in the brain at multiple spatiotemporal scales. However, these analyses require developing novel methods to assess causality between binary valued spikes and continuous-valued fields, which have fundamentally different statistical profiles and time-scales. Thus classical measures of causality cannot be directly applied in multiscale networks. We develop a novel parametric method to assess causality for multiscale spike-field activities by computing directed information. Directed information is an information theoretic measure of causality but is in general hard to estimate. Our method estimates the causality in two steps. First, we construct point process generalized linear models (GLM) for each neuron's spiking activity to estimate its firing rate using the history of both spikes and fields and compute the directed information to spike nodes from any node. Second, we construct regression models for fields using the history of the estimated firing rates and the history of fields, and then compute the directed information to each field node from any node. In both steps, we estimate model parameters using maximum likelihood and devise statistical tests to assess the significance of the causality. Using simulated data from basic three-node structures and a ten-node network, we show that our method can asymptotically identify the true causality. This method could help uncover functional connectivity in the brain at multiple spatiotemporal scales. PMID- 30440949 TI - Estimation of Functional Dependence in High-Dimensional Spike-Field Activity. AB - Behavior is encoded across spatiotemoral scales of brain activity, from small scale spikes to large-scale local field potentials (LFP). Identifying the functional dependence between spikes and LFP networks during behavior can help understand neural encoding and improve future neurotechnologies, but is difficult to achieve. First, spikes and LFP have different statistical characteristics (binary spikes vs. continuous LFPs) and time-scales. Second, given the prohibitively large number of spike channels and LFP features recorded in today's experiments, learning dependencies between all recorded signals is challenging and prone to overfitting. To solve this challenge, we present a model-based approach to estimate the functional dependence between high-dimensional field features and neuronal spikes. We model the binary time-series of spikes for each neuron as a point process dependent on the behavioral states and LFP features across the network. Given the prohibitively large number of possible spike-LFP dependency parameters, we first employ an Ll-regularization technique to learn the point process model during both supervised and unsupervised learning to ease detection of significant dependency parameters. We then use the Akaike information criterion (AIC) to enforce model sparsity by incorporating only a minimum number of non-zero dependency parameters into the point process model based on a trade-off between model complexity and its prediction power. Using extensive numerical simulations, we show that our method (i) can correctly identify the functional dependencies and thus improve the prediction of spiking activity and (ii) can improve the prediction of spiking activity with significantly fewer number of parameters compared to when regularization is not enforced. Our approach may serve as a tool to investigate brain connectivity patterns across spatiotemporal scales. PMID- 30440950 TI - Imputing Missing Values in EEG with Multivariate Autoregressive Models. AB - Wearable measurement for electroencephalogram (EEG) is expected to enable brain computer interfaces, biomedical engineering, and neuroscience studies in real environments. When wearable devices are in practical use, only the user (subject) can take care of measurement, unlike laboratory- oriented experiments, where experimenters are always with the subject. As a result, measurement troubles such as artifact contamination or electrode impairment cannot be easily corrected, and EEG recordings will become incomplete, including many missing values. If the missing values are imputed (interpolated) and complete data without missing entries are available, we can employ existing signal analysis techniques that assume compete data. In this paper, we propose an EEG signal imputation method based on multivariate autoregressive (MAR) modeling and its iterative estimation and simulation, inspired by the multiple imputation procedure. We evaluated the proposed method with real data with artificial missing entries. Experimental results show that the proposed method outperforms popular baseline interpolation methods. Our iterative scheme is simple yet effective, and can be the foundation for many extensions. PMID- 30440951 TI - Improved MUP Template Estimation Using Local Time Warping and Kernel Weighted Averaging. AB - A motor unit potential (MUP) template, which represents the shapes of the MUPs within a MUP train, provides information related to the morphology and physiology of the sampled motor unit. This work presents an improved MUP template estimation technique that uses local time warping and kernel weighted ensemble averaging. An analysis of the algorithm, and a description of the improvements compared with spike triggered averaging is given. MUP template estimates were evaluated using simulated EMG signals with a known gold standard template for each motor unit potential train. Statistically significant reduction in template estimation error is shown, both within the baseline and duration portions of a MUP. PMID- 30440952 TI - EMG-based Real Time Facial Gesture Recognition for Stress Monitoring. AB - An electromyogram (EMG) signal acquisition system capable of real time classification of several facial gestures is presented. The training data consist of the facial EMG collected from 10 individuals (5 female/5 male). A custom designed sensor interface integrated circuit (IC) consisting of an amplifier and an ADC, implemented in 65nm CMOS technology, has been used for signal acquisition [1]. It consumes 3.8nW power from a 0.3V battery. Feature extraction and classification is performed in software every 300ms to give real-time feedback to the user. Discrete wavelet transforms (DWT) are used for feature extraction in the time-frequency domain. The dimensionality of the feature vector is reduced by selecting specific wavelet decomposition levels without compromising the accuracy, which reduces the computation cost of feature extraction in embedded implementations. A support vector machine (SVM) is used for the classification. Overall, the system is capable of identifying several jaw movements such as clenching, opening the jaw and resting in real-time from a single channel EMG data, which makes the system suitable for providing biofeedback during sleeping and awake states for stress monitoring, bruxism, and several orthodontic applications such as temporomandibular joint disorder (TMJD). PMID- 30440953 TI - Real-Time Hand Motion Recognition Using sEMG Patterns Classification. AB - Increasing performance while decreasing the cost of sEMG prostheses is an important milestone in rehabilitation engineering. The different types of prosthetic hands that are currently available to patients worldwide can benefit from more effective and intuitive control. This paper presents a real-time approach to classify finger motions based on surface electromyography (sEMG) signals. A multichannel signal acquisition platform implemented using components off the shelf is used to record forearm sEMG signals from 7 channels. sEMG pattern classification is performed in real time, using a Linear Discriminant Analysis approach. Thirteen hand motions can be successfully identified with an accuracy of up to 95.8% and of 92.7% on average for 8 participants, with an updated prediction every 192 ms. PMID- 30440954 TI - Analysis of Sequential Visibility Motifs in Isometric Surface Electromyography Signals in Fatiguing Condition. AB - Muscle fatigue is the inability to exert the required force. Surface Electromyography (sEMG) is a technique used to study the muscle's electrical property. These generated signals are complex and nonstationary in nature. In this work, an attempt is made to utilize graph signal processing methods such as Sequential Visibility motif for the analysis of muscle fatigue condition. The sEMG signals of 41 healthy adult volunteers are acquired from the biceps brachii muscle during isometric contraction with a 6 Kg load. The subjects are asked to perform the exercise until they are unable to continue. The signals are preprocessed, and the first and last 500 ms of the signal are considered for analysis. The segmented signals are subjected to sequential visibility graph algorithm. Further, the number of motifs for a subgraph of four is calculated. The results show that the signals are unique for each subject. The frequency of higher degree motif is more in the case of fatigue. The frequency of each unique motif is capable of differentiating nonfatigue and fatigue conditions. Nonparametric statistical test result indicates all features are significant with p<0.05. This method of analysis can be extended to other varied neuromuscular conditions. PMID- 30440955 TI - Long-Term Depression Learning in Spinal Cord Networks. AB - Investigating learning in networks of spinal cord neurons can provide insight into the dynamics of connectivity in human spinal cords. It may also hold implications for developing neural prosthetics and neurocomputers. Culturing neural networks on microelectrode arrays (MEAs) allows for the repeated observation and stimulation of electrophysiological activity in vitro. Here we used MEAs to demonstrate learning in networks of spinal cord neurons. This was done by exposing E17 mouse spinal cord cultures to high frequency artificial spike trains, or tetanization. Unexpectedly, when comparing the networks' responses to low-frequency probing stimulations before and after tetanization, the cultures were found to demonstrate long-term depression (LTD). LTD was most significantly observed between 500-1000 ms after low-frequency probing. These results indicate that periodic high-frequency excitation of spinal cord networks can result in decreased synaptic efficacy. PMID- 30440956 TI - Preliminary Study of Time to Recovery of Rat Sciatic Nerve from High Frequency Alternating Current Nerve Block. AB - High-Frequency alternating current nerve block has great potential for neuromodulation-based therapies. However, no precise measurements have been made of the time needed for nerves to recover from block once the signal has been turned off. This study aims to characterise time to recovery of the rat sciatic nerve after 30 seconds of block at varying amplitudes and frequencies. Experiments were carried out invivo to quantify recovery times and recovery completeness within 0.7 s from the end of block. The sciatic nerve was blocked with an alternating square wave signal of amplitude and frequency ranging from 2 to 9mA and 10 to 50 kHz respectively. To determine the recovery dynamics the nerve was stimulated at 100 Hz after cessation of the blocking stimulus. Electromyogram signals were measured from the gastrocnemius medialis and tibialis anterior muscles during trials as indicators of nerve function. This allowed for nerve recovery to be measured with a resolution of 10 ms. This resolution is much greater than previous measurements of nerve recovery in the literature. Times for the nerve to recover to a steady state of activity ranged from 20 to 430 milliseconds and final relative recovery activity at 0.7 seconds spanned 0.2 to 1 approximately. Higher blocking signal amplitudes increased recovery time and decreased recovery completeness. These results suggest that blocking signal properties affect nerve recovery dynamics, which could help improve neuromodulation therapies and allow more precise comparison of results across studies using different blocking signal parameters. PMID- 30440957 TI - Capacitive Micromachined Ultrasonic Transducer (CMUT) ring array for transcranial ultrasound neuromodulation. AB - Non-invasive brain stimulation of small animals plays an important role in neuroscience especially in understanding fundamental mechanisms of brain disorders. Here, we report a miniaturized ultrasound transducer array designed for non-invasive brain stimulation of mouse for the first time. We designed and fabricated a Capacitive Micromachined Ultrasonic Transducer (CMUT) ring array that operates at 183 kHz in immersion. The fabricated transducer ring array exhibited a focal length of 2.25 mm and a maximum intensity of 175 mW/cm2. Because the array was fabricated in a ring shape, a natural focus was achieved and thus, no additional focusing circuitries or acoustic lens were required. Thus, a compact packaging was achieved with minimum surgical procedures for in vivo mouse experiments. Using the developed micromachined transducer array and simple packaging, we successfully induced the motor responses of a mouse. The success rate of ultrasound stimulation was quantified by recording the electromyography (EMG) signal during the stimulation. While the current ultrasound neuromodulation system is limited to acute experiments, the presented light (< 1 g) and compact ultrasound neuromodulation system with a natural focus would enable chronic ultrasound neuromodulation experiments on freely-moving mice. PMID- 30440958 TI - Improved Target Specificity of Transcranial Focused Ultrasound Stimulation (TFUS) using Double-Crossed Ultrasound Transducers. AB - Ultrasound neuromodulation is a promising stimulation modality because of its non invasiveness, focusing and steering capability, and relatively high spatial resolution compared to the other stimulation modalities. However, despite the high lateral resolution, the ultrasound beam in the axial direction is relatively long, especially when compared to the small size of the mouse brain. Here, we report a new ultrasound focusing technique for small animal in vivo experiments where a high spatial resolution in both lateral and axial directions is achieved by crossing two ultrasound beams. The focal volume of a full width half maximum (FWHM) of our proposed system is only 0.161 mm3 and the focal diameter in the axial direction is about 1 mm, which is ten times smaller than the previously reported ultrasound neuromodulation system. Thus, the proposed system enables targeting a sub-region of a mouse brain using ultrasound for the first time. We also demonstrate successful stimulation of the motor cortex through in vivo mice experiments where the movement of forepaw of the mouse was observed using the double-crossed ultrasound transducers. Moreover, by sweeping the focal point in the z-axis and measuring the success rate of stimulated movements, we show that our double-transducer system targeted a region with 2 mmresolution in the dorsal ventral (DV) coordinates. The success rate of the double-crossed ultrasound stimulation was quantified by recording the electromyography (EMG) signals during the stimulation. Our results show that the double-crossed ultrasound transducer system with a ten times higher spatial resolution enables highly specific and noninvasive stimulation of small animals and thus enables versatile in vivo experiments to study functional connectivities of brain circuits. PMID- 30440959 TI - Bayesian Optimization of Asynchronous Distributed Microelectrode Theta Stimulation and Spatial Memory. AB - There is a great need for an electrical stimulation therapy to treat medication resistant, surgically ineligible epileptic patients that successfully reduces seizure incidence with minimal side effects. Critical to advancing such therapies will be identifying the trade-offs between therapeutic efficacy and side effects. One novel treatment developed in the tetanus toxin rat model of mesial temporal lobe epilepsy, asynchronous distributed microelectrode stimulation (ADMETS) in the hippocampus has been shown to significantly reduce seizure frequency. However, our results have demonstrated that ADMETS has a negative effect on spatial memory that scales with the amplitude of stimulation. Given the high dimensional space of possible stimulation parameters, it is difficult to construct a mapping from variations in stimulation to behavioral effect. In this project, we present a novel, principled approach using closed-loop Bayesian optimization to tune stimulation that successfully maximize a desired objective - performance on a spatial memory assay. PMID- 30440960 TI - Noninvasive Detection of Motor-Evoked Potentials in Response to Brain Stimulation Below the Noise Floor-How Weak Can a Stimulus Be and Still Stimulate. AB - Motor-evoked potentials (MEP) are one of the most important responses to brain stimulation, such as supra-threshold transcranial magnetic stimulation (TMS) and electrical stimulation. The understanding of the neurophysiology and the determination of the lowest stimulation strength that evokes responses requires the detection of even smallest responses, e.g., from single motor units, but available detection and quantization methods are rather simple and suffer from a large noise floor. The paper introduces a more sophisticated matched-filter detection method that increases the detection sensitivity and shows that activation occurs well below the conventional detection level. In consequence, also conventional threshold definitions, e.g., as 50 MUV median response amplitude, turn out to be substantially higher than the point at which first detectable responses occur. The presented method uses a matched-filter approach for improved sensitivity and generates the filter through iterative learning from the presented data. In contrast to conventional peak-to-peak measures, the presented method has a higher signal-to-noise ratio (>=14 dB). For responses that are reliably detected by conventional detection, the new approach is fully compatible and provides the same results but extends the dynamic range below the conventional noise floor. The underlying method is applicable to a wide range of well-timed biosignals and evoked potentials, such as in electroencephalography. PMID- 30440961 TI - Daily Stress Monitoring Using Heart Rate Variability of Bathtub ECG Signals. AB - Physical, environmental and psychological stressors can lead to chronic diseases. Changes in physiological parameters during stress can be evaluated using heart rate variability (HRV). A study is conducted with one participant on a daily basis over six months. Bathtub ECG is measured during his daily bathing and used for HRV analysis. The HRV stress index (SI) is proposed to quantity the stress in the study. SI is computed and found to be significantly higher in either mental stress or physiological stress. The variations of SI show in high accordance with the work schedules of the participant. PMID- 30440962 TI - Classification of Heart Diseases Based On ECG Signals Using Long Short-Term Memory. AB - Heart disease classification based on electrocardiogram(ECG) signal has become a priority topic in the diagnosis of heart diseases because it can be obtained with a simple diagnostic tool of low cost. Since early detection of heart disease can enable us to ease the treatment as well as save people's lives, accurate detection of heart disease using ECG is very important. In this paper, we propose a classification method of heart diseases based on ECG by adopting a machine learning method, called Long Short-Term Memory (LSTM), which is a state-of-the art technique analyzing time series sequences in deep learning. As suitable data preprocessing, we also utilize symbolic aggregate approximation (SAX) to improve the accuracy. Our experiment results show that our approach not only achieves significantly better accuracy but also classifies heart diseases correctly in smaller response time than baseline techniques. PMID- 30440963 TI - Mathematical Modeling of Arterial Blood Pressure Using Photo- Plethysmography Signal in Breath-hold Maneuver. AB - recent research has shown that each apnea episode results in a significant rise of the beat-to-beat blood pressure followed by a drop to the pre-episode levels when patient resumes normal breathing. While the physiological implications of these repetitive and significant oscillations are still unknown, it is of interest to quantify them. Since current array of instruments deployed for polysomnography studies does not include beat-to-beat measurement of blood pressure, but includes oximetry which can supply pulsatile photoplethysmography (PPG) signal, in addition to percent oxygen saturation. Hence, we have investigated a new method for continuous estimation of systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure waveforms from PPG. Peaks and troughs of PPG waveform are used as input to a 5th order autoregressive moving average model to construct estimates of SBP, DBP, and MBP waveforms. Since breath hold maneuvers are shown to faithfully simulate apnea episodes, we evaluated the performance of the proposed method in 7 subjects (4 F; $32 ?pm 4$ yrs., BMI $24.57 ?pm 3.87$ kg/m2) in supine position doing 5 breath holding maneuvers with 90s of normal breathing between them. The modeling error ranges were (all units are in mmHg $) 0.88 ?pm 4.87$ to $- 2.19 ?pm 5.73($ SBP); $0.29 ?pm 2.39$ to $- 0.97 ?pm 3.83($ DBP); and $- 0.42 ?pm 2.64$ to $- 1.17 ?pm 3.82($ MBP). The cross validation error ranges were $0.28 ?pm 6.45$ to $- 1.74 ?pm 6.55($ SBP); $0.09 ?pm 3.37$ to $0.97 ?pm 3.67($ DBP); and $0.33 ?pm 4.34$ to $- 0.87 ?pm 4.42($ MBP). The overall level of estimation error, as measured by the root mean squared of the model residuals, was less than 7 mmHg. PMID- 30440964 TI - Automated Diabetic Macular Edema (DME) Analysis Using Fine Tuning with Inception Resnet-v2 on OCT Images. AB - (DME) is an important task in optical coherence tomography (OCT) images of the eye. A relatively simple and practical approach is proposed in this paper. A pre trained convolutional neural network (CNN) is fine tuned for a classification of DME versus normal cases. The fine-tuned Inception-Resnet-v2 CNN model can effectively identify pathologies in comparison to classical learning. Experiments were carried out on the publicly available data set of the Singapore Eye Research Institute (SERI). The developed model was also compared to other fine tuned models, such as Resnet-50 and Inception-v3. The proposed method achieved 100% classification accuracy with the Inception-Resnet-v2 model using a leave-one-out crossvalidation strategy. For robustness, the model trained on the SERI dataset was tested on another dataset provided by the Chinese University HongKong (CUHK), also with 100% accuracy. The proposed method is a potentially impactful tool for accurately detecting DME vs. normal cases. PMID- 30440965 TI - Are There Categories of Corneal Shapes? AB - This study investigates the possible existence of different natural corneal shape categories. This is important to better describe cornea for both diagnostic and therapeutic assessments. We started by describing corneal shape of different populations as a function of influencing clinical data i.e. age, ametropia and gender. This was done by averaging Zernike polynomial (ZP) decomposition of the anterior surfaces in each subgroup. The results showed small but significant differences of shape that are supported by the literature. This motivated us to examine the feasibility of characterizing the normal corneal shape with an automatic method of clustering independent of any clinical a priori knowledge. Since we did not know beforehand the number of corneal categories, agglomerative hierarchical clustering was applied on ZP coefficients for a large database. The dendrogram based on the Ward's distance was evaluated with two different clustering validity indexes (coefficient of determination R2 and semi partial R2 (SPR2). The optimal number of categories was around four showing corneal shapes ranging from flatter to steeper. PMID- 30440966 TI - Multi-Cell Multi-Task Convolutional Neural Networks for Diabetic Retinopathy Grading. AB - Diabetic Retinopathy (DR) is a non-negligible eye disease among patients with Diabetes Mellitus, and automatic retinal image analysis algorithm for the DR screening is in high demand. Considering the resolution of retinal image is very high, where small pathological tissues can be detected only with large resolution image and large local receptive field are required to identify those late stage disease, but directly training a neural network with very deep architecture and high resolution image is both time computational expensive and difficult because of gradient vanishing/exploding problem, we propose a Multi-Cell architecture which gradually increases the depth of deep neural network and the resolution of input image, which both boosts the training time but also improves the classification accuracy. Further, considering the different stages of DR actually progress gradually, which means the labels of different stages are related. To considering the relationships of images with different stages, we propose a Multi Task learning strategy which predicts the label with both classification and regression. Experimental results on the Kaggle dataset show that our method achieves a Kappa of 0.841 on test set which is the 4th rank of all state-of-the arts methods. Further, our Multi-Cell Multi-Task Convolutional Neural Networks (M2CNN) solution is a general framework, which can be readily integrated with many other deep neural network architectures. PMID- 30440967 TI - Sensitivity of Cross-Trained Deep CNNs for Retinal Vessel Extraction. AB - Automatic segmentation of vascular network is a critical step in quantitatively characterizing vessel remodeling in retinal images and other tissues. We proposed a deep learning architecture consists of 14 layers to extract blood vessels in fundoscopy images for the popular standard datasets DRIVE and STARE. Experimental results show that our CNN characterized by superior identifying for the foreground vessel regions. It produces results with sensitivity higher by 10% than other methods when trained by the same data set and more than 1% with cross training (trained on DRIVE, tested with STARE and vice versa). Further, our results have better accuracy $> 0 .95$% compared to state of the art algorithms. PMID- 30440968 TI - Anatomical Biomarkers for Adolescent Major Depressive Disorder from Diffusion Weighted Imaging using SVM Classifier. AB - Adolescent Major Depressive Disorder (MDD) is a common and serious mental illness that could lead to tragic outcomes including chronic adult disability and suicide. In this paper, we explore anatomical features and apply machine learning approaches to identify responsive biomarkers distinguishing MDD patients from healthy subjects. The features of interest include metrics in two categories: a) anatomical connectivity defined by diffusion tensor imaging measurements between a pair of brain regions, and b) topological measurements from anatomical networks. A combination of p-value based filtering and minimum redundancy maximum relevance method is performed to select features for optimal classification accuracy. A leave-one-out cross-validation method is used for the classification performance evaluation. The proposed methodology achieves an improved accuracy of 78%, 90.39% sensitivity, and 79.66% precision for 79 subjects. The most distinguishing features are the betweenness centrality of the right lingual gyrus of the ADC network at 12% sparsity, the participation coefficient of the right lateral occipital sulcus of the ADC network at 22% sparsity, the participation coefficient of the right pars opercularis of the AD network at 16% sparsity, and the participation coefficient of the right lateral orbitofrontal cortex in the ADC network at 10% sparsity. Those network measures reflect the change of connectivity between the regions and their associated anatomical subnetworks. PMID- 30440969 TI - A Quantitative Model for Estimating the Scale of Photochemically Induced Ischemic Stroke. AB - Photothrombosis is a technique that can induce ischemic cortical infarcts using the photodynamic effect of anionic xanthene dyes, typically Rose Bengal, to cause occlusion of cerebral blood circulation. The ability to quantitatively predict the scale of the lesion in photothrombotic procedures can offer crucial insight in the development and implementation of light-induced stroke models in animals. In this article, we introduced a quantitative model that could estimate the normalized light intensity distribution in tissue which scatters photons from a collimated beam. We simulated the penetration and scattering profile of light of Rose Bengal's characteristic absorption wavelengths in mouse cortex. We further illustrated that our model could estimate the spatial extent of effective region under photothrombotic protocols, and how this model can be used to titrate the intensity and geometry of light beams used to generate infarcts of desired dimensional characteristics. PMID- 30440970 TI - Visual Displacement Perception in Parkinson's Disease Analyzed Using a Computer Generated Graphical Tool. AB - Parkinson's Disease (PD) is typically classified by the onset of motor impairments, however, non-motor symptoms are also present in all disease stages. Vision abnormalities contribute to the non-motor PD deficits, yet little research has studied how PD affects visual perceptions with no produced motor responses. This provides motivation for the current study which focuses on examining allocentric visual displacement perception - information used for object identification - in PD patients. To study this PD participants OFF and ON Levodopa therapy, and age-matched healthy control participants were tested. A modular graphics toolbox was implemented to carry out the perceptual testing. Individuals with PD were shown to have impairments in displacement perception of the larger tested magnitudes when both OFF and ON Levodopa compared to control participants, suggesting impairments in visual displacement processing pathways. These abnormalities could contribute to difficulties some PD patients have with visual recognition and visuospatial navigation. Furthermore, the study validated the graphical tool as a means of quantifying perceptual abilities that can be expanded to many perceptual modalities and paired with robotic devices. PMID- 30440971 TI - Altered Connectivity in Autistic Adults during Complex Facial Emotion Recognition: A Study of EEG Imaginary Coherence. AB - Difficulties in Facial Emotion Recognition (FER) are commonly associated with individuals diagnosed with Autism Spectrum Disorder (ASD). However, the mechanisms underlying these impairments remain inconclusive. While atypical cortical connectivity has been observed in autistic individuals, there is a paucity of investigation during cognitive tasks such as FER. It is possible that atypical cortical connectivity may underlie FER impairments in this population. Electroencephalography (EEG) Imaginary Coherence was examined in 22 autistic adults and 23 typically developing (TD) matched controls during a complex, dynamic FER task. Autistic adults demonstrated reduced coherence between both short and long range inter-hemispheric electrodes. By contrast, short range intra hemispheric connectivity was increased in frontal and occipital regions during FER. These findings suggest altered network functioning in ASD. PMID- 30440972 TI - Deep Learning Enabled Automatic Abnormal EEG Identification. AB - In hospitals, physicians diagnose brain-related disorders such as epilepsy by analyzing electroencephalograms (EEG). However, manual analysis of EEG data requires highly trained clinicians or neurophysiologists and is a procedure that is known to have relatively low inter-rater agreement (IRA). Moreover, the volume of the data and rate at which new data is acquired makes interpretation a time consuming, resource hungry, and expensive process. In contrast, automated analysis offers the potential to improve the quality of patient care by shortening the time to diagnosis, reducing manual error, and automatically detecting debilitating events. In this paper, we focus on one of the early decisions made in this process which is identifying whether an EEG session is normal or abnormal. Unlike previous approaches, we do not extract hand-engineered features but employ deep neural networks that automatically learn meaningful representations. We undertake a holistic study by exploring various pre processing techniques and machine learning algorithms for addressing this problem and compare their performance. We have used the recently released "TUH Abnormal EEG Corpus" dataset for evaluating the performance of these algorithms. We show that modern deep gated recurrent neural networks achieve 3.47% better performance than previously reported results. PMID- 30440973 TI - Design of Soft Robotic Actuation for Supporting Eyelid Closure Movement. AB - We have been developing a facial wearable robot to support the eyelid movements of patients with facial paralysis, especially on one side of the face [1]. This robot has a mechanism for supporting eyelid movements, made from a soft material, which is called the eyelid gating mechanism (ELGM). The ELGM deforms by simple rotational actuation inputs and its deformation is customized to the eyelid movements. Therefore, this robot can provide non-invasive and gentle support for eyelid movements. We herein describe the design rule of the ELGM, and based on this, we conducted a deformation analysis with a non-linear finite element method. We verified the deformation trend from the results, and developed three prototypes based on this trend. Using these prototypes, we conducted a clinical study with facial paralysis patients to evaluate if the ELGM is capable of assisting in closing the eyelid. PMID- 30440974 TI - Modified Sequence Method to Assess Baroreflex Sensitivity in Rats. AB - Baroreceptors respond to fluctuations in blood pressure (BP) by modifying physiology in order to maintain a homeostatic set point. Baroreflex sensitivity (BRS) is used to quantify baroreceptor function and is a useful metric for tracking cardiovascular disease state and treatment effects. Pathological conditions such as hypertension (HTN) alter baroreflex function and reduce BRS. Traditionally, the sequence method is used to measure BRS, in which the linear slope of concomitant changes in BP and RR intervals are assessed. However, in rats, a high respiratory rate reduces the reliability of the sequence method. Here, we present a modified sequence method that captures BRS at lower frequencies and decreases the variability of the BRS estimate. This method was demonstrated using ECG and BP data from two groups of HTN rats: Sham rats and rats treated with vagus nerve stimulation. The modified sequence method resulted in lower BRS estimates than the traditional sequence technique when applied to the same data sets. Additionally, the modified sequence method resulted in lower BRS estimate variability. PMID- 30440975 TI - Effects of instructed meditation augmented by computer-rendered artificial virtual environment on heart rate variability. AB - Previous research has supported the use of virtual reality (VR) to decrease stress, anxiety, perceptions of pain, and increase positive affect. However, the effect of VR on blood pressure (BP) and autonomic function in healthy populations have not been explored. This study quantifies the effect of instructed meditation augmented by a virtual environment (VE) on BP and heart rate variability (HRV) during rest and following physical (isometric handgrip) or mental (serial sevens subtraction) stress. Sixteen healthy participants underwent all conditions, and those that responded to the stress tests were included in the analysis of stress recovery. Results showed that under resting conditions, VE had no significant effect on BP or HRV when compared to seated rest and the VE video on a 2D screen. Following serial sevens, VE maintained the increased low frequency (LF) power of HRV $( 66 ?pm 4$ normalized units (n.u.)) compared to seated rest $( 55 ?pm 5?mathrm {n}$.u., $?mathrm {p}=0.0060)$; VE maintained the decreased high frequency (HF) power of HRV $( 34 ?pm 4?mathrm {n}$.u.) compared to seated rest $( 44 ?pm 5?mathrm {n}$.u., $?mathrm {p}=0.014)$; and VE maintained the increased LF/HF ratio $( 2.4 ?pm 0.5)$ compared to seated rest $( 1.6 ?pm 0.3$, $?mathrm {p}=0.012)$. Hence, after mental stress, VE sustains the increased sympathetic drive and reduced parasympathetic drive. VE may act as a stimulatory driver for autonomic activity and BP. Further studies are required to investigate the effect of different types of VE on BP and autonomic function. PMID- 30440976 TI - Variations of Heart Rate, Pulse Arrival Time and Blood Pressure in a Versatile Laboratory Protocol. AB - Many studies dealing with blood pressure modeling are evaluated based on a single type of provocation. This paper investigates widely used provocations such as controlled breathing, mental arithmetic and Stroop tests, Valsalva maneuver, cold pressor and muscle tension and combines them in a versatile laboratory protocol. The protocol was tested in an experiment where pulse arrival time (PAT) and heart rate (HR) were measured with chest ECG and finger PPG sensors and blood pressure (BP) with continuous fingercuff monitor. The experiment results show that mental tasks provoked HR, BP and PAT very little while cold pressor and muscle tension had strong impact in all parameters. Valsalva maneuver had strongest impact in HR and PAT but the effect was transient like. We also predicted systolic BP based on the PAT values. We selected nine points in the protocol to calculate linear prediction model for each subject and then fitted data points to the models. If only the calibration points are taken into account, the correlation between the predicted and measured systolic BP was 0.91. When all the data points are fed into model, correlation was 0.75. PMID- 30440977 TI - Baroreflex Sensitivity During Listening to Music Computed from Time Domain Sequences and Frequency Domain Transfer Function. AB - Listening to music has been known to affect autonomic function of cardiovascular regulation. Baroreflex is a feedback control loop that uses rate changes of the heart in order to regulate beat by beat changes in blood pressure (BP). In this study, we used two approaches to compute measures of sensitivity of the baroreflex (BRS), a time domain sequence approach and frequency domain transfer functions. Subjects listened to slow and fast tempo songs during the study. Electrocardiogram (ECG) and non-invasive continuous BP were recorded in 14 subjects (7 males and females). From these signals, either beat by beat or equi sampled in time RR intervals and systolic BP (SBP) were computed. BRS was then estimated using RR and SBP. Our results show that the sequence method consistently provided higher values of BRS than the transfer function method (up to two fold). The two measures were reasonably well correlated $( ?mathrm {R}>0.84)$ during control and the slow song, but not during the fast song. The BRS was lower $( ?sim 20$%) than control when listening to fast songs $( ?mathrm {p}<0.005)$. These results show the effects of listening to songs on BRS changes, but also show that the two methods to estimate BRS, although reasonably correlated, do not always provide similar estimates of BRS. PMID- 30440978 TI - Comparison of Different Strategies to Assess Cardiac Baroreflex Sensitivity Based on Transfer Function Technique in Patients Undergoing General Anesthesia. AB - Baroreflex sensitivity (BRS) can be noninvasively assessed from heart period (HP) and arterial pressure (AP) variability series via the estimation of the gain of the transfer function (TF) in the low frequency (LF, 0.04-0.15 Hz) band. However, different strategies can be adopted to pick the value of the TF gain and different fiducial AP values can be considered. In this study we compared different strategies to reduce the TF gain into a unique maker: i) sampling the TF gain in correspondence of the maximum of the HP-AP squared coherence; ii) sampling the TF gain at the weighted average of the central frequencies of AP spectral components; iii) calculating the average of the TF gain in the LF band. Indexes were computed using alternatively systolic AP (SAP) or diastolic AP (DAP) series in combination with HP. Results were obtained in 129 patients undergoing coronary artery bypass graft surgery before (PRE) and after (POST) the induction of general anesthesia with propofol and remifentanil. The reduction of BRS during general anesthesia is expected as a result of overall depression of the cardiovascular control even in this group of pathological subjects already featuring a low BRS before general anesthesia induction. We found that the expected decrease of BRS was observed regardless of the strategy using DAP. Moreover, regardless of series (i.e., SAP or DAP), the sampling of TF gain at the weighted average of the central frequencies of the AP spectral components has the greatest statistical power in distinguishing the two experimental conditions. We recommend the use of this strategy in assessing BRS via TF analysis and a more frequent exploitation of the DAP series. PMID- 30440979 TI - The Role of Baroreflex Sensitivity in Acute Hypotensive Episodes Prediction in the Intensive Care Unit. AB - A life threatening condition in Intensive Care Unit (ICU) is the Acute Hypotensive Episode (AHE). Patients experiencing an AHE may suffer from irreversible organ damage associated with increased mortality. Predicting the onset of AHE could be of pivotal importance to establish appropriate and timely interventions. We propose a method that, using waveforms widely acquired in ICU, like Arterial Blood Pressure (ABP) and Electrocardiogram (ECG), will extract features relative to the cardiac system to predict whether or not a patient will experience a hypotensive episode. Specifically, we want to assess if there are hidden patterns in the dynamics of baroreflex able to improve the prediction of AHEs. We will investigate the predictive power of features related to the baroreflex by performing classifications with and without them. Results are obtained using 17 classifiers belonging to different model families: classification trees, Support Vector Machines (SVMs), K-Nearest Neighbors (KNNs) replicated with different set of hyper-parameters and logistic regression. On average, the use of baroreflex features in the AHE prediction process increases the Area Under the Curve (AUC) by 10%. PMID- 30440980 TI - FES Coupled With A Powered Exoskeleton For Cooperative Muscle Contribution In Persons With Paraplegia. AB - This paper describes the effects of a novel functional electrical stimulation (FES) system which has been integrated in a powered exoskeleton to provide up to 10 channels of stimulation to users with paraplegia via surface electrodes. Experimental data collected from three users with spinal cord injury (SCI) indicate the system reduced the exoskeleton motor torques necessary to perform sit-to-stand transitions in the exoskeleton. All subjects exhibited reduced muscle spasticity immediately after walking in the exoskeleton with FES. Additionally, one subject with stretch-reflex spasms exhibited increased joint excursion and reduced exoskeleton motor torques required to achieve over-ground gait when FES was incorporated. PMID- 30440981 TI - Effects of Exoskeleton Training Intervention on Net Loading Force in Chronic Spinal Cord Injury. AB - The goal of this study was to understand the rehabilitative effects of longitudinal overground exoskeleton training $( >100$ hours) on gait mechanics, especially foot loading, for gains in walking speed in an individual with chronic motorincomplete SCI. Biomechanical measures included: normalized plantar loading forces, walking speed and bilateral weight transfer ratio during walking in the EksoGT $^{?mathrm{ TM}}$ exoskeleton. Longitudinal training with a robotic exoskeleton yielded improvements in clinical outcomes (AIS classification, ISNCSCI motor scores and 10MWT) and provided functional gains in terms of biomechanical outcomes (plantar forces, weight transfer point) to increase overall walking speed. PMID- 30440982 TI - A Velocity-Based Flow Field Control Approach for Reshaping Movement of Stroke Impaired Individuals with a Lower-Limb Exoskeleton. AB - This paper describes a controller for guiding and assisting leg movement during walking with a lower limb exoskeleton with actuated hip and knee joints. The primary novel aspect of the controller is that it employs a virtual flow field to influence movement during swing, rather than a more typical potential-energy based field. The controller was tested on a single stroke subject. The stroke subject's leg kinematics demonstrate that the controller is capable of appropriately influencing leg kinematics during overground walking. PMID- 30440983 TI - Repeatability of EMG activity during exoskeleton assisted walking in children with cerebral palsy: implications for real time adaptable control. AB - Effective solutions for gait rehabilitation in children with cerebral palsy (CP) remain elusive. Wearable robotic exoskeletons offer the potential to greatly increase the dosage and intensity of gait training in this population, which may improve outcomes. We recently reported that a robotic exoskeleton significantly improved knee extension in children with crouch gait from CP. Longitudinal studies are necessary to fully understand long term biomechanical effects of exoskeleton gait training. Given that children's gait can change both as they develop and throughout their therapy, advanced control strategies which can adapt assistance over time may be beneficial. But, stride-to-stride variability makes it difficult to ascertain the effects of exoskeleton assistance and therefore complicates implementation of adaptable control algorithms. Here, we examine the use of the variance ratio (VR), a previously published measure, to assess the effect of exoskeleton assistance on knee extensor and flexor EMG variability in children with CP. Our results show that VR was significantly increased ($p<0.001)$ compared to baseline during walking with exoskeleton assistance. After five practice sessions, we found that VR was reduced though still greater than baseline levels. Given its sensitivity to exoskeleton assistance and ease of computation, VR may be a useful measure in the future for evaluating stride-to stride variability in real time to inform algorithmic decision making for autonomous adaptable control. PMID- 30440984 TI - Mechanisms for improving walking speed after longitudinal powered robotic exoskeleton training for individuals with spinal cord injury. AB - The goal of this study was to establish strideparameter gait models correlated to speed on individuals with chronic SCI and able-bodied controls walking with a powered robotic exoskeleton (EksoGT $^{?mathrm{ TM}}$). Longitudinal exoskeleton training $( >100$ hours) across eight individuals with SCI resulted in a 30% increase in walking speed. A simple linear regression between step length, stride length for given speed were very tightly correlated along a line of best fit $( ?mathrm {p}<$.001). The temporal parameters of stride time, stance time and double support time depicted a non-linear exponentially decaying relationship for given walking speed. The research findings indicate that although longitudinal exoskeleton training reduces the temporal parameters, increases in spatial parameters are only marginal. PMID- 30440985 TI - Robotic Exoskeleton Gait Training for Inpatient Rehabilitation in a Young Adult with Traumatic Brain Injury. AB - Severe and moderate traumatic brain injury (TBI) causes motor deficits leading to impairments in functional ambulation. Motor recovery involves intensive rehabilitation through physical therapy. Current practices in rehabilitation results in variable recovery of motor function and may result in residual gait deviations. Wearable robotic exoskeletons can provide the user with intensive, goal-directed repetition of movement as well as provide the user with stability and balance during gait, compared to conventional physical therapy. During the acute stage of recovery, the brain is healing and relearning and increased intensive motor rehabilitation throughout this stage could result in improved functional ambulation, especially in individuals with severe impairments who are not independent ambulators. This pilot study evaluates the effect of early intervention robotic exoskeleton gait training on lower extremity biomechanics on a 21 year old young adult with TBI. PMID- 30440986 TI - Inverse Kinematic Assessment of Rehabilitative Therapy in Children Using Orthotics. AB - Pathologic movement patterns are characterized by abnormal kinematics that alter how muscles support the body during walking. Individual muscles are often the target of interventions with physical therapy and surgery alike, yet the tools to assess individual muscles clinically remain limited. The aim of this study is to assess OpenSim as a clinical tool for individualized rehabilitative evaluation of children using orthotics. This anatomic and kinematic modeling study was focused on pre- and post-treatment assessment of gait characteristics in fourteen children using orthotic devices. A range of four to twelve acceptable gait capture trials was collected for each child before therapy began and again after four weeks of treatment. The effects of therapy were significant in four of the lower extremity muscle analyses, three of the temporal parameters, and eighteen of the spatial parameters. All muscle lengths showed less deviation from normal values after physical therapy across all subjects. Results of this study support the further evaluation of OpenSim as a tool to improve quantitative assessment of musculoskeletal dynamics during the course of rehabilitative therapy in children using orthotics. PMID- 30440987 TI - A low cost, handheld E-nose for renal diseases early diagnosis. AB - In the last decade, the use of electronic olfaction systems for the early diagnosis of several pathologies by breath analysis has been investigated. In this study, an electronic nose including seven polyaniline sensors has been developed. An impedance measurement circuit and a micro-computer to process the sensor responses were studied to give a pre-diagnosis conclusion. The measurement accuracy is 97% when the E-nose is exposed to a simulated human breath and different concentration of ammonia, from 500 ppb to 2.8 ppm. The described prototype weights about 300 g and can be used for 14 hours with a smartphone battery. PMID- 30440988 TI - Evaluation of Dynamic Time Warp Barycenter Averaging (DBA) for its Potential in Generating a Consensus Nanopore Signal for Genetic and Epigenetic Sequences. AB - Epigenetics is a chemical modification to DNA without changes in the base sequence. While it is known that epigenetic modifications have far reaching implications on how genes are expressed, it is difficult to identify what the modification is or where it can be found. A next-generation method of sequencing called nanopore sequencing may be the solution. Nanopore sequencing runs a voltage bias across the DNA sequence and outputs a unique electric response to each genetic unit. Epigenetic modifications may then be identified by their distinct electric response. In this paper we provide preliminary results of applying dynamic time warp Barycenter Averaging (DBA) to multiple noisy nanopore streams to generate a consensus signal that can be used to identify genetic sequences and their modifications. DBA convergence rates, time complexity, together with qualitative and quantitative metrics to compare the consensus signal with gold standards are evaluated. PMID- 30440989 TI - Towards the Ambulatory Assessment of Movement Quality in Stroke Survivors using a Wrist-worn Inertial Sensor. AB - Stroke is a leading cause of long-term disability that may lead to significant functional motor impairments in the upper limb (UL). Wrist-worn inertial sensors have emerged as an objective, minimally-obtrusive tool to monitor UL motor function in the real-world setting, such that rehabilitation interventions can be individually tailored to maximize functional performance. However, current wearable solutions focus on capturing the quantity of movement without considering the quality of movement. This paper introduces a novel approach to unobtrusively estimate the quality of UL movements in stroke survivors using a single wrist-worn inertial sensor during any type of voluntary UL movements. The proposed method exploits kinematic characteristics of voluntary limb movements that are optimized by the central nervous system during motor control. This work demonstrates that the proposed method could extract clinically important information during random UL movements in 16 stroke survivors, showing a statistically significant correlation to the Functional Ability Scale - a clinically validated score for movement quality. PMID- 30440990 TI - A Configurable Portable System for Ambulatory Monitoring of Gastric Bioelectrical Activity and Delivering Electrical Stimulation. AB - The purpose of this paper is to develop and validate a configurable system that can wirelessly acquire gastric electrical activity called slow waves, and deliver high energy electrical pulses to modulate its activity. The system is composed of a front-end unit, and an external stationary backend unit that is connected to a computer. The front-end unit contains a recording module with four channels, and a stimulating module with two channels. Commercial off-theshelf components were used to develop front- and back-end units. A graphical user interface (GUI) was designed in LabVIEW to process and display the recorded data in realtime, and store the data for off-line analysis. Besides, the gain of the analog conditioning circuit as well as the stimulation pulse configuration is programmable directly through the GUI. The system was successfully validated on bench top. The benchtop studies showed an appropriate frequency response for analog conditioning and digitization resolution to acquire gastric slow waves. Moreover, the system was able to deliver electrical pulses at amplitudes up to +/ 24 mA and +/-12 mA to a load of up to 0.5 k $?Omega $ and 1 $?textbf{k}?Omega $, respectively. This study reports the first high-energy stimulator that can be controlled wirelessly and integrated into a gastric bioelectrical activity monitoring system. The system can be used for treating functional gastrointestinal disorders. PMID- 30440992 TI - Integrating Signal Processing Modules of Hearing Aids into a Real-Time Smartphone App. AB - This paper presents the integration of three major modules of the signal processing pipeline that go into a typical digital hearing aid as a real-time smartphone app. These modules include voice activity detection, noise reduction, and compression. The steps taken to allow the real-time implementation of this integration or signal processing pipeline are discussed. These steps can be utilized to create similar signal processing pipelines or integrated apps to evaluate hearing improvement algorithms. The real-time characteristics of the developed integrated app are reported as well as an objective evaluation of its noise reduction. PMID- 30440991 TI - A Novel Diagnostic System for Infectious Diseases Using Solid-State Nanopore Devices. AB - Nanopore-based diagnostic systems are a promising tool for counting viruses in a specimen one by one. However, despite intensive R&D efforts, it remains difficult to recognize virus subtypes by nanopore devices. We thus propose a novel diagnostic system that combines a specialized virus recognition procedure with a nanopore detection procedure. This recognition procedure consists of three steps: 1) capture target viruses using specific probes for recognition; 2) release captured targets; and 3) detect released targets by nanopore. Proof-of-concept tests are conducted using avidin-modified fluorescent particles (as a model for viruses) and biotin-modified alkane thiol (as a model for probes). The avidin modified particles are confirmed to be captured on electrode by biotin-modified probes and then, the particles are electrochemically released from the electrode. Consequently, the released particles are successfully detected by nanopore devices. Furthermore, the concept is also proved by using human influenza viruses (H1N1, A/PR/8/34) and sugar chain (6'-sialyllactose)-modified probes. This suggests that our concept is applicable to various infectious diseases by changing probes (ligands). PMID- 30440993 TI - Towards Non-invasive Labour Detection: A Free-Living Evaluation. AB - In this paper we show early evidence of the feasibility of detecting labour during pregnancy, non-invasively and in free-living. In particular, we present machine learning models aiming at dealing with the challenges of unsupervised, free-living data collection, such as identifying periods of high quality data and detecting physiological changes as labour approaches. During a first phase, physiological data including electrohysterography (EHG, the electrical activity of the uterus), heart rate (HR) and gestational age (GA) were collected in laboratory conditions for model development. In particular, data were collected 1) during simulated activities of daily living, aiming at eliciting artifacts and developing diagnostic models for free-living data 2) during pregnancy, including labour, aiming at developing labour probability models from clean, supervised physiological recordings. Machine learning models using datasets 1) and 2) were deployed in free-living, longitudinally, in 142 pregnant women, between week 22 of pregnancy and delivery. A total of 1014 hours of data and an average of 7 hours per person were collected. Output of the developed models was analyzed to determine the feasibility of detecting labour non-invasively using physiological data, acquired with a single sensor placed on the abdomen. Results showed that the probability of being in labour for recordings collected during the last 24 hours of pregnancy was consistently higher than the probability during any other pregnancy week. Thus, non-invasive labour detection from physiological data seems promising. PMID- 30440994 TI - Estimating Running Performance Combining Non-invasive Physiological Measurements and Training Patterns in Free-Living. AB - In this work, we use data acquired longitudinally, in free-living, to provide accurate estimates of running performance. In particular, we used the HRV4Training app and integrated APIs (e.g. Strava and TrainingPeaks) to acquire different sets of parameters, either via user input, morning measurements of resting physiology, or running workouts to estimate running 10 km running time. Our unique dataset comprises data on 2113 individuals, from world class triathletes to individuals just getting started with running, and it spans over 2 years. Analyzed predictors of running performance include anthropometrics, resting heart rate (HR) and heart rate variability (HRV), training physiology (heart rate during exercise), training volume, training patterns (training intensity distribution over multiple workouts, or training polarization) and previous performance. We build multiple linear regression models and highlight the relative impact of different predictors as well as trade-offs between the amount of data required for features extraction and the models accuracy in estimating running performance (10 km time). Cross-validated root mean square error (RMSE) for 10 km running time estimation was 2.6 minutes (4% mean average error, MAE, 0.87 R2), an improvement of 58% with respect to estimation models using anthropometrics data only as predictors. Finally, we provide insights on the relationship between training and performance, including further evidence of the importance of training volume and a polarized training approach to improve performance. PMID- 30440995 TI - A Fast Respiratory Rate Estimation Method using Joint Sparse Signal Reconstruction based on Regularized Sparsity Adaptive Matching Pursuit. AB - Many algorithms have been used to estimate respiratory rate (RR) from Photoplethysmography (PPG) recently. However, the accuracy and time consumption are still a challenging issue. In this paper, we propose a novel algorithm for RR estimation using Joint Sparse Signal Reconstruction (JSSR) based on Regularized Sparsity Adaptive Matching Pursuit (RSAMP) in a real-time fashion. The algorithm has been tested on Capnobase dataset and the results showed that the mean absolute error (MAE) and root mean squared error between estimates and references are 1.09 breaths per minute (bpm) and 2.44 bpm, respectively. And our method only costs 0.54 seconds for calculation. PMID- 30440996 TI - Near-Infrared Spectroscopy studies on TBI patients with Modified Multiscale Entropy analysis. AB - Functional near-infrared spectroscopy (fNIRS) is an emerging non-invasive functional brain imaging technique, through detecting the changes of hemoglobin concentrations to investigate brain activities in various tasks. The aim of this study is to investigate the complexity of near-infrared spectroscopy signals during resting state and upper limb movements. Experimental study was designed by applying NIRS to collect the data especially for both healthy subjects and traumatic brain injury (TBI) patients. The modified multiscale entropy (MMSE) algorithm was employed to assess the complexity of fNIRS signals which may reflect the changes of brain activity when people underwent brain injury. The results that the mean MMSE of oxyhemoglobin values was lower in TBI patients compared to healthy subjects, indicated that MMSE was feasible to measure complexity of cerebral near-infrared spectroscopy signals in TBI patients, and that brain injury was associated with the decreased complexity of cerebrovascular reactivity. Moreover, measurement of complexity of brain signals has potential to provide significant guidance for rehabilitation. PMID- 30440997 TI - Features Extraction for Cuffless Blood Pressure Estimation by Autoencoder from Photoplethysmography. AB - Several studies have been proposed to estimate blood pressure (BP) with cuffless devices using only a Photoplethysmograph (PPG) sensor on the basis of the physiological knowledge that the PPG changes depend on the state of the cardiovascular system. In these studies, machine learning algorithms were used to extract various features from the wave height and the elapsed time from the rising point of the pulse wave to feature points have been used to estimate the BP. However, the accuracy is still not adequate to be used as medical equipment because their features cannot express fully information of the pulse waveform which changes according to the BP. And, no other effective knowledge about the pulse waveform for estimating BP has been found yet. Therefore, in this study, we focus on the autoencoder which can extract complex features and can add new features of the pulse waveform for estimating the BP. By using autoencoder, we extracted 100 features from the coupling signal of the pulse wave and from its first-order differentiation and second-order differentiation. The result of examination with 1363 test subjects show that the correlation coefficients and the standard deviation of the difference between the measured BP and the estimated BP got improved from R = 0.67, SD = 13.97 without autoencoder to R = 0.78, SD = 11.86 with autoencoder. PMID- 30440998 TI - Respiratory and cardiac monitoring at night using a wrist wearable optical system. AB - Sleep monitoring provides valuable insights into the general health of an individual and helps in the diagnostic of sleep-derived illnesses. Polysomnography, is considered the gold standard for such task. However, it is very unwieldy and therefore not suitable for long-term analysis. Here, we present a non-intrusive wearable system that, by using photoplethysmography, it can estimate beat-to-beat intervals, pulse rate, and breathing rate reliably during the night. The performance of the proposed approach was evaluated empirically in the Department of Psychology at the University of Fribourg. Each participant was wearing two smart-bracelets from Ava as well as a complete polysomnographic setup as reference. The resulting mean absolute errors are 17.4ms (MAPE 1.8%) for the beat-to-beat intervals, 0.13beats-per-minute (MAPE 0.20%) for the pulse rate, and 0.9breaths-per-minute (MAPE 6.7%) for the breath rate. PMID- 30440999 TI - Wearable textile based on silver plated knitted sensor for respiratory rate monitoring. AB - Wearable systems are gaining broad acceptance for monitoring physiological parameters in several medical applications. Among a number of approaches, smart textiles have attracted interest because they are comfortable and do not impair patients' movements. In this article, we aim at developing a smart textile for respiratory monitoring based on a piezoresistive sensing element. Firstly, the calibration curve of the system and its hysteresis have been investigated. Then, the proposed system has been assessed on 6 healthy subjects. The volunteers were invited to wear the system to monitor their breathing rate. The results of the calibration show a good mean sensitivity (i.e., approximately 0.11V.%-1); although the hysteresis is not negligible, the system can follow the cycles also at high rates (up to 36 cycle.min-1). The feasibility assessment on 6 volunteers (two trials for each one) shows that the proposed system can estimate with good accuracy the breathing rate. Indeed, the results obtained by the proposed system were compared with the ones collected with a spirometer, used as reference. Considering all the experiments, a mean percentage error was approximately 2%. In conclusion, the proposed system has several valuable features (e.g., the sensing element is lightweight, the sensitivity is high, and it is possible to develop comfortable smart textile); in addition, the promising performances considering both metrological properties and assessment on volunteers foster future tests focused on: i) the possibility of developing and system embedding several sensing elements, and ii) to develop a wireless acquisition system, to allow comfortable and long-term acquisition in both patients and during sport activities. PMID- 30441000 TI - Effect Of Compression Garments On Cardiovascular Function During Recovery Phase. AB - The aim of this present research was to determine whether the cardiovascular function has been affected by wearing compression garments during the recovery phase. Fourteen subjects (men, $?text{n}=$7; women, $?textbf{n}=$7; $24.7 ?pm 4.5$ years, $166.0 ?pm 7.6$ cm; $60.9 ?pm 12.0$ kg) completed a running protocol on a treadmill. Each subject participated in two running experiments, using either compression garments (CGs) or non- compression garments (NCGs) during exercise and 2 hours recovering time. Electrocardiogram (ECG) signals were collected during 2 hours recovery using wearable sensors. The present work indicated a statistically significant difference between CGs and NCGs from 90 minutes recovery onwards $( ?mathrm {p}<0.05)$. ECG parameters showed some significant difference in heart rate (HR), ST and corrected QT (QTc $) ( ?mathrm {p}<0.05)$. Therefore, the cardiovascular function was positively influenced by the application of CGs during the recovery phase. PMID- 30441001 TI - E-BiInSn Enhanced Rigidity Alterable Artificial Bandage. AB - surgery, orthopedic cast is often implemented to stabilize and fix anatomical structures like broken bones. Plaster could harden after mixed with water, thus it is commonly utilized with cotton bandage to form a solid structure to encase a limb or other body parts. As plaster is heavy and impervious, cast could easily result in itching, rashes, allergic contact dermatitis or other cutaneous complications. In this paper we present a novel implementation for surgical fixation with low melting point alloy (LMPA) stuffed in silicone tubes, which is dubbed "LMPA enhanced bandage The alloy is heated by an enameled copper wire to alter the stiffness. When the alloy is in solid state, the bandage could withstand high load without significant deformation, while if heated to its melting point, the entire bandage would soften. We present several conceptual experiments to evaluate the mechanical performance and body fixation of the proposed bandage. Phase change process and temperature variation were recorded by an infrared camera. Preliminary results showed that the present fixation bandage design owns sufficient mechanical strength and necessary thermal response performance to meet the requirement of clinical applications. PMID- 30441002 TI - An Ultra-miniaturized Near Infrared Spectroscopy System to Assess Sleep Apnea in Children with Down Syndrome. AB - Down syndrome is one of the health disorders that interferes with regular and healthy sleep. Most children with Down syndrome are referred to a sleep clinic for the assessment of the severity of their apnea. Regular polysomnography based assessment of apnea has been challenging with this sensitive patient population. We present our efforts towards developing a flexible adhesive bandage sized near infrared spectroscopy system (pediBand) for home-assessment of apnea in children with Down syndrome. Combined with inertial measurement units, pediBand record heart rate, heart rate variability, respiratory rate, arterial oxygen saturation and cerebral oxygen saturation. These are the essential parameters to assess sleep apnea and could also potentially be used in the assessment of sleep performance in general. A modified version of pediBand system was evaluated on adult patients and successfully demonstrated the changes in hemodynamic system triggered by sleep apnea. PMID- 30441003 TI - Accelerometer based Active Snore Detection for Behavioral Modification. AB - Habitual snoring has been known to increase the risk for serious health problems in addition to affecting the quality of others' sleep. Several recent consumer products aim to automatically detect snoring events and wake the snorer to elicit a posture change. In this paper, we present a study comparing two of the methods, electromyography vs. accelerometry, proposed for automated snoring detection and incorporation of these into a wearable system. The study includes (a) the testing of various sensor configurations and placements to obtain optimal electromyography and accelerometry signals, (b) a review of the accuracy of a variety of snore detection algorithms from previously attained biological signals, and (3) design of an embedded device with integrated sensors and haptic feedback capability. Our preliminary results indicate superiority of accelerometry over electromyography. Further research opportunities to prove the concept and improve the design are then detailed for future work. PMID- 30441004 TI - Gold foil-based biosensor for the determination of hydrogen peroxide. AB - Hydrogen peroxide ($?text{H}_{?mathbf {2}} ?mathbf {O} _{?mathbf {2}}$) plays a critical role in the regulation of multifarious physiological processes. We developed a sensor containing a mercaptopropionic acid (MPA) monolayer covalently immobilized with Horseradish peroxidase (HRP) enzyme for the electrochemical detection of hydrogen peroxide ($?textbf{H}_{?mathbf {2}} ?mathbf {O} _{?mathbf {2}}$). A gold foil substrate was chemically treated with nitric acid and were used as working electrode. Platinum wire and Ag-Ag/Cl were used as counter and reference electrodes, respectively. The acid treated gold electrode with the immobilized enzyme shown to have improved catalytic activity in the reduction of $?textbf{H}_{?mathbf {2}} ?mathbf {O} _{?mathbf {2}}$. The steady-state current response increases linearly with $?textbf{H}_{?mathbf {2}} ?mathbf {O} _{?mathbf {2}}$ concentration from 10 $?mu ?textbf{M}$ to 9 mM with a low detection limit of 60 $?mu ?textbf{M}$ and showed a sensitivity of 0.4 mA/ mM cm$^{?mathbf {2}}$. This electrochemical sensor is demonstrated to be highly selective and sensitive in the presence of interfering analytes. The improved activity and simple preparation method of the electrode makes the MPAHRP modified gold electrode promising for being developed as an attractive robust material for electrochemical $?textbf{H}_{?mathbf {2}} ?mathbf {O} _{?mathbf {2}}$ sensing. PMID- 30441005 TI - Portable Fluorescence Detection Platform with Integrating Sphere. AB - A platform coupled with an integrating sphere for portable fluorescence detection was presented in this paper. The detector under testing has a demonstrated lower limit of detection 0.4 nM for detecting fluorescein solutions and 0.00128 ng/mL for detecting SYBR-Green stained dsDNA in this preliminary work. The signal-to noise ratio analysis suggests that the limit of detection could be even lower than presented herein. PMID- 30441006 TI - Capacitive Micromachined Ultrasonic Transducer (CMUT)-based Biosensor for Detection of Low Concentration Neuropeptide. AB - Accurate detection of neuropeptides in cerebrospinal fluid (CSF) plays an important role in both indepth studies and early diagnosis of neurological diseases. Here, we report a biosensor based on Capacitive Micromachined Ultrasonic Transducer (CMUT) which is capable of detecting low concentrations (pg $?sim $ ng/ml) of a neuropeptide involved with the progression of Alzheimer's diseases, somatostatin (SST). A 10-MHz CMUT was fabricated and utilized as a physical resonant sensor which detects the change in the concentration of analyte through the mass-loading mechanism. The resonant plate was sequentially coated with protein G and antibodies to provide specificity to SST; Cysteine-tagged protein G layer enables controlled immobilization of antibodies in a welloriented manner. The change in the resonant frequency of the CMUT sensor was measured after incubating the sensor in various concentrations of SST. The significant shifts in the resonant frequency were observed for SST concentrations in the range of 10 pg/ml $?sim 1$ ng/ml. Compared to the previously reported biosensors developed for SST detection, our sensor shows discernable responses for SST that are $?sim 6$ orders of magnitude lower in concentration. Thus, this work demonstrates the potential of the CMUT resonant sensor as a promising biosensor platform for detection of neuropeptides involved with neurodegenerative diseases that often exist in low concentrations in CSF. PMID- 30441007 TI - Label-free Paper-based Immunosensor with Graphene Nanocomposites for Electrochemical Detection of Follicle-stimulating Hormone. AB - Follicle-stimulating hormone (FSH) is an important indicator of ovarian reserve function in women in clinical testing. In this work, a label-free paper-based immunosensor was developed for electrochemical rapid detection of FSH. A hydrophilic channel surrounded with hydrophobic barriers was firstly fabricated on the chromatography paper by wax printing technology. Then three electrodes were screen-printed on the circle zones of the channel, in which one carbon electrode further modified by reduced graphene-oxide /thionine /gold nanoparticles nanocomposites and FSH monoclonal antibody was used as the working electrode to provide sensitivity of the immunosensor. The detection of FSH is based on the decreased electrochemical current of Thi produced from the specific binding of the FSH and anti-FSH, and the decrease of the current is proportional to the concentration of the FSH. The experimental results exhibited that the immunosensor could be used to detect the standard FSH in range of 1-100 mIU/mL with the detection limit of 1 mIU/mL. And the proposed immunosensor had been successfully applied to detect FSH in serum samples. PMID- 30441008 TI - Identification of Biomarkers with Different Classifiers in Urine Test. AB - Biomarkers in urine samples are widely used in clinical diagnosis. Involving image processing and data analysis, urinalysis is very popular in hospitals because of its convenience and speediness; and the most important reason is its high accuracy rating. This paper presents colorimetric recognition for urine test device with different algorithms aiming to find a good-performance classifier. Those algorithms can train a set of data and get a model to discriminate the test data. Almost the accuracy of each classifier is beyond 92%, even 99%. Although the classifier that has highest average accurate rate of recognition is K-Nearest Neighbor, we cannot overlook the performance of Support Vector Machine, which perform best in protein test. In order to compare these eight algorithms, we use Python simulation to validate the results and show the accuracy of each classifier. PMID- 30441009 TI - A Mobile App for the Remote Monitoring and Assistance of Patients with Parkinson's Disease and their Caregivers. AB - The remote monitoring of patients is based on digital systems that enable the remote collection, usually at home, of health data and its transmission to health centers. The telemedicine paradigm is of particular interest in chronic diseases, fragile population and elderly monitoring. Parkinson's disease (PD) is a neurodegenerative disorder having high impact on the lives of patients and their families. Such a disease impacts on the physical and psychological abilities of the patient and may have an effect on the relationship among family members. The strict monitoring of PD patients and their caregivers is of paramount importance in the implementation of prompt actions counteracting the worsening of the disease or that of the caring process. In this paper we present a mobile App developed for PD patients and their caregiver. The App aims at improving the communication among the patient/caregiver and the specialists, covering aspects related to both the disease symptoms and the caring process. In the paper we describe the App along with results collected during a one year experimentation on a cohort of 10 patients and 7 caregivers. The results show that the approach is accepted by patients and caregivers. Furthermore, obtained results demonstrate that the monitoring system is effective in the identification of dangerous conditions for the patient and useful in the implementation of reactive health management strategies. PMID- 30441010 TI - Identification of Parkinson's Disease Utilizing a Single Self-recorded 20-step Walking Test Acquired by Smartphone's Inertial Measurement Unit. AB - Parkinson's disease (PD) is a degenerative and long-term disorder of the central nervous system, which often causes motor symptoms, e.g., tremor, rigidity, and slowness. Currently, the diagnosis of PD is based on patient history and clinical examination. Technology-derived decision support systems utilizing, for example, sensor-rich smartphones can facilitate more accurate PD diagnosis. These technologies could provide less obtrusive and more comfortable remote symptom monitoring. The recent studies showed that motor symptoms of PD can reliably be detected from data gathered via smartphones. The current study utilized an open access dataset named "mPower" to assess the feasibility of discriminating PD from non-PD by analyzing a single self-administered 20-step walking test. From this dataset, 1237 subjects (616 had PD) who were age and gender matched were selected and classified into PD and non-PD categories. Linear acceleration (ACC) and gyroscope (GYRO) were recorded by built-in sensors of smartphones. Walking bouts were extracted by thresholding signal magnitude area of the ACC signals. Features were computed from both ACC and GYRO signals and fed into a random forest classifier of size 128 trees. The classifier was evaluated deploying 100-fold cross-validation and provided an accumulated accuracy rate of 0.7 after 10k validations. The results show that PD and non-PD patients can be separated based on a single short-lasting self-administered walking test gathered by smartphones' built-in inertial measurement units. PMID- 30441011 TI - Activity Tracking with Momentary Assessments. AB - Task and activity tracking has been an effective industrial management and research technique for generations. It is applied to workflow optimization, group coordination, task sequencing, individual time management and environmental exposures. Appropriately, task tracking technologies are migrating to personal mobile devices. At the same time, individual survey approaches have been advanced tremendously as mobile apps. We report on a method of dynamic task registration with momentary assessment systems in natural environments that apply knowledge of context. We describe how the app was refined by a user acceptance study and its deployment in studies on agricultural exposure and industrial operations. PMID- 30441012 TI - CEA: Clinical Event Annotator mHealth Application for Real-time Patient Monitoring. AB - This research develops a novel dynamic mobile health (mHealth) application (app), called the Clinical Event Annotator (CEA). The CEA comprises of a native Android tablet app and an administrative web app. The native app is used at the patient bedside to manually annotate clinical events in real-time. Event types include patient monitor alarms, routine care, clinical interventions, and patient movements. The app can be dynamically updated with user-defined customized events. The web app generates reports of the annotation sessions. The CEA app is developed to support a clinical study that explores the use of pressure-sensitive mats (PSM) in the neonatal intensive care unit (NICU) to detect the respiratory rate (RR), heart rate (HR), and movement of critically ill neonatal patients. High-fidelity CEA app annotations are synced with a backend database that enables integration and synchronization with independently acquired patient monitoring data, such as RR, HR, and contact pressure data from the PSM. The gold standard CEA annotations serve the purpose of retrospectively training machine learning algorithms for clinical event detection. Preliminary test results from use of the app in the clinical study are presented. Development of the CEA app is a unique and novel contribution that addresses the well-known problem of manually annotating physiologic data streams to support clinical data mining applications. PMID- 30441013 TI - Congestive Heart Failure Risk Assessment Monitoring through Internet of things and mobile Personal Health Systems. AB - Congestive heart failure (CHF) occurs when the heart cannot provide the necessary cardiac output for the metabolic needs of the human body. The most prominent symptoms are increased venous pressure, abnormal heart and breathing rate, tiredness and leg swelling. Most important pathogenesis influence are: age, gender, high blood pressure, alcohol and smoking, sedentary lifestyle and diet, genetic predisposition and family history, diabetes, and atherosclerosis. Common causes are considered to be valvular heart disease, coronary heart disease and hypertension. CHF diagnosis can be achieved through physical examination (i.e., blood pressure, body mass index, blood tests) and echocardiography. In this work, we present a smart mobile application and internet of things capable of the early detection and real-time monitoring of CHF exacerbations, enforcing prevention on a daily basis. We refer to the architectural elements of our approach accounting for the integration of a secure access scheme, following GDPR regulation, as a novel biometric solution to increase security and access. A first validation of the system is also presented. PMID- 30441014 TI - Severity Classification of Chronic Obstructive Pulmonary Disease and Asthma with Heart Rate and SpO2 Sensors. AB - Asthma and Chronic Obstructive Pulmonary Disease are chronic and long-term lung diseases. Disease monitoring with minimal sensors with high efficacy can make the disease control simple and practical for patients. We propose a model for the severity assessment of the diseases through wearables and compatible with mobile health applications, using only heart rate and SpO2 (from pulse oximeter sensor). Patient data were obtained from the MIMIC- III Waveform Database Matched Subset. The dataset consists of 158 subjects. Both heart rate and SpO2 signal of patients are analyzed via the proposed algorithm to classify the severity of the diseases. Strategically, a rule-based threshold approach in real time evaluation is considered for the categorization scheme. Furthermore, a method is proposed to assess severity as an Event of Interest (EOI) from the computed metrics in retrospective. This type of autonomous system for real-time evaluation of patient's condition has the potential to improve individual health through continual monitoring and self- management, as well as improve the health status of the overall Smart and Connected Community (SCC). PMID- 30441015 TI - Low temperature approach for high density electrical feedthroughs for neural implants using maskless fabrication techniques. AB - Implantable electronic packages for neural implants utilize reliable electrical feedthroughs that connect the inside of a sealed capsule to the components that are exposed to the surrounding body tissue. With the ongoing miniaturization of implants requiring ever higher integration densities of such feedthroughs new technologies have to be investigated. The presented work investigates the sealing of vertical feedthroughs in aluminum-oxide-substrates with gold stud-bumps. The technology enables integration densities of up to 1600/cm 2 while delivering suitable water leak rates for realistic implantation durations of miniaturized packages (feedthrough-count $>50$, package-volume $<2$ cm $^{3})$ of more than 50 years. All manufacturing steps require temperatures below $420 ^{?circ}?mathrm {C}$ and are suitable for maskless rapid prototyping. PMID- 30441016 TI - An Energy-Efficient, Inexpensive, Spinal Cord Stimulator with Adaptive Voltage Compliance for Freely Moving Rats. AB - This paper presents the design and fabrication of an implantable control unit intended for epidural spinal cord stimulation (ESCS) in rats. The device offers full programmability over stimulation parameters and delivers a constant current to an electrode array to be located within the spinal canal. It implements an adaptive voltage compliance in order to reduce the unnecessary power dissipation often experienced in current-controlled stimulation (CCS) devices. The compliance is provided by an adjustable boost converter that offers a voltage output in the range of 6.24 V to 28 V, allowing the device to deliver currents up to 1 mA through loads up to $25 ?mathrm {k}?Omega $. The system has been fabricated using discrete components, paving the way to an inexpensive product that can easily be manufactured and batch produced. The control unit occupies a total volume of ~13.5 cm3 and therefore fulfills the size restrictions of a system to be implanted in a rat. Results indicate that by adjusting the voltage compliance a total power efficiency up to 35.5% can be achieved, saving around 60 mW when using lower stimulation currents or operating on smaller impedances. The achieved efficiency is the highest compared to similar stateof-the-art systems. PMID- 30441017 TI - PDMS Gasket Underfill for Long-Term Insulation of High-Density Interconnections in Active Implantable Medical Devices. AB - This work presents reliability investigations of silicone gasket as solid underfill for interconnection interfaces in hybrid implant systems with high channel count flexible electrode arrays and hermetically packed electronics. The gasket is fabricated by laser structuring thin sheet of silicone rubber. The surface activation of silicone sheet ensures mechanical bonds with the mating surfaces thereby improving the mechanical stability of the assembly and the insulation of the interconnects. The gasket samples with $10 ?times 10$ openings for interconnect pads, each with diameter of $270 ?mu ?mathrm {m}$ and a center to center pitch size of $490 ?mu ?mathrm {m}$, were sandwiched between a polyimide array and a metallized ceramic substrate. The gasket maintained high insulation impedance of $15 ?pm 0.30 ?mathrm {M}?Omega $ between the adjacent interconnects with markedly capacitive behavior (phase angle, $- 89 ^{?circ})$ after 17 weeks in soaked conditions under accelerated aging at $60 ^{?circ}?mathrm {C}$. The gasket also survived electrical stresses and sustained high impedance $(10.93 ?mathrm {M}?Omega $ with phase angle of $- 88 ^{?circ})$ when subjected to constant 3 VDC for 100 days. PMID- 30441018 TI - Experimental factors effecting stability of Electrochemical Impedance Spectroscopy Measurements. AB - Impedance measurement using Electrochemical Impedance Spectroscopy is a widely utilized technique in neural electrodes. Research and clinical devices that incorporate stimulating and recording microelectrodes routinely characterize the material's integrity and its functionality through impedance measurement. Nominal impedance values ensure a stable neural electrode-tissue contact capable of passing through power efficient electric signals with desired signal-tonoise ratio or effective volume coverage. However, the complexity of the in vivo environment limits the usage of the three-electrode setup, which has been accepted as the ideal method in providing a stable impedance measurement. Impedance data measured from microelectrodes in threeelectrode and two-electrode setups show that the two setups have similar outcomes in terms of the impedance modulus over a 0.5 Hz-100 kHz frequency range. Usage of a platinum counter electrode lowered the overall variance in impedance readings compared to the stainless steel counter electrode. However, correlation coefficient values $(>0.97)$ between three-electrode and two-electrode setups show that impedance values seldom deviate due to changes in electrode setup. Based on the results of this study, the usage of the two-electrode setup in vivo allowed acceptable electrochemical impedance spectroscopy accuracy, and the utilization of a platinum counter electrode is recommended to reduce measurement variance. PMID- 30441019 TI - Neurophysiological Evaluation of a Customizable MUECoG-based Wireless Brain Implant. AB - The number of implantable bidirectional neural interfaces available for neuroscientific research applications is still limited, despite the rapidly increasing number of customized components. We previously reported on how to translate available components into "ready-to-use" wireless implantable systems utilizing components off-the-shelf (COTS). The aim of the present study was to verify the viability of a micro-electrocorticographic ($?mu $ECoG) device built by this approach. Functionality for both neural recording and stimulation was evaluated in an ovine animal model using acoustic stimuli and cortical electrical stimulation, respectively. We show that auditory evoked responses were reliably recorded in both time and frequency domain and present data that demonstrates the cortical electrical stimulation functionality. The successful recording of neuronal activity suggests that the device can compete with existing implantable systems as a neurotechnological research tool. PMID- 30441020 TI - Cardiovascular variability in young male and female subjects in health and orthostatic intolerance. AB - The aim of this study was to investigate the effect of head-up tilt (HUT) test on male and female young patients, diagnosed with orthostatic intolerance (OI), in comparison to male and female healthy subjects. Twenty seven OI patients (21 women, 6 men) and 26 age-matched healthy subjects (13 women, 13 men) were enrolled in a 70 degrees HUT test. In addition to hemodynamic variables, cardiovascular and respiratory parameters were determined using linear and nonlinear methods to analyze heart rate (HRV) and blood pressure variability (BPV). During the complete test, HRV was lower in healthy men than in female controls. Decreased HRV and increased BPV were observed in female patients compared to healthy women. Furthermore, systolic BPV was increased in male and female patients. However, linear (rmssd) and nonlinear (plvar2) parameters indicated that diastolic BPV decreased in male patients during orthostatic phase, but remained unchanged in female patients. Findings indicated gender dependent mechanisms for the regulation of diastolic blood pressure during orthostatic stress in patients. PMID- 30441021 TI - Motion Artifact Removal for PPG Signals based on Accurate Fundamental Frequency Estimation and Notch Filtering. AB - This study proposes a new method for motion artifact (MA) removal in Photoplethysmography (PPG) signal that combines accurate heart rate (HR) frequency estimation and notch filtering. The method applies LMS-Newton adaptive filtering to reduce motion artifact noise and uses a novel HR correction stage for accurate HR frequency estimation. Notch filters are used to recover clean PPG signal from HR frequency and second harmonic frequency of PPG. On a widely used dataset of 12 recordings, our method achieves an averaged HR error of 0. 92bpm and a Pearson correlation of 0.997. Experimental results further show that our method can recover the PPG waveform with clear dicrotic peaks even for strongly MA-corrupted PPG signal. PMID- 30441022 TI - Reconstructed Dynamics of the Imaging Photoplethysmogram. AB - Human photoplethysmogram (PPG) is one of the signals widely applied for health monitoring. Development of the new techniques made possible evolution of traditional contact PPG which was measured at red and near-infrared light (NIR) to the contactless, imaging PPG (iPPG) that can be recorded at various light wavelengths, including ambient visible light. However, despite the numerous advantages of iPPG its applications demonstrated so far are quite limited. The NIR PPG was previously found to be useful for various applications in the area of physiological and mental health monitoring by utilizing advanced methods of nonlinear time-series analysis applied on its reconstructed dynamics. The main purpose of this study is to demonstrate data-driven approach with time-delay reconstructed attractor obtained from the iPPG. The results of this study demonstrated that the iPPG dynamics can be reconstructed with fine data resolution, and its time-delay-reconstructed trajectory is almost deterministic, though contains noise. The obtained results might be useful for further applied studies on the iPPG. PMID- 30441023 TI - A 3.3 V, 8.89 MUA and 5.5 ppm/ degrees C CMOS bandgap voltage reference for power telemetry in retinal prosthesis systems. AB - A 3.3 V CMOS bandgap reference (BGR) was presented in this study that utilizes MOS transistors operating in the sub-threshold region. The complexity of the circuit and the dependency of the voltage reference on power supply variations are simultaneously decreased through the use of a new compensation circuit technique. The proposed BGR is simulated using a 0.35 $?mu ?mathrm{m}$ CMOS standard process. Consequently, a 5.53 ppm/ degrees C temperature coefficient is obtained in the -40~+125 degrees C temperature range, the maximum power supply rejection ratio is - 62 dB, and a 2.033 mV/V voltage line regulation is achieved for the $2.3?sim 4.3$ V supply voltage. The proposed circuit dissipates a supply current of 8.89 IJA at a 3.3 V supply voltage, and the active area is 112 $?mu ?mathrm{m}?times 60 ?mu ?mathrm{m}$. PMID- 30441024 TI - Interface Adhesion in Implantable Chip-in-Foil Systems. AB - Bioelectronic medicine requires miniaturized implants to selectively interface small target structures in the autonomous nervous system. Long-term stable non hermetic packaging techniques have to be developed for smallest implantable electronics and interfaces. A process for the fabrication of chip-in-foil implants is proposed that combines a flip-chip approach for bare die embedding with a silicone rubber backbone. The conducting tracks are structured on polyimide (PI), enabling the use of microsystems fabrication technologies. The long-term stability of the interface between PI and silicone rubber is investigated by peel tests in phosphate buffered saline after prolonged soaking at $37 ^{circ}?mathrm {C}$. With a peel force of 721 mN after 14 days of soaking, the combination of 10-nm-thick titanium oxide and the adhesion promoter Dow Corning 1200 OS leads to the highest interface stability of the tested methods. This conforms to the results of atomic force microscopy measurements, where this treatment increased the surface roughness from 0.44 nm to 46.45 nm. The devised interface enables the construction of a chip-in-foil system with silicone rubber for height levelling in combination with polyimide-based micro structuring. PMID- 30441025 TI - Long-term in vivo performance of novel ultrasound powered implantable devices. AB - Neuromodulation devices have been approved for the treatment of epilepsy and seizures, with many other applications currently under research investigation. These devices rely on implanted battery powered pulse generators, that require replacement over time. Miniaturized ultrasound powered implantable devices have the potential to eliminate the need for batteries in neuromodulation devices. While these devices have been assessed in vitro, long-term in vivo assessment is required to determine device safety and performance. In this study, we developed a multi-stage long-term test platform to assess the performance of miniaturized ultrasound powered implantable devices. PMID- 30441026 TI - Vascular Graft Pressure-Flow Monitoring Using 3D Printed MWCNT-PDMS Strain Sensors. AB - Real-time monitoring of arteriovenous graft blood flow would provide early warning of graft failure to permit interventions such as angioplasty or graft replacement to avoid catastrophic failure. We have developed a new type of flexible pulsation sensor (FPS) consisting of a 3D printed elastic cuff wrapped around a graft and thus not in contact with blood. The FPS uses multi-walled carbon nanotubes (MWCNTs) dispersed in polydimethylsiloxane (PDMS) as a piezoresistive sensor layer, which is embedded within structural thixotropic PDMS. These materials were specifically developed to enable sensor additive manufacturing via 3D Bio-plotting, and the resulting strain sensor is more compliant and has a wider maximum strain range than graft materials. Here, we analyze the strain transduction mechanics on a vascular graft and describe the memristive properties of MWCNT-PDMS composites, which may be mitigated using AC biasing. In vitro testing of the FPS on a vascular graft phantom showed a robust, linear sensor output to pulsatile flows (170-650 mL/min) and pressures (62-175 mmHg). The FPS showed an RMS error when measuring pressure and flow of 7.7 mmHg and 29.3 mL/min, with a mean measurement error of 6.5% (pressure) and 8.0% (flow). PMID- 30441027 TI - A Low-Power Injection-Locked VCO for an Implantable MICS Band Transmitter with Wireless Frequency Reference and Tune-while-Lock Channel Calibration. AB - This paper presents the design of an 800 MHz VCO for both free-running and injection locked operation in a novel low power transmitter with wireless frequency reference, operating in the MICS band (402-405 MHz). The transmitter employs simultaneous tuning and locking, to set the desired channel with a minimal injected power. The VCO is designed and fabricated in a 0.13 $?mu ?mathrm{m}$ SiGe BiCMOS process and has a core area of 0.5 $?mathrm{m}?mathrm{m}^{2}$. The measurement of the free-running VCO shows -107 dBc/Hz phase noise at 300 kHz frequency offset. If locked to an external frequency reference the VCO shows 118 dBc/Hz phase noise at 300 KHz offset, while consuming 3 mA from a 1.2 V supply (3.6 mW). When the VCO is tuned during the locking, 20 dBm of reference power is required to enable operation in the whole MICS band. The measured phase noise of the free-running VCO ensures reliable calibration of the proposed transmitter and the locked VCO satisfies all requirements of an implantable device using MICS band data transmission. Therefore, this VCO presents a key building block of an injection locked, frequency agile, implantable transmitter for the MICS band. PMID- 30441028 TI - Sensors Selection for Continuous Monitoring of Bowel State and Activity. AB - New research and diagnosis tools are needed to continuously measure bowel state and activity. We investigated functionality of several sensors in vivo and in vitro. Five sensor types, including pressure, infrared, color, conductivity and capacitance, were tested to validate functionality inside the colon. Initial wired prototypes were tested and calibrated in benchtop testing and then inserted intraluminally into pig colon and rectum in three acute surgical procedures. The results from both benchtop and in-vivo testing correlate and indicate that pressure, conductivity, and capacitance measurements could provide information on the state of the bowel and its activity. PMID- 30441029 TI - Spectral Imaging Of Thermal Damage Induced During Microwave Ablation In The Liver. AB - Induction of thermal damage to tissue through delivery of microwave energy is frequently applied in surgery to destroy diseased tissue such as cancer cells. Minimization of unwanted harm to healthy tissue is still achieved subjectively, and the surgeon has few tools at their disposal to monitor the spread of the induced damage. This work describes the use of optical methods to monitor the time course of changes to the tissue during delivery of microwave energy in the porcine liver. Multispectral imaging and diffuse reflectance spectroscopy are used to monitor temporal changes in optical properties in parallel with thermal imaging. The results demonstrate the ability to monitor the spatial extent of thermal damage on a whole organ, including possible secondary effects due to vascular damage. Future applications of this type of imaging may see the multispectral data used as a feedback mechanism to avoid collateral damage to critical healthy structures and to potentially verify sufficient application of energy to the diseased tissue. PMID- 30441030 TI - Endogenous Fluorescence Lifetime Imaging (FLIM) Endoscopy For Early Detection Of Oral Cancer And Dysplasia. AB - We have performed a pilot clinical study, in which multispectral endogenous fluorescence (or autofluorescence) lifetime imaging (FLIM) was performed on clinically suspicious oral lesions of 73 patients undergoing tissue biopsy for oral dysplasia and cancer diagnosis. The results from this pilot study indicated that mild-dysplasia and early stage oral cancer could be detected from benign lesions using a computed aided diagnosis system developed based on biochemical and metabolic biomarkers derived from the endogenous FLIM images. The diagnostic performance of this novel FLIM clinical tool was estimated using a leave onepatient-out cross-validation approach, which reported levels of sensitivity >90%, specificity >85%, and Area Under the Receiving Operating Curve (ROC-AUC) >0.9. PMID- 30441031 TI - Monkey-MIMMS: Towards Automated Cellular Resolution Large- Scale Two-Photon Microscopy In The Awake Macaque Monkey. AB - The size and curvature of the macaque brain present challenges for two photon laser scanning microscopy (2P-LSM). General access to the cortex requires 5-axis positioning over a range of motion wider than existing designs offer. In addition, movement artifacts due to physiological pulsations and bodily movement present particular challenges. We present a microscope and implant platform that allows for repeatable, motorized positioning and stable imaging at any point on the dorsal convexity of macaque cortex. While testing the system to image neurons expressing fluorescent proteins in an awake macaque, motion artifacts were limited to several microns. PMID- 30441032 TI - Fast And Robust Heart Rate Estimation From Videos Through Dynamic Region Selection. AB - Remote heart rate (HR) estimation from videos is useful because it facilitates monitoring ongoing health conditions without sensors that are often uncomfortable to wear. In the HR estimation from videos, choice of the image region, at which the HR is calculated, is critically important as it greatly affects the estimation accuracy. In this paper, a novel algorithm for HR estimation that uses dynamic region selection is proposed. The image regions that clearly contain pulse waveforms are quickly found by a region selector using a machine learning technique. In addition, the proposed method enhances the robustness of tracking the temporal change of the HR by using a particle filter. The experimental results show that the proposed method achieves the absolute average error less than 1.1BPM (Beats Per Minute) with the processing time less than 0.6s for a single HR estimation. PMID- 30441033 TI - Sensibility Assessment For User Interface And Training Program Of An Upper-Limb Rehabilitation Robot, D-SEMUL. AB - Upper-limb rehabilitation training for hemiplegic patients has been primarily conducted by human therapists, and, hence, their use of training methods and conditions strongly depends on their expertise. The force control and motion sensing functions of rehabilitation robots are expected to be used for the qualitative training/assessment in the next-generation computerized rehabilitation. In this study, we developed a desktop rehabilitation robot for upper limbs (D-SEMUL). In addition, we also assessed the usability of its user interface and the affinity (acceptance) of the training program with a questionnaire for elderly hemiplegic/non-hemiplegic participants (nine hemiplegic, five males and four females and seven non-hemiplegic, two males and five females). The results indicated that the touchscreen is acceptable for the user interface, and the background music used significantly affects the affinity of the program. PMID- 30441034 TI - The Effectiveness Of Compression Garments On EEG During a Running Test. AB - The specific purpose of this present paper was to investigate whether the EEG activity has been affected by wearing whole body compression garments during a running test. Ten subjects (men, n=5; women, n=5; age: 24.11 +/- 4.48 years; height: 163.56 +/- 7.70 cm; chest: 87.78 +/- 6.92 cm; weight: 58.67 +/- 10.96 kg; BMI: 21.77 +/- 2.63 kg.m-2) completed a running protocol on a treadmill. Each subject participated in two running trials, wearing either a compression garment (CG) or a non-compression garment (NCG) during exercise. Electroencephalogram (EEG) signals were collected during exercise using wearable sensors. The present study revealed a statistically significant difference between CGs and NCGs in alpha, beta and theta power spectral density (p<0.05). Therefore, the brain activity was influenced by the application of CGs during the running test. This result would also recommends an application of CGs in training as well as in competition. PMID- 30441035 TI - Ensemble learning based on overlapping clusters of subjects to predict microsleep states from EEG. AB - Microsleeps are brief and involuntary instances of complete loss of sleep-related consciousness. We present a novel approach of creating overlapping clusters of subjects and training of an ensemble classifier to enhance the prediction of microsleep states from EEG. Overlapping clusters are created using Kullback Leibler divergence between responsive state features of each pair of training subjects. Highly correlated features within each overlapping cluster are discarded. The remaining features are selected via Fisher score based ranking followed by an average of 5-fold cross-validation areas under the curves of receiver operating characteristics (AUCRoc) of a linear discriminant analysis (LDA) classifier. The decisions of LDA classifiers on overlapping clusters are fused using weighted average. We evaluated this new approach on 16-channel EEG data from 8 subjects who had performed a 1-D visuomotor task for two l-h sessions. Joint entropy features were extracted from a 5-s window of EEG with steps of 0.25 s Test performances were evaluated using leave-one-subject-out cross-validation. Our ensemble of overlapping clusters of subjects achieved a mean prediction performance, phi, of 0.42 compared with 0.39 for a single LDA classifier and 0.37 for generalized stacking. PMID- 30441036 TI - The Impact Of Freezing Of Gait On Balance Perception And Mobility In Community Living With Parkinson'S Disease. AB - This pilot study investigated the impact of freezing of gait, objectively measured with three inertial sensors, on mobility function during seven days of communityliving monitoring in people with Parkinson's disease.Twenty-four subjects with PD, of which 14 experiencing freezing of gait, were recruited in this study. Subjects wore three inertial sensors (Opals, APDM) attached to both feet and the lumbar region for a week of continuous monitoring. Walking bouts, of at least 10s, were first identified, and then features of freezing, quantity and quality of mobility were extracted and averaged across the seven days.Results showed significant impairments in freezing and quality of mobility in the freezers group compared to the nonfreezers. Our measures of average and variability of time spent freezing was associated to the subjects' perception of freezing, assessed with the New Freezing of Gait Questionnaire. These preliminary results are introducing promising measures of mobility impairments measured during community-living in PD. PMID- 30441037 TI - Perception of Mechanical Impedance During Active Ankle and Knee Movement. AB - During locomotion, energy flow through the legs is governed by the mechanical impedance of each joint. These mechanical properties, including stiffness and damping, have recently been quantified at the ankle joint. However, the relevance of these properties in human sensorimotor control is unclear. An important aspect of sensorimotor control is the ability to sense small changes in stimuli. Thus, we investigated the human ability to detect small changes in the stiffness and damping components of leg joint impedance when interacting with a mechanical system coupled to the ankle or knee. The perception threshold was determined via a psychophysical paradigm that required subjects to compare the mechanical impedance of virtual spring-mass-damper systems. Subjects reliably detected impedance changes of 11% and 12% at the ankle and knee, respectively. Additionally, the perception of stiffness and damping were comparable, indicating that the biomechanical relevance of the stiffness and damping components of impedance may be similar. Finally, these results offer novel insight into the design and control of impedance-based technologies, such as prostheses and exoskeletons. PMID- 30441038 TI - Analysis Of Nociceptive Evoked Potentials During Multi-Stimulus Experiments Using Linear Mixed Models. AB - Neural processing of sensory stimuli can be studied using EEG by estimation of the evoked potential using the averages of large sets of trials. However, it is not always possible to include all stimulus parameters in a conventional analysis, since this would lead to an insufficient amount of trials to obtain the evoked potential by averaging. Linear mixed models use dependencies within the data to combine information from all data for the estimation of the evoked potential. In this work, it is shown that in multi-stimulus EEG data the quality of an evoked potential estimate can be improved by using a linear mixed model. Furthermore, the linear mixed model effectively deals with correlation between parameters in the data and reveals the influence of individual stimulus parameters. PMID- 30441039 TI - Investigation of the Influence of ECoG Grid Spatial Density on Decoding Hand Flexion and Extension. AB - Electrocorticogram (ECoG) has been used as a reliable modality to control a brain machine interface (BMI). Recently, promising results of high-density ECoG have shown that non redundant information can be recorded with finer spatial resolution from the cortical surface. In this study, highdensity ECoG was recorded intraoperatively from two patients during awake brain surgery while performing instructed hand flexion and extension. Event related desynchronization (ERD) were found in the low frequency band (LFB: 8-32 Hz) band while event related synchronization (ERS) were found in the high frequency band (HFB: 60-200 Hz). The classification between hand flexion and extension was performed by using common spatial pattern (CSP) as a feature extraction technique and linear discriminant analysis (LDA) as a classifier. In order to compare the high-density ECoG and normal ECoG in terms of classifying between hand flexion and extension, we simulated a typical clinical ECoG (8 mm spacing) by averaging the neural activity of nearest four channels. The same classification methods were applied on the averaged recordings. In HFB, the classification error rate using simulated ECoG greatly increased and lagged the movement onset compared to the original highdensity ECoG. In LFB, the differences between them were not prominent. These results indicated that high-density ECoG is able to capture non-redundant task related information from the motor cortex and potentially serves as a better modality to drive a neural prosthetic compared to typical clinical electrodes. PMID- 30441040 TI - EEG Complexity Maps to Characterise Brain Dynamics during Upper Limb Motor Imagery. AB - The Electroencephalogram (EEG) can be considered as the output of a nonlinear system whose dynamics is significantly affected by motor tasks. Nevertheless, computational approaches derived from the complex system theory has not been fully exploited for characterising motor imagery tasks. To this extent, in this study we investigated EEG complexity changes throughout the following categories of imaginary motor tasks of the upper limb: transitive (actions involving an object), intransitive (meaningful gestures that do not include the use of objects), and tool-mediated (actions using an object to interact with another one). EEG irregularity was quantified following the definition of Fuzzy Entropy, which has been demonstrated to be a reliable quantifier of system complexity with low dependence on data length. Experimental results from paired statistical analyses revealed minor topographical changes between EEG complexity associated with transitive and tool-mediated tasks, whereas major significant differences were shown between the intransitive actions vs. the others. Our results suggest that EEG complexity level during motor imagery tasks of the upper limb are strongly biased by the presence of an object. PMID- 30441041 TI - Chaotic Analysis of Hippocampal and Cortical Sleep EEG during Various Vigilance States. AB - In this paper, we investigate the hippocampal and cortical sleep EEG of adult rats at different sleep stages by employing Lyapunov exponent and third-order cumulant measures to quantify and compare the chaotic and nonlinear behavior of EEG obtained during vigilance states of quiet- waking, slow-wave sleep, and rapid eye movement (REM) sleep. Lyapunov exponent was computed to characterize the EEG for chaos and third-order cumulant was used to measure the deviations from Gaussianity of the signal. Our results show positive Lyapunov exponents for all EEG states indicating a Iow- dimensional chaos for both REM and non-REM system. Furthermore, REM sleep EEG exhibits the largest Lyapunov exponent in both hippocampal and cortical EEG amongst other vigilance states. We also identified non-zero third-order cumulant for all the vigilance states which suggests their non- Gaussian behavior. PMID- 30441042 TI - A New Sympathovagal Balance Index from Electrodermal Activity and Instantaneous Vagal Dynamics: A Preliminary Cold Pressor Study. AB - Sympathovagal balance, an autonomic index resulting from the sympathetic and parasympathetic influences on cardiovascular control, has been extensively used in the research practice. The current assessment is based on analyzing Heart Rate Variability (HRV) series in the frequency domain by regarding the ratio between the low and high frequency components (LF/HF). Nevertheless, LF and HF powers are known to be both influenced by vagal activity which strongly bias the accuracy of this method. To this extent, in this study we combine time-varying estimates from electrodermal activity (EDA) and HRV to propose a novel index of sympathovagal balance. Particularly, sympathetic activity is estimated from the EDA power calculated within the 0.045-0.25Hz bandwidth $(EDA_{Symp})$, whereas parasympathetic dynamics is measured instantaneously through a point-process modeling framework devised for heartbeat dynamics $(HF_{pp})$. We test our new index $SV = EDA_{Symp/HF_{pp}}$ on data gathered from 22 healthy subjects (7 females and 15 males) undergoing a 3 minutes gold standard protocol for sympathetic elicitation as the cold-pressor test (CPT). Results show that the activation of the proposed sympathovagal tone is consistent with CPT elicitation and is associated with a significantly higher statistical discriminant power than the standard LF/HF ratio, also revealing different dynamics between female and male subjects. PMID- 30441043 TI - ROAST: An Open-Source, Fully-Automated, Realistic Volumetric-Approach-Based Simulator For TES. AB - Research in the area of transcranial electrical stimulation (TES) often relies on computational models of current flow in the brain. Models are built on magnetic resonance images (MRI) of the human head to capture detailed individual anatomy. To simulate current flow, MRIs have to be segmented, virtual electrodes have to be placed on the scalp, the volume is tessellated into a mesh, and the finite element model is solved numerically to estimate the current flow. Various software tools are available for each step, as well as processing pipelines that connect these tools for automated or semi-automated processing. The goal of the present tool - ROAST - is to provide an end-to-end pipeline that can automatically process individual heads with realistic volumetric anatomy leveraging open-source software (SPM8, iso2mesh and getDP) and custom scripts to improve segmentation and execute electrode placement. When we compare the results on a standard head with other major commercial software for finite element modeling (ScanIP, Abaqus), ROAST only leads to a small difference of 9% in the estimated electric field in the brain. We obtain a larger difference of 47% when comparing results with SimNIBS, an automated pipeline that is based on surface segmentation of the head. We release ROAST as an open-source, fully-automated pipeline at https://www.parralab.org/roast/. PMID- 30441044 TI - Neuroengineering Tools For Studying The Effect Of Intracortical Microstimulation In Rodent Models. AB - Intracortical microstimulation can be successfully used to manipulate neuronal activity and connectivity, thus representing a potentially powerful tool to steer neuroplasticity occurring after brain injury. Activity-dependent stimulation (ADS), in which the spikes recorded from a single neuron are used to trigger stimulation at another cortical location, is able to potentiate cortical connections between distant brain areas. Here, we developed an experimental procedure and a computational pipeline aimed at investigating the ability of ADS to induce changes in intra-cortical activity of healthy anesthetized rats. PMID- 30441045 TI - The Effect of Movement Phase on the Contralaterally Coordinated Paired Associative Stimulation-Induced Excitability. AB - Paired associative stimulation (PAS) has been shown to increase corticospinal excitability (CSE) providing a promising adjuvant therapeutic approach for stroke. Combining PAS with movement of the stimulated limb may further increase enhancement of CSE, however, individuals with moderate to severe stroke may not be able to engage in the necessary repetitive voluntary movements of the paretic limb. The objective of this study was to investigate the feasibility of contralaterally coordinated PAS (ccPAS) applied to the resting hand extensors during fast extension of the contralateral hand. A potential dependency of CSE modulation on the phase of the movement of the opposite hand was evaluated. Eleven participants each completed three session: PAS applied to the resting right hand during the preparation phase of the extension of the contralateral (left) hand; PAS applied during the execution phase of the left hand extension; and PAS applied with both hands at rest. Motor evoked potentials (MEPs) were evoked from the right extensor digitorum communis (EDC) and flexor digitorum superficialis (FDS) muscles prior and immediately after each session. PAS delivered during the muscle contraction of the left hand and PAS delivered at rest both increased the MEP amplitude in the right EDC. PAS delivered before the left hand movement onset led to a decrease in the MEP amplitude measured in the right EDC muscle. We conclude that PAS induced bidirectional changes in the amplitude of MEPs that were dependent on the phase of the movement of the opposite hand. PMID- 30441046 TI - Effect of Aging on Cortical Current Flow Due to Transcranial Direct Current Stimulation: Considerations for Safety. AB - While intracranial volume is thought to be fixed throughout the lifespan, there is little doubt that the brain shrinks with age and it is most precipitous after about the age of 50. This as a consequence reflects an increase in cranial cerebrospinal fluid (CSF) with age. Of the myriad factors influencing brain current flow, these changes in CSF volume are expected to play a profound role given its high electrical conductivity. The aim of this study is to investigate the effects of agerelated morphological changes on brain current flow patterns due to transcranial Direct Current Stimulation (tDCS). Anatomical MRI data were collected for 5 healthy subjects spanning 5 decades of life (ages: 43 to 85). Finite element models derived from the MRI were used to calculate cortical electrical field values during tDCS. The widely used C3-Fp2 (M1-SO) and the F3-F4 montage along with two High Definition-tDCS electrode montages 4X1 (C3-centered) and 4X1 (F3-centered) were simulated. Peak induced electrical field at the intended brain target (assumed to be directly underneath the electrode) and at non-intended brain regions was compared with the individual brain atrophy coefficients. Findings across 4 subjects (ages: 43 to 75) indicate reduced peak electrical field with increasing age. However, this trend reverses for the oldest subject. While age-related morphological changes lead to significant changes in current flow distribution, they are not substantially different than younger adults. The predictions of this study are the first step to assess safety of tDCS in elderly subjects and provide a rational path in customizing stimulation dose for trials involving them. PMID- 30441047 TI - Cortical Brain Stimulation with Endovascular Electrodes. AB - Electrical stimulation of neural tissue and recording of neural activity are the bases of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and drug-resistant neurological disorders. Safety and efficacy are key aspects for the clinical acceptance of therapeutic neural stimulators. The cortical vasculature has been shown to be a safe site for implantation of electrodes for chronically recording neural activity, requiring no craniotomy to access high-bandwidth, intracranial EEG. This work presents the first characterization of endovascular cortical stimulation measured using cortical subdural surface recordings. Visual stimulation was used to verify electrode viability and cortical activation was compared with electrically evoked activity. Due to direct activation of the neural tissue, the latency of responses to electrical stimulation was shorter than for that of visual stimulation. We also found that the center of neural activation was different for visual and electrical stimulation indicating an ability of the stentrode to provide localized activation of neural tissue. PMID- 30441048 TI - Stimulation Effect of Inter-subject Variability in tDCS-Multi-scale Modeling Study. AB - Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation method that is convenient and popular in clinical use. However, there is a practical issue in applying tDCS; it is difficult to optimize the montage for each individual because of inherent inter-subject variability. Thus, the stimulation effect of such individual anatomical head variation has been investigated using anatomically realistic models. In this work, we developed a multi-scale computational model, which combined head models based on magnetic resonance imaging (MRI) and multi-compartmental neuronal models of pyramidal neurons (PNs), to investigate both the macroscopic and microscopic effects oftDCS. We constructed three different head models and compared the stimulation effects of tDCS in the primary cortex area (Brodmann area 4) with respect to the electric fields induced and steady-state membrane polarizations. We observed that the electric field behavior and induced somatic polarizations varied across subjects in accordance with the thicknesses of cerebrospinal fluid (CSF) and skull measured in each model. Thus, we concluded that variations in the CSF and skull might be correlated with the effects of tDCS. PMID- 30441049 TI - Signal-Adaptive Denoising Of Event-Related Potentials. AB - In the present study we propose a data-driven, fully unsupervised denoising approach for multi-trial univariate signals. The proposed methodology is based on Empirical Mode Decomposition (EMD) and hence also applicable for transient or non stationary signals. The rationale of the presented method is that different realizations (multiple trials) of the same underlying process have also similar intrinsic signal components. These components may be extracted by EMD for each single realization and finally, the entirety of all signal components forms clusters of corresponding components with similar spectral characteristics. A denoising is then tantamount to identifying the cluster(s) containing high frequency noise components. The effectiveness of the proposed methodology is demonstrated on the basis of visual event-related potentials (ERPs) of dyslexic and normal control children. We could show that the novel method allows for a reliable ERP estimation and that it provides a tool for an objective extraction of ERPs on both a single-subject as well as on a single-trial basis. PMID- 30441050 TI - Analysis of Spontaneous EEG Activity in Alzheimer's Disease Using Weighted Visibility Graph. AB - This study was aimed at characterizing spontaneous electroencephalography (EEG) activity in Alzheimer's disease (AD) using a novel approach named weighted visibility graph (WVG). More than 10 minutes of spontaneous EEG were recorded from 15 AD patients and 15 age-matched normal controls. Two graph metrics, clustering coefficient and average weighted degree, are extracted in different frequency bands for each EEG channel based on the WVG methodology. Furthermore, statistical analysis was performed in different bands and channels for both groups. It is demonstrated that AD patients are characterized with a significant increase of clustering coefficient and degree in theta band, which can be observed in most brain regions. Our results suggest that the WVG method can be are effective to distinguish different brain states (AD and normal) and may provide further insights into the underlying brain dynamics in AD. PMID- 30441051 TI - Dynamic Time-frequency Feature Extraction for Brain Activity Recognition. AB - The biomedical signal classification accuracy on motor imagery is not always satisfactory, partially because not all the important features have been effectively extracted. This paper proposes an improved dynamic feature extraction approach based on a time-frequency representation and an optimal sequence similarity measurement. Since the wavelet packet decomposition (WPD) generates more detailed signal variation information and the dynamic time warping (DTW) helps optimally measure the sequence similarity, more important features are kept for classification. We apply the extracted features from our proposed method to Electroencephalogram (EEG) based motor imagery through the OpenBCI device and obtain higher classification accuracy. Compared with traditional feature extraction methods, there is a significant classification accuracy improvement from 83.53% to 90.89%. Our work demonstrates the importance of the advanced feature extraction in time series data analysis, e.g. biomedical signal. PMID- 30441052 TI - Compressed Sensing of EEG with Gabor Dictionary: Effect of Time and Frequency Resolution. AB - Electroencephalogram (EEG) signals have been widely used to analyze brain activities so as to diagnose certain brain-related diseases. They are usually recorded for a fairly long interval with adequate resolution, consequently requiring a considerable amount of memory space for storage and transmission. Recently compressed sensing (CS) has been proposed in order to effectively compress EEG signals. However, its performance is closely dependent on how a compression dictionary is built. Through our study, we notice that building the best fit over-complete Gabor dictionary plays an important role in this task. In this paper, we evaluate the effect of different time and frequency step sizes in building Gabor atoms on the performance of EEG signal compression using CS with three common EEG databases used by the research community. Taking the Normalized Mean Square Error (NMSE) as a performance metric, we present a quantitative study with an attempt to provide more insight on how to adopt CS in EEG signal compression. PMID- 30441053 TI - The Embedding Transform. A Novel Analysis of Non-Stationarity in the EEG. AB - We introduce a novel technique to analyze nonstationarity in single-channel Electroencephalogram (EEG) traces: the Embedding Transform. The approach is based on Walter J. Freeman's studies concerning active and rest stages and deviations from Gaussianity. Specifically, we generalize his idea in order to include cases where the neuromodulations are sparse in time. Specifically, the transform maps the temporal sequences to a set of $?ell ^{2}$-norms where modulated patters are emphasized. In this way, the background, chaotic activity can be modeled as the main lobe of the distribution, while the relevant synchronizations (or desynchronizations) fall on the right (or left) tail of the density of such norms. We test the algorithm on two different datasets: alpha bursts on synthetic data simulated in the BESA software and low-gamma oscillations in the motor cortex from the Brain-Computer Interface (BCI) Competition 4 Dataset 4. The results are promising and place the Embedding Transform as a quick, single parameter tool to effectively assess which channels (or regions) are actively engaged in particular behaviors and which are in a more silent type of stage. PMID- 30441054 TI - Automated Detection of High Frequency Oscillations in Human Scalp Electroencephalogram. AB - High frequency oscillations (HFOs) > 80 Hz are a promising biomarker of epileptic tissue. Recent evidence has shown that spontaneous HFOs can be recorded from the scalp, but detection of these electrographic events remains a challenge. Here, we modified a simple automatic detector, used originally for intracranial EEG (iEEG) recordings, to detect ripples and fast ripples in scalp EEG. We analyzed scalp EEG recordings of seven subjects and validated our detector and artifact rejection algorithm via visual review. Of the candidate events marked by the detector, 40% and 60% were confirmed to be ripples and fast ripples, respectively, by human visual review, making this algorithm suitable for supervised detection. Detected HFOs occurred at a rate of <1/min in most channels, and the average duration was 47 and 24 ms for ripples and fast ripples, respectively. The simplicity of the algorithm, with only a single parameter, enables the consistent application of automatic detection across recording modalities, and it could therefore be a tool for the assessment and localization of epileptic activity. PMID- 30441055 TI - A New Method for the Anterior Mitral Leaflet Segmentation in Echocardiography Videos using the Virtual M-mode Space. AB - Rheumatic heart disease is responsible for the heart valve damage, caused by repeated episodes of rheumatic fever. The disease commonly inflames and scars the mitral valve of the heart, resulting in thicker, less mobile leaflets, with associated decrease in cardiac efficiency. It is important to measure and quantity the early manifestations of this disease, including variations of the thickness, shape and mobility of the leaflets. These manifestations are visible in an echocardiographic screening process. The first step towards the defined objective is to segment the anterior mitral leaflet throughout the cardiac cycle, enabling the future automatic quantification of mentioned clinical parameters. In this work, a new algorithm for the segmentation of the whole region of the anterior mitral leaflet in the virtual M-mode space is proposed. The algorithm requires a single initialization point on the posterior wall of the aorta, in the first frame of the video. A junction point is then computed, showing the location where the two leaflets connect. This junction point helps to automatically redefine the range of virtual M-mode images required to completely segment the region of the anterior mitral leaflet. The segmented anterior mitral leaflet region in the virtual M-mode space is transferred back to regular image space and its shape refined using localized active contours. Results suggest the suitability of the proposed algorithm for the segmentation of anterior mitral leaflet with a median Dice Similarity Coefficient of 0.63, and with median precision and recall of 58% and 73% respectively. PMID- 30441056 TI - B-Mode Ultrasound Based Diagnosis of Liver Cancer With CEUS Images as Privileged Information. AB - Contrast-enhanced ultrasound (CEUS) is a valuable imaging modality for diagnosis of liver cancers. However, the complexity of CEUS-based diagnosis limits its wide application, and the B-mode ultrasound (BUS) is still the most popular diagnosis modality in clinical practice. In order to promote BUS-based computer-aided diagnosis (CAD) for liver cancers, we propose a learning using privileged information (LUPI) based CAD with BUS as the diagnosis modality and CEUS as PI. Particularly, the multimodal restricted Boltzmann machine (MRBM) works as a LUPI paradigm. That is, one BUS image and three CEUS images from the arterial phase, portal venous phase and delayed phase, respectively, are used to train three multimodal restricted Boltzmann machine (MRBM) models during training stage, but only the BUS data will be fed to MRBM to generate new feature representation at testing phase. A multiple empirical kernel learning machine (MEKLM) classifier is then performed on three new feature vectors from three MRBM models for classification of liver cancers. The experimental results show that the proposed MRBM-MEKLM algorithm outperforms all the compared algorithms, suggesting the effectiveness of the proposed LUPI-based CAD for liver cancer. PMID- 30441057 TI - Contrast-Enhanced Ultrasound to Quantifyc Perfusion in a Machine-Perfused Pig Liver. AB - This paper introduces a non-invasive, contrastenhanced ultrasound (CEUS) infusion method to quantify the health of viable donor livers. The method uses the infusion of microbubbles and their destruction and subsequent replenishment to measure the perfusion rate in the liver microvasculature. The proposed method improves on the previous parameter extraction approaches applied to the flashreplenishment technique by addressing the effects of the microbubble mixing within the perfusate bath and destruction rate. By doing so, the tissue perfusion rate can be extracted from the data even though the microbubble concentration is not constant throughout image acquisition. The measured changes in the tissue perfusion rate showed that CEUS infusion is a viable biomarker for assessing liver health. PMID- 30441058 TI - Multiple Empirical Kernel Mapping Based Broad Learning System for Classification of Parkinson's Disease With Transcranial Sonography. AB - Transcranial sonography (TCS) has become more popular for diagnosis of Parkinson's disease (PD), and the TCS-based computer-aided diagnosis (CAD) for PD also attracts considerable attention, in which classifier is a critical component. Broad learning system (BLS) is a newly proposed single layer feedforward neural network for classification. In BLS, the original input features are mapped to several new feature representations to form the feature nodes, and then these mapped features are expanded to enhancement nodes by random mapping in a wide sense. However, random mapping performed for enhancement nodes is too simple and the generated features lack interpretability together with relative low representation. In this work, we propose a multiple empirical kernel mapping (MEKM) based BLS (MEKM-BLS) algorithm, which adopts MEKM to map the data of feature nodes to enhancement nodes. MEKM-BLS then has more meaningful enhancement layer in feedforward neural network. Moreover, the experiment for PD diagnosis with TCS shows that MEKM-BLS achieves superior performance to the original BLS algorithm. PMID- 30441059 TI - Automatic Segmentation of Neonatal Ventricles from Cranial Ultrasound for Prediction of Intraventricular Hemorrhage Outcome. AB - Intraventricular hemorrhage (IVH) followed by post hemorrhagic hydrocephalus (PHH) in premature neonates is one of the recognized reasons of brain injury in newborns. Cranial ultrasound (CUS) is a noninvasive imaging tool that has been used widely to diagnose and monitor neonates with IVH. In our previous work, we showed the potential of quantitative morphological analysis of lateral ventricles from early CUS to predict the PHH outcome in neonates with IVH. In this paper, we first present a new automatic method for ventricle segmentation in 2D CUS images. We detect the brain bounding box and brain mid-line to estimate the anatomical positions of ventricles and correct the brain rotation. The ventricles are segmented using a combination of fuzzy c-means, phase congruency, and active contour algorithms. Finally, we compare this fully automated approach with our previous work for the prediction of the outcome of PHH on a set of 2D CUS images taken from 60 premature neonates with different IVH grades. Experimental results showed that our method could segment ventricles with an average Dice similarity coefficient of 0.8 +/- 0.12. In addition, our fully automated method could predict the outcome of PHH based on the extracted ventricle regions with similar accuracy to our previous semi-automated approach (83% vs. 84%, respectively, p value = 0.8). This method has the potential to standardize the evaluation of CUS images and can be a helpful clinical tool for early monitoring and treatment of IVH and PHH. PMID- 30441060 TI - Automated Myocardial Wall Motion Classification using Handcrafted Features vs a Deep CNN-based mapping. AB - Compared to other modalities such as computed tomography or magnetic resonance imaging, the appearance of ultrasound images is highly dependent on the expertise of the sonographer or clinician making the image acquisition, as well as the machine used, making it a challenge to analyze due to the frequent presence of artefacts, missing boundaries, attenuation, shadows, and speckle. In addition, manual contouring of the epicardial and endocardial walls exhibits large inconsistencies and variations as it is strongly dependent on the sonographer's training and expertise. Hence, in this paper we propose a fully automated image analysis framework to ultimately perform wall motion abnormality classification in 2D+T images. We explore both traditional Random Forests classification with handcrafted features and spatio-temporal hierarchical aggregation of information with a deep learning CNN-based approach. Regarding the later classifier, we also investigate the effect of local phase information retrieval through the use of Feature Asymmetry (FA), and demonstrate that pre-processing videos with FA enables the spatio-temporal CNN to better discover relevant left ventricle endocardial abstractions from low-level features to high-level representations automatically. PMID- 30441061 TI - A Deep Learning Framework for the Remote Detection of Parkinson'S Disease Using Smart-Phone Sensor Data. AB - The assessment of Parkinson's disease (PD) using wearable sensors in non-clinical environments presents an opportunity for objective disease classification and severity prediction on a high-frequency and longitudinal basis. However, many challenges exist in analysing remotely collected data due to many sources of data corruption. Using a cohort of 1,815 participants (866 controls and 949 with PD) we implement a range of classification algorithms on Alternate Finger Tapping test data collected on smart-phones in remote environments. We compare the disease classification ability of two traditional machine learning methods against two state-of-the-art deep learning approaches, determining if the latter is successful without the definition of an explicit feature set. We find the deep learning approaches capable of disease classification, often outperforming traditional methods. We show similarities between the participants successfully classified through use of a manually extracted feature set, and the features learnt by a convolutional neural network. Finally, we discuss the broader challenges of analysing remotely collected datasets whilst highlighting the suitability of deep learning for assessing PD when large participant numbers are available. PMID- 30441062 TI - EEG CLassification Via Convolutional Neural Network-Based Interictal Epileptiform Event Detection. AB - Diagnosis of epilepsy based on visual inspection of electroencephalogram (EEG) abnormalities is an inefficient, time-consuming, and expert-centered process. Moreover, the diagnosis based on ictal epileptiform events is challenging as the ictal patterns are infrequent. Consequently, the development of an automated, fast, and reliable epileptic EEG diagnostic system is essential. The interictal epileptiform discharges (IEDs) are recurring patterns that are highly suggestive of epilepsy. In this paper, we propose an epileptic EEG classification system based on IED detection. The proposed system comprises of three modules: pre processing, waveform-level classification, and EEG-level classification. We employ a Convolutional Neural Network (CNN) for waveform-level classification and a Support Vector Machine (SVM) for EEG-level classification. We evaluated the proposed system on a dataset of 156 EEGs recorded at Massachusetts General Hospital (MGH), Boston. The system achieved a mean 4-fold classification accuracy of 83.86% for classifying EEGs with and without IEDs. PMID- 30441063 TI - Seizure Reduction using Model Predictive Control. AB - This study presents a model predictive control approach for seizure reduction in a computational model of epilepsy. The differential dynamic programming (DDP) algorithm is implemented in a model predictive fashion to optimize a controller for suppressing seizures in a chaotic oscillator model. The chaotic oscillator model uses proportional-integral (PI) controller to represent the internal control mechanism that maintains stable neural activity in a healthy brain. In the pathological case, the gains of this PI controller are reduced, preventing sufficient feedback to suppress correlation increase between normal and pathological brain dynamics. This increase in correlation leads to synchronization of oscillator dynamics leading to the destabilization of neural activity and epileptic behavior. The pathological case of the chaotic oscillator model is formulated as an optimal control problem, which we solve using the dynamic programming principle. We propose using model predictive control with differential dynamic programming optimization as a possible method for controlling epileptic seizures in known models of epilepsy. PMID- 30441064 TI - Supra-Spinal Modulation Of Walking In Healthy Individuals And Persons With Multiple Sclerosis: A fNIRS Mobile Imaging Study. AB - Multiple sclerosis (MS) is one of the neurodegenerative diseases that damage the nervous system and inflicts cognitive and motor deficits. In motor domain, MS mainly causes slower gait resulting in challenges in activities of daily living. Premotor cortices are affected by MS, where several imaging studies have reported re-organization in the activity and connectivity of these regions. Recent advancements in mobile imaging technologies and signal processing techniques have made it possible to study supraspinal modulation of walking in able-bodied individuals and persons with injuries or neurological disorders. Functional near infrared spectroscopy (fNIRS), for example, was used in studying dual-tasking in MS population. In the current study, we used fNIRS to record activities of premotor and supplementary motor areas in MS and healthy populations during standing and walking. Fourteen healthy controls and 14 persons with MS were tested during overground walking. Results show higher right premotor cortex activities compared with left premotor and bilateral supplementary motor areas in the MS group. In the healthy control group, activity was higher during walking in all the four studied brain regions. These results confirm the role of the premotor cortices in movement planning and in modulating walking activities; they also confirm that individuals with mild MS have a similar premotor control strategy as healthy controls while performing the same physical task. PMID- 30441065 TI - Development of Sensor-Based Measures of Upper Extremity Interlimb Coordination. AB - The development of motor impairment after the onset of an injury such as stroke may result in long-term compensatory behaviors. Because compensation often evolves in ambient settings (outside the purview of monitoring clinicians), there is a need for quantitative tools capable of accurately detecting the subtleties of compensation and related reduction in interlimb coordination. Improvement in interlimb coordination may serve as a marker of recovery from stroke, and rehabilitation progress. The current study investigates measures of upper extremity interlimb coordination in persons post-stroke and healthy controls. It introduces a novel algorithm for objective characterization of interlimb coordination during the performance of real-world tasks. PMID- 30441067 TI - Transfer Function Between Intracranial Pressure and Aortic Blood Pressure and Carotid Blood Flow. AB - The compliance of the intracranial space is such that the intracranial pressure (ICP) waveform is approximately the aortic blood pressure (BP) waveform minus the dominant harmonic (heart rate (HR)) of that waveform. This has been tested across species of different resting HR. Whether this filter characteristic holds true for large changes in HR, or under changed ICP, has not been examined. This study tested these changes in 11 anesthetized rats instrumented to measure and change ICP, HR, aortic BP, and carotid blood flow. The aortic BP to ICP and carotid blood flow to ICP transfer function was determined for normal ICP at paced HRs of 300, 400 and 500 bpm, and at raised ICP at HRs of 400 and 500 bpm. The aortic BP to ICP transfer function magnitude showed a dependency on HR HR (-0.15+/-0.04 *10 3 bpm-1, p<0.001) and mean ICP (4.4+/-0.6 *10-3 mmHg-1). The carotid blood flow to ICP transfer function magnitude showed a dependency on mean ICP (11.1+/-1.8 *10-3 mmHg/ml/min/mmHg, p<0.001) but not on HR. The changes with different HRs indicates a degree of non-linearity in the system. Though small, this may need to be accounted for in understanding the relationship between systemic BP and flow and ICP. This data is useful in understanding the relationship between cardiovascular signals and ICP, valuable in advancing the ability to estimate ICP non-invasively. PMID- 30441066 TI - Source Connectivity Analysis Can Assess Recovery of Acute Mild Traumatic Brain Injury Patients. AB - In this study we investigated whether source connectivity analysis of resting state Magnetoencephalographic (MEG) activity could separate mild traumatic brain injury (mTBI) patients from age-and sex-matched controls. For each subject, we used artifact-free data recorded on three sessions to estimate intracranial sources which were then projected onto a standardized brain atlas for common reference. The statistical and topological properties of functional brain networks, estimated using Granger causality, were analyzed using MANOVA, with group and recording session as the independent variables and number of in-going and out-going connections in each atlas region as dependent variables. Overall, mTBI subjects showed a larger number of stronger connections compared to controls. The number and topology of in-going and out-going connections were significantly different across the two groups in areas involved with spatial memory, perception of visual space, emotion formation and processing, learning, and memory. Additionally, differences between patients and controls were decreasing across the three sessions indicating patient improvement. Our results suggest that connectivity analysis may be used as a reliable biomarker of mTBI and can also help with the diagnosis and assessment of patient recovery. PMID- 30441068 TI - Estimation of Three-dimensional Blood Flow with Ultrasound - Continuity Equation on Multiplane Dual-angle Doppler Imaging. AB - Atherosclerosis plays the major role in myocardial infarction and stroke and its pathophysiology is closely related to blood flow. Among clinical imaging modalities, ultrasound has the highest temporal resolution. Doppler ultrasound has been clinically applied for blood flow measurement and several parameters obtained with Doppler have been considered as essential for diagnosis. However, conventional Doppler method merely measures one-dimensional component of the blood flow along the ultrasonic beam. Based on previous approaches with multi angle Doppler measurement for two-dimensional (2D) blood flow, this study aims to expand 2D flow measurement into three-dimensional (3D) flow estimation by applying continuity equation on multiplane 2D velocity mapping. The algorithm was validated by numerical simulation based on computational fluid dynamics and comparison with particle image velocimetry of carotid artery model. The method visualized 3D spiral flow in the carotid artery bifurcation model where 2D blood flow showed Iaminar flow. Clinical application of 3D blood flow visualization will provide important information on pathophysiology in common sites of atherosclerosis. PMID- 30441069 TI - Left Ventricular Blood Flow Dynamics In Aortic Stenosis Before And After Aortic Valve Replacement. AB - Surgical intervention for aortic valve stenosis (AS) has been established; however its diagnosis based on echocardiographic assessment is still limited by aortic valvular velocity, aortic valvular pressure gradients, and color Doppler imaging. Echo-dynamography (EDG) is a method to determine intracardiac flow dynamics, such as two-dimensional blood flow velocity, vortex, and dynamic pressure. These flow dynamics may be influenced by left ventricular (LV) wall motion and the resistance in LV outflow caused by AS. The objective of the present study was to assess the changes and differences in LV vortices and vorticity before and after AS surgery. Five patients who underwent aortic valve replacement surgery for AS and five control patients were included. Besides routine echocardiographic measurement, EDG was applied to determine the two dimensional blood flow vector and vorticity. The LV vortex flow in the isovolumetric contraction phase had multiple formations in preoperative cases. The clockwise vortex was found in all cases postoperatively; the vortex formation showed no significant difference between postoperative and normal control groups. EDG may serve important information on LV flow dynamics, non-invasively. PMID- 30441070 TI - Valuation Of Implanted-Stent Impact On Coronary Artery Trifurcation Blood Flow By Using CFD. AB - We investigated the influence of stent implanted in left main coronary artery trifurcation on blood flow by means of CFD. We simulated various stent positions and arrangement patterns considering KBT. The velocity and WSS (wall shear stress) distribution were found to depend on the stent arrangements. In addition, a strut position inhibiting the inflow velocity peaks into the branched (LCX) vessel exhibited a strong impact, which provided suppression of WSS on the high lateralside surface of the LCX entrance. By KBT, such an impact of stent implantation can be avoided. PMID- 30441071 TI - Different Blood Flow Models in Coronary Artery Diseases: Effects on hemodynamic parameters. AB - Coronary arteries are medium-small caliber vessels, in which low shear rate values are encountered, where non-Newtonian blood effects cannot be neglected. This work aims to study a comparison between Newtonian and non-Newtonian blood behaviors in a cohort offorty-eight 3D patient-specific stenotic vessels (right (RCA), left (LAD) and circumflex (LCX) coronary artery) at different grades of stenosis. Numerical simulation was carried out by means of Computational Fluid Dynamics (CFD) Analysis to investigate the blood velocity and distribution of the shear stress indices at different times of the cardiac cycle. A statistical analysis was performed to have a prediction ofincrement or decrement ofthe various hemodynamic parameters. The results show that the non-Newtonian effects are mostly important in shear stress indices distributions. PMID- 30441072 TI - On the Relationship Between Human Motor Control Performance and Kinematic Synergies in Upper Limb Prosthetics. AB - Current prosthesis command interfaces only allow for a single degree of freedom to be commanded at a time, making coordinated motion difficult to achieve. Thus it becomes crucial to develop methods that complement these interfaces to allow for intuitive coordinated arm motion. Kinematic synergies have been shown as an alternate method where the motion of the prosthetic device is coordinated with that of the residual limb. In this paper, the mapping between the parameters of a kinematic synergy model and a measure of task performance is established experimentally in order to test the applicability of online optimization methods for the identification of synergies. To achieve this, a cost function that captures the objective of the reaching task and a linear kinematic synergy model were chosen. A human experiment was developed in a Virtual Reality (VR) platform in order to determine the synergy-performance relationship. The experiments were performed on 10 able-bodied subjects. The relationship observed between the synergy parameter and the reaching task cost function suggests existing online optimization methods may be applicable. PMID- 30441073 TI - Design and Preliminary Assessment of Lightweight Swing-Assist Knee Prosthesis. AB - This paper presents the design and control of a lightweight swing assist (SA) knee prosthesis. The SA knee relies on passive stability to provide support during the stance phase of walking and incorporates a small motor and battery to actively assist the knee motion during the swing phase. A prototype SA knee was constructed and experimentally evaluated on a single transfemoral amputee. The experiments consisted of treadmill walking at three speeds, first on a dailyuse passive prosthesis and subsequently on the SA prosthesis prototype, while recording motion capture and ground reaction force data from which prosthesis knee kinematics and affectedside hip torque were computed. A comparison of the passive daily-use prosthesis and the SA prosthesis indicates that the SA prosthesis provides more consistent and repeatable knee motion and reduces pre swing peak hip torque across all walking speeds. PMID- 30441074 TI - Real-Time Onboard Recognition of Gait Transitions for A Bionic Knee Exoskeleton in Transparent Mode. AB - To achieve smooth locomotion transitions, locomotion intent prediction is very important for the control of knee exoskeleton. In this study, we develop a multi sensor based locomotion intent prediction system based on Support Vector Machine (SVM), which can identify the current locomotion mode (sit, sit-to-stand, stand, level-ground walking, or stand-to-sit) and detect the locomotion transition between these modes onboard online. Two IMUs are mounted on the unilateral front of thigh part and shank part of the knee exoskeleton, and each of them generates 9 channels data. To evaluate the performance of this prediction system, several experiments are conducted on five healthy subjects. Average recognition accuracy is 96.89% +/- 0.23%. Most transitions can be detected before the onsets of the transitions and no missed detections are observed for all the trials of the five able-bodied subjects. PMID- 30441075 TI - Assist-as-Needed Controller to a Task-based Knee Rehabilitation Exoskeleton. AB - This research aims to design and implement an assist-as-needed controller and patient recovery tracking system into a novel task based knee rehabilitation exoskeleton device. The level of support from the exoskeleton is measured through the force sensing resistors (FSR) placed in the interface of lower- leg and the exoskeleton. The signal from the FSR is used as a feedback to control the actuator torque. The intent of the user to start, stop, move left, and right are associated with muscle activities, surface electromyography (sEMG) signals in the upper-leg. The preliminary results have shown that the system has provided the user a visual display of the amount of recovery and history while providing full autonomy to control the exoskeleton device. The successful implementation of these features can eliminate the need of constant supervision, and hence saves time and reduces cost of the rehabilitation process; which can also be used in a home-based or telerehabilitation settings. PMID- 30441076 TI - In vitro Measurement of Release Kinetics of Temperature Sensitive Liposomes with a Fluorescence Imaging System. AB - Temperature sensitive liposomes (TSL) are a promising type of nanoparticles for localized drug delivery. TSL typically release the contained drug at mild hyperthermic temperatures (40-42 degrees C). Combined with localized hyperthermia, this allows for local drug delivery. In vitro characterization of TSL involves measurements of drug release at varying temperatures, but current methods are inadequate due to low temporal resolution of ~8 - 10 seconds. We present a novel method for measuring the drug release with sub-second temporal resolution. In the proposed system, the TSL entrapping the fluorescent drug (Doxorubicin) are pumped through a capillary tube. The tube is rapidly heated to a desired temperature via Peltier element. Since fluorescence increases as drug is released from TSL, drug release kinetics can be measured via fluorescent imaging. By fitting exponential models, we calculated the time constants of drug release at temperatures of 39.5, 40.5 and 41.5.C were about 6.09, 2.06 and 1.03 seconds, respectively. Our initial tests show that the developed system can measure TSL release at subsecond resolution, and thus allow adequate in vitro evaluation of TSL formulations. PMID- 30441077 TI - Evaluation of Deep Thermal Rehabilitation System Using Resonant Cavity Applicator During Knee Experiments. AB - This paper evaluates experiments on the knee using a new heating rehabilitation system. For effective thermal rehabilitation of osteoarthritis, it is necessary to heat the deep tissue inside the knee joint. Our new rehabilitation system is based on the re-entrant type resonant cavity applicator which was developed for deep hyperthermia treatment in our previous studies. Our experimental results using agar phantoms showed our heating system is able to heat the deep tissue inside the knee without physically contacting the surface skin. In this study, we developed a prototype applicator and experimented on a healthy human subject's knee under clinical conditions. To evaluate heating performance, we conducted heating experiments with our resonant cavity applicator and a conventional microwave diathermy system and compared the results. The experimental results of temperature increase distributions inside the human body were estimated by ultrasound imaging techniques. The estimated results from our knee experiments show that our heating system is able to heat knee tissue more deeply than microwave diathermy systems can and thus would be effective for deep thermal rehabilitation applications in clinics. PMID- 30441078 TI - An Intelligent Theranostics Method Using Optical Coherence Tomography Guided Automatic Laser Ablation for Neurosurgery. AB - Methods to reduce the high disability and fatality rate of neurosurgery caused by surgeon tremor and uncertainty of intraoperative tumor boundary have long been greatly concerned. We have proposed an intelligent theranostics method for a compact integrated diagnosis and therapeutic platform to automatically excise the brain tumor with high precision. To perform this operation, hardware combination of a benchtop spectral domain optical coherence tomography (SD-OCT) and a high power laser has been implemented by a customized fiber combiner. By the double clad fiber out of the combiner which works as both the OCT sample arm fiber and the ablation laser output fiber, an in situ theranostics process without registration can be conducted. The SD-OCT image analysis from both en face and depth perspectives shows the structural information intuitively and accordingly generate the ablation-guiding grid. Based on the grid, the continuous wave high power laser ablates ex vivo porcine brain models in submillimeter automatically. The feasibility of this theranostics method has been verified by the comparison of attenuation maps before and after ablation, and the contrast of its pathology. PMID- 30441079 TI - Intuitive Hand-held Instrument for Loose Body Removal in Arthroscopic Synovial Chondromatosis Surgery. AB - In order to treat synovial chondromatosis in minimally invasive way, the loose bodies in the joint cavity should be removed with arthroscopic surgery. However, since the joint cavity is narrow and round, it is difficult to approach with conventional straight surgical tools. To overcome this, existing studies have proposed motorized steerable surgical instruments, but they do not provide haptic feedback and intuitive understanding of the position of the end-effector. In this paper, we developed a motorless steerable arthroscopic surgery instrument. It was designed with the ergonomic aspects for intuitive manipulation. It is geometrically modeled to define the mechanical parameters; diameter 5 mm, bending angle 90 degrees . Design values and clinical significance were verified by an experiment and a phantom test. PMID- 30441081 TI - Evaluation of the Effect of Uterine Fibroids on Microwave Endometrial Ablation Profiles. AB - Thermal ablation of the endometrial lining of the uterus is a minimally-invasive technique for treatment of menorrhagia. We have previously presented a 915 MHz microwave triangular loop antenna for endometrial ablation. Uterine fibroids are benign pelvic tumors, of considerably different water content compared to normal uterus, and may change the shape of the uterus. Collectively, these changes introduced by fibroids may alter the pattern of microwave endometrial ablation. In this study, we have investigated the effect of 1 - 3 cm diameter uterine fibroids in different locations around the uterine cavity on ablation profiles following 60 W, 150 s microwave exposure with a loop antenna. Our computational model predicts ablation zone extents within 1 +/- 0.8 of ablation zones observed in experiments in ex vivo tissue. The maximum change in simulated ablation depths due to the presence of fibroids was 1.1 mm. In summary, this simulation study suggests that 1 - 3 cm diameter uterine fibroids can be expected to have minimal impact on the extent of microwave endometrial ablation patterns. PMID- 30441080 TI - A New Model for RF Ablation Planning in Clinic. AB - Numerical simulations provide effective way to acquire detailed temperature field during radiofrequency ablation (RF). Based on the patient's real electrical resistance and RF power, we have designed a theoretical model suitable for clinical treatment planning. The human body is assumed to be two cylinders with the inner cylinder simulating the liver with real liver electrical conductivity, while the electrical conductivity of the out cylinder adjusted to match the real resistance recorded when treated with RFA. The orthogonal-array method has been applied to analyze the impact of the main geometric parameters. Results show that a limited range of model parameters with the same resistance and power condition results in similar prediction of ablation range. In addition, RF heating experiments have been performed in the liver of a live pig to validate this model. The simulated temperature fits well with the real temperature. The comparison of the results predicted using the proposed model and previous models finds that the previous uniform-electrical-conductivity model would significantly underestimates or overestimates the ablation range based on the magnitude of the electrical resistance recorded. PMID- 30441082 TI - A Novel Sleep Stage Scoring System: Combining Expert-Based Rules with a Decision Tree Classifier. AB - Overnight polysomnography (PSG) is the gold standard tool used to characterize sleep and for diagnosing sleep disorders. PSG is a non-invasive procedure that collects various physiological data which is then scored by sleep specialists who assign a sleep stage to every 30-second window of the data according to predefined scoring rules. In this study, we aimed to automate the process of sleep stage scoring of overnight PSG data while adhering to expert-based rules. We developed an algorithm utilizing a likelihood ratio decision tree classifier and extracted features from EEG, EMG and EOG signals based on predefined rules of the American Academy of Sleep Medicine Manual. Specifically, features were computed in 30-second epochs in the time and the frequency domains of the signals and used as inputs to the classifier which assigned each epoch to one of five possible stages: N3, N2, N1, REM or Wake. The algorithm was trained and tested on PSG data from 38 healthy individuals with no reported sleep disturbances. The overall scoring accuracy was 80.70% on the test set, which was comparable to the training set. Our results imply that the automatic classification is highly robust, fast, consistent with visual scoring and is highly interpretable. PMID- 30441083 TI - Cognitive DDx Assistant in Rare Diseases. AB - There are between 6,000 - 7,000 known rare diseases today. Identifying and diagnosing a patient with rare disease is time consuming, cumbersome, cost intensive and requires resources generally available only at large hospital centers. Furthermore, most medical doctors, especially general practitioners, will likely only see one patient with a rare disease if at all. A cognitive assistant for differential diagnosis in rare disease will provide the knowledge on all rare diseases online, help create a list of weighted diagnosis and access to the evidence base on which the list was created. The system is built on knowledge graph technology that incorporates data from ICD-10, DOID, medDRA, PubMed, Wikipedia, Orphanet, the CDC and anonymized patient data. The final knowledge graph comprised over 500,000 nodes. The solution was tested with 101 published cases for rare disease. The learning system improves over training sprints and delivers 79.5 % accuracy in finding the diagnosis in the top 1 % of nodes. A further learning step was taken to rank the correct result in the TOP 15 hits. With a reduced data pool, 51% of the 101 cases were tested delivering the correct result in the TOP 3 - 13 (TOP 6 on average) for 74% of these cases. The results show that data curation is among the most critical aspects to deliver accurate results. The knowledge graph technology demonstrates its power to deliver cognitive solutions for differential diagnosis in rare disease that can be applied in clinical practice. PMID- 30441084 TI - Sparse Modeling of Mandibular Reconstruction Procedures Using Statistical Geometric Features. AB - This paper introduces a sparse modeling method that uses statistical geometric features for automated pre-operative planning. It further shows the application of this method to mandibular reconstruction with fibular segments. With this method, instead of using all the training data, only a small number of data that have similar features to the test data are selected and appropriately synthesized to reconstruct patient-specific plans. We compared the performance of three automated planning models using 120 patterns of mandibular reconstruction data manually planned by oral surgeons. The sparseness of the data selection and the efficacy of the automated planning framework were quantitatively confirmed. PMID- 30441085 TI - A Clinical Interpretable Approach Applied to Cardiovascular Risk Assessment. AB - The effectiveness of predictive models in supporting the Clinical Decision is closely related with their clinical interpretability, i.e.the model should provide clear information on how to reach a specific classification/decision. In fact, the development of interpretable and accurate predictive models assumes a key importance as these tools can be very useful in Clinical Decision Support Systems (CDSS). The development of those models may comprise two main perspectives; existent clinical knowledge (clinical expert knowledge, clinical guidelines, current models, etc.) as well as data driven approaches able to extract (new) knowledge from recent clinical datasets. This work focuses in knowledge extraction from recent datasets (data driven) based on computational intelligence techniques. The main hypothesis that supports this work is that individuals with similar characteristics present a similar risk prof ile. Thus, this work addresses the development of stratification models able to learn distinct groups (or classes) of subjects assessing the similarity between characterizing variables. In particular, in the current study a data-driven supervised cluster approach is proposed aiming the derivation of meaningful rules directly from the dataset. The validation was performed based on the largest Portuguese coronary artery disease patient's dataset, provided by the Portuguese Society of Cardiology and comprising 13902 acute coronary syndrome patients. The goal was to assess the risk of death 30 days after admission. The models' performance was assessed through the sensitivity, specificity and geometric mean values. The obtained results show the potential of this approach, as they represent an acceptable performance (GM= 72%) while the clinical interpretability of the model is assured through the derived rules. Despite the achieved results, there are several research directions to be followed in order to enhance this work. PMID- 30441086 TI - Doubly-Robust Estimation of Effect of Imaging Resource Utilization on Discharge Decisions in Emergency Departments. AB - Cluster analysis provides a data-driven multidimensional approach for identifying distinct subgroups of patients in a cohort. Each of the clusters represents a particular health condition with specific clinical trajectory and medical needs. Patients visiting emergency rooms do not share the same health condition, therefore discriminating between groups may have implications for diagnostic testing and resource utilization. We carried out this retrospective cohort study on 13825 patients who visited the emergency rooms in three Emory hospitals presenting with head trauma and non-stroke-like non-specific neurologic symptoms from January 2010 to September 2015. We utilized k-means clustering to find five distinct subgroups. Then, we investigated if getting an emergency head CT scan could have a statistically significant effect on getting discharged from the hospital. Adjusted effect estimation method was applied on each cluster to estimate the association between receiving a diagnostic test (e.g., head CT scan) on the disposition status. Out of five patient subgroups in the cohort, the chance of getting discharged for two clusters were significantly affected by getting a head CT scan. They both include comparatively older, African American or black patients who arrived in the ER with EMS, the latter suggesting critical health conditions. PMID- 30441087 TI - Deriving High Performance Alerts from Reduced Sensor Data for Timely Intervention in Acute Hypotensive Episodes. AB - Alerting critical health conditions ahead of time leads to reduced mortality rates. Recently wirelessly enabled medical sensors have become pervasive in both hospital and ambulatory settings. These sensors pour out voluminous data that are generally not amenable to direct interpretation. For this data to be practically useful for patients, they must be translatable into alerts that enable doctors to intervene in a timely fashion. In this paper we present a novel three-step technique to derive high performance alerts from voluminous sensor data: A data reduction algorithm that takes into account the medical condition at personalized patient level and thereby converts raw multi-sensor data to patient and disease specific severity representation, which we call as the Personalized Health Motifs (PHM). The PHMs are then modulated by criticality factors derived from interventional time and severity frequency to yield a Criticality Measure Index (CMI). In the final step we generate alerts whenever the CMI crosses patientdisease-specific thresholds. We consider one medical condition called Acute Hypotensive Episode (AHE). We evaluate the performance of our CMI derived alerts using 7,200 minutes of data from the MIMIC II [7] database. We show that the CMI generates valid alerts up to 180 minutes prior to onset of AHE with accuracy, specificity, and sensitivity of 0.76, 1.0 and 0.67 respectively, outperforming alerts from raw data. PMID- 30441088 TI - Detecting Reach to Grasp Activities using Motion and Muscle Activation Data. AB - The performance of activities of daily living (ADLs) is directly related to recovery of motor function after an incident such as stroke. Because the recovery process occurs primarily in the home, many efforts have sought to capture gross body motion and limb motion using wearable sensors. One component of function not easily quantified but nonetheless important is the ability to interact with the environment using the upper extremities. In particular, environmental interaction requires the performance of reach-to-grasp (RTG) tasks. The goal of the proposed approach is to determine the extent to which the commercial Myo armband sensor provides a noninvasive mechanism for monitoring and recording RTG task performance. Our results indicated that accelerometer and rate gyroscope data varied significantly between task types, and that a classifier using motion and muscle activation data was capable of distinguishing between gestures with 93% accuracy. PMID- 30441090 TI - Combined Regression and Classification Models for Accurate Estimation of Walking Speed Using a Wrist-worn IMU. AB - Walking speed is an important quantity not only in fitness applications but also for Iifestyle and health monitoring purposes. With the recent advances in MEMS technology, miniature body-worn sensors have been used for ambulatory walking speed estimation using regression models. However, studies show that these models are more prone to errors in slow walking regime compared to normal and fast walking regimes. To address this issue, our study proposes a combined classification and regression walking speed estimation model. An experimental evaluation was performed on 10 healthy subjects during treadmill walking trials using a smartwatch. The experimental results show that including the classification model can improve the accuracy of walking speed estimation in the slow speed regime by about 22%. The results show that the proposed combined model has error of less than around 13% for various walking speed regimes. PMID- 30441089 TI - Classification of Human Posture from Radar Returns Using Ultra-Wideband Radar. AB - There is a great need for new technology that helps ensure the well-being of senior citizens who have compromised health and are at an elevated risk of injury due to falls. Being able to detect posture and postural changes may be helpful in prediction and prevention of impending falls. Ultra-Wideband (UWB) radar is an attractive means for patient monitoring because it is inexpensive, capable of penetrating obstacles, privacy preserving and it consumes little power. In this paper, classification of postures, namely sitting, standing and lying is presented using stand-off sensing using UWB radar in an indoor environment. It is found that using location specific classifiers, overall accuracy can be improved. In this paper, a decision tree classifier capable of achieving 85% overall accuracy is proposed. This classifier uses 33 features from 10 second data sample segments. PMID- 30441091 TI - Ni-doped Liquid Metal Printed Highly Stretchable and Conformable Strain Sensor for Multifunctional Human-Motion Monitoring. AB - A highly stretchable and conformable strain sensor fabricated by Ni-doped liquid metal (Ni-GaIn) is designed to record and reconstruct human motion at elbow, knee, heel and even fingers to realize multifunctional human-activity monitoring. The new electronic ink of Ni-GaIn is directly and rapidly printed onto luminous soft substrate to manufacture strain sensor with excellent stretchable and stable electrical properties. Composed of the Ni-GaIn sensors, multifunctional sensor system is demonstrated to work well as human-machine interface, which integrates various functions including measurement and reconstruction. This sensor system provides potential applications for quantifying human motion and is also critical for personal healthcare, prosthetic control and soft robotics in the near future. PMID- 30441092 TI - An intelligent wearable device for human's cervical vertebra posture monitoring. AB - Long-term abnormal cervical curvature may lead to irreversible pathological changes in the cervical spine and cause serious paralysis. However, early abnormal cervical curvature can be corrected via cervical vertebra posture monitoring and therapeutic intervention. Therefore, for physicians, an effective monitoring system is necessary for detecting the patient's disease as early as possible. The main purpose of this study is to develop a wearable intelligent system to monitor cervical postures using a single tri-axis accelerometer. This system has a small size and lower power consumption can be easily worn for long term. In order to evaluate the performance of the developed device, first, we used our prototype to classify seven different neck postures. The obtained results across five participants indicated that the average classification accuracy are 100% for each postures. Furthermore, our proposed device could distinguish four different cervical curvature levels according to pitch angles in the sagittal plane of body. Moreover, it could record the length of time during which neck posture is maintained at each cervical curvature levels, which is regarded as an important indicator for evaluating patients' neck status in clinical practice. Finally, we have developed a mobile application software and installed it in a smart phone to enable physicians monitor the status of patients' neck on-line with ease and achieve remote diagnosis. PMID- 30441093 TI - Confusion State Induction and EEG-based Detection in Learning. AB - Confusion, as an affective state, has been proved beneficial for learning, although this emotion is always mentioned as negative affect. Confusion causes the learner to solve the problem and overcome difficulties in order to restore the cognitive equilibrium. Once the confusion is successfully resolved, a deeper learning is generated. Therefore, quantifying and visualizing the confusion that occurs in learning as well as intervening has gained great interest by researchers. Among these researches, triggering confusion precisely and detecting it is the critical step and underlies other studies. In this paper, we explored the induction of confusion states and the feasibility of detecting confusion using EEG as a first step towards an EEG-based Brain Computer Interface for monitoring the confusion and intervening in the learning. 16 participants EEG data were recorded and used. Our experiment design to induce confusion was based on tests of Raven's Standard Progressive Matrices. Each confusing and not confusing test item was presented during 15 seconds and the raw EEG data was collected via Emotiv headset. To detect the confusion emotion in learning, we propose an end-to-end EEG analysis method. End-to-end classification of Deep Learning in Machine Learning has revolutionized computer vision, which has gained interest to adopt this method to EEG analysis. The result of this preliminary study was promising, which showed a 71.36% accuracy in classifying users' confused and unconfused states when they are inferring the rules in the tests. PMID- 30441094 TI - Hardware Implementation of an Adaptive Data Acquisition System for Real-World EEG. AB - Collecting EEG involves digitizing a very small signal across a vast potential dynamic range, particularly within real-world neuroimaging conditions, where noise can be especially prominent. Conventional methods require highresolution, power-hungry data acquisition systems (DAQs), creating limits on usable time before manual interaction is necessary for recharge. Here, we discuss continued work on an alternative DAQ approach capable of acquiring high resolution data with ultra-low power use by adjusting parameters of the analog front end (AFE) in real time to allow use of low-resolution ADCs. This work compares signal quality of a hardware implementation of our adaptive AFE DAQ to that of an industry standard DAQ. Results demonstrate successful reconstruction of signals in both clean and noisy EEG monitoring environments at low bit-depths while maintaining high correlation and low standard deviation of error. This suggests promise for a fully integrated implementation with substantially lower power consumption. PMID- 30441095 TI - Cancellation Method of Signal Fluctuations in Brain Function Measurements Using Near-Infrared Spectroscopy. AB - To estimate brain activity, it is important to improve the accuracy of brain function measurements by using near-infrared spectroscopy. The detection of signals is vital for correcting any disturbances or changes in the skin blood volume. We developed a cancellation method for brain probes placed on the scalp in the configuration of an equilateral triangle. In this configuration, 12 types of target signals were detected between the vertices, and 6 types of correction signals were detected between the vertices and the center of the triangle. We measured the changes in the blood volume resulting from the specific postural changes of the subject and applied the correction method using three calculation methods. The measured results showed that the correction signals were effective in reducing the disturbances. The correction was based on the cross-correlation coefficient and the amplitude ratio of signals. PMID- 30441096 TI - Vocal Stereotypy Detection: An Initial Step to Understanding Emotions of Children with Autism Spectrum Disorder. AB - A system has been developed to automatically record and detect behavioral patterns and vocal stereotypy which is also known as vocal stimming, a non-verbal vocalization often observed in children with Autism Spectrum Disorder (ASD). The system incorporates audio, video and wearable accelerometer based sensors. Microphones and video camera were used to collect data and were used for analysis. KSVD, which is a generalized version of the k-means clustering algorithms for dictionary learning, was used to detect vocal stereotypy. Observing the subspace that the data lives in allows us to detect vocal stimming and sounds of frustration. The proposed system was able to detect vocalized stimming with detection rate between 73 - 93 percent. PMID- 30441097 TI - Simultaneous Measurement of Swallowing Sound and Mechanomyogram of Submental Muscle with PVDF Film. AB - The difficulty of swallowing, called dysphagia, causes aspiration pneumonia which is particularly a big health concern in aging society. Therefore, prevention and treatment of dysphagia would contribute to extending healthy-life and QOL of elderly people and decreasing healthcare cost. Conventional reliable methods for evaluating swallowing function require special equipment and are not suitable for long-term monitoring at home or welfare facilities. Therefore, various kinds of quantitative assessment method using biological signals such as swallowing sound, electromyography, and so forth have been proposed as a non-invasive and accessible method. The goal of this study is to realize comprehensive quantitative assessment of swallowing function using multiple biological signals simultaneously measured by a single sensor device. In this study, we propose the use of PolyVinylidene DiFluoride (PVDF) film to measure both mechanomyogram (MMG) signal for evaluating muscle activity and swallowing sound for detecting swallowing sequence. In our previous study, we confirmed PVDF film can detect MMG signal of swallowing-related muscles. We conducted experiments to confirm that PVDF film can detect swallowing sound in this study. The experimental results indicated that swallowing sound can be measured in parallel with MMG signal at the same position by changing frequency band of the signal of PVDF film. PMID- 30441098 TI - Evaluation of ReminX as a Behavioral Intervention for Mild to Moderate Dementia. AB - Dementia is a growing global challenge that is difficult to treat. Pharmaceutical treatment approaches have had limited success, leading to an increased focus on nonpharmaceutical approaches to the treatment of dementia. A clinical pilot study was performed to evaluate whether ReminX digital therapeutic software, based on reminiscence therapy, has the potential to improve emotional functioning in patients with Alzheimer's disease and related dementias. ReminX allows the uploading of pictures and narration to create slideshow stories depicting important moments in the patient's life. Fourteen patients were evaluated in their home, and their emotional health was assessed both before and after using ReminX. Results indicated that patients reported significantly less anxiety, depression, and overall emotional distress after having viewed their story. Furthermore, patient's caregivers also reported that the patient appeared less emotionally distressed. The effect sizes for the significant results ranged from 0.76 to 0.91. These effect sizes, which were larger than anticipated, suggest that digitally-delivered reminiscence therapy can have an immediate and positive impact on emotional functioning in patients with dementia. In addition, the accessibility, scalability, and ease of use of the software platform suggests that this technology holds great promise as a product for use in both the home and senior care settings. PMID- 30441099 TI - Ontology-based Dementia Care Support System. AB - In this paper, we have designed an ontology-based knowledge system for caring person with dementia at home or care facility. Proposed system contains an ontology that describes the knowledge of dementia patient, dementia symptoms, indoor environment, qualitative things and various patient's situation happening during daily life. We first describe the overall system architecture of the proposed system targeting at supporting caregivers or family members that can provide appropriate care guides for distinct symptoms of a dementia patient. We have tested the feasibility of the proposed system with two different prototypal application systems: robot platform and knowledge sharing system. PMID- 30441100 TI - Ballistocardiogram Based Identity Recognition: Towards Zero-Effort Health Monitoring in an Internet-of-Things (IoT) Environment. AB - Ballistocardiography (BCG), a measure of body vibrations due to ejection of blood into aorta, has the potential to become a 'zero-effort' cardiovascular health monitoring technology, i.e., a technology that requires little or no engagement on part of the user for its operation. In order for any zero-effort monitoring technology to function without any input from the user, it is important that such a methodology can accurately perform identity recognition and thus continuously provide results and feedback to each user. However, most of the recent work on BCG has focused mainly on the estimation of parameters related to mechanical health and the use of BCG to identify a user has not been explored thoroughly. In this paper, we examine, using discrete cosine transform based features and multi class linear classifier, the use of BCG heartbeats for identity recognition. We demonstrate from the BCG data of 52 healthy subjects collected using a modified floor tile that an average accuracy of 96.15% can be achieved for correct identification of each subject standing on the tile. Based on these results, we anticipate that such a BCG system, trained for a set of users, can be easily installed at different locations in the house and provide continuous and unobtrusive feedback to users for diagnostic monitoring and quantified-self. PMID- 30441101 TI - A multimodal virtual keyboard using eye-tracking and hand gesture detection. AB - A large number of people with disabilities rely on assistive technologies to communicate with their families, to use social media, and have a social life. Despite a significant increase of novel assitive technologies, robust, non invasive, and inexpensive solutions should be proposed and optimized in relation to the physical abilities of the users. A reliable and robust identification of intentional visual commands is an important issue in the development of eye movements based user interfaces. The detection of a command with an eyetracking system can be achieved with a dwell time. Yet, a large number of people can use simple hand gestures as a switch to select a command. We propose a new virtual keyboard based on the detection of ten commands. The keyboard includes all the letters of the Latin script (upper and lower case), punctuation marks, digits, and a delete button. To select a command in the keyboard, the user points the desired item with the gaze, and select it with hand gesture. The system has been evaluated across eight healthy subjects with five predefined hand gestures, and a button for the selection. The results support the conclusion that the performance of a subject, in terms of speed and information transfer rate (ITR), depends on the choice of the hand gesture. The best gesture for each subject provides a mean performance of $8 . 77 ?pm 2 .90$ letters per minute, which corresponds to an ITR of $57 . 04 ?pm 14 .55$ bits per minute. The results highlight that the hand gesture assigned for the selection of an item is inter-subject dependent. PMID- 30441102 TI - A Gaze-Based Virtual Keyboard Using a Mouth Switch for Command Selection. AB - Portable eye-trackers provide an efficient way to access the point of gaze from a user on a computer screen. Thanks to eyetracking, gaze-based virtual keyboard can be developed by taking into account constraints related to the gaze detection accuracy. In this paper, we propose a new gaze-based virtual keyboard where all the letters can be accessed directly through a single command. In addition, we propose a USB mouth switch that is directly connected through a computer mouse, with the mouse switch replacing the left click button. This approach is considered to tackle the Midas touch problem with eye-tracking for people who are severely disabled. The performance is evaluated on 10 participants by comparing the following three conditions: gaze detection with mouth switch, gaze detection with dwell time by considering the distance to the closest command, and the gaze detection within the surface of the command box. Finally, a workload using NASA TLX test was conducted on the different conditions. The results revealed that the proposed approach with the mouth switch provides a better performance in terms of typing speed (36.6 +/- 8.4 letters/minute) compared to the other conditions, and a high acceptance as an input device. PMID- 30441103 TI - A 0.9m Long 0.5gf Resolution Catheter-based Force Sensor for Real-Time Force Monitoring of Cardiovascular Surgery. AB - This paper presents a 0.9m long capacitive force sensor for a catheter integration, which measures a contact force to inner vessel wall or organs with a resolution of 0.5gf. The force sensor is implemented with a thin flexible printed circuit board (FPCB) encapsulated by a force sensitive medium, multilayer polydimethylsiloxane (PDMS). The parasitic capacitance $( ?mathrm {C}_{P})$ inherent in long catheters significantly degrades the sensing accuracy of capacitive force sensors. To account for this, this work proposes a sensor interface with $?mathrm {C}_{P}$ canceller. By removing the 348pF (91.5%) of $?mathrm {C}_{?mathrm{P}}$with the $?mathrm {C}_{?mathrm{P}}$ canceller, the capacitive force sensor achieves a capacitance resolution of 16aF equivalent to a force error of 0.5gf, which is a $10 ?times $ improvement compared to the conventional sensor interface. The proposed force sensor offers great potential for real-time force monitoring of cardiovascular surgery. PMID- 30441104 TI - Assessment of Inspiratory Muscle Activation using Surface Diaphragm Mechanomyography and Crural Diaphragm Electromyography. AB - The relationship between surface diaphragm mechanomyography (sMMGdi), as a noninvasive measure of inspiratory muscle mechanical activation, and crural diaphragm electromyography (oesEMGdi), as the invasive gold standard measure of diaphragm electrical activation, had not previously been examined. To investigate this relationship, oesEMGdi and sMMGdi were measured simultaneously in 6 healthy subjects during an incremental inspiratory threshold loading protocol, and analyzed using fixed sample entropy (fSampEn). A positive curvilinear relationship was observed between mean fSampEn sMMGdi and oesEMGdi (r = 0.67). Accordingly, an increasing electromechanical ratio was also observed with increasing inspiratory load. These findings suggest that sMMGdi could provide useful noninvasive measures of inspiratory muscle mechanical activation. PMID- 30441105 TI - Comparison of Automated and Manual Peripheral Oxygen Saturation Control Applied to One Human Subject at a High Target Range. AB - Newborn infants, mainly those born prematurely, often require respiratory support with a varying concentration of the fraction of inspired oxygen (FiO$_{?mathbf {2}}$) to keep the peripheral oxygen saturation (SpO$_{?mathbf {2}}$) within the desired range to prevent adverse health effects due to both high and low SpO$_{?mathbf {2}}$. Manual adjustment, by nurses, is the common practice. However, the efficacy of the manual control is questionable. A novel automatic controller is evaluated clinically with application to one human subject at a high target SpO$_{?mathbf {2}}$. The automatic controller demonstrated the ability to improve oxygen saturation control over the everyday routine manual control by increasing the proportion of time where SpO$_{?mathbf {2}}?textbf{v}$alues were within the desired range. PMID- 30441106 TI - Assessment of Respiratory Muscle Activity with Surface Electromyographic Signals Acquired by Concentric Ring Electrodes. AB - The assessment of respiratory muscle activity by surface electromyography (sEMG) is a promising noninvasive technique for the diagnosis and monitoring of chronic obstructive pulmonary disease. The diaphragm is the most important muscle in breathing, although in forced inspiration other muscles, such as sternocleidomastoid, are activated and contribute to the respiratory process. The measurement of the sEMG in these muscles (sEMGdi and sEMGscm, respectively) by means of two electrodes in conventional bipolar configuration (BEs) is a common practice to evaluate the respiratory muscle activity and allows to indirectly quantify the level of muscular activation. However, the resulting signals are usually contaminated by electrocardiographic (ECG) activity, hindering the assessment of the activity of these muscles. sEMG signals can also be recorded using concentric ring electrodes (CREs). CREs have greater spatial resolution and attenuate distant bioelectrical interferences. In this scenario, the objective of this work has been to evaluate the applicability of CREs for the acquisition of sEMGdi and sEMGscm. For this purpose, both sEMG signals were recorded simultaneously with BEs and CREs in healthy subjects while performing an inspiratory load protocol. To evaluate the effect of the cardiac interference, the ratio between the mean power in inspiratory segments without ECG and the mean power in expiratory segments with ECG (Rcardio) was calculated. Additionally, the ratio between the mean power in inspiratory segments without ECG and the mean power in expiratory segments without ECG (Rinex) was also calculated. The results revealed that the Rcardio and bandwidth is greater in sEMG signals acquired with the CREs, while the Rinex is higher in the signals acquired with BEs. These results suggest that the use of CREs is a recommended alternative for the acquisition of sEMG in muscles with high cardiac interference, such as the diaphragm muscle. PMID- 30441107 TI - Anti-Windup and Disturbance Rejection Controller Design of an Automated Oxygen Control System for Premature Infants. AB - For premature infants, the peripheral oxygen saturation (SpO2) level has significant effects on their health. Manual control of the fraction of inspired oxygen (FiO2) by nursing staff is not only a highly labor intensive solution, but also a hard task to maintain infants' SpO2 within the safe range. For this clinical need, an automated oxygen control system for premature infants is developed, which is based on PI control and derivative feedback (DF) control. Clinical tests showed that, when there is either a manual-automatic mode switch and tube feeding, integral windup may occur which will lead to the degradation of control performance. To overcome this problem, an anti-windup control strategy is developed. Due to blood oxygen desaturations caused by unknown disturbances, a disturbance observer is adopted with the disturbance estimate used for disturbance rejection. According to the results of dynamic simulations, the controller with anti-windup and disturbance rejection design has the best performance among all controllers, it could achieve bumpless transfer during mode switching, decrease FiO2 in a timely manner when feeding is finished, and can shorten the recovery time from desaturation events and after feeding. This controller could minimize the time that SpO2 is outside the safe range, which is promising for clinical application. PMID- 30441108 TI - A Modular Implant System for Multimodal Recording and Manipulation of the Primate Brain. AB - Neural circuitry can be investigated and manipulated using a variety of techniques, including electrical and optical recording and stimulation. At present, most neural interfaces are designed to accommodate a single mode of neural recording and/or manipulation, which limits the amount of data that can be extracted from a single population of neurons. To overcome these technical limitations, we developed a chronic, multi-scale, multi-modal chamber-based neural implant for use in non-human primates that accommodates electrophysiological recording and stimulation, optical manipulation, and wide field imaging. We present key design features of the system and mechanical validation. We also present sample data from two non-human primate subjects to validate the efficacy of the design in vivo. PMID- 30441109 TI - A wireless, smartphone controlled, battery powered, head mounted light delivery system for optogenetic stimulation. AB - This paper reports the design, fabrication and characterization of a head mounted, flexible, and ultralight optogenetic system that enables wireless delivery of light into the brains of awake and freely behaving animals. The project is focused on miniaturized design, light weight (2.7g), small volume, low cost (< 25 USD) and simple fabrication. The chip, the substrate material, the battery, and the micro light emitting diode (MULED) are commercially available. The device implementation consists of one step photolithography, soldering, and packaging along with Arduino programming. In vivo study is carried out where the battery-powered MULED stimulates the visual cortex of a rat with parameters that can be controlled wirelessly via a smart-phone user interface application. The efficacy of optical stimulation is validated using c-Fos as a report of light evoked neuronal activity. PMID- 30441110 TI - Effect of Asymmetric, Charge Balanced Stimuli on Elicited Compound Neural Action Potentials. AB - Whether via cuff or intrafascicular electrode, peripheral neural stimulations often rely on symmetric, charge balanced paradigms. To date, few investigations have been carried out which systematically decompose the features of a stimulus waveform. Factors such as pulse-width, amplitude, and the timing with which they are presented may have significant effects on the quality of the stimuli. This work seeks to fill this gap in knowledge and share insight into how selection of electrical stimuli may affect the resultant neural activation in peripheral nerves. In particular, we found that, although there is some variance, over the parameter range tested there was not a significant effect on neural fiber recruitment percent due to waveform selection. PMID- 30441111 TI - Parylene neural probe with embedded CMOS multiplexing amplifier. AB - We present a method for embedding integrated circuit chips in parylene neural probes where Anisotropic Conductive Film (ACF) electrically and physically connects the chip to the probe. Adequate insulation of the assembly is verified up to 150 h in vitro (testing ongoing). A custom-designed 8-to-1 multiplexing amplifier for neural application was fabricated in a 0.18 MUm CMOS process. As a feasibility demonstration, the $830 ?mu ?mathrm {m}?times 1030 ?mu ?mathrm {m}$ die was connected to a parylene probe on a glass substrate. Preliminary results of the amplifier tests indicate similar performance in air and in phosphate buffered saline (PBS), and demonstrate around 200 V/V amplification of signals in saline. PMID- 30441112 TI - Magnetically Balanced Power and Data Telemetry for mm-scale Neural Implants. AB - Millimeter-sized implants for neural interface have been of great interest in the neuroengineering field due to their minimal invasiveness and great potential as an alternative to conventional bulky neural interfacing systems. However, their size poses great challenges not only on wireless power transmission, but also on uplink (implant to outside) data communication. One of most feasible data communication methods is load-shift keying based on the backscattering principle utilizing the existing inductive power link. This method consumes minimal power inherently, but its achievable modulation index is infinitesimal so that it is greatly challenging to detect the transmitted data on the outside. In this paper, we explore new schemes using a separate data reception coil that is magnetically balanced with the power coil. Due to its minimal crosstalk between the power transmission coil and data coil, a much higher data modulation index can be achieved. In addition to circular coils, we also present elliptical magnetic balanced coil structures. According to finite element model stimulations with a realistic brain tissue model in Ansys HFSS and time domain simulation in Cadence, up to $ 15?times $ improvement in data modulation index can be achieved compared to conventional methods. PMID- 30441113 TI - Chronically Implantable Package Based on Alumina Ceramics and Titanium with High density Feedthroughs for Medical Implants. AB - Implantable package to hermetically encapsulate electronics inside human body is critical for active implant devices such as neuroprothesestextbf. To meet the demanding package requirement for smaller size and higher feedthrough density, we propose a high-density (100+ feedthroughs for 10 mm diameter) ceramic/metal composite package with helium leakage rate on the 10-10 Pa m3/s, at the same time possessing the best cytotoxicity level of Grade 0, which enable the chronic implant in human. Pure alumina substrate co-sintered with platinum (Pt) paste filled in micrometer holes have demonstrated extremely good hermetical seal and biocompatibility, then its braze joint with a titanium(Ti) ring was achieved, followed by the laser welding with a Ti cap. Standard helium leakage rate and cytotoxicity experiments have shown each component and joint interface are qualified for 100-year chronic implant, which is significant for various active implant instruments. PMID- 30441114 TI - A Distributed Descriptor Characterizing Structural Irregularity of EEG Time Series for Epileptic Seizure Detection. AB - This paper presents a novel descriptor aiming at anomaly detection in sequential data, like epileptic seizure detection with EEG time series. The descriptor is derived from the eigenvalue decomposition (EVD) of a Hankel-form data matrix generated from the raw time series. Simulation trials imply that the descriptor is capable of characterizing the structural aspect of a time series. In addition, we deploy the proposed descriptor as a feature extractor and apply it on Bonn Seizure Database which is widely used in seizure detection. The high accuracies on classification problems are comparable with the state-of-the-art so validate the effectiveness of our method. PMID- 30441115 TI - An Unsupervised Methodology for the Detection of Epileptic Seizures Using EEG Signals: A Multi-Dataset Evaluation. AB - Although the electroencephalogram (EEG) is the most commonly used means to monitor epileptic patients, public EEG datasets are very scarce making it difficult to develop and validate seizure detection algorithms. In this work an unsupervised seizure detection methodology is used to isolate ictal EEG segments without requiring any apriori information or human intervention. Seizures are detected using four simple seizure detection conditions that are activated when rhythmical activity from different brain areas is simultaneously concentrated in the alpha (8-13 Hz), theta (4-7 Hz) or delta (1-3 Hz) frequency range. Then, only a small proportion of the EEG segments that are most likely to contain ictal activity is selected and presented to the physician for the final evaluation. In this way, large volumes of EEG signals can be annotated in a fraction of the time and effort that would be otherwise required. Using EEG data from 33 sessions from the Temple University Hospital (TUH) EEG Corpus, our unsupervised methodology reached, on average, 84.92% seizure detection sensitivity with 3.46 false detections per hour of EEG signals. PMID- 30441117 TI - MCA Based Epilepsy EEG Classification Using Time Frequency Domain Features. AB - In this work, we proposed a morphological component analysis (MCA) based method for epilepsy classification using the explicit dictionary of independent redundant transforms to decomposes the electroencephalogram (EEG) by considering it's morphology. Output components of MCA are represented into analytical form by using Hilbert transform. Then features, parameter's ratio of bandwidth square, mean square frequency and fractional contributions to dominant frequency were extracted to discriminate epilepsy EEG by support vector machine (SVM). These features have shown classification results comparable to previous works. PMID- 30441116 TI - Rapid Annotation of Seizures and Interictal-ictal Continuum EEG Patterns. AB - Seizures, status epilepticus, and seizure-like rhythmic or periodic activities are common, pathological, harmful states of brain electrical activity seen in the electroencephalogram (EEG) of patients during critical medical illnesses or acute brain injury. Accumulating evidence shows that these states, when prolonged, cause neurological injury. In this study we developed a valid method to automatically discover a small number of homogeneous pattern clusters, to facilitate efficient interactive labelling by EEG experts. 592 time domain and spectral features were extracted from continuous EEG (cEEG) data of 369 ICU (intensive care unit) patients. For each patient, feature dimensionality was reduced using principal component analysis (PCA), retaining 95% of the variance. K-medoids clustering was applied to learn a local dictionary from each patient, consisting of k=100 exemplars/words. Changepoint detection (CPD) was utilized to break each EEG into segments. A bag-of-words (BoW) representation was computed for each segment, specifically, a normalized histogram of the words found within each segment. Segments were further clustered using the BoW histograms by Affinity Propagation (AP) using a chi2 distance to measure similarities between histograms. The resulting 30 50 clusters for each patient were scored by EEG experts through labeling only the cluster medoids. Embedding methods t-SNE (t distributed stochastic neighbor embedding) and PCA were used to provide a 2D representation for visualization and exploration of the data. Our results illustrate that it takes approximately 3 minutes to annotate 24 hours of cEEG by experts, which is at least 60 times faster than unaided manual review. PMID- 30441118 TI - Improved Detection and Classification of Convulsive Epileptic and Psychogenic Non epileptic Seizures Using FLDA and Bayesian Inference. AB - A high number of patients with epileptic seizures (ES) are misdiagnosed due to prevalence of mimic conditions. The clinical characteristics of mimics are often similar to ES. The events mostly misdiagnosed are of psychogenic origin and are termed as psychogenic non-epileptic seizures (PNES). The gold standard for diagnosis of PNES is video-electroencephalography monitoring (VEM), which is a resource demanding process. Hence, need for a more object method of PNES diagnosis is created. Accelerometer sensors have been used previously for the diagnosis of ES. In this work, we present a new approach for detection and classification of PNES using wrist-worn accelerometer device. Various time, frequency and wavelet space features are extracted from the accelerometry signal. Feature compression is then performed using Fisher linear discriminant analysis (FLDA). A Bayesian classifier is then trained using kernel estimator method. The algorithm was trained and tested on data collected from 16 patients undergoing VEM. When tested, the algorithm detected all seizures with 20 false alarms and correctly classified 100% PNES and 75% ES, respectively of the detected seizures. PMID- 30441119 TI - Fully Automatic Finger Extensor Tendon Segmentation in Ultrasound Images of the Metacarpophalangeal Joint. AB - In this work a fully automatic system to identify the extensor tendon on ultrasound images of the metacarpophalangeal joint is proposed. These images are used to diagnose rheumatic diseases which are one of the main causes of impairment and pain in developed countries. The early diagnosis of these conditions is crucial to a proper treatment and follow-up and so, a system such as the one proposed here, could be useful to automatically extract relevant information from the resulting images. This work is an extension of a previous published work which uses manual annotations of the skin line, metacarpus and phalange to guide the extensor tendon segmentation. By introducing automatic segmentations of all structures, we expect to create a fully automatic system, which is more interesting to the possible end-users. Results show that, despite an expected loss in the performance, it is still possible to correctly identify the extensor tendon with a Confidence of 88% considering a maximum allowed Modified Hausdorff Distance of 0.5mm. PMID- 30441120 TI - Clumped Nuclei Segmentation with Adjacent Point Match and Local Shape-Based Intensity Analysis in Fluorescence Microscopy Images. AB - Highly clumped nuclei captured in fluorescence microscopy images are commonly observed in a wide spectrum of tissue-related biomedical investigations. To ensure the quality of downstream biomedical analyses, it is essential to accurately segment clustered nuclei. However, this presents a technical challenge as fluorescence intensity alone is often insufficient for recovering the true nuclei boundaries. In this paper, we propose an segmentation algorithm that identifies point pair connection candidates and evaluates adjacent point connections with a formulated ellipse fitting quality indicator. After connection relationships are determined, we recover the resulting dividing paths by following points with specific eigenvalues from the image Hessian in a constrained searching space. We validate our algorithm with 560 image patches from two classes of tumor regions of seven brain tumor patients. Both qualitative and quantitative experimental results suggest that our algorithm is promising for dividing overlapped nuclei in fluorescence microscopy images widely used in various biomedical research. PMID- 30441121 TI - Segmentation of Both Diseased and Healthy Skin From Clinical Photographs in a Primary Care Setting. AB - This work presents the first segmentation study of both diseased and healthy skin in standard camera photographs from a clinical environment. Challenges arise from varied lighting conditions, skin types, backgrounds, and pathological states. For study, 400 clinical photographs (with skin segmentation masks) representing various pathological states of skin are retrospectively collected from a primary care network. 100 images are used for training and fine-tuning, and 300 are used for evaluation. This distribution between training and test partitions is chosen to reflect the difficulty in amassing large quantities of labeled data in this domain. A deep learning approach is used, and 3 public segmentation datasets of healthy skin are collected to study the potential benefits of pretraining. Two variants of U-Net are evaluated: U-Net and Dense Residual U-Net. We find that Dense Residual U-Nets have a 7.8% improvement in Jaccard, compared to classical U Net architectures (0.55 vs. 0.51 Jaccard), for direct transfer, where fine-tuning data is not utilized. However, U-Net outperforms Dense Residual U-Net for both direct training (0.83 vs. 0.80) and fine-tuning (0.89 vs. 0.88). The stark performance improvement with fine-tuning compared to direct transfer and direct training emphasizes both the need for adequate representative data of diseased skin, and the utility of other publicly available data sources for this task. PMID- 30441122 TI - Automated Kidney Segmentation for Traumatic Injured Patients through Ensemble Learning and Active Contour Modeling. AB - Traumatic abdominal injury can lead to multiple complications including laceration of major organs such as kidneys. Contrast-enhanced Computed Tomography (CT) is the primary imaging modality for evaluating kidney injury. However, the traditional visual examination of CT scans is time consuming, non-quantitative, prone to human error, and costly. In this work we propose a kidney segmentation method using machine learning and active contour modeling. We first detect an initialization mask inside the kidney and then evolve its boundary. This model is specifically developed and evaluated on trauma cases. Our experimental results show the average recall score of 92.6% and average Dice similarity value of 88.9%. PMID- 30441123 TI - Segmentation of cervical nuclei using SLIC and pairwise regional contrast. AB - A framework to detect and segment nuclei from cervical cytology images is proposed in this study. Poor contrast, spurious edges, degree of overlap, and intensity inhomogeneity make the nuclei segmentation task more complex in overlapping cell images. The proposed technique segments cervical nuclei by merging over-segmented SLIC superpixel regions using a novel region merging criteria based on pairwise regional contrast and image gradient contour evaluations. The framework was evaluated using the first overlapping cervical cytology image segmentation challenge - ISBI 2014 dataset. The result shows that the proposed framework outperforms the state-of-the-art algorithms in nucleus detection and segmentation accuracies. PMID- 30441124 TI - OCT Fluid Segmentation using Graph Shortest Path and Convolutional Neural Network. AB - Diagnosis and monitoring of retina diseases related to pathologies such as accumulated fluid can be performed using optical coherence tomography (OCT). OCT acquires a series of 2D slices (Bscans). This work presents a fully-automated method based on graph shortest path algorithms and convolutional neural network (CNN) to segment and detect three types of fluid including sub-retinal fluid (SRF), intra-retinal fluid (IRF) and pigment epithelium detachment (PED) in OCT Bscans of subjects with age-related macular degeneration (AMD) and retinal vein occlusion (RVO) or diabetic retinopathy. The proposed method achieves an average dice coefficient of 76.44%, 92.25% and 82.14% in Cirrus, Spectralis and Topcon datasets, respectively. The effectiveness of the proposed methods was also demonstrated in segmenting fluid in OCT images from the 2017 Retouch challenge. PMID- 30441125 TI - A Multi-site Heart Pacing Study Using Wirelessly Powered Leadless Pacemakers. AB - In this work, we report an energy-efficient switched capacitor based millimeter scale pacemaker (5 mm *7.5 mm) and a multi-receiver wireless energy transfer system operating at around 200 MHz, and use them in a proof-of-concept multi-site heart pacing study. Two pacemakers were placed on two beating Langendorff rodent heart models separately. By utilizing a single transmitter positioned 20-30 cm away, both Langendorff hearts captured the stimuli simultaneously and were electromechanically coupled. This study provides an insight for future energy efficient and distributed cardiac pacemakers that can offer cardiac resynchronization therapies. PMID- 30441126 TI - Analysis of the Movement of ICD Leads During Cardiac Contraction as Determinant of Intracardiac Impedance. AB - Intracardiac impedance (ICI) has been proposed as an indicator of cardiac status in heart failure patients. We introduce a biophysical model of the measurement setup and apply it to the movement of ICD leads reconstructed from clinical routine X-ray recordings in a study population of 12 patients. Tilting of the right ventricular lead is found to be a major determinant of ICI changes during cardiac contraction with a mean contribution of 42+/-23%. The relative position between right and left ventricular lead is the second major contributor (40+/ 22%). However, the contributions of the components of movement strongly differ between the patients. The proposed method provides means for a better interpretation of ICI measurements and for an improvement of its performance for monitoring heart failure status. PMID- 30441127 TI - In vivo estimation of the Young's modulus in normal human dermis. AB - Skin elastic properties change during a cutaneous disorder or in the aging process. Deep knowledge of skin layers helps monitoring and diagnosing structural changes. High frequency ultrasound (HF-US) has been recently introduced to diagnose and evaluate some dermatological disorders in the clinical practice. US elastography adds elasticity information of the analyzed tissue. In particular, harmonic elastography estimates the speed of shear waves produced by external vibration sources, in order to relate the shear wave speed to the Young's modulus. In the epidermis and dermis layers, shear waves are not generated; in contrast, surface acoustic waves (SAWs) exist as they propagate in the top of the tissue. This study uses crawling wave sonoelastography for the estimation of SAWs in human thigh dermis in vivo. Experiments were performed in ten volunteers in the range of 200 - 500 Hz. As other studies suggest, SAW speed needs to be compensated to reach shear wave speed, for calculating the Young's modulus. Thus, the SAW speed estimated was corrected when it propagates in solidUS gel interface. Specifically, the elasticity modulus found was $18.35 ?pm 1.04$ KPa for a vibration frequency of 200 Hz. Results suggest that the elasticity modulus can be estimated in vivo using crawling wave HF-US for skin application and shows potential for future application in skin disorders. PMID- 30441128 TI - The Structure of Human Sebaceous Glands and Its Relation to Skin Viscoelasticity. AB - High-frequency ultrasound has realized high-resolution observation of deep part of the dermis in vivo. The size of sebaceous glands was evaluated by three dimensional ultrasound microscopy with the ultrasonic frequency of 120 MHz. The viscoelasticity of the same regions was measured by well-established biomechanical equipment. There was no significant difference between the size of sebaceous glands in cheek and forearm. The skin's ability to recover to its initial position after deformation was significantly higher in forearm than in cheek. Both sizes of sebaceous glands in cheek and forearm were positively correlated with the parameter of viscoelasticity. The size of the sebaceous glands in the deep part of the dermis can be a parameter of skin viscoelasticity. High-frequency ultrasound imaging contributes to the evaluation of human skin morphology as well as functions. PMID- 30441129 TI - Miniaturization of External Mechanical Vibration for Shear Wave Elastography Imaging. AB - Ultrasound shear wave elastography is increasingly used as a non-invasive and quantitative tissue elasticity characterization method. External mechanical vibration (EMV) is an alternative to acoustic radiation force (ARF) for shear wave generation, due to its potential for inducing larger local displacements using lower power. The physical space and mass required for incorporating mechanical vibration sources makes it challenging to integrate EMV into commercial ultrasound systems in a compact and ergonomic manner. In this paper we present the design of a miniature EMV-equipped ultrasound probe that is suitable for clinical tests. Custom vibration motors were designed and tested towards optimizing the "volume-toshear-wave-amplitude" ratio. Then the mechanical design and integration of vibration motors into commercial ultrasound probes is introduced, where the spatial placement and housing of the motors is designed to improve the ergonomics of the device and the performance of the motors. PMID- 30441130 TI - Multiparametric QUS Analysis for Placental Tissue Characterization. AB - Multiparametric Quantitative Ultrasound (QUS) holds promise for characterizing placental tissue and detecting placental disorders. In this study, we simultaneously extract two qualitatively different QUS parameters, namely attenuation coefficient estimate (ACE) and shear wave speed from ultrasound radio frequency data acquired using a shear wave vibro elastography (SWAVE) method. The study comprised data from 59 post-delivery clinically normal placentas. The shear wave speed was found to be equal to 1.74 +/- 0.13 m/s whereas the attenuation coefficient estimate was 0.57 +/- 0.48 dB/cm-MHz. This provides a baseline for future studies of placental disorders. PMID- 30441131 TI - Research of the Regulation Effect of Transcranial Alternating Current Stimulation on Vigilant Attention. AB - Vigilant attention plays an important role in some industries and everyday life. However, the relationship between the variation of vigilant attention and phase synchronization is still unknown. This study utilized a revised version of the psychomotor vigilance test (PVT) to elicit vigilance decrement while collecting electroencephalogram (EEG) and using inter-site phase clustering (ISPC) to analyze phase synchronization. The theta tACS modulates phase synchronization between LPFC and MPFC so as to affect the performance of vigilant attention. The result is the tACS of theta band canregulate the EEG phase synchronization in the corresponding frequency band, suggesting that tACS has certain regulation effect on the time-frequency characteristics of EEG and the vigilant attention. PMID- 30441132 TI - A New Mathematical Force Model that Predicts the Force-pulse Amplitude Relationship of Human Skeletal Muscle. AB - Current functional electrical stimulation (FES) systems vary the stimulation intensity to control the muscle force in order to produce precise functional movements. However, mathematical model that predicts the intensity effect on the muscle force is required for model-based controller design. The most previous force model designed by Ding et al was validated only for a standardized stimulation pulse amplitude (intensity). Thus, the purpose of this study was to adapt the Ding et al model to be able to predict the force-pulse amplitude relationship. The experimental results tested on quadriceps femoris muscles of healthy subjects (N=5) show that our adapted model accurately predicts the force response for trains of a wide range of stimulation intensities (30-100 mA). The accurate predictions indicate that our adapted model could be used for designing model-based control strategies to control the muscle force through FES. PMID- 30441133 TI - A sensor fusion approach for inertial sensors based 3D kinematics and pathological gait assessments: toward an adaptive control of stimulation in post stroke subjects. AB - Pathological gait assessment and assistive control based on functional electrical stimulation (FES) in post-stroke individuals, brings out a common need to robustly quantify kinematics facing multiple constraints. This study proposes a novel approach using inertial sensors to compute dorsiflexion angles and spatio temporal parameters, in order to be later used as inputs for online close-loop control of FES. 26 post-stroke subjects were asked to walk on a pressure mat equipped with inertial measurement units (IMU) and passive reflective markers. A total of 930 strides were individually analyzed and results between IMU-based algorithms and reference systems compared. Mean absolute (MA) errors of dorsiflexion angles were found to be less than 4 degrees , while stride lengths were robustly segmented and estimated with a MA error less than 10 cm. These results open new doors to rehabilitation using adaptive FES closed-loop control strategies in "foot drop" syndrome correction. PMID- 30441134 TI - Movement Speed Estimation Based on Foot Acceleration Patterns. AB - Wearable sensors are important in today's athlete training ecosystems and also for the monitoring of therapeutic rehabilitation processes or even the diagnosis of diseases. In the future, wearables will be integrated directly into clothing and require dedicated, low-energy consuming algorithms that still maintain high accuracy. We developed a novel algorithm for the task of movement speed determination based on wearables that track only the acceleration of one foot. It consists of three algorithm blocks that perform step segmentation, step detection and speed estimation, all having linear computation complexity and able to work in real-time on state-of-the-art embedded microprocessors. Using a reference dataset collected from a motion capturing device for nine subjects and 795 steps in total, a parametric regression algorithm was trained and evaluated using a comprehensive leave-one-subject-out crossvalidation. It is able to estimate the movement speed with a mean relative error of 6.9 +/- 5.5 %. Furthermore, we evaluated our approach on lightgate-based reference measurements using 12 subjects and different running movement styles. Here, our algorithm achieved a mean relative error of 16.5 +/- 8.4 %. A final evaluation with realistic football specific movements in a three-aside cage-based soccer game was done with a GPS based reference measurement system, where the speed profile over a 30 minutes game of our method had a Pearson correlation of 0.85 to the GPS-based reference speed profile. PMID- 30441135 TI - Transfer learning approach for fall detection with the FARSEEING real-world dataset and simulated falls. AB - Falls are very rare and extremely difficult to acquire in free living conditions. Due to this, most of prior work on fall detection has focused on simulated datasets acquired in scenarios that mimic the real-world context, however, the validation of systems trained with simulated falls remains unclear. This work presents a transfer learning approach for combining a dataset of simulated falls and non-falls, obtained from young volunteers, with the real-world FARSEEING dataset, in order to train a set of supervised classifiers for discriminating between falls and non-falls events. The objective is to analyze if a combination of simulated and real falls could enrich the model. In the real-world, falls are a sporadic event, which results in imbalanced datasets. In this work, several methods for imbalance learning were employed: SMOTE, Balance Cascade and Ranking models. The Balance Cascade obtained less misclassifications in the validation set.There was an improvement when mixing the real falls and simulated non-falls compared to the case when only simulated falls were used for training. When testing with a mixed set with real falls and simulated non-falls, it is even more important to train with a mixed set. Moreover, it was possible to onclude that a model trained with simulated falls generalize better when tested with real falls, than the opposite. The overall accuracy obtained for the combination of different datasets were above 95 %. PMID- 30441136 TI - A Novel Time-Domain Descriptor for Improved Prediction of Upper Limb Movement Intent in EMG-PR System. AB - Electromyogram pattern recognition (EMG-PR) based control is a potential method capable of providing intuitively dexterous control functions in upper limb prostheses. Meanwhile, the feature extraction method adopted in EMG-PR based control is considered as an important factor that influences the performance of the prostheses. By exploiting the limitations of the existing feature extraction methods, this study proposed a new feature extraction method to effectively characterize EMG signal patterns associated with different limb movement intent. The performance of the proposed 2-dimensional novel time-domain feature set (NTDFS) was investigated using classification accuracy and feature space separability metrics across five subjects' EMG recordings, and compared with four different existing methods. In comparison to four other previously proposed feature extraction methods, the NTDFS achieved significantly better performance with increment in accuracy in the range of 5.20% ~ 8.40% at p<0.05. Additionally, by applying principal component analysis (PCA) technique, the PCA feature space for NTDFS show obvious class separability in comparison to the other existing feature extraction methods. Thus, the proposed NTDFS may facilitate the development of accurate and robust clinically viable EMG-PR based prostheses. PMID- 30441137 TI - Hand Gesture Recognition with Inertial Sensors. AB - Dyscalculia is a learning difficulty hindering fundamental arithmetical competence. Children with dyscalculia often have difficulties in engaging in lessons taught with traditional teaching methods. In contrast, an educational game is an attractive alternative. Recent educational studies have shown that gestures could have a positive impact in learning. With the recent development of low cost wearable sensors, a gesture based educational game could be used as a tool to improve the learning outcomes particularly for children with dyscalculia. In this paper, two generic gesture recognition methods are proposed for developing an interactive educational game with wearable inertial sensors. The first method is a multilayered perceptron classifier based on the accelerometer and gyroscope readings to recognize hand gestures. As gyroscope is more power demanding and not all low-cost wearable device has a gyroscope, we have simplified the method using a nearest centroid classifier for classifying hand gestures with only the accelerometer readings. The method has been integrated into open-source educational games. Experimental results based on 5 subjects have demonstrated the accuracy of inertial sensor based hand gesture recognitions. The results have shown that both methods can recognize 15 different hand gestures with the accuracy over 93%. PMID- 30441138 TI - Automated Finger Chase (ballistic tracking) in the Assessment of Cerebellar Ataxia. AB - A hallmark of cerebellar disease is impaired accuracy of intended movement which is often summarized as ataxia or incoordination. The diagnosis and assessment of cerebellar ataxia (CA) is primarily based on the expert clinician's visual and auditory observations of the performance of these tasks, and as such, a significant level of subjectivity is implied. In order to address the limitations of this subjectivity we designed a novel automated system, utilizing the Microsoft Kinect device, to capture the finger chase task (in the assessment of upper limb ataxia) which is a part of the assessment of cerebellar upper limb function. Capturing the movements of the marker attached on the subject's finger when following the target point generated by the program that mimics the finger movement of the clinician, we were able to capture the disability and provide a novel objective measure of the CA affecting upper limb function. In our approach, we essentially quantified the difference between the intended and achieved trajectories using Dynamic Time Warping (DTW) technique. Further, signal delay times and directional changes of the velocity of the marker were considered in characterizing the disability associated with patient's finger movements. Finally, Principal Component Analysis (PCA) was employed to combine all the relevant features, reduce feature dimension while enhancing the robustness. This analysis demonstrates a significant separation between normal subjects and CA patients, highlighting this approach as a potential diagnostic aid in the objective assessment of Cerebellar ataxia. PMID- 30441139 TI - Studying the interactions in a mammalian nerve fiber: a functional modeling approach. AB - Modern therapeutic interventions are increasingly favoring electrical stimulation to treat neurophysiological dis-orders. These therapies are associated with suboptimal efficacy since most neurostimulation devices operate in an open-loop manner $(i.e.$, stimulation settings like frequency, amplitude are preprogrammed). A closed-loop system can dynamically adjust stimulation parameters and may provide efficient therapies. Computational models used to design these systems vary in complexity which can adversely affect their real time performance. In this study, we compare two models of varying degrees of complexity. We constructed two computational models of a myelinated nerve fiber (functional versus mechanistic) each receiving two inputs: the underlying physiological activity at one end of the fiber, and the external stimulus applied to the middle of the fiber. We then defined relay reliability as the percentage of physiological action potentials that make it to the other end of the nerve fiber. We applied the two inputs to the fiber at various frequencies and analyze reliability. We found that the functional model and the mechanistic model have similar reliability properties, but the functional model significantly decreases the computational complexity and simulation run time. This modeling effort is the first step towards understanding and designing closed loop, real-time neurostimulation devices. PMID- 30441140 TI - Correction of Toe-Walking Gait in Children with Spastic Cerebral Palsy by using Electrical Stimulation Therapy. AB - Toe-walking is a very common gait abnormality seen in children with Cerebral Palsy (CP). The present study aims to improvise the toe-walking gait by applying Electrical Stimulation (ES) therapy of the Tricep Surae (TS) muscles. The study was carried out on sixteen children with spastic CP with unilateral toe-walking gait problem, divided into the intervention group that received both ES therapy along with conventional physiotherapy treatment and the control group that received only conventional physiotherapy treatment. Both groups were treated for 60 (30 + 30) minutes per day, for 5 days a week, up to 12 weeks. The gait data were analyzed for spatiotemporal and parameters influencing the walking capacity. The results showed that those children who received the intervention had a significant increase in gait speed by 17.67 % (p = 0.019) and decrease in stride length by 10.25 % (p = 0.037), resulting in improvement of body balance. There was a significant percentage increase in initial contact (heel strike) of 85.71 % (p = 0.000) and flat foot position (loading response) of 49.2 % (p = 0.005), confirming reduction in toe-walking. There was also an increase in the swing power by 39.8 % (p = 0.028) and ground impact by 19.5 % (p = 0.003) suggesting a change in foot contact pattern. The results indicate that ES therapy on TS muscle along with conventional physiotherapy may correct the toe-walking gait in children with spastic hemiplegic CP. PMID- 30441141 TI - Features of Referred Sensation Areas for Artificially Generated Sensory Feedback A Case Study. AB - Phantom limb pain (PLP) is a frequent consequence of amputation. Recent evidence suggests that the pathophysiological mechanisms of PLP are related to neuroplastic changes in the cortex, as consequence of the lost sensory feedback. Formation of referred sensation areas (RSAs) may follow amputation. Sensations may be evoked in the lost body part upon stimulation of RSAs that may be exploited as artificial sensory feedback. The RSAs, however, have also shown to change over time. Features of RSAs in the case of a 36 year old male with right arm amputation aiming to identify placement of electrodes for sensory feedback are reported in this paper. The arm was amputated at shoulder level following patient's request five years after a vehicle accident that resulted in brachial plexus injury and consequent severe arm paralysis with residual sensory functionality up to 20 %. RSAs were characterized over five sessions within 27 days using mechanical stimuli (brushing over the area or applying light pressure). Tests of electrical stimuli were applied hrough two surface electrodes covering one or multiple RSAs to generate evoked sensations. Location and extent of RSAs as well as the type and location of sensations evoked in the phantom limb were stable within the session (tested up to 30 minutes) and dynamic between sessions. Partial overlapping of RSAs with associated evoked sensation of same or different type was observed for different sessions. Various painful and non painful sensations were evoked by both mechanical and electrical stimuli dependent on location of the applied stimulus and assessment time. Mechanical andelectrical stimuli applied at the same location evoked the same or different types of sensation in the phantom limb. RSAs may be a promising pathway for delivering sensory feedback for PLP treatment. Features, however, of RSAs may highly influence the efficiency of the PLP treatment. PMID- 30441142 TI - The Influence of Environment Stimulation on Learning and Memory Function in Rats with Medication Chemotherapy. AB - OBJECTIVE: To study the effect of environmental intervention on chembrain. METHODS: SD rats were randomized into the experimental group and the control group. The control group was given peritoneal injection of cyclophosphamide, methotrexate and 5-fluorouracil and the experimental group received the enriched environmental intervention on the basis of the control group. The differences in learning and memory, EMG and dentate gyrus neurons were compared between the two groups. RESULTS: Escape latency in the experimental group was significantly shortened than that in the control group. The number of dentate gyrus NeuN (neuron-specific nuclear protein) positive cells in the experimental group was higher than that in the control group. The experimental group of action ability in the Agile and external stimuli is better than that of the control group. CONCLUSION: Enriched environmentalintervention can effectively improve the ability of chembrain in learning, memory and ability of action. PMID- 30441143 TI - Customization of Synergy-Based FES for Post-Stroke Rehabilitation of Upper-Limb Motor Functions. AB - Functional Electrical Stimulation (FES) provides a promising technology for rehabilitation of upper-limb motor functions following stroke. It enables activation of individual muscles to assist restoration of impaired muscle synergies toward normal patterns. However, there lacks a systematic approach to optimize the FES stimulation patterns delivered to patients with stroke. Our preliminary work demonstrated that it is feasible to use muscle synergy patterns to guide the generation of FES patterns. Here, we present the methodology of customizing synergy-based FES using parameterized formulae with three strategies: weight-sensitive, variability-sensitive, and duration-sensitive. Each of them is comprised of two parameter sets, which represent different directions of parameter search. Two patients with ischemic stroke were recruited to participate in the preliminary test of these strategies. Preliminary results indicate that all strategies could increase the peak velocity in reaching movements, but only the "variability-sensitive" strategy restrained unwanted shoulder excursions. This pilot study demonstrates the feasibility to explore in the parameter space the directions, along which the clinical benefit of synergy-based FES can be tracked and continuously optimized. PMID- 30441144 TI - Optimized tDCS for Targeting Multiple Brain Regions: An Integrated Implementation. AB - Transcranial direct current stimulation (tDCS) aims to deliver weak electric current into the brain to modulate neural activities. Based on the volume conductor model of the head, optimization algorithm can be used to determine a specific montage of high-definition electrodes on the scalp to achieve targeted stimulation. However, simultaneous targeting for multiple disconnected regions can rarely be found in the literature. Here we attempted to provide an integrated solution for optimized tDCS to target multiple brain regions (either a single point or brain structures). By improving the "maxintensity" routine previously published in [1], we are able to target two regions of interest (ROI) in the brain simultaneously.For ROIs more than two, we show that the "max-focality" algorithm using weighted least-square in [1] can be further improved by putting the L1-norm constraint on the stimulation current as apenalty term into the cost function. Up to five ROIs can be targeted at the same time without violating the safety criteria. Further analysis shows that, for multiple targets, a trade-off exists between targeting accuracy and the number of electrodes needed. We implemented all these algorithms in Soterix software HD-TargetsTM. PMID- 30441145 TI - Efficient Modeling of Acoustic Feedback Path in Hearing Aids by Voice Activity Detector-Supervised Multiple Noise Injections. AB - Adaptive Feedback Cancellation (AFC) techniques are widely used to eliminate the undesired acoustic feedback effect arising in the Hearing Aid Devices (HADs) due to the coupling between the speaker and the microphone of the HAD. This paper proposes a method to eliminate the acoustic feedback effect in the HADs in presence of noisy environment. The method involves utilization of a computationally efficient Spectral Flux feature-based voice activity detector (VAD), which controls the process of Noise Injection in the proposed AFC algorithm (SFNIAFC). The proposed algorithm's performance is objectively evaluated using Misalignment (MISA) and Perceptual Evaluation of Speech Quality (PESQ) criteria for realistic noisy conditions. The simulations performed for the proposed method shows faster convergence and reduction in the MISA values with high PESQ values in comparison to the earlier method. Subjective test results support the effectiveness and better performance of the proposed algorithm for the HAD applications over earlier method. PMID- 30441146 TI - A Simple Preprocessing Technique for ESPRIT Suitable for Non-Contact Vital Sensing Using a Doppler Sensor. AB - Non-contact vital sensing using a Doppler sensor enables us to remotely measure vital signs such as respirations and heartbeats. In addition to such vital signs, the direction of arrival (DOA) of the multiple persons or animals is of our interest. For example, if a robot can detect DOAs of multiple living bodies, the robot is capable of tracing the living bodies, or discover them under disaster fields. ESPRIT is a well-known super-resolution DOA estimation method. However, it is also well-known that its performance is limited by the number of antennas and the coherence of the multiple incoming signals. This paper proposes to use a parameter estimation method so-called ARS, as a preprocessing of ESPRIT to overcome the above-mentioned impairments. The performance of the proposed method is verified through computer simulations. PMID- 30441147 TI - Local Interval Estimation Improves Accuracy and Robustness of Heart Rate Variability Derivation from Photoplethysmography. AB - Heart rate variability (HRV) can contain useful information about a subject, but its derivation traditionally relies on conductive electrocardiography (ECG) with adhesive electrodes. While photoplethysmography (PPG) can be acquired in much less intrusive ways, its signal differs fundamentally from ECG. First, it represents mechanical cardiac activity instead of electrical. Second, fiducial points of its waveform are much smoother compared to the QRS complex of the ECG. Still, studies have shown that meaningful HRV parameters can be extracted using PPG which small differences compared to ECG. In this work, we evaluate an algorithm termed "continuous local interval estimator (CLIE)" that analyzes the signal's entire waveform instead of individual fiducial points with respect to its potential in deriving beat-to-beat intervals and the time-domain HRV parameters SDNN, RMSSD, and pNN50 from the PPG. For evaluation, a polysomnography dataset consisting of more than 900,000 recorded heart beats from 33 subjects was used. The performance of CLIE was compared to three peak-detection strategies (peak-to-peak, peak-to-peak of first derivative, troth-to-troth) often found in the literature. For interval estimation and the proposed HRV parameters, CLIE outperformed the reference methods in terms of accuracy. Moreover, when the signal was contaminated with simulated noise, the performance of CLIE was affected only minimally compared to the references. While an adaptive prior could increase the performance of CLIE for very noisy signals, its application was found to deteriorate results when no noise was added. Thus, CLIE was found to be an accurate and robust tool when deriving HRV parameters from PPG signals, which can be augmented by an adaptive prior for potentially noisy signals, such as PPG imaging or wearable PPG. PMID- 30441148 TI - A State-Space Approach for Detecting Stress from Electrodermal Activity. AB - The human body responds to neurocognitive stress in multiple ways through its autonomic nervous system. Increases in heart rate, salivary cortisol and skin conductance level are often observed accompanying high levels of stress. Stress can also take on different forms including emotional, cognitive and motivational. While a precise definition for stress is lacking, a pertinent issue is to quantify the state of psychological stress manifested in the nervous system. State-space models have previously been applied to estimate an unobserved neural state (e.g. learning, consciousness) from physiological signal measurements and data collected during behavioral experiments. In this paper, we relate stress to the probability that a phasic driver impulse occurs in skin conductance signals. We apply state-space modeling to extracted binary measures to continuously track a stress level across episodes of cognitive and emotional stress as well as relaxation. Results demonstrate a promising approach for tracking stress through wearable devices. PMID- 30441149 TI - Combining Adaptive Filter and Phase Vocoder for Heart Rate Monitoring Using Photoplethysmography During Physical Exercise. AB - This study presents a robust heart rate monitoring algorithm using photoplethysmography (PPG) signal during physical exercise. The proposed method combines two stage: motion artifact removal and frequency refinement. The cascaded normalized least mean square adaptive filter is used to attenuate the noise introduced by motion artifacts in the PPG signal. A phase vocoder technique is used to refine the frequency calculated by Fourier Transform, from which the heart rate is finally tracked. On a publicly available database of twelve PPG recordings, the proposed technique obtains an average absolute error (AAE) of 1.08 beat per minute (BPM). Person correlation coefficient of 0.997 is achieved between true heart rate and estimated heart rate. In contrast to other available approaches, the proposed method has merely one parameter to tune in spectral peak tracking step for heart rate estimation. PMID- 30441150 TI - A Heart Rate Driven Kalman Filter for Continuous Arousal Trend Monitoring. AB - This paper proposes a continuous and unsupervised approach of monitoring the arousal trend of an individual from his heart rate using Kalman Filter. The state space model of the filter characterizes the baseline arousal condition. Deviations from this baseline model are used to recognize the arousal trend. A publicly available dataset, DECAF, comprising the physiological responses of 30 subjects while watching 36 movie clips inducing different emotions, is used to validate the proposed technique. For each clip, annotations of arousal given by experts per second are used to quantify the ground truth of arousal change. Experimental results suggest that the proposed algorithm achieves a median correlation of 0.53 between the computed and expected arousal levels which is significantly higher than that achievable by the state-of-the-art technique. PMID- 30441151 TI - Deep Motion Analysis for Epileptic Seizure Classification. AB - Visual motion clues such as facial expression and pose are natural semiology features which an epileptologist observes to identify epileptic seizures. However, these cues have not been effectively exploited for automatic detection due to the diverse variations in seizure appearance within and between patients. Here we present a multi-modal analysis approach to quantitatively classify patients with mesial temporal lobe (MTLE) and extra-temporal lobe (ETLE) epilepsy, relying on the fusion of facial expressions and pose dynamics. We propose a new deep learning approach that leverages recent advances in Convolutional Neural Networks (CNN) and Long Short-Term Memory (LSTM) networks to automatically extract spatiotemporal features from facial and pose semiology using recorded videos. A video dataset from 12 patients with MTLE and 6 patients with ETLEin an Australian hospital has been collected for experiments. Our experiments show that facial semiology and body movements can be effectively recognized and tracked, and that they provide useful evidence to identify the type of epilepsy. A multi-fold cross-validation of the fusion model exhibited an average test accuracy of 92.10%, while a leave-one-subject-out cross-validation scheme, which is the first in the literature, achieves an accuracy of 58.49%. The proposed approach is capable of modelling semiology features which effectively discriminate between seizures arising from temporal and extra-temporal brain areas. Our approach can be used as a virtual assistant, which will save time, improve patient safety and provide objective clinical analysis to assist with clinical decision making. PMID- 30441152 TI - Extracting Thickness Profiles of Anterior Mitral Leaflets in Echocardiography Videos. AB - Rheumatic heart disease is the serious consequence of repeated episodes of acute rheumatic fever. It is the major cause of heart valve damage resulting in morbidity and mortality. Its early detection is considered vital to control the disease's progression. The key manifestations that are visible in the early stages of this disease are changes in the thickness, shape and mobility of the mitral valve leaflets. Echocardiography based screening is sensitive enough to identify these changes in early stages of the disease. In this work, an automatic approach is proposed to measure, quantify and analyze the thickness of the anterior mitral leaflet, in an echocardiographic video. The shape of the anterior mitral leaflet is simplified via morphological skeletonization and spline modelling to get the central line of the leaflet. To analyze the overall thickness from the tip to its base, the anterior mitral leaflet is divided into four quartiles. In ach quartile the thickness is measured as the length of the line segment resulting from the intersection of the contour with the normal direction of the central point of each quartile. Finally, the thickness is analyzed by measuring the variance per quartile, divided by leaflet position (open, straight and closed). The comparison between the normal and pathological leaflets are also presented, exhibiting statistical significant differences in all quartiles, especially near the tip of the leaflet. PMID- 30441153 TI - Lagrangian Motion Magnification revisited: Continuous, Magnitude Driven Motion Scaling for Psychophysiological Experiments. AB - Video motion magnification forms a relatively novel family of visualization techniques, that aim to magnify imperceivably small motions in videos. The most prominent techniques are based on Eulerian video processing and local phase shifting, which modify pixel time courses, rather than relying on explicit motion estimation.In this work, we show that under ideal conditions in the context of psychophysiological experiments, a Lagrangian motion magnification approach based on dense optical flow estimation, can be superior to Eulerian motion magnification strategies. We present a novel, continuous and motion magnitude driven forward warping scheme of small motions, which implements motion compensation and magnification into a single motion estimation step. Our approach does not rely on temporal filtering and works in the presence of large motion. It does not require the explicit identification of fast moving objects and more generally no segmentation and or matting in the image domain is necessary. We apply our method to the visualization of blinking related modulations in micro saccadic eye movements ((i.a.. iridodonesis), pupil dilation (hippus) and micro expression analysis. PMID- 30441154 TI - A System for Accurate Tracking and Video Recordings of Rodent Eye Movements using Convolutional Neural Networks for Biomedical Image Segmentation. AB - Research in neuroscience and vision science relies heavily on careful measurements of animal subject's gaze direction. Rodents are the most widely studied animal subjects for such research because of their economic advantage and hardiness. Recently, video based eye trackers that use image processing techniques have become a popular option for gaze tracking because they are easy to use and are completely noninvasive. Although significant progress has been made in improving the accuracy and robustness of eye tracking algorithms, unfortunately, almost all of the techniques have focused on human eyes, which does not account for the unique characteristics of the rodent eye images, e.g., variability in eye parameters, abundance of surrounding hair, and their small size. To overcome these unique challenges, this work presents a flexible, robust, and highly accurate model for pupil and corneal reflection identification in rodent gaze determination that can be incrementally trained to account for variability in eye parameters encountered in the field. To the best of our knowledge, this is the first paper that demonstrates a highly accurate and practical biomedical image segmentation based convolutional neural network architecture for pupil and corneal reflection identification in eye images. This new method, in conjunction with our automated infrared videobased eye recording system, offers the state of the art technology in eye tracking for neuroscience and vision science research for rodents. PMID- 30441155 TI - Detection of Atypical and Typical Infant Movements using Computer-based Video Analysis. AB - The diagnosis of cerebral palsy (CP) is difficult before 2 years of age. The general movements assessment (GMA) is a method for predicting CP from the spontaneous movements of infants in the first months of life. This assessment has shown high accuracy in predicting CP, but its use is limited by a lack of trained clinicians and its subjective nature. An objective and cost-effective alternative is the automatic videobased assessment of infant movements. Retrospective videos with clinical GMA outcomes were evaluated against eligibility criteria for the automatic analysis consisting of a skin model for segmentation and large displacement optical flow (LDOF) for motion tracking. Kinematic features were extracted to classify the movements as typical or atypical using different classification algorithms. Preliminary classification results obtained from the analysis of 127 videos of preterm infants showed up to 92% of accuracy in predicting CP. A computerbased assessment would provide clinicians with an objective tool for early diagnosis of CP, to facilitate early intervention and improve functional outcomes. PMID- 30441156 TI - Cooperative Cooking: A Novel Virtual Environment for Upper Limb Rehabilitation. AB - Motor rehabilitation technologies commonly include virtual environments that motivate patients to exercise more often or more intensely. In this paper, we present a novel virtual rehabilitation environment in which two people work together to prepare meals. The players' roles can be fixed or undefined, and optional challenges can be added in the form of flies that must be swatted away. A preliminary evaluation with 12 pairs of unimpaired participants showed that participants prefer cooperating over exercising alone and feel less pressured when cooperating. Furthermore, participants enjoyed the addition of flies and preferred not to have defined roles. Finally, no significant decrease in exercise intensity was observed as a result of cooperation. These results indicate that cooperation could improve motor rehabilitation by increasing motivation, though the virtual environment needs to be evaluated with participants with motor impairment. PMID- 30441157 TI - Selective relay of afferent sensory-induced action potentials from peripheral nerve to brain and the effects of electrical stimulation. AB - Electrical stimulation of peripheral nerve fibers and dorsal column fibers is used to treat acute and chronic pain. Recent studies have shown that sensitized A fibers maybe involved in the relay of pain information. These nerve fibers also carry sensory-induced action potentials (APs), such as proprioception, mechanoreception, etc. Electrical stimulation of these nerve fibers can result in interactions between sensory-induced APs and stimulation-induced APs. For example, the sensory-induced APs can collide with stimulus APs, and thus may never be relayed to the brain. In this study, we aimed to quantify the effects of stimulation frequency on these interactions. Specifically, we focused on the goal of stimulation to simultaneously (i) block noxious sensory signals while (ii) relaying innocuous sensory signals from the periphery to the brain via a myelinated nerve fiber. We defined a performance metric called the "selective relay $(SR)$ " measure. Specifically, we constructed a tractable model of a nerve fiber that receives two inputs: the underlying sensory activity at the bottom of the fiber (noxious or innocuous), and the external stimulus applied to the middle of the fiber. We then defined relay reliability, $R$, as the percentage of sensory APs that make it to the top of the fiber. $SR$ is then a product of relaying innocuous sensory information while blocking noxious pain stimuli, i.e., $SR=R_{?mathrm {s}?mathrm {e}?mathrm {n}}(1-R_{?mathrm {p}?mathrm {a}?mathrm {i}?mathrm {n}})$. We applied the two inputs to the fiber at various frequencies and analyzed relay reliability and then we studied selective relay assuming noxious and innocuous stimuli produce APs with distinct frequencies. We found that frequency stimulation between 50-100Hz effectively blocks relay of low frequency pain signals, allowing mid-to-high frequency sensory signals to transmit to the brain. PMID- 30441158 TI - Quantitative EEG as Biomarkers for the Monitoring of Post-Stroke Motor Recovery in BCI and tDCS Rehabilitation. AB - This study investigates the neurological changes in the brain activity of chronic stroke patients undergoing different types of motor rehabilitative interventions and their relationship with the clinical recovery using the Quantitative Electroencephalography (QEEG) features. Over a period of two weeks, 19 hemiplegic chronic stroke patients underwent 10 sessions of upper extremity motor rehabilitation using a brain-computer interface paradigm (BCI group, n=9) and transcranial direct current stimulation coupled BCI paradigm (tDCS group, n=10). The pre- and post-treatment brain activations, as well as the intervention induced changes in the neuronal activity, were quantified using 11 QEEG features and their relationship with clinical motor improvement was investigated. Significant treatment-induced change in the relative theta power was observed in the BCI group and the change was significantly correlated with the clinical improvements. Also, in the BCI group, the relative theta power and interactions between the theta, alpha, and beta power were identified as monitory biomarkers of motor recovery. On the contrary, the tDCS group was characterized by the significant change in brain asymmetry. Furthermore, we observed significant intergroup differences in the predictive capabilities of post-intervention QEEG features between the BCI and tDCS group. Based on the intergroup differences observed in this study and convergent results from the other neuroimaging analysis performed on the same cohort, we suggest that distinctly different mechanisms of neuronal recovery were facilitated by tDCS and BCI interventions and these treatment specific mechanisms can be encapsulated using QEEG. PMID- 30441159 TI - Elbow training device using the Mechanically Adjustable Stiffness Actuator(MASA). AB - This paper presents an elbow training device using the Mechanically Adjustable Stiffness Actuator(MASA) for stroke survivors with hemiplegia. The MASA is a series elastic actuator whose mechanical stiffness is variable. Stiffness and the neutral position of the spring is mechanically changed using two identical actuators. Since assisting torque of the actuators is transmitted through the springs, changing stiffness of the MASA results in different level of assistance by the actuators. Then, according to the performance of the patients during given tracking tasks, the level of assistance is controlled via changing stiffness. A prototype of the rehabilitation device using the MASA is introduced and a preliminary experiments with 10 healthy subjects show the level of assistance changes. PMID- 30441160 TI - Towards Robot-Based Cognitive and Motor Assessment Across the HIV-Stroke Spectrum. AB - There is an increasing population of people living with both HIV and stroke around the world with no effective neurorehabilitation strategies to deal with the combination of physical, cognitive, and social impairment that result from both diseases. This gap is caused by a lack of tools that are able to assess the various impairments across the HIV-stroke spectrum. Rehabilitation robotics provide a potential approach to address this problem. In this study, we implement a motor and cognitive task on the Haptic TheraDrive, a single degree-of-freedom upper limb rehabilitation robot. We collect data on healthy and HIV-stroke subjects from both upper limbs. Our preliminary data show that mean performance error on a trajectory tracking task and total score and reaction time on the n back task are metrics that show differences between HIV-stroke patients and a healthy population. PMID- 30441161 TI - Electrocorticographic Activity of the Brain During Micturition. AB - Current therapies for neurogenic bladder do not allow spinal cord injury patients to regain conscious control of urine storage or voiding. Novel neural technologies may provide means to improve or restore the connection between the brain and the bladder; however, the specific brain areas and their underlying neural activities responsible for micturition must be better understood in order to design such technologies. In this retrospective study, we analyzed electrocorticographic (ECoG) data obtained from epilepsy patients who underwent ECoG grid implantation for epilepsy surgery evaluation, in the hopes of determining specific electrophysiological activity associated with micturition. Our results indicate modulation of the delta (delta, 0.1-4 Hz) and low-gamma (?gamma, 25-50 Hz) activity in the peri-Sylvian area and the inferior temporal lobe. These findings suggest involvement of the insular cortex and the uncinate fasciculus in micturition, important structures related to sensation and decision making. To date, this is the first known study utilizing ECoG data to elucidate the electrophysiological activity of the brain associated with bladder control and sensation. PMID- 30441162 TI - Non-Invasive Continuous-Time Blood Pressure Estimation from a Single Channel PPG Signal using Regularized ARX Models. AB - Continuous blood pressure (BP) monitoring can help in preventing hypertension and other cardiovascular diseases. In principle, an indirect non-invasive continuous time measurement of BP is possible by exploiting the photoplethysmography (PPG) signal, which can be obtained through wearable optical sensor devices. However, a model of the PPG-to-BP dynamical system is needed. In this study, we investigate if autoregressive with exogenous input (ARX) models with kernel-based regularization are suited for the scope. We analyzed 10 PPG time-series acquired on different individuals by a wearable optical sensor and correspondent BP reference values to evaluate feasibility of continuous BP estimation from a single PPG source. This first proof-of-concept study shows promising results in continuous BP estimation during resting states. PMID- 30441163 TI - Sensitivity of Video-Based Pulse Arrival Time to Dynamic Blood Pressure Changes. AB - Estimating blood pressure (BP) from pulse arrival time (PAT) by image-based (skin video) photoplethysmography (iPPG) is of increasing interest due to the non contact method advantage (over cuff-based methods) and potential for BP measurement to be built into portable devices such as mobile phones. The relationship between pulse transit time extracted from iPPG has been investigated during stable BP. The sensitivity of beat-to-beat iPPG-PAT to dynamic changes in BP has not been explored. This study investigated the correlation between iPPG PAT and diastolic BP (DBP) during 1-minute seated rest and 3-minute isometric handgrip exercise. 15 healthy participants (9 female, 34+/-13 years) were recruited. Video was recorded from subjects' faces at 30 frames per second using a standard web-camera with simultaneous measurement of the electrocardiogram and noninvasive finger BP. The iPPG waveform was from the averaged green channel intensity of regions of the forehead or cheek. PAT was calculated from the R-wave ofthe electrocardiogram to the foot of the iPPG or finger BP waveform respectively for direct comparison. Handgrip exercise caused a steady increase in DBP (75+/-9 to 87+/-13 mmHg, p<0.001). Beat-to-beat iPPG-PAT and DBP was negatively correlated (mena +/-SE -1.33+/-1.70 ms/mmHg, P=0.0024) as was finger PAT (mean +/-SE -0.5S +/-0.39 ms/mmHg, P<0.001). The proportion of individual significant negative regression slopes between DBP and finger-PAT and between DBP and iPPG-PAT was not significantly different. Despite high variability of the correlation between iPPG-PAT and DBP among subjects, iPPG-PAT can track dynamic changes in BP. PMID- 30441164 TI - Effect of Respiration on the Characteristic Ratios of Oscillometric Pulse Amplitude Envelope in Blood Pressure Measurement. AB - Systolic and diastolic blood pressures (BPs) are important physiological parameters for disease diagnosis. Systolic and diastolic characteristic ratios derived from oscillometric pulse waveform have been widely used to estimate automated non-invasive BPs in oscillometric BP measurement devices. The oscillometric pulse waveform is easily influenced by respiration, which may cause variability to the characteristic ratios and subsequently BP measurement. This study quantitatively investigated how respiration patterns (i.e., normal breathing and deep breathing) affect the systolic and diastolic characteristic ratios. The study was performed with clinical data collected from 39 healthy subjects, and each subject conducted BP measurements during normal and deep breathings. Analytical results showed that the systolic characteristic ratio increased significantly from 0.52 +/- 0.13 under normal breathing to 0.58 +/- 0.14under deep breathing (p < 0.05), and the diastolic characteristic ratio was not significantly affected from 0.75 +/- 0.12 under normal breathing to 0.76 +/- 0.13 under deep breathing (p = 0.48). In conclusion, deep breathing significantly affected the systolic characteristic ratio, suggesting that automated oscillometric BP device which is validated under resting condition should be strictly used for measurements under resting condition. PMID- 30441165 TI - Real-Time Sclera Force Feedback for Enabling Safe Robot-Assisted Vitreoretinal Surgery. AB - One of the major yet little recognized challenges in robotic vitreoretinal surgery is the matter of tool forces applied to the sclera. Tissue safety, coordinated tool use and interactions between tool tip and shaft forces are little studied. The introduction of robotic assist has further diminished the surgeon's ability to perceive scleral forces. Microsurgical tools capable of measuring such small forces integrated with robotmanipulators may therefore improve functionality and safety by providing sclera force feedback to the surgeon. In this paper, using a force-sensing tool, we have conducted robotassisted eye manipulation experiments to evaluate the utility of providing scleral force feedback. The work assesses 1) passive audio feedback and 2) active haptic feedback and evaluates the impact of these feedbacks on scleral forces in excess of aboundary. The results show that in presence of passive or active feedback, the duration of experiment increases, while the duration for which scleral forces exceed a safe threshold decreases. PMID- 30441166 TI - Novel Robotic Approach for Minimally Invasive Aortic Heart Valve Surgery. AB - Aortic heart valve replacement is a major surgical intervention, traditionally requiring a large thoracotomy. However, current advances in Minimally Invasive Surgery and Surgical Robotics can offer the possibility to perform the intervention through a narrow mini thoracotomy. The presented surgical robot and proposed surgical scenario aims to provide a highly controllable means for efficiently conducting valve replacement by endoscopic vision. The robot, consisting of a series of joints, is a cable actuated manipulator for reaching the operative site and delivering the valve at the required position. The robot is equipped with endoscopic cameras (to find the hinge points) and three stabilizing flaps (to stabilize the manipulator) for guarantying the proper valve placement. The manipulator is validated by experimental results of flaps' force and camera visions in artificial vessels. PMID- 30441167 TI - Non-Contact Tissue Ablations with High-Speed Laser Scanning in Endoscopic Laser Microsurgery. AB - The use of laser scanners in soft tissue microsurgery results in high quality ablations with minimal thermal damage to surrounding tissue. However, current scanner technologies for microsurgery are limited to free-beam lasers, requiring direct line-of-sight from outside the patient to the surgical site. Developing compact laser manipulation systems is crucial to introduce laser scanning capabilities in hard-toreach surgical sites. Recently, we developed a magnetic laser scanner as a tip module of an endoscopic system. The device provides 2D position control and fast scanning of a laser beam. In this work, the previous prototype is revised to enable its use with a CO2 laser source. The advantages of non-contact tissue ablations with fast scanning are discussed with comparative tissue ablation experiments coupling the system with a $CO_{2$ laser source. Results show that the magnetic laser scanner provides narrower ablations and less thermal damage compared to ablations performed with a bare flexible waveguide. These results highlight the potential of the proposed technology to improve soft tissue ablation quality in hard-to-reach surgical sites. PMID- 30441168 TI - Adaptation of Translated Frame-Based Approach for Forward Kinematics in a Radiosurgical Snake-Like Robot. AB - Snake-like robots are a typical serial-link manipulator newly adopted to assist human experts during medical procedures. Of the several prototypes that have been proposed for surgical repair of abdominal organs and delivery of radiation doses, only a very few attained FDA clearance and commercialization for clinical usage. This can be ascribed to complexities inherent with teleoperation of the redundant robots when controlled via single-ports or interactions with other organs both along the surgical path and the operation area. In this study, translated frame based approach is adapted for forward kinematics of snake-like robots that have orthogonal joints. This is realized by modifying the conventional standard DH approach commonly used for frame translation in serial robots. The adapted method is validated with model of a newly proposed radiosurgical snake-like robot. Validation results show that adapted method requires reduced execution times for both workspace generation and inverse kinematics of the snake robot. PMID- 30441169 TI - Robotics-Assisted Surgical Skills Evaluation based on Electrocortical Activity. AB - Skills assessment in Robotics-Assisted Minimally Invasive Surgery (RAMIS) is mainly performed based on temporal, motion-based and outcome-based metrics. While these components are essential for the proper assessment of skills in RAMIS, they do not suffice for full representation of all underlying aspects of skilled performance. Besides such commonplace components of skills, there exist other elements to be taken into account for comprehensive skills assessment. Among such elements are cognitive states (such as levels of stress, attention, concentration) that can directly affect performance. Investigating the impact of electrocortical activity and cognitive states of RAMIS surgeons over their performance has, however, received little attention in the literature. Therefore, in this paper, novel performance metrics based on electroencephalography (EEG) signals are studied for potential augmentation into RAMIS training and its assessment platform. For this purpose, a user study was conducted involving 23 novices and 9 expert RAMIS surgeons. The participants were asked to perform two tasks on the dv-Trainer(r), (Mimic Technologies) RAMIS simulator, while their brain EEG signals were being measured using the Muse EEG headband (InteraXon Inc.). The performance metrics were defined as mean values of band powers of EEG signals over various ranges of frequency. Statistical analysis was performed to evaluate metrics over 5 different ranges of frequency for 4 electrode locations and during 2 RAMIS training tasks. The results indicated statistically significant differences in electrocortical activity between novices and experts in temporoparietal and left frontal regions of their brain for mid to high frequency ranges. Overall, RAMIS experts showed lower levels of electrocortical activity in those regions compared to novices. The results indicate that electrocortical activity measured by EEG signals have the potential to provide useful information for skills assessment in RAMIS. PMID- 30441170 TI - Estimating The Quality of Electroconvulsive Therapy Induced Seizures Using Decision Tree and Fuzzy Inference System Classifiers. AB - Electroconvulsive therapy (ECT) is an effective and widely used treatment for major depressive disorder, in which a brief electric current is passed through the brain to trigger a brief seizure. This study aims to identify seizure quality rating by utilizing a set of seizure parameters. We used 750 ECT EEG recordings in this experiment. Four seizure related parameters, (time of slowing, regularity, stereotypy and post-ictal suppression) are used as inputs to two classifiers, decision tree and fuzzy inference system (FIS), to predict seizure quality ratings. The two classifiers produced encouraging results with error rate of 0.31 and 0.25 for FIS and decision tree, respectively. The classification results show that the four seizure parameters provide relevant information about the rating of seizure quality. Automatic scoring of seizure quality may be beneficial to clinicians working in this field. PMID- 30441171 TI - Electrical Interaction between Implantable Vagus Nerve Stimulation Device and Implantable Cardiac Rhythm Management Device. AB - BACKGROUND: Autonomic regulation therapy via vagus nerve stimulation (VNS) was recently approved as a therapy for chronic heart failure, and will likely be utilized in patients who are also indicated for cardiac rhythm management device implantation. This study is designed to assess the degree to which VNS is likely to cause interference in the cardiac sensing of an implantable cardiac rhythm management device. METHODS: A VNS stimulation lead and a cardiac sensing lead were placed in a simulated biological medium. A nonconductive carrier frame was used to position the leads at a precise electrode spacing. Stimulation was delivered through the VNS Therapy lead at a maximum output current and a variety of combinations of stimulation frequencies from 5-30 Hz and stimulation pulse widths from 130-1000 MUs. The electrode spacing began at 0 cm and was increased in 1 cm increments until the measured signal dropped below the cardiac rhythm management device noise floor for sensing. The test was conducted with both bipolar and unipolar sensing. RESULTS: In the bipolar sensing configuration, the maximum sensed signal amplitude was 687 MUV at an electrode separation of 0 cm, signal frequency of 30 Hz, pulse width of 1000 MUs, and output current of 3.5 mA. In the unipolar sensing configuration, the maximum amplitude was 406 MUV. In both configurations, the measured signal with maximum stimulation intensity decreased significantly with electrode separation, and dropped below the noise floor at an electrode spacing of 3.0 cm. The sensed signal amplitude was further attenuated at lower stimulation amplitudes and pulse widths. CONCLUSION: Even at maximum neural stimulation intensity of 3.5 mA, at an electrode separation of at least 3.0 cm, neural stimulation did not result in a detectable level of interference with either bipolar or unipolar sensing. Because this separation is significantly smaller than the minimum electrode separation of 15 cm in clinical practice, VNS Therapy is not expected to interfere with the function of implantable cardiac devices. PMID- 30441172 TI - Acute cardiovascular and hemodynamic effects of vagus nerve stimulation in conscious hypertensive rats. AB - Hypertension (HTN) affects over 1 billion people worldwide, with a significant number who are unable to control their blood pressure (BP) with conventional therapies. Recently, novel device-based therapies targeting the autonomic nervous system have been evaluated for treating HTN, including vagus nerve stimulation (VNS). Numerous studies have indicated the beneficial effects of chronic VNS in various models of HTN, however the acute effects of VNS on physiological responses have not been widely investigated. To better understand the acute effects of VNS, this study evaluates cardiovascular and hemodynamic responses from conscious hypertensive rats implanted with VNS stimulators and physiological telemeters for simultaneous monitoring of BP and heart rate (HR) as therapy is applied. We demonstrated that there are no acute changes in mean BP, HR and contractility measures as a result of VNS stimulation. However, there were significant increases in both HR variability and BP variability during VNS, which returned to baseline levels immediately at the cessation of therapy. The small acute changes observed during intermittent VNS could be additive, leading to beneficial chronic changes in BP and HR control, and may help in furthering the understanding of beneficial effects demonstrated in chronic use of VNS therapy. PMID- 30441173 TI - Neurophysiologic and Chronic Safety Testing of a Miniaturized Active Implanted Device with Integrated Electrodes for Bioelectronic Medicine Applications. AB - New dosing paradigms in bioelectronic medicine applications, such as low duty cycle stimulation of the vagus nerve to treat inflammatory disorders, enable architectural shifts in active implantable devices that benefit patients. Herein, we describe various features of the MicroRegulator (MR), an innovative neurostimulation system that includes a unique electrode-integrated implantable nerve stimulator. To verify efficient activation of neuronal targets within the vagus nerve, a geometric emulator of the MR (identical form and electrical contact properties as the clinical MR device) was tested in situ and neurophysiologic outcomes were compared to a control electrode in wide clinical use. The data demonstrated comparable patterns of compound potentials evoked from the MR emulator and the control electrode, with the MR emulator requiring a lower threshold current to depolarize the nerve. To verify chronic mechanical safety, the MR emulator was implanted for 2 months on the vagus nerves of canines. Blood flow through the major cervical vessels was unaffected, and pathologic and histologic findings included normal foreign body encapsulation and an absence of demyelination and nerve damage. Together these finding support the feasibility of the MR system for clinical translation. PMID- 30441175 TI - A novel numerical approach to stimulation of a specific brain region using transcranial focused ultrasound. AB - One of the biggest challenges associated with transcranial application of focused ultrasound is the presence of skull in wave propagation resulting in the attenuation and diffraction of sound waves, which leads to disruption and shifting of the acoustic focus in the brain. In this study, we were motivated to find an optimal transducer position to effectively deliver sufficient acoustic energy to the target in the brain whilst minimizing the effects of skull on wave propagation in a computationally inexpensive way. We hypothesized that the placement of a single-element focused ultrasound transducer which gives the lowest reflection coefficient would be the optimal position. We tested our hypothesis by conducting numerical investigations of wave propagation through the skull targeting the primary motor hand representation (M1) and the supplementary motor area (SMA). The optimal transducer positions were determined using our method (reflection coefficients were lowest), whereby the simulated magnitudes of the acoustic pressure values at the M1 and the SMA were respectively 91% and 92% greater than those when the reflection coefficients were greatest. PMID- 30441174 TI - A 41.2 nJ/class, 32-Channel On-Chip Classifier for Epileptic Seizure Detection. AB - A 41.2 nJ/class, 32-channel, patient-specific onchip classification architecture for epileptic seizure detection is presented. The proposed system-on-chip (SoC) breaks the strict energy-area-delay trade-off by employing area and memoryefficient techniques. An ensemble of eight gradient-boosted decision trees, each with a fully programmable Feature Extraction Engine (FEE) and FIR filters are continuously processing the input channels. In a closed-loop architecture, the FEE reuses a single filter structure to execute the top-down flow of the decision tree. FIR filter coefficients are multiplexed from a shared memory. The 540 * 1850 MUm2 prototype with a 1kB register-type memory is fabricated in a TSMC 65nm CMOS process. The proposed on-chip classifier is verified on 2253 hours of intracranial EEG (iEEG) data from 20 patients including 361 seizures, and achieves specificity of 88.1% and sensitivity of 83.7%. Compared to the state-of the-art, the proposed classifier achieves 27 * improvement in Energy-AreaLatency product. PMID- 30441176 TI - Fusion of Deep Convolutional Neural Networks for Microaneurysm Detection in Color Fundus Images. AB - Microaneurysms (MAs) are common signsof several diseases, appearing as small circular darkish spots in color fundus images. The presence of even a single MA may suggest diseases (e.g. diabetic retinopathy), thus, their reliable recognition is a critical issue in both human clinical practice and computer aided systems. As for their automatic recognition, deep learning techniques became very popular in the recent years. In this paper, we also apply such deep convolutional neural network (DCNN) based techniques; however, we organize them into a supernetwork with a fusionbased approach. The combination of the member DCNNs is achieved with interconnecting them in a joint fully-connected layer. The advantage of the method is that this large architecture can be trained as a single neural network, and thus, the member DCNNs are also trained with taking the predictions of the other members into consideration. The competitiveness of our approach is also validated with experimental studies, where the ensemble based system outperformed each member DCNN. As a primary application domain with strong clinical motivation, the methodology was tested for image-level classification. More specifically, a retinal image is divided into subimages to provide the required inputs for the DCNN-based architecture, and the whole image is labeled as a positive case, if the presence of MA is predicted in any of the subimages. Additionally, we also demonstrate how our architecture can be trained to accurately localize MAs with training only the local neighborhoods of the lesions; empirical tests showing solid performance are also enclosed. PMID- 30441177 TI - Predict In-Hospital Code Blue Events using Monitor Alarms through Deep Learning Approach. AB - Bedside monitors in hospital intensive care units (ICUs) are known to produce excessive false alarms that could desensitize caregivers, resulting in delayed or even missed clinical interventions to life-threatening events. Our previous studies proposed a framework aggregating information in monitor alarm data by mining frequent alarm combinations (i.e., SuperAlarm) that are predictive to clinical endpoints, such as code blue events, in an effort to address this critical issue. In the present pilot study, we hypothesize that sequential deep learning models, specifically long-short term memory (LSTM), could capture time depend features in continuous alarm sequences preceding code blue events and these features may be predictive of these endpoints. LSTM models are trained from continuous alarm sequences in various window lengths preceding code blue events, and the preliminary results showed the best performance reached an AUC of 0.8549. With the selection of optimal cutoff threshold, the 2-hour window model achieved 85.75% sensitivity and 72.61% specificity, respectively. PMID- 30441178 TI - Towards Finger Motion Capture System Using FBG Sensors. AB - This paper introduces a novel finger motion capture system using FBG (fiber Bragg grating) optical sensors. We develop two types of sensors to seamlessly reconstruct finger motion from strains induced in the FBGs. First, the shape sensor incorporates three optical fibers with multiple FBGs to reconstruct the position and orientation of a finger joint in 3D. In addition, the angle sensor is designed to measure the high curvature of bending on the finger joints. By deploying the two types of sensors on the fingers, we can reconstruct various finger motion in real time without drift over time. The accuracies of the fabricated FBG sensors are evaluated, resulting in an average error of 1.49 mm for the shape sensor at the distal tip (1.9% for the full length of the sensor) and 0.21 degrees error for the angle sensor. We finally demonstrate finger motion tracking with the FBG sensors in real time, while measuring the multi-DOF motion at the carpometacarpal joint of the thumb and also the high curvatures of bending motion at the metacarpophalangeal and interphalangeal joints of the thumb and the index finger. PMID- 30441179 TI - Dental pH Opti-Wand (DpOW): measuring oral acidity to guide enamel preservation. AB - Undetected caries can lead to painful cavities and surgical restorations. Lack of proper detection tools makes caries prevention dependent on dentist's expertise and presents obstacles in oral health monitoring. To overcome this problem, we have developed a new approach to predict early stages of enamel demineralization caused by oral bacteria. These bacteria metabolize sugars in our food and produce organic acids that lead to cavities. Measuring the acidity level can help predict early stages of tooth decay. pH paper or pH electrodes can be used to monitor acidity, but neither are able to track pH levels in all dental locations. Our device, DpOW, is a noncontact optics-based pH device that uses changes in the spectral fluorescence of FDA allowed fluorescein dye to measure acidity levels in difficult to access dental locations such as occlusal fissures. A prototype has been tested over a wide pH range (7.12 to 3.89) and shown to track the change in pH with 0.94 correlation coefficient. PMID- 30441180 TI - Performance Evaluation and Improvement of PER and Throughput in Galvanic-Coupling Intra-Body Communication Systems. AB - This study examined the following communication characteristics of contact and partially non-contact galvanic intra-body communication (IBC) systems using a human-body path loss model developed previously: 1) packet error rate (PER) calculation for the contact and partially non-contact IBC path, and PER improvement by the low-density parity check (LDPC) error correction code; and 2) signal-to-noise ratio (SNR) estimation using the blind SNR prediction method and throughput optimization using adaptive coding. The following results were obtained for these characteristics: 1) Applying the LDPC coding rate 3/4 through 1/4 can improve the required SNR by approximately 8~20 dB when PER = 10-2; and 2) the blind SNR prediction method can estimate SNR precisely, thus realizing appropriate throughput communication. PMID- 30441181 TI - Wireless Channel Modeling for Leadless Cardiac Pacemaker: Effects ofVentricular Blood Volume. AB - In this paper, the effects of ventricular blood volume change on the cardiac wireless channel modeling at 2.4 GHz are presented for future multi-node leadless capsule pacemakers. Numerical electromagnetic simulations are implemented in the anatomical model of human body and experiments are done in a homogeneous liquid phantom. The results show that the coupling between the capsule antennas decreases with increasing blood volume, as the blood is a highly attenuating medium. The received power varies by 3.1 dB for the implant-to-implant link inside the heart and varies by 1.3 dB for the heart implant to sub-cutaneous implant, during the diastole and systole cycle. The findings are useful to develop an intra-body communication between leadless pacemakers providing timing information for synchronized pacing in a multi-chamber leadless pacemaker system. PMID- 30441183 TI - Characterization and Classification of Human Body Channel as a function of Excitation and Termination Modalities. AB - Human Body Communication (HBC) has recently emerged as an alternative to radio frequency transmission for connecting devices on and in the human body with order(s) of magnitude lower energy. The communication between these devices can give rise to different scenarios, which can be classified as wearable-wearable, wearable-machine, machine-machine interactions. In this paper, for the first time, the human body channel characteristics is measured for a wide range of such possible scenarios (14 vs. a few in previous literature) and classified according to the form-factor of the transmitter and receiver. The effect of excitation/termination configurations on the channel loss is also explored, which helps explain the previously unexplained wide variation in HBC Channel measurements. Measurement results show that wearable-wearable interaction has the maximum loss (upto -50 dB) followed by wearable-machine and machinemachine interaction (min loss of 0.5 dB), primarily due to the small ground size of the wearable devices. Among the excitation configurations, differential excitation is suitable for small channel length whereas single ended is better for longer channel. PMID- 30441182 TI - Development of a Novel Wearable Ring-Shaped Biosensor. AB - We report on the preliminary results obtained out of a wearable module designed to be encompassed within a ring-shaped system aimed at providing healthcare services. The module is composed of two sensors for the measuring of Galvanic Skin Response (GSR) and Heart Rate Variability (HRV). A first device validation was carried out by involving four subjects who were asked to perform tasks providing different stress-related statuses. A comparison of physiological parameters measured by the module with those measured by a commercial HRV-GSR sensor chosen as gold standard was made. Two out of the three HRV parameters and all of the GSR parameters measured with the module resulted consistent (mostly differing less than 10%) with the same parameters measured by the gold standard. The work reported in this paper set a milestone for the realization of a system exploiting sensor fusion to provide active ageing, stress detection, activity recognition and e-health services has been achieved. PMID- 30441184 TI - A Method of Secure Compressed Sensing for Physiological Signals in Healthcare Internet-of-Things Applications. AB - With the increasing demand forinformation interaction and data transmission in medical and healthcare Internet of Things applications, effective and secure transmissions of data become particularly important. To address this problem, this paper focuses on a novel method of secure compressed sensing, which can be readily applied to physiological signals and other kinds of health signals. The method is able to efficiently reduce the sampling data and at the same time secure them without an extra significant computational cost, where a key is bound to the compressed sensing process with a symmetric cryptography design. Different from traditional methods, the novelty of this method is to combine the compression and encryption processes in an efficient way. Results of experimental analyses show that the proposed method can provide good security at the same compression rate. PMID- 30441185 TI - Channel Loss in Contactless Human Body Communication. AB - Human body communication (HBC) utilizes human body as the transmission medium to facilitate data communications in a wireless body area network (WBAN). It normally uses a pair of transmitting (Tx) and receiving (Rx) electrodes clinging to the body surface to form a low-loss body channel, so a higher energy efficiency can be achieved in comparison to conventional wireless communications. In HBC, the Tx electrode can be shared with vital sign monitoring electrode, such as ECG electrode or EEG electrode, to inject the signal into body. As for the Rx electrode, it can be either in direct contact to body surface or placed in proximity to body surface. The late case forms a contactless HBC communication, which find more applications in the WBAN, e.g. a smart phone in one's pocket to receive ECG signal from the chest electrode. In view of the adverse effect caused by the contactless case, this paper presents a study on the path loss of contactless HBC, which are investigated by finite element method (FEM) and verified by actual measurements. An empirical formula for path loss and contactless space is derived, showing that the path loss is increased by 18 dB when the distance between electrode and body increases from 1 mm to 10 mm. It also shows a 5 dB reduction on path loss with a 50% increase of the electrode size. PMID- 30441186 TI - Predicting beta bursts from local field potentials to improve closed-loop DBS paradigms in Parkinson's patients. AB - Motor symptoms in Parkinson's disease (PD) correlate with an excess in synchrony in the beta frequency band (13-30Hz) of local field potentials recorded from basal ganglia circuits. Recent results have suggested that this abnormal activity arises as a result of changes in specific dynamical features of the underlying neural signatures. In particular, patterns of activity in the beta band have been shown to be structured in bursts of longer durations and higher amplitudes in untreated patients with PD. Closed-loop deep brain stimulation (DBS) paradigms that specifically target these pathological bursts of activity hold promises to help trim, and thus normalize, their abnormal behavior in real-time. Here, we developed classification algorithms that predict pathological beta bursts based on ongoing changes in LFP frequency dynamics. We then compared simulations of prediction-based DBS profiles with existing 'adaptive DBS' alternatives. We show that model-driven stimulation profiles are more precise in restricting the delivery of stimulation to bursts that are considered pathological, while preserving physiological ones. The overall stimulation time required is also diminished, thus supporting longer battery life. These results represent a conceptual and algorithmic framework for the development of more precise DBS strategies that are selectively tailored to the electrophysiological profile of each patient. PMID- 30441187 TI - Data Driven Spatial Filtering Can Enhance Abstract Myoelectric Control in Amputees. AB - Myoelectric control based on multi-sensor techniques can provide an enhanced signal to noise ratio but increases hardware cost and complexity. Sensor arrays are also attractive in a prosthetics context when exact muscle positions are unknown, such as may be the case after limb loss. We present preliminary data obtained while four amputee participants engaged in an abstract myoelectric decoding task. The decoder was controlled by muscles of the forearm or upper arm depending on the level of limb loss. We compare performance using a pair of surface electromyography sensors and while using a data driven weighting of eight sensors. Performance rates demonstrate that amputee participants are able to learn the myoelectric task. Results trend strongly toward enhanced performance when using multiple spatially weighted sensors. Further studies are required to test whether the use of additional myoelectric sensing hardware in abstract decoding would lead to effective prosthesis control. PMID- 30441188 TI - Continuous Versus Discrete Simultaneous Control of Prosthetic Fingers. AB - Modern, commercially available hand prostheses offer the potential of individual digit control. However, this feature is often not utilized due to the lack of a robust scheme for finger motion estimation from surface electromyographic (EMG) measurements. Regression methods have been proposed to achieve closed-loop finger position, velocity, or force control. In this paper, we propose an alternative approach, based on open-loop action-based control, which could be achieved through simultaneous finger motion classification. We compare the efficacy of continuous closed-loop and discrete open-loop control on the task of controlling the five degrees of actuation (DOAs) of a dexterous robotic hand. Eight normally limbed subjects were instructed to teleoperate the hand using a data glove and the two control schemes under investigation in order to match target postures presented to them on a screen as closely as possible. Results indicate that, firstly, the performance of the two control methods is comparable and, secondly, that experience can lead to significant performance improvement over time, regardless of the method used. These results suggest that prosthetic finger control in a continuous space can be potentially achieved by means of myoelectric classification and discrete, action-based control and hence encourage further research in this direction. PMID- 30441189 TI - Identifying multiscale hidden states to decode behavior. AB - A key element needed in a brain-machine interface (BMI) decoder is the encoding model, which relates the neural activity to intended movement. The vast majority of work have used a representational encoding model, which assumes movement parameters are directly encoded in neural activity. Recent work have in turn suggested the existence of neural dynamics that represent behavior. This recent evidence motivates developing dynamical encoding models with hidden states that encode movement. Regardless of their type, encoding models have vastly characterized a single scale of activity, e.g., either spikes or local field potentials (LFP). In our recent work we developed a multiscale representational encoding model to simultaneously characterize and decode discrete spikes and continuous field activity. However, learning a multiscale dynamical model from simultaneous spike-field recordings in the presence of hidden states is challenging. Here we present an unsupervised learning algorithm for estimating a multiscale state-space model with hidden states and validate it using spike-LFP activity during a reaching movement. We use the learned multiscale statespace model and a corresponding decoder to identify hidden states from spike-LFP activity. We then decode the movement trajectories using these hidden states. We find that the identified states can accurately decode the trajectories. Moreover, we demonstrate that adding LFP to spikes improves the decoding accuracy, suggesting that our unsupervised learning algorithm incorporates information across scales. This learning algorithm could serve as a new tool to study encoding across scales and to enhance future BMI systems. PMID- 30441190 TI - Improved Training Paradigms and Motor-decode Algorithms: Results from Intact Individuals and a Recent Transradial Amputee with Prior Complex Regional Pain Syndrome. AB - Working towards improved neuromyoelectric control of dexterous prosthetic hands, we explored how differences in training paradigms affect the subsequent online performance of two different motor-decode algorithms. Participants included two intact subjects and one participant who had undergone a recent transradial amputation after complex regional pain syndrome (CRPS) and multi-year disuse of the affected hand. During algorithm training sessions, participants actively mimicked hand movements appearing on a computer monitor. We varied both the duration of the hold-time (0.1 s or 5 s) at the end-point of each of six different digit and wrist movements, and the order in which the training movements were presented (random or sequential). We quantified the impact of these variations on two different motordecode algorithms, both having proportional, six-degree-offreedom (DOF) control: a modified Kalman filter (MKF) previously reported by this group, and a new approach - a convolutional neural network (CNN). Results showed that increasing the hold-time in the training set improved run-time performance. By contrast, presenting training movements in either random or sequential order had a variable and relatively modest effect on performance. The relative performance of the two decode algorithms varied according to the performance metric. This work represents the first-ever amputee use of a CNN for real-time, proportional six-DOF control of a prosthetic hand. Also novel was the testing of implanted high-channelcount devices for neuromyoelectric control shortly after amputation, following CRPS and long-term hand disuse. This work identifies key factors in the training of decode algorithms that improve their subsequent run-time performance. PMID- 30441191 TI - A Pilot Study on Using Forcemyography to Record Upper-limb Movements for Human machine Interactive Control. AB - Forcemyography (FMG) is a useful method to record real-time body motions, which has application potentials for human-machine interactive control. The FMG registers the change of force distribution in the normal direction on muscle surface during limb movements, and the body motions can be recognized by decoding the FMG patterns. In this study, we used FMG to record upper-limb movements and evaluated the influence of different configurations of signal channel and feature on motion classification performances. A four-channel wearable FMG acquisition system was developed to record seven upper-limb movements on each of six able bodied subjects. The preliminary results showed that the signal channel number has significant influence on motion classification performance; however, the influence of signal feature number on motion classification was insignificant. In addition, the influence of channel combination and feature combination were also discussed in this paper. This work would support the application potential of FMG for body motion recording and may provide useful instructions for the application of FMG in human-machine interactive control. PMID- 30441192 TI - Finger-Wearable Blood Pressure Monitor. AB - Convenient and painless blood pressure measurement can enable increased user adoption of regular monitoring and early intervention for hypertension, which is a significant cause of mortality worldwide. This paper introduces a fingerwearable blood pressure measurement device to enable frequent daytime and nocturnal monitoring. The blood pressure measurement is achieved using a two dimensional capacitive tactile sensor array that is located next to a digital artery. A pumpdriven pneumatic bladder presses the tactile array and the finger towards each other to obtain a pressure sweep versus time. The digital artery pressure waveform data collected during this sweep are used to estimate arterial blood pressure. A clinical study (N =97) was conducted to obtain training (N =49) and validation (N =19) data for blood pressure algorithm development and test (N =29) data to determine the estimation accuracy compared to brachial dual-observer auscultation. On the test set, the mean and standard deviation of the error in the systolic blood pressure estimate are 0.9 mmHg and 6.9 mmHg, respectively, while the corresponding quantities for diastolic blood pressure are -3.2 mmHg and 7.0 mmHg, respectively. These results compare favorably to blood pressure accuracy requirements specified by international standards. PMID- 30441193 TI - Using Moving Average Method to Recognize Systole and Diastole on Seismocardiogram without ECG Signal. AB - Seismocardiogram (SCG) is a cardio-mechanical signal generated by the heart activities and it can be obtained by placing an accelerometer on the chest. Recently, SCG was used to estimate heart operation by evaluating systolic and diastolic events but the SCG must be coupled to the ECG timing in order to analyze and recognize the events on the SCG waveform. In this study, a low complex algorithm is proposed to identify the regions containing systolic and diastolic points in real time without referencing to the ECG. The method uses the slope, a moving average threshold, and systolic interval constraint to identify the systoles and diastoles. The ECG signal was also collected for manual annotation and comparison. This moving average method has an average error rate of 4% for systolic detection and 9% for diastolic detection on the eight testing subjects. The average processing time of the moving average method is 75.2ms for one-minute data which is suitable for realtime wearable device for healthcare applications. PMID- 30441194 TI - A Hybrid Hierarchical Framework for Free Weight Exercise Recognition and Intensity Measurement with Accelerometer and ECG Data Fusion. AB - Accurate recognition and effective monitoring of physical activities (PA) in daily life is a goal of many healthcare fields. Existing PA recognition approaches are mostly designed for specific scenarios and often lack extensibility for application in other areas, thereby limiting their usefulness. In this paper, we present a hybrid hierarchical framework that successfully combines two of the main specific-sensor-based PA methods into an effective hybrid solution for general weight exercise applications. The fusion solution separates free weight and non-free weight activities and then further classifies free weight exercises, whilst measuring quantities of repetitions and sets, thus providing a measure of intensity. By fusing accelerometer and electrocardiogram (ECG) data, a One Class Support Vector Machine (OC-SVM) and a Hidden Markov Model (HMM) are applied for exercise recognition and we use semantic inference for determining the intensity of the exercise. The results are based on data from 10 healthy subjects (age: 30 +/- 5; BMI: 25 +/- 5.5 kg/m^2; body fat: 20.5 +/- 5.4), which shows good accuracy in exercise recognition and intensity measurement. This framework can be extended to support additional types of PA recognition in complex applications. PMID- 30441195 TI - Detecting Cardiac Activity by Capacitive Electrodes from a Single Point on the Wrist. AB - Ballistocardiography (BCG) is the measurement of body movement by forces associated with heart contraction that can be used for monitoring cardiac activity. It has already been measured by force sensor and accelerometer. In this research, we developed a capacitive wristband that provides a method for single point, continuous BCG measurement, which has the potential to become a new type of sensor for wearable health care. The aim of this paper is to validate that the signal detected by capacitive electrodes is actually the BCG signal. Signals from four healthy subjects were acquired by a capacitive wristband together with Electrocardiogram (ECG). The capacitive signal was validated by both morphology matching analysis and wave occurrence time matching analysis to show that it is indeed BCG signal. JJ intervals extracted from BCG were shown to have potential to be surrogate of ECG RR series in heart rate variability analysis. PMID- 30441196 TI - Performance of graphene ECG electrodes under varying conditions. AB - Smart garments for invisible health sensing have been available for a number of years, with heart sensing typically performed using silver loaded conductive threads integrated into the fabric to pick up the electrocardiogram. Recent work has investigated printed graphene textiles as an alternative to this, which are potentially more environmentally friendly, cost-effective, and can be performed after garment manufacturing. This paper presents an exploration of second order factors on the performance of graphene textile electrodes for electrocardiogram measurements. We prepare graphenebased textile electrodes using a simple and highly scalable continuous padding method. We then analyze two metrics: the change in heart rate estimation error, and the changes in signal-to-noise ratio; under two separate conditions: an extended record length, and varying temperatures; to recreate the some of the conditions the material would experience when being worn in real-life. We report that neither the heart rate estimation error or the signal-to-noise ratio are significantly affected after a long record or with varying temperature. These tests indicate that graphene electrodes are suitable for electrocardiogram measurements in a wearable that will be subjected to these conditions. PMID- 30441197 TI - Monitoring of Pulse Pressure and Arterial Pressure Waveform Changes during the Valsalva Maneuver by a Portable Ultrasound System. AB - This work presents non-invasive evaluation of the arterial blood pressure (ABP) waveform during the Valsalva maneuver. Ultrasound scanning is conducted to acquire blood flow and arterial distension signals. Motion-tolerant ultrasound measurement schemes are employed by using two wide rectangular transducers. Pulse pressure (PP) estimated at the common carotid artery is compared to that of a finger waveform measured by a volume clamping device. The changes of PP are correlated between the two measurements. A more depressed dicrotic notch during the Valsalva strain is observed, and beat-to-beat variations of PP and a pulse rate caused by respiration and baroreflex is observed during the control. This validation suggests novel opportunities to investigate the pathophysiology of cardiovascular diseases through the noninvasive ABP waveform monitoring during the stress test. PMID- 30441198 TI - Kick LL: A Smartwatch for Monitoring Respiration and Heart Rate using Photoplethysmography. AB - With the growing popularity of wearable devices in the consumer space, interest in leveraging this technological platform in the medical field is rising. In this report, we describe a smartwatch capable of measuring respiration and heart rate using photoplethysmography (PPG). The device couples a photosensor, specifically tuned bandpass filters, and frequency content analysis to extract respiration and heart rate from the PPG signal. The results from the experimental device were compared to a commercial chest strap heart rate monitor. Respiratory rate measurements agreed within 1 breath per minute and heart rate measurements agreed within 3-4 beats per minute of the reference device. Furthermore, the device was packaged in an untethered wristwatch allowing for realtime measurements and analysis. PMID- 30441199 TI - A novel electrochemical sensor for non-invasive monitoring of lithium levels in mood disorders. AB - Lithium is the main drug for the treatment of mood disorders. Due to its narrow therapeutic window, Therapeutic Drug Monitoring (TDM) is a norm during therapy in order to avoid adverse effects. Consequently, patients are obliged to frequent check-ups in hospitals to determine their serum concentration and optimize accordingly the drug dose. Wearable sensors have attracted a growing interest in the research community in recent years owing to their promising impact in personalized healthcare. In particular, sweat diagnosis has seen an enormous expansion and is currently entering the market thanks to the large availability and simple collection of this fluid. In this paper a novel approach for non invasive decentralized monitoring of lithium drug concentration through sweat analysis is proposed for the first time. An all-solid-state Ion- Selective Electrode (ISE) with a nanostructured Solid-Contact (SC) is used to detect lithium ions in sweat. The sensor offers near-Nernstian behaviour (57:6+/-2:1 mV/decade) in the concentration range of interest. In addition, it shows fast response (15-30 s), good reversibility and small potential drift over time. A wide pH stability window (pH 4-12) is also proved. PMID- 30441200 TI - Drinking Water Quality Monitoring: An Alternative Approach to Microbial Contamination Events. AB - The nonstop growing of world population and consequent increase in water demands, as raise the interest in continuous and real-time drinking water monitoring systems. The following study aims to study Tryptophan Intrinsic Fluorescence as a method for detecting microbial contamination events in drinking water. PMID- 30441201 TI - A Precise Sampling Strip with Microstructures. AB - This paper presents a precise sampling microstructure formed as a paper strip. We have been developing dialysis system that can be implanted into a human body as an artificial kidney. For the safe use of our artificial kidney, the patients' urine needs to be constantly monitored to detect the abnormal value of ion concentration essential for human life. We are conceiving the monitoring system based on sampling by a paper strip. In this study, we fabricated the strip consisting of slanted and interlocked micropillars for the sampling, known as synthetic microfluidic paper. The paper-like substrate can be fabricated with a well-controlled geometry and subsequently enables precise sampling. Through the conducted experiments, it was shown that synthetic microfluidic paper had better mechanical properties, showed more precision in sampling than paper filter as well as corresponding liquid holding capability to the paper filter. Our proposed paper-based sampling system is expected to lead to the development of minimally invasive ion monitoring system with quantitative sampling strip. PMID- 30441202 TI - Low Power Consumption device for Biological Stability Monitoring in Drinking Water. AB - Water monitoring has an unquestionable value for people's safety. Despite this, most systems are expensive to operate due to high power consumption or high measuring time. This translates to an inefficient system. This study proposes a design for a low power consumption system to monitor water quality. By using a simple 3D printed design that includes UV LEDs, a filter, a lens and a photosensor. The tests performed in this paper is to show the effect the lens provides and the limited power consumption of the overall system as well as the sensitivity of the system. PMID- 30441203 TI - Detection of Human Chorionic Gonadotropin (hCG) Hormone using Digital Lateral Flow Immunoassay. AB - The main goal of this work was to establish a hybrid device incorporating an electrochemical-based transducer on a conventional lateral flow assay strip in order to perform an on-chip fast testing method for the detection of various bio analyses. In this context, the expected development of the digital lateral-flow immunoassay to be considered a reliable low-cost instrument improves the future of the very simple and flexible approach oflateral-flow assays. It is anticipated to achieve a digital quantitative lateral-flow immunoassay by exploring the electrochemical transducers alongwith recognition elements for digitization of commercially available rapid tests. As a preliminary step, the described technique will be validated using two standard electrochemical measurements (amperometric and impedimetric) across two electrodes fixed onto the surface of LFA strip. The LFA strips were prepared at the factory for pregnancy tests and modified by adding two parallel copper electrodes at the lab. These strips were proven by in-vitro experiments to be reusable lasting for 20-30 multiple days. Further on, the detection of hCG Ab-Ag interaction using these strips was performed. Two different types of measurements, namely amperometric and impedimetric, were used which yielded similar results to those reported in literature with screen-printed micro-electrodes. In addition, different concentrations of NaCl and hCG Ag solution were investigated. However, the expected linear concentration response was obtained. A promising proof-of-concept have been achieved through this study. Further studies are needed to complete the development of fully printed disposable electrochemical devices that are able to either display a digital result directly or transmit data to a mobile phone using RFID/NFC. PMID- 30441204 TI - Hermetic packaging for implantable microsystems: Effectiveness of sequentially electroplated AuSn alloy. AB - With modern microtechnology, there is an aggressive miniaturization of smart devices, despite an increasing level of integration and overall complexity. It is therefore becoming increasingly important to be achieve reliable, compact packaging. For implantable medical devices (IMDs), the package must additionally provide a high quality hermetic environment to protect the device from the human body. For chip-scale devices, AuSn eutectic bonding offers the possibility of forming compact seals that achieve ultra-low permeability. A key feature is this can be achieved at process temperatures of below 350315 degrees C, therefore allowing for the integration of sensors and microsystems with CMOS electronics within a single package. Issues however such as solder wetting, void formation and controlling composition make formation of high-quality repeatable seals highly challenging. Towards this aim, this paper presents our experimental work characterizing the eutectic stack deposition. We detail our designmethods and process flow, share our experiences in controlling electrochemical deposition of AuSn alloy and finally discuss usability of sequential electroplating process for the formation of hermetic eutectic bonds. PMID- 30441205 TI - Microfluidic Spectrophotometer for Neurotransmitter Detection Based on Gold Nanoparticles: Preliminary Results. AB - A microfluidic-based spectrophotometer for neurotransmitters sensing is presented in this paper. In addition, a neurotransmitter photo-fingerprint is analyzed to evaluate the feasibility of selective neurotransmitter detection using optical techniques. The aim of this work is to detect major neurotransmitters (NTs) using a compact, portable and cost effective optical system for selective and real time NT concentration monitoring. Micro-spectroscopic detection of NTs is challenging because most of them are transparent to visible light. Nevertheless, they interfere with the absorption spectrum of gold nanoparticles (Au-NP), which exhibit maximum absorbance in the range of 520 nm. We observed an Au-NP maximum absorbance shift of up to 4nm in presence of NTs. Based on this shift, it is possible to detect NTs using visible ligh by using vertical-cavity surface emitting laser (VCSEL) as light sources and an integrated system-on-chip (SoC) spectrophotometer. PMID- 30441206 TI - Occipital EEG Activity for the Detection of Nocturnal Hypoglycemia. AB - Nocturnal hypoglycemia is dangerous that threatens patients because of its unclear symptoms during sleep. This paper is a study of hypoglycemia from 8 patients with type 1 diabetes (T1D) at night. O1 and O2 EEG data of the occipital lobe associated with glycemic episodes were analyzed. Frequency features were computed from Power Spectral Density using Welch's method. Centroid alpha frequency reduced significantly ($?mathrm{P}?lt 0.0001$) while centroid theta increased considerably ($?mathrm{P}?lt 0.01$). Spectral entropy of the unified theta-alpha band rose significantly ($?mathrm{P}?lt 0.005$). These occipital features acted as the input of a Bayesian regularized neural network for detecting hypoglycemic episodes. The classification results were 73% and 60% of sensitivity and specificity, respectively. PMID- 30441207 TI - Calculating RF-Induced Voltages for Implanted Medical Devices in MRI Using Computational Human Models. AB - Despite its import as a diagnostic tool, patients with active implantable medical devices (AIMDs) are generally denied access to magnetic resonance imaging (MRI). The complexity of MRI environments stems from a multiplicity of fields and numerous scan parameters. In order to perform a risk assessment for RF-induced malfunction, manufacturers perform electromagnetic simulations using computational human models (CHMs) to calculate RF induced energy at the AIMD ports. This work explores the impact of the CHMs on the calculation of RF-induced voltages at the RF antenna port for cardiovascular implantable electronic devices (CIEDs). PMID- 30441208 TI - Classification of Therapeutic Hand Poses Using Convolutional Neural Networks. AB - Measurement of finger active range of motion (ARoM) is essential to quantify outcomes accurately after hand surgery and during rehabilitation. Currently, finger ARoM is measured by a hand-held goniometer, which introduces measurement error. Moreover, this method is time-consuming. To speed up and simplify this process, we developed a system to measure the ARoM automatically. However, to assess the ARoM for all joints, different hand poses are required. The goal, then, is to design a classifier that achieves accurate and automatic discovery of the hand pose. According to the detected pose, the system will apply the appropriate algorithm to measure the ARoM for all fingers. Furthermore, this will enable a camera capture control system to provide the best view by moving the camera as required by each algorithm. A critical part of the system is the classifier because it controls the accuracy and compute time of the measurement. In this paper, we describe a study of different classifiers for hand pose and include results. The best classifier achieves 99% accuracy in classifying 400 test samples from five previously unseen human subjects with a compute time of 8ms per sample. PMID- 30441209 TI - KardiaTool: An Integrated POC Solution for Non-invasive Diagnosis and Therapy Monitoring of Heart Failure Patients. AB - The aim of this work is to present KardiaTool platform, an integrated Point of Care (POC) solution for noninvasive diagnosis and therapy monitoring of Heart Failure (HF) patients. The KardiaTool platform consists of two components, KardiaPOC and KardiaSoft. KardiaPOC is an easy to use portable device with a disposable Lab-on-Chip (LOC) for the rapid, accurate, non-invasive and simultaneous quantitative assessment of four HF related biomarkers, from saliva samples. KardiaSoft is a decision support software based on predictive modeling techniques that analyzes the POC data and other patient's data, and delivers information related to HF diagnosis and therapy monitoring. It is expected that identifying a source comparable to blood, for biomarker information extraction, such as saliva, that is cost-effective, less invasive, more convenient and acceptable for both patients and healthcare professionals would be beneficial for the healthcare community. In this work the architecture and the functionalities of the KardiaTool platform are presented. PMID- 30441210 TI - Analyses of Baropodometry Protocols Through Bibliometric Research. AB - The posture of the foot is an important and complex aspect of the human body that implies a constant and coherent adaptation, and keeps the body segments in alignment. Baropodometry is a quantitative exam that evaluates the distribution of pressures at different points in the plantar region and the foot contact area. The objective of the study was to know evaluation protocols that used Barapodometry and to verify which variables were observed after the examination. It was analyzed 43 publications, between 2014 and November 2017, indexed in the Web of Science database and / or IEEE. It was verified that the year with the most publications was 2016 and the language with the highest incidence was English. Italy was the country with the highest number of articles published. In relation to the profile of the participants the most studied were those affected by Parkinson's Disease; the most used positioning protocol was bipodal barefoot support with separated feet with open eyes and then closed and arms along the body, the analyzes performed after the examination were on the stabilization area and anteroposterior and lateral velocity of balance. It was concluded that the examination can be effective in the diagnosis of disorders of static and dynamic equilibrium in the different disorders. PMID- 30441211 TI - Comparison between thermal recovery in women with Raynaud's Phenomenon and not diagnosed women using thermography. AB - Thermography detects the infrared radiation emanated from bodies and transduces it in electrical analog signal. It has application as a complementary exam in several medical segments, including the reheating study to detect diseases like Raynaud's Phenomenon (RP). In this way, the aim of this study is to compare the heating behavior of the RP women and not diagnosed (ND) women for selection of diagnosis criteria. This retrospective study was undertaken in the city of Curitiba, Brazil. For the study, twenty-four volunteer women, with the age range of 30-70 years, were taken to participate of a survey, 12 of them have the clinical diagnostic of Secondary Raynauld's Phenomenon, and twelve women were not diagnosed. Volunteers answered an anamnesis and had the central body temperature measured. They were oriented to keep the hands free and to do not touch anything during 15 minutes for acclimatization. Then, the hands were immersed for 60 seconds in a container with water at 10 degrees C. New pictures were taken every five minutes during twenty minutes after the immersion. The heating curve of the right hand shows that RP women's hands are colder than ND women and are slower to reheat the temperature after cold stress. The ring (fourth finger) has a linear behavior in both hands. It was the coldest one and the slowest to reheat. Statistical difference was observed in critical times of reheating at 15 and 20 minutes after the cold stress. These results show that this finger could become a reference in studies to determine cutting points and to facilitate the clinical diagnosis of RP. PMID- 30441212 TI - Selective Collection and Condensation of Exhaled Breath for Glucose Detection. AB - Exhaled breath condensate (EBC) is a promising non-invasive sample for the detection of various analytes, such as glucose. However, the methods used to collect EBC are highly inconsistent; the variable dilution factors associated with water vapor and the inclusion of dead space air significantly impact the reliability of reported analyte concentrations in EBC. For example, current EBC glucose measurements have resulted in dilution factors ranging from 1/1000 to 1/50000 [1]. There is a need for a systematic and selective EBC collection method to ensure accurate analyte detection and quantification. Herein, we develop and characterize a low-cost, portable condenser which selectively collects exhaled breath that has been exchanged with lung fluid in a temperature-based manner. We demonstrate that for ~15 L of exhaled air, our device can condense reproducible volumes of EBC $({?lt} 130~ {?mu } ?mathrm {L})$ in under 3 minutes (p > 0.05, n = 3). Furthermore, our results indicate that a higher concentration of glucose can be detected in the collected sample with selective valve opening (p < 0.05, n = 3). The development of this device enables a repeatable and robust collection method to enable the evaluation of correlations between analytes in EBC and blood. PMID- 30441213 TI - Intuitive Visualization of Innervation Zones Based on Surface-EMG Signals. AB - The purpose of this study was to develop a user-friendly presentation of surface EMG data in near-time for intraoperative nerve-monitoring. We have built a novel surface-EMG probe as a diagnostic device to investigate innervation patterns of sphincter muscles in further clinical diagnostic studies. S-EMG data were recorded from 20 healthy volunteers from the orbicularis oris muscles. We developed an automated analysis based on correlation in order to find phase inversions and thus innervation zones automatically. We compared our automated analysis with manual, visual analysis. Both techniques were reviewed for variance and showed reproducible results. Data from automated analysis were compared to visually analyzed data showing high consistency. Based on our automated analysis, we created an intuitive visualization of all measurements per person. We displayed the quality and quantity of the phase inversions found in a subject thus allowing for simple identification of innervation zones. We conclude that our set-up showed sufficient reliability for detection of motoric endplate activity and can be used for further clinical neurophysiological studies. PMID- 30441214 TI - Point-of-Care Assessment of Folate Status in Women of Reproductive Age Using a Fluorescence Lateral Flow Assay. AB - Folate is an essential vitamin to the development of a fetus in early pregnancy. Maternal folate supplementation around the time of conception has been shown to decrease the risk of neural tube defects (NTDs), a class of serious birth defects. The closure of the neural tube before the 28th day after conception necessitates that the folate intake must take place before most women know that they are pregnant. Therefore, screening women of reproductive age for folate status would allow for an improved understanding of the need for supplementation in women who could become pregnant as well as the effectiveness of current supplementation and fortification recommendations. Current folate assessment is limited to labbased assays which require expensive equipment, trained personnel, and are time-intensive. Our point-of-care diagnostic test quantifies levels of folate in human serum with the use of a lateral flow assay and a portable imaging device. We have designed an assay which uses fluorescent particles, folate binding protein, and antibodies to measure serum folate. This test could be used in resource-limited settings, where access to laboratory infrastructure is limited and where knowledge of folate status in women of reproductive age is lacking. By increasing our understanding of folate status around the world, we can improve implementation of folic acid supplementation and fortification and therefore reduce the risk of NTDs. PMID- 30441215 TI - Black-box Model Identification of Physical Activity in Type-l Diabetes Patients. AB - In this paper we consider the problem of predicting future values of glucose in type-1 diabetes. In particular, we investigate the benefit of including physical activity, measured by an off-the-shelf wearable device, to other physiologic signals frequently used to predict blood-glucose concentration, namely injected insulin, carbohydrates intake, and past glucose samples measured by a Continuous Glucose Monitoring (CGM) sensor. Derivation of individualized predictors is crucial to cope with the wide inter- and intra-subject variability: learning and updating patient-specific models of the glucose-insulin system and using them to design personalized control actions has the potential to improve substantially patients' quality oflife. On data collected by 6 subjects for 5 days, we identify a black-box liner model that uses insulin and meal as inputs and glucose as output. Prediction Error Method (PEM) is used for parameter estimation. The personalized model is employed to derive patient-tailored predictors. This procedure is then repeated using a further physiological input, accounting for physical activity. The prediction accuracy of the two models, including or not physical activity, was compared on the basis of two metrics commonly used in system identification, namely Coefficient of Determination (COD) and Root Mean Squared Error. The models identified with physical activity have better performance, increasing the 3-hr prediction COD by mean +/- standard deviation of 18.5% +/- 30.1%. PMID- 30441216 TI - Development of a Human Infant Feeding Reinforcement System. AB - We present a custom-made device that enables the study of food reinforcement in infants younger than nine months. This device called INFERS (INfant FEeding Reinforcement System) consists of a smart feeding controller and milk delivery components which has been constructed using custom and off-the-shelf components. Testing on three infants to date shows that INFERS functions properly and enables us to collect data on infant feeding activity and correlate this with the amount of effort infants must expend to get the milk. PMID- 30441217 TI - 3-Stage Miller Cross-Coupled Load based Photodiode Readout for Glucose Monitoring. AB - An innovative 3-stage miller compensted, cross-coupled load, based photodiode front end readout is designed for glucose monitoring. The Near Infrared Spectroscopy (NIRS) technique is used for the optical sensing of glucose non invasively. The stable 3-stage open loop amplifier is designed for a gain of 68.3 dB, phase margin of 65 degrees , GBW of 12.6 MHz and has a power consumption of 0.26 mW. The transimpedance amplifier achieves a gain of 84.46 dB, phase margin of 65 degrees , has an input referred noise of 20.4 pAHz and consumes 0.55 mW of power from a 3.3 V supply using a 0.18 $?mu ?mathrm{m}$ CMOS technology node. PMID- 30441218 TI - Identification of the relationships between noncontact capacitive sensing signals and continuous grasp forces: Preliminary study. AB - This study explores the relationships between noncontact capacitive sensing signals and continuous grasp forces. It is a crucial step towards the volitional control of robotic systems based on the noncontact sensing approach. We firstly designed a measurement system including the capacitive sensing front-ends, the grasp force sensor, the signal sampling circuits and the graphic user interface. The capacitive sensing front-end was specifically designed for human forearm signal sampling, which was worn outside of the clothes. After implementation of the system, we carried out experiments on five healthy subjects, and the sensing bands were customized with their arm shapes. The grasp force and the capacitance signals were record simultaneously when the subjects gradually increased the force according to instruction. Linear regression and quadratic regression were used to evaluate the regulated signals. For each subject, at least one channel of capacitance signals were linear correlated to the normalized grasp force with ${{R}^{2}}?ge 0.85$. We found there was inter-subject similarity on the capacitance-force relationships. Cross validation on grasp force estimation with capacitance signals were also carried out, and the average relative estimation error was about 18%. The results proved the feasibility of the noncontact capacitive sensing method for human joint force estimation. PMID- 30441220 TI - Dynamically Mapping Socket Loading Conditions During Real Time Operation of an Upper Limb Prosthesis. AB - A continuing problem faced by amputees is that extended use of a prosthesis leads to discomfort along the residual limb. In this work, we use a novel pressure sensor array and an inertial measuring unit to monitor the changes in the pressure distribution within an upper limb socket in response to its position and the real time performance of a grasping task. These experiments illustrate that the operation of a prosthetic hand produces distinct features in the time derivative and spatial component of the sensor outputs, which correspond to the orientation and task-dependent changes in loading conditions within the socket. The significance of this study is that it highlights the use of a combined pressure sensor array and inertial measuring unit as a way to characterize the loading conditions within a prosthesis based on both temporal and spatial information during movement. This method of real time pressure sensing in prosthetic sockets will be useful for adaptive socket technology aimed towards decreasing the discomfort caused by long-term use of a prosthesis. PMID- 30441219 TI - A Novel Variable Stiffness Compliant Finger Exoskeleton for Rehabilitation Based on Electromagnet Control. AB - In this study, we present the design of a variable stiffness finger exoskeleton for hand rehabilitation, to meet the requirements of different human users and versatile rehabilitation task. This paper describes the design principle and fabrication of the variable stiffness finger exoskeleton which combines a variable stiffness beam and a 3D printed compliant finger exoskeleton. Experimental studies have shown that by using the electromagnetic force, exoskeleton stiffness variation is achievable. Therefore, the proposed variable stiffness finger exoskeleton is capable of adapting the versatile tasks and providing a soft, wearable device for hand rehabilitation of different human users. PMID- 30441221 TI - Modeling of Hand and Forearm Link using Inertial Sensors. AB - In this paper, we describe our hand and forearm motion measuring system using inertial sensors. Although a sensor axis is often used to measure human body motion, it is prone to attachment and offset error, and, because a hand is made of five parallel links, it is not suitable for hand measurement. Therefore, we propose a method of modeling the hand and forearm link using only sensors. To model a finger link, a compass' azimuth deviation is important because it may affect the intersection of the fingers. Therefore, before modeling, we applied correction and alternative methods using the angular velocity direction. As a result, the deviation between the sensors decreased to 1/5. During the modeling, we estimated the sensor's position vectors on the distal and next distal segments from each joint, and calculated the relationship matrices between the sensors through initial posture during estimation. We created the hand and forearm link model by combining the position vectors and relationship matrices. Comparison with optical motion capture showed that the hand shape without intersection of the fingers matched well, but there was offset because the forearm sensors deviated from the estimated positions. Although we must improve the attachment to the forearm, these methods proved effective for hand motion measurement. PMID- 30441222 TI - A Practical Approach for Evaluation of Socket Pistoning for Lower Limb Amputees. AB - Although fit of the socket-suspension system is critical to lower limb amputees, monitoring of the fit is largely based on user feedback, which is subjective and often unreliable. Pistoning, defined as the relative displacement between the socket and the residual limb, is a well-accepted indicator of the fit of the socket-suspension system. However, opacity and rigidity of everyday prosthetic sockets make measurement of pistoning a challenging task. In this paper, we describe the development of a pistoning evaluation procedure that relies on two motion capture systems: a magnetic motion capture system used to measure the motion of the residual limb and an optical motion capture system used to measure the motion of the socket. Through synchronization of the two motion capture systems, the motion of the residual limb relative to the socket can be determined to derive the amplitude of pistoning. Here, we evaluated the performance of our approach through repeated calibration and a treadmill walking task with an amputee. Results demonstrate that this procedure, which does not rely on radiography unlike some existing methods, can be used to evaluate the fit of amputees' everyday sockets. PMID- 30441223 TI - Development of Sensorised Resistance Band for Objective Exercise Measurement: Activities Classification Trial. AB - Resistance bands are often used in resistance training programs for older adults. Despite their widespread use, there is a lack of objective assessment of the actual strength, speed and precision of the movements during these exercises. Therefore, this paper presents the development of a sensorised resistance-band and a preliminary trial of activities classification by using artificial intelligence. The results show that in the preliminary trial, the classification accuracy of 4 different activities reached over 96% using accelerometer data only. A future study will be based on the sensorised resistance band to quantify resistance band exercises objectively in elderly people. PMID- 30441224 TI - Design of a low-cost MRI compatible plantarflexion force measurement device. AB - Investigating the neural correlates of ankles' joint rotation is critical to better understand the underlying deficit in balance or posture control in the clinical population. This work describes the design and characteristics of a low cost MRI compatible isometric plantarflexion force measurement device. The device is fully adjustable to the particular height and shoe size of participants. Each individual force sensor has an operational linear range up to 80-100kg amounting to a force range up to 180kg when combining the two sensors, which is well above the maximal force for the majority of the population. Preliminary neuroimaging tests suggest that performing submaximal ankle plantar flexions on the device induce minimal motion artifacts on fMRI signal that are within an acceptable range. PMID- 30441225 TI - Automatic Detection of Preferred Retinal Locus (PRL) for Low Vision Rehabilitation using Oculometrics Analysis. AB - Low vision rehabilitation is an important step towards individuals with Age related macular degeneration (AMD) regaining useful functional vision and quality of life. One of the key steps in low vision rehabilitation is the determination of the preferred retinal locus (PRL). Currently, localization of PRL is performed manually though the guidance of a low vision therapist and the process is highly time-consuming, labour-intensive and subjective. In this paper, we present an automated system to objectively and accurately locate an individual's PRL with the aid of gaze tracking technology. We also propose a graph-based method for false fixation detection to improve the system robustness. We validated the reliability of the system by using eye tracking technology to simulate central vision loss on people with normal vision. Experimental results show the potential use of eye tracking in detecting PRL for low vision rehabilitation. PMID- 30441226 TI - A Novel Method to Determine Dynamic Temperature Trends Applied to In-Shoe Temperature Data During Walking. AB - Body temperature is one of the fundamental measures considered in the assessment of health and well-being, with various medical conditions known to give rise to abnormal changes in temperature. In particular, abnormal variations in dynamic temperature patterns during walking or exercise may be linked to a range of foot problems, which are of particular concern in diabetic patients.A number of studies have investigated normative temperature patterns of a population by considering data from multiple participants and averaging results after an acclimatisation interval. In this work we demonstrate that the temperature patterns obtained using such an approach may not be truly representative of temperature changes in a population, and the averaging process adopted may yield skewed results.An alternative approach to determine generic reference temperature patterns based on a minimization of root mean square differences between time shifted versions of temperature data collected from multiple participants is proposed. The results obtained indicate that this approach can yield a general trend that is more representative of actual temperature changes across a population than conventional averaging methods. The method we propose is also shown to better capture and link the effects of factors that influence dynamic temperature trends, which could in turn lead to a better understanding of underlying physiological phenomena. PMID- 30441228 TI - Interval Kernels for Combining Biometric Measurements from Multiple Prostate Samples per Patient in Prognostic Models with Transductive Semi-Supervised Support Vector Regression. AB - Prostate cancer is the most prevalent form of cancer and second most common form of cancer deaths among men in the United States. Physicians work with patients to make difficult treatment decisions. They are often aided by a multitude of prognostic models to assess risk and predict outcomes. These survival analysis models may analyze features characterizing biomolecular and histomorphic properties of the solid tumor sample. Commonly, multiple samples per patient are analyzed and features are combined in some way to generate a single result, such as by taking the median measurement. Recently, support vector regression approaches paired with a semi-supervised transduction framework have proven powerful in building such prognostic models. Separately, there has been work presenting the use of interval kernels to capture the range of measurements across multiple samples as an "interval" via the Hausdorff distance within a kernel based support vector approach. This paper presents the first results in exploring a combination of these two concepts. Namely, using an interval kernel based support vector approach within the aforementioned transduction framework to build prognostic models leveraging information from multiple tumor samples per patient. The results show that interval kernels yield more accurate prognostic models, and the semi-supervised transduction framework further improves performance. This suggests that this novel combination of unique recent advances can help build better prognostic models and improve the treatment of prostate cancer. PMID- 30441227 TI - Deviations of acoustic low-level descriptors in speech features of a set of triplets, one with autism. AB - Verbal speech of children diagnosed with ASD is explored in order to identify patterns autism has left in speech, and to model such patterns for implementing automatic diagnostic and screening frameworks. In this study, we identify the deviations of acoustic low-level descriptors (LLDs) in voice of an autistic adolescent from her typically developing triplet siblings. The goal is to identify the atypicality in voice introduced by autism under minimum gender, age, genetic, and language bias and use the gained insights to build a more generalized model by adding more subjects hierarchically. We report the most significant LLDs that describe the deviations of acoustic features due to autism for categories of utterances and feature groups. PMID- 30441229 TI - Automatic System for Obstructive Sleep Apnea Events Detection Using Convolutional Neural Network. AB - Obstructive Sleep Apnea (OSA) is characterized by repetitive episodes of airflow reduction (hypopnea) or cessation (apnea), which, as a prevalent sleep disorder, can cause people to stop breathing for 10 to 30 seconds at a time and lead to serious problems such as daytime fatigue, impaired memory, and depression. This work intends to explore automatic detection of OSA events with 1-second annotation based on blood oxygen saturation, oronasal airflow, and ribcage and abdomen movements. Deep Learning (DL) technology, specifically, Convolutional Neural Network (CNN), is employed as a feature detector to learn the characteristics of the highorder correlation among visible data and corresponding labels. A fully-connected layer in the last stage of the CNN is connected to the output layer and constructs the desired number of outputs for sleep apnea events classification. A leave-one-out cross-validation has been conducted on the PhysioNet Sleep Database provided by St. Vincents University Hospital and University College Dublin, and an average accuracy of $79 .61$% across normal, hypopnea, and apnea, classes is achieved. PMID- 30441230 TI - A Fully Automated System for Sizing Nasal PAP Masks Using Facial Photographs. AB - We present a fully automated system for sizing nasal Positive Airway Pressure (PAP) masks. The system is comprised of a mix of HOG object detectors as well as multiple convolutional neural network stages for facial landmark detection. The models were trained using samples from the publicly available PUT and MUCT datasets while transfer learning was also employed to improve the performance of the models on facial photographs of actual PAP mask users. The fully automated system demonstrated an overall accuracy of 64.71% in correctly selecting the appropriate mask size and 86.1% accuracy sizing within 1 mask size. PMID- 30441231 TI - Rapid Anxiety and Depression Diagnosis in Young Children Enabled by Wearable Sensors and Machine Learning. AB - This paper presents a new approach for diagnosing anxiety and depression in young children. Currently, diagnosis requires hours of structured clinical interviews and standardized questionnaires spread over days or weeks. We propose the use of a 90-second fear induction task during which time participant motion is monitoring using a commercially available wearable sensor. Machine learning and data extracted from the most clinically feasible 20-second phase of the task are used to predict diagnosis in a sample of children with and without an internalizing diagnosis. We examine the performance of a variety of feature sets and modeling approaches to identify the best performing logistic regression that provides a diagnostic accuracy of 80%. This accuracy is comparable to existing diagnostic techniques, but at a small fraction of the time and cost currently required. These results point toward the future use of this approach in a clinical setting for diagnosing children with internalizing disorders. PMID- 30441232 TI - SCOSY: A Biomedical Collaboration Recommendation System. AB - Finding relevant scientific articles and collaborators is a time-consuming and challenging task in today's information-rich environment. Despite this challenge, the study and development of recommendation systems, based on the authors' collaboration network, productivity and area of research, as topics of interest, have not been practically deployed in healthcare organizations. To address this known practice gap and to promote collaboration, Schosy was developed. This system collects publication metadata from PubMed, as the data source, and combining Collaborative and ContentBased Filtering techniques coupled with the Latent Dirichlet Allocation Topic Modeling algorithm, it recommends collaborators based on the authors' work, collaboration among the authors, Medical Subject Headings (MeSH) terms and the productivity of relevant researchers. As a result, this system provides an interpretable latent structure for collaborators and biomedical databases in order to enhance the experience of finding collaboration, for and by researchers and non-technical users. PMID- 30441233 TI - Identification of Optimum Panel of Blood-based Biomarkers for Alzheimer's Disease Diagnosis Using Machine Learning. AB - With the increasing number of people living with Alzheimer's disease (AD), there is a need for low-cost and easy to use methods to detect AD early to facilitate access to appropriate care pathways. Neuroimaging biomarkers (such as those based on PET and MRI) and biochemical biomarkers (such as those based on CSF) are recommended by international guidelines to facilitate diagnosis. However, neuroimaging is expensive and may not be widely available and CSF testing is invasive. Bloodbased biomarkers offer the potential for the development of a low cost and more time efficient tool to detect AD to complement CSF and neuroimaging as blood is much easier to obtain. Although no single blood biomarker is yet able to detect AD, combinations of biomarkers (also called panels) have shown good results. However, a large number of biomarkers are often needed to achieve a satisfactory detection performance. In addition, it is difficult to reproduce reported results within and across different study cohorts because of data overfitting and lack of access to the datasets used in the studies. In this study, our focus is to identify an optimum panel (in terms of the least number of blood biomarkers to meet the specified diagnostic performance of 80% sensitivity and specificity) based on a widely accessible data set, and to demonstrate a testing methodology that reinforces reproducibility of results. Realizing a panel with reduced number of markers will have significant impact on the complexity and cost of diagnosis and potential development of cost-effective point of care devices. PMID- 30441234 TI - Prediction of One-Year Transplant-Free Survival after Norwood Procedure Based on the Pre-Operative Data. AB - This paper discusses computational modeling of predictive risk factors for neonates undergoing a Norwood surgical procedure, a multi-stage cardiac procedure that restores functional systemic circulation in patients such as neonates with Hypoplastic Left Heart Syndrome (HLHS). In this model, we apply machine learning based binary classication to 549 cases reported by the Pediatric Heart Networks Single Ventricle Reconstruction Trial. We use neural networks classier to predict risk factors for individual patients undergoing a Norwood procedure for the repair of HLHS. Results indicate that independent risk can be calculated with 85% accuracy and 0.94 area under the receiver operating characteristics curve. This model may help physicians provide counseling for families and medically optimize patients prior to surgery by modifying individual risk factors. PMID- 30441235 TI - 3D Shape-based Body Composition Prediction Model Using Machine Learning. AB - A booming development of 3D body scan and modeling technologies has facilitated large-scale anthropometric data collections for biomedical research and applications. However, usages of the digitalized human body shape data are relatively limited due to a lack of corresponding medical data to establish correlations between body shapes and underlying health information, such as the Body Fat Percentage (BFP). We present a novel prediction model to estimate the BFP by analyzing 3D body shapes. We introduce the concept of "visual cue" by analyzing the second-order shape descriptors. We first establish our baseline regression model for feature selection of the zeroth-order shape descriptors. Then, we use the visual cue as a shape-prior to improve the baseline prediction. In our study, we take the Dual-energy X-ray Absorptiometry (DXA) BFP measure as the ground truth for model training and evaluation. DXA is considered the "gold standard" in body composition assessment. We compare our results with the clinical BFP estimation instrument-the BOD POD. The result shows that our prediction model, on the average, outperforms the BOD POD by 20.28% in prediction accuracy. PMID- 30441236 TI - A Spark-based Analytic Pipeline for Seizure Detection in EEG Big Data Streams. AB - Around 1% of the people in the world suffer from epilepsy, which is the second most neurological disorder in the human after stroke. The spontaneous recurrence of seizures is the main clinical manifestation of the epilepsy. Real time detecting the seizure in the Electroencephalogram (EEG) signal is a clinical way in the diagnosis and treatment of epilepsy. The unpredicted nature of the epileptic seizures, necessitates continuous monitoring and recording of the brain activities using high-throughput neurophysiological data acquisition systems over extended periods of time. The sheer volume and the velocity of the data generated from continuous monitoring the brain activities make real-time seizure detection a big data analytic problem. In this paper, we present a Spark-based machine learning approach to the seizure detection problem using linear dimensionality reduction and classification. Using this approach, we achieved an average accuracy, sensitivity, specificity across all patients $(?mathrm{N=24)$ of 99.32%, 99.41%, and 95.25%, respectively. Also, the average Iatency of the Spark based seizure detection framework is about 0.38 ms. PMID- 30441237 TI - Personalized Gaussian Processes for Forecasting of Alzheimer's Disease Assessment Scale-Cognition Sub-Scale (ADAS-Cog13). AB - In this paper, we introduce the use of a personalized Gaussian Process pGP model to predict per-patient changes in ADAS-Cog13-a significant predictor of Alzheimer's Disease (AD) in the cognitive domain - using data from each patient's previous visits, and testing on future (held-out) data. We start by learning a population-level model using multi- modal data from previously seen patients using a base Gaussian Process (GP) regression. The pGP is then formed by adapting the base GP sequentially over time to a new (target) patient using domain adaptive GPs [1]. We extend this personalized approach to predict the values of ADAS-Cog13 over the future 6, 12, 18, and 24 months. We compare this approach to a GP model trained only on past data of the target patients tGP, as well as to a new approach that combines pGP with tGP. We find that this new approach (pGP+tGP) leads to significant improvements in accurately forecasting future ADAS-Cog13 scores. PMID- 30441238 TI - Eye movements - an early marker of cognitive dysfunctions. AB - Cognitive impairments or dysfunctions are one of the major issues of aging population and medical conditions like brain damage, stroke etc. Assessment of cognitive functioning is usually done by medical practitioners using various standard psychological tests which require expert interventions. In the present study we have tried to use eye tracking as a possible option for assessment of cognitive functions while executing a digitized digit symbol substitution task. The standard task has been modified so that more detail insights of one's cognitive state can be obtained without any manual intervention. Results show that it is possible to get more information like attention, perception etc. It also gives insight about the performance of an individual and can be used for analyzing the executive functions like processing speed, memory etc. PMID- 30441239 TI - Evaluation for the Necessity of Medical Imaging Tests Prescription in Neurology. AB - The evaluation and control algorithms for the necessity of medical prescription testing, comprises useful tool for health professionals. It is beyond doubt that a connection between illness, symptoms, medical tests and prescriptions is essential and thus algorithms facilitating such approaches should be available to health professionals. Such informatics tools require the implementation of smart, interactive tools and not just linear, information storing websites. Such algorithms should be dynamic, that is their output should change based on the input as for example, in the serial input of symptoms to clinical examination to subsequent diagnosis. Slight variations in symptomatology can greatly alter diagnosis and subsequent physical testing and prescription. The present work presents a novel algorithm for the control of medical prescription testing in neurology, by utilizing decision trees for the connection of symptomatology to diagnosis and prescription for neurological conditions and disease. To the best of our knowledge this is the first time that such an approach is proposed. PMID- 30441240 TI - CHANGE: Cardiac Health Analysis Using Graph Eigenvalues. AB - Coronary Artery Disease (CAD) is an important problem in cardiac health and is a leading cause of human mortality. Prior arts have shown that features extracted from non-invasive Photoplethysmogram (PPG) signal are effective in classifying CAD. In this paper, we represent cardiac health as a graph (CHG) in order to exploit the dependencies of PPG features as well as the metadata features. We then compute spectral features from the eigenvalues of the graph Laplacian of CHG. Finally, k-means algorithm is employed for classifying the data into CAD and non-CAD. Unsupervised experiments on a cohort with 32 participants yields 88% accuracy and demonstrates advantage of the proposed formulation over a baseline and two state-of-the-art approaches. PMID- 30441241 TI - Risk Prediction of Heart Failure Decompensation Events in Multiparametric Feature Spaces. AB - Cardiac function deterioration of heart failure patients is frequently manifested by the occurrence of decompensation events. One relevant step to adequately prevent cardiovascular status degradation is to predict decompensation episodes in order to allow preventive medical interventions. In this paper we introduce a methodology with the goal of finding relevant feature spaces from multiple physiological parameters which may have predictive value in decompensation events. The best performance was obtained for the feature space comprising the following features: mean weight, standard deviation of the blood pressure and mean of extra-thoracic impedance in a time window of 20 days. Results were achieved by applying leave-one-out validation and correspond to a geometric mean of 88.32%. The obtained performance suggests that the methodology has the potential to be used in decision support solutions and assist in the prevention of this public health burden. PMID- 30441242 TI - A Novel Atrial Fibrillation Prediction Algorithm Applicable to Recordings from Portable Devices. AB - Atrial Fibrillation (AFib) is by itself a strong risk factor for many life threatening heart diseases. An estimated 2.7 to 6.1 million people in the United States have AFib. With the aging of the U.S. population, this number is expected to increase. In this preliminary study, a heart rate-duration criteria region is proposed to automatically label symptomatic AFib events using recordings from portable ECG monitors. A Markov Chain algorithm is implemented to classify prediction intervals that are 2 minutes before the symptomatic AFib events. The method yields an overall accuracy value of 82% with 0.91 AUC. PMID- 30441243 TI - Early Prediction of Sepsis in EMR Records Using Traditional ML Techniques and Deep Learning LSTM Networks. AB - Sepsis is a life-threatening condition caused by infection and subsequent overreaction by the immune system. Physicians effectively treat sepsis with early administration of antibiotics. However, excessive use of antibiotics on false positive cases cultivates antibiotic resistant bacterial strains and can waste resources while false negative cases result in unacceptable mortality rates. Accurate early prediction ensures correct, early antibiotic treatment; unfortunately, prediction remains daunting due to error-ridden electronic medical records (EMRs) and the inherent complexity of sepsis. We aimed to predict sepsis using only the first 24 and 36 hours of lab results and vital signs for a patient. We used the Medical Information Mart for Intensive Care III (MIMIC3) dataset to test machine learning (ML) techniques including traditional methods (i.e., random forest (RF) and logistic regression (LR)) as well as deep learning techniques (i.e., long short-term memory (LSTM) neural networks). We successfully created a data pipeline to process and clean data, identified important predictive features using RF and LR techniques, and trained LSTM networks. We found that our best performing traditional classifier, RF, had an Area Under the Curve (AUC-ROC) score of 0.696, and our LSTM networks did not outperform RF. PMID- 30441244 TI - Interpretable Machine Learning Techniques for Causal Inference Using Balancing Scores as Meta-features. AB - Estimating individual causal effect is important for decision making in many fields especially for medical interventions. We propose an interpretable and accurate algorithm for estimating causal effects from observational data. The proposed scheme is combining multiple predictors' outputs by an interpretable predictor such as linear predictor and if then rules. We secure interpretability using the interpretable predictor and balancing scores in causal inference studies as meta-features. For securing accuracy, we adapt machine learning algorithms for calculating balancing scores. We analyze the effect of t-PA therapy for stroke patients using real-world data, which has 64,609 records with 362 variables and interpret results. The results show that cross validation AUC of the proposed scheme is little less than original machine learning scheme; however, the proposed scheme provides interpretability that t-PA therapy is effective for severe patients. PMID- 30441245 TI - Validation of Improvements of Robotic Devices for Nursing Care using a Sensing Dummy Simulating Human Body. AB - The population in advanced countries is rapidly aging, and these countries are faced with various issues pertaining to the rapidly aging population. It is expected that manpower shortages for nursing care of the elderly will be resolved using robotic devices. A method is necessary for quantifying the load of the human body that is envisaged to encourage the widespread use of robotic devices for nursing care. Therefore, we developed a sensing human dummy consisted of several sensors that emulated the stiffness of the human body and its shape. In a previous study, we developed the buttock dummy that consisted of emulated bones and soft tissue. In this study, we mounted force sensors, and emulated blade bones and soft skin. We compared the robotic beds "Resyone" with "Resyone Plus" and showed that the latter elicited improved comfort with respect to the former. In these experiments, we used the sensing dummy and the visual markers to evaluate the load and the posture of users. From the validation experiments, the shear force of the sacral bone of Resyone Plus was determined to be lower than that for Resyone owing to the movement of the foot. PMID- 30441246 TI - Methodologies for workforce optimization in Hospital's Emergency Department. AB - Nurse workforce optimization and scheduling in hospital units is a complex data science and operation research problem. Traditional manual estimation and preparation of nurse staffing and scheduling with the help of a subject matter expert might leads to over staffing or under staffing of different type of nurses such as core, float pool, overtime and agency, which impacts the patient care delivery and cost significantly. The situation becomes worse in case of emergency department as the patient head on bed occupancy is very dynamic in nature and many times the department might be overcrowded with no beds for the patients. Therefore, it is very difficult to design manual optimal workforce optimization of nurses for emergency units. To address this problem, we have developed methodologies to model emergency department head on bed occupancy and optimize various type of nurse staffing to run the hospital with optimal budget. PMID- 30441247 TI - A Different Approach for Digital Pathology: Lexicon-semantic Analysis of Histopathological Reports for the Assessment of their Quality. AB - An analysis of the costs related to the processes involved in a pathological analysis of a biopsy justifies the traditional view of digital pathology. However, this traditional conception has left aside another important aspect of this process, the writing of pathological reports. The efficiency and effectiveness of this subprocess has been raised in recent years as a challenge in the field of digital pathology. This work explores in this aspect offering a system of lexical-semantic analysis to determine the usefulness of pathological reports. It is a tool that assists the pathologist in the drafting of a useful report and establishes the bases for the management of the veracity of information in the automatic generation of pathological reports. PMID- 30441248 TI - How is the Doctor Feeling? ICU Provider Sentiment is Associated with Diagnostic Imaging Utilization. AB - The judgment of intensive care unit (ICU) providers is difficult to measure using conventional structured electronic medical record (EMR) data. However, provider sentiment may be a proxy for such judgment. Utilizing 10 years of EMR data, this study evaluates the association between provider sentiment and diagnostic imaging utilization. We extracted daily positive / negative sentiment scores of written provider notes, and used a Poisson regression to estimate sentiment association with the total number of daily imaging reports. After adjusting for confounding factors, we found that (1) negative sentiment was associated with increased imaging utilization $(p < 0.01)$, (2) sentiment's association was most pronounced at the beginning of the ICU stay $(p < 0.01)$, and (3) the presence of any form of sentiment increased diagnostic imaging utilization up to a critical threshold $(p < 0.01)$. Our results indicate that provider sentiment may clarify currently unexplained variance in resource utilization and clinical practice. PMID- 30441249 TI - Can Mixed-Reality Improve the Training of Medical Procedures? AB - One cause of preventable death is a lack of proper skills for providing critical care. The conventional course taught to non-medical individuals involves instructions of advanced emergency procedures routinely limited to a verbal block of instructions in a standardized presentation (for example, an instructional video).In the present study, we evaluate the benefits of using an OST-HMD for training of caregivers in an emergency medical environment. A rich user interface was implemented that provides 3D visual aids including images, text and tracked 3D overlays corresponding to each task that needs to be performed. A user study with 20 participants is conducted which involves training of two tasks where each subject performs one task with the HMD and the other with standard training. Two evaluations were performed, with the first immediately after the training followed by a second one three weeks later. Our results indicate that using a mixed reality HMD is more engaging, improves the time-on-task, and increases the confidence level of users in providing emergency and critical care. PMID- 30441251 TI - Evaluating ICU Clinical Severity Scoring Systems and Machine Learning Applications: APACHE IV/IVa Case Study. AB - Clinical scoring systems have been developed for many specific applications, yet they remain underutilized for common reasons such as model inaccuracy and difficulty of use. For intensive care units specifically, the Acute Physiology and Chronic Health Evaluation (APACHE) score is used as a decision-making tool and hospital efficacy measure. In an attempt to alleviate the general underlying limitations of scoring instruments and demonstrate the utility of readily available medical databases, machine learning techniques were used to evaluate APACHE IV and IVa prediction measures in an open-source, teleICU research database. The teleICU database allowed for large-scale evaluation of APACHE IV and IVa predictions by comparing predicted values to the actual, recorded patient outcomes along with preliminary exploration of new predictive models for patient mortality and length of stay in both the hospital and the ICU. An increase in performance was observed in the newly developed models trained on the APACHE input variables highlighting avenues of future research and illustrating the utility of teleICU databases for model development and evaluation. PMID- 30441250 TI - Definition and representation of a process to engineer a multi-user information management application for continuity of care. AB - This article describes the procedure of definition and design of a process for the continuity care unit to improve the attention to the patient and his/her ecosystem providing a novel alternative to the conventional methods. This work was done under the framework of the MiniQ project, funded by EIT Health to improve the management of poly-medicated patients. PMID- 30441252 TI - A Standing Function Evaluation System Based on Virtual Light Touch Contact and Factor Analysis. AB - This paper proposes a standing function evaluation system on the basis of factor analysis for indices related to standing characteristics. For this approach, five standing function factors were checked in a large-scale experiment using the results of extraction from 48 indices based on factor analysis. Five factors were extracted from these indices, and the related score radar charts indicated that most factors changed with age. The evaluation results suggest that the system facilitates intuitive comprehension of standing-related factors based on these charts. PMID- 30441253 TI - Personal Health Data: Access and Perceived Value in Denmark. AB - This study explores how accessible and valuable Personal Health Data are in Denmark. This paper uses a qualitative inquiry which was adopted to provide information about (1) the accessibility of data available, (2) and the perceived value of data by recruiting 8 healthy Danish individuals who were instructed to access their personal health data, and were then prompted to discuss how accessible and valuable they perceived their personal health data to be. In total, participants accessed 31 datasets and wearable sensor data through 23 web applications and 8 mobile applications. They reported on search and access challenges in interviews and through journaling. Our results suggest that participants were satisfied with the access they had to their personal health data, however the participants expressed disappointment in ways the data was presented for them by the services and platforms. Thus, we concluded that the perceived value of personal data were found to be dependent on the usability and personalization features of the services, rather than on the data itself. PMID- 30441254 TI - Robust Ensemble Learning to Identify Rare Disease Patients from Electronic Health Records. AB - There is substantial interest in developing prediction models capable of identifying rare disease patients in population-scale databases such as electronic health records (EHRs). Deriving these models is challenging for many reasons, perhaps the most important being the limited number of patients with 'gold standard' confirmed diagnoses from which to learn. This paper presents a new cascade learning methodology which induces accurate prediction models from noisy 'silver standard' labeled data-patients provisionally labeled as positive for the target disease based on unconfirmed evidence. The algorithm combines unsupervised feature selection, supervised ensemble learning, and unsupervised ensemble clustering to enable robust learning from noisy labels. The efficacy of the approach is illustrated through a case study involving the detection of Iipodystrophy patients in a country-scale database of EHRs. The case study demonstrates our algorithm outperforms state-ofthe-art prediction techniques and can discover previously undiagnosed patients in large EHR databases. PMID- 30441255 TI - Towards the Establishment of a Biomedical Ontology for the Primary Sjogren's Syndrome. AB - Primary Sjogren's Syndrome (pSS) has been characterized as a hypersensitivity reaction type II systemic autoimmune chronic disease causing exocrine gland dysfunction mainly affecting women near the menopausal age. pSS patients exhibit dryness of the main mucosal surfaces and are highly prone to lymphoma development. This paper presents a first biomedical ontology for pSS based on a reference model which was determined by pSS clinical experts. The ensuing ontology constitutes the fundamental basis for mapping pSS-related ontologies from international cohorts to a common ontology. The ontology mapping (i.e., schematic interlinking) procedure is, in fact, a preliminary step to harmonize heterogeneous medical data obtained from various cohorts. PMID- 30441256 TI - A FHIR-Enabled Streaming Sepsis Prediction System for ICUs. AB - Sepsis is a common disease with very costly, potentially deadly implications. Early prediction of Sepsis and initiation of antibiotic is widely considered as an important determinant of patient survival. Cross-institutional validation and implementation of algorithms for early prediction of Sepsis at a minimum require common data formats, streaming analytic platforms for timely risk assessment, and interoperable and standardized interfaces. In this work we present an open-source cloud-based analytic pipeline, which receives de-identified patient data from an interoperable server and produces real-time Sepsis risk scores for Intensive Care Unit (ICU) patients. PMID- 30441257 TI - An Empirical Study of Questionnaires for the Diagnosis of Pediatric Obstructive Sleep Apnea. AB - Pediatric Obstructive Sleep Apnea (OSA) is a chronic disorder characterized by the disruption in sleep due to involuntary and temporary cessation of breathing. Definitive diagnosis of OSA requires an intrusive and expensive approach based on polysomnography where the children spend a night in the hospital under the supervision of a sleep technician. The prevalence of OSA is increasing, making the traditional diagnostic approach prohibitively expensive. There has been increasing interest in designing inexpensive approaches to screen children such as the use of questionnaires. In this paper, we study the efficacy of five widely used and representative questionnaires on their ability to diagnose and stratify OSA. Our experiments show that the diagnostic ability of each of these questionnaires is insufficient for widespread clinical use. Using techniques from data mining, we identify the most informative questions and propose a new questionnaire. We show that machine learning models trained based on the answers to our questionnaire can stratify OSA with higher accuracy. PMID- 30441258 TI - A Distributed Storage Model for Healthcare Big Data Designed on HBase. AB - With the explosive growth of healthcare data, traditional relational database management systems (RDBMS) are limited in scalability, storage of unstructured data, concurrency and cost. Thus we proposed a snowflake model based on HBase with a multi-table structure and three kinds of index tables for efficient assess of large-scale health records. A guideline for designing of index tables was proposed which covers the demands of most healthcare data processing applications. A benchmark test was carried out with six types of queries on a large dataset comprising 750 million records to compare the performance of the proposed model against the traditional tall-table model on HBase. We found that the snowflake model was more efficient than the tall-table model. The adoption of index tables could greatly improve the query speed and provided real-time queries for two models. In general, snowflake model could be used for managing large scale healthcare data as an advantageous alternative. PMID- 30441259 TI - Comparison of Gaussian Processes Methods to Linear methods for Imputation of Sparse Physiological Time Series. AB - Physiological timeseries such as vital signs contain important information about a patient and are used in different clinical application; however, they suffer from missing values and sampling irregularity. In recent years, Gaussian Processes have been used as sophisticated nonlinear value imputation methods on time series, however there is a lack of comparison to other simpler methods. This paper compares the ability of five methods that can be used in missing data imputation in physiological time series. These models are linear interpolation as the baseline, cubic spline interpolation, and three non-linear methods: Single Task Gaussian Processes, Multi-Task Gaussian Processes, and Multivariate Imputation Chained Equations. We used seven intraoperative physiological time series from 27,481 patients. Piecewise aggregate approximation was employed as a dimensionality reduction and resampling strategy. Linear interpolation and cubic splining show overall superiority in prediction of the missing values, compared to the other complex models. The performance of the kernel-based methods suggest that they are highly sensitive to the kernel width and require incorporation of domain knowledge for fine-tuning. PMID- 30441261 TI - Automatic extraction of the 3D symmetry line of back surface: application on scoliotic adolescents. AB - We propose a new method to extract automatically the symmetry line of the 3D back surface of patients affected by scoliosis. Our method is based on the detection of local symmetry planes computed on thick layers of the back. Results have been obtained on a sample of 112 scoliotic adolescents and we compare the symmetry line obtained by our method with a reference line defined by clinicians. We also study the influence of the scoliosis severity and of the Body Mass Index on the results. PMID- 30441260 TI - SMCT - An Innovative Tool for Mental Health Analysis of Twitter Data. AB - Mental health conditions affect individuals, families and the wider community. It is estimated by the Australian Institute of Health and Welfare that 45% of Australians will experience some form of mental health issue in their lifetime. The World Health Organization (WHO; Switzerland) has assessed that mental health is a cornerstone of overall health.Large-scale collection of data related to mental health is traditionally difficult and carried out infrequently. It is a challenge for researchers to assess seasonal, weekly or diurnal mental health trends. Social media has been demonstrated to present opportunities to extend traditional data collection techniques, particularly the expression of an individual's state of mind.The "Social Media Collection Tool" (SMCT) is a research tool developed to collect Twitter data for mental health analysis. Data collected is filtered to identify "of interest" users, allowing for cross sectional analysis. Additionally, SMCT provides the capability to "re-poll" of interest users to develop a contextual understanding for these users on Twitter, providing a longitudinal analysis. SMCT, for the first time, combined the two data analysis techniques into a single tool.In demonstrative analysis scenarios the SMCT has collected more than 500,000 tweets and identified almost 6,000 as being of interest. The tool has also been used to investigate trends in the responses made by other users to an of interest tweet. PMID- 30441262 TI - Automatic tooth segmentation of dental mesh using a transverse plane. AB - This paper proposes an automatic method to separate the gingiva and individual teeth from a dental mesh. We define a transverse plane that produces a cross section of tooth lingual and labial surfaces, preserving the shape of individual teeth. The upper vertices from the transverse plane, which belong to the tooth, are projected onto the transverse plane, and partitioned into individual teeth. We apply region growing to the remaining non-segmented parts to determine the cluster the vertices belong to, and the proposed approach is fully automatic, i.e., segmentation does not require user interaction for feature point search or tooth boundary markers. The proposed segmentation method is applied to several dental mesh models to demonstrate its robustness. PMID- 30441263 TI - Exploring different impaired speed of genetic-related brain function and structures in schizophrenic progress using multimodal analysis. AB - Schizophrenia (SZ) is a highly heritable disease exhibiting substantial structural and functional brain impairments. The duration of illness and medication use may cause different presentations of impairments in patients. To understand the progressive variations of the disease, most recent studies have reported brain functional or structural abnormalities associated with illness duration, but a comprehensive study of pathology underlying brain structure, function and illness duration is still limited. In this work, we employed a three way parallel independent component analysis (pICA) algorithm to jointly analyze grey matter volume(GM), functional connectivity (FC) and single nucleotide polymorphisms (SNPs) from drug-naive first-episode [FESZ], chronic schizophrenia [CSZ]) and healthy controls[HC], aiming to identify the linked alterations in SNP GM-FC components, and evaluate the impairment speed of imaging measures associated with SZ-susceptible genetic variants in different disease stages (FESZ and CSZ). Results demonstrated significant group differences on GM and FC in hippocampus, temporal gyrus and cerebellum between SZ and HC, which are also significantly correlated with SNPs residing in genes like GABBR2, SATB2, CACNA1C, PDE4B, involved in pathways of cell junction, synapse and neuron projection. Moreover, two-sample t-tests showed that GM volume and FC strength presented similar trends of progressive decrease with the increase of the illness duration (HC>FESZ>CSZ). Besides that genetic-related GM and FC components both showed significant associations with illness duration, FC indicates the higher impairment speed than GM, suggesting that functional connectivity may serve as a more sensitive measure to detect the disruptions in SZ at the very early stage. PMID- 30441264 TI - Radiomics: a Novel CT-Based Method of Predicting Postoperative Recurrence in Ovarian Cancer. AB - In order to predict the 3-year recurrence of advanced ovarian cancer before surgery, we retrospective collected 94 patients to analyze by using a novel radiomics method. A total of 575 3D imaging features used for radiomics analysis were extracted, and 7 features were selected from computed tomography (CT) images that were most strongly associated with 3-year clinical recurrence-free survival (CRFS) probability to build a radiomics signature. The area under the Receiver Operating Characteristic (ROC) curve (AUC) of 0.8567 (95% CI: 0.7251-0.9498) and 0.8533 (95% CI: 0.7231-0.9671) were obtained in the training cohort and validation cohort with the logistic regression classification model respectively. Experimental results show that CT-based radiomics features were closely associated with the recurrence of advanced ovarian cancer. It is possible to prejudge the recurrence of ovarian cancer before surgery. PMID- 30441265 TI - Adapted K-Core Decomposition and Visualization for Functional Magnetic Resonance Imaging Connectivity Networks. AB - Medical imaging modalities, such as functional magnetic resonance imaging (fMRI) are being increasingly used to study the human brain. Analysis of the images has led to findings describing diseases, such as schizophrenia and post-traumatic stress disorder. One of the most widely used methods of analysis involves creating functional connectivity network (FCN) abstractions. These summarize the temporal relationships between regions of interest (ROIs) in the brain and can be used to easily compare subjects, e.g. healthy against schizophrenia. Visual analytics is widely used to facilitate such analysis, with existing approaches designed to enable and simplify detailed interpretation of single networks and pairs of networks in comparison. Prior to such detailed analysis, grouping and aggregation is often performed on the data, which is a time consuming and difficult task. Existing methods for doing this are commonly statistical, while others visualize the cohort without presenting vital network details of the individual FCNs. Thus, there is an opportunity for alternative visual analytics to facilitate the grouping by incorporating the network details. Graph decomposition, such as k-core decomposition, can be used to simplify the representation of networks, while retaining these vital network details. In this study, we propose an adapted k-core decomposition algorithm and visualization, which calculates the connected component information of nodes in the FCNs, a key detail in analysis. Our visualization combines this information with the decomposition to display more details about FCNs at a high-level than contemporary approaches. We present a prototype of our method, demonstrating the ability to group and aggregate the data without the loss of vital network details for further detailed analysis. PMID- 30441266 TI - Automatic detection of early gastric cancer in endoscopic images using a transferring convolutional neural network. AB - Endoscopic image diagnosis assisted by machine learning is useful for reducing misdetection and interobserver variability. Although many results have been reported, few effective methods are available to automatically detect early gastric cancer. Early gastric cancer have poor morphological features, which implies that automatic detection methods can be extremely difficult to construct. In this study, we proposed a convolutional neural network-based automatic detection scheme to assist the diagnosis of early gastric cancer in endoscopic images. We performed transfer learning using two classes (cancer and normal) of image datasets that have detailed texture information on lesions derived from a small number of annotated images. The accuracy of our trained network was 87.6%, and the sensitivity and specificity were well balanced, which is important for future practical use. We also succeeded in presenting a candidate region of early gastric cancer as a heat map of unknown images. The detection accuracy was 82.8%. This means that our proposed scheme may offer substantial assistance to endoscopists in decision making. PMID- 30441267 TI - Localisation of Colorectal Polyps by Convolutional Neural Network Features Learnt from White Light and Narrow Band Endoscopic Images of Multiple Databases. AB - Algorithms for localising colorectal polyps have been studied extensively; however, they were often trained and tested using the same database. In this study, we present a new application of a unified and real-time object detector based on You-Only-Look-Once (YOLO) convolutional neural network (CNN) for localizing polyps with bounding boxes in endoscopic images. The model was first pre-trained with non-medical images and then fine-tuned with colonoscopic images from three different databases, including an image set we collected from 106 patients using narrow-band (NB) imaging endoscopy. YOLO was tested on 196 white light (WL) images of an independent public database. YOLO achieved a precision of 79.3% and sensitivity of 68.3% with time efficiency of 0.06 sec/frame in the localization task when trained by augmented images from multiple WL databases. In conclusion, YOLO has great potential to be used to assist endoscopists in localising colorectal polyps during endoscopy. CNN features of WL and NB endoscopic images are different and should be considered separately. A large scale database that covers different scenarios, imaging modalities and scales is lacking but crucial in order to bring this research into reality. PMID- 30441268 TI - Surgical Suturing with Depth Constraints: Image-based Metrics to Assess Skill. AB - Suturing is one of the most fundamental surgical skills, requiring careful and systematic instruction for skilled performance. In this paper, we evaluate the performance of attending surgeons and surgical residents on an open surgery suturing task to examine if the introduction of different depth levels affects their performance. A vision algorithm is used to extract metrics meaningful in the assessment of suturing skill. As subjects perform a suturing task on the platform, our vision algorithm computes metrics identified to be potentially useful in assessing suturing skill: distances from optimal entry and optimal exit points, stitch length, stitch time, idle time, needle swept area, needle tip trace distance, needle tip area, and needle sway length. Preliminary experimental data from a study with 5 attending surgeons and 7 surgical residents are presented. Results demonstrate that the metrics of distance from optimal exit points, idle time, needle swept area, needle tip trace distance, needle tip area, and needle sway length are useful in quantifying the effect of depth constraints on suturing performance. PMID- 30441269 TI - Study of the photoneutron generation caused by a LinAc Beryllium window with a 6 MeV treatment beam. AB - In most conventional radiation therapy treatments, special attention is payed for neutron contamination when working with energy beams above 8 MeV and generally it is only considered for shielding requirements, not for dose study in patients or employees. The present work is focused on studying the unwanted generated photoneutrons in a Medical Linear Accelerator (LinAc) Varian TrueBeam using a 6 MeV radiation treatment beam. To that, Monte Carlo (MC) simulation code MCNP6.1.1 was used. This version of the code allows the use of unstructured mesh geometries as a novelty, offering more reliable results and higher speed computation. The particularity of the studied LinAc is the presence of a beryllium filter at the treatment head. Since Beryllium causes photonuclear reactions (gamma, n) at energies much lower than other LinAc composing materials, this work aims to analyze if this type of units, when using low energy treatment beams (6 MeV), produce neutron pollution and to ensure that this unwanted radiation can be considered negligible. PMID- 30441270 TI - A Reference-Less Time-Division-Duplex Transceiver IC for a 5-Fr 6-Electrode Renal Denervation Catheter in 0.18-MUm 70-V BCDMOS. AB - This paper presents the first time-division-duplex transceiver IC for a 5-Fr 6 electrode renal denervation (RDN) catheter for treatment of resistant hypertension. Each IC encapsulated in a platinum electrode implements an RDN catheter with 37.5 % of diameter reduction, which enables minimally invasive surgery with reduced complications. The six electrodes sharing only four electrical wires perform packet communication with an external power control unit for independent operation and deliver the designated RF energy to the renal artery wall while measuring local temperature and impedance. Two 500- kHz 21-Vrms AC signals with +/-35-V DC potentials are used as supplies to transfer up to 6-W RF ablation signal with 120-Vpp swing while maintaining the maximum DC supply voltages of the ICs less than the break-down voltage of 70 V. The proposed RDN IC fabricated in 0.18-MUm HV BCDMOS occupies 2.1 mm2. PMID- 30441271 TI - A Steerable Endoscope for Transnasal Skull Base Surgery. AB - In this paper, we described the development of an endoscopic system with the application of minimally invasive observation for a pituitary tumor or a craniopharyngioma. The end-effector was manufactured by attaching an image sensor to the end of a manipulator with a diameter of 3 mm (smaller than a commercial endoscope) by making slits on a biocompatible PAI (Polyamide-imide) tube. The end effector having 2 degrees of freedom for bending is designed not only to cover most of the FOVs (92.8% of the goal) with commercially available fixed-angle endoscopes at 0, 30, and 70 degrees, but also to be able to maneuver the endoscope intuitively. The system consists of a controller, a foot switch, and the end-effector. Through qualitative experiments, basic verification of the proposed system was tested and the potential of this study was recognized through user evaluations from 3 specialists, which generated positive feedback upon the operational procedures. PMID- 30441272 TI - A phantom study to create synthetic CT from orthogonal twodimensional cine MRI and evaluate the effect of irregular breathing. AB - An exciting innovation in radiotherapy is the use of real-time MRI for treatment adaptation. This study proposes an in-silico framework for the generation of 3D synthetic CT (sCT) from orthogonal interleaved 2D cine MRI data to overcome the lack of electron density information in MR images. The method uses pre-treatment data to build a patient breathing motion model. This model is then driven by surrogates extracted from cine MR images during the treatment. The effect of irregular breathing on the motion model is also evaluated by simulating different motion components related to uncorrelated diaphragm, chest and tumor motion. 3D sCT were successfully created for each of the 512 cine MRI pairs in the digital phantom study. The analysis showed that the diaphragm position was a good surrogate to rescale the 3D breathing motion for the current regular breathing phase. However, respiratory and tumor motion were correlated in only 59% of the phases, resulting in tumor position uncertainties of up to 3mm. The inclusion of additional chest and tumor motion information improved the accuracy for irregular changes in breathing pattern and enhanced the tumor position uncertainties to less than 1mm. This study successfully demonstrated a proof-ofprinciple for a digital phantom dataset based on patient parameters, providing a way to create real-time 3D electron density volumes and enhancing the need to account for irregular breathing pattern. PMID- 30441273 TI - Design, Fabrication and Validation of a Precursor Pulsed Electromagnetic Field Device for Bone Fracture Repair. AB - Pulsed electromagnetic field (PEMF) stimulation has been utilized in the medical field since the early 20th century. A number of therapeutic devices have been developed for the treatment of bone fractures and other medical applications. Most of these devices are backed by limited quantitative evidence. In this paper we present the development of a PEMF device for the purposes of determining, through in vitro experimentation, the exposure parameters required to give the most optimal fracture repair. Following electromagnetic field characterization, the device was shown to match well with computational field simulations. The exposure system has been validated through adipose-derived stem cell viability studies with an exposure frequency of 5 Hz and an intensity of 1.1 mT, for a duration of seven days at 30 minutes per day. Under the specific field characteristics chosen, the fatty-tissue derived stem cell proliferation was not hindered and in fact was stimulated $( 0. 025 < P < 0.01)$ by the PEMF exposure. With continued experimentation of numerous exposure conditions at the cellular scale, it will be possible to quantitatively determine the optimal exposure conditions required to produce the most rapid fresh fracture repair. Following this, there is significant potential for development of an optimized wearable device suitable for enhancing repair of all types of bone fractures. PMID- 30441274 TI - Electrical Characterization of Human Biological Tissue for Irreversible Electroporation Treatments. AB - Irreversible electroporation (IRE) is a cancer therapy that uses short, high voltage electrical pulses to treat tumors. Due to its predominantly non-thermal mechanism and ability to ablate unresectable tumors, IRE has gained popularity in clinical treatments of both liver and pancreatic cancers. Existing computational models use electrical properties of animal tissue that are quantified a priori to predict the area of treatment in three dimensions. However, the changes in the electrical properties of human tissue during IRE treatment are so far unexplored. This work aims to improve models by characterizing the dynamic electrical behavior of human liver and pancreatic tissue. Fresh patient samples of each tissue type, both normal and tumor, were collected and IRE pulses were applied between two parallel metal plates at various voltages. The electrical conductivity was determined from the resistance using simple relations applicable to cylindrical samples. The results indicate that the percent change in conductivity during IRE treatments varies significantly with increasing electric field magnitudes. This percent change versus applied electric field behavior can be fit to a sigmoidal curve, as proposed in prior studies. The generic conductivity data from human patients from this work can be input to computational software using patient-specific geometry, giving clinicians a more accurate and personalized prediction of a given IRE treatment. PMID- 30441275 TI - An Energy Efficient Programmable Neuro-Mimicking Stimulator IC for Implantable Electroceutical Systems. AB - Energy efficient programmable neuro-mimicking stimulator is designed for implantable electroceutical systems (IES). To provide clinically-proved stimulation waveforms, a complex waveform programmer (CWP) is proposed. It makes a number of pulses, trains and clusters in a time sequence with the separate dead time slots. Due to CWP, the single period of one therapy can be up to 24 hours. Moreover, VCOMP decision-loop is applied to guarantee more than 90% of energy efficiency. It finds contact impedance, ZE, to make sure VCOMP has the only tight margin for driving ISTIM. In addition, the novel stimulation method based on the silicon neuron cell (SNC) is proposed to mimic behaviors of a real-neuron cell. Due to the SNC artificial neuron model, the proposed stimulator can mimic 4 different types of neural spikes with 10uW power consumption. PMID- 30441276 TI - A 32-Channel Wireless Configurable System for Electrical Stimulation of the Stomach. AB - We have designed and developed a configurable system that can generate and deliver a variety of electrical pulses suitable for gastrointestinal studies. The system is composed of a front-end unit, and a back-end unit that is connected to a computer. The front-end unit contains a stimulating module with 32 channels configured to generate two different current pulses, simultaneously. Commercial off-the-shelf components were used to develop front- and back-end units. A graphical user interface was designed in LabVIEW that allows configuration of the stimulation pulses through the back-end unit in real-time. The system was successfully validated on bench top. The bench-top studies showed the capability of the system to deliver bipolar, monopolar and unbalanced electrical pulses to a maximum load of 1.5 kOmega, at amplitudes up to +/-10 mA with resolution of 10 MUA, and pulse widths varying between 80 MUs to 60 s with the resolution of 80 MUs. This study reports the first multi-channel bipolar stimulator that is designed for gastrointestinal studies, and can be configured wirelessly. The system can be used for treating functional gastrointestinal disorders in future. PMID- 30441277 TI - Impact of Electrode Number on the Performance of High-Definition Transcranial Direct Current Stimulation (HD-tDCS). AB - Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation for treating brain disorders by applying constant current through scalp towards the targeted cortex regions. Precisely activating or inhibiting a specific area without interfering other parts in the brain is a challenge of tDCS. Recently high-definition tDCS (HD-tDCS) with optimization technique attracts a lot of attention due to the improved focality. Unlike conventional tDCS which utilizes two large pads to deliver current to certain area, HD-tDCS employs tens of smaller electrodes. The purpose of this work is to study the effect of the electrode number on the performance of HD-tDCS. A realistic head model with four layers of tissue was constructed with different electrode montages. A systematic simulation study was conducted using targets in different regions with different functions to analyze the focusing capability, stimulation accuracy, and the intensity of constrained least square based optimized HD-tDCS. Results show that better performance in all three aspects can be achieved by increasing the electrode number. PMID- 30441278 TI - Uterosacral Nerve Stimulation via Cuff Electrode: A Preliminary Animal Study for Potential Application to Treatment of Preterm Labor. AB - Preterm labor occurs in about 12% of all pregnancies, accounting for at least 75% of neonatal deaths. The neonatal outcomes depend on mainly the gestational age at delivery. The lower the gestational age, the higher the risk of morbidity and mortality. The management of preterm labor involves early detection of high-risk women, prevention and treatment. In this study, the feasibility and stability of implantable cuff electrodes detection and inhibition of uterine contractions for preterm labor treatment were investigated by in-vivo mouse test. In order to check functionality of implanted electrodes, acute in-vivo test at mouse uterosacral ligament was performed by using cuff electrode which stimulate and record nerve activity. As results, the electrical stimulation via a stimulating cuff electrode at mouse uterosacral ligament was properly applied and nerve fiber's signal was recorded via the recording electrode. In addition, the implanted cuff electrodes could obtain stable recording signal to the periodic electrical stimulation for 7 weeks. PMID- 30441279 TI - Simulation of pH-Regulated Electrokinetic Ion Transport in Nanopores with Polyelectrolyte Brushes. AB - Nanopores with polyelectrolyte brushes in a pHregulated ion channel have been simulated. Electrokinetic ion transport was studied taking account of the effects of pH, presence of multiple ionic species and bulk ionic concentration. A continuum-based model that composed of coupled Poisson-Nernst- Planck equations for the ionic mass transport with electric potential, and Navier-Stokes and Brinkman equations for the fluid flow, were employed. Our results demonstrate that the bulk ionic concentration and pH together can greatly influence the charge of the polyelectrolyte brushes, the distribution of electric potential in the nanopore and also the fluid flow is sensitive to the pH variations. PMID- 30441280 TI - Cell Attachment on Inside-Outside Surface and Cell Encapsulation in Wall of Microscopic Tubular Scaffolds for Vascular Tissue-Like Formation. AB - By using the microfluidic spinning technology we generated tiny hydrogel tubular scaffolds. Fibroblast (NIH/3T3) cell cultures were performed for seventeen days to demonstrate the potential of cell attachment on surfaces and encapsulation in the wall of he microscopic scaffolds for blood vessel-like structure forming. Over theculture period, the NIH/3T3 confluence reached around 80?%, and 100?% on the inside and outside scaffolds' surface respectively while cells proliferated and coalesced in cell group in the hydrogel wall. These results could further be applied to endothelial co-culturing for forming engineered blood vessel. PMID- 30441281 TI - Application of Electrically Charged Carbon Nanodots@glass in DNA and Cell Engineering. AB - Water-soluble carbon nanodots (C-dots) prepared from food, or food wastes generally have a size below 10 nm and emit fluorescence upon the UV radiation with environmental safe specialty. These features of C-dots have been taken advantages in the areas of drug delivery as well as the inhibition of cancer cell growth as green carbon nanoparticles. The electrically physical, chemical characteristics and the mechanisms of their various applications, however, remain unclear. In the present work, we were attempted to develop the C-dots that carry charges which can be later embedded in the glass beads to achieve a specific biological microscopic process. The prepared C-dots were discovered to be able to be used in DNA extraction without affecting DNA cleavage; in addition, they can be used in semi-3D cell culture especially for cancer cells. These electrically charged C-dots@glass beads developed in the present work showed a great potential in diagnosis and drug delivery targeting tumor cells. PMID- 30441282 TI - Exploring new treatment for spinalized rats by synergising robotic rehabilitation system and regenerative medicine. AB - Spinal cord injury (SCI) is a traumatic event which leads to the loss of sensory and motor functions of the body. Complete recovery of these functions are usually limited due to the inability of the damaged axons within the central nervous system (CNS) to regenerate autonomously. Here, a combinatorial regenerative and rehabilitative approach to regrow damaged axons was proposed. Sprague-Dawley rats were subjected to a severe T9-T10 full tranection injury with a 2mm gap. Neurotrophin-3 (NT-3) loaded fibrous scaffold was implanted within the gap to provide topographical guidance for the axons to cross the injured region. To study the effect of rehabilitation, the rats were separated into 2 groups; those that undergo rehabilitation (trained, N=4) and those that do not undergo rehabilitation (untrained, N=3). In order to rehabilitate the rats, a rehabilitation robotic system consisting of a body weight support, hindlimb manipulator, and treadmill was developed. Preliminary results showed that rats which underwent rehabilitation had more robust axonal regeneration within the scaffold after 1 month. However, the Basso, Beattie, and Bresnahan (BBB) score, which is an indicator of locomotor recovery, do not show much significance between trained and untrained rats. PMID- 30441283 TI - The Role of Temperature, Ammonia and Nitrite to bioluminescence of Aliivibrio fischeri: towards a new sensor for aquaculture. AB - Recirculating Aquaculture Systems (RAS) present an innovative, clean and practical way of producing fish intensively. Stress caused by high concentrations of chemical species such as nitrite and un-ionized ammonia, affects fish health and growth and therefore the sustainability of RAS would require an online monitoring for those chemical stressors. This work reveals a study on the suitability of Aliivibrio fischeri as a toxicity sensor for un-ionized ammonia and nitrite. Temperature variation effects were also considered. An EC50 of 0.17 mg/L was found for nitrite and 0.57 mg/L for un-ionized ammonia. It was concluded that Allivibrio fischeri is suitable as an indicator for nitrite in aquaculture at optimal salinity and temperature conditions. PMID- 30441284 TI - 3D Nano-crystal Platinum for High-performance Neural Electrode. AB - A novel three-dimensional (3D) nano-crystal platinum (Pt) was introduced as a high-performance layer on the Pt substrate to provide extremely large surface, which significantly reduced electrical impedance by ~ and increased the cathodic charge storage capacity (CSCc) up to ~100 mC?textbullet(27 times) compared with that of bare Pt electrodes. In addition, the 3D nano-crystal Pt coating exhibited great mechanical and electrochemical stability as well as biocompatibility, which was critical and beneficial for effective neural stimulation/recording electrodes for practical applications. PMID- 30441285 TI - Reduction the Initial-Burst Release of Doxorubicin from Polymeric Depot as a Local Drug Delivery System for Cancer Treatment. AB - A sustained release that can be controllable is an ultimate goal for the delivery of drugs in drug delivery systems including in situ depots. However, one of the major persistent problems in the controlled release delivery system development is the initial burst release of the loaded drug which can minimize the effectiveness of the system. Our primary research objective was to reduce the initial burst release of Doxorubicin (Dox) encapsulated in polymeric depots by incorporating deprotonated Dox into the depots. The drug release profile and cytotoxicity effect of various concentrations of hydrophobic Dox-loaded depots were studied. In the first 24 hours after forming the depots, the release of Dox reached 82.9 +/- 0.6% in Dox.HCl depots. Interestingly, the initial burst releases of 5, 10 and 15% wt/wt hydrophobic Dox-loaded PLEC depots were reduced to 48.5 +/- 10.0, 29.2 +/- 7.8 and 18.9 +/- 0.9%, respectively. Moreover, 15% hydrophobic Dox-loaded PLEC depots maintained their stability up to 14 days and their in vitro cytotoxicity ability against human hepatocellular carcinoma cell line (HepG2). Taken together, this study suggested that the presence of hydrophobic Dox in Dox-loaded PLEC depots reduced the initial burst release phenomenon of the drug and the depots still maintained their function as a local drug delivery system. PMID- 30441286 TI - Control of hydroxyapatite film orientation by RF magnetron sputtering. AB - Hydroxyapatite (HAp) is compatible with bone tissue and used as a bone prosthetic material especially for the implants coating. The c-axis of biological apatite (BAp) in bone is mainly oriented along the bone axis direction due to the mechanical stress produced in this direction. Then, the coating of implant with c axis parallel oriented HAp thin film is expected to improve the healing speed. In this study, fabrication of oriented HAp thin films was performed by using a RF magnetron sputtering technique. The control of the HAp orientation in the film was achieved by changing the gas conditions, distance and angle between the target and substrate during sputtering. PMID- 30441287 TI - Stroke Volume, Ejection Fraction and Cardiac Health Monitoring using Impedance Cardiography. AB - In recent years occurrence of cardiac ailments have seen an exponential rise. In view of this it is highly important to monitor one's cardiac health. Currently employed methods for cardiac health monitoring are costly, require expert supervision and are available only at central hospitals. In order to overcome these obstacles, we have proposed a novel, non-invasive, cardiac health monitoring mechanism based on Impedance Cardiography (ICG). In this work we have proposed a methodolgy for determination of stroke volume (SV), left ventricular ejection fraction (LVEF), left ventricular end systolic volume (LVESV), and iso volumetric relaxation time (IVRT), based on ICG. The proposed models report $?mathrm{r}^{2}$ values of 0.86, 0.97, 0.99, and 0.96 for SV, LVESV, LVEF, and IVRT, respectively. The proposed methodology also provides us an insight into the use of ICG for cardiac health monitoring, and diagnosis of critical cardiac ailments. PMID- 30441288 TI - HOLOBALANCE: An Augmented Reality virtual trainer solution forbalance training and fall prevention. AB - Balance disorders affect a large number of older people, leading to falls. To promote independence, self-care and the quality of living of the long-lived population, an innovative solution is devoped to act as a virtual trainer for people that suffer from vestibular dysfunction related balance disorders. Our solution offers a virtual balance therapy, supported by Information and Communication Technology devices, to monitor user's activity during the day and provide real time feedback for the correct execution of physiotherapy exercises. Wearable sensors are utilized to monitor user activity, while during the execution of exercises, cameras are used to track the body of the user. An Augmented Reality headset is used to project the virtual trainer's 3D avatar in front of the user, providing real time guidance for the correct execution of the exercises. PMID- 30441289 TI - An Automatic Cycling Performance Classifier System Based on the Crank Arm Force Measurement Data. AB - This paper describes the development of an automatic cycling performance measurement system with a Fuzzy Logic Controller (FLC), using Mamdani Inference method, to classify the performance of the cyclist. From data of the average power, its standard deviation and the effective force bilateral asymmetry index, a score that represents the cyclist performance is determined. Data are acquired using an experimental crank arm load cell force platform developed with built-in strain gages and conditioning circuit that measure the force that is applied to the bicycle pedal during cycling with a linearity error under 0.6%. A randomized block experiment design was performed with 15 cyclists of 29+/-5 years with a body mass of 73+/-9kg and a height of 1.78+/-0.07m. The average power reached by the subjects was 137.63+/-59.6W; the mean bilateral asymmetry index, considering all trials, was 67.01+/-6.23%. The volunteers cycling performance scores were then determined using the developed FLC; the mean score was 25.4% +/- 16.9%. ANOVA showed that the subject causes significant variation on the performance score. PMID- 30441290 TI - Comparing Manual and Machine Annotations of Emotions in Non-acted Speech. AB - Psychological well-being at the workplace has increased the demand for detecting emotions with higher accuracies. Speech, one of the most non-obtrusive modes of capturing emotions at the workplace, is still in need of robust emotion annotation mechanisms for non-acted speech corpora. In this paper, we extend our experiments on our non-acted speech database in two ways. First, we report how participants themselves perceive the emotion in their voice after a long gap of about six months, and how a third person, who has not heard the clips earlier, perceives the emotion in the same utterances. Both annotators also rated the intensity of the emotion. They agreed better in neutral (84%) and negative clips (74%) than in positive ones (38%). Second, we restrict our attention to those samples that had agreement and show that the classification accuracy of 80% by machine learning, an improvement of 7% over the state-of-the-art results for speakerdependent classification. This result suggests that the high-level perception of emotion does translate to the low-level features of speech. Further analysis shows that the silently expressed positive and negative emotions are often misinterpreted as neutral. For the speaker-independent test set, we report an overall accuracy of 61%. PMID- 30441291 TI - The Analytical Study in the Assessment of Body Segment Composition Using Electrical Impedance in Patients with Schizophrenia. AB - Bioelectrical impedance analysis technology was used tomeasure whole body parameters and electrical resistance and reactance of specific body regions in schizophrenia patients after long-term medication use. Patient data was compared to that of a control group of subjects to analyze metabolic differences. Our experimental group was composed of 60 schizophrenia patients, and the control group was composed of 30 normal subjects. T-test and ANOVA analyses were conducted to compared differences between groups, with confidencev intervals set at 95%. T-test results showed significant differences in body fat levels between groups (F=4.753, p=0.031<0.05). Additionally, we also found significant differences in upper body resistance and reactance (F=78.433, p=0.000<0.05, F=67.488, p=0.000<0.05), which could be related to accumulation of body fat. These results show correlation between schizophrenia and development of metabolic syndrome. PMID- 30441292 TI - Walk Identification using a smart carpet and Mel-Frequency Cepstral Coefficient (MFCC) features. AB - We have developed a real-time system for inhome activity monitoring which could be used to assist the independent living of elders. Our system is a context aware, and unobtrusive floor-based sensor, which recognizes persons walking or falling, monitors their moving activities and stores the data for regular functional assessment. Here we report an in-depth analysis of the waveform generated by the sensors. We studied the analog characteristics of the signals such as power spectrum, pulse width, number of peeks, and signal shape. Then, we used the Mel-Frequency Cepstral Coefficient to extract features which later were utilized in the classification process. We have evaluated the performance of our technique using the dataset collected from 10 subjects who performed walks under different environmental conditions. We were able to use computational features of the generated waveform, by extracting the Mel Frequency Cepstral Coefficients and using computation intelligence to distinguish different people with an average accuracy of 82%. PMID- 30441293 TI - Parkinson's Disease Classification of mPower Walking Activity Participants. AB - Motion sensor data collected using Sage Bionetwork's mPower application on the Apple iPhone to record participant activities is analyzed to classify samples as positive or negative for Parkinson's Diagnosis. Pre-processing of the data showed differences in the time and frequency dimensions for features derived from Apple Core motion data. Several classic machine learning classification algorithms were trained on seventy-seven derived data points for best precision, recall, and F-1 score. Accuracy as high as ninety-two percent were achieved, with the best results attained from decision tree and multi-layered artificial neural network algorithms. This research shows that motion data produced on the Apple iPhone using the mPower application shows promise as an accessible platform to classify participants for presence of Parkinson's Disease signs. PMID- 30441294 TI - Monitoring Sucking Abilities in Newborns: Design and Validation on Adult Of a Wearable System for Non-Invasive Deglutition Detection. AB - Nutritive Sucking (NS) is one of the earliest motor activity performed by infants, strictly related to both neurological and motor development of newborns. The main components of NS are sucking, respiration and deglutition. Despite its recognized importance, current clinical practice lacks quantitative tools for the assessment of NS. This work aims to identify a non-invasive objective method to assess deglutition. In details, we propose a new sensor fusion approach to merge both inertial and acoustic data in order to estimate deglutition time. The algorithm uses two classification criteria: one is based on signal intensity thresholding and the other on the evaluation of Waveform Dimension Trajectory (WDT). Our preliminary results on 9 healthy adult volunteers show that the sensor fusion of audio and IMU signals provides a high precision (0.93) and a good recall (0.72). Moreover, the algorithm has a good accuracy (0.84) and high specificity (0.95). PMID- 30441295 TI - A high-throughput impedimetric platform for cellular analysis: Design, Implementation and Experimental Results. AB - A high-throughput impedance spectroscopy measurement system was designed and developed for the purpose of biological analysis. This platform consists of a microchip containing a microelectrode array and a multiplexing interface system. Herein we put forward the proposed platform and demonstrate its functionality by performing impedance analysis using N2a cells and its associated medium. The early experimental results demonstrated the high-through impedimetric system to be a strong basis for future modification and development. PMID- 30441296 TI - Piezoelectric Tooth Aligner for Accelerated Orthodontic Tooth Movement. AB - In this paper, we propose a device that can induce vibration to potentially accelerate the rate of orthodontic tooth movement and thus reduce the duration of the orthodontic treatment. This is accomplished by harmonically exciting a polyvinylidene fluoride (PVDF) piezoelectric actuators to generate vibration and hence generate cyclic loading at 30 Hz. PVDF is a popular piezoelectric polymer because of its high flexibility, biocompatibility, and low cost. Generally, application of cyclic loading (vibration) reverses bone loss, stimulates bone mass, induces cranial growth, and accelerates tooth movement. This reduce the pain experience and discomfort associated with the orthodontic treatment and also enhances the patient compliance with the treatment. Vibration has the advantage of minimal side effects in comparison to medicinal treatments. The device is attached to either a positioner or teeth aligner. The main advantage of this work is that the device can be adjusted and repositioned in a different location of the teeth aligner. We propose one device that incorporates vibration, harmonic function generation, and the housing unit for the battery and processor. Current approaches require an external device, which is relatively cumbersome to the patient. Theoretical analysis based on the distributed parameter model is utilized to justify our claim. Piezoelectric actuation behavior is simulated using Finite Element Analysis. PMID- 30441297 TI - Geometry-Based Model for U-Shaped Strain Gauges on Medical Needles. AB - The knowledge of needle location during insertions is essential for the success of interventional radiology procedures. As the needle is susceptible to undergo deformations during its insertion into tissues, several methods have been proposed to monitor the needle deformed shape. Thus, instrumented needles with U shaped strain gauges are currently being developed to reconstruct the shape of the needle from gauge acquisitions. These acquisitions are used in combination with gauge model to obtain estimate of the strain of the needle. The current modeling is limited as it does not consider the geometry of the gauge. This paper introduces a more complete model for U-shaped strain gauge which, unlike the current model, takes into account the width of the gauge. Thus, the impact of width modeling on the strain estimate can be measured and used to improve strain estimation accuracy. Results with real characteristics of instrumented needle devices show that the differences of strain estimate are around few percents. Finally, by taking into account the width and the length of the gauge our model includes the effets of the gauge size on the strain estimation and makes the miniaturization of the gauge less necessary. PMID- 30441298 TI - Harmonic Error Cancellation for Accurate Square-wave-based Bio-Impedance Measurements. AB - Bio-impedance spectroscopy, which measures impedance of the tissue over a frequency range, has been widely used to provide crucial information for monitoring human health. Its conventional methods using sine wave current stimulation of the tissue and sine wave demodulation of the resultant voltage provide an accurate impedance measurement, but involve bulky components and power inefficiency due to sinusoidal waveform generation and analog signal multiplication. Instead, the method using square wave clocks can be much more area and power efficient, but inherently has substantial errors in the measured result due to the presence of harmonics in square waves. In this paper we propose a technique to cancel the errors caused by harmonics of the square wave stimulation and demodulation. The technique, based on the fact that the magnitude ratio of all the harmonics of a square wave are known, cancels out harmonic errors by subtracting or adding the square-wave-based measured results at higher harmonics to the fundamental output as a simple post-processing calculation. Simulation results using a generic electrode and tissue model show that this technique can provide a precise measurement of the bio-impedance with <0.5% magnitude error and < 0.2 phase error considering just five frequency multiples. Because this method does not involve sinusoidal signal generation and analog mixing, it is adequate to be integrated in a wearable health monitoring device at low area and power overhead. PMID- 30441299 TI - Inkjet Printed Parallel Plate Capacitors Using PVP Polymer Dielectric Ink on Flexible Polyimide Substrates. AB - Inkjet printing (IJP) is an exciting new additive manufacturing technology that promises monolithic electronic circuit fabrication of $?mu ?mathrm{m}$ thin low cost large-area electronic low-cost body-worn flexible sensors. In this work, we demonstrate inkjet printed multilayer metal-dielectric-metal capacitors on flexible polyimide (PI) substrate by formulating a custom dielectric ink based on Poly 4-vinylphenol (PVP). Silver nanoparticle ink was used for printing theconductive parallel metal plates. We also demonstrate control over the capacitance values by varying the design parameters and succeeded in printing capacitors in the range 8.8 pF to 467 pF, with excellent repeatability on flexible PI substrates. A functional LC circuit using these printed capacitors has been designed and demonstrated to have a resonance frequency of 24.3 MHz. These results are a vital step forward towards monolithic printing of flexible electronic circuits using IJP technique formany applications such as body-worn sensors. PMID- 30441300 TI - Carbon Nanospikes on Silicon Wafer for Amperometric Biosensing Applications. AB - Carbon electrodes have gained wide popularity in biosensing applications in recent years. In this paper, we discuss carbon nanospikes fabricated using plasma enhanced chemical vapor deposition on a silicon wafer. Carbon nanospikes are preferred over other carbon nanostructures due to their batch reproducibility. Scanning electron microscope and Raman spectroscopy demonstrate spike-like and defectrich structure of the electrodes. Hydrogen peroxide has been chosen as the sensing analyte since it plays a vital role in various neurological disease states and is a byproduct of various electrochemical reactions. PMID- 30441301 TI - Study of Clinical Sample Detection for LH With Lateral Flow Immunochromatographic Strip Using Support Vector Regression. AB - Membrane-based lateral flow immuno-chromatographic strip (LFICS) is widely used in the measurement of Luteinizing hormone (LH) because of its advantages such as easy to handle, low costs, room temperature storage and transport, no need for long storage or transportation of samples and no requirement for skilled technicians. However, LFICS can only provide qualitative or semi-quantitative results without quantitative information, which greatly limited its application. In this paper, we developed a novel quantitative detection method for LFICS using support vector regression (SVR). Canny edge detection operator and fuzzy c-means (FCM) clustering algorithm were also used to extract test line, control line and background part from LFICS images taken by smartphone. The features extracted from test line, control line and background part were used as the input features of SVR model to obtain LH concentration. Measurements of standard sample and clinical sample using proposed method were conducted. Concentration results of standard LH solutions obtained from this method showed a fine linear relationship (r = 0.985) from 1.0 to 250.0 mIU/mL. Seventy-eight clinical serum samples were detected and its corresponding correlation coefficient was 0.918. The method was used to track the urine LH level of a volunteer during ovulation, and quantitative results could be obtained within 15 min. PMID- 30441302 TI - Fabrication and Interrogation of Refractive Index Biosensors Based on Etched Fiber Bragg Grating (EFBG). AB - We discuss the fabrication and interrogation of a fiber-optic refractive index sensors based on wet-etched fiber Bragg grating (EFBG). The fabrication is based on chemical etching of an FBG through an HF-free etching solution (ammonium fluoride and sulfuric acid), which progressively depletes the fiber cladding exposing the core to the outer medium. Microscope inspection of the fiber and real-time detection of the Bragg wavelength allow controlling the sensitivity. The proposed interrogation method is based on a spline interpolation, that measures the change of Bragg wavelength when the FBG is exposed to variations of the refractive index in the surrounding medium. An experimental validation has been carried out, for small refractive index variations (up to $1.85?times 10^{ 3}$ RIU), in order to verify the progressive change of sensitivity through fiber etching. The proposed EFBG sensing unit is a building block for functionalized fiber optic biosensors. PMID- 30441303 TI - A Novel Approach for Swallow Detection by Fusing Throat Acceleration and PPG Signal. AB - Swallow, as one of the most complex somatic reflexes, is a mirror of our daily ingestion and physical health. In recent years, accelerometry has become a simple and popular tool for non-invasive swallow detection. However, very few physiological signals are used in this field. In this paper, we first notice that swallowing causes significant throat photoplethysmogram (PPG) waveform fluctuation. With this inspiration, we present a novel approach for swallow detection by fusing throat acceleration (ACC) and PPG signal. The support vector machine (SVM) classifier is employed and a score level fusion method is used to access and fuse the information from ACC and PPG signal. The fusion result achieves 90.5{?% precision as well as 60.0{?% specificity, higher than the PPG based detection and the ACC based detection. The experiment result shows that our method combines the characteristics of ACC and PPG signal, providing better overall performance in swallow detection. PMID- 30441304 TI - EMG Channel Selection for Improved Hand Gesture Classification. AB - Electromyographic activities (EMG) from upper limb muscles exhibit distinct patterns associated with different hand gestures. To capture these EMG activities, an appropriate number of sensors (channels) affixed at right locations is needed. This paper presents a novel approach to automatically identify EMG channels most salient to classifying different hand gestures. The proposed approach is based on a regularized generative-discriminative encoding of time-series EMG data. The proposed approach 1) encodes each time-series channel of multi-channel EMG observations into a generative hidden Markov model (HMM), 2) constructs a shared probabilistic embedding space, where EMG observations are represented in terms of pair-wise distances between the channel-specific HMMs, 3) weighs different dimensions of the shared probabilistic space using multinomial logistic regression with group least absolute shrinkage and selection operator (group Lasso) penalty, with each group corresponding to channel-specific distances (i.e., distances between a channel and the rest of the channels), 4) determines salient channels based on the weighted parameters, and 5) classifies gestures based on the identified salient channels. The performance of the proposed approach was evaluated using the NinaPro2 dataset. The identified salient EMG channels improved classification accuracies as high as 11{% compared with the case where all the channels were used. PMID- 30441305 TI - Preliminary Finite Element Model for Hydrogen Peroxide-based Glucose Sensors. AB - The development of continuous glucose monitoring and insulin control algorithms have enabled the recent development of closed-loop artificial pancreas technology. However, despite these advancements, glucose sensor accuracy and reliability under physiologic conditions and over long periods of monitoring continue to be limiting factors in achieving a truly closed-loop artificial pancreas. To develop improved sensor technology, glucose sensor dynamics and performance need to be modeled accurately under physiologic conditions. A three dimensional hydrogen-based glucose sensor model was developed to predict steady state sensor performance. The finite element model, which included a three electrode system and relevant electrochemical reactions for electrochemical current calculation, was developed on COMSOL Multiphysics software. The results were validated using an experimental setup measuring various hydrogen peroxide concentrations ranging from 5 mM to 35 mM. The model predicted a linear relationship between current ranging from $5 . 1 ?mu A$ to $35 . 8 ?mu A$ for the aforementioned glucose concentrations. Experimental data demonstrated a linear relationship between hydrogen peroxide concentration within the same range, and current measurements ranging from $9 . 4 ?mu A$ to $60 . 6 ?mu A$. The model and experimental data differed consistently by percentages between 40-46 % for all concentrationstested. This consistent scaling error can be attributed to the difference in electrode geometric area and electrochemical active area. Future iterations of the model must take into consideration the effective electrode area. PMID- 30441306 TI - Flexible Non-contact Electrodes for Bioelectrical Signal Monitoring. AB - Physiological signals such as ECG and EMG are closely related with human health and a long term monitoring of the physiological signals would be beneficial to detect possible disorders at the early stage. The wet electrodes currently used in the clinics require adhesives gels to record high-quality signals, which might cause discomfort of the patients and introduce some risk of skin allergy. Non contact capacitive electrodes that can be operated without skin contact have been developed in previous studies, but these electrodes were rigid with electronic components on the back, which might not be an optimal solution for long term healthcare monitoring. In this study, a flexible non-contact electrode without any electronic components on both sides was designed for the long term acquisition of bioelectrical signals to maximize subject comfort. The flexible electrode was made up of multi-layer flexible printed circuits (FPC) materials and could be bent according to the local shape to achieve better non-contact capacitive coupling with the skin. The performance of the proposed flexible electrode was compared with that of the conventional wet electrodes in different signal recording conditions. The results showed that the proposed non-contact flexible electrode can capture high quality ECG and EMG signals, and its performance was comparable to the commonly used wet electrodes. This study might provide a reliable solution with great patient comfort for the long-term monitoring of biological signals. PMID- 30441308 TI - A Wrist-Worn Strap with an Array of Electrodes for Robust Physiological Sensing. AB - Robust sensing is one of the main challenges for wearable physiological monitoring because of the high dependency on the placement of electrodes on the body, retaining suitable contact between electrodes and skin, and the effect of motion artifacts. In this paper, we present a wrist-worn strap that includes a 2 D array of 48 miniature electrodes covering the bottom side of the wrist with good contact with the skin. Good skin contact directly impacts the sensing robustness. The array provides local measurements between adjacent electrodes that span the whole bottom side of the wrist with an area of 6.25*4.60 cm for robust sensing. The array allows for the automatic selection of the correct electrodes at the right location regardless of changes in the device placement on the wrist. In addition, using a large number of electrodes over a large area on the wrist ensures continuous contact of some electrodes with the skin during motion since all of the electrodes will not lose contact with the skin at the same time. We measured the electrode-skin impedance of the fabricated electrodes versus frequency and compared to other types of electrodes. We demonstrated good contact between all electrodes of the array and the skin by measuring electrode skin impedance less than 10 k$?Omega$ at 16 kHz for all locations on the wrist strap. We also conducted measurements of impedance while the wearer was bending the wrist to validate the continuous contact of at least a subset of electrodes with the skin during such movements. PMID- 30441307 TI - Disposable Stiffness Sensor for Endoscopic Examination. AB - Since direct manual palpation is not possible in minimally invasive procedures, there is an active field of applied research which aims to retrieve the human sense of touch and feedback tissue properties through artificial tactile feedback. This paper presents an innovative stiffness sensor to be embedded at the tip of a commercial endoscopic camera. The sensor structure is based on multiple cantilever beams, which act as springs with different stiffness when indented into soft tissue. Geometric features mounted on the beams are tracked during physical contact. Movements of thecantilevers result in shape variations of the features in the camera images. The feature size is then segmented and related to the force exerted into the contact location. As beams of different elasticity are integrated, it is possible to estimate the stiffness properties of the soft tissue by employing only visual information. In this paper, Finite Element Analysis (FEA) was implemented to simulate and estimate how contact forces will affect the material and design of the prototype. A calibration device has been developed and used to validate the outcome of the FEA simulations. An experimental test showed the ability of the proposed mechanism to compute the stiffness of a soft phantom. PMID- 30441309 TI - A Novel Calibration Procedure of Pulse Transit Time based Blood Pressure measurement with Heart Rate and Respiratory Rate. AB - Pulse transit time (PTT) has been a promising non-invasive and cuff-less method to measure blood pressure (BP). However, to achieve acceptable accuracy, subject specific and frequent calibration is required to model the complex non-Iinear dynamic between BP and PTT, limiting the practicality of PTT-based methods. The BP-PTT relationship is often modelled by the Moens-Korteweg (M-K) equation. Previous studies have found that the M-K equation is only able to model high frequency variations of BP, with low frequency variations modulated by the vasomotor tone, which is regulated by the sympathetic nervous system (SNS). In this paper we present a novel calibration procedure that accounts for the influence of the SNS on the BP-PTT relationship. This is achieved by identifying the state of the SNS during calibration based on heart rate (HR), respiratory rate (RR), and PTT itself. The performance of the proposed procedure has been tested on 10 subjects over a period of 4 weeks. The results showed that the measurement differences were 1.04 mmHg +/- 6.88 mmHg, and -2.16mmHg +/- 6.60 mmHg for systolic and diastolic blood pressure, respectively. Furthermore, the proposed procedure was found to make a significant improvement of measurement precision when compared to the previous one-point calibration method, demonstrating the potential of the new procedure for accurate long-term BP tracking. PMID- 30441310 TI - Effect of Position and Fastening Belt Pressure on the Accuracy of PPG-Based Heart Rate Sensor. AB - Photoplethysmography (PPG) is simple, non-invasive and unobtrusive, so it has been commonly used for heart rate (HR) sensing during exercise. PPG-based HR sensor can be applied for almost any part of human body where there is an artery close to the sensor, just by stabilizing it on the skin surface with belt. However, in order to make the HR sensor stable even during vigorous exercise, it requires a high fastening belt pressure, which results in discomfort for the sensor wearer. In this paper, we investigate the relationship between fastening belt pressure and accuracy for PPG-based HR sensors put on two positions such as forearm and wrist. First of all, we conducted a preliminary experiment using 10 subjects to associate fastening belt pressure (from 10hPa to 90hPa) to human comfort or discomfort (loose, moderate, tight, and very tight). Then, we conducted an experiment to measure HR for 10 subjects during exercise, changing the belt pressure and exercise intensity. Experimental results reveal that the forearm position gives higher accuracy for HR sensing than the wrist position, however, exercise severely introduces motion artifact (MA) even for the for earm position. Therefore, if we want to achieve higher accuracy during exercise with moderate fastening belt pressure, a technique to cancel MA is required even for forearm-type PPG-based HR sensors. PMID- 30441311 TI - Unconstrained Monitoring of Biological Signals Using an Aortic Pulse Wave Sensor. AB - This paper proposes a system to extract biological signals from aortic pulse waves which are measured by a microphone type pulse wave sensor. Theproposed system enables extraction of three biological signals corresponding to respiratory rate, pulse pressure wave, and RR interval simply by sitting on the seat on which the sensor is laid. Experiment results demonstrated that the mean absolute errors between the signals measured by the proposed system and the conventional sensors are as low as 0.38 times per minute for the respiratory rate, 11.2 mmHg for the pulse pressure wave, and 16.6 ms for the RR interval. The proposed system thus may be applied to monitor the physiological state of a human subject to prevent accident caused by health condition. PMID- 30441312 TI - Children Activity Recognition: Challenges and Strategies. AB - In this paper, we study the problem of children activity recognition using smartwatch devices. We introduce the need for a robust children activity model and challenges involved. To address the problem, we employ two deep neural network models, specifically, Bi-Directional LSTM model and a fully connected deep network and compare the results to commonly used models in the area. We demonstrate that our proposed deep models can significantly improve results compared to baseline models. We further show benefits of activity intensity level detection in health monitoring and verify high performance of our proposed models in this task. PMID- 30441313 TI - Psychophysiological Stress Assessment Among On-Duty Firefighters. AB - Firefighting is a hazardous profession commonly exposed to high stress that can interfere with firefighter's health and performance. Nevertheless, on-duty stress levels quantitative evaluations are very rare in the literature. In order to investigate firefighters' occupational health in terms of stress perceptions, symptoms, and quantified physiological reactions under real-world conditions, an ambulatory assessment protocol was developed. Therefore, cardiac signal from firefighters ($N =6$) was continuously monitored during two shifts within a working week with a medical clinically certified equipment (VitalJacket(r)), allowing continuous electrocardiogram (ECG) and actigraphy measurement. Psychological data were collected with an android application, collecting potential stressful events, stress symptoms, and stress appraisal. A total of 130 hours of medical-quality ECG were collected, from which heart rate variability (HRV) metrics were extracted and analyzed. Statistical significant differences were found in some HRV metrics - AVNN, RMSSD, pNN50 and LF/HF - between events and non-events, showing higher levels of physiological stress during events (p<0.05). Stress symptoms increase from the beginning to the end of the shift (from 1.54 +/- 0.52 to 2.01 +/- 0.73), however the mean stress self-perception of events was very low (3.22 +/- 2.38 in a scale ranging from 0 to 10). Negative and strong correlations were also found between stress symptoms and some time-domain ECG measures (AVNN, SDNN and pNN50). It can be concluded that stress may not always be detected when using merely self-reports. These results enhance the importance of combining both self-report and ambulatory high-quality physiological stress measures in occupational health settings. Future studies should investigate not only what causes stress but also its impact on health and well-being of these professionals, in order to contribute to the design of efficient stress-management interventions. PMID- 30441314 TI - System Level Framework for Assessing the Accuracy of Neonatal EEG Acquisition. AB - Significant research has been conducted in recent years to design low-cost alternatives to the current EEG monitoring systems used in healthcare facilities. Testing such systems on a vulnerable population such as newborns is complicated due to ethical and regulatory considerations that slow down the technical development. This paper presents and validates a method for quantifying the accuracy of neonatal EEG acquisition systems and electrode technologies via clinical data simulations that do not require neonatal participants. The proposed method uses an extensive neonatal EEG database to simulate analogue signals, which are subsequently passed through electrical models of the skin-electrode interface, which are developed using wet and dry EEG electrode designs. The signal losses in the system are quantified at each stage of the acquisition process for electrode and acquisition board losses. SNR, correlation and noise values were calculated. The results verify that low-cost EEG acquisition systems are capable of obtaining clinical grade EEG. Although dry electrodes result in a significant increase in the skin-electrode impedance, accurate EEG recordings are still achievable. PMID- 30441315 TI - A Pilot Study of an Unobtrusive Bed-Based Sleep Quality Monitor for Severely Disabled Autistic Children. AB - The link between daytime performance and sleep quality for severely disabled autistic children is not entirely understood. This paper presents nighttime data collected from a child with severe disabilities during a three-night pilot study conducted at Heartspring, Wichita, KS, using a bed-based system capable of unobtrusively tracking parameters for sleep quality assessment. The 'average sample correlation coefficient signal-to-noise ratio' is compared for ballistocardiograms acquired using four electromechanical film sensors versus four load cell sensors. The "best" signal or sensing modality depends on the subject's sleeping position. These results affirm the importance of a bed system that is robust in its ability to track sleep quality accurately regardless of sleeping position. PMID- 30441316 TI - A System for Assessment of Canine-Human Interaction during Animal-Assisted Therapies. AB - Animal-assisted therapies (AAT) are becoming increasingly common to help hospitalized patients, especially in oncology units. There is a critical need for methods and technologies that can enable a quantifiable understanding of AAT to objectively demonstrate its efficacy and improve its efficiency. In this paper, we present our preliminary efforts towards the development of wireless sensor systems to simultaneously detect the related behavioral (activity level, movement, stroking) and physiological signals (heart rate/variability) of humans and animals during their interaction. To detect heart rate, we tested two different techniques based on wearable or contactless electrocardiography. In this preliminary evaluation, we were able to assess these parameters successfully and identify the design challenges towards deployment of these systems in larger clinical studies. PMID- 30441317 TI - Estimating Localized Bio-impedance with Measures from Multiple Redundant Electrode Configurations. AB - In most bio-impedance applications, measurements are collected from a single electrode configuration though multi-electrode systems could monitor different tissue sites or serve as a source of redundancy in case of electrode malfunction. However, comparison of impedance data collected from different electrode configurations is difficult. This article proposes an approach to estimate the current tissue impedance collected from a fixed electrode configuration using measurements from different sites of the same localized tissue. Estimated impedance is calculated using the ratio between impedance values from different electrode configurations collected prior to the electrode malfunction event. This approach is validated using measurements of a human forearm collected from 3 kHz to 1 MHz collected with 4 electrode configurations over 3 days. The estimation results using this approach show maximum estimation errors of 2.3% and 16.9% for the resistance and reactance, respectively, compared to the measured impedance. PMID- 30441318 TI - Characterization Study of Neck Photoplethysmography. AB - This paper presents a comparison between finger and neck photoplethysmography (PPG) in order to assess the potential and limitations of this, non conventionally used, body site for application in pulse oximetry. PPG signals were recorded at both sites from healthy subjects to inspect the differences in average waveforms, as well as in oxygen saturation (SpO2) and heart rate (HR) estimation. The results show significant differences in the average PPG pulse waveforms for different contour features such as diastolic or dicrotic notch amplitude, among others. The results show that the HR estimated from signals obtained with the neck sensor are strongly correlated to the output of the reference finger (R=0.862, MAE=1.27 BPM), whereas SpO2 measurements are not that accurately predicted (R=0.129, MAE=11.7%). Spectrograms under different breathing conditions revealed that the respiratory frequency is more predominant in neck PPG than in finger, which has a great potential for respiratory rate (RR) extraction. These are very promising results for the suitability of the neck as an alternative location for monitoring of respiratory diseases, and specifically for sleep apnea. PMID- 30441319 TI - Low-Cost, USB Connected and Multi-Purpose Biopotential Recording System. AB - Several research arenas and clinical applications are reliant on biopotential recordings, such as electroencephalography (EEG), electromyography (EMG), electrocardiography (ECG), and neural interfaces including brain computer interface (BCI). Here, we present a low-cost, biopotential, acquisition hardware platform board (PSUEEG platform) suitable for a wide range of recording tasks. Implementations of the hardware include applications requiring 8 or 16 channels of biopotential recordings, and 3-axis accelerometer measurements, among other modalities. The device firmware allows for flexible software configuration through USB. Power and data are transmitted between the device and base computer through an electrically isolated USB. The device is compatible with a range of computer operating systems, including Windows, Linux, and OSX. Additionally, we have crafted data acquisition under a range of programming platforms, including C++, Python, MATLAB Simulink, and LabView. Notably, we have demonstrated the interface with the Matlab PsychToolbox and the popular BCI2000 platform. The acquisition system with can be used in educational and research-based applications, neural interfaces, and clinical interfaces. For education and research, we have utilized this platform in BCI work, as well as demonstrated comparable classification performance for different paradigms. PMID- 30441320 TI - A Modified Mask for Continuous Cardiac Monitoring during Positive Airway Pressure Therapy. AB - A Positive Airway Pressure mask was modified to be able to measure the heart rate of the wearer during Positive Airway Pressure (PAP) therapy. The mask was modified by attaching sensors to measure Electrocardiography (ECG) and Photoplethysmography (PPG) signals, from which a heart rate was extracted. The ECG signal was recorded using stainless steel electrodes positioned on the wearer's head and neck. The PPG signal was measured from the wearer's forehead using a reflectance pulse oximeter attached to the mask. The modified device was tested on 19 healthy participants (mean age30.5 +/- 9 years) in a simulated sleeping environment. For both the ECG and PPG signals, the device was able to correctly identify more than 95% of heartbeats for the majority of the participants. However, it was found that by combining the ECG and PPG heartbeat data, the percentage of heartbeats that could be detected was increased to 99%. The results showed that it may be possible to use this device to monitor sleep apnoea patients during PAP therapy in their homes. PMID- 30441321 TI - Power Wheelchair Footplate Pressure and Positioning Sensor. AB - Power wheelchair users are at risk for severe injuries caused by foot mis position on the footplate. This can lead to collisions or foot dragging which are severe or lifethreatening injuries for people with spinal cord injuries. The foot cannot be safely immobilized due to tilting pressure relief injuries, therefore, the foot can easily fall into a vulnerable position without the user realizing it. To reduce the likelihood of injury, we have developed a sensor for monitoring foot position in real time, as the wheelchair is driven. The sensor uses an array of force-sensing resistors and infrared distance sensors to detect the pressure and location of the foot within the immediate confines of the footplate. Sensor arrays with 23 force sensors and 14 infrared sensors per foot were fabricated on standard printed circuit boards and encapsulated in a durable thermoplastic urethane for environmental resistance. Fabricated sensors transmitted foot pressures and position data at 10 Hz using a Bluetooth Low Energy radio. An iOS app was developed to notify users of vulnerable foot position. Measured results confirmed the functionality of the system over typical foot pressures, and indicated that the device is ready for next-stage clinical trials with spinal cord injured power wheelchair users. PMID- 30441322 TI - Stable Contactless Sensing of Vital Signs Using RGB-Thermal Image Fusion System with Facial Tracking for Infection Screening. AB - Infrared thermography (IRT) has been used to screen febrile passengers in international airports for over a decade. However, fever-based infection screening using IRT suffered from low sensitivity because measurements can be affected by ambient temperature, humidity, etc. In our previous study, we proposed an RGB-thermal image fusion system to measure vital signs i.e., the RGB camera detects tiny changes in color from facial skin, associated with blood flow, to estimate heart rate, and IRT senses temperature changes around the nasal area, caused by respiration, to measure respiratory rate). The inclusion of heart and respiratory rates lead to increased screening accuracy. In the present study, to promote the widespread use of our system in real-world settings, a face detection and tracking method was developed and implemented into the system, thereby enabling the accurate and stable measurement of vital signs. We assessed heart and respiratory rate estimation via an RGB-thermal image fusion system using Bland-Altman plots and statistical analysis. PMID- 30441323 TI - Bed Sensor System with Multiple Weight Sensor Units for Urine Accumulation Measurement in Bladder. AB - Urinary incontinence is highly prevalent in elderly populations. Some elderly people with dementia cannot feel or express the desire to urinate, which makes continence care difficult in elderly people with dementia. Therefore, a system to estimate the proper timing for urination is needed. Because bladder volume is associated with the desire to void, it can be employed to estimate the proper timing. In this study, we developed a new bed sensor system that non-invasively and unconstrainedly measures urine accumulation in the bladder. To capture the slight weight change due to body alignment changes caused by body sinking in bed mattress, the system takes measurements in five body areas (head, torso, buttock, thigh, and lower limb) with five separate sensor units. We measured weight change during bladder voiding and urine accumulation in a human subject. Interestingly, the weight around head as well as buttock measured by the newly developed sensor system gradually increased when urine accumulated in the bladder, which suggested that the weight changes might reflect urine accumulation. PMID- 30441324 TI - Data Compression via Low Complexity Delta Transition Lossless Encoding for Remote Physiological and Environmental Monitoring. AB - Continuous remote physiologic and environmental monitoring, employing an ever increasing array of sensors, is now commonplace. Given the significant amount of data being digitized, two common sources of energy consumption can be targeted to improve device runtime: data storage and data transmission. One embedded method to maximize device runtime is inline low energy data compression. Herein we present a low complexity data encoding scheme. We list and characterize the parameters necessary for encoding. The encoding method is then evaluated and tuned using contrived data with varying degrees of covariance, as well as open source electrocardiography (ECG) data. Finally, the encoding method is evaluated with tri-axial accelerometry and ECG data previously collected on a Mount Everest Expedition using a remote physiologic monitor that was specifically designed for long autonomous runtimes. With the described low overhead delta transition lossless encoding method, the Mt. Everest device runtime would have doubled from two to four weeks of continuous recording. Finally, this approach would be beneficial given a requirement to transmit data wirelessly in real time, since the total transmission power and energy would be reduced by an amount related to the compression ratio. PMID- 30441325 TI - Development of a Lightweight Flexible Construction Work Assist Suit Using Pneumatic Rubber Artificial Muscles. AB - We developed an assist suit with lightweight, flexible artificial muscles of pneumatic rubber for reducing muscle load in the lumbar region. We designed two assist forces to control the artificial muscles with pulse width modulation based on the measured EMG of the spinal column muscle and estimated the torque of the hip joint. The experimental results confirmed the developed work assist suit could unload muscle activity during bending and stretching exercises. We also proposed to use an EMG measurement device at the wearer's temple to control the assist timing and confirmed the feasibility of detecting the intention of the wearer. PMID- 30441326 TI - Capacitive Sensors Array for Plantar Pressure Measurement Insole fabricated with Flexible PCB. AB - Diabetic foot is a pathology associated with diabetic neuropathy, where the vast majority of diabetic foot infections terminate in surgical intervention; from debridement to amputation of the involved limb. Commonly, diabetic foot infections come from ulceration produced by high-pressure areas under the foot. For this reason, researchers have been working on a continuous measurement system to detect the high-pressure areas in-shoe in a low cost way. This paper presents the design and implementation of a continuous monitoring device to measure the pressure in-shoe. The pressure sensors are built from commercial flexible PCB and a dielectric sheet. The system measures the pressure distribution in 8 points and sends the information by a wireless Bluetooth link to a personal computer and gives information to the patient in real time. PMID- 30441327 TI - Wearable Fetal Monitoring Solution for Improved Mobility During Labor & Delivery. AB - Electronic fetal monitoring (EFM) is used widely during labor & delivery, but existing solutions limit patient mobility, are uncomfortable, and do not consistently capture fetal heart rate (FHR) and uterine activity (UA) signals. A wireless EFM system was developed that features wearable US and tocodynamometer devices that conform to the body and do not require cables or belts. Benchtop testing demonstrated that the devices can accurately and consistently measure simulated FHRs and UAs over clinically meaningful ranges and body curvatures. The wearable EFM devices are expected to provide more reliable signal capture independent of maternal movement and repositioning, while also significantly improving patient comfort and mobility. PMID- 30441328 TI - Pre-impact Alarm System for Fall Detection Using MEMS Sensors and HMM-based SVM Classifier. AB - Accidental fall can cause physical injury, fracture and other health complication, especially for elderly people living alone. Aimed to provide timely assistance after the occurrence of falling down, a pre-fall alarm system was proposed. In order to test the reliability of pre-fall alarm system, eighteen subjects who worn this device on the waist were required to participate in a series of experiments. The acceleration and angular velocity time series extracted from human motion processes were used to described human motion features. HMM-based SVM classifier was used to determine the maximum separation boundary between fall and Activities of Daily Living (ADLs). The fall detection results showed 94.91% accuracy, 97.22% Sensitivity and 93.75% Specificity. The proposed device can accurately recognize fall event, achieve additional functions, and have advantages of small size and low power consumption. Based on the findings, this pre-impact fall alarm system with detection algorithm could potentially be useful for monitoring the state of physical function in elderly population. PMID- 30441329 TI - Wearable EMG Shirt for Upper Limb Training. AB - This work presents a wearable shirt fitted with dry electrodes to measure EMG in upper limbs during physical exercise. The hardware acquires signals from 6 channels and transmits wirelessly to a PC via Bluetooth. In the PC, EMG signals are analyzed to give feedback to the user regarding the exercise being performed. To alert for muscle fatigue, the Dimitrov index is used, with much better results that classic mean or median EMG frequency tracking. The system is able to monitor EMG activity and provide valuable information in real-time for professional and amateur athletes and their sports coach, improving their training protocols. PMID- 30441330 TI - Tele-monitoring and tele-rehabilitation of the shoulder muscular-skeletal diseases through wearable systems. AB - In this work we present the development and preliminary testing of a wearable technology-enabled platform for the remote rehabilitation of a large number of shoulder muscular-skeletal diseases. The presented system (Shoulphy) is conceived to lead and assess the patient, wearing a minimal set of inertial sensors, through personalized physical rehabilitation programs under the remote supervision of the physician/therapist. We have introduced a minimal inertial sensor set and an associated biomechanical reconstruction method based on a bi articular model of the shoulder. We have tested the system in classical shoulder rehabilitation exercises and we have demonstrated that the system is able to discriminate between correct and compensatory movement strategies. PMID- 30441331 TI - Predicting Walking Intentions using sEMG and Mechanical sensors for various environment. AB - Predicting the motion intentions of a user is very challenging when controlling an exoskeleton robot. When only a mechanical sensor is used, a change in the motion is detected during the user's movement. An electromyographic (EMG) signal, which is a biological signal, is detected by the activation of the muscles before the actual movement of a person. Using the EMG signal, the motion intention can be identified before the actual movement, and the delay in time in controlling the exoskeletal robot can be shortened to reduce the resistance felt by the user. In this paper, the surface electromyographic (sEMG) signal is used together with a mechanical sensor to identify the walking environment according to the walking gait cycle. In the classification, the combination of sensors was varied, and information from one leg and two legs was analyzed by the different gait periods before and after heel contact and toe off. As a result of the classification into three sensor combinations, sEMG, kinetic, and kinematic sensors, at the pre heel contact time before walking, a 96.8% and 98.6% accuracy was obtained for information from one and two legs, respectively. In the same gait environment, it was shown that the gait prediction can be performed based on the time unit by dividing the time interval before starting the gait. An average accuracy of 84.4% was obtained when the time was divided by the environment in intervals of 100ms before heel contact, and the average was 90.9% when it was divided by an interval of 200ms before heel contact. PMID- 30441332 TI - Real-time Action Recognition and Fall Detection Based on Smartphone. AB - This paper presents a smartphone application which has realized action recognition and fall detection. The application identifies the holding pattern of smartphone by the data of light sensor, distance sensor and accelerometer sensor, which reduce the impact of recognition resulting from the smartphone's different positions. And then the application uses data collected from the acceleration sensor, the direction angle sensor and the gyro sensor to distinguish fall from daily actions. The results of human motion recognition are uploaded to the server. For the purpose of real time, the network stability of the application is improved by the method of multi-layer detection based on heartbeat packet. Experiments prove that the way of improving network stability can reduce the rate of losing packet. The accuracy of action recognition achieves more than 90%. PMID- 30441333 TI - An Optimised Algorithm for Accurate Steps Counting From Smart-Phone Accelerometry. AB - Step counting from smart-phones allows a wide range of applications related to fitness and health. Estimating steps from phones' accelerometers is challenging because of the multitude of ways a smart-phone can be carried. We focus our work on the windowed peak detection algorithm, which has previously been shown to be accurate and efficient and thus suitable for mobile devices. We explore and optimise further the algorithm and its parameters making use of data collected by three volunteers holding the phone in six different positions. In order to simplify the analysis of the data, we also built a novel device for the detection of the ground truth steps. Over the collected data set, the algorithm reaches 95% average accuracy. We implemented the algorithm for the Android OS and released it as an open source project. A separate dataset was collected with the algorithm running on the smart-phone for further validation. The validation confirms the accuracy of the algorithm in real-time conditions. PMID- 30441334 TI - Subject Count Estimation by Using Doppler Radar Occupancy Sensor. AB - Occupancy information and occupant counts can save significant amount of energy for occupant related building automation systems. Doppler radar occupancy detection sensor not only can detect the human presence but also has the potential to count the number of occupants. Continuous wave Doppler radar monitoring system is employed for occupant count estimation. The received signal strength (RSS) which is directly related to radar cross section is used as a measure for occupant counts. The preliminary results show RSS is a promising tool for occupant number estimation. PMID- 30441335 TI - A Human Tracking and Physiological Monitoring FSK Technology for Single Senior at Home Care. AB - Respiration monitoring for apnea diagnosis and movement tracking for physical activity analysis are essential and valuable indicators of underlying medical conditions in senior health care. Compared with other health sensing technologies, radar has shown its advantages in terms of non-contact implementation, immunity to ambient light and temperature changes, hardware simplicity, and long range coverage. Among various radar types, frequency-shift keying (FSK) radar inherits the ability to measure respiration from Doppler radar, while also having the ability to track the absolute range of a moving target with much less bandwidth requirement than frequency modulated continuous wave (FMCW) radar and ultra-wideband (UWB) radar. Therefore, in this paper, an FSK radar system is employed for both remote respiration monitoring and absolute range tracking. Fundamental theory and operating principle of FSK system are detailed. Respiration monitoring and range tracking experiments of a human subject were performed in an indoor environment. Results are presented to demonstrate the practical feasibility of the FSK sensing technology being applied to single senior home care applications. PMID- 30441336 TI - Finger-Worn Sensors for Accurate Functional Assessment of the Upper Limbs in Real World Settings. AB - Remote monitoring of stroke survivors' upper limb performance (stroke-affected vs. unaffected limbs) can provide clinicians with information regarding the true impact of rehabilitation in the real-world settings, which allows opportunities to administer individually tailored therapeutic interventions. In this work, we examine the use of finger-worn accelerometers, which are capable of capturing gross-arm as well as fine-hand movements, in order to quantitatively compare the performance of the upper limbs during goal-directed activities of daily living (ADLs). In this proof-of-concept study, data were collected over an eight-hour duration from ten neurologically intact individuals who wore the sensors and continued with their daily living. The sensor-based measure was compared to two clinically validated measures of handedness, i.e., Waterloo Handedness Questionnaire and Fazio Laterality Inventory, that quantity the level of preference of the limbs in performing ADLs. The results yielded statistically significant correlations to the Waterloo and Fazio scores with Pearson correlation coefficients of 0.90 and 0.87 respectively, which was substantially superior compared to the previously studied measure based on wrist-worn accelerometers. We believe this study presents an opportunity to accurately monitor the goal-directed use of the upper limbs in the real-world settings. PMID- 30441337 TI - Development of a Smart Home-Based Package for Unobtrusive Physiological Monitoring. AB - Home-based programs have been shown to be effective in improving health conditions, patient self-management, quality of life, and health outcomes. However, there is mixedevidence on the effectiveness of these programs due to limitations in the intervention tools that are used, primarily the burden that is placed on the user, especially among seniors. In this paper we developed a novel home-based package that measures critically important physiological information such that neither active compliance or interaction from the user is required. To this end, we embedded passive sensors (including load cells, electrodes, pulse sensor and color sensors) into common household items such as tiling, furniture and wall. The smart package measures subject's electrocardiogram (ECG), photoplethysmogram (PPG), ballistocardiogram (BCG), electromyogram (EMG) and imaging photoplethysmogram (IPPG). In contrast to the previous studies, the proposed package measures all the physiological information unobtrusively, simultaneously and in a synchronized manner such that all the data samples corresponding to different intervals of a specific cardiovascular cycle can be identified. Such information can be analyzed by a clinician or be used for a higher level information extraction such as beat-to-beat blood pressure estimation. In addition, the proposed package is the first and only homebased technology that can simultaneously and unobtrusively capture both mechanical and electrical characteristics of user's heart activities. This results in a more accurate home-based vital parameters monitoring. PMID- 30441338 TI - Detection of Echinocyte during Perfusion with Oxygenator Based on Continuous Blood Viscosity Monitoring. AB - We applied our proposed continuous blood viscosity monitoring system for cardiopulmonary bypass to an experimental model that introduced echinocytes, and we confirm the viscosity change detection due to red blood cell (RBC) deformability decline. For the in vitro experiment, a test circuit including an oxygenator and a controlled bovine blood sample with excessive alkalemia to induce the echinocyte were prepared, and a perfusion experiment was performed. During the experiment, the anticoagulated bovine blood sample maintained a hematocrit of approximately 22%, temperature of 37 degrees C, and more than 800 s of the activated clotting time. The estimated viscosity obtained from the proposed system was 2.10 mPas at the beginning of the experiment and 3.58 mPas at the end of the experiment, and it increased 1.48 mPas during the experiment. According to the scanning electron micrographs of blood samples, the echinocytes with multiple spicules at the beginning of the experiment and distorted spherical RBCs including the echinocytes with multiple spicules at the end of experiment were observed. We conclude that the system may be helpful for clinical perfusion management, because it detected the presence of echinocytes as the blood viscosity in an oxygenator flow pass increased. PMID- 30441339 TI - Considering Plasma Insulin Concentrations in Adaptive Model Predictive Control for Artificial Pancreas Systems. AB - Adaptive and personalized model predictive control (MPC) algorithms that explicitly consider insulin dosing constraints are necessary to prevent overdose induced hypoglycemia in type 1 diabetes. A personalized plasma insulin concentration (PIC) estimator is integrated with adaptive models to characterize the temporal dynamics of PIC and blood glucose concentration (BGC). The dynamic profile trajectories of the PIC and BGC are used to adapt the control problems and constraints on-line to accurately reflect the concurrent metabolic state of the individuals and improve glucose regulation. The adaptive MPC algorithm, explicitly considering the PIC in the insulin dose computations, is demonstrated to effectively control BGC without any manual user input on meal information while avoiding excessive insulin administration that can cause hypoglycemia. Simulation results demonstrate the ability of the proposed approach with an average 71.14 % of time spent in the target range (BGC epsilon [70, 180]mg/dL). PMID- 30441340 TI - Clinical Decision Support for Early Detection of Prediabetes and Type 2 Diabetes Mellitus Using Wearable Technology. AB - Worldwide spending on long-term and chronic care conditions is increasing to a point that requires immediate interventions and advancements to reduce the burden of the healthcare cost. This research is focused on early detection of prediabetes and type 2 diabetes mellitus (T2DM) using wearable technology. An artificial intelligence model was developed based on adaptive-neuro fuzzy interference to detect prediabetes and T2DM via individualized monitoring. The key contributing factors to the proposed model include heart rate, heart rate variability, breathing rate, breathing volume, and activity data (steps, cadence and calories). The data was collected using an advanced wearable body vest. The real-time data was combined with manual recordings of blood glucose, height, weight, age and sex. The model analyzed the data alongside a clinical knowledge base. Fuzzy rules were used to establish baseline values via existing interventions, clinical guidelines and protocols. The proposed model was tested and validated using Kappa analysis and achieved an overall agreement of 91%. PMID- 30441341 TI - Towards an ASIC-based Fluoroscopic Capsule for the Early Cancer Detection in the Small Intestine. AB - Early micro-cancer detection in the small intestine can be realized using infrared fluorescence endoscopy (IRFE) in conjunction with an infrared fluorescence biomarker. In this paper, we present a third-generation capsule that detects weak fluorescence signals emitted by low concentrations of indocyanine green (ICG). An applicationspecific integrated circuit (ASIC) has been designed and fabricated that integrates many of the peripheral components of the capsule system. The ASIC enables the system to have greater sensitivity whilst reducing the capsule size and lowering the power consumption. PMID- 30441342 TI - Achieving Ultra-Conformability With Polyimide-Based ECoG Arrays. AB - Micro-electrode arrays for electrocorticography (ECoG) represent the best compromise between invasiveness and signal quality, as they are surface devices that still allow high sensitivity recordings. In this work, an assessment of different technical aspects determining the ultimate performance of ultra conformable polyimide-based MUECoG arrays is conducted via a finite element model, impedance spectroscopy measurements and recordings of sensorimotor evoked potentials (SEPs) in rats. The finite element model proves that conformability of thin-film arrays can be achieved with polyimide, a non-stretchable material, by adjusting its thickness according to the curvature of the targeted anatomical area. From the electrochemical characterization of the devices, intrinsic thermal noise of platinum and gold electrodes is estimated to be 3-5 MUV. Results show that electrode size and in vitro impedance do not influence the amplitude of the recorded SEPs. However, the use of a reference on-skull (a metal screw), as compared to reference on-array (a metal electrode surrounding the recording area), provides higher-amplitude SEPs. Additionally, the incorporation of a grounded metal shield in the thin-film devices limits crosstalk between tracks and does not compromise the recording capabilities of the arrays. PMID- 30441344 TI - Direct Measurement of Mass Transport in Actuation of Conducting Polymers Nanotubes. AB - Nanostructured Conducting polymer (CP) actuators are promising materials for biomedical applications such as drug release systems. However, understanding the actuation behavior at the nano-scale has not yet been explored. In this work, poly(3,4-ethylenedioxythiophene) (PEDOT) and poly(pyrrole) (PPy) nanotubes doped with a large counter ion (i.e. poly(styrene sodium sulfonate) (PSS)) were fabricated using electrochemical deposition of PEDOT and PPy around poly(L lactide) (PLLA) nanofiber templates, followed by template removal in chloroform. The actuation and mass transport behavior of PPy and PEDOT nanotubes were investigated and compared. The nanotubes were subjected to a redox process using cyclic voltammetry in 0.1M NaPSS electrolyte solution as the potential swept between -0.8 V and +0.4 V for 20 cycles at 10, 50, 100, and 200 mV/s scan rates. The mass transport behavior of these nanotubes was characterized via electrochemical quartz crystal microbalance (EQCM) technique. The EQCM results showed that PEDOT nanotubes had a higher mass exchange capability than their PPy counterparts, especially at higher scan rates. Also, it was revealed that PPy nanotubes were more sensitive to the scan rate than the PEDOT nanotubes, and the maximum mass exchange capability of the PPy nanotubes was noticeably reduced by increasing the scan rate. PMID- 30441343 TI - Impact of Reactive Obstacle on Molecular Communication between Nanomachines. AB - Molecular communication is an emerging technology for communication between bio nanomachines in an aqueous environment. In this paper, we examine the effect of a reactive obstacle, which is placed in the diffusive molecular communication channel, on the expected number of the received molecules at the receiver. We develop a particle-based simulator that can predict the number of the received molecules for both passive and absorptive receivers by considering the impact of the reactive obstacle within the communication channel. The impacts of the reaction probability and radius of the obstacle on the received signal are examined and compared with the case of absence of the obstacle. The results show significant impact for the obstacle on the received signal, particularly, for obstacle with high reaction probability and large size. PMID- 30441345 TI - Single Molecule Free Solution Hydrodynamic Separation for Size Profiling of Serum Cell-Free DNA. AB - Circulating cell-free DNA (cfDNA) has accumulated significant interest as a noninvasive biomarker. One important accessible parameter, the cfDNA size distribution, appears to be of significant value. Here, we introduce our single molecule free solution hydrodynamic separation platform (SML-FSHS) for robust characterization of the cfDNA size profile from human serum. The platform utilizes hydrodynamic separation for DNA sizing and cylindrical illumination confocal spectroscopy (CICS) for highly sensitive single molecule detection and quantification of DNA molecules. We first used a custom wide dynamic range DNA ladder (50 bp-23 kbp) stained with an intercalating dye to create a calibration curve relating DNA retention time to DNA size in base pairs. From this, we demonstrate that the system can profile the cfDNA size distributions in a clinical sample with wide sizing dynamic range and high resolution ~5% of fragment length) all in a single run. The method consumes negligible (3pL) volume of precious sample and minimizes sample processing bias that affects other methods such as PCR and sequencing. We also compare the cfDNA size distributions from stage 1V cancer patients with normal patient samples and demonstrate that specific cfDNA size ranges may correlate with disease state. In addition, we can absolutely quantify cfDNA and gate out the contributions of cellular contamination by size. With these properties, we believe that this platform can help to accelerate future circulating DNA research. PMID- 30441346 TI - Focused Ion Beam-Based Milling, Imaging and Analysis of 3D Tumor Spheroids. AB - We investigate the structural cellular alterations in breast cancer spheroids at various growth stages using transmission electron microscopy (TEM), focused ion beam (FIB), and scanning electron microscopy (SEM) imaging. Samples sliced by FIB milling were studied for 3D analysis and construction. The imaging results of different spheroid ages were compared for a better understanding of cancer spheroid models. This study will serve as a pilot study and reference control for further studies with the 3D tumor model including nanoparticles interaction and mechanical characterization. PMID- 30441347 TI - Mouse embryo assay to evaluate polydimethylsiloxane (PDMS) embryo-toxicity. AB - In vitro embryo culture to support In Vitro Fertilization (IVF) procedures is a well-established but still critical technique. In the last decade first attempts to use microfluidic devices in IVF have shown positive results, enabling to control the culture conditions and to preserve the quality of the embryos during their development. In this study we completed an industry standard mouse embryo assay (MEA) to exclude potential toxic effects of PDMS. PMID- 30441348 TI - Active, artificial hair cells for biomimetic sound detection based on active cantilever technology. AB - We aim at building and studying artificial hair cells (AHC) based on MEMS technology to understand the extraordinary sound perception of the human ear and build a sensor system with similar properties. These perception properties, i.e. detecting six orders of sound pressure level and simultaneously frequency differences of only 3-5 Hz, are obtained mainly due to the sophisticated biological sensors in the inner ear, called hair cells, which convert the acoustic waves into electric signals. They amplify weak inputs and compress larger ones, known as compressive nonlinearity, thus enabling this impressive dynamic range, typically not captured by current engineering solutions. We tackle this demand by building artificial hair cells on the basis of smart, self actuated and self-sensing mechanical resonator beams with suitable actuation feedback. Thereby, we take advantage of the fact that the compressive nonlinearity arises naturally in dynamical systems tuned to a bifurcation point. This tuning is achieved by an appropriate feedback loop inspired by physiological models. Initial results on the detection properties of a single AHC will be shown demonstrating amplification and a decreased width of the resonance peak. PMID- 30441349 TI - Single Locked Nucleic Acid-enhanced nanopore genetic discrimination of pathogenic serotypes and cancer driver mutations. AB - Rapid and accurate detection of single-nucleotide polymorphism (SNP) in pathogenic mutants is crucial for broad fields from food safety monitoring to disease diagnostics and prognosis. Here, we developed a nanopore single-molecule sensor, coupled with the locked nucleic acid (LNA) technique, to accurately discriminate SNPs for detection of Shiga toxin producing Escherichia coli (STEC) O157:H7 pathogen serotype, and cancer-derived driver mutations EGFR L858R and KRAS G12D. This sensitive method, with a simplified, low cost, easy-to-operate LNA design, can be applied in food science and medical detection that need rapid and accurate determination of genetic variations. PMID- 30441350 TI - Automatic Planar Asymmetric Lipid Bilayer Membrane Formation toward Biological High-Throughput Assay. AB - This paper describes automation of planar lipid bilayer formation by introducing a stepping motor to a microfluidic device. Planar lipid bilayers or lipid vesicles are useful to understand biological reactions and to investigate the interaction between lipids and proteins. Therefore, to acquire large amount of the information, high-throughput production of planar lipid bilayers or giant vesicles (GVs) is necessary. The droplet split-and-contact method, which enhances the efficiencies of both planar lipid bilayer formation and GV generation, needs to be automated for increasing the throughput. Previous droplet split-and-contact devices were manipulated manually; hence, the influence of manipulation on planar lipid bilayer formation was not evaluated quantitatively. First, to develop an automated system for generating asymmetric planar lipid bilayers, a stepping motor, which allows to control the angular speed of the rotor, is integrated into the droplet split- and-contact device (Fig. $1(?mathrm{b)$). Next, we assessed planar lipid bilayer generation at various angular speeds and found the speed limit for bilayer formation. Finally, we generated asymmetric planar lipid bilayers that have different lipid composition on outer and inner leaflets using this automated device and confirmed the asymmetry of the planar lipid bilayers by generating GVs. PMID- 30441351 TI - Computational Platform Based on Deep Learning for Segmenting Ventricular Endocardium in Long-axis Cardiac MR Imaging. AB - This paper presents an automated computational platform based on deep learning (DL) approach for left ventricular (LV) and right ventricular (RV) endocardium segmentation in long-axis cine cardiovascular magnetic resonance (CMR). The proposed method uses modified deep U-Net convolutional networks. We trained our model using 4800 images from 40 human subjects (20 healthy volunteers, 20 patients with various cardiac diseases) and validated the technique in 6000 images from 50 subjects (10 healthy volunteers, 40 patients). An average Dice metric of 0.929 +/- 0.036 along with an average Jaccard index of 0.869 +/- 0.059 were achieved for all the studied subjects. In addition, a high level of correlation and agreement with the ground truth contours for LV ejection fraction (R=0.975), LV fractional area change (R=0.959 to 0.971), and RV fractional area change (R=0.927) were observed. The proposed DL-based segmentation process took less than 3 seconds per subject (or < 30 milliseconds per image over 120 images for each subject). Therefore, our proposed framework offers a promising means to achieve fully automated and rapid segmentation for both LV and RV endocardium in long-axis cine CMR images using an appropriately trained deep convolutional neural network. PMID- 30441352 TI - Cardiac Image Segmentation Using Memory Persistence Methodology. AB - This paper presents a novel computer-aided framework for cardiac image segmentation using a methodology based on memory persistence. The primary concept is to mimic the process of human cognition in the segmentation of time-varying images (i.e., 2D + time or 3D + time), by remembering and exploiting results of previously segmented frames, to aid in segmentation of the region of interest with poor or ambiguous boundaries. The framework involves an intelligent image segmentation process which incorporates an automatic contour initialization mechanism, and a segmentation refinement mechanism that iteratively improves the segmentation results. The proposed framework is general and can integrate most existing image segmentation algorithms in the literature. The experimental results show the benefits of the proposed framework achieving insensitivity to contour initialization, high automation and better segmentation accuracy as compared to the original algorithm and its standard temporal constraint version. PMID- 30441353 TI - Hemodynamic Evaluation of an Intra-Atrial Blood Pump on a Pulsatile Mock Circulatory Loop. AB - An intra-atrial pump (IAP) was proposed that would be affixed to the atrial septum to support the compromised left ventricle (LV) without harming the ventricular tissue in patients with early-stage heart failure. The IAP is designed to operate in parallel with the LV, drawing blood from the left atrium and unloading the LV. In previous hydraulic studies, different blade geometries were tested for the IAP; however, it is important to know how the blade geometry affects the IAP's hemodynamic performance in the human cardiovascular system. In this study, a mock circulatory loop (MCL) with physiological response was used to evaluate the hemodynamic effects of IAP blade geometry and connection configuration in the human cardiovascular system. In a $2 ?times 2$ study, two different blade geometries (with steep vs flat pressure/flow curves) were tested in two different connection configurations: the proposed configuration (left atrium to aorta) and the conventional configuration for LVADs (LV to aorta). We found that atrial cannulation is feasible and creates a beneficial hemodynamic environment, although it is inferior to the one created by ventricular cannulation. The steepgradient pump performed better than the flat-gradient pump in atrial insertion. PMID- 30441354 TI - In Vivo Hemodynamic Evaluation of CH-VAD in a Bovine Model for 14 Days. AB - The CH-VAD is a centrifugal-flow magnetically levitated (maglev) left ventricular assist device (LVAD) used to treat end-stage heart failure. It is implanted in the chest cavity; the inflow cannula is inserted into the apex of the left ventricle, and the outflow graft is anastomosed to the aorta. Among several key VAD system improvements, the CH-VAD has a smaller body size than other LVADs and its maglev system offers a large-gap design that makes it superior in terms of hemocompatibility. In this study, we implanted the CH-VAD in a calf and evaluated the hemodynamic and hemocompatibility characteristics over a 14-day period. The hemodynamic parameters, the pump data, and blood test results were recorded throughout the study. The results showed that the CH-VAD provided hemodynamic stability. Hemocompatibility testing indicated negligible hemolysis throughout the study, and no signs of infection were seen. On necropsy, the results showed only expected focal mild-to-moderate adhesions between the pericardial sac (along the pump) and the adjacent rib cage, and between the pericardial sac and the heart. Gross examination of internal organs was unremarkable. Examination of the CH-VAD after explantation revealed no evidence of thrombus formation internally or around the inflow or outflow cannulas. PMID- 30441355 TI - Development of an Intelligent Ventricular Assist Device with a Function of Sensorless Thrombus Detection. AB - Thrombus is one of the major problems in ventricular assist devices (VADs). However, method for detecting thrombus in early stage has not been established yet. In this study, we propose an intelligent function that the VAD itself can detect thrombus automatically and alert it to medical staffs. In the proposed method, thrombus formation inside a blood pump is detected by monitoring blood viscosity. This viscosity measurement is performed by using magnetic levitation system for the impeller. Hence, it can be implemented without any additional sensors or mechanisms in principle. For verification of the method, at first, we visualized inside of the pump during thrombus formation with measuring blood viscosity by using erythrocytes removed porcine blood. The result showed that the viscosity of the blood increased as blood coagulation progressed. Then, we conducted in vitro principle verification experiments with three different whole porcine blood. In all experiments, the measured blood viscosity increased and small thrombus was observed inside the pump. From these results, we confirmed that the proposed method has a possibility to detect and predict the thrombus in early stage. PMID- 30441356 TI - In Vivo Feasibility Study of an Intra-Atrial Blood Pump for Partial Support of the Left Ventricle. AB - We are designing an intra-atrial pump (IAP) that will be affixed to the atrial septum and support the compromised left ventricle (LV) in patients with early stage heart failure without harming the ventricular tissue. It will operate in parallel with the LV, drawing blood from the left atrium and unloading the LV. In previous hydraulic and hemodynamic studies, different blade geometries were tested for the IAP, and the hemodynamic results obtained using a mock circulatory loop showed that the IAP can successfully reduce end-diastolic volume and increase the total systemic flow rate. In the current study, we used a bovine model to validate the in vitro hemodynamic results and better understand how the IAP interacts with the cardiovascular system in vivo. Because this was the first study assessing the complete device in a living system, it was also necessary to determine the best manufacturing techniques and ideal sensor placements. In the bovine model, we were able to successfully implant the IAP across the atrial septum with the outflow graft connected to a peripheral artery. The implanted IAP was capable of providing partial support (1-3 L/min) in vivo. These results indicate that atrial cannulation is feasible and creates a beneficial hemodynamic environment. PMID- 30441357 TI - Developing a Computational Model of Renal Nerves and Surgical System for Laparoscopic Renal Denervation. AB - The sympathetic nervous system was known to play an important role in resistant hypertension. Surgical sympathectomy for renal sympathetic nerve removal were performed since the 1930s. Although effective, it had many serious side effects and complications due to non-selective property. Recently, catheter based RDN system using radiofrequency (RF) ablation was developed and considered promising, however, it failed in sham controlled trial. Therefore, there are needs for safe and effective RDN strategies considering the anatomical structure of the renal arteries and sympathetic nerves. In this paper, we propose a novel surgical instruments for laparoscopic renal denervation (RDN) to treat of resistant hypertension through a 3D realistic model using nephrectomy tissues. Laparoscopic RDN is a new surgical approach to remove renal sympathetic nerves. PMID- 30441358 TI - InSilc: 3D Reconstruction and plaque characterization tool. AB - Coronary artery disease (CAD) is the leading cause of mortality in Europe and worldwide. Atherosclerosis is the most common pathologic process that is highly related with CAD, while the implantation of drug-eluting Bioresorbable Vascular Scaffolds (BVS) is the most promising procedure for treating patients with CAD. InSilc is an textbfin silico clinical trial (ISCT) platform for the development and assessment of drugeluting BVS. The InSilc platform provides insight in the performance of drug-eluting BVS in their short term and medium/long term through the Mechanical Modelling Module, the Deployment Module, the Fluid Dynamics Module, the Myocardial Perfusion Module, the Drug-delivery Module and the Degradation Module. In order for the aforementioned modules to be developed, the utilization of the reconstructed patient specific arterial segment and the BVS design are required, which is achieved through the 3D reconstruction and plaque characterization tool.In this study, the overall architecture of the InSilc platform is presented with special emphasis on the 3D reconstruction and plaque characterization tool. The tool will be able to implement different medical image processing workflows. The workflows will require minimum user intervention in order to be used in large scale clinical trials. PMID- 30441359 TI - Modeling Cardiac Hemodynamic Response During Exercise in Health and Hypertrophic Cardiomyopathy. AB - INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is associated with altered hemodynamics in the left ventricular outflow tract and tissue abnormalities. Exercise testing has become an integral and powerful tool for the noninvasive evaluation of HCM and, in some patients, it could define a treatment strategy. Obiective: To model the hemodynamic alterations during exercise in healthy and HCM patients, obtained by noninvasive methods. METHODS: Cardiac output (CO), heart rate (HR), arterial blood pressure (ABP) and Total Peripheral Resistance (TPR) were assessed during exercise. The evaluation included a curve-fitting approach (sigmoidal model) that allowed a quantitative comparison of CO profiles. RESULTS: When compared to controls, patients with HCM showed reduced peak exercise cardiac output and demonstrated high peripheral resistance during exercise. Analysis of modeled it CO curves revealed a higher maximum rate of recovery in healthy individuals than in HCM patients. CONCLUSION: The application of the sigmoidal model showed to be efficient in the characterization of CO dynamics for the different studied groups. PMID- 30441360 TI - A Stochastic and Mathematically Integrative Model of the Gender Modulation of Cardiorespiratory Activity. AB - Breath-to-breath interval (BBI) and heartbeat-toheartbeat interval (RRI) variability intrinsically contain a combination of random and temporally scaled characteristics. The objective of this study was to design and test a stochastic and mathematically integrative model (SIM) of cardiorespiratory function that could replicate any genderbased differences in breathing or heartrate variability during a calm, resting state. BBI and RRI sequences were recorded from 12 healthy subjects. Inter-breath and inter-beat memory were estimated with an autocorrelation function, and discrete probability density functions were created by fitting polynomial curves to the normalized histograms of each sequence. The SIM generated an artificial BBI or RRI sequence by constructing a random series of interval values selected from a discrete PDF, and then integrating the series with parameters from the autocorrelation analysis. Fractal scaling was quantified with detrended fluctuation analysis. A significant gender difference was identified in the autocorrelation coefficients of the BBI. The SIM produced artificial BBI and RRI sequences with significant fractal scaling as compared to randomly-shuffled surrogate data (p < 0.001), and with fractal-scaling characteristics similar to the original human data. The SIMgenerated BBI sequences also exhibited the same significant gender-based differences as identified in the human data (p < 0.01). In conclusion, this research demonstrated a stochastic and integrative model that replicated the gender-based differences in fractal scaling in resting human breathing patterns. PMID- 30441361 TI - A Preliminary Computational Model for Hypoxic Acidosis in Cardiac Myocytes. AB - Intracellular acidosis induced by hypoxia resulted from myocardial ischemia damages myocardium. However, the detailed mechanisms of hypoxic acidosis are not quantitatively explained. The purpose of this study is to create a novel computational model which can reproduce intracellular acidosis caused by myocardial ischemia. We constructed a computational model of myocardium, by using a mathematical ventricular cell model which includes pH regulation and a computational model of myocardial microcirculation for calculating extracellular conditions. The present model reproduced cellular hypoxia in an ischemic condition simulated by a reduced blood flow, and intracellular pH reduction in response to the hypoxia. PMID- 30441362 TI - Fluid-structure Interaction in the Cerebral Venous Transverse Sinus. AB - The biomechanics of the cerebral venous system plays an important role in determining blood flow to the brain. Computational approaches to help elucidate the role of the cerebral venous system in health and disease have largely focused on lumped-parameter models and one-dimensional computational fluid dynamics simulations. To expand upon the prior work, and to investigate the possible role of cerebral venous collapse in normal physiology and pathological conditions, we developed a fluid-structure interaction (FSI) model of the cerebral venous transverse sinus (TS), coupled to a lumpedparameter representation of the upstream cerebral circulation to provide boundary conditions for the FSI simulation. We simulated the effects of local venous hemodynamics on the TS distention and investigated TS vascular collapse under increased intracranial pressure, as has been hypothesized in the pathogenesis of idiopathic intracranial hypertension. Our baseline simulations reproduced pressures and flows in the cerebral venous system that compared favorably with what has been reported in the literature. The FSI simulations under increased intracranial pressure showed a decreased venous flow through and progressive collapse of the TS veins. Our simulations captured the dynamic behavior of the vascular collapse and may help shed light on the interactions between the cerebrovascular and cerebrospinal fluid spaces in health and disease. PMID- 30441363 TI - In Vitro Hemodynamic Evaluation of Right Ventricle-Pulmonary Artery Continuity Reconstruction Through a Trileaflet Expanded Polytetrafluoroethylene Valved Conduit. AB - Percutaneous pulmonary valve implantation is a technique to treat narrowed pulmonary valves or leaky pulmonary valves in congenital heart disease. This technique provides a promising strategy to reduce surgical risk. In clinical cases, due to stent size restrictions, commercial valve stents are sometimes unsuitable for children or certain patients. Hence, handmade pulmonary valved conduits prove useful because a customized size can be obtained for valve replacement. We propose a meta-learning-based intelligent model to train an estimator (including two sub-estimators) to determine optimal trileaflet parameters for customized trileaflet valve reconstruction. The purpose of this study was to investigate the hemodynamic and functional consequences of the novel design by employing a mock circulation system. We recorded the diastolic valve leakage and calculated the pulmonary regurgitation, regurgitation fraction, and ejection efficiency in a pulsatile setting. The prosthetic leaflet behavior was assessed using an endoscope camera and the pressure drops through valves were measured. All the in vitro parameters indicated that the expanded polytetrafluoroethylene (ePTFE) valved conduits were not inferior to commercial mechanical or tissue valve conduits and could decrease the regurgitation volume and increase the efficiency. Compatible early clinical outcomes were also identified between ePTFE valved conduits and other valved conduits used for right ventricular outflow tract reconstruction. The ePTFE valved conduits could be implanted in relatively small patients. An in vitro experimental study provided evidence that a handmade ePTFE valved conduit could be an attractive alternative to other commercialized valved conduits used for right ventricle-pulmonary artery continuity reconstruction. PMID- 30441364 TI - A Fully Discrete Open Source Framework for the Simulation of Vascular Remodelling. AB - In this paper we present a novel computational framework for the theoretical study of the interaction between haemodynamics and vessel biology, with particular applications to the study of vascular remodelling. We introduce the mathematical formulation, validate the numerical method against an analytical solution derived for a simplified case, and present a case study of tissue remodelling in response to flow. PMID- 30441365 TI - A Clinical Decision Support Platform for the Risk Stratification, Diagnosis, and Prediction of Coronary Artery Disease Evolution. AB - SMARTool aims to perform accurate risk stratification of coronary artery disease patients as well as to provide early diagnosis and prediction of disease progression. This is achieved by the acquisition of data from about 263 patients including computed tomography angiographic images, clinical, molecular, biohumoral, exposome, inflammatory and omics data. Data are collected in two time points with a followup period of approximately 5 years. In the first step, data mining techniques are implemented for the estimation of risk stratification. In the next step, patients, who are classified as medium to high risk are considered for coronary imaging and computational modelling of blood flow, plaque growth and stenosis severity assessment. Additionally, patients with increased stenosis are selected for stent deployment. All the above modules are integrated in a cloud based platform for the clinical decision support (CDSS) of patients with coronary artery disease. The work presents preliminary results employing the SMARTool dataset as well as the concept and architecture of the under development platform. PMID- 30441366 TI - Local Evaluation of Variation in Pulse Wave Velocity over the Cardiac Cycle using Single-Element Ultrasound Transducer. AB - A method and system for single-site measurement of local pulse wave velocity (PWV) and its variation over the cardiac cycle are presented. The proposed system employs a single-element ultrasound transducer and associated custom technology to record arterial diameter and wall thickness waveforms in real-time. Simultaneously acquired blood pressure, diameter and wall thickness parameters were used to evaluate diastolic local PWV (CD) and systolic local PWV (Cs) from an arterial site of interest. The developed prototype system was validated on a cohort of 15 subjects (age $=43?pm 12$ years) that includes normotensives and hypertensives. Cs and CD measurements were obtained from the left carotid artery. A significant difference between carotid Cs and CD $(?Delta ?mathrm{C})$ was observed in all recruited subjects (group average $?Delta ?mathrm{C} = 0.92?pm 0.76?mathrm{m}/?mathrm{s})$, illustrating the arterial pressure dependency of local PWV. The absolute values of Cs and CD were within a range of 3.39 m/s to 7.5 m/s and 3.12 m/s to 5.82 m/s respectively. Normotensive versus hypertensive group-wise analysis was performed to investigate the degree of variation in the carotid local PWV over a cardiac cycle among different BP categories. Study results demonstrated that the proposed approach has a potential to provide valuable surrogate markers for cardiovascular risk assessment. PMID- 30441367 TI - Flow Mediated Dilation in Cirrhosis: A Pilot Study in Different Stages of the Disease. AB - INTRODUCTION: Cirrhosis is associated with changes in the cardiovascular system, where the circulatory dysfunction is compensated by the development of a hyperdynamic circulation. Endothelial function can be understood as the endothelium capability to release Nitric Oxide (NO) where an impairment in the normal development of this process constitutes a main step in the genesis and progression of atherosclerosis, a major cause of cardiovascular events. In recent years, non-invasive measurements have gained attention, due to the potential complications associated to invasive procedures. OBJECTIVE: To evaluate endothelial function (EF) in patients with cirrhosis, in different stages of the disease, complemented with hemodynamic measurements. METHODS: Individuals were divided in three age groups, according to the severity of their disease. EF was assessed by using the flow mediated dilation technique (FMD), jointly with noninvasive determination of cardiac output (CO), total peripheral resistance (TPR) and arterial compliance (AC). RESULTS: TPR showed a decrease in advanced severity while AC had an increase. Particularly, EF was found to be higher in CHC group, decreasing in CHB and more pronounceably in CHA. Concomitantly, an inverse behavior was observed regarding CO evolution. CONCLUSION: EF was noninvasively evaluated in cirrhosis, in terms of the progression of the disease. Hyperdynamic states in the more advanced condition were accompanied by a higher vascular reactivity, probably associated with higher peripheral NO release and increased AC. PMID- 30441368 TI - In Silico analysis of stent deployment- effect of stent design. AB - Coronary artery disease (CAD) remains the leading cause of death in Europe and worldwide. One of the most common pathologic processes involved in CAD is atherosclerosis. Coronary stents are expandable scaffolds that are used to widen the occluded arteries and enable the blood flow restoration. To achieve an adequate delivery and placement of coronary stents different parameters play a significant role. Due to the strain that the stents are exposed to and the forces they should withstand, the stent design is dominant. This study focuses on investigating the effect of the stent design in two finite element models using two stents with difference in the strut thickness. The in silico deployment is performed in a reconstructed patient specific arterial segment. The results are analyzed in terms of stress in the stent and the arterial wall and demonstrate how stent expansion is extensively affected by the scaffold's design. PMID- 30441369 TI - Carotid Local Pulse Wave Velocity Measurement using Dual- Element Accelerometric Patch Probe. AB - In this work, we demonstrate an accelerometric patch probe with two microelectromechanical accelerometer sensors for local pulse wave velocity (PWV) measurement from the carotid artery. Dual acceleration plethysmogram (APG) signals were acquired from a small section of the artery by keeping the sensors at 32 mm apart. A custom analog front-end circuit (inter-channel delay $< 0.15$ ms) was used for reliable signal acquisition. Simultaneously acquired dual APG signals were processed in real-time and local PWV was evaluated in a beat-by-beat manner. A transversal study on a cohort of 15 volunteers (4 males, 11 females, mean age = $25.6 ?pm 1.92$ years) was conducted to validate the developed prototype system. During the study, carotid local PWV and brachial blood pressure (BP) parameters were recorded from both sitting and standing posture. The absolute values of measured carotid local PWV were in the range of 3 m/s - 4.2 m/s (beat-to-beat variation $=$ 2.61% - 13.07%). Measured local PWV values significantly correlated with brachial systolic BP ($?textbf{R}^{?mathbf {2}} =$ 0.87) and diastolic BP ($?textbf{R}_{?mathbf {?, }}^{?mathbf {2}} ?quad =$ 0.79). Logarithmic functions provided the best monotonic model for carotid local PWV versus brachial BP parameters for the recorded data points. The developed population-specific mathematical models were then used for cuffless evaluation of BP parameters from carotid local PWV. The root-mean-square error in the estimated systolic and diastolic pressure was 7.53 mmHg and 6.0 mmHg respectively. Study results illustrate the potential application of the developed dual-accelerometric system in non-invasive, continuous cuffless BP measurement techniques. PMID- 30441370 TI - An In-Vivo Study on Intra-Day Variations in Vascular Stiffness using ARTSENS Pen. AB - This work presents investigations on intraday variations in arterial stiffness. For this purpose, an in-vivo study was conducted on five subjects over a duration of five consecutive days. Five stiffness index ($?beta $) measurements were obtained per day for each individual. Our clinically validated ARTSENS device was used to perform fully automated reliable stiffness measurements on the carotid artery. For each measurement, two trials were performed and averaged. These trials were observed to be repeatable with the coefficient of variation $< 0.72$%. For each day, one measurement that was performed immediately after the lunch was subject to intervention due to the consumed food, which significantly $( ?mathrm {p}< 0.001)$ deviated from the mean baseline $?beta $ of the day. Such significant deviations were not observed for the rest measurements that were performed in the absence of an intervention. Two subjects who consumed caffeinated beverages during the lunch exhibited an increment in $?beta $ measurement (taken immediately after lunch) as compared to mean baseline $?beta $ of the day. Further, there was no significant (p $=$ 0.97) difference between the mean baseline $?beta $ measured over a day and the mean baseline $?beta $ measured over the entire course of the study. Results obtained from the present study demonstrated that the arterial stiffness does not vary significantly over a short period but varies progressively. However, significant temporary variations in stiffness could be observed due to dietary interventions. PMID- 30441371 TI - Flexible MRI Compatible Brain Probes. AB - The exact localization of signal recording probes or deep stimulation probes by magnetic resonance imaging (MRI) has significant importance in studying and understanding how the brain functions. But the magnetic susceptibility of the probes itself distorts the MRI image and creates error in position measurement. In this paper we propose an MRI compatible flexible probe with magnetic susceptibility that is well matched with the brain tissue. The well-matched magnetic susceptibility of the probe enables high resolution structural and functional MRI even at ultra-high Bfield strengths. The MRI images shows almost zero artifacts around the implanted probe in the phantom tissue. PMID- 30441372 TI - Electrophysiological Detection of Cortical Neurons under Gamma-Aminobutyric Acid and Glutamate Modulation Based on Implantable Microelectrode Array Combined with Microinjection. AB - Understanding the relationships between different cortical neurons under excitatory or inhibitory modulation is important for researches of many neurological disorders. In order to monitor the neural activities in cortex under gamma-aminobutyric acid (GABA) and glutamate (Glu) modulation, an implantable microelectrode array (MEA) was combined with microinjection capillary. The neurons in motor cortex of rat were modulated by GABA and Glu injection, and multichannel neural electrophysiological signals were simultaneously recorded. Spike analysis showed that the interneurons recorded by the MEA were inhibited after GABA injection and excited after Glu injection, but one pyramidal neuron was found to be not sensitive to the drug. The local field potentials (LFP) were most affected in the frequency band of 5~10 Hz after Glu injection, which greatly increased the amplitudes of the spindle-like waveforms. The MEA combined with microinjection provided a low-cost and effective tool for neurological drug modulation and evaluation in brain tissue. PMID- 30441373 TI - Micro-folded 3D neural electrodes fully integrated in polyimide. AB - Recent neural interfaces are characterized by high functionality and good adaptation to the target tissue. Still, the underlying manufacturing process is mainly planar and so are the device and contact surface. Therefore, three dimensional structures to contact neuronal tissue are desired to gain higher selectivity. In the present study, local bending structures integrated in flexible electrode arrays based on polyimide are investigated. The bending is achieved by the contraction of a second polyimide (Durimide) that is embedded into grooves with a width of a few micrometers. The angle of the bending can be controlled with a high accuracy from 3 to 20 degrees by changing the geometry of the grooves and the imidization temperature These bending structures can be combined to achieve any desired angle for specific applications. PMID- 30441374 TI - 3D Printed Cranial Window System for Chronic MUECoG Recording. AB - Chronic studies of flexible MUECoG electrodes and the electrode-brain interface have been limited by the inability to assess tissue response over time. The electrophysiological system presented here combines epidural microelectrocorticographic (MUECoG) recording capabilities with the ability to visualize tissue response over time through light microscopy and optical coherence tomography (OCT). With the ability to interchange both the electrode and the electronics, and a flushing port for injection of flushing saline and/or drugs, this 3D printed system has future applications in chronic electrophysiology, optogenetics, and advanced imaging methods. PMID- 30441375 TI - Implantable Glass Waveguides and Coating Materials for Chronic Optical Medical Applications. AB - An innovative fabrication process of glass waveguides on silicon substrates for miniaturized implants is presented. Thin glass was bonded on oxidized silicon wafers and patterned using wet etching. Multimode waveguides with different shapes and a low surface roughness as well as low scattering of light were successfully fabricated. For efficient coupling of light and accurate alignment, KOH-grooves were etched in the silicon with respect to the glass waveguides to attach optical fibers from external light sources. Towards higher biostability, several coating materials were evaluated in accelerated in vitro tests in 60 degrees C PBS for the first time over a long period of time regarding their optical properties. Ti02, SiC, polyimide, Parylene C and SU-8 showed a very stable optical transmittance after 320 days in accelerated aging while PECVDSi3N4 showed significant changes within the first days. PMID- 30441377 TI - Graph-based Dimensionality Reduction of EEG Signals via Functional Clustering and Total Variation Measure for BCI Systems. AB - In this paper, we propose a novel and intuitively pleasing graph-based spatio temporal feature extraction framework for classification of motor imagery tasks from elec- troencephalography (EEG) signals for brain-computer interface systems (BCIs). In particular, to account for the observation that measurements obtained from the EEG channels form a non-uniformly distributed sensor field, a representation graph is constructed using geographical distances between sensors to form connectivity neighborhoods. By capitalizing on the fact that functionality of different connectivity neighborhoods varies based on the intensity of the performed activity and concentration level of the subject, we formed an initial func- tional clustering of EEG electrodes by designing a separate adjacency matrix for each identified functional cluster. Using a collapsing methodology based on total variation measures on graphs, the overall model will eventually be reduced (collapsed) into two functional clusters. The proposed framework offers two main superiorities over its state-of-the-art counterparts: (i) First, the resulting dimensionality reduction is subject adaptive and respects the brain plasticity of subjects, and; (ii) Second, the proposed methodology identifies active regions of the brain during the motor imagery task, which can be used to re-align EEG electrodes to improve accuracy during consecutive data collection sessions. The experimental results based on Dataset IVa from BCI Competition III show that the proposed method can provide higher classification accuracy as compared to the other existing methods. PMID- 30441376 TI - Application of Parylene-Based Flexible Multi-Electrode Array for Recording From Subcortical Brain Regions From Behaving Rats. AB - Obtaining multiple single-unit recordings in particular neural networks from behaving animals is crucial for the understanding of cognitive functions of the brain. Attaining stable, chronic recordings from the brain is also the foundation to develop effective cortical prosthetic devices. However, severe immune response caused by micromotion between stiff implants and surrounding brain tissue often limits the lifetime of penetrating, neural recording devices. To reduce the stiffness mismatch between recording devices and brain tissue, we developed a flexible, polymer based multi-electrode array for recording single neuron activities from the rat hippocampus, a major subcortical structure of the rat brain. Parylene C, a biocompatible polymer, was used as the structural and insulation material of the multi-electrode array. 64 platinum (Pt) recording electrodes were placed in groups along each shank to conform to the anatomical distribution of hippocampal principle neurons. The multi-electrode array was chronically implanted in three animals. After recovery, neural activity together with movement traces were collected from the behaving animals. PMID- 30441378 TI - Multiscale Decomposition of Cardiovascular and Cardiorespiratory Information Transfer under General Anesthesia. AB - The analysis of short-term cardiovascular and cardiorespiratory regulation during altered conscious states, such as those induced by anesthesia, requires to employ time series analysis methods able to deal with the multivariate and multiscale nature of the observed dynamics. To meet this requirement, the present study exploits the extension to multiscale analysis of recently proposed information decomposition methods which allow to quantify, from short realizations, the amounts of joint, unique, redundant and synergistic information transferred within multivariate time series. These methods were applied to the spontaneous variability of heart period (HP), systolic arterial pressure (SAP) and respiration (RESP) in patients undergoing coronary artery bypass graft monitored before and after the induction of general anesthesia. We found that, after anesthesia induction, information is processed within the cardiovascular network in a scale-dependent way: at short time scales, a shift from synergistic to redundant information transferred from SAP and RESP to HP occurs, which is associated with enhanced baroreflex-mediated respiratory effects on arterial pressure; at longer time scales, the increased information transfer from SAP to HP denotes an enhancement of the baroreflex coupling related to slow cardiovascular oscillations. PMID- 30441379 TI - A new Modelling Framework to Study Time-Varying Directional Brain-Heart Interactions: Preliminary Evaluations and Perspectives. AB - We propose a novel modelling framework to study non-stationary, directional brain heart interplay in a time varying fashion. Considering electroencephalographic (EEG) signals and Heart Rate Variability (HRV) series as inputs, a new multivariate formulation is derived from proper coupling functions linking cortical electrical activity and heartbeat dynamics generation models. These neural-autonomic coupling rules are formalised according to the current knowledge on the central autonomic network and fully parametrised in adaptive coefficients quantifying the information outflow from-brain-to- heart as well as from-heart-to brain. Such coefficients can be effectively estimated by solving the model inverse problem, and profitably exploited for a novel assessment of brain-heart interactions. Here we show preliminary experimental results gathered from 27 healthy volunteers undergoing significant sympatho-vagal perturbations through cold-pressor test and discuss prospective uses of this novel methodological frame work. Specifically, we highlight how the directional brain-heart coupling significantly increases during prolonged baroreflex elicitation with specific time delays and throughout specific brain areas, especially including fronto parietal regions and lateralisation mechanisms in the temporal cortices. PMID- 30441380 TI - Exploration of Web-Sites Affects Autonomic Responses Related to Unconscious Emotions. AB - In this work we are interested in analyzing any correlations between physiological parameters, extracted from signals such as Electrocardiogram, respiratory signal and Skin Conductance, and self-reported indices related to emotional or cognitive stimulations. For this purpose, an experiment involving twenty participants with a mean age of 25+/-5 years of both sexes (13 males and 7 females) was carried out. The protocol included the navigation in simulated web sites and the vision of two different commercial products (utilitarian and hedonistic). At the end of the navigation, a questionnaire was submitted to the subject in order to measure his/her feelings and emotions in a qualitative and subjective way. Quantitative features were extracted from the physiological signals recorded during the execution of the protocol. We performed a correlation analysis between self-reported and physiological responses related to Arousal, Pleasure, Expectancy and Situational Involvement. Findings showed that when a consumer is exposed to a utilitarian product, the physiological emotional responses are disassociated from the self-reported ones. For the hedonistic product, instead, self-reported measures significantly correlate with physiological arousal features like the combined effect of cardiac and respiratory activity and the Heart Rate. PMID- 30441381 TI - Human-Machine Interaction Assessment by Neurophysiological Measures: A Study on Professional Air Traffic Controllers. AB - This study aims at investigating the possibility to employ neurophysiological measures to assess the humanmachine interaction effectiveness. Such a measure can be used to compare new technologies or solutions, with the final purpose to enhance operator's experience and increase safety. In the present work, two different interaction modalities (Normal and Augmented) related to Air Traffic Management field have been compared, by involving 10 professional air traffic controllers in a control tower simulated environment. Experimental task consisted in locating aircrafts in different airspace positions by using the sense of hearing. In one modality (i.e. "Normal"), all the sound sources (aircrafts) had the same amplification factor. In the "Augmented" modality, the amplification factor of the sound sources located along the participant head sagittal axis was increased, while the intensity of sound sources located outside this axis decreased. In other words, when the user oriented his head toward the aircraft position, the related sound was amplified. Performance data, subjective questionnaires (i.e. NASA-TLX) and neurophysiological measures (i.e. EEG-based) related to the experienced workload have been collected. Results showed higher significant performance achieved by the users during the "Augmented" modality with respect to the "Normal" one, supported by a significant decreasing in experienced workload, evaluated by using EEG-based index. In addition, Performance and EEG-based workload index showed a significant negative correlation. On the contrary, subjective workload analysis did not show any significant trend. This result is a demonstration of the higher effectiveness of neurophysiological measures with respect to subjective ones for Human-Computer Interaction assessment. PMID- 30441382 TI - A Framework for Physiological Response Prediction with Joint Activity State optimization. AB - Physiological responses are essential for health monitoring. However, modeling the complex interactions be- tween them across activity and environmental factors can be challenging. In this paper, we introduce a framework that identifies the state of an individual based on their activity, trains predictive models for their physiological response within these states, and jointly optimizes for the states and the models. We apply this framework to respiratory rate prediction based on heart rate and physical activity, and test it on a dataset of 9 individuals performing various activities of daily life. PMID- 30441383 TI - Discriminating ADHD From Healthy Controls Using a Novel Feature Selection Method Based on Relative Importance and Ensemble Learning. AB - Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder that often persists into adulthood, resulting in adverse effects on work performance and social function. The current diagnosis of ADHD primarily depends on the judgment of clinical symptoms, which highlights the need for objective imaging biomarkers. In this study, we aim to classify ADHD (both children and adults [34/112]) from age-matched healthy controls (HCs [28/77]) with functional connectivity (FCs) pattern derived from resting-state functional magnetic resonance imaging (rs-fMRI) data. However, the neuroimaging classification of brain disorders often meets a situation of high dimensional features were presented with limited sample size. Thus an efficient method that is able to reduce original feature dimension into a much more refined subspace is highly desired. Here we proposed a novel Feature Selection method based on Relative Importance and Ensemble Learning (FS_RIEL). Compared with traditional feature selection methods, FS_RIEL algorithm improved the ADHD classification by about 15% in both child and adult ADHD classification, achieving 80-86% accuracy. Moreover, we found the most frequently selected FCs were mainly involved in frontoparietal network, default network, salience network, basal ganglia network and cerebellum network in both child and adult ADHD cohorts, which indicates that ADHD is characterized by a widely-impaired brain connectivity profile that may serve as potential biomarkers for its early diagnosis. PMID- 30441384 TI - QRS Detection and Measurement Method of ECG Paper Based on Convolutional Neural Networks. AB - In this paper, we propose an end-to-end approach to addressing QRS complex detection and measurement of Electrocardiograph (ECG) paper using convolutional neural networks (CNNs). Unlike conventional detection solutions that convert images to digital data, our method can directly detect QRS complex in images using Faster-RCNN, then the R-peak can be located and measured through a CNN. Validated by clinical ECG data in the St.-Petersburg Institute of Cardiological Technics 12-lead Arrhythmia Database and real ECG paper from Peking University People's Hospital, the proposed method can achieve the recall of 98.32%, the precision of 99.01% in detecting and 0.012 mv of mean absolute error in measuring. Experimental results demonstrate the superior performance of our method over conventional solutions, which would pave the way to detect and measure ECG paper using CNNs. PMID- 30441385 TI - Toward Lung Tumor Localization based on Strain Variability of Lung Surface during Video-Assisted Thoracoscopic Surgery. AB - Tumor localization, especially in case of minimally invasive lung tumor resection surgery, is extremely challenging due to the continuous motion of the organ. This motion can be troublesome as it results in spatial discrepancy corresponding to preoperative and intraoperative tumor location. In order to characterize lung tissue stiffness for the purpose of lung tumor localization, in this paper, we present a novel characterization approach based on variability in resistance of the healthy region vs. the tumorous region resulting from lung motion. The proposed approach is numerically validated on a Finite Element (FE) model of the lung with varying surface stiffnesses, where higher stiffness represents tumor and lower stiffness corresponds to healthy lung tissue. The numerical simulation validates the sensitivity of our mechanism for different grades of tumors by demonstrating that the strain on the healthy tissue is 31.8 and 67.1 times higher than that on the tumor surface for a selected relative stiffness variation of 3.6x and 24.4x respectively, at a pressure of 1.6 KPa. Additionally, a framework is developed to validate the proposed approach in a video of a video-assisted thoracoscopic surgery (VATS), where multiple landmarks on the lung surface are tracked. This enables us to quantify the motion of points residing on healthy surface and tumorous surface. The motion data is further analyzed to study the relative surface strain, and it is shown that the proposed approach differentiates a tumor from healthy surface. PMID- 30441386 TI - Analysis of Cellular Feature Differences of Astrocytomas with Distinct Mutational Profiles Using Digitized Histopathology Images. AB - Cellular phenotypic features derived from histopathology images are the basis of pathologic diagnosis and are thought to be related to underlying molecular profiles. Due to overwhelming cell numbers and population heterogeneity, it remains challenging to quantitatively compute and compare features of cells with distinct molecular signatures. In this study, we propose a self-reliant and efficient analysis framework that supports quantitative analysis of cellular phenotypic difference across distinct molecular groups. To demonstrate efficacy, we quantitatively analyze astrocytomas that are molecularly characterized as either Isocitrate Dehydrogenase (IDH) mutant (MUT) or wildtype (WT) using imaging data from The Cancer Genome Atlas database. Representative cell instances that are phenotypically different between these two groups are retrieved after segmentation, feature computation, data pruning, dimensionality reduction, and unsupervised clustering. Our analysis is generic and can be applied to a wide set of cell-based biomedical research. PMID- 30441387 TI - Development of a contactless energy harvesting system driven by contraction of skeletal muscle for implantable medical devices. AB - We propose a contactless energy harvesting system driven by the contraction of an electrically-stimulated skeletal muscle to be used to supply electrical energy to implantable medical devices. In order to realize a durable generator, the one proposed here has a contactless clutch mechanism with parallel leaf springs, with which the generator can be driven without friction. In this system, the muscle connected to the parallel leaf spring is intentionally contracted by electrical stimulation. The generator can be driven not only in the contraction phase of the muscle, but also relaxation phase. The result an evaluation showed that the prototype could generate 26.1 $?mu ?mathrm{W}$ with an efficiency of 13.7%. Finally, we conducted an animal experiment using the gastrocnemius muscle of a toad with a weighing of200 g The generator was driven in the contraction phase generating 1.37 $?mu ?mathrm{W}$ of power from the energy supplied by the muscle. PMID- 30441388 TI - Sensitivity optimization of Printed Spiral Coil for Wireless Resistive Analog Passive (WRAP) Sensors using Genetic Algorithm. AB - Body-worn battery-less Wireless Resistive Analog Passive (WRAP) sensor can be unobtrusive while collecting physiological data continuously. Inductive connection between a pair of Printed Spiral Coils (PSC) eliminates the intrusive wires. Inductive connection of primary and secondary PSC enabled us to probe the body signals using the inductive link. The primary side voltage is modulated by the sensed body signal at the secondary PSC. The coil physical characteristics influence the sensitivity which is defined as observed voltage changes over the sensor variation. We have previously reported an iterative method to optimize the coil specifications for maximum sensitivity with constrained coil prof ile size by maximizing the power transfer efficiency from primary to secondary. In this study sensitivity is maximized by first, driving an analytical multivariable equation of circuit components and physical characteristics, and then using Genetic Algorithm (GA) to maximize it with considering the size and fabrication constraints. The results are compared to the other methods that shows a higher result in the range of 102 comparing to the best alternate methods (sqp). It helps us to detect smaller physiological signals in the noisy environment. PMID- 30441389 TI - Subcutaneous Solar Energy Harvesting for Self-Powered Wireless Implantable Sensor Systems. AB - This paper presents the study of subcutaneous solar energy harvesting for implantable sensor systems. The characteristics of a flexible solar panel under a 3 mm thick porcine skin are measured under different ambient light conditions. The output power of the solar panel when covered by the skin varies from tens of micro Watts to a few milli Watts depending on the light source. A low-power implantable sensor prototype is proposed to evaluate the performance of the subcutaneous solar energy harvester. It consists of a power management circuit, a temperature sensor and a Bluetooth low energy (BLE) module. The average working current of the prototype is $400 ?mu ?mathrm {A}$ (transient BLE transmission current is 8 mA), while its sleep current is only $7 ?mu ?mathrm {A}$. Experimental results show that the subcutaneous solar energy harvester illuminated by both sunlight and artificial light sources can power the implantable prototype. PMID- 30441390 TI - Blood-Separating Device Without Energy Source for Implantable Medical Devices. AB - Coagulation of blood inside the implanted medical device is quite a critical problem to limit the lifetime. In this paper, we propose a microfluidic blood separating device using curved and branched channels. It utilizes centrifugal force on curved flow and separates blood flow into blood cell rich and blood cell poor ones at the bifurcation. Though it cannot separate the plasma from blood cells completely, the blood with small concentrations of blood cells will have low coagulatibity and extend the lifetime of the implant medical device. The device does not require any external pumps or valves, i.e., the system does not need any power sources but the blood pressure. We conducted experiments with a titanium foil which contacted to human whole blood with different hematocrit values for 7 days. The device was experimentally characterized with respect to the channel design. The former experiments suggested that lower concentration of blood cells helps avoiding blood coagulations, and the latter showed that the separation by our device is mainly affected by the flow rate and channel curvature. PMID- 30441391 TI - A Novel Flexible Sensor for Muscle Shape Change Monitoring in Limb Motion Recognition. AB - Human limb movement intent recognition fundamentally provides the control mechanism for assistive devices such as exoskeleton and limb prosthesis. While different biopotential signals have been utilized for limb movement intent decoding, they seldom could account for spatial information associated with changes in muscle shape that could also be used to characterize the limb motor intent. Therefore, this study developed a novel nano gold stretchable-flexible sensor that captures spatial information associated with the muscle shape change signal (MSCS) during different muscle activation patterns. The novel sensor consists of 2-channels to acquire MSCS at a sampling rate of 125 Hz, corresponding to multiple classes of upper limb movements acquired across six able-bodied subjects. By utilizing the linear discriminant analysis algorithm on the acquired data with a single extracted feature, an overall average motion decoding accuracy of 90.9% was achieved. In addition, the waveform analysis results show that the novel sensor's recordings were less affected by external interferences, thus yielding high quality signals. This study is the first to utilize nano gold stretchable-flexible material for sensor fabrication in pattern recognition of upper limb movement intent, which may facilitate the development of effective assistive devices. PMID- 30441392 TI - Improving EEG Source Localization with a Novel Regularization: Spatiotemporal Graph Total Variation (STGTV) Method. AB - Electroencephalography (EEG) source Iocalization aims at reconstructing the current density on the brain cortex from scalp EEG recordings. It of ten starts with a generative model that maps brain activity to the EEG recording, and then solves the inverse problem. Previously proposed method graph fractional-order total variation (gFOTV) is based on spatial regularization, and was shown superior to some other existing spatial-regularized methods in simulation tests. However, the gFOTV addresses inverse problem for one time point at a time. The resultant estimated times series of brain activity is a simple concatenation of reconstructions independently performed at each time instance, and risks spurious temporal discontinuity due to overfitting noise in EEG recordings. In addition, the performance is subject to low signal-to-noise ratio (SNR) and small number of electrodes, which happens in realistic EEG recordings. To account for the generally continuous temporal variation in brain activity, but also allow for properly triggering abrupt changes, we propose a novel formulation that incorporates spatiotemporal regularization. Specifically, our method, called spatiotemporal graph total variation (STGTV) adopts graph fractional-order total variation (gFOTV) for spatial regularization and total variation (TV) for temporal regularization. The gFOTV encourages spatially smooth source distributions, and the temporal TV enhances temporal consistency in estimated activity maps. The introduction of implicit temporal coupling by temporal TV also helps with noise cancelation and enhances SNR. In a simulation study, the performance of the proposed method was compared against that from the gFOTV regularization alone. The results showed that the proposed STGTV method significantly improved gFOTV, with lower Iocalization errors and less spuriously discovered sources. PMID- 30441393 TI - A Comparison of Point and Complete Electrode Models in a Finite Difference Model of Invasive Electrode Measurements. AB - Invasive electrophysiological measurement of brain activity is commonly employed during epilepsy surgery to provide final validation of required resection regions. These data are critical to clinical decision making, but manual expert analysis of these data can be complicated by the need to relate individual electrode measurements to specific brain regions. To improve analysis of these data with source analysis, accurate bioelectric models are needed. Given the proximity of the measurement locations to the generating cortical sources, modeling of electrodetissue interactions is particularly important for invasive measurements. Here, we evaluate the effect of a finite difference complete electrode model on the accuracy of leadfield computations for invasive electrocorticography. Our results show that in the vicinity of electrode locations, use of the simpler point electrode model produces large topographic and magnitude differences that will likely impact the accuracy of computed source localizations. PMID- 30441394 TI - Motor Attempt EEG Paradigm as a Diagnostic Tool for Disorders of Consciousness. AB - To investigate whether a motor attempt EEG paradigm coupled with functional electrical stimulation can detect command following and, therefore, signs of conscious awareness in patients with disorders of consciousness, we recorded nine patients admitted to acute rehabilitation after a brain lesion. We extracted peak classification accuracy and peak session discriminant power (PSDP) and we assessed their correlation to the established coma recovery scale revised (CRS-R) and the agreement with diagnosis based on the novel motor behavior tool (MBT). Only PSDP correlated significantly with CRS-R and it also outperformed peak accuracy regarding the MBT. We conclude that PSDP might be more suitable than accuracy to complement CRS-R and MBT in evaluating ambiguous cases and in detecting cognitive motor dissociation. PMID- 30441395 TI - Preparation-Free Measurement of Event-Related Potential in Oddball Tasks From Hairy Parts Using Candle-Like Dry Microneedle Electrodes. AB - This paper reports successful measurement of even-related potential (ERP) using candle-like dry microneedle electrodes, which can acquire high-quality electroencephalogram (EEG) from hairy parts without any pretreatment. In our previous work, we successfully measured spontaneous EEG activity and its application to assess the stress state of the subjects. ERPs originate from electrophysiological response to stimulus and are one of the most important indices to capture the cognitive and sensory activities. In this work, using the candle-like dry microelectrodes, we demonstrate successful measurement of ERPs elicited by oddball tasks. Two oddball tasks using pure tone stimuli and speech stimuli were assigned to the subjects, where EEG was acquired from the parietal region (Cz in international 10-20 system). Note that no pretreatment, such as removal of hairs and abrasion of the scalp, was applied. As a result, P300 and mismatch negativity (MMN) were successfully measured in the both oddball tasks from the averaged EEG after the stimuli. Based on these results and given the attractive natures of the candle-like dry microneedle electrodes; they do not need any skin treatment and conductive gels and they can measure EEG from the hairy parts, the developed electrodes will accelerate cognitive neuroscience research using ERPs. PMID- 30441396 TI - Automatic Independent Component Scalp Map Analysis of Electroencephalogram During Motor Preparation. AB - This work presents a method for automatic independent component (IC) scalp map analysis of electroencephalogram during motor preparation in visuomotor tasks. The strength of this approach is the analysis of the IC scalp maps based on the apriori given mask. This uses an image processing approach, comparable to visual classification used by experts, to automate the selection of relevant ICs in visuomotor tasks. Thirty iterations of the Infomax ICA algorithm were used to test the reliability of the ICs. ICs above 95% quality index were used for IC scalp topography image analysis. Here, we used a linkage-clustering algorithm for IC clustering and gap statistic to estimate the number of clusters. After classifying the components with our approach, the labels were compared to those from well-known MARA ("Multiple Artifact Rejection Algorithm") - an open-source EEGLAB plug-in. It was found that 334 of the 568 labels were in-agreement. MARA labeled 81 out of the 177 source-related components, and 238 out of the 319 non source-related components, as artifacts. Here, the strength of our approach lies in using an image-processing algorithm to identify the task-specific ICs whereas MARA focuses on the automatic classification of the artifactual ICs by combining stereotyped artifact-specific spatial and temporal features that depend on the electrode montage. After "artefactual" ICs are removed, task-specific ICs still remains to be identified from the remaining "good" ICs where our scalp topography image analysis approach can be applied. Our IC scalp topography image analysis is focused on task-specific IC selection based on an apriori mask, which is not limited to specific EEG features and/or electrode configurations for high-density EEG. PMID- 30441397 TI - Effect of Botulinum Toxin on the Spatial Distribution of Biceps Brachii EMG Activity Using a Grid of Surface Electrodes: A Case Study. AB - Botulinum toxin (BT) is widely prescribed by physicians for managing spasticity post stroke. In an ongoing study, we examine the spatial pattern of muscle activity in biceps brachii of stroke survivors before and after receiving BT, examined over the course of 11 weeks (2 weeks before - 9 weeks after). We hypothesize that BT alters muscle electrophysiology by disrupting fiber neuromuscular transmission in an inhomogeneous manner and we seek to detect these changes using grid surface electromyography (sEMG). Also, we obtained B-mode ultrasound images to have an accurate interpretation of sEMG data by looking at the fiber angle and subcutaneous fat thickness distribution across muscle. Here, we are reporting a single case where a chronic stroke survivor received BT injection in the biceps brachii (BB). A 16x8 sEMG electrode grid was used to capture the muscle activity distribution of BB during sustained non-fatiguing isometric contraction at 40% of maximal voluntary (MVC) elbow flexion. We obtained the root mean squared (RMS) maps of the signal recorded at each of the $16 ?times 8$ electrodes. We observed substantial changes in the RMS pattern of BB muscle after receiving BT. More than 80% decrease in sEMG amplitude (RMS) was observed for the channels around the BT injection site as well as about 74% elbow flexion force reduction at the time point of 3-4 weeks post-injection. We also found significant differences between the spatial voluntary activation pattern of pre and post BT RMS maps. We further observed a non-uniform effect and recovery caused by the BT on the distribution of muscle activity. In conclusion, we observed evidence of alteration of the amplitude and pattern of muscle activity after botulinum toxin injection and can document the capability of grid recordings to detect these pattern changes. Our major goals target further investigation to provide an indepth understanding of the effect of botulinum toxin injection at motor unit level. PMID- 30441398 TI - Inter-Limb Muscle Synergy of Hands-and-Knees Crawling in Typical Developing Infants and Infants with Developmental Delay. AB - The aim of this study was to quantify and compare the inter-limb muscle coordination during crawling between typically developing infants and infants with developmental delay. Typically developing (TD, $?text{N}=$20) infants and infants with at risk of developmental delay (ARDD, $?textbf{N}=$33) or confirmed developmental delayCDD, N=14) participated in this study. Surface electromyography of eight muscles from arms and legs and the corresponding joint kinematic data were collected while they were crawling on hands and knees at their self-selected velocity. The number of used inter-limb muscle synergies during crawling was identified by nonnegative matrix factorization algorithm. Our results showed that there was no significant difference in the number of used muscle synergies between ARDD and TD infants during crawling. However, a reduced number of synergies were identified in infants with CDD, as compared to that in TD and ARDD infants, indicating constrained neuromuscular control strategy during crawling in developmental delayed infants. The absence of inter-limb muscle synergies may be one of the mechanisms underlying the impairments of crawling in developmental delayed infants, who are at high risk of cerebral palsy. This result also suggests that the metrics of muscle synergy during infant crawling, such as the number of synergy, may be feasible as a biomarker for early diagnosis of infants with cerebral palsy. PMID- 30441399 TI - Robust Pattern Recognition Myoelectric Training for Improved Online Control within a 3D Virtual Environment. AB - It has been shown that maintaining a neutral arm position during collection of pattern recognition training data for myoelectric prosthesis control results in high offline classification accuracies; however, that precision does not translate to real-time applications, when the arm is used in different positions. Previous studies have shown that collecting training data with the arm in a variety of positions can improve pattern recognition control systems. In this work, we extended these findings to real-time myoelectric control in an immersive testing environment using virtual reality. We show that collecting training data for a pattern recognition algorithm under dynamic conditions, where the user moves their arm, significantly improves control efficiency and achievement of testing metrics. PMID- 30441400 TI - Differential Activation of Biceps Brachii Muscle Compartments for Human-Machine Interfacing. AB - A central challenge for myoelectric limb prostheses resides in the fact that, as the level of amputation becomes more proximal, the number of functions to be replaced increases, while the number of muscles available to collect input signals for control decreases. Differential activation of compartments from a single muscle could provide additional control sites. However, such feat is not naturally under voluntary control. In this study, we investigated the feasibility of learning to differentially activate the two heads of the bicep brachii muscle (BBM), by using biofeedback via high-density surface electromyography (HD-sEMG). Using a one degree of freedom Fitts' law test, we observed that eight subjects could learn to control the center of gravity of BBM's myoelectric activity. In addition, we examined the activations patterns of BBM that allow for the decoding of distal hand movements. These patterns were found highly individual, but different enough to allow for decoding of motor volition of distal joints. These findings represent promising venues to increase the functionality of myoelectrically controlled upper limb prostheses. PMID- 30441401 TI - Recurrent Neural Network Based Early Prediction of Future Hand Movements. AB - This work focuses on a system for hand prostheses that can overcome the delay problem introduced by classical approaches while being reliable. The proposed approach based on a recurrent neural network enables us to incorporate the sequential nature of the surface electromyogram data and the proposed system can be used either for classification or early prediction of hand movements. Especially the latter is a key to a latency free steering of a prosthesis. The experiments conducted on the first three Ninapro databases reveal that the prediction up to 200 ms ahead in the future is possible without a significant drop in accuracy. Furthermore, for classification, our proposed approach outperforms the state of the art classifiers even though we used significantly shorter windows for feature extraction. PMID- 30441402 TI - Models of Motor Learning Generalization. AB - This study used evidence from trial-by-trial errors to understand how humans can generalize what they learn across different movement directions while reaching. We trained 15 healthy subjects to reach in six directions in the presence of challenging visuomotor distortions. We then tested a number of candidate models suggested by the literature of how the brain might use error to improve performance. Our cross-validated results point to a discrete affine model whose generalization, or influence of practice in one direction to neighboring directions, is reduced nearly to zero by 60 degrees away, and the subjects learned 6.25 times more from the error that was observed at a movement direction than neighboring directions. PMID- 30441404 TI - Neuroprostheses: method to evaluate the information content of stimulation strategies. AB - We propose a framework to evaluate the information content of different stimulation strategies used in neuroprosthetic implants. We analyze the responses of retinal ganglion cells to electrical stimulation using an information theory framework. This methodology allows us to calculate the information content by looking at the consistency of neural responses generated across multiple repetitions of the same stimulation protocol. PMID- 30441403 TI - Studying the Effects of Deep Brain Stimulation and Medication on the Dynamics of STN-LFP Signals for Human Behavior Analysis. AB - This paper presents the results of our recent work on studying the effects of deep brain stimulation (DBS) and medication on the dynamics of brain local field potential (LFP) signals used for behavior analysis of patients with Parkinson's disease (PD). DBS is a technique used to alleviate the severe symptoms of PD when pharmacotherapy is not very effective. Behavior recognition from the LFP signals recorded from the subthalamic nucleus (STN) has application in developing closed loop DBS systems, where the stimulation pulse is adaptively generated according to subjects' performing behavior. Most of the existing studies on behavior recognition that use STN-LFPs are based on the DBS being "off". This paper discovers how the performance and accuracy of automated behavior recognition from the LFP signals are affected under different paradigms of stimulation on/off. We first study the notion of beta power suppression in LFP signals under different scenarios (stimulation on/off and medication on/off). Afterward, we explore the accuracy of support vector machines in predicting human actions ("button press" and "reach") using the spectrogram of STN-LFP signals. Our experiments on the recorded LFP signals of three subjects confirm that the beta power is suppressed significantly when the patients take medication (p-value < 0.002) or stimulation (p-value < 0.0003). The results also show that we can classify different behaviors with a reasonable accuracy of 85% even when the high-amplitude stimulation is applied. PMID- 30441405 TI - Bistability in Hodgkin-Huxley-type equations. AB - We study how initial conditions of the Hodgkin-Huxley model affect the dynamics of simulated neurons. We systematically vary the amplitudes of depolarization currents in order to bring neuron dynamics to stable equilibrium. Our results demonstrate that simulated neurons can have spontaneous spiking or a silent state, depending on the initial conditions. We propose the methodology to study the circumstances under which Purkinje cells transit between hyperpolarized quiescent state (down state) and a depolarized spiking state (up state). We show that results derived using the Hodgkin-Huxley methodology should be carefully analyzed before suggesting a direct relevance to neuroprosthetic implants. PMID- 30441406 TI - A Comparison Study of Point-Process Filter and Deep Learning Performance in Estimating Rat Position Using an Ensemble of Place Cells. AB - The emergence of deep learning techniques has provided new tools for the analysis of complex data in the field of neuroscience. In parallel, advanced statistical approaches like point-process modeling provide powerful tools for analyzing the spiking activity of neural populations. How statistical and machine learning techniques compare when applied to neural data remains largely unclear. In this research, we compare the performance of a point-process filter and a long short term memory (LSTM) network in decoding the 2D movement trajectory of a rat using the neural activity recorded from an ensemble of hippocampal place cells. We compute the least absolute error (LAE), a measure of accuracy of prediction, and the coefficient of determination (R2), a measure of prediction consistency, to compare the performance of these two methods. We show that the LSTM and point process filter provide comparable accuracy in predicting the position; however, the point-process provides further information about the prediction which is unavailable for LSTM. Though previous results report better performance using deep learning techniques, our results indicate that this is not universally the case. We also investigate how these techniques encode information carried by place cell activity and compare the computational efficiency of the two methods. While the point-process model is built using the receptive field for each place cell, we show that LSTM does not necessarily encode receptive fields, but instead decodes the movement trajectory using other features of neural activity. Although it is less robust, LSTM runs more than 7 times faster than the fastest point process filter in this research, providing a strong advantage in computational efficiency. Together, these results suggest that the point-process filters and LSTM approaches each provide distinct advantages; the choice of model should be informed by the specific scientific question of interest. PMID- 30441407 TI - Continuous Phase Estimation for Phase-Locked Neural Stimulation Using an Autoregressive Model for Signal Prediction. AB - Neural oscillations enable communication between brain regions. Closed-loop brain stimulation attempts to modify this activity by stimulation locked to the phase of concurrent neural oscillations. If successful, this may be a major step forward for clinical brain stimulation therapies. The challenge for effective phase-locked systems is accurately calculating the phase of a source oscillation in real time. The basic operations of filtering the source signal to a frequency band of interest and extracting its phase cannot be performed in real time without distortion. We present a method for continuously estimating phase that reduces this distortion by using an autoregressive model to predict the future of a filtered signal before passing it though the Hilbert transform. This method outperforms published approaches on real data and is available as a reusable open source module. We also examine the challenge of compensating for the filter phase response and outline promising directions of future study. PMID- 30441408 TI - State Space Oscillator Models for Neural Data Analysis. AB - Neural oscillations reflect the coordinated activity of neuronal populations across a wide range of temporal and spatial scales, and are thought to play a significant role in mediating many aspects of brain function, including atten- tion, cognition, sensory processing, and consciousness. Brain oscillations are typically analyzed using frequency domain methods such as nonparametric spectral analysis, or time domain methods based on linear bandpass filtering. A typical analysis might seek to estimate the power within an oscillation sitting within a particular frequency band. A common approach to this problem is to estimate the signal power within that band, in frequency domain using the power spectrum, or in time domain by estimating the power or variance in a bandpass filtered signal. A major conceptual flaw in this approach is that neural systems, like many physiological or physical systems, have inherent broad-band 1/P' dynamics, whether or not an oscillation is present. Calculating power-in-band, or power in a bandpass filtered signal, can therefore be misleading, since such calculations do not distinguish between broadband power within the band of interest, and true underlying oscillations. In this paper, we present an approach for analyzing neural oscillations using a combination of linear oscillatory models. We estimate the parameters of these models using an expectation maximization (EM) algorithm, and employ AIC to select the appropriate model and identify the oscillations present in the data. We demonstrate the application of this method to univariate electroencephalogram (EEG) data recorded at quiet rest and during propofol induced unconsciousness. PMID- 30441409 TI - A neuroprotective brain stimulation for vulnerable cerebellar Purkinje cell after ischemic stroke: a study with low-intensity focused ultrasound. AB - The role of established contralateral cerebrocerebellar connections on cerebellar injury during stroke has been increasingly revealed in recent years. An extensive number of studies have investigated alteration in inter-hemispheric correlation in order to find brain regions whose responses are specific to restore functional loss and enhance adaptive neural plasticity after stroke. Although, several non invasive brain stimulation studies have proven their efficacy in the treatment of stroke recovery, finding more effective brain regions that responsible for stroke rehabilitation as well as optimizing neural stimulation protocol are the main goals of further investigations. In this study, the lateral cerebellar nucleus (LCN) was exposed to Low-Intensity Focused Ultrasound (LIFU) to reduce the cerebellar damage resulting from crossed cerebellar diaschisis (CCD) phenomenon after cerebral ischemia. A mouse brain ischemia was induced by middle cerebral artery occlusion (MCAO). A level of decrease in Purkinje cell (PC) number and a quantity of myeloperoxidase (MPO) positive neutrophils in the cerebral cortex were compared between stroke and stroke+LIFU groups after MCAO. In stroke+LIFU group, the increased ipsilateral water content due to tissue swelling was observed, showing an attenuation of brain edema. Prominently, the reduction of the neuroimmune reactivity at the infarct core and the peri-infarct regions, and the increased rate of survival among PCs clearly demonstrated primary evidence of neuroprotective effect induced by LIFU-mediated cerebellar modulation. PMID- 30441410 TI - Characterization of Stimulation Artifact Behavior in Simultaneous Electrocorticography Grid Stimulation and Recording. AB - Bi-directional brain-computer interfaces (BCIs) require simultaneous stimulation and recording to achieve closed-loop operation. It is therefore important that the interface be able to distinguish between neural signals of interest and stimulation artifacts. Current bi-directional BCIs address this problem by temporally multiplexing stimulation and recording. This approach, however, is suboptimal in many BCI applications. Alternative artifact mitigation methods can be devised by investigating the mechanics of artifact propagation. To characterize stimulation artifact behaviors, we collected and analyzed electrocorticography (ECoG) data from eloquent cortex mapping. Ratcheting and phase-locking of stimulation artifacts were observed, as well as dipole-like properties. Artifacts as large as +/-1,100 MUV appeared as far as 15-37 mm away from the stimulating channel when stimulating at 10 mA. Analysis also showed that the majority of the artifact power was concentrated at the stimulation pulse train frequency (50 Hz) and its super-harmonics (100, 150, 200 Hz). Lower frequencies (0-32 Hz) experienced minimal artifact contamination. These findings could inform the design of future bi-directional ECoG-based BCIs. PMID- 30441411 TI - Simulations of a birdcage coil B1+ field on a human body model for designing a 3T multichannel TMS/MRI head coil array. AB - This article considers a new type of integrated multichannel Transcranial Magnetic Stimulator and Magnetic Resonance Imaging (TMS/MRI) system at 3T that is currently being designed. The system will enable unprecedented spatiotemporal control of the TMS-induced electric fields (Efields) with simultaneous rapid whole-head MRI acquisition to record the brain activity. A critical design question is how TMS coil elements interact with the transmit field (${?mathrm B}_{1}^{+}$) of the volume coil integrated in 3T MRI systems. In general, the TMS coils are not designed to have any resonant characteristics at the MRI frequency, they may potentially disturb the RF field due to the eddy currents induced. This is especially a concern with a multichannel TMS setup where the subject's head will be largely covered with the stimulation coils. Therefore, we investigated this problem by computational simulations with realistic TMS coil geometries and a birdcage transmit coil in conjunction with a human body model. We compared the ${?mathrm B}_{1}^{+}$ interaction effects of a commercially available MR compatible TMS coil with our coil prototype. In both cases, the results show small local changes in the transmit field ${?mathrm B}_{1}^{+}$of the birdcage coil. Maximal Average Specific Absorption Rate (SAR) values over 1g tissue were found to be slightly lower when the TMS elements were present. We conclude that it should be feasible and safe to use the conventional body transmit coil even when an array of TMS coils is used. PMID- 30441412 TI - Characterizing cortical responses evoked by electrical stimulation of the mouse infraorbital nerve. AB - In recent years, the trigeminal nerve (CN V) has become a popular target for neuromodulation therapies to treat of a variety of diseases due to its access to neuromodulatory centers. Despite promising preclinical and clinical data, the mechanism of action of trigeminal nerve stimulation (TNS) remains in question. In this work, we describe the development and evaluation of a neural interface targeting the mouse trigeminal nerve with the goal of enabling future mechanistic research on TNS. We performed experiments designed to evaluate the ability of a peripheral nerve interface (i.e. cuff electrode) to stimulate the infraorbital branch of the trigeminal nerve. We found that both artificial and naturalistic stimulation of the trigeminal nerve elicited robust cortical responses in the somatosensory cortex that scaled with increases in stimulus amplitude. These results suggest that an infraorbital nerve interface is a suitable candidate for examining the neural mechanisms of TNS in the mouse. PMID- 30441413 TI - PEDOT:PSS electrodes for acute experimental evaluation of vagus nerve stimulation on rodents. AB - The vagus nerve (VN) is involved in the autonomic regulation of many physiological systems (cardiovascular, respiratory, gastrointestinal, etc.) and its stimulation is already an approved therapy for refractory epilepsy and depression. Other pathologies are thought to be treatable through vagus nerve stimulation (VNS), such as heart failure, cardiac arrhythmia, inflammation or auto-immune diseases. However, the efficacy of the stimulation is not always optimal, partly due to the materials and the architecture of currently available electrodes. Standard electrodes, composed of metallic rings that stimulate the whole diameter of the nerve, are not adapted to experimentations involving spatial selectivity. Efficient and selective charge injection is usually difficult to achieve simultaneously, especially in experimental setups using rodents, due to the thin diameter of their VN. In this paper, we show that we can take advantage of the high charge injection property of conducting polymers to acutely stimulate the vagus nerve in rodents, using individual active electrodes with dimensions $725?,?,?mu ?mathrm{m}?times ?,450?,?,?mu?mathrm{m}$. A particular PEDOT:PSS architecture integrating 12 active electrodes is developed and applied to the VN of one rat. A closed-loop VNS system developed in our previous works is used to stimulate the VN while analyzing the heart rate response. Results show the feasibility of this kind of electrodes for acute VNS on rodents and open the path towards new experimentations focused on selective stimulation and recording. PMID- 30441414 TI - Transcranial Direct Current Stimulation of the Leg Motor Area - is it partly somatosensory? AB - Non-invasive brain stimulation such as transcranial direct current stimulation (tDCS) involves passing low currents through the brain and is a promising tool for the modulation of cortical excitability. We computationally investigated the effects of the size of the anode in the conventional montage (contralateral supraorbital cathode) using finite element analysis (FEA) for the targeted leg area of the motor cortex where tDCS is challenging due to the depth and orientation of the leg motor area in the inter-hemispheric fissure. We used FEA to develop two anode sizes (same cathode size) with the same current density but different electric field magnitude at the targeted leg area of the motor cortex. Then, we evaluated the effects of the two anode sizes via neurophysiological testing on twelve healthy subjects, seven males and five females (age: 21-36 years, all right-leg dominant). Here, conventional anodal tDCS electrode montage for the leg area of the motor cortex used a large-anode (5cmx7cm, current strength 2mA) which was compared based on transcranial magnetic stimulation (TMS) induced motor evoked potentials (MEP) with a small-anode (3.5cmx1cm at 0.2mA) montage of the same current density at the skin-electrode interface and identical contralateral supraorbital cathode placement. Small-anode decreased the electric field magnitude by almost one-tenth but still got a similar statistically significant $(?mathrm {P}<0.05)$ increase in the cortical excitability (MEP) at the targeted leg motor area when compared to sham tDCS. Since the electric field magnitude was similar at the scalp (skin-electrode interface) level but differed significantly at the leg motor area in the inter-hemispheric fissure, so a possible contribution of scalp sensory nerve responses to electrocutaneous stimulation is proposed. PMID- 30441415 TI - Personalised meal eating behaviour analysis via semi-supervised learning. AB - Automated monitoring and analysis of eating behaviour patterns, i.e., "how one eats", has recently received much attention by the research community, owing to the association of eating patterns with health-related problems and especially obesity and its comorbidities. In this work, we introduce an improved method for meal micro-structure analysis. Stepping on a previous methodology of ours that combines feature extraction, SVM micro-movement classification and LSTM sequence modelling, we propose a method to adapt a pretrained IMU-based food intake cycle detection model to a new subject, with the purpose of improving model performance for that subject. We split model training into two stages. First, the model is trained using standard supervised learning techniques. Then, an adaptation step is performed, where the model is fine-tuned on unlabeled samples of the target subject via semisupervised learning. Evaluation is performed on a publicly available dataset that was originally created and used in [1] and has been extended here to demonstrate the effect of the semisupervised approach, where the proposed method improves over the baseline method. PMID- 30441416 TI - Deep Unsupervised Representation Learning for Abnormal Heart Sound Classification. AB - Given the world-wide prevalence of heart disease, the robust and automatic detection of abnormal heart sounds could have profound effects on patient care and outcomes. In this regard, a comparison of conventional and state-of-theart deep learning based computer audition paradigms for the audio classification task of normal, mild abnormalities, and moderate/severe abnormalities as present in phonocardiogram recordings, is presented herein. In particular, we explore the suitability of deep feature representations as learnt by sequence to sequence autoencoders based on the auDeep toolkit. Key results, gained on the new Heart Sounds Shenzhen corpus, indicate that a fused combination of deep unsupervised features is well suited to the three-way classification problem, achieving our highest unweighted average recall of 47.9% on the test partition. PMID- 30441417 TI - Validating an Algorithm for Automatic Scoring of Inspiratory Flow Limitation Within a Range of Recording Settings. AB - Inspiratory Flow Limitation (IFL) is a phenomenon associated with narrowing of the upper airway, preventing an increase in inspiratory airflow despite an elevation in intrathoracic pressure. It has been shown that quantification of IFL might complement information provided by standard indices such as the apnea hypopnea index (AHI) in characterizing sleep disordered breathing and identifying subclinical disease. Defining guidelines for visual scoring of IFL has been of increasing interest, and automated methods are desirable to avoid inter-scorer variability and allow analysis of large datasets. In addition, as recording instrumentation and practices may vary across hospitals and laboratories, it is useful to assess the influence of the recording parameters on the accuracy of the automated classification. We employed nasal pressure signals recorded as part of polysomnography (PSG) studies in 7 patients. Two experts independently classified approximately 2000 breaths per subject as IFL or non-IFL, and we used the consensus scoring as the gold standard. For each breath, we derived features indicative of the shape and frequency content of the signals and used them to train and validate a Support Vector Machine (SVM) to distinguish IFL from non-IFL breaths. We also assessed the effect of signal filtering (down-sampling and baseline-removal) on classification performance. The performance of the classifier was excellent (accuracy ~93%) for the raw signals (collected at 125 Hz with no filtering), and decreased for increasing high-pass cut-off frequencies (fc = [0.05, 0.1, 0.15, 0.2] Hz) down to 84% for fc= 0.2 Hz and for decreasing sampling rate (fs = [20, 50, 75, 100] Hz) down to ~85% for fs=20 Hz. Loss of performance was minimized when the classifier was re-trained using data with matched filtering characteristics (accuracy > 89%). We can conclude that the SVM feature-based algorithm provides a reliable and efficient tool for breath-by breath classification. PMID- 30441418 TI - Optical spectroscopic ultrasound displacement imaging. AB - Photoacoustic imaging has been intensively studied in recent years, and many of the achievements have already been applied in important biomedical and clinical applications, e.g. spectroscopic photoacoustic imaging to extract functional and molecular information. However, spectroscopic photoacoustic imaging requires expensive and bulky tunable laser source, which severely hinder its further development towards portable device. In this paper, we propose a novel imaging method, named optical spectroscopic ultrasound displacement (OSUD) imaging, which enables optical spectroscopic imaging in deep scattering tissue using multiple low-cost continuous-wave laser sources and ultrasound imaging equipment. The principle of the OSUD imaging method will be introduced, and followed by preliminary experimental results. The OSUD imaging may provide another pathway to provide spectroscopic optical absorption contrast in deep scattering tissue beyond commonly used photoacoustic imaging. PMID- 30441419 TI - Wavelet de-noising method with adaptive threshold selection for photoacoustic tomography. AB - Photoacoustic (PA) tomography enables imaging of optical absorption property in deep scattering tissue by listening to the PA wave. However, it is an open challenge that the conversion efficiency from light to sound based on PA effect is extremely low. The consequence is the poor signal-to-noise ratio (SNR) of PA signal especially in scenarios of low laser power and deep penetration. The conventional way to improve PA signal's SNR is data averaging, which however severely limits the imaging speed. In this paper, we propose a new adaptive wavelet threshold de-noising (aWTD) algorithm, and apply it in photoacoustic tomography to increase the PA signal's SNR without sacrificing the signal fidelity and imaging speed. PA image quality in terms of contrast is also significantly improved. The proposed method provides the potential to develop real-time low-cost PA tomography system with low-power laser source. PMID- 30441420 TI - Optical Resolution Photoacoustic Microscopy With Fast Laser Scanning and Fixed Photoacoustic Detector. AB - Photoacoustic (PA) imaging is rapidly progressing imaging modality in which very short pulsed laser causes thermal expansion to generate PA signal. In previous PA microscope systems, relatively long time was required for image acquisition because they required mechanical scan of the PA transducer. The objective of the present study is to develop fast laser scanning optical resolution photoacoustic microscopy (OR-PAM) with fixed PA signal detector to realize very high frame rate PA imaging. Q-switched Nd:YAG laser with the wavelength of 532 nm, pulse width of 5.5 ns and pulse repetition rate of up to 50 kHz was equipped in the system. Low frequency PA detector was comprised of a glass prism configuring acoustic focusing and a polymethyl methacrylate (PMMA) prism with 5 MHz PZT (lead zirconate titanate) transducer. High frequency PA detector was comprised of the same glass prism and a glass prism with ZnO (zinc oxide) thin film transducer. Galvano scanner operating in the air was controlled by a microcomputer to scan laser beam. PA signal was detected with the fixed PA detector thus realized the frame rate of 5 fps for C-mode equivalent to 500 fps for B-mode. The lateral resolution of the low frequency system was found to be 11.6 MUm and the blood vessel on the surface of cod roe was clearly visualized. The system may be applicable for imaging blood flow and vascular dynamics of micro vessel. PMID- 30441421 TI - Hybrid multi-wavelength photoacoustic imaging. AB - Multi-wavelength photoacoustic (PA) imaging has been studied extensively to explore the spectroscopic absorption contrast of biological tissues. To generate strong PA signals, a high-power wavelength-tunable pulsed laser source has to be employed, which is bulky and quite expensive. In this paper, we propose a hybrid multi-wavelength PA imaging (hPAI) method based on combination of single wavelength pulsed and multi-wavelength continuous-wave (CW) laser sources. By carefully controlling laser illumination sequence (pulse-CW-pulse), and extracting the PA signals' difference before and after heating of CW lasers, the optical absorption property of multi-wavelength CW lasers could be obtained. Compared with conventional PA imaging, the proposed hPAI shows much lower system cost due to the usage of single-wavelength pulsed laser and cheap CW lasers. Theoretical analysis and analytical model are presented in this paper, followed by proof-of-concept experimental results. PMID- 30441422 TI - Pattern-learning-based Noise Elimination Algorithm in Photoacoustic Sensing and Imaging. AB - As one of the fastest-growing imaging modalities in recent years, photoacoustic (PA) imaging has attracted tremendous research interest for various applications including anatomical, functional and molecular imaging. However, the PA signal's amplitude is usually quite weak and can be easily distorted by instrumental noise and interference, which can severely degrade the image quality. To improve the PA signal's signal-to-noise ratio efficiently, this paper introduces a pattern learning based PA (PLPA) detection method to eliminate the periodically interference noise for PA sensing and imaging. Both simulation and experimental results are demonstrated to prove the validity of the proposed algorithm. PMID- 30441423 TI - Individual working memory capacity traced from multivariate pattern classification of EEG spectral power. AB - Working Memory (WM) processing is central for human cognitive behavior. Using neurofeedback training to enhance the individual WM capacity is a promising technique but requires careful consideration when choosing the feedback signal. Feedback in terms of univariate spectral power (specifically theta and alpha power) has yielded questionable behavioral effects. However, a promising new direction for WM neurofeedback training is by using a measure of WM that is extracted by multivariate pattern classification. This study recorded EEG oscillatory activity from 15 healthy participants while they were engaged in the n-back task, n?[1,2]. Univariate measures of the theta, alpha, and theta-over alpha power ratio and a measure of WM extracted from multivariate pattern classification (of n-back task load conditions) was compared in relation to individual n-back task performance. Results show that classification performance is positively correlated to individual 2-back task performance while theta, alpha and thetaover-alpha power ratio is not. These results suggest that the discriminability of multivariate EEG oscillatory patterns between two WM load conditions reflects individual WM capacity. PMID- 30441424 TI - Decoding Synergy-Based Hand Movements using Electroencephalography. AB - In this paper, scalp electroencephalographic (EEG) signals were recorded from 10 subjects during hand grasping. Six objects that span different grasp types were used. Grasp kinematics were recorded using CyberGlove. From a training subset of the data, kinematic synergies were determined and their reconstruction weights in these grasps were calculated. EEG features (power spectral densities in four low and high frequency bands) were trained on kinematic synergy weights using multivariate linear regression. Using this model, kinematics from testing subset of data were decoded from EEG with 3-fold cross validation. Results are compared to chance level to determine if reconstruction weights are related to EEG features. Results indicate that EEG features can decode synergy-based movement generation. Study implications and future implementations were discussed. PMID- 30441425 TI - Estimation of Finger Joint Angle Based on Neural Drive Extracted from High Density Electromyography. AB - Robust human-machine interactions require accurate and intuitive interfaces. Neural signals associated with muscle activities are widely used as the interface signals. This preliminary study evaluated the feasibility of a novel neural-drive based interface in estimating the individual finger joint angles. The motor unit pool discharge probability was used to predict the neural drive associated with the fine control of the finger joint angle during individual finger extension movement. To obtain the neural drive information, individual motor unit discharge events were extracted from the decomposition of high-density surface electromyogram (sEMG) signals, and discharge events from different motor units were pooled to from a composite discharge event train. The neural-drive-based estimate was obtained by calculating the probability (normalized frequency) of the populational motor unit discharge. The global EMG signal (root-mean-squared value) was also used to estimate the joint angles as a control condition. Our preliminary results showed that the accuracy and stability of the neural-drive based approach outperformed the classic EMG-based method. Our findings suggest that the novel neural-drive-based interface could be used as a promising control input for intuitive dynamic control of a robotic hand. PMID- 30441426 TI - Semi-simulation Experiments for Quantifying the Performance of SSVEP-based BCI after Reducing Artifacts from Trapezius Muscles. AB - Muscular artifacts often contaminate electroencephalograms (EEGs) and deteriorate the performance of brain-computer interfaces (BCIs). Although many artifact reduction techniques are available, most of the studies have focused on their reduction ability (i.e. reconstruction errors), and it has been missing to evaluate their effect on the performance of BCIs. This study aims at evaluating the performance of a state-of-the-art muscular artifact reduction technique on a scenario of a steady-state visual evoked potentials (SSVEPs)based BCI. The performance was evaluated based on a semisimulation setting using a benchmark dataset of SSVEPs artificially contaminated by muscular artifacts acquired from the trapezius. Our results showed that combining the artifact reduction method and the classification algorithm based on the task-related component analysis gained improved classification accuracy. Interestingly, the artifact reduction setting minimizing the reconstruction errors, i.e. elaborately recovering the true EEG waveforms, was inconsistent to the one maximizing the classification performance. The results suggest that artifact reduction methods should be tuned so as to tomaximize performance of BCIs. PMID- 30441427 TI - Follow the Light - From Low-Energy Defibrillation to Multi-Site Photostimulation. AB - One major cause of death in the industrialized world is sudden cardiac death, which so far can be reliably treated only by applying strong electrical shocks. Developing improved methods, aiming at lowering shock intensity and associated side effects potentially has significant clinical implications. Thus, optogenetic stimulation using structured illumination has been introduced as a promising experimental tool to investigate mechanisms underlying multi-site pacing and to optimize potential low-energy approaches. Furthermore, an objective of this work is to strengthen the application of optogenetic tools for cardiac arrhythmia research, which in turn is expected to improve applicable technologies towards tissue-protective defibrillation. PMID- 30441428 TI - Cardiac Conduction Velocity Estimation During Wavefront Collision. AB - Catheter ablation therapy is an effective approach to treat different arrhythmias. Cardiac conduction velocity (Cv), extracted from intracardiac electrograms, shows the speed and direction of the wavefront propagation at different sites and is an insightful feature to guide ablation therapy. To create a propagation map, a small mapping catheter with a high density of electrodes is usually used to sequentially collect electrograms from different sites in a desired chamber of the heart. The CV and isochrone surface estimations are very challenging during complex arrhythmias such as atrial fibrillation, where multiple wavefronts simultaneously excite different cardiac sites. Specifically, the performances of CV estimators significantly degrade at catheter sites where wave- fronts collide. This is mainly because during collision, different wavefronts pass the areas under different electrodes of the catheter. Consequently, the activation times of the electrodes are the results of different wavefronts, and there are sharp changes in isochrone line patterns in the vicinity of the collision's border. In this paper, we propose a method that is able to identify the collision sites and improve the estimation of CV and isochrone maps. The proposed method finds the electrodes of the catheter that are excited by a similar wavefront and then estimates the corresponding isochrone lines for that wavefront. Our simulation results confirmed the efficiency of the proposed method during collision. PMID- 30441429 TI - Short-Term Model-Based Multiscale Complexity Analysis of Cardiac Control Provides Complementary Information to Single-Scale Approaches. AB - The study compares a recently proposed shortterm model-based linear multiscale complexity approach to a single-scale application of the same method and to a model-free nonlinear one based on the computation of conditional entropy with the aim at assessing the complementary information. Comparison was carried out over 24 hours Holter recordings of heart period variability during daytime and nighttime in 12 healthy men (age: 34-55 years). Single-scale methods were able to detect the increased complexity of the cardiac control during nighttime. Multiscale complexity analysis showed that this increase was due to an increase of complexity in the low frequency band (from 0.04 to 0.15 Hz), while complexity in the range of frequencies typical of the respiratory rate was unmodified. Regardless of the method (i.e. linear or nonlinear) single-scale complexity indexes were uncorrelated to the multiscale ones. We conclude that short-term model-based linear multiscale complexity approach provides complementary information to single-scale methods in an application devoted to the analysis of cardiac control from 24 hours Holter recordings. PMID- 30441430 TI - Automatic T-Wave Alternans Identification in Indirect and Direct Fetal Electrocardiography. AB - Fetal T-wave alternans (TWA) is a still littleknown marker for severe fetus-heart instabilities and may be related to some currently unjustified fetal deaths. Automatically detecting TWA on direct fetal electrocardiograms (DFECG) means possibility of providing fetuses the right treatment during delivery. Instead, automatically identifying TWA on indirect fetal electrocardiograms (IFECG) means possibility of providing fetuses the right treatment even during pregnancy, when taking actions for outcome improvement is still possible. Moreover, TWA identification from IFECG is noninvasive, and thus safe for both fetuses and mothers. The aim of this work was testing the heart-rate adaptive match filter (HRAMF) for automatic TWA identification in IFECG and comparing HRAMF performance in IFECG against DFECG. To this aim, simultaneously recorded DFECG and IFECG tracings from 5 healthy fetuses were used ("Abdominal and Direct Fetal Electrocardiogram Database" from Physionet). TWA measurements (frequency, mean amplitude, maximum amplitude, and amplitude standard deviation) in IFECG (1.09+/ 0.04 Hz, 11+/-5 MUV, 21+/-12 MUV and 7+/-3 MUV) were of the same order of magnitude of those in DFECG (1.07+/-0.02 Hz, 9+/-2 MUV, 30+/-11 MUV and 6+/-2 MUV). Moreover, a direct correlation (n) was found between maximum TWA and fetal heart rate (IFECG: rho=0.999; P=0.022; DEFEG: rho=0.642; P=0.243). Thus, HRAMF was able to detect TWA from IFECG as well as from DFECG. PMID- 30441431 TI - Phase Relation between Depolarization and Repolarization Alternans in ECG. AB - T-Wave Alternans (TWA) in the electro cardiogram (ECG) has been widely investigated as a potential predictor of ventricular arrhythmia. However, large clinical trials show that TWA has a high negative predictive value (NPV) but poor positive predictive value (PPV). Therefore, there is need for exploration of approaches to improve PPV of TWA. More recent studies suggest that whether alternans is spatially concordant or discordant affects arrhythmic potential. Results of our previous animal and simulation studies show that the phase relation between depolarization and repolarization alternans has an effect on the transition of concordant to discordant alternans. Towards the eventual goal of developing indexes that complement TWA and improve prediction of arrhythmia, the objectives in this study were to verify the existence of R wave amplitude alternans (RWAA, a surrogate of depolarization alternans) and investigate the phase relationship between RWAA and TWA in clinical grade ECGs. Results show that RWAA does occur in ECGs and that the phase relationship between RWAA and TWA can be labile. These results support further investigation of the co-occurrence of these alternans for prediction of arrhythmic events. PMID- 30441432 TI - Respiratory Sinus Arrhythmia Quantified with Linear and Non-Linear Techniques to Classify Dilated and Ischemic Cardiomyopathy. AB - In congestive heart failure (CHF), dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) are two highly related pathologies that are not fully characterized. The aim of this study is to assess respiratory sinus arrhythmia (RSA) index of the parasympathetic system, in order to discriminate between both pathologies, DCM and ICM. For this, ECG-signals of 49 subjects (12 DCM patients, 21 ICM patients, 6 ICM patients with diabetes mellitus (DM) type II and 10 control subjects) from the database HERIS II and of 173 subjects (50 DCM, 50 ICM, 15 DCM with DM type II, 15 ICM with DM type II and 47 control subjects) from the database MUSIC2 were analyzed. The RSA was quantified using linear and non-linear analysis methods (fractal dimension and entropy). The results showed a significant difference between ICM and DCM subjects (p=0.013) with a sensitivity of 83% and specificity of 90%. Decreasing RSA values were present in CHF patients, especially in ICM patients, in comparison with healthy subjects. Alterations in the parasympathetic system due to DM were also identified. PMID- 30441433 TI - A Novel Artifact Reconstruction Method Applied to Blood Pressure Signals. AB - Physiological records are one of the most relevant elements to obtain objective information from the patients. The presence of artifacts in biomedical signals can give misleading in the analysis of information that these signals give. The blood pressure signal is one of the records clearly affected by different artifacts, especially the ones due from the calibration episodes. We propose a method to reconstruct different episodes of artifacts in these signals. This method is sustained on the detection of the events of the signal, differentiating between to the physiological cycles and the artifacts. The performance of the method is based on the detection of the cycles and artifact's position, the identification of the number of cycles to reconstruct, and the prediction of the cycle model used to generate the missing cycles. The parameter thetaE represents the difference between the area under the curve when two events are compared. The value of this parameter is low when two similar events are compared like the physiological cycles, whereas it is high comparing a cycle with an artifact. An adaptive threshold is defined to identify the artifact episodes. The number of cycles to reconstruct is generated considering the same number of their neighbours physiological cycles, to left and right, of the original signal. Finally, the performance of the method has been analyzed comparing the number of events and artifacts detected and their correct reconstruction. According to the results, the reconstruction error was less than 1% in all cases. PMID- 30441434 TI - Design of a Microbiota Sampling Capsule using 3D-Printed Bistable Mechanism. AB - Microbiota analysis is a fundamental element for a better understanding of microbiota role, its relationship with the human body and its impact on different pathologies. There is today no non-invasive tool for easy collection of the microbiota in the small intestine. In this paper, we describe the development of such a device that opens the way to new diagnostic techniques. The device is based on a capsule designed as a passive system to maximize the safety during its use. Originality of the design relies in the use of a bistable mechanism obtained using additive manufacturing in order to provide a compact design with integration of opening, sampling and closing functions within the capsule. Design, implementation and initial lab evaluation of sampling are presented. PMID- 30441435 TI - Remote Estimation of Video-Based Vital Signs in Emotion Invocation Studies. AB - The goal of this study is to examine the influence of various imitated and video invoked emotions on the vital signs (respiratory and pulse rates). We also perform an analysis of the possibility to extract signals from sequences acquired with cost-effective cameras. The preliminary results show that the respiratory rate allows for better separation of some emotions than the pulse rate, yet this relation highly depends on a subject. The invoked positive emotion resulted in a respiratory rate difference >1.8 bpm, comparing to the average respiration rate of all neutral results (in 89% of observations). Visual facial expression in many cases was insufficient for emotion recognition (in video based experiment only 11.4% of visual responses were classified as an expected emotion). PMID- 30441436 TI - Daytime sleepiness affects gait auditory synchronization ability. AB - Sleep disturbances in modern life lead to cognitive and motor performance impairments in everyday tasks such as gait. The most common symptom of these disturbances is daytime sleepiness, which can be assessed by questionnaires such as the Epworth Sleep Scale (ESS). The ESS evaluates sleep health and daytime dysfunction. The goal of this study is to assess the influence of sleepiness on a motorauditory synchrony task, rhythmed gait. High and low sleepiness clusters were formed based on the participants ESS scores. Walking on a treadmill, two different rhythmic auditory stimulus conditions were set with a metronome: isochronous and non-isochronous. Reflective markers on both heels with seven infrared cameras were used to assess the difference between footfall and metronome beep, what is named synchronization error (SE). There was a tendency to anticipate the beep in the HS group when compared to the LS group only in the non isochronous stimulus condition that was statistically significant. Sleep disturbances that generate daytime sleepiness may bring detrimental effects on brain areas that could be responsible for the real-time adjustment of gait and sustained attention. These impairments may be responsible for the larger synchronization error with larger relative phase of the group with high sleepiness. More studies are necessary involving other parameters of sleep and gait to identify sleep disturbances through gait analysis. PMID- 30441437 TI - Neonatal EEG Interpretation and Decision Support Framework for Mobile Platforms. AB - This paper proposes and implements an intuitive and pervasive solution for neonatal EEG monitoring assisted by sonification and deep learning AI that provides information about neonatal brain health to all neonatal healthcare professionals, particularly those without EEG interpretation expertise. The system aims to increase the demographic of clinicians capable of diagnosing abnormalities in neonatal EEG. The proposed system uses a low-cost and low-power EEG acquisition system. An Android app provides single-channel EEG visualization, traffic-light indication of the presence of neonatal seizures provided by a trained, deep convolutional neural network and an algorithm for EEG sonification, designed to facilitate the perception of changes in EEG morphology specific to neonatal seizures. The multifaceted EEG interpretation framework is presented and the implemented mobile platform architecture is analyzed with respect to its power consumption and accuracy. PMID- 30441438 TI - Development and Pilot Testing of a Novel Electromechanical Device to Measure Wrist Rigidity in Parkinson's Disease. AB - Quantitative assessment of the muscle tone is important when studying patients with neurological disorders such as Parkinson's disease (PD). For the assessment of therapeutic progress, quantitative and objective outcome measures are needed. This article presents a novel electromechanical device to monitor the quantitative rigidity of the wrist joint against passive movement. The novel device is equipped with an electrical motor to move the wrist joint in a flexion extension manner with different velocity profiles. The accuracy of the device was measured in terms of position, velocity and torque accuracy. The feasibility of the measurement procedure was tested in a pilot study with four PD patients and 12 healthy controls (HC), at velocities of 10 degrees /s,50 degrees /s, and 100 degrees /s. {The position and velocity of the developed device were (0.005 +/- 0.105) degrees and (0.734 +/-0.276) degrees /s, unloaded, and (0.003 +/- 0.113) degrees and (0.013 +/- 0.038) degrees /s, loaded with a relaxed arm, respectively. The torque accuracy was (15.029 +/- 2.235) mNm. The comparison of the median rigidity between the PD patients and HC showed significant differences at all tested velocities, during both flexion and extension movements. This device proved to have sufficient accuracy and sensitivity to precisely measure the interaction torque at the wrist joint and to differentiate PD rigidity from normal muscle tone. The device, thus provides a quantitative and objective measure of rigidity in PD. PMID- 30441439 TI - Manometric recordings bring out post-stimulus refractory states in the anal canal in neonates. AB - Anorectal manometry is a diagnostic technique used to investigate the correct mechanical performance of the internal anal sphincter (IAS). By distending the rectal ampulla while recording changes in the luminal pressure, this method allows for characterizing the anorectal reflex. It can also provide, indirectly, information about the electrical activity of the IAS. In this study, seventeen neonates having 24-hour delayed passage of meconium or presenting distal intestinal obstruction symptoms underwent anorectal manometry to discard Hirschsprung's disease. All patients had normal anorectal reflex. The time delay between stimulation of the rectal ampulla and the relaxation of the anal canal was studied. The average period of the pressure fluctuations was 5.44 +/- 0.13s. The overall duration of the relaxation time was 9.71 +/- 0.21s. The maximum lag between the onset of the stimulus and the relaxation of the IAS was 2.90 s, and was achieved when the stimulus was applied following a local maximum of the pressure wave. The existence of a refractory period during the suprathreshold depolarization of smooth muscle cells can explain the evidence of a temporal delay between the stimulus and the mechanical response. In occasions, relaxation appeared first distally. This phenomenon can be explained by the arrangement and morphology of bipolar cells, which may evidence the anisotropic propagation of the mechanical activity. These data may contribute to depict the alterations in excitability underlying the relaxation reflex by means of manometric recording of the anal canal. PMID- 30441440 TI - Image-Based Computational Fluid Dynamic Analysis for Surgical Planning of Sequential Grafts in Coronary Artery Bypass Grafting. AB - Coronary bypass grafting (CABG) is a surgical procedure for anastomosing small grafts to the coronary vessels. The bypass graft bridges the occluded or diseased coronary artery, allowing sufficient blood flow to deliver oxygen and nutrients to the heart muscles. Patient-specific (PS) anatomy obtained from coronary computed tomography angiography (CCTA) was used to generate a 3D aorto-coronary model (pre-surgery). Additionally, three more models with idealized grafts (individual and sequential grafts), were created using Boolean operations to represent post-surgery configuration. Fractional flow reserve (FFR) and wall shear stress (WSS) were estimated from the computational fluid dynamics (CFD). The pre-surgical FFR values for all the three left coronary arteries were significant (FFR<.80). The flow was restored (FFR>0.80) distal to stenosis in all the three post- surgical idealized graft models. Peak WSS values of 468, 336 and 295 dynes/cm2 were observed at the toe of the individual end-to-side anastomosis for the three graft models. More importantly, low WSS (< 100 dynes/cm2) prevails at the heel and the walls opposite to the anastomosis in the sequential graft models. The prevailing low WSS at the heel and the wall bed opposite to anastomosis, in a sequential graft model, reduces restenosis rates and promotes a uniform hemodynamic environment for a better long-term patency of the graft. PS- CFD simulations based on CCTA can be helpful in assessing the hemodynamic parameters of graft models for optimal surgical planning. PMID- 30441441 TI - Estimating the Intensity and Anisotropy of Tumor Treating Fields Jsing Singular Value Decomposition. Towards a More Comprehensive Estimation of Anti-tumor Efficacy. AB - Tumor treating fields (TTFields) is an anticancer treatment that inhibits tumor growth with alternating electrical fields. Finite element (FE) methods have been used to estimate the TTFields intensity as a measure of treatment "dose". However, TTFields efficacy also depends on field direction and exposure time. Here we propose a new FE based approach, which uses all these parameters to quantify the average field intensity and the amount of unwanted directional field correlation (fractional anisotropy, FA). The method is based on principal component decomposition of the sequential TTFields over one duty cycle. Using a realistic head model of a glioblastoma patient, we observed significant unwanted FA in many regions of the brain, which may potentially affect therapeutic efficacy. FA varied between different array layouts and indicated a different order of array performance than predicted from the field intensity. Tumor resection nullified differences in field distributions between layouts and increased FA considerably. Our results question the rationale for the use of macroscopically orthogonal array layouts to reduce field correlation and rather indicate that arrays should be placed to maximize pathology coverage and field intensity. The proposed calculation framework has several potential applications, incl. improved treatment planning, technology development, and accurate prognostication models. Future studies are required to validate the method. PMID- 30441442 TI - Effective Diffusion and Tortuosity in Brain White Matter. AB - Patients affected by glioblastomas have a very low survival rate. Emerging techniques, such as convection enhanced delivery (CED), need complex numerical models to be effective; furthermore, the estimation of the main parameters to be used to instruct constitutive laws in simulations represents a major challenge. This work proposes a new method to compute tortuosity, a key parameter for drug diffusion in fibrous tissue, starting from a model which incorporates the main white matter geometrical features. It is shown that tortuosity increases from 1.35 to 1.85 as the extracellular space width decreases. The results are in good agreement with experimental data reported in the literature. PMID- 30441443 TI - Long-acting Insulin in Diabetes Therapy: In Silico Clinical Trials with the UVA/Padova Type 1 Diabetes Simulator. AB - The University of Virginia /Padova Type 1 Diabetes (TID) simulator has been widely used for testing artificial pancreas controllers, and, recently, novel insulin formulations and glucose sensors. However, a module describing the pharmacokinetics of the new long-acting insulin analogues is not available. The aim of this contribution is to reproduce multiple daily insulin injection (MDI) therapy, with insulin glargine 100 U/mL (Gla-100) as basal insulin, using the TID simulator. This was achieved by developing a model of Gla-100 and by incorporating it into the simulator. The methodology described here can be extended to other insulins, allowing an extensive in silico testing of different long-acting insulin analogues under various settings before starting human trials. PMID- 30441444 TI - Automatic Screening to Detect 'At Risk' Child Speech Samples using a Clinical Group Verification framework. AB - Pediatric speech sound disorders (SSD) encompass a wide range of speech production deficits that can interfere with children's educational growth, social engagement and employment opportunities. Early detection of SSDs can facilitate timely intervention and minimize the potential for life-long adverse effects, but distinguishing between typical and atypical speech production in preschoolers is challenging due to developmental and individual variability in speech acquisition. In this study we apply Gaussian Mixture Models to speech samples from 3- to 6-year-old children, recorded by parents using an iOS app. Speech language pathologists previously classified the samples as positive ('at risk' speech, warranting a referral for a speech-language evaluation) or negative ('no risk' speech). In a series of exploratory analyses, novel distance measures and group scoring techniques are developed which show good subject-level prediction accuracy. Our results provide evidence that it may be feasible to use Speech Processing and Speaker Verification techniques to model and screen speech samples from children for possible speech sound disorders. PMID- 30441445 TI - Mapping ADL Motion Capture Data to BLUE SABINO Exoskeleton Kinematics and Dynamics. AB - Design of an upper-arm exoskeleton requires knowledge of human operational ranges and workspace distributions. Motion capture recordings of right-arm motion during common tasks, known as activities of daily living (ADLs), are taken to represent a plausible workspace for an exoskeleton. An inverse kinematic model of BLUE SABINO (BiLateral Upper-extremity Exoskeleton for Simultaneous Assessment of Biomechanical and Neuromuscular Output), driven by ADL data is established to map right-arm joint locations to exoskeleton motor joint space. A kinematic representation of a human right-arm driven by ADL data is implemented via a vector analysis utilizing quaternion rotation/translation and used to visualize ADL recordings. A model of the BLUE SABINO exoskeleton whose motion is driven by the mapped motorjoint-space data is used to validate the mapping graphically. The available ADL database is mapped to motor joint space. Motor position distributions are generated from the resulting dataset and estimates of robot range of motion, (ROM) and statistics for shoulder motor positions are established. A kinematically and inertially accurate model of the BLUE SABINO is developed by exporting SolidWorksOR part models into SimScape Multibody (MathWorks). The model is used to produce operational torque estimates for shoulder motors. Initial simulations indicate that the motors of interest have been properly sized. PMID- 30441446 TI - A New Fully Automated Random-Forest Algorithm for Sleep Staging. AB - Rapid eye movement (REM) sleep behavior disorder is considered the prodromal stage of alpha-synucleinopathies. Its diagnosis requires careful detection of REM sleep and the gold standard manual sleep staging is inconsistent and expensive. This work proposes a new automatic sleep staging model to add robust automation to such applications, using only electroencephalography (EEG) and electrooculography (EOG) recordings. The publicly available ISRUC-Sleep database was used to optimize the design of the proposed model. The model was trained and tested on subgroup-I consisting of 100 subjects with evidence of having different sleep disorders and the polysomnographic data were manually scored by two individual experts. We divided the EOG and EEG recordings in overlapping moving 33-s epochs with step of 3s and for each of them we computed several time and frequency-domain features. The features were used to train a random forest classifier that was able to label each 33-s epoch with the probabilities of being wakefulness, REM and non-REM. The mean of the probability values of ten 33-s epochs were calculated, and the sleep stage with the highest probability was chosen to classify a 30-s epoch and matched with the manual staged hypnogram. The performance of the model was tested using 20-fold cross validation scheme. When the epochs where the scorers agreed were used, the classification achieved an overall accuracy of 92.6% and a Cohen's kappa of 0.856. Future validation on RBD patients is needed, but these performances are promising as first step of development of an automated diagnosis of RBD. PMID- 30441447 TI - Early Identification of Patentable Medical Innovations. AB - There is considerable interest in developing methods for early detection of medical advances which are likely to lead to effective treatments. Because the number of potentially significant discoveries published each year is very large, practically-useful detection must be accomplished using computational models. This paper considers a key component of this detection process - early identification of patentable innovations - and presents a novel machine learning based prediction model to perform the identification. Experiments demonstrate the efficacy of the proposed approach. PMID- 30441448 TI - A Deep Deterministic Policy Gradient Approach to Medication Dosing and Surveillance in the ICU. AB - Medication dosing in a critical care environment is a complex task that involves close monitoring of relevant physiologic and laboratory biomarkers and corresponding sequential adjustment of the prescribed dose. Misdosing of medications with narrow therapeutic windows (such as intravenous [IV] heparin) can result in preventable adverse events, decrease quality of care and increase cost. Therefore, a robust recommendation system can help clinicians by providing individualized dosing suggestions or corrections to existing protocols. We present a clinician-in-the-loop framework for adjusting IV heparin dose using deep reinforcement learning (RL). Our main objectives were to learn a new IV heparin dosing policy based on the multi-dimensional features of patients, and evaluate the effectiveness of the learned policy in the presence of other confounding factors that may contribute to heparin-related side effects. The data used in the experiments included 2598 intensive care patients from the publicly available MIMIC database and 2310 patients from the Emory University clinical data warehouse. Experimental results suggested that the distance from RL policy had a statistically significant association with anticoagulant complications $(p< 0.05)$, after adjusting for the effects of confounding factors. PMID- 30441449 TI - Prediction of ICU Readmissions Using Data at Patient Discharge. AB - Unplanned readmissions to ICU contribute to high health care costs and poor patient outcomes. 6-7% of all ICU cases see a readmission within 72 hours. Machine learning models on electronic health record data can help identify these cases, providing more information about short and long-term risks to clinicians at the time of ICU discharge. While time-toevent techniques have been used in clinical care, models that identify risks over time using higher-dimensional, non linear machine learning models need to be developed to present changes in risk with non-linear techniques. This work identifies risks of ICU readmissions at 24 hours, 72 hours, 7 days, 30 days, and bounceback readmissions in the same hospital admission with an AUROC for 72 hours of 0.76 and for bounceback of 0.84. PMID- 30441450 TI - Using Machine Learning Algorithms to Enhance the Management of Suicide Ideation. AB - Combat veterans; especially those with mental health conditions are an at risk group for suicidal ideation and behaviour. This study attempts to use machine learning algorithm to predict suicidal ideation (SI) in a treatment seeking veteran population. Questionnaire data from 738 patients consisting of veterans, still serving members of the Canadian Forces (CF) and Royal Canadian Mountain Police (RCMP) were examined to determine the likelihood of suicide ideation and to identify key variables for tracking the risk of suicide. Unlike conventional approaches we use pattern recognition methods, known collectively as machine learning (ML), to examine multivariate data and identify patterns associate with suicidal ideation. Our findings show that accurate prediction of SI of over 84.4% can be obtained with 25 variables, and 81% using as little as 10 variables primarily obtained from the patient health questionnaire (PHQ). Surprisingly the best identifiers for SI did not come from occupational experiences but rather the patient quality of health, signifying that these findings could be applied to the general population. Our results suggest that ML could assist clinicians to develop a better screening aid for suicidal ideation and behaviour. PMID- 30441452 TI - Medhere: A Smartwatch-based Medication Adherence Monitoring System using Machine Learning and Distributed Computing. AB - Poor medication adherence threatens an individual's health and is responsible for substantial medical costs in the United States annually. In order to improve medication adherence rates and provide timely reminders, we developed a smartwatch application that collects data from embedded inertial sensors, which include an accelerometer and gyroscope, to monitor a series of actions happening during an individual's medication intake. After the collected data was delivered to a server, Apache Spark was used to distribute the data and apply machine learning algorithms in order to predict several discrete actions including medication intake. By utilizing these tools, we were able to preprocess high frequency sensor data and apply a random forest algorithm, yielding high frequency and recall of the aforementioned actions. PMID- 30441451 TI - Undersampling and Bagging of Decision Trees in the Analysis of Cardiorespiratory Behavior for the Prediction of Extubation Readiness in Extremely Preterm Infants. AB - Extremely preterm infants often require endotracheal intubation and mechanical ventilation during the first days of life. Due to the detrimental effects of prolonged invasive mechanical ventilation (IMV), clinicians aim to extubate infants as soon as they deem them ready.Unfortunately, existing strategies for prediction of extubation readiness vary across clinicians and institutions, and lead to high reintubation rates. We present an approach using Random Forest classifiers for the analysis of cardiorespiratory variability to predict extubation readiness. We address the issue of data imbalance by employing random undersampling of examples from the majority class before training each Decision Tree in a bag. By incorporating clinical domain knowledge, we further demonstrate that our classifier could have identified 71% of infants who failed extubation, while maintaining a success detection rate of 78%. PMID- 30441454 TI - Exploring the Feasibility of EMG Based Interaction for Assessing Cognitive Capacity in Virtual Reality. AB - With the growth and aging of the world population, the prevalence of cognitive diseases and disabilities like dementia and mild cognitive impairments increases. To determine the influence of such diseases, find therapeutic effects and further improve quality of life, cognitive assessment and training is required. This can be done with the application of high immersive technologies like virtual reality.In this paper we evaluate the feasibility of an electromyography (EMG) arm muscle-motion based interaction technique for controlling a VR cognitive performance diagnostic and training environment. Therefore, we compared the state of-theart controller input to our EMG based approach in terms of presence and user experience.Results show significant differences in terms of Novelty and Dependability. Since there are only few significant differences regarding presence and user experience, the advantage of applying a more demanding physical motion interaction approach (EMG), seems to be a promising method with the potential of having a positive effect on the cognitive training progress. This is mainly caused by the fact that the implemented gesture interaction reinforces the connection between decision making and action execution. PMID- 30441453 TI - Monitoring the Effect of Contact Pressure on Bioimpedance Measurements. AB - This paper presents preliminary results on the effect of contact pressure on bioimpedance measurements in an excised section of human colon tissue. The impedance measurements were performed with a small diameter probe suitable for in vivo use, which is capable of measuring contact force. Force measurements are performed by fiber optic sensor which consisted of a Fiber Bragg Grating. The obtained results highlight the importance on limiting the applied pressure during bioimpedance measurements. PMID- 30441455 TI - Performance of conformable, dry EEG sensors. AB - We have recently developed a conformable solid state material solution (carbon nanofiber filled polydimethylsilisoxane, CNF-PDMS) for electroencephalography (EEG) electrodes. In this study, we tested the efficacy of electrodes molded from this material to record well studied neural phenomena using a battery of standard laboratory tasks. Event related potential (ERP) and eyes open/closed results show performance matching that of commercially available metal-pin based dry EEG electrode, while summary statistics (correlation and RMSE) show matched and even improved ability to track local and global fluctuations in EEG. We present baseline data that demonstrates CNFPDMS is a viable solution for conformable, safe, dry EEG electrodes. PMID- 30441456 TI - Signal Quality and Electrode-Skin Impedance Evaluation in the Context of Wearable Electroencephalographic Systems. AB - Recent advancement in technology has brought about increase in the application areas of wearable electroencephalographic devices. In that, new types of electrodes take place, and particular attention is needed to ensure the required quality of obtained signals. In this study, we evaluate electrode-skin impedance and signal quality for several kinds of electrodes when used in conditions typical for wearable devices. Results suggest that active dry electrode coated with gold alloy is superior while it was challenging to obtain appropriate signal quality when using passive dry electrodes. We also demonstrate electrode-skin impedance measurement using the analog frontend ADS1299, which is suitable for implementation in wearable devices. PMID- 30441457 TI - Smartphone-based Compression-Induced Scope with Temperature Sensor for Inflammatory Breast Cancer Screening. AB - The Smartphone-based Compression-induced Scope (SCIS) is a mobile device designed to sense the mechanical properties of tumors. Here, an SCIS system with an infrared temperature (SCIS-T) sensor is developed. The color and texture information of target skin are extracted from the SCIST images using a color based edge detection technique and a texture filter. This new system provides mechanical properties (size, elasticity) of the inclusion as well as the skin surface (color, temperature, texture) characteristics. The application of this system is in the identification of inflammatory breast cancer, which is characterized by color, texture, and temperature change. The device is tested using chicken breast phantoms with embedded silicone inclusion. PMID- 30441458 TI - Estimation of Spherical Refractive Errors Using Virtual Reality Headset. AB - Refractive errors are the most common visual defects in humans. They are corrected using lenses whose power is determined using expensive and bulky devices operated by trained professionals. This limits the outreach of eye- health care. We exploit commercial virtual reality (VR) setup to create a portable and inexpensive system for subjective estimation of spherical refractive errors. In doing so, we aim to keep hardware additions simple and to a minimum. We add a plain reflecting mirror in a VR headset to project optotypes on programmable focal planes at varying distances from the subject's eye. An interactive interface uses feedback from the user to estimate accommodation range and spherical refractive errors automatically. We compute the range and precision of our system, and validate them in a user trial study. The proposed setup strongly agrees with clinical subjective refraction. PMID- 30441459 TI - NOS.E: A New Fast Response Electronic Nose Health Monitoring System. AB - We present a practical electronic nose (e-nose) sys-tem, NOS.E, for the rapid detection and identification of human health conditions. By detecting the changes in the composition of an individual's respiratory gases, which have been shown to be linked to changes in metabolism, e-nose systems can be used to characterize the physical health condition. We demonstrated our system's viability with a simple data set consists of breath collected under three different scenarios from one volunteer. Our preliminary results show the popular classifier SVM can discriminate NOS.E's responses under the three scenarios with high performance. In future work, we will aim to gather a more varied data set to test NOS.E's abilities. PMID- 30441460 TI - On the Effective Differentiation and Monitoring of Variable Degrees of Hyperbilirubinemia Severity Through Noninvasive Screening Protocols. AB - The presence of abnormal amounts of bilirubin in the blood stream and skin, usually referred to as hyperbilirubinemia, is associated with a wide range of pathologies that can pose considerable risks for human health. The early and effective screening of the severity degrees of this medical condition can play an important role on the selection of the appropriate treatment for the associated pathologies. This, in turn, can minimize the need for more aggressive and costly therapeutic interventions which can themselves pose considerable risks for morbidity and mortality. The current noninvasive protocols used to differentiate these severity degrees, however, are hindered by the relatively limited knowledge about the impact of different amounts of extravascular bilirubin on skin spectral responses and on the onset of jaundice, the resulting yellow-tinted skin appearance. In this paper, we address this open problem through controlled in silico experiments supported by measured data provided in the related literature. Our experimental findings bring biophysically-based insights to bear on the clarification of this biomedical entanglement, and unveil optical features that can potentially lead to more effective screening protocols for the noninvasive differentiation and monitoring of variable degrees of hyperbilirubinemia severity. PMID- 30441461 TI - EmoSense: Automatically Sensing Emotions From Speech By Multi-way Classification. AB - Reliably detecting emotions is a topic of current research in understanding mental health. Among the many modes of detecting emotion, audio has a prominent place. In this paper, we propose a two-level, multi-way classifier applied to classification of seven emotions from the standard Emo-DB database. The multi-way classifier is an automated methodology of analyzing a confusion matrix of a first level classifier to build more classifiers at the next level. A random forest classifier is used on state-of-the-art features for analyzing affective speech. The confusion matrix from this classification level is analyzed to decide, for each class, which other classes are most confused by using a threshold on the misclassification rate. For the chosen pairs, second level classifiers are built and trained on the same data. Its performance on the training-set (73.3{?%) as well as a non-intersecting training set (72.9{?%) are both better than state-of the-art performance. We initiate a possible explanation of the performance improvement by considering the confusion among emotions placed on Russel's circumplex model. PMID- 30441462 TI - A Data-Driven Human Activity Classification Method for an Intelligent Hospital Bed. AB - Bedridden patients always need more attention in order to prevent unexpected falling, bedsores and other dangerous situations in daily care. This work proposes a data-driven classification method to recognize different bed-related human activities including exiting the bed, turning over, stretching out for something on the bedside table, sitting up and lying down by analyzing the real time signals that are acquired from four load cells installed around the hospital bed. Considering the dynamic characteristics of the signals, dynamic principal component analysis (DPCA), here serving as a pre-processing step, is firstly utilized to extract both static and dynamic relations from the variables. Then the final statistical model for each class is established by Gaussian mixture model (GMM) with Figueiredo-Jain algorithm that can optimally select the number of components. An alarm will be triggered when a noteworthy action is detected. The proposed method has achieved superior performance using the experimental data from 10 adult volunteers. The results move a step forward towards the design of an intelligent hospital bed for practical applications. PMID- 30441463 TI - Change Detection of Sleeping Conditions based on Multipoint Ambient Sensing of Comforter on Bed. AB - This paper describes a method for the detection of changes in sleeping conditions using multipoint ambient sensing for safety and amenity in the sleep environment. This method continuously detects changes during sleep, such as the movements of the person and bedding based on the measurement of acceleration, temperature and humidity of the comforter. Through the measurement of these ambient conditions, this system improves sleep quality and prevents accidents, such as falling off the bed. In this study, a basic system using internet of things (IoT) devices is constructed, and performance verification is conducted. The experimental results show the feasibility of the proposed method. PMID- 30441464 TI - InstaBP: Cuff-less Blood Pressure Monitoring on Smartphone using Single PPG Sensor. AB - Cuff-less Blood Pressure (BP) monitoring has gained interest of the research community in recent years, due to its importance in continuous and non-invasive monitoring of BP for early detection of hypertension, thereby reducing mortality. Several approaches that involve photoplethysmography (PPG) and Pulse Transit Time (PTT) have been explored with promising results; however the requirement of two sensors makes them obtrusive for continuous use. Single PPG sensor approaches using machine learning have also been attempted, but there are certain deficiencies in these methods as they go for a one-size-fits-all approach. In this work, we develop an ensemble of BP prediction models based on demographic and physiological partitioning. Also, we incorporate a set of unique PPG features into our models, which results in test accuracies of 5 mmHg Mean Absolute Error (MAE) for Diastolic BP, and 6.9 mmHg MAE for Systolic BP. Given our marked improvement over ubiquitous models (18% for Diastolic BP and 11.5% for Systolic BP), this approach opens up avenues where single PPG sensor based methods can predict BP with a high degree of accuracy. This is a big step towards developing continuous BP monitoring systems, and can help in better management of cardiac health. PMID- 30441465 TI - Vision-based Bed Detection for Hospital Patient Monitoring System. AB - In recent years, as a way to prevent patient fall-down, studies have been conducted using patient room cameras to detect the patient behavior of leaving the bed. It is very important to specify the patient bed location in the process of detecting patient behavior using camera images. In this study, we propose a method to specify the patient bed location using a monocular camera. In this proposal, we convert a camera image viewpoint into a bird's-eye view image as a preprocessing step. By using planer perspective transformation, it is possible to display the bed as a rectangular shape with a fixed ratio, even if the bed location or camera position is changed. Therefore, it is possible to detect the bed location with a high degree of accuracy by means of machine learning. The simulation experiment results confirm that the average error and standard deviation of the bed coordinates are 7.9 and 5.0 pixels, respectively; in the practical scene, we confirm that the average error and standard deviation of the bed coordinates are 12.1 and 8.2 pixels, respectively. PMID- 30441466 TI - Thermal Camera Based Physiological Monitoring with an Assistive Robot. AB - This paper presents a physiological monitoring system for assistive robots using a thermal camera. It is based on the detection of subtle changes in temperature observed on different parts of the face. First, we segment and estimate these face regions on thermal images. Then, by applying Fourier analysis on temperature data, we estimate respiration and heartbeat rate. This physiological monitoring system has been integrated in an assistive robot for elderly people at home, as part of the ENRICHME project. Its performance has been evaluated on a new thermal dataset for physiological monitoring, which is made publicly available for researchpurposes. PMID- 30441467 TI - Classification of sEMG Signals for the Detection of Vocal Fatigue based on VFI Scores. AB - In this new research, we expand on our previous system for vocal fatigue detection by adding five new features in the classifier. We also perform further testing on 37 test subjects. The goals were: 1) to classify subjects performing normal versus simulated pressed vocal gestures; 2) to distinguish vocally healthy from vocally fatigued subjects as determined by VFI score on factor 1; and 3) to determine the validity of the labels vis-a-vis the choice of this same VFI-factor 1 boundary. As the results demonstrated, the choice of classifier and the new features were quite appropriate, while there is margin for better choices of the VFI-factor-1 boundary. PMID- 30441468 TI - Deniosing Autoencoder-based Modification of RRI data with Premature Ventricular Contraction for Precise Heart Rate Variability Analysis. AB - The fluctuation of an RR interval (RRI) on an electrocardiogram (ECG) is called heart rate variability (HRV). HRV reflects the autonomic nerve activity, thus HRV analysis has been used for health monitoring such as stress estimation, drowsiness detection, epileptic seizure prediction, and cardiovascular disease diagnosis. However, RRI and HRV features are easily affected by arrhythmia, which deteriorates the health monitoring performance. Premature ventricular contraction (PVC) is common arrhythmia that many healthy persons have. Thus, a new methodology for dealing with RRI fluctuation disturbed by PVC needs to be developed for realizing precise health monitoring. To modify RRI data affected by PVC, the present work proposes a new method based on a denoising autoencoder (DAE), which reconstructs original input data from the noisy input data by using a neural network. The proposed method, referred to as DAE-based RRI modification (DAERM), aims to correct the disturbed RRI data by regarding PVC as artifacts. The present work demonstrated the usefulness of the proposed DAE-RM through its application to real RRI data with artificial PVC (PVC-RRI). The result showed that DAE-RM successfully modified PVC-RRI data. In fact, the root means squared error (RMSE) of the modified RRI was improved by 83.5% from the PVC-RRI. The proposed DAERM will contribute to realizing precise HRV-based health monitoring in the future. PMID- 30441469 TI - Spatial Patterning from an Integrated Wnt/beta-catenin and Notch/Delta Gene Circuit. AB - Classically, the Wnt/beta-catenin and Notch /Delta signaling pathways were thought to operate through separate mechanisms, performing distinct roles in tissue patterning. However, it has been shown that b-catenin activates transcription of Hesl, a signaling intermediate in the Notch /Delta pathway that controls its lateral inhibition mechanism. To investigate this non-canonical crosstalk mechanism, a new gene circuit, integrating the two pathways, is proposed and simulated in two-cell and multi-cell environments. This model also captures both Paneth cell- mediated and mesenchymal Wnt production. The simulations verify that the gene circuit is temporally bistable and capable of forming a pattern on a multi-cell grid. Last, the model exhibits a bifurcation based on the steady state concentration of Wnt and the relative amount of control b-catenin has over the Hesl promoter, providing a possible mechanism to explain why a homogeneous population of transit amplifying cells is observed directly above the more diverse stem niche. PMID- 30441470 TI - Stochastic Modeling of the Co-Regulation between Early and E8 Promoters in Human Papillomavirus. AB - High risk HPV can induce cervical and oropharyngeal cancerous Iesions. The initial phase of the infection is characterized by a fine regulation of the viral DNA replication, in order to maintain 10-100 DNA copies per cell. Such regulation is primarily controlled by El and E2 proteins produced by the early promoter. The recently discovered E8 promoter is capable to co-regulate the early one in order to maintain a low and constant viral DNA copy number.The aim of this study is to develop a novel stochastic mathematical model of the co-regulation between the E8 and the early promoter, with the main purpose to rigorously show the E8 promoter capability to finely regulate the HPV transcripts which control the DNA replication in the first stages of the infection.The model, condensing the biological knowledge present in literature, describes the interaction between the two promoters and shows how the E8 co-regulation is capable to reject the stochastic noise of E2 gene expression to a higher extent than the early promoter negative auto-feedback. This proves the capability of the E8 promoter to finely control the HPV genomes copy number. PMID- 30441471 TI - Automated Extension of Cell Signaling Models with Genetic Algorithm. AB - The number of published results in biology and medicine is growing at an exceeding rate, and thus, extracting relevant information for building useful models is becoming very laborious. Furthermore, with the newly published information, previously built models need to be extended and updated, and with the voluminous literature, it is necessary to automate the model extension process. In this work, we introduce a methodology for extending logical models of cell signaling networks using a Genetic Algorithm (GA). The proposed procedure is developed to optimally search for a subset of biological interactions that extend logical models while preserving their desired behavior. To evaluate the effectiveness of the proposed methodology, we randomly removed a subset of elements from an existing T cell differentiation model, and mixed them with randomly created interactions to mimic the output of literature reading. We then used the GA to search for the extensions that optimally reconstructed the model. The simulation results showed that the GA was able to find a set of extensions that preserved the desired behavior of the model with fewer elements than the original model. The results demonstrate that the GA is an efficient tool for model extension, and suggest that it can be used for model reduction as well. PMID- 30441472 TI - Identifying progressive gene network perturbation from single-cell RNA-seq data. AB - Identifying the gene regulatory networks that control development or disease is one of the most important problems in biology. Here, we introduce a computational approach, called PIPER (ProgressIve network PERturbation), to identify the perturbed genes that drive differences in the gene regulatory network across different points in a biological progression. PIPER employs algorithms tailor made for single cell RNA sequencing (scRNA-seq) data to jointly identify gene networks for multiple progressive conditions. It then performs differential network analysis along the identified gene networks to identify master regulators. We demonstrate that PIPER outperforms state-of-the-art alternative methods on simulated data and is able to predict known key regulators of differentiation on real scRNA-Seq datasets. PMID- 30441473 TI - Improving the Detection of Protein Complexes by Predicting Novel Missing Interactome Links in the Protein-Protein Interaction Network. AB - Identifying protein complexes within a protein-protein interaction (PPI) networks is a crucial task in computational biology that helps to facilitate a better understanding of the cellular mechanisms it is possible to observe in various organisms. Datasets of predicted PPIs have been determined using high-throughput experimental technology. However, the datasets typically contain many spurious interactions. It is essential that these interactions, observed in the given datasets, are validated before they are employed to predict protein complexes. This paper describes the identification of missing interactome links in the PPI network as a way of improving the detection of protein complexes. The missing links have been identified by extracting several topological features. These are subsequently employed in conjunction with a two-class boosted decision-tree classifier to develop a machine-learning model that is capable of distinguishing between existing and non-existing interactome links. The model was trained on a PPI network that consisted of 1,622 proteins and 9,074 interactions, then tested on another PPI network that consisted of 1,430 proteins and 6,531 interactions. All 6,531 interactions were identified with a precision of 0.994 and a recall of 1. The model was also able to detect 37 novel interactions that were then validated using a STRING database of known and predicted PPIs. The detection of the protein complexes using CIusterONE was improved by the inclusion of the 37 novel interactions. PMID- 30441474 TI - Smart Data Analytics approach to model Complex Biochemical Oscillations in Hippocampal Neurons. AB - Calcium spiking can be used for drug screening studies in pharmaceutical industries. However, performing experiments for multiple drugs and doses are highly expensive. The oscillatory behavior of calcium spiking data demonstrates extreme nonlinearity and phase singularity. This makes it more challenging to construct physics-based models for the experimental observations. In this scenario, data based modelling, such as Artificial Neural Networks (ANN), and thereafter the model based prediction of calcium profiles may offer a cost effective and time saving solution. Therefore, a novel ANN building algorithm is presented in the current work, where data based simultaneous estimation of ANN architecture and nonlinear activation function stands out as the main highlight. The resultant ANN was then used to learn the oscillatory behavior in calcium ion concentration data, obtained from hippocampal neurons of rats by fluorescent labelling and confocal imaging. The paper shows that the novel technique can be used in general for emulating biochemical oscillations (with or without drug injection) and can be implemented to predict the cell-drug responses for intermediated doses. The proposed algorithm can also be used for obtaining high resolution data from low resolution experimental measurements. PMID- 30441475 TI - In Situ Measurement of Stimulus Induced pH Changes Using ThinFilm Embedded IrOx pH Electrodes. AB - The high complexity of the biological response to implanted materials builds a serious barrier against implanted recording and stimulation electrode arrays to succeed in clinically relevant chronic studies. Some of the cell and molecular interactions and their contribution to inflammation and device failure are still unclear. The interrelated mechanisms leading to tissue damage and electrode array failure during simultaneous faradaic, electrochemical reactions and biological response under electrical stimulation are not understood sufficiently. One variable, with which inflammatory and electrode surface processes can be analyzed and assessed, is the pH change in the immediate environment of the material tissue interface. Here, the greatest challenges are in the biocompatibility and in-vivo long-term stability of selected sensor materials, the measurement of small transient pH oscillations and positioning of the sensor at a defined and nearest possible distance in the micrometer range, to the site of activity without the pH sensing being affected by the material- issue interactions itself. This work represents the in-situ measurement of local and transient pH changes at apulsed electrode with an embedded in-vivo compatible pH sensor and therein differentiating from current approaches of pH sensing during electrical stimulation. PMID- 30441476 TI - Investigating Upper Limb Movement Classification on Users with Tetraplegia as a Possible Neuroprosthesis Interface. AB - Spinal cord injury (SCI), stroke and other nervous system conditions can result in partial or total paralysis of individual's limbs. Numerous technologies have been proposed to assist neurorehabilitation or movement restoration, e.g. robotics or neuroprosthesis. However, individuals with tetraplegia often find difficult to pilot these devices. We developed a system based on a single inertial measurement unit located on the upper limb that is able to classify performed movements using principal component analysis. We analyzed three calibration algorithms: unsupervised learning, supervised learning and adaptive learning. Eight participants with tetraplegia (C4C7) piloted three different postures in a robotic hand. We achieved 89% accuracy using the supervised learning algorithm. Through offline simulation, we found accuracies of 76% on the unsupervised learning, and 88% on the adaptive one. PMID- 30441477 TI - A Novel uECoG Electrode Interface for Comparison of Local and Common Averaged Referenced Signals. AB - Micro-electrocorticography (uECoG) is a minimally invasive neural interface that allows for recording from the surface of the brain with high spatial and temporal resolution [1], [2]. However, discerning multi-unit and local field potential (LFP) activity with potentially highly-correlated signals across a dense uECoG array can be challenging. Here we describe a novel uECoG design to compare the effect of referencing recordings to a local reference electrode and common average referencing (CAR). The filtering effect and the significant increase in signal to noise ratio of the evoked response (ESNR) can be seen after re referencing for both types of referencing. In a preliminary analysis, re referencing the uECoG signals can increase recording performance at high contact densities in the auditory cortex. This also provides promising evidence for a versatile in-house fabricated uECoG electrode. PMID- 30441478 TI - in vitro Reactive-Accelerated-Aging (RAA) Assessment of Tissue-Engineered Electronic Nerve Interfaces (TEENI). AB - A reactive-accelerated-aging (RAA) soak-test has been employed to challenge microfabricated neural interface devices against an aggressive environment that mimics worstcase chronic physiological inflammation. The RAA tests were able to determine the ability of different materials to increase the adhesive strength of the polyimide and platinum-goldplatinum metallization thin-film interface. It was found that a 3-day RAA soak-test at 87 degrees C in phosphate buffered saline with 10 to 20 mM hydrogen peroxide resulted in adhesive failure of the metal polyimide interface when titanium was used as the primary adhesion promotor. The addition of hydrogenated amorphous silicon carbide was able to eliminate the onset of adhesive failure of the metal-polyimide interface during 7-day RAA soak tests. However, sporadic cracking of the silicon carbide layer resulted in a minority of broken metal interconnects that resulted in failed electrodes. These tests have demonstrated the ability of RAA soak tests to provide rapid in vitro assessment of microfabricated neural interfaces and thereby reduce the time needed to develop synthetic methods to fabricate chronically reliable devices. PMID- 30441479 TI - On-chip Detection of Single Vesicle Release from Neuroblastoma Cells using Monolithic CMOS Bioelectronics. AB - Neuroblastoma cells are often used as a cell model to study Parkinson's disease, which causes reduced dopamine release in substantia nigra, the midbrain that controls movements. In this paper, we developed a 1024-ch monolithic CMOS sensor array that has the spatiotemporal resolution as well as low-noise performance to monitor single vesicle release of dopamine from neuroblastoma cells. The CMOS device integrates 1024 on-chip electrodes with an individual size of $15 ?mu ?mathrm{m}?times 15 ?mu ?mathrm{m}$ and 1024 transimpedance amplifiers for each electrode, which are each capable of measuring sub-pA current. Thus, this device can be used to study the detailed molecular dynamics of dopamine secretion at single vesicle resolution. PMID- 30441480 TI - Carbon Fiber Electrodes for in Vivo Spinal Cord Recordings. AB - Development of micro electrode arrays for neural recording is an active field that thrives on novel materials and fabrication techniques offered by micro fabrication technology. The material and mechanical properties of microelectrode arrays have a critical role on the quality and longevity of neural signals. In this study, carbon fiber microelectrode (CFME) bundles were developed and implanted in the spinal cord of experimental animals for textbf{?textit{in vivo{recording. Neural data analysis revealed that single spikes could successfully be recorded and sorted. Removal of approximately $75 ?mu ?mathrm{m}$ of the parylene-C coating at the tips of the fibers increased the signalto-noise ratio. Connecting multiple (three) carbon fiber filaments to the same recording channel did not deteriorate the signal quality compared to that of undesheathed fibers. Immunohistochemistry showed that electrode tips were splayed in tissue after implantation and CF bundles had a small footprint with mild encapsulation around them. These results are very promising for the use of CFME bundles for recordings of spinal cord signals in behaving animals. PMID- 30441481 TI - A Modified Common Spatial Pattern Algorithm Customized for Feature Dimensionality Reduction in fNIRS-Based BCIs. AB - Functional near-infrared spectroscopy (fNIRS) is a non-invasive multi-channel imaging tool for assessing brain activities, which has shown its high potential in brain-computer interface (BCI) technique. Most previous studies have focused on constructing high dimensional features from whole channels, adding to the complexity of their classifiers. Another multi-channel source for BCI is electroencephalograph (EEG), which possesses different spatial and temporal features from fNIRS. In EEG field, Common Spatial Pattern (CSP) algorithm is widely used aimed at dimensionality reduction. In our article, we modified it based on the characteristics of fNIRS and evaluated its effectiveness in discriminating Mental Arithmetic (MA) against resting status in an open-access dataset. The Modified Common Spatial Pattern algorithm significantly outperforms CSP algorithm in fNIRS-based BCI and shows its potential in further BCI related explorations. PMID- 30441482 TI - Realization of Direction Selective Motor Learning in the Artificial Cerebellum: Simulation on the Vestibuloocular Reflex Adaptation. AB - The vestibule-ocular reflex (VOR) has been one of the most popular model systems to investigate the role of the cerebellum in adaptive motor control. VOR motor learning can be experimentally induced by continuous application of combination of head rotating stimulus and optokinetic stimulus. For instance, in phase application of those stimuli decreases VOR gain defined by eye velocity of VOR in the dark divided by head velocity, while out of phase of those increases VOR gain. It has been known that VOR gain is modifiable context-dependently. Namely, VOR gains for leftward and rightward head rotations can be respectively increased and decreased simultaneously. The cerebellar signal processing underlying the context dependent VOR motor learning, however, is not fully uncovered. In the present study, we simulated direction selective VOR motor learning, using the artificial cerebellar neuronal network model that we developed to understand the origin of the cerebellar motor learning. PMID- 30441483 TI - A Randomised Ensemble Learning Approach for Multiclass Motor Imagery Classification Using Error Correcting Output Coding. AB - Common Spectral Pattern (CSP) algorithm remains predominant for feature extraction from multichannel EEG motor imagery data. However, multiclass classification of from this featureset has been a challenging job. Different approaches have been proposed to be applied on featureset of different EEG subbands to achieve significant classification accuracy. Ensemble learning is very effective in this context to achieve higher accuracy in Brain-Computer Interface (BCI) domain. In this study, we have proposed enhanced classification algorithms to achieve higher classification accuracies. The methods were evaluated against the motor imagery data from Dataset 2a of the publicly available BCI Competition IV (2008). This dataset consists of 22 channels EEG data of 9 subjects for four different movements. A tree based ensemble approach for supervised classification, Extra-Trees algorithm, has been proposed in this paper and also evaluated for its efficacy on this dataset to classify between left hand and right hand movement imaginations. Moreover, this classifier has its inherent capability to select optimum features. Furthermore, in this paper an extension of the binary classification into multiclass domain is also implemented with error correcting output codes (ECOC) approach using the same dataset. Subject-specific frequency bands $?alpha$ (8-12Hz) and $?beta$ (12-30Hz) along with $HG$ (70-100Hz) were considered to extract CSP features. We have achieved an individual peak accuracy of 98z and 84z in binary class and multiclass classification respectively. Furthermore, the results yielded a mean kappa value of 0.58 across all the subjects. This kappa value is higher than of the winner of competition and also from the most of the other approaches applied in this dataset. PMID- 30441484 TI - A Deep Convolutional Neural Network Based Classification Of Multi-Class Motor Imagery With Improved Generalization. AB - Motor imagery (MI) based brain-computer interface (BCI) plays a crucial role in various scenarios ranging from post-traumatic rehabilitation to control prosthetics. Computer-aided interpretation of MI has augmented prior mentioned scenarios since decades but failed to address interpersonal variability. Such variability further escalates in case of multi-class MI, which is currently a common practice. The failures due to interpersonal variability can be attributed to handcrafted features as they failed to extract more generalized features. The proposed approach employs convolution neural network (CNN) based model with both filtering (through axis shuffling) and feature extraction to avail end-to-end training. Axis shuffling is performed adopted in initial blocks of the model for 1D preprocessing and reduce the parameters required. Such practice has avoided the overfitting which resulted in an improved generalized model. Publicly available BCI Competition-IV 2a dataset is considered to evaluate the proposed model. The proposed model has demonstrated the capability to identify subject specific frequency band with an average and highest accuracy of 70.5% and S3.6% respectively. Proposed CNN model can classify in real time without relying on accelerated computing device like GPU. PMID- 30441485 TI - A Robust Low-Cost EEG Motor Imagery-Based Brain-Computer Interface. AB - Motor imagery (MI) based Brain-Computer Interfaces (BCIs) are a viable option for giving locked-in syndrome patients independence and communicability. BCIs comprising expensive medical-grade EEG systems evaluated in carefully-controlled, artificial environments are impractical for take-home use. Previous studies evaluated low-cost systems; however, performance was suboptimal or inconclusive. Here we evaluated a low-cost EEG system, OpenBCI, in a natural environment and leveraged neurofeedback, deep learning, and wider temporal windows to improve performance. $?mu-$rhythm data collected over the sensorimotor cortex from healthy participants performing relaxation and right-handed MI tasks were used to train a multi-layer perceptron binary classifier using deep learning. We showed that our method outperforms previous OpenBCI MI-based BCIs, thereby extending the BCI capabilities of this low-cost device. PMID- 30441486 TI - Current source density estimates improve the discriminability of scalp-level brain connectivity features related to motor-imagery tasks. AB - Recent progress in the number of studies involving brain connectivity analysis of motor imagery (MI) tasks for brain-computer interface (BCI) systems has warranted the need for pre-processing methods. The objective of this study is to evaluate the impact of current source density (CSD) estimation from raw electroencephalogram (EEG) signals on the classification performance of scalp level brain connectivity feature based MI-BCI. In particular, time-domain partial Granger causality (PGC) method was implemented on the raw EEG signals and CSD signals of a publicly available dataset for the estimation of brain connectivity features. Moreover, pairwise binary classifications of four different MI tasks were performed in inter-session and intra-session conditions using a support vector machine classifier. The results showed that CSD provided a statistically significant increase of the AUC: 20.28% in the inter-session condition; 12.54% and 13.92% with session 01 and session 02, respectively, in the intra-session condition. These results show that pre-processing of EEG signals is crucial for single-trial connectivity features based MI-BCI systems and CSD can enhance their overall performance. PMID- 30441487 TI - Group Sparsity based Sparse-Sampling CT Reconstruction. AB - Classical total variation (TV) based iterative re-construction algorithms assume that the signal is piecewise smooth, which causes reconstruction results to suffer from the over-smoothing effect. To address this problem, this work presents a novel computed tomography (CT) reconstruction method for the sparse sampling problem called the group- sparsity regularization-based simultaneous algebraic reconstruction technique (GSR-SART). Group-based sparse representation, which utilizes the concept of a group as the basic unit of sparse representation instead of a patch, is introduced as the image domain prior regularization term to eliminate the over-smoothing effect. By grouping the nonlocal patches into different clusters with similarity measured by Euclidean distance, the sparsity and nonlocal similarity in a single image are simultaneously explored. The split Bregman iteration algorithm is applied to obtain the numerical scheme. Experimental results demonstrate that our method both qualitatively and quantitatively outperforms several existing reconstruction methods, including filtered back projection, expectation maximization, SART, and TV-based projections onto convex sets. PMID- 30441488 TI - Discrete Heat Kernel Smoothing in Irregular Image Domains. AB - We present the discrete version of heat kernel smoothing on graph data structure. The method is used to smooth data in an irregularly shaped domains in 3D images. New statistical properties of heat kernel smoothing are derived. As an application, we show how to filter out noisy data in the lung blood vessel trees obtained from computed tomography. The method can be further used in representing the complex vessel trees parametrically as a linear combination of basis functions and extracting the skeleton representation of the trees. PMID- 30441489 TI - A Novel 3D Connection Algorithm of Mitochondria From ATUM-SEM Stacks Based on Segmentation Information in Context. AB - Recent researches have shown that the relation between mitochondrial function and degenerative disorders is closely related to aging, such as Alzheimer's and Parkinson's diseases. Because these studies expose the need for detailed analysis of high-resolution physical alterations in mitochondria, three dimensional (3D) visualization of mitochondria from electron microscopy (EM) images is coming into prominence. To this end, how to develop suitable segmentation algorithms and connection algorithms has attracted our attentions. Since previous algorithms have shown preferable segmentation performance on mitochondria with different shapes and sizes. In this paper, we propose to utilize the segmentation information instead of detection information in context to obtain the mitochondrial connection relation in adjacent layers. Additionally, different from previous methods, we present a novel and effective connection approach by obtaining sparse matrixes and implementing a forward connection mode. Experiments on automated tape-collecting ultramicrotome scanning electron microscopy (ATUM SEM) stacks demonstrate that our approach can effectively handle with the case of split and merge, and achieve a comparable connection quality measured by split error and merge error. PMID- 30441490 TI - Compressive Sensing for Breast Microwave Imaging. AB - This work proposes a novel microwave imaging (MWI) multi-frequency technique, which combines compressive sensing (CS) with the well-known distorted Born iterative method (DBIM) to enhance the accuracy in the imaging procedure. CS strategies are emerging as a promising tool in MWI applications, which can also reduce the number of data samples. The proposed approach is based on an iterative shrinkage thresholding algorithm (ISTA), which has been modified to include an automatic and adaptive selection of multi-threshold values. The proposed implementation is applied in reconstruction of two-dimensional numerical heterogeneous breast phantoms, where it outer-performs the standard thresholding implementation and proves to be an interesting tool for medical imaging applications. PMID- 30441491 TI - Scanning Acoustic Microscopy Image Super-Resolution using Bilateral Weighted Total Variation Regularization. AB - Scanning acoustic microscopy (SAM) is an imaging modality used to obtain 2D maps of acoustical and mechanical properties of soft tissues and uses ultrasound transducers operating at very high-frequencies. Such transducers are challenging and costly to manufacture, and SAM systems at higher frequencies become more sensitive to experimental issues. Nevertheless, biomedical applications of SAM often require spatial resolutions nearly as good as light microscopy. In addition, stained histology photomicrographs of thin sections of tissues are easily obtained with the necessary resolution and accuracy. Consequently, the aim of this study is to introduce a bilateral approach that enhances the resolution of SAM images by leveraging the co-registered high-resolution histology image. We propose to use bilateral weighted total variation regularization to solve the super-resolution problem. A fast matrix-less solver is developed by utilizing the Alternating Direction Method of Multipliers (ADMM) and solving the least squares problem in one ADMM step in the Fourier domain. Reconstruction results on experimentally recorded SAM and histology data show promising improvement over the classical techniques. PMID- 30441492 TI - Low-dose CT Denoising with Dilated Residual Network. AB - Low-dose Computed Tomography (CT) is considered a solution for reducing the risk of X-ray radiation; however, lowering the X-ray current results in a degraded reconstructed image. To improve the quality of the image, different noise removal techniques have been proposed. Con- volutional neural networks also have shown promising results in denoising the low-dose CT images. In this paper, a deep residual network with dilated convolution is proposed. The identity mappings pass the signal to the higher layers and improve the performance of the network and its training time. Moreover, employing dilated convolution helps to increase the receptive field faster. Dilated convolution makes it possible to achieve good results with fewer layers and less computational costs. The proposed network learns end to end mapping from low-dose to normal-dose CT images. PMID- 30441493 TI - A Radiating Near-Field 24 GHz Radar Stethoscope. AB - A prototype 24 GHz radar stethoscope has been developed for the diagnosis of heart sounds when direct contact with the skin is contraindicated. It is shown that a vibration sensing, bi-static radar operating in the near-field has a sensitivity maximum at a non-zero range and that maximum is proportional to the square of the radar operating frequency. By placing the instrument in the near field, close to, but not touching the skin, a 20 dB sensitivity increase can be demonstrated. The transmitter antenna has a hot spot in the near-field which further increases the stethoscope's sensitivity. The instrument is a modified, Doppler radar based, commercial RF motion detector that transmits very low RF power. When used as a stethoscope it is shown to pose no radiation hazard to the patient or medical personnel. An example is given to illustrate that the non contact radar stethoscope has an audio output that is comparable in characteristics and quality to a conventional, skin-contact, acoustic stethoscope. PMID- 30441494 TI - A Model for Waveform Dissimilarities in Dual-Depth Reflectance-PPG. AB - The pressure wave is attenuated as it travels through the vascular bed of tissue. Consequently, reflectance photoplethysmography (PPG) waveforms probed using dual penetrating wavelengths, such as green (G) and red R; the deepest) are dissimilar. To unravel the dual-depth aspect of PPG, we modeled the wavelength dependency of the shape of reflection-PPG signals in G (520-580 nm) and R (625 720nm). Skin compression perturbs the relative contributions of the dermal and subdermal blood volume variations sources (BVVs) to PPG and was used to verify our model. We acquired reflectance-PPG in G and R on the finger of nine subjects (ages, 26-32 yrs). Two parameters were used for describing dual-depth dissimilarities: the phase shift, $?phi $, between the first harmonics of the subdermal and dermal BVVs, and the observed phase shift (PS) between PPG signals in G and R. The average $?phi $ was 37.6, CI 95% [22.0, 53.2] degrees. At uncompressed skin, this corresponds to an average PS of 12.5, [7.8, 17.2] degrees. Our results suggest that phase parameters may enable microvascular characterization and diagnosis. PMID- 30441495 TI - BioEssence: A Wearable Olfactory Display that Monitors Cardio-respiratory Information to Support Mental Wellbeing. AB - This work introduces a novel wearable olfactory display that provides just-in time release of scents based on the physiological state of the wearer. The device can release up to three scents and passively captures subtle chest vibrations associated with the beating of the heart and respiration through clothes.BioEssenceiscontrolledviaacustom-madesmartphone app that allows the creation of physiological rules to trigger different scents (e.g., when the heart rate is above 80 beats per minute, release lavender scent). The device is wireless and lightweight, and it is designed to be used during daily life, clipped on clothes around the sternum area or used as a necklace. We provide a description of the design and implementation of the prototype and potential use cases in the context of mental wellbeing. PMID- 30441496 TI - Evaluation of a Visual Localization System for Environment Awareness in Assistive Devices. AB - A major hurdle for the widespread use of wearable assistive devices is determining, moment-by-moment, the control mode appropriate for a given terrain when faced with a complex, multi-terrain environment. Current control strategies focus mainly on measurements of user behavior and less on environment information. Here we demonstrate the application of location estimates from a vision-based localization system to obtain environment awareness by delineating various terrains into regions. Given the current location and region occupied by the user, a controller could be built to select appropriate modes, predict transitions, or to add error correction. We quantify the positional accuracy of location estimates, how well these estimates translate to classifying current region, and transitions. Performance was evaluated on eight participants without amputation wearing the sensor on the shank of the leg. We investigated the performance of an instantaneous region classifier, which used location estimates alone, and a time-history based region classifier, which used a Neural Network on a time history of location and height estimates to accomplish environment awareness. Four types of regions and six types of transitions were tested. The classifier using height estimates and time history provided accurate region labels at least 96% of the time, and accurately detected region transitions within 110 milliseconds. These results demonstrate the promise of localization for control of robotic assistive technology. PMID- 30441497 TI - A New Method to Prevent Unintentional Child Poisoning. AB - Unintentional child poisoning represents an increasingly important health issue in the United States and worldwide, partially due to increased use of drugs and food supplements. Biometric authentication is complex for pill bottles, but we propose a new method of user identification using touch capacitance during bottle opening attempts. A smart pill bottle could generate an immediate warning to deter a child from opening the bottle and send an alert to parents/guardians. In this paper, we present principle of operation and implementation of a prototype "safe bottle We present the results of pilot testing with 5 adults and 3 children using support vector machine (SVM) and neural network (NN). From 232 bottle opening events, our optimized NN generated no false detections of children as adults and four false detections of adults as children. Preliminary results indicate that smart pill bottles can be used to reliably detect children trying to open pill bottles and reduce risk of child-poisoning events. PMID- 30441498 TI - Use of Average Vertical Velocity and Difference in Altitude for Improving Automatic Fall Detection from Trunk Based Inertial and Barometric Pressure Measurements. AB - Despite the extensive research that has been carried out on automatic fall detection using wearable sensors, falls in the elderly cannot be detected effectively yet. Although recent fall detection algorithms that evaluate the descent, impact and post impact phases of falls, often using vertical velocity, vertical acceleration and trunk angle respectively, tend to be more accurate than the algorithms that do not consider them, they still lack the desired accuracy required to be used among frail older adults. This study aims to improve the accuracy of fall detection algorithms by incorporating average vertical velocity and difference in altitude as additional parameters to the vertical velocity, vertical acceleration and trunk angle parameters. We tested the proposed algorithms on data recorded from a comprehensive set of falling experiments with 12 young participants. Participants wore waist-mounted accelerometer, gyroscope and barometric pressure sensors and simulated the most common types of falls observed in older adults, along with near-falls and activities of daily living (ADLs). Our results showed that, while the base algorithm with the three parameters provided 91.8% specificity, the addition of difference in altitude and average vertical velocity improved the specificity to 98.0% and 99.6%, respectively. PMID- 30441499 TI - Pseudo CT Estimation using Patch-based Joint Dictionary Learning. AB - Magnetic resonance (MR) simulators have recently gained popularity; it avoids the unnecessary radiation exposure associated with Computed Tomography (CT) when used for radiation therapy planning. We propose a method for pseudo CT estimation from MR images based on joint dictionary learning. Patient-specific anatomical features were extracted from the aligned training images and adopted as signatures for each voxel. The most relevant and informative features were identified to train the joint dictionary learning-based model. The well-trained dictionary was used to predict the pseudo CT of a new patient. This prediction technique was validated with a clinical study of 12 patients with MR and CT images of the brain. The mean absolute error (MAE), peak signal-to-noise ratio (PSNR), normalized cross correlation (NCC) indexes were used to quantify the prediction accuracy. We compared our proposed method with a state-of-the-art dictionary learning method. Overall our proposed method significantly improves the prediction accuracy over the state-of-the-art dictionary learning method. We have investigated a novel joint dictionary Iearning- based approach to predict CT images from routine MRIs and demonstrated its reliability. This CT prediction technique could be a useful tool for MRI-based radiation treatment planning or attenuation correction for quantifying PET images for PET/MR imaging. PMID- 30441500 TI - Data-Driven Synthetic Cerebrovascular Models For Validation Of Segmentation Algorithms. AB - We introduce a novel method to generate biologically grounded synthetic cerebrovasculature models in a datadriven fashion. First, the centerlines of vascular filaments embedded in an acquired imaging volume are obtained by a segmentation algorithm. That imaging volume is reconstructed from a graph encoding of the centerline (i.e., generating the model's ground truth) and the segmentation algorithm is applied to the resultant volume. As the location and characteristics of the vasculature embedded in this volume are known,theaccuracyofthesegmentationalgorithmcanbeassessed. Moreover, because the synthetic volume was reconstructed directly from biological data, an assessment is made on embedded filaments that are representative of the topologicalandgeometricalcharacteristicsofthedataset. Webelieve thatsuchmodels will provide the means necessary for the enhanced evaluation of vascular segmentation algorithms. PMID- 30441501 TI - Lossless Compression of Angiogram Foreground with Visual Quality Preservation of Background. AB - By increasing the volume of telemedicine information, the need for medical image compression has become more important. In angiographic images, a small ratio of the entire image usually belongs to the vasculature that provides crucial information for diagnosis. Other parts of the image are diagnostically less important and can be compressed with higher compression ratio. However, the quality of those parts affects the overall understanding of the image as well. Existing methods compress foreground and background of angiographic images using different techniques. In this paper, we first utilize a convolutional neural network to segment vessels and then represent a hierarchical block processing algorithm capable of both eliminating the background redundancies and preserving the overall visual quality of angiograms. PMID- 30441502 TI - Significant Dimension Reduction of 3D Brain MRI using 3D Convolutional Autoencoders. AB - Content-based image retrieval (CBIR) is a technology designed to retrieve images from a database based on visual features. While the CBIR is highly desired, it has not been applied to clinical neuroradiology, because clinically relevant neuroradiological features are swamped by a huge number of noisy and unrelated voxel information. Thus, effective dimension reduction is the key to successful CBIR. We propose a novel dimensional compression method based on 3D convolutional autoencoders (3D-CAE), which was applied to the ADNI2 3D brain MRI dataset. Our method succeeded in compressing 5 million voxel information to only 150 dimensions, while preserving clinically relevant neuroradiological features. The RMSE per voxel was as low as 8.4%, suggesting a promise of our method toward the application to the CBIR. PMID- 30441503 TI - A Simulated Inverted Pendulum to Investigate Human Sensorimotor Control. AB - Sensorimotor control regulates balance and stability as well as adaptation to the external environment. We introduce the use of a simulated inverted pendulum to study human sensorimotor control, demonstrating that this system introduces similar control challenges to human subjects as a physical inverted pendulum. Participants exhibited longer stabilization of the system as the pendulum length between the hand and the center of mass increased while the required control input varied in a non-monotonic, yet predictable manner. Finally, we show that the experimental results can be modelled as a PD controller with a time delay of $?tau = 140$ ms, matching the human visuomotor delay. Our results provide evidence of the importance of vision in a control of unstable systems and serve as a proof of concept of a simulated inverted pendulum. PMID- 30441504 TI - Influence of Visual Feedback on the Sensorimotor Control of an Inverted Pendulum. AB - We examine the visual influence of stabilization in human sensorimotor control using a simulated inverted pendulum. As the inverted pendulum is fully simulated, we are able to manipulate the visual feedback independently from the dynamics during the motor control task. Human subjects performed a balancing task of an upright pendulum on a robotic manipulandum in two different visual feedback conditions. First we examined how subjects perform a task where the visual feedback is congruent with the pendulum dynamics. Second we tested how subjects performed when the physical dynamics were fixed but the visual feedback of the pendulum length was modulated. Subjects exhibited deficits in the control of the pendulum when haptic and visual feedback did not match, even when the visual feedback provided more sensitive information about the state of the pendulum. Overall we demonstrate the importance of accurate feedback regarding task dynamics for stabilization. PMID- 30441505 TI - Myoelectric signals and pattern recognition from implanted electrodes in two TMR subjects with an osseointegrated communication interface. AB - Permanent implantation of electrodes for prosthetic control is now possible using an osseointegrated implant as a long-term stable communication interface (e OPRA). The number of myoelectric sites to host such electrodes can be increased by Targeted Muscle Reinnervation (TMR). Traditionally, patients need to wait several months before the TMR signals are strong enough to be recorded by electrodes placed over the skin. In this study, we report the evolution of the TMR myoelectric signals recorded from two subjects via implanted electrodes using e-OPRA, and monitored for up to 48 weeks after surgery. The signals were analyzed with regard to amplitude (signal-to-noise ratio), independence (cross correlation) and myoelectric pattern recognition (classification accuracy). TMR signals appeared at the first follow-up, one month post-surgery, and developed around 20 dB by the last. Cross-correlation between signals decreased over time and converged to a few percentage points. Classification accuracies were over 97% by the last follow up. These preliminary results suggest that implanted electrodes via the e-OPRA interface allow for an earlier and more effective use of motor signals from TMR sites compared to conventional skin surface electrodes. PMID- 30441506 TI - Effects of Mapping Uncertainty on Visuomotor Adaptation to Trial-By-Trial Perturbations with Proportional Myoelectric Control. AB - Myoelectric control based on classification of distinct gestures discretizes the output space available to the user, which can make it difficult to react appropriately to novel scenarios such as changing limb position. While proportional myoelectric control is noisy in comparison to pattern recognition control, this noise may be an important component of skill acquisition. Here we implemented a two-dimensional proportional myoelectric controller to investigate the effects of movement direction and mapping uncertainty on adaptation to trial by-trial perturbations. We found that subjects who practiced hitting targets despite trial-by-trial random modifications of the control mapping adapted to perturbations faster than a control group with low mapping variability. Our findingssuggestthatexposuretoavariablemappingencourages exploratory behavior and underlies a change in adaption rate, which could potentially be used to train myoelectric control users to achieve more robust control. PMID- 30441507 TI - Reconstructing Neural Activity and Kinematics Using a Systems-Level Model of Sensorimotor Control. AB - There are two popular and largely independent approaches to study the sensorimotor control system (SCS). One is to construct systems-level models of the SCS that characterize dynamics of motor regions in the brain, alpha motor neurons, and the musculoskeletal system to reconstruct motor behavior. These models view the brain as a feedforward and feedback controller that actuates the musculoskeletal system, and have been useful in understanding how the SCS generates movements. Another approach is to measure neural activity and movements simultaneously in primate and human subjects,and the nanalyze the data tounder standhow the brain encodes and controls movement. In this paper, we combine these two approaches by fitting parameters of a systems-level model of the SCS to neural activity and behavior measured from a nonhuman primate executing four types of reach-tograsp tasks. We applied a nonlinear least squares estimation to fit parameters of the model components that characterize cerebrocerebellar processing of movement error and muscles that are actuated by alpha motor neurons receiving commands from primary motor cortex (M1). Our fitted SCS model accurately reconstructs firing rate activity of six populations of M1 neurons and associated reaching trajectories. This study paves the way for the validation of systems-level models of the SCS using experimental data. PMID- 30441508 TI - Quantification of Upper-Extremity Movement Pattern in Patients with Stroke using Touchscreen: A Pilot Study. AB - Humans typically move slower if the movement needs to be more accurate. Such a tradeoff between movement speed and accuracy is quantified in Fitts' Law as a linear relationship between the movement time (MT) and the index of difficulty (ID). For patients with stroke, the detailed pattern of speed-accuracy tradeoff is likely affected due to disrupted neuromuscular control in stroke. In this study, we adapted a previously published iPad software program designed for the test of Fitts' Law in children with dystonia. Subjects were asked to touch targets with different sizes and distances on the touchscreen. Data from 3 patients with stroke suggest that the post-stroke upper-extremity movements still obey Fitts' Law, but the affected side showed larger slopes, and higher endpoint errors compared with the unaffected side. Moreover, the success rate in the affected side was significantly higher than healthy controls, but not than the unaffected side. Our preliminary data suggest that Fitts' Law provides a promising toolkit for quantitatively assessing the movement behavior in stroke. PMID- 30441509 TI - A Maximum Likelihood Formulation To Exploit Heart Rate Variability for Robust Heart Rate Estimation From Facial Video. AB - The problem of estimating the heart rate (HR) from a racial video is considered. A typical approach for this problem is to use independent component analysis (ICA) on the red, blue, green intensity prof iles averaged over the facial region. This provides estimates of the underlying source signals, whose spectral peaks are used to predict HR in every analysis window. In this work, we propose a maximum likelihood formulation to optimally select a source signal in each window such that the predicted HR trajectory not only corresponds to the most likely spectral peaks but also ensures a realistic HR variability (HRV) across analysis windows. The likelihood function is efficiently optimized using dynamic programming in a manner similar to Viterbi decoding. The proposed scheme for HR estimation is denoted by vICA. The performance of vICA is compared with a typical ICA approach as well as a recently proposed sparse spectral peak tracking (SSPT) technique that ensures that the predicted HR does not vary drastically across analysis windows. Experiments are performed in a five fold setup using racial videos of 15 subjects recorded using two types of smartphones (Samsung Galaxy and iPhone) at three different distances (6inches, lfoot, 2feet) between the phone camera and the subject. Mean absolute error (MAE) between the original and predicted HR reveals that the proposed vICA scheme performs better than the best of the baseline schemes, namely SSPT by -8.69%, 52.77% and 8.00% when Samsung Galaxy phone was used at a distance of 6inches, lfoot, and 2feet respectively. These improvements are 12.13%, 13.59% and 18.34% when iPhone was used. This, in turn, suggests that the HR predicted from a racial video becomes more accurate when the smoothness of HRV is utilized in predicting the HR trajectory as done in the proposed vICA. PMID- 30441510 TI - Eyelid and Blink Tracking in an Animal Model of Facial Palsy. AB - Facial palsy (FP) is a clinical condition resulting from damage to the facial nerve. We hypothesize that activity can be restored in the injured side, by electrical stimulation of its muscle, using the activity of muscles on the healthy side as a control input. To explore this hypothesis, we are using a rat model of FP, which treats blinking and whisking as the features of interest in facial movement. This paper describes the development of a novel methodology for the automatic detection and measurement of eyelid displacement and blinks in video records of the rat. Specifically, the active contour approach was used to localize and track rodent eyes in a head-fixed video. The algorithm is initialized manually marking the eye contour in the first frame of the video; subsequent frames are analyzed automatically based on an energy function that depends on image features in the region of interest. Our results demonstrate that our novel technique detects blinks in video recordings with a success rate of 100% and a high correlation between the algorithm output and the manual validation. PMID- 30441511 TI - Drowsiness Estimation from Low-Frame-Rate Facial Videos using Eyelid Variability Features. AB - This paper proposes a method of estimating drowsiness from low-frame-rate facial videos by using eyelid variability features. Since eyelid variability involves slow motions, drowsiness can be estimated more accurately with these features at low frame rate than the conventional blink-related features, in which movements may be made in only some hundred milliseconds per blink. The correlation between the ground-truth drowsiness labels and the estimated drowsiness values is compared through facial videos with frame rates ranging from 3 to 30 frames per second (fps). With conventional blink-related features, the correlation drops from 0.59 (at 30 fps) to 0.28 (at 3 fps), while, with the proposed eyelid variability features, the correlation remains nearly constant, from 0.55 (at 30 fps) to 0.53 (at 3 fps). This characteristic makes it useful for drowsiness estimation with a low computational cost. PMID- 30441512 TI - A neural-network-based investigation of eye-related movements for accurate drowsiness estimation. AB - Many studies reported that eye-related movements, e.g., blank stares, blinking and drooping eyelids, are highly indicative symptoms of drowsiness. However, few researchers have investigated the computational efficacy accounted for drowsiness estimation by these eye-related movements. This paper thus analyzes two typical eye-related movements, i.e., eyelid movements Xel(t) and eyeball movements Xeb(t), and investigates neural-network-based approaches to model temporal correlations. Specifically, we compare the effectiveness of three combinations of eye-related movements, i.e., [Xel(t)], [Xeb(t)], and [Xel(t),Xeb(t)], for drowsiness estimation. Furthermore, we investigate the usefulness of two typical types of neural networks, i.e., CNN-Net and CNNLSTM-Net, for better drowsiness modeling. The experimental results show that [Xel(t),Xeb(t)] can achieve a better performance than [Xel(t)] for short time drowsiness estimation while [Xeb(t)]alone performs worse even than the baseline method (PERCLOS). In addition, we found that CNN-Net are more effective for accurate drowsiness level modeling than CNNLSTM-Net. PMID- 30441513 TI - Investigating Bodily Responses to Unknown Words: a Focus on Facial Expressions and EEG. AB - Occurrences of unknown words in a conversation can be challenging and often prevent people from engaging in fluent communication with each other. Even worse, currently very little is known about possible bodily responses when a listener comes across unknown words, especially when context information is not available in the conversation to facilitate understanding. In this work, we look at facial expressions and electroencephalography (EEG) as two potential body signals that may convey whether users are having difficulties understanding the words they hear. We performed an experiment to measure the reaction of users during a vocabulary dictation test using meaningful words and pseudowords. Participants were asked to classify words as they heard them into different categories. As a result, we did not see any significant differences in the facial expressions of our participants. However, significant differences were observed in event-related potentials (ERPs) within the time range of 100ms-300ms since the onset of stimuli, with pseudowords showing significantly stronger negative responses than meaningful words. Starting at about 550ms and up to around 750ms, pseudowords elicited significantly stronger negative responses, primarily over the parietal and central brain regions. Analyses for single-electrode sites revealed that pseudowords elicited more negative responses than real words in all investigated regions except the left temporal and lateral frontal regions from 500ms to 700ms since stimuli onset. These results could pave the way for future work that aims to develop real-time solutions for facilitating communication between users with different language backgrounds. PMID- 30441514 TI - An EMG Pattern Classification Method Based on a Mixture of Variance Distribution Models. AB - This paper proposes an electromyogram (EMG) pattern classification method based on a mixture of variance distribution models. A variance distribution model is a stochastic model of raw surface EMG signals in which the EMG variance is taken as a random variable, allowing the representation of uncertainty in the variance. In this paper, we extend the variance distribution model to the multidimensional case and enhance its flexibility for multichannel and processed EMG signals. The enhanced model enables the accurate classification of EMG patterns while considering the uncertainty in the EMG variance. The robustness and applicability of the proposed method are demonstrated through a simulation experiment using artificially generated data and EMG classification experiments using two real datasets. PMID- 30441515 TI - Performance of Combined Surface and Intramuscular EMG for Classification of Hand Movements. AB - The surface EMG (sEMG) has been used as control source for upper limb prosthetics since decades. Previous studies suggested that intramuscular EMG showed promising results for upper limb prosthetics. This study investigates the strength of combined surface and intramuscular EMG (cEMG) for improved myoelectric control. Five able-bodied subjects and three transradial amputees were evaluated using offline classification error as performance metric. Six surface and intramuscular channels were recorded concurrently from each subject for seven consecutive days and Stacked sparse autoencoders (SSAE) and LDA classifiers were used for classification. As a control source, either sEMG channels were used or combined channels were used with reduced features using PCA. In the within session analysis, cEMG $( 2.21 ?pm 1.19${%) outperformed the sEMG ($4.63 ?pm 2.07${%) for both able-bodied and amputee subjects using SSAE. For between session analysis, cEMG outperformed the sEMG for both able-bodied and amputee subjects with percentage points difference of 7.93. These results imply cEMG can significantly improve the performance of pattern recognition based myoelectric control scheme for amputee subjects too and further improvement can be made by utilizing SSAE which show improved performance as compared to LDA. PMID- 30441516 TI - Using Antonyan Vardan Transform and Extreme Learning Machines for Accurate sEMG Signal Classification. AB - In this paper, we present an evaluation of an adaptation of the Antonyan Vardan Transform (AVT) used in combination with an Extreme Learning Machines (ELM) classifier to process surface electromyography (sEMG) data used to classify six finger movements and a rest state. A total of 12 assays formed by three repetitions performed by four volunteers is analyzed. Additionally, a sample-by sample output label comparison was performed to make a more comprehensive analysis of the system which was tested on a PC and embedded on a Rasp.berry Pi platform. Compared to literature papers, our system was capable to match or outperform similar solutions even using a simpler model, reaching mean accuracy rates above 94. PMID- 30441517 TI - Optimal feature set for finger movement classification based on sEMG. AB - One of the most important electrophysiological signal is the Electromyography (EMG) signal, which is widely used in medical and engineering studies. This signal contains a wealth of information about muscle functions. Therefore, the EMG signal is becoming increasingly important and has started to be used in many applications like finger movement rehabilitation. However, an advanced EMG signal analysis method is required for efficient usage of such applications. This signal analysis can include signal detection, decomposition, processing, and classification. There are many approaches in studying the EMG signals, however, one of the important factor of analyzing is to get the most efficient and effective features that can be extracted from the raw signal. This paper presents the best feature extraction set compared to previous studies. Where eighteen well known features algorithm has been tested using the sequential forward searching (SFS) method to get excellent classification accuracy in a minimum processing time. Among these novel features only four combinations have been selected with perfect results, which are; Hjorth Time Domain parameters (HTD), Mean Absolute Value (MAV), Root Mean Square (RMS) and Wavelet Packet Transform (WPT). The superiority of this feature set has been proven experimentally, and the results show that the classification accuracy could reach up to 99% to recognize the individual and combined for ten classes of finger movements using only two EMG channels. PMID- 30441518 TI - Isometric Finger Pose Recognition with Sparse Channel SpatioTemporal EMG Imaging. AB - High fidelity myoelectric control of prostheses and orthoses isparamount to restoring lost function to amputees and neuro-muscular disease sufferers. In this study we prove that patio-temporal imaging can be used to allow convolutional neural networks to classify sparse channel EMG samples from a consumer-grade device with over 94 % accuracy. 10,572 images are generated from 960 samples of simple and complex isometric finger poses recorded from 4 fully intact subjects. Real-time classification of 12 poses is achieved with a 250ms continuous overlapping window. PMID- 30441519 TI - An Investigation of Temporally Inspired Time Domain Features for Electromyographic Pattern Recognition. AB - This paper presents a novel set of temporally inspiredtime domain features for electromyographic (EMG) pattern recognition. The proposed methods employ simple time series measures derived from peak detection, and could better reflect EMG activity over time. Multiple EMG datasets consisting of 68 able-bodied and transradial amputee subjects performing a large variety of hand, wrist, fingers, and grasping movements are used to evaluate the performance of the proposed features and to design robust EMG feature sets. The results show that the average classification accuracy of two novel features, the mean prominence of local peaks and valleys, outperform several commonly used time domain features, autoregressive coefficients, histogram, and zero crossing, by 8{?%, 11{?%, and 17{?%, respectively. The proposed features are also shown to provide additional information as part of a robust feature set when compared to the common Hudgins' timedomain feature set, as selected by sequential forward selection and through empirical feature set design. PMID- 30441520 TI - Grid Generation for Rendering Realistic X-ray Images of Narrow Blood Vessels in Real-time Angiography Simulation. AB - This paper proposes a method to generate grids to render realistic X-ray images of the narrow blood vessels in real-time angiography simulation. The vertexes of the narrow blood vessels are projected onto the image-rendering plane. The grids aligned in the vessel direction are generated using the projected boundary vertexes on the image-rendering plane. The average computation time of the entire simulation is reduced by 80.17% compared to the simulation using the uniform grids. The results of the questionnaire survey show that the rendered X-ray images are realistic and useful to be applied to the angiography simulation. PMID- 30441521 TI - K-edge spectral computed tomography with a photon counting detector and discrete reconstruction. AB - X-ray K-Edge Subtraction Computed Tomography (KES-CT) is based on the acquisition of two images at different energies, one below and one above the Kedge of a contrast agent. KES-CT is mainly performed at synchrotron facilities where a tunable monochromatic X-ray beam is available. Thanks to innovative Photon Counting Xray Detectors (PCXDs), it would be desirable to collect the two images in a single shot with a conventional polychromatic Xray spectrum. This approach, sometimes called spectral-CT or color-CT eliminates the risk of misregistration due to motion between consecutive acquisitions and it should allow for scans with much lower doses of contrast medium. Spectral CT is considered very promising but its practical application is being hampered by several practical issues, one of these being the charge sharing affecting the energy resolution of PCXDs. However, latest generations of PCXDs implement hardware solutions to cope with the charge sharing effects, thus allowing sharper color sensitivity. This work presents a K edge spectral CT imaging preliminary protocol based on the Pixirad-I/PixieIII detector where discrete tomography is used to present the reconstructed slices as color images. Results show that when a solution for the charge sharing issue is considered and refined reconstruction methods are applied, accurate K-edge subtraction imaging with conventional sources can be performed. PMID- 30441522 TI - Respiratory Motion Correction Using A Novel Positron Emission Particle Tracking Technique: A Framework Towards Individual Lesion-Based Motion Correction. AB - Respiratory motion during PET/CT imaging is a matter of concern due to degraded image quality and reduced quantitative accuracy caused by motion artifacts. One class of motion correction methods relies on hardware-based respiratory motion tracking systems in order to use respiratory cycles for correcting motion artifacts. Another class of hardware-free methods extract motion information from the reconstructed images or sinograms. Hardware-based methods, however, are limited by calibration requirement, patient discomfort, lack of adaptability during scanning, presence of electronic drift during respiratory monitoring etc. Extracting motion information from reconstructed images is also limited by the fact that the original raw information requires significant processing before it can be used. Hence the motivation behind this work is to introduce a software based approach that can be applied on raw 64-bit listmode data. The basic design of the proposed method is based on the fundamentals of Positron Emission Particle Tracking (PEPT) with additional incorporation of Time of Flight (TOF) information. Respiratory motion of patients has been extracted from the raw PET data by tracking a point source attached to the patient in areas on and near the chest. The key objective of this work is to describe a new process by which this particle tracking based motion correction system can eventually be lesion specific and correct the motion for a particular lesion within the patient. This work thus serves as a framework for lesion specific motion correction. PMID- 30441523 TI - Validation and Application of a Physically Nonlinear ID Computational Model for Bifurcated Arterial Networks. AB - Reduced fluid-structure interaction models are the key component of hemodynamic simulation. In this work, a multi-purpose computational model applicable to specific physiological components such as arterial, venous and cerebrospinal fluid circulatory systems has been developed based on the Hamilton's variational principle. This model encompasses a viscous Newtonian fluid structure interaction (FSI) framework for the large compliant bifurcated arterial networks and its subsystems. This approach provides the groundworks for a correct formulation of reduced FSI models with an account for arbitrary non-linear viscoelastic properties of a compliant vascular tree. The hyperbolic properties of the derived mathematical model are analyzed and used to construct the Lax-Wendroff finite volume numerical scheme, with second order accuracy in time and space. The computational algorithm is validated against well-known numerical and in vitro experimental data reported in the literature for the case of human arterial trees, comprising 55 and 37 main arterial vessels. Utilizing the physics based nonlinear constitutive framework, this model can be adequately tested, calibrated and applied for patient-specific clinical diagnosis and prediction. PMID- 30441525 TI - Three-Element Fractional-Order Viscoelastic Arterial Windkessel Model. AB - Arterial hemodynamic assessment has always been essential for clinical Cardiovascular System (CVS) diagnosis. Using Windkessel (WK) lumped parametric model as non-invasive measurement tool provides the potential of achieving a very convenient, computational inexpensive and accurate prediction of the arterial parameters. Many versions of WK models have been proposed and extensively studied, over the last century. In general, they can be classified into two categories: elastic and viscoelastic models. Recently, several studies have discussed the potential of describing the arterial wall viscoelasticity using fractional order models, reducing the number of parameters and exposing a natural response. Hence, a key missing item in the arterial Windkessel modeling is a fractional-order analog component that can provide a reliable, realistic and reduced representation of the fractional viscoelasticity behavior. In this paper, we present, for the first time, a three-element fractional-order viscoelastic Windkessel model. The proposed model incorporates a fractional-order capacitor that substitutes the ideal capacitor of standard three-elements WK model. The latter non-ideal element combines both resistive and capacitive properties which displays viscoelastic behavior of the arterial vessel. The contribution of both properties is controlled by the fractional differentiation order alpha enabling an accurate and reliable physiological description. PMID- 30441524 TI - Regulation of maternal-fetal heart rates and coupling in mice fetuses. AB - The aim of this preliminary study is to investigate if there is any evidence of maternal-fetal heart rate coupling in mice fetuses and how the coupling patterns are regulated by vagal nervous system on beat by beat. Total of 6 pregnant female mice were divided into two groups [control (N=3) and vagal blockade (N=3)]. On 17.5-day beat-to-beat heart rates of mothers and fetuses (MHR and FHR) were simultaneously measured for 20 minutes (10 minutes under normal condition and 10 minutes with saline (to control group) and atropine (to the vagal blockade group)) solution by using an invasive maternal and fetal electrocardiogram techniques with needle electrodes. Results show that occasional strong maternal fetal heart rate coupling (strength was measured by $?lambda$) appeared and its patterns changed with atropine infusion (no change with saline). Additionally, fisher's exact test shows that changes (increase/decrease from pre to post injection values) in mean, rmssd and power spectral density (PSD) (2~4 Hz) of MHR, rmssd FHR and PSD (2~4 Hz) of${?lambda }$were found to be significantly (p<0.05) associated with treatment types (saline/ atropine). The presented results and protocol allow for the first time in the assessment of autonomic regulation of maternal and fetal heart and their interactions, which will further enhance the value of the mouse as a murine model of heritable human pregnancy and perinatal complications due to maternal conditions. PMID- 30441526 TI - An Enhanced Mechanistic Model For Capnography, With Application To CHF-COPD Discrimination. AB - Capnography records CO2 partial pressure in exhaled breath as a function of time or exhaled volume. Time-based capnography, which is our focus, is a point-of care, noninvasive, effort-independent and widely available clinical monitoring modality. The generated waveform, or capnogram, reflects the ventilation perfusion dynamics of the lung, and thus has value in the diagnosis of respiratory conditions such as chronic obstructive pulmonary disease (COPD). Effective discrimination between normal respiration and obstructive lung disease can be performed using capnogram-derived estimates of respiratory parameters in a simple mechanistic model of CO2 exhalation. We propose an enhanced mechanistic model that can capture specific capnogram characteristics in congestive heart failure (CHF) by incorporating a representation of the inertance associated with fluid in the lungs. The 4 associated parameters are estimated on a breath-by breath basis by fitting the model output to the exhalations in the measured capnogram. Estimated parameters from 40 exhalations of 7 CHF and 7 COPD patients were used as a training set to design a quadratic discriminator in the parameter space, aimed at distinguishing between CHF and COPD patients. The area under the ROC curve for the training set was 0.94, and the corresponding equal-error-rate value of approximately 0.1 suggests classification accuracies of the order of 90% are attainable. Applying this discriminator without modification to 40 exhalations from each CHF and COPD patient in a fresh test set, and deciding on a simple majority basis whether the patient has CHF or COPD, results in correctly labeling all 8 out of the 8 CHF patients and 6 out of the 8 COPD patients in the test set, corresponding to a classification accuracy of 87.5%. PMID- 30441527 TI - Experimental Validation of a Closed-Loop Respiratory Control Model using Dynamic Clamp. AB - We have previously introduced a model for closed-loop respiratory control incorporating an explicit conductance-based model of bursting pacemaker cells driven by hypoxia sensitive chemosensory feedback. Numerical solution of the model equations revealed two qualitatively distinct asymptotically stable dynamical behaviors: one analogous to regular breathing (eupnea), and a second analogous to pathologically rapid, shallow breathing (tachypnea). As an experimental test of this model, we created a hybrid in vitrolin silico circuit. We used Real Time eXperimental Interface (RTXI) dynamic clamp to incorporate a living pacemaker cell recorded in vitro into a numerical simulation of the closed loop control model in real time. Here we show that the hybrid circuit can sustain the same bistable behavior as the purely computational model, and we assess the ability of the hybrid circuit to recover from simulated bouts of transient hypoxia. PMID- 30441528 TI - In-Vitro Evaluation of Cardiac Energetics and Coronary Flow with Volume Displacement and Rotary Blood Pumps. AB - Bridge to recovery with left ventricular assist device (LVAD) support has been more prominent with volume displacement pumps (VDPs) than with rotary blood pumps (RBPs), which may be due to VDPs providing greater ventricular unloading and coronary artery flow. To compare ventricular unloading and coronary flow of VDPs and RBPs in a repeatable environment, a physiologic coronary circulation was added to a pre-existing mock circulatory loop. In this study, a physiologic coronary circulation, mimicking a healthy or diseased auto-regulatory response was implemented in a mock circulatory loop. Using the mock circulation loop, a VDP with original (Bjork-Shiley) and then replacement (jellyfish) valves was operated in clinically recommended modes and compared to full and partial assist RBP operating at constant speed and rapid speed modulated modes. The Bjork-Shiley VDP resulted in increased pressure-volume area, which resulted in greater coronary artery flow when compared to the improved jellyfish valves. Full assist RBP support reduced left ventricular stroke work, pressure-volume area and coronary flow compared to partial assist, whilst the effect of speed modulation modes was not as significant. Of all LVAD operating modes, the counter-pulsed VDP with jellyfish valves demonstrated the greatest reduction in pressure-volume area and improved coronary flow. This study provides a basis for further investigation into RBP speed modulation profiles to match the improved haemodynamic performance of VDPs. PMID- 30441529 TI - Respiratory Rate Derived from Pulse Photoplethysmographic Signal by Pulse Decomposition Analysis. AB - A novel technique to derive respiratory rate from pulse photoplethysmographic (PPG) signals is presented. It exploits some morphological features of the PPG pulse that are known to be modulated by respiration: amplitude, slope transit time, and width of the main wave, and time to the first reflected wave. A pulse decomposition analysis technique is proposed to measure these features. This technique allows to decompose the PPG pulse into its main wave and its subsequent reflected waves, improving the robustness against noise and morphological changes that usually occur in long-term recordings. Proposed methods were evaluated with a data base containing PPG and plethysmography-based respiratory signals simultaneously recorded during a paced-breathing experiment. Results suggest that normal ranges of spontaneous respiratory rate (0.1-0.5 Hz) can be accurately estimated (median and interquartile range of relative error less than 5%) from PPG signals by using the studied features. PMID- 30441530 TI - Investigating the Relationship between the Ratings of Perceived Exertion and Tone Entropy of Heart Rate Variability during a Graded Exercise. AB - This study explored the autonomic nervous system (ANS) adaptation in relation to exercise and how this correlates with the ratings of perceived exertion (Borg RPE) over four ranges 6-8; 9-12; 13-16; 17-20, by using the time domain parameters and the multi-lag Tone-Entropy (T-E) of heart rate variability (HRV). ECG signals were collected from ten subjects who were recruited to participate in a graded exercise protocol on a treadmill. Results showed that SDNN and RMSSD decreased from lower to higher Borg-RPE, indicating a decrease in HRV. Entropy significantly decreased along the first 3 Borg-RPE ranges but increased in the recovery phase in which Tone values became negative (high HRV). As Borg-RPE values increased to the 17-20 range, Tone values decreased and Entropy increased compared to the 13-16 interval suggesting vagal predominance as opposed to HRV time domain results. The highest value of Tone was observed in the Borg-RPE 9-12 range indicating paramount sympathetic dominance. The use of multi-lag in T-E 2D space improved the separation of HRV with reference to the Borg-RPE intervals (p<0.05), except between the 13-16 and 17-20 ranges of the Borg-RPE. Results highlighted the analytical power of T-E in assessing both HRV changes and the sympatho-vagal balance throughout a graded exercise. Potentially, T-E analysis can be applied to assess rehabilitation settings and to get further information on ANS modulation at high exercise intensities. PMID- 30441531 TI - Stress Resilience Measurement With Heart-Rate Variability During Mental And Physical Stress. AB - Stress management is particularly important for healthcare of modern people. In stress research, heart-rate variability (HRV), indicating the change of time intervals in successive heart beats, significantly contributed due to its close relationship with autonomic nervous system. However, the adaptive response to stress, also known as stress resilience, has not been studied much yet. We collected electrocardiogram during mental and physical stress, experimentally designed by mental arithmetic tasks and physical activities for 14 healthy subjects. As a result, we found that resting HRV parameters, particularly associated with the parasympathetic activity, had significant positive correlations with reactivity and recovery from mental and physical stress. These HRV parameters can be used as a measure of stress resilience quantitatively. Our findings suggest that these parameters can help one's stress management by enabling to predict the adaptive response to upcoming stressful events. PMID- 30441532 TI - A Fast Principal Component Analysis Method For Calculating The ECG Derived Respiration. AB - In this paper, we present a principal component analysis (PCA) method for estimating the respiration from overnight ECG recording. In comparison to other published methods, our method is very fast to compute and has low memory requirements, which makes it suitable for processing long duration ECG recordings. We used our method to derive respiratory features for the ECG which were then used to identify epochs of sleep apnoea from the ECG. Three classifiers including the extreme learning machine (ELM), linear discriminant analysis, and support vector machine were used to detect sleep apnoea. The method was evaluated on the MIT PhysioNet Apnea-ECG database. Apnoea detection was evaluated with leave-one-record-out cross-validation. Our PCA method obtained the highest accuracy of 74% by ELM classifier. We conclude that the fast PCA method is useful to apply PCA to long ECG recordings. PMID- 30441533 TI - Cardiorespiratory Phase Synchronization increases during certain mental stimuli in healthy subjects. AB - Several neurological and mechanical non-linear mechanisms relate the respiratory and cardiovascular systems to one another. Besides the well-known modulation of heart rate by respiration, another form of non-linear interaction between both systems is Cardiorespiratory Phase Synchronization (CRPS). In this study we investigated CRPS on a group of 27 healthy individuals subject to a stimulation protocol with five different mental states: a basal state, a videogame, a comedy video, a suspense video and a reading state. Acontinuous measure of CRPS was calculated from the phase synchrogram between respiratory and electrocardiographic signals. Periods of CRPS were characterized by their average duration (AvDurSync) and by the percentage of synchronized time (%Sync) within each mental state. These measures were studied considering two thresholds: a minimum amplitude and a minimum duration for synchronization. Each subject exhibited a particular pattern of phase locking ratios along the different mental states. We observed that, in all states, %Sync decreased and AvDurSync increased in proportion to the minimum duration threshold. Both measures were inversely proportional to the minimum amplitude threshold.uring the videogame, subjects showed a significantly higher %Sync as compared to any other mental stimulus, irrespective of the minimum duration threshold. Mental stimulation can be an alternative approach to enhance cardiorespiratory coupling when subjects have difficulties to perform aerobic exercise, such as in patients with Chronic Obstructive Pulmonary Disease or Chronic Heart failure. PMID- 30441534 TI - Myocardial Ischemia Diagnosis Using a Reduced Lead System. AB - This research presents a novel statistical model for diagnosing acute myocardial infarction (AMI). The model is based on features extracted from a reduced lead system consisting of a subset of three leads from the standard 12-lead ECG. We selected a set of relevant parameters commonly used in the clinical practice for ECG-based AMI diagnosis, namely ST elevation and T-wave maximum. We also selectedfeatures, not used in clinical practice, that were derived from vectorcardiography and computed on the reduced three-lead system (pseudo-VCG parameters). To validate the model, we used 104 patients coming from the Physionet STAFF III database which contains 12-lead ECG recordings at baseline and in coronary artery occlusion condition during angioplasty (PTCA). Results show that pseudo-VCG features are able to diagnose AMI slightly better than ST elevation and T-wave maximum features together (area under the ROC curve (AUC) 0.87 vs AUC 0.85). When combining pseudo-VCG features together with ST elevation, and T-wave maximum, the performance improved significantly (AUC 0.95, sensitivity 89.6% and specificity 82.7%). Results indicate a potential for diagnosing AMI using the proposed reduced lead system and the selected set of features. We suggest its possible use for diagnosing AMI in long-term, ambulatory and home monitoring situations, allowing an earlier and faster diagnosis. PMID- 30441535 TI - Automated Versatile DIY Microscope Platform. AB - A versatile robot platform is presented that can be used to design low-cost custom made microscopes in do-ityourself construction. All components like the framework, the linear drives, robot controller and driver, the illumination and the camera are described as well as optional features like fluorescence microscopy and auto-focus. Finally, an application for automated imaging of 3D cell cultures in 96-well microplates is presented. PMID- 30441536 TI - Clinical Application of Multiple Vital Signs-Based Infection Screening System in a Mongolian Hospital: Optimization of Facial Temperature Measurement by Thermography at Various Ambient Temperature Conditions Using Linear Regression Analysis. AB - Fever is one significant sign of infection. Hence, infrared thermography systems are important for detecting infected suspects in public places. Reliable temperature measurements by thermography are influenced by several factors, including environmental conditions. This paper proposes a linear regression analysis-based facial temperature optimization method to improve the accuracy of multiple vital signs-based infection screening at various ambient temperatures. To obtain the relationship between ambient temperature and thermography measurements, 20 instances of axillary temperature, thermography measurements of facial temperature, and five different ambient temperature values at the time of measurement were used as a training set for a linear regression model. Temperatures from a total of 30 subjects were recalculated by the model. The screening system was evaluated using the temperature both before and after optimization to demonstrate the accuracy of the optimization method. A k-nearest neighbor algorithm was used to classify potentially infected patients from healthy subjects. Although the system has already been evaluated in restricted environmental conditions, this is the first time it was tested in Ulaanbaatar, Mongolia. The results show that the Pearson's correlation coefficient between optimum and axillary temperatures increased to r = 0.82. Paired t-tests revealed that the optimized temperature became statistically highly significant (p<0.001) for differentiating potentially infected patients from healthy subjects. Finally, the system achieved a sensitivity score of 91% and a negative predictive value of 92%. These values are higher than those obtained without temperature optimization. The proposed optimization method is feasible and can notably improve screening performance. PMID- 30441537 TI - Arterial Pulse Waveform Characteristics Difference between the Three Trimesters of Healthy Pregnant Women. AB - During pregnancy, the pregnant mother undergoes significant physiological changes in order to accommodate the developing fetus. In recent years, arterial pulse wave has been widely used to reflect these physiological changes. The aim of this study was to investigate the changes of radial pulse and photoplethysmography (PPG) pulse waveform characteristic with gestational age in normal pregnant women. 40 pregnant women volunteers were recruited from February 2016 to September 2016 from the Haidian Maternal & Child Health Hospital in Beijing. Both radial pulses and PPG pulses were recorded simultaneously using a PowerLab data collection system at a sampling rate of 1000Hz for offline analysis. Their pulses were measured from each pregnant woman at three trimesters (first trimester between week 11-13; second trimester between week 20-22 and the third trimester between week 3739). Three waveform characteristics (total pulse area; pulse area1: the area before the notch position; pulse area2: the area after the notch position) were derived. The results showed that the total pulse area and pulse area2 from both radial and PPG pulses decreased significantly between two paired consecutive trimesters (all P<0.01, except the comparisons between the second and third trimesters for PPG pulses). In summary, this study has quantified the pulse waveform characteristic differences in terms of pulse areas between the three trimesters, providing useful scientific evidence to better understand the cardiovascular physiological changes during normal pregnancy. PMID- 30441538 TI - Optimization of Tetrapolar Impedance Electrodes in Microfluidic Devices for Point of Care Diagnostics using Finite Element Modeling. AB - Electrophoresis is widely applied in the field of biochemistry and molecular biology. Tetrapolar electrical impedance sensing (TEIS) has been shown capable of replacing the conventional detection technology in order to develop a point of care electrophoretic analyzer. Besides the advantages of reduced influence of electrode polarization, TEIS is affected by sensitivity distribution depending on the electrode design. A well reported practice outside of electrophoresis, systematic investigation of the effects of sensitivity distribution on the TEIS in microfluidic devices has not been conducted. Here we utilize finite element modeling, backed by experimental results, to optimize the sensor design within an electrophoretic separation device. Numerous sensor designs were validated regarding detectability, sensitivity and spatial resolution. The results show, that minimizing the distance between the central/pick-up electrodes increases sensitivity and spatial resolution whereas the distance between the central electrodes and the outer electrode do not influence sensitivity and spatial resolution. PMID- 30441539 TI - Low-Cost Mobile Device for Screening of Atherosclerosis and Coronary Arterial Disease. AB - In the context of global health, telemedicine, and low-resource settings, we present a non-invasive smart-phone based device that can be used to screen for atherosclerosis,which is the leading factor for ischemic heart attacks and strokes. Using acustom Android mobile application, our device computes Pulse Wave Velocity(PWV) using the pulse signals from photo-plethysmographic (PPG) probes, which are simultaneously clipped onto the ear, index finger, and big toe of a human subject. Unlike other designs which require the use of an ECG reference, our mobile device uses only PPG signals and is entirely powered by the mobile phone via the USB port. Using the ear signal as a reference, we derived PWV values from two locations: the right index finger, and the right big toe.We present data from a recent clinical study with 78 participants (age 26 to 74) who were divided into three groups: Coronary Arterial Disease ("CAD"), hypertensive group ("PreCAD"), and Healthy controls. The CAD group was clinically diagnosed and confirmed with a CT-scan and calcium scoring. PWV values derived from the finger was found to have too much variance to be clinically useful. However, PWV values derived from the toe location showed significant differences between the groups, even after accounting for age. Measured PWV values were: 10.07 (8.51 12.01) for the older CAD group, 9.39 (7.44-9.75) for the younger CAD group, 8.26 (7.26-9.22) for the older Pre-CAD group, 10.57 m/s (8.5-11.2) for the younger Pre CAD group, 7.13 m/s (5.97-7.69) for older healthy controls, and 6.71 m/s (4.86 7.26) for the younger healthy control subjects. These results demonstrate good potential value of this mobile PWV device as a simple low-cost screening tool for atherosclerosis and coronary arterial disease. PMID- 30441540 TI - 3D Bioprinting of Cyanobacteria for Solar-driven Bioelectricity Generation in Resource-limited Environments. AB - We demonstrate a hybrid biological photovoltaic device by forming a 3D cooperative biofilm of cyanobacteria and heterotrophic bacteria. 3D bioprinting technique was applied to engineer a cyanobacterial encapsulation in hydrogels over the heterotrophic bacteria. The device continuously generated bioelectricity from the heterotrophic bacterial respiration with the organic biomass supplied by the cyanobacterial photosynthesis. This innovative device platform can be the most suitable power source for unattended sensors, especially for those deployed in remote and resource-limited field locations. PMID- 30441541 TI - Donation of neural stem cells? Post mortal viability of spinal cord neuronal cells. AB - Transplantation of cells into central nervous system (CNS) shows a potential for treatment of post-traumatic and neurodegenerative diseases. Cadaver-derived neural cells can help reducing deficit of allogeneic material ready for transplantation. In this study we analyze post-mortal survival of spinal cord neural cells. Maximal time when alive neuronal cells can be recovered form spinal cord of the animals was determined as 56hr for human-size animal and 18hr for rat. Cells with surface expression of ganglioside GD2 and antigen CD24 constituted up to one percent of all recovered alive cells in earlier samples with time dependent decline in percentage. GD2-positive cells from rat spinal cord demonstrated spontaneous and induced electrical activity, which reduces with time post mortem. PMID- 30441542 TI - Using cell-seeded electrospun patch for myocardial injury: in-vitro and in rat model. AB - Electrospinning has been widely used to fabricate scaffolds and commonly used biodegradable polymers. Cellular cardiomyoplasty is a type of regenerative medicine that has potential use for treatment of myocardial infarction or terminal cardiac failure. The aims of this study are to use electrospinning to create cardiovascular patches and to assess their potential therapeutic use by transplantation into the hearts of rats. Tissue engineering scaffolds were generated by use of electrospinning, in which the fibers consist of nanoscale-to microscale fibers whose diameters are comparable to those of essential components of the extracellular matrix. A polymer solution was pumped at a constant rate through a syringe with a small-diameter needle that is connected to a high voltage source, so that an electric field is created between the needle and a metallic collecting plate. The final product is a mat composed of individual continuous nanofibers. Cell survival, cell characteristics, and growth factors of electrospun patches of different thicknesses using bone marrow and human cardiac stem cells were tested. The results demonstrated that the cells can survive in Poly-caprolactone (PCL) patches, even deep within these patches. The PCL patches are nontoxic and do not alter cell properties. Transplantation of these patches into the hearts of a rat model of myocardial infarction led to strong compliance and good survival.The use of PCL cellular patches is feasible method for cellular transplantation. Future studies should attempt to use orientated electrospun cellular patches to improve overall cell survival within deeper layers of these patches. PMID- 30441543 TI - Digital High-Resolution Melt Platform for Rapid and Parallelized Molecule-by Molecule Genetic Profiling. AB - This work presents a microfluidic Digital High-Resolution Melt platform for absolute quantitation and sensitive detection of locus-specific sequence variations on a molecule-by-molecule basis. The platform provides a facile means for assessment of hundreds to thousands of single DNA copies by digitizing template molecules in a 4096 1-nL array microfluidic device and observing the sequence-dependent fluorescence changes during temperature ramping. The analytical capability of this platform is demonstrated in several applications, such as digital assay characterization, detection and assessment of DNA methylation heterogeneity, and detection of rare biomarkers at frequencies as low as 0.0005% target to background molecules. PMID- 30441544 TI - Integrated Bacterial Identification and Antimicrobial Susceptibility Testing for Polymicrobial Infections Using Digital PCR and Digital High-Resolution Melt in a Microfluidic Array Platform. AB - In diagnosing bacterial infection, rapid bacterial identification (ID) and antimicrobial susceptibility testing (AST) are critical to clinicians in order to provide an effective treatment in a timely manner. The gold standard, culture based approach provides both ID and antimicrobial susceptibility but requires several days of turnaround time. Especially in polymicrobial infections, where there are more than one organisms interacting collectively that can complicate the treatment. Here, we demonstrate a rapid bacterial diagnostic approach that is capable of bacterial ID/AST in heterogeneous samples within less than 4 hours by using digital PCR (dPCR) and digital high-resolution melt via microfluidic devices. By utilizing dPCR, we are able to quantify amount of nucleic acid, which correlates to phenotypic responses of {?bf individual pathogens in a mixed sample and also shorten the required time of antibiotic exposure. In addition, we employ a machine learning algorithm to automatically identify bacterial species based on melt profiles of 16S rRNA gene. PMID- 30441545 TI - Active or Passive On-Demand Droplet Merging in a Microfluidic Valve-Based Trap. AB - A microfluidic valve-based trap enabling controlled capture, release, and temporary immobilization of droplets together with on-demand merging of selected droplets is presented in this paper. The microfluidic trap technology can merge droplets passively or in active manner via a pneumatically actuated membrane. A microchip is developed with two functional units of droplet generator and merging mechanism to implement the passive or active merging performance of the microfluidic valve-based trap using a low and high surfactant concentrated continuous oil-phase. PMID- 30441546 TI - Seizure Prediction In EEG Records Based On Spatial-Frequency Features And Preictal Period Selection. AB - Algorithms can automatically predict seizures to reduce the occurrences of accidental injury and improve living conditions of patients. This paper proposes a novel patient-specific algorithm based on multi-channel scalp EEG recordings. 26 features for each channel are extracted from each one-second data, including 8 absolute spectral powers, 8 normalized spectral powers, 8 power spectral entropies, the shortest path length and clustering coefficient. Then, a new step to select the most discriminative five minute preictal period is proposed. The features of preictal period are combined with that of five minute non-seizure period to form a training set in order to achieve the maximum linear separability criteria. Then, the effective features of each channel are selected by Elastic Net. At the same time, greedy algorithm is used to select effective channels. The ten minute effective features obtained from effective channels are input to Logistic Regression. The algorithm is tested on 62 seizures from 12 patients in 217 hours of recordings in MIT database. Results are finally given by average of each 1 minute values of Logistic Regression. It is shown that the proposed algorithm can achieve a sensitivity of 91% and an averaged false positive rate of 0.3 per hour. PMID- 30441547 TI - Importance of Recalibrating Models for Type 2 Diabetes Onset Prediction: Application of the Diabetes Population Risk Tool on the Health and Retirement Study. AB - A timely prediction of type 2 diabetes (T2D) onset is important for early intervention to prevent, or at least postpone, its incidence. Several models to predict T2D onset according to individual risk factors were proposed. However, their practical applicability is limited by the fact that they often perform suboptimally when applied to a different population. A solution to overcome this limitation is model recalibration, which consists in updating the model parameters. The aim of this work is to demonstrate the benefits of T2D predictive model recalibration. For the purpose, we considered as case study the Diabetes Population Risk Tool (DPoRT), originally tuned for the Canadian population, and we applied it to data collected in older Americans in the Health and Retirement Study (HRS). A subset of 30,274 subjects was extracted from HRS and divided into a training (N=24,219) and a test set (N=6,055) stratifying for sex and diabetes incidence. The DPoRT was recalibrated by re-estimating all model coefficients on the training set, and then assessed on the test set by comparing the performance of recalibrated vs original model. Model discriminatory ability and calibration were assessed by the concordance index (C-index) and the expected to observed event probability ratio (E/O), respectively. Results show that the recalibrated DPoRT presents similar discriminatory ability to the original model, with C-index equal to 0.68 vs. 0.67 in men, 0.73 vs. 0.73 in women, and better calibration than the original model, with E/O ratio equal to 0.75 vs. 4.57 in men, 0.81 vs. 2.53 in women. Results confirm that recalibration is a key step to be performed before the application of predictive models to different populations in order to guarantee an accurate prediction of diabetes incidence. PMID- 30441548 TI - Improving Young Stroke Prediction by Learning with Active Data Augmenter in a Large-Scale Electronic Medical Claims Database. AB - Electronic medical claims (EMC) database has been successfully used for predicting occurrences of stroke and a variety of other diseases. However, inadequate predictive performances have been observed in cases of rare occurrences due to both insufficient training samples and highly imbalanced class distribution. In this work, our aim is to improve stroke prediction, especially for young age group (25-45 year-old) in a large population-based EMC database (552,898 subjects). We learn a young stroke predictive deep neural network model using a novel active data augmenter. The augmenter selects the most informative EHR data samples from old age stroke patients. This approach achieves 9.3% and 8.2% area under the receiver operating characteristic curve (AUC) value improvements compared to training directly with only young age group data and training all age groups data, respectively. We further provide analyses on the AUC values obtained as a function of the training data size, and the amount and the type of augmented data samples. PMID- 30441549 TI - Predictive Value of Prothrombin Time for All-cause Mortality in Acute Myocardial Infarction Patients. AB - Acute myocardial infarction (AMI) is a serious cardiovascular disease caused by acute or persistent ischemic and anoxia of the coronary artery. A more practical and effective risk model is still remained to be established for AMI patients. This study aims to investigate the predictive value of prothrombin time (PT) in AMI patients. In this study, 2734 AMI patients available in the public MIMIC III clinical database were investigated, with 629 deaths occurring within 2-year follow-up. More than 20 risk factors including demographics, clinical disease history, laboratory test information, surgery history, and mediation information were analyzed as potential predictors for all-cause mortality in AMI patients. After adjustment for other covariates, PT was showed to be a significant risk factor for all-cause mortality in AMI patients (adjusted hazard ratio, 4.04; 95% confidence interval, 2.83 to 5.75) from Cox regression analysis. We also developed a comprehensive risk model for AMI mortality using multivariate Cox proportional hazards model based on the above 20 risk factors. Combined with PT, the model achieved a good accuracy with an AUC (area under ROC curve) of 0.843. Overall, PT is an independent predictor for 2-year mortality in AMI, and it might be useful in identifying AMI patients with a high risk for mortality. PMID- 30441550 TI - Robust Prediction Of Treatment Times In Concurrent Patient Care. AB - Outpatient centers comprised of many concurrent clinics increasingly see higher patient volumes. In these centers, decisions to improve clinic flow must account for the high degree of interdependence when critical personnel or equipment is shared between clinics. Discrete event simulation models have provided clinical decision support, but rarely address high-volume clinics with shared resources. While highly complex models are now capable of representing clinics in detail, validation techniques often do not evaluate model predictive performance when presented with new data. Cross-validation provides a means to evaluate the robustness of model treatment time predictions when ongoing data collection in clinics is impractical. Ensuring robust predictions assures validity in the use of models to optimize clinic performance. We apply cross-validation in evaluating a model of glaucoma clinic service at Duke Eye Center. In-person observation is used to verify the accuracy of operations data collected through electronic health records (EHR). From the EHR data, we formulate a stochastic reward net model, employing phase-type distributions to represent treatment durations, and solved through discrete event simulation. The model is formulated in two configurations to represent (1) concurrent demand on clinic staff, or (2) independently functioning clinics. Evaluating these two alternatives in cross validation studies, we find model prediction accuracy improves when interdependence is explicitly modeled in the examined setting. PMID- 30441551 TI - Cancer Type Prediction and Classification Based on RNA-sequencing Data. AB - Pan-cancer analysis is a significant research topic in the past few years. Due to many advancing sequencing technologies, researchers possess more resources and knowledge to identify the key factors that could trigger cancer. Furthermore, since The Cancer Genome Atlas (TCGA) project launched, using machine learning (ML) techniques to analyze TCGA data has been recognized as a useful solution in the line of research. Therefore, this study uses RNA-sequencing data from TCGA and focuses on classifying thirty-three types of cancer patients. Five ML algorithms include decision tree (DT), k nearest neighbor (kNN), linear support vector machine (linear SVM), polynomial support vector machine (poly SVM), and artificial neural network (ANN) are conducted to compare the performances of their accuracies, training time, precisions, recalls, and F1-scores. The results show that linear SVM with a 95.8% accuracy rate is the best classifier in this study. Several critical and sophisticated data pre-processing experiments are also presented to clarify and to improve the performance of the built model. PMID- 30441552 TI - Fusing non-contact vital sign sensing modalities - first results. AB - A wearable multi-sensor system allowing synchronized unobtrusive measurements of 4 vital signs at a dedicated location of interest is presented. The 4*U sensor is capable of synchronously measuring magnetic impedance, reflective photoplethysmography, capacitive electrocardiogram and seismocardiography (ballistocardiography). The hardware of all modalities is described and some preliminary results are reported. PMID- 30441553 TI - Evaluation of a real-time low-power cardiorespiratory sensor for the IoT. AB - A wide variety of sensors have been developed in the biomedical engineering community for telemedicine and personalized healthcare applications. However, they usually focus on sensor connectivity and embedded signal processing, at the expense of the sensing part. This observation lead to the development and exhaustive evaluation of a new ECGbased cardiorespiratory IoT sensor. In order to improve the robustness of our IoT-based sensor, we discuss in detail the influence of electrodes placement and nature. Performance assessment of our sensor resulted in a best-case sensitivity of 99.95% and a precision of 99.89% for an abdominal positioning of wet electrodes, while a sensitivity of 99.47% and a precision of 99.31% were observed using a commercialgrade dry electrodes belt. Consequently, we prove that our sensor is fit for the comfortable medical-grade monitoring of the cardiorespiratory activity in order to provide insights of patients health in a telemedicine context. PMID- 30441554 TI - Preliminary Investigations for Non-invasive Temperature Change Detection in Thermotherapy by Means of UWB Microwave Radar. AB - Non-invasive differential temperature monitoring by means of ultra-wideband sensing is a promising approach concerning temperature controlling during thermotherapy. In this paper the principal of temperature difference detection by UWB radar is explained and appropriate phantom measurements are discussed. In a first step, temperature dependent dielectric properties of the phantom materials (sunflower oil and distilled water) are analyzed. Subsequently, temperature dependent phantom measurements are conducted where the temperature dependent signal changes of the received UWB signals are investigated. Results show a linear behavior between the received differential radar signals and the temperature differences of the target in the considered temperature range. Furthermore, investigations show that temperature changes of the target, which are common in thermal therapy (e.g., hyperthermia), are detectable by means of UWB radar. PMID- 30441555 TI - Wireless Smartphone Control using Electromyography and Automated Gesture Recognition. AB - In this paper, a wearable, wireless system is demonstrated using electromyography (EMG) signals for realtime control of a smartphone device. The system allows gesturebased control of a smartphone or tablet computer without physical contact, direct line of sight, or significant movement. Additionally, automated gesture detection is shifted to the smartphone, eliminating the need for robust computing hardware. The electronic system and gesture prediction algorithm are described, and measured results are presented and for multiple users. The system demonstrates a maximum true positive detection rate of 92% for a trained user, using three distinct hand gestures. The EMG-based detection system serves as a proof-of-concept for providing wireless, gesture-based control of computer interfaces using low-cost consumer hardware. PMID- 30441556 TI - Body Sensor Networks Powered by an NFC-Coupled Smartphone in the Pocket. AB - This paper proposes a body sensor network (BSN) on clothing that is wirelessly powered by a smartphone in a pocket. The network consists of a host device and multiple sensor nodes, which are distributed on a wear and are electrically connected with conductive threads. The smartphone with a built-in near field communication (NFC) feature powers the host, which is fixed at the pocket. These devices are wired to a special cloth embroidered with conductive threads by using a special connector consisting of a pin & socket without one-to-one wiring. In the proposed BSN, the host device and the smartphone are coupled via NFC radio within the pocket. Energy harvesting with NFC radio wave requires maintaining antennas within several centimeters to obtain enough power. Positioning and fixing of the smartphone is required within the pocket. A proposed host device can expand the range of energy harvesting by using multiple antennas and a power aggregation circuit. The experimental results demonstrate the feasibility of the batteryless BSNs system. PMID- 30441557 TI - In-field Remote Fingerprint Authentication using Human Body Communication and On Hub Analytics. AB - In this emerging data-driven world, secure and ubiquitous authentication mechanisms are necessary prior to any confidential information delivery. Biometric authentication has been widely adopted as it provides a unique and non transferable solution for user authentication. In this article, the authors envision the need for an infield, remote and on-demand authentication system for a highly mobile and tactical environment, such as critical information delivery to soldiers in a battlefield. Fingerprint-based in-field biometric authentication combined with the conventional password-based techniques would ensure strong security of critical information delivery. The proposed in-field fingerprint authentication system involves: (i) wearable fingerprint sensor, (ii) template extraction (TE) algorithm, (iii) data encryption, (iv) on-body and long-range communications, all of which are subject to energy constraints due to the requirement of small form-factor wearable devices. This paper explores the design space and provides an optimized solution for resource allocation to enable energy efficient in-field fingerprint- based authentication. Using Human Body Communication (HBC) for the on-body data transfer along with the analytics (TE algorithm) on the hub allows for the maximum lifetime of the energy-sparse sensor. A custom-built hardware prototype using COTS components demonstrates the feasibility of the in-field fingerprint authentication framework. PMID- 30441558 TI - GearVision: Smartphone Based Head Mounted Perimeter For Detection Of Visual Field Defects. AB - Automated visual field perimetry is widely used for the evaluation of visual field defects caused by ophthalmological and neurodegenerative diseases. This test is typically performed using the Humphrey Perimeter or Octopus Perimeter. However, their high cost and large footprint limit their use to the clinical setting. This in turn limits their reach especially in the context of screening in remote environments and personal setting. In this paper, we report the development and testing of GearVision, a portable, accessible and compact virtual reality based visual field perimeter. It enables regular visual field testing in a cost-effective and convenient manner. Currently, GearVision is meant to augment the existing perimetry system and hence facilitate the detection of visual field defects early and without expert supervision or the need for hospital visits. In addition to the development of standard 30-2 suprathreshold and full threshold perimetry tests, we have proposed methods to improve test reliability and compliance. These include optional rest intervals during the test to reduce errors caused by strain or fatigue and improved false positive estimation based on statistical analysis of a patient's response times. We have tested the proposed system on 21 subjects and validated its capability to detect visual field defects. PMID- 30441559 TI - High Intraocular Pressure Detection from Frontal Eye Images: A Machine Learning Based Approach. AB - This paper presents a novel framework to detect the status of intraocular pressure (normal/high) using solely frontal eye image analysis. The framework is based on machine learning approaches to extract six features from frontal eye images. These features include Pupil/Iris ratio, red area percentage, mean redness level of the sclera, and three novel features from the sclera contour (angle, area and distance). Four hundred frontal eye images were used as the image database. The images were taken and annotated by ophthalmologists at Princess Basma Hospital. The proposed framework is fully automated and once the six features were extracted, two classifiers (decision tree and support vector machine) were applied to obtain the status of the eye in terms of eye pressure. The overall accuracy of the proposed framework is 95.5% using the decision tree classifier. PMID- 30441560 TI - Sample Entropy of Speed Power Spectrum as a Measure of Laparoscopic Surgical Instrument Trajectory Smoothness. AB - In this study the complexity of the speed power spectrum is assessed as a metric for measuring trajectory smoothness. There are a variety of published methods for analyzing trajectory smoothness but many lack validity. This preliminary study took an information theoretic approach to assess trajectory smoothness by applying the sample entropy measure to the speed power spectrum of simulated and experimental trajectories. The complexity measurements of the speed power spectrum were compared to a traditional jerk-based measure of trajectory smoothness, namely $?log $-dimensionless jerk. The approach was first tested on basic simulated shape tracings with varying locations of sporadic movement, simulated as Gaussian noise. This method was duplicated in an experimental setting with the same shapes and locations of sporadic movement by capturing the trace trajectories using an electromagnetic motion tracking system. Finally, this approach was applied to kinematic data of laparoscopic surgical instrument tips, captured over 105 iterations of a basic surgical task. Analysis from all three testing scenarios showed that there is a statistically significant linear correlation between $?log $-dimensionless jerk and the sample entropy of speed power spectra. PMID- 30441561 TI - Craniectomy Effects on Resting State Functional Connectivity and Cognitive Performance in Immature Rats. AB - Experimental models have been proven to be valuable tools to understand downstream cellular mechanisms of Traumatic Brain Injury (TBI). The models allow for reduction of confounding variables and tighter control of varying parameters. It has been recently reported that craniectomy induces pro-inflammatory responses, which therefore needs to be properly addressed given the fact that craniectomy is often considered a control procedure for experimental TBI models. The current study aims to determine whether a craniectomy induces alterations in Resting State Network (RSN) in a developmental rodent model. Functional Magnetic Resonance Imaging (fMRI) data-driven RSN show clusters of peak differences (left caudate putamen, somatosensory cortex, amygdala and piriform cortex) between craniectomy and control group, four days post-craniectomy. In addition, the Novel Object Recognition (NOR) task revealed impaired working memory in the craniectomy group. This evidence supports craniectomy-induced neurological changes which need to be carefully addressed, considering the frequent use of craniectomy as a control procedure for experimental models of TBI. PMID- 30441562 TI - Cancer Detection at your Fingertips: Smartphone-Enabled DNA Testing. AB - High molecular weight cell-free DNA (hmw cfDNA) found in biological fluid, such as blood, is a promising biomarker for cancer detection. Due to the abundance of background apoptotic cell-free DNA in blood, quantifying the native concentration of hmw cfDNA using existing methods is technically challenging, time consuming, and expensive. We have developed a novel technology which utilizes Alternating Current Electrokinetics (ACE) to isolate hmw cfDNA directly from blood. Furthermore, we integrated this technology into a handheld device which utilizes a smartphone for power, instruction transmission, optical detection, image processing, and data transmission. The detection of hmw cfDNA in blood plasma demonstrated the performance of the device. We are continuing development of this device as a future point of care in vitro diagnostic. PMID- 30441563 TI - A Novel Modular Headmount Design for non-invasive Scalp EEG Recordings in Awake Animal Models. AB - We have designed and developed a novel, noninvasive modular headmount to be used for awake animal scalp electroencephalography (EEG). The design is based on a developing rat that will accommodate rapid head growth. Desired characteristics include non-invasiveness, adjustable quantity and positioning, light weight, and tolerability by the animal. Axial Dependent Modular Electrode Mount (ADMEM), as designed here, addresses the aforementioned constraints by using light-weight and adjustable materials. The initial prototype of ADMEM has been tested in vivo with rat pups, using the open field test to assess for stress and anxiety at two post installation time-points: one day after ADMEM installation (acute time-point) and four days after ADMEM installation (sub-acute time-point). There was no significant difference in normal developmental weight gain between Control and ADMEM rat groups. Although no significant difference was found in the level of anxiety between groups at the acute time-point, the ADMEM group spent significantly less time in the center of the open field test, suggesting higher anxiety. The test also showed no difference in the measured traveled distances between Control and ADMEM groups on either time-points. PMID- 30441564 TI - A comparison of feature selection methods when using motion sensors data: a case study in Parkinson's disease. AB - The objective of this study is to investigate the effects of feature selection methods on the performance of machine learning methods for quantifying motor symptoms of Parkinson's disease (PD) patients. Different feature selection methods including step-wise regression, Lasso regression and Principal Component Analysis (PCA) were applied on 88 spatiotemporal features that were extracted from motion sensors during hand rotation tests. The selected features were then used in support vector machines (SVM), decision trees (DT), linear regression, and random forests models to calculate a so-called treatment-response index (TRIS). The validity, testretest reliability and sensitivity to treatment were assessed for each combination (feature selection method plus machine learning method). There were improvements in correlation coefficients and root mean squared error (RMSE) for all the machine learning methods, except DTs, when using the selected features from step-wise regression inputs. Using step-wise regression and SVM was found to have better sensitivity to treatment and higher correlation to clinical ratings on the Unified PD Rating Scale as compared to the combination of PCA and SVM. When assessing the ability of the machine learning methods to discriminate between tests performed by PD patients and healthy controls the results were mixed. These results suggest that the choice of feature selection methods is crucial when working with data-driven modelling. Based on our findings the step-wise regression can be considered as the method with the best performance. PMID- 30441565 TI - Mobile Gait Analysis using Personalised Hidden Markov Models for Hereditary Spastic Paraplegia Patients. AB - Gait analysis provides a quantitative method to assess disease progression or intervention effect on gait disorders. While mobile gait analysis enables continuous monitoring in free living conditions, state of the art gait analysis for diseases such as hereditary spastic paraplegia (HSP) is currently limited to motion capture systems which are large and expensive. The challenge with HSP is its heterogeneous nature and rarity, leading to a wide range of ages, severity and gait patterns as well as small patient numbers. We propose a sensor-based mobile solution, based on a personalised hierarchical hidden Markov Model (hHMM) to extract spatio-temporal gait parameters. This personalised hHMM achieves a mean absolute error of 0.04 s +/- 0.03 s for stride time estimation with respect to a GAITRite(r) reference system. We use the successful extraction of initial ground contact to explore the limits of the double integration method for such heterogeneous diseases. While our personalised model compensates for the heterogeneity of the disease, it would require a new model per patient. We observed that the general model was sufficient for some of the less severely affected patients. PMID- 30441566 TI - Artificial Neural Network for Laparoscopic Skills Classification Using Motion Signals from Apple Watch. AB - The acquisition of laparoscopic technical skills is constrained by the limited training opportunities and the necessity of having staff physicians on site to provide feedback to the trainees. In addition, the assessment tools used to measure trainees performance are not always sensitive enough to detect different levels of expertise. To address this problem, two Apple Watches worn on inexperienced subjects in laparoscopy were used to record their motion signals (attitude, rotation rate and acceleration) during multiple practices of the peg transfer task in a fundamentals of laparoscopic surgery (FLS) trainer box. This training process was carried out through a massed practice methodology (two hours of training), in which subjects were assessed following the guidelines of the FLS program. Subsequently, a series of metrics were estimated from the acquired motion signals and the Spearman's rank correlation coefficient was used to select the most statistically significant attributes. Then, a classification model based on artificial neural networks was trained, using these attributes as model inputs, to classify trainees according to their level of expertise into three classes: low, intermediate and high. Using this approach, an average classification performance of F1=86.11% was achieved on a test subset. This suggests that new technologies, such as smartwatches, can be used to complement surgical training by including motion-based metrics to improve current clinical education and offering a new source of feedback through objective assessment. PMID- 30441567 TI - A Binary Classification of Cardiovascular Abnormality Using Time-Frequency Features of Cardio-mechanical Signals. AB - This paper introduces a novel method of binary classification of cardiovascular abnormality using the time-frequency features of cardio-mechanical signals, namely seismocardiography (SCG) and gyrocardiography (GCG) signals. A digital signal processing framework is proposed which utilizes decision tree and support vector machine methods with features generated by continuous wavelet transform. Experimental measurements were collected from twelve patients with cardiovascular diseases as well as twelve healthy subjects to evaluate the proposed method. Results reveal an overall accuracy of more than 94% with the best performance achieved from SVM classifiers with GCG training features. This suggests that the proposed solution could be a promising method for classifying cardiovascular abnormalities. PMID- 30441568 TI - Simple Gait Symmetry Measures Based on Foot Angular Velocity: Analysis in Post Stroke Patients. AB - In this paper, we propose symmetry measures for post stroke assessment based on gait signal profiles from inertial sensors. Ten healthy controls and eight post stroke patients performed 6-Minute Walk Tests while wearing an inertial sensor on top of each shoe. Symmetry measures based on the linear correlation and the normalized sample distance between left and right foot pitch angular velocity showed high discriminating power to differentiate post stroke gait from healthy controls (Cliff's D = 0.95, Wilcoxon test p<0.001). The proposed symmetry measures are simple to estimate and do not require spatiotemporal gait parameters while they provide comparable discriminating power than symmetry measures based on spatiotemporal gait characteristics such as maximum angular velocity and stance ratio of each cycle. The proposed symmetry measures have the potential for generalization in wearable sensor based gait symmetry assessment. PMID- 30441569 TI - Electromechanical Model to Predict Cardiac Resynchronization Therapy. AB - Cardiac resynchronization therapy (CRT) can substantially improve dyssynchronous heart failure and reduce mortality. However, one-third of the CRT patients derive no measurable benefit from CRT, due to suboptimal placement of the left ventricular (LV) lead. We introduce a pipeline for improved CRT-therapy by creating an electromechanical model using patient-specific geometric parameters allowing individualization of therapy. The model successfully mimics expected changes when variables for tension, stiffness, and conduction are entered. Changing LV pacing site had a notable effect on maximum pressure gradient (dP/dtmax) in the presence of cardiac scarring, causing non-uniform excitation propagation through the LV. Tailoring CRT to the individual requires simulations with patient-specific biventricular meshes including cardiac geometry and conductivity properties. PMID- 30441570 TI - Propagation of Parametric Uncertainty in Aliev-Panfilov Model of Cardiac Excitation. AB - Models of cardiac electrophysiology are useful for studying heart functions and cardiac disease mechanisms. However, cardiac models often have a great level of complexity, and it is often computationally prohibitive to simulate tissue and organ activities in a real-time fashion. To address the challenge, simplified models such as Aliev-Panfilov model are developed to reduce model complexity, while providing necessary details of cardiac functions. Simplified models may induce uncertainty, which can deteriorate the accuracy and reliability of cardiac models. In addition, model parameters are calibrated with noisy data and cannot be known with certainty. It is important to assess the effect of parametric uncertainty on model predictions. For the probabilistic, time-invariant parametric uncertainty, a generalized polynomial chaos (gPC) expansion-based method is presented in this work to quantify and propagate uncertainty onto model predictions. Using gPC, a measure of confidence in model predictions can be quickly estimated. As compared with sampling-based uncertainty propagation techniques, e.g., Monte Carlo (MC) simulations, the gPC-based method in this work shows its advantages in terms of computational efficiency and accuracy, which has the potentials for dealing with complicated cardiac models, e.g., 2D tissue and 3D organ models. PMID- 30441571 TI - Computational Fluid Dynamics Analysis to Predict Endothelial Cells Migration During Flow Exposure Experiment With Placement of Two Stent Wires. AB - Stent deployment is currently used for many cardiovascular treatments. During its application, the presence of the stent inside the blood vessel will indeed cause some change in both flow environment and also vessel wall's cellular conditions. This research intends to learn about the flow phenomenon of how vessel wall endothelial cells (ECs) react to the presence of stent wires within a microfluidic flow chamber environment. Computational fluid dynamics (CFD) simulation analysis of the microfluidic flow chamber system has been performed for observing the hemodynamics phenomena in the chamber. Moreover, CFD method also can be beneficial as a planning step for a successful experimental study. We found that under the two wires configurations, high wall shear stress (WSS) area is developed on the downstream side of the wires. Based on the analysis of WSS and WSS gradients (WSSG) conditions, ECs morphological change and migration are likely to occur some specific area. PMID- 30441572 TI - Global Sensitivity Analysis of a Cardiovascular Model for the Study of the Autonomic Response to Head-up Tilt Testing. AB - This paper proposes the integration and analysis of a mathematical model representing the cardiovascular system and its short-term autonomic response to head-up tilt (HUT) testing. A Latin Hypercube Sampling method was applied to design an optimal experimental space, including 19 model parameters coming from the cardiovascular and baroreflex control systems. Then, a global, variance-based sensitivity analysis was applied to quantity the effects of these parameters on heart rate and systolic blood pressure. Results highlight the relevant influence of the intrinsic heart rate and the sympathetic and parasympathetic baroreflex gains on heart rate regulation, as well as the impact of left ventricle diastolic parameters on systolic blood pressure. Moreover, a significant effect of right ventricle dynamics on blood pressure was noted. These results provide valuable information for the application of such an integrated model for the analysis of the autonomic mechanisms regulating the cardiovascular response induced by postural changes. In particular, they suggest a convenient set of parameters to be identified in a subject-specific manner. PMID- 30441574 TI - Design of an Interactive Simulation Environment for Arrays of Cardiac Cells. AB - The electrical activity of cardiac cells is complex and their collective action difficult to visualize. Understanding what is happening, overall and cell by cell, requires detailed simulation. Here the design of such a simulation is defined by a list of required tasks. An example of the performance of such a simulation is presented, and its time to completion is measured. PMID- 30441573 TI - Computational Analysis of the Action of Chloroquine on Short QT Syndrome Variant 1 and Variant 3 in Human Ventricles. AB - AIMS: The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQTI and SQT3, SQTS variants, result from gain-of-function mutations (N588K and D172N, respectively) in the KCNH2-encoded and KCNJ2-encoded potassium channels, in which treatment with potassium channel blocking agents has demonstrated some efficacy. This study used in silico modelling to gain mechanistic insights into the actions of anti malarial drug chloroquine (CQ) in the setting of SQTI and SQT3. METHODS AND RESULTS: The ten Tusscher et al. human ventricle model was modified to a Markov chain formulation of $I_{J}$=50% reduction in Apnoea Hypopnoea Index (AHI) resulting in an AHI of less than 10 after the treatment process. Leaveone-out cross validation results using a Quadratic Neural Network showed an overall accuracy of 63%, with 63% sensitivity and 63% specificity for correctly predicting treatment response which is an improvement on previously published results. PMID- 30441714 TI - In-Home Sleep Apnea Severity Classification using Contact-free Load Cells and an AdaBoosted Decision Tree Algorithm. AB - We present a method for automated diagnosis and classification of severity of sleep apnea using an array of non-contact pressure-sensitive sensors placed underneath a mattress as an alternative to conventional obtrusive sensors. Our algorithm comprises two stages: i) A decision tree classifier that identifies patients with sleep apnea, and ii) a subsequent linear regression model that estimates the Apnea-Hypopnea Index (AHI), which is used to determine the severity of sleep disordered breathing. We tested our algorithm on a cohort of 14 patients who underwent overnight home sleep apnea test. The machine learning algorithm was trained and performance was evaluated using leave-one-patient-out cross validation. The accuracy of the proposed approach in detecting sleep apnea is 86.96%, with sensitivity and specificity of 81.82% and 91.67%, respectively. Moreover, classification of severity of the sleep disorder was correctly assigned in 11 out of 14 cases, and the mean absolute error in the AHI estimation was calculated to be 3.83 events/hr. PMID- 30441715 TI - Gas Embolization in a Rodent Model of Hepatocellular Carcinoma Using Acoustic Droplet Vaporization. AB - Trans-arterial embolization is a commonly used therapy in unresectable hepatocellular carcinoma. Current methods involve the careful placement of an intraarterial catheter and the deposition of embolizing particles. Gas embolotherapy has been proposed as an embolization method with the potential for high spatial resolution without the need for a catheter. This method involves vaporizing intravenouslyadministered droplets into gas bubbles using focused ultrasound - a process termed acoustic droplet vaporization. The bubbles can become lodged in the vasculature, thereby creating an embolus. Here, we initially demonstrate the feasibility of achieving significant targeted embolization with this method in the rat cremaster using intravital microscopy. The therapy was then tested in an ectopic xenograft mouse model of hepatocellular carcinoma. Gas embolotherapy was shown to maintain the tumor volume at baseline over a twoweek treatment course while control groups showed significant tumor growth. These preliminary results demonstrate thatgas embolotherapy could serve as an effective noninvasive method for the management of unresectable hepatocellular carcinoma. PMID- 30441716 TI - Design of A Novel Wearable LIPUS Treatment Device for Mental Health Treatment. AB - Low-intensity pulsed ultrasound (LIPUS) has been proven to be an effective treatment modality to improve bone fractures, soft tissue regeneration and neuromodulation. Recently, it has been shown for treating mental health diseases. In this paper, a novel wearable LIPUS treatment device, including a wearable headband and a LIPUS generator, is designed. The circuit in the LIPUS generator is specially built to generate LIPUS for stimulating the brain via temples. Considering comfortableness and safety, we designed a flexible cap to cover ultrasound transducer. The custommade replaceable transducer cap can be refilled by different ultrasound coupling agents. We demonstrated how polyurethane rubber caps filled with different ultrasound coupling agents affect the ultrasound transmission intensity. Milli-Q water is identified to be the best ultrasound coupling agent for the polyurethane rubber cap with about 39.76% LIPUS intensity transmission. PMID- 30441717 TI - Transcranial Ultrasound Improves Behavioral Performance via Anti Neuroinflammation. AB - The purpose of this study was to investigate the protective role of low-intensity pulsed ultrasound (LIPUS) against lipopolysaccharide (LPS)-induced neuroinflammation and memory impairments in a mouse model. A 1.0 MHz focused ultrasound transducer was exploited to sonicate the brain noninvasively with 50 ms burst lengths at a 5% duty cycle, a repetition frequency of 1 Hz. Mice subjected to LPS administration (250 MUg/kg, i.p.) were treated with LIPUS daily for 7 days. The levels of inflammatory markers were estimated in brain tissue using western blot. After LIPUS treatment, the neuroprotective effects of LIPUS in mice were assessed by behavioral analysis using the Morris water maze. The average escape latencies were significantly shortened in LPS plus LIPUS-treated mice from the sixth day of the acquisition phase. Furthermore, LIPUS significantly reduced the protein levels of TNF-alpha, IL-1beta, and IL-6 in the mice brain induced by LPS. LIPUS treatment shows neuroprotection by inhibiting LPS-induced activation of TLR4 inflammatory signaling. Our data showed that LIPUS attenuated LPS-induced memory impairment via suppression of neuroinflammatory activity. PMID- 30441718 TI - Ultrasound-Induced Insulin Release as a Potential Novel Treatmentfor Type 2 Diabetes Mellitus. AB - Therapeutic ultrasound presents a potential novel treatment for type 2 diabetes mellitus that utilizes the non-invasive application of ultrasound energy to treat secretory defects in the earlier stages of the disease. Our previous studies have shown that ultrasound is capable of stimulating insulin release from pancreatic beta cells, safely and effectively. This study aims to both examine the calcium dependent mechanisms of ultrasound-mediated insulin release from pancreatic beta cells using three complementary modalities - carbon fiber amperometry, ELISA studies, and Ca2+ fluorescence imaging - and to study the translational potential of therapeutic ultrasound using transgenic hyperglycemic mice for safety and efficacy studies. PMID- 30441719 TI - Histotripsy for Non-Invasive Ablation of Hepatocellular Carcinoma (HCC) Tumor in a Subcutaneous Xenograft Murine Model. AB - Histotripsy fractionates tissue through a mechanical, non-invasive ultrasonic ablation process that precisely controls acoustic cavitation while utilizing real time ultrasound (US) imaging guidance. This study investigates the potential, feasibility and tumor volume reduction effects of histotripsy for liver cancer ablation in a subcutaneous in vivo murine Hepatocellular Carcinoma (HCC) model. Hep3B tumors were generated in the right flanks of 14 NSG and 7 NOD-SCID mice. The mice were grouped as follows: A (acute, NSG with n=9 treatment and n=1 control), B (chronic, NSG with n=2 treatment and n=2 control) and C (chronic NODSCID, with n=6 treatment and n=1 control). Treatment was performed when the tumor diameters reached >5 mm. 1-2 cycle histotripsy pulses at 100 Hz PRF (p- >30 MPa) were delivered using a custom built 1 MHz therapy transducer attached to a motorized positioner, which scanned the transducer focus to traverse the targeted tumor volume, guided by real-time US imaging. Tumor ablation effectiveness was assessed by obtaining T1, T2 and T2* weighted MR images. Post euthanasia, treated tumor, brain, and lung tissue samples were harvested for histology. Histology of acute group A showed fractionation of targeted region with a sharp boundary separating it from untreated tissue. Groups B and C demonstrated effective tumor volume reduction post treatment on MRI as the homogenate and edema were resorbed within 23 weeks. However, as the tumor was subcutaneous, it was not possible to set adequate treatment margin and since the mice were immune-compromised, residual viable tumor cells eventually developed into tumor regrowth at 3-9 weeks after histotripsy. Groups B and C showed no signs of metastasis in the lung and brain. Our study successfully demonstrated the potential of histotripsy for non invasive HCC ablation in a subcutaneous murine model. Additional work is ongoing to study the response of histotripsy in immune-competent orthotopic liver tumor models. PMID- 30441720 TI - Real-time Optical Imaging of Microbubble Destruction with an Acoustic Lens Attached Ultrasonic Diagnostic Probe in Microfluidic Capillary Models. AB - In this work, an ultrasonic diagnostic system with an attachable acoustic lens was demonstrated for real-time optical imaging of ultrasound-mediated microbubble destruction in a microfluidic capillary model using an inverted microscope. Microbubble destruction under ultrasonic pressure was monitored via an EM-CCD camera with the frame rate of 70 fps. The acoustic field distribution of the transducer with the attachable acoustic lens was simulated via a finite element method (FEM) and measured by a hydrophone. The result of acoustic field distribution shows unfocused beam profiles with 50% decreased pressure of original focal area. With the unfocused beam, inertial cavitation of the microbubbles as a function of transducer input voltages of 30-60 Vpp was studied. In addition, the acoustic cavitation parameters such as frequency of 2 MHz, pulse length of 16 MUs, and pulse repetition frequency (PRF) of 1 kHz were investigated under static and dynamic flow conditions in the microfluidic model. In our system, above 45 Vpp, the microbubbles were destroyed more than 50% within 20 seconds so that the threshold for the inertial cavitation was determined to be 45 Vpp in the channel without flow. In the microfluidic capillary model with fluidic flow, it is investigated that shape of microbubble mass continuously changed with acoustic pressure with 60 Vpp. PMID- 30441721 TI - A Portable Device Integrated with Aligned Carbon Nanotubes for Sensitive Virus Capture and Detection. AB - Point-of-care virus diagnosis is highly desirable in worldwide infectious disease control. Here we report a hand-held device for capturing viruses by applying physical size based exclusion inside a point-of-care device integrated with vertically aligned carbon nanotube (VACNT) nanostructures to achieve label-free and high throughput virus capture. The microfluidic device is constructed from a VACNT channel wall synthesized bottom-up via chemical vapor deposition (CVD). The VACNT has ~117 nm average gap size and ~97& porosity. By bonding with a polydimethylsiloxane (PDMS) cover sealing the top, the aqueous sample containing virus particles filter through the VACNT channel wall under negative pressure applied at the outlet end. We have demonstrated that the device is capable of filtering 50 MUL of PBS containing ~6.3 * 104 counts of lentivirus particles in 10 minutes with 97& of capture efficiency, quantified by the cell infectious titration technique. PMID- 30441722 TI - Aligned Conducting Polymer Nanotubes for Neural Prostheses. AB - The long-term performance of neural microelectrodes relies on biocompatibility and sensitivity of the electrode-tissue interface. Current neural electrodes are limited by poor electrical performance including high initial impedance and low charge storage capacity. In addition, they are mechanically hard which causes cellular reactive response to the implanted electrode. In this report, we have demonstrated a new templating method for fabrication of highly aligned conducting polymer nanotube. The structure of nanotubes can be precisely modulated by varying the time of electropolymerization. The electrical performance of poly(pyrrole) (PPY) and poly(3,4-ethylenedioxythiophine) (PEDOT) nanotubes including impedance and charge storage capacity were studied and compared as the surface morphology and structure of nanotube varied during the fabrication process. PEDOT nanotubes were found to have lower impedance than PPY nanotubes. By contrast, PPY nanotubes were shown to have higher charge storage capacity. These finding suggest that aligned conducting polymer nanotubes may enhance the long-term performance of neural microelectrodes. PMID- 30441723 TI - Fabrication and testing of multielectrode matrix of disordered Si nanowires for brain tissue sensing. AB - In the field of neuroscience there is interest on manufacturing new recording devices. The relationship between individual action potentials of neurons and field potentials in multicellular records is complex. For this reason, there is a big interest in multielectrode arrays. This work describes the unconventional fabrication process of an alternative multielectrode and its use for sensing neuronal activity. It consists of a matrix of Si nanowires randomly distributed, coated with Ag nanoparticles, and with macrometric Ag back contacts. The Si nanowires are prepared by metal-assisted chemical etching of a Si wafer, which is an economical and highly reproducible technique. Recordings using the multielectrode array of randomly distributed Si nanowires look promising and comparable with recordings obtained with other multielectrode devices. PMID- 30441724 TI - Cross-linked electrospun gelatin nanofibers for cell-based assays. AB - The present study evaluates the crosslinking of electrospun gelatin nanofibers by physical and chemical methods to further elucidate the importance of the application of gelatin scaffold platforms for cell-based assays. The dehydrothermally cross-linked electrospun gelatin scaffolds were unable to retained their structure morphology and integrity upon exposure to 1X PBS or cell culture media. The DHT and EDC/Sulfo-NHS cross-linked gelatin scaffolds exhibited fiber diameter on average in the nanometer range. Subsequently, we utilized 1X PBS and cell culture media to evaluate the stability of the nanofibers in solution. The immersion evaluation indicated that the chemically crosslinked gelatin nanofibers maintained their random nanofiber distribution and morphology. However, a high degree of swelling was observed in the presence of cell culture media. Overall, the gelatin scaffold demonstrated good performance in PBS and cell culture media. Hence, EDC/Sulfo-NHS crosslinked electrospun gelatin nanofibrous scaffolds have good biocompatibility and are promising bio-scaffolds for cell-based assays. PMID- 30441725 TI - Physical Activity and Sleep Analysis of Heart Failure Patients using Multi-sensor Patches. AB - Traditional heart failure markers fail to reliably predict heart-failure related hospitalisations and deaths. Multi- sensor patch data can provide an objective insight into activity and sleep patterns of patients and may therefore improve the performance of current risk-quantification algorithms. This work aimed to establish the feasibility of collecting multi-sensor patch data from heart failure patients and to perform an initial analysis of activity and sleep patterns of heart failure patients in relation to disease severity. 13 heart failure patients from the SUPPORT-HF study were provided with chest-worn multisensor patches and asked to wear the devices continuously for up to seven consecutive days. Using a combination of impedance, heart rate and accelerometer data participants' sleep and wakefulness information were extracted and analyzed in relation to self-reported symptom scores. Patch data for eleven patients were of high enough quality to be included in the analysis, accounting for 63 patient days worth of data. The heart failure patients slept for an average of 8.3 hours a night and experienced 2.8 sleep interruptions. Potential differences in sleep angle, heart rate and wake-time activity were found for patients with different heart failure severity. Larger studies are necessary to create a more coherent picture of the potential of activity and sleep as a markers for heart failure deterioration. PMID- 30441726 TI - Applying Data Preprocessing Methods to Predict Premature Birth. AB - Data mining and pattern classification tools have{enabled prediction of several medical outcomes with high levels of accuracy. This is due to the capability of handling large datasets, even those with missing values. Preterm birth (PTB) can have damaging long-term effects for infants and rates have been increasing over the last two decades worldwide. The purpose of this work was to investigate whether preprocessing methods, when applied to two different prenatal datasets, can improve prediction accuracy of our software tool to predict PTB. The primary software used within this work was R. The software was used to deal with missing values and class imbalances found in these two datasets. The results show that in comparison to our past work, we have managed to increase the performance of the prediction tool using the metrics of sensitivity, specificity, and ROC values. PMID- 30441727 TI - Key Marker Selection for the Detection of Early Parkinson' s Disease using Importance-Driven Models. AB - The detection of early Parkinson' s disease (PD) is crucial for PD management. Most of previous efforts on PD diagnosis focus more on improving PD detection accuracies by trying using features from more modalities, which results in a common question: is it true that the more features available, the better the performance of the diagnosis system? This paper proposes an importance-driven approach for the detection of PD. The importance of features based on gradient boosting is firstly learned. The ranked features based on feature importance are input to a progressive learning pipeline to find key features of PD. The experiment results show that a comparable PD classification performance can be obtained with much less key features and therefore fewer modalities of tests are required. Such findings have critical socioeconomic values. PMID- 30441728 TI - A Machine Learning Approach for the Prediction of the Progression of Cardiovascular Disease based on Clinical and Non-Invasive Imaging Data. AB - Nowadays, cardiovascular diseases are very common and are considered as the main cause of morbidity and mortality worldwide. Coronary Artery Disease (CAD), the most typical cardiovascular disease is diagnosed by a variety of medical imaging modalities, which involve costs and complications. Therefore, several attempts have been undertaken to early diagnose and predict CAD status and progression through machine learning approaches. The purpose of this study is to present a machine learning technique for the prediction of CAD, using image-based data and clinical data. We investigate the effect of vascular anatomical features of the three coronary arteries on the graduation of CAD. A classification model is built to predict the future status of CAD, including cases of "no CAD" patients, "non obstructive CAD" patients and "obstructive CAD" patients. The best accuracy was achieved by the implementation of a tree-based classifier, J48 classifier, after a ranking feature selection methodology. The majority of the selected features are the vessel geometry derived features, among the traditional risk factors. The combination of geometrical risk factors with the conventional ones constitutes a novel scheme for the CAD prediction. PMID- 30441729 TI - Deploying Predictive Models In A Healthcare Environment - An Open Source Approach. AB - Despite dramatic progress in the application of predictive modeling and data mining techniques to problems in modern medicine, a major challenge facing technical practitioners is that of delivering models to clinicians. We have developed an easily implementable framework for publishing predictive models written in R or Python in a way that allows them to be consumed by practically any downstream clinical application, as well as allowing them to be reused in a wide variety of environments without modification. The approach makes models available as web services embedded in containers and uses only open source technology. We provide a template, practical explanation and discussion of involved technologies for a model production framework. We currently use this framework to deliver a model for predicting readmission to hospital following discharge to skilled nursing facilities. The flexibility and simplicity of this methodology will allow it to be readily adopted at a wide variety of institutions. We also provide source code for an example model. PMID- 30441730 TI - A Multi-Domain Continuum Model of Electrical Stimulation of Healthy and Degenerate Retina. AB - A continuum multi-domain model of electrical stimulation of the retina is presented and validated against retinal ganglion cell (RGC) excitation thresholds reported in a recently published in vitro experimental study. We applied our model to investigate the response of the RGC layer to electrical stimulation during mid-to-late stage retinal degeneration for both epiretinal and suprachoroidal configurations. Interestingly, our model predicted that suprachoroidal stimulation of the degenerate retina required increased current thresholds, mainly because of the presence of the glial scar layer. In contrast, epiretinal stimulation thresholds were almost similar for both healthy and degenerate models. The latter finding implies that there is no influence of the glial scar layer on epiretinal stimulation current thresholds. PMID- 30441731 TI - A Cerebellar Spiking Neural Model for Phase Reversal of Vestibulo-ocular Reflex. AB - Cerebellum possesses very rich motor control and learning capability which is critical for animals. In this study, we proposed a spiking neural network model of cerebellum for gain and phase adaptation in vestibulo-ocular reflex (VOR). VOR is a critical adaptive reflexive eye movement for maintaining a stable visual field. In this model (with neuron number at the order of 104), synaptic plasticity at parallel fiber-Purkinje cell synapses was considered. In particular, we have shown that the inhibitory inputs from molecular layer interneurons on Purkinje cells play a critical role in phase adaptation of VOR. The inhibitory input from interneurons indirectly affects the strength of long term potentiation (LTP) and long-term depression (LTD), resulting in more drastic phase shift upon learning and hence allowing phase reversal of VOR. The strength of inhibitory input also affects the maximum phase shift that can be achieved. Our result is consistent with experiments in mutant mice with blocked inhibitory inputs. PMID- 30441732 TI - Clustering Based Kernel Reinforcement Learning for Neural Adaptation in Brain Machine Interfaces. AB - Reinforcement learning (RL) interprets subject's movement intention in Brain Machine Interfaces (BMIs) through trial-and-error with the advantage that it does not need the real limb movements. When the subjects try to control the external devices purely using brain signals without actual movements (brain control), they adjust the neural firing patterns to adapt to device control, which expands the state-action space for the RL decoder to explore. The challenge is to quickly explore the new knowledge in the sizeable state-action space and maintain good performance. Recently quantized attention-gated kernel reinforcement learning (QAGKRL) was proposed to quickly explore the global optimum in Reproducing Kernel Hilbert Space (RKHS). However, its network size will grow large when the new input comes, which makes it computationally inefficient. In addition, the output is generated using the whole input structure without being sensitive to the new knowledge. In this paper, we propose a new kernel based reinforcement learning algorithm that utilizes the clustering technique in the input domain. The similar neural inputs are grouped, and a new input only activates its nearest cluster, which either utilizes an existing sub-network or forms a new one. In this way, we can build the sub-feature space instead of the global mapping to calculate the output, which transfers the old knowledge effectively and also consequently reduces the computational complexity. To evaluate our algorithm, we test on the synthetic spike data, where the subject's task mode switches between manual control and brain control. Compared with QAGKRL, the simulation results show that our algorithm can achieve a faster learning curve, less computational time, and more accuracy. This indicates our algorithm to be a promising method for the online implementation of BMIs. PMID- 30441733 TI - Modeling Nonlinear Synaptic Dynamics: A Laguerre-Volterra Network Framework for Improved Computational Efficiency in Large Scale Simulations. AB - Synapses are key components in signal transmission in the brain, often exhibiting complex non-linear dynamics. Yet, they are often crudely modelled as linear exponential equations in large-scale neuron network simulations. Mechanistic models that use detailed channel receptor kinetics more closely replicate the nonlinear dynamics observed at synapses, but use of such models are generally restricted to small scale simulations due to their computational complexity. Previously, we have developed an ''input-output'' (IO) synapse model using the Volterra functional series to estimate nonlinear synaptic dynamics. Here, we present an improvement on the IO synapse model using the extbf{Laguerre-Volterra network (LVN) framework. We demonstrate that utilization of the LVN framework helps reduce memory requirements and improves the simulation speed in comparison to the previous iteration of the IO synapse model. We present results that demonstrate the accuracy, memory efficiency, and speed of the LVN model that can be extended to simulations with large numbers of synapses. Our efforts enable complex nonlinear synaptic dynamics to be modelled in large-scale network models, allowing us to explore how synaptic activity may influence network behavior and affects memory, learning, and neurodegenerative diseases. PMID- 30441734 TI - Tractography Analysis for Electroconvulsive Therapy. AB - Computational human head models have been used in electrophysiological studies, and they have been able to provide useful information that is unable or difficult to acquire from experimental or imaging studies. However, most of these models are purely volume conductor models that overlooked the electric excitability of axons in the white matter of the brain. This study combined a finite element (FE) model of electroconvulsive therapy (ECT) with a whole-brain tractography analysis as well as the cable theory of neuronal excitation. We have reconstructed a whole brain tractogram with 500 neural fibres from the diffusion-weighted magnetic resonance scans, and extracted the information on electrical potential from the FE ECT model of the same head. We then calculated the first and second spatial derivatives of the electrical potential, which describes the activating function for homogenous axons and investigated sensitive regions of white matter activation. PMID- 30441735 TI - Decoding Position to Analyze Spatial Information Encoding in a Large-Scale Neuronal Network Model of Rat Dentate Gyrus. AB - Spatial information is encoded by the hippocampus, and the factors that contribute to the amount of information that can be encoded and the transformation of spatial information through the trisynaptic circuit remain an important issue. A large-scale neuronal network model of the rat entorhinal dentate system was developed with multicompartmental representations of the neurons within the dentate gyrus. Spatial information was introduced to the network via grid cell activity, and the spatial information encoding capabilities of the network were assessed using a recursive decoding algorithm to estimate the position of a virtual rat using the dentate activity. To obtain a measure for the information that the network could convey, decoding error was calculated for different decoding population sizes. Decoding error decreased exponentially as a function of population size. Therefore, the time constant and the asymptote of the error curve could be used as metrics to compare the changes in encoding performance. In conjunction with the large-scale model, this paradigm can be used to characterize how neural properties, network composition, and the interactions between different subfields affect spatial information encoding. PMID- 30441736 TI - Simulating the Outcome of Heart Allocation Policies Using Deep Neural Networks. AB - We created a system to simulate the heart allocation process in a transplant queue, using a discrete event model and a neural network algorithm, which we named the Lund Deep Learning Transplant Algorithm (LuDeLTA). LuDeLTA is utilized to predict the survival of the patients both in the queue and after transplant. We tried four different allocation policies: wait time, clinical rules and allocating the patients using either LuDeLTA or The International Heart Transplant Survival Algorithm (IHTSA) model. Both IHTSA and LuDeLTA were used to evaluate the results. The predicted mean survival for allocating according to wait time was about 4,300 days, clinical rules 4,300 days and using neural networks 4,700 days. PMID- 30441737 TI - Influence of the Cochlear Implant Electrode Array Placement on the Current Spread in the Cochlea. AB - Three-dimensional (3D) computational models of the inner ear have been utilised to assist in investigating the factors that influence cochlear implant (CI) outcomes. A volume conductor cochlear model with an implanted electrode array was reconstructed from X-ray microtomography $(?mu$ CT) scans of a cadaveric human temporal bone. To mimic an in-vivo setting, the cochlea was embedded in a head model. The finite element (FE) method was used to analyse the electrical potential $?varphi$ in the cochlear nerve as a result of CI stimulation. In order to study the influence of electrode array placement on the current spread within the cochlea and the modiolus, computer simulations with six electrode array placements were conducted. $?varphi$ was evaluated at the tip of nerve fibres reconstructed within the cochlear nerve so as to predict the stimulation of a neuron population. It was found in most cases that a medial electrode array placement produced a narrower $?varphi$ peak at the fibre tip than a lateral one, although the differences were small. PMID- 30441738 TI - Brachytherapy organ dose estimation using Monte Carlo simulations of realistic patient models. AB - Radiation Therapy Planning Systems (RTPS) currently used in hospitals contain algorithms based on deterministic simplifications that do not properly consider electrons lateral transport in the areas where there are changes of density, and as a result, erroneous dose predictions could be produced. According to this, the present work proposes the use of Monte Carlo method in brachytherapy planning systems, which could affect positively on the radiotherapy treatment planning, since it provides results that are more accurate and takes into account the in homogeneities density variations. This paper presents a Monte Carlo (MC) simulation of a brachytherapy prostate treatment with I-125 seeds, using the latest version of MCNP, v.6.1.1. To that, a 3D model of the anatomy of a real anonymized patient is created from the segmentation of Computed Tomography (CT) images. Treatment over this 3D model is simulated and the dose given to each organ is obtained. These doses are compared with those calculated by deterministic planning system used in hospital demonstrating the effectiveness of MC method in the planning of brachytherapy treatments, because of not only the results precision but also regarding the affordable computing times. PMID- 30441739 TI - Unveiling the Impact of Distinct Melanosome Arrangements on the Attenuation of Cancer-Inducing Ultraviolet Radiation. AB - The exposure of human skin to ultraviolet radiation (UVR) can trigger a wide array of biological responses, including photocarcinogenesis. Melanin, either in colloidal form or encapsulated into melanosomes, is known to be the main UVR attenuation substance acting within the cutaneous tissues. Although many studies have addressed the protective role of this pigment against the harmful effects of UVR exposure, the impact of different melanosome arrangements on the mitigation of these effects remains to be quantitatively verified. The difficulties to resolve this open question can be mainly attributed to the intrinsic practical limitations of in vivo and in vitro experiments involving skin specimens. In this paper, we describe controlled in silico experiments that allowed us to overcome such limitations and provide quantitative evidence for the clarification of this question. Besides contributing to a more robust understanding of the physiological parameters associated with cutaneous UVR attenuation, our findings can be incorporated into the development of more effective strategies for the evaluation of individuals' susceptibility to UVR exposure. Such strategies are essential for the prevention of UVR-induced pathologies, particularly skin cancer. PMID- 30441740 TI - Molecular Dynamics Simulation Study of Electrokinetics Transport of Aqueous Solution through Functionalized Carbon Nanotubes: A New Membrane Model for Nanopours Based Biosensors. AB - DNA sequencing is an essential process for determining the nucleotides on a DNA strands and this process is of high importance in medicine and biomedical research. Nanopore based DNA sequencing has been widely researched and analyzed during last years and this is very important to improve all parameters involved in the process of DNA translocating through these nanopours. Ionic current resolution is a key parameter in designing these nanopours for better measuring of this infinitesimal current that is in order of nano A or even pico A. Here by means of molecular dynamics simulation we showed that using fluorinated carbon nanotubes while embedded inside silicon membrane results a higher ionic current compared to pristine carbon nanotubes. We simulated pristine carbon nanotubes (PCNT) and fluorinated carbon nanotubes (FCNT) with chirality of (8,8) and (10,10) which corresponds to diameter of 1.07 nm and 1.34 nm respectively. Ionic current analysis of these inorganic nanopours functionalized with carbon nanomaterials showed that it could double or triple the magnitude of ionic current. For FCNT (8,8) the magnitude of ionic current was 1.984 nA while it was 0.891 nA for PCNT (8,8) embedded in silicon nanopore. Our study introduces the fluorination of carbon nanotubes as potential method for designing high resolution DNA sequencing nanopore devices. PMID- 30441741 TI - Mathematical Modeling of Bacteria-Enabled Drug Delivery System Penetration into Multicellular Tumor Spheroids. AB - Bacteria-based cancer treatment is a promising approach to address the need for targeted tumor therapies in an effort to avoid the systemic toxicity inherent in conventional chemotherapy. A number of bacterial strains have been shown to preferentially colonize tumors and impart therapeutic benefits. However, the physical underpinnings of bacteria intratumoral transport remain poorly studied. It is hypothesized that cell Iysis in hypoxic and necrotic regions of tumors creates a niche in which some bacteria thrive. To understand if preferential growth plausibly explains the experimentally observed bacterial colonization profiles, we have developed a mathematical model incorporating transport and growth dependent on tumor cell Iysate. We fit model parameters to experimental data, showing that our formulation captures experimentally observed trends. Moreover, we find that bacteria have a higher effective diffusivity than nanoparticles alone, demonstrating transport advantages to designing bacteria based cancer therapy. This model serves as a first step towards building computational tools for designing optimized bacteria- based chemotherapeutic delivery systems. PMID- 30441742 TI - Improving the Diagnostic Ability of Oximetry Recordings in Pediatric Sleep Apnea Hypopnea Syndrome by Means of Multi-Class AdaBoost. AB - Pediatric sleep apnea-hypopnea syndrome (SAHS) is a highly prevalent respiratory disorder that may impose many negative effects on the health and development of children. Due to the drawbacks of overnight polysomnography (PSG), the gold standard diagnosis technique, automated analysis of nocturnal oximetry has emerged as a simplified alternative. In order to improve diagnosis ability of oximetry, we propose to evaluate the usefulness of AdaBoost, a classification boosting algorithm, in the context of pediatric SAHS. A database composed of 981 SpO2 recordings from pediatric subjects was used. For this purpose, a signal processing approach divided into two main stages was conducted: (i) feature extraction, where 3% oxygen desaturation index (ODI3), spectral, and nonlinear features were computed from the oximetry signal, and (ii) AdaBoost classification, where an AdaBoost.M2 model was trained with these features in order to determine the severity of pediatric SAHS according to the apnea-hypopnea index (AHI): AHI<1 events per hour (e/h), 1<=AHI<5 e/h, and AHI>=5 e/h. Our AdaBoost.M2 model achieved a Cohen's kappa of 0.474 in an independent test set in the 3-class classification task. In addition, high accuracies were obtained when using the AHI cutoffs for diagnosis of mild (AHI=1 e/h) and moderate-to-severe (AHI=5 e/h) SAHS: 80.9% and 82.9%, respectively. These results achieved slightly higher diagnostic accuracies than ODI3 as well as state-of-the-art studies. Therefore, AdaBoost could help to enhance the diagnostic ability of the oximetry signal to assess pediatric SAHS severity. PMID- 30441743 TI - Differences between morphological and electrophysiological retinal ganglion cell classes. AB - Retinal prostheses work by delivering electrical pulses to the surviving retinal neurons. A pattern of electrical stimulation can generate a perception of vision in blind patients. To improve efficacy of retinal implants, it is important to understand how different classes of retinal neurons respond to electrical stimulation and if a classification can be made based on the electrophysiological properties of neurons. We use previously recorded patch clamp data from retinal ganglion cells classified into morphological classes (A,B,C, D) and functional types (ON, OFF, ON-OFF). We use a machine learning technique to separate data based on the recorded electrophysiological parameters. Results show that the clusters discovered using the machine learning technique do not correspond to the morphological or functional classes used by neuroscientists. PMID- 30441744 TI - Integrated Signal Encoding and Analysis System for Actigraphy-based Long-term Monitoring of Periodic Limb Movements in Sleep. AB - There has been a boom in the development of wearable devices for wellness and healthcare applications. Numerous studies have been conducted on the utility of employing wearable devices for the long-term monitoring of biosignals. Despite their efficacy, the potential for practical implementation faces many hurdles such as memory usage, power consumption, denoising, and efficient data transmission. Of the many wearables being used, the actigraph has been a popular choice amongst experts for identifying motion abnormalities such as periodic leg movements (PLMs) in sleep and the activities of patients suffering from various medical illnesses. In this paper, we present an efficient pulse code modulation based, 3-bit, signal encoding technique, which when applied to long-term (6-8 hours), 16-bit sleep actigraphy signals, generates 3-bit encoded, accelerometry data with an average compression ratio of 92%, an average increase in the signal to-noise (SNR) ratio by 20 dB and an average reduction of memory usage by 92%. The proposed technique also eliminates the need to apply filters for denoising, by retaining only characteristic signal information in the quantized version. The proposed technique, in general, could be applied to accelerometer-based wearables and has the potential to provide efficient memory and power usage in long-term monitoring applications. PMID- 30441745 TI - A machine learning approach to reconstruction of heart surface potentials from body surface potentials. AB - Invasive cardiac catheterisation is a precursor to ablation therapy for ventricular tachycardia. Invasive cardiac diagnostics are fraught with risks. Decades of research has been conducted on the inverse problem of electrocardiography, which can be used to reconstruct Heart Surface Potentials (HSPs) from Body Surface Potentials (BSPs), for non-invasive cardiac diagnostics. State of the art solutions to the inverse problem are unsatisfactory, since the inverse problem is known to be ill-posed. In this paper we propose a novel approach to reconstructing HSPs from BSPs using a Time-Delay Artificial Neural Network (TDANN). We first design the TDANN architecture, and then develop an iterative search space algorithm to find the parameters of the TDANN, which results in the best overall HSP prediction. We use recorded BSPs and HSPs from individuals suffering from serious cardiac conditions to validate our TDANN. The results are encouraging, in that the predicted and recorded HSPs have an average correlation coefficient of 0.7 under diseased conditions. PMID- 30441746 TI - EMBC 2018 Keynote & Plenary Speakers. AB - Provides an abstract for each of the keynote presentations and may include a brief professional biography of each presenter. The complete presentations were not made available for publication as part of the conference proceedings. PMID- 30441747 TI - Knowledge, Attitudes, and Practices about Zika among a University Community Located in an Endemic Zone in Mexico. AB - To assess the knowledge, attitudes, and practices about the Zika virus in both students and workers at the University of Veracruz, an online survey was conducted. The participants were divided into two groups: one according to sex, the other according to whether they were workers or students. Their answers were classified into knowledge, attitudes, and practices and they were rated as low, medium, and high. The results showed that knowledge about Zika prevailing among the university population is considered as medium in 79.4% of the study population. Most respondents know that the mosquito spreads the Zika virus (98.8%) and the clinical characteristics, while sexual transmission by the virus is little known (36.85%). Both the univariate analysis (OR (CI5) 0.227 (0.070 0.735), p = 0.013] and multivariate analysis (OR (CI95) 0.234 (0.071-778), p = 0.018] showed that belonging to the health sciences area is related to having a greater knowledge about Zika. Despite the existing knowledge, a low level of prevention practices prevails in the whole community (55%). A medium level of knowledge about Zika prevailed, while proper implementation of preventive measures for Zika is low, despite the fact that the state of Veracruz-the place where the University is located-is an endemic area. PMID- 30441748 TI - Contribution of Chemical Modifications and Conformational Epitopes to IgE Binding by Ara h 3. AB - Roasting is known to change the allergenic properties of peanuts. To study these observations at a molecular level, the relationship of IgE binding to the structure of Ara h 3 from raw and roasted peanuts was assessed. Ara h 3 (A3) was purified from raw (R), light roast (LR) and dark roast (DR) peanuts, the purity was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) and the secondary structures were compared with circular dichroism (CD) spectroscopy. In order to understand the contribution of structure to IgE binding, the R A3 was partially denatured (PD) by heat treatment (65 degrees C for 2 h), subjected to CD spectroscopy and IgE spot blot analysis with sera from peanut- allergic individuals. While we observed that the secondary structure of purified A3 from R and LR peanut in solution was affected by the reduction of disulfide bonds and heat treatment when purified from the peanut following the roasting process, only small alterations were seen in the secondary structure. The purified LR A3 bound higher levels of IgE than the RA3. CD spectroscopy of PD A3 revealed a reduction in the percentage of alpha helices, and serum IgE binding. Therefore, while A3 purified from roasted peanuts did not show significant changes in secondary structure, it showed higher IgE binding than R A3. Therefore, the higher IgE binding to LR A3 was more likely to be due to chemical modifications than structural changes. However, a decrease in the IgE binding was seen if R A3 was deliberately unfolded, indicating that the structure played an important role in IgE binding to A3. PMID- 30441749 TI - Drug Release of Hybrid Materials Containing Fe(II)Citrate Synthesized by Sol-Gel Technique. AB - The use of oral iron integration is commonly recommended for the treatment of iron deficiency, nevertheless the diagnosis and treatment of this disease could clearly be improved. The aim of this work was the synthesis of therapeutic systems, iron (II) based, by sol-gel method. In an SiO2 matrix, we embedded different weight percentages of polyethylene glycol (PEG6, 12, 24 wt%) and ferrous citrate (Fe(II)C5, 10, 15 wt%) for drug delivery applications. Fourier Transform Infrared (FTIR) spectroscopy was used to study the interactions among different components in the hybrid materials. Release kinetics in a simulated body fluid (SBF) were investigated and the amount of Fe2+ released was detected by Ultraviolet-Visible spectroscopy (UV-VIS) after reaction with ortho phenantroline. Furthermore, the biological characterization was carried out. The bioactivity of the synthesized hybrid materials was evaluated by the formation of a layer of hydroxyapatite on the surface of samples soaked in SBF using FTIR spectroscopy. Finally, also, the potential antibacterial properties of the different materials against two different bacteria, E. coli and P. aeruginosa, were investigated. PMID- 30441750 TI - Recent Developments in Compact Membrane Reactors with Hydrogen Separation. AB - Hydrogen production and storage in small and medium scale, and chemical heat storage from renewable energy, are of great interest nowadays. Micro-membrane reactors for reforming of methane, as well as for the dehydrogenation of liquid organic hydrogen carriers (LOHCs), have been developed. The systems consist of stacked plates with integrated palladium (Pd) membranes. As an alternative to rolled and electroless plated (Pd) membranes, the development of a cost-effective method for the fabrication of Pd membranes by suspension plasma spraying is presented. PMID- 30441751 TI - Monitoring Migraine Cycle Dynamics with an Easy-to-Use Electrophysiological Marker-A Pilot Study. AB - Migraine attacks can cause significant discomfort and reduced functioning for days at a time, including the pre-ictal and post-ictal periods. During the inter ictsal period, however, migraineurs seem to function normally. It is puzzling, therefore, that event-related potentials of migraine patients often differ in the asymptomatic and inter-ictal period. Part of the electrophysiological dynamics demonstrated in the migraine cycle are attention related. In this pilot study we evaluated an easy-to-use new marker, the Brain Engagement Index (BEI), for attention monitoring during the migraine cycle. We sampled 12 migraine patients for 20 days within one calendar month. Each session consisted of subjects' reports of stress level and migraine-related symptoms, and a 5 min EEG recording, with a 2-electrode EEG device, during an auditory oddball task. The first minute of the EEG sample was analyzed. Repetitive samples were also obtained from 10 healthy controls. The brain engagement index increased significantly during the pre-ictal (p ~ 0.001) and the ictal (p ~ 0.020) periods compared with the inter ictal period. No difference was observed between the pre-ictal and ictal periods. Control subjects demonstrated intermediate Brain Engagement Index values, that is, higher than inter-ictal, yet lower than pre-ictal. Our preliminary results demonstrate the potential advantage of the use of a simple EEG system for improved prediction of migraine attacks. Further study is required to evaluate the efficacy of the Brain Engagement Index in monitoring the migraine cycle and the possible effects of interventions. PMID- 30441753 TI - Comment on: The Vitamin D-Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554. AB - In response to a recent article by Jones et al. (Nutrients 10: 554-568, 2018) [1], we agree that three distinctive features evolved in Homo erectus prior to the emergence of modern humans.[...]. PMID- 30441752 TI - Ultrasonic Based Tissue Modelling and Engineering. AB - Systems and devices for in vitro tissue modelling and engineering are valuable tools, which combine the strength between the controlled laboratory environment and the complex tissue organization and environment in vivo. Device-based tissue engineering is also a possible avenue for future explant culture in regenerative medicine. The most fundamental requirements on platforms intended for tissue modelling and engineering are their ability to shape and maintain cell aggregates over long-term culture. An emerging technology for tissue shaping and culture is ultrasonic standing wave (USW) particle manipulation, which offers label-free and gentle positioning and aggregation of cells. The pressure nodes defined by the USW, where cells are trapped in most cases, are stable over time and can be both static and dynamic depending on actuation schemes. In this review article, we highlight the potential of USW cell manipulation as a tool for tissue modelling and engineering. PMID- 30441754 TI - Integrated Management of Skin NTDs-Lessons Learned from Existing Practice and Field Research. AB - Integration of neglected tropical diseases (NTDs) into the public health agenda has been a priority in global health for the last decade. Because a number of these diseases share not only the geographical distribution, but also a common feature which is skin involvement, bringing together a sub-group of 'skin NTDs' is one way forward to promote further integration among NTDs. With these diseases, which include leprosy, Buruli ulcer, yaws, mycetoma, lymphatic filariasis, and leishmaniasis, patients may be left with life-long deformities and disabilities when diagnosis and treatment are delayed. Stigma is another serious consequence of skin NTDs as it places a large barrier on the economic activities and social life of a patient. As a result, this creates a vicious cycle and obstructs a key goal of society, the elimination of poverty. Enhancement in surveillance systems as well as the further development of diagnostic methods, improvement in treatment and management, and identification of preventative measures for skin NTDs are therefore urgently needed. This article summarizes the existing practices and field research on skin NTDs and identifies potential synergies that could be achieved by adopting this integrated approach. PMID- 30441756 TI - Animal Welfare and Mountain Products from Traditional Dairy Farms: How Do Consumers Perceive Complexity? AB - This qualitative study aims to investigate consumers' perceptions toward dairy cow welfare in traditional mountain farms. While consumers' understanding of conventional dairy production and animal welfare has already been investigated, how consumers perceive animal welfare in traditional mountain dairy farming remains still unexplored. Focus group interviews were conducted with consumers having different degrees of geographical proximity to mountains and with an explicit interest in local dairy products. The results of this qualitative study show that participants expect mountain farming to be on a smaller scale when compared to non-mountain farming systems and expect mountain products to be healthier. Similarly, all participants consider origin, locality, and small-scale production as relevant quality attributes of mountain cheese. However, the appreciation of these abstract features did not necessarily result in their recognition when sample pictures of traditional husbandry systems were provided especially in the case of urban participants. This study contributes to reveal the gap between urban consumers' conception of mountain farming and the actual farming practices. It also indicates the need to promote an effective science based dialogue on animal welfare that goes beyond an anthropomorphic perspective and tackles the complexity of farming systems in relation to the context in which they are located. PMID- 30441755 TI - Protective Effects of Five Structurally Diverse Flavonoid Subgroups against Chronic Alcohol-Induced Hepatic Damage in a Mouse Model. AB - Alcoholic liver disease (ALD) has become one of the major global health problems, with augmented morbidity and mortality. Evidence indicates that flavonoids can reduce the risk of ALD owing to their biological properties. However, the effect of structurally different flavonoid subclasses on alleviating alcohol-induced liver damage in a same model has never been studied. In this study, mice were supplemented with five kinds of flavonoid subgroups, apigenin (flavone), quercetin (flavonol), naringenin (flavanone), (-)-epigallocatechin gallate (flavanol), and genistein (isoflavone), in the same dose (0.3 mmol kg-1 body weight) and then given 50% alcohol by gastric perfusion for five consecutive weeks. The results demonstrated that genistein and naringenin had greater benefits in terms of mitigating fibrosis and apoptosis, respectively, in the liver. Lipid deposition, partial inflammatory-related factors (nuclear factor kappa B p65, cyclooxygenase-2, and interleukin-6 levels), and hepatic histopathological alterations were similarly attenuated by five kinds of flavonoids. All the flavonoids also showed different degrees of influence on protecting against alcoholic liver injury on other aspects, such as serum biochemistry makers, hepatic lipid accumulation, lipid peroxidation, antioxidant capacities, and inflammation. PMID- 30441757 TI - Recent Advances in Zika Virus Vaccines. AB - The recent outbreaks of Zika virus (ZIKV) infections and associated microcephaly in newborns has resulted in an unprecedented effort by researchers to target this virus. Significant advances have been made in developing vaccine candidates, treatment strategies and diagnostic assays in a relatively short period of time. Being a preventable disease, the first line of defense against ZIKV would be to vaccinate the highly susceptible target population, especially pregnant women. Along those lines, several vaccine candidates including purified inactivated virus (PIV), live attenuated virus (LAV), virus like particles (VLP), DNA, modified RNA, viral vectors and subunit vaccines have been in the pipeline with several advancing to clinical trials. As the primary objective of Zika vaccination is the prevention of vertical transmission of the virus to the unborn fetus, the safety and efficacy requirements for this vaccine remain unique when compared to other diseases. This review will discuss these recent advances in the field of Zika vaccine development. PMID- 30441758 TI - Autographa Californica Multiple Nucleopolyhedrovirus Enters Host Cells via Clathrin-Mediated Endocytosis and Direct Fusion with the Plasma Membrane. AB - The cell entry mechanism of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is not fully understood. Previous studies showed that AcMNPV entered host cells primarily through clathrin-mediated endocytosis, and could efficiently infect cells via fusion with the plasma membrane after a low-pH trigger. However, whether AcMNPV enters cells via these two pathways simultaneously, and the exact manner in which AcMNPV particles are internalized into cells remains unclear. In this study, using single-virus tracking, we observed that AcMNPV particles were first captured by pre-existing clathrin-coated pits (CCP), and were then delivered to early endosomes. Population-based analysis of single-virus tracking and quantitative electron microscopy demonstrated that the majority of particles were captured by CCPs and internalized via invagination. In contrast, a minority of virus particles were not delivered to CCPs, and were internalized through direct fusion with the plasma membrane without invagination. Quantitative electron microscopy also showed that, while inhibition of CCP assembly significantly impaired viral internalization, inhibition of endosomal acidification blocked virus particles out of vesicles. Collectively, these findings demonstrated that approximately 90% of AcMNPV particles entered cells through clathrin-mediated endocytosis and 10% entered via direct fusion with the plasma membrane. This study will lead toward a better understanding of AcMNPV infection. PMID- 30441759 TI - TIM-1 Promotes Japanese Encephalitis Virus Entry and Infection. AB - Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus, the leading cause of viral-induced encephalitis. Several host molecules have been identified as the JEV attachment factor; however, the molecules involved in JEV entry remain poorly understood. In the present study, we demonstrate that TIM-1 is important for efficient infection by JEV. Firstly, three TIM-1 variants (V1, V2, and V3) were cloned from A549 cells, and we revealed that only ectopically TIM-1 V2 expression in 293T cells significantly promotes JEV attachment, entry and infection. Point mutation of phosphatidylserine (Ptdser) binding pocket in the TIM-1 IgV domain dampened JEV entry, indicating that TIM-1-mediated JEV infection is Ptdser-dependent. Furthermore, we found the cytoplasmic domain of TIM-1 is also required for enhancing JEV entry. Additionally, knock down of TIM-1 expression in A549 cells impaired JEV entry and infection, but not attachment, suggesting that additional factors exist in A549 cells that allow the virus to bind. In conclusion, our findings demonstrate that TIM-1 promotes JEV infection as an entry cofactor, and the polymorphism of TIM-1 is associated with JEV susceptibility to host cells. PMID- 30441760 TI - Mesenchymal Stem Cells and Transforming Growth Factor-beta3 (TGF-beta3) to Enhance the Regenerative Ability of an Albumin Scaffold in Full Thickness Wound Healing. AB - Pressure ulcers are one of the most common forms of skin injury, particularly in the spinal cord injured (SCI). Pressure ulcers are difficult to heal in this population requiring at least six months of bed rest. Surgical treatment (grafting) is the fastest recovery time, but it still requires six weeks of bed rest plus significant additional costs and a high recurrence rate. A significant clinical benefit would be obtained by speeding the healing rate of a non-surgical treatment to close to that of surgical treatment (approximately doubling of healing rate). Current non-surgical treatment is mostly inactive wound coverings. The goal of this project was to look at the feasibility of doubling the healing rate of a full-thickness defect using combinations of three treatments, for the first time, each shown to increase healing rate: application of transforming growth factor-beta3 (TGF-beta3), an albumin based scaffold, and mesenchymal stem cells (MSCs). At one week following surgery, the combined treatment showed the greatest increase in healing rate, particularly for the epithelialization rate. Although the target level of a 100% increase in healing rate over the control was not quite achieved, it is anticipated that the goal would be met with further optimization of the treatment. PMID- 30441763 TI - The Mediating Role of Family and Food-Related Life Satisfaction in the Relationships between Family Support, Parent Work-Life Balance and Adolescent Life Satisfaction in Dual-Earner Families. AB - This study explored the associations between family support and satisfaction with life, food-related life and family life. It also assessed the associations between both parents' work-life balance and satisfaction with life, food-related life and family life among adolescent children from dual-earner families. Questionnaires were administered to 303 dual-earner families with one child between 10 and 17 years in Temuco, Chile. Adolescents answered the Satisfaction with Life Scale (SWLS), Satisfaction with Food-related Life scale (SWFoL), Satisfaction with Family Life scale (SWFaL) and the Family subscale of the Multidimensional Scale of Perceived Social Support. Both parents answered the Work-life Balance (WLB) scale. Using structural equation modelling and having controlled for adolescents' gender, age and socioeconomic status, we confirmed that adolescent life satisfaction is associated with satisfaction with family life and food-related life. Food-related life satisfaction and family life satisfaction had complete mediating roles between perceived family support and adolescents' life satisfaction. Satisfaction with food-related life also had a complete mediating role between both parents' WLB and adolescents' life satisfaction. Satisfaction with family life had a complete mediating role between mothers' WLB and adolescents' life satisfaction. In addition, mothers' WLB was positively associated with perceived family support among adolescents. These findings suggest the need to improve family support and work-life balance among mothers in order to enhance adolescents' satisfaction with different domains of life in dual-earner families. PMID- 30441762 TI - Metabolomic Signature in Sera of Multiple Sclerosis Patients during Pregnancy. AB - Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, neurodegeneration, and degradation of the myelin sheath. Epidemiological studies have shown that the female gender is more susceptible than the male gender to MuS development, with a female-to-male ratio of 2:1. Despite this high onset, women have a better prognosis than men, and the frequency of the relapsing phase decreases during pregnancy, while it increases soon after birth. Therefore, it is interesting to investigate hormonal fluctuations during pregnancy and whether they correlate with metabolic signatures. To gain a deeper inside into the biochemical mechanism of such a multifactorial disease, we adopted targeted metabolomics approaches for the determination of many serum metabolites in 12 pregnant women affected by MuS by mass spectrometry analysis. Our data show a characteristic hormonal fluctuation for estrogens and progesterone, as expected. They also highlight other interesting hormonal alterations for cortisol, corticosterone, 11-deoxycortisol, 4-androstene-3,17-dione, testosterone, and 17alpha-hydroxyprogesterone. Furthermore, a negative correlation with progesterone levels was observed for amino acids and for acylcarnitines, while an imbalance of different sphingolipids pathways was found during pregnancy. In conclusion, these data are in agreement with the characteristic clinical signs of MuS patients during pregnancy and, if confirmed, they may add an important tessera in the complex mosaic of maternal neuroprotection. PMID- 30441764 TI - Hyperspectral Imaging for Evaluating Impact Damage to Mango According to Changes in Quality Attributes. AB - Evaluation of impact damage to mango (Mangifera indica Linn) as a result of dropping from three different heights, namely, 0.5, 1.0 and 1.5 m, was conducted by hyperspectral imaging (HSI). Reflectance spectra in the 900-1700 nm region were used to develop prediction models for pulp firmness (PF), total soluble solids (TSS), titratable acidity (TA) and chroma (?b*) by a partial least squares (PLS) regression algorithm. The results showed that the changes in the mangoes' quality attributes, which were also reflected in the spectra, had a strong relationship with dropping height. The best predictive performance measured by coefficient of determination (R2) and root mean square errors of prediction (RMSEP) values were: 0.84 and 31.6 g for PF, 0.9 and 0.49 oBrix for TSS, 0.65 and 0.1% for TA, 0.94 and 0.96 for chroma, respectively. Classification of the degree of impact damage to mango achieved an accuracy of more than 77.8% according to ripening index (RPI). The results show the potential of HSI to evaluate impact damage to mango by combining with changes in quality attributes. PMID- 30441765 TI - Breast Cancer: An Examination of the Potential of ACKR3 to Modify the Response of CXCR4 to CXCL12. AB - Upon binding with the chemokine CXCL12, the chemokine receptor CXCR4 has been shown to promote breast cancer progression. This process, however, can be affected by the expression of the atypical chemokine receptor ACKR3. Given ACKR3's ability to form heterodimers with CXCR4, we investigated how dual expression of both receptors differed from their lone expression in terms of their signalling pathways. We created single and double CXCR4 and/or ACKR3 Chinese hamster ovary (CHO) cell transfectants. ERK and Akt phosphorylation after CXCL12 stimulation was assessed and correlated with receptor internalization. Functional consequences in cell migration and proliferation were determined through wound healing assays and calcium flux. Initial experiments showed that CXCR4 and ACKR3 were upregulated in primary breast cancer and that CXCR4 and ACKR3 could form heterodimers in transfected CHO cells. This co-expression modified CXCR4's Akt activation after CXCL12's stimulation but not ERK phosphorylation (p < 0.05). To assess this signalling disparity, receptor internalization was assessed and it was observed that ACKR3 was recycled to the surface whilst CXCR4 was degraded (p < 0.01), a process that could be partially inhibited with a proteasome inhibitor (p < 0.01). Internalization was also assessed with the ACKR3 agonist VUF11207, which caused both CXCR4 and ACKR3 to be degraded after internalization (p < 0.05 and p < 0.001), highlighting its potential as a dual targeting drug. Interestingly, we observed that CXCR4 but not ACKR3, activated calcium flux after CXCL12 stimulation (p < 0.05) and its co expression could increase cellular migration (p < 0.01). These findings suggest that both receptors can signal through ERK and Akt pathways but co-expression can alter their kinetics and internalization pathways. PMID- 30441767 TI - Identification of Heterotrimeric G Protein gamma3 Subunit in Rice Plasma Membrane. AB - Heterotrimeric G proteins are important molecules for regulating plant architecture and transmitting external signals to intracellular target proteins in higher plants and mammals. The rice genome contains one canonical alpha subunit gene (RGA1), four extra-large GTP-binding protein genes (XLGs), one canonical beta subunit gene (RGB1), and five gamma subunit genes (tentatively named RGG1, RGG2, RGG3/GS3/Mi/OsGGC1, RGG4/DEP1/DN1/OsGGC3, and RGG5/OsGGC2). RGG1 encodes the canonical gamma subunit; RGG2 encodes the plant-specific type of gamma subunit with additional amino acid residues at the N-terminus; and the remaining three gamma subunit genes encode the atypical gamma subunits with cysteine abundance at the C-terminus. We aimed to identify the RGG3/GS3/Mi/OsGGC1 gene product, Ggamma3, in rice tissues using the anti-Ggamma3 domain antibody. We also analyzed the truncated protein, Ggamma3?Cys, in the RGG3/GS3/Mi/OsGGC1 mutant, Mi, using the anti-Ggamma3 domain antibody. Based on nano-liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, the immunoprecipitated Ggamma3 candidates were confirmed to be Ggamma3. Similar to alpha (Galpha) and beta subunits (Gbeta), Ggamma3 was enriched in the plasma membrane fraction, and accumulated in the flower tissues. As RGG3/GS3/Mi/OsGGC1 mutants show the characteristic phenotype in flowers and consequently in seeds, the tissues that accumulated Ggamma3 corresponded to the abnormal tissues observed in RGG3/GS3/Mi/OsGGC1 mutants. PMID- 30441761 TI - Sulforaphane from Cruciferous Vegetables: Recent Advances to Improve Glioblastoma Treatment. AB - Sulforaphane (SFN), an isothiocyanate (ITC) derived from cruciferous vegetables, particularly broccoli and broccoli sprouts, has been widely investigated due to its promising health-promoting properties in disease, and low toxicity in normal tissue. Although not yet fully understood, many mechanisms of anticancer activity at each step of cancer development have been attributed to this ITC. Given the promising data available regarding SFN, this review aimed to provide an overview on the potential activities of SFN related to the cellular mechanisms involved in glioblastoma (GBM) progression. GBM is the most frequent malignant brain tumor among adults and is currently an incurable disease due mostly to its highly invasive phenotype, and the poor efficacy of the available therapies. Despite all efforts, the median overall survival of GBM patients remains approximately 1.5 years under therapy. Therefore, there is an urgent need to provide support for translating the progress in understanding the molecular background of GBM into more complex, but promising therapeutic strategies, in which SFN may find a leading role. PMID- 30441766 TI - Role of Ca2+ in Mediating Plant Responses to Extracellular ATP and ADP. AB - Among the most recently discovered chemical regulators of plant growth and development are extracellular nucleotides, especially extracellular ATP (eATP) and extracellular ADP (eADP). Plant cells release ATP into their extracellular matrix under a variety of different circumstances, and this eATP can then function as an agonist that binds to a specific receptor and induces signaling changes, the earliest of which is an increase in the concentration of cytosolic calcium ([Ca2+]cyt). This initial change is then amplified into downstream signaling changes that include increased levels of reactive oxygen species and nitric oxide, which ultimately lead to major changes in the growth rate, defense responses, and leaf stomatal apertures of plants. This review presents and discusses the evidence that links receptor activation to increased [Ca2+]cyt and, ultimately, to growth and diverse adaptive changes in plant development. It also discusses the evidence that increased [Ca2+]cyt also enhances the activity of apyrase (nucleoside triphosphate diphosphohydrolase) enzymes that function in multiple subcellular locales to hydrolyze ATP and ADP, and thus limit or terminate the effects of these potent regulators. PMID- 30441768 TI - Fast Phase-Only Positioning with Triple-Frequency GPS. AB - In this contribution, we study the phase-only ambiguity resolution and positioning performance of GPS for short baselines. It is well known that instantaneous (single-epoch) ambiguity resolution is possible when both phase and code (pseudorange) data are used. This requires, however, a benign multipath environment due to the severe effects multipath has on the code measurements. With phase-only processing, one would be free from such severe effects, be it that phase-only processing requires a change in receiver-satellite geometry, as a consequence of which it cannot be done instantaneously. It is thus of interest to know how much change in the relative receiver-satellite geometry is needed to achieve successful phase-only ambiguity resolution with correspondingly high precision baseline solutions. In this contribution, we study the two-epoch phase only performance of single-, dual-, and triple-frequency GPS for varying time spans from 60 s down to 1 s. We demonstrate, empirically as well as formally, that fast phase-only very-precise positioning is indeed possible, and we explain the circumstances that make this possible. The formal analyses are also performed for a large area including Australia, a part of Asia, the Indian Ocean, and the Pacific Ocean. We remark that in this contribution "phase-only" refers to phase only measurements in the observation model, while the code data are thus only used to compute the approximate values needed for linearizing the observation equations. PMID- 30441770 TI - Transport of Apolipoprotein B-Containing Lipoproteins through Endothelial Cells Is Associated with Apolipoprotein E-Carrying HDL-Like Particle Formation. AB - Passage of apolipoprotein B-containing lipoproteins (apoB-LPs), i.e., triglyceride-rich lipoproteins (TRLs), intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs), through the endothelial monolayer occurs in normal and atherosclerotic arteries. Among these lipoproteins, TRLs and IDLs are apoE-rich apoB-LPs (E/B-LPs). Recycling of TRL-associated apoE has been shown to form apoE-carrying high-density lipoprotein (HDL)-like (HDLE) particles in many types of cells. The current report studied the formation of HDLE particles by transcytosis of apoB-LPs through mouse aortic endothelial cells (MAECs). Our data indicated that passage of radiolabeled apoB-LPs, rich or poor in apoE, through the MAEC monolayer is inhibited by filipin and unlabeled competitor lipoproteins, suggesting that MAECs transport apoB-LPs via a caveolae-mediated pathway. The cholesterol and apoE in the cell-untreated E/B-LPs, TRLs, IDLs, and LDLs distributed primarily in the low-density (LD) fractions (d <= 1.063). A substantial portion of the cholesterol and apoE that passed through the MAEC monolayer was allotted into the high-density (HD) (d > 1.063) fractions. In contrast, apoB was detectable only in the LD fractions before or after apoB-LPs were incubated with the MAEC monolayer, suggesting that apoB-LPs pass through the MAEC monolayer in the forms of apoB-containing LD particles and apoE-containing HD particles. PMID- 30441771 TI - A Deep Learning Approach on Building Detection from Unmanned Aerial Vehicle-Based Images in Riverbank Monitoring. AB - Buildings along riverbanks are likely to be affected by rising water levels, therefore the acquisition of accurate building information has great importance not only for riverbank environmental protection but also for dealing with emergency cases like flooding. UAV-based photographs are flexible and cloud-free compared to satellite images and can provide very high-resolution images up to centimeter level, while there exist great challenges in quickly and accurately detecting and extracting building from UAV images because there are usually too many details and distortions on UAV images. In this paper, a deep learning (DL) based approach is proposed for more accurately extracting building information, in which the network architecture, SegNet, is used in the semantic segmentation after the network training on a completely labeled UAV image dataset covering multi-dimension urban settlement appearances along a riverbank area in Chongqing. The experiment results show that an excellent performance has been obtained in the detection of buildings from untrained locations with an average overall accuracy more than 90%. To verify the generality and advantage of the proposed method, the procedure is further evaluated by training and testing with another two open standard datasets which have a variety of building patterns and styles, and the final overall accuracies of building extraction are more than 93% and 95%, respectively. PMID- 30441769 TI - Experimental Evidence of the Antitumor, Antimetastatic and Antiangiogenic Activity of Ellagic Acid. AB - Ellagic acid (EA) is a naturally occurring polyphenolic compound endowed with strong antioxidant and anticancer properties that is present in high quantity in a variety of berries, pomegranates, and dried fruits. The antitumor activity of EA has been mostly attributed to direct antiproliferative and apoptotic effects. Moreover, EA can inhibit tumour cell migration, extra-cellular matrix invasion and angiogenesis, all processes that are crucial for tumour infiltrative behaviour and the metastatic process. In addition, EA may increase tumour sensitivity to chemotherapy and radiotherapy. The aim of this review is to summarize the in vitro and in vivo experimental evidence supporting the anticancer activity of pure EA, its metabolites, and EA-containing fruit juice or extracts in a variety of solid tumour models. The EA oral administration as supportive therapy to standard chemotherapy has been recently evaluated in small clinical studies with colorectal or prostate cancer patients. Novel formulations with improved solubility and bioavailability are expected to fully develop the therapeutic potential of EA derivatives in the near future. PMID- 30441772 TI - Evaluating the Performance of Functionalized Carbon Structures with Integrated Optical Fiber Sensors under Practical Conditions. AB - An Optical Frequency Domain Reflectometry (OFDR) based fiber optic sensor scheme "embedded" in concrete for the purpose of structural health monitoring (SHM) of carbon concrete composites (C3) is presented. The design, while strengthening the concrete structure, also aims to monitor common SHM parameters such as strain and cracks. This was achieved by weaving the carbon fiber together with optical fiber, based on a specialized technique that uses an embroidery setup where both the carbon and optical fiber are woven on a water dissolvable polymer substrate. The performance of the sensing scheme was characterized in-situ utilizing the OFDR based technique and the results presented. The sensors embedded on a custom made concrete block were subjected to varying strain via a three point bending test to destruction and the results discussed. The intended dual-achievement of the scheme thus proposed in SHM and strengthening the C3 is demonstrated. The suitability of the OFDR scheme for C3 is combined with a fibre Bragg grating (FBG)-based approach, and discussed in detail. PMID- 30441773 TI - Sensor-Based Detection of the Severity of Hyperkeratosis in the Teats of Dairy Cows. AB - The aim of this study was to evaluate whether the severity of hyperkeratosis (HK) in the teats of dairy cows can be assessed by a dielectric measurement. The study focused on surveying the occurrence of hyperkeratosis in a total of 241 teats of lactating dairy cows. A scoring system consisting of four categories was used to macroscopically assess the severity of HK. Additionally, the dielectric constant (DC) of all teats with milkability was measured in a double iteration with the MoistureMeterD (Delfin Technologies, Kuopio, Finland) on four different days. The Spearman rank correlation coefficient revealed a negative correlation between the DC and HK score (rs = -0.55 to -0.36). The results of the regression analysis showed that the DC values differed significantly between healthy teat ends (<=2) and teat ends with HK (>=3). Thus, the non-invasive measurement of DC provides a promising method of objectively assessing the occurrence and severity of HK. PMID- 30441774 TI - Automatic Extraction and Detection of Characteristic Movement Patterns in Children with ADHD Based on a Convolutional Neural Network (CNN) and Acceleration Images. AB - Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder, which is characterized by inattention, hyperactivity and impulsive behaviors. In particular, children have difficulty keeping still exhibiting increased fine and gross motor activity. This paper focuses on analyzing the data obtained from two tri-axial accelerometers (one on the wrist of the dominant arm and the other on the ankle of the dominant leg) worn during school hours by a group of 22 children (11 children with ADHD and 11 paired controls). Five of the 11 ADHD diagnosed children were not on medication during the study. The children were not explicitly instructed to perform any particular activity but followed a normal session at school alternating classes of little or moderate physical activity with intermediate breaks of more prominent physical activity. The tri axial acceleration signals were converted into 2D acceleration images and a Convolutional Neural Network (CNN) was trained to recognize the differences between non-medicated ADHD children and their paired controls. The results show that there were statistically significant differences in the way the two groups moved for the wrist accelerometer (t-test p-value <0.05). For the ankle accelerometer statistical significance was only achieved between data from the non-medicated children in the experimental group and the control group. Using a Convolutional Neural Network (CNN) to automatically extract embedded acceleration patterns and provide an objective measure to help in the diagnosis of ADHD, an accuracy of 0.875 for the wrist sensor and an accuracy of 0.9375 for the ankle sensor was achieved. PMID- 30441775 TI - The H2S Donor GYY4137 Stimulates Reactive Oxygen Species Generation in BV2 Cells While Suppressing the Secretion of TNF and Nitric Oxide. AB - GYY4137 is a hydrogen sulfide (H2S) donor that has been shown to act in an anti inflammatory manner in vitro and in vivo. Microglial cells are among the major players in immunoinflammatory, degenerative, and neoplastic disorders of the central nervous system, including multiple sclerosis, Parkinson's disease, Alzheimer's disease, and glioblastoma multiforme. So far, the effects of GYY4137 on microglial cells have not been thoroughly investigated. In this study, BV2 microglial cells were stimulated with interferon-gamma and lipopolysaccharide and treated with GYY4137. The agent did not influence the viability of BV2 cells in concentrations up to 200 MUM. It inhibited tumor necrosis factor but not interleukin-6 production. Expression of CD40 and CD86 were reduced under the influence of the donor. The phagocytic ability of BV2 cells and nitric oxide production were also affected by the agent. Surprisingly, GYY4137 upregulated generation of reactive oxygen species (ROS) by BV2 cells. The effect was mimicked by another H2S donor, Na2S, and it was not reproduced in macrophages. Our results demonstrate that GYY4137 downregulates inflammatory properties of BV2 cells but increases their ability to generate ROS. Further investigation of this unexpected phenomenon is warranted. PMID- 30441776 TI - Sandwich Electrochemical Immunosensor for Early Detection of Tuberculosis Based on Graphene/Polyaniline-Modified Screen-Printed Gold Electrode. AB - A rapid and sensitive sandwich electrochemical immunosensor was developed based on the fabrication of the graphene/polyaniline (GP/PANI) nanocomposite onto screen-printed gold electrode (SPGE) for detection of tuberculosis biomarker 10 kDa culture filtrate protein (CFP10). The prepared GP/PANI nanocomposite was characterized using Fourier transform infrared spectroscopy (FTIR) and field emission scanning electron microscopy (FESEM). The chemical bonding and morphology of GP/PANI-modified SPGE were studied by Raman spectroscopy and FESEM coupled with energy dispersive X-ray spectroscopy, respectively. From both studies, it clearly showed that GP/PANI was successfully coated onto SPGE through drop cast technique. Cyclic voltammetry was used to study the electrochemical properties of the modified electrode. The effective surface area for GP/PANI modified SPGE was enhanced about five times compared with bare SPGE. Differential pulse voltammetry was used to detect the CFP10 antigen. The GP/PANI-modified SPGE that was fortified with sandwich type immunosensor exhibited a wide linear range (20-100 ng/mL) with a low detection limit of 15 ng/mL. This proposed electrochemical immunosensor is sensitive, low sample volume, rapid and disposable, which is suitable for tuberculosis detection in real samples. PMID- 30441777 TI - Novel Competitive Fluorescence Sensing Platform for L-carnitine Based on Cationic Pillar[5]Arene Modified Gold Nanoparticles. AB - Supramolecular host-guest interaction and sensing between cationic pillar[5]arenes (CP5) and L-carnitine were developed by the competitive host guest recognition for the first time. The fluorescence sensing platform was constructed by CP5 functionalized Au nanoparticles (CP5@Au-NPs) as receptor and probe (rhodamine 123, R123), which shown high sensitivity and selectivity for L carnitine detection. Due to the negative charge and molecular size properties of L-carnitine, it can be highly captured by the CP5 via electrostatic interactions and hydrophobic interactions. The host-guest mechanism between PP5 and L carnitine was studied by 1H NMR and molecular docking, indicating that more affinity binding force of CP5 with L-carnitine. Therefore, a selective and sensitive fluorescent method was developed. It has a linear response of 0.1-2.0 and 2.0-25.0 MUM and a detection limit of 0.067 MUM (S/N = 3). The fluorescent sensing platform was also used to detect L-carnitine in human serum and milk samples, which provided potential applications for the detection of drugs abuse and had path for guarding a serious food safety issues. PMID- 30441778 TI - Natural Products to Fight Cancer: A Focus on Juglans regia. AB - Even if cancer represents a burden for human society, an exhaustive cure has not been discovered yet. Low therapeutic index and resistance to pharmacotherapy are two of the major limits of antitumour treatments. Natural products represent an excellent library of bioactive molecules. Thus, tapping into the natural world may prove useful in identifying new therapeutic options with favourable pharmaco toxicological profiles. Juglans regia, or common walnut, is a very resilient tree that has inhabited our planet for thousands of years. Many studies correlate walnut consumption to beneficial effects towards several chronic diseases, such as cancer, mainly due to the bioactive molecules stored in different parts of the plant. Among others, polyphenols, quinones, proteins, and essential fatty acids contribute to its pharmacologic activity. The present review aims to offer a comprehensive perspective about the antitumour potential of the most promising compounds stored in this plant, such as juglanin, juglone, and the ellagitannin metabolites urolithins or deriving from walnut dietary intake. All molecules and a chronic intake of the fruit provide tangible anticancer effects. However, the scarcity of studies on humans does not allow results to be conclusive. PMID- 30441780 TI - Photosystem II Extrinsic Proteins and Their Putative Role in Abiotic Stress Tolerance in Higher Plants. AB - Abiotic stress remains one of the major challenges in managing and preventing crop loss. Photosystem II (PSII), being the most susceptible component of the photosynthetic machinery, has been studied in great detail over many years. However, much of the emphasis has been placed on intrinsic proteins, particularly with respect to their involvement in the repair of PSII-associated damage. PSII extrinsic proteins include PsbO, PsbP, PsbQ, and PsbR in higher plants, and these are required for oxygen evolution under physiological conditions. Changes in extrinsic protein expression have been reported to either drastically change PSII efficiency or change the PSII repair system. This review discusses the functional role of these proteins in plants and indicates potential areas of further study concerning these proteins. PMID- 30441779 TI - Potential Involvement of Peripheral Leptin/STAT3 Signaling in the Effects of Resveratrol and Its Metabolites on Reducing Body Fat Accumulation. AB - Bioactive compounds such as polyphenols have increased in importance in recent years, and among them, resveratrol (3,5,4'-trihydroxy-trans-stilbene) has generated great interest as an anti-obesity agent. Recent investigations have highlighted the importance of leptin signaling in lipid metabolism in peripheral organs. The aims of this study were (1) to investigate whether resveratrol can reduce fat accumulation in peripheral tissues by increasing their leptin sensitivity and (2) to identify which resveratrol-derived circulating metabolites are potentially involved in these metabolic effects. Serum leptin levels and the leptin signaling pathway were assessed in diet-induced obese rats. Moreover, serum metabolites of resveratrol were studied by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MSn). The daily consumption of 200 mg/kg of resveratrol, but not doses of 50 and 100 mg/kg, reduced body weight and fat accumulation in obese rats and restored leptin sensitivity in the periphery. These effects were due to increases in sirtuin 1 activity in the liver, leptin receptors in muscle and protection against endoplasmic reticulum (ER)-stress in adipose tissue. In general, the resveratrol metabolites associated with these beneficial effects were derived from both phase II and microbiota metabolism, although only those derived from microbiota increased proportionally with the administered dose of resveratrol. In conclusion, resveratrol reversed leptin resistance caused by diet-induced obesity in peripheral organs using tissue specific mechanisms. PMID- 30441782 TI - Norovirus Outbreak Associated with Swimming in a Recreational Lake Not Influenced by External Human Fecal Sources in The Netherlands, August 2012. AB - Swimming in fecally contaminated recreational water may lead to gastrointestinal illness. A recreational water-associated outbreak of norovirus (NoV) infections affecting at least 100 people in The Netherlands occurred in August 2012. Questionnaire responses from patients indicated swimming in recreational lake Zeumeren as the most likely cause of illness. Most patients visited the lake during the weekend of 18-19 August, during which the weather was exceptionally warm (maximum temperatures 32-33 degrees C), and visitor numbers elevated. Patients, mostly children, became ill with gastroenteritis 1-6 days (median 2 days) after exposure. Four stool samples from patients were NoV GI positive. Subsurface sandy soil from one of the beaches where most patients swam was NoV GI positive; the water sample was negative. The epidemiological curve and the timeline of investigation based on reported symptoms demonstrate the difficulty in discovering the source in recreational water outbreaks. A NoV outbreak in a recreational lake that is not subjected to external fecal contamination sources shows the need for active communication about human shedding of viruses during and after diarrheal episodes and the advice to refrain from swimming, even a few weeks after the symptoms have resolved. PMID- 30441781 TI - Initial Assessment of the LEO Based Navigation Signal Augmentation System from Luojia-1A Satellite. AB - A low Earth orbiter (LEO)-based navigation signal augmentation system is considered as a complementary of current global navigation satellite systems (GNSS), which can accelerate precise positioning convergence, strengthen the signal power, and improve signal quality. Wuhan University is dedicated to LEO based navigation signal augmentation research and launched one scientific experimental satellite named Luojia-1A. The satellite is capable of broadcasting dual-frequency band ranging signals over China. The initial performance of the Luojia-1A satellite navigation augmentation system is assessed in this study. The ground tests indicate that the phase noise of the oscillator is sufficiently low to support the intended applications. The field ranging tests achieve 2.6 m and 0.013 m ranging precision for the pseudorange and carrier phase measurements, respectively. The in-orbit test shows that the internal precision of the ephemeris is approximate 0.1 m and the clock stability is 3 * 10-10. The pseudorange and carrier phase measurement noise evaluated from the geometry-free combination is about 3.3 m and 1.8 cm. Overall, the Luojia-1A navigation augmentation system is capable of providing useable LEO navigation augmentation signals with the empirical user equivalent ranging error (UERE) no worse than 3.6 m, which can be integrated with existing GNSS to improve the real-time navigation performance. PMID- 30441783 TI - Metal Oxide Nanoparticle Based Electrochemical Sensor for Total Antioxidant Capacity (TAC) Detection in Wine Samples. AB - A single-use electrochemical screen-printed electrode is reported based on biomimetic properties of nanoceria particles (CeNPs). The developed tool showed an easy approach compared to the classical spectrophotometric methods reported in literature in terms of ease of use, cost, portability, and unnecessary secondary reagents. The sensor allowed the detection of the total antioxidant capacity (TAC) in wine samples. The sensor has been optimized and characterized electrochemically and then tested with antioxidant compounds occurred in wine samples. The electrochemical CeNPs modified sensor has been used for detection of TAC in white and red commercial wines and the data compared to the 2,2'-azino bis(3-ethylbenzthiazoline-6-sulphonic acid (ABTS)-based spectrophotometric method. Finally, the obtained results have demonstrated that the proposed sensor was suitable for the simple and quick evaluation of TAC in beverage samples. PMID- 30441784 TI - Performance Analysis of NDT-based Graph SLAM for Autonomous Vehicle in Diverse Typical Driving Scenarios of Hong Kong. AB - Robust and lane-level positioning is essential for autonomous vehicles. As an irreplaceable sensor, Light detection and ranging (LiDAR) can provide continuous and high-frequency pose estimation by means of mapping, on condition that enough environment features are available. The error of mapping can accumulate over time. Therefore, LiDAR is usually integrated with other sensors. In diverse urban scenarios, the environment feature availability relies heavily on the traffic (moving and static objects) and the degree of urbanization. Common LiDAR-based simultaneous localization and mapping (SLAM) demonstrations tend to be studied in light traffic and less urbanized area. However, its performance can be severely challenged in deep urbanized cities, such as Hong Kong, Tokyo, and New York with dense traffic and tall buildings. This paper proposes to analyze the performance of standalone NDT-based graph SLAM and its reliability estimation in diverse urban scenarios to further evaluate the relationship between the performance of LiDAR-based SLAM and scenario conditions. The normal distribution transform (NDT) is employed to calculate the transformation between frames of point clouds. Then, the LiDAR odometry is performed based on the calculated continuous transformation. The state-of-the-art graph-based optimization is used to integrate the LiDAR odometry measurements to implement optimization. The 3D building models are generated and the definition of the degree of urbanization based on Skyplot is proposed. Experiments are implemented in different scenarios with different degrees of urbanization and traffic conditions. The results show that the performance of the LiDAR-based SLAM using NDT is strongly related to the traffic condition and degree of urbanization. The best performance is achieved in the sparse area with normal traffic and the worse performance is obtained in dense urban area with 3D positioning error (summation of horizontal and vertical) gradients of 0.024 m/s and 0.189 m/s, respectively. The analyzed results can be a comprehensive benchmark for evaluating the performance of standalone NDT-based graph SLAM in diverse scenarios which is significant for multi-sensor fusion of autonomous vehicle. PMID- 30441785 TI - The Impact of Potassium Channel Gene Polymorphisms on Antiepileptic Drug Responsiveness in Arab Patients with Epilepsy. AB - This study aims to investigate the effects of the three potassium channel genes KCNA1, KCNA2, and KCNV2 on increased susceptibility to epilepsy as well as on responsiveness to antiepileptic drugs (AEDs). The pharmacogenetic and case control cohort (n = 595) consisted of 296 epileptic patients and 299 healthy individuals. Epileptic patients were recruited from the Pediatric Neurology clinic at the Queen Rania Al Abdullah Hospital (QRAH) in Amman, Jordan. A custom platform array search for genetic association in Jordanian-Arab epileptic patients was undertaken. The MassARRAY system (iPLEX GOLD) was used to genotype seven single nucleotide polymorphisms (SNPs) within three candidate genes (KCNA1, KCNA2, and KCNV2). Only one SNP in KCNA2, rs3887820, showed significant association with increased risk of susceptibility to generalized myoclonic seizure (p-value < 0.001). Notably, the rs112561866 polymorphism of the KCNA1 gene was non-polymorphic, but no significant association was found between the KCNA1 (rs2227910, rs112561866, and rs7974459) and KCNV2 (rs7029012, rs10967705, and rs10967728) polymorphisms and disease susceptibility or drug responsiveness among Jordanian patients. This study suggests that a significant association exists between the KCNA2 SNP rs3887820 and increased susceptibility to generalized myoclonic seizure. However, the present findings indicate that the KCNA1 and KCNV2 SNPs do not influence disease susceptibility and drug responsiveness in epileptic patients. Pharmacogenetic and case-control studies involving a multicenter and multiethnic approach are needed to confirm our results. To improve the efficacy and safety of epilepsy treatment, further studies are required to identify other genetic factors that contribute to susceptibility and treatment outcome. PMID- 30441786 TI - Metagenomic Next-Generation Sequencing Reveals Individual Composition and Dynamics of Anelloviruses during Autologous Stem Cell Transplant Recipient Management. AB - Over recent years, there has been increasing interest in the use of the anelloviruses, the major component of the human virome, for the prediction of post-transplant complications such as severe infections. Due to an important diversity, the comprehensive characterization of this viral family over time has been poorly studied. To overcome this challenge, we used a metagenomic next generation sequencing (mNGS) approach with the aim of determining the individual anellovirus profile of autologous stem cell transplant (ASCT) patients. We conducted a prospective pilot study on a homogeneous patient cohort regarding the chemotherapy regimens that included 10 ASCT recipients. A validated viral mNGS workflow was used on 108 plasma samples collected at 11 time points from diagnosis to 90 days post-transplantation. A complex interindividual variability in terms of abundance and composition was noticed. In particular, a strong sex effect was found and confirmed using quantitative PCR targeting torque teno virus, the most abundant anellovirus. Interestingly, an important turnover in the anellovirus composition was observed during the course of the disease revealing a strong intra-individual variability. Although more studies are needed to better understand anellovirus dynamics, these findings are of prime importance for their future use as biomarkers of immune competence. PMID- 30441787 TI - Structural and Fluorine Plasma Etching Behavior of Sputter-Deposition Yttrium Fluoride Film. AB - Yttrium fluoride (YF3) films were grown on sapphire substrate by a radio frequency magnetron using a commercial ceramic target in a vacuum chamber. The structure, composition, and plasma etching behavior of the films were systematically investigated. The YF3 film was deposited at a working pressure of 5 mTorr and an RF power of 150 W. The substrate-heating temperature was increased from 400 to 700 degrees C in increments of 100 degrees C. High-resolution transmission electron microscopy (HRTEM) and X-ray diffraction results confirmed an orthorhombic YF3 structure was obtained at a substrate temperature of 700 degrees C for 2 h. X-ray photoelectron spectroscopy revealed a strongly fluorinated bond (Y-F bond) on the etched surface of the YF3 films. HRTEM analysis also revealed that the YF3 films became yttrium-oxyfluorinated after exposure to fluorocarbon plasma. The etching depth was three times lower on YF3 film than on Al2O3 plate. These results showed that the YF3 films have excellent erosion resistance properties compared to Al2O3 plates. PMID- 30441788 TI - Influence of Oxygen Vacancy Behaviors in Cooling Process on Semiconductor Gas Sensors: A Numerical Analysis. AB - The influence of oxygen vacancy behaviors during a cooling process in semiconductor gas sensors is discussed by the numerical analysis method based on the gradient-distributed oxygen vacancy model. A diffusion equation is established to describe the behaviors of oxygen vacancies, which follows the effects of diffusion and exclusion in the cooling process. Numerical analysis is introduced to find the accurate solutions of the diffusion equation. The solutions illustrate the oxygen vacancy distribution profiles, which are dependent on the cooling rate as well as the temperature interval of the cooling process. The gas-sensing characteristics of reduced resistance and response are calculated. Both of them, together with oxygen vacancy distribution, show the grain size effects and the re-annealing effect. It is found that the properties of gas sensors can be controlled or adjusted by the designed cooling process. The proposed model provides a possibility for sensor characteristics simulations, which may be beneficial for the design of gas sensors. A quantitative interpretation on the gas-sensing mechanism of semiconductors has been contributed. PMID- 30441790 TI - A Secure and Efficient Group Key Management Protocol with Cooperative Sensor Association in WBANs. AB - The wireless body area network (WBAN) is considered as one of the emerging wireless techniques in the healthcare system. Typical WBAN sensors, especially implantable sensors, have limited power capability, which restricts their wide applications in the medical environment. In addition, it is necessary for the healthcare center (HC) to broadcast significant notifications to different patient groups. Considering the above issues, in this paper, the novel practical WBAN system model with group message broadcasting is built. Subsequently, a secure and efficient group key management protocol with cooperative sensor association is proposed. In the proposed protocol, the Chinese remainder theorem (CRT) is employed for group key management between HC and the personal controller (PC), which also supports batch key updating. The proposed sensor association scheme is motivated by coded cooperative data exchange (CCDE). The formal security proofs are presented, indicating that the proposed protocol can achieve the desired security properties. Moreover, performance analysis demonstrates that the proposed protocol is efficient compared with state-of-the-art group key management protocols. PMID- 30441789 TI - A Comparison of Electrochemical Performance of Carbon Aerogels with Adsorption Metal Ions for Super Capacitors. AB - Environmental problems caused by metal ions have caused widespread concern in recent years. In this work, carbon aerogels (CAs) adsorbing different metal ions were prepared. The adsorption performance and kinetics of metal ions (Cu(II), Cr(VI), and Fe(III)) on carbon aerogels were systematically investigated. The results indicated that the maximum adsorption capacity of Cu(II) was 424 mg.g-1 in 600 mg.L-1 copper solution. Adsorption performances of Cu(II), Cr(VI), and Fe(III) on CAs well fitted with a pseudo-second-order kinetic model. The structures and morphologies of metal-containing samples were characterized by scanning electron micrographs (SEM), Energy Dispersive Spectrometer (EDS), transmission electron microscope (TEM), and X-ray diffraction (XRD). The results demonstrated that the texture and electrochemical performance of CAs adsorbing metal ions exhibited a clear change. The specific surface area of CAs for adsorbing copper ions was 450 m2.g-1 and they showed a small average pore diameter (7.16 nm). Furthermore, CAs adsorbing metals could be used for the super capacitor. The specific capacitance of CAs adsorbing copper ions could reach 255 F.g-1 at a current density of 1.0 A.g-1. The CA-Cu electrode materials exhibited excellent reversibility with a cycling efficiency of 97% after 5000 cycles. PMID- 30441791 TI - Impact of Drinking Water Quality on the Development of Enteroviral Diseases in Korea. AB - Enterovirus diseases are fecal-orally transmitted, and its transmission may be closely related with the drinking water quality and other environmental factors. This study aimed to assess the association between environmental factors including drinking water quality and the incidence of enteroviral diseases in metropolitan provinces of Korea. Using monthly number of hand-foot-mouth disease (HFMD), aseptic meningitis (AM) and acute hemorrhage conjunctivitis (AHC) cases, generalized linear Poisson model was applied to estimate the effects of environmental factors on the monthly cases. An increase of mean temperature was associated with an increase of enteroviral diseases at 0-2 months lag, while an increase of turbidity was associated with increase in HFMD at 1 month lag and a decrease in AHC. An increase of residual chlorine in municipal drinking water was associated with a decrease in HFMD and AHC 2 and 3 months later. An increase of pH was associated with a maximum increase in AM 3 months later. The meta-analysis revealed the effects of the provincial and pooled variation in percent change of risks of environmental factors on HFMD, AM, and AHC cases at specific selected lags. This study suggests that the drinking water quality is one of the major determinants on enteroviral diseases. PMID- 30441792 TI - Ordering a Normal Diet at the End of Surgery-Justified or Overhasty? AB - Early re-alimentation is advocated by enhanced recovery pathways (ERP). This study aimed to assess compliance to ERP-set early re-alimentation policy and to compare outcomes of early fed patients and patients in whom early feeding was withhold due to the independent decision making of the surgeon. For this purpose, demographic, surgical and outcome data of all consecutive elective colorectal surgical procedures (2011-2016) were retrieved from a prospectively maintained institutional ERP database. The primary endpoint was postoperative ileus (POI). Surgical 30-day outcome and length of stay were compared between patients undergoing the pathway-intended early re-alimentation pattern and patients in whom early re-alimentation was not compliant. Out of the 7103 patients included, 1241 (17.4%) were not compliant with ERP re-alimentation. Patients with delayed re-alimentation presented with more postoperative complications (37 vs. 21%, p < 0.001) and a prolonged length of hospital stay (8 +/- 7 vs. 5 +/- 4 days, p < 0.001). While male gender (odds ratio (OR) 1.24; 95% confidence interval (CI) 1.04-1.32), fluid overload (OR 1.38; 95% CI 1.16-1.65) and high American Society of Anaesthesiologists (ASA) score (OR 1.51; 95% CI 1.27-1.8) were independent risk factors for POI, laparoscopy (OR 0.51; 95% CI 0.38-0.68) and ERP compliant diet (OR 0.46; 95% CI 0.36-0.6) were both protective. Hence, this study provides further evidence of the beneficial effect of early oral feeding after colorectal surgery. PMID- 30441793 TI - Reply: "Comment on: The Vitamin D-Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas, Nutrients 2018, 10, 554". AB - We thank Elias and Williams for their interest in our review [...]. PMID- 30441795 TI - Chaotic Manifold Analysis of Four-Screw Extruders Based on Lagrangian Coherent Structures. AB - The four-screw extruder (FSE) is a novel equipment for polymer processing. In this paper, from a new viewpoint of Lagrangian coherent structures (LCS), two dimensional fluid transport and chaotic mixing characteristics within three kinds of novel industrial FSEs are explored based on LCS to better understand the flow and mixing natures in the FSEs. Firstly, based on the finite-time invariant manifold theory, the finite-time Lyapunov exponent (FTLE) and LCS of FSEs are calculated by considering the different initial time. Hyperbolic LCSs from the FTLE maps are adopted to identify chaotic mixing manifolds in FSEs. Moreover, particle tracking and Poincare sections are used to illustrate the different fluid motions in the above three isolated regions. Finally, the effects of relative rotating directions and layout of four screws on the chaotic manifolds in FESs are discussed in order to enhance local mixing performance. Furthermore, quantitative mixing measures, such as the segregation scale, logarithmic of stretching, and mean-time mixing efficiency are employed to compare the mixing efficiencies in three kinds of FSEs. The results show that the relative rotating directions and positions of four screws can change the chaotic manifolds and increase mixing performance in local poor mixing regions. FTLE and LCS analysis are helpful to better understand the chaotic mixing nature in the novel screw extruders. PMID- 30441794 TI - The Role of the Anti-Aging Protein Klotho in IGF-1 Signaling and Reticular Calcium Leak: Impact on the Chemosensitivity of Dedifferentiated Liposarcomas. AB - By inhibiting Insulin-Like Growth Factor-1-Receptor (IGF-1R) signaling, Klotho (KL) acts like an aging- and tumor-suppressor. We investigated whether KL impacts the aggressiveness of liposarcomas, in which IGF-1R signaling is frequently upregulated. Indeed, we observed that a higher KL expression in liposarcomas is associated with a better outcome for patients. Moreover, KL is downregulated in dedifferentiated liposarcomas (DDLPS) compared to well-differentiated tumors and adipose tissue. Because DDLPS are high-grade tumors associated with poor prognosis, we examined the potential of KL as a tool for overcoming therapy resistance. First, we confirmed the attenuation of IGF-1-induced calcium (Ca2+) response and Extracellular signal-Regulated Kinase 1/2 (ERK1/2) phosphorylation in KL-overexpressing human DDLPS cells. KL overexpression also reduced cell proliferation, clonogenicity, and increased apoptosis induced by gemcitabine, thapsigargin, and ABT-737, all of which are counteracted by IGF-1R-dependent signaling and activate Ca2+-dependent endoplasmic reticulum (ER) stress. Then, we monitored cell death and cytosolic Ca2+-responses and demonstrated that KL increases the reticular Ca2+-leakage by maintaining TRPC6 at the ER and opening the translocon. Only the latter is necessary for sensitizing DDLPS cells to reticular stressors. This was associated with ERK1/2 inhibition and could be mimicked with IGF-1R or MEK inhibitors. These observations provide a new therapeutic strategy in the management of DDLPS. PMID- 30441796 TI - Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics. AB - Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer's disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis. PMID- 30441797 TI - A Method for Fault Detection and Diagnostics in Ventilation Units Using Virtual Sensors. AB - Buildings represent a significant portion of global energy consumption. Ventilation units are complex components, often customized for the specific building, responsible for a large part of energy consumption. Their faults impact buildings' energy efficiency and occupancy comfort. In order to ensure their correct operation, proper fault detection and diagnostics methods must be applied. Hardware redundancy, an effective approach to detect faults, leads to increased costs and space requirements. We propose exploiting physical relations inside ventilation units to create virtual sensors from other sensors' readings, introducing redundancy in the system. We use two different measures to detect when a virtual sensor deviates from the physical one: coefficient of determination for linear models, and acceptable range. We tested our method on a real building at the University of Southern Denmark, developing three virtual sensors: temperature, airflow, and fan speed. We employed linear regression models, statistical models, and non-linear regression models. All models detected an anomalous strong oscillation in the temperature sensors. Readings fell outside the acceptable range and the coefficient of determination dropped. Our method showed promising results by introducing redundancy in the system, which can benefit several applications, such as fault detection and diagnostics and fault tolerant control. Future work will be necessary to discover thresholds and set up automatic fault detection and diagnostics. PMID- 30441799 TI - Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor. AB - Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40-50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 uM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery. PMID- 30441798 TI - A Web-Based Calculator for the Prediction of Severe Neurodevelopmental Impairment in Preterm Infants Using Clinical and Imaging Characteristics. AB - Although the most common forms of brain injury in preterm infants have been associated with adverse neurodevelopmental outcomes, existing MRI scoring systems lack specificity, do not incorporate clinical factors, and are technically challenging to perform. The objective of this study was to develop a web-based, clinically-focused prediction system which differentiates severe neurodevelopmental outcomes from normal-moderate outcomes at two years. Infants were retrospectively identified as those who were born <=30 weeks gestation and who had MRI imaging at term-equivalent age and neurodevelopmental testing at 18 24 months. Each MRI was scored on injury in three domains (intraventricular hemorrhage, white matter injury, and cerebellar hemorrhage) and clinical factors that were strongly predictive of an outcome were investigated. A binary logistic regression model was then generated from the composite of clinical and imaging components. A total of 154 infants were included (mean gestational age = 26.1 +/- 1.8 weeks, birth weight = 889.1 +/- 226.2 g). The final model (imaging score + ventilator days + delivery mode + antenatal steroids + retinopathy of prematurity requiring surgery) had strong discriminatory power for severe disability (AUC = 0.850), with a PPV (positive predictive value) of 76% and an NPV (negative predictive value) of 90%. Available as a web-based tool, it can be useful for prognostication and targeting early intervention services to infants who may benefit the most from such services. PMID- 30441800 TI - In Situ FT-IR Characterization of CuZnZr/Ferrierite Hybrid Catalysts for One-Pot CO2-to-DME Conversion. AB - CO2 hydrogenation to dimethyl ether (DME) is a promising strategy to drive the current chemical industry towards a low-carbon scenario since DME can be used as an eco-friendly fuel as well as a platform molecule for chemical production. A Cu ZnO-ZrO2/ferrierite (CZZ/FER) hybrid grain was recently proposed as a catalyst for CO2-to-DME one-pot conversion exhibiting high DME productivity thanks to the unique shape-selectivity offered by ferrierite zeolite. Nevertheless, such a catalyst deactivates but no direct evidence has been reported of activity loss over time. In this work, CZZ/FER catalysts with different acidity levels were characterized with the FTIR technique before and after reactions, aiming to give new insights about catalyst deactivation. Results show that activity loss can be related to both (i) copper particle sintering, which decreases CO2 activation towards methanol, and (ii) acidity loss due to H+/Cu2+ ion exchange. PMID- 30441801 TI - Hydrothermally Synthesized Mg-Based Spinel Nanoferrites: Phase Formation and Study on Magnetic Features and Microwave Characteristics. AB - Three kinds of magnesium-based spinel nanoferrites with the chemical formulas of MgFe2O4 (Mg ferrite), Mg0.9Mn0.1Fe2O4 (Mg-Mn ferrite), and Mg0.9Mn0.1In0.1Fe1.9O4 (Mg-Mn-In ferrite) were synthesized by hydrothermal route. We report the composition-dependent magnetic parameters and microwave properties of Mg-based ferrite nanoparticles. XRD results revealed that the Mg-based ferrite nanoparticles exhibited a cubic spinel structure and had an average nanocrystallite size in the range of 5.8-2.6 nm. Raman spectroscopy analysis confirmed the formation of cubic-spinel phase Mg-based nanoferrites. The room temperature magnetization measurements indicated that the Mg ferrite nanoparticles had superparamagnetic behavior; whereas the Mg-Mn and Mg-Mn-In ferrite nanoparticles exhibited a paramagnetic nature. The microwave properties of obtained ferrite nanoparticles were studied by alternating current (AC) magnetic susceptibility measurement and electron paramagnetic resonance (EPR) spectroscopy. It was found that the un-substituted Mg ferrite sample exhibited microwave characteristics better than those of the Mn substituted and Mn-In co substituted Mg ferrite samples. PMID- 30441802 TI - Solid Lipid Nanoparticles for Dibucaine Sustained Release. AB - Dibucaine (DBC) is among the more potent long-acting local anesthetics (LA), and it is also one of the most toxic. Over the last decades, solid lipid nanoparticles (SLN) have been developed as promising carriers for drug delivery. In this study, SLN formulations were prepared with the aim of prolonging DBC release and reducing its toxicity. To this end, SLN composed of two different lipid matrices and prepared by two different hot-emulsion techniques (high pressure procedure and sonication) were compared. The colloidal stability of the SLN formulations was tracked in terms of particle size (nm), polydispersity index (PDI), and zeta potential (mV) for 240 days at 4 degrees C; the DBC encapsulation efficiency was determined by the ultrafiltration/centrifugation method. The formulations were characterized by differential scanning calorimetry (DSC), electron paramagnetic resonance (EPR), and release kinetic experiments. Finally, the in vitro cytotoxicity against 3T3 fibroblast and HaCaT cells was determined, and the in vivo analgesic action was assessed using the tail flick test in rats. Both of the homogenization procedures were found suitable to produce particles in the 200 nm range, with good shelf stability (240 days) and high DBC encapsulation efficiency (~72-89%). DSC results disclosed structural information on the nanoparticles, such as the lower crystallinity of the lipid core vs. the bulk lipid. EPR measurements provided evidence of DBC partitioning in both SLNs. In vitro (cytotoxicity) and in vivo (tail flick) experiments revealed that the encapsulation of DBC into nanoparticles reduces its intrinsic cytotoxicity and prolongs the anesthetic effect, respectively. These results show that the SLNs produced are safe and have great potential to extend the applications of dibucaine by enhancing its bioavailability. PMID- 30441804 TI - Experimental Investigation on the Creep Property of Carbon Fiber Reinforced Polymer Tendons under High Stress Levels. AB - Carbon fiber reinforced polymer (CFRP) tendons are generally used as prestressing members to take full advantage of their high strength. Their creep property is one of the key factors influencing the reliability and safety of the structures, especially under sustained high stress. In this study, using a new wedge-type anchorage system, experimental research was carried out on the creep behavior of CFRP tendons under high stress levels from 0.69 to 0.85 fu. All the tests lasted for a duration of 1000 h. It was found that the creep coefficient tends to increase with the stress level. Compared to their static properties, the residual strength of CFRP tendons after creep tests is 4.54% lower while the after-creep elastic modulus is 6.99% higher. Through data analysis, a semi-logarithm linear relationship between the creep coefficient and time was established, and the creep coefficients at 1 million hours were extrapolated. PMID- 30441803 TI - Gender and Age Stratified Analyses of Nutrient and Dietary Pattern Associations with Circulating Lipid Levels Identify Novel Gender and Age-Specific Correlations. AB - Dyslipidemia is a precursor to a myriad of cardiovascular diseases in the modern world. Age, gender, and diet are known modifiers of lipid levels, however they are not frequently investigated in subset analyses. Food and nutrient intakes from National Health and Nutrition Examination Study 2001-2013 were used to assess the correlation between lipid levels (high-density lipoprotein (HDL) cholesterol, triglycerides (TG), low-density lipoprotein (LDL) cholesterol, and total cholesterol (TC):HDL cholesterol ratio) and nutritional intake using linear regression. Associations were initially stratified by gender and significant gender correlations were further stratified by age. Analyses were performed at both the dietary pattern and nutrient level. Dietary pattern and fat intake correlations agreed with the literature in direction and did not demonstrate gender or age effects; however, we observed gender and age interactions among other dietary patterns and individual nutrients. These effects were independent of ethnicity, caloric intake, socioeconomic status, and physical activity. Elevated HDL cholesterol levels correlated with increasing vitamin and mineral intake in females of child bearing age but not males or older females (>=65 years). Moreover, increases in magnesium and retinol intake correlated with HDL cholesterol improvement only in females (all age groups) and males (35-64), respectively. Finally, a large amount of gender-specific variation was associated with TG levels. Females demonstrated positive associations with sugar and carbohydrate while males show inverse associations with polyunsaturated fatty acid (PUFA) intake. The female-specific association increased with the ratio of carbohydrate: saturated fatty acid (SFA) intake, suggesting that gender specific dietary habits may underlie the observed TG-nutrient correlations. Our study provides evidence that a subset of previously established nutrient-lipid associations may be gender or age-specific. Such discoveries provide potential new avenues for further research into personalized nutritional approaches to treat dyslipidemia. PMID- 30441805 TI - A Feasibility Study of Transformer Winding Temperature and Strain Detection Based on Distributed Optical Fibre Sensors. AB - The temperature distribution and deformation of the transformer windings cannot be measured in a distributed manner by the traditional method and failure location cannot be performed. To solve these problems, we present a transformer winding temperature and strain based on a distributed optical fibre sensing detection method. The design of the optical fibre winding composite model is developed and simulated winding temperature rise test and local deformation test distinguish between measuring the winding temperature and the strain curve. The test results show that the distributed optical fibre can transmit wire strain efficiently. Optical fibres, in the process of winding, have a certain pre stress. Using the Brillouin-Raman joint measuring method, one can effectively extract the optical fibre temperature and strain information and measure the length of the winding direction of the temperature and strain distribution curve to a temperature measurement precision of +/-2 degrees C and strain detection accuracy of +/-50 MUepsilon. The system can carry out local hot spot and deformation localisation, providing new ideas for the transformer winding state monitoring technology. PMID- 30441806 TI - Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells. AB - Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla sp., reduced spheroid formation in CSC221, DLD1, and HT29 cells. In addition, mRNA expressions and protein levels of cancer stem markers aldehyde dehydrogenase-1 (ALDH1), cluster of differentiation 133 (CD133), CD44, Lgr5, and Musashi-1 were reduced after tumidulin treatment. Tumidulin decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli) promoter in reporter assays, and western blotting confirmed decreased Gli1, Gli2, and Smoothened (SMO) protein levels. Moreover, the tumidulin activity was not observed in the presence of Gli and SMO inhibitors. Together, these results demonstrate for the first time that tumidulin is a potent inhibitor of colorectal cancer cell stemness. PMID- 30441807 TI - SS1P Immunotoxin Induces Markers of Immunogenic Cell Death and Enhances the Effect of the CTLA-4 Blockade in AE17M Mouse Mesothelioma Tumors. AB - SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells. Both properties are associated with immunogenic cell death. Furthermore, we treated these tumors with intra tumoral SS1P and systemic CTLA-4. We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner. In addition, SS1P induced calreticulin expression on the surface of AE17M cells. These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy. In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy. The surviving mice were protected from tumor re-challenge, indicating the development of anti tumor immunity. These findings support the use of intra-tumoral SS1P in combination with anti-CTLA-4. PMID- 30441808 TI - Screening for Depressive Mood During Acute Chikungunya Infection in Primary Healthcare Settings. AB - Background: We aimed to screen for depressive mood experienced during acute chikungunya (CHIKV) infection, and to evaluate the association of several exposures with the risk of depressive symptoms. Methods: A cross-sectional analysis of a multicenter cohort study took place and data from 354 adult individuals with confirmed CHIKV infection were analyzed. Participants were recruited in primary health care settings and the Patient Health Questionnaire-2 (PHQ-2) was used. Prevalence odds ratios (OR) and 95% confidence intervals (CIs) estimated by means of logistic models were used. Results: Depressive mood (PHQ-2 score 3 or higher) was reported by 44.1% of individuals. Subjects with articular effusion (OR = 3.37, 95% CI 1.77-8.11), gastrointestinal manifestations (diarrhea, vomiting or abdominal pain, OR = 1.97, 95 CI 1.21-3.19), and higher length of severe arthralgia (reference <= 14 days: 15-30 days, OR = 3.38, 95% CI 1.78-6.41; >= 30 days, OR = 1.69, 95% CI 0.95-3.01) were more likely to self report depressive mood. Increasing age (>= 40 years old, OR = 0.55, 95% CI 0.31 0.95) and rash (OR = 0.54, 95% CI 0.30-0.98) were associated with a decreased risk of depressive mood. Conclusions: Depressive mood seemed to be a frequent event among analyzed individuals, and markers associated with its risk were identified. PMID- 30441809 TI - HGF/MET and the Immune System: Relevance for Cancer Immunotherapy. AB - An overactivation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) axis promotes tumorigenesis and tumor progression in various cancer types. Research data recently evidenced that HGF/MET signaling is also involved also in the immune response, mainly modulating dendritic cells functions. In general, the pathway seems to play an immunosuppressive role, thus hypothesizing that it could constitute a mechanism of primary and acquired resistance to cancer immunotherapy. Recently, some approaches are being developed, including drug design and cell therapy to combine MET and programmed cell death receptor-1 (PD-1)/programmed cell death receptor-ligand 1 (PD-L1) inhibition. This approach could represent a new weapon in cancer therapy in the future. PMID- 30441810 TI - Chemical Profiles of Incense Smoke Ingredients from Agarwood by Headspace Gas Chromatography-Tandem Mass Spectrometry. AB - Agarwood, the resinous wood in the heartwood of Aquilaria trees, has been used as incense in traditional Chinese medicine for its sedative, aphrodisiac, carminative, and anti-emetic effects. Grading of agarwood is usually based on its physical properties. Therefore, it is important to develop analytic methods for judgment and grading of agarwood. Here, we created a headspace (HS) preheating system that is combined with gas chromatography-mass spectrometry (HS GC-MS) to analyze the chemical constituents in the incense smoke produced by agarwood. Incense smoke generated in the HS preheating system was injected directly to GC MS for analysis. A total of 40 compounds were identified in the incense smoke produced by Kynam agarwood, the best agarwood in the world. About half of the compounds are aromatics and sesquiterpenes. By analyzing chemical constituents in the incense smoke produced by Vietnamese, Lao, and Cambodian varieties of agarwood, we found that butyl hexadecanoate, butyl octadecanoate, bis(2 ethylhexyl) 1,2-benzenedicarboxylate, and squalene were common in the aforementioned four varieties of agarwoods. 2-(2-Phenylethyl) chromone derivatives were identified only in the incense smoke produced by Kynam agarwood, and were the major ingredient (27.23%) in the same. In conclusion, this is the first study that analyzes chemical profiles of incense smoke produced by agarwood using HS GC-MS. Our data showed that 2-(2-phenylethyl) chromone derivatives could be used to assess quality of agarwoods. Moreover, HS GC/MS may be a useful tool for grading quality of agarwood. PMID- 30441812 TI - Characterization of Heterotrimeric G Protein gamma4 Subunit in Rice. AB - Heterotrimeric G proteins are the molecule switch that transmits information from external signals to intracellular target proteins in mammals and yeast cells. In higher plants, heterotrimeric G proteins regulate plant architecture. Rice harbors one canonical alpha subunit gene (RGA1), four extra-large GTP-binding protein genes (XLGs), one canonical beta-subunit gene (RGB1), and five gamma subunit genes (tentatively designated RGG1, RGG2, RGG3/GS3/Mi/OsGGC1, RGG4/DEP1/DN1/qPE9-1/OsGGC3, and RGG5/OsGGC2) as components of the heterotrimeric G protein complex. Among the five gamma-subunit genes, RGG1 encodes the canonical gamma-subunit, RGG2 encodes a plant-specific type of gamma-subunit with additional amino acid residues at the N-terminus, and the remaining three gamma subunit genes encode atypical gamma-subunits with cysteine-rich C-termini. We characterized the RGG4/DEP1/DN1/qPE9-1/OsGGC3 gene product Ggamma4 in the wild type (WT) and truncated protein Ggamma4?Cys in the RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutant, Dn1-1, as littele information regarding the native Ggamma4 and Ggamma4?Cys proteins is currently available. Based on liquid chromatography tandem mass spectrometry analysis, immunoprecipitated Ggamma4 candidates were confirmed as actual Ggamma4. Similar to alpha-(Galpha) and beta-subunits (Gbeta), Ggamma4 was enriched in the plasma membrane fraction and accumulated in the developing leaf sheath. As RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutants exhibited dwarfism, tissues that accumulated Ggamma4 corresponded to the abnormal tissues observed in RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutants. PMID- 30441813 TI - Protection of Superconducting Industrial Machinery Using RNN-Based Anomaly Detection for Implementation in Smart Sensor. AB - Sensing the voltage developed over a superconducting object is very important in order to make superconducting installation safe. An increase in the resistive part of this voltage (quench) can lead to significant deterioration or even to the destruction of the superconducting device. Therefore, detection of anomalies in time series of this voltage is mandatory for reliable operation of superconducting machines. The largest superconducting installation in the world is the main subsystem of the Large Hadron Collider (LHC) accelerator. Therefore a protection system was built around superconducting magnets. Currently, the solutions used in protection equipment at the LHC are based on a set of hand crafted custom rules. They were proved to work effectively in a range of applications such as quench detection. However, these approaches lack scalability and require laborious manual adjustment of working parameters. The presented work explores the possibility of using the embedded Recurrent Neural Network as a part of a protection device. Such an approach can scale with the number of devices and signals in the system, and potentially can be automatically configured to given superconducting magnet working conditions and available data. In the course of the experiments, it was shown that the model using Gated Recurrent Units (GRU) comprising of two layers with 64 and 32 cells achieves 0.93 accuracy for anomaly/non-anomaly classification, when employing custom data compression scheme. Furthermore, the compression of proposed module was tested, and showed that the memory footprint can be reduced four times with almost no performance loss, making it suitable for hardware implementation. PMID- 30441814 TI - Cross-Sectional Analysis of Overall Dietary Intake and Mediterranean Dietary Pattern in Patients with Crohn's Disease. AB - The primary objective of this study was to explore the macro- and micro-nutrient intakes and dietary patterns of patients with Crohn's disease (CD). Secondary objectives were to (a) compare the micronutrient intakes of CD patients with a representative sample of individuals, (b) describe the macro- and micronutrient intakes of male and female CD patients, and (c) describe Mediterranean diet scores (P-MDS) of male and female CD patients in remission that were recruited from an inflammatory bowel disease (IBD) clinic in Calgary, AB. Consecutive patients with ileal and/or colonic CD in endoscopic remission were recruited for participation in this cross-sectional study. Sixty-seven patients were enrolled with a mean age of 45, and a Body Mass Index (BMI) >= 25. Compared with the representative sample, patients with CD had similar energy, protein, carbohydrate, and total fat intake. However, polyunsaturated fats (PUFA), omega-6 and 3, and monounsaturated fats (MUFA) were lower in CD patients and dietary fiber intake was higher (p < 0.05). Vitamins C, D, thiamin, niacin, magnesium, phosphorus, zinc, and potassium were all significantly lower in all CD patients when compared to the representative sample (p < 0.05). Few patients with CD met the P-MDS criteria and overall scores were low (mean 4.5, Standard Deviation (SD) = 1.1 in males and 4.7, SD = 1.8 in females). The CD patients in this study had suboptimal dietary intakes and patterns and these data may be used to inform future dietary interventions in this population to improve intake. PMID- 30441815 TI - Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents. AB - The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or alpha haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco friendly catalyst using the solvent-drop grinding method. The structure of the synthesized compounds was elucidated using elemental and spectroscopic analyses (IR, NMR, and Mass). The activity of these compounds against human hepatocellular carcinoma cell line (HepG2) was tested and the results showed that the pyrazoline 11f, which has a fluorine substituent, is the most active. The antimicrobial activities of the newly synthesized compounds were determined against two fungi and four bacterial strains, and the results indicated that some of the newly synthesized pyrazolines are more potent than the standard drugs against test organisms. PMID- 30441817 TI - Joint Relay Selection and Power Allocation through a Genetic Algorithm for Secure Cooperative Cognitive Radio Networks. AB - In cooperative cognitive radio networks (CCRNs), there has been growing demand of transmitting secondary user (SU) source information secretly to the corresponding SU destination with the aid of cooperative SU relays. Efficient power allocation (PA) among SU relays and multi-relay selection (MRS) are a critical problem for operating such networks whereas the interference to the primary user receiver is being kept below a tolerable level and the transmission power requirements of the secondary users are being satisfied. Subsequently, in the paper, we develop the problem to solve the optimal solution for PA and MRS in a collaborative amplify and-forward-based CCRNs, in terms of maximizing the secrecy rate (SR) of the networks. It is found that the problem is a mixed integer programming problem and difficult to be solved. To cope with this difficulty, we propose a meta-heuristic genetic algorithm-based MRS and PA scheme to maximize the SR of the networks while satisfying transmission power and the interference requirements of the networks. Our simulation results reveal that the proposed scheme achieves near optimal SR performance, compared to the exhaustive search scheme, and provides a significant SR improvement when compared with some conventional relay selection schemes with equal power allocation. PMID- 30441818 TI - The Development of Assays for Heparanase Enzymatic Activity: Towards a Gold Standard. AB - The enzyme heparanase, an endo-beta-glucuronidase, degrades heparan sulfate (HS) chains on the cell surface and in the extracellular matrix. Heparanase regulates numerous biological processes that drive tumour growth, metastasis and angiogenesis. In addition to its key role in cancer progression, it has also been implicated in an ever-growing number of other diseases, particularly those associated with inflammation. The importance of heparanase in biology has led to numerous efforts over the years to develop assays to monitor its activity and to screen for new inhibitors as potential drug candidates. Despite these efforts and the commercialization of a few kits, most heparanase assays are still complex, labour intensive, costly or have limited application. Herein we review the various methods for assaying heparanase enzymatic activity, focusing on recent developments towards new assays that hold the promise of accelerating research into this important enzyme. PMID- 30441816 TI - Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. AB - Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host's response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C. PMID- 30441819 TI - Carbohydrate Supplementation Does Not Improve 10 km Swimming Intermittent Training. AB - The aim of the present study was to test the effectiveness of carbohydrate (CHO) feeding supplemented every 2.5-km, as in official races, on the performance, rating of perceived exertion (RPE), and glycaemia during a 10-km intermittent training workout in elite open-water swimmers. A randomized crossover design was used. Participants completed two 10-km intermittent training sessions (20 * 500 m). The relative velocity was expressed in percentage of a single 500-m. Glycaemia was monitored by continuous glucose monitoring. Participants had to ingest either 1 L of tap water (WAT; 0.50 L.h-1) or 120 g of CHO in the form of 8% solution (60 g.h-1). The 15-point RPE scale was used during the trials. A two way ANOVA for repeated measures was performed (p < 0.05). The relative velocity of each 500-m was not significantly different between the two trials. No significant differences emerged in the relative velocity of the last 500-m between trials. Average RPE was not statistically different between the two trials (11 +/- 3 in WAT and 12 +/- 3 in CHO). In the last 500-m, glycaemia was significantly higher in the CHO trial (5.92 +/- 0.47 mmol.L-1 in CHO; 5.61 +/- 0.61 mmol.L-1 in WAT). CHO ingestion did not improve performance or affect RPE during a 10-km intermittent training in elite open-water swimmers. PMID- 30441820 TI - A Noninvasive TDR Sensor to Measure the Moisture Content of Rigid Porous Materials. AB - The article presents the potential application of the time domain reflectometry (TDR) technique to measure moisture transport in unsaturated porous materials. The research of the capillary uptake phenomenon in a sample of autoclaved aerated concrete (AAC) was conducted using a TDR sensor with the modified construction for non-invasive testing. In the paper the basic principles of the TDR method as a technique applied in metrology, and its potential for measurement of moisture in porous materials, including soils and porous building materials are presented. The second part of the article presents the experiment of capillary rise process in the AAC sample. Application of the custom sensor required its individual calibration, thus a unique model of regression between the readouts of apparent permittivity of the tested material and its moisture was developed. During the experiment moisture content was monitored in the sample exposed to water influence. Monitoring was conducted using the modified TDR sensor. The process was additionally measured using the standard frequency domain (FD) capacitive sensor in order to compare the readouts with traditional techniques of moisture detection. The uncertainty for testing AAC moisture, was expressed as RMSE (0.013 cm3/cm3) and expanded uncertainty (0.01-0.02 cm3/cm3 depending on moisture) was established along with calibration of the applied sensor. The obtained values are comparable to, or even better than, the features of the traditional invasive sensors utilizing universal calibration models. Both, the TDR and capacitive (FD) sensor enabled monitoring of capillary uptake phenomenon progress. It was noticed that at the end of the experiment the TDR readouts were 4.4% underestimated and the FD readouts were overestimated for 12.6% comparing to the reference gravimetric evaluation. PMID- 30441811 TI - Epigenetic Regulation by lncRNAs: An Overview Focused on UCA1 in Colorectal Cancer. AB - Colorectal cancers have become the second leading cause of cancer-related deaths. In particular, acquired chemoresistance and metastatic lesions occurring in colorectal cancer are a major challenge for chemotherapy treatment. Accumulating evidence shows that long non-coding (lncRNAs) are involved in the initiation, progression, and metastasis of cancer. We here discuss the epigenetic mechanisms through which lncRNAs regulate gene expression in cancer cells. In the second part of this review, we focus on the role of lncRNA Urothelial Cancer Associated 1 (UCA1) to integrate research in different types of cancer in order to decipher its putative function and mechanism of regulation in colorectal cancer cells. UCA1 is highly expressed in cancer cells and mediates transcriptional regulation on an epigenetic level through the interaction with chromatin modifiers, by direct regulation via chromatin looping and/or by sponging the action of a diversity of miRNAs. Furthermore, we discuss the role of UCA1 in the regulation of cell cycle progression and its relation to chemoresistance in colorectal cancer cells. PMID- 30441821 TI - An Antithrombotic Strategy by Targeting Phospholipase D in Human Platelets. AB - Phospholipase D (PLD) is involved in many biological processes. PLD1 plays a crucial role in regulating the platelet activity of mice; however, the role of PLD in the platelet activation of humans remains unclear. Therefore, we investigated whether PLD is involved in the platelet activation of humans. Our data revealed that inhibition of PLD1 or PLD2 using pharmacological inhibitors effectively inhibits platelet aggregation in humans. However, previous studies have showed that PLD1 or PLD2 deletion did not affect mouse platelet aggregation in vitro, whereas only PLD1 deletion inhibited thrombus formation in vivo. Intriguingly, our data also showed that the pharmacological inhibition of PLD1 or PLD2 does not affect mouse platelet aggregation in vitro, whereas the inhibition of only PLD1 delayed thrombus formation in vivo. These findings indicate that PLD may play differential roles in humans and mice. In humans, PLD inhibition attenuates platelet activation, adhesion, spreading, and clot retraction. For the first time, we demonstrated that PLD1 and PLD2 are essential for platelet activation in humans, and PLD plays different roles in platelet function in humans and mice. Our findings also indicate that targeting PLD may provide a safe and alternative therapeutic approach for preventing thromboembolic disorders. PMID- 30441822 TI - Evolution of Dislocation Loops Induced by Different Hydrogen Irradiation Conditions in Reduced-Activation Martensitic Steel. AB - Hydrogen can be induced in various ways into reduced-activation ferritic/martensitic (RAFM) steels when they are used as structural materials for advanced nuclear systems. However, because of the fast diffusion of hydrogen in metals, the effect of hydrogen on the evolution of irradiation-induced defects was almost neglected. In the present work, the effect of hydrogen on the evolution of dislocation loops was investigated using a transmission electron microscope. Specimens of reduced-activation ferritic/martensitic (RAFM) steels were irradiated with hydrogen ions to 5 * 1020 H+ * m-2 at 523-823 K, and to 1 * 1020 H+ * m-2 - 5 * 1020 H+ * m-2 at 723 K. The experimental results reveal that there is an optimum temperature for dislocation loop growth, which is ~723 K, and it is greater than the reported values for neutron irradiations. Surprisingly, the sizes of the loops produced by hydrogen ions, namely, 93 nm and 286 nm for the mean and maximum value, respectively, at the peak dose of 0.16 dpa under 723 K, are much larger than that produced by neutrons and heavy ions at the same damage level and temperature. The results indicate that hydrogen could enhance the growth of loops. Moreover, 47.3% 1 2 a0 <111> and 52.7% a0 <100> loops were observed at 523 K, but 1 2 a0 <111> loops disappeared and only a0 <100> loops existed above 623 K. Compared with the neutron and ion irradiations, the presence of hydrogen promoted the formation of a0 <100> loops. PMID- 30441824 TI - Accuracy of Commonly-Used Imaging Modalities in Assessing Left Atrial Appendage for Interventional Closure: Review Article. AB - Periprocedural imaging assessment for percutaneous Left Atrial Appendage (LAA) transcatheter occlusion can be obtained by utilizing different imaging modalities including fluoroscopy, magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound imaging. Given the complex and variable morphology of the left atrial appendage, it is crucial to obtain the most accurate LAA dimensions to prevent intra-procedural device changes, recapture maneuvers, and prolonged procedure time. We therefore sought to examine the accuracy of the most commonly utilized imaging modalities in LAA occlusion. Institutional Review Board (IRB) approval was waived as we only reviewed published data. By utilizing PUBMED which is an integrated online website to list the published literature based on its relevance, we retrieved thirty-two articles on the accuracy of most commonly used imaging modalities for pre-procedural assessment of the left atrial appendage morphology, namely, two-dimensional transesophageal echocardiography, three dimensional transesophageal echocardiography, computed tomography, and three dimensional printing. There is strong evidence that real-time three-dimensional transesophageal echocardiography is more accurate than two-dimensional transesophageal echocardiography. Three-dimensional computed tomography has recently emerged as an imaging modality and it showed exceptional accuracy when merged with three-dimensional printing technology. However, real time three dimensional transesophageal echocardiography may be considered the preferred imaging modality as it can provide accurate measurements without requiring radiation exposure or contrast administration. We will present the most common imaging modality used for LAA assessment and will provide an algorithmic approach including preprocedural, periprocedural, intraprocedural, and postprocedural. PMID- 30441825 TI - Cyanobacterial Blooms and Microcystins in Southern Vietnam. AB - Studies on cyanobacteria in Vietnam are limited and mainly restricted to large reservoirs. Cyanobacterial blooms in small water bodies may pose a health risk to local people. We sampled 17 water bodies in the vicinity of urban settlements throughout the Mekong basin and in southeast Vietnam. From these, 40 water samples were taken, 24 cyanobacterial strains were isolated and 129 fish, 68 snail, 7 shrimp, 4 clam, and 4 duck samples were analyzed for microcystins (MCs). MCs were detected up to 11,039 ug/L or to 4033 ug/g DW in water samples. MCs were detected in the viscera of the animals. MC-LR and MC-RR were most frequently detected, while MC-dmLR, MC-LW, and MC-LF were first recorded in Vietnam. Microcystis was the main potential toxin producer and the most common bloom forming species. A potential health hazard was found in a duck-fish pond located in the catchment of DauTieng reservoir and in the DongNai river where raw water was collected for DongNai waterwork. The whole viscera of fish and snails must be completely removed during food processing. Cyanobacterial monitoring programs should be established to assess and minimize potential public health risks. PMID- 30441826 TI - Real-Time Underwater StereoFusion. AB - Many current and future applications of underwater robotics require real-time sensing and interpretation of the environment. As the vast majority of robots are equipped with cameras, computer vision is playing an increasingly important role it this field. This paper presents the implementation and experimental results of underwater StereoFusion, an algorithm for real-time 3D dense reconstruction and camera tracking. Unlike KinectFusion on which it is based, StereoFusion relies on a stereo camera as its main sensor. The algorithm uses the depth map obtained from the stereo camera to incrementally build a volumetric 3D model of the environment, while simultaneously using the model for camera tracking. It has been successfully tested both in a lake and in the ocean, using two different state-of-the-art underwater Remotely Operated Vehicles (ROVs). Ongoing work focuses on applying the same algorithm to acoustic sensors, and on the implementation of a vision based monocular system with the same capabilities. PMID- 30441827 TI - Development of Biomarkers for Inhibition of SLC6A19 (B0AT1)-A Potential Target to Treat Metabolic Disorders. AB - Recent studies have established that dietary protein restriction improves metabolic health and glucose homeostasis. SLC6A19 (B0AT1) is the major neutral amino acid transporter in the intestine and carries out the bulk of amino acid absorption from the diet. Mice lacking SLC6A19 show signs of protein restriction, have improved glucose tolerance, and are protected from diet-induced obesity. Pharmacological blockage of this transporter could be used to induce protein restriction and to treat metabolic diseases such as type 2 diabetes. A few novel inhibitors of SLC6A19 have recently been identified using in vitro compound screening, but it remains unclear whether these compounds block the transporter in vivo. To evaluate the efficacy of SLC6A19 inhibitors biomarkers are required that can reliably detect successful inhibition of the transporter in mice. A gas chromatography mass spectrometry (GC-MS)-based untargeted metabolomics approach was used to discriminate global metabolite profiles in plasma, urine and faecal samples from SLC6A19ko and wt mice. Due to inefficient absorption in the intestine and lack of reabsorption in the kidney, significantly elevated amino acids levels were observed in urine and faecal samples. By contrast, a few neutral amino acids were reduced in the plasma of male SLC6A19ko mice as compared to other biological samples. Metabolites of bacterial protein fermentation such as p-cresol glucuronide and 3-indole-propionic acid were more abundant in SLC6A19ko mice, indicating protein malabsorption of dietary amino acids. Consistently, plasma appearance rates of [14C]-labelled neutral amino acids were delayed in SLC6A19ko mice as compared to wt after intra-gastric administration of a mixture of amino acids. Receiver operating characteristic (ROC) curve analysis was used to validate the potential use of these metabolites as biomarkers. These findings provide putative metabolite biomarkers that can be used to detect protein malabsorption and the inhibition of this transporter in intestine and kidney. PMID- 30441828 TI - Title Synergistic Effect of Al2O3 Inclusion and Pearlite on the Localized Corrosion Evolution Process of Carbon Steel in Marine Environment. AB - The initiation and evolution of the localized corrosion in carbon steel were investigated in a simulated marine environment of Xisha Island in the South China Sea. In the initial stage, localized corrosion occurred in the form of corrosion spot. The localized corrosion morphology and electrochemical information during corrosion process were tracked by field emission scanning electron microscopy energy dispersive spectrometry (FE-SEM-EDS), scanning vibrating electrode technique (SVET) and scanning Kelvin probe force microscopy (SKPFM). Localized corrosion was induced by the microcrevices around Al2O3 inclusions. The occluded cells and oxygen concentration cell formed in the pits could accelerate the localized corrosion. Pearlite accelerated the dissolution of the inside and surrounding ferrite via the galvanic effect between Fe3C and ferrite. Overall, the localized corrosion was initiated and evaluated under a synergistic effect of crevice corrosion, occluded cells, oxygen concentration cell and the galvanic couple between FeC3 and ferrite. PMID- 30441823 TI - Impacts of Cancer on Platelet Production, Activation and Education and Mechanisms of Cancer-Associated Thrombosis. AB - Platelets are small anucleate cells that are traditionally described as the major effectors of hemostasis and thrombosis. However, increasing evidence indicates that platelets play several roles in the progression of malignancies and in cancer-associated thrombosis. A notable cross-communication exists between platelets and cancer cells. On one hand, cancer can "educate" platelets, influencing their RNA profiles, the numbers of circulating platelets and their activation states. On the other hand, tumor-educated platelets contain a plethora of active biomolecules, including platelet-specific and circulating ingested biomolecules, that are released upon platelet activation and participate in the progression of malignancy. The numerous mechanisms by which the primary tumor induces the production, activation and aggregation of platelets (also known as tumor cell induced platelet aggregation, or TCIPA) are directly related to the pro-thrombotic state of cancer patients. Moreover, the activation of platelets is critical for tumor growth and successful metastatic outbreak. The development or use of existing drugs targeting the activation of platelets, adhesive proteins responsible for cancer cell-platelet interactions and platelet agonists should be used to reduce cancer-associated thrombosis and tumor progression. PMID- 30441829 TI - Highly Efficient Red Cabbage Anthocyanin Inserted TiO2 Aerogel Nanocomposites for Photocatalytic Reduction of Cr(VI) under Visible Light. AB - In sharp contrast to conventional photosensitization methods in which the organic pigments were often adsorbed, herein we present a study on natural vegetable pigment inserted TiO2 aerogel nanocomposites and we directly use red cabbage anthocyanin (RCP) as a structure-directing agent. It was found that pure TiO2 aerogel nanocomposite did not exhibit any meaningful activity for photocatalytic reduction of Cr(VI). However, the photocatalytic reduction activity was greatly improved by the RCP inserted TiO2 aerogel nanocomposites under visible-light irradiation, which was approximately 2- and 12.3-fold higher than that of TiO2 aerogel conventionally photosensitized by RCP and pure TiO2 aerogel nanocomposites, respectively. It also exhibited good stability and could be reused at least three times without losing a significant amount of its activity. PMID- 30441830 TI - Two-Dimensional Fluorescence Lifetime Correlation Spectroscopy: Concepts and Applications. AB - We review the basic concepts and recent applications of two-dimensional fluorescence lifetime correlation spectroscopy (2D FLCS), which is the extension of fluorescence correlation spectroscopy (FCS) to analyze the correlation of fluorescence lifetime in addition to fluorescence intensity. Fluorescence lifetime is sensitive to the microenvironment and can be a "molecular ruler" when combined with FRET. Utilization of fluorescence lifetime in 2D FLCS thus enables us to quantify the inhomogeneity of the system and the interconversion dynamics among different species with a higher time resolution than other single-molecule techniques. Recent applications of 2D FLCS to various biological systems demonstrate that 2D FLCS is a unique and promising tool to quantitatively analyze the microsecond conformational dynamics of macromolecules at the single-molecule level. PMID- 30441831 TI - Remote Stimulation of Sciatic Nerve Using Cuff Electrodes and Implanted Diodes. AB - We demonstrate a method of neurostimulation using implanted, free-floating, inter neural diodes. They are activated by volume-conducted, high frequency, alternating current (AC) fields and address the issue of instability caused by interconnect wires in chronic nerve stimulation. The aim of this study is to optimize the set of AC electrical parameters and the diode features to achieve wireless neurostimulation. Three different packaged Schottky diodes (1.5 mm, 500 um and 220 um feature sizes) were tested in vivo (n = 17 rats). A careful assessment of sciatic nerve activation as a function of diode-dipole lengths and relative position of the diode was conducted. Subsequently, free-floating Schottky microdiodes were implanted in the nerve (n = 3 rats) and stimulated wirelessly. Thresholds for muscle twitch responses increased non-linearly with frequency. Currents through implanted diodes within the nerve suffer large attenuations (~100 fold) requiring 1-2 mA drive currents for thresholds at 17 uA. The muscle recruitment response using electromyograms (EMGs) is intrinsically steep for subepineurial implants and becomes steeper as diode is implanted at increasing depths away from external AC stimulating electrodes. The study demonstrates the feasibility of activating remote, untethered, implanted microscale diodes using external AC fields and achieving neurostimulation. PMID- 30441832 TI - Ionic Exchange Resins and Hydrogels for Capturing Metal Ions in Selected Sweet Dessert Wines. AB - Samples of sweet and dessert wines, Vin Santo (VSR) from Malvasia grapes, and Granello (GR) from Sauvignon grapes were collected and analyzed for the content of selected macro- and micro-nutrients (Na, K, Mg, Ca, Mn, Fe, Cu and Zn) and of Pb. GR wines had low levels for Fe, Cu and Zn, when compared to VSR and in particular Zn was two orders of magnitude lower. Methods to decrease the content of Zn and Cu in VSR, as well as those for reducing, at the same time, the concentrations of Ca, Mg and K in both VSR and GR, to avoid the formation of opalescence and depots of metal tartrates, were studied. Synthetic hydrogels containing l-histidine residue were tested. The overall relative lowering effects were by ca 4, 23, and 12% for K, Mg and Ca contents, and ca 6, 27 and 10%, for Mn, Cu and Zn contents, in GR wine samples. Commercial ion exchange resin Lanxess Lewatit L-207 and L-208 were then assayed, being legally allowed in the agro-food industry. The L-207 resin revealed great lowering effects on the concentrations of Mn, Cu and Zn, being 75, 91 and 97%, respectively, in VSR wines and 77, 76 and 92%, respectively, in GR wines. The content of Zn was reduced from 49.3 +/- 1.2 mg/L in the original wine, down to 1.1 +/- 0.1 mg/L, within 48 h soaking. The effects on the character of the dessert wines by the resin L-207 was also taken under control, measuring pH and color index. The color index changed by ca 15% and pH by ca 6% upon treatment of VSR wine with L-207 resins (48 h). PMID- 30441833 TI - Emerging Role of Purine Metabolizing Enzymes in Brain Function and Tumors. AB - The growing evidence of the involvement of purine compounds in signaling, of nucleotide imbalance in tumorigenesis, the discovery of purinosome and its regulation, cast new light on purine metabolism, indicating that well known biochemical pathways may still surprise. Adenosine deaminase is important not only to preserve functionality of immune system but also to ensure a correct development and function of central nervous system, probably because its activity regulates the extracellular concentration of adenosine and therefore its function in brain. A lot of work has been done on extracellular 5'-nucleotidase and its involvement in the purinergic signaling, but also intracellular nucleotidases, which regulate the purine nucleotide homeostasis, play unexpected roles, not only in tumorigenesis but also in brain function. Hypoxanthine guanine phosphoribosyl transferase (HPRT) appears to have a role in the purinosome formation and, therefore, in the regulation of purine synthesis rate during cell cycle with implications in brain development and tumors. The final product of purine catabolism, uric acid, also plays a recently highlighted novel role. In this review, we discuss the molecular mechanisms underlying the pathological manifestations of purine dysmetabolisms, focusing on the newly described/hypothesized roles of cytosolic 5'-nucleotidase II, adenosine kinase, adenosine deaminase, HPRT, and xanthine oxidase. PMID- 30441834 TI - Motion-Aware Correlation Filters for Online Visual Tracking. AB - The discriminative correlation filters-based methods struggle deal with the problem of fast motion and heavy occlusion, the problem can severely degrade the performance of trackers, ultimately leading to tracking failures. In this paper, a novel Motion-Aware Correlation Filters (MACF) framework is proposed for online visual object tracking, where a motion-aware strategy based on joint instantaneous motion estimation Kalman filters is integrated into the Discriminative Correlation Filters (DCFs). The proposed motion-aware strategy is used to predict the possible region and scale of the target in the current frame by utilizing the previous estimated 3D motion information. Obviously, this strategy can prevent model drift caused by fast motion. On the base of the predicted region and scale, the MACF detects the position and scale of the target by using the DCFs-based method in the current frame. Furthermore, an adaptive model updating strategy is proposed to address the problem of corrupted models caused by occlusions, where the learning rate is determined by the confidence of the response map. The extensive experiments on popular Object Tracking Benchmark OTB-100, OTB-50 and unmanned aerial vehicles (UAV) video have demonstrated that the proposed MACF tracker performs better than most of the state-of-the-art trackers and achieves a high real-time performance. In addition, the proposed approach can be integrated easily and flexibly into other visual tracking algorithms. PMID- 30441835 TI - Phylogeny and Mycotoxin Characterization of Alternaria Species Isolated from Wheat Grown in Tuscany, Italy. AB - Wheat, the main source of carbohydrates worldwide, can be attacked by a wide number of phytopathogenic fungi, included Alternaria species. Alternaria species commonly occur on wheat worldwide and produce several mycotoxins such as tenuazonic acid (TA), alternariol (AOH), alternariol-monomethyl ether (AME), and altenuene (ALT), provided of haemato-toxic, genotoxic, and mutagenic activities. The contamination by Alternaria species of wheat kernels, collected in Tuscany, Italy, from 2013 to 2016, was evaluated. Alternaria contamination was detected in 93 out of 100 field samples, with values ranging between 1 and 73% (mean of 18%). Selected strains were genetically characterized by multi-locus gene sequencing approach through combined sequences of allergen alt1a, glyceraldeyde-3-phosphate dehydrogenase, and translation elongation factor 1alpha genes. Two well defined groups were generated; namely sections Alternaria and Infectoriae. Representative strains were analyzed for mycotoxin production. A different mycotoxin profile between the sections was shown. Of the 54 strains analyzed for mycotoxins, all strains included in Section Alternaria produced AOH and AME, 40 strains (99%) produced TA, and 26 strains (63%) produced ALT. On the other hand, only a very low capability to produce both AOH and AME was recorded among the Section Infectoriae strains. These data show that a potential mycotoxin risk related to the consumption of Alternaria contaminated wheat is high. PMID- 30441836 TI - Antitumor Effect of the Essential Oil from the Leaves of Croton matourensis Aubl. (Euphorbiaceae). AB - Croton matourensis Aubl. (synonym Croton lanjouwensis Jabl.), popularly known as "orelha de burro", "maravuvuia", and/or "sangrad'agua", is a medicinal plant used in Brazilian folk medicine as a depurative and in the treatment of infections, fractures, and colds. In this work, we investigated the chemical composition and in vitro cytotoxic and in vivo antitumor effects of the essential oil (EO) from the leaves of C. matourensis collected from the Amazon rainforest. The EO was obtained by hydrodistillation using a Clevenger-type apparatus and characterized qualitatively and quantitatively by gas chromatography coupled to mass spectrometry (GC-MS) and gas chromatography with flame ionization detection (GC FID), respectively. In vitro cytotoxicity of the EO was assessed in cancer cell lines (MCF-7, HCT116, HepG2, and HL-60) and the non-cancer cell line (MRC-5) using the Alamar blue assay. Furthermore, annexin V-FITC/PI staining and the cell cycle distribution were evaluated with EO-treated HepG2 cells by flow cytometry. In vivo efficacy of the EO (40 and 80 mg/kg/day) was demonstrated in C.B-17 severe combined immunodeficient (SCID) mice with HepG2 cell xenografts. The EO included beta-caryophyllene, thunbergol, cembrene, p-cymene, and beta-elemene as major constituents. The EO exhibited promising cytotoxicity and was able to cause phosphatidylserine externalization and DNA fragmentation without loss of the cell membrane integrity in HepG2 cells. In vivo tumor mass inhibition rates of the EO were 34.6% to 55.9%. Altogether, these data indicate the anticancer potential effect of C. matourensis. PMID- 30441837 TI - Parenting Practices as a Mediator in the Association Between Family Socio Economic Status and Screen-Time in Primary Schoolchildren: A Feel4Diabetes Study. AB - The aim of this study was to examine the mediating effects of specific parenting practices on the association between family socio-economic status (SES) and screen-time of 6- to 9-year-old children from families with an increased risk of developing type 2 diabetes. This cross-sectional study, focusing on families with an increased risk of developing type 2 diabetes, used the Belgian baseline data of the Movie Models intervention, integrated within the European Feel4Diabetes intervention, and included 247 parents (57.6% lower SES family; 78.0% mothers) who completed a questionnaire. Mediating effects were tested using MacKinnon's product-of-coefficients test via multilevel linear regression analyses. Being consistent concerning rules about gaming (beta = 0.127; standard error = 0.055; 95% CI = 0.020; 0.234) and avoiding negative role modeling concerning TV-time (beta = -0.082; standard error = 0.040; 95% CI = -0.161; -0.003) significantly mediated the inverse association between family SES and children's screen-time. Parents from lower SES families were more consistent concerning rules about gaming and watched more TV nearby their child compared to parents from higher SES families, and these parenting practices were related to more screen-time. No other parenting practices were found to mediate this association. Thus, parents from lower SES families with a higher risk for developing type 2 diabetes might limit their own TV-time nearby their child to reduce their child's screen-time. Future research should examine other possible mediating factors to develop effective interventions targeting this important at-risk group. PMID- 30441838 TI - An Energy-Efficient Clustering Routing Protocol for Wireless Sensor Networks Based on AGNES with Balanced Energy Consumption Optimization. AB - To further prolong the lifetime of wireless sensor network (WSN), researchers from various countries have proposed many clustering routing protocols. However, the total network energy consumption of most protocols is not well minimized and balanced. To alleviate this problem, this paper proposes an energy-efficient clustering routing protocol in WSNs. To begin with, this paper introduces a new network structure model and combines the original energy consumption model to construct a new method to determine the optimal number of clusters for the total energy consumption minimization. Based on the balanced energy consumption, then we optimize the AGglomerative NESting (AGNES) algorithm, including: (1) introduction of distance variance, (2) the dual-cluster heads (D-CHs) division of the energy balance strategy, and (3) the node dormancy mechanism. In addition, the CHs priority function is constructed based on the residual energy and position of the node. Finally, we simulated this protocol in homogeneous networks (the initial energy = 0.4 J, 0.6 J and 0.8 J) and heterogeneous networks (the initial energy = 0.4-0.8 J). Simulation results show that our proposed protocol can reduce the network energy consumption decay rate, prolong the network lifetime, and improve the network throughput in the above two networks. PMID- 30441839 TI - On-Chip Tunable Cell Rotation Using Acoustically Oscillating Asymmetrical Microstructures. AB - The precise rotational manipulation of cells and other micrometer-sized biological samples is critical to many applications in biology, medicine, and agriculture. We describe an acoustic-based, on-chip manipulation method that can achieve tunable cell rotation. In an acoustic field formed by the vibration of a piezoelectric transducer, acoustic streaming was generated using a specially designed, oscillating asymmetrical sidewall shape. We also studied the nature of acoustic streaming generation by numerical simulations, and our simulation results matched well with the experimental results. Trapping and rotation of diatom cells and swine oocytes were coupled using oscillating asymmetrical microstructures with different vibration modes. Finally, we investigated the relationship between the driving voltage and the speed of cell rotation, showing that the rotational rate achieved could be as large as approximately 1800 rpm. Using our device, the rotation rate can be effectively tuned on demand for single cell studies. Our acoustofluidic cell rotation approach is simple, compact, non contact, and biocompatible, permitting rotation irrespective of the optical, magnetic, or electrical properties of the specimen under investigation. PMID- 30441840 TI - Oxidation of 5-methylaminomethyl uridine (mnm5U) by Oxone Leads to Aldonitrone Derivatives. AB - Oxidative RNA damage is linked to cell dysfunction and diseases. The present work focuses on the in vitro oxidation of 5-methylaminomethyl uridine (mnm5U), which belongs to the numerous post-transcriptional modifications that are found in tRNA. The reaction of oxone with mnm5U in water at pH 7.5 leads to two aldonitrone derivatives. They form by two oxidation steps and one dehydration step. Therefore, the potential oxidation products of mnm5U in vivo may not be only aldonitrones, but also hydroxylamine and imine derivatives (which may be chemically more reactive). Irradiation of aldonitrone leads to unstable oxaziridine derivatives that are susceptible to isomerization to amide or to hydrolysis to aldehyde derivative. PMID- 30441842 TI - Induction of Recombinant Lectin Expression by an Artificially Constructed Tandem Repeat Structure: A Case Study Using Bryopsis plumosa Mannose-Binding Lectin. AB - Lectin is an important protein in medical and pharmacological applications. Impurities in lectin derived from natural sources and the generation of inactive proteins by recombinant technology are major obstacles for the use of lectins. Expressing recombinant lectin with a tandem repeat structure can potentially overcome these problems, but few studies have systematically examined this possibility. This was investigated in the present study using three distinct forms of recombinant mannose-binding lectin from Bryopsis plumosa (BPL2)-i.e., the monomer (rD1BPL2), as well as the dimer (rD2BPL2), and tetramer (rD4BPL2) arranged as tandem repeats. The concentration of the inducer molecule isopropyl beta-D-1-thiogalactopyranoside and the induction time had no effect on the efficiency of the expression of each construct. Of the tested constructs, only rD4BPL2 showed hemagglutination activity towards horse erythrocytes; the activity of towards the former was 64 times higher than that of native BPL2. Recombinant and native BPL2 showed differences in carbohydrate specificity; the activity of rD4BPL2 was inhibited by the glycoprotein fetuin, whereas that of native BPL2 was also inhibited by d-mannose. Our results indicate that expression as tandem repeat sequences can increase the efficiency of lectin production on a large scale using a bacterial expression system. PMID- 30441841 TI - Effects of Meal Timing on Postprandial Glucose Metabolism and Blood Metabolites in Healthy Adults. AB - We examined the effects of meal timing on postprandial glucose metabolism, including the incretin response and metabolites in healthy adults. Nineteen healthy young men completed two trials involving blood collection in a fasting state and at 30, 60 and 120 min after meal provision in a random order: (1) morning (~0900 h) and (2) evening (~1700 h). The blood metabolome of eight participants was analyzed using capillary electrophoresis-mass spectrometry. Postprandial glucose concentrations at 120 min (p = 0.030) and glucose-dependent insulinotropic polypeptide concentrations (p = 0.005) at 60 min in the evening trials were higher than those in the morning trials. The incremental area under the curve values of five glycolysis, tricarboxylic acid cycle and nucleotide related metabolites and 18 amino acid-related metabolites were higher in the morning trials than those in the evening trials (p < 0.05). Partial least-squares analysis revealed that the total metabolic change was higher in the morning. Our study demonstrates that a meal in the evening exacerbates the state of postprandial hyperglycemia in healthy adults. In addition, this study provides insight into the difference of incretion and blood metabolites between breakfast and dinner, indicating that the total metabolic responses tends to be higher in the morning. PMID- 30441843 TI - Hemodialysis Impact on Motor Function beyond Aging and Diabetes-Objectively Assessing Gait and Balance by Wearable Technology. AB - Motor functions are deteriorated by aging. Some conditions may magnify this deterioration. This study examined whether hemodialysis (HD) process would negatively impact gait and balance beyond diabetes condition among mid-age adults (48-64 years) and older adults (65+ years). One hundred and ninety-six subjects (age = 66.2 +/- 9.1 years, body-mass-index = 30.1 +/- 6.4 kg/m2, female = 56%) in 5 groups were recruited: mid-age adults with diabetes undergoing HD (Mid-age HD+, n = 38) and without HD (Mid-age HD-, n = 40); older adults with diabetes undergoing HD (Older HD+, n = 36) and without HD (Older HD-, n = 37); and non diabetic older adults (Older DM-, n = 45). Gait parameters (stride velocity, stride length, gait cycle time, and double support) and balance parameters (ankle, hip, and center of mass sways) were quantified using validated wearable platforms. Groups with diabetes had overall poorer gait and balance compared to the non-diabetic group (p < 0.050). Among people with diabetes, HD+ had significantly worsened gait and balance when comparing to HD- (Cohen's effect size d = 0.63-2.32, p < 0.050). Between-group difference was more pronounced among older adults with the largest effect size observed for stride length (d = 2.32, p < 0.001). Results suggested that deterioration in normalized gait speed among HD+ was negatively correlated with age (r = -0.404, p < 0.001), while this correlation was diminished among HD-. Interestingly, results also suggested that poor gait among Older HD- is related to poor ankle stability, while no correlation was observed between poor ankle stability and poor gait among Older HD+. Using objective assessments, results confirmed that the presence of diabetes can deteriorate gait and balance, and this deterioration can be magnified by HD process. Among HD- people with diabetes, poor ankle stability described poor gait. However, among people with diabetes undergoing HD, age was a dominate factor describing poor gait irrespective of static balance. Results also suggested feasibility of using wearable platforms to quantify motor performance during routine dialysis clinic visit. These objective assessments may assist in identifying early deterioration in motor function, which in turn may promote timely intervention. PMID- 30441844 TI - Gadolinium Chloride Rescues Niemann-Pick Type C Liver Damage. AB - Niemann-Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer/foam measured by India ink endocytosis, decreased the levels CD68-A marker of Kupffer cells in the liver-and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated. PMID- 30441845 TI - Magnetic Characterization in the Rayleigh Region of Nanocrystalline Magnetic Cores. AB - We report on the structural and magnetic characterization of two nanocrystalline Finemet-type magnetic cores. The nanocrystalline structure developed after annealing the amorphous precursor alloy at 550 degrees C for 30 and 60 min of annealing time. Structural analysis carried out by means of X-ray diffraction providing useful information on the grain size mean and partial volume of the nanocrystalline phase. The magnetic characterization was focused mainly in the Rayleigh region which, influenced by the intergranular coupling, was found to be more efficient in the sample treated for a longer time with a finer nanocrystalline structure. PMID- 30441847 TI - Annealing and Stretching Induced High Energy Storage Properties in All-Organic Composite Dielectric Films. AB - High discharged energy density and charge-discharge efficiency, in combination with high electric breakdown strength, maximum electric displacement and low residual displacement, are very difficult to simultaneously achieve in single component polymer dielectrics. Plenty of researches have reported polymer based composite dielectrics filled with inorganic fillers, through complex surface modification of inorganic fillers to improve interface compatibility. In this work, a novel strategy of introducing environmentally-friendly biological polyester into fluoropolymer matrix has been presented to prepare all-organic polymer composites with desirable high energy storage properties by solution cast process (followed by annealing or stretching post-treatment), in order to simplify the preparation steps and lower the cost. Fluoropolymer with substantial ferroelectric domains (contributing to high dielectric response) as matrix and poly (3-hydroxybutyrate-co-3-hydroxyvalerate) with excellent linear polarization property (resulting in high breakdown strength) as filler were employed. By high temperature annealing, the size of ferroelectric domains could be improved and interfacial air defects could be removed, leading to elevated high energy storage density and efficiency in composite. By mono-directional stretching, the ferroelectric domains and polyester could be regularly oriented along stretching direction, resulting in desired high energy storage performances as well. Besides, linear dielectric components could contribute to high efficiency from their strong rigidity restrain effect on ferroelectric component. This work might open up the way for a facile fabrication of promising all-organic composite dielectric films with high energy storage properties. PMID- 30441848 TI - The Application of Lipid Membranes in Biosensing. AB - The exploitation of lipid membranes in biosensors has provided the ability to reconstitute a considerable part of their functionality to detect trace of food toxicants and environmental pollutants. This paper reviews recent progress in biosensor technologies based on lipid membranes suitable for food quality monitoring and environmental applications. Numerous biosensing applications based on lipid membrane biosensors are presented, putting emphasis on novel systems, new sensing techniques, and nanotechnology-based transduction schemes. The range of analytes that can be currently using these lipid film devices that can be detected include, insecticides, pesticides, herbicides, metals, toxins, antibiotics, microorganisms, hormones, dioxins, etc. Technology limitations and future prospects are discussed, focused on the evaluation/validation and eventually commercialization of the proposed lipid membrane-based biosensors. PMID- 30441846 TI - Starchy Carbohydrates in a Healthy Diet: The Role of the Humble Potato. AB - Potatoes have been an affordable, staple part of the diet for many hundreds of years. Recently however, there has been a decline in consumption, perhaps influenced by erroneous reports of being an unhealthy food. This review provides an overview of the nutritional value of potatoes and examines the evidence for associations between potato consumption and non-communicable diseases. Potatoes are an important source of micronutrients, such as vitamin C, vitamin B6, potassium, folate, and iron and contribute a significant amount of fibre to the diet. However, nutrient content is affected by cooking method; boiling causes leaching of water-soluble nutrients, whereas frying can increase the resistant starch content of the cooked potato. Epidemiological studies have reported associations between potato intake and obesity, type 2 diabetes and cardiovascular disease. However, results are contradictory and confounded by lack of detail on cooking methods. Indeed, potatoes have been reported to be more satiating than other starchy carbohydrates, such as pasta and rice, which may aid weight maintenance. Future research should consider cooking methods in the study design in order to reduce confounding factors and further explore the health impact of this food. PMID- 30441850 TI - Real-Life Implementation of a GPS-Based Path-Following System for an Autonomous Vehicle. AB - This work is meant to report on activities at TU Delft on the design and implementation of a path-following system for an autonomous Toyota Prius. The design encompasses: finding the vehicle parameters for the actual vehicle to be used for control design; lateral and longitudinal controllers for steering and acceleration, respectively. The implementation covers the real-time aspects via LabVIEW from National Instruments and the real-life tests. The deployment of the system was enabled by a Spatial Dual Global Positioning System (GPS) system providing more accuracy than the regular GPS. The results discussed in this work represent the first autonomous tests on the Toyota Prius at TU Delft, and we expect the proposed system to be a benchmark against which to test more advanced solutions. The tests show that the system is able to perform in real-time while satisfying comfort and trajectory tracking requirements: in particular, the tracking error was within 16 cm, which is compatible with the 13 cm precision of the Spatial Dual GPS, whereas the longitudinal and lateral acceleration are within comfort levels as defined by available experimental studies. PMID- 30441849 TI - Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients. AB - Constitutional loss-of-function pathogenic variants in the tumor suppressor genes BRCA1 and BRCA2 are widely associated with an elevated risk of ovarian cancer (OC). As only ~15% of OC individuals carry the BRCA1/2 pathogenic variants, the identification of other potential OC-susceptibility genes is of great clinical importance. Here, we established the prevalence and spectrum of the germline pathogenic variants in the BRCA1/2 and 23 other cancer-related genes in a large Polish population of 333 unselected OC cases. Approximately 21% of cases (71/333) carried the BRCA1/2 pathogenic or likely pathogenic variants, with c.5266dup (p.Gln1756Profs*74) and c.3700_3704del (p.Val1234Glnfs*8) being the most prevalent. Additionally, ~6% of women (20/333) were carriers of the pathogenic or likely pathogenic variants in other cancer-related genes, with NBN and CHEK2 reported as the most frequently mutated, accounting for 1.8% (6/333) and 1.2% (4/333) of cases, respectively. We also found ten pathogenic or likely pathogenic variants in other genes: 1/333 in APC, 1/333 in ATM, 2/333 in BLM, 1/333 in BRIP1, 1/333 in MRE11A, 2/333 in PALB2, 1/333 in RAD50, and 1/333 in RAD51C, accounting for 50% of all detected variants in moderate- and low-penetrant genes. Our findings confirmed the presence of the additional OC-associated genes in the Polish population that may improve the personalized risk assessment of these individuals. PMID- 30441851 TI - Immobilized Gold Nanoparticles Prepared from Gold(III)-Containing Ionic Liquids on Silica: Application to the Sustainable Synthesis of Propargylamines. AB - A cycloaurated phosphinothioic amide gold(III) complex was supported on amorphous silica with the aid of an imidazolium ionic liquid (IL) physisorbed in the SiO2 pores (SiO2-IL) and covalently bonded to the SiO2 (SiO2@IL). Gold(0) nanoparticles (AuNPs) were formed in situ and subsequently immobilized on the SiO2-IL/SiO2@IL phase. The resulting catalytic systems Au-SiO2-IL and Au-SiO2@IL promoted the solvent-free A3 coupling reaction of alkynes, aldehydes, and amines in high yields under solvent-free conditions with very low catalyst loading and without the use of additives. The Au-SiO2@IL catalyst showed good recyclability and could be reused at least five times with yields of propargylamines of >=80%. This synthetic method provides a green and low cost way to effectively prepare propargylamines. Additionally, 31P high resolution magic angle spinning (HRMAS) NMR spectroscopy is introduced as a simple technique to establish the Au loading of the catalyst. PMID- 30441852 TI - Cardiac Targeting Peptide, a Novel Cardiac Vector: Studies in Bio-Distribution, Imaging Application, and Mechanism of Transduction. AB - Our previous work identified a 12-amino acid peptide that targets the heart, termed cardiac targeting peptide (CTP). We now quantitatively assess the bio distribution of CTP, show a clinical application with the imaging of the murine heart, and study its mechanisms of transduction. Bio-distribution studies of cyanine5.5-N-Hydroxysuccinimide (Cy5.5) labeled CTP were undertaken in wild-type mice. Cardiac targeting peptide was labeled with Technetium 99m (99mTc) using the chelator hydrazino-nicotinamide (HYNIC), and imaging performed using micro-single photon emission computerized tomography/computerized tomography (SPECT/CT). Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMCs) were incubated with dual-labeled CTP, and imaged using confocal microscopy. TriCEPs technology was utilized to study the mechanism of transduction. Bio-distribution studies showed peak uptake of CTP at 15 min. 99mTc-HYNIC-CTP showed heart-specific uptake. Robust transduction of beating human iPSC-derived CMCs was seen. TriCEPs experiments revealed five candidate binding partners for CTP, with Kcnh5 being felt to be the most likely candidate as it showed a trend towards being competed out by siRNA knockdown. Transduction efficiency was enhanced by increasing extracellular potassium concentration, and with Quinidine, a Kcnh5 inhibitor, that blocks the channel in an open position. We demonstrate that CTP transduces the normal heart as early as 15 min. 99mTc-HYNIC-CTP targets the normal murine heart with substantially improved targeting compared with 99mTc Sestamibi. Cardiac targeting peptide's transduction ability is not species limited and has human applicability. Cardiac targeting peptide appears to utilize Kcnh5 to gain cell entry, a phenomenon that is affected by pre-treatment with Quinidine and changes in potassium levels. PMID- 30441853 TI - Sensors for Deformation Monitoring of Large Civil Infrastructures. AB - In the maintenance of large infrastructures such as dams, bridges, railways, underground structures (tunnels, mines) and others, monitoring of deformations plays a key role in maintaining the safety serviceability conditions and for mitigating any consequences due to ageing factors and possible structural failures. [...]. PMID- 30441854 TI - Microwave Irradiation Assists the Synthesis of a Novel Series of bis-Arm s Triazine Oxy-Schiff Base and Oxybenzylidene Barbiturate Derivatives. AB - A novel series of s-triazines incorporating 4-hydroxybenzaldehyde and 4-hydroxy-3 methoxybenzaldehyde was prepared and fully characterized. The reaction was carried out via stepwise nucleophilic aromatic substitution of chlorine atoms in cyanuric chloride. The first chlorine was substituted by different amines (morpholine, piperidine, or diethylamine) to afford 2,4-dichloro-6-substituted 1,3,5-triazine. The second and third chlorines were substituted by benzaldehyde derivatives in the presence of Na2CO3 as a HCl scavenger to afford the target products: s-triazine oxyaldehyde derivatives (dipodal). The dipodal derivatives were reacted with acid hydrazide, hydralazine, barbituric, or thiobarbituric acid derivatives using conventional heating or microwave irradiation to afford the di arm s-triazine oxy-Schiff base and oxybenzylidene barbiturate derivatives in good yields. Microwave irradiation done in less solvent afforded the target product in less reaction time with good yield and purity. These types of derivatives might have special interest in coordination and medicinal chemistry. PMID- 30441855 TI - Dielectric Metasurface-Based High-Efficiency Mid-Infrared Optical Filter. AB - Dielectric nanoresonantors may generate both electric and magnetic Mie resonances with low optical loss, thereby offering highly efficient paths for obtaining integrated optical devices. In this paper, we propose and design an optical filter with a high working efficiency in the mid-infrared (mid-IR) range, based on an all-dielectric metasurface composed of silicon (Si) nanodisk arrays. We numerically demonstrate that, by increasing the diameter of the Si nanodisk, the range of the proposed reflective optical filter could effectively cover a wide range of operation wavelengths, from 3.8 MUm to 4.7 MUm, with the reflection efficiencies reaching to almost 100%. The electromagnetic eigen-mode decomposition of the silicon nanodisk shows that the proposed optical filter is based on the excitation of the electric dipole resonance. In addition, we demonstrate that the proposed filter has other important advantages of polarization-independence and incident-angle independence, ranging from 0 degrees to 20 degrees at the resonance dip, which can be used in a broad range of applications, such as sensing, imaging, and energy harvesting. PMID- 30441856 TI - Bioinformatics and Functional Assessment of Toxin-Antitoxin Systems in Staphylococcus aureus. AB - Staphylococcus aureus is a nosocomial pathogen that can cause chronic to persistent infections. Among different mediators of pathogenesis, toxin-antitoxin (TA) systems are emerging as the most prominent. These systems are frequently studied in Escherichia coli and Mycobacterial species but rarely explored in S. aureus. In the present study, we thoroughly analyzed the S. aureus genome and screened all possible TA systems using the Rasta bacteria and toxin-antitoxin database. We further searched E. coli and Mycobacterial TA homologs and selected 67 TA loci as putative TA systems in S. aureus. The host inhibition of growth (HigBA) TA family was predominantly detected in S. aureus. In addition, we detected seven pathogenicity islands in the S. aureus genome that are enriched with virulence genes and contain 26 out of 67 TA systems. We ectopically expressed multiple TA genes in E. coli and S. aureus that exhibited bacteriostatic and bactericidal effects on cell growth. The type I Fst toxin created holes in the cell wall while the TxpA toxin reduced cell size and induced cell wall septation. Besides, we identified a new TA system whose antitoxin functions as a transcriptional autoregulator while the toxin functions as an inhibitor of autoregulation. Altogether, this study provides a plethora of new as well as previously known TA systems that will revitalize the research on S. aureus TA systems. PMID- 30441857 TI - Fear of Terror and Psychological Well-Being: The Moderating Role of Emotional Intelligence. AB - The purpose of this study was to empirically explore whether or not the level of emotional intelligence of adolescents mitigates the potential adverse effects of the fear of terror on their psychological well-being. Data for this study were collected through a voluntary survey from a sample of 385 adolescents residing in the terrorism-affected provinces of Pakistan: Khyber Pakhtunkhwa (KPK) and Balochistan. The results from the structural equation modeling revealed that fear of terrorism had a significant negative relationship with the psychological well being of adolescents. The study results further revealed that emotional intelligence significantly moderated the relationship between the fear of terrorism and the psychological well-being of the adolescents. Therefore, the negative relationship was stronger for those with low emotional intelligence and weaker for those with high emotional intelligence. This study also discusses several practical implications along with suggestions for future research. PMID- 30441858 TI - Evaluation of Three Peptide Immobilization Techniques on a QCM Surface Related to Acetaldehyde Responses in the Gas Phase. AB - The quartz-crystal microbalance is a sensitive and universal tool for measuring concentrations of various gases in the air. Biochemical functionalization of the QCM electrode allows a label-free detection of specific molecular interactions with high sensitivity and specificity. In addition, it enables a real-time determination of its kinetic rates and affinity constants. This makes QCM a versatile bioanalytical screening tool for various applications, with surface modifications ranging from the detection of single molecular monolayers to whole cells. Various types of biomaterials, including peptides mapping the binding sites of olfactory receptors, can be deposited as a sensitive element on the surface of the electrodes. One of key ways to ensure the sensitivity and accuracy of the sensor is provided by application of an optimal and repeatable method of immobilization. Therefore, effective sensors operation requires development of an optimal method of deposition. This paper reviews popular techniques (drop casting, spin-coating, dip-coating) for coating peptides on piezoelectric crystals surface. Peptide (LEKKKKDC-NH2) derived from an aldehyde binding site in the HarmOBP7 protein was synthesized and used as a sensing material for the biosensor. The degree of deposition of the sensitive layer was monitoring by variations in the sensors frequency. The highest mass threshold for QCM measurements for peptides was approximately 16.43 ug.mm-2 for spin coating method. Developed sensor exhibited repeatable response to acetaldehyde. Moreover, responses to toluene was observed to evaluate sensors specificity. Calibration curves of the three sensors showed good determination coefficients (R2 > 0.99) for drop casting and dip coating and 0.97 for the spin-coating method. Sensors sensitivity vs. acetaldehyde were significantly higher for the dip-coating and drop-casting methods and lower for spin-coating one. PMID- 30441859 TI - An Adaptive Filtering Approach Based on the Dynamic Variance Model for Reducing MEMS Gyroscope Random Error. AB - To improve the dynamic random error compensation accuracy of the Micro Electro Mechanical System (MEMS) gyroscope at different angular rates, an adaptive filtering approach based on the dynamic variance model was proposed. In this paper, experimental data were utilized to fit the dynamic variance model which describes the nonlinear mapping relations between the MEMS gyroscope output data variance and the input angular rate. After that, the dynamic variance model was applied to online adjustment of the Kalman Filter measurement noise coefficients. The proposed approach suppressed the interference from the angular rate in the filtering results. Dynamic random errors were better estimated and reduced. Turntable experiment results indicated that the adaptive filtering approach compensated for the MEMS gyroscope dynamic random error effectively both in the constant angular rate condition and the continuous changing angular rate condition, thus achieving adaptive dynamic random error compensation. PMID- 30441860 TI - Identification of Novel Gymnodimines and Spirolides from the Marine Dinoflagellate Alexandrium ostenfeldii. AB - Cyclic imine toxins are neurotoxic, macrocyclic compounds produced by marine dinoflagellates. Mass spectrometric screenings of extracts from natural plankton assemblages revealed a high chemical diversity among this toxin class, yet only few toxins are structurally known. Here we report the structural characterization of four novel cyclic-imine toxins (two gymnodimines (GYMs) and two spirolides (SPXs)) from cultures of Alexandrium ostenfeldii. A GYM with m/z 510 (1) was identified as 16-desmethylGYM D. A GYM with m/z 526 was identified as the hydroxylated degradation product of (1) with an exocyclic methylene at C-17 and an allylic hydroxyl group at C-18. This compound was named GYM E (2). We further identified a SPX with m/z 694 as 20-hydroxy-13,19-didesmethylSPX C (10) and a SPX with m/z 696 as 20-hydroxy-13,19-didesmethylSPX D (11). This is the first report of GYMs without a methyl group at ring D and SPXs with hydroxyl groups at position C-20. These compounds can be conceived as derivatives of the same nascent polyketide chain, supporting the hypothesis that GYMs and SPXs are produced through common biosynthetic genes. Both novel GYMs 1 and 2 were detected in significant amounts in extracts from natural plankton assemblages (1: 447 pg; 2: 1250 pg; 11: 40 pg per mL filtered seawater respectively). PMID- 30441861 TI - Biological Activity of the Carrier as a Factor in Immunogen Design for Haptens. AB - Immunoanalytical methods are frequently employed in the detection of hazardous small molecular weight compounds. However, antibody development for these molecules is a challenge, because they are haptens and cannot induce a humoral immune response in experimental animals. Immunogenic forms of haptens are usually prepared by conjugating them to a protein carrier which serves as an immune stimulator. However, the carrier is usually considered merely as a bulk mass, and its biological activity is ignored. Here, we induced an endocytic receptor, transferrin receptor, by selecting its ligand as a carrier protein to enhance antibody production. We conjugated aflatoxin, a potent carcinogenic food contaminant, to transferrin and evaluated its potential to stimulate antibody production with respect to ovalbumin conjugates. Transferrin conjugates induced aflatoxin-specific immune responses in the second immunization, while ovalbumin conjugates reached similar antibody titers after 5 injections. Monoclonal antibodies were successfully developed with mice immunized with either of the conjugates. PMID- 30441862 TI - Large-Scale Analyses of Site-Specific Evolutionary Rates across Eukaryote Proteomes Reveal Confounding Interactions between Intrinsic Disorder, Secondary Structure, and Functional Domains. AB - Various structural and functional constraints govern the evolution of protein sequences. As a result, the relative rates of amino acid replacement among sites within a protein can vary significantly. Previous large-scale work on Metazoan (Animal) protein sequence alignments indicated that amino acid replacement rates are partially driven by a complex interaction among three factors: intrinsic disorder propensity; secondary structure; and functional domain involvement. Here, we use sequence-based predictors to evaluate the effects of these factors on site-specific sequence evolutionary rates within four eukaryotic lineages: Metazoans; Plants; Saccharomycete Fungi; and Alveolate Protists. Our results show broad, consistent trends across all four Eukaryote groups. In all four lineages, there is a significant increase in amino acid replacement rates when comparing: (i) disordered vs. ordered sites; (ii) random coil sites vs. sites in secondary structures; and (iii) inter-domain linker sites vs. sites in functional domains. Additionally, within Metazoans, Plants, and Saccharomycetes, there is a strong confounding interaction between intrinsic disorder and secondary structure alignment sites exhibiting both high disorder propensity and involvement in secondary structures have very low average rates of sequence evolution. Analysis of gene ontology (GO) terms revealed that in all four lineages, a high fraction of sequences containing these conserved, disordered-structured sites are involved in nucleic acid binding. We also observe notable differences in the statistical trends of Alveolates, where intrinsically disordered sites are more variable than in other Eukaryotes and the statistical interactions between disorder and other factors are less pronounced. PMID- 30441864 TI - A Review on Flexible and Transparent Energy Storage System. AB - Due to the broad application prospect, flexible and transparent electronic device has been widely used in portable wearable devices, energy storage smart window and other fields, which owns many advantages such as portable, foldable, small quality, low-cost, good transparency, high performance and so on. All these electronic devices are inseparable from the support of energy storage device. Energy storage device, like lithium-ion battery and super capacitor, also require strict flexibility and transparency as the energy supply equipment of electronic devices. Here, we demonstrate the development and applications of flexible and transparent lithium-ion battery and super capacitor. In particular, carbon nanomaterials are widely used in flexible and transparent electronic device, due to their excellent optical and electrical properties and good mechanical properties. For example, carbon nanotubes with high electrical conductivity and low density have been widely reported by researchers. Otherwise, graphene as an emerging two-dimensional material with electrical conductivity and carrier mobility attracts comparatively more attention than that of other carbon nanomaterials. Substantial effort has been put on the research for graphene-based energy storage system by researchers from all over the world. But, there is still a long way to accomplish this goal of improving the performance for stretchable and transparent electronic device due to the existing technical conditions. PMID- 30441863 TI - Ethinylestradiol and Levonorgestrel as Active Agents in Normal Skin, and Pathological Conditions Induced by UVB Exposure: In Vitro and In Ovo Assessments. AB - The link between melanoma development and the use of oral combined contraceptives is not fully elucidated, and the data concerning this issue are scarce and controversial. In the present study, we show that the components of oral contraceptives, ethinylestradiol (EE), levonorgestrel (LNG), and their combination (EE + LNG) +/- UVB (ultraviolet B radiation) induced differential effects on healthy (human keratinocytes, fibroblasts, and primary epidermal melanocytes, and murine epidermis cells) and melanoma cells (human-A375 and murine-B164A5), as follows: (i) at low doses (1 uM), the hormones were devoid of significant toxicity on healthy cells, but in melanoma cells, they triggered cell death via apoptosis; (ii) higher doses (10 uM) were associated with cytotoxicity in all cells, the most affected being the melanoma cells; (iii) UVB irradiation proved to be toxic for all types of cells; (iv) UVB irradiation + hormonal stimulation led to a synergistic cytotoxicity in the case of human melanoma cells A375 and improved viability rates of healthy and B164A5 cells. A weak irritant potential exerted by EE and EE + LNG (10 uM) was assessed by the means of a chick chorioallantoic membrane assay. Further studies are required to elucidate the hormones' cell type-dependent antimelanoma effect and the role played by melanin in this context. PMID- 30441865 TI - First-Principles Studies of Adsorptive Remediation of Water and Air Pollutants Using Two-Dimensional MXene Materials. AB - Water and air pollution is a critical issue across the whole world. Two dimensional transition metal carbide/nitride (MXene) materials, due to the characteristics of large specific surface area, hydrophilic nature and abundant highly active surficial sites, are able to adsorb a variety of environmental pollutants, and thus can be used for environmental remediation. First-principles method is a powerful tool to investigate and predict the properties of low dimensional materials, which can save a large amount of experimental costs and accelerate the research progress. In this review, we summarize the recent research progresses of the MXene materials in the adsorptive remediation of environmental pollutants in polluted water and air using first-principles simulations, and try to predict the research direction of MXenes in the adsorptive environmental applications from first-principles view. PMID- 30441867 TI - Study on the Preferred Application-Oriented Index for Mental Fatigue Detection. AB - Most of the research on mental fatigue evaluation has mainly concentrated on some indexes that require sophisticated and large instruments that make the detection of mental fatigue cumbersome, time-consuming, and difficult to apply on a large scale. A quick and sensitive mental fatigue detection index is necessary so that mentally fatigued workers can be alerted in time and take corresponding countermeasures. However, to date, no studies have compared the sensitivity of common objective evaluation indexes. To solve these problems, this study recruited 56 human subjects. These subjects were evaluated using six fatigue indexes: the Stanford sleepiness scale, digital span, digital decoding, short term memory, critical flicker fusion frequency (CFF), and speed perception deviation. The results of the fatigue tests before and after mental fatigue were compared, and a one-way analysis of variance (ANOVA) was performed on the speed perception deviation. The results indicated the significance of this index. Considering individual differences, the relative fatigue index (RFI) was proposed to compare the sensitivity of the indexes. The results showed that when the self rated fatigue grade changed from non-fatigue to mild fatigue, the ranges of RFI values for digital span, digital decoding, short-term memory, and CFF were 0.175 0.258, 0.194-0.316, 0.068-0.139, and 0.055-0.075, respectively. Correspondingly, when the self-rated fatigue grade changed to severe fatigue, the ranges of RFI values for the above indexes were 0.415-0.577, 0.482-0.669, 0.329-0.396, and 0.114-0.218, respectively. These results suggest that the sensitivity of the digital decoding, digital span, short-term memory, and CFF decreased sequentially when the self-evaluated fatigue grade changed from no fatigue to mild or severe fatigue. The RFI individuality of the speed perception deviation is highly variable and is not suitable as an evaluation index. In mental fatigue testing, digital decoding testing can provide faster, more convenient, and more accurate results. PMID- 30441868 TI - THz Spectroscopic Investigation of Wheat-Quality by Using Multi-Source Data Fusion. AB - In order to improve the detection accuracy for the quality of wheat, a recognition method for wheat quality using the terahertz (THz) spectrum and multi source information fusion technology is proposed. Through a combination of the absorption and the refractive index spectra of samples of normal, germinated, moldy, and worm-eaten wheat, support vector machine (SVM) and Dempster-Shafer (DS) evidence theory with different kernel functions were used to establish a classification fusion model for the multiple optical indexes of wheat. The results showed that the recognition rate of the fusion model for wheat samples can be as high as 96%. Furthermore, this approach was compared to the regression model based on single-spectrum analysis. The results indicate that the average recognition rates of fusion models for wheat can reach 90%, and the recognition rate of the SVM radial basis function (SVM-RBF) fusion model can reach 97.5%. The preliminary results indicated that THz-TDS combined with DS evidence theory analysis was suitable for the determination of the wheat quality with better detection accuracy. PMID- 30441869 TI - Detection and Tracking of Moving Targets for Thermal Infrared Video Sequences. AB - The joint detection and tracking of multiple targets from raw thermal infrared (TIR) image observations plays a significant role in the video surveillance field, and it has extensive applied foreground and practical value. In this paper, a novel multiple-target track-before-detect (TBD) method, which is based on background subtraction within the framework of labeled random finite sets (RFS) is presented. First, a background subtraction method based on a random selection strategy is exploited to obtain the foreground probability map from a TIR sequence. Second, in the foreground probability map, the probability of each pixel belonging to a target is calculated by non-overlapping multi-target likelihood. Finally, a delta generalized labeled multi-Bernoulli ( delta -GLMB) filter is employed to produce the states of multi-target along with their labels. Unlike other RFS-based filters, the proposed approach describes the target state by a pixel set instead of a single point. To meet the requirement of factual application, some extra procedures, including pixel sampling and update, target merging and splitting, and new birth target initialization, are incorporated into the algorithm. The experimental results show that the proposed method performs better in multi-target detection than six compared methods. Also, the method is effective for the continuous tracking of multi-targets. PMID- 30441866 TI - Gut Microbiota and Their Neuroinflammatory Implications in Alzheimer's Disease. AB - The bidirectional communication between the central nervous system (CNS) and the gut microbiota plays a pivotal role in human health. Increasing numbers of studies suggest that the gut microbiota can influence the brain and behavior of patients. Various metabolites secreted by the gut microbiota can affect the cognitive ability of patients diagnosed with neurodegenerative diseases. Nearly one in every ten Korean senior citizens suffers from Alzheimer's disease (AD), the most common form of dementia. This review highlights the impact of metabolites from the gut microbiota on communication pathways between the brain and gut, as well as the neuroinflammatory roles they may have in AD patients. The objectives of this review are as follows: (1) to examine the role of the intestinal microbiota in homeostatic communication between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis; (2) to determine the underlying mechanisms of signal dysfunction; and (3) to assess the impact of signal dysfunction induced by the microbiota on AD. This review will aid in understanding the microbiota of elderly people and the neuroinflammatory roles they may have in AD. PMID- 30441871 TI - Outage-Based Resource Allocation for DF Two-Way Relay Networks with Energy Harvesting. AB - A joint resource allocation algorithm to minimize the system outage probability is proposed for a decode-and-forward (DF) two-way relay network with simultaneous wireless information and power transfer (SWIPT) under a total power constraint. In this network, the two sources nodes exchange information with the help of a passive relay, which is assumed to help the two source nodes' communication without consuming its own energy by exploiting an energy-harvesting protocol, the power splitting (PS) protocol. An optimization framework to jointly optimize power allocation (PA) at the source nodes and PS at the relay is developed. Since the formulated joint optimization problem is non-convex, the solution is developed in two steps. First, the conditionally optimal PS ratio at the relay node for a given PA ratio is explored; then, the closed-form of the optimal PA in the sense of minimizing the system outage probability with instantaneous channel state information (CSI) is derived. Analysis shows that the optimal design depends on the channel condition and the rate threshold. Simulation results are obtained to validate the analytical results. Comparison with three existing schemes shows that the proposed optimized scheme has the minimum system outage probability. PMID- 30441872 TI - Small Molecules Enhance Scaffold-Based Bone Grafts via Purinergic Receptor Signaling in Stem Cells. AB - The need for bone grafts is high, due to age-related diseases, such as tumor resections, but also accidents, risky sports, and military conflicts. The gold standard for bone grafting is the use of autografts from the iliac crest, but the limited amount of accessible material demands new sources of bone replacement. The use of mesenchymal stem cells or their descendant cells, namely osteoblast, the bone-building cells and endothelial cells for angiogenesis, combined with artificial scaffolds, is a new approach. Mesenchymal stem cells (MSCs) can be obtained from the patient themselves, or from donors, as they barely cause an immune response in the recipient. However, MSCs never fully differentiate in vitro which might lead to unwanted effects in vivo. Interestingly, purinergic receptors can positively influence the differentiation of both osteoblasts and endothelial cells, using specific artificial ligands. An overview is given on purinergic receptor signaling in the most-needed cell types involved in bone metabolism-namely osteoblasts, osteoclasts, and endothelial cells. Furthermore, different types of scaffolds and their production methods will be elucidated. Finally, recent patents on scaffold materials, as wells as purinergic receptor influencing molecules which might impact bone grafting, are discussed. PMID- 30441873 TI - Mass Transfer Coefficient in Multi-Stage Reformer/Membrane Modules for Hydrogen Production. AB - Hydrogen is a promising energy carrier, and is exploitable to extract energy from fossil fuels, biomasses, and intermittent renewable energy sources and its generation from fossil fuels, with CO2 separation at the source being one of the most promising pathways for fossil fuels' utilization. This work focuses on a particular configuration called the Reformer and Membrane Module (RMM), which alternates between stages of Steam Reforming (SR) reactions with H2 separation stages to overcome the thermodynamic limit of the conventional SR. The configuration has numerous advantages with respect to the more widely studied and tested membrane reactors, and has been tested during a pilot-scale research project. Although numerous modelling works appeared in the literature, the design features of the material exchanger (in the so-called RMM architecture) of different geometrical configurations have not been developed, and the mass transfer correlations, capable of providing design tools useful for such membrane modules, are not available. The purpose of this work is therefore to apply a physical-mathematical model of the mass transfer, in three different geometries, considering both concentration polarization and membrane permeation, in order to: (i) simulate the cited experimental results; (ii) estimate the scaling-up correlations for the "material exchange modules"; and (iii) identify the mass transfer limiting regime in relation to the gas mass flow rate. PMID- 30441870 TI - MiR-375 Regulation of LDHB Plays Distinct Roles in Polyomavirus-Positive and Negative Merkel Cell Carcinoma. AB - MicroRNA-375 (miR-375) is deregulated in multiple tumor types and regulates important targets involved in tumorigenesis and metastasis. This miRNA is highly expressed in Merkel cell carcinoma (MCC) compared to normal skin and other non MCC skin cancers, and its expression is high in Merkel cell polyomavirus (MCPyV) positive (MCPyV+) and low in MCPyV-negative (MCPyV-) MCC tumors. In this study, we characterized the function and target of miR-375 in MCPyV+ and MCPyV- MCC cell lines. Ectopic expression of miR-375 in MCPyV- MCC cells resulted in decreased cell proliferation and migration, as well as increased cell apoptosis and cell cycle arrest. However, in MCPyV+ MCC cells, inhibition of miR-375 expression reduced cell growth and induced apoptosis. Additionally, the expression of lactate dehydrogenase B (LDHB), a known target of miR-375, was inversely correlated with miR-375. Silencing of LDHB reduced cell growth in MCPyV- cell lines, while its silencing in MCPyV+ cell lines rescued the cell growth effect mediated by miR-375 inhibition. Together, our results suggest dual roles of miR 375 and LDHB in MCPyV and non-MCPyV-associated MCCs. We propose that LDHB could be a therapeutic target in MCC and different strategies should be applied in virus- and non-virus-associated MCCs. PMID- 30441874 TI - lncRNA Expression after Irradiation and Chemoexposure of HNSCC Cell Lines. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cause of cancer mortality in the world. To improve the quality of diagnostics and patients' treatment, new and effective biomarkers are needed. Recent studies have shown that the expression level of different types of long non-coding RNAs (lncRNAs) is dysregulated in HNSCC and correlates with many biological processes. In this study, the response of lncRNAs in HNSCC cell lines after exposure to irradiation and cytotoxic drugs was examined. The SCC-040, SCC-25, FaDu, and Cal27 cell lines were treated with different radiation doses as well as exposed to cisplatin and doxorubicin. The expression changes of lncRNAs after exposure to these agents were checked by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Target prediction was performed using available online tools and classified into specific biological processes and cellular pathways. The results indicated that the irradiation, as well as chemoexposure, causes changes in lncRNA expression and the effect depends on the cell line, type of agents as well as their dose. After irradiation using the dose of 5 Gy significant dysregulation of 4 lncRNAs, 10 Gy-5 lncRNAs, and 20 Gy-3 lncRNAs, respectively, were observed in all cell lines. Only lncRNAs Zfhx2as was down-regulated in all cell lines independently of the dose used. After cisplatin exposure, 14 lncRNAs showed lower and only two higher expressions. Doxorubicin resulted in lower expressions of eight and increased four of lncRNAs. Common effects of cytotoxic drugs were observed in the case of antiPEG11, BACE1AS, PCGEM1, and ST7OT. Analysis of the predicted targets for dysregulated lncRNAs indicated that they are involved in important biological processes, regulating cellular pathways connected with direct response to irradiation or chemoexposure, cellular phenotype, cancer initiating cells, and angiogenesis. Both irradiation and chemoexposure caused specific changes in lncRNAs expression. However, the common effect is potentially important for cellular response to the stress and survival. Further study will show if lncRNAs are useful tools in patients' treatment monitoring. PMID- 30441876 TI - Snake Venom Peptides: Tools of Biodiscovery. AB - Nature endowed snakes with a lethal secretion known as venom, which has been fine tuned over millions of years of evolution. Snakes utilize venom to subdue their prey and to survive in their natural habitat. Venom is known to be a very poisonous mixture, consisting of a variety of molecules, such as carbohydrates, nucleosides, amino acids, lipids, proteins and peptides. Proteins and peptides are the major constituents of the dry weight of snake venoms and are of main interest for scientific investigations as well as for various pharmacological applications. Snake venoms contain enzymatic and non-enzymatic proteins and peptides, which are grouped into different families based on their structure and function. Members of a single family display significant similarities in their primary, secondary and tertiary structures, but in many cases have distinct pharmacological functions and different bioactivities. The functional specificity of peptides belonging to the same family can be attributed to subtle variations in their amino acid sequences. Currently, complementary tools and techniques are utilized to isolate and characterize the peptides, and study their potential applications as molecular probes, and possible templates for drug discovery and design investigations. PMID- 30441875 TI - Correlates of Transitions in Tobacco Product Use by U.S. Adult Tobacco Users between 2013-2014 and 2014-2015: Findings from the PATH Study Wave 1 and Wave 2. AB - More than half of adult tobacco users in the United States (U.S.) transitioned in tobacco product use between 2013-2014 and 2014-2015. We examine how characteristics of adult tobacco users in the U.S. relate to transitions in tobacco product use. Population Assessment of Tobacco and Health (PATH) Study data were analyzed from 12,862 adult current tobacco users who participated in Wave 1 (W1, 2013-2014) and Wave 2 (W2, 2014-2015). Three types of transitions were examined-(1) adding tobacco product(s); (2) switching to non-cigarette tobacco product(s); and (3) discontinuing all tobacco use-among those currently using: (1) any tobacco product; (2) cigarettes only (i.e., exclusive cigarette); and (3) cigarettes plus another tobacco product(s) (i.e., poly-cigarette). Multinomial logistic regression analyses determined relative risk of type of transition versus no transition as a function of demographic and tobacco use characteristics. Transitions in tobacco product use among adult tobacco users were common overall, but varied among different demographic groups, including by age, sex, sexual orientation, race/ethnicity, educational attainment, and poverty level. Further, cigarette smokers with higher dependence scores were more likely to add product(s) and less likely to discontinue tobacco use compared to those with low dependence scores. That high nicotine dependence is a barrier to discontinuing tobacco use adds evidence to support policy to lower nicotine content of cigarettes and to evaluate new products for their potential to reduce cigarette use. PMID- 30441877 TI - A Hybrid Approach to Short-Term Load Forecasting Aimed at Bad Data Detection in Secondary Substation Monitoring Equipment. AB - Bad data as a result of measurement errors in secondary substation (SS) monitoring equipment is difficult to detect and negatively affects power system state estimation performance by both increasing the computational burden and jeopardizing the state estimation accuracy. In this paper a short-term load forecasting (STLF) hybrid strategy based on singular spectrum analysis (SSA) in combination with artificial neural networks (ANN), is presented. This STLF approach is aimed at detecting, identifying and eliminating and/or correcting such bad data before it is provided to the state estimator. This approach is developed to improve the accuracy of the load forecasts and it is tested against real power load data provided by electricity suppliers. Depending on the week considered, mean absolute percentage error (MAPE) values which range from 1.6% to 3.4% are achieved for STLF. Different systematic errors, such as gain and offset error levels and outliers, are successfully detected with a hit rate of 98%, and the corresponding measurements are corrected before they are sent to the control center for state estimation purposes. PMID- 30441878 TI - Degradation of Triclosan and Carbamazepine in Two Agricultural and Garden Soils with Different Textures Amended with Composted Sewage Sludge. AB - Composted sewage sludge (CSS) has been extensively used in agriculture and landscaping, offering a practical solution for waste disposal. However, some pharmaceutical and personal care products (PPCPs) like triclosan (TCS) and carbamazepine (CBZ) have restricted its land application. In this study, CSS was added to agricultural soil and garden soil at 0%, 5%, 10%, and 25% (w/w soil), and 4 mL of TCS and CBZ stock solution (1000 mg/L in methanol) was spiked into soil amended with CSS of each bottle to arrive at the concentration of 10 mg/kg. Samples were then collected after incubation for 120 days and analyzed for concentrations and half-life (t1/2) of TCS and CBZ, and soil physicochemical properties, together with enzyme activities. The results showed that TCS was degraded completely during the incubation period. In contrast, only about 5.82 21.43% CBZ was degraded. CSS amendment inhibited TCS and CBZ degradation and prolonged t1/2 compared to the control, and the t1/2 of TCS and CBZ increased with CSS addition amount in all treatments except for CBZ in the garden soil amended with 10% CSS. Correlation studies showed a significantly positive relationship between t1/2 of TCS and CBZ and total organic carbon (TOC), while a significantly negative relationship between t1/2 of the two PPCPs and pH was observed. Alkaline phosphatase showed a significantly negative relationship with the Ct/C0 of TCS in garden soil amended with 25% CSS and CBZ in the control. The urease activity was negatively correlated with the Ct/C0 of TCS in 10% and 25% CSS treatments and CBZ in 10% CSS treatment for garden soil. PMID- 30441879 TI - Thermoplastic PCL-b-PEG-b-PCL and HDI Polyurethanes for Extrusion-Based 3D Printing of Tough Hydrogels. AB - Novel tough hydrogel materials are required for 3D-printing applications. Here, a series of thermoplastic polyurethanes (TPUs) based on poly(E-caprolactone)-b poly(ethylene glycol)-b-poly(E-caprolactone) (PCL-b-PEG-b-PCL) triblock copolymers and hexamethylene diisocyanate (HDI) were developed with PEG contents varying between 30 and 70 mol%. These showed excellent mechanical properties not only when dry, but also when hydrated: TPUs prepared from PCL-b-PEG-b-PCL with PEG of Mn 6 kg/mol (PCL7-PEG6-PCL7) took up 122 wt.% upon hydration and had an E modulus of 52 +/- 10 MPa, a tensile strength of 17 +/- 2 MPa, and a strain at break of 1553 +/- 155% in the hydrated state. They had a fracture energy of 17976 +/- 3011 N/mm2 and a high tearing energy of 72 kJ/m2. TPUs prepared using PEG with Mn of 10 kg/mol (PCL5-PEG10-PCL5) took up 534% water and were more flexible. When wet, they had an E-modulus of 7 +/- 2 MPa, a tensile strength of 4 +/- 1 MPa, and a strain at break of 147 +/- 41%. These hydrogels had a fracture energy of 513 +/- 267 N/mm2 and a tearing energy of 16 kJ/m2. The latter TPU was first extruded into filaments and then processed into designed porous hydrogel structures by 3D-printing. These hydrogels can be used in 3D printing of tissue engineering scaffolds with high fracture toughness. PMID- 30441880 TI - Changing to a Low-Polyphenol Diet Alters Vascular Biomarkers in Healthy Men after Only Two Weeks. AB - Bioactive dietary compounds play a critical role in health maintenance. The relation between bioactive compound intake and cardiovascular health-related biomarkers has been demonstrated in several studies, although mainly with participants who have altered biochemical parameters (high blood pressure, high cholesterol, metabolic syndrome, etc.). The aim of this study was to evaluate if adopting a diet low in polyphenol-rich food for two weeks would affect vascular biomarkers in healthy men. In a crossover study, 22 healthy men were randomly assigned to their usual diet (UD), consuming healthy food rich in polyphenols, or to a low antioxidant diet (LAD), with less than two servings of fruit and vegetables per day and avoiding the intake of cocoa products, coffee and tea. As a marker of compliance, total polyphenols in urine were significantly lower after the LAD than after the UD (79 +/- 43 vs. 123 +/- 58 mg GAE/g creatinine). Nitric oxide levels were also reduced (52 +/- 28 in LAD vs. 80 +/- 34 uM in UD), although no significant changes in cellular adhesion molecules and eicosanoids were observed; however, an increasing ratio between thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) was reached (p = 0.048). Thus, a slight dietary modification, reducing the consumption of polyphenol-rich food, may affect vascular biomarkers even in healthy individuals. PMID- 30441881 TI - Hot Deformation Behavior of Homogenized Mg-13.5Gd-3.2Y-2.3Zn-0.5Zr Alloy via Hot Compression Tests. AB - Mg-Gd-Y-Zn-Zr Mg alloys show excellent performance in high-end manufacturing due to its strength, hardness and corrosion resistance. However, the hot deformation and dynamic recrystallization (DRX) behaviors of Mg-13.5Gd-3.2Y-2.3Zn-0.5Zr were not studied. For this article, hot compression behavior of homogenized high rare earth (RE) content Mg-13.5Gd-3.2Y-2.3Zn-0.5Zr (wt%) alloy was investigated by using the Gleeble-3500D thermo-simulation test machine under the temperature of 350-500 degrees C and the strain rate of 0.001-1 s-1. It was found that the high flow stress corresponded to the low temperature and high strain rate, which showed DRX steady state curve during the hot compression. The hot deformation average activation was 263.17 kJ/mol, which was obtained by the analysis of the hyperbolic constitutive equation and the Zener-Hollomon parameter. From observation of the microstructure, it was found that kink deformation of long period stacking ordered (LPSO) phase was one of the important coordination mechanisms of hot deformation at low temperature. The processing map with the strain of 0.5 was established under the basis of dynamic material model (DMM); it described two high power dissipation domains: one appearing in the temperature range of 370-440 degrees C and the strain rate range of 0.001-0.006 s-1, the other appearing in the temperature range of 465-500 degrees C and strain rate range of 0.001-0.05 s-1, in which dynamic recrystallization (DRX) mainly ocurred. The highest degree of DRX was 18% from the observation of the metallographic. PMID- 30441882 TI - Development of a Highly Active Fluorescence-Based Detector for Yeast G Protein Coupled Receptor Ste2p. AB - Twenty analogs of [Orn6,D-Ala9]alpha-factor were synthesized and assayed for their biological activities: seven analogs of [Orn6,X9]alpha-factor, seven analogs of [X6,D-Ala9]alpha-factor, five analogs of [X5,X6,D-Ala9]alpha-factor, and native alpha-factor (X = amino acids). Their biological activities (halo, gene induction, and affinity) were measured using S. cerevisiae Y7925 and LM102 and compared with those of native alpha-factor (100%). G protein-coupled receptor was expressed in strain LM102 containing pESC-LEU-STE2 vector. [Dap6,D-Ala9]alpha factor with weak halo activity (10%) showed the highest receptor affinity (> 230%) and the highest gene induction activity (167%). [Arg6,D-Ala9]alpha-factor showed the highest halo activity (2,000%). The number of active binding sites per cell (about 20,000 for strain LM102) was determined using a newly-designed fluorescence-based detector, [Arg6,D-Ala9]alpha-factor-Edan, with high sensitivity (12,500-fold higher than the absorption-based detector [Orn6]alpha factor-[Cys]3). PMID- 30441883 TI - Anti-Inflammatory Effect of Asterias amurensis Fatty Acids through NF-kappaB and MAPK Pathways against LPS-Stimulated RAW264.7 Cells. AB - Asterias amurensis (starfish) is a marine organism that is harmful to the fishing industry, but is also a potential source of functional materials. The present study was conducted to analyze the profiles of fatty acids extracted from A. amurensis tissues and their anti-inflammatory effects on RAW264.7 macrophage cells. In different tissues, the component ratios of saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids differed; particularly, polyunsaturated fatty acids such as dihomo-gamma-linolenic acid (20:3n-6) and eicosapentaenoic acid (20:5n-3) were considerably different. In lipopolysaccharide-stimulated RAW264.7 cells, fatty acids from A. amurensis skin, gonads, and digestive glands exhibited anti-inflammatory activities by reducing nitric oxide production and inducing nitric oxide synthase gene expression. Asterias amurensis fatty acids effectively suppressed the expression of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in lipopolysaccharide-stimulated cells. Cyclooxygenase-2 and prostaglandin E2, which are critical inflammation biomarkers, were also significantly suppressed. Furthermore, A. amurensis fatty acids reduced the phosphorylation of nuclear factor-kappaB p-65, p38, extracellular signal-related kinase 1/2, and c-Jun N-terminal kinase, indicating that these fatty acids ameliorated inflammation through the nuclear factor-kappaB and mitogen-activated protein kinase pathways. These results provide insight into the anti-inflammatory mechanism of A. amurensis fatty acids on immune cells and suggest that the species is a potential source of anti-inflammatory molecules. PMID- 30441884 TI - Optimized Expression, Purification, and Rapid Detection of Recombinant Influenza Nucleoproteins Expressed in Sf9 Insect Cells. AB - Accurate and rapid diagnosis of influenza infection is essential to enable early antiviral treatment and reduce the mortality associated with seasonal and epidemic infections. Immunochromatography is one of the most common methods used for the diagnosis of seasonal human influenza; however, it is less effective in diagnosing pandemic influenza virus. Currently, rapid diagnostic kits for pandemic influenza virus rely on the detection of nucleoprotein (NP) or hemagglutinin (HA). NP detection shows higher specificity and is more sensitive than HA detection. In this study, we time-dependently screened expression conditions, and herein report optimal conditions for the expression of recombinant nucleoprotein (rNP), which was 48 h after infection. In addition, we report the use of the expressed rNP in a rapid influenza diagnostic test (SGT i flex Influenza A&B Test). We constructed expression vectors that synthesized rNP (antigen) of influenza A and B in insect cells (Sf9 cells), employed the purified rNP to the immunoassay test kit, and clearly distinguished NPs of influenza A and influenza B using this rapid influenza diagnostic kit. This approach may improve the development of rapid test kits for influenza using NP. PMID- 30441885 TI - Complete Genome of Bacillus subtilis subsp. subtilis KCTC 3135T and Variation in Cell Wall Genes of B. subtilis Strains. AB - The type strain Bacillus subtilis subsp. subtilis KCTC 3135T was deeply sequenced and annotated, replacing a previous draft genome in this study. The tar and tag genes were involved in synthesizing wall teichoic acids (WTAs), and these genes and their products were previously regarded as the distinguishing difference between B. s. subtilis and B. s. spizizenii. However, a comparative genomic analysis of B. subtilis spp. revealed that both B. s. subtilis and B. s. spizizenii had various types of cell walls. These tar and tag operons were mutually exclusive and the tar genes from B. s. spizizenii were very similar to the genes from non-Bacillus bacteria, unlike the tag genes from B. s. subtilis. The results and previous studies suggest that the tar genes and the tag genes are not inherited after subspecies speciation. The phylogenetic tree based on whole genome sequences showed that each subspecies clearly formed a monophyletic group, while the tree based on tar genes showed that monophyletic groups were formed according to the cell wall type rather than the subspecies. These findings indicate that the tar genes and the presence of ribitol as a cell-wall constituent were not the distinguishing difference between the subspecies of B. subtilis and that the description of subspecies B. s. spizizenii should be updated. PMID- 30441886 TI - Erratum to: Outer Membrane Vesicles Derived from Salmonella Enteritidis Protect against the Virulent Wild-Type Strain Infection in a Mouse Model. AB - This erratum is being published to correct the error of Fig. 1B in page 1522. The previous Fig. 1B should be replaced with the below new Fig. 1B. The corrected version of this article is available in the Archive (http://jmb.or.kr). PMID- 30441887 TI - Association between Body Fat and Bone Mineral Density in Normal-Weight Middle Aged Koreans. AB - Background: Osteoporosis and osteopenia are characterized by reduced bone mineral density (BMD) and increased fracture risk. Although the risk of fractures is higher in underweight people than in overweight people, the accumulation of body fat (especially abdominal fat) can increase the risk of bone loss. This study aimed to evaluate the association between body fat percentage and BMD in normal weight middle-aged Koreans. Methods: This study included 1,992 adults (mean age, 48.7 years; 52.9% women). BMD and body fat were measured using dual-energy X-ray absorptiometry. Multiple linear regression analyses and analysis of covariance were used to assess the association between BMD and body fat. Body fat percentage was grouped by cut-off values. The cut-off values were 20.6% and 25.7% for men with a body mass index of 18.5-22.9 kg/m2 , while the cut-off values were 33.4% and 36% for women. Results: Body fat percentage tended to be negatively associated with BMD. Increased body fat percentage was associated with reduced BMD in normal-weight middle-aged adults. The effects of body fat percentage on BMD in normal-weight individuals were more pronounced in men than in women. Conclusion: There was a negative correlation between BMD and body fat percentage in middle-aged Korean men and women with normal body weight. This association was stronger in men than in women. PMID- 30441888 TI - Capsule Endoscopy in Refractory Diarrhea-Predominant Irritable Bowel Syndrome and Functional Abdominal Pain. AB - BACKGROUND/AIMS: Capsule endoscopy is a diagnostic method for evaluating the small bowel lumen and can detect undiagnosed lesions. The aim of this study was to evaluate the diagnostic yield and clinical impact of capsule endoscopy in patients with refractory diarrhea-predominant irritable bowel syndrome and functional abdominal pain. METHODS: This study involved a retrospective analysis of prospectively collected data, maintained in a database. Patients with refractory diarrhea-predominant irritable bowel syndrome and functional abdominal pain within the period of March 2012 to March 2014 were included. Capsule endoscopy was used to detect small bowel pathologies in both groups. RESULTS: Sixty-five patients (53.8% female) fulfilled the inclusion criteria and had a mean (+/-standard deviation) age of 50.9+/-15.9 years. Clinically significant lesions were detected via capsule endoscopy in 32.5% of the patients in the abdominal pain group and 54.5% of the patients in the diarrhea group. Overall, 48% of patients had small bowel pathologies detected during the capsule endoscopy study. Inflammatory lesions and villous atrophy were the most frequent lesions identified in 16.9% and 15.3% of patients in the abdominal pain and the diarrhea groups, respectively. CONCLUSION: Routine use of capsule endoscopy in patients with irritable bowel syndrome should not be recommended. However, in patients with refractory conditions, capsule endoscopy may identify abnormalities. PMID- 30441889 TI - Radiomics and radiogenomics of primary liver cancers. AB - Concurrent advancements in imaging and genomic biomarkers have created opportunities to identify non-invasive imaging surrogates of molecular phenotypes. In order to develop such imaging surrogates radiomics and radiogenomics/imaging genomics will be necessary; there has been consistent progress in these fields for primary liver cancers. In this article we evaluate the current status of the field specifically with regards to hepatocellular carcinoma and intrahepatic cholangiocarcinoma, highlighting some of the up and coming results that were presented at the annual Radiological Society of North America Conference in 2017. There are an increasing number of studies in this area with a bias towards quantitative feature measurement, which is expected to benefit reproducibility of the findings and portends well for the future development of biomarkers for diagnosis, prognosis, and treatment response assessment. We review some of the advancements and look forward to some of the exciting future applications that are anticipated as the field develops. PMID- 30441890 TI - Regioselective Nucleophilic Alkylation/Arylation of B-H Bonds in o-Carboranes: An Alternative Method for Selective Cage Boron Functionalization. AB - A new protocol for regioselective nucleophilic cage B-H substitution in o carboranes has been proposed that is complementary to the strategies of transition metal catalysis and electrophilic substitution. Magnesium-mediated site-selective nucleophilic cage B(3,6)-H and B(9)-H substitution reactions of o carboranes give a series of B(3,6)-dialkylated and B(9)-alkylated/arylated o carboranes in high yields. Both steric and electronic factors of cage C substituents play crucial roles in controlling the site selectivity. PMID- 30441891 TI - Efficient Hydrolysis of Raw Microalgae Starch by an alpha-Amylase (AmyP) of Glycoside Hydrolase Subfamily GH13_37. AB - Microalgae starch is receiving increasing attention as a renewable feedstock for biofuel production. Raw microalgae starch from Tetraselmis subcordiformis was proven to be very efficiently hydrolyzed by an alpha-amylase (AmyP) of glycoside hydrolase subfamily GH13_37 below the temperature of gelatinization (40 degrees C). The hydrolysis degree reached 74.4 +/- 2.2% for 4% raw microalgae starch and 53.2 +/- 1.7% for 8% raw microalgae starch after only 2 h. The hydrolysis efficiency was significantly stimulated by calcium ions. The enzyme catalysis of AmyP and its mutants (Q306A and E347A) suggested that calcium ions contributed to the hydrolysis of cyclic structures in raw microalgae starch by a distinctive calcium-binding site Ca2 of AmyP. The study explored raw microalgae starch as a new resource for cold enzymatic hydrolysis and extended our knowledge on the function of calcium in amylolytic enzyme. PMID- 30441892 TI - Selective Labeling Aldehydes in DNA. AB - A naphthalimide hydroxylamine probe has been designed and synthesized to selectively label the whole natural aldehydes present in DNAs including 5 formylcytosine, 5-formyluracil, and abasic sites. The fluorescence characteristics of the generated nucleosides have been examined in detail, and the reaction activities of hydroxylamine, amine groups toward aldehydes in DNA have been discussed with others, which will be a vital reference for designing chemicals for selective labeling of DNAs. PMID- 30441893 TI - Chemoselective and Highly Rate Accelerated Intramolecular Aza-Morita-Baylis Hillman Reaction. AB - Despite being a very useful C-C bond forming and highly applicative reaction, Morita-Baylis-Hillman (MBH) reaction has been limited by its excessive slow reaction rate, including its intramolecular version. In certain cases, reaction time may even go to weeks and months. A highly chemoselective and rate accelerated intramolecular MBH reaction of just 15 min has been developed. The product dihydroquinoline, being unstable, was converted to an important quinoline framework. In some cases IMBH adducts were isolable, thus confirming the reaction path. Control experiments toward mechanism investigation have been carried out. Use of sodium sulfide has emerged as a rate accelerating catalyst in DMF-EtOH solvent system. Reaction intermediate for IMBH pathway was isolated and characterized. Other aspects such as the application of IMBH adduct for Michael addition and amidation have also been carried out. PMID- 30441894 TI - In Silico Screening of Comprehensive Two-Dimensional Centrifugal Partition Chromatography * Liquid Chromatography for Multiple Compound Isolation. AB - Isolation of unknown compounds for structural identification and the collection of target molecules to generate unavailable standards remain a challenge when dealing with complex samples. While tedious multistep purification is commonly used, it is not appropriate for a limited amount of sample or when a full recovery of expensive molecules is required. Two-dimensional preparative chromatography in a comprehensive mode provides an effective means to collect a large number of molecules in such a case. However, there is currently a lack of metrics to estimate preparative performances with a minimal number of experiments. An in silico comparative study of various pairs of chromatographic systems is proposed, focusing on the occupation rate and the homogeneity of peak spreading in the 2D separation space. Off-line combination of centrifugal partition chromatography (CPC) with liquid chromatography (LC) exhibits numerous advantages for 2D preparative separation. Our in silico approach was illustrated through the isolation of eight bioactive compounds with very similar structures from Cyclopia genistoides plant by CPC*LC. The column screening was performed considering predictive 2D plots in light of the preparative performance descriptors and compared to real 2D preparative separations. PMID- 30441895 TI - Distinction Between Active and Passive Targeting of Nanoparticles Dictate Their Overall Therapeutic Efficacy. AB - The role of nanoparticles in cancer medicine is vast with debate still surrounding the distinction between therapeutic efficacy of actively targeted nanoparticles versus passively targeted systems for drug delivery. While it is commonly accepted that methodologies that result in homing a high concentration of drug loaded nanoparticles to the tumor is beneficial, the role of intracellular trafficking of these nanoparticles in dictating the overall therapeutic outcome remains unresolved. Herein we demonstrate that the therapeutic outcome of drug loaded nanoparticles is governed beyond simply enabling nanoparticle internalization in cells. Using two model polymeric nanoparticles, one decorated with the GE11 peptide for active targeting of the epidermal growth factor receptor (EGFR) and the other without, we demonstrate that EGFR mediated intracellular internalization results in an enhanced therapeutic effect compared to the nontargeted formulation. Our findings demonstrate that the intracellular destination of nanoparticles beyond its ability to internalize is an important parameter that has to be accounted for in the design of targeted drug delivery systems. PMID- 30441896 TI - Identification of Stabilizing High-Valent Active Sites by Operando High-Energy Resolution Fluorescence-Detected X-ray Absorption Spectroscopy for High Efficiency Water Oxidation. AB - Composite electrocatalysts have exhibited high activities toward water electrolysis, but the catalytically active sites really in charge of the reaction are still debatable while the conventional in situ X-ray spectroscopies are not capable of conclusively identifying the interaction of these materials with the electrolyte because of the complexity of catalysis. In this work, by utilization of operando Kbeta1,3 high-energy resolution fluorescence-detected X-ray absorption spectroscopy (HERFD-XAS) with a small incident angle, the operando quadrupole transition obviously showed that oxygen directly interacted with 3d orbitals of Co ions rather than that of Fe ions. Most importantly, Fe ions can promote the stabilization of the Co ions under a higher valent state during water oxidation, which may lead to a stable intermediate of reactant and its superior intrinsic activity. Accompanied by the first-principle calculations, the intermediates between 3d orbitals for surface Co ions and O 2p orbitals for the attaching hydroxide ions were ascribed to this orbital hybridization. Because of the unvaried structural features in conventional in situ techniques, operando HERFD-XAS revealed the remarkable change of chemical status to correlate with the orbital interaction rather than with the structural variation. This operando HERFD-XAS approach corresponding to the local orbital interaction in reactant/catalyst interface can potentially offer synergetic strategies toward realizing the chemical reactions or reaction pathways in various fields. PMID- 30441897 TI - Nucleic Acid Strand Displacement with Synthetic mRNA Inputs in Living Mammalian Cells. AB - Strand displacement reactions are widely used in DNA nanotechnology as a building block for engineering molecular computers and machines. Here, we demonstrate that strand displacement-based probes can be triggered by RNA expressed in mammalian cells, thus taking a step toward adapting the DNA nanotechnology toolbox to a cellular environment. We systematically compare different probe architectures in order to identify a design that works robustly in living cells. Our optimized strand displacement probe combines chemically modified nucleic acids that enhance stability to degradation by cellular nucleases with structural elements that improve probe retention in the cytoplasm. We visualize probe binding to individual mRNA carrying 96 repeats of a target sequence in the 3'UTR. We find that RNA counts based on live cell imaging using a strand displacement probe are comparable to counts from independent measurement based on fluorescence in situ hybridization experiments. We used probes with scrambled toeholds and scrambled binding domains to demonstrate that target recognition indeed occurs through toehold-mediated strand displacement. Our results demonstrate that strand displacement probes can work reliably in mammalian cells and lay the groundwork for future applications of such probes for live-cell imaging and molecular computing. PMID- 30441898 TI - Pressure Stabilization of Criegee Intermediates Formed from Symmetric trans Alkene Ozonolysis. AB - We explore the pressure dependence of a stabilized Criegee Intermediate (sCI) formation from a sequence of trans-alkene ozonolysis reactions. To study the effect of carbon chain length on the stabilization, we select five symmetric trans-alkenes ranging from trans-2-butene (C4) through trans-7-tetradecene (C14). We measure the pressure falloff curves for each alkene from 50 to 900 Torr in a flow reactor using conversion of SO2 to H2SO4 with and without an OH scavenger, and subsequent detection of H2SO4 with a nitrate chemical ionization mass spectrometer to constrain sCI yields. As the length of the carbon chain increases, we observe a systematic increase in Criegee Intermediate stabilization at a given pressure, along with a systematic decrease in the low-pressure limit. Our results also suggest that for these symmetrical systems the anticonformer of the Criegee Intermediate stabilizes before (at lower pressure than) the syn conformer. PMID- 30441899 TI - Au(I)-Catalyzed Access to 1 H-Pyrrolo[1,2- a]indol-2(3- H)-ones via Oxidation of Terminal Alkynes. AB - A facile gold-catalyzed oxidation of terminal alkynes for the construction of 1 H pyrrolo[1,2- a]indol-2(3- H)-ones is reported. Under relatively simple procedures, various 1 H-pyrrolo[1,2- a]indol-2(3- H)-ones derivatives were obtained in good to excellent yields, thus providing an efficient route for the construction of 1 H-pyrrolo[1,2- a]indol-2(3- H)-ones derivatives. PMID- 30441900 TI - Metal-Air Transistors: Semiconductor-Free Field-Emission Air-Channel Nanoelectronics. AB - Scattering-free transport in vacuum tubes has always been superior to solid-state transistors. It is the advanced fabrication with mass production capability at low cost which drove solid-state nanoelectronics. Here, we combine the best of vacuum tubes with advanced nanofabrication technology. We present nanoscale, metal-based, field emission air channel transistors. Comparative analysis of tungsten-, gold-, and platinum-based devices is presented. Devices are fabricated with electron beam lithography, achieving channel lengths less than 35 nm. With this small channel length, vacuum-like carrier transport is possible in air under room temperature and pressure. Source and drain electrodes have planar, symmetric, and sharp geometry. Because of this, devices operate in bidirection with voltages <2 V and current values in few tens of nanoamperes range. The experimental data shows that influential operation mechanism is Fowler-Nordheim tunnelling in tungsten and gold devices, while Schottky emission in platinum device. The presented work enables a technology where metal-based switchable nanoelectronics can be created on any dielectric surface with low energy requirements. PMID- 30441901 TI - Conformal Hydrogel Coatings on Catheters To Reduce Biofouling. AB - Reducing biofouling while increasing lubricity of inserted medical catheters is highly desirable to improve their comfort, safety, and long-term use. We report here a simple method to create thin (~30 MUm) conformal lubricating hydrogel coatings on catheters. The key to this method is a three-step process including shape-forming, gradient cross-linking, and swell-peeling (we label this method as SGS). First, we took advantage of the fast gelation of agar to form a hydrogel layer conformal to catheters; then, we performed a surface-bound UV cross-linking of acrylamide mixed in agar in open air, purposely allowing gradual oxygen inhibition of free radicals to generate a gradient of cross-linking density across the hydrogel layer; and finally, we caused the hydrogel to swell to let the non-cross-linked/loosely attached hydrogel fall off, leaving behind a surface bound, thin, and mostly uniform hydrogel coating. This method also allowed easy incorporation of different polymerizable monomers to obtain multifunctionality. For example, incorporating an antifouling, zwitterionic moiety sulfobetaine in the hydrogel reduced both in vitro protein adsorption and in vivo foreign-body response in mice. The addition of a biocidal N-halamine monomer to the hydrogel coating deactivated both Staphylococcus aureus ( S. aureus) and Escherichia coli ( E. coli) O157:H7 within 30 min of contact and reduced biofilm formation by 90% compared to those of uncoated commercial catheters when challenged with S. aureus for 3 days. The lubricating, antibiofouling hydrogel coating may bring clinical benefits in the use of urinary and venous catheters as well as other types of medical devices. PMID- 30441902 TI - Sequence-Dependent Effects of Monovalent Cations on the Structural Dynamics of Trinucleotide-Repeat DNA Hairpins. AB - Repetitive trinucleotide DNA sequences at specific genetic loci are associated with numerous hereditary, neurodegenerative diseases. The propensity of single stranded domains containing these sequences to form secondary structure via extensive self-complementarity disrupts normal DNA processing to create genetic instabilities. To investigate these intrastrand structural dynamics, a DNA hairpin system was devised for single-molecule fluorescence study of the folding kinetics and energetics for secondary structure formation between two interacting, repetitive domains with specific numbers of the same trinucleotide motif (CXG), where X = T or A. Single-molecule FRET (smFRET) data show discrete conformational transitions between unstructured and closed hairpin states. The lifetimes of the closed hairpin states correlate with the number of repeats, with (CTG)N:(CTG)N domains maintaining longer-lived, closed states than equivalent sized (CAG)N:(CAG)N domains. NaCl promotes similar degree of stabilization for the closed hairpin states of both repeat sequences. Temperature-based, smFRET experiments reveal that NaCl favors hairpin closing for (CAG)N:(CAG)N by pre ordering single-stranded repeat domains to accelerate the closing transition. In contrast, NaCl slows the opening transition of CTG hairpins; however, it promotes misfolded conformations that require unfolding. Energy diagrams illustrate the distinct folding pathways of (CTG)N and (CAG)N repeat domains and identify features that may contribute to their gene-destabilizing effects. PMID- 30441903 TI - Ion-Specific Hydration States of Zwitterionic Poly(sulfobetaine methacrylate) Brushes in Aqueous Solutions. AB - The ion-specific hydration states of zwitterionic poly(3-(N-2 methacryloyloxyethyl-N,N-dimethyl)ammonatopropane sulfonate) (PMAPS) brushes in various aqueous solutions were investigated by neutron reflectivity (NR) and atomic force microscopy (AFM). The asymmetric hydration state of the PMAPS brushes was verified from the NR scattering-length density profiles, while the variation in their swollen thickness was complementary determined from AFM topographic images. The extent of swelling and the dimensions of swollen chain structure in the PMAPS brushes were dependent on the ion species and salt concentration in the solutions. Anion specificity was clearly observed, whereas cations exhibited weaker modulation in ion-specific hydration states. The anion specificity could be ascribed to ion-specific interactions between the quaternary ammonium cation in sulfobetaine and the anions. The weak cation specificity was attributed to the intrinsically weak cohesive interactions between the weakly hydrated sulfonate anion in sulfobetaine and the strongly hydrated cations. The ion-specific hydration of PMAPS brushes was largely consistent with the ion specific aggregation state of the PMAPS chains in aqueous solutions. PMID- 30441904 TI - Hydration and Ionic Conductivity of Model Cation and Anion-Conducting Ionomers in Buffer Solutions (Phosphate, Acetate, Citrate). AB - We studied the gravimetric and volumetric water uptake and ionic conductivity of two model ionomers, cation-conducting sulfonated poly(ether ether ketone) (SPEEK) and anion-conducting polysulfone-trimethylammonium chloride (PSU-TMA), after immersion in phosphate, acetate, and citrate buffer solutions. The equilibrium swelling of SPEEK and PSU-TMA ionomer networks was determined as a function of the pH and buffer composition. The hydration data can be interpreted using the osmotic swelling pressure dependence on the ion-exchange capacity of the ionomers and the concentration of the electrolyte solutions. In the case of SPEEK, anisotropic swelling is observed in diluted buffer solutions, where the swelling pressure is higher. The large water uptake observed for citrate ions is due to the large hydration of this bulky anion. The ionic conductivity is related to the conducting ions and, in the case of SPEEK, to sorbed excess electrolyte. The highest ionic conductivity is observed after immersion in phosphate buffers. Ionic cross-linking is, for the first time, observed in the case of an anion conducting ionomer in the presence of divalent citrate ions, which limits the volumetric swelling and decreases the ionic conductivity of PSU-TMA. PMID- 30441905 TI - Effect of Composition and Molecular Structure of Poly(l-lactic acid)/Poly(ethylene oxide) Block Copolymers on Micellar Morphology in Aqueous Solution. AB - The effect of the hydrophobic block length in diblock (PLLA x- b-PEO113, x = 64, 166, 418) and triblock (PLLA y- b-PEO91- b-PLLA y, y = 30, 52, 120) copolymers of l-lactic acid and ethylene oxide on the structure of micelles prepared by dialysis was studied by wide- and small-angle X-ray scattering in dilute aqueous solution, dynamic light scattering, transmission electron microscopy, atomic force microscopy, and force spectroscopy. It was found that the size of the crystalline PLLA core is weakly dependent on the PLLA block length. In addition to individual micelles, a number of their micellar clusters were detected with characteristic distance between adjacent micelle cores decreasing with an increase in PLLA block length. This effect was explained by the change in the conformation of PEO chains forming the micellar corona because of their overcrowding. Force spectroscopy experiments also reveal a more stretched conformation of the PEO chains for the block copolymers with a shorter PLLA block. A model describing the structure of the individual micelles and their clusters was proposed. PMID- 30441906 TI - Minireview: Laser-Induced Formation of Microbubbles-Biomedical Implications. AB - Recent work is summarized that shows how microbubbles may have potential utility in biomedical situations as (i) highly localized generators of intense white light in an aqueous environment, (ii) disruptors of matter in aqueous solution, (iii) essential precursors in laser-writing structures on substrates on which biological cells can be spatially aligned, and (iv) mediators in the fabrication of hierarchical nanostructures that enhance signals in biological Raman spectroscopy. Indeed, microbubbles generated upon laser irradiation of surfaces have many more ramifications than originally thought, with implications in the laser modification of surfaces producing either hydrophilicity or hydrophobicity. Many more possibilities remain to be explored and exploited. PMID- 30441907 TI - Engineering Improved Photoswitches for the Control of Nucleocytoplasmic Distribution. AB - Optogenetic techniques use light-responsive proteins to study dynamic processes in living cells and organisms. These techniques typically rely on repurposed naturally occurring light-sensitive proteins to control subcellular localization and activity. We previously engineered two optogenetic systems, the light activated nuclear shuttle (LANS) and the light-inducible nuclear exporter (LINX), by embedding nuclear import or export sequence motifs into the C-terminal helix of the light-responsive LOV2 domain of Avena sativa phototropin 1, thus enabling light-dependent trafficking of a target protein into and out of the nucleus. While LANS and LINX are effective tools, we posited that mutations within the LOV2 hinge-loop, which connects the core PAS domain and the C-terminal helix, would further improve the functionality of these switches. Here, we identify hinge-loop mutations that favorably shift the dynamic range (the ratio of the on- to off-target subcellular accumulation) of the LANS and LINX photoswitches. We demonstrate the utility of these new optogenetic tools to control gene transcription and epigenetic modifications, thereby expanding the optogenetic "tool kit" for the research community. PMID- 30441908 TI - sdAb-DB: The Single Domain Antibody Database. AB - The Single Domain Antibody Database, or sdAb-DB, ( www.sdab-db.ca ) is the first freely available repository for single domain antibodies and related classes of proteins. Due to their small size, modular structure, and ease of expression, single domain antibodies (sdAb) have a wide range of applications, including as a rational design tool, and are therefore of great interest for synthetic biologists and bioengineers. However, to enable effective use and sharing of existing sdAbs, including those with engineered functions ( e.g., fusions with fluorescent proteins), as well as the rational design and engineering of new sdAbs, it is necessary to have access to sequences and experimental data. We have therefore developed a publicly available, sdAb-focused database, providing access to manually curated sdAb data from protein databases, published scientific articles, and user submissions. The sdAb-DB is an open-source repository and sharing platform for the sdAb community, providing access to performance data and basic bioinformatic tools for use with previously described and validated sdAbs, as well as for the engineering of new sdAb-based designs and proteins. PMID- 30441910 TI - In This Issue, Volume 13, Issue 11. PMID- 30441911 TI - Experimental and theoretical studies of the Xe-OH(A/X) quenching system. AB - New multi-reference, global ab initio potential energy surfaces (PESs) are reported for the interaction of Xe atoms with OH radicals in their ground X2Pi and excited A2Sigma+ states, together with the non-adiabatic couplings between them. The 2A' excited potential features a very deep well at the collinear Xe-OH configuration whose minimum corresponds to the avoided crossing with the 1A' PES. It is therefore expected that, as with collisions of Kr + OH(A), electronic quenching will play a major role in the dynamics, competing favorably with rotational energy transfer within the 2A' state. The surfaces and couplings are used in full three-state surface-hopping trajectory calculations, including roto electronic couplings, to calculate integral cross sections for electronic quenching and collisional removal. Experimental cross sections, measured using Zeeman quantum beat spectroscopy, are also presented here for comparison with these calculations. Unlike similar previous work on the collisions of OH(A) with Kr, the surface-hopping calculations are only able to account qualitatively for the experimentally observed electronic quenching cross sections, with those calculated being around a factor of two smaller than the experimental ones. However, the predicted total depopulation of the initial rovibrational state of OH(A) (quenching plus rotational energy transfer) agrees well with the experimental results. Possible reasons for the discrepancies are discussed in detail. PMID- 30441912 TI - Communication: Substantial impact of the orientation of transition dipole moments on the dynamics of diatomics in laser fields. AB - The formation of light-induced conical intersections (LICIs) between electronic states of diatomic molecules has been thoroughly investigated over the past decade. In the case of running laser waves, the rotational, vibrational, and electronic motions couple via the LICI giving rise to strong nonadiabatic phenomena. In contrast to natural conical intersections (CIs) which are given by nature and hard to manipulate, the characteristics of LICIs are easily modified by the parameters of the laser field. The internuclear position of the created LICI is determined by the laser energy, while the angular position is given by the orientation of the transition dipole moment (TDM) with respect to the molecular axis. In the present communication, using MgH+ as a showcase example, we exploit the strong impact of the orientation of the TDMs exerted on the light induced nonadiabatic dynamics. Comparing the photodissociations induced by parallel or perpendicular transitions, a clear signature of the created LICIs is revealed in the angular distribution of the photofragments. PMID- 30441913 TI - Explicitly correlated Gaussian functions with shifted-center and projection techniques in pre-Born-Oppenheimer calculations. AB - Numerical projection methods are elaborated for the calculation of eigenstates of the non-relativistic many-particle Coulomb Hamiltonian with selected rotational and parity quantum numbers employing shifted explicitly correlated Gaussian functions, which are, in general, not eigenfunctions of the total angular momentum and parity operators. The increased computational cost of numerically projecting the basis functions onto the irreducible representations of the three dimensional rotation-inversion group is the price to pay for the increased flexibility of the basis functions. This increased flexibility allowed us to achieve a substantial improvement for the variational upper bound to the Pauli allowed ground-state energy of the H3+={p+,p+,p+,e-,e-} molecular ion treated as an explicit five-particle system. We compare our pre-Born-Oppenheimer result obtained for this molecular ion with rotational-vibrational calculations carried out on a potential energy surface. PMID- 30441914 TI - Erratum: "Molecular nitrogen-N2 properties: The intermolecular potential and the equation of state" [J. Chem. Phys. 126, 194501 (2007)]. PMID- 30441915 TI - Field-theoretic simulations of bottlebrush copolymers. AB - Traditional particle-based simulations struggle with large bottlebrush copolymers, consisting of many side chains grafted to a backbone. Field theoretical simulations (FTS) allow us to overcome the computational demands in order to calculate their equilibrium behavior. We consider bottlebrushes where all grafts are symmetric diblock copolymers, focusing on the order-disorder transition (ODT) and the size of ordered domains. Increasing the number of grafts and decreasing the spacing between them both raise the transition temperature. The ODT and lamellar period asymptotically approach constants as the number of grafts increases. As the spacing between grafts becomes large, the bottlebrushes behave like diblock copolymers, and as it becomes small, they behave like starblock copolymers. In between, the period increases, reaching a maximum when the spacing is approximately 0.35 times the length of the grafts. A comparison of FTS with mean-field calculations allows us to assess the effect of compositional fluctuations. Fluctuations suppress ordering, while having little effect on the period, as is the case for diblock copolymers. PMID- 30441916 TI - Reduced scaling Hilbert space variational Monte Carlo. AB - We show that for both single-Slater-Jastrow and Jastrow geminal power wave functions the formal cost scaling of Hilbert space variational Monte Carlo can be reduced from fifth to fourth order in the system size, thus bringing it in line with the long-standing scaling of its real space counterpart. While traditional quantum chemistry methods can reduce costs related to the two-electron integral tensor through various tensor decomposition methods, we show that such approaches are ineffective in the presence of Hilbert space Jastrow factors. Instead, we develop a simple semi-stochastic approach that can take similar advantage of the near-sparsity of this four-index tensor. Through demonstrations on alkanes of increasing length, we show that accuracy and overall statistical uncertainty are not meaningfully affected and that a total cost crossover is reached as early as 50 electrons when using a minimal basis. Further study will be needed to assess where the crossover occurs in more compact molecular geometries and larger basis sets and to explore how in that context the crossover can be accelerated. PMID- 30441917 TI - Accurate prediction of nuclear magnetic resonance shielding constants: An extension of the focal-point analysis method for magnetic parameter calculations (FPA-M) with improved efficiency. AB - Previously, we have proposed a method, FPA-M, for focal-point analysis of magnetic parameter calculations [Sun et al., J. Chem. Phys. 138, 124113 (2013)], where the shielding constants at equilibrium geometries sigmae are calculated with the second order Moller-Plesset perturbation (MP2) approach, which are extrapolated to the complete basis set (CBS) limit and then augmented by the [sigmae(CCSD(T)) - sigmae(MP2)] difference at a valence triple-zeta (VTZ) basis set, where CCSD(T) stands for the coupled cluster singles and doubles model with a perturbative correction for triple excitations. This FPA-M(MP2) method provides satisfactory results to approach to the corresponding CCSD(T)/CBS values for elements of the first two rows in the periodic tables. A series of extensions have been explored here, which replace the MP2/CBS with the Hartree-Fock (HF)/CBS for efficiency. In particular, the [sigmae(CCSD(T)) - sigmae(MP2)] VTZ difference is replaced by a step-wise correction from the [sigmae(CCSD(T)) - sigmae(MP2)] difference at a valence double-zeta basis set plus the [sigmae(MP2) - sigmae(HF)] VTZ difference, leading to a new scheme, denoted here as FPA-M(HF'). A systematical comparison has demonstrated that the FPA-M(HF') method provides an excellent balance between accuracy and efficiency, which makes routinely accurate calculations of the shielding constants for medium-sized organic molecules and biomolecules feasible. PMID- 30441918 TI - Quantifying conformations of ester vibrational probes with hydrogen-bond-induced Fermi resonances. AB - Solvatochromic shifts of local vibrational probes report on the strength of the surrounding electric fields and the probe's hydrogen bonding status. Stretching vibrational mode of the ester carbonyl group is a popular solvatochromic reporter used in the studies of peptides and proteins. Small molecules, used to calibrate the response of the vibrational probes, sometimes involve Fermi resonances (FRs) induced by inter-molecular interactions. In the present work, we focus on the scenario where FR does not appear in the infrared spectrum of the ester carbonyl stretching mode in aprotic solvents; however, it is intensified when a hydrogen bond with the reporter is established. When two molecules form hydrogen bonds to the same carbonyl oxygen atom, FR leads to strong hybridization of the involved modes and splitting of the absorption peak. Spectral overlap between the Fermi doublets associated with singly and doubly hydrogen-bonded carbonyl groups significantly complicates quantifying different hydrogen-bonded conformations. We employed a combination of linear and third-order (2DIR) infrared spectroscopy with chemometrics analysis to reveal the individual line shapes and to estimate the occupations of the hydrogen-bonded conformations in methyl acetate, a model small molecule. We identified a hydrogen-bond-induced FR in complexes of methyl acetate with alcohols and water and found that FR is lifted in larger molecules used for control experiments-cholesteryl stearate and methyl cyanoacetate. Applying this methodology to analyze acetonitrile-water solutions revealed that when dissolved in neat water, methyl acetate occupies a single hydrogen-bonding conformation, which is in contrast to the conclusions of previous studies. Our approach can be generally used when FRs prevent direct quantification of the hydrogen bonding status of the vibrational probe. PMID- 30441919 TI - Graph theory for automatic structural recognition in molecular dynamics simulations. AB - Graph theory algorithms have been proposed in order to identify, follow in time, and statistically analyze the changes in conformations that occur along molecular dynamics (MD) simulations. The atomistic granularity level of the MD simulations is maintained within the graph theoric algorithms proposed here, isomorphism is a key component together with keeping the chemical nature of the atoms. Isomorphism is used to recognize conformations and construct the graphs of transitions, and the reduction in complexity of the isomorphism has been achieved by the introduction of "orbits" and "reference snapshots." The proposed algorithms are applied to MD trajectories of gas phase molecules and clusters as well as condensed matter. The changes in conformations followed over time are hydrogen bond(s), proton transfer(s), coordination number(s), covalent bond(s), multiple fragmentation(s), and H-bonded membered rings. The algorithms provide an automatic analysis of multiple trajectories in parallel, and can be applied to ab initio and classical MD trajectories alike, and to more coarse grain representations. PMID- 30441920 TI - Low scaling EOM-CCSD and EOM-MBPT(2) method with natural transition orbitals. AB - A low-scaling method is presented for the equation-of-motion coupled-cluster theory with single and double (EOM-CCSD) excitations and its second-order many body perturbation theory [EOM-MBPT(2)] approximations. For a simple description of an excited state, the particular orbitals, phiI and phiA , are selected from the natural transition orbitals (NTOs, phi ), where I and A refer to NTO occupied and virtual orbital indices. They are chosen based on the largest eigenvalues of the transition density matrix. We expect the phiI and phiA pair to be dominant in representing excited states in EOM calculations. Therefore, the double excitation vector, R 2 which scale as ~O 2 V 2, can be modified to keep only a few dominant excitations. Our work indicates that the most important contributions of the R 2 vector define smaller subspaces that scale as ~OV, ~O 2 V, and ~OV 2, where O and V refer to the occupied and virtual orbitals in the NTO basis. Thus, the scaling for the EOM part becomes ~M 5. The energy changes due to R 2 truncation are small (the mean average deviation from untruncated EOM-CCSD is ~0.03 eV). We show that this approach works relatively well with various types of NTOs, ranging from configuration singles to time-dependent density functional theory making ~M 5 scaling calculations possible with the use of MBPT(2) as the reference state. PMID- 30441921 TI - Dissipative particle dynamics simulations of tri-block co-polymer and water: Phase diagram validation and microstructure identification. AB - In this study, the phase diagram of Pluronic L64 and water is simulated via dissipative particle dynamics (DPD). The peculiar structures that form when the concentration varies from dilute to dense (i.e., spherical and rod-like micelles, hexagonal and lamellar phases, as well as reverse micelles) are recognized, and predictions are found to be in good agreement with experiments. A novel clustering algorithm is used to identify the structures formed, characterize them in terms of radius of gyration and aggregation number and cluster mass distributions. Non-equilibrium simulations are also performed, in order to predict how structures are affected by shear, both via qualitative and quantitative analyses. Despite the well-known scaling problem that results in unrealistic shear rates in real units, results show that non-Newtonian behaviors can be predicted by DPD and associated with variations of the observed microstructures. PMID- 30441922 TI - Nuclear spin blockade of laser ignition of intramolecular rotation in the model boron rotor B13+11. AB - The boron rotor B13+11 consists of a tri-atomic inner "wheel" that may rotate in its pseudo-rotating ten-atomic outer "bearing"-this concerted motion is called "contorsion." B13+11 in its ground state has zero contorsional angular momentum. Starting from this initial state, it is a challenge to ignite contorsion by a laser pulse. We discover, however, that this is impossible, i.e., one cannot design any laser pulse that induces a transition from the ground to excited states with non-zero contorsional angular momentum. The reason is that the ground state is characterized by a specific combination of irreducible representations (IRREPs) of its contorsional and nuclear spin wavefunctions. Laser pulses conserve these IRREPs because hypothetical changes of the IRREPs would require nuclear spin flips that cannot be realized during the interaction with the laser pulse. We show that all excited target states of B13+11 with non-zero contorsional angular momentum have different IRREPs that are inaccessible by laser pulses. Conservation of nuclear spins thus prohibits laser-induced transitions from the non-rotating ground to rotating target states. We discover various additional constraints imposed by conservation of nuclear spins, e.g., laser pulses can change clockwise to counter-clockwise contorsions or vice versa, but they cannot stop them. The results are derived in the frame of a simple model. PMID- 30441923 TI - Plastic deformation of a permanently bonded network: Stress relaxation by pleats. AB - We show that a flat two dimensional network of connected vertices, when stretched, may deform plastically by producing "pleats", system spanning linear structures with width comparable to the lattice spacing, where the network overlaps on itself. To understand the pleating process, we introduce an external field that couples to local non-affine displacements, i.e., those displacements of neighbouring vertices that cannot be represented as a local affine strain. We obtain both zero and finite temperature phase diagrams in the strain-field plane. Pleats occur here as a result of an equilibrium first-order transition from the homogeneous network to a heterogeneous phase where stress is localised within pleats and eliminated elsewhere. We show that in the thermodynamic limit, the un pleated state is always metastable at vanishing field for infinitesimal strain. Plastic deformation of the initially homogeneous network is akin to the decay of a metastable phase via a dynamical transition. We make predictions concerning local stress distributions and thermal effects associated with pleats which may be observable in suitable experimental systems. PMID- 30441924 TI - Nanoscale domains in ionic liquids: A statistical mechanics definition for molecular dynamics studies. AB - One of the many open questions concerning Ionic Liquids (ILs) is the existence of nanoscale supra-molecular domains which characterize the bulk. The hypothesis of their existence does not meet a general consensus since their definition seems to be based on ad hoc arbitrary criteria rather than on general and solid first principles of physics. In this work, we propose a suitable definition of supra molecular domains based on first principles of statistical mechanics. Such principles can be realized through the application of a recently developed computational tool which employs adaptive molecular resolution. The method can identify the smallest region of a liquid for which the atomistic details are strictly required, while the exterior plays the role of a generic structureless thermodynamic reservoir. We consider four different imidazolium-based ILs and show that indeed one can quantitatively represent the liquid as a collection of atomistically self-contained nanodroplets embedded in a generic thermodynamic bath. Such nanodroplets express a characteristic length scale for heterogeneity in ILs. PMID- 30441925 TI - Publisher's Note: "Anharmonic vibrational spectroscopy of polycyclic aromatic hydrocarbons (PAHs)" [J. Chem. Phys. 149, 144102 (2018)]. PMID- 30441926 TI - Simpler is often better: Computational efficiency of explicitly correlated two electron basis sets generated by the regularized Krylov sequences of Nakatsuji. AB - A measure Delta of computational efficiency of the explicitly correlated basis sets (XCBSs) generated by the regularized Krylov sequences of Nakatsuji (also known as "the free complement" or "the free iterative CI" method) is derived from the convergence characteristics of the underlying iterative process. A complete mathematical definition of this process, which includes a crucial projection operator undefined in previous publications, is provided. Comparison of the values of Delta pertaining to several XCBSs designed for the helium isoelectronic series (for which Delta = -K -1/3 ln epsilon, where epsilon is the error in the computed energy and K is the number of the basis functions comprising the basis set) leads to a surprising conclusion that, among sufficiently large XCBSs, those stemming from the seed basis sets (SBSs) independent of the interelectron distance are the most efficient ones. Consequently, taking into account the simplicity of the resulting matrix elements of diverse quantum-mechanical operators, the XCBSs generated from the {exp(-zetas), s 1/2 exp(-zetas)} SBS (where s is the first of the Hylleraas coordinates) appear to be best suited for extremely accurate electronic structure calculations on helium-like species. PMID- 30441927 TI - Perspective: Computational chemistry software and its advancement as illustrated through three grand challenge cases for molecular science. AB - The field of computational molecular sciences (CMSs) has made innumerable contributions to the understanding of the molecular phenomena that underlie and control chemical processes, which is manifested in a large number of community software projects and codes. The CMS community is now poised to take the next transformative steps of better training in modern software design and engineering methods and tools, increasing interoperability through more systematic adoption of agreed upon standards and accepted best-practices, overcoming unnecessary redundancy in software effort along with greater reproducibility, and increasing the deployment of new software onto hardware platforms from in-house clusters to mid-range computing systems through to modern supercomputers. This in turn will have future impact on the software that will be created to address grand challenge science that we illustrate here: the formulation of diverse catalysts, descriptions of long-range charge and excitation transfer, and development of structural ensembles for intrinsically disordered proteins. PMID- 30441928 TI - Conformations of polyelectrolyte molecular brushes: A mean-field theory. AB - We present a mean-field theory for the solution properties of polyelectrolyte molecular brushes, comprising multiple ionically charged side chains tethered to the main chain (backbone). The power-law dependences for local and large-scale conformational properties, i.e., the brush thickness, extension of spacers between the grafts, and end-to-end distance for the main chain macromolecule, are derived as a function of architectural parameters (the lengths of the main chain and of the grafts, grafting density). We demonstrate that at high grafting density or/and a large fraction of charged monomer units in the grafts, the localization of counterions in the intra-molecular volume occurs and we specify the onset of this transition. We prove that such localization of the counterions is accompanied by full extension of the main chain of the polyelectrolyte molecular brush in salt-free solution. This stretching of the main chain is relaxed upon an increase in the salt concentration. The dependence of the macromolecular dimensions of the polyelectrolyte molecular brush on the salt concentration is derived, and multiple power-law exponents valid in different salt concentration ranges are predicted. PMID- 30441929 TI - Discrete flux and velocity fields of probability and their global maps in reaction systems. AB - Stochasticity plays important roles in reaction systems. Vector fields of probability flux and velocity characterize time-varying and steady-state properties of these systems, including high probability paths, barriers, checkpoints among different stable regions, as well as mechanisms of dynamic switching among them. However, conventional fluxes on continuous space are ill defined and are problematic when at the boundaries of the state space or when copy numbers are small. By re-defining the derivative and divergence operators based on the discrete nature of reactions, we introduce new formulations of discrete fluxes. Our flux model fully accounts for the discreetness of both the state space and the jump processes of reactions. The reactional discrete flux satisfies the continuity equation and describes the behavior of the system evolving along directions of reactions. The species discrete flux directly describes the dynamic behavior in the state space of the reactants such as the transfer of probability mass. With the relationship between these two fluxes specified, we show how to construct time-evolving and steady-state global flow maps of probability flux and velocity in the directions of every species at every microstate and how they are related to the outflow and inflow of probability fluxes when tracing out reaction trajectories. We also describe how to impose proper conditions enabling exact quantification of flux and velocity in the boundary regions, without the difficulty of enforcing artificial reflecting conditions. We illustrate the computation of probability flux and velocity using three model systems, namely, the birth-death process, the bistable Schlogl model, and the oscillating Schnakenberg model. PMID- 30441930 TI - Adlayer structure and lattice size effects on catalytic rates predicted from KMC simulations: NO oxidation on Pt(111). AB - Repulsive and/or attractive interactions between surface adsorbates have an important effect on the structure of the adsorbate layer and consequently on the rate of heterogeneous catalytic reactions. Thus, developing reaction models that take into account adsorbate-adsorbate interactions is crucial for making accurate predictions of the catalytic rate and surface coverage during reaction. In the present work, we employ kinetic Monte Carlo simulation to model the catalytic NO oxidation on Pt (111), adopting a cluster expansion (CE) Hamiltonian approach for treating the aforementioned interactions. We investigate CEs of increasing complexity, ranging from pairwise 1st nearest neighbor to long-range and many body terms. We show that energetic models incorporating solely short-range interactions result in ordered adlayer structures, which are disrupted by anti phase boundaries and defective regions when the size of the periodic lattice is non-commensurate to the structure of the stable adlayer. We find that O2 dissociates on sites located in these defective regions, which are predominantly responsible for the activity, and the predicted catalytic rate is strongly depended on the lattice size. Such effects are absent when employing non-periodic lattices, whereon the catalytic activity appears more intense on edges/corner sites. Finally, inclusion of long-range interactions in the model Hamiltonian induces relative disorder in the adsorbate layer, which is ascribed to the "softening" of the repulsive interactions between adspecies. Under these circumstances, the distribution of activation energies for O2 dissociation is broader as compared to short-range interaction models and on this basis we explain the disparate catalytic rate predictions when using different CEs. PMID- 30441931 TI - Effect of substrate interactions on the glass transition and length-scale of correlated dynamics in ultra-thin molecular glass films. AB - Interfacial interactions can play an important role in the glass transition temperature (T g ) and relaxation dynamics of ultra-thin glass polymer films. We have recently shown that similar to the polymeric systems in ultra-thin molecular glass films of N, N'-Bis(3-methylphenyl)-N, N'-diphenylbenzidine (TPD), the T g is reduced and dynamics are enhanced. Furthermore, in molecular glass systems, as the film thickness is reduced below ~30 nm, the dynamics at the two interfaces correlate such that the range of the gradients in the dynamics induced by the free surface narrows compared to thicker films. These observations indicate that the dynamics of the glassy thin films are strongly correlated and cannot be explained by a simple two-layer model consisting of a bulk and a thin interfacial layer with a constant thickness and constant range of dynamical gradients. Here, we investigate the effect of film/substrate interactions on the film dynamics by varying the TPD/substrate interfacial interactions. We show that thin TPD films with thicknesses below ~60 nm show a smaller extent of T g reduction and enhanced dynamics when supported on a near-neutral substrate (wetting) compared to a weakly interacting (dewetting) substrate. However, the ~30 nm length scale, where the activation energy significantly reduces from its bulk value as measured by the onset of the glass transition remains unchanged. Coarse-grained molecular dynamics simulation also shows a narrowing in the range of relaxation times once the thickness is sufficiently reduced for the two interfaces to dynamically correlate, consistent with previous work. These results suggest that the length scale for the correlated dynamics is independent of interfacial interactions and the polymeric nature of the film and may originate from the bulk glass properties. PMID- 30441932 TI - Quantum system partitioning at the single-particle level. AB - We discuss the partitioning of a quantum system through subsystem separation by unitary block-diagonalization (SSUB) applied to a Fock operator. For a one particle Hilbert space, this separation can be formulated in a very general way. Therefore, it can be applied to very different partitionings ranging from those driven by features in the molecular structure (such as a solute surrounded by solvent molecules or an active site in an enzyme) to those that aim at an orbital separation (such as core-valence separation). Our framework embraces recent developments of Manby and Miller as well as the older ones of Huzinaga and Cantu. Projector-based embedding is simplified and accelerated by SSUB. Moreover, it directly relates to decoupling approaches for relativistic four-component many electron theory. For a Fock operator based on the Dirac one-electron Hamiltonian, one would like to separate the so-called positronic (negative-energy) states from the electronic bound and continuum states. The exact two-component (X2C) approach developed for this purpose becomes a special case of the general SSUB framework and may therefore be viewed as a system-environment decoupling approach. Moreover, for SSUB, there exists no restriction with respect to the number of subsystems that are generated-in the limit, decoupling of all single-particle states is recovered, which represents exact diagonalization of the problem. The fact that a Fock operator depends on its eigenvectors poses challenges to all system-environment decoupling approaches and is discussed in terms of the SSUB framework. Apart from improved conceptual understanding, these relations bring about technical advances as developments in different fields can immediately cross-fertilize one another. As an important example, we discuss the atomic decomposition of the unitary block-diagonalization matrix in X2C-type approaches that can inspire approaches for the efficient partitioning of large total systems based on SSUB. PMID- 30441933 TI - Electronic structure theory gives insights into the higher efficiency of the PTB electron-donor polymers for organic photovoltaics in comparison with prototypical P3HT. AB - The electron donor poly-thienothiophene-benzodithiophene (PTB) polymer series displays remarkable properties that lead to more efficient bulk heterojunction (BHJ) organic solar cells. In this work, the ground and four excited states (bright S 1 and dark S 2-S 4) of three different members of the PTBn (n = 1, 6, 7) series were studied and compared with the prototypical poly(3-hexylthiophene) (P3HT) donor polymer. Time-dependent density functional theory was employed to investigate oligomers of similar sizes (~50 A). Charge alternation electron accumulation and depletion regions of the four transitions are concentrated on the inner units, thereby favoring interaction with the electron acceptor in a BHJ. The bright S 1 transition energies of PTBn are about 0.2 eV lower as compared to P3HT, thereby allowing a better match of their levels with the typical C60-type acceptor moiety in a BHJ. Side chains play a minor role in the electronic spectrum (less than ~0.1 eV). The most efficient PTB7 transfers more electronic charge from its electron-rich benzodithiophene subunit to its electron deficient thieno[3,4-b] thiophene subunit as compared to PTB1 and PTB6. We show that the dipolar effect, a partial concentration of negative and positive charges on the different parts of the donor polymer that favors charge separation, is more pronounced in PTBn polymers and typically an order of magnitude larger as compared to P3HT. These effects are conspicuous for the most efficient polymer of the series, PTB7, with its fluorine substituent shown to play a crucial role. PMID- 30441934 TI - Lung cancer. AB - Lung cancer is one of the most common cancers worldwide. Approximately 85 % of lung cancers are non-small cell lung cancers while 15 % are small cell lung cancers. Histologically, following subtypes of non-small cell cancer are distinguished: adenocarcinoma (38.5 % of all lung cancers), squamous cell carcinoma (20 %) and large cell carcinoma (3 %). Over recent years, the incidence of adenocarcinoma has been increasing. Squamous cell carcinoma is more commonly associated with smoking while adenocarcinoma is the most common histological type in non-smokers. The treatment of non-small cell lung cancer is decided according to clinical stage, morphological diagnosis, and the performance status of the patient. Early-stage patients are typically indicated for surgery. In some cases, adjuvant therapy is indicated. In locally advanced and metastatic stages, chemotherapy, biological treatment, and, recently, immunotherapy is indicated. Radiotherapy should also be considered for locally advanced disease. In small cell lung cancer, the combination of etoposide and cisplatin or etoposide and carboplatin is still considered standard chemotherapy. Radiotherapy is an integral part of treatment of either type of lung cancer. Keywords: lung cancer, non-small cell lung cancer, small cell lung cancer, chemotherapy, biological therapy, radiotherapy, immunotherapy. PMID- 30441935 TI - Idiopathic pulmonary fibrosis: Does the time for change of diagnostic and therapeutic recommendations come? AB - Idiopathic pulmonary fibrosis (IPF) belongs to the most severe and difficult-to treat lung diseases, with median survival 2-3 years if not treated. The disease arises in genetically disposed individuals of middle and older age based on repeated alveolar injuries. Fibroproliferative healing of these lesions form the pathogenetic background of the disease, leading to the end-stage pulmonary fibrosis. Our knowledge of pathogenesis, diagnosis and treatment of IPF increases dynamically since the beginning of new millennium. Progressive breathlessness, crepitus and clubbed fingers are typical for diagnosis of IPF. Radiologic picture of IPF in high resolution CT imaging is characterized by usual interstitial pneumonia, however nearly half of the patients do not have this typical pattern. The careful evaluation of clinical picture, radiologic findings and additional investigations as bronchoalveolar lavage differential cell count and immunologic results, by multidisciplinary team is essential in these cases. In minority of the patients lung biopsy, either surgical or cryobiopsy, is recommended. Only last 7 years causal treatment of IPF with antifibrotic drugs is available. Nevertheless, antifibrotic treatment only slows down the disease progression. Minor part of the patients with end-stage-diseased is referred for lung transplant. Palliative and symptomatic care is an integral part of IPF treatment. Key words: idiopathic pulmonary fibrosis, typical and atypical radiologic findings, cryobiopsy, antifibrotic treatment, lung transplantation, palliative care. PMID- 30441936 TI - Treatment of tobacco dependence as a standard part of oncology care. AB - After the oncological diagnosis, smoking has a major impact on survival, course and effectiveness of oncology treatment, and quality of the further life. Smoking worsens surgery outcomes, reduces the effectiveness of radiation therapy and chemotherapy, increases the risk of side effects of oncology treatment, and increases the incidence of tumor duplication or other comorbidities like venous thrombosis, cardiovascular diseases or infections. The article contains a summary of practical recommendations for oncology patients, including smoke-free environments, the importance of zero exposure to tobacco smoke, clear advice to stop smoking to smokers and offer of tobacco dependence treatment. Except of brief intervention within few tens of seconds up to 10 minutes, intensive treatment should be available, for example in special tobacco-dependence centers. In the documentation smoking status should be recorded including exposure to passive smoking, interventions to smokers (both active and passive) should be empathically repeated. The motivation to treat tobacco dependence should be mainly related to their specific oncological diagnosis, prognosis, course and effectiveness of its treatment. Treatment of tobacco dependence should be an obvious part of quality oncological care by doctors and nurses in intensity according to their time availability. Keywords: tobacco smoking, smoking cessation, nicotine dependence, chemotherapy, pharmacological interactions, adverse effects, cancer. PMID- 30441937 TI - Alcohol as an issue of the public health in the Czech Republic: facts and context. AB - Alcohol consumption has a direct impact on the extent of the alcohol related damage, including health and quality of life impacts. Alcohol policy, especially the availability of alcoholic beverages, affects the overall alcohol consumption. The Czech Republic is a very liberal country in relation to alcohol consumption and is known for the widespread availability of cheap alcohol beverages. The Czech Republic is regularly ranked among countries with the highest per capita rate of alcohol consumption in international comparison. Excessive drinking of alcoholic beverages has a negative impact on health and socio-economic situation of a large part of the Czech population. Czech policy should be inspired by foreign experience which shows that limitation of alcohol availability is an effective way of reducing overall alcohol consumption and related harms, including health impacts. Keywords: alcohol, alcohol policy, alcohol consumption, alcohol related damage, health of the Czech population. PMID- 30441938 TI - The origin and development of fat droplet and its role in health and illness. AB - Lipid droplets are found in most cells, where they are needed for lipid metabolism and energy homeostasis. Their biogenesis is still not entirely described process, in which an organelle with monomolecular layer on the surface originates from two-layer membrane of the smooth endoplasmic reticulum. Large lipid droplets can be formed either by growth or by fusion of smaller lipid droplets. Their basic functions are controlled lipid deposition and lipid metabolism and the protection of the intracellular environment from lipotoxicity. Currently, dysfunction of lipid droplet is associated with a number of diseases such as obesity, cardiometabolic syndrome, tumor and neurodegenerative diseases, lipodystrophy and cachexia. Keywords: lipid droplet, adipocyte, endoplasmic reticulum, perilipin, obesity, type 2 diabetes mellitus, lipodystroph. PMID- 30441939 TI - Aulus Cornelius Celsus and a regimen. AB - Aulus Cornelius Celsus worked up the basic principles of regimen in the first book of his encyclopedic treatise De medicina. In fact, it deals with ancient, broader concept of regimen as a way of living, including recommendation with respect of food, body care, work and leisure, environment as well as other factors. Celsus made no secret that Hippocrates and his disciples served to him as authorities. From number of cited examples follows that there is a consensus among these authors, especially in views concerning the impact of weather and seasons on human health. However, in characteristic of other spheres way of living the both authors diverge. Yet Celsus' work is steeped in the ideas of ancient philosophy, especially of theory of equilibrium, limit and restraint in all spheres of living and in that the author looks at the health comprehensively, in connection between health physical and mental and environmental conditions, thus Celsus' concept of lifestyle is similar to modern times concept of lifestyle. Keywords: Aulus Cornelius Celsus, regimen, way of living, theory of equilibrium, limit and restraint, mental hygiene. PMID- 30441940 TI - Celiac disease in children and adolescents. AB - Celiac disease can be defined as a small bowel disorder characterized by mucosal inflammation, villous atrophy and crypt hyperplasia, which occurs upon exposure to dietary gluten and which demonstrates improvement after withdrawal of gluten from the diet. Keywords: celiac disease, children, adolescents. PMID- 30441941 TI - Diagnostics and treatment of children with acute seizures on paediatric intensive care unit. AB - 218 children were admitted to paediatric clinic for acute seizures within last 5 years. Out of them, 14 children (7%) were admitted to paediatric intensive care unit (PICU) with repeated or prolonged seizures. Two children were hospitalized twice. The average age of children in time of admission was 12 months, most of the children were healthy before admission, had normal psychomotor development. The most frequent seizure manifestation was asymmetric clonic seizure. Hypoventilation and/or unconsciousness was the most frequent indication for PICU admission in addition to seizures. Febrile seizure was the most frequent diagnosis in children with shorter or less frequent episodes of seizure. Children with severe course and pharmacoresistant seizure were likely to have genetic diagnosis. The MRI scan was normal in most of the children, interictal EEG was mostly without specific finding. Midazolam was the first lime anticonvulsive medication used in most of the children, while phenobarbital, levetiracetam or phenytoin were the preferred second line drugs. Keywords: acute seizures, asymmetric clonic seizure, febrile seizure, children, paediatric intensive care unit. PMID- 30441942 TI - Modern methods in diagnostics and research of molecular bases of rare diseases. AB - Rare diseases represent a heterogeneous group of approximately 8000 various disorders and affect nearly 8 % of the population. The local and international studies of human genomes help to increase the knowledge about genetic variability of the man and due to effective sharing of clinical and molecular data in the registries enable casual diagnostics of the broad spectrum of rare and complex diseases in 55-65 % of the cases. With the diagnostics in the remaining group of patients, new methods and technologies studying human genome are of importance including genetic and functional analyses of genomic variants and their combinations with the aims to recognize and interpret the significances of the somatic mosaics, genetic heterogeneity of individual disorders, the presence of eventual phenocopy, different penetrance and expressivity of individual mutation and diseases with the oligogenic inheritance. Recently, the increasing significance of analyses of noncoding regions in human DNA were recognized including the impact of repetitive and homologs regions on transcription and structure of mRNA. For the diagnostics of genetic causality in patients is necessary to focus on analyses of biologic fluids, tissues, cultivated cells and animal models prepared by methods of cell reprogramming or directed mutagenesis. In this paper, the overview of methods and their importance and limitation is described including whole exome sequencing (WES), whole genome sequencing, functional and homolog cloning, functional complementation, mapping of genes with the help of binding analyses and matching of the results from individual genome with genetic variability in the adequate population. In our institutions, we performed WES in > 520 patients with successful diagnostics above 50 %. In addition, in our group of 225 patients with rare diseases we compared the result of WES with the results of direct sequencing of individual genes indicated by clinical geneticist from various regions of the country and we recognized much higher diagnostic and economic value of WES. Modern diagnostics of rare diseases is time and money consuming and requires close cooperation between patients, their families, attending physicians, clinical geneticists and experts from various laboratories involved in biologic oriented research. It represents a big challenge for organisers and payers of the health care system. Keywords: are diseases, complex disorders, whole exome sequencing, gene mapping. PMID- 30441943 TI - A horizontal transmission of genetic information and its importance for development of antibiotics resistance. AB - Genetic information is transmitted among organisms through two pathways - vertically from generation to generation (from parents to progeny) and horizontally (laterally) by direct exchange of genetic material across species barriers. These are primarily prokaryotes, in which the exchange of genes or whole gene segments by horizontal transmission is quite common. They can dynamically and in a relatively short time generate highly diverse genomes, which does not allow the vertical transmission. As a result, prokaryotes can rapidly acquire new properties such as virulence and pathogenicity as well as resistance to toxins, including antibiotics, by which they increase their adaptability. Therefore, reinfection-resistant microorganisms are always more difficult to treat than infections caused by non-resistant bacteria. Antibiotic resistance today is a global problem of health care service. Not only does the number of diseases caused by resistant pathogenic strains of bacteria increase, but also the cost of treatment increases disproportionately, the length of hospitalization is prolonged, and mortality is often rising. Therefore, when indicating antibiotic therapy, it is important to keep in mind that both overuse and abuse of antibiotics contribute to the spread of antibiotic resistance genes. This is equally true for antibiotic applications in veterinary medicine, agriculture, including aquacultures, or in the food industry. Keywords: horizontal transmission of genetic information, endosymbiosis, antibiotic resistance, risks of the emergence and spread of antibiotic resistance, prevention of antibiotic resistance. PMID- 30441944 TI - Queue management systems are not a necessary measure for the protection of personal data. AB - The new legislation, in particular the General Regulation on Personal Data Protection (GDPR), constitutes relatively demanding criteria on healthcare. However, the institute of medical secrets, which is an ancient medical practice and is part of various legal and professional regulations, contains many elements of today's protection of personal data and is not new among the professional medical public. Under the GDPR, however, there are steps that can be labelled as at least controversial. Such disputable measures have recently been to introduce electronic queue management systems, as we know from post offices. They are not a necessary measure for the protection of personal data in the waiting rooms of ambulances, they are not required by law, even with regard to GDPR and from the point of view of medical ethics are even at least problematic. If GDPR is applied in a similar way, it does not really benefit from the protection of personal data, and a useful tool like GDPR will be undoubtedly discredited. Keywords: electronic queue management systems, GDPR, medical ethics, personal data protection, patient. PMID- 30441945 TI - Short view on origins of paediatric health care in Prague. AB - The first charity for protection of orphans in Prague was opened in the 16th century by Italian living in Prague. The first outpatient department for sick children in Prague was opened by Johann Melitsch in 1790 in the Saint Lazare hospital in Charles Square. In the same hospital, the first paediatric department with 9 beds was opened by Eduard Kratzman in 1842. Relatively low mortality of hospitalized children that time must be explained. Sick infants were not admitted to hospitals but sent to the orphan institutes with mainly social care, therefore in middle of the 19th century the infant mortality in these establishments was extremely high, during some years nearly 100 %. The first hospital for children in Prague was built by Josef Loschner in Charles Square in 1853, where a number of distinguished paediatricians worked including Gottfried Ritter von Rittershain, who described dermatitis exfoliativa Ritter, Alois Epstein, who described Epsteins pearls by newborns, Adalbert Czerny, who studied glycogen and later became a head of Paediatric clinic in Berlin, Leopold Moll, who was an initiator of the care for mother and child and later became a head of Paediatric clinic in Vienna, Dusan Lambl, who described flagellate (nowadays Giardia lamblia) in the stool of children with diarrhoe, and Bohdan Neureutter, who after the splitting of the Charles-Ferdinand-University on the in German speaking and Czech speaking parts opened the Czech paediatric hospital at the corner of streets Benatska and Vinicna. Due to increasing requirement of paediatric beds in Prague, simultaneous constructions of two paediatric centres were started in Prague. The first, areal with four buildings for German paediatric clinic was opened in 1901, which still serve as the second largest paediatric department in Prague, of course with much lower number of beds than 100 years ago. The second one, the Czech paediatric Frantz Josef I. hospital was opened in 1902, but due to construction of the bridge across the Nusle valley was demolished in 1970 and it's clinics were transferred to the hospital in Motol. Keywords: history of paediatric health care. PMID- 30441946 TI - Periodic fevers and other autoinflammatory diseases. AB - Autoinflammatory diseases represent a relatively new and rapidly evolving group of rare disorders associated with mutations of genes encoding proteins with a key regulatory role in inflammatory response. Gradual discovery of mechanisms that link genetic disorder with its biochemical and immunological consequences leading to continuous or episodic inflammatory stimulation has enabled introduction of directed immunotherapies. Periodic fever syndromes belong to the so far best known entities: familial Mediterranean fever, mevalonate kinase deficiency, cryopyrinopathies and TNF-receptor associated periodic syndrome. These inherited disorders usually manifest in childhood with variably long febrile episodes accompanied with the spectrum of other skin and organ inflammatory features and elevation of laboratory markers of inflammation. Uncontrolled disease may lead to secondary amyloidosis. Directed anti-inflammatory therapy can prevent evolution of organ damage. In children benign syndrome of periodic fever with aphtae, pharyngitis and cervical adenitis is the most common self-limited disorder without clear genetic disposition. Following other autoinflammatory disease groups are described - pyogenic syndromes, disorders with skin and bone manifestations, granulomatous diseases, monogenic vasculopathies and diseases associated with proteasome disorder. Diagnosis of autoinflammatory diseases is often delayed due to their extreme rarity. Increasing efficacy and availability of molecular-genetic testing and centralization of diagnostics and clinical care in a specialized center for children as well as adults can in the future improve quality of care for patients with these rare conditions. Keywords: autoinflammatory diseases (AID), periodic fever syndromes, FMF, CAPS, MKD, TRAPS, PFAPA, NGS. PMID- 30441947 TI - Prenatal diagnostics of chromosomal aberrations in the Czech Republic: Actual data and important trends. AB - The main goal of this study was to analyse the spectrum of chromosomal aberrations that were diagnosed during prenatal diagnostics in the Czech Republic in 2016. We present a retrospective epidemiological analysis that is based on the official data from the National Registry of Congenital Anomalies that is run by the Institute of Health Information and Statistics of the Czech Republic. Additional data were obtained actively from the departments of medical genetics and prenatal diagnostics under the guidance of the Czech Society of Medical Genetics and Genomics. In 2016 there were 577 cases of chromosomal aberrations identified during prenatal diagnostics in the Czech Republic. The most important group of aberrations were the three main autosomal trisomies - Down, Edwards and Patau syndromes which were identified in 64.8 % of cases. The most frequent of them was the Down syndrome, that was identified in 271 cases (47 % of all cases identified in 2016). Other aberrations (including the abnormalities of the gonosomes and other autosomal anomalies) were still identified in more than one third of cases, although the screening programs do not primarily focus on them. Combined screening in the first trimester and following prenatal diagnostics mostly identify main autosomal trisomies. Screening is currently the most important clinical referral for the invasive prenatal diagnostics procedures. We also observe important time trend of decreasing numbers of invasive diagnostics procedures - while the overall prenatal detection rate of chromosomal aberrations is not negatively affected. Keywords: hromosomal aberrations, prenatal diagnostics, prenatal screening. PMID- 30441948 TI - Lymph node syndrome associated with cat scratch disease in children and adults. AB - A retrospective evaluation of a group of patients with cat-scratch disease which is focused on epidemiological context, clinical picture, serological diagnosis and treatment in children and adults. Seventy-three patients with catch-scratch disease (CSD) were diagnosed at the Clinic of infectious medicine in 2008-2017, the group consisted of 37 children and 36 adults. Injury, or at least contact with cat, localization of lymph node syndrome and other clinical signs were investigated. Serological diagnosis was based on detection of IgM and IgG antibodies against Bartonella henselae. Duration of lymph node syndrome and antibodies against B. henselae were observed. Findings of granulomatous inflammation in extirpated lymph node supported suspicion of CSD. 66 of 73 patients had contact with cat, only 22 patients reported injury caused by cat. Cervical lymph nodes were affected the most often, in 32 patients. Extirpation of lymph node was performed in 19 patients. Positive IgM antibodies were detected in 47 patients. Between the group of children and adults important differences in any followed parameters were not observed. In the group of 73 patients with cat scratch disease cervical lymph nodes were affected the most often. Positive IgM antibodies were detected in 47 patients, lymph node extirpation was performed in 19 patients. Considerable differences in course of disease in children and adults were not found out. Keywords: cat-scratch disease, lymph node syndrome, serology, extirpation. PMID- 30441949 TI - ONE-YEAR FOLLOW-UP OUTCOMES OF TREATMENT OF WET AGE-RELATED MACULAR DEGENERATION WITH AFLIBERCEPT. AB - PURPOSE: To evaluate one-year follow-up outcomes of treatment with aflibercept in patients with newly diagnosed wet age-related macular degeneration (ARMD). METHOD: Retrospective evaluation of treatment of 28 eyes of 28 patients with an average age of 74.2 years who were treated with aflibercept at the Department of Ophthalmology at Kralovske Vinohrady University Hospital. All patients were treated according to the summary of product characteristics (SPC), i.e. with an initial 3 injections at monthly intervals, followed by 4 injections every 2 months. We evaluated the change in best corrected visual acuity (BCVA) on Early Treatment of Diabetic Retinopathy Study (ETDRS) optotypes, and the change of central retinal thickness (CRT) with the aid of optical coherence tomography (OCT). RESULTS: The average initial BCVA value was 61.5 letters of ETDRS optotype. After the initial 3 injections, BCVA improved to 70.5 letters, after one year of treatment there was a slight decrease to 68.1 letters. Better or same visual acuity was recorded in 25 eyes (89.3%), a deterioration occurred in 3 eyes (10.7%). CRT was reduced from an initial average value of 360.9 um to 253.3 um after the initial phase and to 233.8 um after one year of treatment. At the end of the observation period, 25 eyes (89.3%) were without signs of activity of the pathology. No complications of treatment were recorded. CONCLUSION: In our cohort we confirm the efficacy and safety of the aflibercept preparation in patients with newly diagnosed wet form ARMD. By adhering to a fixed therapeutic regime it is possible to obtain similarly excellent results of treatment in real clinical practice as in clinical trials. Key words: aflibercept, anti-VEGF therapy, optical coherence tomography, wet form ARMD The authors of the study declare that no conflict of interest exists in the compilation, theme and subsequent publication of this professional communication, and that it is not supported by any pharmaceuticals company. PMID- 30441950 TI - The use of micropulse laser in patients with diabetic macular edema at the Department of Ophthalmology, Faculty Hospital Hradec Kralove. AB - INTRODUCTION: Diabetic macular edema (DME) is the most frequent cause of decreased vision in patiens with diabetes type 2. DME is caused by increased permeability of macular capillaries. The aim of our study was to retrospectively evaluate the results of micropulse laser treatment, 577 nm wavelength, in pacients with DME with follow-up three months and one year. METHODS: The retrospective trial with one year follow-up includes 63 eyes of 37 patients with diabetic macular edema treated from September 2015 to January 2017. Most patients had diabetes type 2 (34 patients), 3 patients had diabetes type 1. Diffuse DME was diagnosed in 54 eyes, focal DME in 9 eyes. Most of the patients (42 eyes) suffered from non proliferative diabetic retinopathy, 21 eyes showed signs of proliferative retinopathy. DME lasted on average for 29 months before initiating with micropulse laser (median 21 months). On average 1,56 laser visits were needed for the treatment of 1 eye, usually in 3 months interval. Photocoagulation of macula was performed in all patients by micropulse laser, 577 nm wavelenght/IQ 577TM IRIDEX). We used 5 % duty cycle. The average glycated hemoglobin in the group was 66,8 mmol/mol, maximal 100 mmol/mol. Estimated data were statistically evaluated by Friedman and Dunn's test. RESULTS: At the end of 1 year period we found out improvement in BCVA (increase of at least 5 letters of ETDRS charts) in 20 eyes, 25 eyes showed stabilisation of BCVA (alltogether 71 % of the group), in 18 eyes we found out decrease of BCVA of more than 5 letters of ETDRS charts. On average we estimated decrease of visual acuity from 62 to 61,1 letters (p > 0,05). After one year we estimated 63 MUm CRT decrease on average, from 442 MUm to 379 MUm (p= 0,0124). CONCLUSION: In our group of DME patiens treated by micropulse laser we have estimated BCVA stabilisation and signifiant improvement of macular edema in 3/4 eyes, confirmed by OCT. We have estimated clinically significant decrease of macular edema in the whole group with one-year follow-up. PMID- 30441952 TI - ACUTE MYOPIA WITH ELEVATION OF INTRAOCULAR TENSION AS AN ADVERSE SIDE EFFECT OF ANTIDEPRESSANT MEDICATION. AB - CASE-REPORT: The author presents case report of acute induced myopia with mild intraocular pressure elevation by young patient using trazodone. The presentation is completed with the documentation of anterior chamber depth and angle changes by using and after discontinuation of trazodone. CONCLUSION: Acute transient myopia may be rare side effect of systemic used drugs in predisposed patients. Early and correct diagnosis is very important, because induced myopia may be accompanied by acute angle-closure glaucoma or supraciliary choroidal effusion. The only correct treatment in this case is discontinuation of the drug. Key words: acute angle-closure glaucoma, acute myopia, antidepressants, side effects, trazodone. PMID- 30441951 TI - Results of the first 12 months treatment of macular edema complicating BRVO in patients treated with ranibizumab. AB - THE AIM OF THE STUDY: Retrospective evaluation of the first 12 months treatment of macular edema in BRVO with ranibizumab based on anatomical and functional parameters. METHODS: 54 eyes with macular edema complicating BRVO were included in the study, with an average initial best corrected visual acuity 4/16 ETDRS charts, an average central retinal thickness 512.3 MUm, and in average 4 months till the beginning of treatment with ranibizumab. After 3 initial injections of 0.5 mg ranibizumab treatment was performed in pro re nata regimen, with adjuvant laser (grid laser photocoagulation) as an additional treatment option. The number of injections administered, the number of eyes where grid laser photocoagulation was provided, functional parameters as a letter gain and BCVA (eyes with final BCVA >= 4/8 ETDRS, final BCVA in according to initial BCVA) and anatomical parameters as a mean CRT and CRT <= 250 MUm, respectively <= 300 MUm were evaluated. RESULTS: In the whole group, an average of 4.8 injections of ranibizumab were administered in the first 12 months. Grid laser photocoagulation was performed in 42 eyes: in 8 eyes prior to the beginning of treatment with ranibizumab, 7 eyes before and during the treatment, 29 eyes only during the treatment. The main gain of letters after 12 months of treatment was +16.5 letters, with 63% (n = 34) eyes earning >= 15 letters. In the whole group 72 % (n = 39) eyes achieved the resulting BCVA >= 4/8 ETDRS after 12 months of treatment. The eyes with initial BCVA >= 4/10 ETDRS resulted in BCVA >= 4/8 ETDRS in 96 % (n = 23 eyes) and 11 eyes even achieved BCVA >= 4/4. The mean CRT after 12 months of treatment was 290.3 MUm, 33.3 % of eyes had final CRT <= 250 MUm, and 64.8 % had final CRT <= 300 MUm. CONCLUSION: When applying a relatively low number of injections in the first year of treatment with ranibizumab, the final best corrected visual acuity was very good at the end of the observation period, and its dependence on the initial best corrected visual acuity was confirmed. Satisfactory results of central retinal thickness were found as well. Key words: branch retinal vein occlusion, macular edema, ranibizuma. PMID- 30441953 TI - CHANGE OF CENTRAL AND PERIPHERAL VISION IN PATIENT WITH SYMPTOMATIC CYST OF RATHKE'S CLEFT FOLLOWING TRANSSPHENOIDAL RESECTION. AB - A seventysix-year-old female was acutely admitted to the Eye Clinic of the University Hospital in Martin with a 1 month history of impaired central and peripheral vision on the right eye. At the admission patient's right eye VA was fingers at 20 cm, the left eye had a central vision preserved. Magnetic resonance of the brain and orbits demonstrated cystic tumor expansion in the sellar region with compression of optic chiasm and optic nerves (more on the right side), in diff. dg. as cystic macroadenoma of the pituitary gland. Endocrinological examination found secondary hyperprolactinaemia from pituitary oppression, other hormonal parameters were without deviation. Consequently, the ENT examination recommended endoscopic resection via the transsphenoid approach. After resection of the lesion and histological examination of the sample, the finding was evaluated as a Rathke's cleft cyst. Symptomatic Rathke's cleft cysts of pituitary gland are rare, but the visual symptoms are typical findings due to chiasm proximity. On ophthalmological examination 3 weeks after surgery has central vision increased significantly (VOD 6/9) on the right eye and peripheral vision has partially adjusted on both eyes. Key words: Rathke's cleft cyst, perimeter, central visual acuity, transsphenoidal endoscopic resection. PMID- 30441954 TI - Comparison of groups with medical and surgical terminations of pregnancy. AB - OBJECTIVE: The aim of this study was to compare two cohorts of subjects who underwent termination of pregnancy up to 49 days of amenorrhoea by medical (pharmacological) termination (faUUT) and surgical instrumental termination of pregnancy (inUUT). DESIGN: Prospective clinical study. SETTING: Department of Gynecology and Obstetrics, Charles University in Prague, 1st Faculty of Medicine, Hospital Na Bulovce. METHODS: From August 2014 to July 2017, a total of 838 terminations of pregnancy up to 49 days of amenorrhoea were performed at our department. Altogether 474 of subjects underwent faUUT and inUUT was performed in 364 of women. We compared the anamnestic, sociodemographic, and health characteristics of women and we evaluated the efficacy, required medical interventions, medication use, the number and characteristics of complications in both groups. RESULTS: Women who underwent faUUT, were fewer with previous delivery (40.9% vs. 75.0%; p < 0.001), but they had more often previous artificial termination of pregnancy (27.8% vs. 19.5%; p = 0.003). The total number of outpatient visits was significant different between both cohorts, both in median (4 vs 1; p < 0.001) and arithmetic mean (3.8 vs. 1.2; p < 0.001). The usage of uterotonics was much higher in faUUT group (25.7% vs. 8.2%; p < 0.001). On the other side, the antibiotic use was similar in both groups (3.2% vs. 4.4%; p < 0.17). The surgical intervention (revisio cavi uteri instrumentalis, RCUI) required after termination of pregnancy was performed in 7.4% of faUUT cases and in 3.0% of inUUT group (p < 0.001). The failure of faUUT was found in 2 (0.4%) subjects. CONCLUSION: The complications and other followed parameters were various between both groups. Medical termination of pregnancy is a safe method with some potential non life-threatening complications. PMID- 30441955 TI - How accurate are we in urethral mobility assessment? Comparison of subjective and objective assessment. AB - OBJECTIVE: The knowledge of the mobility of urethra plays important role in patients with stress urinary incontinence and its assessment is a part of standard urogynecological examination. It has been assumed that increased mobility is associated with higher likelihood of successful treatment. There is arbitrary defined cut-off for hypermobile urethra - descend of more than 15 mm or 30-degree resp. 50-degree rotation or more during Valsalva manoeuvre. Clinically we routinely categorize mobility of the urethra as high mobile or hypermobile urethras, low mobile urethra and the situation in-between as mobile urethras. But how accurate are we with such a subjective assessment? We have provided retrospective analysis of mobility of the urethra assessed during the clinical examination by transperineal ultrasound (US) with subjective scoring of the mobility (low, norm, hyper) and compared this assessment with detailed measurement of descent and rotation of the urethra. DESIGN: Retrospective cohort study. SETTING: Ob/Gyn department First Faculty of Medicine, Charles University and General University Hospital, Prague. METHODS: This is a retrospective analysis of urethral mobility of women diagnosed with urodynamic stress incontinence (USI) and treated with tension free vaginal slings during the period 01/2009 - 10/2016. For each patient, there was available description of mobility at the time of preoperative assessment (low-, norm- or hyper-mobile) and we compared this assessment with measured parameters of bladder neck mobility analysed later from stored 4D US volumes. We have measured dorsocaudal movement of the bladder neck (BN) (H-distance). This is the distance of the BN from the horizontal line at the level of lower margin of the symphysis and we compared the position at rest and at Valsalva. Secondly, we measured rotation of the urethra using the gama angle - angle between the line connecting BN to lower margin of symphysis and axis of symphysis at rest and during the Valsalva manoeuvre. Mobility of the BN is the difference between the rest and Valsalva position. We compared the objective parameters of mobility with subjective assessment. We have provided correlation of both objective parameters. RESULTS: 427 patients were treated during the analysed period, 393 had available stored 4D US volume for analysis. Mean age 56.5 years (min 29, max 87, SD 7.9), mean BMI 27.4 (min 18.3, max 39.6, SD 7.9), mean parity 2.14. Mean descent of the bladder neck was 11.8 mm (min -1, max 37; SD 6.9) Mean rotation of the bladder neck was 38.8 degree (min 5, max 118, SD 20.0). When we subjectively assessed the mobility as low the mean mobility was 23.9 degrees resp. 7.3 mm, for normal 34.8 degrees resp. 10.4 mm and 48.6 degrees resp. 15 mm for hypermobile uretras. We have found good correlation of both parameters - H-distance, gama angle - r = 0.693. CONCLUSION: Subjective assessment of mobility of the urethra seems to be reasonably accurate for distinguishing between low and hypermobile uretra. PMID- 30441956 TI - The role of hormonal therapy in patients with uterine carcinoma. AB - OBJECTIVE: The aim of the study was to describe the role of hormonal therapy in the treatment of malignant uterine tumors, indications, the effect of the treatment and to verify its safety in our study cohort. We also present an overview of recent studies on that topic. DESIGN: Unicentric retrospective observational study and review of recent literature. SETTING: Department of Obstetrics and Gynecology, Masaryk University, University Hospital Brno. METHODS: The results of recent relevant studies and reviews published in English until December 2017 were used for the review. The publications were searched using the PubMed server. All patients diagnosed in our oncogynecological center between 2010 and 2016 and who were treated hormonally - either in primary therapy or in relapse settings, were included in our study. We were interested in age, BMI, stage of disease, histological type and grade of tumor, occurrence of adverse effects, duration of survival, reasons for choosing hormonal therapy. Medroxyprogesterone-acetate or megestrol-acetate was used in the treatment. RESULTS: Between 2010 and 2016, 415 malignant tumors of the uterus were diagnosed in our oncology center. Recurrence of the disease occurred in 31 patients (8%), on average 16 months after primary treatment. Primary hormonal therapy was used in only 19 patients (5%), mostly because of contraindications of another treatment due to high age, comorbidities or obesity. Median age of patients was 83 years, mean BMI 41, median survival of patients who died was 8 months. Five patients (16%) were treated hormonally for the recurrence. Median survival from diagnosis of recurrence was 20 months. One patient (4%) experienced partial pulmonary embolism. CONCLUSION: Hormonal therapy plays an irreplaceable role in uterine cancer patients, especially in primary non-operable patients, in treatment of a relapse, or in a fertility-sparing procedure. This treatment option is safe, with minimal adverse effects. PMID- 30441957 TI - A rare complication of long-term vaginal prolapse. AB - OBJECTIVE: Description of rare complication of long-term uterine prolaps. Desing: Case report. SETTING: Department of Obstetric and Gynecology, University Hospital Ostrava. CASE REPORT: A seventy-years-old pacient with longterm complete uterine prolaps underwent vaginal hysterectomy with colpoclesis at department of Obstetric and Gynecology of university hospital Ostrava in August 2017. The surgery was planned more than year ago, when patient had no symptoms. But due to patient's injury, it was postponed and the condition was already complicated by urine incontinency. The surgery was complicated by bladder lesion, because it was suggested as a pelvis tumor. Correction of cystolithiasis was planned at a second time, when suprapubic cystoli-thotomy was performed after 16 days. Temporary urinary derivation was ensured by bilateral nephrostomy, epicystostomy and urinal catetrization for low residual bladder capacity after surgery. CONCLUSION: Bladder stones are a rare complication of otherwise relatively frequent complete urogenital prolaps in women. Major causes include micturition disorder and chronic urinary tract infection which is caused by vaginal and uterus descensus. PMID- 30441958 TI - Nerozpoznana preeklampsie, ktera se rozvinula do eklamptickeho zachvatu s fatalnim koncem. AB - OBJECTIVE: A fatal case of a 37 year old women in the fifth month of pregnancy, who showed no signs of life and who could not be revived is reported. DESIGN: Case report. SETTINGS: Forensic expert in healthcare, Liberec; Department of Health Care Disciplines and Population Protection, Faculty of Biomedical engineering, Czech Technical University in Prague; Department of Biology, Faculty of Education, J. Selye University, Komarno, Slovak republic; Laboratory of Veterinary Histopathology in Komarno, Slovak republic. METHODS: The forensic necropsy was done. Toxicological and histological investigation of sampled material were done. RESULTS: The autopsy revealed bleeding into the brain chambers. The toxicology results were negative. The histopathological examination showed glomerulonephritis, bloody lungs, and massive bleeding in all sampled organs. From this it was concluded that her dead was caused by unrecognized preeclampsia, which developed into eclamptic attack with fatal consequence. CONCLUSION: To avoid these fatalities we recommend that the possibility of preeclampsia is investigated early in pregnancy especially in women with high blood pressure, for whom we also recommend more frequent controls in these early stages of pregnancy. We also recommend more intensive medical care for pregnant women with preeclamptic signs, including the possibility of a shorter schedule of management in specialist care in hospital, from the first symptoms onwards. PMID- 30441959 TI - Acute enteroviral meningoencephalitis as unusual cause of diplopia in pregnancy and puerperium. AB - OBJECTIVE: To describe unusual cause of diplopia in early puerperal period. DESIGN: Case report. SETTING: Department of Obstetrics and Gynecology, 2nd Faculty of Medicine and Faculty Hospital Motol. CASE REPORT: 34-year-old patient at 39 weeks of gestation complaining fever, headache and blurring of vision was referred to our medical center. She underwent caesarean section for tachycardia of fetus. Symptoms remained during early puerperium. We describe diagnostic and treatment hesitations. CONCLUSION: The cause of her complains was viral meningoencephalitis which led in postencephalitic syndrome. PMID- 30441960 TI - Zoon vulvitis - a rare form of chronic inflammation of the vulva. AB - OBJECTIVE: Description of finding out rare disease Zoon vullvitis. Desing: Case report and differential diagnosis. SETTING: Department of Obstetric and Gynecology, University Hospital Ostrava. CASE REPORT: Zoon vulvitis or plasma cell vulvitis (PCV) belongs to extremely rare and often misdiagnosed inflammatory disease of the vulva. Lesions may look like shiny, sharply bordered , erythematosus patches or macular lesions. Less than 50 cases have been reported. This article is devoted to clinical findings, differential diagnosis and treatment of PCV. We present one clinical case with typical clinical and histopathological manifestations. Risk of dysplasia exists and long-term follow up is desirable. PMID- 30441961 TI - Implantation and diagnostics of endometrial receptivity. AB - OBJECTIVE: Literature review of endometrial receptivity in embryo implantation and its diagnostic possibilities. DESIGN: Literature review. SETTING: Department of Obstetrics and Gynecology, University Hospital, Faculty of Medicine, Palacky University, Olomouc; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc. RESULTS: Endometrial tissue is very dynamic, undergoing cyclic proliferation, differentiation and cell transportation, especially of immune system cells under the influence of circulating estradiol and progesterone. Endometrial remodelling during embryo implantation is controlled by decidual cells senescence and effectivity of their immunologic destruction. Endometrial receptivity can be assessed by transcriptomic profiling of endometrial biopsy using ERA system or proteomic analysis of either endometrial secretome or cervical mucus by gel electrophoresis (DIGE) or mass spectrometry (MS). CONCLUSION: With respect to recent discoveries in endometrial physiology and molecular biology, clinical application of proteomic approaches in research of potential biomarkers of endometrial receptivity could be of interest. PMID- 30441962 TI - Late morbidity in cesarean section scar syndrome. AB - OBJECTIVE: To summarize recent knowledge on ethiology, diagnostic management and treatment possibilities of cesarean section scar syndrome (isthmocoele). DESIGN: Review article. SETTING: Department of Gynaecology and Obstetrics, Faculty Hospital and Palacky University, Olomouc; Department of Gynaecology and Obstetrics, Vitkovicka nemocnice, Ostrava-Vitkovice. METHODS: A literature review of published data on cesarean section scar syndrome (isthmocoele). RESULTS: Cesarean section scar syndrome may be associated with subsequent complications including postmenstrual spotting or bleeding, dysmenorrhoea, abdominal pain, dyspareunia, infertility, scar pregnancy, a morbidly adherent placenta, scar dehiscence or rupture in later pregnancy. Ethiopathogenesis of isthmocoele remains poorly understood. Magnetic resonance, sonohysterography and transvaginal ultrasound are the gold standard imaging techniques for diagnosis. Surgical treatment is still controversial but should be offered to symptomatic women. CONCLUSIONS: Given the association between an isth-mocoele and gynaecological symptoms, obstetric complications and infertility, it is important to focus on preventive strategies of its development. PMID- 30441964 TI - Frozen section: history, indications, contraindications and quality assurance. AB - Frozen section represents one of the most imortant procedures carried out by the pathologist. At the same time, it's one of the most difficult and most stressful tasks in the practice of pathology. The basic rule and the only correct indication for intraoperative consultation is that the result will determine the further conduction of the surgical procedure or will change the immediate patient care after operation. Successful accomplishment of intraoperative consultation requires knowledge of clinical history, familiarity with the surgical procedure technique, a keen knowledge of gross and microscopic pathology and a perfect work of the lab. Regular participation in quality assurance programs is associated with lower discordance rates between frozen section and final section diagnoses and a lower frequency of deferred diagnoses. Both the pathologist and the surgeon should realize the limitations of frozen section technique and, although no formal absolute contraindications to the use of frozen sections exist, there are situations when frozen section should be refused, although only after communication with the surgeon. Keywords: frozen section - history - indications - contraindications - quality assurance. PMID- 30441963 TI - Possibilities and real meaning of assessment of ovarian reserve. AB - OBJECTIVE: To summarize the posibilities of diagnosis of diminished ovarian reserve. DESIGN: Survey of contemporary knowledge. SETTINGS: PPCHC, Sanus Jihlava; PPCHC, Sanus Hradec Kralove; Reprogenesis, Brno. METHODS: Review of literature. CONCLUSION: Voluntary or involuntary motherhood postmonement to the third decade of woman's life needs presice evaluation of the ovarian reserve before the infertility treatment. Contemporary there are: 1 hormonal tests (basal and dynamic), 2 ultrasonographic markers of ovarian reserve. The most perspective markers of ovarian reserve seems AMH a AFC. PMID- 30441965 TI - Frozen section examination of pancreas, gallbladder, extrahepatic biliary tree, liver, and gastrointestinal tract. AB - The main indications for intraoperative consultation of gastrointestinal tract, liver, and pancreatobiliary system are to evaluate the resection margin and to make a tissue diagnosis of lesions for which preoperative histology is not aviable for various reasons. Special situations include the evaluation of liver donor biopsies for the presence of steatosis and inflamation, or determination that ganglion cells are present in the bowel wall at the level where the anastomosis will be placed in case of Hirschprung's disease. The most worrisome pitfalls include differentiating pancreatic ductal carcinoma from chronic pancreatitis, distinguishing biliary tree and gallbladder carcinoma from reactive changes caused by inflammation, and recognizing the presence of diffuse adenocarcinoma at the resection margin of the esophagus and stomach. Keywords: frozen section - gastrointestinal tract - liver - gallbladder - extrahepatic biliary tree - pancreas. PMID- 30441966 TI - Intraoperative diagnosis of the head and neck lesions, thyroid and parathyroid gland, bone and soft tissue, and genitourinary tract. AB - In this article, indications and pitfalls in frozen section diagnosis in selected organs and systems are discussed. The main indications for frozen section examination of head and neck and genitourinary system lesions are to evaluate the resection margin and the metastatic involvement of lymph nodes. Recently, intraoperative consultation has been introduced for identification of patients who might benefit from testis-sparing surgery. Preoperative fine-needle aspiration has greatly diminished the need for frozen section evaluation of thyroid lesions. The only reasonable indication for intraoperative examination of the thyroid is a lesion suspected of malignancy for which preoperative cytology is not aviable for various reasons. In contrast, frozen section is still routinely requested at many institutions to confirm the presence of parathyroid lesions, although precise differentiation between parathyroid hyperplasia, adenoma, and carcinoma is not possible in most cases by histological assesment alone. Tumors of bone and soft tissue are relatively rare, and most pathologists are unfamiliar with intraoperative consultation of these lesions. However, in many cases, limb-sparing management of bone and soft tissue sarcomas is dependent on intraoperative histological diagnosis. Accurate diagnosis is possible in most instances by correlating the histology with clinical and radiological data. In selected cases, histochemistry and/or intraoperative immunohistochemistry may be helpful in diagnosis of bone lesions. Keywords: frozen section - head and neck - thyroid gland - parathyroid gland - soft tissue - urogenital tract. PMID- 30441967 TI - Esophageal dysplasia and adenocarcinoma: a study with double immunostaining for intestinal and gastric markers. AB - Columnar lined esophagus is a complication of long term gastroesophageal reflux disease and the main precursor of esophageal adenocarcinoma. Incomplete intestinal metaplasia in reflux esophagitis represents one of the most important risk factors for neoplastic transformation through the metaplasia-dysplasia adenocarcinoma sequence. However, recent studies suggest that cardiac type mucosa also shows molecular abnormalities which are similar to those of incomplete intestinal metaplasia. Immunohistochemically, three types of esophageal dysplasia and adenocarcinoma are recognized: adenomatous-intestinal, hybrid/mixed and foveolar gastric types. We are interested in the phenotypes of these dysplasias and adenocarcinomas, especially in the possible relationship between them. For this reason, we evaluated the immunohistochemical expression of intestinal and gastric markers in a series of 30 cases of esophageal high-grade dysplasia (high grade intraepithelial neoplasia) and of 70 adenocarcinomas. For immunohistochemical classification, we used double immunohistochemical reactions CDX2/MUC5AC and CDX2/MUC6, respectively. In cases of incomplete intestinal metaplasia, hybrid/mixed high-grade dysplasia and hybrid/mixed adenocarcinoma, we found the expression of gastric mucins MUC5AC and MUC6 only in cells with intestinal differentiation (with nuclear positivity for CDX2). The double immunostaining excluded the presence of the cells with "pure" foveolar gastric phenotype in hybrid lesions. Thus, the hybrid category actually represents the intestinal type dysplasia/adenocarcinoma (which is known to have a better prognosis than the foveolar gastric type). Keywords: immunohistochemistry - double immunostaining - reflux esophagitis - Barrett esophagus - esophageal dysplasia - esophageal adenocarcinoma. PMID- 30441968 TI - Results of morphological screening for Lynch syndrome during the period 2013 2016. AB - The introduction of a screening system for Lynch syndrome in pathology laboratories in Plzen yielded 24 diagnoses of Lynch syndrome during the period of 2013-2016, 20 of them presenting with colorectal cancer. In 8 of those 24 cases germline mutations of MMR genes, previously not recognized as pathogenic with certainty, were detected. Although the frequency of Lynch syndrome in patients with colorectal cancer was only 0.34 % in total, following introduction of the universal immunohistochemical investigation of MMR (mismatch repair) proteins expression in all colorectal cancers examined in Sikl's Institute of Pathology the frequency per year in this department reached 2.4 %. The results favor universal immunohistochemical screening for Lynch syndrome in colorectal and endometrial cancer cases over a selective approach based on a combination of clinical and morphological criteria. Increased effectiveness of the universal approach is not brought about only by higher sensitivity of the immunohistochemical examination per se, but also by the possibility of automation of the process leading to increased adherence even of pathologists not directly engaged in Lynch syndrome management. However, the introduction of a nation-wide universal screening system requires support from the government and health insurance companies. Keywords: colorectal cancer - endometrial cancer - immunohistochemistry - Lynch syndrome - MMR - screening. PMID- 30441969 TI - Histopathology of Neuroendocrine Neoplasms of the Gastrointestinal System. AB - BACKGROUND: Tumors arising from neuroendocrine cells are defined as epithelial neoplasms with predominantly neuroendocrine differentiation. They comprise a distinct group of tumors with a characteristic histological structure and functional properties that develop at various sites, particularly the gastrointestinal system (67%) and lungs (25%). Although such tumors are usually slow-growing and indolent, almost all have malignant potential and most can produce active hormones. Clinical signs vary, and many are dependent on the site at which the tumor develops. Although these tumors were identified more than 130 years, their classification remains unclear. PURPOSE: This review provides a comprehensive overview of the human neuroendocrine system and its neoplasms, from their discovery to current terminology and classifications. In addition, the clinical symptomatology and macroscopic/microscopic features of tumors arising from endocrine cells of the gastrointestinal tract are described, with an emphasis on their classification, diagnostic criteria for their grading and TNM (tumor, node, metastasis) staging, and how these tumors differ according to their localization in the gastrointestinal tract. CONCLUSION: Tumors arising from neuroendocrine cells are rare and can cause typical symptoms of carcinoid syndrome. However, most of these tumors are asymptomatic, which, together with their typical small size and localization in the gut, makes them difficult to access endoscopically and often leads to diagnosis at an advanced stage. To successfully diagnose and treat tumors arising from neuroendocrine cells, they should be assessed using a differential diagnostic procedure and be histopathologically classified, graded, and staged according to specified criteria and the latest classifications and guidelines. Although the terms "carcinoid", "neuroendocrine tumor", and "neuroendocrine carcinoma" are often used synonymously in the literature and by professionals, more precise terminology is required for nomenclature and classification. Key words: gastrointestinal neuroendocrine neoplasms - neuroendocrine tumors - neuroendocrine carcinomas - classification - NET - NEC The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 21. 3. 2018 Accepted: 16. 4. 2018. PMID- 30441970 TI - A Possible Role of Human Herpes Viruses Belonging to the Subfamily Alphaherpesvirinae in the Development of Some Cancers. AB - Seroepidemiological studies suggest that human herpes simplex virus type 1 (HSV 1) and 2 (HSV-2) are linked with several types of cancer; however, they do not appear to play a direct role and are considered to be cofactors. The abilities of HSV-1 and -2 to transform cells in vitro can be demonstrated by suppressing their lytic ability via irradiation with a specific dose of ultraviolet light, photoinactivation in the presence of photosensitizers (e.g., neutral red or methylene blue), and culture under specific conditions. Several mechanisms have been proposed to explain the actions of these viruses. According to the hit-and run mechanism, viral DNA initiates transformation by interacting with cellular DNA and thereby inducing mutations and epigenetic changes, but is not involved in other stages of neoplastic progression. By contrast, according to the hijacking mechanism, viral products in infected cells can activate signaling pathways and thereby cause uncontrolled proliferation. Such products include RR1PK, an oncoprotein that activates the Ras pathway and is encoded by the HSV-2 gene ICP10. Virus-encoded microRNAs may act as cofactors in tumorigenesis of serous ovarian carcinoma and some prostate tumors. Herpes virus-associated growth factors that facilitate or suppress transformation may play important roles in tumor formation. Finally, there is much evidence that HSV-2 increases the risk of cervical cancer after infection of human papilloma viruses. Key words: HSV-1 - HSV-2 - cancer - mechanisms of transformation This work was supported by APVV 0621-12. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 29. 11. 2016 Accepted: 20. 3. 2018. PMID- 30441971 TI - Potential of the Flavonoid Quercetin to Prevent and Treat Cancer - Current Status of Research. AB - Naturally occurring bioactive compounds are promising candidates to prevent and treat cancer. Quercetin is a well-known plant flavonoid that is reported to have anticancer actions in vitro and in vivo. This review focuses on the molecular mechanisms underlying the chemopreventive effect of quercetin and its therapeutic potential in oncology. Quercetin elicits biphasic, hormetic, dose-dependent effects. It acts as an antioxidant and thus elicits chemopreventive effects at low concentrations, but functions as a pro-oxidant and may therefore elicit chemotherapeutic effects at high concentrations. Quercetin has multiple intracellular molecular targets with the potential to reverse treatment resistance and affect pleiotropic signaling processes that are altered in cancer cells. Studies suggest that quercetin binds to several receptors that play important roles in carcinogenesis, regulates expression of various genes, induces epigenetic changes, and interferes with enzymes that metabolize chemical carcinogens. In addition, it also elicits anti-inflammatory and antiviral effects. The ability of quercetin to induce apoptosis of cancer cells without affecting non-cancer cells has been documented using various cell lines. Quercetin also has antiangiogenic and antimetastatic properties. When used in combination with chemotherapy and radiotherapy, quercetin can act as a sensitizer and protect non-cancer cells from the side effects of currently used cancer therapies. The safety and potential usefulness of quercetin for the prevention and treatment of cancer have been documented in both animal experiments and a phase I clinical trial. Current studies are focused on nano-formulations to overcome the low bioavailability of natural quercetin, which limits its clinical use as an antitumor agent. Key words: quercetin - flavonoid - chemoprevention - oxidative stress - apoptosis - antitumor agent - cancer therapy - cancer The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 22. 1. 2018 Accepted: 16. 4. 2018. PMID- 30441972 TI - Use of Trastuzumab for Neoadjuvant Therapy of HER2+ Breast Cancer - 5-Years of Experience in a Single Clinic. AB - BACKGROUND: Trastuzumab (Herceptin(r) - H) has been the standard-of-care for patients with HER2+ breast cancer (BC) since 2009 in the Czech Republic. Neoadjuvant application of H increases the number of patients who achieve pathological complete remission (pCR) and improves patients' outcomes. AIM: This study aimed to assess the effect of neoadjuvant therapy (NAT) with H in patients with early HER2+ BC and to correlate the therapeutic outcome with overall survival (OS). We defined pCR as no invasive carcinoma (ypT0) or in situ residual carcinoma (ypTis) in breast tissue and no invasive carcinoma in axillary lymphatic nodes (ypN0). To correlate pCR with the hormone dependency of BC, we compared the number of patients who achieved pCR between those with hormone dependent (estrogen receptor (ER) +) BC and those with hormone-negative (ER-) BC. RESULTS: We evaluated data from 148 patients with HER2+ BC, most of whom were at stage II. Of these, 50.7% were premenopausal women and 45.9% had ER- BC. Most patients were treated with anthracyclines followed by taxanes and H. pCR was reported in 50% of patients (74/148). ER+ BC regressed more often to ypTis stage (24/35), ER- BC to ypT0ypN0 stage (26/39). The 1-year OS rate of patients who achieved pCR was significantly higher than that of patients who did not (100.0% vs. 95.3%, p = 0.009). Median OS was not achieved in pCR patients group. CONCLUSION: Patients who achieved pCR had a better prognosis than patients who did not. Key words: neoadjuvant therapy - trastuzumab - early breast cancer - pathological complete remission - prognosis The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 14. 9. 2017 Accepted: 15. 2. 2018. PMID- 30441973 TI - Detection of FLT3 Mutations in Patients from Eastern Slovakia. AB - BACKGROUND: The study investigated FLT3 gene mutations in patients from eastern Slovakia using a simple molecular method. PATIENTS AND METHODS: We analyzed 141 patients with primary acute myeloid leukemia (AML) and 8 patients with AML that developed from myelodysplastic syndrome (MDS) who were aged 19-81 years. DNA isolated from peripheral blood and/or bone marrow was analyzed by PCR. FLT3 internal tandem duplication (FLT3-ITD) was detected by amplification of exons 14 and 15. Point mutations in the FLT3 tyrosine kinase domain (FLT3-TKD) were detected by digesting the PCR product of exon 20 with the restriction endonuclease EcoRV. Fragments were separated electrophoretically. PCR products of the positive samples were also analyzed using a microchip device (Bioanalyzer 2100). RESULTS: LT3-ITD and point mutations in the FLT-TKD were detected in 19 and 8% of patients, resp. Two patients (1%) harbored both types of mutations. Patients with and without FLT3 mutations were called FLT+ and FLT-, resp. Most FLT3+ patients had no chromosomal aberrations (59%) or harbored the t (15; 17) translocation in PML-RARA (15%). The mortality rate was 33% among FLT3+ patients and 10% among FLT3-patients. Among FLT3+ patients, the mortality rates of patients with FLT3-ITD and point mutations of the FLT-TKD were almost the same. A 77-year-old female patient with both FLT3-ITD and a point mutation in the FLT3 TKD was in remission. The eight patients who developed AML from MDS were assessed separately. Of these, three patients were FLT3+; two patients displayed FLT3-ITD, and one patient harbored a point mutation in the FLT3-TKD. No other genetic aberrations were detected. FLT3+ patients lived for longer than FLT3-patients. These analyses of FLT3 gene mutations in patients from eastern Slovakia are consistent with published data from other databases. CONCLUSION: The applied PCR method is reliable, relatively fast, and affordable, and can be used for routine monitoring of FLT3 gene mutations. FLT3 mutations can be verified using a microchip as an alternative to capillary electrophoresis. Key words: acute myelogenous leukemia - DNA - PCR - mutation - FLT3-ITD - FLT3-TKD The study was supported by the European Regional Development grant OPVaV-2009/2.2/05- -SORO (ITMS code: 26220220143). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical paper Submitted: 19. 10. 2017 Accepted: 15. 2. 2018. PMID- 30441974 TI - Effects of Treatment with Crizotinib on Non-small Cell Lung Carcinoma with ALK Translocation in the Czech Republic. AB - BACKGROUND: Patients with advanced anaplastic lymphoma kinase (ALK) -positive non small cell lung cancer (NSCLC) may gain significant benefit from treatment with the first-generation ALK inhibitor crizotinib. This study investigated the effects of crizotinib in advanced ALK-positive NSCLC patients via analyzing data submitted to the TULUNG registry by pneumo-oncology centers in the Czech Republic. PATIENTS AND METHODS: We analyzed the data of 60 NSCLC patients submitted to the TULUNG registry by pneumo-oncology centers who had ALK translocation confirmed by fluorescence in situ hybridization and complete data records from 2011 to 2017. RESULTS: The median age of patients was 58 years. A total of 53% of patients were men, 90% had adenocarcinomas, 61.7% were smokers or ex-smokers, and 65% had a performance status of 0. Upon initiation of crizotinib therapy, most patients were at stage IV (88.3%) and the remainder were at stage IIIA or IIIB. Crizotinib was the second-line therapy in 71.7% of patients. A total of 20% of patients suffered side effects, while 11.7% suffered grade 3 and 4 adverse effects. A total of, 6.7, 25, 21.7, and 25% of patients displayed a complete response, a partial response, stable disease, and progressive disease, resp. Progression-free survival (PFS) was 5.8 months. Overall survival (OS) was 27.9 months from the initiation of the first-line therapy and 12.6 from the initiation of crizotinib therapy. PFS and OS were longer among nonsmokers and ex smokers than among smokers (PFS, 9.7 vs. 5.8 vs. 3.8 months, p = 0.029; OS, 26.8 vs. 15.3 vs. 7.0 months, p = 0.015). CONCLUSION: Targeted crizotinib therapy is well tolerated and has significant benefit in patients with advanced ALK-positive NSCLC. Although international guidelines recommend that crizotinib is only used as a first-line therapy, it is used as a second-line and higher-line therapy in the Czech Republic. Clinical studies provide evidence that targeted therapy elicits better effects and less toxicity than routine chemotherapy. Key words: ALK translocation - crizotinib - targeted biological therapy - tyrosine kinase inhibitors This work was supported by AZV grant No. 17- 30748A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 17. 1. 2018 Accepted: 20. 2. 2018. PMID- 30441975 TI - Selected Genetic Polymorphisms Associated with Hypoxia and Multidrug Resistance in Monoclonal Gammopathies Patients. AB - BACKGROUND: Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, including hypoxia-inducible factors (HIFs). Activation of HIF-1alpha is associated with increased expression of P-glycoprotein and multidrug resistance in cancer cells. In this retrospective study, we analyzed candidate single-nucleotide polymorphisms (SNPs) in HIF-1alpha and HIF-1beta associated with risk of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). PATIENTS AND METHODS: Genotypes of SNPs associated with hypoxia were determined in an independent cohort of monoclonal gammopathies (MG) (275 MM and 228 MGUS patients) and in 219 cancer-free controls by real time polymerase chain reaction allelic discrimination. RESULTS: When MM patients were compared to controls, protective role of CG genotype compared to CC in HIF-1beta (rs2228099) for MM development was observed (OR = 0.65; CI 0.45-0.95; p = 0.026). Even after adjustment for patients' age and body mass index (BMI), there were significantly lower odds (OR = 0.55; p = 0.045) of developing MM patients of CG genotype in comparison to CC genotype. Log-rank test confirmed association of GT haplotype (rs11549467, rs2057482) in HIF-1alpha with better overall survival (median 41.8 months; (CI 35.1-48.5)) for "none GT" and median 93.8 months (CI 31.3-156.4) for "at least one GT" haplotype (p = 0.0500). Further, significant associations between SNPs in MDR1 and outcome of MM were found in 110 MM patients that underwent bortezomib-based treatment. CONCLUSION: Our study showed a genetic predisposition for risk of MG development and/or outcome of MM patients; nevertheless, further studies are needed to confirm our initial analysis. PMID- 30441976 TI - Resection of Abdominal, Pelvic and Retroperitoneal Tumors. AB - BACKGROUND: Mesenchymal malignancies are relatively rare tumors with distinct behaviors that are usually surgically removal. However, it is sometimes impossible to perform such surgery according to standardized procedures. In particular, surgical removal of intraperitoneal and retroperitoneal tumors differs among individuals. CASE REPORTS: We present two cases with intra abdominal and retroperitoneal sarcomas who were treated at our comprehensive oncology center. The first patient was a 36-year-old male who was initially diagnosed with a tumor in the subrenal space that measured 95 * 90 * 140mm, contacted the inferior vena cava and right kidney, and had the same blood supply as the upper pole of the right kidney. Primary histological analysis indicated that the tumor was a schwannoma. After further examinations, the tumor was removed and the right kidney was preserved. A ganglioneuroblastoma was diagnosed based on definitive histological analysis. Adjuvant radiotherapy was administered to the tumor bed. The patient is disease-free at 1 year after resection. The second patient was a 52-year-old male who was diagnosed with a liposarcoma in the retroperitoneal space that measured 50 * 36 * 15cm and weighed 14kg upon resection. Resection involved left-side nephrectomy and adrenalectomy. Adjuvant chemotherapy with IFO/ADM was administered. A recurrence in the tumor bed was resected 31 months after the primary resection. Three new foci appeared in the retroperitoneal space after another 18 months and were removed. Another recurrence in the left funiculus was removed after a further 6 months. The patient has been disease-free for 3 months. CONCLUSIONS: Treatment of soft tissue sarcoma is complex and should be performed at a comprehensive oncology center if possible. Preoperative biopsy is essential. Key words: sarcoma - surgical procedures Supported by MZ CR-RVO (MOU,00209805). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 6. 3. 2018 Accepted: 20. 3. 2018. PMID- 30441977 TI - Alcohol abuse in road traffic: medical-legal aspects. AB - Alcohol-affected road users - pedestrians or drivers are a significant risk factor for road accidents and injuries. Therefore, the issue of alcohol-related traffic accidents is logically a subject of great attention. However, the statistics results of the General Prosecutor's Office of the Slovak Republic and of the Police Force of the Slovak Republic clearly confirm the fact that in the Slovak Republic the above-mentioned problem of the whole society is not sufficiently eliminated. The legislation implemented since 2011 should therefore lead to more substantial and effective prevention in this area. From the point of view of the current knowledge from the Forensic Medicine Department, the current legislative regulation of the Slovak Republic is still insufficient and will require some changes. It can be assumed that the issue of controlling the influence of alcohol on road users will be a subject of harmonization throughout the European area. The aim of this thesis is to analyse individual aspects of the present state and their epicritical evaluation. Keywords: alcohol - driver - prevention - forensic medicine - legislation. PMID- 30441979 TI - Mesenchymal stem cells and type 1 diabetes treatment. AB - Type 1 diabetes represents a serious disease which is caused by autoimmune destruction of insulin-producing B cells in the pancreas. Administration of exogenous insulin cannot replace sensitive and gentle regulation of blood glucose levels that is established by B cells in healthy individuals. Pancreas or islet transplantation is limited by a shortage of donor pancreas and by complications associated with transplantations. For those reasons, new approaches of treatment are being searched, the using of mesenchymal stem cells (MSCs) envisions a promising tool for cell-based therapy of type 1 diabetes. MSCs have a significant impact on the regulation of the immune system, are a potent source of various cytokines and growth factors and manifest multilineage differentiation abilities. In context of type 1 diabetes, MSCs can transdifferentiate into insulin-producing cells, support the regeneration of residual B cells by production of trophic and growth factors or participate in the suppression of the autoimmune reaction against B cells. This review is focused on perspectives and mechanisms of MSC based therapy and its limitations. Key words: autoimmune reaction - differentiation - mesenchymal stem cells - type 1 diabetes. PMID- 30441978 TI - The Scottish model of vancomycin dosing and therapeutic drug monitoring improves both efficacy and safety of vancomycin therapy. AB - OBJECTIVE: Vancomycin therapeutic drug monitoring (TDM) is recommended for better treatment efficacy and safety. The Scottish Antimicrobial Prescribing Group model recommends weight-based loading dose, next 3-4 doses based on creatinine clearance and maintenance doses according to trough concentrations. METHODS: Retrospective cohort study of all adult patients treated with vancomycin before and after introducing the guideline in a large Czech hospital in 2015 compares the success rate in achieving recommended trough concentrations (10-20 mg/l) during first measurement and efficiency of maintaining these concentrations subsequently. Assessment of vancomycin related nephrotoxicity is included. RESULTS: In 2014, 74/163 (45.4 %) patients achieved recommended concentrations in the first measurement, compared to 101/160 (63.1 %) patients in 2016 (chi2; p = 0.001). Recommended trough concentrations in more than half of subsequent measurements were detected in 51/105 patients (48.6 %) in 2014 and in 80/117 patients (68.4 %) in 2016. Not a single level in subsequent measurements within the range was detected in 28 (26.7 %) cases in 2014 and in 10 (8.5 %) cases in 2016 (Mann-Whitney; p = 0.026). There was no difference in nephropathy occurrence (chi2; p = 0.286). CONCLUSION: The adopted Scottish model of vancomycin TDM resulted in very significantly higher achievement of recommended trough concentrations during first measurements and significantly more effective maintenance of subsequent concentrations, without increased nephrotoxicity. Key words: guideline - therapeutic drug monitoring - vancomycin. PMID- 30441980 TI - How to diagnose cardiac sarcoidosis? AB - Sarcoidosis is a systemic granulomatous disease of unknown etiology that can affect any organ including the heart. Clinical manifestations of heart disease are seen in about 5 % of patients, but histology shows a higher rate of heart involvement by sarcoidosis. Therefore, heart sarcoidosis is underdiagnosed because of clinically non-symptomatic course in some patients or physicians simply do not think about this heart involvement. Echocardiography, Holter monitoring, magnetic resonance imaging, positron emission tomography/computed tomography, thallium scintigraphy, and endomyocardial biopsy are methods of investigation when suspected of heart involvement by sarcoidosis. In particular, magnetic resonance has gained importance recently in the diagnosis of cardiac sarcoidosis. Key words: cardiac sarcoidosis - diagnostics - therapy. PMID- 30441981 TI - Future of pharmacological treatment of non-alcoholic steatohepatitis in terms of key pathophysiological mechanisms. AB - Obesity reaches the dimensions of the global epidemic. It directly contributes to an increase in the prevalence of systemic diseases associated with obesity. Obesity and overweight globally cause 3.5 million deaths annually [1]. Non alcoholic fatty liver disease has become the most common chronic liver disease in developed countries and is considered to be a liver manifestation of metabolic syndrome. The extent and burden of the disease are increasing and reaching epidemic proportions because of its close association with the epidemic of obesity and diabetes mellitus type [2]. It affects 30 % of the adult population [2]. There is an alarming increase in prevalence among children and adolescents. However, in the group of patients with high cardiometabolic risk, we can see a significantly higher prevalence of NAFLD. Prevalence in obese patients is 75 -92 %, in diabetic patients prevalence is between 60 -70 % [3]. A significant proportion of patients with NAFLD will suffer from a progressive form of the disease - non-alcoholic steatohepatitis (NASH), which is associated with the development of advanced liver fibrosis, cirrhosis, and its complications. The growing prevalence of NASH in the near future will bring the advanced cohort of our patients to the stage of an advanced liver disease. If the adverse epidemiological trend is not reversed, in the next decade the most common cause of liver transplantation will be NASH. A steadily rising trend can be seen in an increase in the number of cases of hepatocellular carcinoma causally related to NASH [4]. Treatment based on the influence of key pathogenetic mechanisms could alter the individual's future as well as the global burden arising with NASH. New molecules with anti-inflammatory and antifibrotic effects will play a key role in the future. Key words: cirrhosis - insulin resistance - metabolic syndrome - NASH. PMID- 30441982 TI - Low-carbohydrate diet in diabetes mellitus treatment. AB - There has been an increasing amount of information about the positive results of low-carbohydrate diet in the treatment of diabetes, pre-diabetes, metabolic syndrome and obesity in the form of randomized trials, their meta-analysis and case studies. Many of these indicate that low carbohydrate diets are safe, could significantly improve the compensation of both types of diabetes and the overall health of the diabetic patients. In successful therapy, this diet leads to weight loss, lower medication doses or prescribing, and in some cases of type 2 diabetes also to remission. However, the low carbohydrate diet is not recognized in Czech diabetology, and concerns remain particularly about its safety. This article is a summary of the current knowledge about low-carbohydrate diet, its benefits, risks and contraindications, and aims to initiate a discussion about its use as one of the options for dietary treatment of diabetics. Key words: diabetes mellitus - ketogenic diet - low-carbohydrate diet - metabolic syndrome - obesity. PMID- 30441983 TI - Controversies in the treatment of gout. AB - The authors discuss current options on the treatment of gout (acute gout attack, prophylaxis, management of hypouricemia) and asymptomatic hyperuricemia. They highlight the differences in individual guidelines in terms of the spectrum of drugs used, their preferences, dosing, dose titration, and goals of treatment as well as different positions over asymptomatic hyperuricemia. Further, the authors provide an overview of latest concepts related to uric acid and its association with some neurologic and cardiovascular diseases. Another issues discussed in the article are the completely different guidelines for general practitioners and their principles. In conclusion, the authors note that answers to some controversies in the treatment of gout can only be provided by data obtained from properly designed and conducted clinical trials. Key words: allopurinol - colchicine - glucocorticoids - gout - non-steroidal anti-inflammatory drugs - uric acid. PMID- 30441984 TI - Endothelial function, its relation to arterial hypertension and the possibility of its modulation. AB - Endothelium has both a protective and a very complex para-, endo- and autocrine functions. Vascular tone is determined as a balance between the production of vasodilating and vasoconstrictive substances. Among the most important vasodilators are nitric oxide (NO), PGI2, endothelial-derived hyperpolarizing factor (EDHF), adenosine and others, among the most important vasoconstrictors, endothelin-1 and angiotensin-2. Therapeutic goal of improving endothelial secretory function should be maximizing production of vasodilators and minimizing production of vasoconstrictors. Improvement of endothelial function can be achieved most effectively by following a healthy lifestyle (changing the diet to a Mediterranean type, sufficient physical activity, weight reduction and smoking cessation) and by initiating the treatment with ACE inhibitors and statins, when indicated. Large number of trials have shown that all of these interventions improve the prognosis of patients and a part of this effect may be mediated by improving endothelial dysfunction. Key words: endothelial dysfunction - endothelium - hypertension. PMID- 30441985 TI - Myocardial injury after carbon monoxide intoxication in suicide attempt, with features of both toxic and tako-tsubo cardiomyopathy: case report. AB - Severe carbon monoxide intoxication may cause tissue injury by hypoxemia and histotoxicity. The affection of the heart muscle often leads to transient global or regional systolic dysfunction of left ventricle or both ventricles and increased occurences of malignant arrhytmias. On the contrary, stress-induced cardiomyopathy is described as temporary segmental loss of contractility, mostly in apical segments of the left ventricle with mid- and basal sparing and less common hypokinesias in mid- or basal parts, or affection of both ventricles. This case report is dedicated to a 34-years old male, who was admitted to the department of emergency medicine after suicide attempt by carbon monoxide poisoning. Echocardiography at admission showed akinesias of midsegments of left ventricle and severe hypokinesias of apical and basal segments. Despite severe cardiogenic shock, adequate therapeutic management including mechanical ventilation, normobaric oxygenotherapy and catecholamine treatment led to a complete somatic recovery after 2 weeks, and without any permanent hypoxemic brain injury. Our case might be a coincidence of toxic cardiomyopathy, caused by carbon monoxide poisoning, and takotsubo cardiomyopathy as a result of long term exposition to combined stress factors that may lead even to a suicide attempt. Both types of cardiomyopathies often occure simultaneously due to similar pathophysiologic mechanisms. Both tako-tsubo and toxic cardiomypathy have good prognosis after overcoming the acute phase. Key words: carbon monoxide - cardiogennic shock - cardiomyopathy - suicide - tako-tsubo cardiomypathy. PMID- 30441986 TI - Trimeresurus albolabris (white-lipped green pit viper) - bite report: case report. AB - Toxicology is a specialized scientific discipline, focusing on microbiological, botanical and animal venoms, poisons and toxins. This discipline includes more than just the chemistry and mode of action of a toxin, but also with the biology of venom or poison producing organism, the structure and function of the venom apparatus, as well as the use of the venom or poison. The discipline of toxicology involves the study of the poison on living organisms and the therapy of the intoxication. A genus Trimeresurus, to which belongs Green Pit Viper, is large and includes around 36 types. Snake venoms have various composition and they can effect cardiovascular and nervous system, kidneys, hemocoagulation, vessel wall and muscle cells. In this article, we are presenting a rare case report about Trimeresurus albolabris, review of literature and general treatment after intoxication with snake venom. Prompt assessment, observation and early specific management are the keys to treat intoxication with snake venom. Key words: hemotoxin - intoxication - snake venom - treatment - Trimeresurus albolabris. PMID- 30441987 TI - Spironolactone in the treatment of hypertension: a neglected molecule. AB - Spironolactone, a mineralocorticoid receptor antagonist, is used in the treatment of hypertension for over 50 years. Due to the absence of morbidity and mortality studies, it is not considered to be a first-choice drug in the treatment of patients with primary hyperaldosteronism. However, it has a secure and stable position in the treatment of resistant hypertension. The effect of spironolactone on blood pressure lowering in antihypertensive combination therapy was demonstrated in several uncontrolled trials. The analysis of ASCOTBPLA study also contributed significantly to this area. In the last 10 years, the higher antihypertensive effect of spironolactone compared to placebo (ASPIRANT) and other antihypertensive drugs (PATHWAY-2) was proved in several randomized studies. The outcomes of morbidity and mortality studies in patients with chronic heart failure are also important for the clinical use of spironolactone in patients with hypertension - spironolactone reduces morbidity and mortality in patients with reduced ejection fraction and morbidity only in patients with normal ejection fraction. The outcomes of above-mentioned clinical studies are reflected in current guidelines in which spironolactone has an indisputable role in the treatment of resistant hypertension, primary hyperaldosteronism, and heart failure with reduced ejection fraction. Key words: current guidelines - heart failure - hypertension - resistant hypertension - spironolactone. PMID- 30441988 TI - Radicality of proximal gastrectomy - a rewiev. AB - Although the incidence of gastric cancer is decreasing worldwide, the number of esophagogastric junction and upper-third gastric carcinomas is gradually growing. This is due to an increasing incidence of reflux esophagitis with Barrett's metaplasia and successful eradication of Helicobacter pylori infection. Treatment options for these tumors include proximal gastrectomy. The only currently accepted indication for proximal gastrectomy is early gastric cancer with no preoperative evidence of lymph node involvement. In Western countries, however, advanced gastric cancers are treated using this method as well in spite of the above recommendation. Oncological radicality is a widely discussed issue. If R0 resection and at least D1+ lymphadenectomy are achieved in proximal gastrectomy, the overall survival is comparable with total gastrectomy in early gastric cancers. Recurrence rate, nevertheless, remains higher for proximal gastrectomy. Key words: proximal gastrectomy - oncological radicality - esophagogastric junction cancer - early gastric cancer. PMID- 30441989 TI - Quality of life after proximal gastrectomy a review. AB - INTRODUCTION: The quality of life in cancer patients has received increasing interest recently. The results published to date have shown a potential benefit of proximal gastrectomy compared to total gastrectomy as regards long-term improvement in the quality of life. Up to 70% of gastrectomized patients suffer from various symptoms negatively influencing the postoperative quality of life. These symptoms are collectively referred to as postgastrectomy syndrome. Proximal gastrectomy may be more beneficial as opposed to total gastrectomy since it preserves a functional part of the stomach and allows alleviation of these symptoms. Numerous questionnaires are used to evaluate the quality of life in gastric cancer patients. The PGSAS-45 questionnaire of the Japanese Postgastrectomy Syndrome Working Party is probably the best validated one. Results of works published to date evaluating the quality of life after proximal gastrectomy are summarized in the text and an overview of basic evaluated parameters is presented. CONCLUSION: The works published so far related to quality of life after proximal gastrectomy have described outcomes only in patients with early gastric cancers or in cT2N0 patients. Further studies with more patients involved, comparison between every single modification of proximal gastrectomy and also inclusion of advanced stages will be necessary to determine the optimal type of surgery. Nevertheless, the majority of studies published to date favor proximal gastrectomy against total gastrectomy in terms of better postoperative quality of life. Key words: gastric cancer - esophagogastric junction cancer - quality of life - proximal gastrectomy. PMID- 30441990 TI - Can the One-Step Nucleic Acid Amplification method of lymph nodes examination make the staging of pulmonary tumours more precise? AB - INTRODUCTION: The aim of this article is to compare the sensitivity of detecting micrometastases in hilar and mediastinal lymph nodes in case of primary (non small cell) and secondary (metastases of colorectal carcinoma) pulmonary tumours using standard histopathological examination with haematoxylin-eosin staining, immunohistochemistry examination with Anti-Cytokeratin 19 antibody and examination based on the One-Step Nucleic Acid Amplification method. METHOD: During radical surgical treatment of primary non-small cell lung carcinoma and pulmonary metastases of colorectal carcinoma, hilar and mediastinal lymph nodes of 100 patients enrolled in the study in the period from 2015 to 2017 were extracted based on a standard classification. These lymph nodes were subsequently divided along the longitudinal axis into 4 identical parts where part one and three on the left were intended for examination based on the One-Step Nucleic Acid Amplification method, whereas parts two and four were subjected to histopathological examination. In evaluating the respective parts of the nodes by histological examination, the nodes were first examined by a standard procedure that involves haematoxylin-eosin staining, followed by immunohistochemistry examination with Anti-Cytokeratin 19 antibody. The One-Step Nucleic Acid Amplification method was performed in the kit supplied by Sysmex (Kobe, Japan) and is based on the detection of cytokeratin 19 mRNA (messenger ribonucleic acid) by reverse transcription coupled with isothermal amplification. RESULTS: A total of 1,426 lymph nodes of the patients enrolled in the study were extracted and examined using the above mentioned methodology. In 78 patients (78%), identical results were obtained using haematoxylin-eosin staining, immunohistochemistry with Anti-Cytokeratin 19 and One-Step Nucleic Acid Amplification. Micrometastases in the lymph nodes using the One-Step Nucleic Acid Amplification method in the absence of the other methods were proven in 16 patients (16%). Only in 3 cases (3%), the examination by haematoxylin-eosin staining, or immunohistochemistry with Anti-Cytokeratin 19, was positive while One-Step Nucleic Acid Amplification was negative. The results obtained by immunohistochemistry with Anti-Cytokeratin 19 antibody were practically the same as those obtained by haematoxylin-eosin staining (97%). CONCLUSION: The results of the study have demonstrated a higher percentage of metastases detected in hilar and mediastinal lymph nodes if the One Step Nucleic Acid Amplification method of examination was used compared to haematoxylin-eosin staining and immunohistochemistry with Anti-Cytokeratin 19 antibody (upstaging in 16%). This shows that the examination of lymph nodes using the One-Step Nucleic Acid Amplification method can have a certain potential to make the pulmonary tumours staging more accurate. On the other hand, immunohistochemistry with Anti-Cytokeratin 19 antibody seems to be not so useful. However, it is necessary to prove this hypothesis in follow-up studies, or where applicable, in a larger cohort of patients. Another task is to ascertain, by careful patient monitoring, the influence of the micrometastases detected in their lymph nodes using the One-Step Nucleic Acid Amplification method on these patients' follow-up. Key words: lung cancer - lymph nodes - H&E - IHC CK19 - OSNA assay. PMID- 30441992 TI - Risk factors and post-operative complications after gastrectomy for cancer. AB - INTRODUCTION: Gastric resections due to carcinoma belong to the most demanding procedures in visceral surgery. This is due to the requirements for the extent of resection and lymphadenectomy, coupled with the need for functional reconstruction of the digestive tract. The procedure is associated with 18-46% morbidity, which delays administration of adjuvant therapy and worsens oncological results. Identification of risk factors for potential complications may play an important role in the indication and perioperative care. The aim of our study is to (i) evaluate the morbidity a mortality of a patient group with post-gastrectomy complications and to (ii) identify associated risk factors. METHOD: This retrospective analysis comprises patients treated in 2005-2016. Gastric resection was performed in 266 adenocarcinoma patients, 172 men and 94 women (median age 66 years). Early post-operative complications following gastrectomy were observed within 60 days. Complications and their severity were evaluated according to the extended form of the Accordion Severity Grading System. Selected demographic risk factors, operative factors and malignancy related factors were analyzed. Multivariate regression (orthogonal projections to latent structure) was used for statistical processing. RESULTS: Overall morbidity and mortality was 34.6% and 3.4%. Serious complications occurred in 51 operated patients (19.2%). 24 patients had two or three complications (9%). The most common grades of severity were grade 2 in 31 patients (11.7%) and grade 4 in 20 patients (10.9%). The duration of hospital stay correlated with the severity of the complication. Most common surgical complications were: intra-abdominal abscess (16.4%, 17 cases), wound complications (5.3%, 14 cases), pancreatitis (4.9%, 13 cases), anastomotic leakage (3.4%, 9 cases), postoperative ileus (3.4%, 9 cases). Respiratory and cardiac complications were the most common non-surgical complications (8.6%, 23 cases and 3.8%, 20 cases, respectively). In the derived statistical model, BMI, the presence of more comorbidities, lesser surgical experience, the length of hospital stay and hospitalization at ICU were identified as risk factors associated with the grade of complication, morbidity, presence of serious complication and multiple complications. CONCLUSION: Gastrectomy plays a fundamental role in the curative treatment of gastric carcinoma; it is, however, associated with substantial morbi-dity and mortality. The best management of complications is their prevention. Preoperatively, the greatest attention should be paid to patients with several comorbidities and higher BMI. Resections should be performed by experienced surgeons. During resection, consideration should be given to the extent of resection and lymphadenectomy. In the postoperative period, the length of hospital stay, especially at ICU, should be reduced to minimum. Analyses of these risk factors may decrease the incidence of complications. Key words: gastric cancer - gastrectomy - risk factors - complications. PMID- 30441991 TI - Pleural empyema - single center experience. AB - INTRODUCTION: Retrospective analysis of a group of patients treated for pleural empyema in the Department of Surgery, University Hospital Pilsen, over the last ten years. METHOD: We evaluated a group of patients treated for pleural empyema in the Department of Surgery, University Hospital in Pilsen, during the period 2007-2016. We focused on the demographic data of this group, the causes of empyema in these patients, surgical procedures performed in connection with empyema, the microbial species found in empyema, and, last but not least, on morbidity and lethality. RESULTS: We treated 103 patients with pleural empyema during the above period - 80 men (77.7%) and 23 women (22.3%) aged 23-83 years (average age 59.4 years). 64 patients had a history of surgical or invasive procedure (62.1%). The length of history was traceable in 55 patients (53.4%) and was 23.1 days on average, remaining unclear in the rest of the group. 1/3 of cases were metapneumonic empyemas, 1/3 postoperative empyemas and 1/3 of the cases were due to other reasons. The most commonly cultivated bacterial genus was Streptococcus, species Staphylococcus aureus. The most common surgery was chest drainage (51%). 13 patients died (lethality 12.6%) after surgery, the most common cause of death being sepsis; postoperative morbidity was 34%. CONCLUSION: Pleural empyema is a serious condition with very high morbidity and lethality. Surgical procedures done to manage empyema are associated with a very high risk of necessary reoperation. Positive mycological culture from empyema seems to be associated with a higher risk of complications and death. Key words: empyema - thoracic drainage - thoracotomy - lung decortication - videothoracoscopy. PMID- 30441993 TI - Liver Tuberculosis a case report. AB - Tuberculosis remains a global health issue affecting millions of people worldwide. Pulmonary form of tuberculosis presents 80-90% of cases with prevalence declining worldwide. On the other hand, extrapulmonary tuberculosis remains at the same level. Extrapulmonary tuberculosis cases are rare at our department. In our article we present a patient who underwent a liver resection with an unexpected finding of liver tuberculosis. In this form of tuberculosis it is difficult to establish a definite diagnosis since clinical symptoms and results of imaging tests maybe equivocal orin determinate. The rare occurrence and the fact that the majority of extrapulmonary tuberculosis cases are not transmitted to other patients lead to lower attention of health professionals. The goal of our article is to bring this rare form of tuberculosis to attention. Inclusion of this form of tuberculosis in differential diagnosis may help to establish correct a diagnosis and therapy. Key words: extrapulmonary tuberculosis - liver. PMID- 30441994 TI - Inverted Meckel's diverticulum: a rare cause of ileo-ileal intussusceptions and lower gastrointestinal bleeding. AB - Intussusception due to an inverted Meckel's diverticulum in adults is rare. We present a case report of a 28-year-old man with Meckel's diverticulum as a cause of ileo-ileal intussusceptions and lower gastrointestinal bleeding. The patient was admitted to the hospital with incomplete small bowel obstruction, abdominal pain and massive rectal bleeding. Surprisingly, pre-operative abdominal USG revealed inhomogeneous target-like mass in the right lower abdominal quadrant as intussusception with an intraluminal polypoid lesion. The patient underwent urgent laparotomy which confirmed ileo-ileal intussusception. The involved segment of small intestine (70 cm) was resected. The surgical specimen contained an elongated polypoid lesion of 8*2.5*2 cm within the ileal lumen. Histopathological examination ascertained an inverted Meckel's diverticulum. In the discussion, we deal with diagnosis and treatment issues of Meckel's diverticulum. Key words: inverted Meckel's diverticulum - intussusceptions - gastrointestinal bleeding - acute abdomen. PMID- 30441995 TI - Pathophysiology, causes and epidemiology of chronic heart failure. AB - The prevalence of heart failure in developed countries is about 1-2 % in general and in patients above 70 years over 10 %. HFpEF is the cause of heart failure from 22 to 73 %, exact data are not available. If compared with HFrEF, patients with HFpEF are older, more frequent women with hypertension and atrial fibrillation, but less myocardial infarction in their history. Heart failure is a hemodynamic disorder and the pathophysiologic basis is cardiac output, cardiac contractility, filling pressures, wall stress during systolic and diastolic function and heart rate. The neurohumoral activation is very important for the diagnosis as well as prognosis and the most sensitive seems to be brain natriuretic peptide (BNP), respectively the precursor NT-proBNP, which become a part of the new diagnostic classification and are a part of modern treatment. Key words: heart failure - hemodynamics - neurohumoral activation. PMID- 30441996 TI - What we know about epidemiology of heart failure in Slovakia and globally. AB - Heart failure (HF) is nowadays some of the most significant causes of mortality and morbidity, as well as one of the leading causes of hospitalization. Increasing number of patients with HF is becoming one of the most burning problems not only for health care, but also for the social welfare system. The knowledge of the epidemiology is crucial for rational planning and management of curative and preventive health care and allocation of research capacities. The sources of data for description of basic epidemiological characteristic of HF in Slovakia come from cross sectional surveys of outpatient care and hospitalization records of patients with heart failure, publicized sources of the National health information center and database of health care provision gathered by health insurer Dovera. Crude prevalence of HF in Slovakia is 2.3%. Age specific prevalence ranging from 31/1 000 in habitants aged 50-54 up to 189/1 000 in the 80-84 age group. Average age in male population was 61.8 (+/- 8) and women 65.6 (+/- 9.3) years. In the functional class NYNA I were 10 %, in class NYHA II 45%, NYHA III 32% a NYHA IV 3 % patients with chronic heart failure. The most prevalent dominant cause of HF, 50-60 % of cases, is ischemic heart disease. Left ventricular ejection fraction of less than 40 % was observed in 26 % of patients followed up in general practice and 43 % of patients in care of the specialists. The exact data on HF incidence in Slovakia are no available. Incidence of hospitalizations for the newly diagnosed HF was 120 in one hundred thousand people a year, which could be considered bottom limit of incidence. The number of hospitalizations for HF grows dramatically from 9 060 in 2005 to 22 112 in 2017. The average length of hospitalization in 2015 was 9.4 +/- 9.7 days. Hospitalization mortality, despite trend to decline, remains high at 6.2 %. It is estimated that prevalence of chronic HF will grow further fueled by population aging, the treatment success of acute cardiovascular and congenital heart diseases, prevention of sudden heart failure, and also prolongation of life expectancy in patients with HF. Both material and human in health care resources need to adapt to this visible trend. Key words: heart failure - hospitalizations incidence - prevalence. PMID- 30441997 TI - Diagnosis of heart failure: the new classification of heart failure. AB - Heart failure (HF) is a clinical syndrome characterized by typical symptoms (e.g. breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g. elevated jugular venous pressure, pulmonary crackles and periphe-ral oedema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. Natriuretic peptides have a significant nega-tive predictive value for excluding of heart failure. Echocardiography is the most important imaging method in heart failure. The new classification distinguishes HF by left ventricule ejection fraction (LV EF) into 3 groups: HF with preserved EF - HFpEF with LV EF >= 50 %, mid-range EF - HFmrEF with LV EF 40-49 % and HF with reduced EF - HFrEF with LV EF < 40 %. A quantity of examination methods is available in heart failure diagnosis and treatment. Key words: classification - diagnosis - echocardiography - heart failure - natriuretic peptides. PMID- 30441998 TI - Pharmacological therapy for chronic heart failure. AB - Pharmacotherapy of chronic heart failure with reduced ejection fraction (HFrEF) is based on convincing evidence of both, the efficacy and the safety of drugs we are using. This evidence was obtained in big and carefully controlled randomised morbidity/mortality trials; therefore we are talking about evidence-based medicine. The basis for the pharmacological treatment is inhibition of pathologically long-term activated neurohumoral systems, mainly of the sympatoadrenal one by betablockers as well as of the renin-angiotensin aldosterone one by ACE inhibitors/sartans and by mineralocorticoid receptor antagonists. The new dual inhibitor sacubitril/valsartan should be considered as more effective substitute of ACE inhibitors/sartans in all stabilised patients. Addition of ivabradin could also be usefull in indicated patients. The role of digoxin had diminished much. At present it is used especially for rate control in heart failure patients with atrial tachyfibrillation. All symptomatic patients should be treated by diuretics. The treatment of heart failure is very complex. The pharmacotherapy has to be complemented by relevant lifestyle changes and in selected patients also by devices and/or surgical therapy including heart transplantation. Key words: betablockers - chronic heart failure - ivabradin - pharmacotherapy - RAAS inhibitors - sacubitril/valsartan. PMID- 30441999 TI - The heart transplantation. AB - The article reviews history, indication and follow-up after heart transplantation, including the mechanical assist devices. Various complications of posttransplant follow-up are mentioned, e.g. rejection, infection, vasculopathy, meta-bolic disorders, hypertension or malignities. Pharmacotherapy used for immunosuppression is discussed. Heart transplantation improves the prognosis of patients with previous heart failure and also their quality of life. Key words: heart transplantation - immunosuppression - mechanical assist devices rejection - terminal heart failure. PMID- 30442000 TI - Comorbidities in heart failure. AB - Comorbidities are important parts of care in patients with heart failure. Comorbidities, as well as their treatments, directly influence the course of heart failure. We present the most comorbidities a their therapy with regard to left ventricular dysfunction. Key words: comorbidities - heart failure. PMID- 30442001 TI - Arrhythmias and conductance disturbances and heart failure. AB - Arrhythmias and conductance disturbances and heart failure have a close relation. Arrhythmias are serious complication, but also etiology of heart failure. So it is not clear, what is the cause and what is a consequence. Atrial fibrillation is a frequent cause, ventricular arrhythmias a frequent consequence and ventricular fibrillation a frequent cause of death in patients with heart failure. Overview are about frequent arrhythmias as well as their therapy with regard to left ventricular dysfunction. Key words: arrhythmias - heart failure. PMID- 30442002 TI - Outpatient treatment of proximal deep vein thrombosis. AB - The treatment of deep vein thrombosis (DVT) is based on anticoagulation with heparin, warfarin and direct oral anti-coagulants. According to the 9th ACCP Recommendation, for patients with DVT of the lower limbs, where the clinical state and home conditions permit, preference is given to home treatment over hospitalization. Despite that, the majority of patients with acute DVT still tend to be hospitalized, in particular when proximal thrombosis from the popliteal vein upward is involved. Furthermore, the recommendations do not describe proximal (iliofemoral) DVT as exceptional and more serious. Randomized and observation studies have shown faster relief from pain and swelling in patients keeping to the regimen of early mobilization wearing compression means, compared to patients keeping bed rest, while the incidence of new cases of PE was the same for both groups. In the acute phase of the disease compression and walking exercise is essential which, along with internal thrombolytic mechanisms of the body, accelerates recanalization and development of the collateral blood vessels in the deep muscular compartment of the lower limb. Two case studies demonstrate an outpatient approach to the therapy of proximal DVT. Key words: compression treatment - direct oral anticoagulants - low molecular weight heparin - venous thromboembolism. PMID- 30442004 TI - Posttraumatic hydrocephalus. AB - Posttraumatic hydrocephalus (PH) is a common complication of craniocerebral trauma. It is necessary to bear this entity in mind, especially when managing craniocerebral trauma patients, because if not detected in time, it can significantly affect morbidity and mortality. It needs to be distinguished from brain atrophy with axonal degeneration, a condition requiring an entirely different treatment approach. Key words: hydrocephalus - posttraumatic - VP shunt - brain CT - progression of neurological status. PMID- 30442003 TI - Chronic subdural hematoma - review article. AB - INTRODUCTION: Chronic subdural hematoma (ChSDH) is, by definition, a subdural collection of blood older than 21 days. It is not exceptional that ChSDH is diagnosed in regional hospitals and thus we believe that basic knowledge on this topic is relevant for every general surgeon. Below, we summarize information on ChSDH and present simple clinical management guidelines. TREATMENT: In asymptomatic patients with ChSDH, monitoring alone may be sufficient. Subdural collections of only a few millimeters are a relatively common incidental finding on graphical examination of the brain, especially in the elderly with brain atrophy. In symptomatic patients, surgical treatment is justified. As a first step, burr hole evacuation of the hematoma in local anesthesia is performed. It is a simple, well-tolerated procedure and advantageous in elderly polymorbid patients. In symptomatic patients with recurrent ChSDH, reoperation using either the same burr hole or a new one is indicated. Patients with multilobulated hematomas that recur after the burr hole are scheduled for a craniotomy. CONCLUSION: ChSDH is a common condition encountered by all general surgeons during their clinical practice. The most common clinical presentations of ChSDH are headache, confusion, hemiparesis and aphasia. Asymptomatic patients may be followed by watchful waiting, whereas symptomatic patients are indicated for surgical treatment. All patients with ChSDH should be referred to a neurosurgical department (preferably a certified level 1 trauma center) with experience in neurotrauma care. PMID- 30442005 TI - Benefits of repeated CT scan in patients with neurosurgical-neurological problems in intensive care retrospective analysis. AB - INTRODUCTION: CT examination of the brain is an integral part of neurointensive care. The examination, however, represents a risk for patients and has side effects. Indications for the procedure should therefore be carefully considered. The aim of the study was to analyze the indications for brain CT and the influence of its result on further treatment. METHOD: A retrospective analysis of CT examinations of the brain performed during 2010 in 263 patients admitted to neurointensive care. The study assessed whether the indication for a CT scan was due to a change in the patient's neurological status or routine, and also whether pharmacological sedation was used. Implications of the CT scan results for the course of treatment were evaluated. RESULTS: 763 CT examinations of brain were performed in the study group. 81% of the patients were under pharmacological sedation at the time of the exam indication, 19% had no sedation and could be clinically evaluated. In both groups, 80% of examinations were indicated on a routine basis. More than half of all CT examination results were evaluated as no change or improvement. Two thirds of them had no impact on the course of further treatment. Results of CT scans indicated due to a change in neurological status led to a change of therapy more often than in routine indications (24.8 vs. 14.2%). The difference was even greater in patients indicated for surgery (19 vs. 8.4%). CONCLUSION: CT scans of the brain are and will continue to be a fundamental part of neurointensive care but cannot replace clinical examination, which is influenced by pharmacological sedation. Results of brain CT scans have led to a change in the course of therapy more frequently when indicated due to a change in neurological status. Rational indication of sedation can contribute to rational indication for brain imaging. Key words: neurointesive care - sedation - CT of the brain. PMID- 30442006 TI - Epidural hematoma - benign or potentially malignant disease? AB - INTRODUCTION: Epidural hematoma (EDH) is generally considered to be a condition with a good prognosis. However, postoperative results of numerous studies have shown that mortality and morbidity remain relatively high. The aim of our article is to evaluate surgical outcomes in patients undergoing EDH evacuation over the last five years. METHODS: Data were analysed retrospectively. Pre-operative GCS was assessed. Location and incidence of associated head injuries were recorded. Two groups were established: 1. "immediate-care-requiring" and "followed-up" patients. Time interval CT - surgery was measured in the first group and the number of CT scans in the second group. Complications were divided into general and surgical. Outcome was evaluated on GOS. RESULTS: 67 patients underwent the surgery. At admittance, GCS was 13-15 in 55%, 9-12 in 8% and 3-8 in 37% of the patients. EDH was mostly located in the temporal region - in 52%. Associated head injuries occurred in 76%. Mean interval CT - operation lasted 2h 15min in the first group. Two pre-operative CT scans were done in 88% of the patients in the second group. General complications occurred in 34% and surgical in 15%. Mortality rate was 6%. 20% of the patients had a GOS of 1-3 and 80% of them had a GOS of 4-5. CONCLUSION: Our results have shown that morbidity and mortality after EDH evacuation are still relatively high. 14% of the patients remained disabled, and 6% died. The outcome depends mostly on preoperative clinical picture and timing of the surgery. Key words: epidural hematoma - evacuation - neurological outcome - timing of the surgery. PMID- 30442007 TI - New AOSpine subaxial cervical spine injury classification and its clinical usage. AB - INTRODUCTION: The main aim of this paper is to introduce a new AOSpine subaxial cervical spine injury classification system to the national medical community since there is no generally accepted classification system until now. METHOD: A description of the new AOSpine subaxial cervical spine injury classification and the basic principles of it exploitation are proposed in this text. Usage of the abovementioned classification in clinical practice is demonstrated on a sample of 48 patients who were investigated and treated at the author's department during the last two years. The assessment of injured spine stability and the surgical approach used are based on the above classification. RESULTS: Type A0 injury was recorded in 5 (10.4%), A1 in 4 (8.3%), A2 in 2 (4.2%), A3 in 1(2.1%), A4 in 7 (14.6%), B2 in 2 (4.2%), B3 in 4 (8.3%), C in 12 (25%), F1 in 2 (4.2%), F2 in 4 (8.3%), F3 in 3 (6.3%) and F4 in 2 (4.2%) patients. Inter-observer agreement on each type of injury was achieved in 64.3%; as regards classification into the main groups A, B, C and D, consensus was reached in 89.3% cases. Eleven (22.9%) patients classified as A0, A1 and F1 were treated conservatively and 37 (77.1%) underwent surgery. CONCLUSION: New AOSpine subaxial cervical spine injury classification represents a useful tool, allowing for proper assessment of injury severity and helping to select the type of eventual surgical procedure. Key words: classification - fracture - cervical spine - subaxial. PMID- 30442008 TI - Subdural empyema case report of a rare disease with a high mortality. AB - Subdural empyema is a rare purulent intracranial infection. Outcome is dependent on the preoperative level of consciousness, therefore an early diagnosis and urgent neurosurgical intervention are necessary. Mortality of subdural empyema remains high, ranging from 6% to 15%. The case report presents a patient with subdural empyema which resulted from sinusitis. The integral and first part of therapy was an urgent neurosurgical drainage of subdural empyema, followed by functional endoscopic sinus surgery performed by ENT surgeon. Conservative treatment consisted of systemic antibiotics and antiedematous therapy. Later the patient developed post-infectious hydrocephalus, which was solved by implantation of a ventriculo-peritoneal shunt. Consequently, cranioplasty was performed. Despite acute onset of the disease and severe neurologic deficit prior to the first neurosurgical intervention, the clinical condition of the patient is favorable after multiple surgeries. The patient is able to live independently without any significant limitations in everyday activities. The presenting symptoms of subdural empyema are reflective of increased intracranial pressure, meningeal irritation, and cerebritis. Radiographic imaging (contrast CT, DWI-MRI, contrast MRI) is an essential diagnostic tool. The integral part of therapy is a neurosurgical evacuation of subdural empyema combined with intravenous antibiotic therapy. Subdural empyema is a rare, rapidly progressing disease which is underestimated by the physicians in many cases. Diagnosis is often delayed and therefore, despite recent progress in treatment, the mortality rate remains high. Key words: empyema - subdural - sinusitis - diagnostic imaging - surgical method. PMID- 30442009 TI - Meralgia paresthetica. AB - Meralgia paresthetica is a compression neuropathy of the lateral femoral cutaneous nerve. Despite its rarity, it is the most common nerve entrapment of the lower limbs. It produces similar symptoms as those associated with the more common L4 or L5 radiculopathy. Therefore, it is often diagnosed late (sometimes only after several years of latency) or not at all. This diagnosis should be considered especially in patients with obesity and diabetes who have chronic irritation of the ventrolateral areas of the thigh not responding to conservative therapy and a negative finding on lumbar MRI. We present our experience with surgical nerve decompression in three patients with pain, paresthesias, and sensory loss within the distribution of the lateral cutaneous nerve of the thigh. They all suffered from severe abdominal obesity. All conservative treatments, including weight reduction attempts, were unsuccessful. Nerve release caused an immediate effect in two cases. One patient experienced a temporary worsening of pain, which gradually improved within one month. In spite of the controversy surrounding the surgical treatment of meralgia (neurolysis or nerve resection), it can be concluded that nerve decompression has a good effect. Nerve resection is, in our view, considered to be a reserve option when primary surgery fails. Key words: meralgia paresthetica - nerve entrapment - peripheral nerve. PMID- 30442010 TI - Rare surgical procedures for proximal nerve lesions - a case report. AB - Peripheral nerve injury can result in serious problems with a severe functional deficit. Solutions of individual cases vary and proper management based on the physician's sound professional experience is fundamental. In case of motor nerve lesions, time is the crucial factor due to the ongoing deterioration of motor end plates. Distal nerve transfers are procedures leading to the reduction of distance between the point of injury and the denervated muscles. The authors describe the case of a young boy with proximal ulnar nerve injury to present the method. Key words: ulnar nerve - nerve transfer - nerve injury. PMID- 30442011 TI - The use of retrosternally placed colon in esophageal replacement. AB - The authors present a review article evaluating the use of the colon as a replacement for the esophagus. We present current indications for both benign and malignant conditions and compare the advantages and disadvantages of the technical possibilities of esophageal reconstruction. The surgical technique utilizing the vascular bundle of the left colic artery and retrosternal location of the colonic conduit is discussed and documented in detail. Furthermore, we describe both early and late complications, including their management. We conclude that the colon is a safe technical possibility for esophageal replacement with satisfactory early and long-term results in cases where gastric conduit is not available. Key words: esophageal replacement with colonic interposition - esophageal replacement complications - colon interposition for esophageal replacement technique - coloplasty - esophageal replacement surgery. PMID- 30442012 TI - Current state of surgical treatment of cancer of the stomach and gastro esophageal junction in the Czech Republic. AB - INTRODUCTION: Analysis of the epidemiology and treatment of cancer of the stomach (CS) and gastro-esophageal junction (GEJ) in the Czech Republic (CR). METHOD: Analysis from the National Cancer Registry (NCR) of the CR examined data up to the year 2013. RESULTS: In CS and GEJ, the incidence is 14.3, mortality is 10.5 and prevalence is 51.1 per 100,000 population. The Karlovy Vary, Olomouc and Moravian-Silesian regions had the highest incidences. The median age at diagnosis is 69 years for men and 72 years for women. Location in the stomach prevails in 85% of the patients, cancer of the gastric cardia occurring in 15%. In men, this ratio is 81 to 19%, in women 90 to 10%. The disease is usually diagnosed late; in 2013, 36% of CS and 32% of GEJ tumors were stage I and II. 53% of CS and 56% of tumors of the GEJ were diagnosed as stage III and IV, and in 11% and 12%, the stage was not determined. In the years 2009-2013 (1,580 patients with CS and GEJ), only 22% were treated surgically, surgery and oncological treatment was given to 21.3%, only non-surgical treatment was received by 15.7% and 41% of patients received no oncological treatment. Overall five-year survival in patients treated between 2010 and 2013 was 32%. At stage I it was 69%, at stage II 41%, at stage III 23% and at stage IV it was 6%. Five-year survival rates according to disease stage and type of treatment given and median of survival were analysed on 8,348 patients with CS and GEJ between 2004 and 2013. Surgery only was performed in 4,116 patients, surgery and radiotherapy was administered to 113 patients, surgery and chemotherapy to 1,855 patients, and 1,125 patients received chemotherapy alone. In 98% of the treated patients, chemotherapy and/or radiotherapy was administered adjuvantly after the surgery. Primary operations were performed at a total of 175 surgical centers, only 22 of them performing more than 10 operations annually. The median of survival differed depending on the number of operations performed: at enters performing more than 20 operations, the median was 24.8 months (m); at enters performing 10-19 operations, the median was 18.2 m; at centers performing 6-9 operations the median was 18.1 m; and at centers performing less than 6 operations, the median was 13.1 m. CONCLUSION: Early diagnosis is key for five-year survival. Treatment is based on surgery; greatest improvement is seen when surgery is combined with chemoradiotherapy, which is usually administered adjuvantly in the CR. At stage I in CS +9.5%, GEJ cancer +26.5%, at stage II in CS +14.7%, GEJ cancer +16.4% and at stage III in CS +13.3%, GEJ cancer +2.6%. Palliative chemo and/or radiotherapy does not prolong five-year survival and must be selected on an individual basis with regard to the expected benefit for the patient. Facilities performing a greater number of surgical procedures have better long-term results. Key words: malignant esophageal tumors - epidemiology - treatment - results. PMID- 30442013 TI - Hybrid thoracoscopic esophagectomy for cancer - retrospective analysis and comparison with transhiatal resection. AB - INTRODUCTION: Minimally invasive methods for esophagectomy have been introduced to reduce postoperative complications. This paper compares open transhiatal esophagectomy and minimally invasive hybrid esophagectomy. Both methods have different extents of lymphadenectomy, transhiatal esophagectomy being considered less radical. METHOD: A single-centre retrospective study comprised 39 patients subjected to transhiatal esophagectomy and 25 patients subjected to hybrid esophagectomy combining thoracoscopy with laparotomy and cervical anastomosis. All patients were operated for middle and distal third carcinoma of the esophagus, including cardia (Siewert II), in the period of 2006-2016 at the Surgery department of Novy Jicin hospital. The data of both groups, in particular the incidence of early postoperative complications and the number of dissected lymph nodes, were statistically compared. Complications are reported according to the International Consensus on Standardization of Data Collection for Complications Associated with Esophagectomy. RESULTS: The duration of operation was significantly longer in the group that underwent hybrid resections (345 vs. 240 min, p<0.001). The number of dissected lymph nodes was comparable in both groups (15 vs. 16, p=0.072). Postoperative pulmonary complications were lower for hybrid operations (16% vs. 30.8%, p=0.243). The most common complication of transhiatal esophagectomy was pleural effusion requiring drainage, which occurred in 7 patients. The most common pulmonary complication of hybrid procedures was respiratory failure, which occurred in 3 patients. Anastomotic leak occurred in 5 patients after transhiatal esophagectomy and in one after thoracoscopic resection (12.8% vs. 4%, p=0.391). 30-day and 90-day mortality was nonsignificantly lower for hybrid resections (0% vs. 5.1%, p=0.516 and 4% vs. 10.3%, p=0.64). Following transhiatal esophagectomy, two patients died as a result of respiratory complications, one died from necrosis of the gastric tube and one from acute myocardial infarction. In the hybrid group, one patient died from respiratory failure. Hybrid resection exhibited lower morbidity (36% vs. 59%, p=0.123). The number of overall complications, irrespective of their severity according to the Clavien-Dindo classification, was statistically in favor of hybrid resection (11 vs. 30, p=0.015). CONCLUSION: In our study, we found that thoracoscopic hybrid resection was a feasible and well-executable method, with a statistically lower incidence of postoperative complications. Thoracoscopy allows lymphadenectomy to be performed to sufficient extent. The large number and various combinations of esophagectomy techniques make it difficult to evaluate and compare the outcomes of individual methods. Preference for a specific resection technique within a given surgical department remains an important factor as clear recommendations for esophageal resections do not yet exist. However, the use of minimally invasive techniques in esophageal resections is gradually becoming a standard. Key words: minimally invasive esophagectomy - thoracoscopy - postoperative complications - lymphadenectomy. PMID- 30442014 TI - Prophylactic ligation of the thoracic duct in the prevention of chylothorax after esophagectomy. AB - INTRODUCTION: Chylothorax after esophageal resection is an uncommon but serious complication with a reported incidence of 1-10%. It occurs after the injury of the thoracic duct or its tributaries. Chylothorax may cause an overall loss of several liters per day and may lead to dehydration, malnutrition and immunosuppression. Therapeutic approach has not been standardized. Prophylactic ligation of the thoracic duct during primary resection has been introduced to decrease the overall incidence of chylothorax. Its oncological benefit is unknown. METHOD: A retrospective single-center study of patients who underwent transthoracic esophagectomy from 2008-2016 for esophageal carcinoma at the Department of Surgery, Hospital Novy Jicin. 58 patients underwent transthoracic esophagectomy (Ivor-Lewis and McKeown). Prophylactic ligation of the thoracic duct was performed in 31 patients (53%). The incidence of chylothorax and the amount of harvested lymph nodes was analysed in the group with thoracic duct ligation (A PTDL 31 patients) and in the non-ligation group (B 27 patients). RESULTS: Overall incidence of chylothorax after transthoracic esophagectomy was 3.4%. Chylothorax occurred in two men (type 3B) in the prophylactic group (6.5%) and it was not observed in the non-ligation group. Statistically significant difference was not confirmed (p=0,494). Chylous leak was successfully treated thoracoscopically and by thoracotomy with repeat ligation of the thoracic duct. Non-significantly more lymph nodes were harvested in the prophylactic group (18 A PTDL vs. 15 B, p=1). CONCLUSION: Prophylactic ligation of the thoracic duct in our study did not reduce the incidence of chylothorax. Redo thoracotomy and redo thoracoscopy for chylothorax is feasible. In patients with high-output and long lasting leaks the indication for redo surgery should be early. Key words: chylothorax - esophageal resection - prophylactic thoracic duct ligation. PMID- 30442015 TI - Successfull therapy of grade III leak after thoracic oesophagectomyusing endoscopic vacuum assisted closure therapy - a case study. AB - INTRODUCTION: Post-oesophagectomy leakage occurs in 1-30% of cases as a significant factor in postoperative morbidity and mortality, accounting for 40% of postoperative deaths. Endoscopic vacuum therapy (EVAC) is, besides stent therapy, clips and surgical therapy, a new endoscopic thera-peutic modality. CASE REPORT: A 72-year-old polymorbid female patient with Siewert type II adenocarcinoma of the distal esophagus (T1b, N0, M0) was indicated for resection of the upper stomach and lower thoracic esophagus from laparotomy and thoracotomy with reconstruction using double-stapling anastomosis. On postoperative day 12, a 3rd degree leakage with propagation into the right pleural cavity was proven on CT. Endoscopy showed a defect affecting 30% of the circumference with a 7*3*3 cm cavity. Because of the leak morphology, EVAC was indicated. The therapy comprised 12 sessions with 3-4-day intervals for a total duration of 40 days with 5 extraluminal and 7 intraluminal applications and negative pressure of 100-125 mmHg. The condition was complicated by global respiratory failure due to severe pneumonia. Artificial ventilation was terminated on the 58th postoperative day. The patient was discharged to a rehabilitation facility on the 90th postoperative day. The follow-up 3 months after discharge confirms satisfactory performance results with full replenishment. CONCLUSION: The therapy of complications of intrathoracic anastomoses after oesophagectomy has shown a trend toward reduced invasiveness and wider implementation of endoscopic methods. In spite of its shortcomings, the use of EVAC is a safe and highly effective therapeutic option even for extensive anastomotic defects. The future use, indications as well as relation to other therapeutic options require further evaluation. Key words: endoscopic vacuum therapy - esophageal leakage - esophagectomy complications - intraoperative endoscopy. PMID- 30442016 TI - Mobilizing the Next Generation of Health Advocates: Building Our Collective Capacity to Advocate for Health Education and Health Equity Through SOPHE Advocacy Summits. AB - In this Career Development commentary, the author highlights the benefits of attending the Society for Public Health Education Advocacy Summit in Washington, D.C. Advocacy is an increasingly necessary skill that allows health educators to advance both the field of public health and their own career development as professionals. Students and practitioners from diverse health education settings get to connect with other professionals, attend skill-building workshops, and increase their ability to influence health policy. From a career development perspective, the Summit provides opportunities to develop professional networks, gain experience and continuing education in several areas of responsibility for health education specialists, and share lessons learned with colleagues in health education and public health. PMID- 30442017 TI - Impact of Exposure to Sexual Violence Prevention Messages on Students' Bystander Behavior. AB - Bystander intervention is a prevention strategy commonly used to address campus sexual violence. Increasingly, there are calls for prevention efforts to be multilevel and ongoing. The current study investigated the impact of receiving varied prevention messages throughout adolescence and into early adulthood to determine whether it influences college students' awareness of sexual violence, willingness to intervene as a helpful bystander, and actual prosocial bystander behavior. These questions were tested through administration of an online survey to a racially and ethnically diverse sample of 1,047 undergraduate students at a large, urban university in the mid-Atlantic. Results found that most students received information about sexual violence prior to coming to campus from a variety of sources, and that the sources varied significantly by gender and race. Regression analysis found that greater exposure to prevention messages prior to coming to college was significantly associated with greater bystander intentions and behavior even after accounting for gender and race and exposure since coming to college. The findings provide initial support to expand the scope of prevention efforts and to begin them prior to college. PMID- 30442018 TI - A Salient Belief Elicitation Examining Adolescents' Meditation Beliefs Using the Reasoned Action Approach. AB - The purpose of this study was to identify adolescents' consequence, referent, and circumstance beliefs about trying to meditate at least twice in the next week in order to inform subsequent meditation intervention design. A survey based on reasoned action approach (RAA) constructs was developed and pilot-tested. Thereafter, adolescents ( N = 129), recruited from a northeastern U.S. high school, responded to open-ended survey questions eliciting beliefs underlying intention to try meditating. Thematic analysis was executed to examine beliefs and frequencies of beliefs. Five types of salient meditation beliefs were identified: advantages (e.g., reduces stress, increases relaxation, improves focus), disadvantages (e.g., slows everything down), supporters and disapprovers (e.g., family and friends), and facilitating circumstances (e.g., more time, fewer distractions). Adolescents recognize meditation as having health benefits but as also taking time. They further viewed meditation as socially acceptable but need sufficient time and a conducive environment to try it. To be effective, interventions designed to promote adolescents' self-regulation through meditation should address identified salient beliefs. PMID- 30442019 TI - The use of silver coating in hip megaprostheses: a systematic review. AB - Retrospective studies of silver-coated hip implants have demonstrated promising results and safety profile, however, the potential benefits are so far unproven in prospective studies. Silver-coated implants may have a role in patients undergoing revision or primary surgery with a high risk of infection but as yet there are no human studies investigating silver in primary hip arthroplasty. Adequately powered robust prospective studies are needed in this area to determine if silver-coated implants would be efficacious and cost-effective. The purpose of this systematic review article is to review the current literature regarding the use of silver in hip arthroplasty. Our review showed that there is some encouraging evidence that silver coatings can reduce infection. PMID- 30442020 TI - Patients undergoing hip arthroscopy with active workers' compensation claims do not demonstrate inferior outcomes at mid-term. AB - INTRODUCTION:: Workers' compensation (WC) claims have been associated with poor short-term outcomes after hip arthroscopy. We aim to report mid-term outcomes and return to work (RTW) among patients with WC claims. METHODS:: Data were prospectively collected and retrospectively reviewed for patients undergoing hip arthroscopy between September 2008 and July 2011. Inclusion criteria were an active WC claim at time of surgery with preoperatively-documented patient reported outcomes (PROs). Exclusion criteria were a previous hip condition and preoperative Tonnis grade >1. Patient-reported WC cases were pair-matched to non WC cases based on body mass index (BMI) +/- 5, age +/- 5 years, gender, preoperative LCEA, labral treatment, and capsular treatment. RESULTS:: 52 patients had minimum 5-year outcomes. Mean age was 40.6 (+/-10.6) years and a mean BMI of 27.5 (+/-5.3). 9 (16.7%) hips underwent secondary arthroscopies. 5 hips (9.3%) were converted to THA. There were 5 (9.3%) reports of numbness, all of which resolved spontaneously. Work status details were available for 49 patients and 47 patients (95.9%) returned to work. 42 WC hips were matched to 42 control hips. At ?5-year follow-up, patient-reported outcomes, visual analogue scale (VAS) and satisfaction were not different between the groups. All magnitudes in improvement were significantly higher in the WC group ( p = < 0.001) except for VAS. No significant differences were found in rates of secondary arthroscopies, conversions to THA, or complications between the groups. CONCLUSIONS:: WC patients have equal favourable mid-term outcomes as non-WC patients after hip arthroscopy for the treatment of femoroacetabular impingement and labral pathology. PMID- 30442021 TI - Wound-Healing Issues Following Rotational Ankle Fracture Surgery: Predictors and Local Management Options. AB - BACKGROUND: The incidence and risk factors of wound-healing complications following rotational ankle fracture surgery are well documented in the literature. However, there is a paucity regarding management options following these complications. The goal of this study was to provide a descriptive analysis of one surgeon's experience managing wound complications in patients who have undergone ankle fracture surgery. METHODS: A total of 215 patients who were operatively treated for an unstable ankle were retrospectively identified. Patient demographics, medical histories, initial injury characteristics, surgical interventions, and clinical follow-up were collected. Twenty-five of these patients developed postoperative wound problems. RESULTS: Of the original cohort of 215 patients, 25 (11.6%) developed wound-healing complications. Their average age was 53.6 +/- 18.0 years; there were 12 males (48.0%). Connective tissue/inflammatory disease (odds ratio [OR] 3.9), cardiovascular disease (OR 3.6), and active smoking (OR 3.3) were associated with an increased likelihood of developing postoperative wound complications. With regard to injuries, open fractures (OR 17.9) had the highest likelihood of developing postoperative complications, followed by type 44-C (OR 2.8) and trimalleolar fractures (OR 2.0). CONCLUSION: Wound complications following open treatment of ankle fractures occurred with an incidence of 11.6% in this series, of which only about half required operative intervention. A third of wounds were managed by orthopaedics in conjunction with plastic surgery. LEVELS OF EVIDENCE: Level III: Retrospective comparative study. PMID- 30442022 TI - Dietary sodium intake is associated with long-term risk of new-onset atrial fibrillation. AB - BACKGROUND: The association between dietary salt intake and hypertension has been well documented. We evaluated the association between dietary sodium intake and the incidence of new-onset atrial fibrillation (AF) during a mean follow-up of 19 years among 716 subjects from the Oulu Project Elucidating Risk of Atherosclerosis (OPERA) cohort. MATERIAL AND METHODS: Dietary sodium intake was evaluated from a seven-day food record. The diagnosis of AF (atrial flutter included) was made if ICD-10 code I48 was listed in the hospital discharge records during follow-up. RESULTS: In the Kaplan-Meier curves, when quartiles of sodium consumption were considered, the cumulative proportional probabilities for AF events were higher in the highest (4th) quartile (16.8%) than in the lower quartiles (1st 6.7%, 2nd 7.3% and 3rd 10.6%) (p = .003). In the Cox regression analysis, sodium consumption (g/1000 kcal) as a continuous variable was independently associated with AF events (Hazard Ratio = 2.1 (95% CI, 1.2 to 3.7) p =.015) when age, body mass index, smoking (pack-years), office systolic blood pressure, left atrium diameter, left ventricular mass index and the use of any antihypertensive therapy were added as covariates. CONCLUSIONS: These findings indicate that sodium intake is associated with the long-term risk of new-onset AF. Further confirmatory studies are needed. Key messages Sodium consumption correlated positively with CV risk factors: age, smoking, SBP, BMI and LDL cholesterol. When quartiles of sodium consumption were considered, the AF incidence was higher in the highest quartile compared to lower quartiles. Sodium consumption as a continuous variable was independently associated with AF events when age, BMI, smoking, SBP, LAD, LVMI and the use of any antihypertensive therapy were considered. PMID- 30442023 TI - Linking occupational therapy models and assessments to the ICF to enable standardized documentation of functioning. AB - BACKGROUND.: The International Classification of Functioning, Disability and Health (ICF) can serve as reference for standardized documentation of health in clinical practice. PURPOSE.: This study aims to bridge the gap between the ICF and occupational therapy specific concepts, represented by occupational therapy models and their derived assessments. METHOD.: Occupational therapy assessments in relation to their models were systematically linked to the ICF, and a compatibility analysis was conducted. To strengthen reliability of the linkings, feedback from the respective assessment hosts was obtained. FINDINGS.: Linking tables were developed for the Assessment of Motor and Process Skills, the Canadian Occupational Performance Measure, and the Model of Human Occupation Screening Tool. Similarities and differences between the ICF and the three assessments and their associated models show how they differ from and complement each other. IMPLICATIONS.: The findings of this study lay the foundation for standardized documentation in occupational therapy and enhance the practicability of the ICF. PMID- 30442024 TI - Factors promoting and impeding HIV testing among adolescents in juvenile drug court. AB - A randomized pilot study compared Risk Reduction Therapy for Adolescents (RRTA) to treatment as usual (TAU); the present study examined whether intervention condition influenced HIV testing, barriers to HIV testing, and HIV communication among adolescents involved in juvenile drug courts overall and by sexual experience. Of 105 participants, 13.3% had HIV pre-treatment testing, whereas 27.2% (of 92 participants) indicated follow-up HIV testing. Sexually active youth in RRTA (but not in TAU) reported a significant increase in HIV testing over time. RRTA demonstrated the greatest increase in HIV testing (8% pre-treatment to 44% follow-up), but not significantly more than TAU. Prevalence of barriers to HIV testing were observed at consistent rates among adolescents who did not get tested for HIV within either treatment condition. Adolescents in both conditions reported increased communication about HIV at follow-up. HIV testing was positively associated with perceived need for testing and testing resource accessibility. Stigma remained a barrier to testing at follow-up for RRTA (22%) and TAU (21%) participants. The RRTA intervention increased HIV testing and both interventions increased adolescents' communication about HIV; however, barriers persisted, warranting treatment modification. PMID- 30442025 TI - Biomarker assays: is it time for a standalone regulatory guidance? PMID- 30442026 TI - A Quality Improvement Intervention to Improve the Efficiency of Arteriovenous Access Placement for Pre-Dialysis Inpatients. AB - The authors aimed to improve the rate of pre-dialysis arteriovenous (AV) access placement for hospitalized patients with advanced chronic kidney disease. The authors developed and implemented a protocol for hospitalized adult patients with an estimated glomerular filtration rate <20 mL/min to streamline the workflow for obtaining AV access. The protocol was piloted on 5 inpatient medical services over 3 months at 1 institution. Specific-Measurable-Achievable-Realistic-Timely (SMART) aims, Fishbone diagrams, Plan-Do-Study-Act cycles, and run charts were used to assess the process and outcomes of the intervention. There were 22 patients in the baseline group and 27 patients in the intervention group. Pre dialysis AV access increased from 23% to 62%. Length of stay did not differ significantly between the baseline group (8.31 days) and the intervention group (8.4 days). Pathways can improve pre-dialysis AV access without significantly increasing length of stay. PMID- 30442027 TI - Development of paper substrate for paper spray MS in high-sensitivity analysis of biological samples. AB - Paper spray (PS) has demonstrated a promising future for direct mass spectrometric analysis. In the process of PS, paper substrate has been demonstrated as a crucial factor in determining the final performance of PS-MS, and therefore much attention is paid to modification of paper substrate. In this review, we systematically introduce the development of paper substrate for PS. Various commercial and modified papers are comprehensively reviewed, and much effort is focused on some physical and chemical approaches for modification of paper substrate. The application of modified paper substrates to biological sample analyses is discussed. The future promising directions of paper substrate for PS are highlighted. PMID- 30442029 TI - Costs of Quality in Clinical Development. AB - BACKGROUND:: The basis for this article is an individual project during a Master of Science program at Cranfield University, UK. Research and development (R&D) costs in the pharmaceutical industry have increased at a rate where costs have doubled compared to previous decades since the 1980s. In parallel, during recent years, there has been an increased focus on quality management within clinical development. Furthermore, pharma companies are talking about quality as a competitive advantage with an increased focus on quality metrics. The objective of this research was to confirm/reject the assumption that costs of quality are not being tracked within clinical development. METHODS:: The key component of this research consists of a survey that was sent out to approximately 15 of the top 50 global pharmaceutical companies. RESULTS:: The research showed that the praxis of tracking and analyzing costs of quality was not widespread within clinical development, although the tools are available and experience from other industries showed that there are potential benefits to be realized, including a reduction of total quality costs. CONCLUSIONS:: Even though tools for analyzing costs of quality have been available since the 1950s, there is little evidence in the literature that quality costs are being tracked and analyzed in clinical development. On the contrary, there are examples that the clinical research part of the pharma industry is stuck in traditional ways of working. However, it is likely that tracking and analyzing costs of quality can help limit the increase of R&D costs. PMID- 30442028 TI - White Matter Injury in Early Brain Injury after Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a major cause of high morbidity, disability, and mortality in the field of neurovascular disease. Most previous SAH studies have focused on improving cerebral blood flow, reducing cerebral vasospasm, reducing neuronal calcium overload, and other treatments. While these studies showed exciting findings in basic science, therapeutic strategies based on the findings have not significantly improved neurological outcomes in patients with SAH. Currently, the only drug proven to effectively reduce the neurological defects of SAH patients is nimodipine. Current advances in imaging technologies in the field of stroke have confirmed that white matter injury (WMI) plays an important role in the prognosis of types of stroke, and suggests that WMI protection is essential for functional recovery and poststroke rehabilitation. However, WMI injury in relation to SAH has remained obscure until recently. An increasing number of studies suggest that the current limitations for SAH treatment are probably linked to overlooked WMI in previous studies that focused only on neurons and gray matter. In this review, we discuss the biology and functions of white matter in the normal brain, and discuss the potential pathophysiology and mechanisms of early brain injury after SAH. Our review demonstrates that WMI encompasses multiple substrates, and, therefore, more than one pharmacological approach is necessary to preserve WMI and prevent neurobehavioral impairment after SAH. Strategies targeting both neuronal injury and WMI may potentially provide a novel future for SAH knowledge and treatment. PMID- 30442030 TI - Prolonged slow expiration technique improves recovery from acute bronchiolitis in infants: FIBARRIX randomized controlled trial. AB - OBJECTIVE:: To examine the effect of prolonged slow expiration respiratory physiotherapy treatment on the acute bronchiolitis severity scale and O2 saturation at short-time and at medical discharge in infants and the hospital stay. DESIGN:: Randomized controlled trial. SETTING:: Infants' unit of university hospital. PARTICIPANTS:: Infants with acute bronchiolitis ( N = 80). INTERVENTION:: Infants were randomized into respiratory treatment (RT) with prolonged slow expiration or treatment as usual (control) for one-week period. MAIN OUTCOME MEASURES:: The primary outcomes were Acute Bronchiolitis Severity Scale score and O2 saturation, recorded shortly after each intervention during the stay and at medical discharge, and the hospital stay. RESULTS:: The RT had a significantly lower Acute Bronchiolitis Severity Scale 10-minute after the first intervention (mean difference -1.7 points, 95% confidence interval (CI) -3.0 to 0.38), 2 hours after (-2.0 points, 95% CI -3.2 to -0.86) and the last day before medical discharge (-1.3 points, 95% CI -2.1 to 0.51). No changes were detected in O2 saturation. The survival analysis of time at medical discharge showed decrease in the average number of days to achieve an Acute Bronchiolitis Severity Scale of less than 2 points (RT: 2.6 days, 95% CI 2.1-3.1; Control: 4.4 days, 95% CI 3.6 5.1). CONCLUSION:: A prolonged slow expiration physiotherapy reduces Acute Bronchiolitis Severity Scale scores and does not change O2 saturation. Infants in RT group stay less days in hospital than infants in control group and no adverse events were detected. PMID- 30442031 TI - Different cardiovascular risk factors and psychosocial burden in symptomatic women with and without obstructive coronary artery disease. PMID- 30442032 TI - DRG-Derived Neural Progenitors Differentiate into Functional Enteric Neurons Following Transplantation in the Postnatal Colon. AB - Cell therapy has great promise for treating gastrointestinal motility disorders caused by intestinal nervous system (ENS) diseases. However, appropriate sources, other than enteric neural stem cells and human embryonic stem cells, are seldom reported. Here, we show that neural progenitors derived from the dorsal root ganglion (DRG) of EGFP mice survived, differentiated into enteric neurons and glia cells, migrated widely from the site of injection, and established neuron muscle connections following transplantation into the distal colon of postnatal mice. The exogenous EGFP+ neurons were physiologically functional as shown by the activity of calcium imaging. This study shows that that other tissues besides the postnatal bowel harbor neural crest stem cells or neural progenitors that have the potential to differentiate into functional enteric neurons in vivo and can potentially be used for intestinal nerve regeneration. These DRG-derived neural progenitor cells may be a choice for cell therapy of ENS disease as an allograft. The new knowledge provided by our study is important for the development of neural crest stem cell and cell therapy for the treatment of intestinal neuropathy. PMID- 30442033 TI - Randomized clinical trial of a community navigation intervention to improve well being in persons living with HIV and other co-morbidities. AB - Long-term survival of people living with HIV (PLWH) is associated with the development of co-morbid conditions and need for symptom management and other efforts to enhance quality of life. We conducted a longitudinal, randomized trial over 36 months to evaluate the effect of a community-based navigator intervention to provide early palliative care to 179 PLWH and other chronic conditions. Outcomes included quality of life, symptom management, coping ability, social support, self-management, and completion of advance directives. Data were analyzed using SAS mixed effects model repeat measurement. Our navigator program showed variable improvement over time of three outcome variables, self-blame, symptom distress, and HIV self-management. However, the program did not improve overall quality of life, social support, or completion of advance directives. PMID- 30442034 TI - The LOOP Estimator: Adjusting for Covariates in Randomized Experiments. AB - BACKGROUND:: When conducting a randomized controlled trial, it is common to specify in advance the statistical analyses that will be used to analyze the data. Typically, these analyses will involve adjusting for small imbalances in baseline covariates. However, this poses a dilemma, as adjusting for too many covariates can hurt precision more than it helps, and it is often unclear which covariates are predictive of outcome prior to conducting the experiment. OBJECTIVES:: This article aims to produce a covariate adjustment method that allows for automatic variable selection, so that practitioners need not commit to any specific set of covariates prior to seeing the data. RESULTS:: In this article, we propose the "leave-one-out potential outcomes" estimator. We leave out each observation and then impute that observation's treatment and control potential outcomes using a prediction algorithm such as a random forest. In addition to allowing for automatic variable selection, this estimator is unbiased under the Neyman-Rubin model, generally performs at least as well as the unadjusted estimator, and the experimental randomization largely justifies the statistical assumptions made. PMID- 30442036 TI - Calcium Channel Blockers and the Risk for Lung Cancer: A Population-Based Nested Case-Control Study. AB - BACKGROUND: It has been suggested that calcium channel blockers (CCBs) may increase the risk of lung cancer; however, current evidence is conflicting and limited. OBJECTIVE: Investigate the associations between CCB use and lung cancer. METHODS: We conducted a population-based nested case-control study. A cohort was formed of patients prescribed their first antihypertensive agent from 2000 to 2014. CCB exposure information was obtained by identification of all prescriptions dispensed during study follow-up. Cases were patients newly diagnosed with lung cancer during follow-up. Each case was matched with 10 controls by age, sex, calendar year of cohort entry, and duration of follow-up. Multivariate conditional logistic regression was used to estimate odds ratios (ORs) with 95% CIs of lung cancer associated with ever use of CCBs. RESULTS: During a median follow-up of 6.2 years, we identified 4174 cases of lung cancer. Ever use of CCBs was associated with an increased risk of lung cancer (adjusted OR = 1.13; 95% CI = 1.06-1.21), when compared with the use of other antihypertensive drugs. A duration-response relation was observed, with the ORs gradually increasing with longer cumulative duration of CCB use (<5 years: OR = 1.12, 95% CI = 1.04-1.20; 5-10 years: OR = 1.22, 95% CI = 1.07-1.40; >10 years: OR = 1.33, 95% CI = 0.90-1.96; P trend < 0.001). Conclusion and Relevance: The results of this large population-based study indicate that the use of CCBs is associated with a modest but significant increase in the risk of lung cancer. This association appeared to increase with longer duration of use. PMID- 30442035 TI - A Bayesian network meta-analysis on the efficacy and safety of eighteen targeted drugs or drug combinations for pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) can be relieved by pharmacological interventions, especially the targeted drug, which is classified into endothelin receptor antagonist, phosphodiesterase 5 inhibitor, prostaglandin I2, soluble guanylate cyclase stimulator and selective non-prostanoid prostacyclin receptor agonist. To solve the contradictions existing in reported trials and provide a comprehensive guideline for clinical practice. PubMed, Embase, Cochrane library, and clinicaltrials.gov were searched. The basic information about the article, trial, arm, intervention, and the detailed data of outcome, including 6 minutes walking distance (6MWD) change, WHO functional class (FC) improvement, Borg dyspnea score (BDS) change, cardiac index (CI) change, mean pulmonary arterial pressure (mPAP) change, mean right arterial pressure (mRAP) change, pulmonary vascular resistance (PVR) change, clinical worsening, hospitalization, death, severe adverse events (SAEs), and withdrawal were extracted. The rank of treatments was estimated. 10,230 cases provided the firsthand comparison data about targeted drugs for treating PAH. For 6MWD, ambrisentan + tadalafil, vardenafil, and sildenafil + bosentan were better than others. Epoprostenol, macitentan, and sildenafil represented a greater WHO FC improvement. Vardenafil and treprostinil were better for BDS. So were bosentan + epoprostenol and bosentan alone for CI. Iloprost plus bosentan, bosentan + epoprostenol, and epoprostenol were better for mPAP. Iloprost plus bosentan, bosentan alone, and selexipag could reduce PVR. Sildenafil, epoprostenol, and vardenafil had the highest probability to reduce the incidence of death and withdrawal. To conclude, vardenafil and iloprost + bosentan showed relatively better performance in both efficacy and safety. However, the therapeutic choice should be made according to both the feature of each therapy and the individual condition. PMID- 30442037 TI - Mortality Following Trajectories of Mobility Limitations: The Modifying Impact of Social Factors. AB - OBJECTIVE: How are trajectories of mobility limitations (MLs) among older adults associated with mortality? Do social factors modify these associations? METHOD: Group-based trajectory modeling was used to identify four trajectories of MLs over a period of 4.5 years among 3,055 older Danes. Mortality analyses were conducted using additive hazard regression models. RESULTS: Compared to older adults without MLs, older adults with high level of MLs who experienced further increase in MLs were associated with the most additional deaths followed by older adults with no MLs at baseline who later experienced limitations and older adults with a medium ML level at baseline who later experienced further increase in limitations. Men and 80-year olds experienced more additional deaths following adverse ML trajectories than women and 75-year olds. DISCUSSION: Trajectories that led to higher ML levels were associated with most additional deaths especially among men and in the oldest age group. PMID- 30442038 TI - Using Metacognitive Methods to Examine Emotion Recognition in Children With ADHD. AB - OBJECTIVE: This study investigated confidence accuracy associations for emotion recognition (ER) in children with ADHD and typically developing children (TD). METHOD: Thirty-nine children with ADHD and 42 TD ( M = 9 years, 11 months, SD = 14.92 months, 26 females) completed an ER task. Intelligence and executive function task performance were also measured. RESULTS: The ADHD group was more confident on ER compared with TD, but no group differences were found on their overall accuracy. Specifically, the ADHD group was more confident in its recognition of sad and angry faces compared with the TD group. On a metacognitive index, the ADHD group displayed lower resolution, suggesting that the TD group was better at discriminating correct from incorrect responses. Higher resolution was associated with lower ADHD symptoms. CONCLUSION: Confidence ratings with reference to performance on a specific task can provide an index of social cognition in children with ADHD. PMID- 30442041 TI - Evaluation of WO2014121383 A1: a process for preparation of rufinamide and intermediates. AB - INTRODUCTION: There is great potential in the synthetic development of rufinamide to treat childhood-onset epilepsy known as Lennox-Gastaut syndrome (LGS). Areas covered: 1,4-disubstituted triazole ring formed by 1,3-dipolar cycloaddition reaction is an important structural motif widely used to construct diverse chemotypes in chemical, biological, and material fields. 1,2,3-triazole ring containing rufinamide, an antiepileptic drug developed by Novartis, is useful in combination with other antiepileptic medicaments for the treatment of childhood onset epilepsy known as LGS. There are numerous synthetic methods used to construct the rufinamide through 1,3-dipolar cycloaddition. The application claims processes for the preparation of rufinamide and their intermediates. The synthetic strategy covered for the synthesis of rufinamide using activated acetylenic esters. The activation is done using N-hydroxy succinimide, N hydroxyphthalimide, 1-hydroxy benzotriazole, and 4-nitro phenol. Expert opinion: The manufacturing route appears to follow the regioselective Cu catalyzed cycloaddtion of 2,6-difluro benzyl azide with or without isolated activated acetylenic esters in three steps that provide a good lead for new synthetic strategy for the rufinamide synthesis. PMID- 30442039 TI - Solutol HS15 based binary mixed micelles with penetration enhancers for augmented corneal delivery of sertaconazole nitrate: optimization, in vitro, ex vivo and in vivo characterization. AB - Keratomycosis is a serious corneal disease that can cause a permanent visual disability if not treated effectively. Sertaconazole nitrate (STZ), a novel broad spectrum antifungal drug, was suggested as a promising treatment. However, its utility in the ocular route is restricted by its poor solubility, along with other problems facing the ocular delivery like short residence time, and the existing corneal barrier. Therefore, the objective of this study was to formulate STZ loaded binary mixed micelles (STZ-MMs) enriched with different penetration enhancers using thin-film hydration method, based on a 31.22 mixed factorial design. Different formulation variables were examined, namely, type of auxiliary surfactant, type of penetration enhancer, and total surfactants: drug ratio, and their effects on the solubility of STZ in MMs (SM), particle size (PS), polydispersity index (PDI), and zeta potential (ZP) were evaluated. STZ-MMs enhanced STZ aqueous solubility up to 338.82-fold compared to free STZ. Two optimized formulations (MM-8 and MM-11) based on the desirability factor (0.891 and 0.866) were selected by Design expert(r) software for further investigations. The optimized formulations were imaged by TEM which revealed nanosized spherical micelles. Moreover, they were examined for corneal mucoadhesion, stability upon dilution, storage effect, and ex vivo corneal permeation studies. Finally, both in vivo corneal uptake and in vivo corneal tolerance were investigated. MM-8 showed superiority in the ex vivo and in vivo permeation studies when compared to the STZ-suspension. The obtained results suggest that the aforementioned STZ loaded mixed micellar system could be an effective candidate for Keratomycosis targeted therapy. PMID- 30442040 TI - Fractured Care: A Window Into Emergency Transitions in Care for LTC Residents With Complex Health Needs. AB - OBJECTIVE: For long-term care (LTC) residents, transfers to emergency departments (EDs) can be associated with poor health outcomes. We aimed to describe characteristics of residents transferred, factors related to decisions during transfer, care received in emergency medical services (EMS), ED settings, outcomes on return to LTC, and times of transfer segments along the transition. METHOD: We prospectively followed 637 transitions to an ED in British Columbia and Alberta, Canada, over a 12-month period. Data were captured through an electronic Transition Tracking Tool and interviews with health care professionals. RESULTS: Common events triggering transfer were falls (26.8%), sudden change in condition (23.5%), and shortness of breath (19.8%). Discrepancies existed between reason for transfer, EMS reported chief complaint, and ED diagnosis. Many transfers resulted in resident return directly to LTC (42.7%). DISCUSSION: Avoidable transfers may put residents at risk of receiving inappropriate care. Standardized communication strategies to highlight changes in resident condition are warranted. PMID- 30442042 TI - Participation in Two Evidence-Based Falls Prevention Programs by Adults Aging With a Long-Term Disability: Case-Control Study of Reach and Effectiveness. AB - OBJECTIVE: Adults aging with a long-term disability (LTD) are at an increased risk for falls. The Older Americans Act Title III-D and Prevention and Public Health Fund (PPHF) support several organizations to deliver falls prevention evidence-based programs designed to reduce risk factors; however, little is understood about the reach and effectiveness of these fall prevention programs for those with LTD compared to those without LTD. This study compared the reach and effectiveness of two evidence-based falls prevention programs between older adults with and without LTD. METHOD: Using a matched case-control design, 105 LTD older adults enrolled in A Matter of Balance (AMOB) or Stepping On were matched to 315 non-LTD older adults on age, sex, race, and education. RESULTS: On average, LTD older adults attended a higher number of class sessions and were significantly more likely to complete the program compared with the matched sample of non-LTD older adults. LTD older adults were equally likely as non-LTD older adults to report significant reductions in self-reported fear of falling, falls-related activity restriction, and improvement in falls self-efficacy following completion of the programs. DISCUSSION: These findings provide preliminary evidence for the effectiveness of these evidence-based falls prevention programs for LTD older adults; however, more research is needed to extend these findings. PMID- 30442043 TI - Health Service Utilization and State Costs Among Adults Aging With Early-Acquired Physical Disabilities in Medicaid Managed Care. AB - OBJECTIVE: We evaluated the impact of Medicaid managed care (MMC) on health service use and state costs among adults with early-acquired physical disabilities. METHOD: Using claims data, we tracked utilization of the emergency department (ED), inpatient admissions, outpatient physician visits, and state expenditures on enrollees who transitioned to MMC ( n = 881). The inverse propensity score weight and a difference-in-differences regression model were used to estimate the impact of MMC using their counterparts who remained in fee for-service ( n = 1,552) as the comparison group. RESULTS: MMC reduced ED use by 3.2% points/month ( p < .001). Relative to younger enrollees (age ?45 years), MMC reduced inpatient admissions of older enrollees (age ?46 years) by 3.3% points/month ( p < .001), and state expenditures by US$839/month ( p < .01). DISCUSSION: MMC could reduce the hospital service use of and state spending on enrollees with early-acquired physical disabilities. This impact may vary depending on the enrollees' age. PMID- 30442044 TI - Parental ADHD Symptoms and Inhibitory Control in Relation to Parenting Among Mothers of Children With and Without ADHD. AB - OBJECTIVE: The study examined how the interplay between maternal ADHD symptoms and maternal inhibitory control and child ADHD is related to parenting behaviors. METHOD: The sample included 141 mothers and their 8- to 12-year-old children, 61 children with ADHD and 80 without. Parenting was measured using self-reports (i.e., overreactive and lax parenting) and observation (i.e., negative and supportive parenting). Maternal inhibitory control was measured using a neurocognitive task. Hierarchical multiple regressions were conducted to predict parenting, controlling for child sex, conduct behaviors, and parenting distress. RESULTS: Interactions between maternal ADHD symptoms and maternal inhibitory control suggested that hyperactive-impulsive symptoms were linked to parenting negativity only when inhibitory control was low, and maternal inattention symptoms were related to lax parenting only when maternal inhibitory control was high or when children did not have ADHD. CONCLUSION: Results indicate the importance of maternal regulation processes in the mechanisms linking maternal ADHD with parenting. PMID- 30442046 TI - Releasing the Tide: How Has a Shock to the Acceptability of Gender-Based Sexual Violence Affected Rape Reporting to Police in India? AB - National household data suggest that more than four million women in India have experienced nonspousal rape. Fewer than 1.5% of victims of sexual violence in India report their assaults to police, though there is some indication of increased rape reporting to police following a very high-profile fatal gang rape in Delhi in December 2012. This study examines effects of the Delhi gang rape on rape reporting to police in India, and assesses the roles played by geography, media access, and women's status and protection factors in that reporting. Triangulated data from Indian crime, census, and police bureau records were used to assess trends in rape reporting to police at national and district levels from 2005 to 2016, using regressions, spatial mapping, and graphical trend analyses. Nationally, there was a 33% increase in annual rapes reported to police after 2012. Subnationally, there was substantial variation in trends; these district level changes were particularly affected by distance from Delhi (0.2 fewer rapes reported to police/100,000 women for each 100 km from Delhi), literacy sex ratio (0.6 more rapes for every increase of 0.1 in male: female literacy ratio), and the presence of a women's police station (1.0 fewer rapes reported to police/100,000 women relative to districts with no women's police station). The 2012 Delhi gang rape significantly affected rape reporting to police in India, with greater increases seen closer to Delhi and in districts with compromised gender equity. Further work to support the rights and safety of women is needed, including bolstering an enabling environment for reporting, legal protections, and responsive criminal justice. PMID- 30442045 TI - Successful decellularization of thick-walled tissue: Highlighting pitfalls and the need for a multifactorial approach. AB - INTRODUCTION:: Decellularization of thick tissue is challenging and varying. Therefore, we tried to establish a multifactorial approach for reliable aortic wall decellularization. METHODS:: Porcine aortic walls were decellularized according to different procedures. Decellularization was performed for 24 (G1), 48 (G2), and 72 h (G3) with a solution of 0.5% desoxycholate and 0.5% dodecyl sulfate. The procedure was characterized using intermittent washing steps, the inclusion of sonication as well as DNase and alpha-galactosidase treatment. The decellularization efficiency was measured by the evaluation of 4',6-diamidino-2 phenylindole and hematoxylin and eosin staining and quantitative DNA assays. Pentachrome and picrosirius red staining, scanning electron microscopy as well as glycosaminoglycan assays were performed to evaluate the effect of the procedure on the extracellular matrix. RESULTS:: 4',6-Diamidino-2-phenylindole and hematoxylin and eosin staining revealed a large amount of remaining nuclei in all groups. However, consecutive DNase treatment had a significant effect. While the remaining DNA was detected in some samples of G1 and G2, samples of G3 were fully decellularized. Glycosaminoglycan content was significantly reduced to 50% after 24 h (G1) but remained constant for G2 and G3. Picrosirius red staining revealed an intact and stable collagen network without any visible defects. Pentachrome staining substantiated these results. Nonetheless, the fiber network remains intact, which could be confirmed by reflection electron microscopy analysis. CONCLUSION:: In this study, we developed a procedure that grants successful decellularization of porcine aortic wall while maintaining the fibrous microstructure. We highlighted the significant effect of DNase and alpha galactosidase treatment. In addition, we could show the need for a multifactorial treatment and comprehensive evaluation protocols for thick tissue decellularization. PMID- 30442047 TI - Risk factors for complications in cancer patients with totally implantable access ports: A retrospective study and review of the literature. AB - OBJECTIVES: To analyze the risk factors for complications associated with the use of totally implantable access ports (TIAPs) in cancer patients. METHODS: Data for 2,713 cancer patients who received a TIAP between January 2010 and September 2016 at a single center were analyzed retrospectively. RESULTS: The average age of the patients was 54.2 +/- 9.92 years, and 1,247 (47.5%) were women. The right subclavian vein was the preferred insertion site. Seventy-seven patients developed early complications and 50 developed late complications. The incidence of complications increased as the number of punctures increased. Percutaneous intervention increased the risk of complications during port insertion, but age, sex, body mass index, and the use of physiological saline solution instead of heparin for washing after port insertion did not increase the risk. The use of ultrasonography during insertion reduced the risk of complications. CONCLUSIONS: Various factors may affect the function of TIAPs in cancer patients both during insertion and follow-up. Age, sex, body mass index, and the use of physiological saline solution for washing did not affect the incidence of complications, but the use of ultrasonography during insertion did affect the complication rate. PMID- 30442049 TI - International journal of audiology reviewer contact information. PMID- 30442048 TI - Gender differences in cigarette smoking and alcohol drinking among adolescents and young adults in Hanoi, Shanghai, and Taipei. AB - OBJECTIVE: This study aimed to examine gender differences in smoking and alcohol drinking behaviors in three Asian cities of Hanoi, Shanghai, and Taipei, and to assess the magnitude of gender differences across the three cities. METHODS: A total of 17,016 adolescents (age: 15-19 years) and young adults (age: 20-24 years) were selected using multi-stage sampling methods and surveyed in face-to face interviews. A total of 16,554 unmarried respondents were included in this analysis. RESULTS: Gender differences were significant for smoking only, drinking only, and both behaviors in each city. Male respondents were 30.66 times more likely to report smoking only than female respondents in Hanoi, followed by Shanghai and Taipei. This pattern was similar for drinking only and both smoking and drinking behaviors. CONCLUSIONS: The magnitude of gender differences in smoking only, drinking only, and both behaviors widely varies across the three cities. Further research can examine how these differences may be used to prevent and reduce smoking and drinking in the adolescent and young adult population. PMID- 30442050 TI - Radiation-induced lung injury: impact on macrophage dysregulation and lipid alteration - a review. AB - Lung cancer continues to be the leading cause of cancer deaths and more than one million lung cancer patients will die every year worldwide. Radiotherapy (RT) plays an important role in lung cancer treatment, but the side effects of RT are pneumonitis and pulmonary fibrosis. RT-induced lung injury causes damage to alveolar-epithelial cells and vascular endothelial cells. Macrophages play an important role in the development of pulmonary fibrosis despite its role in immune response. These injury activated macrophages develop into classically activated M1 macrophage or alternative activated M2 macrophage. It secretes cytokines, interleukins, interferons, and nitric oxide. Several pro-inflammatory lipids and pro-apoptotic proteins cause lipotoxicity such as LDL, FC, DAG, and FFA. The overall findings in this review conclude the importance of macrophages in inducing toxic/inflammatory effects during RT of lung cancer, which is clinically vital to treat the radiation-induced fibrosis. PMID- 30442051 TI - Understanding sex offender community supervision: A mixed methods approach. AB - The process of transitioning from prison to the community poses unique challenges for those who have been convicted of sexually based offenses. Due to the realities associated with the unique challenges facing these individuals, the community supervision process fluctuates along the correctional continuum which polarizes rehabilitative and control. The current study examines how this fluctuation relates to both the supervision process and correctional outcomes. Furthermore, the literature suggests five specific checkpoints along this continuum which are measured both qualitatively and quantitatively. The five checkpoints are Social Reintegration, Community Reentry, Status Maintenance, Statutory Compliance, and Risk Management. Overall, all five checkpoints are included in some way in the community supervision process; and analyses show significant links between the checkpoints and correctional outcomes. PMID- 30442052 TI - Management of postprandial hyperglycaemia and weight gain in women with gestational diabetes mellitus using a novel telemonitoring system. AB - OBJECTIVES: The purpose of this study was to investigate the effect of remotely delivered telemedicine dietary advice on monitoring of blood glucose levels and weight gain of women with gestational diabetes mellitus (GDM). METHODS: Women with GDM were recruited and randomly allocated into two groups: a Tele-GDM group that received a telemonitoring device, and a control group that was followed-up traditionally. A telemonitoring service calculated the ratio of reaching or exceeding the pregnancy weight gain target (according to pre-pregnancy weight), following Institute of Medicine guidelines for healthy pregnancy weight gain. RESULTS: The sample comprised 27 women in the Tele-GDM group and 30 in the control group. At the end of pregnancy, the Tele-GDM group showed significantly lower 2-hour postprandial glucose levels than the control group. Most women in the Tele-GDM group reached their recommended range of weight gain at the end of pregnancy. Additionally, the Tele-GDM group showed significantly lower weight gain than the control group. CONCLUSIONS: Telemonitoring can facilitate close monitoring of women with GDM and motivate patients to adopt a healthy lifestyle. PMID- 30442054 TI - Aesthetic improvements of radial forearm flap donor site by autologous fat transplantation. AB - Despite its reliability, radial forearm (RF) flap is still affected by high donor site morbidity with poor cosmetic and functional outcomes after coverage with skin grafts. Having fat grafting demonstrated promising and effective filling and rejuvenating properties, we considered and tested it as a valuable alternative to dermal substitutes for the aesthetic improvement of RF flap donor site. Thirty three patients with previous RF free flap reconstruction and poor donor site outcomes after full-thickness skin grafting to RF region were evaluated for secondary fat injection to improve outcomes. Objective and subjective assessments of results with standardized ultrasonographic soft tissue thickness measurements, cutaneous sensibility tests with the pressure-specified sensory device and scar assessment scale (POSAS) have been performed. Bivariate statistical analyses were performed comparing outcomes with contralateral healthy forearm. All cases showed significant improvement in soft tissue thickness (p< 0.031), cutaneous sensibility and scar appearance, with improved patient's and observers' scar assessment scores (<0.001). In conclusion, fat transplantation is an effective procedure that provided us with an adjunctive autologous layer in-between skin graft and underlying fascia, as well as a rejuvenating effect on skin and scars. PMID- 30442053 TI - FGF-2-containing dalteparin/protamine nanoparticles (FGF-2&D/P NPs) ameliorate UV induced skin photoaging in hairless mice. AB - UVB exposure penetrates deeply into the dermis to alter skin barrier function, which is a primary factor in skin photoaging. We previously reported that dalteparin and protamine nanoparticles (D/P NPs) are effective carriers of FGF-2. This study aimed to examine the ability of FGF-2-containing D/P NPs (FGF-2&D/P NPs) to ameliorate UVB-induced skin photoaging in hairless mice. Dorsal skin of HR-1 hairless mice were exposed to UVB irradiation 5 days/week for 8 weeks (UV (+): final total, 2700 mJ/cm2). Mice were divided into four groups: Non-UVB (UV ( )) + saline, UV (+) + saline, UV (+) + FGF-2&D/P NPs, UV (+) + FGF-2, and UV (+) + D/P NPs, and following UVB irradiation, FGF-2&D/P NPs, FGF-2, and D/P NPs were applied to the groups of mice just after each UVB irradiation. Each group was subjected to evaluation of skin changes (elasticity), and histological examination using hematoxylin & eosin and terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) staining. UVB irradiation of mice significantly induced a decline in elasticity and acanthosis, which was alleviated by application of FGF-2&D/P NPs. Furthermore, TUNEL-staining showed the proportions of apoptotic dermal fibroblast cells (DFCs) and epidermal keratinocyte cells (EKCs) in the UV (+) + FGF-2&D/P NPs group were significantly lower than those in the UV (+) + saline, UV (+) + FGF-2, and UV (+) + D/P NPs groups. Thus, FGF-2&D/P NPs may be effective in preventing skin photoaging accelerated by UVB irradiation such as declining elasticity, acanthosis, and apoptosis of DFCs and EKCs. PMID- 30442055 TI - Role of the tissue-type plasminogen activator -7351C > T and plasminogen activator inhibitor 1 4G/5G gene polymorphisms in central serous chorioretinopathy. AB - BACKGROUND: Central serous chorioretinopathy (CSC) is a common chorioretinal disease, characterized by choroidal hyperpermeability leading to neurosensory and/or retinal pigment epithelial detachments. Hypofibrinolysis due to higher plasma concentrations of plasminogen activator type 1 (PAI-1) or lower activity of tissue-type plasminogen activator (t-PA) has been implicated in the pathogenesis of CSC. Functional polymorphisms in the PAI-1 (SERPINE1) and t-Pa (PLAT) are thus potential risk factors for CSC. The aim of the present study was therefore to investigate a hypothesized association between the PAI-1 4G/5G and the t-PA -7351C > T gene variants and the presence of CSC. METHODS: The present study comprised 172 CSC patients and 313 control subjects. Genotypes of the PAI-1 4G/5G and the t-PA -7351C > T polymorphisms were determined by TaqManTM fluorogenic 5'-exonuclease assays. RESULTS: Allelic frequencies or genotype distributions of neither the PAI-1 4G/5G nor the t-PA -7531C > T polymorphisms were significantly different between patients with CSC and control subjects (PAI 1 4G/4G: 24.4% vs. 20.4, p = 0.36; t-PA -7351CC: 42.4% vs. 46.0%, p = 0.50). After adjusting for age and gender presence of the PAI-1 4G/4G genotype was associated with a non-significant odds ratio (OR) of 1.21 (95% confidence interval [95% CI]: 0.77-1.92, p = 0.41), while homozygosity for the t-PA -7351C allele yielded a non-significant OR of 0.91 (95% CI: 0.62-1.33, p = 0.62) for CSC. CONCLUSION: The present study suggests that both the t-PA -7351C > T and the PAI-1 4G/5G gene variants are unlikely major risk factors for CSC. PMID- 30442056 TI - Intraoperative assessment of tubules in predicting microdissection testicular sperm extraction outcome in men with Sertoli cell-only syndrome. AB - OBJECTIVE: This study aimed to assess the value of measuring the tubule diameter during microdissection testicular sperm extraction (micro-TESE) in predicting outcomes in patients with Sertoli cell-only syndrome (SCOS). METHODS: Fifty-six consecutive patients with SCOS were included. Patients were classified into two groups on the basis of the diameter of seminiferous tubules measured against 5/0 surgical suture (>=100 um or <100 um). RESULTS: The sperm retrieval rate (SRR) in men with a tubule diameter >=100 um was significantly lower than that in those with <100 um (3.1% vs. 25.0%). The SRR from the contralateral testis in men with a tubule diameter >=100 um was lower than that in those with <100 um (0% vs. 14.3%). Men with a tubule diameter >=100 um had a significantly larger testis and lower follicle-stimulating hormone levels than did men with <100 um (8.1 +/- 2.4 vs. 5.3+/-1.8 mL, 19.9 +/- 9.7 vs. 25.9 +/- 7.1 mIU/mL, respectively). CONCLUSIONS: The diameter of tubules is a useful predictor for a successful SRR in men with SCOS. Intraoperative assessment of homogeneous large tubules allows some men to perform a limited (superficial) contralateral micro-TESE after no spermatozoa are initially identified. PMID- 30442057 TI - Intraarterial indocyanine green (ICG) fluorescence augmentation by marking embryonal resection areas in colorectal surgery: a feasibility study in a porcine model. AB - AIM: In this pilot animal study we examined whether it is possible to visualize the embryonal resection layers by using intraarterial indocyanine green (ICG) staining when performing total mesorectal excision (TME) for carcinoma of the rectum. MATERIAL AND METHODS: We injected ICG into the inferior mesenteric artery (AMI) of four swines to see whether the watershed area of the arterial supply zone can be sufficiently visualized by fluorescence imaging in order to mark the right dissection area along the fascia parietalis before and during resection. RESULTS: We observed a fluorescence signal in all the supplied areas of AMI but not in other parts of the abdominal cavity or other organs. Additionally, the mesorectum also showed a sharp border between colored and non-colored tissue. CONCLUSION: In this study we present that resection borders may be determined before resection based on ICG-perfusion and we showed that intraoperative exclusive coloring of the rectum including the mesorectum is possible. Visualizing resection borders based on ICG-perfusion before settling the first cut may be a new approach in oncological surgery. PMID- 30442059 TI - Cannabis consumption and psychosis or schizophrenia development. AB - OBJECTIVE:: Cannabis consumption produces psychopathology, in some cases psychotic episodes, which are of our interest in this work. However, the relationship between cannabis use and psychosis has not been fully elucidated. The objectives of this work are to (1) review the current state of knowledge on the association of cannabis use with the risk of the development of psychosis or psychotic symptoms in people without schizophrenia and (2) assess the consistency of the hypothesis that cannabis use is associated with increased risk of psychosis in people without schizophrenia. METHOD:: This work included research done in humans until May 2018 with the keywords 'cannabis' and 'psychosis', published in English and Spanish, in the PubMed database. RESULTS:: In all, 66 papers were analyzed, of which 23 were cohort trials and 43 were reviews. CONCLUSION:: Cannabis use doubles the risk of developing psychosis in vulnerable people. There even exists a relationship regarding the dose used and the age of first use. Gene-environment interactions that modulate the association between cannabis use and the presence of psychosis have also been described. PMID- 30442058 TI - Stigma associated with mental illness among Asian men in Vancouver, Canada. AB - BACKGROUND:: Due to racism, xenophobic nationalism, acculturation pressures and patriarchal social relations, Asian men in Western societies may be particularly susceptible to negative experiences and beliefs regarding mental illness and treatment services. AIMS:: We examine factors associated with stigma toward mental illness among Asian men in Canada. METHODS:: Between 2013 and 2017, 428 self-identified Asian men living in proximity to Vancouver, Canada, were recruited and completed self-administered questionnaires assessing social stigma and self-stigma. The degree to which these variables were associated with the men's sociodemographic characteristics was analyzed. RESULTS:: Multivariable regression revealed that social stigma was significantly predicted by age, immigration, employment status and experience with mental illness. Together, these variables accounted for 12.36% of variance in social stigma. Interaction terms were added to the regression models to examine whether the effects of immigration on social stigma varied by age and experience with mental illness, but none of the interaction terms were statistically significant. Among the 94 Asian men identified as living with mental illness, self-stigma was predicted by age, immigration and employment status, which together accounted for 14.97% of variance in self-stigma. CONCLUSION:: These results offer new knowledge about the factors predicting stigma toward mental illness among Asian men in Western societies. PMID- 30442060 TI - Quality of life in patients with toe-to-hand transplantation. AB - OBJECTIVE: Toe-to-hand transplantation is a reliable procedure that replaces like with-like in cases of a lost thumb or finger. The aim of this study is to investigate the effects of toe transplantation on patients from the perspectives of quality of life (QOL) and disability. METHODS: Ten patients with traumatic amputation of a digit underwent reconstruction with toe transplantation. The mean age at injury was 40.2 years (range 17-59 years). Reconstructive options were 5 wrap-around flaps to 2 thumbs and 3 index fingers; 2 second-toe transplantations to 2 middle fingers, and 3 hemipulp-free flaps from the great toe to a thumb and an index finger. We hypothesized that toe transplantation would improve postoperative QOL and disability. Outcome assessments included completion of the SF-36, SAFE-Q, and DASH questionnaires before and after reconstruction. Scores on each test were calculated and intra-individual comparisons were made. RESULTS: All scores for the eight SF-36 health domains improved, with a significant difference in Vitality from before to after surgery. In contrast, scores for all five SAFE-Q items worsened, with significant changes for the 'Pain and Pain Related' and 'Physical Functioning and Daily Living' subscales. DASH scores improved after surgery in all cases. CONCLUSIONS: Our results suggest that toe-to hand transplantation for amputated finger reconstruction is a good option in terms of improved QOL. However, worsened SAFE-Q scores imply that donor site problems could be expected and must be taken into account during surgical planning. PMID- 30442061 TI - Late-onset biopsy-proven lupus nephritis without other associated autoimmune diseases: severity and long-term outcome. AB - BACKGROUND/PURPOSE: Lupus nephritis (LN) usually develops within the first years of systemic lupus erythematosus (SLE) onset and rarely after that. There are scarce studies comparing early- versus late-onset nephritis (before versus after five years of SLE diagnosis). The aim of this study was to compare the severity and long-term outcome (after 7 years) in these two, late-onset and early-onset, nephritis groups. METHODS: This study included 93 patients from rheumatology tertiary centers from Brazil and Italy, all of them with biopsy-proven LN with > 7 years follow-up. Patients were divided in two groups: early-onset nephritis ( n = 75) and late-onset nephritis ( n = 18). Clinical and laboratorial data were obtained using a standardized electronic chart database protocol carried out at 1 6 months interval and established in 2000. Patients >50 years or with concomitant autoimmune diseases were excluded. Variables evaluated at the LN presentation were Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), creatinine, albumin, anti-DNA positivity and nephritis class. Variables evaluated at the long term outcome (after 7 years) were Systemic Lupus International Collaborating Clinics Damage Index (SDI), creatinine, dialysis and mortality. RESULTS: The average time of LN presentation was 10.94 +/- 3.73 years for the late-onset and 1.20 +/- 1.60 years for the early-onset group. Their similar nephritis duration (12.44 +/- 3.2 versus 13.28 +/- 4.03 years, p = 0.41) and comparable mean ages (49.17 +/- 9.9 versus 44.11 +/- 10.8 years old, p = 0.06) allow a more accurate comparison. Regarding severity, late-onset was similar to early-onset group: SLEDAI (8 (range: 6-22) versus 12 (range: 2-24), p = 0.47), creatinine (1.36 +/- 0.94 versus 1.36 +/- 1.13 mg/dl, p = 0.99); albumin (2.84 +/- 0.65 versus 2.59 +/ 0.84 mg/dl, p = 0.30); proteinuria (3.77 +/- 2.18 versus 5.01 +/- 4.51 g/vol, p = 0.26); proliferative nephritis (44% ( n = 8) versus 60% ( n = 45), p = 0.23). There was also no difference in the long-term outcomes between groups: SDI (1 (range: 0-5) versus 0.5 (range: 0-5), p = 0.27); creatinine (2.04 +/- 2.38 versus 1.69 +/- 2.26 mg/dl, p = 0.56); dialysis (22% ( n = 4) versus 13% ( n = 10), p = 0.46) and mortality (0% ( n = 0) versus 12% ( n = 9), p = 0.19). CONCLUSION: This study provides novel evidence of comparable long-term outcomes between late-onset and early-onset nephritis, which is most likely explained by the observation that at presentation, the clinical, laboratorial and histological features of late onset and early-onset nephritis are similar. This suggests that there should be no distinct treatment targets and therapeutic interventions for the late- and early-onset groups. PMID- 30442062 TI - A preliminary study on time-compressed speech recognition in noise among teenage students who use personal listening devices. AB - OBJECTIVE: To compare speech perception obtained with different time compression rates in teenagers that do or do not use personal listening devices (PLDs). DESIGN: Teenagers in a high school were recruited to complete questionnaires reporting their recreational noise exposure using PLDs. The dose of individual recreational noise exposure was calculated. The individuals with the most and least doses of recreational noise were selected and grouped into PLD users and non-PLD users. Normal rate and time-compressed (60% and 70%) speech recognition in quiet and noisy conditions was measured. STUDY SAMPLE: PLD user and non-PLD user group each included 20 participants. RESULTS: ANOVA analysis showed that the effect of group, background, compression rate, and interactions between any two factors are significant. Post hoc analysis showed that the speech recognition scores with normal rate in quiet and noise and those obtained from time compressed speech in the quiet condition were not significantly different between PLD users and non-PLD users. However, differences in the time-compressed speech recognition scores (60% and 70%) in noisy conditions between the two groups were statistically significant. CONCLUSIONS: The fast-speed speech recognition in noise decreased significantly in PLD users compared with that in non-PLD users selected by extreme entertainment exposure. PMID- 30442063 TI - No influence of initial naloxone dosage: a significant misunderstanding. PMID- 30442064 TI - Acute hyperammonemia in children under deferasirox treatment: cutting the Gordian knot. PMID- 30442065 TI - Negotiated ethical responsibility: Bruneian nurses' ethical concerns in nursing practice. AB - BACKGROUND:: There has been wide interest shown in the manner in which ethical dimensions in nursing practice are approached and addressed. As a result, a number of ethical decision-making models have been developed to tackle these problems. However, this study argued that the ethical dimensions of nursing practice are still not clearly understood and responded to in Brunei. RESEARCH AIM:: To explore how Bruneian nurses define ethical concerns they meet in everyday practice in the medical surgical wards of three Brunei hospitals. RESEARCH DESIGN:: A qualitative study was employed. Interviews were conducted with 28 practising and administrative nurses of three hospitals. Interview data were analysed via a constant comparative method. ETHICAL CONSIDERATION:: The study's protocol was reviewed and approved by the Ethical Committee of the School of Health in Social Science at the University of Edinburgh and the Medical Health Research Ethics Committee of the Ministry of Health, Brunei. FINDINGS:: The nurses described three ethical dimensions in their practice, namely: 'nurse at work' which illustrates the ethical dimensions within the work environment; 'nurse and doctor' which elucidates the ethical dimensions in the nurse and doctor relationship; and 'nurse and patient' which further examines ethical aspects in patient care. Nurses responded to the ethical dimensions in the ward setting with the aim of avoiding the conflict and maintaining ward harmony. DISCUSSION:: The data provide new insights into how nurses respond to ethical dimension in the ward settings where it puts strong emphasis on the nurses' understanding of responsibility placed upon them as professional nurses. CONCLUSION:: With these findings, it is recommended that further support is needed for nurses to be aware of the ethical dimension in their practice and to respond to ethical concerns accordingly. PMID- 30442066 TI - Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies. AB - The study highlights the significance of co-application of bioactive components into liposomal gel formulations and their comparison to azithromycin for treatment of Acne. A Design of Experiments (DoE) approach was utilized to obtain optimized liposomal formulation encapsulating curcumin, with size and zeta potential of ~100 nm and ~14 mV, respectively, characterized by DLS, HR-TEM, FESEM, and AFM. The curcumin liposomal dispersion depicted excellent stability over the period of 60 days, which was further converted in gel form using Carbopol. Pharmacokinetics of curcumin-loaded liposomal gel showed that Tmax for curcumin was achieved within 1 h of post application in both stratum corneum and skin, indicating quick penetration of nano-sized liposomes. Stratum corneum depicted Cmax of 688.3 ng/mL and AUC0-t of 5857.5 h * ng/mL, while the skin samples displayed Cmax of 203.3 ng/gm and AUC0-t of 2938.1 h * ng/gm. Lauric acid and azithromycin liposomal gel formulations were prepared as per the optimum parameters obtained by DoE. In antibacterial activity using agar diffusion assay, lauric acid gel formulation revealed ~1.5 fold improved antibacterial effect than curcumin gel formulation. Interestingly, their co-application (1:1) exhibited significantly enhanced antibacterial effect against both macrolide-sensitive (1.81 versus 1.25 folds) and resistant strains of P. acnes (2.93 versus 1.22 folds) than their individual counterparts. The in vivo studies in rat ear model displayed a ~2 fold reduction in comedones count and cytokines (TNF-alpha and IL 1beta) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group. PMID- 30442067 TI - A novel synthetic cannabinoid (Cumyl-4-cyano-BINACA) resulting in hyperthermia, rhabdomyolysis, and renal failure in a 29-year-old patient: it's not meningitis. PMID- 30442068 TI - Examining Effort-Reward Imbalance and Depressive Symptoms Among Turkish University Workers. AB - The body of research pertaining to work-related stress and health among Turkish workers is sparse. It was the aim of this study to test the feasibility of two work stress scales of the Turkish short version of the Effort-Reward Imbalance (ERI-SV) questionnaire among staff and faculty in an academic university setting. We also assessed and examined if work stress was associated with depressive symptoms, using Center for Epidemiological Studies-Depression (CES-D) scale. The two ERI-SV scales and the CES-D scale were distributed to 170 study subjects employed at a southern university in Turkey, in which 67% ( n = 114/170) responded. We examined Cronbach's alpha coefficients for the internal consistency of the two main work stress scales of the ERI-SV, and scale structural validity was assessed using exploratory factor analysis. Logistic regression was performed to test the hypothesis of associations of work stress with depressive symptoms. Cronbach's alpha coefficients were .75 and .76 for the scales "Effort" and "Reward," respectively. Two separate factors were extracted according to the theoretical assumption of the ERI model. Associations between ERI and depressive symptoms were significant (odds ratio [OR] = 3.80 for Effort-Reward [E-R] ratio with an increase per SD, and 7.39 for the high work stress group as defined by an E-R ratio > 1.0). This study provides evidence of the feasibility of the short version of the Turkish ERI questionnaire by pointing to a strong association of stressful work with depressive symptoms in this group of academic workers. Further psychometric properties of the ERI questionnaire are required before its wider application in research and practice. PMID- 30442069 TI - Combining information from multiple bone turnover markers as diagnostic indices for osteoporosis using support vector machines. AB - CONTEXT: Osteoporosis (OP) is a progressive systemic bone disease. Dual-energy X ray absorptiometry (DXA) is routinely employed and is considered the gold standard method for the diagnosis of OP. OBJECTIVE: We aimed to investigate the potential use of combined information from multiple bone turnover markers (BTMs) as a clinical diagnostic tool for OP. MATERIALS AND METHODS: A total of 9053 Chinese postmenopausal women (2464 primary OP patients and 6589 healthy controls) were recruited. Serum levels of six common BTMs, including BAP, BSP, CTX, OPG, OST and sRANKL were assayed. Models based on support vector machine (SVM) were constructed to explore the efficiency of different combinations of multiple BTMs for OP diagnosis. RESULTS: Increasing the number of BTMs used in generating the models increased the predictive power of the SVM models for determining the disease status of study subjects. The highest kappa coefficient for the model with one BTM (BAP) compared to DXA was 0.7783. The full model incorporating all six BTMs resulted in a high kappa coefficient of 0.9786. CONCLUSION: Our findings showed that although single BTMs were not sufficient for OP diagnosis, appropriate combinations of multiple BTMs incorporated into the SVM models showed almost perfect agreement with the DXA. PMID- 30442070 TI - H2Oh No! The importance of reporting your water source in your in vivo microbiome studies. AB - Water is a fundamental part of any in vivo microbiome experiment however, it is also one of the most overlooked and underreported variables within the literature. Currently there is no established standard for drinking water quality set by the Canadian Council on Animal Care. Most water treatment methods focus on inhibiting bacterial growth within the water while prolonging the shelf-life of bottles once poured. When reviewing the literature, it is clear that some water treatment methods, such as water acidification, alter the gut microbiome of experimental animals resulting in dramatic differences in disease phenotype progression. Furthermore, The Jackson Lab, one of the world's leading animal vendors, provides acidified water to their in-house animals and is often cited in the literature as having a dramatically different gut microbiome than animals acquired from either Charles River or Taconic. While we recognize that it is impossible to standardize water across all animal facilities currently conducting microbiome research, we hope that by drawing attention to the issue in this commentary, researchers will consider water source as an experimental variable and report their own water sources to facilitate experimental reproducibility. Moreover, researchers should be cognisant of potential phenotypic differences observed between commercial animal vendors due to changes in the gut microbiome as a result of various sources of water used. PMID- 30442071 TI - Predictors of Sexual Violence Across Young Women's Relationship Histories. AB - The goal of the current study was to identify risk factors that predict sexual intimate partner violence (IPV) victimization across young women's relationship histories, within a socioeconomically diverse sample recruited from a university, a 2-year college, and community organizations serving low-income young women. We interviewed 148 young women aged 18 to 24 years about partner victimization (physical IPV, coercive control, and sexual IPV) within each of their relationships (up to four relationships, beginning with their first; 388 in total). We used the life history calendar to structure the interviews and obtain detailed information about each relationship, including age difference between participants and their partners, and relationship length. We used multilevel modeling to examine primary caregiver highest grade completed (an indicator of socioeconomic status [SES]), participant age, age difference, relationship length, setting, and physical IPV/coercive control as predictors of sexual IPV during their first relationship and across Relationships 1 to 4. Sexual IPV during participants' first relationship was inversely associated with SES and age, and positively associated with physical IPV/coercive control; 2-year college and community participants reported lower rates of sexual IPV during the first relationship, compared with university participants. The trajectory of sexual IPV across Relationships 1 to 4 declined among university participants and increased among 2-year college participants; age difference and physical IPV/coercive control positively covaried with sexual IPV across Relationships 1 to 4. Low SES, young age, large age difference, and the presence of physical IPV and coercive control may be risk factors for sexual IPV victimization within adolescent relationships. Sexual violence prevention and intervention approaches should incorporate these risk factors, and be designed to reach an increasingly socioeconomically diverse population across a variety of settings, to be effective. PMID- 30442072 TI - BMP-7/Smad expression in dedifferentiated Schwann cells during axonal regeneration and upregulation of endogenous BMP-7 following administration of PTH (1-34). AB - PURPOSE:: To determine the expression and distribution of bone morphogenetic protein (BMP)-7 and related molecules during peripheral nerve regeneration and to assess whether administration of parathyroid hormone (PTH) drug (1-34) potentiates the intrinsic upregulation of BMP-7/Smad signaling. METHODS:: The rat sciatic nerves were crushed with an aneurysm clip resulting in axonal degeneration. In the normal nerve, and at 1, 2, 4, and 8 weeks after injury, BMP 7, BMP receptors, p-Smad 1/5/8, and Noggin, the endogenous BMP antagonist, were evaluated. Additionally, the distribution of BMP-7 was assessed by fluorescent double immunostaining. In vitro studies were also performed to examine the effect of BMP-7 and PTH (1-34) administration on rat Schwann cells (SCs). RESULTS:: Aneurysm clip made reliable animal model of the nerve injury with recovery at 8 weeks after the injury. BMP-7/Smad protein and mRNA were significantly upregulated on axon-SCs units at 1 week after injury, and this upregulated expression was maintained for 4 weeks. Besides, significant upregulation of Noggin's expression was observed on axon-SCs units at 2 weeks after injury. Moreover, fluorescent double immunostaining showed co-localization between expression of BMP-7 and p75NTR during axonal regeneration. In the in vitro study, administration of BMP-7 induced significant proliferation of SCs. Application of PTH (1-34) upregulated BMP-7 on SCs. DISCUSSION/CONCLUSION:: BMPs were reported to be involved in protection and recovery after injury as well as in neurogenesis. Our current study showed that BMP/Smad signaling molecules were upregulated on dedifferentiated SCs after peripheral nerve injury and that administration of BMP-7 increased SC viability in vitro. These results suggested that axonal regeneration could be induced via upregulation of endogenous BMP-7 on SCs by PTH (1-34) administration. PMID- 30442074 TI - A review of HIV testing strategies among MSM (2005-2015): Changes and continuities due to the biomedicalization of responses to AIDS. AB - Global AIDS policy points to a new prevention rationale centred on the identification and treatment of people infected with HIV, particularly among the so-called key populations. This study analyses the continuities and changes in HIV testing strategies based on a meta-narrative review of academic output (2005 2015) focusing on men who have sex with men. We reviewed 65 articles based on their prevention approaches, testing strategies and the involvement of non governmental organisations (NGOs) and community-based organisations. The analysis found continuities in HIV testing strategies in addition to changes. A new focus is reflected in the expansion and diversification of testing offered, the reduced importance of counselling, an emphasis on condom use associated with test results and on the absence of active participation of NGOs in implementing social responses to AIDS. Our findings indicate a systematic lack of problematising the potential ethical, political and cultural issues surrounding HIV testing as a strategy to control the epidemic. The findings of our study reinforce criticisms of the biomedicalization of current HIV-related policies, and reiterate the importance of combining progress achieved in increasing access to diagnosis and treatment with the historical achievements of social responses to AIDS. PMID- 30442073 TI - Application of sandwich spatial estimation method in cancer mapping: A case study for breast cancer mortality in the Chinese mainland, 2005. AB - High-accuracy spatial distribution estimation is crucial for cancer prevention and control. Due to their complicated pathogenic factors, the distributions of many cancers' mortalities appear blocky, and spatial heterogeneity is common. However, most of the commonly used cancer mapping methods are based on spatial autocorrelation theory. Sandwich estimation is a new method based on spatial heterogeneity theory. A modified sandwich estimation method suitable for the estimation of cancer mortality distribution is proposed in this study. The variances of cancer mortality data are used to fuse sandwich estimation results from various auxiliary variables, the feasibility of which in estimating cancer mortality distributions is explained theoretically. The breast cancer (BC) mortality of the Chinese mainland in 2005 was taken as a case, and the accuracy of the modified sandwich estimation method was compared with that of the Hierarchical Bayesian (HB), the Co-Kriging (CK) and the Ordinary Kriging (OK) methods. The accuracy of the modified sandwich estimation method was better than the HB, the CK and the OK methods, and the estimation result from the modified sandwich estimation method was more likely to be acceptable. Therefore, this study represents an attempt to apply the sandwich estimation method to the estimation of cancer mortality distributions with strong spatial heterogeneity, which holds great potential for further application. PMID- 30442075 TI - A Systematic Review of Barriers to Access-to-Care in Hispanics With Type 2 Diabetes. AB - INTRODUCTION: A systematic review was conducted to highlight current barriers to access-to-care for Hispanics with type 2 diabetes (T2D). METHOD: PubMed and CINAHL databases (2010-2015) using PRISMA guidelines. 84 studies were identified, 12 quantitative studies were selected for review remained based on inclusion/exclusion criteria. There were five research questions: (1) What samples/settings were included? (2) What theories guided each study? (3) What were the study aims and (4) designs? (5) What barriers of access-to-care were identified? Barriers were placed into three categories set a priori. RESULTS: The word "barrier" was in one study aim. Barriers of self (92%), provider (50%), and environment (25%) were identified. Self-care behaviors (diet and exercise), individual resources (cost factors), lack of providers specializing in T2D, and environmental factors affect Hispanics with T2D access-to-care. DISCUSSION: These barriers to access underscore current importance to Hispanics with T2D. A follow up review should be conducted as new barriers are expected to emerge. PMID- 30442077 TI - Induced Abortions Among Women Having Undergone Total Hip Replacement: A Nationwide Register Study in Finland. AB - BACKGROUND AND AIMS:: No previous studies have analyzed the connection between total hip replacement and induced abortion. We evaluated the nationwide induced abortion rates among women with and without total hip replacement. MATERIALS AND METHODS:: Data for this cohort study were gathered from national registers from 1987 to 2007. All fertile-aged (15-44 years old) females who had undergone primary total hip replacement in Finland were selected. The total hip replacement patient group comprised 1713 women and the reference group 5148 women. Information on all pregnancies for both groups before and after total hip replacement/index date was gathered from the medical birth register and the register of induced abortion. Logistic regression model was used to analyze the adjusted odds ratio for induced abortion. Adjustment was made for age at induced abortion, parity, previous induced abortions, previous deliveries, and marital status. RESULTS:: Women had higher induced abortion proportions after total hip replacement (17.9%) compared with women before total hip replacement (14.1%) and the referents (13.9%), but the differences were not statistically significant. Women in the total hip replacement patient group had significantly more induced abortions after total hip replacement due to maternal health issues (14.7%) compared with the referents (2.7%), p = 0.003. Patients in the total hip replacement group were not more likely to have their pregnancy ending in induced abortion than the women in the reference group (odds ratio 1.32, 95% confidence interval 0.89-1.96, p = 0.17). However, in the adjusted analysis, there was a trend for higher risk for pregnancy to end in induced abortion in the total hip replacement group in relation to the reference group (adjusted odds ratio 1.50 (confidence interval 0.99-2.28, p = 0.05). CONCLUSION:: The total hip replacement patient group had higher, but statistically insignificant, induced abortion proportions compared with the reference group before and after the operation. After total hip replacement, the patients were not more likely to have a pregnancy ending in induced abortion. This finding remained statistically insignificant after adjusting with possible confounders. PMID- 30442076 TI - Identification of new factors associated to walking impairment in patients with vascular-type claudication. AB - OBJECTIVES: Mechanisms of walking limitation in arterial claudication are incompletely elucidated. We aimed to identify new variables associated to walking limitation in patients with claudication. METHODS: We retrospectively analyzed data of 1120 patients referred for transcutaneous exercise oxygen pressure recordings (TcpO2). The outcome measurement was the absolute walking time on treadmill (3.2 km/h, 10% slope). We used both: linear regression analysis and a non-linear analysis, combining support vector machines and genetic explanatory in 800 patients with the following resting variables: age, gender, body mass index, the presence of diabetes, minimal ankle to brachial index at rest, usual walking speed over 10 m (usual-pace), number of comorbid conditions, active smoking, resting heart rate, pre-test glycaemia and hemoglobin, beta-blocker use, and exercise-derived variables: minimal value of pulse oximetry, resting chest-TcpO2, decrease in chest TcpO2 during exercise, presence of buttock ischemia defined as a decrease from rest of oxygen pressure index <=15 mmHg. We tested the models over 320 other patients. RESULTS: Independent variables associated to walking time, by decreasing importance in the models, were: age, ankle to brachial index, usual-pace; resting TcpO2, body mass index, smoking, buttock ischemia, heart rate and beta-blockers for the linear regression analysis, and were ankle to brachial index, age, body mass index, usual-pace, decrease in chest TcpO2, smoking, buttock ischemia, glycaemia, heart rate for the non-linear analysis. Testing of models over 320 new patients gave r = 0.509 for linear and 0.575 for non-linear analysis (both p < 0.05). CONCLUSION: Buttock ischemia, heart rate and usual-pace are new variables associated to walking time. PMID- 30442078 TI - Comparative assessment of shift in hearing threshold among handicraft operatives in India. AB - This case-control exploratory study is first of its kind to assess the noise exposure and loss in hearing threshold (HT) due to the occupational use of hand tools used for handicraft work. Sixty male participants involved in different crafts trade and a reference group of 50 office workers were selected. The sound pressure levels under actual work conditions were measured as per the method outlined in IS 7194:1994. The mean equivalent sound pressure level was quite high (96.37 dB(A)), exceeding the exposure limit of 90 dB(A). Audiometric tests were conducted to compare the HT between both the groups. In agreement with dose consumed, the exposed workers exhibit moderate hearing impairment in the frequency range of 1500-6000 Hz. The association of HT at different frequencies among occupation were detected using post-hoc multiple comparisons. 95% of the workers showed hearing handicap at some level and noise-induced hearing loss increases with higher age and experience. Interventions in the hand tools, implementation of hearing conservation programmes and practice of personal protective equipments have been suggested. Practitioner Summary: As the primary outcomes, comparative assessment of the shift in hearing threshold was analyzed in anticipation to develop a better work system. Results from the study report that the sound pressure level was fairly high and 95% of the handicraft operatives showed hearing handicap at some level. PMID- 30442079 TI - Palliative care for case managers: building capacity to extend community-based palliative care to underserved older adults. AB - Palliative care has demonstrated effectiveness in alleviating the biological, emotional, social, and spiritual symptoms that accompany serious illness, and improving quality of life for seriously ill individuals and their family members. Despite increasing availability, there are significant disparities in access to and utilization of palliative care, particularly among diverse, low-income, and community-dwelling older adults with chronic illness. Training frontline service providers is a novel approach to expanding access to palliative care among underserved elders. This article presents a process and outcome evaluation of a palliative care curriculum that was developed and piloted for geriatric case managers in a large urban area. We describe the background, planning, design, implementation, and preliminary outcomes associated with a pilot implementation of the curriculum. We conclude with implications for replicating efforts to enhance frontline providers' knowledge, skills, and self-efficacy in extending palliative care to communities that lack access to critical supports for their burdensome symptoms. PMID- 30442080 TI - The effect of angiotensin-converting enzyme inhibitors on clinical outcomes in patients with ischemic cardiomyopathy and midrange ejection fraction: a post hoc subgroup analysis from the PEACE trial. AB - BACKGROUND:: There have been significant advances in the treatment of patients with cardiomyopathy with reduced ejection fraction (EF < 40%). However, there is a dearth of information in the treatment of patients with cardiomyopathy and midrange EF (40-50%). Current guidelines state to treat these patients similarly to patients with cardiomyopathy and preserved EF. Data from the Prevention of Events with Angiotensin-Converting Enzyme Inhibition (PEACE) trial were used to elucidate whether angiotensin-converting enzyme (ACE) inhibitors improve clinical outcomes in patients with ischemic cardiomyopathy and midrange EF. METHODS:: A post hoc subgroup analysis of the PEACE trial was conducted to evaluate the effect of ACE inhibitors in a subgroup of patients with ischemic cardiomyopathy and midrange EF (40-50%). A Chi-square test and a Student's t-test were used to examine and compare the binary and continuous variables of baseline characteristics and outcomes between experimental and comparison groups. RESULTS:: We studied a subgroup of patients from the PEACE trial with ischemic cardiomyopathy and midrange EF ( n = 2512 of 8290 total patients). Patients were assigned to either the interventional group ( n = 1247) or the placebo group ( n = 1265). There were no significant differences in baseline demographic and health characteristics between the two groups. During a total of 7 years (mean 4.7 years) of follow up, the risk of composite outcomes [all-cause mortality, nonfatal myocardial infarction, and stroke; relative risk (RR) 0.79, 95% confidence interval (CI) 0.63-0.98; p = 0.03] and all-cause mortality (RR 0.85, 95% CI 0.73-0.99; p = 0.03) was reduced in patients treated with trandolapril. CONCLUSION:: This study revealed the benefit of ACE inhibitors among patients with ischemic cardiomyopathy and midrange EF. PMID- 30442081 TI - Examining the asymmetry in judgments of racism in self and others. AB - Across three experiments, participants were provided with a list of racist behaviors that purportedly were enacted from a fellow student but in fact were based on the participants' own behaviors. People consistently evaluated themselves as less racist than this comparison other, even though this other's racist behaviors were identical to their own. Studies 2a and 2b demonstrate this effect is quite robust and even occurs under social pressure and social consensus conditions in which participants were free to express their racial biases. Thus, it appears that people are less likely to base their racist trait ratings on behavioral evidence when evaluating themselves compared to when they are evaluating another. Taken together, this work provides evidence for the consistency and robustness of self-enhanced social comparisons as applied to the trait domain of racism. Further, this work sheds insight into why people deny they are racist when they act racist. PMID- 30442082 TI - Use of polygenic risk scores of nicotine metabolism in predicting smoking behaviors. AB - AIM: This study tests whether polygenic risk scores (PRSs) for nicotine metabolism predict smoking behaviors in independent data. MATERIALS & METHODS: Linear regression, logistic regression and survival analyses were used to analyze nicotine metabolism PRSs and nicotine metabolism, smoking quantity and smoking cessation. RESULTS: Nicotine metabolism PRSs based on two genome wide association studies (GWAS) meta-analyses significantly predicted nicotine metabolism biomarkers (R2 range: 9.2-16%; minimum p = 7.6 * 10-8). The GWAS top hit variant rs56113850 significantly predicted nicotine metabolism biomarkers (R2 range: 14 17%; minimum p = 4.4 * 10-8). There was insufficient evidence for these PRSs predicting smoking quantity and smoking cessation. CONCLUSION: Results suggest that nicotine metabolism PRSs based on GWAS meta-analyses predict an individual's nicotine metabolism, so does use of the top hit variant. We anticipate that PRSs will enter clinical medicine, but additional research is needed to develop a more comprehensive genetic score to predict smoking behaviors. PMID- 30442083 TI - Thermotherapy: Improving the vascular access cannulation procedure. AB - INTRODUCTION AND OBJECTIVES:: Vascular access is essential to perform an adequate hemodialysis. Needle cannulation in vascular access is usually painful. There is little scientific evidence on the analgesic effect of thermotherapy. The aim of this study was to evaluate the analgesic effect of thermotherapy on vascular access cannulation. METHODS:: We performed a 2-week single center prospective study. Demographic data and vascular access location were collected. The main outcome was pain perceived in vascular access cannulation measured by the visual analog scale. We performed two phases of study: phase I was performed with usual cannulation procedure, and in phase II, we applied local thermotherapy for 15 min (hot packs: 60 s, 600 W). Also, main hemodynamic data, local, and vascular access related complications were recorded. RESULTS:: A total of 34 patients were enrolled, with a mean age of 67.3 +/- 16.4 years and 49.1 +/- 66.3 months on hemodialysis. Main cardiovascular risk factors are hypertension (81.8%) and diabetes mellitus (39.4%). Most common vascular access is left radiocephalic fistula (45.5%). Mean weekly/patient cannulation is 6.03 +/- 0.2. Mean visual analog scale is 3.8 +/- 2.4. At the end of the study, thermotherapy on the vascular access revealed a significant decrease in visual analog scale (3.9 +/- 2.4 vs 2.6 +/- 2.0, p = 0.002), without hemodynamic changes pre- and post intervention, nor changes in analgesic or antihypertensive treatment. One patient had a mild surface erythema. No further complications related to vascular access were observed. CONCLUSION:: (1) Thermotherapy on the vascular access reduced the pain caused by needle cannulation in our patients, without complications related to vascular access. (2) We will consider its clinical application in those painful vascular access cannulations at our hemodialysis unit. (3) Further studies are required to assess other potential beneficial effects added to thermotherapy in vascular access cannulation procedure. PMID- 30442084 TI - The effect of stellate ganglion block on the function of arteriovenous fistulas for hemodialysis: A randomized trial. AB - BACKGROUND AND PURPOSE:: The best access for hemodialysis is an autologous arteriovenous fistula (AVF). The most helpful way for vasodilation in the upper limb is stellate ganglion block. We aim to evaluate the effect of stellate ganglion block on outcome of vascular access for dialysis. MATERIALS AND METHODS:: Some 105 hemodialysis patients were randomly allocated to three groups: In group 1, stellate ganglion block was performed before fistula surgery. Group 2 had stellate ganglion block after surgery and group 3 was control group without any block. Primary outcome for all groups was functional dialysis, which is defined as successful hemodialysis for 1 month. RESULTS:: The three groups were similar in age, gender, and underlying diseases. Stellate ganglion block before operation had a meaningful increase in successful hemodialysis rate, when compared with the other groups (p = 0.02). CONCLUSION:: Stellate ganglion block before arteriovenous fistula surgery in the upper limbs improves hemodialysis success rate. PMID- 30442085 TI - Reporting Harassment and Stalking to the Police: A Qualitative Study of Victims' Experiences. AB - To date, there have been few studies with victims of stalking in the United Kingdom, and this is the first to have been conducted following the clarification of stalking as a criminal offense in 2012. In 2016, Her Majesty's Inspectorate of Constabulary Fire and Rescue Services (HMICFRS) and Her Majesty's Crown Prosecution Inspectorate (HMCPSI) announced the first ever inspection into harassment and stalking in England and Wales. This article presents research commissioned by HMICFRS as part of the inspection. In particular, we explore how victims described the response of the police and situate this within the context of changing legislation and previous research in the field. In total, 35 people shared their experiences of reporting harassment and stalking, 14 people completed an online survey, and 21 participants were interviewed. Responses were analyzed thematically and a series of themes were identified. The analysis suggests that despite the clarification of stalking as a criminal office in 2012, the majority of participants described poor responses from the police-with many describing police inaction, or inappropriate action-in addition to feeling blamed and not being taken seriously. The article considers possible explanations for these issues and concludes by calling for harassment and stalking legislation in England and Wales to be clarified, and for police training to shift the focus of the investigation from the behavior of the offender, to the emotional impact on the victim. PMID- 30442087 TI - Association of migraines with brain tumors: a nationwide population-based study. AB - BACKGROUND: Several studies examined headaches as a symptom of brain neoplasms. Nevertheless, very few studies attempted to specifically evaluate the role of headaches as a risk factor. This study aimed to investigate the risk of migraine occurrence in the preceding years among patients diagnosed with brain tumors and unaffected controls. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database. In total, 11,325 adults with a first-time brain tumor diagnosis were included as cases, together with 11,325 unaffected matched controls. Each individual was traced in the healthcare claims dataset for a prior diagnosis of migraines. Conditional logistic regressions were performed to calculate the odds ratio (OR) and the corresponding 95% confidence interval (CI) to present the association between brain tumors and having previously been diagnosed with migraines. RESULTS: We found that among patients with and those without brain tumors, 554 (4.89%) and 235 (2.08%) individuals, respectively, were identified as having a prior migraine diagnosis. Compared to unaffected controls, patients with brain tumors experienced an independent 2.45-fold increased risk of having a prior migraine diagnosis. The risks were even higher among men (odds ratio (OR) = 3.04, 95% confidence interval (CI) = 2.29~ 4.04) and after patients who had received a prior migraine diagnosis within 3 years were excluded (OR = 1.91, 95% CI = 1.59~ 2.29). CONCLUSIONS: This is the first report demonstrating the occurrence of brain tumors to be associated with a prior migraine history, for both men and women, in a population-based study. PMID- 30442086 TI - Learning protein binding affinity using privileged information. AB - BACKGROUND: Determining protein-protein interactions and their binding affinity are important in understanding cellular biological processes, discovery and design of novel therapeutics, protein engineering, and mutagenesis studies. Due to the time and effort required in wet lab experiments, computational prediction of binding affinity from sequence or structure is an important area of research. Structure-based methods, though more accurate than sequence-based techniques, are limited in their applicability due to limited availability of protein structure data. RESULTS: In this study, we propose a novel machine learning method for predicting binding affinity that uses protein 3D structure as privileged information at training time while expecting only protein sequence information during testing. Using the method, which is based on the framework of learning using privileged information (LUPI), we have achieved improved performance over corresponding sequence-based binding affinity prediction methods that do not have access to privileged information during training. Our experiments show that with the proposed framework which uses structure only during training, it is possible to achieve classification performance comparable to that which is obtained using structure-based features. Evaluation on an independent test set shows improved performance over the PPA-Pred2 method as well. CONCLUSIONS: The proposed method outperforms several baseline learners and a state-of-the-art binding affinity predictor not only in cross-validation, but also on an additional validation dataset, demonstrating the utility of the LUPI framework for problems that would benefit from classification using structure-based features. The implementation of LUPI developed for this work is expected to be useful in other areas of bioinformatics as well. PMID- 30442089 TI - The publication trend of neuropathic pain in the world and China: a 20-years bibliometric analysis. AB - BACKGROUND: There has been tremendous change on neuropathic pain research in the past 20 years in China and around the world. We analyzed the global trend of neuropathic pain research and compared China's quantity and quality of neuropathic pain-related publications with other developed countries. METHODS: Using terms "neuropathic pain", we retrieved related publications from the Web of Science (WOS) database and PubMed database. From different aspects, such as the number of papers, total citations, average citations per item, H-index, research types, orientation, institutions, journals and funding, global neuropathic pain publications were classified and analyzed. RESULTS: From 1998 to 2017, 21,733 articles regarding neuropathic pain research were published worldwide. Of these, 9.394% were contributed by authors from Chinese institutions, which followed USA and ranked second. However, the quality indicators of publications, including total citations, average citations per item and H-index, were relatively low in China. High contribution journals and the 10 most-cited articles on neuropathic pain in world and China were also listed, which also can reflect the quality of neuropathic pain. Based on National Natural Science Foundation of China (NSFC), basic research was the main articles type, accounting for 32.91% of China's neuropathic pain research. CONCLUSION: Global neuropathic pain research increased rapidly during the 1998 to 2017 period. The USA was still the leader of neuropathic research. Although China had made great achievements, there was a significant gap in the high-quality studies between China and other leading countries. PMID- 30442088 TI - An emotion recognition subtyping approach to studying the heterogeneity and comorbidity of autism spectrum disorders and attention-deficit/hyperactivity disorder. AB - BACKGROUND: Emotion recognition dysfunction has been reported in both autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). This suggests that emotion recognition is a cross-disorder trait that may be utilised to understand the heterogeneous psychopathology of ASD and ADHD. We aimed to identify emotion recognition subtypes and to examine their relation with quantitative and diagnostic measures of ASD and ADHD to gain further insight into disorder comorbidity and heterogeneity. METHODS: Factor mixture modelling was used on speed and accuracy measures of auditory and visual emotion recognition tasks. These were administered to children and adolescents with ASD (N = 89), comorbid ASD + ADHD (N = 64), their unaffected siblings (N = 122), ADHD (N = 111), their unaffected siblings (N = 69), and controls (N = 220). Identified classes were compared on diagnostic and quantitative symptom measures. RESULTS: A four-class solution was revealed, with the following emotion recognition abilities: (1) average visual, impulsive auditory; (2) average-strong visual and auditory; (3) impulsive/imprecise visual, average auditory; (4) weak visual and auditory. The weakest performing class (4) contained the highest percentage of patients (66.07%) and the lowest percentage controls (10.09%), scoring the highest on ASD/ADHD measures. The best performing class (2) demonstrated the opposite: 48.98% patients, 15.26% controls with relatively low scores on ASD/ADHD measures. CONCLUSIONS: Subgroups of youths can be identified that differ both in quantitative and qualitative aspects of emotion recognition abilities. Weak emotion recognition abilities across sensory domains are linked to an increased risk for ASD as well as ADHD, although emotion recognition impairments alone are neither necessary nor sufficient parts of these disorders. PMID- 30442090 TI - Cognitive dysfunction and migraine. AB - Cognitive dysfunction has recently gained attention as a significant problem among migraine sufferers. All of the clinical studies show poor cognitive performance during migraine attacks, though, the interictal data are conflicting. Migraineurs show impaired cognitive function interictally in most of the clinic based studies. Population-based studies did not reveal a difference in cognitive functions between migraineurs and controls. The specific cognitive domains involved are information processing speed, basic attention, executive functions, verbal and non-verbal memory and verbal skills. Neurophysiological, imaging and pharmacological studies support clinical symptoms of cognitive impairment in migraine. Longitudinal studies do not suggest progressive cognitive decline over time in migraine patients. Preventive medications and comorbid disorders such as depression and anxiety can impact cognitive function, but cannot fully explain the cognitive impairment in migraine. In contrast to migraine, tension type or cluster headache are not associated with cognitive impairment, at least during headache-free periods. PMID- 30442092 TI - A preliminary integrated genetic map distinguishes every chromosome pair and locates essential genes related to abiotic adaptation of Crassostrea angulata/gigas. AB - BACKGROUND: The re-sequencing of C. angulata has revealed many polymorphisms in candidate genes related to adaptation to abiotic stress that are not present in C. gigas; these genes, therefore, are probably related to the ability of this oyster to retain high concentrations of toxic heavy metals. There is, in addition, an unresolved controversy as to whether or not C. angulata and C. gigas are the same species or subspecies. Both oysters have 20 metacentric chromosomes of similar size that are morphologically indistinguishable. From a genomic perspective, as a result of the great variation and selection for heterozygotes in C. gigas, the assembly of its draft genome was difficult: it is fragmented in more than seven thousand scaffolds. RESULTS: In this work sixty BAC sequences of C. gigas downloaded from NCBI were assembled in BAC-contigs and assigned to BACs that were used as probes for mFISH in C. angulata and C. gigas. In addition, probes of H3, H4 histone, 18S and 5S rDNA genes were also used. Hence we obtained markers identifying 8 out the 10 chromosomes constituting the karyotype. Chromosomes 1 and 9 can be distinguished morphologically. The bioinformatic analysis carried out with the BAC-contigs annotated 88 genes. As a result, genes associated with abiotic adaptation, such as metallothioneins, have been positioned in the genome. The gene ontology analysis has also shown many molecular functions related to metal ion binding, a phenomenon associated with detoxification processes that are characteristic in oysters. Hence the provisional integrated map obtained in this study is a useful complementary tool for the study of oyster genomes. CONCLUSIONS: In this study 8 out of 10 chromosome pairs of Crassostrea angulata/gigas were identified using BAC clones as probes. As a result all chromosomes can now be distinguished. Moreover, FISH showed that H3 and H4 co-localized in two pairs of chromosomes different that those previously escribed. 88 genes were annotated in the BAC-contigs most of them related with Molecular Functions of protein binding, related to the resistance of the species to abiotic stress. An integrated genetic map anchored to the genome has been obtained in which the BAC-contigs structure were not concordant with the gene structure of the C. gigas scaffolds displayed in the Genomicus database. PMID- 30442093 TI - Improving the normalization of complex interventions: part 1 - development of the NoMAD instrument for assessing implementation work based on normalization process theory (NPT). AB - BACKGROUND: Understanding and measuring implementation processes is a key challenge for implementation researchers. This study draws on Normalization Process Theory (NPT) to develop an instrument that can be applied to assess, monitor or measure factors likely to affect normalization from the perspective of implementation participants. METHODS: An iterative process of instrument development was undertaken using the following methods: theoretical elaboration, item generation and item reduction (team workshops); item appraisal (QAS-99); cognitive testing with complex intervention teams; theory re-validation with NPT experts; and pilot testing of instrument. RESULTS: We initially generated 112 potential questionnaire items; these were then reduced to 47 through team workshops and item appraisal. No concerns about item wording and construction were raised through the item appraisal process. We undertook three rounds of cognitive interviews with professionals (n = 30) involved in the development, evaluation, delivery or reception of complex interventions. We identified minor issues around wording of some items; universal issues around how to engage with people at different time points in an intervention; and conceptual issues around the types of people for whom the instrument should be designed. We managed these by adding extra items (n = 6) and including a new set of option responses: 'not relevant at this stage', 'not relevant to my role' and 'not relevant to this intervention' and decided to design an instrument explicitly for those people either delivering or receiving an intervention. This version of the instrument had 53 items. Twenty-three people with a good working knowledge of NPT reviewed the items for theoretical drift. Items that displayed a poor alignment with NPT sub-constructs were removed (n = 8) and others revised or combined (n = 6). The final instrument, with 43 items, was successfully piloted with five people, with a 100% completion rate of items. CONCLUSION: The process of moving through cycles of theoretical translation, item generation, cognitive testing, and theoretical (re)validation was essential for maintaining a balance between the theoretical integrity of the NPT concepts and the ease with which intended respondents could answer the questions. The final instrument could be easily understood and completed, while retaining theoretical validity. NoMAD represents a measure that can be used to understand implementation participants' experiences. It is intended as a measure that can be used alongside instruments that measure other dimensions of implementation activity, such as implementation fidelity, adoption, and readiness. PMID- 30442094 TI - Improving the normalization of complex interventions: part 2 - validation of the NoMAD instrument for assessing implementation work based on normalization process theory (NPT). AB - INTRODUCTION: Successful implementation and embedding of new health care practices relies on co-ordinated, collective behaviour of individuals working within the constraints of health care settings. Normalization Process Theory (NPT) provides a theory of implementation that emphasises collective action in explaining, and shaping, the embedding of new practices. To extend the practical utility of NPT for improving implementation success, an instrument (NoMAD) was developed and validated. METHODS: Descriptive analysis and psychometric testing of an instrument developed by the authors, through an iterative process that included item generation, consensus methods, item appraisal, and cognitive testing. A 46 item questionnaire was tested in 6 sites implementing health related interventions, using paper and online completion. Participants were staff directly involved in working with the interventions. Descriptive analysis and consensus methods were used to remove redundancy, reducing the final tool to 23 items. Data were subject to confirmatory factor analysis which sought to confirm the theoretical structure within the sample. RESULTS: We obtained 831 completed questionnaires, an average response rate of 39% (range: 22-77%). Full completion of items was 50% (n = 413). The confirmatory factor analysis showed the model achieved acceptable fit (CFI = 0.95, TLI = 0.93, RMSEA = 0.08, SRMR = 0.03). Construct validity of the four theoretical constructs of NPT was supported, and internal consistency (Cronbach's alpha) were as follows: Coherence (4 items, alpha = 0.71); Collective Action (7 items, alpha = 0.78); Cognitive Participation (4 items, alpha = 0.81); Reflexive Monitoring (5 items, alpha = 0.65). The normalisation scale overall, was highly reliable (20 items, alpha = 0.89). CONCLUSIONS: The NoMAD instrument has good face validity, construct validity and internal consistency, for assessing staff perceptions of factors relevant to embedding interventions that change their work practices. Uses in evaluating and guiding implementation are proposed. PMID- 30442091 TI - Phylotranscriptomics suggests the jawed vertebrate ancestor could generate diverse helper and regulatory T cell subsets. AB - BACKGROUND: The cartilaginous fishes diverged from other jawed vertebrates ~ 450 million years ago (mya). Despite this key evolutionary position, the only high quality cartilaginous fish genome available is for the elephant shark (Callorhinchus milii), a chimaera whose ancestors split from the elasmobranch lineage ~ 420 mya. Initial analysis of this resource led to proposals that key components of the cartilaginous fish adaptive immune system, most notably their array of T cell subsets, was primitive compared to mammals. This proposal is at odds with the robust, antigen-specific antibody responses reported in elasmobranchs following immunization. To explore this discrepancy, we generated a multi-tissue transcriptome for small-spotted catshark (Scyliorhinus canicula), a tractable elasmobranch model for functional studies. We searched this, and other newly available sequence datasets, for CD4+ T cell subset-defining genes, aiming to confirm the presence or absence of each subset in cartilaginous fishes. RESULTS: We generated a new transcriptome based on a normalised, multi-tissue RNA pool, aiming to maximise representation of tissue-specific and lowly expressed genes. We utilized multiple transcriptomic datasets and assembly variants in phylogenetic reconstructions to unambiguously identify several T cell subset specific molecules in cartilaginous fishes for the first time, including interleukins, interleukin receptors, and key transcription factors. Our results reveal the inability of standard phylogenetic reconstruction approaches to capture the site-specific evolutionary processes of fast-evolving immune genes but show that site-heterogeneous mixture models can adequately do so. CONCLUSIONS: Our analyses reveal that cartilaginous fishes are capable of producing a range of CD4+ T cell subsets comparable to that of mammals. Further, that the key molecules required for the differentiation and functioning of these subsets existed in the jawed vertebrate ancestor. Additionally, we highlight the importance of considering phylogenetic diversity and, where possible, utilizing multiple datasets for individual species, to accurately infer gene presence or absence at higher taxonomic levels. PMID- 30442096 TI - Creative adapting in a fluid environment: an explanatory model of paramedic decision making in the pre-hospital setting. AB - BACKGROUND: Paramedics work in a highly complex and unpredictable environment which is characterized by ongoing decision-making. Decisions made by paramedics in the prehospital setting have implications for patient safety, transport, treatment, and health resource utilization. The objective of this study was; a) to understand how paramedics conduct decision-making in the field, and b) to develop a grounded theory of paramedic decision-making in the prehospital setting. METHOD: This study was conducted using classical grounded theory. Paramedics (n = 13) with five or more years' experience, who worked in a large urban center in Western Canada were interviewed. Field observations were conducted, each lasting 12 h, with five different ambulance crews. The data were analyzed and coded using the constant comparative method. RESULTS: The resultant theory, Creative Adapting in a Fluid Environment, indicates paramedic decision making is a fluid iterative process. Unpredictable and dynamic features of the prehospital environment require paramedics to use a flexible and creative approach to decision-making. The model consists of the three categories constructing a malleable model, revising the model, and situation-specific action. Two additional components, safety and extrication, are considered at each stage of the call. These two components in conjunction with the three categories influence how decisions are made and enacted. CONCLUSION: Paramedic decision making is highly contextual and requires accurate interpretation and flexible cognitive constructs that are rapidly adaptable. Evaluation of paramedic decision making needs to account for the complex and dynamic interaction between the environment, patient characteristics, available resources, and provider experience and knowledge. PMID- 30442095 TI - Less renal allograft fibrosis with valganciclovir prophylaxis for cytomegalovirus compared to high-dose valacyclovir: a parallel group, open-label, randomized controlled trial. AB - BACKGROUND: Cytomegalovirus (CMV) prophylaxis may prevent CMV indirect effects in renal transplant recipients. This study aimed to compare the efficacy of valganciclovir and valacyclovir prophylaxis for CMV after renal transplantation with the focus on chronic histologic damage within the graft. METHODS: From November 2007 through April 2012, adult renal transplant recipients were randomized, in an open-label, single-center study, at a 1:1 ratio to 3-month prophylaxis with valganciclovir (n = 60) or valacyclovir (n = 59). The primary endpoint was moderate-to-severe interstitial fibrosis and tubular atrophy assessed by protocol biopsy at 3 years evaluated by a single pathologist blinded to the study group. The analysis was conducted in an intention-to-treat population. RESULTS: Among the 101 patients who had a protocol biopsy specimen available, the risk of moderate-to-severe interstitial fibrosis and tubular atrophy was significantly lower in those treated with valganciclovir (22% versus 34%; adjusted odds ratio, 0.31; 95% confidence interval, 0.11-0.90; P = 0.032 by multivariate logistic regression). The incidence of CMV disease (9% versus 2%; P = 0.115) and CMV DNAemia (36% versus 42%; P = 0.361) were not different at 3 years. CONCLUSIONS: Valganciclovir prophylaxis, as compared with valacyclovir, was associated with a reduced risk of moderate-to-severe interstitial fibrosis and tubular atrophy in patients after renal transplantation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12610000016033 ). Registered on September 26, 2007. PMID- 30442097 TI - Intravascular NK/T-cell lymphoma, Epstein-Barr virus positive with multiorgan involvement: a clinical dilemma. AB - BACKGROUND: Intravascular lymphoma is a rare type of non-Hodgkin lymphoma mostly of B-cell lineage. A few cases of intravascular lymphoma have been found to be of NK/T-cell origin, mainly affecting the skin and central nervous system. CASE PRESENTATION: A 54-year-old Caucasian man sought care because of a 2 weeks history of jaundice and intermittent fever, not responsive to antibiotics and antipyretics. Laboratory tests showed low blood oxygen concentration and pancytopenia. Serum microbiological tests were negative. Computerized tomography (CT) scan revealed hepatosplenomegaly and diffuse ground-glass opacities in both lungs without interlobular septal thickening. Despite oxygen therapy, the clinical conditions rapidly deteriorated leading to death 3 days after admission. Autopsy revealed a multiorgan involvement by an Epstein-Barr virus positive NK/T cell lymphoma, strikingly growing within the blood vessel lumina, in absence of skin lesions. CONCLUSIONS: The current case highlights the pathological features of this rare entity, the protean clinical presentation of which is often misleading, resulting in delayed diagnosis and treatment. PMID- 30442099 TI - Development of standard clinical endpoints for use in dengue interventional trials: introduction and methodology. AB - BACKGROUND: As increasing numbers of dengue vaccines and therapeutics are in clinical development, standardized consensus clinical endpoint definitions are urgently needed to assess the efficacy of different interventions with respect to disease severity. We aimed to convene dengue experts representing various sectors and dengue endemic areas to review the literature and propose clinical endpoint definitions for moderate and severe disease based on the framework provided by the WHO 2009 classification. METHODS: The endpoints were first proposed and discussed in a structured expert consultation. After that, the Delphi method was carried out to assess the usefulness, validity and feasibility of the standardized clinical disease endpoints for interventional dengue research. RESULTS: Most respondents (> 80%) agreed there is a need for both standardized clinical endpoints and operationalization of severe endpoints. Most respondents (67%) felt there is utility for moderate severity endpoints, but cited challenges in their development. Hospitalization as a moderate endpoint of disease severity or measure of public health impact was deemed to be useful by only 47% of respondents, but 89% felt it could bring about supplemental information if carefully contextualized according to data collection setting. Over half of the respondents favored alignment of the standard endpoints with the WHO guidelines (58%), but cautioned that the endpoints could have ramifications for public health practice. In terms of data granularity of the endpoints, there was a slight preference for a categorical vs numeric system (e.g. 1-10) (47% vs 34%), and 74% of respondents suggested validating the endpoints using large prospective data sets. CONCLUSION: The structured consensus-building process was successful taking into account the history of the debate around potential endpoints for severe dengue. There is clear support for the development of standardized endpoints for interventional clinical research and the need for subsequent validation with prospective data sets. Challenges include the complexity of developing moderate disease research endpoints for dengue. PMID- 30442100 TI - Gadoxetic acid-enhanced magnetic resonance imaging significantly influences the clinical course in patients with colorectal liver metastases. AB - BACKGROUND: Gadoxetic acid (PrimovistTM)-enhanced magnetic resonance imaging (P MRI) scans have higher accuracy and increased detection of small colorectal liver metastases (CRLM) compared to CT scans or conventional MRI scans. But, P-MRI scans are still inconsistently acquired in the diagnostic work up of patients with CRLM. The aim of this study was to determine the influence of P-MRI scans on treatment plan proposition and subsequently the clinical course of the patient. METHODS: Eighty-three consecutive patients with potentially resectable CRLM based on a conventional CT scan underwent P-MRI scanning prior to treatment. Treatment plans proposed by the multidisciplinary team were compared before and after P-MRI scanning and related to the final treatment and diagnosis, the accuracy for the CT scan and P-MRI scan was calculated. RESULTS: P-MRI scans led to a change of treatment in 15 patients (18%) and alteration of extensiveness of local therapy in another 17 patients (20%). All changes were justified leading to an accuracy of 93% for treatment proposition based on P-MRI scan, compared to an accuracy of 75% for the CT scan. CONCLUSIONS: P-MRI scans provide additional information that can aid in proposing the most suitable treatment for patients with CRLM and might prevent short-term reintervention. PMID- 30442098 TI - Mollusc genomes reveal variability in patterns of LTR-retrotransposons dynamics. AB - BACKGROUND: The three superfamilies of Long Terminal Repeat (LTR) retrotransposons are a widespread kind of transposable element and a major factor in eukaryotic genome evolution. In metazoans, recent studies suggested that Copia LTR-retrotransposons display specific dynamic compared to the more abundant and diverse Gypsy elements. Indeed, Copia elements show a relative scarcity and the prevalence of only a few clades in specific hosts. Thus, BEL/Pao seems to be the second most abundant superfamily. However, the generality of these assumptions remains to be assessed. Therefore, we carried out the first large-scale comparative genomic analysis of LTR-retrotransposons in molluscs. The aim of this study was to analyse the diversity, copy numbers, genomic proportions and distribution of LTR-retrotransposons in a large host phylum. RESULTS: We compare nine genomes of molluscs and further added LTR-retrotransposons sequences detected in databases for 47 additional species. We identified 1709 families, which enabled us to define 31 clades. We show that clade richness was highly dependent on the considered superfamily. We found only three Copia clades, including GalEa and Hydra which appear to be widely distributed and highly dominant as they account for 96% of the characterised Copia elements. Among the seven BEL/Pao clades identified, Sparrow and Surcouf are characterised for the first time. We find no BEL or Pao elements, but the rare clades Dan and Flow are present in molluscs. Finally, we characterised 21 Gypsy clades, only five of which had been previously described, the C-clade being the most abundant one. Even if they are found in the same number of host species, Copia elements are clearly less abundant than BEL/Pao elements in copy number or genomic proportions, while Gypsy elements are always the most abundant ones whatever the parameter considered. CONCLUSIONS: Our analysis confirms the contrasting dynamics of Copia and Gypsy elements in metazoans and indicates that BEL/Pao represents the second most abundant superfamily, probably reflecting an intermediate dynamic. Altogether, the data obtained in several taxa highly suggest that these patterns can be generalised for most metazoans. Finally, we highlight the importance of using database information in complement of genome analyses when analyzing transposable element diversity. PMID- 30442101 TI - Distribution of virulence genes and their association with antimicrobial resistance among uropathogenic Escherichia coli isolates from Iranian patients. AB - BACKGROUND: Urinary tract infections (UTIs) are one of the most frequent diseases encountered by humans worldwide. The presence of multidrug-resistant (MDR) uropathogenic Escherichia coli (UPEC) harboring several virulence factors, is a major risk factor for inpatients. We sought to investigate the rate of antibiotic resistance and virulence-associated genes among the UPECs isolated from an Iranian symptomatic population. METHODS: A total of 126 isolates from inpatients with UTI from different wards were identified as UPEC using the conventional microbiological tests. After identification of UPECs, all the isolates were subjected to antimicrobial susceptibility test and polymerase chain reaction (PCR) to identify the presence of 9 putative virulence genes and their association with the clinical outcomes or antimicrobial resistance. RESULTS: The data showed that the highest and the lowest resistance rates were observed against ampicillin (88.9%), and imipenem (0.8%), respectively. However, the frequency of resistance to ciprofloxacin was found to be 55.6%. High prevalence of MDR (77.8%) and extended-spectrum beta-lactamase (ESBL) (54.8%) were substantial. PCR results revealed the frequency of virulence genes ranged from 0 to 99.2%. Among 9 evaluated genes, the frequency of 4 genes (fimH, sfa, iutA, and PAI marker) was > 50% among all the screened isolates. The iutA, pap GII, and hlyA genes were more detected in the urosepsis isolates with significantly different frequencies. The different combinations of virulence genes were characterized as urovirulence patterns. The isolates recovered from pyelonephritis, cystitis, and urosepsis cases revealed 27, 22, and 6 virulence patterns, respectively. A significant difference was determined between ESBL production with pap GII, iutA, and PAI marker genes. CONCLUSIONS: Our study highlighted the MDR UPEC with high heterogeneity of urovirulence genes. Considering the high rate of ciprofloxacin resistance, alternative drugs and monitoring of the susceptibility profile for UPECs are recommended. PMID- 30442102 TI - Methodological development of tools to measure how women are treated during facility-based childbirth in four countries: labor observation and community survey. AB - BACKGROUND: Efforts to improve maternal health are increasingly focused on improving the quality of care provided to women at health facilities, including the promotion of respectful care and eliminating mistreatment of women during childbirth. A WHO-led multi-country research project aims to develop and validate two tools (labor observation and community survey) to measure how women are treated during facility-based childbirth. This paper describes the development process for these measurement tools, and how they were implemented in a multi country study (Ghana, Guinea, Myanmar and Nigeria). METHODS: An iterative mixed methods approach was used to develop two measurement tools. Methodological development was conducted in four steps: (1) initial tool development; (2) validity testing, item adjustment and piloting of paper-based tools; (3) conversion to digital, tablet-based tools; and (4) data collection and analysis. These steps included systematic reviews, primary qualitative research, mapping of existing tools, item consolidation, peer review by key stakeholders and piloting. RESULTS: The development, structure, administration format, and implementation of the labor observation and community survey tools are described. For the labor observations, a total of 2016 women participated: 408 in Nigeria, 682 in Guinea, and 926 in Ghana. For the community survey, a total of 2672 women participated: 561 in Nigeria, 644 in Guinea, 836 in Ghana, and 631 in Myanmar. Of the 2016 women who participated in the labor observations, 1536 women (76.2%) also participated in the community survey and have linked data: 779 in Ghana, 425 in Guinea, and 332 in Nigeria. CONCLUSIONS: An important step to improve the quality of maternity care is to understand the magnitude and burden of mistreatment across contexts. Researchers and healthcare providers in maternal health are encouraged to use and implement these tools, to inform the development of more women-centered, respectful maternity healthcare services. By measuring the prevalence of mistreatment of women during childbirth, we will be able to design and implement programs and policies to transform maternity services. PMID- 30442104 TI - Validation of 3D echocardiographic volume detection of left atrium by human cadaveric casts. AB - BACKGROUND: Left atrial volume is a prognostic factor in cardiac pathologies. We aimed to validate left atrial volume detection with 3D and 2D echocardiography (3DE and 2DE) by human cadaveric casts. 3DE facilitates measurement of atrial volume without geometrical assumptions or dependence on imaging angle in contrast to 2DE methods. METHODS: For method validation, six water-filled balloons were submerged in a 20-l water tank and their volumes were measured with 3DE. Seven human cadaveric left atrial casts were prepared of silicone and were transformed into ultrasound-permeable casts. Casts were imaged in the same setting, so that 3DE and 2DE of casts represented transthoracic apical view. Left ventricle analysis softwares GE 4D Auto LVQ and TomTec 4D LV-Function were used for 3DE volumetry. RESULTS: Balloon volumes ranged 37 to 255 ml (mean 126 ml). 3DE resulted in an excellent volumetric agreement with balloon volumes, absolute bias was - 3.7 ml (95% CI -5.9 to - 1.4). Atrial cast volumes were 38 to 94 ml (mean 56.6 ml). 3DE and 2DE volumes were excellently correlated with cast volumes (r = 0.96 to 0.99). Biases were for GE 4D LVQ -0.7 ml (95% CI -6.1 to 4.6), TomTec 4D LV-Function 3.3 ml (- 1.9 to 8.5) and 2DE 2.9 ml (- 4.0 to 9.9). 3DE resulted in lower limits of agreement and showed no volume-related bias in contrast to area length method. CONCLUSIONS: We conclude that measurement of human cadaveric left atrial cast volumes by 3DE is in excellent agreement with true cast volumes. PMID- 30442103 TI - Identification of novel LEPR mutations in Pakistani families with morbid childhood obesity. AB - BACKGROUND: Mutations in the genes encoding leptin (LEP), the leptin receptor (LEPR), and the melanocortin 4 receptor (MC4R) are known to cause severe early onset childhood obesity. The aim of the current study was to examine the prevalence of damaging LEP, LEPR, and MC4R mutations in Pakistani families having a recessive heritance of early-onset obesity. METHODS: Using targeted resequencing, the presence of rare mutations in LEP, LEPR, and MC4R, was investigated in individuals from 25 families suspected of having autosomal recessive early-onset obesity. Segregation patterns of variants were assessed based on chip-based genotyping. RESULTS: Homozygous LEPR variants were identified in two probands. One carried a deletion (c.3260AG) resulting in the frameshift mutation p.Ser1090Trpfs*6, and the second carried a substitution (c.2675C > G) resulting in the missense mutation p.Pro892Arg. Both mutations were located within regions of homozygosity shared only among affected individuals. Both probands displayed early-onset obesity, hyperphagia and diabetes. No mutations were found in LEP and MC4R. CONCLUSIONS: The current study highlights the implication of LEPR mutations in cases of severe early-onset obesity in consanguineous Pakistani families. Through targeted resequencing, we identified novel damaging mutations, and our approach may therefore be utilized in clinical testing or diagnosis of known forms of monogenic obesity with the aim of optimizing obesity treatment. PMID- 30442105 TI - Feasibility of the string test for tuberculosis diagnosis in children between 4 and 14 years old. AB - BACKGROUND: The enteric string test can be used to obtain a specimen for microbiological confirmation of tuberculosis in children, but it is not widely used for this. The aim of this analysis to evaluate this approach in children with tuberculosis symptoms. METHODS: We conducted a cross-sectional study to assess children's ability to complete the test (feasibility), and self-reported pain (tolerability). We examined caregivers' and children's willingness to repeat the procedure (acceptability) and described the diagnostic yield of cultures for diagnostic tools. We stratified estimates by age and compared metrics to those derived for gastric aspirate (GA). RESULTS: Among 148 children who attempted the string test, 34% successfully swallowed the capsule. Feasibility was higher among children aged 11-14 than in children 4-10 years (83% vs 22% respectively, p < 0.0001). The string test was better tolerated than GA in both age groups; however, guardians and older children reported higher rates of willingness to repeat GA than the string test (86% vs. 58% in children; 100% vs. 83% in guardians). In 9 children with a positive sputum culture, 6 had a positive string culture. The one children with a positive gastric aspirate culture also had a positive string culture. CONCLUSION: Although the string test was generally tolerable and accepted by children and caregivers; feasibility in young children was low. Reducing the capsule size may improve test success rates in younger children. PMID- 30442106 TI - Associations between perceived barriers and benefits of using HIV pre-exposure prophylaxis and medication adherence among men who have sex with men in Western China. AB - BACKGROUND: To investigate the associations between the perceived barriers and benefits of using HIV pre-exposure prophylaxis medication, including worries about the side effects, disliking taking drugs, perceived burden of taking medication, positive expectations as to the efficacy of the drugs, favourable doctor-patient relationships, and medication adherence among men who have sex with men (MSM) to provide a target for improving medication adherence and reducing HIV infection among MSM. METHODS: MSM were recruited in western China from April 2013 to October 2014, administered oral tenofovir (TDF) daily and followed up every 12 weeks for 2 years. At each follow-up, the medication rate was calculated based on the self-reported number of missed doses over 2 weeks, and then, the medication adherence was evaluated. The barriers and benefits perceived during medication were obtained by a self-administered questionnaire, and their effects on medication adherence were analysed by linear mixed models. RESULTS: A total of 411 participants were enrolled in this study, and 1561 follow up observation points were obtained. The average medication rate was 0.62 +/- 0.37, and the medication rate increased with longer follow-up (P < 0.05). The medication rate was higher among MSM who were divorced (compared to those who were unmarried, P < 0.0001). MSM with more positive expectations as to the efficacy of the drugs showed higher rates of medication (P < 0.0001), while those who were more worried about side effects had a lower medication rate (P = 0.0208). In contrast, the dislike of taking the drugs and the burden perceived during medication had no effects on the actual medication rate of taking TDF (P > 0.05). CONCLUSION: How to obtain and maintain high medication adherence among MSM is the key to the PrEP intervention strategy for effective reduction of HIV infection. For MSM in China, we should deepen their understanding of the effectiveness and safety of PrEP and increase their confidence in PrEP, thereby improving their medication adherence. TRIAL REGISTRATION: ChiCTR-TRC-13003849 . Registered on 24/06/2013. PMID- 30442107 TI - Multidisciplinary treatment for patients with stage IV gastric cancer: the role of conversion surgery following chemotherapy. AB - BACKGROUND: With advances in gastric cancer chemotherapy, conversion surgery has drawn attention as a new strategy to improve the outcome of stage IV disease. We investigated the efficacy of conversion surgery following chemotherapy for patients with stage IV gastric cancer. METHODS: We retrospectively reviewed clinico-pathologic variables and oncologic outcomes for 101 patients with stage IV gastric cancer who were treated with systemic chemotherapy followed by gastrectomy with intension of curative resection from January 2005 to December 2012. RESULTS: In terms of the best response from palliative chemotherapy, complete or partial response were observed in 65 patients (64.4%) in overall. Complete response of metastatic site were observed in 72 (71.3%) and 66 (65.3%) patients as best and pre-operative response, respectively. The overall complete macroscopic resection, rate was 56.4%. Eleven patients (10.9%) received combined metastasectomy. There was no postoperative surgery-related mortality for 1 month. The median overall survival time was 26.0 months. Multivariable analysis identified complete macroscopic resection, chemotherapy response (complete response/partial response) of metastatic sites, and change in CEA level as independent prognostic factors contributing to overall survival. CONCLUSIONS: Patients with stage IV gastric cancer who exhibit a good clinical response to chemotherapy might obtain greater survival benefit from gastrectomy following chemotherapy compared with patients who exhibit a poor response to chemotherapy. Prospective, randomized trials are required to determine the best strategy for combining initial chemotherapy with subsequent gastrectomy. PMID- 30442108 TI - Influence of exogenous growth hormone administration on circulating concentrations of alpha-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study. AB - BACKGROUND: The CKD-associated decline in soluble alpha-Klotho (alpha-Klotho) levels is considered detrimental. Some studies suggest a direct induction of alpha-Klotho concentrations by growth hormone (GH). In the present study, the effect of exogenous GH administration on alpha-Klotho concentrations in a clinical cohort with mild chronic kidney disease (CKD) and healthy subjects was studied. METHODS: A prospective, single-center open case-control pilot study was performed involving 8 patients with mild CKD and 8 healthy controls matched for age and sex. All participants received subcutaneous GH injections (Genotropin(r), 20 mcg/kg/day) for 7 consecutive days. alpha-Klotho concentrations were measured at baseline, after 7 days of therapy and 1 week after the intervention was stopped. RESULTS: alpha-Klotho concentrations were not different between CKD patients and healthy controls at baseline (554 (388-659) vs. 547 (421-711) pg/mL, P = 0.38). Overall, GH therapy increased alpha-Klotho concentrations from 554 (405-659) to 645 (516-754) pg/mL, P < 0.05). This was accompanied by an increase of IGF-1 concentrations from 26.8 +/- 5.0 nmol/L to 61.7 +/- 17.7 nmol/L (P < 0.05). GH therapy induced a trend toward increased alpha-Klotho concentrations both in the CKD group (554 (388-659) to 591 (358-742) pg/mL (P = 0.19)) and the healthy controls (547 (421-711) pg/mL to 654 (538-754) pg/mL (P = 0.13)). The change in alpha-Klotho concentration was not different for both groups (P for interaction = 0.71). alpha-Klotho concentrations returned to baseline levels within one week after the treatment (P < 0.05). CONCLUSIONS: GH therapy increases alpha-Klotho concentrations in subjects with normal renal function or stage 3 CKD. A larger follow-up study is needed to determine whether the effect size is different between both groups or in patients with more severe CKD. TRIAL REGISTRATION: This trial is registered in EudraCT ( 2013-003354-24 ). PMID- 30442109 TI - Environmental factors and risk of delirium in geriatric patients: an observational study. AB - BACKGROUND: Patients with delirium have increased risk of death, dementia and institutionalization, and prognosis differs between delirium motor subtypes. A few studies have identified associations between environmental factors like room transfers and time spent in the emergency department (ED) and delirium, but no studies have investigated if environmental factors may influence delirium motor subtypes. We wanted to explore if potentially stressful events like ward transfers, arriving ED at nighttime, time spent in ED and nigthttime investigations were associated with development of delirium (incident delirium) and delirium motor subtypes. METHODS: We used the DSM-5 criteria to diagnose delirium and the Delirium Motor Subtype Scale for motor subtyping. We defined hyperactive and mixed delirium as delirium with hyperactive symptoms, and hypoactive and no-subtype delirium as delirium without hyperactive symptoms. We registered ward-transfers, time of arrival in ED, time spent in ED and nighttime investigations (8 p.m. to 8 a.m.), and calculated Global Deterioration Scale (GDS) and Cumulative Illness Rating Scale (CIRS) to adjust for cognitive impairment and comorbidity. We used logistic regression analyses with incident delirium and delirium with hyperactive symptoms as outcome variables, and ward transfers, arriving ED at nighttime, time spent in ED and nighttime investigations as exposure variables, adjusting for age, GDS and CIRS in the analyses for incident delirium. RESULTS: We included 254 patients, mean age 86.1 years (SD 5.2), 49 (19.3%) had incident delirium, 22 with and 27 without hyperactive symptoms. There was a significant association between nighttime investigations and incident delirium in both the unadjusted (odds ratio (OR) 2.22, 95% confidence interval (CI) 1.17 to 4.22, p = 0.015) and the multiadjusted model (OR 2.61, CI 1.26 to 5.40, p = 0.010). There were no associations between any other exposure variables and incident delirium. No exposure variables were associated with delirium motor subtypes. CONCLUSIONS: Nighttime investigations were associated with incident delirium, even after adjusting for age, cognitive impairment and comorbidity. We cannot out rule that the medical condition leading to nighttime investigations is the true delirium-trigger, so geriatric patients must still receive emergency investigations at nighttime. Hospital environment in broad sense may be a target for delirium prevention. PMID- 30442110 TI - Clinical significance and prognosis of serum tenascin-C in patients with sepsis. AB - BACKGROUND: Tenascin-C is a pro-inflammatory glycoprotein with various biological functions. High expression of tenascin-C is found in inflammation, tissue remodeling, and autoimmune diseases. However, its expression and clinical significance in sepsis remain unclear. This study was designed to investigate the relationship between serum tenascin-C levels and disease severity and prognosis in patients with sepsis. METHODS: A total of 167 patients with sepsis admitted to the ICU were enrolled. Lood samples were collected within 24 h of admission. Serum tenascin-C levels were measured by enzyme-linked immunosorbent assay (ELISA). Follow-up was performed to observe 30-day mortality. RESULTS: Serum tenascin-C levels were significantly elevated in patients with sepsis compared with non-sepsis controls (P < 0.001). Serum tenascin-C levels were higher in nonsurvivors (58 cases) who died within 30 days (34.5%) compared to survivors (109 cases) (P < 0.001). In patients with sepsis, serum tenascin-C levels were significantly positively correlated with SOFA scores (P = 0.011), serum creatinine (P = 0.006), C-reactive protein (CRP) (P = 0.001), interleukin-6 (IL 6) (P < 0.001), and tumor necrosis factor alpha (TNF-alpha) (P = 0.026). Logistic multivariate regression models showed that serum tenascin-C levels were independent contributor of 30-day mortality. Kaplan-Meier curves showed that septic patients with high levels of serum tenascin-C (>=56.9 pg/mL) had significantly higher 30-day mortality than those with lower serum tenascin-C (< 56.9 pg/mL) (P < 0.001). CONCLUSION: Elevated serum tenascin-C was found in septic patients and associated with severity and poor prognosis. PMID- 30442112 TI - Seasonal prevalence of hyponatremia in the emergency department: impact of age. AB - BACKGROUND: Hyponatremia is one of the most commonly encountered electrolyte disorders in emergency department (ED). Seasonal fluctuations of the prevalence of hyponatremia has been reported. We investigated the impact of age on the seasonal prevalence of hyponatremia in the emergency department in Japan. METHODS: Total of 8377 patients presented to the ED between January 2015 and December 2016 were reviewed. The adult group aged between 18 and 64 years old consisted of 3656 patients and the elderly group aged over 65 years consisted of 4721 patients. Information collected included age, sex, serum sodium, and serum creatinine. Hyponatremia was defined as a serum sodium leve1 < 135 mEq/L and severe hyponatremia was defined as a serum sodium level < 125 mEq/L. RESULTS: Prevalence of hyponatremia was significantly higher in the elderly group than in the adult group (17.0% vs. 5.7%, p < 0.001). Similarly, the prevalence of severe hyponatremia was significantly higher in the elderly group than in the adult group (1.9% vs. 0.3%, p < 0.001). Prevalence of hyponatremia and severe hyponatremia was significantly higher in the elderly group than in the adult group in all seasons. In the elderly group, there was a significant correlation between weather high temperature during summer and prevalence of hyponatremia (r = 0.510, p = 0.011). CONCLUSION: There was a major impact of age on the seasonal prevalence of hyponatremia and severe hyponatremia. Strategies to prevent hyponatremia and severe hyponatremia should be taken especially in the elderly patients during summer. PMID- 30442111 TI - MicroRNAs and their targets in cucumber shoot apices in response to temperature and photoperiod. AB - BACKGROUND: The cucumber is one of the most important vegetables worldwide and is used as a research model for study of phloem transport, sex determination and temperature-photoperiod physiology. The shoot apex is the most important plant tissue in which the cell fate and organ meristems have been determined. In this study, a series of whole-genome small RNA, degradome and transcriptome analyses were performed on cucumber shoot apical tissues treated with high vs. low temperature and long vs. short photoperiod. RESULTS: A total of 164 known miRNAs derived from 68 families and 203 novel miRNAs from 182 families were identified. Their 4611 targets were predicted using psRobot and TargetFinder, amongst which 349 were validated by degradome sequencing. Fourteen targets of six miRNAs were differentially expressed between the treatments. A total of eight known and 16 novel miRNAs were affected by temperature and photoperiod. Functional annotations revealed that "Plant hormone signal transduction" pathway was significantly over represented in the miRNA targets. The miR156/157/SBP-Boxes and novel mir153/ethylene-responsive transcription factor/senescence-related protein/aminotransferase/acyl-CoA thioesterase are the two most credible miRNA/targets combinations modulating the plant's responsive processes to the temperature-photoperiod changes. Moreover, the newly evolved, cucumber-specific novel miRNA (novel-mir153) was found to target 2087 mRNAs by prediction and has 232 targets proven by degradome analysis, accounting for 45.26-58.88% of the total miRNA targets in this plant. This is the largest sum of genes targeted by a single miRNA to the best of our knowledge. CONCLUSIONS: These results contribute to a better understanding of the miRNAs mediating plant adaptation to combinations of temperature and photoperiod and sheds light on the recent evolution of new miRNAs in cucumber. PMID- 30442114 TI - Research on the treatment effects and drug resistances of long-term second-line antiretroviral therapy among HIV-infected patients from Henan Province in China. AB - BACKGROUND: HIV/AIDS patients who fail to respond to first-line treatment protocols are switched to second-line ART. Identifying factors that influence effective second-line treatment can improve utilization of limited medical resources. We investigated the efficacy of long-term second-line anti-retroviral therapy (ART) after first-line virologic failure as well as the impact of non nucleotide reverse transcriptase inhibitor (NNRTI), nucleotide reverse transcriptase inhibitor (NRTI), and protease inhibitor (PI) resistance mutations and medication adherence on ineffective viral suppression. METHODS: A total of 120 patients were evaluated at 6, 12, 18, 24, and 48 months after initiation of second-line ART; a paper questionnaire was administered via a face-to-face interview and venous blood samples were collected. CD4+ T cell count, viral load, and drug resistance genotypes were quantified. RESULTS: CD4+ T cell counts increased from 170 cells/MUL (IQR 100-272) at baseline to 359 cells/MUL (IQR 236 501) after 48 months of second-line treatment. Viral load (log10) decreased from 4.58 copies/mL (IQR 3.96-5.17) to 1.00 copies/mL (IQR 1.00-3.15). After switching to second-line ART, nine patients newly acquired the NRTI drug-resistant mutation, M184 V/I. No major PI resistance mutations were detected. Logistical regression analysis indicated that medication adherence < 90% in the previous month was associated with ineffective viral suppression; baseline high/low/moderate level resistance to 3TC/TDF was protective towards effective viral suppression. CONCLUSIONS: Long-term second line ART was effective in the Henan region of China. Drug resistance mutations to NRTIs were detected in patients receiving second-line ART, suggesting that drug resistance surveillance should be continued to prevent the spread of resistant strains. Patient medication adherence supervision and management should be strengthened to improve the efficacy of antiviral treatment. PMID- 30442113 TI - Re-programming of Pseudomonas syringae pv. actinidiae gene expression during early stages of infection of kiwifruit. AB - BACKGROUND: Pseudomonas syringae is a widespread bacterial species complex that includes a number of significant plant pathogens. Amongst these, P. syringae pv. actinidiae (Psa) initiated a worldwide pandemic in 2008 on cultivars of Actinidia chinensis var. chinensis. To gain information about the expression of genes involved in pathogenicity we have carried out transcriptome analysis of Psa during the early stages of kiwifruit infection. RESULTS: Gene expression in Psa was investigated during the first five days after infection of kiwifruit plantlets, using RNA-seq. Principal component and heatmap analyses showed distinct phases of gene expression during the time course of infection. The first phase was an immediate transient peak of induction around three hours post inoculation (HPI) that included genes that code for a Type VI Secretion System and nutrient acquisition (particularly phosphate). This was followed by a significant commitment, between 3 and 24 HPI, to the induction of genes encoding the Type III Secretion System (T3SS) and Type III Secreted Effectors (T3SE). Expression of these genes collectively accounted for 6.3% of the bacterial transcriptome at this stage. There was considerable variation in the expression levels of individual T3SEs but all followed the same temporal expression pattern, with the exception of hopAS1, which peaked later in expression at 48 HPI. As infection progressed over the time course of five days, there was an increase in the expression of genes with roles in sugar, amino acid and sulfur transport and the production of alginate and colanic acid. These are both polymers that are major constituents of extracellular polysaccharide substances (EPS) and are involved in biofilm production. Reverse transcription-quantitative PCR (RT-qPCR) on an independent infection time course experiment showed that the expression profile of selected bacterial genes at each infection phase correlated well with the RNA-seq data. CONCLUSIONS: The results from this study indicate that there is a complex remodeling of the transcriptome during the early stages of infection, with at least three distinct phases of coordinated gene expression. These include genes induced during the immediate contact with the host, those involved in the initiation of infection, and finally those responsible for nutrient acquisition. PMID- 30442115 TI - Illness beliefs about depression among patients seeking depression care and patients seeking cardiac care: an exploratory analysis using a mixed method design. AB - BACKGROUND: Treatment of depression in cardiac patients is difficult. Patients' illness beliefs regarding depression are associated with outcomes. The aim of the mixed-methods study was to test whether patients in routine care for depression differ from patients with depression in routine care for cardiac diseases regarding illness beliefs about depression. METHODS: A consecutive sample of n = 217 patients with depressive disorder was recruited from routine care for depression (N = 148) and routine care for cardiac diseases (N = 69). Beliefs about depression were measured by the Brief-Illness Perception Questionnaire. Causal beliefs were categorized using qualitative methods. To investigate differences regarding other illness beliefs, we performed an ANCOVA controlling for sociodemographic and clinical differences by propensity score matching. RESULTS: Patients in routine care for cardiac diseases attributed their depression more often to physical illnesses (48% vs. 16%) and less often to their self (30% vs. 47%), problems at work (25% vs. 35%), childhood (25% vs. 30%), and negative life events (19% vs. 25%) in contrast to patients in routine care for depression. Patients in routine care for cardiac diseases reported beliefs of lower disability, burden, and treatment-control and of higher self-control in contrast to patients in routine care for depression. CONCLUSIONS: Illness beliefs especially causal beliefs differ between patients in routine care for cardiac diseases and routine care for depression. Future research should investigate effects of these illness beliefs. We recommend exploring patients' illness beliefs about depression in routine care for cardiac diseases and routine care for depression. PMID- 30442117 TI - Fatty acid binding protein 7 may be a marker and therapeutic targets in clear cell renal cell carcinoma. AB - BACKGROUND: To identify potential therapeutic target in clear cell renal cell carcinoma (ccRCC), we performed a transcriptome analysis. Our analysis showed that fatty acid binding protein 7 (FABP7) has the highest mean differential overexpression in ccRCC compared to normal kidney. We aimed to investigate the significance of FABP7 in ccRCC. METHODS: Immunohistochemical staining for 40 advanced ccRCC cases was performed to investigate correlation between clinicopathological parameters and FABP7. They were composed of 40-83 years old cases with 33 male, 22 cases with pT >= 3, 19 cases with M1, and 16 cases with grade 3. The effect of gene knockdown was analysed by a cell viability assay and invasion assay in FABP7-overexpressing cell lines (SKRC7 and SKRC10). RESULTS: Our immunohistochemical analysis showed that higher FABP7 expression significantly correlated with distant metastasis and poor cancer-specific survival (CSS; both p < 0.05). Functional suppression of FABP7 significantly inhibited SKRC10 cell growth (p < 0.05) and resulted in a significant reduction of the invasive potential (p < 0.01), but did not cause growth inhibition of SKRC7 cells. We found that The Cancer Genome Atlas Research Network (TCGA) database shows FABP6 and 7 as equally overexpressed in the FABP family. Functional suppression of fatty acid binding protein 6 (FABP6) resulted in significant growth inhibition of SKRC7 cells (p < 0.005). CONCLUSIONS: Functional suppression of FABP7 significantly reduced cell viability and invasive potential in a ccRCC cell line. FABP7 may play a role in progression in some metastatic ccRCCs. The suppressed function may be compensated by another FABP family member. PMID- 30442118 TI - Human immunodeficiency virus infection disclosure status to infected school aged children and associated factors in bale zone, Southeast Ethiopia: cross sectional study. AB - BACKGROUND: Human immunodeficiency virus (HIV) positive status disclosure is an essential component of Pediatric care and long term disease management. Children have a right to know their HIV diagnosis result. However, Pediatric HIV disclosure is complex and varies in different communities. This study aimed to assess the prevalence of HIV-positive status disclosure to infected children and associated factors among caregivers of infected children. METHODOLOGY: A facility based mixed methods research design study was conducted in Bale Zone of South East Ethiopia. Randomly selected caregivers of HIV-positive children were interviewed using structured questionnaires for quantitative study and 17 in depth interviews of health care workers and caregivers were conducted for qualitative data. Content analysis was done for qualitative data and logistic regression analysis was used to see the association between different variables and HIV-positive disclosure status. Odds ratio with 95% CI was computed to determine the presence and strength of the associated factors. RESULTS: A total of 200 caregivers of school aged (6-14 years) children participated in the study. Only 57 (28.5%) of the care givers disclosed HIV-positive status to the child for whom they were caring. The main reason for disclosure delay was due to fear of negative consequences, perception on maturity of the child, and fear of social rejection and stigma. Having social support [AOR = 2.7, 95% CI: (1.1-6.4)], caring for a child between 10 and 14 years with HIV [AOR = 6.5, 95% CI: (2.1 20.2)], a child diagnosed with HIV at age > 5 years [AOR = 2.8, 95% CI: (1.1 7.1)], and children on antiretroviral therapy (ART) with follow-up for > 5 years [AOR = 4.7, 95% CI: (1.8-11.2)] had significant association with HIV- positive status disclosure to infected children. CONCLUSION: The frequency of HIV infection disclosure to infected children was very low in our cohort. Having social support, having an older child with HIV, a long period of ART follow-up and HIV diagnosis after age of five years were positively associated with HIV positive status disclosure to infected children. Giving age appropriate counselling to children, social support to the caregivers and working on related factors are very important to improve the observed low disclosure status. PMID- 30442116 TI - Mapping the Pax6 3' untranslated region microRNA regulatory landscape. AB - BACKGROUND: PAX6 is a homeodomain transcription factor that acts in a highly dosage-sensitive manner to regulate the development and function of the eyes, nose, central nervous system, gut, and endocrine pancreas. Several individual microRNAs (miRNA) have been implicated in regulating PAX6 in different cellular contexts, but a more general view of how they contribute to the fine-tuning and homeostasis of PAX6 is poorly understood. RESULTS: Here, a comprehensive analysis of the Pax6 3' untranslated region was performed to map potential miRNA recognition elements and served as a backdrop for miRNA expression profiling experiments to identify potential cell/tissue-specific miRNA codes. Pax6 3'UTR pull-down studies identified a cohort of miRNA interactors in pancreatic alphaTC1 6 cells that, based on the spacing of their recognition sites in the Pax6 3'UTR, revealed 3 clusters where cooperative miRNA regulation may occur. Some of these interacting miRNAs have been implicated in alpha cell function but have not previously been linked to Pax6 function and may therefore represent novel PAX6 regulators. CONCLUSIONS: These findings reveal a regulatory landscape upon which miRNAs may participate in the developmental control, fine-tuning and/or homeostasis of PAX6 levels. PMID- 30442119 TI - Inotuzumab ozogamicin is effective in relapsed/refractory extramedullary B acute lymphoblastic leukemia. AB - BACKGROUND: Extramedullary involvement of B-cell Acute Lymphoblastic Leukemia (EM ALL) is a rare occurrence, characterized by dismal outcome and the absence of a defined and shared therapeutic approach. In the landscape of innovative compounds, inotuzumab ozogamicin (IO) is a promising drug, whose mechanism of action relies on the killing of CD22 positive leukemic cells, through the delivery, after cell binding, of a molecule of calicheamicin. CASE PRESENTATION: We report two cases of CD22 positive relapsed EM-ALL treated with IO, obtained as compassionate use. Case 1, a 66 years old woman, affected by Philadelphia (Ph) negative B-ALL, relapsed with extramedullary involvement after 6 standard chemotherapy courses, who reached a complete metabolic response with IO treatment. Case 2, a 67 years old man with Ph positive B-ALL, initially treated with ponatinib, a third generation tyrosine-kinase inhibitor (TKI), obtaining a prolonged deep molecular remission. Nevertheless, for skin relapse during TKI treatment, the patient received local radiotherapy and, shortly after, standard chemotherapy, as multiple abdominal sites of relapse were detected too, with no response. The patient then received IO, obtained as compassionate use, with a good metabolic response. CONCLUSIONS: These two cases suggest a possible key role of IO in the setting of advanced CD22 positive ALL, and underline its potential activity also in patients with EM involvement, relapsed after or refractory to conventional chemotherapy. Despite the well known hepatotoxic effect of the compound (Sinusoid Occlusive Syndrome), neither of them had such adverse event, moreover the second patient safely underwent allogeneic bone marrow transplantation. PMID- 30442121 TI - Comparing the eating out experiences of consumers seeking to avoid different food allergens. AB - BACKGROUND: Eating outside the home is challenging for consumers with food allergy (FA) and intolerance (FI) and lack of allergen information provision in eating out venues can lead to unnecessary restrictions. Following European legislation (2014) designed to improve allergen information provision, little is known about differences in information provision experienced by consumers seeking to avoid particular allergens, or how this impacts on their eating out experiences. This study compared the information provision that consumers with FA/FI to different allergens experience when eating out. METHODS: Using mixed methods, participants were recruited from across the UK and took part in self report surveys or in-depth interviews. Surveys were completed by 232 participants avoiding either gluten (n = 66), nuts (peanuts/tree nuts) (n = 94), or milk (n = 74), and responses were subject to quantitative analyses. Interviews were carried out with 49 participants avoiding either gluten (n = 13), nuts (n = 14), milk (n = 13) or a combination of these allergens (n = 9), and analysed using the framework approach. RESULTS: Although general improvements in information provision following the legislation were reported, variations in provision between allergen groups led participants seeking to avoid milk to conclude that their dietary needs were less well-understood and seen as less important. These perceptions were reflected in a reluctance to involve eating out venue staff in deliberations about the potential for milk-free meal options. CONCLUSIONS: The provision of visual indicators of the presence of milk and of staff trained in allergen-awareness would improve the eating out experiences of consumers seeking to avoid milk. Medical professions can play a key role in encouraging these patients to pursue their right to make enquiries about allergens in order to avoid accidental milk ingestion when eating out. PMID- 30442120 TI - Randomized controlled trial of an 8-week intervention combining self-care and hypnosis for post-treatment cancer patients: study protocol. AB - BACKGROUND: Cancer has a lot of consequences on patients' quality of life (such as cancer-related fatigue (CRF), sleep difficulties and emotional distress) and on patients' partners and their relationship, such as distress and communication difficulties. These consequences are undertreated, and interventions based on hypnosis often focus on breast cancer patients only. This paper describes the study protocol of a longitudinal randomized controlled trial aiming to assess the efficacy of an 8-week intervention combining hypnosis and self-care to improve cancer patients' CRF, sleep and emotional distress and to indirectly improve their partners' distress. METHODS: A power analysis required a total sample of 88 patients. To test the efficacy of the intervention, results of the experimental group receiving the intervention will be compared to those of the control group. Data will be collected by questionnaires, relaxation tasks, an attentional bias task, and everyday life assessments measured at four different times: 1.) before inclusion in the study (baseline); 2.) after the intervention; and 3.) at 4- and 12-month follow-up. Partners' symptoms will also be evaluated with questionnaires at the same measurement times. DISCUSSION: There is a growing interest in alternative approaches (such as hypnosis) in addition to standard therapies in oncology settings. The results of this study should be useful for improving knowledge about long-term efficacy of hypnosis-based group interventions for CRF, sleep and distress among all types of cancer patients and their partners, and to better understand the mechanisms of emotional regulation in cancer patients through the attentional bias task. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03144154). Retrospectively registered on the 1st of May, 2017. PMID- 30442123 TI - Immunohistochemical characterization of the M4 macrophage population in leprosy skin lesions. AB - BACKGROUND: Since macrophages are one of the major cell types involved in the Mycobacterium leprae immune response, roles of the M1 and M2 macrophage subpopulations have been well defined. However, the role of M4 macrophages in leprosy or other infectious diseases caused by mycobacteria has not yet been clearly characterized. This study aimed to investigate the presence and potential role of M4 macrophages in the immunopathology of leprosy. METHODS: We analyzed the presence of M4 macrophage markers (CD68, MRP8, MMP7, IL-6, and TNF-alpha) in 33 leprosy skin lesion samples from 18 patients with tuberculoid leprosy and 15 with lepromatous leprosy by immunohistochemistry. RESULTS: The M4 phenotype was more strongly expressed in patients with the lepromatous form of the disease, indicating that this subpopulation is less effective in the elimination of the bacillus and consequently is associated with the evolution to one of the multibacillary clinical forms of infection. CONCLUSION: M4 macrophages are one of the cell types involved in the microbial response to M. leprae and probably are less effective in controlling bacillus replication, contributing to the evolution to the lepromatous form of the disease. PMID- 30442122 TI - Cardiovascular disease risk and comparison of different strategies for blood pressure management in rural India. AB - BACKGROUND: Non-optimal blood pressure (BP) levels are a major cause of disease burden globally. We describe current BP and treatment patterns in rural India and compare different approaches to BP lowering in this setting. METHODS: All individuals aged >=40 years from 54 villages in a South Indian district were invited and 62,194 individuals (84%) participated in a cross-sectional study. Individual 10-year absolute cardiovascular disease (CVD) risk was estimated using WHO/ISH charts. Using known effects of treatment, proportions of events that would be averted under different paradigms of BP lowering therapy were estimated. RESULTS: After imputation of pre-treatment BP levels for participants on existing treatment, 76.9% (95% confidence interval, 75.7-78.0%), 5.3% (4.9-5.6%), and 17.8% (16.9-18.8%) of individuals had a 10-year CVD risk defined as low (< 20%), intermediate (20-29%), and high (>=30%, established CVD, or BP > 160/100 mmHg), respectively. Compared to the 19.6% (18.4-20.9%) of adults treated with current practice, a slightly higher or similar proportion would be treated using an intermediate (23.2% (22.0-24.3%)) or high (17.9% (16.9-18.8%) risk threshold for instituting BP lowering therapy and this would avert 87.2% (85.8-88.5%) and 62.7% (60.7-64.6%) more CVD events over ten years, respectively. These strategies were highly cost-effective relative to the current practice. CONCLUSION: In a rural Indian community, a substantial proportion of the population has elevated CVD risk. The more efficient and cost-effective clinical approach to BP lowering is to base treatment decisions on an estimate of an individual's short-term absolute CVD risk rather than with BP based strategy. CLINICAL TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2013/06/003753 , 14 June 2013. PMID- 30442124 TI - Classifying human promoters by occupancy patterns identifies recurring sequence elements, combinatorial binding, and spatial interactions. AB - BACKGROUND: Characterizing recurring sequence patterns in human promoters has been a challenging undertaking even nowadays where a near-complete overview of promoters exists. However, with the more recent availability of genomic location (ChIP-seq) data, one can approach that question through the identification of characteristic patterns of transcription factor occupancy and histone modifications. RESULTS: Based on the ENCODE annotation and integration of sequence motifs as well as three-dimensional chromatin data, we have undertaken a re-analysis of occupancy and sequence patterns in human promoters. We identify clear groups of CAAT-box and E-box sequence motif containing promoters, as well as a group of promoters whose interaction with an enhancer appears to be mediated by CCCTC-binding factor (CTCF) binding on the promoter. We also extend our analysis to inactive promoters, showing that only a surprisingly small number of inactive promoters is repressed by the polycomb complex. We also identify combinatorial patterns of transcription factor interactions indicated by the ChIP seq signals. CONCLUSION: Our analysis defines subgroups of promoters characterized by stereotypic patterns of transcription factor occupancy, and combinations of specific sequence patterns which are required for their binding. This grouping provides new hypotheses concerning the assembly and dynamics of transcription factor complexes at their respective promoter groups, as well as questions on the evolutionary origin of these groups. PMID- 30442125 TI - Obstetric brachial plexus injuries (OBPIs): health-related quality of life in affected adults and parents. AB - BACKGROUND: Obstetric brachial plexus injuries (OBPIs) are rare but can have significant implications for those affected, their caregivers and the health system. Symptoms can range from restricted movement to complete paralysis of the arm. We investigated health-related quality of life in adults with OBPIs and parents of children with permanent OBPIs, compared these with population norms, and investigated whether certain socio-demographic or clinical factors were associated with the quality of life in these cohorts. METHODS: A cross-sectional study examined 50 affected adults and 78 parents. Participants completed EQ-5D-5 L and characteristics questionnaires. EQ-5D-5 L responses were mapped onto an EQ 5D-3 L value set to generate utility scores. Mean utility scores were compared with English population norms. Univariable and multivariable linear regression models were conducted to assess for associations between participant characteristics and the utility scores. RESULTS: The overall mean utility scores for affected adults and parents were 0.56 (SD 0.28) and 0.80 (SD 0.19) respectively. Affected adults (95% CI (- 0.38, - 0.22), p < 0.001) and parents of children with permanent OBPIs (95% CI (- 0.10, - 0.02), p = 0.007) had lower mean utility scores, and therefore quality of life, compared to English population norms. For affected adults, previous OBPI surgery (95% CI (0.01, 0.25), p = 0.040), employment in non-manual work (95% CI (0.06, 0.30), p = 0.005) and having a partner (95% CI (0.04, 0.25), p = 0.009) appeared to be positively associated with the utility score. Affected adults receiving disability benefits related to OBPIs appeared to have worse utility scores than those not receiving any disability benefits (95% CI (- 0.31, - 0.06), p = 0.005). For parents, employment was associated with better utility scores (95% CI (0.02, 0.20), p = 0.024) but the presence of one or more medical condition appeared to be associated with worse utility scores (95% CI (- 0.16, - 0.04), p = 0.001). CONCLUSIONS: Adults with OBPIs and parents of children with permanent OBPIs reported worse utility scores, and therefore quality of life, compared to the English general population. We also identified certain characteristics as possible factors to consider when dealing with utility scores in these cohorts. The utility scores in this study can be used in future economic evaluations related to OBPIs. PMID- 30442126 TI - Consolidation of pathology services in England: have savings been achieved? AB - BACKGROUND: During the last decade, pathology services in England have undergone profound changes with an extensive consolidation of laboratories. This has been driven by some national reviews forecasting a national reduction of costs by L250 L500 million ($315-$630 million) a year as a result. The main aim of this paper is to describe the financial impact of such consolidation, with a specific focus on the forecasted savings. A secondary aim is to describe the development of private sector involvement in laboratory services in a traditionally publicly funded healthcare system and the development of pathology staff size. METHODS: In the English scenario, the majority of hospitals and laboratories are publicly funded and a survey was sent as Freedom of Information request to all directors of pathology. A descriptive comparison of savings among consolidated and non consolidated pathology services was made by using the pathology budgets in two different periods (2015 versus 2010), adjusted by inflation and increased activity. RESULTS: The hub-and-spoke model has been implemented as part of the consolidation process of pathology services in England. Consolidated pathology networks have achieved higher savings compared to non-consolidated single laboratories. There has been an increased role of private providers and savings were achieved with negligible personnel redundancies. CONCLUSIONS: Consolidated units have on average achieved larger cost savings than non-consolidated units but further analysis with stronger research design is required to independently evaluate the impact of pathology consolidation on both savings and quality. PMID- 30442127 TI - Unequal power relations and partner violence against women in Tanzania: a cross sectional analysis. AB - BACKGROUND: Research on factors associated with partner violence against women is often framed within the context of gender inequality and power imbalances between husbands and wives-inequalities that are considered products of broader structural systems. Tanzania, a patriarchal society where high levels of partner violence exists, has gone through rapid economic and social changes over the past two decades. Increasing numbers of women are seeking paid work, and men's ideals of manhood have reshaped with evidence of extra marital relations and alcohol use. Nationally representative population-based data documents 46.2% of ever married women have experienced physical or sexual partner violence in their lifetime; 29.6% in the past year. In order to plan appropriate interventions to end violence against women, factors consistently associated with abuse need to be understood. METHODS: This study uses "couples" data from the 2015 Tanzania Demographic and Health Survey to examine correlates of past year partner violence against women. Multivariate regression analysis was used to explore individual and relational-level variables-including socio-demographic characteristics and history of abuse among women, partner behavioural characteristics, and indicators of gender and economic inequality-among 1278 married and cohabiting couples. RESULTS: At the individual level, women's experiences of non-partner violence (sexual abuse by a non-partner and witnessing violence in childhood) was strongly associated with risk and highlights that all forms of violence against women serve to keep them subordinated. Partner behavioural characteristics (polygamy and problematic alcohol use) were also associated with risk. Household socio economic status, however, was not significantly associated with women's risk in the final multivariate model. At the relational-level, men's age difference of 10 or more years; and any employment (compared to none/unpaid) were associated with lower risk. When considering attitudes tolerant towards wife abuse, the strongest association with risk of violence was when both partners held tolerant views. CONCLUSION: The findings support the assertions of violence being associated with women's prior/additional experiences of abuse and with men's harmful expressions of masculinity. In addition to interventions that focus on transforming gender norms and attitudes (at the individual and community levels), addressing economic, legal and political structural barriers are also required. PMID- 30442128 TI - Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury. AB - BACKGROUND: Endothelial barrier dysfunction is central to the pathogenesis of sepsis-associated acute lung injury (ALI). Microtubule (MT) dynamics in vascular endothelium are crucial for the regulation of endothelial barrier function. Unfractionated heparin (UFH) possesses various biological activities, such as anti-inflammatory activity and endothelial barrier protection during sepsis. METHODS: Here, we investigated the effects and underlying mechanisms of UFH on lipopolysaccharide (LPS)-induced endothelial barrier dysfunction. C57BL/6 J mice were randomized into vehicle, UFH, LPS and LPS + UFH groups. Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis. Mice in the LPS + UFH group received intravenous UFH 0.5 h prior to LPS injection. Human pulmonary microvascular endothelial cells (HPMECs) were cultured for analyzing the effects of UFH on LPS-induced and nocodazole-induced hyperpermeability, F-actin remodeling, and LPS-induced p38 MAPK activation. RESULTS: UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes, and increased the lung W/D ratio and Evans blue accumulation in vivo. Both in vivo and in vitro studies showed that UFH pretreatment blocked the LPS-induced increase in guanine nucleotide exchange factor (GEF-H1) expression and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, and microtubule (MT) disassembly in LPS-induced ALI mouse model and human pulmonary microvascular endothelial cells (HPMECs). These results suggested that UFH ameliorated LPS induced endothelial barrier dysfunction by inhibiting MT disassembly and GEF-H1 expression. In addition, UFH attenuated LPS-induced hyperpermeability of HPMECs and F-actin remodeling. In vitro, UFH pretreatment inhibited LPS-induced increase in monomeric tubulin expression and decrease in tubulin polymerization and acetylation. Meanwhile, UFH ameliorates nocodazole-induced MTs disassembly and endothelial barrier dysfunction.Additionally, UFH decreased p38 phosphorylation and activation, which was similar to the effect of the p38 MAPK inhibitor, SB203580. CONCLUSIONS: UFH exert its protective effects on pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization and is associated with the p38 MAPK pathway. PMID- 30442129 TI - The influence of hay steaming on clinical signs and airway immune response in severe asthmatic horses. AB - BACKGROUND: Avoidance of antigenic stimuli was found to significantly reverse airway obstruction of horses with severe equine asthma (sEA). To date, no published study investigated the influence of steaming hay on lower airway condition of sEA-affected horses. The objectives were to determine the clinical, cytological and cytokine respiratory responses of both sEA and control (CTL) horses experimentally exposed to steamed or dry hay. RESULTS: A cohort of 6 sEA horses and 6 CTL horses was involved in this field study. On day 0, both groups were fed with steamed hay for 5 consecutive days, followed by a wash-out period of 26 days prior to be fed with dry hay for 5 consecutive days. Investigations performed 2 days prior to and 5 days after each challenge included clinical score, tracheal mucus accumulation, and bronchoalveolar lavage fluid (BALF) cytology and cytokine mRNA expression. Feeding steamed hay significantly decreased its mould content (P < 0.001). Mucus score significantly increased when feeding dry hay (P = 0.01). No significant influence of challenge type was found on clinical score. Percentages of neutrophils (P < 0.001) as well as mRNA expression of IL-1beta (P = 0.024), IL-6R (P = 0.021), IL-18 (P = 0.009) and IL 23 (P = 0.036) in BALF of sEA affected horses were significantly increased after both (steamed and dry hay) challenges. Relative mRNA expression of IL-1beta, IL 6R and IL-23 in BALF were also significantly correlated to neutrophil percentages and both clinical and tracheal mucus score. CONCLUSIONS: Steaming significantly decreased mould content but inconsistently influenced the respiratory response of sEA affected horses when fed hay. Based on BALF cytology and cytokine profiles, its relevance might be controversial as a non-medicinal therapy for sEA-affected horses. PMID- 30442130 TI - Does cultural capital contribute to educational inequalities in food consumption in the Netherlands? A cross-sectional analysis of the GLOBE-2011 survey. AB - BACKGROUND: The importance of culture for food consumption is widely acknowledged, as well as the fact that culture-based resources ("cultural capital") differ between educational groups. Since current explanations for educational inequalities in healthy and unhealthy food consumption (e.g. economic capital, social capital) are unable to fully explain this gradient, we aim to investigate a new explanation for educational inequalities in healthy food consumption, i.e. the role of cultural capital. METHODS: Data were obtained cross sectionally by a postal survey among participants of the GLOBE study in the Netherlands in 2011 (N = 2953; response 67.1%). The survey measured respondents' highest attained educational level, food-related cultural capital (institutionalised, objectivised and incorporated cultural capital), economic capital (e.g. home ownership, financial strain), social capital (e.g. social support, health-related social leverage, interpersonal relationships), and frequency of consumption of healthy and unhealthy food products. Two general outcomes (overall healthy food consumption, and overall unhealthy food consumption), and seven specific food consumption outcomes were constructed, and prevalence ratios (PR) were estimated in Poisson regression models with robust variance. RESULTS: Cultural capital was significantly associated with all food outcomes, also when social and economic capital were taken into account. Those with low levels of cultural capital were more likely to have a lower overall healthy food consumption (PR 1.35, 95% CI 1.22-1.49), a lower consumption of whole wheat bread (PR 1.21, 95% CI 1.05-1.38), vegetables (PR 1.55, 95% CI 1.40 1.71), and meat-substitutes and fish (PR 1.74, 95% CI 1.53-1.97), and a higher consumption of fried food (PR 1.59, 95% CI 1.31-1.93). Social capital was positively associated with overall healthy food consumption, whole wheat bread consumption, and the consumption of fish and meat-substitutes, and economic capital with none of the outcomes. The PR of the lowest educational group to have a low overall healthy food consumption decreased from 1.48 (95% CI 1.28-1.73) to 1.22 (95% CI 1.04-1.43) when cultural, social and economic capital were taken into account. CONCLUSIONS: Cultural capital contributed to the explanation of educational inequalities in food consumption in The Netherlands, over and above economic and social capital. The socialisation processes through which cultural capital is acquired could offer new entry-points for the promotion of healthy food consumption among low educational groups. PMID- 30442131 TI - Safety of Safety Evaluation of Pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl. AB - Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos-methyl, and a failure to detect any neurobehavioral effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleading. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution. PMID- 30442132 TI - Fear and rumours regarding placental biopsies in a malaria-in-pregnancy trial in Benin. AB - BACKGROUND: A multi-country, community-based trial on scheduled screening and treatment for malaria in pregnancy was conducted in Benin, The Gambia and Burkina Faso. Despite standardized procedures and outcomes, the study became subject to rumours and accusations of placenta being sold for mystical and financial gain by trial staff, leading to drop-out rates of 30% and the consequent halting of placental biopsy sampling in Benin. This paper explores the role of socio cultural beliefs related to placenta and identified additional factors contributing these rumours. METHODS: A qualitative comparative emergent-theory design was used to assess social factors related to trial implementation and uptake in the three countries. Data from participant observation, informal conversations, group discussions and interviews were triangulated and analysed with NVivo Qualitative Analysis software. RESULTS: Despite similar sociocultural beliefs about the sacred nature of the placenta in all three study countries, these beliefs did not affect participation rates in Burkina Faso and The Gambia and placenta-related rumours only emerged in Benin. Therefore, the presence of beliefs is not a sufficient condition to have generated placenta-selling fears. The rumours in Benin reflected the confluence of placenta-related beliefs and factors related to the implementation of the trial (including a catalysing adverse event and miscommunication during the informed consent procedure). Furthermore, distinct socio-political factors contributed to the emergence of rumours, including the historical distrust in governmental organizations and the tense relationship between some of the actors involved in the trial. CONCLUSION: Transdisciplinary social science research designs should accompany the implementation of the trial. The integration of multiple stakeholders' knowledge and involvement is required to define and solve upcoming barriers. PMID- 30442133 TI - Agrimonia procera exerts antimicrobial effects, modulates the expression of defensins and cytokines in colonocytes and increases the immune response in lipopolysaccharide-challenged piglets. AB - BACKGROUND: Because antibiotic use in livestock is assumed to contribute to the emerging public health crisis of antibiotic resistance, alternatives are required. Phytogenic additives are extensively studied due to their antibiotic properties. Components of Agrimonia species have been reported as candidate antimicrobials that possess antioxidative and anti-inflammatory properties. We studied the impact of Agrimonia procera (AP) on the growth of selected strains of gut bacteria, the effect of AP on the mRNA abundance of genes involved in inflammation and bacterial defense in a colon carcinoma cell line, the effect of AP in piglets challenged with lipopolysaccharides, and the effect of AP on the growth performance of healthy piglets. RESULTS: The in vitro growth rate of different bacteria strains was negatively affected by AP, especially in Pediococcus pentosaceus and all tested E. coli strains. Stimulation of Caco-2 cells with TNFalpha resulted in elevated mRNA expression of CXCL1, IL-8 and GPX2. After pretreatment of cells with AP, stimulation of Caco-2 cells with TNFalpha still resulted in elevated mRNA expression of CXCL1 and IL-8 at all measured points in time. However, mRNA expression in AP-pretreated cells was lower after 6 h and 24 h. In addition, expression of DEFB1 and GPX2 was significantly elevated after TNFalpha stimulation. In vivo, application of lipopolysaccharides induced significantly increased animal body temperatures. Piglets pretreated with AP prior to lipopolysaccharide application showed a faster and larger increase in body temperature than controls. In addition, piglets pretreated with AP appeared to release more TNFalpha than controls. In healthy piglets, AP treatment had no impact on growth performance parameters. Fecal dry matter and total plasma antioxidant capacity tended to be higher in piglets treated with AP than in control piglets (P = 0.055 and P = 0.087, respectively). CONCLUSIONS: AP has antimicrobial effects in vitro and stimulated the expression of proinflammatory cytokines in Caco-2 cells. The additive had no effect on growth in healthy piglets but increased the immune response in LPS-treated animals. In addition, AP appeared to have antioxidative effects in vivo. Therefore, AP merits testing as a future alternative to antibiotics in animal husbandry. PMID- 30442134 TI - Levels of human proteins in plasma associated with acute paediatric malaria. AB - BACKGROUND: The intimate interaction between the pathophysiology of the human host and the biology of the Plasmodium falciparum parasite results in a wide spectrum of disease outcomes in malaria. Development of severe disease is associated with a progressively augmented imbalance in pro- and anti-inflammatory responses to high parasite loads and sequestration of parasitized erythrocytes. Although these phenomena collectively constitute common denominators for the wide variety of discrete severe malaria manifestations, the mechanistic rationales behind discrepancies in outcome are poorly understood. Exploration of the human pathophysiological response by variations in protein profiles in plasma presents an excellent opportunity to increase the understanding. This is ultimately required for better prediction, prevention and treatment of malaria, which is essential for ongoing elimination and eradication efforts. RESULTS: An affinity proteomics approach was used to analyse 541 paediatric plasma samples collected from community controls and patients with mild or severe malaria in Rwanda. Protein profiles were generated with an antibody-based suspension bead array containing 255 antibodies targetting 115 human proteins. Here, 57 proteins were identified with significantly altered levels (adjusted p-values < 0.001) in patients with malaria compared to controls. From these, the 27 most significant proteins (adjusted p-values < 10-14) were selected for a stringent analysis approach. Here, 24 proteins showed elevated levels in malaria patients and included proteins involved in acute inflammatory response as well as cell adhesion. The remaining three proteins, also implicated in immune regulation and cellular adhesivity, displayed lower abundance in malaria patients. In addition, 37 proteins (adjusted p-values < 0.05) were identified with increased levels in patients with severe compared to mild malaria. This set includes, proteins involved in tissue remodelling and erythrocyte membrane proteins. Collectively, this approach has been successfully used to identify proteins both with known and unknown association with different stages of malaria. CONCLUSION: In this study, a high-throughput affinity proteomics approach was used to find protein profiles in plasma linked to P. falciparum infection and malaria disease progression. The proteins presented herein are mainly involved in inflammatory response, cellular adhesion and as constituents of erythrocyte membrane. These findings have a great potential to provide increased conceptual understanding of host-parasite interaction and malaria pathogenesis. PMID- 30442136 TI - Continuities and changes in spatial patterns of under-five mortality at the district level in India (1991-2011). AB - BACKGROUND: India has the largest number of under-five deaths globally, and large variations in under-five mortality persist between states and districts. Relationships between under-five mortality and numerous socioeconomic, development and environmental health factors have been explored at the national and state levels, but the possible spatial heterogeneity in these relationships has seldom been investigated at the district level. This study seeks to unravel local variation in key determinants of under-five mortality based on the 1991 and 2011 censuses. METHODS: Using geocoded district-level data from the last two census rounds (1991 and 2011) and ordinary least squares and geographically weighted regressions, we identify district-specific relationships between under five mortality rate and a series of determinants for two periods separated by 20 years (1986-1987 and 2006-2007). To identify spatial groupings of coefficients, we perform a cluster analysis based on t-values of the geographically weighted regression. RESULTS: The geographically weighted regression analysis shows that relationships between the under-five mortality rate and factors for socioeconomic, development, and environmental health factors vary spatially in terms of direction, strength, and extent when considering: female literacy and labor force participation; share of scheduled castes and scheduled tribes; access to electricity; safe water and sanitation; road infrastructure; and medical facilities. This spatial heterogeneity is accompanied by significant changes over time in the roles that these factors play in under-five mortality. Important local determinants of under-five mortality in 2011 were female literacy, female labor force participation, access to sanitation facilities and electricity; while the key local determinants in 1991 were road infrastructure, safe water, and medical facilities. We identify six different clusters based on geographically weighted regression coefficients that broadly encompass the same districts in both periods; but these clusters do not follow the regional boundaries suggested by the previous studies. In particular, the high mortality states of India that are often typically classified as high focus states were classified into three different clusters based on the relationship of the factors associated with under five mortality. CONCLUSION: This study demonstrates the utility of combining geographically weighted regression and cluster analyses as a methodological approach to study local-level variation in public health indicators, and it could be applied in any country using aggregate-level information from census or survey data. Identifying local predictors of under-five mortality is important for designing interventions in specific districts. Additional reduction in under-five mortality will only be possible with intervention programs designed at the local level, which take into consideration local level determinants of under-five mortality. PMID- 30442135 TI - Hybrid, metal oxide-peptide amphiphile micelles for molecular magnetic resonance imaging of atherosclerosis. AB - BACKGROUND: Atherosclerosis, a major source of cardiovascular disease, is asymptomatic for decades until the activation of thrombosis and the rupture of enlarged plaques, resulting in acute coronary syndromes and sudden cardiac arrest. Magnetic resonance imaging (MRI) is a noninvasive nuclear imaging technique to assess the degree of atherosclerotic plaque with high spatial resolution and excellent soft tissue contrast. However, MRI lacks sensitivity for preventive medicine, which limits the ability to observe the onset of vulnerable plaques. In this study, we engineered hybrid metal oxide-peptide amphiphile micelles (HMO-Ms) that combine an inorganic, magnetic iron oxide or manganese oxide inner core with organic, fibrin-targeting peptide amphiphiles, consisting of the sequence CREKA, for potential MRI imaging of thrombosis on atherosclerotic plaques. RESULTS: Hybrid metal oxide-peptide amphiphile micelles, consisting of an iron oxide (Fe-Ms) or manganese oxide (Mn-Ms) core with CREKA peptides, were self-assembled into 20-30 nm spherical nanoparticles, as confirmed by dynamic light scattering and transmission electron microscopy. These hybrid nanoparticles were found to be biocompatible with human aortic endothelial cells in vitro, and HMO-Ms bound to human clots three to five times more efficiently than its non targeted counterparts. Relaxivity studies showed ultra-high r2 value of 457 mM-1 s-1 and r1 value of 0.48 mM-1 s-1 for Fe-Ms and Mn-Ms, respectively. In vitro, MR imaging studies demonstrated the targeting capability of CREKA-functionalized hybrid nanoparticles with twofold enhancement of MR signals. CONCLUSION: This novel hybrid class of MR agents has potential as a non-invasive imaging method that specifically detects thrombosis during the pathogenesis of atherosclerosis. PMID- 30442138 TI - Patients' perception of the information security management in health centers: the role of organizational and human factors. AB - BACKGROUND: Researchers paid little attention to understanding the association of organizational and human factors with patients' perceived security in the context of health organizations. This study aims to address numerous gaps in this context. Patients' perceptions about employees' training on security issues, monitoring on security issues, ethics, physical & technical protection and trust in hospitals were identified as organizational and human factors. METHODS: After the development of 12 hypotheses, a quantitative, cross-sectional, self administered survey method was applied to collect data in 9 hospitals in Iran. After the collection of 382 usable questionnaires, the partial least square structural modeling was applied to examine the hypotheses and it was found that 11 hypotheses were empirically supported. RESULTS: The results suggest that patients' trust in hospitals can significantly predict their perceived security but no significant associations were found between patients' physical protection mechanisms in the hospital and their perceived information security in a hospital. We also found that patients' perceptions about the physical protection mechanism of a hospital can significantly predict their trust in hospitals which is a novel finding by this research. CONCLUSIONS: The findings imply that hospitals should formulate policies to improve patients' perception about such factors, which ultimately lead to their perceived security. PMID- 30442137 TI - Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design. AB - BACKGROUND: Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline. METHODS: We developed the guideline in seven overlapping stages: 1) Building on prior research to inform the need for a guideline; 2) A scoping literature review to inform future stages; 3) Drafting the first checklist version involving an External Expert Panel; 4) A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders; 5) A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document; 6) Refining and finalising the checklist; and 7) Writing-up and dissemination of the E&E document. The CONSORT Executive Group oversaw the entire development process. RESULTS: Delphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies. CONCLUSIONS: We hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements. PMID- 30442139 TI - Peer teacher training for health professional students: a systematic review of formal programs. AB - BACKGROUND: Skills in peer teaching, assessment and feedback are documented internationally as required graduate attributes for health professional students, placing emphasis on universities to prepare health professional graduates with teaching skills. The aim of this systematic review was to determine the rational, design, content and evaluation of student peer teacher training skills programs across the health professions. METHODS: In October 2017, a search was conducted of five databases (Pubmed, Embase, CINAHL, ERIC and Cochrane Collection) using combinations of key search terms: 'Student as teacher', 'near-peer teaching', 'student teacher', 'peer teacher', 'peer-to-peer', 'undergraduate', 'medical education', 'curriculum', 'program', 'training', 'allied health', 'health science', 'pharmacy', 'nurse', and 'medicine', with results restricted to articles published in English within the decade. Articles were excluded if they were not original research, focused on a teaching approach other than peer assisted learning or teaching, did not adequately describe a student teacher training component of at least 3 hrs duration, or addressed only clinical skills training and not teaching skills training. RESULTS: The two authors independently assessed 42 full-text articles for eligibility, with 19 articles satisfying criteria for inclusion. Dominating results were uni-disciplinary, faculty-led, non-mandated programs, targeting participants in senior years of training. Medicine was the dominant profession, with an obvious underrepresentation of the other health professions. Common program content included the foundations of education theory, teaching methods and techniques, and providing feedback. Summary and comparison of program design is restricted by gaps and inconsistencies in reporting, while the evaluation of programs remains largely subjective. CONCLUSIONS: Teaching is increasingly recognised as a core professional skill across the health workforce, with expectations to teach peers and colleagues, within and across professional disciplines, as well as to educate patients. Students, faculty and institutes may benefit from training programs being designed for implementation in any health profession; and further to this, implemented within an interprofessionally context. Consistent reporting of teacher training programs, and objective methods of evaluation would enable more in-depth investigation. PMID- 30442140 TI - Can high-cost spending in the community signal admission to hospital? A dynamic modeling study for urgent and elective cardiovascular patients. AB - BACKGROUND: Much of the research on high-cost patients in healthcare has taken a static approach to studying what is actually a dynamic process. High-cost patients often utilize services across multiple sectors along care pathways, but due to the cross-sectional nature of many study designs, we lack a clear understanding of the temporal relationship between high-cost spending in community and acute care. Studying care trajectories for high cost patients with cardiovascular disease (CVD) can shed light on the dynamic interplay between community-based and acute care along the care continuum, and provide information about signals in community care that may indicate future elective and urgent hospitalizations. METHODS: Using linked health administrative data in Ontario, Canada, 74,683 incident cases with cardiovascular disease were identified between the years 2009 and 2011. Patients were followed for 36 months (total study duration 2009-2014) until the first urgent or elective admission to hospital for a heart-related condition. We used an extended Cox survival model with competing risks to study the relationship between high-cost spending in community care with two mutually exclusive outcomes: urgent or elective hospitalizations. RESULTS: Elective hospitalizations were most clearly signaled by a high-cost utilization of community-based specialist services in the month prior to hospital admission (hazard ratio 9.074, p < 0.0001), while urgent hospitalizations were signaled by high cost usage across all community-based sectors of care (from general practitioner & specialist visits, home care, laboratory services and emergency department (ED) usage). Urgent hospitalizations were most clearly signaled by high cost usage in ED in the month prior to hospital admission (hazard ratio 2.563, p < 0.0001). CONCLUSION: By studying the dynamic nature of patient care trajectories, we may use community-based spending patterns as signals in the system that can point to future and elective hospitalizations for CVD. These community-based spending signals may be useful for identifying opportunities for intervention along the care trajectory, particularly for urgent CVD patients for whom future hospitalizations are difficult to anticipate. PMID- 30442141 TI - Self-recordings of upper arm elevation during cleaning - comparison between analyses using a simplified reference posture and a standard reference posture. AB - BACKGROUND: To reduce ergonomic risk factors in terms of awkward and constrained postures and high velocities, it is important to perform adequate risk assessments. Technical methods provide objective measures of physical workload. These methods have so far mainly been used by researchers. However, if written instructions how to apply the sensors and how to adopt the reference posture are provided, together with triaxial accelerometers, it may be possible for employees to record their own physical workload. The exposure in terms of e.g. upper arm elevations could then easily be assessed for all workers in a workplace. The main aims of this study were: 1) to compare analyses for self-recording of upper arm elevation during work using a simplified reference posture versus using a standard reference posture, and 2) to compare the two reference postures. METHODS: Twenty-eight cleaners attached an accelerometer to their dominant upper arm and adopted a simplified reference according to a written instruction. They were thereafter instructed by a researcher to adopt a standard reference. Upper arm elevations were recorded for 2 or 3 days. Each recording was analysed twice; relative to the simplified reference posture and relative to the standard reference posture. The group means of the differences in recorded upper arm elevations between simplified and standard reference analyses were assessed using Wilcoxon signed ranks test. Furthermore, we calculated the group mean of the differences between the simplified reference posture and the standard reference posture. RESULTS: For arm elevation during work (50th percentile), the group mean of the differences between the two analyses was 0.2 degrees (range -7 - 10 degrees ). The group mean of the differences between the two references was 9 degrees (range 1 - 21 degrees ). The subjects were able to follow the instructions in the protocol and performed self-recording of upper arm elevation and velocity. CONCLUSIONS: The small difference between the two analyses indicates that recordings performed by employees themselves are comparable, on a group level, with those performed by researchers. Self-recordings in combination with action levels would provide employers with a method for risk assessment as a solid basis for prevention of work-related musculoskeletal disorders. PMID- 30442142 TI - Metformin causes cancer cell death through downregulation of p53-dependent differentiated embryo chondrocyte 1. AB - BACKGROUND: Metformin is the most commonly used first-line medicine for type II diabetes mellitus. Acting via AMP-activated protein kinase, it has been used for more than 60 years and has an outstanding safety record. Metformin also offers protection against cancer, but its precise mechanisms remain unclear. METHODS: We first examined the cytotoxic effects of metformin in the HeLa human cervical carcinoma and ZR-75-1 breast cancer cell lines using assays of cell viability, cleaved poly-ADP-ribose polymerase, and Annexin V-fluorescein isothiocyanate apoptosis, as well as flow cytometric analyses of the cell cycle profile and reactive oxygen species (ROS). We later clarified the effect of metformin on p53 protein stability using transient transfection and cycloheximide chase analyses. RESULTS: We observed that metformin represses cell cycle progression, thereby inducing subG1 populations, and had induced apoptosis through downregulation of p53 protein and a target gene, differentiated embryo chondrocyte 1 (DEC1). In addition, metformin increased intracellular ROS levels, but N-acetyl cysteine, a ROS scavenger, failed to suppress metformin-induced apoptosis. Further results showed that metformin disrupted the electron transport chain and collapsed the mitochondrial membrane potential, which may be the cause of the elevated ROS levels. Examination of the mechanisms underlying metformin-induced HeLa cell death revealed that reduced stability of p53 in metformin-treated cells leads to decreases in DEC1 and induction of apoptosis. CONCLUSION: The involvement of DEC1 provides new insight into the positive or negative functional roles of p53 in the metformin-induced cytotoxicity in tumor cells. PMID- 30442143 TI - Real time PCR detection of common CYP2D6 genetic variants and its application in a Karen population study. AB - BACKGROUND: Plasmodium vivax malaria is characterized by relapses arising from the hypnozoite stages in the liver. The only currently registered drug for radical treatment to prevent relapse is primaquine. Primaquine, a prodrug, requires metabolism through the liver cytochrome CYP2D6 isoenzyme to its active metabolite. Mutations in the CYP2D6 gene may thus affect primaquine efficacy. A SNPs genotyping technique was developed to characterize the CYP2D6 genetic variants and tested this in the patients with Plasmodium vivax infection collected in a Karen population on the Thailand-Myanmar border, where P. vivax malaria is endemic. METHODS: Direct sequencing of PCR-reamplified products (DSP) was used to uncover exonic CYP2D6 sequence variations. Subsequently, an allele specific oligonucleotide probe real-time SNPs genotyping (ASO) assay was developed for rapid detection of the four clinically relevant CYP2D6 variants occurring in this population. These two in-house developed assays were used to genotype CYP2D6 mutations in blood samples obtained from 70 Karen adults. RESULTS: Results showed a high degree of concordance between the DSP and ASO methods. Six CYP2D6 point mutations were identified within the Karen population: C100T, C1039T, G1661C, G1846A, C2850T and G4180C, at frequencies of 0.43, 0.43, 0.76, 0.02, 0.32 and 0.76, respectively. The CYP2D6*2, *4, *5, *10 and *36 allelic frequencies were 0.33, 0.02, 0.03, 0.40 and 0.01, respectively. Alleles conferring an intermediate CYP2D6 metabolizer phenotype comprised 46% of the total number of alleles. CONCLUSION: The newly developed ASO assay is a reliable and rapid tool for large-scale CYP2D6 genotyping. The high frequency of the CYP2D6*10 allele in the Karen population warrants further assessment of its association with the radical curative efficacy of primaquine. PMID- 30442144 TI - Four-octyl itaconate activates Keap1-Nrf2 signaling to protect neuronal cells from hydrogen peroxide. AB - BACKGROUND: Four-octyl itaconate (OI), the itaconate's cell-permeable derivative, can activate Nrf2 signaling via alkylation of Keap1 at its cysteine residues. The current study tested the potential neuroprotective function of OI in hydrogen peroxide (H2O2)-treated neuronal cells. METHODS: SH-SY5Y neuronal cells and epigenetically de-repressed (by TSA treatment) primary murine neurons were treated with OI and/or H2O2. Nrf2 pathway genes were examined by Western blotting assay and real-time quantitative PCR analysis. Neuronal cell death was tested by the LDH and trypan blue staining assays. Apoptosis was tested by TUNEL and Annexin V assays. RESULTS: In SH-SY5Y neuronal cells and primary murine neurons, OI activated Nrf2 signaling, causing Keap1-Nrf2 disassociation, Nrf2 protein stabilization and nuclear translocation, as well as expression of Nrf2-regulated genes (HO1, NQO1 and GCLC) and ninjurin2 (Ninj2). Functional studies showed that OI attenuated H2O2-induced reactive oxygen species (ROS) production, lipid peroxidation and DNA damage as well as neuronal cell death and apoptosis. shRNA mediated knockdown, or CRISPR/Cas9-induced knockout of Nrf2 almost abolished OI induced neuroprotection against H2O2. Keap1 is the primary target of OI. Keap1 knockout by CRISPR/Cas9 method mimicked and abolished OI-induced actions in SH SY5Y cells. Introduction of a Cys151S mutant Keap1 in SH-SY5Y cells reversed OI induced Nrf2 activation and anti-H2O2 neuroprotection. CONCLUSIONS: OI activates Keap1-Nrf2 signaling to protect SH-SY5Y cells and epigenetically de-repressed primary neurons from H2O2 in vitro. PMID- 30442145 TI - Greek students' attitudes, perception and knowledge regarding generic medicines in times of economic crisis: a cross-sectional study. AB - BACKGROUND: The penetration of generic medicines in the pharmaceutical market is influenced, among others, by the consumer's attitude upon them. The attitude of students in health management and recent alumni is particularly important, as they constitute tomorrow's policymakers. The aim of our study was to assess their attitude, perception and knowledge towards generic medicines. METHODS: A cross sectional study was undertaken, involving students in Health Management and recent alumni. The ATtitude TOwards GENerics (ATTOGEN) validated questionnaire was used, which consists of 18 items, yielding 6 scales (trust, state audit, knowledge, drug quality, drug substitution and fiscal impact), with all item responses expressed on a 5-point Likert scale and higher scores denoting greater disagreement. Correlation coefficients were computed and independent sample tests were performed using non-parametrical statistical methods. RESULTS: A total of 1402 students were interviewed, with a female predominance (62.88%). The mean (SD) scores for the six scales of the ATTOGEN questionnaire were: Trust: 2.877 (0.940), State audit: 3.251 (0.967), Knowledge: 1.537 (0.688), Drug quality: 2.708 (0.971), Drug substitution: 3.828 (1.127) and Fiscal impact: 2.299 (0.860). Trust over generics was statistically significantly associated with all ATTOGEN scales (all p < 0.001). In addition, the increased level of knowledge about generics was associated with recognition of the generic medicines' quality equivalence (p < 0.001) and positive fiscal impact (p = 0.018). Pharmacists declared having a superior knowledge of generic medicines, being more satisfied with the information they receive about them and strongly believing in drug substitution (p < 0.001). Comparatively to other professionals, pharmacists also indicated substantial differences between branded and generic medicines more often (p < 0.001). They also argued to a greater extent that generic medicines were invented and promoted to resolve the financial crisis of social security institutions at the expense of citizens (p < 0.001). CONCLUSIONS: This study demonstrated a mixed attitude of students regarding generic medicines. Trust and knowledge emerged as key factors shaping the students' attitude towards generics. Among students, pharmacists exhibited a distinct response pattern. This study underlines the importance of addressing and correcting health management students' misbeliefs about generics' quality and utility. PMID- 30442146 TI - Decisions in health technology assessment: should we speak with one voice? AB - Decisions regarding the regulation of individual medicines differ from country to country. In the case of Relenza, Mulinari and Davis (Health Res Policy Syst 15:93, 2017) have suggested that these inconsistencies are primarily due to processes, statistical methodologies and technical capacity varying between regulatory agencies. They go on to name specific individuals involved in the evaluation of this anti-influenza medicine and imply that differences in the judgements of these individuals has affected public policy concerning the market access of this medicine.This Commentary argues that what may appear as inconsistent decision-making may in fact be due to differences in the applicability of the evidence base to the local population and health system for which each regulator has responsibility. If health technology assessors are providing nuanced judgements on the effectiveness of a medicine for the local population, differences in regulation and reimbursement decisions are to be expected. PMID- 30442148 TI - Targeted retail coupons influence category-level food purchases over 2-years. AB - BACKGROUND: Targeted coupons strongly influence purchasing behavior and may represent an innovative approach for improving dietary behaviors. METHODS: The retail analytics firm, Dunnhumby, provided secondary retail data containing grocery transactions, targeted coupon exposures, and coupon use for 2500 households over 2-years. The USDA Quarterly At-Home Food Purchasing Database was used to categorize individual foods into 52 categories and combined into 12 food groups. Mixed effects linear models estimated the difference-in-difference effects of coupon exposure on category-level purchase rate/wk. pre- and post campaign; models also tested effect modification by food category. RESULTS: Category-level food purchases significantly increased post-campaign. Mean (SD) food purchases/wk. Among exposed households (17.34 (13.08) units/wk) vs. unexposed households (3.75 (4.59) units/wk) were higher (p < 0.001). Difference in-difference effects of coupon exposure showed a higher increase in purchase rate among exposed vs. unexposed households (5.73 vs. 0.67, p < 0.001). Food category significantly modified the association between coupon exposure and coupon campaign. Category-level purchase rate among exposed vs. unexposed households was relatively higher in less healthful (e.g. convenience foods) vs. more healthful categories (e.g. nuts) with a 1.17 unit/wk. increase in convenience foods purchase (p < 0.001) vs. a 0.03 unit/wk. increase in nuts (p < 0.001). Exploratory analyses suggested that price elasticity of food categories for targeted coupons (1.02-2.81) was higher than previous estimates for untargeted coupons. CONCLUSION: Across food categories, coupon exposure increased category-level purchase rate, with a relatively larger effect size for less healthful than more healthful categories. Promising results from this preliminary study suggest that experimental research is warranted to determine whether targeting with the explicit purpose of improving dietary quality can more effectively influence diet, and whether it can do so more cost effectively. PMID- 30442149 TI - A multiplex xTAG assay for the simultaneous detection of five chicken immunosuppressive viruses. AB - BACKGROUND: Chicken anemia virus (CAV), avian reovirus (ARV), infectious bursal disease virus (IBDV), Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) all cause immunosuppressive disease in birds through vertical or horizontal transmission. Mixed infections with these immunosuppressive pathogens lead to atypical clinical signs and obstruct accurate diagnoses and epidemiological investigations. Therefore, it is essential to develop a high-throughput assay for the simultaneous detection of these immunosuppressive viruses with high specificity and sensitivity. The aim of this study was to establish a novel method using a RT-PCR assay combined with fluorescence labeled polystyrene bead microarray (multiplex xTAG assay) to detect single or mixed viral infections. RESULTS: The results showed that the established xTAG assay had no nonspecific reactions with avian influenza virus (AIV), infectious bronchitis virus (IBV), newcastle disease virus (NDV), infectious laryngotracheitis virus (ILTV), Mycoplasma gallisepticum (MG) and Mycoplasma synoviae (MS). The limit of detection was 1.0 * 103 copies/MUL for IBDV and 1.0 * 102copies/MUL for the other four viruses. Ninety field samples were tested and the results were confirmed using conventional RT-PCR methods. The detection results of these two methods were 100% consistent. The established multiplex xTAG assay allows a high throughput and simultaneous detection of five chicken immunosuppressive viruses. CONCLUSION: The multiplex xTAG assay has been showed to be an additional tool for molecular epidemiology studies of five chicken immunosuppressive viruses in the poultry industry. PMID- 30442147 TI - Platycodin D inhibits platelet function and thrombus formation through inducing internalization of platelet glycoprotein receptors. AB - BACKGROUND: Platycodin D (PD) is one of the major bioactive components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties, such as antiviral, anti-inflammatory, and anti-cancer activities. However, whether it affects platelet function remains unclear. This study aims to evaluate the role of PD in platelet function and thrombus formation. METHODS: Platelets were treated with PD followed by measuring platelet aggregation, activation, spreading, clot retraction, expression of glycoprotein receptors. Moreover, mice platelets were treated with PD and infused into wild type mice for analysis of in vivo hemostasis and arterial thrombosis. RESULTS: Platycodin D treatment significantly inhibited platelet aggregation in response to collagen, ADP, arachidonic acid and epinephrine, reduced platelet P-selectin expression, integrin alphaIIbbeta3 activation, spreading on fibrinogen as well as clot retraction, accompanied with decreased phosphorylation of Syk and PLCgamma2 in collagen-related peptide or thrombin-stimulated platelets. Moreover, PD treated mice platelets presented significantly impaired in vivo hemostasis and arterial thrombus formation. Interestingly, PD induced internalization of glycoprotein receptors alphaIIbbeta3, GPIbalpha and GPVI. However, GM6001, cytochalasin D, BAPTA-AM and wortmannin did not prevent PD-induced internalization of receptors. CONCLUSIONS: Our study demonstrates that PD inhibits platelet aggregation, activation and impairs hemostasis and arterial thrombosis, suggesting it might be a potent anti-thrombotic drug. PMID- 30442150 TI - Developing a model for integrating sexual and reproductive health services with HIV prevention and care in KwaZulu-Natal, South Africa. AB - BACKGROUND: There are few rigorous studies evaluating the benefits of vertical versus integrated delivery of healthcare services, and limited published studies describing conceptual models of integration at service-delivery level in public healthcare facilities. This article seeks to fill this gap, by describing the development of a district-based model for integrating sexual and reproductive health (SRH) and HIV services in KwaZulu-Natal, South Africa. METHODS: Baseline data were collected from seven urban public healthcare facilities through client and provider interviews, and a facility inventory was completed to assess current service integration practices. Feedback sessions were held with health providers from participating facilities to share data collected and explore appropriate integration scenarios. A conceptual model of potential service integration was then designed, and subsequently implemented and evaluated in the research sites. RESULTS: Key principles of the model included a focus on health system strengthening and strong community input and involvement. The model was designed primarily to support the integration of family planning into HIV services, and included measures to improve client and commodity monitoring; capacity building through training and mentorship; and a 'health navigation' strategy to strengthen referrals within and between public healthcare facilities. Endline evaluation data were collected in the same facilities following implementation of the model. CONCLUSIONS: This manuscript demonstrates the utility of the conceptual model. It shows that service integration can be accomplished in a phased manner with support of community and healthcare providers. In addition, local context must be taken into account and the components of the model should be flexible to suit the needs of the health system. PMID- 30442151 TI - The role of imaging in the skeletal involvement of mucopolysaccharidoses. AB - This article discusses the role of imaging modalities including radiography, multi-detector computed tomography, magnetic resonance imaging, and ultrasound in diagnosing and monitoring skeletal abnormalities in mucopolysaccharidoses (MPS). The advantages and disadvantages of these different imaging tools will be discussed, along with their feasibility in this class of patients. As the musculoskeletal involvement is common to all MPS and is one of the main reasons for seeking medical attention, an increased awareness among paediatricians, rheumatologists, orthopaedists, radiologists, and other musculoskeletal specialists on the possible spectrum of abnormalities observed could facilitate a timely diagnosis, an appropriate severity evaluation, and better management. PMID- 30442152 TI - Varicella zoster virus differentially alters morphology and suppresses proinflammatory cytokines in primary human spinal cord and hippocampal astrocytes. AB - BACKGROUND: Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that produces varicella and zoster. VZV can infect multiple cell types in the spinal cord and brain, including astrocytes, producing myelopathy and encephalopathy. While studies of VZV-astrocyte interactions are sparse, a recent report showed that quiescent primary human spinal cord astrocytes (qHA-sps) did not appear activated morphologically during VZV infection. Since astrocytes play a critical role in host defenses during viral infections of the central nervous system, we examined the cytokine responses of qHA-sps and quiescent primary human hippocampal astrocytes (qHA-hps) to VZV infection in vitro, as well as the ability of conditioned supernatant to recruit immune cells. METHODS: At 3 days post-infection, mock- and VZV-infected qHA-sps and qHA-hps were examined for morphological changes by immunofluorescence antibody assay using antibodies directed against glial fibrillary acidic protein and VZV. Conditioned supernatants were analyzed for proinflammatory cytokines [interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma, and tumor necrosis factor-alpha] using the Meso Scale Discovery multiplex ELISA platform. Finally, the ability of conditioned supernatants to attract peripheral blood mononuclear cells (PBMCs) was determined using a chemotaxis assay. Quiescent primary human perineurial cells (qHPNCs) served as a control for VZV-induced cytokine production and PBMC migration. To confirm that the astrocytes have the ability to increase cytokine secretion, qHA-sps and qHA-hps were treated with IL 1beta and examined for morphological changes and IL-6 secretion. RESULTS: VZV infected qHA-sps displayed extensive cellular processes, whereas VZV-infected qHA hps became swollen and clustered together. Astrocytes had the capacity to secrete IL-6 in response to IL-1beta. Compared to mock-infected cells, VZV-infected qHA sps showed significantly reduced secretion of IL-2, IL-4, IL-6, IL-12p70, and IL 13, while VZV-infected qHA-hps showed significantly reduced IL-8 secretion. In contrast, levels of all 10 cytokines examined were significantly increased in VZV infected qHPNCs. Consistent with these results, conditioned supernatant from VZV infected qHPNCs, but not that from VZV-infected qHA-sps and qHA-hps, recruited PBMCs. CONCLUSIONS: VZV-infected qHA-sps and qHA-hps have distinct morphological alterations and patterns of proinflammatory cytokine suppression that could contribute to ineffective viral clearance in VZV myelopathy and encephalopathy, respectively. PMID- 30442153 TI - Ca2+-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling. AB - BACKGROUND: The intermediate-conductance Ca2+-activated K+ channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer's disease (AD). METHODS: KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1-/-/APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca2+ level in beta-amyloid (Abeta) induced reactive astrocytes in vitro. RESULTS: KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Abeta stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca2+ entry (SOCE) through an interaction with the Ca2+ channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca2+ overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1-/-/APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1-/-/APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1-/-/APP/PS1 mice. CONCLUSIONS: Overall, these results suggest that KCa3.1 is involved in the regulation of Ca2+ homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss. PMID- 30442154 TI - Machine learning algorithms for activity recognition in ambulant children and adolescents with cerebral palsy. AB - BACKGROUND: Cerebral palsy (CP) is the most common physical disability among children (2.5 to 3.6 cases per 1000 live births). Inadequate physical activity (PA) is a major problem effecting the health and well-being of children with CP. Practical, yet accurate measures of PA are needed to evaluate the effectiveness of surgical and therapy-based interventions to increase PA. Accelerometer-based motion sensors have become the standard for objectively measuring PA in children and adolescents; however, current methods for estimating physical activity intensity in children with CP are associated with significant error and may dramatically underestimate HPA in children with more severe mobility limitations. Machine learning (ML) models that first classify the PA type and then predict PA intensity or energy expenditure using activity specific regression equations may be more accurate than standalone regression models. However, the feasibility and validity of ML methods has not been explored in youth with CP. Therefore, the purpose of this study was to develop and test ML models for the automatic identification of PA type in ambulant children with CP. METHODS: Twenty two children and adolescents (mean age: 12.8 +/- 2.9 y) with CP classified at GMFCS Levels I to III completed 7 activity trials while wearing an ActiGraph GT3X+ accelerometer on the hip and wrist. Trials were categorised as sedentary (SED), standing utilitarian movements (SUM), comfortable walking (CW), and brisk walking (BW). Random forest (RF), support vector machine (SVM), and binary decision tree (BDT) classifiers were trained with features extracted from the vector magnitude (VM) of the raw acceleration signal using 10 s non-overlapping windows. Performance was evaluated using leave-one-subject out cross validation. RESULTS: SVM (82.0-89.0%) and RF (82.6-88.8%) provided significantly better classification accuracy than BDT (76.1-86.2%). Hip (82.7-85.5%) and wrist (76.1-82.6%) classifiers exhibited comparable prediction accuracy, while the combined hip and wrist (86.2-89.0%) classifiers achieved the best overall performance. For all classifiers, recognition accuracy was excellent for SED (94.1-97.9%), good to excellent for SUM (74.0-96.6%) and brisk walking (71.5-86.0%), and modest for comfortable walking (47.6-70.4%). When comfortable and brisk walking were combined into a single walking class, recognition accuracy ranged from 90.3 to 96.5%. CONCLUSIONS: ML methods provided acceptable classification accuracy for detection of a range of activities commonly performed by ambulatory children with CP. The resultant models can help clinicians more effectively monitor bouts of brisk walking in the community. The results indicate that 2-step models that first classify PA type and then predict energy expenditure using activity specific regression equations are worthy of exploration in this patient group. PMID- 30442155 TI - Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe: methodological uncertainties. AB - BACKGROUND: To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. METHODS: A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. RESULTS: 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1.4 (0.7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one third (50/159) did not use randomisation, half the trials (75/159) were open label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP - mean(SD) 190.5 (202.5) - was lower than that required for the qualification of clinically-relevant adverse reactions. CONCLUSIONS: The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base. PMID- 30442156 TI - Newborn screening in mucopolysaccharidoses. AB - Newborn screening (NBS) methods and therapeutic options have become increasingly available for mucopolysaccharidoses (MPS), and there is a clear evidence that early intervention significantly improves the outcome. It is recommended that mucopolysaccharidosis type I (MPS I) is included in the US newborn screening panel, and this is currently underway in some NBS programs in the world. The key factors in recommending MPS I for inclusion in NBS are the strongly improved efficacy of early-onset therapy and the improved performance of screening tests. Two studies on MPS I screening have been conducted in Italy. In the Tuscany Umbria pilot NBS, eight infants were confirmed positive, and alpha-L-iduronidase (IDUA) gene molecular analysis showed that seven had either homozygosity or compound heterozygosity for pseudodeficiency alleles. p.Ala79Thr and p.His82Gln changes were demonstrated in four and three infants, respectively, six of which were of African origin. Only one infant had transitory elevation of urine glycosaminoglycans (GAGs) (by quantitative analysis) and she is in follow-up at the time of writing. In the North East Italy experience, there was one affected newborn for 66,491 screened. In this patient treatment started at 1 month of age. In the North East Italy experience the incidence of pseudodeficiency was very high (1:6044), with a high incidence of pseudodeficiency from patients of African origin.A significant problem that is encountered in the follow-up of infants with abnormal NBS and variants of unknown significance (VUS) on molecular analysis results relates to those who cannot be positively identified as either affected or unaffected. Long-term follow-up of these infants, and of those detected with late-onset disorders, will be essential to document the true risks and benefits of NBS. The availability of treatments in MPS II, IVA, VI, and VII with a better clinical outcome when started early in life, and the availability of a combined multiple assay for MPS, may be a prerequisite for new pilot NBS studies in the near future. PMID- 30442157 TI - Designing and implementing two facilitation interventions within the 'Facilitating Implementation of Research Evidence (FIRE)' study: a qualitative analysis from an external facilitators' perspective. AB - BACKGROUND: The 'Facilitating Implementation of Research Evidence' study found no significant differences between sites that received two types of facilitation support and those that did not on the primary outcome of documented compliance with guideline recommendations. Process evaluation highlighted factors that influenced local, internal facilitators' ability to enact the roles as envisaged. In this paper, the external facilitators responsible for designing and delivering the two types of facilitation intervention analyse why the interventions proved difficult to implement as expected, including the challenge of balancing fidelity and adaptation. METHODS: Qualitative data sources included notes from monthly internal-external facilitator teleconference meetings, from closing events for the two facilitation interventions and summary data analyses from repeated interviews with 16 internal facilitators. Deductive and inductive data analysis was led by an independent researcher to evaluate how facilitation in practice compared to the logic pathways designed to guide fidelity in the delivery of the interventions. RESULTS: The planned facilitation interventions did not work as predicted. Difficulties were encountered in each of the five elements of the logic pathway: recruitment and selection of appropriate internal facilitators, preparation for the role, ability to apply facilitation knowledge and skills at a local level, support and mentorship from external facilitators via monthly teleconferences, working collaboratively and enabling colleagues to implement guideline recommendations. Moreover, problems were cumulative and created tensions for the external facilitators in terms of balancing the logic pathway with a more real-world, flexible and iterative approach to facilitation. CONCLUSION: Evaluating an intervention that is fluid and dynamic within the methodology of a randomised controlled trial is complex and challenging. At a practical level, relational aspects of facilitation are critically important. It is essential to recruit and retain individuals with the appropriate set of skills and characteristics, explicit support from managerial leaders and accessible mentorship from more experienced facilitators. At a methodological level, there is a need for attention to the balance between fidelity and adaptation of interventions. For future studies, we suggest a theoretical approach to fidelity, with a focus on mechanisms, informed by prospective use of process evaluation data and more detailed investigation of the context-facilitation dynamic. PMID- 30442158 TI - Transcranial direct current stimulation (tDCS) for upper limb rehabilitation after stroke: future directions. AB - Transcranial Direct Current Stimulation (tDCS) is a potentially useful tool to improve upper limb rehabilitation outcomes after stroke, although its effects in this regard have shown to be limited so far. Additional increases in effectiveness of tDCS in upper limb rehabilitation after stroke may for example be achieved by (1) applying a more focal stimulation approach like high definition tDCS (HD-tDCS), (2) involving functional imaging techniques during stimulation to identify target areas more exactly, (3) applying tDCS during Electroencephalography (EEG) (EEG-tDCS), (4) focusing on an effective upper limb rehabilitation strategy as an effective base treatment after stroke. Perhaps going even beyond the application of tDCS and applying alternative stimulation techniques such as transcranial Alternating Current Stimulation (tACS) or transcranial Random Noise Stimulation (tRNS) will further increase effectiveness of upper limb rehabilitation after stroke. PMID- 30442159 TI - Neutrophil to lymphocyte ratio predicts intracranial hemorrhage after endovascular thrombectomy in acute ischemic stroke. AB - BACKGROUND: The development of intracranial hemorrhage (ICH) in acute ischemic stroke is associated with a higher neutrophil to lymphocyte ratio (NLR) in peripheral blood. Here, we studied whether the predictive value of NLR at admission also translates into the occurrence of hemorrhagic complications and poor functional outcome after endovascular treatment (EVT). METHODS: We performed a retrospective analysis of consecutive patients with anterior circulation ischemic stroke who underwent EVT at a tertiary care center from 2012 to 2016. Follow-up scans were examined for non-procedural ICH and scored according to the Heidelberg Bleeding Classification. Demographic, clinical, and laboratory data were correlated with the occurrence of non-procedural ICH. RESULTS: We identified 187 patients with a median age of 74 years (interquartile range [IQR] 60-81) and a median baseline National Institutes of Health Stroke scale (NIHSS) score of 18 (IQR 13-22). A bridging therapy with recombinant tissue-plasminogen activator (rt PA) was performed in 133 (71%). Of the 31 patients with non-procedural ICH (16.6%), 13 (41.9%) were symptomatic. Patients with ICH more commonly had a worse outcome at 3 months (p = 0.049), and were characterized by a lower body mass index, more frequent presence of tandem occlusions, higher NLR, larger intracranial thrombus, and prolonged rt-PA and groin puncture times. In a multivariate analysis, higher admission NLR was independently associated with ICH (OR 1.09 per unit increase, 95% CI (1.00-1.20, p = 0.040). The optimal cutoff value of NLR that best distinguished the development of ICH was 3.89. CONCLUSIONS: NLR is an independent predictor for the development of ICH after EVT. Further studies are needed to investigate the role of the immune system in hemorrhagic complications following EVT, and confirm the value of NLR as a potential biomarker. PMID- 30442160 TI - Anesthesiological risks in mucopolysaccharidoses. AB - BACKGROUND: Patients suffering from mucopolysaccharidosis are among the most complex from the anesthesiological point of view, especially regarding the management of the airway. The evidence base for anesthesia management is often limited to case reports and small case series. AIMS: To identify useful information about experience with each subtype of mucopolysaccharidosis reported in the literature and propose a guide on the best options for airway management to the anesthesiologists who take care of these patients. METHODS: A query of the PubMed database specific for "anesthesia" and "mucopolysaccharidosis" and a further query specific for "mucopolysaccharidosis and difficult airway management" was conducted. We looked for those items that offered practical guidance to anesthesiological management. We did not exclude case reports, especially those that reported a specific technique, because of their practical suggestions. RESULTS: We identified 15 reviews, 17 retrospective case series, 5 prospective studies, and 28 case reports that focused on airway managements in anesthesia or had practical suggestions for preoperative evaluation and risk assessment. An accurate preoperative evaluation and the need for an experienced team are emphasized in all the reviewed articles and for each type of mucopolysaccharidosis. Many suggestions on how to plan the perioperative period have been highlighted. Insertion of a laryngeal mask airway generally improves ventilation and facilitates intubation with a fiberoptic bronchoscope. Furthermore, the videolaryngoscope is very useful in making intubation easier and facilitating bronchoscope passage. CONCLUSIONS: Patients with mucopolysaccharidosis are at high risk for anesthesia-related complications and require a high level of attention. However, a multidisciplinary approach, combined with expertise in the use of new techniques and new devices for airway management, makes anesthesiological management safer. Further research with prospective studies would be useful. PMID- 30442162 TI - Mucopolysaccharidoses: early diagnostic signs in infants and children. AB - Mucopolysaccharidoses (MPS) comprise a group of lysosomal disorders that are characterized by progressive, systemic clinical manifestations and a coarse phenotype. The different types, having clinical, biochemical, and genetic heterogeneity, share key clinical features in varying combinations, including joint and skeletal dysplasia, coarse facial features, corneal clouding, inguinal or abdominal hernias, recurrent upper respiratory tract infections, heart valve disease, carpal tunnel syndrome, and variable neurological involvement. In the severe forms, these features usually appear in the first months of life, but a correct diagnosis is often reached later when suggestive signs are manifest. All MPS types may have severe or attenuated presentations depending on the residual enzymatic activity of the patient. Based on data from the literature and from personal experience, here we underline the very early signs of the severe forms which should alert the paediatrician on their first appearance. A few early signs are typical of MPS (i.e. gibbus) while many are unspecific (hernias, upper airway infections, organomegaly, etc.), and finding the association of many unspecific signs might prompt the paediatrician to search for a common cause and to carefully look for other more specific signs (gibbus and other skeletal deformities, heart murmur). We stress the need to increase awareness of MPS among paediatricians and other specialists to shorten the still existing diagnostic delay. A timely diagnosis is mandatory for the commencement of treatment as soon as possible, when available, to possibly obtain better results. PMID- 30442161 TI - Biochemical and molecular analysis in mucopolysaccharidoses: what a paediatrician must know. AB - Mucopolysaccharidoses (MPS) are rare inherited disorders caused by a deficit of the lysosomal hydrolases involved in the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). They are all monogenic defects, transmitted in an autosomal recessive way, except for MPS type II which is X-linked. The enzymatic deficit causes a pathologic accumulation of undegraded or partially degraded substrates inside lysosomes as well as in the extracellular compartment. MPS generally present with recognizable signs and symptoms to raise a clinical suspicion. However, although they have individual peculiarities, often signs and symptoms may overlap between different MPS types. Therefore, a deeper evaluation of specific disease biomarkers becomes necessary to reach an appropriate diagnosis. This paper stresses the central role of the laboratory in completing and confirming the clinical suspicion of MPS according to a standardized procedure: first, a biochemical evaluation of the patient samples, including qualitative/quantitative urinary GAG analysis and a determination of enzyme activities, and then the molecular diagnosis. We also encourage a constant and close communication between clinicians and laboratory personnel to address a correct and early MPS diagnosis. PMID- 30442163 TI - Early diagnosis and management of cardiac manifestations in mucopolysaccharidoses: a practical guide for paediatric and adult cardiologists. AB - Mucopolysaccharidoses (MPS) are a group of hereditary disorders caused by lysosomal storage of glycosaminoglycans (GAGs) and characterized by a wide variability of phenotypes from severe fetal-neonatal forms to attenuated diseases diagnosed in adult individuals. The clinical picture generally worsens with age due to progressive storage involving mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye, and ear. Cardiac storage of GAGs involves valves, heart muscle, and vessels (particularly the coronary arteries), and can be specific in relation to different MPS types and enzyme defects. MPS I, II, and VI are those with the most severe cardiac involvement. The cardiologist is a key figure in MPS, and their role is expanding from cardiac-specific management to early diagnosis when the mild disease phenotypes have not yet been recognized by other specialists. Familial and personal history, electrocardiography, imaging, and laboratory findings represent important steps in the clinical investigation of these patients. New treatments have led to an increased need for cardiologists to be on the lookout for MPS patients since they can significantly improve the lives of people with MPS if they suspect the diagnosis and refer them for enzyme replacement therapy or bone marrow transplantation. PMID- 30442164 TI - The surgical management of non-malignant aerodigestive fistula. AB - BACKGROUND: Acquired aerodigestive fistula (ADF) are rare, but associated with significant morbidity. Surgery affords the best prospect of cure. We present our experience of the surgical management of ADFs at a specialist unit, highlighting operative techniques, challenges and assess clinical outcomes following intervention. We also illustrate findings of a Hospital Episodes Statistics search for ADFs. METHODS: A prospectively-maintained database was searched to identify all patients diagnosed with an ADF who were managed at our institution. Of 48 patients with an ADF, eight underwent surgical intervention. RESULTS: Four patients underwent an exploration of the ADF with primary repair of the defect. Two of these patients had proximal ADFs, amenable to repair through a neck incision, and two required a thoracotomy. Two patients suffered fistulae secondary to endoscopic therapy and underwent oesophageal exclusion surgery, with subsequent staged reconstruction. Two patients with previous Tuberculosis had a lung segmentectomy and lobectomy respectively, and a further patient in remission after treatment for lymphoma underwent oesophageal resection with synchronous reconstruction. Three patients suffered a complication, with one post-operative mortality. The remaining seven patients all achieved normal oral alimentation, with no evidence of ADF recurrence at a median follow-up of 32 months. CONCLUSIONS: Surgery to manage ADFs is effective in restoring normal alimentation and alleviates soiling of the airway, with a very low risk of recurrence. Several operative techniques can be utilised dependent on the features of the ADF. Early referral to specialist units is advocated, where the expertise to facilitate the complete management of patients is present, within a multi-disciplinary setting. PMID- 30442165 TI - A realist process evaluation within the Facilitating Implementation of Research Evidence (FIRE) cluster randomised controlled international trial: an exemplar. AB - BACKGROUND: Facilitation is a promising implementation intervention, which requires theory-informed evaluation. This paper presents an exemplar of a multi country realist process evaluation that was embedded in the first international randomised controlled trial evaluating two types of facilitation for implementing urinary continence care recommendations. We aimed to uncover what worked (and did not work), for whom, how, why and in what circumstances during the process of implementing the facilitation interventions in practice. METHODS: This realist process evaluation included theory formulation, theory testing and refining. Data were collected in 24 care home sites across four European countries. Data were collected over four time points using multiple qualitative methods: observation (372 h), interviews with staff (n = 357), residents (n = 152), next of kin (n = 109) and other stakeholders (n = 128), supplemented by facilitator activity logs. A combined inductive and deductive data analysis process focused on realist theory refinement and testing. RESULTS: The content and approach of the two facilitation programmes prompted variable opportunities to align and realign support with the needs and expectations of facilitators and homes. This influenced their level of confidence in fulfilling the facilitator role and ability to deliver the intervention as planned. The success of intervention implementation was largely dependent on whether sites prioritised their involvement in both the study and the facilitation programme. In contexts where the study was prioritised (including release of resources) and where managers and staff support was sustained, this prompted collective engagement (as an attitude and action). Internal facilitators' (IF) personal characteristics and abilities, including personal and formal authority, in combination with a supportive environment prompted by managers triggered the potential for learning over time. Learning over time resulted in a sense of confidence and personal growth, and enactment of the facilitation role, which resulted in practice changes. CONCLUSION: The scale and multi-country nature of this study provided a novel context to conduct one of the few trial embedded realist-informed process evaluations. In addition to providing an explanatory account of implementation processes, a conceptual platform for future facilitation research is presented. Finally, a realist-informed process evaluation framework is outlined, which could inform future research of this nature. TRIAL REGISTRATION: Current controlled trials ISRCTN11598502 . PMID- 30442167 TI - Ocular features in mucopolysaccharidosis: diagnosis and treatment. AB - Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in different parts of the eye. Ocular problems are very common in MPS children, and the cornea, sclera, trabecular meshwork, retina, and optic nerve may all be involved. Early diagnosis is very important to preserve the visual function, and the diagnosis requires experience and different evaluations. Follow-up is mandatory to allow a correct pathway to consequent therapy. This article aims to provide a review of ocular alterations and treatment options in MPS. The ophthalmologist is sometimes the first physician who can suspect a metabolic disease and can help to make the correct diagnosis. It is important to stimulate awareness of MPS among ophthalmologists. PMID- 30442166 TI - Preemptive intrathecal administration of endomorphins relieves inflammatory pain in male mice via inhibition of p38 MAPK signaling and regulation of inflammatory cytokines. AB - BACKGROUND: Preemptive administration of analgesic drugs reduces perceived pain and prolongs duration of antinociceptive action. Whereas several lines of evidence suggest that endomorphins, the endogenous mu-opioid agonists, attenuate acute and chronic pain at the spinal level, their preemptive analgesic effects remain to be determined. In this study, we evaluated the anti-allodynic activities of endomorphins and explored their mechanisms of action after preemptive administration in a mouse model of inflammatory pain. METHODS: The anti-allodynic activities of preemptive intrathecal administration of endomorphin 1 and endomorphin-2 were investigated in complete Freund's adjuvant (CFA)-induced inflammatory pain model and paw incision-induced postoperative pain model. The modulating effects of endomorphins on the expression of p38 mitogen-activated protein kinase (p38 MAPK) and inflammatory mediators in dorsal root ganglion (DRG) of CFA-treated mice were assayed by real-time reverse transcription polymerase chain reaction (RT-PCR), Western blotting, or immunofluorescence staining. RESULTS: Preemptive intrathecal injection of endomorphins dose dependently attenuated CFA-induced mechanical allodynia via the mu-opioid receptor and significantly reversed paw incision-induced allodynia. In addition, CFA-caused increase of phosphorylated p38 MAPK in DRG was dramatically reduced by preemptive administration of endomorphins. Repeated intrathecal application of the specific p38 MAPK inhibitor SB203580 reduced CFA-induced mechanical allodynia as well. Further RT-PCR assay showed that endomorphins regulated the mRNA expression of inflammatory cytokines in DRGs induced by peripheral inflammation. CONCLUSIONS: Our findings reveal a novel mechanism by which preemptive treatment of endomorphins attenuates inflammatory pain through regulating the production of inflammatory cytokines in DRG neurons via inhibition of p38 MAPK phosphorylation. PMID- 30442168 TI - The new frame for Mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are genetic, progressive, lysosomal storage disorders affecting virtually all organs and systems. The first MPS were clinically identified about 100 years ago. Nowadays, the enzyme defects and related genes are known for all 11 different enzyme defects. Treatments are available for many MPS but these have only partial efficacy, especially when started late. The problems to solve are: 1) the need for an earlier diagnosis (neonatal screening? improving the awareness of physicians?); 2) prompt access to therapies; 3) improving the efficacy of the available treatments; 4) finding new treatments; and 5) the availability of specialist experts in MPS who can meet the traditional needs of MPS patients. This introduction to the IJP Supplement on MPS is a brief comment on the different papers accepted for this volume, which are in turn the elaboration of the lectures given at a meeting on the future of mucopolysaccharidoses held in Milan on 8-9 May 2017. PMID- 30442169 TI - Species richness, cultural importance, and prioritization of wild spices for conservation in the Sudano-Guinean zone of Benin (West Africa). AB - BACKGROUND: Spices have always been used for their flavor-enhancement characteristics and for their medicinal properties. In Benin, scientific research on spices is scarce, despite their importance in the local population's daily needs. This study investigated the diversity of wild spices and documented the associated traditional knowledge that can be used for their valuation, domestication, and sustainable management in the Sudano-Guinean Zone of Benin. METHODS: Data were collected during field expeditions using semi-structured interviews in ten localities across the three phytodistricts of the zone. Species richness and Shannon's diversity index were estimated using species accumulation curves. Use report (UR), cultural importance, use value (UV) index, and informant consensus factor (Fic) were used to assess traditional knowledge on wild species, their local importance, and informants' agreement among sociolinguistic groups. Priority wild spices were finally identified using an approach combining eight criteria (native status, economic value, ethnobotanical value, global distribution, national distribution, in-situ and ex-situ conservation status, legislation, and threats assessment) in four prioritization methods (point scoring procedure, point scoring procedure with weighting, compound ranking system, and binomial ranking system). RESULTS: A total of 14 species, belonging to 12 genera and 9 families, were inventoried. The most prominent families were Zingiberaceae (21.43%), Annonaceae (21.43%), and Rutaceae (14.29%). More than 200 specific uses were reported, with the Tchabe people holding the greatest level of knowledge (70 uses; UR = 5.70 +/- 0.33). The culturally most important spices differed among sociolinguistic groups. Most of the informants agree on the use of the species among (Fic = 0.72-0.98) and across the considered use categories (Fic = 0.88-0.99). The highest UV were registered for Aframomum alboviolaceum (UV = 0.93), Lippia multiflora (UV = 0.76), and Aframomum angustifolium (UV = 0.18). Overall, people perceived wild spices as declining due to agriculture, grazing, and drought. Five species, A. alboviolaceum, L. multiflora, Monodora tenuifolia, Xylopia aethiopica, and Z. zanthoxyloides, were the most prioritized for conservation. CONCLUSIONS: This study provides information relevant for the implementation of conservation and domestication actions of wild spices in Benin. Priority species could be integrated into traditional agroforestry systems (e.g., home gardens). However, for this to be effective, further research should be undertaken on morphological and genetic diversity and propagation methods of priority wild spices. PMID- 30442170 TI - ENT and mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) are a heterogeneous group of inherited metabolic disorders, each associated with a deficiency in one of the enzymes involved in glycosaminoglycan (GAG) catabolism. Over time, GAGs accumulate in cells and tissues causing progressive damage, a variety of multi-organ clinical manifestations, and premature death. Ear, nose, and throat (ENT) disorders affect more than 90% of MPS patients and appear in the early stage of MPS; also reported are recurrent otitis media and persistent otitis media with effusion, macroglossia, adenotonsillar hypertrophy, nasal obstruction, obstructive sleep apnoea syndrome (OSAS), hearing loss, and progressive respiratory disorders. Undiagnosed MPS patients are frequently referred to otolaryngologists before the diagnosis of MPS is confirmed. Otolaryngologists thus have an early opportunity to recognize MPS and they can play an increasingly integral role in the multidisciplinary approach to the diagnosis and management of many children with MPS. The ENT commitment is therefore to suspect MPS when non-specific ENT pathologies are associated with repeated surgical treatments, unexplainable worsening of diseases despite correct treatment, and with signs, symptoms, and pathological conditions such as hepatomegaly, inguinal hernia, macrocephaly, macroglossia, coarse facial features, hydrocephalous, joint stiffness, bone deformities, valvular cardiomyopathy, carpal tunnel syndrome, and posture and visual disorders. PMID- 30442171 TI - Clinical hints to diagnosis of attenuated forms of Mucopolysaccharidoses. AB - The mucopolysaccharidoses (MPS) are clinically similar but also heterogeneous in terms of major or minor involvement of different organs/systems, burden of disease, and rate of progression. The attenuated forms of MPS, due to their less severe presentations, are more difficult to diagnose and often receive a significantly delayed diagnosis. On the other hand, the diagnosis is very important since the attenuated forms may benefit from earlier treatments. The aim of this paper is to describe the natural history and the clinical signs useful to arise a suspicion of an attenuated form of MPS. MPS patients usually show a cluster of signs and symptoms, one of which may be the trigger for an evaluation by a specialist. Individuals with attenuated MPS are mostly cognitively normal, and dysmorphisms of the facies may be mild or absent. The most frequently involved organs/systems are the osteoarticular system, heart, and eyes. These patients may also have hepatosplenomegaly, hearing loss, and respiratory problems. When they are referred to a specialist (rheumatologist, cardiologist, ophthalmologist, surgeon, orthopedist, etc.) for their main complaint, the other signs and symptoms are likely to be missed in the medical history. To avoid missing data and to save time, we propose a semistructured medical history form to be filled in by the patients or their caregivers while waiting for evaluation by a specialist. PMID- 30442172 TI - Correction to: HSP60 critically regulates endogenous IL-1beta production in activated microglia by stimulating NLRP3 inflammasome pathway. AB - Upon publication of the original article [1], it was noticed that there is an error in Fig. 10, the dialog box in panel (b) was missing. The correct Fig. 10 is shown below. PMID- 30442173 TI - Orthopaedic challenges for mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are a group of diseases characterized by abnormal accumulation of glycosaminoglycans (GAGs). Although there are differences among the various disease types, the osteoarticular system is always involved. The aim of the present study was to establish a framework for MPS-related orthopaedic manifestations and for their treatment. The authors, affiliated to three different Italian Orthopaedic Centres, report data taken from the literature reviewed in light of their accumulated professional experience. Bone alterations make up what is known as dysostosis multiplex, involving the trunk and limbs and with typical radiological findings. Joints are affected by pathological tissue infiltrations. The cervical spinal cord is involved, with stenosis and cervical and occipitocervical instability. In MPS there is a much higher incidence of scoliosis compared with healthy subjects without any particular distinctive feature. Kyphosis of the spine is more frequent and also more severe because of its possible neurological complications, and it is localized at the thoracolumbar level with a malformed vertebra at the top of the deformity. Evolving forms, and those associated with neurological damage, require anteroposterior spine fusion. The hip is invariably involved, with dysplasia affecting the femoral neck (coxa valga), the femoral epiphysis (loss of sphericity, osteonecrosis), and the femoral acetabulum which is flared. All these features explain the tendency to progressive hip migration. Genu valgum is often found (a deviation of the physiological axis with an obtuse angle opening laterally). This deformity is often localized at the proximal tibial metaphysis; it causes functional limitations and leads to an irregular erosion of the articular cartilage. In young patients who still have the growth plate, it is possible to execute a medial hemiepiphysiodesis, a temporary inhibition of cartilage growth, with progressive axis correction. In this paper, the characterisation of clinical features and the review of treatments are divided into separate sections based on the part of the body involved. The conclusions of each section are presented as a summary. One section discusses the high risk of anaesthesia-related complications requiring the collaboration of specifically trained personnel. PMID- 30442174 TI - Facilitating Implementation of Research Evidence (FIRE): an international cluster randomised controlled trial to evaluate two models of facilitation informed by the Promoting Action on Research Implementation in Health Services (PARIHS) framework. AB - BACKGROUND: Health care practice needs to be underpinned by high quality research evidence, so that the best possible care can be delivered. However, evidence from research is not always utilised in practice. This study used the Promoting Action on Research Implementation in Health Services (PARIHS) framework as its theoretical underpinning to test whether two different approaches to facilitating implementation could affect the use of research evidence in practice. METHODS: A pragmatic clustered randomised controlled trial with embedded process and economic evaluation was used. The study took place in four European countries across 24 long-term nursing care sites, for people aged 60 years or more with documented urinary incontinence. In each country, sites were randomly allocated to standard dissemination, or one of two different types of facilitation. The primary outcome was the documented percentage compliance with the continence recommendations, assessed at baseline, then at 6, 12, 18, and 24 months after the intervention. Data were analysed using STATA15, multi-level mixed-effects linear regression models were fitted to scores for compliance with the continence recommendations, adjusting for clustering. RESULTS: Quantitative data were obtained from reviews of 2313 records. There were no significant differences in the primary outcome (documented compliance with continence recommendations) between study arms and all study arms improved over time. CONCLUSIONS: This was the first cross European randomised controlled trial with embedded process evaluation that sought to test different methods of facilitation. There were no statistically significant differences in compliance with continence recommendations between the groups. It was not possible to identify whether different types and "doses" of facilitation were influential within very diverse contextual conditions. The process evaluation (Rycroft-Malone et al., Implementation Science. doi: 10.1186/s13012-018-0811-0) revealed the models of facilitation used were limited in their ability to overcome the influence of contextual factors. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11598502 . Date 4/2/10. The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 223646. PMID- 30442175 TI - Children with mixed developmental language disorder have more insecure patterns of attachment. AB - BACKGROUND: Developmental Language disorders (DLD) are developmental disorders that can affect both expressive and receptive language. When severe and persistent, they are often associated with psychiatric comorbidities and poor social outcome. The development of language involves early parent-infant interactions. The quality of these interactions is reflected in the quality of the child's attachment patterns. We hypothesized that children with DLD are at greater risk of insecure attachment, making them more vulnerable to psychiatric comorbidities. Therefore, we investigated the patterns of attachment of children with expressive and mixed expressive- receptive DLD. METHODS: Forty-six participants, from 4 years 6 months to 7 years 5 months old, 12 with expressive Specific Language Impairment (DLD), and 35 with mixed DLD, were recruited through our learning disorder clinic, and compared to 23 normally developing children aged 3 years and a half. The quality of attachment was measured using the Attachment Stories Completion Task (ASCT) developed by Bretherton. RESULTS: Children with developmental mixed language disorders were significantly less secure and more disorganized than normally developing children. CONCLUSIONS: Investigating the quality of attachment in children with DLD in the early stages could be important to adapt therapeutic strategies and to improve their social and psychiatric outcomes later in life. PMID- 30442176 TI - Post esophagectomy diaphragmatic hernia: a case report of a rare cause of acute respiratory distress. AB - BACKGROUND: Diaphragmatic hernia is frequent among the elderly and is usually associated with mild chronic digestive and respiratory symptoms. CASE PRESENTATION: An elderly post-esophagectomy male patient, in the early postoperative period of cardiac surgery, presented with acute respiratory distress. An emergent surgery was performed to reduce a giant diaphragmatic herniation. CONCLUSIONS: An acute transhiatal herniation can cause serious respiratory impairment; surgical repair should be considered in select patients of cardiac surgery. PMID- 30442177 TI - Gene therapy for mucopolysaccharidoses: in vivo and ex vivo approaches. AB - Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency in lysosomal enzymes catalyzing the stepwise degradation of glycosaminoglycans (GAGs). The current therapeutic strategies of enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation have been reported to reduce patient morbidity and to improve their quality of life, but they are associated with persistence of residual disease burden, in particular at the neurocognitive and musculoskeletal levels. This indicates the need for more efficacious treatments capable of effective and rapid enzyme delivery to the affected organs, especially the brain and the skeleton. Gene therapy (GT) strategies aimed at correcting the genetic defect in patient cells could represent a significant improvement for the treatment of MPS when compared with conventional approaches. While in-vivo GT strategies foresee the administration of viral vector particles directly to patients with the aim of providing normal complementary DNA to the affected cells, ex-vivo GT approaches are based on the ex-vivo transduction of patient cells that are subsequently infused back. This review provides insights into the state-of-art accomplishments made with in vivo and ex vivo GT-based approaches in MPS and provide a vision for the future in the medical community. PMID- 30442178 TI - Computational analysis reveals histotype-dependent molecular profile and actionable mutation effects across cancers. AB - BACKGROUND: Comprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor typing. The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology. The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates. Here, we present a computational approach that facilitates the systematic analysis of the histological context dependency of mutational effects by integrating genomic and proteomic tumor profiles across cancers. METHODS: To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis. Finally, the proteins were ranked by their contribution to profile differences to identify proteins characteristic of oncogenic mutation effects across cancers. RESULTS: We apply our approach to four current proposals of molecular tumor classifications and major therapeutically relevant actionable genes. All 12 actionable genes evaluated show effects on the protein level in the corresponding tumor type and showed additional mutation-related protein profiles in 21 tumor types. Moreover, our analysis identifies consistent cross-cancer effects for 4 genes (FGFR1, ERRB2, IDH1, KRAS/NRAS) in 14 tumor types. We further use cell line drug response data to validate our findings. CONCLUSIONS: This computational approach can be used to identify mutational signatures that have protein-level effects and can therefore contribute to preclinical in silico tests of the efficacy of molecular classifications as well as the druggability of individual mutations. It thus supports the identification of novel targeted therapies effective across cancers and guides efficient basket trial designs. PMID- 30442179 TI - Cerebral and occipito-atlanto-axial involvement in mucopolysaccharidosis patients: clinical, radiological, and neurosurgical features. AB - BACKGROUND: Neurosurgical features of mucopolysaccharidosis (MPS) patients mainly involve the presence of cranio-vertebral junction (CVJ) abnormalities and the development of communicating hydrocephalus. CVJ pathology is a critical aspect that severely influences the morbidity and mortality of MPS patients. Hydrocephalus is slowly progressing; it must be differentiated from cerebral atrophy, and rarely requires treatment. The aim of this paper was to review the literature concerning these conditions, highlighting their clinical, radiological, and surgical aspects to provide a practical point of view for clinicians. RESULTS: CVJ involvement may present with cervical pain, unsteady gait, frequent falls, and progressive impairment of autonomous ambulation, an acute tetraplegia even after minor trauma. Magnetic resonance imaging (MRI) of the cervical spine, including active dynamic flexion and extension scans, is the most powerful imaging technique for detecting spinal cord compression at the CVJ in MPS patients. The main radiological features include atlanto-axial subluxation, odontoid hypoplasia, periodontoid soft tissue masses, spinal canal narrowing, and spinal cord compression. Together with MRI, fine-cut computed tomography (CT) scans with coronal and sagittal three-dimensional reconstructions are important diagnostic tools in the preoperative workup thanks to the information gleaned about bone structure conformation and angles. Finally, angio CT slices are equally useful in preoperative planning, defining vertebral artery position in relation to bony structures. Surgery of the CVJ is proposed both to treat cord compression with MRI signs of myelopathy or as a preventive treatment in patients at high risk of cord damage. Among different surgical options, we always suggest performing decompression and instrumented stabilization. Hydrocephalus may occasionally present clinically with intracranial hypertension symptoms such as headache, vomiting, and high sight impairment. Neurocognitive symptoms may be hidden by the constitutive cognitive impairment. MRI with a study of dynamic cerebrospinal fluid (CSF) flow is helpful to differentiate from ventriculomegaly, which does not require treatment. Ventriculo-peritoneal shunt placement is the gold standard to treat hydrocephalus, although endoscopic third ventriculostomy has recently shown good results in some patients. CONCLUSION: Early recognition of CVJ pathology and hydrocephalus is critical to avoid the development of severe complications. A multidisciplinary approach involving physicians, neuroradiologists, and neurosurgeons is needed to detect such conditions and to select patients eligible for surgery. PMID- 30442180 TI - Modeling hallmark pathology using motor neurons derived from the family and sporadic amyotrophic lateral sclerosis patient-specific iPS cells. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) represents a devastating, progressive, heterogeneous, and the most common motor neuron (MN) disease. To date, no cure has been available for the condition. Studies with transgenic mice have yielded significant results that help us understand the underlying mechanisms of ALS. Nonetheless, none of more than 30 large clinical trials over the past 20 years proved successful, which led some researchers to challenge the validity of the preclinical models. METHODS: Human-induced pluripotent cells (iPSCs) were established by introducing Sendai virus into fibroblast cells. We established TDP-43 HES by inserting CAG-TDP43 (G298S) cassette or the CAG-EGFP cassette into PPP1R12C-locus of human embryonic stem cells (ESC, H9) by TALEN mediated homologous recombination. iPSCs or HESC were differentiated to motor neurons and non-motor neuron as control. Relevant biomarkers were detected in different differentiated stages. TDP-43 aggregates, neurofilament, and mitochondria analyses were performed. RESULTS: In this study, using iPSCs-derived human MN from an ALS patient with a TDP43 G298S mutation and two sporadic ALS patients, we showed that both sporadic and familial ALS were characterized by TDP 43 aggregates in the surviving MN. Significantly higher neurofilament (NF) inclusion was also found in ALS MN compared with wild-type (WT) GM15 controls (P < 0.05). The neurite mitochondria density was significantly lower in ALS MN than that in the control MNs. Transgenesis of TDP-43 G298S into AAVS locus in human embryonic stem cells reproduced phenotype of patient-derived G289S MN. By challenging MNs with a proteasome inhibitor, we found that MNs were more vulnerable to MG132, with some accompanying phenotype changes, such as TDP43 translocation, NF inclusion, mitochondria distribution impairment, and activation of caspase3. CONCLUSIONS: Our results suggested that changes in TDP43 protein, NF inclusion, and distribution impairment of mitochondria are common early pathology both in familial and sporadic ALS. These findings will help us gain insight into the pathogenesis of the condition and screen relevant drugs for the disease. PMID- 30442181 TI - Conferring DNA virus resistance with high specificity in plants using virus inducible genome-editing system. AB - The CRISPR/Cas9 system has recently been engineered to confer resistance to geminiviruses in plants. However, we show here that the usefulness of this antiviral strategy is undermined by off-target effects identified by deep sequencing in Arabidopsis. We construct two virus-inducible CRISPR/Cas9 vectors that efficiently inhibit beet severe curly top virus (BSCTV) accumulation in both transient assays (Nicotiana benthamiana) and transgenic lines (Arabidopsis). Deep sequencing detects no off-target effect in candidate sites of the transgenic Arabidopsis. This kind of virus-inducible genome-editing system should be widely applicable for generating virus-resistant plants without off-target costs. PMID- 30442182 TI - Evaluation of CD38 expression in Sudanese patients with chronic lymphocytic leukemia. AB - OBJECTIVE: The objective of this study was to evaluate the cluster of differentiation-38 (CD38) expression in Sudanese patients with chronic lymphocytic leukemia (CLL) and to determine its association with clinical and laboratory characteristics of the disease. RESULTS: We conducted a cross sectional study on 99 patients diagnosed with CLL in Khartoum Oncology Hospital in Khartoum, Sudan. Immunophenotyping and CD38 expression levels were measured with four-color flowcytometry. The results of physical examination and blood analyses were used for assigning a modified Rai clinical staging system. The collected data were analyzed using the Statistical Package for the Social Science, version 22 (SPSS Inc., Chicago, IL, USA). According to our findings, the frequencies of 7%, 20%, and 30% cutoff levels of CD38 expressions were 68.7%, 41.4%, and 36.4% respectively. CD38 cutoff level of 7% showed a significant association with hemoglobin concentration (P = 0.04), whereas other cutoff levels showed insignificant results. All the three cutoff levels showed insignificant associations with the other clinical and laboratory variables. In conclusion, the CD38 expression at a cutoff level of 7% seems to be more valuable clinically than higher cutoff levels in Sudanese CLL patients. PMID- 30442184 TI - Possible strategies to cross the blood-brain barrier. AB - The mucopolysaccharidoses (MPS) are a heterogeneous group of in-born metabolic conditions caused by genetic defects that result in the absence or severe deficiency of one of the lysosomal hydrolases responsible for the degradation of glycosaminoglycans (GAGs). Such enzyme deficiency causes accumulation of GAGs that begins in infancy and progressively worsens, often affecting several organs including the central nervous system (CNS) inducing mental retardation, progressive neurodegeneration, and premature death. Over the last years, enormous progress has been made in the treatment of many MPS types, and available treatments are efficacious for many of them. Nevertheless, treatment of MPS with CNS involvement is limited mostly because of delivery impediments related to the presence of the blood-brain barrier (BBB). This chapter presents an overview of the BBB and of the different strategies that have been developed to overcome the problem of drug transport at the BBB, assuring efficient delivery of therapeutic agents to the brain. PMID- 30442183 TI - Maternal omega-3 fatty acid intake during neurodevelopment does not affect pup behavior related to depression, novelty, or learning. AB - OBJECTIVE: Previously, we showed that consumption of a diet supplemented with omega-3 polyunsaturated fatty acids (n-3FAs) for two rounds of gestation and lactation increased the ability of rat dams to cope with stress when compared to dams that ingested a diet lacking n-3FAs. The objective of this study was to determine if the diets of these dams affected the behavior of their pups later in life. To isolate the neurodevelopmental effects of n-3FAs, pups from the second gestation were weaned to a diet adequate in n-3FAs. Pup testing began at 8 weeks of age and consisted of the forced swim, open field, and hole board tests to examine depression-related behavior, reaction to novelty, and learning and memory, respectively. RESULTS: Given the considerable difference in the n-3FA content of the maternal diet, we expected a large effect size, however with the exception of rearing duration, maternal diet did not affect behavior in any of the tests conducted. These results suggest that maternal n-3FA supplementation during neurodevelopment likely does not affect offspring behavior when a diet adequate in n-3FA is provided post-weaning. Rather, we hypothesize that brain n 3FAs at the time of testing confer altered behavior and corroborate the need for additional research. PMID- 30442185 TI - Human neural stem cell-derived neuron/astrocyte co-cultures respond to La Crosse virus infection with proinflammatory cytokines and chemokines. AB - BACKGROUND: La Crosse virus (LACV) causes pediatric encephalitis in the USA. LACV induces severe inflammation in the central nervous system, but the recruitment of inflammatory cells is poorly understood. A deeper understanding of LACV-induced neural pathology is needed in order to develop treatment options. However, there is a severe limitation of relevant human neuronal cell models of LACV infection. METHODS: We utilized human neural stem cell (hNSC)-derived neuron/astrocyte co cultures to study LACV infection in disease-relevant primary cells. hNSCs were differentiated into neurons and astrocytes and infected with LACV. To characterize susceptibility and responses to infection, we measured viral titers and levels of viral RNA, performed immunofluorescence analysis to determine the cell types infected, performed apoptosis and cytotoxicity assays, and evaluated cellular responses to infection using qRT-PCR and Bioplex assays. RESULTS: hNSC derived neuron/astrocyte co-cultures were susceptible to LACV infection and displayed apoptotic responses as reported in previous in vitro and in vivo studies. Neurons and astrocytes are both targets of LACV infection, with neurons becoming the predominant target later in infection possibly due to astrocytic responses to IFN. Additionally, neuron/astrocyte co-cultures responded to LACV infection with strong proinflammatory cytokine, chemokine, as well as MMP-2, MMP 7, and TIMP-1 responses. CONCLUSIONS: hNSC-derived neuron/astrocyte co-cultures reproduce key aspects of LACV infection in humans and mice and are useful models to study encephalitic viruses. Specifically, we show astrocytes to be susceptible to LACV infection and that neurons and astrocytes are important drivers of the inflammatory responses seen in LACV infection through the production of proinflammatory cytokines and chemokines. PMID- 30442186 TI - Safety and efficacy of Momordica charantia Linnaeus in pre-diabetes and type 2 diabetes mellitus patients: a systematic review and meta-analysis protocol. AB - BACKGROUND: Momordica charantia Linnaeus (Cucurbitaceae) has been used traditionally as a nutritious food and as a herbal medicine for type 2 diabetes mellitus. However, human studies that investigated its glycemic control have generated inconsistent findings. Therefore, this systematic review and meta analysis is aimed at evaluating the safety and efficacy of M. charantia L. preparations in human studies that have investigated its role in glycemic control. METHODS: This protocol has been prepared according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The review will include randomized clinical trials and non-randomized clinical trials. The included studies will have assessed glycemic control of M. charantia preparations with placebo or standard oral anti-hyperglycemic agents in adult pre diabetes and/or type 2 diabetes mellitus patients and have at least 4 weeks of follow-up. The primary outcomes of review are fasting blood glucose levels, glycosylated hemoglobin A1c, and post-prandial blood glucose level. Electronic database search for published literatures will be conducted without language restriction in EMBASE, MEDLINE/PubMed, the Cochrane Library, SCOPUS, Web of Sciences, and CINAHL databases. Search for gray literatures and references of the retrieved full-text articles will be conducted in Google, Google Scholar, OpenGrey, ProQuest dissertations & Theses, British Library EThos, and university digital library systems. Two independent reviewers will later evaluate full texts, extract data, and assess risk of bias of eligible articles. Publication biases will be assessed by testing asymmetry of funnel plot using Egger's or Begg's tests while heterogeneity will be assessed using Cochran Q test, P value, and I2. Revman software version 5.3 will be used for meta-analysis including subgroup and sensitivity analysis. DISCUSSION: This systematic review and meta analysis will investigate both safety and efficacy of M. charantia preparations in type 2 diabetes mellitus. The review results will be published in a peer reviewed journal. The results will bring better understanding of clinical outcomes in treatment of type 2 diabetes mellitus patients and highlight gaps for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018083653 . PMID- 30442187 TI - To send or not to send: weighing the costs and benefits of mailing an advance letter to participants before a telephone survey. AB - OBJECTIVE: A letter was mailed to half the participants (Letter = 137; No Letter = 138) of a 5-year follow-up survey regarding smoking cessation before attempting contact for a telephone interview. The primary outcome was the number of completed surveys per group (response rate). Secondary analyses of the number of telephone calls placed and a cost analysis were performed. RESULTS: No conclusive effect was found on the response rates per group (59.1% Letter, 50.0% No Letter; p = 0.147). Additionally, a logistic regression, controlling for demographics, revealed that there was no direct effect of sending the letter on response rate (p = 0.369). Non-parametric analysis showed significantly fewer calls (U = 7962.5, z = - 2.274, p < 0.05 two-tailed) and significantly lower costs (U = 11112.00, z = 2.521, p < 0.05 two-tailed) in reaching participants in the Letter group. Mailing an advance letter to participants did not appear to effect response rates between the groups, even when controlling for demographics. However, further analysis examining the number of call attempts and the costs per group revealed the letter may have had other effects. These findings suggest that additional analyses may be merited when evaluating the effectiveness of methods to increase participation, such as an advance letter, especially in cases where the literature largely supports its effectual use. Trial registration ClinicalTrials.gov NCT03097445. Registered 31 March 2017. PMID- 30442188 TI - Neurobehavioral phenotypes of neuronopathic mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are a group of lysosomal multisystemic, chronic, and progressive diseases characterized by the storage of glycosaminoglycans (GAGs) that may affect the central nervous system. Neuronopathic MPS such as MPS IH, MPS II, MPS IIIA-D, and MPS VII are characterized by neurocognitive regression. In severe MPS I (MPS IH, or Hurler syndrome) initial developmental trajectory is usually unremarkable but cognitive development shows a plateau by 2 to 4 years of age and then progressively regresses with aging. Patients with neuronopathic MPS II have a plateau of cognitive and adaptive development on average by 4 to 4.5 years of age, although there is significant variability, followed by progressive neurocognitive decline. In patients with classic MPS III, developmental trajectory reaches a plateau around 3 years of age, followed by regression. Sleep disturbances and behavioral problems occur early in MPS II and III with features of externalizing disorders. Acquired autism-like behavior is often observed in children with MPS III after 4-6 years of age. Impaired social and communication abilities do occur, but MPS III children do not have restricted and repetitive interests such as in autism spectrum disorder. MPS type VII is an ultra-rare neuronopathic MPS with a wide clinical spectrum from very severe with early mortality to milder phenotypes with longer survival into adolescence and adulthood. Most patients with MPS VII have intellectual disability and severely delayed speech development, usually associated with hearing impairment. Cognitive regression in neuronopathic MPS runs parallel to a significant decrease in brain tissue volume. Assessment of the developmental profile is challenging because of low cognitive abilities, physical impairment, and behavioral disturbances. Early diagnosis is crucial as different promising treatment approaches have been extensively studied in animal MPS models and are currently being applied in clinical trials. PMID- 30442191 TI - Can automated content analysis be used to assess and improve the use of evidence in mental health policy? A systematic review. AB - BACKGROUND: This review assesses the utility of applying an automated content analysis method to the field of mental health policy development. We considered the possibility of using the Wordscores algorithm to assess research and policy texts in ways that facilitate the uptake of research into mental health policy. METHODS: The PRISMA framework and the McMaster appraisal tools were used to systematically review and report on the strengths and limitations of the Wordscores algorithm. Nine electronic databases were searched for peer-reviewed journal articles published between 2003 and 2016. Inclusion criteria were (1) articles had to be published in public health, political science, social science or health services disciplines; (2) articles had to be research articles or opinion pieces that used Wordscores; and (3) articles had to discuss both strengths and limitations of using Wordscores for content analysis. RESULTS: The literature search returned 118 results. Twelve articles met the inclusion criteria. These articles explored a range of policy questions and appraised different aspects of the Wordscores method. DISCUSSION: Following synthesis of the material, we identified the following as potential strengths of Wordscores: (1) the Wordscores algorithm can be used at all stages of policy development; (2) it is valid and reliable; (3) it can be used to determine the alignment of health policy drafts with research evidence; (4) it enables existing policies to be revised in the light of research; and (5) it can determine whether changes in policy over time were supported by the evidence. Potential limitations identified were (1) decreased accuracy with short documents, (2) words constitute the unit of analysis and (3) expertise is needed to choose 'reference texts'. CONCLUSIONS: Automated content analysis may be useful in assessing and improving the use of evidence in mental health policies. Wordscores is an automated content analysis option for comparing policy and research texts that could be used by both researchers and policymakers. PMID- 30442189 TI - Enzyme replacement therapy: efficacy and limitations. AB - Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT. PMID- 30442190 TI - Inflammation markers and cognitive performance in breast cancer survivors 20 years after completion of chemotherapy: a cohort study. AB - BACKGROUND: Inflammation is an important candidate mechanism underlying cancer and cancer treatment-related cognitive impairment. We investigated levels of blood cell-based inflammatory markers in breast cancer survivors on average 20 years after chemotherapy and explored the relation between these markers and global cognitive performance. METHODS: One hundred sixty-six breast cancer survivors who received post-surgical radiotherapy and six cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy on average 20 years before enrollment were compared with 1344 cancer-free women from a population-based sample (50-80 years old). Breast cancer survivors were excluded if they used adjuvant hormonal therapy or if they developed relapse, metastasis, or second primary malignancies. Systemic inflammation status was assessed by the granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Cognitive performance was assessed using an extensive neuropsychological test battery from which the general cognitive factor was derived to evaluate global cognitive performance. We examined the association between cancer, the general cognitive factor, and inflammatory markers using linear regression models. RESULTS: Breast cancer survivors had a lower general cognitive factor than non-exposed participants from the comparator group (mean difference = -0.21; 95% confidence interval (CI) -0.35 to -0.06). Inflammatory markers were higher in cancer survivors compared with non exposed participants (mean difference for log(GLR) = 0.31; 95% CI 0.24 to 0.37, log(PLR) = 0.14; 95% CI 0.09 to 0.19, log(SII) = 0.31; 95% CI 0.24 to 0.39). The association between higher levels of inflammatory markers and lower general cognitive factor was statistically significant in cancer survivors but not among non-exposed participants. We found a group-by-inflammatory marker interaction; cancer survivors showed additional lower general cognitive factor per standard deviation increase in inflammatory markers (P for interaction for GLR = 0.038, PLR = 0.003, and SII = 0.033). CONCLUSIONS: This is the first study to show that (1) cancer survivors have increased levels of inflammation on average 20 years after treatment and (2) these inflammatory levels are associated with lower cognitive performance. Although this association needs verification by a prospective study to determine causality, our findings can stimulate research on the role of inflammation in long-term cognitive problems and possibilities to diminish such problems. PMID- 30442192 TI - First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor. AB - OBJECTIVES: In vivo evaluations of a gonadotropin releasing hormone-receptor single photon emission computed tomography radiotracer for non-invasive detection of gonadotropin releasing homone-receptors in brain. RESULTS: We have used a simple, robust and high-yielding procedure to radiolabel an alpha-halogenated bioactive compound with high radiochemical yield. Literature findings showed similar alpha-halogenated compounds suitable for in vivo evaluations. The compound was found to possess nano molar affinity for the gonadotropin releasing hormone-receptor in a competition dependent inhibition study. Furthermore, liquid chromatography-mass spectrometry analysis in saline, human and rat serum resulted in 46%, 52% and 44% stability after incubation for 1 h respectively. In addition, rat brain single photon emission computed tomography and biodistribution studies gave further insight into the nature of the compound as a radiotracer. PMID- 30442193 TI - The prostaglandin H2 analog U-46619 improves the differentiation efficiency of human induced pluripotent stem cells into endothelial cells by activating both p38MAPK and ERK1/2 signaling pathways. AB - BACKGROUND: We have shown that the differentiation of human-induced pluripotent stem cells (hiPSCs) into endothelial cells (ECs) is more efficient when performed with a 3-dimensional (3D) scaffold of biomaterial than in monolayers. The current study aims to further increase hiPSC-EC differentiation efficiency by deciphering the signaling pathways in 3D scaffolds. METHODS AND RESULTS: We modified our 3D protocol by using U-46619 to upregulate both p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, which increased the differentiation efficiency (as measured by CD31 expression) to as high as 89% in two established hiPSC lines. The differentiated cells expressed arteriovenous, but not lymphatic, markers; formed tubular structures and EC lumen in vitro; had significantly shorter population-doubling times than monolayer differentiated hiPSC-ECs; and restored perfusion and vascularity in a murine hind limb ischemia model. The differentiation efficiency was also > 85% in three hiPSC lines that had been derived from patients with diseases or disease symptoms that have been linked to endothelial dysfunction. CONCLUSIONS: These observations demonstrate that activating both p38MAPK and ERK1/2 signaling pathways with U 46619 improves the efficiency of arteriovenous hiPSC-EC differentiation and produces cells with greater proliferative capacity. PMID- 30442195 TI - Heart rate variability in hyperthyroidism on sub Saharan African patients: a case control study. AB - OBJECTIVE: We aimed to determine heart rate variability in freshly diagnosed untreated hyperthyroidism patients. We enrolled 10 patients (9 females) and 10 matched controls for sex and age. Each eligible patient underwent five different tests according to Ewing battery tests for cardiac autonomic dysfunction assessment. HRV was assessed during each maneuver and on 24 h using a continuous electrocardiogram with automatic estimation of SDNN, RMSSD, LF HF and HF/LH ratio. Results of tests were compared between hyperthyroidism patients and matched controls using the non-parametric test of Mann-Whitney. RESULTS: Heart rate was significantly higher in patients with thyrotoxicosis (82.91 +/- 10.99 vs 67.04 +/- 6.80; 0.006) compared to their controls. On time-domain analysis, there was a trend towards reduction in SDNN (39.52 vs. 63.75; p = 0.2) as well as the RMSSD (30.44 vs 64.03; p = 0.09) in patients with hyperthyroidism. The frequency domain analysis showed non-significant higher values for the LF (43.87 vs 38.85 +/- 12.85; p = 0.8) and lower for the HF (32.54 vs 43.39; p = 0.3). Test's results were mostly impaired in hyperthyroid patients and all patients presented abnormal results for parasympathetic activity. Untreated and recently diagnosed hyperthyroidism is associated to an altered parasympathetic activity in sub Saharan African patients. PMID- 30442197 TI - Changes and predictive value for treatment outcome of the compulsive exercise test (CET) during a family-based intervention for adolescents eating disorders. AB - BACKGROUND: The aim of this study was to explore changes in the Compulsive Exercise Test (CET) following a family-based intervention in adolescents with restrictive eating disorders (ED). It was hypothesized that compulsive exercise would improve with successful intervention against the ED but also that a high level of compulsive exercise at presentation would be associated with a less favourable outcome. METHOD: The CET, the Eating Disorders Examination Questionnaire (EDE-Q), and body mass index were available for 170 adolescents at presentation and at a one-year follow-up. Treatment was a family-based intervention and included that all exercise was stopped at start of treatment. Recovery was defined as EDE-Q score < 2.0 or absence of an ED at an interview. RESULTS: Exercise for weight control and for avoiding low mood, which are related to ED cognitions, decreased in recovered patients. Exercise for improving mood did not change in either recovered or not recovered patients. The CET subscale scores at presentation did not independently predict recovery. CONCLUSION: Compulsive exercise is one of several ED related behaviours which needs to be targeted at the start of treatment. With successful treatment it decreases in parallel with other ED related cognitions and behaviours but without a loss of the ability to enjoy exercise. PMID- 30442198 TI - Epilepsy control with carbamazepine monotherapy from a genetic perspective. AB - BACKGROUND: Ethnicity variation is one of the main factors that may affect drug response in clinical practice. As MTHFR gene affects different transcriptome and proteome which affect the clinical response of drugs. Purpose of the current study was to observe possible variations in plasma levels of carbamazepine monotherapy and seizures' control in Pakhtun population of Khyber Pakhtunkhwa (KP) in the context of MTHFR (C677T and A1298C) gene polymorphisms. METHODS: Blood was collected from the epileptic patients treated with carbamazepine monotherapy for the first time following respective oral doses on its steady state concentration after 3 h of morning dose at 3rd and 6th month of the therapy. Plasma carbamazepine levels were determined using reverse phase high performance liquid chromatography after method validation. MTHFR (C677T, AA298C) gene was genotyped. Patients were followed on 3rd and 6th month of the therapy for monitoring of response to carbamazepine therapy. RESULTS: Following for 3rd and 6th month of duration of carbamazepine therapy, poor seizure controlled patients were more likely noticed in heterozygous variants (677CT and 1298 AC) of MTHFR gene (P < 0.05). There was no significant (P > 0.05) difference in the dose and plasma level of carbamazepine among different genotypes of MTHFR (C677T and A1298C) gene. Similarly, the difference in dose and plasma level of carbamazepine was not significant (P > 0.05) in the responder and non-responder people with epilepsy. CONCLUSION: Our study suggests that heterozygous variants of MTHFR (C677T and A1298C) gene are associated with poor seizure control in Pakhtun population of KP despite the fact that plasma level of carbamazepine were found within the therapeutic range. PMID- 30442196 TI - The quality of clinical practice guidelines for management of pediatric type 2 diabetes mellitus: a systematic review using the AGREE II instrument. AB - AIMS: Pediatric type 2 diabetes mellitus (T2DM) is a relatively new disease with increasing incidence corresponding to the obesity epidemic among youth. It is important for clinicians to have access to high-quality clinical practice guidelines (CPGs) for appropriate management of pediatric patients with T2DM. The objective of this systematic review was to evaluate overall quality of CPGs for the management of pediatric T2DM using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) tool. METHODS: We searched MEDLINE, Embase, CINAHL, Trip, National Guideline Clearinghouse, and grey literature to identify eligible CPGs. We also searched the webpages of national and international diabetes and pediatric organizations globally. We included CPGs from national and international diabetes and pediatric associations that were published as standalone guidelines for T2DM in children and adolescents (2-18 years of age). We also included pediatric and adult guidelines for type 1 diabetes if they included a section addressing T2DM management in children and adolescents. We retrieved the two most recent guidelines from each organization when available to assess change in quality over time. We excluded individual studies and systematic reviews that made treatment recommendations as well as CPGs that were developed for a single institution. RESULTS: We included 21 unique CPGs in this systematic review. Of the included guidelines, 12 were developed or updated between 2012 and 2014. Five of all included CPGs were specific to pediatric populations. The analysis revealed that "Rigour of Development" (mean 45%, SD 28.68) and "Editorial Independence" (mean 45%, SD 35.19) were the lowest scoring domains on the AGREE II for the majority of guidelines, whereas "Clarity of Presentation" was the highest scoring domain (mean 72%, SD 18.89). CONCLUSIONS: Overall, two thirds of the pediatric T2DM guidelines were moderate to low quality and the remaining third ranked higher in quality. Low quality was especially due to the scores for the "Rigour of Development" domain, which directly measures guideline development methodology. It is important that future guidelines and updates of existing guidelines improve the methodology of development and quality of reporting in order to appropriately guide physicians managing children and adolescents with T2DM. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016034187. PMID- 30442194 TI - Ring chromosome 15 - cytogenetics and mapping arrays: a case report and review of the literature. AB - BACKGROUND: Ring chromosome 15 has been associated in previous studies with different clinical characteristic such as cardiac problems, digit and musculoskeletal abnormalities, and mental and motor problems among others. Only 97 clinical cases of ring chromosome 15 syndrome have been reported since 1966 and a common phenotype for these patients has not been established. CASE PRESENTATION: The present case report describes a 15-month-old girl from the Amazon region of Ecuador, of Mestizo ancestry, who after cytogenetic tests showed a 46,XX,r(15) karyotype in more than 70% of metaphases observed. Her parents were healthy and non-related. The pregnancy was complicated and was positive for intrauterine growth retardation. Her birth weight was 1950 g, her length was 43.5 cm, and she had a head circumference of 29.3. In addition to postnatal growth delay, she had scant frontal hair, small eyes, hypertelorism, low-set of ears, flattened nasal bridge, anteverted nostrils, down-turned mouth, three cafe au lait spots, and delayed dentition. CONCLUSIONS: Despite the frequency of some phenotypes expressed in the different clinical cases reviewed and the present case, a common phenotype for patients with ring 15 could not be determined and it is restricted to the region of the chromosome lost during the ring formation. PMID- 30442199 TI - Anterior chamber fibrinoid syndrome after cataract extraction in a patient on ibrutinib for B-cell chronic lymphocytic leukemia: a case report and review of the literature. AB - BACKGROUND: Ibrutinib is a tyrosine kinase inhibitor commonly used in patients with chronic lymphocytic leukemia. Based on the published literature, it has a very sound ophthalmologic safety profile. In the following, we describe a case of anterior chamber fibrinoid syndrome in a patient on ibrutinib for B-cell chronic lymphocytic leukemia after uncomplicated cataract extraction. CASE PRESENTATION: A 75-year-old white man with B-cell chronic lymphocytic leukemia on ibrutinib therapy and without significant past ocular history presented 1 day after uncomplicated phacoemulsification with in-the-bag intraocular lens implantation with multiple, discrete, pigmented cords in the anterior chamber. His vision was 20/100 and intraocular pressure was 43 mmHg. There was no hypopyon, hyphema, or cellular reaction. The dilated fundus examination was unremarkable. He was diagnosed as having fibrinoid syndrome and started on topical prednisolone, brimonidine, timolol-dorzolamide, and orally administered acetazolamide. Within 2 weeks, the fibrin cords disappeared completely, vision improved to 20/30, and the intraocular pressure normalized off all medications. CONCLUSIONS: The precise etiology of fibrinoid syndrome remains unclear. This is the first case of fibrinoid syndrome in a patient on ibrutinib, which is known to cross the blood brain barrier and induce intraocular changes. It is important to differentiate this syndrome from toxic anterior segment syndrome and endophthalmitis, and to initiate appropriate treatment. The fibrin bands tend to be exquisitely sensitive to topical steroids and to resolve within a few weeks without sequelae. PMID- 30442200 TI - A new case report of severe mucopolysaccharidosis type VII: diagnosis, treatment with haematopoietic cell transplantation and prenatal diagnosis in a second pregnancy. AB - A new patient with severe mucopolysaccharidosis (MPS) type VII is reported. Non immune hydrops fetalis (NIHF) was diagnosed during pregnancy. At birth, he showed generalized hydrops and dysmorphic features typical of MPS. Many diagnoses were excluded before reaching the diagnosis of MPS VII at 8 months of life. During the first year of life he had frequent respiratory infections associated with restrictive and obstructive bronchopneumopathy and underwent three surgical interventions: decompression of the spinal cord at the craniocervical junction, bilateral inguinal hernia, and bilateral clubfoot. At 14 months of life he underwent successful haematopoietic cell transplantation (HCT). During the following 10 months, his bronchopneumopathy progressively worsened, needing chronic pharmacological treatment and O2 administration. The patient died of respiratory insufficiency during a respiratory syncytial virus infection at 25 months of age. Molecular analysis showed the homozygous variant c.1617C > T, leading to the synonymous mutation p.Ser539=. This caused aberrant splicing with partial skipping of exon 10 (r.1616_1653del38) and complete skipping of exon 9 (r.1392_1476del85; r.1616_1653del38). No transcript of normal size was evident. The parents were both confirmed to be carriers. In a subsequent pregnancy, a prenatal diagnosis showed an affected fetus. Ultrasound examination before abortion showed NIHF. The skin and placenta examination by electron microscopy showed foamy intracytoplasmic vacuoles with a weakly electron-dense substrate. MPS VII is a very rare disease but it is possible that some cases go undiagnosed for several reasons, including that MPS VII, and other lysosomal storage diseases, are not included in the work-up for NIHF in many institutions, and the presence of anasarca at birth may be confounding for the recognition of the typical facial characteristics of the disease. This is the eighth patient affected by MPS VII who has undergone HCT. It is not possible to draw conclusions about the efficacy of HCT in MPS VII. Treatment with enzyme replacement is now available and will probably be beneficial for the patients who have a milder form with no or little cognitive involvement. Increased awareness among clinicians is needed for prompt diagnosis and to offer the correct treatment as early as possible. PMID- 30442201 TI - Circular RNAs are abundantly expressed and upregulated during repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells. AB - BACKGROUND: Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exhibit strong and powerful potential in repairing different diseases. The expression profile of circular RNA (circRNA) provides valuable insight for regulation of the repair process and exploration of reparative effect mechanisms. METHODS: Human endometrial stromal cells (ESCs) were cultured with mifepristone to obtain damaged ESCs, which were then cocultured with or without WJ-MSCs (cocultured group versus non-cocultured group) to observe the reparative effect upon damaged ESCs by WJ-MSCs. CircRNA microarray was performed between the two groups. Based on the transcriptomics data, the differential gene expression profiles of the two groups were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and network analysis methods. Screening of a circRNA database was performed, and the results were confirmed by quantitative polymerase chain reaction (qPCR). RESULTS: WJ-MSCs exerted a reparative effect upon damaged ESCs in the cocultured group such as improved cell morphology, higher proliferative ability, and lower apoptosis rate. CircRNA array showed that 7757 circRNAs were differentially expressed in ESCs from the cocultured group. Mitotic cell cycle, cell cycle process, and nuclear division ranked top in the GO upregulated list of the two groups, while DNA replication and cell cycle ranked top in the KEGG pathway analysis upregulated list of the two groups. The nine most aberrantly expressed circRNAs were selected for further verification in the same cohort of samples by microarray analysis. Seven of the nine most aberrantly circRNAs were confirmed to be significantly upregulated in the cocultured group. And four of the seven circRNAs (hsa_circ_0015825, hsa-circRNA4049-38, hsa circRNA5028-15, and hsa_circ_0111659) expression both in ESCs and WJ-MSCs tended to decrease with time by qPCR. The levels of the remaining three circRNAs (hsa circRNA8881-21, hsa_circ_0020492 and hsa_circ_ 0026141) did not change significantly over time in either ESCs or WJ-MSCs. Moreover, we focused on hsa_circRNA_0111659 and predicted its miRNAs and targeted mRNA. The association of circRNA-miRNA-mRNA is likely to be involved in regulating the repair of endometrial damage. CONCLUSIONS: Our results presented the abundant and upregulated circRNAs profile during repair of the damaged endometrium by WJ-MSCs and provided a novel perspective for circRNAs in the regulation of WJ-MSCs for endometrial repair. PMID- 30442202 TI - Diffusion-weighted imaging of rectal cancer on repeatability and cancer characterization: an effect of b-value distribution study. AB - BACKGROUND: To explore the effect of b-value distributions on the repeatability and diagnostic performance of the ADC value in rectal cancer patients using multiple b-values and mono-exponential model diffusion-weighted imaging (DWI). METHODS: Thirty-two preoperative rectal cancer patients, without receiving neoadjuvant therapy, were scanned on a 3 Tesla magnetic resonance imaging scanner using DWI with 10 b-values ranging from 0 to 2000 s/mm2. The apparent diffusion coefficient (ADC) value was calculated using a mono-exponential model and 31 b value combinations consisting of 2 to 10 b-values were explored. Regions of interest with the maximum cross-sectional tumour size were outlined on the ADC map by two independent observers. Intraclass correlation coefficients (ICC), coefficient of variation (CV), and Bland-Altman plots between the two observers were calculated and evaluated to determine repeatability. Areas under receiver operating characteristic curves (AUCs) were evaluated for rectal cancer characterization. Correlations between the mean ADC values and T stage were assessed using the Spearman correlation coefficient (rho). alpha (= ICC + AUC + |rho|- CV - |bias|) was defined and used to assess the optimal b-value distribution. RESULTS: Postoperative pathology tests revealed 4 patients with T1, 10 patients with T2, and 18 patients with T3 stages. There were no significant difference in age and sex between the two groups (T1-2 vs. T3). Excellent reproducibility was observed for ADC values between two observers with ICC and CV values ranging from 0.920 to 0.998, and 1.475 to 5.568%, respectively. The mean percent difference and rho between the paired measurements was ranged from - 2.7 to 1.2% and from - 0.759 to - 0.407, respectively. The b-value combinations with the top three alpha values were b(0, 1000 s/mm2), b(500, 1500, 2000 s/mm2) and b(100, 1000, 1500 s/mm2) for alpha = 2.581, 2.571 and 2.569, respectively. CONCLUSIONS: The number of b-values and their distributions influenced the repeatability of the ADC values and their diagnostic performance. The optimal b value combination was 0 and 1000 s/mm2 for DWI examination of rectal cancer patients. PMID- 30442203 TI - Aerosolized antibiotics for ventilator-associated pneumonia: a pairwise and Bayesian network meta-analysis. AB - BACKGROUND: Aerosolized antibiotics have been proposed as a novel and promising treatment option for the treatment of ventilator-associated pneumonia (VAP). However, the optimum aerosolized antibiotics for VAP remain uncertain. METHODS: We included studies from two systematic reviews and searched PubMed, EMBASE, and Cochrane databases for other studies. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis. RESULTS: Eight observational and eight randomized studies were identified for this analysis. By pairwise meta-analysis using intravenous antibiotics as the reference, patients treated with aerosolized antibiotics were associated with significantly higher rates of clinical recovery (risk ratio (RR) 1.21, 95% confidence interval (CI) 1.09-1.34; P = 0.001) and microbiological eradication (RR 1.42, 95% CI 1.22-1.650; P < 0.0001). There were no significant differences in the risks of mortality (RR 0.88, 95% CI 0.74-1.04; P = 0.127) or nephrotoxicity (RR 1.00, 95% CI 0.72-1.39; P = 0.995). Using network meta-analysis, clinical recovery benefits were seen only with aerosolized tobramycin and colistin (especially tobramycin), and microbiological eradication benefits were seen only with colistin. Aerosolized tobramycin was also associated with significantly lower mortality when compared with aerosolized amikacin and colistin and intravenous antibiotics. The assessment of rank probabilities indicated aerosolized tobramycin presented the greatest likelihood of having benefits for clinical recovery and mortality, and aerosolized colistin presented the best benefits for microbiological eradication. CONCLUSIONS: Aerosolized antibiotics appear to be a useful treatment for VAP with respect to clinical recovery and microbiological eradication, and do not increase mortality or nephrotoxicity risks. Our network meta-analysis in patients with VAP suggests that clinical recovery benefits are associated with aerosolized tobramycin and colistin (especially tobramycin), microbiological eradication with aerosolized colistin, and survival with aerosolized tobramycin, mostly based on observational studies. Due to the low levels of evidence, definitive recommendations cannot be made before additional, large randomized studies are carried out. PMID- 30442205 TI - Structural changes in amygdala nuclei, hippocampal subfields and cortical thickness following electroconvulsive therapy in treatment-resistant depression: longitudinal analysis. AB - BACKGROUND: Electroconvulsive therapy (ECT) is the treatment of choice for severe mental illness including treatment-resistant depression (TRD). Increases in volume of the hippocampus and amygdala following ECT have consistently been reported.AimsTo investigate neuroplastic changes after ECT in specific hippocampal subfields and amygdala nuclei using high-resolution structural magnetic resonance imaging (MRI) (trial registration: clinicaltrials.gov - NCT02379767). METHOD: MRI scans were carried out in 14 patients (11 women, 46.9 years (s.d. = 8.1)) with unipolar TRD twice before and once after a series of right unilateral ECT in a pre-post study design. Volumes of subcortical structures, including subfields of the hippocampus and amygdala, and cortical thickness were extracted using FreeSurfer. The effect of ECT was tested using repeated-measures ANOVA. Correlations of imaging and clinical parameters were explored. RESULTS: Increases in volume of the right hippocampus by 139.4 mm3 (s.d. = 34.9), right amygdala by 82.3 mm3 (s.d. = 43.9) and right putamen by 73.9 mm3 (s.d. = 77.0) were observed. These changes were localised in the basal and lateral nuclei, and the corticoamygdaloid transition area of the amygdala, the hippocampal-amygdaloid transition area and the granule cell and molecular layer of the dentate gyrus. Cortical thickness increased in the temporal, parietal and insular cortices of the right hemisphere. CONCLUSIONS: Following ECT structural changes were observed in hippocampal subfields and amygdala nuclei that are specifically implicated in the pathophysiology of depression and stress-related disorders and retain a high potential for neuroplasticity in adulthood.Declaration of interestS.K. has received grants/research support, consulting fees and/or honoraria within the past 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/S, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe and Servier. R.L. received travel grants and/or conference speaker honoraria from Shire, AstraZeneca, Lundbeck A/S, Dr. Willmar Schwabe GmbH, Orphan Pharmaceuticals AG, Janssen-Cilag Pharma GmbH, and Roche Austria GmbH. PMID- 30442206 TI - Vitamin D intake, serum 25-hydroxy vitamin D and pulmonary function in paediatric patients with cystic fibrosis: a longitudinal approach. AB - Pancreatic-insufficient children with cystic fibrosis (CF) receive age-group specific vitamin D supplementation according to international CF nutritional guidelines. The potential advantageous immunomodulatory effect of serum 25 hydroxy vitamin D (25(OH)D) on pulmonary function (PF) is yet to be established and is complicated by CF-related vitamin D malabsorption. We aimed to assess whether current recommendations are optimal for preventing deficiencies and whether higher serum 25(OH)D levels have long-term beneficial effects on PF. We examined the longitudinal relationship between vitamin D intake, serum 25(OH)D and PF in 190 CF children during a 4-year follow-up period. We found a significant relationship between total vitamin D intake and serum 25(OH)D (beta = 0.02; 95 % CI 0.01, 0.03; P = 0.000). However, serum 25(OH)D decreased with increasing body weight (beta = -0.79; 95 % CI -1.28, -0.29; P = 0.002). Furthermore, we observed a significant relationship between serum 25(OH)D and forced expiratory volume in 1 s (beta = 0.056; 95 % CI 0.01, 0.102; P = 0.018) and forced vital capacity (beta = 0.045; 95 % CI 0.008, 0.082; P = 0.017). In the present large study sample, vitamin D intake is associated with serum 25(OH)D levels, and adequate serum 25(OH)D levels may contribute to the preservation of PF in children with CF. Furthermore, to maintain adequate levels of serum 25(OH)D, vitamin D supplementation should increase with increasing body weight. Adjustments of the international CF nutritional guidelines, in which vitamin D supplementation increases with increasing weight, should be considered. PMID- 30442207 TI - Interpreting physical and mental metaphors: Is Theory of Mind associated with pragmatics in middle childhood? AB - We investigated the association between individual differences in metaphor understanding and Theory of Mind (ToM) in typically developing children. We distinguished between two types of metaphors and created a Physical and Mental Metaphors task, echoing a similar distinction for ToM. Nine-year-olds scored lower than older age-groups in ToM as well as in the interpretation of mental, but not physical, metaphors. Moreover, nine-year-olds (but not older children) who are better in ToM are also better in interpreting mental, but not physical, metaphors. This suggests that the link between metaphor and ToM is stronger when metaphorical interpretation involves mental aspects, and it is more evident in early rather than later childhood. PMID- 30442204 TI - New treatments for the mucopolysaccharidoses: from pathophysiology to therapy. AB - Enzyme replacement therapy is currently considered the standard of care for the treatment of mucopolysaccharidoses (MPS) type I, II, VI, and IV. This approach has shown substantial efficacy mainly on somatic symptoms of the patients, but no benefit was found for other clinical manifestations, such as neurological involvement. New strategies are currently being tested to address these limitations, in particular to obtain sufficient therapeutic levels in the brain. Intrathecal delivery of recombinant enzymes or chimeric enzymes represent promising approaches in this respect. Further innovation will likely be introduced by the recent advancements in the knowledge of lysosomal biology and function. It is now clear that the clinical manifestations of MPS are not only the direct effects of storage, but also derive from a cascade of secondary events that lead to dysfunction of several cellular processes and pathways. Some of these pathways may represent novel therapeutic targets and allow for development of novel or adjunctive therapies for these disorders. PMID- 30442208 TI - Magnesium absorption as influenced by the rumen passage kinetics in lactating dairy cows fed modified levels of fibre and protein. AB - The potassium sensitive magnesium absorption through the rumen wall may be influenced by additional dietary properties, such as diet type, forage type or forage to concentrate ratio. These properties are likely associated to rumen passage kinetics modified by dietary fibre content. The study aimed to assess the effects of rumen passage kinetics on apparent Mg absorption and retention in lactating dairy cows fed modified levels of fibre. Six lactating Red-Holstein and Holstein cows, including four fitted with ruminal cannulas were randomly assigned to a 3 * 3 cross-over design. The experimental diets consisted of early harvested low NDF (341 g NDF/kg DM) and late harvested high NDF (572 g NDF/kg DM) grass silage (80% DM) and of concentrates (20% of DM). As the low-fibre diet was excessive in protein, a third high-fibre diet was formulated to be balanced in digestible protein with the low-fibre diet to avoid any eventual confounding effects of NDF and protein excess. All diets were formulated to contain iso-Ca, P, -Mg, -K and -Na. Passage kinetics of solid and liquid phase of rumen digesta were evaluated using ruminal marker disappearance profiles. Cows fed the low fibre diet had compared to the other diets, an up to 40% lower solid and 26% lower liquid phase volume of rumen digesta and a 10% numerically higher fractional rumen liquid passage rate. Rumen pH lost 0.6 units and Mg concentration in the rumen liquid phase tripled when cows were fed the low-fibre diet. Faecal Mg excretion was up to 14% higher in cows fed the low-fibre diet and Mg absorbability was 12% compared to up to 19% in other diets. Urinary Mg excretion in cows fed the low-fibre diet was half of the ones in the other treatments, but Mg retention was not affected. Dietary protein excess neither affected rumen passage kinetics nor Mg absorption and retention. Absorption of Mg was correlated with rumen liquid volume which both decreased with decreasing daily NDF intake (NDFi, 11.8 +/- 2.4 l/kg NDFi). Consequently, daily Mg absorption decreased by 1.32 +/- 0.28 g/kg decreasing NDFi. To conclude, in addition to the known antagonistic effect of dietary K, the present data indicate that Mg absorption was dependent from NDFi which modified rumen liquid volume, but was independent of dietary protein excess likely associated to low NDF herbages. PMID- 30442209 TI - Electron Beam-Induced Carbon Erosion and the Impact on Electron Probe Microanalysis. AB - Electron beam-induced carbon contamination is a balance between simultaneous deposition and erosion processes. Net erosion rates for a 25 nA 3 kV beam can reduce a 5 nm C coating by 20% in 60 s. Measurements were made on C-coated Bi substrates, with coating thicknesses of 5-20 nm, over a range of analysis conditions. Erosion showed a step-like increase with increasing electron flux density. Both the erosion rate and its rate of change increase with decreasing accelerating voltage. As the flux density decreases the rate of change increases more rapidly with decreasing voltage. Time-dependent intensity (TDI) measurements can be used to correct for errors, in both coating and substrate quantifications, resulting from carbon erosion. Uncorrected analyses showed increasing errors in coating thickness with decreasing accelerating voltage. Although the erosion rate was found to be independent of coating thickness this produces an increasing absolute error with decreasing starting thickness, ranging from 1.5% for a 20 nm C coating on Bi at 15 kV to 14% for a 5 nm coating at 3 kV. Errors in Bi Malpha measurement are <1% at 5 kV or above but increase rapidly below this, both with decreasing voltage and increasing coating thickness to 20% for a 20 nm coated sample at 3 kV. PMID- 30442210 TI - Hearing recovery from deafness caused by bromate intoxication. AB - OBJECTIVES: Sodium bromate is a strong oxidant, and bromate intoxication can cause irreversible severe-to-profound sensorineural hearing loss. This paper reports the first case in the English literature of bromate-induced hearing loss with hearing recovery measured by formal audiological assessment.Case reportA 72 year-old woman was admitted to hospital with complaints of profound hearing loss, nausea, diarrhoea and anuria after bromate ingestion in a suicide attempt. On admission, pure tone audiometry and auditory brainstem responses showed profound bilateral deafness. Under the diagnosis of bromate-induced acute renal failure and sensorineural hearing loss, continuous haemodiafiltration was performed. When dialysis was discontinued, pure tone audiometry and auditory brainstem responses showed partial threshold recovery from profound deafness. CONCLUSION: Severe-to profound sensorineural hearing loss is a common symptom of bromate intoxication. Bromate-induced hearing loss may be partially treated, and early application of continuous haemodiafiltration might be useful as a treatment for this intractable condition. PMID- 30442211 TI - Feed deprivation in Merino and Terminal sired lambs: (1) the metabolic response under resting conditions. AB - The aim of this study was to examine the metabolic response to feed deprivation up to 48 h in low and high yielding lamb genotypes. It was hypothesised that Terminal sired lambs would have decreased plasma glucose and increased plasma non esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHOB) concentrations in response to feed deprivation compared to Merino sired lambs. In addition, it was hypothesised that the metabolic changes due to feed deprivation would also be greater in progeny of sires with breeding values for greater growth, muscling and leanness. Eighty nine lambs (45 ewes, 44 wethers) from Merino dams with Merino or Terminal sires with a range in Australian Sheep Breeding Values (ASBVs) for post weaning weight (PWT), post-weaning eye muscle depth and post-weaning fat depth (PFAT) were used in this experiment. Blood samples were collected via jugular cannulas every 6 h from time 0 to 48 h of feed deprivation for the determination of plasma glucose, NEFA, BHOB and lactate concentration. From 12 to 48 h of feed deprivation plasma glucose concentration decreased (P < 0.05) by 25% from 4.04 +/ 0.032 mmol/l to 3.04 +/- 0.032 mmol/l. From 6 h NEFA concentration increased (P < 0.05) from 0.15 +/- 0.021 mmol/l by almost 10-fold to 1.34 +/- 0.021 mmol/l at 48 h of feed deprivation. Feed deprivation also influenced BHOB concentrations and from 12 to 48 h it increased (P < 0.05) from 0.15 +/- 0.010 mmol/l to 0.52 +/ 0.010 mmol/l. Merino sired lambs had a 8% greater reduction in glucose and 29% and 10% higher NEFA and BHOB response, respectively, compared to Terminal sired lambs (P < 0.05). In Merino sired lambs, increasing PWT was also associated with an increase in glucose and decline in NEFA and BHOB concentration (P < 0.05). In Terminal sired lambs, increasing PFAT was associated with an increase in glucose and decline in NEFA concentration (P < 0.05). Contrary to the hypothesis, Merino sired lambs showed the greatest metabolic response to fasting especially in regards to fat metabolism. PMID- 30442212 TI - The leg strength of two commercial strains of meat chicken subjected to different incubation profiles. AB - Lower egg shell temperatures (EST) during the first 2 weeks of incubation, notionally known as Slow start incubation, extended the standing time of a 5-week old fast feathering meat chicken parent line. This study was designed to evaluate the effect of Slow start incubation on the standing ability of commercial meat chickens. Eggs from two strains of meat chickens, Strains 1 and 2, were incubated using either the Slow start incubation, (the initial EST was 36.75 degrees C followed by a gradual increase in EST, reaching 37.8 degrees C at day 16 of incubation), or Control incubation (EST 37.75 degrees C to 38 degrees C from the start of incubation until day 18 of incubation). Eggs were observed every 6 h from 468 h until 516 h of incubation to identify chick hatch window. At 516 h of incubation all chicks were taken out of the incubator (take-off). Chicks from each Strain and incubation treatment were randomly selected for assessment of chick weight, chick length, yolk sac weight, serum Ca and P, and femoral bone ash (BA). All unhatched eggs were inspected to determine the stage of embryo failure. Remaining chicks were grown for 5 weeks in floorpens. Weekly feed intake (FI), chick weight and feed conversion ratio (FCR) were determined. At 35 days of age the standing ability of visibly male birds was assessed in a latency-to-lie test. Compared to the Control, Slow start incubation delayed the average hatch time of both strains by ~13 h, and reduced hatchability with 4.6% live but unhatched chicks, which was most evident in Strain 2. Significant differences due to main effects only were observed at take-off. Strain 1 chicks were significantly heavier and longer with higher serum Ca but significantly lower BA and serum P than Strain 2. Slow start incubation generated significantly heavier chicks that were shorter, but had significantly heavier yolk sacs, lower serum Ca but higher serum P than Control incubated chicks. During the 1st week post hatch Strain 1 Control incubated chicks had significantly higher FI and higher FCR than all other Strain and incubation treatments. At 35 days of age Slow start incubated birds of both Strains stood significantly longer than those from the Control incubation. This experiment clearly demonstrated the ability of Slow start incubation of commercial meat chickens to improve their leg strength. PMID- 30442213 TI - Psychiatrists, spirituality and religion. AB - SummaryThe consensus within psychiatry is that patients' religion/spirituality are legitimate topics in assessment and treatment. Religion/spirituality can help people cope with mental illness, but their use as therapeutic tools is controversial. Despite the publication of position statements by national and international psychiatric organisations, there is no clarity over therapeutic boundaries.Declaration of interestR.P. and R.H. are atheists. C.C.H.C. is an ordained Anglican and a past Chair of the Royal College of Psychiatrists Spirituality and Psychiatry Special Interest Group. He writes here in a personal capacity. PMID- 30442214 TI - The Reinstatement Effect in Human Predictive Learning: Contextual Modulation and the Impact of Extinction Reminders. AB - One of the most relevant phenomena both from a theoretical and clinical perspective is extinction. In particular, several researchers are interested in the response recovery effects from extinction. Reinstatement is an effect that has been proposed as a laboratory model to study relapse from extinction-based therapeutic treatments. We designed two experiments with humans to evaluate the reinstatement effect in a predictive learning task. In both experiments, participants learned a specific relationship between two cues (X and Y) and two outcomes (O1 and O2) during the first phase. Throughout extinction, both cues were presented without outcomes. After an exposure to the original outcomes, reinstatement of the first-learned information was observed during testing in both experiments. However, we found that the reinstatement effect was contextual modulated (Experiment 1; etap2 = .78, 90% CI [.48, .86], p < .0001). Furthermore, in Experiment 2 we showed a reduction of reinstatement when an extinction reminder was used etap2 = .45, 90% CI [.07, .65], p = .012. Theoretical implications are discussed, and some potential uses are mentioned. PMID- 30442215 TI - A simple, quick, validated method of recording the nasal cycle in humans using a subjective scale. AB - BACKGROUND: Studies on the nasal cycle can be limited by time-consuming rhinomanometric measurements. However, quantifiable subjective assessment of nasal airflow has been limited by poor correlation with rhinomanometric data, even when investigating patients with a deviated nasal septum. METHODS: Thirty healthy participants attended two study days for rhinomanometric and subjective assessment of nasal airflow (using the subjective ordinal scale). A nasal partitioning ratio was calculated for both measures. RESULTS: Objective and subjective nasal partitioning ratios were compared; strong correlations were seen, with a correlation coefficient of 0.64 (p < 0.00001) on day 1 and 0.68 (p < 0.00001) on day 2. CONCLUSION: The use of the subjective ordinal scale and nasal partitioning ratio provides a sensitive tool for assessing relative nasal airflow, with results that correlate strongly with rhinomanometric data. This finding strongly suggests that this combination could be used for future subjective assessment of the nasal cycle. PMID- 30442216 TI - Sow environment during gestation: part II. Influence on piglet physiology and tissue maturity at birth. AB - Sow environment during gestation can generate maternal stress which could alter foetal development. The effects of two group-housing systems for gestating sows on piglet morphological and physiological traits at birth were investigated. During gestation, sows were reared in a conventional system on a slatted floor (C, 18 sows), demonstrated as being stressful for sows or in an enriched system in larger pens and on deep straw bedding (E, 19 sows). On gestation day 105, sows were transferred into identical individual farrowing crates on a slatted floor. Farrowing was supervised to allow sampling from piglets at birth. In each litter, one male piglet of average birth weight was euthanized immediately after birth to study organ development and tissue traits. Blood samples were collected from 6 or 7 piglets per litter at birth and 2 piglets per litter at 4 days of lactation (DL4). At birth, mean piglet BW did not differ between groups (P > 0.10); however, the percentage of light ( 0.10) between C and E piglets, but the insulin to glucose ratio was greater (P = 0.02) in C than in E piglets. Compared with E piglets, C piglets had a lighter gut at birth (P = 0.01) and their glycogen content in longissimus muscle was lower (P < 0.01). In this muscle, messenger RNA levels of PAX7, a marker of satellite cells and of PPARGC1A, a transcriptional coactivator involved in mitochondriogenesis and mitochondrial energy metabolism, were greater (P < 0.05), whereas the expression level of PRDX6, a gene playing a role in antioxidant pathway, was lower (P = 0.03) in C than in E piglets. Other studied genes involved in myogenesis did not differ between C and E piglets. No system effect was observed on target genes in liver and subcutaneous adipose tissue. On DL4, C piglets exhibited a lower plasma antioxidant capacity than E piglets (P = 0.002). In conclusion, exposure of sows to a stressful environment during gestation had mild negative effects on the maturity of piglets at birth. PMID- 30442217 TI - Group Therapy for Patients with Adjustment Disorder in Primary Care. AB - A high percentage of patients have a diagnosis of adjustment disorder (AD) when they arrive at primary care (PC) appointments. However, most of them do not receive adequate psychological treatment. The present study's aim is to determine the efficacy of a group psychological treatment program in patients with AD. The sample consisted of patients with AD from two PC units in Valencia, from which two groups were randomly generated: A treatment group (n = 31) and a waiting-list group (n = 20), homogeneous in terms of socio-demographic and psychometric variables prior to treatment. Treatment consisted of eight one-hour group sessions held on a weekly basis; taking a cognitive-behavioral approach, they addressed aspects like controlling anxiety, cognitive restructuring, and coping techniques. The variables analyzed were: Psychopathology (Revised Symptom Inventory, SCL-90-R), health-related quality of life (Health Questionnaire, SF 12), and risk of suicidal behavior (Suicide Risk Scale). Means comparisons, ANCOVAs, and tests of effect size were performed. Statistically significant differences were observed in the variables, such that after intervention, the experimental group exhibited less anxious (F = 4.11, p =.048, eta2 = .08) and depressive symptoms (F = 2.41, p =.029, eta 2= .10) and higher quality of life related to physical (F = 7.17, p =.010, eta2 = .13) and emotional health (F = 10.31, p =.002, eta2 = .18). For the reasons above, we conclude that a comprehensive approach to emotional distress in PC, including group psychological interventions, is one solution for the demand for social services, and could provide savings on economic as well as human costs. PMID- 30442218 TI - Feed deprivation in Merino and Terminal sired lambs: (2) the metabolic response under pre-slaughter conditions and impact on meat quality and carcass yield. AB - Under current Australian industry pre-slaughter guidelines, lambs may be off feed for up to 48 h before slaughter. The purpose of this study was to examine what proportion of circulating metabolites at slaughter are due to stress and feed deprivation and if this response differs between Merino and Terminal genotypes. In addition the effect of feed deprivation on carcass weight and meat quality was examined. Jugular blood samples were collected from 88 Merino and Terminal sired lambs at rest and at slaughter following 24, 36 and 48 h of feed deprivation and plasma analysed for glucose, lactate, non-esterified fatty acids (NEFA) and beta hydroxybutyrate (BHOB). From the same carcasses hot carcass weight (HCWT) were measured as well as a suite of meat quality traits measured such as M. longissimus lumborum (loin) and M. semitendinosus pH at 24 h postmortem. Loin samples were also analysed for intramuscular fat content and Warner-Bratzer Shear Force. Merino sired lambs had a higher NEFA response compared to Terminal sired lambs at slaughter after 24, 36 and 48 h of feed deprivation, with NEFA levels up to 35% higher than previously reported in the same animals at rest in animal house conditions, whereas BHOB response to feed deprivation was not affected by sire type (P>0.05) and similar to previously reported at rest. In addition to the metabolic effects, increasing feed deprivation from 36 h was associated with a 3% reduction in HCWT and dressing percentage as well as causing increased ultimate pH in the M. semitendinosus in Merino sired lambs. Findings from this study demonstrate that Merino and Terminal sired lambs differ in their metabolic response to feed deprivation under commercial slaughter conditions. In addition, commercial feed deprivation appears to have a negative effect on ultimate pH and carcass weight and warrants further investigation. PMID- 30442219 TI - Comments on letter to the editor by Faniyan et al. in response to Imported leishmaniasis in Sweden 1993-2016. PMID- 30442220 TI - Trends in and correlations between antibiotic consumption and resistance of Staphylococcus aureus at a tertiary hospital in China before and after introduction of an antimicrobial stewardship programme. AB - The overuse of antibiotics and the rapid emergence of antibiotic resistance prompted the launch of an antimicrobial stewardship programme in 2011. This study aimed to investigate the trends and correlations between antibiotic consumption and resistance of Staphylococcus aureus in a tertiary hospital of northwest China from 2010 to 2016. Trends were analysed by linear regression, and correlations were assessed by an autoregressive integrated moving average model. The total consumption of antibiotics halved during the 7-year study period, while the rates of resistance of S. aureus decreased significantly or remained stable; methicillin-resistant S. aureus (MRSA) declined markedly, from 73.3% at the beginning of the study to 41.4% by the end. This latter decrease was significantly correlated with the consumption of several classes of antibiotics. In conclusion, reduction in antibiotic use impacted significantly on resistance rates and contributed to a decline in MRSA prevalence. PMID- 30442221 TI - WHICH DATABASES SHOULD BE USED TO IDENTIFY STUDIES FOR SYSTEMATIC REVIEWS OF ECONOMIC EVALUATIONS? AB - OBJECTIVES: This study investigated which databases and which combinations of databases should be used to identify economic evaluations (EEs) to inform systematic reviews. It also investigated the characteristics of studies not identified in database searches and evaluated the success of MEDLINE search strategies used within typical reviews in retrieving EEs in MEDLINE. METHODS: A quasi-gold standard (QGS) set of EEs was collected from reviews of EEs. The number of QGS records found in nine databases was calculated and the most efficient combination of databases was determined. The number and characteristics of QGS records not retrieved from the databases were collected. Reproducible MEDLINE strategies from the reviews were rerun to calculate the sensitivity and precision for each strategy in finding QGS records. RESULTS: The QGS comprised 351 records. Across all databases, 337/351 (96 percent) QGS records were identified. Embase yielded the most records (314; 89 percent). Four databases were needed to retrieve all 337 references: Embase + Health Technology Assessment database + (MEDLINE or PubMed) + Scopus. Four percent (14/351) of records could not be found in any database. Twenty-nine of forty-one (71 percent) reviews reported a reproducible MEDLINE strategy. Ten of twenty-nine (34.5 percent) of the strategies missed at least one QGS record in MEDLINE. Across all twenty-nine MEDLINE searches, 25/143 records were missed (17.5 percent). Mean sensitivity was 89 percent and mean precision was 1.6 percent. CONCLUSIONS: Searching beyond key databases for published EEs may be inefficient, providing the search strategies in those key databases are adequately sensitive. Additional search approaches should be used to identify unpublished evidence (grey literature). PMID- 30442222 TI - Effect of Skin Maceration Treatment on Aroma Profiles of Kiwi Wines Elaborated with Actinidia deliciosa "Xuxiang" and A. chinensis "Hort16A". AB - Background: Kiwi has become an important and promising fruit to ferment kiwi wine in recent years in China. Objective: The objective of this study was to evaluate the effect of skin maceration treatment on aroma profiles of kiwi wine elaborated with two representative kiwi varieties (Actinidia deliciosa "Xuxiang" and A. chinensis "Hort16A"). Methods: Aroma profiles were characterized using solid phase microextraction GC-MS method. Principal component analysis was used to separate and group the wines as well as for identifying the aroma components that best differentiate the wines. Results: Esters and alcohols were the two most abundant compounds in kiwi wine. Skin maceration treatment gave rise to a positive effect of aroma profiles, resulting in a significant increase of terpenes. A total of 11 volatile compounds were found at concentrations higher than their odor threshold in kiwi wine samples. Conclusions: The study could play a role in laying a foundation for the development of the kiwi fruit wine industry. Highlights: Different aroma profiles were presented because of variety differences. Skin maceration treatment gave rise to a positive effect of aroma profiles, which resulted in a significant increase of terpenes. PMID- 30442223 TI - Dynamic Analysis of Nucleosides and Carbohydrates during Developmental Stages of Cordyceps militaris in Silkworm (Bombyxmori). AB - Background: Cultured Cordyceps militaris is very popular. Objective: To gain dynamic insight into activity markers in fruiting body of Cordyceps militaris (C. militaris) in Bombyxmori (B. mori), also named silkworm. Methods: The development stages of samples at 3, 9, 12, 19, 27, and 33 days after inoculation (DAI) were collected. HPLC coupled with diode array detection and evaporative light scattering detection method (HPLC-DAD-ELSD) was used to determine eight makers, including six nucleosides and two carbohydrates from the samples. Results: C. militaris cultured 33 DAI with fifth star silkworm larva could accumulate higher levels of cordycepin (13.43 mg/g) than the highest reported cordycepin (8.57 g/L). The contents of cordycepin, adenosine, and trehalose were gradually increased with the formation of C. militaris fruiting bodies on silkworm larva, while mannitol was decreased. The change of guanosine was similar to uracil. Conclusions: Results suggested that mannitol could be accumulated in a short period during mycelium growth and could metabolize and transform into energy store and trehalose during fruit body formation. The inosine in the insect was completely utilized and transformed. The synergistic formation of cordycepin and adenosine or differences in metabolized pathways are a great possibility according to the same trend. Highlights: This research offered some reference to further find a certain regularity or metabolic mechanism. PMID- 30442225 TI - Relation of Vasoplegia in the Absence of Primary Graft Dysfunction to Mortality Following Cardiac Transplantation. AB - Vasoplegia following cardiac transplantation is associated with increased morbidity and mortality. Previous studies have not accounted for primary graft dysfunction (PGD). The definition of vasoplegia is based on pressor requirement at 48 hours, many PGD parameters may have normalized after the initial 24 hours on inotropes. We surmised that the purported negative effects of vasoplegia following transplantation may in part be driven by PGD. We reviewed 240 consecutive adult cardiac transplants at our center between 2012 and 2016. The severity of vasoplegia was evaluated as a risk factor for 1-year survival, and the analysis was repeated for the subgroup of 177 patients who did not develop PGD. Overall, 63 (26%) of patients developed mild, moderate, or severe PGD. In those without PGD, vasoplegia was associated with length of stay but not with short- or long-term mortality. Moderate and/or severe vasoplegia occurred in 35 (15%) patients and was associated with higher short-term mortality, length of stay, and PGD. Multivariate logistic regression identified body mass index >=35 kg/m2, left ventricular assist device before transplantation, and use of extracorporeal membrane oxygenation as joint risk factors for vasoplegia. In patients without PGD, only left ventricular assist device before transplantation was associated with vasoplegia. In conclusion, our results show that, in the sizeable subgroup of patients with no signs of PGD, vasoplegia had a much more modest impact on post-transplant morbidity and no significant effect on 1- and 3 year survival. This suggests that PGD may be a confounder when assessing vasoplegia as a risk factor for adverse outcomes. PMID- 30442224 TI - Acute Coronary Syndromes in Heart Transplant Recipients (from a National Database Analysis). AB - With an expanding and aging heart transplant population, the incidence of acute coronary syndromes (ACS) is expected to increase. Our study aims to report current trends in in-hospital management and outcomes in heart transplant recipients presenting with ACS. We conducted an analysis of the National Inpatient Sample (2007 to 2014) to study the trends in hospitalization, in hospital management, and outcomes in heart transplant recipients with a primary diagnosis of ACS. We included patients with ST elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and those with unstable angina pectoris (UAP). A total of 1,621 ACS (NSTEMI/UAP-76% vs STEMI-24%) hospitalizations were identified. Despite 1,327 (81%) of patients who underwent left heart catheterization, coronary revascularization was performed in only 576 patients (36%). Mortality was significantly higher in patients presenting with STEMI versus NSTEMI/UAP (28% vs 11%, respectively; p <0.05) and those who did not undergo revascularization (19% vs 7%; p <0.05). Cardiogenic shock (CS) was diagnosed in 14.5% patients. Mechanical circulatory support utilization was higher in CS group compared with non-CS group (69% vs 2.8%; p <0.05), as was in hospital mortality (39% vs 10%; p <0.05). Repeat transplantation during the index hospitalization was done in 4.5% of ACS patients. In conclusion, in heart transplant recipients, ACS is associated with a high incidence of CS and in hospital mortality. Aggressive treatment strategy that includes revascularization, mechanical circulatory support use (in those developing CS), and urgent retransplantation in suitable candidates seems to lead to better results than a more conservative strategy. PMID- 30442226 TI - Effects of Hepatitis C Virus Antibody-Positivity on Cardiac Function and Long Term Prognosis in Patients With Adult Congenital Heart Disease. AB - It was reported that hepatitis C virus (HCV) antibody-positivity adversely affects cardiac function. As the screening for HCV began in 1992, we hypothesized that HCV antibody-positive rate would be high in adult congenital heart disease (ACHD) patients who underwent heart surgery before 1992 and adversely affected cardiac function and long-term prognosis. We retrospectively enrolled 243 ACHD patients (mean age 25.9 years) who underwent cardiac surgery before 1992 and visited our hospital from 1995 to 2015. We compared clinical characteristics including cardiac function and long-term prognosis between HCV antibody-positive (n = 48) and antibody-negative (n = 195) patients. The composite end point (CEP) included cardiac death, heart failure hospitalization, lethal ventricular arrhythmias, and cardiac reoperation. The prevalence of reduced systemic ventricular ejection fraction <50% was significantly higher in the HCV antibody positive group compared with the HCV antibody-negative group (17 vs 5.4%, p = 0.014). During a mean follow-up period of 10.1 years (interquartile range 6 to 14 years), the CEP was noted in 51 patients. Kaplan-Meier analysis showed the HCV antibody-positive group had significantly poor event-free survival than the HCV antibody-negative group (log-rank, p = 0.002). In contrast, HCV ribonucleic acid positivity was not a significant predictor of the CEP in the HCV antibody positive group (log-rank, p = 0.442). Furthermore, the HCV antibody-positivity was significantly associated with the CEP in both univariable and multivariable Cox regression models (hazard ratio 2.37, 95% confident interval 1.32 to 4.15, p = 0.005 and 1.96, 1.06 to 3.63, p = 0.032, respectively). In conclusion, these results suggest that more attention should be paid to HCV antibody-positivity in the management of ACHD patients. PMID- 30442227 TI - Anatomical basis of drug delivery to the inner ear. AB - The isolated anatomical position and blood-labyrinth barrier hampers systemic drug delivery to the mammalian inner ear. Intratympanic placement of drugs and permeation via the round- and oval window are established methods for local pharmaceutical treatment. Mechanisms of drug uptake and pathways for distribution within the inner ear are hard to predict. The complex microanatomy with fluid filled spaces separated by tight- and leaky barriers compose various compartments that connect via active and passive transport mechanisms. Here we provide a review on the inner ear architecture at light- and electron microscopy level, relevant for drug delivery. Focus is laid on the human inner ear architecture. Some new data add information on the human inner ear fluid spaces generated with high resolution microcomputed tomography at 15 MUm resolution. Perilymphatic spaces are connected with the central modiolus by active transport mechanisms of mesothelial cells that provide access to spiral ganglion neurons. Reports on leaky barriers between scala tympani and the so-called cortilymph compartment likely open the best path for hair cell targeting. The complex barrier system of tight junction proteins such as occludins, claudins and tricellulin isolates the endolymphatic space for most drugs. Comparison of relevant differences of barriers, target cells and cell types involved in drug spread between main animal models and humans shall provide some translational aspects for inner ear drug applications. PMID- 30442228 TI - The potential beneficial role of isoflavones in type 2 diabetes mellitus. AB - Diabetes is a chronic global disease afflicting a substantial number of people worldwide. Different mechanisms have been highlighted in the progression of this disease such as dysfunction of pancreatic beta-cells, insulin resistance, elevated levels of free fatty acids which result in overproduction of reactive oxygen species, as well as pancreatic beta-cell failure and apoptosis. Isoflavones, are polyphenolic phytochemicals found in most leguminous plants, and have been identified as potentially useful antidiabetic agents. The pleiotropic effects of isoflavones include the targeting of numerous cell signaling pathways involved in the pathogenesis of diabetes. Several observational studies have supported the direct relationship between isoflavones intake and a lowered risk of diabetes. The aim of this review was to summarize relevant findings on the effects of isoflavone intake and risk of type II diabetes mellitus (T2DM), and to highlight some of the possible anti-diabetic molecular mechanisms of these polyphenols. Despite the promising therapeutic effects of isoflavones to moderate risk of T2DM, the underlying mechanisms for their preventive effects are still largely unknown. The acceptable human dosage levels of these polyphenols remain a debatable topic as these have a profound influence on the observed benefits. Considerable numbers of well-controlled, long-term human clinical studies of these phytochemicals are highly recommended. Furthermore, combinations of isoflavones and their derivatives in combination with other naturally isolated compounds, and perhaps even those drugs currently used therapeutically to control diabetes mellitus in clinical practice, may be worth exploring in the future. PMID- 30442229 TI - Increased total iron and zinc intake and lower heme iron intake reduce the risk of esophageal cancer: A dose-response meta-analysis. AB - Several epidemiological studies investigated the relationship between dietary intake of essential trace elements and the risk of esophageal cancer (EC), yielding inconsistent results. We therefore conducted a systematic meta-analysis to investigate and quantify the putative association between the intake of various essential trace elements and the risk of EC. We searched Embase, PubMed, and Web of Science for eligible articles published through April 2018 reporting the odds ratio (OR) with 95% confidence interval (95% CI). Pooled results were then calculated using fixed and random effect models. A total of 20 articles containing 4855 cases from 1 387 482 participants were included in our analysis. We found a significant inverse correlation between total iron intake and the risk of EC (OR = 0.81, 95% CI: 0.70-0.94), particularly in Asian populations. A dose response analysis revealed that each 5 mg/day increase in total iron intake was associated with a 15% reduction in EC risk (OR = 0.85, 95% CI: 0.79-0.92). In contrast, each 1 mg/day increase in heme iron intake was associated with a 21% increase in EC risk (OR = 1.21, 95% CI: 1.02-1.45). Lastly, a pooled risk estimate revealed that each 5 mg/day increase in zinc intake was associated with a 15% reduction in EC risk (OR = 0.85, 95% CI: 0.77-0.93). Taken together, our analysis indicates that increased dietary intake of total iron and zinc, as well as decreased heme iron intake, may be associated with a lower risk of developing esophageal cancer. These findings have important public health implications with respect to preventing this relatively common form of cancer. PMID- 30442230 TI - Vitamin D is associated with lower limb muscle strength and grip strength in Middle Eastern- and African-born immigrants in Sweden. AB - There is increasing evidence that vitamin D status is associated with muscle function. Vitamin D deficiency is common in immigrants. We hypothesized that there was a positive association between vitamin D status and muscle strength in immigrants. The aim of this study was to examine associations between vitamin D status and muscle strength in an immigrant population in Sweden. All immigrants aged 25-65 years, born in 9 African or Middle East countries, and living in a district in Umea (n = 1306) were invited. A total of 111 men and 105 women (16.5%) completed the study. Lower limb muscle strength was examined using a standardized muscle function indices of muscle strength. Grip strength was examined using a JAMAR hand dynamometer. Serum 25-hydroxyvitamin D [25(OH)D] was measured using liquid chromatography-tandem mass spectrometry. The analyses were adjusted for sex, age, height, body mass index, years since immigration, 25(OH)D, vitamin D deficiency, physical activity, and medical and socioeconomic factors. Twelve percent of the immigrants had vitamin D deficiency [25(OH)D levels <25 nmol/L]. In multivariable analyses, reduced lower limb muscle strength remained linearly associated with lower 25(OH)D concentrations (P = .008) and weaker grip strength remained associated with vitamin D deficiency (P = .022) after adjustments. The association between vitamin D deficiency and reduced lower limb muscle strength did not reach statistical significance (P = .052). The results demonstrate that vitamin D deficiency and low 25(OH)D concentrations were associated with muscle weakness in immigrants. PMID- 30442231 TI - Poor bioavailability of vitamin D2 from ultraviolet-irradiated D2-rich yeast in rats. AB - Ultraviolet-irradiated yeast (Saccharomyces cerevisiae) can be used to biofortify bakery products with vitamin D, but in bread, it was not effective in increasing serum 25-hydroxyvitamin D [25(OH)D] in humans, possibly because of the low digestibility of the yeast matrix. We investigated the effects of vitamin D2-rich intact yeast cells and their separated fraction, yeast cell walls, which we hypothesized to provide vitamin D2 in a more bioavailable form, on serum 25(OH)D and its metabolites in growing female Sprague-Dawley rats (n = 54) compared to vitamin D2 and D3 supplements (8 treatment groups: 300 or 600 IU vitamin D/d, and a control group, 8-week intervention). The D3 supplement groups had the highest 25(OH)D concentrations, and the vitamin D2 supplement at the 600-IU dose increased 25(OH)D better than any yeast form (P < .001 for all, analysis of covariance, adjusted for body weight). There were no significant differences between the yeast forms at the same dose (P > .05). Serum 24,25-dihydroxyvitamin D (a vitamin D catabolite) concentrations and the trend in the differences between the groups were in line with 25(OH)D (P < .001 for all). The 24,25 dihydroxyvitamin D to 25(OH)D ratio between the D2 supplement and the yeast groups did not differ (P > .05). These findings do not support the hypothesis: the ability of the different ultraviolet-treated vitamin D2-containing yeast forms to increase 25(OH)D did not differ, and the poor bioavailability of vitamin D2 in the yeasts compared D3 or D2 supplements could not be explained by the increased vitamin D catabolism in the yeast-treated groups. PMID- 30442232 TI - Oral administration of palatinose vs sucrose improves hyperglycemia in normal C57BL/6J mice. AB - Palatinose is a sucrose analog with a slower digestion rate than that of sucrose. For this reason, palatinose shows better effects on hepatic lipogenesis and cholesterol homeostasis compared with sucrose. We hypothesized that supplementation with palatinose instead of sucrose improves postprandial hyperglycemia and hyperinsulinemia in mice. Herein, we compared the digestion rates in vitro and observed physiological changes in vivo between sucrose- and palatinose-containing diets given to mice. Palatinose was hydrolyzed only by enzymes of the small intestine and was digested more slowly compared with sucrose in vitro. In mice, a diet containing palatinose resulted in significantly lower body weight gain and food efficiency rate values than those given a diet with sucrose. In this study, changes in serum biochemistry; hepatic fatty acid synthesis; cholesterol homeostasis; glucogenic, proinflammatory cytokines; and oxidative stress-related genes and proteins in the palatinose- and sucrose-fed mice were measured. Compared with the mice fed the sucrose diet, the palatinose diet resulted in lower serum glucose, insulin, and total cholesterol levels, as well as lower expression of several lipogenesis-related genes and proteins. Histological analysis of hepatic cells of palatinose-fed mice showed normal morphology. In conclusion, palatinose intake results in lower hepatic lipogenesis and better cholesterol homeostasis than the effects from sucrose. PMID- 30442233 TI - A high weekly dose of cholecalciferol and calcium supplement enhances weight loss and improves health biomarkers in obese women. AB - Obesity, a chronic condition associated with several life-threatening diseases, affects a significant proportion of the global population and has long been associated with vitamin D deficiency. The prevalence of both obesity and vitamin D deficiency has increased dramatically in Jordan in recent decades, especially among women. Few studies in Jordan and the surrounding area address this issue. In this study, we hypothesize that calcium and vitamin D have beneficial effects on weight reduction and metabolic profile in obese women. The objective of this study is to examine the effect of vitamin D3 and calcium supplementation on anthropometric measurements and some blood metabolites. Forty-five obese female subjects with vitamin D deficiency were recruited by a dietitian and randomly assigned to the same weight loss diet in addition to the following treatments (4 groups): control (CON), no prescribed supplements; vitamin D3 (Diet/D), given a high weekly dose of cholecalciferol (50 000 IU/subject/week); calcium (Diet/Ca), given 1200 mg/dL calcium/subject/day; vitamin D3 plus Ca (Diet/Ca/D), given cholecalciferol (50 000 IU/subject/week) and calcium (1200 mg/dL calcium/subject/day). Results revealed that after 3 months of supplementation, the Diet/Ca/D group subjects experienced a significant reduction (P <= .05) in weight (10.49 kg), BMI (4.61 +/- 2 kg/m2), waist circumference (11.41 +/- 8.9 cm), body fat percentage (2.43 +/- 1.7%), FBG (25.81 +/- 11.4 mg/dL), PTH (27.58 +/- 8.9 pg/mL), cholesterol (0.56 +/- 0.2 mmol/L), and triglycerides (0.53 +/- 0.21 mmol/L) when compared to the Diet/Ca and the CON groups. Interestingly, however, the CON group showed a significant increase in serum PTH concentration (9.51 +/- 3.8 pg/mL, P <= .05). Based on these results, a combined Ca and vitamin D3 supplement appears to enhance weight loss and improve some of the blood metabolic profiles in obese women subjected to a weight loss diet, thus supporting our study hypothesis. PMID- 30442234 TI - Vitamin D3 prevents cardiovascular diseases by lowering serum total homocysteine concentrations in overweight reproductive women: A randomized, placebo-controlled clinical trial. AB - Obesity and overweight are associated with vitamin D deficiency and hyperhomocysteinemia, all of which are contributing factors for developing cardiovascular disease (CVD). Therefore, we hypothesized that improving serum 25 hydroxyvitamin D [25(OH)D] levels may decrease the body weight and total homocysteine concentrations among overweight reproductive women. To test our hypothesis, a randomized, double-blind placebo-controlled clinical trial, registered under ClinicalTrials.gov Identifier No. NCT03310307, was conducted on 100 overweight reproductive women that were allocated into two groups, namely, the treatment group (n = 50), which received 50 000 IU vitamin D3 per week, and the placebo group (n = 50), and followed for 2 months. Participants' 25(OH)D, homocysteine, parathyroid hormone, calcium, phosphorus, body weight and body mass index (BMI) were measured and compared before and after treatment. The results showed that there was a significant decrease in homocysteine levels after the first and second months of vitamin D3 intervention in the treatment group, and no significant changes were seen in the placebo group throughout the period of follow up. Statistically significant (P <= .05) reductions in homocysteine concentration, body weight, BMI, and parathyroid hormone levels were noticed in the treatment group compared to the placebo. Meanwhile, 25(OH)D, calcium and phosphorus levels were statistically significantly (P <= .05) increased in the treatment group. In conclusion, vitamin D3 intervention with a treatment dose of 50 000 IU per week for at least 2 months can help decrease BMI and homocysteine levels, which in turn will help prevent or minimize the risk of CVD among overweight women of reproductive age. PMID- 30442235 TI - Time-restricted feeding mitigates high-fat diet-enhanced mammary tumorigenesis in MMTV-PyMT mice. AB - Erratic eating behavior disrupts the daily feeding and fasting pattern and leads to metabolic dysfunction and chronic diseases including cancer. In the present study, we tested the hypothesis that time-restricted feeding of a high-fat diet (HFD) to the dark phase does not enhance mammary tumorigenesis in MMTV-PyMT mice. Female mice were assigned to 3 groups and fed the standard AIN93G diet or an HFD with or without dark phase restricted feeding (12 hours). The duration of restricted feeding was 8 weeks. The HFD group had 24% more body fat mass than the AIN93G group; the body fat mass of the restricted group remained similar to that of the AIN93G group. Energy intake of the restricted group was similar to that of the HFD and AIN93G groups. The median mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the AIN93G, HFD, and restricted groups, respectively. Mammary tumor progression was 241% higher in the HFD group than that in the AIN93G group; there was no significant difference in tumor progression between the restricted and AIN93G groups. Plasma concentrations of leptin, monocyte chemoattractant protein 1, plasminogen activator inhibitor-1, angiopoietin-2, vascular endothelial growth factor, and hepatocyte growth factor were significantly higher in the HFD group than those in the control group; these measurements were similar between the restricted and control groups. In conclusion, feeding restricted to the dark phase mitigates the HFD-enhanced mammary tumorigenesis; this may be related to the lower body adiposity and associated inflammatory and angiogenic signals. PMID- 30442236 TI - Higher Mediterranean Diet scores are not cross-sectionally associated with better cognitive scores in 20- to 70-year-old Dutch adults: The NQplus study. AB - Adherence to the Mediterranean Diet (MedDiet) has been suggested to reduce the risk of age-related cognitive decline. Therefore, we hypothesized that adults consuming a more Mediterranean-like diet were more likely to have better cognitive scores. We investigated cross-sectional associations between MedDiet adherence and cognitive performance using data of 1607 Dutch men and women aged 20-70 years. Dietary intake was assessed using a 183-item Food Frequency Questionnaire. MedDiet adherence was defined by a 0-9 point scale; which was based on intakes of vegetables, legumes, fruits/nuts, cereals, fish/seafood, meat/poultry, dairy, ethanol and the MUFA:SFA ratio. Cognitive function was assessed with a neuropsychological test battery. Linear regression analyses adjusted for relevant covariates showed a significant inverse association between MedDiet adherence and everyday memory: specifically beta = -0.107 +/- 0.046 points (P = .02) for the total population and beta = -0.139 +/- 0.055 points (P = .01) for those aged >=50 years. Further exploration of the individual MedDiet food groups suggested that the association between MedDiet and every day memory was predominantly driven by the MUFA:SFA ratio. Moreover, associations were observed between higher ethanol intake with better semantic memory and language production (beta = 0.016 +/- 0.008 P = .05), higher vegetable intake with better processing speed (beta = 0.005 +/- 0.002, P = .02), and higher legumes intake with poorer processing speed (beta = -0.014 +/- 0.006, P = .03). Thus, in this Dutch cohort, higher MedDiet adherence was associated with poorer everyday memory. PMID- 30442237 TI - MiR-138-5p affects insulin resistance to regulate type 2 diabetes progression through inducing autophagy in HepG2 cells by regulating SIRT1. AB - Insulin resistance (IR) is considered as a major factor of type 2 diabetes (T2D), which is seriously detrimental to human health. In our present study, we found that the expression of miR-138-5p was increased in the insulin-resistant HepG2 cells induced by TNF-alpha. Therefore, we hypothesized that miR-138-5p might play a regulatory role in the IR. To examine this hypothesis, HepG2 cells were transfected with miR-138-5p inhibitor. Silencing of miR-138-5p increased glucose uptake and glycogen synthesis of TNF-alpha-stimulated HepG2 cells and decreased glucose concentration in medium, suggesting that downregulation of miR-138-5p suppressed IR in HepG2 cells. Besides that, we found that sirtuin 1 (SIRT1) was the target gene of the miR-138-5p. Moreover, co-transfection with SIRT1-siRNA and miR-138-5p inhibitor suppressed glucose uptake and glycogen synthesis of HepG2 cells compared with miR-138-5p inhibitor-transfected group, indicating that downregulation of SIRT1 weakened the inhibitory effect of miR-138-5p inhibitor on IR. In addition, overexpressed SIRT1 increased Beclin1, LC3 II/I level, and the number of GFP-LC3 dots and decreased p62 level, whereas downregulation of SIRT1 had the opposite effects. Our results demonstrated that overexpressed SIRT1 activated autophagy in HepG2 cells. Moreover, we observed that 3-methyladenine (an inhibitor of autophagy) treatment decreased the high glucose uptake and glycogen synthesis of miR-138-5p inhibitor-transfected HepG2 cells, suggesting that the inhibition of autophagy abolished the inhibitory effect of miR-138-5p inhibitor on IR in HepG2 cells. Taken together, this study suggested that miR-138 5p contributed to the TNF-alpha-induced IR, possibly through inducing autophagy in HepG2 cells by regulating SIRT1. MiR-138-5p might be a potential and promising target for the treatment of IR. PMID- 30442238 TI - Editorial: ISBM 10. PMID- 30442240 TI - Feedback and constraints: rethinking medication safety countermeasures. PMID- 30442239 TI - Postoperative nausea self-reporting in Spanish-speaking children: reducing the grey zone in patient-reported outcomes. PMID- 30442241 TI - Hidden pandemic of postoperative complications-time to turn our focus to health systems analysis. PMID- 30442242 TI - Implementing risk calculators: time for the Trojan Horse? PMID- 30442243 TI - Deceptive defences: rethinking safety interventions in complex adaptive systems. PMID- 30442244 TI - Ketamine and depression. PMID- 30442245 TI - Differences in regional cerebral oximetry during cardiac surgery for patients with or without postoperative cerebral ischaemic lesions evaluated by magnetic resonance imaging. AB - BACKGROUND: Near infrared spectroscopy (NIRS) is widely used to monitor regional cerebral tissue oxygenation (rScO2). We compared rScO2 values during cardiac surgery in patients with or without new cerebral ischaemic lesions on diffusion weighted magnetic resonance imaging (DWI). We hypothesised patients with new cerebral lesions would have impaired tissue oxygenation reflected in their rScO2 values. METHODS: NIRS and DWI data were collected in 152 elective cardiac surgery patients. Absolute rScO2 values, duration of desaturation below thresholds (baseline, 10%, and 20%), and accumulated cerebral desaturation load were compared between patients with or without new cerebral lesions on DWI. Primary outcome was time below 10% from rScO2 baseline. RESULTS: The time below 10% from rScO2 baseline was significantly longer for patients with new cerebral lesions than for patients without [median (inter-quartile range): 11.0 (0.4; 37.5) min vs 1.8 inter-quartile range: (0.05; 20.9) min, P=0.02]. Furthermore, they had a higher accumulated desaturation load below baseline (P=0.02) and 10% below baseline (P=0.02). Finally, their absolute minimum rScO2 value was significantly lower (P=0.01). However, the frequency of patients with desaturation below 10% and 20% was comparable between patients with and without new cerebral lesions. Receiver-operating characteristic curve analysis did not identify a clear-cut critical threshold among the investigated rScO2 variables. CONCLUSIONS: Use of NIRS identified significant group differences in rScO2 values between patients with or without new ischaemic lesions. However, a critical threshold could not be identified because of a high variation in NIRS values across both groups. CLINICAL TRIAL REGISTRATION: NCT 02185885. PMID- 30442246 TI - Are high-sensitivity troponins always reliable? Donor-recipient troponin transfusion in liver transplantation. AB - Blood troponins are used to diagnose perioperative myocardial injury and infarction. During liver transplantation, a passive donor-recipient troponin transfer with the graft may result in an increase of troponins in the transplant recipient questioning the diagnosis of myocardial injury. We present a case of liver transplantation with sudden elevation of recipient's serum troponin levels immediately after graft reperfusion and its subsequent normalization in which myocardial damage and other non-ischaemic potential causes were ruled out. Patient consent for publication was obtained prior to submission of the manuscript. PMID- 30442247 TI - Venous air embolism: ultrasonographic diagnosis and treatment with hyperbaric oxygen therapy. AB - A man with neuromuscular respiratory failure requiring intubation and ventilation suffered a venous air embolism during inadvertent administration of 5 ml of air. Ultrasound (US) imaging confirmed an air embolus in the left subclavian vein, which was only partially treated by US-guided aspiration. The embolus completely resolved on US imaging during hyperbaric oxygen therapy, and the patient recovered with no complications secondary to the embolism. Venous air embolism is under-recognised, and can cause siginificant neurological morbidity and death if untreated. When available, urgent hyperbaric oxygen therapy appears to be an effective approach. PMID- 30442248 TI - Measuring non-technical skills of anaesthesiologists in the operating room: a systematic review of assessment tools and their measurement properties. AB - BACKGROUND: Non-technical skills, such as communication or leadership, are integral to clinical competence in anaesthesia. There is a need for valid and reliable tools to measure anaesthetists' non-technical performance for both initial and continuing professional development. This systematic review aims to summarise the measurement properties of existing assessment tools to determine which tool is most robust. METHODS: Embase (via OVID), Medline and Medline in Process (via OVID), and reference lists of included studies and previously published relevant systematic reviews were searched (through August 2017). Quantitative studies investigating the measurement properties of tools used to assess anaesthetists' intraoperative non-technical skills, either in a clinical or simulated environment, were included. Pairs of independent reviewers determined eligibility and extracted data. Risk of bias was assessed using the COSMIN checklist. RESULTS: The search yielded 978 studies, of which 14 studies describing seven tools met the inclusion criteria. Of these, 12 involved simulated crisis settings only. The measurement properties of the Anaesthetists' Non-Technical Skills (ANTS) tool were most commonly assessed (n=9 studies), with studies of two types of validity (content, concurrent) and two types of reliability (internal consistency, interrater). Most of these studies, however, were at serious risk of bias. CONCLUSIONS: Though there are seven tools for assessing the non-technical skills of anaesthetists, only ANTS has been extensively investigated with regard to its measurement properties. ANTS appears to have acceptable validity and reliability for assessing non-technical skills of anaesthetists in both simulated and clinical settings. Future research should consider additional clinical contexts and types of measurement properties. PMID- 30442249 TI - Association of preoperative anaemia with postoperative morbidity and mortality: an observational cohort study in low-, middle-, and high-income countries. AB - BACKGROUND: Anaemia is associated with poor postoperative outcomes, but few studies have described the impact of preoperative anaemia in low- and middle- (LMICs), and high-income countries (HICs). METHODS: This was a planned analysis of data collected during an international 7 day cohort study of adults undergoing elective inpatient surgery. The primary outcome was in-hospital death, and the secondary outcomes were in-hospital complications. Anaemia was defined as haemoglobin <12 g dl-1 for females and <13 g dl-1 for males. Hierarchical three level mixed-effect logistic regression models were constructed to examine the associations between preoperative anaemia and outcomes. RESULTS: We included 38 770 patients from 474 hospitals in 27 countries of whom 11 675 (30.1%) were anaemic. Of these, 6886 (17.8%) patients suffered a complication and 198 (0.5%) died. Patients from LMICs were younger with lower ASA physical status scores, but a similar prevalence of anaemia [LMIC: 5072 (32.5%) of 15 585 vs HIC: 6603 (28.5%) of 23 185]. Patients with moderate [odds ratio (OR): 2.70; 95% confidence interval (CI): 1.88-3.87] and severe anaemia (OR: 4.09; 95% CI: 1.90-8.81) were at an increased risk of death in both HIC and LMICs. Complication rates increased with the severity of anaemia. Compared with patients in LMICs, those in HICs experienced fewer complications after an interaction term analysis [LMIC (OR: 0.92; 95% CI: 0.87-0.97) vs HIC (OR: 0.86; 95% CI: 0.84-0.87); P<0.01]. CONCLUSIONS: One-third of patients undergoing elective surgery are anaemic. These patients have an increased risk of complications and death. The prevalence of anaemia is similar amongst patients in LMICs despite their younger age and lower risk profile. CLINICAL TRIAL REGISTRATION: ISRCTN51817007. PMID- 30442250 TI - Procedural sedation of elderly patients by emergency physicians: a safety analysis of 740 patients. AB - BACKGROUND: The elderly are perceived as a high-risk group for procedural sedation. Concern exists regarding the safety of sedation of this patient group by emergency physicians, particularly when using propofol. METHODS: We analysed prospectively collected data on patients aged 75 yr or older undergoing sedation between October 2006 and March 2017 in the emergency department of a single centre. We used the World Society of Intravenous Anaesthesia International Sedation Task Force adverse event tool, stratifying identified adverse events according to consensus agreement. RESULTS: Of 740 consecutive patients (median age 84 yr), 571 patients received propofol, 142 morphine and midazolam, and 27 other agents. We identified 19 sentinel events: 2 cases of hypoxia, 10 of apnoea (without hypoxaemia), 5 of hypotension, and 2 of both hypoxaemia and hypotension. We also identified 30 moderate, 41 minor, and 7 minimal risk adverse events. There were no adverse outcomes. CONCLUSIONS: We observed safe sedation practice in this high-risk group of patients in this department. A sentinel adverse event rate of 2.6% including a hypoxaemia rate of 0.5%, with no adverse outcomes sets a benchmark for elderly sedation. We recommend quality pre-oxygenation, an initial propofol bolus of no more than 0.5 mg kg-1, and a robust training and governance framework. PMID- 30442251 TI - Effect of intravenous S-ketamine on the MAC of sevoflurane: a randomised, placebo controlled, double-blinded clinical trial. AB - BACKGROUND: Ketamine is routinely used in operating theatres, emergency departments, ICUs, and even outpatient units. Despite the widespread use of ketamine, only basic aspects of its interactions with inhalation anaesthetic agents are known, and formal testing of interactions in humans is lacking. The minimum alveolar concentration (MAC) of inhalation anaesthetics is used to guide the depth of anaesthesia, and several drugs are known to influence the MAC. The aim of this study was to investigate whether intravenous application of ketamine influences the MAC of sevoflurane in humans. METHODS: Adult patients undergoing elective surgery were included in this randomised, double-blinded, placebo controlled study. Patients were assigned to one of three groups, each of which received a bolus of placebo, 0.5 mg kg-1S-ketamine, or 1 mg kg-1S-ketamine followed by an infusion of the same amount per hour after inhalation induction with sevoflurane was performed. The response to skin incision (movement vs non movement) was recorded. The MAC of sevoflurane was assessed using an up-and-down titration method. RESULTS: Sixty patients aged 30-65 yr were included. Each group consisted of 20 patients. The MAC of sevoflurane was higher in the placebo group (2.1 (sd 0.1) %) than in the low-dose ketamine group (0.9 (0.1)%, P<0.01) and the high-dose ketamine group (0.5 (0.1)%, P<0.01). In addition, the MAC of sevoflurane was higher in the low-dose ketamine group compared with the high-dose ketamine group (P<0.01). CONCLUSIONS: The administration of S-ketamine significantly and dose-dependently reduced the MAC of sevoflurane in humans. CLINICAL TRIAL NUMBER: EudraCT ref. no. 2012-001908-38. PMID- 30442252 TI - Micro-fragmented fat injection reduces sepsis-induced acute inflammatory response in a mouse model. AB - BACKGROUND: Severe sepsis has a high mortality rate. There is increasing evidence that human mesenchymal stem cells possess immunomodulatory properties in sepsis, particularly those from adipose tissue. We hypothesised that micro-fragmented human fat, obtained with minimal alteration of the stromal vascular niche, attenuates the inflammatory response and improves outcome in a murine model of sepsis. METHODS: Micro-fragmented fat, lipoaspirate, or saline was administered intraperitoneally 2 h after caecal ligation and puncture (CLP) in C57Bl/6RJ ketamine-xylazine anaesthetised mice. The primary endpoint was the inflammatory score. Secondary endpoints included survival, physiological, histological, and biological parameters. RESULTS: In CLP mice, micro-fragmented fat administration significantly decreased the median (range) inflammatory score compared with saline [17 (14-20) vs 9 (8-12), P=0.006]. Secondary endpoints were also significantly improved in micro-fragmented fat-treated compared with saline treated CLP mice. Improvement in inflammatory score and in survival was suppressed when micro-fragmented fat was co-administered with liposomes loaded with clodronate (macrophage toxin) or NS-398 (cyclo-oxygenase 2 inhibitor), but not with SC-560 (cyclo-oxygenase 1 inhibitor). CONCLUSIONS: In a murine model of severe sepsis, micro-fragmented fat improved early inflammatory status and outcome, at least in part, by a cyclo-oxygenase-2-mediated mechanism. The potential therapeutic value of micro-fragmented fat in severe sepsis warrants further investigation. PMID- 30442253 TI - Dexmedetomidine attenuation of renal ischaemia-reperfusion injury requires sirtuin 3 activation. AB - BACKGROUND: Dexmedetomidine attenuates renal ischaemia and reperfusion (I/R) injury, but its mechanism of action is unclear. As sirtuin 3 (SIRT3) activation can alleviate acute kidney injury, we investigated whether dexmedetomidine acts through SIRT3 to reduce renal I/R injury. METHODS: The potential involvement of SIRT3 in dexmedetomidine attenuation of renal I/R injury was tested in HK2 cells subjected to hypoxia/reoxygenation and C57BL/6J mice subjected to renal I/R. A short interfering RNA targeting SIRT3 was used in some experiments to examine the potential role of SIRT3. Cell death and mitochondrial membrane potential (Deltapsim) were analysed in cultured cells. Mitochondrial damage in mice was assessed using electron microscopy and markers for renal function. Expression of cyclophilin D, cytochrome c, and SIRT3, and the level of cyclophilin D acetylation were determined. RESULTS: Hypoxia/reoxygenation of HK2 cells increased cell death, cytochrome C expression, and cyclophilin D acetylation, and decreased Deltapsim and SIRT3 expression (P<0.05). Dexmedetomidine attenuated these changes. The dexmedetomidine effects were enhanced by SIRT3 overexpression and eliminated by SIRT3 knockdown. I/R in mice damaged renal function, and increased histological lesions, mitochondrial damage, cytochrome c expression, and cyclophilin D acetylation, while SIRT3 activity was decreased by 51% (P<0.05). Dexmedetomidine inhibited these changes in mice expressing normal levels of SIRT3, but not in SIRT3-knockdown mice. CONCLUSIONS: Dexmedetomidine appears to act, at least in part, by up-regulating SIRT3 to inhibit mitochondrial damage and cell apoptosis and thereby protect against renal I/R injury. PMID- 30442254 TI - Neuroprotection by anaesthetics in rodent models of traumatic brain injury: a systematic review and network meta-analysis. AB - BACKGROUND: Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates. METHODS: After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative-hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality. RESULTS: Sixteen studies, involving 32 comparisons, were included (546 animals). The treatment improved the neurological outcomes by 35%; 95% confidence interval: 26-44%; P<0.001. The statistical heterogeneity was small (12%), but the 95% prediction interval for the estimate was wide (15-56%). The statistical power was low: 61% (90% confidence interval: 22-86%). The small sample size in the studies was a serious shortcoming reducing the statistical heterogeneity and obscuring differences in outcome between drugs and between experimental conditions. CONCLUSIONS: Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes. PMID- 30442255 TI - Remifentanil as an adjunct to anaesthesia for electroconvulsive therapy fails to confer long-term benefits. AB - BACKGROUND: Adding the MU-opioid receptor agonist remifentanil to agents used to induce general anaesthesia in electroconvulsive therapy (ECT) can reduce the required doses of induction agents and their unfavourable effects on seizure threshold and quality. However, whether remifentanil has favourable long-term treatment effects in terms of response and remission rates, speed of response and remission, and side-effects has not been studied. METHODS: This retrospective, register-based cohort study involved patients with major depression consecutively treated at two units at different hospitals in Norway with the same ECT procedure. Both units used thiopental for ECT anaesthesia, but only one unit added remifentanil (R+; n=47; 541 sessions), whereas the other did not (R-; n=119; 1166 sessions). A Cox proportional hazards model for interval-censored data was conducted to examine the effects of remifentanil on the time to response and remission from depressive symptoms, whilst adjusting for age, sex, and baseline depression score. RESULTS: Both R+ and R- patients showed substantial reductions of depressive symptoms, with no difference in the response (76% in both groups) or remission (63% vs 65%) rate. However, R+ patients responded (hazard ratio=0.59; 95% confidence interval: 0.4-0.8) and remitted (hazard ratio=0.72; 95% confidence interval: 0.5-1.0) more slowly, and reported more often side-effects of nausea (30% vs 8%; P<0.001), dizziness (22% vs 8%; P=0.027), and headache (48% vs 23%; P=0.004). CONCLUSIONS: The use of adjunctive remifentanil was associated with more short-term side-effects and no favourable long-term clinical outcomes. The practice of routinely adding remifentanil to barbiturate anaesthesia should therefore be reconsidered. PMID- 30442256 TI - Mismatch negativity to predict subsequent awakening in deeply sedated critically ill patients. AB - BACKGROUND: Mismatch negativity (MMN) is the neurophysiological correlate of cognitive integration of novel stimuli. Although MMN is a well-established predictor of awakening in non-sedated comatose patients, its prognostic value in deeply sedated critically ill patients remains unknown. The aim of this prospective, observational pilot study was to investigate the prognostic value of MMN for subsequent awakening in deeply sedated critically ill patients. METHODS: MMN was recorded in 43 deeply sedated critically ill patients on Day 3 of ICU admission using a classical 'odd-ball' paradigm that delivers rare deviant sounds in a train of frequent standard sounds. Individual visual analyses and a group level analysis of recordings were performed. MMN amplitudes were then analysed according to the neurological status (awake vs not awake) at Day 28. RESULTS: Median (inter-quartile range) Richmond Assessment Sedation Scale (RASS) at the time of recording was -5 (range, from -5 to -4.5). Visual detection of MMN revealed a poor inter-rater agreement [kappa=0.17, 95% confidence interval (0.07 0.26)]. On Day 28, 30 (70%) patients had regained consciousness while 13 (30%) had not. Quantitative group level analysis revealed a significantly greater MMN amplitude for patients who awakened compared with those who had not [mean (standard deviation) = -0.65 (1.4) vs 0.08 (0.17) MUV, respectively; P=0.003). CONCLUSIONS: MMN can be observed in deeply sedated critically ill patients and could help predict subsequent awakening. However, visual analysis alone is unreliable and should be systematically completed with individual level statistics. PMID- 30442258 TI - Effects of moderate and severe arterial hypotension on intracerebral perfusion and brain tissue oxygenation in piglets. AB - BACKGROUND: Hypotension is common in anaesthetised children, and its impact on cerebral oxygenation is unknown. The goal of the present study was to investigate the effects of moderate systemic arterial hypotension (mHT) and severe hypotension (sHT) on cerebral perfusion and brain tissue oxygenation in piglets. METHODS: Twenty-seven anaesthetised piglets were randomly allocated to a control group, mHT group, or sHT group. Cerebral monitoring comprised a tissue oxygen partial pressure ( [Formula: see text] ) and laser Doppler (LD) perfusion probe advanced into the brain tissue, and a near-infrared spectroscopy sensor placed over the skin measuring regional oxygen saturation (rSO2). Arterial hypotension was induced by blood withdrawal and i.v. nitroprusside infusion [target MAP: 35 38 (mHT) and 27-30 (sHT) mm Hg]. Data were analysed at baseline, and every 20 min during and after treatment. RESULTS: Compared with control, [Formula: see text] decreased equally with mHT and sHT [mean (SD) after 60 min: control: 17.1 (6.4); mHT: 6.4 (3.6); sHT: 7.2 (4.3) mm Hg]. No differences between groups were detected for rSO2 and LD during treatment. However, in the sHT group, rSO2 increased after restoring normotension [from 49.3 (9.5) to 58.9 (8.9)% Post60]. sHT was associated with an increase in blood lactate [from 1.5 (0.4) to 2.4 (0.9) mmol L-1], and a decrease in bicarbonate [28 (2.4) to 25.8 (2.6) mmol L-1] and base excess [4.7 (1.9) to 2.0 (2.7) mmol L-1] between baseline and 60 min after the start of the experiment. CONCLUSIONS: Induction of mHT and sHT by hypovolaemia and nitroprusside infusion caused alterations in brain tissue oxygenation in a piglet model, but without detectable changes in brain tissue perfusion and regional oxygen saturation. PMID- 30442257 TI - Sevoflurane based anaesthesia does not affect already impaired cerebral autoregulation in patients with type 2 diabetes mellitus. AB - BACKGROUND: The baroreflex regulates arterial blood pressure (BP). During periods when blood pressure changes, cerebral blood flow (CBF) is kept constant by cerebral autoregulation (CA). In patients with diabetes mellitus (DM), low baroreflex sensitivity (BRS) is associated with impaired CA. As sevoflurane-based anaesthesia obliterates BRS, we hypothesised that this could aggravate the already impaired CA in patients with DM resulting in a 'double-hit' on cerebral perfusion leading to increased fluctuations in blood pressure and cerebral perfusion. METHODS: On the day before surgery, we measured CBF velocity (CBFV), heart rate, and BP to determine BRS and CA efficacy (CBFVmean-to-BPmean-phase lead) in 25 patients with DM and in 14 controls. During the operation, BRS and CA efficacy were determined during sevoflurane-based anaesthesia. Patients with DM were divided into a group with high BRS (DMBRS?) and a group with low BRS (DMBRS?). Values presented are median (inter-quartile range). RESULTS: Preoperative vs intraoperative BRS was 6.2 (4.5-8.5) vs 1.9 (1.1-2.5, P<0.001) ms mm Hg-1 for controls, 5.8 (4.9-7.6) vs 2.7 (1.5-3.9, P<0.001) ms mm Hg-1 for patients with DMBRS?, and 1.9 (1.5-2.8) vs 1.1 (0.6-2.5, P=0.31) ms mm Hg-1 for patients with DMBRS?. Preoperative vs intraoperative CA efficacy was 43 degrees (38-46) vs 43 degrees (38-51, P=0.30), 44 degrees (36-49) vs 41 degrees (32 49, P=0.52), and 34 degrees (28-40) vs 30 degrees (27-38, P=0.64) for controls, DMBRS?, and DMBRS? patients, respectively. CONCLUSIONS: In diabetic patients with low preoperative BRS, preoperative CA efficacy was also impaired. In controls and diabetic patients, CA was unaffected by sevoflurane-based anaesthesia. We therefore conclude that sevoflurane-based anaesthesia does not contribute to a 'double-hit' phenomenon on cerebral perfusion. CLINICAL TRIAL REGISTRATION: NCT 03071432. PMID- 30442259 TI - Validation of the pictorial Baxter Retching Faces scale for the measurement of the severity of postoperative nausea in Spanish-speaking children. AB - BACKGROUND: As the intensity of nausea, a subjective symptom, is difficult to estimate in children, vomiting is used as the objective clinical endpoint in managing paediatric postoperative nausea and vomiting. The pictorial Baxter Retching Faces (BARF) scale is a validated quantitative measure of paediatric nausea, but versions in languages other than English have not been validated. METHODS: Healthy Spanish-speaking children aged 7-18 yr (n=184) undergoing elective ambulatory surgery rated perioperative pain and nausea using visual analogue (VAS) and pictorial Faces Pain Scale - Revised and BARF scales, along with a Likert scale measurement of symptom changes. Parents kept a post-discharge diary. RESULTS: Postoperative BARF scores were significantly higher in patients receiving anti-emetics {mean [standard deviation (sd)]: 4.6 (3.4) vs 0.9 (1.6); P<0.001}. Nausea scores obtained prior to rescue anti-emetics were higher than preoperative values [mean (sd) increase: 4.0 (3.6); P<0.001], and decreased after therapy [decrease: 2 (2.4); P=0.03]. The Spearman correlation [95% confidence interval (CI)] between the BARF and VAS nausea scores was 0.72 (0.64-0.78), and significantly stronger than BARF and pain score correlation [0.3 (0.1-0.4)]. The minimum (sd) clinically relevant difference was 1.2 (1.7) for both BARF and VAS nausea scales. The intra-class coefficient (95% CI) of BARF scores was 0.88 (0.76 0.94). The BARF scale had excellent performance in predicting patient-perceived need for anti-emetics (area under the curve-receiver operating characteristic: 0.899; 95% CI: 0.82-0.98). CONCLUSIONS: The BARF scale has construct, convergent, discriminant, and test-retest validity in measuring nausea severity in Spanish speaking children, and may be a useful instrument in the management of paediatric postoperative nausea and vomiting. CLINICAL TRIAL REGISTRATION: NCT02007109. PMID- 30442260 TI - Diagnostic accuracy of a calibrated abdominal compression to predict fluid responsiveness in children. AB - BACKGROUND: Fluid administration to increase stroke volume index (SVi) is a cornerstone of haemodynamic resuscitation. We assessed the accuracy of SVi variation during a calibrated abdominal compression manoeuvre (DeltaSVi-CAC) to predict fluid responsiveness in children. METHODS: Patients younger than 8 yr with acute circulatory failure, regardless of their ventilation status, were selected. SVi, calculated as the average of five velocity-time integrals multiplied by the left ventricular outflow tract surface area, was recorded at four different steps: baseline, after an abdominal compression with a calibrated pressure of 25 mm Hg, after return to baseline, and then after a volume expansion (VE) of 10 ml kg-1 lactated Ringer solution over 10 min. Patients were classified as responders if SVi variation after volume expansion (DeltaSVi-VE) increased by at least 15%. RESULTS: The 39 children included had a median [inter-quartile range (IQR)] age of 9 [5-31] months. Twenty patients were fluid responders and 19 were non-responders. DeltaSVi-CAC correlated with DeltaSVi-VE (r=0.829; P<0.001). The area under the receiver operating characteristic curve (ROCAUC) was 0.94 [95% confidence interval (CI), 0.85-0.99]. The best threshold for DeltaSVi-CAC was 11% with a specificity of 95% [95% CI, 84-100] and a sensitivity of 75% [95% CI, 55 95]. ROCAUC of respiratory variation of IVC diameter (DeltaIVC) was 0.53 [95% CI, 0.32-0.72]. CONCLUSION: DeltaSVi-CAC during abdominal compression was a reliable method to predict fluid responsiveness in children with acute circulatory failure regardless of their ventilation status. CLINICAL TRIALS REGISTRATION: CPP Lyon sud est II: n degrees ANSM 2015-A00388-41 Clinicaltrial.gov: NCT02505646. PMID- 30442261 TI - Seldinger vs modified Seldinger techniques for ultrasound-guided central venous catheterisation in neonates: a randomised controlled trial. AB - BACKGROUND: Central venous catheterisation in neonates is difficult. The purpose of this study was to compare the Seldinger and modified Seldinger techniques for ultrasound-guided internal jugular vein catheterisation in neonates. METHODS: In this randomised, controlled trial, 120 neonates (<=1 month old) requiring central venous catheterisation under general anaesthesia were allocated into either the Seldinger (n=60) or the modified Seldinger (n=60) group. The primary outcome was the incidence of successful catheterisation on the first attempt. We also assessed the incidences of successful puncture on the first attempt, successful guide wire insertion on the first attempt, and successful final catheterisation. RESULTS: The primary outcome, the incidence of successful catheterisation on the first attempt was higher in the modified Seldinger group than in the Seldinger group (83% vs 65%; relative risk=1.282; 95% confidence interval, 1.032-1.594; P=0.025). The incidence of successful guide wire insertion on the first attempt was also higher in the modified Seldinger group (95% vs 75%; relative risk=1.267; 95% confidence interval, 1.082-1.482; P=0.003). Other incidences did not differ significantly between the groups. CONCLUSIONS: For ultrasound-guided internal jugular vein catheterisation in neonates, the modified Seldinger technique showed superiority over the Seldinger technique in terms of successful catheterisation and guide wire insertion on the first attempt. CLINICAL TRIAL REGISTRATION: NCT02688595. PMID- 30442262 TI - Facilitated self-reported anaesthetic medication errors before and after implementation of a safety bundle and barcode-based safety system. AB - BACKGROUND: Anaesthetic medication administration errors are a significant threat to patient safety. In 2002, we began collecting data about the rate and nature of anaesthetic medication errors and implemented a variety of measures to reduce errors. METHODS: Facilitated self-reporting of errors was carried out in 2002 2003. Subsequently, a medication safety bundle including 'smart' infusion pumps were implemented. During 2014 facilitated self-reporting commenced again. A barcode-based medication safety system was then implemented and the facilitated self-reporting was continued through 2015. RESULTS: During 2002-2003, a total of 11 709 paper forms were returned. There were 73 reports of errors (0.62% of anaesthetics) and 27 reports of intercepted errors (0.23%). During 2014, 14 572 computerised forms were completed. There were 57 reports of errors (0.39%) and 11 reports of intercepted errors (0.075%). Errors associated with medication infusions were reduced in comparison with those recorded in 2002-2003 (P<0.001). The rate of syringe swap error was also reduced (P=0.001). The reduction in error rate between 2002-2003 and 2014 was statistically significant (P=0.0076 and P=0.001 for errors and intercepted errors, respectively). From December 2014 through December 2015, 24 264 computerised forms were completed after implementation of a barcode-based medication safety system. There were 56 reports of errors (0.23%) and six reports of intercepted errors (0.025%). Vial swap errors in 2014-2015 were significantly reduced compared with those in 2014 (P=0.004). The reduction in error rate after implementation of the barcode-based medication safety system was statistically significant (P=0.0045 and P=0.021 for errors and intercepted errors, respectively). CONCLUSIONS: Reforms intended to reduce medication errors were associated with substantial improvement. PMID- 30442263 TI - Organisational factors and mortality after an emergency laparotomy: multilevel analysis of 39 903 National Emergency Laparotomy Audit patients. AB - BACKGROUND: Studies across healthcare systems have demonstrated between-hospital variation in survival after an emergency laparotomy. We postulate that this variation can be explained by differences in perioperative process delivery, underpinning organisational structures, and associated hospital characteristics. METHODS: We performed this nationwide, registry-based, prospective cohort study using data from the National Emergency Laparotomy Audit organisational and patient audit data sets. Outcome measures were all-cause 30- and 90-day postoperative mortality. We estimated adjusted odds ratios (ORs) for perioperative processes and organisational structures and characteristics by fitting multilevel logistic regression models. RESULTS: The cohort comprised 39 903 patients undergoing surgery at 185 hospitals. Controlling for case mix and clustering, a substantial proportion of between-hospital mortality variation was explained by differences in processes, infrastructure, and hospital characteristics. Perioperative care pathways [OR: 0.86; 95% confidence interval (CI): 0.76-0.96; and OR: 0.89; 95% CI: 0.81-0.99] and emergency surgical units (OR: 0.89; 95% CI: 0.80-0.99; and OR: 0.89; 95% CI: 0.81-0.98) were associated with reduced 30- and 90-day mortality, respectively. In contrast, infrequent consultant-delivered intraoperative care was associated with increased 30- and 90 day mortality (OR: 1.61; 95% CI: 1.01-2.56; and OR: 1.61; 95% CI: 1.08-2.39, respectively). Postoperative geriatric medicine review was associated with substantially lower mortality in older (>=70 yr) patients (OR: 0.35; 95% CI: 0.29 0.42; and OR: 0.64; 95% CI: 0.55-0.73, respectively). CONCLUSIONS: This multicentre study identified low-technology, readily implementable structures and processes that are associated with improved survival after an emergency laparotomy. Key components of pathways, perioperative medicine input, and specialist units require further investigation. PMID- 30442265 TI - Use of cardiopulmonary exercise testing in the perioperative period. Comment on Br J Anaesth 2018; 121: 496-7. PMID- 30442266 TI - Neuroprotective properties of xenon in different types of CNS injury. PMID- 30442267 TI - Characterising the effect of propofol on complexity and stability in the EEG power spectrum. PMID- 30442268 TI - Syringe labels seen through the eyes of the colour-deficient clinician. PMID- 30442269 TI - Monitoring transpulmonary pressure during anaesthesia using the PEEP-step method. PMID- 30442270 TI - Prospective randomised trial of the Integrated Pulmonary IndexTM in low-acuity inpatients. PMID- 30442271 TI - Hip fracture outcomes in patients with chronic obstructive pulmonary disease. PMID- 30442273 TI - Assessing Lung Cancer Screening Programs under Uncertainty in a Heterogeneous Population. AB - BACKGROUND: Lung cancer screening can reduce cancer mortality. Most implementation studies focus only on low-dose computed tomography (LDCT) and clinical attributes of screening and do not include preferences of potential participants. In this study we evaluated the perceived value of screening programs based on LDCT, breath analysis (BA), or blood biomarkers (BB) according to the perspective of the target population. METHODS: A multi-criteria decision analysis framework was adopted. The weights of seven attributes of screening (sensitivity, specificity, radiation burden, duration of screening process, waiting time until results are communicated, location of screening, and mode of screening) were obtained from an earlier study that included a broad sample from the Netherlands. Performance data for the screening modalities was obtained from clinical trials and expert opinion. Parameter uncertainty about clinical performances was incorporated probabilistically, while heterogeneity in preferences was analyzed through subgroup analyses. RESULTS: The mean overall values were 0.58 (CI: 0.57 to 0.59), 0.57 (CI: 0.56 to 0.59), and 0.44 (CI: 0.43 to 0.45) for BB, BA, and LDCT, respectively. Seventy-seven per cent of respondents preferred BB or BA. For most subgroups, the overall values were similar to those of the entire sample. BA had the highest value for respondents who would have been eligible for earlier screening trials. DISCUSSION: BB and BA seem valuable to participants because they can be applied in a primary care setting. Although LDCT still seems preferable given its strong and positive evidence base, it is important to take non-clinical attributes into account to maximize attendance. PMID- 30442274 TI - Budget Impact of Next-Generation Sequencing for Molecular Assessment of Advanced Non-Small Cell Lung Cancer. AB - BACKGROUND: Genetic testing for nonsquamous advanced non-small cell lung cancer (aNSCLC) is recommended to guide first-line therapy. Activating mutations can be identified via single-gene testing or next-generation sequencing (NGS). OBJECTIVES: To evaluate the budget impact of NGS instead of single-gene testing for tissue-based molecular assessment of aNSCLC from the US health care payer perspective. METHODS: An annual cohort of newly diagnosed patients with nonsquamous aNSCLC in a hypothetical 1-million-member health care plan was evaluated using a Markov model over 5 years. Epidemiology and testing rates (EGFR, ALK, ROS1, BRAF, MET, HER2, and RET) were from the literature. Treatments were determined by available genetic information. Safety, progression, and survival with targeted therapy or chemotherapy were from randomized clinical trials. Single-gene testing and first-line and maintenance treatment costs were from RED BOOK and Medicare fee schedules; NGS testing, adverse event, and progression costs to payers were from the literature. RESULTS: Three hundred sixteen testing-eligible patients with aNSCLC were expected annually, of whom 179 undergo genetic testing. Of 57 patients expected to have activating mutations, single-gene testing identified 35, whereas NGS identified 54. NGS, instead of single-gene testing, decreased expected testing procedure-related costs to the health plan payer by $24,651. First-line and maintenance treatment costs increased by $842,205, offset by a $385,000 decrease in second-line treatment and palliative care costs. Over 5 years, total budget impact was $432,554 ($0.0072 per member per month). CONCLUSIONS: NGS is expected to identify more patients with activating mutations, thereby better enabling selection for targeted therapy and clinical trial enrollment. The budget impact to US payers is expected to be minimally cost-additive. PMID- 30442275 TI - Predictors of Drug Shortages and Association with Generic Drug Prices: A Retrospective Cohort Study. AB - BACKGROUND: Prescription drug shortages can disrupt essential patient care and drive up drug prices. OBJECTIVE: To evaluate some predictors of shortages within a large cohort of generic drugs in the United States and to determine the association between drug shortages and changes in generic drug prices. METHODS: This was a retrospective cohort study. Outpatient prescription claims from commercial health plans between 2008 and 2014 were analyzed. Seven years of data were divided into fourteen 6-month periods; the first period was designated as the baseline period. The first model estimated the probability of experiencing a drug shortage using drug-specific competition levels, market sizes, formulations (e.g., capsules), and drug prices as predictors. The second model estimated the percentage change in drug prices from baseline on the basis of drug shortage duration. RESULTS: From 1.3 billion prescription claims, a cohort of 1114 generic drugs was identified. Low-priced generic drugs were at a higher risk for drug shortages compared with medium- and high-priced generic drugs, with odds ratios of 0.60 (95% confidence interval [CI] 0.44-0.82) and 0.72 (95% CI 0.52-0.99), respectively. Compared with periods of no shortage, drug shortages lasting less than 6 months, 6 to 12 months, 12 to 18 months, and at least 18 months had corresponding price increases of 6.0% (95% CI 4.7-7.4), 10.9% (95% CI 8.5-13.4), 14.2% (95% CI 10.6-17.9), and 14.0% (95% CI 9.1-19.2), respectively. CONCLUSIONS: Study findings may not be generalizable to drugs that became generic after 2008 or those commonly used in an inpatient setting. The lowest priced drugs are at a substantially elevated risk of experiencing a drug shortage. Periods of drug shortages were associated with modest increases in drug prices. PMID- 30442276 TI - Valuation of EuroQol Five-Dimensional Questionnaire, Youth Version (EQ-5D-Y) and EuroQol Five-Dimensional Questionnaire, Three-Level Version (EQ-5D-3L) Health States: The Impact of Wording and Perspective. AB - BACKGROUND: Valuations of health states were affected by the wording of the two instruments (EQ-5D-3L and EQ-5D-Y) and by the perspective taken (child or adult). OBJECTIVES: There is a growing demand for value sets for the EQ-5D-Y (EQ-5D instrument for younger populations). Given the similarities between EQ-5D-Y and EQ-5D-3L, we investigated whether valuations of health states were affected by the differences in wording between the two instruments and by the perspective taken in the valuation exercise (child or adult). STUDY DESIGN: Respondents were randomly assigned to EQ-5D-3L or EQ-5D-Y (instrument) and further into two groups that either valued health states for an adult or for a 10-year-old child (perspective). The valuation tasks were composite time trade-off (C-TTO) and discrete choice experiments (DCE), including comparisons with death (DCE + death). Members of the adult general population in four countries (Germany, Netherlands, Spain, England) participated in computer-assisted personal interviews. METHODS: Two-way multivariate analysis of variance (MANOVA) and post hoc tests were used to compare C-TTO responses and chi-square tests were conducted to compare DCE + death valuations. RESULTS: A significant interaction effect between instrument and perspective for C-TTO responses was found. Significant differences by perspective (adult and child) occurred only for the EQ 5D-3L. Significant differences in values between instruments (EQ-5D-3L and EQ-5D Y) occurred only for the adult perspective. Both significant results were confirmed by the DCE + death results. When comparing EQ-5D-3L for adult perspective and EQ-5D-Y for child perspective, values were also significantly different. CONCLUSIONS: The results identified an interaction effect between wording of the instrument and perspective on elicited values, suggesting that current EQ-5D-3L value sets should not be employed to assign values to EQ-5D-Y health states. PMID- 30442277 TI - Calculating the Expected Value of Sample Information Using Efficient Nested Monte Carlo: A Tutorial. AB - OBJECTIVE: The expected value of sample information (EVSI) quantifies the economic benefit of reducing uncertainty in a health economic model by collecting additional information. This has the potential to improve the allocation of research budgets. Despite this, practical EVSI evaluations are limited partly due to the computational cost of estimating this value using the gold-standard nested simulation methods. Recently, however, Heath et al. developed an estimation procedure that reduces the number of simulations required for this gold-standard calculation. Up to this point, this new method has been presented in purely technical terms. STUDY DESIGN: This study presents the practical application of this new method to aid its implementation. We use a worked example to illustrate the key steps of the EVSI estimation procedure before discussing its optimal implementation using a practical health economic model. METHODS: The worked example is based on a three-parameter linear health economic model. The more realistic model evaluates the cost-effectiveness of a new chemotherapy treatment, which aims to reduce the number of side effects experienced by patients. We use a Markov model structure to evaluate the health economic profile of experiencing side effects. RESULTS: This EVSI estimation method offers accurate estimation within a feasible computation time, seconds compared to days, even for more complex model structures. The EVSI estimation is more accurate if a greater number of nested samples are used, even for a fixed computational cost. CONCLUSIONS: This new method reduces the computational cost of estimating the EVSI by nested simulation. PMID- 30442278 TI - Psychometric Evaluation of the Patient's Knee Implant Performance Questionnaire. AB - OBJECTIVES: To evaluate the psychometric properties of Patient's Knee Implant Performance Questionnaire (PKIP), a new patient-reported measure of knee implant functional performance assessing patient experiences before and after primary total knee arthroplasty (TKA). METHODS: The psychometric analysis sample (n = 761) was based on an ongoing, multisite, prospective, noncomparative, longitudinal study of patients undergoing TKA. The PKIP was completed at three study visits: presurgery (visit 1), less than 1 year (visit 3, days 1-303), and minimum 1 year (visit 4, days 304-668). Visit 2 was an operative visit. Supporting outcome measures were collected at each study visit. The PKIP structure and its psychometric properties were assessed as part of a secondary data analysis using an interim data cut before the end of the clinical trial. RESULTS: The PKIP includes four subscales (confidence, stability, activity modification, and satisfaction) and an overall PKIP score. The overall PKIP score met internal consistency (visit 4 = 0.79) and test-retest reliability (intraclass correlation coefficient = 0.77) standards. Correlations between the PKIP and other measures (e.g., the American Knee Society score and the Knee Injury and Osteoarthritis Outcome Score) provided evidence of construct validity. The PKIP was capable of discriminating between groups of patients with better or worse knee function. The effect size for the overall PKIP score was 2.96 from baseline to visit 4, indicating that the PKIP was highly responsive. CONCLUSIONS: The reliability, validity, and responsiveness of the PKIP support its use among patients undergoing TKA. PMID- 30442279 TI - General Population Norms for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. AB - BACKGROUND: The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale is an internationally used validated measure. General population-based age- and sex-specific percentile norms are, however, not published to date, although these are needed as reference for the interpretation of clinical research data. OBJECTIVES: To assess the FACIT-Fatigue Scale in a large representative sample of the German general population to examine psychometric characteristics and factorial structure and to provide population-based norms. METHODS: A nationally representative face-to-face household survey was conducted in Germany using the FACIT-Fatigue Scale. Item characteristics were examined. Internal consistency was determined using the Cronbach alpha. Dimensionality was analyzed using confirmatory factor analysis (CFA) and bifactor analysis. Scale score differences relating to sex and age were assessed. Sex- and age-specific percentiles were computed for the entire scale range. RESULTS: Of 2426 participants, 55.7% were women, and the mean age was 49.8 +/- 17.4 years. The FACIT-Fatigue Scale mean was 43.5 +/- 8.3. Cronbach alpha was high at 0.92. Although fit indices of the CFA were below desired levels (root mean squared error of approximation = 0.144, comparative fit index = 0.846, and Tucker-Lewis index = 0.815), item loadings in the CFA and bifactor analysis confirm the scale's unidimensionality. Women were more fatigued than men, and participants who were 70 years or older showed higher fatigue scores than younger respondents. Thus, sex- and age-specific population based percentiles were provided. CONCLUSIONS: Reliability and validity of the German translation of the FACIT-Fatigue Scale were confirmed. This study provides general population-based sex- and age-specific FACIT-Fatigue Scale percentile norms for the first time, thereby contributing to a meaningful interpretation of clinical research data. PMID- 30442280 TI - Mapping ALSFRS-R and ALSUI to EQ-5D in Patients with Motor Neuron Disease. AB - BACKGROUND: The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is the preferred measure of health outcome in clinical trials in motor neuron disease (MND). It, however, does not provide a preference-based health utility score required for estimating quality-adjusted life-years in economic evaluations for health technology assessments. OBJECTIVES: To develop algorithms for mapping from measures used in MND clinical studies to allow for future prediction of the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) utility in populations of patients with MND when utility data have not been collected. METHODS: Direct mapping models were developed using ordinary least squares and Tobit regression analyses to estimate EQ-5D-5L utilities (based on English tariffs), with ALSFRS-R total, domain, and item scores used as explanatory variables, using patient-level data from a UK cohort study. Indirect mapping models were also used to map EQ-5D-5L domains, using the same variables, along with the Neuropathic Pain Scale and the Hospital and Anxiety Depression Scale for MND using multinomial logistic regression analysis. Goodness of fit was assessed along with predicted values for each mapping model. RESULTS: The best performing model predicting EQ-5D-5L utilities used five items of the ALSFRS-R items as explanatory variables in a stepwise ordinary least squares regression. The mean squared error was 0.0228, and the mean absolute error was 0.1173. Prediction was good, with 55.4% of estimated values within 0.1 and 91.4% within 0.25 of the observed EQ-5D-5L utility value. Indirect mapping using the Neuropathic Pain Scale and the Hospital and Anxiety Depression Scale for MND provided less predictive power than direct mapping models. CONCLUSIONS: This is the first study to present mapping algorithms to crosswalk between ALSFRS-R and EQ-5D-5L. This analysis demonstrates that the ALSFRS-R can be used to estimate EQ 5D-5L utilities when they have not been collected directly within a trial. PMID- 30442281 TI - Time Trade-Off Value Set for EQ-5D-3L Based on a Nationally Representative Chinese Population Survey. AB - OBJECTIVES: To obtain a nationally representative Chinese three-level EuroQol five-dimensional questionnaire value set based on the time trade-off (TTO) method. METHODS: A multistage, stratified, clustered random nationally representative Chinese sample was used. The study design followed an adapted UK Measurement and Valuation of Health protocol. Each respondent valued 11 random states plus state 33333 and "unconscious" using the TTO method in face-to-face interviews. Three types of models were explored: ordinary least squares, general least squares, and weighted least squares models. RESULTS: In total, 5939 inhabitants aged 15 years and older were interviewed. Of these, 5503 satisfactorily interviewed participants were included in constructing models. An ordinary least squares model including 10 dummies without constant and N3 had a mean absolute error of 0.083 and a correlation coefficient of 0.899 between the predicted and mean values. Goodness-of-fit indices of two models based on split subsample were similar. CONCLUSIONS: TTO values were higher in our study compared with those in a study carried out in urban areas, which is mirrored by the higher values in rural areas. Several other aspects, in addition to the valuation procedure, might have influenced the results, such as factors beyond demographic factors such as view on life and death and believing in an afterlife, which need further investigation. Future studies using the three-level EuroQol five dimensional questionnaire should consider using this value set based on a nationally representative sample of the Chinese population. PMID- 30442282 TI - Health State Values Derived from People with Multiple Sclerosis for a Condition Specific Preference-Based Measure: Multiple Sclerosis Impact Scale-Eight Dimensions-Patient Version (MSIS-8D-P). AB - OBJECTIVE: In economic evaluation, health outcomes are commonly quantified using quality-adjusted life-years (QALYs) derived from the preferences of a sample of the general population. It can be argued that this approach ignores the preferences of people with experience of the condition, and that patient preferences have a place in the valuation of health outcomes. Here we report the estimation of a preference-based index for an existing condition-specific preference-based measure for multiple sclerosis (MS), the MSIS-8D, based on the preferences of people with MS. STUDY DESIGN: Internet time trade-off (TTO) survey, eliciting preferences from people with MS. METHODS: We elicited preferences from a sample of people with MS (N = 1635) across 169 MSIS-8D health states, using the TTO technique. We fitted ordinary least squares and random effects models to the survey data to estimate values for all health states described by the MSIS-8D. RESULTS: The new patient-derived index (the MSIS-8D-P) provides values ranging from 0.893 for the best possible health state to 0.138 for the worst state. The MSIS-8D-P exhibits good discriminative validity, identifying expected significant differences between groups based on presence/absence of MS, type of MS, and duration since diagnosis. CONCLUSIONS: The MSIS-8D-P index of values for MS-specific health states provides an opportunity to estimate QALYs based on patient preferences, for use in economic evaluations of treatments for MS. More broadly, it adds to the methods and data available to consider the health-related quality of life of people with MS to inform resource allocation and individual-level decisions regarding treatments for MS. PMID- 30442283 TI - A Systematic Review of Patient-Reported Satisfaction with Oral Medication Therapy in Patients with Type 2 Diabetes. AB - OBJECTIVE: To provide a comprehensive comparative evaluation of the psychometric properties of satisfaction with medication surveys used for patients with type 2 diabetes (T2D) in clinical trials. METHODS: Instruments identified through a comprehensive literature search were evaluated based on the following criteria: disease specificity, peer-reviewed publication (administered in English in patients with T2D on oral therapy), and availability of psychometric properties. RESULTS: Eight instruments (Diabetes Medication Satisfaction [DiabMedSat]; Diabetes Treatment Satisfaction Questionnaire, status version [DTSQs]; Diabetes Medication System Rating Questionnaire [DMSRQ]; Diabetes Medication System Rating Questionnaire-Short Form [DMSRQ-SF]; Diabetes Tablet Treatment Questionnaire [DTTQ]; Perceptions About Medications for Diabetes [PAM-D]; Satisfaction with Oral Anti-Diabetic Agent Scale [SOADAS]; Diabetes Medication Satisfaction Tool [DMSAT]) were included in the study based on the predefined inclusion criteria. Seven of the instruments (all but DTTQ) utilized patients in the survey development process. All eight instruments could be completed within 15 minutes and thus were considered practical. DiabMedSat, DMSRQ, and DMSRQ-SF encompassed broader aspects of satisfaction than the other instruments. All of the instruments reviewed showed substantial floor or ceiling effects, except for DMSAT and DiabMedSat, without complete information. The DMSRQ and DMSRQ-SF each satisfied the criteria for reliability. DiabMedSat, DTSQs, DMSRQ, DMSRQ-SF, SOADAS, and DMSAT showed favorable convergent and discriminant validity. All of the instruments except DTTQ were determined to satisfactorily meet the criteria of responsiveness. CONCLUSION: Although it is up to researchers to decide which instrument to use according to the resources available and specific aims of their studies, DMSRQ and DSMRQ-SF were recommended based on the evaluative criteria employed in this study. PMID- 30442285 TI - Deciphering the Unknowns of Stroke After Aortic Valve Interventions. PMID- 30442284 TI - Stroke After Surgical Versus Transfemoral Transcatheter Aortic Valve Replacement in the PARTNER Trial. AB - BACKGROUND: Transfemoral-transcatheter aortic valve replacement (TF-TAVR) is increasingly used to treat aortic stenosis, but risk of post-procedure stroke is uncertain. OBJECTIVES: The purpose of this study was to assess stroke risk and its association with quality of life after surgical aortic valve replacement (SAVR) versus TF-TAVR. METHODS: The authors performed a propensity-matched study of 1,204 pairs of patients with severe aortic stenosis treated with SAVR versus TF-TAVR in the PARTNER (Placement of AoRTic TraNscathetER Valves) trials from April 2007 to October 2014. Outcomes were: 1) 30-day neurological events; 2) time varying risk of neurological events early (<=7 days) and late (7 days to 48 months) post-procedure; and 3) association between stroke and quality of life 1 year post-procedure by the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score. RESULTS: Thirty-day stroke (5.1% vs. 3.7%; p = 0.09) was similar, but 30-day major stroke (3.9% vs. 2.2%; p = 0.018) was lower after TF TAVR than SAVR. In both groups, risk of stroke peaked in the first post-procedure day, followed by a near-constant low-level risk to 48 months. Major stroke was associated with a decline in quality of life at 1 year in both SAVR (KCCQ score median [15th, 85th percentile]: 79 [53, 94] without major stroke vs. 64 [30, 94] with major stroke; p = 0.03) and TF-TAVR (78 [49, 96] without major stroke vs. 60 [8, 99] with major stroke; p = 0.04). CONCLUSIONS: Despite similar early-peaking (<1 day post-procedure) neurological risk profiles, SAVR is associated with a higher risk of early major stroke than TF-TAVR. Periprocedural strategies are needed to reduce stroke risk after aortic valve procedures. (Placement of AoRTic TraNscathetER Valve Trial [PARTNER]; NCT00530894). PMID- 30442286 TI - Differences in Risk of Sudden Cardiac Death Between Blacks and Whites. AB - BACKGROUND: Prior studies have consistently demonstrated that blacks have an approximate 2-fold higher incidence of sudden cardiac death (SCD) than whites; however, these analyses have lacked individual-level sociodemographic, medical comorbidity, and behavioral health data. OBJECTIVES: The purpose of this study was to evaluate whether racial differences in SCD incidence are attributable to differences in the prevalence of risk factors or rather to underlying susceptibility to fatal arrhythmias. METHODS: The Reasons for Geographic and Racial Differences in Stroke study is a prospective, population-based cohort of adults from across the United States. Associations between race and SCD defined per National Heart, Lung, and Blood Institute criteria were assessed. RESULTS: Among 22,507 participants (9,416 blacks and 13,091 whites) without a history of clinical cardiovascular disease, there were 174 SCD events (67 whites and 107 blacks) over a median follow-up of 6.1 years (interquartile range: 4.6 to 7.3 years). The age-adjusted SCD incidence rate (per 1,000 person-years) was higher in blacks (1.8; 95% confidence interval [CI]: 1.4 to 2.2) compared with whites (0.7; 95% CI: 0.6 to 0.9), with an unadjusted hazard ratio of 2.35; 95% CI: 1.74 to 3.20. The association of black race with SCD risk remained significant after adjustment for sociodemographics, comorbidities, behavioral measures of health, intervening cardiovascular events, and competing risks of non-SCD mortality (hazard ratio: 1.97; 95% CI: 1.39 to 2.77). CONCLUSIONS: In a large biracial population of adults without a history of cardiovascular disease, SCD rates were significantly higher in blacks as compared with whites. These racial differences were not fully explained by demographics, adverse socioeconomic measures, cardiovascular risk factors, and behavioral measures of health. PMID- 30442287 TI - Ancestry and the Promise of Improved Risk Prediction for Sudden Death. PMID- 30442289 TI - Formins Emerge as a Cause of Hypertrophic Cardiomyopathy: New Genes for Thick Hearts. PMID- 30442288 TI - Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. AB - BACKGROUND: The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES: This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS: FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS: The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 +/- 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 +/- 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS: FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels. PMID- 30442291 TI - The Clinical Course of a Genetic Dilated Cardiomyopathy: Letting the Cat Out of the BAG3. PMID- 30442292 TI - Cardiac Phenotypes in Hereditary Muscle Disorders: JACC State-of-the-Art Review. AB - Hereditary muscular diseases commonly involve the heart. Cardiac manifestations encompass a spectrum of phenotypes, including both cardiomyopathies and rhythm disorders. Common biomarkers suggesting cardiomuscular diseases include increased circulating creatine kinase and/or lactic acid levels or disease-specific metabolic indicators. Cardiac and extra-cardiac traits, imaging tests, family studies, and genetic testing provide precise diagnoses. Cardiac phenotypes are mainly dilated and hypokinetic in dystrophinopathies, Emery-Dreifuss muscular dystrophies, and limb girdle muscular dystrophies; hypertrophic in Friedreich ataxia, mitochondrial diseases, glycogen storage diseases, and fatty acid oxidation disorders; and restrictive in myofibrillar myopathies. Left ventricular noncompaction is variably associated with the different myopathies. Conduction defects and arrhythmias constitute a major phenotype in myotonic dystrophies and skeletal muscle channelopathies. Although the actual cardiac management is rarely based on the cause, the cardiac phenotypes need precise characterization because they are often the only or the predominant manifestations and the prognostic determinants of many hereditary muscle disorders. PMID- 30442293 TI - Operational Efficiency and Effective Management in the Catheterization Laboratory: JACC Review Topic of the Week. AB - Operational efficiency is a core business principle in which organizations strive to deliver high-quality goods or services in a cost-effective manner. This concept has become increasingly relevant to cardiac catheterization laboratories, as insurers move away from fee-for-service reimbursement and toward payment determined by quality measures bundled per episode of care. Accordingly, this review provides a framework for optimizing efficiency in the cardiac cath lab. The authors outline a management method based on the Nadler-Tushman Congruence Model, a commonly used business tool by which a company can assess whether its key elements are aligned with its strategy. Standardized metrics of cath lab efficiency are proposed, which can be used in public reports on this topic moving forward. Attention is paid to understanding balance sheets to track the financial health of the cath lab. Specific cost-saving measures are described, and examples of strategies used to save supply expenses are provided. PMID- 30442294 TI - Developing a Mobile Application for Global Cardiovascular Education. AB - Technological revolution in the field of medical education is here, and it is time to embrace it. Adoption of on-the-go learning style, portability of smartphones, and expression of concepts with interactive illustrations and their global reach have made application (app)-based learning an effective medium. An educational mobile app, BIFURCAID, was developed to simplify and teach complex coronary bifurcation intervention. This app has been downloaded worldwide. The survey results revealed its widespread acceptance and success. The authors believe that educational apps can have a significant impact on shaping the future of cardiovascular education in the 21st century. This experience with developing and testing the app could work as a template for other medical educators. PMID- 30442295 TI - Scaling STEMI Care Internationally: ACC's Global STEMI Quality Improvement Initiative. PMID- 30442296 TI - Building Bridges in Cardiology and Radiology: Why Collaboration Is the Future of Cardiovascular Imaging. PMID- 30442290 TI - Dilated Cardiomyopathy Due to BLC2-Associated Athanogene 3 (BAG3) Mutations. AB - BACKGROUND: The BAG3 (BLC2-associated athanogene 3) gene codes for an antiapoptotic protein located on the sarcomere Z-disc. Mutations in BAG3 are associated with dilated cardiomyopathy (DCM), but only a small number of cases have been reported to date, and the natural history of BAG3 cardiomyopathy is poorly understood. OBJECTIVES: This study sought to describe the phenotype and prognosis of BAG3 mutations in a large multicenter DCM cohort. METHODS: The study cohort comprised 129 individuals with a BAG3 mutation (62% males, 35.1 +/- 15.0 years of age) followed at 18 European centers. Localization of BAG3 in cardiac tissue was analyzed in patients with truncating BAG3 mutations using immunohistochemistry. RESULTS: At first evaluation, 57.4% of patients had DCM. After a median follow-up of 38 months (interquartile range: 7 to 95 months), 68.4% of patients had DCM and 26.1% who were initially phenotype-negative developed DCM. Disease penetrance in individuals >40 years of age was 80% at last evaluation, and there was a trend towards an earlier onset of DCM in men (age 34.6 +/- 13.2 years vs. 40.7 +/- 12.2 years; p = 0.053). The incidence of adverse cardiac events (death, left ventricular assist device, heart transplantation, and sustained ventricular arrhythmia) was 5.1% per year among individuals with DCM. Male sex, decreased left ventricular ejection fraction. and increased left ventricular end-diastolic diameter were associated with adverse cardiac events. Myocardial tissue from patients with a BAG3 mutation showed myofibril disarray and a relocation of BAG3 protein in the sarcomeric Z-disc. CONCLUSIONS: DCM caused by mutations in BAG3 is characterized by high penetrance in carriers >40 years of age and a high risk of progressive heart failure. Male sex, decreased left ventricular ejection fraction, and enlarged left ventricular end-diastolic diameter are associated with adverse outcomes in patients with BAG3 mutations. PMID- 30442297 TI - RESPONSE: Collaboration and Collegiality: The Dual Pillars of Cardiovascular Imaging Now and in the Future. PMID- 30442298 TI - HF Mortality Trends Under Medicare Readmissions Reduction Program at Penalized and Nonpenalized Hospitals. PMID- 30442300 TI - Understanding the Complex Link Between Cardiac Function and Pre-Eclampsia. PMID- 30442299 TI - Characterization of Recurrent Strokes With and Without Patent Foramen Ovale Closure. PMID- 30442301 TI - Reply: Understanding the Complex Link Between Cardiac Function and Pre-Eclampsia. PMID- 30442302 TI - Anticoagulants for Cardioembolism Prevention in Atrial Fibrillation Patients: Potential Bias From Real-World Studies. PMID- 30442303 TI - Reply: Anticoagulants for Cardioembolism Prevention in Atrial Fibrillation Patients: Potential Bias From Real-World Studies. PMID- 30442304 TI - Sex-Based Differences in Outcomes of Oral Anticoagulation: Does Antiplatelet Therapy Matter? PMID- 30442305 TI - Reply: Sex-Based Differences in Outcomes of Oral Anticoagulation: Does Antiplatelet Therapy Matter? PMID- 30442306 TI - Opisthorchiasis and the Microbiome. AB - The liver flukes Opisthorchis viverrini, O. felineus, and Clonorchis sinensis are closely related fish-borne trematodes endemic in East Asia, Eurasia, and Siberia. Following ingestion, the parasites locate to the biliary tree, where chronic infection frequently leads to cholangiocarcinoma (CCA). Infection with C. sinensis or O. viverrini is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Infection with O. felineus may also be carcinogenic. The mechanism(s) by which infection with these liver flukes culminates in CCA remain elusive, although they are likely to be multi-factorial. Not yet well studied is the influence of opisthorchiasis on the microbiome of the host despite reports that helminth parasites are capable of affecting the microbiome, potentially modulating gastrointestinal inflammation in response to the appearance of pathogenic strains of bacteria. Here, we review recent findings related to opisthorchiasis and the microbiome and related issues. In the hamster, a tractable model of infection with liver fluke and of infection-induced biliary morbidity and CCA, infection with O. viverrini perturbs the microbiome of the gastrointestinal tract, including increasing numbers of Lachnospiraceae, Ruminococcaceae, Lactobacillaceae, and others, while decreasing Porphyromonadaceae, Erysipelotrichaceae, and Eubacteriaceae. In addition, a complex microbial community associates with the parasites within the biliary tree, including Helicobacter pylori and related bacteria. Moreover, higher rates of infection with Helicobacter occur in Thailand in persons with opisthorchiasis in a liver fluke infection intensity-dependent manner. Experimental infection of hamsters with Opisthorchis felineus results in increased alpha diversity of the microbiota diversity in the biliary tract. In humans, infection with O. felineus modifies the composition of the biliary microbiome, with increasing numbers of species of Klebsiella, Aggregatibacter, Lactobacillus, Treponema, and others. Several phylotypes of Archaea occurred solely in bile from persons infected with O. felineus. PMID- 30442307 TI - Integrative EcoHealth/One Health Approach for Sustainable Liver Fluke Control: The Lawa Model. AB - The Lawa model is a successful integrative and sustainable means of controlling opisthorchiasis in Thailand. The model integrates the EcoHealth and One Health holistic approaches with systems thinking to target the interruption of Opisthorchis viverrini transmission. Using the six principles of EcoHealth and emphasizing the three domains of One Health (human-animal-ecosystem), the program targets each step of the parasite life cycle, thus maximizing the chances of interrupting the life cycle of the parasite. The main drivers of success are the village health volunteers and health-promoting hospitals, together with the support of the government and academia. The success of the model has led to continuous expansion, adoption nationally and internationally and application to the control of other neglected tropical diseases as well as noncommunicable diseases. PMID- 30442308 TI - The Socioeconomic Burden of Cholangiocarcinoma Associated With Opisthorchis viverrini Sensu Lato Infection in Northeast Thailand: A Preliminary Analysis. AB - The northeast of Thailand, which is the poorest region of the country, has the highest incidence of cholangiocarcinoma (CCA) worldwide. This is associated with infection with the liver fluke Opisthorchis viverrini. Although an estimated 20,000 people die every year of this disease, the socioeconomic impact of this mortality on the victims' family and the community in which he or she lived remains unknown. Here, we provide background information on the socioeconomic groups most effected by CCA and provide a qualitative estimate of the likely financial burden on the family and community. Most victims of CCA are small-scale farmers. Mortality occurs most commonly in males between the ages of 40 and 65, having either children or grandchildren to support. Costs can be divided between premortality with the family paying for transport and accommodation to the hospital, as well as costs not covered by the Thai Universal Health Coverage scheme. The main costs, however, are likely to be postmortem with loss of income and potentially the loss of a major contributor to farm work. What is urgently required is a quantitative estimate of the costs of CCA and long-term studies of the families and communities affected to determine where and how the burden of CCA falls. PMID- 30442309 TI - RNA Interference as an Approach to Functional Genomics Genetic Manipulation of Opisthorchis viverrini. AB - The availability of genome and transcriptome data of the liver fluke Opisthorchis viverrini provides the foundation for exploration of gene function and its effect on host-parasite interactions and pathogenesis of O. viverrini-associated bile duct cancer. Functional genomics approaches address the function of DNA at levels of the gene, RNA transcript and protein product using informative manipulations of the genome, epigenome, transcriptome, proteome, microbiome and metabolome. Advances in functional genomics for O. viverrini have thus far focused on RNA interference. The flukes have been transfected with double-stranded RNAs aiming to silence target gene expression. In general, this approach for functional genomics investigation of this pathogen has been found to be tractable and efficient: suppression of messenger RNA expression in O. viverrini results in reduction of protein activity and phenotypic changes. Future perspectives for functional genomics of this liver fluke and close phylogenetic relatives are also discussed. PMID- 30442310 TI - Opisthorchis viverrini Proteome and Host-Parasite Interactions. AB - The omics technologies have improved our understanding of the molecular events that underpin host-parasite interactions and the pathogenesis of parasitic diseases. In the last decade, proteomics and genomics in particular have been used to characterize the surface and secreted products of the carcinogenic liver fluke Opisthorchis viverrini and revealed important roles for proteins at the host-parasite interface to ensure that the flukes can migrate, feed and reproduce in a hostile environment. This review summarizes the advances made in this area, primarily focusing on discoveries enabled by the publication of the fluke secreted proteomes over the last decade. Protein families that will be covered include proteases, antioxidants, oncogenic proteins and the secretion of exosome like extracellular vesicles. Roles of these proteins in host-parasite interactions and pathogenesis of fluke-induced hepatobiliary diseases, including cholangiocarcinogenesis, are discussed. Future directions for the application of this knowledge to control infection and disease will also be discussed. PMID- 30442311 TI - Immune Response to Opisthorchis viverrini Infection and Its Role in Pathology. AB - Human liver fluke infection caused by Opisthorchis viverrini is a major public health problem in Mekong countries such as Thailand, Laos, Cambodia, Vietnam, and Myanmar with over 10 million infected through consumption of fish containing infective metacercariae. With no tissue migration phase and living entirely within the larger secondary (intrahepatic) bile ducts, liver flukes are only exposed to a biliary mucosal immune response, while their excretory and secretory products also stimulate chronic inflammation of biliary epithelium. Neither mucosal nor tissue immune responses appear to cause parasite death or protect against newly established flukes, as evidenced by the persistence of infection for decades in the body and rapid reinfection following treatment. Experimental studies suggest that specific immune suppressive mechanisms may promote parasite persistence, therefore allowing continued secretion of parasite products that damage the biliary epithelium, both directly through mechanical damage and mitogenicity and through innate and adaptive inflammatory responses. Chronic infection is associated with several hepatobiliary diseases, specifically gallbladder and bile duct inflammation (cholecystitis and cholangitis), periductal fibrosis, and cholangiocarcinoma, the fatal bile duct cancer. Various studies have linked the chronic immune response to parasite antigens to both fibrosis and many steps in the carcinogenic process. Here, we review research based understandings of the basic immune response to liver fluke infection and its roles in host protection and immunopathogenesis from available literature and also from recent studies conducted by the authors. PMID- 30442312 TI - Update on Pathogenesis of Opisthorchiasis and Cholangiocarcinoma. AB - Infection with the food-borne liver fluke Opisthorchis viverrini causes cholangiocarcinoma (CCA). Whereas the cause of CCA in the West remains obscure, the principal risk factor in Thailand is opisthorchiasis. Here, we review recent findings on the pathogenesis of opisthorchiasis and CCA focusing on helminth molecules/toxic metabolites, host-parasite interaction, endocytosis, immunopathology/inflammatory responses, free radical production, molecular genetic alterations, and multifactorial including coinfections driving to CCA development. PMID- 30442313 TI - Aptamers in Therapeutics and Drug Delivery. PMID- 30442314 TI - The Sanctuary of Sleep. PMID- 30442315 TI - Sleep research in non-Western populations reveals novel insights about the breadth and diversity of human sleep patterns. PMID- 30442316 TI - Explore sleep health under one roof. PMID- 30442317 TI - The influence of age- and sex-specific labor demands on sleep in Namibian agropastoralists. AB - OBJECTIVE: To understand the basics of sleep quality in a pastoralist population and to explore predictors of this variation. DESIGN: Cross-sectional. SETTING: Northern Namibia, dry seasons of 2016 and 2017. PARTICIPANTS: The Himba, a nonindustrial seminomadic agropastoralist population without access to the electrical grid. MEASUREMENTS: Using Actiwatch-2 devices, 75 participants completed 721 days of wear. We calculated sleep duration, efficiency, and activity counts before and after sunset/sunrise and onset/offset. Participants were also interviewed about sleeping arrangements and nighttime disruptions. RESULTS: Himba show lower sleep duration and efficiency than other populations studied, and men had substantially lower duration and efficiency than women. Sex differences were not attenuated when napping was included with total sleep time. Age predicted longer sleep duration and lower evening and morning activity levels. Number of adult co-sleepers predicted increased sleep duration and efficiency in women. Livestock disturbance was not a commonly reported cause of nighttime waking. CONCLUSIONS: These findings support predictions that pastoralist groups may have lower sleep quality than other subsistence populations, but this does not appear to be a consequence of noise from livestock. Instead, lower sleep quality appears to be the result of subsistence and social activities, particularly for men and young adults overall. PMID- 30442318 TI - Does the moon influence sleep in small-scale societies? AB - OBJECTIVES: The lunar cycle is expected to influence sleep-wake patterns in human populations that have greater exposure to the environment, as might be found in forager populations that experience few environmental buffers. We investigated this "moonlight" hypothesis in two African populations: one composed of hunter gatherers (with minimal environmental buffering) and the other rural agriculturalists (with low-to-moderate environmental buffering). SETTING: Research was conducted on Hadza hunter-gatherers from the Sengele community near Lake Eyasi in northern Tanzania and in Mandena, Madagascar, in a rural community of approximately 4000 farmers. PARTICIPANTS: Thirty-one adult Hadza and 21 Malagasy adults were recruited. MEASUREMENTS: We used the CamNtech Motionwatch 8 actigraph and generated data on an epoch-by-epoch, 1-minute basis. RESULTS: In general support of the moonlight hypothesis, we uncovered an association between sleep-wake patterns and lunar cycle (ie., moonlight) for Hadza hunter-gatherers. However, the direction of the effect was opposite to what we predicted: as the potential for exposure to moonlight increased, activity generally shifted to a pattern of less nighttime activity and greater daytime activity. No significant effects were found in the Malagasy agriculturalists. CONCLUSIONS: The proposal that human behaviors are linked with moon phase is a popular belief that persists despite the absence of consistent evidence. We provide the first direct evidence that lunar cycle is linked to sleep-wake pattern in a hunter-gatherer society, suggesting that moonlight does not inhibit sleep-wake patterns in the ways that electric lighting does. PMID- 30442319 TI - What sleep research can learn from history. AB - This article, in noting the recent interest of historians in sleep, assesses both the difficulties and the advantages of studying human sleep in the past. The history of sleep affords important new perspectives not only on everyday life in earlier centuries but also on the underlying origins of contemporary sleep disorders, including middle-of-the-night insomnia. PMID- 30442320 TI - The Possums Infant Sleep Program: parents' perspectives on a novel parent-infant sleep intervention in Australia. AB - AIM: To evaluate parental perspectives on the acceptability and usefulness of a 'cued-care' approach to infant sleep implemented in an Australian primary care setting. The Possums Infant Sleep Program aims to empower parents to better understand their infant's sleep and their responses to it, and optimize healthy function of the infant's biological sleep regulators to protect against excessive night-waking. METHODS: The evaluation was undertaken by an independent infant sleep researcher, with no previous involvement in the Possums program. Parents' experiences of the sleep intervention were captured using a mixed methods approach involving (a) group discussions of sleep issues between parents and clinic staff, (b) discussions with parents who volunteered to provide face-to face feedback, and (c) an online survey designed in light of the information gained from a and b. A one-year audit of clinic registrations provided contextual data. RESULTS: Sixty-four clinic clients fully (45) or partially (19) provided answers to survey questions. Respondents were primarily mothers, mean age 34, with a postgraduate qualification and high family income. Their term infants were predominantly breastfed and attended the clinic for feeding and/or sleeping difficulties across the first year of life. Almost all embraced the Possums approach, describing it as challenging and life changing. Audit data confirmed the survey sample reflected the general clinic population. CONCLUSIONS: The Possums Infant Sleep Program was acceptable to parents, and highly valued. Recipients reported reduced stress, less concern about perceived sleep problems (frequent night-waking, short-day-time naps, delayed sleep onset), and better quality of life. PMID- 30442321 TI - Infant co-sleeping patterns and maternal sleep quality among Hadza hunter gatherers. AB - OBJECTIVE: Despite widespread interest in maternal-infant co-sleeping, few quantified data on sleep patterns outside of the cultural west exist. Here, we provide the first report on co-sleeping behavior and maternal sleep quality among habitually co-sleeping hunter-gatherers. DESIGN: Data were collected among the Hadza of Tanzania who live in domiciles constructed of grass huts with no access to synthetic lighting or climate controlled sleeping environments. Using interview data, we recorded baseline ethnographic data on co-sleeping. Using actigraph data, we tested whether sleep quality, sleep-wake activity, and/or sleep duration differs among breastfeeding women, non-breastfeeding women, and men. MEASUREMENTS: CamNtech Motionwatch 8 actigraphs were used to collect 1 minute, epoch-by-epoch data on a sample of 33 adults. Functional linear modeling (FLM) was used to characterize sleep-wake patterns and a linear mixed-effects model was used to assess factors that drive sleep duration and quality. RESULTS: The FLM suggests that breastfeeding mothers were early risers and had reduced day time activity. Additionally, total number of co-sleepers, not breastfeeding, was associated with less sleep duration and quality, suggesting that greater number of co-sleepers may be a primary driver of poorer sleep. CONCLUSION: The current study makes important contributions to the cross-cultural literature on sleep and augments our understanding of maternal-infant co-sleeping. The majority of Hadza participants co-sleep with at least one other individual and the majority of married couples sleep with their spouse and their children on the same sleeping surface. Our preliminary sleep quality data suggest that breastfeeding does not negatively impact maternal sleep quality. PMID- 30442322 TI - Impacts of nocturnal breastfeeding, photoperiod, and access to electricity on maternal sleep behaviors in a non-industrial rural Bolivian population. AB - OBJECTIVES: We tested 4 main predictions, derived from life history theory and self-evident human diurnality, regarding maternal sleep behaviors in a non industrialized population in which mother-nursling co-sleeping is universal and prolonged: (1) Night breastfeeding incurs a sleep cost to co-sleeping mothers; (2) Night breastfeeding increases with infant age, causing mothers to sleep less; (3) Sleep duration co-varies with darkness duration; (4) Access to electricity reduces sleep duration. DESIGN: Mothers self-recorded and reported nursing and sleep behaviors for a 48-hour period once per month (median = 5 months). SETTING: Rural Bolivian altiplano homesteads, primarily reliant on agropastoralism, scattered throughout the countryside surrounding a main town (altitude 3800 m; 17 degrees 14'S, 65 degrees 55'W; darkness duration 10-12 hours over the year). PARTICIPANTS: One hundred eighty-four co-sleeping mother-infant pairs (infant age 22-730 days). MEASUREMENTS: Breastfeeding frequency, and retiring and rising times for 885 48-hour observation periods. RESULTS: Maternal sleep duration covaried with darkness duration. Sleep duration was shorter in those with access to electricity (ie, living nearer to town) than those without access (more distant homesteads). Night breastfeeding rate was fairly steady until it began to decline after the first year postpartum. At a given infant age, higher night breastfeeding rates were associated with less maternal sleep. As their infants aged, mothers without electricity slept more, whereas mothers with access slept less. CONCLUSIONS: During the first year postpartum, more frequent night nursing shortens maternal sleep more than any other predictor variable. For older infants, the effect of night nursing diminishes, and even modest "modernization" (eg, access to electricity) is associated with shorter maternal sleep. PMID- 30442323 TI - Agreement between subjective and objective measures of sleep duration in a low middle income country setting. AB - OBJECTIVES: Describe sleep duration in adult Sri Lankans and determine the bias and agreement of self-report and actigraphic assessments. DESIGN: Validation sub study nested within the Colombo Twin and Singleton Study (2012-2015). SETTING: Colombo, Sri Lanka. PARTICIPANTS: 175 adults with actigraphy, randomly selected from 3497 participants with self-reported sleep assessed in a population-based cohort. MEASUREMENTS: Self-reported sleep duration, ascertained by the Pittsburgh Sleep Quality Index (PSQI), was compared to a minimum of four days of actigraphy. Bias and agreement were assessed using the Bland-Altman method and a novel application of criterion cut-point analysis. Objective measurements of wake after sleep onset (WASO) and sleep efficiency were evaluated. RESULTS: Sri Lankans have short sleep duration; averaging 6.4h (SD 1.5) self-reported and 6.0h (SD 0.9) actigraphically. Poor sleep quality was prevalent with an average WASO of 49 min., and sleep efficiency <85%. Bias was observed, with self-report consistently over-reporting sleep on average by 27.6 min (95% CI: -0.68, -0.24) compared to objective measures, but wide individual variation in disagreement, ranging from over-reporting by 3.34h to under-reporting by 2.42h. A criterion cut-point method also failed to define agreed definitions of short and long sleep duration. CONCLUSIONS: Sleep in Sri Lankan adults, whether measured subjectively or objectively, is of short duration and suboptimal objective quality by High Income Country consensus standards. Given the high cardiometabolic morbidity in Sri Lanka and poor measurement agreement observed, this warrants further investigation and supports the need for culturally appropriate, reliable, and valid assessment for analytic epidemiology in non-Western settings. PMID- 30442264 TI - The ASOS Surgical Risk Calculator: development and validation of a tool for identifying African surgical patients at risk of severe postoperative complications. AB - BACKGROUND: The African Surgical Outcomes Study (ASOS) showed that surgical patients in Africa have a mortality twice the global average. Existing risk assessment tools are not valid for use in this population because the pattern of risk for poor outcomes differs from high-income countries. The objective of this study was to derive and validate a simple, preoperative risk stratification tool to identify African surgical patients at risk for in-hospital postoperative mortality and severe complications. METHODS: ASOS was a 7-day prospective cohort study of adult patients undergoing surgery in Africa. The ASOS Surgical Risk Calculator was constructed with a multivariable logistic regression model for the outcome of in-hospital mortality and severe postoperative complications. The following preoperative risk factors were entered into the model; age, sex, smoking status, ASA physical status, preoperative chronic comorbid conditions, indication for surgery, urgency, severity, and type of surgery. RESULTS: The model was derived from 8799 patients from 168 African hospitals. The composite outcome of severe postoperative complications and death occurred in 423/8799 (4.8%) patients. The ASOS Surgical Risk Calculator includes the following risk factors: age, ASA physical status, indication for surgery, urgency, severity, and type of surgery. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.805 and good calibration with c statistic corrected for optimism of 0.784. CONCLUSIONS: This simple preoperative risk calculator could be used to identify high-risk surgical patients in African hospitals and facilitate increased postoperative surveillance. CLINICAL TRIAL REGISTRATION: NCT03044899. PMID- 30442324 TI - Sleep pattern, socioenvironmental factors, and use of electronic devices among Nigerian school-attending adolescents. AB - OBJECTIVES: To determine the sleep pattern among Nigerian school-attending adolescents and its association with socioenvironmental factors and the use of electronic devices. DESIGN: Descriptive cross-sectional survey. SETTING: Public and private secondary schools in Ile-Ife, Osun State, Nigeria. PARTICIPANTS: Multistage sampling technique was used to select 346 school-attending adolescents aged 10-19 years. MEASUREMENTS: A modified version of the Adolescent Sleep Habits Survey Questionnaire was administered to respondents in the school setting using the facilitated self-administration method. RESULTS: Participants' mean age was 13.5+/-2.29 years, and the male-female ratio was 1:1.1. The mean total sleep duration on weekends of 9 hours (h) 08 minutes (min) +/- 113 min was significantly higher than that of weekdays (7 h 15 min +/- 86 min) (P < .001). About half of the respondents (48.7 %) had access to a computer. Majority of the respondents (80.9%) use one or more electronic device at bedtime, although cell phone was used by more than half (52.3%) of the respondents at bedtime. The proportion of adolescents with short sleep duration was 44.4% for weekdays and 5.5% for weekends. Lower social class and non-use of computers in the night time were independent predictors of adequate sleep duration on weekdays, whereas female sex, age (early adolescence), and polygamous family setting were independent predictors of sufficient sleep on weekends. CONCLUSION: A high proportion of school-attending adolescents have insufficient sleep on weekdays and significantly sleep less during weekdays compared to weekends. There is a need to target adolescents, parents, and school authorities with education on sleep issues. PMID- 30442325 TI - Associations between long self-reported sleep, obesity and insulin resistance in a cohort of premenopausal Black and White South African women. AB - OBJECTIVES: South African women have disproportionately high levels of overweight and obesity, and ethnic differences in obesity and insulin resistance have been observed. We investigated associations between self-reported sleep duration, obesity and insulin resistance in Black and White South African women. DESIGN: Cross-sectional. PARTICIPANTS: Black normal-weight (n = 122), Black obese (n = 133), White normal-weight (n = 87) and White obese (n = 63) urban South African women, aged 18 to 45y. MEASUREMENTS: Participants completed questionnaires capturing self-reported sleep duration, demographic, socioeconomic, medical history and lifestyle information. Body composition and fasting blood glucose and insulin concentrations were measured. RESULTS: The Black women reported longer sleep than the White women (median: 8 h, interquartile range: 8-10 h v 7(7-8) respectively, P < .001). Adjusted models indicated that women sleeping <7 h sleep were less likely to be obese (P = .035) or insulin resistant (P = .032), while those sleeping >9 h were more likely to be insulin resistant (P = .014) than those sleeping 7 to 9 h. Shorter self-reported sleep was associated with less insulin resistance (<7 h v 7-9 h: P = .018) and longer sleep with more insulin resistance (>9 h v 7-9 h: P = .047) in the Black but not White women. CONCLUSIONS: Future research that objectively measures sleep duration is needed to confirm these observations and investigate potential factors contributing to the relationship between sleep and risk for non-communicable diseases in different ethnic groups. PMID- 30442326 TI - Perceived stress and worldview influence sleep quality in Bolivian and United States university students. AB - OBJECTIVE: This study investigated predictors of poor sleep quality among American and Bolivian students. DESIGN: A cross-sectional survey was designed and administered to undergraduate university students. SETTING AND PARTICIPANTS: Psychology classes from 2 public universities (Texas, USA, and Bolivia) were convenience sampled (n = 80 American students; 60 Bolivian students). MEASUREMENTS: We used a sleep quality index and the Perceived Stress Scale. We added questions concerning worldview, sleep hygiene, sleep deficiency, health behaviors, and demographics. RESULTS: Five variables predicted poor sleep quality: perceived stress, sleep hygiene, sleep deficiency, worldview, and site. Greater stress positively associated with poorer sleep in both cultures. Yet, Bolivian students reported significantly more stress than American students but experienced significantly better sleep quality. Worldview, a measure of optimism or pessimism about the world, negatively associated with sleep quality in both cultures. CONCLUSION: Three variables that predict sleep quality (worldview, sleep hygiene, and sleep deficiency) did not differ significantly between countries. Only perceived stress differed by country but contrary to the predicted direction. Thus, this work reveals new avenues for future work to the investigation of sleep in different cultures. Lastly, we offer recommendations to ameliorate poor sleep in university students. PMID- 30442327 TI - PER3 gene regulation of sleep-wake behavior as a function of latitude. AB - OBJECTIVES: We searched for interactions between PER3 gene VNTR polymorphism, latitude, sleep duration, diurnal sleepiness, and social jetlag. DESIGN: We selected samples from 3 distinct cities along the latitudinal range of Brazil and comprising the same time zone. SETTING: Undergraduate universities located in 3 major cities of Brazil. PARTICIPANTS: A total of 980 undergraduate students: 276 from Maceio (latitude 9 degrees ), 358 from Campinas (latitude 22 degrees ), and 346 from Porto Alegre (latitude 30 degrees ). MEASUREMENTS: PER3 variable number of tandem repeats genotyping, diurnal sleepiness, sleep duration (weekdays and weekend), chronotype, and social jetlag. RESULTS: Latitude is associated with a differential expression of circadian and sleep profiles. We observed a shift toward eveningness with increased latitude and increased social jetlag and diurnal sleepiness at latitude 30 degrees . Moreover, our results suggest that the PER3 variable number of tandem repeats polymorphism has a modulatory effect on these circadian and sleep profiles: the variant PER34/4 is associated with a smaller difference in the sleep duration on weekdays among different latitudes and is associated with longer sleep duration on weekends just at latitude 30 degrees , even when compared to both other genotypes at the same latitude. On the other hand, irrespective of the genotype, volunteers from latitude 30 degrees expressed increased social jetlag and diurnal sleepiness. CONCLUSIONS: The seasonal variation in the light/dark cycle, tied to latitude, together with the tight social time constraints that young adults are subjected to during weekdays, generates differences in the sleep phenotypes. Volunteers with the PER34/4 variant who live farther from the equator have a greater increase in their weekend sleep duration. PMID- 30442328 TI - Using Light to Endow Stem-Cell-Derived Cardiomyocytes With Virtual IK1 Conductances. PMID- 30442330 TI - Regulation of immune responses by E3 ubiquitin ligase Cbl-b. AB - Casitas B lymphoma-b (Cbl-b), a RING finger E3 ubiquitin ligase, has been identified as a critical regulator of adaptive immune responses. Cbl-b is essential for establishing the threshold for T cell activation and regulating peripheral T cell tolerance through various mechanisms. Intriguingly, recent studies indicate that Cbl-b also modulates innate immune responses, and plays a key role in host defense to pathogens and anti-tumor immunity. These studies suggest that targeting Cbl-b may represent a potential therapeutic strategy for the management of human immune-related disorders such as autoimmune diseases, infections, tumors, and allergic airway inflammation. In this review, we summarize the latest developments regarding the roles of Cbl-b in innate and adaptive immunity, and immune-mediated diseases. PMID- 30442329 TI - Integrated cognitive behavioral therapy for comorbid cannabis use and anxiety disorders: A pilot randomized controlled trial. AB - Cannabis use disorder (CUD) is the most common illicit substance use disorder and individuals with CUD have high rates of comorbid anxiety disorders. Comorbidity between CUD and anxiety disorders is of public health relevance given that although motivation enhancement therapy (MET) combined with cognitive-behavioral therapy (CBT) is an efficacious intervention for CUD, outcomes are worse for patients with elevated anxiety. The current study tested the acceptability and efficacy of the integration of a transdiagnostic anxiety CBT (i.e., treatment of patients with any anxiety disorder) with MET-CBT (integrated cannabis and anxiety reduction treatment, or ICART) for CUD compared to MET-CBT alone. Treatment seeking cannabis users (56.4% male, Mage = 23.2, 63.3% non-Hispanic White) with CUD and at least one comorbid anxiety disorder were randomly assigned to ICART (n = 27) or MET-CBT (n = 28). Patients in the ICART condition attended significantly more treatment sessions than those in the MET-CBT condition. Patients in the ICART condition were more likely to be abstinent post-treatment than those in MET CBT. Further, treatment produced decreases in cannabis use and related problems. Notably, therapy type did not moderate the impact of treatment on frequency of use and related problems. Together, these data suggest that ICART may be at least as efficacious as a gold-standard psychosocial CUD treatment, MET-CBT, for a difficult-to-treat subpopulation of cannabis users. PMID- 30442331 TI - Effects of the fungicide ortho-phenylphenol (OPP) on the early development of sea urchin eggs. AB - In this study, we assessed the impact of imidazole fungicide ortho-phenylphenol (OPP) on the early development of a marine invertebrate, the sea urchin, a marine bioindicator. Fungicides are widely used and have been reported to accumulate not only in farm soil but also in freshwater and seawater sediments. Therefore, it is essential to clarify the effects of OPP on marine environments. Toxicity was estimated as the inhibition ratio of the 120 min-embryo and/or the 24 h-embryo development. The addition of OPP to embryos of the two sea urchin species, Scaphechinus mirabilis (S. mirabilis) and Strongylocentrotus nudus (S. nudus), at 0.1 mM or higher, resulted in acute toxicity (cell death). The IC50 value of the 120 min-embryos or the 24 h-embryos for S. mirabilis and S. nudus with OPP was around 0.06 mM, indicating that fertilized eggs and embryos of the sea urchin are more sensitive to OPP than higher vertebrates. In addition, in the presence of OPP (0.005-0.05 mM), the proportion (%) of the gastrula keeping the fertilization membrane increased, suggesting that OPP (0.005-0.05 mM) inhibited the hatching process, possibly by affecting the hatching enzyme activity. PMID- 30442332 TI - AT2 receptor stimulation inhibits phosphate-induced vascular calcification. AB - Vascular calcification is a common finding in atherosclerosis and in patients with chronic kidney disease. The renin-angiotensin system plays a role in the pathogenesis of cardiovascular remodeling. Here, we examined the hypothesis that angiotensin II type 2 receptor (AT2) stimulation has inhibitory effects on phosphate-induced vascular calcification. In vivo, calcification of the thoracic aorta induced by an adenine and high-phosphate diet was markedly attenuated in smooth muscle cell-specific AT2-overexpressing mice (smAT2-Tg) compared with wild type and AT2-knockout mice (AT2KO). Similarly, mRNA levels of relevant osteogenic and vascular smooth muscle cell marker genes were unchanged in smAT2-Tg mice, while their expression was significantly altered in wild-type mice in response to high dietary phosphate. Ex vivo, sections of thoracic aorta were cultured in media supplemented with inorganic phosphate. Aortic rings from smAT2-Tg mice showed less vascular calcification compared with those from wild-type mice. In vitro, calcium deposition induced by high-phosphate media was markedly attenuated in primary vascular smooth muscle cells derived from smAT2-Tg mice compared with the two other mouse groups. To assess the underlying mechanism, we investigated the effect of PPAR-gamma, which we previously reported as one of the possible downstream effectors of AT2 stimulation. Treatment with a PPAR-gamma antagonist attenuated the inhibitory effects on vascular calcification observed in smAT2-Tg mice fed an adenine and high-phosphate diet. Our results suggest that AT2 activation represents an endogenous protective pathway against vascular calcification. Its stimulation may efficiently reduce adverse cardiovascular events in patients with chronic kidney disease. PMID- 30442334 TI - Preface to the Special Issue dedicated to the X Latin-American Congress of Environmental Mutagenesis, Carcinogenesis and Teratogenesis Association (X ALAMCTA Meeting). PMID- 30442333 TI - Patient relevant bleeding complications; it's bleeding complicated. PMID- 30442335 TI - Effects of rapamycin on the mechanistic target of rapamycin (mTOR) pathway and telomerase in breast cancer cells. AB - The mTOR pathway and the enzyme telomerase are two key players commonly upregulated in cancers. They render survival and proliferative advantage to cancer cells, and are regarded as attractive anticancer targets. Rapamycin, a macrolide antibiotic and mTOR inhibitor, has recently also been implicated in telomerase inhibition and telomere attrition, although the mechanisms remain poorly understood. Using breast cancer cells (MCF-7 and MDA-MB-231) wherein telomerase activity and mTOR pathway are concurrently overexpressed, this study sought to unravel novel mechanisms by which rapamycin may affect these pathways. Short term treatment with an acute dose of rapamycin inhibited the mTOR pathway and telomerase activity and induced G1 arrest. This arrest was independent of cyclin D1 and p21 levels and was not mediated by DNA damage in both cell types. While long term treatment with a clinically relevant dose of rapamycin resulted in compromised population doubling capacity and mTOR pathway inhibition, there was no effect on telomere functionality and telomerase activity as evidenced by our assessments of hTERT protein levels, in vitro telomerase activity, telomere length and telomere FISH analyses. We also found that sustained rapamycin treatment leading to Akt activation may play a role in resistance in the more invasive MDA-MB-231 cells. In summary, rapamycin specifically inhibits the activation of mTOR pathway. Moreover, we show for the first time that while acute short-term treatment with rapamycin induces telomerase inhibition, it does not affect telomerase activity nor does it inflict telomere dysfunction in breast cancer cells upon chronic long-term treatment with a clinically relevant dose. These findings may be useful while designing combinatorial treatment strategies with rapamycin inhibition in the clinic. PMID- 30442336 TI - gammaH2AX prefers late replicating metaphase chromosome regions. AB - DNA damage response (DDR) constitutes a protein pathway to handle eukaryotic DNA lesions in the context of chromatin. DDR engages the recruitment of signaling, transducer, effector, chromatin modifiers and remodeling proteins, allowing cell cycle delay, DNA repair or induction of senescence or apoptosis. An early DDR event includes the epigenetic phosphorylation of the histone variant H2AX on serine 139 of the C-termini, so-called gammaH2AX. GammaH2AX foci detected by immunolabeling on interphase nuclei have been largely studied; nonetheless gammaH2AX signals on mitotic chromosomes are less understood. The CHO9 cell line is a subclone of CHO (Chinese hamster ovary) cells with original and rearranged Z chromosomes originated during cell line transformation. As a result, homologous chromosome regions have been relocated in different Z-chromosomes. In a first quantitative analysis of gammaH2AX signals on immunolabeled mitotic chromosomes of cytocentrifuged metaphase spreads, we reported that gammaH2AX139 signals of both control and bleomycin-exposed cultures showed statistically equal distribution between CHO9 homologous chromosome regions, suggesting a possible dependence on the structure/function of chromatin. We have also demonstrated that bleomycin-induced gammaH2AX foci map preferentially to DNA replicating domains in CHO9 interphase nuclei. With the aim of understanding the role of gammaH2AX signals on metaphase chromosomes, the relation between 5-ethynyl-2'-deoxyuridine (EdU) labeled replicating chromosome regions and gammaH2AX signals in immunolabeled cytocentrifuged metaphase spreads from control and bleomycin treated CHO9 cultures was analyzed in the present work. A quantitative analysis of colocalization between EdU and gammaH2AX signals based on the calculation of the Replication Related Damage Distribution Index (RDDI) on confocal metaphase images was performed. RDDI revealed a colocalization between EdU and gammaH2AX signals both in control and bleomycin-treated CHO9 metaphases, suggesting that replication may be involved in H2AX phosphorylation. The possible mechanisms implicated are discussed. PMID- 30442337 TI - DNA damage and repair in individuals with ataxia-telangiectasia and their parents. AB - Ataxi A-T elangiectasia (AT) is a multisystem, complex and rare disease inherited in an autosomal recessive manner. Homozygous individuals have a variety of pathological manifestations, however, heterozygotes only present a higher risk of developing cancer. We evaluated the background levels of DNA damage (basal damage) and cell response to bleomycin or ionizing radiation using Comet assay and the cytokinesis-block micronucleus (CBMN) test in individuals with AT, their parents and controls. To evaluate DNA repair, the challenge experiment with ionizing radiation was performed using Comet assay, and different recovery times were evaluated. Results showed that basal MN frequencies differ between patients, parents and controls. Meanwhile, using the Comet assay, the results from the basal analysis do not differ between the groups, but monitoring the kinetics of DNA repair, we verified that the group of patients showed a delay in repair, compared to controls. Another finding was the nuclear bud (NBUD) frequency: spontaneous and induced cell cultures (with bleomycin and radiation) showed clear differences between patients, parents and controls. The CBMN assay and repair measurement with the Comet assay can help in the diagnosis of AT patients and ATM gene carriers, as complementary methods. The use of genomic instability evaluation techniques for the identification of the heterozygotes in families, where at least one member is affected, may be of great clinical importance. PMID- 30442338 TI - Filling gaps in translesion DNA synthesis in human cells. AB - During DNA replication, forks may encounter unrepaired lesions that hamper DNA synthesis. Cells have universal strategies to promote damage bypass allowing cells to survive. DNA damage tolerance can be performed upon template switch or by specialized DNA polymerases, known as translesion (TLS) polymerases. Human cells count on more than eleven TLS polymerases and this work reviews the functions of some of these enzymes: Rev1, Pol eta, Pol iota, Pol kappa, Pol theta and Pol zeta. The mechanisms of damage bypass vary according to the lesion, as well as to the TLS polymerases available, and may occur directly at the fork during replication. Alternatively, the lesion may be skipped, leaving a single stranded DNA gap that will be replicated later. Details of the participation of these enzymes are revised for the replication of damaged template. TLS polymerases also have functions in other cellular processes. These include involvement in somatic hypermutation in immunoglobulin genes, direct participation in recombination and repair processes, and contributing to replicating noncanonical DNA structures. The importance of DNA damage replication to cell survival is supported by recent discoveries that certain genes encoding TLS polymerases are induced in response to DNA damaging agents, protecting cells from a subsequent challenge to DNA replication. We retrace the findings on these genotoxic (adaptive) responses of human cells and show the common aspects with the SOS responses in bacteria. Paradoxically, although TLS of DNA damage is normally an error prone mechanism, in general it protects from carcinogenesis, as evidenced by increased tumorigenesis in xeroderma pigmentosum variant patients, who are deficient in Pol eta. As these TLS polymerases also promote cell survival, they constitute an important mechanism by which cancer cells acquire resistance to genotoxic chemotherapy. Therefore, the TLS polymerases are new potential targets for improving therapy against tumors. PMID- 30442339 TI - Increased genetic damage found in waste picker women in a landfill in Paraguay measured by comet assay and the micronucleus test. AB - Cateura landfill located in Asuncion-Paraguay is the site of final disposal of tons of garbage of all kinds coming from urban, industrial and commercial areas. Due to an inadequate waste management system, there is a big concern in our country on how it can affect people working within the landfill as waste pickers. When a high risk of exposure affecting workers in their work places is supposed, defining biomarkers of genotoxic damage is obligatory. The principal aim of this study was to evaluate the genetic damage in occupationally exposed women in their work environments through two established biomarkers: the single-cell gel electrophoresis assay (SCGE) accomplished in peripheral blood and the micronucleus test performed in exfoliated cells from oral mucosa (BMCyT). This is an analytical observational cohort study involving 50 women occupationally exposed and 34 unexposed women. A statistically significant increase (p < 0.05) in the parameters to measure genotoxicity was observed in the garbage recyclers of the landfill, compared to the control group. The frequency of Micronuclei (MN) and other nuclear abnormalities such as karyolytic and karyorrhectic cells were higher in exposed women. In addition, significant differences in the % of DNA in the tail of comets between exposed and control groups were found. Our results suggest that the increase in DNA damage and nuclear alterations found in exposed waste pickers women can be explained as a result to their direct contact with chemicals, many of them identified as genotoxic and other alleged mutagens. This chronic exposure could be diminished by using safety procedures and suitable personal protective equipment inside the workplace. The burden of morbidity due to occupational exposure to genotoxic agents in this place is unknown, therefore, these types of studies should be addressed in order to advice to authorities on social policies of protection of landfills workers. PMID- 30442340 TI - Chromosomes forever Prof. Maximo Eduardo Drets (1930-2017). PMID- 30442341 TI - Genetic damage in environmentally exposed populations to open-pit coal mining residues: Analysis of buccal micronucleus cytome (BMN-cyt) assay and alkaline, Endo III and FPG high-throughput comet assay. AB - DNA and chromosomal damage in individuals occupationally exposed to coal mining residues have repeatedly been reported in lymphocytes and epithelial cells, suggesting a systemic exposure-response in which generation of oxidative damage may play a major role. Nevertheless, the understanding of this mechanism is still incomplete, particularly in regard to environmental exposures. This study aimed to evaluate DNA damage using the cytome assay (BMN-cyt) in buccal cells and its relation to primary and oxidative DNA damage in lymphocytes, assessed by the high throughput alkaline and modified (FPG-ENDO III) Comet assay in individuals with environmental exposure to coal mining residues in northern Colombia. Considering metals from coal mining activities as the main source of reactive oxygen species (ROS) generation, the concentrations of inorganic elements in blood samples was also assessed. The analysis revealed that frequencies of BMN-cyt parameters related to DNA damage (micronuclei), cytokinesis (binucleated cells) and cell death (condensed chromatin, karyorrhexis, pyknosis and karyolysis) were significantly higher in individuals that were environmentally exposed to coal compared to the unexposed group. The level of % Tail DNA in the alkaline and the modified Comet assay was 4.0 and 4.3 times higher among exposed individuals than in unexposed controls respectively. Increased MN frequencies in buccal cells were correlated with increased %Tail DNA in alkaline and FPG Comet assay. Additionally, exposed individuals had higher concentrations of Cr, Ni, Mn, and Br in the blood compared to unexposed controls. %Tail DNA in alkaline Comet assay was highly correlated with Al, Mn, and Br concentrations, while %Tail DNA in the FPG Comet assay correlated with Mn levels. These results suggest that oxidative damage, particularly purine oxidation, may play an essential role in DNA damage in individuals exposed to coal residues and that some inorganic elements are related to this effect. PMID- 30442342 TI - Shorter telomere length and DNA hypermethylation in peripheral blood cells of coal workers. AB - Coal is a mixture of several chemicals, mainly inorganic elements and polycyclic aromatic hydrocarbons, many of which have mutagenic and carcinogenic effects. Pneumoconiosis, fibrosis, asbestosis, silicosis, emphysema, loss of lung function and cancer are some examples of coal-related disorders. The aim of this study was to analyze coal miners with respect to telomere length (TL) and percentage (%) of global DNA methylation. The study involved 82 participants divided into two groups: 55 workers exposed to coal and 27 non-exposed individuals. DNA was isolated from peripheral blood samples from all individuals. Telomeres were measured by quantitative real time polymerase chain reaction (qPCR) and global DNA methylation levels were performed by the relative quantitation of 5-methyl-2' deoxycytidine (5-mdC) by high-performance liquid chromatography (HPLC). TL measurements showed a mean of 9,199 bp (+/-4,196) for non-exposed and 7,545 bp (+/-2,703) for exposed groups, and% of global DNA methylation a mean of 2.78% (+/ 0.41) for non-exposed and 3.00% (+/-0.37) for exposed individuals. Occupationally exposed individuals showed a significant decrease of TL (P < 0.05; Mann-Whitney test) and increase in the percentage of global DNA methylation (P < 0.05; Mann Whitney test) when compared to the non-exposed group. This study showed that occupational exposure to coal and products of combustion is positively associated with TL and DNA methylation. Previously, we have evaluated the same individuals using comet assay, micronucleus (MN) test, oxidative stress and inorganic elements. No correlations were observed between TL and methylation with previous data in the exposed group. Further studies are needed to determine whether these alterations are associated with induced disease outcomes and if these events could be determinants to identify cancer risk. PMID- 30442343 TI - A history of the development of the Latin American mutagenesis society: ALAMCTA. AB - The Asociacion Latinoamericana de Mutagenesis, Carcinogenesis y Teratogenesis Ambiental (ALAMCTA) is the organizational structure encompassing the five national environmental mutagenesis societies of Latin America. It was founded in 1980 and has held 10 congresses and had 10 presidents, representing members from throughout Latin America. This brief review describes the founding of ALAMCTA and the key events associated with it, including the initiation in 1993 of the influential Alexander Hollaender Courses in Mexico City, and the hosting of the 11th International Conference on Environmental Mutagens (ICEM) in 2013 in Foz do Iguacu, Brazil. The ALAMCTA has proven to be a central organizing structure for scientists throughout the Latin America, aiming to meet, collaborate, exchange ideas, and promote the science of genetic toxicology and environmental mutagenesis. It has served to integrate scientists from diverse cultures and two language groups on a vast continent to know each other and to work towards common goals of improving public health, supporting basic research, and identifying and trying to solve environmental problems. Given its long history of 37 years and solid foundation due to the dedicated efforts of so many scientists from throughout the region, ALAMCTA is poised to play a critical role in Latin American science long into the future. PMID- 30442344 TI - Polymorphisms of genes related to metabolism of lead (Pb) are associated with the metal body burden and with biomarkers of oxidative stress. AB - Individual susceptibility to the toxic effects induced by exposure to lead (Pb) may be affected by several variables, such as environmental factors, as well as intrinsic variations among the individuals, which are hypothetically associated to genetic differences in enzymes metabolizing the metal. Aim of the present study was to evaluate the effects of polymorphisms of glutathione (GSH)-genes related to the antioxidant status and Pb metabolism (GCLC, rs17883901 and GCLM, rs41303970) on Pb levels in blood (B-Pb) and plasma (P-Pb), as well as Pb-related effects on activity of glutathione-peroxidase (GPX) and on GSH concentrations. A cross-sectional study with 236 adults (men, >18 years old) was carried out with workers from automotive battery factories, Brazil. B-Pb and P-Pb were determined by ICP-MS; blood GPX and GSH were determined by spectrophotometry and qPCR TaqMan assays were used for genotyping. A questionnaire was applied in order to collect socio-demographic, lifestyle and time of exposure. The mean B-Pb level was 211 +/ 118 MUg/L and P-Pb was 6.05 +/- 7.13 MUg/L. GCLM are associated with changes of B-Pb and P-Pb; individuals who carry at least one polymorphic allele for GCLM gene had lower metal levels in the blood and plasma (beta = -1.5; p = 0.0080; beta = -0.12 and p = 0.050). In addition, individuals carrying at least one polymorphic allele for the GCLC gene had higher concentrations of GSH than the non-polymorphic ones, as a function of B-Pb (beta = 0.072; p = 0.029). Significant associations were also observed with GCLC polymorphism on GSH concentrations (as a function of P-Pb), that is, polymorphic individuals tended to have higher concentrations of GSH than non-polymorphic ones (beta = 0.072; p = 0.030), while those individuals who are polymorphic for GCLM had higher activities of GPX, compared to the non-variant genotype (beta = 0.19; p = 0.028). Taken together, our data indicate that polymorphisms related to Pb toxicokinetics modify the metal body burden and Pb-related antioxidant effects. PMID- 30442345 TI - Evaluation of the genotoxic properties of nickel oxide nanoparticles in vitro and in vivo. AB - Nickel-based nanoparticles (NPs) are new products with an increasing number of industrial applications that were developed in recent years. NiO NPs are present in several nanotechnological industrial products, and the characterization of their genotoxic potential is essential. The present study assessed the genotoxicity of NiO NPs in vivo and in vitro using the somatic mutation and recombination test in somatic cells of Drosophila melanogaster (SMART), the cytokinesis - block micronucleus assay (CBMN), and the comet assay in a V79 cell line. The NiO NPs used in this study were about 30 nm in mean size. Larvae of Drosophila melanogaster were exposed to 5 mL of five different concentrations (1.31, 2.62, 5.25, 10.5, and 21 mg/mL) of NiO NPs. In turn, V79 cells were treated with a concentration range of 15-2000 MUg/mL NiO NPs. The SMART showed that all concentrations of NiO NPs are genotoxic to the standart (ST) cross when compared to the negative control. On the other hand, only the highest concentration (21 mg/mL) was genotoxic to the HB cross. Somatic recombination was the preferential mechanism lesions were induced in D. melanogaster. The results show that NiO NPs were mutagenic to V79 cells as assessed by the CBMN assay. Significant differences in the frequencies of micronuclei (MN) were observed using the highest NiO NP concentrations (250 and 500 MUg/mL) in the 4- and 24-h treatments, but when 125 MUg/mL NiO NPs was used, such difference was observed only in the 4-h exposure time. The comet assay revealed that 62, 125, 250 and 500 MUg/mL NiO NPs induced a significant increase in DNA damage. The results observed in this study indicate that NiO NPs are genotoxic and mutagenic in vitro and in vivo. PMID- 30442346 TI - Caliphruria subedentata (Amaryllidaceae) decreases genotoxicity and cell death induced by beta-amyloid peptide in SH-SY5Y cell line. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuritic plaques (NPs), and neurofibrillary tangles (NFTs). beta-Amyloid peptide 1-4 2 (Abeta(1-42)) is the principal component of NPs and is associated with oxidative stress, as well as dysfunction of cholinergic neurotransmission system and cell death. Nevertheless, one of the most promising therapeutic approaches for patients with AD is based on the pharmacological intervention to increases acetylcholine levels and reduces oxidative stress in AD brain. Previous studies have indicated that alkaloids from Amaryllidaceae family exhibit a wide range of biological activities. The purpose of this study was to investigate whether C. subedentata extract may modulate Abeta(1-42)- induced genotoxicity in SH-SY5Y cell line. Here, we conducted a set of bioassays to measure: viability, clonogenic survival, cell death, chromosome damage and DNA strand breaks. The results showed that Abeta(1-42) significantly inhibited cell viability through necrosis rather than apoptosis, increased the percentage of DNA damage and caused mitochondrial morphological alterations. Treatment with the C. subedentata extract led to a significant recovery of cell survival, decreased necrotic cell death and exerted an induction of antigenotoxic effects; additionally, the extract caigused inhibition of acetylcholinesterase (AChE). The present study confirms neuroprotective activities of C. subedentata belonging Amaryllidaceae family and provide a novel information to clarify the mechanisms by which the extracts decrease DNA damage levels induced by Abeta(1-42). PMID- 30442347 TI - Protective effects of neocuproine copper chelator against oxidative damage in NSC34 cells. AB - In this work, we aim to provide evidence for the protective effect of a copper chelator, neocuproine (NeoCu), against the oxidative stress in NSC34 cells, which inhibits biomolecule oxidation and cell death. Results obtained with the comet assay allowed to determine the increase in oxidized purines and pyrimidines by H2O2 exposure, and their changes after the addition of NeoCu. We also observed a higher ATP7b activity in nuclei and a higher Cu concentration inside the cells, proving that the NeoCu acts directly in DNA to promote cell recovery in oxidative stress conditions, also observed in Reactive Oxygen Species (ROS) detection assay by Flow Cytometry. Based on these results, we propose that NeoCu is a promising drug for the protection of motor neuron cells during oxidative stress caused by neurodegenerative diseases in this system. PMID- 30442348 TI - In vivo antigenotoxic activity of Diplotaxis tenuifolia against cyclophosphamide induced DNA damage: Relevance of modulation of hepatic ABC efflux transporters. AB - Several epidemiological studies have demonstrated that a diet with high contents of cruciferous vegetables (which belong to the Brassicaceae family) may reduce the incidence of cancer and neurodegenerative diseases. However, some authors have postulated that they might bring about toxic effects. Therefore, the aim of this study was to assess the effects of chronic administration of Diplotaxis tenuifolia (wild rocket), a species found in Argentina, concerning its putative genotoxicity or antigenotoxicity against the DNA damage inducer cyclophosphamide, and its ability to modulate the hepatic expression of ABC efflux transporters on mice. The alkaline comet assay and the micronucleus test were used as genotoxicity biomarkers, and the ABC transporter expression was analyzed by Western-blotting. D. tenuifolia juice exhibited no genotoxicity in any of the three tested doses (p > 0.05), showing instead a protective effect against genotoxic damage induced by cyclophosphamide (p < 0.001) in a dose-dependent behavior. Furthermore, hepatic expression of ABCB1 remained unchanged in both sexes at every dose, whereas ABCG2 expression increased in females (p < 0.05) and males (p < 0.01) at the highest dose. Regarding ABCC2, sex-related differences were observed (p < 0.05), its expression decreasing in females (p < 0.05) and increasing in males (p < 0.05). The modulation of these transporters may contribute to the antigenotoxic effects of D. tenuifolia since they act as universal detoxifiers, excreting xenobiotics to the cellular exterior. Phytochemicals present in the juice such as glucosinolates, quercetin and kaempherol may be responsible for these beneficial effects. PMID- 30442349 TI - Evaluation of resveratrol radiomodifying potential for radiotherapy treatment. AB - Radiotherapy is widely used for cancer treatment. However, its adverse effects that may develop during the course of treatment have forced to search agents to protect biological systems against the deleterious effects of radiation. Resveratrol (3,4,5-trihydroxy-trans-stilbene; RSV) is a natural polyphenol currently promoted for its beneficial pleiotropic effects on health, which has been shown to exhibit antioxidant properties while inhibiting the growth of tumor cells. In radioresistant tumors, RSV could contribute to reduce recurrence and treatment failure. We evaluated the radiomodulatory and genotoxic effects of RSV in CHO-k1 and A549 cell lines and in peripheral human blood lymphocytes through both conventional and hypofractionated protocols, due to the widespread use of hypofractionation in recent years. RSV genotoxic and cytotoxic action was assessed at 15 and 60 MUM concentrations with the comet and the MTT assay and in cell proliferation experiments. Our results show that RSV administration to tumor cells at a dose of 60 MUM exerted a genotoxic effect and that this concentration also had the capacity of modulating the cytomolecular damage induced by 4 and 16 Gy. These doses are delivered in conventional and hypofractionated radiotherapy, respectively. In both treatments, a radiosensitizing effect was evidenced by the decrease in cell viability that was exacerbated over time. These effects were not found in peripheral blood, suggesting that RSV had a dual response. Although the results obtained in CHO-k1 transformed cells corroborated the genotoxic effect of the 60 MUM dose of RSV observed in the tumor system, they also showed a radio protective effect at the lowest dose (15 MUM). While more studies are necessary, our results together with the good systemic tolerance of RSV and the lack of toxicity position the compound as a potential candidate for the prevention and treatment of cancer as well as for the optimization of the radiotherapeutic ratio. PMID- 30442350 TI - Single nucleotide polymorphisms in ATM, TNF-alpha and IL6 genes and risk of radiotoxicity in breast cancer patients. AB - Although oncological therapies have improved in the last decades, breast cancer (BC) remains a serious health problem worldwide. Radiotherapy (RT) is one of the most frequently used treatments for cancer aimed at eliminating tumor cells. However, it can also alter the surrounding normal tissue, especially the skin, and patient reactions may vary as a result of extrinsic and intrinsic factors. We evaluated the association of gene polymorphisms ATM Asp1853Asn, IL-6 G-174C and TNF-alpha G-308A involved in central phenotype pathways and development of individual radiosensitivity in BC patients with an exacerbated response to RT. Although univariate analysis results did not show a significant association with this trait, the interaction analysis between polymorphisms showed an increased risk of patients presenting wild-type TNF-alpha G-308A genotype and mutant IL-6 G 174C genotype, and heterozygous TNF-alpha G-308A genotype and heterozygous IL-6G 174C genotype. On the other hand, our results showed that breast size and patient age influenced the determination of RT-associated effects. Considering that the trait is multifactorial, other significant elements for the determination of individual radiosensitivity should be considered, together with the establishment of specific polymorphic variants. PMID- 30442351 TI - Base excision repair (OGG1 and XRCC1) and metabolism (PON1) gene polymorphisms act on modulation of DNA damage and immune parameters in tobacco farmers. AB - Pesticides are one of the most frequently investigated chemical, due to their multiple uses in agricultural and public health areas. This study evaluates lymphocytes CBMN (cytokinesis-block micronucleus cytome assay), inflammatory markers, inorganic elements in blood samples, and the relationship of these parameters with XRCC1Arg194Trp, OGG1Ser326Cys and PON1Gln192Arg polymorphisms in a population of tobacco farmers. The study population comprised 129 agricultural workers exposed to pesticides and 91 nonexposed. Farmers had significantly increased NPB (nuclear plasmatic bridge), MN (micronucleus) and NBUD (nuclear bud) frequencies, as well as IL-6 (interleukin 6) and TNF-alpha (tumor necrosis factor alpha) serum levels, and decreased cytokines CD4+/CD8+ ratio. In the exposed group, XRCC1 Trp/- was correlated with decreased NDI (nuclear division index), and OGG1 Cys/- was associated with higher levels of NPB and decreased levels of IL-6. The combined effects of PON1 Arg/- and XRCC1 Arg/Arg were associated with increased NPB frequencies. In addition, the combination of PON1 Arg/- with XRCC1 Trp/- or OGG1 Cys/- influenced in increased levels of necrosis in farmers. Furthermore, tobacco farmers showed a positive correlation between TNF-alpha levels and NPB, CD4+/CD8+ ratio and NBUD; and IL-6 levels with both MN and NDI. The duration of years of work at tobacco fields was correlated positively with NBUD frequency. Sulfur, chlorine and potassium were found at increased levels in the exposed group when compared to the nonexposed one. These findings provide evidence that tobacco farmers' exposure have increased DNA damage and alter the immune system's response, and that XRCC1 and OGG1 polymorphisms could influence both biomarkers results. PMID- 30442352 TI - BCL2 and miR-181a transcriptional alterations in umbilical-cord blood cells can be putative biomarkers for obesity. AB - Several findings suggest that in utero stressor stimuli can alter fetal development by promoting transcriptional changes, and predisposing the neonate to diseases later in life. This study aimed to investigate whether a hyperglycemic environment in pregnant women with gestational diabetes mellitus (GDM) is able to cause fetal genetic alterations and predispose neonates to obesity. Transcriptional alteration of SIRT1, TP53 and BCL2 genes, miR-181a (a SIRT1 or BCL2 regulator) and telomere length were evaluated in placental and umbilical cord blood cells. Healthy (HP; n = 20) and GDM (n = 20) pregnant women and their respective neonates were included in the study. Additionally, obese (n = 20) and eutrophic (n = 20) adults also participated as reference populations. Gene expression data showed down-regulation of BCL2 in umbilical-cord and peripheral blood cells from GDM neonates and obese adults, respectively. The miR-181a was down-regulated only in umbilical-cord blood cells of GDM neonates. Telomere length presented no significant difference. In conclusion, our study demonstrated that the GDM hyperglycemic intrauterine environment promotes transcriptional alterations in BCL2 and miR-181a in neonate umbilical-cord blood cells. Furthermore, both GDM neonates and obese subjects share the same transcriptional alteration in BCL2. Considering the relationship between obesity development and the functions regulated by these two genes, BCL2 and miR-181a could be adopted as potential biomarkers for childhood obesity. However, further study designs are recommended to confirm this hypothesis. PMID- 30442353 TI - Polymorphisms in IMPDH2, UGT2B7, and CES2 genes influence the risk of graft rejection in kidney transplant recipients taking mycophenolate mofetil. AB - The immunosuppressant mycophenolic acid (MPA), derived from the prodrug mycophenolate mofetil (MMF), is a drug used widely by kidney transplant recipients. This drug selectively inhibits inosine monophosphate dehydrogenase that controls the proliferation of lymphocytes, aiding in the prevention of rejection of the transplanted organ. Polymorphisms in key genes involved in MMF metabolism may alter the function of the enzymes encoded by them and contribute to interindividual variability in the response to the drug and its efficacy. The aim of this study was to investigate the association of nine polymorphic variants of eight genes involved in MMF pharmacokinetics, with rejection and adverse effects exhibited by kidney transplant recipients who use this drug. Our sample comprised 145 kidney transplant recipients undergoing post-transplant treatment whose immunosuppressive therapy consisted of MMF and corticosteroid combined or not with a calcineurin inhibitor or mTOR inhibitor. The average age of the patients was 46.9 +/- 12.5 years, and they underwent transplantation 7 +/- 5.71 years ago. The combination of the T/C and C/C genotypes of the polymorphism rs11706052 (IMPDH2) was associated with a 4.2-fold protection, and the combination of the genotypes A/G and G/G of the polymorphism rs7438135 (UGT2B7) showed a 2.4-fold protection, against rejection. The association of T/C and C/C genotypes in the SNP rs11706052 (IMPDH2) with the occurrence of rejection episodes considering only patients who received immunosuppressive drug MMF associated with cyclosporine or tacrolimus and corticoids, demonstrated association with a protection against rejection 15.6-fold. The T/T genotype of the polymorphism rs2241409 (CES2) was associated with a 7.2-fold increased risk of rejection. Therefore, these polymorphisms that showed a strong association with rejection episodes should be considered in future studies on new prognostic markers for rejection in patients treated with MMF. PMID- 30442354 TI - Changes in Cervicocephalic Kinesthetic Sensibility, Widespread Pressure Pain Sensitivity, and Neck Pain After Cervical Thrust Manipulation in Patients With Chronic Mechanical Neck Pain: A Randomized Clinical Trial. AB - OBJECTIVE: The purpose of the current randomized clinical trial was to examine the effects of cervical thrust manipulation or sham manipulation on cervicocephalic kinaesthetic sense, pain, pain-related disability, and pressure pain sensitivity in patients with mechanical neck pain. METHODS: Fifty-four individuals with neck pain were randomly assigned to receive either a cervical manipulation (right or left) or a sham manipulation. Immediate outcomes included cervical kinesthetic sense as assessed by joint position sense error (JPSE) and pressure pain thresholds (PPTs). At 1 week, neck pain intensity (numerical pain rate scale) and neck pain-related disability (Neck Disability Index [NDI]) outcomes were also collected. RESULTS: The mixed-model analysis of covariance revealed a significant group * time interaction in favor of the cervical thrust manipulation group for the JPSE on rotation and extension. There was also a significant interaction for changes in PPTs at C5 to C6 and tibialis anterior. At the 1-week follow-up, a significant interaction existed for neck-related disability but not for neck pain at rest, worst pain, or lowest pain experienced the preceding week. CONCLUSIONS: Our results suggest that cervical spine thrust manipulation improves JPSE, PPT and NDI in participants with chronic mechanical neck pain. Furthermore, changes in JPSE and NDI were large and surpass published minimal detectable changes for these outcome measures. In addition, the effect sizes of PPTs were medium; however, only C5 to C6 zygapophyseal joint exceeded the minimal detectable change. In contrast, cervical thrust manipulation did not improve neck pain intensity at 1 week after the intervention. PMID- 30442356 TI - Neck Muscle Stiffness in Participants With and Without Chronic Neck Pain: A Shear Wave Elastography Study. AB - OBJECTIVES: The purpose of the present study was to investigate differences in neck muscle stiffness between patients with chronic neck pain and asymptomatic control group. METHODS: Thirty-five patients with chronic neck pain and 35 age matched asymptomatic participants enrolled in the study. Shear wave velocity (SWV) of upper trapezius, levator scapulae, splenius capitis, and sternocleidomastoid muscles were obtained using an ACUSON S3000 Ultrasonography Device (Siemens Medical Solutions, Mountain View, California). In patients with chronic neck pain, pain intensity was measured by Numerical Rating Scale and disability level was measured by Neck Disability Index. RESULTS: The SWV of splenius capitis was similar in both groups (P = .985); however, SWV of upper trapezius (P = .001), levator scapulae (P = .038), and sternocleidomastoid (P = .001) of the patients with chronic neck pain were higher compared with the asymptomatic controls groups. Numerical Rating Scale and Neck Disability Index scores did not correlate with the SWV of the selected muscles (P > .05). CONCLUSIONS: Stiffness of upper trapezius, levator scapulae, and sternocleidomastoid muscles in patients with neck pain were higher compared to asymptomatic participants. In addition, severity of pain and disability did not correlate to stiffness of these muscles in patient with chronic neck pain. PMID- 30442355 TI - Comparison of Treatment Outcomes in Nonspecific Low-Back Pain Patients With and Without Modic Changes Who Receive Chiropractic Treatment. AB - OBJECTIVE: The aim of this study was to determine if there was a difference in outcomes in patients with nonspecific low back pain, both with and without Modic changes (MCs), who received chiropractic care. METHODS: This prospective outcomes study included 112 patients with low back pain without disc herniation on magnetic resonance imaging. All patients were treated with spinal manipulative therapy. At baseline, the numerical rating scale (NRS) and Bournemouth Questionnaire (BQ) for disability were collected. The NRS, BQ, and Patient's Global Impression of Change (primary outcome) were collected at the follow-up time points of 1 week, 1 month, and 3 months to assess overall improvement. Magnetic resonance imaging scans were analyzed for the presence of MCs and, if present, classified as Modic I or II. The chi2 test was used to compare the proportion of patients reporting clinically relevant "improvement" between patients with and without MCs and between Modic I and Modic II patients. The unpaired Student t test was used to compare NRS and BQ at baseline and change scores at all follow-up time points. RESULTS: For the primary outcome measure, the proportion of patients reporting relevant "improvement" (Patient's Global Impression of Change), and for the secondary outcome measures (NRS and BQ change scores), there were no significant differences between Modic positive and Modic negative patients or between Modic I and Modic II patients. CONCLUSION: Neither the presence nor absence of MCs nor the Modic change category were related to treatment outcomes for patients with low back pain without disc herniation who received chiropractic care. PMID- 30442357 TI - Immediate Effects of Thoracic Spine Manipulation Upon Shoulder Functionality in Patients With Sutured Rotator Cuff Repair: A Prospective Study. AB - OBJECTIVES: The purpose of this study was to evaluate the immediate effect of thoracic spine manipulation upon active flexion and abduction mobility of the shoulder, spine temperature, and the size of the subacromial space as measured by ultrasound in 3 positions (internal, neutral, and external rotation) of the glenohumeral joint in patients who have undergone surgery because of subacromial impingement. METHODS: Quasi-experimental, prospective, short-term effect study with consecutively sampled participants. Thirty-two patients had undergone subacromial decompression together with supraspinatus tendon suture. The following variables were studied: age, sex, dominant shoulder, presurgery evolution time, working status, surface temperature of dorsal segment with limited mobility, premanipulation functional assessment using the Spanish version of the Upper Limb Functional Index Scale, goniometric range of motion measurement at glenohumeral joint before and after manipulation, and ultrasound measurement of subacromial space before and after manipulation. RESULTS: Significant differences and small effect size were found in measurements for flexion and abduction movements after thoracic spine manipulation (P > .001; ES > 0.2) and subacromial space measurements in neutral rotation and external rotation (P > .001), but without clinical relevance effect size (<0.2). CONCLUSIONS: Active shoulder flexion and abduction mobility increase after manipulation of thoracic spine in patients who have undergone surgery for rotator cuff suture. Subacromial space increases significantly with shoulder in neutral and external rotation position after manipulation. No differences were found regarding surface temperature of manipulated area. PMID- 30442358 TI - Intrarater and Inter-rater Reliability of Maximal Voluntary Neck Muscle Strength Assessment Using a Handheld Dynamometer in Women With Headache and Healthy Women. AB - OBJECTIVE: This study aimed to determine the inter-rater and intrarater reliability, agreement, and minimal detectable change (MDC) of the neck muscle strength test using a handheld dynamometer in healthy women and women with headaches. METHODS: Neck muscle strength in maximal voluntary contraction was measured using the Lafayette Manual Muscle Testing attached to a nonelastic belt in 25 women with migraines and in 25 healthy women. Three repetitions of flexion, extension, and lateral flexion were performed. The tests were performed by 2 examiners on the same day, with a 10-minute interval, and by 1 examiner, with a 1 week interval. The reliability was verified by the intraclass correlation coefficient, the agreement determined by standard error measurement, and the MDC calculated. RESULTS: The protocol exhibited moderate to excellent intrarater and inter-rater reliabilities in both groups (intraclass correlation coefficientrange, 0.53-0.90). The standard error measurement ranged from 0.43 to 1.81 and the MDC from 1.49 up to 4.61. CONCLUSION: Quantification of neck muscle strength using the handheld dynamometer with an attached nonelastic belt exhibited moderate to excellent intra- and inter-rater reliability in women with and without migraines. Moreover, the standard error measurement and MDC were proven to be useful in the interpretation of data and in guiding clinical decisions. PMID- 30442359 TI - The hippocampus of birds in a view of evolutionary connectomics. AB - The avian brain displays a different brain architecture compared to mammals. This has led the first pioneers of comparative neuroanatomy to wrong conclusions about bird brain evolution by assuming that the avian telencephalon is a hypertrophied striatum. Based on growing evidence from divers analysis demonstrating that most of the avian forebrain is pallial in nature, this view has substantially changed during the past decades. Further, birds show cognitive abilities comparable to or even exceeding those of some mammals, even without a "six-layered" cortex. Beside higher associative regions, most of these cognitive functions include the processing of information in the hippocampal formation (HF) that shares a homologue structure in birds and mammals. Here we show with 3D polarized light imaging (3D-PLI) that the HF of pigeons like the mammalian HF shows regional specializations along the anterior-posterior axis in connectivity. In addition, different levels of adult neurogenesis were observed in the subdivisions of the HF per se and in the most caudal regions pointing towards a functional specialization along the anterior-posterior axis. Taken together our results point to species specific morphologies but still conserved hippocampal characteristics of connectivity, cells and adult neurogenesis if compared to the mammalian situation. Here our data provides new aspects for the ongoing discussion on hippocampal evolution and mind. PMID- 30442360 TI - Relation of Living in a "Food Desert" to Recurrent Hospitalizations in Patients With Heart Failure. AB - Food deserts (FD), low-income areas with low access to healthful foods, are associated with higher burden of cardiovascular risk factors. Few studies have examined the impact of FD on clinical outcomes in heart failure (HF). FD status was assessed in 457 HF patients (mean age 55.9 +/- 12.5 years; 50.3% Black) using the Food Desert Research Atlas. The Andersen-Gill extension of Cox model was used to examine the association of living in a FD with risk of repeat hospitalization (all-cause and HF-specific). Patients living in a FD were younger (p = 0.01), more likely to be Black (p <0.0001), less educated (p = 0.003), and less likely to have commercial insurance (p = 0.003). During a median follow-up of 827 (506, 1,379) days, death occurred in 60 (13.1%) subjects, and hospitalizations occurred in 262 (57.3%) subjects. There was no difference in the risk of death based on FD status. The overall frequency of all-cause (94.1 vs 63.6 per 100 patient-years) and HF-specific (59.6 vs 30.5 per 100 patient-years) hospitalizations was higher in subjects who lived in a FD. After adjustment for covariates, living in a FD was associated with an increased risk of repeat all-cause (hazard ratio 1.39, 95% confidence interval 1.19 to 1.63; p = 0.03) and HF-specific (hazard ratio 1.30, 95% confidence interval 1.02 to 1.65; p = 0.03) hospitalizations. In conclusion, patients living in a FD have a higher risk of repeat all-cause and HF-specific hospitalization. PMID- 30442361 TI - Intensity-Dependent Benefit of Statins in Survival Among Prospective Kidney Transplant Patients. AB - Statin use in patients listed for in kidney transplant is believed to be beneficial. However, the optimum statin dose for improved survival in this high risk population is unknown. Our study aimed to determine the impact of prekidney transplant statin dosage on survival postkidney transplant. In this retrospective cohort study, we enrolled patients who underwent kidney transplant from January 2005 to September 2015 at Rush University Medical. Data on the statin use and intensity used before kidney transplant were obtained. The patient population was stratified into 2 groups based on prekidney transplant use of statins. Patients using any form of statin, without regard to the type and dose, were placed in the statin groups, whereas the rest were categorized as the no statin group. The statin group was further classified into low-intensity, moderate-intensity, and high-intensity statin subgroups based on the present atherosclerotic cardiovascular disease definition of statin intensity. The primary outcome was patient survival after kidney transplant. A total of 687 patients had data on statin use before kidney transplant were followed. Median follow-up time was 3.4 years (interquartile range 1.2 to 5.6 years). Multivariate analysis showed that the use of statins prekidney transplant was associated with improved survival postkidney transplant compared with prestatin group (Hazard ratio 0.56, confidence intervals 0.32 to 1.00, p = 0.05). When patients on statins were stratified by statin intensity, Kaplan-Meier survival analysis revealed a significant dose-dependent improvement in survival. Multivariate analysis showed that the relation between statin intensity and survival was maintained even after adjusting for confounder (hazard ratio 0.30, confidence intervals 0.18 to 0.51, p <0.001). In conclusion, our data indicate statistically significant survival benefit in patients receiving high-intensity statin before kidney transplant. PMID- 30442362 TI - Prevalence and Outcomes of Isolated Tricuspid Valve Surgery Among Medicare Beneficiaries. AB - We sought to characterize the clinical outcomes and to identify predictors of mortality undergoing isolated tricuspid valve surgery in the United States. We identified 5,164 patients undergoing isolated tricuspid valve surgery from the Centers for Medicare and Medicaid Services Medicare Provider Analysis and Review data between January 2003 and December 2014. The primary outcome was all cause 1 year mortality. A backward elimination method was performed to identify predictors of 1-year mortality. Tricuspid valve repair was performed in 2,494 (48.3%) patients and tricuspid valve replacement was performed in 2,670 (51.7%) patients. Perioperative and 1-year mortality rates were 9.9% and 24.1%, respectively. Predictors of 1-year mortality were age (p <0.001), chronic heart failure (p = 0.001, cirrhosis (p <0.001), carcinoid syndrome (p <0.001), chronic kidney disease (p = 0.001), secondary pulmonary hypertension (p = 0.023), endocarditis (p = 0.005), decubitus ulcer (p <0.001), malnutrition (p <0.001), replacement (p = 0.013), emergency procedure (p <0.001), and preprocedural shock (p <0.001). The C-statistic for 1-year mortality was 0.70 (95% confidence interval, 0.67 to 0.73). In conclusion, isolated tricuspid valve surgery is infrequently performed in the United States, and is associated with high 1-year mortality. Patients at higher risk for mortality can be identified based on the presence of a number of comorbidities at the time of surgery. PMID- 30442363 TI - Neighborhood Socioeconomic Status and Adverse Outcomes in Patients With Cardiovascular Disease. AB - Neighborhood socioeconomic status (nSES) is associated with cardiovascular morbidity and mortality in the general population; however, its effect on high risk patients with prevalent coronary artery disease (CAD) is unclear. We hypothesized "double jeopardy," whereby the association between nSES and adverse outcomes would be greater in high-risk patients with heart failure (HF) and/or previous myocardial infarction (MI) compared with those without. We followed 3,635 patients (mean age 63.2 years, 42% with HF, 25% with previous MI) with known or suspected CAD over a median of 3.3 years for all-cause death and cardiovascular death or nonfatal MI. Patients were categorized by a composite nSES score, and proportional hazards models were used to determine the association between nSES and outcomes. Cross-product interaction terms for previous MI * nSES and HF * nSES were analyzed. Compared with high nSES patients, low nSES patients had increased risk of all-cause death (hazard ratio [HR] = 1.61; 95% confidence interval [CI] = 1.20, 2.15) and cardiovascular death or MI (subdistribution HR [sHR] = 1.82; 95% CI = 1.30, 2.54). Associations were more pronounced among patients without HF or previous MI. Low nSES patients without HF had a higher risk of all-cause death (HR = 2.27; 95% CI = 1.41, 3.65) compared with those with HF (HR = 1.21; 95% CI = 0.82, 1.77, P interaction = 0.04). Similarly, low nSES patients without previous MI had a higher risk of cardiovascular death or MI (sHR = 2.72; 95% CI = 1.73, 4.28) compared with those with previous MI (sHR = 1.02; 95% CI = 0.58, 1.81, P interaction = 0.02). In conclusion, low nSES was independently associated with all-cause death and cardiovascular death or MI in patients with CAD; however, associations were greater in patients without HF or previous MI compared with those with HF or MI. PMID- 30442364 TI - Three differential expression profiles of miRNAs as potential biomarkers for lung adenocarcinoma. AB - Owing to the poor prognosis, novel biomarkers for lung adenocarcinoma (LACA) are needed nowadays. The aim of the study was to identify the differential miRNAs expression between lung cancer and normal tissues and evaluate the prognostic values of the miRNAs. Multidimensional data of 528 samples were retrieved from The Cancer Genome Atlas archive. Data analysis was based on a computational approach to detect survival-associated molecular signatures. A total of 191 differentially expressed miRNAs were identified between LACA tissues and normal tissues, including 88 up-regulated and 103 down-regulated miRNAs. The Kaplan Meier survival method revealed the prognostic function of the three miRNAs (miR 1293, miR-873 and miR-1914). Cox regression analysis showed that the three-miRNA signature was an independent prognostic factor in LACA. The functional enrichment analysis suggested that the target genes of three miRNAs may be involved in various pathways related to the cancer. This study demonstrated that the three miRNA signature (miR-1293, miR-873 and miR-1914) could be used as a prognostic marker in LACA. PMID- 30442365 TI - Klotho prevents DEX-induced apoptosis in MC3T3-E1 osteoblasts through the NF kappaB signaling pathway. AB - Dexamethasone (DEX) is a commonly used anti-inflammatory drug and an immunosuppressive drug used in clinical practice to treat a variety of diseases. Glucocorticoid-induced osteoporosis (GIOP) is a consequence of high dose, or a long-term low dose use of glucocorticoids (GCs). These treatment regimens can cause a variety of bone-related adverse effects, leading to increased osteoblast and bone cell apoptosis. Evidence suggests that klotho (KL) can inhibit GIOP. It is unknown whether KL attenuates DEX-induced apoptosis in MC3T3-E1 cells or the underlying mechanisms involved. In the present study, we found that MC3T3-E1 cells pretreated with DEX led to the up-regulation of cleaved-caspase-3, and down regulation of caspase-3, which were inhibited by KL transfection. Furthermore, flow cytometry and western blot analysis revealed that the NFkappaB inhibitor pyrrolidine dithiocarbamate (PDTC) could restore the DEX-induced caspase-3 decrease and inhibit the DEX-induced cleaved caspase-3 increase. We observed that DEX stimulated the degradation of IkappaBalpha(NFkappaB inhibitor alpha) and the translocation of NFkappaB, which were suppressed by KL transfection. These findings therefore, indicate a protective role for KL against osteoblastic cell apoptosis induced by DEX, via the NF-kappaB signaling pathway. PMID- 30442367 TI - Epidermal growth factor induced macropinocytosis directs branch formation of lung epithelial cells. AB - Lung branching morphogenesis is a complex system involving many molecular interactions to filling the three dimensional spaces; however, the underlying developmental mechanisms are still not fully understood. In this paper, we have investigated the effect of epidermal growth factor (EGF) on normal human bronchial epithelial cells and their three-dimensional (3D) branching pattern formation by using in vitro experiments and mathematical simulation. The results show that EGF is essential for 3D branch pattern formation and its receptor is highly expressed at the tip of branches to generate the drive force for cells to migrate. Macropinocytosis induced by EGFR expression is firmly contributed to the nutrition uptake at the tip of branches. Our findings for effective branching formation of human lung cells contribute to further understanding molecular mechanisms of organogenesis, and the important mechanisms also possibly participate in related lung disease such as malformation. PMID- 30442366 TI - LncRNA DLX6-AS1/miR-129-5p/DLK1 axis aggravates stemness of osteosarcoma through Wnt signaling. AB - Osteosarcoma is the most common primary bone tumor and occurs most frequently in adolescents. Cancer stem cells (CSCs) are resistant to chemotherapy and radiotherapy, and can drive cancer recurrence. In this study, we aimed to investigate the effect of Long noncoding RNAs (lncRNAs) DLX6-AS1 on osteosarcoma stemness and the underlying mechanism involved. DLX6-AS1 enhanced osteosarcoma stemness in vitro and in vivo. Moreover, DLX6-AS1 competitively interacted with miR-129-5p to DLK1, resulting in activation of Wnt signaling and promotion of stemness in osteosarcoma. DLX6-AS1 functionally interplayed with miR-129-5p to form a reciprocal feedback loop to activate Wnt signaling. High DLX6-AS1 expression was observed in osteosarcoma tissues, and predicted a poor prognosis for osteosarcoma patients. Our study suggests that DLX6-AS1, combined with miR 129-5p and DLK1, can be utilized as factors for the clinical diagnosis and prognosis of osteosarcoma, and may be potential targets for the treatment of osteosarcoma. PMID- 30442368 TI - A histidine-rich elastin-like polypeptide functions as a quickly detectable and easily purifiable protein fusion tag. AB - Although many protein fusion tags have been developed for recombinant protein production to improve protein yields or facilitate purification, determining the expression and purification of the fusion protein still remain to be a time consuming and laborious procedure. In this work, we designed a histidine-rich elastin-like polypeptide (HRELP) fusion tag and found that it could be efficiently expressed in E. coli cells and specifically stained with Pauly's reagent in a couple of minutes post SDS-PAGE analysis. Moreover, in Pauly's reagent-stained polyacrylamide gels, only the bands of HRELP fusion proteins were yellow and could be clearly visualized with little background. Furthermore, both HRELPs and HRELP20-BMP2 fusion protein could be purified by a method of pH shift mediated inverse transition cycling (ITC). In our opinion, the HRELP established in this study may be considered as a multifunctional protein tag which could make its fusion proteins being quickly detected by Pauly staining and simply purified by pH-triggered ITC in addition to having the potential to sustained release its fusion proteins. PMID- 30442369 TI - Long noncoding RNA MAGI2-AS3 regulates CCDC19 expression by sponging miR-15b-5p and suppresses bladder cancer progression. AB - Bladder cancer (BCa) belongs to a popular urological malignancy and leads to large numbers of deaths worldwide. Recently, emerging evidences indicate that long noncoding RNAs (lncRNAs) are closely related with BC occurrence and progression. However, the function of lncRNA MAGI2-AS3 remains poorly understood in BC. In this present study, we screened out a novel lncRNA MAGI2-AS3 whose expression was downregulated in BCa tissues. We showed that MAGI2-AS3 downregulation in BCa patients indicated a poor prognosis. Functionally, we showed that MAGI2-AS3 overexpression inhibits proliferation, migration and invasion of BCa cells. Moreover, ectopic expression of MAGI2-AS3 suppresses BCa growth in vivo. Bioinformatics analysis revealed that MAGI2-AS3 could serve as a competing endogenous RNA (ceRNA) for miR-15b-5p. In the meantime, miR-15b-5p directly targeted CCDC19, a tumor suppressor in BCa. Rescue assays demonstrated that knockdown of CCDC19 restored the proliferation, migration and invasion of BCa cells suppressed by MAGI2-AS3 overexpression. In conclusion, this study identified a novel mechanism that MAGI2-AS3/miR-15b-5p/CCDC19 signaling pathway regulates BCa progression. PMID- 30442370 TI - LncRNA LINC00319 accelerates ovarian cancer progression through miR-423-5p/NACC1 pathway. AB - Long noncoding RNA (lncRNA) LINC00319 has been reported to promote carcinogenesis of lung cancer and cutaneous squamous cell carcinoma. However, the role and mechanism of LINC00319 in ovarian cancer progression is unclear. In this study, LINC00319 expression was found to be upregulated in ovarian cancer tissues and cell lines. And our evidence showed that LINC00319 could be a potential prognostic biomarker for patients with ovarian cancer. Cell Counting Kit-8 (CCK 8), colony formation and transwell assays indicated that LINC00319 upregulation promoted proliferation, migration and invasion of ovarian cancer cells. Bioinformatics analysis and luciferase reporter assay revealed that LINC00319 worked as the sponge for miR-423-5p. Furthermore, miR-423-5p directly targeted NACC1. qRT-PCR and western blot results demonstrated that LINC00319 upregulates NACC1 expression through inhibiting miR-423-5p in ovarian cancer cells. Moreover, we observed an inverse expression correlation between miR-423-5p and LINC00319 or between miR-423-5p and NACC1 in ovarian cancer tissues. Finally, rescue assay showed that NACC1 restoration rescued the potentials of proliferation, migration and invasion in LINC00319-depleted ovarian cancer cells. In conclusion, our findings demonstrated that LINC00319 promotes ovarian cancer progression through upregulating NACC1 expression by restraining miR-423-5p. PMID- 30442371 TI - Exosome swarms eliminate airway pathogens and provide passive epithelial immunoprotection through nitric oxide. AB - BACKGROUND: Nasal mucosa-derived exosomes (NMDEs) harbor immunodefensive proteins and are capable of rapid interepithelial protein transfer. OBJECTIVES: We sought to determine whether mucosal exposure to inhaled pathogens stimulates a defensive swarm of microbiocidal exosomes, which also donate their antimicrobial cargo to adjacent epithelial cells. METHODS: We performed an institutional review board approved study of healthy NMDE secretion after Toll-like receptor (TLR) 4 stimulation by LPS (12.5 MUg/mL) in the presence of TLR4 inhibitors. Interepithelial transfer of exosomal nitric oxide (NO) synthase and nitric oxide was measured by using ELISAs and NO activity assays. Exosomal antimicrobial assays were performed with Pseudomonas aeruginosa. Proteomic analyses were performed by using SOMAscan. RESULTS: In vivo and in vitro LPS exposure induced a 2-fold increase in NMDE secretion along with a 2-fold increase in exosomal inducible nitric oxide synthase expression and function through TLR4 and inhibitor of nuclear factor kappaB kinase activation. LPS stimulation increased exosomal microbiocidal activity against P aeruginosa by almost 2 orders of magnitude. LPS-stimulated exosomes induced a 4-fold increase in NO production within autologous epithelial cells with protein transfer within 5 minutes of contact. Pathway analysis of the NMDE proteome revealed 44 additional proteins associated with NO signaling and innate immune function. CONCLUSIONS: We provide direct in vivo evidence for a novel exosome-mediated innate immunosurveillance and defense mechanism of the human upper airway. These findings have implications for lower airway innate immunity, delivery of airway therapeutics, and host microbiome regulation. PMID- 30442372 TI - Impact of rib fixation on quality of life after major trauma with multiple rib fractures. AB - INTRODUCTION: Multiple rib fractures have been shown to reduce quality of life both in the short and long term. Treatment of rib fractures with operative fixation reduces ventilator requirements, intensive care unit stay, and pulmonary complications in flail chest patients but has not been shown to improve quality of life in comparative studies to date. We therefore wanted to analyse a large cohort of multiple fractured rib trauma patients to see if rib fixation improved their quality of life. METHODS: Retrospective review (January 2012 - April 2015) of prospectively collected data on 1482 consecutive major trauma patients admitted to The Alfred Hospital with rib fractures. The main outcome measures were Quality of Life over 24 months post injury assessed using the Glasgow Outcome Scale Extended (GOSErate) and Short Form (SF12) health assessment forms and a pain questionnaire. RESULTS: 67 (4.5%) patients underwent rib fixation and were older, with a higher incidence of flail chest injury, and higher AIS and ISS scores than the remainder of the cohort. Rib fixation provided no benefit in pain, SF-12 or GOSErate scores over 24 months post injury. CONCLUSIONS: This study has not been able to demonstrate any quality of life benefit of rib fixation over 24 months post injury in patients with major trauma. PMID- 30442373 TI - Geriatric distal femoral fractures: A retrospective study of 30 day mortality. AB - INTRODUCTION: Distal femoral fractures have many of the same challenges as hip fractures, but there has been limited research into outcomes following these. The aim of this study was to assess 30 day mortality following distal femoral fractures in comparison to hip fractures presenting to a single institution Secondary outcomes included risk factors for mortality, post-operative complications and union. METHODS: A retrospective case series of all distal femoral fragility fractures in patients over 65, and hip fractures over a 5 year period at a single institution. RESULTS: 88 distal femoral fractures and 2837 hip fractures fulfilled the inclusion criteria. In the distal femoral fractures there were 80 females and 8 males with a mean age of 82.4 (range 65-103). The mean age of the hip fractures was 83.7 (range 65-106) and there were 2066 females and 771 males. The overall 30 day mortality for hip fractures was 7.7% and was 9.1% for distal femoral fractures. The risk ratio was 1.1777(95% CI 0.6009-2.3080) (p = 0.6338). There was no significant difference in 30 day mortality between the two fracture types. Of the 88 distal femoral fractures 75 (85.2%) underwent open reduction internal fixation, 5 (5.7%) intramedullary nail and 8 (9.1%) conservative treatment. 11.4% suffered a medical complication. 9.1% patients required at least 1 further surgical procedure. The union rate was 94.3%. The 1 year mortality was 34.1%. CONCLUSIONS: There is no significant difference in 30 day mortality between distal femoral and hip fractures. Distal femoral fractures occur in a complex group of patients that is similar to hip fractures. They have high mortality and complication rates. PMID- 30442374 TI - Carbohydrate antigen 125 in heart failure. New era in the monitoring and control of treatment. AB - In recent years, we have seen a great interest in the search for new biomarkers in heart failure (HF), fundamentally in the field of diagnosis, prognosis, monitoring and as a therapeutic guide. However, most of them do not meet the required criteria for daily clinical practice. The carbohydrate antigen 125 (CA 125) is the mucin 16 glycoprotein (MUC16) antibody, and its use has been restricted to the therapeutic monitoring of ovarian cancer; however, its elevation is confirmed in other non-tumour processes such as HF. In this last scenario, CA 125 is synthesised by serous epithelial cells in response to congestion and/or inflammatory stimuli. In recent years, increasing evidence has emerged suggesting that plasma levels of this glycoprotein could be useful as a biomarker in HF. CA 125 levels correlate with clinical, haemodynamic and echocardiographic parameters related to the severity of the disease, as well as being independently associated with mortality or readmission due to HF. From the clinical perspective, CA 125 provides information on the degree of extravascular congestion present in HF. Recent evidence consistently shows that its kinetics after admission due to decompensation offer an excellent predictive capacity for adverse events and to guide treatment, mainly diuretic. These qualities make it an ideal candidate for use in evolutionary monitoring and to guide depletive treatment in HF. PMID- 30442375 TI - Symptom severity and quality of life in patients with atrial fibrillation: Psychological function outweighs clinical predictors. AB - BACKGROUND: The key drivers of symptom severity and health-related quality of life (hr-QOL) in patients with atrial fibrillation (AF) remain unclear. We aimed to determine the relative contribution to symptom severity and hr-QOL of clinical factors including left ventricular (LV) diastolic function and ventricular rate control during AF and of psychological functioning. METHODS: Seventy-eight consecutive patients with symptomatic AF and preserved LV systolic function underwent detailed evaluation of i) AF symptom severity and hr-QOL; ii) clinical factors including left ventricular (LV) diastolic function, AF burden, and ventricular rate during AF and iii) state and trait aspects of psychological functioning. RESULTS: Moderate-to-severe AF-related symptoms were reported by 64% of the study population whilst 36% reported no more than mild symptoms. Worse symptom severity was associated with a higher score on the Perceived Stress Scale (16.7 +/- 4.4 vs. 5.4 +/- 4.4, p < 0.0001) and higher prevalence of the Type D Personality (20/50 vs. 4/28, p = 0.012). In multivariable models, only a predisposition to subjectively appraise life situations as stressful (higher PSS score) and a personality with a higher degree of negative affectivity and social inhibition (higher TDPS score) were independent predictors of higher AF symptom severity and poorer hr-QOL. No clinical factors including AF burden, ventricular rates during AF or LV diastolic function were significant predictors of AF specific symptoms or hr-QOL. CONCLUSION: In a tertiary AF population with preserved LV systolic function, only psychological functioning consistently predicts both AF-related symptoms and hr-QOL. LV diastolic function, AF burden, and ventricular rate during AF are not independent predictors. PMID- 30442376 TI - Characterization of the dynamic changes in left ventricular morphology and function induced by exercise training and detraining. AB - BACKGROUND: Although exercise-induced cardiac hypertrophy has been intensively investigated, its development and regression dynamics have not been comprehensively described. In the current study, we aimed to characterize the effects of regular exercise training and detraining on left ventricular (LV) morphology and function. METHODS: Rats were divided into exercised (n = 12) and control (n = 12) groups. Exercised rats swam 200 min/day for 12 weeks. After completion of the training protocol, rats remained sedentary for 8 weeks (detraining period). Echocardiographic follow-up was performed regularly to obtain LV long- and short-axis recordings for speckle-tracking echocardiography analysis. Global longitudinal and circumferential strain and systolic strain rate were measured. LV pressure-volume analysis was performed using additional groups of rats to obtain haemodynamic data. RESULTS: Echocardiographic examinations showed the development of LV hypertrophy in the exercised group. These differences disappeared during the detraining period. Strain and strain rate values were all increased after the training period, whereas supernormal values rapidly reversed to the control level after training cessation. Load-independent haemodynamic indices, e.g., preload recruitable stroke work, confirmed the exercise-induced systolic improvement and complete regression after detraining. CONCLUSIONS AND TRANSLATIONAL ASPECT: Our results provide the first comprehensive data to describe the development and regression dynamics of morphological and functional aspects of physiological hypertrophy in detail. Speckle-tracking echocardiography has been proven to be feasible to follow-up changes induced by exercise training and detraining and might provide an early possibility to differentiate between physiological and pathological conditions. PMID- 30442377 TI - Accuracy of surgical guides from 2 different desktop 3D printers for computed tomography-guided surgery. AB - STATEMENT OF PROBLEM: Different factors influence the degree of deviation in dental implant position after computed tomography-guided surgery. The surgical guide-manufacturing process with desktop 3D printers is such a factor, but its accuracy has not been fully evaluated. PURPOSE: The purpose of this in vitro study was to evaluate the deviation in final dental implant position after the use of surgical guides fabricated from 2 different desktop 3D printers using a digital workflow. MATERIAL AND METHODS: Twenty 3D-printed resin models were prepared with missing maxillary premolar. After preoperative planning, 10 surgical guides were produced with a stereolithography printer and 10 with a digital light-processing (DLP) printer. A guided surgery was performed; 20 dental implants (3.8*12 mm) were installed, and a digital scan of the dental implants was made. Deviations between the planned and final position of the dental implants were evaluated for both the groups. RESULTS: A statistically significant difference between stereolithography and DLP were found for deviation at entry point (P=.023) and the vertical implant position (P=.009). Overall lower deviations were found for the guides from the DLP printer, with the exception of deviation in horizontal implant position. CONCLUSIONS: The tested desktop 3D printers were able to produce surgical guides with similar deviations with regard to the final dental implant position, but the DLP printer proved more accurate concerning deviations at entry point and vertical implant position. PMID- 30442378 TI - Corrigendum to: "Nuclear EGFR as a molecular target in cancer" [Radiother Oncol 108 (2013) 370-77]. PMID- 30442379 TI - Systematic Review of the Literature: Best Practices. AB - Reviews of published scientific literature are a valuable resource that can underline best practices in medicine and clarify clinical controversies. Among the various types of reviews, the systematic review of the literature is ranked as the most rigorous since it is a high-level summary of existing evidence focused on answering a precise question. Systematic reviews employ a pre-defined protocol to identify relevant and trustworthy literature. Such reviews can accomplish several critical goals that are not easily achievable with typical empirical studies by allowing identification and discussion of best evidence, contradictory findings, and gaps in the literature. The Association of University Radiologists Radiology Research Alliance Systematic Review Task Force convened to explore the methodology and practical considerations involved in performing a systematic review. This article provides a detailed and practical guide for performing a systematic review and discusses its applications in radiology. PMID- 30442380 TI - E-cigarette burn injuries: Comprehensive review and management guidelines proposal. AB - INTRODUCTION: Electronic cigarettes (EC) have been reported to be associated with burns secondary to explosions of the device or battery, or contact from overheating, resulting in flame, contact or chemical burns. In addition to this, there have also been reported cases of soft tissue and bony trauma with or without associated burns. Using collective evidence, this review aims to summarise all reported burns associated with ECs, and its implications on immediate management with a particular focus on surgical treatment. METHODS: A search was conducted on PubMed, EMBASE and Medline for all case reports, case series and letters to editors published since 2014, using terms "electronic cigarette", "e-cigarette", "vaping" and "burn". The search was repeated by the co author to avoid bias and a review of the bibliographies of each paper was conducted to ensure all relevant cases were included. The mechanisms, type and severity of burn injury, and management and treatment outcomes of the patients were recorded. Exclusion criteria included non-English articles, explosions with no associated burn and publications with insufficient information. RESULTS: 90 patients from 19 case series or case reports were included. With the exception of one study, gender was recorded with a male predominance (95.6%). Mean age is 30.1years (range 18-59). The most common type of burn was flame. However, there were reports of chemical burns associated with ECs. The mean total body surface area (TBSA) affected was 4.9% (range 1-27.25%) with the majority of burns being mixed partial and full thickness. 22 patients underwent excision and autologous skin grafting within range of three to 21days. One patient had a full thickness contact burn excised and closed, one patient received a xenograft following debridement and one had biosynthetic skin dressing. 42 patients were managed conservatively with dressings or ointments. DISCUSSION: In this review over a three-year period (2015-2017), 90 cases of EC related burn injuries were reported, however, this is likely an underestimation of the problem. The suggested mechanism for EC related injuries is battery malfunction. ECs are powered by Lithium ion batteries which are susceptible to "thermal runaway" reactions, which result in device overheating with potential for subsequent explosion. We explain hypothesized triggers for these reactions and mechanisms of other injuries associated with ECs such as chemical burns and blast injury. CONCLUSION: EC-associated burn injury results in combined thermal and chemical burns, which should be managed in tandem. Explosion injuries sustained whilst using the device may result in both facial trauma or inhalation injury and therefore should be reviewed with a high index of clinical suspicion. It is noted that there is no agreed standard for management for such burns by specialist bodies in the UK. We suggested a treatment algorithm to provide guidance for the burn injuries associated with ECs. PMID- 30442381 TI - Predictors of withdrawal of life support after burn injury. AB - INTRODUCTION: Discussions regarding withdrawal of life support after burn injury are challenging and complex. Often, providers may facilitate this discussion when the extent of injury makes survival highly unlikely or when the patient's condition deteriorates during resuscitation. Few papers have evaluated withdrawal of life support in burn patients. We therefore sought to determine the predictor of withdrawal of life support (WLS) in a regional burn center. METHODS: We conducted a retrospective analysis of all burn patients from 2002 to 2012. Patient characteristics included age, gender, burn mechanism, percentage total body surface area (%TBSA) burned, presence of inhalation injury, hospital length of stay, and pre-existing comorbidities. Patients <17years of age and patients with unknown disposition were excluded. Patients were categorized into three cohorts: Alive till discharge (Alive), death by withdrawal of life support (WLS), or death despite ongoing life support (DLS). DLS patients were then excluded from the study population. Multivariate logistic regression was used to estimate predictors of WLS. RESULTS: 8,371 patients were included for analysis: 8134 Alive, 237 WLS. Females had an increased odd of WLS compared to males (OR 2.03, 95% CI 1.18-3.48; p=0.010). Based on higher CCI, patients with pre-existing comorbidities had an increased odd of WLS (OR 1.28, 95% CI 1.08-1.52; p=0.005). There was a significantly increased odds for WLS (OR 1.09, 95% CI 1.06-1.12; p<0.001) with increasing age. Similarly, there was an increased odd for WLS (OR 1.08, 95% CI 1.07-1.51; p<0.001) with increasing %TBSA. An increased odd of WLS (OR 2.47, 95% CI 1.05-5.78; p=0.038) was also found in patients with inhalation injury. CONCLUSION: The decision to withdraw life support is a complex and difficult decision. Our current understanding of predictors of withdrawal of life support suggests that they mirror those factors which increase a patient's risk of mortality. Further research is needed to fully explore end-of-life decision making in regards to burn patients. The role of patient's sex, particularly women, in WLS decision making needs to be further explored. PMID- 30442382 TI - Immunolocalization of VEGF/VEGFR system in human fetal vomeronasal organ during early development. AB - The vomeronasal system (VNS) is an accessory olfactory structure present in most mammals adhibited to the detection of specific chemosignals implied in social and reproductive behavior. The VNS comprises the vomeronasal organ (VNO), vomeronasal nerve and accessory olfactory bulb. VNO is characterized by a neuroepithelium constituted by bipolar neurons and supporting and stem/progenitor cells. In humans, VNO is present during fetal life and is supposed to possess chemoreceptor activity and participate in gonadotropin-releasing hormone neuronal precursor migration toward the hypothalamus. Instead, the existence and functions of VNO in postnatal life is debated. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) have been demonstrated to play fundamental roles in various neurogenic events. However, there are no data regarding the localization and possible function of VEGF/VEGFRs in human fetal VNO. Therefore, this study was conceived to investigate the expression of VEGF/VEGFRs in human VNO in an early developmental period (9-12 weeks of gestation), when this organ appears well structured. Coronal sections of maxillofacial specimens were subjected to peroxidase-based immunohistochemistry for VEGF, VEGFR-1 and VEGFR-2. Double immunofluorescence for VEGF, VEGFR-1 or VEGFR-2 and the neuronal marker protein gene product 9.5 (PGP 9.5) was also performed. VEGF expression was evident in the entire VNO epithelium, with particularly strong reactivity in the middle layer. Strongly VEGF-immunostained cells with aspect similar to bipolar neurons and/or their presumable precursors were detected in the middle and basal layers. Cells detaching from the basal epithelial layer and detached cell groups in the surrounding lamina propria showed moderate/strong VEGF expression. The strongest VEGFR-1 and VEGFR-2 expression was detected in the apical epithelial layer. Cells with aspect similar to bipolar neurons and/or their presumable precursors located in the middle and basal layers and the detaching/detached cells displayed a VEGFR 1 and VEGFR-2 reactivity similar to that of VEGF. The basal epithelial layer exhibited stronger staining for VEGFRs than for VEGF. Cells with morphology and VEGF/VEGFR expression similar to those of the detaching/detached cells were also detected in the middle and basal VNO epithelial layers. Double immunofluorescence using anti-PGP 9.5 antibodies demonstrated that most of the VEGF/VEGFR immunoreactive cells were neuronal cells. Collectively, our findings suggest that during early fetal development the VEGF/VEGFR system might be involved in the presumptive VNO chemoreceptor activity and neuronal precursor migration. PMID- 30442383 TI - Corrigendum to "Effect of levetiracetam on extracellular amino acid levels in the dorsal hippocampus of rats with temporal lobe epilepsy" [Epilepsy Res. 140 (2018) 111-119]. PMID- 30442384 TI - Evaluating the urban-rural paradox: The complicated relationship between distance and the receipt of guideline-concordant care among cervical cancer patients. AB - OBJECTIVE: Urban-rural health disparities are often attributed to the longer distances rural patients travel to receive care. However, a recent study suggests that distance to care may affect urban and rural cancer patients differentially. We examined whether this urban-rural paradox exists among patients with cervical cancer. METHODS: We identified individuals diagnosed with cervical cancer from 2004 to 2013 using a statewide cancer registry linked to multi-payer, insurance claims. Our primary outcome was receipt of guideline-concordant care: surgery for stages IA1-IB1; external beam radiation therapy (EBRT), concomitant chemotherapy, and brachytherapy for stages IB2-IVA. We estimated risk ratios (RR) using modified Poisson regressions, stratified by urban/rural location, to examine the association between distance to nearest facility and receipt of treatment. RESULTS: 62% of 999 cervical cancer patients received guideline-concordant care. The association between distance and receipt of care differed by type of treatment. In urban areas, cancer patients who lived >=15 miles from the nearest surgical facility were less likely to receive primary surgical management compared to those <5 miles from the nearest surgical facility (RR: 0.77, 95% CI: 0.60-0.98). In rural areas, patients living >=15 miles from the nearest brachytherapy facility were more likely to receive treatment compared to those <5 miles from the nearest brachytherapy facility (RR: 1.71, 95% CI: 1.14-2.58). Distance was not associated with the receipt of chemotherapy or EBRT. CONCLUSIONS: Among cervical cancer patients, there is evidence supporting the urban-rural paradox, i.e., geographic distance to cancer care facilities is not consistently associated with treatment receipt in expected or consistent ways. Healthcare systems must consider the diverse and differential barriers encountered by urban and rural residents to improve access to high quality cancer care. PMID- 30442385 TI - NCK1 promotes the angiogenesis of cervical squamous carcinoma via Rac1/PAK1/MMP2 signal pathway. AB - OBJECTIVE: The study was to explore the roles of Nck1 in the angiogenesis of cervical squamous cell carcinoma (CSCC). METHODS: mRNA and protein levels were evaluated with real-time quantitative PCR and immunohistochemisty/western blotting respectively. The cancer microvessel density (MVD) was assayed with CD34 endothelial labeling. Nck1 gene knock-in (SiHa-Nck1+) and knock-down (SiHa-Nck1-) were achieved by gene transfection and siRNA respectively. Protein level from cellular supernatant was measured with ELISA. Proliferation, migration and tube formation of the Human Umbilical Vein Endothelial cells (HUVECs) were evaluated by CCK-8 cell viability assay, transwell chamber assay and in vitro Matrigel tubulation assay respectively. RESULTS: Nck1 level gradually increased from normal cervical epithelia to high-grade CIN, overexpressed in CSCC and was associated with cancer MVD. The ability of proliferation, migration and tube formation of HUVECs was enhanced in SiHa-Nck1+-treated while decreased in SiHa NcK1--treated cells compared to SiHa-control-treated cells. Mechanistically, RAC1 GTP, p-PAK1 and MMP2 were increased in SiHa-NCK1+ cells and pretreatment with the Rac1 inhibitor (NSC23766) significantly decreased their levels. Furthermore, inhibition of PAK1 reduced MMP2 level in SiHa-Nck1+ cells whereas the level of Rac1-GTP was unaltered. Also, inhibition of Rac1 or PAK1 impaired angiogenesis inducing capacity of cancer cells. CONCLUSIONS: Nck1 promotes the angiogenesis inducing capacity of CSCC via the Rac1/PAK1/MMP2 signal pathway. PMID- 30442386 TI - Pulse Wave Imaging in Carotid Artery Stenosis Human Patients in Vivo. AB - Carotid stenosis involves narrowing of the lumen in the carotid artery potentially leading to a stroke, which is the third leading cause of death in the United States. Several recent investigations have found that plaque structure and composition may represent a more direct biomarker of plaque rupture risk compared with the degree of stenosis. In this study, pulse wave imaging was applied in 111 (n = 11, N = 13 plaques) patients diagnosed with moderate (>50%) to severe (>80%) carotid artery stenosis to investigate the feasibility of characterizing plaque properties based on the pulse wave-induced arterial wall dynamics captured by pulse wave imaging. Five (n = 5 patients, N = 20 measurements) healthy volunteers were also imaged as a control group. Both conventional and high-frame-rate plane wave radiofrequency imaging sequences were used to generate piecewise maps of the pulse wave velocity (PWV) at a single depth along stenotic carotid segments, as well as intra-plaque PWV mapping at multiple depths. Intra-plaque cumulative displacement and strain maps were also calculated for each plaque region. The Bramwell-Hill equation was used to estimate the compliance of the plaque regions based on the PWV and diameter. Qualitatively, wave convergence, elevated PWV and decreased cumulative displacement around and/or within regions of atherosclerotic plaque were observed and may serve as biomarkers for plaque characterization. Intra-plaque mapping revealed the potential to capture wave reflections between calcified inclusions and differentiate stable (i.e., calcified) from vulnerable (i.e., lipid) plaque components based on the intra-plaque PWV and cumulative strain. Quantitatively, one-way analysis of variance indicated that the pulse wave-induced cumulative strain was significantly lower (p < 0.01) in the moderately and severely calcified plaques compared with the normal controls. As expected, compliance was also significantly lower in the severely calcified plaques regions compared with the normal controls (p < 0.01). The results from this pilot study indicated the potential of pulse wave imaging coupled with strain imaging to differentiate plaques of varying stiffness, location and composition. Such findings may serve as valuable information to compensate for the limitations of currently used methods for the assessment of stroke risk. PMID- 30442387 TI - Carnitine and extra trace elements change stability of paediatric parenteral nutrition admixtures? AB - INTRODUCTION: High concentrations of trace elements (TE), in particular zinc and selenium, along with carnitine, are often added to parenteral admixtures in paediatric patients on long-term Parenteral Nutrition (PN). We aim to evaluate whether lipid droplet diameters of these admixtures maintain the recommended range of 0.4-1.0 MUm. MATERIALS AND METHODS: Stability studies were carried out on six parenteral admixtures with carnitine, trace elements and electrolytes added in different amounts. Each admixture was formulated with five different lipid emulsions with or without fish oil. Analyses were performed at time 0 (t = 0) and 24, 48, 72, 96 (t = 96) hours after compounding. Droplet diameters were determined by Light Scattering-Reverse Fourier Optics Technique. Samples, stored at 4 degrees C, were triple tested for a total of 450 analyses. Regression analyses were performed using panel-data techniques. RESULTS: During the 4 days, lipid droplet diameters were in the expected range of 0.4-1.0 MUm regardless of trace element and carnitine amounts in all admixtures apart from those containing fish-oil based emulsions and calcium concentrations equal to 4.5 mmol/L. In these latter admixtures, 12% of droplet diameters were larger than 1.0 MUm and 2% exceeded 5.0 MUm immediately after compounding. CONCLUSION: Carnitine and high concentrations of trace elements do not affect PN admixtures stability and can be safely infused in long-term home-PN paediatric patients and prematures. Only high calcium concentrations in compresence with fish oil based lipid emulsions seem to change PN stability. PMID- 30442388 TI - The unexpected identification of the cannabimimetic, 5F-ADB, and dextromethorphan in commercially available cannabidiol e-liquids. AB - Electronic cigarettes (e-cigarettes) were developed as an alternative method for nicotine delivery and had a significant surge in popularity. E-liquids are formulations used in e-cigarettes, and consist of a ratio of propylene glycol (PG) and vegetable glycerin (VG), a pharmaceutical and/or herbal remedy and, usually, a flavoring agent. Presented is the evaluation of nine cannabidiol (CBD) e-liquids from a single manufacturer for cannabinoids and other psychoactive compounds by Direct Analysis in Real Time Mass Spectrometry (DART-MS) and Gas Chromatography Mass Spectrometry (GC/MS). The analysis of these products resulted in the detection of CBD in all nine produces and the unexpected detections of 5 fluoro MDMB-PINACA (5F-ADB) in four of the products and dextromethorphan (DXM) in one of the products. The analysis of these products illustrates the potential quality control issues that can occur in an unregulated industry. CBD products are believed by many users to offer heath benefits, but the detection of a dangerous cannabimimetic, 5F-ADB, and DXM in these products illustrates the need for oversight. PMID- 30442389 TI - Ion fragmentations via photoelectron activated radical relays and competed hole oxidization on semiconductor nanoparticles for mass spectrometry. AB - Structural identification is challenging in mass spectrometric imaging because of inadequate sample quantities and limited sampling time in each pixel for tandem mass spectrometry (MS/MS) experiments, which are usually used for the generation of fragment ions. We report herein the observation of a cascade of highly specific chemical bond cleavages via a low-energy photoelectron activated radical relays and a competed hole oxidization on surfaces of (Bi2O3)0.07(CoO)0.03(ZnO)0.9 semiconductor nanoparticles irradiated with the 3rd harmonic (355 nm) of the Nd3+: YAG laser. Distinguished from high energy electron impact (EI), this approach generates gaseous radical anions through the exothermic capture of low-energy tunneling electrons that are not able to cause extensive vibrational excitations. It was found not only original radical center but also secondary or even tertiary radical centers cause specific bond cleavages exclusively on alpha positions. The original radical center directly activates the cleavages of alpha-positioned chemical bonds that cause the formation of secondary radical centers. Ion fragmentations proceed along the newly formed radical centers that further activate the cleavages of their alpha-positioned chemical bonds. Using 8 compounds, we have demonstrated various radical reactions involved in desulfonation, cyclization, and ring contraction reactions as well as competed hole oxidization-generated hydroxyl radical substitution reactions. The interpretable fragment ions provide unambiguous experimental evidences for structural elucidation of drug residues and metabolites in mass spectrometric imaging of tissue slices without tandem mass spectrometry (MS/MS). PMID- 30442390 TI - Electrochemical impedance-based DNA sensor using pyrrolidinyl peptide nucleic acids for tuberculosis detection. AB - A label-free electrochemical DNA sensor based on pyrrolidinyl peptide nucleic acid (acpcPNA)-immobilized on a paper-based analytical device (PAD) was developed. Unlike previous PNA-based electrochemical PAD (ePAD) sensors where the capture element was placed directly on the electrode, acpcPNA was covalently immobilized onto partially oxidized cellulose paper allowing regeneration by simple PAD replacement. As an example application, a sensor probe was designed for Mycobacterium tuberculosis (MTB) detection. The ePAD DNA sensor was used to determine a synthetic 15-base oligonucleotide of MTB by measuring the fractional change in the charge transfer resistance (Rct) obtained from electrochemical impedance spectroscopy (EIS). The Rct of [Fe(CN)6]3-/4- before and after hybridization with the target DNA could be clearly distinguished. Cyclic voltammetry (CV) was used to verify the EIS results, and showed an increase in peak potential splitting in a similar stepwise manner for each immobilization step. Under optimal conditions, a linear calibration curve in the range of 2-200 nM and the limit of detection 1.24 nM were measured. The acpcPNA probe exhibited very high selectivity for complementary oligonucleotides over single-base mismatch, two-base-mismatch and non-complementary DNA targets due to the conformationally constrained structure of the acpcPNA. Moreover, the ePAD DNA sensor platform was successfully applied to detect PCR-amplified MTB DNA extracted from clinical samples. The proposed paper-based electrochemical DNA sensor has potential to be an alternative device for low-cost, simple, label free, sensitive and selective DNA sensor. PMID- 30442391 TI - Multiplex quantification of metals in airborne particulate matter via smartphone and paper-based microfluidics. AB - On-site spatial variation study of airborne trace metals has been known to be the key to providing a comprehensive evaluation of air pollution information at any targeted location. However, the existing portable approaches either do not allow sample analysis in the longitudinal direction or is not yet practically applicable due to due to the lack of a portable detection method. In this paper, by integrating paper based colorimetric detection via cellphone and unmanned aerial vehicle (UAV) in-air sampling, we present an approach for on-site multiaxial quantification of airborne trace metals in an arrayed format. Using a self-built sampler mounting on a UAV, our approach enables automatic, multiaxial air PM sampling. In addition, by relying only on a cellphone and a custom-made field reaction kit, samples collected in-air can be readily processed, detected in an arrayed format and interpreted on-site within 30 min. Finally, an ultrafast batch-to-batch paper microfluidic chip fabrication protocol enables 48 chips to be fabricated under 30 s at a cost of 1.92 $, making the approach well-suited for disposable on-site use. Our system was first calibrated for 6 metals commonly found in airborne PM (i.e. Co, Cu, Fe, Mn, Cr and Ni), and the corresponding metals detection limits were found to be 8.16, 45.84, 1.86 * 102, 10.08, 1.52 * 102 and 80.40 ng. The validity of our approach was then demonstrated by characterizing 6 metals commonly found in air PM using a certified ash sample, and the experimentally determined metal weight percentage showed a good agreement with the manufacture certified value. Finally, the approach was used for on-site airborne trace metals spatial variation study at 4 difference locations in Fuzhou City (China), thus demonstrating the significance of our approach in supplementing air pollution information gathering and progressing rapid, on-site air toxicity assessment research. PMID- 30442392 TI - Sensor array for qualitative and quantitative analysis of metal ions and metal oxyanion based on colorimetric and chemometric methods. AB - Gold nanoparticle (AuNP)-based colorimetric sensor is sensitive for the detection of metal ions and metal oxyanion in aqueous solution. However, this method is usually not suitable for multi-objective analysis in complex mixture systems because it is suffering from interference of co-existents. In the present paper, we proposed a sensitive, flexible, low-cost, and multi-units sensor method for the qualitative and quantitative analysis of metal ions and metal oxyanion based on the global ultraviolet and visible (UV-Vis) spectra of amino acid-gold nanoparticles (amino acid-AuNPs) sensors in the range of 230-800 nm. Different amino acids (L-Histidine, L-Lysine, L-Methionine, D-Penicillium) which can prevent the aggregation of the AuNPs in NaCl solution, were investigated to build sensor arrays responding to different ions induced AuNPs aggregation. The UV-Vis spectra that Cd2+, Ba2+, Mn2+, Ni2+, Cu2+, Fe3+, Cr3+, Cr2O72-, Sn4+, Pb2+ induce amino acid-AuNPs displayed different characteristics and the ions were classified correctly by using partial least squares-discriminant analysis (PLS-DA). Taking the advantage of the multivariate analysis and sensor arrays, we simultaneously quantified the ions in binary and ternary mixture systems (Cr3+/Cr2O72-, Fe3+/Cd2+, Fe3+/Cr3+/Cr2O72-). Data fusion methods further improved the prediction accuracy of the chemometric models built on multi-amino acids-AuNPs sensors. The proposed method has a potential for analyzing metal ions and metal oxyanion in much more complex mixture systems. PMID- 30442393 TI - Recent advances in LC-MS/MS methods to determine endocannabinoids in biological samples: Application in neurodegenerative diseases. AB - Endocannabinoids (ECs) are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors [cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)]. Many ECs have been characterized; anandamide (AEA) and 2 arachidonoyl glycerol (2-AG) are still considered the primary ECs signaling mediators. Dysregulation of ECs has been implicated in a wide range of pathologies, including neurodegenerative diseases. Understanding how ECs participate in neurological diseases is important to describe the pathology and to establish new treatments. Considering the physicochemical properties of ECs, liquid chromatography coupled to tandem mass spectrometry has become the reference method to determine these endogenous substances, in trace levels, in different biological samples. This review describes the recent advances in LC MS/MS methods designed to determine ECs in complex biological matrixes. The advantages, limitations, selectivity, matrix effect, and sensitivity associated with each approach are emphasized. This article comprises three sections: (I) sample preparation techniques (conventional, microextraction, and online systems), (II) chromatographic methods (especially LC-MS/MS), and (III) relationship between ECs levels and neurodegenerative diseases. PMID- 30442394 TI - Quantitative Raman assays for on-site analysis of stockpiled drugs. AB - We present a rapid Raman assay for on-site analysis of stockpiled drugs in aqueous solution. This approach was tested on Tamiflu (oseltamivir phosphate). Tamiflu is a drug approved by the FDA for treatment of influenza and is the most common antiviral included in stockpiles for use in the event of a national emergency. Rapid assays were performed on three concentrations (30, 45, and 75 mg) of oseltamivir using three different portable & handheld Raman instruments. PLS regression models were developed to establish a calibration curve and applied to the Tamiflu samples. Raman assay values were compared against the standard HPLC assay to demonstrate the viability of this approach, yielding an average assay value within 0.3% of that obtained from the HPLC analysis for the 35 different capsules analyzed. The Raman method demonstrates the potential for rapid screening of stockpiled pharmaceuticals on-site using portable Raman instrumentation and readily available consumables for sample preparation. In addition to routine screening to ensure product quality past the expiration date, this approach could also be used to assist in rapid deployment of such medications in the case of a national emergency. PMID- 30442395 TI - In situ laser-induced codeposition of copper and different metals for fabrication of microcomposite sensor-active materials. AB - We report one-step in situ laser-induced synthesis of the conductive copper microstructures doped with iron, zinc, nickel, and cobalt with highly developed surface area. It was observed that the presence of chlorides of the aforementioned metals in the solutions used in our experiments increases the deposition rate and the amount of copper in the resulting deposits; it also leads to the deposit miniaturization. The laser deposition from solutions containing cobalt (II) chloride of concentration more than 0.003 M results in fabrication of copper microelectrode with better electrochemical properties than those deposited from solutions containing chlorides of other metals of the same concentration. Moreover, copper microelectrode doped with cobalt has demonstrated good reproducibility and long-run stability as well as sensitivity and selectivity towards determination of hydrogen peroxide (limit of detection-0.2 MUM) and d glucose (limit of detection-2.2 MUM). Thus, in this article we have shown the opportunity to manufacture two-phase microcomposite materials with good electrical conductivity and electrochemical characteristics using in situ laser induced metal deposition technique. These materials might be quite useful in development of new perspective sensors for non-enzymatic detection of such important analytes as hydrogen peroxide and glucose. PMID- 30442396 TI - Exploring a phage-based real-time PCR assay for diagnosing Acinetobacter baumannii bloodstream infections with high sensitivity. AB - In the present study, we developed a phage-based real-time quantitative PCR (qPCR) methodology for sensitive diagnosis of bloodstream infection (BSI) caused by Acinetobacter baumannii (A. baumannii). An isolated A. baumannii phage p53 was used for Taqman qPCR through detecting phage replication in live A. baumannii cells in serum samples. At the phage concentration of 103 PFU/mL, the sensitive detection of A. baumannii (down to 10 CFU in 100 MUL serum) has been obtained within 4 h in spiked serum samples without bacteria isolation and DNA extraction. Subsequent testing of 22 simulated serum samples spiked by different strains has shown that the results from the phage-based Taqman qPCR method have 100% agreement with the spiked concentrations of the bacteria. The assay built in this study, gathering all the advantages for detections of high rapidity, high sensitivity, good specificity, being able to detect only live bacteria not dead bacteria and no DNA extraction or purifications, can be developed to detecting other bacterial pathogens in serum or other complicated samples through switching to other types of phages and realize the rapid and sensitive detection of bacteria in BSI, which would potentially be applied for fast diagnosis in sepsis clinically. PMID- 30442397 TI - Sensitive and selective colorimetric detection of alkaline phosphatase activity based on phosphate anion-quenched oxidase-mimicking activity of Ce(IV) ions. AB - As alkaline phosphatase (ALP) plays crucial roles in disease warning and dephosphorylation-related cellular regulation, it is widely recognized as an important biomarker for clinical diagnosis. In this work, we proposed a facile colorimetric assay based on phosphate anion-quenched oxidase-mimicking activity of Ce(IV) ions for sensitive and selective detection of ALP activity. Free Ce(IV) ions exhibited a strong oxidase-like capability (providing a 40-fold catalytic turnover number compared with CeO2) to catalyze the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) into its blue product TMBox mediated by dissolved O2 at neutral pH, thus triggering a remarkable color reaction visually. When PO43- was added, its strong affinity to Ce(IV) ions rapidly precipitated the free Ce(IV) ions, resulting in the quenching of their enzymatic ability. Given that ALP catalyzed the hydrolysis of adenosine triphosphate to produce PO43-, determination of ALP activity could be achieved using the colorimetric assay with no need of complicated instrumentation and protocol. As demonstrated, our assay offered a highly sensitive readout for ALP activity in two linear scopes of 0-50 U L-1 and 50-250 U L-1, providing a detection limit down to 2.3 U L-1. Besides, it could provide specific response toward ALP against other enzymes and biological species. Furthermore, the developed assay was successfully applied to evaluate ALP activity in human plasma accurately and reliably, indicating its great promise as a powerful and convenient tool for monitoring of ALP activity in clinical practice. PMID- 30442398 TI - Functional and biocompatible polymeric ionic liquid (PIL) - Decorated immunomagnetic nanospheres for the efficient capture of rare number CTCs. AB - This work demonstrated an effective strategy for the capture, identification and determination of multiple types of circulating tumor cells (CTCs) on functional and biocompatible immunomagnetic nanosphere interfaces (IMNs). The IMNs were achieved by functionalizing superparamagnetic iron oxide nanospheres (Fe3O4) with polymerized ionic liquid (PIL), and then coating with epithelial-cell-adhesion molecule antibody (anti-EpCAM). The IMNs exhibited outstanding cell capture efficiency (above 95%) and specificity when employed to separate multiple EpCAM positive tumor cells, due to the abundant carboxyl groups in the structure of PIL, which enhanced the coupling efficiency of MNs with anti-EpCAM by chemical bonding between carboxyls and amines, thereby enabling more target cells adhered onto IMNs. Under the optimized capture conditions, IMNs were shown an excellent cell capture performance in the range of 5-400 cells/mL in three different cases (e.g., PBS, MCF-7 and THP-1 mixed cell suspension, lysed blood). More significantly, our results indicated that with modification of PIL, in addition to the capture efficiency, the cell viability rate of CTCs was also greatly improved (98%) owing to the nontoxic and biocompatible properties of PIL, which realized the proliferation of the rare number CTCs for further molecular characterization. Finally, the IMNs were successfully applied to the isolation and detection of CTCs in cancer patient peripheral blood samples and as low as one CTC in the whole blood was captured and identified by the ICC method. PMID- 30442399 TI - Hydrophilic interaction liquid chromatography of aminoglycoside antibiotics with a diol-type stationary phase. AB - Owing to their pronounced polarity, hydrophilic interaction liquid chromatography (HILIC) can be considered as the elective choice for the LC analysis of aminoglycoside (AG) antibiotics. In the present work, a gradient program was optimized for the first time with a diol-type stationary phase and an evaporative light scattering detector (ELSD), thus allowing the almost complete separation of the nine analysed AGs: spectinomycin, dihydrostreptomycin, streptomycin A, gentamicin C1, amikacin, kanamycin A, paromomycin, apramycin and neomycin. In the optimized analysis conditions, analyte retention was found to be governed by a multimodal mechanism encompassing electrostatic, partitioning and hydrophilic interactions. However, the gradient mode of elution complicated a deep understanding of the influence of each contribution on the retention behaviour. The developed HILIC-ELSD method was applied for the analysis of commercial tablets containing neomycin co-formulated with the polypeptide antibiotic bacitracin. The method was fully validated according to the guidelines enshrined in the International Conference on Harmonization (ICH). The use of the diol-type stationary phase was well suited for implementing a successful 2D-HPLC system. Indeed, in order to cope with the absence of chemoselectivity for the couples amikacin/kanamycin and paromomycin/apramycin, a successful 2D-HPLC method was implemented with the "heart-cut" approach and the use of either heptafluorobutyric (for the former) or perfluorooctanoic acid (for the latter) as the ion-pair reagent in the second RP-LC dimension. PMID- 30442400 TI - Heterogeneity assessment of antibody-derived therapeutics at the intact and middle-up level by low-flow sheathless capillary electrophoresis-mass spectrometry. AB - Antibody-based pharmaceuticals often encompass a complex structural heterogeneity requiring enhanced analytical methods for reliable characterization of variants and degradation products. We have explored the capabilities of low-flow sheathless capillary electrophoresis-mass spectrometry (CE-MS) for the high resolution and sensitive profiling of antibody therapeutics. Near-zero electroosmotic flow was achieved by employing a novel neutral capillary coating that also prevents protein adsorption. CE-MS analysis of intact model proteins using an acidic background electrolyte demonstrated satisfactory performance, with overall migration-time RSDs below 2.2% from three different capillaries tested. For system evaluation, three nanobody preparations, including mono- and bivalent forms, and three monoclonal antibodies (mAbs) were analyzed. Intact nanobodies were resolved from their degradation products, which could be assigned to deamidated, cleaved, and truncated forms at the C-terminal tag. Excellent resolution of isomeric deamidated products was obtained. The mAbs were analyzed intact and after digestion by the endoproteinase IdeS (middle-up approach). CE-MS of intact mAbs provided resolution of clipped species (e.g. light chain and light chain-heavy chain fragments) from the native protein. Moreover, glycoforms containing sialic acids were resolved from their non-sialylated counterparts. For IdeS-digested, F (ab)2 and Fc/2 portions where efficiently resolved for the three mAbs. Whereas the migration time of the Fc/2 fragments was fairly similar, the migration time of the F (ab)2 part was strongly varied among the mAbs. For all mAbs, separation of Fc/2 charge variants - including sialylated glycoforms and other post-translational modifications, such as loss of C-terminal lysine or asparagine deamidation - was achieved. This allowed a detailed and reliable assessment of the Fc/2 heterogeneity (18-33 proteoforms) of the three analyzed mAbs. PMID- 30442401 TI - Over 1000-fold improvement in an online preconcentration of trace anionic compounds by capillary electrophoresis with ionic liquid micelle-based three-step stacking. AB - A sensitive, simple, and environmentally friendly online three-step stacking strategy combining field-enhanced sample injection, sweeping and micelle to solvent stacking has been developed to determine trace amounts of organic anionic analytes in complex biological samples. A green ionic liquid, 1-dodecyl-3 methylimidazolium hydrogen sulfate, was first introduced as a micellar solution and used for electroosmotic flow reversal in this stacking strategy. The mechanism of stacking has been discussed, and parameters affecting three-step stacking preconcentration efficiency have been optimized. The capillary coated with an ionic liquid was easy to prepare, regenerable and repeatable (RSD<2.16%) and yielded a high efficiency. Under optimal conditions, the sensitivity improvement increased up to 2424-fold when compared with the normal capillary zone electrophoresis mode. The peak shape and separation efficiency of the model basic organic acids showed a significant enhancement when compared to traditional capillary zone electrophoresis. The optimized method showed great potential for quantitative analysis of trace concentration analytes in complex matrices. PMID- 30442402 TI - Corrigendum to "Ultrasensitive detection of endotoxins using computationally designed nanoMIPs" [ACA 935 (2016) 239-248]. PMID- 30442403 TI - Corrigendum to "Comprehensive evaluation of untargeted metabolomics data processing software in feature detection, quantification and discriminating marker selection" [ACA 1029, (2018) 50-57]. PMID- 30442404 TI - Corrigendum to "Optimization and validation of a fast digestion method for the determination of major and trace elements in breast milk by ICP-MS" [ACA 1040 (2018) 49-62]. PMID- 30442405 TI - Recent advances in microfluidic technology for manipulation and analysis of biological cells (2007-2017). AB - The pivotal role of microfluidic technology in life science and biomedical research is now widely recognized. Indeed, microfluidics as a research tool is unparalleled in terms of its biocompatibility, robustness, efficient reagent consumption, and controlled fluidic, surface, and structure environments. The controlled environments are essential in assessing the complex behavior of cells in response to microenvironmental cues. The strengths of microfluidics also reside in its amenability to integration with other analytical platforms and its capacity for miniaturization, parallelization and automation of biochemical assays. Following previous review on the applications of microfluidic devices for cell-based assays in 2006, we have monitored the progress in the field and summarized the advances in microfluidic technology from 2007 to 2017, with a focus on microfluidics development for applications in cell manipulation, cell capture and detection, and cell treatment and analysis. Moreover, we highlighted novel commercial microfluidic products for biomedical and clinical purposes that were introduced in the review period. Thus, this review provides a comprehensive source for recent developments in microfluidics and presents a snapshot of its remarkable contribution towards basic biomedical research and clinical science. We recognize that although enormous amounts of evidence have reinforced the promise of microfluidic technology across diverse applications, much remains to be done to realize its full potential in mainstream biomedical science and clinical practice. PMID- 30442406 TI - KIMBLE: A versatile visual NMR metabolomics workbench in KNIME. AB - The problem of reproducibility of scientific research is a serious issue in biomedical sciences. In addition to experimental repeatability, limiting the (pre ) analytical variance is also essential. To address this problem in the field of metabolomics, we have designed KIMBLE, the KNIME-based Integrated MetaBoLomics Environment, a novel platform for the processing and analysis of NMR metabolomics data. It consists of an elaborate NMR metabolomics workflow in the KNIME workflow management system that handles both targeted and untargeted metabolomics. The workflow provides a self-documenting way of transforming raw time-domain NMR data into metabolic insights. Parameters for the quantification of a number of interesting metabolites in urine are included in the workflow, and several useful statistical analysis and visualization tools are incorporated as well. The workflow comes with an interesting sports-induced ketosis dataset so that new users can easily get acquainted with the platform. The user is free to adapt and extend the workflow to his or her personal needs. The KIMBLE workflow, the KNIME software and all the required libraries are installed in a VirtualBox virtual machine that allows for facile installation and use by non-experts. PMID- 30442407 TI - Flow rate independent gradient generator and application in microfluidic free flow electrophoresis. AB - Microfluidic gradient generators have been employed in several works in the literature. However, these are typically application specific and especially limited in the range of flow rates that result in the required concentration gradient outputs. Here, a flow rate independent gradient generator designed as a modified Christmas tree-like microfluidic channel network including micromixers at each channel branch is demonstrated. The device was characterized theoretically, modeled using finite element analysis and tested experimentally. Input flow rates up to 200 MUl/min, resulting in a maximum speed of about 333 mm/s, for the generation of linear and mirrored linear gradients were demonstrated. As an application example, the gradient generator was monolithically integrated with microfluidic free-flow electrophoresis for the separation/concentration of fluorophores using a novel E-field gradient free-flow electrophoresis mode. The separation of fluorophores, having different charge stages, showed concentration factors of up to 10 fold. In addition, an extended theoretical description of the realizable concentration gradients and the electric field gradient is presented as supplementary information. PMID- 30442408 TI - Fabrication of cost-effective and efficient paper-based device for viscosity measurement. AB - Use of paper-based devices for affordable diagnostics is gaining interest due to unique advantages such as affordability, portability, easy disposability and inherent capillarity. As capillary transportation is an integral component of paper-based devices, low sample volume with faster measurement becomes an additional advantage. We have developed a simple, paper-based microfluidic device suitable for measuring the viscosity of Newtonian fluids as well as a few non Newtonian fluids with sample volume as little as 12-20 MUL. The results could be obtained much faster than the conventional methods. A comparative analysis of the results obtained with our paper-based viscometer and with that of the conventional Ostwald viscometer shows a correlation coefficient greater than 0.99. Apart from viscosity measurement, the paper-based devices were tested for protein denaturation and polymer molecular weight determination. Our results show that the paper-based viscometer could be a potential alternative for the conventional viscometers in the viscosity range from 0.9 cP up till ~40 cP, with added benefits in terms of time, cost and low sample volume requirement. PMID- 30442409 TI - Microchips for detection of exfoliated tumor cells in urine for identification of bladder cancer. AB - Bladder cancer (BC) is a common malignancy, and it accounts for one of the highest management costs among urogenital cancers. As a non-invasive method, urine cytology plays an important role in the detection of exfoliated tumor cells (ETCs) for early diagnosis of BC. However, urine cytology suffers from its low sensitivity and reliance on microscopic examination. To address this issue, an integrated filtration device was developed with a pore size of 5 MUm that isolated and enriched ETCs from discarded urine samples, and then quantified ETCs using a microchip ELISA method. The results revealed that the number of urinary ETCs from BC patients (n = 35) was obviously higher than the number of ETCs from healthy donors (n = 20). The ROC curve showed that the integrated filtration microfluidic device had a sensitivity of 77.1% when the specificity was set at 90% in identifying BC patients. Thus, the integrated filtration device holds great potential for the screening of BC or the follow-up analysis of treatment efficacy in point-of-care (POC) settings. PMID- 30442410 TI - Initial Emergency Department Visit and Follow-Up Care for Concussions among Children with Medicaid. AB - OBJECTIVE: To describe the rates and patterns of initial emergency department (ED) encounters and follow-up care for concussions among Medicaid-insured children before and after the 2013 enactment of Ohio concussion law. STUDY DESIGN: Using a time-series design, this study analyzed concussion claim data obtained from Partners for Kids, a pediatric accountable-care organization in Ohio. A total of 12 512 concussions and 48 238 associated claims for services between January 1, 2008, and June 30, 2017, with an initial ED encounter among Medicaid-insured children (ages 0-18 years) were analyzed. The effect of the law on the odds of follow-up care were assessed using generalized estimating equations models, adjusted for sex, age group, and residence location. RESULTS: Of the total 12 512 concussions, 63.9% occurred in male patients, 70.1% in patients ages 10-18 years, and 65.2% in patients from urban areas. The rate of initial ED encounters for concussions increased from 2008 to 2014 (2.8 to 4.9 per 10 000 members), followed by a decrease in 2016 (4.2 per 10 000 members). A significant increase in follow-up care after the initial ED encounter was observed from pre-law to post-law (OR 1.73, 95% CI 1.61, 1.86). A shift in follow up care was observed from radiology and ambulance services in pre-law to primary care providers in post-law. CONCLUSIONS: The Ohio concussion law may have influenced the patterns of initial ED visit and follow-up care for concussions among Medicaid-insured children. Future studies evaluating the impact of the law should analyze the utilization patterns among children with various insurance/payment types. PMID- 30442411 TI - Cardiovascular Autonomic Control Is Altered in Children Born Preterm with Sleep Disordered Breathing. AB - BACKGROUND: To assess if the effects of sleep disordered breathing (SDB) on heart rate (HR) and HR variability, as a measure of autonomic control, were more severe in a group of children born preterm compared with a group of children born at term referred to our sleep laboratory for assessment of SDB. STUDY DESIGN: Children (3-12 years of age) referred for polysomnographic assessment of SDB were recruited; 50 born preterm (<37 weeks of gestation) and 50 at term, matched for age and SDB severity. The mean HR and HR variability using power spectral analysis were calculated for each child for wake and sleep, and stages N1, N2, N3, and rapid eye movement sleep. RESULTS: Ex-preterm children were born between 23 and 35 weeks of gestational age (29.3 +/- 3.6; mean +/- SEM). There were no differences in the demographic, sleep, or respiratory characteristics between the groups. High-frequency power (reflecting parasympathetic activity) was greater in the ex-preterm children in both N2 and N3 (P < .05 for both) and total power was greater in N3 (P < .05). When the children were divided by SDB severity, these effects were most marked in those preterm born children with moderate to severe disease. CONCLUSIONS: Preterm born children matched for age and SDB severity with children born at term showed no differences in sleep characteristics; however, they did exhibit increased parasympathetic tone during non-rapid eye movement sleep. PMID- 30442412 TI - Health Indicators of Lesbian, Gay, Bisexual, and Other Sexual Minority (LGB+) Youth Living in Rural Communities. AB - OBJECTIVE: To investigate whether the intersectionality of being lesbian, gay, bisexual, and other sexual minority youth (LGB+) and living in a rural community may portend worse concurrent health indicators than identifying as heterosexual and/or living in a nonrural community. STUDY DESIGN: Data were collected online between 2010 and 2011 from 5100 13- to-18-year-old youth across the US. Youth were randomly recruited from within the Harris Panel Online and through targeted outreach efforts to LGBT+ youth by a youth-focused nonprofit. The survey questionnaire was self-administered and included measures used in the present study and other measures related to the goal of the Teen Health and Technology study. RESULTS: Living in a rural community was not associated with additional challenges beyond those posed by LGB+ status. Instead, most noted differences in indicators of psychosocial challenge were between LGB+ and heterosexual youth, regardless of rural vs nonrural community living status. For example, sexual minority youth, both male and female, were more likely to have used substances, have depressive symptomatology, have low self-esteem, and report being bullied in the past year compared with both rural and nonrural heterosexual youth. CONCLUSIONS: Findings suggest that LGB+ youth living in rural areas are equally likely to face psychosocial challenges as LGB+ youth living in nonrural areas. Pediatricians and other healthcare providers who work with youth should be mindful of creating LGB+ inclusive environments that can promote self-disclosure by youth who may benefit from additional health services or clinical support for psychosocial challenges. PMID- 30442413 TI - Adolescence and Socioeconomic Factors: Key Factors in the Long-Term Impact of Leukemia on Scholastic Performance-A LEA Study. AB - OBJECTIVE: To evaluate the association between medical and social environmental factors and the risk of repeating a grade in childhood leukemia survivors. STUDY DESIGN: A cross-sectional study of childhood leukemia survivors, recruited through the LEA cohort (Leucemie de l'Enfant et de l'Adolescent [French Childhood Cancer Survivor Study for Leukemia]) in 2014. An adjusted logistic regression model was used to identify variables linked to repeating a grade after the diagnosis among the survivors, and the rates of repeating a grade were compared between the survivors and their siblings using a multilevel logistic regression model. RESULTS: The mean age at inclusion of the 855 participants was 16.2 +/- 7.0 years, and the mean duration of follow-up from diagnosis to evaluation was 10.2 +/- 6.2 years. After disease onset, 244 patients (28.5%) repeated a grade, with a median interval of 4 years (IQR, 2-8 years). Independent factors associated with repeating a grade were male sex (OR, 1.78; 95% CI, 1.21-2.60), adolescence (OR, 2.70; 95% CI, 1.63-4.48), educational support during the treatment period (OR, 3.79; 95% CI, 2.45-5.88), low parental education level (OR, 2.493; 95% CI, 1.657-3.750), and household financial difficulties (OR, 2.62; 95% CI, 1.607-4.28). Compared with siblings, survivors were at greater risk of repeating a grade (OR, 1.87; 95% CI, 1.48-2.35). CONCLUSIONS: The most vulnerable patients seemed to be adolescents and those with parents of low socioeconomic status. Improving the schooling career of leukemia survivors will require that the medical community more carefully consider the social status of patients. PMID- 30442415 TI - Developmental potential of slow-developing embryos: day-5 morulae compared with day-5 cavitating morulae. AB - OBJECTIVE: To describe and compare the ongoing pregnancy rate between morulae and cavitating morulae (CAVM) transferred on day 5, to describe and compare the blastulation rate between day 5 morulae and CAVM, and to describe the pregnancy rate of these slow-developing blastocysts during a frozen embryo transfer (FET) cycle. DESIGN: Retrospective cohort study. SETTING: Single tertiary care medical center. PATIENT(S): Delayed-development embryos: 3,321 cycles that included 10,304 embryos on day 5 that were cultured until day 6. INTERVENTION(S): Development of morula and CAVM to the blastocyst stage. MAIN OUTCOME MEASURE(S): Blastulation rate. RESULT(S): The fresh embryo transfers comprised 186 patients with 82 embryos at the morula stage and 104 embryos at the CAVM stage. The pregnancy rate (15.8% vs. 21.1%) and the ongoing pregnancy rate (15.8% vs. 17.3%) were comparable between the groups. The study group included 10,304 day-5 delayed embryos: 5,395 morulae and 4,909 CAVM on day 5. The blastulation rate was statistically significantly higher in the CAVM group compared with the morula group (39.2% vs. 20.4%). We included 201 FET cycles: 77 warmed blastocysts that developed from a morula on day 5 and 124 warmed blastocysts that developed from CAVM on day 5. The clinical pregnancy rate was comparable between the two groups per embryo transfer (21.3% vs. 24.7%). CONCLUSION(S): Transferring of fresh, slow developing embryos seems to improve the cycle outcomes compared with culturing for another day and then vitrifying and thawing later. PMID- 30442416 TI - Clinical relation among dural adhesion without dural ossification, dural ossification, and dural laceration. PMID- 30442414 TI - Using Digital Droplet Polymerase Chain Reaction to Detect the Mosaic GNAS Mutations in Whole Blood DNA or Circulating Cell-Free DNA in Fibrous Dysplasia and McCune-Albright Syndrome. AB - The GNAS postzygotic mosaic activating mutations involved in fibrous dysplasia and McCune-Albright syndrome (MAS) are not detectable in leukocytes by Sanger sequencing. Digital droplet polymerase chain reaction detects GNAS mutations in 7 of 12 patients (58.3%) suspected to have fibrous dysplasia/MAS from whole blood DNA, and in 4 of 5 patients (80%) from circulating cell-free DNA. PMID- 30442417 TI - Thrust manipulation may not decrease the intensity of chronic low back pain. Letter to the editor regarding "Manipulation and mobilization for treating chronic low back pain: a systematic review and meta-analysis" by Coulter et al. PMID- 30442418 TI - Response to letter to the editor entitled "thrust manipulation may not decrease the intensity of chronic low back pain" concerning "manipulation and mobilization for treating chronic low back pain: a systematic review and meta-analysis" by Coulter et al. TSJ; doi: 10.1016/j.spinee.2018.01.013. PMID- 30442419 TI - Novel anterior decompression with vertebral segment anterior sliding: neglected impact on the esophagus. PMID- 30442420 TI - Discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by the use of docking models. AB - We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor. PMID- 30442421 TI - Oxidative nucleophilic substitution selectively produces cambinol derivatives with antiproliferative activity on bladder cancer cell lines. AB - Methyltrioxorhenium mediated oxidative addition/elimination nucleophilic substitution yielded alkylamino and arylamino cambinol derivatives characterized by anti-proliferative activity against wild-type and p53 mutated MGH-U1 and RT112 bladder cancer cell lines. Some of the novel compounds showed an activity higher than that of the lead compound. The reaction was highly regioselective, affording for the first time a panel of C-2 cambinol substitution products. Aliphatic primary and secondary amines, and primary aromatic amines, were used as nitrogen centered nucleophiles. Surprisingly, the antiproliferative activity of C-2 substituted cambinol derivatives was not correlated to the induction of p53 protein, as evaluated by the analysis of the cell viability on wild-type and p53 mutated cancer cell lines, and further confirmed by western blot analyses. These data suggest that they exert their antiproliferative activity by a mechanism completely different from cambinol. PMID- 30442422 TI - Cluster Enrollment: A Screening Tool for Stroke Risk Factors in Minority Women Caregivers. AB - BACKGROUND AND PURPOSE: Women minorities have an overall increased lifetime incidence of cerebrovascular disease. The provision of risk factor modification in this group can prove difficult. In a population-based study, we used cluster enrollment to identify vascular risk factors in the female caregivers of stroke survivor study participants. METHODS: Obese women caregivers were identified as part of Swipe out Stroke, a Phase I PROBE study assessing the use of SmartPhone based intervention for dietary modification in minority stroke survivors. After written informed consent was obtained, both patients and caregivers were screened for vascular risk factors at study enrollment. Descriptive statistics were used to depict the study population. Continuous baseline variables were compared using 2 sample t-test or Wilcoxon rank-sum test by caregivers and patients. Categorical baseline variables were compared using Fisher's exact test. RESULTS: Thirty-six stroke patients (63.9% African-American, 36.1% Hispanic) and thirteen female caregivers (69.2% African-American, 30.8% Hispanic) were enrolled. Mean age, patients - 54.1 (SD 9.4), caregivers - 51.3 (SD 15.6) years, education, employment status and family history of stroke or obesity did not differ significantly. Compared to stroke patients, female caregivers were significantly less likely to self-report hypertension (69.2 versus 97.2%; P = 0.01) and hyperlipidemia (16.7 versus 60%; P = 0.02). Female caregivers were more likely to have elevated systolic blood pressure (147.6 vs 127.7 mmHg; P = 0.05), total cholesterol (207.5 versus 167 mg/dL; P = 0.01) and low density lipoprotein values (119.5 versus 88 mg/dL; P = 0.03) compared to stroke patients. CONCLUSIONS: Using cluster enrollment, we discovered minority female caregivers were more likely to have unknown or poorly controlled vascular risk factors compared to stroke patients. Innovative health screening tools may benefit the extended family of minority patients participating in clinical trials. PMID- 30442423 TI - Source of Education, Source of Care, Access to Glucometers, and Independent Correlates of Diabetes Knowledge in Ethiopian Adults with Diabetes. AB - BACKGROUND: Knowledge, self-care and access to diabetes-related resources is critical to diabetes management. However, there is paucity of data on source of education, source of care, and access to diabetes-related resources in the developing world, including Ethiopia. OBJECTIVE: To examine source of education, source of care, access to diabetes-related resources, and correlates of diabetes knowledge in a random sample of adults with diabetes in Ethiopia. METHODS: A sample of 337 subjects was selected using systematic random sampling. Validated questionnaires were used to obtain data on source of education, source of care, access to diabetes-related resources, and diabetes knowledge. Multiple logistic and linear models were used to assess independent correlates of owning a glucometer and good diabetes knowledge. RESULTS: Response rate was 91.1%. Correlates of access to glucometer were being >=55 years of age (OR = 2.6 95% CI 1.0 to 6.73), having high school (OR = 3.5; 95% CI: 1.17 to 10.41) and college education (OR = 5.2; 95% CI: 1.67 to 16.27), higher income (OR = 3.3; 95% CI: 1.19 to 9.19), and receiving DM care in private hospital/clinics (OR = 9.4; 95% CI: 2.24 to 39.31). Independent correlates of poor diabetes knowledge were being age 40-54, being single, lack of education, lower monthly income (0-499 birr or $0 - $18.11), getting DM care from public hospitals, treatment with oral medications, and not owning a glucometer. CONCLUSIONS: This study provides new insights on source of education, source of care, access to diabetes-related resources (e.g. glucometers, test strips), and correlates of diabetes knowledge in developing countries like Ethiopia that are experiencing an increasing prevalence of diabetes. PMID- 30442424 TI - Innovative surgical guidance for label-free real-time parathyroid identification. AB - BACKGROUND: Difficulty in identifying the parathyroid gland during neck operations can lead to accidental parathyroid gland excisions and postsurgical hypocalcemia. A clinical prototype called as PTeye was developed to guide parathyroid gland identification using a fiber-optic probe that detects near infrared autofluorescence from parathyroid glands as operating room lights remain on. An Overlay Tissue Imaging System was designed concurrently to detect near infrared autofluorescence and project visible light precisely onto parathyroid gland location. METHODS: The PTeye and the Overlay Tissue Imaging System were tested in 20 and 15 patients, respectively, and a modified near-infrared imaging system was investigated in 6 patients. All 41 patients underwent thyroidectomy or parathyroidectomy. System accuracy was ascertained with surgeon's visual confirmation for in situ parathyroid glands and histology for excised parathyroid glands. RESULTS: There was no observable difference between near-infrared autofluorescence of healthy and diseased parathyroid glands. The PTeye identified 98% of the parathyroid gland, whereas the near-infrared imaging system and the Overlay Tissue Imaging System identified 100% and 97% of the parathyroid glands, respectively. CONCLUSION: The PTeye can guide in real-time parathyroid gland identification even with ambient operating room lights. The near-infrared imaging system performs parathyroid gland imaging with high sensitivity, whereas the Overlay Tissue Imaging System enhances parathyroid gland visualization directly within the surgical field without requiring display monitors. These label-free technologies can be valuable adjuncts for identifying parathyroid glands intraoperatively. PMID- 30442425 TI - Reliability of distal tibio-fibular syndesmotic instability measurements using weightbearing and non-weightbearing cone-beam CT. AB - BACKGROUND: To investigate the reliability and reproducibility of syndesmosis measurements on weightbearing (WB) cone-beam computed tomography (CBCT) images and compare them with measurements obtained using non-weightbearing (NWB) images. METHODS: In this IRB-approved, retrospective study of 5 men and 9 women with prior ankle injuries, simultaneous WB and NWB CBCT scans were taken. A set of 21 syndesmosis measurements using WB and NWB images were performed by 3 independent observers. Pearson/Spearman correlation and intra-class correlation (ICC) were used to assess intra- and inter-observer reliability, respectively. RESULTS: We observed substantial to perfect intra-observer reliability (ICC=0.72-0.99) in 20 measurements. Moderate to perfect agreement (ICC=0.45-0.97) between observers was noted in 19 measurements. CONCLUSION: Measurements evaluating the distance between tibia and fibula in the axial plane 10mm above the plafond had high intra and inter-observer reliability. Mean posterior tibio-fibular distance, diastasis, and angular measurement were significantly different between WB and NWB images. PMID- 30442426 TI - The American Opioid Crisis: The Inexorable March to Death and Addiction. PMID- 30442427 TI - More Isn't Always Better: Time to Derive a Different Strategy for Renal Cell Carcinoma Surveillance. PMID- 30442428 TI - Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling. AB - We review some of the latest approaches to analysing cardiac electrophysiology data using machine learning and predictive modelling. Cardiac arrhythmias, particularly atrial fibrillation, are a major global healthcare challenge. Treatment is often through catheter ablation, which involves the targeted localised destruction of regions of the myocardium responsible for initiating or perpetuating the arrhythmia. Ablation targets are either anatomically defined, or identified based on their functional properties as determined through the analysis of contact intracardiac electrograms acquired with increasing spatial density by modern electroanatomic mapping systems. While numerous quantitative approaches have been investigated over the past decades for identifying these critical curative sites, few have provided a reliable and reproducible advance in success rates. Machine learning techniques, including recent deep-learning approaches, offer a potential route to gaining new insight from this wealth of highly complex spatio-temporal information that existing methods struggle to analyse. Coupled with predictive modelling, these techniques offer exciting opportunities to advance the field and produce more accurate diagnoses and robust personalised treatment. We outline some of these methods and illustrate their use in making predictions from the contact electrogram and augmenting predictive modelling tools, both by more rapidly predicting future states of the system and by inferring the parameters of these models from experimental observations. PMID- 30442429 TI - Corrigendum to "A little bit faster: Lower extremity joint kinematics and kinetics as recreational runners achieve faster speeds" [J. Biomech. 71 (2018) 167-175]. PMID- 30442430 TI - Effect of simulated joint instability and bracing on ankle and subtalar joint flexibility. AB - It is clinically challenging to distinguish between ankle and subtalar joints instability in vivo. Understanding the changes in load-displacement at the ankle and subtalar joints after ligament injuries may detect specific changes in joint characteristics that cannot be detected by investigating changes in range of motion alone. The effect of restricting joints end range of motion with ankle braces was already established, but little is known about the effect of an ankle brace on the flexibility of the injured ankle and subtalar joints. Therefore, the purposes of this study were to (1) understand how flexibility is affected at the ankle and subtalar joints after sectioning lateral and intrinsic ligaments during combined sagittal foot position and inversion and during internal rotation and (2) investigate the effect of a semi-rigid ankle brace on the ankle and subtalar joint flexibility. Kinematics and kinetics were collected from nine cadaver feet during inversion through the range of ankle flexion and during internal rotation. Motion was applied with and without a brace on an intact foot and after sequentially sectioning the calcaneofibular ligament (CFL) and the intrinsic ligaments. Segmental flexibility was defined as the slope of the angle-moment curve for each 1 Nm interval. Early flexibility significantly increased at the ankle and subtalar joint after CFL sectioning during inversion. The semi-rigid ankle brace significantly decreased early flexibility at the subtalar joint during inversion and internal rotation for all ligament conditions and at the ankle joint after all ligaments were cut. PMID- 30442432 TI - Efficacy of the presence of an emergency physician in prehospital major trauma care: A nationwide cohort study in Japan. AB - PURPOSE: The beneficial effect of the presence of an emergency physician in prehospital major trauma care is controversial. The aim in this study is to assess whether an emergency physician on scene can improve survival outcome of critical trauma patients. METHODS: This retrospective cohort study was conducted by using nationwide trauma registry data between 2004 and 2013 in Japan. Severe trauma patients (injury severity score (ISS) >= 16) who were transported directly to the hospital from the injury site were included in our analysis. Patients who were predicted to be untreatable (abbreviated injury score (AIS) = 6 and/or cardiopulmonary arrest at least one time before hospital arrival) were excluded. Participants were divided into either a physician or paramedics group based on the prehospital practitioner. The primary outcome was survival rate at discharge. Multivariable logistic regression analysis was performed to compare the outcome with adjustment for age, gender, ISS, cause of injury, and pre-hospital vital signs. RESULTS: A total of 30,283 patients were eligible for the selection criteria (physician: 1222, paramedics: 29,061). Overall, 172 patients (14.1%) died in the physician group compared to 3508 patients (12.1%) in the paramedics group. Patients in the physician group had higher ISSs than those in the paramedics group. In multivariable logistic regression, the physician group had an odds ratio (OR) of 1.16 (95% confidence interval (CI) = 0.97 to 1.40, p = 0.11) for in-hospital survival. CONCLUSIONS: Our results failed to show a difference in survival at discharge between non-physician-staffed ambulances and physician-staffed ambulances. PMID- 30442431 TI - Pharmacoeconomic impact of an alternative workflow process for stroke. AB - OBJECTIVE: The objective of this study was to evaluate a new multidisciplinary process in which intravenous alteplase (tPA) waste, used for acute ischemic stroke (AIS), was salvaged in an attempt to maximize cost effectiveness without impacting door-to-needle (DTN) administration times. DESIGN: This was a retrospective cohort between May 2017 and February 2018. The primary endpoint evaluated for this study was the total tPA salvaged and total cost savings in U.S. dollars. Secondary endpoints evaluated included overall DTN time in minutes. SETTING: Emergency department of a primary stroke center. PATIENTS: A convenience sample of sequential adult (>18 years) patients who received tPA in the ED for AIS were included for analysis. INTERVENTIONS: New stroke process which involved bedside mixing of tPA and salvaging of excess waste in the main central pharmacy. MEASUREMENTS AND MAIN RESULTS: A total of 50 patients were included in the final analysis. There were 25 patients included in the new process and old process groups respectively. A total of 605 mg of alteplase was salvaged from 25 patients in the new process group which was associated with an estimated cost savings of over $120,000 annually. Patients in the new process group had statistically faster average (52 min vs. 60 min; p = 0.01) and median (50 min vs. 58 min; p = 0.03) DTN administration times. CONCLUSION: Preliminary data, in this pilot study, utilizing a multidisciplinary model for tPA administration led to significant cost savings of tPA and decreases in overall DTN administration times. PMID- 30442433 TI - Indexing the Event Calculus: Towards practical human-readable Personal Health Systems. AB - Personal Health Systems (PHS) are mobile solutions tailored to monitoring patients affected by chronic non communicable diseases. In general, a patient affected by a chronic disease can generate large amounts of events: for example, in Type 1 Diabetic patients generate several glucose events per day, ranging from at least 6 events per day (under normal monitoring) to 288 per day when wearing a continuous glucose monitor (CGM) that samples the blood every 5 minutes for several days. Just by itself, without considering other physiological parameters, it would be impossible for medical doctors to individually and accurately follow every patient, highlighting the need of simple approaches towards querying physiological time series. Achieving this with current technology is not an easy task, as on one hand it cannot be expected that medical doctors have the technical knowledge to query databases and on the other hand these time series include thousands of events, which requires to re-think the way data is indexed. Anyhow, handling data streams efficiently is not enough. Domain experts' knowledge must be explicitly included into PHSs in a way that it can be easily readed and modified by medical staffs. Logic programming represents the perfect programming paradygm to accomplish this task. In this work, an Event Calculus based reasoning framework to standardize and express domain-knowledge in the form of monitoring rules is suggested, and applied to three different use cases. However, if online monitoring has to be achieved, the reasoning performance must improve dramatically. For this reason, three promising mechanisms to index the Event Calculus Knowledge Base are proposed. All of them are based on different types of tree indexing structures: k-d trees, interval trees and red-black trees. The paper then compares and analyzes the performance of the three indexing techniques, by computing the time needed to check different type of rules (and eventually generating alerts), when the number of recorded events (e.g. values of physiological parameters) increases. The results show that customized jREC performs much better when the event average inter-arrival time is little compared to the checked rule time-window. Instead, where the events are more sparse, the use of k-d trees with standard EC is advisable. Finally, the Multi-Agent paradigm helps to wrap the various components of the system: the reasoning engines represent the agent minds, and the sensors are its body. The said agents have been developed in MAGPIE, a mobile event based Java agent platform. PMID- 30442435 TI - Assessing progress of the Pan American Health Organization's Policy Research for Health in member states. AB - The improvement of health in the twenty-first century is inextricably linked to research for health. In response to growing international appeal to address regional health needs, the Pan American Health Organization (PAHO) and its Member States approved the Policy on Research for Health (CD49/10) in 2009. This document represents the flagship regional policy on research for health and outlines how health systems and services in the region can be strengthened through research. It has been implemented by the two components of PAHO -the Member States and the Pan American Sanitary Bureau. The policy contained a specific directive mandating PAHO to report on its implementation, development of subsequent strategies, and action plans targeting its governing bodies. The Americas are the first World Health Organization (WHO) region to issue a regional Policy on Research for Health, which was harmonized with WHO's Strategy on Research for Health, approved in 2010. Attending to the recommendations issued by PAHO's Advisory Committee on Health Research and WHO's Advisory Committee on Health Research, the PAHO Department of Knowledge Management, Bioethics and Research set out to advance the assessment of the implementation of the Policy on Research for Health through the creation of a monitoring and evaluation Scorecard. Indicators relevant to the Policy on Research for Health objectives were mapped from the Compendium of Impact and Outcome Indicators, with new indicators created. A practical framework based on available indicator data was proposed to generate a baseline policy assessment and incorporate a means of incrementally enhancing the measurements. In this case study, we outline the iterations of the PAHO Policy on Research for Health Scorecard, as well as the lessons learned throughout the development process that may be a valuable guide for health research entities monitoring and evaluating the progress of their own policies. PMID- 30442434 TI - Probabilistic cost-utility analysis and expected value of perfect information for the Oncotype multigenic test: a discrete event simulation model. AB - OBJECTIVE: To carry out a cost-utility analysis of the application of the Oncotype genomic test to inform the decision to use or not to use chemotherapy in the Basque Country (Spain). METHOD: The cost-utility study was carried out using a discrete event simulation model representing the natural history of breast cancer. The decision of treatment with chemotherapy based on Oncotype was compared with the standard of treatment based on clinical-pathological criteria. The model included clinical data from Basque hospitals and the literature and was processed by deterministic and probabilistic analysis to calculate the incremental cost-effectiveness ratio (ICER), the cost-effectiveness plane, the acceptability curve and the expected value of perfect information. The study adopted both a health and societal perspective. RESULTS: From a health perspective, the deterministic analysis estimated an ICER for Oncotype of 17,453 euros/quality-adjusted life year (QALY), discount included, and 9,613 euros/QALY without the discount. Eighty five percent (85%) of the simulations were below the efficiency threshold for Spain. The parametric variability associated with the Oncotype results was the main uncertainty factor in the decision. CONCLUSIONS: Oncotype is a cost-effective intervention from a health system perspective since each QALY gained costs less than 25,000 euros. From a societal perspective, it is dominant since it provides greater health and is accompanied by cost savings. PMID- 30442436 TI - Cochlear implantation after canal wall down mastoidectomy - Outcomes after partial mastoid obliteration. AB - OBJECTIVE: To describe and evaluate the partial mastoid obliteration of the so called radical mastoid cavity after canal-wall down mastoidectomy (CWD) for cochlear implantation (CI) compared to overclosure of the external ear canal as two stage procedures. METHODS: Out of 1020 patients undergoing cochlear implantation between January 1st, 2003 and June 15th, 2016 at the Department of Otolaryngology, Head & Neck Surgery, University Hospital Cologne, eight patients underwent obliteration of the radical cavity prior to cochlear implantation. In four additional patients, the external ear canal was overclosed prior to cochlear implantation. RESULTS: Patients undergoing partial mastoid obliteration (five ?, 4 left ears) and overclosure of the external ear canal (one ?, 3 left ears) averaged 56years and 61years, respectively. The radical cavities had been present for 21.8years on average before partial obliteration and for 19.5years before overclosure. Cochlear implantation following mastoid obliteration was performed after a mean period of 5.1months and 3.8months after overclosure. After partial mastoid obliteration, complete insertion of all electrodes was achieved and the clinical courses were uneventful for all patients. Likewise, no patient revealed any complications after overclosure of the external ear canal. CONCLUSION: Partial mastoid obliteration with bone pate and cartilage after canal wall down mastoidectomy can be advocated as a feasible alternative technique that allows for a safe subsequent cochlear implantation. PMID- 30442437 TI - Effects of l-carnitine administration on health-related quality of life during cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma. AB - OBJECTIVES: Cancer-related fatigue impairs daily functioning and negatively impacts health-related quality of life (HRQoL). Our previous study revealed that cisplatin-based chemoradiotherapy (CRT) impairs the carnitine system and carnitine deficiency leads to poor physical functioning. This open label, randomized, controlled prospective study investigated the effects of l-carnitine administration on plasma carnitine concentration, CRT-induced fatigue, and decline in HRQoL in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Patients were divided into experimental group (received 1000mg of oral liquid l-carnitine once daily for 8 weeks) and control group. The primary and secondary endpoints were the change in HRQoL scores and the change in carnitine levels, respectively, from baseline (pre-CRT) to after CRT. RESULTS: The mean total plasma carnitine concentration in the control group decreased significantly, 2 weeks after the end of chemotherapy, while no significant differences were seen in the l-carnitine group. l-carnitine administration, therefore, kept the physical functioning score unchanged. CONCLUSION: Our study shows that patients who receive CRT experience chemotherapy-induced damage of carnitine homeostasis leading to deficiency of carnitine and impairment of HRQoL. l-carnitine administration is beneficial in improving the HRQoL in patients with HNSCC. PMID- 30442438 TI - Efficacy of anti-PD-1 therapy in a patient with brain metastasis of parotid carcinoma: A case report. AB - CheckMate 141, an open-label, randomized phase III trial of nivolumab, indicated that treatment with nivolumab prolonged overall survival of patients with platinum-refractory, recurrent head and neck squamous cell carcinoma. Herein, we describe a case of brain metastasis of parotid carcinoma in which a good response was achieved after nivolumab treatment. The patient was a 67-year-old woman with parotid carcinoma (cT4bN0M0) who received induction chemotherapy followed by chemoradiation. Computed tomography and magnetic resonance imaging performed 10 weeks after the primary treatment revealed a residual tumor and brain and lung metastases. Thereafter, chemotherapy comprising cisplatin, 5-FU, and cetuximab was performed. Unfortunately, the tumor volume increased 5 months after chemotherapy, after which she received immunotherapy with biweekly nivolumab. After six cycles of nivolumab administration, the brain and lung metastases shrank markedly. Nivolumab had an intracranial effect in the patient with brain metastases of parotid carcinoma. This case report highlights the efficacy of nivolumab in the management of head and neck cancer with brain metastasis. PMID- 30442439 TI - Embryopathy Associated With a Vitamin Therapy. PMID- 30442440 TI - Optimizing Neurocritical Care Follow-Up Through the Integration of Neuropsychology. AB - BACKGROUND: Pediatric critical care survivors often suffer persisting multisystem health problems and are left with treatment needs that go unmet due to limits in current care models. We proposed that integration of neuropsychology into neurocritical care follow-up provides incremental benefit to the identification and treatment of persisting complications and reduction in co-morbidities. BASIC PROCEDURES: The aims of this study were three-fold. First, we described pilot programs at two pediatric hospitals as models for implementing systematic follow up care with interdisciplinary clinic teams consisting of critical care, neurology, and neuropsychology. Second, we described working models specific to neuropsychological service delivery in these programs. Third, we presented preliminary data from the first six months of one of the pilot programs in order to examine incremental benefit of neuropsychology in improving patient care and parent satisfaction. MAIN FINDINGS: A total of 16 patients (age range three to 17 years) were seen by neuropsychology within the first six months of the program. Results showed that integration of neuropsychology into follow-up care resulted in recommendations being made for services or concerns not already addressed in 81% of cases. Parents reported high satisfaction, endorsing the highest possible rating on 96% of all items. Parents reported that neuropsychological consultation improved their understanding and communication with their child, and helped them know what to expect from their child during postacute recovery. CONCLUSIONS: Results of this pilot study suggest that integration of neuropsychology into neurocritical care follow-up programs contributes to parent satisfaction and may provide incremental benefit to patient care. PMID- 30442441 TI - Metabolomic insights into the mechanisms underlying tolerance to salinity in different halophytes. AB - Salinity is among the most detrimental and diffuse environmental stresses. Halophytes are plants that developed the ability to complete their life cycle under high salinity. In this work, a mass spectrometric metabolomic approach was applied to comparatively investigate the secondary metabolism processes involved in tolerance to salinity in three halophytes, namely S. brachiata, S. maritima and S. portulacastrum. Regarding osmolytes, the level of proline was increased with NaCl concentration in S. portulacastrum and roots of S. maritima, whereas glycine betaine and polyols were accumulated in S. maritima and S. brachiata. Important differences between species were also found regarding oxidative stress balance. In S. brachiata, the amount of flavonoids and other phenolic compounds increased in presence of NaCl, whereas these metabolites were down regulated in S. portulacastrum, who accumulated carotenoids. Furthermore, distinct impairment of membrane lipids, hormones, alkaloids and terpenes was observed in our species under salinity. Finally, several other nitrogen containing compounds were involved in response to salinity, including amino acids, serotonin and polyamine conjugates. In conclusion, metabolomics highlighted that the specific mechanism each species adopted to achieve acclimation to salinity differed in the three halophytes considered, although response osmotic stress and oxidative imbalance have been confirmed as the key processes underlying NaCl tolerance. PMID- 30442442 TI - A comprehensive study on the main physiological and biochemical changes occurring during growth and on-tree ripening of two apple varieties with different postharvest behaviour. AB - Apple quality and the storage potential likely depend on a range of physiological and biochemical events occurring throughout fruit development and ripening. In this study, we investigated the major physiological (ethylene production and respiration) and biochemical changes (related to sugar and malic acid content as well as antioxidant metabolism) occurring during growth and on-tree ripening of two apple varieties ('Granny Smith' (GS) and 'Early Red One' (ERO)) with known differences in their postharvest behaviour, mainly firmness loss and susceptibility to superficial scald. Our results demonstrate that the higher storability and the limited loss of firmness of 'GS' fruit was associated to a higher acid content, mainly malic acid, that seemed to be regulated already at fruit set (20 DAFB). The reduced loss of firmness during storage in 'GS' was also associated to the fruit inability to produce ethylene upon harvest resulting from very low 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) activity. Sugar accumulation, on the other hand, was similar among both varieties as was also observed for the rate of fruit growth or the fruit respiration pattern. In addition, the higher susceptibility of 'GS' if compared to 'ERO' to superficial scald was not associated to peroxidative damage (malondialdehyde accumulation) nor to higher levels of the sesquiterpene alpha-farnesene but rather mediated by a fruit antioxidant imbalance resulting from higher H2O2 levels and lower antioxidant (peroxidase) enzymatic capacity. The interplay between ethylene, respiration and antioxidants or sugars and organic acids during apple growth and development is further discussed. PMID- 30442443 TI - Elevating the standard of endoscope processing: Terminal sterilization of duodenoscopes using a hydrogen peroxide-ozone sterilizer. AB - BACKGROUND: The health care community is increasingly aware of the processing challenges and infection risks associated with duodenoscopes owing to published reports of outbreaks and regulatory recalls. Studies have demonstrated that the current practices are inadequate for consistently producing patient-ready endoscopes. Alternatively, terminal sterilization would offer a greater margin of safety and potentially reduce the risk of patient infection. The purpose of this study was to evaluate the efficacy of a hydrogen peroxide-ozone sterilizer with regulatory clearance for terminal sterilization of duodenoscopes. METHODS AND RESULTS: Validation studies were performed under laboratory simulated-use and clinical in-use conditions. The overkill method study demonstrated a reduction of at least 6-log of Geobacillus stearothermophilus spores at half-cycle, providing a sterility assurance level of 10-6. In addition, the sterilizer achieved a 6-log reduction of G stearothermophilus in the presence of inorganic and organic soils in a simulated-use study. The clinical in-use study confirmed that the sterilizer achieved sterilization of patient-soiled duodenoscopes under actual use conditions. CONCLUSIONS: Simulated-use and clinical in-use studies demonstrated the efficacy of a hydrogen peroxide-ozone sterilizer for terminal sterilization of duodenoscopes. This offers health care facilities a viable alternative for duodenoscope processing to enhance patient safety as part of a comprehensive infection control strategy. PMID- 30442444 TI - Mumps outbreak with high complication rates among residents in a university teaching hospital. AB - According to the US Advisory Committee on Immunization Practices recommendations, only health care personnel (HCP) with adequate evidence of immunity should be exposed to patients with a suspected diagnosis of mumps. Here we report a hospital-outbreak scenario among medical residents with no previous vaccination record against mumps who had a high rate of complications. We also describe the importance and impact of full and proper vaccination, as well as isolation, of HCP in stopping the outbreak and, finally, review opportunities for improving the safety of HCP. PMID- 30442445 TI - Convexity subarachnoid haemorrhage associated with ipsilateral carotid artery occlusion. PMID- 30442446 TI - Is there scientific evidence for the use of venlafaxine to treat neuropathic pain? PMID- 30442447 TI - Speed sensorless model predictive current control of doubly-fed induction machine drive using model reference adaptive system. AB - This paper presents a speed sensorless control scheme named as finite control set model predictive current control (FCS-MPCC) using a modified fictitious ohmic quantity (R) based model reference adaptive system (MRAS) for grid-connected doubly-fed induction machine (DFIM) drive. The variables of the reference model of this speed sensorless scheme (R-MRAS) are represented in stationary reference frame while those for the adaptive model are denoted in synchronously rotating reference frame. The sensorless formulation thus obtained is completely independent of any stator/rotor resistance terms. The scheme is also devoid of any stator/rotor flux estimation. Moreover, the intuitiveness of FCS-MPCC brings in additional flexibility in comparison to the conventional control techniques like field oriented control (FOC) and direct torque control (DTC). The overall scheme demonstrates faster execution time than FOC/DTC based control of DFIM drive. The proposed control algorithm is simulated and tested for limited speed range application in MATLAB/Simulink. The validation of simulation results are further done by experimentation on a dSPACE-1103 based DFIM laboratory setup. PMID- 30442448 TI - Guillain-Barre syndrome subtypes: A clinical electrophysiological study of 100 patients. AB - INTRODUCTION: A retrospective analysis was performed to document the clinical and electrophysiological features of Guillain-Barre syndrome (GBS) subtypes using different diagnostic criteria. METHODS: One hundred GBS patients were included. Clinical and laboratory features were analyzed, and patients were classified according to four sets of diagnostic criteria. Electrodiagnostic criteria were also analyzed. RESULTS: A total of 69 patients met Asbury and Cornblath's criteria, 96 met Van der Meche's criteria, 99 met Wakerley's diagnostic classification and 86 met level 1 or 2 of the Brighton criteria. Rates of GBS subtypes were: 69% classic GBS; 8% Miller-Fisher syndrome; 12% paraparetic GBS; 2% pharyngeal-cervical-brachial GBS; and 9% unclassified. Those for electrodiagnostic subtypes were 52% demyelinating and 9% axonal according to Hadden's criteria vs 41% demyelinating and 41% axonal as per Rajabally's criteria. CONCLUSION: In this study of case distribution within the GBS spectrum of a retrospective cohort of French patients, the application of new diagnostic criteria enabled accurate diagnoses and classifications of the different subtypes, and also increased the recognition of axonal GBS. PMID- 30442450 TI - Young children's sentence comprehension: Neural correlates of syntax-semantic competition. AB - Sentence comprehension requires the assignment of thematic relations between the verb and its noun arguments in order to determine who is doing what to whom. In some languages, such as English, word order is the primary syntactic cue. In other languages, such as German, case-marking is additionally used to assign thematic roles. During development children have to acquire the thematic relevance of these syntactic cues and weigh them against semantic cues. Here we investigated the processing of syntactic cues and semantic cues in 2- and 3-year old children by analyzing their behavioral and neurophysiological responses. Case marked subject-first and object-first sentences (syntactic cue) including animate and inanimate nouns (semantic cue) were presented auditorily. The semantic animacy cue either conflicted with or supported the thematic roles assigned by syntactic case-marking. In contrast to adults, for whom semantics did not interfere with case-marking, children attended to both syntactic and to semantic cues with a stronger reliance on semantic cues in early development. Children's event-related brain potentials indicated sensitivity to syntactic information but increased processing costs when case-marking and animacy assigned conflicting thematic roles. These results demonstrate an early developmental sensitivity and ongoing shift towards the use of syntactic cues during sentence comprehension. PMID- 30442449 TI - Postictal pure retrograde amnesia: Response. PMID- 30442451 TI - Vertebrobasilar dolichoectasia presenting simultaneously with ischemic and hemorrhagic strokes. AB - BACKGROUND: Vertebrobasilar dolichoectasia (VBDE) can present with brainstem- compressive symptoms, cerebral ischemia, or hemorrhage. Herein we describe a unique patient with VBDE who presented with hemorrhage and cerebral ischemia simultaneously. CASE: Patient is a 76-year-old man presenting with an acute, symptomatic left pontine ischemic stroke heralded by ataxic dysarthria and right ataxic-hemiparesis. MRI scan of the brain demonstrated acute cerebral ischemia in the left pons, a small right thalamic hemorrhage, and evidence of VBDE. CONCLUSION: The perforating vessels branching off of the pathologic VBDE may result in both ischemia and hemorrhage. This is the first known case, to our knowledge, in which hemorrhage and cerebral ischemia occurred simultaneously. PMID- 30442452 TI - Intracranial multiple myeloma with intraparenchymal involvement: Case report and literature review. AB - Intraparenchymal extension of multiple myeloma is a rare manifestation of the disease. Here, we present a case of a patient with multiple myeloma lesions situated adjacent to the meninges and intraparenchymally. PMID- 30442453 TI - Predictive factors of overall survival in primary intracranial pure choriocarcinoma. AB - The incidence of primary intracranial pure choriocarcinoma (PIPC) is extremely rare. Only several case and case series have been previously reported; therefore, there is still lack of knowledge about the prognosis and its standard treatment. We performed a collective study of all reported cases of PIPC to identify the predictive factors related with OS. A comprehensive search was performed on Pubmed's electronic database using the terms "primary intracranial choriocarcinoma" and "malignant germ cell tumor". Data about gender, various location, the presence of intratumoral hemorrhage, metastasis and treatment modalities were extracted from the published articles and we analyzed the overall survival based on this predictive factors. 51 cases were eligible and met the inclusion criteria. The majority of the patients were in the child population (44.7%) age between 6 and 12 years old. 77.1% of the patient were male and 22.9% were female. Tumor located other than suprasellar and pineal area showed better prognosis. Median OS of PIPC was 22 months. Patient underwent gross total resection had better outcomes compared with those who only had partial or subtotal resection. Adjuvant therapy (especially chemotherapy) significantly improved OS (p = 0.000, log-rank test). PIPC is chemosensitive and metastasis is the predictive factor for poor prognosis. PMID- 30442454 TI - Person-centered care: The struggle persists. PMID- 30442455 TI - Sonochemical and sonoelectrochemical production of hydrogen. AB - Reserves of fossil fuels such as coal, oil and natural gas on earth are finite. The continuous use and burning of these fossil fuel resources in the industrial, domestic and transport sectors has resulted in the extremely high emission of greenhouse gases, GHGs (e.g. CO2) and solid particulates into the atmosphere. Therefore, it is necessary to explore pollution free and more efficient energy sources in order to replace depleting fossil fuels. The use of hydrogen (H2) as an alternative fuel source is particularly attractive due to its very high specific energy compared to other conventional fuels and its zero GHG emission when used in a fuel cell. Hydrogen can be produced through various process technologies such as thermal, electrolytic, photolytic and biological processes. Thermal processes include gas reforming, renewable liquid and biooil processing, biomass and coal gasification; however, these processes release a huge amount of greenhouse gases. Production of electrolytic hydrogen from water is an attractive method to produce clean hydrogen. It could even be a more promising technology when combining water electrolysis with power ultrasound to produce hydrogen efficiently where sonication enhances the electrolytic process in several ways such as enhanced mass transfer, removal of hydrogen and oxygen (O2) gas bubbles and activation of the electrode surface. In this review, production of hydrogen through sonochemical and sonoelectrochemical methods along with a brief description of current hydrogen production methods and power ultrasound are discussed. PMID- 30442456 TI - Associations of renal function with urinary excretion of metals: Evidence from NHANES 2003-2012. AB - BACKGROUND: Urinary metals are considered measures of long-term exposures of metals, such as cadmium (Cd). Some studies indicate reduced renal function may affect the urinary excretion of several metals in general population making assessments difficult. OBJECTIVES: To examine whether reduced renal function is associated with reduced urinary excretion of 12 metals or their metabolites and, in turn, an underestimated measure of Cd in general population. METHODS: We conducted analyses using data from the National Health and Nutrition Examination Survey (NHANES) 2003-2012. Multiple linear regression models were used to examine the associations between urinary metal levels and estimated glomerular filtration rate (eGFR). Restricted cubic spline regression models were used to evaluate the nonlinearity. RESULTS: Urinary metal levels significantly increased (p < 0.001) with increasing eGFR, except for antimony (p = 0.172). Urinary levels of arsenic, dimethylarsonic acid, cobalt, molybdenum and tungsten increased linearly with eGFR, while Cd, lead, mercury, barium, cesium and thallium increased nonlinearly (p < 0.001) with eGFR. Based on a restricted cubic spline regression model, we found, corresponding to a fixed blood Cd adverse cutpoint of 5 MUg/L, predicted urinary Cd cutpoints substantially varied from 0.78-1.21 MUg/g for urinary Cd between those aged <40 years and who had chronic kidney disease and those aged 60 years or over with normal renal function, respectively. CONCLUSION: Reduced renal function is associated with reduced urinary metals; and associations are also observed across the eGFR range not just in the reduced range. Urinary abnormal cutpoints of metals are likely dependent on eGFR and age. The associations between urinary exposure of metals and disease risk are likely underestimated without considering the modifying effect of renal function. PMID- 30442457 TI - Multivariate prediction of multiple sclerosis using robust quantitative MR-based image metrics. AB - OBJECTIVES: The current work investigates the performance of different multivariate supervised machine learning models to predict the presence or absence of multiple sclerosis (MS) based on features derived from quantitative MRI acquisitions. The performance of these models was evaluated for images which are significantly degraded due to subject motion, a problem which is often observed in clinical routine diagnostics. Finally, the difference between a true multivariate analysis and the corresponding univariate analysis based on single parameters alone was addressed. MATERIALS AND METHODS: 52 MS patients and 45 healthy controls where scanned on a 3T system. The datasets showed variable degrees of motion-associated artefacts. For each dataset, the average of T1, T2*, total and myelin bound water content was determined in white and grey matter. Based on these parameters, different multivariate models were trained and their cross-validated performance to predict the presence of MS was evaluated. Furthermore, the univariate distributions of each quantitative parameter were employed to define optimised cut-offs that differentiate MS patients from healthy controls. RESULTS: For data not affected by motion, 83.7% of all subjects were correctly classified using a crossvalidated multivariate model. Inclusion of data with significant artefacts reduces the rate of correct classification to 74.5%. T1 in grey and myelin water content in white matter where the most discriminating variables in the multivariate analysis. In contrast, the total water content in white matter and the ratio of white and grey matter total water content each resulted in 77% correct classifications in a univariate regression analysis. CONCLUSION: The results demonstrate that even simple quantitative MRI-based measures allow for an automated prediction of the presence/absence of multiple sclerosis with good specificity. Importantly, even highly degraded datasets due to motion-artefacts could be correctly classified, especially when pooling features derived from grey and white matter. Finally, the advantage of a multivariate over a univariate analysis of quantitative MR data was shown. PMID- 30442458 TI - Evaluating the association of TNF alpha promoter haplotype with its serum levels and the risk of PCOS: A case control study. AB - Poly cystic ovary syndrome is the major cause of anovulatory infertility. TNF alpha, pro-inflammatory cytokine is associated with obesity, insulin resistance and hyperandrogenism, therefore in present study we tried to find the association between TNF alpha promoter polymorphisms, TNF alpha levels and the risk of PCOS. Present case control study was carried on 400 women of age 16-40 years. TNF alpha levels were measured by ELISA whereas promoter polymorphisms were evaluated by PCR-RFLP. Haplotype and Linkage disequilibrium analysis was also done. TNF alpha level was significantly higher in PCOS group (13.24 +/- 9.78) than control (5.5 +/- 3.8). Haplotype analysis revealed that GGTCT, AGTCT, AGCCT and AACCT are the susceptible haplotypes associated with TNF alpha level. rs361525 and rs1799964 were found to be associated with the risk of PCOS (p = 0.0006, 0.015). GGCCT, AATAT, GATAT (most susceptible), AGCCT, GGTCT and GATCT are the susceptible haplotypes for PCOS. Significant difference between TNF alpha levels in PCOS and Control group suggest it's one of the promising candidates for the marker of inflammation (sensitivity and specificity 91.23 and 94.56% respectively, with area under the curve 0.907 at 95% CI 0.8723-0.9512). Presence of GGCCT haplotype suggests the susceptibility towards PCOS which needs to be further verified. In addition to this, present study not only provides a pavement for the diagnosis, but also monitoring and management of PCOS too. PMID- 30442459 TI - Serum cytokine levels differ according to major cardiovascular risk factors in patients with lower limb atherosclerosis. AB - Different cardiovascular risk factors present a heterogenic manifestation of lower limb atherosclerosis. The molecular mechanisms behind this phenomenon remain unknown. We aimed to clarify this phenomenon by studying the association of major cardiovascular risk factors with the profile of serum cytokines in 226 consecutive patients with lower limb atherosclerosis treated at a department of Vascular Surgery during a one-year enrollment period. Increasing age independently associated with higher levels of IFN-gamma inducible factors MIG, CTACK and IP-10 (P < 0.001 for all). Patients with chronic kidney disease had higher serum levels of MIF, IL-16 and SCF (P = 0.001 or less for all). Smoking and hypertension associated with IL-17 (P = 0.037 and 0.015, respectively). In addition, smoking associated with growth factors known to induce myeloid progenitor cell proliferation: GM-CSF (P = 0.035), PDGF (P = 0.024), bFGF (P = 0.026), and HGF (P = 0.030). Dyslipidemia also associated with myeloproliferative factors: MIB-1alpha (P = 0.005) and PDGF (P = 0.01). Type II diabetes associated with Th2 mediated inflammation: IL-5 (P < 0.001), IL-7 (P = 0.004) and IL-13 (P = 0.015). Major cardiovascular risk factors are associated with different circulating cytokines implicating different immunological pathology. PMID- 30442460 TI - Laparoscopic Ladd's procedure for malrotation in infants and children is still a controversial approach. AB - BACKGROUND: Open Ladd's procedure is the gold standard for the correction of intestinal malrotation and laparoscopic approach remains controversial. This study aimed to evaluate our experience in laparoscopic management of malrotation. METHODS: Single center retrospective study including patients who underwent a laparoscopic assessment of intestinal malrotation with correction if appropriate between 2007 and 2017. RESULTS: Sixty-five patients (median age 7 months) had a laparoscopic assessment with and without correction of malrotation. Forty-five (69%) were symptomatic, including 16 (25%) with a midgut volvulus. The procedure was completed laparoscopically in 55 (86%) patients in 110 min (30-190). Conversions happened more frequently at the beginning of the experience. With a follow-up of 12.5 months (8 days-5.3 years), morbidity rate was 15% and 4 (6%) patients underwent a redo surgery, all in the first 5 months after surgery, compared with 3/53 (6%) in a contemporaneous group undergoing open Ladd's. CONCLUSION: This is the largest series reported so far of the laparoscopic management of malrotation. Laparoscopic Ladd's procedure is reliable but still exposes to open conversion which may be in part owing to a learning curve. A low conversion threshold is important in cases with volvulus. The redo rate is similar to that of the open procedure. LEVEL OF EVIDENCE: Level III retrospective comparative treatment study. PMID- 30442461 TI - Use of prostaglandin E1 to treat pulmonary hypertension in congenital diaphragmatic hernia. AB - BACKGROUND/PURPOSE: Prostaglandin E1 (PGE) has been used to maintain ductus arteriosus patency and unload the suprasystemic right ventricle (RV) in neonates with congenital diaphragmatic hernia (CDH) and severe pulmonary hypertension (PH). Here we evaluate the PH response in neonates with CDH and severe PH treated with PGE. METHODS: We performed a retrospective chart review of CDH infants treated at our center between 2011 and 2016. In a subset, PGE was initiated for echocardiographic evidence of severe PH, metabolic acidosis, or hypoxemia. To assess PH response, we evaluated laboratory data, including B-type natriuretic peptide (BNP) and echocardiograms before and after PGE treatment. Categorical and continuous data were analyzed with Fisher's exact tests and Mann-Whitney t-tests, respectively. RESULTS: Fifty-seven infants were treated with PGE a mean 17 +/- 2 days. BNP levels declined after 1.4 +/- 0.2 days of treatment and again after 5.2 +/- 0.6 days. After 6 +/- 0.8 days of treatment, echocardiographic estimates of severe PH by tricuspid regurgitation jet velocity, ductus arteriosus direction, and ventricular septum position also improved significantly. Treatment was not associated with postductal hypoxemia or systemic hypoperfusion. CONCLUSIONS: In patients with CDH and severe PH, PGE is well tolerated and associated with improved BNP and echocardiographic indices of PH, suggesting successful unloading of the RV. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: Level III. PMID- 30442462 TI - Hepatoportoenterostomy Surgery Technique. AB - Biliary atresia (BA) is a pathology that causes jaundice in children because of an obstruction of the biliary tract and, despite being considerate a rare disease, the incidence can reach 1/2400 live births on the Pacific region. The etiology is unknown until these days. If untreated, the progress of this condition leads to cirrhosis and death. The hepatoportoenterostomy associated with the liver transplant has completely changed the natural history of this disorder. The early operation (within 60 days after birth) is the most important prognostic factor of the Kasai portoenterostomy surgery. Up to 90% of the patients survive with a normal quality of live after the treatment of BA. PMID- 30442463 TI - Stochastic analysis of a heterogeneous micro-finite element model of a mouse tibia. AB - Finite element (FE) analysis can be used to predict bone mechanical environments that can be used for many important applications, such as the understanding of bone mechano-regulation mechanisms. However, when defining the FE models, uncertainty in bone material properties may lead to marked variations in the predicted mechanical environment. The aim of this study is to investigate the influence of uncertainty in bone material property on the mechanical environment of bone. A heterogeneous FE model of a mouse tibia was created from micro computed tomography images. Axial compression loading was applied, and all possible bone density-modulus relationships were considered through stochastic analysis. The 1st and 3rd principal strains (epsilon1 and epsilon3) and the strain energy density (SED) were quantified in the tibial volume of interest (VOI). The bounds of epsilon1, epsilon3, and SED were determined by the bounds of the density-modulus relationship; the bone mechanical environment (epsilon1, epsilon3, and SED) and the bone density-modulus relationship exhibit the same trend of change; the relative percentage differences caused by bone material uncertainty are up to 28%, 28%, and 21% for epsilon1, epsilon3, and SED, respectively. These data provide guidelines on the adoption of bone density modulus relationship in heterogeneous FE models. PMID- 30442464 TI - Nativity and Occupational Determinants of Physical Activity Participation Among Latinos. AB - INTRODUCTION: Latinos in the U.S. bear a disproportionate burden of cardiovascular risk factors, including physical inactivity. Previous research among Latinos has focused on leisure-time physical activity, limiting understanding of the different ways in which populations, particularly working class groups, achieve recommended levels of physical activity. This study examined associations of race/ethnicity; nativity; and leisure-time, transportation, and occupation-related physical activity among Latino and non Latino white adults. METHODS: Participants sampled in the 2007-2012 waves of the National Health and Nutrition Examination Survey self-reported domain-specific physical activity. Data were analyzed in 2016-2017 using multivariable log binomial regression models to examine differences in meeting guidelines for each physical activity domain separately and as total physical activity among Latinos (n=4,692) and non-Latino whites (n=7,788). Models were adjusted for sociodemographic characteristics and health status and tested interactions between nativity and occupational categories. RESULTS: In adjusted models, foreign-born Latinos (prevalence ratio=0.70, 95% CI=0.63, 0.77) and U.S.-born Latinos (prevalence ratio=0.85, 95% CI=0.76, 0.95) were least likely to meet physical activity guidelines through occupation-related and leisure time physical activity, when compared with non-Latino whites. By contrast, foreign-born Latinos were more likely to meet physical activity guidelines through transportation physical activity than non-Latino whites (prevalence ratio=1.26, 95% CI=1.01, 1.56) and were proportionately more likely to participate in vigorous modes of physical activity. Interaction results indicated that foreign-born Latinos were the least likely to meet physical activity guidelines compared with U.S.-born Latinos and non-Latino whites if they worked in non-manual occupational categories. All racial/ethnic groups working in manual occupations saw the largest increase (40%-50%) in meeting physical activity guidelines when occupation-related physical activity was combined with leisure-time and transportation physical activity. CONCLUSIONS: These findings suggest variability in the relationship between nativity and the physical activity domain Latinos engage in compared with non-Latino whites, with occupation contributing substantially to meeting physical activity recommendations for all population groups. PMID- 30442465 TI - Risk factors associated with postoperative prosthetic graft patency in Leriche syndrome. AB - BACKGROUND: In Leriche syndrome, postoperative graft thrombosis remains one of the most significant clinical challenges. METHODS: We reviewed 51 patients who underwent surgery for aortoiliac occlusive disease at our hospital from January 2007 to December 2014. The factors associated with graft patency were determined using the Cox proportional hazard model. RESULTS: The 2-year prosthetic graft patency rate was 72.5%. Younger age (p = 0.017, Odd ratio (OR) = 1.112), postoperative uncontrolled hypertension (p = 0.044, OR = 3.797), and associated Trans Atlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease II (TASC II) D femoropopliteal lesion (p = 0.008, OR = 11.139) were significantly related factors for prosthetic graft patency after surgical repair. The existing comorbidities of the patients that indicated the need for axillo bifemoral bypass seemed to be related to lower graft patency or other complications. CONCLUSIONS: For better graft patency after an open surgical repair of Leriche syndrome, strict postoperative hypertension control and distal run-off resolution are necessary. PMID- 30442466 TI - Letter to the Editor on "The Role of Perioperative Statin Use in the Prevention of Delirium After Total Knee Replacement Under Spinal Anesthesia". PMID- 30442467 TI - Piriformis-Sparing Minimally Invasive Versus the Standard Posterior Approach for Total Hip Arthroplasty: A 10-Year Follow-Up of a Randomized Control Trial. AB - BACKGROUND: Despite the popularity of minimally invasive approaches in total hip arthroplasty, studies regarding their impact on soft tissues and long-term benefits are lacking. This study aims to compare the 10-year functional outcome of the piriformis-sparing minimally invasive approach to the standard posterior approach for total hip arthroplasty surgery. METHODS: Hundred patients were randomized, 48 patients to the piriformis-sparing approach and 52 to the standard approach. Primary outcomes were hip function and piriformis muscle volume and grade on magnetic resonance imaging. Secondary outcomes were pain, satisfaction score, and complications. Evaluators were blinded to allocation. Participants were followed up to 10 years. RESULTS: Ten years following surgery, both groups reported excellent pain relief, improved hip function, and high satisfaction. The significant differences were improvement in piriformis muscle volume (P = .001) and muscle grade (P = .007) in the piriformis-sparing group compared to the standard group. There were no significant differences in all other outcomes. CONCLUSION: Aside from being less injurious to the piriformis muscle, the piriformis-sparing approach offered the same long-term functional benefits as the standard posterior approach at 10 years. PMID- 30442468 TI - Changes to country-specific hepatitis A travel vaccination recommendation for UK travellers in 2017-responding to a vaccine shortage in the national context. AB - OBJECTIVES: A routine review of hepatitis A travel vaccination recommendations was brought forward in June 2017 due to hepatitis A vaccine shortages and a concurrent outbreak in men who have sex with men (MSM). There were three objectives: first, to document the review process for changing the recommendations for the UK travellers in June 2017. Second, to study the impact of these changes on prescribing in general practice in 2017 compared with the previous 5 years. Third, to study any changes in hepatitis A notifications in June-October 2017 compared with the previous 5 years. STUDY DESIGN: This is an observational study. METHODS: Travel vaccination recommendations for countries with either low-risk (<20%) or high-risk (>90%) status according to child hepatitis A seroprevalence were not changed. A total of 67 intermediate-risk countries with existing recommendations for most travellers and with new data on rural sanitation levels were shortlisted for the analysis. Data on child hepatitis A seroprevalence, country income status, access to sanitation in rural areas and traveller volumes were obtained. Information about the vaccine supply was obtained from Public Health England. Changes to the existing classification were made through expert consensus, based on countries' hepatitis A seroprevalence, sanitation levels, level of income, volume of travel and hepatitis A traveller cases. Data on the number of combined and monovalent hepatitis A-containing vaccines prescribed in England, 2012-2017, were obtained from the National Health Service Business Service Authorities. The number of monthly prescriptions for January-September 2017 was compared with the mean number of prescriptions for the same month in the previous 5 years (t-test, alpha = 5%, df = 4). The number of hepatitis A cases notified in June-October 2017 not related to the MSM outbreak was compared with the number of notifications in the same months in previous years. RESULTS: A total of 36 countries were downgraded based on good access (80+% of population) to sanitation in rural areas and the intermediate-risk status in terms of child hepatitis A seroprevalence. For these countries, vaccination would only be recommended to travellers staying long term, visiting friends and relatives or staying in areas without good sanitation. There was a significant decline in hepatitis A vaccine prescriptions in June-September 2017, and there was no increase in the number of notifications. CONCLUSIONS: Hepatitis A vaccination recommendations for travel were revised in 2017 following a systematic approach to maintain continuity of supply after a hepatitis A vaccine shortage and increased hepatitis A vaccine demand related to a large outbreak. Improved access to good sanitation in rural areas and low seroprevalence estimates among children have led to 36 countries to no longer require vaccination for most travellers. These changes do not seem to have impacted on hepatitis A notifications in England, although further research will be needed to quantify the impact more precisely. PMID- 30442469 TI - Factors in cattle affecting embryo transfer pregnancies in recipient animals. AB - The use of embryo transfer (ET) in cattle is important for profitability and improved genetic gains. The advent of the commercial embryo collection and transfer industry has led to advancements in multiple techniques and practices. Specific variables, however, have historically affected pregnancy rates but an understanding of the magnitude of these effects in the current industry is limited. Transfer location (cranial, middle, or caudal third of the uterine horn ipsilateral to the ovary with a CL), transfer score (range of 1-3 with 1 being excellent and 3 poor, based on difficulty of accessing the site of embryo deposition), and amount of time to complete a transfer, therefore, were recorded. These variables were collected in a setting designed to mimic commercial production practices as well as exaggerated time (due to data collection) to assess effects on pregnancy rates. Fresh and frozen in vivo-derived embryos (n = 256) from Bos taurus cows were transferred to Bos taurus recipients. There tended to be more pregnancies when embryos were deposited in the cranial part of the uterus (P = 0.08) compared to the middle and caudal third of the uterus. With a lesser degree of difficulty in transfers (score 1), there tended to be more pregnancies established (P = 0.07). When lesser time was needed for transferring embryos and collecting data, there were greater pregnancy rates (P = 0.03). Thus, these traditionally accepted variables of influence (site of embryo placement in uterus, difficulty, and time) continue to influence ET pregnancy success. PMID- 30442470 TI - Analyzing hedyotis diffusa mechanisms of action from the genomics perspective. AB - BACKGROUND AND OBJECTIVE: Hedyotis diffusa is an herb used for anti-cancer, anti oxidant, anti-inflammatory, and anti-fibroblast treatment in the clinical practice of Traditional Chinese Medicine. However, its pharmacological mechanisms have not been fully established and there is a lack of modern scientific verification. One of the best ways to further understand Hedyotis diffusa's mechanisms of action is to analyze it from the genomics perspective. METHODS: In this study, we used network pharmacology approaches to infer the herb-gene interactions, the herb-pathway interactions, and the gene families. We then analyzed Hedyotis diffusa's mechanisms of action using the genomics context combined with the Traditional Chinese Medicine clinical practice and the pharmacological research. RESULTS: The results obtained in the pathway and gene family analysis were consistent with the Traditional Chinese Medicine clinical experience and the pharmacological activities of Hedyotis diffusa. CONCLUSIONS: Our approach can identify related genes and pathways correctly with little a priori knowledge, and provide potential directions to facilitate further research. PMID- 30442471 TI - Propanol - Sugar aqueous biphasic systems as a suitable platform for biomolecules extraction. AB - Aiming at designing efficient extraction processes, this work proposes the novel aqueous biphasic systems (ABS) composed of sugars and alcohols. The complete liquid-liquid phase diagrams (binodal curves and tie-lines) for several ternary systems of {water + 1-propanol / 2-propanol + sugar (mono- and di-saccharides, and their polyols)} were determined, for the first time. The main factors which affect the phase separation ability of these systems, such as temperature, structure and stereochemistry of sugars, and the alcohol type were discussed. In all the studied ABS, the top phase is alcohol-rich with lower water content, while the bottom phase is sugar-rich with higher water content. The partitioning behavior of two alkaloids (caffeine and codeine) and a flavoring antioxidant (vanillin) in the produced ABS was evaluated. In all the partitioning experiments, caffeine and vanillin have a preferable tendency to concentrate in the more hydrophobic alcohol-rich phase, however, codeine preferentially migrate to the more hydrophilic sugar-rich phase. The selectivity index of the alcohol sugar ABS to separate compounds of the same family (caffeine and codeine) was calculated and found to be higher than 25 at optimum conditions. In general, the more soluting-out ability of sugars, the more difference in the water content of the coexisting phases, and the longer tie-line length lead to the better extraction performance of the propanol-sugar ABS. Heating has a favorable effect on the preferential partitioning of caffeine and codeine, but it is unfavorable for extraction of vanillin. From the results gathered, the novel ABS produced in this work provide efficient and money-saving extraction platforms, and can selectively separate similar biomolecules. PMID- 30442472 TI - Metal organic frameworks-derived magnetic nanoporous carbon for preconcentration of organophosphorus pesticides from fruit samples followed by gas chromatography flame photometric detection. AB - In this work, magnetic nanoporous carbons (MNPCs) based on Zn/Co-MOFs was synthesized via a facial one-step carbonization method. The prepared MNPCs exhibited high specific surface areas, good chemical stability and high extraction efficiency for interest organophosphorus pesticides (OPPs). The good extraction performance of the MNPCs for interest OPPs can be primarily attributed to pi-pi interaction and hydrophobic interaction between MNPCs and OPPs. Based on it, MNPCs-based MSPE-GC-FPD method was established for the quantification of five OPPs in fruit samples. The main experimental conditions for MSPE of five target OPPs were investigated systematically and optimized, such as the desorption solvent and volume, extracted volume, ionic strength, extraction time and desorption time. Under the optimal conditions, the limits of detection (LODs, S/N = 3) were found to be in the range of 0.018 (ethion) -0.045 (malathion) MUg/L. The linearity was 0.05-100 MUg/L for phorate, diazinon, ethion and 0.1-100 MUg/L for malathion, fenthion respectively. The reproducibility of the method was in the range of 3.5-9.7%. The recovery experiments were carried out by spiking target OPPs at three concentration levels to validate the accuracy of the proposed method, and the recoveries for target OPPs were 84-116%. The results show that the proposed method in this work can be successfully used to analyze OPPs residue in fruit sample. PMID- 30442473 TI - Simultaneous determination of dietary isoprenoids (carotenoids, chlorophylls and tocopherols) in human faeces by Rapid Resolution Liquid Chromatography. AB - An analytical method was validated for the quantitative determination of isoprenoids compounds in faecal samples, based on liquid-liquid extraction from a small aliquot (0.3-0.5 g of sample) and subsequent analysis by Rapid Resolution Liquid Chromatography (RRLC) on a C30 column. An excellent linear response was observed over the range specified for all dietary isoprenoids, as confirmed by the correlation coefficient, which ranged from 0.9977 to 0.9999. LODs ranged from 0.002 MUg to 0.036 MUg for lutein and alpha-tocopherol, respectively. Depending on the compound, LOQs ranged from 0.001 MUg (lutein) to 0.120 MUg (alpha tocopherol). For accuracy testing, spiking of faeces samples with trans-beta-apo 8'-carotenal, alpha-tocopherol and chlorophyll a were performed (three concentration levels). Excellent recoveries were obtained in all levels (>90%). The intra-day RSD% ranged from 0.86 to 9.78%. The inter-day RSD% was not higher than 10%, except to alpha-tocopherol (11.34%). In order to assess the applicability of the method faecal samples from a baby fed with different purees formulated from various vegetables were analysed during a six month period. alpha carotene, beta-carotene, capsanthin, lycopene, lutein, phytoene, phytofluene, violaxanthin, zeaxanthin and zeta-carotene), and their isomers were identified and quantified using this method. Besides, 2 tocopherols and 9 chlorophylls and derivatives were identified and quantified in the faecal samples analysed. This method is suitable to determine dietary isoprenoids from complex matrices such as human faeces within 28 min. PMID- 30442474 TI - The effect of increasing centrifugal acceleration/force and flow rate for varying column aspect ratios on separation efficiency in Counter-Current Chromatography. AB - Increasing column/tubing aspect ratio has been shown in a feasibility study to improve column efficiency when operating in reversed phase mode. This paper contains a thorough investigation on how increases in mobile phase flow and centrifugal force field affect stationary phase retention and column efficiency (as measured by the resolution between adjacent peaks) for columns wound with rectilinear tubing of different aspect ratio. The study uses a Mini CCC instrument operating from 1500 to 2100 rpm (126-246 g) to compare three columns with the same cross-sectional area but different aspect ratio - rectangular horizontal (force field perpendicular to the flat side - aspect ratio 3.125); square (aspect ratio 1.0) and rectangular vertical (flat side parallel with force field - aspect ratio 0.32). Columns are compared by measuring stationary phase retention, resolution and normalized resolution for 3 different mobile phase flow rates 2, 4 and 8 ml/min in both normal phase and reversed phase modes. The results with rectilinear tubing are compared to conventional circular tubing with the same cross-sectional area. The results show that resolution increases with aspect ratio and that at the highest aspect ratio the highest flow rate can maintain a high efficiency only if the highest g-field of 246 g is used. When comparing the rectangular horizontal tubing which gave the best results with conventional circular tubing with the same cross-sectional area a 45% improvement was found in reversed phase mode and a 51% improvement in normal phase mode over the conventional circular cross-section tubing. In other words, a rectangular horizontally wound bobbin with half the length of tubing can achieve the same result as a circular one. These are very significant results for halving separation times analytically or enabling designers to produce new instruments of the same capacity with a much-reduced size. PMID- 30442475 TI - Critical period plasticity-related transcriptional aberrations in schizophrenia and bipolar disorder. AB - Childhood critical periods of experience-dependent plasticity are essential for the development of environmentally appropriate behavior and cognition. Disruption of critical periods can alter development of normal function and confer risk for neurodevelopmental disorders. While genes and their expression relevant to neurodevelopment are associated with schizophrenia, the molecular relationship between schizophrenia and critical periods has not been assessed systematically. Here, we apply a transcriptome-based bioinformatics approach to assess whether genes associated with the human critical period for visual cortex plasticity, a well-studied model of cortical critical periods, are aberrantly expressed in schizophrenia and bipolar disorder. Across two dozen datasets encompassing 522 cases and 374 controls, we find that the majority show aberrations in expression of genes associated with the critical period. We observed both hyper- and hypo critical period plasticity phenotypes at the transcriptome level, which partially mapped to drug candidates that reverse the disorder signatures in silico. Our findings indicate plasticity aberrations in schizophrenia and their treatment may need to be considered in the context of subpopulations with elevated and others reduced plasticity. Future work should leverage ongoing consortia RNA-sequencing efforts to tease out the sources of plasticity-related transcriptional aberrations seen in schizophrenia, including true biological heterogeneity, interaction between normal development/aging and the disorder, and medication history. Our study also urges innovation towards direct assessment of visual cortex plasticity in humans with schizophrenia to precisely deconstruct the role of plasticity in this disorder. PMID- 30442476 TI - Reward-driven decision-making impairments in schizophrenia. AB - The ability to use feedback to guide optimal decision-making is essential for goal-directed behaviour. While impairments in feedback-driven decision-making have been associated with schizophrenia and depression, this has been examined primarily in the context of binary probabilistic choice paradigms. In real-world decision-making, however, individuals must make choices when there are more than two competing options that vary in the frequency and magnitude of potential rewards and losses. Thus, the current study examined win-stay/lose-shift (WSLS) behaviour on the Iowa Gambling Task (IGT) in order to evaluate the influence of immediate rewards and losses in guiding real-world decision-making in patients with schizophrenia and major depressive disorder. Fifty-one patients with schizophrenia, 43 patients with major depressive disorder, and 51 healthy controls completed the IGT, as well as a series of clinical and cognitive measures. WSLS was assessed by quantifying trial-by-trial behaviour following rewards and losses on the IGT. Multivariate analyses of variance revealed that patients with schizophrenia demonstrated intact lose-shift behaviour, but significantly reduced win-stay rates compared to healthy controls. In contrast, no WSLS impairments emerged in the depressed group. Win-stay impairments in the schizophrenia group were significantly related to deficits in motivation and cognition. Patients with schizophrenia exhibit impaired reward-driven decision making in the context of multiple choices with concurrent rewards and losses, and this appears to be driven by a reduced propensity for advantageous win-stay behaviour. With the importance of reward learning and decision-making in generating goal-directed behaviour, these findings suggest a potential mechanism contributing to the motivation deficits seen in schizophrenia. PMID- 30442477 TI - Psychotic like experiences as part of a continuum of psychosis: Associations with effort-based decision-making and reward responsivity. AB - Research examining psychotic disorders typically involves comparison between individuals with a clinical disorder and healthy controls. However, research suggests that psychotic symptoms, such as delusions and hallucinations, may exist on a continuum ranging from variation in healthy individuals to diagnosable psychotic disorders. On this continuum, some individuals endorse occasional psychotic like experiences (PLEs) that do not cause sufficient impairment or distress to warrant a clinical diagnosis. Given this continuum model, one might expect to observe impairments in those with PLEs in the same behavioral domains impaired in schizophrenia. Thus, we examined two domains typically impaired in schizophrenia, effort allocation and reward responsivity, in a large university sample (n = 126). Participants completed tasks assessing effort-based decision making, reward responsivity, and questionnaires assessing PLEs. Greater PLEs were associated with greater effort expenditure regardless of probability of receiving a reward or reward value. Higher PLEs were related to greater positive feelings when receiving rewards. Importantly, these relationships remained the same when controlling for other symptoms such as depression, anhedonia, and anxiety. These findings suggest that PLEs may be associated with hypersensitivity to reward at the less severe end of the psychotic continuum, with effort to attain a reward expended in a potentially inefficient manner. This pattern is consistent with models of hyperdopaminergic states in psychotic individuals not taking antipsychotic medications, given the role of dopamine in modulating effort allocation and reward anticipation. PMID- 30442478 TI - A systematic review of therapist effects: A critical narrative update and refinement to review. AB - OBJECTIVE: To review the therapist effects literature since Baldwin and Imel's (2013) review. METHOD: Systematic literature review of three databases (PsycINFO, PubMed and Web of Science) replicating Baldwin and Imel (2013) search terms. Weighted averages of therapist effects (TEs) were calculated, and a critical narrative review of included studies conducted. RESULTS: Twenty studies met inclusion criteria (3 RCTs; 17 practice-based) with 19 studies using multilevel modeling. TEs were found in 19 studies. The TE range for all studies was 0.2% to 29% (weighted average = 5%). For RCTs, 1%-29% (weighted average = 8.2%). For practice-based studies, 0.2-21% (weighted average = 5%). The university counseling subsample yielded a lower TE (2.4%) than in other groupings (i.e., primary care, mixed clinical settings, and specialist/focused settings). Therapist sample sizes remained lower than recommended, and few studies appeared to be designed specifically as TE studies, with too few examples of maximising the research potential of large routine patient datasets. CONCLUSIONS: Therapist effects are a robust phenomenon although considerable heterogeneity exists across studies. Patient severity appeared related to TE size. TEs from RCTs were highly variable. Using an overall therapist effects statistic may lack precision, and TEs might be better reported separately for specific clinical settings. PMID- 30442479 TI - Oral polio vaccine response in the MAL-ED birth cohort study: Considerations for polio eradication strategies. AB - BACKGROUND: Immunization programs have leveraged decades of research to maximize oral polio vaccine (OPV) response. Moving toward global poliovirus eradication, the WHO recommended phased OPV-to-IPV replacement on schedules in 2012. Using the MAL-ED prospective birth cohort data, we evaluated the influence of early life exposures impacting OPV immunization by measuring OPV response for serotypes 1 and 3. METHODS: Polio neutralizing antibody assays were conducted at 7 and 15 months of age for serotypes 1 and 3. Analyses were conducted on children receiving >=3 OPV doses (n = 1449). History of vaccination, feeding patterns, physical growth, home environment, diarrhea, enteropathogen detection, and gut inflammation were examined as risk factors for non-response [Log2(titer) < 3] and Log2(titer) by serotype using multivariate regression. FINDINGS: Serotype 1 seroconversion was significantly higher than serotype 3 (96.6% vs. 89.6%, 15 months). Model results indicate serotypes 1 and 3 failure was minimized following four and six OPV doses, respectively; however, enteropathogen detection and poor socioeconomic conditions attenuated response in both serotypes. At three months of age, bacterial detection in stool reduced serotype 1 and 3 Log2 titers by 0.34 (95% CI 0.14-0.54) and 0.53 (95% CI 0.29-0.77), respectively, and increased odds of serotype 3 failure by 3.0 (95% CI 1.6-5.8). Our socioeconomic index, consisting of Water, Assets, Maternal education, and Income (WAMI), was associated with a 0.79 (95% CI 0.15-1.43) and 1.23 (95% CI 0.34-2.12) higher serotype 1 and 3 Log2 titer, respectively, and a 0.04 (95% CI 0.002-0.40) lower odds of serotype 3 failure. Introduction of solids, transferrin receptor, and underweight were differentially associated with serotype response. Other factors, including diarrheal frequency and breastfeeding practices, were not associated with OPV response. INTERPRETATION: Under real-world conditions, improved vaccination coverage and socio-environmental conditions, and reducing early life bacterial exposures are key to improving OPV response and should inform polio eradication strategies. PMID- 30442481 TI - Botulinum toxin for Pisa syndrome: An MRI-, ultrasound- and electromyography guided pilot study. AB - INTRODUCTION: Pisa syndrome is a disabling, medication-resistant, postural abnormality that may affect 7-10% of patients with Parkinson's disease. In this study, we sought to assess the efficacy of botulinum toxin injections in Parkinson's disease-associated Pisa syndrome using a Magnetic Resonance Imaging-, Ultrasonography-, and Electromyography-guided combined approach. METHODS: We conducted a pilot study to evaluate the efficacy of botulinum toxin type-A injection in paraspinal and non-paraspinal axial muscles after a Magnetic Resonance Imaging and ultrasound-guided electromyography evaluation. Inclusion criteria were Pisa syndrome, idiopathic Parkinson's disease, and stable dopaminergic medications. Exclusion criteria were previous treatment with botulinum toxin, history of major spine surgery, and severe orthopedic diseases. As primary endpoint, we measured the rate of patients improving by at least 5 degrees in the lateral trunk flexion 2 months after therapy. Secondary endpoints were the extent of lateral trunk flexion improvement, and changes in PS associated pain/discomfort, measured by the Visual Analogue Scale. RESULTS: Out the 15 patients initially enrolled, 13 completed the follow-up assessment, while 2 joined a rehabilitation program and were excluded from the analyses. The rate of responders was 84.6% (n = 11/13), with 40% average reduction in trunk bending. Pain/discomfort improved in all patients, with 52.2% amelioration at the Visual Analogue Scale. The procedure was well tolerated in all cases, without side effects or complications. CONCLUSION: A combined imaging and EMG botulinum toxin approach to Pisa syndrome may yield a success rate greater than 80% in Parkinson's disease. PMID- 30442480 TI - Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection. AB - Vaccination is an effective strategy to prevent pneumococcal diseases. Currently, licensed vaccines include the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV), which target some of the most common of the 94 serotypes of S. pneumoniae based on their capsular composition. However, it has been reported that PPSV is not effective in children aged less than 2 years old and PCV induces serotype replacement, which means that the pneumococcal population has changed following widespread introduction of these vaccines, and the non-vaccine serotypes have increased in being the cause of invasive pneumococcal disease. Therefore, it is important that there is development of novel pneumococcal vaccines to either replace or complement current polysaccharide-based vaccines. Our previous study suggested that S. pneumoniae releases elongation factor Tu (EF-Tu) through autolysis followed by the induction of proinflammatory cytokines in macrophages via toll-like receptor 4, that may contribute to the development of pneumococcal diseases. In this study, we investigated the expression of EF-Tu in various S. pneumoniae strains and whether EF-Tu could be an antigen candidate for serotype-independent vaccine against pneumococcal infection. Western blotting and flow cytometry analysis revealed that EF-Tu is a common factor expressed on the surface of all pneumococcal strains tested, as well as intracellularly. In addition, we demonstrate that immunization with recombinant (r) EF-Tu induced the production of inflammatory cytokines and the IgG1 and IgG2a antibodies in mice, and increased the CD4+ T cells proportion in splenocytes. We also reveal that anti-EF-Tu serum increased the phagocytic activity of mouse peritoneal macrophages against S. pneumoniae infection, independent of their serotypes. Finally, our results indicate that mice immunized with rEF-Tu were significantly and non-specifically protected against lethal challenges with S. pneumoniae serotypes (2 and 15A). Therefore, pneumococcal EF-Tu could be an antigen candidate for the serotype-independent vaccine against pneumococcal infection. PMID- 30442482 TI - [Management of a tracheal adenoid cystic medico-surgical carcinoma]. AB - Adenoid cystic carcinoma or cylindroma is a rare tumor of the trachea which arises from mucous secreting cells. Its evolution and growth are slow but it is often fatal in the absence of radical treatment. The latter relies on a surgical sleeve resection of the pathological area, with a tracheo-tracheal anastomosis. Therapeutic bronchoscopy plays a crucial role in the clinical improvement of patients before surgery which will be performed under better conditions. For inoperable patients, radiotherapy has proved its efficacy, unlike conventional chemotherapy. The finding of biomarkers expressed by tumor cells could lead to target therapies. This case report illustrates the efficient combination of therapeutic bronchoscopy and surgery for the treatment of adenoid cystic carcinoma affecting central airways. PMID- 30442483 TI - Introduction to part two of a three-part theme on hereditary bleeding disorders. PMID- 30442484 TI - Barriers to adopt the Health Promoting Hospitals (HPH) initiative in Iran: The Q method derived perspectives of front line practitioners. AB - OBJECTIVE: This study aimed to investigate prospects of a sample of Iranian front line health care professionals about their perceived barriers to implement the HPH initiative. METHODS: The six stages Q methodology was applied to systematically envisage divergent perspectives of the 33 health professionals (7 physicians, 2 managerial and 24 nurses) working in the 10 educational hospitals in Iran. RESULTS: Analysis of the study participants' viewpoints (the Q-sorts) resulted in a five factor solution (accounted for 48% of the total variance) to endorse main barriers of the HPH implementation in the typical Iranian hospitals. The health professionals' dominant biomedical approach and their deficit commitment to health promotion programs, inappropriate decision-making mechanisms and insufficiency of the organizational infrastructure in the Iranian national health system (INHS) were among the important emanated factors to sustainably maintain the HPH program. CONCLUSION: The identified barriers reflect the spheres that need to be focused in interventions to facilitate the successful implementation of the HPH initiative in Iran and other developing countries. PRACTICE IMPLICATIONS: Despite the existent consensus about overall merits of the HPH to fulfill best interests of hospitalized patients, major challenges deems to exist for operability of this beneficial undertaking in Iran. PMID- 30442485 TI - [Efficiency of the acute geriatric units compared to the rest of the hospital departments. A 5-year audit of the case-mix adjusted for diagnosis-related group]. AB - INTRODUCTION: Hospital occupancy rate by older patients is high, and it will be even higher in the future. Their hospital stay is usually longer, making it important for hospitals to develop structures with the best efficiency possible. METHOD: Hospital discharges of patients older than 75years with the 15 most frequent Diagnosis-Related Groups (DRG) in Geriatrics were recorded during a 5 year period in a 1,200-bed hospital. Length of stay was compared between the two acute geriatric units (AGU), one in the general hospital (GH) and another in an affiliate hospital (AH), as well as with the rest of departments. RESULTS: A total of 14,948 discharged patients were included. Length of stay was 2.9 (25%) days shorter in AGU units than in the rest of departments. Differences were 22% (9.2 vs 11.7days) in 2011, 16% (9.3 vs 11.1days) in 2012, 21% (9.3 vs 11.1days) in 2013, 34% (7.4 vs 11.1days) in 2014, and 25% (8.3 vs 11days) in 2015 in the GH. Differences were 18% (10.4 vs 12.7days) in 2011, 19% (9.5 vs 11.7days) in 2012, 25% (8.8 vs 11.7days) in 2013, 24% (8.8 vs 11.6days) in 2014, and 32% (9 vs 13.1days) in 2015 at the AH, all of them with a P<.05. CONCLUSIONS: AGU are 25% more efficient than the rest of hospital departments in managing hospital admissions of patients older than 75years. PMID- 30442486 TI - Screening for retinopathy of prematurity by telemedicine in a tertiary level neonatal intensive care unit in France: Review of a six-year period. AB - PURPOSE: To analyze the prevalence and risk factors for retinopathy of prematurity (ROP) and severe (treatment-requiring) ROP. METHODS: A retrospective study was conducted in a level III neonatal unit in Bordeaux, France, from 2009 to 2015. Four hundred and nineteen preterm infants who were screened for ROP exclusively by RetCam were included. RESULTS: ROP of any degree was diagnosed in 27.68% of infants. Stages 1, 2, 3 and 4 ROP was found in 44%, 46%, 9% and 1% of subjects, respectively. No stage 5 ROP was observed. 28/419 infants (6.6%) were treated exclusively with laser photocoagulation. No intravitreal anti-VEGF injections or surgical treatments were performed. No infants born at>31 weeks or with BW>1110g required ROP treatment. On multivariate analysis, risk factors for ROP development were low birth weight, low gestational age at birth, high duration of invasive mechanical ventilation, shock or use of vasopressors. On multivariate analysis, risk factors for severe, treatment-requiring ROP were male gender, gestational age<=27 weeks and Apgar score at 5minutes<=7. CONCLUSION: In our 6-year series, ROP was successfully identified on screening exclusively by telemedicine, and no surgical treatment was required. This study identifies known ROP risk factors, but the Apgar score at 5minutes as a risk factor for severe ROP requires further studies in order to be confirmed. PMID- 30442487 TI - Ligneous conjunctivitis due to plasminogen deficit: Diagnostic and therapeutic approach. With literature review. AB - Ligneous conjunctivitis is a rare and poorly understood pathology. Infections and repeated microtraumas are often involved in acute disease flare-ups. This masquerade may lead to misdiagnosis and delayed treatment. We report two cases of ligneous conjunctivitis, describing various presentations of its natural history and focusing on the treatment of this rare disease. PMID- 30442488 TI - Advanced proliferative diabetic retinopathy during pregnancy. PMID- 30442489 TI - [Anatomical and functional results of macular hole surgery using a temporal inverted internal limiting membrane flap. Experience with 24 cases]. AB - PURPOSE: To evaluate the anatomical and functional outcomes of macular hole (MH) surgery with a temporal inverted internal limiting membrane (ILM) flap technique. METHODS: Monocentric retrospective study of 24 patients who were operated on for macular hole between March 2014 and April 2017 at Nancy University Hospital. All patients underwent pars plana vitrectomy with the inverted ILM flap technique. ILM peeling was restricted to the temporal side of the fovea, and the macular hole was then covered with the ILM flap, followed by SF6 tamponnade and first day face-down positioning. The main outcome measures included macular hole closure rate and visual acuity at 1 month postoperatively. RESULTS: Eight men and 16 women of mean age 67.0+/-5.4 years were included. The mean axial length was 23.5+/-1.2mm. The mean diameter of the MH was 362+/-123MUm. Closure of the MH was achieved in 23 of 24 eyes (95.8%) after one surgery. The mean BVCA improved significantly from 0.71+/-0.20 logMar to 0.29+/-0.22 logMar (P<0.001) at 1 month postoperatively, for a gain of 0.42+/-0.24 logMar. CONCLUSION: Macular hole surgery with the inverted ILM flap technique results in good anatomical and functional outcomes, comparable to those obtained with the classic technique with complete ILM peeling. PMID- 30442490 TI - [Iridoschisis]. PMID- 30442491 TI - Pseudomonas aeruginosa colonization causes PD-L1 overexpression on monocytes, impairing the adaptive immune response in patients with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is an endotoxin tolerance (ET)-related disease. Given that increased PD-L1 has been reported in ET, its expression and physiological effects on cystic fibrosis monocytes should be studied. METHODS: We analyzed the phenotype and ex vivo response of immune system cells in 32 patients with CF, 19 of them colonized by Pseudomonas aeruginosa. An in vitro model was developed of Pseudomonas aeruginosa colonization using purified lipopolysaccharides (LPS) from one of the most prevalent strains in patients with CF (a CF-adapted Pseudomonas aeruginosa ST395 clone). Changes in the immune response, including cytokine production and T-lymphocyte proliferation, as well as expression of PD-L1, were evaluated. RESULTS: PD-L1 was overexpressed in the monocytes of patients with CF compared with healthy volunteers, and levels of this immune checkpoint were associated with Pseudomonas aeruginosa colonization. In addition, patients with Pseudomonas aeruginosa colonization showed a patent ET status, including poor inflammatory response, reduced HLA-DR expression and T lymphocyte proliferation impairment. PD-L1/PD-1 blocking assays reverted the impaired adaptive response. Ultimately, monocytes from healthy volunteers cultured in the presence of the clinically relevant strain of Pseudomonas aeruginosa or serum collected from patients with CF colonized by Pseudomonas aeruginosa reproduced the previous observed features. CONCLUSIONS: Pseudomonas aeruginosa colonization in patients with CF was associated with PD-L1 overexpression and impaired T cell response, and LPS from this pathogen induced the observed phenotype. Our findings open new avenues for the use of anti-PD-1/PD L1 immunotherapy in patients with CF who are colonized by Pseudomonas aeruginosa. PMID- 30442492 TI - Role of Iterative Reconstruction Algorithm for the Assessment of Myocardial Infarction with Dual Energy Computed Tomography. AB - RATIONALE AND OBJECTIVES: Low monochromatic energy levels (40 keV) derived from delayed enhancement dual energy cardiac computed tomography (DE-DECT) allow the evaluation of myocardial infarcts (MI) among stable patients, although at the expense of high image noise. We explored whether the application of adaptive statistical iterative reconstruction (ASIR) to 40-keV DE-DECT (unavailable with previous software versions) might improve image quality and detection of MI in stable patients. MATERIALS AND METHODS: We prospectively enrolled patients with a history of previous MI, and performed delayed-enhancement cardiac magnetic resonance (DE-CMR) and DE-DECT within the same week. DE-DECT images were reconstructed with 0% and 60% ASIR. RESULTS: MI was identified in 18 (80%) patients with both DE-CMR and DE-DECT. On a per segment basis, we did not identify significant differences regarding the diagnostic performance of DE-DECT with and without ASIR [area under receiver operating characteristic curve 0.86 vs. 0.83, p = 0.10]. The application of ASIR improved the signal-to-noise ratio of DE-DECT with 0% ASIR compared to DE-DECT with 60% ASIR (6.07 +/- 2.1 vs. 11.1 +/- 4.5, p < 0.0001). However, qualitative assessment of MI image quality (3.35 +/- 1.2, vs. 3.55 +/- 1.1, p = 0.10) and diagnostic confidence (4.40 +/- 0.9 vs. 4.60 +/- 0.8, p = 0.10) were not significantly improved. Using DE-DECT with 60% ASIR, a threshold over 199 HU showed a sensitivity of 67% and a specificity of 92% for the detection of segments with MI. CONCLUSION: In this study, DE-DECT allowed accurate detection of MI among stable patients compared with DE-CMR, and the application of ASIR improved signal-to-noise ratio of DE-DECT, although the diagnostic performance showed only non-significant improvements. PMID- 30442493 TI - Representation of Women on Radiology Journal Editorial Boards: A 40-Year Analysis. AB - RATIONALE AND OBJECTIVES: We examined female representation on editorial boards of four prominent radiology journals. We compared editorial board representation to female academic radiology career advancement and the proportion of female authorship in three journals over four decades. METHODS: We collected data on the gender of editorial board members as listed on mastheads of Radiology, American Journal of Roentgenology (AJR), Academic Radiology, and the Journal of the American College of Radiology in 5-year intervals plus the most recent year available (1973-2017), and the gender of their editors-in-chief for all years since each journal's inception. We compared Radiology, AJR, and Academic Radiology data to published data on gender of the journals' authors, all US medical students, and academic radiologists over time. RESULTS: Gender was determined for 171 editors-in-chief (100%) and 2139 (100%) editorial board members listed in the selected journals for each of the study years. The proportion of women on editorial boards increased from 1.4% (1 of 69) in 1978 to 18.8% (73 of 388) in 2013 (P < .001), but remained below the proportion of female first authors (7.5% in 1978 and 27.1% in 2013) and female faculty in radiology (11.5% in 1978 and 28.1% in 2013). None of the four general radiology journals had a female editor-in-chief during the study period. CONCLUSIONS: Female representation on editorial boards has increased over time, but still lags behind increases seen in female first authorship in radiology journals and radiology faculty appointments over the last four decades. There was no female editor-in chief during the study period. PMID- 30442494 TI - Inflammation and Hypoxia: HIF and PHD Isoform Selectivity. AB - Cells sense and respond to hypoxia through the activity of the transcription factor HIF (hypoxia-inducible factor) and its regulatory hydroxylases, the prolyl hydroxylase domain enzymes (PHDs). Multiple isoforms of HIFs and PHDs exist, and isoform-selective roles have been identified in the context of the inflammatory environment, which is itself frequently hypoxic. Recent advances in the field have highlighted the complexity of this system, particularly with regards to the cell and context-specific activity of HIFs and PHDs. Because novel therapeutic agents which regulate this pathway are nearing the clinic, understanding the role of HIFs and PHDs in inflammation outcomes is an essential step in avoiding off target effects and, crucially, in developing new anti-inflammatory strategies. PMID- 30442495 TI - Toxic Protein Spread in Neurodegeneration: Reality versus Fantasy. AB - Over the past decade, the importance of the propagation of amyloidogenic proteins such as alpha-synuclein and tau in the pathogenesis of neurodegenerative diseases has been supported by numerous neuropathological and experimental studies. While these proteins behave similarly to prions, recent evidence suggests the existence of fundamental differences, as they can propagate in the absence of endogenous template, they do not exhibit a strict 'strain' behavior, and they may not be transmissible between individuals. We therefore propose to name these proteins 'prionoids'. In this review we critically assess the extent of the overlap between these two entities and evaluate how the propagation of prionoids can fit into the wider system dysfunction seen in the brains of patients with Alzheimer's and Parkinson's diseases. PMID- 30442496 TI - Pharmacovigilating cardiotoxicity of immune checkpoint inhibitors. PMID- 30442498 TI - Interleukin 2 plus anti-GD2 immunotherapy: helpful or harmful? PMID- 30442499 TI - Pre-emptive azacitidine for relapse prevention in acute myeloid leukaemia. PMID- 30442497 TI - Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs. METHODS: In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540. FINDINGS: We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11.21 [95% CI 9.36-13.43]; IC025 3.20), pericardial diseases (12 800 vs 95, 3.80 [3.08-4.62]; IC025 1.63), and vasculitis (33 289 vs 82, 1.56 [1.25-1.94]; IC025 0.03), including temporal arteritis (696 vs 18, 12.99 [8.12-20.77]; IC025 2.59) and polymyalgia rheumatica (1709 vs 16, 5.13 [3.13-8.40]; IC025 1.33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (chi2 test for overall subgroup comparison, p<0.0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (chi2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0.0001). INTERPRETATION: Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy). FUNDING: The Cancer Institut Thematique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014 2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation. PMID- 30442500 TI - Evolution of monoclonal antibodies in multiple myeloma. PMID- 30442501 TI - Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. AB - BACKGROUND: Immunotherapy with the chimeric anti-GD2 monoclonal antibody dinutuximab, combined with alternating granulocyte-macrophage colony-stimulating factor and intravenous interleukin-2 (IL-2), improves survival in patients with high-risk neuroblastoma. We aimed to assess event-free survival after treatment with ch14.18/CHO (dinutuximab beta) and subcutaneous IL-2, compared with dinutuximab beta alone in children and young people with high-risk neuroblastoma. METHODS: We did an international, open-label, phase 3, randomised, controlled trial in patients with high-risk neuroblastoma at 104 institutions in 12 countries. Eligible patients were aged 1-20 years and had MYCN-amplified neuroblastoma with stages 2, 3, or 4S, or stage 4 neuroblastoma of any MYCN status, according to the International Neuroblastoma Staging System. Patients were eligible if they had been enrolled at diagnosis in the HR-NBL1/SIOPEN trial, had completed the multidrug induction regimen (cisplatin, carboplatin, cyclophosphamide, vincristine, and etoposide, with or without topotecan, vincristine, and doxorubicin), had achieved a disease response that fulfilled prespecified criteria, had received high-dose therapy (busulfan and melphalan or carboplatin, etoposide, and melphalan) and had received radiotherapy to the primary tumour site. In this component of the trial, patients were randomly assigned (1:1) to receive dinutuximab beta (20 mg/m2 per day as an 8 h infusion for 5 consecutive days) or dinutuximab beta plus subcutaneous IL-2 (6 * 106 IU/m2 per day on days 1-5 and days 8-12 of each cycle) with the minimisation method to balance randomisation for national groups and type of high-dose therapy. All participants received oral isotretinoin (160 mg/m2 per day for 2 weeks) before the first immunotherapy cycle and after each immunotherapy cycle, for six cycles. The primary endpoint was 3-year event-free survival, analysed by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT01704716, and EudraCT, number 2006-001489-17, and recruitment to this randomisation is closed. FINDINGS: Between Oct 22, 2009, and Aug 12, 2013, 422 patients were eligible to participate in the immunotherapy randomisation, of whom 406 (96%) were randomly assigned to a treatment group (n=200 to dinutuximab beta and n=206 to dinutuximab beta with subcutaneous IL-2). Median follow-up was 4.7 years (IQR 3.9-5.3). Because of toxicity, 117 (62%) of 188 patients assigned to dinutuximab beta and subcutaneous IL-2 received their allocated treatment, by contrast with 160 (87%) of 183 patients who received dinutuximab beta alone (p<0.0001). 3-year event-free survival was 56% (95% CI 49-63) with dinutuximab beta (83 patients had an event) and 60% (53-66) with dinutuximab beta and subcutaneous IL-2 (80 patients had an event; p=0.76). Four patients died of toxicity (n=2 in each group); one patient in each group while receiving immunotherapy (n=1 congestive heart failure and pulmonary hypertension due to capillary leak syndrome; n=1 infection-related acute respiratory distress syndrome), and one patient in each group after five cycles of immunotherapy (n=1 fungal infection and multi-organ failure; n=1 pulmonary fibrosis). The most common grade 3-4 adverse events were hypersensitivity reactions (19 [10%] of 185 patients in the dinutuximab beta group vs 39 [20%] of 191 patients in the dinutuximab plus subcutaneous IL-2 group), capillary leak (five [4%] of 119 vs 19 [15%] of 125), fever (25 [14%] of 185 vs 76 [40%] of 190), infection (47 [25%] of 185 vs 64 [33%] of 191), immunotherapy-related pain (19 [16%] of 122 vs 32 [26%] of 124), and impaired general condition (30 [16%] of 185 vs 78 [41%] of 192). INTERPRETATION: There is no evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab beta, given as an 8 h infusion, improved outcomes in patients with high-risk neuroblastoma who had responded to standard induction and consolidation treatment. Subcutaneous IL-2 with dinutuximab beta was associated with greater toxicity than dinutuximab beta alone. Dinutuximab beta and isotretinoin without subcutaneous IL-2 should thus be considered the standard of care until results of ongoing randomised trials using a modified schedule of dinutuximab beta and subcutaneous IL-2 are available. FUNDING: European Commission 5th Frame Work Grant, St. Anna Kinderkrebsforschung, Fondation ARC pour la recherche sur le Cancer. PMID- 30442502 TI - Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. AB - BACKGROUND: B-cell maturation antigen (BCMA) is a cell-surface receptor of the tumour necrosis superfamily required for plasma cell survival. BMCA is universally detected on patient-derived myeloma cells and has emerged as a selective antigen to be targeted by novel treatments in multiple myeloma. We assessed the safety, tolerability, and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, in patients with relapsed and refractory multiple myeloma. METHODS: We did an international, multicentre, open-label, first-in human phase 1 study with dose escalation (part 1) and dose expansion (part 2) phases, at nine centres in the USA, Canada, and the UK. Adults with histologically or cytologically confirmed multiple myeloma, Eastern Cooperative Oncology Group performance status 0 or 1, and progressive disease after stem cell transplantation, alkylators, proteasome inhibitors, and immunomodulators were recruited for this study. In part 1, patients received GSK2857916 (0.03-4.60 mg/kg) through 1 h intravenous infusions once every 3 weeks. In part 2, patients received the selected recommended phase 2 dose of GSK2857916 (3.40 mg/kg) once every 3 weeks. Primary endpoints were maximum tolerated dose and recommended phase 2 dose. Secondary endpoints for part 2 included preliminary anti-cancer clinical activity. All patients who received one or more doses were included in this prespecified administrative interim analysis (data cutoff date June 26, 2017), which was done for internal purposes. This study is registered with ClinicalTrials.gov, number NCT02064387, and is ongoing, but closed for recruitment. FINDINGS: Between July 29, 2014, and Feb 21, 2017, we treated 73 patients: 38 patients in the dose-escalation part 1 and 35 patients in the dose expansion part 2. There were no dose-limiting toxicities and no maximum tolerated dose was identified in part 1. On the basis of safety and clinical activity, we selected 3.40 mg/kg as the recommended phase 2 dose. Corneal events were common (20 [53%] of 38 patients in part 1 and 22 [63%] of 35 in part 2); most (18 [47%] in part 1 and 19 [54%] in part 2) were grade 1 or 2 and resulted in two treatment discontinuations in part 1 and no discontinuations in part 2. The most common grade 3 or 4 events were thrombocytopenia (13 [34%] of 38 patients in part 1 and 12 [34%] of 35 in part 2) and anaemia (6 [16%] in part 1 and 5 [14%] in part 2). There were 12 treatment-related serious adverse events and no treatment-related deaths. In part 2, 21 (60.0%; 95% CI 42.1-76.1) of 35 patients achieved an overall response. INTERPRETATION: At the identified recommended phase 2 dose, GSK2857916 was well tolerated and had good clinical activity in heavily pretreated patients, thereby indicating that this might be a promising candidate for the treatment of relapsed or refractory multiple myeloma. FUNDING: GlaxoSmithKline. PMID- 30442504 TI - "We are fierce, independent thinkers and intelligent": Social capital and stigma management among mothers who refuse vaccines. AB - Despite measurable benefits of childhood vaccines, mothers with high levels of social privilege are increasingly refusing some or all vaccines for their children. These mothers are often clustered geographically or networked socially, providing information, emotional support, and validation for each other. Mothers who reject vaccines may face disapproval from others, criticism in popular culture, negative interactions with healthcare providers, and conflicts with people they know, which serve to stigmatize them. This article uses qualitative data from in-depth interviews with parents who reject vaccines, ethnographic observations, and analyses of online discussions to examine the role of social capital in networks of vaccine-refusing mothers. Specifically, this article explores how mothers provide each other information critical of vaccines, encourage a sense of one's self as empowered to question social expectations around vaccination, provide strategies for managing stigma that results from refusing vaccines, and define a sense of obligation to extend social capital to other mothers. In examining these strategies and tensions, we see how social capital can powerfully support subcultural norms that contradict broader social norms and provide sources of social support. Even as these forces are experienced as positive, they work in ways that actively undermine community health, particularly for those who are the most socially vulnerable to negative health outcomes from infection. PMID- 30442503 TI - Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. AB - BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018. FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24 month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0.0001; one-sided binomial test for null hypothesis pexp<=0.3). With a median follow-up of 13 months (IQR 8.5-22.8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6.6 [95% CI 3.7-11.8], p<0.0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment. INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, Jose Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation. PMID- 30442505 TI - Synthesis and biological evaluation of novel N-substituted nipecotic acid derivatives with a trans-alkene spacer as potent GABA uptake inhibitors. AB - Our study presents the synthesis and structure-activity relationship (SAR) of novel N-substituted nipecotic acid derivatives closely related to DDPM-1457 [(S) 2a], a chemically stable analog of (S)-SNAP-5114 (1), in the pursuit of finding new and potent mGAT4 selective inhibitors. Iminium ion chemistry served as key step for the preparation of the desired, new N-substituted nipecotic acid derivatives containing a variety of different heterocycles attached to the nipecotic acid moiety via a trans-alkene spacer. The target compounds were characterized with regard to their potency at and subtype selectivity for the GABA transporters mGAT1-mGAT4. PMID- 30442506 TI - Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC. AB - Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib's toxicity caused by AZ5104, the N demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical. PMID- 30442507 TI - Design, synthesis and antifungal evaluation of borrelidin derivatives. AB - Borrelidin, a nitrile containing 18-membered polyketide macrolide, display potent antifungal activity. In this study, a library of borrelidin derivatives were synthesized. Their structures were elucidated by detailed spectroscopic data analysis. The antifungal activity and cytotoxicity of these target compounds were evaluated by broth microdilution and 3-(4,5-dimethylthiazol-2-yl)-3,5 phenytetrazoliumromide (MTT) methods. Among forty-seven prepared analogues, compound 3b had the inhibitory effect on Candida albicans and Candida parapsilosis (MIC: 50 and 12.5 MUg/mL, respectively). Furthermore, compounds 4n and 4r presented better antifungal activity against Aspergillus fumigatus with 12.5 MUg/mL MIC value, which were insensitive to borrelidin. Preliminary structure-activity relationships (SAR) revealed that the ester analogues containing fragment -OCH2CH2N- had an important effect on the antifungal activity. Meanwhile, the molecular docking study indicated the carboxyl substituents in BN could provide extra interaction with pathogenic fungal threonyl-tRNA synthetase (ThrRS). PMID- 30442508 TI - Cost of managing meningitis and encephalitis among infants and children in the United States. AB - A retrospective cohort study design was used to assess the use and costs of diagnostic tests, medication, and total hospitalization costs for pediatric patients with suspected meningitis/encephalitis who received a lumbar puncture (LP) procedure. Related costs were calculated by timing of LP performed and infectious etiology for infants (<1 year) and children (1-17 years). A total of 3030 infants and 3635 children with suspected ME diagnosed between 2011 and 2014 were included in the study. The mean hospitalization cost for infants and children was $12,759 and $11,119, respectively, with medication and laboratory test costs of $834 and $1771 for infants and $825 and $855 for children, respectively. Total visit cost increased with delayed LP procedure, ICU stay, and if the etiology was viral (other than enterovirus or arbovirus) or bacterial. Higher diagnostic and treatment costs were associated with delayed LP procedure, etiologic agent, and ICU stay. PMID- 30442509 TI - How safe is doxycycline for young children or for pregnant or breastfeeding women? AB - Tetracycline antimicrobials entered into clinical usage in the late 1940s. Permanent dental staining from tetracyclines was first appreciated in 1956, eventually leading to avoidance of this class of antibiotics whenever possible in young children and pregnant or breastfeeding women. Doxycycline, introduced in 1967, binds calcium less avidly than prior tetracyclines and is regarded by some authorities as safe to prescribe for pregnant women and young children. Review of the available data, however, suggests that this interpretation may be incorrect or at least premature. In conclusion, until more definitive data are developed, doxycycline should continue to be only selectively prescribed for young children and pregnant or breastfeeding women for whom alternative, safer antibiotics are not available, and courses of treatment should be of as short a duration as possible. PMID- 30442510 TI - Hands-Only Cardiopulmonary Resuscitation Education: A Comparison of On-Screen With Compression Feedback, Classroom, and Video Education. AB - STUDY OBJECTIVE: We compare 3 methods of hands-only cardiopulmonary resuscitation (CPR) education, using performance scores. A paucity of research exists on the comparative effectiveness of different types of hands-only CPR education. This study also includes a novel kiosk approach that has not previously been studied, to our knowledge. METHODS: A randomized, controlled study compared participant scores on 4 hands-only CPR outcome measures after education with a 25- to 45 minute practice-while-watching classroom session (classroom), 4-minute on-screen feedback and practice session (kiosk), and 1-minute video viewing (video only). Participants took a 30-second compression test after initial training and again after 3 months. RESULTS: After the initial education session, the video-only group had a lower total score (compressions correct on hand placement, rate, and depth) (-9.7; 95% confidence interval [CI] -16.5 to -3.0) than the classroom group. There were no significant differences on total score between classroom and kiosk participants. Additional outcome scores help explain which components negatively affect total score for each education method. The video-only group had lower compression depth scores (-9.9; 95% CI -14.0 to -5.7) than the classroom group. The kiosk group outperformed the classroom group on hand position score (4.9; 95% CI 1.3 to 8.6) but scored lower on compression depth score (-5.6; 95% CI -9.5 to -1.8). The change in 4 outcome variables was not significantly different across education type at 3-month follow-up. CONCLUSION: Participants exposed to the kiosk session and those exposed to classroom education performed hands-only CPR similarly, and both groups showed skill performance superior to that of participants watching only a video. With regular retraining to prevent skills decay, the efficient and free hands-only CPR training kiosk has the potential to increase bystander intervention and improve survival from out-of hospital cardiac arrest. PMID- 30442511 TI - [Diving and asthma: Literature review]. AB - INTRODUCTION: Scuba diving has long been contraindicated for asthmatics. Recommendations are evolving towards authorisation under certain conditions. Our objective was to review the literature on the risks associated with scuba diving among asthmatics and about recommendations on this subject. MATERIALS AND METHODS: We used the MEDLINE and LiSSa databases, until June 2018, in French, English or Spanish language, with the keywords "asthma AND diving" and "asthme plongee" respectively. References to the first degree were analyzed. RESULTS: We have included 65 articles. Risk of bronchospasm is well documented, particularly in cold and/or deep water, or in the event of exposure to allergens (compressor without filter). Nonasthmatic atopic divers may be at greater risk of developing bronchial hyper-reactivity. Although the theoretical risk exists, epidemiological studies do not seem to show an over-risk of barotrauma, decompression sickness or arterial gas embolism in asthmatics. French, British, American, Spanish and Australian societies agreed on the exclusion of patients with moderate to severe persistent asthma, FEV1<80%, active asthma in the last 48hours, exercise/cold asthma and poor physical fitness. CONCLUSION: A diver's examination should include a triple assessment: asthma control, number of exacerbations and treatment compliance. Homogenizing the recommendations would improve the framework for the practice of diving among asthmatics and allow larger studies in this population. Communicating the current recommendations remains important to divers, dive instructors and doctors in the context of the development of scuba diving. PMID- 30442512 TI - Patients' and prescribers' perception of contact lenses as a potential ocular drug delivery system. AB - Contact lenses (CLs) designed to deliver medication gradually to the eye are being developed and investigated for the use in ocular drug delivery. The aim of the current research is to determine patients' acceptance of the use of lenses for ocular drug delivery. In addition, the study aimed to seek the views and perceptions of healthcare professionals (HCPs) on CLs as a method of ocular drug delivery and whether it will be prescribed to treat ocular conditions. This was a cross-sectional survey targeted at patients and HCPs. Two separate questionnaires were created with open-closed ended and multiple response questions, gauging the perceptions and acceptance of CLs as drug delivery tool. The patients' survey was distributed in John Radcliffe (JR), Oxford and Moorfields eye hospital (MEH), London, UK. The HCPs' questionnaire was manually distributed and was also devised on Survey Monkey and sent by email to ophthalmologists, optometrists, opticians, GPs and hospital and community pharmacists. The data were analysed using SPSS statistical software and Excel. Over 60% (92/151) of patients would accept the use of CLs for their ocular treatment with the highest acceptance being reported by patients in the age group of 30-49 years old. The most frequently used conventional treatment formulation was eye drops as indicated by 87% (131/151) of the responses. More than half of eye drop users (57%, 75/131) indicated that they would accept using CLs expecting them to reduce the frequency of application of the medicine and be less time consuming. Interestingly, half of HCPs were not aware of CLs as an ocular drug delivery method; nevertheless, a total of 65 HCPs out of the 112 surveyed stated that they would prescribe/dispense CLs to treat ocular disease. PMID- 30442513 TI - Lid-parallel conjunctival fold (LIPCOF) morphology imaged by optical coherence tomography and its relationship to LIPCOF grade. AB - PURPOSE: Lid-parallel conjunctival folds (LIPCOF) are a well-accepted clinical sign in dry eye diagnosis. Commonly, LIPCOF is classified by grading the number of folds observed by slit-lamp microscope. This study investigated the relationship between subjective grading scale and LIPCOF morphology imaged by optical coherence tomography (OCT). METHODS: Temporal and nasal LIPCOF of 42 subjects (mean age 27.3 +/- 8.4 (SD) years; 13 M, 29 F) were observed and classified by an experienced optometrist using the Pult LIPCOF grading scale (0: no permanent, lid-parallel conjunctival fold; 1: one fold; 2: two folds, 3: three or more folds). Additionally, LIPCOF cross-sectional area (LIPCOF-A) and fold count (LIPCOF-C), as imaged by OCT (Cirrus HD; Carl Zeiss Meditec, Jena, Germany), were analysed with ImageJ 1.50 (http://rsbweb.nih.gov/ij). Correlations between subjective grading and LIPCOF-A and LIPCOF-C were analysed by Spearman correlation, differences between subjective grading and LIPCOF-C were analysed by Wilcoxon test. RESULTS: For temporal and nasal sectors, mean subjective LIPCOF grade was 1.43 +/- 0.86 grade units and 0.57 +/- 0.80 grade units, mean LIPCOF-C was 1.67 +/- 0.82 folds and 0.69 +/- 0.78 folds, and mean LIPCOF-A was 0.0676 +/- 0.0236mm2 and 0.0389 +/- 0.0352 mm2, respectively. Subjective temporal and nasal LIPCOF grade was significantly correlated to LIPCOF-C (r = 0.610, p < 0.001 and r = 0.645, p < 0.001, respectively), and to LIPCOF-A (r = 0.612, p < 0.001 and r = 0.583, p < 0.001, respectively). LIPCOF-C was not statistical different to subjective LIPCOF grade (p = 0.07 and p = 0.239; temporal and nasal sectors, respectively). CONCLUSIONS: OCT allows for better imaging of finer details of LIPCOF morphology, and especially of LIPCOF area. OCT evaluation of LIPCOF area correlated well with subjective grading and appears to be a promising objective method for LIPCOF classification. PMID- 30442514 TI - Novel in vitro method to determine pre-lens tear break-up time of hydrogel and silicone hydrogel contact lenses. AB - PURPOSE: To develop an in vitro model to determine pre-lens non-invasive break-up time (NIBUT) and to subsequently use this method to compare the NIBUT over contemporary daily disposable (DD) contact lenses (CL). METHODS: Three silicone hydrogel (SH) and two conventional hydrogel (CH) DD CLs were incubated in an artificial tear solution (ATS). A model blink cell (MBC) was utilised to mimic intermittent air exposure. CLs were repeatedly submerged for 3 seconds (s) and exposed to air for 10 s over periods of 2, 6, 12, and 16 hours (h). NIBUTs (n = 4) were determined out of the blister pack (T0) and at the end of each incubation period. RESULTS: Overall, nesofilcon A showed the longest NIBUTs (p < 0.001). At T0, CHs revealed significantly longer NIBUTs (p <= 0.001) than SHs. After 2 h, nesofilcon A showed the longest NIBUT, however, this was only statistically significant compared with delefilcon A (p <= 0.001). After 6 h, nesofilcon A NIBUT was significantly longer than all other CLs (p <= 0.001). Etafilcon A showed a significantly longer NIBUT (p <= 0.001) after 12 h and delefilcon A had the longest NIBUT (p <= 0.001) after 16 h. Statistically significant (p <= 0.05) changes of NIBUT within the lens materials varied between time points. After 16 h, all CLs showed significant reductions in NIBUTs (p <= 0.001) in comparison to T0. CONCLUSION: NIBUT values reduced gradually over time and varying levels of deposition impacted measured pre-lens NIBUTs. While NIBUT of CH materials are longer immediately out of the blister pack, after tear film exposure, the NIBUTs obtained using this methodology became very similar. PMID- 30442515 TI - The treatment of ocular hypotony after trabeculectomy with a scleral lens: A case series. AB - PURPOSE: Ocular hypotony after trabeculectomy may be treated medically, surgically and with a tamponade. Three cases are reported in which a scleral lens was applied to treat ocular hypotony after mitomycin C (MMC) augmented trabeculectomy. METHODS: In this retrospective case series the records of three eyes of three patients who developed ocular hypotony after they had undergone trabeculectomy augmented with MMC were evaluated. The patients were between 11 and 69 years of age and the intraocular pressure (IOP) after surgery ranged between 3 and 6 mmHg. All three patients showed a negative Seidel test; one had suspected hypotonic maculopathy and one had a collapsed anterior chamber. After unsuccessful treatment with large bandage lenses all three patients were subsequently fitted with a scleral lens. The scleral lens was fitted to fully cover and compress the bleb. Scleral lenses were worn continuously with a check up after one night of wear and subsequent check-ups when needed. One patient continued to wear the scleral lens for a further 6.5 months on a daily wear basis. RESULTS: In all three eyes the IOP was higher after wearing the scleral lens. Two patients stopped wearing the scleral lens after the IOP was stable. One patient developed a cataract; the cataract surgery was combined with a bleb revision and scleral lens wear was therefore discontinued. DISCUSSION: The scleral lens might be a useful tool in the treatment of ocular hypotony after trabeculectomy augmented MMC surgery. The effect of the scleral lens on the ocular pressure is unpredictable. Caution is advised in vulnerable corneas due to risk factors such as hypoxia and infection. Further research is warranted to establish the safety of the procedure, the patient selection and the overall success in a larger patient group. PMID- 30442516 TI - Review of Enhanced Recovery after Surgery Principles Used for Scheduled CD: Perioperative Process Evaluation. AB - There is an increasing body of evidence to support the success of Enhanced Recovery After Surgery (ERAS) for a wide range of surgical procedures. There has been little formalized application, however, of ERAS principles in obstetrical surgery. The aim of this review was to examine the evidence base of perioperative care for patients undergoing CD and to determine the feasibility of developing an ERAS Society guideline for this obstetrical care plan. The literature on enhanced recovery programs was reviewed, including fast track surgery and perioperative care components in the preoperative, intraoperative, and postoperative phases of CD. These studies included RCTs, prospective cohort studies, non-RCT studies, meta-analyses, systematic reviews, reviews, and case studies. This is not a systematic review because each ERAS topic area would require a new question. Certain ERAS elements have the potential to benefit patients undergoing CD. These elements include patient education, preoperative optimization, prophylaxis against thromboembolism, antimicrobial prophylaxis, postoperative nausea and vomiting prevention, hypothermia prevention, perioperative fluid management, postoperative analgesia, ileus prevention, breastfeeding promotion, and early mobilization. ERAS has the potential to be successfully implemented in CD on the basis of the evidence obtained from this review. The knowledge transfer and implementation will require multidisciplinary coordination in the preoperative, intraoperative, and postoperative phases and the development of a formalized ERAS guideline. PMID- 30442517 TI - A Survey of Thoracic Anesthesia Practice in Chongqing City, China. PMID- 30442518 TI - Severe Prosthetic Mitral Stenosis Misinterpreted as Severe Aortic Regurgitation. PMID- 30442519 TI - Physicians' Ability to Visually Estimate Left Ventricular Ejection Fraction, Right Ventricular Enlargement, and Paradoxical Septal Motion After a 2-Day Focused Cardiac Ultrasound Training Course. AB - OBJECTIVE: Focused cardiac ultrasound (FCU) can provide useful information for the management of shock and acute respiratory distress syndrome. This study aimed to determine whether a 2-day focused cardiac ultrasound training course could enable critical care physicians to interpret ultrasound images in terms of left ventricular ejection fraction (LVEF), ratio of right ventricular end-diastolic area to left ventricular end-diastolic area (R/LVEDA), and septal kinetics. DESIGN: A prospective analysis of an image test score. SETTING: Ultrasound training programs in 7 regions across China. PARTICIPANTS: Two hundred forty seven critical care physicians. INTERVENTIONS: All participants received a 2-day FCU training, including 4 sessions of basic heart function appraisal, 3 sessions of hands-on practice, and 1 session of image interpretation. MEASUREMENTS AND MAIN RESULTS: The post-training total scores were considerably higher than those of pretraining (75.6% v 58.9%, respectively, p < 0.001). After the course, the trainees obtained considerably higher scores on images with LVEF <30% than on images with LVEF 30% to 54% and LVEF >=55% (100% v 60.0% and 60.0%, respectively, p < 0.001). The trainees obtained considerably higher scores on images with R/LVEDA >1 than on images with R/LVEDA 0.6 to 1 and R/LVEDA <0.6 (90.0% v 80.0% and 80.0%, p = 0.042 and p < 0.001, respectively). The trainees obtained considerably higher scores on images with paradoxical septal movement (PSM) than on images without PSM (100% v 75.0%, respectively, p < 0.001). CONCLUSION: The physicians' abilities to assess LVEF, RV enlargement, and PSM improved after the training course, and they demonstrated more accurate estimations of the most obviously abnormal images. PMID- 30442520 TI - The burden of digestive disease across Europe: Facts and policies. AB - The past decade has witnessed a significant increase in the incidence of GI diseases across Europe. There are clear differences in outcomes for patients in Europe based on geographical and economic differences, and there is a worrying inequality in the provision of healthcare across the continent. Recent demographic studies have highlighted the heavy burden of GI disease across Europe. There is increasing demand for endoscopic procedures which are becoming increasingly more complex and demand further expertise and training. A co ordinated and cohesive approach to research, specialist training and healthcare funding is required to overcome these inequalities. PMID- 30442521 TI - Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis. AB - BACKGROUND: Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated. METHODS: Wild-type, Car null, Pxr-null, and Car/Pxr-null mice were treated with a CAR/PXR agonist or vehicle and administered 2.5% DSS in the drinking water. The typical clinical symptoms, histological scoring, proinflammatory cytokine, and apoptosis were analyzed. RESULTS: Mice treated with the PXR agonist pregnenolone-16alpha carbonitrile (PCN) were protected from DSS-induced colitis, as in a previous study. Mice treated with the CAR agonist, 4-bis[2-(3,5 dichloropyridyloxy)]benzene (TCPOBOP) were also protected from DSS-induced colitis. Interestingly, the protective effects of PCN in the Car-null mice and those of TCPOBOP in the Pxr-null mice both decreased. PCN or TCPOBOP pretreatment significantly decreased the macrophage and monocyte infiltration in DSS-induced colitis. PXR and CAR agonists reduced the mRNA expression of several proinflammatory cytokines in a PXR- and CAR-dependent manner, respectively. CAR inhibited apoptosis by inducing Gadd45b. PXR inhibited TNF-alpha and IL-1b and CAR induced Gadd45b in in vitro cell analyses. CONCLUSIONS: We showed that CAR and PXR cooperatively ameliorate DSS-induced colitis. PXR and CAR protected against DSS-induced colitis by inhibiting proinflammatory cytokines and apoptosis, respectively. PMID- 30442522 TI - Risk stratification in acute coronary syndromes: When less is more. PMID- 30442523 TI - Natural Disease History, Outcomes, and Co-mutations in a Series of Patients With BRAF-Mutated Non-small-cell Lung Cancer. AB - BACKGROUND: BRAF mutations occur in 1% to 4% of non-small-cell lung cancer (NSCLC) cases. Previous retrospective studies have reported similar outcomes for BRAF-mutated NSCLC as compared with wild-type tumors without a known driver mutation or tumors harboring other mutations. However, select cases of prolonged survival have also been described, and thus, the natural history of BRAF-mutated NSCLC remains an area of ongoing study. The aim of this series was to describe the natural history, clinical outcomes, and occurrence of co-mutations in patients with BRAF-mutated NSCLC. PATIENTS AND METHODS: Patients with BRAF mutated NSCLC seen at Stanford University Medical Center from January 1, 2006 through July 31, 2015 were reviewed. The Kaplan-Meier method was used to calculate median overall survival, and the generalized Wilcoxon test was used to compare median survivals across subgroups of patients. RESULTS: Within a cohort of 18 patients with BRAF-mutated NSCLC, V600E mutations were most common (72%; 13/18). Clinicopathologic features were similar between patients with V600E versus non-V600E mutations, although there was a trend toward more patients with non-V600E mutations being heavy smokers (80% vs. 31%; P = .12). Co-occurring mutations in TP53 were identified most commonly (28%; 5/18). The median overall survival for the entire cohort was 40.1 months, and the median survival from the onset of metastases (n = 16) was 28.1 months. Survival rates at 2 and 5 years from the onset of metastases were 56% and 13%, respectively. CONCLUSION: The clinical behavior of BRAF-mutated NSCLC is variable, but favorable outcomes can be seen in a subset of patients. PMID- 30442524 TI - Association Between Immune-related Adverse Events and Efficacy of Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) are available for first- and further lines of treatment of patients with advanced non-small-cell lung cancer (NSCLC). These treatments are associated with adverse events called immune related adverse events (IRAEs). The incidence, diagnosis, and treatment of IRAEs are quite acknowledged; however, the link between IRAEs and the efficacy of ICIs requires further clarification. The objectives of this study were to assess the association between IRAEs incidence and severity and ICIs efficacy in patients with advanced NSCLC. METHODS: In this retrospective study, clinical, biological, treatment, and outcome data were collected from patients with advanced NSCLC who received at least 1 cycle of ICIs from April 2013 to February 2017. The primary endpoint was to assess the association of IRAEs incidence with overall survival (OS). Secondary endpoints were the association of IRAEs with progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). RESULTS: Overall, 270 patients were studied. The median OS was 14 months, median PFS was 2.6 months, ORR was 13%, and DCR was 51%. OS, PFS, and ORR were significantly better for patients with IRAEs compared with patients with no IRAEs, translating to median OS not reached versus 8.21 months, respectively (hazard ratio, 0.29; 95% confidence interval [CI], 0.18-0.46; P < .001); PFS was 5.2 versus 1.97 months (hazard ratio, 0.42; 95% CI, 0.32-0.57; P < .001); and ORR was 212.9% versus 5.7% (odds ratio, 4.9; 95% CI, 2.18-11.05; P < .001). CONCLUSIONS: This report presents the largest case series showing longer OS and PFS and better ORR when IRAEs occurred in a population of patients with advanced NSCLC treated with ICIs. The biological background for this phenomenon is being explored prospectively. PMID- 30442525 TI - Revisiting Desmond Doss (1919-2006): Merging Combat Medicine and Benevolence on the Battlefield. AB - Conscientious objectors are typically defined only by their unwillingness to serve in the armed forces. Desmond Doss participated in World War II as a combat medic and a conscientious objector by providing emergency medicine on active battlefields while refusing to handle a weapon or harm another human being. Born and raised with humility, Doss developed spiritually as a Seventh Day Adventist. Although fixated on the Ten Commandments and "Thou shall not kill," Doss felt a call to serve and voluntarily enlisted in the U.S. Army with aspirations of becoming a combat medic. Throughout his training he was met with physical, spiritual, and political obstacles as his superiors unsuccessfully tried to convince him and eventually to force him out of the military or to take up arms and fight. Doss was granted his request as a combat medic, was not required to handle a weapon or fight, and was deployed with the 307th Infantry Regiment overseas. His heroism on the battlefield saved hundreds of lives and earned him the Medal of Honor. A thorough yet concise examination of Doss' formative years, the obstacles presented by the country he aimed to serve, how he evolved from a conscientious objector to a combat medic worthy of emulation, and his lasting legacy is a necessary reminder of what we risk when courageous people are limited by outdated and potentially unconstitutional policies and perceptions. PMID- 30442526 TI - Factors associated with and screening models of national immunization programme vaccine series completion among preschool children in Fujian Province, south eastern China. AB - BACKGROUND: An effective method for the rapid identification of vulnerable preschool children at risk of not completing the national immunization programme (NIP) vaccine series in China is still lacking. METHODS: A cross-sectional study involving 772 preschool children born between September 1 2009 and August 31, 2011 was conducted in 2015 in Fujian Province, south-eastern China. The data were collected by face-to-face interviews with the parents or guardians of the children using a standard questionnaire. RESULTS: Children who received the first dose of a hepatitis B vaccine (HepB) less than 24h after birth and those who received one or more doses of surrogate for-fee vaccines (SFVs) were more likely to complete the NIP vaccine series with adjusted odds ratios (ORs) of 3.12 (95% confidence interval [CI]: 1.19-8.23) and 4.74 (1.41-15.90), respectively. The cut off value of the prediction score for the completion of the NIP vaccine series was 92.5%, and the sensitivity, specificity, and positive and negative predictive values were 87.5%, 47.1%, 11.4% and 98.0%, respectively. CONCLUSIONS: The receipt of a timely first dose of HepB and one or more doses of SFVs were associated with and good predictors of NIP vaccine series completion by preschool children in Fujian, China. PMID- 30442527 TI - Plasmodium: More Don'ts. PMID- 30442528 TI - Initial forensic evaluation of Takotsubo syndrome and its causal relationship to a traumatic event. PMID- 30442529 TI - A Preliminary Study of Vocal Health Among Collegiate A Cappella Singers. AB - OBJECTIVE: Collegiate a cappella groups have grown significantly in popularity and prominence; however, there have been few studies that evaluate the vocal health of this subgroup of young singers. The objective of this preliminary study was to conduct a multiparametric evaluation of the vocal health characteristics of a sample of collegiate a cappella singers. We further tested whether differences in vocal health assessments exist between a cappella singers with and without vocal training and trained collegiate singers who do not participate in a cappella groups. STUDY DESIGN: Point prevalence study. METHODS: Forty-one collegiate singers participated in this study. Participants were divided into the following three groups: trained singers (TS), trained a cappella singers (ATS), and untrained a cappella singers (AUS). Participants were administered a set of surveys to assess self-perception of singing voice health and perceived access and attitudes toward voice-related health care. Acoustic and laryngoscopic assessments of participant's speaking and singing voice was performed and validated vocal health questionnaires administered as a means to objectively evaluate for the presence of voice problems. RESULTS: Overall, 87.5% of the ATS and 60% of the AUS groups reported experiencing problems with their singing voice. However, no vocal abnormalities were detected during laryngoscopic and acoustic assessments. Furthermore, minimal differences between any of the measured vocal health parameters were observed between the TS, ATS, and AUS groups. CONCLUSION: Collectively, a high percentage of collegiate a cappella singers with and without vocal training report singing voice problems. However, our sample of a cappella singers did not have increased singing voice problems as compared to vocally trained collegiate singers not in a cappella groups. We did find that a cappella singers may be more inclined to seek information about maintaining a healthy singing voice from their fellow musicians as opposed to singing teachers or other voice health professionals. Singing teachers, otolaryngologists, and speech-language pathologists may need to play a more active role in educating a cappella singers regarding maintaining good vocal health. PMID- 30442530 TI - Trajectories of Antipsychotic Drug Use Over 10 Years in a French Community-Based Sample of Persons Aged 50 and Older. AB - OBJECTIVE: To identify the temporal prescribing patterns of antipsychotics among persons aged 50 and older and to explore the demographic and clinical characteristics associated with each trajectory of antipsychotic drug use. METHODS: This was a historical fixed cohort study on a community-based sample of persons affiliated with the French Insurance Healthcare system. Data from community drug reimbursement claims were collected by the French Insurance Healthcare system over the period 2006-2015. The study included 160,853 persons aged 50 and older. Trajectories of antipsychotic drug use were identified by examining the distribution of antipsychotic use within consecutive 3-month periods over the entire follow-up period. Latent class analyses were used to identify distinct trajectories. Multivariate polynomial logistic regression models were used to explore the characteristics independently associated with trajectories. RESULTS: Five trajectories of antipsychotic use were identified: null or very low use (93.8%), occasional use (2%), decreasing use (1.6%), chronic use (1.5%), and increasing use (1.1%). Occasional users were older and had a lower use of other psychotropic drugs and a high use of health resources. Chronic users had the highest frequency of chronic psychiatric diseases and were less likely to present with dementia or Parkinson disease. Persons with increasing use of antipsychotics were more frequently males and had a high frequency of dementia; half of them died over the follow-up period compared with 20% in the total sample. CONCLUSION: Further studies should explore whether the benefit-risk ratio of antipsychotic drugs in older adults differs according to trajectories of use. PMID- 30442531 TI - Sleep Disturbances and Inflammatory Biomarkers in Schizophrenia: Focus on Sex Differences. AB - OBJECTIVES: Persons with schizophrenia, and women in particular, are at high risk for sleep disturbances and inflammatory activation. The sleep-inflammation link has been reported to be stronger in women within the general population. This study sought to examine the sleep-inflammation link in persons with schizophrenia and its relationship with demographic, clinical and cognitive variables. DESIGN: Cross-sectional case-control study. PARTICIPANTS: Community-dwelling outpatients with schizophrenia (N=144, 46% women) and non-psychiatric comparison (NC) participants (N=134, 52% women), age 26-65 years. MEASUREMENTS: Reported sleep disturbances (sleep quality and duration), and mental and physical health were assessed. Cognitive assessments included executive functioning (Delis-Kaplan Executive Function System) and global cognitive functioning (Telephone Interview for Cognitive Status - modified.) Inflammatory biomarkers included pro inflammatory cytokines [high sensitivity C-Reactive Protein (hs-CRP), Interleukin (IL)-6, Tumor Necrosis Factor-alpha (TNF-alpha)] and an anti-inflammatory cytokine (IL-10). RESULTS: The schizophrenia group had longer sleep duration, worse sleep quality, and increased levels of hs-CRP, IL-6, and TNF-alpha compared to NCs. Women with schizophrenia were less likely to have good sleep quality and had elevated levels of hs-CRP and IL-6 compared to men with schizophrenia. In the schizophrenia group, worse sleep quality and global cognitive functioning were associated with higher hs-CRP and IL-6 levels. Female sex and younger age were also associated with higher hs-CRP levels. CONCLUSIONS: Sleep disturbances and increased inflammation, which were common in schizophrenia, were associated in persons with schizophrenia. Moreover, women with schizophrenia had worse sleep quality and inflammation than men. Further examination of the sleep-inflammation links, their contribution to clinical outcomes, and sex-specific factors is warranted. PMID- 30442532 TI - Using Skype to Beat the Blues: Longitudinal Data from a National Representative Sample. AB - OBJECTIVES: This study aimed to determine whether use of certain types of online communication technology is associated with subsequent depressive symptoms. DESIGN: Nationally representative, population-based prospective cohort. SETTING: Data were obtained from the 2012 and 2014 waves of the Health and Retirement Study (HRS). PARTICIPANTS: 1,424 community-residing older adults (mean age, 64.8) in the United States. MEASUREMENTS: We examined associations between use of four communication technologies (email, social networks, video chat, and instant messaging) in 2012 and depressive symptoms (eight-item Center for Epidemiologic Studies Depression scale) at two-year follow-up. RESULTS: 564 participants (39.6%) did not use any communication technologies, 314 (22.1%) used email only, and 255 (17.9%) used video chat (e.g., Skype). Compared to non-users (13.1%, 95% CI: 9.5-16.7%) or those who used only email (14.3%, 95% CI: 10.1-18.5%), users of video chat had approximately half the probability of depressive symptoms (6.9%, 95% CI: 3.5-10.3%, Wald Chi2 test, Chi2(1)=13.82, p < 0.001; 7.6%, 95% CI: 3.6 11.6, Wald Chi2 test, Chi2(1)=13.56, p < 0.001). Use of email, social media, and instant messaging were not associated with a lower risk of depression. CONCLUSIONS: Older adults who use video chat such as Skype, but not other common communication technologies, have a lower risk of developing depression. PMID- 30442533 TI - Sensing Mitochondrial Acetyl-CoA to Tune Respiration. AB - Fatty acid synthesis (FAS) in mitochondria produces a key metabolite called lipoic acid. However, a new study by Van Vranken et al.[1] (Mol. Cell 2018;71:567 580) shows that mitochondrial FAS regulates the assembly of oxidative phosphorylation complexes, thereby functioning as a nutrient sensor for mitochondrial respiration. PMID- 30442534 TI - Bacterial Excretion of Cytoplasmic Proteins (ECP): Occurrence, Mechanism, and Function. AB - The excretion of cytoplasmic and signal-peptide-less proteins (ECP) by microorganisms and eukaryotes remains a fascinating topic. In principle, it appears to be a waste of energy. However, it turns out that - extracellularly - some cytoplasmic proteins (CPs) exert a completely different function such as contributing to pathogenicity or evasion of the immune system. Such CPs have been referred to as 'moonlighting' proteins. ECP is boosted by many endogenous or external factors that impair the membrane or cell wall structure. There are also differences regarding their mode of release. In some microorganisms they appear to be released directly, while in others they are embedded in membrane vesicles, or bound to the cell envelope. Some CPs might be promising candidates for vaccine developments against major bacterial pathogens. PMID- 30442535 TI - The use of chemogenetic approaches in alcohol use disorder research and treatment. AB - Several novel techniques were developed recently to explore neural circuit mechanisms of neuropsychiatric disorders. These techniques include the Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic tools, which represent valuable platforms for selective and non-invasive control of neural activity with a high degree of spatial resolution. Among all variants, Gq- and Gi-DREADDs are widely used by neuroscientists to dissect out the circuitry and cellular signals. This review is focused on strategies to access a specific neuronal population or circuit using the DREADD technique and summarizes the current knowledge of the DREADDs' application in alcohol use disorder research and therapeutics. PMID- 30442536 TI - Clinical outcomes one year and beyond after combination sirolimus eluting endothelial progenitor cell capture stenting during primary percutaneous coronary intervention in ST-segment elevation myocardial infarction. AB - BACKGROUND/PURPOSE: Primary percutaneous coronary intervention (PCI) during acute ST-segment elevation myocardial infarction (STEMI) represents a thrombotic milieu and is associated with delayed healing after stenting. The pro-healing combination sirolimus eluting endothelial progenitor cell (EPC) capture stents encourage early endothelialization after stenting and may be beneficial in the STEMI population. We aim to evaluate the clinical outcomes one year and beyond for patients with STEMI who received the combination sirolimus eluting EPC capture stents during primary PCI. METHODS/MATERIAL: All STEMI patients implanted with combination sirolimus eluting EPC capture stents during primary PCI from November 2013 to December 2016 were enrolled. The primary outcome was target lesion failure (TLF) at in-hospital, one-month, one-year and beyond one year. RESULTS: A total of 260 consecutive STEMI patients (283 lesions) were implanted with 313 combination sirolimus eluting EPC capture stents during primary PCI. Mean age was 56.1 +/- 11.2 years and 88.8% were male. One in ten patients (10.9%) had cardiogenic shock on presentation, 7.3% needed mechanical ventilation and 7.7% had intra-aortic balloon pump inserted. A total of 97.9% of lesions achieve final TIMI 3 flow. Device success was seen in all patients. At extended follow up period (median 23.4 months), the clinical outcomes were TLF 8.8%, major adverse cardiovascular events 10.8%, cardiac mortality 4.2%, target vessel myocardial infarction 3.4%, target lesion revascularization 3.8%, and definite stent thrombosis 1.9%. CONCLUSIONS: This study demonstrated acceptable clinical outcomes for an all-comers STEMI patients undergoing primary PCI with the use of combination sirolimus eluting EPC cell capture stents. PMID- 30442538 TI - Radical prostatectomy after previous TUR-P: Oncological, surgical, and functional outcomes. AB - OBJECTIVES: To examine oncological, surgical, and functional outcomes of radical prostatectomy (RP) in patients with history of transurethral resection of the prostate (TUR-P). MATERIALS AND METHODS: Retrospective analysis of 18,681 RP patients including 470 patients with previous TUR-P at a single institution (2002 2015). Kaplan-Meier as well as multivariable Cox and logistic regression analyses compared surgical, oncological, and functional outcomes between TUR-P and non-TUR P patients after propensity score matching (nearest neighbor in a 1:3 fashion). RESULTS: After propensity score adjustment, pathological and surgical results were similar between both groups. Specifically, rates of positive surgical margins and nerve-sparing (NS) procedure did not differ between groups (positive surgical margins: 18.5% vs. 17.2%, P = 0.7; nerve-sparing: 89.4% vs. 91.6%, P = 0.5). In addition, there was no difference in mean operating room time (185 vs. 184 minutes, P = 0.6), blood loss (710 vs. 666 ml, P = 0.1), and catheterization time (12 days, P = 0.3). In multivariable analyses, TUR-P patients did not exhibit higher risk of biochemical recurrence, metastatic progression, or mortality (all P > 0.05). However, TUR-P patients exhibited higher risk for urinary incontinence at third month (OR: 1.47; 95% confidence interval [CI] 1.01 2.12, P = 0.04) and first year (OR: 2.06; 95% CI 1.23-3.42, P = 0.006) and worse 1-year erectile function recovery (OR: 0.48; 95% CI 0.27-0.86, P = 0.02). CONCLUSIONS: This large series of TUR-P RP patients demonstrated that RP could be safely performed in patients with history of TUR-P without compromising oncological results. However, functional outcomes were worse for patients with previous TUR-P. PMID- 30442537 TI - Transradial versus transfemoral access for percutaneous coronary intervention of unprotected left main coronary artery stenosis: A systematic review and meta analysis. AB - INTRODUCTION: PCI of ULMS is frequently performed through TFA because of technical complexity and safety concern. Studies have shown comparable efficacy and safety of TRA versus TFA, however, these studies are few in number. We intended to compare the clinical outcomes between transradial access (TRA) and transfemoral access (TFA) in patients undergoing percutaneous coronary intervention (PCI) for unprotected left main coronary artery stenosis (ULMS) by performing a meta-analysis. METHOD: A systematic search of database, including, PubMed, Web of Science, Google scholar and Cochrane Database were performed by two independent reviewers. Studies were included comparing "TRA" versus "TFA" in patients undergoing PCI in ULMS. The primary outcome was a procedural success rate. Secondary outcomes were major bleeding, access site complications, in hospital and long term: major adverse cardiac events (MACE), myocardial infarction (MI) and cardiovascular mortality. RESULTS: Eight studies were included in the analysis. The procedural success rate was 97.3% and there was no statistically significant difference between TRA and TFA groups (OR, 1.41 [CI 0.64, 3.12], I2 = 26%). The rates of access site complications (OR, 0.17 [CI 0.07, 0.41], I2 = 16%), major bleeding (OR, 0.39 [CI 0.17, 0.86], I2 = 0%) and all-cause mortality (OR, 0.28 [CI 0.12, 0.64], I2 = 0%) were lower in the TRA group. There were no significant differences in in-hospital and long term cardiovascular mortality, MI and MACE between the two groups. CONCLUSION: In contrast to TFA, TRA is associated with reduced bleeding and access site complications, with similar procedural success rate in patients undergoing PCI of ULMS. PMID- 30442539 TI - [Nephrotoxicity of plasma volume expanders]. AB - Expansion of extracellular volume is a treatment traditionally proposed to correct abnormalities of renal perfusion and prevent ischemic injury. However, vascular filling is not at risk for tissue oxygenation and renal function. The use of synthetic colloids exposes the patient to the risk of developing lesions such as osmotic nephrosis. Hyperoncotic colloids reduce glomerular filtration pressure. The nephrotoxicity of hydroxyethyl starches is now clearly established regardless of their characteristics. Colloids have never demonstrated their superiority as plasma volume expanders, they should be abandoned in favour of crystalloid solutions. PMID- 30442540 TI - Human stem cell-derived monocytes and microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2. AB - INTRODUCTION: Murine microglia expressing the Alzheimer's disease-linked TREM2R47H mutation display variable decrease in phagocytosis, while impaired phagocytosis is reported following loss of TREM2. However, no data exist on TREM2+/R47H human microglia. Therefore, we created human pluripotent stem cell (hPSC) monocytes and transdifferentiated microglia-like cells (tMGs) to examine the effect of the TREM2+/R47H mutation and loss of TREM2 on phagocytosis. METHODS: We generated isogenic TREM2+/R47H, TREM2+/-, and TREM2-/- hPSCs using CRISPR/Cas9. Following differentiation to monocytes and tMGs, we studied the uptake of Escherichia coli fragments and analyzed amyloid plaque clearance from cryosections of APP/PS1+/- mouse brains. RESULTS: We demonstrated that tMGs resemble cultured human microglia. TREM2+/- and TREM2-/- hPSC monocytes and tMGs phagocytosed significantly less E. coli fragments and cleared less amyloid plaques than wild-type hPSC progeny, with no difference for TREM2+/R47H progeny. DISCUSSION: In vitro phagocytosis of hPSC monocytes and tMGs was not affected by the TREM2+/R47H mutation but was significantly impaired in TREM2+/- and TREM2-/- progeny. PMID- 30442541 TI - From One to Many: Representing Not Only Actions, but Interactions in the Brain. AB - Observing others is a pervasive way of learning about the social world, but little is known about the neural correlates of observing more than one individual. A recent neuroimaging study demonstrates that activity in the human motor system tracks multiple actions and that anterior cingulate cortex is involved to monitor motor conflict. PMID- 30442542 TI - Urology Mythbusters: should hydronephrosis grade be used to decide which newborns should undergo voiding cystourethrogram? AB - In this episode of Mythbusters the premise that among infants with prenatally identified urinary tract dilation (UTD), voiding cystourethrogram (VCUG) should be performed in those with higher grade UTD but not in those with lower grade UTD is critically examined. It is concluded that severity of dilation is not strongly associated with risk of vesicoureteral reflux or other anomalies diagnosed by VCUG. Therefore, using hydronephrosis grade to decide which infants with UTD should undergo VCUG is not evidence based. PMID- 30442543 TI - Correspondence: the complexities of cystopexy. PMID- 30442544 TI - Modified staged repair of bladder exstrophy: a strategy to prevent penile ischemia while maintaining advantage of the complete primary repair of bladder exstrophy. AB - INTRODUCTION: Penile ischemic injury is a reported catastrophic complication after complete primary repair of exstrophy (CPRE). Aiming to improve the bladder exstrophy-epispadias repair outcomes, the study institution adopted a modified staged exstrophy repair to incorporate the advantages of CPRE by avoiding concurrent epispadias repair and adding bilateral ureteral re-implantation and bladder neck tailoring (staged repair of bladder exstrophy with bilateral ureteral re-implantation [SRBE-BUR]) at the initial repair. It was hypothesized that such modifications minimize penile complications and prevent upper tract deterioration while enhancing bladder resistance and consequent capacity. Here, a comparative series of outcomes between CPRE and SRBE-BUR is reported. METHODS: A retrospective cohort study including all exstrophy-epispadias male neonates managed in the study institution from January 2000 to December 2014 was performed. Patients were divided into those who underwent CPRE-BUR (group 1) and SRBE-BUR (group 2) (Figure). Baseline characteristics, peri-operative data, and long-term surgical outcomes were collected and analyzed for between-group comparison. Fisher exact and Mann-Whitney U tests were performed for statistical analysis. RESULTS: A total of 21 eligible patients were included: 10 in group 1 and 11 in group 2. Baseline characteristics were comparable. Two patients in group 1 had intra-operative penile ischemic injury (one with subsequent penile tissue loss), whereas none of the group 2 patients had intra-operative complications. No significant difference between the groups was noted for operative time; however, significantly lesser blood loss was noted in group 2. Comparable long-term surgical outcomes such as additional surgical intervention, urinary continence, bladder capacity, vesicoureteral reflux, hydronephrosis and recurrent urinary tract infections (UTIs) were noted. In addition, although subjective, better penile length and cosmesis were achieved by staging the repair (Figure). CONCLUSION: The SRBE with bilateral ureteral re-implantation is a safe alternative for the repair of the exstrophy-epispadias repair as it prevents the catastrophic complication of penile tissue loss, while having comparable long term outcomes with the CPRE. Delaying epispadias repair avoids penile injury besides possible improvement of its overall cosmesis. PMID- 30442545 TI - An altered spatiotemporal gait adjustment during a virtual obstacle crossing task in patients with diabetic peripheral neuropathy. AB - This study investigates spatiotemporal gait adjustments that occur while stepping over virtual obstacles during treadmill walking in people with/without diabetic peripheral neuropathy (DPN). Eleven adults with Type 2 diabetes mellitus, ten DPN, and 11 age-matched healthy adults (HTY) participated in this study. They stepped over forthcoming virtual obstacles during treadmill walking. Outcomes such as success rate, spatiotemporal gait characteristics during obstacle crossing, and correlations between these variables were evaluated. The results partially supported our hypotheses that when comparing with HTY and DM, people with DPN adopted a crossing strategy which decreased obstacle crossing success rate and maximal toe elevation, and increased stride time and stance time during virtual obstacle crossing. This might be due to the compromised somatosensory functions of their lower extremity which may increase the risk of falling. This study also found an inter-leg relationship which may be applied to future stepping or obstacle crossing training that incorporates both legs as a means for improving outcomes of the trailing leg during daily obstacle negotiation. PMID- 30442546 TI - Altered spinal-level sensorimotor control related to pain and perceived instability in people with chronic ankle instability. AB - OBJECTIVES: To compare soleus spinal reflex excitability, presynaptic inhibition and recurrent inhibition between chronic ankle instability (CAI), acute Lateral Ankle Sprain coper (LAS-coper) and healthy populations. The relationship between spinal reflex excitability and pain and perceived instability in people with CAI was also examined. DESIGN: Cross-sectional laboratory experiment. METHODS: Twelve individuals with CAI, twelve 'copers' and twelve healthy age, limb and gender matched controls participated. Soleus H-reflex recruitment curves, pre-synaptic excitability and recurrent inhibition of the spinal-reflex pathway were examined during static double- and single-leg stance. Reporting of pain and perceived instability were used to perform a regression analysis on measures of soleus spinal excitability in people with CAI, LAS-coper and healthy controls. RESULTS: Soleus spinal reflex excitability was greater during single-leg stance in CAI compared to healthy and coper individuals (p=<0.001). Pre-synaptic inhibition was three-times less in CAI participants compared to both healthy controls and copers (p=<0.001). There were no differences between healthy and coper participants in spinal-level measures of sensorimotor control. Reports of pain explained 15-16% of the variance in soleus spinal reflex excitability and presynaptic inhibition during single and double-leg stance, while perceived instability explained 20% of the variance in spinal reflex during single leg stance only. CONCLUSIONS: CAI participants presented with an inability to suppress soleus spinal reflexes during tasks with increased postural threat; likely due to disinhibition of pre synaptic mechanisms. Pain and perceived instability may contribute to changes in spinal-level sensorimotor control in CAI. PMID- 30442547 TI - Assessing the utility of yearly pre-season laboratory screening for athletes on a major professional sports team. AB - OBJECTIVES: Professional athletes undergo annual pre-season laboratory screening, although clinical evidence supporting the practice is limited and no uniform set of guidelines on pre-season laboratory screening exists. The aim of this study was to assess the clinical value of annual pre-season laboratory screening tests for a major professional sports team over multiple years. DESIGN: Retrospective chart review. METHODS: A retrospective analysis was performed of all laboratory results as well as screening ECGs for a single major professional sports team over a 9-year timeframe (2009-2017). RESULTS: The data show that 10.01% of initial screening test results were abnormal and 40.32% of abnormal tests resulted in additional testing. Overall, only 0.35% of initial tests resulted in a clinically significant outcome. Non-US born players showed a significantly higher average rate of abnormal tests/year compared to US-born players (p-value 0.006), but there was no difference in clinically significant outcomes. There was no relationship between athlete age and laboratory screening outcomes. CONCLUSIONS: In our study population, yearly pre-season laboratory screening of professional athletes did not yield substantial clinically significant outcomes and would not be warranted under normal clinical standards. Future best practice guidelines should combine research concerning effects of family medical history, race, gender, country of origin, and type of sport on athlete health when creating recommendations for which pre-season laboratory screenings may be pertinent even with evidence of little utility. PMID- 30442548 TI - Variability of within-step acceleration and daily wellness monitoring in Collegiate American Football. AB - OBJECTIVES: It is commonplace to consider accelerometer load and any resultant neuromuscular fatigue in training programs. With these data becoming accepted in sport alongside wellness questionnaires this study aimed to investigate if a deeper analysis of the accelerometry data can provide actionable insight into training-induced disruptions. DESIGN: Accelerometer data from Collegiate American Football athletes (n=63) were collected during training and matches across a regular season. METHODS: These data were processed to: identify instances of high speed running, extract step waveforms from those sections, and determine the variability of those waveforms via a within- and between-section co-efficient of multiple determination. Athletes completed wellness questionnaires prior to sessions that were used to flag areas of muscle soreness as well as fatigue, or disturbed sleep quality. Linear mixed models were used to assess associations between inter stride variability and flags in wellness/soreness markers. RESULTS: An increase in acute (7d) load saw an increased stride variability in these athletes. Feeling less fatigued and/or lower muscle soreness was associated with higher stride variability. CONCLUSIONS: The assessment of variability has the potential to identify athletes who are displaying physical symptoms that would indicate the need to modify training. PMID- 30442549 TI - Long-term outcomes of combined hepatocellular-cholangiocarcinoma after hepatectomy or liver transplantation: A systematic review and meta-analysis. AB - BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy. We conducted a systematic review and meta-analysis to assess the evidence available on the long-term outcomes of cHCC-CC patients after either hepatectomy or liver transplantation (LT). DATA SOURCES: Relevant studies published between January 2000 and January 2018 were identified by searching PubMed and Embase and reviewed systematically. Data were pooled using a random effects model. RESULTS: A total of 42 observational studies involving 1691 patients (1390 for partial hepatectomy and 301 for LT) were included in the analysis. The median tumor recurrence and 5-year overall survival (OS) rates were 65% (range 38%-100%) and 29% (range 0-63%) after hepatectomy versus 54% (range 14%-93%) and 41% (range 16%-73%) after LT, respectively. Meta-analysis found no significant difference in OS and tumor recurrence between LT and hepatectomy groups. CONCLUSION: Hepatectomy rather than LT should be considered as the prior treatment option for cHCC-CC. PMID- 30442550 TI - A randomized clinical trial evaluating maxillary sinus augmentation with different particle sizes of demineralized bovine bone mineral: histological and immunohistochemical analysis. AB - This study was performed to investigate sinus floor augmentation with two different particle sizes of demineralized bovine bone mineral (DBBM) by means of histological and immunohistochemical (IHC) analysis. A randomized clinical trial was conducted involving 10 individuals requiring two-stage bilateral maxillary sinus augmentation for implant installation. The patients were randomly divided into two groups following a split-mouth design: the maxillary sinus on one side was filled with small-sized particles (0.25-1mm) and on the contralateral side with large-sized particles (1-2mm). After a healing period of 8 months, 25 implants were placed. During implant site preparation, bone biopsies were obtained from each sinus, perpendicular to the long axis of the implant (buccal palatal direction), for descriptive and histomorphometric analyses. IHC staining for protein expression of osteocalcin (OCN), vascular endothelial growth factor (VEGF), and tartrate-resistant acid phosphatase (TRAP) was also performed. Histomorphometric analysis revealed no statistically significant difference in the percentage of biomaterial (32.4+/-8.56% and 38.0+/-6.92%), newly formed bone (36.1+/-9.60% and 36.7+/-5.79%), or connective tissue (30.4+/-8.63% and 23.8+/ 6.16%) between the small- and large-sized particle groups, respectively. IHC analysis did not reveal differences in the expression of OCN, VEGF, or TRAP. These findings suggest that both particle sizes of DBBM are effective for bone augmentation in the maxillary sinus. PMID- 30442551 TI - Effects of auriculotherapy and midazolam for anxiety control in patients submitted to third molar extraction. AB - Anxiety is common and still represents a barrier to appropriate professional care for patients requiring dental treatment. The aim of this study was to compare the effects of auriculotherapy and midazolam for the control of anxiety in patients submitted to third molar extractions. This was a randomized, double-blind, controlled, crossover clinical trial. Thirty healthy volunteers requiring bilateral third molar extraction received midazolam 15mg (oral) and sham auriculotherapy during one session, and a placebo tablet (oral) and auriculotherapy during the other; the sessions were randomized. The level of anxiety was assessed through questionnaires and physical parameters (blood pressure, heart rate, and oxygen saturation (SpO2)) at three time points: baseline, on the day of surgery, and at follow-up. No significant differences between the protocols were observed for blood pressure and SpO2. Auriculotherapy induced a lower heart rate than midazolam during some periods. Auriculotherapy induced more events remembered after surgery than midazolam (P<0.0001). More undesirable effects were observed with midazolam (P<0.0001). However, patient preference for auriculotherapy (53.3%) was not higher than preference for midazolam (46.7%). Auriculotherapy showed an anxiolytic effect equivalent to the midazolam effect, without the undesirable effects usually attributed to the benzodiazepine. PMID- 30442552 TI - Comparison of rim-sparing versus rim-removal techniques in deep lateral wall orbital decompression for Graves' orbitopathy. AB - The aim of this study was to compare the surgical outcomes of deep lateral orbital decompression using the rim-sparing technique versus the rim-removal technique in Graves' orbitopathy (GO). A retrospective cohort study of 75 orbits in 50 patients with GO was performed. Proptosis, best corrected visual acuity (BCVA), intraocular pressure (IOP), upper and lower lid margin to reflex distances (MRD-1 and MRD-2, respectively), diplopia, ocular restriction, and GO quality of life (GO-QOL) questionnaire results were analyzed pre- and postoperatively. The average proptosis reduction ranged from 3.5mm to 6.7mm with the rim-sparing technique and from 3.6mm to 6.7mm with the rim-removal technique (P>0.05). All orbits with dysthyroid optic neuropathy in the rim-sparing group and 87.5% of such orbits in the rim-removal group showed improved BCVA (P=0.321). Reductions in IOP, MRD-1, and MRD-2 were observed with both techniques. Patients in the rim-sparing group had greater improvements in GO-QOL appearance score (P=0.043). In conclusion, rim-sparing orbital decompression provides efficacious outcomes with greater improvements in patient quality of life than the rim removal technique. The rim-sparing technique should be considered as a preferable option because it preserves the integrity of the lateral vertical maxillary buttress and bony protection for the orbital contents. PMID- 30442553 TI - Response to the Letter to the Editor regarding "Impact of crack cocaine use on the occurrence of oral lesions and micronuclei". PMID- 30442554 TI - Cost analysis of oral and maxillofacial free flap reconstruction for patients at an institution in China. AB - Free flap transplantation has become a mainstay for the restoration of oral and maxillofacial defects. However, the complexity of the surgical procedure and long hospitalization time result in high hospitalization costs. This study was performed to retrospectively analyse the composition of hospitalization expenses and factors influencing this for 507 patients who underwent oral and maxillofacial free flap transplantation at a representative medical institution in China. The aim was to provide evidence for the reasonable control of expenditure and effective utilization of medical resources, and to gain an indirect reflection of the healthcare model characteristics of public hospitals in China. The average hospitalization cost was found to be US$ 9265+/-2284. Factors affecting hospitalization expenses were the type of free flap, tracheotomy, postoperative complications, and length of stay. The largest proportion of hospitalization expenses was the cost of materials (44.94%). Although the total hospitalization cost was lower than that in Western countries, the medical burden of patients was higher, and the corresponding medical charges do not fully reflect the value of medical services. We recommend reducing hospitalization expenses and the medical burden by shortening the hospital stay, selecting reasonably priced medical materials, strengthening airway management of patients undergoing tracheotomy, and enhancing the control and treatment of comorbidities in order to reduce the incidence of postoperative complications. PMID- 30442555 TI - Injury patterns of medial meniscus posterior root tears. AB - INTRODUCTION: Medial meniscus posterior root tear (MMPRT) can occur in middle aged patients who have a posteromedial painful popping during light activities. MMPRTs are more common in patients with increased age, female gender, sedentary lifestyle, obesity, and varus knee alignment. However, injury mechanisms of minor traumatic MMPRTs are still unclear. We hypothesized that high flexion activities are the major cause of MMPRTs. The aim of this study was to clarify injury patterns of MMPRTs. MATERIALS AND METHODS: One hundred patients were diagnosed having MMPRTs after posteromedial painful popping episodes. Details of posteromedial painful popping episode, situation of injury, and position of injured leg were obtained from the patients by careful interviews. Injury patterns were divided into 8 groups: descending knee motion, walking, squatting, standing up action, falling down, twisting, light exercise, and minor automobile accident. RESULTS: A descending knee motion was the most common cause of MMPRTs (38%) followed by a walking injury pattern (18%) and a squatting action related to high flexion activities of the knee (13%). The other injury patterns were less than 10%. DISCUSSION: Descending knee motions associated with descending stairs, step, and downhill slope are the most common injury pattern of MMPRTs. High flexion activities of the knee are not the greatest cause of MMPRTs. Our results suggest that the descending action with a low knee flexion angle may trigger minor traumatic MMPRTs. LEVEL OF EVIDENCE: IV, retrospective cohort study. PMID- 30442556 TI - A Regional Network Organization for Thrombectomy for Acute Ischemic Stroke in the Anterior Circulation; Timing, Safety, and Effectiveness. AB - BACKGROUND: Mechanical thrombectomy (MT) in association with intravenous thrombolysis is recommended for treatment of acute ischemic stroke (AIS), with large vessel occlusion (LVO) in the anterior circulation. Because MT is only available in comprehensive stroke centers (CSC), the challenge of stroke organization is to ensure equitable access to the fastest endovascular suite. Our aim was to evaluate the feasibility, efficacy, and safety of MT in patients initially managed in 1 CSC (mothership), compared with patients first managed in primary stroke center (PSC), and then transferred to the CSC for MT (drip-and ship). METHODS: We retrospectively analyzed 179 consecutive patients (93 in the mothership group and 86 in the drip-and-ship group), with AIS secondary to LVO in the anterior cerebral circulation and a clinical-radiological mismatch (NIHSS >= 8 and DWI-ASPECT score >=5), up to 6 hours after symptoms onset. We evaluated 3 month functional modified Rankin scale (mRS), periprocedural time management, mortality, and symptomatic intracranial haemorrhage (sICH). RESULTS: Despite significant longer process time in the drip-and-ship group, mRS <= 2 at 3 months (39.8% versus 44.1%, P = .562), Thrombolysis in cerebral infarction 2b-3 (85% versus 78%, P = .256), and sICH (7.0% versus 9.7%, P = .515) were similar in both group regardless of baseline clinical or radiological characteristics. After multivariate logistic regression, the predictive factors for favorable outcome were age (odds ratio [OR] -5years= 1.32, P < .001), initial NIHSS (OR -5points = 1.59, P = .010), absence of diabetes (OR = 3.35, P = .075), and the delay magnetic resonance imagining-puncture (OR -30min = 1.16, P = .048). CONCLUSIONS: Our study showed encouraging results from a regional protocol of MT comparing patients transferred from PSC or brought directly in CSC. PMID- 30442557 TI - Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels as a Biomarker of Acute Intracerebral Hemorrhage. AB - BACKGROUND: Correct diagnosis of cerebral stroke type, hemorrhagic or ischemic, is essential in the early stage to establish the optimum treatment. The diagnosis is mainly determined based on imaging studies. Other more available diagnostic methods are desirable, such as blood sample examination. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) is very important in vascular dysfunction induced by oxidized low-density lipoprotein, including cell apoptosis. The present study evaluated LOX-1 as a biomarker for cerebral stroke. SUBJECTS AND METHODS: Patients with newly diagnosed stroke were prospectively enrolled between February and July 2014. LOX-1 serum values were measured twice, within 24 hours and 2 months after the onset. RESULTS: A total of 16 patients were enrolled; 7 patients with intracerebral hemorrhage (ICH) and 9 patients with cerebral infarction. Median LOX-1 values of patients with ICH and infarction in the acute phase were 1825.8 and 593.9 pg/mL, respectively, significantly higher in patients with ICH than in patients with infarction (P < .0001). CONCLUSION: LOX-1 serum level has potential as a biomarker of ICH. PMID- 30442558 TI - Intraindividual comparison of 68Ga-DOTATATE PET / CT vs 11C-Choline PET / CT in patients with prostate cancer in biochemical relapse: in vivo evaluation of the expression of somatostatin receptors. AB - BACKGROUND AND OBJECTIVES: To prospectively compare the detection rate of 68Ga DOTATATE versus 11C-choline PET/CT in patients with prostate cancer in biochemical relapse, and to evaluate somatostatin receptor expression in vivo to plan targeted therapies (177Lu-DOTATATE). MATERIAL AND METHODS: We prospectively analysed 64 patients with biochemical relapse (median PSA: 4.25 ng/mL). A PET/CT was performed with 11C-choline, and another with 68Ga-DOTATATE. The SUVmax was measured in all lesions. The correlative images, histopathology and/or clinical and biochemical follow-up were taken as the reference standard. RESULTS: The overall detection rate per patient was 48.43% for 68Ga-DOTATATE and 46.87% for 11C-choline. The results were concordant in 53 cases (82.81%). The maximum SUV of 11C-choline was significantly higher than that of 68Ga-DOTATATE for all the concordant lesions (n=130): 6.17 (1.7-15.5) versus 4.38 (1.37-26.7), median (range) for each radiotracer, respectively (p < .0001). The sensitivity and specificity values per patient were the same for both techniques: 0.82 (0.65 0.93) and 0.9 (0.73-0.98), respectively. Although the difference was not significant, the sensitivity was lower in patients with lower PSA levels: 0.63 vs. 0.89; p=.13. A significant correlation was found between the SUVmax of both tracers (r = 0.41, n = 130, p <.0001). CONCLUSIONS: 68Ga-DOTATATE PET/CT and 11C choline PET/CT seem to have a high capacity to detect pathological lesions in the assessment of patients with prostate cancer with biochemical relapse. Further studies are required to test the potential complementary value of these PET/CT techniques, and to evaluate the potential role of 8Ga-DOTATATE for planning somostatin receptor-mediated therapies (177Lu-DOTATATE). PMID- 30442559 TI - Anthropometric indices to predict insulin resistance in women with polycystic ovary syndrome in China. AB - RESEARCH QUESTION: Which anthropometric index (waist-to-height ratio, waist circumference, waist-to-hip ratio and body mass index) is the best in predicting insulin resistance among Chinese women with polycystic ovary syndrome? DESIGN: A total of 1124 patients with polycystic ovary syndrome at the Reproductive Endocrinology Division of West China Second University Hospital of Sichuan University were enrolled in this study. Identification of insulin resistance was based on homeostasis model assessment of insulin resistance scores 2.77 or over. Receiver operator characteristic analysis was carried out using the four anthropometric indices as the continuous variables and insulin resistance as the categorical variable to obtain the areas under the curve. RESULT: The area under the curve for the waist-to-height ratio (0.748 +/- 0.019) was greater than those for waist circumference (0.739 +/- 0.019), body mass index (0.738 +/- 0.017), and waist-to-hip ratio (0.659 +/- 0.020) in the prediction of insulin resistance. The waist-to-height ratio also had the highest Youden indices compared with those of waist circumference, body mass index, and waist-to-hip ratio; the waist-to-height ratio cut-off was 0.49. CONCLUSION: The waist-to-height ratio with a cut-off of 0.49 was the most accurate anthropometric indicator for predicting insulin resistance among Chinese women with polycystic ovary syndrome. PMID- 30442560 TI - The Single Word Auditory Comprehension (SWAC) test: A simple method to identify receptive language areas with electrical stimulation. AB - OBJECTIVES: Resective surgery for medically refractory epilepsy in proximity to speech receptive areas requires balancing adequate resection of the epileptogenic zone for optimal seizure control with preservation of function. We develop a simple test (Single Word Auditory Comprehension or SWAC) to localize speech receptive areas by evaluating patients' ability to comprehend a single word. METHODS: Patients were studied during presurgical or intraoperative assessment for epilepsy with intracranial electrodes. They were asked to listen to a common word (target word) and to describe what it meant without saying the target word. Electrical stimulation (trains of biphasic 2-ms pulses, 50 Hz for 3 s) was delivered while the patient listened to the target word, not while the patient explained the meaning of the word. In six patients, SWAC test was carried out during extraoperative chronic recordings, and in one patient in the operating theater under local anesthesia. RESULTS: Among the 7 patients where the test identified deficits, 6 underwent resection (4 temporal, 1 supramarginal, and 1 occipital). Two patients showed temporary minor speech deficits after resection. No patient showed permanent speech deficits after resection. CONCLUSION/SIGNIFICANCE: The SWAC test is reliable, simple and fast to implement, and suitable for intraoperating mapping. It could be used as a simple initial test to identify receptive language areas where more complex additional tests can be performed. PMID- 30442562 TI - Does attending a Delphi consensus conference impact surgeon attitudes? Survey results from the Americas HepatoPancreatoBiliary Association consensus conference on small asymptomatic pancreatic neuroendocrine tumors. AB - BACKGROUND: Management of asymptomatic small well-differentiated (panNET) <2 cm remains controversial. A consensus conference was held on this topic. The impact of attending the conference and participating in the audience response survey on surgeon's clinical approach to pancreatic neuroendocrine tumors was assessed. METHODS: Audience members were surveyed using a smartphone real-time response system at the beginning and end of the conference. RESULTS: The majority of 75 attendees underwent fellowship training, and 30% had >10 years experience as attending surgeons. Previously published consensus statements on the topic were considered insufficient to guide surgical practice by 82% of attendees, and over 96% desired additional data. After review of the data, consensus statements, and decision-making process, a significant number of participants changed their opinions regarding indications for tissue biopsy (p = 0.001), size thresholds for excision (p = 0.002), and regional lymph node dissection (p = 0.002) independent of whether a consensus was reached by the content-expert panel. CONCLUSIONS: This represented the first Delphi process consensus on the topic, and the survey confirmed the topic as well-chosen and timely. Attendees changed opinions on management of panNET regardless of whether formal consensus was reached. Therefore, statements of consensus combined with presentation of literature and live discussion served to impact attendees' approach to this disease. PMID- 30442563 TI - Short Stay EVAR is Safe and Cost Effective. AB - INTRODUCTION: Reducing length of stay (LOS) following surgery offers the potential to improve resource utilisation. Endovascular aneurysm repair (EVAR) is now delivered with a low level of morbidity and as such may be deliverable as a "23 hour stay" intervention. This systematic review aims to assess the safety and feasibility of a short stay EVAR pathway. METHODS: A database search of Ovid MEDLINE (1996 - April 2018) and Embase (1974 - April 2018) was completed. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. A Newcastle-Ottawa Scale was applied to assess study bias. RESULTS: In total, 570 papers were identified through the literature search, of which 32 abstracts were screened. This led to nine papers being assessed for eligibility. From five suitable studies, 450 (75%) patients were successfully discharged the same or next day after EVAR. Complications most often occurred within 3 hours of surgery, and major complications requiring intensive treatment unit admission occurred within 6 hours. Readmission rates were 0-5% for those discharged early, with no difference in 30 day readmission. Early discharge led to a statistically significant cost saving of L13,360 (LOS four days) to L9844 (LOS one day). CONCLUSION: Selected patients can safely undergo EVAR using a short stay pathway. A period of monitoring 6 h post-operatively for low risk patients would be sufficient. Reducing length of stay after EVAR in the UK from the current median of three days to 1.5 days would free 4361 bed days and lead to a saving of approximately L1,800,000 annually. PMID- 30442561 TI - Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults. AB - BACKGROUND: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0.012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 * 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 * 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH. PMID- 30442564 TI - Associations between county-level voter turnout, county-level felony voter disenfranchisement, and sexually transmitted infections among women in the Southern United States. AB - PURPOSE: Voting may play a critical role in the allocation of social and structural resources to communities, which in turn shapes neighborhood environments, and ultimately, an individual's sexually transmitted infection (STI) risk. We assessed relationships among county-level voter turnout and felony voter disenfranchisement, and STIs. METHODS: This cross-sectional multilevel analysis included 666 women in Alabama, Florida, Georgia, Mississippi, and North Carolina enrolled in the Women's Interagency HIV Study between 2013 and 2015. Having a baseline bacterial STI (chlamydia, gonorrhea, trichomoniasis, or early syphilis) was determined by laboratory testing. We used generalized estimating equations to test relationships between county-level voter turnout in the 2012 general election, county-level percentage of felony disenfranchised voters, and STI prevalence. RESULTS: Eleven percent of participants had an STI. Higher voter turnout corresponded to lower STI prevalence (prevalence ratio = 0.84, 95% confidence interval = 0.73-0.96 per 4 percentage point higher turnout). Greater felony voter disenfranchisement corresponded to higher STI prevalence (prevalence ratio = 1.89, 95% confidence interval = 1.10-3.24 per 4 percentage point higher disenfranchisement). CONCLUSIONS: STI prevalence was inversely associated with voter turnout and positively associated with felony voter disenfranchisement. Research should assess causality and mechanisms through which civic engagement shapes sexual health. Expanding political participation, including eliminating discriminatory voting laws, could influence sexual health. PMID- 30442565 TI - Novel technique of filler injection in the temple area using the vein detection device. PMID- 30442566 TI - Epstein-Barr Virus-Positive Mucocutaneous Ulcer: Case Report and Review of the First 100 Published Cases. PMID- 30442568 TI - Bryan Traynor: serious science from a funny fellow. PMID- 30442567 TI - Change in Pain Score after Administration of Analgesics for Lower Extremity Fracture Pain during Hospitalization. AB - BACKGROUND: Effective acute pain management following injury is critical to improve short-and long-term patient outcomes. Analgesics can effectively reduce pain intensity, yet half of injury patients report moderate to severe pain during hospitalization. PURPOSE: The primary aim of this study was to identify the analgesic, different analgesic combinations, or analgesic and adjuvant analgesic combination that generated the largest percent change from pre- to post-analgesic pain score. DESIGN: This was a descriptive retrospective cohort study of 129 adults admitted with lower extremity fractures to a trauma center. METHODS: Name, dose, and frequency of analgesics and adjuvant analgesics administered from admission to discharge were collected from medical records. Percent change was calculated from pain scores documented on the 0-10 numeric rating scale. RESULTS: The analgesic with largest percent change from pre- to post-administration pain score was hydromorphone 2 mg IV (53%) for the emergency department and morphine 4 mg IV (54%) for the in-patient unit. All analgesics administered in the emergency department and ~50% administered on the in-patient unit produced a minimal (15%) decrease in pain score. CONCLUSIONS: This study revealed that few analgesics administered in the emergency department and the in-patient unit to patients with lower extremity fractures provide adequate pain relief. In the emergency department, all analgesics administered resulted in at least minimal improvement of pain. On the in-patient unit 13 analgesic doses resulted at least minimal improvement in pain while nine doses did not even reach 20% change in pain. Findings from this study can be used guide the treatment of fracture pain in the hospital. PMID- 30442569 TI - Factors Influencing Dietary Practices Among Ghanaian Residents and Liberians Living in a Protracted Refugee Situation in Ghana. AB - OBJECTIVE: Examine dietary practices among Liberian refugees living in a protracted refugee situation and Ghanaians living among them. DESIGN: Qualitative data were collected via audio-taped in-depth interviews as part of a larger mixed methods cross-sectional study. SETTING: Buduburam Refugee Settlement and neighboring villages, Ghana. PARTICIPANTS: Twenty-seven Liberian and Ghanaian women aged >=16 years, who lived with >=1 other female generation. PHENOMENON OF INTEREST: Similarities and differences in factors influencing dietary practices among Liberian refugees living in Buduburam Refugee Settlement and Ghanaians living in and around this settlement. ANALYSIS: Domains, themes, and subthemes were confirmed through a highly iterative coding and consensus process. ATLAS.ti (version 7.5.10) was used to finalize coding and extract quotations. RESULTS: Seven domains emerged forming direct and indirect pathways influencing dietary patterns among Liberian refugees and Ghanaians: social support, food availability, nutrition knowledge, cultural food beliefs, food access, food preparation, and national identity. CONCLUSIONS AND IMPLICATIONS: Findings provide important insights into crucial factors driving dietary practices among refugees and local communities in and around a former protracted refugee settlement. Results strongly suggest that nutrition education, food availability, and access issues should be addressed with culturally sensitive programs targeting both the refugee and host communities. PMID- 30442570 TI - Intrapersonal and Environmental Barriers to Physical Activity Among Blacks and Latinos. AB - OBJECTIVE: To understand perceived barriers and facilitators to physical activity (PA) among at-risk African American and Hispanic adolescents and adults in a low income community. DESIGN: Qualitative research was conducted in 2014-2015 using focus groups and a sociodemographic survey. SETTING: Three high schools in South Los Angeles, California. PARTICIPANTS: Eight high school-aged adolescent focus groups (n = 64) and 8 adult focus groups (n = 47). PHENOMENON OF INTEREST: Perceived barriers and facilitators to PA among predominantly obese and overweight African American and Hispanic adolescents and adults. ANALYSIS: Groups were audio recorded, transcribed, coded, and analyzed using an inductive approach. RESULTS: Participants reported that PA resources were available on school campuses (eg, sports teams) and in the community (eg, sidewalks, local parks, fitness classes). Key barriers to PA were intrapersonal (lack of motivation and time constraints) and environmental (safety concerns), whereas facilitators included interpersonal factors (social support). Participants provided valuable insights, including recommendations to increase noncompetitive programs at schools, develop shared-use agreements, and address safety concerns at local parks and public recreational spaces. CONCLUSIONS AND IMPLICATIONS: The findings suggest that future efforts to promote PA among at-risk minority groups should address intrapersonal and social environmental factors. Community-based programmatic and policy recommendations are provided. PMID- 30442571 TI - Molecular survey and genetic characterization of Anaplasma marginale isolates in cattle from two regions of Russia. AB - Anaplasma marginale is an intraerythrocytic tick-borne rickettsial pathogen that causes bovine anaplasmosis, an economically important disease of cattle worldwide. Major surface protein MSP1alpha has been used as a stable marker in identifying geographical strains of A. marginale. The genetic diversity of A. marginale based on MSP1alpha has been reported in several countries all over the world. Only a few molecular surveys of A. marginale strains have been conducted in Russia. The aim of this study was molecular detection and characterization of A. marginale isolates in cattle from two regions of Russia. Blood samples from 62 cattle were collected and screened for the presence of A. marginale by real-time PCR targeting the msp4 gene. Anaplasma marginale DNA was detected in 26 cattle (42%). The partial msp1alpha gene containing tandem repeat sequences and msp4 gene were amplified from msp4-positive samples, cloned and sequenced. Sequence analysis revealed that two msp4 genotypes were found. The genetic diversity of A. marginale strains was analyzed based on the MSP1alpha tandem repeats structure and 5'-UTR microsatellite. Sixteen new genotypes of A. marginale were found in 17 animals. Seven animals (41%) were infected by more than one genotype. Eight new tandem repeats are described for the first time. The number of repeats differed between 1 and 6 across the isolates. The msp1alpha microsatellite analysis revealed that six genotypes were identified; one of them was not previously described. Phylogenetic analysis revealed that Russian isolates formed four separate clades. The tandem repeat and microsatellite analyses of the msp1alpha gene showed a high genetic diversity among the isolates. The present study provided the first evidence of genetic diversity of A. marginale in cattle in Russia. PMID- 30442572 TI - Editorial overview: New advances in social neuroscience: from neural computations to social structures. PMID- 30442573 TI - Correction to Lancet Child Adolesc Health 2018; 2: 569-81. PMID- 30442574 TI - Using the theory of planned behavior to investigate community pharmacists' beliefs regarding engaging patients about prescription drug misuse. AB - INTRODUCTION: Opioid misuse causes over 50,000 deaths in America each year. Prescription drug monitoring program (PDMP) databases serve as a useful decision analysis tool in managing patients with known or potential opioid use disorder (OUD). To date, however, little research has sought to determine how pharmacists use PDMPs to engage patients with potential OUD. OBJECTIVES: To elicit modal salient beliefs of community pharmacists regarding their willingness to engage patients (i.e., provide interventional counseling) with suspected controlled substance misuse as identified from reviewing PDMP data. METHODS: Focus groups were conducted among Texas community pharmacists using the theory of planned behavior as a theoretical framework. Open-ended questions were used to capture behavioral beliefs, normative beliefs and control beliefs associated with pharmacists' engagement. Qualitative analysis using ATLAS.ti software was conducted to identify modal salient beliefs elicited by at least 20% of the study sample. RESULTS: A total of 31 community pharmacists participated. Fifteen behavioral beliefs, thirteen normative beliefs and eleven control beliefs were identified as modal salient beliefs. The most prevalent behavioral belief was the disadvantage associated with patient confrontations. Pharmacists also believed that engaging patients may cause loss of customers/business but may help patients receive appropriate counseling. When asked about their normative beliefs, pharmacists identified regulatory agencies (e.g., pharmacy boards, law enforcement) and family/friends of patients as groups of individuals who influence their willingness to refer. Time required for counseling was found to be the most commonly cited control belief. CONCLUSION: The results illustrate some of the challenges faced by community pharmacists when considering engagement of patients with misuse of prescription opioids. Addressing these barriers to patient engagement is critical to increasing pharmacist willingness to engage patients with potential OUD. PMID- 30442575 TI - No more status quo: A multi-dimensional framework for primary care medication use and safety. PMID- 30442576 TI - Health care for individuals with fragile X Syndrome: Understanding access and quality. AB - BACKGROUND: Previous research suggests that individuals with intellectual or developmental disabilities (IDD) may experience challenges accessing quality health care. OBJECTIVE/HYPOTHESIS: This study explored parent perceptions of access and quality of health care services for children with fragile X syndrome (FXS), the leading hereditary cause of intellectual/developmental disabilities. METHODS: Nearly 600 primary caregivers of at least one child with FXS completed an online survey on access, barriers, and quality of health care for their family member with FXS (N = 731). RESULTS: In a convenience sample of well-educated and affluent caregivers, the majority did not report experiencing difficulties with access to services. Caregivers of younger children and those with lower family incomes reported greater challenges with health care access. Nearly 40% of caregivers indicated that their child's PCP was not as knowledgeable about FXS related needs as they would prefer, indicating a possible knowledge gap on the part of providers. CONCLUSIONS: These factors represent potential barriers to quality health care for individuals with FXS, with potential lifelong effects ranging from delayed age of diagnosis to difficulty accessing a PCP in adulthood. PMID- 30442577 TI - Characteristics and outcomes of stent occlusion after iliocaval stenting. AB - OBJECTIVE: With increasing use of iliocaval stenting, complications have become more noticeable. Stent occlusion is one such outcome that has not been studied in detail. Characteristics of stent occlusion in addition to outcomes after recanalization are presented. METHODS: An analysis of 3468 initial iliocaval stents placed during an 18-year period from 1997 to 2015 was performed. A total of 102 stent occlusions were identified, amounting to a 3% stent occlusion rate. Characteristics evaluated included onset after stent placement, techniques used for restoring patency, and their outcome. Kaplan-Meier analysis was used to assess stent patency. Regression analysis was used to evaluate risk factors for stent occlusion. RESULTS: Stent occlusions occurred at a median of 5.8 months after placement. The occluded stent could be reopened after a wide range of intervals, the longest being 14 years. The majority (69%) of occlusions were chronic (>30 days) and the remainder (31%) were acute; 77% of the occlusions occurred in post-thrombotic limbs. The most common technique used to recanalize the acutely occluded stent was pharmacomechanical thrombectomy, whereas wire recanalization with balloon angioplasty was the technique most used for chronic occlusions. Of the 102 occluded stents, patency was achieved in 75 of 88 (84%) attempts. After successful recanalization, the median primary patency was 7 +/- 1.9 months, median primary assisted patency was 7.5 +/- 3.5 months, and median secondary patency was 25 +/- 8.3 months. Clinically, there was improvement in the visual analog scale pain scores from a median of 3.5 to 1 (P < .01), in the median grade of swelling from 2 to 1 (P < .01), and in the mean Venous Clinical Severity Score from 6.4 to 3.8 (P < .01) after recanalization. A 40% ulcer healing rate was noted after recanalization during a median follow-up period of 17 months. There were no significant adverse events or mortality. Regression analysis revealed stent placement for native vein occlusion as the only statistically significant predictor of stent occlusion. CONCLUSIONS: Stent occlusion after iliocaval stenting is a rare occurrence. Recanalization of occluded stents can be performed with minimal morbidity even months to years after occlusion with good outcomes. Long-term patency of occluded stents that were recanalized is poor compared with patency of the initially placed stent. PMID- 30442578 TI - Discussion. PMID- 30442579 TI - Increased risk of acute kidney injury with percutaneous mechanical thrombectomy using AngioJet compared with catheter-directed thrombolysis. AB - OBJECTIVE: The objective of this study was to investigate the risk of postoperative acute kidney injury (AKI) in patients with acute iliofemoral deep venous thrombosis (IFDVT) who underwent percutaneous pharmacomechanical thrombectomy (PMT) using AngioJet (Boston Scientific, Marlborough, Mass) or catheter-directed thrombolysis. METHODS: Electronic medical records of patients with acute IFDVT from January 2014 to September 2017 were reviewed. Those who received PMT with AngioJet (AJ-PMT group) or catheter-directed thrombolysis (CDT group) were included in this study. Baseline characteristics were recorded and compared. Postoperative serum creatinine concentration was compared with baseline serum creatinine concentration to determine the occurrence of postoperative AKI. Hemolysis was diagnosed on the basis of the decrease of hematocrit (HCT) and the occurrence of hematuria. The incidence of postoperative AKI in the two groups was analyzed. Univariable analysis and logistic regression analysis were used to determine risk factors that contribute to postoperative AKI. RESULTS: A total 198 patients with acute IFDVT were included (79 in the AJ-PMT group, 119 in the CDT group). Baseline data of the two groups were of no statistical difference. The AJ PMT group suffered more from acute hemolysis (P = .018). Compared with baseline HCT, the absolute HCT reduction of each group was of statistical significance (P < .01). The percentage change of absolute HCT of the two groups was of statistical significance (P < .01). Univariate analysis and multivariate analysis demonstrated that percutaneous AJ-PMT (odds ratio [OR], 2.82; 95% confidence interval [CI], 1.16-6.82; P = .02), history of major surgery within 3 months of endovascular intervention (OR, 8.51; 95% CI, 2.90-24.94; P < .01), and HCT drop >14% (OR, 2.73; 95% CI, 1.08-6.87; P = .03) are independent risk factors that raise the odds of postoperative AKI. CONCLUSIONS: In patients with acute IFDVT, AJ-PMT will raise the risk of postoperative AKI compared with CDT, especially in patients with a history of major surgery within 3 months of endovascular intervention. AJ-PMT causes more hemolysis and hematuria. An HCT drop >14% may indicate upcoming AKI. PMID- 30442580 TI - Treatment pattern of consecutive patients with chronic venous disease. AB - BACKGROUND: No clear data exist on the treatment patterns in patients with chronic venous disease. This study was designed to determine how such patients were treated in our center. METHODS: Consecutive patients presenting for a vein consultation at our center were collected during a 9-month period, allotting for at least 6 months of follow-up. All patients had a detailed history and physical examination by experienced vascular surgeons and a complete venous ultrasound evaluation by registered vascular technologists having experience in venous imaging. Charts were reviewed for patient factors including body mass index, age, clinical class (Clinical, Etiology, Anatomy, and Pathophysiology [CEAP] classification), and treatment. Deidentified data from the chart review were entered into a local database. Queries were designed to identify trends in the data. The results of the queries were exported to a spreadsheet program for analysis per patient and per limb. RESULTS: There were 506 patients evaluated for venous disease during a period of 9 months. We identified 200 patients with chronic venous disease who required superficial vein treatment. There were 136 (68%) women. Ablation was required in 156 patients (78%), whereas 44 (22%) required only adjunctive therapy (microphlebectomy or sclerotherapy). The average number of ablations in patients with venous disease was 1.3 (259 ablations in 200 patients). In patients who needed at least one ablation, the average was 1.7 ablations per patient (259 ablations in 156 patients). Unilateral ablation was done in 94 patients (60%), and 62 patients (40%) had bilateral treatment. Of those who underwent unilateral ablations, 61% required adjunctive treatment of the contralateral limb. In patients who required only adjunctive therapy (no ablation), 73% underwent bilateral treatment. There were 182 limbs (45.5%) that did not require ablation as no reflux was found in the saphenous systems. Of the 156 patients who underwent ablation, 218 limbs had at least one ablation; 52% of limbs had C2 disease and on average underwent 1.1 ablations/limb. Only 7 of 113 (6%) limbs required more than one ablation. Average ablations per limb increased with clinical class, C3 having 1.2 ablations/limb, C4 having 1.4 ablations/limb, and C5 and C6 having 1.56 ablations/limb. CONCLUSIONS: Patients with venous disease required on average 1.3 ablations/patient. Most (78%) require at least one ablation for an average of 1.7 ablations/patient. There were 182 limbs (45.5%) with no saphenous reflux that did not require an ablation. The average number of ablations/limb increased with CEAP class. PMID- 30442581 TI - Evaluation of patency rates of different lymphaticovenous anastomosis techniques and risk factors for obstruction in secondary upper extremity lymphedema. AB - OBJECTIVE: Lymphaticovenous anastomosis (LVA) is one of the surgical treatments for lymphedema. Lymphaticovenous side-to-end anastomosis (LVSEA) and lymphaticovenous end-to-end anastomosis (LVEEA) are the most commonly used procedures; however, only a few reports have evaluated direct anastomosis. We used indocyanine green fluorescence lymphography to evaluate and to compare both techniques. METHODS: Eighteen patients (67 anastomoses) with secondary upper extremity lymphedema were evaluated 6 months postoperatively. After injection of indocyanine green, anastomoses that were obviously patent were considered patent, and the others were considered unpatent. In addition, we evaluated the risk factors for obstruction using the following five points: dyeing of the lymphatic vessel by patent blue, lymphatic flow, venous regurgitation, lymphatic vessel degeneration, and runoff after the anastomosis. RESULTS: There were 44 LVSEAs and 23 LVEEAs performed, of which 14 (32%) and 8 (35%) were patent, respectively. Risk factors for obstruction in these 67 anastomoses were evaluated. However, no significant difference was found. CONCLUSIONS: Patency of an LVA anastomosis is not high and not different between LVSEA and LVEEA. However, if anastomotic occlusion occurs, lymphatic obstruction is more likely with LVEEA than with LVSEA. Therefore, when LVA is performed, we recommend LVSEA principally and LVEEA only when the potential for consequences and risk of obstruction are low. PMID- 30442582 TI - Persistently low inferior vena cava filter retrieval rates in a population-based cohort. AB - BACKGROUND: Practice patterns associated with inferior vena cava (IVC) filter placement have seen considerable variation in the last decade. We used a statewide administrative database to examine trends in IVC filter placement and retrieval in the general population. METHODS: We reviewed Florida state inpatient and ambulatory surgery databases from 2004 to 2014. International Classification of Diseases, Ninth Revision diagnosis and procedure codes and Current Procedural Terminology codes were searched for patients undergoing inpatient or outpatient IVC filter placement, and each patient was longitudinally tracked to the time of inpatient or outpatient filter retrieval. For inpatient filter placements, associated diagnoses were reviewed to identify indications for placement. Univariate and multivariate logistic regression models were constructed to identify factors associated with improved retrieval rates. RESULTS: During the 11 year period, 131,791 IVC filter placements were identified, with a 50% increase from 2004 to 2010 and a 24% decline from 2010 to 2014. Median age at filter placement was 71 years (interquartile range, 57-81 years). Mean follow-up after filter placement was 17.3 +/- 25.5 months. Only 8637 filters (6.6%) were retrieved. The annual retrieval rate trended upward, from 3.4% in 2004 to 8.5% in 2013 (P < .001). Median filter dwell time was 96.5 days (interquartile range, 44 178 days). Diagnoses associated with filter placement included venous thromboembolism (75.9%), trauma (35.0%), hemorrhage (29.9%), malignant disease (29.4%), and stroke (5.1%). Retrieval rates were highest in younger patients (34.0% in patients younger than 20 years) and lowest in Medicare patients (2.5%). In a multivariate logistic regression model, Medicare was associated with decreased retrieval rates (odds ratio, 0.33; 95% confidence interval, 0.31-0.35; P < .001) after adjusting for age and associated diagnoses. Weaker risk factors included increased age, white race, and diagnoses of deep venous thrombosis, pulmonary embolism, and malignant disease. A trauma diagnosis was associated with improved retrieval. To further investigate the Medicare effect, a propensity score-matched model was created to better account for confounding effects. In this model, Medicare persisted as a risk factor for decreased filter retrieval (odds ratio, 0.43; 95% confidence interval, 0.40-0.46; P < .001). CONCLUSIONS: IVC filter placements, after a substantial increase between 2004 and 2010, have been declining since 2010. Retrieval rates in the general population are steadily improving but continue to lag behind those described in center-specific literature. Increased age and Medicare as the primary payer are the strongest risk factors for lack of filter retrieval. Widespread improvements on a national scale are needed to improve the appropriateness of filter placements and to enhance filter retrieval rates. PMID- 30442583 TI - Surgical and endovascular central venous reconstruction combined with thoracic outlet decompression in highly symptomatic patients. AB - BACKGROUND: Subclavian vein stenosis or occlusion at the thoracic outlet is a problem associated with certain anatomic and environmental stresses (venous thoracic outlet syndrome [VTOS]), the presence of central venous catheters, and the high flows associated with arteriovenous (AV) access in the limb. We describe our experience with open and endovascular techniques for restoring patency in highly symptomatic patients. METHODS: A prospectively collected database of patients was queried for patients treated for central venous obstructive disease in the setting of highly symptomatic VTOS and ipsilateral AV access from October 2011 to August 2016. RESULTS: During the study period, 54 procedures were performed in 53 patients (68% male; mean age, 50.1 years). Indications for operation were venous outflow obstruction in patients with conventional VTOS (n = 19) or costoclavicular junction stenosis associated with ipsilateral dialysis access (n = 34). All patients had significant symptoms of swelling or pain. Eight patients underwent on-table pharmacomechanical thrombolysis for acute occlusion. All patients underwent costoclavicular junction decompression, 48 by infraclavicular first rib resection and 5 by claviculectomy; 6 patients underwent sternoclavicular rotation (Molina procedure) in addition to rib resection for further exposure. Surgical reconstruction of the vein was employed in 18 patients (33%); 9 underwent interposition grafting, 1 had jugular turndown, and 8 had patch angioplasty. The one patient undergoing two procedures suffered acute occlusion after patch repair followed by jugular turndown. Four patients underwent surgical reconstruction after thrombolysis. Endovascular procedures were performed in 36 patients (67%); 23 underwent venous angioplasty alone, and 13, all with hemodialysis access-associated stenosis, underwent stenting. Mean operative time was 135 (+/-63.5) minutes, and mean estimated blood loss was 238 (+/-261) mL. Median length of stay was 4 days. Perioperative complications were noted in 14 (26.4%) patients, including wound complications (n = 6), cardiac complications (n = 4), reocclusion (n = 3), and hemothorax requiring chest tube placement (n = 1) in a patient undergoing on-table thrombolysis. Mean follow-up was 13.6 (0.6-58.5) months. Initial clinical symptom relief was experienced in 100% of patients at the time of hospital discharge. During follow-up, 5 (9.4%) patients developed recurrent symptoms, 6 (11.3%) had reocclusion of the central system, and 16 (30.2%) required reintervention for restenosis, all but 2 in patients with ipsilateral hemodialysis access. Mean time to reintervention was 134 (+/-285) days. CONCLUSIONS: Given our decision-making threshold, both open and endovascular procedures are associated with relatively low morbidity and high efficacy for treatment of central venous occlusion in both symptomatic VTOS and AV access-associated subclavian vein disease. Restenosis is common in patients with a patent ipsilateral hemodialysis access. PMID- 30442584 TI - What Is Better for Predicting Morbidity of Robotic Partial Nephrectomy-A Score or Your Clinical Judgement? AB - BACKGROUND: Little is known about the predictive value of surgeon's judgement to estimate perioperative outcomes following robotic partial nephrectomy (RPN). OBJECTIVE: To evaluate the accuracy of surgeon's intuition to estimate perioperative outcomes of patients undergoing RPN and compare its predictive value with that of objective scoring systems. DESIGN, SETTING, AND PARTICIPANTS: We prospectively analysed 100 consecutive patients who underwent RPN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RENAL, PADUA, and MAP scores were calculated based on preoperative imaging. The surgeon gave a subjective estimation of the technical difficulty and the risk of postoperative complications of RPN immediately before and after surgery using a visual analogue scale (VAS). Correlation between scores, VAS, estimated blood loss (EBL), operative time (OT), and warm ischaemia time (WIT) were examined. Logistic regression analyses were performed to identify the best predictors of overall complications. Receiver operating characteristic (ROC) curve analysis was used to assess the accuracy of VAS and scoring systems to predict trifecta achievement. RESULTS AND LIMITATIONS: RENAL, PADUA, and MAP scores significantly correlated with surgeon's pre- and postoperative VAS evaluation, with the RENAL score showing the strongest correlation (r=0.49 and r=0.34, respectively). Pre- and postoperative VAS scores had the strongest correlation with EBL (r=0.48 and r=0.59, respectively), OT (r=0.44 and r=0.65, respectively), and WIT (r=0.37 and r=0.47, respectively). In multivariate analysis adjusted for anticoagulant/antiplatelet treatment, body mass index, surgeon's experience, and Charlson comorbidity index, only surgeon's prediction could significantly predict overall complications (odds ratio=5.42, p <0.001). Finally, surgeon's intuition was better to predict trifecta accomplishment than all radiological scores (ROC areas under the curves were 0.76 and 0.77 for pre- and postoperative VAS scores, respectively). CONCLUSIONS: Surgeon's clinical assessment is a good predictor of perioperative outcomes of RPN and seems to perform better than conventional scores. PATIENT SUMMARY: In this report, we found that surgeon's clinical feeling can better predict perioperative morbidity of robotic partial nephrectomy than conventional radiological scores. PMID- 30442585 TI - Corrigendum to "Trunk sway response to consecutive slip perturbations between subjects with and without recurrent low back pain" [Musculoskelet. Sci. Pract. 33C (2018) 84-89]. PMID- 30442586 TI - Pneumonia is a neglected problem: it is now time to act. PMID- 30442587 TI - Effectiveness of influenza vaccination on influenza-associated hospitalisations over time among children in Hong Kong: a test-negative case-control study. AB - BACKGROUND: The protection conferred by influenza vaccination is generally thought to last less than a year, necessitating annual revaccination. However, the speed with which influenza vaccine effectiveness might decline during a year is unknown, which is of particular importance for locations with year-round influenza activity. We aimed to assess how influenza vaccine effectiveness changes by time intervals between vaccination and admission to hospital, taking advantage of almost year-round circulation of influenza in Hong Kong. METHODS: In this test-negative case-control study, we analysed vaccine effectiveness in children (aged 6 months to 17 years) who were admitted to hospital in Hong Kong over 5 consecutive years (2012-17). We included those who were admitted to general wards in four public hospitals in Hong Kong with a fever (>=38 degrees C) and any respiratory symptom, such as runny nose, cough, or sore throat. We used direct immunofluorescence assay and reverse transcription PCR to detect influenza virus infection, and recorded children's influenza immunisation history. We compared characteristics of positive cases and negative controls and examined how vaccine effectiveness changed by time between vaccination and admission to hospital with regression analyses. FINDINGS: Between Sept 1, 2012, and Aug 31, 2017, we enrolled 15 695 children hospitalised for respiratory infections, including 2500 (15.9%) who tested positive for influenza A or B and 13 195 (84.1%) who tested negative. 159 (6.4%) influenza-positive cases and 1445 (11.0%) influenza-negative cases had been vaccinated. Most vaccinations were done by December of each influenza vaccination season. Influenza-related admissions to hospital occurred year-round, with peaks in January through March in most years and a large summer peak in 2016; pooled vaccine effectiveness for children of all ages was 79% (95% CI 42-92) for September to December, 67% (57-74) for January to April, and 43% (25-57) for May to August. Vaccine effectiveness against influenza A or B was estimated as 79% (95% CI 64-88) within 0.5-2 months of vaccination, 60% (46-71) within >2-4 months, 57% (39-70) within >4-6 months, and 45% (22-61) within >6-9 months. In separate analyses by type and subtype, we estimated that vaccine effectiveness declined by 2-5 percentage points per month. INTERPRETATION: Influenza vaccine effectiveness decreased during the 9 months after vaccination in children in Hong Kong. Our findings confirm the importance of annual vaccination in children. Influenza vaccines that provide broader and longer-lasting protection are needed to provide year-round protection in regions with irregular influenza seasonality or lengthy periods of influenza activity. FUNDING: Health and Medical Research Fund, Hong Kong and the Research Grants Council, Hong Kong. PMID- 30442589 TI - Concerns over low uptake of flu vaccination in social care. PMID- 30442588 TI - Perioperative mortality and morbidity after sublobar versus lobar resection for early-stage non-small-cell lung cancer: post-hoc analysis of an international, randomised, phase 3 trial (CALGB/Alliance 140503). AB - BACKGROUND: Increased detection of small-sized, peripheral, non-small-cell lung cancer has renewed interest in sublobar resection instead of lobectomy, the traditional standard of care for early-stage lung cancer. We aimed to assess morbidity and mortality associated with lobar and sublobar resection for early stage lung cancer. METHODS: CALGB/Alliance 140503 is a multicentre, international, non-inferiority, phase 3 trial in patients with peripheral non small-cell lung cancer clinically staged as T1aN0. Patients were recruited from 69 academic and community-based institutions in Australia, Canada, and the USA. Patients were randomly assigned intraoperatively to either lobar or sublobar resection. The random assignment was based on permuted block randomisation without concealment and was stratified according to radiographic tumour size, histology, and smoking status. The primary endpoint of the trial is disease-free survival; here, we report a post-hoc, exploratory, comparative analysis of perioperative mortality and morbidity associated with lobar and sublobar resection. Perioperative mortality was defined as death from any cause within 30 days and 90 days of surgical intervention and was calculated for all randomised patients. Morbidity was graded using Common Terminology Criteria for Adverse Events version 4.0. All analyses were done on an intention-to-treat basis for randomised patients with data available. This trial is registered with ClinicalTrials.gov, number NCT00499330. FINDINGS: Between June 15, 2007, and March 13, 2017, 697 patients were randomly allocated to either lobar resection (n=357) or sublobar resection (n=340; 59% wedge resection). Six (0.9%) patients died by 30 days, four (1.1%) after lobar resection and two (0.6%) after sublobar resection; by 90 days, ten (1.4%) patients had died, six (1.7%) after lobar resection and four (1.2%) after sublobar resection (difference at 30 days, 0.5%, 95% CI -1.1 to 2.3; difference at 90 days, 0.5%, 95% CI -1.5 to 2.6). An adverse event of any grade occurred in 193 (54%) of 355 patients after lobar resection and 172 (51%) of 337 patients after sublobar resection. Adverse events of grade 3 or worse occurred in 54 (15%) patients assigned lobar resection and in 48 (14%) patients assigned sublobar resection. No differences between surgical approaches were noted in cardiac or pulmonary complications. Grade 3 haemorrhage (requiring transfusion) occurred in six (2%) patients assigned lobar resection and eight (2%) patients assigned sublobar resection. Prolonged air leak occurred in nine (3%) patients after lobar resection and two (1%) patients after sublobar resection. INTERPRETATION: Our post-hoc analysis showed that perioperative mortality and morbidity did not seem to differ between lobar and sublobar resection in physically and functionally fit patients with clinical T1aN0 non small-cell lung cancer. These data may affect the daily choices made by patients and their doctors in establishing the best treatment approach for stage I lung cancer. FUNDING: National Cancer Institute. PMID- 30442590 TI - A new low represents a new high in surgical safety. PMID- 30442591 TI - How long are children protected by influenza vaccination? PMID- 30442592 TI - Improvement of a rapid direct blood culture microbial identification protocol using MALDI-TOF MS and performance comparison with SepsiTyper kit. AB - Fast diagnosis of pathogens is critical to guarantee the most adequate therapy for infections; bacterial culture methods, which constitute the actual gold standard, are precise and sensitive but rather slow. Today, new methods have been made available to enable faster diagnosis, with the Matrix-Assisted Laser Desorption Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS) technique being the most promising. Even if simpler and faster than traditional bacterial culture methods, analysis of positive blood cultures via MALDI-TOF MS requires a preliminary extraction process of samples. In this study, we compared two extraction protocols for bacterial identification directly from positive blood cultures using the Bruker MALDI Biotyper system (Bruker Daltonics, Billerica, MA). In particular, we evaluated the time employed and the overall performance for their accurate identification. In this work, the performances of a commercial extraction kit, named SepsiTyperTM Kit, and those of the protocol developed by Treibmann et al. were evaluated and proven to be similar. However, the SELTERS method represents the best compromise price/performance. Lastly, an in-house developed analysis protocol has been tested, and the introduced optimizations granted a performance level equal if not better than the SepsiTyper kit, a reduced processing time and reduced costs. PMID- 30442593 TI - Neuroergonomics of car driving: A critical meta-analysis of neuroimaging data on the human brain behind the wheel. AB - Car driving, an everyday life activity, has been under the scope of investigation for long. Neurosciences and psychology have contributed to better understand the human processes engaged while driving, to such an extent that a meta-analysis of all available fMRI data is now possible to extract the most relevant information. Using the Activation Likelihood Estimation method, we therefore conducted such a meta-analysis on 9 studies, representing 27 neuroimaging contrasts and 131 participants. We identified a network composed of brain areas underlying the cognitive abilities required for driving: sensorimotor coordination, sensory and attentional processing, high-level cognitive control and allocation of attentional resources. We complemented this meta-analysis with a neuroergonomics approach combining driving control knowledge, distinguishing the strategical, tactical and operational levels, with neuroscientific knowledge and models on cognitive control operated by the prefrontal cortex. The results exposed the distinct neural circuits engaged behind the wheel depending on the task performed. Based on the combination of neuroscientific and ergonomic knowledge, a hybrid car driving framework is also proposed. PMID- 30442594 TI - Delimiting the knowledge space and the design space of nanostructured lipid carriers through Artificial Intelligence tools. AB - Nanostructured lipid carriers (NLC) are biocompatible and biodegradable nanoscale systems with extensive application for controlled drug release. However, the development of optimal nanosystems along with a reproducible manufacturing process is still challenging. In this study, a two-step experimental design was performed and databases were successfully modelled using Artificial Intelligence techniques as an innovative method to get optimal, reproducible and stable NLC. The initial approach, including a wide range of values for the different variables, was followed by a second set of experiments with variable values in a narrower range, more suited to the characteristics of the system. NLC loaded with rifabutin, a hydrophobic drug model, were produced by hot homogenization and fully characterized in terms of particle size, size distribution, zeta potential, encapsulation efficiency and drug loading. The use of Artificial Intelligence tools has allowed to elucidate the key parameters that modulate each formulation property. Stable nanoparticles with low sizes and polydispersions, negative zeta potentials and high drug loadings were obtained when the proportion of lipid components, drug, surfactants and stirring speed were optimized by FormRules(r) and INForm(r). The successful application of Artificial Intelligence tools on NLC formulation optimization constitutes a pioneer approach in the field of lipid nanoparticles. PMID- 30442595 TI - "Magnus nano-bullets" as T1/T2 based dual-modal for in vitro and in vivo MRI visualization. AB - Tissue specific T1/T2 dual contrast abilities for magnetic resonance imaging (MRI) have great significance in initial detection of cancer lesions. Herein, we developed a novel kind of Magnus nano-bullets (Mn-DTPA-F-MSNs) distinguished by magnetic (Fe3O4-NPs) head combined with mesoporous (SiO2) persist body, respectively. Subsequently, modify mesoporous SiO2 group and finally loaded with Mn2+. These Magnus nano-bullets have relaxivity value (r1 = 5.12 mM-1 s-1) and relaxivity value (r2 = 265.32 mM-1 s-1); they were > 2 folds in comparison to control at 3.0 T. Meanwhile, Magnus nano-bullets also offered significant enhancements for the detection of Glutathione (GSH), a biomarker that has been showed a redox responsive T1-weighted MRI effect in vitro and in vivo evaluations with good biocompatibility. Therefore, our finding endorses that Magnus nano bullets offer a "smart" and tremendous strategy for greater GSH responsive T1/T2 dual MRI image probes for future biomedical applications. PMID- 30442596 TI - Autophagy induction impairs Wnt/beta-catenin signalling through beta-catenin relocalisation in glioblastoma cells. AB - Autophagy is an evolutionary conserved process mediating lysosomal degradation of cytoplasmic material. Its involvement in cancer progression is highly controversial, due to its dual role in both limiting tumoural transformation and in protecting established tumoral cells from unfavorable conditions. Little is known about the cross-talk between autophagy and intracellular signalling pathways, as well as about autophagy impact on signalling molecules turnover. An aberrantly activated Wnt/beta-catenin signalling is responsible for tumour proliferation, invasion, and stemness maintenance. Here we show that autophagy negatively regulates Wnt/beta-catenin signalling in glioblastoma multiforme (GBM) cells, through Dishevelled degradation. We also provide the first evidence that autophagy promotes beta-catenin relocalisation within the cell, by inducing a decrease of the nuclear protein fraction. In particular, upon autophagy induction, beta-catenin appears mainly localized in sub-membrane areas where it associates with N-cadherin to form epithelial-like cell-cell adhesion structures. Our data indicate, for the first time, that autophagy induction results in Wnt signalling attenuation and in beta-catenin relocalisation within the GBM cell. These findings further support the idea that autophagy modulation could represent a potential therapeutical strategy to contrast GBM progression. PMID- 30442597 TI - Sparse EEG Source Localization Using LAPPS: Least Absolute l-P (0 < p < 1) Penalized Solution. AB - OBJECTIVE: The electroencephalographic (EEG) inverse problem is ill-posed owing to the electromagnetism Helmholtz theorem and since there are fewer observations than the unknown variables. Apart from the strong background activities (ongoing EEG), evoked EEG is also inevitably contaminated by strong outliers caused by head movements or ocular movements during recordings. METHODS: Considering the sparse activations during high cognitive processing, we propose a novel robust EEG source imaging algorithm, LAPPS (Least Absolute -P (0 < p < 1) Penalized Solution), which employs the -loss for the residual error to alleviate the effect of outliers and another -penalty norm (p=0.5) to obtain sparse sources while suppressing Gaussian noise in EEG recordings. The resulting optimization problem is solved using a modified ADMM algorithm. RESULTS: Simulation study was performed to recover sparse signals of randomly selected sources using LAPPS and various methods commonly used for EEG source imaging including WMNE, -norm, sLORETA and FOCUSS solution. The simulation comparison quantitatively demonstrates that LAPPS obtained the best performances in all the conducted simulations for various dipoles configurations under various SNRs on a realistic head model. Moreover, in the localization of brain neural generators in a real visual oddball experiment, LAPPS obtained sparse activations consistent with previous findings revealed by EEG and fMRI. CONCLUSION: This study demonstrates a potentially useful sparse method for EEG source imaging, creating a platform for investigating the brain neural generators. SIGNIFICANCE: This method alleviates the effect of noise and recovers sparse sources while maintaining a low computational complexity due to the cheap matrix-vector multiplication. PMID- 30442598 TI - Improved Decoupling for Low Frequency MRI Arrays using Non-conventional Preamplifier Impedance. AB - OBJECTIVE: In this study, we describe a method to improve preamplifier decoupling in low frequency MRI receive coil arrays, where sample loading is low and coils exhibit a high Q-factor. METHODS: The method relies on the higher decoupling obtained when coils are matched to an impedance higher than 50 Omega. Preamplifiers with inductive (and low resistive) input impedance, increase even further the effectiveness of the method. RESULTS: We show that for poorly sample loaded coils, coupling to other elements in an array is a major source of SNR degradation due to a reduction of the coil Q-factor. An 8-channel 13C array at 32 MHz for imaging of the human head has been designed following this strategy. The improved decoupling even allowed constructing the array without overlapping of neighboring coils. Parallel imaging performance is also evaluated demonstrating a better spatial encoding of the array due to its non-overlapped geometry. CONCLUSION: The proposed design strategy for coil arrays is beneficial for low frequency coils where the coil thermal noise is dominant. The method has been demonstrated on an 8-channel array for the human head for 13C MRI at 3 T (32 MHz), with almost 2-fold SNR enhancement when compared to a traditional array of similar size and number of elements. SIGNIFICANCE: The proposed method is of relevance for low frequency arrays, where sample loading is low, and noise correlation is high due to insufficient coil decoupling. PMID- 30442599 TI - Speed-of-Sound Imaging Based on Reflector Delineation. AB - OBJECTIVE: Speed-of-sound (SoS) has large potential for tissue and pathology differentiation. We aim to develop a novel Ultrasound Computed Tomography (USCT) technique that can reconstruct local SoS in tissue on conventional ultrasound machines with hand-held linear arrays. METHODS: A passive reflector is placed opposite the tissue sample as an echogenic reference to measure the time-of flight (ToF) of ultrasound wave- fronts. A Dynamic Programming algorithm provides a robust ToF measurements based on global optimization of all transmit- receive echo data. An Anisotropically-Weighted Total Variation (AWTV) algorithm allows sharp delineation of focal lesions based on limited-angle USCT data. RESULTS: Inclusions, which are not visible in conventional ultrasound, could be delineated in SoS images. AWTV allows to reconstruct focal lesions with a contrast-ratio of 93.7% of their nominal value, compared to that of 31.5% with conventional least squares based algebraic tomographic reconstruction. In full-wave simulations of realistic heterogeneous breast models, a high CR of 84.3% is observed, with the reconstruction filtering out background heterogeneity. In experiments, our proposed method quantifies SoS in a homogeneous background with an accuracy of 0.93ms, allowing to differentiate several tissue types. CONCLUSION: We validate our method using numerical simulations with ray-tracing and full- wave models, and phantom and ex-vivo data. Preliminary in- vivo results show the potential of this new technique to detect and differentiate malignant and benign lesions in the breast. SIGNIFICANCE: Breast cancer is the most common cancer in women. Ultrasound B-mode only provides qualitative information about breast lesions, whereas USCT can provide quantitative tissue imaging biomarkers, such as SoS. The proposed method can potentially be implemented as a complementary modality to ultrasound for tissue and disease differentiation. PMID- 30442600 TI - SPFTN: A Joint Learning Framework for Localizing and Segmenting Objects in Weakly Labeled Videos. AB - Object localization and segmentation in weakly labeled videos are two interesting yet challenging tasks. Models built for simultaneous object localization and segmentation have been explored in the conventional fully supervised learning scenario to boost the performance of each task. However, none of the existing works has attempted to jointly learn object localization and segmentation models under weak supervision. To this end, we propose a joint learning framework called Self-Paced Fine-Tuning Network (SPFTN) for localizing and segmenting objects in weakly labelled videos. Learning the deep model jointly for object localization and segmentation under weak supervision is very challenging as the learning process of each single task would face serious ambiguity issue due to the lack of bounding-box or pixel-level supervision. To address this problem, our proposed deep SPFTN model is carefully designed with a novel multi-task self-paced learning objective, which leverages the task-specific prior knowledge and the knowledge that has been already captured to infer the confident training samples for each task. By aggregating the confident knowledge from each single task to mine reliable patterns and learning deep feature representation for both tasks, the proposed learning framework can address the ambiguity issue under weak supervision with simple optimization. Comprehensive experiments on the large scale YouTube-Objects and DAVIS datasets demonstrate that the proposed approach achieves superior performance when compared with other state-of-the-art methods and the baseline networks/models. PMID- 30442601 TI - Robust Kronecker Component Analysis. AB - Dictionary learning and component analysis models are fundamental for learning compact representations relevant to a given task. The model complexity is encoded by means of structure, such as sparsity, low-rankness, or nonnegativity. Unfortunately, approaches like K-SVD that learn dictionaries for sparse coding via Singular Value Decomposition (SVD) are hard to scale, and fragile in the presence of outliers. Conversely, robust component analysis methods such as the Robust Principal Component Analysis (RPCA) are able to recover low-complexity representations from data corrupted with noise of unknown magnitude and support, but do not provide a dictionary that respects the structure of the data, and also involve expensive computations. In this paper, we propose a novel Kronecker decomposable component analysis model, coined as Robust Kronecker Component Analysis (RKCA), that combines ideas from sparse dictionary learning and robust component analysis. RKCA has several appealing properties, including robustness to gross corruption; it can be used for low-rank modeling, and leverages separability to solve significantly smaller problems. We design an efficient learning algorithm by drawing links with tensor factorizations, and analyze its optimality and low-rankness properties. The effectiveness of the proposed approach is demonstrated on real-world applications, namely background subtraction and image denoising and completion, by performing a thorough comparison with the current state of the art. PMID- 30442602 TI - Splenomegaly Segmentation on Multi-modal MRI using Deep Convolutional Networks. AB - The findings of splenomegaly, abnormal enlargement of the spleen, is a non invasive clinical biomarker for liver and spleen disease. Automated segmentation methods are essential to efficiently quantify splenomegaly from clinically acquired abdominal magnetic resonance imaging (MRI) scans. However, the task is challenging due to (1) large anatomical and spatial variations of splenomegaly, (2) large inter- and intra-scan intensity variations on multi-modal MRI, and (3) limited numbers of labeled splenomegaly scans. In this paper, we propose the Splenomegaly Segmentation Network (SS-Net) to introduce the deep convolutional neural network (DCNN) approaches in multimodal MRI splenomegaly segmentation. Large convolutional kernel layers were used to address the spatial and anatomical variations, while the conditional generative adversarial networks (GAN) were employed to leverage the segmentation performance of SS-Net in an end-to-end manner. A clinically acquired cohort containing both T1-weighted (T1w) and T2 weighted (T2w) MRI splenomegaly scans was used to train and evaluate the performance of multi-atlas segmentation (MAS), 2D DCNN networks, and a 3D DCNN network. From the experimental results, the DCNN methods achieved superior performance to the state-of-the-art MAS method. The proposed SS-Net method achieved the highest median and mean Dice scores among investigated baseline DCNN methods. PMID- 30442603 TI - Synthesizing Chest X-Ray Pathology for Training Deep Convolutional Neural Networks. AB - Medical datasets are often highly imbalanced with over-representation of prevalent conditions and poor representation of rare medical conditions. Due to privacy concerns, it is challenging to aggregate large datasets between health care institutions.We propose synthesizing pathology in medical images as a means to overcome these challenges. We implement a deep convolutional generative adversarial network (DCGAN) to create synthesized chest X-rays based upon a modest sized labeled dataset. We used a combination of real and synthesized images to train deep convolutional neural networks (DCNNs) to detect pathology across five classes of chest X-rays. Comparative study of DCNNs trained with combination of real and synthesized images showed that these networks can outperform similar networks trained solely with real images in pathology classification. This improved performance is largely attributable to the balancing of the dataset using DCGAN synthesized images, where classes that are lacking in example images are preferentially augmented. PMID- 30442604 TI - Impact of High-Intensity Ultrasound on Strength of Surgical Mesh when Treating Biofilm Infections. AB - The use of cavitation-based ultrasound histotripsy to treat infections on surgical mesh has shown great potential. However, any impact of the therapy on the mesh must be assessed before the therapy can be applied in the clinic. The goal of this study was to determine if the cavitation-based therapy would reduce the strength of the mesh thus compromising the functionality of the mesh. First, S. aureus biofilms were grown on surgical mesh samples and exposed to high intensity ultrasound pulses. For each exposure, the effectiveness of the therapy was confirmed by counting the number of colony forming units (CFUs) on the mesh. Most of the exposed meshes had no CFUs with an average reduction of 5.4-log10 relative to the sham exposures. To quantify the impact of the exposure on mesh strength, the force required to tear the mesh and the maximum mesh expansion before damage were quantified for control, sham, and exposed mesh samples. There was no statistical difference between the exposed and sham/control mesh samples in terms of ultimate tensile strength and corresponding mesh expansion. The only statistical difference was with respect to mesh orientation relative to the applied load. The tensile strength increased by 1.36 N while the expansion was reduced by 1.33 mm between the different mesh orientations. PMID- 30442605 TI - An FPGA-Based Backend System for Intravascular Photoacoustic and Ultrasound Imaging. AB - The integration of intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging produces an imaging modality with high sensitivity and specificity which is particularly needed in interventional cardiology. Conventional side-looking IVUS imaging with a single-element ultrasound (US) transducer lacks forward-viewing capability, which limits the application of this imaging mode in intravascular intervention guidance, Doppler-based flow measurement, and visualization of nearly or totally blocked arteries. For both side-looking and forward-looking imaging, the necessity to mechanically scan the US transducer limits the imaging frame rate, and therefore arraybased solutions are desired. In this paper, we present a lowcost, compact, high-speed, and programmable imaging system based on a field-programmable gate array (FPGA) suitable for dual-mode forward-looking IVUS/IVPA imaging. The system has 16 US transmit and receive channels and functions in multiple modes including interleaved photoacoustic (PA) and US imaging, hardware-based high-frame-rate US imaging, software-driven US imaging, and velocity measurement. The system is implemented in the register-transfer level, and the central system controller is implemented as a finite state machine. The system was tested with a capacitive micromachined ultrasonic transducer (CMUT) array. A 170-frames-per-second (FPS) US imaging frame rate is achieved in the hardware-based high-frame-rate US imaging mode while the interleaved PA and US imaging mode operates at a 60-FPS US and a laser-limited 20-FPS PA imaging frame rate. The performance of the system benefits from the flexibility and efficiency provided by low-level implementation. The resulting system provides a convenient backend platform for research and clinical IVPA and IVUS imaging. PMID- 30442606 TI - Natural shear wave imaging in the human heart: normal values, feasibility and reproducibility. AB - Left ventricular myocardial stiffness could offer superior quantification of cardiac systolic and diastolic function when compared to the current diagnostic tools. Shear wave elastography in combination with acoustic radiation force has been widely proposed to non-invasively assess tissue stiffness. Interestingly, shear waves can also result from intrinsic cardiac mechanical events (e.g., closure of valves) without the need for external excitation. However, it remains unknown whether these natural shear waves always occur, how reproducible they can be detected and what the normal range of shear wave propagation speed is. The present study therefore aimed at establishing the feasibility of detecting shear waves created after mitral valve closure (MVC) and aortic valve closure (AVC), the variability of the measurements, and at reporting the normal values of propagation velocity. Hereto, a group of 30 healthy volunteers was scanned with high frame rate imaging (>1000 Hz) using an experimental ultrasound system transmitting a diverging wave sequence. Tissue Doppler velocity and acceleration were used to create septal color M-modes, on which the shear waves were tracked and their velocities measured. Overall the methodology was capable of detecting the transient vibrations that spread throughout the intraventricular septum in response to the closure of the cardiac valves in 92% of the recordings. Reference velocities of 3.2+/-0.6 m/s at MVC and 3.5+/-0.6 m/s at AVC were obtained. Moreover, in order to show the diagnostic potential of this approach, 2 patients (one with cardiac amyloidosis and one undergoing a dobutamine stress echocardiography) were scanned with the same protocol and showed markedly higher propagation speeds: the former presented velocities of 6.6 m/s and 5.6 m/s; the latter revealed normal propagation velocities at baseline, and largely increased during the dobutamine infusion (>15 m/s). Both cases showed values consistent with the expected changes in stiffness and cardiac loading conditions. PMID- 30442607 TI - NNWarp: Neural Network-based Nonlinear Deformation. AB - NNWarp is a highly re-usable and efficient neural network (NN) based nonlinear deformable simulation framework. Unlike other machine learning applications such as image recognition, where different inputs have a uniform and consistent format (e.g. an array of all the pixels in an image), the input for deformable simulation is quite variable, high-dimensional, and parametrization-unfriendly. Consequently, even though the neural network is known for its rich expressivity of nonlinear functions, directly using an NN to reconstruct the force displacement relation for general deformable simulation is nearly impossible. NNWarp obviates this difficulty by partially restoring the force-displacement relation via warping the nodal displacement simulated using a simplistic constitutive model - the linear elasticity. In other words, NNWarp yields an incremental displacement fix per mesh node based on a simplified (therefore incorrect) simulation result other than synthesizing the unknown displacement directly. We introduce a compact yet effective feature vector including geodesic, potential and digression to sort training pairs of per-node linear and nonlinear displacement. NNWarp is robust under different model shapes and tessellations. With the assistance of deformation substructuring, one NN training is able to handle a wide range of 3D models of various geometries. Thanks to the linear elasticity and its constant system matrix, the underlying simulator only needs to perform one pre-factorized matrix solve at each time step, which allows NNWarp to simulate large models in real time. PMID- 30442608 TI - Automatic Musculoskeletal and Neurological Disorder Diagnosis with Relative Joint Displacement from Human Gait. AB - Musculoskeletal and neurological disorders are common devastating companions of ageing, leading to a reduction in quality of life and increased mortality. Gait analysis is a popular method for diagnosing these disorders. However, manually analysing the motion data is a labour-intensive task, and the quality of the results depends on the experience of the doctors. In this paper, we propose an automatic framework for classifying musculoskeletal and neurological disorders among older people based on 3D motion data. We also propose two new features to capture the relationship between joints across frames, known as 3D Relative Joint Displacement (3DRJDP) and 6D Symmetric Relative Joint Displacement (6DSymRJDP), such that relative movement between joints can be analyzed. To optimize the classification performance, we adapt feature selection methods to choose an optimal feature set from the raw feature input. Experimental results show that we achieve a classification accuracy of 84.29% using the proposed relative joint features, outperforming existing features that focus on the movement of individual joints. Considering the limited open motion database for gait analysis focusing on such disorders, we construct a comprehensive, openly accessible 3D full-body motion database from 45 subjects. PMID- 30442609 TI - Restoring Natural Forearm Rotation in Transradial Osseointegrated Amputees. AB - Osseointegrated transradial prostheses have the potential to preserve the natural range of wrist rotation, which improves the performance of activities of daily living and reduces compensatory movements that potentially lead to secondary health problems over time. This is possible by enabling the radius and the ulna bone to move with respect to each other, restoring the functionality of the original distal-radioulnar joint. In this paper we report on psychophysics tests performed on an osseointegrated transradial amputee with the aim to understand the extent of mobility of the implants that is required to preserve natural forearm rotation. Based on these experiments, we designed and developed an attachment device between the implants and the hand prosthesis that serves as an artificial distal radio-ulnar joint. This device was fitted on an osseointegrated transradial amputee and its functionality assessed by means of the Southampton Hand Assessment Procedure (SHAP) and the Minnesota Manual Dexterity test (MMDT). We found that axial rotation of the implants is required to preserve forearm rotation, to distribute loads equally over the two implants (60% radius - 40% ulna), and to enable loading of the implants without unpleasant feelings for the patient. Higher function was recorded when our attachment device enabled forearm rotation: SHAP from 61 to 71, MMDT from 258s to 231s. Natural forearm rotation can be successfully restored in transradial amputees by using osseointegration and our novel mechanical attachment to the hand prosthesis. PMID- 30442610 TI - An Asynchronous Control Paradigm Based on Sequential Motor Imagery and Its Application in Wheelchair Navigation. AB - In this paper, an asynchronous control paradigm based on sequential motor imagery (sMI) is proposed to enrich the control commands of a MI-based brain-computer interface (BCI). We test the feasibility and report the performance of this para digm in wheelchair navigation control. By sequentially imaging left- and right hand movements, the subjects can complete four sMI tasks in an asynchronous mode, which are then encoded to control six steering functions of a wheelchair, including moving forward, turning left, turning right, accelerating, decelerating and stopping. Two experiments, a simulated experiment and an online wheelchair navigation experiment, were conducted to evaluate the performance of the proposed approach in seven subjects. In summary, the subjects completed 99 of 105 experimental trials along a predefine route. The success rate was 94.2%, indicating the practicality and effectiveness of the proposed asynchronous control paradigm in wheelchair navigation control. PMID- 30442611 TI - Instrumental Assessment of Stair Ascent in People with Multiple Sclerosis, Stroke and Parkinson's Disease: a Wearable-Sensor Based Approach. AB - Stair ascent is a challenging daily-life activity highly related to independence. This task is usually assessed with clinical scales suffering from partial subjectivity and limited detail in evaluating different task's aspects. In this study we instrumented the assessment of stair ascent in people with Multiple Sclerosis (MS), stroke (ST) and Parkinson's disease (PD) to analyze the validity of the proposed quantitative indexes and characterize subjects' performances. Participants climbed 10 steps wearing a magneto-inertial sensor (MIMU) at sternum level. Gait pattern features (step frequency, symmetry, regularity, harmonic ratios), and upper trunk sway were computed from MIMU signals. Clinical mDGI (modified Dynamic Gait Index) and mDGI-Item 8 ("Up stairs") were administered. Significant correlations with clinical scores were found for gait pattern features (rs>=0.536) and trunk pitch sway (rs<=-0.367) demonstrating their validity. Instrumental indexes showed alterations in the three pathological groups compared to healthy subjects, and significant differences, not clinically detected, among MS, ST and PD. MS showed the worst performance, with alterations of all gait pattern aspects and larger trunk pitch sway. ST showed worsening in gait pattern features, but not in trunk motion. PD showed fewer alterations consisting in reduced step frequency and trunk yaw sway. These results suggest that the use of a MIMU provided valid objective indexes revealing between-group differences in stair ascent not detected by clinical scales. Importantly, the indexes includes upper trunk measures, usually not present in clinical tests, and provides relevant hints for tailored rehabilitation. PMID- 30442612 TI - Sleep quality estimation by cardiopulmonary coupling analysis. AB - The gold standard for assessment of sleep quality is the polysomnography where physiological signals are used to generate both quantitative and qualitative measurements. Despite the production of highly accurate results, polysomnography is a complex, uncomfortable and expensive process, inaccessible to a large group of the population. Home monitoring devices were developed to address these issues, fitting the growing perspective of health care and focusing in prevention and wellness. The objective of this work was to develop an algorithm capable of estimating the quality of sleep, by analyzing the cyclic alternating pattern rate. The algorithm uses a single-lead electrocardiogram to produce a spectrographic measure of the cardiopulmonary coupling that in turn was fed to a classifier to estimate the non-rapid eye movement sleep and the presence of the cyclic alternating pattern. Two classifiers were tested, a feedforward neural network and a deep stacked autoencoder, with the second achieving better results, correctly classifying 77% of the subjects sleep quality (either good or bad). The developed method can be implemented in a home monitoring device to estimate the sleep quality in a non-invasive way and improve the detection of pathologies. PMID- 30442614 TI - Calcium Spike Patterns Reveal Linkage of Electrical Stimulus and MSC Osteogenic Differentiation. AB - Mesenchymal stromal/stem cells (MSCs) are easily obtained multipotent cells, which are widely applied in regenerative medicine. Electrical stimulation (ES) has a promoting effect on bone healing and osteogenic differentiation of MSCs. Direct and alternating currents (AC) are extensively used to promote the osteogenic differentiation of MSCs in vivo and in vitro. However, information on conducting effective differentiation remains scarce. In this study, we propose a method to optimize ES parameters based on calcium spike patterns of MSCs. Calcium spike frequency decreases as the osteogenic differentiation of MSC progresses. Furthermore, we tested various ES parameters through real-time monitoring of calcium spike patterns. We efficiently initiated the process of osteogenic differentiation in MSCs by using the optimal parameters of AC, including voltage, signal shapes, frequency, and duty time. This method provides a new approach to optimize osteogenic differentiation and is potentially useful in clinical treatment, such as of bone fractures. PMID- 30442613 TI - Communication and Information Theory of Single Action Potential Signals in Plants. AB - Many plants, such as Mimosa pudica (the "sensitive plant"), employ electrochemical signals known as action potentials (APs) for rapid intercellular communication. In this paper, we consider a reaction-diffusion model of individual AP signals to analyze APs from a communication- and information theoretic perspective. We use concepts from molecular communication to explain the underlying process of information transfer in a plant for a single AP pulse that is shared with one or more receiver cells. We also use the chemical Langevin equation to accommodate the deterministic as well as stochastic component of the system. Finally we present an information-theoretic analysis of single action potentials, obtaining achievable information rates for these signals. We show that, in general, the presence of an AP signal can increase the mutual information and information propagation speed among neighboring cells with receivers in different settings. PMID- 30442615 TI - Inter-IC for Wearables (IWe): Power and Data Transfer over Double-sided Conductive Textile. AB - We propose a power and data transfer network on a conductive fabric material based on an existing serial communication protocol, Inter-Integrated Circuit (IC). We call the proposed network inter-IC for wearables (IWe). Continuous dc power and IC-formatted data are simultaneously transferred to tiny sensor nodes distributed on a double-sided conductive textile. The textile comprises two conductive sides, isolated from each other, and is used as a single planar transmission line. IC data are transferred along with dc power supply based on frequency division multiplexing. Two carriers are modulated with the clock and the data signals of IC. A modulation and demodulation circuit is designed such that off-the-shelf IC-interfaced sensor ICs can be used. The novelty of this work is that a special filter to enable passive modulation is designed by locating its impedance poles and zeros at the appropriate frequencies. The term ''passive modulation'' herein implies that the sensor nodes do not generate carrier waves by themselves; instead, they reflect only the externally supplied careers for modulation. The proposed scheme enables the flexible implementation of wearable sensor systems in which multiple off-the-shelf tiny sensors are distributed throughout the system. PMID- 30442616 TI - Topic-Based Algorithm for Multilabel Learning With Missing Labels. AB - In multilabel learning (MLL), each instance can be assigned by several concepts simultaneously from a class dictionary. Usually, labels in the class dictionary have semantic correlations and semantic hierarchy. Instances can be categorized into different topics. Each topic has its own label candidates, and some topics have overlapped label candidates. In this paper, we propose a novel MLL method to deal with missing labels. The proposed algorithm can recover the label matrix according to local, topic-wise, and global semantic properties. Specifically, in the global level, label consistency, label-wise semantic correlations, and semantic hierarchy are exploited; in the local level, label importance and instance-wise semantic correlations in each topic are extracted; and in the topic level, label importance similarities and instance-wise semantic similarities between topics are mined. The experimental results on five image data sets in different applications demonstrate the effectiveness of the proposed approach. PMID- 30442617 TI - Neural Network Filtering Control Design for Nontriangular Structure Switched Nonlinear Systems in Finite Time. AB - This paper solves the finite-time switching control issue for the nonstrict feedback nonlinear switched systems. The controlled plants contain immeasurable states, arbitrarily switchings, and the unknown functions which are constructed with the whole states. Neural network is used to simulate the uncertain systems and a filter-based state observer is designed to estimate the immeasurable states in this paper, respectively. Based on the backstepping recursive technique and the common Lyapunov function method, a finite-time switching control method is presented. Due to the developed finite-time control strategy, the closed-loop signals can be ensured to be bounded under arbitrarily switchings, and the outputs of systems can quickly track the desired reference signals in finite time. The effectiveness of the proposed method is given through its application to a mass-spring-damper system. PMID- 30442618 TI - Global Nonfragile Synchronization in Finite Time for Fractional-Order Discontinuous Neural Networks With Nonlinear Growth Activations. AB - This paper is concerned with the global nonfragile Mittag-Leffler synchronization and the global synchronization in finite time for fractional-order discontinuous neural networks, where activation functions are discontinuous at 0, or modeled as a local Holder functions with the nonlinear growth property in a neighborhood of 0. First, two lemmas concerned with the convergence with respect to an absolutely continuous function are developed. Second, a new property, which introduces an inequality of the fractional derivative for the variable upper limit integral with respect to the nonsmooth integrable function, is presented and applied in the synchronization results' analysis. In addition, under the fractional Filippov differential inclusion framework, by utilizing the Lur'e Postnikov-type Lyapunov functional, nonsmooth analysis method, and the convergence properties developed in this paper, the synchronization conditions are derived in the form of linear matrix inequalities. Moreover, the upper bound of the setting time for the global nonfragile synchronization in finite time is calculated accurately. Finally, two illustrations are presented to verify the correctness of the theoretical results. PMID- 30442619 TI - Tracking Sparse Linear Classifiers. AB - In this paper, we investigate the problem of sparse online linear classification in changing environments. We first analyze the tracking performance of standard online linear classifiers, which use gradient descent for minimizing the regularized hinge loss. The derived shifting bounds highlight the importance of choosing appropriate step sizes in the presence of concept drifts. Notably, we show that a better adaptability to concept drifts can be achieved using constant step sizes rather than the state-of-the-art decreasing step sizes. Based on these observations, we then propose a novel sparse approximated linear classifier, called sparse approximated linear classification (SALC), which uses a constant step size. In essence, SALC simply rounds small weights to zero for achieving sparsity and controls the truncation error in a principled way for achieving a low tracking regret. The degree of sparsity obtained by SALC is continuous and can be controlled by a parameter which captures the tradeoff between the sparsity of the model and the regret performance of the algorithm. Experiments on nine stationary data sets show that SALC is superior to the state-of-the-art sparse online learning algorithms, especially when the solution is required to be sparse; on seven groups of nonstationary data sets with various total shifting amounts, SALC also presents a good ability to track drifts. When wrapped with a drift detector, SALC achieves a remarkable tracking performance regardless of the total shifting amount. PMID- 30442620 TI - Low-Voltage Low-Power Integrable CMOS Circuit Implementation of Integer- and Fractional-Order FitzHugh-Nagumo Neuron Model. AB - The low-voltage low-power sinh-domain (SD) implementations of integer- and fractional-order FitzHugh-Nagumo (FHN) neuron model have been introduced in this paper. Besides, the effect of fractional-orders on the external excitation current and dynamics of the neuron has been examined in this paper. The proposed SD designs of FHN neuron model have the benefits of: 1) low-voltage operation; 2) integrability, due to resistor-less design and the employment of only grounded components; 3) electronic tunability of performance parameters; and 4) low-power implementation due to the inherent properties of SD technique. HSPICE simulator tool and Taiwan Semiconductor Manufacturing Company, Hsinchu, Taiwan 130-nm CMOS process was used to evaluate and verify the correct functioning of the model. In addition, to experimentally verify the operation of the proposed fractional-order FHN neuron model, field-programmable analog array (FPAA) implementation of the model has been presented, and the proper functioning of the model has been verified. To the best of the authors' knowledge, this is the first paper that describes the electronic realization of the fractional-order FHN neuron model. In addition, it is the first time that the FPAA implementation of any fractional order neuron model has been presented. PMID- 30442621 TI - Extreme Learning Machine With Affine Transformation Inputs in an Activation Function. AB - The extreme learning machine (ELM) has attracted much attention over the past decade due to its fast learning speed and convincing generalization performance. However, there still remains a practical issue to be approached when applying the ELM: the randomly generated hidden node parameters without tuning can lead to the hidden node outputs being nonuniformly distributed, thus giving rise to poor generalization performance. To address this deficiency, a novel activation function with an affine transformation (AT) on its input is introduced into the ELM, which leads to an improved ELM algorithm that is referred to as an AT-ELM in this paper. The scaling and translation parameters of the AT activation function are computed based on the maximum entropy principle in such a way that the hidden layer outputs approximately obey a uniform distribution. Application of the AT ELM algorithm in nonlinear function regression shows its robustness to the range scaling of the network inputs. Experiments on nonlinear function regression, real world data set classification, and benchmark image recognition demonstrate better performance for the AT-ELM compared with the original ELM, the regularized ELM, and the kernel ELM. Recognition results on benchmark image data sets also reveal that the AT-ELM outperforms several other state-of-the-art algorithms in general. PMID- 30442622 TI - Secure Similar Patients Query on Encrypted Genomic Data. AB - Both individuals and enterprises produce genomic data rapidly and continuously. There is a need to outsource such data to the cloud for better flexibility. Outsourcing also helps data owners by eliminating the local storage management problem. To protect data privacy and security, data owners must encrypt the sensitive data before outsourcing. Since genomic data is enormous in volume, executing researchers' queries securely and efficiently is a challenging task. In this paper, we introduce an indexing algorithm based on the prefix-tree to support similar patient queries. The proposed method guarantees the following: (1) data privacy, (2) query privacy, and (3) output privacy. The privacy is guaranteed through encryption and garbled circuits considering the semi-honest adversary model. The overall computation is scalable and fast enough for real life biomedical applications. Moreover, experimental results show that our method performs better than existing state-of-art techniques in this domain. PMID- 30442623 TI - Exploring active learning based on representativeness and uncertainty for biomedical data classification. AB - Nowadays there is an abundance of biomedical data, such as images, genetic sequences, among others. However, there is a lack of annotation to such volume of data, due to the high costs involved to perform this task. Thus it is mandatory to develop techniques to ease the burden of human annotation. To reach such goal active learning strategies can be applied. However, the state-of-the-art active learning methods, generally, are not feasible to lead with real-world datasets. Another important issue, that is generally neglected by these methods, is related to the conception that the classifier tends to learn more and more at each iteration. Their adopted selection criteria do not properly exploit the knowledge of the classifier. Therefore, in the present paper, we propose the use of an active learning approach, in order to leverage the learning process, including the proposal of a novel active learning strategy. The main difference of our proposed strategy is related to the participation of the classifier in an extremely active way in its learning process. So, we can better maximize and prioritize the knowledge that is obtained by the classifier at each iteration, making use of this knowledge in a more appropriate and useful way when selecting more informative samples. To do so, in our selection criteria, we give significant importance to the classifications suggested by the classifier. In addition, jointly with the participation and the knowledge of the classifier, we consider both uncertainty and representativeness criteria through a fine-grained analysis of the samples. Experimental results show that our novel active learning approach outperforms state-of-the-art active learning methods, considering several supervised classifiers. Hence, dealing with real dataset problems in a better way, equalizing the trade-off between annotation task and higher accuracy rates. PMID- 30442624 TI - Neurocognitive Assessment in Virtual Reality Through Behavioral Response Analysis. AB - The ability to detect and diagnose neurocognitive disorders at the earliest possible moment is key to a better prognosis for the patient. Two of the earliest indicators of potential neurocognitive problems are motor and visual dysfunction. Motor disorders and problems in visual cognition can be seen in many neurocognitive disorders, resulting in abnormal physical reactions to visual stimuli. Analyzing physical behaviors when presented with such stimuli can provide insights into the visual perception and motor abilities of an individual, yet there is currently no unbiased, objective, general-purpose tool that analyzes attention and motor behavior to assess neurocognitive function. We propose a novel method of neurocognitive function assessment that tests the patient's cognition using Virtual Reality (VR) with eye tracking and motion analysis. By placing the patient in a controlled virtual environment and analyzing their movements, we can evoke certain physical responses from subjects for neurocognitive assessment. We have developed a prototype system that places the subject in a virtual baseball field and captures their full body motion as they try to catch baseballs. This scenario tests the subject's ability to determine the landing time and position of the ball, as well as the test subject's balance, motor skills, attention, and memory. Preliminary tests with 20 healthy normal individuals demonstrate the ability of this tool to assess the test subject's balance, memory, attention, and reaction to visual stimuli. This platform has a twofold contribution: it is used to assess several neurocognitive constructs that affect visual and motor capability neutrally and objectively based on controlled stimuli, and it enables objective comparison between different neurocognitive disorders research in this field. PMID- 30442625 TI - Cooperative Fault Diagnosis for Uncertain Nonlinear Multiagent Systems Based on Adaptive Distributed Fuzzy Estimators. AB - This paper presents a cooperative fault diagnosis scheme for a class of uncertain nonlinear multiagent systems component and sensor faults in individual agents. Since the faulty system affects the healthy systems through interconnections, for each agent an estimator is designed to collect neighboring output estimations errors to consider its faulty effects on others, when computing its estimations for local state and faulty parameters. A new structure of distributed estimators is proposed by filtering regressor signals and sharing them among agents. Then, the sharings of signals are planned by properly constructing auxiliary graphs for undirected and directed networks. Two conditions are given to preselect estimators parameters for the convergences of the estimation errors. Unlike the existing results dealing with one common parameter with full state measurement and only for undirected graphs, this paper presents an output measurement-based approach for multiple parameters in undirected/directed networks. It shows that for the faults not providing persistent excitation in a signal agent, it is possible to estimate the faults exactly if the they excite all agents persistently. A simulation example of a group of single-link flexible-joint robots is given to verify the effectiveness of the proposed method. PMID- 30442626 TI - Adaptive Synchronization of Reaction-Diffusion Neural Networks and Its Application to Secure Communication. AB - This paper is mainly concerned with the synchronization problem of reaction diffusion neural networks (RDNNs) with delays and its direct application in image secure communications. An adaptive control is designed without a sign function in which the controller gain matrix is a function of time. The synchronization criteria are established for an error model derived from master-slave models through solving the set of linear matrix inequalities derived by constructing the suitable novel Lyapunov-Krasovskii functional candidate, Green's formula, and Wirtinger's inequality. If the proposed sufficient conditions are satisfied, then the global asymptotic synchronization of the error model is guaranteed. The numerical illustrations are provided to demonstrate the validity of the derived synchronization criteria. In addition, the role of system parameters is picturized through the chaotic nature of RDNNs and those unprecedented solutions is utilized to promote better security of image transactions. As is evident, the enhancement of image encryption algorithm is designed with two levels, namely, image watermarking and diffusion process. The contributions of this paper are discussed as concluding remarks. PMID- 30442627 TI - Fast Covariance Matrix Adaptation for Large-Scale Black-Box Optimization. AB - Covariance matrix adaptation evolution strategy (CMA-ES) is a successful gradient free optimization algorithm. Yet, it can hardly scale to handle high-dimensional problems. In this paper, we propose a fast variant of CMA-ES (Fast CMA-ES) to handle large-scale black-box optimization problems. We approximate the covariance matrix by a low-rank matrix with a few vectors and use two of them to generate each new solution. The algorithm achieves linear internal complexity on the dimension of search space. We illustrate that the covariance matrix of the underlying distribution can be considered as an ensemble of simple models constructed by two vectors. We experimentally investigate the algorithm's behaviors and performances. It is more efficient than the CMA-ES in terms of running time. It outperforms or performs comparatively to the variant limited memory CMA-ES on large-scale problems. Finally, we evaluate the algorithm's performance with a restart strategy on the CEC'2010 large-scale global optimization benchmarks, and it shows remarkable performance and outperforms the large-scale variants of the CMA-ES. PMID- 30442628 TI - Observer Design of Discrete-Time Fuzzy Systems Based on an Alterable Weights Method. AB - This paper proposes an improvement on observer design of discrete-time fuzzy systems based on an alterable weights method. Different from the recent result, a more effective ranking-based switching mechanism is developed by introducing a bank of alterable weights for the sake of making use of the size difference information of the normalized fuzzy weighting functions more freely than before. Therefore, a positive result can be provided in this paper, that is, less conservative conditions of designing feasible fuzzy observers can be obtained than those existing results, while the computational cost of designing feasible fuzzy observers is even less than the up-to-date one. Finally, two numerical examples are given to show the progressiveness of the proposed method. PMID- 30442629 TI - Adaptive Decentralized Controller Design for a Class of Switched Interconnected Nonlinear Systems. AB - This paper is concerned with the switched decentralized adaptive control design problem for switched interconnected nonlinear systems under arbitrary switching, where the actuator failures may occur infinite times and the control directions are allowed to be unknown. By introducing a Nussbaum-type function and an integrable auxiliary signal, a switched decentralized adaptive control scheme is developed to deal with the potentially infinite times of actuator failures and the unknown control directions. The basic idea is to design different parameter update laws and control laws for distinct switched subsystems. It is proved that the state variables of the resulting closed-loop system are asymptotically stable. Finally, a numerical simulation on a double-inverted pendulum model is given to verify the proposed control scheme. PMID- 30442630 TI - A case of juvenile localized scleroderma with anti-topoisomerase I antibody. PMID- 30442631 TI - Treatments and outcomes in juvenile linear scleroderma: a narrative systematic review. PMID- 30442632 TI - Many pustules that itch.... AB - Furuncular myiasis is a cutaneous parasitosis that occurs in tropical regions. It is manifested by lesions with the appearance of pustules, because of the presence of the fly larva in the skin. This misleading appearance can delay diagnosis. The extraction of these Cayor worms can be facilitated by the use of a comedo extractor. PMID- 30442633 TI - Pneumocystis jirovecii pneumonia infection in pemphigus patients treated with rituximab: an observational nationwide epidemiological study in Taiwan. PMID- 30442634 TI - Paradoxical ulcerative colitis during treatment with secukinumab for psoriasis. PMID- 30442635 TI - Chlamydia muridarum plasmid induces mouse oviduct pathology by promoting chlamydial survival and ascending infection and triggering host inflammation. AB - BACKGROUND: Infection with plasmid-free Chlamydia trachomatis and Chlamydia muridarum fails to induce severe pathology, however, the mechanisms underlying this phenotype are unclear. OBJECTIVES: To elucidate the mechanisms of chlamydial plasmid-mediated pathology in mouse oviducts. MATERIALS & METHODS: BALB/c mice were intravaginally infected with either plasmid-competent or plasmid-free C. muridarum strains. To compare the survival and ascending infection of these strains, vaginal swabs and genital tract tissues were collected and cultured with HeLa cells to monitor the recovery of live organisms. In addition, Chlamydia strains were intrabursally inoculated into the oviducts of mice to assess pathogenicity. Cytokine levels in the vaginal swabs collected from both the plasmid-competent and plasmid-free C. muridarum-infected mice were detected using Bio-Plex Pro Mouse Cytokine, Chemokine, and Growth Factor Assays. RESULTS: The plasmid-competent C. muridarum strain induced hydrosalpinx formation in mouse oviducts following intravaginal inoculation, however, this was not the case for the plasmid-free C. muridarum strain. The lack of hydrosalpinges in response to the plasmid-free C. muridarum strain correlated with its significantly reduced ability to survive and disseminate to the upper genital tract. Furthermore, the plasmid-free C. muridarum failed to induce hydrosalpinx formation in mice, even when the strain was intrabursally injected into oviducts. A comparison of the cytokine levels in mouse vaginal secretions showed that the plasmid-free C. muridarum strain induced less IL-15, LIF, MIP-2, IL-1alpha, IL-1beta, TNF-alpha, and RANTES. CONCLUSION: C. muridarum plasmid contributes to oviduct pathology by: promoting bacterial survival and ascending infection, and triggering host inflammatory responses. PMID- 30442636 TI - Defining and Predicting Pain Volatility in Users of the Manage My Pain App: Analysis Using Data Mining and Machine Learning Methods. AB - BACKGROUND: Measuring and predicting pain volatility (fluctuation or variability in pain scores over time) can help improve pain management. Perceptions of pain and its consequent disabling effects are often heightened under the conditions of greater uncertainty and unpredictability associated with pain volatility. OBJECTIVE: This study aimed to use data mining and machine learning methods to (1) define a new measure of pain volatility and (2) predict future pain volatility levels from users of the pain management app, Manage My Pain, based on demographic, clinical, and app use features. METHODS: Pain volatility was defined as the mean of absolute changes between 2 consecutive self-reported pain severity scores within the observation periods. The k-means clustering algorithm was applied to users' pain volatility scores at the first and sixth month of app use to establish a threshold discriminating low from high volatility classes. Subsequently, we extracted 130 demographic, clinical, and app usage features from the first month of app use to predict these 2 volatility classes at the sixth month of app use. Prediction models were developed using 4 methods: (1) logistic regression with ridge estimators; (2) logistic regression with Least Absolute Shrinkage and Selection Operator; (3) Random Forests; and (4) Support Vector Machines. Overall prediction accuracy and accuracy for both classes were calculated to compare the performance of the prediction models. Training and testing were conducted using 5-fold cross validation. A class imbalance issue was addressed using a random subsampling of the training dataset. Users with at least five pain records in both the predictor and outcome periods (N=782 users) are included in the analysis. RESULTS: k-means clustering algorithm was applied to pain volatility scores to establish a threshold of 1.6 to differentiate between low and high volatility classes. After validating the threshold using random subsamples, 2 classes were created: low volatility (n=611) and high volatility (n=171). In this class-imbalanced dataset, all 4 prediction models achieved 78.1% (611/782) to 79.0% (618/782) in overall accuracy. However, all models have a prediction accuracy of less than 18.7% (32/171) for the high volatility class. After addressing the class imbalance issue using random subsampling, results improved across all models for the high volatility class to greater than 59.6% (102/171). The prediction model based on Random Forests performs the best as it consistently achieves approximately 70% accuracy for both classes across 3 random subsamples. CONCLUSIONS: We propose a novel method for measuring pain volatility. Cluster analysis was applied to divide users into subsets of low and high volatility classes. These classes were then predicted at the sixth month of app use with an acceptable degree of accuracy using machine learning methods based on the features extracted from demographic, clinical, and app use information from the first month. PMID- 30442639 TI - NHS announces major overhaul of national cancer screening programmes in England. PMID- 30442637 TI - Feasibility, Acceptability, and Adoption of Digital Fingerprinting During Contact Investigation for Tuberculosis in Kampala, Uganda: A Parallel-Convergent Mixed Methods Analysis. AB - BACKGROUND: In resource-constrained settings, challenges with unique patient identification may limit continuity of care, monitoring and evaluation, and data integrity. Biometrics offers an appealing but understudied potential solution. OBJECTIVE: The objective of this mixed-methods study was to understand the feasibility, acceptability, and adoption of digital fingerprinting for patient identification in a study of household tuberculosis contact investigation in Kampala, Uganda. METHODS: Digital fingerprinting was performed using multispectral fingerprint scanners. We tested associations between demographic, clinical, and temporal characteristics and failure to capture a digital fingerprint. We used generalized estimating equations and a robust covariance estimator to account for clustering. In addition, we evaluated the clustering of outcomes by household and community health workers (CHWs) by calculating intraclass correlation coefficients (ICCs). To understand the determinants of intended and actual use of fingerprinting technology, we conducted 15 in-depth interviews with CHWs and applied a widely used conceptual framework, the Technology Acceptance Model 2 (TAM2). RESULTS: Digital fingerprints were captured for 75.5% (694/919) of participants, with extensive clustering by household (ICC=.99) arising from software (108/179, 60.3%) and hardware (65/179, 36.3%) failures. Clinical and demographic characteristics were not markedly associated with fingerprint capture. CHWs successfully fingerprinted all contacts in 70.1% (213/304) of households, with modest clustering of outcomes by CHWs (ICC=.18). The proportion of households in which all members were successfully fingerprinted declined over time (rho=.30, P<.001). In interviews, CHWs reported that fingerprinting failures lowered their perceptions of the quality of the technology, threatened their social image as competent health workers, and made the technology more difficult to use. CONCLUSIONS: We found that digital fingerprinting was feasible and acceptable for individual identification, but problems implementing the hardware and software lead to a high failure rate. Although CHWs found fingerprinting to be acceptable in principle, their intention to use the technology was tempered by perceptions that it was inconsistent and of questionable value. TAM2 provided a valuable framework for understanding the motivations behind CHWs' intentions to use the technology. We emphasize the need for routine process evaluation of biometrics and other digital technologies in resource-constrained settings to assess implementation effectiveness and guide improvement of delivery. PMID- 30442640 TI - Petition against "cruel" and "ridiculous" guidance on access to medicinal cannabis attracts 400 000 signatures. PMID- 30442638 TI - Effect of Increasing Levels of Web-Based Behavioral Support on Changes in Physical Activity, Diet, and Symptoms in Men With Prostate Cancer: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: More than 3.1 million men in the United States are prostate cancer survivors. These men may improve their physical function, quality of life, and potentially their prognosis by adopting healthier lifestyle habits. The internet provides a scalable mechanism to deliver advice and support about improving physical activity and dietary habits, but the feasibility and acceptability of a Web-based lifestyle intervention and the dose of support necessary to improve health behaviors are not yet known. OBJECTIVES: The Community of Wellness is a Web-based intervention focused on supporting exercise and healthy dietary practices for men with prostate cancer. The objectives of this study were to determine the feasibility, acceptability, and preliminary efficacy of the Community of Wellness Web portal among prostate cancer survivors by conducting a randomized controlled trial (RCT) comparing 4 levels of additive Web-based content and interaction with participants: Level 1 (Teaching; Control), Level 2 (Teaching + Tailoring), Level 3 (Teaching + Tailoring + Technology), and Level 4 (Teaching + Tailoring + Technology + Touch). METHODS: This is a single-blinded RCT comparing 3 levels of behavioral support within the Community of Wellness Web portal intervention (Levels 2 to 4) with each other and with the control condition (Level 1). The control condition receives general static Web-based educational information only on physical activity and dietary habits, self efficacy for behavior change, motivation for physical activity, and changes in anxiety and treatment-related side effects. We will enroll and randomize 200 men with prostate cancer equally to 4 levels of the Community of Wellness Web-based intervention for 3 months (50 men per level). Surveys will be completed by self report at baseline, 3 months (immediately postintervention), and 6 months (3 months postintervention). Feasibility and acceptability will be assessed by enrollment statistics, Web-based usage metrics, and surveys at the 3-month time point. We will also conduct focus groups after the postintervention follow-up assessment in a sample of enrolled participants to evaluate elements of usability and acceptability that cannot be obtained via surveys. RESULTS: Enrollment is ongoing, with 124 enrolled. Study completion (6-month follow-up) is expected by July 2019. CONCLUSIONS: The goal of the study is to identify the level of support that is feasible, acceptable, promotes behavior change, and improves health in men with prostate cancer to inform future efforts to scale the program for broader reach. TRIAL REGISTRATION: ClinicalTrials.gov NCT03406013; https://clinicaltrials.gov/ct2/show/NCT03406013 (Archived by WebCite at http://www.webcitation.org/73YpDIoTX). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11257. PMID- 30442641 TI - Wrapping up the fats-a structure of the lipid droplet biogenesis protein seipin. AB - The lipid droplet (LD) biogenesis protein seipin is crucial for formation of normal LDs, but its exact functional role has been enigmatic. In this issue, Sui et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201809067) report the cryo--electron microscopy structure of seipin, which provides novel insights into how seipin might mediate LD formation. PMID- 30442642 TI - Dynamic nanoscale morphology of the ER surveyed by STED microscopy. AB - The endoplasmic reticulum (ER) is composed of interconnected membrane sheets and tubules. Superresolution microscopy recently revealed densely packed, rapidly moving ER tubules mistaken for sheets by conventional light microscopy, highlighting the importance of revisiting classical views of ER structure with high spatiotemporal resolution in living cells. In this study, we use live-cell stimulated emission depletion (STED) microscopy to survey the architecture of the ER at 50-nm resolution. We determine the nanoscale dimensions of ER tubules and sheets for the first time in living cells. We demonstrate that ER sheets contain highly dynamic, subdiffraction-sized holes, which we call nanoholes, that coexist with uniform sheet regions. Reticulon family members localize to curved edges of holes within sheets and are required for their formation. The luminal tether Climp63 and microtubule cytoskeleton modulate their nanoscale dynamics and organization. Thus, by providing the first quantitative analysis of ER membrane structure and dynamics at the nanoscale, our work reveals that the ER in living cells is not limited to uniform sheets and tubules; instead, we suggest the ER contains a continuum of membrane structures that includes dynamic nanoholes in sheets as well as clustered tubules. PMID- 30442643 TI - The interdependence of gene-regulatory elements and the 3D genome. AB - Imaging studies, high-resolution chromatin conformation maps, and genome-wide occupancy data of architectural proteins have revealed that genome topology is tightly intertwined with gene expression. Cross-talk between gene-regulatory elements is often organized within insulated neighborhoods, and regulatory cues that induce transcriptional changes can reshape chromatin folding patterns and gene positioning within the nucleus. The cause-consequence relationship of genome architecture and gene expression is intricate, and its molecular mechanisms are under intense investigation. Here, we review the interdependency of transcription and genome organization with emphasis on enhancer-promoter contacts in gene regulation. PMID- 30442644 TI - Archetypal roles of an abscisic acid receptor in drought and sugar responses in liverworts. AB - Abscisic acid (ABA) controls seed dormancy and stomatal closure through binding to the intracellular receptor Pyrabactin resistance1 (Pyr1)/Pyr1-like/Regulatory components of ABA receptors (PYR/PYL/RCAR) in angiosperms. Genes encoding PYR/PYL/RCAR are thought to have arisen in the ancestor of embryophytes, but the roles of the genes in non-vascular plants have not been determined. In the liverwort Marchantia polymorpha, ABA reduces growth and enhances desiccation tolerance through increasing accumulation of intracellular sugars and various transcripts such as those of Late Embryogenesis Abundant (LEA)-like genes. In this study, we analyzed a gene designated MpPYL1, which is closely related to PYR/PYL/RCAR of angiosperms, in transgenic liverworts. Transgenic lines overexpressing MpPYL1-GFP showed ABA-hypersensitive growth with enhanced desiccation tolerance, whereas Mppyl1 generated by CRISPR-Cas9-mediated genome editing showed ABA-insensitive growth with reduced desiccation tolerance. Transcriptome analysis indicated that MpPYL1 is a major regulator of abiotic stress-associated genes, including all 35 ABA-induced LEA-like genes. Furthermore, these transgenic plants showed altered responses to extracellular sucrose, suggesting that ABA and PYR/PYL/RCAR function in sugar responses. The results presented here reveal an important role of PYR/PYL/RCAR in the ABA response, which was likely acquired in the common ancestor of land plants. The results also indicate the archetypal role of ABA and its receptor in sugar response and accumulation processes for vegetative desiccation tolerance in bryophytes. PMID- 30442646 TI - Pfizer could owe NHS L500m for extending pregabalin patent for pain. PMID- 30442647 TI - Serum IgG N-glycans act as novel serum biomarkers of ankylosing spondylitis. PMID- 30442645 TI - CNBP controls IL-12 gene transcription and Th1 immunity. AB - An inducible program of inflammatory gene expression is a hallmark of antimicrobial defenses. Recently, cellular nucleic acid-binding protein (CNBP) was identified as a regulator of nuclear factor-kappaB (NF-kappaB)-dependent proinflammatory cytokine gene expression. Here, we generated mice lacking CNBP and found that CNBP regulates a very restricted gene signature that includes IL 12beta. CNBP resides in the cytosol of macrophages and translocates to the nucleus in response to diverse microbial pathogens and pathogen-derived products. Cnbp-deficient macrophages induced canonical NF-kappaB/Rel signaling normally but were impaired in their ability to control the activation of c-Rel, a key driver of IL-12beta gene transcription. The nuclear translocation and DNA-binding activity of c-Rel required CNBP. Lastly, Cnbp-deficient mice were more susceptible to acute toxoplasmosis associated with reduced production of IL 12beta, as well as a reduced T helper type 1 (Th1) cell IFN-gamma response essential to controlling parasite replication. Collectively, these findings identify CNBP as important regulator of c-Rel-dependent IL-12beta gene transcription and Th1 immunity. PMID- 30442648 TI - Comparing patient-perceived and physician-perceived remission and low disease activity in psoriatic arthritis: an analysis of 410 patients from 14 countries. AB - BACKGROUND: The objective was to compare different definitions of remission and low disease activity (LDA) in patients with psoriatic arthritis (PsA), based on both patients' and physicians' perspectives. METHODS: In ReFlap (Remission/Flare in PsA; NCT03119805), adults with physician-confirmed PsA and >2 years of disease duration in 14 countries were included. Remission was defined as very low disease activity (VLDA), Disease Activity index for PSoriatic Arthritis (DAPSA) <=4, and physician-perceived and patient-perceived remission (specific question yes/no), and LDA as minimal disease activity (MDA), DAPSA <14, and physician-perceived and patient-perceived LDA. Frequencies of these definitions, their agreement (prevalence-adjusted kappa), and sensitivity and specificity versus patient defined status were assessed cross-sectionally. RESULTS: Of 410 patients, the mean age (SD) was 53.9 (12.5) years, 50.7% were male, disease duration was 11.2 (8.2) years, 56.8% were on biologics, and remission/LDA was frequently attained: respectively, for remission from 12.4% (VLDA) to 36.1% (physician-perceived remission), and for LDA from 25.4% (MDA) to 43.9% (patient-perceived LDA). Thus, patient-perceived remission/LDA was frequent (65.4%). Agreement between patient perceived remission/LDA and composite scores was moderate to good (kappa range, 0.12-0.65). When patient-perceived remission or LDA status is used as reference, DAPSA-defined remission/LDA and VLDA/MDA had a sensitivity of 73.1% and 51.5%, respectively, and a specificity of 76.8% and 88.0%, respectively. Physician perceived remission/LDA using a single question was frequent (67.6%) but performed poorly against other definitions. CONCLUSION: In this unselected population, remission/LDA was frequently attained. VLDA/MDA was a more stringent definition than DAPSA-based remission/LDA. DAPSA-based remission/LDA performed better than VLDA/MDA to detect patient-defined remission or remission/LDA. Further studies of long-term outcomes are needed. PMID- 30442649 TI - Mechanisms and Clinical Significance of Pharmacokinetic-based Drug-drug Interactions with Drugs Approved by the U.S. Food and Drug Administration in 2017. AB - Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained a majority of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. OATP1B1/1B3 played a significant role, mediating more than half of the drug interactions with AUC changes >= 5-fold. As victims, five new drugs were identified as sensitive substrates, namely abemeciclib, midostaurin, and neratinib for CYP3A, and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and BCRP. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes >= 5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes < 2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom therapeutic management is already complex due to poly-therapy. PMID- 30442650 TI - CHARACTERIZATION OF STEREOSELECTIVE METABOLISM, INHIBITORY EFFECT ON URIC ACID UPTAKE TRANSPORTERS, AND PHARMACOKINETICS OFLESINURAD ATROPISOMERS. AB - Lesinurad (Zurampic), a selective inhibitor of uric acid reabsorption transporters used clinically for the treatment of gout, is a racemate of two atropisomers. The objectives were to evaluate the stereoselectivity of the metabolism, the inhibitory potency on (URAT1 and OAT4), and the clinical pharmacokinetics of the two atropisomers. In vitro incubations with human liver microsomes (HLM) or recombinant CYP2C9 and CYP3A4 and hydrolases were carried out to characterize metabolic stereoselectivity for the formation of two major metabolites in human, M3 (hydroxylation) and M4 (a dihydrodiol metabolite). Formation of M3 and M4 were catalyzed predominately by CYP2C9. M4 was formed via an epoxide intermediate, M3c, which was subsequently hydrolyzed by microsomal epoxide hydrolase to M4. The formation of M3 with atropisomer 1 in HLM was approximately twice that formed with atropisomer 2, whereas M4 formation with atropisomer 1 was 8- to 12-fold greater than that with atropisomer 2. There were no significant differences in the plasma protein binding among lesinurad and the two atropisomers. Following oral administration of 400 mg lesinurad once daily for 14 days to healthy humans, the systemic exposure (steady state Cmax,SS and AUCtau) of atropisomer 1 was approximately 30% lower than that of atropisomer 2, whereas renal clearance was similar. In vitro cell-based assays using HEK293 cells stably expressing URAT1 and OAT4 demonstrated that atropisomer 2 was approximately 4-fold more potent against URAT1 than atropisomer 1 and equally active against OAT4. In conclusion, lesinurad atropisomers showed stereoselectivity in clinical pharmacokinetics, metabolism, and inhibitory potency against URAT1. PMID- 30442651 TI - Bioavailability, Biotransformation, and Excretion of the Covalent BTK Inhibitor Acalabrutinib in Rats, Dogs, and Humans. AB - Acalabrutinib is a targeted, covalent inhibitor of Bruton tyrosine kinase (BTK) with a unique 2-butynamide warhead that has relatively lower reactivity than other marketed acrylamide covalent inhibitors. A human [14C] microtracer bioavailability study in healthy subjects revealed moderate intravenous clearance (39.4 l/h) and an absolute bioavailability of 25.3 +/- 14.3% (N = 8). Absorption and elimination of acalabrutinib following a 100 mg [14C] microtracer acalabrutinib oral dose were rapid, with maximum concentration reached in <1 h and elimination half-life values <2 h. Low concentrations of radioactivity persisted longer in the blood cell fraction and a peripheral blood mononuclear cell (PBMC) subfraction (enriched in target BTK) relative to plasma. [14C]acalabrutinib was extensively metabolized to over three dozen metabolites detectable by liquid chromatography-tandem mass spectrometry (LC-MS/MS), with primary metabolism by cytochrome P450 (CYP) 3A-mediated oxidation of the pyrrolidine ring, thiol conjugation of the butynamide warhead, and amide hydrolysis. A major active, circulating, pyrrolidine ring-opened metabolite, ACP 5862, was produced by CYP3A oxidation. Novel enol thioethers from the 2 butynamide warhead arose from glutathione and/or cysteine Michael additions and were subject to hydrolysis to a beta-ketoamide. Total radioactivity recovery was 95.7 +/- 4.6% (n = 6), with 12.0% of dose in urine and 83.5% in feces. Excretion and metabolism characteristics were generally similar in rat and dog. Acalabrutinib's highly selective, covalent mechanism of action, coupled with rapid absorption and elimination, enables high and sustained BTK target occupancy following twice daily administration. PMID- 30442652 TI - Transient Receptor Potential (TRP) Ion Channel - Dependent Toxicity of Silica Nanoparticles and Poly(amido amine) (PAMAM) Dendrimers. AB - Fundamental to the design and development of nanoparticles for applications in nanomedicine is a detailed understanding of their biological fate and potential toxic effects. Transient receptor potential (TRP) ion channels are a large superfamily of cation channels with varied physiological functions. This superfamily is classified into six related subfamilies; TRPC (canonical), V (vanilloid), M (melastatin), A (ankyrin), P (polycystin) and ML (mucolipin). TRPA1, M2 and M8 are nonselective Ca2+-permeable cation channels which regulate calcium pathways under oxidative stress. Some of these channels are highly expressed in immune cells where they can regulate cytokine production and inflammatory responses. Using a series of well characterized silica nanoparticles with variations in size (approximately 50-350 nm in diameter) and porosity, as well as cationic and anionic poly(amido amine) (PAMAM) dendrimers of similar size, we examined the toxicity of these nanoparticles to HEK-293 cells overexpressing different TRP channels. Our data shows that the toxicity of smaller and mesoporous silica nanoparticles was influenced by expression of the TRPM2 and TRPM8 channels, while only mesoporous SiNPs showed TRPA1-related toxicity. Additionally, TRPA1 and TRPM2 played a role in the toxicity of cationic dendrimers, but not for anionic dendrimers. TRPV4 does not seem to play a significant role in silica nanoparticle or PAMAM toxicity. PMID- 30442653 TI - A pragmatic utility function to describe the risk-benefit composite of opioid and non-opioid analgesic medication. AB - It is not straightforward to simultaneously evaluate benefits and harms of pain management, as different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here we construct "pragmatic" utility functions based on measurements of benefit and harms, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with end-points analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1 the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2 the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased towards zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from two previous studies. Results yielded valuable insights into the utility of treatment and may be highly educative for physicians and may be used in development of potent analgesics with serious side effects. PMID- 30442654 TI - Alpha-tocopherol potentiates the cervical resistance decreasing effects of COX inhibitors in pregnant rats: the putative role of cyclooxygenase-2 inhibition. AB - Vitamin E and their analogues as antioxidant and lipid soluble compounds can have diverse effects on the physiological processes. By binding to receptors and enzymes, they may modify the action of drugs. It has been proved that alpha tocopherol succinate modifies the effects of beta2 agonist terbutaline and cyclooxygenase (COX) inhibitors on rat trachea and myometrium. Our aim was to investigate how alpha-tocopherol and COX inhibitors may influence cervical resistance in rats. The cervical resistance of non-pregnant and 22-day-pregnant Sprague-Dawley rats was determined in an isolated organ bath in vitro. Alpha tocopherol-succinate (10-7 M) was used, while the COX non-selective diclofenac (10-6 M), the COX-2 selective rofecoxib (10-6 M) and the COX-1 selective SC-560 (10-6 M) were applied as inhibitors. The COX activities of the cervices were measured by enzyme-immunoassay. The modifying effect of single doses of COX inhibitors and tocopherol on the onset of labor was investigated in vivo. The cervical resistance of non-pregnant samples was not changed by either alpha tocopherol or COX inhibitors. On pregnant cervices, tocopherol, diclofenac or rofecoxib pretreatment decreased cervical resistance that was further reduced by COX-inhibitors after pretreatment with tocopherol. Alpha-tocopherol elicited a significant COX-2 enzyme inhibition in pregnant cervical samples. By co administration of tocopherol and rofecoxib, the parturition was initiated earlier than in the other groups. It is supposed that COXs play a significant role not only in cervical ripening, but also in the contraction of the cervical smooth muscle a few hours before parturition. This latter action may be developed by COX 2 liberated prostaglandins. PMID- 30442655 TI - Enough data to draw conclusions about vitamin D and bone health. PMID- 30442656 TI - Chain length of saturated fatty acids regulates mitochondrial trafficking and function in sensory neurons. AB - Dyslipidemia associated with T2D leads to diabetic neuropathy, a complication characterized by sensory neuronal dysfunction and peripheral nerve damage. Sensory dorsal root ganglion (DRG) neurons are dependent on axonal mitochondrial energy production facilitated by mitochondrial transport mechanisms that distribute mitochondria throughout the axon. Since long chain saturated fatty acids (SFAs) damage DRG neurons and medium chain SFAs are reported to improve neuronal function, we evaluated the impact of SFA chain length on mitochondrial trafficking, mitochondrial function, and apoptosis. DRG neurons were exposed to SFAs with C12:0-C18:0 chain lengths and evaluated for changes in mitochondrial trafficking, mitochondrial polarization, and apoptosis. DRG neurons treated with C16:0 and C18:0 SFAs showed a significant decrease in the percentage of motile mitochondria and velocity of mitochondrial trafficking, whereas C12:0 and C14:0 SFAs had no impact on motility. Treatment with C16:0 and C18:0 SFAs exhibited mitochondrial depolarization correlating with impaired mitochondrial motility; the C12:0- and C14:0-treated neurons retained mitochondrial polarization. The reduction in mitochondrial trafficking and function in C16:0- and C18:0-treated DRG neurons correlated with apoptosis that was blocked in C12:0 and C14:0 SFA treatments. These results suggest that SFA chain length plays an important role in regulating axonal mitochondrial trafficking and function in DRG neurons. PMID- 30442657 TI - Smoking uptake in UK children: analysis of the UK Millennium Cohort Study. AB - We used data from 11 577 children in the UK Millennium Cohort Study, collected at approximately 14 years of age (early teens), to assess characteristics associated with smoking, and generated regional estimates of numbers of smokers. 13.8% of UK early teens studied had ever smoked; 1.9% were current smokers. This corresponds to 2 28 136 and 39 653 (13-14 year olds) in the UK, respectively. Ever smoking risk increased if caregivers (26.0% vs 10.9%) or friends smoked (35.1% vs 4.0%), with a dose-response effect for friends' smoking. Caregiver and peer-group smoking remain important drivers of child smoking uptake and thus important targets for intervention. PMID- 30442658 TI - Cardiac arrest by inhalation of deodorant spray. AB - Drug abuse by inhalation of volatile household product substances is uncommon, however, it can have devastating consequences. This case report describes the fatal outcome of deodorant inhalation by a 19-year-old patient in a detoxification clinic who developed a cardiac arrest after inhaling butane from a deodorant spray. Despite initial successful resuscitation, he developed a postanoxic encephalopathy with a status epilepticus resistant to extensive treatment. Inhalant abuse can be a cause of death in young patients. PMID- 30442659 TI - Receptor selectivity from minimal backbone modification of a polypeptide agonist. AB - Human parathyroid hormone (PTH) and N-terminal fragments thereof activate two receptors, hPTHR1 and hPTHR2, which share ~51% sequence similarity. A peptide comprising the first 34 residues of PTH is fully active at both receptors and is used to treat osteoporosis. We have used this system to explore the hypothesis that backbone modification of a promiscuous peptidic agonist can provide novel receptor-selective agonists. We tested this hypothesis by preparing a set of variants of PTH(1-34)-NH2 that contained a single beta-amino-acid residue replacement at each of the first eight positions. These homologs, each containing one additional backbone methylene unit relative to PTH(1-34)-NH2 itself, displayed a wide range of potencies in cell-based assays for PTHR1 or PTHR2 activation. The beta-scan series allowed us to identify two homologs, each containing two alpha->beta replacements, that were highly selective, one for PTHR1 and the other for PTHR2. These findings suggest that backbone modification of peptides may provide a general strategy for achieving activation selectivity among polypeptide-modulated receptors, and that success requires consideration of both beta2- and beta3-residues, which differ in terms of side-chain location. PMID- 30442660 TI - Mesoscale structure, mechanics, and transport properties of source rocks' organic pore networks. AB - Organic matter is responsible for the generation of hydrocarbons during the thermal maturation of source rock formation. This geochemical process engenders a network of organic hosted pores that governs the flow of hydrocarbons from the organic matter to fractures created during the stimulation of production wells. Therefore, it can be reasonably assumed that predictions of potentially recoverable confined hydrocarbons depend on the geometry of this pore network. Here, we analyze mesoscale structures of three organic porous networks at different thermal maturities. We use electron tomography with subnanometric resolution to characterize their morphology and topology. Our 3D reconstructions confirm the formation of nanopores and reveal increasingly tortuous and connected pore networks in the process of thermal maturation. We then turn the binarized reconstructions into lattice models including information from atomistic simulations to derive mechanical and confined fluid transport properties. Specifically, we highlight the influence of adsorbed fluids on the elastic response. The resulting elastic energy concentrations are localized at the vicinity of macropores at low maturity whereas these concentrations present more homogeneous distributions at higher thermal maturities, due to pores' topology. The lattice models finally allow us to capture the effect of sorption on diffusion mechanisms with a sole input of network geometry. Eventually, we corroborate the dominant impact of diffusion occurring within the connected nanopores, which constitute the limiting factor of confined hydrocarbon transport in source rocks. PMID- 30442662 TI - Ubiquilin 2 modulates ALS/FTD-linked FUS-RNA complex dynamics and stress granule formation. AB - The ubiquitin-like protein ubiquilin 2 (UBQLN2) has been genetically and pathologically linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but its normal cellular functions are not well understood. In a search for UBQLN2-interacting proteins, we found an enrichment of stress granule (SG) components, including ALS/FTD linked heterogeneous ribonucleoprotein fused in sarcoma (FUS). Through the use of an optimized SG detection method, we observed UBQLN2 and its interactors at SGs. A low complexity, Sti1-like repeat region in UBQLN2 was sufficient for its localization to SGs. Functionally, UBQLN2 negatively regulated SG formation. UBQLN2 increased the dynamics of FUS-RNA interaction and promoted the fluidity of FUS-RNA complexes at a single-molecule level. This solubilizing effect corresponded to a dispersal of FUS liquid droplets in vitro and a suppression of FUS SG formation in cells. ALS-linked mutations in UBQLN2 reduced its association with FUS and impaired its function in regulating FUS-RNA complex dynamics and SG formation. These results reveal a previously unrecognized role for UBQLN2 in regulating the early stages of liquid-liquid phase separation by directly modulating the fluidity of protein-RNA complexes and the dynamics of SG formation. PMID- 30442661 TI - Quantitation of class IA PI3Ks in mice reveals p110-free-p85s and isoform selective subunit associations and recruitment to receptors. AB - Class IA PI3Ks have many roles in health and disease. The rules that govern intersubunit and receptor associations, however, remain unclear. We engineered mouse lines in which individual endogenous class IA PI3K subunits were C terminally tagged with 17aa that could be biotinylated in vivo. Using these tools we quantified PI3K subunits in streptavidin or PDGFR pull-downs and cell lysates. This revealed that p85alpha and beta bound equivalently to p110alpha or p110beta but p85alpha bound preferentially to p110delta. p85s were found in molar-excess over p110s in a number of contexts including MEFs (p85beta, 20%) and liver (p85alpha, 30%). In serum-starved MEFs, p110-free-p85s were preferentially, compared with heterodimeric p85s, bound to PDGFRs, consistent with in vitro assays that demonstrated they bound PDGFR-based tyrosine-phosphorylated peptides with higher affinity and co-operativity; suggesting they may act to tune a PI3K activation threshold. p110alpha-heterodimers were recruited 5-6* more efficiently than p110beta-heterodimers to activated PDGFRs in MEFs or to PDGFR-based tyrosine phosphorylated peptides in MEF-lysates. This suggests that PI3Kalpha has a higher affinity for relevant tyrosine-phosphorylated motifs than PI3Kbeta. Nevertheless, PI3Kbeta contributes substantially to acute PDGF-stimulation of PIP3 and PKB in MEFs because it is synergistically, and possibly sequentially, activated by receptor-recruitment and small GTPases (Rac/CDC42) via its RBD, whereas parallel activation of PI3Kalpha is independent of its RBD. These results begin to provide molecular clarity to the rules of engagement between class IA PI3K subunits in vivo and past work describing "excess p85," p85alpha as a tumor suppressor, and differential receptor activation of PI3Kalpha and PI3Kbeta. PMID- 30442663 TI - Genetic deletion of vesicular glutamate transporter in dopamine neurons increases vulnerability to MPTP-induced neurotoxicity in mice. AB - A subset of midbrain dopamine (DA) neurons express vesicular glutamate transporter 2 (VgluT2), which facilitates synaptic vesicle loading of glutamate. Recent studies indicate that such expression can modulate DA-dependent reward behaviors, but little is known about functional consequences of DA neuron VgluT2 expression in neurodegenerative diseases like Parkinson's disease (PD). Here, we report that selective deletion of VgluT2 in DA neurons in conditional VgluT2-KO (VgluT2-cKO) mice abolished glutamate release from DA neurons, reduced their expression of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB), and exacerbated the pathological effects of exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Furthermore, viral rescue of VgluT2 expression in DA neurons of VglutT2-cKO mice restored BDNF/TrkB expression and attenuated MPTP-induced DA neuron loss and locomotor impairment. Together, these findings indicate that VgluT2 expression in DA neurons is neuroprotective. Genetic or environmental factors causing reduced expression or function of VgluT2 in DA neurons may place some individuals at increased risk for DA neuron degeneration. Therefore, maintaining physiological expression and function of VgluT2 in DA neurons may represent a valid molecular target for the development of preventive therapeutic interventions for PD. PMID- 30442664 TI - pH-dependent thermodynamic intermediates of pHLIP membrane insertion determined by solid-state NMR spectroscopy. AB - The applications of the pH low insertion peptide (pHLIP) in cancer diagnosis and cross-membrane cargo delivery have drawn increasing attention in the past decade. With its origin as the transmembrane (TM) helix C of bacteriorhodopsin, pHLIP is also an important model for understanding how pH can affect the folding and topogenesis of a TM alpha-helix. Protonations of multiple D/E residues transform pHLIP from an unstructured coil at membrane surface (known as state II, at pH >= 7) to a TM alpha-helix (state III, pH <= 5.3). While these initial and end states of pHLIP insertion have been firmly established, what happens at the intervening pH values is less clear. However, the intervening pH range is most relevant to pHLIP-cell interactions in the acidic extracellular tumor environment (and in the endosomes within cells). Here, using advanced solid-state NMR spectroscopy with palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine unilamellar vesicles as the model membrane, we systematically examined the state of pHLIP-membrane interactions (in terms of the membrane locations of D/E residues, as well as lipid dynamics) at the intervening pH values of 6.4, 6.1, and 5.8, along with the known states at pH 7.4 and 5.3. Thermodynamic intermediate states distinct from the initial and end states were discovered to exist at each of the intervening pH examined. They support a multistage model of pHLIP insertion in which the D/E titrations occur in a defined sequence at distinct intermediate pH values. This multistage model has important ramifications in pHLIP applications. PMID- 30442665 TI - Molecular dynamics simulations of nucleotide release from the circadian clock protein KaiC reveal atomic-resolution functional insights. AB - The cyanobacterial clock proteins KaiA, KaiB, and KaiC form a powerful system to study the biophysical basis of circadian rhythms, because an in vitro mixture of the three proteins is sufficient to generate a robust ~24-h rhythm in the phosphorylation of KaiC. The nucleotide-bound states of KaiC critically affect both KaiB binding to the N-terminal domain (CI) and the phosphotransfer reactions that (de)phosphorylate the KaiC C-terminal domain (CII). However, the nucleotide exchange pathways associated with transitions among these states are poorly understood. In this study, we integrate recent advances in molecular dynamics methods to elucidate the structure and energetics of the pathway for Mg.ADP release from the CII domain. We find that nucleotide release is coupled to large scale conformational changes in the KaiC hexamer. Solvating the nucleotide requires widening the subunit interface leading to the active site, which is linked to extension of the A-loop, a structure implicated in KaiA binding. These results provide a molecular hypothesis for how KaiA acts as a nucleotide exchange factor. In turn, structural parallels between the CI and CII domains suggest a mechanism for allosteric coupling between the domains. We relate our results to structures observed for other hexameric ATPases, which perform diverse functions. PMID- 30442666 TI - Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. AB - The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72 However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8 -/- mice were rescued by triple knockout of the endosomal Toll like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8 -/- mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8 -/- macrophages. Smcr8 -/- mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand-receptor contact causes inflammatory disease in SMCR8-deficient mice. PMID- 30442667 TI - The CD4-CD8- MAIT cell subpopulation is a functionally distinct subset developmentally related to the main CD8+ MAIT cell pool. AB - Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells predominantly express the CD8alpha coreceptor (CD8+), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8alpha represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8+ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORgammat/T-bet ratio, and express less IFN-gamma and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8+ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8+ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8+ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8+ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship. PMID- 30442668 TI - MARCH3 attenuates IL-1beta-triggered inflammation by mediating K48-linked polyubiquitination and degradation of IL-1RI. AB - The proinflammatory cytokine IL-1beta plays critical roles in inflammatory and autoimmune diseases. IL-1beta signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1beta-triggered signaling. Overexpression of MARCH3 inhibited IL 1beta-triggered activation of NF-kappaB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1beta injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1beta stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3 mediated IL-1RI degradation is an important mechanism for attenuating IL-1beta triggered inflammatory response. PMID- 30442670 TI - Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks. AB - During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage. PMID- 30442669 TI - Permanent neuroglial remodeling of the retina following infiltration of CSF1R inhibition-resistant peripheral monocytes. AB - Previous studies have demonstrated that ocular injury can lead to prompt infiltration of bone-marrow-derived peripheral monocytes into the retina. However, the ability of these cells to integrate into the tissue and become microglia has not been investigated. Here we show that such peripheral monocytes that infiltrate into the retina after ocular injury engraft permanently, migrate to the three distinct microglia strata, and adopt a microglia-like morphology. In the absence of ocular injury, peripheral monocytes that repopulate the retina after depletion with colony-stimulating factor 1 receptor (CSF1R) inhibitor remain sensitive to CSF1R inhibition and can be redepleted. Strikingly, consequent to ocular injury, the engrafted peripheral monocytes are resistant to depletion by CSF1R inhibitor and likely express low CSF1R. Moreover, these engrafted monocytes remain proinflammatory, expressing high levels of MHC-II, IL 1beta, and TNF-alpha over the long term. The observed permanent neuroglia remodeling after injury constitutes a major immunological change that may contribute to progressive retinal degeneration. These findings may also be relevant to other degenerative conditions of the retina and the central nervous system. PMID- 30442672 TI - Contrasting temporal difference and opportunity cost reinforcement learning in an empirical money-emergence paradigm. AB - Money is a fundamental and ubiquitous institution in modern economies. However, the question of its emergence remains a central one for economists. The monetary search-theoretic approach studies the conditions under which commodity money emerges as a solution to override frictions inherent to interindividual exchanges in a decentralized economy. Although among these conditions, agents' rationality is classically essential and a prerequisite to any theoretical monetary equilibrium, human subjects often fail to adopt optimal strategies in tasks implementing a search-theoretic paradigm when these strategies are speculative, i.e., involve the use of a costly medium of exchange to increase the probability of subsequent and successful trades. In the present work, we hypothesize that implementing such speculative behaviors relies on reinforcement learning instead of lifetime utility calculations, as supposed by classical economic theory. To test this hypothesis, we operationalized the Kiyotaki and Wright paradigm of money emergence in a multistep exchange task and fitted behavioral data regarding human subjects performing this task with two reinforcement learning models. Each of them implements a distinct cognitive hypothesis regarding the weight of future or counterfactual rewards in current decisions. We found that both models outperformed theoretical predictions about subjects' behaviors regarding the implementation of speculative strategies and that the latter relies on the degree of the opportunity costs consideration in the learning process. Speculating about the marketability advantage of money thus seems to depend on mental simulations of counterfactual events that agents are performing in exchange situations. PMID- 30442673 TI - Efavirenz and Efavirenz-like Compounds Activate Human, Murine, and Macaque Hepatic IRE1alpha-XBP1. AB - Efavirenz (EFV), a widely used antiretroviral drug, is associated with idiosyncratic hepatotoxicity and dyslipidemia. Here we demonstrate that EFV stimulates the activation in primary hepatocytes of key cell stress regulators: inositol requiring 1alpha (IRE1alpha) and X-box binding protein 1 (XBP1). Following EFV exposure, XBP1 splicing (indicating activation) was increased 35.7 fold in primary human hepatocytes. Paralleling this, XBP1 splicing and IRE1alpha phosphorylation (p-IRE1alpha, active IRE1alpha) were elevated 36.4-fold and 4.9 fold, respectively, in primary mouse hepatocytes. Of note, with EFV treatment, 47.2% of mouse hepatocytes were apoptotic; which was decreased to 23.9% in the presence of STF083010, an inhibitor of XBP1 splicing. Experiments performed using pregnane X receptor (PXR)-null mouse hepatocytes revealed that EFV-mediated XBP1 splicing and hepatocyte death were not dependent on PXR, which is a nuclear receptor transcription factor that plays a crucial role in the cellular response to xenobiotics. Interestingly, incubation with the primary metabolite of EFV, 8 hydroxyEFV (8-OHEFV), only resulted in 10.3-, and 2.9-fold increased XBP1 splicing in human and mouse hepatocytes and no change in levels of p-IRE1alpha in mouse hepatocytes. To further probe the structure-activity relationship of IRE1alpha-XBP1 activation by EFV, 16 EFV analogs were employed. Of these, an analog in which the EFV alkyne is replaced with an alkene and an analog in which the oxazinone oxygen is replaced by a carbon stimulated XBP1 splicing in human, mouse, and macaque hepatocytes. These data demonstrate that EFV and compounds sharing the EFV scaffold can activate IRE1alpha-XBP1 across humans, mice, and macaques. PMID- 30442671 TI - Rapid evolution of decreased host susceptibility drives a stable relationship between ultrasmall parasite TM7x and its bacterial host. AB - Around one-quarter of bacterial diversity comprises a single radiation with reduced genomes, known collectively as the Candidate Phyla Radiation. Recently, we coisolated TM7x, an ultrasmall strain of the Candidate Phyla Radiation phylum Saccharibacteria, with its bacterial host Actinomyces odontolyticus strain XH001 from human oral cavity and stably maintained as a coculture. Our current work demonstrates that within the coculture, TM7x cells establish a long-term parasitic association with host cells by infecting only a subset of the population, which stay viable yet exhibit severely inhibited cell division. In contrast, exposure of a naive A. odontolyticus isolate, XH001n, to TM7x cells leads to high numbers of TM7x cells binding to each host cell, massive host cell death, and a host population crash. However, further passaging reveals that XH001n becomes less susceptible to TM7x over time and enters a long-term stable relationship similar to that of XH001. We show that this reduced susceptibility is driven by rapid host evolution that, in contrast to many forms of phage resistance, offers only partial protection. The result is a stalemate where infected hosts cannot shed their parasites; nevertheless, parasite load is sufficiently low that the host population persists. Finally, we show that TM7x can infect and form stable long-term relationships with other species in a single clade of Actinomyces, displaying a narrow host range. This system serves as a model to understand how parasitic bacteria with reduced genomes such as those of the Candidate Phyla Radiation have persisted with their hosts and ultimately expanded in their diversity. PMID- 30442674 TI - Clue to the diagnosis on chest X-ray in a child with neck swelling. AB - Differentiated thyroid cancer is a rare disease in children and adolescents and manifests exclusively in the form of papillary thyroid cancer (PTC). We present a rare case of PTC who presented initially with lung symptoms and miliary nodules on chest X-ray. This case emphasises the important differential of miliary mottling of the lungs.A 7-year-old girl presented with history of neck swelling and change in voice for the past 9 months and progressively worsening dyspnoea for 5 months. She was assessed elsewhere and treated with multiple courses of antibiotics without relief, as well as levothyroxine 50 ug daily for new hypothyroidism. Her initial thyroid function tests were not available.There was a history of weight loss, but no cough or night sweats. There was no history of tuberculosis (TB) contact or environmental exposure. On examination, child was tachypnoeic, tachycardic and requiring oxygen. Her initial chest X-ray is shown in figure 1 She was initially treated as suspected TB rather than immunodeficiency with antitubercular drugs (rifampicin/isoniazid/pyrazinamide/streptomycin). Bronchoscopy was negative for TB, bacteria, fungus and malignant cells, with lung biopsy (shown in figures 2 and 3). HIV and quantiferon results were negative.edpract;archdischild-2018 315856v1/F1F1F1Figure 1Chest x-ray. edpract;archdischild-2018 315856v1/F2F2F2Figure 2H&E stain. edpract;archdischild-2018-315856v1/F3F3F3Figure 3Immunohistochemistry of the lung tissue.The thyroid profile done while on levothyroxine was as below:TSH: 14.7 mill IU/L (0.6-4.1).Free T3: 5.2 pmol/L (4.10-7.90).Free T4: 15.2 pmol/L (11.6-32.8).Thyroglobulin: 31 ug/L (1.40-78).TPO Ab: >600 IU/mL (normal high <=34).Thyroglobulin Ab: >4000 (normal high <=115). QUESTIONS: What is the abnormality in the chest X-ray and possible differential diagnosis?What are the histology findings in lung biopsy depicted in light microscopy figure 2 and immunohistochemistry in figure 3?The family asks you: what is the diagnosis and treatment? Are there any side effects? What is the likely outcome? PMID- 30442675 TI - Fifteen-minute consultation: How to use an interpreter in a medical consultation. AB - The use of interpreters is essential in our multicultural society. The families and patients we treat come from differing backgrounds, cultures and spoken language. Many are not proficient in, or may even entirely lack, the ability to communicate effectively in English. As health professionals, we must meet their needs and manage the risks to provision of good quality care that language barriers may introduce. Use of an interpreter or interpreting service is an important skill, which is rarely formally taught in undergraduate or postgraduate curricula. Here, we present some of the pitfalls of using an interpreter, and offer some tips on getting the best out of their use. PMID- 30442676 TI - Guideline review: Epinephrine use in anaphylaxis (AAP guideline 2017). PMID- 30442677 TI - Direct Rap1/Talin1 interaction regulates platelet and neutrophil integrin activity in mice. AB - Targeting Talin1 to the plasma membrane is a crucial step in integrin activation, which in leukocytes is mediated by a Rap1/RIAM/Talin1 pathway whereas in platelets is RIAM-independent. Recent structural, biochemical and cell biological studies suggested a direct Rap1/Talin1 interaction as an alternative mechanism to recruit Talin1 to the membrane and induce integrin activation. To test whether this pathway is of relevance in vivo, we generated Rap1-binding-deficient Talin1 knockin (Tln13mut) mice. Although Tln13mut mice show no obvious abnormalities, their platelets exhibit reduced integrin activation, aggregation, adhesion and spreading resulting in prolonged tail-bleeding times and delayed thrombus formation and vessel occlusion in vivo. Surprisingly, neutrophil adhesion to different integrin ligands and beta2 integrin-dependent phagocytosis are also significantly impaired, which causes a profound leukocyte adhesion and extravasation defect in Tln13mut mice. In contrast, macrophages exhibit no defect in adhesion and spreading despite reduced integrin activation. Taken together, our findings suggest that the direct Rap1/Talin1 interaction is of particular importance in regulating the activity of different integrin classes expressed on platelets and neutrophils, which both depend on very fast and dynamic integrin mediated responses. PMID- 30442678 TI - Neutrophil alpha-defensins promote thrombosis in vivo by altering fibrin formation, structure and stability. AB - Inflammation and thrombosis are integrated, mutually reinforcing processes, but the inter-regulatory mechanisms are incompletely defined. Here, we examined the contribution of alpha-defensins (alpha-defs), antimicrobial proteins released from activated human neutrophils, on clot formation in vitro and in vivo. Activation of the intrinsic pathway of coagulation stimulates release of alpha defs from neutrophils. alpha-defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro. Transgenic mice (Def++) expressing human alpha-def-1 developed larger, occlusive, neutrophil-rich clots after partial inferior vena cava (IVC) ligation than formed in wild type (WT) mice. IVC thrombi extracted from Def++ mice were composed of a fibrin meshwork that was denser and contained a higher proportion of tightly packed compressed polyhedral erythrocytes than developed in WT mice. Def++ mice were resistant to thromboprophylaxis with heparin. Inhibiting activation of the intrinsic pathway of coagulation, bone marrow transplantation from WT mice or provision of colchicine to Def++ mice to inhibit neutrophil degranulation, decreased plasma levels of alpha-defs, caused phenotypic reversion characterized by smaller thrombi comparable to those formed in WT mice, and restored responsiveness to heparin. These data identify alpha defs as a potentially important and tractable link between innate immunity and thrombosis. PMID- 30442679 TI - Cerebral cavernous malformations form an anticoagulant vascular domain. AB - Cerebral cavernous malformations (CCM) are common brain vascular dysplasias prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here we show that central nervous system (CNS) hemorrhage in CCM is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions and in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1ECKO ) or Pdcd10 (Pdcd10ECKO ), which cause CCM formation, result in increased levels of vascular TM and EPCR, and in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10 Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of one or two copies of the Thbd gene decreases brain hemorrhage in Pdcd10ECKO mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10ECKO mice. Thus, a local increase in the endothelial co-factors that generate anticoagulant APC can contribute to bleeding in CCMs and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs. PMID- 30442680 TI - How I treat Philadelphia chromosome positive acute lymphoblastic leukemia. AB - The introduction of agents targeted at specific molecular events is changing the treatment paradigms in a number of malignancies. Historically, we have relied entirely on DNA-interactive, cytotoxic drugs for treating patients with leukemia. Increased understanding of the leukemic cell biology and pathogenesis, and the ways they evade the immune surveillance mechanisms, will likely lead to the development of more effective agents, and regimens less reliant on chemotherapy, able to achieve deep levels of disease eradication. In Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL), the introduction of increasingly potent tyrosine kinas inhibitors (TKIs) has revolutionized therapy. These drugs have been established as the cornerstone of any therapeutic strategy in this disease and a number of trials have better defined the best ways to incorporate them into the established paradigms. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic cell transplant (alloHCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease (MRD), we are entering an era where we hope to diminish our reliance on transplantation and cytotoxic chemotherapy in this disease. PMID- 30442681 TI - Inhibition of monoacylglycerol lipase for the treatment of liver disease: tempting but still playing with fire. PMID- 30442682 TI - Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer. AB - The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2(HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, four in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer, but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Further, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Further, there is a rapidly growing number of new therapeutics targeting HER2 including small molecule inhibitors, antibody-drug conjugates and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2-targeted therapies. PMID- 30442683 TI - PIK3CA Amplification Associates with Aggressive Phenotype but Not Markers of AKT MTOR Signaling in Endometrial Carcinoma. AB - Purpose: Amplification of PIK3CA, encoding the PI3K catalytic subunit alpha, is common in uterine corpus endometrial carcinoma (UCEC) and linked to an aggressive phenotype. However, it is unclear whether PIK3CA amplification acts via PI3K activation. We investigated the association between PIK3CA amplification, markers of PI3K activity, and prognosis in a large cohort of UCEC specimens.Experimental Design: UCECs from 591 clinically annotated patients including 83 tumors with matching metastasis (n = 188) were analyzed by FISH to determine PIK3CA copy number status. These data were integrated with mRNA and protein expression and clinicopathologic data. Results were verified in The Cancer Genome Atlas dataset.Results: PIK3CA amplifications were associated with disease-specific mortality and with other markers of aggressive disease. PIK3CA amplifications were also associated with other amplifications characteristic of the serous-like somatic copy-number alteration (SCNA)-high subgroup of UCEC. Tumors with PIK3CA amplification also demonstrated an increase in phospho-p70S6K but had decreased levels of activated phospho-AKT1-3 as assessed by Reverse Phase Protein Arrays and an mRNA signature of MTOR inhibition.Conclusions: PIK3CA amplification is a strong prognostic marker and a potential marker for the aggressive SCNA-high subgroup of UCEC. Although PIK3CA amplification associates with some surrogate measures of increased PI3K activity, markers for AKT1-3 and MTOR signaling are decreased, suggesting that this signaling is not a predominant pathway to promote cancer growth of aggressive serous-like UCEC. Moreover, these associations may reflect features of the SCNA-high subgroup of UCEC rather than effects of PIK3CA amplification itself. Clin Cancer Res; 1-12. (c)2018 AACR. PMID- 30442684 TI - Molecular Profiling of Cohorts of Tumor Samples to Guide Clinical Development of Pembrolizumab as Monotherapy. AB - Purpose: Molecular profiling of large databases of human tumor gene expression profiles offers novel opportunities for informing decisions in clinical development programs.Experimental Design: Gene expression profile of programmed death ligand 1 (PD-L1) was explored in a dataset of 16,000 samples, including approximately 4,000 metastatic tumors, across >25 tumor types prevalent in the United States, looking for new indications for the programmed death 1 (PD-1) inhibitor pembrolizumab. PD-L1 expression was highly concordant with several genomic signatures indicative of immune-inflamed tumor microenvironment. Prevalence of activated immune-inflamed tumors across all tumor types was explored and used to rank tumor types for potential response to pembrolizumab monotherapy.Results: The analysis yielded 3 tiers of indications in which high levels of PD-L1 and immune-inflamed signatures were found in up to 40% to 60%, 20% to 40%, and 0% to 20% of tumors. Tier 1 contained novel indications known at the time of analysis to be responsive to PD-1 checkpoint blockade in the clinic (such as melanoma and non-small cell lung cancer), as well as indications not studied in the clinic previously, including microsatellite instability-high colorectal, head and neck, bladder, and triple-negative breast cancers. Complementary analysis of an Asian/Pacific cancer dataset (gastric cancer) revealed high prevalence of immune-inflamed tumors in gastric cancer. These data contributed to prioritization of these indications for clinical development of pembrolizumab as monotherapy.Conclusions: Data highlight the value of molecular profiling in identifying populations with high unmet needs with potentially favorable response characteristics and accelerating development of novel therapies for these patients. Clin Cancer Res; 1-10. (c)2018 AACR. PMID- 30442687 TI - Celebrating 35 Years of the AJNR: November 1983 edition. PMID- 30442686 TI - Prognostic value of D-dimer and markers of coagulation for stratification of abdominal aortic aneurysm growth. AB - Abdominal aortic aneurysm (AAA) is associated with high morbidity and mortality and is an established cause of unbalanced hemostasis. A number of hemostatic biomarkers have been associated with AAA; however, the utility of hemostatic biomarkers in AAA diagnosis and prognosis is unclear. The aim of the present study was to characterize the potential prognostic value of D-dimer and markers of altered hemostasis in a large cohort of patients with AAAs characterized by either fast or slow aneurysm growth (frequency matched for baseline diameter) and subaneurysmal dilations. We measured plasma concentrations of thrombin antithrombin (TAT) complex, platelet factor 4 (PF4), and D-dimer in 352 patients with either fast-growing AAAs (>2 mm/y), slow-growing AAAs (<2 mm/y), subaneurysmal aortic dilations, or nonaneurysmal aortas. Plasma D-dimer and TAT were significantly elevated in both AAA and subaneurysmal dilation patients compared with controls. Individuals with D-dimer levels >=500 ng/mL had 3.09 times the odds of subaneurysms, 6.23 times the odds of slow-growing AAAs, and 7.19 times the odds of fast-growing AAAs than individuals with D-dimer level <500 ng/mL. However, no differences in D-dimer concentration were noted between fast- and slow-growing aneurysms. Plasma D-dimer and TAT were strong independent predictors of AAA growth rate with multivariate analysis revealing a 500-ng/mL increase in D-dimer or 1-ug/mL increase in TAT led to additional 0.21-mm and 0.24 mm changes in aortic diameter per year, respectively. Rising levels of plasma TAT, in addition to D-dimer, may predict disease progression and aneurysm growth in patients with AAA or subaneurysmal dilation. PMID- 30442689 TI - Sick certification by general practitioners is an unethical conflict of interest. PMID- 30442688 TI - Standards of Practice in Acute Ischemic Stroke Intervention: International Recommendations. PMID- 30442691 TI - NHS staff shortages could reach 250 000 by 2030 without urgent action, experts warn. PMID- 30442690 TI - Open letter to Simon Stevens to ensure that tobacco dependence treatment is provided for every smoker cared for by the NHS, as part of the long term plan. PMID- 30442692 TI - Two-Layered Susceptibility Vessel Sign and High Overestimation Ratio on MRI Are Predictive of Cardioembolic Stroke. AB - In a prospective study among patients in the THRombectomie des Arteres Cerebrales trial, we analyzed the diagnostic accuracy of 2 imaging biomarkers, the 2-layered susceptibility vessel sign and a high overestimation ratio, obtained on pretreatment brain T2* sequences, to identify cardioembolic stroke etiology (107/260 patients). In combination, these 2 biomarkers, on 1.5T or 3T systems (159 and 101 patients, respectively), demonstrated high specificity (0.77 at 1.5T and 1 at 3T) and their simultaneous presence is highly associated with cardioembolism. PMID- 30442693 TI - Hypertension Is Associated with White Matter Disruption in Apparently Healthy Middle-Aged Individuals. AB - BACKGROUND AND PURPOSE: Traditional cardiovascular risk factors have been associated with white matter disease. Because hypertension results in vascular stiffness and impaired cerebral perfusion, we hypothesized that it would be the most relevant risk factor for microstructural white matter disruption in apparently healthy middle-aged individuals with a family history of early-onset coronary artery disease. MATERIALS AND METHODS: This was a cross-sectional analysis of participants in the Genetic Study of Atherosclerosis Risk with DTI. Regional fractional anisotropy of 181 segmented brain regions was measured using Eve WM Atlas. Risk factors were examined using univariate analysis for 48 regions representing deep WM structures. Minimal multivariable linear regression models adjusting for age, sex, and race and maximal linear regression models adjusting for cardiovascular risk factors were performed for regions meeting the Bonferroni threshold in the initial analysis. RESULTS: Included were 116 subjects (mean age, 49 +/- 11 years; 57% men) with a moderate load of cardiovascular risk factors. Subjects with hypertension had significantly lower regional fractional anisotropy in the right cingulum and left stria terminalis in the minimal and maximal regression models. Additionally, there was lower regional fractional anisotropy in the left fornix in the maximal model and right sagittal stratum in the minimal model. Systolic blood pressure values were significantly associated with regional fractional anisotropy in the left superior longitudinal fasciculus in the maximal model. There were no significant differences among regional fractional anisotropy values for other cardiovascular risk factors. CONCLUSIONS: In middle-aged apparently healthy individuals with susceptibility to vascular disease, among all known cardiovascular risk factors, hypertension was associated with microstructural WM disruption. PMID- 30442694 TI - Single-Needle Lateral Sacroplasty Technique. AB - Sacral insufficiency fractures result in significant morbidity, and percutaneous sacroplasty has emerged as a promising technique for their treatment. We present a technical note regarding our method of treating these fractures using a "single needle" lateral technique with a combination of conebeam CT and biplane fluoroscopy. We treated 10 patients, in whom the median Visual Analog Scale pain score decreased from 7.0 to 0 (P < .001). We concluded that single-needle sacroplasty is feasible and safe using this technique. PMID- 30442695 TI - ERRATUM. PMID- 30442696 TI - MRI, Magnetoencephalography, and Surgical Outcome of Oligodendrocytosis versus Focal Cortical Dysplasia Type I. AB - BACKGROUND AND PURPOSE: Abnormalities of oligodendrocytes have been reported in surgical specimens of patients with medically intractable epilepsy. The aim of this study was to compare the MR imaging, magnetoencephalography, and surgical outcome of children with oligodendrocytosis relative to focal cortical dysplasia I. MATERIALS AND METHODS: Oligodendrocytosis included oligodendroglial hyperplasia, oligodendrogliosis, and oligodendroglial-like cells in the white matter, gray matter, or both from children with medically intractable epilepsy. Focal cortical dysplasia I included radial and tangential cortical dyslamination. The MR imaging, magnetoencephalography, type of operation, location, and seizure outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I were compared. RESULTS: Eighteen subjects (39.1%) had oligodendrocytosis, 21 (45.7%) had focal cortical dysplasia I, and 7 (15.2%) had oligodendrocytosis + focal cortical dysplasia I. There were no significant differences in the type of seizures, focal or nonfocal epileptiform discharges, magnetoencephalography, and MR imaging features, including high T1 signal in the cortex, high T2/FLAIR signal in the cortex or subcortical white matter, increased cortical thickness, blurring of the gray-white junction, or abnormal sulcation and gyration among those with oligodendrocytosis, focal cortical dysplasia I, or oligodendrocytosis + focal cortical dysplasia I (P > .01). There were no significant differences in the extent of resection (unilobar versus multilobar versus hemispherectomy), location of the operation (temporal versus extratemporal versus both), or seizure-free outcome of oligodendrocytosis, focal cortical dysplasia I, and oligodendrocytosis + focal cortical dysplasia I (P > .05). CONCLUSIONS: Oligodendrocytosis shared MR imaging and magnetoencephalography features with focal cortical dysplasia I, and multilobar resection was frequently required to achieve seizure freedom. In 15% of cases, concurrent oligodendrocytosis and focal cortical dysplasia I were identified. The findings suggest that oligodendrocytosis may represent a mild spectrum of malformations of cortical development. PMID- 30442697 TI - Toward Better Understanding of Flow Diversion in Bifurcation Aneurysms. AB - BACKGROUND AND PURPOSE: Flow diversion is being increasingly used to treat bifurcation aneurysms. Empiric approaches have generally led to encouraging results, and a growing body of animal and ex vivo literature addresses the fate of target aneurysms and covered branches. Our prior investigations highlighted the dynamic nature of metal coverage provided by the Pipeline Embolization Device and suggested strategies for creating optimal single and multidevice constructs. We now address the geometric and hemodynamic aspects of jailing branch vessels and neighboring target aneurysms. MATERIALS AND METHODS: Fundamental electric and fluid dynamics principles were applied to generate equations describing the relationships between changes in flow and the degree of vessel coverage in settings of variable collateral support to the jailed territory. Given the high complexity of baseline and posttreatment fluid dynamics, in vivo, we studied a simplified hypothetic system with minimum assumptions to generate the most conservative outcomes. RESULTS: In the acute setting, Pipeline Embolization Devices modify flow in covered branches, principally dependent on the amount of coverage, the efficiency of collateral support, and intrinsic resistance of the covered parenchymal territory. Up to 30% metal coverage of any branch territory is very likely to be well-tolerated regardless of device or artery size or the availability of immediate collateral support, provided, however, that no acute thrombus forms to further reduce jailed territory perfusion. CONCLUSIONS: Basic hemodynamic principles support the safety of branch coverage during aneurysm treatment with the Pipeline Embolization Device. Rational strategies to build bifurcation constructs are feasible. PMID- 30442698 TI - Isolated Internal Auditory Canal Diverticula: A Normal Anatomic Variant Not Associated with Sensorineural Hearing Loss. AB - BACKGROUND AND PURPOSE: Bony internal auditory canal diverticula are relatively common, occurring in approximately 5% of temporal bone CTs. Internal auditory canal diverticula have historically been considered incidental; however, a recent publication reported that internal auditory canal diverticula are associated with sensorineural hearing loss. The objective of this study was to further characterize this potential association in a large cohort of patients. MATERIALS AND METHODS: A total of 1759 patients undergoing high-resolution temporal bone CT were collected during a 6-year interval, and audiometric data were obtained from those with internal auditory canal diverticula. To assess any association of isolated internal auditory canal diverticula with sensorineural hearing loss, we excluded from further analysis patients with concomitant otosclerosis and bilateral diverticula and those without audiometric data, leaving 22 index cases. Audiometric data for the ear with a diverticulum was compared with that in the contralateral ear, to serve as an internal control. RESULTS: Of 1759 patients, 82 (4.7%) had either unilateral (n = 33, 40%) or bilateral (n = 49, 60%) internal auditory canal diverticula. The co-incidence of otosclerosis and internal auditory canal diverticula was 34% (n = 28). There was no correlation between patient age and diverticulum size on either side. Among the index cases with isolated unilateral internal auditory canal diverticula and complete audiometric data, word recognition scores and the prevalence and severity of sensorineural hearing loss were not significantly different comparing the internal auditory canal diverticulum side to its contralateral control. CONCLUSIONS: This study did not find a statistically significant association between ears with internal auditory canal diverticula and worsening sensorineural hearing loss or word recognition. Internal auditory canal diverticula most likely represent a normal anatomic variant in ears without otosclerosis. PMID- 30442699 TI - Natural History of Endoscopic Third Ventriculostomy in Adults: Serial Evaluation with High-Resolution CISS. AB - BACKGROUND AND PURPOSE: Endoscopic third ventriculostomy is a well-accepted treatment choice for hydrocephalus and is used most frequently with a known impediment to CSF flow between the third ventricle and basal cisterns. However, there are scarce data on the imaging evolution of the defect in the floor of the third ventricle and how this affects patency rates and clinical outcomes. The purpose of this study was to assess whether, and how, the endoscopic third ventriculostomy defect changes in size with time. MATERIALS AND METHODS: All high resolution endoscopic third ventriculostomy protocol MRIs performed between 2009 through 2014 were retrospectively identified. Two fellowship-trained neuroradiologists, blinded to clinical information, independently reviewed all retrospective cases. RESULTS: A total of 98 imaging studies were included from 34 patients. The average change in the area throughout the studied period was 0.02 mm2/day (7.5 mm2/year), with a higher increase in size noted in the first 3 postsurgical months, with a gradual decrease in the degree of defect-size change. Use of the NICO Myriad device was correlated with the area of the endoscopic third ventriculostomy defect on the last follow-up, demonstrating a larger final defect size in patients in whom the surgical technique included debridement of the endoscopic third ventriculostomy defect walls with the NICO Myriad device (28.21 versus 11.25 mm, P < .05). CONCLUSIONS: High-resolution MR imaging with sagittal CISS images is useful in the postoperative evaluation of endoscopic third ventriculostomies. Such findings may prove useful in determining the optimal duration of follow-up with MR imaging of patients who have undergone endoscopic third ventriculostomy. PMID- 30442700 TI - Contralateral Approach to Coil Embolization of Proximal A1 Aneurysms Using the Anterior Communicating Artery. AB - BACKGROUND AND PURPOSE: Aneurysms arising from the proximal A1 segment of the anterior cerebral artery are rare, and their distinctive configurations often pose technical challenges during endovascular embolization. Herein, we present 11 patients with proximal A1 aneurysms requiring a contralateral approach (via the anterior communicating artery) to coil embolization. MATERIALS AND METHODS: From a prospectively collected data repository, we retrieved records of 11 patients consecutively treated for proximal A1 aneurysms between January 2011 and March 2018. In each instance, coil embolization was performed by the contralateral route. Outcomes were analyzed in terms of morphologic features and clinical status. RESULTS: Aneurysms in all 11 patients were directed posteriorly and were small (<5 mm). A contralateral approach (via the anterior communicating artery) was used after ipsilateral attempts at aneurysm selection failed in each instance, despite using a variety of microcatheters. Single punctures and single guiding catheters sufficed in 9 patients, but 2 patients required dual punctures and 2 guiding catheters. All endovascular treatments ultimately yielded excellent outcomes. Although 1 symptomatic infarct was manifested in the course of ipsilateral treatment, no morbidity or mortality resulted from the contralateral access. CONCLUSIONS: Due to angio-anatomic constraints, a contralateral strategy for coil embolization of proximal A1 aneurysms is acceptable if ipsilateral access is technically prohibitive and the vessels (contralateral A1 and anterior communicating artery) are amenable to the passage of microdevices. PMID- 30442701 TI - Reply. PMID- 30442702 TI - T1-Hyperintense Plaques on Intracranial-versus-Extracranial Vessel Wall MRI. PMID- 30442703 TI - Cuba pulls more than 8000 doctors out of Brazil after qualifications are questioned. PMID- 30442704 TI - Accuracy of Provider-Documented Child Immunization Status at Hospital Presentation for Acute Respiratory Illness. AB - OBJECTIVES: To assess (1) the accuracy of child immunization status documented by providers at hospital presentation for acute respiratory illness and (2) the association of provider-documented up-to-date (UTD) status with immunization receipt during and after hospitalization. METHODS: We conducted a retrospective cohort analysis of children <=16 years old treated for asthma, croup, bronchiolitis, or pneumonia at a children's hospital between July 2014 and June 2016. Demographics, clinical characteristics, and provider-documented UTD immunization status (yes or no) at presentation were obtained from the medical record. We compared provider-documented UTD status to the gold standard: the child's UTD status as documented in the Washington State Immunization Information System (WAIIS). The sensitivity, specificity, and positive predictive value of provider-documented UTD status were calculated. We assessed the association of provider-documented UTD status and immunization during and within 30 days posthospitalization using multivariable logistic regression. RESULTS: Among 478 eligible children, 450 (94%) had provider-documented UTD status at hospital presentation and an active WAIIS record. Overall, 92% and 42% were UTD by provider documentation and WAIIS records, respectively, with provider-documented UTD status having 98.4% sensitivity (95% confidence interval [CI]: 95.4%-99.7%), 12.2% specificity (95% CI: 8.5%-16.8%), and 44.6% positive predictive value (95% CI: 39.7%-49.5%). Per WAIIS records, 20% and 44% of children who were due for vaccines received a vaccine during or within 30 days posthospitalization, respectively. There was no significant association between provider-documented UTD status and immunization during or after hospitalization. CONCLUSIONS: Provider-documented UTD immunization status at hospital presentation for children with respiratory illnesses overestimates UTD status, creating missed opportunities for immunization during and after hospitalization. PMID- 30442706 TI - All doctors need training on "fit notes". PMID- 30442705 TI - Radiation combined with macrophage depletion promotes adaptive immunity and potentiates checkpoint blockade. AB - Emerging evidence suggests a role for radiation in eliciting anti-tumour immunity. We aimed to investigate the role of macrophages in modulating the immune response to radiation. Irradiation to murine tumours generated from colorectal (MC38) and pancreatic (KPC) cell lines induced colony-stimulating factor 1 (CSF-1). Coincident with the elevation in CSF-1, macrophages increased in tumours, peaking 5 days following irradiation. These tumour-associated macrophages (TAMs) were skewed towards an immunosuppressive phenotype. Macrophage depletion via anti-CSF (aCSF) reduced macrophage numbers, yet only achieved tumour growth delay when combined with radiation. The tumour growth delay from aCSF after radiation was abrogated by depletion of CD8 T cells. There was enhanced recognition of tumour cell antigens by T cells isolated from irradiated tumours, consistent with increased antigen priming. The addition of anti-PD-L1 (aPD-L1) resulted in improved tumour suppression and even regression in some tumours. In summary, we show that adaptive immunity induced by radiation is limited by the recruitment of highly immunosuppressive macrophages. Macrophage depletion partly reduced immunosuppression, but additional treatment with anti-PD L1 was required to achieve tumour regression. PMID- 30442707 TI - Job-exposure matrices addressing lifestyle factors. PMID- 30442708 TI - The Clinical Impact of the Genomic Landscape of Mismatch Repair-Deficient Cancers. AB - : The mismatch repair (MMR) system which detects and corrects base mismatches and insertions and deletions that occur during DNA synthesis is deregulated in approximately 20% of human cancers. MMR-deficient tumors have peculiar properties, including early-onset metastatic potential but generally favorable prognosis, and remarkable response to immune therapy. The functional basis of these atypical clinical features has recently started to be elucidated. Here, we discuss how the biological and clinical features of MMR-deficient tumors might be traced back to their ability to continuously produce new somatic mutations, leading to increased levels of neoantigens, which in turn stimulate immune surveillance. SIGNIFICANCE: Tumors carrying defects in DNA MMR accumulate high levels of mutations, a feature linked to rapid tumor progression and acquisition of drug resistance but also favorable prognosis and response to immune-checkpoint blockade. We discuss how the genomic landscape of MMR-deficient tumors affects their biological and clinical behaviors. PMID- 30442710 TI - Preoperative physiotherapy education prevented postoperative pulmonary complications following open upper abdominal surgery. PMID- 30442709 TI - PPT1 promotes tumor growth and is the molecular target of chloroquine derivatives in cancer. AB - Clinical trials repurposing lysosomotropic chloroquine (CQ) derivatives as autophagy inhibitors in cancer demonstrate encouraging results, but the underlying mechanism of action remains unknown. Here we report a novel dimeric CQ (DC661) capable of deacidifying the lysosome and inhibiting autophagy significantly better than HCQ. Using an in situ photoaffinity pulldown strategy, we identified palmitoyl-protein thioesterase 1 (PPT1) as a molecular target shared across monomeric and dimeric CQ derivatives. HCQ and Lys05 also bound to and inhibited PPT1 activity, but only DC661 maintained activity in acidic media. Knockout of PPT1 in cancer cells using CRISPR-Cas9 editing abrogates autophagy modulation and cytotoxicity of CQ derivatives, and results in significant impairment of tumor growth similar to that observed with DC661. Elevated expression of PPT1 in tumors correlates with poor survival in patients in a variety of cancers. Thus, PPT1 represents a new target in cancer that can be inhibited with CQ derivatives. PMID- 30442712 TI - The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway. AB - The transcriptional coactivator WW domain-binding protein 2 (WBP2) is an emerging oncogene and serves as a node between the signaling protein Wnt and other signaling molecules and pathways, including epidermal growth factor receptor, estrogen receptor/progesterone receptor, and the Hippo pathway. The upstream regulation of WBP2 is well-studied, but its downstream activity remains unclear. Here, we elucidated WBP2's role in triple-negative breast cancer (TNBC), in which Wnt signaling is predominantly activated. Using RNAi coupled with RNA-Seq and MS analyses to identify Wnt/WBP2- and WBP2-dependent targets in MDA-MB231 TNBC cells, we found that WBP2 is required for the expression of a core set of genes in Wnt signaling. These included AXIN2, which was essential for Wnt/WBP2-mediated breast cancer growth and migration. WBP2 also regulated a much larger set of genes and proteins independently of Wnt, revealing that WBP2 primes cells to Wnt activity by up-regulating G protein pathway suppressor 1 (GPS1) and TRAF2- and NCK-interacting kinase (TNIK). GPS1 activated the c-Jun N-terminal kinase (JNK)/Jun pathway, resulting in a positive feedback loop with TNIK that mediated Wnt-induced AXIN2 expression. WBP2 promoted TNBC growth by integrating JNK with Wnt signaling, and its expression profoundly influenced the sensitivity of TNBC to JNK/TNIK inhibitors. In conclusion, WBP2 links JNK to Wnt signaling in TNBC. GPS1 and TNIK are constituents of a WBP2-initiated cascade that primes responses to Wnt ligands and are also important for TNBC biology. We propose that WBP2 is a potential drug target for JNK/TNIK-based precision medicine for managing TNBC. PMID- 30442711 TI - Evidence-based practice education for healthcare professions: an expert view. AB - Internationally, evidence-based practice (EBP) is recognised as a foundational element of healthcare professional education. Achieving competency in this area is a complex undertaking that is reflected in disparities between 'best EBP' and actual clinical care. The effective development and implementation of professional education to facilitate EBP remains a major and immediate challenge. To ascertain nuanced perspectives on the provision of EBP education internationally, interviews were conducted with five EBP education experts from the UK, Canada, Australia and New Zealand. Definitive advice was provided in relation to (1) EBP curriculum considerations, (2) teaching EBP and (3) stakeholder engagement in EBP education. While a considerable amount of EBP activity throughout health profession education is apparent, effectively embedding EBP throughout curricula requires further development, with a 'real world' pragmatic approach that engenders dialogue and engagement with all stakeholders required. PMID- 30442713 TI - Proteolysis of methylated Sox2 protein is regulated by L3MBTL3 and CRL4DCAF5ubiquitin ligase. AB - SOX2 is a dose-dependent master stem cell protein that controls the self-renewal and pluripotency or multipotency of embryonic stem (ES) cells and many adult stem cells. We have previously found that SOX2 protein is monomethylated at lysine residues 42 (K42) and 117 (K117) by SET7 methyltransferase to promote SOX2 proteolysis, whereas LSD1 and PHF20L1 act on both methylated K42 and K117 to prevent SOX2 proteolysis. However, the mechanism by which the methylated SOX2 protein is degraded remains unclear. Here, we report that L3MBTL3, a protein with the MBT methylation binding domain, is required for SOX2 proteolysis. Our studies showed that L3MBTL3 preferentially binds to the methylated K42 in SOX2, although mutation of K117 also partially reduces the interaction between SOX2 and L3MBTL3. The direct binding of L3MBTL3 to the methylated SOX2 protein leads to the recruitment of the CRL4-DCAF5 ubiquitin E3 ligase to target SOX2 protein for ubiquitin-dependent proteolysis. While loss of either LSD1 or PHF20L1 destabilizes SOX2 protein and impairs the self-renewal and pluripotency of mouse ES cells, knockdown of L3MBTL3 or DCAF5 is sufficient to restore the protein levels of SOX2 and rescue the defects of mouse ES cells caused by LSD1 or PHF20L1 deficiency. We also found that retinoic acid-induced differentiation of mouse ES cells is accompanied with the enhanced degradation of the methylated SOX2 protein at both K42 and K117. Our studies provide novel insights into the mechanism by which the methylation-dependent degradation of SOX2 protein is controlled by the L3MBTL3-CRL4-DCAF5 ubiquitin ligase complex. PMID- 30442714 TI - Tralokinumab did not demonstrate oral corticosteroid-sparing effects in severe asthma. AB - Long-term oral corticosteroid (OCS) use in patients with severe asthma is associated with significant adverse effects.This 40-week, randomised, double blind trial evaluated the OCS-sparing potential of tralokinumab in patients with severe, uncontrolled asthma requiring maintenance OCS treatment plus inhaled corticosteroids/long-acting beta2-agonists. Overall, 140 patients were randomised to tralokinumab 300 mg or placebo (n=70 each) administered subcutaneously every 2 weeks. The primary endpoint was percent change from baseline in average OCS dose at Week 40, while maintaining asthma control. Secondary endpoints included proportion of patients with a prescribed maintenance OCS dose of <=5 mg, those with a >=50% reduction in prescribed maintenance OCS dose and asthma exacerbation rate. Safety was also assessed.At Week 40, the percent reduction from baseline in the final daily average OCS dose was not significantly different between tralokinumab and placebo (37.62% versus 29.85%; p=0.271). There were no significant between-treatment differences for any secondary endpoint. Overall, reporting of adverse events (AEs) and serious AEs were similar for the tralokinumab and placebo groups. Although a greater proportion of tralokinumab treated patients reported upper respiratory tract infections (35.7% versus 14.3%), there were no reported cases of pneumonia.Overall, tralokinumab did not demonstrate an OCS-sparing effect in patients with severe asthma. PMID- 30442715 TI - The Potential Impact of Azithromycin in Idiopathic Pulmonary Fibrosis. PMID- 30442716 TI - No relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone. AB - Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug-drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (Group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (Group 2, n=17) continued to receive pirfenidone alone (801 mg thrice-daily) for 7 days, then co administered with nintedanib (150 mg twice-daily) for a further 7 days, before single doses of both treatments on day 16.In Group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax), respectively. In Group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when co-administered in IPF patients. PMID- 30442717 TI - CT abnormalities antedating mesothelioma diagnosis - a perspective on the natural history. PMID- 30442718 TI - MEK5 promotes lung adenocarcinoma. PMID- 30442719 TI - Cardiovascular incidents in male professional football players with negative preparticipation cardiac screening results: an 8-year follow-up. AB - BACKGROUND: Preparticipation cardiac screening of athletes aims to detect cardiovascular disease at an early stage to prevent sudden cardiac arrests and deaths. Few studies have described the cardiovascular outcomes in athletes classified as negative on screening. OBJECTIVE: To identify cardiovascular incidents in a cohort of male professional football players who were cleared to play after a negative screening result. METHODS: This is a retrospective 8-year follow-up study of 595 professional male football players in Norway who underwent preparticipation cardiac screening by experienced cardiologists, including electrocardiography (ECG) and echocardiography, in 2008. We performed a media search to identify sudden cardiovascular incidents between January 2008 and February 2016. Incidents were cross-checked with medical records. RESULTS: Six of the 595 players (1%), all classified as negative on cardiac screening, experienced severe cardiovascular incidents during follow-up. Retrospective review revealed abnormal ECG findings in one case, not recognised at the time of screening. Three players suffered a sudden cardiac arrest (all resuscitated successfully), one a myocardial infarction, one a transient ischaemic attack and one atrial flutter. Three of the players ignored chest pain, paresis, dyspnoea or near-syncope, two completed a match with symptoms before seeking medical assistance, one player's symptoms were misinterpreted and received inappropriate treatment initially, and two players were discharged from hospital without proper follow-up, despite having serious cardiovascular symptoms. CONCLUSIONS: A comprehensive preparticipation cardiac screening did not identify a subset of 6 of 595 players who experienced subsequent cardiovascular incidents as being at risk. It is important to remind athletes that a normal cardiac screening exam does not protect against all cardiac diseases. Timely reporting of symptoms is essential. PMID- 30442720 TI - Elite football teams that do not have a winter break lose on average 303 player days more per season to injuries than those teams that do: a comparison among 35 professional European teams. AB - OBJECTIVE: To compare injury rates among professional men's football teams that have a winter break in their league season schedule with corresponding rates in teams that do not. METHODS: 56 football teams from 15 European countries were prospectively followed for seven seasons (2010/2011-2016/2017)-a total of 155 team-seasons. Individual training, match exposure and time-loss injuries were registered. Four different injury rates were analysed over four periods within the season, and linear regression was performed on team-level data to analyse the effect of winter break on each of the injury rates. Crude analyses and analyses adjusted for climatic region were performed. RESULTS: 9660 injuries were reported during 1 447 011 exposure hours. English teams had no winter break scheduled in the season calendar: the other European teams had a mean winter break scheduled for 10.0 days. Teams without a winter break lost on average 303 days more per season due to injuries than teams with a winter break during the whole season (p<0.001). The results were similar across the three periods August-December (p=0.013), January-March (p<0.001) and April-May (p=0.050). Teams without a winter break also had a higher incidence of severe injuries than teams with a winter break during the whole season (2.1 severe injuries more per season for teams without a winter break, p=0.002), as well as during the period January March (p=0.003). A winter break was not associated with higher team training attendance or team match availability. Climatic region was also associated with injury rates. CONCLUSIONS: The absence of a scheduled winter break was associated with a higher injury burden, both before and during the two periods following the time that many European teams take a winter break. Teams without a winter break (English clubs) had a higher incidence of severe injuries following the time of the year that other teams (other European clubs) had their scheduled break. PMID- 30442721 TI - Structure of the sensory domain of McpX from Sinorhizobium meliloti the first known bacterial chemotactic sensor for quaternary ammonium compounds. AB - The alpha-proteobacterium Sinorhizobium meliloti can live freely in the soil or engage in a symbiosis with its legume host. S. meliloti facilitates nitrogen fixation in root nodules, thus providing pivotal, utilizable nitrogen to the host. The organism has eight chemoreceptors, namely McpT to McpZ and IcpA that facilitate chemotaxis. McpX is the first known bacterial sensor of quaternary amine compounds (QACs) such as choline and betaines. Because QACs are exuded at chemotaxis-relevant concentrations by germinating alfalfa seeds, McpX has been proposed to contribute to host-specific chemotaxis. We have determined the crystal structure of the McpX periplasmic region (McpXPR) in complex with the proline betaine at 2.7 A resolution. In the crystal the protein forms a symmetric dimer with one proline betaine molecule bound to each monomer of McpXPR within membrane distal CACHE module. The ligand is bound through cation- interactions with four aromatic amino acid residues. Mutational analysis in conjunction with binding studies revealed that a conserved aspartate residue is pivotal for ligand binding. We discovered that, in a striking example of convergent evolution, the ligand binding site of McpXPR resembles that of a group of structurally unrelated betaine binding proteins including ProX and OpuAC. Through this comparison and docking studies we rationalized the specificity of McpXPR for this specific group of ligands. Collectively, our structural, biochemical, and molecular docking data have revealed the molecular determinants in McpX that are crucial for its rare ligand specificity for QACs. PMID- 30442722 TI - Disability related to chronic graft-versus-host disease after alternative donor hematopoietic cell transplantation. AB - We determined the incidence of disability related to chronic graft-versus-host disease (bronchiolitis obliterans, grade >= 2 keratoconjunctivitis sicca, sclerotic features or esophageal stricture) for 3 categories of alternative donor: cord blood, haplorelated marrow or peripheral blood with posttransplant cyclophosphamide, and unrelated single HLA-allele mismatched peripheral blood. Among 396 consecutive hematopoietic cell transplantation recipients, 129 developed chronic graft-versus-host disease with incidences in each group of 18% for cord blood, 24% for haplorelated, and 55% for unrelated single HLA-allele mismatched peripheral blood; after a median follow-up of 48, 60, and 46 months, respectively, from diagnosis. Disability rates were significantly lower for cord blood (hazard ratio 0.13; 95% cumulative incidence (CI): 0.1-0.4) and for the haplorelated group (HR 0.31; 95%CI: 0.1-0.7) compared to unrelated single HLA allele mismatched peripheral blood. Cord blood recipients were also >2-fold more likely to return to work/school by 3 years from chronic graft-versus-host disease onset (HR 2.54; 95%CI: 1.1-5.7, p=.02), and the haplorelated group trended similarly (HR 2.38; 95%CI: 1.0-5.9, p=.06). Cord blood recipients were more likely to discontinue immunosuppression than unrelated single HLA-allele mismatched peripheral blood (HR 3.96; 95%CI: 1.9-8.4, p=.0003), similar to the haplorelated group (HR 4.93; 95%CI: 2.2-11.1, p=.0001). Progression-free survival and non-relapse mortality did not differ between donor groups. Our observations that compared to unrelated single HLA-allele mismatched peripheral blood, recipients of cord blood and haplorelated grafts less often developed disability related to chronic graft-versus-host disease, and more likely resumed work/school, should help better counsel pre-hematopoietic cell transplant candidates. PMID- 30442723 TI - EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. AB - EXPAND (phase 1b, dose-finding study) evaluated the starting dose of ruxolitinib in patients with myelofibrosis with baseline platelet counts of 50-99x109/L. The study consisted of dose-escalation and safety-expansion phases. Based on the baseline platelet counts, patients were assigned to stratum 1 (75-99x109/L) or stratum 2 (50-74x109/L), with the primary objective of determining the maximum safe starting dose; key secondary objectives included safety and efficacy. At week 48 data cutoff (stratum 1, N=44; stratum 2, N=25), 24.6% (17 of 69) of patients were still receiving treatment. The maximum safe starting dose was established as ruxolitinib 10 mg twice daily in both strata. Thrombocytopenia (grade 4 [stratum 1, N=1; stratum 2, N=2]) was the only reported dose-limiting toxicity (study drug related) at 10 mg twice daily. In the maximum safe starting dose cohort (stratum 1, N=20; stratum 2, N=18), adverse events (regardless of study drug relationship) led to treatment discontinuation in 15.0% and 33.3% of patients in stratum 1 and stratum 2, respectively, and dose adjustment/interruption in 45.0% and 66.7% of patients in stratum 1 and stratum 2, respectively. Three cases of on-treatment deaths were reported at the maximum safe starting dose. Spleen response was achieved at week 48 in 33.3% and 30.0% of patients in stratum 1 and stratum 2, respectively. Improvements in the Total Symptom Score were also observed. In this study, ruxolitinib demonstrated acceptable tolerability in both the strata at the maximum safe starting dose of 10 mg twice daily (NCT01317875). . PMID- 30442724 TI - In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis. AB - Myelosuppression is a major and frequently dose limiting side-effect of anticancer therapy and responsible for most treatment-related morbidity and mortality. In addition, repeated cycles of DNA damage and cell death of hematopoietic stem and progenitor cells, followed by compensatory proliferation and selection pressure, lead to genomic instability and pave the way for therapy related myelodysplastic syndromes and secondary acute myeloid leukemia. Protection of hematopoietic stem and progenitor cells from chemo- and radiotherapy in patients with solid tumors would reduce both immediate complications and long-term sequelae. EGF and PGE2 were reported to prevent chemo or radiotherapy-induced myelosuppression in mice. We tested both molecules for potentially protective effects on human CD34+ cells in vitro and established a xenograft mouse model to analyze stress resistance and regeneration of human hematopoiesis in vivo. EGF was neither able to protect human stem and progenitor cells in vitro nor to promote hematopoietic regeneration following sublethal irradiation in vivo. PGE2 significantly reduced in vitro apoptotic susceptibility of human CD34+ cells to taxol and etoposide. This could, however, be ascribed to reduced proliferation rather than to a change in apoptosis signaling and BCL-2 protein regulation. Accordingly, dmPGE2 did not accelerate regeneration of the human hematopoietic system in vivo. Also repeated treatment of sublethally irradiated xenograft mice with known antiapoptotic substances such as human FLT3L and TPO, which suppress transcription of the proapoptotic BCL-2 proteins BIM and BMF, did only marginally promote human hematopoietic regeneration in vivo. PMID- 30442725 TI - New insight into antiphospholipid syndrome: antibodies to beta2glycoprotein I domain 5 fail to induce thrombi in rats. AB - Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of beta2glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analysed the in vivo pro-coagulant effect of two groups of 5 serum IgG each reacting selectively with domain 1 or domain 5 in LPS treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy and vascular deposition of beta2glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-beta2glycoproteinI antibodies served as controls. All the anti domain 1 positive IgG exhibited potent pro-coagulant activity while the anti domain 5 positive and the negative control IgG failed to promote blood clot and vessels occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound beta2glycoprotein I while able to interact with fluid-phase beta2glycoproteinI. These findings may explain the failure of anti domain 5 antibodies to exhibit in vivo thrombogenic effect and the interaction of these antibodies with circulating beta2glycoproteinI suggest their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining really at risk patients for more appropriate treatments to avoid recurrences and disability. PMID- 30442726 TI - A prospective description of HIV-associated multicentric Castleman disease in Malawi. PMID- 30442727 TI - TP53 aberrations in chronic lymphocytic leukemia: an overview of the clinical implications of improved diagnostics. AB - Chronic lymphocytic leukemia is associated with a highly heterogeneous disease course in terms of clinical outcomes and responses to chemoimmunotherapy. This heterogeneity is partly due to genetic aberrations identified in chronic lymphocytic leukemia cells such as mutations of TP53 and/or deletions in chromosome 17p [del(17p)], resulting in loss of one TP53 allele. These aberrations are associated with markedly decreased survival and predict impaired response to chemoimmunotherapy thus being among the strongest predictive markers guiding treatment decisions in chronic lymphocytic leukemia. Clinical trials demonstrate the importance of accurately testing for TP53 aberrations [both del(17p) and TP53 mutations] before each line of treatment to allow for appropriate treatment decisions that can optimize patient outcomes. The current report reviews the diagnostic methods to better detect TP53 disruption, the role of TP53 aberrations in treatment decisions and current therapies available for patients with chronic lymphocytic leukemia carrying these abnormalities. The standardization in sequencing technologies for accurate identification of TP53 mutations and the importance of continued evaluation of TP53 aberrations throughout initial and subsequent lines of therapy remain unmet clinical needs as new therapeutic alternatives become available. PMID- 30442729 TI - I'm Conflicted. Are You? PMID- 30442728 TI - Ibrutinib for the treatment of relapsed/refractory mantle cell lymphoma: extended 3.5-year follow-up from a pooled analysis. PMID- 30442730 TI - The Adrenal Gland as a Sanctuary Site of Metastases After Pembrolizumab Treatment: A Case Series. AB - Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention. PMID- 30442732 TI - A US Registry-Based Assessment of Use and Impact of Chemotherapy in Stage I HER2 Positive Breast Cancer. AB - Background: Despite the paucity of evidence supporting chemotherapy in the treatment of node-negative, HER2-positive breast cancer measuring <2 cm, use of trastuzumab-based chemotherapy has increased over the past decade. Therefore, we used the National Cancer Database to evaluate the use and impact of chemotherapy on survival in this population. Methods: We identified female patients aged 18 to 70 years with node-negative, HER2-positive breast cancer measuring <2 cm. A propensity-matched cohort model was used to control for risk factors known to influence survival. Primary end points assessed were receipt of chemotherapy and overall survival (OS). Results: In our propensity-matched cohort model (n=8,222), adjuvant chemotherapy (ACT) was associated with a lower 5-year OS rate in T1mi breast cancer (n=626; 89.1% [95% CI, 81.8%-93.5%] vs 99.1% [96.6%-99.8%]), no significant effect in T1a disease (n=2,901; 95.4% [93.2%-96.9%] vs 96.9% [94.1% 98.3%]), and improved 5-year OS in T1b (n=2,340; 97.1% [95.1%-98.4%] vs 92.3% [88.5%-94.9%]) and T1c tumors (n=2,355; 95.9% [93.5%-97.5%] vs 91.5% [88.4% 93.9%]). In the entire cohort of 21,148 patients who met the inclusion criteria, ACT was associated with lower 5-year OS in T1mi (89.6% [83.7%-93.4%] vs 98.1% [96.6%-98.9%]) and T1a tumors (94.9% [92.9%-96.3%] vs 96.5% [94.6%-97.7%]), and improved 5-year OS in T1b (96.8% [95.6%-97.7%] vs 92.3% [88.7%-94.8%]) and T1c tumors (95.8% [94.9%-96.5%] vs 91.6% [88.5%-93.9%]). Increased use of ACT was observed over the study period. From 2010 to 2013, annual treatment rates were 71.5%, 72.4%, 73.3%, and 74.4%, respectively (trend test, P<.0001). Conclusions: Our data support the use of ACT for HER2-positive, node-negative T1b and T1c breast cancer, whereas no benefit was observed for ACT in T1mi and T1a HER2 positive, node-negative breast cancer. Although use of ACT is increasing in node negative, HER2-positive breast cancer <2 cm, our findings caution against its use in the smallest of these tumors (T1mi and T1a) due to lack of survival benefit. PMID- 30442731 TI - NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018. AB - Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE. PMID- 30442733 TI - Impact of a Clinical Decision Support System on Guideline Adherence of Surveillance Recommendations for Colonoscopy After Polypectomy. AB - Background: Surveillance colonoscopy is required in patients with polyps due to an elevated colorectal cancer (CRC) risk; however, studies suggest substantial overuse and underuse of surveillance colonoscopy. The goal of this study was to characterize guideline adherence of surveillance recommendations after implementation of an electronic medical record (EMR)-based Colonoscopy Pathology Reporting and Clinical Decision Support System (CoRS). Methods: We performed a retrospective cohort study of patients who underwent colonoscopy with polypectomy at a safety-net healthcare system before (n=1,822) and after (n=1,320) implementation of CoRS in December 2013. Recommendations were classified as guideline-adherent or nonadherent according to the US Multi-Society Task Force on CRC. We defined surveillance recommendations shorter and longer than guideline recommendations as potential overuse and underuse, respectively. We used multivariable generalized linear mixed models to identify correlates of guideline adherent recommendations. Results: The proportion of guideline-adherent surveillance recommendations was significantly higher post-CoRS than pre-CoRS (84.6% vs 77.4%; P<.001), with fewer recommendations for potential overuse and underuse. In the post-CoRS period, CoRS was used for 89.8% of cases and, compared with cases for which it was not used, was associated with a higher proportion of guideline-adherent recommendations (87.0% vs 63.4%; RR, 1.34; 95% CI, 1.23-1.42). In multivariable analysis, surveillance recommendations were also more likely to be guideline-adherent in patients with adenomas but less likely among those with fair bowel preparation and those with family history of CRC. Of 203 nonadherent recommendations, 70.4% were considered potential overuse, 20.2% potential underuse, and 9.4% were not provided surveillance recommendations. Conclusions: An EMR-based CoRS was widely used and significantly improved guideline adherence of surveillance recommendations. PMID- 30442735 TI - Undertreatment of High-Risk Localized Prostate Cancer in the California Latino Population. AB - Background: The NCCN Clinical Practice Guidelines in Oncology recommend definitive therapy for all men with high-risk localized prostate cancer (PCa) who have a life expectancy >5 years or who are symptomatic. However, the application of these guidelines may vary among ethnic groups. We compared receipt of guideline-concordant treatment between Latino and non-Latino white men in California. Methods: California Cancer Registry data were used to identify 2,421 Latino and 8,636 non-Latino white men diagnosed with high-risk localized PCa from 2010 through 2014. The association of clinical and sociodemographic factors with definitive treatment was examined using logistic regression, overall and by ethnicity. Results: Latinos were less likely than non-Latino whites to receive definitive treatment before (odds ratio [OR], 0.79; 95% CI, 0.71-0.88) and after adjusting for age and tumor characteristics (OR, 0.84; 95% CI, 0.75-0.95). Additional adjustment for sociodemographic factors eliminated the disparity. However, the association with treatment differed by ethnicity for several factors. Latino men with no health insurance were considerably less likely to receive definitive treatment relative to insured Latino men (OR, 0.34; 95% CI, 0.23-0.49), an association that was more pronounced than among non-Latino whites (OR, 0.63; 95% CI, 0.47-0.83). Intermediate-versus high-grade disease was associated with lower odds of definitive treatment in Latinos (OR, 0.75; 95% CI, 0.59-0.97) but not non-Latino whites. Younger age and care at NCI-designated Cancer Centers were significantly associated with receipt of definitive treatment in non-Latino whites but not in Latinos. Conclusions: California Latino men diagnosed with localized high-risk PCa are at increased risk for undertreatment. The observed treatment disparity is largely explained by sociodemographic factors, suggesting it may be ameliorated through targeted outreach, such as that aimed at younger and underinsured Latino men. PMID- 30442734 TI - Evaluation of New Tests and Interventions for Prostate Cancer Management: A Systematic Review. AB - Background: Inaccurate risk classification and the burden of unnecessary biopsies are a challenge due to the limited ability of current risk assessment tools and modalities to diagnose prostate cancer (PCa) and distinguish indolent from aggressive disease. This systematic review assesses newly developed tests and interventions with high evidence of clinical utility that might be adopted in clinical practice during PCa management before initial and repeat biopsy, after positive biopsy, and after radical treatment. Methods: The Cochrane, Embase, MEDLINE, and Web of Science databases were searched for studies pertaining to the clinical utility of PCa diagnostic tests. Outcomes of interest were (1) a measure of the percentage of altered decision-making, (2) decrease in number of unnecessary biopsies, (3) decrease or increase in treatment intensity, and (4) risk reclassification after test results. Results: The search yielded 2,940 articles, of which 46 met the inclusion criteria. We found clinical utility evidence on the Prostate Health Index (PHI), 4Kscore test, MRI, OncotypeDX, Decipher test, Prolaris, ConfirmMDx, Progensa PCA3, NADiA ProsVue, and ProMark. No evidence was identified for Prostarix, ProstaVysion, Prostate Core Mitomic Test, and Mi-Prostate Score. The interventions demonstrated their clinical utility in terms of change in treatment recommendations, decrease/increase in interventional treatment, decrease in biopsy, and risk reclassification. At diagnosis after a positive biopsy, ProMark, OncotypeDX, Prolaris, and MRI guided the use of active surveillance. Use of NADiA ProsVue, Decipher, and Prolaris aided in the decision to add adjuvant therapy post-prostatectomy. PHI, 4Kscore, and MRI used prior initial and repeat biopsies, and ConfirmMDx and Progensa PCA3 used prior repeat biopsies to improve prediction of biopsy outcome, allowing a decrease in unnecessary biopsies. Conclusions: This systematic review suggests that implementation of these tests in clinical practice could effectuate personalized treatment of PCa. Further clinical and economic evaluation studies of long-term PCa outcomes are warranted to provide further guidance. PMID- 30442736 TI - Breast Cancer Screening and Diagnosis, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology. AB - The NCCN Guidelines for Breast Cancer Screening and Diagnosis have been developed to facilitate clinical decision making. This manuscript discusses the diagnostic evaluation of individuals with suspected breast cancer due to either abnormal imaging and/or physical findings. For breast cancer screening recommendations, please see the full guidelines on NCCN.org. PMID- 30442737 TI - Diagnosis and Management of High-Risk Breast Lesions. AB - Atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are nonmalignant breast lesions that confer a 4- to 10-fold increased risk for breast cancer in women. Often, AH and LCIS are diagnosed through breast biopsy due to a mammographic or palpable finding. Although AH and LCIS are benign breast disease, further management is necessary due to their high-risk nature and premalignant potential. Over the decades, management of AH and LCIS has changed as more is learned about these disease processes. This review explores the studies evaluating the risk for breast cancer in women with AH or LCIS and the clinical management of these lesions, which can include a combination of surgical excision, surveillance, and risk-reduction therapy. PMID- 30442739 TI - Electronic Clinical Decision Tools for Improving Adherence to Colon Cancer Surveillance Guidelines: Can the Chips Finally Fall Into Place? PMID- 30442738 TI - Screening Mammography for Average-Risk Women: The Controversy and NCCN's Position. AB - Breast cancer remains the most common nonskin cancer among women and a leading cause of morbidity and mortality. Early detection through screening and advances in treatment have contributed to a 39% mortality reduction in the United States since 1990. The NCCN Guidelines for Breast Cancer Screening and Diagnosis recommend annual mammographic screening for average-risk women beginning at age 40 years. Mammographic screening and subsequent treatment reduces breast cancer mortality based on a wide range of studies. This article highlights NCCN's position on screening mammography and the screening controversy. PMID- 30442741 TI - Ischaemic heart disease and pregnancy. AB - Although ischaemic heart disease is currently rarely encountered in pregnancy, occurring between 2.8 and 6.2 per 100 000 deliveries, it is becoming more common as women delay becoming pregnant until later life, when medical comorbidities are more common, and because of the higher prevalence of obesity in the pregnant population. In addition, chronic inflammatory diseases, which are more common in women, may contribute to greater rates of acute myocardial infarction (AMI). Pregnancy itself seems to be a risk factor for AMI, although the exact mechanisms are not clear. AMI in pregnancy should be investigated in the same manner as in the non-pregnant population, not allowing for delays, with investigations being conducted as they would outside of pregnancy. Maternal morbidity following AMI is high as a result of increased rates of heart failure, arrhythmia and cardiogenic shock. Delivery in women with history of AMI should be typically guided by obstetric indications not cardiac ones. PMID- 30442742 TI - Seventy-one-year-old woman followed with CMR during the course of systemic vasculitis. AB - CLINICAL INTRODUCTION: A 71-year-old woman was diagnosed with systemic vasculitis in 2009 and received specific therapy (corticosteroids, cytostatic agents or rituximab in differing order). A transthoracic echocardiography (TTE) in 2013 for follow-up purposes of complications showed hyperechogenic endocardium of the whole left ventricular (LV) apex and cardiac MRI (CMR) was followed to further examine this finding. Using CMR, an apical LV thrombus was detected along with abnormal signal intensities within the endocardium (figure 1A). As a consequence, the existing medication was extended by phenprocoumon to treat the LV thrombus. For tracking the pathologic image features as well as for follow-up of the LV thrombus, serial CMRs were performed at our hospital from 2013 to 2018 (figure 1A). Because of the increasing hyperintense (white arrowheads) and hypointense (red arrowheads) signal spots in cine images of the apex (figure 1A), differently weighted sequences in short-axis view were acquired in the CMR of 2018 (figure 1B). QUESTION: Which of the following is the most likely diagnosis in CMR?Microvascular ischaemiaCircular oedemaEndomyocardial fibrosisHaemorrhageApical lipoma. PMID- 30442743 TI - Novel high-sensitivity cardiac troponin I assay in patients with suspected acute coronary syndrome. AB - BACKGROUND: High-sensitivity cardiac troponin assays enable the early risk stratification of patients with suspected acute coronary syndrome to identify those at low risk of myocardial infarction or cardiac death. We evaluated the performance of a novel high-sensitivity cardiac troponin I assay in early rule out pathways. METHODS: In 1920 patients with suspected acute coronary syndrome, cardiac troponin was measured using the Siemens Atellica high-sensitivity cardiac troponin I assay (99th centile: 34 ng/L women, 53 ng/L men). We evaluated three pathways which use either low risk-stratification thresholds of cardiac troponin (High-SensitivityTroponin in the Evaluation of patients with Acute Coronary Syndrome (High-STEACS) and the European Society of Cardiology (ESC) 1 hour pathway) or the 99th centile diagnostic threshold (ESC 3 hour pathway) to rule out myocardial infarction. RESULTS: The primary outcome of myocardial infarction or cardiac death at 30 days occurred in 14.4% (277/1920). The High-STEACS pathway ruled out 63% of patients (1218/1920), with five missed events for a negative predictive value (NPV) of 99.5% (95% CI (CI) 99.1% to 99.8%). Similar performance was observed for the ESC 1 hour pathway with an NPV of 99.0% (97.6% to 99.8%). In contrast, the ESC 3 hour pathway ruled out 65% of patients (1248/1920), but missed 25 events for an NPV of 98.0% (97.1% to 98.7%). CONCLUSIONS: A novel high sensitivity cardiac troponin I assay can safely identify patients at low risk of myocardial infarction or cardiac death. Diagnostic pathways that use low cardiac troponin concentrations for risk stratification miss fewer events than those that rely on the 99th centile to rule out myocardial infarction. TRIAL REGISTRATION: NCT1852123. PMID- 30442744 TI - Tachycardia after acute deceleration injury. AB - A 29-year-old man crashed at high speed into another vehicle at traffic lights. He was able to get out of his van but then collapsed after running a few metres. On arrival in the emergency department he was conscious, with a pulse of 140 beats/min and blood pressure of 110/32 mm Hg. He had collapsing arterial pulses and an early diastolic murmur. He had a chest radiograph (figure 1A) and a skeletal survey which demonstrated multiple fractures, involving his left hand, right femur, right calcaneus, and left first and second ribs. A CT scan of the thorax was performed with a radiological contrast agent but without gated images because of the tachycardia (Figure 1B). The blood pressure and pulse were attributed to blood loss into the right thigh. Urgent cardiology review and bedside echocardiography were requested before he had emergency orthopaedic surgery (figure 1C, D) (online supplementary video 1) DC1SP110.1136/heartjnl-2018 314082.supp1Supplementary file 1 heartjnl;heartjnl-2018-314082v1/F1F1F1Figure 1(A D) Chest radiograph, CT thorax with contrast, parasternal long-axis transthoracic view (grey scale) and with colour flow. The arrow in section C highlights the area of significance (mobile linear structure). QUESTION: What is the most likely diagnosis?Traumatic dissection of the aortic root.Subaortic membrane or diaphragm.Traumatic transection of the aorta.Traumatic rupture of the aortic valve.Myocardial rupture. PMID- 30442745 TI - Do you know TAFRO? PMID- 30442746 TI - Knick-knack PADIMAC. PMID- 30442747 TI - Charcot-Leyden crystals: solving an enigma. PMID- 30442748 TI - Int"Dll"igent control of T-cell pathology in GVHD. PMID- 30442749 TI - Acquired alpha-thalassemia associated with myelodysplastic syndromes. PMID- 30442750 TI - Rituximab prevents long-term relapses in TTP. PMID- 30442751 TI - Reporter Genes for PET Imaging of CAR T Cells Offers Insight into Adoptive Cell Transfer. PMID- 30442752 TI - First-in-human trial of 64Cu-SARTATE PET imaging of patients with neuroendocrine tumours demonstrates high tumor uptake and retention, potentially allowing prospective dosimetry for peptide receptor radionuclide therapy. AB - Imaging of somatostatin receptor (SSTR) expression is an established technique for staging of neuroendocrine neoplasia (NEN) and determining the suitability of patients for peptide receptor radionuclide therapy (PRRT). PET/ CT utilizing 68Ga labeled somatostatin analogues (SSAs) is superior to earlier agents, but the rapid physical decay of the radionuclide poses logistic and regulatory challenges. 64Cu has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide 67Cu. Based on promising pre-clinical studies, we have performed a first-time-in-human trial of 64Cu MeCOSar-octreotate (64Cu-SARTATE) to assess its safety and ability to localise disease at early and late imaging time-points. Methods: In a prospective trial, 10 patients with known NEN and positive 68Ga-DOTA-octreotate (GaTate) PET/CT underwent serial PET/CT imaging at 30 min, 1, 4 and 24 hours following injection of 64Cu-SARTATE. Adverse reactions were recorded and laboratory testing was performed during infusion and at 1 and 7 days post-imaging. Images were analysed for lesion and normal organ uptake and clearance to assess lesion contrast and perform dosimetry estimates. Results: 64Cu-SARTATE was well tolerated during infusion and throughout the study, with three patients experiencing mild infusion related events. High lesion uptake and retention were observed at all imaging time-points. There was progressive hepatic clearance over time, providing highest lesion to liver contrast at 24 hours. Image quality remained high at this time. Comparison of 64Cu-SARTATE PET/CT obtained at 4 hours to GaTate PET/CT obtained at 1 hour indicated comparable or superior lesion detection in all patients, especially in the liver. As expected, highest early physiologic organ uptake was observed in the kidneys, liver and spleen. Conclusion: 64Cu-SARTATE is safe and has excellent imaging characteristics. High late-retention in tumour and clearance from the liver suggests suitability for diagnostic studies as well as for prospective dosimetry for 67Cu-SARTATE PRRT, while the half-life of 64Cu would also facilitate GMP production and distribution to sites without access to 68Ga. PMID- 30442753 TI - Zirconium-89 chloride can be used for immuno-PET radiochemistry without loss of antigen reactivity in vivo. AB - Zirconium-89 (89Zr) immuno-PET continues to be assessed in numerous clinical trials. This report evaluates the use of zirconium-89 chloride (89Zr-ZrCl4) in the radiolabelling of monoclonal antibodies (mAbs) conjugated with desferrioxamine B (DFO), describes its effects on radiopharmaceutical reactivity toward antigen and offers guidance on how to ensure long-term stability and purity. Methods: 89Zr-Zr-DFO-trastuzumab and 89Zr-Zr-DFO-cetuximab were prepared using 89Zr-ZrCl4 The stability of each was evaluated for 7 days in 20 mM histidine/240 mM sucrose buffer, 0.25 M sodium acetate (NaOAc) buffer containing 5 mg.mL-1 n-acetyl-L-cysteine (NAC) or 0.25 M NaOAc containing 5 mg.mL-1 L methionine (L-MET). To assess antigen reactivity, 89Zr-Zr-DFO-trastuzumab was evaluated using the Lindmo method and tested in PET/CT imaging of mouse models of human epidermal growth factor receptor 2 (HER2+/-) lung cancer. Results: Using 89Zr-ZrCl4, 89Zr-Zr-DFO-trastuzumab and 89Zr-Zr-DFO-cetuximab were prepared with increased specific activity and retained purities of 95% after 3 days when formulated in sodium acetate buffer containing L-MET. Based upon Lindmo analysis and small animal PET/CT imaging, 89Zr-Zr-DFO-trastuzumab remained reactive toward antigen after being prepared with 89Zr-ZrCl4 Conclusion: 89Zr-ZrCl4 facilitated the radiosynthesis of 89Zr-immuno-PET agents with increased specific activity. L MET enhanced long-term solution stability better than all other formulations examined, and 89Zr-Zr-DFO-trastuzumab remained reactive toward antigen. While further evaluation is necessary, these initial results suggest that 89Zr-ZrCl4 may be useful in immuno-PET radiochemistry as radiolabeled mAbs are increasingly integrated into precision medicine strategies. PMID- 30442754 TI - Awake 18F-FDG PET imaging of memantine-induced brain activation and test-retest in freely running mice. AB - Positron emission tomography (PET) scans of the mouse brain are usually performed with anesthesia to immobilize the animal. However, it is desirable to avoid the confounding factor of anesthesia in mouse-brain response. Methods: We develop and validate brain PET imaging of awake, freely moving mice. Head-motion tracking is performed using radioactive point source markers and we use the tracking information for PET-image motion correction. Regional 18F-Fluorodeoxyglucose (18F FDG) brain uptake in a test, retest, and memantine challenge study was performed in awake (n = 8) and anesthetized (n = 8) C57BL/6 mice. An awake uptake period was considered for the anesthesia scans. Results: Awake (motion corrected) PET images showed an 18F-FDG uptake pattern comparable to the pattern of anesthetized mice. The test-retest variability (represented by the intraclass correlation coefficient (ICC)) of the regional standardized uptake value (SUV) quantification in the awake images (0.424-0.555) was marginally lower compared to anesthesia images (ICC, 0.491-0.629) over the different regions. The increased memantine induced 18F-FDG uptake was more pronounced in awake (+63.6%) than in anesthesia (+24.2%) animals. Additional behavioral information, acquired during awake scans, showed increased motor activity on a memantine challenge (total distance travelled, 18.2 +/- 5.28 m) compared to test-retest (6.49 +/- 2.21 m). Conclusion: The present method enables brain PET imaging on awake mice, thereby avoiding the confounding effects of anesthesia on the PET reading. It allows the simultaneous measurement of behavioral information during PET acquisitions. The method does not require any additional hardware, and it can be deployed in typical high-throughput scan protocols. PMID- 30442755 TI - Data-driven gross patient motion detection and compensation: Implications for coronary 18F-NaF PET imaging. AB - Patient motion degrades image-quality, affecting the quantitative assessment of PET-images. This affects studies of coronary lesions where micro-calcification processes are targeted. Coronary PET imaging protocols require up to 30-min scans, introducing the risk of gross patient motion (GPM) during the acquisition. Here, we investigate the feasibility of an automated data-driven method for detection of GPM during the PET-acquisition. Methods: Twenty-eight patients with stable coronary disease underwent a 30-min PET acquisition 1 hour after injection of 248+/-10 MBq 18F- Sodium Fluoride (NaF), followed by a coronary computed tomography angiography (CTA) scan. An automated data-driven GPM detection technique tracking the center-of-mass (CoM) of the count rates for every 200 milliseconds in the PET list-mode data was devised and evaluated. Two patient motion patterns were considered: sudden repositioning (motion >0.5 mm within 3 seconds) and general repositioning (motion >0.3 mm over 15 seconds or more). After reconstruction of diastolic images, individual GPM frames with focal coronary uptake were co-registered in 3D, creating a GPM-compensated (GPMC) image series. Lesion motion was reported for all lesions with focal uptake. Relative differences in maximum standard uptake value (SUVmax) and target to background ratio (TBR) between GPMC and non-GPMC (standard electrocardiogram gated data) diastolic PET images were compared in three separate groups defined by the maximum motion observed in the lesion (<5, 5-10 and >10 mm). Results: A total of 35 18F-NaF-avid lesions were identified in 28 patients. An average of 3.5+/-1.5 GPM frames were considered for each patient, resulting in an average frame duration of 7+/-4 (range, 3 - 21) min. Mean per-patient motion was: 7+/-3 mm (maximum 13.7 mm). GPMC increased SUVmax and TBR in all lesions with motion >5 mm. Lesions with 5-10 mm motion (N = 15) had SUVmax and TBR increased by 4.6+/ 5.6% (P = 0.02) and 5.8+/-6.4% (p<0.002) respectively; lesions with motion >=10 mm (N = 15) had SUVmax and TBR increased by 5.0+/-5.3% (P = 0.009) and 11.5+/ 10.1% (P = 0.001) respectively. GPM correction led to diagnostic reclassification of 3 (11%) patients. Conclusion: GPM during coronary 18F-NaF PET-imaging is common and may affect the quantitative accuracy. An automated retrospective compensation of this motion is feasible and should be considered for coronary PET imaging. PMID- 30442756 TI - Early experience of rechallenge 177Lu-PSMA radioligand therapy after an initial good response in patients with mCRPC. AB - Aim: To retrospectively evaluate the feasibility of rechallenge 177Lu-Prostate specific membrane antigen (177Lu-PSMA) radioligandtherapy (RLT). Material & Methods: Rechallenge RLT was defined as subsequent treatment with 177Lu-PSMA after initial exposure with excellent response followed by progression. Biochemical, radiographic, clinical antitumor response and adverse events were analysed. Prostate-specific antigen progression-free survival (PSA-PFS) and overall survival (OS) were calculated. Results: Eight patients underwent a median of 2 (range:1-4) cycles of 177Lu-PSMA-I&T rechallenge. Maximum PSA-decrease of 50% was achieved in 3 (37.5%) of patients. Radiographic response was favorable in 3 patients, whilst 4 exhibited progressive disease. Eastern-Cooperative-Oncology Group (ECOG) Performance-Status was stable during therapy in all patients. No grade 4 toxicity was noticed and grade 3 toxicity occurred in 3 (37.5%) patients. The median PSA-PFS and OS were 3.2 (95%CI:2.6-3.7) and 14.0 (95%CI:6.2-21.8) months, respectively. Conclusion: In a small patient cohort with initial excellent response 177Lu-PSMA rechallenge is still active, with lower efficacy and increased toxicity levels. PMID- 30442758 TI - Different radionuclides in DOTA-EB-TATE effect different uptake in somatostatin receptor positive HEK293 cells. PMID- 30442757 TI - A Prospective, Multi-site, International Comparison of F-18 fluoro-methyl choline, multi-parametric magnetic resonance and Ga-68 HBED-CC (PSMA-11) in men with High-Risk Features and Biochemical Failure after Radical Prostatectomy: Clinical Performance and Patient Outcomes. AB - Background: A significant proportion of men with rising PSA following radical prostatectomy (RP) fail prostate fossa salvage radiotherapy (SRT). This study assessed the ability of F18 fluoro-methyl-choline PET/CT(FCH), Ga-68 HBED-CC PSMA 11 PET/CT (PSMA) and pelvic multi-parametric magnetic resonance imaging (pelvic MRI) to identify men who will best benefit from SRT. Methods: Prospective, multisite, imaging study in men with rising PSA post RP, high-risk features (PSA > 0.2ng/mL and either Gleason Score (GS) > 7 or PSA doubling time <10 months, or PSA >1.0ng/mL) and negative /equivocal conventional imaging (CT and bone scan) being considered for SRT. FCH (91/91), Pelvic MRI (88/91) and PSMA (31/91) (Australia only) were performed within two weeks. Imaging was interpreted by experienced local and central reads blinded to other imaging results with consensus for discordance. Imaging results were validated using a composite reference standard. Expected management was documented pre and post- imaging, and all treatments, biopsies and PSA collected for 3 years. Treatment response to SRT was defined as > 50% PSA reduction without androgen deprivation therapy. Results: Median GS, PSA at imaging and PSA doubling time were 8, 0.42(IQR 0.29-0.93) ng/mL, and 5.0 (IQR 3.3-7.6) months, respectively. Overall recurrent PCa was detected in 28% (25/88) with pelvic MRI, 32% (29/91) FCH and 42% (13/31) PSMA. This was within the prostate fossa (PF) in 21.5% (19/88), 13% (12/91) and 19% (6/31), with extra PF sites in 8% (7/88), 19% (17/91), and 32% (10/31) for MRI, FCH and PSMA (< 0.004). 94% (16/17) extra- PF sites on FCH were within the field of view of pelvic MRI. The detection rate for intrapelvic extra-PF disease was 90% (9/10) for PSMA and 31% (5/16) for MRI compared to FCH. Imaging changed expected management in 46% (42/91) FCH, and 23% (21/88) MRI. PSMA provided additive management change over FCH in a further 23% (7/31). Treatment response to SRT was higher in men with negative or PF confined vs. extra PF disease. FCH 73% (32/44) vs. 33% (3/9) (p< 0.02), pelvic MRI 70% (32/46) vs 50% (2/4), P = ns) and PSMA 88% (7/8) vs. 14% (1/7) (p<0.005). Men with negative imging (MRI, FCH +/ PSMA) had high (78%) response rates to SRT. Conclusion: FCH and PSMA had high detection rates for extra PF disease in men with negative/equivocal conventional imaging and BCR post RP. This impacted management and treatment responses to SRT, suggesting an important role for PET in triaging men being considered for curative SRT. PMID- 30442759 TI - Two Pif1-family DNA Helicases Cooperate in Centromere Replication and Segregation in Saccharomyces cerevisiae. AB - Pif1 family helicases are found in virtually all eukaryotes. Saccharomyces cerevisiae (Sc) encodes two Pif1 family helicases, ScPif1 and Rrm3. ScPif1 is multi-functional, required not only for maintenance of mitochondrial DNA but also for multiple distinct nuclear functions. Rrm3 moves with the replication fork and promotes movement of the fork through ~1400 hard-to-replicate sites, including centromeres. Here we show that ScPif1, like Rrm3, bound robustly to yeast centromeres but only if the centromere was active. While Rrm3 binding to centromeres occurred in early to mid S phase, about the same time as centromere replication, ScPif1 binding occurred later in the cell cycle when replication of most centromeres is complete. However, the timing of Rrm3 and ScPif1 centromere binding was altered by the absence of the other helicase, such that Rrm3 centromere binding occurred later in pif1-m2 cells, and ScPif1 centromere binding occurred earlier in rrm3Delta cells. As shown previously, the modest pausing of replication forks at centromeres seen in WT cells was increased in the absence of Rrm3. While lack of ScPif1 did not result in increased fork pausing at centromeres, pausing was even higher in rrm3Delta pif1Delta cells than in rrm3Delta cells. Likewise, centromere function as monitored by the loss rate of a centromere plasmid was increased in rrm3Delta but not pif1Delta cells and was even higher in rrm3Delta pif1Delta cells than in rrm3Delta cells. Thus, ScPif1 promotes centromere replication and segregation but only in the absence of Rrm3. These data also hint at a potential post-S phase function for ScPif1 at centromeres. These studies add to the growing list of ScPif1 functions that promote chromosome stability. PMID- 30442760 TI - The Role of Maternal HP1a in Early Drosophila Embryogenesis via Regulation of Maternal Transcript Production. AB - Heterochromatin protein 1a (HP1a) is a highly conserved and versatile epigenetic factor that can both silence and activate transcription. However, the function of HP1a in development has been under-investigated. Here, we report the role of maternal HP1a in producing maternal transcripts that drive early Drosophila embryogenesis. Maternal HP1a up-regulates genes involved in translation, mRNA splicing, and cell division but down-regulates genes involved in neurogenesis, organogenesis, and germline development, which all occur later in development. Our study reveals the earliest contribution of HP1a during oogenesis in regulating the production of maternal transcripts that drive early Drosophila embryogenesis. PMID- 30442761 TI - Seven days in medicine: 7-13 November 2018. PMID- 30442762 TI - Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. AB - The leucine zipper-like transcriptional regulator 1 (LZTR1) protein, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, is implicated in human disease, yet its mechanism of action remains unknown. We found that Lztr1 haploinsufficiency in mice recapitulates Noonan syndrome phenotypes, whereas LZTR1 loss in Schwann cells drives dedifferentiation and proliferation. By trapping LZTR1 complexes from intact mammalian cells, we identified the guanosine triphosphatase RAS as a substrate for the LZTR1-CUL3 complex. Ubiquitome analysis showed that loss of Lztr1 abrogated Ras ubiquitination at lysine-170. LZTR1-mediated ubiquitination inhibited RAS signaling by attenuating its association with the membrane. Disease associated LZTR1 mutations disrupted either LZTR1-CUL3 complex formation or its interaction with RAS proteins. RAS regulation by LZTR1-mediated ubiquitination provides an explanation for the role of LZTR1 in human disease. PMID- 30442763 TI - A linear cobalt(II) complex with maximal orbital angular momentum from a non Aufbau ground state. AB - Orbital angular momentum is a prerequisite for magnetic anisotropy, although in transition metal complexes it is typically quenched by the ligand field. Here, by reducing the basicity of the carbon donor atoms in a pair of alkyl ligands, we synthesize a cobalt(II) dialkyl complex, Co(C(SiMe2ONaphthyl)3)2, wherein the ligand field is sufficiently weak that interelectron repulsion and spin-orbit coupling play a dominant role in determining the electronic ground state. Assignment of a non-Aufbau (d x 2 -y 2, d xy )3(d xz , d yz )3(d z 2)1 electron configuration is supported by dc magnetic susceptibility data, experimental charge density maps, and ab initio calculations. Variable-field far-infrared spectroscopy and ac magnetic susceptibility measurements further reveal slow magnetic relaxation via a 450 cm-1 magnetic excited state. PMID- 30442764 TI - Structure of human TFIID and mechanism of TBP loading onto promoter DNA. AB - The general transcription factor IID (TFIID) is a critical component of the eukaryotic transcription preinitiation complex (PIC) and is responsible for recognizing the core promoter DNA and initiating PIC assembly. We used cryo electron microscopy (cryo-EM), chemical crosslinking-mass spectrometry (CX-MS) and biochemical reconstitution to determine the complete molecular architecture of TFIID and define the conformational landscape of TFIID in the process of TATA box binding protein (TBP) loading onto promoter DNA. Our structural analysis revealed five structural states of TFIID in the presence of TFIIA and promoter DNA, showing that the initial binding of TFIID to the downstream promoter positions the upstream DNA and facilitates scanning of TBP for a TATA-box and the subsequent engagement of the promoter. Our findings provide a mechanistic model for the specific loading of TBP by TFIID onto the promoter. PMID- 30442765 TI - The multiple merger assembly of a hyperluminous obscured quasar at redshift 4.6. AB - Galaxy mergers and gas accretion from the cosmic web drove the growth of galaxies and their central black holes at early epochs. We report spectroscopic imaging of a multiple merger event in the most luminous known galaxy, WISE J224607.56 052634.9 (W2246-0526), a dust-obscured quasar at redshift 4.6, 1.3 billion years after the Big Bang. Far-infrared dust continuum observations show three galaxy companions around W2246-0526 with disturbed morphologies, connected by streams of dust likely produced by the dynamical interaction. The detection of tidal dusty bridges shows that W2246-0526 is accreting its neighbors, suggesting that merger activity may be a dominant mechanism through which the most luminous galaxies simultaneously obscure and feed their central supermassive black holes. PMID- 30442766 TI - LZTR1 is a regulator of RAS ubiquitination and signaling. AB - In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of the Drosophila LZTR1 ortholog CG3711 resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation of LZTR1 led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. Because LZTR1 disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale for LZTR1 involvement in a variety of inherited and acquired human disorders. PMID- 30442767 TI - Electron-scale dynamics of the diffusion region during symmetric magnetic reconnection in space. AB - Magnetic reconnection is an energy conversion process which occurs in many astrophysical contexts including the Earth's magnetosphere, where the process can be investigated in-situ by spacecraft. We present the encounter of a reconnection site in Earth's magnetotail by the Magnetospheric Multiscale spacecraft, where reconnection involves symmetric inflow conditions. The electron-scale plasma measurements revealed i) super-Alfvenic electron jets reaching 15,000 km/s, ii) electron meandering motion and acceleration by the electric field, producing multiple crescent-shaped structures in the velocity distributions, iii) the spatial dimensions of the electron diffusion region with an aspect ratio of 0.1 0.2, consistent with fast reconnection. The well-structured multiple layers of electron populations indicate that, despite the presence of turbulence near the reconnection site, the dominant electron dynamics are mostly laminar. PMID- 30442768 TI - Discriminative learning of similar objects enhances memory for the objects and contexts. AB - How to improve our episodic memory is an important issue in the field of memory. In the present study, we used a discriminative learning paradigm that was similar to a paradigm used in animal studies. In Experiment 1, a picture (e.g., a dog) was either paired with an identical picture, with a similar picture of the same concept (e.g., another dog), or with a picture of a different concept (e.g., a cat). Then, after intervals of 10 min, 1 d, and 1 wk, participants were asked to perform a 2-alternative forced-choice (2AFC) task to discriminate between a repeated and a similar picture, followed by the contextual judgment. In Experiment 2, eye movements were measured when participants encoded the pairs of pictures. The results showed that by discriminative learning, there was better memory performance in the 2AFC task for the "same" and "similar" conditions than for the "different" condition. In addition, there was better contextual memory performance for the "similar" condition than for the other two conditions. With regard to the eye movements, the participants were more likely to fixate on the lure objects and made more saccades between the target and lure objects in the "similar" (versus "different") condition. The number of saccades predicted how well the targets were remembered in both the 2AFC and contextual memory tasks. These results suggested that with discriminative learning of similar objects, detailed information could be better encoded by distinguishing the object from similar interferences, making the details and the contexts better remembered and retained over time. PMID- 30442769 TI - Post-encoding stress enhances mnemonic discrimination of negative stimuli. AB - Stress influences how we remember emotional events and how these events shape future behaviors. However, the impact of stress on memory specificity for emotional events has yet to be examined. To this end, the present study utilized a mnemonic discrimination task that taxes hippocampal pattern separation, the process of distinguishing between overlapping experiences, thereby allowing us to better understand the mechanisms by which stress affects gist versus detail memory of emotional events. Participants encoded scenes composed of negative or neutral objects placed on neutral backgrounds and then underwent a psychosocial stressor or matched control task. Twenty-four hours later during testing, objects were presented separately, with some identical old objects (targets), some new objects (foils), and some similar but not identical objects (lures). Target recognition was enhanced for negative compared to neutral objects in both the stress and control groups. Interestingly, post-encoding stress selectively enhanced mnemonic discrimination of negative versus neutral objects, which was not the case in the control group. Measures of salivary cortisol revealed a quadratic inverted U relationship between negative mnemonic discrimination and cortisol increase. These findings suggest that moderate cortisol release following stress is associated with enhanced memory precision for negative information. PMID- 30442771 TI - Duration-specific effects of outcome devaluation in temporal control are differentially sensitive to amount of training. AB - This study demonstrates that overtraining in temporal discrimination modifies temporal stimulus control in a bisection task and produces habitual responding, as evidenced through insensitivity to food devaluation. Rats were trained or overtrained in a 2- versus 8-sec temporal discrimination task, with each duration associated with a lever (left or right) and food (grain or sucrose). Overtraining produced a leftward shift in the bisection point. Devaluation treatment induced a differential loss of responding depending on stimulus duration (short versus long) and the level of training (training versus overtraining). The relationships between timing behavior and habitual behavior are discussed. PMID- 30442770 TI - Intermediate-term memory in Aplysia involves neurotrophin signaling, transcription, and DNA methylation. AB - Long-term but not short-term memory and synaptic plasticity in many brain areas require neurotrophin signaling, transcription, and epigenetic mechanisms including DNA methylation. However, it has been difficult to relate these cellular mechanisms directly to behavior because of the immense complexity of the mammalian brain. To address that problem, we and others have examined numerically simpler systems such as the hermaphroditic marine mollusk Aplysia californica. As a further simplification, we have used a semi-intact preparation of the Aplysia siphon withdrawal reflex in which it is possible to relate cellular plasticity directly to behavioral learning. We find that inhibitors of neurotrophin signaling, transcription, and DNA methylation block sensitization and classical conditioning beginning ~1 h after the start of training, which is in the time range of an intermediate-term stage of plasticity that combines elements of short and long-term plasticity and may form a bridge between them. Injection of decitabine (an inhibitor of DNA methylation that may have other actions in these experiments) into an LE sensory neuron blocks the neural correlates of conditioning in the same time range. In addition, we found that both DNA and RNA methylation in the abdominal ganglion are correlated with learning in the same preparations. These results begin to suggest the functions and integration of these different molecular mechanisms during behavioral learning. PMID- 30442772 TI - Mirtazapine added to SSRIs or SNRIs for treatment resistant depression in primary care: phase III randomised placebo controlled trial (MIR). PMID- 30442773 TI - Contraception: drive to increase use by women in poorest countries is stalling, report finds. PMID- 30442774 TI - Spontaneous transitions of actin-bound tropomyosin toward blocked and closed states. AB - After muscle contraction, myosin cross-bridge heads detach from thin actin filaments during relaxation. Structural and kinetic data of cross-bridge-thin filament interactions have shown that tropomyosin's position on F-actin is biased toward the blocked or closed states when myosin detaches. It is not clear if structural linkages between tropomyosin and myosin cross-bridge heads, or tropomyosin and Ca2+-free troponin, drive the process or whether tropomyosin movement is energetically independent of myosin and troponin influence. Here we provide in silico data about tropomyosin dynamics on troponin/myosin-free F-actin indicating that tropomyosin moves from the open state toward blocked- or closed state positions on actin. To follow transitions inherent to tropomyosin itself on F-actin, we performed MD simulations initiated from the blocked-, open-, and intermediate-state models and followed tropomyosin over the surface of F-actin in the absence of myosin and troponin. These MD simulations maintain tropomyosin in a cable-like conformation, including the tropomyosin overlap domain, while allowing tropomyosin to retain most of its motional freedom. Tropomyosin shows considerable azimuthal movement away from the open state toward the surrounds of a more energetically favorable blocked B-state position over F-actin. In contrast, little movement away from the B-state location is observed. Our results are consistent with previous predictions based on electrostatic interaction energy landscapes determined by rigid-body translocation of tropomyosin. They support the view that in the absence of myosin, i.e., when myosin cross-bridges detach from actin, the blocked- or closed-state positions of tropomyosin are energetically favored, while the open state is not. PMID- 30442775 TI - 3-Chlorodiphenylamine activates cardiac troponin by a mechanism distinct from bepridil or TFP. AB - Despite extensive efforts spanning multiple decades, the development of highly effective Ca2+ sensitizers for the heart remains an elusive goal. Existing Ca2+ sensitizers have other targets in addition to cardiac troponin (cTn), which can lead to adverse side effects, such as hypotension or arrhythmias. Thus, there is a need to design Ca2+-sensitizing drugs with higher affinity and selectivity for cTn. Previously, we determined that many compounds based on diphenylamine (DPA) were able to bind to a cTnC-cTnI chimera with moderate affinity (Kd ~10-120 uM). Of these compounds, 3-chlorodiphenylamine (3-Cl-DPA) bound most tightly (Kd of 10 uM). Here, we investigate 3-Cl-DPA further and find that it increases the Ca2+ sensitivity of force development in skinned cardiac muscle. Using NMR, we show that, like the known Ca2+ sensitizers, trifluoperazine (TFP) and bepridil, 3-Cl DPA is able to bind to the isolated N-terminal domain (N-domain) of cTnC (Kd of 6 uM). However, while the bulky molecules of TFP and bepridil stabilize the open state of the N-domain of cTnC, the small and flexible 3-Cl-DPA molecule is able to bind without stabilizing this open state. Thus, unlike TFP, which drastically slows the rate of Ca2+ dissociation from the N-domain of isolated cTnC in a dose dependent manner, 3-Cl-DPA has no effect on the rate of Ca2+ dissociation. On the other hand, the affinity of 3-Cl-DPA for a cTnC-TnI chimera is at least an order of magnitude higher than that of TFP or bepridil, likely because 3-Cl-DPA is less disruptive of cTnI binding to cTnC. Therefore, 3-Cl-DPA has a bigger effect on the rate of Ca2+ dissociation from the entire cTn complex than TFP and bepridil. Our data suggest that 3-Cl-DPA activates the cTn complex via a unique mechanism and could be a suitable scaffold for the development of novel treatments for systolic heart failure. PMID- 30442776 TI - Comment on "Predicting reaction performance in C-N cross-coupling using machine learning". AB - Ahneman et al (Reports, 13 April 2018) applied machine learning models to predict C-N cross-coupling reaction yields. The models use atomic, electronic, and vibrational descriptors as input features. However, the experimental design is insufficient to distinguish models trained on chemical features from those trained solely on random-valued features in retrospective and prospective test scenarios, thus failing classical controls in machine learning. PMID- 30442777 TI - Response to Comment on "Predicting reaction performance in C-N cross-coupling using machine learning". AB - We demonstrate that the chemical-feature model described in our original paper is distinguishable from the nongeneralizable models introduced by Chuang and Keiser. Furthermore, the chemical-feature model significantly outperforms these models in out-of-sample predictions, justifying the use of chemical featurization from which machine learning models can extract meaningful patterns in the dataset, as originally described. PMID- 30442780 TI - News at a glance. PMID- 30442779 TI - Reform and cooperation in China. PMID- 30442778 TI - SFXN1 is a mitochondrial serine transporter required for one-carbon metabolism. AB - One-carbon metabolism generates the one-carbon units required to synthesize many critical metabolites, including nucleotides. The pathway has cytosolic and mitochondrial branches, and a key step is the entry, through an unknown mechanism, of serine into mitochondria, where it is converted into glycine and formate. In a CRISPR-based genetic screen in human cells for genes of the mitochondrial pathway, we found sideroflexin 1 (SFXN1), a multipass inner mitochondrial membrane protein of unclear function. Like cells missing mitochondrial components of one-carbon metabolism, those null for SFXN1 are defective in glycine and purine synthesis. Cells lacking SFXN1 and one of its four homologs, SFXN3, have more severe defects, including being auxotrophic for glycine. Purified SFXN1 transports serine in vitro. Thus, SFXN1 functions as a mitochondrial serine transporter in one-carbon metabolism. PMID- 30442781 TI - Vote heralds fresh start for science panel. PMID- 30442782 TI - Eruption made 536 'the worst year to be alive'. PMID- 30442783 TI - Obesity gives unexpected boost to anticancer drugs. PMID- 30442784 TI - Fresh fights roil evidence-based medicine group. PMID- 30442785 TI - Reprogrammed cells could tackle brain damage. PMID- 30442787 TI - Ice age impact. PMID- 30442786 TI - Large galaxy found lurking on the Milky Way's far side. PMID- 30442788 TI - Lighting up the nighttime. PMID- 30442789 TI - Endothelial cell transitions. PMID- 30442790 TI - A target to suppress inflammation. PMID- 30442791 TI - Cell types behaving in their natural habitat. PMID- 30442792 TI - Polarimetry enabled by nanophotonics. PMID- 30442794 TI - Preventing chemical weapons as sciences converge. PMID- 30442795 TI - Climate change drives tree mortality. PMID- 30442796 TI - Halt speculation on U.S. embassy in Cuba. PMID- 30442798 TI - NextGen VOICES: Transition challenges. PMID- 30442799 TI - Optimizing the diet. PMID- 30442797 TI - Standardizing return of participant results. PMID- 30442800 TI - Dietary fat: From foe to friend? AB - For decades, dietary advice was based on the premise that high intakes of fat cause obesity, diabetes, heart disease, and possibly cancer. Recently, evidence for the adverse metabolic effects of processed carbohydrate has led to a resurgence in interest in lower-carbohydrate and ketogenic diets with high fat content. However, some argue that the relative quantity of dietary fat and carbohydrate has little relevance to health and that focus should instead be placed on which particular fat or carbohydrate sources are consumed. This review, by nutrition scientists with widely varying perspectives, summarizes existing evidence to identify areas of broad consensus amid ongoing controversy regarding macronutrients and chronic disease. PMID- 30442801 TI - A time to fast. AB - Nutrient composition and caloric intake have traditionally been used to devise optimized diets for various phases of life. Adjustment of meal size and frequency have emerged as powerful tools to ameliorate and postpone the onset of disease and delay aging, whereas periods of fasting, with or without reduced energy intake, can have profound health benefits. The underlying physiological processes involve periodic shifts of metabolic fuel sources, promotion of repair mechanisms, and the optimization of energy utilization for cellular and organismal health. Future research endeavors should be directed to the integration of a balanced nutritious diet with controlled meal size and patterns and periods of fasting to develop better strategies to prevent, postpone, and treat the socioeconomical burden of chronic diseases associated with aging. PMID- 30442802 TI - The gut microbiota at the intersection of diet and human health. AB - Diet affects multiple facets of human health and is inextricably linked to chronic metabolic conditions such as obesity, type 2 diabetes, and cardiovascular disease. Dietary nutrients are essential not only for human health but also for the health and survival of the trillions of microbes that reside within the human intestines. Diet is a key component of the relationship between humans and their microbial residents; gut microbes use ingested nutrients for fundamental biological processes, and the metabolic outputs of those processes may have important impacts on human physiology. Studies in humans and animal models are beginning to unravel the underpinnings of this relationship, and increasing evidence suggests that it may underlie some of the broader effects of diet on human health and disease. PMID- 30442803 TI - Swifter, higher, stronger: What's on the menu? AB - The exploits of elite athletes delight, frustrate, and confound us as they strive to reach their physiological, psychological, and biomechanical limits. We dissect nutritional approaches to optimal performance, showcasing the contribution of modern sports science to gold medals and world titles. Despite an enduring belief in a single, superior "athletic diet," diversity in sports nutrition practices among successful athletes arises from the specificity of the metabolic demands of different sports and the periodization of training and competition goals. Pragmatic implementation of nutrition strategies in real-world scenarios and the prioritization of important strategies when nutrition themes are in conflict add to this variation. Lastly, differences in athlete practices both promote and reflect areas of controversy and disagreement among sports nutrition experts. PMID- 30442804 TI - Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates. AB - Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals. PMID- 30442806 TI - Light-driven fine chemical production in yeast biohybrids. AB - Inorganic-biological hybrid systems have potential to be sustainable, efficient, and versatile chemical synthesis platforms by integrating the light-harvesting properties of semiconductors with the synthetic potential of biological cells. We have developed a modular bioinorganic hybrid platform that consists of highly efficient light-harvesting indium phosphide nanoparticles and genetically engineered Saccharomyces cerevisiae, a workhorse microorganism in biomanufacturing. The yeast harvests photogenerated electrons from the illuminated nanoparticles and uses them for the cytosolic regeneration of redox cofactors. This process enables the decoupling of biosynthesis and cofactor regeneration, facilitating a carbon- and energy-efficient production of the metabolite shikimic acid, a common precursor for several drugs and fine chemicals. Our work provides a platform for the rational design of biohybrids for efficient biomanufacturing processes with higher complexity and functionality. PMID- 30442805 TI - Templated nanofiber synthesis via chemical vapor polymerization into liquid crystalline films. AB - Extrusion, electrospinning, and microdrawing are widely used to create fibrous polymer mats, but these approaches offer limited access to oriented arrays of nanometer-scale fibers with controlled size, shape, and lateral organization. We show that chemical vapor polymerization can be performed on surfaces coated with thin films of liquid crystals to synthesize organized assemblies of end-attached polymer nanofibers. The process uses low concentrations of radical monomers formed initially in the vapor phase and then diffused into the liquid-crystal template. This minimizes monomer-induced changes to the liquid-crystal phase and enables access to nanofiber arrays with complex yet precisely defined structures and compositions. The nanofiber arrays permit tailoring of a wide range of functional properties, including adhesion that depends on nanofiber chirality. PMID- 30442807 TI - Wafer-scale single-crystal hexagonal boron nitride film via self-collimated grain formation. AB - Although polycrystalline hexagonal boron nitride (PC-hBN) has been realized, defects and grain boundaries still cause charge scatterings and trap sites, impeding high-performance electronics. Here, we report a method of synthesizing wafer-scale single-crystalline hBN (SC-hBN) monolayer films by chemical vapor deposition. The limited solubility of boron (B) and nitrogen (N) atoms in liquid gold promotes high diffusion of adatoms on the surface of liquid at high temperature to provoke the circular hBN grains. These further evolve into closely packed unimodal grains by means of self-collimation of B and N edges inherited by electrostatic interaction between grains, eventually forming an SC-hBN film on a wafer scale. This SC-hBN film also allows for the synthesis of wafer-scale graphene/hBN heterostructure and single-crystalline tungsten disulfide. PMID- 30442808 TI - Beyond the molecular movie: Dynamics of bands and bonds during a photoinduced phase transition. AB - Ultrafast nonequilibrium dynamics offer a route to study the microscopic interactions that govern macroscopic behavior. In particular, photoinduced phase transitions (PIPTs) in solids provide a test case for how forces, and the resulting atomic motion along a reaction coordinate, originate from a nonequilibrium population of excited electronic states. Using femtosecond photoemission, we obtain access to the transient electronic structure during an ultrafast PIPT in a model system: indium nanowires on a silicon(111) surface. We uncover a detailed reaction pathway, allowing a direct comparison with the dynamics predicted by ab initio simulations. This further reveals the crucial role played by localized photoholes in shaping the potential energy landscape and enables a combined momentum- and real-space description of PIPTs, including the ultrafast formation of chemical bonds. PMID- 30442809 TI - Protein assemblies ejected directly from native membranes yield complexes for mass spectrometry. AB - Membrane proteins reside in lipid bilayers and are typically extracted from this environment for study, which often compromises their integrity. In this work, we ejected intact assemblies from membranes, without chemical disruption, and used mass spectrometry to define their composition. From Escherichia coli outer membranes, we identified a chaperone-porin association and lipid interactions in the beta-barrel assembly machinery. We observed efflux pumps bridging inner and outer membranes, and from inner membranes we identified a pentameric pore of TonB, as well as the protein-conducting channel SecYEG in association with F1FO adenosine triphosphate (ATP) synthase. Intact mitochondrial membranes from Bos taurus yielded respiratory complexes and fatty acid-bound dimers of the ADP (adenosine diphosphate)/ATP translocase (ANT-1). These results highlight the importance of native membrane environments for retaining small-molecule binding, subunit interactions, and associated chaperones of the membrane proteome. PMID- 30442811 TI - Climbing out of the bottle. PMID- 30442810 TI - Small-molecule inhibitor of OGG1 suppresses proinflammatory gene expression and inflammation. AB - The onset of inflammation is associated with reactive oxygen species and oxidative damage to macromolecules like 7,8-dihydro-8-oxoguanine (8-oxoG) in DNA. Because 8-oxoguanine DNA glycosylase 1 (OGG1) binds 8-oxoG and because Ogg1 deficient mice are resistant to acute and systemic inflammation, we hypothesized that OGG1 inhibition may represent a strategy for the prevention and treatment of inflammation. We developed TH5487, a selective active-site inhibitor of OGG1, which hampers OGG1 binding to and repair of 8-oxoG and which is well tolerated by mice. TH5487 prevents tumor necrosis factor-alpha-induced OGG1-DNA interactions at guanine-rich promoters of proinflammatory genes. This, in turn, decreases DNA occupancy of nuclear factor kappaB and proinflammatory gene expression, resulting in decreased immune cell recruitment to mouse lungs. Thus, we present a proof of concept that targeting oxidative DNA repair can alleviate inflammatory conditions in vivo. PMID- 30442812 TI - Changes in cell fate determine the regenerative and functional capacity of the developing kidney before and after release of obstruction. AB - Congenital obstructive nephropathy is a major cause of chronic kidney disease (CKD) in children. The contribution of changes in the identity of renal cells to the pathology of obstructive nephropathy is poorly understood. Using a partial unilateral ureteral obstruction (pUUO) model in genetically modified neonatal mice, we traced the fate of cells derived from the renal stroma, cap mesenchyme, ureteric bud (UB) epithelium, and podocytes using Foxd1Cre, Six2Cre, HoxB7Cre, and Podocyte.Cre mice respectively, crossed with double fluorescent reporter (membrane-targetted tandem dimer Tomato (mT)/membrane-targetted GFP (mG)) mice. Persistent obstruction leads to a significant loss of tubular epithelium, rarefaction of the renal vasculature, and decreased renal blood flow (RBF). In addition, Forkhead Box D1 (Foxd1)-derived pericytes significantly expanded in the interstitial space, acquiring a myofibroblast phenotype. Degeneration of Sine Oculis Homeobox Homolog 2 (Six2) and HoxB7-derived cells resulted in significant loss of glomeruli, nephron tubules, and collecting ducts. Surgical release of obstruction resulted in striking regeneration of tubules, arterioles, interstitium accompanied by an increase in blood flow to the level of sham animals. Contralateral kidneys with remarkable compensatory response to kidney injury showed an increase in density of arteriolar branches. Deciphering the mechanisms involved in kidney repair and regeneration post relief of obstruction has potential therapeutic implications for infants and children and the growing number of adults suffering from CKD. PMID- 30442815 TI - Retraction: Disruption of the NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Gene in Mice Causes Myelogenous Hyperplasia. PMID- 30442814 TI - Posttranslational Modifications of PD-L1 and Their Applications in Cancer Therapy. AB - Posttranslational modifications (PTM) of PD-L1 have emerged as important regulatory mechanisms that modulate immunosuppression in patients with cancer. In exposure to inflammatory cytokines, cancer cells and antigen-presenting cells, such as macrophages and dendritic cells, express PD-L1 to inhibit the activity of effector T cells through PD-1 engagement. Recent studies suggested that glycosylation, phosphorylation, ubiquitination, sumoylation, and acetylation play important roles in the regulation of PD-L1 protein stability and translocation and protein-protein interactions. Aberrant alterations of PTMs directly influence PD-L1-mediated immune resistance. On the basis of the newly identified regulatory signaling pathways of PD-L1 PTMs, researchers have investigated the cancer therapeutic potential of natural food compounds, small-molecule inhibitors, and mAbs by targeting PD-L1 PTMs. Results of these preclinical studies demonstrated that targeting PTMs of PD-L1 yields promising antitumor effects and that clinical translation of these therapeutic strategies is warranted. Cancer Res; 78(22); 6349-53. (c)2018 AACR. PMID- 30442816 TI - Lymphopaenia as a predictor of sarcoidosis in patients with a first episode of uveitis. AB - BACKGROUND/AIMS: The diagnostic properties of conventional diagnostic tests (ACE and chest radiography) for sarcoidosis-associated uveitis are not ideal. The diagnostic value of lymphopaenia for sarcoidosis-associated uveitis is investigated. METHODS: A retrospective study of 191 consecutive patients with a first uveitis episode visiting the ophthalmology department (Erasmus Medical Center, Rotterdam, The Netherlands). Receiver operating characteristics (ROC) analysis was performed and compared with known ROC values from literature of conventional diagnostic tests for sarcoidosis-associated uveitis. An ideal cut off was determined for lymphopaenia by calculation of the highest Youden index. RESULTS: Out of all patients with first uveitis attack, 32/191 or 17% were subsequently diagnosed with biopsy-proven or radiological diagnosis of sarcoidosis. Lymphopaenia (<1.5*109/L) was significantly more often observed in patients with sarcoidosis-associated uveitis compared with patients with non sarcoidosis-associated uveitis (p<0.05). The sensitivity and specificity of lymphopaenia was 75 % and 77 %, respectively. The optimal cut-off for lymphopaenia for diagnosing sarcoidosis-associated uveitis was 1.47 *109/L. Lymphopaenia resulted in a 12.0 (95% CI 4.7 to 30.5 fold risk for having sarcoidosis, corrected for sex, race and age at onset of uveitis in patients with a first uveitis attack. CONCLUSION: Lymphopaenia is a non-invasive and useful marker for diagnosing sarcoidosis-associated uveitis. PMID- 30442817 TI - Genetic variants in a sodium-dependent vitamin C transporter gene and age-related cataract. AB - BACKGROUND: Cataract is a major health burden in many countries and a significant problem in India. While observational studies show lower cataract risk with increasing dietary or plasma vitamin C, randomised controlled trials of supplements have been negative. Genetic variants in vitamin C transporter proteins (SLC23A1), especially rs33972313, may provide evidence on a causal association of vitamin C with cataract. METHODS: We used data from a randomly selected population-based study in people aged 60 years and above in north and south India. Of 7518 sampled, 5428 (72%) were interviewed for socioeconomic and lifestyle factors, attended hospital for lens imaging and blood collection and were subsequently genotyped for rs33972313 and rs6596473. Mixed or pure types of cataract were graded by the Lens Opacity Classification System III as nuclear (2404), cortical (494) or posterior subcapsular cataract (PSC) (1026); 1462 had no significant cataract and no history of cataract surgery and 775 had bilateral aphakia/pseudophakia. RESULTS: rs33972313 was associated with cortical (OR 2.16; 95% CI 1.34 to 3.49, p=0.002) and PSC (OR 1.68; 95% CI 1.06 to 2.65, p=0.03) but not with nuclear cataract. In analyses of pure cataracts, associations were found only between rs33972313 and pure cortical cataracts (OR 2.29; 95% CI 1.12 to 4.65, p=0.03) and with a standardised cortical opacity score. There was no association with rs6596473 and any cataract outcomes. CONCLUSIONS: Using an established genetic variant as a proxy for lifetime ascorbate concentrations, our results support a causal association of vitamin C with cataract. PMID- 30442818 TI - Government social assistance programmes are failing to protect the health of low income populations: evidence from the USA and Canada (2003-2014). AB - BACKGROUND: Social policies that improve the availability and distribution of key socioeconomic resources such as income, wealth and employment are believed to present the most promising avenue for reducing health inequalities. The present study aims to estimate the effect of social assistance recipiency on the health of low-income earners in the USA and Canada. METHODS: Drawing on nationally representative survey data (National Health Interview Survey and the Canadian Community Health Survey), we employed propensity score matching to match recipients of social assistance to comparable sets of non-recipient 'controls'. Using a variety of matching algorithms, we estimated the treatment effect of social assistance recipiency on self-rated health, chronic conditions, hypertension, obesity, smoking, binge drinking and physical inactivity. RESULTS: After accounting for underlying differences in the demographic and socioeconomic characteristics of recipients and non-recipients, we found that social assistance recipiency was associated with worse health status or, at best, the absence of a clear health advantage. This finding was consistent across several different matching strategies and a diverse range of health outcomes. CONCLUSIONS: From a public health perspective, our findings suggest that interventions are warranted to improve the scope and generosity of existing social assistance programmes. This may include reversing welfare reforms implemented over the past several decades, increasing benefit levels and untethering benefit recipiency from stringent work conditionalities. PMID- 30442819 TI - Why caesarean is more unequally concentrated among better-off people in Tehran? A concentration index decomposition approach. AB - BACKGROUND: Iran, as one of the low-income and middle-income countries, has experienced a remarkable increase in the caesarean section (CS) rate during the past three decades. Although several studies have been conducted on the prevalence and risk factors affecting CS, but few studies were done regarding socioeconomic factors influencing the CS rate. The aim of this study was to identify socioeconomic inequalities and its determinants in CS in Tehran, capital of Iran. METHODS: A population-based cross-sectional study was conducted on 5170 pregnancies in Tehran, since 2015. Principal component analysis was applied to measure the asset-based economic status. Concentration index was used to measure socioeconomic inequality in CS and then decomposed in to its determinants. RESULTS: The concentration index and its 95% CI for CS history was 0.102 (0.091 to 0.112). Decomposition of the concentration index showed that economic status had the largest contribution (49.2%) to socioeconomic inequality in CS. Mother's education (14.9%), father's occupation (13.3%) and father's nationality (9.7%) had the next high positive contribution to measured inequality in CS, respectively. CONCLUSIONS: CS is mostly concentrated among women with high economic status. The identified contributing factors should be addressed to decrease the socioeconomic inequalities as possible. PMID- 30442820 TI - Relationship Between Increased Fecal Calprotectin Levels and Interstitial Lung Disease in Systemic Sclerosis. AB - OBJECTIVE: To evaluate the relationship between fecal calprotectin (FC) and interstitial lung disease (ILD) in systemic sclerosis (SSc). METHODS: The study enrolled 129 outpatients with SSc. Data about disease characteristics, in particular lung involvement, were collected and FC was measured. RESULTS: Patients with ILD (35, 27.1%) had higher values of FC (p < 0.001). In multivariate analysis, these variables were associated with increased risk of ILD: diffuse disease subset, higher modified Rodnan skin score, longer disease duration, higher severity scores, steroid treatment, and higher FC levels, while diverticulosis was protective. CONCLUSION: ILD is independently associated with increased FC levels in SSc. PMID- 30442821 TI - Associations of Multiple NOTCH4 Exonic Variants with Systemic Sclerosis. AB - OBJECTIVE: Findings from previous genome-wide association studies indicated an association of the NOTCH4 gene with systemic sclerosis (SSc). This is a followup study to fine-map exonic variants of NOTCH4 in SSc. METHODS: All exons of NOTCH4 were sequenced and analyzed in a total of 1006 patients with SSc and 1004 controls of US white ancestry with the Ion Torrent system. Identified SSc associated variants were confirmed with Sanger sequencing, and then examined in a Chinese Han cohort consisting of 576 patients with SSc and 574 controls. The NOTCH4 variants were analyzed for association with SSc as a whole and with SSc clinical and autoantibody subtypes with and without the influence of specific HLA class II alleles that had been previously identified as major genetic factors in SSc. RESULTS: A total of 12 SSc-associated and SSc subtype-associated exonic variants of NOTCH4 were identified in the US cohort. Three of them are nonsynonymous single-nucleotide polymorphisms and 1 is a CTG tandem repeat that encodes for a poly-leucine, all of which are located in the NOTCH4 extracellular domain (NECD). Conditional logistic regression analysis on SSc-associated HLA class II alleles indicated an independent association of the NOTCH4 variants with SSc autoantibody subtypes. Analysis of the Chinese cohort supported a genetic contribution of NOTCH4 to SSc and its subtypes. CONCLUSION: Multiple NOTCH4 exonic variants were associated with SSc and/or SSc subtypes. Several of these variants encode nonsynonymous sequence changes occurring in the NECD, which implicates a potentially functional effect of NOTCH4. PMID- 30442822 TI - Utility of Anakinra in Acute Crystalline Diseases: A Retrospective Study Comparing a University Hospital with a Veterans Affairs Medical Center. AB - OBJECTIVE: To evaluate the efficacy and safety of anakinra in inpatient management of acute gout and pseudogout. METHODS: Hospitalized patients with acute gout (n = 77) or pseudogout (n = 11) or both (n = 3) were analyzed for response to anakinra and adverse effects. RESULTS: Half of all patients had comorbidities limiting the treatment choice. Anakinra was well tolerated, and 92% of gout flares and 79% of pseudogout flares responded to treatment. CONCLUSION: Anakinra is an effective and safe treatment for acute gout and pseudogout in hospitalized patients, particularly in those with comorbidities. PMID- 30442825 TI - Hepatic Safety of Febuxostat Compared with Allopurinol in Gout Patients with Fatty Liver Disease. AB - OBJECTIVE: Febuxostat has superior renal safety to allopurinol, but data on its hepatic safety are limited. Thus we compared the hepatotoxicity of febuxostat and allopurinol, and the clinical factors associated with hepatotoxicity, in patients with gout and fatty liver disease (FLD). METHODS: We included gout patients treated with allopurinol or febuxostat who were diagnosed with fatty liver based on ultrasonography or computed tomography. Hepatotoxicity was defined as follows: (1) elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT) at least 3* the upper limit of normal, when the baseline AST/ALT was normal; or (2) doubling of the baseline AST/ALT, when the baseline AST/ALT was elevated. The factors associated with hepatotoxicity were evaluated by Cox regression analysis. RESULTS: Of 134 patients identified with gout and FLD, 32 (23.9%) received febuxostat and 102 (76.1%) received allopurinol. There were no significant differences in age, body mass index, comorbidity, or disease severity between the groups; however, the incidence of hepatotoxicity was significantly lower in the febuxostat group (3/32, 9.4%) than in the allopurinol group (36/102, 35.3%, p = 0.005). Diabetes (HR 3.549, 95% CI 1.374-9.165, p = 0.009) and colchicine use (HR 11.518, 95% CI 5.515-24.054, p < 0.001) were associated with a higher risk of hepatotoxicity, whereas febuxostat use was associated with a lower risk of hepatotoxicity (HR 0.282, 95% CI 0.086-0.926, p = 0.037). CONCLUSION: In the 32 patients studied, febuxostat was well tolerated in patients with gout and FLD. However, the presence of diabetes and colchicine use may increase the risk of hepatotoxicity. PMID- 30442824 TI - Factors Influencing the Uptake of Canadian Research Findings into the Care of Children with Arthritis: A Healthcare Provider Perspective. AB - OBJECTIVE: To determine barriers and facilitators to the uptake of findings from the Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) study into clinical care by pediatric rheumatologists (PR) and allied health professionals (AHP) caring for children with juvenile idiopathic arthritis (JIA) in Canada. METHODS: PR and AHP participated in this qualitative study through telephone interviews. Interview guides were developed using the Theoretical Domains Framework and focused on the use of information from the ReACCh-Out study in the practice of counseling patients and families. A directed content analysis approach was used for coding. RESULTS: Nineteen interviews (8 PR and 11 AHP) were completed. All PR had knowledge of the ReACCh-Out study. Three major themes were identified: (1) both groups are motivated to use information from research in clinical care; (2) volume and emotional effect of information on families are barriers; and (3) specific timepoints in care trigger providing this information. AHP had less knowledge of the ReACCh-Out study, did not feel it was their primary role to provide this information, and have a desire for more opportunity to participate in academic forums related to research. CONCLUSION: We have described a comprehensive overview of the barriers and facilitators perceived by healthcare providers in the translation of knowledge from JIA research into use in clinical practice. These findings provide a foundation for the development of knowledge translation strategies in the care of children with JIA and other rheumatic diseases. PMID- 30442826 TI - Fertility and Ovarian Reserve among Women with Rheumatoid Arthritis. AB - OBJECTIVE: We sought to identify causes for infertility in women with and without rheumatoid arthritis (RA). METHODS: Women with RA were matched to healthy controls. Differences in anti-Mullerian hormone (AMH) and anovulation were analyzed. RESULTS: Women with RA had lower AMH (beta -1.05, 95% CI -2.09 to 0.005), but no difference was observed when AMH was log-transformed. No difference in anovulation was observed. Infertility prevalence was similar between groups, primarily attributable to polycystic ovary syndrome in healthy controls but largely unexplained in women with RA. CONCLUSION: AMH was lower in women with RA, but reasons for infertility among women with RA remain unknown. PMID- 30442827 TI - Longitudinal Assessment of Patient-reported Outcome Measures in Systemic Sclerosis Patients with Gastroesophageal Reflux Disease - Scleroderma Clinical Trials Consortium. AB - OBJECTIVE: Validated gastrointestinal (GI) symptoms scales are used in clinical practice to assess patient-reported GI involvement. We sought to determine whether University of California, Los Angeles (UCLA) GI Tract Questionnaire (GIT) 2.0 Reflux scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Reflux scale, and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) are sensitive to identifying changes in GI symptoms following therapeutic intervention in participants with systemic sclerosis (SSc) and gastroesophageal reflux disease (GERD). METHODS: Participants with active GERD were recruited during clinical visits at 6 international SSc centers. Patient-reported outcome surveys and the GI self-reported questionnaire were completed at baseline and again at 4 weeks following a single intervention, and patients were classified as "improved" or "not improved." Effect size (ES) was calculated to assess the sensitivity to change. ES was interpreted as 0.50-0.79 as moderate effect and >= 0.80 as large effect. RESULTS: There were 116 participants with SSc and active GERD who enrolled. The average age was 53.8 years and mean disease duration was 12.0 years. The UCLA GIT 2.0 Reflux scale and PROMIS Reflux scale had a significant correlation at baseline (0.61, p < 0.0001), and both instruments correlated with the QOLRAD domains (-0.56 to -0.71). In participants who had the UCLA GIT 2.0, PROMIS Reflux scale, and QOLRAD administered over 2 timepoints (n = 57) and were classified as improved, the ES was large for the UCLA GIT 2.0 and PROMIS Reflux scale, and moderate to large across all QOLRAD domains. CONCLUSION: The UCLA GIT 2.0 Reflux scale, PROMIS Reflux scale, and QOLRAD are sensitive to change and can be included in future clinical trials. PMID- 30442828 TI - A Comparison of Radiographic Joint Space Width Measurements Versus Ultrasonographic Assessment of Cartilage Thickness in Children with Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Joint space narrowing (JSN) is a measurable outcome of tissue degeneration in arthritis. JSN is usually assessed by conventional radiography. Ultrasonographic (US) measurement of joint cartilage thickness has been validated in healthy children, and US measurement of the distal femoral cartilage has been validated in a group of patients with juvenile idiopathic arthritis (JIA). Our aim was to compare the measures of cartilage thickness of the proximal cartilage site in the second metacarpophalangeal (MCP), second proximal interphalangeal (PIP), and knee joints as assessed by US to joint space width (JSW) as measured by computerized radiography in children with JIA. METHODS: The study included 74 children with JIA aged 5-15 years (median 11.3 yrs). MCP and PIP joints were assessed at one midline spot. Knee joints were assessed at the medial and lateral femoral condylar areas. Only the proximal cartilage site in the joints was assessed by US, whereas the complete JSW was assessed by radiography. RESULTS: We assessed 136 second MCP, 138 second PIP, and 146 knee joints. We found a high level of agreement between US and radiographic measures of cartilage thickness and JSW: r = 0.82-0.86 (second MCP), r = 0.50-0.55 (second PIP), and r = 0.52 0.81 (knee); p < 0.001 for all 8 assessed sites. CONCLUSION: US measurements of cartilage thickness of the proximal site of the second MCP, second PIP, and knee joints correlated well with radiographic JSW measurements in the finger and knee joints of children with JIA. However, US does not measure the distal cartilage, which may limit its use in the assessment of JSN. PMID- 30442829 TI - An Adult Fatal Case with a STAT1 Gain-of-function Mutation Associated with Multiple Autoimmune Diseases. AB - Primary immunodeficiency diseases (PID) are a heterogeneous group of diseases with variable genetic etiologies. Although immunodeficiency is a hallmark of susceptibility to infection, autoimmunity is clearly a prevalent feature. PMID- 30442823 TI - Nailfold Capillaroscopy Characteristics of Antisynthetase Syndrome and Possible Clinical Associations: Results of a Multicenter International Study. AB - OBJECTIVE: To describe nailfold videocapillaroscopy (NVC) features of patients with antisynthetase syndrome (AS) and to investigate possible correlations with clinical and serological features of the disease. METHODS: We retrospectively analyzed NVC images of 190 patients with AS [females/males 3.63, mean age 49.7 +/ 12.8 yrs, median disease duration 53.7 mos (interquartile range 82), 133 anti Jo1 and 57 non-anti-Jo1-positive patients]. For each patient, we examined number of capillaries, giant capillaries, microhemorrhages, avascular areas, ramified capillaries, and the presence of systemic sclerosis (SSc)-like pattern. Finally, we correlated NVC features with clinical and serological findings of patients with AS. Concomitantly, a historical cohort of 75 patients with antinuclear antibody-negative primary Raynaud phenomenon (RP) and longterm followup was used as a control group (female/male ratio 4.13/1, mean age 53.9 +/- 17.6 yrs) for NVC measures. RESULTS: NVC abnormalities were observed in 62.1% of AS patients compared with 29.3% of primary RP group (p < 0.001). An SSc-like pattern was detected in 67 patients (35.3%) and it was associated with anti-Jo1 antibodies (p = 0.002) and also with a longer disease duration (p = 0.004). Interestingly, there was no significant correlation between the presence of SSc-like pattern and RP, and only 47% of patients with SSc-like pattern had RP. CONCLUSION: NVC abnormalities are commonly observed in AS, independently from the occurrence of RP. The presence of an SSc-like pattern could allow identification of a more defined AS subtype, and prospective studies could confirm the association with clinical and serological features of AS. PMID- 30442830 TI - Uptake and Clinical Utility of Multibiomarker Disease Activity Testing in the United States. AB - OBJECTIVE: The clinical utility of the multibiomarker disease activity (MBDA) test for rheumatoid arthritis (RA) management in routine care in the United States has not been thoroughly studied. METHODS: Using 2011-2015 Medicare data, we linked each patient with RA to their MBDA test result. Initiation of a biologic or Janus kinase (JAK) inhibitor in the 6 months following MBDA testing was described. Multivariable adjustment evaluated the likelihood of adding or switching biologic/JAK inhibitor, controlling for potential confounders. For patients with high MBDA scores who added a new RA therapy and were subsequently retested, lack of improvement in the MBDA score was evaluated as a predictor of future RA medication failure, defined by the necessity to change RA medications again. RESULTS: Among 60,596 RA patients with MBDA testing, the proportion adding or switching biologics/JAK inhibitor among those not already taking a biologic/JAK inhibitor was 9.0% (low MBDA), 11.8% (moderate MBDA), and 19.7% (high MBDA, p < 0.0001). Similarly, among those already taking biologics/JAK inhibitor, the proportions were 5.2%, 8.3%, and 13.5% (p < 0.0001). After multivariable adjustment, referent to those with low disease MBDA scores, the likelihood of switching was 1.51-fold greater (95% CI 1.35-1.69) for patients with moderate MBDA scores, and 2.62 (2.26-3.05) for patients with high MBDA scores. Among those with high MBDA scores who subsequently added a biologic/JAK inhibitor and were retested, lack of improvement in the MBDA score category was associated with likelihood of future RA treatment failure (OR 1.61, 95% CI 1.27 2.03). CONCLUSION: The MBDA score was associated with both biologic and JAK inhibitor medication addition/switching and subsequent treatment outcomes. PMID- 30442831 TI - Rheumatoid Arthritis-Interstitial Lung Disease in the United States: Prevalence, Incidence, and Healthcare Costs and Mortality. AB - OBJECTIVE: Interstitial lung disease (ILD) is commonly associated with rheumatoid arthritis (RA) and can have significant morbidity and mortality. The objective of this study was to calculate the prevalence, incidence, healthcare costs, and mortality of RA-related ILD (RA-ILD) in the United States. METHODS: This retrospective cohort analysis used the Truven Health MarketScan Commercial and Medicare Supplemental health insurance databases from 2003 to 2014 and the Social Security Administration death database. Patients with RA-ILD were selected based on diagnoses on medical claims. Outcomes were 1-year prevalence and incidence of RA-ILD among the general enrollee population, all-cause and respiratory-related healthcare costs (2014 US$), and all-cause survival for a subset of newly diagnosed patients with vital status information. This analysis was descriptive. No statistical testing was conducted. RESULTS: Prevalence of RA-ILD ranged from 3.2 to 6.0 cases per 100,000 people across the 10-year period and incidence ranged from 2.7 to 3.8 cases per 100,000 people. There were 750 incident patients with 5 years of followup data. Over that time, 72% had an inpatient admission and 76% had an emergency room visit. Mean total 5-year costs were US$173,405 per patient (SD $158,837). Annual per-patient costs were highest in years 1 and 5. At 5 years after first diagnosis in the data, 35.9% of patients were alive. CONCLUSION: Prevalence of RA-ILD increased over time. For patients who could be followed over a 5-year period, healthcare use and costs were somewhat stable over time, but were substantial. RA-ILD is associated with decreased survival. PMID- 30442832 TI - JAK2 Specificity and Thrombosis Risk: Potential Role of Antiphospholipid Antibodies. AB - Janus kinase (JAK) inhibitors are a relatively new addition to our tools for treatment of rheumatoid arthritis (RA)1 They are responsible for transduction of more than 38 cytokinases2, with diffuse metabolic/immunologic implications. PMID- 30442833 TI - Preliminary Validation of the Digital Ulcer Clinical Assessment Score in Systemic Sclerosis. AB - OBJECTIVE: To date, "healed/non-healed" and clinical judgment are the only available assessment tools for digital ulcers (DU) in patients with systemic sclerosis (SSc). The aim of our study is to examine a preliminary composite DU clinical assessment score (DUCAS) for SSc for face, content, and construct validity. METHODS: Patients with SSc presenting at least 1 finger DU were enrolled and assessed with the Health Assessment Questionnaire-Disability Index, Cochin scale, visual analog scale (VAS) for DU-related pain, patient global DU status, and global assessment as patient-reported outcomes (PRO), and physician VAS for DU status (phyGDU) as an SSc-DU expert physician/nurse measure. The DUCAS included 7 DU-related variables selected by a committee of SSc DU experts and weighted on a clinical basis. Face validity was examined by consensus and partial construct validity was tested through convergent correlation with other measures of hand function, using Spearman's correlations. A range of patients with SSc was examined. A linear regression model with backward stepwise analysis was used to determine the relationship of individual variables with the primary clinical parameter, phyGDU. RESULTS: Forty-four patients with SSc (9 males, mean age 55 +/ 15 yrs, mean disease duration 9.9 +/- 5.8 yrs) were enrolled in the study. Overall DUCAS showed significant positive correlations with all abovementioned PRO (r > 0.4, p < 0.01). When all scores and scales were modeled, only DUCAS significantly predicted phyGDU (r = 0.59, R2 = 0.354, Akaike information criterion = 385.4). CONCLUSION: Preliminarily, we suggest that the DUCAS may be a new clinical score for SSc-related DU, having face and content validity and convergent/divergent correlations (construct validity). These early data suggest that this score deserves further evaluation. PMID- 30442836 TI - Gender bias is alive and well in the vet profession. PMID- 30442835 TI - Gender discrimination is alive and well. PMID- 30442834 TI - Downregulation of basal myosin-II is required for cell shape changes and tissue invagination. AB - Tissue invagination drives embryo remodeling and assembly of internal organs during animal development. While the role of actomyosin-mediated apical constriction in initiating inward folding is well established, computational models suggest relaxation of the basal surface as an additional requirement. However, the lack of genetic mutations interfering specifically with basal relaxation has made it difficult to test its requirement during invagination so far. Here we use optogenetics to quantitatively control myosin-II levels at the basal surface of invaginating cells during Drosophila gastrulation. We show that while basal myosin-II is lost progressively during ventral furrow formation, optogenetics allows the maintenance of pre-invagination levels over time. Quantitative imaging demonstrates that optogenetic activation prior to tissue bending slows down cell elongation and blocks invagination. Activation after cell elongation and tissue bending has initiated inhibits cell shortening and folding of the furrow into a tube-like structure. Collectively, these data demonstrate the requirement of myosin-II polarization and basal relaxation throughout the entire invagination process. PMID- 30442837 TI - News section PDF. PMID- 30442838 TI - Reptile illness is caused by bad husbandry. PMID- 30442839 TI - Livestock industry should act on bovine TB too. PMID- 30442840 TI - Supporting graduates as they move to practice. PMID- 30442841 TI - Breed disposition for urinary incontinence uncovered by RVC. PMID- 30442842 TI - What do vet students really think of EMS? PMID- 30442844 TI - Saving bears from the bile farming trade. AB - Matthew Limb reports on the UK vet who has been to China to help rescued bears. PMID- 30442845 TI - Medicines update. PMID- 30442847 TI - Selected highlights from other journals. PMID- 30442846 TI - Communicating with clients about safety measures in the veterinary practice. PMID- 30442848 TI - Support needed to prepare clients for Brexit. PMID- 30442849 TI - Ensuring animal welfare after Brexit. PMID- 30442850 TI - Environmental dangers of veterinary antiparasitic agents. PMID- 30442851 TI - Valuing and respecting colleagues. PMID- 30442852 TI - Unlocking the genetic basis of diabetes in Burmese cats. PMID- 30442853 TI - Correction: Export certificates to be signed by non-vets. PMID- 30442855 TI - Death notice. PMID- 30442854 TI - Valuing and respecting colleagues. PMID- 30442856 TI - Step away from the troll pit. PMID- 30442858 TI - Setting achievable goals. PMID- 30442857 TI - Elaine Christine Hawkins. AB - A brave vet who threw her energy into dealing positively with everything that was placed in her way. PMID- 30442859 TI - Finding yoga helped me thrive as a vet. AB - Vet Chloe Hannigan works as a locum in the UK and abroad, and also teaches yoga to vet professionals, helping them care for their physical and mental health. PMID- 30442860 TI - Final-year student diary. AB - Vet student Rosie Perrett is doing rotations. Starting at Liverpool's small animal teaching hospital, she finds interacting with clients and their pets is the real deal. PMID- 30442862 TI - Does What Goes Around Always Come Around? PMID- 30442863 TI - Monoclonal Gammopathies and Kidney Disease: Searching for Significance. PMID- 30442864 TI - Home-Based Kidney Care, Patient Activation, and Risk Factors for CKD Progression in Zuni Indians: A Randomized, Controlled Clinical Trial. AB - BACKGROUND AND OBJECTIVES: The burden of CKD is greater in ethnic and racial minorities and persons living in rural communities, where access to care is limited. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 12-month clinical trial was performed in 98 rural adult Zuni Indians with CKD to examine the efficacy of a home-based kidney care program. Participants were randomized by household to receive usual care or home-based care. After initial lifestyle coaching, the intervention group received frequent additional reinforcement by community health representatives about adherence to medicines, diet and exercise, self-monitoring, and coping strategies for living with stress. The primary outcome was change in patient activation score, which assesses a participant's knowledge, skill, and confidence in managing his/her own health and health care. RESULTS: Of 125 randomized individuals (63 intervention and 62 usual care), 98 (78%; 50 intervention and 48 usual care) completed the 12-month study. The average patient activation score after 12 months was 8.7 (95% confidence interval, 1.9 to 15.5) points higher in the intervention group than in the usual care group after adjusting for baseline score using linear models with generalized estimating equations. Participants randomized to the intervention had 4.8 (95% confidence interval, 1.4 to 16.7) times the odds of having a final activation level of at least three ("taking action") than those in the usual care group. Body mass index declined by 1.1 kg/m2 (P=0.01), hemoglobin A1c declined by 0.7% (P=0.01), high sensitivity C-reactive protein declined by 3.3-fold (P<0.001), and the Short-Form 12 Health Survey mental score increased by five points (P=0.002) in the intervention group relative to usual care. CONCLUSIONS: A home-based intervention improves participants' activation in their own health and health care, and it may reduce risk factors for CKD in a rural disadvantaged population. PMID- 30442865 TI - Novel Models for Health Care Delivery for CKD for Disadvantaged Populations. PMID- 30442866 TI - Sleep Quality and Sleep Duration with CKD are Associated with Progression to ESKD. AB - BACKGROUND AND OBJECTIVES: Shorter or longer sleep duration and poor sleep quality are risk factors for numerous cardio-metabolic diseases, cardiovascular disease, and mortality in subjects with normal kidney function. The association of sleep duration and sleep quality with health outcomes in patients with CKD remains uncertain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A 4-year prospective cohort study in 17 nephrology centers in Japan, the CKD Japan Cohort (CKD-JAC) Study, assessed an association of self-reported sleep duration and sleep quality, on the basis of the Pittsburgh Sleep Quality Index (PSQI) questionnaire, with incidence of ESKD in 1601 patients with eGFR 10-59 ml/min per 1.73 m2 using multivariable-adjusted Cox proportional hazards models. RESULTS: Baseline sleep duration and PSQI global score for the 1601 patients were mean+/ SD 7.0+/-1.3 hours and median 4 (interquartile range, 3-7), respectively. Poor sleep quality (PSQI global score >=6) was common (n=588 [37%]). During a median of 4.0 (2.6-4.3) years of the follow-up period, 282 (18%) patients progressed to ESKD. After adjusting for age, sex, eGFR, urinary albumin excretion, smoking status, body mass index, history of diabetes and cardiovascular disease, systolic BP, blockade of the renin-angiotensin system, use of hypnotics, and Beck depression inventory score, both shorter (<=5 hour) and longer (>8 hour) sleep duration were associated with ESKD (adjusted hazard ratios [95% confidence intervals] for <=5.0, 5.1-6.0, 6.1-7.0, 7.1-8.0, and >=8.0 hours were 2.05 [1.31 to3.21], 0.98 [0.67 to 1.44], 1.00 [reference], 1.22 [0.89 to 1.66], and 1.48 [1.01 to 2.16]), suggesting a U-shaped relationship between sleep duration and ESKD. PSQI global score >=6 was also associated with incidence of ESKD (adjusted hazard ratios [95% confidence intervals] for PSQI global score <=5 and >=6 were 1.00 [reference] and 1.33 [1.03 to 1.71]). CONCLUSIONS: Shorter (<=5 hour) and longer (>8 hour) sleep duration and poor sleep quality (PSQI global score >=6) were associated with ESKD in patients with CKD. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2018_11_15_CJASNPodcast_18_12_.mp3. PMID- 30442867 TI - Association of Monoclonal Gammopathy with Progression to ESKD among US Veterans. AB - BACKGROUND AND OBJECTIVES: Whether patients with monoclonal protein are at a higher risk for progression of kidney disease is not known. The goal of this study was to measure the association of monoclonal protein with progression to ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective cohort study of 2,156,317 patients who underwent serum creatinine testing between October 1, 2000 and September 30, 2001 at a Department of Veterans Affairs medical center, among whom 21,898 had paraprotein testing within 1 year before or after cohort entry. Progression to ESKD was measured using linked data from the US Renal Data System. RESULTS: Overall, 1,741,707 cohort members had an eGFR>=60 ml/min per 1.73 m2, 283,988 had an eGFR of 45-59 ml/min per 1.73 m2, 103,123 had an eGFR of 30-44 ml/min per 1.73 m2 and 27,499 had an eGFR of 15-29 ml/min per 1.73 m2. The crude incidence of ESKD ranged from 0.7 to 80 per 1000 person-years from the highest to lowest eGFR category. Patients with low versus preserved eGFR were more likely to be tested for monoclonal protein but no more likely to have a positive test result. In adjusted analyses, a positive versus negative test result was associated with a higher risk of ESKD among patients with an eGFR>=60 ml/min per 1.73 m2 (hazard ratio, 1.67; 95% confidence interval, 1.22 to 2.29) and those with an eGFR of 15-29 ml/min per 1.73 m2 (hazard ratio, 1.38; 95% confidence interval, 1.07 to 1.77), but not among those with an eGFR of 30-59 ml/min per 1.73 m2 . Progression to ESKD was attributed to a monoclonal process in 21 out of 76 versus seven out of 174 patients with monoclonal protein and preserved versus severely reduced eGFR at cohort entry. CONCLUSIONS: The detection of monoclonal protein provides little information on ESKD risk for most patients with a low eGFR. Further study is required to better understand factors contributing to a positive association of monoclonal protein with ESKD risk in patients with preserved and severely reduced levels of eGFR. PMID- 30442869 TI - Home-Based Care for CKD for High-Risk Populations. PMID- 30442870 TI - Urotensin-II gene rs228648 polymorphism associated with the risk of diabetes mellitus. AB - Background : Urotensin-II(UII) rs228648 polymorphism has been reported to be associated with the risk of diabetes mellitus(DM) with inconsistent results. This study sought to reassess the relationship between this polymorphism and susceptibility to DM by meta-analysis. Methods : Relevant eligible studies and whole genome association study(GWAS) data electronically searched were pooled to evaluate the strength of the association with odds ratios (ORs) and 95% confidence intervals (CIs). Results : Seven case-control studies involving 894 cases and 1186 controls were finally included in the meta-analysis. Overall analyses indicated that UII gene rs228648 variant was significantly associated with reduced risk of DM (allele, A vs. G: OR=0.68, 95%CI=0.56-0.82; dominant, AA+GA vs. GG: OR=0.70, 95%CI=0.53- 0.91; homozygote, AA vs. GG: OR=0.41, 95%CI =0.28-0.61; recessive, AA vs. GA+GG: OR=0.36, 95%CI=0.19-0.71). In subgroup analyses based on ethnicity, the results showed a significant association of rs228648 polymorphism with decreased risk of DM in Chinese population under all five genetic models as well as in non-Chinese population under heterozygote and recessive models. Stratified analyses by specific type of DM also presented a significant association for common diabetes mellitus(CDM) under allele and homozygote as well as gestational diabetes mellitus(GDM) under all genetic models except for homozygote model. However, the synthetic analysis with GWAS data suggested an increased risk of DM with rs228648 effect allele in European population (OR=1.01, 95%CI=1.00-1.02). Conclusion : The present meta-analysis preliminarily suggested a potentially opposite role of rs228648 polymorphism associated with DM risk in the Chinese and European population. Further studies are in great request to verify the results. PMID- 30442868 TI - Adrenocorticotropic Hormone for Childhood Nephrotic Syndrome: The ATLANTIS Randomized Trial. AB - BACKGROUND AND OBJECTIVES: There is renewed interest in adrenocorticotropic hormone (ACTH) for the treatment of nephrotic syndrome. We evaluated the efficacy and safety of ACTH in children with frequently relapsing or steroid-dependent nephrotic syndrome in a randomized trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants aged 2-20 years old with frequently relapsing or steroid-dependent nephrotic syndrome were enrolled from 16 sites in the United States and randomized 1:1 to ACTH (repository corticotropin injection) or no relapse-preventing treatment. ACTH treatment regimen was 80 U/1.73 m2 administered twice weekly for 6 months, followed by 40 U/1.73 m2 administered twice weekly for 6 months. The primary outcome was disease relapse during the first 6 months. Participants in the control group were offered crossover to ACTH treatment if they relapsed within 6 months. Secondary outcomes were relapse after ACTH dose reduction and treatment side effects. RESULTS: The trial was stopped at a preplanned interim analysis after enrollment of 31 participants because of a lack of discernible treatment efficacy. Fourteen out of 15 (93%) participants in the ACTH arm experienced disease relapse in the first 6 months, with a median time to first relapse of 23 days (interquartile range, 9-32), compared with 15 out of 16 (94%) participants and at a median of 21 days (interquartile range, 14 51) in the control group. There was no difference in the proportion of relapsed patients (odds ratio, 0.93; 95% confidence interval, 0.05 to 16.40; P>0.99) or time to first relapse (hazard ratio, 1.03; 95% confidence interval, 0.50 to 2.15; P=0.93). Thirteen out of 16 participants in the control group crossed over to ACTH treatment. Three out of 28 participants completed 12 months of ACTH treatment; the others exited the trial because of frequent relapses or side effects. There were no disease relapses after ACTH dose reduction among the three participants. Most side effects were mild and similar to side effects of corticosteroids. CONCLUSIONS: ACTH at 80 U/1.73 m2 administered twice weekly was ineffective at preventing disease relapses in pediatric nephrotic syndrome. PMID- 30442871 TI - Study of expression analysis of SIRT4 and the coordinate regulation of bovine adipocyte differentiation by SIRT4 and its transcription factors. AB - Sirtuins, NAD+-dependent deacylases and ADP-ribosyltransferases, are critical regulators of metabolism involved in many biological processes, and are involved in mediating adaptive responses to the cellular environment. SIRT4 is a mitochondrial sirtuin and has been shown to play a critical role in maintaining insulin secretion and glucose homeostasis. As a regulator of lipid homeostasis, SIRT4 can repress fatty acid oxidation and promote lipid anabolism in nutrient replete conditions. Using real-time quantitative PCR (qPCR) to explore the molecular mechanisms of transcriptional regulation of bovine SIRT4 during adipocyte differentiation, we found that bovine SIRT4 is expressed at high levels in bovine subcutaneous adipose tissue. SIRT4 knockdown led to decreased expression of adipogenic differentiation marker genes during adipocyte differentiation. The core promoter of bovine SIRT4 was identified in the -402/-60 bp region of the cloned 2-kb fragment containing the 5'-regulatory region. Binding sites were identified in this region for E2F transcription factor-1 (E2F1), CCAAT/enhancer-binding protein beta (CEBPbeta), homeobox A5 (HOXA5), interferon regulatory factor 4 (IRF4), paired box 4 (PAX4), and cAMP responsive element-binding protein 1 (CREB1) by using Electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. We also found that E2F1, CEBPbeta, and HOXA5 transcriptionally activate SIRT4 expression, whereas, IRF4, PAX4, and CREB1 transcriptionally repress SIRT4 expression. We further verified that SIRT4 knockdown could affect the ability of these transcription factors to regulate the differentiation of bovine adipocytes. In conclusion, our results shed light on the mechanisms underlying the transcriptional regulation of SIRT4 expression in bovine adipocytes. PMID- 30442872 TI - Molecular Mechanism by Which Apis cerana cerana MKK6 ( AccMKK6 )-Mediated MAPK Cascades Regulate the Oxidative Stress Response. AB - Mitogen-activated protein kinase kinases (MKKs) are important components of the MAPK signaling pathways, which play a key role in responding to stress and inflammatory stimuli. Here, a new MKK gene, AccMKK6 , was identified and functionally analyzed in A. cerana cerana Real-time quantitative PCR (qPCR) and western blot analysis demonstrated that the AccMKK6 expression level was upregulated by several environmental stresses. Moreover, the knockdown of AccMKK6 by RNA interference technology altered the expression levels of some antioxidant genes. In addition, the knockdown of AccMKK6 resulted in increased malonyldialdehyde (MDA) concentration and decreased antioxidant-related enzymes activity in honeybees. To explore the MAPK signaling pathways involved in AccMKK6 , we identified the transcription factor kayak in A. cerana cerana We analyzed the interactions of AccMKK6, Accp38b and Acckayak using the yeast two-hybrid system. AccMKK6 and Acckayak showed similar expression profiles after several stress treatments. In addition, the expression level of Acckayak was significantly increased when AccMKK6 was silenced. Therefore, we speculate that AccMKK6 may be involved in the MAPK cascades, which play a crucial role in counteracting oxidative stress caused by external stimuli. PMID- 30442873 TI - Anti-tumoral potential of MDA19 in human osteosarcoma via suppressing PI3K/Akt/mTOR signaling pathway. AB - Osteosarcoma (OS) is the most common primary malignancy of skeleton with higher mortality rates among children and young adults worldwide, whereas effective and secure therapies have also been sought by researches with ongoing efforts. The purpose of this study was to investigate the impact of MDA19 on OS and explore its potential mechanism. Cell Counting Kit-8 (CCK8) and colony formation assay were employed to evaluate the potential effect of MDA19 on U2OS and MG-63 cells proliferation. Moreover, transwell migration and invasion assay were performed to assess the influence of MDA19 on U2OS and MG-63 cells migration and invasion. In addition, Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V FITC/PI) staining and flow cytometry were used to examine apoptotic ratio of the U2OS and MG-63 cells. Meanwhile, western blot analysis was applied to explore change of relevant mechanism proteins in OS cells treated with MDA19. Our study showed that MDA19 had anti-proliferative activity of OS cells in a dose-dependent and time-dependent manner, simultaneously, inhibition of colony formation was also observed in U2OS and MG-63 cells after incubation of MDA19. Besides, MDA19 could significantly inhibit the number of migrated and invaded OS cells and markedly increase the OS cells apoptosis rate. Mechanistically, we detected detectable reductions of apoptosis related proteins, (epithelial-mesenchymal transition) EMT related proteins and activity of phosphatidylinositol 3 kinase(PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling in U2OS and MG 63 cells exposure to MDA19. Overall, the current study indicates in vitro anti proliferative, anti-metastatic and pro-apoptotic potential of MDA19 in U2OS and MG-63 cells. PMID- 30442874 TI - miR-384 induces apoptosis and autophagy of non-small cell lung cancer(NSCLC) cells through the negative regulation of Collagen alpha-1(X) chain(COL10A1) gene. AB - This study aims to investigate the mechanism of miR-384 in NSCLC cell apoptosis and autophagy by regulating COL10A1. Bioinformatics methods were applied to evaluate potential miRNAs and genes that might correlate with NSCLC. Tumor and adjacent tissues from 104 NSCLC patients were collected and human NSCLC A549 cell line was selected for subsequent experiments. A549 cells were treated with miR 384 mimic, miR-384 inhibitor or knockdown of COL10A1. Quantitative real-time polymerase chain reaction(qRT-PCR) and western blotting were utilized to detect the levels of miR-384, COL10A, Survivin, Bcl-2, Bax, Bcl-xl, Beclin 1 and LC3 in tissues and cells. A series of biological assays including 3-(4,5) dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide(MTT), Annexin V FITC(fluoresceine isothiocyanate)/PI(propidium iodide) staining, immunofluorescence, monodansylcadaverine(MDC) staining were conducted to investigate the effects of miR-384 and COL10A1 on NSCLC cells. Tumorigenicity assay for nude rats was applied. Results obtained from this study indicated that miR-384 down-regulated COL10A1 by targeting it. Compared to adjacent tissues, miR 384 expression was obviously reduced while COL10A1 expression was significantly enhanced in NSCLC tissues (all P < 0.05). Outcomes in vivo and vitro suggested cell proliferation and tumorigenicity were inhibited while cell apoptosis and autophagy were induced in NSCLC cells treated with up-regulation of miR-384 or silence of COL10A1. In miR-384 inhibitor group, cell proliferation was improved while cell apoptosis was reduced and cell autophagy was decreased while tumorigenicity of cells was strengthened. Based on the findings of our study it was established that miR-384 could down-regulate COL10A1 levels, subsequently inhibiting cell proliferation and promoting cell apoptosis and autophagy in NSCLC cells. PMID- 30442875 TI - Intellectual Disability in Children Conceived Using Assisted Reproductive Technology. AB - OBJECTIVES: To examine whether children conceived using assisted reproductive technology (ART) have a higher risk of intellectual disability (ID) compared with non-ART-conceived children and describe known causes of ID in these groups. METHODS: We linked ID and ART data from population-based registers in Western Australia. Our cohort included live births from 1994 to 2002 (n = 210 627) with at least 8 years of follow-up. The prevalence of ID was compared between ART- and non-ART-conceived children, and risk of ID was estimated using Poisson regression with robust SEs. We also stratified by plurality and gestation at delivery. RESULTS: Children conceived using ART had a small increased risk of ID (risk ratio 1.58; 95% confidence interval 1.19-2.11) even when analyses were restricted to singleton births (risk ratio 1.56; 95% confidence interval 1.10-2.21). The risk of ID was more than doubled for those born very preterm, for severe ID, and after intracytoplasmic sperm injection (ICSI) treatments. Children conceived using ICSI had a greater risk of ID than those conceived using in vitro fertilization and were more likely to have a known genetic cause for ID (27.6% vs 12.9% in vitro fertilization and 11.9% non-ART). CONCLUSIONS: The risk of ID was increased in children born after ART in Western Australia from 1994 to 2002. More recent cohorts should be examined to assess the impact of important changes in ART clinical practice. Our results are particularly pertinent because multiple embryo transfers are routinely performed in many countries, increasing the risk of preterm birth, and ICSI use rates are high. PMID- 30442876 TI - Assisted Reproductive Technology and Developmental Outcomes. PMID- 30442877 TI - Vascular inflammation in aging. PMID- 30442878 TI - Glucose negatively affects Nrf2/SKN-1-mediated innate immunity in C. elegans. AB - High glucose levels negatively affect immune response. However, the underlying mechanisms are not well understood. Upon infection, the round worm C. elegans induces multiple gene transcription programs, including the Nrf2/SKN-1-mediated detoxification program, to activate the innate immunity. In this study, we find that high glucose conditions inhibit the SKN-1-mediated immune response to Salmonella typhimurium, exacerbate the infection and greatly decrease survival. The effect of glucose shows specificity to SKN-1 pathway, as UPRmit and UPRER that are known to be induced by infection, are not affected. Hyper-activation of SKN-1 by wdr-23 RNAi restores partly the immune response and increases the survival rate in response to S. typhimurium. In all, our study reveals a molecular pathway responsible for glucose's negative effect on innate immunity, which could help to better understand diseases associated with hyperglycemia. PMID- 30442879 TI - Carney Syndrome Presented as a Pathological Spine Fracture in a 35-Year-Old Male. AB - BACKGROUND Carney complex (CNC) is a genetic disorder that presents as an adrenocorticotropic hormone (ACTH)-independent variant of endogenous Cushing syndrome. It was first reported in 1985 and was described as a form of multiple endocrine hyperplasia associated with mutations of the c-AMP-dependent protein kinase (PRKAR1A) gene that causes bilateral adrenal hyperplasia. We report a case of an incidentally found CNC in a 35-year-old male, and this case report focuses on the diagnostic scheme as well as the surgical treatment of this rare challenging condition. CASE REPORT A-35-year-old male presented with pathological thoracic spine fracture. The patient exhibited obesity, facial flushing, red purplish streaks on the abdominal wall, multiple pigmented nevi of the trunk, and hypertension. Family history was positive for cardiac myxoma. Laboratory investigation showed ACTH-independent Cushing syndrome. Abdominal magnetic resonance imaging and computed tomography scan showed bilateral adrenal hyperplasia. The ensuing Liddle test revealed the characteristic paradox increase of 24-hours urine cortisol for CNC. After a bilateral retroperitoneoscopic adrenalectomy, histologic examination confirmed the presence of bilateral primary pigmented nodular adrenocortical disease (PPNAD). Genetic testing revealed a unique mutation of the responsible PRKAR1A gene. CONCLUSIONS CNC presence was suspected due to the family history. Its characteristic pathologic manifestation called PPNAD, clinically presents as an ACTH-independent Cushing syndrome with paradoxical positive response of urinary glucocorticosteroid excretion after dexamethasone administration (Liddle's test). Bilateral retroperitoneoscopic adrenalectomy constitutes an acceptable surgical option for PPNAD. PMID- 30442880 TI - Relationship Between Fat Mass and Obesity-Associated (FTO) Gene Polymorphisms with Obesity and Metabolic Syndrome in Ethnic Mongolians. AB - BACKGROUND The distribution of fat mass and obesity-associated gene (FTO) genes rs9939609 and rs1421085 in obese and normal ethnic Mongolians was analyzed to investigate the association of FTO gene polymorphisms with obesity and metabolic syndrome in ethnic Mongolians. MATERIAL AND METHODS The genotypes of FTO genes rs9939609 and rs1421085 in 500 subjects were detected by allele-specific PCR (AS PCR). General characteristics and clinical biochemical indicators were compared between the obesity group and the control group. The correlation between different genotypes and obesity metabolic index was also analyzed. RESULTS Body mass, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR), SBP, DBP, FPG, triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) were higher, while HDL-C was lower in the obesity group compared with controls. The frequencies of TT genotype and T allele in the obesity group were higher than those in the control group. The frequencies of these 3 genotypes and allele frequencies of Rs1421085 were comparable between the 2 groups (P>0.05). The risk of obesity in Mongolian individuals carrying rs9939609 AT genotype was 1.312 times higher and the risk in those carrying AA genotype was 1.896 times higher than in individuals with TT genotype. The body weight, BMI, WC, HC, and WHR in individuals with rs9939609 AA and AT genotypes were significantly higher than in those with TT genotype. CONCLUSIONS The AT/AA genotype and allele A of rs9939609 are associated with an increased risk of obesity. PMID- 30442881 TI - Results of Adult Living Donor Liver Transplantation with Sixth-Decade Donors: A Propensity Score Matching Study in a High-Volume Institution. AB - BACKGROUND We assessed the prognostic impact of donor age on the outcome of adult living donor liver transplantation (LDLT). MATERIAL AND METHODS The study population comprised adult donor and recipients of right lobe grafts for LDLT performed from January 2005 to December 2016. There were 35 living donors aged >=50 years (old-age donor group). As a control group, donors in their 20s (young age donor group) were selected after one-to-one propensity score matching based on sex, model for end-stage liver disease (MELD) score, and primary diagnosis. RESULTS Donor age was 52.5+/-1.5 years versus 25.4+/-3.1 years in the old- and young-age donor groups, respectively. Remnant volumes of the 2 groups were 38.9+/ 3.0% versus 38.1+/-2.9%, respectively (p=0.98). One-month regeneration rate of the remnant liver was 101.1+/-10.6% versus 104.5+/-11.8%, respectively (p=0.08), and there was no significant difference in the incidences of donor complications. Mean MELD score was 15 versus 14, respectively (p=0.82). Graft-to-recipient weight ratio was 1.02+/-0.43 versus 0.91+/-0.63, respectively (p=0.28). In the recipients, biliary complication occurred in 11.4% versus 8.6%, respectively (p=0.12), and there was no difference in 5-year survival rates of both groups (p=0.15). The 1-week and 1-month regeneration rates of the remnant left liver were 71.6+/-9.9% and 100.1+/-10.6% in the old-age group, respectively, whereas those were 80.2+/-12.1% and 104.5+/-11.8% in the young-age group, respectively (p=0.08). CONCLUSIONS Right lobe grafts from donors aged >=50 years showed the usual recovery of graft function but rather delayed liver regeneration. Thus, old aged donors should be selected prudently after consideration of hepatic resection rate, graft size, and hepatic steatosis. PMID- 30442882 TI - [Implementing a population-based rare diseases registry in Spain: the Navarre's experience]. AB - In 2012, the Spanish Rare Disease Registries Research Network (Spain-RDR) was consolidated with the aim of creating a Spanish population-based Rare Diseases Registry. In order to achieve this, each of the 17 Spanish Regions had to develop its own regional registry with a common agreed methodology. The Population-based Rare Disease Registry of Navarre was created in 2013 and, since then, its implementation is been carried out. Navarre assumed the agreed list within the Spanish Network, which included 934 codes of the International Classification of Diseases, 9th Revision, Clinical Modification. Initially, the main data source used to capture cases was the Assisted Morbidity Registry of Navarre, which includes the Minimum Basic Data Set of every regional hospital discharges (both public and private). Afterwards, new data sources were been added and ongoing validation studies of captured cases were been developed. Population-based rare diseases registries are fundamental for the study and quantification of this type of diseases since the classification and coding systems used in the current healthcare information systems are very nonspecific. The analysis and cross referencing of data among multiple data sources is essential to maximize case detection capacity. Due to the low prevalence of these diseases, a high false positives rate among the detected cases greatly affects the estimation of epidemiological indicators, which makes it necessary to validate the cases by verifying the diagnoses. PMID- 30442883 TI - Polymorphism of serotonin transporter gene in male subjects with antisocial behavior and MMA fighters. AB - In our study, the frequencies of serotonin transporter gene (5-HTT) polymorphisms and their combinations are compared in the healthy male subjects with antisocial behavior, in general, and in those with its particular forms, as well as in the reference group of MMA fighters. Subjects convicted of unlawful actions were classified into those convicted of violent crimes or non-violent ones. The group of subjects convicted of violent crimes was further subdivided into those convicted of murder, or robbery, or of inflicting grave body injuries. The group of MMA fighters was selected from the subjects without a prior history of antisocial behavior or criminal record in the subjects or their relatives. The frequency of D allele in the groups of convicted subjects and MMA fighters was higher, than in the population sample. Furthermore, the frequencies of D/D and 12/12 genotype combinations were shown to be higher in the group of convicted subjects, especially, in habitual criminals and those convicted of grave crimes or murder. The predisposition of MMA fighters to violent behavior and physical aggressive suppression of an opponent is successfully implemented in their professional career; however, this behavioral pattern appears to represent the controlled aggression. PMID- 30442884 TI - Long noncoding RNA AC003092.1 promotes temozolomide chemosensitivity through miR 195/TFPI-2 signaling modulation in glioblastoma. AB - Temozolomide (TMZ) and radiation therapy combination for glioblastoma (GB) patients has been considered as the most effective therapy after surgical procedure. However, the overall clinical prognosis remains unsatisfactory due to intrinsic or developing resistance to TMZ. Recently, increasing evidence suggested that long noncoding RNAs (lncRNAs) play a critical role in various biological processes of tumors, and have been implicated in resistance to various drugs. However, the role of lncRNAs in TMZ resistance is poorly understood. Here, we found that the expression of lncRNA AC003092.1 was markedly decreased in TMZ resistance (TR) of GB cells (U87TR and U251TR) compared with their parental cells (U87 and U251). In patients with glioma, low levels of lncRNA AC003092.1 were correlated with increased TMZ resistance, higher risk of relapse, and poor prognosis. Overexpression of lncRNA AC003092.1 enhances TMZ sensitivity, facilitates cell apoptosis, and inhibits cell proliferation in TMZ-resistant GB cells. In addition, we identified that lncRNA AC003092.1 regulates TMZ chemosensitivity through TFPI-2-mediated cell apoptosis in vitro and in vivo. Mechanistically, further investigation revealed that lncRNA AC003092.1 regulates TFPI-2 expression through miR-195 in GB. Taken together, these data suggest that lncRNA AC003092.1 could inhibit the function of miR-195 by acting as an endogenous CeRNA, leading to increased expression of TFPI-2; this promotes TMZ induced apoptosis, thereby making GB cells more sensitive to TMZ. Our findings indicate that overexpression of lncRNA AC003092.1 may be a potential therapy to overcome TMZ resistance in GB patients. PMID- 30442886 TI - Valley coherent exciton-polaritons in a monolayer semiconductor. AB - Two-dimensional transition metal dichalcogenides (TMDs) provide a unique possibility to generate and read-out excitonic valley coherence using linearly polarized light, opening the way to valley information transfer between distant systems. However, these excitons have short lifetimes (ps) and efficiently lose their valley coherence via the electron-hole exchange interaction. Here, we show that control of these processes can be gained by embedding a monolayer of WSe2 in an optical microcavity, forming part-light-part-matter exciton-polaritons. We demonstrate optical initialization of valley coherent polariton populations, exhibiting luminescence with a linear polarization degree up to 3 times higher than displayed by bare excitons. We utilize an external magnetic field alongside selective exciton-cavity-mode detuning to control the polariton valley pseudospin vector rotation, which reaches 45 degrees at B = 8 T. This work provides unique insight into the decoherence mechanisms in TMDs and demonstrates the potential for engineering the valley pseudospin dynamics in monolayer semiconductors embedded in photonic structures. PMID- 30442885 TI - Proteolysis of histidine kinase VgrS inhibits its autophosphorylation and promotes osmostress resistance in Xanthomonas campestris. AB - In bacterial cells, histidine kinases (HKs) are receptors that monitor environmental and intracellular stimuli. HKs and their cognate response regulators constitute two-component signalling systems (TCSs) that modulate cellular homeostasis through reversible protein phosphorylation. Here the authors show that the plant pathogen Xanthomonas campestris pv. campestris responds to osmostress conditions by regulating the activity of a HK (VgrS) via irreversible, proteolytic modification. This regulation is mediated by a periplasmic, PDZ domain-containing protease (Prc) that cleaves the N-terminal sensor region of VgrS. Cleavage of VgrS inhibits its autokinase activity and regulates the ability of the cognate response regulator (VgrR) to bind promoters of downstream genes, thus promoting bacterial adaptation to osmostress. PMID- 30442887 TI - Correspondence: Osteonecrosis in childhood acute lymphoblastic leukemia: a retrospective cohort study of the Italian Association of Pediatric Haemato Oncology (AIEOP). PMID- 30442888 TI - Author Correction: Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity. AB - The original version of this Article omitted the middle initial of the author Jesse E. Hanson. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30442889 TI - Organic field-effect optical waveguides. AB - Integrating electronics and photonics is critically important for the realization of high-density and high-speed optoelectronic circuits. However, it remains challenging to achieve this target due to the difficulty of merging many different areas of science and technology. Here, we show an organic integrated optoelectronic device, namely, organic field-effect optical waveguide, integrating field-effect transistor and optical waveguide together. In such device, the propagation of optical waveguide in the active organic semiconductor can be tuned by the third terminal-the gate electrode of transistor, giving a controllable modulation depth as high as 70% and 50% in parallel and perpendicular directions of charge transport versus optical waveguide, respectively. Also, the optical waveguide with different directions can turn the field-effect of the device with the photodependence ratio up to 14800. The successful integration of active field-effect transistor with semiconductor waveguide modulator expands opportunities for creating scalable integration of electronics and photonics in a chip. PMID- 30442890 TI - Photoreduction of gaseous oxidized mercury changes global atmospheric mercury speciation, transport and deposition. AB - Anthropogenic mercury (Hg(0)) emissions oxidize to gaseous Hg(II) compounds, before deposition to Earth surface ecosystems. Atmospheric reduction of Hg(II) competes with deposition, thereby modifying the magnitude and pattern of Hg deposition. Global Hg models have postulated that Hg(II) reduction in the atmosphere occurs through aqueous-phase photoreduction that may take place in clouds. Here we report that experimental rainfall Hg(II) photoreduction rates are much slower than modelled rates. We compute absorption cross sections of Hg(II) compounds and show that fast gas-phase Hg(II) photolysis can dominate atmospheric mercury reduction and lead to a substantial increase in the modelled, global atmospheric Hg lifetime by a factor two. Models with Hg(II) photolysis show enhanced Hg(0) deposition to land, which may prolong recovery of aquatic ecosystems long after Hg emissions are lowered, due to the longer residence time of Hg in soils compared with the ocean. Fast Hg(II) photolysis substantially changes atmospheric Hg dynamics and requires further assessment at regional and local scales. PMID- 30442891 TI - Non-equilibrium Model for Nanofluid Free Convection Inside a Porous Cavity Considering Lorentz Forces. AB - In current article, transportation of CuO nanoparticles through a porous enclosure is demonstrated. The enclosure has complex shaped hot wall. Porous media has been simulated via two temperature equations. Magnetic force impact on nanofluid treatment was considered. Control volume based finite element method has been described to solve current article in vorticity stream function form. Single phase model was chosen for nanofluid. Nanofluid characteristics are predicted via KKL model. Roles of solid-nanofluid interface heat transfer parameter (Nhs), porosity, Hartmann and Rayleigh numbers have been illustrated. Outputs illustrated that conduction mode reduces with augment of Ra. Increasing magnetic forces make nanofluid motion to decrease. Temperature gradient of nanofluid decreases with augment of Nhs. Reducing porosity leads to enhance in Nusselt number. PMID- 30442892 TI - Pathogenesis and genetic characteristics of novel reassortant low-pathogenic avian influenza H7 viruses isolated from migratory birds in the Republic of Korea in the winter of 2016-2017. AB - In this study, we characterized H7 subtype low-pathogenicity (LP) influenza A viruses (IAVs) isolated from wild bird habitats in the Republic of Korea from 2010 to early 2017. Through national surveillance, 104 H7 IAVs were isolated, accounting for an average of 14.9% of annual IAV isolations. In early 2017, H7 subtypes accounted for an unusually high prevalence (43.6%) of IAV detections in wild birds. Phylogenetic analysis revealed that all the viruses isolated in the winter of 2016-2017 fell within cluster II of group C, belonging to the Eurasian lineage of H7 IAVs. Notably, cluster II of group C included the H7 gene from the highly pathogenic H7N7 IAV that was detected in northeastern Italy in April of 2016. Through a gene-constellation analysis, the H7 LPIAVs that we isolated constituted >=11 distinct genotypes. Because the viruses belonging to the genotypes G2.1 and G1 were observed most frequently, we compared the replication and transmission of representative viruses to these genotypes in specific pathogen-free chickens. Notably, the representative G2.1 strain was capable of systemic replication and efficient transmission in chickens (as evidenced by virus isolation and histopathological examination) without any clinical signs except mortality (in one infected chicken). The efficient subclinical viral replication and shedding of the G2.1 virus in chickens may facilitate its silent spread among poultry after introduction. Given that wild birds harbor novel strains that could affect poultry, our results highlight the need for enhanced IAV surveillance in both wild birds and poultry in Eurasia. PMID- 30442893 TI - Role of flow of information in the speedup of quantum evolution. AB - Quantum evolution can be accelerated in a non-Markovian environment. Previous results show that the formation of a system-environment bound state governs the quantum speedup. Although a stronger bound state in the system-environment spectrum may seem like it should cause greater speed of evolution, this seemingly intuitive thinking may not always be correct. We illustrate this by investigating a classical-driven qubit interacting with a photonic crystal waveguide in the presence of a mirror, resulting in non-Markovian dynamics for the system. Within the considered model, we show the influence of the mirror and the classical field on the evolution speed of the system. In particular, we find that the formation of a bound state is not the essential reason for the acceleration of evolution. The quantum speedup is attributed to the flow of information, regardless of the direction in which the information flows. Our conclusion can also be used in other non-Markovian environments. PMID- 30442894 TI - Wide-range tuning of interfacial exchange coupling between ferromagnetic Au/Co and ferrimagnetic Tb/Fe(Co) multilayers. AB - The ability to perform wide-range tuning of the magnetic field required to switch the magnetization of ferromagnetic layers with perpendicular magnetic anisotropy is of great importance for many applications. We show that, for (Au/Co)2(3) multilayers, this field can be changed from minus several kOe to plus several kOe because of changes to the coupling with a ferrimagnetic multilayer [either (Tb/Fe)6 or (Tb/Co)6] across a Au spacer (either homogeneous 1 nm thick or wedge shaped). The adjustable parameters are the ratio of sublayer thicknesses of the ferrimagnet and the sequence of layers around the Au spacer. The change of the sequence from Co/Au/Co to Tb/Au/Co is accompanied by both the reduction of the interaction energy and the change of the magnetic field sign necessary to switch the magnetization of ferromagnetic multilayers. For a 1 nm thick Au spacer this fields change from positive (negative) to negative (positive) if the ferrimagnet is dominated by the transition metal (rare earth) as a result of its composition. The characteristic oscillatory behavior of RKKY-like coupling is demonstrated using a system with a wedge-shaped Au spacer. PMID- 30442896 TI - Ultrafast air bonding between SiC ceramic and SnAgTi alloy under the action of ultrasounds. AB - With the aim of overcoming the limitations of traditional soldering ceramic methods for power device packaging, a simple but ultrafast bonding technology is reported. The effect and mechanism of ultrasonic action on the interfacial bonding and microstructure is investigated and thoroughly discussed. An ultrafast interfacial bond between SiC ceramics and SnAgTi active solder has been successfully achieved through a reaction at the interface at a low temperature of 250 degrees C in the extremely short time. High-resolution transmission electron microscopy (HRTEM) revealed that a silica layer on the surface of SiC reacted with Ti from the SnAgTi active solder to form a nanometer-thickness amorphous titania layer at the interface under the ultrasonic action, which creates an exceptional interfacial structure and facilitates bonding between the two dissimilar crystals. A discontinuous titania layer at the interface was identified within 0.1 s. With further increasing ultrasonic action time to 1 s, a continuous titania layer with a thickness of 7.6 +/- 0.5 nm formed at the interface. A new interfacial reaction mechanism was revealed and it was found that ultrasound accelerated the reaction of liquid active solder/ceramic. Our finding demonstrated that ultrasound could be an effective approach for joining ceramics which is difficult to wet by a liquid metal at low temperature. The combined impact of ultrasonic cavitation and streaming dominated the mechanism and kinetics of the rapid interfacial reaction. PMID- 30442895 TI - Bayes-Like Integration of a New Sensory Skill with Vision. AB - Humans are effective at dealing with noisy, probabilistic information in familiar settings. One hallmark of this is Bayesian Cue Combination: combining multiple noisy estimates to increase precision beyond the best single estimate, taking into account their reliabilities. Here we show that adults also combine a novel audio cue to distance, akin to human echolocation, with a visual cue. Following two hours of training, subjects were more precise given both cues together versus the best single cue. This persisted when we changed the novel cue's auditory frequency. Reliability changes also led to a re-weighting of cues without feedback, showing that they learned something more flexible than a rote decision rule for specific stimuli. The main findings replicated with a vibrotactile cue. These results show that the mature sensory apparatus can learn to flexibly integrate new sensory skills. The findings are unexpected considering previous empirical results and current models of multisensory learning. PMID- 30442897 TI - Molecular modelling of mitofusin 2 for a prediction for Charcot-Marie-Tooth 2A clinical severity. AB - Charcot-Marie-Tooth disease type 2A (CMT2A) is an autosomal dominant neuropathy caused by mutations in the mitofusin 2 gene (MFN2). More than 100 MFN2 gene mutations have been reported so far, with majority located within the GTPase domain encoding region. These domain-specific mutations present wide range of symptoms with differences associated with distinct amino acid substitutions in the same position. Due to the lack of conclusive phenotype-genotype correlation the predictive value of genetic results remains still limited. We have explored whether changes in the protein structure caused by MFN2 mutations can help to explain diseases phenotypes. Using a stable protein model, we evaluated the effect of 26 substitutions on the MFN2 structure and predicted the molecular consequences of such alterations. The observed changes were correlated with clinical features associated with a given mutation. Of all tested mutations positive correlation of molecular modelling with the clinical features reached 73%. Our analysis revealed that molecular modelling of mitofusin 2 mutations is a powerful tool, which predicts associated pathogenic impacts and that these correlate with clinical outcomes. This approach may aid an early diagnosis and prediction of symptoms severity in CMT2A patients. PMID- 30442898 TI - Functional traits of a native and an invasive clam of the genus Ruditapes occurring in sympatry in a coastal lagoon. AB - The main objective of this study was to evaluate the functional traits regarding bioturbation activity and its influence in the nutrient cycling of the native clam species Ruditapes decussatus and the invasive species Ruditapes philippinarum in Ria de Aveiro lagoon. Presently, these species live in sympatry and the impact of the invasive species was evaluated under controlled microcosmos setting, through combined/manipulated ratios of both species, including monospecific scenarios and a control without bivalves. Bioturbation intensity was measured by maximum, median and mean mix depth of particle redistribution, as well as by Surface Boundary Roughness (SBR), using time-lapse fluorescent sediment profile imaging (f-SPI) analysis, through the use of luminophores. Water nutrient concentrations (NH4-N, NOx-N and PO4-P) were also evaluated. This study showed that there were no significant differences in the maximum, median and mean mix depth of particle redistribution, SBR and water nutrient concentrations between the different ratios of clam species tested. Significant differences were only recorded between the control treatment (no bivalves) and those with bivalves. Thus, according to the present work, in a scenario of potential replacement of the native species by the invasive species, no significant differences are anticipated in short- and long-term regarding the tested functional traits. PMID- 30442900 TI - Smallest known raptor tracks suggest microraptorine activity in lakeshore setting. AB - Ongoing studies of a multiple track-bearing horizons from massive excavations in the Jinju Formation (Lower Cretaceous) of South Korea have yielded a remarkable diversity of avian, non-avian dinosaur, pterosaur, crocodilian and mammal tracks, many very small and well preserved. Here we report diminutive, didactyl tracks (~1.0 cm long) assigned to a new dromaeosaurid ichnogenus Dromaeosauriformipes, which resembles the larger, but still quite small, ichnogenus Dromaeosauripus, also from the same formation only 30 km away. These diminutive tracks are consistent with the foot size of smaller dromaeosaurid taxa like Early Cretaceous Microraptor from China, and may represent diminutive species or juveniles of larger species. The association of tracks with lakeshore sediments is consistent with the evidence that Microraptor was a fish eater. Two trackways and isolated tracks indicate variable trackmaker gaits and speeds. If oviparous, as assumed for most non-avian dinosaur neonates, the trackmakers must have hatched from tiny eggs. Previous studies of the Korean Cretaceous indicate the presence of other diminutive (~1.0 cm long) theropod tracks (Minisauripus). Such occurrences strongly suggest that small tracks attributed to juveniles, or very small tetrapod species, are more common than previously supposed especially where suitable preservation conditions prevailed. PMID- 30442899 TI - Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptor. AB - Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 A away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design. PMID- 30442901 TI - Pseudomonas aeruginosa mutants defective in glucose uptake have pleiotropic phenotype and altered virulence in non-mammal infection models. AB - Pseudomonas spp. are endowed with a complex pathway for glucose uptake that relies on multiple transporters. In this work we report the construction and characterization of Pseudomonas aeruginosa single and multiple mutants with unmarked deletions of genes encoding outer membrane (OM) and inner membrane (IM) proteins involved in glucose uptake. We found that a triple DeltagltKGF DeltagntP DeltakguT mutant lacking all known IM transporters (named GUN for Glucose Uptake Null) is unable to grow on glucose as unique carbon source. More than 500 genes controlling both metabolic functions and virulence traits show differential expression in GUN relative to the parental strain. Consistent with transcriptomic data, the GUN mutant displays a pleiotropic phenotype. Notably, the genome-wide transcriptional profile and most phenotypic traits differ between the GUN mutant and the wild type strain irrespective of the presence of glucose, suggesting that the investigated genes may have additional roles besides glucose transport. Finally, mutants carrying single or multiple deletions in the glucose uptake genes showed attenuated virulence relative to the wild type strain in Galleria mellonella, but not in Caenorhabditis elegans infection model, supporting the notion that metabolic functions may deeply impact P. aeruginosa adaptation to specific environments found inside the host. PMID- 30442902 TI - Pre-existing Symptoms and Healthcare Utilization Prior to Diagnosis of Neuroendocrine Tumors: A SEER-Medicare Database Study. AB - The incidence and prevalence of neuroendocrine tumors (NETs) are continually increasing. While it is known that NET symptoms often predate diagnosis, their prevalence and impact on resource utilization and costs are largely unknown. We identified 9,319 elderly patients diagnosed with NETs between 1/2003 and 12/2011 from the Surveillance, Epidemiology and End Results (SEER)-Medicare. We examined the patients' conditions potentially associated with NET, resource utilization and costs during the year before diagnosis. We found that NET patients were more likely to have diagnoses of hypertension (63.8% vs. 53.3%), abdominal pain (22.2% vs. 7.6%), heart failure (11.7% vs. 8.0%), diarrhea (5.8% vs. 1.8%), peripheral edema (5.4% vs. 3.8%) and irritable bowel syndrome (1.2% vs. 0.5%) compared to the non-cancer control group. They also had much higher resource utilization including number of outpatient visits (mean: 22.1 vs. 17.2), percentage with ER visits (20.9% vs. 11.6%), and hospitalizations (28.4% vs. 17.0%). Similarly, NET patients incurred significantly higher total (mean: $14602 vs. $9464), outpatient (mean: $5987 vs. $4253), and inpatient costs (mean: $8615 vs. $5211). This first population-based study on the pre-diagnosis symptoms and healthcare utilization found that NET patients were more likely to have certain conditions and incur higher resource utilizations and costs. PMID- 30442904 TI - Author Correction: Hypnotic analgesia reduces brain responses to pain seen in others. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442903 TI - Association between aromatase in human brains and personality traits. AB - Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer's disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using 11C cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of 11C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both. PMID- 30442905 TI - Author Correction: Extraordinarily potent proinflammatory properties of lactoferrin-containing immunocomplexes against human monocytes and macrophages. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442907 TI - Selective colonization ability of human fecal microbes in different mouse gut environments. AB - Mammalian hosts constantly interact with diverse exogenous microbes, but only a subset of the microbes manage to colonize due to selective colonization resistance exerted by host genetic factors as well as the native microbiota of the host. An important question in microbial ecology and medical science is if such colonization resistance can discriminate closely related microbial species, or even closely related strains of the same species. Using human-mouse fecal microbiota transplantation and metagenomic shotgun sequencing, we reconstructed colonization patterns of human fecal microbes in mice with different genotypes (C57BL6/J vs. NSG) and with or without an intact gut microbiota. We found that mouse genotypes and the native mouse gut microbiota both exerted different selective pressures on exogenous colonizers: human fecal Bacteroides successfully established in the mice gut, however, different species of Bacteroides selectively enriched under different gut conditions, potentially due to a multitude of functional differences, ranging from versatility in nutrient acquisition to stress responses. Additionally, different clades of Bacteroides cellulosilyticus strains were selectively enriched in different gut conditions, suggesting that the fitness of conspecific microbial strains in a novel host environment could differ. PMID- 30442906 TI - Synergistic effect of surface phosphorylation and micro-roughness on enhanced osseointegration ability of poly(ether ether ketone) in the rabbit tibia. AB - This study was aimed to investigate the osseointegration ability of poly(ether ether ketone) (PEEK) implants with modified surface roughness and/or surface chemistry. The roughened surface was prepared by a sandblast method, and the phosphate groups on the substrates were modified by a two-step chemical reaction. The in vitro osteogenic activity of rat mesenchymal stem cells (MSCs) on the developed substrates was assessed by measuring cell proliferation, alkaline phosphatase activity, osteocalcin expression, and bone-like nodule formation. Surface roughening alone did not improve MSC responses. However, phosphorylation of smooth substrates increased cell responses, which were further elevated in combination with surface roughening. Moreover, in a rabbit tibia implantation model, this combined surface modification significantly enhanced the bone-to implant contact ratio and corresponding bone-to-implant bonding strength at 4 and 8 weeks post-implantation, whereas modification of surface roughness or surface chemistry alone did not. This study demonstrates that combination of surface roughness and chemical modification on PEEK significantly promotes cell responses and osseointegration ability in a synergistic manner both in vitro and in vivo. Therefore, this is a simple and promising technique for improving the poor osseointegration ability of PEEK-based orthopedic/dental implants. PMID- 30442909 TI - Mycobiome diversity: high-throughput sequencing and identification of fungi. AB - Fungi are major ecological players in both terrestrial and aquatic environments by cycling organic matter and channelling nutrients across trophic levels. High throughput sequencing (HTS) studies of fungal communities are redrawing the map of the fungal kingdom by hinting at its enormous - and largely uncharted - taxonomic and functional diversity. However, HTS approaches come with a range of pitfalls and potential biases, cautioning against unwary application and interpretation of HTS technologies and results. In this Review, we provide an overview and practical recommendations for aspects of HTS studies ranging from sampling and laboratory practices to data processing and analysis. We also discuss upcoming trends and techniques in the field and summarize recent and noteworthy results from HTS studies targeting fungal communities and guilds. Our Review highlights the need for reproducibility and public data availability in the study of fungal communities. If the associated challenges and conceptual barriers are overcome, HTS offers immense possibilities in mycology and elsewhere. PMID- 30442908 TI - Androgen induced cellular proliferation, neurogenesis, and generation of GnRH3 neurons in the brain of mature female Mozambique tilapia. AB - The neuroplastic mechanisms in the fish brain that underlie sex reversal remain unknown. Gonadotropin-releasing hormone 3 (GnRH3) neurons control male reproductive behaviours in Mozambique tilapia and show sexual dimorphism, with males having a greater number of GnRH3 neurons. Treatment with androgens such as 11-ketotestosterone (KT), but not 17beta-estradiol, increases the number of GnRH3 neurons in mature females to a level similar to that observed in mature males. Compared with oestrogen, the effect of androgen on neurogenesis remains less clear. The present study examined the effects of 11-KT, a non-aromatizable androgen, on cellular proliferation, neurogenesis, generation of GnRH3 neurons and expression of cell cycle-related genes in mature females. The number of proliferating cell nuclear antigen-positive cells was increased by 11-KT. Simultaneous injection of bromodeoxyuridine and 11-KT significantly increased the number of newly-generated (newly-proliferated) neurons, but did not affect radial glial cells, and also resulted in newly-generated GnRH3 neurons. Transcriptome analysis showed that 11-KT modulates the expression of genes related to the cell cycle process. These findings suggest that tilapia could serve as a good animal model to elucidate the effects of androgen on adult neurogenesis and the mechanisms for sex reversal in the fish brain. PMID- 30442910 TI - Well-timed toxin export. PMID- 30442911 TI - Defense sequestration associated with narrowing of diet and ontogenetic change to aposematic colours in the spotted lanternfly. AB - Bright colours in distasteful prey warn off predators, but processes associated with ontogenetic acquisition of warning colours and distasteful compounds have been studied in only a few organisms. Here, we study spotted lanternflies (Lycorma delicatula; Fulgoridae) that change to red colouration when they narrow their host plant preferences to primarily the tree of heaven (Ailanthus altissima; Simaroubaceae), which is chemically defended by quassinoids. In experiments, we showed that birds taste-avoided lanternflies collected on Ailanthus but not those collected on the secondary hosts. Birds also taste avoided seeds infused with ailanthone, the main quassinoid sequestered from Ailanthus by lanternflies as shown through mass spectrometry analyses. Hence, the narrowing of host preferences by lanternflies synchronizes the timing of change to red colour with the acquisition of quassinoid defenses. A schematic graphical population-level model of these processes is provided. This is the first report of quassinoid sequestration by insects and the first evidence that Simaroubaceae plants provide defensive chemicals to insects. This is the first report of a fulgoroid insect sequestering identified chemical defenses. The results highlight the importance of the pan-tropical taxon Fulgoridae for evolutionary biology of complex aposematic strategies and for understanding the links between timing of defense sequestration, timing of host plant preference shifts, and timing of colour change. PMID- 30442912 TI - Changes in bursal B cells in chicken during embryonic development and early life after hatching. AB - The bursa of Fabricius, the primary lymphoid organ for B cell development found only in birds, offers novel approaches to study B cell differentiation at various developmental stages. Here, we explored the changes and mechanism involved in the developmental stages of bursal B cells. The bursal B cells rapidly increased in the late embryonic stage and around hatching, which coincided with changes in specific cell surface markers. Moreover, the cells in the bursa were divided by size into small (low forward- and side-scatter) or large (high forward- and side scatter) via flow cytometry. It is intriguing that the proportion of small and large B cells was reversed during this period. Because little is known about this phenomenon, we hypothesized that size-based B cell population could be used as an indicator to distinguish their status and stage during B cell development in chicken. The results demonstrated that large B cells are actively proliferating cells than small B cells. Additionally, large B cells showed higher mRNA expression of both proliferation- and differentiation-associated genes compared to small B cells. Taken together, these data show that large bursal B cells are the main source of proliferation and differentiation during B cell development in chickens. PMID- 30442913 TI - Expression profiling of lncRNAs and mRNAs reveals regulation of muscle growth in the Pacific abalone, Haliotis discus hannai. AB - Long non-coding RNAs (lncRNAs) are known to play a major role in the epigenetic regulation of muscle development. Unfortunately there is little understanding of the mechanisms with which they regulate muscle growth in abalone. Therefore, we used RNA-seq to study the muscle transcriptomes of six Haliotis discus hannai specimens: three large (L_HD group) and three small (S_HD group). We identified 2463 lncRNAs in abalone muscle belonging to two subtypes: 160 anti-sense lncRNAs and 2303 intergenic lncRNAs (lincRNAs). In the L_HD group, we identified 204 significantly differentially expressed lncRNAs (55 upregulated and 149 downregulated), and 2268 significantly differentially expressed mRNAs (994 upregulated and 1274 downregulated), as compared to the S_HD group. The bioinformatics analysis indicated that lncRNAs were relate to cell growth, regulation of growth, MAPK signaling pathway, TGF-beta signaling pathway, PI3K Akt and insulin signaling pathway, which involved in regulating muscle growth. These findings contribute to understanding the possible regulatory mechanisms of muscle growth in Pacific abalone. PMID- 30442914 TI - Electron waiting times in hybrid junctions with topological superconductors. AB - We investigate the waiting time distributions (WTDs) of superconducting hybrid junctions, considering both conventional and topologically nontrivial superconductors hosting Majorana bound states at their edges. To this end, we employ a scattering matrix formalism that allows us to evaluate the waiting times between the transmissions and reflections of electrons or holes. Specifically, we analyze normal-metal-superconductor (NIS) junctions and NISIN junctions, where Cooper pairs are spatially split into different leads. The distribution of waiting times is sensitive to the simultaneous reflection of electrons and holes, which is enhanced by the zero-energy state in topological superconductors. For the NISIN junctions, the WTDs of trivial superconductors feature a sharp dependence on the applied voltage, while for topological ones they are mostly independent of it. This particular voltage dependence is again connected to the presence of topological edge states, showing that WTDs are a promising tool for identifying topological superconductivity. PMID- 30442916 TI - Martian magmatism from plume metasomatized mantle. AB - Direct analysis of the composition of Mars is possible through delivery of meteorites to Earth. Martian meteorites include ~165 to 2400 Ma shergottites, originating from depleted to enriched mantle sources, and ~1340 Ma nakhlites and chassignites, formed by low degree partial melting of a depleted mantle source. To date, no unified model has been proposed to explain the petrogenesis of these distinct rock types, despite their importance for understanding the formation and evolution of Mars. Here we report a coherent geochemical dataset for shergottites, nakhlites and chassignites revealing fundamental differences in sources. Shergottites have lower Nb/Y at a given Zr/Y than nakhlites or chassignites, a relationship nearly identical to terrestrial Hawaiian main shield and rejuvenated volcanism. Nakhlite and chassignite compositions are consistent with melting of hydrated and metasomatized depleted mantle lithosphere, whereas shergottite melts originate from deep mantle sources. Generation of martian magmas can be explained by temporally distinct melting episodes within and below dynamically supported and variably metasomatized lithosphere, by long-lived, static mantle plumes. PMID- 30442915 TI - Developmental induction of human T-cell responses against Candida albicans and Aspergillus fumigatus. AB - The origin of human T-cell responses against fungal pathogens early in life is not clearly understood. Here, we show that antifungal T-cell responses are vigorously initiated within the first years of life against lysates and peptides of Candida albicans or Aspergillus fumigatus, presented by autologous monocytes. The neonatal responding T-cell pool consists of 20 different TCR-Vbeta families, whereas infant and adult pools display dramatically less variability. Although we demonstrate no bias for anti-fungal IL-4 expression early in life, there was a strong bias for anti-fungal IL-17 production. Of note, only T-cells from neonates and infants show an immediate co-expression of multiple cytokines. In addition, only their T-cells co-express simultaneously transcription factors T-bet and RORgammat in response to fungi and subsequently their target genes IL-17 and IFNgamma. Thus, T-cells of neonates and infants are predetermined to respond quickly with high plasticity to fungal pathogens, which might give an excellent opportunity for therapeutic interventions. PMID- 30442917 TI - Cerebrospinal Fluid Levels of Autophagy-related Proteins Represent Potentially Novel Biomarkers of Early-Stage Parkinson's Disease. AB - The roles of autophagy-related proteins as diagnostic or monitoring biomarkers in Parkinson's disease (PD) have not been clearly elucidated. We recruited 32 patients with early-stage PD and 28 control subjects, and evaluated parkinsonian motor symptoms and dopamine transporter imaging data. Cerebrospinal fluid (CSF) levels of LC3B, Beclin1, and LAMP-2 were estimated using ELISAs, and CSF levels of ATG5, ATG7, and p62 were examined by immunoblotting. Additionally, we also assessed the levels of alpha-synuclein, total tau, and phosphorylated tau in CSF using ELISAs. Significant differences in the levels of LC3B, LAMP-2, and Beclin1 were observed between the PD and control groups. Using 29.8 pg/mL as the cut-off value for a diagnostic biomarker of PD, CSF LC3B levels exhibited high sensitivity (96.9%) and specificity (89.3%) with an area under the curve of 0.982. Furthermore, LC3B was significantly correlated with the asymmetry index in the caudate and putamen, as estimated by a semi-quantitative analysis of [18F] N (3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) positron emission tomography (PET). CSF levels of LC3B represented a potential diagnostic and prognostic biomarker of early-stage PD in patients. Based on our findings, molecular biological changes in PD are associated with dysregulation of the lysosomal autophagy pathway. PMID- 30442918 TI - A Rabbit Corneal Endothelial Dysfunction Model Using Endothelial-Mesenchymal Transformed Cells. AB - Unlike humans, rabbit corneal endothelial wounds are known to spontaneously heal. The current study was aimed to develop a new rabbit bullous keratopathy model using corneal endothelial cells that were induced to undergo endothelial mesenchymal transformation (EMT). EMT was induced in rabbit corneal endothelial cells (RCECs) by culturing with TGFbeta and basic FGF Supplemented Medium. The corneal endothelia in recipient rabbits were mechanically scraped from the corneal endothelial surface inside an 8 mm mark. Then, a suspension of EMT induced RCECs (EMT-RCECs) was injected into the anterior chamber. Eyes injected with freshly isolated RCECs (Fresh RCECs group) and eyes that were scraped without injection of cells (Scrape group) were used as controls. Immediately following operation, subepithelial and stromal edema was observed with increased central corneal thickness and corneal opacity in all groups. In the EMT-RCECs group, bullous keratopathy persisted for 42 days up to the end of the study. In the Fresh-RCECs and Scrape groups, corneal transparency and thickness recovered by 7 days after treatment and was maintained up to 42 days. The activated fibroblast marker, alpha-SMA, was observed spanning from corneal endothelium to corneal stroma in the EMT-RCECs group. Interestingly, alpha-SMA was upregulated in the Scrape-group as well. In all groups, there was no damage to other intraocular structures, and intraocular pressure was normal throughout the observation period. Transplanting a fresh donor cornea effectively treated corneal edema due to bullous keratopathy. This model is a promising tool for pre clinical trials in the development of new therapies against corneal endothelial dysfunction. PMID- 30442919 TI - Interspecific formation of the antimicrobial volatile schleiferon. AB - Microorganisms release a plethora of volatile secondary metabolites. Up to now, it has been widely accepted that these volatile organic compounds are produced and emitted as a final product by a single organism e.g. a bacterial cell. We questioned this commonly assumed perspective and hypothesized that in diversely colonized microbial communities, bacterial cells can passively interact by emitting precursors which non-enzymatically react to form the active final compound. This hypothesis was inspired by the discovery of the bacterial metabolite schleiferon A. This bactericidal volatile compound is formed by a non enzymatic reaction between acetoin and 2-phenylethylamine. Both precursors are released by Staphylococcus schleiferi cells. In order to provide evidence for our hypothesis that these precursors could also be released by bacterial cells of different species, we simultaneously but separately cultivated Serratia plymuthica 4Rx13 and Staphylococcus delphini 20771 which held responsible for only one precursor necessary for schleiferon A formation, respectively. By mixing their headspace, we demonstrated that these two species were able to deliver the active principle schleiferon A. Such a joint formation of a volatile secondary metabolite by different bacterial species has not been described yet. This highlights a new aspect of interpreting multispecies interactions in microbial communities as not only direct interactions between species might determine and influence the dynamics of the community. Events outside the cell could lead to the appearance of new compounds which could possess new community shaping properties. PMID- 30442920 TI - Liver-specific Repin1 deficiency impairs transient hepatic steatosis in liver regeneration. AB - Transient hepatic steatosis upon liver resection supposes functional relationships between lipid metabolism and liver regeneration. Repin1 has been suggested as candidate gene for obesity and dyslipidemia by regulating key genes of lipid metabolism and lipid storage. Herein, we characterized the regenerative potential of mice with a hepatic deletion of Repin1 (LRep1-/-) after partial hepatectomy (PH) in order to determine the functional significance of Repin1 in liver regeneration. Lipid dynamics and the regenerative response were analyzed at various time points after PH. Hepatic Repin1 deficiency causes a significantly decreased transient hepatic lipid accumulation. Defects in lipid uptake, as analyzed by decreased expression of the fatty acid transporter Cd36 and Fatp5, may contribute to attenuated and shifted lipid accumulation, accompanied by altered extent and chronological sequence of liver cell proliferation in LRep1-/- mice. In vitro steatosis experiments with primary hepatocytes also revealed attenuated lipid accumulation and occurrence of smaller lipid droplets in Repin1 deficient cells, while no direct effect on proliferation in HepG2 cells was observed. Based on these results, we propose that hepatocellular Repin1 might be of functional significance for early accumulation of lipids in hepatocytes after PH, facilitating efficient progression of liver regeneration. PMID- 30442921 TI - Identification of genetic variants associated with tacrolimus metabolism in kidney transplant recipients by extreme phenotype sampling and next generation sequencing. AB - An extreme phenotype sampling (EPS) model with targeted next-generation sequencing (NGS) identified genetic variants associated with tacrolimus (Tac) metabolism in subjects from the Deterioration of Kidney Allograft Function (DeKAF) Genomics cohort which included 1,442 European Americans (EA) and 345 African Americans (AA). This study included 48 subjects separated into 4 groups of 12 (AA high, AA low, EA high, EA low). Groups were selected by the extreme phenotype of dose-normalized Tac trough concentrations after adjusting for common genetic variants and clinical factors. NGS spanned > 3 Mb of 28 genes and identified 18,661 genetic variants (3961 previously unknown). A group of 125 deleterious variants, by SIFT analysis, were associated with Tac troughs in EAs (burden test, p = 0.008), CYB5R2 was associated with Tac troughs in AAs (SKAT, p = 0.00079). In CYB5R2, rs61733057 (increased allele frequency in AAs) was predicted to disrupt protein function by SIFT and PolyPhen2 analysis. The variants merit further validation. PMID- 30442922 TI - Author Correction: Impaired perceptual learning in a mouse model of Fragile X syndrome is mediated by parvalbumin neuron dysfunction and is reversible. AB - The original and corrected Acknowledgements are shown in the accompanying Author Correction. PMID- 30442923 TI - Cytoplasmic Pin1 expression is increased in human cutaneous melanoma and predicts poor prognosis. AB - The prolyl isomerase Pin1 is widely over-expressed or over-activated in cancers and promotes tumorigenesis. The authors investigated the expression level of Pin1 and analyzed the prognostic value of Pin1 expression using a large-scale melanoma tissue microarray study. Two independent sets of tissue microarrays were employed, including 114 melanoma cases in the discovery set and 424 in the validation set (538 cases in total), 32 normal nevi and 86 dysplastic nevi 118 cases of nevi. The subcellular Pin1 expression in different stages of melanocytic lesions and its prognostic significance were studied. High expression (IRS 0-8) of cytoplasmic Pin1 was observed in 3.13%, 8.33%, 16.49% and 22.76% of the biopsies in normal nevi, dysplastic nevi, primary melanoma and metastatic melanoma, respectively. Significant differences for cytoplasmic Pin1 staining were observed between normal nevi and metastatic melanoma (P = 0.011, chi2 test), between dysplastic nevi and primary melanoma (P = 0.046, chi2 test) and between dysplastic nevi and metastatic melanoma (P = 0.016, chi2 test). Kaplan-Meier survival analysis showed that increased cytoplasmic Pin1 expression was associated with a worse 5-year melanoma-specific survival of melanoma (P < 0.001) and metastatic melanoma patients (P = 0.004). Multivariate Cox regression analysis showed that cytoplasmic Pin1 expression is an independent prognostic factor in melanoma. Our data indicate that cytoplasmic Pin1 plays an important role in melanoma pathogenesis and progression, and serve as a potential prognostic marker for melanoma. PMID- 30442924 TI - Author Correction: Neuroimmune disorders of the central nervous system in children in the molecular era. AB - In the original version of this Review published online and in print, the contribution of attendees of the International Neuroimmune Meeting to the content of the Review was not acknowledged. The author list has been corrected in the PDF and HTML versions of this article to acknowledge that the Review was written on behalf of attendees of the International Neuroimmune Meeting, and the names of the attendees have been added to the HTML version. PMID- 30442925 TI - Prevention of radiation-induced bystander effects by agents that inactivate cell free chromatin released from irradiated dying cells. AB - Radiation-induced bystander effect (RIBE) is a poorly understood phenomenon wherein non-targeted cells exhibit effects of radiation. We have reported that cell-free chromatin (cfCh) particles that are released from dying cells can integrate into genomes of surrounding healthy cells to induce DNA damage and inflammation. This raised the possibility that RIBE might be induced by cfCh released from irradiated dying cells. When conditioned media from BrdU-labeled irradiated cells were passed through filters of pore size 0.22 um and incubated with unexposed cells, BrdU-labeled cfCh particles could be seen to readily enter their nuclei to activate H2AX, active Caspase-3, NFkappaB, and IL-6. A direct relationship was observed with respect to activation of RIBE biomarkers and radiation dose in the range of 0.1-0 Gy. We confirmed by FISH and cytogenetic analysis that cfCh had stably integrated into chromosomes of bystander cells and had led to extensive chromosomal instability. The above RIBE effects could be abrogated when conditioned media were pre-treated with agents that inactivate cfCh, namely, anti-histone antibody complexed nanoparticles (CNPs), DNase I and a novel DNA degrading agent Resveratrol-copper (R-Cu). Lower hemi-body irradiation with gamma-rays (0.1-50 Gy) led to activation of H2AX, active Caspase-3, NFkappaB, and IL-6 in brain cells in a dose-dependent manner. Activation of these RIBE biomarkers could be abrogated by concurrent treatment with CNPs, DNase I and R-Cu indicating that activation of RIBE was not due to radiation scatter to the brain. RIBE activation was seen even when mini-beam radiation was delivered to the umbilical region of mice wherein radiation scatter to brain was negligible and could be abrogated by cfCh inactivating agents. These results indicate that cfCh released from radiation-induced dying cells are activators of RIBE and that it can be prevented by treatment with appropriate cfCh inactivating agents. PMID- 30442926 TI - Soy-Induced Fecal Metabolome Changes in Ovariectomized and Intact Female Rats: Relationship with Cardiometabolic Health. AB - Phytoestrogens are plant-derived compounds found in a variety of foods, most notably, soy. These compounds have been shown to improve immuno-metabolic health, yet mechanisms remain uncertain. We demonstrated previously that dietary phytoestrogen-rich soy (SOY) rescued metabolic dysfunction/inflammation following ovariectomy (OVX) in female rats; we also noted remarkable shifts in gut microbiota in SOY vs control diet-fed rats. Importantly, specific bacteria that significantly increased in those fed the SOY correlated positively with several favorable host metabolic parameters. One mechanism by which gut microbes might lead to such host effects is through production of bacterial metabolites. To test this possibility, we utilized non-targeted gas chromatography-mass spectrometry (GCMS) to assess the fecal metabolome in those previously studied animals. Partial least square discriminant analysis (PLSDA) revealed clear separation of fecal metabolomes based on diet and ovarian state. In particular, SOY-fed animals had greater fecal concentrations of the beneficial bacterial metabolite, S-equol, which was positively associated with several of the bacteria upregulated in the SOY group. S-equol was inversely correlated with important indicators of metabolic dysfunction and inflammation, suggesting that this metabolite might be a key mediator between SOY and gut microbiome-positive host health outcomes. PMID- 30442927 TI - c-Jun N-terminal kinases differentially regulate TNF- and TLRs-mediated necroptosis through their kinase-dependent and -independent activities. AB - Tumor necrosis factor (TNF) and Toll-like receptor (TLR)3/TLR4 activation trigger necroptotic cell death through downstream signaling complex containing receptor interacting protein kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase-domain-like (MLKL). However, the regulation of necroptotic signaling pathway is far less investigated. Here we showed that c-Jun N-terminal kinases (JNK1 and JNK2) displayed kinase-dependent and -independent functions in regulating TNF- and TLRs-mediated necroptosis. We found that RIPK1 and RIPK3 promoted cell-death-independent JNK activation in macrophages, which contributed to pro-inflammatory cytokines production. Meanwhile, blocking the kinase activity of JNK dramatically reduced TNF and TLRs-induced necroptotic cell death. Consistently, inhibition of JNK activity protected mice from TNF-induced death and Staphylococcus aureus-mediated lung damage. However, depletion of JNK protein using siRNA sensitized macrophages to necroptosis that was triggered by LPS or poly I:C but still inhibited TNF-induced necroptosis. Mechanistic studies revealed that RIPK1 recruited JNK to the necrosome complex and their kinase activity was required for necrosome formation and the phosphorylation of MLKL in TNF- and TLRs-induced necroptosis. Loss of JNK protein consistently suppressed the phosphorylation of MLKL and necrosome formation in TNF-triggered necroptosis, but differentially promoted the phosphorylation of MLKL and necrosome formation in poly I:C-triggered necroptosis by promoting the oligomeration of TRIF. In conclusion, our findings define a differential role for JNK in regulating TNF- and TLRs-mediated necroptosis by their kinase or scaffolding activities. PMID- 30442928 TI - Revised diagnostic criteria for plasma cell leukemia: results of a Mayo Clinic study with comparison of outcomes to multiple myeloma. AB - The current definition of plasma cell leukemia (PCL)- >= 20% circulating plasma cells (CPCs) on peripheral smear and plasma cell count >= 2 * 109/L-may be too stringent. We reviewed outcomes of 176 multiple myeloma (MM) patients diagnosed between 1971 and 2016, and who had CPCs detectable at diagnosis, to determine whether a lower threshold could be used to diagnose PCL. Median overall survival (mOS) was 1.1 years (95% CI 0.8-1.4) and was similar between patients with < 5% (n = 54, mOS = 1.4 years [0.7-2.0]), 5-19% (n = 63, mOS = 1.1 years [0.7-1.4]), and >= 20% CPCs (n = 59, mOS = 1.1 years [0.7-1.5], p = 0.349). As survival was similar between those with 5-19% and >= 20% CPCs, we stratified patients by < 5% (mOS = 1.4 years [0.7-2.0]) and >= 5% CPCs (mOS = 1.1 years [0.8-1.4], p = 0.154). Outcomes of those with >= 5% CPCs were much poorer when compared with a cohort of MM patients diagnosed between 1971 and 2016, who did not have CPCs at diagnosis (n = 9724, mOS = 4.4 yrs [4.3-4.5], p < 0.001); survival was also lower in patients diagnosed after 2001 with >= 5% CPCs (n = 62, mOS = 1.4 years [0.8 2.5]) compared with patients with standard risk (n = 1326, mOS = 7.5 years [7.0 8.7]) and high-risk MM (n = 381, mOS = 4.3 years [3.5-4.9], p < 0.001). We therefore propose that the definition of PCL be revised to patients with >= 5% CPCs on peripheral blood smear, who otherwise meet diagnostic criteria for MM. PMID- 30442930 TI - A 5'-BODIPY End-label for Monitoring DNA Duplex-Quadruplex Exchange. AB - Fluorescent probes that can distinguish different DNA topologies through changes in optical readout are sought after for DNA-based diagnostics. In this work, the 4,4-difluoro-4-bora-3a, 4a-diaza-s-indacene (BODIPY) chromophore attached to cyanophenyl substituents (BODIPY-CN) has been tethered to the 5'-end of the 15 mer thrombin binding aptamer (TBA) that contains the guanine (G) nucleobase. TBA folds into a unimolecular antiparallel G-quadruplex (GQ) upon binding thrombin and certain metal ions. The 5'-BODIPY-CN-TBA sample possesses a Stokes shift of ~40 nm with wavelengths of excitation/emission at 550/590 nm and exhibits a 2 fold increase in emission intensity compared to the free BODIPY-CN in aqueous buffer that possesses a brightness (epsilonPhifl) of ~16,956 M-1. cm-1. However, when 5'-BODIPY-CN-TBA is base-paired to a complementary strand in the B-form duplex, the emission of the BODIPY-CN end-label increases 7-fold, 14-fold compared to the free-dye. This signal-on response enables the BODIPY-CN end-label to serve as a quencher-free fluorescent probe for monitoring duplex-GQ exchange. The visible end-label minimally perturbs GQ stability and thrombin binding affinity, and the modified TBA can act as a combinatorial logic circuit having INHIBIT logic functions. These attributes make BODIPY-CN a highly useful end label for creating nanomolecular devices derived from G-rich oligonucleotides. PMID- 30442929 TI - A conserved enhancer regulates Il9 expression in multiple lineages. AB - Cytokine genes are regulated by multiple regulatory elements that confer tissue specific and activation-dependent expression. The cis-regulatory elements of the gene encoding IL-9, a cytokine that promotes allergy, autoimmune inflammation and tumor immunity, have not been defined. Here we identify an enhancer (CNS-25) upstream of the Il9 gene that binds most transcription factors (TFs) that promote Il9 gene expression. Deletion of the enhancer in the mouse germline alters transcription factor binding to the remaining Il9 regulatory elements, and results in diminished IL-9 production in multiple cell types including Th9 cells, and attenuates IL-9-dependent immune responses. Moreover, deletion of the homologous enhancer (CNS-18) in primary human Th9 cultures results in significant decrease of IL-9 production. Thus, Il9 CNS-25/IL9 CNS-18 is a critical and conserved regulatory element for IL-9 production. PMID- 30442932 TI - Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. AB - CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis. PMID- 30442931 TI - Developmental dynamics of butterfly wings: real-time in vivo whole-wing imaging of twelve butterfly species. AB - Colour pattern development of butterfly wings has been studied from several different approaches. However, developmental changes in the pupal wing tissues have rarely been documented visually. In this study, we recorded real-time developmental changes of the pupal whole wings of 9 nymphalid, 2 lycaenid, and 1 pierid species in vivo, from immediately after pupation to eclosion, using the forewing-lift method. The developmental period was roughly divided into four sequential stages. At the very early stage, the wing tissue was transparent, but at the second stage, it became semi-transparent and showed dynamic peripheral adjustment and slow low-frequency contractions. At this stage, the wing peripheral portion diminished in size, but simultaneously, the ventral epithelium expanded in size. Likely because of scale growth, the wing tissue became deeply whitish at the second and third stages, followed by pigment deposition and structural colour expression at the fourth stage. Some red or yellow (light colour) areas that emerged early were "overpainted" by expanding black areas, suggesting the coexistence of two morphogenic signals in some scale cells. The discal spot emerged first in some nymphalid species, as though it organised the entire development of colour patterns. These results indicated the dynamic wing developmental processes common in butterflies. PMID- 30442933 TI - Reply to 'Flawed assumptions compromise water yield assessment'. PMID- 30442934 TI - Targeting fidelity of adenine and cytosine base editors in mouse embryos. AB - Base editing directly converts a target base pair into a different base pair in the genome of living cells without introducing double-stranded DNA breaks. While cytosine base editors (CBE) and adenine base editors (ABE) are used to install and correct point mutations in a wide range of organisms, the extent and distribution of off-target edits in mammalian embryos have not been studied in detail. We analyze on-target and proximal off-target editing at 13 loci by a variety of CBEs and ABE in more than 430 alleles generated from mouse zygotic injections using newly generated and published sequencing data. ABE predominantly generates anticipated A*T-to-G*C edits. Among CBEs, SaBE3 and BE4, result in the highest frequencies of anticipated C*G-to-T*A products relative to editing byproducts. Together, these findings highlight the remarkable fidelity of ABE in mouse embryos and identify preferred CBE variants when fidelity in vivo is critical. PMID- 30442935 TI - Parity transitions in the superconducting ground state of hybrid InSb-Al Coulomb islands. AB - The number of electrons in small metallic or semiconducting islands is quantised. When tunnelling is enabled via opaque barriers this number can change by an integer. In superconductors the addition is in units of two electron charges (2e), reflecting that the Cooper pair condensate must have an even parity. This ground state (GS) is foundational for all superconducting qubit devices. Here, we study a hybrid superconducting-semiconducting island and find three typical GS evolutions in a parallel magnetic field: a robust 2e-periodic even-parity GS, a transition to a 2e-periodic odd-parity GS, and a transition from a 2e- to a 1e periodic GS. The 2e-periodic odd-parity GS persistent in gate-voltage occurs when a spin-resolved subgap state crosses zero energy. For our 1e-periodic GSs we explicitly show the origin being a single zero-energy state gapped from the continuum, i.e., compatible with an Andreev bound states stabilized at zero energy or the presence of Majorana zero modes. PMID- 30442937 TI - Bronchiectasis. PMID- 30442936 TI - Si and Ge based metallic core/shell nanowires for nano-electronic device applications. AB - One dimensional heterostructure nanowires (NWs) have attracted a large attention due to the possibility of easily tuning their energy gap, a useful property for application to next generation electronic devices. In this work, we propose new core/shell NW systems where Ge and Si shells are built around very thin As and Sb cores. The modification in the electronic properties arises due to the induced compressive strain experienced by the metal core region which is attributed to the lattice-mismatch with the shell region. As/Ge and As/Si nanowires undergo a semiconducting-to-metal transition on increasing the diameter of the shell. The current-voltage (I-V) characteristics of the nanowires show a negative differential conductance (NDC) effect for small diameters that could lead to their application in atomic scale device(s) for fast switching. In addition, an ohmic behavior and upto 300% increment of the current value is achieved on just doubling the shell region. The resistivity of nanowires decreases with the increase in diameter. These characteristics make these NWs suitable candidates for application as electron connectors in nanoelectronic devices. PMID- 30442938 TI - ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit. PMID- 30442939 TI - SEPROGADIC - serum protein-based gastric cancer prediction model for prognosis and selection of proper adjuvant therapy. AB - Gastric cancer (GC) patients usually receive surgical treatment. Postoperative therapeutic options such as anticancer adjuvant therapies (AT) based on prognostic prediction models would provide patient-specific treatment to decrease postsurgical morbidity and mortality rates. Relevant prognostic factors in resected GC patient's serum may improve therapeutic measures in a non-invasive manner. In order to develop a GC prognostic model, we designed a retrospective study. In this study, serum samples were collected from 227 patients at a 4-week recovery period after D2 lymph node dissection, and 103 cancer-related serum proteins were analyzed by multiple reaction monitoring mass spectrometry. Using the quantitative values of the serum proteins, we developed SEPROGADIC (SErum PROtein-based GAstric cancer preDICtor) prognostic model consisting of 6 to 14 serum proteins depending on detailed purposes of the model, prognosis prediction and proper AT selection. SEPROGADIC could clearly classify patients with good or bad prognosis at each TNM stage (1b, 2, 3 and 4) and identify a patient subgroup who would benefit from CCRT (combined chemoradiation therapy) rather than CTX (chemotherapy), or vice versa. Our study demonstrated that serum proteins could serve as prognostic factors along with clinical stage information in patients with resected gastric cancer, thus allowing patient-tailored postsurgical treatment. PMID- 30442940 TI - Metastable silica high pressure polymorphs as structural proxies of deep Earth silicate melts. AB - Modelling of processes involving deep Earth liquids requires information on their structures and compression mechanisms. However, knowledge of the local structures of silicates and silica (SiO2) melts at deep mantle conditions and of their densification mechanisms is still limited. Here we report the synthesis and characterization of metastable high-pressure silica phases, coesite-IV and coesite-V, using in situ single-crystal X-ray diffraction and ab initio simulations. Their crystal structures are drastically different from any previously considered models, but explain well features of pair-distribution functions of highly densified silica glass and molten basalt at high pressure. Built of four, five-, and six-coordinated silicon, coesite-IV and coesite-V contain SiO6 octahedra, which, at odds with 3rd Pauling's rule, are connected through common faces. Our results suggest that possible silicate liquids in Earth's lower mantle may have complex structures making them more compressible than previously supposed. PMID- 30442941 TI - PLOD3 promotes lung metastasis via regulation of STAT3. AB - Procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD3), a membrane-bound homodimeric enzyme, hydroxylates lysyl residues in collagen-like peptides; however, its role in lung cancer is unknown. This study aimed to investigate the role of PLOD3 as a pro-metastatic factor and to elucidate the underlying mechanism. First, we experimentally confirmed the release of PLOD3 in circulation in animal models, rendering it a potential serum biomarker for lung cancer in humans. Thereafter, we investigated the effects of PLOD3 overexpression and downregulation on cancer cell invasion and migration in vitro and in vivo, using human lung cancer cell lines and a mouse tumor xenograft model, respectively. Further, PLOD3 levels were determined in lung tissue samples from lung cancer patients. Functional analyses revealed that PLOD3 interacts with STAT3, thereby expressing matrix metalloproteinases (MMP-2 and MMP-9) and with urokinase plasminogen activator (uPA) to enhance tumor metastasis. PLOD3 and the STAT3 pathway were significantly correlated in the metastatic foci of lung cancer patients; PLOD3-STAT3 levels were highly correlated with a poor prognosis. These results indicate that PLOD3 promotes lung cancer metastasis in a RAS-MAP kinase pathway-independent manner. Therefore, secreted PLOD3 serves as a potent inducer of lung cancer metastasis and a potential therapeutic target to enhance survival in lung cancer. PMID- 30442943 TI - Ribosomal protein S6 kinase 1 promotes the survival of photoreceptors in retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a heterogeneous group of inherited disorders caused by mutations in genes that are mostly expressed by rod photoreceptors, which results in initial death of rods followed by cone photoreceptors. The molecular mechanisms that lead to both rod and cone degeneration are not yet fully understood. The mTOR pathway is implicated in RP. However, it remains unclear whether S6K1 plays an essential role downstream of the mTOR pathway in mediating photoreceptor survival in RP. Our in vitro studies demonstrated that PTEN (phosphatase and tensin homolog) overexpression deactivated mTOR activity and induced 661W cone cell apoptosis. In addition, we identified that S6K1 but not 4EBP1 was the downstream effector of PTEN neurotoxicity using gain- and loss-of function approaches. Moreover, our in vivo data corroborated the results of our in vitro studies. S6K1 overexpression either in rods or cones promoted these cell survival and function and improved visual performance in the rd10 mouse model of RP. Our data demonstrated that S6K1 was the downstream effector of mTOR and that S6K1 was critical for both rod and cone survival in RP. Our findings make a strong case for targeting S6K1 as a promising therapeutic strategy for promoting the survival of photoreceptors in RP. PMID- 30442942 TI - Conditional deletion of Rcan1 predisposes to hypertension-mediated intramural hematoma and subsequent aneurysm and aortic rupture. AB - Aortic intramural hematoma (IMH) can evolve toward reabsorption, dissection or aneurysm. Hypertension is the most common predisposing factor in IMH and aneurysm patients, and the hypertensive mediator angiotensin-II induces both in mice. We have previously shown that constitutive deletion of Rcan1 isoforms prevents Angiotensin II-induced aneurysm in mice. Here we generate mice conditionally lacking each isoform or all isoforms in vascular smooth muscle cells, endothelial cells, or ubiquitously, to determine the contribution to aneurysm development of Rcan1 isoforms in vascular cells. Surprisingly, conditional Rcan1 deletion in either vascular cell-type induces a hypercontractile phenotype and aortic medial layer disorganization, predisposing to hypertension-mediated aortic rupture, IMH, and aneurysm. These processes are blocked by ROCK inhibition. We find that Rcan1 associates with GSK-3beta, whose inhibition decreases myosin activation. Our results identify potential therapeutic targets for intervention in IMH and aneurysm and call for caution when interpreting phenotypes of constitutively and inducibly deficient mice. PMID- 30442945 TI - Author Correction: Aggravation of acute kidney injury by mPGES-2 down regulation is associated with autophagy inhibition and enhanced apoptosis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442946 TI - PARP3, a new therapeutic target to alter Rictor/mTORC2 signaling and tumor progression in BRCA1-associated cancers. AB - PARP3 has been shown to be a key driver of TGFbeta-induced epithelial-to mesenchymal transition (EMT) and stemness in breast cancer cells, emerging as an attractive therapeutic target. Nevertheless, the therapeutic value of PARP3 inhibition has not yet been assessed. Here we investigated the impact of the absence of PARP3 or its inhibition on the tumorigenicity of BRCA1-proficient versus BRCA1-deficient breast cancer cell lines, focusing on the triple-negative breast cancer subtype (TNBC). We show that PARP3 knockdown exacerbates centrosome amplification and genome instability and reduces survival of BRCA1-deficient TNBC cells. Furthermore, we engineered PARP3-/- BRCA1-deficient or BRCA1-proficient TNBC cell lines using the CRISPR/nCas9D10A gene editing technology and demonstrate that the absence of PARP3 selectively suppresses the growth, survival and in vivo tumorigenicity of BRCA1-deficient TNBC cells, mechanistically via effects associated with an altered Rictor/mTORC2 signaling complex resulting from enhanced ubiquitination of Rictor. Accordingly, PARP3 interacts with and ADP ribosylates GSK3beta, a positive regulator of Rictor ubiquitination and degradation. Importantly, these phenotypes were rescued by re-expression of a wild-type PARP3 but not by a catalytic mutant, demonstrating the importance of PARP3's catalytic activity. Accordingly, reduced survival and compromised Rictor/mTORC2 signaling were also observed using a cell-permeable PARP3-specific inhibitor. We conclude that PARP3 and BRCA1 are synthetic lethal and that targeting PARP3's catalytic activity is a promising therapeutic strategy for BRCA1-associated cancers via the Rictor/mTORC2 signaling pathway. PMID- 30442944 TI - A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity. AB - The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcgammaR interactions. Here, we have designed an Fc-free tumor targeted 4-1BB-agonistic trimerbody, 1D8N/CEGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8N/CEGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8N/CEGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcgammaR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy. PMID- 30442947 TI - The anticonvulsive Phenhydan(r) suppresses extrinsic cell death. AB - Different forms of regulated cell death-like apoptosis and necroptosis contribute to the pathophysiology of clinical conditions including ischemia-reperfusion injury, myocardial infarction, sepsis, and multiple sclerosis. In particular, the kinase activity of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) is crucial for cell fate in inflammation and cell death. However, despite its involvement in pathological conditions, no pharmacologic inhibitor of RIPK1 mediated cell death is currently in clinical use. Herein, we screened a collection of clinical compounds to assess their ability to modulate RIPK1 mediated cell death. Our small-scale screen identified the anti-epilepsy drug Phenhydan(r) as a potent inhibitor of death receptor-induced necroptosis and apoptosis. Accordingly, Phenhydan(r) blocked activation of necrosome formation/activation as well as death receptor-induced NF-kappaB signaling by influencing the membrane function of cells, such as lipid raft formation, thus exerting an inhibitory effect on pathophysiologic cell death processes. By targeting death receptor signaling, the already FDA-approved Phenhydan(r) may provide new therapeutic strategies for inflammation-driven diseases caused by aberrant cell death. PMID- 30442948 TI - Dysregulation of autophagy and stress granule-related proteins in stress-driven Tau pathology. AB - Imbalance of neuronal proteostasis associated with misfolding and aggregation of Tau protein is a common neurodegenerative feature in Alzheimer's disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important AD precipitating factor, we previously reported that environmental stress and high glucocorticoid (GC) levels induce accumulation of aggregated Tau; however, the molecular mechanisms for such process remain unclear. Herein, we monitor a novel interplay between RNA-binding proteins (RBPs) and autophagic machinery in the underlying mechanisms through which chronic stress and high GC levels impact on Tau proteostasis precipitating Tau aggregation. Using molecular, pharmacological and behavioral analysis, we demonstrate that chronic stress and high GC trigger mTOR-dependent inhibition of autophagy, leading to accumulation of Tau aggregates and cell death in P301L-Tau expressing mice and cells. In parallel, we found that environmental stress and GC disturb cellular homeostasis and trigger the insoluble accumulation of different RBPs, such as PABP, G3BP1, TIA-1, and FUS, shown to form stress granules (SGs) and Tau aggregation. Interestingly, an mTOR-driven pharmacological stimulation of autophagy attenuates the GC-driven accumulation of Tau and SG-related proteins as well as the related cell death, suggesting a critical interface between autophagy and the response of the SG-related protein in the neurodegenerative potential of chronic stress and GC. These studies provide novel insights into the RNA-protein intracellular signaling regulating the precipitating role of environmental stress and GC on Tau driven brain pathology. PMID- 30442949 TI - Exploring the Sulfatase 1 Catch Bond Free Energy Landscape using Jarzynski's Equality. AB - In non-covalent biological adhesion, molecular bonds commonly exhibit a monotonously decreasing life time when subjected to tensile forces (slip bonds). In contrast, catch bonds behave counter intuitively, as they show an increased life time within a certain force interval. To date only a hand full of catch bond displaying systems have been identified. In order to unveil their nature, a number of structural and phenomenological models have been introduced. Regardless of the individual causes for catch bond behavior, it appears evident that the free energy landscapes of these interactions bear more than one binding state. Here, we investigated the catch bond interaction between the hydrophilic domain of the human cell surface sulfatase 1 (Sulf1HD) and its physiological substrate heparan sulfate (HS) by atomic force microscopy based single molecule force spectroscopy (AFM-SMFS). Using Jarzynski's equality, we estimated the associated Gibbs free energy and provide a comprehensive thermodynamic and kinetic characterization of Sulf1HD/HS interaction. Interestingly, the binding potential landscape exhibits two distinct potential wells which confirms the recently suggested two state binding. Even though structural data of Sulf1HD is lacking, our results allow to draft a detailed picture of the directed and processive desulfation of HS. PMID- 30442951 TI - Winding around non-Hermitian singularities. AB - Non-Hermitian singularities are ubiquitous in non-conservative open systems. Owing to their peculiar topology, they can remotely induce observable effects when encircled by closed trajectories in the parameter space. To date, a general formalism for describing this process beyond simple cases is still lacking. Here we develop a general approach for treating this problem by utilizing the power of permutation operators and representation theory. This in turn allows us to reveal a surprising result that has so far escaped attention: loops that enclose the same singularities in the parameter space starting from the same point and traveling in the same direction, do not necessarily share the same end outcome. Interestingly, we find that this equivalence can be formally established only by invoking the topological notion of homotopy. Our findings are general with far reaching implications in various fields ranging from photonics and atomic physics to microwaves and acoustics. PMID- 30442950 TI - Atomic scale insights into structure instability and decomposition pathway of methylammonium lead iodide perovskite. AB - Organic-inorganic hybrid perovskites are promising candidates for the next generation solar cells. Many efforts have been made to study their structures in the search for a better mechanistic understanding to guide the materials optimization. Here, we investigate the structure instability of the single crystalline CH3NH3PbI3 (MAPbI3) film by using transmission electron microscopy. We find that MAPbI3 is very sensitive to the electron beam illumination and rapidly decomposes into the hexagonal PbI2. We propose a decomposition pathway, initiated with the loss of iodine ions, resulting in eventual collapse of perovskite structure and its decomposition into PbI2. These findings impose important question on the interpretation of experimental data based on electron diffraction and highlight the need to circumvent material decomposition in future electron microscopy studies. The structural evolution during decomposition process also sheds light on the structure instability of organic-inorganic hybrid perovskites in solar cell applications. PMID- 30442954 TI - Lessons learned from a multicentre clinical trial in Africa. PMID- 30442953 TI - Identification of soybean peptide leginsulin variants in different cultivars and their insulin-like activities. AB - We have recently reported that green soybean cultivar, echigomidori, and not the yellow cultivar, fukuyutaka, is a rich source of hormone-like peptide leginsulin consisting of 37 amino acids (Leg_1_37, PDB 1JU8A) and its C-terminal glycine deletant, Leg_1_36. Green soybean is mature, but the color of the seedcoat and cotyledon remains green. Therefore, in this study, we examined the leginsulin content in different varieties of 11 colored soybeans (including green, yellow, red, brown and black) and edamame (immature soybean). Profile analysis of soybean constituents by LC-MS showed that Leg_1 (36 + 37) detected as a prominent peak in 3 green and 1 yellow soybean cultivar was the strongest contributor in principal component analysis, indicating Leg_1 is the most characteristic feature for distinguishing soybean cultivars. However, smaller amounts of leginsulin-like peptides, defined as Leg_2 and Leg_3, were detected in other samples. The cDNA sequences and LC-MS/MS analyses revealed that Leg_2 was a homologue of Leg_1 with three amino acid substitutions derived from SNPs, while Leg_3 was a Leg_1/Leg_2 paralog. Expression levels of Leg_1 were markedly higher than Leg_2 and Leg_3. Additionally, in glucose uptake assay, purified TRX-His-tag fused recombinant Leg_1_37 prepared by bacterial expression showed stronger insulin-like activities than other variants including Leg_2, Leg_3, and their Gly deletants in myotube like differentiated L6 and C2C12 cells. These results suggest that dietary consumption of soybean seed, especially including a higher amount of Leg_1_37, could be useful for lowering of blood glucose. PMID- 30442952 TI - Reading ability and phoneme categorization. AB - Dyslexia is associated with abnormal performance on many auditory psychophysics tasks, particularly those involving the categorization of speech sounds. However, it is debated whether those apparent auditory deficits arise from (a) reduced sensitivity to particular acoustic cues, (b) the difficulty of experimental tasks, or (c) unmodeled lapses of attention. Here we investigate the relationship between phoneme categorization and reading ability, with special attention to the nature of the cue encoding the phoneme contrast (static versus dynamic), differences in task paradigm difficulty, and methodological details of psychometric model fitting. We find a robust relationship between reading ability and categorization performance, show that task difficulty cannot fully explain that relationship, and provide evidence that the deficit is not restricted to dynamic cue contrasts, contrary to prior reports. Finally, we demonstrate that improved modeling of behavioral responses suggests that performance does differ between children with dyslexia and typical readers, but that the difference may be smaller than previously reported. PMID- 30442955 TI - Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles. AB - The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI2. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI2, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means. PMID- 30442956 TI - Rapid and selective recovery of palladium from platinum group metals and base metals using a thioamide-modified calix[4]arene extractant in environmentally friendly hydrocarbon fluids. AB - A novel macrocyclic calix[4]arene extractant having a long alkyl chain thioamide, 25,26,27,28-tetrakis(N-n-octylthiocarbamoyl)methoxy-5,11,17,23-tetra-tert butylcalix[4]arene (1), was synthesized from 25,26,27,28-tetrakis(N-n octylcarbamoyl)methoxy-5,11,17,23-tetra-tert-butylcalix[4]arene (2) using Lawesson's reagent. Extractant 1 was characterized using 1H NMR, 13C NMR, FT-IR spectroscopy, and elemental analysis. The Pd(II) extraction abilities of 1 and 2 were studied in high-boiling-point and environmentally friendly hydrocarbon diluents. Pd(II) extraction experiments were conducted using single-metal Pd(II) solutions, simulated mixed palladium group metal (PGM) solutions, and acid leached automotive catalyst residue solutions. Different experimental conditions, including the shaking time, HCl/HNO3 concentration, Pd(II) concentration, extractant concentration, and the organic/aqueous phase ratio, were studied systematically. Extractant 1 showed very selective (> 99.9%) Pd(II) extraction from the mixed PGM/base metal solutions and the acid-leached automotive catalyst residue solution. Conversely, the Pd(II) extraction ability of extractant 2 was found to be negligible. Extractant 1 showed very fast extraction kinetics and a high extraction capacity as compared to those of the commercial extractant di-n octyl sulfide. Effective stripping of Pd(II) from 1 was performed using HCI, HNO3, NH3, and HCl-thiourea solutions. Furthermore, 1 was successfully recycled over five extraction/stripping cycles. The Pd(II) extraction mechanism of 1 was studied using FT-IR spectroscopy. Extractant 1 exhibited very selective Pd(II) extraction and high acid stability, demonstrating its industrial applicability for the extraction of Pd(II) from leached automotive catalyst liquors containing PGMs and base metals. PMID- 30442957 TI - Bronchiectasis. AB - Bronchiectasis refers to abnormal dilatation of the bronchi. Airway dilatation can lead to failure of mucus clearance and increased risk of infection. Pathophysiological mechanisms of bronchiectasis include persistent bacterial infections, dysregulated immune responses, impaired mucociliary clearance and airway obstruction. These mechanisms can interact and self-perpetuate, leading over time to impaired lung function. Patients commonly present with productive cough and recurrent chest infections, and the diagnosis of bronchiectasis is based on clinical symptoms and radiological findings. Bronchiectasis can be the result of several different underlying disorders, and identifying the aetiology is crucial to guide management. Treatment is directed at reducing the frequency of exacerbations, improving quality of life and preventing disease progression. Although no therapy is licensed for bronchiectasis by regulatory agencies, evidence supports the effectiveness of airway clearance techniques, antibiotics and mucolytic agents, such as inhaled isotonic or hypertonic saline, in some patients. Bronchiectasis is a disabling disease with an increasing prevalence and can affect individuals of any age. A major challenge is the application of emerging phenotyping and endotyping techniques to identify the patient populations who would most benefit from a specific treatment, with the goal of better targeting existing and emerging treatments and achieving better outcomes. PMID- 30442958 TI - Lattice-contraction triggered synchronous electrochromic actuator. AB - Materials with synchronous capabilities of color change and actuation have prospects for application in biomimetic dual-stealth camouflage and artificial intelligence. However, color/shape dual-responsive devices involve stimuli that are difficult to control such as gas, light or magnetism, and the devices show poor coordination. Here, a flexible composite film with electrochromic/actuating (238 degrees bending angle) dual-responsive phenomena, excellent reversibility, high synchronization, and fast response speed (< 5 s) utilizes a single active component, W18O49 nanowires. From in situ synchrotron X-ray diffraction, first principles calculations/numerical simulations, and a series of control experiments, the actuating mechanism for macroscopic deformation is elucidated as pseudocapacitance-based reversible lattice contraction/recovery of W18O49 nanowires (i.e. nanostructure change at the atomic level) during lithium ion intercalation/de-intercalation. In addition, we demonstrate the W18O49 nanowires in a solid-state ionic polymer-metal composite actuator that operates stably in air with a significant pseudocapacitive actuation. PMID- 30442959 TI - A tRNA-derived RNA Fragment Plays an Important Role in the Mechanism of Arsenite induced Cellular Responses. AB - Chronic exposure to environmental heavy metals is a worldwide health concern. It is acknowledged to be an important cause of lower respiratory tract damage in children. However, the molecular mechanisms underlying the heavy metal-induced cellular stress/toxicity are not completely understood. Small non-coding RNAs (sncRNAs), such as microRNAs (miRNA) and more recently identified tRNA-derived RNA fragments (tRFs), are critical to the posttranscriptional control of genes. We used deep sequencing to investigate whether cellular sncRNA profiles are changed by environmental heavy metals. We found that the treatment of arsenite, an important groundwater heavy metal, leads to abundant production of tRFs, that are ~30 nucleotides (nts) long and most of which correspond to the 5'-end of mature tRNAs. It is unlikely for these tRFs to be random degradation by-products, as the type of induced tRFs is heavy metal-dependent. Three most inducible tRFs and their roles in arsenite-induced cellular responses were then investigated. We identified that p65, an important transcription factor belonging to NF-kappaB family and also a key factor controlling inflammatory gene expression, is a regulated target of a tRF derived from 5'-end of mature tRNA encoding AlaCGC (tRF5-AlaCGC). tRF5-AlaCGC activates p65, subsequently leading to enhanced secretion of IL-8 in arsenite response. In this study, we also identified that endonuclease Dicer and angiogenin temporally control the induction of tRF5 AlaCGC, providing an insight into the control of tRF biogenesis and subsequently the prevention of cellular damage. PMID- 30442961 TI - Demographic stochasticity drives epidemiological patterns in wildlife with implications for diseases and population management. AB - Infectious diseases raise many concerns for wildlife and new insights must be gained to manage infected populations. Wild ungulates provide opportunities to gain such insights as they host many pathogens. Using modelling and data collected from an intensively monitored population of Pyrenean chamois, we investigated the role of stochastic processes in governing epidemiological patterns of pestivirus spread in both protected and hunted populations. We showed that demographic stochasticity led to three epidemiological outcomes: early infection fade-out, epidemic outbreaks with population collapse, either followed by virus extinction or by endemic situations. Without re-introduction, the virus faded out in >50% of replications within 4 years and did not persist >20 years. Test-and-cull of infected animals and vaccination had limited effects relative to the efforts devoted, especially in hunted populations in which only quota reduction somewhat improve population recovery. Success of these strategies also relied on the maintenance of a high level of surveillance of hunter-harvested animals. Our findings suggested that, while surveillance and maintenance of population levels at intermediate densities to avoid large epidemics are useful at any time, a 'do nothing' approach during epidemics could be the 'least bad' management strategy in populations of ungulates species facing pestivirus infection. PMID- 30442962 TI - Dog characteristics and future risk of asthma in children growing up with dogs. AB - There is observational evidence that children exposed to dogs in early life are at lower risk of asthma. It is unknown whether this association is modified by dog characteristics such as sex, breed, number of dogs, and dog size. The aim of this study was to determine whether different dog characteristics modify the risk of asthma among children exposed to dogs during their first year of life. In the main analysis, we used national register data for all children born in Sweden from Jan 1st 2001 to Dec 31st 2004 with a registered dog in the household during their first year of life (n = 23,585). We used logistic regression models to study the association between dog characteristics and the risk of asthma or allergy diagnosis and medication at age six. The prevalence of asthma at age six was 5.4%. Children exposed to female dogs had lower risk of asthma compared to those exposed to male dogs, odds ratio, OR = 0.84 (95% confidence interval, CI 0.74 to 0.95). Children with two dogs or more had lower risk of asthma than those with one dog only, OR = 0.79 (95% CI 0.65 to 0.95). Children whose parents had asthma and allergy had a higher frequency of exposure to dog breeds anecdotally described as "hypoallergenic" compared to those parents without asthma or allergy (11.7% vs 7.6%, p < 0.001). Exposure to these breeds were associated with higher risk of allergy OR = 1.27 (95% CI 1.02 to 1.59) but not asthma. In conclusion, we found evidence of an association between the sex of dog and the number of dogs with a lower risk of childhood asthma in dog-exposed children. PMID- 30442960 TI - Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood. AB - One-carbon metabolism is essential for multiple cellular processes and can be assessed by the concentration of folate metabolites in the blood. One-carbon metabolites serve as methyl donors that are required for epigenetic regulation. Deficiencies in these metabolites are associated with a variety of poor health outcomes, including adverse pregnancy complications. DNA methylation is known to vary with one-carbon metabolite concentration, and therefore may modulate the risk of adverse pregnancy outcomes. This study addresses changes in one-carbon indices over pregnancy and the relationship between maternal and child DNA methylation and metabolite concentrations by leveraging data from 24 mother infant dyads. Five of the 13 metabolites measured from maternal blood and methylation levels of 993 CpG sites changed over the course of pregnancy. In dyads, maternal and fetal one-carbon concentrations were highly correlated, both early in pregnancy and at delivery. The 993 CpG sites whose methylation levels changed over pregnancy in maternal blood were also investigated for associations with metabolite concentrations in infant blood at delivery, where five CpG sites were associated with the concentration of at least one metabolite. Identification of CpG sites that change over pregnancy may result in better characterization of genes and pathways involved in maintaining a healthy, term pregnancy. PMID- 30442963 TI - Rapid detection of colistin resistance in Acinetobacter baumannii using MALDI-TOF based lipidomics on intact bacteria. AB - With the dissemination of extremely drug resistant bacteria, colistin is now considered as the last-resort therapy for the treatment of infection caused by Gram-negative bacilli (including carbapenemase producers). Unfortunately, the increase use of colistin has resulted in the emergence of resistance as well. In A. baumannii, colistin resistance is mostly caused by the addition of phosphoethanolamine to the lipid A through the action of a phosphoethanolamine transferase chromosomally-encoded by the pmrC gene, which is regulated by the two component system PmrA/PmrB. In A. baumannii clinical isolate the main resistance mechanism to colistin involves mutations in pmrA, pmrB or pmrC genes leading to the overexpression of pmrC. Although, rapid detection of resistance is one of the key issues to improve the treatment of infected patient, detection of colistin resistance in A. baumannii still relies on MIC determination through microdilution, which is time-consuming (16-24 h). Here, we evaluated the performance of a recently described MALDI-TOF-based assay, the MALDIxin test, which allows the rapid detection of colistin resistance-related modifications to lipid A (i.e phosphoethanolamine addition). This test accurately detected all colistin-resistant A. baumannii isolates in less than 15 minutes, directly on intact bacteria with a very limited sample preparation prior MALDI-TOF analysis. PMID- 30442964 TI - Author Correction: Quantitative 3-D morphometric analysis of individual dendritic spines. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30442966 TI - Incorporating terminal velocities into Lagrangian stochastic models of particle dispersal in the atmospheric boundary layer. AB - Lagrangian stochastic models for simulation of tracer-particle trajectories in turbulent flows can be adapted for simulation of particle trajectories. This is conventionally done by replacing the zero-mean fall speed of a tracer-particle with the terminal speed of the particle. Such models have been used widely to predict spore and pollen dispersal. Here I show that this modification predicts that particles become uniformly distributed throughout the air column, which is at variance with the seminal experimental studies of Hirst et al. (1967) that demonstrated spore concentrations (and pollen concentrations) declined exponentially with height in unstable air. This discrepancy arises because the terminal speed, which is a Lagrangian property of a particle, has always been treated as if it were an Eulerian property of an ensemble of particles. In this study models are formulated correctly. I show that the mean acceleration of a tracer-particle should be replaced by the mean acceleration of a particle. Model predictions for aerial density profiles then agreed with the observations of Hirst et al. (1967) and with observations of ground-level concentrations but differed significantly from predictions obtained using conventional models. In accordance with the results of numerical simulations, the models also predict that particles are moving downwind marginally more slowly than the wind itself. Finally, the new modelling approach can be extended to predict the dispersal of small insects with active flight behaviours. PMID- 30442965 TI - Marine mammal acoustic detections in the Greenland and Barents Sea, 2013 - 2014 seasons. AB - While the Greenland and Barents Seas are known habitats for several cetacean and pinniped species there is a lack of long-term monitoring data in this rapidly changing environment. Moreover, little is known of the ambient soundscapes, and increasing off-shore anthropogenic activities can influence the ecosystem and marine life. Baseline acoustic data is needed to better assess current and future soundscape and ecosystem conditions. The analysis of a year of continuous data from three passive acoustic monitoring devices revealed species-dependent seasonal and spatial variation of a large variety of marine mammals in the Greenland and Barents Seas. Sampling rates were 39 and 78 kHz in the respective locations, and all systems were operational at a duty cycle of 2 min on, 30 min off. The research presents a description of cetacean and pinniped acoustic detections along with a variety of unknown low-frequency tonal sounds, and ambient sound level measurements that fall within the scope of the European Marine Strategy Framework (MSFD). The presented data shows the importance of monitoring Arctic underwater biodiversity for assessing the ecological changes under the scope of climate change. PMID- 30442967 TI - Insights into the Chemistry of Non-Enzymatic Browning Reactions in Different Ribose-Amino Acid Model Systems. AB - Reactions between sugars and amino acids in the Maillard reaction produce a multitude of compounds through interconnected chemical pathways. The course of the pathways changes depending on the nature of the amino acids and sugars as well as the processing conditions (e.g. temperature, water activity). Some partial pathways have been elucidated using labelled precursors but the process is very time intensive. Here, we use rapid, non-targeted analysis with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) to deliver the molecular formulae and ion intensities of the compounds generated from reaction of four amino acids with ribose (10 h at 100 degrees C) to study the effect of amino acid side chains on the reaction pathways. Using van Krevelen diagrams, known chemical changes during the reaction (e.g. dehydration or decarboxylation) can be studied. Comparison of the data from the four amino acids studied, showed a common pathway, which involved 73 Maillard reaction products (MRPs) where the differences were due only to the nature of the amino acid side chain. From the more than 1400 different molecular formulae found, pathways unique to the amino acids were also identified and the order of reactivity was lysine >cysteine >isoleucine ~ glycine. While unequivocal identification of the compounds cannot be achieved with FT-ICR-MS, applying known chemical transformations found in the Maillard reaction, not only identifies new and known pathways, but also integrates the MRPs into a general Maillard reaction scheme that better represents the totality of the Maillard reaction. PMID- 30442968 TI - A diagnosis of the plasma waves responsible for the explosive energy release of substorm onset. AB - During geomagnetic substorms, stored magnetic and plasma thermal energies are explosively converted into plasma kinetic energy. This rapid reconfiguration of Earth's nightside magnetosphere is manifest in the ionosphere as an auroral display that fills the sky. Progress in understanding of how substorms are initiated is hindered by a lack of quantitative analysis of the single consistent feature of onset; the rapid brightening and structuring of the most equatorward arc in the ionosphere. Here, we exploit state-of-the-art auroral measurements to construct an observational dispersion relation of waves during substorm onset. Further, we use kinetic theory of high-beta plasma to demonstrate that the shear Alfven wave dispersion relation bears remarkable similarity to the auroral dispersion relation. In contrast to prevailing theories of substorm initiation, we demonstrate that auroral beads seen during the majority of substorm onsets are likely the signature of kinetic Alfven waves driven unstable in the high-beta magnetotail. PMID- 30442970 TI - A novel dry-bonding approach to reduce collagen degradation and optimize resin dentin interfaces. AB - In dentistry, the wet-bonding approach relies on water to maintain demineralized collagen expanded for proper resin infiltration; nevertheless, hydrolytic instability of the resin-dentin interface is inevitable with current bonding techniques. Considering dimethyl sulfoxide's (DMSO) ability to "biomodify" collagen and precipitate enzymes, the aim was to test whether the use of DMSO would permit adequate resin bonding to H3PO4-etched dehydrated dentin and assess its impact on collagen degradation by host-derived enzymes. Etched dentin surfaces from extracted sound human molars were randomly bonded in wet or dry conditions using aqueous or ethanolic DMSO solutions as pretreatments and bonding resins with or without DMSO. Bonded teeth were sectioned into resin-dentin slabs for confocal in situ zymography and beams for microtensile bond strength test. Demineralized powdered dentin was incubated in the tested DMSO -media and a hydroxyproline assay evaluated dissolution of collagen peptides. Zymography was performed on protein extracts obtained from dry and wet H3PO4-ecthed dentin powder treated with the DMSO- media. The correlative biochemical analysis demonstrated that reduction of water content during dentin hybridization by the innovative dry-bonding approaches with DMSO is effective to inactivate host derived MMP-2 and MMP-9 and thus reduce collagen degradation while simultaneously optimizing resin-dentin bonding. PMID- 30442969 TI - Characterization of human breast tissue microbiota from core needle biopsies through the analysis of multi hypervariable 16S-rRNA gene regions. AB - Breast microbiota compositions are not well understood, and a few recent reports have begun to explore the correlation between breast tissue dysbiosis and cancer. Given that various methods for breast microbiota detection were used, the aim of the present paper was to clarify which hypervariable region of the 16S-rRNA gene (V2, V3, V4, V6 + 7, V8, and V9) is the most informative for breast tissue microbiota. Core needle biopsies (CNBs) were compared with surgical excision biopsies (SEBs) to find a less invasive form of recovery useful for the analysis of a larger statistical population and potentially for diagnostic use of breast tissue microbiota. Finally, this study was the first to analyse the breast microbiota of tumours and paired normal tissues of a Mediterranean population. Our findings showed that the V3 region is the most informative for breast tissue microbiota, accounting for 45% of all reads. No significant differences were found between CNB and SEB specimens in terms of total reads and numbers of Operational Taxonomic Units (OTUs). Moreover, we find that more similarities than differences exist between tumours and adjacent normal tissues. Finally, the presence of the Ralstonia genus is associated with breast tissue. PMID- 30442971 TI - Solid and macroporous Fe3C/N-C nanofibers with enhanced electromagnetic wave absorbability. AB - A series of solid and macroporous N-doped carbon nanofibers composed of Fe3C nanoparticles (named as solid Fe3C/N-C NFs, solid Fe3C/N-C NFs-1, solid Fe3C/N-C NFs-2, macroporous Fe3C/N-C NFs, macroporous Fe3C/N-C NFs-1 and macroporous Fe3C/N-C NFs-2, respectively) were prepared through carbonization of as electrospun nanofiber precursors. The results show that the magnetic Fe3C nanoparticles (NPs) dispersed homogeneously on the N-doped carbon fibers; as prepared six materials exhibit excellent microwave absorption with a lower filler content in comparison with other magnetic carbon hybrid nanocomposites in related literatures. Particularly, the solid Fe3C/N-C NFs have an optimal reflection loss value (RL) of -33.4 dB at 7.6 GHz. For solid Fe3C/N-C NFs-2, the effective absorption bandwidth (EAB) at RL value below -10 dB can be up to 6.2 GHz at 2 mm. The macroporous Fe3C/N-C NFs have a broadband absorption area of 4.8 GHz at 3 mm. The EAB can be obtained in the 3.6-18.0 GHz frequency for the thickness of absorber layer between 2 and 6 mm. These Fe3C-based nanocomposites can be promising as lightweight, effective and low-metal content microwave absorption materials in 1-18 GHz. PMID- 30442972 TI - Author Correction: Lymphoblastoid cell lines from Diamond Blackfan anaemia patients exhibit a full ribosomal stress phenotype that is rescued by gene therapy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442973 TI - Yield trends, variability and stagnation analysis of major crops in France over more than a century. AB - France is a major crop producer, with a production share of approx. 20% within the European Union. Yet, a discussion has recently started whether French yields are stagnating. While for wheat previous results are unanimously pointing to recent stagnation, there is contradictory evidence for maize and few to no results for other crops. Here we analyse a data set with more than 120,000 yield observations from 1900 to 2016 for ten crops (barley, durum and soft wheat, maize, oats, potatoes, rapeseed, sugar beet, sunflower and wine) in the 96 mainland French departements (NUTS3 administrative division). We dissect the evolution of yield trends over time and space, analyse yield variation and evaluate whether growth of yields has stalled in recent years. Yields have, on average across crops, multiplied four-fold over the course of the 20th century. While absolute yield variability has increased, the variation relative to the mean has halved - mean yields have increased faster than their variability. But growth of yields has stagnated since the 1990's for winter wheat, barley, oats, durum wheat, sunflower and wine on at least 25% of their areas. Reaching yield potentials is unlikely as a cause for stagnation. Maize, in contrast, shows no evidence for stagnation. PMID- 30442974 TI - A biomimicry design for nanoscale radiative cooling applications inspired by Morpho didius butterfly. AB - In nature, novel colors and patterns have evolved in various species for survival, recognizability or mating purposes. Investigations of the morphology of various butterfly wings have shown that in addition to the pigmentation, micro and nanostructures within the wings have also allowed better communication systems and the pheromone-producing organs which are the main regulators of the temperature within butterfly wings. Within the blue spectrum (450-495 nm), Morpho didius butterfly exhibit iridescence in their structure-based wings' color. Inspired by the rich physics behind this concept, we present a designer metamaterial system that has the potential to be used for near-field radiative cooling applications. This biomimicry design involves SiC palm tree-like structures placed in close proximity of a thin film in a vacuum environment separated by nanoscale gaps. The near-field energy exchange is enhanced significantly by decreasing the dimensions of the tree and rotating the free standing structure by 90 degrees clockwise and bringing it to the close proximity of a second thin film. This exchange is calculated by using newly developed near field radiative transfer finite difference time domain (NF-RT-FDTD) algorithm. Several orders of enhancement of near-field heat flux within the infrared atmospheric window (8-13 MUm bandwidth) are achieved. This spectrally selective enhancement is associated with the geometric variations, the spatial location of the source of excitation and the material characteristics, and can be tuned to tailor strong radiative cooling mechanisms. PMID- 30442975 TI - Controlling aflatoxin contamination and propagation of Aspergillus flavus by a soy-fermenting Aspergillus oryzae strain. AB - Aflatoxins (AFs) are a group of carcinogenic and immunosuppressive mycotoxins that threaten global food safety. Globally, over 4.5 billion people are exposed to unmonitored levels of AFs. Aspergillus flavus is the major source of AF contamination in agricultural crops. One approach to reduce levels of AFs in agricultural commodities is to apply a non-aflatoxigenic competitor, e.g., Afla Guard, to crop fields. In this study, we demonstrate that the food fermenting Aspergillus oryzae M2040 strain, isolated from Korean Meju (a brick of dry fermented soybeans), can inhibit aflatoxin B1 (AFB1) production and proliferation of toxigenic A. flavus in lab culture conditions and peanuts. In peanuts, 1% inoculation level of A. oryzae M2040 could effectively displace the toxigenic A. flavus and inhibit AFB1 production. Moreover, cell-free culture filtrate of A. oryzae M2040 effectively inhibited AFB1 production and A. flavus growth, suggesting A. oryzae M2040 secretes inhibitory compounds. Whole genome-based comparative analyses indicate that the A. oryzae M2040 and Afla-Guard genomes are 37.9 and 36.4 Mbp, respectively, with each genome containing ~100 lineage specific genes. Our study establishes the idea of using A. oryzae and/or its cell free culture fermentate as a potent biocontrol agent to control A. flavus propagation and AF contamination. PMID- 30442976 TI - Adipose-derived stem cells alleviate liver apoptosis induced by ischemia reperfusion and laparoscopic hepatectomy in swine. AB - Hepatic ischemia-reperfusion (I/R) injury is inevitable during hepatectomy and may cause both postoperative morbidity and mortality. Regenerative medicine suggested adipose-derived stem cells (ADSCs) as an attractive tool for the treatment of liver diseases. In this study, we investigated the effect of ADSCs in an I/R model combined with laparoscopic hepatectomy in swine. Eighteen Bama miniature pigs were randomly divided into Sham, IRI, and ADSCs groups. ADSCs (1 * 106/kg) were injected through liver parenchyma immediately after hemihepatectomy. The apoptosis-related role of ADSCs was studied. The results showed that ADSCs transplantation reduced both pathological and ultrastructural changes and decreased the number of apoptotic-positive cells. In the ADSCs group, Fas, Fas ligand (FasL) protein, and mRNA were downregulated and the enzyme activities of Caspase3, Caspase8, and Caspase9 were significantly decreased. In addition, ADSC therapy significantly increased the ratio of Bcl-2/Bax protein and mRNA compared to the IRI group. In conclusion, ADSCs attenuated both I/R and hepatectomy induced liver apoptosis in a porcine model, and offers a potential therapeutic option for hepatic I/R and hepatectomy. PMID- 30442977 TI - T1-weighted Grey Matter Signal Intensity Alterations After Multiple Administrations of Gadobutrol in Patients with Multiple Sclerosis, Referenced to White Matter. AB - The aim of the study was to investigate the signal-intensity-(SI)-ratio changes in the basal ganglia, the pulvinar thalami (PN), and the dentate nucleus (DN) using frontal white matter (FWM) as reference area, in patients with multiple sclerosis after frequent administrations of gadobutrol. A control group (group I) was compared to three stratified patient groups (group II: mean applications of gadobutrol 3.7; group III: 7.5 applications; group IV: 13.8 applications). SI ratios of the pallidum, putamen, caudate nucleus, and pulvinar thalami were calculated with: 1. FWM, and 2. PN. DN-to-pons and DN-to-FWM ratios were also calculated. The most significant SI-ratio-changes were found by comparing group I and IV for both reference values. However, by using FWM as reference an SI-ratio increase was observed, while an SI-ratio decrease was seen if referenced to the PN. DN-to-FWM showed an SI-ratio increase, too. The PN revealed a significant SI ratio increase itself, correlating with the number of gadolinium applications, when referenced to FWM. Therefore, SI-ratio calculations using the thalamus as reference might be flawed. In addition, a minor gadolinium accumulation is possible, if FWM was used as reference area. Further studies are necessary to verify our results. PMID- 30442979 TI - The step-like evolution of Arctic open water. AB - September open water fraction in the Arctic is analyzed using the satellite era record of ice concentration (1979-2017). Evidence is presented that three breakpoints (shifts in the mean) occurred in the Pacific sector, with higher amounts of open water starting in 1989, 2002, and 2007. Breakpoints in the Atlantic sector record of open water are evident in 1971 in longer records, and around 2000 and 2011. Multiple breakpoints are also evident in the Canadian and Russian halves. Statistical models that use detected breakpoints of the Pacific and Atlantic sectors, as well as models with breakpoints in the Canadian and Russian halves and the Arctic as a whole, outperform linear trend models in fitting the data. From a physical standpoint, the results support the thesis that Arctic sea ice may have critical points beyond which a return to the previous state is less likely. From an analysis standpoint, the findings imply that de meaning the data using the breakpoint means is less likely to cause spurious signals than employing a linear detrend. PMID- 30442980 TI - CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-beta signaling. AB - Metastasis is the process through which the primary cancer cells spread beyond the primary tumor and disseminate to other organs. Most cancer patients die of metastatic disease. EMT is proposed to be the initial event associated with cancer metastasis and how it occurred is still a mystery. CtBP is known as a co repressor abundantly expressed in many types of cancer and regulates genes involved in cancer initiation, progression, and metastasis. We found that CtBP regulates intracellular cholesterol homeostasis in breast cancer cells by forming a complex with ZEB1 and transcriptionally repressing SREBF2 expression. Importantly, CtBP repression of intracellular cholesterol abundance leads to increased EMT and cell migration. The reason is that cholesterol negatively regulates the stability of TGF-beta receptors on the cell membrane. Interestingly, TGF-beta is also capable of reducing intracellular cholesterol relying on the increased recruitment of ZEB1 and CtBP complex to SREBF2 promoter. Thus, we propose a feedback loop formed by CtBP, cholesterol, and TGF-beta signaling pathway, through which TGF-beta triggers the cascade that mobilizes the cancer cells for metastasis. Consistently, the intravenous injection of breast cancer cells with ectopically CtBP expression show increased lung metastasis depending on the reduction of intracellular cholesterol. Finally, we analyzed the public breast cancer datasets and found that CtBP expression negatively correlates with SREBF2 and HMGCR expressions. High expression of CtBP and low expression of SREBF2 and HMGCR significantly correlates with high EMT of the primary tumors. PMID- 30442981 TI - Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. AB - Aberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERalpha+ luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERalpha+ luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERalpha+ patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERalpha+ luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics. PMID- 30442978 TI - Amyloid beta toxic conformer has dynamic localization in the human inferior parietal cortex in absence of amyloid plaques. AB - Amyloid beta (Abeta) plays a critical role in the pathogenesis of Alzheimer's disease. Nevertheless, its distribution and clearance before Abeta plaque formation needs to be elucidated. Using an optimized immunofluorescent staining method, we examined the distribution of Abeta in the post-mortem parietal cortex of 35 subjects, 30 to 65 years of age, APOE epsilon3/epsilon3, without AD lesions. We used 11A1, an antibody against an Abeta conformer which forms neurotoxic oligomers. 11A1 immunoreactivity (IR) was present in cortical neurons, pericapillary spaces, astrocytes and the extracellular compartment at 30 years of age. The percentage of neurons with 11A1 IR did not change with age, but the number and percentage of astrocytes with 11A1 IR gradually increased. Notably, the percentage of pericapillary spaces labeled with 11A1 IR declined significantly in the 5th decade of the life, at the same time that 11A1 IR increased in the extracellular space. Our findings indicate that the Abeta toxic conformer is normally present in various cell types and brain parenchyma, and appears to be constitutively produced, degraded, and cleared from the inferior parietal cortex. The decrease in pericapillary Abeta and the concomitant increase of extracellular Abeta may reflect an age-associated impairment in Abeta clearance from the brain. PMID- 30442982 TI - Electric field-controlled transformation of the eigenmodes in a twisted-nematic Fabry-Perot cavity. AB - The polarized optical states in the transmission spectrum of a twisted-nematic Fabry-Perot cavity with the distinctly broken Mauguin's waveguide regime have been theoretically and experimentally investigated. Specific features of the electric field-induced transformation of the polarization and spectral characteristics of eigenmodes of the neighboring series at the overlap resonant frequencies have been examined. It is demonstrated that the linear polarizations of eigenmodes at the cavity boundaries remain nearly orthogonal and their frequency trajectories reproduce the avoided crossing phenomenon. The experimental data are confirmed analytically and by the numerical simulation of light transmission through the investigated anisotropic multilayer with the use of a Berreman matrix method. The results obtained can be generalized to any materials with the helix response. PMID- 30442985 TI - Fast response paper based visual color change gas sensor for efficient ammonia detection at room temperature. AB - We show that a cheap, disposable type rapid paper sensor (working at room temperature) can be made using perovskite halide CH3NH3PbI3 (MAPI) to detect presence of the toxic ammonia gas (NH3)by just color change, where the black colored MAPI film (on the paper) changes to yellow color in presence of a very low concentration of NH3 gas. The sensor can detect presence of NH3 gas in open or closed atmosphere down to around 10 ppm with a response time of nearly 10 sec which decreases to few seconds when the concentration exceeds 20 ppm. The easy to fabricate sensor paper being a visual sensor does not need any other extra equipment for its operation. The sensor is not sensitive to moisture with RH upto 90% and does not also respond to gases like Methane (CH4), Nitrous Oxide (N2O), Carbon dioxide (CO2) etc in the test chamber each up to a concentration of 500 ppm. Conversion/decomposition of MAPI to PbI2 on exposure to NH3 has been proposed as the mechanism of color change and the mechanism has been established using a collection of techniques like XRD, EDX, UV-Visible absorption and Photo Luminescence. PMID- 30442984 TI - Responses to climatic and pathogen threats differ in biodynamic and conventional vines. AB - Viticulture is of high socio-economic importance; however, its prevalent practices severely impact the environment and human health, and criticisms from society are raising. Vine managements systems are further challenged by climatic changes. Of the 8 million hectares grown worldwide, conventional and organic practices cover 90% and 9% of acreage, respectively. Biodynamic cultivation accounts for 1%. Although economic success combined with low environmental impact is widely claimed by biodynamic winegrowers from California, to South Africa, and France, this practice is still controversial in viticulture and scientific communities. To rethink the situation, we encouraged stakeholders to confront conventional and biodynamic paradigms in a Participative-Action-Research. Co designed questions were followed up by holistic comparison of conventional and biodynamic vineyard managements. Here we show that the amplitude of plant responses to climatic threats was higher in biodynamic than conventional management. The same stood true for seasonal trends and pathogens attacks. This was associated with higher expression of silencing and immunity genes, and higher anti-oxidative and anti-fungal secondary metabolite levels. This suggests that sustainability of biodynamic practices probably relies on fine molecular regulations. Such knowledge should contribute to resolving disagreements between stakeholders and help designing the awaited sustainable viticulture at large. PMID- 30442983 TI - Clinical performance of an analytically validated assay in comparison to microarray technology to assess PITX2 DNA-methylation in breast cancer. AB - Significant evidence has accumulated that DNA-methylation of the paired-like homeodomain transcription factor 2 (PITX2) gene can serve as a prognostic and predictive biomarker in breast cancer. PITX2 DNA-methylation data have been obtained so far from microarray and polymerase chain reaction (PCR)-based research tests. The availability of an analytically validated in vitro methylation-specific real-time PCR assay format (therascreen PITX2 RGQ PCR assay) intended for the determination of the percent methylation ratio (PMR) in the (PITX2) promoter 2 prompted us to investigate whether the clinical performance of these different assay systems generate comparable clinical outcome data. Mathematically converted microarray data of a previous breast cancer study (n = 204) into PMR values leads to a PITX2 cut-off value at PMR 14.73. Recalculation of the data to experimentally equivalent PMRs with the PCR PITX2 assay leads to a cut-off value at PMR 12 with the highest statistical significance. This cut-off predicts outcome of high-risk breast cancer patients to adjuvant anthracycline based chemotherapy (n = 204; Hazard Ratio 2.48; p < 0.001) comparable to microarray generated results (n = 204; Hazard ratio 2.32; p < 0.0001). The therascreen PITX2 RGQ PCR assay is an analytically validated test with high reliability and robustness and predicts outcome of high-risk breast cancer patients to anthracycline-based chemotherapy. PMID- 30442987 TI - Different structures of berberine and five other protoberberine alkaloids that affect P-glycoprotein-mediated efflux capacity. AB - Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities. PMID- 30442986 TI - Understanding the role of bitter taste perception in coffee, tea and alcohol consumption through Mendelian randomization. AB - Consumption of coffee, tea and alcohol might be shaped by individual differences in bitter taste perception but inconsistent observational findings provide little insight regarding causality. We conducted Mendelian randomization analyses using genetic variants associated with the perception of bitter substances (rs1726866 for propylthiouracil [PROP], rs10772420 for quinine and rs2597979 for caffeine) to evaluate the intake of coffee, tea and alcohol among up to 438,870 UK Biobank participants. A standard deviation (SD) higher in genetically predicted bitterness of caffeine was associated with increased coffee intake (0.146 [95%CI: 0.103, 0.189] cups/day), whereas a SD higher in those of PROP and quinine was associated with decreased coffee intake (-0.021 [-0.031, -0.011] and -0.081 [ 0.108, -0.054] cups/day respectively). Higher caffeine perception was also associated with increased risk of being a heavy (>4 cups/day) coffee drinker (OR 1.207 [1.126, 1.294]). Opposite pattern of associations was observed for tea possibly due to the inverse relationship between both beverages. Alcohol intake was only negatively associated with PROP perception (-0.141 [-1.88, -0.94] times/month per SD increase in PROP bitterness). Our results reveal that bitter perception is causally associated with intake of coffee, tea and alcohol, suggesting a role of bitter taste in the development of bitter beverage consumption. PMID- 30442988 TI - Effects of Involved Laser Photons on Radiation and Electron-Positron Pair Production in one Coherence Interval in Ultra Intense Lasers. AB - Electron radiation and gamma photon annihilation are two of the major processes in ultra intense lasers (UIL). Understanding their behavior in one coherence interval (CI) is the basis for UIL-matter interaction researches. However, most existing analytic formulae only give the average over many CIs. Present understanding of these two multi-photon processes in one CI usually assume that they emit forward and their spectra have a cutoff at the energy of the electron/gamma. Such assumptions ignore the effects of involved laser photons (EILP). We deduced the formulae for these two processes in one CI with EILP included and give the conditions for the EILP to be significant. Strong EILP introduces new behaviors into these two processes in one CI, such as large angle emission and emit particles above the usually assumed cutoff. Simulations show that the EILP would be significant when laser intensity reaches 2 * 1022 W/cm2, which is within the reach of state-of-art lasers. PMID- 30442989 TI - Author Correction: Metabolic gene expression and epigenetic effects of the ketone body beta-hydroxybutyrate on H3K9ac in bovine cells, oocytes and embryos. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442990 TI - Inhibition of FAO in AML co-cultured with BM adipocytes: mechanisms of survival and chemosensitization to cytarabine. AB - Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), and leukemia cells continuously adapt to deficiency of nutrients acquiring chemoresistant profiles in the BM microenvironment. We have previously shown that fatty acid metabolism is a key energy pathway for survival of acute myeloid leukemia (AML) cells in the adipocyte-abundant BM microenvironment. The novel fatty acid beta-oxidation (FAO) inhibitor avocatin B, an odd-numbered carbon lipid derived from the avocado fruit, induced apoptosis and growth inhibition in mono-cultured AML cells. In AML cells co-cultured with BM adipocytes, FAO inhibition with avocatin B caused adaptive stimulation of free fatty acid (FFA) uptake through upregulation of FABP4 mRNA, enhanced glucose uptake and switch to glycolysis. These changes reflect the compensatory response to a shortage of FFA supply to the mitochondria, and facilitate the protection of AML cells from avocatin B-induced apoptosis in the presence of BM adipocytes. However, the combination treatment of avocatin B and conventional anti-AML therapeutic agent cytarabine (AraC) increased reactive oxygen species and demonstrated highly synergistic effects on AML cells under BM adipocyte co-culture condition. These findings highlight the potential for combination regimens of AraC and FAO inhibitors that target bone marrow-resident chemoresistant AML cells. PMID- 30442992 TI - Author Correction: Development and validation of a risk prediction model for work disability: multicohort study. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30442991 TI - Tracing whale myoglobin evolution by resurrecting ancient proteins. AB - Extant cetaceans, such as sperm whale, acquired the great ability to dive into the ocean depths during the evolution from their terrestrial ancestor that lived about 50 million years ago. Myoglobin (Mb) is highly concentrated in the myocytes of diving animals, in comparison with those of land animals, and is thought to play a crucial role in their adaptation as the molecular aqualung. Here, we resurrected ancestral whale Mbs, which are from the common ancestor between toothed and baleen whales (Basilosaurus), and from a further common quadrupedal ancestor between whale and hippopotamus (Pakicetus). The experimental and theoretical analyses demonstrated that whale Mb adopted two distinguished strategies to increase the protein concentration in vivo along the evolutionary history of deep sea adaptation; gaining precipitant tolerance in the early phase of the evolution, and increase of folding stability in the late phase. PMID- 30442993 TI - Asymmetric flows and drivers of herbaceous plant invasion success among Mediterranean-climate regions. AB - Understanding the mechanisms that support the arrival, establishment and spread of species over an introduced range is crucial in invasion ecology. We analysed the unintentionally introduced herbaceous species that are naturalised in the five Mediterranean-climate regions. There is an asymmetry in the species flows among regions, being the Iberian Peninsula the main donor to the other regions. At interregional scale, the species' capacity to spread among regions is related to the ecological versatility of the species in the donor area (Iberian Peninsula). At intraregional scale, the species' capacity to successfully occupy a complete region first depends on the time elapsed from its introduction and afterwards on the degree of occurrence in the region of origin, which is commonly related to its chance of coming into contact with humans. Information on exotic species in their origin region provides insights into invasion process and decision-making to reduce the risks of future invasions. PMID- 30442994 TI - Improvement of balance in young adults by a sound component at 100 Hz in music. AB - About 80% of young people use personal listening devices (PLDs) including MP3 players to listen to music, which consists of sound components with various frequencies. Previous studies showed that exposure to noise of high intensities affected balance in humans. However, there is no information about a frequency dependent effect of sound components in music from a PLD on balance in young people. In this study, we determined the associations between sound component levels (dB) at 100, 1000 and 4000 Hz in music from a portable listening device (PLD) and balance objectively determined by posturography in young adults (n = 110). We divided the subjects into two groups (low and high exposure groups) based on cut-off values of sound component levels at each frequency using receiver operating characteristic (ROC) curves. Balance in the high exposure group (>=46.6 dB) at 100 Hz was significantly better than that in low exposure group in logistic regression models adjusted for sex, BMI, smoking status and alcohol intake, while there were no significant associations at 1000 and 4000 Hz. Thus, this study demonstrated for the first time that the sound component at 100 Hz with more than 46.6 dB in music improved balance in young adults. PMID- 30442997 TI - Species distribution models of European Turtle Doves in Germany are more reliable with presence only rather than presence absence data. AB - Species distribution models (SDMs) can help to describe potential occurrence areas and habitat requirements of a species. These data represent key information in ecology and conservation, particularly for rare or endangered species. Presence absence (PA) and presence only (PO) records of European Turtle Doves Streptopelia turtur in Germany were used to run SDMs, whilst climate and land coverage variables provided environmental information. GLM (Generalised Linear model), GBM (Generalised Boosted model), CTA (Classification Tree analysis), SRE (Surface Range Envelope) and RF (Random Forests) algorithms were run with both datasets. Best model quality was obtained with PO in the RF algorithm (AUC 0.83). PA and PO probability maps differed substantially, but both excluded mountainous regions as potential occurrence areas. However, PO probability maps were more discriminatory and highlighted a possible distribution of Turtle Doves near Saarbrucken, west of Dusseldorf, in the Black Forest lowlands and Lusatia. Mainly, the climate variables 'minimum temperature in January' and 'precipitation of the warmest quarter' shaped these results, but variables like soil type or agricultural management strategy could improve future SDMs to specify local habitat requirements and develop habitat management strategies. Eventually, the study demonstrated the utility of PO data in SDMs, particularly for scarce species. PMID- 30442998 TI - FIRST FLORENCE FERENCZI SPECIAL ISSUE. PMID- 30442996 TI - Hyperactivated stallion spermatozoa fail to exhibit a rheotaxis-like behaviour, unlike other species. AB - The journey of spermatozoa through the female genital tract is facilitated by rheotaxis, or the cell's preference to swim against a flow, as well as thigmotaxis, the wall tracking behaviour, which guides them to the site of fertilisation. The aim of this study was to characterise the rheotactic and thigmotactic response of stallion sperm within a microfluidic channel. Stallion sperm rheotaxis was assessed within the microfluidic channel with regard to: (i) A range of flow velocities, (ii) Varying media viscosity and (iii) Sperm hyperactivation. Sperm distribution across the microfluidic channel was also studied and compared to human and ram sperm. Stallion sperm progressed furthest at a velocity range of 10-30 um/s, with an optimum velocity of 20 um/s. A flow viscosity of 2.5cP or greater reduced sperm rheotaxis (P < 0.05). Stallion sperm that were hyperactivated were unable to exhibit rheotaxis within the microfluidic channel, whereas, both hyperactivated human and ram sperm did exhibit positive rheotaxis under the same conditions. The number of sperm swimming near the microfluidic channel walls was higher than in the microfluidic channel centre (P < 0.05). This is the first study to illustrate that stallion sperm are rheotactically responsive and increasing viscosity reduces this response. We also demonstrated that sperm are predominantly inclined to swim along a surface and uniquely, hyperactivated stallion sperm are non-progressive and do not exhibit a rheotactic response unlike other species. PMID- 30442995 TI - Deciphering the evolutionary signatures of pinnipeds using novel genome sequences: The first genomes of Phoca largha, Callorhinus ursinus, and Eumetopias jubatus. AB - The pinnipeds, which comprise seals, sea lions, and walruses, are a remarkable group of marine animals with unique adaptations to semi-aquatic life. However, their genomes are poorly characterized. In this study, we sequenced and characterized the genomes of three pinnipeds (Phoca largha, Callorhinus ursinus, and Eumetopias jubatus), focusing on site-wise sequence changes. We detected rapidly evolving genes in pinniped lineages and substitutions unique to pinnipeds associated with amphibious sound perception. Phenotypic convergence-related sequence convergences are not common in marine mammals. For example, FASN, KCNA5, and IL17RA contain substitutions specific to pinnipeds, yet are potential candidates of phenotypic convergence (blubber, response to hypoxia, and immunity to pathogens) in all marine mammals. The outcomes of this study will provide insight into targets for future studies of convergent evolution or gene function. PMID- 30442999 TI - Role of filler and its heterostructure on moisture sorption mechanisms in polyimide films. AB - Moisture sorption and diffusion exacerbate hygrothermal aging and can significantly alter the chemical and mechanical properties of polymeric-based components over time. In this study, we employ a multi-pronged multi-scale approach to model and understand moisture diffusion and sorption processes in polyimide polymers. A reactive transport model with triple-mode sorption (i.e., Henry's, Langmuir, and pooling), experiments, and first principles atomistic computations were combined to synergistically explore representative systems of Kapton H and Kapton HN polymers. We find that the CaHPO4 processing aid used in Kapton HN increases the total moisture uptake (~0.5 wt%) relative to Kapton H. Henry's mode is found to play a major role in moisture uptake for both materials, accounting for >90% contribution to total uptake.However, the pooling mode uptake in Kapton HN was ~5 times higher than in Kapton H. First principles thermodynamics calculations based on density functional theory predict that water molecules chemisorb (with binding energy ~17-25 kcal/mol) on CaHPO4 crystal surfaces. We identify significant anisotropy in surface binding affinity, suggesting a possible route to tune and mitigate moisture uptake in Kapton-based systems through controlled crystal growth favoring exposure of CaHPO4 (101) surfaces during manufacturing. PMID- 30443000 TI - A postzygotic KRAS mutation in a patient with Schimmelpenning syndrome presenting with lipomatosis, renovascular hypertension, and diabetes mellitus. AB - Schimmelpenning syndrome is a rare neurocutaneous disorder categorized as a mosaic RASopathy due to postzygotic HRAS or KRAS mutations. We report a 6-year old girl diagnosed with Schimmelpenning syndrome due to a postzygotic KRAS G12D mutation. The patient had three atypical symptoms of Schimmelpenning syndrome: renovascular hypertension, congenital lipomatosis, and diabetes mellitus. The first two symptoms may overlap with phenotypes of other neurocutaneous syndromes or congenital lipomatous overgrowth syndrome due to mosaic RASopathies or other somatic mosaic mutations. We propose that impaired glucose tolerance was caused by KRAS mutation and a novel clinical phenotype of Schimmelpenning syndrome. Our study indicated that clinical diagnosis of Schimmelpenning syndrome or related conditions should be reorganized with genetic diagnosis of postzygotic mutation. Moreover, further accumulation of genetically proven cases with mosaic RASopathies should be used to more accurately characterize phenotypic presentations of this syndrome and develop a future therapeutic strategy, such as molecular-targeted therapy. PMID- 30443001 TI - Telomerase gene expression bioassays indicate metabolic activation of genotoxic lower chlorinated polychlorinated biphenyls. AB - Polychlorinated biphenyls (PCBs) are ubiquitously occurring pollutants with different chemical and toxicological properties. In this study we evaluated blood plasma samples of two PCB-exposed cohorts for their ability to alter telomerase (hTERT) gene expression. Blood plasma from PCB-exposed individuals inhibited hTERT expression depending solely on the concentration of lower chlorinated PCBs, with the lowest observed adverse effect level (LOAEL) at a plasma concentration between 0.5 and 2 ug/L of LC PCBs. Individual OH-metabolites derived from the WHO indicator congeners PCB 28 and PCB 101 mimicked these effects on hTERT expression in vitro with high toxicity, including DNA damage. However, by the combination of different OH-metabolites, the bio effective PCB concentration was reduced and the respective effects on hTERT expression could be increased. At a concentration which showed no toxic activity in MTT assay, hTERT inhibition reflected the interference of OH-PCBs with the mitochondrial respiratory chain, which could lead to the production of reactive oxygen species (ROS). As individual OH metabolites already showed a much stronger inhibition of hTERT gene expression at a lower concentration than their parental compounds, the hTERT gene expression bioassay described in this study seems to indicate metabolic activation of LC PCBs rather than the mere effect of LC PCBs on their own. In summary, this study provides dose-response linkages between effects of lower chlorinated PCBs and their concentrations in human plasma. PMID- 30443003 TI - Author Correction: A reassortant H9N2 influenza virus containing 2009 pandemic H1N1 internal-protein genes acquired enhanced pig-to-pig transmission after serial passages in swine. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30443004 TI - Personalized DNA methylomics. PMID- 30443002 TI - Communal breeding affects offspring behaviours associated with a competitive social environment. AB - Communal breeding is characterised by shared care of offspring produced by more than one female, and can affect the behavioural development of young. The decision to care communally can vary according to local conditions, and has been hypothesised to occur more frequently when social competition is intense. However, it is unknown whether communal rearing of young influences adult behaviours likely to be adaptive under competitive conditions. Here, using a controlled experimental approach, we investigate effects of communal rearing on competitive and exploratory behaviours of adult male house mice. In tests of competitive scent marking, only communally-reared subjects discriminated between related and unrelated rivals, depositing more scent marks in close proximity to unrelated males. Communally-reared subjects also displayed higher exploratory tendencies, with an increased probability of crossing a water barrier, while not exhibiting higher activity levels in an open field test. Since exploration tendencies and discrimination between kin and non-kin are likely to be advantageous when dispersing from the natal territory or in a high density population, our findings suggest that communal rearing prepares male house mice for a competitive social environment. Our results add to growing evidence that the early social environment influences development of important behavioural competences to cope with social challenges later in life. PMID- 30443005 TI - A proxy-year analysis shows reduced soil temperatures with climate warming in boreal forest. AB - Scientists unequivocally agree that winter air temperature (TA) in northern high latitudes will increase sharply with anthropogenic climate change, and that such increases are already pervasive. However, contrasting hypotheses and results exist regarding the magnitude and even direction of changes in winter soil temperature (TS). Here we use field and satellite data to examine the 'cold soil in a warm world' hypothesis for the first time in the boreal forest using a proxy year approach. In a proxy warm year with a mean annual temperature similar to that predicted for ~2080, average winter TS was reduced relative to the baseline year by 0.43 to 1.22 degrees C in open to forested sites. Similarly, average minimum and maximum winter TS declined, and the number of freeze-thaw events increased in the proxy warm year, corresponding to a reduction in the number of snow-covered days relative to the baseline year. Our findings indicate that early soil freezing as a result of delayed snowfall and reduced snow insulation from cold winter air are the main drivers of reduced winter active-layer TS (at ~2-cm depth) under warming conditions in boreal forest, and we also show that these drivers interact strongly with forest stand structure. PMID- 30443006 TI - The relationship between repeated measurement of casual and 24-h urinary sodium to-potassium ratio in patients with chronic kidney disease. AB - This study aimed to clarify the relationship between repeated measurements of casual (spot) and 24-h urinary sodium-to-potassium (Na/K) ratios in patients with chronic kidney disease (CKD). A total of 61 inpatients with CKD, 31 in stage 1-3 (eGFR [estimated glomerular filtration rate] >= 30 ml/min/1.73 m2) and 30 in stage 4-5 (eGFR < 30 ml/min/1.73 m2), aged 20-85 consuming a low-sodium diet (NaCl [sodium chloride] 6 g/day) were recruited. Urinary Na, K, and Na/K ratios were measured in both casual urine samples and 2-day, 24 h urine samples, and then analyzed by correlation and Bland-Altman analyses. Mean 24-h urine Na/K ratio was higher in participants in stage 4-5 (5.1) than in participants in stage 1-3 (4.1) CKD. Casual urine Na/K ratio was strongly correlated with 2-day, 24-h urine Na/K ratio by sampling 4 casual urine specimens every morning and evening in participants in stage 1-3 (r = 0.69-0.78), but not in stage 4-5 (r = 0.12 0.19). The bias for mean Na/K ratio between 2-day, 24-h urine, and the 4 casual urine sampling ranged from -0.86 to 0.16 in participants in stage 1-3, and the quality of agreement for the mean of this casual urine sampling was similar to that of sampling 8 casual urine samples for estimating 2-day, 24-h values. Methods using repeated casual urine Na/K ratios may provide a reasonable estimation of 24-h urine Na/K ratio in normotensive and hypertensive as well as individuals with stage 1-3, but not stage 4-5 CKD. PMID- 30443007 TI - Empagliflozin reduces blood pressure and uric acid in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. AB - The antidiabetic effect of empagliflozin in patients with type 2 diabetes mellitus has been explored in several trials. We performed this meta-analysis determining the effects of empagliflozin on blood pressure, uric acid, estimated glomerular filtration rate, blood lipids, blood glucose, and body weight in patients with type 2 diabetes mellitus. We searched three electronic databases (Pubmed, Web of Science, and Cochrane Central) for all published articles evaluating the effects of empagliflozin on blood glucose or blood pressure in subjects with type 2 diabetes mellitus. Total 5781 patients were included in 12 randomized controlled trials with a follow-up of 28 +/- 22 weeks. Empagliflozin 10 or 25 mg reduced systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight in patients with type 2 diabetes mellitus (all p < 0.001). There were no differences for changes of estimated glomerular filtration rate between empagliflozin 10 or 25 mg and placebo in these patients (all p > 0.05). In conclusion, empagliflozin reduces systolic and diastolic blood pressure, uric acid, hemoglobin A1c, fasting plasma glucose, and body weight. These data suggest the beneficial effects of empagliflozin on these cardiovascular risk factors in patients with type 2 diabetes mellitus. PMID- 30443008 TI - Hybrid in vitro diffusion cell for simultaneous evaluation of hair and skin decontamination: temporal distribution of chemical contaminants. AB - Most casualty or personnel decontamination studies have focused on removing contaminants from the skin. However, scalp hair and underlying skin are the most likely areas of contamination following airborne exposure to chemicals. The aim of this study was to investigate the interactions of contaminants with scalp hair and underlying skin using a hybrid in vitro diffusion cell model. The in vitro hybrid test system comprised "curtains" of human hair mounted onto sections of excised porcine skin within a modified diffusion cell. The results demonstrated that hair substantially reduced underlying scalp skin contamination and that hair may provide a limited decontamination effect by removing contaminants from the skin surface. This hybrid test system may have application in the development of improved chemical incident response processes through the evaluation of various hair and skin decontamination strategies. PMID- 30443009 TI - An assessment of true and false positive detection rates of stepwise epistatic model selection as a function of sample size and number of markers. AB - Association studies have been successful at identifying genomic regions associated with important traits, but routinely employ models that only consider the additive contribution of an individual marker. Because quantitative trait variability typically arises from multiple additive and non-additive sources, utilization of statistical approaches that include main and two-way interaction marker effects of several loci in one model could lead to unprecedented characterization of these sources. Here we examine the ability of one such approach, called the Stepwise Procedure for constructing an Additive and Epistatic Multi-Locus model (SPAEML), to detect additive and epistatic signals simulated using maize and human marker data. Our results revealed that SPAEML was capable of detecting quantitative trait nucleotides (QTNs) at sample sizes as low as n = 300 and consistently specifying signals as additive and epistatic for larger sizes. Sample size and minor allele frequency had a major influence on SPAEML's ability to distinguish between additive and epistatic signals, while the number of markers tested did not. We conclude that SPAEML is a useful approach for providing further elucidation of the additive and epistatic sources contributing to trait variability when applied to a small subset of genome-wide markers located within specific genomic regions identified using a priori analyses. PMID- 30443010 TI - Author Correction: Stretching Reduces Tumor Growth in a Mouse Breast Cancer Model. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30443012 TI - Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation. AB - Mismatch-repair deficiency testing plays a critical role in the identification of proband in Lynch Syndrome families and triaging patients with high stage or recurrent solid malignancies for check point inhibitor (Pembrolizumab) immunotherapy. We compared microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci between microsatellite instability high endometrial carcinoma (n = 50) and microsatellite instability high colorectal cancer (n = 19). The endometrial cancer cohort included 45 endometrioid, 1 serous, and 4 clear cell carcinomas. Overall, 52% (26/50) of microsatellite instability high endometrial cancers showed minimal microsatellite shift (defined as a one to three nucleotide repeat shift at an involved locus) observed at least at one locus. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%). Noticeably, 11 of the 26 cases (42%) showed only minimal shift. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, 65% (17/26) had combined MLH1 and PMS2 loss, 8% (2/26) had combined MSH2 and MSH6 loss, 13% (3/26) had MSH6 loss and 15% (4/26) had loss of PMS2 by immunohistochemistry. In contrast, only 16% (3/19) had minimal microsatellite shift seen in colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas. In conclusion, microsatellite instability high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. Microsatellite instability high endometrial cancers also have more frequent loss of MSH-6. Diagnostically, recognition of minimal microsatellite shift is crucial for accurate interpretation of microsatellite instability PCR data of endometrial carcinoma. PMID- 30443011 TI - Characterisation of a diazinon-metabolising glutathione S-transferase in the silkworm Bombyx mori by X-ray crystallography and genome editing analysis. AB - Previously, we found an unclassified glutathione S-transferase 2 (bmGSTu2) in the silkworm Bombyx mori that conjugates glutathione to 1-chloro-2,4-dinitrobenzene and also metabolises diazinon, an organophosphate insecticide. Here, we provide a structural and genome-editing characterisation of the diazinon-metabolising glutathione S-transferase in B. mori. The structure of bmGSTu2 was determined at 1.68 A by X-ray crystallography. Mutation of putative amino acid residues in the substrate-binding site showed that Pro13, Tyr107, Ile118, Phe119, and Phe211 are crucial for enzymatic function. bmGSTu2 gene disruption resulted in a decrease in median lethal dose values to an organophosphate insecticide and a decrease in acetylcholine levels in silkworms. Taken together, these results indicate that bmGSTu2 could metabolise an organophosphate insecticide. Thus, this study provides insights into the physiological role of bmGSTu2 in silkworms, detoxification of organophosphate insecticides, and drug targets for the development of a novel insecticide. PMID- 30443013 TI - Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia. AB - There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann-Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20 90%) in PUNLMP, 30% (range 5-100%) in PUC-LG, 20% (range 1-100%), in PUC-HG, 35% (range 5-100%) in UC but staining was rarely detected (range 0-10%) in normal urothelial mucosa. Defining cases in which K17 was detected in >=10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80 96%) and the specificity was 88% (95% CI: 70-95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens. PMID- 30443015 TI - Targeting NAD+ synthesis to boost mitochondrial function and protect the kidney. PMID- 30443014 TI - ALMS1-NKCC2 interactions. PMID- 30443016 TI - Effector and regulatory B cells in immune-mediated kidney disease. AB - B cells have a central role in many autoimmune diseases, including in those with renal involvement, as well as in the immunological response to kidney transplantation. The majority of B cell studies have focused on their pathological role as antibody producers. However, these cells have broad functions in immune responses beyond immunoglobulin secretion, including antigen presentation to T cells and cytokine production. Importantly, not all B cell subsets enhance immune responses. Regulatory B (Breg) cells attenuate inflammation and contribute to the maintenance of immune tolerance. Breg cells are numerically deficient and/or dysfunctional in several autoimmune diseases that can affect the kidneys, including systemic lupus erythematosus and anti neutrophil cytoplasmic antibody-associated vasculitis, as well as in some groups of renal transplant recipients with alloimmune graft damage. B cell-targeting biologics have been trialled with promising results in diverse immune-mediated renal conditions. These therapies can affect both pro-inflammatory B cells and Breg cells, potentially limiting their long-term efficacy. Future strategies might involve the modulation of pro-inflammatory B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B cell subsets in patients may lead to the discovery of novel biomarkers that could help to predict disease relapse or progression. PMID- 30443018 TI - Author Correction: Circulating Fibroblast Growth Factor 21 is Associated with Subsequent Renal Injury Events in Patients Undergoing Coronary Angiography. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30443019 TI - Control and dysregulation of redox signalling in the gastrointestinal tract. AB - Redox signalling in the gastrointestinal mucosa is held in an intricate balance. Potent microbicidal mechanisms can be used by infiltrating immune cells, such as neutrophils, to protect compromised mucosae from microbial infection through the generation of reactive oxygen species. Unchecked, collateral damage to the surrounding tissue from neutrophil-derived reactive oxygen species can be detrimental; thus, maintenance and restitution of a breached intestinal mucosal barrier are paramount to host survival. Redox reactions and redox signalling have been studied for decades with a primary focus on contributions to disease processes. Within the past decade, an upsurge of exciting findings have implicated subtoxic levels of oxidative stress in processes such as maintenance of mucosal homeostasis, the control of protective inflammation and even regulation of tissue wound healing. Resident gut microbial communities have been shown to trigger redox signalling within the mucosa, which expresses similar but distinct enzymes to phagocytes. At the fulcrum of this delicate balance is the colonic mucosal epithelium, and emerging evidence suggests that precise control of redox signalling by these barrier-forming cells may dictate the outcome of an inflammatory event. This Review will address both the spectrum and intensity of redox activity pertaining to host-immune and host-microbiota crosstalk during homeostasis and disease processes in the gastrointestinal tract. PMID- 30443020 TI - Loss of miR-144 signaling interrupts extracellular matrix remodeling after myocardial infarction leading to worsened cardiac function. AB - We have previously shown that MicroRNA (miR) -144 is a key modulator of the acute cardioprotection associated with remote ischemic preconditioning and post myocardial infarction (MI) remodeling. In this study we examine the biology of the remodeling response after permanent ligation of the left anterior descending coronary artery in male miR-144 KO mice, and wild-type littermates (WT). Collagen content and cross linking were determined by hydroxyproline and pyridinoline assays, MI size and scar thickness were measured post PicoSirius Red staining, and cardiac function was evaluated by echocardiography. miR-144 KO mice developed normally with normal cardiac function, however after MI, infarction size was greater and scar thickness was reduced in miR-144 KO mice compared with WT littermates. miR-144 KO mice had a lower incidence of acute cardiac rupture compared with WT littermates early after MI but there was impaired late remodeling, reflected by increased total cardiac collagen content and collagen cross-linkage associated with changes in Zeb1/LOX1 axis, and decreased left ventricular ejection fraction. We conclude that miR-144 is involved in extracellular matrix remodeling post MI and its loss leads to increased myocardial fibrosis and impaired functional recovery. PMID- 30443017 TI - The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain. AB - The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature. PMID- 30443021 TI - Sigma-2 Receptor/TMEM97 and PGRMC-1 Increase the Rate of Internalization of LDL by LDL Receptor through the Formation of a Ternary Complex. AB - CRISPR/Cas gene studies were conducted in HeLa cells where either PGRMC1, TMEM97 or both proteins were removed via gene editing. A series of radioligand binding studies, confocal microscopy studies, and internalization of radiolabeled or fluorescently tagged LDL particles were then conducted in these cells. The results indicate that PGRMC1 knockout (KO) did not reduce the density of binding sites for the sigma-2 receptor (sigma2R) radioligands, [125I]RHM-4 or [3H]DTG, but a reduction in the receptor affinity of both radioligands was observed. TMEM97 KO resulted in a complete loss of binding of [125I]RHM-4 and a significant reduction in binding of [3H]DTG. TMEM97 KO and PGRMC1 KO resulted in an equal reduction in the rate of uptake of fluorescently-tagged or 3H-labeled LDL, and knocking out both proteins did not result in a further rate of reduction of LDL uptake. Confocal microscopy and Proximity Ligation Assay studies indicated a clear co-localization of LDLR, PGRMC1 and TMEM97. These data indicate that the formation of a ternary complex of LDLR-PGRMC1-TMEM97 is necessary for the rapid internalization of LDL by LDLR. PMID- 30443023 TI - Treatment patterns and adherence to antihypertensive combination therapies in Japan using a claims database. AB - Fixed-dose combinations (FDCs) for blood pressure control can simplify prescribing, improve medication adherence, and be cost-effective. In Japan, real world data about the class effects of antihypertensive drugs on medication adherence are limited. Using the nationwide database of medical health claims from Diagnosis Procedure Combination hospitals, treatment patterns and adherence were analyzed for 47,891 patients prescribed antihypertensive medication between April 2014 and March 2015. Adherence was assessed by the proportion of days covered (expressed as % PDC). Patients were prescribed a mean of 2.0 +/- 1.0 antihypertensive drugs and 2.4 +/- 1.7 pills for their index prescription. Mean adherence overall was 91.5% PDC and was inversely correlated with the number of antihypertensive drugs or pills prescribed on the index date. Mean % PDC was significantly higher (all P < 0.0001) for CCB + ARB versus ARB + thiazide diuretic combinations and for CCB + ARB + beta-blocker versus CCB + ARB + thiazide diuretic combinations. Adherence was significantly higher (P < 0.0001) for FDC (CCB + ARB) versus corresponding single-drug combinations, but not for other comparisons of FDCs versus single-drug combinations. On the other hand, FDCs were not always used effectively; specifically, FDCs were frequently used concomitantly with a single agent(s) from the same drug class(es) as the FDC. From the results of our study, no clear differences were observed in medication adherence according to the presence or absence of FDC formulations, and there were cases in which FDCs were not being utilized effectively to simplify prescribing. PMID- 30443022 TI - High fish density delays wound healing in Atlantic salmon (Salmo salar). AB - In this study, we look closer at how high fish densities influence wound repair mechanisms in post-smolt Atlantic salmon. The fish were wounded with a 5 mm skin punch biopsy needle and stocked at two different densities, a high fish density (100 kg/m3) treatment and a low fish density treatment (20 kg/m3) serving as the control. The healing wounds were followed for 57 days with samples taken 1, 3, 7, 14, 36, 43 and 57 days post wounding. The transcriptomic analysis suggests that high fish density enhance inflammation and represses cell proliferation, tissue secretion and collagen synthesis in the healing wounds. The histological analysis further showed delayed epidermal and dermal repair in the high fish density treatment compared to control. The overall wound contraction was also altered by the treatment. In conclusion, high fish density enhances immune responses and delay tissue repair, which ultimately results in delayed wound healing. PMID- 30443024 TI - A standardized herbal extract PM014 ameliorates pulmonary fibrosis by suppressing the TGF-beta1 pathway. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease pathologically characterized by loss of epithelial cells and activation of fibroblasts and myofibroblasts. The etiology of IPF remains unclear and the disease pathology is poorly understood with no known efficacious therapy. PM014 is an herbal extract that has been shown to have beneficial effects in pulmonary diseases, which are likely to exert anti-inflammatory bioactions. In the present study, we observed that bleomycin (BLM) caused increased inflammatory infiltration as well as collagen deposition in lungs of mice on day 14 after treatment. Administration of PM014 suppressed BLM-induced inflammatory responses and fibrotic changes in dose-dependent manner in mice. Additionally, we provided in vitro evidence suggesting that PM014 inhibited TGF-beta1-induced epithelial mesenchymal transition (EMT) and fibroblast activation in alveolar epithelial cells and human lung fibroblasts from healthy donor and IPF patients. PM014 appeared to target TGF-beta1 signaling via Smad-dependent pathways and p38 mitogen-activated protein kinases (MAPKs) pathways. Taken together, our data suggest that PM014 administration exerts a protective effect against lung fibrosis and highlight PM014 as a viable treatment option that may bring benefits to patient with IPF. PMID- 30443025 TI - Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways. AB - Besides their well-known roles in digestion and fat solubilization, bile acids (BAs) have been described as signaling molecules activating the nuclear receptor Farnesoid-X-receptor (FXRalpha) or the G-protein-coupled bile acid receptor-1 (GPBAR-1 or TGR5). In previous reports, we showed that BAs decrease male fertility due to abnormalities of the germ cell lineage dependent on Tgr5 signaling pathways. In the presentstudy, we tested whether BA exposure could impact germ cell DNA integrity leading to potential implications for progeny. For that purpose, adult F0 male mice were fed a diet supplemented with cholic acid (CA) or the corresponding control diet during 3.5 months prior mating. F1 progeny from CA exposed founders showed higher perinatal lethality, impaired BA homeostasis and reduced postnatal growth, as well as altered glucose metabolism in later life. The majority of these phenotypic traits were maintained up to the F2 generation. In F0 sperm cells, differential DNA methylation associated with CA exposure may contribute to the initial programming of developmental and metabolic defects observed in F1 and F2 offspring. Tgr5 knock-out mice combined with in vitro strategies defined the critical role of paternal Tgr5 dependent pathways in the multigenerational impacts of ancestral CA exposure. PMID- 30443027 TI - Large modulation capacity in graphene-based slot modulators by enhanced hybrid plasmonic effects. AB - We present an effective scheme to improve the modulation capacity in graphene based silicon modulator by employing the double slots configuration with hybrid plasmonic effects. Two modulators, i.e., metal-insulator-metal and insulator metal-insulator configurations have been demonstrated, showing that the double slots design can significantly improve the modulation efficiency. The obtained modulation efficiency is up to 0.525 dB/MUm per graphene layer, far exceeding previous studies. It can be found that the light-graphene interaction plays a pivotal role in the modulation efficiency, whereas the height of metal has profound influence on the modulation. Our results may promote various future modulation devices based on graphene. PMID- 30443026 TI - Deciphering the molecular basis of mycobacteria and lipoglycan recognition by the C-type lectin Dectin-2. AB - Dectin-2 is a C-type lectin involved in the recognition of several pathogens such as Aspergillus fumigatus, Candida albicans, Schistosoma mansonii, and Mycobacterium tuberculosis that triggers Th17 immune responses. Identifying pathogen ligands and understanding the molecular basis of their recognition is one of the current challenges. Purified M. tuberculosis mannose-capped lipoarabinomannan (ManLAM) was shown to induce signaling via Dectin-2, an activity that requires the (alpha1 -> 2)-linked mannosides forming the caps. Here, using isogenic M. tuberculosis mutant strains, we demonstrate that ManLAM is a bona fide and actually the sole ligand mediating bacilli recognition by Dectin-2, although M. tuberculosis produces a variety of cell envelope mannoconjugates, such as phosphatidyl-myo-inositol hexamannosides, lipomannan or manno(lipo)proteins, that bear (alpha1 -> 2)-linked mannosides. In addition, we found that Dectin-2 can recognize lipoglycans from other bacterial species, such as Saccharotrix aerocolonigenes or the human opportunistic pathogen Tsukamurella paurometabola, suggesting that lipoglycans are prototypical Dectin-2 ligands. Finally, from a structure/function relationship perspective, we show, using lipoglycan variants and synthetic mannodendrimers, that dimannoside caps and multivalent interaction are required for ligand binding to and signaling via Dectin-2. Better understanding of the molecular basis of ligand recognition by Dectin-2 will pave the way for the rational design of potent adjuvants targeting this receptor. PMID- 30443029 TI - Author Correction: All-optical control of light on a graphene-on-silicon nitride chip using thermo-optic effect. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30443030 TI - Estimation of the ion-trap assisted electrical loads and resulting BBR shift. AB - Capacitive, inductive and resistive loads of an ion-trap system, which can be modelled as LCR circuits, are important to know for building a high accuracy experiment. Accurate estimation of these loads is necessary for delivering the desired radio frequency (RF) signal to an ion trap via an RF resonator. Of particular relevance to the trapped ion optical atomic clock, determination of these loads lead to accurate evaluation of the Black-Body Radiation (BBR) shift resulting from the inaccurate machining of the ion-trap itself. We have identified different sources of these loads and estimated their values using analytical and finite element analysis methods, which are found to be well in agreement with the experimentally measured values. For our trap geometry, we obtained values of the effective inductive, capacitive and resistive loads as: 3.1 MUH, 3.71 (1) MUH, 3.68 (6) MUH; 50.4 pF, 51.4 (7) pF, 40.7 (2) pF; and 1.373 Omega, 1.273 (3) Omega, 1.183 (9) Omega by using analytical, numerical and experimental methods, respectively. The BBR shift induced by the excess capacitive load arising due to machining inaccuracy in the RF carrying parts has been accurately estimated, which results to a fractional frequency shift of 6.6 * 10-17 for an RF of 1 kV at 2pi * 15 MHz and with +/-10 MUm machining inaccuracy. This needs to be incorporated into the total systematic uncertainty budget of a frequency standard as it is about one order of magnitude higher than the present precision of the trapped ion optical clocks. PMID- 30443031 TI - Abdominal aortic aneurysm: update on pathogenesis and medical treatments. AB - Abdominal aortic aneurysm (AAA) rupture is an important cause of death in adults. Currently, the only treatment for AAA is open or endovascular surgical repair. In most parts of the developed world, AAAs can be identified at an early stage as a result of incidental imaging and screening programmes. Randomized clinical trials have demonstrated that early elective surgical repair of these small AAAs is not beneficial, and an unmet clinical need exists to develop medical therapies for small AAAs that limit or prevent the progressive expansion and rupture of the aneurysm. A large amount of research is currently being performed to increase the understanding of AAA pathogenesis and ultimately lead to the development of medical therapies, such as drug-based and cell-based strategies for this disease. This Review summarizes the latest research findings and current theories on AAA pathogenesis, including discussion of the pros and cons of current rodent models of AAA, and highlights potential medical therapies for AAA, summarizing previous, ongoing and potential clinical trials of medical interventions for small AAAs. This expanding volume of research on AAA is expected to result in a range of novel medical therapies for AAA within the next decade. PMID- 30443028 TI - Safe and efficient novel approach for non-invasive gene electrotransfer to skin. AB - Gene transfer into cells or tissue by application of electric pulses (i.e. gene electrotransfer (GET)) is a non-viral gene delivery method that is becoming increasingly attractive for clinical applications. In order to make GET progress to wide clinical usage its efficacy needs to be improved and the safety of the method has to be confirmed. Therefore, the aim of our study was to increase GET efficacy in skin, by optimizing electric pulse parameters and the design of electrodes. We evaluated the safety of our novel approach by assaying the thermal stress effect of GET conditions and the biodistribution of a cytokine expressing plasmid. Transfection efficacy of different pulse parameters was determined using two reporter genes encoding for the green fluorescent protein (GFP) and the tdTomato fluorescent protein, respectively. GET was performed using non-invasive contact electrodes immediately after intradermal injection of plasmid DNA into mouse skin. Fluorescence imaging of transfected skin showed that a sophistication in the pulse parameters could be selected to get greater transfection efficacy in comparison to the standard ones. Delivery of electric pulses only mildly induced expression of the heat shock protein Hsp70 in a luminescent reporting transgenic mouse model, demonstrating that there were no drastic stress effects. The plasmid was not detected in other organs and was found only at the site of treatment for a limited period of time. In conclusion, we set up a novel approach for GET combining new electric field parameters with high voltage short pulses and medium voltage long pulses using contact electrodes, to obtain a high expression of both fluorescent reporter and therapeutic genes while showing full safety in living animals. PMID- 30443032 TI - RNA sequencing-based analysis of the laying hen uterus revealed the novel genes and biological pathways involved in the eggshell biomineralization. AB - Eggshell is the outermost calcified covering of an egg that protects it from microbial invasion and physical damage, and is critical for egg quality. However, understanding of the genes/proteins and the biological pathways regulating the eggshell formation is still obscure. We hypothesized that the transcriptomic analysis of the chicken uteri using RNA-sequencing may reveal novel genes and biological pathways involved in the eggshell biomineralization. RNA-sequence analysis using uteri of laying hens at 15-20 h post-ovulation (layers, n = 3) and non-laying (non-layers, n = 3) hens was carried out. About 229 differentially expressed genes (DEGs) were up-regulated in the layers compared to the non layers. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Ingenuity Pathway Analysis (IPA) revealed more than ten novel genes and biological pathways related to calcium transport and mineralization in the uterus. Based on the enriched pathways and molecular function analysis, 12 DEGs related to eggshell mineralization were further analyzed in the uteri of layers (3 h and 15-20 h post ovulation), non-layers and molters using qPCR. Expressions of OC-116 (regulator of mineralization), OTOP2 (modulator of cellular calcium influx), CALCB (intracellular release of Ca-ions), STC2 (increases alkaline phosphatase activity), and ATP2C2 (cellular import of Ca-ions) were significantly higher in the uteri of laying hen at 15-20 h post-ovulation. This study identified the involvement of novel genes and their proposed biological pathways in the regulation of eggshell formation. PMID- 30443033 TI - Author Correction: Subwavelength angle-sensing photodetectors inspired by directional hearing in small animals. AB - In the version of this Letter originally published, Zongfu Yu was mistakenly not noted as being a corresponding author; this has now been corrected in all versions of the Letter. PMID- 30443035 TI - Neurodegenerative polyglutamylation. PMID- 30443034 TI - Active Confirmation Bias in the Evaluative Processing of Food Images. AB - Predictive processing is fundamental to many aspects of the human mind, including perception and decision-making. It remains to be elucidated, however, in which way predictive information impacts on evaluative processing, particularly in tasks that employ bivalent stimulus sets. Various accounts, including framing, proactive interference, and cognitive control, appear to imply contradictory proposals on the relation between prediction and preference formation. To disambiguate whether predictive cues produce congruent biases versus opponent mechanisms in evaluative processing, we conducted two experiments in which participants were asked to rate individual food images. The image database included appetitive and aversive items. In each trial, a cue predicted, with varying degrees of reliability, the valence of the impending food image. In both experiments, we found that the ratings exhibited congruent biases as a function of the reliability of the predictive cue, with the highest evaluations following the most reliable positive-valence predictions. Eye prepositioning further showed a selective spatial bias suggestive of response preparation in line with the predictions. The response times also exhibited a pattern of results consistent with selective preparation, producing slow responses following invalid predictions. The data suggested an active form of evaluative processing, implementing a confirmation bias that aims to accommodate the prediction. PMID- 30443037 TI - FDA reconsiders cardiovascular outcomes trials for diabetes drugs, 10 years on. PMID- 30443038 TI - Author Correction: Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30443036 TI - Psychophysiological correlates between emotional response inhibition and posttraumatic stress symptom clusters. AB - Post-traumatic Stress Disorder (PTSD) is characterized by diverse executive function impairments as well as abnormal emotion processing. The goal of the present study was to examine the relationships between emotional response inhibition and distinct PTSD symptom clusters from a six-factor DSM-5 model. Event-related potentials (ERPs) were measured in an emotional Go/NoGo task among 58 adult survivors from a deadly earthquake. Overall, the commission errors were lower and reaction time was faster for negative pictures compared to neutral pictures. The negative pictures elicited a smaller N2 but larger P3 amplitude compared to neutral and positive pictures, and larger P3 amplitude was further associated with a faster response. Multivariate regression models showed that the PCL score was related to smaller NoGo-N2 amplitude in the negative context, suggesting that the severity of posttraumatic stress symptoms is associated with worse conflict detection. Furthermore, the severity of anhedonia symptom cluster rather than negative affect symptom cluster was associated with fewer commission errors in the positive context, and this result provided electrophysiological evidence for the six-factor model, i.e., a distinction should be made between negative affect symptom cluster and anhedonia symptom cluster. PMID- 30443039 TI - Roles of oxides of nitrogen on quality enhancement of soybean sprout during hydroponic production using plasma discharged water recycling technology. AB - This study was performed to assess the effect of plasma-discharged water recycling technology as irrigation water on soybean sprout production. Two different types of irrigation water were used individually for cultivation, including plasma discharged water as a source of oxides of nitrogen and tap water, irrigation water was recycled for every 30 minutes. Plasma discharged irrigation water reduced overall 4.3 log CFU/ml aerobic microbe and 7.0 log CFU/ml of artificially inoculated S. Typhimurium within 5 minutes and 2 minutes, respectively, therefore sprout production occurs in a hygienic environment. Using of plasma-discharged water for cultivation, increases the amount of ascorbate, asparagine, and gamma-aminobutyric acid (GABA) significantly (p < 0.05), in the part of cotyledon and hypocotyl of soybean sprout during 1 to 4 days of farming. A NO scavenger, 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (cPTIO), was added in irrigation water to elucidate the roles of the oxides of nitrogen such as NO3-, NO2- generated in plasma discharged water. It was observed that all three nutrients decreased in the cotyledon part, whereas ascorbate and GABA contents increased in the hypocotyl and radicle part of bean sprout for the same duration of farming. The addition of NO scavenger in the irrigation water also reduced growth and overall yield of the soybean sprouts. A recycling water system with plasma-discharged water helped to reduce the amount of water consumption and allowed soybean sprouts growth in a hygienic environment during the hydroponic production. PMID- 30443040 TI - On the Hydrogen Bond Strength and Vibrational Spectroscopy of Liquid Water. AB - In the present work, we introduce two new metrics i.e. hydrogen-bond strength and charge-transfer between the donor/acceptor water molecules as a measure of hydrogen-bond rearrangement dynamics. Further, we also employ a simple model based on energy flux through the donor-acceptor water pairs to quantify the extent of the local hydrogen-bond network reorganization. Most importantly, we report a linear relationship between the OH stretch frequency and the charge and energy transfer through donor-acceptor water pairs. We demonstrate that the vibrational frequency fluctuations, which are used to determine third-order non linear spectroscopic observables like the short-time slope of three pulse photon echo, can be used as an analog of the fluctuations in the hydrogen-bond strength and charge-transfer. The timescales obtained from our hydrogen-bond strength correlation and charge-transfer correlation decay are in excellent agreement with the computed frequency-time correlation function, as well as with recent vibrational echo experiments. PMID- 30443041 TI - Co-expression of the Hemagglutinin and Neuraminidase by Heterologous Newcastle Disease Virus Vectors Protected Chickens against H5 Clade 2.3.4.4 HPAI Viruses. AB - Avian influenza remains an important zoonotic disease with a significant global impact. The spread of H5 highly pathogenic avian influenza (HPAI) viruses (clade 2.3.4.4) by migratory birds has caused outbreaks in wide geographic regions (Asia, Europe, and North America) with great economic losses during 2014-2015. Efficient vaccines and vaccination approaches are needed to enhance protective immunity against HPAI viruses. Although several vaccination strategies have been developed, none has been satisfactory. Our strategy has been to use avirulent vaccine strain of Newcastle disease virus (NDV) as a vaccine vector for HPAI viruses. For poultry vaccination, we previously generated a new platform of chimeric NDV vector to overcome preexisting maternal antibodies to NDV in poultry. In this study, we have generated vaccine candidates targeting H5 clade 2.3.4.4 HPAI viruses by using our chimeric NDV and conventional NDV strain LaSota vectors for a heterologous prime-boost immunization approach. Co-expression of the HA and NA proteins by our vaccine vectors induced enhanced HPAI virus specific immune responses in specific-pathogen free and broiler chickens prior to challenge. Further, these vaccine candidates efficiently protected broiler chickens from mortality, clinical signs, and shedding of homologous and heterologous H5 HPAI viruses and highly virulent NDV, thus providing a dual vaccination approach in the field. PMID- 30443042 TI - Individual-specific functional connectivity markers track dimensional and categorical features of psychotic illness. AB - Neuroimaging studies of psychotic disorders have demonstrated abnormalities in structural and functional connectivity involving widespread brain networks. However, these group-level observations have failed to yield any biomarkers that can provide confirmatory evidence of a patient's current symptoms, predict future symptoms, or predict a treatment response. Lack of precision in both neuroanatomical and clinical boundaries have likely contributed to the inability of even well-powered studies to resolve these key relationships. Here, we employed a novel approach to defining individual-specific functional connectivity in 158 patients diagnosed with schizophrenia (n = 49), schizoaffective disorder (n = 37), or bipolar disorder with psychosis (n = 72), and identified neuroimaging features that track psychotic symptoms in a dimension- or disorder specific fashion. Using individually specified functional connectivity, we were able to estimate positive, negative, and manic symptoms that showed correlations ranging from r = 0.35 to r = 0.51 with the observed symptom scores. Comparing optimized estimation models among schizophrenia spectrum patients, positive and negative symptoms were associated with largely non-overlapping sets of cortical connections. Comparing between schizophrenia spectrum and bipolar disorder patients, the models for positive symptoms were largely non-overlapping between the two disorder classes. Finally, models derived using conventional region definition strategies performed at chance levels for most symptom domains. Individual-specific functional connectivity analyses revealed important new distinctions among cortical circuits responsible for the positive and negative symptoms, as well as key new information about how circuits underlying symptom expressions may vary depending on the underlying etiology and illness syndrome from which they manifest. PMID- 30443043 TI - The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. AB - The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and beta-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers. PMID- 30443044 TI - HIV infection alters the human epigenetic landscape. AB - Many complex diseases or traits are the results of both genetic and environmental factors. The environmental factors affect the human body by modifying its epigenetics, which controls the activity of genomes without mutating it. Viral infection is one of the common environmental factors for complex diseases. For example, the human immunodeficiency virus (HIV) infection can cause acquired immune deficiency syndrome (AIDS), HBV, and HCV infections are associated with hepatocellular carcinoma, and human papillomavirus infection is a causal factor in cervical carcinoma. In this study, to investigate how HIV infection affects DNA methylation, we analyzed the blood DNA methylation data of 485 512 sites in 44 HIV- and 142 HIV + patients. Several advanced computational methods were applied to identify the core distinctive features that were different between the HIV patients and the healthy controls. These methods can be used for differentiating HIV-infected patients from uninfected ones. These core distinctive DNA methylation features were confirmed to be functionally connected to premature aging and abnormal immune regulation, two typical pathological symptoms of HIV infection, revealing the potential regulatory mechanisms of HIV infection on the DNA methylation status of the host cells and provided novel insights on the pathogenesis of HIV infection and AIDS. PMID- 30443045 TI - Trends in referral format and dental notation used in primary care referrals to dental specialists. PMID- 30443046 TI - Dismantling Knowledge Boundaries at NASA: The Critical Role of Professional Identity in Open Innovation. AB - Using a longitudinal in-depth field study at NASA, I investigate how the open, or peer-production, innovation model affects R&D professionals, their work, and the locus of innovation. R&D professionals are known for keeping their knowledge work within clearly defined boundaries, protecting it from individuals outside those boundaries, and rejecting meritorious innovation that is created outside disciplinary boundaries. The open innovation model challenges these boundaries and opens the knowledge work to be conducted by anyone who chooses to contribute. At NASA, the open model led to a scientific breakthrough at unprecedented speed using unusually limited resources; yet it challenged not only the knowledge-work boundaries but also the professional identity of the R&D professionals. This led to divergent reactions from R&D professionals, as adopting the open model required them to go through a multifaceted transformation. Only R&D professionals who underwent identity refocusing work dismantled their boundaries, truly adopting the knowledge from outside and sharing their internal knowledge. Others who did not go through that identity work failed to incorporate the solutions the open model produced. Adopting open innovation without a change in R&D professionals' identity resulted in no real change in the R&D process. This paper reveals how such processes unfold and illustrates the critical role of professional identity work in changing knowledge-work boundaries and shifting the locus of innovation. PMID- 30443048 TI - Human Capital and the Wealth of Nations?. AB - We reevaluate the role of human capital in determining the wealth of nations. We use standard human capital theory to estimate stocks of human capital and allow the quality of human capital to vary across countries. Our model can explain differences in schooling and earnings profiles and, consequently, estimates of Mincerian rates of return across countries. We find that effective human capital per worker varies substantially across countries. Cross-country differences in Total Factor Productivity (TFP) are significantly smaller than found in previous studies. Our model implies that output per worker is highly responsive to changes in TFP and demographic variables. PMID- 30443047 TI - Design of Potent Inhibitors for Human Brain Memapsin 2 (beta-Secretase). PMID- 30443049 TI - Citizenship and Punishment: The Salience of National Membership in U.S. Criminal Courts. AB - When compared to research on the association between immigration and crime, far less attention has been given to the relationship between immigration, citizenship, and criminal punishment. As such, several fundamental questions about how noncitizens are sanctioned and whether citizenship is a marker of stratification in U.S. courts remain unanswered. Are citizens treated differently than noncitizens-both legal and undocumented-in U.S. federal criminal courts? Is the well-documented Hispanic-white sentencing disparity confounded by citizenship status? Has the association between citizenship and sentencing remained stable over time? And are punishment disparities contingent on the demographic context of the court? Analysis of several years of data from U.S. federal courts indicates that citizenship status is a salient predictor of sentencing outcomes more powerful than race or ethnicity. Other notable findings include the following: accounting for citizenship substantially attenuates disparities between whites and Hispanics; the citizenship effect on sentencing has grown stronger over time; and the effect is most pronounced in districts with growing noncitizen populations. These findings suggest that as international migration increases, citizenship may be an emerging and powerful axis of sociolegal inequality. PMID- 30443050 TI - Influence of short periods of increased water temperature on species composition and photosynthetic activity in the Baltic periphyton communities. AB - Periphyton plays a vital ecological role in shallow, well-lit ecosystems which are vulnerable to rapidly changing environmental conditions, including raising temperature due to global warming. Nevertheless, little is known on the effect of increased temperatures on the taxonomic structure and functioning of periphytic communities. In this study, the influence of short-term temperature increase on the species composition and photosynthetic activity of the Baltic periphytic communities was investigated. The collected communities were exposed to increased temperature of 23 degrees C (ca. 4 degrees C above the summer average) for 72 h. After this time, species composition of the communities was studied under light microscope and their photosynthetic performance was evaluated using PAM fluorometry. Results showed that the biomass of cyanobacteria slightly increased. There were significant changes in the abundance of diatom species, among which Fragilaria fasciculata and Navicula ramosissima, were negatively affected by the elevated temperature and their cell number significantly decreased, whereas, Diatoma moniliformis and N. perminuta were stimulated by the increased temperature. Additionally, a shift towards higher abundance of smaller taxa was also observed. The higher quantum yield of photosystem II (PSII) (higher PhiPSII) accompanied by the lower value of non-photochemical quenching (NPQ) observed in communities kept at 23 degrees C showed more efficient photosynthesis. This was further confirmed by the changes in rapid light curves (higher photosynthetic capacity, rETRmax, and photoacclimation index, Ek). The obtained data constitute evidence that short periods of increased temperature significantly affect the structure and functioning of the Baltic periphyton. PMID- 30443051 TI - Content in Simple Signalling Systems. AB - Our understanding of communication and its evolution has advanced significantly through the study of simple models involving interacting senders and receivers of signals. Many theorists have thought that the resources of mathematical information theory are all that are needed to capture the meaning or content that is being communicated in these systems. However, the way theorists routinely talk about the models implicitly draws on a conception of content that is richer than bare informational content, especially in contexts where false content is important. This article shows that this concept can be made precise by defining a notion of functional content that captures the degree to which different states of the world are involved in stabilizing senders' and receivers' use of a signal at equilibrium. A series of case studies is used to contrast functional content with informational content, and to illustrate the explanatory role and limitations of this definition of functional content. 1 Introduction 2 Modelling Framework 3 Two Kinds of Content 3.1 Informational content 3.2 Functional content 4 Cases 4.1 Case 1: Simplest case 4.2 Case 2: Partial pooling 4.3 Case 3: Bottleneck 4.4 Case 4: Partial common interest 4.5 Case 5: Deception 4.6 Case 6: A further problem arising from divergent interests 5 Discussion Appendix . PMID- 30443052 TI - Parliamentarians in government delegations: An old question still not answered. AB - Why do governments include parliamentarians in the delegations to international negotiations? Conduct of the diplomatic negotiations is among the most tightly controlled prerogatives of the executive, and executives have been historically dominant in the conduct of foreign policy. This article draws on the participation of members of parliaments in national delegations to the Review Conferences of the Non-Proliferation Treaty over the past 40 years. The emerging patterns show that legitimation through oversight is unlikely to be the reason for participation. Drawing on literature on institutional variation in legislative-executive relations, the data indicate that executives are more interested in co-opting the parliamentarians, in order to make them less opposed to the government's policy. PMID- 30443053 TI - Probing the future - Can gastric ultrasound herald a change in perioperative fasting guidelines? PMID- 30443054 TI - Perioperative stroke - Prediction, Prevention, and Protection. AB - Stroke culminates into 6.2 million deaths annually and is thereby a leading cause of disability and death worldwide. In patients undergoing noncardiac, nonneurological surgery, perioperative stroke can eventuate into a catastropic aftermath with almost eight-fold rise in mortality. In cardiac, neurological, and carotid surgery, stroke rate accounts to be high (2.2%-5.2%) and is a significant instigator of morbidity and mortality as well. These facts kindle interest to review the predictive parameters, preventive measures, and all the possibilities in the management and protection against perioperative stroke. PMID- 30443055 TI - Anaesthesiologist and social media: Walking the fine line. AB - Social media use is pervasive in society and has been rapidly amalgamated into the lives of anaesthesiologists. Using social media as an educational resource and ensuring an appropriate online presence is essential for professional growth. However, there are huge lacunae in editorial responsibility, peer review, and accountability of educational content on social media networks. The anaesthesiologist needs to be aware of the numerous shortcomings and must use social media responsibly. Following etiquettes, adopting a code of conduct and a high sense of professionalism is expected from the anaesthesiologist while posting on social media. Anaesthesiologists need to decide on their social media goals, like interaction with colleagues, continuing medical education or patient education, and then register for social media accounts accordingly. The need of the hour is comprehensive social media guidelines for anaesthesiologists, endorsed by institutions, societies, and professional health-care associations in India. PMID- 30443056 TI - Effectiveness of standard fasting guidelines as assessed by gastric ultrasound examination: A clinical audit. AB - Background and Aims: An audit was conducted between July 2017 and November 2017 to assess the adequacy of American Society of Anesthesiologists (ASA) fasting guidelines on 246 patients by means of gastric ultrasonography (USG). The relevance of this audit is that many of our patients have one or more risk factors for aspiration such as diabetes mellitus, chronic kidney disease (CKD), gastro-oesophageal reflux disease (GERD), and obesity. Methods: This audit was a prospective observational study which included all patients posted for surgery within the audit period. Patients were fasted according to ASA fasting guidelines. Their gastric content was assessed preoperatively using USG. The residual gastric volume was calculated using a validated formula. Statistical correlation between gastric volumes and the risk factors were analysed. Results: Of 246 patients, 69 (28.04%) had high residual gastric volume. We found no correlation between hours of fasting and residual gastric volume (P = 0.47). We found a linear correlation between rising body mass index and residual gastric volume (P < 0.0001). Patients with GERD had 2.3 times higher risk. The CKD patient subgroup had 24 patients (30%) with high residual gastric volume. No incidents of aspiration were noted. Conclusion: In our audit, we found that risk factor association has a greater effect on residual gastric volume than hours of fasting. While the current fasting guidelines are adequate for healthy individuals, they are not conclusive in patients with risk factors. Ultrasound assessment of preoperative gastric volume is an effective screening tool in patients with risk factors. PMID- 30443057 TI - Preoperative assessment of gastric contents and volume using bedside ultrasound in adult patients: A prospective, observational, correlation study. AB - Background and Aims: Pulmonary aspiration of gastric contents is a serious complication of anaesthesia. The aim of this study was to determine, with the help of ultrasound, the gastric volume and content in fasted patients presenting for elective surgeries and correlate the results with fasting times and co morbidities of the patients. Methods: The study was conducted in 100 adult patients presenting for elective surgery. A preoperative bedside gastric ultrasound scan was done in supine and right lateral position. Gastric contents were noted, and gastric volume was calculated at the level of the gastric antrum. Gastric volume was estimated by measuring antral cross-sectional area (CSA) and using a mathematical model. Gastric volume in the right lateral decubitus (RLD) position was taken as the final reading. Analysis of variance and Student's t test were done for statistical significance and P < 0.05 was considered statistically significant. Results: Six out of 100 patients had solid gastric contents and 16 had >1.5 ml/kg clear liquids, although they had been fasting between 10 and 15 hours. Patients suffering from diabetes and chronic kidney disease had statistically significant increase in CSA in both supine and RLD. We also found increase in estimated gastric volume as the BMI of the patients increased. Conclusion: Our study showed that fasting for more than 6-10 hours does not guarantee an empty stomach. Those with co-morbidities like diabetes mellitus, obesity and chronic kidney disease (CKD) appear more prone to have unsafe gastric contents. PMID- 30443058 TI - Comparing epidural and wound infiltration analgesia for total abdominal hysterectomy: A randomised controlled study. AB - Background and Aims: Continuous wound infiltration (CWI) is emerging as an alternative to continuous epidural infusion (CEI). This study compared postoperative pain scores of CEI with CWI in patients undergoing total abdominal hysterectomy (TAH). Methods: This prospective randomised controlled trial included 102 patients planned for TAH who were randomised into either Group E (CEI) or Group L (CWI). The catheter (epidural/wound infiltration) was inserted in Group E before induction) and Group L at the end of surgery. General anaesthesia was administered according to standard protocol. At the end of surgery, both groups received 10 mL bolus of 0.2% ropivacaine followed by infusion at 6 mL/h through the respective catheters. They also received intravenous patient-controlled analgesia with morphine. The primary outcome was the visual analogue score at rest (VASR) and at deep breathing (VASDB) post operatively. Secondary outcomes were post-operative morphine consumption, side effects and patient satisfaction. Results: The mean VASR between two groups were comparable up to 8 h. Group E showed significantly reduced VASR compared to Group L at 12 h (2.32 +/- 0.59 vs 2.62 +/- 0.67, P = 0.019) and 24 h (2.30 +/- 0.58 vs 2.62 +/- 0.57, P = 0.006). Group E showed significantly reduced VASDB compared to Group L at 5 min and from 4 to 24 h. Total morphine consumption, side effects and patient satisfaction were comparable. Conclusion: We conclude that CEI is a superior analgesic technique compared to CWI in total abdominal hysterectomy in terms of reduced pain scores. PMID- 30443059 TI - Continuous spinal anaesthesia: A retrospective analysis of 318 cases. AB - Background and Aims: Continuous spinal anaesthesia (CSA) is an underutilised anaesthetic technique. Our objectives were to evaluate the use of CSA in our institution, its efficacy, ease to use and safety. Methods: This was a retrospective analysis conducted in a tertiary centre. Records of all patients who underwent surgery and received CSA between December 2008 and July 2017 were reviewed. Their demographic profiles, type and duration of surgery were analysed. The outcomes measured were the success of CSA, technical evaluation and difficulties encountered, intraoperative haemodynamics, usage of vasopressors and any reported complications. Statistical analysis was done using Chi-square test. Results: Three hundred and eighteen patients (94%) successfully underwent surgery using CSA. Twenty cases (6%) had failed CSA, of which five of them had CSA insertion failure, while the rest failed to complete the operation under CSA, thus requiring conversion to general anaesthesia. Patients who have had an initial intrathecal local anaesthetic (LA) volume >=1.5 ml had higher odds (odds ratio (OR) 2.78; 95% confidence interval [CI], 1.70-4.57) of developing hypotension compared to those who had <1.5 ml (P < 0.001). There were no reported post-dural puncture headache, neurological sequelae or infection. Conclusion: CSA is a useful anaesthetic technique with low failure rate. The key to achieving haemodynamic stability is by giving a small initial bolus, then titrating the block up to required height using aliquots of 0.5 ml of intrathecal LA through the catheter. PMID- 30443060 TI - Comparison of palonosetron and dexamethasone with ondansetron and dexamethasone for postoperative nausea and vomiting in postchemotherapy ovarian cancer surgeries requiring opioid-based patient-controlled analgesia: A randomised, double-blind, active controlled study. AB - Background and Aims: Patients undergoing ovarian cancer surgery after chemotherapy and requiring opioid-based patient-controlled analgesia (PCA) are at high-risk of postoperative nausea and vomiting (PONV). We aimed to assess the effect of palonosetron and dexamethasone combination for these patients for prevention of PONV. Methods: This study included 2 groups and 150 patients. At the time of wound closure, patients in group A received ondansetron 8 mg intravenous (IV) + dexamethasone 4 mg IV and group B received palonosetron 0.075 mg IV + dexamethasone 4 mg IV. Postoperatively for 48 hours, group A patients received ondansetron 4 mg 8 hourly IV, group B patients received normal saline 8 hourly IV in 2 cc syringe. The primary objective was the overall incidence of PONV. Independent t-test, Chi-square test, and Fisher's exact test were used and multivariate regression analysis was done. Results: Vomiting was significantly higher in group A (37.3%) as compared with group B (21.3%) at 0-48 hours (P = 0.031). Significantly more patients in Group A had nausea as compared with group B at 90-120 minutes (30.66% vs 18.66%, P = 0.043) and 6-24 hours (32.0% vs 22.66%, P = 0.029). PCA opioid usage in microgram was significantly higher in group A at 0-24 hours (690.53 +/- 332.57 vs 576.85 +/- 250.79, P = 0.024) and 0 48 hours (1126.10 +/- 512.18 vs 952.13 +/- 353.85, P = 0.030). Conclusion: Palonosetron with dexamethasone is more effective than ondasetron with dexamethasone for prevention of PONV in post-chemotherapy ovarian cancer surgeries receiving opioid-based patient controlled analgesia. PMID- 30443061 TI - EO technique provides better mask seal than the EC clamp technique during single handed mask holding by novices in anaesthetised and paralysed patients. AB - Background and Aims: Bag mask ventilation (BMV) allows for oxygenation and ventilation of patients until a definitive airway is secured and when definitive airway is difficult/impossible. This study hypothesised that the EO (thumb and index finger form a O shape around the mask) technique of mask holding provides better mask seal with the novices compared to the classic EC clamp technique (thumb and index finger form a C shape around the mask). Methods: Sixty patients participated in this double blinded, prospective, crossover study. The patients were randomly allocated to either EC or EO group. After adequate anaesthesia and neuromuscular blockade, a novice (experience of less than five attempts at BMV) held the mask with preferred hand with the allotted technique, while the ventilator provided five breaths at set pressure control of 15 cm H2O with one second each for inspiration and expiration. After recording the exhaled tidal volume (primary objective) for each breath for five consecutive breaths, the study was repeated with the other technique. Secondary outcome variables were minute ventilation, audible mask and epigastric leak. Results: The tidal volume and minute ventilation were significantly better with EO technique compared with the EC technique (P = 0.001, a tidal volume difference of 46 mL and P = 0.001, a minute volume difference of 0.51 L). Conclusion: The EO technique provides better mask seal (superior tidal volumes) than the conventional EC technique during single-handed mask holding performed by novices in the absence of other factors contributing to difficulty in mask ventilation. PMID- 30443062 TI - Pattern of anaesthetic equipment contamination and infection prevention in anaesthesia practice at university hospitals. AB - Background and Aims: Infection control is essential in anaesthetic practice for both personnel and equipment used. This study aims to evaluate knowledge of anaesthesiologists about infection control practices and to detect the pattern of anaesthetic devices contamination. Methods: Cross-sectional observational study at two university hospitals was done. Self-administered questionnaires were distributed to 80 anaesthesiologists and 90 nursing staff. Forty-four samples were taken from rigid laryngoscopes (22 pairs from handle and blade) for detection of bacterial or fungal contamination. Same laryngoscopes were tested for occult blood. Results: The response rate among the physicians was 72% while for nurses 94.4%. The responses were variable reflecting lack of adequate knowledge and unsatisfactory compliance to infection control practices. Tested samples showed no fungal growth. Fourteen (31.8%) samples were negative for bacteriological contamination and 5/44 (11.4%) showed gram-positive bacilli; gram positive cocci were isolated from 12 samples (27.3%) where Staphylococcus epidermidis and Staphylococcus aureus, respectively, shared 18.2% and 9.1% of the total samples. Gram-negative bacilli were isolated from 13 samples (29.5%), of which Klebsiella spp. were most frequent (11.4%). Both Pseudomonas aeruginosa and Acinetobacter baumannii were isolated from 6.8% each. Citerobacter spp. was isolated from 4.5%. Occult blood was found in 45.5% of samples. Conclusion: The current study showed contamination of ready-to-use laryngoscopes in operative theatres and ICUs. PMID- 30443063 TI - Sevoflurane versus isoflurane in shoulder arthroscopy in beach chair position in patients with prior interscalene brachial plexus block: A prospective randomised equivalency-based haemodynamic evaluation trial. AB - Background and Aims: There is a paucity of literature on comparative effects of different inhalational anaesthetics in beach chair position (BCP) for shoulder arthroscopy. We aimed to investigate and compare the haemodynamic effects, anaesthetic and surgical outcomes between two inhalational agents. Methods: In this randomised study, patients of age 18-60 years, were allotted to two groups (29, sevoflurane and 28, isoflurane) and received protocol-based anaesthesia. Intraoperatively, different haemodynamic and other data were recorded. Results: All mean of averages of individual subject's vitals were comparable between the groups [P = 0.681, 0.325, 0.803, and 0.051, respectively for systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR)]. Higher mean HR was recorded for maximum readings of isoflurane (P = 0.028). Equivalency was observed for SBP, MBP, and DBP (P = 0.000, 002, and 0.027, respectively). Process capability indices indicated that sevoflurane had better values (Pp: 0.55 versus 0.41, Ppk: 0.35 versus 0.22) for SBP as with MBP (Pp: 0.62 versus 0.51, Ppk: 0.36 versus 0.33). For achieving optimal vision, higher pump pressures (PPs) were demanded by surgeon (P = 0.025) and higher differences observed between initial and highest PPs (P = 0.027), in isoflurane subjects. Multivariable analysis revealed that no continuous predictor was able to predict the quality of vision except additional pump flow factor, for both groups. Conclusion: Both inhalational agents demonstrated equivalent haemodynamic effects. Increased arthroscopic PP requirements were observed with isoflurane anaesthesia. Sevoflurane may be superior to isoflurane during BCP arthroscopy. PMID- 30443064 TI - Combination of lumbar erector spinae plane block and transmuscular quadratus lumborum block for surgical anaesthesia in hemiarthroplasty for femoral neck fracture. AB - Femur neck fractures may occur in elderly patients with multiple co-morbidities. Spinal or general anaesthesia may not be safe in such patients, leading to a search for other safer alternatives. Herein, we report a case in which a never previously reported combination of quadratus lumborum block (QLB) and erector spinae plane block (ESPB) was successfully used as the main anaesthetic method for hemiarthroplasty. An 86-year-old female patient with severe aortic stenosis was scheduled for internal fixation or hemiarthroplasty due to right femoral neck fracture. Following sedoanalgesia, the patient was placed in lateral decubitis position and ESPB and transmuscular QLB were performed from the fourth lumbar vertebra level. Adequate and effective surgical anaesthesia was achieved and hemiarthroplasty was performed. The combination of lumbar ESPB and QLB can be used for the anaesthesia management in high-risk patients undergoing hemiarthroplasty. PMID- 30443065 TI - Fluoroscopic-guided erector spinae plane block: A feasible option. AB - Erector spinae plane block (ESPB) is a new truncal block which has been used successfully to manage many acute and painful conditions including multiple fractured ribs. This block is primarily an ultrasound-guided block. We have evaluated the feasibility of fluoroscopic guidance for this block. We have reported two cases of severe chest pain due to multiple fractured ribs managed successfully with ESPB given under fluoroscopic guidance. PMID- 30443066 TI - Erector spinae plane block: Relatively new block on horizon with a wide spectrum of application - A case series. AB - Erector spinae plane (ESP) block is an interfascial plane block where a local anaesthetic is injected in a plane preferably below the erector spinae muscle. It is supposed to work at the origin of spinal nerves based on cadaveric and contrast study. It has emerged as an effective and safe analgesic regional technique. It has a wide variety of applications ranging from control of acute postoperative pain to chronic pain. In this series, we report a series of six cases, which include postoperative pain management in breast, thoracic, and abdominal surgeries along with management of two chronic pain cases to illustrate the potential uses of continuous and single-shot ESP block. PMID- 30443067 TI - Extubation success can be better predicted by diaphragmatic excursion using ultrasound compared to rapid shallow breathing index. PMID- 30443068 TI - Anaesthetic management of tracheal restenosis in operated cases of tracheal resection and anastomosis: A retrospective review. PMID- 30443069 TI - A fatal and deceiving case of copper sulphate poisoning. PMID- 30443070 TI - Perioperative management of living donor related liver transplantation in an infant for Maple syrup urine disease. PMID- 30443071 TI - Intraoperative error in estimation of blood loss due to change in the size of abdominal swab. PMID- 30443072 TI - Implications of accessory pectoral muscles for ultrasound-guided thoracic wall blocks. PMID- 30443073 TI - Bifid epiglottis, high-arched palate, and mental disorder in a patient with Pallister-Hall syndrome. PMID- 30443074 TI - Perioperative management of a neonate with Cantrell's pentalogy. PMID- 30443075 TI - Caution: Intravenous cannula should not be used for arterial cannulation. PMID- 30443076 TI - Response to comments: Modification of intravenous cannula for arterial line insertion: Simple yet effective technique. PMID- 30443077 TI - Concerns while monitoring patients during awake craniotomy with intraoperative magnetic resonance imaging. PMID- 30443079 TI - Out-of-autoclave manufacturing of GLARE panels using resistance heating. AB - Autoclave manufacturing of fibre metal laminates, such as GLARE, is an expensive process. Therefore, there is an increasing interest to find cost-effective out-of autoclave manufacturing processes without diminishing the laminate quality. The aim of this study is to evaluate the quality of fibre metal laminate panels adhesively bonded and cured using resistance heating. Three manufacturing processes are compared for different layups with an embedded steel mesh at the mid-plane: autoclave curing, resistance bonding of two (autoclave-cured) panels and complete out-of-autoclave resistance curing of panels. Interlaminar shear strength tests and optical microscopy analysis showed that resistance bonding is a promising technique, leading to results comparable to autoclave curing. Resistance curing led to an interlaminar shear strength decrease of 30-60%. A study of the correlation between degree of cure and distance from the mesh revealed the potential of resistance bonding to be used for flexible embedded mesh geometries and on-site repairs. PMID- 30443078 TI - Imaging optical fields below metal films and metal-dielectric waveguides by a scanning microscope. AB - Laser scanning confocal fluorescence microscopy (LSCM) is now an important method for tissue and cell imaging when the samples are located on the surfaces of glass slides. In the past decade, there has been extensive development of nano-optical structures that display unique effects on incident and transmitted light, which will be used with novel configurations for medical and consumer products. For these applications, it is necessary to characterize the light distribution within short distances from the structures for efficient detection and elimination of bulky optical components. These devices will minimize or possibly eliminate the need for free-space light propagation outside of the device itself. We describe the use of the scanning function of a LSCM to obtain 3D images of the light intensities below the surface of nano-optical structures. More specifically, we image the spatial distributions inside the substrate of fluorescence emission coupled to waveguide modes after it leaks through thin metal films or dielectric coated metal films. The observed spatial distribution were in general agreement with far-field calculations, but the scanning images also revealed light intensities at angles not observed with classical back focal plane imaging. Knowledge of the subsurface optical intensities will be crucial in the combination of nano-optical structures with rapidly evolving imaging detectors. PMID- 30443081 TI - Remembering One's Representative: How District Magnitude and List Type Affect Candidate Recognition. AB - District magnitude and list type shape the incentives for politicians to develop a personal vote. If voters also react to these strategies, their knowledge about candidates should be influenced by these features of the electoral system. This article directly tests the responsiveness of voters by employing individual-level survey data from the Comparative Study of Electoral Systems. As district magnitude increases, more people remember at least one candidate in closed list systems, but there is no such effect in open list systems. These influences are also larger for non-voters than for voters. A measure of political contact is not affected in this way. The differential effect of district magnitude can be explained by a different campaign focus. PMID- 30443080 TI - Populism and Support for Protectionism: The Relevance of Opposition to Trade Openness for Leftist and Rightist Populist Voting in The Netherlands. AB - Leftist and rightist populist parties in Western Europe both oppose trade openness. Is support for economic protectionism also relevant for their electorates? We assess this in the Netherlands, where both types of populist parties have seats in parliament. Analyses of representative survey data (n = 1,296) demonstrate that support for protectionism drives voting for such parties, as do the well-established determinants of political distrust (both populist constituencies), economic egalitarianism (leftist populist constituency) and ethnocentrism (rightist populist constituency). Surprisingly, support for protectionism does not mediate the relationship between economic egalitarianism and voting for left-wing populists, or the link between political distrust and voting for either left-wing or right-wing populist parties. In contrast, support for protectionism partly mediates the association between ethnocentrism and voting for right-wing populists. We discuss the largely independent role of protectionism in populist voting in relation to the cultural cleavage in politics and electoral competition, and also provide suggestions for future research. PMID- 30443082 TI - Working against many grains: Rethinking difference, emancipation and agency in the counter-discourse of an ethnic minority women's organisation in Belgium. AB - In this article, we aim to contribute to feminist academic debates about multiculturalism and secularism/religion by drawing upon an analysis of an ethnic minority women's organisation in Belgium that has been active since 1999: ella. The analysis focuses upon the way in which ella constructs notions of empowerment and emancipation by discussing structural inequalities, cultural-ethnic values and religious authority and identity. First, we look at how ella formulates its ideas about the emancipation trajectories of minoritised women and the potential role of religious belonging. Second, we look at ella's discussion of religious interpretation and gender/sexual diversity. Here, we explore assumptions about the relationship between religious authority and minoritised women's and LGBTQs' desires and pursuit for knowledge. We conclude by considering ella as an affirmative-critical actor of multiculturalism, and an implicit agent of religious reform. PMID- 30443083 TI - A Stereoselective Anti-Aldol Route to (3R,3aS,6aR)-Hexahydrofuro[2,3-b] furan-3 ol: A Key Ligand for a New Generation of HIV Protease Inhibitors. AB - A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step. PMID- 30443085 TI - Synthetic studies of microtubule stabilizing agent peloruside A: an asymmetric synthesis of C10-C24 segment. AB - An asymmetric synthesis of the C10-C24 fragment of the potent antitumor macrolide, peloruside A is described. All three stereogenic centers have been enantioselectively constructed utilizing Evans alkylation, Brown asymmetric allylboration, and a substrate controlled epoxide formation. Other key reactions involved Grubbs's ring-closing olefin metathesis and Ando's Z-selective olefination reaction. PMID- 30443084 TI - Synthesis of Bioactive Natural Products by Asymmetric syn- and anti-Aldol Reactions. AB - The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described. PMID- 30443086 TI - Exclusion as urban policy: The Dutch 'Act on Extraordinary Measures for Urban Problems'. AB - The Dutch government introduced the Act on Extraordinary Measures for Urban Problems in 2006 to bolster local regeneration efforts. The act enables local governments to stop specific groups of deprived households from moving into designated neighbourhoods. More specifically, the Act allows local governments to refuse a residence permit to persons who have lived in the metropolitan region for less than six years and who do not receive an income from work, pensions or student loans. The policy is based on the idea that reducing the influx of poor newcomers improves liveability by providing a temporary relief of the demand for public services and by making neighbourhoods demographically 'balanced' or 'socially mixed'. This review examines the socio-spatial effects of the Act in Rotterdam between 2006 and 2013. While the Act produces socio-demographic changes, the state of the living environment in designated areas seems to be worsening rather than improving. Our findings show that the policy restricts the rights of excluded groups without demonstrably improving safety or liveability. The review concludes with a reflection on how the Act may signify a broader change in European statecraft and urban policy. PMID- 30443087 TI - Governing the global locally: Agonistic democracy practices in The Hague's Schilderswijk. AB - Cities have become stages for (inter)national conflicts over political and religious identity, democratic values and ownership of place. These 'glocal urban conflicts' challenge local actors to respond immediately and effectively in ways that prevent escalation and strengthen democratic relations. The theory of agonistic democracy provides a valuable model that celebrates difference and inclusiveness to foster democracy. There is, however, little understanding of how these agnostic ideals are practiced in rapidly unfolding situations. This article provides a case study to further our understanding of dealing with conflicts where global tensions are enacted at the street level. It proposes an interpretative approach that brings into focus how a decentred network of local professionals practice agnostic democracy in action. The local government of The Hague was challenged to 'govern the global locally' when young Muslims waved flags allying with ISIS on the streets of the Schilderswijk neighbourhood. A series of local demonstrations required appropriate responses in a highly mediatised conflict. The analysis provides three 'critical moments' that function as a lens to study governance practices that underscore diversity as a political resource. Practices of 'governing meaning' and 'governing the street' addressed concerns about security, ownership and local grievances. PMID- 30443088 TI - Africa's new cities: The contested future of urbanisation. AB - New private property investments in Africa's cities are on the rise, and they often take the form of entirely new cities built up from scratch as comprehensively planned self-contained enclaves. As these new city-making trajectories are expanding and empirical research is emerging, there is a need to provide more conceptual clarity. We systematically examine the diversity of new cities in Africa; elicit their financial trajectories; and set an agenda for critically examining their actual and expected implications, by learning transnational lessons from debates on gated communities, peri-urban land governance and displacement, and older waves of new city building. Although most new cities are private-led projects, they are inserted into diverse and dynamic political economies with states ranging from developmentalist to neoliberal to absent. The consumptive and supply-driven character of many projects so far (resembling gated communities for middle and higher classes), their insertion into 'rurban' spaces with complex land governance arrangements, and their tendency to implement post-democratic private-sector-driven governance will make them at best unsuitable for solving Africa's urban problems, and at worst they will increase expulsions and enclosures of the poor, public funding injustice and socio-spatial segregation and fragmentation. PMID- 30443089 TI - Nothing Much for Philosophers. AB - In this article, I argue that by discarding the significance of philosophical methods and tools, the picture of field philosophy offered in Socrates Tenured is more akin to public interest consulting than to philosophy. PMID- 30443090 TI - Analyzing Relationships of Necessity Not Just in Kind But Also in Degree: Complementing fsQCA With NCA. AB - Analyzing relationships of necessity is important for both scholarly and applied research questions in the social sciences. An often-used technique for identifying such relationships-fuzzy set Qualitative Comparative Analysis (fsQCA) has limited ability to make the most out of the data used. The set-theoretical technique fsQCA makes statements in kind (e.g., "a condition or configuration is necessary or not for an outcome"), thereby ignoring the variation in degree. We propose to apply a recently developed technique for identifying relationships of necessity that can make both statements in kind and in degree, thus making full use of variation in the data: Necessary Condition Analysis (NCA). With its ability to also make statements in degree ("a specific level of a condition is necessary or not for a specific level of the outcome"), NCA can complement the in kind analysis of necessity with fsQCA. PMID- 30443091 TI - To the Edge of the Urban Landscape: Homelessness and the Politics of Care. AB - Homelessness is an obvious moral challenge, given the fact that it is a problem that millions of people in the developed world have to deal with on a daily basis. In the relatively scarce literature on this subject, there appear to be roughly-three main approaches, namely, what I will refer to as the "difference approach," the "liberal approach" and the "care approach." In the paper I will critically review these three moral perspectives on the issue of homelessness. I will argue that the difference approach and the liberal approach in the end are unconvincing. Homelessness can hardly be interpreted in terms of an internally valued group identity nor in terms of autonomy and its preconditions. I will defend a version of the care approach instead, an approach that focuses on the concrete and particular needs of the homeless. PMID- 30443092 TI - Intraday News Trading: The Reciprocal Relationships Between the Stock Market and Economic News. AB - This study investigates the interdependent relationships between the stock market and economic news in the U.S. context. 2,440 economic tweets from Reuters and Bloomberg published in September 2015 were analyzed within short-term intervals (5 minutes, 20 minutes, and 1 hour) as well as 50 influential Bloomberg market coverage stories distributed via their terminals for the same period of time. Using Vector Auto Regression analyses, it was found that news volume, news relevance, and expert opinion in tweets seem to influence the fluctuation of the Dow Jones Industrial Average (DJI) positively, while economic news appears to respond to market fluctuation with less coverage, including fewer retweets, favorites, updates, or expert opinions conveyed. Inspecting the influential market stories by Bloomberg, the results imply that while Bloomberg terminals provide firsthand information on the market to professionals, tweets rather seem to offer follow-up reporting to the public. Furthermore, given that the effect of economic tweets on the DJI fluctuations was found to be strongest within longer time intervals (i.e., 1 hour), the findings imply that public traders need more time to evaluate information and to make a trading decision than professional investors. PMID- 30443093 TI - Between Academia and Civil Society: The Origins of Latin American Studies in the Netherlands. AB - Dutch Latin American studies as a field of academic teaching and research emerged in the late 1960s and became consolidated in the 1970s and 1980s. It began as a purely academic endeavor, but in a changing Dutch and global society in the 1970s it rapidly became connected to and influenced by social and political processes in Latin America. The strong Christian and social-democratic traditions in the Netherlands allowed for strong links between academic researchers and civil society organizations. This resulted in the productive coexistence of academic and more political objectives and activities and allowed Dutch Latin American studies to grow into a dynamic field. A review of this experience calls attention to the importance of local conditions for understanding the consequences of the Cold War for academic research. Los estudios holandeses sobre Latinoamerica emergieron como un campo de investigacion y ensenanza academica a finales de la decada de 1960, consolidandose durante los setenta y ochenta. Comenzaron como una actividad puramente academica, pero en la cambiante sociedad holandesa y global de los anos setenta, rapidamente se vincularon a y fueron influenciados por los procesos politicos y sociales de America Latina. La fuerte tradicion cristiana y social-democratica de Holanda dio lugar a poderosos vinculos entre investigadores academicos y organizaciones civiles. Esto llevo a la coexistencia de metas y actividades academicas al igual que aquellas de indole mas politica, transformando a los estudios holandeses sobre Latinoamerica en un campo dinamico. Un vistazo a esta experiencia resalta la importancia de las condiciones locales para una debida comprension de las consecuencias de la Guerra Fria en la investigacion academica. PMID- 30443094 TI - The effects of phonological skills and vocabulary on morphophonological processing. AB - Morphophonological processing involves the phonological analysis of morphemes. Item-specific phonological characteristics have been shown to influence morphophonological skills in children. This study investigates the relative contributions of broad phonological skills and vocabulary to production and judgement accuracies of the Dutch past tense and diminutive, two morphophonological processes. Typically developing children (age 5;0-10;0, N = 114) were asked to produce and judge real and nonce diminutives and regular past tenses. Phonological processing skills were measured using a phonological awareness, digit span and nonword repetition task; vocabulary using the PPVT. Phonological skills and vocabulary contributed significantly to the production and judgement of the past tense and diminutive. The results underline the relation between phonological skills and the lexicon and the processing of morphophonology. These findings go further than showing the importance of the item-specific phonological context of the stem and suffix: they indicate that more general skills in the domain of phonology and vocabulary are involved. PMID- 30443095 TI - Cultural Distance and Firm Internationalization: A Meta-Analytical Review and Theoretical Implications. AB - This paper presents the most comprehensive review and meta-analysis of the literature on cultural distance and firm internationalization to date. We analyze the effects of cultural distance on key strategic decisions throughout the entire process of internationalization. For the preinvestment stage, we examine the decisions on where to invest (location choice), how much to invest (degree of ownership), and how to organize the foreign expansion (entry and establishment mode). For the postinvestment stage, we examine the decisions of how to integrate the foreign subsidiary into the organization (transfer of practices) as well as the performance effects of cultural distance at both the subsidiary and the firm level. We find that firms are less likely to expand to culturally distant locations but if they do, they prefer greenfield investments and integrate subsidiaries more through transfer of management practices. Cultural distance does not seem to affect how much capital firms invest and whether they enter through a joint venture or full ownership. Interestingly, cultural distance has a strong negative effect on subsidiary performance but no effect on the performance of the whole multinational company. In addition, we find that the effects of cultural distance are not sensitive to time, but they are sensitive to the cultural framework used (e.g., Hofstede vs. Global Leadership and Organizational Behavior Effectiveness) and the home country of the company (developed vs. emerging market). Based on our study, we feel confident to offer some theoretical insights, recommendations for improving the validity and reliability of cultural distance research, and ideas for future research. PMID- 30443096 TI - Supporting Governance of Economic Development: The PAANEEAC Experience in Central Africa. AB - This article aims to evaluate PAANEEAC (Projet d'appui au developpement des associations nationales pour l'evaluation environnementale en Afrique Centrale), the program to support the development of national associations (NAs) for environmental impact assessment (EIA) in Central Africa. PAANEEAC's objective is to improve the governance of investment decisions through strengthening capacities for EIA. From the literature explaining the failure of donor-induced capacity development programs, the article deduces conditions for success. The empirical assessment of PAANEEAC is based on document review, extensive interviews, and observations. It concludes that PAANEEAC managed to create platforms in which stakeholders meet with the common objective of improving EIA systems, and that this led to measurable, albeit modest improvements in EIA systems. Furthermore, PAANEEAC met most of the success conditions, which was instrumental for its performance. PMID- 30443097 TI - How Do Friends and Strangers Play the Game Taboo? A Study of Accuracy, Efficiency, Motivation, and the Use of Shared Knowledge. AB - According to common belief, friends communicate more accurately and efficiently than strangers, because they can use uniquely shared knowledge and common knowledge to explain things to each other, while strangers are restricted to common knowledge. To test this belief, we asked friends and strangers to play, via e-mail and face-to-face, the word-description game Taboo, in which objects need to be described without using certain "taboo" words. When descriptions were sent via e-mail, there was no difference in accuracy (number of correct answers) nor in efficiency (number of words per correct answer) between friends and strangers. When descriptions were given face-to-face, friends were more accurate than strangers, but not more efficient (number of seconds and words per correct answer). Shared knowledge did not predict accuracy or efficiency. Hence, our findings do not support the idea that friends only need a few words to understand each other. PMID- 30443098 TI - A New Dawn in Nationalism Studies? Some Fresh Incentives to Overcome Historiographical Nationalism. AB - Nationalism studies does not seem to be a very innovative field of research. The path-breaking views of Anderson, Gellner and Hobsbawm - all published in 1983 - still form the starting point for almost all existing investigations. Moreover, most recent studies focus on one national case, which implicitly results in a vast collection of 'unique' trajectories. However, over the last few years a number of highly original studies on the origins of nationalism, nation-state formation, banal nationalism, methodological nationalism and nation-building in a global perspective seem to announce a new dawn. Some of these refreshing interpretations - which will be discussed in this article - clearly demonstrate that historiographical nationalism still has a preponderant role in history writing. In the concluding paragraphs I will emphasize the need to overcome not only methodological nationalism, but also the terminological and normative nationalism that still dominates our discipline. PMID- 30443099 TI - Child-rearing values: The impact of intergenerational class mobility. AB - This study contrasts two theoretical perspectives on the relationship between intergenerational class mobility and child-rearing values. According to the dissociative thesis, which describes social mobility as a disruptive experience leading to insecurity, social isolation, stress and frustration, socially mobile individuals less often prefer community-oriented qualities such as tolerance and respect for other people, unselfishness, good manners and obedience. The beneficiary thesis, on the other hand, predicts that socially mobile individuals have a stronger preference for individual-based values such as hard work, determination, responsibility, independence and thrift. In both cases, these mobility effects are thought to be stronger for more extremely mobile individuals and for downwardly mobile compared with upwardly mobile individuals. However, using Dutch data from the European Values Study 2008, hardly any significant intergenerational mobility effects are found. Maybe intergenerational mobility is not such an extraordinary experience as mobility theory would lead us to believe, or mobile individuals adjust themselves very quickly to their new situation. PMID- 30443100 TI - Exit programmes for female jihadists: A proposal for conducting realistic evaluation of the Dutch approach. AB - Europe has seen an increase of women joining or sympathizing with the terrorist organization ISIS. These women are often considered victims and passive agents, but their threat should not be underestimated. Effective counter-measures are essential, especially now the so-called caliphate is in decline and many females want to return home. Exit programmes to deradicalize, disengage, reintegrate or rehabilitate are often part of a broader programme to prevent and counter violent extremism (CVE). Little is known about the effectiveness of such exit programmes, in particular in relation to female violent extremism. Drawing on municipal exit programmes in the Netherlands as a case study, the article researches how realistic evaluation can be used to measure the effectiveness of exit programmes. It also shows that the realistic evaluation method is beneficial for further theory development on the phenomenon of female violent extremism. PMID- 30443101 TI - Do local economic interests matter when regulating nationally significant infrastructure? The case of renewable energy infrastructure projects. AB - Government policy in the UK, as in many countries, sees investment in infrastructure projects - particularly large ones - as a key means of supporting the national economy. But where does this leave local economic interests in the loci of these projects? And how does the regulation of such projects handle these interests? These are the questions addressed by this paper in the context of renewable energy projects that are regulated by the Nationally Significant Infrastructure Projects regime. Drawing on original research into the regulation of 12 projects - and using thematic analysis of key documents and focus groups with local participants - the analysis highlights the limited understanding of the local economy presented, the challenges that local businesses face in participating and the partial protection offered to them. It concludes by proposing agendas for reforms and future research. PMID- 30443102 TI - Design, Construction, and Initial Results of a Prototype Multi-Contrast X-Ray Breast Imaging System. AB - By integrating a grating-based interferometer with a clinical full field digital mammography (FFDM) system, a prototype multi-contrast (absorption, phase, and dark field) x-ray breast imaging system was developed in this work. Unlike previous benchtop-based multi-contrast x-ray imaging systems that usually have relatively long source-to-detector distance and vibration isolators or dampers for the interferometer, the FFDM hardware platform is subject to mechanical vibration and the constraint of compact system geometry. Current grating fabrication technology also imposes additional constraints on the design of the grating interferometer. Based on these technical constraints and the x-ray beam properties of the FFDM system, three gratings were designed and integrated with the FFDM system. When installing the gratings, no additional vibration damping device was used in order to test the robustness of multi-contrast imaging system against mechanical vibration. The measured visibility of the diffraction fringes was 23+/-3%, and two images acquired 60 minutes apart demonstrated good system reproducibility with no visible signal drift. Preliminary results generated from the prototype system demonstrate the multi-contrast imaging capability of the system. The three contrast mechanisms provide mutually complementary information of the phantom object. This prototype system provides a much needed platform for evaluating the true clinical utility of the multi-contrast x-ray imaging method for the diagnosis of breast cancer. PMID- 30443104 TI - Numerical investigation on 2D viscoelastic fluid due to exponentially stretching surface with magnetic effects: an application of non-Fourier flux theory. AB - Two-dimensional flow of Casson fluid toward an exponentially stretched surface in view of Cattaneo-Christove flux theory is discoursed in current communication. Flow pattern within boundary layer under the effectiveness of magnetic field is also contemplated in the communication. Non-dimensionalized governing expressions are attained through transformation procedure. To anticipate the fascinating features of present work, solution of resulted nonlinear differential system is computed with the collaborated help of shooting scheme and Runge-Kutta method. The influence of involved variables on velocity and temperature fields is scrutinized. Contribution of thermal relaxation is explicitly pointed out. Evaluation of convective heat transfer and friction factor in the fluid flow is visualized through graphs and tables. Additionally, the assurance of present work is affirmed by developing comparison with previous findings in the literature which sets a trade mark for the implementation of numerical approach. It is inferred from the thorough examination of the analysis that present formulation reduces to classical Fourier's problem by considering Lambda=0 . Furthermore, decreasing pattern in temperature distribution is depicted in the presence of Cattaneo-Christove flux law as compared to heat transfer due to the Fourier's law. PMID- 30443105 TI - Unemployment and the Division of Housework in Europe. AB - Unemployment, especially in insecure times, has devastating effects on families, but it is not clear what happens to domestic work. On the one hand, unemployment frees up time for more housework by both men and women. On the other hand, once unemployed, women may take on more additional housework than men do, either because they capitalize on their time to act out traditional gender roles or because unemployment compounds women's general disadvantage in household bargaining. Multi-level analyses based on the European Social Survey show that both men and women perform more housework when unemployed. However, the extra domestic work for unemployed women is greater than for unemployed men. They also spend more time on housework when their husband is unemployed. Compared to their employed counterparts, unemployed women, but not men, perform even more housework in a country where the unemployment rate is higher. PMID- 30443103 TI - The Physiologic and Psychophysical Consequences of Severe-to-Profound Hearing Loss. AB - Substantial loss of cochlear function is required to elevate pure-tone thresholds to the severe hearing loss range; yet, individuals with severe or profound hearing loss continue to rely on hearing for communication. Despite the impairment, sufficient information is encoded at the periphery to make acoustic hearing a viable option. However, the probability of significant cochlear and/or neural damage associated with the loss has consequences for sound perception and speech recognition. These consequences include degraded frequency selectivity, which can be assessed with tests including psychoacoustic tuning curves and broadband rippled stimuli. Because speech recognition depends on the ability to resolve frequency detail, a listener with severe hearing loss is likely to have impaired communication in both quiet and noisy environments. However, the extent of the impairment varies widely among individuals. A better understanding of the fundamental abilities of listeners with severe and profound hearing loss and the consequences of those abilities for communication can support directed treatment options in this population. PMID- 30443106 TI - The social-political challenges behind the wish to die in older people who consider their lives to be completed and no longer worth living. AB - In the Netherlands, physician-assisted dying has been legalized since 2002. Currently, an increasing number of Dutch citizens are in favour of a more relaxed interpretation of the law. Based on an ethos of self-determination and autonomy, there is a strong political lobby for the legal right to assisted dying when life is considered to be completed and no longer worth living. Building on previous empirical research, this article provides a critical ethical reflection upon this social issue. In the first part, we discuss the following question: what is the lived experience of older people who consider their lives to be completed and no longer worth living? We describe the reported loss of a sense of autonomy, dignity and independence in the lives of these older people. In the second part, from an ethics of care stance, we analyse the emerging social and political challenges behind the wish to die. Empirically grounded, the authors argue that the debate on 'completed life in old age' should primarily focus not on the question of whether or not to legitimize a self-directed death but on how to build an inclusive society where people may feel less unneeded, useless and marginalized. PMID- 30443107 TI - Labour Constitutions and Market Logics: A Socio-Historical Approach. AB - The article evaluates labour law's strategies of coping with the pressure put on its project of realizing justice by a hegemony of economic perspectives on labour markets. Its consequences for a methodology of labour law are set out by critically engaging with recent proposals made by Simon Deakin and Ruth Dukes. It is argued that a socio-historical perspective on the role of legal models in actually shaping labour relations can enrich the concept of a 'labour constitution'. PMID- 30443108 TI - The Governmentalization of the Trade Union and the Potential of Union-Based Resistance. The Case of Undocumented Migrant Domestic Workers in the Netherlands Making Rights Claims. AB - Ambivalence about rights is well known: rights may both challenge existing injustices while simultaneously re-enforcing sovereign regulatory control over citizens. In this article, we focus on the paradox that potentially radical and transformative claims to rights are made at a site - civil society - that under liberal governmentality has increasingly become a site of government. By exploring the unionization of undocumented migrant domestic workers (MDWs) in the Netherlands, we aim to show how rights claims are shaped and controlled by civil society. Using the analytical category of (in)visibility, the case study discloses the dualistic role of the union. On the one hand, the union operated as a site of resistance supporting undocumented MDWs to make their rights claims. On the other hand, it operated as a site of government of the same undocumented MDWs by selectively promoting work-related rights claims and excluding more radical claims for the right to come and go. PMID- 30443109 TI - Elections, news cycles, and attention to disasters. AB - Purpose: Political elections, especially presidential elections, have a tendency to overshadow other events, including disasters. Response to disasters during elections, such as Hurricane Matthew and the Baton Rouge flooding in 2016, are often dependent on attention given to them from the media, as well as prominent political figures and political candidates candidates. The purpose of this paper is to explore how election cycles affect government response to disasters and ultimately demonstrate the dependency of crisis communication on media agenda setting for presenting saliency of disaster risk and needs. Design/methodology/approach: Responses from presidential candidates Donald Trump and Hillary Clinton, as well as President Barack Obama, in regards to the Baton Rouge flooding and Hurricane Matthew, were observed using media reports and social media accounts. These results were matched with key events from the presidential election timeline. Findings: There is a positive relationship between news exposure and attention, and also between attention and civic response. In regards to the 2016 presidential election, news coverage of the release of the Donald Trump-Billy Bush tape distracted national attention from the approach, landfall, and recovery of Hurricane Matthew. Information subsidies provided by the candidates directed the media agenda away from the needs of the communities and individuals impacted by these disasters. Originality/value: Disasters are often assumed to be value-free because they are "blind to politics." Here, it is argued that this was not the case in relation to these two disasters. Thus, the authors encouraged more research be conducted to clarify the impact that political elections have on strategic news coverage of disasters and ultimately on disaster response. PMID- 30443110 TI - Pediatric Surgical Diseases and Legacy of Pediatric Surgery in Adults - Responsibility of Pediatric Surgeons. PMID- 30443111 TI - Vestibulo-Rectal Pull Through in H-Fistula in Girls. AB - Aims and Objectives: Vestibulo-rectal pull-through (VRPT) in H-fistula in girls was first described by Chatterjee et al. We are presenting our experience with this approach in 47 cases. Materials and Methods: We have total 47 cases of which one is a recurrent fistula operated outside. A circumferential incision is made around the fistula in the vestibule; fistula tract is dissected liberally and delivered by invagination into the bowel. Then, the fistula tract is excised adequately and closed from within the bowel lumen so that no anterior outpouching of the rectum remains. The perineal body is repaired through the vestibular incision. In no cases, protective colostomy was performed. Only the recurrent fistula case had colostomy done in another institution. Results: Complete cure was obtained in 45 out of 47 cases. Two of our earlier cases had recurrences perhaps due to inadequate mobilization, but in later cases, we had no recurrence. Conclusion: VRPT yields good result without the need for colostomy. Incisions on the perineal skin or the anal verge are avoided, thus improving the cosmetic outcome. PMID- 30443112 TI - A Randomized Control Trial Comparing Outcome after Stented and Nonstented Anderson-Hynes Dismembered Pyeloplasty. AB - Aim: The aim of the study was to compare the efficacy and postoperative complications of stented and nonstented open pediatric dismembered pyeloplasty for ureteropelvic junction (UPJ) obstruction. Settings and Design: A balanced, parallel group, prospective randomized controlled trial comparing stented and nonstented Anderson-Hynes Dismembered Pyeloplasty. Subjects and Methods: It included 42 children who required Anderson-Hynes dismembered pyeloplasty for UPJ obstruction (UPJO). Patients were randomized into stented (double "J" [DJ] stent) and nonstented pyeloplasty groups. The intraoperative and postoperative course was compared. Both groups were analyzed for problems such as dysuria, frequency, pain, hematuria and urinary tract infection, and postoperative renal status. Statistical Analysis: Mann-Whitney U-test, Fisher's exact test, Student's t tests, and Chi-squared test were used. Results: Surgical duration was significantly shorter for the nonstented group as compared to the stented group (60.4 +/- 6.49 min vs. 78.9 +/- 8.17 min). The intraoperative negotiation of DJ stent was troublesome in 21.7% patients belonging to the stented group. The hospital stay was comparable in both groups (4.67 +/- 1.9 vs. 4.28 +/- 0.67 days). Patients in stented group had experienced dysuria, loin pain, lower abdominal spasmodic pain, and frequency significantly higher than nonstented group. However, the other problems such as fever, hematuria, and urinary tract infections were more common in stented group, but the difference was not statistically significant. There was no difference in resolution of hydronephrosis in both groups. Conclusions: There is no statistically significant difference in resolution of hydronephrosis following nonstented or stented dismembered pyeloplasty in children with UPJO. However, the patient is more symptomatic due to stent in the postoperative period. PMID- 30443113 TI - Stricture Urethra in Children: An Indian Perspective. AB - Background: Pediatric urethral stricture and its treatment have functional implications in the growing child. Subjects and Methods: A retrospective study of records on urethral strictures encountered in our institution between January 2005 and May 2016 yielded 23 boys against a backdrop of 19,250 admissions during the same period; stenosis and strictures after hypospadias repair were not included in this study. Demographic data were collected from the charts, and the success of repair was assessed clinically by success of repair was assessed clinically by observing for presence or absence of symptoms such as dribbling, straining at voiding, adequacy of urinary stream and radiologicaly by assessing the micturition phase of voiding cystourethrogram. Success was defined as successful initiation, flow, and completion of voiding with radiological evidence of reestablishment of urethral continuity. Results: The most common cause of urethral stricture was perineal or pelvic trauma (56.5%). Three after surgery for anorectal malformation (13.04%) and 2 (8.6%) followed otherwise unspecified urethritis. Transperineal and transpubic anastomotic routes were used for surgery. Redo surgery was required in 47.8%. The overall success rate was 82%. A self-catheterizable mitrofanoff channel was created as part of the primary procedure in 63.6% (7/11) or after the failure of the first procedure in 36.3% (4/11). Conclusion: The majority of urethral strictures are long-segment strictures or those with complete disruption not amenable to endoscopic techniques. The aim of the surgery is to obtain end-to-end opposition of healthy proximal and distal urethra. The route - transperineal or transpubic - which will give the best access to the ends of the urethra is determined by the location and extent of the stricture and the alteration in anatomy as a consequence of the pelvic fracture. Even after the introduction of laser and endoscopic techniques, surgical repair is required to tackle the majority of urethral strictures in children. PMID- 30443114 TI - Trends in Referral Pattern of Antenatally Diagnosed Surgical Abnormalities in a Tertiary Care Center in North India. AB - Aim: Pregnant women with antenatally diagnosed surgical abnormalities of the fetus are often referred for pediatric surgical consultation for likely outcome and prognosis. In this study, we analyzed the gestational age at referral to see the benefits of the same in decision-making and also looked for any change in trends of referral pattern over a period with the increasing availability of ultrasonography (USG). Materials and Methods: Records of pregnant women referred for antenatal counselling over an eight year period were analyzed. This was an observational study conducted in the Pediatric surgery outpatient department of a tertiary care centre from 2008-2015. All pregnant women referred for antenatal counseling were included, with the diagnosis of fetal abnormalities being based on USG. Abnormalities were classified by system involved. Comparison of data before and after the year 2012 was done to look for change in trends. Patients with poor prognostic outcome were further analyzed. Results: A total of 1211 women were analyzed, with 490 (40.7%) presenting between 2008 and 2011 and 719 (59.3%) between 2012 and 2015. Overall, in those with likely poor prognostic outcome (n = 482), 189 (39.2%) patients presented at <20 weeks gestation, 106 (22%) between 21 and 24 weeks gestation, and 187 (38.8%) after 24 weeks of gestation. Genitourinary abnormalities (n = 220; 46%) accounted for the most common poor prognostic outcome group in all gestational ages. Conclusion: Nearly two-thirds (61%) of the patients with poor outcome were referred after 20 weeks of gestation, i.e., beyond the permissible time for termination. Fetal sonography expertise between 16 and 20 weeks should be improved as a priority by the government in peripheral centers. PMID- 30443115 TI - Persistent Mullerian Duct Syndrome: A Single-Center Experience. AB - Context: Persistent Mullerian duct syndrome (PMDS) is a rare disorder. It is a type of male pseudohermaphroditism, usually presenting as "Hernia Uteri Inguinalis". Aims: This study aims to present our experience of PMDS, over a 7 year period. Settings and Design: Our center is a tertiary care facility, situated in Tamil Nadu, a southern state of India. Subjects and Methods: This is a retrospective study. The study period was from 2007 to 2015. Seven cases presented during that period. The difficulties in diagnosis, treatment options discussed, along with a review of literature are presented. Results: Seven cases of PMDS presented over 8 years. Only four were diagnosed preoperatively. Mullerian remnants were excised in five cases. Conclusions: PMDS is rare. Orchiopexy should be the goal of treatment. PMID- 30443116 TI - Demographic Study and Management of Colonic Atresia: Single-Center Experience with Review of Literature. AB - Context and Aim: The aim of this study is to highlight the rarity of this disorder and its associated anomalies and our objective was to review our experience in the management of colonic atresia (CA) with respect to staged surgery versus one-step procedure for a better outcome of the disease. Settings and Design: A randomized, controlled, single-center study conducted over a period of 4 years from October 2013 to 2017. Subjects and Methods: Nine cases were operated for CA of which three underwent primary anastomosis and six underwent initial colostomy followed by definitive surgery. Age, sex, body weight, clinical presentation, type of atresia, site, time interval of operation, associated anomalies, initial procedure, postoperative complications, final procedure, biopsy, hospital stay, and outcome were noted. Statistical Analysis Used: Microsoft Excel was used for statistical analysis. Results: Out of 9 patients, 6 were males and 3 were females, 7 patients survived and 2 patients died (mortality 22.2%), of which one patient with primary anastomosis had leak and sepsis and one patient with primary anastomosis had associated Hirschsprung's disease (HD). Mean time gap for operation was 12.8 h and mean hospital stay was 3.5 days for initial colostomy and 21 days for primary anastomosis. Wound dehiscence occurred in 4 patients. Malrotation was found in 3 patients, HD in 2 patients, cardiac anomaly in 2, Meckel's diverticulum in 1, and cleft lip in 1 patient. Type IIIa atresia was found in in 6 patients, Type I in 2, and Type II in 1 patient. The most common site was transverse colon (n = 5). Conclusion: Diagnosis and management of CA is a challenge. Early presentation and diagnosis should be prompt. Staged procedure with initial colostomy followed by definitive procedure is the preferred choice. Associated anomaly HD must be ruled out. PMID- 30443117 TI - Whipple's Pancreaticoduodenectomy in Pediatric Patients: An Experience from a Tertiary Care Center. AB - Purpose: Whipple's pancreaticoduodenectomy (WPD) is rarely required in children. However, WPD is the only option with pathologies involving the head of the pancreas requiring surgical excision. The objective of our study was to review our experience with WPD performed on children. Materials and Methods: A retrospective analysis of case records was conducted on all patients <18 years of age, who underwent WPD at our center over the last 20 years. Data regarding demographics, signs, and symptoms at presentation, diagnostic imaging and procedures, pathologic reports, surgical and medical treatment, and follow-up were collected to study the indications and safety and outcomes of WPD in children. Results: Five patients had been planned for a WPD during the study (1995-2015); but in one patient, the procedure was abandoned, the rest four patients formed the study group. Male to female ratio was 3:1. Median age at the time of surgery was 9 years (11 months-12 years). The most common presentation was obstructive jaundice (50%, 2/4). Radiological imaging was able to accurately predict the surgical procedure required in all except one case. The mean operating time was 205 min (180-240 min). There were no intraoperative complications. The mean intraoperative blood loss was 85 mL (20-150 mL). The youngest patient requiring WPD was an 11-month-old child. Oral feeding was established by the 7th postoperative day (range 5-7 days) in all cases. There were no cases of anastomotic leak or pancreatic or jejunal fistulae. One patient developed features of subacute intestinal obstruction after discharge and required re-exploration. There was no intra- or post-operative mortality. Conclusion: WPD is safe and efficacious procedure in a selected group of children. The overall efficacy of surgical treatment combined with the relatively low severity of complications leads us to recommend WPD in children when indicated. PMID- 30443118 TI - Gastric Deserosalization: What Lies Behind Closed Doors. AB - Congenital intestinal malrotation has a wide spectrum of presentation varying from incidental detection to recurrent episodes of benign abdominal pain to frank gastrointestinal obstruction, mid-gut volvulus, and bowel gangrene. Herein, we report the first case of congenital intestinal malrotation leading to gastric deserosalization. Intraoperative findings were conspicuous by the presence of midgut volvulus and gastric perforation in the posterior wall. There are a few more dimensions uncovered by this case, a brief reference to each has been considered necessary. PMID- 30443119 TI - Concurrent Congenital Fibrolipomatous Hamartoma and Congenital Nevus of Infancy: A Syndromic or Chance Association. AB - Congenital nevi and fibrolipomatous hamartoma are benign tumors of childhood, the latter being very uncommon. Fibrous hamartoma of infancy typically occurs in <2 years of life. The concurrence of these two lesions is extremely rare. We report a case of congenital fibrolipomatous hamartoma and congenital nevus of infancy in a 6-month-old male infant. Clinically, a suspicion of benign versus malignant lesion beneath the giant congenital nevus prompted its surgical removal. The histopathology confirmed it to be a compound lesion with benign melanocytic nevi and fascicles of spindle cells with eosinophilic cytoplasm representing hamartoma. Several types of melanocytic combined lesions have been noted with neuroectodermal and mesenchymal components. Sometimes, malignant soft-tissue neoplasm such as liposarcoma, rhabdomyosarcoma, and ganglioneuroblastoma do occur. This case report highlights the role of prompt surgical excision and histopathological examination. PMID- 30443120 TI - Primary Iliopsoas Abscess in an Infant: A Case Report. AB - Primary iliopsoas abscess (IPA) is rare in the infantile period. However, if treatment is not initiated soon, aggressive, and adequate, there is high risk for mortality or permanent damage to the hip joints. We present the case of a preterm neonate who presented at 2 months of age with swelling and restricted movements of the left leg for the past 1 week. A diagnosis of idiopathic left IPA was made due to Staphylococcus aureus which was drained surgically and treated with systemic antibiotics. Currently, the baby is 6 months old with no evidence of any sequelae. PMID- 30443121 TI - Report of Massive Bleed after Chest-drain Insertion in a Case of Job's (hyper IgE) Syndrome. AB - Chest-drain insertion is considered to be a benign procedure. A 6-year-old girl who is a known case of hyper-IgE/Job's syndrome presented to us following three episodes of fresh bleed following chest-drain insertion for the left lung abscess. The site of bleed was localized to be the ruptured pseudoaneurysm of the anterior segmental branch of the left pulmonary artery. For successful management, various pitfalls and gray areas have been highlighted: (a) the procedure of chest-drain insertion has a potential for many complications some of which may be life-threatening, (b) the importance of proper history taking and a complete evaluation of all patients before surgical intervention, (c) role of ultrasound-guided chest-drain insertion, and (d) the importance of lateral and pragmatic approach with multidisciplinary involvement in such unusual and challenging cases cannot be overemphasized. PMID- 30443122 TI - Teratoma in the Hepatoduodenal Ligament. AB - A teratoma is not an uncommon tumor in the pediatric age group. It has a predilection for specific sites, but a teratoma arising from the hepatoduodenal ligament (HDL) is very rare. Only 15 cases of HDL teratoma have been reported so far. Due to the proximity to important structures, it is imperative that the correct anatomical localization is done preoperatively to avoid intraoperative surprises. Herein, we report a case of HDL teratoma in a toddler who underwent a successful excision. The relevant literature is also discussed briefly from a pediatric surgeon's perspective. PMID- 30443123 TI - Yolk Sac Tumor of Stomach: Case Report and Review of Literature. AB - Gastric yolk sac tumors (YSTs) are very rare. Only seven cases of pure YST of the stomach, with a median age of 65 years, and five cases of YST combined with adenocarcinoma have been reported. We report a 3-year-old boy who presented to us with recurrent episodes of melena and anemia of 2 months' duration. Upper gastrointestinal endoscopy revealed a deeply excavated ulcer on the lesser curvature, 4 cm from the gastroesophageal junction. Computed tomography (CT) abdomen revealed large heterogeneously enhancing soft-tissue mass lesion in the lesser sac with indistinct fat planes with the lesser curvature of the stomach with multiple peripherally enhancing lesions in both lobes of liver and omentum, suggestive of metastasis. Serum alpha-fetoprotein (AFP) was 21,000 ng/ml. Tru-cut biopsy from the mass was suggestive of YST. Following three courses of chemotherapy based on Cisplatin, Etoposide and Bleomycin (PEB), sleeve gastrectomy with excision of the mass with omentectomy with biopsy of the liver nodules with a sampling of perigastric lymph nodes was done. Histopathology revealed only necrotic tissue with no evidence of residual malignancy. Three month follow-up CT revealed no residual mass with AFP of 3 ng/ml. PMID- 30443124 TI - Anesthetic and Surgical Management of Mucoid Retention Cyst in the Vallecular Region: An Airway Challenge. AB - : Growth of any kind in the oropharynx poses a threat to the airway especially during anaesthesia. Being aware of the challenges and adequately equipped to handle the situation is the duty of the anesthesiologist. Methods and Material: An eight year old girl diagnosed case of multiple mucous cysts presented to the outpatient department for excision of a lower lip mucous cyst. So an ultrasound was done which revealed a large intramural mucous cyst. After a preanaesthetic checkup she was posted for the excision of the cyst. Results: The girl was posted for Elective surgery and was induced without prior premedication as she had revealed a history of snoring in supine position. After preoxygenating with 100% oxygen, she was induced with Injection Ketamine and Sevoflurane. She started desaturated abruptly so nasal airway and finally # 2.5 LMA was inserted but SpO2 didn't improve. With backup of Ent and paediatric surgeons direct larngoscopy was attempted and #5 ETT was inserted successfully. Following which the huge vallecular cyst was removed. PMID- 30443125 TI - An Enigmatic Route to the Contralateral Pelvicalyceal System on Antegrade Pyelogram. AB - Introduction: The authors present the rare yet enigmatic phenomenon of 'pyelo renal' backflow. Case Presentation: An eight-month-old boy with multiple congenital anomalies underwent left Anderson-Hynes Pyeloplasty for pelvi-ureteric junction obstruction. Antegrade dye-study done through the nephrostomy revealed obstruction at the level of the pelvi-ureteric junction, yet the contrast was visualized in the pelvis of contralateral kidney and urinary bladder (pyelo venous backflow) masquerading as vesicoureteric reflux. The phenomenon of 'pyelo renal' backflow along with pyelo-tubular, pyelo-interstitial, pyelo-sinusal and pyelo-lymphatic backflow have been described and the respective mechanisms discussed. Conclusion: The phenomenon is known to happen in the presence of obstruction to outflow from renal pelvis thereby creating a closed compartment. Injection of contrast at a pressure above the critical limit may result in forniceal tears and back-flow of contrast into the renal tubules and beyond. PMID- 30443126 TI - Penile Dislocation with Inversion. PMID- 30443127 TI - Pneumoperitoneum: Not Always due to an Intestinal Perforation!! PMID- 30443128 TI - Male Cloaca - An Additional Rare Variant of Anorectal Malformation. PMID- 30443129 TI - Prolapsed, herniated, or extruded intervertebral disc-treatment by only stabilization. PMID- 30443130 TI - Diaphragma sellae: Anatomical and surgical implication in surgery for pituitary adenomas - Highlighting contributions by Goel. PMID- 30443131 TI - Cervical fusion for degenerative disease: A comprehensive cost analysis of hospital complications in the United States from 2002 to 2014. AB - Purpose: Recent data suggest great variability in costs for surgical hospitalization for spinal surgery. However, the magnitude of expenditures attributable to complications is unknown. The purpose of this study is to describe cost of care associated with surgical and medical complications after cervical spine surgery. Materials and Methods: A retrospective cohort study utilizing the National Inpatient Sample years 2002-2014 was conducted. A weighted sample of 901,508 adults undergoing elective cervical fusion for degenerative indications was extracted using diagnostic and procedure codes. Twelve categories of major complications were identified, and patient/hospital variables were evaluated as predictors of the overall reimbursed cost using multivariate regression. Mean differences (B) and 95% confidence intervals were reported. Results: The mean age was 52.2 +/- 11.4 years, with 5.2% of patients experiencing a complication. Mean overall increase in inflation-adjusted cost associated with complication was $16,435 +/- 10,358, varying significantly by type of complication, surgical approach, and number of levels fused. The most common complications and their attributed costs were dysphagia (1.6%, B = $2624 [2476 2771], P < 0.001), pulmonary complications (1.0%, B = $9334 [9110-9558], P < 0.001), and device-related complications (0.9%, B = $3125 [2927-3324], P < 0.001). The costliest complications were infection (0.1%, B = $25359 [24723 25994], P < 0.001), thromboembolism (0.1%, B = $17480 [16808-18153], P < 0.001), and neurological complications (0.2%, B = $10098 [9629-10567], P < 0.001). Conclusions: Although complications are rare after elective cervical fusion, they are associated with dramatically increase costs of care as high as $25,359 in the setting of postoperative infection. Improved understanding of the economic magnitude of complications may help guide efforts in reducing health care spending and improving perioperative care. PMID- 30443132 TI - Management of occipitocervical junction and upper cervical trauma. AB - Objective: The treatment modality of occipitocervical junction (OCJ) and upper cervical traumas carries great importance because of unique form of bone, complex ligamentous, and neurovascular structure. Materials and Methods: Eighty-eight patients were admitted to Mersin University Department of Neurosurgery between January 2007 and January 2017 for injuries of the OCJ and upper cervical spine and evaluated retrospectively. In the group, there were 60 male, 28 female patients in the mean age of 42.9 (18-87) years. Among those, 2 occipital condyle fractures, 28 C1 fractures (26 isolated and 2 with transverse ligament injury), 9 combined C1/C2 fractures, 6 rotatory C1/C2 dislocations, and 43 C2 fractures (32 odontoid, 5 Hangman's, and 6 miscellaneous fractures) were diagnosed. In addition to clinical cases, ten cadavers were used to study the OCJ in a step-wise manner. Results: Occipital condyle fractures, isolated C1 fractures, and rotatory C1/C2 dislocations were treated conservatively. Two patients with C1 fracture including transverse ligament injury were operated in one of the methods of C1-C2 fusion which is posterior sublaminar wiring. Five patients having Type II odontoid fracture were treated surgically. One instable Hangman's fracture patient was treated as anterior cervical discectomy and fusion. Conclusions: Cases with isolated C1 fracture with intact transverse ligament should be conservatively treated without surgical approach. Atlas fractures with transverse ligament rupture, odontoid Type II fractures with dislocation >6 mm, and unstable Hangman's fractures required surgical treatment. Vital neurovascular, ligamentous, and accompanying bone structures should be evaluated for diagnosis and treatment modality. In addition, patient's health status, patient's treatment preference, and surgical team experience are the affecting factors for the decision of surgery. PMID- 30443133 TI - Microendoscopic discectomy for lumbar disc herniations. AB - Introduction: Lumbar disc herniation is one of the main causes of discogenic low back pain and reported to affect 60%-80% of people during their lifetime. The two main surgical modalities for intervertebral disc surgery are standard open discectomy and minimally invasive discectomy which include percutaneous endoscopic lumbar discectomy and microendoscopic discectomy (MED). We report our experience with the same technique of MED to evaluate the efficacy of MED for lumbar disc pathology. Aims and Objectives: The aims and objectives were to study the efficacy, advantages, and associated limitations and complications of MED in lumbar disc herniations. Materials and Methods: This study was carried out on 300 patients who had single-level herniated disc. The procedure was done by Microscopic Endoscopic Tubular Retraction System. Preoperative assessment of Visual Analog Scale (VAS) and modified Suezawa and Schreiber (MSS) clinical scoring system was documented 1 day prior to surgery. Postoperative results were determined to be excellent, good, fair, or poor according to MacNab criteria and also evaluated by MSS clinical scoring system on postoperative day 7 and after 6 months. Results: A total of 187 patients were males and 113 patients were females and a majority of patients were in the age group of 31-40 years. A total of 192 patients had disc herniations at L4-L5 level. The mean operative time was 82 min and the mean hospital stay was 5.3 days. Eighteen cases (6%) developed postoperative complications including discitis, dysesthesia, recurrent prolapsed intervertebral disc, residual disc, dural tear, and nerve root injury. Mean preoperative VAS score was 8.7 and the mean postoperative VAS scores at postoperative day 7 and at 6 months were 2.25 and 1.12, respectively. The mean preoperative MSS score was 3.27 and the MSS scores at postoperative day 7 and at 6 months were 7.42 and 8.2, respectively. The overall successful outcome of the endoscopic discectomy after 6-month follow-up on the basis of VAS improvement percentage was 87.6%, MSS scoring percentage was 91.6%, and MacNab scoring percentage was 92.67%. Conclusion: MED is a safe and effective technique. It offers decreased blood loss, shorter operative time, shorter in-hospital stay, decreased need for pain medication, decreased rate of infection, and a shorter return to work time. Limitations of this technique include a learning curve which is related to surgery time, complications, conversion to open procedures, and recurrent disc herniation. PMID- 30443134 TI - Novel L5-S1 interbody fusion technique for root anomalies or abnormal root configurations of L5-S1 foramens. AB - Purpose: We show in this study that if a root anomaly does not permit access to the disc space in the usual way, the technique we define here can be used. If the patient has a root anomaly or an abnormal root configuration at this level, inevitably, an anterior approach is preferred. Materials and Methods: The patient's previous skin incision was used; the L5-S1 space was reached laterally without entering the midline. The dura in the midline and the L5 and S1 roots on both sides were exposed. They were reached through the adjacent points of both S1 pedicles by going around the upper edge of the sacrum, allowing the disc space to be evacuated. An autologous bone graft was placed on both sides of the space. T10 S1 pedicle screws were placed. An L1 pedicle osteotomy was performed and joined using two rods. Results: The patient's back and leg pain disappeared after the surgery. The plain X-rays showed that the sagittal balance was restored. In this case, it is impossible to see the disc space because the nerve root blocks its view. Conclusions: The classic approach in such cases is to perform a fusion by either a transperitoneal or retroperitoneal approach or by performing a posterior intertransverse fusion. However, it is very challenging to execute an anterior L5 S1 fusion on a patient with pelvic retroversion. When the spinopelvic junction is included in the fusion, one common problem observed is pseudarthrosis. The surgical technique defined in this article makes it possible to drill the bone tissue through the disc space and the upper surface of the sacrum, accessing the pedicle bone. Then, a discectomy is performed at the disc space, a bone graft is placed, and a posterior lumbar interbody fusion is performed. PMID- 30443135 TI - A novel surgical technique aiding the reduction of lumbar spondylolisthesis using the JazzTM Band. AB - Posterior reduction and fusion of spondylolisthesis has a number of recognized and accepted procedural difficulties dependent on its severity. The JazzTM Band is a novel system designed primarily for posterior fixation of the spine; however, its uses can be applied to a breadth of spinal conditions. Its benefits include that one size will fit all spinal levels; the connector is designed for multiple union rod diameters and reduced comorbidity when compared with other surgical methods. We present a case of a 26-year-old female with an L5/S1 spondylolisthesis slip angle of 117.4 degrees . A 25 degrees improvement in the spondylolisthesis slip angle was achieved with the use of the JazzTM Band. The JazzTM Band demonstrates excellent short-term results, and in order to determine the clinical outcomes and efficacy of the JazzTM Band system, long-term results and analysis should be performed. PMID- 30443136 TI - Comparison of the outcomes of cage-stand-alone with cage-with-plate fixation in one level and two levels for treating cervical disk diseases. AB - Introduction: Anterior cervical discectomy and fusion (ACDF) surgery is an accepted method for many spinal cord abnormalities. The purpose of this study was to evaluate the outcomes of treating patients with spinal cord lesions at one level or two levels through ACDF with cage-stand-alone (ACDF-CA) and ACDF with cage-with-plate fixation (ACDF-CP) surgery and comparing these results with each other. Methods: In this prospective, cross-sectional, descriptive study, eighty patients undergoing ACDF surgery were enrolled according to the inclusion and exclusion criteria. Demographic data, before and after surgery findings, and clinical symptoms were investigated. Data were collected by means of visual analog scale (VAS) and Neck Disability Index (NDI) questionnaires. The adverse effects and surgical outcomes were evaluated based on Odom's criteria and patients' satisfaction. The collected data of the groups were then compared and assessed. Results: There was no significant difference between the groups in regards of gender, age, duration of surgery to visit, surgical level, preoperative and postoperative VAS and cervical range of motion, preoperative NDI, results based on Odom's criteria, and satisfaction of patients (P > 0.05). The VAS, NDI, and range of motion scores were significantly reduced in the four groups after the operation compared to the preoperative stage. Postoperative NDI scores in the ACDF-CA group at one level were significantly lower than other groups (P < 0.05). Conclusion: Both of the methods revealed acceptable outcomes in comparison to the preoperative stage, and despite some minor differences, there are generally no significant differences in outcomes and complications. PMID- 30443137 TI - Lateral suboccipital retrosigmoid retrocondylar approach for foramen magnum meningiomas. AB - Objective: The objective of the study was to describe our approach and the surgical technique and analyze its safety and the outcome for foramen magnum meningiomas (FMMs). Methods: From 1986 to 2016, 15 FMM patients were operated on using the lateral suboccipital retrocondylar approach. Results: In this series, there were 12 (80%) female and 3 (20%) male patients. The patients ranged in age from 33 to 63 years. There was no operative dead, but two patients died during the follow-up period, which varied from 1 to 24 years (mean, 10.2 years). Twelve patients (80%) achieved Glasgow Outcome Scale 4 or 5. Gross total resection was achieved in 13 (86.6.7%) patients. Conclusions: The majority of FMM can be safely removed using the lateral suboccipital retrocondylar approach without condylar resection, associated to meticulous microsurgical technique. PMID- 30443138 TI - Modified high cervical approach for C3-4 anterior pathology in difficult neck patients. AB - Introduction: The anterior approach to cervical pathologies is a time-tested versatile approach. It is, however, associated with a number of pharyngo-tracheo laryngeal complications (PTL complications) such as dysphonia, dysphagia, and aspiration, more commonly in high cervical C3-4 inclusive pathologies and even more so in patients with "difficult neck." The modified high cervical approach was devised and employed to address these issues at our institution. Materials and Methods: Patients who underwent surgery for anterior cervical C3-4 inclusive pathologies between January 2015 and April 2018 were included in the study. Parameters for considering difficult neck were defined. Patient subgroup with difficult neck underwent surgery through a modified high cervical approach, whereas others underwent surgery through a standard approach. The incidence of pharyngo-tracheo-laryngeal complications in both subgroups of this patient set was compared among itself as well with a similar patient set with the same two subgroups, both of which underwent surgery through standard approach alone from May 2010 to December 2014 - before the introduction of modified high cervical approach. Results: A total of 280 patients underwent surgery for C3-4 level pathology between May 2010 and April 2018. There were 197 males and 93 females in this population. Mean age was 45.8 +/- 6.3 years. Incidence of pharyngo-tracheo laryngeal complications was 20.3% in patients who underwent surgery before the employment of modified high cervical approach - 32.4% of difficult neck and 16.6% of others developed features of pharyngo-tracheo-laryngeal complications. After employment of modified high cervical approach, 16.67% of difficult neck and 16.2% of other patients developed features of pharyngo-tracheo-laryngeal complications. Conclusion: The modified high cervical technique is a good surgical option to prevent pharyngo-tracheo-laryngeal complications in cases of anterior C3-4 pathology when operating of patients with difficult neck. PMID- 30443139 TI - Percutaneous endoscopic ventral facetectomy: An innovative substitute of open decompression surgery for lateral recess stenosis surgical treatment? AB - Background: Percutaneous transforaminal endoscopic surgery (PTES) constitutes an innovative method principally recruited for the treatment of lumbar disc herniation. Indication spectrum of PTES is constantly widened in current years. Hence, PTES has been proposed to represent a satisfactory alternative for the treatment of lateral recess stenosis (LRS), being defined as percutaneous endoscopic ventral facetectomy (PEVF) in these cases. The aim of this original study is to determine, for the first time in the literature, the outcomes of PEVF, especially in otherwise healthy nonelderly patients with LRS, alongside with special focus in health-related quality of life (HRQoL) assessment. Materials and Methods: Eighty-five otherwise healthy individuals from 58 to 64 years were diagnosed with LRS, being subjected to successful PEVF. Patients were prospectively evaluated in 6 weeks, in 3, 6, and 12 months, and in 2 years postoperatively. Visual analog scales (VASs) were separately utilized for leg and low back pain evaluation (VAS-LP and VAS-BP, respectively), whereas Short Form-36 (SF-36) questionnaire was sequentially implemented for HRQoL assessment. Results: All indexes of SF-36 as well as VAS-LP featured maximal amelioration in 6 weeks postoperatively, with subsequent further enhancement until 3 months and successor stabilization until 2 years. In contrast, VAS-BP presented minimal quantitative amelioration in 6 weeks, featuring no additional alterations. Values of all indexes in all follow-up intervals were demonstrated to be statistically significant in comparison with preoperative values (P < 0.05). No remarkable differentiation was observed between distinct parameters of SF-36. Conclusions: PEVF implementation in nonelderly patients with LRS was displayed to be safe and effective, providing alongside considerable improvement in HRQoL 2 years postoperatively. PMID- 30443140 TI - Transforaminal lumbar interbody fusion with expandable cages: Radiological and clinical results of banana-shaped and straight implants. AB - Purpose: Expandable titanium transforaminal lumbar interbody fusion (TLIF) devices are a relatively new group of implants allowing restoration of lumbar lordosis (LL) and thus improvement of sagittal alignment. The purpose of our study is to compare clinical and radiological results of two different expandable TLIF devices. Materials and Methods: In a retrospective study, patients who underwent TLIF surgery with a banana-shaped or straight TLIF cage in our spine center were analyzed. Primary outcome was change of disc height (DH), segmental lordosis angle (SLA), and lumbar lordotic angle (LLA). Moreover, basic patients parameters and cage subsidence were evaluated. Results: Sixty-one patients were studied (33 banana-shaped and 28 straight cages). DH changed in the banana group from 4.8 mm (standard deviation SD 2.5) to 10.4 (SD 2.4) and in the straight cage group from 6.2 mm (SD 2.5) to 9.6 mm (SD 1.7). The difference was statistically significant (P = 0.03). In addition, SLA correction was higher in the banana group with 5.8 degrees (SD 5.0)-3.7 degrees (SD 3.6), but not significant. LLA improved in the straight group with 5.2 (SD 6.4) compared to 3.7 degrees (SD 5.8) in the banana group. We found subsidence in four patients (6.6%) in the banana-shaped group and nine cases (14.8%) in the other group. Conclusions: Expandable titanium implants show similar improvements in restoring segmental and global lordosis. Banana-shaped expandable cages offer higher potency restoring the intervertebral DH and show less rates of subsidence compared to straight expandable cages. PMID- 30443141 TI - Giant cell glioblastoma with spinal and spinal leptomeningeal metastasis in a child: A rare presentation of a rare tumor. AB - Giant cell glioblastoma (GCG) is a rare subtype of classic glioblastoma multiforme with favorable prognosis and little is known about its metastatic potential. We hereby present a unique case of GCG in a 7-year-old child who developed spinal and spinal leptomeningeal metastasis during adjuvant therapy. She succumbed to it in spite of salvage therapy. PMID- 30443142 TI - Giant cell tumor with pathological fracture of C2 with C1-C2 instability: A rare case with review of literature. AB - Giant cell tumor (GCT) or osteoclastoma is a benign, locally aggressive tumor with a tendency to recur. Involvement of the axial skeleton is very rare and majority of them are seen in the sacrum. The authors report a rare case of a 19 year-old female who presented with a C2 dens GCT with a pathological fracture and atlantoaxial dislocation. The patient was operated in two stages: first stage, with posterior instrumentation and stabilization followed by the second stage, tumor resection by anterior transoral approach. The residual tumor cavity was packed with autologous corticocancellous bone grafts. At a 5-year follow-up, computed tomography scan showed a C1-C2 fusion mass. There was no radiological or clinical evidence of tumor recurrence with the patient having good functional outcome without any neurological deficit. PMID- 30443143 TI - Rare manifestation of common disease with an unique method of minimally invasive spine stabilization: Cervical 2-3 facet lesion. AB - Cervical granulomatous infections of the posterior elements are very rare, it is often difficult to diagnose due to rarity and variable presentation of symptoms. Any cervical surgical procedure carries a certain morbid risk to the patient. We present a case of cervical 2-3 facet joint lesion which was managed by a minimally invasive technique with a favorable outcome. PMID- 30443144 TI - Basilar impression in osteogenesis imperfecta treated with staged halo traction and posterior decompression with short-segment fusion. AB - Basilar impression is a cranial base abnormality associated with osteogenesis imperfecta (OI) with serious neurologic implications but controversial treatment options. Combined anterior and posterior decompression with long-segment posterior fusion is often recommended. We report a patient with OI (Sillence type III) with basilar impression treated with halo traction followed by posterior surgery. The patient was a 12-year-old female with a presentation of hiccups and change in upper extremity function. Diagnostic imaging revealed syringomyelia, compensated hydrocephalus, basilar impression, and Chiari type I malformation. The patient was treated with halo traction followed by posterior decompression fusion from the occipital bone to C2. Bone fusion and improved syrinx were evident on images during the 5 years of follow-up. Five years after surgery, syrinx recurred and the fourth ventricular catheter was revised. The treatment with halo traction followed by posterior-only surgery of basilar impression associated with OI resulted in a good postoperative outcome. PMID- 30443145 TI - Nonunited secondary ossification centers of the spinous processes of vertebrae at multiple levels presenting as aberrant articulations in an adult. PMID- 30443146 TI - Labour politics and the EU's new economic governance regime (European Unions): a new European Research Council project. PMID- 30443147 TI - The waiting game: How securitization became the solution for the growth problem of the Eurozone. AB - This paper takes a closer look at those parts of the European Commission's Capital Market Union (CMU) that bear upon the attempt to set up a new market for securitizations, called 'simple, transparent and standardized securitizations', in brief STS-securitization. The 'puzzle' at its heart is the discrepancy between narratives and content. While the narrative is about the construction of a US style market-based financial system to overcome the problems of Europe's bank based system and help medium-sized enterprises, the first legal initiative aims to create a European market for securitizations, which are a source of funding for large (mortgage) banks and as such are squarely at odds with the headline goals of the Capital Market Union. The paper discusses in detail key passages from the proposal to tease out the discrepancy between story and fact and ventures an explanation based on the identification of the interest coalitions behind the package. PMID- 30443148 TI - Feeding Ecology in Oligocene Mylodontoid Sloths (Mammalia, Xenarthra) as Revealed by Orthodentine Microwear Analysis. AB - Recently, dental microwear analysis has been successfully employed to xenarthran teeth. Here, we present new data on use wear features on 16 molariforms of Orophodon hapaloides and Octodontotherium grande. These taxa count among the earliest sloths and are known from the Deseadan SALMA (late Oligocene). Modern phylogenetic analyses classify Octodontotherium and Orophodon within Mylodontoidea with whom they share lobate cheek teeth with an outer layer of cementum and a thick layer of orthodentine. Similar target areas of 100MUm2 were analyzed on the orthodentine surface of each tooth by stereomicroscopic microwear and by SEM microwear. Results were unlike those of extant sloths (stereomicroscopic microwear: Bradypus, Choloepus) and published data from fossil sloths (SEM microwear: Acratocnus, Megalonyx, Megatherium, Thinobadistes); thus, both approaches independently indicate a different feeding ecology for the Oligocene taxa. The unique microwear results suggest that both taxa fed on plant material with low to moderate intrinsic toughness (foliage, twigs) but also proposes intake of tougher food items (e.g., seeds). Frequent gouging of the tooth surfaces can be explained by exogenous influence on microwear, such as possible intake of abrasive grit. We suggest an unspecialized herbivorous diet for Octodontotherium and Orophodon utilizing diverse food resources of their habitat. These interpretations support the reconstruction of (1) Deseadan environments as open habitats with spreading savannas/grasslands and (2) both taxa as wide-muzzled bulk feeders at ground level. PMID- 30443149 TI - Predicting Entrepreneurial Career Intentions: Values and the Theory of Planned Behavior. AB - Integrating predictions from the theory of human values with the theory of planned behavior (TPB), our primary goal is to investigate mechanisms through which individual values are related to entrepreneurial career intentions using a sample of 823 students from four European countries. We find that openness and self-enhancement values relate positively to entrepreneurial career intentions and that these relationships are partly mediated by attitudes toward entrepreneurship, self-efficacy, and, to a lesser extent, by social norms. Values and TPB constructs partially mediated cross-country differences in entrepreneurial intentions. Spanish students showed lower entrepreneurial intentions as compared to Dutch, German, and Polish students, which could be traced back to lower self-enhancement values (power and achievement), less positive attitudes toward entrepreneurship, and differences in social norms. PMID- 30443150 TI - European Lone Actor Terrorists Versus "Common" Homicide Offenders: An Empirical Analysis. AB - The term "Lone Actor" has been applied to a variety of violent individuals who are thought to act out of ideological motivations using terrorist tactics. So far, much of the research is U.S.-based. There is an empirical vacuum of Lone Actor violence in Europe and a conceptual gap in how these acts may be understood as a variation of homicidal behavior. We examine and compare characteristics of European Lone Actors to European "common" homicide offenders. Lone Actor terrorists constitute a heterogeneous group that is similar to homicide offenders but differs in terms of substance use, weapon use, and target. These findings may be understood in the context of instrumental versus expressive aims. PMID- 30443151 TI - Educational policy and intergenerational mobility. AB - In the United States, there is considerable variation in intergenerational mobility across states. We argue that the distribution of public school spending across school districts under public school finance systems affects intergenerational mobility within the United States. We build a dynamic model in which school districts vote over public school spending per pupil taking the finance system as given. We embed this model with median voting at the district level within a fairly standard model of human capital accumulation. Our model can replicate the relationship between the distribution of public school spending and intergenerational mobility observed in data. Furthermore, three counterfactual simulations suggest that i) the correlation between parental human capital and a child's learning ability plays a significant role in explaining the cross-state variation in intergenerational mobility, ii) a more equal distribution of public school spending under a foundation program by relaxing a borrowing constraint improves intergenerational mobility, especially when a child's learning ability is not highly dependent on parental human capital, and iii) switching to a full state funding program improves intergenerational mobility, but not enormously. This is because full state funding limits public school spending, which hinders intergenerational mobility. PMID- 30443152 TI - Building a Digital Wind Farm. AB - The purpose of this paper is to provide a high level, holistic overview of the work being undertaken in the wind energy industry. It summarises the main techniques used to simulate both aerodynamic and structural issues associated with wind turbines and farms. The motivation behind this paper is to provide new researchers with an outlook of the modelling and simulation landscape, whilst highlighting the trends and direction research is taking. Each section summarises an individual area of simulation and modelling, covering the important historical research findings and a comprehensive analysis of recent work. This segregated approach emphasises the key components of wind energy. Topics range in geometric scales and detail, ranging from atmospheric boundary layer modelling, to fatigue and fracture in the turbine blades. More recent studies have begun to combine a range of scales and physics to better approximate real systems and provide higher fidelity and accurate analyses to manufacturers and companies. This paper shows a clear trend towards coupling both scales and physics into singular models utilising high performance computing system. PMID- 30443153 TI - A Review of Trimming in Isogeometric Analysis: Challenges, Data Exchange and Simulation Aspects. AB - We review the treatment of trimmed geometries in the context of design, data exchange, and computational simulation. Such models are omnipresent in current engineering modeling and play a key role for the integration of design and analysis. The problems induced by trimming are often underestimated due to the conceptional simplicity of the procedure. In this work, several challenges and pitfalls are described. PMID- 30443154 TI - Correction to: How are the village health volunteers delivering malaria testing and treatment services and what are the challenges they are facing? A mixed methods study in Myanmar. AB - [This corrects the article DOI: 10.1186/s41182-018-0110-0.]. PMID- 30443155 TI - Political parties and climate policy: A new approach to measuring parties' climate policy preferences. AB - This study presents an innovative approach to hand-coding parties' policy preferences in the relatively new, cross-sectoral field of climate change mitigation policy. It applies this approach to party manifestos in six countries, comparing the preferences of parties in Denmark, France, Germany, Ireland, Italy and the United Kingdom over the past two decades. It probes the data for evidence of validity through content validation and convergent/discriminant validation and engages with the debate on position-taking in environmental policy by developing a positional measure that incorporates 'pro' and 'anti' climate policy preferences. The analysis provides evidence for the validity of the new measures, shows that they are distinct from comparable measures of environmental policy preferences and argues that they are more comprehensive than existing climate policy measures. The new measures strengthen the basis for answering questions that are central to climate politics and to party politics. The approach developed here has important implications for the study of new, complex or cross cutting policy issues and issues that include both valence and positional aspects. PMID- 30443156 TI - District-level explanations for supporter involvement in political parties: The importance of electoral factors. AB - Traditional analyses of grass roots involvement in political parties have focussed almost exclusively on formal members. However, recent analyses across a range of democracies have shown that non-members (supporters) are playing important roles within political parties, including election campaigning, candidate and leader selection, online policy deliberations and even policy formation. The growing literature on this topic suggests that the involvement of supporters may be a function of party structure and availability of online recruitment. Using new data collected at the 2015 British general election, this article extends the examination of supporter involvement but challenges these assumptions. It shows that supporter activity is better explained by responses to electoral factors and that the focus on online recruitment seriously underplays the enduring importance of human contact. PMID- 30443157 TI - 'Unqueer' kinship? Critical reflections on 'marriage fraud' in mainland China. AB - This article explores the controversial kinship practice in mainland China of 'gay' men marrying unwitting women. It questions the 'marriage fraud' discourse that condemns the men involved while pitying their wives, or tongqis. Taking an ethnographic approach, this article considers the major flaws of this popular discourse: the idealized-package of marriage-love-sex, the oft-neglected difficulties of living outside marriage, and most importantly, the essentialization of homosexuality. It also examines the im/possibility for married 'gay' men to be honest in their marriages. Finally, it cautions that honesty, if used as a decontextualized ethical yardstick for queer kinship, may obscure the racist and homophobic prejudices that exist both outside and inside queer communities. Accordingly, this article proposes that we shift to 'opacity' as an epistemological, methodological and ethical parameter that radically queers kinship (studies). PMID- 30443158 TI - Asymmetric Syntheses of Potent Antitumor Macrolides Cryptophycin B and Arenastatin A. AB - Efficient and highly stereoselective syntheses of cryptophycin B and arenastatin A, potent cytotoxic agents, are described. An ester-derived titanium enolate mediated syn-aldol reaction was employed to generate the stereocenters C-5 and C 6. The route is convergent and provides a convenient access to the synthesis of structural variants of cryptophycins as well as members of its family. PMID- 30443159 TI - The Conformation of the Mannopyranosyl Phosphate Repeating Unit of the Capsular Polysaccharide of Neisseria meningitidis Serogroup A and Its Carba-Mimetic. AB - Neisseria meningitidis serogroup A (MenA) is an aerobic diplococcal Gram-negative bacterium responsible for epidemic meningitis disease. Its capsular polysaccharide (CPS) has been identified as the primary virulence factor of MenA. This polysaccharide suffers from chemical lability in water. Thus, the design and synthesis of novel and hydrolytically stable structural analogues of MenA CPS may provide additional tools for the development of therapies against this disease. In this context, the structural features of the natural phosphorylated monomer have been analyzed and compared to those of its carba-analogue, where the endocyclic oxygen has been replaced by a methylene moiety. The lowest energy geometries of the different molecules have been calculated using a combination of quantum mechanical techniques and molecular dynamics simulations. The predicted results have been compared and validated using NMR experiments. The results indicate that the more stable designed glycomimetics may adopt the conformation adopted by the natural monomer, although they display a wider flexibility around the torsional degrees of freedom. PMID- 30443160 TI - Synthesis of 3-Amino-1-benzothiophene-1,1-diones by Alkyne Directed Hydroarylation and 1/N->3/C-Sulfonyl Migration. AB - A completely regioselective and highly stereoselective palladium-catalyzed intramolecular hydroarylation of arenesulfonyl ynamines to benzothiazoles was developed. The presence of an electron-withdrawing group on the triple bond of the sulfonyl ynamine was crucial for the success of the reaction and our mechanistic studies suggest an alkyne-directed 5-exo-dig cyclization pathway. The products easily underwent photoinduced rearrangement to 3-amino-1-benzothiophene 1,1-diones (up to 35 % yields after two steps). PMID- 30443161 TI - Administration of CoCl2 Improves Functional Recovery in a Rat Model of Sciatic Nerve Transection Injury. AB - Peripheral nerve injury is known to activate the hypoxia-inducible factor-1alpha (HIF-1alpha) pathway as one of pro-regenerative transcriptional programs, which could stimulate multiple injury-induced gene expression and contribute to axon regeneration and functional recovery. However, the role of HIF-1alpha in peripheral nerve regeneration remains to be fully elucidated. In this study, rats were divided into three groups and treated with sham surgery, surgery with cobalt chloride (CoCl2) and surgery with saline, respectively. Sciatic functional index, morphologic evaluations of muscle fibers, and never conduction velocity were performed to measure the functional recovery at 12 weeks postoperatively. In addition, the effects of CoCl2 on the expression of HIF-1alpha, glial cell line derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were determined at mRNA levels; as well as HIF-1alpha, the dual leucine zipper kinase (DLK), the c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), BDNF and NGF were measured at protein level at 4 weeks postoperatively. Systemic administration of CoCl2 (15 mg/kg/day intraperitoneally) significantly promoted functional recovery of rats with sciatic nerve transection injury. This study demonstrated in rats treated with CoCl2, the expression of HIF-1alpha, GDNF, BDNF and NGF was significantly increased at mRNA level, while HIF-1alpha, DLK, p-JNK, BDNF and NGF was significantly increased at protein level. PMID- 30443162 TI - Role of Sirolimus in renal tubular apoptosis in response to unilateral ureteral obstruction. AB - Renal tubule cell apoptosis plays a pivotal role in the progression of chronic renal diseases. The previous study indicates that Sirolimus is effective on unilateral ureteral obstruction (UUO)-induced renal fibrosis. However, the role of Sirolimus in renal tubular apoptosis induced by UUO has not yet been addressed. The aim of this study was to determine the role of Sirolimus in renal tubular apoptosis induced by UUO. Male Sprague-Dawley rats were divided into three groups, sham-operated rats, and after which unilateral ureteral obstruction (UUO) was performed: non-treated and sirolimus-treated (1mg/kg). After 4, 7 and 14 d, animals were sacrificed and blood, kidney tissue samples were collected for analyses. Histologic changes and interstitial collagen were determined microscopically following HE and Masson's trichrome staining. The expression of PCNA was investigated using immunohistochemistry and the expression of Bcl-2, Bax, caspase-9, and caspase-3 were investigated using Western blot in each group. Tubular apoptotic cell deaths were assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Sirolimus administration resulted in a significant reduction in tubulointerstitial fibrosis scores. After UUO, there was an increase in tubular and interstitial apoptosis in untreated controls as compared to Sirolimus treatment rats (P<0.05). In addition, the expression of PCNA, Bcl-2, Bax, caspase-9, and caspase-3 in obstructed kidney was characterized by immunohistochemistry and Western blot analyses demonstrating that sirolimus treatment significantly reduced PCNA, Bax, caspase-9 and cleaved caspase-3 expression compared to those observed in controls (P<0.05), whereas, Bcl-2 in the obstructed kidney were decreased in untreated controls compared to Sirolimus treatment rats subjected to the same time course of obstruction (P<0.05). We demonstrated a marked renoprotective effect of sirolimus by inhibition of UUO-induced renal tubular apoptosis in vivo. PMID- 30443163 TI - Biology of MiR-17-92 Cluster and Its Progress in Lung Cancer. AB - MicroRNAs, a class of short endogenous RNAs, acting as post-transcriptional regulators of gene expression, mostly silence gene expression via binding imperfectly matched sequences in the 3'UTR of target mRNA. MiR-17-92, a highly conserved gene cluster, has 6 members including miR-17, miR-18a, miR-19a, miR 20a, miR-19b-1 and miR-92a. The miR-17-92 cluster, regarded as oncogene, is overexpressed in human cancers. Lung cancer is the leading cause of death all over the world. The molecular mechanism of lung cancer has been partly known at the levels of genes and proteins in last decade. However, new prognosis biomarkers and more target drugs should be developed in future. Therefore, noncoding RNAs, especially miRNAs, make them as new potentially clinical biomarkers for diagnosis and prognosis. In this review, we focus the current progress of miR-17-92 cluster in lung cancer. PMID- 30443164 TI - Plasmodium falciparum Treated with Artemisinin-based Combined Therapy Exhibits Enhanced Mutation, Heightened Cortisol and TNF-alpha Induction. AB - The artemisinin-based combined therapy (ACT) post-treatment illness in Plasmodium falciparum-endemic areas is characterized by vague malaria-like symptoms. The roles of treatment modality, persistence of parasites and host proinflammatory response in disease course are unknown. We investigated the hypothesis that ACT post-treatment syndrome is driven by parasite genetic polymorphisms and proinflammatory response to persisting mutant parasites. Patients were categorized as treated, untreated and malaria-negative. Malaria positive samples were analyzed for Pfcrt, Pfmdr1, K13 kelch gene polymorphisms, while all samples were evaluated for cytokines (TNF-alpha, IL-12p70, IL-10, TGF-beta, IFN-gamma) and corticosteroids (cortisol and dexamethasone) levels. The treated patients exhibited higher levels of parasitemia, TNF-alpha, and cortisol, increased incidence of parasite genetic mutations, and greater number of mutant alleles per patient. In addition, corticosteroid levels declined with increasing number of mutant alleles. TGF-beta levels were negatively correlated with parasitemia, while IL-10 and TGF-beta were negatively correlated with increasing number of mutant alleles. However, IL-12 displayed slight positive correlation and TNF alpha exhibited moderate positive correlation with increasing number of mutant alleles. Since post-treatment management ultimately results in patient recovery, the high parasite gene polymorphism may act in concert with induced cortisol and TNF-alpha to account for ACT post-treatment syndrome. PMID- 30443165 TI - Mechanical Properties and Porosity of Acrylic Cement Bone Loaded with Alendronate Powder. AB - Aseptic loosening is the most common complication of joint replacement. Previous studies showed that acrylic bone cement loaded with a commercially-available alendronate powder (APAC) had good promise against wear debris-mediated osteolysis for prevention of aseptic loosening. The purpose of the present study was to investigate the effect of adding alendronate powder to an acrylic bone cement on quasi-static mechanical properties (namely, compressive strength, compressive modulus, tensile strength, and flexural strength), fatigue life, porosity, and microstructure of the cement. The results showed that adding up to 1 wt./wt.% alendronate powder exerted no detrimental effect on any of the quasi static mechanical properties. However, the fatigue life of APAC decreased by between ~17% and ~27 % and its porosity increased by between ~ 5-7 times compared with corresponding values for the control cement (no alendronate powder added). Fatigue life was negatively and significantly correlated with porosity. Considering that fatigue life of the cement plays a significant role in joint replacement survival, clinical use of APAC cannot be recommended. PMID- 30443167 TI - Erratum: LncRNA AFAP1-AS Functions as a Competing Endogenous RNA to Regulate RAP1B Expression by sponging miR-181a in the HSCR: Erratum. AB - [This corrects the article DOI: 10.7150/ijms.18392.]. PMID- 30443166 TI - Effects of polymethylmethacrylate on the stability of screw fixation in mandibular angle fractures: A study on sheep mandibles. AB - Aim: Malfixed miniplates can impair fracture healing, and the screw pilot holes may widen during repeated fixation trials. This in vitro study explored the extent to which screw fixation of mandibular angle fractures could be improved by augmenting the drilling holes with polymethylmethacrylate (PMMA). Materials and Methods: We measured stabilization by recording specimen displacement under a vertical force of 50 N applied using a hydraulic tester. We included 20 hemimandibles from sheep (average weight 40 kg). The specimens were randomly divided into two groups of 10 and pilot holes were created in the angulus region using a drill 1.2 mm in diameter. Next, we performed osteotomies simulating angulus fracture repair. In group 1, the fracture site was fixed using non compression miniplates and four screws were inserted to the maximal possible extent employing a mechanical screwdriver. In group 2, the pilot drill holes were filled with PMMA prior to miniplate fixation. Then vertical forces of 50 N were applied to the molar region and the displacements were measured. The Shapiro Wilks test was used to compare the two groups. Result: The maximum average displacement in the experimental group was significantly lower than that in the control group (p=0.026). Thus, PMMA-augmented screws better stabilized bone, affording reliable fixation. PMID- 30443168 TI - Borrelia burgdorferi basic membrane protein A stimulates murine macrophage to secrete specific chemokines. AB - In this study, we investigated the mechanisms that lead to the production of proinflammatory mediators by the murine macrophage cell line, RAW264.7, when these cells are exposed in vitro to recombinant Borrelia burgdorferi basic membrane protein A (rBmpA). Using antibody protein microarray technology with high-throughput detection ability for detecting 25 chemokines in culture supernatant the RAW264.7 cell culture supernatants at 12 and 24 h post stimulation with rBmpA, we identified two chemokines, a monocyte chemoattractant protein-5 (MCP-5/CCL12) and a macrophage inflammatory protein-2 (MIP-2/CXCL2), both of which increased significantly after stimulation. We then chose these two chemokines for further study. Enzyme-linked immunosorbent assay and real-time polymerase chain reaction revealed that with the increase of rBmpA concentration, MCP-5/CCL12 and MIP-2/CXCL2 showed concentration-dependent increases (p <0.01).Our results indicate that the rBmpA could stimulate the secretion of several specific chemokines and induce Lyme arthritis. PMID- 30443169 TI - Influence of DNA methylation on the expression of OPG/RANKL in primary osteoporosis. AB - Purpose: A key factor in regulating bone absorption is the proportion of RANKL/OPG. Although many reports showing diverse transcription factors or epigenetic modification could be responsible for regulating RANKL&OPG ratio, there is still little exploration on promoter methylation status of both genes in osteoporotic bone tissues. Our aim is to investigate the changes of methylation in CpG island of these genes' promoters in patients with primary osteoporosis. Methods: The diagnosis of osteoporosis was based on the results of dual energy X ray absorptiometry measurements. All femoral bone tissues were separated in surgeries. After extracting total RNA, we checked the relative expression levels of OPG and RANKL by quantitative real time PCR. The genomic DNA of Non-OPF (Non osteoporotic fracture bone tissues) & OPF (osteoporotic fracture bone tissues) were treated by bisulfite modification, and methylation status of CpG sites in the CpG island of OPG/RANKL promoters were determined by DNA sequencing. Results: RANKL expression in the OPF group was significantly higher than that in Non-OPF group, and the CpG methylation status in RANKL gene promoter was significantly lower. However, for OPG, lower gene expression level and higher methylation degree were found in the OPF group. Conclusion: Our study demonstrated that DNA methylation influenced the transcriptional expression of OPG and RANKL, which probably take on a "main switch" role in pathogenesis of primary osteoporosis. PMID- 30443171 TI - NDRG1 Downregulates ATF3 and Inhibits Cisplatin-Induced Cytotoxicity in Lung Cancer A549 Cells. AB - N-myc downstream regulated gene 1 (NDRG1) plays a variety of roles in human cancers. Our previous studies showed that NDRG1 expression is elevated in non small cell lung cancer and contributes to cancer growth. However, its function in apoptosis and chemoresistance in malignant tumors, including lung cancer, is not yet fully understood. In this study, we investigated the roles of NDRG1 in chemoresistance to cisplatin in lung cancer cells. We found that overexpression of NDRG1 significantly reduced cisplatin-induced cytotoxicity in lung cancer A549 cells, while overexpression of activating transcription factor 3 (ATF3), a stress inducible gene found to be associated with apoptosis in some human cancers, significantly promoted cytotoxicity (P < 0.05). Further investigation showed that overexpression of NDRG1 significantly downregulated ATF3 and P53 expression in A549 cells, while overexpression of ATF3 significantly upregulated P53 expression (P < 0.05). In addition, cisplatin significantly upregulated ATF3, phospho P53(ser46), and cleaved caspase 3 expression in lung cancer cells, but overexpression of NDRG1 in the presence of cisplatin reduced the level of these proteins elevated by cisplatin (P < 0.05). While, overexpression of ATF3 significantly promoted the cytoxicity induced by cisplatin in 1299 cells (p<0.05) (Figure 4), but overexpression of NDRG1 didn't regulate the cytoxicity induced by cisplatin (p>0.05). These results indicate that NDRG1 may contribute to cisplatin resistance in lung cancer, possibly due to its function in the regulation of ATF3 expression. PMID- 30443170 TI - Comparison of Oxidative Stress Effects on Senescence Patterning of Human Adult and Perinatal Tissue-Derived Stem Cells in Short and Long-term Cultures. AB - Human Mesenchymal Stem Cells (hMSCs) undergo senescence in lifespan. In most clinical trials, hMSCs experience long-term expansion ex vivo to increase cell number prior to transplantation, which unfortunately leads to cell senescence, hampering post-transplant outcomes. Hydrogen peroxide (H2O2) in vitro represents a rapid, time and cost-effective tool, commonly used as oxidative stress tantalizing the stem cell ability to cope with a hostile environment, recapitulating the onset and progression of cellular senescence. Here, H2O2 at different concentrations (ranging from 50 to 400 MUM) and time exposures (1 or 2 hours - h), was used for the first time to compare the behavior of human Adipose tissue-derived Stem Cells (hASCs) and human Wharton's Jelly-derived MSCs (hWJ MSCs), as representative of adult and perinatal tissue-derived stem cells, respectively. We showed timely different responses of hASCs and hWJ-MSCs at low and high subculture passages, concerning the cell proliferation, the cell senescence-associated beta-Galactosidase activity, the capability of these cells to undergo passages, the morphological changes and the gene expression of tumor protein p53 (TP53, alias p53) and cyclin dependent kinase inhibitor 1A (CDKN1A, alias p21) post H2O2 treatments. The comparison between the hASC and hWJ-MSC response to oxidative stress induced by H2O2 is a useful tool to assess the biological mechanisms at the basis of hMSC senescence, but it could also provide two models amenable to test in vitro putative anti-senescence modulators and develop anti-senescence strategies. PMID- 30443172 TI - Simvastatin Protects Heart from Pressure Overload Injury by Inhibiting Excessive Autophagy. AB - Cardiac hypertrophy is an independent predictor of cardiovascular morbidity and mortality. To identify the mechanisms by which simvastatin inhibits cardiac hypertrophy induced by pressure overload, we determined effects of simvastatin on 14-3-3 protein expression and autophagic activity. Simvastatin was administered intragastrically to Sprague-Dawley (SD) rats before abdominal aortic banding (AAB). Neonatal rat cardiomyocytes (NRCs) were treated with simvastatin before angiotensin II (AngII) stimulation. 14-3-3, LC3, and p62 protein levels were determined by western blot. Autophagy was also measured by the double-labeled red fluorescent protein-green fluorescent protein autophagy reporter system. Simvastatin alleviated excessive autophagy, characterized by a high LC3II/LC3I ratio and low level of p62, and blunted cardiac hypertrophy while increasing 14-3 3 protein expression in rats that had undergone AAB. In addition, it increased 14 3-3 expression and inhibited excessive autophagy in NRCs exposed to AngII. Our study demonstrated that simvastatin may inhibit excessive autophagy, increase 14 3-3 expression, and finally exert beneficial effects on cardioprotection against pressure overload. PMID- 30443173 TI - Ethanol Extract from Brucea Javanica Seed Inhibits Angiogenesis Mediated by Platelet Derived Growth Factor Receptor-beta. AB - The present study aimed to investigate the effects of ethanol extract from Brucea javanicaseed (EEBJS) on the angiogenesis of human umbilical vein endothelial cells (HUVECs) and the possible molecular signal involved. Firstly, a Matrigel based in vitro angiogenesis assay demonstrated that EEBJS inhibited the angiogenesis of HUVECs in a dose-dependent manner. Then by using porcine aortic endothelial cells which stably express human PDGFR-beta, we found that the inhibition of angiogenesis was mediated by PDGFR-beta. Taken together, we conclude that EEBJS inhibited the angiogenesis function of the vascular endothelial cells mediated by PDGFR-beta, and postulate that it might contribute to the therapeutic effects of EEBJS on malignant tumors. PMID- 30443174 TI - Comparisons of Pressure-controlled Ventilation with Volume Guarantee and Volume controlled 1:1 Equal Ratio Ventilation on Oxygenation and Respiratory Mechanics during Robot-assisted Laparoscopic Radical Prostatectomy: a Randomized-controlled Trial. AB - Background: During robot-assisted laparoscopic radical prostatectomy (RALP), steep Trendelenburg position and carbon dioxide pneumoperitoneum are inevitable for surgical exposure, both of which can impair cardiopulmonary function. This study was aimed to compare the effects of pressure-controlled ventilation with volume guarantee (PCV with VG) and 1:1 equal ratio ventilation (ERV) on oxygenation, respiratory mechanics and hemodynamics during RALP. Methods: Eighty patients scheduled for RALP were randomly allocated to either the PCV with VG or ERV group. After anesthesia induction, volume-controlled ventilation (VCV) was applied with an inspiratory to expiratory (I/E) ratio of 1:2. Immediately after pneumoperitoneum and Trendelenburg positioning, VCV with I/E ratio of 1:1 (ERV group) or PCV with VG using Autoflow mode (PCV with VG group) was initiated. At the end of Trendelenburg position, VCV with I/E ratio of 1:2 was resumed. Analysis of arterial blood gases, respiratory mechanics, and hemodynamics were compared between groups at four times: 10 min after anesthesia induction (T1), 30 and 60 min after pneumoperitoneum and Trendelenburg positioning (T2 and T3), and 10 min after desufflation and resuming the supine position (T4). Results: There were no significant differences in arterial blood gas analyses including arterial oxygen tension (PaO2) between groups throughout the study period. Mean airway pressure (Pmean) were significantly higher in the ERV group than in the PCV with VG group T2 (p<0.001) and T3 (p=0.002). Peak airway pressure and hemodynamic data were comparable in both groups. Conclusion: PCV with VG was an acceptable alternative to ERV during RALP producing similar PaO2 values. The lower Pmean with PCV with VG suggests that it may be preferable in patients with reduced cardiovascular function. PMID- 30443175 TI - Effect of mistletoe on endometrial stromal cell survival and vascular endothelial growth factor expression in patients with endometriosis. AB - Research Question: To evaluate the effect of mistletoe on the cell viability of patients with endometriosis, the expression levels of vascular endothelial growth factor (VEGF) were measured, and the change in the expression level of VEGF following mistletoe treatment was recorded. Design: Forty reproductive-aged women with endometriosis (stage I/II [group 1, n=20], and stage III/IV [group 2, n=20]) were prospectively enrolled. Twenty women who underwent gynaecologic operations for benign conditions were selected as the control group. Both eutopic and ectopic endometrial tissues were obtained from the endometriosis patients. The endometrial tissues were cultured and the stromal cells were separated. The cells were cultured for 24 hours with peritoneal fluid from patients and controls with and without mistletoe supplementation (200 ng/mL), respectively. The MTT assay was used to assess cell viability, and VEGF expression was analysed by Western blotting and ELISA. Results: Using peritoneal fluid from endometriosis patients treated with mistletoe, we found that both eutopic and ectopic endometrial stromal cell viability increased after treatment with peritoneal fluid from patients with early-stage (I and II) endometriosis. After mistletoe treatment, the cell viability was decreased, in both eutopic and ectopic endometrial stromal cells in all stages of endometriosis. These findings were verified consistently by evaluating the expression and concentration of VEGF, a marker of angiogenesis. Conclusions: The present study showed that mistletoe can reduce the cell viability of endometrial stromal cells and the peritoneal fluid-induced elevation of VEGF in eutopic and ectopic endometrial stromal cells obtained from endometriosis patients, especially in the early stage. Mistletoe might have anti angiogenic activity on endometrial stromal cells and thus is a potential candidate for the treatment of endometriosis. PMID- 30443176 TI - Tumorous imaginal disc 1 (TID1) inhibits isoproterenol-induced cardiac hypertrophy and apoptosis by regulating c-terminus of hsc70-interacting protein (CHIP) mediated degradation of Galphas. AB - Dilated cardiomyopathy (DCM) is the most common form of non-ischemic cardiomyopathy. It is characterized by ventricular chamber dilation, and myocyte hypertrophy. Human tumorous imaginal disc 1 (Tid1), a chaperone protein and response to regulate number of signaling molecules in the mitochondria or cytosol. Tid1 also plays a major role in preventing DCM; however, the role of Tid1 in isoproterenol (ISO)-induced cardiac apoptosis and hypertrophy remains unclear. H9c2 cells were pretreated Tid1 before ISO-induced hypertrophy and apoptosis and then evaluated by IHC, TUNEL assay, IFC, Co-IP, and Western blot. From the IHC experiment, we found that Tid1 proteins were increased in tissues from different stages of human myocardial infarction. Using H9c2 cardiomyoblast cells we found that Tid1 was decreased by ISO treatment. However, over-expression of Tid1S suppressed NFATc3, BNP and calcineurin protein expression and inhibited NFATc3 nuclear translocation in ISO induced cardiomyoblast cells. On the other hand, Tid1S over-expression activated survival proteins p-AKTser473 and decreased caspase-3 and cytochrome c expression. We also found that overexpression of Tid1 enhanced CHIP expression, and induced CHIP to ubiquitinate Galphas, resulting in increased Galphas degradation. Our study showed that Galphas is a novel substrate of CHIP, and we also found that the Tid1-CHIP complex plays an essential role in inhibiting ISO induced cardiomyoblast hypertrophy and apoptosis. PMID- 30443177 TI - Microarray Analysis of Differentially-expressed MicroRNAs in Acquired Middle Ear Cholesteatoma. AB - Objectives: To analyze the miRNAs expression profiling between acquired middle ear cholesteatoma and normal skin, and to identify several novel miRNAs which may be involved in the etiopathogenesis of middle ear cholesteatoma. Methods: MiRNA microarray technology was adopted to analyze the miRNA expression profiling between acquired middle ear cholesteatoma and normal skin. qRT-PCR was used to validate selected differentially expressed miRNAs. Results: The miRNA microarray technology showed totally 44 upregulated (miRNA-21-3p, miRNA-584-5p, miRNA-16-1 3p, etc) and 175 downregulated (miRNA-10a-5p, miRNA-152-5p, miRNA-203b-5p, etc) miRNAs in cholesteatoma tissues with 2-fold change compared with normal skin. The qRT-PCR validation was in accordance with the microarray results partly: miRNA-21 3p and miRNA-16-1-3p expressed significantly higher while miRNA-10a-5p exhibited an obviously decreased expression in middle ear cholesteatoma tissues when compared with normal skin. The GO and KEGG pathway analyses provided clues that these differentially expressed miRNAs might play essential roles in the etiopathogenesis of middle ear cholesteatoma, including cell proliferation, apoptosis, cell cycle, differentiation, bone resorption and remodeling process. Conclusions: Our study suggests possible roles of differentially expressed miRNAs in the pathogenesis of middle ear cholesteatoma. Targeting on these miRNAs may provide a new strategy for cholesteatoma therapy in the future. PMID- 30443179 TI - A SHOX2 loss-of-function mutation underlying familial atrial fibrillation. AB - Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients. PMID- 30443180 TI - Pin1 Is Involved in HDAC6-mediated Cancer Cell Motility. AB - Histone deacetylase 6 (HDAC6), a member of the HDAC enzymes, has been reported to play substantial roles in many cellular processes. Evidence shows that deregulation of HDAC6 may be involved in the progression of some cancers, neurodegenerative diseases, and inflammatory disorders. However, little is known regarding the effect of post-translational modification of HDAC6 on cellular localization and biological functions. In the present study, we identified four phosphorylation sites on HDAC6 under normal conditions by mass spectrometry analysis. Two phosphorylation sites, pSer22 and pSer412, are recognized as Pin1 (peptidyl-prolyl cis/trans isomerase NIMA-interacting 1) substrates. Pin1 can interact with HDAC6 and be involved in HDAC6-mediated cell motility. Pin1 depletion abrogates HDAC6-induced cell migration and invasion in H1299 lung cancer cells. The findings of this study suggest that Pin1 might regulate HDAC6 mediated cell motility through alteration of protein conformation and function. Our results indicate the complexity of activity regulation between HDAC6 and Pin1, expanding knowledge regarding the multifunctional roles of Pin1 in tumorigenesis and cancer progression. PMID- 30443181 TI - Inhibition of AKT suppresses the initiation and progression of BRCA1-associated mammary tumors. AB - Despite the high incidence of BRCA1-mutant breast cancer, few substantial improvements in preventing or treating such cancers have been made. Using a Brca1 mutant mouse model, we examined the contribution of AKT to the incidence and growth of Brca1-mutated mammary tumors. A haploinsufficiency of Akt1 in Brca1 mutant mouse model significantly decreased mammary tumor formation from 54% in Brca1co/coMMTV-Cre mice to 22% in Brca1 co/coMMTV-Cre Akt1+/- mice. Notably, treatment of tumor-bearing Brca1-mutant mice with the AKT-inhibitor, MK-2206, yielded partial response or stable disease up to 91% of mice in maximum response. MK-2206 treatment also significantly reduced tumor volume and delayed recurrence in allograft and adjuvant studies, respectively. A correlation analysis of MK 2206 responses with gene expression profiles of tumors at baseline identified seven genes that were differentially expressed between tumors that did and did not respond to MK-2206 treatment. Our findings enhance our understanding of the involvement of AKT signaling in BRCA1-deficient mammary tumors and provide preclinical evidence that targeted AKT inhibition is a potential strategy for the prevention and therapeutic management of BRCA1-associated breast cancer. PMID- 30443178 TI - The Pivotal Role of Thymus in Atherosclerosis Mediated by Immune and Inflammatory Response. AB - Atherosclerosis is one kind of chronic inflammatory disease, in which multiple types of immune cells or factors are involved. Data from experimental and clinical studies on atherosclerosis have confirmed the key roles of immune cells and inflammation in such process. The thymus as a key organ in T lymphocyte ontogenesis has an important role in optimizing immune system function throughout the life, and dysfunction of thymus has been proved to be associated with severity of atherosclerosis. Based on previous research, we begin with the hypothesis that low density lipoprotein or cholesterol reduces the expression of the thymus transcription factor Foxn1 via low density lipoprotein receptors on the membrane surface and low density lipoprotein receptor related proteins on the cell surface, which cause the thymus function decline or degradation. The imbalance of T cell subgroups and the decrease of naive T cells due to thymus dysfunction cause the increase or decrease in the secretion of various inflammatory factors, which in turn aggravates or inhibits atherosclerosis progression and cardiovascular events. Hence, thymus may be the pivotal role in coronary heart disease mediated by atherosclerosis and cardiovascular events and it can imply a novel treatment strategy for the clinical management of patients with atherosclerosis in addition to different commercial drugs. Modulation of immune system by inducing thymus function may be a therapeutic approach for the prevention of atherosclerosis. Purpose of this review is to summarize and discuss the recent advances about the impact of thymus function on atherosclerosis by the data from animal or human studies and the potential mechanisms. PMID- 30443183 TI - miR-186-5p Promotes Apoptosis by Targeting IGF-1 in SH-SY5Y OGD/R Model. AB - In recent years, accumulating evidence has revealed that microRNAs play critical roles in ischemia stroke. This study was designed to investigate the expression level and effects of microRNA (miR)-186-5p on ischemia stroke, and its underlying molecular mechanism. Firstly, we demonstrated that miR-186-5p were significantly up-regulated and induced apoptosis in oxygen and glucose deprivation/reperfusion (OGD/R) model. Moreover, we found that miR-186-5p reduced the expression of insulin-like growth factor (IGF)-1, an essential factor for the development of the nervous system. Meanwhile, miR-186-5p inhibitor enhanced cell viability and IGF-1 expression. Furthermore, IGF-1 was confirmed as a direct target gene of miR 186-5p by luciferase activity assay. In addition, miR-186-5p was upregulated in ischemia stroke patients' serum compared with healthy donors. These data demonstrated that miR-186-5p was an adverse factor by inducing neuron apoptosis and suppressing IGF-1 in ischemia stroke model, and suggested that miR-186-5p may be a diagnostic marker and potential therapeutic target for ischemia stroke patients. PMID- 30443182 TI - Novel CD44-downstream signaling pathways mediating breast tumor invasion. AB - CD44, also known as homing cell adhesion molecule is a multi-structural cell molecule involved in cell-cell and cell-extracellular matrix communications. CD44 regulates a number of central signaling pathways, including PI3K/AKT, Rho GTPases and the Ras-MAPK pathways, but also acts as a growth/arrest sensor, and inhibitor of angiogenesis and invasion, in response to signals from the microenvironment. The function of CD44 has been very controversial since it acts as both, a suppressor and a promoter of tumor growth and progression. To address this discrepancy, we have previously established CD44-inducible system both in vitro and in vivo. Next, using microarray analysis, we have identified and validated Survivin, Cortactin and TGF-beta2 as novel CD44-downstream target genes, and characterized their signaling pathways underpinning CD44-promoted breast cancer (BC) cell invasion. This report aims to update the literature by adding and discussing the impact of these novel three signaling pathways to better understand the CD44-signaling pathways involved in BC tumor cell invasion. PMID- 30443185 TI - Prognostic Dynamic Nomogram Integrated with Inflammation-Based Factors for Non Small Cell Lung Cancer Patients with Chronic Hepatitis B Viral Infection. AB - Chronic inflammation plays an important role in tumor progression. The aim of this study was to develop an effective predictive dynamic nomogram integrated with inflammation-based factors to predict overall survival (OS) of non-small cell lung cancer (NSCLC) patients with chronic hepatitis B viral (HBV) infection. We retrospectively analyzed NSCLC patients with HBV infection from Sun Yat-sen University Cancer Center between 2008 and 2010. Univariate and multivariate Cox survival analyses were performed to identify prognostic factors associated with OS of patients. All of the independent prognostic factors were utilized to build the dynamic nomogram. The predictive accuracy of the dynamic nomogram was evaluated concordance index (C-index), decision curve analysis and were compared with previous reported model and traditional TNM staging system. According to the total points (TPS) by dynamic nomogram, we further stratified patients into different risk groups. A total of 203 patients were included. Multivariate Cox analysis showed TNM stage (P = 0.019), treatment (P < 0.001), C-reactive protein (P = 0.020) and platelet (P = 0.012) were independent prognostic factors of OS. The dynamic nomogram was established by involving all the factors above. The C index of dynamic nomogram for predicting OS was 0.76 (95%CI: 0.72-0.80), which was statistically higher than that of traditional TNM staging system (0.70, 95%CI: 0.66-0.74, P<0.001). Decision curve analysis demonstrated that the dynamic nomogram was better than the TNM staging system. The predictive accuracy of the current model keeping almost the same accuracy as previous one. Based on the total points (TPS) of dynamic nomogram, we divided the patients into 3 subgroups: low risk (TPS <= 107), intermediate risk (107< TPS <= 149), and high risk (TPS > 149). The differences of OS rates were significant in the subgroups. We propose a novel dynamic nomogram model based on inflammatory prognostic factors that is highly predictive of OS in NSCLC patients with HBV infection and outperforms the traditional TNM staging system. PMID- 30443186 TI - Prior Knowledge Driven Joint NMF Algorithm for ceRNA Co-Module Identification. AB - MRNA and lncRNA serve as a type of endogenous RNA in cell, which can competitively bind to the same miRNA through miRNA response elements (MREs), thereby regulating their respective expression levels, playing an important role in post-transcriptional regulation, and regulating the progress of tumors. The proposed competing endogenous RNA (ceRNA) hypothesis provides novel clues for the occurrence and development of tumors, but the integrative analysis methods of diverse RNA data are significantly limited. In order to find out the relationship among miRNA, mRNA and lncRNA, the previous studies only used individual dataset as seeds to search two other related data in the database to construct ceRNA network, but it was difficult to identify the synchronized effects from multiple regulatory levels. Here, we developed the joint matrix factorization method integrating prior knowledge to map the three types of RNA data of lung cancer to the common coordinate system and construct the ceRNA network corresponding to the common module. The results show that more than 90% of the modules are closely related to cancer, including lung cancer. Furthermore, the resulting ceRNA network not only accurately excavates the known correlation of the three types of RNA molecular, but also further discovers the potential biological associations of them. Our work provides support and foundation for future biological validation how competitive relationships of multiple RNAs affects the development of tumors. PMID- 30443187 TI - Copper Nanoparticles Show Obvious in vitro and in vivo Reproductive Toxicity via ERK Mediated Signaling Pathway in Female Mice. AB - Copper nanoparticles (Cu-NPs) and other inorganic nanomaterials have caused increasing concern owing to be widely used. Early studies have reported that they can result in injuries to the kidney, liver and spleen of mice; cause embryonic damage; and inhibit the reproductive capacity of red worms. However, few studies have reported the toxicity of Cu-NPs on the reproductive systems of mammals. In the present work, we explored the cytotoxicity of Cu-NPs in human extravillous trophoblast cells and in the reproductive organs of mice. Cu-NPs induced ovarian and placental pathophysiology and dysfunction in mice. These nanoparticles also induced apoptosis and suppressed the proliferation of human extravillous trophoblast cells and caused cell cycle arrest at the G2/M phase in a time-and dose-dependent manner. Cu-NPs can significantly damage the mitochondrial membrane potential (MMP), which suggests that Cu-NPs can activate the mitochondria mediated apoptosis signaling pathway. We also observed that Cu-NPs significantly inhibit the expression of BRAF, ERK, and MITF expression, all of which are important genes in the ERK signaling pathway. Our research demonstrated that Cu NPs exert obvious reproductive toxicity in mice by disrupting the balance of sex hormones and exert cytotoxicity on human extravillous trophoblast cells, and ERK signaling and the mitochondrial apoptosis pathway made great contribution to the toxicity of Cu-NPs on female mice. PMID- 30443188 TI - The HDAC Inhibitor Quisinostat (JNJ-26481585) Supresses Hepatocellular Carcinoma alone and Synergistically in Combination with Sorafenib by G0/G1 phase arrest and Apoptosis induction. AB - The high activity of Histone deacetylases (HDACs) in hepatocellular carcinoma (HCC) usually positively correlates with poor prognosis of patients. Accordingly histone deacetylases inhibitors (HDACis) are considered to be potential agents treating patients with HCC. In our study, we evaluated effect of quisinostat alone and in combination with sorafenib in HCC cells via inducing G0/G1 phase arrest through PI3K/AKT/p21 pathway and apoptosis by JNK/c-Jun/caspase3 pathway in vitro and in vivo. The proliferation assay and flow cytometry were used to measure the viability, cell cycle and apoptosis. And Western blot assay was carried out to determine expression alternations of related proteins. Moreover HCCLM3 xenograft was further performed to detect antitumor effect of quisinostat in vivo. Here, we found that quisinostat impeded cell proliferation, and remarkably induced G0/G1 phase arrest and apoptosis in HCC cells in a dose dependent manner. G0/G1 phase arrest was observed by alterations in PI3K/AKT/p21 proteins. Meanwhile the JNK, c-jun and caspase-3 were activated by quisinostat in a dose-dependent manner. Correspondingly quisinostat facilitated G0/G1 cycle arrest and apoptosis in HCC cells through PI3K/AKT/p21 pathways and JNK/c- jun/caspase3 pathways. Moreover, the potent tumor-suppressive effects facilitated by quisinostat, was significantly potentiated by combination with sorafenib in vitro and vivo. The combination treatment of quisinostat and sorafenib markedly suppressed cell proliferation and induced apoptosis in a synergistic manner. Moreover the therapy of quisinostat combined with sorafenib could apparently decrease tumor volume of a HCCLM3 xenograft model. Our study indicated that quisinostat, as a novel chemotherapy for HCC, exhibited excellent antitumor activity in vitro and vivo, which was even enhanced by the addition of sorafenib, implying combination of quisinostat with sorafenib a promising and alternative therapy for patients with advanced hepatocellular carcinoma. PMID- 30443189 TI - Effect of RIF1 on response of non-small-cell lung cancer patients to platinum based chemotherapy by regulating MYC signaling pathway. AB - Platinum-based chemotherapy is used as first-line therapy for advanced non-small cell lung cancer (NSCLC). However, there is no effective indicator to predict whether the patient would be chemo-resistant or sensitive to the therapy. In addition, it is urgent to elucidate the mechanisms of cisplatin resistance. RIF1 plays important roles in DNA replication regulation and DNA repair pathway. However, the role of RIF1 in NSCLC progression and chemotherapy response is still unknown. In this study, we found that RIF1 expression was correlated with the response of NSCLC patients to platinum-based chemotherapy (n=89, P=0.002). Among patients who have been treated with platinum chemo-therapy, those with high levels of RIF1 expression had significantly shorter survival than those with low RIF1 expression (P<0.05). RIF1 knockdown increased sensitivity to cisplatin in NSCLC patients both in vitro and in vivo. Moreover, RIF1 knockdown induced G0/G1 phase arrest and increased cisplatin-induced apoptosis and DNA damage. Further investigation showed that RIF1 regulated the expression of MYC and MYC downstream targets, including the cell cycle and double-stranded break (DSB) repair genes which might mediate the effect of RIF1 on cellular response to cisplatin. Overexpression of MYC could reverse the inhibition of MYC targets by RIF1 knockdown. Taken together, these data revealed that RIF1 played an important role in regulating MYC and MYC-activated genes, which in turn contributes to cellular response to cisplatin and NSCLC patients' response to platinum-based chemotherapy. RIF1 might serve as a novel biomarker for predicting platinum-based chemo-sensitivity and the prognosis of NSCLC patients, so as to guide the chemotherapy regimen adjustment for individual patient with NSCLC and improve their clinical outcomes. PMID- 30443184 TI - Evaluating the Remote Control of Programmed Cell Death, with or without a Compensatory Cell Proliferation. AB - Organisms and their different component levels, whether organelle, cellular or other, come by birth and go by death, and the deaths are often balanced by new births. Evolution on the one hand has built demise program(s) in cells of organisms but on the other hand has established external controls on the program(s). For instance, evolution has established death program(s) in animal cells so that the cells can, when it is needed, commit apoptosis or senescent death (SD) in physiological situations and stress-induced cell death (SICD) in pathological situations. However, these programmed cell deaths are not predominantly regulated by the cells that do the dying but, instead, are controlled externally and remotely by the cells' superior(s), i.e. their host tissue or organ or even the animal's body. Currently, it is still unclear whether a cell has only one death program or has several programs respectively controlling SD, apoptosis and SICD. In animals, apoptosis exterminates, in a physiological manner, healthy but no-longer needed cells to avoid cell redundancy, whereas suicidal SD and SICD, like homicidal necrosis, terminate ill but useful cells, which may be followed by regeneration of the live cells and by scar formation to heal the damaged organ or tissue. Therefore, "who dies" clearly differentiates apoptosis from SD, SICD and necrosis. In animals, apoptosis can occur only in those cell types that retain a lifelong ability of proliferation and never occurs in those cell types that can no longer replicate in adulthood. In cancer cells, SICD is strengthened, apoptosis is dramatically weakened while SD has been lost. Most published studies professed to be about apoptosis are actually about SICD, which has four basic and well-articulated pathways involving caspases or involving pathological alterations in the mitochondria, endoplasmic reticula, or lysosomes. PMID- 30443191 TI - PKM2 Inhibitor Shikonin Overcomes the Cisplatin Resistance in Bladder Cancer by Inducing Necroptosis. AB - Cisplatin-based chemotherapy often results in the development of chemo-resistance when used to treat bladder cancer (BC), which is difficult to overcome. Recent data indicate that pyruvate kinase M2 (PKM2), a glycolytic enzyme for Warburg effect, is strongly upregulated in BC, and contributes to the cisplatin resistance in BC. However, the underlying mechanisms remain unclear. In this study, we also found that the expression level of PKM2 is also higher in cisplatin resistant BC cells and tumors. Down-regulation of PKM2 by siRNA or inhibition of PKM2 by shikonin re-sensitized the cisplatin resistant T24 cells. Shikonin and cisplatin together exhibit significantly greater killing effects than when used alone. Interestingly, we found shikonin kills the T24 cisplatin resistant cells by inducing necroptosis, as the cell death could not inhibited by apoptosis inhibitor, z-VAD, but compromised by RIP3 inhibitor, GSK872, or RIP3 siRNA. In contrast, shikonin induced apoptosis in T24 parental cells. We further investigate the underlying mechanism, and found that the dysregulation of Bcl-2 family proteins, including Bcl-2, PUMA, Bax, play an important role in deciding that shikonin kills the BC cells by necroptosis or apoptosis. Collectively, our results suggested that inducing necroptosis is an alternative way to overcome the apoptosis resistant in BC therapy, and orchestrating the regulation of Bcl-2, PUMA, and Bax in BC cisplatin resistant cells may improve the therapy effect of cisplatin in BC tumor. PMID- 30443190 TI - SIRT3 Activation by Dihydromyricetin Suppresses Chondrocytes Degeneration via Maintaining Mitochondrial Homeostasis. AB - Mitochondrial dysfunction is an important contributor to the development of osteoarthritis (OA). Sirtuin 3 (SIRT3) regulates diverse mitochondrial proteins to maintain mitochondrial homeostasis, and dihydromyricetin (DHM) is reported as a potential SIRT3 activator. This study aims to explore the relevance of SIRT3 and OA, as well as the therapeutic effects of DHM on mitochondrial homeostasis in TNF-alpha-treated chondrocytes. The relationship between SIRT3 and OA was confirmed by detecting SIRT3 level in vitro and in vivo. Mitochondrial dysfunction was evaluated in chondrocytes with or without SIRT3 knockdown. Furthermore, the effects of DHM on mitochondrial homeostasis were performed in TNF-alpha-treated rat chondrocytes in vitro. In this study, our results showed that the SIRT3 level was decreased in mouse OA cartilage, corresponding to the reduced SIRT3 level in TNF-alpha-treated chondrocytes in vitro. SIRT3 knockdown induced mitochondrial dysfunction in chondrocytes. Moreover, our study demonstrated that DHM might activate SIRT3 to protect rat chondrocytes from TNF alpha-induced degeneration and protective effects of DHM on mitochondrial homeostasis in chondrocytes attributed to enhanced SIRT3. Collectively, SIRT3 deficiency is implicated in OA development and DHM exerts anti-degeneration effect by maintaining mitochondrial homeostasis via a SIRT3-dependent manner in chondrocytes. PMID- 30443192 TI - DJ-1 Deficiency Protects Hepatic Steatosis by Enhancing Fatty Acid Oxidation in Mice. AB - Our previous studies have shown that DJ-1 play important roles in progression of liver diseases through modulating hepatic ROS production and immune response, but its role in hepatic steatosis remains obscure. In the present study, by adopting a high-fat-diet (HFD) induced mice model, we found that DJ-1 knockout (DJ-1 -/- ) mice showing decreased HFD-induced obesity and visceral adipose accumulation. In line with these changes, there were also reduced liver weight and ameliorated hepatic triglyceride (TG) accumulation in DJ-1-/- mice compared to wild-type (WT) mice. And there were also decreased blood glucose levels and insulin resistance and reduced glucose metabolic disorder in DJ-1-/- mice, whereas there were no significant differences in total cholesterol (TC) and serum lipid in two groups of mice. Mechanistically, we found that there were no differences in food intake in these two genotypes of mice. Furthermore, there were no significant differences in fatty acid synthesis and glycolysis, but the expression of key enzymes in fatty acid oxidation and the tricarboxylic acid (TCA) cycle, such as Cpt1alpha, Pparalpha, Acox1, Cs, Idh1 and Idh2, was increased in DJ-1-/- mice liver, suggesting that there was enhanced fatty acids oxidation and TCA cycle in DJ-1-/- mice. Our data indicate that deletion of DJ-1 enhancing fatty acids oxidation resulting in lower hepatic TG accumulation in mice, which protecting mice hepatic steatosis. PMID- 30443193 TI - Generation of Mesenchymal Stem Cells from Human Embryonic Stem Cells in a Complete Serum-free Condition. AB - Mesenchymal stem cells (MSC) have been derived from a variety of tissues, and cultured either in animal serum-containing (SC) or serum-free (SF) media. We have previously derived MSC from human embryonic stem cells via an intermediate trophoblast step (named EMSC), which also have immunosuppressive and therapeutic effects on animal models of autoimmune disease. To promote the clinical application of this new source of MSC, we report here EMSC derived and cultured in a SF medium MesenCult (SF-EMSC) in comparison with a SC medium (SC-EMSC). SF EMSC derived in MesenCult also expressed typical MSC markers CD73, CD90, and CD105, and manifested multipotency to differentiate to osteocytes, chondrocytes, and adipocytes. Comparably, CD105+ cells reached 90% about one week slower in the SF than SC conditions, and the proliferation rate was slightly faster for SF-EMSC than SC-EMSC at later passages. Both SF- and SC-EMSC responded similarly to the inflammatory stimulus IFNgamma. However, the inflammatory cytokines IL-6 and IL-8 were expressed much less in SF-EMSC than SC-EMSC. Furthermore, knockdown of P16INK4A in both SF- and SC-EMSC reduced replicative senescence. Together, our results suggest that EMSC can be generated in a complete SF condition, and SF EMSC are largely similar to SC-EMSC. However, it takes longer time to derive EMSC in the SF than SC conditions, and the SF-EMSC proliferate faster at later passages and produce less of the inflammatory cytokines IL-6 and IL-8 than SC EMSC. This study provides important information for production of clinically applicable EMSC. PMID- 30443196 TI - Empathically designed responses as a gateway to advice in Dutch counseling calls. AB - Previous conversation analytic studies of institutional interaction included analyses of empathy in interaction. These studies revealed that professionals may use empathy displays not only to validate the client's worry, but also to perform actions oriented to other institutional goals and tasks such as closing off a troubles-telling sequence. In this article, we present an analysis of empathically designed responses in Dutch telephone counseling. The data consist of 36 calls from the Alcohol and Drugs Info Line. In some of the calls, clients' troubles-telling includes 'emotion discourse', that is, descriptions of their feelings/emotions. Counselors may respond to these descriptions using conventional empathy displays like 'I can imagine that' and 'I understand that' in a range of verbal and prosodic variations. The analysis reveals that these responses open up advice sequences that vary in the extent to which they treat the client's articulated feelings as valid. Most are affiliating, treating the client's feelings as the basis for advice, while some are less affiliative, putting the client's feelings into perspective or implicitly questioning their legitimacy. Hence, empathically designed responses are pivots to advice-giving. PMID- 30443195 TI - Saikosaponin A Protects From Pressure Overload-Induced Cardiac Fibrosis via Inhibiting Fibroblast Activation or Endothelial Cell EndMT. AB - Saikosaponin A (SSA) is a triterpenoid saponin with many pharmacological activities, including anti-inflammatory and antioxidant effects. The effect of SSA on cardiac remodeling and fibrosis, however, remains unclear. Aortic banding surgery was used to establish a mouse cardiac remodeling and fibrosis model. Mice were subjected to an intraperitoneal (i.p.) injection of SSA (5 mg/kg/d or 40 mg/kg/d) 2 weeks after surgery for 28 days. As a result, SSA had limited effect on cardiac hypertrophy but decreased cardiac fibrosis remarkably. Neonatal rat cardiomyocytes were isolated and cultured with SSA (1 and 30 MUM). Both 1 and 30 MUM SSA reduced atrial natriuretic peptide transcription induced by angiotensin II. Adult mouse cardiac fibroblasts were isolated and cultured with SSA (1, 3, 10 and 30 MUM). Only 10 and 30 MUM SSA ameliorated transforming growth factor beta (TGFbeta)-induced fibroblast activation and function. Mouse heart endothelial cells were isolated and stimulated with TGFbeta and cocultured with SSA (1, 3, 10 and 30 MUM). Only 1 and 3 MUM SSA ameliorated TGFbeta-induced endothelium mesenchymal transition (EndMT). Consistently, only the 5 mg/kg/d treatment relieved pressure overload-induced EndMT in vivo. Furthermore, we found that high dosages of SSA (10 and 30 MUM) inhibited the TGFbeta/smad pathway in fibroblasts, while low dosages of SSA (1 and 3 MUM) inhibited the Wnt/beta-catenin pathway in endothelial cells. The Smad pathway activator SRI-011381 eliminated SSA (30 MUM) induced protective effects on fibroblasts. The Wnt pathway activator WAY-262611 eliminated SSA (1 MUM)-induced protective effects on endothelial cells. In summary, this study indicates the potential application of SSA in the treatment of myocardial fibrosis in cardiac fibrosis, with different target effects associated with different dosages. PMID- 30443197 TI - On autoethnography. PMID- 30443194 TI - Comparison of the Effects of BMSC-derived Schwann Cells and Autologous Schwann Cells on Remyelination Using a Rat Sciatic Nerve Defect Model. AB - Schwann cells (SCs) are primarily responsible for the formation of myelin sheaths, yet bone marrow mesenchymal stem cell (BMSC)-derived SCs are often used to replace autologous SCs and assist with the repair of peripheral nerve myelin sheaths. In this study, the effects of the two cell types on remyelination were compared during the repair of peripheral nerves. Methods: An acellular nerve scaffold was prepared using the extraction technique. Rat BMSCs and autologous SCs were extracted. BMSCs were induced to differentiate into BMSC-derived SCs (B dSCs) in vitro. Seed cells (BMSCs, B-dSCs, and autologous SCs) were cocultured with nerve scaffolds (Sca) in vitro. Rats with severed sciatic nerves were used as the animal model. A composite scaffold was used to bridge the broken ends. After surgery, electrophysiology, cell tracking analyses (EdU labeling), immunofluorescence staining (myelin basic protein (MBP)), toluidine blue staining, and transmission electron microscopy were conducted to compare remyelination between the various groups and to evaluate the effects of the seed cells on myelination. One week after transplantation, only a small number of B dSCs expressed MBP, which was far less than the proportion of MBP-expressing autologous SCs (P<0.01) but was higher than the proportion of BMSCs expressing MBP (P<0.05). Four weeks after surgery, the electrophysiology results (latency time, conductive velocity and amplitude) and various quantitative indicators of remyelination (thickness, distribution, and the number of myelinated fibers) showed that the Sca+B-dSC group was inferior to the Sca+autologous SC group (P<0.05) but was superior to the Sca+BMSC group (P<0.05). Conclusions: Within 4 weeks after surgery, the use of an acellular nerve scaffold combined with B-dSCs promotes remyelination to a certain extent, but the effect is significantly less than that of the scaffold combined with autologous SCs. PMID- 30443198 TI - 'Handled with care': Diffuse policing and the production of inequality in Amsterdam. AB - The intersection of race and the criminal justice system has been a longstanding topic of activism, public debate and research in the US context. In recent years, European countries have also seen a growing social and academic debate about the way racialized minorities are policed. Based on ethnographic research in Amsterdam, this article argues that in order to understand such racialized policing, we have to go beyond a narrow focus on the police itself, and instead examine the broader institutional landscape tasked with security. This institutional landscape is made up of penal and welfare actors who together enact what I call diffuse policing. Such diffuse policing envelops targeted persons and spaces in a dense web of surveillance, and disciplinary and reform interventions that are hard to escape or challenge. This article explores the cumulative effects of this dense security landscape, and argues that it produces significant inequalities among youths in Amsterdam. PMID- 30443199 TI - Children Use Nonverbal Cues from an Adult to Evaluate Peers. AB - What factors contribute to children's tendency to view individuals as having different traits and abilities? The present research tested whether young children are influenced by adults' nonverbal behaviors when making inferences about peers. In Study 1, participants (5-6 years) viewed multiple videos of interactions between a 'teacher' and two 'students;' all individuals were unfamiliar to participants. In each clip, the students behaved similarly, but the teacher did not: She either smiled, nodded, touched, or shook her head at one student, and looked at the other student with a neutral expression. In Study 1, children tended to infer that students were smarter, nicer, and stronger if the teacher behaved more positively toward them. Study 2 pitted differences in the teacher's behavior against differences in the students' performance. When asked who was smarter, children selected lower-performing students who received more positive nonverbal cues from the teacher rather than higher-performing students who received less positive cues. The findings indicate that an authority figure's nonverbal behaviors can influence children's inferences about others, shedding light on one mechanism guiding young children's evaluations of people in their social world. PMID- 30443200 TI - Reducing Uncertainties in Carbonate Clumped Isotope Analysis Through Consistent Carbonate-Based Standardization. AB - About a decade after its introduction, the field of carbonate clumped isotope thermometry is rapidly expanding because of the large number of possible applications and its potential to solve long-standing questions in Earth Sciences. Major factors limiting the application of this method are the very high analytical precision required for meaningful interpretations, the relatively complex sample preparation procedures, and the mass spectrometric corrections needed. In this paper we first briefly review the evolution of the analytical and standardization procedures and discuss the major remaining sources of uncertainty. We propose that the use of carbonate standards to project the results to the carbon dioxide equilibrium scale can improve interlaboratory data comparability and help to solve long-standing discrepancies between laboratories and temperature calibrations. The use of carbonates reduces uncertainties related to gas preparation and cleaning procedures and ensures equal treatment of samples and standards. We present a set of carbonate standards of diverse composition, discuss how they can be used to correct for mass spectrometric biases, and demonstrate that their use significantly improves the comparability among four laboratories. We propose that the use of these standards or of a similar set of carbonate standards will improve the comparability of data across laboratories. PMID- 30443201 TI - Decreased Protein Quality Control Promotes the Cognitive Dysfunction Associated With Aging and Environmental Insults. AB - Background: Most neurodegenerative diseases are sporadic and develop with age. Degenerative neural tissues often contain intra- and extracellular protein aggregates, suggesting that the proteostasis network that combats protein misfolding could be dysfunctional in the setting of neurodegenerative disease. Binding immunoglobulin protein (BiP) is an endoplasmic reticulum (ER) chaperone that is crucial for protein folding and modulating the adaptive response in early secretory pathways. The interaction between BiP and unfolded proteins is mediated by the substrate-binding domain and nucleotide-binding domain with ATPase activity. The interaction facilitates protein folding and maturation. BiP has a recovery motif at the carboxyl terminus. The aim of this study is to examine cognitive function in model mice with an impaired proteostasis network by expressing a mutant form of BiP lacking the recovery motif. We also investigated if impairments of cognitive function were exacerbated by exposure to environmental insults, such as inhaled anesthetics. Methods: We examined cognitive function by performing radial maze testing with mutant BiP mice and assessed the additional impact of general anesthesia in the context of proteostasis dysfunction. Testing over 8 days was performed 10 weeks, 6 months, and 1 year after birth. Results: Age-related cognitive decline occurred in both forms of mice. The mutant BiP and anesthetic exposure promoted cognitive dysfunction prior to the senile period. After senescence, when mice were tested at 6 months of age and at 1 year old, there were no significant differences between the two genotypes in terms of the radial maze testing; furthermore, there was no significant difference when tested with and without anesthetic exposure. Conclusion: Our data suggest that aging was the predominant factor underlying the impairment of cognitive function in this study. Impairment of the proteostasis network may promote age-related neurodegeneration, and this is exacerbated by external insults. PMID- 30443202 TI - Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function. AB - Exercise has been shown to improve or rescue cognitive functioning in both humans and rodents, and the augmented actions of neurotrophins within the hippocampus and associated regions play a significant role in the improved neural plasticity. The septohippocampal circuit is modified by exercise. Beyond an enhancement of spatial working memory and a rescue of hippocampal activity-dependent acetylcholine (ACh) efflux, the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band (MS/dB) is observed following exercise (Hall and Savage, 2016). To determine which neurotrophin, brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), is critical for exercise induced cholinergic improvements, control and amnestic rats had either NGF or BDNF sequestered by TrkA-IgG or TrkB-IgG coated microbeads placed within the dorsal hippocampus. Hippocampal ACh release within the hippocampus during spontaneous alternation was measured and MS/dB cholinergic neuronal phenotypes were assessed. Sequestering NGF, but not BDNF, abolished the exercise-induced recovery of spatial working memory and ACh efflux. Furthermore, the re-emergence of the cholinergic/nestin neuronal phenotype within the MS/dB following exercise was also selectively dependent on the actions of NGF. Thus, exercise-induced enhancement of NGF within the septohippocampal pathway represents a key avenue for aiding failing septo-hippocampal functioning and therefore has significant potential for the recovery of memory and cognition in several neurological disorders. PMID- 30443203 TI - Network Brain-Computer Interface (nBCI): An Alternative Approach for Cognitive Prosthetics. AB - Brain computer interfaces (BCIs) have been applied to sensorimotor systems for many years. However, BCI technology has broad potential beyond sensorimotor systems. The emerging field of cognitive prosthetics, for example, promises to improve learning and memory for patients with cognitive impairment. Unfortunately, our understanding of the neural mechanisms underlying these cognitive processes remains limited in part due to the extensive individual variability in neural coding and circuit function. As a consequence, the development of methods to ascertain optimal control signals for cognitive decoding and restoration remains an active area of inquiry. To advance the field, robust tools are required to quantify time-varying and task-dependent brain states predictive of cognitive performance. Here, we suggest that network science is a natural language in which to formulate and apply such tools. In support of our argument, we offer a simple demonstration of the feasibility of a network approach to BCI control signals, which we refer to as network BCI (nBCI). Finally, in a single subject example, we show that nBCI can reliably predict online cognitive performance and is superior to certain common spectral approaches currently used in BCIs. Our review of the literature and preliminary findings support the notion that nBCI could provide a powerful approach for future applications in cognitive prosthetics. PMID- 30443204 TI - A Novel Biomarker of Compensatory Recruitment of Face Emotional Imagery Networks in Autism Spectrum Disorder. AB - Imagery of facial expressions in Autism Spectrum Disorder (ASD) is likely impaired but has been very difficult to capture at a neurophysiological level. We developed an approach that allowed to directly link observation of emotional expressions and imagery in ASD, and to derive biomarkers that are able to classify abnormal imagery in ASD. To provide a handle between perception and action imagery cycles it is important to use visual stimuli exploring the dynamical nature of emotion representation. We conducted a case-control study providing a link between both visualization and mental imagery of dynamic facial expressions and investigated source responses to pure face-expression contrasts. We were able to replicate the same highly group discriminative neural signatures during action observation (dynamical face expressions) and imagery, in the precuneus. Larger activation in regions involved in imagery for the ASD group suggests that this effect is compensatory. We conducted a machine learning procedure to automatically identify these group differences, based on the EEG activity during mental imagery of facial expressions. We compared two classifiers and achieved an accuracy of 81% using 15 features (both linear and non-linear) of the signal from theta, high-beta and gamma bands extracted from right-parietal locations (matching the precuneus region), further confirming the findings regarding standard statistical analysis. This robust classification of signals resulting from imagery of dynamical expressions in ASD is surprising because it far and significantly exceeds the good classification already achieved with observation of neutral face expressions (74%). This novel neural correlate of emotional imagery in autism could potentially serve as a clinical interventional target for studies designed to improve facial expression recognition, or at least as an intervention biomarker. PMID- 30443206 TI - Seizure-Induced Arc mRNA Expression Thresholds in Rat Hippocampus and Perirhinal Cortex. AB - Immediate-early genes (IEGs) are rapidly and transiently induced following excitatory neuronal activity including maximal electroconvulsive shock treatment (ECT). The rapid RNA response can be blocked by the sodium channel antagonist tetrodotoxin (TTX), without blocking seizures, indicating a role for electrical stimulation in electroconvulsive shock-induced mRNA responses. In behaving animals, Arc mRNA is selectively transcribed following patterned neuronal activity and rapidly trafficked to dendrites where it preferentially accumulates at active synapses for local translation. Here we examined whether there is a relationship between the current intensities that elicit seizures and the threshold for Arc mRNA transcription in the rat hippocampus and perirhinal cortex (PRC). Animals received ECT of varying current intensities (0, 20, 40 65, 77 and 85 mA) and were sacrificed 5 min later. While significantly more CA1, CA3 and perirhinal pyramidal cells expressed Arc at the lowest stimulus intensity compared to granule cells, there was an abrupt threshold transition that occurred in all four regions at 77 mA. This precise threshold for Arc expression in all temporal lobe neurons examined may involve regulation of the calcium-dependent mechanisms that are upstream to activity-dependent IEG transcription. PMID- 30443207 TI - CD34 and CD117 Stemness of Lineage-Negative Cells Reverses Memory Loss Induced by Amyloid Beta in Mouse Model. AB - A majority of the neurodegenerative disorders including Alzheimer's disease are untreatable and occur primarily due to aging and rapidly changing lifestyles. The rodent Alzheimer's disease models are critical for investigating the underlying disease pathology and screening of novel therapeutic targets in preclinical settings. We aimed to characterize the stemness properties of human umbilical cord blood (hUCB) derived lineage-negative (Lin-) stem cells based on CD34 and CD117 expression as well as surface morphology using flow cytometry and scanning electron microscopy, respectively. The efficacy of the stem cells was tested by its capacity to rescue the injury caused by intrahippocampal delivery of varying doses of amyloid beta. The hUCB Lin- stem cells reversed memory loss due to Abeta42-induced injury more effectively at micromolar concentration, and not picomolar concentration. More studies are required to delineate the underlying molecular events associated with hUCB Lin- stem cells. PMID- 30443205 TI - Hypoxia Inducible Factor as a Central Regulator of Metabolism - Implications for the Development of Obesity. AB - The hypothalamus plays a major role in the regulation of food intake and energy expenditure. In the last decade, it was demonstrated that consumption of high-fat diets triggers the activation of an inflammatory process in the hypothalamus, inducing neurofunctional alterations and contributing to the development of obesity. Hypoxia-inducible factors (HIFs) are key molecules that regulate cellular responses to inflammation and hypoxia, being essential for the normal cell function and survival. Currently, evidence points to a role of HIF pathway in metabolic regulation that could also be involved in the progression of obesity and metabolic diseases. The challenge is to understand how HIF modulation impacts body mass gain and metabolic disorders such as insulin resistance. Distinct animal models with tissue-specific knocking-out or overexpression of hypoxia signaling pathway genes revealed a cell-specificity in the activation of HIF pathways, and some of them have opposite phenotypes among the various HIFs gain- and loss-of-function mouse models. In this review, we discuss the major findings that provide support for a role of HIF pathway involvement in the regulation of metabolism, especially in glucose and energy homeostasis. PMID- 30443208 TI - Frontal EEG Asymmetry and Middle Line Power Difference in Discrete Emotions. AB - A traditional model of emotion cannot explain the differences in brain activities between two discrete emotions that are similar in the valence-arousal coordinate space. The current study elicited two positive emotions (amusement and tenderness) and two negative emotions (anger and fear) that are similar in both valence and arousal dimensions to examine the differences in brain activities in these emotional states. Frontal electroencephalographic (EEG) asymmetry and midline power in three bands (theta, alpha and beta) were measured when participants watched affective film excerpts. Significant differences were detected between tenderness and amusement on FP1/FP2 theta asymmetry, F3/F4 theta and alpha asymmetry. Significant differences between anger and fear on FP1/FP2 theta asymmetry and F3/F4 alpha asymmetry were also observed. For midline power, midline theta power could distinguish two negative emotions, while midline alpha and beta power could effectively differentiate two positive emotions. Liking and dominance were also related to EEG features. Stepwise multiple linear regression results revealed that frontal alpha and theta asymmetry could predict the subjective feelings of two positive and two negative emotions in different patterns. The binary classification accuracy, which used EEG frontal asymmetry and midline power as features and support vector machine (SVM) as classifiers, was as high as 64.52% for tenderness and amusement and 78.79% for anger and fear. The classification accuracy was improved after adding these features to other features extracted across the scalp. These findings indicate that frontal EEG asymmetry and midline power might have the potential to recognize discrete emotions that are similar in the valence-arousal coordinate space. PMID- 30443210 TI - The Application of Mobile fNIRS in Marketing Research-Detecting the "First-Choice Brand" Effect. AB - Recent research in the field of "neuro-marketing" shows promise to substantially increase knowledge on marketing issues for example price-perception, advertising efficiency, branding and shopper behaviour. Recently, an innovative and mobile applicable neuroimaging method has been proposed, namely functional near-infrared spectroscopy (fNIRS). However, this method is, in the research field of marketing, still in its infancy and is, consequently, lacking substantial validity. Against this background, this research work applied a convergent validity approach to challenge the validity of (mobile) fNIRS in the field of "neuro-marketing" and consumer neuroscience. More precisely, we aim to replicate a robust and well-investigated neural effect previously detected with fMRI-namely the "first-choice-brand" effect-by using mobile fNIRS. The research findings show that mobile fNIRS appears to be an appropriate neuroimaging method for research in the field of "neuro-marketing" and consumer neuroscience. Additionally, this research work presents guidelines, enabling marketing scholars to utilise mobile fNIRS in their research work. PMID- 30443209 TI - Within- and Between-Session Prefrontal Cortex Response to Virtual Reality Exposure Therapy for Acrophobia. AB - Exposure Therapy (ET) has demonstrated its efficacy in the treatment of phobias, anxiety and Post-traumatic Stress Disorder (PTSD), however, it suffers a high drop-out rate because of too low or too high patient engagement in treatment. Virtual Reality Exposure Therapy (VRET) is comparably effective regarding symptom reduction and offers an alternative tool to facilitate engagement for avoidant participants. Neuroimaging studies have demonstrated that both ET and VRET normalize brain activity within a fear circuit. However, previous studies have employed brain imaging technology which restricts people's movement and hides their body, surroundings and therapist from view. This is at odds with the way engagement is typically controlled. We used a novel combination of neural imaging and VR technology-Functional Near-Infrared Spectroscopy (fNIRS) and Immersive Projection Technology (IPT), to avoid these limitations. Although there are a few studies that have investigated the effect of VRET on a brain function after the treatment, the present study utilized technologies which promote ecological validity to measure brain changes after VRET treatment. Furthermore, there are no studies that have measured brain activity within VRET session. In this study brain activity within the prefrontal cortex (PFC) was measured during three consecutive exposure sessions. N = 13 acrophobic volunteers were asked to walk on a virtual plank with a 6 m drop below. Changes in oxygenated (HbO) hemoglobin concentrations in the PFC were measured in three blocks using fNIRS. Consistent with previous functional magnetic resonance imaging (fMRI) studies, the analysis showed decreased activity in the DLPFC and MPFC during first exposure. The activity increased toward normal across three sessions. The study demonstrates potential efficacy of a method for measuring within-session neural response to virtual stimuli that could be replicated within clinics and research institutes, with equipment better suited to an ET session and at fraction of the cost, when compared to fMRI. This has application in widening access to, and increasing ecological validity of, immersive neuroimaging across understanding, diagnosis, assessment and treatment of, a range of mental disorders such as phobia, anxiety and PTSD or addictions. PMID- 30443211 TI - Orbitofrontal Lesion Alters Brain Dynamics of Emotion-Attention and Emotion Cognitive Control Interaction in Humans. AB - Patients with lesion to the orbitofrontal cortex (OFC) experience challenges in emotional control and emotion-guided behaviors. The OFC is known to participate in executive functions and attentional control of emotion and our previous research suggests OFC lesion alters the balance between voluntary and involuntary attention and cognitive control within the context of emotion. To better understand how OFC lesion affects the dynamics and interaction of these functions, we studied EEG and performance of 12 patients with lesion to the OFC and 11 control subjects with intact OFC in a Go/NoGo visual reaction time (RT) task with neutral targets and intervening threat-related emotional distractors (Executive RT Test). Event-related potentials (ERPs), specifically N2P3 peak-to peak amplitude and the following late positive potential (LPP), were used to measure allocation of attention and cognitive control to emotional distractors. Task performance and Behavior Rating Inventory of Executive Functions-Adult version (BRIEF-A) scores were used to assess executive functions. As expected, the Control group showed increased N2P3 amplitude in the context of threat related distractors, particularly over the right hemisphere, while LPP was not modulated by these distractors. In contrast, patients with OFC lesion showed no such impact of threat-related distractors on N2P3 amplitude but exhibited increased and prolonged left-lateralized impact of threat on LPP in the Go condition. In NoGo-condition, the N2P3 amplitude was increased in both groups due to threat, but the impact was seen earlier, i.e., at the N2 peak in the OFC group and later at the P3 peak in Controls. The OFC group committed more errors in the Executive RT Test and reported more problems in BRIEF-A, thus both objective and subjective evidence for challenges in executive functions was obtained in patients with orbitofrontal lesion. Furthermore, the time-course of attention allocation and cognitive control towards task-irrelevant emotional stimuli was altered as evidenced by ERPs. We conclude that orbitofrontal lesion is associated with altered neural dynamics underlying the interaction of involuntary attention to emotion and cognitive control. These alterations in brain dynamics may underlie some of the challenges patients encounter in everyday life when emotional events interact with cognitive demands. PMID- 30443213 TI - Di'ao Xinxuekang Capsule, a Chinese Medicinal Product, Decreases Serum Lipids Levels in High-Fat Diet-Fed ApoE-/- Mice by Downregulating PCSK9. AB - Numerous risk factors are responsible for the development of atherosclerosis, for which an increased serum level of low-density lipoprotein cholesterol (LDL-C) is a driving force. By binding to the low-density lipoprotein cholesterol receptor (LDLR) and inducing LDLR degradation, proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis regulation. The inducement of PCSK9 expression is also an important reason for statin intolerance. The Di'ao Xinxuekang (DXXK) capsule extracted from Dioscorea nipponica Makino is a well known traditional Chinese herbal medicinal product used in atherosclerotic cardiovascular disease. Although DXXK has been widely used in atherosclerotic cardiovascular treatment for nearly 30 years, studies on the potential mechanisms of the lipid-lowering effect are very limited. The purpose of the present study was to demonstrate the possible involvement of the PCSK9/LDLR signaling pathway in the lipid-lowering and antiatherosclerotic effect of DXXK in high-fat diet-fed ApoE-/- mice. The results showed that DXXK treatment alleviated hyperlipidemia, fat accumulation, and atherosclerosis formation in ApoE-/- mice. Furthermore, changes in the expression of PCSK9 mRNA in liver tissue and the circulating PCSK9 level in ApoE-/- mice were both reversed after DXXK treatment, and upregulation of LDLR in the liver was also detected in the protein level in DXXK-treated mice. Our study is the first to show that DXXK could alleviate lipid disorder and ameliorate atherosclerosis with downregulation of the PCSK9 in high-fat diet-fed ApoE-/- mice, suggesting that DXXK may be a potential novel therapeutic treatment and may support statin action in the treatment of atherosclerosis. PMID- 30443214 TI - Do Corticosteroids Still Have a Place in the Treatment of Chronic Pain? AB - Corticosteroids have played a standard role in the multimodal pain management in the treatment of chronic spinal pain (cervical and lumbar) and osteoarthritis pain over the past three decades. In this review we discuss different types of injectable steroids that are mainly used for injection into the epidural space (for the treatment of radicular back and neck pain), and as intra-articular injections for different types of osteoarthritis related pain conditions. Furthermore, we discuss different approaches taken for epidural corticosteroid injections and spinal surgical rates when injections fail to resolve painful conditions, as well as the possibility of using local anesthetics alone for neuraxial injections, instead of in combination with corticosteroids. While we present some beneficial effects of newly available treatment options for low back pain and osteoarthritis pain, such as use of PRP and hyaluronic acid, corticosteroids remain important considerations in the management of these chronic pain conditions. PMID- 30443212 TI - Phytochemical and Pharmacological Role of Liquiritigenin and Isoliquiritigenin From Radix Glycyrrhizae in Human Health and Disease Models. AB - The increasing lifespan in developed countries results in age-associated chronic diseases. Biological aging is a complex process associated with accumulated cellular damage by environmental or genetic factors with increasing age. Aging results in marked changes in brain structure and function. Age-related neurodegenerative diseases and disorders (NDDs) represent an ever-growing socioeconomic challenge and lead to an overall reduction in quality of life around the world. Alzheimer's disease (AD) and Parkinson's disease (PD) are most common degenerative neurological disorders of the central nervous system (CNS) in aging process. The low levels of acetylcholine and dopamine are major neuropathological feature of NDDs in addition to oxidative stress, intracellular calcium ion imbalance, mitochondrial dysfunction, ubiquitin-proteasome system impairment and endoplasmic reticulum stress. Current treatments minimally influence these diseases and are ineffective in curing the multifunctional pathological mechanisms. Synthetic neuroprotective agents sometimes have negative reactions as an adverse effect in humans. Recently, numerous ethnobotanical studies have reported that herbal medicines for the treatment or prevention of NDDs are significantly better than synthetic drug treatment. Medicinal herbs have traditionally been used around the world for centuries. Radix Glycyrrhizae (RG) is the dried roots and rhizomes of Glycyrrhiza uralensis or G. glabra or G. inflata from the Leguminosae/Fabaceae family. It has been used for centuries in traditional medicine as a life enhancer, for the treatment of coughs and influenza, and for detoxification. Diverse chemical constituents from RG have reported including flavanones, chalcones, triterpenoid saponins, coumarines, and other glycosides. Among them, flavanone liquiritigenin (LG) and its precursor and isomer chalcone isoliquiritigenin (ILG) are the main bioactive constituents of RG. In the present review, we summarize evidence in the literature on the structure and phytochemical properties and pharmacological applications of LG and ILG in age-related diseases to establish new therapeutics to improve human health and lifespan. PMID- 30443215 TI - Chemoinformatics Strategies for Leishmaniasis Drug Discovery. AB - Leishmaniasis is a fatal neglected tropical disease (NTD) that is caused by more than 20 species of Leishmania parasites. The disease kills approximately 20,000 people each year and more than 1 billion are susceptible to infection. Although counting on a few compounds, the therapeutic arsenal faces some drawbacks such as drug resistance, toxicity issues, high treatment costs, and accessibility problems, which highlight the need for novel treatment options. Worldwide efforts have been made to that aim and, as well as in other therapeutic areas, chemoinformatics have contributed significantly to leishmaniasis drug discovery. Breakthrough advances in the comprehension of the parasites' molecular biology have enabled the design of high-affinity ligands for a number of macromolecular targets. In addition, the use of chemoinformatics has allowed highly accurate predictions of biological activity and physicochemical and pharmacokinetics properties of novel antileishmanial compounds. This review puts into perspective the current context of leishmaniasis drug discovery and focuses on the use of chemoinformatics to develop better therapies for this life-threatening condition. PMID- 30443216 TI - Relative Contributions of Myostatin and the GH/IGF-1 Axis in Body Composition and Muscle Strength. AB - Myostatin, a negative regulator of muscle growth, is considered a potential therapeutic agent for individuals suffering from various muscle wasting and strength declining diseases because inhibiting Mstn signaling leads to muscular hypertrophy. In this study we investigate the interaction between myostatin and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in muscle function and strength. To this end, we measured hind limb grip strength and myostatin levels in two mouse models of GH gene manipulation; GH receptor knockout (GHR-/-) mice which have reduced GH/IGF-1 action, and bovine GH transgenic (bGH) mice which have excess GH/IGF-1 action. We found that specific muscle force was significantly reduced in bGH mice, and significantly increased in GHR-/- mice, compared to their respective littermate wild type controls. The expression of the mature form of myostatin was significantly increased in bGH mice, and unchanged in GHR-/- mice. In the bGH mice, the high levels of mature myostatin were accompanied by increase body weight and lean mass, consistent with other published results indicating that the IGF-1 signaling pathway is dominant over that of Mstn. Our results also suggest that in these mouse models there is an inverse relationship between muscle strength and levels of myostatin and GH, since constitutive overexpression of GH resulted in elevated levels of mature myostatin in muscle, accompanied by a reduction in strength. By contrast, in the GHR-/- mice with reduced levels of IGF-1, mature myostatin levels were unchanged and muscle strength was increased. PMID- 30443217 TI - Black Garlic Improves Heart Function in Patients With Coronary Heart Disease by Improving Circulating Antioxidant Levels. AB - Background: Black garlic (BG) has many health-promoting properties. Objectives: We aimed to explore the clinical effects of BG on chronic heart failure (CHF) in patients with coronary heart disease (CHD). Design: The main components of BG were measured by gas chromatography-mass spectrometry (GC-MS) and its antioxidant properties were determined by the clearance rate of free radicals. One hundred twenty CHF patients caused by CHD were randomly and evenly assigned into BG group and placebo group (CG). The duration of treatment was 6 months. Cardiac function was measured according to the New York Heart Association (NYHA) functional classification system. The following parameters were measured, including walking distance, BNP precursor N-terminal (Nt-proBNP), left-ventricular ejection fraction (LVEF) value, and the scores of quality of life (QOL). The circulating antioxidant levels were compared between two groups. Results: There are 27 main compounds in BG with strong antioxidant properties. BG treatment improved cardiac function when compared with controls (P < 0.05). The QOL scores and LVEF values were higher in the BG group than in the CG group while the concentration of Nt proBNP was lower in the BG group than in the CG group (P < 0.05). Circulating antioxidant levels were higher in the BG group than in the CG group. Antioxidant levels had positive relation with QOL and LVEF values, and negative relation with Nt-proBNP values. Conclusion: BG improves the QOL, Nt-proBNP, and LVEF in CHF patient with CHD by increasing antioxidant levels. PMID- 30443219 TI - Changes of Maximum Leg Strength Indices During Adulthood a Cross-Sectional Study With Non-athletic Men Aged 19-91. AB - Age-related loss of muscle mass and function, also called sarcopenia, was recently added to the ICD-10 as an independent condition. However, declines in muscle mass and function are inevitable during the adulthood aging process. Concerning muscle strength as a crucial aspect of muscle function, maximum knee extension strength might be the most important physical parameter for independent living in the community. In this study, we aimed to determine the age-related decline in maximum isokinetic knee extension (MIES) and flexion strength (MIFS) in adult men. The primary study hypothesis was that there is a slight gradual decrease of MIES up to ~age 60 years with a significant acceleration of decline after this "changepoint." We used a closed kinetic chain system (leg-press), which is seen as providing functionally more relevant results on maximum strength, to determine changes in maximum isokinetic hip/leg extensor (MIES) and flexor strength (MIFS) during adulthood in men. Apart from average annual changes, we aimed to identify whether the decline in maximum lower extremity strength is linear. MIES and MIFS data determined by an isokinetic leg-press of 362 non-athletic, healthy, and community-dwelling men 19-91 years old were included in the analysis. A changepoint analysis was conducted based on a multiple regression analysis adjusted for selected co-variables that might confound the proper relationship between age and maximum strength. In summary, maximum isokinetic leg-strength decline during adulthood averaged around 0.8-1.0% p.a.; however, the reduction was far from linear. MIES demonstrated a non significant reduction of 5.2 N/p.a. (~0.15% p.a.) up to the estimated breakpoint of 52.0 years and an accelerated loss of 44.0 N/p.a. (~1.3% p.a.; p < 0.001). In parallel, the decline in MIFS (10.0 N/p.a.; ~0.5% p.a.) prior to the breakpoint at age 59.0 years was significantly more pronounced. Nevertheless, we observed a further marked accelerated loss of MIFS (25.0 N/p.a.; ~1.3% p.a.) in men >=60 years. Apart from the "normative value" and closed kinetic chain aspect of this study, the practical application of our results suggests that sarcopenia prophylaxis in men should be started in the 5th decade in order to address the accelerated muscle decline of advanced age. PMID- 30443218 TI - Cold Acclimation Favors Metabolic Stability in Drosophila suzukii. AB - The invasive fruit fly pest, Drosophila suzukii, is a chill susceptible species, yet it is capable of overwintering in rather cold climates, such as North America and North Europe, probably thanks to a high cold tolerance plasticity. Little is known about the mechanisms underlying cold tolerance acquisition in D. suzukii. In this study, we compared the effect of different forms of cold acclimation (at juvenile or at adult stage) on subsequent cold tolerance. Combining developmental and adult cold acclimation resulted in a particularly high expression of cold tolerance. As found in other species, we expected that cold-acclimated flies would accumulate cryoprotectants and would be able to maintain metabolic homeostasis following cold stress. We used quantitative target GC-MS profiling to explore metabolic changes in four different phenotypes: control, cold acclimated during development or at adult stage or during both phases. We also performed a time-series GC-MS analysis to monitor metabolic homeostasis status during stress and recovery. The different thermal treatments resulted in highly distinct metabolic phenotypes. Flies submitted to both developmental and adult acclimation were characterized by accumulation of cryoprotectants (carbohydrates and amino acids), although concentrations changes remained of low magnitude. After cold shock, non-acclimated chill-susceptible phenotype displayed a symptomatic loss of metabolic homeostasis, correlated with erratic changes in the amino acids pool. On the other hand, the most cold-tolerant phenotype was able to maintain metabolic homeostasis after cold stress. These results indicate that cold tolerance acquisition of D. suzukii depends on physiological strategies similar to other drosophilids: moderate changes in cryoprotective substances and metabolic robustness. In addition, the results add to the body of evidence supporting that mechanisms underlying the different forms of acclimation are distinct. PMID- 30443220 TI - Specialized Positioning of Myonuclei Near Cell-Cell Junctions. AB - Skeletal muscles are large cells with multiple nuclei that are precisely positioned. The importance of the correct nuclear position is highlighted by the correlation between mispositioned nuclei and muscle disease (Spiro et al., 1966; Gueneau et al., 2009). Myonuclei are generally considered to be equivalent and therefore how far nuclei are from their nearest neighbor is the primary measurement of nuclear positioning. However, skeletal muscles have two specialized cell-cell contacts, the neuromuscular (NMJ) and the myotendinous junction (MTJ). Using these cell-cell contacts as reference points, we have determined that there are at least two distinct populations of myonuclei whose position is uniquely regulated. The post-synaptic myonuclei (PSMs) near the NMJ, and the myonuclei near the myotendinous junction myonuclei (MJMs) have different spacing requirements compared to other myonuclei. The correct positioning of pairs of PSMs depends on the specific action of dynein and kinesin. Positions of the PSMs and MJMs relative to the junctions that define them depend on the KASH domain protein, Klar. We also found that MJMs are positioned close to the MTJ as a consequence of muscle stretching. Our study defines for the first time that nuclei in skeletal muscles are not all equally positioned, and that subsets of distinct myonuclei have specialized rules that dictate their spacing. PMID- 30443221 TI - Cold Water Immersion Enhanced Athletes' Wellness and 10-m Short Sprint Performance 24-h After a Simulated Mixed Martial Arts Combat. AB - Objective: The aim of the present study was to examine the effect of Cold Water Immersion (CWI) on the recovery of physical performance, hematological stress markers and perceived wellness (i.e., Hooper scores) following a simulated Mixed Martial Arts (MMA) competition. Methods: Participants completed two experimental sessions in a counter-balanced order (CWI or passive recovery for control condition: CON), after a simulated MMAs competition (3 * 5-min MMA rounds separated by 1-min of passive rest). During CWI, athletes were required to submerge their bodies, except the trunk, neck and head, in the seated position in a temperature-controlled bath (~10 degrees C) for 15-min. During CON, athletes were required to be in a seated position for 15-min in same room ambient temperature. Venous blood samples (creatine kinase, cortisol, and testosterone concentrations) were collected at rest (PRE-EX, i.e., before MMAs), immediately following MMAs (POST-EX), immediately following recovery (POST-R) and 24 h post MMAs (POST-24), whilst physical fitness (squat jump, countermovement-jump and 5- and 10-m sprints) and perceptual measures (well-being Hooper index: fatigue, stress, delayed onset muscle soreness (DOMS), and sleep) were collected at PRE EX, POST-R and POST-24, and at PRE-EX and POST-24, respectively. Results: The main results indicate that POST-R sprint (5- and 10-m) performances were 'likely to very likely' (d = 0.64 and 0.65) impaired by prior CWI. However, moderate improvements were in 10-m sprint performance were 'likely' evident at POST-24 after CWI compared with CON (d = 0.53). Additionally, the use of CWI 'almost certainly' resulted in a large overall improvement in Hooper scores (d = 1.93). Specifically, CWI 'almost certainly' resulted in improved sleep quality (d = 1.36), stress (d = 1.56) and perceived fatigue (d = 1.51), and 'likely' resulted in a moderate decrease in DOMS (d = 0.60). Conclusion: The use of CWI resulted in an enhanced recovery of 10-m sprint performance, as well as improved perceived wellness 24-h following simulated MMA competition. PMID- 30443222 TI - Why F-ATP Synthase Remains a Strong Candidate as the Mitochondrial Permeability Transition Pore. PMID- 30443224 TI - Hemoglobin Changes After Long-Term Intermittent Work at High Altitude. AB - Chronic high altitude hypoxia leads to an increase in red cell numbers and hemoglobin concentration. However, the effects of long-term intermittent hypoxia on hemoglobin concentration have not fully been studied. The aim of this study was to evaluate hemoglobin levels in workers commuting between an elevation of 3,800 m (2-week working shift) and lowland below 1,700 m (2 weeks of holiday). A total of 266 healthy males, aged from 20 to 69 years (mean age 45.9 +/- 0.6 years), were included into this study. The duration of intermittent high altitude exposure ranged from 0 to 21 years. Any cardiac or pulmonary disorder was excluded during annual check-ups including clinical examination, clinical lab work (blood cell count, urine analysis, and biochemistry), ECG, echocardiography, and pulmonary function tests. The mean hemoglobin level in workers was 16.2 +/- 0.11 g/dL. Univariate linear regression revealed an association of the hemoglobin levels with the years of exposure. Hemoglobin levels increased 0.068 g/dL [95% CI: 0.037 to 0.099, p < 0.001] for every year of intermittent high altitude exposure. Further, after adjusting for other confounding variables (age, living at low or moderate altitude, body mass index, and occupation) using multivariable regression analysis, the magnitude of hemoglobin level changes decreased, but remained statistically significant: 0.046 g/dL [95% CI: 0.005 to 0.086, p < 0.05]. Besides that, a weak linear relationship between hemoglobin levels and body mass index was revealed, which was independent of the years of exposure to high altitude (0.065 g/dL [95% CI: 0.006 to 0.124, p < 0.05]). We concluded that hemoglobin levels have a linear relationship with the exposure years spent in intermittent hypoxia and body mass index. PMID- 30443226 TI - Person-Environment Fit and Employee Creativity: The Moderating Role of Multicultural Experience. AB - Previous research has demonstrated the positive effects of congruent personal and environmental characteristics on creativity. None of them, however, has tested the formal theory of person-environment fit for predicting creativity in the context of multicultural experiences. This study examined the effects of two versions of person-environment fit (Demands-abilities fit and Needs-supplies fit) on employee creativity in China, taking into account the moderating role of multicultural experiences. The results, based on the data of East Asian Social Survey in the Chinese General Social Survey (CGSS) in 2015, showed employees with demands-abilities fit have lower creativity than those with demands-abilities misfit; nevertheless, the demands-abilities fit creates a growing impact on employee creativity with increasing multicultural experience. Additionally, the higher the needs-supplies fit, the stronger the employee creativity; and, the needs-supplies fit creates a growing impact on employee creativity with increasing multicultural experience. It shows that different versions of person environment fit have different effects on employee creativity and multicultural experience moderated the effects of person-environment fit on employee creativity. Implications for research and practice are discussed. PMID- 30443223 TI - The Role of Leukocytes in Diabetic Cardiomyopathy. AB - Diabetes is predominant risk factor for cardiovascular diseases such as myocardial infarction and heart failure. Recently, leukocytes, particularly neutrophils, macrophages, and lymphocytes, have become targets of investigation for their potential role in a number of chronic inflammatory diseases such as diabetes and heart failure. While leukocytes contribute significantly to the progression of diabetes and heart failure individually, understanding their participation in the pathogenesis of diabetic heart failure is much less understood. The present review summarizes the role of leukocytes in the complex interplay between diabetes and heart failure, which is critical to the discovery of new targeted therapies for diabetic cardiomyopathy. PMID- 30443227 TI - A Lacanian Approach to Medical Demand, With a Focus on Pediatric Genetics: A Plea for Subjectivization. AB - Current psychological research on contemporary medicine, and in particular genetics, often targets the underpinnings of patients' attitudes and behaviors with respect to biomedical knowledge and healthcare practices. But few studies approach these underpinnings as manifestations of the unconscious, while so doing could (in particular) help understand patients' apparent difficulties to understand information, and to subsequently act accordingly (e.g., in making therapeutic decisions, etc.). We hypothesize that Lacan's (1966) remarks ("The place of psychoanalysis in medicine") on the transferential nature of the demand addressed by the patient (or his family) to the doctor can help account for these issues: demand filters medical information received from the practitioner, and thereby motivates subsequent decisions. In this paper, we try and shed light on this thesis, and focus on pediatric genetics. We start by describing the manifest doctor-patient-family relationship in the pediatric genetics consultation, in order to show where unconscious determinants can come to play a role (1). We then explain Lacan's theory of demand: what the patient unknowingly demands is knowledge (savoir), the object of which is the body of jouissance - the libidinal experience of one's body through the first libidinal exchanges with the Other of early infancy, whereby the subject is assigned by the Other (subjectification) a specific fantasmatic status organizing his desire. Patients' understanding and attitudes thus vary so greatly because of this pre-existing filter. Healing and cure are merely apparent objects of the medical demand, which is an invocative drive seeking knowledge on the cause of one's desire: medical demand is an instance of transference. Doctors should thus enable patient subjectivization, i.e., help them realize that their demand's genuine object lies in their pre existing subjective coordinates (2). In pediatric genetics, apparently paradoxical family attitudes heavily draw on what G. Raimbault, drawing on Lacan, called implicit demand, the object of which is knowledge about the family fantasy giving shape to the guilt of possibly transmitting the disease. We give a clinical example, then show how the concept of demand helped us elaborate the core of a research project on the subjective effects of a genetic deafblindness handicap (3). PMID- 30443225 TI - Early Post-stroke Depression and Mortality: Meta-Analysis and Meta-Regression. AB - Background: Post-stroke depression (PSD) is a common and serious complication after stroke. In this systematic review and meta-analysis, we evaluated the association between early PSD and mortality, considering depressive symptoms occurring within the first 3 months after the neurological event. Methods: This meta-analysis was conducted following Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and based on studies indexed till May 2018 in PubMed and Web of Science databases. The relative risk (RR) for mortality in individuals with PSD, as compared with non-depressed ones, was estimated. Findings were pooled according to a random-effects model. Meta-regression and subgroup analyses were carried out. Results: We included seven studies, accounting for 119,075 individuals, of whom 17,609 suffering from an early PSD. We found higher rates of mortality in subjects with PSD as compared with non depressed ones (RR = 1.50; 95%CI: 1.28 to 1.75; p < 0.001). Heterogeneity across studies was moderate (I 2 = 50.7%). Subgroup analysis showed a slightly higher effect of PSD on short-term mortality (RR = 1.70; p < 0.001), as compared with long-term one (RR = 1.35; p = 0.01). According to relevant meta-regression analyses, the estimate was influenced by sample proportion of men (p = 0.043). Conclusions: Despite some limitations, our study shows the negative impact of early PSD on survival rates. Mechanisms underlying this association still need to be elucidated and several interpretations can be hypothesized. Future research should test if an early management of depression may increase life expectancy after stroke. PMID- 30443228 TI - Early Home-Life Antecedents of Children's Locus of Control. AB - Children's external locus of control has been linked to a wide variety of negative academic achievement, personality, and social adjustment outcomes. The purpose of this study was to discover which features of early home environment may facilitate the development of external as opposed to internal control expectancies in children. We use an exposome approach to analyze data from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study, a longitudinal study starting in pregnancy in England in 1990-1992. Details of parents and their study children were collected prospectively, and children's locus of control was assessed at age 8 using an abbreviated form of the most frequently used measure of children's locus of control (Nowicki-Strickland Internal External locus of control scale). A series of stepwise logistic regression analyses were undertaken to determine the strongest independent associations. The final model (n = 4,075 children) comprised 13 variables - those with the strongest associations with the child becoming externally oriented were two that were positive indicators of the mother being distracted (TV on almost the whole time, and a consideration that pets should be treated as members of the family), three that were indicators of protective (negative) effects of interaction between mother and child (child was breast fed, mother read stories to the child, mother cuddled the baby when he/she woke at night), and two divergent indicators of maternal health behavior (more frequent cleaning of the child's hands before a meal which was associated with a heightened risk of become external, and providing a healthy-type of diet, which was associated with a reduced risk of becoming external). The findings suggest that inadequate early maternal interaction with the child is associated with an increased risk of the child being externally oriented by the age of 8. PMID- 30443229 TI - Quality of Life and PTSD Symptoms, and Temperament and Coping With Stress. AB - Due to advances in medicine, a malignant neoplasm is a chronic disease that can be treated for a lot of patients for many years. It may lead to profound changes in everyday life and may induce fear of life. The ability to adjust to a new situation may depend on temperamental traits and stress coping strategies. The research presented in this paper explores the relationships between quality of life, PTSD symptoms, temperamental traits, and stress coping in a sample of patients diagnosed with cancer. One hundred and twenty nine participants aged 24 81 years, 69 females diagnosed with breast cancer and 60 males diagnosed with lung cancer completed Formal Characteristics of Behavior - Temperament Inventory, Coping Inventory for Stressful Situations, PTSD Inventory, and Quality of life SF 36 questionnaire. Higher level of emotional reactivity and higher level of perseveration was associated with lower emotional quality of life. Higher level of emotion oriented-coping and higher level of avoidant-distracted coping was associated with higher level of PTSD symptoms. Emotion-oriented coping and avoidant-distracted coping are ineffective in dealing with stress in the case of patients diagnosed with cancer, because they are associated with a higher level of PTSD symptoms. The significance of temperamental traits for quality of life in the situation of the patients is marginal. Control of specific factors concerned with current health and treatment status is needed the future research. PMID- 30443230 TI - Arts-Based Research Approaches to Studying Mechanisms of Change in the Creative Arts Therapies. AB - The purpose of this preliminary qualitative research study is to explore the role and function of multiple dynamic interactive aesthetic and intersubjective phenomena in the creative arts therapies process relative to transformation in perception, behavior, relationship, and well-being. A group of doctoral students and faculty studied these phenomena in an analogous creative arts therapies laboratory context using a method called Intrinsic Arts-Based Research. Intrinsic Arts-Based Research is a systematic study of psychological, emotional, relational, and arts-based phenomena, parallel to those emergent in the creative arts therapies, using individual and collective intrinsic immersive and reflective experience in combination with qualitative and arts-based research methods. Our primary goal was to simulate the creative arts therapies experience in order to identify, document, and describe the complex transformative phenomena that occur at the nexus of arts-based expression, reflection, and relationships in the arts therapies. For the purposes of this paper transformation is defined as ".... a significant reconfiguration of perception and thought resulting in the lessening of psychic restraint and pain, allowing for the emergence of new psychological perspectives that contribute to living a more creative life" (Gerber et al., 2012, p. 45). Through a deductive thematic analysis of written accounts of these simulated creative arts therapies experiences by participant/researchers in the laboratory we identified three primary dynamic and interactive broad constructs that together, with more specific modifying themes, might account for and describe change within the creative arts therapies. These broad dynamic interactive themes are: ruptures, resolutions, and transformation; relationship and intersubjectivity; and, arts-based expressive processes. The more specific modifying themes include: dialectical rupture and resolution, relational attunements and ruptures, imaginational flow, transcendence and ruptures, sensory/kinesthetic/embodied ways of knowing, and intersubjective transcendence. We propose that change in the creative arts therapies is driven more by a dynamic system of interactive phenomena the varying combinations of which create conditions for relational attunement, imagination, dialectical tensions and creative resolutions, and the ultimately creative transformation. PMID- 30443231 TI - What Is the Structure of Time? A Study on Time Perspective in the United States, Poland, and Nigeria. AB - The aim of this article was to analyze the fit of the model of time perspective, measured by the Zimbardo Time Perspective Inventory (ZTPI; Zimbardo and Boyd, 1999), to data collected in three countries: the United States (N = 283), Poland (N = 510), and Nigeria (N = 357). Confirmatory factor analysis, exploratory structural equation modeling, an expected parameter change and parallel analysis were used. The best-fitted model of time perspective was the one in the United States, and the least fitted model was the one in Nigeria. Possible sources of misspecifications in the model of time perspective were discussed. We also present an analysis of the fit of the four-factor model of time perspective. The four-factor model was very well fitted in the United States and in Poland. Results were discussed in the context of clock time and event time theory. PMID- 30443233 TI - A Link Between Local Enrichment and Scalar Diversity. AB - Several recent studies have shown that different scalar terms are liable to give rise to scalar inferences at different rates (Doran et al., 2009, 2012; van Tiel et al., 2016). A number of potential factors have been explored to account for such Scalar Diversity. These factors can be seen as methodological in origin, or as motivated by widely discussed analyses of scalar inferences. Such factors allow us to explain some of the variation, but they leave much of it unexplained. In this paper, we explore two new potential factors. One is methodologically motivated, related to the choice of items in previous studies. The second is motivated by theoretical approaches which go beyond the standard Gricean approach to pragmatic effects. In particular, we consider dual route theories which allow for scalar inferences to be explained either using 'global' pragmatic derivations, like those set out in standard Gricean theory, or using local adjustments to interpretation. We focus on one such theory, based on the Bayesian Rational Speech Act approach (RSA-LU, Bergen et al., 2016). We show that RSA-LU predicts that a scalar term's liability to certain kinds of local enrichment will explain some Scalar Diversity. In three experiments, we show that both proposed factors are active in the scalar diversity effect. We conclude with a discussion of the grammatical approach to local effects and show that our results provide better evidence for dual route approaches to scalar effects. PMID- 30443234 TI - Border Crossing and the Logics of Space: A Case Study in Pro-Environmental Practices. AB - We investigate whether and how workers in a transnational oil corporation carry practices, meanings, and identities between the places of work and home, focusing on environmental and health and safety practices, in order to understand the larger question, how can environmentally relevant practices be generalized in society at large? Our theoretical starting point is that societal institutions function according to different logics (Thornton et al., 2012) and the borders (Clark, 2000) between these institutions create affordances and constraints on the transfer of practices between these places. By connecting their theoretical ideas, we suggest that these provide an alternative critique and explanatory account of the transfer of environmental practices between home and work than a "spillover" approach. We employ life history interviews to explore the development and complexity of the causes, justifications, and legitimations of people's actions, social relationships, and the structural constraints which govern relationships between these spaces. While Clark's concepts of permeable, strong, or blended borders are useful heuristic tools, people may simultaneously strengthen, transgress, or blend the borders between work and home in terms of practices, meanings, identities, or institutional logics. Individuals have to be understood as creators of the border crossing process, which is why their life histories and the ways in which their identities and their attachments to places (i.e., institutions) are shaped by the logics of these places are important. For environmental practices to travel from work to home, they need to become embedded in a company culture that allows their integration into workers' identities. PMID- 30443232 TI - Acute Stress Attenuates Cognitive Flexibility in Males Only: An fNIRS Examination. AB - Cognitive processes that afford us the ability to control thoughts and achieve goal-directed behavior are known as executive functions. Empirical evidence in the past few years has demonstrated that executive functions can be influenced by acute stress. The impact of acute stress on cognitive flexibility, a key aspect of executive functions, has received little attention in the literature. We present the results of two experiments conducted to examine the effect of acute stress on cognitive flexibility. Acute stress was induced using the cold pressor task. Cognitive flexibility was assessed using the Wisconsin Card Sorting Test (WCST). Across both experiments acute stress had an attenuating effect on task switching on the WCST. Our findings also indicate that this effect was moderated by the participant's gender. In Study 1, we observed that following stress exposure male participants in the stress condition made more perseverative errors than participants in the control group. In Study 2, we examined the bilateral hemodynamics in the prefrontal cortex (PFC) during acute stress induction using functional near infrared spectroscopy (fNIRS). Our analysis indicated that functional oxyHb signals fluctuated with greater amplitude than systemic components for participants in the stress group relative to those in the control group. In addition, oxyHb levels post stress induction were correlated with performance on the WCST for the male participants in the stress group only. Concordant with previous reports, our findings indicate that acute stress impacts cognitive flexibility in males and females differentially. Our work also demonstrates the feasibility of using fNIRS as a practical and objective technique for the examination of hemodynamics in the PFC during acute stress. PMID- 30443235 TI - How Do I Narrate My Marriage: The Relationship Between Attachment Orientation and Quality of Autobiographical Memory. AB - Attachment orientations play important roles in the generation of emotional autobiographical memory (AM). However, little research has considered the quality of autographical narratives, which may reflect the structure and content of internal working models (IWMs) of attachment. The purpose of the current study was to investigate the relationship between attachment orientations and narrative quality of marriage-related autobiographical memories. Ninety-four married adults were asked to retrieve two episodes of emotional autobiographical memories. The coherence and vividness of their narratives were then coded. Results indicated that adults who were highly avoidant were more likely to present their memories in a less coherent way and to describe negative memories with more perceptual details. In contrast, attachment anxiety was associated with lower vividness of negative memories. The current findings suggest that an attachment schematic processing strategy was used in narrating the attachment-related experiences. PMID- 30443236 TI - Brain State-Dependent Brain Stimulation. PMID- 30443237 TI - Socially Anxious Tendencies Affect Impressions of Others' Positive and Negative Emotional Gazes. AB - Socially anxious tendencies have potential to become social anxiety disorder (SAD), which is characterized by fear of social situations associated with being evaluated or embarrassed by others. In particular, others' gazes induce social anxiety. People with SAD have a negative interpretation bias toward ambiguous emotions in others' faces; however, negative interpretation bias toward ambiguous emotions in others' gazes has not been fully investigated. We used an impression judgment task to examine negative interpretation bias toward others' gazes among people with socially anxious tendencies. We generated emotionally ambiguous gazes (positive, negative, and neutral) using a morphing technique with 10% steps (neutral, 10-100% negative, and 10-100% positive). Participants (all male) were asked to judge whether the stimulus was positive or negative. Each participant's level of social anxiety was examined using the Japanese version of the Social Phobia Inventory (SPIN-J), which measures three symptom dimensions: fear, avoidance, and physiological arousal. To examine the influence of socially anxious tendencies in the impression judgment task, we calculated the point of subjective equality (PSE) using a two-step logistic curve fitted to individual participant's responses. The negative emotional intensity of the PSE became lower as the fear score became higher (p < 0.05). This result suggests individuals with a high tendency toward social anxiety tend to interpret subtle negative emotional gazes as a negative emotion and regard these gazes as a threat. PMID- 30443238 TI - Lives on the Line: The Online Lives of Girls and Women With and Without a Lifetime Eating Disorder Diagnosis. AB - This study aimed to compare the scope, internet use patterns, and degree of online need satisfaction of girls and women with and without a lifetime eating disorder (ED) diagnosis. Participants were 122 females aged 12-30, 53 with a lifetime ED diagnosis recruited via a hospital-based treatment program, and 69 age-matched controls recruited via normative social media sites. Participants completed questionnaires assessing disordered eating, body image, positive and negative affect, general distress, and life satisfaction, and completed an online survey about the scope of their internet use, the frequency of watching and posting pictures and videos, online friendships and social comparison, fulfillment of needs online, and mood after internet use. All questionnaire scores differed significantly between groups in the expected directions. Whereas overall, ED and control groups spent similar amounts of time online (6.21, SD = 5.13), they spent this time differently. ED participants reported devoting 56.7% of their online time to eating, weight and body image, versus 29.1% for controls, and spent significantly more time than controls on forums and blogs (t = -5.3, p < 0.0001, Cohen's d = 0.87). They also engaged more often in social comparison (t = 3.6, p < 0.005, Cohen's d = 0.65), had a higher online-offline friend ratio (t = 3.7, p < 0.0001, Cohen's d = 0.65), and more online friends with ED (t = 5.4, p < 0.0001, Cohen's d = 0.89). In comparison to controls, ED participants reported that their use of forums and blogs gave them more eating- and weight-related advice, and a greater sense of belonging, social support, and safety resulting from anonymity, with effect sizes of 0.63-0.96. However, they also reported more negative affect after posting online. Most online behaviors and patterns correlated positively with measures of symptomatology and negatively with measures of psychological health, in both groups. Internet use was rarely addressed in therapy. Professionals, families and friends should help people with disordered eating and EDs to broaden the scope of their internet use. They should invest less in food- and weight-related forums/blogs, expand their "real life" social lives and develop their interpersonal skills, so that their legitimate needs can be satisfied face-to-face, rather than virtually. Clinicians should address the online lives of their ED clients in therapy. PMID- 30443239 TI - Cerebral Hemodynamics in Speech-Related Cortical Areas: Articulation Learning Involves the Inferior Frontal Gyrus, Ventral Sensory-Motor Cortex, and Parietal Temporal Sylvian Area. AB - Although motor training programs have been applied to childhood apraxia of speech (AOS), the neural mechanisms of articulation learning are not well understood. To this aim, we recorded cerebral hemodynamic activity in the left hemisphere of healthy subjects (n = 15) during articulation learning. We used near-infrared spectroscopy (NIRS) while articulated voices were recorded and analyzed using spectrograms. The study consisted of two experimental sessions (modified and control sessions) in which participants were asked to repeat the articulation of the syllables "i-chi-ni" with and without an occlusal splint. This splint was used to increase the vertical dimension of occlusion to mimic conditions of articulation disorder. There were more articulation errors in the modified session, but number of errors were decreased in the final half of the modified session; this suggests that articulation learning took place. The hemodynamic NIRS data revealed significant activation during articulation in the frontal, parietal, and temporal cortices. These areas are involved in phonological processing and articulation planning and execution, and included the following areas: (i) the ventral sensory-motor cortex (vSMC), including the Rolandic operculum, precentral gyrus, and postcentral gyrus, (ii) the dorsal sensory-motor cortex, including the precentral and postcentral gyri, (iii) the opercular part of the inferior frontal gyrus (IFGoperc), (iv) the temporal cortex, including the superior temporal gyrus, and (v) the inferior parietal lobe (IPL), including the supramarginal and angular gyri. The posterior Sylvian fissure at the parietal temporal boundary (area Spt) was selectively activated in the modified session. Furthermore, hemodynamic activity in the IFGoperc and vSMC was increased in the final half of the modified session compared with its initial half, and negatively correlated with articulation errors during articulation learning in the modified session. The present results suggest an essential role of the frontal regions, including the IFGoperc and vSMC, in articulation learning, with sensory feedback through area Spt and the IPL. The present study provides clues to the underlying pathology and treatment of childhood apraxia of speech. PMID- 30443240 TI - Human Microbe-Disease Association Prediction With Graph Regularized Non-Negative Matrix Factorization. AB - A microbe is a microscopic organism which may exists in its single-celled form or in a colony of cells. In recent years, accumulating researchers have been engaged in the field of uncovering microbe-disease associations since microbes are found to be closely related to the prevention, diagnosis, and treatment of many complex human diseases. As an effective supplement to the traditional experiment, more and more computational models based on various algorithms have been proposed for microbe-disease association prediction to improve efficiency and cost savings. In this work, we developed a novel predictive model of Graph Regularized Non negative Matrix Factorization for Human Microbe-Disease Association prediction (GRNMFHMDA). Initially, microbe similarity and disease similarity were constructed on the basis of the symptom-based disease similarity and Gaussian interaction profile kernel similarity for microbes and diseases. Subsequently, it is worth noting that we utilized a preprocessing step in which unknown microbe disease pairs were assigned associated likelihood scores to avoid the possible negative impact on the prediction performance. Finally, we implemented a graph regularized non-negative matrix factorization framework to identify potential associations for all diseases simultaneously. To assess the performance of our model, cross validations including global leave-one-out cross validation (LOOCV) and local LOOCV were implemented. The AUCs of 0.8715 (global LOOCV) and 0.7898 (local LOOCV) proved the reliable performance of our computational model. In addition, we carried out two types of case studies on three different human diseases to further analyze the prediction performance of GRNMFHMDA, in which most of the top 10 predicted disease-related microbes were verified by database HMDAD or experimental literatures. PMID- 30443242 TI - Elevated CO2 Has Little Influence on the Bacterial Communities Associated With the pH-Tolerant Coral, Massive Porites spp. AB - Ocean acidification (OA) as a result of increased anthropogenic CO2 input into the atmosphere carries consequences for all ocean life. Low pH can cause a shift in coral-associated microbial communities of pCO2-sensitive corals, however, it remains unknown whether the microbial community is also influenced in corals known to be more tolerant to high pCO2/low pH. This study profiles the bacterial communities associated with the tissues of the pCO2-tolerant coral, massive Porites spp., from two natural CO2 seep sites in Papua New Guinea. Amplicon sequencing of the hypervariable V3-V4 regions of the 16S rRNA gene revealed that microbial communities remained stable across CO2 seep sites (pH = 7.44-7.85) and adjacent control sites (ambient pH = 8.0-8.1). Microbial communities were more significantly influenced by reef location than pH, with the relative abundance of dominant microbial taxa differing between reefs. These results directly contrast with previous findings that increased CO2 has a strong effect on structuring microbial communities. The stable structure of microbial communities associated with the tissues of massive Porites spp. under high pCO2/low pH conditions confirms a high degree of tolerance by the whole Porites holobiont to OA, and suggest that pH tolerant corals such as Porites may dominate reef assemblages in an increasingly acidic ocean. PMID- 30443244 TI - Microbial Production of Ethanol From Sludge Derived From an Urban Wastewater Treatment Plant. AB - A collection of lipase-producing microorganisms was isolated from sludge derived from an urban wastewater treatment plant. The microorganisms with the highest levels of lipase activity were selected in order to use triglycerides present in the sludge effectively and were then transformed with pdc:adhB genes for the production of ethanol. The transgenic strains showed high growth rates in diluted sludge and produced lipase protein in order to utilize fat present in the sludge, which provides an abundant source of carbon. Using sludge derived from treated wastewater as nutrient source, ethanol was produced by certain transgenic species belonging to the genera Proteus. Different forms of sludge were tested for maximal ethanol production, with dehydrated sludge being found to produce the best performance. PMID- 30443241 TI - Cross-Talk Between Gluten, Intestinal Microbiota and Intestinal Mucosa in Celiac Disease: Recent Advances and Basis of Autoimmunity. AB - Celiac disease (CD) is an autoimmune disorder of the small intestine, caused by gluten induced inflammation in some individuals susceptible to genetic and environmental influences. To date, pathophysiology of CD in relation to intestinal microbiota is not known well. This review relies on contribution of intestinal microbiome and oral microbiome in pathogenesis of CD based on their interactions with gluten, thereby highlighting the role of upper gastrointestinal microbiota. It has been hypothesized that CD might be triggered by additive effects of immunotoxic gluten peptides and intestinal dysbiosis (microbial imbalance) in the people with or without genetic susceptibilities, where antibiotics may be deriving dysbiotic agents. In contrast to the intestinal dysbiosis, genetic factors even seem secondary in disease outcome thus suggesting the importance of interaction between microbes and dietary factors in immune regulation at intestinal mucosa. Moreover, association of imbalanced counts of some commensal microbes in intestine of CD patients suggests the scope for probiotic therapies. Lactobacilli and specific intestinal and oral bacteria are potent source of gluten degrading enzymes (glutenases) that may contribute to commercialization of a novel glutenase therapy. In this review, we shall discuss advantages and disadvantages of food based therapies along with probiotic therapies where probiotic therapies are expected to emerge as the safest biotherapies among other in-process therapies. In addition, this review emphasizes on differential targets of probiotics that make them suitable to manage CD as along with glutenase activity, they also exhibit immunomodulatory and intestinal microbiome modulatory properties. PMID- 30443243 TI - Biodegradation and Biotransformation of Indole: Advances and Perspectives. AB - Indole is long regarded as a typical N-heterocyclic aromatic pollutant in industrial and agricultural wastewater, and recently it has been identified as a versatile signaling molecule with wide environmental distributions. An exponentially growing number of researches have been reported on indole due to its significant roles in bacterial physiology, pathogenesis, animal behavior and human diseases. From the viewpoint of both environmental bioremediation and biological studies, the researches on metabolism and fates of indole are important to realize environmental treatment and illuminate its biological function. Indole can be produced from tryptophan by tryptophanase in many bacterial species. Meanwhile, various bacterial strains have obtained the ability to transform and degrade indole. The characteristics and pathways for indole degradation have been investigated for a century, and the functional genes for indole aerobic degradation have also been uncovered recently. Interestingly, many oxygenases have proven to be able to oxidize indole to indigo, and this historic and motivating case for biological applications has attracted intensive attention for decades. Herein, the bacteria, enzymes and pathways for indole production, biodegradation and biotransformation are systematically summarized, and the future researches on indole-microbe interactions are also prospected. PMID- 30443245 TI - Mycobacterium abscessus: Shapeshifter of the Mycobacterial World. AB - In this review we will focus on unique aspects of Mycobacterium abscessus (MABS) which we feel earn it the designation of "shapeshifter of the mycobacterial world." We will review its emergence as a distinct species, the recognition and description of MABS subspecies which are only now being clearly defined in terms of pathogenicity, its ability to exist in different forms favoring a saprophytic lifestyle or one more suitable to invasion of mammalian hosts, as well as current challenges in terms of antimicrobial therapy and future directions for research. One can see in the various phases of MABS, a species transitioning from a free living saprophyte to a host-adapted pathogen. PMID- 30443246 TI - Isolation and Characterization of Human Monoclonal Antibodies That Recognize the Influenza A(H1N1)pdm09 Virus Hemagglutinin Receptor-Binding Site and Rarely Yield Escape Mutant Viruses. AB - The influenza A virus rapidly mutates to escape from antibodies. Here, we isolated and characterized three human monoclonal antibodies (mAbs) that neutralize A(H1N1)pdm09 viruses. Generation of escape mutant viruses suggested that these antibodies recognized conserved residues of the receptor-binding site (RBS) of hemagglutinin (HA) and that mutant viruses that escaped from these mAbs rarely appeared. Moreover, the escape mutant viruses grew significantly slower than wild-type virus, indicating their reduced fitness. These results indicate that these three human mAbs against the RBS of HA have the potential to be anti influenza agents with a low propensity for the development of resistant viruses. PMID- 30443248 TI - Linoleic Acids Overproducing Lactobacillus casei Limits Growth, Survival, and Virulence of Salmonella Typhimurium and Enterohaemorrhagic Escherichia coli. AB - Probiotics, particularly lactic acid bacteria, are biologic agents which limit the growth, virulence, and survival/colonization of various enteric bacterial pathogens and serve as potential alternatives to antibiotics. Mechanisms that contribute to this antimicrobial effect include producing bioactive metabolites/acids, increasing nutrient and receptor-mediated competition, and modulating gut microbiome ecology. However, these functions of common probiotic strains are limited due to the finite quantity of metabolites they produce and their total number in the gut ecosystem. Conjugated linoleic acids (CLAs), critical metabolites of Lactobacillus, have multiple beneficial effects on human health including anti-carcinogenesis, anti-inflammation, anti-oxidation, and anti pathogenicity. In this study, we aim to overexpress the myosin cross-reactive antigen gene (mcra) in Lactobacillus casei (LC) to enhance the production of CLA and investigate its effectiveness against enteric bacterial pathogens, specifically Salmonella enterica serovar Typhimurium (ST) and enterohaemorrhagic Escherichia coli (EHEC). By inserting mcra in L. casei, we generated LC-CLA and found the total linoleic acid production by an individual bacterial cell was raised by 21-fold. The adherence ability of LC-CLA on human epithelial cells increased significantly and LC-CLA competitively excluded both ST and EHEC in a mixed-culture condition. Furthermore, LC-CLA significantly altered the physicochemical properties, biofilm formation abilities, interactions with host cells of both ST and EHEC, and triggered anti-inflammatory activities of host cells. These findings offer insights on applying a genetically engineered probiotic to control gut intestinal infections caused by ST and EHEC and prevent foodborne enteric illness in human. PMID- 30443247 TI - Post-translational Modification Control of HBV Biological Processes. AB - Hepatitis B virus infection remains a global healthy issue that needs to be urgently solved. Novel strategies for anti-viral therapy are based on exploring the effective diagnostic markers and therapeutic targets of diseases caused by hepatitis B virus (HBV) infection. It is well-established that not only viral proteins themselves but also key factors from the host control the biological processes associated with HBV, including replication, transcription, packaging, and secretion. Protein post-translational modifications (PTMs), such as phosphorylation, acetylation, methylation, and ubiquitination, have been shown to control protein activity, regulate protein stability, promote protein interactions and alter protein subcellular localization, leading to the modulation of crucial signaling pathways and affected cellular processes. This review focuses on the functions and effects of diverse PTMs in regulating important processes in the HBV life cycle. The potential roles of PTMs in the pathogenesis of HBV-associated liver diseases are also discussed. PMID- 30443249 TI - The Probiotic Effectiveness in Preventing Experimental Colitis Is Correlated With Host Gut Microbiota. AB - Current evidence to support extensive use of probiotics in inflammatory bowel disease is limited and factors that contribute to the inconsistent effectiveness of clinical probiotic therapy are not completely known. Here, we used Bifidobacterium longum JDM 301 as a model probiotic to study potential factors that may influence the effect of probiotics in experimental colitis. We found that the effect of B. longum JDM 301 in tempering experimental colitis varied across individual mice even with the same genetic background. The probiotic efficacy was highly correlated with the host gut microbial community features. Consumption of a diet rich in fat could exacerbate mucosal injury-induced colitis but could not change the host responsiveness to B. longum JDM 301 treatment, suggesting of potential mechanistic differences between regulating colitis pathogenesis, and modulating probiotic efficacies by the gut microbiota. Together, our results suggest that personalized microbiome features may modify the probiotic therapeutic effect and support the idea of personalized probiotic medicine in inflammatory bowel disease. PMID- 30443250 TI - Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. AB - Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis. PMID- 30443252 TI - Early Growth Response Gene-2 Is Essential for M1 and M2 Macrophage Activation and Plasticity by Modulation of the Transcription Factor CEBPbeta. AB - The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) macrophages are reprogrammed into an M1-like phenotype following treatment with IFNgamma and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse in vitro and in vivo models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL 13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNgamma, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPbeta and PPARgamma in M2 macrophages, and CEBPbeta was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPbeta was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non responsiveness of macrophages to their activation. PMID- 30443251 TI - MicroRNAs: Pleiotropic Regulators in the Tumor Microenvironment. AB - MicroRNAs (miRNAs) are small non-coding RNAs that typically inhibit the translation and stability of messenger RNAs (mRNAs). They are ~22 nucleotides long and control both physiological and pathological processes. Altered expression of miRNAs is often associated with human diseases. Thus, miRNAs have become important therapeutic targets, and some clinical trials investigating the effect of miRNA-based therapeutics in different types of diseases have already been conducted. The tumor microenvironment (TME) comprises cells such as infiltrated immune cells, cancer-associated endothelial cells (CAEs) and cancer associated fibroblasts (CAFs), and all the components participate in the complicated crosstalk with tumor cells to affect tumor progression. Altered miRNAs expression in both these stromal and tumor cells could drive tumorigenesis. Thus, in this review, we discuss how aberrantly expressed miRNAs influence tumor progression; summarize the crosstalk between infiltrated immune cells, CAEs, CAFs, and tumor cells through miRNAs, and clarify the important roles of miRNAs in the tumor microenvironment, which may facilitate the clinical application of miRNA-based therapies. PMID- 30443253 TI - Non-apoptotic Fas (CD95) Signaling on T Cells Regulates the Resolution of Th2 Mediated Inflammation. AB - Fas (CD95/APO-1) and its ligand (FasL/CD95L) promote the resolution of type 2 lung inflammation and eosinophilia. We previously found that Fas-deficiency on T cells, but not eosinophils, delayed resolution of inflammation. However, Fas can signal both cell death and have a positive signaling function that can actually activate cells. In this study, we investigated whether Fas-induced death or Fas activated signaling pathways promote resolution of allergic lung inflammation. By increasing T cell survival through two Fas-independent pathways, using Bim deficient T cells or Bcl-xL overexpressing T cells, no differences in resolution of Th2-mediated inflammation was observed. Furthermore, Th2 cells were inherently resistant to Fas-mediated apoptosis and preferentially signaled through non apoptotic pathways following FasL treatment. Utilizing Fas-mutant mice deficient in apoptotic but sufficient for non-apoptotic Fas signaling pathways, we demonstrate that non-apoptotic Fas signaling in T cells drives resolution of Th2 mediated airway inflammation. Our findings reveal a previously unknown role for non-apoptotic Fas signaling on Th2 cells in the induction of resolution of type 2 inflammation. PMID- 30443254 TI - Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice. AB - Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf 2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor. PMID- 30443255 TI - Cutaneous Vasculitis and Digital Ischaemia Caused by Heterozygous Gain-of Function Mutation in C3. AB - It is now increasingly recognized that some monogenic autoinflammatory diseases and immunodeficiencies cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of non-consanguineous parents who presented with cutaneous vasculitis, digital ischaemia and hypocomplementaemia. A heterozygous p.R1042G gain-of-function mutation (GOF) in the complement component C3 gene was identified as the cause, resulting in secondary C3 consumption and complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum C3 with normal C4 levels. The same heterozygous mutation and immunological defects were also identified in another symptomatic sibling and his father. C3 deficiency due GOF C3 mutations is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4. PMID- 30443256 TI - Dendritic Cells Are Critical for the Activation and Expansion of Vdelta2+ T Cells After Allogeneic Hematopoietic Transplantation. AB - gammadelta T cells perform antitumor and antiviral effector functions and are involved in both innate and adaptive immunity. Vdelta2+ T cells represent the predominant gammadelta T subset in the peripheral blood of healthy subjects. Vdelta2+ T cells can be selectively activated and expanded by phosphoantigens (pAgs). Dendritic cells (DCs), as potent antigen-presenting cells, are capable of mediating pAgs-triggered Vdelta2+ T cells expansion. However, the association between DCs and Vdelta2+ T cell recovery in the context of hematopoietic stem cell transplantation (HSCT) remains unclear. We previously demonstrated that the recovery of Vdelta2+ T cells was hampered and inversely correlated with Epstein Barr virus (EBV) reactivation in patients undergoing haploidentical HSCT (haploHSCT). Whether Vdelta2+ T cells from haploHSCT recipients can be expanded by stimulation with aminobisphosphonates or pAg-presenting DCs is of particular interest. Herein, we showed that Vdelta2+ T cells recovered after haploHSCT failed to expand after ex-vivo stimulation with pamidronate. In addition, we found that the recovery of DC subsets was significantly decreased, and the concentration of myeloid DCs (mDCs) correlated significantly with Vdelta2+ T cell recovery in the setting of allogeneic HSCT. Furthermore, coculture of peripheral lymphocytes from recipients with monocyte-derived and pamidronate-pretreated autologous or allogeneic DCs induced the successful expansion of Vdelta2+ T cells. Of note, allogeneic DCs from third-party donors stimulated a significantly higher efficiency of Vdelta2+ T cell expansion than autologous DCs. More importantly, the memory features were well-retained and the cytotoxic cytokines production capacity was significantly enhanced in the expanded Vdelta2+ T cells. Taken together, these results suggest that the frequency and function of DCs are critical for the recovery of Vdelta2+ T cells after allogeneic HSCT. The fact that vigorous expansions of Vdelta2+ T cells were induced by phosphoantigen pretreated DCs, especially by allogeneic third-party DCs, provides additional options for the development of individualized immunotherapy strategies that utilize the anti-viral and anti-leukemic effects of gammadelta T cells in the context of hematopoietic transplantation. PMID- 30443257 TI - Manipulation of Salmonella Typhi Gene Expression Impacts Innate Cell Responses in the Human Intestinal Mucosa. AB - Although immunity induced by typhoid fever is moderated and short-lived, typhoid vaccination with the attenuated Ty21a oral vaccine generates long-lasting protection rates reaching up to 92%. Thus, there are important differences on how wild-type Salmonella and typhoid vaccine strains stimulate host immunity. We hypothesize that vaccine strains with different mutations might affect gut inflammation and intestinal permeability by different mechanisms. To test this hypothesis, we used an in vitro organotypic model of the human intestinal mucosa composed of human intestinal epithelial cells, lymphocytes/monocytes, endothelial cells, and fibroblasts. We also used six Salmonella enterica serovar Typhi (S. Typhi) strains: the licensed Ty21a oral vaccine, four typhoid vaccine candidates (i.e., CVD 908, CVD 909, CVD 910, and CVD 915) and the wild-type Ty2 strain. We found that genetically engineered S. Typhi vaccine strains elicit differential host changes not only in the intestinal permeability and secretion of inflammatory cytokines, but also in the phenotype and activation pathways of innate cells. These changes were distinct from those elicited by the parent wild type S. Typhi and depended on the genetic manipulation. In sum, these results emphasize the importance of carefully selecting specific manipulations of the Salmonella genome in the development of typhoid vaccines. PMID- 30443258 TI - Genes at the Crossroad of Primary Immunodeficiencies and Cancer. AB - Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients. PMID- 30443259 TI - 3D Molecular Cytology of Hop (Humulus lupulus) Meiotic Chromosomes Reveals Non disomic Pairing and Segregation, Aneuploidy, and Genomic Structural Variation. AB - Hop (Humulus lupulus L.) is an important crop worldwide, known as the main flavoring ingredient in beer. The diversifying brewing industry demands variation in flavors, superior process properties, and sustainable agronomics, which are the focus of advanced molecular breeding efforts in hops. Hop breeders have been limited in their ability to create strains with desirable traits, however, because of the unusual and unpredictable inheritance patterns and associated non Mendelian genetic marker segregation. Cytogenetic analysis of meiotic chromosome behavior has also revealed conspicuous and prevalent occurrences of multiple, atypical, non-disomic chromosome complexes, including those involving autosomes in late prophase. To explore the role of meiosis in segregation distortion, we undertook 3D cytogenetic analysis of hop pollen mother cells stained with DAPI and FISH. We used telomere FISH to demonstrate that hop exhibits a normal telomere clustering bouquet. We also identified and characterized a new sub terminal 180 bp satellite DNA tandem repeat family called HSR0, located proximal to telomeres. Highly variable 5S rDNA FISH patterns within and between plants, together with the detection of anaphase chromosome bridges, reflect extensive departures from normal disomic signal composition and distribution. Subsequent FACS analysis revealed variable DNA content in a cultivated pedigree. Together, these findings implicate multiple phenomena, including aneuploidy, segmental aneuploidy, or chromosome rearrangements, as contributing factors to segregation distortion in hop. PMID- 30443260 TI - A Phospholipase C-Like Protein From Ricinus communis Increases Hydroxy Fatty Acids Accumulation in Transgenic Seeds of Camelina sativa. AB - There have been strong interests in producing unusual fatty acids in oilseed crops to provide renewable industrial feedstock. Results are so far largely disappointing since much lower amounts of such fatty acids accumulate in genetically engineered seeds than in their original natural sources. It has been suggested that the flux of unusual fatty acids through phosphatidylcholine (PC) represents a major bottleneck for high accumulation of such fatty acids in triacylglycerol (TAG). We show here that a phospholipase C-like protein (RcPLCL1) from castor bean, which accumulates nearly 90% of the hydroxylated ricinoleic acid in its seed TAG, increases the amount of hydroxy fatty acids (HFAs) when co expresses with the fatty acid hydroxylase (RcFAH12) in transgenic seed of Camelina sativa. RcPLCL1 shows hydrolyzing activities on both PC and phosphatidylinositol substrates in our in vitro assay conditions. The PC-PLC activity of the RcPLCL1 may have increased the efficiency of HFA-PC to diacylglycerol conversion, which explains our observation of increased HFA contents in TAG concomitant with decreased HFA in the membrane lipid PC during seed development. Consequently, this may also alleviate the potential detrimental effect of HFA on germination of the engineered camelina seeds. Our results provide new knowledge that will help design effective strategies to engineer high levels of HFAs in transgenic oilseeds. PMID- 30443261 TI - Heat Stress Tolerance in Rice (Oryza sativa L.): Identification of Quantitative Trait Loci and Candidate Genes for Seedling Growth Under Heat Stress. AB - Productivity of rice, world's most important cereal is threatened by high temperature stress, intensified by climate change. Development of heat stress tolerant varieties is one of the best strategies to maintain its productivity. However, heat stress tolerance is a multigenic trait and the candidate genes are poorly known. Therefore, we aimed to identify quantitative trait loci (QTL) for vegetative stage tolerance to heat stress in rice and the corresponding candidate genes. We used genotyping-by-sequencing to generate single nucleotide polymorphic (SNP) markers and genotype 150 F8 recombinant inbred lines (RILs) obtained by crossing heat tolerant "N22" and heat susceptible "IR64" varieties. A linkage map was constructed using 4,074 high quality SNP markers that corresponded to 1,638 recombinationally unique events in this mapping population. Six QTL for root length and two for shoot length under control conditions with 2.1-12% effect were identified. One QTL rlht5.1 was identified for "root length under heat stress," with 20.4% effect. Four QTL were identified for "root length under heat stress as percent of control" that explained the total phenotypic variation from 5.2 to 8.6%. Three QTL with 5.3-10.2% effect were identified for "shoot length under heat stress," and seven QTL with 6.6-19% effect were identified for "shoot length under heat stress expressed as percentage of control." Among the QTL identified six were overlapping between those identified using shoot traits and root traits: two were overlapping between QTL identified for "shoot length under heat stress" and "root length expressed as percentage of control" and two QTL for "shoot length as percentage of control" were overlapping a QTL each for "root length as percentage of control" and "shoot length under heat stress." Genes coding 1,037 potential transcripts were identified based on their location in 10 QTL regions for vegetative stage heat stress tolerance. Among these, 213 transcript annotations were reported to be connected to stress tolerance in previous research in the literature. These putative candidate genes included transcription factors, chaperone proteins (e.g., alpha-crystallin family heat shock protein 20 and DNAJ homolog heat shock protein), proteases, protein kinases, phospholipases, and proteins related to disease resistance and defense and several novel proteins currently annotated as expressed and hypothetical proteins. PMID- 30443264 TI - Foreword. PMID- 30443262 TI - The Phenylpropanoid Case - It Is Transport That Matters. AB - Phenylpropanoids fulfill numerous physiological functions, essential for plant growth and development, as well as plant-environment interactions. Over the last few decades, many studies have shown that exquisite regulatory mechanisms at multiple levels control the phenylpropanoid metabolic pathway. Deciphering this pathway not only provides a greater, basic understanding of plant specialized metabolism, but also enhances our ability to rationally design plant metabolic pathways for future applications. Despite the identification of the participating enzymes of this complex, biosynthetic machinery, we still lack a complete picture of other genes, enzymes, and metabolites essential for regulation and compartmentation/distribution of phenylpropanoids. Compartmentation, as well as distribution, are critical for the fate/functioning of those molecules, and their effective biosynthesis. At the cellular level, we have narrowed down our understanding of these processes to organelles. Furthermore, various, overlapping, but not exclusive scenarios of phenylpropanoid distribution within the cell have also been described. The cross-membrane dynamics, but also intercellular communication of different branches from phenylpropanoid biosynthesis have become an exciting research frontier in plant science. The intra- and intercellular channeling of intermediates by various transport mechanisms and notably membrane transporters could be a meaningful tool that ensures, inter alia, efficient metabolite production. PMID- 30443263 TI - A systematic review of wellbeing in children: a comparison of military and civilian families. AB - Background: Children in military families have uniquely different childhood experiences compared to their civilian peers, including a parent in employment and a stable familial income, frequent relocations, indirect exposure to and awareness of conflict, and extended separation from parents or siblings due to deployment. However, whether children from military families have poorer wellbeing than non-military connected children is not well understood. Method: We conducted a systematic review to explore the relationship between military family membership (e.g. parent or sibling in the military) and child wellbeing compared to non-military connected controls. Searches for this review were conducted in September 2016 and then updated in February 2018. Results: Nine studies were identified, eight were cross-sectional. All studies utilised self-report measures administered in US school settings. On the whole, military connected youth were not found to have poorer wellbeing than civilian children, although those with deployed parents and older military connected children were at greater risk of some adjustment difficulties (e.g. substance use, externalising behaviour). Although only assessed in two studies, having a sibling in the military and experiencing sibling deployment was statistically significantly associated with substance use and depressive symptoms. Conclusions: This study is unique in its direct comparison of military and non-military connected youth. Our results highlight the need to examine the impact of military service in siblings and other close relatives on child wellbeing. Given the adverse impact of poor mental health on child functioning, additional research is needed ensure appropriate, evidence-based interventions are available for youth in military families. PMID- 30443265 TI - 'Primary' Microvascular Angina: Clinical Characteristics, Pathogenesis and Management. AB - Microvascular angina (MVA), i.e. angina caused by abnormalities of the coronary microcirculation, is increasingly recognised in clinical practice. The pathogenetic mechanisms of MVA are heterogeneous and may involve both structural and functional alterations of coronary microcirculation, and functional abnormalities may variably involve an impairment of coronary microvascular dilatation and an increased microvascular constrictor activity. Both invasive and non-invasive diagnostic tools exist to identify patients with MVA in clinical practice. Prognosis has been reported to be good in primary MVA patients, although the prognostic implications of coronary microvascular dysfunction (CMVD) in more heterogeneous populations of angina patients need further assessment. Management of primary MVA can be challenging, but pharmacological and non pharmacological treatments exist that allow satisfactory control of symptoms in most patients. PMID- 30443267 TI - Common and Uncommon CTO Complications. AB - Despite the ongoing development of technical skills, increasing operator experience and improvements in medical devices, percutaneous coronary interventions (PCI) for chronic total occlusions (CTO) are still the most challenging procedures in interventional cardiology for coronary artery disease. Due to the complexity of the procedures, there is an increased complication rate compared with PCIs for the treatment of non-occlusive disease. This may significantly increase procedural morbidity and potentially mortality. CTO-PCI related complications include all the usual complications that are seen in routine PCI in addition to unique issues such as inadvertent occlusion of donor vessels or injury of collateral channels causing haemodynamic instability or ischaemia. To minimise the morbidity associated with these procedures, it is important to be aware of potential complications and recognise them in a timely fashion. Should they arise, operators should be able to deal with them in a safe and efficient manner. PMID- 30443266 TI - Risk Stratification in Patients with Coronary Artery Disease: A Practical Walkthrough in the Landscape of Prognostic Risk Models. AB - Although a combination of multiple strategies to prevent and treat coronary artery disease (CAD) has led to a relative reduction in cardiovascular mortality over recent decades, CAD remains the greatest cause of morbidity and mortality worldwide. A variety of individual factors and circumstances other than clinical presentation and treatment type contribute to determining the outcome of CAD. It is increasingly understood that personalised medicine, by taking these factors into account, achieves better results than "one-size-fitsall" approaches. In recent years, the multiplication of risk scoring systems for CAD has generated some degree of uncertainty regarding whether, when and how predictive models should be adopted when making clinical decisions. Against this background, this article reviews the most accepted risk models for patients with evidence of CAD to provide practical guidance within the current landscape of tools developed for prognostic risk stratification. PMID- 30443268 TI - FFRCT for Complex Coronary Artery Disease Treatment Planning: New Opportunities. AB - Coronary computed tomography (CT) is well established for the assessment of symptomatic patients with suspected but not yet confirmed coronary artery disease with high diagnostic accuracy and risk prediction. Until recently, coronary computed tomography angiography (CTA) has played a limited role in the management of complex coronary artery disease (CAD) and in planning revascularisation strategies. With the advent of FFRCT, enabling anatomy and physiology with a single study and the ability to adjudicate lesion specific pressure loss, the potential of combined coronary CT angiography (CCTA) and fractional flow reserve (FFR) computed from non-invasive CT angiography (FFRCT) to inform treatment decision-making and help guide revascularisation has been recognised. In this review, we highlight the evolving role of FFRCT in the management of complex CAD; the opportunities, the data and the unanswered questions. PMID- 30443269 TI - Culprit Vessel Only Versus Complete Revascularisation in Patients with ST-Segment Elevation Myocardial Infarction - Should we Stay or Stage? AB - Multivessel coronary artery disease (MVCAD) is common in patients with ST elevation myocardial infarction (STEMI), thereby negatively affecting mortality and outcome. Currently there is increasing evidence that complete revascularisation should be considered in haemodynamically stable patients. There are few larger randomised controlled trials available showing a lower risk of major adverse cardiac events after complete revascularisation, mainly driven by a reduction of repeat revascularisation. However, these trials are not adequately powered to show a mortality benefit or reduced risk of myocardial infarction. As there are several possible strategies, the presence of MVCAD often poses a therapeutic dilemma for interventional cardiologists and there is still ongoing debate on when and how to perform complete revascularisation. Pending further trials that may clarify which strategy is best, an individualised approach should be adopted. PMID- 30443270 TI - ORBITA: What Goes Around, Comes Around... Or Does It? AB - Current guidelines recommend percutaneous coronary intervention (PCI) in patients with ongoing stable angina symptoms despite optimal medical therapy (OMT), although trials have shown no reduction in death or myocardial infarction. The recently published ORBITA trial compared OMT + PCI with OMT + 'placebo' PCI in patients with angina and single-vessel coronary artery disease (CAD), and found no significant difference in treadmill exercise time between the two groups after six weeks. The trial concluded that invasive procedures can be assessed with placebo control while numerous editorials interpreted the trial as showing that PCI has no role in the management of stable angina. However, the highly selected patient population, low ischaemic burden and level of symptoms and high proportion of non-flow-limiting stenoses on invasive physiological testing mean that, while ground-breaking in terms of its methodology, ORBITA does not add to the current evidence base supporting ischaemia-guided revascularisation if symptoms are not controlled on medical therapy alone. PMID- 30443271 TI - Delayed Coronary Occlusion After Transcatheter Aortic Valve Implantation: Implications for New Transcatheter Heart Valve Design and Patient Management. AB - Transcatheter aortic valve implantation has revolutionised the treatment of patients with severe aortic stenosis and is the preferred treatment option for patients with elevated surgical risk. Outcomes have continually improved, but because of the nature of the procedure infrequent catastrophic complications, such as coronary obstruction, persist. Recently, data were published regarding delayed coronary obstruction (DCO), a phenomenon in which the obstruction occurs after the index procedure. DCO has important consequences for future research. In this article we will explore the implications for new transcatheter heart valve design and approaches to patient management to minimise the risk of DCO occurring. PMID- 30443272 TI - Annular Rupture During Transcatheter Aortic Valve Implantation: Predictors, Management and Outcomes. AB - Transcatheter aortic valve implantation (TAVI) is the treatment of choice in patients with symptomatic severe aortic stenosis who are either inoperable or at high risk for conventional surgical aortic valve replacement. Recent data have also shown favourable outcomes in patients deemed to be at intermediate operative risk, which expands the application of this novel technology. Despite its success, TAVI has been associated with rare life-threatening complications. Of these, aortic annular rupture is considered to be the most devastating. Advances in pre-procedural screening and patient selection have reduced the incidence of annular rupture. When this complication occurs, early recognition and prompt management are essential. This article is intended to provide a comprehensive review of the predictors, management and clinical outcomes of aortic annular rupture. PMID- 30443273 TI - Alternate Access for TAVI: Stay Clear of the Chest. AB - Transcatheter aortic valve implantation (TAVI) is currently performed through an alternative access in 15% of patients. The transapical access is progressively being abandoned as a result of its invasiveness and poor outcomes. Existing data does not allow TAVI operators to favour one access over another - between transcarotid, trans-subclavian and transaortic - because all have specific strengths and weaknesses. The percutaneous trans-subclavian access might become the main surgery-free alternative access, although further research is needed regarding its safety. Moreover, the difficult learning curve might compromise its adoption. The transcaval access is at an experimental stage and requires the development of dedicated cavo-aortic crossing techniques and closure devices. PMID- 30443274 TI - Aminotriazole Mn(I) Complexes as Effective Catalysts for Transfer Hydrogenation of Ketones. AB - A catalytic system based on complexes comprising abundant and cheap manganese together with readily available aminotriazole ligands is reported. The new Mn(I) complexes are catalytically competent in transfer hydrogenation of ketones with 2 propanol as hydrogen source. The reaction proceeds under mild conditions at 80 degrees C for 20 h with 3 % of catalyst loading using either KO t Bu or NaOH as base. Good to excellent yields were obtained for a wide substrate scope with broad functional group tolerance. The obtained results by varying the substitution pattern of the ligand are consistent with an out-sphere mechanism for the H-transfer. PMID- 30443275 TI - Performance of silver, zinc, and iron nanoparticles-doped cotton filters against airborne E. coli to minimize bioaerosol exposure. AB - To overcome limitations of existing air-cleaning filters in capturing and deactivating aerosolized microorganisms, this study was embarked to evaluate novel Ag, Zn, and Fe nanoparticle-doped cotton filters (AgCt, ZnCt, FeCt), as biocidal filters for bioaerosol attenuation. To evaluate the biocidal activity of the nanocomposite filters, the survival of lab-generated E. coli after collection on each filter material was compared to collection on an undoped cotton control filter and in a BioSampler. Relative humidity (RH) affected the survival of bacteria on the filters, and the optimal RH was found to be 50 +/- 5%. The physical removal efficiency (PRE) determined by an optical particle counter was 99.9 +/- 0.7% for ZnCt, 97.4 +/- 1.2% for AgCt, and 97.3 +/- 0.6% for FeCt, where the control showed only 77.4 +/- 6.3% for particles > 500 nm. The doped filters showed 100% viable removal efficiency (VRE). Importantly, the VRE of the nanocomposite filters after four cycles remained nearly 99% and was greater than the cotton control filter at 76.6 +/- 3.2%. Adding to its benefits, the AgCt filters had a lower pressure drop than the FeCt and ZnCt filters and the cotton control. The permeability for the cotton control filter was 3.38 * 10-11 m2 while that for the AgCt filter was slightly higher (3.64 * 10-11 m2) than the other filters as well. Overall, these results suggest that nanocomposite-doped filter media, particularly AgCt, can provide effective protection against airborne pathogens with a lower pressure drop, elevated collection efficiency, and better disinfection capability as compared to untreated cotton filters, which are all important features for practical biocidal applications. Graphical abstract. PMID- 30443276 TI - Multi-level policies for air quality: implications of national and sub-national emission reductions on population exposure. AB - Poor air quality and related health impacts are still an issue in many cities and regions worldwide. Integrated assessment models (IAMs) can support the design of measures to reduce the emissions of precursors affecting air pollution. In this study, we apply the SHERPA (screening for high emission reduction potentials for air quality) model to compare spatial and sectoral emission reductions, given country-scale emission targets. Different approaches are tested: (a) country "uniform" emission reductions, (b) emission reductions targeting urban areas, (c) emission reductions targeting preferential sectors. As a case study, we apply the approaches to the implementation of the National Emission Ceiling Directive. Results are evaluated in terms of the reduction in average population exposure to PM2.5 overall in a country and in its main cities. Results indicate that the reduction of population exposure to PM2.5 highly depends on the way emission reductions are implemented. This work also shows the usefulness of the SHERPA model to support national authorities implementing national emission reduction targets while, at the same time, addressing their local air quality issues. PMID- 30443277 TI - Cognitive Behavioural Therapy for Psychosis: A Health Technology Assessment. AB - Background: Cognitive behavioural therapy (CBT) for psychosis is a distinct type of psychotherapy that has been recommended together with antipsychotic drugs and comprehensive usual care in the management of schizophrenia, a complex mental health disorder associated with a high economic and societal burden. The objectives of this report were to assess the effectiveness, harms, cost effectiveness, and lived experience of CBT for psychosis in improving outcomes for adults with a primary diagnosis of schizophrenia. Methods: We performed literature searches on March 28 and April 5, 2017, and undertook a qualitative synthesis of systematic reviews of the clinical and economic literature comparing CBT for psychosis with any comparator interventions (e.g., usual care, waitlist control, or pharmacotherapy) in adults with a diagnosis of schizophrenia as defined by any criteria (including related disorders such as schizoaffective disorder).We developed an individual-level state-transition probabilistic model for a hypothetical cohort of adults aged 18 years and older starting with first episode psychosis. We compared three strategies: usual care, CBT for psychosis by physicians, and CBT for psychosis by regulated nonphysician therapists. The CBT was provided in person together with usual care including pharmacotherapy: 16 structured sessions (individual or group) for first-episode psychosis and 24 individual sessions for relapse or treatment-resistant disease. We calculated incremental cost-effectiveness ratios (ICERs) over 5 years using the Ontario Ministry of Health and Long-Term Care perspective and a discount rate of 1.5%. We also estimated the 5-year budget impact of publicly funding CBT for psychosis in Ontario.In addition, we interviewed 13 people with lived experience of schizophrenia and psychosis about their values and preferences surrounding CBT and other treatments. Results: CBT for psychosis compared with usual care significantly improved overall psychotic symptoms (standard mean difference [SMD] -0.33, 95% confidence interval [CI] -0.45 to -0.21), positive symptoms (e.g., hallucinations) (SMD -0.34, 95% CI -0.58 to -0.10), auditory symptoms (SMD 0.39, 95% Cl not reported, P < .005), delusions (SMD 0.33, 95% CI not reported, P < .05) and negative symptoms (e.g., blunt affect) (SMD -0.32, 95% CI -0.59 to 0.04) at end of treatment. No significant differences were observed for social function, distress associated with psychosis, relapse, or quality of life.Compared with any control, CBT for psychosis significantly improved overall psychotic symptoms, positive symptoms, auditory hallucinations, delusions, and negative symptoms. Compared with other forms of therapy, CBT for psychosis showed inconsistent results at end of treatment for overall psychotic symptoms, positive symptoms, auditory hallucinations, and delusions. In people with first-episode psychosis, CBT for psychosis was not significantly more effective for the prevention of relapse when compared with other forms of therapy or usual care (odds ratio [OR] 1.11, 95% CI 0.63-1.95 and OR 1.15, 95% CI 0.65-2.04, respectively).Low-intensity CBT for psychosis (fewer than 16 face-to-face sessions) compared with any type of treatment significantly improved overall psychotic symptoms and social function at follow-up (SMD -0.40, 95% CI -0.74 to 0.06 and SMD -0.57, 95% CI -0.81 to -0.33, respectively).In the cost-utility analysis, CBT for psychosis provided by nonphysician therapists compared with usual care was associated with increases in both quality-adjusted life-years (mean 0.1159 QALYs, 95% credible interval [CrI] 0.09-0.14) and costs (mean $2,494, 95% Crl $1,472-$3,544), yielding an ICER of $21,520 per QALY gained. CBT for psychosis provided by physicians was dominated because it was equally effective but more expensive (mean $2,976, 95% CrI $2,822-$3,129; ICER of CBT for psychosis vs. usual care: $47,196/QALY gained).Assuming a 20% increase in access per year (from 0% at baseline to 100% in year 5), we estimated the total 5-year net budget impact of publicly funding CBT for psychosis would be about $15.2 million for nonphysician providers and about $35.4 million if provided by psychiatrists. It is estimated that by the year 2021, approximately 110 nonphysician therapists or 150 physicians would be needed to provide CBT for psychosis to more than 12,000 adults with schizophrenia (including about 8,500 incident cases) in Ontario.People with schizophrenia and their family members reported positive experiences with CBT for psychosis. They felt it provided effective tools to help manage their schizophrenia but stressed that it was only effective in conjunction with medication to control psychotic episodes and overcome a patient's denial of illness. Geographic and financial barriers have restricted access to this psychotherapy. Conclusions: Compared with usual care or any control, CBT for psychosis significantly improved psychotic symptoms, based on evidence of moderate to adequate quality; no significant improvements were observed for social function, relapse, or quality of life outcomes. People affected by schizophrenia reported that CBT for psychosis was valuable in conjunction with antipsychotic medication but that access to this type of psychotherapy is limited. Adding CBT for psychosis to usual care in the management of adult schizophrenia probably represents good value for money in Ontario. Depending on the type of provider, therapy format, and rate of access, the net budget impact to Ontario's publicly funded health system would likely be between $15 million to $35 million over the next 5 years. PMID- 30443279 TI - Remote Monitoring of Implantable Cardioverter-Defibrillators, Cardiac Resynchronization Therapy and Permanent Pacemakers: A Health Technology Assessment. AB - Background: Under usual care, people with an implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy with or without a defibrillator (CRT-D and CRT-P, respectively), or a permanent pacemaker have follow-up in-person clinic visits. Remote monitoring of these devices allows the transfer of the information stored in the device so that it can be accessed by the clinic personnel via a secured website. Methods: We completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, and patient preferences for remote monitoring of ICDs, CRTs, and permanent pacemakers plus clinic visits compared with clinic visits alone. This is an update of a 2012 health technology assessment. In addition to the eligible randomized controlled trials (RCTs) from the 2012 publication, we included RCTs identified through a systematic literature search on June 1, 2017. We assessed the risk of bias of each study using the Cochrane risk of bias tool and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We conducted an economic evaluation to determine the cost-effectiveness of remote monitoring blended with in-clinic follow-up compared to in-clinic follow-up alone in patients with an ICD, a CRT-D, or a pacemaker. We determined the budget impact of blended remote monitoring in patients implanted with ICD, CRT-D, CRT-P, or pacemaker devices from the perspective of the Ontario Ministry of Health and Long-Term Care. To understand patient experiences with remote monitoring, we interviewed 16 patients and family members. Results: Based on 15 RCTs in patients with implanted ICDs or CRT-Ds, remote monitoring plus clinic visits resulted in fewer patients with inappropriate ICD shocks within 12 to 37 months of follow-up (moderate quality evidence; absolute risk difference -0.04 [95% confidence interval -0.07 to -0.01]), fewer total clinic visits (moderate quality evidence), and a shorter time to detection and treatment of events (moderate quality evidence) compared with clinic visits alone. There was a similar risk of major adverse events (moderate quality evidence).Based on 6 RCTs in patients with pacemakers, remote monitoring plus clinic visits reduced the arrhythmia burden (high quality evidence), the time to detection and treatment of arrhythmias (high quality evidence), and the number of clinic visits (moderate quality evidence]) compared with clinic visits alone. Here again, there was a similar risk of major adverse events (high quality evidence).Results from the economic evaluation showed that among ICD and CRT-D recipients, blended remote monitoring (remote monitoring plus in-clinic follow ups) was more costly (incremental value of $4,354 per person) and more effective, providing higher quality-adjusted life years (incremental value of 0.19), compared to in-clinic follow-up alone. Among pacemaker recipients, blended remote monitoring was less costly (with an incremental saving of $2,370 per person) and more effective (with an incremental value of 0.12 quality-adjusted life years) than with in-clinic follow-up alone. We estimated that publicly funding remote monitoring could result in cost savings of $14 million over the first five years.Participants using remote monitoring reported that these devices provide important medical and safety benefits in managing their heart condition. Remote cardiac monitoring provides patients and their family members with an increased freedom. Their belief that the device will help with earlier detection of technical or clinical problems reduces the amount of stress and distraction their condition causes in their lives. Conclusions: Remote monitoring of ICDs, CRT-Ds, and pacemakers plus clinic visits resulted in improved outcomes without increasing the risk of major adverse events compared with clinic visits alone. Remote monitoring is a cost effective option for patients implanted with cardiac electronic devices. Patients reported positive experiences using remote monitoring, and perceived that the device provided important medical and safety benefits. PMID- 30443278 TI - Bilateral Cochlear Implantation: A Health Technology Assessment. AB - Background: Sensorineural hearing loss occurs as a result of damage to the hair cells in the cochlea, or to the auditory nerve. It negatively affects learning and development in children, and employment and economic attainment in adults. Current policy in Ontario is to provide unilateral cochlear implantation for patients with bilateral severe to profound sensorineural hearing loss. However, hearing with both ears as a result of bilateral cochlear implantation may offer added benefits. Methods: We completed a health technology assessment, which included an evaluation of clinical benefits and harms, value for money, budget impact, and patient preferences related to bilateral cochlear implantation. We performed a systematic literature search for studies on bilateral cochlear implantation in adults and children from inception to March 2017. We conducted a cost-utility analysis with a lifetime horizon from a public payer perspective and analyzed the budget impact of publicly funding bilateral cochlear implantation in adults and children in Ontario for the next 5 years. Finally, we conducted interviews with adults who have sensorineural hearing loss and unilateral or bilateral cochlear implants, and with parents of children with bilateral cochlear implants. Results: We included 24 publications (10 in adults, 14 in children) in the clinical evidence review. Compared with unilateral cochlear implantation, bilateral cochlear implantation improved sound localization, speech perception in noise, and subjective benefits of hearing in adults and children with severe to profound sensorineural hearing loss (GRADE: moderate to high). Bilateral cochlear implantation also allowed for better language development and more vocalization in preverbal communication in children (GRADE: moderate). The safety profile was acceptable.Bilateral cochlear implantation was more expensive and more effective than unilateral cochlear implantation. The incremental cost-effectiveness ratio was $48,978/QALY in adults and between $27,427/QALY and $30,386/QALY in children. Cost-effectiveness was highly dependent on the quality-of-life values used. We estimated that the net budget impact of publicly funding bilateral cochlear implantation for adults in Ontario would be between $510,000 and $780,000 per year for the next 5 years.Patients described the social and emotional effects of hearing loss, and the benefits and challenges of using cochlear implants. Conclusions: Based on evidence of moderate to high quality, we found that bilateral cochlear implantation improved hearing in adults and children with severe to profound sensorineural hearing loss. Bilateral cochlear implantation was potentially cost-effective compared to unilateral cochlear implantation in adults and children. Patients with sensorineural hearing loss reported the positive effects of cochlear implants, and patients with unilateral cochlear implants generally expressed a desire for bilateral implants. PMID- 30443280 TI - Structured Education and Neuromuscular Exercise Program for Hip and/or Knee Osteoarthritis: A Health Technology Assessment. AB - Background: Osteoarthritis is a chronic disorder and the most common form of arthritis. The joints most commonly affected are the hip and knee. The progression of osteoarthritis results in the breakdown of tissues and cartilage and the loss of joint function, causing symptoms such as pain, stiffness, reduced physical function, and limited movement. Although there is no cure for osteoarthritis, treatment options are available to manage symptoms and optimize quality of life. Clinical guidelines recommend education, exercise, and weight loss (when necessary) as the first line of treatment. Methods: We conducted a health technology assessment, which included an evaluation of the effectiveness, safety, and cost-effectiveness of a structured education and neuromuscular exercise program for the management of hip and/or knee osteoarthritis. We also assessed the budget impact of publicly funding such a program, and we spoke with people with osteoarthritis to gain an understanding of their preferences and values. We performed a systematic review of the clinical and economic literature published between January 1, 2008, and October 4, 2017. We also performed a grey literature search of health technology assessment websites. We assessed the risk of bias of each study, and we assessed the quality of the body of evidence according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group criteria. To evaluate the cost-effectiveness of a structured education and neuromuscular exercise program for adults with knee osteoarthritis, we conducted a cost-utility analysis from the perspective of the Ontario Ministry of Health and Long-Term Care. We also estimated the budget impact of publicly funding such a program in Ontario over the next 5 years. To contextualize the potential value of this type of program as a treatment option, we spoke with people with hip and/or knee osteoarthritis. Results: Ten studies met our inclusion criteria for the clinical evidence review. Compared with usual care, a structured education and neuromuscular exercise program showed statistically significant short-term improvements in pain (GRADE low) and physical function (GRADE moderate), as well as statistically significant long term improvements in performing activities of daily living (GRADE moderate) and in quality of life (GRADE moderate). The short-term improvements in pain and physical function appeared to be sustained into the medium term. Compared with patient education, a structured education and neuromuscular exercise program showed statistically significant short-term improvements in pain (GRADE low) and physical function (GRADE low) and sustained long-term improvement in physical function.Our primary economic evaluation showed that, compared with usual care, a group-based structured education and neuromuscular exercise program consisting of two educational sessions and 24 exercise sessions for the management of knee osteoarthritis was associated with an incremental cost of $719 (95% confidence interval [CI]: $410-$1,118) and an incremental quality-adjusted survival of 0.03 quality-adjusted life-years (QALYs) (95% CI: -0.006 to 0.06), resulting in an incremental cost-effectiveness ratio (ICER) of $23,967 per QALY gained. The budget impact of publicly funding a group-based structured education and neuromuscular exercise program consisting of two educational sessions and 24 exercise sessions would range from $21.4 million to $91.6 million per year over the next 5 years. The budget impact of publicly funding a program consisting of two educational sessions and 12 exercise sessions would range from $12.4 million to $53.2 million per year over the next 5 years.People with hip and/or knee osteoarthritis with whom we spoke reported on the negative impact of osteoarthritis on their physical functioning and quality of life. Those with experience of a structured education and neuromuscular exercise program reported favourably on the program, stating they felt that participation in the program had strengthened their muscles and reduced the negative impact of their symptoms. The cost of such programs was reported as a barrier to access. Conclusions: There is moderate-quality evidence that, compared with usual care, a structured education and neuromuscular exercise program improves physical function, quality of life, and the ability to perform activities of daily living. There is low quality evidence that, compared with usual care, this type of program improves pain. Low-quality evidence suggests that, compared with patient education, a structured education and neuromuscular exercise program improves pain and physical function.A group-based structured education and neuromuscular exercise program may be cost-effective for the nonsurgical management of knee osteoarthritis. Publicly funding a group-based structured education and neuromuscular exercise program for hip and/or knee osteoarthritis in Ontario would lead to additional costs to the health system of $21.4 million to $91.6 million per year over the next 5 years. If the program could be delivered with a smaller number of 12 exercise sessions, the budget impact would be reduced to between $12.4 million and $53.2 million over the next 5 years.Structured education and neuromuscular exercise programs are perceived favourably by people with hip and/or knee osteoarthritis. However, the cost of such programs may be a barrier to access. PMID- 30443281 TI - Delivery of Automated External Defibrillators (AED) by Drones: Implications for Emergency Cardiac Care. AB - Purpose of Review: Out-of-hospital cardiac arrest (OHCA) remains a significant health problem in the USA and only 8.6% of victims survive with good neurological function, despite advances in emergency cardiac care. The likelihood of OHCA survival decreases by 10% for every minute without resuscitation. Recent Findings: Automatic external defibrillators (AEDs) have the potential to save lives yet public access defibrillators are underutilized (< 2% of the time) because they are difficult to locate and rarely available in homes or residential areas, where the majority (70%) of OHCA occur. Even when AEDs are within close proximity (within 100 m), they are not used 40% of the time. PMID- 30443282 TI - Mediated Personalization of Executive European Union Politics: Examining Patterns in the Broadsheet Coverage of the European Commission, 1992-2016. AB - The personalization of politics is a popular thesis but often challenged when it comes to media personalization. While previous research compared the prominence of different types of political actors across national political contexts, this article situates its research in the context of European Union (EU) politics and, thereby, studies similar reference points across countries. Its focus lies on the European Commission and its members. Personalization is conceptualized as individualization and presidentialization, respectively. The article proposes that the EU integration process provides journalists with the opportunity to report more often about individual politicians, while political developments should further incentivize journalists to personalize their news from Brussels. To test this argument, the article investigates personalization patterns in seven broadsheets from Ireland, Britain, France, the Netherlands, Denmark, Italy, and Poland. In total, 119,070 articles are analyzed by automated content analysis over a period of twenty-five years. The article finds no pan-European trend toward greater personalization of politics with respect to news coverage of EU executive politics. The findings nonetheless provide important implications for future research. The article particularly discusses the universal applicability of the phenomenon, the time frame for analysis, and journalistic styles in covering European politics. PMID- 30443284 TI - V-ATPase in cancer progression: Two sides of the same coin. PMID- 30443283 TI - Start Spreading the News: A Comparative Experiment on the Effects of Populist Communication on Political Engagement in Sixteen European Countries. AB - Although populist communication has become pervasive throughout Europe, many important questions on its political consequences remain unanswered. First, previous research has neglected the differential effects of populist communication on the Left and Right. Second, internationally comparative studies are missing. Finally, previous research mostly studied attitudinal outcomes, neglecting behavioral effects. To address these key issues, this paper draws on a unique, extensive, and comparative experiment in sixteen European countries (N = 15,412) to test the effects of populist communication on political engagement. The findings show that anti-elitist populism has the strongest mobilizing effects, and anti-immigrant messages have the strongest demobilizing effects. Moreover, national conditions such as the level of unemployment and the electoral success of the populist Left and Right condition the impact of populist communication. These findings provide important insights into the persuasiveness of populist messages spread throughout the European continent. PMID- 30443285 TI - Clinical application of cfDNA: moving in the right direction, but still a long way to go. PMID- 30443286 TI - Mutant molecular chaperone activates cytokine receptor as a homomultimer. PMID- 30443287 TI - ASXL1 as a critical regulator of epigenetic marks and therapeutic potential of mutated cells. PMID- 30443288 TI - Rise of the specialized onco-ribosomes. PMID- 30443290 TI - The potent and selective cyclin-dependent kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile combination partner in preclinical cancer models. AB - Inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) is associated with robust antitumor activity. Ribociclib (LEE011) is an orally bioavailable CDK4/6 inhibitor that is approved for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, in combination with an aromatase inhibitor, and is currently being evaluated in several additional trials. Here, we report the preclinical profile of ribociclib. When tested across a large panel of kinase active site binding assays, ribociclib and palbociclib were highly selective for CDK4, while abemaciclib showed affinity to several other kinases. Both ribociclib and abemaciclib showed slightly higher potency in CDK4-dependent cells than in CDK6-dependent cells, while palbociclib did not show such a difference. Profiling CDK4/6 inhibitors in large-scale cancer cell line screens in vitro confirmed that RB1 loss of function is a negative predictor of sensitivity. We also found that routinely used cellular viability assays measuring adenosine triphosphate levels as a proxy for cell numbers underestimated the effects of CDK4/6 inhibition, which contrasts with assays that assess cell number more directly. Robust antitumor efficacy and combination benefit was detected when ribociclib was added to encorafenib, nazartinib, or endocrine therapies in patient-derived xenografts. PMID- 30443289 TI - Biothiols and oxidative stress markers and polymorphisms of TOMM40 and APOC1 genes in Alzheimer's disease patients. AB - Alzheimer's disease (AD) is a progressive disease, with frequently observed improper biothiols turnover, homocysteine (Hcy) and glutathione (GSH). GSH protects cells from oxidative stress and may be determined by 8-oxo-2' deoxyguanosine (8-oxo2dG) level and its repair enzyme 8-oxoguanine DNA glycosylase (OGG1). The presence of unfavorable alleles, e.g., in APOE cluster, TOMM40 or APOC1 is known to facilitate the dementia onset under oxidative stress. The aim of the study was to analyze rs1052452, rs2075650 TOMM40 polymorphisms, rs4420638 APOC1, and their correlation with Hcy, GSH, 8-oxo2dG, OGG1 levels in plasma of AD patients and controls. We recruited 230 individuals: 88 AD, 80 controls without (UC), 62 controls with (RC) positive family history of AD. The TOMM40 genotype was determined by HRM and capillary electrophoresis, while APOC1 by HRM. The concentrations of OGG1, 8-oxo2dG were determined by ELISA, whereas Hcy, GSH by HPLC/EC. We showed that over 60% of AD patients had increased Hcy levels (p<0.01 vs. UC, p<0.001 vs. RC), while GSH (p<0.01 vs. UC), 8-oxo2dG (p<0.01 vs. UC, p<0.001 vs. RC) were reduced. Minor variants: rs10524523-L, rs4420638-G, rs2075650-G were significantly overrepresented in AD. For rs4420638 G, rs2075650-G variants, the association remained significant in APOE E4 non carriers. The misbalance of analyzed biothiols, and 8-oxo2dG, OGG1 were more pronounced in carriers of major variants: rs10524523-S/VL, rs4420638-A, rs2075650 A. We showed, for the first time, that APOC1 and TOMM40 rs2075650 polymorphisms may be independent risk factors of developing AD, whose major variants are accompanied by disruption of biothiols metabolism and inefficient removal of DNA oxidation. PMID- 30443291 TI - Immortalized murine fibroblast cell lines are refractory to reprogramming to pluripotent state. AB - To date different cell types of various mammalian species have been reprogrammed to induced pluripotent stem cells (iPSCs) using Yamanaka's cocktail of transcription factors (Oct4, Klf4, Sox2, and cMyc). It has been shown that several primary human cancer cell lines could be reprogrammed to iPSCs. We sought if immortalized mouse fibroblast cell lines could also be reprogrammed to iPSCs. The approach of generating iPSCs from such cells should be valuable in different experimental settings as it allows clonally derive cell lines carrying mutations whose impact on reprogramming could be next evaluated. Therefore, we investigated reprogramming of widely used immortalized cell lines (NIH3T and STO), as well as of de novo immortalized fibroblast line (tKM) with the use of highly effective lentiviral polycistronic OKSM expression system. Our reprogramming experiments have shown that in contrast to mouse embryonic fibroblasts (MEFs), none of the immortalized cell lines can be reprogrammed to pluripotent state. Contrary to colonies derived from MEFs, those derived from the immortalized cells lines (1) developed much later, (2) contained large round cells, not typical for iPSCs, and (3) were negative for trusted markers of matured iPSCs, Nanog and SSEA1. Immortalized cell lines NIH3T and STO are known to be mostly aneuploid, whereas tKM population includes cells with normal karyotype, however, neither cell type can be reprogrammed. Thus our data argue that aneuploidy per se is not a reason for the observed refractoriness of mouse immortalized cells to reprogramming to pluripotent state. PMID- 30443292 TI - Integration of stereotactic radiotherapy in the treatment of metastatic colorectal cancer patients: a real practice study with long-term outcome and prognostic factors. AB - Background: There are very few clinical or prognostic studies on the role of SRT (Stereotactic Radiation Therapy) in the continuum of care of metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients affected by oligo-mCRC were treated with SRT before or after front-line standard treatments. SRT was delivered according to a risk-adapted protocol. Total body CT (Computed Tomography) scan was done before therapy and every three months thereafter. The radiologic responses to therapy were evaluated by RECIST (Response Evaluation Criteria In Solid Tumors). FDG-PET (FluoroDeoxyGlucose - Positron Emission Tomography) was done before and after SRT; metabolic responses were evaluated by using the EORTC (European Organization for Research and Treatment of Cancer) criteria. The Kaplan-Meier product limit method was applied to graph Overall Survival (OS) and Progression-Free Survival (PFS). Results: Forty-seven patients were included. Twenty-one patients had disease limited to lungs, 9 to lung and liver, 7 only to liver, 10 to multiple sites. The median prescription SRT dose was 60 Gy per organ in 3 fractions (median biological effective dose of 180 Gy). The reduction of delta SUVmax (maximum Standardized Uptake Value) correlated with the local control (p<0.001) and two-years survival (p=0.003). At univariate analysis, localization of primary tumor, site of metastases, KRAS (Kirsten RAt Sarcoma) oncogene mutational status, response to first-line chemotherapy, response to SRT and number of treated lesions predicted both PFS and OS. Discussion: This real practice experience suggests that further studies are needed to analyze the promising role of SRT in the multidisciplinary management of mCRC. PMID- 30443294 TI - ROS1-rearranged putative lung adenocarcinoma presenting as carcinoma of unknown primary site: a case report. AB - Carcinoma of unknown primary site (CUP) is diagnosed only in 2-9% of all cancer cases. Adenocarcinomas account for approximately 60% of CUP, and some of these are putative lung adenocarcinomas. The frequency of driver oncogene positivity in the putative lung adenocarcinomas is unknown, and the efficacy of targeting therapies for the driver oncogene is also unknown. This is the first case report of C-ros oncogene 1 (ROS1)-rearranged putative lung adenocarcinoma presenting as CUP showing a good response to ROS1 inhibitor therapy. A 55-year-old woman presented with neck lymphadenopathy. Computed tomography and [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) showed swelling of the bilateral supraclavicular, left accessory, mediastinal, and abdominal lymph nodes. The pathological analysis of the lymph node specimen biopsy indicated adenocarcinoma with cytokeratin 7 and thyroid transcription factor-1 positivity. Thus, this case was identified as ROS1- rearranged putative lung adenocarcinoma presenting as CUP. Oral crizotinib, an ROS1 inhibitor, was administered at a dose of 250 mg twice daily. Four weeks later, several swollen nodes showed marked improvement, and eight weeks later, FDG PET showed almost no uptake. In conclusion, putative lung adenocarcinoma presenting as CUP may involve ROS1 rearrangement, and ROS1 inhibitor therapy may be effective. PMID- 30443293 TI - Chemical modulation of autophagy as an adjunct to chemotherapy in childhood and adolescent brain tumors. AB - Brain tumors are the leading cause of cancer-related death in children and are the most challenging childhood cancer in relation to diagnosis, treatment, and outcome. One potential novel strategy to improve outcomes in cancer involves the manipulation of autophagy, a fundamental process in all cells. In cancer, autophagy can be thought of as having a "Janus"-like duality. On one face, especially in the early phases of cancer formation, autophagy can act as a cellular housekeeper to eliminate damaged organelles and recycle macromolecules, thus acting as tumor suppressor. On the other face, at later stages of tumor progression, autophagy can function as a pro-survival pathway in response to metabolic stresses such as nutrient depravation, hypoxia and indeed to chemotherapy itself, and can support cell growth by supplying much needed energy. In the context of chemotherapy, autophagy may, in some cases, mediate resistance to treatment. We present an overview of the relevance of autophagy in central nervous system tumors including how its chemical modulation can serve as a useful adjunct to chemotherapy, and use this knowledge to consider how targeting of autophagy may be relevant in pediatric brain tumors. PMID- 30443295 TI - Correction: Tumor driven by gain-of-function HER2 H878Y mutant is highly sensitive to HER2 inhibitor. AB - [This corrects the article DOI: 10.18632/oncotarget.5221.]. PMID- 30443296 TI - Correction: Overexpression of wildtype EGFR is tumorigenic and denotes a therapeutic target in non-small cell lung cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.6461.]. PMID- 30443298 TI - Erratum: Functional analysis of MKP-1 and MKP-2 in breast cancer tamoxifen sensitivity. AB - [This corrects the article DOI: 10.18632/oncotarget.1795.]. PMID- 30443297 TI - Correction: EGFR kinase domain mutation positive lung cancers are sensitive to intrapleural perfusion with hyperthermic chemotherapy (IPHC) complete treatment. AB - [This corrects the article DOI: 10.18632/oncotarget.6491.]. PMID- 30443299 TI - Comparative evaluation of platelet rich plasma in socket healing and bone regeneration after surgical removal of impacted mandibular third molars. AB - Background. Surgical removal of mandibular third molars results in pain, swelling and bony defects, causing prolonged postoperative recovery. The growth factors present in platelet-rich plasma (PRP) can accelerate the healing, thereby shortening postoperative recovery period. This study was undertaken to evaluate the role of PRP in postoperative socket healing, pain, swelling and bone regeneration following surgical removal of impacted mandibular third molars. Methods. The present case-control study was conducted on 20 patients with identical bilateral mandibular third molar impaction. PRP was placed randomly on one side of 3rd molar extraction socket and the contralateral side was used as control. Evaluation of soft tissue healing, pain, swelling and radiologic bone density was carried out. Results. Soft tissue healing was better in the PRP compared to the control site. Immediate postoperative assessment of pain scores showed no significant difference between the two groups (Mann-Whitney U test). On the 7th day, pain scores were lower in case site compared to the control site. Measurement of swelling on the 1st, 3rd and 7th day showed statistically significant differences between the case and control sites (P<0.0001). Postoperative mean bone density at the 3rd and 6th postoperative months was significantly higher in the case site compared to the control site (P=0.00001). Conclusion. The results showed an improvement in wound healing and swelling and an increase in the bone density at PRP site. The growth factors in PRP would improve the hard and soft tissue healing 3 months after molar surgery. PMID- 30443300 TI - Evaluation of the effect of IL-36gamma expression on chronic periodontitis by enhancing the MAPK and TLR4 signaling pathways: A basic research. AB - Background. Periodontitis is an infectious and inflammatory disease of the supporting tissues of the tooth caused by specific microorganisms or a group of microorganisms and, if not treated, leads to progressive degradation of the supporting tissues and subsequent loss of the teeth affected. The aim of this study was to evaluate the effects of IL-36gamma on periodontitis by enhancing the TLR4 and MAPK signaling pathways. Methods. In this pilot study, 50 patients with generalized moderate-to-severe chronic periodontitis and 50 individuals with healthy periodontium, who were candidates for crown lengthening (CL), were selected based on inclusion criteria. The tissue samples were taken during pocket depth surgery (for the test group) and CL surgery (for the control group). The macrophage cells of the inflammatory tissues were extracted and stimulated by TLR4 proteins in a time-dependent manner; then IL-36gamma levels in macrophages were investigated. Data were analyzed using descriptive statistics (means +/- standard deviations and frequency percentages). Repeat measurement test was used to compare IL36gamma expression in MAPK and TLR4 pathways at different time intervals. ANCOVA was used to compare IL36gamma expression at different time intervals between the two pathways. Statistical analysis was performed using SPSS 17 at a significance level of P<0.05. Results. The results of the current study showed a significant relation between TLR4 and IL-36gamma (P<0.001); in tissues with generalized moderate-to-severe chronic periodontitis, there was a significant relation between the condition and IL-36gamma (P<0.0001). This study also showed that TLR4 and MAPK levels increased in the presence of IL-36gamma. Conclusion. According to the present study, it was concluded that IL-36gamma concentrations increased in periodontitis, which could trigger MAPK and TLR4 pathways. PMID- 30443301 TI - Effect of periodontal therapy on maxillary sinus mucous membrane thickening in chronic periodontitis: A split-mouth study. AB - Background. This study evaluated the effect of periodontal therapy on mucous membrane thickening in maxillary sinus in chronic periodontitis patients using radiovisiography (RVG) and cone-beam computed tomography (CBCT). Methods. The study population included 30 patients diagnosed with chronic periodontitis, exhibiting bilateral mucosal thickening of maxillary sinus. The selected sites were randomly assigned to group I (control group - not receiving periodontal therapy) and group II (test group - receiving periodontal therapy). The clinical parameters and mucosal thickening of the maxillary sinus were evaluated at baseline and after 9 months. Results. There was a significant decrease in the PPD, CAL as well as mucosal thickening in group II while, group I showed an increase in these parameters. In group II at the end of 9 months the mean mucosal thickening reduction as assessed by CBCT was 0.76+/-0.18, 0.73+/-0.24, 0.88+/ 0.42 and 1.13+/-0.43 mm at the most anterior point (AP), the most posterior point (PP), the mid-point (MP), point of maximum thickness (MT) as well as in the length of the thickened mucosal lining, respectively. Conclusion. The results of our study indicated a reduction in the mucosal thickening of the maxillary sinus after surgical periodontal therapy. The trial was registered with the Clinical Trial Registry of India (Trial REF/ 2016/02/010805). PMID- 30443302 TI - Low serum vitamin D and early dental implant failure: Is there a connection? A retrospective clinical study on 1740 implants placed in 885 patients. AB - Background. Since osseointegration depends on bone metabolism, low levels of vitamin D in the blood may negatively affect bone formation around dental implants. To date, only a few studies have investigated the possible connection between serum levels of vitamin D and early dental implant failure (EDIF), i.e. failure that occurs within 4 months after placement, before the connection of the prosthetic abutment. The aim of this study was to investigate whether there is a relationship between low serum levels of vitamin D and EDIF. Methods. Data used for this retrospective study were derived from the records of a private dental clinic. Inclusion criteria were patients who had been treated with dental implants, inserted with a submerged technique from January 2003 to December 2017. EDIF was the outcome of this study. Chi-squared test was used to investigate the effect of patient-related variables (age, gender, smoking habit, history of periodontal disease and serum levels of vitamin D) on EDIF. Results. Originally, 885 patients treated with 1,740 fixtures were enrolled in this study. Overall, 35 EDIFs (3.9%) were reported. No correlation was found between EDIF and the patients' gender (P=0.998), age (P=0.832), smoking habit (P=0.473) or history of periodontal disease (P=0.386). Three EDIFs (11.1%) were reported in 27 patients with serum levels of vitamin D <10 ng/mL, 20 EDIFs (4.4%) in 448 patients with levels between 10 and 30 ng/mL, and 12 EDIFs (2.9%) in 410 patients with levels >30 ng/mL. Although there was a clear trend toward an increased incidence of EDIF with lowering of serum vitamin D levels, no statistically significant difference (P=0.105) was found among these three groups. Conclusion. Within its limitations (retrospective design, low number of patients with severe blood levels of vitamin D enrolled), this study failed to demonstrate a significant relationship between low serum levels of vitamin D and increased risk of EDIF. However, since a dramatic increase in EDIFs with lowering of vitamin D levels in the blood has been reported, further clinical studies with appropriate design (prospective or randomized controlled studies on a larger sample of severely deficient patients) are needed to better investigate this topic. PMID- 30443303 TI - Effect of lateral oblique cyclic loading on microleakage and screw loosening of implants with different connections. AB - Background. The implant connection type might affect microleakage and screw loosening in two-piece implants. The aim of this study was to measure microleakage and screw loosening of two connections of Noble Biocare implant system before and after cyclic loading. Methods. Twelve samples were categorized into two groups: external hexagon (Branemark) and internal hexagon connection (Noble Active) and two implants as controls. The abutments were tightened to a 35 Ncm torque. Initial torque loss (ITL) was measured five minutes after retightening the abutment, using a digital torque wrench. The samples were covered with putty material to the abutment-implant junction. Customized metal crowns with 45 degrees inclinations were placed on the abutments and cyclic loading was performed accordingly. Thereafter, the secondary torque loss (STL) was measured. Microleakage test was also performed. Data were analyzed with Mann Whitney and Wilcoxon tests (alpha=0.05). Results. There were no statistically significant differences between the two phases of gamma counting between and within two groups (P>0.05). However, STL after cyclic loading was less than ITL in both groups (P=0.042). Conclusion. Connection type and cyclic loading had no significant effect on microleakage. Furthermore, the internal connection had less TL as compared to the external connection. In addition, the STLs were less than ITLs in both groups. PMID- 30443304 TI - Comparison of the maximum hand-generated torque by professors and postgraduate dental students for tightening the abutment screws of dental implants. AB - Background. Dental implants are utilized with an ever-increasing rate. One of the causes of abutment screw loosening has been identified as inadequate preload. The objective behind this study was to compare the maximum hand-generated torque for tightening abutment screws by professors and postgraduate dental students using a digital torquemeter with 0.1 N/cm precision. Methods. In a laboratory study conducted in Dental Implant Department of Faculty of Dentistry, Tabriz University of Medical Sciences, the maximum hand-generated torque for tightening abutment screws by professors and postgraduate dental students was investigated, using a digital torquemeter with 0.1 N/cm precision. Results. The participants consisted of 36 (41.9%) females and 50 (58.1%) males, totaling 86 participants, of whom 45 (46.87%) and 41 (53.13%) were university professors and postgraduate dental students, respectively. The mean age of the participants was 33.4+/-10.2 years with an age range of 25-60 years; 50 (58.1%) participants were in the 25-34-year, 23 (26.7%) in the 35-47-year, and 13 (15.1%) in the 48-60-year age range. The mean age of professors and postgraduate dental students was 41+/-8.3 and 25.1+/ 3.3 years, respectively. The means of maximum torques generated by female and male professors were 14.3+/-3 and 20.8+/-4.2, respectively. The means of maximum torques generated by female and male postgraduate dental students were 14.7+/-3.4 and 18.7+/-4.3, respectively. Statistical analyses showed no significant differences between the mean maximum torques generated by professors and postgraduate dental students (P=0.051). Conclusion. In the present study, the mean maximum torque generated by professors was higher than that generated by postgraduate dental students. However, the difference was not statistically significant. The mean maximum torque generated by male subjects was significantly higher. No interaction was seen between the studied groups and sex. However, there was a statistically significant difference between the mean maximum torques generated in different age ranges; i.e., the maximum torque generated in the 25 34-year age range was lower than that in the other two age groups. Finally, the effect of age range on the mean maximum torque was similar in both groups. PMID- 30443305 TI - Effect of different periodontal ligament simulating materials on the incidence of dentinal cracks during root canal preparation. AB - Background. The present study was undertaken to evaluate the incidence of dentinal cracks during root canal preparation with different periodontal ligament simulating materials in vitro. Methods. Seventy freshly extracted human mandibular first premolars were selected and divided into 7 groups in terms of simulating material: group 1: polyether impression material; group 2: polyvinyl acetate adhesive; group 3: polyvinyl siloxane impression material; group 4: cyanoacrylate adhesive; group 5: epoxy resin adhesive; group 6: positive control, without any periodontal ligament simulation; and group 7: negative control, where neither a periodontal ligament simulating material was used nor canal preparation was carried out. Root canal preparation was carried out in all the groups followed by sectioning of roots at 3 mm, 6 mm and 9 mm. The sections were evaluated under a stereomicroscope at *2.5 for the presence or absence of cracks. Chi-squared test was used to compare the appearance of defective roots between the different experimental groups. Results. The least number of cracks were found in the negative control group, followed by group 1 where polyether impression material was used for periodontal ligament simulation. The difference was significant with a P-value of 0.002 for coronal sections. Conclusion. Under the limitation of the present study, polyether and polyvinyl siloxane (light body) can both be used for simulation of periodontal ligament. PMID- 30443306 TI - Effect of pH on solubility of white Mineral Trioxide Aggregate and Biodentine: An in vitro study. AB - Background. The aim of this study was to evaluate the effect of acidic, neutral and alkaline environments on the solubility of white mineral trioxide aggregate (WMTA) and Biodentine (BD). Methods. Thirty-nine ring molds were randomly divided into three groups of A, B, and C (n = 12) with pH values of 7.4, 4.4 and 10.4, respectively, and an empty mold was used as a control. Each group was further divided into two subgroups (1 and 2) according to the material studied. The samples in groups A, B and C were transferred into synthetic tissue fluid buffered at pH values of 7.4, 4.4 and 10.4, respectively, and kept in an incubator at 37 degrees C with 100% humidity. Daily solubility at 1-, 2-, 5-, 14 , 21-, and 30-day intervals and cumulative solubility up to 5-, 14-, and 30-day intervals were calculated. Statistical analysis was carried out with independent samples t-test, two-way ANOVA and post hoc Tukey tests using SPSS 18. Statistical significance was set at P<0.05. Results. Both WMTA and BD exhibited the highest solubility in acidic pH with 5.4235+/-0.1834 and 10.7516+/-0.0639 mean cumulative solubility values at 30-day interval, respectively. At all exposure times, BD was significantly more soluble than WMTA (P<0.001). Conclusion. Acidic periapical environment jeopardized the solubility of both WMTA and BD, affecting their sealing characteristics in clinical applications like perforation repair procedures and blunderbuss canals. PMID- 30443307 TI - Comparison of cyclic fatigue resistance of XP-endo Shaper, HyFlex CM, FlexMaster and Race instruments. AB - Background. The aim of this study was to compare the cyclic fatigue resistance of XP-endo Shaper, HyFlex CM, FlexMaster and Race rotary instruments at body temperature (37+/-1 degrees C). Methods. Twenty XP-endo Shaper (#30/.01), 20 HyFlex CM (#30/.04), 20 FlexMaster (#30/.04) and 20 Race (#30/.04) instruments were tested at body temperature (n=20). The instruments were evaluated in artificial canals with a 3-mm radius of curvature and 60 degrees angle of curvature to the center of the 1.5-mm-wide canal. Each instrument was rotated until fracture occurred and the number of cycles to failure (NCF) recorded. Data were analyzed using one-way ANOVA and Tukey HSD tests (P<0.05). Results. The difference in the NCF of all the instruments was statistically significant (P<0.05). The order of the instruments from the highest to the lowest NCF was as follows: XP-endo Shaper (3064.0+/-248.1), HyFlex CM (1120.5+/-106.1), FlexMaster (569.8+/-48.4) and Race (445.5+/-53.5). Conclusion. Under the limitations of the present study, XP-endo Shaper instruments were more resistant to cyclic fatigue than the #30/.04 nickel-titanium rotary instruments immersed in water at simulated body temperature. PMID- 30443308 TI - Comparative study of the usability of two software programs for visualization and analysis of digital orthodontic models. AB - Background. Software programs for visualization and analysis of digital orthodontic models, apart from presenting the necessary features for diagnosis and treatment planning, also need to be user-friendly. This characteristic refers to software' usability, a measure that evaluates how easy it is to use it is by a specific group of professionals. The aim of this study was to compare the usability of free available versions of two software programs for visualization and analysis of digital orthodontic models. Methods. Digimodel(r) and OrthoCAD(r) usability were evaluated through their interface analysis and executing the following procedures: malocclusion classification and models analysis (arch length and tooth-size discrepancies). Results. Digimodel(r) and OrthoCAD(r) software programs had an installer only for Windows platform, occupied less than 110 megabytes of virtual space and only read files from their respective manufacturers. None possessed Portuguese as a language option. Both allowed visualization of the models in different axes through options present in initial screen, at a click. For model analysis, both software programs required to measure tooth to tooth and performed necessary calculations automatically. However, OrthoCAD(r) software program was less intuitive because the option for these actions was among several others, within menus, which could cause confusion during navigation. In addition, the marking of points did not always obey the clicked site. Conclusion. The free access version of the evaluated software programs exhibited usability limitations related to language, supported file format and even the model analysis execution for orthodontic diagnosis. Although OrthoCAD(r) was inferior, both did not meet orthodontists' clinical demand against these factors in the evaluated versions. PMID- 30443309 TI - Comparison of sedative effects of oral midazolam/chloral hydrate and midazolam/promethazine in pediatric dentistry. AB - Background. The aim of this investigation was to compare the sedative effects of oral midazolam/chloral hydrate and midazolam/promethazine combinations on fearful children needing dental treatment. Methods. This crossover double-blind clinical trial was conducted on 30 children aged 2-6 years, who had at least two similar teeth needing pulp treatment. Standard vital signs were recorded before and after premedication. Wilson sedation scale was used to judge the level of sedation. Cases were divided into two groups based on the sequence of medication received. This was to overcome the sequence effect. Group I received oral midazolam (0.4 mg/kg/chloral hydrate (50 mg/kg) at the first visit while they received midazolam (0.4 mg/kg)/promethazine (5 mg/kg) in their second visit. Group II received the premedication in the opposite sequence. The operator and child were blinded to the medication administered. Sedative efficacy of the two combinations were assessed and judged by two independent pediatric dentists based on the Wilson scale. Data were analyzed with ANOVA and paired t-test. Results. Only 10% of children who received chloral hydrate with midazolam exhibited high improvement in their behavior while 53% showed reasonable positive changes and 12% had no change or even deterioration of behavior. The difference between the effect of the two combination drugs was statistically significant (P<0.05) in favor of the chloral hydrate group. Conclusion. The results showed a significant difference in the sedation level induced between the two groups. Midazolam/chloral hydrate combination more effectively improved the co-operation for dental treatment. PMID- 30443310 TI - An innovative technique for palatal reservoir construction in complete dentures: A case report. AB - The retention and comfort of wearing prosthesis mainly depends on saliva. In reduced saliva conditions, such as xerostomia or radiation therapy, the oral mucosa tends to become dry and ulcerated, leading to the patient's inability to retain the prosthesis. Various techniques have been reported in the literature regarding the use of a reservoir with holes in dentures. The results have not been satisfactory because the flow of the salivary substitute could not be controlled and with frequent cleaning of the denture being necassary to maintain the patency of the reservoir holes. A newer technique for incorporation of a palatal reservoir with controlled artificial salivary flow in complete denture is being explained in this article, which improved the denture retention, comfort, mastication and speech of the patient. PMID- 30443313 TI - Synchronous volvulus of the sigmoid and transverse colon in a 26-year-old male. AB - We present a 26-year-old male patient who presented with complete bowel obstruction and peritonitis. His abdominal X-rays showed grossly distended large bowels with air-fluid levels. A differential diagnosis of sigmoid volvulus was entertained and the patient was taken for an exploratory laparotomy. Intraoperatively, we found a sigmoid volvulus and a concurrent transverse colon volvulus. A subtotal colectomy and colostomy was performed. The histopathology results showed mucosal and submucosal congestion, chronic inflammation, and no malignancy or dysplasia. Synchronous volvulus of the sigmoid and transverse colon is an extremely rare. Management includes endoscopic derotation and decompression followed by semi-elective surgery in non-complicated cases. When endoscopic decompression has failed or there is suspicion of necrosis or perforation, surgery is mandatory. PMID- 30443312 TI - Necrotizing fasciitis caused by Kocuria rosea in an immunocompromised patient. AB - This case report describes an immunocompromised patient with a skin boil that progressed to necrotizing fasciitis. The aim of this brief report is to raise awareness regarding necrotizing soft tissue infections caused by an unusual organism, Kocuria rosea, a typically non-pathogenic organism, and outline the course of treatment currently considered to be the standard of care. PMID- 30443311 TI - Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model. AB - Background: Altered neuronal development is discussed as the underlying pathogenic mechanism of autism spectrum disorders (ASD). Copy number variations of 16p11.2 have recurrently been identified in individuals with ASD. Of the 29 genes within this region, quinolinate phosphoribosyltransferase (QPRT) showed the strongest regulation during neuronal differentiation of SH-SY5Y neuroblastoma cells. We hypothesized a causal relation between this tryptophan metabolism related enzyme and neuronal differentiation. We thus analyzed the effect of QPRT on the differentiation of SH-SY5Y and specifically focused on neuronal morphology, metabolites of the tryptophan pathway, and the neurodevelopmental transcriptome. Methods: The gene dosage-dependent change of QPRT expression following Chr16p11.2 deletion was investigated in a lymphoblastoid cell line (LCL) of a deletion carrier and compared to his non-carrier parents. Expression of QPRT was tested for correlation with neuromorphology in SH-SY5Y cells. QPRT function was inhibited in SH-SY5Y neuroblastoma cells using (i) siRNA knockdown (KD), (ii) chemical mimicking of loss of QPRT, and (iii) complete CRISPR/Cas9 mediated knock out (KO). QPRT-KD cells underwent morphological analysis. Chemically inhibited and QPRT-KO cells were characterized using viability assays. Additionally, QPRT-KO cells underwent metabolite and whole transcriptome analyses. Genes differentially expressed upon KO of QPRT were tested for enrichment in biological processes and co-regulated gene-networks of the human brain. Results: QPRT expression was reduced in the LCL of the deletion carrier and significantly correlated with the neuritic complexity of SH-SY5Y. The reduction of QPRT altered neuronal morphology of differentiated SH-SY5Y cells. Chemical inhibition as well as complete KO of the gene were lethal upon induction of neuronal differentiation, but not proliferation. The QPRT-associated tryptophan pathway was not affected by KO. At the transcriptome level, genes linked to neurodevelopmental processes and synaptic structures were affected. Differentially regulated genes were enriched for ASD candidates, and co-regulated gene networks were implicated in the development of the dorsolateral prefrontal cortex, the hippocampus, and the amygdala. Conclusions: In this study, QPRT was causally related to in vitro neuronal differentiation of SH-SY5Y cells and affected the regulation of genes and gene networks previously implicated in ASD. Thus, our data suggest that QPRT may play an important role in the pathogenesis of ASD in Chr16p11.2 deletion carriers. PMID- 30443315 TI - Colonic perforation due to amebiasis, a rare and lethal complication. AB - Amebiasis is still a major healthcare concern, especially in developing countries like Ecuador. The lack of sanitary control and hygiene measures make parasites infections still a burden for patients and physicians. Despite infections due to this parasites are usually mild, severe infections and fatal outcomes although rare still occur. Bowel perforation is a rare complication of amebiasis, and unfortunately, it continues to be almost fatal. We present a case of an Ecuadorian patient who presented to the emergency room with an acute abdomen, despite adequate surgery and critical care, the patient regrettably died. Bowel perforation due to Entamoeba histolytica was the final diagnosis. PMID- 30443314 TI - Hybrid method with explorative laparoscopy and anterior open approach for re recurrent inguinal hernia. AB - The new guidelines of the HerniaSurge group recommend that only an expert hernia surgeon should repair a re-recurrent inguinal hernia. We report the efficacy of the hybrid method with explorative laparoscopy and anterior open approach for re recurrent inguinal hernia repair. A 61-year-old man underwent anterior open preperitoneal mesh repair for right inguinal direct hernia and laparoscopic transabdominal preperitoneal repair for recurrence. Two years after the second surgery, re-recurrent inguinal hernia was confirmed. We carried out explorative laparoscopy for the re-recurrent inguinal hernia, which revealed a re-recurrent hernia orifice. We performed the anterior open approach while observing from the abdominal cavity. Explorative laparoscopy can help in accurately determining the orifice of the re-recurrent inguinal hernia. Based on that information, the hernia sac can be reached through the shortest route using the anterior open approach. PMID- 30443316 TI - Two cases of intestinal injuries due to seat belt without seat belt sign. AB - Although seat belts save lives after motor vehicle accidents, they may cause different types of injuries such as abdominal wall, intra-abdominal, neck and spine or vascular injuries. Seat belt sign indicates the severity of injuries, and usually the risk of intra-abdominal injuries is high when the seat belt sign exists. Here, we present two cases of intra-abdominal injuries caused by seat belts without seat belt sign. PMID- 30443317 TI - Objective demonstration of improvement of neurogenic bowel dysfunction in a case of spinal cord injury following stem cell therapy. AB - Constipation in spinal cord injury patients is a frequent complication that leads to a reduction of quality of life, extensive psychological and economic strain on patients and healthcare systems. We report a 58-year-old man with an incomplete SCI secondary to L1 vertebral fracture, presented gait disorder with neurogenic bowel and bladder dysfunction. He received 300 million autologous mesenchymal stromal cells (MSC) in the subarachnoid space by lumbar puncture. After the third administration of MSC the patient had an important improvement in almost every functional scale of spinal cord injury, especially in the Krogh's Neurogenic Bowel Dysfunction scale. Our present observation supports recent clinical findings about the benefit of autologous stem cell therapy for the improvement of bowel dysfunction in patients suffering spinal cord injury. PMID- 30443318 TI - Additional unloading of the left ventricle using the Impella LP 2.5 during extracorporeal life support in cases of pulmonary congestion. AB - Extracorporeal life support (ECLS) is used for the treatment of severe cardiogenic shock. However, pulmonary congestion can progress to a severe problem with ECLS therapy. We report our experience with the Impella system for severe pulmonary congestion with ECLS therapy. We used the Impella system for two patients, which led to successful unloading of the left ventricle. Impella implantation during ECLS support appears to be a promising concept. However, more evidence is required for further evaluation. PMID- 30443319 TI - Large intra-abdominal desmoid tumour posing diagnostic and therapeutic challenges, a case report. AB - We present the case of a 46-year-old gentleman originally from China who presented to the acute surgical assessment unit complaining of upper abdominal discomfort, dyspepsia and early satiety ongoing for the previous 6 months. On exam he had a palpable mass in the left upper quadrant. He underwent an esophagogastroduodenoscopy which was normal and later received a CT abdomen which identified a well-circumscribed soft tissue mass in the mesenteric fat and lying adjacent to the transverse colon with no obvious cleavage plane between them. Colonoscopy was then performed which was normal. After discussion at MDT he was taken for laparotomy. At laparotomy the mass was found to be adherent to major vessels, small bowel and large bowel necessitating an extended right hemicolectomy and small bowel resection. The mass itself could not be completely excised. Histology from the resected specimen confirmed desmoid tumour. PMID- 30443320 TI - A nutrition problem solved by a two-step endoscopic removal of a non-adjustable gastric band. AB - Bariatric surgery is an effective approach for weight loss and short-term improvement in metabolic disorders. Stenosis is a common complication of gastric banding. Balloon dilatation or gastrotomy has been employed in this setting. Few studies have indicated endoscopic removal of the band a feasible procedure. We present a 60-year-old female who underwent gastric banding in 1985 and suffered from late stenosis and malnutrition. Endoscopy revealed a severe stenosis. A two step procedure was performed. Initially a coated stent was placed into the stenosis to achieve pressure necrosis. Two weeks later, the stent was removed and the band was removed endoscopically. The procedure was performed without any complications. The patient was discharged the next day. A follow-up after 2 months revealed no problems with stenosis or malnutrition. The procedure was a safe, efficient and convenient way of handling late stenosis after gastric banding. PMID- 30443321 TI - Compound volvulus: a case report and literature review. AB - Compound volvulus is an uncommon cause of acute abdomen and involves the twisting of the loops of ileum around the base of the sigmoid or vice versa. It is a surgical emergency that is often missed pre-operatively. We are reporting this case and reviewing the relevant literature to increase the awareness of this condition. A 37-year-old female presented at the Emergency Unit of our hospital with features thought to be acute peritonitis secondary to typhoid perforation and a differential of rupture appendix. She had laparotomy with the finding of a gangrenous twisted terminal ileum around the base of the sigmoid for which a right hemicolectomy and sigmoidopexy were done. Compound volvulus, though rare, can still be encountered in our environment. Prompt identification, adequate resuscitation and expedient intervention will reduce morbidity and mortality. PMID- 30443322 TI - Right external iliac artery thrombus following the use of resuscitative endovascular balloon occlusion of the aorta for placenta accreta. AB - A 33-year-old female, 32 weeks and 1 day gestation, with known placenta accreta who presented to the emergency department with 2 h of severe abdominal pain, nausea and vomiting. She became hypotensive and underwent emergency cesarean section. Emergency general surgery was consulted for placement of a resuscitative endovascular balloon for aortic occlusion (REBOA). After successful delivery, the balloon was inflated in zone 3 and systolic blood pressure rose from 70 to 170 mmHg. The patient underwent hysterectomy for ongoing hemorrhage. The patient was taken to the surgical intensive care unit. The patient was noted to have pulses following removal of the sheath. Arterial brachial indices and arterial duplex was performed 48 h after sheath removal. The patient was found to have complete occlusion of the right external iliac artery. Vascular surgery was consulted and cut-down performed with thrombus removal via fogarty catheter. The patient was discharged 2 days later without further complication. PMID- 30443323 TI - Hemorrhagic necrosis of small bowel following small bowel obstruction as a late complication of sex reassignment surgery-a gap in transgender care. AB - For decades, Thailand has been at the forefront of sex reassignment surgeries. The neovagina created by recto-sigmoid vaginoplasty is much more complex procedure when compared with penile skin version technique, but yielded more satisfactory functional outcomes. We reported an unusual case of life-threatening small bowel obstruction following previously successful recto-sigmoid vaginoplasty in a transgender woman. Transgender individuals have unique healthcare needs. However, various gaps still exist to provide multi-disciplinary care for these patients. The rate of adhesive small bowel obstruction is highest in the early period of any intra-abdominal post-operative surgeries, but the risk remains life-long. Transgender women receiving complicated vaginoplasty should be instructed to continue long-term follow-up to ensure early detection and management of post-operative complications. PMID- 30443325 TI - Functionalizing cell-mimetic giant vesicles with encapsulated bacterial biosensors. AB - The design of vesicle microsystems as artificial cells (bottom-up synthetic biology) has traditionally relied on the incorporation of molecular components to impart functionality. These cell mimics have reduced capabilities compared with their engineered biological counterparts (top-down synthetic biology), as they lack the powerful metabolic and regulatory pathways associated with living systems. There is increasing scope for using whole intact cellular components as functional modules within artificial cells, as a route to increase the capabilities of artificial cells. In this feasibility study, we design and embed genetically engineered microbes (Escherichia coli) in a vesicle-based cell mimic and use them as biosensing modules for real-time monitoring of lactate in the external environment. Using this conceptual framework, the functionality of other microbial devices can be conferred into vesicle microsystems in the future, bridging the gap between bottom-up and top-down synthetic biology. PMID- 30443324 TI - The hallmarks of living systems: towards creating artificial cells. AB - Despite the astonishing diversity and complexity of living systems, they all share five common hallmarks: compartmentalization, growth and division, information processing, energy transduction and adaptability. In this review, we give not only examples of how cells satisfy these requirements for life and the ways in which it is possible to emulate these characteristics in engineered platforms, but also the gaps that remain to be bridged. The bottom-up synthesis of life-like systems continues to be driven forward by the advent of new technologies, by the discovery of biological phenomena through their transplantation to experimentally simpler constructs and by providing insights into one of the oldest questions posed by mankind, the origin of life on Earth. PMID- 30443327 TI - Urea-mediated anomalous diffusion in supported lipid bilayers. AB - Diffusion in biological membranes is seldom simply Brownian motion; instead, the rate of diffusion is dependent on the time scale of observation and so is often described as anomalous. In order to help better understand this phenomenon, model systems are needed where the anomalous diffusion of the lipid bilayer can be tuned and quantified. We recently demonstrated one such model by controlling the excluded area fraction in supported lipid bilayers (SLBs) through the incorporation of lipids derivatized with polyethylene glycol. Here, we extend this work, using urea to induce anomalous diffusion in SLBs. By tuning incubation time and urea concentration, we produce bilayers that exhibit anomalous behaviour on the same scale as that observed in biological membranes. PMID- 30443326 TI - Human ubiquitin-like proteins as central coordinators in autophagy. AB - Autophagy is one of the most versatile recycling systems of eukaryotic cells. It degrades diverse cytoplasmic components such as organelles, protein aggregates, ribosomes and multi-enzyme complexes. Not surprisingly, any failure of autophagy or reduced activity of the pathway contributes to the onset of various pathologies, including neurodegeneration, cancer and metabolic disorders such as diabetes or immune diseases. Furthermore, autophagy contributes to the innate immune response and combats bacterial or viral pathogens. The hallmark of macroautophagy is the formation of a membrane sack that sequesters cytoplasmic cargo and delivers it to lysosomes for degradation. More than 40 autophagy related (ATG) proteins have so far been identified. A unique protein-conjugation system represents one of the core components of this highly elaborate machinery. It conjugates six homologous ATG8 family proteins to the autophagic membrane. In this review, we summarize the current knowledge regarding the various functions of ATG8 proteins in autophagy and briefly discuss how physical approaches and in vitro reconstitution contributed in deciphering their function. PMID- 30443329 TI - Membrane remodelling by a lipidated endosomal sorting complex required for transport-III chimera, in vitro. AB - The complexity of eukaryotic cells is underscored by the compartmentalization of chemical signals by phospholipid membranes. A grand challenge of synthetic biology is building life from the 'bottom-up', for the purpose of generating systems simple enough to precisely interrogate biological pathways or for adapting biology to perform entirely novel functions. Achieving compartmentalization of chemistries in an addressable manner is a task exquisitely refined by nature and embodied in a unique membrane remodelling machinery that pushes membranes away from the cytosol, the ESCRT-III (endosomal sorting complex required for transport-III) complex. Here, we show efforts to engineer a single ESCRT-III protein merging functional features from its different components. The activity of such a designed ESCRT-III is shown by its ability to drive the formation of compartments encapsulating fluorescent cargo. It appears that the modular nature of ESCRT-III allows its functional repurposing into a minimal machinery that performs sophisticated membrane remodelling, therefore enabling its use to create eukaryotic-like multi-compartment architectures. PMID- 30443331 TI - From statistical inference to a differential learning rule for stochastic neural networks. AB - Stochastic neural networks are a prototypical computational device able to build a probabilistic representation of an ensemble of external stimuli. Building on the relationship between inference and learning, we derive a synaptic plasticity rule that relies only on delayed activity correlations, and that shows a number of remarkable features. Our delayed-correlations matching (DCM) rule satisfies some basic requirements for biological feasibility: finite and noisy afferent signals, Dale's principle and asymmetry of synaptic connections, locality of the weight update computations. Nevertheless, the DCM rule is capable of storing a large, extensive number of patterns as attractors in a stochastic recurrent neural network, under general scenarios without requiring any modification: it can deal with correlated patterns, a broad range of architectures (with or without hidden neuronal states), one-shot learning with the palimpsest property, all the while avoiding the proliferation of spurious attractors. When hidden units are present, our learning rule can be employed to construct Boltzmann machine-like generative models, exploiting the addition of hidden neurons in feature extraction and classification tasks. PMID- 30443330 TI - Towards fungal computer. AB - We propose that fungi Basidiomycetes can be used as computing devices: information is represented by spikes of electrical activity, a computation is implemented in a mycelium network and an interface is realized via fruit bodies. In a series of scoping experiments, we demonstrate that electrical activity recorded on fruits might act as a reliable indicator of the fungi's response to thermal and chemical stimulation. A stimulation of a fruit is reflected in changes of electrical activity of other fruits of a cluster, i.e. there is distant information transfer between fungal fruit bodies. In an automaton model of a fungal computer, we show how to implement computation with fungi and demonstrate that a structure of logical functions computed is determined by mycelium geometry. PMID- 30443328 TI - Liquid-liquid phase separation in artificial cells. AB - Liquid-liquid phase separation (LLPS) in biology is a recently appreciated means of intracellular compartmentalization. Because the mechanisms driving phase separations are grounded in physical interactions, they can be recreated within less complex systems consisting of only a few simple components, to serve as artificial microcompartments. Within these simple systems, the effect of compartmentalization and microenvironments upon biological reactions and processes can be studied. This review will explore several approaches to incorporating LLPS as artificial cytoplasms and in artificial cells, including both segregative and associative phase separation. PMID- 30443332 TI - Something has to give: scaling combinatorial computing by biological agents exploring physical networks encoding NP-complete problems. AB - On-chip network-based computation, using biological agents, is a new hardware embedded approach which attempts to find solutions to combinatorial problems, in principle, in a shorter time than the fast, but sequential electronic computers. This analytical review starts by describing the underlying mathematical principles, presents several types of combinatorial (including NP-complete) problems and shows current implementations of proof of principle developments. Taking the subset sum problem as example for in-depth analysis, the review presents various options of computing agents, and compares several possible operation 'run modes' of network-based computer systems. Given the brute force approach of network-based systems for solving a problem of input size C, 2C solutions must be visited. As this exponentially increasing workload needs to be distributed in space, time, and per computing agent, this review identifies the scaling-related key technological challenges in terms of chip fabrication, readout reliability and energy efficiency. The estimated computing time of massively parallel or combinatorially operating biological agents is then compared to that of electronic computers. Among future developments which could considerably improve network-based computing, labelling agents 'on the fly' and the readout of their travel history at network exits could offer promising avenues for finding hardware-embedded solutions to combinatorial problems. PMID- 30443333 TI - Thermodynamic efficiency of contagions: a statistical mechanical analysis of the SIS epidemic model. AB - We present a novel approach to the study of epidemics on networks as thermodynamic phenomena, quantifying the thermodynamic efficiency of contagions, considered as distributed computational processes. Modelling SIS dynamics on a contact network statistical-mechanically, we follow the maximum entropy (MaxEnt) principle to obtain steady-state distributions and derive, under certain assumptions, relevant thermodynamic quantities both analytically and numerically. In particular, we obtain closed-form solutions for some cases, while interpreting key epidemic variables, such as the reproductive ratio of a SIS model, in a statistical mechanical setting. On the other hand, we consider configuration and free entropy, as well as the Fisher information, in the epidemiological context. This allowed us to identify criticality and distinct phases of epidemic processes. For each of the considered thermodynamic quantities, we compare the analytical solutions informed by the MaxEnt principle with the numerical estimates for SIS epidemics simulated on Watts-Strogatz random graphs. PMID- 30443334 TI - A thermodynamically consistent model of finite-state machines. AB - Finite-state machines (FSMs) are a theoretically and practically important model of computation. We propose a general, thermodynamically consistent model of FSMs and characterize the resource requirements of these machines. We model FSMs as time-inhomogeneous Markov chains. The computation is driven by instantaneous manipulations of the energy levels of the states. We calculate the entropy production of the machine, its error probability, and the time required to complete one update step. We find that a sequence of generalized bit-setting operations is sufficient to implement any FSM. PMID- 30443335 TI - Computational modelling unravels the precise clockwork of cyanobacteria. AB - Precisely timing the regulation of gene expression by anticipating recurring environmental changes is a fundamental part of global gene regulation. Circadian clocks are one form of this regulation, which is found in both eukaryotes and prokaryotes, providing a fitness advantage for these organisms. Whereas many different eukaryotic groups harbour circadian clocks, cyanobacteria are the only known oxygenic phototrophic prokaryotes to regulate large parts of their genes in a circadian fashion. A decade of intensive research on the mechanisms and functionality using computational and mathematical approaches in addition to the detailed biochemical and biophysical understanding make this the best understood circadian clock. Here, we summarize the findings and insights into various parts of the cyanobacterial circadian clock made by mathematical modelling. These findings have implications for eukaryotic circadian research as well as synthetic biology harnessing the power and efficiency of global gene regulation. PMID- 30443336 TI - Intrinsic limits of information transmission in biochemical signalling motifs. AB - All living things have evolved to sense changes in their environment in order to respond in adaptive ways. At the cellular level, these sensing systems generally involve receptor molecules at the cell surface, which detect changes outside the cell and relay those changes to the appropriate response elements downstream. With the advent of experimental technologies that can track signalling at the single-cell level, it has become clear that many signalling systems exhibit significant levels of 'noise,' manifesting as differential responses of otherwise identical cells to the same environment. This noise has a large impact on the capacity of cell signalling networks to transmit information from the environment. Application of information theory to experimental data has found that all systems studied to date encode less than 2.5 bits of information, with the majority transmitting significantly less than 1 bit. Given the growing interest in applying information theory to biological data, it is crucial to understand whether the low values observed to date represent some sort of intrinsic limit on information flow given the inherently stochastic nature of biochemical signalling events. In this work, we used a series of computational models to explore how much information a variety of common 'signalling motifs' can encode. We found that the majority of these motifs, which serve as the basic building blocks of cell signalling networks, can encode far more information (4-6 bits) than has ever been observed experimentally. In addition to providing a consistent framework for estimating information-theoretic quantities from experimental data, our findings suggest that the low levels of information flow observed so far in living system are not necessarily due to intrinsic limitations. Further experimental work will be needed to understand whether certain cell signalling systems actually can approach the intrinsic limits described here, and to understand the sources and purpose of the variation that reduces information flow in living cells. PMID- 30443337 TI - Haematopoietic stem cells: entropic landscapes of differentiation. AB - The metaphor of a potential epigenetic differentiation landscape broadly suggests that during differentiation a stem cell approaches a stable equilibrium state from a higher free energy towards a stable equilibrium state which represents the final cell type. It has been conjectured that there is an analogy to the concept of entropy in statistical mechanics. In this context, in the undifferentiated state, the entropy would be large since fewer constraints exist on the gene expression programmes of the cell. As differentiation progresses, gene expression programmes become more and more constrained and thus the entropy would be expected to decrease. In order to assess these predictions, we compute the Shannon entropy for time-resolved single-cell gene expression data in two different experimental set-ups of haematopoietic differentiation. We find that the behaviour of this entropy measure is in contrast to these predictions. In particular, we find that the Shannon entropy is not a decreasing function of developmental pseudo-time but instead it increases towards the time point of commitment before decreasing again. This behaviour is consistent with an increase in gene expression disorder observed in populations sampled at the time point of commitment. Single cells in these populations exhibit different combinations of regulator activity that suggest the presence of multiple configurations of a potential differentiation network as a result of multiple entry points into the committed state. PMID- 30443338 TI - Semantic information, autonomous agency and non-equilibrium statistical physics. AB - Shannon information theory provides various measures of so-called syntactic information, which reflect the amount of statistical correlation between systems. By contrast, the concept of 'semantic information' refers to those correlations which carry significance or 'meaning' for a given system. Semantic information plays an important role in many fields, including biology, cognitive science and philosophy, and there has been a long-standing interest in formulating a broadly applicable and formal theory of semantic information. In this paper, we introduce such a theory. We define semantic information as the syntactic information that a physical system has about its environment which is causally necessary for the system to maintain its own existence. 'Causal necessity' is defined in terms of counter-factual interventions which scramble correlations between the system and its environment, while 'maintaining existence' is defined in terms of the system's ability to keep itself in a low entropy state. We also use recent results in non-equilibrium statistical physics to analyse semantic information from a thermodynamic point of view. Our framework is grounded in the intrinsic dynamics of a system coupled to an environment, and is applicable to any physical system, living or otherwise. It leads to formal definitions of several concepts that have been intuitively understood to be related to semantic information, including 'value of information', 'semantic content' and 'agency'. PMID- 30443340 TI - Recent advances in understanding and managing myasthenia gravis. AB - Autoimmune myasthenia gravis (MG) is a neuromuscular junction disorder marked clinically by fatigable muscle weakness and serologically by the presence of autoantibodies against acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), or lipoprotein-related protein 4 (LPR4). Over the past few decades, the mortality of patients with MG has seen a dramatic decline secondary to evolving interventions in critical care and medical management. In the past 2 to 3 years, there have been several changes in standard of care for the treatment of MG. These changes include confirmation of the benefit of thymectomy versus medical management alone in AChR patients and a new US Food and Drug Administration approved medication for refractory MG. There are also several exciting new prospective drugs in the pipeline, which are in different stages of clinical trial testing. PMID- 30443339 TI - Maternal immunisation: What have been the gains? Where are the gaps? What does the future hold? AB - The vaccination of pregnant women has enormous potential to protect not only mothers from vaccine-preventable diseases but also their infants through the passive acquisition of protective antibodies before they are able to themselves acquire protection through active childhood immunisations. Maternal tetanus programmes have been in place since 1989, and as of March 2018, only 14 countries in the world were still to reach maternal neonatal tetanus elimination status. This has saved hundreds of thousands of lives. Building on this success, influenza- and pertussis-containing vaccines have been recommended for pregnant women and introduced into immunisation programmes, albeit predominantly in resource-rich settings. These have highlighted some important challenges when additional immunisations are introduced into the antenatal context. With new vaccine candidates, such as respiratory syncytial virus (RSV) and group B streptococcus (GBS), on the horizon, it is important that we learn from these experiences, identify the information gaps, and close these to ensure safe and successful implementation of maternal vaccines in the future, particularly in low and middle-income countries with a high burden of disease. PMID- 29707204 TI - Loss of Zbtb32 in NOD mice does not significantly alter T cell responses. AB - Background : We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2 + dendritic cells (DCs) in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2 + DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production. Methods : To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis. Results : Although NOD.Zbtb32 -/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly, in vitro stimulation of lymphocytes from NOD.Zbtb32 -/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes. Conclusions : The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype. PMID- 30443344 TI - Association between intensity of STI screening and development of antimicrobial resistance in N. gonorrhoeae in 12 cities in the USA: An ecological study. AB - In this study, we assessed if there was a city-level association between sexually transmitted infection (STI) screening intensity in men who have sex with men and antimicrobial sensitivity in Neisseria gonorrhoeae in the United States, 2007 to 2013. We found positive associations between STI screening intensity and increases in minimum inhibitory concentrations for cefixime and azithromycin, but not ceftriaxone. PMID- 30443341 TI - Clinical management of herpes simplex virus infections: past, present, and future. AB - Infection with herpes simplex virus (HSV) types 1 and 2 is ubiquitous in the human population. Most commonly, virus replication is limited to the epithelia and establishes latency in enervating sensory neurons, reactivating periodically to produce localized recurrent lesions. However, these viruses can also cause severe disease such as recurrent keratitis leading potentially to blindness, as well as encephalitis, and systemic disease in neonates and immunocompromised patients. Although antiviral therapy has allowed continual and substantial improvement in the management of both primary and recurrent infections, resistance to currently available drugs and long-term toxicity pose a current and future threat that should be addressed through the development of new antiviral compounds directed against new targets. The development of several promising HSV vaccines has been terminated recently because of modest or controversial therapeutic effects in humans. Nevertheless, several exciting vaccine candidates remain in the pipeline and are effective in animal models; these must also be tested in humans for sufficient therapeutic effects to warrant continued development. Approaches using compounds that modulate the chromatin state of the viral genome to suppress infection and reactivation or induce enhanced antiviral immunity have potential. In addition, technologies such as CRISPR/Cas9 have the potential to edit latent viral DNA in sensory neurons, potentially curing the neuron and patient of latent infection. It is hoped that development on all three fronts-antivirals, vaccines, and gene editing-will lead to substantially less HSV morbidity in the future. PMID- 30443343 TI - Using different methods to process forced expiratory volume in one second (FEV 1) data can impact on the interpretation of FEV 1 as an outcome measure to understand the performance of an adult cystic fibrosis centre: A retrospective chart review. AB - Background: Forced expiratory volume in one second (FEV 1) is an important cystic fibrosis (CF) prognostic marker and an established endpoint for CF clinical trials. FEV 1 is also used in observation studies, e.g. to compare different centre's outcomes. We wished to evaluate whether different methods of processing FEV 1 data can impact on a centre's outcome. Methods: This is a single-centre retrospective analysis of routinely collected data from 2013-2016 which included 208 adults with CF. Year-to-year %FEV 1 change was calculated by subtracting best %FEV 1 at Year 1 from Year 2 (i.e. negative values indicate %FEV 1 decline), and compared using Friedman test. Three methods were used to process %FEV 1 data. First, %FEV 1 calculated with Knudson equation was extracted directly from spirometer machines. Second, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and Knudson equation. Third, FEV 1 volume were extracted then converted to %FEV 1 using clean height data and GLI equation. In addition, %FEV 1 decline calculated using GLI equation was adjusted for baseline %FEV 1 to understand the impact of case-mix adjustment. Results: There was a trend of reduction in %FEV 1 decline with all three data processing methods but the magnitude of %FEV 1 decline differed. Median change in %FEV 1 for 2013-2014, 2014 2015 and 2015-2016 was -2.0, -1.0 and 0.0 respectively using %FEV 1 in Knudson equation whereas the median change was -1.1, -0.9 and -0.3 respectively using %FEV 1 in the GLI equation. A statistically significant p-value (0.016) was only obtained when using %FEV 1 in Knudson equation extracted directly from spirometer machines. Conclusions: Although the trend of reduction in %FEV 1 decline was robust, different data processing methods yielded varying results when %FEV 1 decline was compared using a standard related group non-parametric statistical test. Observational studies with %FEV 1 decline as an outcome measure should carefully consider and clearly specify the data processing methods used. PMID- 30443346 TI - Historical watershed stressors for the Laurentian Great Lakes. AB - : This report provides a detailed set of historical stressor data for 60 watersheds comprising the Laurentian Great Lakes basin. Archival records were transcribed from public records to create quantitative data on human activities: population, mining, deforestation, and agriculture. Yearly records of stressors are provided from 1780 through 2010. These data may be used to track historical impacts on Great Lakes coastal and open water conditions. They may further be used to examine corresponding effects on response variables such as biological communities quantified during monitoring and palaeoecological programmes. Open Practices: This article has earned an Open Data badge for making publicly available the digitally-shareable data necessary to reproduce the reported results. The data is available at https://doi.org/10.1594/PANGAEA.885879. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki. PMID- 30443345 TI - Alterations of brain local functional connectivity in amnestic mild cognitive impairment. AB - Background: Resting-state functional magnetic resonance imaging studies using a regional homogeneity (ReHo) method have reported that amnestic mild cognitive impairment (aMCI) was associated with abnormalities in local functional connectivity. However, their results were not conclusive. Methods: Seed-based d Mapping was used to conduct a coordinate-based meta-analysis to identify consistent ReHo alterations in aMCI. Results: We identified 10 studies with 11 datasets suitable for inclusion, including 378 patients with aMCI and 435 healthy controls. This meta-analysis identified significant ReHo alterations in patients with aMCI relative to healthy controls, mainly within the default mode network (DMN) (bilateral posterior cingulate cortex [PCC], right angular gyrus, bilateral middle temporal gyri, and left parahippocampal gyrus/hippocampus), executive control network (right superior parietal lobule and dorsolateral prefrontal cortex), visual network (right lingual gyrus and left middle occipital gyrus), and sensorimotor network (right paracentral lobule/supplementary motor area, right postcentral gyrus and left posterior insula). Significant heterogeneity of ReHo alterations in the bilateral PCC, left parahippocampal gyrus/hippocampus, and right superior parietal lobule/angular gyrus was observed. Exploratory meta regression analyses indicated that general cognitive function, gender distribution, age, and education level partially contributed to this heterogeneity. Conclusions: This study provides provisional evidence that aMCI is associated with abnormal ReHo within the DMN, executive control network, visual network, and sensorimotor network. These local functional connectivity alterations suggest coexistence of functional deficits and compensation in these networks. These findings contribute to the modeling of brain functional connectomes and to a better understanding of the neural substrates of aMCI. Confounding factors merit much attention and warrant future investigations. PMID- 30443348 TI - Crystal engineering, crystals and crystallography. AB - Crystal engineering is moving into new domains with reducing distance and time scales and new ways of thinking about crystals and crystallography. Its intersections with other subjects are varied and numerous. PMID- 30443347 TI - Onset timing of statin-induced musculoskeletal adverse events and concomitant drug-associated shift in onset timing of MAEs. AB - To evaluate the onset timing of musculoskeletal adverse events (MAEs) that develop during statin monotherapy and to determine whether concomitant drugs used concurrently with statin therapy shifts the onset timing of MAEs. Cases in which statins (atorvastatin, rosuvastatin, simvastatin, lovastatin, fluvastatin, pitavastatin, and pravastatin) were prescribed were extracted from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) Data Files. The onset timing of MAEs during statin monotherapy was evaluated by determining the difference between statin start date and MAE onset date. The use of concomitant drugs with statin therapy was included in the analysis. Statins used in combination with concomitant drugs were compared with statin monotherapy to determine if the use of concomitant drugs shifted the onset timing of MAEs. The onset of MAEs was significantly faster with atorvastatin and rosuvastatin than with simvastatin. A difference in onset timing was not detected with other statins because the number of cases was too small for analysis. When evaluating concomitant drug use, the concomitant drugs that shifted the onset timing of MAEs could not be detected. Statins with strong low-density lipoprotein cholesterol lowering effects (atorvastatin and rosuvastatin) contributed not only to a high risk of MAE onset, but also to a shorter time-to-onset. No concomitant drug significantly shifted the onset timing of MAEs when used concurrently with statins. PMID- 30443349 TI - A corrective prescription for GISAXS. AB - A new 'unwarping' algorithm presented by Liu and Yager in this issue constructs SAXS data consistent with experimental GISAXS data, eliminating many of the complications arising in GISAXS that are commonly modeled within the framework of the distorted-wave Born approximation. The method promises to open new pathways for processing, modeling and analyzing GISAXS data using techniques developed for SAXS. PMID- 30443350 TI - Biological single-particle imaging using XFELs - towards the next resolution revolution. AB - Better injectors resulting from careful iterative optimization used at high repetition XFELs in combination with better detectors and further developed algorithms might, in the not so distant future, result in a 'resolution revolution' in SPI, enabling the molecular and atomic imaging of the dynamics of biological macromolecules without the need to freeze or crystallize the sample. PMID- 30443351 TI - Photocage-initiated time-resolved solution X-ray scattering investigation of protein dimerization. AB - This work demonstrates a new method for investigating time-resolved structural changes in protein conformation and oligomerization via photocage-initiated time resolved X-ray solution scattering by observing the ATP-driven dimerization of the MsbA nucleotide-binding domain. Photocaged small molecules allow the observation of single-turnover reactions of non-naturally photoactivatable proteins. The kinetics of the reaction can be derived from changes in X-ray scattering associated with ATP-binding and subsequent dimerization. This method can be expanded to any small-molecule-driven protein reaction with conformational changes traceable by X-ray scattering where the small molecule can be photocaged. PMID- 30443352 TI - Rayleigh-scattering microscopy for tracking and sizing nanoparticles in focused aerosol beams. AB - Ultra-bright femtosecond X-ray pulses generated by X-ray free-electron lasers (XFELs) can be used to image high-resolution structures without the need for crystallization. For this approach, aerosol injection has been a successful method to deliver 70-2000 nm particles into the XFEL beam efficiently and at low noise. Improving the technique of aerosol sample delivery and extending it to single proteins necessitates quantitative aerosol diagnostics. Here a lab-based technique is introduced for Rayleigh-scattering microscopy allowing us to track and size aerosolized particles down to 40 nm in diameter as they exit the injector. This technique was used to characterize the 'Uppsala injector', which is a pioneering and frequently used aerosol sample injector for XFEL single particle imaging. The particle-beam focus, particle velocities, particle density and injection yield were measured at different operating conditions. It is also shown how high particle densities and good injection yields can be reached for large particles (100-500 nm). It is found that with decreasing particle size, particle densities and injection yields deteriorate, indicating the need for different injection strategies to extend XFEL imaging to smaller targets, such as single proteins. This work demonstrates the power of Rayleigh-scattering microscopy for studying focused aerosol beams quantitatively. It lays the foundation for lab-based injector development and online injection diagnostics for XFEL research. In the future, the technique may also find application in other fields that employ focused aerosol beams, such as mass spectrometry, particle deposition, fuel injection and three-dimensional printing techniques. PMID- 30443353 TI - Structure determination and crystal chemistry of large repeat mixed-layer hexaferrites. AB - Hexaferrites are an important class of magnetic oxides with applications in data storage and electronics. Their crystal structures are highly modular, consisting of Fe- or Ba-rich close-packed blocks that can be stacked in different sequences to form a multitude of unique structures, producing large anisotropic unit cells with lattice parameters typically >100 A along the stacking axis. This has limited atomic-resolution structure solutions to relatively simple examples such as Ba2Zn2Fe12O22, whilst longer stacking sequences have been modelled only in terms of block sequences, with no refinement of individual atomic coordinates or occupancies. This paper describes the growth of a series of complex hexaferrite crystals, their atomic-level structure solution by high-resolution synchrotron X ray diffraction, electron diffraction and imaging methods, and their physical characterization by magnetometry. The structures include a new hexaferrite stacking sequence, with the longest lattice parameter of any hexaferrite with a fully determined structure. PMID- 30443354 TI - Towards the theoretical limitations of X-ray nanocrystallography at high intensity: the validity of the effective-form-factor description. AB - X-ray free-electron lasers (XFELs) broaden horizons in X-ray crystallography. Facilitated by the unprecedented high intensity and ultrashort duration of the XFEL pulses, they enable us to investigate the structure and dynamics of macromolecules with nano-sized crystals. A limitation is the extent of radiation damage in the nanocrystal target. A large degree of ionization initiated by the incident high-intensity XFEL pulse alters the scattering properties of the atoms leading to perturbed measured patterns. In this article, the effective-form factor approximation applied to capture this phenomenon is discussed. Additionally, the importance of temporal configurational fluctuations at high intensities, shaping these quantities besides the average electron loss, is shown. An analysis regarding the applicability of the approach to targets consisting of several atomic species is made, both theoretically and via realistic radiation-damage simulations. It is concluded that, up to intensities relevant for XFEL-based nanocrystallography, the effective-form-factor description is sufficiently accurate. This work justifies treating measured scattering patterns using conventional structure-reconstruction algorithms. PMID- 30443355 TI - Conformational aspects of polymorphs and phases of 2-propyl-1H-benzimidazole. AB - This paper reports on the polymorphism of 2-propyl-1H-benzimidazole (2PrBzIm) induced by temperature change. Upon heating, an irreversible reconstructive-type phase transition at T = 384 K from the ordered form I (P212121) to a new polymorph, form II HT (Pcam), was observed. The structural transformation between forms I and II involves significant changes in the crystal packing, as well as a key conformational variation around the propyl chain of the molecule. After the first irreversible phase transition, the II HT form undergoes two further (reversible) phase transitions upon cooling at 361 K (II RT) and 181 K (II LT). All three phases (forms II HT, II RT and II LT) have almost identical crystal packing and, given the reversibility of the conversions as a function of temperature, they are referred to as form II temperature phases. They differ, however, with respect to conformational variations around the propyl chain of 2PrBzIm. Energy calculations of the gas-phase conformational energy landscape of this compound about its flexible bonds allowed us to classify the observed conformational variations of all forms into changes and adjustments of conformers. This reveals that forms I and II are related by conformational change, and that two of the form II phases (HT and RT) are related by conformational adjustment, whilst the other two (RT and LT) are related by conformational change. We introduce the term 'conformational phases' for different crystal phases with almost identical packing but showing changes in conformation. PMID- 30443356 TI - Signal-to-noise, spatial resolution and information capacity of coherent diffraction imaging. AB - It is shown that the average signal-to-noise ratio (SNR) in the three-dimensional electron-density distribution of a sample reconstructed by coherent diffractive imaging cannot exceed twice the square root of the ratio of the mean total number of scattered photons detected during the scan and the number of spatially resolved voxels in the reconstructed volume. This result leads to an upper bound on Shannon's information capacity of this imaging method by specifying the maximum number of distinguishable density distributions within the reconstructed volume when the radiation dose delivered to the sample and the spatial resolution are both fixed. If the spatially averaged SNR in the reconstructed electron density is fixed instead, the radiation dose is shown to be proportional to the third or fourth power of the spatial resolution, depending on the sampling of the three-dimensional diffraction space and the scattering power of the sample. PMID- 30443357 TI - Single-particle imaging without symmetry constraints at an X-ray free-electron laser. AB - The analysis of a single-particle imaging (SPI) experiment performed at the AMO beamline at LCLS as part of the SPI initiative is presented here. A workflow for the three-dimensional virus reconstruction of the PR772 bacteriophage from measured single-particle data is developed. It consists of several well defined steps including single-hit diffraction data classification, refined filtering of the classified data, reconstruction of three-dimensional scattered intensity from the experimental diffraction patterns by orientation determination and a final three-dimensional reconstruction of the virus electron density without symmetry constraints. The analysis developed here revealed and quantified nanoscale features of the PR772 virus measured in this experiment, with the obtained resolution better than 10 nm, with a clear indication that the structure was compressed in one direction and, as such, deviates from ideal icosahedral symmetry. PMID- 30443358 TI - Unwarping GISAXS data. AB - Grazing-incidence small-angle X-ray scattering (GISAXS) is a powerful technique for measuring the nanostructure of coatings and thin films. However, GISAXS data are plagued by distortions that complicate data analysis. The detector image is a warped representation of reciprocal space because of refraction, and overlapping scattering patterns appear because of reflection. A method is presented to unwarp GISAXS data, recovering an estimate of the true undistorted scattering pattern. The method consists of first generating a guess for the structure of the reciprocal-space scattering by solving for a mutually consistent prediction from the transmission and reflection sub-components. This initial guess is then iteratively refined by fitting experimental GISAXS images at multiple incident angles, using the distorted-wave Born approximation (DWBA) to convert between reciprocal space and detector space. This method converges to a high-quality reconstruction for the undistorted scattering, as validated by comparing with grazing-transmission scattering data. This new method for unwarping GISAXS images will broaden the applicability of grazing-incidence techniques, allowing experimenters to inspect undistorted visualizations of their data and allowing a broader range of analysis methods to be applied to GI data. PMID- 30443359 TI - Three-beam convergent-beam electron diffraction for measuring crystallographic phases. AB - Under almost all circumstances, electron diffraction patterns contain information about the phases of structure factors, a consequence of the short wavelength of an electron and its strong Coulombic interaction with matter. However, extracting this information remains a challenge and no generic method exists. In this work, a set of simple analytical expressions is derived for the intensity distribution in convergent-beam electron diffraction (CBED) patterns recorded under three-beam conditions. It is shown that these expressions can be used to identify features in three-beam CBED patterns from which three-phase invariants can be extracted directly, without any iterative refinement processes. The octant, in which the three-phase invariant lies, can be determined simply by inspection of the indexed CBED patterns (i.e. the uncertainty of the phase measurement is +/-22.5 degrees ). This approach is demonstrated with the experimental measurement of three-phase invariants in two simple test cases: centrosymmetric Si and non-centrosymmetric GaAs. This method may complement existing structure determination methods by providing direct measurements of three-phase invariants to replace 'guessed' invariants in ab initio phasing methods and hence provide more stringent constraints to the structure solution. PMID- 30443360 TI - Structures of collagen IV globular domains: insight into associated pathologies, folding and network assembly. AB - Basement membranes are extracellular structures of epithelia and endothelia that have collagen IV scaffolds of triple alpha-chain helical protomers that associate end-to-end, forming networks. The molecular mechanisms by which the noncollagenous C-terminal domains of alpha-chains direct the selection and assembly of the alpha1alpha2alpha1 and alpha3alpha4alpha5 hetero-oligomers found in vivo remain obscure. Autoantibodies against the noncollagenous domains of the alpha3alpha4alpha5 hexamer or mutations therein cause Goodpasture's or Alport's syndromes, respectively. To gain further insight into oligomer-assembly mechanisms as well as into Goodpasture's and Alport's syndromes, crystal structures of non-collagenous domains produced by recombinant methods were determined. The spontaneous formation of canonical homohexamers (dimers of trimers) of these domains of the alpha1, alpha3 and alpha5 chains was shown and the components of the Goodpasture's disease epitopes were viewed. Crystal structures of the alpha2 and alpha4 non-collagenous domains generated by recombinant methods were also determined. These domains spontaneously form homo oligomers that deviate from the canonical architectures since they have a higher number of subunits (dimers of tetramers and of hexamers, respectively). Six flexible structural motifs largely explain the architectural variations. These findings provide insight into noncollagenous domain folding, while supporting the in vivo operation of extrinsic mechanisms for restricting the self-assembly of noncollagenous domains. Intriguingly, Alport's syndrome missense mutations concentrate within the core that nucleates the folding of the noncollagenous domain, suggesting that this syndrome, when owing to missense changes, is a folding disorder that is potentially amenable to pharmacochaperone therapy. PMID- 30443361 TI - Small-angle neutron scattering studies on the AMPA receptor GluA2 in the resting, AMPA-bound and GYKI-53655-bound states. AB - The AMPA receptor GluA2 belongs to the family of ionotropic glutamate receptors, which are responsible for most of the fast excitatory neuronal signalling in the central nervous system. These receptors are important for memory and learning, but have also been associated with brain diseases such as Alzheimer's disease and epilepsy. Today, one drug is on the market for the treatment of epilepsy targeting AMPA receptors, i.e. a negative allosteric modulator of these receptors. Recently, crystal structures and cryo-electron microscopy (cryo-EM) structures of full-length GluA2 in the resting (apo), activated and desensitized states have been reported. Here, solution structures of full-length GluA2 are reported using small-angle neutron scattering (SANS) with a novel, fully matched out detergent. The GluA2 solution structure was investigated in the resting state as well as in the presence of AMPA and of the negative allosteric modulator GYKI 53655. In solution and at neutral pH, the SANS data clearly indicate that GluA2 is in a compact form in the resting state. The solution structure resembles the crystal structure of GluA2 in the resting state, with an estimated maximum distance (D max) of 179 +/- 11 A and a radius of gyration (R g) of 61.9 +/- 0.4 A. An ab initio model of GluA2 in solution generated using DAMMIF clearly showed the individual domains, i.e. the extracellular N-terminal domains and ligand binding domains as well as the transmembrane domain. Solution structures revealed that GluA2 remained in a compact form in the presence of AMPA or GYKI-53655. At acidic pH only, GluA2 in the presence of AMPA adopted a more open conformation of the extracellular part (estimated D max of 189 +/- 5 A and R g of 65.2 +/- 0.5 A), resembling the most open, desensitized class 3 cryo-EM structure of GluA2 in the presence of quisqualate. In conclusion, this methodological study may serve as an example for future SANS studies on membrane proteins. PMID- 30443362 TI - Tailoring structural and magnetic properties of Mn3-x Fe x Ga alloys towards multifunctional applications. AB - This study investigated the structural and magnetic properties of Mn3-x Fe x Ga alloys (x = 0, 0.2, 0.4, 0.6, 0.8, 1) under different heat-treatment conditions. A tetragonal structure was observed in samples that were heat treated at 623 K for three days followed by quenching in ice water. These tetragonal alloys present large coercive fields in the range 0.8-5 kOe and low saturation magnetization, and have great potential for application in spin-transfer torque based devices. A hexagonal structure was observed in samples subjected to heat treatment at 883 K for three days following quenching in ice water. A moderate decrease in the coercive field has been observed for the hexagonal alloys compared with those with a tetragonal structure. However, the Mn3-x Fe x Ga alloys with a hexagonal structure exhibit other attractive magnetic properties, including collinear and non-collinear magnetic properties, holding high promise for technological applications. A face-centred-cubic (f.c.c.) structure was observed when subjected to annealing at 1073 K for three days followed by quenching in ice water. In contrast to the tetragonal and hexagonal structures, all f.c.c. alloys exhibit antiferromagnetic behaviour. This versatile material can display a wide range of multi-functionalities attributed to its tuneable crystal structure. This investigation will guide the design of multiple structures of these materials in order to utilise the wide functionalities for practical applications. PMID- 30443364 TI - Determination of chemical ordering in the complex perovskite Pb(Cd1/3Nb2/3)O3. AB - Pure-phase Pb(Cd1/3Nb2/3)O3 (PCN) single crystals and ceramics with a complex perovskite structure are synthesized for the first time. The local chemical ordering in PCN has been investigated by X-ray diffraction (including diffuse scattering) and Cs-corrected transmission electron microscopy experiments. It is concluded that the PCN samples have large coherent chemical ordering regions that even extend to the long range, and the ordering model is consistent with beta type chemical ordered regions. The antiphase domain boundaries were also observed. Two dielectric anomaly peaks were found in these two types of samples, one of which indicates possible relaxor behaviour. The novel structure of the completely ordered regions and its relationship with the electrical properties make PCN a unique material for the fundamental understanding of chemically substituted perovskites. PMID- 30443363 TI - Dynamics of soft nanoparticle suspensions at hard X-ray FEL sources below the radiation-damage threshold. AB - The application of X-ray photon correlation spectroscopy (XPCS) at free-electron laser (FEL) facilities enables, for the first time, the study of dynamics on a (sub-)nanometre scale in an unreached time range between femtoseconds and seconds. For soft-matter materials, radiation damage is a major limitation when going beyond single-shot applications. Here, an XPCS study is presented at a hard X-ray FEL on radiation-sensitive polymeric poly(N-isopropylacrylamide) (PNIPAM) nanoparticles. The dynamics of aqueous suspensions of densely packed silica PNIPAM core-shell particles and a PNIPAM nanogel below the radiation-damage threshold are determined. The XPCS data indicate non-diffusive behaviour, suggesting ballistic and stress-dominated heterogeneous particle motions. These results demonstrate the feasibility of XPCS experiments on radiation-sensitive soft-matter materials at FEL sources and pave the way for future applications at MHz repetition rates as well as ultrafast modes using split-pulse devices. PMID- 30443365 TI - Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals. AB - The single-crystal X-ray structure of a 6-component organic-salt alloy (hexanary) of naftopidil (1) (an active pharmaceutical ingredient) with benzoic acid (2) and four different hydroxy-substituted benzoic acids, i.e. salicylic acid (3), 2,3-di hydroxybenzoic acid (4), 2,4-di-hydroxybenzoic acid (5) and 2,6-di-hydroxybenzoic acid (6), is reported. The hexanary assembly originates from the observation that the binary salts of naftopidil with the above acids are isostructural. In addition to the 6-component solid, we also describe five 5-component, ten 4 component, and ten 3-component organic-salt alloys of naftopidil (1) with carboxylic acids (2)-(6). These alloys were obtained from different combinations of the acids with the drug. The synthetic design of the multicomponent organic alloys is based on the rationale of geometrical factors (shape and size) and chemical interactions (hydrogen bonds). The common supramolecular synthon in all these crystal structures was the cyclic N+-H?O- and O-H?O hydrogen-bonded motif of (9) graph set between the 2-hy-droxyammonium group of naftopidil and the carboxyl-ate anion. This ionic synthon is strong and robust, directing the isostructural assembly of naftopidil with up to five different carboxylic acids in the crystal structure together with the lower-level multicomponent adducts. Solution crystallization by slow evaporation provided the multicomponent organic salts and alloys which were characterized by a combination of single-crystal X ray diffraction, powder X-ray diffraction, NMR and differential scanning calorimetry techniques. PMID- 30443366 TI - Self-adapted clustering of solute atoms into a confined two-dimensional prismatic platelet with an ellipse-like quasi-unit cell. AB - This paper reports a new structured prismatic platelet, self-assembled by an ellipse-like quasi-unit cell, precipitated in Mg-In-Yb and Mg-In-Ca ternary alloys and aged isothermally at 200 degrees C using aberration-corrected high angle annular dark-field scanning transmission electron microscopy combined with density functional theory computations. The ordered stacking of solute atoms along the [0001]alpha direction based on elliptically shaped self-adapted clustering leads to the generation of the quasi-unit cell. The bonding of these ellipse-like quasi-unit-cell rods by the Mg atomic columns along the <>alpha directions formed a two-dimensional planar structure, which has three variants with a {}alpha habit plane and full coherence with the alpha-Mg matrix. This finding is important for understanding the clustering and stacking behaviors of solute atoms in condensed matter, and is expected to guide the future design of novel high-strength Mg alloys strengthened by such high-density prismatic platelets. PMID- 30443367 TI - Committee machine that votes for similarity between materials. AB - A method has been developed to measure the similarity between materials, focusing on specific physical properties. The information obtained can be utilized to understand the underlying mechanisms and support the prediction of the physical properties of materials. The method consists of three steps: variable evaluation based on nonlinear regression, regression-based clustering, and similarity measurement with a committee machine constructed from the clustering results. Three data sets of well characterized crystalline materials represented by critical atomic predicting variables are used as test beds. Herein, the focus is on the formation energy, lattice parameter and Curie temperature of the examined materials. Based on the information obtained on the similarities between the materials, a hierarchical clustering technique is applied to learn the cluster structures of the materials that facilitate interpretation of the mechanism, and an improvement in the regression models is introduced to predict the physical properties of the materials. The experiments show that rational and meaningful group structures can be obtained and that the prediction accuracy of the materials' physical properties can be significantly increased, confirming the rationality of the proposed similarity measure. PMID- 30443368 TI - Crystal structure, interaction energies and experimental electron density of the popular drug ketoprophen. AB - The crystal and molecular structure of the pure (S)-enantiomer of the popular analgesic and anti-inflammatory drug ketoprophen (alpha-ket) is reported. A detailed aspherical charge-density model based on high-resolution X-ray diffraction data has been refined, yielding a high-precision geometric description and classification of the O-H?O interactions as medium strength hydrogen bonds. The crystal structure of the racemic form of ketoprophen (beta ket) was also redetermined at 100 K, at 0.5 A resolution. A previously unreported disorder (10% occupancy) was discovered. In contrast to the racemic beta-ket case, the (S)-enantiomer crystallizes with two independent molecules in the asymmetric unit with two distinct conformations. The major difference between the beta-ket and alpha-ket crystal forms lies in the formation of distinct hydrogen bonded motifs: a closed ring motif in beta-ket versus infinite chains of hydrogen bonds in the chiral alpha-ket structure. However, the overall crystal packing of both forms is surprisingly similar, with close-packed layers of antiparallel oriented benzo-phenone moieties bound by C-H?pi interactions. Notably, the most important stabilizing term in the total lattice energies in both instances proved to be the dispersion related to these interactions. Both forms of the title compound (alpha- and beta-ket) were additionally characterized by differential scanning calorimetry and thermogravimetric analysis. PMID- 30443369 TI - Deep Consensus, a deep learning-based approach for particle pruning in cryo electron microscopy. AB - Single-particle cryo-electron microscopy (cryo-EM) has recently become a mainstream technique for the structural determination of macromolecules. Typical cryo-EM workflows collect hundreds of thousands of single-particle projections from thousands of micrographs using particle-picking algorithms. However, the number of false positives selected by these algorithms is large, so that a number of different 'cleaning steps' are necessary to decrease the false-positive ratio. Most commonly employed techniques for the pruning of false-positive particles are time-consuming and require user intervention. In order to overcome these limitations, a deep learning-based algorithm named Deep Consensus is presented in this work. Deep Consensus works by computing a smart consensus over the output of different particle-picking algorithms, resulting in a set of particles with a lower false-positive ratio than the initial set obtained by the pickers. Deep Consensus is based on a deep convolutional neural network that is trained on a semi-automatically generated data set. The performance of Deep Consensus has been assessed on two well known experimental data sets, virtually eliminating user intervention for pruning, and enhances the reproducibility and objectivity of the whole process while achieving precision and recall figures above 90%. PMID- 30443370 TI - Structure-based mechanism of action of a viral poly(ADP-ribose) polymerase 1 interacting protein facilitating virus replication. AB - Poly(ADP-ribose) polymerase 1 (PARP-1), an enzyme that modifies nuclear proteins by poly(ADP-ribosyl)ation, regulates various cellular activities and restricts the lytic replication of oncogenic gammaherpesviruses by inhibiting the function of replication and transcription activator (RTA), a key switch molecule of the viral life cycle. A viral PARP-1-interacting protein (vPIP) encoded by murine gammaherpesvirus 68 (MHV-68) orf49 facilitates lytic replication by disrupting interactions between PARP-1 and RTA. Here, the structure of MHV-68 vPIP was determined at 2.2 A resolution. The structure consists of 12 alpha-helices with characteristic N-terminal beta-strands (Nbeta) and forms a V-shaped-twist dimer in the asymmetric unit. Structure-based mutagenesis revealed that Nbeta and the alpha1 helix (residues 2-26) are essential for the nuclear localization and function of vPIP; three residues were then identified (Phe5, Ser12 and Thr16) that were critical for the function of vPIP and its interaction with PARP-1. A recombinant MHV-68 harboring mutations of these three residues showed severely attenuated viral replication both in vitro and in vivo. Moreover, ORF49 of Kaposi's sarcoma-associated herpesvirus also directly interacted with PARP-1, indicating a conserved mechanism of action of vPIPs. The results elucidate the novel molecular mechanisms by which oncogenic gammaherpesviruses overcome repression by PARP-1 using vPIPs. PMID- 30443371 TI - Prescription drug coverage in Canada: a review of the economic, policy and political considerations for universal pharmacare. AB - Background: Canadians have long been proud of their universal health insurance system, which publicly funds the cost of physician visits and hospitalizations at the point of care. Prescription drugs however, have been subject to a patchwork of public and private coverage which is frequently inefficient and creates access barriers to necessary medicine for many Canadians. Methods: A narrative review was undertaken to understand the important economic, policy and political considerations regarding implementation of universal prescription drug access in Canada (pan-Canadian pharmacare). PubMed, SCOPUS and google scholar were searched for relevant citations. Citation trails were followed for additional information sources. Published books, public reports, press releases, policy papers, government webpages and other forms of gray literature were collected from iterative internet searches to provide a complete view of the current state on this topic. Main findings: Regarding health economics, all five of the reviewed pharmacare simulation models have shown reductions in annual prescription drug expenditure. However, differing policy and cost assumptions have resulted in a wide range of cost-saving estimates between models. In terms of policy, a single payer, 'first-dollar' coverage model, using a minimum national formulary, is the model most frequently advocated by the academic community, healthcare professions and many public and patient groups. In contrast, a multi-payer, catastrophic 'last-dollar' coverage model, more similar to the current "patchwork" state of public and private coverage, is preferred by industry drug manufacturers and private health insurance companies. Primary concerns from the detractors of universal, single-payer, 'first-dollar' coverage are the financing required for its implementation and the access barriers that may be created for certain patient populations that are not majorly present in the current public-private payer mix. Conclusion: Canada patiently awaits to see how the issue of prescription drug coverage will be resolved through the work of the Advisory Council on the Implementation of National Pharmacare. The overarching and ongoing discourse on policy and program implementation may be construed as a political debate informed by divergent public and private interests. PMID- 30443372 TI - Vulvar lichen sclerosus in a prepubertal girl. PMID- 30443373 TI - MEASUREMENT WITHOUT THEORY, ONCE AGAIN. AB - Bailey and Collins (2011) argue that Greenwood, Seshadri, and Vandenbroucke's (2005) hypothesis that the baby boom was partly due to a burst of productivity in the household sector is not supported by evidence. This conclusion is based on regression results showing that appliance ownership is negatively correlated with fertility. They also argue that the Amish, who limit the use of modern technology, had a baby boom. First, it is demonstrated that a negative correlation between appliance ownership and fertility can arise naturally in Greenwood, Seshadri, and Vandenbroucke's model. Second, evidence is presented casting doubt on the presumed technology phobia of the Amish. PMID- 30443374 TI - Crystal structure of di-chlorido-bis-{MU-2-meth-oxy-6-[(methyl-imino)-meth yl]phenolato}{2-meth-oxy-6-[(methyl-imino)-meth yl]phenolato}cadmium(II)cobalt(III) monohydrate. AB - The title compound, [CoCd(C9H10NO2)3Cl2].H2O, is a solvatomorph of the corresponding hemihydrate recently published by us [Nesterova et al. (2018 ?). Appl. Cat. A, 560, 171-184]. The current structure reveals different cell parameters and space group compared with the published one while both are monoclinic with almost the same cell volume. The title compound is formed of discrete neutral dinuclear mol-ecules with no crystallographically imposed symmetry and water mol-ecules of crystallization. The overall geometry about the cobalt(III) ion is octa-hedral with an N3O3 environment; each ligand acts as a meridional ONO donor. The CdII coordination sphere approximates an irregular square pyramid with a chlorine atom at the apex. There is significant shortening of a Cd-O bond length to the oxygen atom of the methoxo group on one of the ligands [2.459 (3) A] compared to the corresponding distance in the published structure [2.724 (7) A], while other Cd-Cl/N/O bonds remain roughly the same. In the crystal lattice, the heterometallic mol-ecules, which are related by the crystallographic n-glide plane and inter-linked by weak hydrogen bonds to solvent water mol-ecules, form columns along [101]. Adjacent columns lie anti-parallel to each other. PMID- 30443375 TI - Crystal structure and Hirshfeld surface analysis of tetra-aqua-bis (isonicotinamide-kappaN 1)nickel(II) fumarate. AB - The reaction of NiCl2 with fumaric acid and isonicotinamide in a basic solution produces the title complex, [Ni(C6H6N2O)2(H2O)4](C4H2O4). The nickel(II) ion of the complex cation and the fumarate anion are each located on an inversion centre. The NiII ion is coordinated octa-hedrally by four water O atoms and two N atoms of isonicotinamide mol-ecules. The fumarate anion is linked to neighbouring complex cations via Owater-H?Ofumarate hydrogen bonds. In the crystal, the complex cations are further linked by O-H?O, N-H?O and C-H?O hydrogen bonds, forming a three-dimensional supra-molecular architecture. Hirshfeld surface analysis and two-dimensional fingerprint plots were used to analyse the inter molecular inter-actions present in the crystal and indicate that the most important contributions for the crystal packing are from H?O/O?H (41.8%), H?H (35.3%) and H?C/C?H (10.2%) inter-actions. PMID- 30443376 TI - Crystal structure of (E)-2,6-dimeth-oxy-4-{[(4-meth-oxy-phen-yl)imino]-meth yl}phenol. AB - In the title compound, C16H17NO4, the dihedral angle between benzene rings is 72.7 (2) degrees . The meth-oxy groups are rotated by 2.4 (2) and -4.9 (2) (benzil-idene moiety) and by 5.6 (3) degrees (aniline moiety) relative to the adjacent benzene ring. In the crystal, the mol-ecules are linked into chains along [101] through C-H?O and O-H?N hydrogen bonds. PMID- 30443377 TI - Crystal structure of 13-(E)-(2-amino-benzyl-idene)parthenolide. AB - The title compound, C21H25NO3 [systematic name: (1aR,4E,7aS,8E,10aS,10bR)-8-(2 amino-benzyl-idene)-1a,5-dimethyl-2,3,6,7,7a,8,10a,10b-octa-hydro oxireno[2',3':9,10]cyclo-deca-[1,2-b]furan-9(1aH)-one], was synthesized by the reaction of parthenolide [systematic name (1aR,7aS,10aS,10bS,E)-1a,5-dimethyl-8 methyl-ene-2,3,6,7,7a,8,10a,10b-octa-hydro-oxireno[2',3':9,10]cyclo-deca-[1,2 b]furan-9(1aH)-one] with 2-iodo-aniline via Heck reaction conditions. The mol ecule is composed of fused ten-, five- (lactone), and three-membered (epoxide) rings. The lactone ring shows a flattened envelope-type conformation (r.m.s. deviation from planarity = 0.0477 A), and bears a 2-amino-benzyl-idene substituent that is disordered over two conformations [occupancy factors 0.901 (4) and 0.099 (4)]. The ten-membered ring has an approximate chair-chair conformation. The dihedral angle between the 2-amino-benzyl-idine moiety (major component) and the lactone ring (mean plane) is 59.93 (7) degrees . There are no conventional hydrogen bonds, but there are a number of weaker C-H?O-type inter actions. PMID- 30443378 TI - Synthesis, crystal structure and Hirshfeld analysis of a new crystalline modification of the radical ion salt octa-methyl-ene-tetra-thia-fulvalenium triiodide (OMTTF)I3. AB - The reaction between 4,5,6,7-tetra-hydro-2-(4,5,6,7-tetra-hydro-1,3-benzodi-thiol 2-yl-idene)-1,3-benzodi-thiole (common name: 4,4',5,5',6,6',7,7'-octa-hydro dibenzo-tetra-thia-fulvalene, OMTTF) and an excess of iodine in tetra-hydro-furan (THF) yielded the respective radical organic polyiodide salt, C14H16S4 +.I3 -. The asymmetric unit contains one and a half formula unit of both the cation and the anion, with the half-ions completed through inversion symmetry. The (OMTTF +) positive charge can be assigned by the bond distances and the planar structure of the C2S2C=CS2C2 central fragment. In the crystal, trimers of triiodide anions are connected through secondary inter-molecular I?I inter-actions into almost linear I9 3- polyanions. The non-centrosymmetric OMTTF radical cations are linked by S?S inter-actions into centrosymmetric dimers, while the centrosymmetric OMTTF cations remain as discrete units. The (OMTTF +) radical cations and the triiodide anions are linked by weak C-H?I and C-H?S inter-actions into a three-dimensional network. This work reports the fourth crystalline modification of the C14H16S4 +.I3 - salt. The three previous modifications were obtained from a mixture of aceto-nitrile and toluene [Konarev et al. (2005 ?). Synth. Met. 151, 231-238]. PMID- 30443379 TI - Crystal structures and Hirshfeld surfaces of four meth-oxy-benzaldehyde oxime derivatives, 2-MeO-XC6H3C=NOH (X = H and 2-, 3- and 4-MeO): different conformations and hydrogen-bonding patterns. AB - The crystal structures of four (E)-meth-oxy-benzaldehyde oxime derivatives, namely (2-meth-oxy-benzaldehyde oxime, 1, 2,3-di-meth-oxy-benzaldehyde oxime, 2, 4-di-meth-oxy-benzaldehyde oxime, 3, and 2,5-di-meth-oxy-benzaldehyde oxime, 4, are discussed. The arrangements of the 2-meth-oxy group and the H atom of the oxime unit are s-cis in compounds 1-3, but in both independent mol-ecules of compound 4, the arrangements are s-trans. There is also a difference in the conformation of the two mol-ecules in 4, involving the orientations of the 2- and 5-meth-oxy groups. The primary inter-molecular O-H(oxime)?O(hy-droxy) hydrogen bonds generate C(3) chains in 1 and 2. In contrast, in compound 3, the O H(oxime)?O(hy-droxy) hydrogen bonds generate symmetric R 2 2(6) dimers. A more complex dimer is generated in 4 from the O-H(oxime)?O(hy-droxy) and C-H(2-meth oxy)?O(hy-droxy) hydrogen bonds. In all cases, further inter-actions, C-H?O and C H?pi or pi-pi, generate three-dimensional arrays. Hirshfeld surface and fingerprint analyses are discussed. PMID- 30443380 TI - A new form of Cd3TeO6 revealing dimorphism. AB - Phase-formation studies in the system CdO-TeO3 using a CsCl/NaCl melt at comparatively low temperatures revealed that tricadmium orthotellurate(VI), Cd3TeO6, is dimorphic. The new modification of Cd3TeO6 is denoted as the beta form and adopts the rhombohedral Mg3TeO6 structure type with one Cd and two O sites in general positions, and two Te sites with site symmetry each. In comparison with the previously reported monoclinic cryolite-type alpha-form that was prepared at higher temperatures, beta-Cd3TeO6 has a much lower density and most likely represents a metastable modification. Whereas the [TeO6] octa-hedra in both polymorphs are very similar and show only minor deviations from ideal values, the polyhedra around the CdII sites are different, with a distorted [CdO6] octa-hedron in both modifications but an additional [CdO8] polyhedron with a [4 + 4] coordination in the alpha-form. PMID- 30443381 TI - Crystal structure of bis-[(S)-2-(2-hy-droxy-benzyl-amino)-4-methyl-penta-noato kappa2 N,O 1](1,10-phenanthroline-kappa2 N,N')cadmium dihydrate. AB - The asymmetric unit of the mononuclear mixed-ligand title complex, [Cd(C13H18NO3)2(C12H8N2)].2H2O, contains two crystallographically independent mol ecules that differ insignificantly in their geometrical parameters. In both, the CdII cation lies on a twofold rotation axis and is coordinated in a distorted octa-hedral fashion to two monodeprotonated residues of the l-leucine-derived ligand (S)-2-(2-hy-droxy-benzyl-amino)-4-methyl-penta-noic acid (L), as well as to a 1,10-phenanthroline ligand in a kappa2 N,N' mode. The former coordinate in an N,O-chelating mode, exhibiting a trans-N,N' mutual disposition. The phenolic oxygen donor groups remain protonated and do not coordinate to the cation but take part in intra- and inter-molecular hydrogen bonds. In the crystal, O-H?O hydrogen bonding results in the formation of a three-dimensional network structure. The contribution to the electron density of two disordered water mol ecules was removed with the SQUEEZE procedure in PLATON [Spek (2015 ?). Acta Cryst. C71, 9-18]. The studied crystal was refined as a two-component inversion twin. The title complex was also characterized by IR and 1H NMR spectroscopic methods. PMID- 30443382 TI - Crystal structure and Hirshfeld surface analysis of (Z)-4-chloro-N'-(4-oxo-thia zol-idin-2-yl-idene)benzene-sulfono-hydrazide monohydrate. AB - The asymmetric unit of the title thia-zole derivative containing a sulfonyl hydrazinic moiety, C9H8ClN3O3S2.H2O, consists of two independent mol-ecules and two water mol-ecules. The central parts of the mol-ecules are twisted as both the mol-ecules are bent at both the S and N atoms. In the crystal, N-H?N, N-H?O, C H?O and O-H?O hydrogen-bonding inter-actions connect the mol-ecules, forming layers parallel to the ab plane. Two-dimensional fingerprint plots associated with the Hirshfeld surface show that the largest contributions to the crystal packing come from O?H/H?O (32.9%) and H?H (22.6%) inter-actions. PMID- 30443383 TI - Crystal structure of N-isopropyl-N-(phen-yl)phenyl-glyoxyl-amide. AB - The title compound [systematic name: 2-oxo-N,2-diphenyl-N-(propan-2 yl)acetamide], C17H17NO2, was synthesized and its photoreactive properties in the crystalline state were investigated. In the mol-ecule, the carbonyl group attached to the phenyl ring adopts an s-trans configuration with respect to the isopropyl group. Moreover, the distance between the C atom of the carbonyl group and the N-bound C atom of the isopropyl group is 3.845 (2) A, which is much longer than 3.2 A, the threshold for photoreactions to take place in the mol ecule. As a result, the crystal did not photoreact upon UV light irradiation. In the crystal, the mol-ecules are linked via weak inter-molecular C-H?O hydrogen bonds, forming a layer structure parallel to the ab plane. PMID- 30443384 TI - Crystal structure and metabolic activity of 4-(thien-2-yl)-2-methyl-5-oxo 1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxy-lic acid eth-oxy-carbonyl-phenyl methyl-ester. AB - In the title compound, C25H25NO5S, which exhibits metabolism-regulating activity, the 1,4-di-hydro-pyridine ring adopts a flattened boat conformation while the cyclo-hexenone ring is in an envelope conformation. Mol-ecules in the crystal are assembled into C(6) chains along the a-axis direction via N-H?O hydrogen bonds. The thienyl fragment is disordered over two sets of sites in a 0.7220 (19):0.2780 (19) ratio. PMID- 30443385 TI - Crystal structure and Hirshfeld analysis of 2-[bis-(1-methyl-1H-indol-3-yl)meth yl]benzoic acid. AB - In the title compound, C26H22N2O2, the dihedral angles between the 1-methyl indole units (A and B) and the benzoic acid moiety (C) are A/B = 64.87 (7), A/C = 80.92 (8) and B/C = 75.05 (8) degrees . An intra-molecular C-H?O inter-action arising from the methyne group helps to establish the conformation. In the crystal, R 2 2(8) carb-oxy-lic acid inversion dimers linked by pairs of O-H?O hydrogen bonds are observed. A Hirshfeld surface analysis shows that the greatest contributions are from H?H, C?H/H?C and O?H/H?O contacts (percentage values = 54.6%, 29.6% and 10.1%, respectively). PMID- 30443386 TI - Structure of 2-chloro-N-(p-tol-yl)propanamide. AB - Two independent samples of the title compound, alternatively 2-chloro-N-(4 methylphenyl)prop-an-amide, C10H12ClNO, 1, were studied using Cu Kalpha, 1a, and Mo Kalpha, 1b, radiation as part of a continuous crystallization study. The mol ecule crystallizes with disorder in the Cl/terminal methyl positions [occupancies for the major disorder component of 0.783 (2) in 1a and and 0.768 (2) in 1b] and exhibits N-C bond lengths of 1.3448 (19), 1.344 (2) A, C=O bond lengths of 1.2233 (18) and 1.2245 (19) A and an acetamide moiety C-N-C-C torsion angle of 179.00 (13), 178.97 (14) degrees for 1a and 1b, respectively. In the crystal, chains along the a axis are formed via N-H?O hydrogen bonds between acetamide groups, as well as C-H?O inter-actions. These chains arrange themselves into parallel running stacks which display weak C-Cl?O=C halogen bonding as well as weak C-H?pi inter-actions. PMID- 30443387 TI - Crystal structure and optical spectroscopic analyses of (E)-3-(1H-indol-2-yl)-1 (4-nitro-phen-yl)prop-2-en-1-one hemihydrate. AB - The asymmetric unit of the title compound, 2C17H12N2O3.H2O comprises two mol ecules of (E)-3-(1H-indol-2-yl)-1-(4-nitro-phen-yl)prop-2-en-1-one and a water mol-ecule. The main mol-ecule adopts an s-cis configuration with respect to the C=O and C=C bonds. The dihedral angle between the indole ring system and the nitro-substituted benzene ring is 37.64 (16) degrees . In the crystal, mol-ecules are linked by O--H?O and N-H?O hydrogen bonds, forming chains along [010]. In addition, weak C-H?O, C-H?pi and pi-pi inter-actions further link the structure into a three-dimensional network. The optimized structure was generated theoretically via a density functional theory (DFT) approach at the B3LYP/6-311 G++(d,p) basis level and the HOMO-LUMO behaviour was elucidated to determine the energy gap. The obtained values of 2.70 eV (experimental) and 2.80 eV (DFT) are desirable for optoelectronic applications. The inter-molecular inter-actions were qu-anti-fied and analysed using Hirshfeld surface analysis. PMID- 30443388 TI - Crystal structure of the thalidomide analog (3aR*,7aS*)-2-(2,6-dioxopiperidin-3 yl)hexa-hydro-1H-iso-indole-1,3(2H)-dione. AB - The title compound, C13H16N2O4, crystallizes in the monoclinic centrosymmetric space group, P21/c, with four mol-ecules in the asymmetric unit, thus there is no crystallographically imposed symmetry and it is a racemic mixture. The structure consists of a six-membered unsaturated ring bound to a five-membered pyrrolidine 2,5-dione ring N-bound to a six-membered piperidine-2,6-dione ring and thus has the same basic skeleton as thalidomide, except for the six-membered unsaturated ring substituted for the aromatic ring. In the crystal, the mol-ecules are linked into inversion dimers by R 2 2(8) hydrogen bonding involving the N-H group. In addition, there are bifurcated C-H?O inter-actions involving one of the O atoms on the pyrrolidine-2,5-dione with graph-set notation R 1 2(5). These inter actions along with C-H?O inter-actions involving one of the O atoms on the piperidine-2,6-dione ring link the mol-ecules into a complex three-dimensional array. There is pseudomerohedral twinning present which results from a 180 degrees rotation about the [100] reciprocal lattice direction and with a twin law of 1 0 0 0 0 0 0 [BASF 0.044 (1)]. PMID- 30443389 TI - Crystal structure and Hirshfeld surface analysis of dimethyl (3aS,6R,6aS,7S)-2 (2,2,2-tri-fluoro-acet-yl)-2,3-di-hydro-1H,6H,7H-3a,6:7,9a-di-epoxy-benzo[de]iso quinoline-3a1,6a-di-carboxyl-ate. AB - The title mol-ecule, C18H16F3NO7, comprises a fused cyclic system containing four five-membered (two di-hydro-furan and two tetra-hydro-furan) rings and one six membered (piperidine) ring. The five-membered di-hydro-furan and tetra-hydro furan rings adopt envelope conformations, and the six-membered piperidine ring adopts a distorted chair conformation. Intra-molecular O?F inter-actions help to stabilize the conformational arrangement. In the crystal structure, mol-ecules are linked by weak C-H?O and C-H?F hydrogen bonds, forming a three-dimensional network. The Hirshfeld surface analysis confirms the dominant role of H?H contacts in establishing the packing. PMID- 30443390 TI - Crystal structure of 5,15-dihexyl-5,15-di-hydro-benzo[2,1-b:4,3-c']dicarbazole hexane 0.375-solvate. AB - The title compound, C38H40N2.0.375C6H14, crystallizes in the monoclinic space group P21/c and has a host-guest structure with the helicene molecules forming a porous structure and mol-ecules of hexane inserted into the holes. The dihedral angles between the two carbazole sections of the right- and left-handed helicenes are 27.44 (3) and 25.63 (3) degrees , respectively. There are no classical pi-pi inter-actions or hydrogen-bonding inter-actions present between adjacent mol ecules in the crystal structure. The hexane solvent mol-ecule shows positional disorder. PMID- 30443391 TI - Crystal structure of (diethyl ether-kappaO)[5,10,15,20-tetra-kis-(2-iso-thio cyanato-phen-yl)porphyrinato-kappa4 N]zinc diethyl ether solvate. AB - The crystal structure of the title compound, [Zn(C48H24N8S4)(C4H10O)].C4H10O, consists of discrete porphyrin complexes that are located on a twofold rotation axis. The ZnII cation is fivefold coordinated by four N atoms of the porphyrin moiety and one O atom of a diethyl ether mol-ecule in a slightly distorted square pyramidal environment with the diethyl ether mol-ecule in the apical position. The porphyrin backbone is nearly planar with the metal cation slightly shifted out of the plane towards the coordinating diethyl ether mol-ecule. All four iso thio-cyanato groups of the phenyl substituents at the meso-positions face the same side of the porphyrin, as is characteristic for picket fence porphyrins. In the crystal structure, the discrete porphyrin complexes are arranged in such a way that cavities are formed in which additional diethyl ether solvate mol-ecules are located around a twofold rotation axis. The O atom of the solvent mol-ecule is not positioned exactly on the twofold rotation axis, thus making the whole mol ecule equally disordered over two symmetry-related positions. PMID- 30443392 TI - Crystal structure and Hirshfeld surface analysis of (E)-N'-benzyl-idene-4-chloro benzene-sulfono-hydrazide and of its (E)-4-chloro-N'-(ortho- and para-methyl benzyl-idene)benzene-sulfono-hydrazide derivatives. AB - (E)-N'-Benzyl-idene-4-chloro-benzene-sulfono-hydrazide, C13H11ClN2O2S, (I), and its ortho- and para-methyl-substituted derivatives, C14H13ClN2O2S, namely (E)-4 chloro-N'-(2-methyl-benzyl-idene)benzene-sulfono-hydrazide, (II), and (E)-4 chloro-N'-(4-methyl-benzyl-idene)benzene-sulfono-hydrazide, (III), have been synthesized, characterized spectroscopically and their crystal structures determined to investigate the effect of the substitution site of the benzyl-idene group on the structural and supra-molecular features in these compounds. Compounds (I) and (II) are isotypic while compound (III) is different. All three mol-ecules are bent at the S atom with C-S-N-N torsion angles of -66.0 (3), -66.0 (3) and -58.4 (2) degrees for (I), (II) and (III), respectively. The hydrazone portions of the mol-ecules, S-N-N=C, are slightly twisted from planarity, with a torsion angle of 166.5 (3) degrees in (I), 165.4 (3) degrees in (II) and 157.9 (2) degrees in (III). The two aromatic rings present in the compounds are inclined to each other by 78.4 (2), 74.8 (2) and 76.9 (1) degrees in (I), (II) and (III), respectively. In the crystal structure of the parent compound (I), and of the ortho-methyl derivative (II), an N-H?O hydrogen bond links the mol-ecules into chains along [001], which are inter-connected by weak inter-molecular C-H?O inter-actions, generating layers lying parallel to the bc plane. In the crystal of the para derivative (III), however, the packing is significantly different. Here mol-ecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers with an R 2 2(8) ring motif. The dimers are then linked by C-Cl?pi inter actions, forming ribbons propagating along [10]. Hirshfeld surface analyses show that the van der Waals inter-actions constitute the major contribution to the inter-molecular inter-actions in the crystal structures of all three compounds. The fingerprint plots indicate that the H?H contacts make the largest contributions to the Hirshfeld surfaces. PMID- 30443394 TI - The methanol sesquisolvate of sodium naproxen. AB - The asymmetric unit of the methanol solvate of sodium naproxen, systematic name: sodium (2S)-2-(6-meth-oxy-naphthalen-2-yl)propano-ate methanol sesquisolvate, Na+.C14H13O3 -.1.5CH3OH, comprises two formula units of the mol-ecular salt and three methanol mol-ecules. One of the sodium cations exhibits a coordination number of six and is bonded to three carboxyl-ate O atoms and three methanol OH groups whereas the second sodium cation has a coordination number of seven, defined by five carboxyl-ate O atoms and two methanol OH groups. Both coordination polyhedra around the sodium cations are considerably distorted. The two types of cations are bridged into polymeric chains extending parallel to [010]. This arrangement is stabilized by intrachain O-H?O hydrogen bonds between methanol ligands as donor and carboxyl-ate O atoms as acceptor groups. The hydro phobic 6-meth-oxy-naphthyl moieties flank the hydro-philic sodium oxygen chains into ribbons parallel to [010]. There are no noticeable inter-molecular inter actions between these ribbons. One of the 6-meth-oxy-naphthyl moieties is disordered over two sets of sites in a 0.723 (3):0.277 (3) ratio. PMID- 30443393 TI - Crystal structures of three halide salts of l-asparagine: an isostructural series. AB - The structures of three monohydrated halide salt forms of l-asparagine are presented, viz. l-asparaginium chloride monohydrate, C4H9N2O3 +.Cl-.H2O, (I), l asparaginium bromide monohydrate, C4H9N2O3 +.Br-.H2O, (II), and l-asparaginium iodide monohydrate, C4H9N2O3 +.I-.H2O, (III). These form an isomorphous and isostructural series. The C-C-C-C backbone of the amino acid adopts a gauche conformation in each case [torsion angles for (I), (II) and (III) = -55.4 (2), 55.6 (5) and -58.3 (7) degrees , respectively]. Each cation features an intra molecular N-H?O hydrogen bond, which closes an S(6) ring. The extended structures feature chains of cations that propagate parallel to the b-axis direction. These are formed by carb-oxy-lic acid/amide complimentary O-H?O + N-H?O hydrogen bonds, which generate R 2 2(8) loops. These chains are linked by further hydrogen bonds mediated by the halide ions and water mol-ecules to give a layered structure with cation and anion layers parallel to the ab plane. Compound (III) was refined as an inversion twin. PMID- 30443395 TI - Synthesis, crystallographic analysis and Hirshfeld surface analysis of 4-bromo-2 {[2-(5-bromo-2-nitro-phen-yl)hydrazin-1-yl-idene]meth-yl}-5-fluoro-phenol. AB - The title compound, C13H8Br2FN3O3, is nearly planar with a dihedral angle of 10.6 (4) degrees between the two benzene rings. Intra-molecular N-H?O and O-H?N hydrogen bonds occur. In the crystal, the mol-ecules are linked by weak C-H?O and C-H?Br hydrogen bonds. The roles of the inter-molecular inter-actions in the crystal packing were clarified using Hirshfeld surface analysis. PMID- 30443396 TI - The first spontaneous resolution of a sulfoxide: Dianin's compound analogue, (R) 4-(4-hy-droxy-phen-yl)-2,2,4-tri-methyl-thia-chroman-1-oxide. AB - The title sulfoxide, C18H20O2S, was prepared by controlled oxidation of thia Dianin's compound using hydrogen peroxide in glacial acetic acid. On recrystallization from glacial acetic acid, it was found to form unsolvated, spontaneously resolved crystals, the initial crystal structure analysis revealing the presence of both sulfoxide epimers in the crystal. On multiple recrystallization a single epimer was observed, with crystallization occurring in the unchanged ortho-rhom-bic space group P212121, with Z' = 1. The mol-ecule possesses a distal conformation, referring to the juxtaposition of the p hydoxyphenyl substituent with respect to its syn-related methyl group, with the sulfoxide oxygen atom anti to the aromatic substituent. The mol-ecular packing features O-H?O hydrogen bond chains running parallel to the b axis of the unit cell. PMID- 30443397 TI - Investigation of nitro-nitrito photoisomerization: crystal structures of trans bis-(acetyl-acetonato-O,O')(pyridine/4-methyl-pyridine/3-hy-droxy-pridine)nitro cobalt(III). AB - The reaction cavities of the nitro groups in the title compounds, trans-bis (acetyl-acetonato-kappa2 O,O')(nitro)(pyridine-kappaN)cobalt(III), [Co(C5H7O2)2(NO2)(C5H5N)], (I), trans-bis-(acetyl-acetonato-kappa2 O,O')(4-methyl pyridine-kappaN)(nitro)cobalt(III), [Co(C5H7O2)2(NO2)(C6H7N)], (II), and trans bis-(acetyl-acetonato-kappa2 O,O')(3-hy-droxy-pyridine-kappaN)(nitro)cobalt(III) monohydrate, [Co(C5H7O2)2(NO2)(C5H5NO)].H2O, (III), have been investigated to reveal that bifurcated inter-molecular C(py)-H?O,O contacts in (III) are unfeasible for the nitro-nitrito photochemical linkage isomerization process. In each structure, the pyridine ring and the Co atom lie on a crystallographic mirror plane; in (I) and (II) the nitro group lies in the same plane, whereas in (III), which crystallizes as a monohydrate, the nitro group is disordered over three orientations in a 0.672 (16):0.164 (8):0.164 (8) ratio; the water mol-ecule of crystallization is statistically disordered over two sites adjacent to the mirror plane. In the crystals of (I) and (II), the mol-ecules are linked into [100] chains by C-H?O hydrogen bonds, whereas the extended structure of (III) features (010) layers linked by O-H?O and C-H?O hydrogen bonds. Compounds (I) and (II) were refined as inversion twins. PMID- 30443398 TI - Crystal structures of the [IrIII{C(C4H6O2)(dppm)-kappa3 P,C,O}(dppm)H](CF3O3S)2 and [IrIII{C(C4H6O2)(dppm)-kappa2 P,C}(CO)(dppm)H](CF3O3S)2 phosphorus ylide complexes, generated by a Wittig-type carbon-carbon coupling reaction of a carbodiphospho-rane PCP ligand system. AB - The reaction of [IrIII{C(dppm)2-kappa3 P,C,P'}ClH(NH3C2)]Cl with ethyl diazo acetate, a well known C=C coupling reagent, leads to the formation of a C=C unit, accompanied by N2 abstraction, reorganization of a dppm subunit and, considered as a whole, to the transformation of the PCP pincer carbodi-phospho-rane system to a phospho-rus ylide ligand. After removal of the halogenides, the iridium center is stabilized by the carbonyl O atom through the formation of a five membered chelate ring. A PCO pincer ligand system is thereby generated, which coordinates the iridium(III) atom threefold in a facial manner. The phospho-rus electron-donor atoms and the ylide carbon atom of the resulting [IrIII{C(C4H6O2)(dppm)-kappa3 P,C,O}(dppm)H](CF3O3S)2 complex, also termed as [bis-(di-phenyl-phosphan-yl)methane]({[(di-phenyl-phosphan-yl)meth-yl]di-phenyl phosphanyl-idene}(eth-oxy-oxoethanyl-idene)methanyl-idene-kappa3 P,C,O)hydridoiridium(III) bis-(tri-fluoro-methane-sulfonate), are in plane and the hydrido ligand and the carbonyl O atom are located trans to each other, perpendicular to the meridional plane. The addition of carbon monoxide causes a replacement of the carbonyl O atom of the acetate subunit by a carbonyl ligand, thereby creating [bis-(di-phenyl-phosphan-yl)methane]-carbon-yl({[(di-phenyl phosphan-yl)meth-yl]di-phenyl-phosphanyl-idene}(eth-oxy-oxoethanyl-idene)methanyl idene-kappa2 P,C}hydridoiridium(III) bis-(tri-fluoro-methane-sulfonate)-di-chloro methane-ethyl acetate (6/2/3) or, more simply, [IrIII{C(C4H6O2)(dppm)-kappa2 P,C}(CO)(dppm)H](CF3O3S)2.0.33CH2Cl2.0.5C4H8O2. One tri-fluoro-meth-ane-sulfonate counter-ion of 3 shows positional disorder in a 2:1 ratio. Complex 4 shows pseudo merohedral twinning (matrix: 0 0 0 0 1 0 1). The di-chloro-methane solvent is disordered over two orientations with occupation factors of 0.5 and 0.166. PMID- 30443399 TI - Crystal structure and Hirshfeld surface analysis of ethyl 2-{4-[(3-methyl-2-oxo 1,2-di-hydro-quinoxalin-1-yl)meth-yl]-1H-1,2,3-triazol-1-yl}acetate. AB - The mol-ecule of the title compound, C16H17N5O3, is build up from two fused six membered rings linked to a 1,2,3-triazole ring, which is attached to an ethyl azido-acetate group. The di-hydro-qinoxalinone portion is planar to within 0.0512 (12) A and is oriented at a dihedral angle of 87.83 (5) degrees with respect to the pendant triazole ring. In the crystal, a combination of inter-molecular C-H?O and C-H?N hydrogen bonds together with slipped pi-stacking [centroid-centroid distance = 3.7772 (12) A] and C-H?pi (ring) inter-actions lead to the formation of chains extending along the c-axis direction. Additional C-H?O hydrogen bonds link these chains into layers parallel to the bc plane and the layers are tied together by complementary pi-stacking [centroid-centroid distance = 3.5444 (12) A] inter-actions. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H?H (44.5%), H?O/O?H (18.8%), H?N/N?H (17.0%) and H?C/C?H (10.4%) inter-actions. PMID- 30443400 TI - Crystal structure and thermal properties of bis-[MU-2-(meth-oxy-carbonyl hydrazinyl-idene)acetato-kappa3 N 1,O:O]bis-[di-aqua-(thio-cyanato kappaN)manganese(II)] tetra-hydrate. AB - The title compound, [Mn2(C4H5N2O4)2(NCS)2(H2O)4].4H2O (I), exists as a centrosymmetric dimer. Each dimeric unit consists of tridentate (O,O,N)-chelating Schiff bases with symmetry-maintained MU-O-bridged carboxyl-ate anions, terminally bound thio-cyanate anions, and ligated and solvated water mol-ecules. The complex exhibits a distorted octa-hedron geometry and the centrosymmetric MU O-bridged carboxyl-ate anions connect the two manganese atoms to form an M 2O2 ring. In the crystal, the mol-ecules are inter-linked via strong N-H?O and O-H?O hydrogen-bonding contacts and weak O-H?S inter-molecular inter-actions, forming a three-dimensional mol-ecular network. PMID- 30443401 TI - Synthesis and structural characterization of four di-chlorido-bis-(cyclo-propyl alkynyl-amidine)-metal complexes. AB - Deliberate hydrolysis of lithium cyclo-propyl-alkynylamidinates, Li[c-C3H5 C=C(NR')2] [R' = i Pr, Cy = cyclo-hex-yl)], afforded the hitherto unknown neutral cyclo-propyl-alkynyl-amidine derivatives c-C3H5-C=C-C(NR')(NHR') [R' = i Pr (1), Cy (2)]. Subsequent reactions of 1 or 2 with metal(II) chlorides, MCl2 (M = Mn, Fe, Co), provided the title complexes di-chlorido-bis-(3-cyclo-propyl-N,N' diisopropyl-prop-2-ynamidine)-manganese(II), [MnCl2(C12H20N2)2], (3), di-chlorido bis-(3-cyclo-propyl-N,N'-diisopropyl-prop-2-ynamidine)-iron(II), [FeCl2(C12H20N2)2], (4), di-chlorido-bis-(N,N'-di-cyclo-hexyl-3-cyclo-propyl-prop 2-ynamidine)-iron(II), [FeCl2(C18H28N2)2], (5), and di-chlorido-bis-(N,N'-di cyclo-hexyl-3-cyclo-propyl-prop-2-ynamidine)-cobalt(II), [CoCl2(C18H28N2)2], (6), or more generally MCl2[c-C3H5-C=C-C(NR')(NHR')]2 [R' = i Pr, M = Mn (3), Fe (4); R' = Cy, M = Fe (5), Co (6)] in moderate yields (30-39%). Besides their spectroscopic data (IR and MS) and elemental analyses, all complexes 3-6 were structurally characterized. The two isopropyl-substituted complexes 3 and 4 are isotypic, and so are the cyclo-hexyl-substituted complexes 5 and 6. In all cases, the central metal atom is coordinated by two Cl atoms and two N atoms in a distorted-tetra-hedral fashion, and the structure is supported by intra-molecular N-H?Cl hydrogen bonds. PMID- 30443402 TI - Crystal structure of 1-butyl-3-{2-[(indan-5-yl)amino]-2-oxoeth-yl}-1H-imidazol-3 ium chloride. AB - In the cation of the title mol-ecular salt, C18H24N3O+.Cl-, an intra-molecular C H?O hydrogen bond stabilizes the almost coplanar orientation of the aromatic ring of the indane unit and the amide plane. In the crystal, the packing is dominated by inter-molecular C-H?Cl hydrogen-bonding inter-actions that result in the formation of slab-like structures propagating along [010]. The slabs are linked by weak C-H?O inter-actions, forming layers lying parallel to (100). The methyl ene carbon atom of the indanyl substituent is disordered over two positions with a refined occupancy ratio of 0.84 (2):0.16 (2). The crystal studied was refined as a twin with matrix [1 0 0.9, 0 0, 0 0 ]; the resulting BASF value is 0.30. PMID- 30443403 TI - Crystal structure and Hirshfeld surface analysis of (4Z)-1-butyl-4-(2-oxo-propyl idene)-2,3,4,5-tetra-hydro-1H-1,5-benzodiazepin-2-one. AB - The asymmetric unit of the title compound, C16H20N2O2, consists of two independent mol-ecules differing slightly in the conformations of the seven membered rings and the butyl substituents, where the benzene rings are oriented at a dihedral angle of 34.56 (3) degrees . In the crystal, pairwise inter molecular C-H?O and complementary intra-molecular C-H?O hydrogen bonds form twisted strips extending parallel to (012). These strips are connected into layers parallel to (111) by additional inter-molecular C-H?O hydrogen bonds. The layers are further joined by C-H?pi inter-actions. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H?H (65.5%), H?C/C?H (16.0%) and H?O/O?H (15.8%) inter actions. PMID- 30443404 TI - Crystal structure and Hirshfeld surface analysis of (E)-1-[(4,7-di-methyl quinolin-2-yl)methyl-idene]semicarbazide dihydrate. AB - In the title compound, C13H14N4O.2H2O, the organic mol-ecule is almost planar. In the crystal, the mol-ecules are linked by O-H?O, N-H?O and O-H?N hydrogen bonds, forming a two-dimensional network parallel to (10). Hirshfeld surface analysis and two-dimensional fingerprint plots indicate that the most important contributions to the crystal packing are from H?H (55.4%), H?O/O?H (14.8%), H?C/C?H (11.7%) and H?N/N?H (8.3%) inter-actions. PMID- 30443405 TI - Crystal structure at 100 K of bis-[1,2-bis-(di-phenyl-phosphan-yl)ethane] nickel(II) bis-(tri-fluoro-methane-sulfonate): a possible negative thermal expansion mol-ecular material. AB - In the title salt, [Ni(C26H24P2)2](CF3SO3)2 or [Ni(dppe)2]2+.(OTf-)2 [dppe = 1,2 bis-(di-phenyl-phosphan-yl)ethane and OTf- = tri-fluoro-methane-sulfonate], the Ni atom (site symmetry ) has a square-planar geometry with the bidentate ligands chelating the metal. As a result of the steric hindrance of the phenyl rings, the counter-ions are blocked from the metal coordination sphere. The dynamic disorder of the anion existing at 296 K is reduced at 100 K and based on these two temperatures, negative thermal expansion behaviour is observed. PMID- 30443406 TI - Crystal structure of bis-(diiso-propyl-ammonium) molybdate. AB - The organic-inorganic title salt, (C6H16N)2[MoO4] or ( i Pr2NH2)2[MoO4], was obtained by reacting MoO3 with diiso-propyl-amine in a 1:2 molar ratio in water. The molybdate anion is located on a twofold rotation axis and exhibits a slightly distorted tetra-hedral configuration. In the crystal structure, the diiso-propyl ammmonium ( i Pr2NH2)+ cations and [MoO4]2- anions are linked to each other through N-H?O hydrogen bonds, generating rings with R 12 12(36) motifs that give rise to the formation of a three-dimensional network. The structure was refined taking into account inversion twinning (ratio of ca 4:1 between the two domains). PMID- 30443407 TI - Crystal structure of [{FeCl3}2(MU-PCHP)2] [PCHP = 1,3-bis-(2-di-phenyl phosphanyleth-yl)-3H-imidazol-1-ium] with an unknown solvent. AB - The crystal structure of the title compound, bis-{MU-1,3-bis-[2-(di-phenyl phosphan-yl)eth-yl]-1H-imidazole-kappa2 P:P'}bis-[tri-chlorido-iron(III)], [Fe2Cl6(C31H31N2P2)2] or [{FeCl3}2(MU-PCHP)2] (PCHP = C31H31N2P2), consists of dinuclear complexes that are located about centres of inversion. The FeIII cation is in a distorted trigonal-bipyramidal coordination with three chloride ligands located in the trigonal plane and two P atoms of symmetry-related PCHP ligands occupying the axial positions. Within the centrosymmetric complex, a pair of intra-molecular C-H?Cl hydrogen bonds between aromatic CH groups and chloride ligands are found. Individual complexes are linked into layers parallel to (01) by inter-molecular C-H?Cl hydrogen bonds. No pronounced inter-molecular inter actions occur between these layers. This arrangement leaves space for disordered solvent mol-ecules. Electron density associated with these additional solvent mol ecules was removed with the SQUEEZE procedure in PLATON [Spek (2015 ?). Acta Cryst. C71, 9-18]. The given chemical formula and other crystal data do not take into account the unknown solvent mol-ecule(s). PMID- 30443408 TI - The outcomes of epiretinal membrane peeling in patients with foveal herniation. AB - Background: To evaluate the surgical outcomes of vitrectomy in patients with foveal herniation associated with epiretinal membrane (ERM). Methods: This was a retrospective case series. The patients who had a foveal herniation associated with ERM, underwent vitrectomy, and had a minimum follow-up period of 12 months were included. The visual and anatomical outcomes were assessed during the first 12 months of follow-up and at the last follow-up visit. The main outcome measure was the reorganization pattern of foveal pit at month 12. Results: Eleven eyes of 11 patients were included. The mean postoperative follow-up period was 14.8 +/- 2.6 months. The foveal contour was completely restored in 5 eyes (45.5%), partially restored in 5 eyes (45.5%), and was not restored in 1 eye (9.1%) at postoperative month 12 follow-up visit. The mean preoperative best corrected visual acuity was 0.61 +/- 0.16 LogMAR and increased to 0.49 +/- 0.16 LogMAR at month 12 (p < 0.0001). The mean preoperative central retinal thickness was 476 +/ 128 micrometers and decreased to 302 +/- 70 micrometers at month 12 (p < 0.0001). Conclusion: The foveal contour was restored in 45.5% of the eyes and visual acuity was significantly increased by a mean of 1.2 LogMAR lines at month 12 in patients with foveal herniation associated with ERM. PMID- 30443409 TI - Endogenous amdoparvovirus-related elements reveal insights into the biology and evolution of vertebrate parvoviruses. AB - Amdoparvoviruses (family Parvoviridae: genus Amdoparvovirus) infect carnivores, and are a major cause of morbidity and mortality in farmed animals. In this study, we systematically screened animal genomes to identify endogenous parvoviral elements (EPVs) disclosing a high degree of similarity to amdoparvoviruses, and investigated their genomic, phylogenetic and protein structural features. We report the first examples of full-length, amdoparvovirus derived EPVs in the genome of the Transcaucasian mole vole (Ellobius lutescens). We also identify four EPVs in mammal and reptile genomes that are intermediate between amdoparvoviruses and their sister genus (Protoparvovirus) in terms of their phylogenetic placement and genomic features. In particular, we identify a genome-length EPV in the genome of a pit viper (Protobothrops mucrosquamatus) that is more similar to a protoparvovirus than an amdoparvovirus in terms of its phylogenetic placement and the structural features of its capsid protein (as revealed by homology modeling), yet exhibits characteristically amdoparvovirus like genome features including: (1) a putative middle ORF gene; (2) a capsid gene that lacks a phospholipase A2 domain; (3) a genome structure consistent with an amdoparvovirus-like mechanism of capsid gene expression. Our findings indicate that amdoparvovirus host range extends to rodents, and that parvovirus lineages possessing a mixture of proto- and amdoparvovirus-like characteristics have circulated in the past. In addition, we show that EPV sequences in the mole vole and pit viper encode intact, expressible replicase genes that have potentially been co-opted or exapted in these host species. PMID- 30443412 TI - Making Sense of the Big Picture: Data Linkage and Integration in the Era of Big Data. PMID- 30443411 TI - Evaluation of intraductal delivery of poly(ethylene glycol)-doxorubicin conjugate nanocarriers for the treatment of ductal carcinoma in situ (DCIS)-like lesions in rats. AB - Ductal carcinoma in situ is the most commonly diagnosed early stage breast cancer. The efficacy of intraductally delivered poly(ethylene glycol)-doxorubicin (PEG-DOX) nanocarriers, composed of one or more DOX conjugated to various PEG polymers, was investigated in an orthotopic ductal carcinoma in situ-like rat model. In vitro cytotoxicity was evaluated against 13762 Mat B III cells using MTT assay. The orthotopic model was developed by inoculating cancer cells into mammary ducts of female Fischer 344 retired breeder rats. The ductal retention and in vivo antitumour efficacy of two of the six nanocarriers (5 kDa PEG-DOX and 40 kDa PEG-(DOX)4) were investigated based on in vitro results. Mammary retention of DOX and PEG-DOX nanocarriers was quantified using in vivo imaging. Histopathologic effects of DOX and PEG-DOX nanocarriers on mammary ductal structure were also investigated. Cytotoxicities of small linear PEG-DOX nanocarriers (5 and 10 kDa) were not different from DOX whereas larger PEG-DOX nanocarriers showed reduced potency. The order of mammary retention was 40 kDa PEG-(DOX)4 > 5 kDa PEG-DOX >> DOX, in normal and tumour-bearing rats. Intraductally administered PEG-DOX nanocarriers and DOX were effective in reducing tumour incidence and increasing survival rate, with no significant differences found among the three treatment groups. However, nanocarriers administered intravenously at the same doses were not effective, and intraductally administered free DOX caused severe local toxicity. Intraductal administration of PEG-DOX nanocarriers is effective and less toxic than that of free DOX, as well as IV DOX/PEG-DOX. Furthermore, PEG-DOX nanocarriers demonstrate the added benefit of prolonging DOX ductal retention, which would necessitate less frequent dosing. PMID- 30443410 TI - Nanodelivery strategies for the treatment of multidrug-resistant bacterial infections. AB - One of the most important health concerns in society is the development of nosocomial infections caused by multidrug-resistant pathogens. The purpose of this review is to discuss the issues in current antibiotic therapies and the ongoing progress of developing new strategies for the treatment of ESKAPE pathogen infections, which is acronymized for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. We not only examine the current issues caused by multidrug resistance but we also examine the barrier effects such as biofilm and intracellular localization exploited by these pathogens to avoid antibiotic exposure. Recent innovations in nanomedicine approaches and antibody antibiotic conjugates are reviewed as potential novel approaches for the treatment of bacterial infection, which ultimately may expand the useful life span of current antibiotics. PMID- 30443413 TI - Digital Epidemiology: Use of Digital Data Collected for Non-epidemiological Purposes in Epidemiological Studies. AB - Objectives: We reviewed digital epidemiological studies to characterize how researchers are using digital data by topic domain, study purpose, data source, and analytic method. Methods: We reviewed research articles published within the last decade that used digital data to answer epidemiological research questions. Data were abstracted from these articles using a data collection tool that we developed. Finally, we summarized the characteristics of the digital epidemiological studies. Results: We identified six main topic domains: infectious diseases (58.7%), non-communicable diseases (29.4%), mental health and substance use (8.3%), general population behavior (4.6%), environmental, dietary, and lifestyle (4.6%), and vital status (0.9%). We identified four categories for the study purpose: description (22.9%), exploration (34.9%), explanation (27.5%), and prediction and control (14.7%). We identified eight categories for the data sources: web search query (52.3%), social media posts (31.2%), web portal posts (11.9%), webpage access logs (7.3%), images (7.3%), mobile phone network data (1.8%), global positioning system data (1.8%), and others (2.8%). Of these, 50.5% used correlation analyses, 41.3% regression analyses, 25.6% machine learning, and 19.3% descriptive analyses. Conclusions: Digital data collected for non epidemiological purposes are being used to study health phenomena in a variety of topic domains. Digital epidemiology requires access to large datasets and advanced analytics. Ensuring open access is clearly at odds with the desire to have as little personal data as possible in these large datasets to protect privacy. Establishment of data cooperatives with restricted access may be a solution to this dilemma. PMID- 30443414 TI - Automated Audiometry: A Review of the Implementation and Evaluation Methods. AB - Objectives: Automated audiometry provides an opportunity to do audiometry when there is no direct access to a clinical audiologist. This approach will help to use hearing services and resources efficiently. The purpose of this study was to review studies related to automated audiometry by focusing on the implementation of an audiometer, the use of transducers and evaluation methods. Methods: This review study was conducted in 2017. The papers related to the design and implementation of automated audiometry were searched in the following databases: Science Direct, Web of Science, PubMed, and Scopus. The time frame for the papers was between January 1, 2010 and August 31, 2017. Initially, 143 papers were found, and after screening, the number of papers was reduced to 16. Results: The findings showed that the implementation methods were categorized into the use of software (7 papers), hardware (3 papers) and smartphones/tablets (6 papers). The used transducers were a variety of earphones and bone vibrators. Different evaluation methods were used to evaluate the accuracy and the reliability of the diagnoses. However, in most studies, no significant difference was found between automated and traditional audiometry. Conclusions: It seems that automated audiometry produces the same results compared with traditional audiometry. However, the main advantages of this method; namely, saving costs and increased accessibility to hearing services, can lead to a faster diagnosis of hearing impairment, especially in poor areas. PMID- 30443415 TI - Effective Validation Model and Use of Mobile-Health Applications for the Elderly. AB - Objectives: Due to the uncontrolled increase of the mobile health applications and their scarce use by elderly for reason of absence credibility of measurements by lack scientific support, the aim of this study was to evaluate the differences between the biophysical measurements based on standard instrument against a mobile application using controlled experiments with elderly to propose an effective validation model of the developed apps. Methods: The subjects of the study (50 people) were elderly people who wanted to check their weight and cardiac status. For this purpose, two mobile applications were used to measure energy expenditure based on physical activity (Activ) and heart rate (SMCa) during controlled walking at specific speeds. Minute-by-minute measurements were recorded to evaluate the average error and the accuracy of the data acquired through confidence intervals by means of statistical analysis of the data. Results: The experimental results obtained by the Activ/SMCa apps showed a consistent statistical similarity with those obtained by specialized equipment with confidence intervals of 95%. All the subjects were advised and trained on the use of the applications, and the initial registration of data to characterize them served to significantly affect the perceived ease of use. Conclusions: This is the first model to validate a health-app with elderly people allowed to demonstrate the anthropometric and body movement differences of subjects with equal body mass index (BMI) but younger. Future studies should consider not only BMI data but also other variables, such as age and usability perception factors. PMID- 30443416 TI - Need Assessment for Smartphone-Based Cardiac Telerehabilitation. AB - Objectives: To identify the current status of smartphone usage and to describe the needs for smartphone-based cardiac telerehabilitation of cardiac patients. Methods: In 2016, a questionnaire survey was conducted in a supervised ambulatory cardiac rehabilitation (CR) program in a university affiliated hospital with the participation of heart failure or heart transplantation patients who were smartphone users. The questionnaire included questions regarding smartphone usage, demands for smartphone-based disease education, and home health monitoring systems. Results were described and analyzed according to principal diagnosis. Results: Ninety-six patients (66% male; mean age, 53 +/- 11 years), including 56 heart failure and 40 heart transplantation patients, completed the survey (completion rate, 95%). The median daily smartphone usage time was 120 minutes (interquartile range, 60-300), and the most frequently used smartphone function was text messaging (61.5%). Of the patients, 26% stated that they searched for health-related information using their smartphones more than 1 time per week. The major source of health-related information was Internet browsing (50.0%), and the least sought source was the hospital's website (3.1%). Patients with heart failure expressed significantly higher needs for disease education on treatment plan, home health monitoring of blood pressure, and body weight (chi2 = 5.79, 6.27, 4.50, p < 0.05). Heart transplantation patients expressed a significant need for home health monitoring of body temperature (chi2 = 5.25, p < 0.05). Conclusions: Heart failure and heart transplantation patients show high usage of and interest in mobile health technology. A smartphone-based cardiac telerehabilitation program should be developed based on high demand areas and modified to suit to each principal diagnosis. PMID- 30443417 TI - Preferences of ICT among Patients with Chronic Kidney Disease Undergoing Hemodialysis: An Ecuadorian Cross-Sectional Study. AB - Objectives: The aim of the present study was to assess the frequency of use, and preferences regarding information and communication technologies (ICTs) among Ecuadorian patients with chronic kidney disease (CKD) undergoing hemodialysis. Methods: We conducted an anonymous cross-sectional survey-based study from January 2016 to April 2017, involving 393 patients with end-stage renal disease from 9 hemodialysis centers, in which they rated their use and preferences of various ICTs through a modified version of the Michigan Questionnaire. The questionnaire collected information regarding demographics, patients' interest in obtaining health-related information through ICTs, and interest in using ICTs as a potential way to communicate with their healthcare providers. A chi-square test for association and adjusted regression analyses were performed. Results: Among all patients who participated, 64.3% reported owning a cellphone, with less than a third reporting active Internet connection. The most used ICT for obtaining information about CKD and/or hemodialysis was web-based Internet, followed by YouTube. SMS was rated the highest to receive and seek health-related information, followed by Facebook. Younger age and higher levels of education were associated with a higher overall usage of ICTs. Finally, more than half of the patients reported interest in using WhatsApp for communicating with their healthcare providers. Conclusions: Understanding the preferences of ICTs among patients with CKD undergoing hemodialysis could help to improve their outcomes through the potential uses and benefits of ICTs. Further research is needed to assess their role in improving the care of patients with chronic diseases. PMID- 30443418 TI - Google Search Trends Predicting Disease Outbreaks: An Analysis from India. AB - Objectives: Prompt detection is a cornerstone in the control and prevention of infectious diseases. The Integrated Disease Surveillance Project of India identifies outbreaks, but it does not exactly predict outbreaks. This study was conducted to assess temporal correlation between Google Trends and Integrated Disease Surveillance Programme (IDSP) data and to determine the feasibility of using Google Trends for the prediction of outbreaks or epidemics. Methods: The Google search queries related to malaria, dengue fever, chikungunya, and enteric fever for Chandigarh union territory and Haryana state of India in 2016 were extracted and compared with presumptive form data of the IDSP. Spearman correlation and scatter plots were used to depict the statistical relationship between the two datasets. Time trend plots were constructed to assess the correlation between Google search trends and disease notification under the IDSP. Results: Temporal correlation was observed between the IDSP reporting and Google search trends. Time series analysis of the Google Trends showed strong correlation with the IDSP data with a lag of -2 to -3 weeks for chikungunya and dengue fever in Chandigarh (r > 0.80) and Haryana (r > 0.70). Malaria and enteric fever showed a lag period of -2 to -3 weeks with moderate correlation. Conclusions: Similar results were obtained when applying the results of previous studies to specific diseases, and it is considered that many other diseases should be studied at the national and sub-national levels. PMID- 30443419 TI - Arousal and Valence Classification Model Based on Long Short-Term Memory and DEAP Data for Mental Healthcare Management. AB - Objectives: Both the valence and arousal components of affect are important considerations when managing mental healthcare because they are associated with affective and physiological responses. Research on arousal and valence analysis, which uses images, texts, and physiological signals that employ deep learning, is actively underway; research investigating how to improve the recognition rate is needed. The goal of this research was to design a deep learning framework and model to classify arousal and valence, indicating positive and negative degrees of emotion as high or low. Methods: The proposed arousal and valence classification model to analyze the affective state was tested using data from 40 channels provided by a dataset for emotion analysis using electrocardiography (EEG), physiological, and video signals (the DEAP dataset). Experiments were based on 10 selected featured central and peripheral nervous system data points, using long short-term memory (LSTM) as a deep learning method. Results: The arousal and valence were classified and visualized on a two-dimensional coordinate plane. Profiles were designed depending on the number of hidden layers, nodes, and hyperparameters according to the error rate. The experimental results show an arousal and valence classification model accuracy of 74.65 and 78%, respectively. The proposed model performed better than previous other models. Conclusions: The proposed model appears to be effective in analyzing arousal and valence; specifically, it is expected that affective analysis using physiological signals based on LSTM will be possible without manual feature extraction. In a future study, the classification model will be adopted in mental healthcare management systems. PMID- 30443420 TI - Design of a Hospice Referral System for Terminally Ill Cancer Patients Using a Standards-Based Health Information Exchange System. AB - Objectives: The demand for hospice has been increasing among patients with cancer. This study examined the current hospice referral scenario for terminally ill cancer patients and created a data form to collect hospice information and a modified health information exchange (HIE) form for a more efficient referral system for terminally ill cancer patients. Methods: Surveys were conducted asking detailed information such as medical instruments and patient admission policies of hospices, and interviews were held to examine the current referral flow and any additional requirements. A task force team was organized to analyze the results of the interviews and surveys. Results: Six hospices completed the survey, and 3 physicians, 2 nurses, and 2 hospital staff from a tertiary hospital were interviewed. Seven categories were defined as essential for establishing hospice data. Ten categories and 40 data items were newly suggested for the existing HIE document form. An implementation guide for the Consolidated Clinical Document Architecture developed by Health Level 7 (HL7 CCDA) was also proposed. It is an international standard for interoperability that provides a framework for the exchange, integration, sharing, and retrieval of electronic health information. Based on these changes, a hospice referral scenario for terminally ill cancer patients was designed. Conclusions: Our findings show potential improvements that can be made to the current hospice referral system for terminally ill cancer patients. To make the referral system useful in practice, governmental efforts and investments are needed. PMID- 30443421 TI - Association between Electronic Medical Record System Adoption and Healthcare Information Technology Infrastructure. AB - Objectives: The objective of this study was to investigate the relationship between the level of Electronic Medical Record (EMR) system adoption and healthcare information technology (IT) infrastructure. Methods: Both survey and various healthcare administrative datasets in Korea were used. The survey was conducted during the period from June 13 to September 25, 2017. The chief information officers of hospitals were respondents. Among them, 257 general hospitals and 273 small hospitals were analyzed. A logistic regression analysis was conducted using the SAS program. Results: The odds of having full EMR systems in general hospitals statistically significantly increased as the number of IT department staff members increased (odds ratio [OR] = 1.058, confidence interval [CI], 1.003-1.115; p = 0.038). The odds of having full EMR systems was significantly higher for small hospitals that had an IT department than those of small hospitals with no IT department (OR = 1.325; CI, 1.150-1.525; p < 0.001). Full EMR system adoption had a positive relationship with IT infrastructure in both general hospitals and small hospitals, which was statistically significant in small hospitals. The odds of having full EMR systems for small hospitals increased as IT infrastructure increased after controlling the covariates (OR = 1.527; CI, 1.317-4.135; p = 0.004). Conclusions: This study verified that full EMR adoption was closely associated with IT infrastructure, such as organizational structure, human resources, and various IT subsystems. This finding suggests that political support related to these areas is indeed necessary for the fast dispersion of EMR systems into the healthcare industry. PMID- 30443422 TI - Automated Detection of Retinal Nerve Fiber Layer by Texture-Based Analysis for Glaucoma Evaluation. AB - Objectives: The retinal nerve fiber layer (RNFL) is a site of glaucomatous optic neuropathy whose early changes need to be detected because glaucoma is one of the most common causes of blindness. This paper proposes an automated RNFL detection method based on the texture feature by forming a co-occurrence matrix and a backpropagation neural network as the classifier. Methods: We propose two texture features, namely, correlation and autocorrelation based on a co-occurrence matrix. Those features are selected by using a correlation feature selection method. Then the backpropagation neural network is applied as the classifier to implement RNFL detection in a retinal fundus image. Results: We used 40 retinal fundus images as testing data and 160 sub-images (80 showing a normal RNFL and 80 showing RNFL loss) as training data to evaluate the performance of our proposed method. Overall, this work achieved an accuracy of 94.52%. Conclusions: Our results demonstrated that the proposed method achieved a high accuracy, which indicates good performance. PMID- 30443423 TI - Bayesian Network Model to Evaluate the Effectiveness of Continuous Positive Airway Pressure Treatment of Sleep Apnea. AB - Objectives: The association between obstructive sleep apnea (OSA) and mortality or serious cardiovascular events over a long period of time is not clearly understood. The aim of this observational study was to estimate the clinical effectiveness of continuous positive airway pressure (CPAP) treatment on an outcome variable combining mortality, acute myocardial infarction (AMI), and cerebrovascular insult (CVI) during a follow-up period of 15.5 years (186 +/- 58 months). Methods: The data set consisted of 978 patients with an apnea-hypopnea index (AHI) >=5.0. One-third had used CPAP treatment. For the first time, a data driven causal Bayesian network (DDBN) and a hypothesis-driven causal Bayesian network (HDBN) were used to investigate the effectiveness of CPAP. Results: In the DDBN, coronary heart disease (CHD), congestive heart failure (CHF), and diuretic use were directly associated with the outcome variable. Sleep apnea parameters and CPAP treatment had no direct association with the outcome variable. In the HDBN, CPAP treatment showed an average improvement of 5.3 percentage points in the outcome. The greatest improvement was seen in patients aged <=55 years. The effect of CPAP treatment was weaker in older patients (>55 years) and in patients with CHD. In CHF patients, CPAP treatment was associated with an increased risk of mortality, AMI, or CVI. Conclusions: The effectiveness of CPAP is modest in younger patients. Long-term effectiveness is limited in older patients and in patients with heart disease (CHD or CHF). PMID- 30443424 TI - Public Acceptance of a Health Information Exchange in Korea. AB - Objectives: We assessed the public acceptance of a health information exchange (HIE) and examined factors that influenced the acceptance and associations among constructs of the Technology Acceptance Model (TAM). Methods: We collected data from a survey of 1,000 individuals in Korea, which was administered through a structured questionnaire. We assessed the validity and reliability of the survey instrument with exploratory factor analysis and Cronbach's alpha coefficients. We computed descriptive statistics to assess the acceptance and performed regression analyses with a structural equation model to estimate the magnitude and significance of influences among constructs of TAM. Results: Eighty-seven percent of the respondents were willing to use the technology, and the average level of agreement with the need for the technology was 4.16 on a 5-point Likert scale. The perception of ease of use of the technology significantly influenced perceptions of usefulness and attitudes about the need for HIE. Perceptions of usefulness influenced attitude and behavioral intention to use HIE, and attitude influenced intention. Age showed a wide range of influences throughout the model, and experience with offline-based information exchange and health status also showed noteworthy influences. Conclusions: The public acceptance of HIE was high, and influences posited by TAM were mostly confirmed by the study results. The study findings indicated a need for an education and communication strategy tailored by population age, health status, and prior experience with offline based exchange to gain public buy-in for a successful introduction of the technology. PMID- 30443425 TI - Laboratory Environment Monitoring: Implementation Experience and Field Study in a Tertiary General Hospital. AB - Objectives: To successfully introduce an Internet of Things (IoT) system in the hospital environment, this study aimed to identify issues that should be considered while implementing an IoT based on a user demand survey and practical experiences in implementing IoT environment monitoring systems. Methods: In a field test, two types of IoT monitoring systems (on-premises and cloud) were used in Department of Laboratory Medicine and tested for approximately 10 months from June 16, 2016 to April 30, 2017. Information was collected regarding the issues that arose during the implementation process. Results: A total of five issues were identified: sensing and measuring, transmission method, power supply, sensor module shape, and accessibility. Conclusions: It is expected that, with sufficient consideration of the various issues derived from this study, IoT monitoring systems can be applied to other areas, such as device interconnection, remote patient monitoring, and equipment/environmental monitoring. PMID- 30443426 TI - Design and Construction of a NLP Based Knowledge Extraction Methodology in the Medical Domain Applied to Clinical Information. AB - Objectives: This research presents the design and development of a software architecture using natural language processing tools and the use of an ontology of knowledge as a knowledge base. Methods: The software extracts, manages and represents the knowledge of a text in natural language. A corpus of more than 200 medical domain documents from the general medicine and palliative care areas was validated, demonstrating relevant knowledge elements for physicians. Results: Indicators for precision, recall and F-measure were applied. An ontology was created called the knowledge elements of the medical domain to manipulate patient information, which can be read or accessed from any other software platform. Conclusions: The developed software architecture extracts the medical knowledge of the clinical histories of patients from two different corpora. The architecture was validated using the metrics of information extraction systems. PMID- 30443427 TI - Ecological Momentary Assessment Using Smartphone-Based Mobile Application for Affect and Stress Assessment. AB - Objectives: This study aimed to describe the process of utilizing a mobile application for ecological momentary assessment (EMA) to collect data on stress and mood in daily life setting. Methods: A mobile application for the Android operating system was developed and installed with a set of questions regarding momentary mood and stress into a smartphone of a participant. The application sets alarms at semi-random intervals in 60-minute blocks, four times a day for 7 days. After obtaining all momentary affect and stress, the questions to assess the usability of the mobile EMA application were also administered. Results: The data were collected from 97 police officers working in Gyeonggi Province of South Korea. The mean completion rate was 60.0% ranging from 3.5% to 100%. The means of positive and negative affect were 18.34 of 28 and 19.09 of 63. The mean stress was 17.92 of 40. Participants responded that the mobile application correctly measured their affect (4.34 +/- 0.83) and stress (4.48 +/- 0.62) of 5-point Likert scale. Conclusions: Our study investigated the process of utilizing a mobile application to assess momentary affect and stress at repeated times. We found challenges regarding adherence to the research protocol, such as completion and delay of answering after alarm notification. Despite this inherent issue of adherence to the research protocol, the EMA still has advantages of reducing recall bias and assessing the actual moment of interest at multiple time points that improves ecological validity. PMID- 30443428 TI - How to Sustain Smart Connected Hospital Services: An Experience from a Pilot Project on IoT-Based Healthcare Services. AB - Objectives: This paper describes an experience of implementing seamless service trials online and offline by adopting Internet of Things (IoT) technology based on near-field communication (NFC) tags and Bluetooth low-energy (BLE) beacons. The services were provided for both patients and health professionals. Methods: The pilot services were implemented to enhance healthcare service quality, improve patient safety, and provide an effective business process to health professionals in a tertiary hospital in Seoul, Korea. The services to enhance healthcare service quality include healing tours, cancer information/education, psychological assessments, indoor navigation, and exercise volume checking. The services to improve patient safety are monitoring of high-risk inpatients and delivery of real-time health information in emergency situations. In addition, the services to provide an effective business process to health professionals include surveys and web services for patient management. Results: Considering the sustainability of the pilot services, we decided to pause navigation and patient monitoring services until the interference problem could be completely resolved because beacon signal interference significantly influences the quality of services. On the other hand, we had to continue to provide new wearable beacons to high-risk patients because of hygiene issues, so the cost increased over time and was much higher than expected. Conclusions: To make the smart connected hospital services sustainable, technical feasibility (e.g., beacon signal interference), economic feasibility (e.g., continuous provision of new necklace beacons), and organizational commitment and support (e.g., renewal of new alternative medical devices and infrastructure) are required. PMID- 30443429 TI - Augmented Reality to Localize Individual Organ in Surgical Procedure. AB - Objectives: Augmented reality (AR) technology has become rapidly available and is suitable for various medical applications since it can provide effective visualization of intricate anatomical structures inside the human body. This paper describes the procedure to develop an AR app with Unity3D and Vuforia software development kit and publish it to a smartphone for the localization of critical tissues or organs that cannot be seen easily by the naked eye during surgery. Methods: In this study, Vuforia version 6.5 integrated with the Unity Editor was installed on a desktop computer and configured to develop the Android AR app for the visualization of internal organs. Three-dimensional segmented human organs were extracted from a computerized tomography file using Seg3D software, and overlaid on a target body surface through the developed app with an artificial marker. Results: To aid beginners in using the AR technology for medical applications, a 3D model of the thyroid and surrounding structures was created from a thyroid cancer patient's DICOM file, and was visualized on the neck of a medical training mannequin through the developed AR app. The individual organs, including the thyroid, trachea, carotid artery, jugular vein, and esophagus were localized by the surgeon's Android smartphone. Conclusions: Vuforia software can help even researchers, students, or surgeons who do not possess computer vision expertise to easily develop an AR app in a user-friendly manner and use it to visualize and localize critical internal organs without incision. It could allow AR technology to be extensively utilized for various medical applications. PMID- 30443430 TI - Impact of the 2013 Floods on the Incidence of Malaria in Almanagil Locality, Gezira State, Sudan. AB - BACKGROUND: Heavy rain hit Sudan in August 2013 with subsequent flash floods in different parts of the country. This study investigated the impact of the flooding on incidence of malaria in Almanagil Locality in central Sudan. METHODS: This observational retrospective study compared malaria data sets during rainfall seasons in the Almanagil Locality in the year of flooding (2013) with those of corresponding rainfall seasons of previous two non-flood years (2011 and 2012). RESULTS: A marked increase of new malaria cases and incidence rate was observed in the 13 sentinel malaria notification sites in the locality (IR increased from 6.09 per 100,000 person-days in 2011 [95 % CI: 5.93-6.26] and 6.48 in 2012 [95 % CI: 6.31-6.65] to 8.24 in 2013 [95 % CI: 8.05-8.43] ; P< 0.0001), with a peaking of the incidence rate in the under-5-years age group (IR for this age group jumped from 9.80 per 100,000 person-days in 2011 [95 % CI: 9.29-10.32] and 10.00 in 2012 [95 % CI: 9.52-10.49] to 15.02 in 2013 [95 % CI: 14.41-15.64]). A noticeable increase in the slide positivity rate (P< 0.0001) was observed in the 12-week period of 2013 (SPR = 20.86% [95 % CI: 20.40 -21.32%]) compared with the same periods in 2011 (SPR = 8.72% [95 % CI: 8.36 -9.08%]) and 2012 (SPR = 12.62% [95 % CI: 12.24 -13.01%]), with a more marked rise of the SPR in the under-5-year age group. Hospital data showed increase in both the inpatient and outpatient incidence proportions in the study period of 2013 compared to those of the years 2011 and 2012. Hospital OPD incidence proportion in 2013 was 19.7% (95% CI: 19.24 20.18%) compared to 12.85% (95% CI: 12.48-13.23%) in 2011, and 12.16% (95% CI: 11.82-12.51%) in 2012. The < 5 year old groups were responsible for the overall rise in the proportion of malaria cases in 2013 , particularly the < 1 year old group which more than doubled in the 2013 period compared to both 2011 and 2012 periods (Age-specific proportion of the outpatient malaria cases of the < 1 year old group in 2013 was19.5% [95% CI: 18.5-20.6%] compared to 7.7% [95% CI: 6.9 8.6%] in 2011 and 8.1% [95% CI: 7.3-8.9%] in 2012. Incidence proportion of severe malaria cases (inpatients) increased to 22.5 % (95 % CI: 21.5 to 23.6 %) in the study period of 2013 compared to 19.8 % (95 % CI: 18.6 to 21.0 %) in 2011 and 18.4 % (95 % CI: 17.4 to 19.5) in 2012. The increase in the proportion of severe malaria cases was mainly due to a higher proportion of children < 5 years of age and especially to a higher proportion of children < 1 year of age. CONCLUSION: The study revealed a significant increase in the incidence rate of malaria in Almanagil Locality following the flash flood of August 2013. The flooding had the highest impact on the malaria incidence of the under-5-years age group, and particularly of the under-1-year age group. PMID- 30443431 TI - Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS). AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular condition manifested by progressive skeletal muscle weakness, cardiopulmonary involvement and cognitive deficits. Neurodevelopmental symptoms and signs are under-appreciated in this population despite the recognition that cognition has a major impact on quality-of-life. We describe the neurodevelopmental needs in a large cohort of young boys with DMD from the DMD Natural History Study (DNHS). We explore the association between neurodevelopmental needs and DMD mutation location, and with glucocorticoid use. Methods: We prospectively evaluated 204 participants between ages 4 to less than 9 years of age with DMD as part of a large, longitudinal, international DNHS. We obtained parent- or primary care-giver report of neurodevelopmental needs as part of their study visit. We assessed the relationship between parent/care-giver neurodevelopmental needs and DMD mutation location, and glucocorticoid use. RESULTS: The neurodevelopmental needs that were most commonly reported included speech delay (33%), mild developmental delay (24%), significant behavioral problems (16.5%), language impairment (14.5%), learning disability (14.5%), attention-deficit hyperactivity disorder (5%) and autism spectrum disorder (3%). Neurodevelopmental needs were more commonly reported by care-givers in those with DMD mutations downstream of exon 51. There was no relationship between care-giver reported neurodevelopmental needs and glucocorticoid use. CONCLUSION: Neurodevelopmental needs are highly prevalent in young boys with DMD. Care-givers report higher neurodevelopmental needs when subjects have DMD mutations downstream of exon 51. Early interventions aimed at cognitive health are critical to improve the quality-of-life of individuals with DMD. TRIAL REGISTRATION: ClinicalTrials.gov NCT00468832. PMID- 30443432 TI - Uganda at Glance of 5.7 Magnitude Earthquake: Lessons for Earthquake Risk Reduction. AB - INTRODUCTION: Uganda remains seismically vulnerable to earthquakes, which constitute one of the most deadly naturally triggered disasters in the world. This is not surprising given the country's location in the East African Rift Valley System. METHOD: This paper draws mainly on the authors' live event experience and some media reports to narratively outline the nature of a sizable earthquake, which measured a magnitude of 5.7 on the Richter scale that struck Uganda and other countries within the Lake Victoria Basin region on 10th September 2016 in the afternoon. RESULTS: Rakai - a district in central region was the worst affected in Uganda. It witnessed the death of four people; 20 people were admitted to the hospital with injuries; a total of 590 people were affected; and serious structural damages mainly in buildings were reported, leaving many either razed to the ground or left with cracks. DISCUSSIONS: Although this earthquake was less devastating in terms of injuries and fatalities compared to two previous earthquakes in Uganda, based on the Modified Mercalli Intensity Scale it was still considered to be severe. Therefore, this paper identified some proactive lessons as far as earthquake risk reduction in Uganda is concerned, which among others include: encouraging earthquake-resistant buildings; the safety of essential infrastructure; earthquake early warning systems supported by free global technologies; and the safety of rescue workers along with prioritizing the psychosocial needs of rescue teams. With all this in mind, the September 2016 earthquake should serve as a timely reminder that there is a real need for the proactive ex-ante earthquake preparedness rather than risking an expensive post-ante approach to responding to any future devastating earthquakes in Uganda. PMID- 30443433 TI - Does the Humanitarian Sector Use Evidence-informed Standards? A Review of the 2011 Sphere Indicators for Wash, Food Security and Nutrition, and Health Action. AB - BACKGROUND: In 1997, the pursuit of greater accountability and effectiveness in humanitarian response prompted a multi-stakeholder collaboration to develop a set of indicators and standards to guide humanitarian practitioners, published later in the form of the Sphere Handbook. Twenty years after the first edition of the Handbook was developed, and in order to guide the 2018 revision, an assessment of the evidence base for current Water, Sanitation and Hygiene (WASH), Food Security and Nutrition, and Health Action indicators, as compared to evidence collated by the 2015 LSHTM Humanitarian Health Evidence Review (HHER), was conducted. METHODOLOGY: In order to assess the utility of the Sphere indicators as a tool with which to monitor and evaluate humanitarian activities, indicators from the WASH, Food Security and Nutrition, and Health Action chapters of the Sphere Handbook were analysed and classified according to the SMART criteria. Each indicator was then assessed based on existing evidence related to the effectiveness of humanitarian health interventions as compiled in the HHER. RESULTS: Of the 159 Sphere indicators intended to guide humanitarian response, only 2 met all of the SMART criteria. The remaining 157 did not provide any time indication for the measurement of the indicator. Furthermore, only 11 standards (23%) and 14 indicators (8%) are supported in part by 33 studies identified in the HHER. Less than one third of studies captured by HHER that explore interventions related to WASH, nutrition, or health could be linked to existing Sphere indicators. CONCLUSION: It is not possible to adequately link the 2011 Sphere indicators and standards to their sources in their current constitution, and they are not sufficiently evidence-informed. In the absence of clear measurement definitions, they do not provide necessarily detailed guidance. While recognising that a number of indicators have emerged as a combination of empirical evidence, expert experience, and "common sense", a focus on fewer indicators, each better defined, is likely to enhance the practical application of the Sphere Handbook in humanitarian settings. PMID- 30443434 TI - Use of a Fibrin Sealant Patch at Cesarean for Conservative Management of Morbidly Adherent Placenta. AB - Background Morbidly adherent placenta represents a surgical challenge and source of maternal morbidity and mortality. We report the use of a fibrin sealant patch to address hemorrhage associated with a morbidly adherent placenta during cesarean delivery. Case A patient underwent repeat cesarean delivery with complete anterior placenta previa and anticipated morbidly adherent placenta. Bleeding persisted following delivery and removal of the placenta, despite uterine artery embolization. A fibrin sealant patch was applied as an adjuvant intervention to the placental bed and hemostasis was achieved without resorting to a hysterectomy. Conclusion Postpartum hemorrhage is an ongoing leading source of maternal morbidity and mortality. A case is presented in which a fibrin sealant patch provided control of focal placental bed bleeding, allowing removal of a focal morbidly adherent placenta and avoidance of hysterectomy. PMID- 30443435 TI - Mermaid Syndrome: A Case Report of a Rare Congenital Anomaly in Full-Term Neonate with Thumb Deformity. AB - The mermaid syndrome (sirenomelia) is an extremely rare anomaly, an incidence of 1 in 100,000 births, in which a newborn born with legs joined together featuring a mermaid-like appearance (head and trunk like humans and tail like fish), and in most cases die shortly after birth. Gastrointestinal and urogenital anomalies and single umbilical artery are clinical outcome of this syndrome. There are two important hypotheses for pathogenesis of mermaid syndrome: vitelline artery steal hypothesis and defective blastogenesis hypothesis. The cause of the mermaid syndrome is unknown, but there are some possible factors such as age younger than 20 years and older than 40 years in mother and exposure of fetus to teratogenics. Here, we introduced 19-year-old mother's first neonate with mermaid syndrome. The mother had gestational diabetes mellitus and neonate was born with single lower limb, ambiguous genitalia, and thumb anomalies, and 4 days after birth, the neonate died due to multiple anomalies and imperforated anus. PMID- 30443436 TI - Observability and Controllability of Nonlinear Networks: The Role of Symmetry. AB - Observability and controllability are essential concepts to the design of predictive observer models and feedback controllers of networked systems. For example, noncontrollable mathematical models of real systems have subspaces that influence model behavior, but cannot be controlled by an input. Such subspaces can be difficult to determine in complex nonlinear networks. Since almost all of the present theory was developed for linear networks without symmetries, here we present a numerical and group representational framework, to quantify the observability and controllability of nonlinear networks with explicit symmetries that shows the connection between symmetries and nonlinear measures of observability and controllability. We numerically observe and theoretically predict that not all symmetries have the same effect on network observation and control. Our analysis shows that the presence of symmetry in a network may decrease observability and controllability, although networks containing only rotational symmetries remain controllable and observable. These results alter our view of the nature of observability and controllability in complex networks, change our understanding of structural controllability, and affect the design of mathematical models to observe and control such networks. PMID- 30443437 TI - Representation of Deep Features using Radiologist defined Semantic Features. AB - Semantic features are common radiological traits used to characterize a lesion by a trained radiologist. These features have been recently formulated, quantified on a point scale in the context of lung nodules by our group. Certain radiological semantic traits have been shown to extremely predictive of malignancy [26]. Semantic traits observed by a radiologist at examination describe the nodules and the morphology of the lung nodule shape, size, border, attachment to vessel or pleural wall, location and texture etc. Deep features are numeric descriptors often obtained from a convolutional neural network (CNN) which are widely used for classification and recognition. Deep features may contain information about texture and shape, primarily. Lately, with the advancement of deep learning, convolutional neural networks (CNN) are also being used to analyze lung nodules. In this study, we relate deep features to semantic features by looking for similarity in ability to classify. Deep features were obtained using a transfer learning approach from both an ImageNet pre-trained CNN and our trained CNN architecture. We found that some of the semantic features can be represented by one or more deep features. In this process, we can infer that some deep feature(s) have similar discriminatory ability as semantic features. PMID- 30443438 TI - Predicting Nodule Malignancy using a CNN Ensemble Approach. AB - Lung cancer is the leading cause of cancer-related deaths globally, which makes early detection and diagnosis a high priority. Computed tomography (CT) is the method of choice for early detection and diagnosis of lung cancer. Radiomics features extracted from CT-detected lung nodules provide a good platform for early detection, diagnosis, and prognosis. In particular when using low dose CT for lung cancer screening, effective use of radiomics can yield a precise non invasive approach to nodule tracking. Lately, with the advancement of deep learning, convolutional neural networks (CNN) are also being used to analyze lung nodules. In this study, our own trained CNNs, a pre-trained CNN and radiomics features were used for predictive analysis. Using subsets of participants from the National Lung Screening Trial, we investigated if the prediction of nodule malignancy could be further enhanced by an ensemble of classifiers using different feature sets and learning approaches. We extracted probability predictions from our different models on an unseen test set and combined them to generate better predictions. Ensembles were able to yield increased accuracy and area under the receiver operating characteristic curve (AUC). The best-known AUC of 0.96 and accuracy of 89.45% were obtained, which are significant improvements over the previous best AUC of 0.87 and accuracy of 76.79%. PMID- 30443439 TI - Imitating the Risky Decision-Making of Peers: An Experimental Study Among Emerging Adults. AB - This experiment examined whether emerging adults imitate the risky decision making of peers and whether peer susceptibility functions as a moderator. Overall, 63 emerging adults participated with a confederate of the same gender. The participants were randomly assigned to the experimental (confederate engaged in risky decision-making) or control (confederate did not engage in risky decision-making) condition. Risky decision-making was measured with the Stop Light Game task, and peer susceptibility was measured with a questionnaire. Linear regression analyses showed that the participants engaged in more risky decision-making when the peer displayed risky decision-making. Peer susceptibility was not found to be a significant moderator of this relationship. The findings showed that health education programs need to consider imitation to reduce the risky decision-making of emerging adults more effectively. PMID- 30443440 TI - QRS Complex Detection and Measurement Algorithms for Multichannel ECGs in Cardiac Resynchronization Therapy Patients. AB - We developed an automated approach for QRS complex detection and QRS duration (QRSd) measurement that can effectively analyze multichannel electrocardiograms (MECGs) acquired during abnormal conduction and pacing in heart failure and cardiac resynchronization therapy (CRT) patients to enable the use of MECGs to characterize cardiac activation in such patients. The algorithms use MECGs acquired with a custom 53-electrode investigational body surface mapping system and were validated using previously collected data from 58 CRT patients. An expert cohort analyzed the same data to determine algorithm accuracy and error. The algorithms: 1) detect QRS complexes; 2) identify complexes of the most prevalent morphology and morphologic outliers; and 3) determine the array specific (i.e., anterior and posterior) and global QRS complex onsets, offsets, and durations for the detected complexes. The QRS complex detection algorithm had a positive predictivity and sensitivity of >=96% for complex detection and classification. The absolute QRSd error was 17 +/- 14 ms, or 12%, for array specific QRSd and 12 +/- 10 ms, or 8%, for global QRSd. The absolute global QRSd error (12 ms) was less than the interobserver variation in that measurement (15 +/- 10 ms). The sensitivity, positive predictivity, and error of the algorithms were similar to the values reported for current state-of-the-art algorithms designed for and limited to simpler data sets and conduction patterns and within the variation found in clinical 12-lead ECG QRSd measurement techniques. These new algorithms permit accurate, real-time analysis of QRS complex features in MECGs in patients with conduction disorders and/or pacing. PMID- 30443441 TI - An Open-Source Feature Extraction Tool for the Analysis of Peripheral Physiological Data. AB - Electrocardiogram, electrodermal activity, electromyogram, continuous blood pressure, and impedance cardiography are among the most commonly used peripheral physiological signals (biosignals) in psychological studies and healthcare applications, including health tracking, sleep quality assessment, disease early detection/diagnosis, and understanding human emotional and affective phenomena. This paper presents the development of a biosignal-specific processing toolbox (Bio-SP tool) for preprocessing and feature extraction of these physiological signals according to the state-of-the-art studies reported in the scientific literature and feedback received from the field experts. Our open-source Bio-SP tool is intended to assist researchers in affective computing, digital and mobile health, and telemedicine to extract relevant physiological patterns (i.e., features) from these biosignals semi-automatically and reliably. In this paper, we describe the successful algorithms used for signal-specific quality checking, artifact/noise filtering, and segmentation along with introducing features shown to be highly relevant to category discrimination in several healthcare applications (e.g., discriminating patterns associated with disease versus non disease). Further, the Bio-SP tool is a publicly-available software written in MATLAB with a user-friendly graphical user interface (GUI), enabling future crowd sourced modification to these tools. The GUI is compatible with MathWorks Classification Learner app for inference model development, such as model training, cross-validation scheme farming, and classification result computation. PMID- 30443442 TI - The Relationship of UGT2B15 Pharmacogenetics and Lorazepam for Anxiety. AB - Anxiety affects over 260 million people worldwide. Benzodiazepines are a class of agents used in combination with other therapies for the management of anxiety. Lorazepam is a commonly prescribed benzodiazepine metabolized by uridine 5' diphosphate-glucuronosyltransferases. Herein, we discuss recent findings regarding the pharmacogenetics of uridine 5'-diphosphate-glucuronosyltransferase 2B15 (UGT2B15), lorazepam, and its role in the treatment of anxiety. PMID- 30443443 TI - Long-term Seizure Disorder Caused by a Dermoid Cyst with Catastrophic Developments. AB - Glioblastoma multiforme (GBM) is a World Health Organization (WHO) grade IV primary malignant astrocytoma. Aneurysms are devastating intracranial neurovascular pathologies. Intracranial dermoid cysts are common, benign lesions which can be clinically silent or associated with seizure disorder. We describe physically adjacent diagnoses of dermoid cyst, intracranial aneurysm, and GBM in a single patient. Records were collected and reviewed to compile the final clinical picture. A 72-year-old male with a long history of seizure disorder, presented with new focal, unilateral neurological deficits. Radiographic evaluation including computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a dermoid cyst with an underlying developing GBM, which also, by happenstance, contained an aneurysm. During open surgical resection, multiple macroscopically distinct tissue types were noted. Histological analysis of tissue from each lesion confirmed the diagnoses including dermoid cyst, GBM, and aneurysm. Pathological analysis revealed the presence of extensive inflammatory cells throughout. Subsequent staining identified CD68 positive cells indicating a probable chronic inflammatory state. Chronic inflammation resulting from the presence of a long term dermoid cyst and ongoing seizures may have led to dystrophic changes in adjacent vasculature and approximating glial tissues, inducing the formation of an aneurysm and a secondary GBM. Therefore, while benign in nature, dermoid cysts can be related to seizure disorder and may cause chronic inflammation in surrounding brain tissue. PMID- 30443444 TI - Outcomes of Staged Treatment for Complex Distal Radius Fractures. AB - Introduction Distal radius fractures are common, but the results and complications of treatment with early external fixation and staged open reduction internal fixation have not been previously reported. Materials and methods Patients who received staged distal radius fracture treatment from 1/1/2008 to 12/31/2015 at the University of Alabama at Birmingham were identified. Patient, injury, and treatment characteristics, as well as complications, were collected from the medical record. Results There were 50 fractures in 47 patients, with mean follow-up of 9.3 months. Thirty-eight were open and 45 were intra-articular. For definitive treatment, 41 received a volar approach and nine a dorsal approach. Twenty wrists experienced one or more complications, including two non unions. Five patients developed infections - one Kirschner wire site infection, one external fixator (ex-fix) pin site infection, and three deep infections. All deep infections occurred in tobacco users. The rate of deep infection with volar approach was 2.4%, compared to 22.2% with dorsal approach. Ex-fix pin sites overlapped radiographically with the plate in 20 fractures, with three deep infections in this group (15%) and no deep infections in the group without overlap. None of these differences reached statistical significance. Conclusions This protocol results in reliable healing of complex fractures, with a 96% union rate. However, 40% sustained complications. We conclude that this protocol is useful for temporizing complex fractures but caution that the complication rate is high. Since recent literature indicates that low-grade open distal radius fractures do not require emergent debridement and that immediate internal fixation is safe, complications might be avoided by restricting this protocol to complex or physiologically unstable patients. PMID- 30443445 TI - Intraoperative Tips for Hand Surgery: A Focus on Reducing Postoperative Scarring and Tendon Rupture. AB - This article is a collection of intraoperative techniques performed by a single hand surgeon with literature support for these techniques for the purpose of circumventing potential limitations intraoperatively. These techniques include the use of a Beaver Blade handle (Beaver, Beaver-Visitec, Waltham, MA, US) to be used as a rasp to smooth intraosseous tunnels during tendon transfers, a Stryker (Stryker, Stryker Corporation, Kalamazoo, MI, US) or Synthes (Deputy Synthes, Johnson & Johnson, West Palm Beach, FL, US) drill as a motorized file for plate deburring, and Insorb forceps (Insorb, Incisive Surgical, Plymouth, MN, US) for skin closure. These tips serve as methods to minimize scarring and circumvent unfortunate obstacles, such as tendon rupture, and the consequential weakened repair that can occur post-operatively. These have not been previously reported in the literature but have been performed by the senior author with no resulting complications. Additionally, the common availability of the equipment allows for a potential economic benefit. PMID- 30443446 TI - Neurocutaneous Melanosis with Leptomeningeal Melanoma Involving Supratentorium and Infratentorium. AB - Neurocutaneous melanoma is a rare congenital syndrome associated with congenital melanocytic nevi with meningeal melanosis or melanoma. The disease is aggressive and has a high propensity for leptomeningeal metastases. We present the case history of a man with neurocutaneous melanoma managed with radical excision followed by hypofractionated adjuvant radiotherapy. One year, eight months later, he had a recurrence of the condition with leptomeningeal spread and was managed with re-excision of the recurrent lesion. Although our patient was disease-free for 20 months after the initial surgery, he survived only approximately five months after the second surgery, which reflects the associated poor prognosis of the disease. PMID- 30443447 TI - Artery of Percheron Infarct: An Acute Diagnostic Challenge with a Spectrum of Clinical Presentations. AB - The artery of Percheron (AOP) is a variant of the paramedian thalamic vasculature that supplies blood to the medial aspect of the thalamus and the rostral midbrain. The presentation of an infarct in this territory varies widely and is often characterized by nonspecific neurological deficits, with altered mental status, decreased level of consciousness, and memory impairment being among the most common. AOP infarcts are often missed on initial computed tomography (CT) scan, and additional imaging is usually not done due to low suspicion for stroke in most cases. There have been an increasing number of reports of AOP infarction, illustrating the diversity of clinical presentations and the challenge this presents to clinicians in the acute setting. Lacking the classic signs of stroke, many of these patients experience a delay in recognition and treatment, with the majority of diagnoses occurring outside the tissue plasminogen activator (tPA) window. This case highlights the unusual presentation and diagnostic difficulty of a patient with an AOP infarct, and serves as a reminder to include thalamic pathology in patients presenting with vague neurological symptoms and no obvious signs of stroke. PMID- 30443448 TI - Survival as a Function of Nonsteroidal Anti-inflammatory Drug Use in Patients with Glioblastoma. AB - Background Findings of both case control and in vitro investigations suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may play a beneficial role in the occurrence, growth, and subsistence of glioblastoma multiforme (GBM) brain tumor in humans. Objective In the present retrospective cohort study, we assessed the impact of NSAID use on survival in patients diagnosed with and treated for GBM brain tumors. Methods The impact of NSAID use and six other potential prognostic indicators of survival were assessed in 71 patients treated for GBM brain tumors from February 2011 to June 2016. Survival analysis and cross-tabulation analyses were performed to examine the potential relationship between NSAID use and occurrence of intracranial hemorrhage over the course of treatment for GBM. Results Kaplan-Meier analysis revealed no significant difference in survival between patients with and without NSAID use (p = 0.75; 95% CI: 10.12, 18.13). Multiple Cox regression analysis identified only treatment with chemotherapy as imposing any statistically significant effect on survival (Hazard Ratio (HR) = 3.31; p < 0.001; 95% CI: 1.80, 6.07). Cross-tabulation revealed no significant effect of NSAID use on occurrence of hemorrhage during treatment, X2 (2, N = 71) = 0.65, p2-Sided = 0.42, (Fisher's Exact Test: p2-sided = 0.56, p1-sided = 0.31). Conclusion These results suggest that history of NSAID use is not a determinant of survival in GBM patients. More rigorous, prospective investigations of the effect of NSAID use on tumor progression are necessary before the utility of this family of drugs in the treatment of GBM can be adequately appraised. PMID- 30443449 TI - Epilepsy and Cannabis: A Literature Review. AB - Epilepsy is considered to be one of the most common non-communicable neurological diseases especially in low to middle-income countries. Approximately one-third of patients with epilepsy have seizures that are resistant to antiepileptic medications. Clinical trials for the treatment of medically refractory epilepsy have mostly focused on new drug treatments, and result in a significant portion of subjects whose seizures remain refractory to medication. The off-label use of cannabis sativa plant in treating seizures is known since ancient times. The active ingredients of this plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the latter considered safer and more effective in treating seizures, and with less adverse psychotropic effects. Clinical trials prior to two years ago have shown little to no significant effects of cannabis in reducing seizures. These trials seem to be underpowered, with a sample size less than 15. In contrast, more recent studies that have included over 100 participants showed that CBD use resulted in a significant reduction in seizure frequency. Adverse effects of CBD overall appear to be benign, while more concerning adverse effects (e.g., elevated liver enzymes) improve with continued CBD use or dose reduction. In most of the trials, CBD is used in adjunct with epilepsy medication, therefore it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications. Future trials may evaluate the efficacy of CBD in treating seizures due to specific etiologies (e.g., post-traumatic, post-stroke, idiopathic). PMID- 30443450 TI - Quantitative Analysis of Tumor-associated Tissue Eosinophilia in Recurring Bladder Cancer. AB - The relatively high incidence of recurrence of bladder cancer is a serious problem in clinical practice. At present, there are no objective microscopic criteria for evaluation of the tendency for local relapse. Besides the phenotypic properties of the tumor parenchymal cells, possible signs in regard to recurrence could also be derived from the peculiarities of the tumor stroma. The stromal reaction, manifested by inflammatory infiltration in the tumor is considered to influence the biological behavior of tumors. Also, a relationship has been reported between the number of eosinophils and the survival of patients. The aim of the present study is to analyze tumor-associated tissue eosinophilia (TATE) and to compare TATE density in the initial foci of age and gender-matched 156 cases of recurrent and non-recurrent bladder cancers; the tumors that have relapsed within six months after removal and contained statistically significant greater numbers of eosinophils in primary cancer sites. These results suggest that TATE may be one of the probable prognostic signs for local relapse of urothelial cancer. PMID- 30443451 TI - Progressive Feeding Intolerance Secondary to a Congenital Spinal Teratoma in a Four-week-old Female. AB - A poorly feeding neonate presents the clinician with a diagnostic challenge. Feeding difficulties and irritability may be due to sepsis, congenital heart disease, inborn errors of metabolism, non-accidental head trauma, as well as a vast variety of other pathologies. Teratomas are rare pediatric tumors that can occasionally present in the immediate neonatal period and can manifest in the infant's central nervous system (CNS) with non-specific symptoms of poor feeding, lethargy, and somnolence. Operative resection remains the cornerstone of treatment; however, there is no well-defined role for adjuvant chemotherapy or radiation in these treatments. We report a case of a four-week-old female presenting with progressive feeding intolerance secondary to a near holocord thoracic spinal teratoma. Her tumor was surgically resected and she was treated with adjuvant chemotherapy and radiation for 13 months and is now in clinical remission. While rare, intramedullary spinal cord lesions should be considered in the differential diagnosis of infants presenting with poor feeding and hypotonia. PMID- 30443452 TI - Hyperuricemia-associated Mesoamerican Nephropathy: Case Report and Review of Literature. AB - Mesoamerican nephropathy (MeN), formerly called chronic kidney disease of unknown cause (CKDu), refers to chronic kidney disease (CKD) that presents in young and middle-aged Central Americans in the absence of any clear etiology. MeN is a relatively new diagnosis with rapidly rising prevalence in specific regions of El Salvador and Nicaragua, Guatemala, and Costa Rica. It is seldom associated with hyperuricemia. We present a case of a patient with gouty arthritis and hyperuricemia with associated CKD due to MeN. We also provide a review of literature of this disease. PMID- 30443453 TI - Hepatic Angiosarcoma: A Challenging Diagnosis. AB - Hepatic angiosarcoma (HA) accounts for 2% of primary liver tumors. Though rare, it is exceptionally deadly. The initial presentation of HA is nonspecific and no tumor markers have been associated with it. In general, liver function is maintained until later stages of the disease, often leading to diagnosis once the disease is already advanced or metastatic. In this report, we present the case of a 54-year-old male whose vague symptoms and non-diagnostic liver biopsy delayed the diagnosis of a rapidly progressing HA. PMID- 30443454 TI - The Prevention and Management of Contrast-induced Acute Kidney Injury: A Mini review of the Literature. AB - Contrast-induced acute kidney injury, also called contrast-induced nephropathy, is one of the main causes of acute renal failure/acute kidney injury (AKI) in hospitalized patients within 48 to 72 hours of contrast media administration during various radiologic procedures. Several factors can be responsible for contrast-induced acute tubular necrosis (ATN); however, patient and procedure related factors play the lead role in determining the development of contrast induced nephropathy. There is no definitive treatment and hydration remains the mainstay preventive strategy. This article will review the incidence, criteria for definitive diagnosis, and an effective approach on how to prevent contrast induced nephropathy in a clinical setup. PMID- 30443455 TI - The Neurocognitive Effects of Ghrelin-induced Signaling on the Hippocampus: A Promising Approach to Alzheimer's Disease. AB - The communication between the gastrointestinal tract and the central nervous system (CNS) allows for certain peptide hormones to influence neurocognitive function. Ghrelin, also known as the 'hunger hormone,' has the unique ability to enter the CNS and interact with the growth hormone secretagogue receptor (GHS-R) within the hippocampus. Upon interaction with ghrelin, a conformational change in the receptor causes an increase in transcription factors to foster a wide array of physiologic changes in response to caloric deprivation. With the GHS-R in a relatively high concentration within the hippocampus, ghrelin can promote memory, spatial, learning, and behavioral effects. In fact, ghrelin appears to also have a neuroprotective and neuromodulatory response once active within the hippocampal dentate gyrus. Through the GHS-R, higher levels of ghrelin may alter cognitive circuitry and offer a possible link to the treatment of some pathologies implicated in neurological dysfunction. Alzheimer's disease (AD) is already becoming a significant target for ghrelin neuroreceptor therapy. In such experimental models, ghrelin has been shown to combat this degenerative process by eliciting an ameliorative and regenerative response. Although trials and research are still ongoing, further studies are indicated as early research into this adjuvant therapy is promising. The research team explored the effects of ghrelin by reviewing the downstream signaling modifications of ghrelin's interaction with a specific CNS receptor, the GHS-R. Although the GHS-R is found in multiple locations within the CNS, the team investigated the role of the GHS-R within the hippocampus to focus solely on the neurocognitive implications of ghrelin. The team noted which signaling pathways in particular that ghrelin initiated and used this approach to determine whether ghrelin may have any therapeutic benefits. The team explored the possible therapeutic indications of ghrelin by looking at studies conducted with a specific neurodegenerative disease known to target the hippocampus. PMID- 30443456 TI - Pain Management in Metastatic Bone Disease: A Literature Review. AB - Cancer means an uncontrolled division of abnormal cells in the body. It is a leading cause of death today. Not only the disease itself but its complications are also adding to the increase in mortality rate. One of the major complications is the pain due to metastasis of cancer. Pain is a complex symptom which has physical, psychological, and emotional impacts that influence the daily activities as well as social life. Pain acts as an alarm sign, telling the body that something is wrong. Pain can manifest in a multitude fashion. Management of bone pain due to metastasis involves different modes with some specific treatments according to the type of primary cancer. Over the years various treatment modalities have been tried and tested to improve the pain management including the use of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, bisphosphonates, tricyclic antidepressants, corticosteroids, growth factors and signaling molecules, ET-1 receptor antagonists, radiotherapy as well as surgical management. The topic of discussion will cover each one of these in detail. PMID- 30443457 TI - Traumatic Pubic-type Anterior Dislocation of the Hip with an Ipsilateral Greater Trochanter Fracture: Case Report and Review of Literature. AB - Due to the inherent stability of the hip joint, hip dislocations constitute a relatively small proportion of all the traumatic dislocations encountered in the emergency department. Among them, the anterior type of hip dislocation is less common than the posterior type of dislocation. Anterior dislocations are usually associated with an injury to other, nearby structures like the acetabulum and femoral head. An ipsilateral greater trochanter fracture with anterior hip dislocation is very sparsely reported in the literature. We report the case of a pubic type of anterior hip dislocation associated with a concomitant ipsilateral greater trochanter fracture. The joint was reduced promptly with traction countertraction under sedation, and the associated fracture was subsequently fixed with two 6.5 mm partially threaded, cannulated, cancellous screws. The patient was symptom-free at the last follow-up of one year with a full range of hip joint motion, and without any evidence of osteonecrosis or osteoarthritis. The mechanism of greater trochanter fracture in such injuries and its management has been discussed. PMID- 30443458 TI - Systemic Lupus Erythematosus: An Overview of the Disease Pathology and Its Management. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with varied natural history and multisystemic involvement. The pathogenesis is multifactorial and complex precipitating the formation of autoantibodies. One of the main factors in SLE is the interaction between environmental triggers and genetic factors. Genome-wide association study technology has led to the identification of more than 80 loci which produce key proteins that lead to small pathophysiological changes and are associated with SLE. There has been an improvement in the management of the disease with newly standardized scores that have been validated in assessing disease activity and quality of life, and have helped in clinical care as well as research. The last five decades have seen a marked improvement in the prognosis of SLE, thanks to better general care and the development of newer immunosuppressive drugs, more specifically biological agents. PMID- 30443459 TI - A Case of Typical Hemolytic Uremic Syndrome in an Adult. AB - Typical hemolytic uremic syndrome (HUS) in adults is an uncommon clinical occurrence and has been rarely reported in the literature. Typical HUS is mainly caused by Shiga toxin-producing Escherichia coli (STEC) and is typically a pediatric disease. Worldwide outbreaks have been reported, one of the largest and most recent being in Germany. We are reporting a case of a 55-year-old male who presented with acute diarrhea. His laboratory parameters were suggestive of HUS and molecular testing was positive for STEC in stools. The patient received supportive therapy, and he recovered clinically with an improvement in his laboratory parameters. We hereby highlight the importance of timely diagnosis of typical HUS in guiding management and avoiding unnecessary testing and treatment. The mainstay of therapy is aggressive and prompt intravenous hydration to help alleviate the acute kidney injury and improve the clinical outcomes. PMID- 30443460 TI - A Comprehensive Review of the Manifestations and Pathogenesis of Zika Virus in Neonates and Adults. AB - The Zika Virus (ZIKV) has been slowly becoming an epidemic in different parts of the world. Since its discovery in 1947, there have been numerous outbreaks affecting many different populations. Currently, there is an ongoing threat of ZIKV in Latin America and the United States of America. ZIKV is mainly spread by the Aedes aegypti mosquito and causes non-specific symptoms such as fever, myalgia, and generalized weakness. In addition to these symptoms, it has been noted the ZIKV is capable of causing associated conditions in adults, particularly in pregnant women as well as in newborns via vertical transmission. These manifestations include microcephaly, lissencephaly, ventriculomegaly, optic neuropathy, and congenital glaucoma, arthralgia, maculopapular rash, and cardiovascular anomalies such as atrial fibrillation. It is important to understand the reason for this specific set of associated conditions that emerge with ZIKV. This paper aims to identify the manifestations of ZIKV in adults and neonates in detail and attempts to understand the pathophysiology behind each one. PMID- 30443461 TI - Burden of Non-cardiac Patients on the Emergency Room of a Rural Cardiac Center in Sindh, Pakistan. AB - Introduction The number of cardiac patients increases on a daily basis, and emergency departments bear much of the burden of non-cardiac patients due to pathological fears of the aftermath of the disease. Therefore, this study aimed to determine the burden of non-cardiac patients on the emergency department of a cardiac center in a rural area of Sindh, Pakistan. Methods This cross-sectional study was conducted at the emergency department of Chandka Medical College Hospital in Larkana. Consecutive patients who presented with cardiac symptoms with no previous history of cardiac disease were included. After a brief history, physical examination, electrocardiogram, and a cardiac enzyme assessment, patients were categorized as cardiac or non-cardiac. Data were analyzed using IBM SPSS Statistics for Windows, Version 21.0. (IBM Corp., Armonk, NY, US) and p <=0.05 was statistically significant. Results Of the 204 patients included, 112 (59.8%) were men, and the mean age was 47 +/- 16 years. Most patients (n = 146; 71.6%) were diagnosed as non-cardiac. The non-cardiac diagnosis was significantly more common among patients without diabetes (n = 123, 77.4% vs. n = 23, 51.1%; p = 0.001), without chest pains (n = 93, 81.6% vs. n = 53, 58.9%; p< 0.001), and without shortness of breath (n = 107, 75.9% vs. n = 39, 61.9%; p = 0.041). Conclusion More than two-thirds of the patients were found to have a non-cardiac mechanism behind their symptoms. A major proportion of the emergency room's cardiology department is occupied by non-cardiac patients. Owing to its direct and indirect implication on an otherwise struggling health system, we suggest chest pain units should be developed to decrease the workload and provide better care to cardiac patients. PMID- 30443462 TI - Carglumic Acid Treatment of a Patient with Recurrent Valproic Acid-induced Hyperammonemia: A Rare Case Report. AB - Valproic acid, first manufactured as an anticonvulsant, is commonly used to treat both neurological and psychiatric conditions. A rare and deadly side effect of this medication is hyperammonemia, presenting as lethargy, confusion, seizure, and, ultimately, coma. In rare circumstances, hyperammonemia can be recurrent and devastating, especially in patients with an underlying N-acetyl glutamate synthase (NAGS) deficiency, as the valproic acid can enhance this enzyme deficiency and inhibit the conversion of ammonia into urea in the liver. For these subtypes of patients, the United States Food and Drug Administration (US FDA) has recently approved carglumic acid, a medication that can act as a scavenger by effectively increasing the levels of NAGS, ultimately enhancing the conversion of ammonia to urea. In our case report, we have mentioned a patient with treatment-resistant bipolar disorder, who presented with elevated ammonia levels secondary to valproic acid treatment. Valproic acid was the only drug that was effective in his case, so we initiated therapy to reduce his elevated ammonia levels. After a thorough evaluation, we found the patient had a genetic NAGS deficiency. Carglumic acid was initiated and proved efficacious in our patient. PMID- 30443463 TI - Managing Chronic Pain in the Elderly: An Overview of the Recent Therapeutic Advancements. AB - A majority of the elderly suffer from chronic pain that significantly alters their daily activities and imposes an enormous burden on health care. Multiple comorbidities and the risk of polypharmacy in the elderly make it a challenge to determine the appropriate drug, dosage, and maintenance of therapy. Opioids are the most commonly used agents for this purpose in the elderly. The aim of this article is to discuss both the current well-established therapies used for managing chronic pain in the elderly and also the emerging newer therapies. PMID- 30443464 TI - Filler Migration and Granuloma Formation After Gluteal Augmentation with Free silicone Injections. AB - Gluteal augmentation may be performed using a variety of techniques, including implant-based, autologous fat grafting, local flaps, impermanent filler injection, or, as in this case, by way of permanent filler injection with free silicone. Of these, free-silicone injections carry one of the highest complication rates, specifically regarding migration of the filler material from the native injection site and induction of painful reactive soft tissue changes at the new filler location. A radiologist providing this diagnosis may assist the clinician, who often cannot obtain a history of illicit silicone injection for gluteal augmentation unless the suspicion is raised. Presented here is a case of painful filler migration to the knee with granuloma formation after free-silicone gluteal injection. PMID- 30443465 TI - Cardiac Arrest Due to Air Embolism: Complicating Image-guided Lung Biopsy. AB - Cardiac arrest due to air embolism is an infrequent complication. Air embolism can be associated with procedures like endoscopic retrograde cholangiopancreatography, endoscopic variceal ligation, operative hysteroscopy, laparoscopic surgery, pacemaker placement, cardiac ablation, fiberoptic bronchoscopy, and decompression sickness. In rare cases, air embolus can be a catastrophic complication of computed tomography (CT) guided lung biopsy, which can lead to cardiac arrest. We present a case of a 67-year-old male chronic smoker with a left lower lobe pulmonary nodule who had a cardiac arrest due to air embolism as a consequence of CT guided biopsy of the pulmonary nodule found on a CT scan of the chest. He was successfully resuscitated and intubated for mechanical ventilation. He was managed conservatively and discharged home in a stable condition. PMID- 30443466 TI - Magnetic Resonance Imaging Volumetry of Primary Nasopharyngeal Cancer in Patients Treated with Induction Gemcitabine and Cisplatin Followed by Concurrent Cisplatin and Volumetric Modulated Arc Therapy. AB - Introduction The addition of induction chemotherapy (IC) to the standard concurrent chemoradiotherapy (CCRT) is under consideration in locally advanced nasopharyngeal carcinoma (LANPC). To-date, no studies have reported primary gross tumour volume (GTVp) changes using gemcitabine and cisplatin as the IC phase in LANPC. We investigated the timing and magnitude of GTVp response throughout sequential gemcitabine and cisplatin IC and CCRT for LANPC. Toxicity and tumour control probability (TCP) analyses are also presented Methods Ten patients with LANPC underwent sequential IC and CCRT between 2011 and 2015. All patients had magnetic resonance imaging (MRI) at three time points: before IC (MRI0), after IC (MRI1), and three months after CCRT (MRI3). Five of the 10 patients had an additional MRI four to five weeks into CCRT (MRI2). GTVp contours were delineated retrospectively using contrast-enhanced MRIs, and each GTVp underwent secondary review by a neuroradiologist. Acute toxicities were graded retrospectively via chart review based on the National Cancer Institute Common Terminology for Adverse Events version 4.0 (NCI CTCAE v4.0). Results Mean GTVp reduction between MRI0 - MRI1 was from 68 cc to 47 cc and from 47 cc to 9 cc between MRI1 - MRI3. In patients with MRI2, the mean GTVp reduction between MRI1 - MRI2 was from 57 cc to 32 cc. Tumour control probability estimates increased by 0.11 after IC. Patients tolerated the treatment well with one Grade IV toxicity event. Conclusion The observed GTVp response and improved tumor control probability support further investigation into the use of IC in LANPC. PMID- 30443467 TI - Differential Diagnosis and Treatment of Restless Legs Syndrome: A Literature Review. AB - Restless legs syndrome (RLS) is a chronic neurological disorder affecting a growing number of people. Patients describe an irresistible urge to move their lower limbs in times of immobility. Due to its vague symptoms and similarity to other disorders, it has become increasingly difficult for primary care clinicians to properly diagnose and manage RLS. As a result, patients with RLS are routinely misdiagnosed and continue their lives without proper management. This literature review examines the current understanding of the disorder, provides key points to assist clinicians in differentiating RLS from similar disorders, and explores recently updated evidence-based guidelines for the effective management of RLS. PMID- 30443468 TI - Bilateral Displacement of the Common Carotid Arteries by a Large Goiter. AB - Large goiters are less common in the developing world due to the use of iodized salt. However, these are seen occasionally. Herein, we report a case of very large goiter identified in a cadaver. This case is also of interest due to the significant lateral displacement of the common carotid arteries (CCA) and the midline shift of the trachea. This case and the salient literature addressing this topic have been discussed. PMID- 30443469 TI - Knowledge, Awareness, and Perceptions Regarding Autism Among Parents in Karachi, Pakistan. AB - Background The prevalence of autism is growing worldwide. Owing to parents being the primary caregivers in most situations, their ability to recognize the signs and symptoms of autism and respond appropriately is of paramount importance in aiming to provide the best healthcare to autistic individuals. This study was conducted with the aim of ascertaining the parent's knowledge and awareness of autism. Methods A cross-sectional survey was conducted among parents residing in Karachi, Pakistan. We excluded any individuals belonging to the medical profession, those who have autistic children, and those who couldn't completely comprehend English and Urdu. A sample size of 339 parents was selected. A validated and pre-tested questionnaire was administered among the study participants to record demographic information, knowledge, and perceptions regarding autism and its signs and symptoms. Data were analyzed using Statistical Package for Social Sciences (SPSS version 23.0, IBM Corp., Armonk, NY, US). A knowledge score was calculated for opinions about autism and its sign and symptoms individually to reflect a participant's overall knowledge regarding autism. Results From our study population, 75% of our population had heard of autism, with those who knew of someone with the disorder displaying greater awareness. However, our participants displayed poor knowledge scores, with a mean score of 5.59 in the section concerning correct opinions on autism and that of 6.84 in the section testing knowledge of signs and symptoms. Despite this, 95.6% of the participants were willing to get their children treated, in the event of them being diagnosed with autism. Conclusion Unfortunately, our population displayed a lack of awareness and knowledge regarding autism. To fill this gap, awareness programs should be conducted to promote parent's knowledge regarding autism, so as to allow for early diagnoses and an appropriate treatment plan/therapy. On a positive note, most were willing to get their children tested and treated in case of a diagnosis. However, only a small number of participants knew of autism centers in Karachi. General practitioners are needed to play a key role in counseling parents about autism. PMID- 30443470 TI - Utilization of Continuous Cardiac Monitoring on Hospitalist-led Teaching Teams. AB - Guidelines for continuous cardiac monitoring (CCM) have focused almost exclusively on cardiac diagnoses, thus limiting their application to a general medical population. In this study, a retrospective chart review was performed to identify the reasons that general medical patients, cared for on hospitalist-led inpatient teaching teams between April 2017 and February 2018, were initiated and maintained on CCM, and to determine the incidence of clinically significant arrhythmias in this patient population. The three most common reasons for telemetry initiation were sepsis (24%), arrhythmias (12%), and hypoxia (10%). Most patients remained on telemetry for more than 48 hours (62%) and a significant number of patients were on telemetry until they were discharged from the hospital (39%). Of the cumulative total of more than 20,573 hours of CCM provided to this patient population, 37% of patients demonstrated only normal sinus rhythm and 3% had a clinically significant arrhythmia that affected management. PMID- 30443471 TI - Comparative Assessment of Cephalometric and Tympanometric Readings in Down Syndrome. AB - Aim The purpose of this study was to conduct a comparative assessment of the various cephalometric and auditory parameters between patients with Down syndrome (DS) and healthy controls. Methods The cephalometric and auditory parameters were divided among 50 participants into two equal sets, DS (n = 25) and controls (n=25), and assessed. While a standard cephalometric analysis was conducted to measure the hard tissue parameters, tympanometry was used to assess the audiological parameters. Results The values of the linear and angular cephalometric parameters of the DS group were found to be lower than the controls. All the controls recorded type A tympanogram while the DS group recorded type A, B, and C tympanograms. A significant relationship was observed in the cephalometric readings - eustachian tube (ET) length, posterior upper facial height (PUFH) length, sella (s)-basion (ba)-palatal length (PL), and s-ba ET angles - among the subjects who presented with type B or C tympanogram in comparison to those with type A. Conclusion Tympanometry, a highly sensitive and relatively simple test to assess audiological parameters, has a significant relationship with a number of cephalometric indicators of growth and development. A deviation from the normal tympanometric readings can be used as an early indicator of the impending craniometric aberrations and handicap. This can be used as an effective tool for early intervention in cases of DS. Patients who have recorded abnormal tympanograms on multiple occasions over a period of six months can be subjected to a further cephalometric analysis. PMID- 30443473 TI - The Global Dilemma: Standardization of Nonoperative Treatment. PMID- 30443472 TI - Process Mining for Trauma Resuscitation. AB - We present our process mining system for analyzing the trauma resuscitation process to improve medical team performance and patient outcomes. Our system has four main parts: trauma resuscitation process model discovery, process model enhancement (or repair), process deviation analysis, and process recommendation. We developed novel algorithms to address the technical challenges for each problem. We validated our system on real-world trauma resuscitation data from the Children's National Medical Center (CNMC), a level 1 trauma center. Our results show our system's capability of supporting complex medical processes. Our approaches were also implemented in an interactive visual analytic tool. PMID- 30443474 TI - Preoperative Nutritional Status as a Risk Factor for Major Postoperative Complications Following Anterior Lumbar Interbody Fusion. AB - Study Design: Retrospective study. Objectives: To determine rates of medical and surgical postoperative complications in adults with hypoalbuminemia undergoing anterior lumbar interbody fusion (ALIF). Methods: This was a retrospective analysis of prospectively collected data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database of patients (>=18 years old) undergoing ALIF procedures, identified by CPT (Current Procedural Terminology) code from 2011 to 2014. Poor nutritional status was defined by a preoperative serum albumin level <3.5 g/dL, and albumin levels above this were considered normal. Multivariate logistic regression models were utilized to assess preoperative risk factors including nutritional status as predictors of specific postoperative complications. Significance was defined as P < .05 and odds ratios (ORs) were calculated with a 95% confidence interval (CI). This model was used to determine the strength of nutritional status as an adjusted predictor of adverse postoperative events. Results: There were 3184 ALIF cases, including 1,275 (40%) of which had preoperative serum albumin levels. 53 (4.15%) patients were classified as having poor nutrition status. Poor preoperative nutritional status was shown to be a strong independent predictor of length of stay >=5 days (OR = 2.56, 95% CI 1.43-4.59, P = .002), urinary tract infection (OR = 5.93, 95% CI 2.11-16.68, P = .001), and sepsis (OR = 5.35, 95% CI 1.13-25.42, P = .035) compared to patients with normal preoperative serum albumin levels. Conclusions: Our analysis shows that patients with poor nutritional status before ALIF are independently at risk for sepsis as well as increased length of stay and urinary tract infection. PMID- 30443475 TI - Radiographic and Clinical Outcomes From the Use of S2 Alar Screws in Surgery for Adult Spinal Deformity. AB - Study Design: Retrospective. Objectives: To evaluate the efficacy of S2 alar screws in surgery for correction of adult spinal deformity (ASD). Methods: We retrospectively reviewed the cases of 23 patients (mean follow-up: 18.5 months, minimum 12 months) who underwent corrective surgery for ASD using S2 alar screws as anchors for instrumentation of lower vertebrae. The background of the patients and their spinopelvic parameters (pelvic incidence [PI], pelvic tilt [PT], lumbar lordosis [LL], thoracic kyphosis [TK], sagittal vertical axis [SVA], and PI-LL) were evaluated. Results: LL was improved from 9.7 +/- 20.5 degrees and SVA from 141.0 +/- 64.0 mm before surgery to 39.0 +/- 9.6 degrees and 51.7 +/- 40.8 mm immediately after surgery, respectively, and 38.2 +/- 12.7 degrees and 70.5 +/- 59.2 mm at final follow-up. In 13 patients without sufficient correction (postoperative PI-LL >=10 degrees ), bone mineral density and postoperative LL were significantly less, and PI, PI-LL, and PT were significantly greater than in patients with postoperative PI-LL <10 degrees , suggesting that these are risk factors for undercorrection. In 5 patients, SVA increased more than 40 mm during follow-up. Postoperative LL was significantly less (31.4 degrees vs 41.0 degrees ) and postoperative PI-LL was significantly greater (21.6 degrees vs 9.3 degrees ) in these patients, suggesting a PI-LL mismatch induces postoperative progression of global malalignment. Conclusions: Use of S2 alar screws as anchors for instrumentation in ASD surgery should be restricted. Their use might be an option for patients with low PI, and without severe osteoporosis, in whom efficient surgical correction can be obtained. PMID- 30443476 TI - Prediction of Scoliosis Curve Correction Using Pedicle Screw Constructs in AIS: A Comparison of Fulcrum Bend Radiographs and Traction Radiographs Under General Anesthesia. AB - Study Design: Retrospective radiographic review. Objectives: Our objectives were to (1) compare the ability of fulcrum bend radiographs and traction radiographs under general anesthesia to predict correction of adolescent idiopathic scoliosis (AIS) using pedicle screw only constructs and (2) compare the fulcrum bend correction index (FBCI) with a new measurement: the traction correction index (TCI). Methods: This is a retrospective radiographic review of 80 AIS patients (62 female and 18 male), who underwent scoliosis correction with pedicle screw only constructs. The mean age at surgery was 14 years (range 9-20 years). Radiographic analysis was carried out on the preoperative and immediate postoperative posteroanterior standing radiographs and the preoperative fulcrum bend radiographs and traction radiographs under general anesthesia. FBCI is calculated by dividing the correction rate by the fulcrum flexibility and TCI is calculated by dividing the correction rate by the traction flexibility. Results: Preoperative mean Cobb angle of 63.9 degrees was corrected to 25.8 degrees postoperatively. The mean fulcrum bending Cobb angle was 37.6 degrees and traction Cobb angle was 26.6 degrees . The mean fulcrum flexibility was 41.1%, traction flexibility 58.4%, and correction rate 59.6%. The median FBCI was 137% and TCI was 104.3%. Conclusions: When comparing fulcrum bend and traction radiographs, we found the traction radiographs to be more predictive of curve correction in AIS using pedicle screw constructs. TCI takes into account the curve flexibility better than FBCI. PMID- 30443477 TI - Does Obesity Explain the Effect of the Metabolic Syndrome on Complications Following Elective Lumbar Fusion? A Propensity Score Matched Analysis. AB - Study Design: Propensity score matched retrospective cohort study. Objectives: Obesity is a major confounder in determining the independent effect of metabolic syndrome (MetS) on complications after spinal surgery. The purpose of this study is to differentiate MetS from obesity as an independent influence on perioperative outcomes after elective lumbar spine fusion. Methods: One- to 3 level posterior spinal fusion cases were identified from the 2011-2014 American College of Surgeons' National Surgical Quality Improvement Program. To determine the effects of MetS outside of obesity itself, patients with MetS were first compared to a no-MetS cohort and then to an obese-only no-MetS cohort. Two propensity score matches based on demographics, comorbidities, surgical complexity, and diagnosis were used to match patients in 1:1 ratios and compare outcomes. Logistic regression with propensity score adjustment was further utilized as a secondary method of reducing selection bias. Results: Out of 18 605 patients that met criteria for inclusion, 1903 (10.2%) met our definition of MetS. Patients with MetS had a higher rate of wound complications (3.8% vs 2.7% obese no MetS, P = .045; vs 2.6% no MetS, P = .035), readmissions (7.4% vs 2.2% obese no MetS, P < .001; vs 4.6% no MetS, P < .001), and extended length of stay (29.1% vs 23.9% obese no MetS, P < .001; vs 23.5% no MetS, P < .001). Patients with MetS were more likely to experience a wound complication (odds ratio = 1.47, 95% confidence interval = 1.02-2.12) or readmission (odds ratio = 1.48, 95% confidence interval = 1.22-1.80). Conclusions: Even after controlling for obesity, MetS is an independent risk factor for adverse short-term outcomes. These findings have various implications for preoperative risk stratification and reduction strategies. PMID- 30443479 TI - Role of Frailty Scoring in the Assessment of Perioperative Mortality in Surgical Management of Tuberculous Spondylodiscitis in the Elderly. AB - Study Design: Retrospective study. Objectives: Treatment of spinal tuberculosis in the elderly involves consideration of compromised physiology, which often poses a clinical challenge to the surgeons to balance surgical safety versus deteriorating function. Frailty scoring has been reported as an effective tool to predict mortality and morbidity in cardiovascular surgery and recently in hip fractures. Its use in spinal surgery is scarcely reported. Methods: We included elderly patients operated for spinal tuberculosis. Demographic, clinical and radiological profile with operative details of instrumentation, blood loss, surgical duration and mortality were noted. Modified frailty score (MFS) was calculated for each patient. There were 26 patients (males 9, females 17) with a mean age of 73.2 years. The patients were divided into those with 30-day postoperative mortality (M) and those who survived (S). The null hypothesis was that the MFS was comparable in both the groups. Results: The M group had 5 patients (19.2%) and the S group consisted of 21 patients. There was no statistical difference between the groups with regard to mean age, sex, number of medical comorbidities, ASA (American Society of Anesthesiologists) grade, Frankel grade C or worse, blood loss, and operative time. The mean MFS in M group was 5 and in S group was 1.8, which was statistically significant (P < .001). Conclusions: Higher MFS is associated with postoperative 30-day mortality in the elderly patients with spinal tuberculosis undergoing surgery. It can be used as a guide to predict 30-day postoperative mortality in these patients. PMID- 30443478 TI - Risk Factors for Postoperative Coronal Balance in Adult Spinal Deformity Surgery. AB - Study Design: A retrospective case-control study. Objectives: To determine factors influencing the ability to achieve coronal balance following spinal deformity surgery. Methods: Following institutional ethics approval, the radiographs of 47 patients treated for spinal deformity surgery with long fusions to the pelvis, were retrospectively reviewed. The postoperative measurements included coronal balance, L4 tilt, and L5 tilt, levels fused, apical vertebral translation and maximum Cobb angle. L4 and L5 tilt angles were measured between the superior endplate and the horizontal. Sagittal parameters including thoracic kyphosis, lumbar lordosis, pelvic incidence, and sagittal vertical axis were recorded. Coronal balance was defined as the distance between the central sacral line and the mid body of C7 being <=40 mm. Surgical factors, including levels fused, use of iliac fixation with and without connectors, use of S2A1 screws, interbody devices, and osteotomies. Statistical tests were performed to determine factors that contribute to postoperative coronal imbalance. Results: Of the 47 patients reviewed, 32 were balanced after surgery and 14 were imbalanced. Coronal balance was 1.30 cm from center in the balanced group compared to 4.83 cm in the imbalanced group (P < .01). Both L4 and L5 tilt were statistically different between the groups. Gender and the use of transverse connectors differed between the groups but not statistically. Conclusions: In adult spinal deformity patients undergoing primary fusions to the pelvis, the ability to level the coronal tilt of L4 and L5 had the greatest impact on the ability to achieve coronal balance in this small series. A larger prospective series can help validate this important finding. PMID- 30443480 TI - Patient-Reported Outcomes and Patient-Reported Satisfaction After Surgical Treatment for Cervical Radiculopathy. AB - Study Design: Retrospective cohort study. Objectives: It is estimated that 10 000 patients seek medical care due to cervical radiculopathy every year in Denmark. Although the natural course is usually favorable, around 20% undergo surgery for cervical degenerative disease every year in Denmark. We aim to evaluate the patient-reported results and satisfaction of anterior cervical decompression and fusion over a 5-year period from a single Danish center for spine surgery. Methods: This study is a retrospective study based on prospectively collected data from 318 consecutive patients treated with anterior cervical decompression and fusion over 1 to 3 levels. Data in the DaneSpine registry was collected pre- and postoperatively, and at 1 year after surgery. The outcome measures were Neck Disability Index (NDI), European Quality of Life 5D (EQ-5D), visual analogue score (VAS), and Short Form-36 Physical Component Summary (SF-36 PCS). Results: Of 318 cases enrolled, 272 (85.5%) had follow-up data available at a minimum 1 year postoperatively. The mean preoperative NDI was 40.0 and improved to 22.7. Mean EQ-5D was 0.50 and improved to 0.70, and mean VAS arm was 60.4 improved to 26.4. All improvements were statistically significant. A total of 74.3% were back to work 1 year after surgery. Achieving minimal clinically important difference (MCID) in VAS neck and SF-36 PCS was strongly correlated to patient satisfaction. Conclusion: Patients who undergo anterior cervical discectomy and fusion can expect improvement in their pain and disability, with 74.3% of patients reporting a positive change in health status after surgery. PMID- 30443481 TI - The Effect of Aging on Cervical Parameters in a Normative North American Population. AB - Study Design: Retrospective cohort study. Objectives: To investigate age-based changes in cervical alignment parameters in an asymptomatic population. Methods: Retrospective review of a prospective study of 118 asymptomatic subjects who underwent biplanar imaging with 3-dimensional capabilities. Demographic and health-related quality of life data was collected prior to imaging. Patients were stratified into 5 age groups: <35 years, 35-44 years, 45-54 years, 55-64 years, and >=65 years. Radiographic measurements of the cervical spine and spinopelvic parameters were compared between age groups. The normal distribution of parameters was assessed followed by analysis of variance for comparison of variance between age groups. Results: C2-C7 lordosis, C0-C7 lordosis, and T1 slope demonstrated significant increases with age. C0-C7 lordosis was significantly less in subjects <35 years compared with >=55 years. Significant differences in T1 slope were identified in patients <35 versus >=65, 35-44 versus >=65, and 45-54 versus >=65 years. T1 slope demonstrated a positive correlation with age. Horizontal gaze parameters did not change linearly with age and mean averages of all age groups were within 10 degrees of one another. Cervical kyphosis was present in approximately half of subjects who were <55 compared with approximately 10% of subjects >=55 years. Differences in pelvic tilt, pelvic incidence-lumbar lordosis, and C7-S1 sagittal vertical axis were identified with age. Conclusions: C0-C7 lordosis, C2-C7 lordosis, and T1 slope demonstrate age based changes while other cervical and horizontal gaze parameters remain relatively constant with age. PMID- 30443482 TI - Severe Lumbar Disability Is Associated With Decreased Psoas Cross-Sectional Area in Degenerative Spondylolisthesis. AB - Study Design: Retrospective cohort. Objectives: Alterations in lumbar paraspinal muscle cross-sectional area (CSA) may correlate with lumbar pathology. The purpose of this study was to compare paraspinal CSA in patients with degenerative spondylolisthesis and severe lumbar disability to those with mild or moderate lumbar disability, as determined by the Oswestry Disability Index (ODI). Methods: We retrospectively reviewed the medical records of 101 patients undergoing lumbar fusion for degenerative spondylolisthesis. Patients were divided into ODI score <=40 (mild/moderate disability, MMD) and ODI score >40 (severe disability, SD) groups. The total CSA of the psoas and paraspinal muscles were measured on preoperative magnetic resonance imaging (MRI). Results: There were 37 patients in the SD group and 64 in the MMD group. Average age and body mass index were similar between groups. For the paraspinal muscles, we were unable to demonstrate any significant differences in total CSA between the groups. Psoas muscle CSA was significantly decreased in the SD group compared with the MMD group (1010.08 vs 1178.6 mm2, P = .041). Multivariate analysis found that psoas CSA in the upper quartile was significantly protective against severe disability (P = .013). Conclusions: We found that patients with severe lumbar disability had no significant differences in posterior lumbar paraspinal CSA when compared with those with mild/moderate disability. However, severely disabled patients had significantly decreased psoas CSA, and larger psoas CSA was strongly protective against severe disability, suggestive of a potential association with psoas atrophy and worsening severity of lumbar pathology. PMID- 30443483 TI - Adjacent Segment Disease After Posterior Lumbar Interbody Fusion: A Case Series of 1000 Patients. AB - Study Design: Retrospective study. Objective: There have been few reports of adjacent segment disease (ASD) after posterior lumbar interbody fusion (PLIF) with large numbers and long follow-up. The purpose of this study was to investigate (1) ASD incidence and time periods after primary PLIF, (2) repeat ASD incidence and time periods, and (3) ASD incidence and time periods by fusion length, age, and preoperative pathologies. Methods: A total of 1000 patients (average age 67 years, average follow-up 8.3 years) who underwent PLIF for degenerative lumbar disorders were reviewed. ASD was defined as a symptomatic condition in which revision surgery was required. Results: The overall ASD rate was 9.0%, and the average ASD period was 4.7 years after primary surgery. With respect to clinical features of ASD, degenerative spondylolisthesis at the cranial fusion segment was the most frequent. In terms of repeat ASD, second and third ASD incidences were 1.1% and 0.4%, respectively. As for ASD by fusion length, age, and preoperative pathologies, ASD incidence was increased by fusion length, while the time period to ASD was significantly shorter in elderly patients and those with degenerative lumbar scoliosis. Conclusions: In the present study, the overall ASD incidence was 9.0%, and the average ASD period was 4.7 years after primary operation. Second and third ASD incidences were 1.1% and 0.4%, respectively. Fusion length affected the ASD incidence, while aging factor and preoperative pathology affected the ASD time period. PMID- 30443484 TI - Patient-Rated Trust of Spine Surgeons: Influencing Factors. AB - Study Design: Descriptive analysis using publicly available data. Objectives: The purpose of this study was 2-fold: to assess patient-rated trustworthiness of spine surgeons as a whole and to assess if academic proclivity, region of practice, or physician sex affects ratings of patient perceived trust. Methods: Orthopedic spine surgeons were randomly selected from the North American Spine Society directory. Surgeon profiles on 3 online physician rating websites, HealthGrades, Vitals, and RateMDs were analyzed for patient-reported trustworthiness. Whether or not the surgeon had published a PubMed-indexed paper in 2016 was assessed with regard to trustworthiness scores. Total number of publications was also assessed. Individuals with >300 publications were excluded due to the likelihood of repeat names. Results: Recent publication and total number of publications has no relationship with online patient ratings of trustworthiness across all surgeons in this study. Region of practice likewise has no influence on mean trust ratings, yet varied levels of correlation are observed. Furthermore, there was no difference in trust scores between male and female surgeons. Conclusion: Total academic proclivity via indexed publications does not correlate with patient perceived physician trustworthiness among spine surgeons as reported on physician review websites. Furthermore, region of practice within the United States does not have an influence on these trust scores. Likewise, there is no difference in trust score between female and male spine surgeons. This study also highlights an increasing utility for physician rating websites in spine surgery for evaluating and monitoring patient perception. PMID- 30443485 TI - Surgical Outcomes and Limitations of Decompression Surgery for Degenerative Spondylolisthesis. AB - Study Design: A retrospective study. Objectives: To investigate surgical outcomes and limitations of decompression surgery for degenerative spondylolisthesis. Methods: One hundred patients with degenerative spondylolisthesis who underwent decompression surgery alone were included in this study. The average follow-up period was 3.7 years. Radiography and magnetic resonance imaging were used for radiological assessment. Patients with a recovery rate of >50% throughout the study period were classified as the control group (Group C), while those with a recovery rate of <50% throughout the study period were classified as the poor group (Group P). Patients that had improved symptoms, and yet later showed neurological deterioration due to foraminal stenosis at the same level were classified as the exiting nerve root radiculopathy group (Group E), while those who showed deterioration due to slip progression at the same level were classified as the traversing nerve root radiculopathy group (Group T). Results: Patient distribution in each group was 73, 12, 7, and 8 in Groups C, P, E, and T, respectively. As for preoperative radiological features, slippage and an upper migrated disc in Group P, disc wedging and an upper migrated disc in Group E, and lamina inclination and posterior opening in Group T were evident. The cutoff value of preoperative slippage with a poor outcome was 13%. Conclusions: Surgical outcomes of decompression surgery for degenerative spondylolisthesis were successful in 73% cases. Preoperative radiological features for poor outcomes were slippage of more than 13%, an upper migrated disc, disc wedging, and lamina inclination. PMID- 30443487 TI - Posterior Subaxial Cervical Spine Screw Fixation: A Review of Techniques. AB - Study Design: A narrative literature review. Objectives: To review the surgical techniques of posterior screw fixation in the subaxial cervical spine. Methods: A broad literature review on the most common screw fixation techniques including lateral mass, pedicle, intralaminar and transfacet screws was performed on PubMed. The techniques and surgical nuances are summarized. Results: The following techniques were described in detail and presented with illustrative figures, including (1) lateral mass screw insertion: by Roy-Camille, Louis, Magerl, Anderson, An, Riew techniques and also a modified technique for C7 lateral mass fixation; (2) pedicle screw fixation technique as described by Abumi and also a freehand technique description; (3) intralaminar screw fixation; and finally, (4) transfacet screw fixation, as described by Takayasu, DalCanto, Klekamp, and Miyanji. Conclusions: Many different techniques of subaxial screw fixation were described and are available. To know the nuances of each one allows surgeons to choose the best option for each patient, improving the success of the fixation and decrease complications. PMID- 30443486 TI - Radiological Fusion Criteria of Postoperative Anterior Cervical Discectomy and Fusion: A Systematic Review. AB - Study Design: Systematic review. Objectives: Diagnosis of pseudarthrosis after anterior cervical fusion is difficult, and often depends on the surgeon's subjective assessment because recommended radiographic criteria are lacking. This review evaluated the available evidence for confirming fusion after anterior cervical surgery. Methods: Articles describing assessment of anterior cervical fusion were retrieved from MEDLINE and SCOPUS. The assessment methods and fusion rates at 1 and 2 years were evaluated to identify reliable radiographical criteria. Results: Ten fusion criteria were described. The 4 most common were presence of bridging trabecular bone between the endplates, absence of a radiolucent gap between the graft and endplate, absence of or minimal motion between adjacent vertebral bodies on flexion-extension radiographs, and absence of or minimal motion between the spinous processes on flexion-extension radiographs. The mean fusion rates were 90.2% at 1 year and 94.7% at 2 years. The fusion rate at 2 years had significant independence (P = .048). Conclusions: The most common fusion criteria, bridging trabecular bone between the endplates and absence of a radiolucent gap between the graft and endplate, are subjective. We recommend using <1 mm of motion between spinous processes on extension and flexion to confirm fusion. PMID- 30443488 TI - Implant Prophylaxis: The Next Best Practice Toward Asepsis in Spine Surgery. AB - Study Design: A literature review. Objectives: An evaluation of the contaminants prevalent on implants used for surgery and the aseptic methods being employed against them. Methods: PubMed was searched for articles published between 2000 and 2017 for studies evaluating the contaminants present on spine implants, and associated pre- and intraoperative implant processing and handling methodology suggested to avoid them. Systematic reviews, observational studies, bench-top studies, and expert opinions were included. Results: Eleven studies were identified whose major focus was the asepsis of implants to reduce the incidence of surgical site infection incidences during surgery. These studies measured the colony forming units of bacteria on sterilized implants and/or gloves from the surgeon, scrub nurse, and assistants, as well as reductions of surgical site infection rates in spine surgery due to changes in implant handling techniques. Additionally, the search included assessments of endotoxins and carbohydrates present on reprocessed implants. The suggested changes to surgical practice based on these studies included handling implants with only fresh gloves, keeping implants covered until the immediate time of use, reducing operating room traffic, avoiding reprocessing of implants (ie, providing terminally sterilized implants), and avoiding touching the implants altogether. Conclusions: Both reprocessing (preoperative) and handling (intraoperative) of implants seem to lead to contamination of sterilized implants. Using a terminally sterilized device may mitigate reprocessing (preoperative implant prophylaxis), whereas the use of fresh gloves for handling each implant and/or a permanent shielding technique (intraoperative implant prophylaxis) could potentially avoid recontamination at the theatre. PMID- 30443490 TI - Gut microbes modulate host response to immune checkpoint inhibitor cancer immunotherapy. PMID- 30443489 TI - Arachidonic Acid Induces the Migration of MDA-MB-231 Cells by Activating Raft associated Leukotriene B4 Receptors. AB - Background: The migration of tumor cells is critical in spreading cancers through the lymphatic nodes and circulatory systems. Although arachidonic acid (AA) and its soluble metabolites have been shown to induce the migration of breast and colon cancer cells, the mechanism by which it induces such migration has not been fully understood. Objective: The effect of AA on migratory responses of the MDA MB-231 cell line (a triple-negative breast cancer cell) was examined and compared with MCF-7 (estrogen-receptor positive) breast cancer cells to elucidate the mechanism of AA-induced migration. Methods: Migrations of breast cancer cells were examined with the help of wound-healing assays. AA-induced eicosanoid synthesis was monitored by RP-HPLC. Cellular localizations of lipoxygenase and lipid rafts were assessed by immunoblot and confocal microscopy. Results: AA treatment stimulated the synthesis of leukotriene B4 (LTB4) and HETE-8, but lowered the levels of prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), and HETE 5 in MDA-MB-231 cells. Further analysis indicated that AA increased the expression of 5-lipoxygenase (5-LOX) in this cell line and inhibiting its expression by small molecule inhibitors lowered the production of LTB4 and reduced migration. In contrast, MCF-7 cells did not show any appreciable changes in eicosanoid synthesis, 5-LOX expression, or cellular migration. Conclusion: Our results suggest that AA treatment activates the BLT1 receptor (present in membrane microdomains) and stimulates the synthesis of LTB4 production, which is likely to be associated with the migration of MDA-MB-231 cells. PMID- 30443492 TI - Long Pentraxin 3-Mediated Fibroblast Growth Factor Trapping Impairs Fibrosarcoma Growth. AB - Fibrosarcomas are soft tissue mesenchymal tumors originating from transformed fibroblasts. Fibroblast growth factor-2 (FGF2) and its tyrosine-kinase receptors (FGFRs) play pivotal roles in fibrosarcoma onset and progression, FGF2 being actively produced by fibroblasts in all stages along their malignant transformation to the fibrosarcoma stage. The soluble pattern recognition receptor long pentraxin-3 (PTX3) is an extrinsic oncosuppressor whose expression is reduced in different tumor types, including soft tissue sarcomas, via hypermethylation of its gene promoter. PTX3 interacts with FGF2 and other FGF family members, thus acting as a multi-FGF antagonist able to inhibit FGF dependent neovascularization and tumor growth. Here, PTX3 overexpression significantly reduced the proliferative and tumorigenic potential of fibrosarcoma cells in vitro and in vivo. In addition, systemic delivery of human PTX3 driven by the Tie2 promoter inhibited the growth of fibrosarcoma grafts in transgenic mice. In a translational perspective, the PTX3-derived small molecule FGF trap NSC12 prevented activation of the FGF/FGFR system in fibrosarcoma cells and reduced their tumorigenic activity in vivo. In conclusion, impairment of the FGF/FGFR system by FGF trap molecules may represent a novel therapeutic approach for the treatment of fibrosarcoma. PMID- 30443491 TI - Cell-Free DNA From Metastatic Pancreatic Neuroendocrine Tumor Patients Contains Tumor-Specific Mutations and Copy Number Variations. AB - Background: Detection of tumor-specific alterations in cell-free DNA (cfDNA) has proven valuable as a liquid biopsy for several types of cancer. So far, use of cfDNA remains unexplored for pancreatic neuroendocrine tumor (PNET) patients. Methods: From 10 PNET patients, fresh frozen tumor tissue, buffy coat and plasma samples were collected. Whole-exome sequencing of primary tumor and germline DNA was performed to identify tumor-specific variants and copy number variations (CNVs). Subsequently, tumor-specific variants were quantified in plasma cfDNA with droplet digital PCR. In addition, CNV analysis of cfDNA was performed using shallow whole-genome sequencing. Results: Tumor-specific variants were detected in perioperative plasma samples of two PNET patients, at variant allele fractions (VAFs) of respectively 19 and 21%. Both patients had metastatic disease at time of surgery, while the other patients presented with localized disease. In the metastatic patients, CNV profiles of tumor tissue and cfDNA were significantly correlated. A follow-up plasma sample of a metastatic patient demonstrated an increased VAF (57%) and an increased chromosomal instability, in parallel with an increase in tumor burden. Conclusions: We are the first to report the presence of tumor-specific genetic alterations in cfDNA of metastatic PNET patients and their evolution during disease progression. Additionally, CNV analysis in cfDNA shows potential as a liquid biopsy. PMID- 30443494 TI - Swiss Journal of Economics and Statistics. PMID- 30443495 TI - On economists as policy advisors with applications to Switzerland. AB - This paper analyses the role of economists in advising political agents. Based on the experience in the recent financial crisis, it starts with the important role of expectations management. Economists should make clear that precise forecasts are not possible but that application of economic principles and careful analysis of data and historical events can substantially improve political decisions. In order to be effective, economic advisors have to be aware of the first best as well as of the political feasibility of proposals. Efficiency is the obvious benchmark, but a large part of policy advice is about finding the least inefficient of the feasible alternatives. The paper argues that a crucial precondition for being an effective policy advisor are communication skills; academics who become policy advisors should not try to impress their peers but rather translate insights in a language that is understandable for educated laypeople. The paper then looks at the special situation of economic policy advice in the Swiss direct democracy before concluding with a summary of the most important preconditions for being a successful policy advisor. PMID- 30443493 TI - Membrane Hsp70-A Novel Target for the Isolation of Circulating Tumor Cells After Epithelial-to-Mesenchymal Transition. AB - The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)-an essential element of the metastatic process-is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the "capture" of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)-cmHsp70.1-can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression. PMID- 30443496 TI - The sovereign money initiative in Switzerland: an economic assessment. AB - The sovereign money initiative will be submitted to the Swiss people in 2018. This paper reviews the arguments behind the initiative and discusses its potential impact. I argue that several arguments are inconsistent with empirical evidence or with economic logic. In particular, controlling sight deposits neither stabilizes credit nor avoids financial crises. Also, assuming that deposits at the central bank are not a liability has implications for fiscal and monetary policy, and Benes and Kumhof (The Chicago Plan Revisited, 2012) do not provide support for the reform as they do not analyze the proposed Swiss monetary reform and their closed-economy model does not fit the Swiss economy. Then, using a simple model with monopolistically competitive banks, the paper assesses quantitatively the impact of removing sight deposits from commercial banks' balance sheets. Even though there is a gain for the state, the overall impact is negative, especially because depositors would face a negative return. Moreover, the initiative goes much beyond what would be the equivalent of full reserve requirement and would impose severe constraints on monetary policy; it would weaken financial stability rather than reinforce it; and it would threaten the trust in the Swiss monetary system. Finally, there is high uncertainty both on the details of the reform and on its impact. PMID- 30443497 TI - Economists: moral realists or real moralists? Comment on Fourcade and Brunetti. PMID- 30443498 TI - Economics: the view from below. PMID- 30443499 TI - Factor substitution in Swiss manufacturing: empirical evidence using micro panel data. AB - This paper analyzes the relationship between factor substitutability and the energy intensity of manufacturing firms. Specifically, we compare the degree of substitutability between the input factors capital, labor, energy, and material for firms with low, medium, and high energy cost shares using a panel of Swiss manufacturing companies covering the period from 1997 to 2008. Our findings indicate substitutability between almost all production factors with one notable exception. Energy and capital are complements in the energy-intensive firm sample: A 1% increase in energy prices decreases capital use by 0.09%. We show that this complementarity is gradually increasing in the energy intensity of firms and draft important policy implications. PMID- 30443500 TI - How does depreciations management affect subsequent fiscal performance? The case of the Swiss cantons. AB - Creative accounting allows governments and, more particularly, finance ministers to somehow manage financial reports to achieve specific and possibly self interested goals. It is usually used to hide deficits. It sometimes also helps to present financial performance as being more worrisome than it actually is. In that case, ministers press more than needed for lower expenses and a higher tax burden. This pressure is expected to tame deficits or increase surpluses over time. Using panel data relative to the 26 Swiss cantons over the period 1980 2013, we estimate econometrically how a political finessing technique like 'depreciations management' affects subsequent government expenses and revenues and thus subsequent financial performance. PMID- 30443501 TI - Inheritance flows in Switzerland, 1911-2011. AB - We estimate the size of inheritance flows in Switzerland over a long span of data, in close analogy to the study for France by Piketty (Q J Econ 126(3):1071 1131, 2011). We find that inheritance flows had been growing more slowly than national income up until the 1970s, but have been outpacing income growth since. According to our central estimates, the annual flow of inheritance amounted to 13.2% of national income in 2011. The share of total wealth that is attributable to inheritance has remained relatively stable over time, fluctuating between 45 and 60%. PMID- 30443502 TI - Interest-parity conditions during the era of the classical gold standard (1880 1914)-evidence from the investment demand for bills of exchange in Europe. AB - This paper examines interest-parity conditions that arguably held as regards the investment demand for bills of exchange during the classical gold standard (1880 1914). Contemporaneous guides to the foreign exchanges report that close connections between the exchange and discount rates arose mainly with bills traded in London and the major financial centres on the European continent. As implied by the interest-parity condition, and in particular when future exchange rate movements were covered by a suitable long-bill transaction, weekly data do suggest that between Paris, Amsterdam, Berlin, Brussels, and London, the return from discounting bills of exchange in the local money market was roughly equivalent to the return from investing in foreign currency bills. PMID- 30443503 TI - International trade and unemployment: towards an investigation of the Swiss case. AB - The topic of this paper has been motivated by the rising unemployment rate of low skilled relative to high-skilled labour in Switzerland. Between 1991 and 2014, Switzerland experienced the highest relative increase in the low-skilled unemployment rate among all OECD countries. A natural culprit for this development is "globalization" as indicated by some mass layoffs in Switzerland and as commonly voiced in public debates all over the world. Our analysis, which is based on panel data covering the years 1991 to 2008 and approximately 33,000 individuals employed in the Swiss manufacturing sector, does not, however, confirm this presumption. We do not find strong evidence for a positive relationship between import competition and (low-skilled) individuals' likelihood of becoming unemployed. PMID- 30443504 TI - Comparative politics and the synthetic control method revisited: a note on Abadie et al. (2015). AB - Recently, Abadie et al. (Am J Polit Sci 59:495-510, 2015) have expanded synthetic control methods by the so-called cross-validation technique. We find that their results are not being reproduced when alternative software packages are used or when the variables' ordering within the dataset is changed. We show that this failure stems from the cross-validation technique relying on non-uniquely defined predictor weights. While the amount of the resulting ambiguity is negligible for the main application of Abadie et al. (Am J Polit Sci 59:495-510, 2015), we find it to be substantial for several of their robustness analyses. Applying well defined, standard synthetic control methods reveals that the authors' results are particularly driven by a specific control country, the USA. PMID- 30443505 TI - Methods to identify linear network models: a review. AB - In many contexts we may be interested in understanding whether direct connections between agents, such as declared friendships in a classroom or family links in a rural village, affect their outcomes. In this paper, we review the literature studying econometric methods for the analysis of linear models of social effects, a class that includes the 'linear-in-means' local average model, the local aggregate model, and models where network statistics affect outcomes. We provide an overview of the underlying theoretical models, before discussing conditions for identification using observational and experimental/quasi-experimental data. PMID- 30443506 TI - The Swiss franc safety premium. AB - This paper applies a recent method proposed by Maggiori (The U.S. Dollar Safety Premium, 2013) to estimate the Swiss franc safety premium. The results show that the three-step instrumental variable approach as used by Maggiori does not work for the Swiss franc exchange rates. The price of risk estimates take unrealistic, negative values. One possible explanation is that the approach as it is used by Maggiori suffers from a measurement error for the expected exchange rate which represents a potential source of imprecision. By using the prediction of an augmented Fama regression to measure the expected exchange rate change, this measurement error can be avoided and the safety premium estimates become more realistic and closer to those obtained with a maximum likelihood-estimated GARCH approach. Overall, however, the GARCH approach still seems to be preferable to the instrumental variable approach. PMID- 30443507 TI - On the rewards to international investing: a safe haven currency perspective. AB - The safe haven property of the Swiss franc presents a specific challenge for internationally minded Swiss-based investors. The central issue is whether the traditional under-performance of Swiss assets is made up by the secular appreciation of the Swiss franc combined with the propensity of the safe haven to strengthen in times of market stress. In this paper, we review the evidence on the terms of this challenge. We conclude that a Swiss bias in asset allocation can lead to considerable return shortfalls over the long run and that systematic currency hedging would not have been historically justified and is unlikely to be in the future. Assuming a fair amount of currency risk thus appears inevitable for long-run Swiss-based investors. PMID- 30443508 TI - Childcare and maternal part-time employment: a natural experiment using Swiss cantons. AB - Fuelled by federal stimuli of 440 million Swiss francs, the staggered expansion of childcare in many cantons allows the evaluation of this family policy on female labour supply. With new cantonal data, this study analyses both the decision to participate in the labour market and the intensity of participation. Empirical results of difference-in-differences regressions show that mothers work at higher percentage rates if they live in cantons that have expanded their childcare services more than the national average. The reform stimulated part time employment of between 20 and 36 h per week by 2 percentage points. The expansion of childcare particularly affected women with two children and upper secondary education, who are married or cohabit with their partner. PMID- 30443509 TI - Openness and productivity of the Swiss economy. AB - This paper analyzes the connection between openness and economic performance in Switzerland. Considering different dimensions of openness, we show that the Swiss economy is classified as relatively open. Nevertheless, there still is potential to further increase international integration, particularly through deregulation in the services sector. We also show that for some branches in the Swiss manufacturing sector, increases in international trade are associated with higher productivity in the long run. With regard to financial openness, we show that in the aftermath of the financial crisis, Switzerland mainly suffered from capital retrenchment. Foreign capital inflows were of minor importance. Short-run costs due to high volatility of capital flows might therefore be lower than widely perceived. PMID- 30443510 TI - Money demand under free banking: Switzerland 1851-1906. AB - This paper studies money demand in Switzerland under free banking before the establishment of the Swiss National Bank. We find that, in addition to income, the banks' balance-sheet-to-GDP ratio and the number of banks were important determinants of long-run money demand. The former variable also played an important role in the monetary adjustment process. We also detect a strong positive long-run impact of real income on the bank's balance-sheet-total-to-GDP ratio and a strong long-run influence of real income and the interest rate spread on the number of banks. PMID- 30443511 TI - The economics of secession: a review of legal, theoretical, and empirical aspects. AB - The aim of this paper is to present a review of the legal, theoretical, and empirical aspects of secessions from an economic perspective. This survey provides interesting insights into recent events such as the Brexit and the threat of secession made for instance by Scotland and Catalonia. International law does not grant a general right to secede, nor does it forbid secession. Furthermore, there are several modalities of secessions, which turn out to be important for new states that want to get an international recognition. For its part, the economic theory shows that the decision for a region to remain in a country (or a union) or to secede eventually results from a trade-off between the benefits of being part of a large country, on the one hand, and the costs often associated to more heterogeneity, on the other hand. The latter are generally more important for those regions which are "far away" from the central (federal) government. Empirical literature confirms the importance of these trade-offs and shows that decentralization may be effective to accommodate secessionist conflicts only if certain conditions are fulfilled. PMID- 30443512 TI - Optimal equity capital requirements for large Swiss banks. AB - Ten years after the worst financial crisis of the post-war period, Switzerland has established a Too-Big-To-Fail (TBTF) framework. Under this framework, the two large Swiss banks are subject to substantial capital requirements. It is not obvious whether the TBTF capital requirements are sufficient to prevent banks from plunging the country into a financial crisis once again. We estimate the social costs and benefits of higher capital requirements for the two large Swiss banks and derive socially optimal capital ratios from the cost-benefit trade-off. Our results show that Swiss TBTF capital requirements still fall short of socially optimal capital ratios. PMID- 30443513 TI - Suggestions for clinical study of exercise rehabilitation. PMID- 30443514 TI - The effects of vision training, neck musculature strength, and reaction time on concussions in an athletic population. AB - A concussion is a major concern across the athletic population. Prevention of concussions can lead to a decrease of 3.8 million concussions that occur annually in the United States. Vision training, increasing neck musculature strength and quick reaction times are thought to be ways to prevent concussions. The purpose of this study is to review the literature on vision training, neck musculature, and reaction time, and how these interventions can prevent concussions. Upon review of the literature, vision training is proven to prevent concussions in a collegiate football setting, but there is no literature on different levels or sports. There are inconclusive results on whether neck musculature strength prevents concussions. There are substantial results concluding reaction time does prevent concussions by allowing the athlete to protect and anticipate head impact lessening the severity of the blow to the head. More research needs to be done for all three interventions to prove across all ages and levels of every sport that vision training, neck musculature strength, and reaction time prevent concussions in an athletic population. If proven true, practitioners in an athletic setting can use vision training, increasing neck musculature strength, and increasing reaction time as interventions to help prevent concussions in an athletic population. PMID- 30443515 TI - Treadmill exercise improves memory function by inhibiting hippocampal apoptosis in pilocarpine-induced epileptic rats. AB - Epilepsy is characterized by recurrent seizures and loss of neurons with abnormal rhythmic firing in the brains. In the present study, we investigated the effect of treadmill exercise on memory function in relation with cell proliferation and apoptosis in the hippocampus using pilocarpine-induced seizure rats. Epilepsy was initiated by intraperitoneal injection of pilocarpine hydrochloride. The rats in the exercise group were forced to run on a motorized treadmill for 30 min once a day for 2 weeks. In the present results, treadmill exercise alleviated short-term and spatial learning memory impairments in the epileptic rats. Treadmill exercise suppressed neuronal degeneration and enhanced neuronal maturation in the epileptic rats. Treadmill exercise suppressed cell proliferation and apoptosis in the epileptic rats. Treadmill exercise alleviated pilocarpine-induced memory impairments and suppressed neuronal loss in the hippocampus through down regulation of apoptosis. These findings offer a possibility that treadmill exercise may provide a preventive or therapeutic value to the epilepsy-induced learning and memory impairments. PMID- 30443516 TI - Treadmill exercise alleviates stress-induced anxiety-like behaviors in rats. AB - Stress is the physiological responses of organisms to harmful or threatening stimuli that allow appropriate behavioral responses to the stressor. In the present study, the effect of treadmill exercise on stress-induced anxiety was evaluated using rats. To induce stress, the rats were exposed to an inescapable electric foot shock. Exposure of rats to the electric foot shock was performed for 7 days. The rats in the exercise groups were made to run on a motorized treadmill for 30 min once a day for 4 weeks stating one day after last electric food shock. Anxiety-like behaviors were determined by open field test and elevated plus-maze test. The expressions of c-Fos and neuronal nitric oxide synthase (nNOS) in the hypothalamus and locus coeruleus were detected by immunohistochemistry. In the present results, locomotor activity in the center of the open field test and the number of entries and time in the open arms of the elevated plus-maze test were reduced in the rats with stress-induced anxiety. Treadmill running enhanced these locomotor activities, the number of entries and time in the stress-induced anxiety rats. c-Fos and nNOS expressions in the hypothalamus and locus coeruleus were increased in the stress-induced rats. Treadmill exercise reduced c-Fos and nNOS overexpressions in the stress-induced rats. In the present study, treadmill exercise ameliorated anxiety-like behaviors in the stress-induced rats. The improving effect of treadmill exercise on anxiety like behaviors might be ascribed to the suppressing effect of exercise on c-Fos and nNOS expressions. PMID- 30443517 TI - Effect of type II collagen extract on immunosuppression induced by methotrexate in rats. AB - This study investigated the effect of type II collagen extract on SD rats with deteriorated immunity caused by methotrexate. The test samples were dosed once a day for 28 days by gastric gavage at dosage 250 mg/kg and 500 mg/kg after methotrexate treatment, and the changes on body weight, total blood leukocyte numbers, the percentages of B-cells, CD4+ T-cells and CD8+ T-cells in the blood and spleen were observed. The changes on body weight, the total blood leukocyte numbers, the total lymphocyte numbers in the spleen, the ratio of CD4+ and CD8+ T cells in the blood and spleen were increased significantly in type II collagen extract groups as compared with the control group. According to the above results, type II collagen extract has an effect of increasing immune responses on rats with deteriorated immunity caused by methotrexate. PMID- 30443518 TI - Barriers towards exercise and physical activity of different ethnic groups in middle-aged female Singaporeans. AB - The government has collaborated with the Health Promotion Board in coming out a bountiful of initiatives for the citizens to engage in exercise. Despite the initiatives, the obesity rate in middle-aged women is still high. This study seeks to understand and identify the vast barriers that prevent middle-aged women from exercising. Purposive sampling and semi-structured interview were conducted for the participants. The analysis of the interview revealed the significance of barriers in three areas: Priority of Family and Work Commitments, Minimal Promotion of Subsidized Initiatives by the Government, and Discrimination through the Usage of Language. It highlights that racial barriers are minimal and better time management would be appropriate to engage a healthier lifestyle. The study suggested female Singaporeans to incorporate sports in the lifestyle, more aggressive promotion of subsidized initiatives and the use of common languages (English) in the exercise class. PMID- 30443519 TI - A relationship between personality and empathy in teenagers' school sports club participation. AB - This study aims to identify the relation between students' participation in sports club activities and personality and sympathy based on the findings obtained from personalty and sympathy study and understand what the interrelational characteristics are. This study investigated a total of 408 individuals (male, 58.3%; female, 41.7%) who have continuously participated in sports club activity in middle schools located at Seoul and Gyeonggi province, Korea. To look at the type of event that they selected, 127 individuals (31.1%) reported that "School sports club event is already defined in school." and 281 (68.9%) reported that "We can select among several school sports club events." The events that they participated in are that 79 individuals participated in basket ball, 47 in line dancing, 96 in badminton, 2 in yoga, 31 in football, 129 in pingpong, and 20 in floorball. In conclusion adolescence is a period that adolescents are physically and mentally developed in terms of personality, morality, creativity, and sociality. During this period, learning and experience are very important for lifetime. Therefore, teenagers' school sports club activity can contribute to fostering positive and desirable personality and stabilizing emotional empathy among student participants. This study identified the relation between personality and empathy in adolescents, which was not studied before. As presented in previous researches, it can be found that positive personality can be cultivated by teenagers' communal activities in school life. The link to connect this with empathy factor is considered to be the very communal activity, sports. PMID- 30443520 TI - The short-term health promotion effect of the whole-body vibration exercise program for the improvement of the agility, the quick reaction ability, and the flexibility of the students aspiring for the physical education-affiliated departments in Korea. AB - The present study aimed to comparatively analyze the effects of the whole-body vibration exercise health promotion program on the agility, the quick reaction ability, and the flexibility of the test-takers. Total 30 test-takers had been prepared for the practical test as the subjects. They were divided into the three groups: the practical college entrance examination group with whole-body vibration exercise, the practical college entrance examination group, and the control group. The measurements of each item were made before and after the program applications of the side steps, the standing long jump, the standing high jump, the sitting trunk flexion, and the trunk forward flexion for 60 min 3 times a week. The side steps showed the significant differences among the groups. Although the standing long jump did not show any significant differences among the groups, the standing high jump showed the significant differences among the groups. Although the sitting trunk flexion showed the significant differences among the groups, the trunk forward flexion did not show any significant differences among the groups. But, the practical college entrance examination program group which carried out the whole-body vibration exercise at the same time showed the highest average value compared to the other groups. It was proven that, to the test-takers who had been preparing for the preparing examination for applying to a physical education-affiliated department, the whole-body vibration exercise program is helpful to the promotion of the health, including the agility, the quick reaction ability, the flexibility, etc. PMID- 30443521 TI - Comparison of muscular strength and balance in athletes with visual impairment and hearing impairment. AB - This study was conducted to compare muscular strength and balance of athletes with visual and hearing impairment. The study was carried out with 20 athletes of national Olympic level sports goalball team and 20 athletes of national Olympic level sports hearing-impaired karate team. Isokinetic muscular strength was assessed by IsoMed 2000 device as concentric-concentric at 60 degrees /sec and 240 degrees /sec. Balance assessment was carried out with the Human Body Equilibrium 360 device. There was no significant difference between groups regarding age, height, weight and body mass index (P>0.05). There were no differences between the dominant and nondominant knee flexion and extension peak torque (PT), % of flexion/extension PT ratio, % of dominant/nondominant PT differences at 60 degrees /sec and 240 degrees /sec velocities (P>0.05). There was no difference between the groups regarding of both leg static balance (P>0.05). However, single leg standing balance was significantly different between groups in favor of athletes with hearing impairment (P<0.001). As a result of our study it was determined that muscular strength and static balance of athletes with visual and hearing impairment were similar, but athletes with visual problems are likely to have lower levels of single leg balance. Strategies to promote single leg balance in athletes with visual impairments are warranted. PMID- 30443522 TI - Changes in training posture induce changes in the chest wall movement and respiratory muscle activation during respiratory muscle training. AB - Postural changes induce changes in chest wall kinematics and eventually pulmonary function, and affect chest wall shape and chest motion. This study aimed to examine the effects of postural change on changes in the chest wall during respiratory muscle training. Using a repeated measures design, this study followed 13 healthy adults (13 men; mean age, 23.73 years). All participants performed four postures (neutral, full trunk rotation, half-range trunk rotation, and lateral ribcage shift postures) during respiratory muscle training. The chest wall movement during the four postures was measured using a three-dimensional motion-analysis system during respiratory muscle training. Surface electromyography data were collected from the diaphragm and sternocleidomastoid muscles, and the asymmetric ratio of muscle activation was calculated based on the collected data. The chest wall movements of the upper costal and middle costal region were greater in the neutral posture than in the full rotation, half rotation, and lateral ribcage shift postures (P<0.05). The respiratory muscle activation on diaphragm of left was greater in the full rotation posture than in the neutral posture, half rotation, and lateral ribcage shift postures (P<0.05). The asymmetric ratio of muscle activation was greater in the full rotation posture than in the neutral posture, half rotation, and lateral ribcage shift postures (P<0.05). This study verified that postural change during respiratory muscle training may affect chest wall movement and muscle activation. Thus, this study recommends respiratory muscle training to be performed in neutral posture. PMID- 30443523 TI - Effect of the body mass index and sexual difference on the muscle activity during trunk exercise: a preliminary study. AB - There was lack of study which evaluated the effects of characteristics of subjects such as the body mass index (BMI) or waist circumference (WC), as well as sexual differences on trunk muscle activities. The purpose of the present study was to compare the abdominal muscle activities among the groups dividing criterion as the BMI, WC, and the gender. As a criterion of BMI and WC, subjects were arranged to three groups. Female subjects who were less than 25 kg/m2 BMI, and less than 90 WC were arranged as female with underweight group (FU), male subjects who were greater than 25 kg/m2 BMI and greater than 85 WC were arranged as male with overweight group (MO), male subjects who were less than 25 kg/m2 BMI and less than 85 WC were arranged in male with underweight group (MU). Surface electromyography responses of the rectus abdominis, internal oblique, external oblique muscles and lumbar level of erector spinae were obtained during the plank and maximal voluntary isometric contraction (MVIC). The MO group showed significantly higher %MVIC value of the internal oblique and lumbar level of erector spinae, compared to the MU group (P<0.05). The %MVIC of the rectus abdominis was significantly greater with the FU group (P<0.05). There were significant differences in the root mean squared (RMS) values from MVIC among the three groups (P<0.05). Regardless of muscles differences, the MO group showed significantly lower RMS activity values than the FU and the MU groups (P<0.05). Present study indicates some considerations of interpreting surface electromyography (sEMG) signal from region overlapping large fat tissue especially for trunk muscles. Individual characteristics such as gender, BMI, and WC could affect the sEMG signals. The female and male with overweight represent relatively high %MVICs during exercise, but it might be due to relatively low RMS values from procedure of MVICs. PMID- 30443524 TI - Personality differences amongst drag racers and archers: implications for sport injury rehabilitation. AB - Personality trait of an athlete is a significant factor in sports injury rehabilitation. The aim of the present study is to investigate whether there are differences in personality traits between male and female, professional and amateur athletes from sports representing two ends of extreme to traditional namely; drag racing and archery. Overall 189 male and female, professional and amateur drag racers (n=144) and archers (n=45) took part in this study. Participants completed the personality traits of extroversion and neuroticism as measured by Eysenck's classic Personality Inventory dimensions and thrill and adventure seeking (TAS), experience seeking (ES), disinhibition (DIS), boredom susceptibility (BS), and sensation seeking (SS) as measured by Zuckerman's Sensation Seeking Scale. The results showed that professionals scored significantly lower on neuroticism compared to amateurs. Drag racers scored significantly higher on TAS, DIS, and SS compared to archers and there were gender differences amongst archers on TAS and SS with males scoring higher than females. Such differences in personality factors and the readiness to take risks, lack of caution, and adventurous spirit can influence the risk of injury in athletes and indeed may influence the outcome of rehabilitation. Practitioners would need to recognise difference in personality traits associated with the type of sport and the choice of interventions strategies. PMID- 30443525 TI - The effects of daily food ingestion on improved immune functions and health promotion of bodybuilding athletes. AB - The purpose of this study was to investigate the effects of different weight reduction methods on the body composition characteristics, cardiopulmonary functions, and health promotion of elite bodybuilding athletes in a comprehensive manner. For this purpose, the study analyzed the effects of two different weight reduction methods on 25 elite bodybuilding athletes registered at the Bodybuilding Association over a period of 6 weeks. There were interactive effects on macronutrients, macrominerals, and antioxidants according to weight reduction methods as the experiment group (6%+/-2%) maintained a certain amount of food intakes across various nutrients including energy intakes or made a slow decrease it, whereas the traditional group (16%+/-4%) made a sharp decrease in it due to relatively greater weight reduction than the experiment group and thus showed pattern differences from it. As for immunity variables, there was an increase to certain cytokines despite the traditional high weight reduction method, but it caused no excessive reduction of immunity or rapid decrease to certain factors of body composition. In addition, there were no significant differences in main and interactive effects on the one-repetition maximum of bench press and squat, which are two functional indicators of health promotion. These findings imply that the low weight reduction method within the range of 6%+/-2% minimized or maintained changes to muscle circumference or mass while causing no improvement to muscular strength. PMID- 30443526 TI - Effects of N-acetylcysteine supplementation on cellular damage and oxidative stress indicators in volleyball athletes. AB - The purpose of this study was to evaluate the effects of N-acetylcysteine (NAC) supplementation on cellular damage and oxidative stress indicators in volleyball athletes. Twenty male volleyball athletes at national level performed a physical training session and were divided into 2 groups, which for 7 days took the placebo substance or NAC. After 7 days the athletes repeated the same training session. In both sessions, blood samples were collected 30 min before and immediately after the training session to measure cellular damage and oxidative stress markers. The main results show that, although higher concentrations of glutathione peroxidase and superoxide dismutase were observed in post-session 1 than those in postsession 2, the other markers showed an increase in antioxidant action after supplementation of NAC, once the effect of experimental conditions (P=0.030) were observed in: time effect (P<0.001) and interaction (P=0.019) for total glutathione; time effect (P<0.001) and interaction (P<0.001) for reduced glutathione; and time effect (P<0.001) for ferric-reducing antioxidant potential. The oxidant action indicated by the protein carbonyl was higher in the placebo group than in the NAC group (P=0.028), but a time effect (P<0.001) for the thiobarbituric acid reactive substances showed lower values in presession 1 than in presession 2. For the cellular damage markers, antagonistic results between markers were found. Based in the results, the supplementation of NAC during a short period was effective in reducing oxidant action and increasing antioxidant action. However, conclusive alterations in the responses of the cellular damage markers were not obtained. PMID- 30443527 TI - Analysis of differences in subjective health status according to characteristics of hospitalized cancer patients. AB - This study is intended to analyze differences in the self-rated health of patients according to the characteristics of hospitalized cancer patients. To this end, this study analyzed the differences in self-rated health according to cancer diagnosis type, cancer stage and adjunctive treatment and analyzed the recognition of difficulties in physical activities during hospitalization. A questionnaire survey was conducted among data of 162 hospitalized cancer patients. For the self-rated health of cancer patients according to diagnosis type, it was lower in the gastric cancer group than in the thyroid cancer group and the breast cancer group. For self-rated health according to cancer stage, it was higher in the order of the stage 3 group, stage 2 group and stage 1 group. For the self-rated health of patients receiving adjunctive treatment, it was the lowest in the chemotherapy+radiotherapy group. And for personal constraints according to cancer stage in the category of "physical," it was higher in the stage 3 group than in the stage 1 group. For hospital environment restrictions according to cancer stage in the category of "tool," it was higher in the stage 1 group than in the stage 3 group. In conclusion, personal constraints on the physical activities of cancer patients appear to be due to fatigue and a lack of motivation, but medical services that influence motivation are critical to individual and continued care strategies for the patients. PMID- 30443528 TI - Exploring the field application of combined cognitive-motor program with mild cognitive impairment elderly patients. AB - This study evaluated combined cognitive-motor program based on Alexander technique and Bartenieff fundamental method for mild cognitive impairment (MCI) patients. The purpose was to explore the field application of combined cognitive motor learning program centering on proprioceptive neuromuscular facilitation, developing sensory-motor coordination and enhancing focused attention to one's whole body. Two practice methods were applied to the 40 MCI elder. The combined cognitive-motor learning program (CM) was applied to the 20 MCI elder while 20 elder took traditional movement learning program (TM). Mini Mental States Examination-Korea (MMSE-K), Time Up & Go Test (TUG), Flexibility Test and Pegboard Test were measured and analyzed. The collected data were analyzed by paired t-test. The results were as follows: Both groups showed similar learning effect in Flexibility Test and Pegboard Test. However, in MMSE-K and TUG, CM group showed significant learning effect than TM group. Our data suggested body awareness and body consciousness through Alexander technique and Bartenieff fundamental program facilitated patients' kinaesthesia: sensory awareness and conscious control of the whole movement. From these results, we conclude that combined cognitive-motor learning program is valuable as alternative program for cognitive development as well as physical development of MCI elder. PMID- 30443529 TI - Progressive treadmill cognitive dual-task gait training on the gait ability in patients with chronic stroke. AB - The purpose of this study was to investigate the effects of progressive treadmill cognitive dual-task training on gait performance in individuals with chronic stroke patients. Twenty-six participants with chronic hemiparesis were recruited to this study and randomly distributed into two groups: progressive treadmill cognitive dual-task gait training (PTCDG group, 13 patients), conventional treadmill gait training (CTG group, 13 patients). All patients underwent 20 sessions of treadmill gait training with a harness (5 times per week, for a total of 4 weeks). The GAITRite was used to analyze gait kinematics, and 10-m walking test (10MWT) wear used as the clinical evaluation indicators. After training, PTCDG group showed significant improvement in gait velocity, cadence, single support time, and 10MWT compared to the control group. However there was no significant difference between the groups in the stride lengths in the affected and unaffected sides. The study verified that progressive treadmill cognitive dual-task gait training had a positive influence on the gait and clinical gait index in chronic stroke patients. PMID- 30443530 TI - Effects of exercise using a mobile device on cardiopulmonary function, metabolic risk factors, and self-efficacy in obese women. AB - The purpose of this study was to determine the effects of a 12-week walking exercise using a mobile device on cardiopulmonary function, metabolic risk factors, and self-efficacy in obese middle-aged women. For this study, 14 middle aged subjects with obesity were included and performed walking exercise of 50% 60% maximum oxygen uptake intensity 3 times a week for 12 weeks. As a result, weight, % body fat, body mass index, and waist circumference significantly reduced. In addition, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and hemoglobin A1c significantly reduced, while high-density lipoprotein cholesterol and flexibility significantly increased. Furthermore, exercise using a mobile device significantly increased self-efficacy. In conclusion, walking exercise using a mobile device is a good method to constantly increase the exercise participation rate, as it improves metabolic risk factor and obesity index, and increases self-efficacy. PMID- 30443531 TI - A study of the physical activity restriction in the cancer patients using hierarchical regression analysis. AB - This study aimed to examine and analyze the relationship between the physical activity of cancer patients during the hospitalization and the change in exercise recognition and restrictions on physical activity in depth. In this study, adult cancer patients aged more than 20 years residing in the metropolitan area (such as Seoul, Gyeonggi, and Incheon) were selected as a population, and 194 cancer patients from five general hospitals located in metropolitan area were selected as subjects by the purposive sampling. The relative importance for the effect on the physical restriction was greater in the order of the time spent in sedentary activities and exercise positive recognition. The relative importance for cognitive psychological restriction was greater in the order of negative exercise recognition, positive exercise recognition, the time spent in sedentary activities, the time spent in ordinary daily activities and the time spent in intentional movement. In the hospital environment restriction, the facility had a statistically significant effect on the movement and positive exercise recognition. But, sociocultural restrictions were not affected by positive exercise recognition. As a result of this study, it was found that the physical activity restrictions of the cancer patients may affect differently depending on the physical activity level, exercise experience, and exercise recognition, requiring the interpretation of the physical activity restrictions in various ways. PMID- 30443532 TI - Six-minute walk test and incremental shuttle walk test in the evaluation of functional capacity in Chagas heart disease. AB - Chagas heart disease (CHD) leads to a progressive functional impairment. Field tests, as the 6-min walk test (6MWT) and the incremental shuttle walk test (ISWT), may be inexpensive approaches in the evaluation of functional capacity of these patients. The present study was addressed to compare the 6MWT and the ISWT measures, and to determine the accuracy of these tests in the identification of functional impairment in patients with CHD. Thirty-five patients with CHD (47.1+/ 8.2 years, NYHA I-III) were evaluated by echocardiography, cardiopulmonary exercise test (CPET), 6MWT, and ISWT. Correlations between the CPET (peak oxygen uptake [peak VO2] and the ratio between ventilation and the carbon dioxide production [VE/VCO2 slope]) and the field tests (walking distances) were also performed. The receiver operating characteristic (ROC) curve was selected to identify the best distances related to identify those patients with functional impairment. There was no difference between distances walked during the 6MWT and ISWT (P=0.694). The Bland-Altman analysis showed good agreement between the field tests. Both 6MWT and ISWT correlated with peak VO2 (r=0.577, P<0.001 and r=0.587, P<0.001, respectively) and ISWT correlated with VE/VCO2 slope (r=-0.339, P=0.003). The cutoff distances of 6MWT and ISWT to identify patients with peak VO2 less than 20 mL/kg/min were 520 m and 400 m, respectively, with no difference between the areas under ROC curves (P=0.276). Both the 6MWT and the ISWT demonstrated accuracy in identify functional impairment in patients with CHD, being useful tools for the risk stratification of these patients. PMID- 30443533 TI - Motor control exercise and patient education program for low resource rural community dwelling adults with chronic low back pain: a pilot randomized clinical trial. AB - This pilot randomized clinical trial assessed the feasibility of implementing motor control exercise (MCE) and patient education (PE) program for the management of chronic low back pain (CLBP) in a low resource rural Nigerian community. Thirty patients with CLBP were recruited and randomly assigned to MCE, PE, or MCE plus PE groups. The MCE program was provided twice a week while the PE program was provided once a week all for 6 weeks. Feasibility was assessed through recruitment rate, treatment compliance, retention/dropout rate, report of adverse events, perceived helpfulness, overall satisfaction, and clinical outcome of pain (numeric pain rating scale) and functional disability (Oswestry Disability Index). Many patients were willing to participate in the study and the recruitment rate was 77%. Treatment compliance in all the three groups were >65% for supervised treatment sessions and <50% for prescribed home program. Retention rate was high and greater overall satisfaction with the interventions was reported. Compared with the baseline, all the three groups improved significantly in pain and disability (P<0.05) after 6 weeks. Pairwise comparison revealed that the MCE plus PE group was superior to the PE group for pain and to the MCE for disability (P<0.05), with large effect size. It was concluded that the designed interventions are promising and conducting a full-scale randomized clinical trial in the future is feasible to confirm the effectiveness of the interventions for the management CLBP in rural Nigeria. (Trial registration: ClinicalTrials.gov, NCT03398174). PMID- 30443534 TI - The effect of exercise therapy, dry needling, and nonfunctional electrical stimulation on radicular pain: a case report. AB - A 43-year-old male, office worker with history of chronic radicular low back pain radiating into the left leg was admitted to a sports medicine research center, neuroscience institute. During the past year, he visited a physiotherapist and orthopedic experts. Magnetic resonance imaging revealed a protruded disc at L4-5 level. Additionally, electromyography indicated that there was bilateral moderate irritation at the L5-S1 root. We designed a management package including exercise therapy, dry needling, and nonfunctional electrical stimulation for four sessions. Outcomes included pain intensity, pain with lumbar flexion, with the numerical rating scale (NRS), visual analogue scale (VAS), and function measured with the Oswestry Disability Index before and after the intervention. After 4 treatment sessions, the patient reported a reduction in pain intensity from a 9 to 2 on the NRS and from 90 to 30 on the VAS. In addition, the patient was able to perform lumbar flexion fully without pain. PMID- 30443535 TI - Effects of 12-week aquatic exercise on cardiorespiratory fitness, knee isokinetic function, and Western Ontario and McMaster University osteoarthritis index in patients with knee osteoarthritis women. AB - The purpose of this study is to investigate the risk factors of metabolic syndrome, cardiorespiratory fitness, knee isokinetic function, and osteoarthritis index inpatients with knee osteoarthritis women. Subjects were divided into the exercise group (n=9, aged 60.89+/-5.06), and the control groups (n=8, aged 61.25+/-1.91). Aquatic exercise was performed for 12 weeks, 3 times a week, 60 min a day. The changes of metabolic syndrome risk factors, cardiorespiratory fitness, knee isokinetic function, and WOMAC index (Western Ontario and McMaster University osteoarthritis index) were measured and analyzed at pre- and postexercise program for verifying exercise effectiveness. As a result, fasting blood glucose (P<0.05), glycosylated hemoglobin (P<0.01), and triglyceride (P<0.05) were significantly decreased in the risk factors of metabolic syndrome. The maximum oxygen uptake in cardiorespiratory fitness was not significantly different. The left and right extensor muscles of knee isokinetic function increased significantly (P<0.01, P<0.01, respectively). There was no significant difference in flexor muscles. Osteoarthritis index was significantly improved in stiffness (P<0.01) and physical function (P<0.05). In conclusion, aquatic exercise can be regarded as an effective exercise program for managing metabolic syndrome risk factors, increasing muscle function, and improving osteoarthritis index in patients with osteoarthritis of the knee. PMID- 30443536 TI - Therapeutic effects of aquatic exercises on a boy with Duchenne muscular dystrophy. AB - Participation in physical activities benefits individuals with disabilities in terms of addressing their social and psychological needs in order for the purposes of quality living. This study reports the findings from a case study conducted with a boy who has Duchenne muscular dystrophy (DMD) in a swimming pool located in the campus of a private university in North Cyprus. The current study reports the adjustments made in the swimming pool in accordance with the needs of the participant, how service quality was increased to cater for these needs and in what ways the participant benefited from the aquatic program. This qualitative investigation aims to shed light onto how aquatic therapy has affected the boy with DMD physically, psychologically, and socially from the parents' perspectives. The results revealed that aquatic therapy had beneficial effects on the participant with DMD in terms of socialization, relaxation, quality of life and self-perception. PMID- 30443537 TI - Whole body vibration to attenuate reduction of explosive force in chronic kidney disease patients: a randomized controlled trial. AB - To investigate whether whole body vibration (WBV) training increases the explosive force of the knee extensors in chronic kidney disease (CKD) patients. Fourteen CKD patients undergoing hemodialysis were randomly allocated in WBV training or Sham group. Explosive force parameters (contractile impulse [CImp] and relative rate of force development [RFDr]) obtained in early (30 and 50 msec) and late phases (100 and 200 msec) of the knee extensors force/time curve. CImp and RFDr obtained at the early phase of force/time curve reduced after the intervention period, with a smaller decline for WBV (CImp at 50 msec [~-15% and 51%, P=0.038], RFDr at 30 msec [~-22% and -52%, P=0.044] and RFDr at 50 msec [~ 11% and -54%; P=0.008]). In the late phase there was a lower decline for WBV group compared to Sham group, respectively: CImp: 100 msec (~-8% and -55%, P=0.025), 200 msec (~-3% and -46%, P= 0.025); RFDr 100 msec (~0.01% and -56%, P=0.033), 200 msec (~-5% and -36%, P=0.004). Three months of WBV training may attenuate the explosive force reduction in CKD patients. PMID- 30443538 TI - Effects of a 6-week aerobic exercise programme on the cardiovascular parameters, body composition, and quality of life of people living with human immune virus. AB - This study evaluated the effects of aerobic exercise program on the cardiovascular parameters, body composition, and quality of life (QoL) of people living with human immune virus (HIV). Patients were recruited from the HIV clinic in a tertiary hospital in Nigeria. Fish bowl method was used to randomize the patients to either experimental or control group. Experimental group received nutritional counseling and aerobic exercise program on a treadmill, 3 times a week for a period of 6 weeks, while the control group received only nutritional counseling. Cardiovascular parameters, aerobic fitness, body composition parameters, and QoL were evaluated at baseline and 6 weeks. Descriptive statistics was used to explore demographic data while the hypothesis was tested using inferential statistics of t-test. Alpha level was set at P<0.05. The result showed that there was an improvement in cardiovascular parameters in both groups, attaining significance in the experimental group (P=0.000). Aerobic fitness increased significantly in experimental group (P=0.000). Body composition decreased significantly while there was a significant difference in the muscle mass (%) between groups (P<0.05). All domains of QoL had a significant improvement in both groups (P<0.005). A 6-week aerobic exercise program in addition to nutritional counseling was able to significantly improve cardiovascular fitness, body composition, and QoL in people living with HIV/acquired immune deficiency syndrome. Nutritional counseling alone can bring about an improvement only in QoL parameters. PMID- 30443539 TI - Controversies in Breastfeeding. AB - When addressing the compatibility of breastfeeding with certain maternal conditions, we need to differentiate between "contraindication" and "obstacle." Failure to distinguish between the two confuses new mothers and their families, and engenders misconceptions about breastfeeding advice by health professionals. Health conditions that may simply impede the initiation and duration of breastfeeding are often wrongly referred to as true contraindications to breastfeed, under the assumption that they might harm the health of the mother and/or that of the nursing infant. Here, we discuss several topics, including breast surgery, prolactinoma, concurrent new pregnancy, hormonal contraception, and use of medications and contrast agents, that continue to raise controversy. While most conditions appear to be compatible with breastfeeding, the major determinants of a woman's final choice of whether to nurse her infant or not are the attitude of health professionals and the state of mind of being an informed mother. PMID- 30443540 TI - Pediatric Central Nervous System Tumors: State-of-the-Art and Debated Aspects. AB - Pediatric neuro-oncology surgery continues to progress in sophistication, largely driven by advances in technology used to aid the following aspects of surgery: operative planning (advanced MRI techniques including fMRI and DTI), intraoperative navigation [preoperative MRI, intra-operative MRI (ioMRI) and intra-operative ultrasound (ioUS)], tumor visualization (microscopy, endoscopy, fluorescence), tumor resection techniques (ultrasonic aspirator, micro instruments, micro-endoscopic instruments), delineation of the resection extent (ioMRI, ioUS, and fluorescence), and intraoperative safety (neurophysiological monitoring, ioMRI). This article discusses the aforementioned technological advances, and their multimodal use to optimize safe pediatric neuro-oncology surgery. PMID- 30443541 TI - Numb Isoforms Deregulation in Medulloblastoma and Role of p66 Isoform in Cancer and Neural Stem Cells. AB - Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance. PMID- 30443542 TI - Role of Lung Function Monitoring by the Forced Oscillation Technique for Tailoring Ventilation and Weaning in Neonatal ECMO: New Insights From a Case Report. AB - Respiratory management during extracorporeal membrane oxygenation (ECMO) is complex. Assessment of lung mechanics might support a patient-tailored ventilatory strategy. We report, for the first time, the use of the forced oscillation technique (FOT) to evaluate lung function during neonatal ECMO to improve the individualization of respiratory support. The patient was a formerly preterm infant at a corrected age of 40 weeks (gestational age 32 weeks) undergoing veno-arterial ECMO for refractory respiratory failure secondary to influenza A (H1N1) pneumonia. We used the FOT as a bedside non-invasive tool for daily monitoring of lung mechanics, from ECMO day 6 (E6) until decannulation. A small-amplitude, 5-Hz oscillatory pressure was overimposed on the ventilation waveform at the airway opening during positive end-expiratory pressure (PEEP) trials. From E6 to E9, lung mechanics changes with PEEP indicated a largely de recruited and easily over-distendable lung that was not recruitable by applying lung-protective PEEP values. After surfactant and steroid administration, oscillatory reactance (Xrs) values began improving, suggesting a more recruited and pressure-recruitable lung. On E11, despite the lack of improvement in the radiographic appearance of the thorax, the FOT measurements showed a more recruited lung. Weaning from ECMO was started, and the patient was extubated within 48 h. The decannulation was successful, and the patient was extubated within 48 h after ECMO weaning. First-year respiratory and neurodevelopmental follow-up evaluation was unremarkable. This report suggests the potential usefulness of the FOT for monitoring the lung mechanics of ventilated newborns during ECMO to achieve individualized respiratory management. Such tailoring might improve neonatal outcomes and support clinicians with the establishment of a timely and safer weaning approach. These findings need to be verified on a larger population. PMID- 30443543 TI - Exploring the Orthogonal Chemoselectivity of 2,4,6-Trichloro-1,3,5-Triazine (TCT) as a Trifunctional Linker With Different Nucleophiles: Rules of the Game. AB - The study involves exploring the three orthogonal sites for aromatic nucleophilic substitution in cyanuric chloride (TCT). The preferential order of incorporation of different nucleophiles (such as alcohol, thiol, and amine) was addressed both experimentally and theoretically. The preferential order for incorporating nucleophiles in TCT was found to be alcohol > thiol > amine. PMID- 30443544 TI - Phenol Derivatives From the Sponge-Derived Fungus Didymellaceae sp. SCSIO F46. AB - Seven new phenol derivatives named coleophomones E and F (1, 2), diorcinols L and M (3, 4), 1-hydroxy-6-methyl-11-methoxy-8-hydroxymethylxanthone (5), porric acid E (6), and 7-(2-hydroxyphenyl) butane-7,8,9-triol (7), were isolated from the EtOAc extract of the marine sponge-derived fungus Didymellaceae sp. SCSIO F46, together with 10 known compounds. Their structures were determined by spectroscopic analyses, including NMR, MS, X-ray diffraction, and theoretical calculations. Each of 1 and 2 contains an unusual spiro [cyclohexane-1,2'-inden] moiety, which is relatively seldom in nature products. Cytotoxic and COX-2 inhibitory activities of all purified compounds were tested and evaluated. Compound 3 displayed obvious cytotoxicities against Huh-7, HeLa, DU145 and HL60 cells (IC50 values 5.7-9.6 MUM) and weak activities against other five cell lines, while 8 showed weak cytotoxicities against HeLa and HL7702 cells. Compound 6 displayed COX-2 inhibitory activity with IC50 value of 3.3 MUM. PMID- 30443545 TI - Bioengineering Human Neurological Constructs Using Decellularized Meningeal Scaffolds for Application in Spinal Cord Injury. AB - Spinal cord injury (SCI) is one of the most devastating conditions echoes with inflammation, enhanced fibrosis and larger axonal gaps due to destruction of neurological cells which has caused continuous increasing mortality rate of SCI patients due to absence of suitable treatment modalities. The restoration of structural and functional aspect of damaged neurological tissues at the lesion site in spinal cord has been challenging. Recent developments have showed tremendous potential of neural stem cell-based strategies to form a neuronal relay circuit across the injury gap which facilitates some levels of improvement in SCI condition. However, to provide better therapeutic responses, critical mass of grafted cells must survive for long-term and differentiate into neuronal cells with well-developed axonal networks. Hence, development of tissue specific biological neuronal constructs is highly desirable to provide mechanical and biological support for long-term survival and function of neurological cells within natural biological niche. In this study, we report development of a tissue specific neuronal constructs by culturing human neural precursor cells on decellularized meningeal scaffolds to provide suitable biological neuronal construct which can be used to support mechanical, structural and functional aspect of damaged spinal cord tissues. This particular tissue specific biological construct is immunologically tolerable and provides precisely orchestral three dimensional platform to choreograph the long-distance axonal guidance and more organized neuronal cell growth. It passes sufficient mechanical and biological properties enriched with several crucial neurotrophins required for long-term survival and function of neurological cells which is required to form proper axonal bridge to regenerate the damaged axonal connectomes at lesion-site in SCI. PMID- 30443546 TI - Dynamic Control of ERG20 and ERG9 Expression for Improved Casbene Production in Saccharomyces cerevisiae. AB - Production of plant metabolites in microbial hosts represents a promising alternative to traditional chemical-based methods. Diterpenoids are compounds with interesting applications as pharmaceuticals, fragrances and biomaterials. Casbene, in particular, serves as a precursor to many complex diterpenoids found in plants from the Euphorbiaceae family that have shown potential therapeutic effects. Here, we engineered the budding yeast Saccharomyces cerevisiae for improved biosynthesis of the diterpene casbene. We first expressed, in yeast, a geranylgeranyl diphosphate synthase from Phomopsys amygdali in order to boost the geranylgeranyl diphosphate pool inside the cells. The enzyme uses isopentenyl diphosphate and dimethylallyl diphosphate to directly generate geranylgeranyl diphosphate. When co-expressing a casbene synthase from Ricinus communis the yeast was able to produce casbene in the order of 30 mg/L. Redirecting the flux from FPP and sterols, by means of the ergosterol sensitive promoter of ERG1, allowed for plasmid-based casbene production of 81.4 mg/L. Integration of the target genes into the yeast genome, together with the replacement of the promoter regions of ERG20 and ERG9 with combinations of ergosterol- and glucose-sensitive promoters, generated a titer of 108.5 mg/L of casbene. We here succeeded to engineer an improved route for geranylgeranyl diphosphate synthesis in yeast. Furthermore, we showed that the concurrent dynamic control of ERG20 and ERG9 expression, using ergosterol and carbon source regulation mechanisms, could substantially improve diterpene titer. Our approach will pave the way for a more sustainable production of GGPP- and casbene-derived products. PMID- 30443547 TI - Zebrafish-A Model Organism for Studying the Neurobiological Mechanisms Underlying Cognitive Brain Aging and Use of Potential Interventions. PMID- 30443548 TI - Identification of Kinases and Phosphatases That Regulate ATG4B Activity by siRNA and Small Molecule Screening in Cells. AB - Autophagy protease ATG4B is a key regulator of the LC3/GABARAP conjugation system required for autophagosome formation, maturation and closure. Members of the ATG4 and the LC3/GABARAP family have been implicated in various diseases including cancer, and targeting the ATG4B protease has been suggested as a potential therapeutic anti-cancer strategy. Recently, it has been demonstrated that ATG4B is regulated by multiple post-translational modifications, including phosphorylation and de-phosphorylation. In order to identify regulators of ATG4B activity, we optimized a cell-based luciferase assay based on ATG4B-dependent release of Gaussia luciferase. We applied this assay in a proof-of-concept small molecule compound screen and identified activating compounds that increase cellular ATG4B activity. Next, we performed a high-throughput screen to identify kinases and phosphatases that regulate cellular ATG4B activity using siRNA mediated knockdown and cDNA overexpression. Of these, we provide preliminary evidence that the kinase AKT2 enhances ATG4B activity in cells. We provide all raw and processed data from the screens as a resource for further analysis. Overall, our findings provide novel insights into the regulation of ATG4B and highlight the importance of post-translational modifications of ATG4B. PMID- 30443549 TI - Usefulness of Topically Applied Sensors to Assess the Quality of 18F-FDG Injections and Validation Against Dynamic Positron Emission Tomography (PET) Images. AB - Background: Infiltrations of 18F-fluorodeoxyglucose (FDG) injections affect positron emission tomography/computed tomography (PET/CT) image quality and quantification. A device using scintillation sensors (Lucerno Dynamics, Cary, NC) provides dynamic measurements acquired during FDG uptake to identify and characterize radioactivity near the injection site prior to patient imaging. Our aim was to compare sensor measurements against dynamic PET image acquisition, our proposed reference in assessing injection quality during the uptake period. Methods: Subjects undergoing routine FDG PET/CT imaging were eligible for this Institutional Review Board approved prospective study. After providing informed consent, subjects had sensors topically placed on their arms. FDG was injected into subjects' veins directly on the PET imaging table. Dynamic images of the injection site were acquired during 45 min of the uptake period. These dynamic image acquisitions and subjects' routine standard static images were evaluated by nuclear medicine physicians for abnormal FDG accumulation near the injection site. Sensor measurements were interpreted independently by Lucerno staff. Dynamic image acquisition interpretation results were compared to the sensor measurement interpretations and to static image interpretations. Results: Twenty four subjects were consented and enrolled. Data from 21 subjects were gathered. During dynamic image acquisition review, physicians interpreted 4 subjects with no FDG accumulation at the injection site, whereas 17 showed evidence of accumulation. In 10 of the 17 cases that showed FDG accumulation, the FDG presence at the injection site resolved completely during uptake corresponding to venous stasis, the temporary sequestration of blood from circulation. Static image interpretation agreed with dynamic images interpretation in 11/21 (52%) subjects. Sensor measurement interpretations agreed with the dynamic images interpretations in 18/21 (86%) subjects. Conclusions: Sensor measurements can be an effective way to identify and characterize infiltrations and venous stasis. Comparable to an infiltration, venous stasis may produce spurious and clinically meaningful measurement bias and possibly even scan misinterpretation. Since the quality and quantification of PET/CT studies are of clinical importance, sensor measurements acquired during the FDG uptake may prove to be a useful quality control measure to reduce infiltration rates and potentially improve patient care. Registration: Clinicaltrials.gov, Identifier: NCT03041090. PMID- 30443551 TI - Brain Plasticity in Mammals: An Example for the Role of Comparative Medicine in the Neurosciences. AB - Comparative medicine deals with similarities and differences between veterinary and human medicine. All mammals share most basic cellular and molecular mechanisms, thus justifying murine animal models in a translational perspective; yet "mice are not men," thus some biases can emerge when complex biological processes are concerned. Brain plasticity is a cutting-edge, expanding topic in the field of Neurosciences with important translational implications, yet, with remarkable differences among mammals, as emerging from comparative studies. In particular, adult neurogenesis (the genesis of new neurons from brain stem cell niches) is a life-long process in laboratory rodents but a vestigial, mostly postnatal remnant in humans and dolphins. Another form of "whole cell" plasticity consisting of a population of "immature" neurons which are generated prenatally but continue to express markers of immaturity during adulthood has gained interest more recently, as a reservoir of young neurons in the adult brain. The distribution of the immature neurons also seems quite heterogeneous among different animal species, being confined within the paleocortex in rodents while extending into neocortex in other mammals. A recent study carried out in sheep, definitely showed that gyrencephalic, large-sized brains do host higher amounts of immature neurons, also involving subcortical, white, and gray matter regions. Hence, "whole cell" plasticity such as adult neurogenesis and immature neurons are biological processes which, as a whole, cannot be studied exclusively in laboratory rodents, but require investigation in comparative medicine, involving large-sized, long-living mammals, in order to gain insights for translational purposes. PMID- 30443550 TI - Heterocellularity and Cellular Cross-Talk in the Cardiovascular System. AB - Cellular specialization and interactions with other cell types are the essence of complex multicellular life. The orchestrated function of different cell populations in the heart, in combination with a complex network of intercellular circuits of communication, is essential to maintain a healthy heart and its disruption gives rise to pathological conditions. Over the past few years, the development of new biological research tools has facilitated more accurate identification of the cardiac cell populations and their specific roles. This review aims to provide an overview on the significance and contributions of the various cellular components: cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, pericytes, and inflammatory cells. It also aims to describe their role in cardiac development, physiology and pathology with a particular focus on the importance of heterocellularity and cellular interaction between these different cell types. PMID- 30443552 TI - The impacts of cough: a cross-sectional study in a Finnish adult employee population. AB - Given the very high prevalence of cough, little is known about its impacts. A questionnaire was sent via e-mail to all public service employees in two towns in Finland. There were 373 subjects with acute cough, 174 with subacute cough and 421 with chronic cough. Cough-related quality of life was assessed with the Leicester Cough Questionnaire (LCQ) and depressive symptoms with Patient Health Questionnaire-2. In addition, data on doctor's visits and sick leave days were collected. Mean LCQ (95% CI) total scores were 16.2 (15.9-16.5), 14.5 (14.1-15.0) and 14.6 (14.3-14.9) among subjects with acute, subacute and chronic cough, respectively (p<0.001). The prevalence of depressive symptoms was 5.4%, 7.5% and 4.8%, respectively, and 5.0% among subjects without current cough (p=0.50). The respective proportions of subjects with at least one doctor's visit due to cough during the previous year were 27.6%, 44.8%, 49.6% and 16.1% (p<0.001). The respective proportions of subjects with at least one sick leave day due to cough during the previous year were 28.9%, 39.1%, 36.3% and 15.3% (p<0.001). Any current cough was associated with an increased the risk of several (three or more) yearly doctor's visit due to any reason (adjusted odds ratio (aOR) 1.49, 95% CI 1.27-1.76) and several (seven or more) yearly sick leave days due to any reason (aOR 1.43, 95% CI 1.22-1.68). Cough decreases quality of life, and has a large socioeconomic impact by increasing doctor's visits and sick leave days. However, it is not associated with depressive symptoms. The impacts of subacute and chronic cough are comparable, and larger than those of acute cough. PMID- 30443554 TI - Circulating desmosine as a biomarker of azithromycin treatment response: a post hoc analysis of the COLUMBUS randomised controlled trial. AB - Circulating desmosine is not reduced by treatment with azithromycin in COPD but elevated desmosine may identify a patient group with a greater treatment response http://ow.ly/vN6N30mhBA1. PMID- 30443553 TI - Expiratory reactance abnormalities in patients with expiratory dynamic airway collapse: a new application of impulse oscillometry. AB - Expiratory dynamic airways collapse (EDAC) is a condition that affects the central airways; it is not well characterised physiologically, with relatively few studies. We sought to characterise impulse oscillometry (IOS) features of EDAC in patients with normal spirometry. Expiratory data were hypothesised to be the most revealing. In addition, we compared IOS findings in chronic obstructive pulmonary disease (COPD) patients with and without EDAC. EDAC was identified at bronchoscopy as 75-100% expiratory closure at the carina or bilateral main bronchi. Four patient groups were compared: controls with no EDAC and normal lung function; lone EDAC with normal lung function; COPD-only patients; and COPD patients with EDAC. 38 patients were studied. Mean IOS data z-scores for EDAC compared to controls showed significantly higher reactance (X) values including X at 5 Hz, resonance frequency and area under the reactance curve (AX). EDAC showed significantly greater expiratory/inspiratory differences in all IOS data compared to controls. Stepwise logistic regression showed that resonant frequency best discriminated between EDAC and normal control, whereas classification and regression tree analysis found AX >=3.523 to be highly predictive for EDAC in cases with normal lung function (14 out of 15 cases, and none out of eight controls). These data show a new utility of IOS: detecting EDAC in patients with normal lung function. PMID- 30443555 TI - Association of low income with pulmonary disease progression in smokers with and without chronic obstructive pulmonary disease. AB - Low socioeconomic status has been associated with chronic obstructive pulmonary disease (COPD) but little is known about its impact on disease progression. We assessed the association of income to symptoms, pulmonary disease severity and progression in smokers with and without COPD. The COPDGene cohort of 4826 smokers who reported annual income in phase 2 was analysed. Those who reported annual income =12 years old presenting to the emergency department with hip or femur fractures and a Likert visual analogue scale >4 had an EP-administered FICB. EPs used a standard intramuscular needle and a lidocaine-epinephrine solution they compounded at the bedside and located the injection site using only anatomic landmarks. EPs evaluated the patient's pain level at 30 minutes and at two hours post-FICB. We also reviewed articles since 2016 that describe the FICB. Results: We enrolled a non-consecutive sample of 10 patients in the case series. Five had femoral neck (hip) fractures and five had femoral shaft fractures. All patients had a reduction in their pain levels after the FICB. On average, the block took effect about three minutes after injection. At 30 minutes all patients reported clinically meaningful pain reduction. The analgesic effect of the compounded agent lasted approximately 200 minutes. No adverse effects were reported. No published journal articles about FICB since 2016 were from resource-poor settings, and only one was from a developing country. Conclusion: This series suggests that the FICB is effective even when performed with the minimal materials that are usually available in resource-poor settings. Methods such as this, which use simplified clinical tests and techniques applicable in resource poor settings, can assist global emergency medicine (EM). We can assist global EM by similarly finding methods to simplify useful clinical tests and techniques that can be used in resource-poor settings. PMID- 30443608 TI - Threatened Respiratory Compromise in the Setting of Isolated Angioedema. AB - Isolated angioedema of the uvula, or Quincke's disease, is a rare condition that can cause respiratory compromise. Although typically self-limiting, episodes of angioedema may require prompt therapy to prevent obstruction of the proximal airway. In this case report we review the appropriate steps for initial evaluation of patients with suspected angioedema, primary etiologies, and appropriate initial therapy. PMID- 30443609 TI - Rib Osteomyelitis in a Pediatric Patient: Case Report and Review of the Literature. AB - We present a case report and review of the literature of rib osteomyelitis in a pediatric patient presenting to the emergency department (ED) with fever and increased work of breathing. The patient was seen on a return visit to the ED after discharge with presumed viral illness approximately 12 hours prior. On the second ED visit, there was concern for occult bacteremia, and work-up ultimately revealed a subperiosteal abscess with rib osteomyelitis, a rare etiology for fever in the pediatric patient. The patient was treated with antibiotics, had surgical debridement, and fully recovered. PMID- 30443610 TI - 48-year-old Man with Fevers, Chest Pain, and a History of Substance Abuse. AB - A 48-year-old male with a history of intravenous (IV) drug use presented to the emergency department (ED) for an area of mild pain and erythema on his chest. He was then triaged to the urgent care, or fast track, area of the ED. He was well appearing with normal lab findings and vital signs, but his workup revealed mediastinitis with osteomyelitis of the manubrium and clavicles, a surgical emergency. His treatment course included IV antibiotics and operative intervention with thoracic surgery. The patient looked too good to be sick, yet he had a life-threatening infection. PMID- 30443611 TI - Point-of-care Ultrasound Diagnosis of an Atypical Acute Aortic Dissection. AB - Aortic dissections have a vast array of clinical presentations that rarely follow traditional teachings. Dissections are rapidly fatal conditions requiring immediate diagnosis and treatment to reduce morbidity and mortality. We present a case of an acute aortic dissection presenting as abrupt onset, atraumatic leg pain with absent distal extremity pulses. The prompt use of point-of-care ultrasound detected an intimal flap within the abdominal aorta allowing immediate surgical consultation and intervention. PMID- 30443612 TI - Acute Hepatitis B with Pancreatitis and Cholecystitis Leading to Acute Liver Failure and Death. AB - Acute liver failure is defined as severe acute liver injury, concurrent with encephalopathy and loss of hepatic synthetic function, in a patient without known pre-existing liver disease. Evaluation of acute liver failure in the emergency department should focus on identification of treatable causes. Acute liver failure from acute hepatitis B infection is a rare but potentially lethal occurrence. Multi-organ dysfunction from acute liver failure may be exacerbated by metabolic and inflammatory reactions associated with acute pancreatitis, which accompanies approximately 5% of cases of acute viral hepatitis. Transplant-free survival rate with liver failure from acute hepatitis B is unfortunately less than 20%. PMID- 30443613 TI - Double Sequence Defibrillation for Out-of-hospital Cardiac Arrest: Unlikely Survival. AB - Survival from out-of-hospital cardiac arrest (OHCA) is highest with early defibrillation and immediate, high-quality cardiopulmonary resuscitation. Return of spontaneous circulation (ROSC) is rare in OHCA. The purpose of this discussion and case report is to highlight the use of double sequence defibrillation (DSD) for refractory ventricular fibrillation (RVF). We present a 58-year-old male with RVF who successfully achieved ROSC after 38 minutes using DSD and had a good neurological outcome. DSD has shown promise in many case reports and case series as a means of increasing ROSC and survival rates in OHCA. PMID- 30443614 TI - Spontaneous Thrombosis of the Aortic Arch after Outpatient Urologic Procedure. AB - A healthy, 42-year-old woman presented to a local community hospital with abdominal pain and left arm pain after laser stone ablation and ureteral stenting performed earlier that day. She was diagnosed with a spontaneous aortic thrombus and embolization of the radial, ulnar and splenic arteries and transferred to a tertiary care facility for cardiothoracic surgery evaluation. This case report discusses her emergency department course, disposition, and one-year outcome. PMID- 30443615 TI - Pacemaker-associated Phlegmasia Cerulea Dolens Treated with Catheter-directed Thrombolysis. AB - Phlegmasia cerulea dolens (PCD) is a rare and severe form of deep venous thrombosis that is classically associated with the lower extremities. We report a case of upper extremity PCD developing abruptly in a 37-year-old female with an indwelling cardiac pacemaker who presented to the emergency department complaining of pain and paresthesias in her left arm, adjoining left chest wall, and inferior neck. Her condition was promptly diagnosed and successfully treated with intravenous unfractionated heparin and balloon venoplasty with catheter directed thrombolysis without any known residual signs or symptoms at hospital discharge. PMID- 30443616 TI - Point-of-care Ultrasonography of a Rare Cause of Hemoperitoneum. AB - A young woman presented to the emergency department with lethargy, hemodynamic instability, and diffuse abdominal tenderness. On point-of-care ultrasound (PoCUS), she was found to have intraperitoneal free fluid and a large pelvic mass, which were discovered intraoperatively to be hemoperitoneum due to ruptured vessels of a uterine leiomyoma. Although rare, a life-threatening, ruptured leiomyoma may be treated surgically if recognized in an expedient fashion. A PoCUS can aid the emergency clinician in prompt diagnosis. PMID- 30443617 TI - FascIOtomy: Ultrasound Evaluation of an Intraosseous Needle Causing Compartment Syndrome. AB - Intraosseous (IO) needles are used in critically ill patients when it is not possible to quickly obtain venous access. While they allow for immediate access, IO infusions are associated with complications including fractures, infections, and compartment syndrome. We present a case where point-of-care ultrasound was used to quickly identify a malfunctioning IO needle that resulted in compartment syndrome of the lower extremity. PMID- 30443618 TI - Fungal Rhino-orbital Cerebritis in a Patient with Steroid-induced Ketoacidosis. AB - Fungal rhino-orbital cerebritis is a devastating opportunistic invasive disease. Survival requires urgent diagnosis. Thus, all patients at risk who present with rhinosinusitis-type symptoms and have co-morbid conditions that decrease their immunocompetence should trigger the clinician's consideration of this disease. Treatment includes antifungals and emergent surgical debridement. PMID- 30443619 TI - Bulbar Muscle Weakness in the Setting of Therapeutic Botulinum Injections. AB - We present a case of new-onset bulbar muscle weakness in the setting of therapeutic botulinum injections for spasticity in a teenaged patient with cerebral palsy. Through a careful history, a systemic effect of the local injections was suspected, and the patient's symptoms improved with a decrease in the dosing of the botulinum injections. PMID- 30443621 TI - Acute Epiglottitis with Concurrent Pneumonia and Septic Shock in an Alcoholic Adult Patient. AB - Historically epiglottitis has been considered a childhood disease. However, the introduction of the Haemophilus influenzae type B vaccine has decreased the incidence of epiglottitis in children. It is important to recognize modern epiglottitis as a disease of adults. This report describes a case of acute bacterial epiglottitis in an adult patient secondary to infection caused by Streptococcus pyogenes, a group A streptococcal infection. This case demonstrates the importance of early recognition of epiglottitis in adults, as they can experience rapid clinical decline. The progression of this disease can lead to abrupt airway obstruction necessitating emergent airway management. PMID- 30443620 TI - Temporary Memory Steal: Transient Global Amnesia Secondary to Nephrolithiasis. AB - Transient global amnesia (TGA) is typified by an abrupt and transient anterograde amnesia, "with repetitive questioning and often variable retrograde amnesia persisting up to 24 hours." A 54-year-old male presented to our emergency department with paroxysms of left-sided flank pain, suggestive of renal colic. Computed tomography (CT) of the abdomen/pelvis revealed a three-millimeter left ureterovesicular-junction calculus. Pain control proved difficult, necessitating multiple doses of opioid and non-opioid analgesia. Subsequently, the patient developed repetitive questioning and perseveration with anterograde amnesia with a negative CT brain and unremarkable further workup. He experienced a complete resolution of symptoms within a 24-hour period, with a discharge diagnosis of TGA secondary to nephrolithiasis. This is the third case of TGA attributed to nephrolithiasis in the medical literature. PMID- 30443622 TI - Under-recognized Etiology of Altered Mental Status in a Patient with Alcoholism. AB - Wernicke's encephalopathy is an important condition for the emergency physician (EP) to consider in patients at risk for malnutrition. A 60-year-old man with history of alcoholism presented with word-finding difficulties, dysmetria, ataxia, and personality changes. After treatment with high-dose thiamine, his neurological status returned to his baseline. Although EPs routinely prescribe thiamine for patients with alcoholism, the common initial dose of 100 mg per day is likely subtherapeutic, and the population of patients at risk for malnutrition is much broader than only those with alcoholism, and includes those with cancer, anorexia nervosa, hyperemesis gravidarum, and others. EPs must be aware of this low-cost, readily available prophylaxis to prevent long-term neurological morbidity. PMID- 30443623 TI - Convulsion and Atrial Fibrillation after Transforaminal Cervical Epidural Lidocaine Injection. AB - Lidocaine has been widely used as a local anesthetic as well as an antiarrhythmic. Its use in epidural anesthesia is increasing, which has introduced new risk and potential for harm not associated with older indications. We present a case of convulsion and atrial fibrillation seen after transforaminal cervical epidural injection with two milliliters of 2% lidocaine (40 milligrams) that resolved with no long-term sequelae. Patient had a negative serum lidocaine level. With cervical epidural injections being a common treatment for radicular pain, it is important for medical providers to be aware of the various complications associated with this procedure. PMID- 30443625 TI - Mercury Ingestion. PMID- 30443624 TI - Limb Ischemia in a Patient with Hyperosmolar Hyperglycemic State. AB - A 61-year-old male with a recent diagnosis of pemphigus vulgaris was brought to the emergency department for altered mental status. He had recently started taking prednisone to manage his autoimmune disease and had a progressive decline in his mental status along with decreased oral intake. Evaluation revealed hyperosmolar hyperglycemic state (HHS) and occlusive arterial thrombosis, a rare but known complication of HHS. He was resuscitated aggressively with intravenous fluids, insulin, and heparin and admitted to the intensive care unit. Emergency physicians should remain vigilant for ischemic complications in patients with HHS. Early recognition and treatment can reduce the morbidity and mortality associated with this endocrine emergency. PMID- 30443626 TI - Flail Chest Resulting from a Rocket-type Firework. PMID- 30443627 TI - Massive Right Breast Hematoma. PMID- 30443628 TI - Eagle Syndrome. PMID- 30443629 TI - A Giant Vocal Cord Polyp Mimics Asthma Attack. PMID- 30443631 TI - Donut Sign on Magnetic Resonance Angiography: Interpret with Caution. PMID- 30443630 TI - Wrist Fracture in a Child Irreducible Due to Soft Tissue Interposition. PMID- 30443632 TI - A Rare Knee Fracture with Underestimated Severity. PMID- 30443633 TI - Malignant Catatonia Mimics Tetanus. PMID- 30443634 TI - Adult Male with Left Arm Pain and Swelling. PMID- 30443635 TI - A Brush with Danger. PMID- 30443636 TI - Point-of-care Cranial Ultrasound in a Hemicraniectomy Patient. PMID- 30443637 TI - Chief Complaint: "There Is Something Burning in my Mouth". PMID- 30443638 TI - A Case of Necrotic Skin Lesions on the Abdomen. PMID- 30443639 TI - Blinking Bug Bite. PMID- 30443640 TI - This Rash Puts You in the ICU. PMID- 30443642 TI - PubMed Central Archiving: A Major Milestone for Current Developments in Nutrition. PMID- 30443641 TI - Evaluation of Sialyllactose Supplementation of a Prebiotic-Containing Formula on Growth, Intestinal Development, and Bacterial Colonization in the Neonatal Piglet. AB - Background: Sialyllactose (SL) is a highly abundant oligosaccharide in human milk that has been shown to influence intestinal maturation and cognitive development and exert bifidogenic effects on the gut microbiota. The SL content of infant formula is significantly less than that of human milk, therefore there is interest in determining the effect of supplementing SL to infant formula at the levels in human milk on neonatal outcomes. Objective: The aim of this study was to investigate the effect of varying doses of dietary SL compared with a milk replacer formula on weight gain, gastrointestinal development, and microbiota composition in piglets. Methods: Thirty-eight intact male piglets were randomly assigned to 1 of 4 experimental diets from 2 to 32-33 d of age. Diets were formulated to contain SL at 0 mg/L (CON), 130 mg/L (LOW), 380 mg/L (MOD), or 760 mg/L (HIGH). At 32-33 d of age, blood was collected for serum chemistry and blood cellular analyses, and coagulation time. Immediately after humane killing, the small intestine was excised and intestinal segments fixed for quantification of mucin-producing goblet cells and morphologic analysis. In addition, mucosal disaccharide activity was assessed. Colonic luminal contents and feces were collected for measurement of pH, dry matter, volatile fatty acids, and the microbiota. Results: SL at <=760 mg/L supported normal growth, intestinal development, and enzyme activity as well as serum chemistries and hematology (P > 0.05). In addition, SL supplementation did not affect overall microbiota structure and diversity in ascending colon contents and feces, but had minor effects on the relative abundances of specific microbes. Conclusions: The findings in this study demonstrate that SL addition to a prebiotic-containing formula was well-tolerated by neonatal piglets, supported normal growth, and did not result in any adverse effects on serum chemistries or intestinal development. PMID- 30443643 TI - Dynamics of DNA Methylation Reprogramming Influenced by X Chromosome Dosage in Induced Pluripotent Stem Cells. AB - How the epigenome of one cell type is remodeled during reprogramming into another unrelated type of cell remains unclear. Overexpression of transcription factors in somatic cells enables the induction of induced pluripotent stem cells (iPSCs). This process entails genome-wide remodeling of DNA methylation, chromatin, and transcription. Recent work suggests that the number of active X chromosomes present in a cell influences remodeling of DNA methylation during somatic cell reprogramming to mouse iPSCs. Female iPSCs with 2 active X chromosomes display global DNA hypomethylation, whereas male XY iPSCs show DNA methylation levels similar to the somatic cells they are derived from. Global DNA methylation erasure in female iPSCs takes place genome-wide and involves repression of DNA methyltransferases. However, on loss of one X chromosome, female iPSCs acquire a DNA methylation landscape resembling that of XY iPSCs. Therefore, it is the X chromosome dosage that dictates global DNA methylation levels in iPSCs. Here, we discuss the evidence that links X chromosome dosage with the regulation of DNA methylation in pluripotent stem cells. We focus on iPSCs reprogramming studies, where X chromosome status is a novel factor impacting our understanding of epigenetic remodeling. PMID- 30443644 TI - Histone Modifications: Epigenetic Mediators of Environmental Exposure Memory. AB - How organisms retain a memory of ancestral environmental exposure is a phenomenon that is still poorly understood. Recently published work by our group and others, regarding environmentally induced transgenerational effects, have identified an array of mechanisms, with a particular focus on histone modifications, that shed some light on the underlying epigenetic processes driving long-term generational effects. PMID- 30443645 TI - Involvement of Epigenetic Promoter DNA Methylation of miR-124 in the Pathogenesis of HIV-1-Associated Neurocognitive Disorders. AB - Despite the efficacy of combination antiretroviral therapy (cART) in controlling viremia, the central nervous system (CNS) continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Transactivator of transcription (HIV-1 Tat) protein. Based on the premise that cART does not impact levels of HIV-1 Tat, and since the CNS is inaccessible to the cART regimens, HIV-1-Tat-mediated neuroinflammation has been implicated as an underlying mediator of HIV-1 associated neurocognitive disorders (HAND). The mechanism(s) underlying the pathogenesis of HAND, however, remain less understood. Understanding the epigenetic/molecular mechanism(s) by which viral proteins such as HIV-1 Tat activate microglia is thus of paramount importance. The study published by Periyasamy et al provides new mechanistic insights into the role of HIV-1-Tat mediated DNA methylation of miR-124 promoter in regulating microglial activation via the MECP2-STAT3 signaling axis. Furthermore, the authors have also reported that exposure of mouse primary microglial cells to HIV-1 Tat notably increased DNA methylation of primary miR-124-1 and primary miR-124-2 promoters (with no change in primary miR-124-3), resulting in turn to downregulated expression of both primary miR-124-1 and primary miR-124-2 as well as mature miR-124 in mouse primary microglial cells. The authors also examined the involvement of MECP2 STAT3 signaling in HIV-1-Tat-mediated microglial activation. Based on these novel findings, it is evident that dysregulation of miR-124 is involved in the pathogenesis of HAND and that restoration of miR-124 could serve as an adjunctive treatment for dampening neuroinflammation associated with HAND. PMID- 30443646 TI - Targeting light versus deep sedation for patients receiving mechanical ventilation. PMID- 30443647 TI - Intention Mining in Medical Process: A Case Study in Trauma Resuscitation. AB - In medical processes such as surgical procedures and trauma resuscitations, medical teams perform treatment activities according to underlying invisible goals or intentions. In this study, we present an approach to uncover these intentions from observed treatment activities. Developed on top of a hierarchical hidden Markov model (H-HMM), our approach can identify multi-level intentions. To accurately infer the H-HMM, we used state splitting method with maximum a posteriori probability (MAP) as the scoring function. We evaluated our approach in both qualitative and quantitative ways, using a case study of the trauma resuscitation process. This dataset includes 123 trauma resuscitation cases collected at a level 1 trauma center. Our results show our intention mining achieved an accuracy of 86.6% in classifying medical teams' intentions. This work is an exploration of unsupervised intention mining of complex real-world medical processes. PMID- 30443648 TI - Complete validation of a continuous and blood-correlated sweat biosensing device with integrated sweat stimulation. AB - A wearable sweat biosensing device is demonstrated that stimulates sweat and continuously measures sweat ethanol concentrations at 25 s intervals, which is then correlated with blood ethanol during a >3 hour testing phase. The testing involves a baseline condition (no ethanol) followed by a rapid blood and sweat rise of ethanol (oral bolus), and finally, the physiological response of the body as ethanol concentrations return to baseline (metabolized). Data sets include multiple in vivo validation trials and careful in vitro characterization of the electrochemical enzymatic ethanol sensor against likely interferents. Furthermore, the data is analyzed through known pharmacokinetic models with a strong linear Pearson correlation of 0.9474-0.9996. The continuous nature of the data also allows analysis of blood-to-sweat lag times that range between 2.3 to 11.41 min for ethanol signal onset and 19.32 to 34.44 min for the overall pharmacokinetic curve lag time. This work represents a significant advance that builds upon a continuum of previous work. However, unresolved questions include operation for 24 hours or greater and with analytes beyond those commonly explored for sweat (electrolytes and metabolites). Regardless, this work validates that sweat biosensing can provide continuous and blood-correlated data in an integrated wearable device. PMID- 30443649 TI - Copper stress in Staphylococcus aureus leads to adaptive changes in central carbon metabolism. AB - Copper toxicity has been a long-term selection pressure on bacteria due to its presence in the environment and its use as an antimicrobial agent by grazing protozoa, by phagocytic cells of the immune system, and in man-made medical and commercial products. There is recent evidence that exposure to increased copper stress may have been a key driver in the evolution and spread of methicillin resistant Staphylococcus aureus, a globally important pathogen that causes significant mortality and morbidity worldwide. Yet it is unclear how S. aureus physiology is affected by copper stress or how it adapts in order to be able to grow in the presence of excess copper. Here, we have determined quantitatively how S. aureus alters its proteome during growth under copper stress conditions, comparing this adaptive response in two different types of growth regime. We found that the adaptive response involves induction of the conserved copper detoxification system as well as induction of enzymes of central carbon metabolism, with only limited induction of proteins involved in the oxidative stress response. Further, we identified a protein that binds copper inside S. aureus cells when stressed by copper excess. This copper-binding enzyme, a glyceraldehyde-3-phosphate dehydrogenase essential for glycolysis, is inhibited by copper in vitro and inside S. aureus cells. Together, our data demonstrate that copper stress leads to the inhibition of glycolysis in S. aureus, and that the bacterium adapts to this stress by altering its central carbon utilisation pathways. PMID- 30443650 TI - Acid-catalyzed synthesis of functionalized arylthio cyclopropane carbaldehydes and ketones. AB - A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes and ketones via a Bronsted acid catalyzed arylthiol addition/ring contraction reaction sequence has been exploited. The procedure led to a wide panel of cyclopropyl carbaldehydes in generally high yields and with broad substrate scope. Mechanistic aspects and synthetic applications of this procedure were investigated. PMID- 30443651 TI - Delocalized excitons and interaction effects in extremely dilute thermal ensembles. AB - Long-range interparticle interactions are revealed in extremely dilute thermal atomic ensembles using highly sensitive nonlinear femtosecond spectroscopy. Delocalized excitons are detected in the atomic systems at particle densities where the mean interatomic distance (>10 MUm) is much greater than the laser wavelength and multi-particle coherences should destructively interfere over the ensemble average. With a combined experimental and theoretical analysis, we identify an effective interaction mechanism, presumably of dipolar nature, as the origin of the excitonic signals. Our study implies that even in highly-dilute thermal atom ensembles, significant transition dipole-dipole interaction networks may form that require advanced modeling beyond the nearest neighbor approximation to quantitatively capture the details of their many-body properties. PMID- 30443652 TI - Long-range oriented graphene-like nanosheets with corrugated structure. AB - A facile molten-salt (MS) route for the scalable synthesis of free-standing, long range oriented and corrugated graphene-like sheets from a copper phthalocyanine (CuPc) precursor is reported. Their unique arrangement and transformation behavior in molten potassium chloride (KCl) play a key role in promoting the successful synthesis of the anisotropic nanostructure. PMID- 30443653 TI - Zinc clasp-based reversible toolset for selective metal-mediated protein heterodimerization. AB - Considering the complex biological quandaries of the tightly woven networks of biological macromolecules, we present an optimized zinc clasp-based toolset from the CD4 co-receptor and Lck protein tyrosine kinase complex for selective, tight and fully reversible protein heterodimerization (log K12 = 18.6). We demonstrated its utility on CD4-tagged proteins with capture from bacterial lysate and constructed molecular baits using a new small-molecule tether. PMID- 30443654 TI - A guide to maximizing the therapeutic potential of protein-polymer conjugates by rational design. AB - Proteins are an important class of therapeutics that have advantages including high target specificity, but challenges to their use include rapid clearance and low physical stability. Conjugation of synthetic polymers is an effective approach to address the drawbacks and enhance other properties such as solubility. In this review, we present various considerations in synthesizing protein-polymer conjugates for therapeutic applications with a focus on the choice of polymer, protein, and conjugation method, as well as characterization and evaluation of the resulting conjugate in order to maximize the therapeutic potential of the protein drug. PMID- 30443655 TI - Molecular characterization of genomic regions for resistance to Pythium ultimum var. ultimum in the soybean cultivar Magellan. AB - KEY MESSAGE: Two novel QTL for resistance to Pythium ultimum var. ultimum were identified in soybean using an Illumina SNP Chip and whole genome re-sequencing. Pythium ultimum var. ultimum is one of numerous Pythium spp. that causes severe pre- and post-emergence damping-off of seedlings and root rot of soybean [Glycine max (L.) Merr.]. The objective of this research was to identify quantitative trait loci (QTL) for resistance to P. ultimum var. ultimum in a recombinant inbred line population derived from a cross of 'Magellan' (moderately resistant) and PI 438489B (susceptible). Two different mapping approaches were utilized: the universal soybean linkage panel (USLP 1.0) and the bin map constructed from whole genome re-sequencing (WGRS) technology. Two genomic regions associated with variation in three disease-related parameters were detected using both approaches, with the bin map providing higher resolution. Using WGRS, the first QTL were mapped within a 350-kbp region on Chr. 6 and explained 7.5-13.5% of the phenotypic variance. The second QTL were positioned in a 260-kbp confidence interval on Chr. 8 and explained 6.3-16.8% of the phenotypic variation. Candidate genes potentially associated with disease resistance were proposed. High resolution genetic linkage maps with a number of significant SNP markers could benefit marker-assisted breeding and dissection of the molecular mechanisms underlying soybean resistance to Pythium damping-off in 'Magellan.' Additionally, the outputs of this study may encourage more screening of diverse soybean germplasm and utilization of genome-wide association studies to understand the genetic basis of quantitative disease resistance. PMID- 30443656 TI - Solid Phase Extraction of Cadmium and Lead from Water by Amberlyst 15 and Determination by Flame Atomic Absorption Spectrometry. AB - Preconcentration of Cd(II) and Pb(II) was carried out by using column solid phase extraction method. Amberlyst 15 was used as solid phase for these analytes. The optimum extraction conditions such as pH (4), type and volume of eluent (5 mL of 2 mol L-1 HNO3) sample flow rate (1 mL min-1) and sample volume (100 mL for Cd(II) and 750 mL for Pb(II)) were determined. The recoveries were found for Cd(II) and Pb(II) as 104% +/- 1% and 102 % +/- 2%, respectively. The limit of detections were found as 0.23 ug L-1 for Cd(II) and 0.13 ug L-1 for Pb(II). The effects of foreign ions were also studied. The method was validated by analyzing standard reference material and spiked water samples. Percent relative error and relative standard deviation were below 3% and 4%, respectively. PMID- 30443657 TI - In-Situ Remediation of Cadmium and Atrazine Contaminated Acid Red Soil of South China Using Sepiolite and Biochar. AB - The in-situ immobilization effect of sepiolite and biochar on the compound pollution of cadmium (Cd) and atrazine in acid red soil of south China was studied. Results showed that in a certain concentration range, sepiolite and biochar can improve the germination rate, ensure normal growth and increase biomass of pakchoi, reduce the content of Cd in edible parts of pakchoi in different degrees and meet international standards, and restrain absorption of atrazine in pakchoi completely. Sepiolite was more effective than biochar for the immobilization of Cd, while biochar was more effective than sepiolite for the immobilization of atrazine. Combined application of sepiolite and biochar in soil contaminated by Cd and atrazine was better than individual applications of sepiolite or biochar. The remediation method applied in this research can effectively repair the acid red soil with combined pollution of Cd and atrazine in south China, while also providing ideas for in-situ remediation of farmland soil with combined pollution of pesticides and metals. PMID- 30443658 TI - Bioaccumulation of Copper and Zinc and the Effects on Antioxidant Enzyme Activities in the Liver of Acipenser stellatus (Pallas, 1771). AB - Although water pollution by metals in the Danube River is considered high, little is known about its impact on sturgeons. In this regard, the aim of this study was to investigate the bioaccumulation of copper and zinc as well as their effects on antioxidant enzymes activities in the liver of Acipenser stellatus. The fish were exposed for 7 and 14 days, to two concentrations of copper and zinc (10% and 25% of LC50 96 h), previously determined as 0.54 mg/L Cu2+ and, 34.22 mg/L Zn2+ respectively. The enzymatic responses of A. stellatus varied greatly depending on metal type, concentration and time. Significant bioaccumulation of the two metals was recorded. Even though the water hardness used in the experiment is known to offer a clear protection against metal contamination, stellate sturgeon remains a sensitive species in the face of metal toxicity. PMID- 30443659 TI - Bioaccumulation of Heavy Metals and their Genotoxic Effect on Freshwater Mussel. AB - Contamination of fresh water bodies like riverine system is utmost concerned environmental issue. This study was aimed to assess the concentration of heavy metals in River Kabul and their bioaccumulation by freshwater mussel. Comet assay was used to evaluate the genotoxic effect of heavy metals on hemocytes of freshwater mussel. The concentration of heavy metals in water was in the order of Zn > Pb > Ni > Cu > Mn > Fe > Cr > Cd, in sediments were Fe > Zn > Cr > Ni > Mn > Pb > Cu > Cd and in the soft tissues of freshwater mussel were in order of Fe > Zn > Mn > Pb > Cu > Cr > Ni > Cd. The hemocytes of mussels from polluted sites showed significantly higher (p < 0.05) DNA damage as compared to reference site. The study showed that pollutants from industries, municipal, domestic and agricultural sources cause heavy metals contamination in River Kabul. PMID- 30443660 TI - Mercury and Organochlorines in the Terrestrial Environment of Schirmacher Hills, Antarctica. AB - We report the levels of mercury (Hg) and nine organochlorine pesticides [OCPs: alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, delta-HCH, alpha Endosulfan, beta-Endosulfan, Endosulfan sulfate, p,p' dichlorodiphenyldichloroethylene (DDE) and p,p'-dichlorodiphenyldichloroethane (DDD)] in the terrestrial environment (moss and soil) and water (OCPs only) of Schirmacher Hills, Antarctica. This area has never been studied for mercury and not for OCPs since 1988. Mercury levels in moss, 66 +/- 37 ng/g dry weight (dw), are comparable to other Antarctic locations. Levels of alpha-HCH, below detection to 4.48 ng/g dw, and p,p'-DDE, below detection to 31 ng/g dw, in mosses are lower or marginally higher than other Antarctic locations. No other OCPs were detected in moss. None of the OCPs were detected in soil. This suggests that Schirmacher Hills may be considered as a background site with respect to mercury and analyzed OCPs, despite the operation of two old research stations (Maitri, est. 1989, and Novolazarevskaya, est. 1961) in the region. PMID- 30443661 TI - Copper Bioaccumulation Kinetics in Swan Mussel, Anodonta cygnea (Linnaeus, 1758) During Waterborne Exposure to CuO Nanoparticles. AB - This study was conducted to investigate bioaccumulation of copper in two internal organs (mantle and foot) of swan mussel, Anodonta cygnea (Linnaeus, 1758) in exposure to copper oxide nanoparticles (CuO NPs). Basal concentration of Cu in the mantle (3.15 +/- 1.09 ug g-1 DW) was significantly (p < 0.05) lower than the foot (5.43 +/- 1.54 ug g-1 DW). At the end of the exposure period, the highest concentration of Cu in both organs belonged to the highest exposure concentration. Calculated bioconcentration factor (BCF) values showed significant (p < 0.05) higher values for the mantle in each day and each exposure concentration (except the lowest exposure concentration) than the foot. For both organs, the highest and lowest BCFs occurred at the lowest and highest exposure concentrations, respectively. Cu concentration in both organs was significantly (p < 0.05) decreased after day 4. Based on the results, it was obvious that exposure to sub-lethal concentrations of CuO NPs would lead to the significant accumulation of copper in mantle and foot that may have adverse effects on this organism. PMID- 30443662 TI - Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries. AB - Global health is transitioning toward a focus on building strong and sustainable health systems in developing countries; however, resources, funding, and agendas continue to concentrate on "vertical" (disease-based) improvements in care. Surgical care in low- and middle-income countries (LMICs) requires the development of health systems infrastructure and can be considered an indicator of overall system readiness. Improving surgical care provides a scalable gateway to strengthen health systems in multiple domains. In this position paper by the Society of University Surgeons' Committee on Global Academic Surgery, we propose that health systems development appropriately falls within the purview of the academic surgeon. Partnerships between academic surgical institutions and societies from high-income and resource-constrained settings are needed to strengthen advocacy and funding efforts and support development of training and research in LMICs. PMID- 30443663 TI - Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode. AB - The non-canonical cyclic nucleotide cUMP and the phosphodiesterase PDE9A both occur in neuronal cells. Using HPLC-coupled tandem mass spectrometry, we characterized the kinetics of PDE9A-mediated cUMP hydrolysis. PDE9A is a low affinity and high-velocity enzyme for cUMP (Vmax = ~ 6 MUmol/min/mg; Km = ~ 401 MUM). The PDE9 inhibitor BAY 73-6691 inhibited PDE9A-catalyzed cUMP hydrolysis (Ki = 590 nM). Docking studies indicate two H-bonds between the cUMP uridine moiety and Gln453/Asn405 of PDE9A. By contrast, the guanosine moiety of cGMP forms three H-bonds with Gln453. cCMP is not hydrolyzed at a concentration of 3 MUM, but inhibits the PDE9A-catalyzed cUMP hydrolysis at concentrations of 100 MUM or more. The probable main reason is that the cytosine moiety cannot act as H bond acceptor for Gln453. A comparison of PDE9A with PDE7A suggests that the preference of the former for cGMP and cUMP and of the latter for cAMP and cCMP is due to stabilized alternative conformations of the side chain amide of Gln453 and Gln413, respectively. This so-called glutamine switch is known to be involved in the regulation of cAMP/cGMP selectivity of some PDEs. PMID- 30443664 TI - Corticosteroid injection is the best treatment in plantar fasciitis if combined with controlled training. AB - PURPOSE: Plantar fasciitis is a very common (lifetime incidence ~ 10%) and long lasting injury with major impact on daily function. Combining corticosteroid injection and physical training (strength training and stretching) was hypothesized to result in a superior effect compared to each treatment separately. METHODS: A single blinded randomized controlled superiority trial conducted in 2013-2014 with a 2-year follow-up (end Sept 2016). 123 consecutive patients (20-65 years) referred to two study centers in Denmark: Institute of Sports Medicine, Bispebjerg Hospital, University of Copenhagen and a private rheumatology clinic with symptoms of plantar fasciitis, and ultrasound measured thickness above 4.0 mm were invited. 25 did not fulfill the inclusion criteria (mainly ultrasound criteria) and 8 refused participation. 90 patients were randomized (pulling sealed envelopes) to 3 groups: (1) 3 months strength training and stretching (n = 30), (2) corticosteroid injections with monthly intervals until thickness < 4.0 mm (maximum 3 injections) (n = 31), (3) combination of the two treatments (n = 29). During the 3 months intervention period load reduction was recommended (cushioning shoes and insoles and abstaining from running and jumping). The main outcome was improvement in Pain at function on a 100-mm VAS score and in Foot Function Index (FFI, range 0-230) at 6 months (Clinicaltrials.gov Identifier: NCT01994759). RESULTS: All groups improved significantly over time, but the combination of corticosteroid injection and training (strength training and stretching) had a superior effect at all time points. The mean difference between the combined treatment and training was 40 points in FFI (95% confidence interval (CI) 63-17 points, p < 0.001) and 20 mm for VAS function pain (CI 35-5 mm, p < 0.01). The mean difference between the combined treatment and corticosteroid injections only was 29 points in FFI (CI 52 7 points, p < 0.01) and 17 mm for VAS function pain (CI 32-2 mm, p < 0.05). All differences were clinically relevant. CONCLUSION: The best treatment for plantar fasciitis is the combination of corticosteroid injections and training (strength training and stretching). This combined treatment is superior both in the short- and in the longterm. Corticosteroid injections combined with controlled training are recommended as first line treatment in patients with plantar fasciitis. LEVEL OF EVIDENCE: 1. PMID- 30443665 TI - Ecotype Variation in Trace Element Content of Hard Tissues in the European Roe Deer (Capreolus capreolus). AB - Animals living in anthropogenic habitats bear a multitude of costs, which are directly or indirectly associated with human activities. Among others, an elevated exposure to environmental pollution can have negative consequences for wildlife populations. We examined the differences in the concentrations of trace elements between the field and forest ecotype of the European roe deer (Capreolus capreolus). Naturally, roe deer inhabited various types of woodlands (forest ecotype), but within the last century, they adapted to life in a human transformed agricultural areas (field ecotype), which could be associated with an increased exposure to pollution. In this study, we measured concentrations of seven trace metals (barium, copper, iron, lead, manganese, strontium, zinc) and fluoride in skull bones and permanent teeth of more than 230 roe deer from 8 study plots in East-Central Europe. We found that field roe deer had higher concentrations of four trace metals (copper, iron, lead, strontium) and fluoride compared with forest roe deer. These differences were consistent with variations in the general level of environmental contamination within the study plots, as assessed with trace element content in wild plants. Our study indicates that bone and teeth of the European roe deer can be used as a valid indicator of environmental pollution. Also, we expect that elevated exposure of field roe deer to environmental pollution can have negative consequences for wild populations of this species, as well as for the consumers of venison. PMID- 30443666 TI - Trace Elements and Polycyclic Aromatic Hydrocarbons Variation Along the Guang Shen Expressway Before and After the 2016 Qingming Festival in Guangzhou. AB - PM2.5 samples (particles with aerodynamic diameter < 2.5 MUm) were collected along the Guang-Shen expressway around the Qingming Festival, one of the most congested periods in China, which started from April 2-4, in 2016. Twenty-five trace elements and 16 priority polycyclic aromatic hydrocarbons (PAHs) of the samples were analyzed. Their major sources at different periods were identified. The concentrations of PAHs distinctly increased with growing traffic flow 2 days before the Qingming Festival (March 31th and April 1st), decreased gradually on the first 2 days of the 3-day festival (April 2nd and 3rd) and rose again on the last day (April 4th). The proportion changing of higher molecular weight containing 5- and 6-ring PAHs (HMW PAHs) closely related to the traffic flow variation were consistent with the concentration variation of PAHs during the experimental period. Indicators of gasoline/diesel engines emission, i.e., Mo, Co, Mn, and Pb showed similar concentration variation with PAHs. The concentrations of trace elements, mainly derived from wear instead of combustion process, such as Cu, Zn, Ti, and Sb, raised significantly during the rainy days. Incremental lifetime cancer risk (ILCR) values were calculated to evaluate the health risk caused by PAH around the Qingming Festival. The ILCR values increased by 3-10 times 2 days before and on the last day of the festival comparing with other days, as a result of traffic related sources, including engine emission and wearing of tires. It concluded by recommending the necessity of traffic diversion to alleviate the health risk to drivers and nearby residents during important festivals. PMID- 30443667 TI - Ulnar focal cortical indentation: a progressive, deforming variant of focal fibrocartilaginous dysplasia. AB - BACKGROUND: Focal fibrocartilaginous dysplasia is a rare growth disturbance of bone resulting in deformity. In the ulna, focal fibrocartilaginous dysplasia is particularly rare, and the characteristic fibroligamentous tether can result in progressive deformity with progressive dislocation of the radial head. The fibroligamentous tether is similar in appearance and function to the Vickers ligament seen in Madelung deformity. The imaging features of ulnar focal fibrocartilaginous dysplasia include a unilateral angular deformity in the ulna with a radiolucent cortical defect and surrounding sclerosis, with secondary radial bowing or radial head dislocation. Focal fibrocartilaginous dysplasia of the ulna has been described using the term ulnar focal cortical indentation. OBJECTIVE: To review the clinical and radiologic features of four cases of ulnar focal cortical indentation occurring in pediatric patients. MATERIALS AND METHODS: We retrospectively reviewed picture archiving and communication system and electronic medical record imaging findings with surgical correlation of ulnar focal cortical indentation at two large specialty pediatric hospitals. RESULTS: Ulnar focal cortical indentation lesions typically arise in the ulnar metaphysis and result in angular forearm deformities with progressive radial deformity including radial head dislocation. Early surgical intervention prevents progression of the deformity and retains range of motion. CONCLUSION: Ulnar focal cortical indentation, although rare, is likely a progressive form of focal fibrocartilaginous dysplasia resulting in significant deformity and disability. Early recognition of the characteristic imaging features is important for early surgical intervention to preserve range of motion and prevent radial head dislocation. PMID- 30443668 TI - Dual phase infusion with bolus tracking: technical innovation for cardiac and respiratory navigated magnetic resonance angiography using extracellular contrast. AB - This technical innovation paper describes a technique for performing cardiac gated, respiratory-navigated cardiovascular magnetic resonance angiography using an extracellular gadolinium-based contrast agent at 1.5 Tesla (T) with a dual phase bolus injection and slow infusion technique. PMID- 30443669 TI - 5-HT2A blockade for dyskinesia and psychosis in Parkinson's disease: is there a limit to the efficacy of this approach? A study in the MPTP-lesioned marmoset and a literature mini-review. AB - Virtually every patient affected by Parkinson's disease (PD) eventually requires treatment with L-3,4-dihydroxyphenylalanine (L-DOPA), which leads to complications such as dyskinesia and psychosis. Whereas blockade of serotonin 2A (5-HT2A) receptors appears to be an effective way to reduce both dyskinesia and psychosis, whether it has the potential to eliminate the two phenomena remains to be determined. In a previous study, we showed that highly selective 5-HT2A receptor blockade with EMD-281,014, at plasma levels comparable to those achieved in the clinic, reduced dyskinesia and psychosis-like behaviours (PLBs), in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we sought to determine whether further increasing the dose would result in greater therapeutic benefit or if maximal effectiveness was achieved at lower doses. Six MPTP-lesioned marmosets with stable dyskinesia and PLBs were administered EMD 281,014 (0.1, 1 and 10 mg/kg) or vehicle in combination with L-DOPA and the effect on dyskinesia, PLBs and parkinsonism was assessed. Administration of EMD 281,014 (0.1, 1 and 10 mg/kg) in combination with L-DOPA resulted in a significant reduction in the severity of dyskinesia, by up to 63%, 64% and 61% (each P < 0.001), when compared to L-DOPA/vehicle. Similarly, the addition of EMD 281,014 (0.1, 1 and 10 mg/kg) to L-DOPA also significantly decreased the severity of PLBs, by up to 54%, 55% and 53% (each P < 0.001), when compared to L DOPA/vehicle. Our results suggest that there might be a ceiling to the reduction of dyskinesia and psychosis that can be achieved through antagonism of 5-HT2A receptors. PMID- 30443670 TI - Correction to: Trunk, head and pelvis interactions in healthy children when performing seated daily arm tasks. AB - The authors inadvertently submitted a wrong figure part for publication. Figure 8b should be as follows. PMID- 30443671 TI - SIU-NewsLetter - December 2018. PMID- 30443672 TI - Surgical consideration in Hunter syndrome: a case of hydrocephalus and a case of epidural hematoma. AB - INTRODUCTION: Hunter syndrome (HS) is a rare X-linked lysosomal storage disorder which affects multiple organ systems. Surgical intervention and general anesthesia should be used with caution because of significant airway complications. CASE REPORT: Two HS patients underwent surgery with different prognosis are presented below. In the first case, symptoms of progressive disabilities on motor function, language, intelligence, and development last for 1 year in a 6-year-old boy; magnetic resonance imaging (MRI) showed severe hydrocephalus. Third ventriculostomy was performed in this patient to relieve the hydrocephalus. Unfortunately, this patient died postoperatively due to postsurgical tracheal collapse. In the second case, an 8-year-old girl was referred to our hospital with epidural hematoma because of a falling accident. Trephination surgery was performed under local anesthesia to remove the hematoma. Three days postsurgical, the patient was discharged uneventfully. CONCLUSION: General anesthesia in HS patients was associated with poor prognosis due to respiratory complications. Local anesthesia and less intensified treatment should be recommended. PMID- 30443673 TI - Neoadjuvant imatinib therapy in rectal gastrointestinal stromal tumors. AB - Rectal gastrointestinal stromal tumor (GIST) is a rare entity. Thus, its clinical features have not been well documented, and optimal treatment strategies have not been established. Surgery for rectal GISTs may be difficult because they are often large in size. In addition, rectal GISTs were found to be associated with high rates of local recurrence, regardless of the surgical procedure, before imatinib was introduced in the early 2000s. Since the introduction of imatinib therapy, accumulating evidence suggests that neoadjuvant imatinib therapy may improve the outcomes of rectal GIST treatment. Neoadjuvant imatinib therapy for rectal GISTs offers a number of potential benefits, including tumor downsizing, reduction in mitotic activity, reduced morbidity, and a reduced risk of recurrence. Less radical procedures may allow for the preservation of the anal sphincter and avoidance of a permanent colostomy. This review summarizes the current status and future perspectives of neoadjuvant imatinib therapy for the treatment of rectal GISTs. PMID- 30443674 TI - Outcome of short versus long interval in two-stage exchange for periprosthetic joint infection: a prospective cohort study. AB - INTRODUCTION: A two-stage exchange is the standard treatment approach for chronic periprosthetic joint infection (PJI). While a 6-8 week interval is commonly used before reimplantation, the optimal length of the prosthesis-free interval has not yet been determined. We evaluated the influence of a short (< 4 weeks) and long (>= 4 weeks) interval on reinfection rate and functional outcome of hip and knee PJI. METHODS: In this prospective cohort, patients undergoing two-stage revision for PJI were assigned to prosthesis reimplantation after a short (< 4 weeks) or long (>= 4 weeks) interval. All patients received standardized antimicrobial therapy, which consisted of antibiogram-adapted, non-biofilm-active antibiotics during the interval and an antimicrobial combination therapy with biofilm-active antibiotics after reimplantation. Follow-up was performed for infection, joint function, pain, need for care and quality of life. RESULTS: Thirty-eight patients undergoing two-stage revision for PJI (18 hips and 20 knees) were included. Short interval was used in 19 patients having a mean interval of 17.9 days (range 7-27 days), long interval in 19 patients having a mean interval of 63.0 days (range 28 204 days). At a mean follow-up of 39.5 months (range 32-48 months), 37 of 38 patients (97.4%) were infection-free. One failure occurred among patients with long interval and none among patients with short interval. Functional results (ROM, HHS, KSS, VAS) and quality of life (SF-36) were similar in both groups. Patients treated with long interval required cumulatively additional 204 inpatient days for nursing care compared to patients with short interval. CONCLUSIONS: This study suggests that two-stage exchange with short interval has a similar outcome than with long interval, when highly active antibiotic therapy is used. Patient inconvenience and care costs due to immobilization were lower when strategies with a short interval were used. PMID- 30443675 TI - Outcome disparities in colorectal cancer: a SEER-based comparative analysis of racial subgroups. AB - PURPOSE: Previous studies of ethnic disparities in colorectal cancer (CRC) have focused mainly on patients of Caucasian and African-American descent. We aimed to evaluate outcomes for a range of races, representing a broader demographic of the US population. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients with CRC diagnosed between 1994 and 2014. We performed unadjusted Kaplan-Meier test and multivariable covariate-adjusted Cox models to calculate the overall and CRC-specific survival of patients according to their race. RESULTS: We identified 401,723 patients diagnosed with CRC between 1994 and 2014. Overall survival (OS) and CRC-specific survival were compared across different races stratified by age, sex, marital status, disease stage and grade, and undergoing surgery as a treatment. Overall, Asian/Pacific Islanders and Hispanics had improved CRC-specific survival compared to Whites (HR = 0.873, 95%CI 0.853-0.893, P < .001, and HR = 0.958, 95%CI 0.937-0.979, P < .001, respectively). Blacks had the worst CRC-specific survival outcomes when compared to Whites (HR = 1.215, 95%CI 1.192-1.238, P < .001). Racial disparity persisted when looking at two different time periods (1994-2003 and 2004-2014). CONCLUSIONS: Asians/Pacific Islanders have improved outcomes from CRC compared to other races. Multifactorial, including genetic, environmental, and socioeconomic factors appear to influence outcomes and need to be addressed separately in order to reduce racial disparities among patients with CRC. PMID- 30443676 TI - Genetic modification of asexual Epichloe endophytes with the perA gene for peramine biosynthesis. AB - Development of grass-endophyte associations with minimal or no detrimental effects in combination with beneficial characteristics is important for pastoral agriculture. The feasibility of enhancing production of an endophyte-derived beneficial alkaloid through introduction of an additional gene copy was assessed in a proof-of-concept study. Sexual and asexual Epichloe species that form symbiotic associations with cool-season grasses of the Poaceae sub-family Pooideae produce bioactive alkaloids that confer resistance to herbivory by a number of organisms. Of these, peramine is thought to be crucial for protection of perennial ryegrass (Lolium perenne L.) from the Argentinian stem weevil, an economically important exotic pest in New Zealand, contributing significantly to pasture persistence. A single gene (perA) has been identified as solely responsible for peramine biosynthesis and is distributed widely across Epichloe taxa. In the present study, a functional copy of the perA gene was introduced into three recipient endophyte genomes by Agrobacterium tumefaciens-mediated transformation. The target strains included some that do not produce peramine, and others containing different perA gene copies. Mitotically stable transformants generated from all three endophyte strains were able to produce peramine in culture and in planta at variable levels. In summary, this study provides an insight into the potential for artificial combinations of alkaloid biosynthesis in a single endophyte strain through transgenesis, as well as the possibility of using novel genome editing techniques to edit the perA gene of non peramine producing strains. PMID- 30443677 TI - Can intrinsic foraging efficiency explain dominance status? A test with functional response experiments. AB - The functional response describes how food abundance affects the intake rate of foraging individuals, and as such, it can influence a wide range of ecological processes. In social species, dominance status can affect the functional response of competing individuals, but studies conducted in an interference-free context have provided contrasting results on the extent of between-individual variability in functional response. We tested the prediction that individuals intrinsically differ in their functional response, and that these differences could predict body weight and dominance status in social species. We used goats as a model species and performed foraging experiments to assess the functional response of these goats in an interference-free context. Our results show that some individuals are consistently better foragers than others, and these individuals were more likely to be heavier and dominant. Parameters of the functional response are, however, more strongly associated with dominance status than with body weight. We conclude that interference while foraging is not needed to explain body weight differences between dominant and subordinate individuals. We suggest that these differences can emerge from intrinsic differences in foraging efficiency between individuals, which could also allow better foragers to demonstrate greater tenacity during agonistic interactions. PMID- 30443678 TI - Case report: relevance of metabolite identification to detect new synthetic opioid intoxications illustrated by U-47700. AB - Today, new psychoactive substances (NPS) producers increasingly appear to be targeting new synthetic opioids (NSOs), and the recent emergence of NSOs is causing considerable concern in North America and in Europe. For toxicologists, NSO detection in a forensic context presents three additional difficulties to the general NPS analytical detection challenge: (i) high frequency of new products, (ii) low concentrations (in MUg/L range and under) in biological samples related to their high opioid potency, and (iii) extensive metabolism. In this context, the present work aims to highlight the relevance of NSO metabolite detection in potential intoxication cases. Illustration is given with U-47700, an emerging NSO, (i) that was identified in a powder recently collected in France and in a fatality case, (ii) whose metabolites were in vitro produced using human liver microsomes and their mass spectra (MS) added in our MS/MS and HRMS libraries, and (iii) for which metabolism data were compared to those of the literature: U-47700 was identified in the powder and at 3040 MUg/L in peripheral blood in the fatality case. In addition, high amounts of several U-47700 metabolites, especially N-desmethyl-U-47700, were observed in urine. Even if metabolite formation may largely depend on the enzymatic activity as well as on the length of the survival time, confrontation of these results to data found in the literature strongly suggests that this metabolite is regularly a better blood and (mainly) urine biomarker of U-47700 intake than U-47700 itself. Indeed, in this fatality and in other previous reports, N-desmethyl-U-47700 produced the main observed chromatographic signal (i) systematically in vitro and (ii) commonly in vivo, especially in urines. N,N-Didesmethyl-U-47700 is also sometimes a better biomarker of U-47700 intake than U-47700 itself. Accordingly, we suggest adding N desmethyl-U-47700 (and N,N-didesmethyl-U-47700) in mass spectrum databases used for toxicological screening in order to reduce the risk of false-negative results in intoxication cases involving U-47700. PMID- 30443680 TI - Multiplexed determination of intracellular messenger RNA by using a graphene oxide nanoprobe modified with target-recognizing fluorescent oligonucleotides. AB - A multiplexed graphene oxide (GO) fluorescent nanoprobe is described for quantification and imaging of messenger RNAs (mRNAs) in living cells. The recognizing oligonucleotides (with sequences complementary to those of target mRNAs) were labeled with different fluorescent dyes. If adsorbed on GO, the fluorescence of the recognizing oligonucleotides is quenched. After having penetrated living cells, the oligonucleotides bind to target mRNAs and dissociate from GO. This leads to the recovery of fluorescence. Using different fluorescent dyes, various intracellular mRNAs can be simultaneously imaged and quantified by a high content analysis within a short period of time. Actin mRNA acts as the internal control. This GO-based nanoprobe allows mRNA mimics to be determined within an analytical range from 1 to 400 nM and a detection limit as low as 0.26 nM. Up to 3 intracellular mRNAs (C-myc, TK1, and actin) can be detected simultaneously in a single living cell. Hence, this nanoprobe enables specific distinction of intracellular mRNA expression levels in cancerous and normal cells. It can be potentially applied as a tool for detection of cancer progression and diagnosis. Graphical abstract A multiplexed graphene oxide (GO) based fluorescent nanoprobe is described for quantification and imaging of intracellular messenger RNAs. After penetrating living cells, the recovered fluorescence of the dissociated recognizing oligonucleotides can be analyzed , and this allows for simultaneous detection of up to 3 intracellular messenger RNAs. PMID- 30443681 TI - Bioequivalence Study Methods with Pharmacokinetic Endpoints for Topical Ophthalmic Corticosteroid Suspensions and Effects of Subject Demographics. AB - PURPOSE: To establish bioequivalence for topical ophthalmic corticosteroid suspensions, some of U.S. product-specific guidances (PSGs) for generic drug products recommend evaluation of aqueous humor (AH) pharmacokinetics (PK). However, the AH PK study is complex because the relationships among AH PK, subject demographics, ocular anatomy, physiology and the compounds' physicochemical characteristics are not well understood. The objective of this research is to provide an overview of the in vivo human AH studies submitted to the U.S. Food and Drug Administration (FDA) for ophthalmic corticosteroid suspensions and to investigate the impact of subject demographics on the human AH PK. METHODS: We summarized demographic data, sampling time points, sample size per time point and PK parameters to investigate correlations in the studies submitted to the FDA. RESULTS: In the evaluation of subject-specific covariates, the area under the concentration-time curves (AUC) and maximum concentrations (Cmax) were significantly different among ethnicities and age groups. Gender was not primarily associated with differences in AH PK. CONCLUSIONS: Our results suggest that the difference in ethnicity and age of the study population play an important role in the AH PK profiles of topical ophthalmic corticosteroid suspensions. Considering the subject-specific covariate effects in designing bioequivalence studies with AH PK endpoints could reduce bias from covariate imbalance and help identify true effects of formulation differences. PMID- 30443683 TI - Alternative switching strategies based on regimens with a low genetic barrier: do clinicians have a choice nowadays? AB - Clinicians sometimes use switching strategies based on regimens such as RAL + ABC/3TC or RPV + ABC/3TC in order to resolve tolerability or safety issues associated with conventional recommended first-line strategies. Despite the low genetic barrier of these regimens, high safety and efficacy rates have been reported in retrospective studies. PMID- 30443679 TI - Elevated monocyte-specific type I interferon signalling correlates positively with cardiac healing in myocardial infarct patients but interferon alpha application deteriorates myocardial healing in rats. AB - Monocytes are involved in adverse left ventricular (LV) remodelling following myocardial infarction (MI). To provide therapeutic opportunities we aimed to identify gene transcripts in monocytes that relate to post-MI healing and evaluated intervention with the observed gene activity in a rat MI model. In 51 MI patients treated by primary percutaneous coronary intervention (PCI), the change in LV end-diastolic volume index (EDVi) from baseline to 4-month follow-up was assessed using cardiovascular magnetic resonance imaging (CMR). Circulating monocytes were collected at day 5 (Arterioscler Thromb Vasc Biol 35:1066-1070, 2015; Cell Stem Cell 16:477-487, 2015; Curr Med Chem 13:1877-1893, 2006) after primary PCI for transcriptome analysis. Transcriptional profiling and pathway analysis revealed that patients with a decreased LV EDVi showed an induction of type I interferon (IFN) signalling (type I IFN pathway: P value < 0.001; false discovery rate < 0.001). We subsequently administered 15,000 Units of IFN-alpha subcutaneously in a rat MI model for three consecutive days following MI. Cardiac function was measured using echocardiography and infarct size/cardiac inflammation using (immuno)-histochemical analysis. We found that IFN-alpha application deteriorated ventricular dilatation and increased infarct size at day 28 post-MI. Moreover, IFN-alpha changed the peripheral monocyte subset distribution towards the pro-inflammatory monocyte subset whereas in the myocardium, the presence of the alternative macrophage subset was increased at day 3 post-MI. Our findings suggest that induction of type I IFN signalling in human monocytes coincides with adverse LV remodelling. In rats, however, IFN alpha administration deteriorated post-MI healing. These findings underscore important but also contradictory roles for the type I IFN response during cardiac healing following MI. PMID- 30443682 TI - Impact of bladder volume on acute genitourinary toxicity in intensity modulated radiotherapy for localized and locally advanced prostate cancer. AB - BACKGROUND AND PURPOSE: To evaluate the effect of changes in bladder volume during high-dose intensity-modulated-radiotherapy (IMRT) of prostate cancer on acute genitourinary (GU) toxicity and prospectively evaluate a simple biofeedback technique for reproducible bladder filling with the aim of reducing acute GU toxicity. METHODS: One hundred ninety-three patients were trained via a biofeedback mechanism to maintain a partially filled bladder with a reproducible volume of 200-300 cc at planning CT and subsequently at each fraction of radiotherapy. We prospectively analyzed whether and to what extent the patients' ability to maintain a certain bladder filling influenced the degree of acute GU toxicity and whether cut-off values could be differentiated. RESULTS: We demonstrated that the ability to reach a reproducible bladder volume above a threshold volume of 180 cc and maintain that volume via biofeedback throughout treatment predicts for a decrease in acute GU toxicity during curative high-dose IMRT of the prostate. Patients who were not able to reach a partial bladder filling to that cut-off value and were not able to maintain a partially filled bladder throughout treatment had a significantly higher risk of developing >=grade 2 GU acute toxicity. CONCLUSION: Our results support the hypothesis that a biofeedback training for the patient is an easy-to-apply, useful, and cost effective tool for reducing acute GU toxicity in high-dose IMRT of the prostate. Patients who are not able to reach and maintain a certain bladder volume during planning and treatment-two independent risk factors-might need special consideration. PMID- 30443685 TI - Green multicomponent synthesis, antimicrobial and antioxidant evaluation of novel 5-amino-isoxazole-4-carbonitriles. AB - BACKGROUND: Design and synthesis of new inhibitor agents to deal with pathogenic microorganisms is expanding. In this project, an efficient, environmentally friendly, economical, rapid and mild procedure was developed for the synthesis of novel functionalized isoxazole derivatives as antimicrobial potentials. METHODS: Multicomponent reaction between malononitrile (1), hydroxylamine hydrochloride (2) and different aryl or heteroaryl aldehydes 3a-i afforded novel 5-amino isoxazole-4-carbonitriles 4a-i in good product yields and short reaction times. Deep eutectic solvent K2CO3/glycerol was used as catalytic reaction media. Structure of all molecules were characterized by different analytical tools. In vitro inhibitory activity of all derivatives was evaluated against a variety of pathogenic bacteria including both Gram-negative and Gram-positive strains as well as some fungi. In addition, their free radical scavenging activities were assessed against DPPH. RESULTS: Broad-spectrum antimicrobial activities were observed with isoxazoles 4a, b, d. In addition, antioxidant activity of isoxazole 4i was proven on DPPH. CONCLUSIONS: In this project, compounds 4a, b, d could efficiently inhibit the growth of various bacterial and fungal pathogens. Antioxidant properties of derivative 4i were also significant. These biologically active compounds are suitable candidates to synthesize new prodrugs and drugs due to the presence of different functional groups on their rings. PMID- 30443686 TI - Complete Genome Sequence of Massilia oculi sp. nov. CCUG 43427T (=DSM 26321T), the Type Strain of M. oculi, and Comparison with Genome Sequences of Other Massilia Strains. AB - Massilia oculi sp. nov. of type strain CCUG 43427T is a Gram-negative, rod shaped, nonspore-forming bacterium, which was recently isolated from the eye of a patient suffering from endophthalmitis and was described as novel species in Massilia genus. In this study, we present the complete genome sequence of this strain by using Pacbio SMRT cell platform and compare this sequence with the genomes of 30 Massilia representative strains. Also, a comprehensive search was conducted for genes and proteins involved in antibiotic resistance and pathogenicity. The genome of CCUG 43427T is 5,844,653 bp with 65.55% GC content. This genome contains four prophages and four genomic islands (GIs). The cobalt/zinc/cadmium transporter locus CzcABCD is included in these GIs. This GI was predicted to play important role in bacterial heavy-metal tolerance. The in silico genome analysis also revealed that this strain contains a lot of antibiotic resistance and pathogenicity related genes. This result suggested that this strain may has evolved a wide arsenal of weapons for pathogenicity and survival. Genome comparison among CCUG 43427T and other 30 Massilia strains revealed that more than 400 genes are unique in CCUG 43427T. Among these, one gene cluster, which was annotated to be important for LOS biosynthesis, catalytic mechanism and the substrate specificity of the enzyme, was predicted to be horizontally transferred by using phylogenies and biased GC content. PMID- 30443684 TI - Dopamine transporter imaging with [18F]FE-PE2I PET and [123I]FP-CIT SPECT-a clinical comparison. AB - BACKGROUND: Dopamine transporter (DAT) imaging may be of diagnostic value in patients with clinically suspected parkinsonian disease. The purpose of this study was to compare the diagnostic performance of DAT imaging with positron emission computed tomography (PET), using the recently developed, highly DAT selective radiopharmaceutical [18F]FE-PE2I (FE-PE2I), to the commercially available and frequently used method with [123I]FP-CIT (FP-CIT) single-photon emission computed tomography (SPECT) in early-stage idiopathic parkinsonian syndrome (PS). METHODS: Twenty-two patients with a clinical de novo diagnosis of PS and 28 healthy controls (HC) participating in an on-going clinical trial of FE PE2I were analyzed in this study. Within the trial protocol, participants are clinically reassessed 2 years after inclusion. A commercially available software was used for automatic calculation of FP-CIT-specific uptake ratio (SUR). MRI based volumes of interest combined with threshold PET segmentation were used for FE-PE2I binding potential relative to non-displaceable binding (BPND) quantification and specific uptake value ratios (SUVR). RESULTS: PET with FE-PE2I revealed significant differences between patients with a clinical de novo diagnosis of PS and healthy controls in striatal DAT availability (p < 0.001), with excellent accuracy of predicting dopaminergic deficit in early-stage PS. The effect sizes were calculated for FE-PE2I BPND (Glass's Delta = 2.95), FE-PE2I SUVR (Glass's Delta = 2.57), and FP-CIT SUR (Glass's Delta = 2.29). The intraclass correlation (ICC) between FE-PE2I BPND FP-CIT SUR was high in the caudate (ICC = 0.923), putamen (ICC = 0.922), and striatum (ICC = 0.946), p < 0.001. Five of the 22 patients displayed preserved striatal DAT availability in the striatum with both methods. At follow-up, a non-PS clinical diagnosis was confirmed in three of these, while one was clinically diagnosed with corticobasal syndrome. In these patients, FE-PE2I binding was also normal in the substantia nigra (SN), while significantly reduced in the remaining patients. FE-PE2I measurement of the mean DAT availability in the putamen was strongly correlated with BPND in the SN (R = 0.816, p < 0.001). Olfaction and mean putamen DAT availability was correlated using both FE-PE2I BPND and FP-CIT SUR (R >= 0.616, p < 0.001). CONCLUSION: DAT imaging with FE-PE2I PET yields excellent basic diagnostic differentiation in early-stage PS, at least as good as FP-CIT SPECT. PMID- 30443687 TI - Radiotherapy with the anti-programmed cell death ligand-1 immune checkpoint blocker avelumab: acute toxicities in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is clinically the most aggressive breast cancer (BC) subtype. There is an urgent need for effective therapies for patients with TNBC. Recent findings confirm the important role of factors related to the immune system in the clinical outcome and response to treatment of TNBC patients. Avelumab selectively binds to PDL1, and competitively blocks its interaction with anti-programmed death 1 (anti-PD-1) antibodies. Unlike anti-PD-1 antibodies, which target T-cells, avelumab targets tumor cells, and is therefore expected to have fewer side effects, including a lower risk of Immune-Related Adverse Events (irAEs). Uncertainties remain regarding a potential synergy resulting in increased toxicities by combining radiotherapy and immune-checkpoint inhibitors (ICIs). Effects of concomitant ICIs with thoracic radiotherapy on pulmonary toxicities is not currently known. There are no published data available on the effects of combining anti-PD-L1 with adjuvant radiotherapy (RT) for BC in a clinical setting. We reported a preliminary experience on the first patient treated at the National Cancer Institute of Milan with the association of avelumab and concomitantly RT for TNBC. PMID- 30443688 TI - Direct and Indirect Associations of Sleep Knowledge and Attitudes With Objective and Subjective Sleep Duration and Quality via Sleep Hygiene. AB - Although a few studies have examined sleep knowledge and attitudes as predictors of sleep behavior, the question of which better predicts actual sleep behavior is still open. Furthermore, the construct of sleep attitudes has been inconsistently defined and measured. We examined both sleep knowledge and attitudes to determine their unique associations with sleep hygiene behaviors, and direct and indirect associations with objective and subjective sleep outcomes. College students (N = 218) completed a series of questionnaires before and after wearing a FitBit Flex accelerometer for 7 days. We collected objective sleep duration and quality using this apparatus, while participants reported subjective sleep outcomes, hygiene behaviors, knowledge, and attitudes. Analyses controlled for self-reported depression, diagnosed sleep disorder, and sleep-related medications. For both objective and subjective measures, more positive sleep attitudes but not greater sleep knowledge was directly associated with longer sleep duration, and indirectly (through sleep hygiene) with better sleep quality. The role of sleep attitudes in sleep-related behaviors and outcomes deserves further investigation as a potentially modifiable factor in sleep intervention efforts. PMID- 30443689 TI - Permanent Housing Placement and Reentry to Services Among Family Recipients of Homelessness Prevention and Rapid Re-Housing Program (HPRP) Assistance. AB - The Homelessness Prevention and Rapid Re-Housing Program (HPRP) provided individuals and families who were either at-risk or currently experiencing homelessness with time-limited financial and housing support services. Evaluations of HPRP showed a high rate of family placement into permanent housing. However, little research has explored immediate and longitudinal outcomes for families enrolled in HPRP. Using Homeless Management Information System data from Indianapolis, Indiana, we examined demographic and program related predictors of families entering permanent housing and their risk of reentry into homeless services following HPRP participation. The sample included 511 families who enrolled in the program from 2009 to 2012, with an average follow-up period of 4.5 years. We conducted analyses separately for Homelessness Prevention (HP) recipients (n = 357) and Rapid Re-Housing (RRH) recipients (n = 154). Results revealed that HP families were more likely to enter permanent housing if they: included adults who were older in age, were enrolled longer in the program, were provided rental arrear services and utility payments, and did not receive legal services. RRH families receiving rental assistance services had significantly greater odds of entering permanent housing. Among permanently housed families, at least one family member in 10.9% of HP recipients and 18.8% of RRH recipients reentered homeless services. HP families with younger children and one veteran family member were at increased risk of reentry to homelessness services. RRH recipients who did not receive moving cost services and had more children were at greater risk of reentry. Study findings suggest a need for future research on HP and RRH interventions that identify unique service needs among families who are experiencing housing instability or homelessness. PMID- 30443691 TI - Chromosome constitution of equal-sized three-cell embryos using next-generation sequencing technology. AB - PURPOSE: To study the chromosome constitution of equal-sized three-cell embryo. METHODS: We determined the chromosome constitution of 105 blastomeres from 35 embryos using multiple annealing and looping-based amplification cycles (MALBAC) together with NGS sequencing technology. Chromosomal copy number variation (CNV) analysis was successfully performed in 27 embryos. We also analyzed radius, perimeter, area, and volume of each blastomere to explore the possibility of selecting the normal embryos. RESULTS: Majority of the embryos (77.8%, 21/27) studied were mosaic or aneuploid, and only 22.2% (6/27) had normal chromosome numbers. The aneuploid chromosomes spread across all chromosomes and the most frequent aneuploidies were for chromosomes 1, 16, and 18 followed by 13, 19, and 21. Statistical analyses showed no significant difference between euploid and aneuploid embryos regarding radius, perimeter, area, and volume of their blastomeres. CONCLUSIONS: Our results showed that majority of the equal-sized three-cell embryos were chromosomally abnormal and could not be distinguished by morphology observation, so they should be given lower priority at selection for transfer. PMID- 30443690 TI - Ultrasonic measurement of sound velocity fluctuations in biological tissue due to ultrasonic heating and estimation of thermo-physical properties. AB - PURPOSE: Tissue characterization in terms of the differences in thermo-physical properties of biological tissues was investigated in this study. The objective was to measure the ratio of variation in sound velocity due to ultrasonic heating and to derive the relational expression between the ratio and thermo-physical properties. METHODS: The ratio of sound velocity variation before and after the temperature rise of tissue samples exposed to ultrasound was measured by ultrasonic pulse echo method. The thermo-physical properties were estimated for a tissue-mimicking material and porcine muscle and fat tissues due to theoretical expression. The transducer for heating had a resonance frequency of 3.2 MHz, and the transducer for measurement of sound velocity variation had a resonance frequency of 5.2 MHz. RESULTS: In the phantom study, the measured values of the temperature rise agreed with the values calculated by a finite element method (FEM). The estimated values of the temperature rise from the sound velocity variations of muscle and fat tissues were 0.36 degrees C and 1.1 degrees C, respectively. Also, the estimated values of thermo-physical properties agreed with the reference values within an error of 10%. CONCLUSIONS: The thermo physical properties of the porcine tissues were measured by sound velocity variation due to ultrasonic heating within the safety regulations. PMID- 30443692 TI - Simulated physiological oocyte maturation has side effects on bovine oocytes and embryos. AB - PURPOSE: Oocyte maturation is a complex process involving nuclear and cytoplasmic modulations, during which oocytes acquire their ability to become fertilized and support embryonic development. The oocyte is apparently "primed" for maturation during its development in the dominant follicle. As bovine oocytes immediately resume meiosis when cultured, it was hypothesized that delaying resumption of meiosis with cyclic nucleotide modulators before in vitro maturation (IVM) would allow the oocytes to acquire improved developmental competence. METHODS: We tested the Simulated Physiological Oocyte Maturation (SPOM) system that uses forskolin and 3-isobutyl-1-methylxanthine for 2 h prior to IVM against two different systems of conventional IVM (Con-IVM). We evaluated the ultrastructure of matured oocytes and blastocysts and also assessed the expression of 96 genes related to embryo quality in the blastocysts. RESULTS: In summary, the SPOM system resulted in lower blastocyst rates than both Con-IVM systems (30 +/- 9.1 vs. 35 +/- 8.7; 29 +/- 2.6 vs. 38 +/- 2.8). Mature SPOM oocytes had significantly increased volume and number of vesicles, reduced volume and surface density of large smooth endoplasmic reticulum clusters, and lower number of mitochondria than Con-IVM oocytes. SPOM blastocysts showed only subtle differences with parallel undulations of adjacent trophectoderm plasma membranes and peripherally localized ribosomes in cells of the inner cell mass compared with Con-IVM blastocysts. SPOM blastocysts, however, displayed significant downregulation of genes related to embryonic developmental potential when compared to Con-IVM blastocysts. CONCLUSIONS: Our results show that the use of the current version of the SPOM system may have adverse effects on oocytes and blastocysts calling for optimized protocols for improving oocyte competence. PMID- 30443693 TI - Challenging encounters as experienced by registered nurses new to the emergency medical service: explored by using the theory of communities of practice. AB - The aim of this study was to explore challenging encounters experienced by registered nurses (RN) during their first year in the emergency medical service by using the social learning theory of communities of practice. During the first year in a new professional practice, a new RN experiences a transition during which the new professional identity is being formed. This is a challenging and demanding period of time. According to the learning theory of communities of practice by Lave and Wenger, individuals' learning and development in a new professional practice occurs through participation in social activity and is influenced by context. This study is based on the qualitative data from semi structured interviews. Thirty-two RNs working in the Swedish emergency medical service were interviewed via telephone during the spring of 2017. A qualitative content analysis with deductive reasoning of the interviews was used. The analysis process generated the main category; New RNs participation is challenged by unpredictability and uncertainty in practice. The main category was based on three generic categories; Loneliness in an unpredictable context, Uncertainty about the team, and Uncertainty in action. The challenges new RNs encounter during the first year relate to all three dimensions of a community of practice; mutual engagement, joint enterprise and shared repertoire. The encountered challenges also relate to the EMS context. Taking into account all these aspects when designing support models for RN's professional development may be advantageous for creating positive development for RNs new to the EMS and/or similar practices. PMID- 30443694 TI - A Fast Method for Estimating Statistical Power of Multivariate GWAS in Real Case Scenarios: Examples from the Field of Imaging Genetics. AB - In GWAS of imaging phenotypes (e.g., by the ENIGMA and CHARGE consortia), the growing number of phenotypes considered presents a statistical challenge that other fields are not experiencing (e.g. psychiatry and the Psychiatric Genetics Consortium). However, the multivariate nature of MRI measurements may also be an advantage as many of the MRI phenotypes are correlated and multivariate methods could be considered. Here, we compared the statistical power of a multivariate GWAS versus the current univariate approach, which consists of multiple univariate analyses. To do so, we used results from twin models to estimate pertinent vectors of SNP effect sizes on brain imaging phenotypes, as well as the residual correlation matrices, necessary to estimate analytically the statistical power. We showed that for subcortical structure volumes and hippocampal subfields, a multivariate GWAS yields similar statistical power to the current univariate approach. Our analytical approach is as accurate but ~ 1000 times faster than simulations and we have released the code to facilitate the investigation of other scenarios, may they be outside the field of imaging genetics. PMID- 30443695 TI - Non-alcoholic fatty liver disease and colorectal cancer survival. AB - PURPOSE: Liver diseases including non-alcoholic fatty liver disease (NAFLD) and ensuing alterations to the micro-environment may affect development of liver metastasis. Mirroring the rise in obesity rates, prevalence of NAFLD is increasing globally. Our objective was to examine the association between NAFLD and mortality in colorectal cancer patients. METHODS: Colorectal Cancer Sarcopenia and Near-term Survival (C-SCANS) is a retrospective cohort study which included 3,262 stage I-III patients, aged 18-80 years, and diagnosed between 2006 and 2011 at Kaiser Permanente Northern California. Cox proportional hazards regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: After up to 10 years of follow-up, 879 deaths, including 451 from CRC were identified. Cases diagnosed with NAFLD before and within 1 month after CRC diagnosis (pre-existing NAFLD; n = 83) had a HR of 1.64 (95% CI 1.06-2.54) for overall and a HR of 1.85 (95% CI 1.03-3.30) for CRC specific mortality compared to those without NAFLD. Findings did not differ significantly by sex, stage, tumor location, and smoking status, and were also similar when restricted to obese patients only. CONCLUSIONS: Independent of body mass index and prognostic indicators, CRC patients with pre-existing NAFLD had a worse prognosis than those without NAFLD. PMID- 30443696 TI - Macrocheles species (Acari: Macrochelidae) associated with human corpses in Europe. AB - The biology of macrochelid mites might offer new venues for the interpretation of the environmental conditions surrounding human death and decomposition. Three human corpses, one from Sweden and two from Spain, have been analysed for the occurrence of Macrochelidae species. Macrocheles muscaedomesticae (Scopoli) females were associated with a corpse that was found in a popular beach area of southeast Spain. Their arrival coincides with the occurrence of one of their major carrier species, the filth fly Fannia scalaris, the activity of which peaks during mid-summer. Macrocheles glaber (Muller) specimens were collected from a corpse in a shallow grave in a forest in Sweden at the end of summer, concurrent with the arrival of beetles attracted by odours from the corpse. Macrocheles perglaber Filipponi and Pegazzano adults were sampled from a corpse found indoors in the rural surroundings of Granada city, south Spain. The phoretic behaviour of this species is similar to that of M. glaber, but it is more specific to Scarabaeidae and Geotrupidae dung beetles, most of which favour human faeces. Macrocheles muscaedomesticae is known from urban and rural areas and poultry farms, M. glaber from outdoors, particularly the countryside, whereas M. perglaber is known from outdoor, rural, and remote, potentially mountainous locations. Macrocheles muscaedomesticae and M. perglaber are reported for the first time from the Iberian Peninsula. This is the first record of M. perglaber from human remains. PMID- 30443697 TI - Detection of Rickettsia spp. in ticks associated to wild mammals in Northeastern Brazil, with notes on an undetermined Ornithodoros sp. collected from marsupials. AB - We report tick infestations and rickettsial detection in ticks infesting free living wild mammals (Monodelphis domestica, Tolypeutes tricinctus, Thrichomys inermis and Kerodon rupestris) captured in the Caatinga ecoregion of Bahia state, northeastern Brazil, during September to December 2016. Overall, 117 ticks (61 larvae, 25 nymphs, 25 males, 6 females) belonging to two genera, and at least three species were collected: Amblyomma auricularium, Amblyomma parvum, Amblyomma sp., Ornithodoros rietcorreai and an unidentified Ornithodoros sp. We provide new host records to the rodent T. inermis parasitized by larva and nymphs of A. auricularium and to the marsupial M. domestica infested by larvae of A. auricularium. Furthermore, we describe new tick-host association for larvae of O. rietcorreai on the rodents K. rupestris and T. inermis. Concerning tick Rickettsia associations, we detected Rickettsia amblyommatis and an uncharacterized species of Rickettsia belonging to the spotted fever group (SFG) in both A. auricularium and A. parvum. Additionally, 'Candidatus Rickettsia andeanae' was detected in A. parvum as well. PMID- 30443698 TI - Gender Difference in the Association Between Executive Function and Autistic Traits in Typically Developing Children. AB - Autistic traits and executive function (EF) were assessed in 413 typically developing children aged 6-9 years. The children were divided into the high- autistic-trait (HAT) and low-autistic-trait (LAT) groups based on their total autistic traits. Results suggested that there were gender differences in specific autistic traits in children with LAT. There were gender-specific associations between EF and autistic traits in children with HAT: the set shifting of EF predicted difficulties in social awareness in boys; whereas all the EF components predicted difficulties in social communication and social cognition in girls. These findings may have implications for developing customized interventions that are targeted at specific autistic deficits in males and females. PMID- 30443699 TI - Life Satisfaction in Adolescents with Autism Spectrum Disorder. AB - We provided evidence regarding the reliability and validity of measures of assets and life satisfaction (LS) for adolescents with autism spectrum disorder (ASD). We identified levels of LS within this population, compared these levels to those of typically developing adolescents, and described the relation between assets and LS. Forty-six adolescents with ASD and their caregivers completed questionnaires assessing LS and assets. Preliminary support was provided for the internal consistency reliability and validity of these measures in adolescents with ASD. Youth with ASD reported moderate to high levels of LS; these were lower than those of typically developing peers. Age moderated the relation between self reported LS and some assets. Implications were discussed within the context of Schalock's (J Disabil Policy Stud 14:204-215, 2004) emerging disability paradigm. PMID- 30443700 TI - Gender Differences and Similarities: Autism Symptomatology and Developmental Functioning in Young Children. AB - A growing body of research suggests that symptoms of autism spectrum disorder (ASD) may present differently in males and females. This study examined gender differences in ASD symptoms and developmental functioning, using the Baby and Infant Screen for Children with aUtism Traits, Part 1 (BISCUIT-Part 1) and the Battelle Developmental Inventory, 2nd Edition (BDI-2), amongst children aged 17 37 months meeting ASD diagnostic criteria (n = 1317). No gender differences were found in regards to overall symptom severity or symptom domains on the BISCUIT Part 1 when gender groups were matched by cognitive ability. Females with ASD had greater motor deficits and less communication impairment compared to their male counterparts as measured by the BDI-2. Secondary analyses examining item endorsement patterns were also conducted. Implications of the findings are discussed. PMID- 30443701 TI - Brief Report: Regional Variations in Characteristics of ASD Hospitalizations in the U.S. AB - Regional differences in ASD inpatient care remain understudied. We used the Nationwide Inpatient Sample to examine contributory causes and potential determinants associated with regional variations in ASD hospitalizations. We performed univariate and multivariate analyses to identify differences in ASD hospitalizations across four U.S. Census Bureau-defined regions. Our results revealed considerable variations in ASD hospitalizations across U.S. regions. Compared with patients in the Northeast, those in the Midwest, South, and West were less likely to be hospitalized for ASD. Significant differences were observed among regions with regard to the effect of health insurance type, hospital length of stay, hospital bed size, hospital location and teaching status on ASD hospitalizations. The region-specific analysis provides direction for further investigation. PMID- 30443702 TI - Systematic review: diagnostic accuracy of non-invasive tests for staging liver fibrosis in autoimmune hepatitis. AB - BACKGROUND AND AIMS: Non-invasive fibrosis assessment has been highly recommended in many liver diseases. However, comparative diagnostic accuracy of laboratory markers, ultrasound and magnetic resonance elastography (MRE) for fibrosis in autoimmune hepatitis (AIH) patients has not been established. METHODS: Medline, Embase and Cochrane Library were searched. Primary outcome was significant fibrosis (SF), advanced fibrosis (AF) and cirrhosis, defined as Metavir stage F >= 2, F >= 3 and F = 4 according to liver biopsy. Hierarchical summary receiver operating characteristic curve (ROC) model was used to evaluate diagnostic accuracy of non-invasive methods. Summary area under ROC (AUROC) and diagnostic odds ratio (DOR) with 95% confidence interval (CI) were calculated. The Grading of Recommendations Assessment, Development and Evaluation system was used to assess quality of evidence. RESULTS: Overall, 16 studies with 861 patients were included, comparing aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), aspartate aminotransferase/alanine aminotransferase ratio, transient elastography (TE), acoustic radiation force impulse, shear wave elastography and MRE versus liver biopsy. Among all non-invasive markers, TE had good performance for fibrosis staging. Summary AUROCs and DORs of TE were 0.90 (95% CI 0.87, 0.92) and 23.7, 0.91 (95% CI 0.89, 0.93) and 31.6, 0.89 (95% CI 0.86, 0.92) and 80.5 for staging SF, AF and cirrhosis, whereas APRI and FIB-4 showed poor performance for detecting AF (DOR, 4.6 and 4.7) and cirrhosis (DOR, 5.5 and 12.9). CONCLUSIONS: TE performs well to stage liver fibrosis in patients with AIH, compared with other laboratory non-invasive indexes. Nevertheless, diagnostic accuracy of APRI and FIB-4 is poor. PMID- 30443703 TI - The impacts of abnormal color vision on people's life: an integrative review. AB - BACKGROUND: This article shows an integrative review on the impact that abnormal color vision may have on the daily routine of individuals. PURPOSE: We followed the PRISMA guidelines for reviews and carried out researches in four databases (Pubmed, Lilacs, Scopus, and Web of Science) using keywords related to the impact of abnormal color vision. METHOD: Initially, 805 articles were retrieved and after a first filtering stage, we selected 74 articles for a detailed analysis of the abstracts in which it was found that a total of 20 studies were in fact related to the topic of this review. We then read the selected studies in full and those included in the final selection were analyzed and categorized into specific topic groups of findings. Seven categories were created in total: "impact on daily routine activities", "occupational impact", "impact on product choice motivation", "emotional impact", "impact on school or professional qualification", "impact on self-care and health", and "advantages". RESULTS: From the definition of these categories we could understand that people with some degree of color vision loss face challenges in different aspects of their daily life, especially in their work activities. Still, the amount of research and hence technical support which could be offered to this population is restricted. Additionally, the scarce availability of publications on the topic and the fact that they include very specific groups of people, such as drivers and medical students, allow us to draw only partial conclusions about the all possible impacts yield by such perceptual difference since they observe the impact of the color-vision deficiency in their daily routine from a specific and precise point of view. CONCLUSIONS: A broader view of the impact of this problem on the daily life of its carriers is fundamental for implementing strategies that allow such people to be included in all sorts of activities or for the impact of this sensory change to be decreased or treated in a way that would reduce the detrimental impacts. PMID- 30443704 TI - A Bayesian Sequential Learning Framework to Parameterise Continuum Models of Melanoma Invasion into Human Skin. AB - We present a novel framework to parameterise a mathematical model of cell invasion that describes how a population of melanoma cells invades into human skin tissue. Using simple experimental data extracted from complex experimental images, we estimate three model parameters: (i) the melanoma cell proliferation rate, [Formula: see text]; (ii) the melanoma cell diffusivity, D; and (iii) [Formula: see text], a constant that determines the rate that melanoma cells degrade the skin tissue. The Bayesian sequential learning framework involves a sequence of increasingly sophisticated experimental data from: (i) a spatially uniform cell proliferation assay; (ii) a two-dimensional circular barrier assay; and (iii) a three-dimensional invasion assay. The Bayesian sequential learning approach leads to well-defined parameter estimates. In contrast, taking a naive approach that attempts to estimate all parameters from a single set of images from the same experiment fails to produce meaningful results. Overall, our approach to inference is simple-to-implement, computationally efficient, and well suited for many cell biology phenomena that can be described by low-dimensional continuum models using ordinary differential equations and partial differential equations. We anticipate that this Bayesian sequential learning framework will be relevant in other biological contexts where it is challenging to extract detailed, quantitative biological measurements from experimental images and so we must rely on using relatively simple measurements from complex images. PMID- 30443705 TI - Non randomized study on the potential of nitisinone to inhibit cytochrome P450 2C9, 2D6, 2E1 and the organic anion transporters OAT1 and OAT3 in healthy volunteers. AB - PURPOSE: Nitisinone inhibits the cytochrome P450 (CYP) subfamilies CYP2C9, CYP2D6, and CYP2E1 and the organic anion transporter (OAT) isoforms OAT1 and OAT3 in vitro. Since the effect of nitisinone on these enzymes and transporters in humans is still unknown, the purpose of this study was to evaluate the effect of nitisinone on these CYP subfamilies and OAT isoforms. METHODS: This was an open label, nonrandomized, two-arm, phase 1 study (EudraCT: 2016-004297-17) in healthy volunteers. The substrates (tolbutamide, metoprolol, and chlorzoxazone for the respective CYPs and furosemide for the OATs) were administered as single doses, before and after 15 days of once daily dosing of 80 mg nitisinone, to determine the AUCinfinity ratios ([substrate+nitisinone]/[substrate]). Nitisinone pharmacokinetics, safety, and tolerability were also assessed, and blood and urine were collected to determine substrate and nitisinone concentrations by LC MS/MS. RESULTS: Thirty-six subjects were enrolled with 18 subjects included in each arm. The least square mean ratio (90% confidence interval) for AUCinfinity was 2.31 (2.11-2.53) for tolbutamide, 0.95 (0.88-1.03) for metoprolol, 0.73 (0.67 0.80) for chlorzoxazone, and 1.72 (1.63-1.81) for furosemide. Clinically relevant nitisinone steady-state concentrations were reached after 12 days: mean Cav,ss of 94.08 MUM. All treatments were well tolerated, and no safety concerns were identified. CONCLUSIONS: Nitisinone did not affect CYP2D6 activity, was a weak inducer of CYP2E1, and was a weak inhibitor of OAT1 and OAT3. Nitisinone was a moderate inhibitor of CYP2C9, and treatment may therefore result in increased plasma concentrations of comedications metabolized primarily via this enzyme. CLINICAL TRIAL REGISTRY IDENTIFICATION: EudraCT 2016-004297-17. PMID- 30443706 TI - Cell Therapy for Ischemic Stroke: How to Turn a Promising Preclinical Research into a Successful Clinical Story. AB - Stroke is a major public health issue with limited treatment. The pharmacologically or mechanically removing of the clot is accessible to less than 10% of the patients. Stem cell therapy is a promising alternative strategy since it increases the therapeutic time window but many issues remain unsolved. To avoid a new dramatic failure when translating experimental data on the bedside, this review aims to highlight the indispensable checkpoints to make a successful clinical trial based on the current preclinical literature. The large panel of progenitors/ stem cells at the researcher's disposal is to be used wisely, regarding the type of cells, the source of cells, the route of delivery, the time window, since it will directly affect the outcome. Mechanisms are still incompletely understood, although recent studies have focused on the inflammation modulation of most cells types. PMID- 30443707 TI - Oxidative Stress and Genomic Damage Induced In Vitro in Human Peripheral Blood by Two Preventive Treatments of Iron Deficiency Anemia. AB - Iron deficiency is the most prevalent nutritional deficiency and the main cause of anemia worldwide. Since children aged 6-24 months are among the most vulnerable groups at risk, daily supplementation with ferrous sulfate is recommended by the Argentine Society of Pediatrics as preventive treatment of anemia. However, a single weekly dose would have fewer adverse side effects and has been therefore proposed as an alternative treatment. Ferrous sulfate is known by its pro-oxidative properties, which may lead to increased oxidative stress as well as lipid, protein, and DNA damage. We analyzed the effect of daily and weekly preventive treatment of iron deficiency anemia (IDA) on cell viability, oxidative stress, chromosome, and cytomolecular damage in peripheral blood cultured in vitro. The study protocol included the following: untreated negative control; bleomycin, hydrogen peroxide, or ethanol-treated positive control; daily 0.14 mg ferrous sulfate-supplemented group; and weekly 0.55 mg ferrous sulfate supplemented group. We assessed cell viability (methyl-thiazolyl-tetrazolium and neutral red assays), lipid peroxidation (thiobarbituric acid reactive substances assay), antioxidant response (superoxide dismutase and catalase enzyme analysis), chromosome damage (cytokinesis-blocked micronucleus cytome assay), and cytomolecular damage (comet assay). Lipid peroxidation, antioxidant response, and chromosome and cytomolecular damage decreased after weekly ferrous sulfate supplementation (p < 0.05), suggesting less oxygen free radical production and decreased oxidative stress and genomic damage. Such a decrease in oxidative stress and genomic damage in vitro positions weekly supplementation as a better alternative for IDA treatment. Further studies in vivo would be necessary to corroborate whether weekly supplementation could improve IDA preventive treatment compliance in children. PMID- 30443708 TI - Stress Responses Against Rare Earth Ions Are Mediated by the JNK and p38 MAPK Pathways in Caenorhabditis elegans. AB - Rare earth (RE) ions at high concentrations are toxic to many organisms as they induce oxidative stress and cause improper incorporation of the ions into calcium binding proteins. Although the mechanism of action underlying the toxicity of REs has been identified, intracellular signaling pathways involved in stress responses against RE ions still remain unclear. In Caenorhabditis elegans, cellular responses against heavy metal stresses are primarily regulated by the c Jun N-terminal kinase (JNK)-like mitogen-activated protein kinase (MAPK) pathway with a minor contribution of the p38-like MAPK pathway. In this study, we found that both JNK- and p38-like MAPK pathways were involved in stress responses against RE. Unlike heavy metal responses, mutations in both the JNK and p38 pathways caused similar hypersensitivity to RE ions. Although the signaling pathways used for these stress responses were found to be similar, the degree of their respective contribution slightly differed between heavy metal and RE ions. PMID- 30443709 TI - Influence of permanent pacemaker implantation after transcatheter aortic valve implantation with new-generation devices. AB - OBJECTIVE: Permanent pacemaker implantation (PPMI) after transcatheter aortic valve implantation (TAVI) is the most common complication after the procedure. PPMI rates remain high with the new-generation TAVI devices despite improved outcomes concerning paravalvular aortic regurgitation and vascular access complications. However, the impact of PPMI on mortality and clinical outcome is still a matter of debate, and data with new-generation devices on this matter are scarce. Therefore, we sought to analyse the influence of PPMI in patients treated with the new-generation devices on one-year outcome. METHODS: We enrolled 612 consecutive patients without prior pacemaker undergoing transfemoral TAVI with the new-generation devices. Patients with or without PPMI were compared with respect to clinical outcome within one year. RESULTS: PPMI was performed in 168 patients (24.4% of the overall study population). There was no significant difference in one-year outcome concerning all-cause mortality (PPMI vs. no-PPMI: 12.2% vs. 12.5%, p = 0.94), rate of major adverse events including cardiac, cerebral or valve-related events and bleeding complications (22.1% vs. 24.5%, p = 0.55) or need for rehospitalisation due to cardiac symptoms (16.1% vs. 18.1%, p = 0.63). In patients with reduced ejection fraction (<45%) there was also no impact of PPMI on one-year mortality (14.3% vs. 15.7%, p = 0.86). Furthermore, multivariate analysis did not reveal PPMI to be independently associated with one year mortality (odds ratio 0.94, 95% confidence interval 0.50-1.74, p = 0.83). CONCLUSIONS: In this large all-comers TAVI population with new-generation devices the need for postprocedural PPMI did not show a statistical significant impact on survival or combined endpoint of major adverse events within one year. PMID- 30443710 TI - Postnatal Administration of Homocysteine Induces Cerebellar Damage in Rats: Protective Effect of Folic Acid. AB - A widely held view suggests that homocysteine (Hcy) can contribute to neurodegeneration through promotion of oxidative stress. There is evidence that homocysteine is toxic to cerebellar Purkinje neurons in vitro; however, in vivo action of Hcy on Purkinje cell has not been investigated so far. Thus, this study was designed to evaluate the Hcy effects on neonatal rat cerebellum and cerebellar oxidative stress. We also evaluated the folic acid effects on biochemical alterations elicited by hyperhomocysteinemia (hHcy) in the cerebellum. Group I received normal saline, group II received Hcy subcutaneously twice a day at 8-h intervals (0.3-0.6 MUmol/g body weight), group III received Hcy + folic acid (0.011 MUmol/g body weight), and group IV received folic acid on postnatal day (PD) 4 until 25. On day 25, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in the cerebellum and motor cortex were assayed. Malondialdehyde (MDA) levels were also evaluated as a marker of lipid peroxidation. Rotarod and locomotor activity tests were performed in PD 25-27. Our results indicated that administration of Hcy increased plasma, cortical, and cerebellar total Hcy levels; reduced GPx activity; and induced lipid peroxidation in the cerebellum. Hcy impaired performance on the rotarod in rats. However, treatment with folic acid significantly attenuated motor coordination impairment, GPx activity reduction, the lipid peroxidation process, and significantly reduced plasma total Hcy levels. Histological analysis indicated that Hcy could decrease Purkinje cell count and folic acid prevented this toxic effect. We conclude that Hcy can induce neurotoxicity and folic acid has neuroprotective effects against cerebellar Hcy toxicity. PMID- 30443712 TI - Modulation of the aggregation of an amyloidogenic sequence by flanking-disordered region in the intrinsically disordered antigen merozoite surface protein 2. AB - The abundant Plasmodium falciparum merozoite surface protein MSP2, a potential malaria vaccine candidate, is an intrinsically disordered protein with some nascent secondary structure present in its conserved N-terminal region. This relatively ordered region has been implicated in both membrane interactions and amyloid-like aggregation of the protein, while the significance of the flanking disordered region is unclear. In this study, we show that aggregation of the N terminal conserved region of MSP2 is influenced in a length- and sequence dependent fashion by the disordered central variable sequences. Intriguingly, MSP2 peptides containing the conserved region and the first five residues of the variable disordered regions aggregated more rapidly than a peptide corresponding to the conserved region alone. In contrast, MSP2 peptides extending 8 or 12 residues into the disordered region aggregated more slowly, consistent with the expected inhibitory effect of flanking-disordered sequences on the aggregation of amyloidogenic ordered sequences. Computational analyses indicated that the helical propensity of the ordered region of MSP2 was modulated by the adjacent disordered five residues in a sequence-dependent manner. Nuclear magnetic resonance and circular dichroism spectroscopic studies with synthetic peptides confirmed the computational predictions, emphasizing the correlation between aggregation propensity and conformation of the ordered region and the effects thereon of the adjacent disordered region. These results show that the effects of flanking-disordered sequences on a more ordered sequence may include enhancement of aggregation through modulation of the conformational properties of the more ordered sequence. PMID- 30443711 TI - Physical capacity, occupational physical demands, and relative physical strain of older employees in construction and healthcare. AB - PURPOSE: To assess age-related differences in physical capacity, occupational physical demands, and relative physical strain at a group level, and the balance between capacity and demands at an individual level, for construction and healthcare workers. METHODS: Shoulder strength, back strength, and aerobic capacity were assessed among construction (n = 62) and healthcare workers (n = 64). During a full working day, accelerometers estimated upper-arm elevation, trunk flexion, and occupational physical activity as indicators of occupational physical demands. Simultaneously, normalised surface electromyography (%sEMGmax) of the upper trapezius and erector spinae muscles, and normalised electrocardiography (percentage heart rate reserve (%HRR)) estimated relative physical strain. Differences between younger (<= 44 years) and older (>= 45 years) workers, as well as the moderating effect of age on the associations between capacity and demands, were analysed per sector. RESULTS: Compared to younger workers, older workers had similar strength and lower aerobic capacity; older construction workers had similar demands while older healthcare workers had higher demands. Compared to younger workers, older employees had unfavourable muscle activity patterns; %HRR had a tendency to be lower for older construction workers and higher for older healthcare workers. Among construction workers, age moderated the associations between shoulder strength and arm elevation (p = 0.021), and between aerobic capacity and occupational physical activity (p = 0.040). Age did not moderate these associations among healthcare workers. CONCLUSIONS: In both sectors, the level of occupational physical demands and the higher relative physical strain in older employees require addressing to promote sustainable work participation among an aging population. PMID- 30443713 TI - ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models. AB - Angiotensin-converting enzyme 2 (ACE2) is a protein consisting of two domains, the N-terminus is a carboxypeptidase homologous to ACE and the C-terminus is homologous to collectrin and responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells. The carboxypeptidase domain not only metabolizes angiotensin II to angiotensin-(1-7), but also other peptide substrates, such as apelin, kinins and morphins. In addition, the collectrin domain regulates the levels of some amino acids in the blood, in particular of tryptophan. Therefore it is of no surprise that animals with genetic alterations in the expression of ACE2 develop a diverse pattern of phenotypes ranging from hypertension, metabolic and behavioural dysfunctions, to impairments in serotonin synthesis and neurogenesis. This review summarizes the phenotypes of such animals with a particular focus on the central nervous system. PMID- 30443714 TI - Dicoumarol Inhibits Multidrug Resistance Protein 1-Mediated Export Processes in Cultured Primary Rat Astrocytes. AB - Dicoumarol is frequently used as inhibitor of the detoxifying enzyme NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1). In order to test whether dicoumarol may also affect the cellular glutathione (GSH) metabolism, we have exposed cultured primary astrocytes to dicoumarol and investigated potential effects of this compound on the cell viability as well as on the cellular and extracellular contents of GSH and its metabolites. Incubation of astrocytes with dicoumarol in concentrations of up to 100 uM did not acutely compromise cell viability nor was any GSH consumption or GSH oxidation to glutathione disulfide (GSSG) observed. However, unexpectedly dicoumarol inhibited the cellular multidrug resistance protein (Mrp) 1-dependent export of GSH in a time- and concentration-dependent manner with half-maximal effects observed at low micromolar concentrations of dicoumarol. Inhibition of GSH export by dicoumarol was not additive to that observed for the known Mrp1 inhibitor MK571. In addition, dicoumarol inhibited also the Mrp1-mediated export of GSSG during menadione-induced oxidative stress and the export of the GSH-bimane-conjugate (GS B) that had been generated in the cells after exposure to monochlorobimane. Half maximal inhibition of the export of Mrp1 substrates was observed at dicoumarol concentrations of around 4 uM (GSH and GSSG) and 30 uM (GS-B). These data demonstrate that dicoumarol strongly affects the GSH metabolism of viable cultured astrocytes by inhibiting Mrp1-mediated export processes and identifies for the first time Mrp1 as additional cellular target of dicoumarol. PMID- 30443716 TI - [Vaccination: Protection for boys against genital warts and cancer via human papillomavirus infection]. AB - Vaccination qualifies as the most effective medical procedure worldwide. Using the example of human papillomavirus(HPV)-associated benign and malignant diseases, the incidence, diagnostics, treatment, particularly however, the option of sustainable elimination of all these entities by achieving herd immunity by a gender balanced inoculation quota of 80% at the age of 9-17 years are shown. PMID- 30443717 TI - Myopathy: Recent Progress, Current Therapies, and Future Directions. PMID- 30443715 TI - Resolvin D2 Relieving Radicular Pain is Associated with Regulation of Inflammatory Mediators, Akt/GSK-3beta Signal Pathway and GPR18. AB - Neuroinflammation induced by protruded nucleus pulposus (NP) has been shown to play a significant role in facilitation of radicular pain. Resolvin D2 (RvD2), a novel member of resolvin family, exhibits potent anti-inflammatory, pro-resolving and antinociceptive effects. But the effect of RvD2 in radicular pain remains unknown. The radicular pain rat models were induced by application of NP to L5 dorsal root ganglion. Each animal received intrathecal injections of vehicle or RvD2 (10 ng ul-1 or 100 ng ul-1). Mechanical thresholds were determined by measuring the paw withdrawal threshold for 7 days. The expressions of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and transforming growth factor-beta1 (TGF-beta1) in ipsilateral lumbar segment of rat spinal dorsal horns were measured by using ELISA and real time-PCR. Western blot was used to measure the expressions of phosphorylated Akt (p-Akt) and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3beta). The expressions and distributions of RvD2 receptor, G-protein-coupled receptor 18 (GPR18), were also explored in the spinal cord of rats by using double-label immunofluorescence. RvD2 treatment caused significant reductions in the intensity of mechanical hypersensitivity and spinal expressions of TNF-alpha and IL-6. Meanwhile, RvD2 increased the expressions of TGF-beta1 and regulated Akt/GSK-3beta signaling. Furthermore, immunofluorescence showed that GPR18 colocalized with neurons and astrocytes in spinal cord. The results suggested that RvD2 might attenuate mechanical allodynia via regulating the expressions of inflammatory mediators and activation of Akt/GSK-3beta signal pathway. RvD2 might offer a hopeful method for radicular pain therapy. PMID- 30443718 TI - Enhanced Recovery in Bariatric Surgery: A Study of Short-Term Outcomes and Compliance. AB - INTRODUCTION: The implementation of Enhanced Recovery After Surgery (ERAS) guidelines has been widely studied among various surgical specialties. We aimed at comparing the perioperative outcomes and compliance with ERAS protocol in bariatric surgery at our center. METHODS: An observational review of a prospectively maintained database was performed. Patients who underwent primary bariatric surgery (gastric bypass or sleeve gastrectomy) between January 2011 and June 2018 were included. Patients were divided into pre- and post-ERAS groups. Data including basic demographic information, length of hospital stay, 30-day perioperative complications, and readmission rates were collected. Compliance with elements of ERAS was assessed using a combination of chart review and a prospectively implemented checklist. P < 0.05 was chosen to be statistically significant. RESULTS: A total of 435 patients were included: 239 patients in the pre-ERAS group and 196 patients in the post-ERAS group. There were no statistical differences in baseline demographics and major comorbidities between the 2 groups. The post-ERAS group had shorter length of hospital stay (2.23 vs 1.23, p < 0.001) and lower rates of 30-day postoperative morbidity (8.7 vs 4%, p = .04). There was no significant difference between the 2 groups with respect to readmissions rates. There was no mortality in either group. Overall compliance rates with ERAS elements were 85%; compliance increased significantly with the implementation of a checklist (p < 0.001). CONCLUSIONS: Implementation of ERAS program for bariatric surgery is safe and feasible. It reduces hospital stay and postoperative morbidity. Easy to implement strategies such as checklists should be encouraged in bariatric programs to aid in implementation and compliance with ERAS elements for perioperative care. PMID- 30443719 TI - National Postoperative Bariatric Surgery Outcomes in Patients with Chronic Kidney Disease and End-Stage Kidney Disease. AB - PURPOSE: Obesity is a major risk factor for end-stage kidney disease (ESKD) and is often a barrier to kidney transplantation. However, limited evidence exists evaluating postoperative bariatric surgery outcomes in patients with chronic kidney disease (CKD) and ESKD. MATERIALS AND METHODS: We performed a retrospective cohort study of patients who underwent bariatric surgery in 2015 2016 using the national Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program dataset. Propensity score matching was used to balance characteristics across patients with CKD and ESKD vs. those without CKD. RESULTS: There were 323,034 patients without CKD, 1694 patients with CKD, and 925 patients with ESKD who underwent bariatric surgery. Patients with CKD and ESKD had a significantly increased risk of 30-day reoperation (CKD odds ratio [OR] 2.25 95% confidence interval [CI] 1.45-3.51; ESKD OR 3.10, 95% CI 1.72-5.61) and readmission (CKD OR 1.98, 95% CI 1.53-2.56; ESKD OR 2.97, 95% CI 2.05-4.31) compared to patients without CKD; mortality risk was elevated in patients with ESKD (OR 11.59, 95% CI 6.71-20.04) but not in those with CKD (OR 1.00, 95% CI 0.32-3.11). Rates of adverse outcomes were < 15% across all groups. There were 12, 50, and 172 deaths per 1000 person-years among patients without CKD, with CKD, and with ESKD, respectively. CONCLUSION: Patients with CKD and ESKD experienced higher risk of postbariatric surgery complications compared to those without kidney disease, although absolute complication rates were low across all groups. CKD and ESKD should not be perceived as contraindications to bariatric surgery. PMID- 30443720 TI - Evaluation of all Types of Metabolic Bariatric Surgery and its Consequences: a Systematic Review and Meta-Analysis. AB - BACKGROUND: Considering conflicting results on the consequences of all types of obesity surgery, we were to summarize them via a systematic review. METHODS: Electronic literature search was done via scientific search engines. After the removal of duplicates and selection of articles of interest, 771 studies were included. RESULTS: Insulin resistance indicators were significantly improved after bariatric surgery. Leptin was also significantly decreased while adiponectin was significantly increased. Although the level of metabolic hormones changed after bariatric surgery, they were not statistically significant. Inflammation indicators were significantly decreased. Significant reduction was also detected in PAI-1 and sICAM-1. CONCLUSIONS: Bariatric surgery is beneficial in morbidly obese patients. Although treating obesity in a surgical way may cause some complications, the weight loss is generally safe and effective. PMID- 30443721 TI - Enantioselective degradation of the chiral alpha-cypermethrin and detection of its metabolites in five plants. AB - Alpha-cypermethrin (alpha-cypermethrin), an important chiral pyrethroid insecticide, is frequently detected in human samples. Because of the possible human health risks caused by alpha-cypermethrin, we studied dynamics, residues, and metabolism of alpha-cypermethrin in five common vegetables (tomato, cucumber, rape, cabbage, and pepper) on enantiomeric levels after foliar spray. alpha Cypermethrin was qualified by a HP-5 column and its enantiomers could be separated by gas chromatograph (GC) using a BGB-172 chiral column. The results of degradation showed that alpha-cypermethrin dissipated rapidly in vegetables with half-lives being only 2.85-8.88 days. Stereoselective degradation was observed on pepper and cucumber while the two metabolites (cis-DCCA and 3-PBA) of alpha cypermethrin were not detected during its dissipation in all plants. This is the first evidence of enantioselective degradation of alpha-cypermethrin in the five common vegetables and the results should be considered in future environmental risk and food safety evaluations. PMID- 30443722 TI - Identification of paddy crop phenological parameters using dual polarized SCATSAT 1 (ISRO, India) scatterometer data. AB - Paddy crop is one of the foremost food crops in the world. Human consumption accounts for 85% of total production of paddy. Paddy delivers 21% of human per capita energy and 15% of per capita protein. The present study focused on estimating the crop phenological parameters. The phenological parameters were estimated using soil moisture active passive (SMAP), MODIS NDVI, and SCATSAT-1 scatterometer data. The statistical models adopted in the study are two-parameter Gaussian distribution and two-parameter logistic distributions. The puddling stage is the first phenological stage, and it is estimated by the application of soil wetness index (SWI) and anomaly method. The transplanting stage is estimated using the anomaly method. The heading stages are estimated using statistical models, and it is found that Gaussian distribution is the best-fitted model. The harvesting stage is identified using SCATSAT-1 scatterometer and MODIS NDVI data. A chi-square test and degrees of freedom are used to identify the performance and comparison of statistical models. Chi-square test measure is equal to 80.561 and corresponding tabulated chi-square value with N-K-1 degrees of freedom that is equal to 117 is 151.929. The null hypothesis is not rejected. PMID- 30443723 TI - Sorption of 14C-carbofuran in Austrian soils: evaluation of fate and transport of carbofuran in temperate regions. AB - Carbofuran is an anticholinesterase carbamate commonly used as an insecticide, nematicide and acaricide in agricultural practice throughout the world. However, data on its sorption in temperate soils from Europe is limited. Laboratory studies were conducted to determine the adsorption of carbofuran on three distinct Austrian soils using batch experiments and radiometric techniques. Carbofuran adsorption capacity of the soils was found to be low in the three soils tested and showed to be related to the soils clay and organic carbon contents. The pesticide presented linear adsorption isotherms in all of the three soils. Due to the low sorption of carbofuran in the soils tested and to its high water solubility, there is a risk of migration to water bodies through run off and consequent negative effects on aquatic organisms and soil biota. PMID- 30443724 TI - Toxic effect and physiological disruption of sodium phosphate to the quagga mussel (Dreissena bugensis). AB - Phosphorous is an essential nutrient for all forms of life; however, the question of toxicity to aquatic species remains largely unanswered, despite many systems that exceed natural phosphorus loads. This study determined the ecotoxicological threshold concentration of phosphorus to the freshwater bivalve Dreissena bugensis using a 96-h bioassay. Sublethal, medial lethal, and lethal levels of sodium phosphate to D. bugensis were found to be 125, 260, and 476 ppm. Physiological biomarkers such as the oxygen consumption and filtration rate were estimated by exposing D. bugensis to five different sublethal concentrations (25, 50, 75, 100, and 125 ppm) of sodium phosphate for 96 h. Both oxygen consumption and filtration rate gradually declined with increasing exposure concentrations and durations, which was significant (alpha < 0.05) for 75, 100, and 125 ppm of sodium phosphate concentrations. Based on the feeding rate and oxygen consumption endpoints, the no-observed effect concentration and the low observed effect concentration were 25 and 75 ppm, respectively. Maximum acceptable toxicant concentration of sodium phosphate was 43.3 ppm. Measured environmental concentration (MEC) of total phosphorus (0.015 ppm; n = 6) was obtained from seasonal field assessments in Saginaw Bay during the years 2008 to 2010. An assessment factor of 1000 was used for calculating the predicted no effect concentration (PNEC) of 0.025 ppm. Risk quotient (RQ) of "0.6" was therefore established using MEC/PNEC (real risk) ratio. Binary ecological classification (RQ < 1) suggested that there is no appreciable risk of phosphorus to D. bungensis in the Saginaw Bay of Lake Huron of Laurentian Great Lakes. PMID- 30443725 TI - NDMA formation from 4,4'-hexamethylenebis (HDMS) during ozonation: influencing factors and mechanisms. AB - N-nitrosodimethylamine (NDMA), a toxic disinfection byproduct commonly associated with chloramination, has recently been found to form from an anti-yellowing agent (4,4'-hexamethylenebis (1,1-dimethylsemicarbazide) (HDMS)) during ozonation but the mechanisms are unclear. In this paper, the potential roles of molecular ozone (O3) and hydroxyl radical (?OH) on NDMA formation from HDMS were investigated under various oxidation conditions (ozone dosages, pH) and different components in water (bromide ion (Br-), bicarbonate ion (HCO3-), sulfate ion (SO42-), and humic acid (HA), as well as natural organic matter (NOM) from a lake). Moreover, HDMS transformation pathways by ozonation were determined. The results indicated that the formation of NDMA was enhanced through the combined effect of O3 and ?OH compared to that by O3 alone (addition of tert-butyl alcohol (tBA) as ?OH scavenger). ?OH itself cannot generate NDMA directly; however, it can transform HDMS to intermediates with higher NDMA yield than parent compound. The NDMA generation was affected (small dosages promoted but high dosages inhibited) by HA or Br- no matter with or without tBA. The presence of SO42- and HCO3- ions lowered NDMA formation through ?OH scavenging effect. Increasing pH not only increased degradation rate constant by enhancing ?OH generation but also affected HDMS dissociation ratio, reaching the maximum NDMA formation at pH 7-8. Natural constituents in selected water matrix inhibited NDMA formation. Impacts of these influencing factors on NDMA formation by only O3 however were significantly less pronounced over that by the joint roles of O3 and ?OH. Based on the result of Q TOF, LC/MS/MS, and GC/MS, the possible transformation pathways of HDMS by ozonation were proposed. The NDMA enhancement mechanism by the combined effect of O3 and ?OH can be attributed to greater amounts of intermediates with higher NDMA yield (such as unsymmetrical dimethylhydrazine (UDMH)) produced. These findings provide new understanding of NDMA formation upon ozonation of typical amine-based compounds. PMID- 30443726 TI - Elastography in the Diagnosis of Pancreatic Malignancies. AB - The study aimed to determine the usefulness of the elastography in the diagnosis of malignancy of solid pancreatic tumors. There were 123 patients (F/M; 51/72, aged 62 +/- 14) enrolled into the study with the diagnosis of pancreatic masses. Malignant pancreatic adenocarcinoma was identified in 78 patients and an inflammatory mass corresponding to chronic pancreatitis in the remaining 45 patients. The mass elasticity of a tumor (A-elasticity) and a reference zone (B elasticity) and the B/A strain ratio were measured. All these elastographic parameters differed between groups and correlated significantly with malignancies (r = 0.841; r = -0.834; r = 0.487, respectively). Receiver operating characteristic (ROC) analysis showed that A-elasticity between 0.05% and 0.14% alone, as well as the B/A strain ratio between 7.87 and 18.23 alone, enabled the recognition of all malignant pancreatic tumors with 100% sensitivity and >= 97.8% specificity. Surprisingly, B-elasticity alone also was helpful in recognizing malignant tumors (71% sensitivity, 80% specificity, 0.74 accuracy, and 0.792 area under the curve), although it appeared worse than A-elasticity and B/A strain ratio (p < 0.001). In multivariable regression analysis, A-elasticity identified 89.5% of malignancies (p < 0.001). A-elasticity and B-elasticity were the only significant independent factors influencing the tumor identification (r2 = 0.927; p < 0.001). The assessment of tumor elasticity appears sufficient to identify malignant tumors of the pancreas. PMID- 30443727 TI - A Feynman dispersion correction: a proof of principle for MNDO. AB - A dispersion correction is introduced and tested for MNDO. The shift in electron density caused by the interaction between oscillating dipoles in the London picture of dispersion is mimicked by adding a small r-7-dependent attractive nucleus-electron potential to the core Hamiltonian. This potential results in a shift in electron density similar to that used by Feynman to explain dispersion. The resulting parameterized self-consistent and inherently multicenter treatment (MNDO-F) gives good results for CHNO compounds that do not exhibit hydrogen bonds, which MNDO cannot reproduce. This "Feynman" dispersion correction is also applicable to Hartree-Fock and density functional theory. Graphical abstract The MNDO-F optimized geometry for a C60-fullerene tetramer in a tetrahedral configuration. PMID- 30443728 TI - Obituary: Professor Graham Ramsay. PMID- 30443729 TI - Targeting low-normal or high-normal mean arterial pressure after cardiac arrest and resuscitation: a randomised pilot trial. AB - PURPOSE: We aimed to determine the feasibility of targeting low-normal or high normal mean arterial pressure (MAP) after out-of-hospital cardiac arrest (OHCA) and its effect on markers of neurological injury. METHODS: In the Carbon dioxide, Oxygen and Mean arterial pressure After Cardiac Arrest and REsuscitation (COMACARE) trial, we used a 23 factorial design to randomly assign patients after OHCA and resuscitation to low-normal or high-normal levels of arterial carbon dioxide tension, to normoxia or moderate hyperoxia, and to low-normal or high normal MAP. In this paper we report the results of the low-normal (65-75 mmHg) vs. high-normal (80-100 mmHg) MAP comparison. The primary outcome was the serum concentration of neuron-specific enolase (NSE) at 48 h after cardiac arrest. The feasibility outcome was the difference in MAP between the groups. Secondary outcomes included S100B protein and cardiac troponin (TnT) concentrations, electroencephalography (EEG) findings, cerebral oxygenation and neurological outcome at 6 months after cardiac arrest. RESULTS: We recruited 123 patients and included 120 in the final analysis. We found a clear separation in MAP between the groups (p < 0.001). The median (interquartile range) NSE concentration at 48 h was 20.6 ug/L (15.2-34.9 ug/L) in the low-normal MAP group and 22.0 ug/L (13.6 30.9 ug/L) in the high-normal MAP group, p = 0.522. We found no differences in the secondary outcomes. CONCLUSIONS: Targeting a specific range of MAP was feasible during post-resuscitation intensive care. However, the blood pressure level did not affect the NSE concentration at 48 h after cardiac arrest, nor any secondary outcomes. PMID- 30443730 TI - Focus on randomised clinical trials. PMID- 30443731 TI - Extraction and Isolation of Natural Organic Compounds from Plant Leaves Using Ionic Liquids. AB - Plants contain many kinds of natural organic compounds, and their compounds possess many useful properties. Natural organic compounds are important for the development of medicines, pesticides, fragrances, cosmetics, and synthetic chemicals. In this chapter, we introduce efficient methods for extraction and isolation of valuable natural organic compounds from various plant leaves by using cellulose-dissolving ionic liquids. High-polarity ionic liquids, which can dissolve cellulose, contribute to the extraction of natural organic compounds from plant leaves probably by breaking down plant cell walls, which are composed of cellulose, hemicellulose, and lignin. Extraction and isolation of shikimic acid from ginkgo leaves, caffeoylquinic acids from sweet potato leaves, and neral and geranial (which combine to form citral) from lemon myrtle leaves were performed. Ionic liquids can achieve extraction rates greater than those achieved with water and other organic solvents. Graphical Abstract. PMID- 30443732 TI - Crop Growers' Adaptive Capacity to Climate Change: A Situated Study of Agriculture in Arizona's Verde Valley. AB - Climate change will pose unprecedented challenges for agricultural producers globally, requiring the ability to adapt to new and unpredictable conditions. This study explores the adaptive capacity of crop growers in the Verde Valley, Arizona (US). Rather than examining pre-determined indicators of adaptive capacity, this study adopts a situated framework that examines material conditions, perceptions, and the larger social context. Interviewers used past experiences and future scenarios to allow factors that enhance or constrain adaptive capacity to emerge from the interviews. Findings reveal adaptation is site specific but general measures can be taken to enhance adaptive capacity. Encouraging diversity in crops and water sources, the use of drought and heat tolerant crops, and the use of water conservation practices will likely increase growers' adaptive capacity. In contrast, lack of support from organizations and government programs, lack of diverse crops and sources of water, lack of awareness about climate change, and growers' confidence in their ability to always adapt impairs adaptive capacity. Verde Valley growers will need increased support from local and national organizations to adapt to projected changes. The situated framework applied in this study reveals important insights and could be used to explore adaptive capacity in other agricultural regions. PMID- 30443733 TI - The chromatin remodeler ZmCHB101 impacts alternative splicing contexts in response to osmotic stress. AB - KEY MESSAGE: Maize SWI3-type chromatin remodeler impacts alternative splicing contexts in response to osmotic stress by altering nucleosome density and affecting transcriptional elongation rate. Alternative splicing (AS) is commonly found in higher eukaryotes and is an important posttranscriptional regulatory mechanism to generate transcript diversity. AS has been widely accepted as playing essential roles in different biological processes including growth, development, signal transduction and responses to biotic and abiotic stresses in plants. However, whether and how chromatin remodeling complex functions in AS in plant under osmotic stress remains unknown. Here, we show that a maize SWI3D protein, ZmCHB101, impacts AS contexts in response to osmotic stress. Genome-wide analysis of mRNA contexts in response to osmotic stress using ZmCHB101-RNAi lines reveals that ZmCHB101 impacts alternative splicing contexts of a subset of osmotic stress-responsive genes. Intriguingly, ZmCHB101-mediated regulation of gene expression and AS is largely uncoupled, pointing to diverse molecular functions of ZmCHB101 in transcriptional and posttranscriptional regulation. We further found ZmCHB101 impacts the alternative splicing contexts by influencing alteration of chromatin and histone modification status as well as transcriptional elongation rates mediated by RNA polymerase II. Taken together, our findings suggest a novel insight of how plant chromatin remodeling complex impacts AS under osmotic stress . PMID- 30443734 TI - Religious Women's Coping with Infertility: Do Culturally Adapted Religious Coping Strategies Contribute to Well-Being and Health? AB - BACKGROUND: Infertility is a source of stress, particularly in pronatalist societies in which a lifestyle without children is viewed as an unacceptable option. The present study examined the relationship between the use of culturally adapted religious coping strategies and emotional adjustment among women coping with fertility problems. METHODS: This is a cross-sectional correlational study. One hundred and eighty-six religious Israeli women undergoing fertility treatment filled out questionnaires assessing their use of culturally adapted religious coping strategies and emotional adjustment (distress/well-being). RESULTS: A path analysis showed that the culturally adapted religious coping strategies of seeking the support of Rabbis and seeking the support of God had a strong correlation with reduced psychological distress, but not with enhanced psychological well-being. Seeking approval and recognition from the community was correlated with reduced distress and enhanced well-being. However, seeking ties and belonging to the community was correlated with increased psychological distress and reduced psychological well-being. Finally, women without children experienced greater psychological distress than women with children and sought more support of Rabbis and fewer ties with the community. CONCLUSIONS: In a pronatalist culture that sanctifies childbirth, infertility is a source of significant distress. Professionals' awareness of the culturally adapted religious coping strategies utilized by their clients may help them conduct culturally sensitive intervention, which may greatly help to enhance emotional adjustment. Future research is recommended to develop instruments that measure culturally adapted strategies and their influence on emotional adjustment over time, in different states of health while comparing different cultures. PMID- 30443737 TI - Emergency department imaging superusers. AB - PURPOSE: To identify and characterize the most frequent users of emergency department (ED) imaging. MATERIALS AND METHODS: All patients with at least one ED visit in 2016 across a four-hospital healthcare system were retrospectively identified and their ED imaging utilization characterized. RESULTS: Overall, 126,940 unique patients underwent 187,603 ED visits (mean 1.5 +/- 1.7) and a total of 192,142 imaging examinations (mean 1.7 +/- 2.7). Fifty-eight percent of patients were imaged (73,672) and underwent a mean 2.6 +/- 2.7 exams. When ranked by ED visits, 1.6% (2007) of patients had >= 4 ED visits (mean 6.1 +/- 5.4). These ED "clinical superusers" accounted for 7.7% (14,409) of total ED visits and underwent 6.8 +/- 5.4 imaging examinations, while non-superusers underwent 1.5 +/ 2.2 (p < 0.01). When ranked by ED imaging utilization, 12.3% (15,575) of patients underwent >= 4 ED imaging examinations and consumed 49.5% (95,053) of all imaging services. A subset of just 1.3% (1608) of ED patients underwent > 10 annual ED examinations (ED "imaging superusers") and accounted for 12.4% (23,787) of all ED imaging services. Only 0.4% (n = 472) of patients were both clinical and imaging superusers. Despite similar ED visits to clinical superusers (6.0 +/- 5.6 vs. 6.1 +/- 5.4, p = 0.92), imaging superusers underwent significantly more imaging (14.8 +/- 4.8 vs. 6.8 +/- 5.4 examinations, p < 0.01). CONCLUSION: Just 12% of ED patients consume 50% of all ED imaging services, and 1.3% consume 12.4%. These ED imaging superusers represent a distinct group from clinical superusers. Prospective identification of this newly described subgroup might permit targeted interventions to control ED imaging volume, restrain costs, and minimize per-patient radiation exposure. PMID- 30443738 TI - Meconium aspiration syndrome requiring ECMO in newborns with gastroschisis: incidence and surgical outcomes. AB - AIM OF THE STUDY: To evaluate the incidence of respiratory failure requiring ECMO in newborns with gastroschisis (GC), compare it to the incidence in the general population, review the surgical outcomes of newborns with GC requiring ECMO and compare them to newborns with GC not requiring ECMO. METHODS: This is a retrospective review of all neonatal admissions for GC from December 2010 to September 2015. MAIN RESULTS: 110 newborns with GC were admitted to our NICU between 12/2010 and 9/2015; 36 were term. Four cases, all term, all prenatally diagnosed, all outborn, developed respiratory failure requiring ECMO secondary to meconium aspiration syndrome (MAS). This 11% (4/36 term GC) represents a 300-fold increase in the incidence of MAS-associated respiratory failure requiring ECMO compared to the general population of term newborns (0.037%). Median time on ECMO was 12 (9-20) days. The time to achieve full enteral feedings in the GC/ECMO group was twice the time of the 106 newborns in the GC/non-ECMO group [median: 70 (48-77) vs. 35 (16-270) days, respectively]. Time to hospital discharge was three times longer in the GC/ECMO group compared to the GC/non-ECMO group (median: 42 [20-282] versus 125 [69-223] days, respectively). All patients survived. CONCLUSION: The incidence of respiratory failure requiring ECMO is remarkably higher in patients with GC than in the general population and much higher in the subgroup of term GC. While infrequent, the possibility of this event supports the concept that fetuses with GC benefit from being delivered at tertiary centers with immediate pediatric surgery and ECMO capabilities. PMID- 30443739 TI - Whole rat stomach decellularisation using a detergent-enzymatic protocol. AB - BACKGROUND: Conditions leading to reduced gastric volume are difficult to manage and are associated to poor quality-of-life. Stomach augmentation using a tissue engineered stomach is a potential solution to restore adequate physiology and food reservoir. Aim of this study was to evaluate the decellularisation of whole rat stomach using a detergent-enzymatic protocol. METHODS: Stomachs harvested from rats were decellularised through luminal and vascular cannulation using 24-h detergent-enzymatic treatment and completely characterized by appropriate staining, DNA and Extracellular matrix -component quantifications. RESULTS: The detergent-enzymatic protocol allows a complete decellularisation of the gastric tissue, with a complete removal of the DNA with two cycles as confirmed by both quantifications and histological analysis. Extracellular matrix components, collagen, fibronectin, laminin and elastin, were optimally preserved by the treatment, while glycosaminoglycans were reduced. CONCLUSION: Gastric tissue can be efficiently decellularised. Scaffolds retained original structure and important components that could enhance integration with other tissues for in vivo transplant. The use of naturally derived material could be potentially considered for the treatment of both congenital and acquired conditions. PMID- 30443735 TI - Molecular imaging with nanoparticles: the dwarf actors revisited 10 years later. AB - We explore present-day trends and challenges in nanomedicine. Creativity in the laboratories continues: the published literature on novel nanoparticles is now vast. Nanoagents are discussed here which are composed entirely of strongly photoluminescent materials, tunable to desired optical properties and of inherently low toxicity. We focus on "quantum nanoparticles" prepared from allotropes of carbon. The principles behind strong, tunable photoluminescence are quantum mechanical: we present them in simple outline. The major industries racing to develop these materials can offer significant technical guidance to nanomedicine, which could help to custom-design strongly signalling nanoagents specifically for stated clinical applications. Since such agents are small, they can be targeted easily, making active targeting possible. We consider it timely now to study the interactions nanoparticles undergo with tissue components in living animals and to learn to understand and overcome the numerous barriers the organism interposes between the blood and targets in or on parenchymal cells. As the near infra-red spectrum opens up, detection of glowing nanoparticles several centimeters deep in a living human subject becomes calculable and we present a simple way to do this. Finally, we discuss the slow-fuse and resource-inefficient entry of nanoparticles into clinical application. A first possible reason is failure to target across the body's barriers, see above. Second, in the sparse translational landscape funding and support gaps yawn widely between academic research and subsequent development. We consider the agendas of the numerous "stakeholders" participating in this sad landscape and point to some faint glimmers of hope for the future. PMID- 30443736 TI - Artificial liver support systems: what is new over the last decade? AB - The liver is a complex organ that performs vital functions of synthesis, heat production, detoxification and regulation; its failure carries a highly critical risk. At the end of the last century, some artificial liver devices began to develop with the aim of being used as supportive therapy until liver transplantation (bridge-to-transplant) or liver regeneration (bridge-to recovery). The well-recognized devices are the Molecular Adsorbent Recirculating SystemTM (MARSTM), the Single-Pass Albumin Dialysis system and the Fractionated Plasma Separation and Adsorption system (PrometheusTM). In the following years, experimental works and early clinical applications were reported, and to date, many thousands of patients have already been treated with these devices. The ability of artificial liver support systems to replace the liver detoxification function, at least partially, has been proven, and the correction of various biochemical parameters has been demonstrated. However, the complex tasks of regulation and synthesis must be addressed through the use of bioartificial systems, which still face several developmental problems and very high production costs. Moreover, clinical data on improved survival are conflicting. This paper reviews the progress achieved and new data published on artificial liver support systems over the past decade and the prospects for these devices. PMID- 30443741 TI - Spinal cord lesions in a pediatric patient with chronic kidney disease and review of literature: Questions. PMID- 30443742 TI - Spinal cord lesions in a pediatric patient with chronic kidney disease and review of literature: Answers. PMID- 30443740 TI - Correction to: Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings : A Midwest Pediatric Nephrology Consortium (MWPNC) study. AB - The original version of this article unfortunately contained a mistake. The subtitle "A Midwest Pediatric Nephrology Consortium (MWPNC) study" was missing. The correct title including subtitle is given above. PMID- 30443743 TI - Long-term renal outcomes of APRT deficiency presenting in childhood. AB - BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD). The purpose of this study was to examine the course of APRT deficiency in patients who presented in childhood. METHODS: The disease course of 21 (35%) patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, who presented with manifestations of APRT deficiency and/or were diagnosed with the disorder before the age of 18 years, was studied. The effect of pharmacotherapy on renal manifestations and outcomes was thoroughly assessed. RESULTS: Fourteen children were placed on allopurinol, 100 (25-200) mg/day, at the age of 2.6 (0.6 16.5) years. Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment. During 18.9 (1.7-31.5) years of pharmacotherapy, stones occurred in two patients and AKI in three. Six adult patients started allopurinol treatment, 200 (100-300) mg/day, at age 29.8 (20.5-42.4) years. Five of these patients had experienced 28 stone episodes and AKI had occurred in two. Stone recurrence occurred in four patients and AKI in two during 11.2 (4.2-19.6) years of allopurinol therapy. Lack of adherence and insufficient dosing contributed to stone recurrence and AKI during pharmacotherapy. At latest follow-up, estimated glomerular filtration rate (eGFR) was 114 (70-163) and 62 (10-103) mL/min/1.73 m2 in those who initiated treatment as children and adults, respectively. All three patients with CKD stages 3-5 at the last follow-up were adults when pharmacotherapy was initiated. CONCLUSION: Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function. PMID- 30443744 TI - Genetic variations in the IL-12B gene in association with IL-23 and IL-12p40 serum levels in ankylosing spondylitis. AB - In the present study, we evaluated the implication of IL12Bpro (rs17860508) and IL12B 3' UTR A/C single nucleotide polymorphisms (SNPs) (rs3212227) for the ankylosing spondylitis (AS) development and the impact of IL12B genetic variations on IL-23 and IL-12p40 production and musculoskeletal disease characteristics. 80 patients with AS and 242 healthy controls were studied. Genotyping for the rs3212227 was performed by restriction fragment length polymorphisms-polymerase chain reaction (PCR) and for the rs17860508 by allele specific PCR. Cytokines were measured by an enzyme-linked immunosorbent assay (ELISA). Clinical status was evaluated by calculation of the Ankylosing Spondylitis Disease Activity Score (ASDAS) using the C-reactive protein (CRP) level, the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI). An association was found for the rs17860508 polymorphism with AS under the allelic, the dominant, and the co dominant models. Rs3212227 was not attributable to AS susceptibility by itself, but the carriage of C allele in the genotype amplifies the genetic risk for AS in the carriers of the high-risk IL12Bpro 2-allele, especially in homozygosity. Circulating IL-23 and IL-12p40 were raised among AS patients, as some of the genotypes of both IL12B polymorphisms positively regulate their expression. Carriage of the IL12Bpro genotype 2.2 has been linked to a worsened functional disability, while 3' UTR CC genotype-with severe disease activity. IL12B polymorphisms can impact AS susceptibility and modulate IL-23 and IL-12p40 production levels, and have a contribution to the disease phenotype. PMID- 30443747 TI - Characteristics of multi-channel Br(E)-MsEP waveforms for the lower extremity muscles in thoracic spine surgery: comparison based on preoperative motor status. AB - PURPOSE: To evaluate the characteristics of brain-evoked muscle action potential [Br(E)-MsEP] waveforms of lower limb muscles in thoracic spine surgery. METHODS: The subjects were 159 patients who underwent thoracic spine surgery with intraoperative Br(E)-MsEP monitoring from January 2009 to December 2015, using a total of 2226 muscles in the extremities. The waveform derivation rate for each lower extremity muscle was examined at baseline and intraoperatively. Data were interpreted based on the preoperative motor status. RESULTS: The preoperative ambulatory and non-ambulatory rates were 38% (60/159, McCormick grades I and II) and 62% (99/159, grades III-V), respectively. Eleven cases (all non-ambulatory) had undetectable baseline waveforms in all muscles, and in 19 cases (12%) a baseline waveform could only be derived from the abductor hallucis (AH). The waveform derivation rate in all lower limb muscles was significantly higher in ambulatory cases (p < 0.05), and the rates for the AH were the highest in both groups (p < 0.05). Postoperative paralysis occurred in 31 cases (19%). A decrease in intraoperative amplitude of >= 70% from baseline occurred in 54 cases and had sensitivity of 100% and specificity of 82% for prediction of postoperative motor deficit. CONCLUSIONS: This is the first study of Br(E)-MsEP waveforms for each lower limb muscle based on preoperative ambulatory status. Detection of waveforms from distal muscles was still possible in a case with preoperative motor deficit, and the AH had an especially high derivation rate, even in cases with preoperative muscle weakness. Collectively, the results support use of Br(E)-MsEP monitoring using the AH in the lower extremities. PMID- 30443745 TI - [Minimally invasive proximal hamstring insertion repair]. AB - OBJECTIVE: Minimally invasive endoscopic reconstruction of avulsion injuries of the proximal hamstring insertion to prevent persistent weakness and pain. INDICATIONS: Fresh retracted 2- and 3-tendon avulsion injuries of the proximal hamstring insertion. Unsuccessful conservative therapy of less retracted injuries. Painful chronic partial lesions of the proximal hamstring insertion. CONTRAINDICATIONS: Major comorbidities with an increased surgical risk, older patients with low functional demands. Chronic injuries without functional deficits. SURGICAL TECHNIQUE: Endoscopic refixation using suture anchors after freshening the footprint on the tuber ischiadicum. Visualization of the sciatic nerve to ensure its protection. POSTOPERATIVE MANAGEMENT: Partial loading with a knee brace for strict prevention of combined knee extension and hip flexion for 4 6 weeks. Start of active exercise and stretching 8 weeks postoperatively. RESULTS: From 2014-2016, 12 patients were treated with an endoscopic reconstruction of the proximal hamstring insertion. After a mean follow-up of 25 months (range 16-34 months), an average visual analog scale (VAS) of 0 (range 0 2) and an average subjective assessment of function (Subjective Hip Value) of 94% (range 80-100%) were found. No neurovascular complications were seen in our collective, in particular no evidence of hypesthesia in the area of the posterior femoral cutaneous nerve. All patients were able to return to their original level of activity (Tegner Activity Scale 5.2 preoperatively vs. 5.2 postoperatively), while the average time until return to sport was 6.5 months (range 3-12 months). All patients were able to return to their original occupation. PMID- 30443748 TI - Tea consumption and bone health in Chinese adults: a population-based study. AB - : Tea is a worldwide drink with controversial effect on bone health. The sex specific associations are unrevealed among general population. This study showed that prolonged moderate tea consumption benefited bone health in women, while no additional benefit with stronger tea. However, tea consumption was not associated with bone health in men. INTRODUCTION: Tea consumption has been shown a potentially beneficial effect on bone health in postmenopausal women. However, little is known about such association in men, and whether stronger tea instead harms bone health due to elevated urinary excretion of calcium associated with caffeine in the tea. The aim of this study was to examine the association between various metrics of tea consumption and bone health. METHODS: The present study included 20,643 participants from the China Kadoorie Biobank (CKB), who have finished both baseline survey (2004-2008) and a re-survey (2013-2014). They were aged 38-86 years at re-survey. Tea consumption was self-reported at both baseline and re-survey. Bone mineral density (BMD) was measured using calcaneal quantitative ultrasound once at re-survey. RESULTS: Compared with non-consumers, prolonged weekly tea consumers in women was associated with higher calcaneus BMD measures, with beta (95% CI) of 0.98 (0.22, 1.74) for BUA, 4.68 (1.74, 7.61) for SOS, and 1.95 (0.81, 3.10) for SI. Among prolonged weekly tea consumers, no linear increase in BMD measures with the amount of tea leaves added was observed. The SOS and SI were higher in consumers with tea leaves 3.0-5.9 g/day than in those with < 3.0 g/day, but were reduced to non-significant for those with >= 6.0 g/day. Tea consumption was not associated with calcaneus BMD measures in men. CONCLUSION: Prolonged moderate tea consumption benefited bone health in women but not in men. For stronger tea consumption with more tea leaves added, neither benefit nor harm to bone health was observed. PMID- 30443749 TI - Structural disorder in the proteome and interactome of Alkhurma virus (ALKV). AB - Infection by the Alkhurma virus (ALKV) leading to the Alkhurma hemorrhagic fever is a common thread in Saudi Arabia, with no efficient treatment or prevention available as of yet. Although the rational drug design traditionally uses information on known 3D structures of viral proteins, intrinsically disordered proteins (i.e., functional proteins that do not possess unique 3D structures), with their multitude of disorder-dependent functions, are crucial for the biology of viruses. Here, viruses utilize disordered regions in their invasion of the host organisms and in hijacking and repurposing of different host systems. Furthermore, the ability of viruses to efficiently adjust and accommodate to their hostile habitats is also intrinsic disorder-dependent. However, little is currently known on the level of penetrance and functional utilization of intrinsic disorder in the ALKV proteome. To fill this gap, we used here multiple computational tools to evaluate the abundance of intrinsic disorder in the ALKV genome polyprotein. We also analyzed the peculiarities of intrinsic disorder predisposition of the individual viral proteins, as well as human proteins known to be engaged in interaction with the ALKV proteins. Special attention was paid to finding a correlation between protein functionality and structural disorder. To the best of our knowledge, this work represents the first systematic study of the intrinsic disorder status of ALKV proteome and interactome. PMID- 30443750 TI - Cardio-oncology: Understanding cardiotoxicity to guide patient focused imaging. AB - Current cancer therapy has led to tremendous improvements in outcomes. These therapies rely both on established therapies, such as anthracyclines and radiation, and molecularly-targeted therapies, such as tyrosine kinase inhibitors and immune modulators. Integrative care for patients with cancer must consider the potential effects of these therapies on a variety of organ systems, including the cardiovascular system. As a result, specialties such as cardio-oncology have developed to identify these effects, determine how to best monitor for these effects, and how to treat and ultimately prevent these effects while allowing the patient to receive the therapy they require for their cancer. This review provides a basis for understanding the cardiovascular effects of cancer therapies so that the most appropriate imaging modality may be selected to prevent and treat these effects. PMID- 30443751 TI - Ventricular synchrony is not significantly determined by absolute myocardial perfusion in patients with chronic heart failure: A 13N-ammonia PET study. AB - BACKGROUND: It is thought that heart failure (HF) patients may benefit from the evaluation of mechanical (dys)synchrony, and an independent inverse relationship between myocardial perfusion and ventricular synchrony has been suggested. We explore the relationship between quantitative myocardial perfusion and synchrony parameters when accounting for the presence and extent of fixed perfusion defects in patients with chronic HF. METHODS: We studied 98 patients with chronic HF who underwent rest and stress Nitrogen-13 ammonia PET. Multivariate analyses of covariance were performed to determine relevant predictors of synchrony (measured as bandwidth, standard deviation, and entropy). RESULTS: In our population, there were 43 (44%) women and 55 men with a mean age of 71 +/- 9.6 years. The SRS was the strongest independent predictor of mechanical synchrony variables (p < .01), among other considered predictors including: age, sex, body mass index, smoking, diabetes mellitus, dyslipidemia, hypertension, rest myocardial blood flow (MBF), and myocardial perfusion reserve (MPR). Results were similar when considering stress MBF instead of MPR. CONCLUSIONS: The existence and extent of fixed perfusion defects, but not the quantitative PET myocardial perfusion parameters (sMBF and MPR), constitute a significant independent predictor of ventricular mechanical synchrony in patients with chronic HF. PMID- 30443752 TI - Focal mass-like cardiac uptake on oncologic FDG PET/CT: Real lesion or atypical pattern of physiologic uptake? AB - BACKGROUND: Cardiac uptake on oncologic FDG PET/CT can be unpredictable. Focal or mass-like cardiac uptake not confined to normal pattern is a real challenge for interpretation due to great variability in physiologic uptake and rarity of either primary or metastatic cardiac neoplasms. METHODS AND RESULTS: Eight patients with suspicious mass-like cardiac uptake on oncologic FDG PET/CT were retrospectively analyzed with correlation to cardiac workups including contrast CT, echocardiography, and repeat PET/CT. Four patients had real cardiac lesions or metastases. Focal uptake was benign and might represent papillary muscle in the other four. SUVmax ratio between the cardiac focus and surrounding background cardiac uptake was statistically higher in the true-positive group than that in the false-positive group. In addition, the patients with true-positive cardiac uptake had more diffuse distant metastases compared to those with false-positive cardiac uptake. CONCLUSIONS: Focal suspicious cardiac uptake on oncology FDG PET/CT warranted further evaluation. SUVmax ratio between the cardiac focus and surrounding background cardiac uptake and status of distant metastases might help to differentiate malignant from benign nature of the focal cardiac uptake on FDG PET/CT. Focal uptake of the right ventricle on oncologic FDG PET/CT is more likely suggestive of a neoplasm. PMID- 30443753 TI - Therapeutic regulation of VE-cadherin with a novel oligonucleotide drug for diabetic eye complications using retinopathy mouse models. AB - AIMS/HYPOTHESIS: A major feature of diabetic retinopathy is breakdown of the blood-retinal barrier, resulting in macular oedema. We have developed a novel oligonucleotide-based drug, CD5-2, that specifically increases expression of the key junctional protein involved in barrier integrity in endothelial cells, vascular-endothelial-specific cadherin (VE-cadherin). CD5-2 prevents the mRNA silencing by the pro-angiogenic microRNA, miR-27a. CD5-2 was evaluated in animal models of ocular neovascularisation and vascular leak to determine its potential efficacy for diabetic retinopathy. METHODS: CD5-2 was tested in three mouse models of retinal dysfunction: conditional Muller cell depletion, streptozotocin induced diabetes and oxygen-induced retinopathy. Vascular permeability in the Muller cell-knockout model was assessed by fluorescein angiography. The Evans Blue leakage method was used to determine vascular permeability in streptozotocin and oxygen-induced retinopathy models. The effects of CD5-2 on retinal neovascularisation, inter-endothelial junctions and pericyte coverage in streptozotocin- and oxygen-induced retinopathy models were determined by staining for isolectin-B4, VE-cadherin and neural/glial antigen 2 (NG2). Blockmir CD5-2 localisation in diseased retina was determined using fluorescent in situ hybridisation. The effects of CD5-2 on VE-cadherin expression and in diabetic retinopathy-associated pathways, such as the transforming growth factor beta (TGF beta) and wingless/integrated (WNT) pathway, were confirmed using western blot of lysates from HUVECs, a mouse brain endothelial cell line and a VE-cadherin null mouse endothelial cell line. RESULTS: CD5-2 penetrated the vasculature of the eye in the oxygen-induced retinopathy model. Treatment of diseased mice with CD5-2 resulted in reduced vascular leak in all three animal models, enhanced expression of VE-cadherin in the microvessels of the eye and improved pericyte coverage of the retinal vasculature in streptozotocin-induced diabetic models and oxygen induced retinopathy models. Further, CD5-2 reduced the activation of retinal microglial cells in the streptozotocin-induced diabetic model. The positive effects of CD5-2 seen in vivo were further confirmed in vitro by increased protein expression of VE-cadherin, SMAD2/3 activity, and platelet-derived growth factor B (PDGF-B). CONCLUSIONS/INTERPRETATION: CD5-2 has therapeutic potential for individuals with vascular-leak-associated retinal diseases based on its ease of delivery and its ability to reverse vascular dysfunction and inflammatory aspects in three animal models of retinopathy. PMID- 30443754 TI - JAK 1/2 Blockade in MDA5 Gain-of-Function. PMID- 30443755 TI - Theoretical investigation of auxiliary electronic acceptors in modifying D-D-pi-A sensitizers for dye-sensitized solar cells. AB - In light of the performance of the SD2 pigments in DSSC, in order to expand the absorption spectral scope, decrease the energy difference between the highest occupied and the lowest unoccupied molecular orbitals, with SD2 dye molecular electron donor and electron acceptor as the fundamental framework, the indole fragment and thiophene derivative in the prototype dye molecule were replaced by the two pi-bridges (labeled PA, PB, respectively) and the four auxiliary electron acceptors (labeled A1, A2, A3, A4, respectively). For the sake of characterizing dye molecules as thoroughly as possible in DSSC, the frontier orbital energy levels, ultraviolet absorption spectra, natural bond orbital analysis, intramolecular charge transfer, charge and hole reorganization energies, parameters influencing the short-circuit current density and the open-circuit photovoltage for these eight individual dye molecules are carried out to try to fully characterize the properties of these dye molecules. According to these computational results of physical quantities and based on the performance of these dye molecules in the above aspects, in this paper, six free molecular models were picked out to combine with titanium dioxide cluster to calculate their geometrical structures, frontier orbital distributions, electron excitation energies, ultraviolet absorption spectra and the composition of the electronic transitions in chloroform solvent with polarizable continuum model. The results of these calculations show that the PA-A2 and PB-A4 dye molecule has better properties in electron transfer and spectral absorption range before and after the adsorption on the titanium dioxide. PMID- 30443756 TI - Citation bias in imaging research: are studies with higher diagnostic accuracy estimates cited more often? AB - OBJECTIVES: To assess the risk of citation bias in imaging diagnostic accuracy research by evaluating whether studies with higher accuracy estimates are cited more frequently than those with lower accuracy estimates. METHODS: We searched Medline for diagnostic accuracy meta-analyses published in imaging journals from January 2005 to April 2016. Primary studies from the meta-analyses were screened; those assessing the diagnostic accuracy of an imaging test and reporting sensitivity and specificity were eligible for inclusion. Studies not indexed in Web of Science, duplicates, and inaccessible articles were excluded. Topic (modality/subspecialty), study design, sample size, journal impact factor, publication date, times cited, sensitivity, and specificity were extracted for each study. Negative binomial regression was performed to evaluate the association of citation rate (times cited per month since publication) with Youden's index (sensitivity + specificity -1), highest sensitivity, and highest specificity, controlling for the potential confounding effects of modality, subspecialty, impact factor, study design, sample size, and source meta-analysis. RESULTS: There were 1016 primary studies included. A positive association between Youden's index and citation rate was present, with a regression coefficient of 0.33 (p = 0.016). The regression coefficient for sensitivity was 0.41 (p = 0.034), and for specificity, 0.32 (p = 0.15). CONCLUSION: A positive association exists between diagnostic accuracy estimates and citation rates, indicating that there is evidence of citation bias in imaging diagnostic accuracy literature. Overestimation of imaging test accuracy may contribute to patient harm from incorrect interpretation of test results. KEY POINTS: * Studies with higher accuracy estimates may be cited more frequently than those with lower accuracy estimates. * This citation bias could lead clinicians, reviews, and clinical practice guidelines to overestimate the accuracy of imaging tests, contributing to patient harm from incorrect interpretation of test results. PMID- 30443757 TI - ASL perfusion features and type of circle of Willis as imaging markers for cerebral hyperperfusion after carotid revascularization: a preliminary study. AB - OBJECTIVES: Cerebral hyperperfusion (CH) could be a disastrous outcome causing complication after carotid revascularization if not managed properly and timely. The aim of this study was to investigate the association between preoperative arterial spin labelling (ASL) perfusion features and circle of Willis (CoW) pattern with CH. METHODS: Forty-eight consecutive carotid stenosis patients who underwent carotid endarterectomy (CEA) or carotid artery stenting (CAS) were enrolled. All patients had single post-labelling delay (PLD) ASL, territory-ASL, and 3-dimensional time-of-flight MR angiography (3D TOF MRA) within 2 weeks before surgery and within 3 days after surgery. Spatial coefficient of variation (CoV) of cerebral blood flow (CBF), whole brain, and territory perfusion volume ratio were calculated from ASL and territory-ASL. Postoperative CoW was classified into two groups based on patency of the first segment of the anterior cerebral arteries (A1) and anterior communicating artery (AcomA). ASL perfusion features, type of CoW, and clinical characteristics were analyzed between CH group and non-CH group to identify CH risk factors. RESULTS: Higher CoV (p = 0.005) of CBF, lower whole brain perfusion volume ratio (p = 0.012), missing any of A1 or AcomA in CoW (p = 0.002 for postoperative MRA and p = 0.004 for preoperative MRA), and large artery stroke history (p = 0.028) were significantly associated with higher risk of CH. Two cases with cerebral hyperperfusion syndrome (CHS) were also discussed, and their perfusion and angiographic features were shown. CONCLUSIONS: Single-PLD ASL and MRA might be useful and non-invasive imaging tools to identify patients with higher risk of CH after carotid revascularization. KEY POINTS: * Cerebral hyperperfusion is a critical complication after carotid endarterectomy or carotid artery stenting. * ASL and MRA can be used to identify patients at higher risk of cerebral hyperperfusion * Pattern of circle of Willis, ASL perfusion features, and whole brain perfusion volume ratio are potential predicting markers for hyperperfusion after carotid revascularization. PMID- 30443758 TI - Radiomics and machine learning may accurately predict the grade and histological subtype in meningiomas using conventional and diffusion tensor imaging. AB - OBJECTIVES: Preoperative, noninvasive prediction of the meningioma grade is important because it influences the treatment strategy. The purpose of this study was to evaluate the role of radiomics features of postcontrast T1-weighted images (T1C), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) maps, based on the entire tumor volume, in the differentiation of grades and histological subtypes of meningiomas. METHODS: One hundred thirty-six patients with pathologically diagnosed meningiomas (108 low-grade [benign], 28 high-grade [atypical and anaplastic]), who underwent T1C and diffusion tensor imaging, were included in the discovery set. The T1C image, ADC, and FA maps were analyzed to derive volume-based data of the entire tumor. Radiomics features were correlated with meningioma grades and histological subtypes. Various machine learning classifiers were trained to build classification models to predict meningioma grades. We tested the model in a validation set (58 patients; 46 low-grade; 12 high-grade). RESULTS: The machine learning classifiers showed variable performances depending on the machine learning algorithms. The best classification system for the prediction of meningioma grades had an area under the curve of 0.86 (95% confidence interval [CI], 0.74-0.98) in the validation set. The accuracy, sensitivity, and specificity of the best classifier were 89.7, 75.0, and 93.5% in the validation set, respectively. Various texture parameters differed significantly between fibroblastic and non-fibroblastic subtypes. CONCLUSIONS: Radiomics feature-based machine learning classifiers of T1C images, ADC, and FA maps are useful for differentiating meningioma grades. KEY POINTS: * Preoperative, noninvasive differentiation of the meningioma grade is important because it influences the treatment strategy. * Radiomics feature-based machine learning classifiers of T1C images, ADC, and FA maps are useful for differentiating meningioma grades. * In benign meningiomas, there were significant differences in the various texture parameters between fibroblastic and non-fibroblastic meningioma subtypes. PMID- 30443759 TI - Letter to the editor: Randomized double-blind trial of short- versus long-acting analgesia at the sacrospinous ligament. PMID- 30443760 TI - External validation of de novo stress urinary incontinence prediction model after vaginal prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) may appear after the correction of pelvic organ prolapse (POP). The aim of this study was to externally validate a described predictive model for de novo SUI and to assess its clinical performance when used as a diagnostic test. METHODS: This was a retrospective descriptive study on a cohort of consecutive women treated in our institution. The main outcome used to validate the model was the presence of objective or subjective SUI 1 year after surgery. A receiver operating characteristic curve was generated from our population to evaluate the predictive accuracy and to compare it with the original model. A cutoff point of >=50% was used to evaluate its clinical performance as a diagnostic test. RESULTS: Of the full cohort, 169 women were suitable for analysis. The rate of de novo SUI was 11.8%. The predictive accuracy of the model in our population was similar to the original [area under the curve (AUC) = 0.69; 95% confidence interval (CI) = 0.58 0.80). However, its performance measures when evaluated as a diagnostic test were low: positive likelihood ratio = 2.71 and negative likelihood ratio = 0.86. Only 15 women presented a positive test result. CONCLUSIONS: External validation of the model found a global predictive accuracy similar to that of the original model. Despite the study being underpowered to give firm conclusions, the test did not show a good clinical performance when applied to our population with low de novo SUI prevalence. A larger sample size is needed to validate the model conclusively. PMID- 30443761 TI - Knockdown of long non-coding HOTAIR enhances the sensitivity to progesterone in endometrial cancer by epigenetic regulation of progesterone receptor isoform B. AB - PURPOSE: Progesterone, particularly medroxyprogesterone acetate (MPA) has been mainly used for young endometrial carcinoma (EC) patients with conservative treatment. However, its treatment benefits are limited by insensitivity or acquired resistance. In this study, we aim to investigate the effect of long non coding RNA HOTAIR on progesterone sensitivity in endometrial cancer, as well as the underlying mechanisms. METHODS: The expression of HOTAIR was detected by quantitative real-time PCR. The impact of MPA on the endometrial cancer cells was examined by MTT, colony formation, apoptosis-related protein detection and flow cytometry. Chromatin immunoprecipitation (ChIP) assay was performed to detect the regulatory mechanism between HOTAIR and progesterone receptor B (PRB). We further confirm the function of HOTAIR in vivo though xenograft tumor assay. RESULTS: We found that HOTAIR inversely correlated with PRB expression in endometrial carcinoma. Knockdown of HOTAIR promoted the MPA sensitivity by upregulating PRB, which can be largely reversed by PRB downregulation. Moreover, inhibiting LSD1, a HOTAIR-associated protein that removed activating H3K4me2 chromatin marks, induced PRB expression and promoted apoptosis induced by MPA. We further showed that silencing HOTAIR strengthened the H3K4me2 occupation on the promotor of PRB. CONCLUSIONS: Our findings provide compelling evidence that HOTAIR and LSD1 collaboratively repress PRB expression and thus mediate progesterone sensitivity in endometrial carcinoma cells. HOTAIR is a potential predictor for progesterone response in EC and down-regulated expression of HOTAIR might be an effective strategy for overcoming progesterone resistance. PMID- 30443762 TI - "When sex influences the brain: implications for Alzheimer disease". PMID- 30443763 TI - Effects of late cyclosporine withdrawal on renal graft function and survival. AB - OBJECTIVE: Attempts to discontinue calcineurin inhibitors (CNIs) early after renal transplantation without conversion to an alternative immunosuppressive have failed due to high rates of acute rejection. Data on "late" CNI withdrawal are lacking so far. DESIGN AND METHOD: We carried out a matched case-control study on the effects of CNI withdrawal on graft loss and mortality in 90 patients (1500 screened) with advanced graft dysfunction (serum creatinine > 3.5 mg/dl) and a cyclosporine-based triple immunosuppressive regimen at the Charite University Hospital, Berlin. RESULTS: Cyclosporine was withdrawn at a mean of 54.0 +/- 32.8 months post-transplant in 45 subjects. Whereas estimated glomerular filtration rate (eGFR) did not significantly differ between the groups at this time (12.4 +/ 2.7 vs. 14.7 +/- 8.9 in the control group, p = 0.08), it was significantly higher in subjects undergoing withdrawal after 120 months (Delta 4.1 ml/min; p < 0.001). In a Cox regression analysis adjusted for age, gender and eGFR, patients with CNI withdrawal showed better survival rates for the combined endpoint death/graft loss (hazard ratio, HR [95% confidence interval]: 0.19 [0.12-0.33], p = 0.001) compared to matched controls. The survival benefit was significant for the endpoints death (p = 0.01) and graft loss (p = 0.001). CONCLUSIONS: CNI withdrawal was associated with improved survival rates in patients with advanced graft dysfunction in this retrospective analysis. PMID- 30443764 TI - Geriatric screening tools predict survival outcomes in older patients with diffuse large B cell lymphoma. AB - The proportion of elderly patients with diffuse large B cell lymphoma (DLBCL) appears to be increasing, with outcomes varying widely because of the patients' heterogeneity. Geriatric assessment is used to predict prognosis in elderly patients with DLBCL, but the utility of two simple screening tools for patients with DLBCL, the Flemish version of the Triage Risk Screening Tool (fTRST) and G8, has remained to be elucidated. We retrospectively assessed patients using fTRST and G8, and evaluated the impacts of the scores on survival outcomes in older patients with newly diagnosed DLBCL. A total of 59 patients aged 65 years or older and who were diagnosed with DLBCL were included. The median age was 77 years (range, 65-91 years), and the initial treatments were R-CHOP (63%) and R THPCOP (31%). The estimated 2-year overall survival (OS) rate was significantly lower in patients with abnormal fTRST scores (>= 2; N = 17) than in those with normal fTRST scores (< 2; N = 42): (50.5% (95% CI, 22.7-73.0%) vs. 82.2% (95% CI, 63.8-91.8%), P = 0.007). The estimated 2-year OS rate was significantly lower also in patients with abnormal G8 scores (<= 14; N = 38) than in those with normal G8 scores (> 14; N = 21): (66.1% (95% CI, 46.7-79.5%) vs. 86.8% (95% CI, 55.7-96.7%), P = 0.03, respectively). These associations were independently significant after adjusting for other significant factors by multivariate analysis. These results suggest that the easy-to-use geriatric screening tools, fTRST and G8, have strong prognostic value for OS in older patients with DLBCL. PMID- 30443765 TI - Impact of N-terminal pro-B-type natriuretic peptide response on long-term prognosis after transcatheter aortic valve implantation for severe aortic stenosis and heart failure. AB - N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels prior to transcatheter aortic valve implantation (TAVI) are known to be associated with outcomes of patients undergoing TAVI. However, little has been known about the NT proBNP response after TAVI. Therefore, we aimed to clarify the role of the NT proBNP response and identify the determinants of the NT-proBNP nonresponse among patients with severe aortic stenosis (AS) and heart failure (HF) undergoing TAVI. We examined 717 patients with severe AS and HF undergoing TAVI. NT-proBNP nonresponders were defined as patients whose NT-proBNP levels decreased by <= 30%. Mean NT-proBNP levels decreased from 7698 +/- 7853 pg/mL (baseline) to 4523 +/- 5173 pg/mL (post-TAVI); 269 patients (38%) were nonresponders. Female gender and prevalence of diabetes mellitus (DM), chronic kidney disease (CKD), atrial fibrillation (AF), and history of coronary artery revascularization were more common for NT-proBNP nonresponders. Permanent pacemaker implantation rate was higher for NT-proBNP nonresponders. In addition to the baseline NT-proBNP level > 7500 pg/smL (hazard ratio [HR], 1.8; p = 0.03), NT-proBNP nonresponse (HR 2.3; p = 0.001) was associated with lower survival rates. Baseline NT-proBNP level <= 7500 pg/mL (OR 3.2; p < 0.001), female gender (odds ratio [OR], 1.5; p = 0.049), DM (OR 1.6; p = 0.016), CKD (OR 1.8; p = 0.001), AF (OR 2.4; p < 0.001), history of coronary revascularization (OR 1.7; p = 0.003), and permanent pacemaker implantation after TAVI (OR 1.7; p = 0.034) were independent determinants of NT proBNP nonresponse. In "conclusion", NT-proBNP response is important for long term survival after TAVI. We should consider the aforementioned determinants, particularly permanent pacemaker implantation, as risk factors for NT-proBNP nonresponse. PMID- 30443766 TI - Risk of venous thromboembolism after endoprosthetic surgeries: lower versus upper extremity endoprosthetic surgeries. AB - Venous thromboembolism (VTE) is a potentially fatal disease. Important risk factors of a provoked VTE are trauma, surgery or immobilization. Especially, patients who undergo hip and knee replacements are at high risk for postoperative VTE. We aimed to compare in-hospital VTE burden and other outcomes after upper and lower extremity endoprosthetic surgeries in Germany. The nationwide German inpatient sample of the years 2005-2015 was used for data analysis. Patients who underwent endoprosthetic joint/bone replacements of the extremities (OPS codes 5 820, 5-822, 5-824 and 5-826) were further stratified in those operated on lower (OPS codes 5-820, 5-822 and 5-826) or upper extremity (OPS code 5-824) joints. Patients operated at upper and lower extremity were compared and lower extremity endoprosthetic surgery was investigated as a predictor for adverse outcomes. Overall, 4,134,088 hospitalized patients with extremity joint endoprosthetic surgeries (64.3% females, 54.0% aged > 70 years) were included in our analysis. Of these, 3,950,668 patients (95.6%) undergo lower and 183,420 (4.4%) upper extremity endoprosthetic joint surgery. VTE [RR 2.60 (95% CI 2.41-2.79), P < 0.001] and all-cause death [RR 1.68 (95% CI 1.58-1.77), P < 0.001] were more common in patients with lower extremity joint surgery. Risk for VTE events [OR 2.69 (2.50-2.90), P < 0.001] and in-hospital death [OR 1.65 (1.56-1.75), P < 0.001] were both higher in lower than in upper extremity joint surgeries independently of age, sex and comorbidities. Patients who undergo lower extremity endoprosthetic joint surgeries, bear a higher risk for VTE and in-hospital death compared to those with upper extremity endoprosthetic joint surgeries. PMID- 30443767 TI - Establishment and evaluation of a model for predicting 3-month mortality in Chinese patients with hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a serious complication of liver disease. To establish a model for predicting 3-month mortality in patients with HE in China. This retrospective study included 609 patients with HE admitted to the Peoples' Hospital, Liaocheng City, China (August 2006 to January 2016). Patients were allocated to a modeling (n = 409) or validation (n = 200) group. Demographic/clinical characteristics, laboratory test results, Model for End Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score were extracted from medical records. A model for predicting death within 3 months after admission was established using logistic regression analysis (modeling group). Model validity (validation group) was assessed using receiver operating characteristic (ROC) curve analysis. 270/409(66.0%) patients died in the modeling group and 142/203(70.0%) died in the validation group. Compared with survivors, patients who died had more severe HE, and higher MELD score, CTP score, incidence of complications including hepatorenal syndrome (HRS) and upper gastrointestinal bleeding, and values for laboratory parameters including red blood cell count(RBC) and total bilirubin(TBIL)(P < 0.05). Regression analysis revealed RBC, TBIL, HE stage, HRS and upper gastrointestinal bleeding as independent factors associated with death (P < 0.05). The area under the ROC curve (AUC) for the model was 0.931.The model had a higher Youden index than MELD or CTP scores and predicted death in the validation group with a sensitivity of 83.1% and specificity of 93.4%. The established model has superior performance to MELD and CTP scores for predicting mortality in patients with HE. PMID- 30443768 TI - Differential regional infarction, neuronal loss and gliosis in the gerbil cerebral hemisphere following 30 min of unilateral common carotid artery occlusion. AB - The degree of transient ischemic damage in the cerebral hemisphere is different according to duration of transient ischemia and cerebral regions. Mongolian gerbils show various lesions in the hemisphere after transient unilateral occlusion of the common carotid artery (UOCCA) because they have different types of patterns of anterior and posterior communicating arteries. We examined differential regional damage in the ipsilateral hemisphere of the gerbil after 30 min of UOCCA by using 2,3,5-triphenyltetrazolium chloride (TTC) staining, cresyl violet (CV) Nissl staining, Fluoro-Jade B (F-J B) fluorescence staining, and NeuN immunohistochemistry 5 days after UOCCA. In addition, regional differences in reactions of astrocytes and microglia were examined using GFAP and Iba-1 immunohistochemistry. After right UOCCA, neurological signs were assessed to define ischemic symptomatic animals. Moderate symptomatic gerbils showed several infarcts, while mild symptomatic gerbils showed selective neuronal death/loss in the primary motor and sensory cortex, striatum, thalamus, and hippocampus 5 days after UOCCA. In the areas, morphologically changed GFAP immunoreactive astrocytes and Iba-1 immunoreactive microglia were found, and their numbers were increased or decreased according to the damaged areas. In brief, our results demonstrate that 30 min of UOCCA in gerbils produced infarcts or selective neuronal death depending on ischemic severity in the ipsilateral cerebral cortex, striatum, thalamus and hippocampus, showing that astrocytes and microglia were differently reacted 5 days after UOCCA. Taken together, a gerbil model of 30 min of UOCCA can be used to study mechanisms of infarction and/or regional selective neuronal death/loss as well as neurological dysfunction following UOCCA. PMID- 30443769 TI - Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer's. AB - Alzheimer's disease (AD) is a fastest growing neurodegenerative condition with no standard treatment. There are growing evidence about the beneficial effects of exercise in brain health promotion and slowing the cognitive decline. The aim of this study was to review the protective mechanisms of treadmill exercise in different models of rodent memory deficits. Online literature database, including PubMed-Medline, Scopus, Google scholar were searched from 2003 till 2017. Original article with English language were chosen according to following key words in the title: (exercise OR physical activity) AND (memory OR learning). Ninety studies were finally included in the qualitative synthesis. The results of these studies showed the protective effects of exercise on AD induced neurodegerative and neuroinflammatory process. Neuroperotective effects of exercise on the hippocampus seem to be increasing in immediate-early gene c-Fos expression in dentate gyrus; enhancing the Wnt3 expression and inhibiting glycogen synthase kinase-3beta expression; increasing the 5-bro-mo-2'-deoxyridine positive and doublecortin-positive cells (dentate gyrus); increasing the level of astrocytes glial fibrillary acidic protein and decrease in S100B protein, increasing in blood brain barrier integrity; prevention of oxidative stress injury, inducing morphological changes in astrocytes in the stratum radiatum of cornu ammonis 1(CA1) area; increase in cell proliferation and suppress apoptosis in dentate gyrus; increase in brain-derived neurotrophic factor and tropomyosin receptor kinase B expressions; enhancing the glycogen levels and normalizing the monocarboxylate transporter 2 expression. PMID- 30443770 TI - Increased Expression of GARP in Papillary Thyroid Carcinoma. AB - Regulatory T cells (Tregs) are immunosuppressive immune cells that play an important role in tumor development. Suppression of Treg function is considered to be an effective strategy for cancer therapy. Glycoprotein A repetitions predominant (GARP) has been found on the surface of activated Tregs. GARP has been recently observed in only a few solid tumors including breast, colon, lung cancers, and melanoma. However, its function in cancers remains unknown. Here, we investigated the expression of GARP in human papillary thyroid carcinoma (PTC) and its prognostic significance. In this study, immunohistochemistry was performed to examine the expression of GARP and Foxp3 in 19 human PTC tissues (including 10 cases with and 9 cases without lymph node metastasis) and 20 benign thyroid diseases (including 10 cases with nodular goiter and 10 cases with adenoma). Compared with benign thyroid diseases, we found a significant increase in the expression of GARP in PTC. Increased GARP expression in PTC was positively correlated with increased expression of Foxp3, which is very important for development of Tregs. But, there is no significant association of elevated expression of GARP with lymph node metastasis in PTC. Our results indicate that GARP is implicated in the development of PTC and might be a potential novel target for anticancer therapy. In addition, our findings further support the existence of a positive-feedback loop between GARP and Foxp3. PMID- 30443771 TI - Correction to: Affinity capillary electrophoresis for identification of active drug candidates in myotonic dystrophy type 1. AB - Unfortunately the name of Jean Jacques Vanden Eynde was missing as co-author of this contribution. The correct list of authors is: Ioan O. Neaga, Stephanie Hambye, Ede Bodoki, Claudio Palmieri, Jean Jacques Vanden Eynde, Eugenie Ansseau, Alexandra Belayew, Radu Oprean, Bertrand Blankert. PMID- 30443772 TI - Silvio Vaz Jr.: Analytical chemistry applied to emerging pollutants. PMID- 30443773 TI - Label-free targeted LC-ESI-MS2 analysis of human milk oligosaccharides (HMOS) and related human milk groups with enhanced structural selectivity. AB - Human milk (HM) supports the healthy development of neonates and exerts many of its beneficial effects via contained free human milk oligosaccharides (HMOS). These HMOS exhibit a complexity and structural diversity that pose a significant analytical challenge. A detailed characterization of HMOS is essential as every individual structure may have a different function/activity. Certain HMOS isomers may even fundamentally differ in their biological function, and especially their characterization by LC or LC-MS is often impaired by co-elution phenomena. Thus, more efficient analytical methodologies with enhanced structural selectivity are required. Therefore, we developed a negative ion mode LC-ESI-MS2 approach featuring straightforward sample preparation, environmentally friendly EtOH gradient elution, and enhanced, semiquantitative characterization of distinct native HMOS by multiple reaction monitoring (MRM). Our MRM-LC-MS setup takes advantage of highly selective, glycan configuration-dependent collision-induced dissociation (CID) fragments to identify individual neutral and acidic HMOS. Notably, many human milk oligosaccharide isomers could be distinguished in a retention time-independent manner. This contrasts with other contemporary MRM approaches relying on rather unspecific MRM transitions. Our method was used to determine the most abundant human milk tri-, tetra-, penta-, and hexaoses semiquantitatively in a single LC-MS assay. Detected HMO structures included fucosyllactoses (e.g., 2'-FL), lacto-N-difucotetraose (LDFT), lacto-N-tetraoses (LNTs), lacto-N-fucopentaoses (e.g., LNFP I, LNFP II and III), lacto-N difucohexaoses (LNDFHs) as well as sialyllactoses (SLs) and tentatively assigned blood group A and B tetrasaccharides from which correct human milk type assignment could be also demonstrated. Correctness of milk typing was validated for milk groups I-IV by high pressure anion exchange chromatography (HPAEC) coupled to pulsed amperometric detection (HPAEC-PAD). Graphical Abstract ?. PMID- 30443774 TI - Elemental imaging (LA-ICP-MS) of zebrafish embryos to study the toxicokinetics of the acetylcholinesterase inhibitor naled. AB - The zebrafish embryo is an important model in ecotoxicology but the spatial distribution of chemicals and the relation to observed effects is not well understood. Quantitative imaging can help to gain insights into the distribution of chemicals in the zebrafish embryo. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is used to quantify the uptake and the uptake kinetics of the bromine (Br) containing organophosphate naled (Dibrom(r), dimethyl-1,2-dibromo-2,2-dichloroethylphosphate) and its distribution in zebrafish embryos using Br as the marker element. During exposure, the Br amounts increase in the embryos parallel to the irreversible inhibition of the acetylcholinesterase (AChE). The final amount of Br in the embryo (545 pmol/embryo) corresponds to a 280-fold enrichment of naled from the exposure solution. However, LC-MS/MS analyses showed that the internal concentration of naled remained below the LOD (7.8 fmol/embryo); also the concentration of its known transformation product dichlorvos remained low (0.85 to 2.8 pmol/embryo). These findings indicate the high reactivity and high transformation rate of naled to other products than dichlorvos. 12C normalized intensity distributions of Br in the zebrafish embryo showed an enrichment of Br in its head region. Kernel density estimates of the LA-ICP-MS data were calculated and outline the high reproducibility between replicated and the shift in the Br distribution during exposure. The Br enrichment indicates a preferential debromination or direct covalent reaction of naled with AChE in this region. Graphical abstract ?. PMID- 30443776 TI - [Annual Report 2016 of the German Pacemaker and Defibrillator-Register. Part 1: Pacemaker : Working Group on Pacemaker and Defibrillators at the IQTIG-Institute for quality assurance and transparency in healthcare]. PMID- 30443777 TI - Clinical and radiological short-term outcomes of pubic symphysis diastasis treated with modified pedicle screw-rod fixation. AB - PURPOSE: Pubic symphysis diastasis with an incidence of approximately 20% in pelvic fractures is a severe lesion which needs to be treated properly. The objective of this retrospective study was to describe and evaluate the clinical and radiological outcomes including its advantages and limitations of this modified minimal invasive technique. METHODS: Totally 29 patients with pubic symphysis diastasis, with or without posterior ring instability, were treated by modified pedicle screw-rod fixation (modified PSRF) between January 2010 and December 2016. The duration from injury to surgery, operation time, intraoperative blood loss as well as complications were recorded. During follow up, the functional outcomes were assessed according to the Majeed evaluation criteria 1 year postoperatively. The evaluation of the postoperative reduction quality was carried out according to Matta criteria. RESULTS: According to Tile classification, there were 9 cases of Type B1 underwent only anterior-modified PSRF and 20 cases of Type C1 experienced anterior-modified PSRF combined with posterior fixation. The duration from injury to operation, operation time and intraoperative blood loss were 3.27 days (range 1-6 days), 42.07 min (range 38-45 min), and 46.14 ml (range 40-55 ml). The results of reduction quality were rated as excellent in 16, good in 11 and fair in 2 based on Matta criteria. The Majeed functional scores ranged from 68 to 95 and there were excellent in 15, good in 12 and fair in 2. No patients experienced incision infection. Slight loosening of middle-two screws was verified during follow-up in one patient. Two patients underwent femoral nerve palsy. Irritation to the LFCN was detected in four patients. CONCLUSIONS: Modified PSRF can be performed as an alternative to manage pubic symphysis diastasis due to its merits of minimal invasive, less blood loss, less soft tissue injuries as well as shorter operation time, even with the early weight-bearing. TRIAL REGISTRATION: Researchregistry3905. PMID- 30443778 TI - Customized virtual surgical planning in bimaxillary orthognathic surgery: a prospective randomized trial. AB - OBJECTIVES: The aim of the present study was to compare conventional (CSP) versus customized virtual surgical planning (VSP) in bimaxillary orthognathic surgery. The primary goal was to compare the accuracy of defined angles. The secondary purpose was to analyze the accuracy of the splints, the time required for surgery, and the costs of both methods. MATERIALS AND METHODS: A total of 21 patients (nCSP = 12; nVSP = 9) treated by two-jaw orthognathic surgery were analyzed prospectively between the years 2014 and 2016. Customized VSP consisted of virtual planning as well as CAD/CAM printing of splints and pre-bent osteosynthesis plates. The evaluated parameters were the difference between planned and postoperative situation (SNA/SNB/ANB), accuracy of splints, time required for surgery (min), and total costs of planning (?). RESULTS: When compared to CSP, VSP appears to be a more accurate method for orthognathic treatment planning with significant differences in the angle outcome (SNA p < 0.001; SNB p = 0.002; ANB p < 0.001). There were significant differences in splint accuracy in favor of CAD/CAM splints (p = 0.007). VSP significantly reduced the duration of operation (p = 0.041). Nevertheless, VSP increased the total costs (481.80 ? vs. 884.00 ?). CONCLUSIONS: When using virtual 3D technology in combination with printed acrylic splints, 3D models of the jaws and pre-bent osteosynthesis, there is a noticeable reduction in the duration of the operation in conjunction with an improvement in accuracy. CLINICAL RELEVANCE: Virtual model surgery and the prefabrication of splints and plates may replace traditional orthognathic surgery as it becomes cost-effective. PMID- 30443775 TI - Synthesis and Characterization of Hierarchical ZSM-5 Zeolites with Outstanding Mesoporosity and Excellent Catalytic Properties. AB - A novel soft-template (ST) is fabricated and successfully employed as mesoporogen to synthesis hierarchical ZSM-5 zeolites with outstanding mesoporosity and high hierarchy factors. The as-produced soft-template can connect steadily with the MFI frameworks by covalent bonds of -Si-O-Si- during the high-temperature hydrothermal crystallization process. This type of connection mode can effectively avoid the formation of amorphous materials, and the specific structure of this soft-template can efficiently introduce plentiful of mesopores with few micropores being consumed. The particles of as-synthesized hierarchical ZSM-5 zeolites are in size of about 1 MUm, which are made up of nanocrystals of 60-150 nm. The structure parameters of these samples are characterized with the techniques of X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, nitrogen sorption, scanning electron microscope (SEM), transmission electron microscope (TEM), NH3 temperature-programmed desorption (NH3-TPD) and thermogravimetric (TG). Due to the nature of zeolites and great microporosity, these hierarchical samples present great tolerance of hydrothermal treatment. And because of the intracrystalline mesopores, large external surface areas, and abundant accessible acid sites, whether in conversion rate of reactants or selectivity of products, the hierarchical samples exhibit excellent catalytic performance in the reactions of alkylation between benzene and benzyl alcohol, cracking of 1,3,5-tri-isopropylbenzene, and thermal cracking of low-density polyethylene (LDPE), respectively. PMID- 30443779 TI - Insulin pump settings and glucose patterns during a 1008-km non-stop bicycle race in a patient with type 1 diabetes mellitus. PMID- 30443781 TI - The incidence and recovery rate of idiopathic vocal fold paralysis: a population based study. AB - PURPOSE: To determine the incidence and spontaneous recovery rate of idiopathic vocal fold paralysis (IVFP) and paresis (IVFp), and the impact of steroid treatment on rates of recovery. METHODS: This retrospective cohort study included all patients with IVFP or IVFp within a large integrated health-care system between January 1, 2008 and December 31, 2014. Patient demographics and clinical characteristics, including time to diagnosis, spontaneous recovery status, time to recovery, and treatment, were examined. RESULTS: A total of 264 patients were identified, 183 (69.3%) with IVFP and 81 (30.7%) with IVFp. Nearly all cases (96.6%) were unilateral and 89.8% of patients were over the age of 45. The combined (IVFP and IVFp) 7-year mean incidence was 1.04 cases per 100,000 persons each year with the highest 7-year mean annual incidence in white patients (1.60 per 100,000). The total rate of spontaneous recovery was 29.5%, where 21.2% had endoscopic evidence of resolution and 8.3% had clinical improvement in their voice without endoscopic confirmation. The median time to symptom resolution was 4.0 months. Use of steroids was not linked with spontaneous recovery in multivariable analyses. CONCLUSION: The annual incidence of VFP (IVFP and IVFp) was 1.04 cases per 100,000 persons, with spontaneous recovery occurring in nearly a third of patients, regardless of steroid use. PMID- 30443780 TI - Outpatient parenteral antimicrobial therapy and antibiotic stewardship: opponents or teammates? AB - PURPOSE: This narrative review aims to describe barriers of outpatient parenteral antimicrobial therapy at home (OPAT), potentially compromising general standards of antibiotic stewardship (ABS) and facilitators of OPAT for ABS. METHODS: After a literature review, five authors determined the barriers and facilitators to discuss in this review. RESULTS: Sixty-six publications were included in the narrative review and seven barriers and five facilitators are discussed in this article. The impracticability of multiple daily dosing during OPAT, the impact of real-life temperature variations, deviations of the infusion rates of elastomeric devices, access to prolonged intravenous antibiotic therapy, not administering loading doses before the initiation of extended or continuous infusions and the transmural nature of care associated with OPAT, can lead to deviations of recommended treatment regimens and sub-optimal clinical and laboratory follow-up, with a risk of inferior clinical outcomes, adverse events, drug-resistance and higher costs. On the other hand, OPAT provides access to treatments with intravenous antibiotics and simultaneously avoids prolonged hospitalization. CONCLUSION: Implementing ABS guidelines in OPAT programs, e.g., by using a multidisciplinary team approach and facility-specific protocols for OPAT with patient selection criteria and instructions for selection, storage, preparation and administration of antibiotics, can improve appropriate antibiotic use. Additionally, further research should examine the effectiveness of these interventions on outcomes of OPAT. PMID- 30443782 TI - Increasing complexity in oncology phase I clinical trials. AB - Clinical trials in oncology have become increasingly complex because of incorporation of predictive biomarkers and patient selection based on molecular profiling of tumors. We have examined the change in procedures and work intensity in phase 1 oncology trials over the years with several parameters used as surrogates of complexity. Categories that were included as events were clinical evaluations, pharmacokinetic (PK) laboratory tests, non-PK laboratory tests, specific molecular or histological characteristics, questionnaires and subjective assessments, routine clinical and physical examinations, imaging, invasive procedures and others. The information was extracted using a standardized form including study type, tumor type, information on agent, participant characteristics and study mandated events during the first 3 cycles of each protocol. A total of 102 phase I oncology and hematology study protocols that were active at a single institution in 1996, 2006 and 2016 were evaluated. In 2016, there were significantly more (P < 0.05) median number of procedures, outpatient tests, subjective assessments, PK's, molecular profiling, biopsies and medication dispensing times. There were higher median numbers of procedures in studies in hematologic malignancies, testing immunotherapies and those with over 15 inclusion or exclusion criteria. These values also differed significantly (P < .005) when the median values were compared in nonparametric tests. Our results suggest that study related procedures in cancer phase I trials have substantially increased over the last two decades. The successful conduct of early-phase oncology clinical trials in future will require additional research resources. PMID- 30443783 TI - Chromatin architecture and virulence-related gene expression in eukaryotic microbial pathogens. AB - A fundamental question in biology is to understand how appropriate transcriptional regulation and dense packaging of the genetic material within the eukaryotic nucleus are achieved. The exquisite gene expression control and other metabolic processes of DNA require a highly complex, multilayered, three dimensional architecture of the chromatin and its specific compartmentalization within the nucleus. Some of these architectural and sub-nuclear positioning mechanisms have been extensively co-opted by eukaryotic pathogens to keep fine expression control and expansion of virulence-related gene families in Plasmodium falciparum, Trypanosoma brucei and Candida glabrata. For example non-linear interactions between distant cis-acting regions and the formation of chromatin loops are required for appropriate regulation of the expression of virulence related multi-gene families encoding cell surface proteins. These gene families are located near the chromosome ends and tethered to the nuclear periphery. Consequently, only one or very few genes of the family are expressed at a time. These genes are involved in antigenic variation in parasites and the generation of subpopulations of cells with diverse antigenic proteins at the surface in some pathogenic fungi, making them highly efficient pathogens. PMID- 30443784 TI - Sleep- and Wake-Like States in Small Networks In Vivo and In Vitro. AB - Wakefulness and sleep are highly complex and heterogeneous processes, involving multiple neurotransmitter systems and a sophisticated interplay between global and local networks of neurons and non-neuronal cells. Macroscopic approaches applied at the level of the whole organism, view sleep as a global behaviour and allow for investigation into aspects such as the effects of insufficient or disrupted sleep on cognitive function, metabolism, thermoregulation and sensory processing. While significant progress has been achieved using such large-scale approaches, the inherent complexity of sleep-wake regulation has necessitated the development of methods which tackle specific aspects of sleep in isolation. One way this may be achieved is by investigating specific cellular or molecular phenomena in the whole organism in situ, either during spontaneous or induced sleep-wake states. This approach has greatly advanced our knowledge about the electrophysiology and pharmacology of ion channels, specific receptors, intracellular pathways and the small networks implicated in the control and regulation of the sleep-wake cycle. Importantly though, there are a variety of external and internal factors that influence global behavioural states which are difficult to control for using these approaches. For this reason, over the last few decades, ex vivo experimental models have become increasingly popular and have greatly advanced our understanding of many fundamental aspects of sleep, including the neuroanatomy and neurochemistry of sleep states, sleep regulation, the origin and dynamics of specific sleep oscillations, network homeostasis as well as the functional roles of sleep. This chapter will focus on the use of small neuronal networks as experimental models and will highlight the most significant and novel insights these approaches have provided. PMID- 30443785 TI - Clinical and Experimental Human Sleep-Wake Pharmacogenetics. AB - Sleep and wakefulness are highly complex processes that are elegantly orchestrated by fine-tuned neurochemical changes among neuronal and non-neuronal ensembles, nuclei, and networks of the brain. Important neurotransmitters and neuromodulators regulating the circadian and homeostatic facets of sleep-wake physiology include melatonin, gamma-aminobutyric acid, hypocretin, histamine, norepinephrine, serotonin, dopamine, and adenosine. Dysregulation of these neurochemical systems may cause sleep-wake disorders, which are commonly classified into insomnia disorder, parasomnias, circadian rhythm sleep-wake disorders, central disorders of hypersomnolence, sleep-related movement disorders, and sleep-related breathing disorders. Sleep-wake disorders can have far-reaching consequences on physical, mental, and social well-being and health and, thus, need be treated with effective and rational therapies. Apart from behavioral (e.g., cognitive behavioral therapy for insomnia), physiological (e.g., chronotherapy with bright light), and mechanical (e.g., continuous positive airway pressure treatment of obstructive sleep apnea) interventions, pharmacological treatments often are the first-line clinical option to improve disturbed sleep and wake states. Nevertheless, not all patients respond to pharmacotherapy in uniform and beneficial fashion, partly due to genetic differences. The improved understanding of the neurochemical mechanisms regulating sleep and wakefulness and the mode of action of sleep-wake therapeutics has provided a conceptual framework, to search for functional genetic variants modifying individual drug response phenotypes. This article will summarize the currently known genetic polymorphisms that modulate drug sensitivity and exposure, to partly determine individual responses to sleep-wake pharmacotherapy. In addition, a pharmacogenetic strategy will be outlined how based upon classical and opto-/chemogenetic strategies in animals, as well as human genetic associations, circuit mechanisms regulating sleep-wake functions in humans can be identified. As such, experimental human sleep-wake pharmacogenetics forms a bridge spanning basic research and clinical medicine and constitutes an essential step for the search and development of novel sleep-wake targets and therapeutics. PMID- 30443786 TI - Functional Interactions Between Sleep and Circadian Rhythms in Learning and Learning Disabilities. AB - The propensity for sleep is timed by the circadian system. Many studies have shown that learning and memory performance is affected by circadian phase. And, of course it is well established that critical processes of memory consolidation occur during and depend on sleep. This chapter presents evidence that sleep and circadian rhythms do not just have separate influences on learning and memory that happen to coincide because of the circadian timing of sleep, but rather sleep and circadian systems have a critical functional interaction in the processes of memory consolidation. The evidence comes primarily from research on two models of learning disability: Down's syndrome model mice and Siberian hamsters. The Down's syndrome model mouse (Ts65Dn) has severe learning disability that has been shown to be due to GABAergic over-inhibition. Short-term, chronic therapies with GABAA antagonists restore learning ability in these mice long term, but only if the antagonist treatments are given during the dark or sleep phase of the daily rhythm. The Siberian hamster is a model circadian animal except for the fact that a light treatment that gives the animal a phase advance on one day and a phase delay on the next day can result in total circadian arrhythmia for life. Once arrhythmic, the hamsters cannot learn. Learning, but not rhythmicity, is restored by short-term chronic treatment with GABA antagonists. Like many other species, if these hamsters are made arrhythmic by SCN lesion, their learning is unaffected. However, if made arrhythmic and learning disabled by the light treatment, subsequent lesions of their SCNs restore learning. SCN lesions also appear to restore learning in the Ts65Dn mice. The collective work on these two animal models of learning disability suggests that the circadian system modulates neuroplasticity. Our hypothesis is that a previously unrecognized function of the circadian system is to dampen neuroplasticity during the sleep phase to stabilize memory transcripts during their transfer to long-term memory. Thus, sleep and circadian systems have integrated roles to play in memory consolidation and do not just have separate but coincident influences on that process. PMID- 30443787 TI - Modulation of the Immune System in Chronic Hepatitis C and During Antiviral Interferon-Free Therapy. AB - The treatment of patients with chronic hepatitis C virus (HCV) infection has changed tremendously over the past 2 years, with an increasing variety of all oral direct-acting antiviral (DAA) treatment regimens available for different HCV genotypes and distinct clinical settings. These treatments have significantly improved safety in patients with advanced liver disease compared with interferon (IFN)-based regimens. HCV modifies the human immune system to escape immunosurveillance via several mechanisms. One of the basic mechanisms of HCV is the ability to "switch" the immune response by reducing the activity of cells responsible for the elimination of virus-infected cells. IFN-free DAA treatment regimens provide a unique opportunity to assess the effect of HCV elimination on the immune system. Abrupt changes in the immune system can in some cases be responsible for two alarming processes: viral reactivation in patients with chronic hepatitis B and recurrence of hepatocellular carcinoma in patients with previous successful cancer treatment. PMID- 30443788 TI - Fluorometric determination of hydroquinone by using blue emitting N/S/P-codoped carbon dots. AB - N/S/P-codoped carbon dots (CDs) are shown to be a viable fluorescent probe in a turn-off-on fluorometric assay for hydroquinone (HQ). The preparation of CDs was carried out using a one-step hydrothermal reaction starting with glyoxal and isocarbophos. The method is based on the formation of ground state complexes between CD and Fe(III) which leads to quenching of blue fluorescence (with excitation/emission peaks at 363/448 nm). On addition of HQ, it will be oxidized by Fe(III) upon which fluorescence recovers. This turn-off-on system can be utilized to quantify HQ. A linear relationship exists between fluorescence recovery and HQ concentration in range between 0.56 and 375 MUM. The limit of detection is 0.16 MUM. The assay was successfully applied to the determination of HQ in spiked water samples and developer samples. Graphical abstract Fluorometric determination of hydroquinone (with good selectivity over catechol and resorcinol) by using blue-emitting N/S/P-codoped carbon dots and the quenching effect of Fe(III). PMID- 30443790 TI - Sclerostin rather than Dickkopf-1 is associated with mSASSS but not with disease activity score in patients with ankylosing spondylitis. AB - OBJECTIVE: To determine the serum levels of Dickkopf-1 (DKK-1) and sclerostin, as well as their correlations with the structural damage assessed by modified stoke ankylosing spondylitis spine score (mSASSS) and the disease activity evaluated by ankylosing spondylitis disease activity score (ASDAS) in patients with ankylosing spondylitis (AS). METHODS: Eighty-eight AS patients, 26 rheumatoid arthritis (RA) patients, and 26 age- and gender-matched healthy controls (HC) were collected from rheumatic clinic of the Second Affiliated Hospital of Zhejiang University, School of Medicine, between March 2015 and July 2015. Demographic data, parameters of ASDAS, and image evaluations of spine (i.e., mSASSS) were collected. The serum levels of DKK-1 and sclerostin were measured using commercially available ELISA kits. RESULTS: Both DKK-1 and sclerostin were significantly higher in the AS patients than in the controls (1855 +/- 84.58 vs. 1406 +/- 99.76 pg/ml and 106 +/- 6.75 vs. 62.78 +/- 6.39 pmol/l, respectively, P < 0.05). The correlation analysis suggested a negative correlation between serum sclerostin and mSASSS (P = 0.019, r2 = 0.062). DKK-1 had a trend of positive correlation with mSASSS, but was not statistically significant (P > 0.05). There was no association between the serum levels of DKK-1 or sclerostin and disease activity assessed by ASDAS (P > 0.05). DKK-1 and sclerostin had a negative correlation (P = 0.013, r2 = 0.07). CONCLUSION: In the present study, the expressions of serum DKK-1 and sclerostin were independent of disease activity. Sclerostin was negatively correlated with the mSASSS, which suggests that sclerostin may be a potential marker indicating the spine ossification process in AS. The specific mechanism remains to be investigated. PMID- 30443789 TI - Development and validation of a delayed presenting clubfoot score to predict the response to Ponseti casting for children aged 2-10. AB - The aim of the study was to develop a simple and reliable clinical scoring system for delayed presenting clubfeet and assess how this score predicts the response to Ponseti casting. We measured all elements of the Dimeglio and the Pirani scoring systems. To determine which aspects were useful in assessing children with delayed presenting clubfeet, 4 assessors examined 42 feet (28 patients) between the ages of 2-10 years. Selected variables demonstrating good agreement were combined to make a novel score and were assessed prospectively on a separate consecutive cohort of children with clubfeet aged 2-10, comprising 100 clubfeet (64 patients). Inter-observer and intra-observer agreement was found to be greatest using the following clinically measured angles of the deformities. These were plantaris, adductus, varus, equinus of the ankle and rotation around the talar head in the frontal plane (PAVER). Measured angles of 1-20, 21-45 and > 45 degrees scored 1, 2 and 3 points, respectively. The PAVER score was derived from both the sum of points derived from measured angles and a multiplier according to age. The sum of the points was multiplied with 1, 1.5 or 2 for ages 2-4, 5-7 and 8-10, respectively. This demonstrated a good association with the total number of casts to achieve a full correction (tau = 0.71). A score greater than 18 out of 30 indicated a cast-resistant clubfoot. The score could be used clinically for prognosis and treatment, and for research purposes to compare the severity of clubfoot deformities. PMID- 30443791 TI - A new classification for proximal femur bone defects in conservative hip arthroplasty revisions. AB - INTRODUCTION: In last three decades, total hip replacement in young patients became an habitual procedure. Principles of bone preservation are pushing many surgeons to implant conservative femoral components in patient younger than 65 years. Despite an overall good survivorship and clinical outcomes of conservative implants, failed cases are reported and the need to revise a conservative femoral component became an occasional procedure (with high prevalence of failed resurfacing implants). METHODS: During conservative femoral component revisions, we analyzed proximal bone stock preservation, considering the type of original component removed, aetiology of failure, timing of revision, and femoral explantation technique. RESULTS: We identified four patterns of proximal femoral changes (types I-IV). We suggest, for each of them, a revision strategy directed toward a "conservative revision procedure" using conservative or primary component. Out of our 21 cases, none underwent further revision due to mechanical failure (follow-up ranging from 6 to 152 months, mean 54 months). We had two cases of re-operation: one for early septic loosening and one for prosthetic modular neck fracture. CONCLUSIONS: If literature offers well-established guidelines to femoral revision of conventional stems, there is, on the other hand, a lack of data about revision strategies in presence of failed conservative implants. Although the mean follow-up of our procedures is still too short (4.5 years) to give final conclusions, we would leave a message: a conservative hip arthroplasty is not a "one time" opportunity for young and active people. A "conservative revision" is a valid option for at least a part of them, when an early failure of primary procedure occurred. PMID- 30443792 TI - Correction to: Pharmacological characterization of the LSD analog N-ethyl-N cyclopropyl lysergamide (ECPLA). AB - The author of this article wanted to change the Acknowledgments section to: These studies were supported by an award from NIDA (R01 DA041336), as well as by the Veteran's Administration VISN 22 Mental Illness Research, Education, and Clinical Center. Receptor binding and functional data were generously. PMID- 30443793 TI - Single stimulation of Y2 receptors in BNSTav facilitates extinction and dampens reinstatement of fear. AB - RATIONALE: Return of fear by re-exposure to an aversive event is a major obstacle in the treatment of fear-related disorders. Recently, we demonstrated that local pharmacological stimulation of neuropeptide Y type 2 receptors (Y2R) in anteroventral bed nucleus of stria terminalis (BNSTav) facilitates fear extinction and attenuates retrieval of remote fear with or without concomitant extinction training. Whether Y2R activation could also protect against re exposure to traumatic events is still unknown. OBJECTIVE: Therefore, we investigated reinstatement of remote fear following early Y2R manipulation in BNSTav in relation to concomitant extinction training in mice. METHODS: We combined local pharmacological manipulation of Y2Rs in BNSTav with or without extinction training and tested for reinstatement of remote fear 15 days later. Furthermore, we employed immediate early gene mapping to monitor related local brain activation. RESULTS: Y2R stimulation by local injection of NPY3-36 into BNSTav facilitated extinction, reduced fear reinstatement at remote stages, and mimicked the influence of extinction in groups without prior extinction training. In contrast, Y2R antagonism (JNJ-5207787) delayed extinction and increased reinstatement. Y2R treatment immediately before remote fear tests had no effect. Concomitantly, Y2R activation at early time points reduced the number of c-Fos positive neurons in BNSTav during testing of reinstated remote fear. CONCLUSION: Local Y2R stimulation in BNSTav promotes fear extinction and stabilizes suppression of reinstated fear through a long-term influence, even without extinction training. Thus, Y2Rs in BNST are crucial pharmacological targets for extinction-based remote fear suppression. PMID- 30443794 TI - Incidence and predictors of acute akathisia in severely ill patients with first episode schizophrenia treated with aripiprazole or risperidone: secondary analysis of an observational study. AB - RATIONALE: In the antipsychotic treatment of schizophrenia with little medication history, especially in drug-naive cases, predictors of side effects are important. However, predictors of antipsychotic-induced akathisia remain unclear. OBJECTIVES: This study aimed to investigate the incidence and predictors of acute akathisia in severely ill patients with first-episode schizophrenia spectrum disorders (FES). METHODS: This is a secondary analysis of our retrospective observational study. Data were obtained from 129 consecutive patients with FES involuntarily hospitalized in a tertiary psychiatric public hospital and treated with aripiprazole or risperidone. The primary outcome was the presence of acute akathisia during the first 1 month. A Cox proportional hazard model was used to examine significant predictors of the onset of akathisia. RESULTS: Acute akathisia was diagnosed in 54 patients (42%). Neither antipsychotics (aripiprazole or risperidone), duration of untreated psychosis, iron deficiency, sex, age nor baseline symptomatic severity was identified as an independent predictor of akathisia. Rapid risperidone initiation significantly increased the onset of akathisia (adjusted hazard ratio [HR], 6.47; 95%; 95% confidence interval [CI], 1.94-21.65; p = 0.002), but rapid aripiprazole initiation did not (adjusted HR, 1.08; 95% CI, 0.50-2.31; p = 0.84). A significant interaction was found between rapid antipsychotic initiation and the risk of akathisia with aripiprazole versus risperidone (p = 0.027). CONCLUSIONS: Severely ill patients with FES initiating aripiprazole or risperidone could have a high risk for akathisia. Rapid risperidone initiation should be avoided because of the risk for akathisia, and careful monitoring of akathisia may be necessary for all patients initiating aripiprazole. PMID- 30443795 TI - Heroin versus cocaine: opposite choice as a function of context but not of drug history in the rat. AB - RATIONALE: Previous studies have shown that rats trained to self-administer heroin and cocaine exhibit opposite preferences, as a function of setting, when tested in a choice paradigm. Rats tested at home prefer heroin to cocaine, whereas rats tested outside the home prefer cocaine to heroin. Here, we investigated whether drug history would influence subsequent drug preference in distinct settings. Based on a theoretical model of drug-setting interaction, we predicted that regardless of drug history rats would prefer heroin at home and cocaine outside the home. METHODS: Rats with double-lumen catheters were first trained to self-administer either heroin (25 MUg/kg) or cocaine (400 MUg/kg) for 12 consecutive sessions. Twenty-six rats were housed in the self-administration chambers (thus, they were tested at home), whereas 30 rats lived in distinct home cages and were transferred to self-administration chambers only for the self administration session (thus, they were tested outside the home). The rats were then allowed to choose repeatedly between heroin and cocaine within the same session for seven sessions. RESULTS: Regardless of the training drug, the rats tested outside the home preferred cocaine to heroin, whereas the rats tested at home preferred heroin to cocaine. There was no correlation between drug preference and drug intake during the training phase. CONCLUSION: Drug preferences were powerfully influenced by the setting but, quite surprisingly, not by drug history. This suggests that, under certain conditions, associative learning processes and drug-induced neuroplastic adaptations play a minor role in shaping individual preferences for one drug or the other. PMID- 30443796 TI - Evaluation of the INTERPRET decision-support system: can it improve the diagnostic value of magnetic resonance spectroscopy of the brain? AB - PURPOSE: We evaluated in a clinical setting the INTERPRET decision-support system (DSS), a software generated to aid in MRS analysis to achieve a specific diagnosis for brain lesions. METHODS: The material consisted of 100 examinations of focal intracranial lesions with confirmed diagnoses. MRS was obtained at 1.5 T using TE 20-30 ms. Data were processed with the LCModel for conventional analysis. The INTERPRET DSS 3.1. was used to obtain specific diagnoses. MRI and MRS were reviewed by one interpreter. DSS analysis was made by another interpreter, in 80 cases by two interpreters. The diagnoses were compared with the definitive diagnoses. For comparisons between DSS, conventional MRS analysis, and MRI, the diagnoses were categorised: high-grade tumour, low-grade tumour, non neoplastic lesion. RESULTS: Interobserver agreement in choosing the diagnosis from the INTERPRET database was 75%. The diagnosis was correct in 38/100 cases, incorrect in 57 cases. No good match was found in 5/100 cases. The diagnostic category was correct with DSS/conventional MRS/MRI in 67/58/52 cases, indeterminate in 5/8/20 cases, incorrect in 28/34/28 cases. Results with DSS were not significantly better than with conventional MRS analysis. All definitive diagnoses did not exist in the INTERPRET database. In the 61 adult patients with the diagnosis included in the database, DSS/conventional MRS/MRI yielded a correct diagnosis category in 48/32/29 cases (DSS vs conventional MRS: p = 0.002, DSS vs MRI: p = 0.0004). CONCLUSION: Use of the INTERPRET DSS did not improve MRS categorisation of the lesions in the unselected clinical cases. In adult patients with lesions existing in the INTERPRET database, DSS improved the results, which indicates the potential of this software with an extended database. PMID- 30443797 TI - Biotransformation of lanthanum by Aspergillus niger. AB - Lanthanum is an important rare earth element and has many applications in modern electronics and catalyst manufacturing. However, there exist several obstacles in the recovery and cycling of this element due to a low average grade in exploitable deposits and low recovery rates by energy-intensive extraction procedures. In this work, a novel method to transform and recover La has been proposed using the geoactive properties of Aspergillus niger. La-containing crystals were formed and collected after A. niger was grown on Czapek-Dox agar medium amended with LaCl3. Energy-dispersive X-ray analysis (EDXA) showed the crystals contained C, O, and La; scanning electron microscopy revealed that the crystals were of a tabular structure with terraced surfaces. X-ray diffraction identified the mineral phase of the sample as La2(C2O4)3.10H2O. Thermogravimetric analysis transformed the oxalate crystals into La2O3 with the kinetics of thermal decomposition corresponding well with theoretical calculations. Geochemical modelling further confirmed that the crystals were lanthanum decahydrate and identified optimal conditions for their precipitation. To quantify crystal production, biomass-free fungal culture supernatants were used to precipitate La. The results showed that the precipitated lanthanum decahydrate achieved optimal yields when the concentration of La was above 15 mM and that 100% La was removed from the system at 5 mM La. Our findings provide a new aspect in the biotransformation and biorecovery of rare earth elements from solution using biomass-free fungal culture systems. PMID- 30443798 TI - Phenotypic antibiotic susceptibility testing of pathogenic bacteria using photonic readout methods: recent achievements and impact. AB - The development of antibiotic resistances in common pathogens is an increasing challenge for therapy of infections and especially severe complications like sepsis. To prevent administration of broad-spectrum and potentially non-effective antibiotics, the susceptibility spectrum of the pathogens underlying the infection has to be determined. Current phenotypic standard methods for antibiotic susceptibility testing (AST) require the isolation of pathogens from the patient and the subsequent culturing in the presence of antibiotics leading to results only after 24-72 h. Since the early initialization of an effective antibiotic therapy is crucial for positive treatment result in severe infections, faster methods of AST are urgently needed. A large number of different assay systems are currently tested for their practicability for fast detection of antibiotic resistance profiles. They can be divided into genotypic ones which detect the presence of certain genes or gene products associated with resistances and phenotypic assays which determine the effect of antibiotics on the pathogens. In this mini-review, we summarize current developments in fast phenotypic tests that use photonic approaches and critically discuss their status. We further outline steps that are required to bring these assays into clinical practice. PMID- 30443799 TI - Impact on mindfulness, emotion regulation, and emotional overeating of a DBT skills training group: a pilot study. AB - PURPOSE: The current study investigated the impact of a modified Dialectical Behavior Therapy skills (DBT) training group for patients at a hospital outpatient weight management clinic. Emotional eating is a problematic strategy for managing unpleasant feelings that can have a deleterious impact on weight management. DBT addresses emotional dysregulation via incorporation of skills aimed at coping with unpleasant affect. METHODS: This study examines outcomes for 18 patients who participated in a 12-week DBT skills building group. A pre-post design with 3-month follow-up investigated the impact of the group on emotional eating, psychological distress, emotion regulation, and mindfulness. RESULTS: Four repeated measures ANOVAs were run to assess for changes related to life difficulties and functioning, emotional overeating, emotion regulation, and mindfulness. Fisher's LSD tests assessed for linear and quadratic trends. Improvements in mindfulness, emotion regulation, and emotional overeating were found; these were maintained at follow-up. CONCLUSIONS: This study demonstrated the utility of a group-based intervention aimed at improving emotion regulation and mindfulness skills among weight management patients. Further study is needed to determine whether improvements in the constructs studied in this research would translate to improved weight management outcomes and in determining the pathway for improvements. LEVEL OF EVIDENCE: Level IV, multiple time series with intervention. PMID- 30443800 TI - The Effect of Using Different Types of Forceps in the Efficacy of Transbronchial Lung Biopsy. AB - BACKGROUND: Transbronchial lung biopsy (TBBX) is a common respiratory diagnostic procedure performed to investigate several lung diseases. There are different types of forceps used to perform this procedure. The alligator and cupped (oval) forceps are most commonly used ones. To date, there are few studies that have compared the efficacy of these two types of forceps. This study compares the two types of forceps relating to the rate of complications and diagnostic value. METHODS: In this retrospective observational study, 40 patients who underwent TBBX using the alligator forceps were compared to a previous group of 40 patients who underwent the same procedure using the cupped forceps. The two groups were compared with respect to the rate of complications (bleeding and pneumothorax), diagnostic value and size of biopsies. RESULTS: The rate of complications was higher in patients who underwent TBBX using alligator forceps, in which seven patients (17.5%) had significant bleeding in the group that used alligator forceps versus three patients (7.5%) in cupped forceps group. Pneumothorax developed in three patients, all of whom were in the alligator forceps group. While there was no significant difference in the adequacy and size of the samples, the diagnostic yield was higher in the cupped forceps group. CONCLUSIONS: The results of the study showed that using cupped forceps in performing TBBX had fewer complications (pneumothorax and bleeding) and a higher diagnostic yield in comparison with alligator forceps, but the difference did not reach a statistical significant value. PMID- 30443802 TI - Taste responsiveness of Western chimpanzees (Pan troglodytes verus) to five food associated saccharides. AB - Using a two-bottle choice test of short duration, we determined taste preference thresholds for sucrose, fructose, glucose, lactose, and maltose in three Western chimpanzees (Pan troglodytes verus). Further, we assessed relative preferences for these five saccharides when presented at equimolar concentrations and determined taste preference difference thresholds for sucrose, that is, the smallest concentration difference at which the chimpanzees display a preference for one of the two options. We found that the chimpanzees significantly preferred concentrations as low as 20 mM sucrose, 40 mM fructose, and 80 mM glucose, lactose, and maltose over tap water. When given a choice between all binary combinations of these five saccharides presented at equimolar concentrations of 100, 200, and 400 mM, respectively, the animals displayed significant preferences for individual saccharides in the following order: sucrose > fructose > glucose = maltose = lactose. The taste difference threshold for sucrose, expressed as Weber ratio (DeltaI/I), was 0.3 and 0.4, respectively, at reference concentrations of 100 and 200 mM. The taste sensitivity of the chimpanzees to the five saccharides falls into the same range found in other primate species. Remarkably, their taste preference thresholds are similar, and with two saccharides even identical, to human taste detection thresholds. The pattern of relative taste preferences displayed by the chimpanzees was similar to that found in platyrrhine primates and to the pattern of relative sweetness as reported by humans. Taken together, the results of the present study are in line with the notion that taste sensitivity for food-associated carbohydrates may correlate positively with phylogenetic relatedness. Further, they support the notion that relative preferences for food-associated carbohydrates, but not taste difference thresholds, may correlate with dietary specialization in primates. PMID- 30443801 TI - A new methodology to derive 3D kinetic parametric FDG PET images based on a mathematical approach integrating an error model of measurement. AB - BACKGROUND: In FDG-PET, SUV images are hampered by large potential biases. Our aim was to develop an alternative method (ParaPET) to generate 3D kinetic parametric FDG-PET images easy to perform in clinical oncology. METHODS: The key points of our method are the use of a new error model of PET measurement extracted from a late dynamic PET acquisition of 15 min, centered over the lesion and an image-derived input function (IDIF). The 15-min acquisition is reconstructed to obtain five images of FDG mean activity concentration and images of its variance to model errors of PET measurement. Our approach is carried out on each voxel to derive 3D kinetic parameter images. ParaPET was evaluated and compared to Patlak analysis as a reference. Hunter and Barbolosi methods (Barbolosi-Bl: with blood samples or Barbolosi-Im: with IDIF) were also investigated and compared to Patlak. Our evaluation was carried on Ki index, the net influx rate and its maximum value in the lesion (Ki,max). RESULTS: This parameter was obtained from 41 non-small cell lung cancer lesions associated with 4 to 5 blood samples per patient, required for the Patlak analysis. Compare to Patlak, the median relative difference and associated range (median; [min;max]) in Ki,max estimates were not statistically significant (Wilcoxon test) for ParaPET (- 3.0%; [- 31.9%; 47.3%]; p = 0.08) but statistically significant for Barbolosi-Bl (- 8.0%; [- 30.8%; 53.7%]; p = 0.001), Barbolosi-Im (- 7.9%; [- 38.4%; 30.6%]; p = 0.007) or Hunter (32.8%; [- 14.6%; 132.2%]; p < 10- 5). In the Bland-Altman plots, the ratios between the four methods and Patlak are not dependent of the Ki magnitude, except for Hunter. The 95% limits of agreement are comparable for ParaPET (34.7%), Barbolosi-Bl (30.1%) and Barbolosi-Im (30.8%), lower to Hunter (81.1%). In the 25 lesions imaged before and during the radio chemotherapy, the decrease in the FDG uptake (DeltaSUVmax or DeltaKi,max) is statistically more important (p < 0.02, Wilcoxon one-tailed test) when estimated from the Ki images than from the SUV images (additional median variation of - 2.3% [- 52.6%; + 19.1%] for DeltaKi,max compared to DeltaSUVmax). CONCLUSION: None of the four methodologies is yet ready to replace the Patlak approach, and further improvements are still required. Nevertheless, ParaPET remains a promising approach, offering a non-invasive alternative to methods based on multiple blood samples and only requiring a late PET acquisition. It allows deriving Ki values, highly correlated and presenting the lowest relative bias with Patlak estimates, in comparison to the other methods we evaluated. Moreover, ParaPET gives access to quantitative information at the pixel level, which needs to be evaluated in the perspective of radiomic and tumour response. TRIAL REGISTRATION: NCT 02821936 ; May 2016. PMID- 30443803 TI - A combined banding method that allows the reliable identification of chromosomes as well as differentiation of AT- and GC-rich heterochromatin. AB - Sonstitutive heterochromatin areas are revealed by differential staining as C positive chromosomal regions. These C-positive bands may greatly vary by location, size, and nucleotide composition. CBG-banding is the most commonly used method to detect structural heterochromatin in animals. The difficulty in identification of individual chromosomes represents an unresolved problem of this method as the body of the chromosome is stained uniformly and does not have banding pattern beyond C-bands. Here, we present the method that we called CDAG for sequential heterochromatin staining after differential GTG-banding. The method uses G-banding followed by heat denaturation in the presence of formamide with consecutive fluorochrome staining. The new technique is valid for the concurrent revealing of heterochromatin position due to differential banding of chromosomes and heterochromatin composition (AT-/GC-rich) in animal karyotyping. PMID- 30443804 TI - Successful Outcomes with Insulin Degludec in Pregnancy: A Case Series. AB - Optimal glycaemic control pre-conception and throughout pregnancy is paramount to achieve the best outcomes and to minimise the risk of complications for the mother and baby. Current long-acting insulin analogues that have been approved by the National Institute for Health and Care Excellence in the UK for use in pregnancy include glargine and detemir. In many patients, these treatments have limitations because of their pharmacokinetic properties thus not enabling optimal glycaemic control. Efforts at rapidly achieving the recommended blood glucose targets with these analogues can be associated with recurrent and/or disabling hypoglycaemia. Degludec is a second-generation ultra-long-acting insulin analogue, which has been shown to mimic endogenous basal insulin production by the pancreas. This may offer patients better control with less hypoglycaemia where first-generation insulins fail. There are currently no randomised controlled studies to support the use of insulin degludec in pregnancy. We report three cases of women who were on insulin degludec during pregnancy and achieved successful outcomes. Two of them were commenced on this during pregnancy because of hypoglycaemia with licenced insulin therapy. All the women showed an improvement in glycaemic control during pregnancy. There was attenuation of a wide glycaemic variability as demonstrated by a continuous glucose monitoring (CGM) system in one of the patients. They all delivered healthy babies. This case series highlights the urgent need for large randomised control trials to establish the safety and efficacy of insulin degludec in pregnancy. PMID- 30443805 TI - Can arbuscular mycorrhizal fungi from non-invaded montane ecosystems facilitate the growth of alien trees? AB - It is generally assumed that recruitment and expansion of alien species along elevation gradients are constrained by climate. But, if plants are not fully constrained by climate, their expansion could be facilitated or hindered by other factors such as biotic interactions. Here, we assessed the composition of arbuscular mycorrhizal fungi (AMF) in soils along an elevation gradient (i.e. 900 m, 1600 m, 2200 m and 2700 m a.s.l.) through a fungal DNA meta-barcoding approach. In addition, we studied in the greenhouse the effects of AMF on growth and phosphorous (P) nutrition of seedlings of the alien trees Gleditsia triacanthos, Ligustrum lucidum and Pyracantha angustifolia cultivated in soils from those elevations, spanning the elevation at which they already form monospecific stands (below 1450 m a.s.l.) and higher elevations, above their current range of distribution in montane ecosystems of Central Argentina. For comparison, we also included in the experiment the dominant native tree Lithraea molleoides that historically occurs below 1300 m a.s.l. Arbuscular mycorrhizal fungal community composition showed strong community turnover with increasing elevation. The effects of these AMF communities on plant growth and nutrition differed among native and alien trees. While P nutrition in alien species' seedlings was generally enhanced by AMF along the whole gradient, the native species benefited only from AMF that occur in soils from the elevation corresponding to its current altitudinal range of distribution. These results suggest that AMF might foster upper range expansion of these invasive trees over non-invaded higher elevations. PMID- 30443806 TI - A Systematic Review and Meta-analysis of Antiretroviral Therapy (ART) Adherence Interventions for Women Living with HIV. AB - A systematic review and meta-analysis was conducted to determine the efficacy of women-focused ART adherence interventions. Included studies (a) reported on a behavioral ART adherence intervention for cis-women living with HIV, (b) measured ART adherence as an outcome, and (c) employed a randomized controlled trial design. Thirteen studies were included in the meta-analysis. Overall, interventions significantly improved ART adherence compared to control conditions (random-effects d = 0.82, 95% CI [0.18, 1.45], p = 0.01), however, this was largely driven by two studies that had effect sizes greater than 3 standard errors above the mean effect size. Key moderators were location, recruitment method, group-based intervention, and alteration of the healthcare system. Innovative behavioral interventions that focus on young women and adolescents, target the critical periods of pregnancy and postpartum and test the integration of multiple levels of intervention to create lasting effects on ART adherence are needed. PMID- 30443808 TI - Time-trial performance is not impaired in either competitive athletes or untrained individuals following a prolonged cognitive task. AB - It has been reported that mental fatigue decreases exercise performance during high-intensity constant-work-rate exercise (CWR) and self-paced time trials (TT) in recreationally-trained individuals. The purpose of this study was to determine whether performance is impaired following a prolonged cognitive task in individuals trained for competitive sport. Ten trained competitive athletes (ATH) and ten untrained healthy men (UNT) completed a 6-min severe-intensity CWR followed by a 6-min cycling TT immediately following cognitive tasks designed to either perturb (Stroop colour-word task and N-back task; PCT) or maintain a neutral (documentary watching; CON) mental state. UNT had a higher heart rate (75 +/- 9 v. 69 +/- 7 bpm; P = 0.002) and a lower positive affect PANAS score (19.9 +/- 7.5 v. 24.3 +/- 4.6; P = 0.036) for PCT compared to CON. ATH showed no difference in heart rate, but had a higher negative affect score for PCT compared to CON (15.1 +/- 3.7 v. 12.2 +/- 2.7; P = 0.029). Pulmonary O2 uptake during CWR was not different between PCT and CON for ATH or UNT. Work completed during TT was not different between PCT and CON for ATH (PCT 103 +/- 12 kJ; CON 102 +/- 12 kJ; P > 0.05) or UNT (PCT 75 +/- 11 kJ; CON 74 +/- 12 kJ; P > 0.05). Compared to CON, during PCT, UNT showed unchanged psychological stress responses, whereas ATH demonstrated increased psychological stress responses. However, regardless of this distinction, exercise performance was not affected by PCT in either competitive athletes or untrained individuals. PMID- 30443807 TI - Alcohol Use Patterns and Subsequent Sexual Behaviors Among Women, Men who have Sex with Men and Men who have Sex with Women Engaged in Routine HIV Care in the United States. AB - Among people with HIV, alcohol use is associated with increased prevalence of sexual transmission behaviors. We examined associations between alcohol use in the prior year and sexual behaviors approximately six months later among 1857 women, 6752 men who have sex with men (MSM) and 2685 men who have sex with women (MSW). Any alcohol use was associated with increased risk of unsafe vaginal sex among women; anal sex and =>2 anal sex partners among MSM; and anal sex, =>2 anal or vaginal sex partners, and unsafe vaginal sex among MSW. In particular, among women >7 alcoholic drinks/week and among MSW =>5 alcoholic drinks/drinking day increased the likelihood of certain subsequent sexual behaviors. For all groups, especially women, the risk of sex under the influence of drugs/alcohol markedly increased with increases in quantity and frequency of alcohol consumption. These different patterns of drinking and sexual behaviors indicate the importance of tailored counseling messages to women, MSM and MSW. PMID- 30443810 TI - Prognostic impact of underlying lung disease in pulmonary wedge resection for lung cancer. AB - BACKGROUND: Pulmonary wedge resection is an option for lung cancer patients with limited cardiopulmonary preservation. As the impact of underlying lung status on the prognosis of such patients remains unclear, we assessed this issue. METHODS: A total of 149 borderline surgical candidates with localized lung cancer who had undergone wedge resection were retrospectively investigated. Clinical variables related to perioperative morbidity, local control rate, and oncological outcomes based on underlying lung disease were analyzed. RESULTS: According to the risk analysis of postoperative complications, underlying lung disease did not influence the surgical morbidity. Postoperative recurrence occurred in 65 patients (locoregional recurrence in 36, distant metastasis in 12, and both simultaneously in 17). Multivariate analysis revealed that emphysema on computed tomography (CT) [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.21-0.99] was an independent indicator of locoregional recurrence. Forty-four patients died of lung cancer and 29 of other causes. Multivariate analysis demonstrated that interstitial lung disease on CT (HR 1.98; 95% CI 1.01-3.89) was a predictor of poor prognosis. CONCLUSION: Pulmonary wedge resection can be safely undergone by lung cancer patients regardless of pulmonary comorbidity, although underlying lung disease may influence the prognosis after wedge resection. PMID- 30443809 TI - Real-world safety experience of tevagrastim/ratiograstim/biograstim and tbo filgrastim, short-acting recombinant human granulocyte colony-stimulating factors. AB - PURPOSE: Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix(r). Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo filgrastim, respectively. METHODS: Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. RESULTS: Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non serious event was bone pain. There was no evidence of immunogenicity. CONCLUSIONS: This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period. PMID- 30443811 TI - Histologic transformation of non-small-cell lung cancer in brain metastases. AB - BACKGROUND: Treatment strategies differ substantially for small-cell lung cancer (SCLC), adenocarcinoma and squamous-cell cancer (SCC). Therefore, it is of important significance to identify histologic transformation. There are no reports on histologic transformation in brain metastases (BM) to date. The aim of this study was to analyze the histologic transformation in BM for the first time. METHODS: Medical records were reviewed and patients with both resected BM and primary tumors were examined retrospectively. The histologic diagnosis was confirmed by H&E staining, and additional diagnostic immunohistochemical stains were performed at the discretion of the pathologists. Characteristics of histologic transformation in BM were analyzed. RESULTS: 3 of 24 patients (12.5%) with both resected BM and primary non-small-cell lung cancers (NSCLCs) had evidence of histologic transformation in BM. One case with SCC transformed to adenocarcinoma in brain, one case with adenocarcinoma transformed to SCLC, and another case with adenocarcinoma transformed to SCC. The three cases of histologic transformation were all spontaneous and had not tested gene status. CONCLUSIONS: We disclosed the histologic transformation of NSCLC in BM at a frequency not as low as expected, and speculated it as an evolution promoted by intratumor heterogeneity, though it warrants further prospective multi institution investigations with comprehensive molecular analysis. Our findings provided further impetus for surgery when the metastatic or recurrent lesion is resectable, and repeated pathologic evaluation to help tailor individualized treatment. PMID- 30443812 TI - An electrochemical chlorpyrifos aptasensor based on the use of a glassy carbon electrode modified with an electropolymerized aptamer-imprinted polymer and gold nanorods. AB - A highly selective and sensitive aptasensor is described for voltammetric determination of the pesticide chlorpyrifos (CPS). The sensor was constructed by modifying a glassy carbon electrode (GCE) with gold nanorods and a polymer that was molecularly imprinted with an aptamer against CPS. This results in double specific recognition. Under optimal conditions and a working potential as low as 0.22 V (vs. Ag/AgCl), the nanotools has a dynamic range that covers the 1.0 fM - 0.4 pM CPS concentration range, and the detection limit is 0.35 fM. This is lower than any of the previously reported methods. This MIP-aptasensor is selective over structural analogs, stable, and adequately reproducible. It was successfully applied to the determination of CPS in spiked food samples. Graphical abstract Impedimetric detection of Chlorpyrifos by using a Fe(CN)63-/4- probe based on double recognition of aptamer-molecular imprinted polymer onto a glassy carbon electrode modified with gold nanorod nanocomposite. The incubation with Chlorpyrifos lead to an increase of electron transfer resistance. PMID- 30443813 TI - Modeling the interactions between stimulation and physiologically induced APs in a mammalian nerve fiber: dependence on frequency and fiber diameter. AB - Electrical stimulation of nerve fibers is used as a therapeutic tool to treat neurophysiological disorders. Despite efforts to model the effects of stimulation, its underlying mechanisms remain unclear. Current mechanistic models quantify the effects that the electrical field produces near the fiber but do not capture interactions between action potentials (APs) initiated by stimulus and APs initiated by underlying physiological activity. In this study, we aim to quantify the effects of stimulation frequency and fiber diameter on AP interactions involving collisions and loss of excitability. We constructed a mechanistic model of a myelinated nerve fiber receiving two inputs: the underlying physiological activity at the terminal end of the fiber, and an external stimulus applied to the middle of the fiber. We define conduction reliability as the percentage of physiological APs that make it to the somatic end of the nerve fiber. At low input frequencies, conduction reliability is greater than 95% and decreases with increasing frequency due to an increase in AP interactions. Conduction reliability is less sensitive to fiber diameter and only decreases slightly with increasing fiber diameter. Finally, both the number and type of AP interactions significantly vary with both input frequencies and fiber diameter. Modeling the interactions between APs initiated by stimulus and APs initiated by underlying physiological activity in a nerve fiber opens opportunities towards understanding mechanisms of electrical stimulation therapies. PMID- 30443814 TI - Using multivariate techniques as a strategy to guide optimization projects for the surface water quality network monitoring in the Velhas river basin, Brazil. AB - Surface water quality monitoring networks are usually deployed and rarely re evaluated with regard to their effectiveness. In this sense, this work sought to evaluate and to guide optimization projects for the water quality monitoring network of the Velhas river basin, using multivariate statistical methods. The cluster, principal components, and factorial analyses, associated with non parametric tests and the analysis of violation to the standards set recommended by legislation, identified the most relevant water quality parameters and monitoring sites, and evaluated the sampling frequency. Thermotolerant coliforms, total arsenic, and total phosphorus were considered the most relevant parameters for characterization of water quality in the river basin. The monitoring sites BV156, BV141, BV142, BV150, BV137, and BV153 were considered priorities for maintenance of the network. The multivariate statistical analysis showed the importance of a monthly sampling frequency, specifically the parameters considered most important. PMID- 30443815 TI - Concomitant carotid endarterectomy and aortic valve replacement in a patient with high risk of perioperative stroke. AB - Surgical strategy for significant carotid artery stenosis complicated with severe aortic valve stenosis is still controversial. Herein, we report a case of 80-year old female in whom 78% stenosis by the NASCET criteria in left internal carotid artery was pointed out during preoperative checkup for symptomatic severe aortic stenosis. Carotid endarterectomy was done concomitantly with aortic valve replacement. No neurological complication occurred perioperatively. PMID- 30443816 TI - Magnitude and direction of aqueductal cerebrospinal fluid flow: large variations in patients with intracranial aneurysms with or without a previous subarachnoid hemorrhage. AB - BACKGROUND: Net cerebrospinal fluid (CSF) flow within the cerebral aqueduct is usually considered to be antegrade, i.e., from the third to the fourth ventricle with volumes ranging between 500 and 600 ml over 24 h. Knowledge of individual CSF flow dynamics, however, is hitherto scarcely investigated. In order to explore individual CSF flow rate and direction, we assessed net aqueductal CSF flow in individuals with intracranial aneurysms with or without a previous subarachnoid hemorrhage (SAH). METHODS: A prospective observational study was performed utilizing phase-contrast magnetic resonance imaging (PC-MRI) to determine the magnitude and direction of aqueductal CSF flow with an in-depth, pixel-by-pixel approach. Estimation of net flow was used to calculate CSF flow volumes over 24 h. PC-MRI provides positive values when flow is retrograde. RESULTS: The study included eight patients with intracranial aneurysms. Four were examined within days after their SAH; three were studied in the chronic stage after SAH while one patient had an unruptured intracranial aneurysm. There was a vast variation in magnitude and direction of aqueductal CSF flow between individuals. Net aqueductal CSF flow was retrograde, i.e., directed towards the third ventricle in 5/8 individuals. For the entire patient cohort, the estimated net aqueductal CSF volumetric flow rate (independent of direction) was median 898 ml/24 h (ranges 69 ml/24 h to 12.9 l/24 h). One of the two individuals who had a very high estimated net aqueductal CSF volumetric flow rate, 8.7 l/24 h retrograde, later needed a permanent CSF shunt. CONCLUSIONS: The magnitude and direction of net aqueductal CSF flow vary extensively in patients with intracranial aneurysms. Following SAH, PC-MRI may offer the possibility to perform individualized assessments of the CSF circulation. PMID- 30443817 TI - Low-dose compared to manufacturer-recommended dose four-factor prothrombin complex concentrate for acute warfarin reversal. AB - BACKGROUND: Four-factor PCC is the recommended standard of care for acute warfarin reversal but optimal dosing is unknown. We aim to show that a low-dose strategy is often adequate and may reduce the risk of thromboembolic events when compared to manufacturer-recommended dosing. METHODS: A weight-based dosing strategy of 15-25 units/kg was established as the institutional standard of care in May 2015. This retrospective, before-and-after cohort analysis included patients receiving 4F-PCC according to a manufacturer-recommended (n = 122) or a low-dose (n = 83) strategy. The primary efficacy outcome was a combination of INR reversal on first check and hemostatic efficacy at 24 h. RESULTS: Demographics, indications for warfarin, and presenting INR values were similar between the two groups. Patients in the manufacturer-recommended dose group received significantly more 4F-PCC than the low dose group (2110 units vs. 1530 units). More patients in the manufacturer-recommended dose group achieved the primary endpoint (75.4% vs. 61.4%), with more patients achieving the target INR on recheck in the manufacturer-recommended dose group (95.9% vs. 84.3%) and no difference in hemostatic efficacy between groups (79.5% vs. 74.7%). There was no difference in thromboembolic events at 72 h (4.1% vs. 1.2%) or at 30 days (8.2% vs. 4.8%). Significantly more patients in the manufacturer-recommended dose group died or were transferred to hospice care during hospitalization (21.3% vs. 9.6%). CONCLUSION: Utilization of a low-dose 4F-PCC strategy resulted in fewer patients achieving target INR reversal, but no difference in hemostatic efficacy, thromboembolic events, or survival. PMID- 30443818 TI - Interventions aimed at overcoming intuitive interference: insights from brain imaging and behavioral studies. AB - Students experience difficulties in comparison tasks that may stem from interference of the tasks' salient irrelevant variables. Here, we focus on the comparison of perimeters task, in which the area is the irrelevant salient variable. Studies have shown that in congruent trials (when there is no interference), accuracy is higher and reaction time is shorter than in incongruent trials (when the area variable interferes). Brain-imaging and behavioral studies suggested that interventions of either activating inhibitory control mechanisms or increasing the level of salience of the relevant perimeter variable could improve students' success. In this review, we discuss several studies that empirically explored these possibilities and their findings show that both types of interventions improved students' performance. Theoretical considerations and practical educational implications are discussed. PMID- 30443819 TI - A Text Mining Pipeline Using Active and Deep Learning Aimed at Curating Information in Computational Neuroscience. AB - The curation of neuroscience entities is crucial to ongoing efforts in neuroinformatics and computational neuroscience, such as those being deployed in the context of continuing large-scale brain modelling projects. However, manually sifting through thousands of articles for new information about modelled entities is a painstaking and low-reward task. Text mining can be used to help a curator extract relevant information from this literature in a systematic way. We propose the application of text mining methods for the neuroscience literature. Specifically, two computational neuroscientists annotated a corpus of entities pertinent to neuroscience using active learning techniques to enable swift, targeted annotation. We then trained machine learning models to recognise the entities that have been identified. The entities covered are Neuron Types, Brain Regions, Experimental Values, Units, Ion Currents, Channels, and Conductances and Model organisms. We tested a traditional rule-based approach, a conditional random field and a model using deep learning named entity recognition, finding that the deep learning model was superior. Our final results show that we can detect a range of named entities of interest to the neuroscientist with a macro average precision, recall and F1 score of 0.866, 0.817 and 0.837 respectively. The contributions of this work are as follows: 1) We provide a set of Named Entity Recognition (NER) tools that are capable of detecting neuroscience entities with performance above or similar to prior work. 2) We propose a methodology for training NER tools for neuroscience that requires very little training data to get strong performance. This can be adapted for any sub-domain within neuroscience. 3) We provide a small corpus with annotations for multiple entity types, as well as annotation guidelines to help others reproduce our experiments. PMID- 30443820 TI - Hemp (Marijuana) reverted Copper-induced toxic effects on the essential fatty acid profile of Labeo rohita and Cirrhinus mrigala. AB - Heavy metals pollution affects the nutritive value of fish. This study examined if the inclusion of dietary hempseed (HS) and hempseed oil (HO) in the diet of the fish could revert the copper-induced toxic effects on muscle fatty acid profile of rohu (Labeo rohita) and mrigal (Cirrhinus mrigala). Fingerlings of both species were exposed to a sub-lethal concentration of copper i.e., 20% of LC50 (1.34 ppm for rohu and 1.52 ppm for mrigal) for 96 h for 30 days. Following exposure, fish were maintained on graded levels of HO (1, 2 and 3%) or on HS (5, 10 and 15%) for 50 days. Copper exposure showed a significant effect on the fatty acid composition of both species; increased their saturated (SFA) to unsaturated (USFA) and altered their omega-3/omega-6 (omega-3/omega-6) ratios. However, feeding graded levels of hempseed products reverted the toxic effects of copper on the fatty acid profile of both the species, significantly increased muscle total fatty acid contents, improved omega-3/omega-6 ratios, and decreased SFA / USFA ratio in % inclusion dependent manner. Furthermore, hempseed product showed a species-specific effect on USFA. The omega-3/omega-6 ratios decreased in the muscle of C. mrigala whereas an increasing trend with an increase in hempseed product % inclusion was observed in L. rohita. Moreover, HS showed a higher impact on both species as compared to HO. With the findings of this study, hempseed product could be recommended as a feed ingredient for enhancing the essential fatty acid contents of fish which in turn can have a good impact on consumer health. PMID- 30443821 TI - Fermentative profile and lactic acid bacterial dynamics in non-wilted and wilted alfalfa silage in tropical conditions. AB - This study was conducted to evaluate the fermentative profile and microbial populations of wilted and non-wilted alfalfa silages ensiled with or without inoculant and the population dynamics of lactic acid bacteria (LAB) of wilted alfalfa plant and theirs silage. A 2 * 2 * 6 factorial arrangement was used, with the absence or presence of wilting (W), with and without bacterial inoculant (I) and six fermentation periods (P) (1, 3, 7, 14, 28 and 56 days), in a completely randomized design, with three replicates. The alfalfa was slightly wilted for 6 h and increased the dry matter content from 133.9 to 233.4 g/kg. It was performed the cultivation, followed by the isolation of LAB from samples of alfalfa forage before ensiling and its silage only in non-inoculated silages, after different fermentation periods. DNA was extracted from the isolated strains of LAB; the 16S rRNA gene sequences were amplified by PCR and the sequences were compared to those available from the GenBank database. Wilting provided silages with lower pH, ammonia nitrogen and acetic acid concentrations. The wilting process did not alter the amount of LAB; however, it affected the LAB diversity of the silages. The Lactobacillus plantarum was the predominant species in non-wilted and wilted silages. PMID- 30443822 TI - Identification of Thiobacillus bacteria in agricultural soil in Iran using the 16S rRNA gene. AB - Thiobacillus, as useful soil bacteria, plays an important role in sulfur cycling. The purpose of this study was to identify the species Thiobacillus thioparus, Thiobacillus novellas and Thiobacillus denitrificans in rainfed and irrigated lands soil in Ajabshir, Ilam, Qorveh, Rojintaak, Sonqor, Kermanshah and Research Farm of Razi University in Iran. Sampling was performed as randomized completely with three replications at depth of 0-30 cm. The Thiobacillus species were determined via 16S rRNA characteristics. The results of agarose gel electrophoresis indicated that T. thioparus was the highest amount in the irrigated land in Research Farm and its lowest amount was in the Rojintaak rainfed land. These species not found in four locations and conditions including the Ajabshir irrigated, Qorveh rainfed, Research Farm rainfed and Rojintaak irrigated lands. The results of the T. novellas indicated that this was found in Ilam irrigated, Qorveh rainfed, Research Farm irrigated, Rojintaak irrigated and Rojintaak rainfed lands. The highest and lowest amount of T. novellas was indicated in the Rojintaak and Ilam irrigated lands respectively. The T. denitrificans gene showed that this bacterium was observed only in both samples of Ajabshir. Our study showed that Thiobacillus was not detected in all of the soils. If sulfur fertilizer is given to the soil without this bacterium, it is necessary to use sulfur fertilizer with Thiobacillus bacteria inoculation for better sulfur oxidation. PMID- 30443823 TI - Identification of O-acetylserine(thiol)lyase (OASTL) genes in sorghum (Sorghum bicolor) and gene expression analysis under cadmium stress. AB - Cysteine (Cys) is the first identified molecule in plant metabolism which includes both sulfur and nitrogen. It can be synthesized in three cellular compartments, containing chloroplast, cytoplasm and mitochondrion. The final step of cysteine biosynthesis is catalyzed by the O-acetylserine(thiol)lyase enzyme (OASTL, E.C. 4.2.99). In the present study, seven members of the OASTL gene family in the sorghum (Sorghum bicolor) genome were identified at a genome-wide scale and comparative bioinformatics analyses were performed between sorghum and Arabidopsis OASTLs. In all OASTL proteins, a pyridoxal-phosphate dependent domain structure (PALP, PF00291) was identified. The gene ontology annotations also revealed that all sorghum OASTL genes have KOG1252 (Cystathionine beta-synthase and related enzyme) and K01738 (cysteine synthase A) activities. In promotor sequences of OASTL genes, diverse cis-acting elements were found, including hormone and light responsiveness, abiotic stress responsiveness, and tissue specific ones (meristem and endosperm). Sorghum OASTL genes demonstrated medium or high level expressions in anatomical parts and developmental stages based on the digital expression data. Expression of OASTL genes were also analyzed under cadmium (Cd) stress in sorghum by Real Time-quantitative PCR (RT-qPCR). The results exclusively showed that OASTL A1-2 gene was 1.12 fold up-regulated in roots, whereas cysteine synthase 26 was 2.25 fold down-regulated in leaves. The predicted 3D structure of OASTLs indicated some structural diversities as well as variations in the secondary structures. PMID- 30443824 TI - Development and application of EST-SSRs markers for analysis of genetic diversity in erect milkvetch (Astragalus adsurgens Pall.). AB - Erect milkvetch (Astragalus adsurgens Pall.) is a major legume forage plant widely grown in Northern China. However, the lack of molecular markers has limited its research into its genetic diversity and work on germplasm improvement. In this study, a total of 39,163 EST-SSR loci were identified from 30,262 unigene sequences in the erect milkvetch transcriptome using Illumina sequencing. Moreover, 22,367 EST-SSR primer pairs (PPs) were successfully designed. In addition, 100 PPs were synthesized and preliminarily screened in two accessions; of these, 90 were determined to be clear and stable EST-SSR markers. Fifty-one PPs were randomly selected in order to assess the genetic diversity of 27 erect milkvetch accessions. The average polymorphism information content of the 51 PPs was 0.682. Greater genetic diversity was detected in accessions from Inner Mongolia and in the group of landrace and wild erect milkvetch accessions. This study provides an important resource for germplasm improvement and genetic diversity analysis in erect milkvetch. PMID- 30443825 TI - Nonadditive expression of lipid metabolism pathway-related genes in intestine of hybrids of Nile tilapia females (Oreochromis niloticus) and blue tilapia males (Oreochromis aureus). AB - Nonadditive expression contributes to heterosis in hybrids. In this study, the expression profiles of twelve lipid metabolism pathway-related genes were investigated in the intestine of Nile tilapia (Oreochromis niloticus) ? * blue tilapia (Oreochromis aureus) ? hybrid. The expression of genes from the hybrid were assigned to nonadditive and additive expression pattern groups and compared with expression patterns from Nile tilapia and blue tilapia. In the intestine of the hybrid, apoA4B was expressed at intermediate levels, but apoB and MTP were assigned to ELD-B and ELD-N categories, respectively. The LPL and LRP1 showed transgressive up-regulation in the hybrid, but LDLR was assigned to the ELD-B category. For fatty acid uptake related genes, only FABP11a was categorized as nonadditive expression with transgressive up-regulation, while CD36 and FABP3 were categorized as additive expression in the intestine of the hybrid. Two genes in triacylglycerol metabolism, namely, FAS and DGAT2, showed transgressive up regulation in the hybrid. Most of the genes analyzed in the present study showed nonadditive expression (8 in 12), and five genes showed transgressive up regulation. These results indicated that the stimulation of lipid metabolism in the hybrid compared to that of its parents. The hyperactive expression of these genes in the hybrid may be associated with the growth and lipid usage vigor. PMID- 30443827 TI - Subcortical axonal loss with glial reactions following partial status epilepticus with neuroradiological findings of reduced subcortical diffusion. AB - Hyperintensity in the subcortical white matter on the diffusion-weighted magnetic resonance image has been described recently, in association with partial status epilepticus. Although this reduced subcortical diffusion is typically seen in patients with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), the exact pathophysiological mechanism is unclear. We report the case of a 3-month-old boy who underwent surgery for intractable epilepsy associated with cortical dysplasia in the left peri-Rolandic area, coincident with the appearance of reduced subcortical diffusion. Neurohistological findings revealed that the most prominent finding was axonal loss with marked astroglial and microglial reactions in the white matter. Neither degenerated neurons nor neurophagocytic microglial accumulation was evident in the cortex. These findings confirm that white matter can be secondarily damaged in patients with partial status epilepticus, and possible pathomechanism of reduced subcortical diffusion is discussed. PMID- 30443828 TI - Multiband ultra-thin flexible on-body transceivers for wearable health informatics. AB - Substantial concentration has been associated to the monitoring of vital signs and human activity using wireless body area networks. However, one of the key technical challenges is to characterize an optimized transceiver geometry for desired isolation/bandwidth and specific absorption rate (SAR) characteristics, independent of transceiver chip on-body location. A microwave performance evaluation of monopole wearable transceiver was completed and results presented. A novel on-body antenna transceiver was designed, simulated and fabricated using an ultra-thin substrate RO 3010 (h = 250 um) that ensures compactness and enhanced flexibility. The designed transceiver was evolved using very high value of dielectric constant using CST(r) Studio Suit and FEKO(r) numerical platforms. The on-body characterization for both fatty and bone tissues was experimentally verified for a bandwidth of 200 MHz. The fabricated configuration and real-time testing provides very promising microwave radiation parameters with a gain of 2.69 dBi, S11 < - 13 dB at an operational frequency of 2.46 GHz. Multi-banding was achieved by introducing fractals in the design of the printed monopole. SAR calculations for feet, head and arm at microwave power levels ranging from 100 to 800 mW are incorporated. Furthermore, the real time data acquisition using developed transceiver and its experimental verification is illustrated. PMID- 30443829 TI - Application of isoxanthopterin as a new pterin marker in the differential diagnosis of hyperphenylalaninemia. AB - BACKGROUND: This study aimed to explore the value of applying a new pterin marker (isoxanthopterin) to the traditional urine pterin analysis to reduce the rate of mis-diagnosis of 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD) and improve the accuracy of diagnosis. METHODS: We compared the urine neopterin (N), biopterin (B), isoxanthopterin (Iso), B% and Iso% levels between patients with phenylalanine hydroxylase deficiency and those with PTPSD, and found the most specific pterin biomarkers by ROC analysis. A positive cut-off value of urine pterins was determined. The effect of combined Iso% + B + B% in reducing PTPSD mis-diagnosis was evaluated, and the different urine pterin levels in PTPSD and false PTPSD (FPTPSD) were compared. The concordance of PTPSD diagnosis by the new pterin scheme and gene mutation analysis was determined. RESULTS: (1) Urinary B, B%, Iso and Iso% were significantly lower in PTPSD than those in phenylalanine hydroxylase-deficiency group (P < 0.01); (2) Iso%, B%, and B were the most specific markers; (3) The positive cut-off values of B, B%, Iso% for PTPSD were < 0.17 mmoL/moLCr, < 5.0%, and < 9.5%, respectively; (4) urinary B + B% + Iso% scheme significantly reduced the false-positive rate of PTPSD compared to traditional ones. The Iso% levels in FPTPSD group were higher than the ones in PTPSD group; (5) an accuracy of diagnosis for PTPSD was increased by 9-19% when Iso% was introduced to urinary pterin scheme. CONCLUSIONS: Iso% is helpful to reduce the rate of misdiagnosis of PTPSD in the diagnosis by urinary pterin analysis for hyperphenylalaninemias and improve the accuracy of diagnosis. This approach is worthy of further development and increased utilization. PMID- 30443831 TI - Thank You to the Annals of Surgical Oncology Expert Reviewer Community. PMID- 30443830 TI - Patterns of Lymph Node Recurrence in Adrenocortical Carcinoma: Possible Implications for Primary Surgical Treatment. AB - BACKGROUND: In the surgical treatment of adrenocortical carcinoma (ACC), lymphadenectomy may improve oncologic outcome. However, patterns of metastatic lymphatic spread in ACC are unknown. METHODS: Clinical data of patients included in the European Network for the Study of Adrenal Tumors (ENSAT) registry were retrospectively reviewed. Inclusion criteria were: nonmetastatic ACC, complete resection of the primary tumor, a disease-free time of > 3 months, and lymph node metastases as the first disease relapse. The retroperitoneal lymphatic drainage area was evaluated by using follow-up imaging. RESULTS: Of 971 patients from the ENSAT registry, 56 patients were included. In left-sided ACC (n = 36), lymphatic recurrence was detected in the left renal hilum (50%), in the perirenal fat tissue cranial to the renal hilum (ventral, 47%; dorsal, 55%), para-aortic (47%), interaorto-caval (22%), and/or in the perirenal fat tissue caudal to the renal hilum (ventral, 20%; dorsal, 17%). In right-sided ACC (n = 20), lymph node metastases were detected in the perirenal fat tissue cranial to the renal hilum (dorsal, 55%; ventral, 45%), interaorto-caval (35%), in the area of the right renal artery (10%), and/or paracaval (15%). Patients with right-sided ACC showed left-paraaortic lymph node recurrences in 10% of cases. CONCLUSION: Metastatic lymphatic spread appears to be more extensive than previously thought. The distribution pattern of lymph node metastases described in our study could be used as a guide for a more extended lymph node dissection. PMID- 30443832 TI - ASO Author Reflections: Predicting Early Recurrence After Trimodality Therapy for Esophageal Adenocarcinoma. PMID- 30443833 TI - The use of 5-aminolevulinic acid in resection of pediatric brain tumors: a critical review. AB - The compound, 5-aminolevulinic acid (5-ALA) is approved for fluorescence-guided resections of malignant gliomas in Europe and other countries for use in adults, but not for children. The application of 5-ALA in children remains an off-label use. Several case reports on fluorescence-guided surgery use in children have been published, yet no prospective study has been conducted. Here we systematically review the reported studies and discuss the usefulness, application, and safety of 5-ALA use in resection of pediatric brain tumors. PMID- 30443826 TI - Of mice and men: models and mechanisms of diabetic cardiomyopathy. AB - Diabetes mellitus increases the risk of heart failure independent of co-existing hypertension and coronary artery disease. Although several molecular mechanisms for the development of diabetic cardiomyopathy have been identified, they are incompletely understood. The pathomechanisms are multifactorial and as a consequence, no causative treatment exists at this time to modulate or reverse the molecular changes contributing to accelerated cardiac dysfunction in diabetic patients. Numerous animal models have been generated, which serve as powerful tools to study the impact of type 1 and type 2 diabetes on the heart. Despite specific limitations of the models generated, they mimic various perturbations observed in the diabetic myocardium and continue to provide important mechanistic insight into the pathogenesis underlying diabetic cardiomyopathy. This article reviews recent studies in both diabetic patients and in these animal models, and discusses novel hypotheses to delineate the increased incidence of heart failure in diabetic patients. PMID- 30443834 TI - Gracious and Tenacious: The Enduring Legacy of Judith Bradford (1943-2017). PMID- 30443835 TI - A Latent Profile Analysis of Bisexual Identity: Evidence of Within-Group Diversity. AB - Bisexual people experience unique psychosocial vulnerabilities and their mental health needs and social identity remain underserved and understudied, respectively. We report results from a latent profile analysis where we identified a preliminary typology of bisexual identity subgroups and its association with demographic and mental health variables. Bisexual+ adults (N = 292) residing in the U.S. were recruited from Amazon Mechanical Turk and administered a demographic survey, indicators of bisexual identity, and measures of internalizing symptoms and self-esteem. Joint consideration of statistical and substantive criteria in the modeling process yielded a well-differentiated and qualitatively distinctive three-profile solution comprised of Affirmative (e.g., having a positive orientation towards one's bisexuality), Vigilant (e.g., being significantly concerned about others' reactions to one's bisexuality), and Ambivalent (e.g., endorsing mixed but generally negative attitudes and beliefs about one's bisexuality) profiles of bisexual identity. Auxiliary analyses revealed conceptually and statistically significant associations among profile membership, demographic covariates, and mental health outcomes. Some key findings included that compared to the Affirmative profile, men and people of color were overrepresented in the Ambivalent profile, whereas men were overrepresented in the Vigilant profile. Bisexuals with a Vigilant profile displayed the poorest mental health constellation. Our findings highlight the categorically heterogeneous nature of bisexual identity, support the relevance of social identity to mental health among bisexuals, and represent the first attempt to model bisexual identity using mixture techniques. Future studies should consider larger and more demographically diverse samples, address replicability and generalizability, examine additional auxiliary variables, and investigate longitudinal developments in profiles. PMID- 30443836 TI - Conditional Overexpression of rtn4al in Muscle of Adult Zebrafish Displays Defects Similar to Human Amyotrophic Lateral Sclerosis. AB - The protein level of muscle-specific human NogoA is abnormally upregulated in amyotrophic lateral sclerosis (ALS) mice and patients. On the other hand, while the presence of miR-206 in muscle cells delays onset and death in ALS, the relationship between these two phenomena remains unclear. Mammalian NogoA protein, also known as Reticulon 4a (Rtn4a), plays an important role in inhibiting the outgrowth of motor neurons. Our group previously identified zebrafish rtn4al as the target gene of miR-206 and found that knockdown of miR 206 increases rtn4al mRNA and Rtn4al protein in zebrafish embryos. It can be concluded from these results that neurite outgrowth of motor neurons is inhibited by Rtn4a1, which is entirely consistent with overexpression of either human NogoA or zebrafish homolog Rtn4al. Since an animal model able to express NogoA/rtn4al at the mature stage is unavailable, we generated a zebrafish transgenic line, Tg(Zalpha:TetON-Rtn4al), which conditionally and specifically overexpresses Rtn4al in the muscle tissue. After doxycycline induction, adult zebrafish displayed denervation at neuromuscular junction during the first week, then muscle disintegration and split myofibers during the third week, and, finally, significant weight loss in the sixth week. These results suggest that this zebrafish transgenic line, representing the inducible overexpression of Rtn4a1 in muscle, may provide an alternative animal model with which to study ALS because it exhibits ALS-like phenotype. PMID- 30443837 TI - Characterization and Cytotoxicity Evaluation of a Marine Sponge Biosilica. AB - Bone fractures characterize an important event in the medical healthcare, being related to traumas, aging, and diseases. In critical conditions, such as extensive bone loss and osteoporosis, the tissue restoration may be compromised and culminate in a non-union consolidation. In this context, the osteogenic properties of biomaterials with a natural origin have gained prominence. Particularly, marine sponges are promising organisms that can be exploited as biomaterials for bone grafts. Thus, the objectives of this study were to study the physicochemical and morphological properties of biosilica (BS) from sponges by using scanning electron microscopy, Fourier-transform infrared, X-ray diffraction (SEM, FTIR and XRD respectively), mineralization, and pH. In addition, tests on an osteoblast precursor cell line (MC3T3-E1) were performed to investigate its cytotoxicity and proliferation in presence of BS. Bioglass (BG) was used as gold standard material for comparison purposes. Sponge BS was obtained, and this fact was proven by SEM, FTIR, and XRD analysis. Calcium assay showed a progressive release of this ion from day 7 and a more balanced pH for BS was maintained compared to BG. Cytotoxicity assay indicated that BS had a positive influence on MC3T3-E1 cells viability and qRT-PCR showed that this material stimulated Runx2 and BMP4 gene expressions. Taken together, the results indicate a potential use of sponge biosilica for tissue engineering applications. PMID- 30443838 TI - Association Between IL7R Promoter Polymorphisms and Multiple Sclerosis in Turkish Population. AB - Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that affects myelin fibers within the central nervous system resulting in neurological impairment. Although the etiology of MS is not fully understood, environmental and genetic factors are thought to play important roles. IL7R gene polymorphisms which are associated with several autoimmune diseases have also been implicated as a genetic factor for MS following genome-wide association studies. To further examine this association, we investigated the association between MS and IL7R gene - 449 (A/G), - 504 (T/C), and - 1085 (G/T) promoter polymorphisms in Turkish population. Three hundred sixty-four MS patients and 191 healthy controls were involved in this study. Three polymorphic regions in the promoter of IL7R were identified and these regions were amplified by appropriate primers. The PCR products were digested by PstI enzyme for - 504 (T/C) SNP and HphI enzyme for - 1085 (G/T) and - 449 (A/G) SNPs and genotyping was done based on digested PCR product sizes. Genotype distributions and allele frequencies of - 449 polymorphism did not show any significant association with MS directly (p = 0.120 and p = 0.490, respectively). But the genotypes of IL7R - 449 GA for AOMS and AA for EOMS were a risk factor in according to age of onset (p = 0.002, OR = 4.021, 95% CI = 1.642-9.845). Furthermore, IL7R - 449 A allele was found to be a risk factor for EOMS (p = 0.011, OR = 1.3, 95% CI = 1.107-1.527). Significant association was seen between IL7R - 504 TC heterozygote genotype and MS (p = 0.02, OR = 1.702, 95% CI = 1.169-2.478). The IL7R - 1085 (G/T) polymorphism did not show association with MS; however, the haplotype of ACG may be susceptibility to MS and RRMS (p = 0.035, OR = 1.349, 95% CI = 1.020-1.785, and p = 0.041, OR = 1.368, 95% CI = 1.012-1.850, respectively) and the haplotypes of ACG, ATT, and GTG demonstrate a protective effect in EOMS (p = 0.008, OR = 0.326, 95% CI = 0.136-0.782, p = 0.012 and p = 0.012, OR = 0.462, 95% CI = 0.249-0.859, respectively). RRMS frequency in the Turkish population was decreased and SPMS frequency was strongly increased based on comparison to results from other populations. Furthermore, male patients had an increased frequency of SPMS significantly (p = 0.033, OR = 1.667, 95% CI = 1.036-2.682). In conclusion, this is the first study to show a significant association between the IL7R promoter polymorphisms and the age of onset of MS. PMID- 30443840 TI - Benchmarking renin suppression and blood pressure reduction of direct renin inhibitor imarikiren through quantitative systems pharmacology modeling. AB - Multiple classes of antihypertensive drugs inhibit components of the renin angiotensin-aldosterone system (RAAS). The primary physiological effector of the RAAS is angiotensin II (AngII) bound to the AT1 receptor (AT1-bound AngII). There is a strong non-linear feedback from AT1-bound AngII on renin secretion. Since AT1-bound AngII is not readily measured experimentally, plasma renin concentration (PRC) and/or activity (PRA) are typically measured to indicate RAAS suppression. We investigated the RAAS suppression of imarikiren hydrochloride (TAK-272; SCO-272), a direct renin inhibitor currently under clinical development. We employed a previously developed quantitative system pharmacology (QSP) model to benchmark renin suppression and blood pressure regulation with imarikiren compared to other RAAS therapies. A pharmacokinetic (PK) model of imarikiren was linked with the existing QSP model, which consists of a mechanistic representation of the RAAS pathway coupled with a model of blood pressure regulation and volume homeostasis. The PK and pharmacodynamic effects of imarikiren were calibrated by fitting drug concentration, PRA, and PRC data, and trough AT1-bound AngII suppression was simulated. We also prospectively simulated expected mean arterial pressure reduction in a cohort of hypertensive virtual patients. These predictions were benchmarked against predictions for several other (previously calibrated) RAAS monotherapies and dual-RAAS therapies. Our analysis indicates that low doses (5-10 mg) of imarikiren are comparable to current RAAS therapies, and at higher doses (25-200 mg), RAAS suppression may be equivalent to existing dual-RAAS combinations (at registered doses). This study illustrates application of QSP modeling to predict phase II endpoints from phase I data. PMID- 30443839 TI - Protective Effect of PACAP on Ischemia/Reperfusion-Induced Kidney Injury of Male and Female Rats: Gender Differences. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts general cytoprotective effects, including protection in different kidney disorders. The aim of our study was to investigate the ischemia/reperfusion induced kidney injury of male and female rats to confirm the protective effects of PACAP in the kidney and to reveal possible gender differences.Male and female Wistar rats underwent unilateral renal artery clamping followed by 24-h, 48-h, or 14-day reperfusion. PACAP was administered intravenously before arterial clamping in half of the rats. Tubular damage, cytokine expression pattern, oxidative stress marker, antioxidative status and signaling pathways were evaluated using histology, immunohistology, cytokine array, PCR, and Western blot. Tubular damage was significantly less severe in the PACAP-treated male and female rats compared to controls. Results of female animals were significantly better in both treated and untreated groups. Cytokine expression, oxidative stress marker and antioxidative status confirmed the histological results. We also revealed that PACAP counteracted the decreased PKA phosphorylation, influenced the expression of BMP2 and BMP4, and increased the expression of the protein Smad1.We conclude that PACAP is protective in ischemia/reperfusion-induced kidney injury in both sexes, but females had markedly less pronounced injury after ischemia/reperfusion, possibly also involving further protective factors, the investigation of which could have future therapeutic value in treating ischemic kidney injuries. PMID- 30443841 TI - Change-Driven M100 Component in the Bilateral Secondary Somatosensory Cortex: A Magnetoencephalographic Study. AB - Our previous demonstration that the M100 somatosensory evoked magnetic field (SEF) has a similar temporal profile, dipole orientation and source location whether induced by activation (ON-M100) or deactivation (OFF-M100) of electrical stimulation suggests a common cortical system to detect sensory change. While we have not recorded such change-driven components earlier than M100 using electrical stimulation, clear M50 responses were reported using both ON and OFF mechanical stimulation (Onishi et al. in Clin Neurophysiol 121:588-593, 2010). To examine the significance of M50 and M100 in reflecting the detection of somatosensory changes, we recorded these waveforms in 12 healthy subjects (9 males and 3 females) by magnetoencephalography in response to mechanical stimulation from a piezoelectric actuator. Onset and offset (ON and OFF) stimuli were randomly presented with three preceding steady state (PSS) durations (0.5, 1.5 and 3 s) in one consecutive session. Results revealed that (i) onset and offset somatosensory events elicited clear M50 and M100 components; (ii) M50 and M100 components had distinct origins, with M50 localised to the contralateral primary somatosensory cortex (cS1) and M100 to the bilateral secondary somatosensory cortex (iS2, cS2); and (iii) the amplitude of M50 in cS1 was independent of the PSS durations, whereas that of M100 in S2 was dependent on the PSS durations for both ON and OFF events. These findings suggest that the M50 amplitude in cS1 reflects the number of activated mechanoreceptors during Onset and Offset, whereas the M100 amplitude in S2 reflects change detection based on sensory memory for Onset and Offset stimuli at least in part. We demonstrated that the M50 in cS1 and M100 in S2 plays different roles in the change detection system in somatosensory modality. PMID- 30443842 TI - The Expression of Interferon Gamma (IFN-gamma) and Interleukin 6 (IL6) in Patients with Acute Lymphoblastic Leukemia (ALL). AB - Interferon gamma (IFN-gamma) and interleukin 6 (IL-6) are including the most important cytokines which have been associated with the biological behavioral and immune responses in malignancies. Based on the critical roles which these two cytokines play against tumor cells, the present study was aimed to investigate the genes expression level of IL6 and IFN-gamma in patients with Acute Lymphoblastic Leukemia and compare with normal controls. Fifty-two patients with ALL and 13 healthy volunteer were under studied. The peripheral blood mononuclear cells of all patients and normal controls were separated by ficoll. The expression of interferon gamma and interleukin 6 genes were determined by RQ-PCR. Finally all data were analyzes using T student, one way ANOVA and Mann-Whitney tests were use to analyze all samples data. Our finding showed that the level of IFN-gamma gene expression was significant decreased in patients with All as compared with healthy controls (83 change fold, p < 0.0001). The level of IL-6 Gene expression was not changeable in B-ALL patients as compared with healthy control (p = 0.4), but in T-ALL patients, was significantly reduced (p < 0.01). The results of present study indicated that IFN-gamma gene expression reduced in ALL patients. It provides a valuable insight that immune system may disrupted in patients with ALL, which cause tumor cells escape from immune surveillance. PMID- 30443843 TI - The Interrelationship of Pharmacologic Ascorbate Induced Cell Death and Ferroptosis. AB - Pharmacologic ascorbate induced cell death and ferroptosis share common features such as iron dependency, production of ROS, lipid peroxidation, caspase independency and the possible involvement of autophagy. These observations lead us to hypothesize that ferroptosis may also be involved in cancer cell death due to pharmacologic ascorbate treatment. Thus cell death of HT-1080 cell line was induced by ferroptosis inducers and pharmacologic ascorbate then the mechanism of cell death was compared. The EC50 value of pharmacologic ascorbate on HT-1080 cell line was found to be 0.5 mM that is in the range of the most ascorbate sensitive cell lines. However either of the specific inhibitors of ferroptosis (ferrostatin-1 and liproxstatin-1) could not elevate the viability of pharmacologic ascorbate treated cells suggesting that ferroptosis was not involved in the pharmacologic ascorbate induced cell death. alpha-tocopherol that could effectively elevate the viability of erastin and RSL3 treated HT1080 cells failed to mitigate the cytotoxic effect of pharmacologic ascorbate further strengthened this assumption. Furthermore at lower concentrations (0.1-0.5 mM) ascorbate could avoid the effects of ferroptosis inducers. Our results indicate that pharmacologic ascorbate induced cytotoxicity and ferroptosis - albeit phenotypically they show similar traits - are governed by different mechanisms. PMID- 30443844 TI - The Gene Mutation Spectrum of Breast Cancer Analyzed by Semiconductor Sequencing Platform. AB - To use the semiconductor sequencing platform (SSP) to analyze the gene mutate spectrum of breast cancer patients. We recruited 46 breast cancer patients, and detected the ER/PR/HER2 expression level of the tumor tissue by immunohistochemistry. In addition, combined with SSP technology, we detected 207 hot mutation regions of 50 breast cancer related genes with multiple polymerase chain reaction (PCR) technology. There were 8 cases of grade I, 18 cases of grade II, 20 cases of grade III in 46 breast cancer patients according to histological grade and 12 cases of ER/PR + HER2 +, 18 cases of ER/PR + HER2-, 13 cases of ER/PR - HER2 +, 20 cases of ER/PR - HER2- according to ER/PR/HER2 status classification. Moreover, we found that there were 33 gene locus mutations of 8 genes including AKT1, APC, BRAF, CDKN2A, KRAS, PTEN, PIK3CA and TP53, but difference was not statistically significant (P > 0.05) when compared these gene mutations (except for PIK3CA) in each groups according to the histological classification of breast cancer and the ER/PR/HER2 classification. PIK3CA mutation rate of grade I was obviously higher than that of grade II ~ III histological grading in breast cancer patients (P < 0.05). Based on our results, we drew a conclusion that the occurrence and development of breast cancer was a process involved multiple genes. Here, we found that PIK3CA played a role in the development of the early stage of breast cancer, which could provide clinical basis for treatment of breast cancer. Moreover, SSP technology could be an effective and sensitive method for detection of gene mutation spectrum in breast cancer. PMID- 30443845 TI - Application of a Fluorescence Imaging System with Indocyanine Green to Protect the Parathyroid Gland Intraoperatively and to Predict Postoperative Parathyroidism. AB - INTRODUCTION: Identifying the parathyroid gland during surgery may be difficult for surgeons. It is critical for them to be able to locate it during thyroidectomy or parathyroidectomy because of the significant function of the parathyroid in the calcium balance. According to recent reports, intrinsic fluorescence of the parathyroid has been found. There is some evidence to suggest that new equipment can detect the fluorescence via imaging technology. In this study, a newly invented intraoperative fluorescence imaging system and indocyanine green (ICG) dye were applied to detect the parathyroid glands and evaluate the vascularization of the parathyroid. METHODS: From 1 May to 8 August 2018, 26 patients underwent total thyroidectomy in Zhuhai People's Hospital. These 26 subjects were recruited in our research. All identified parathyroid glands were scored visually from grade 0 to grade 2 according to the vascularity of the parathyroid before ICG angiography was performed. After ICG angiography, the parathyroid glands were scored from 0 to 2 according to the fluorescence intensity (FI). RESULTS: Visual scores were significantly higher than ICG angiography scores. In the 22 patients with at least one parathyroid gland with an ICG score of 2, postoperative parathyroidism (PTH) levels were in the normal range. Of the four patients with no parathyroid gland with an ICG score of 2, two developed transient hypoparathyroidism, with recovery on postoperative day (POD) 7 for the first patient and after 3 months for the second. CONCLUSION: This study has shown that a fluorescence imaging system applied with indocyanine green is a safe, easy and effective method to protect the parathyroid and predict postoperative parathyroidism. TRIAL REGISTRATION: Chinese Clinical Trial Registry no. ChiCTR1800016864. PMID- 30443846 TI - The Core Components of Evidence-Based Social Emotional Learning Programs. AB - Implementing social emotional learning (SEL) programs in school settings is a promising approach to promote critical social and emotional competencies for all students. However, there are several challenges to implementing manualized SEL programs in schools, including program cost, competing demands, and content that is predetermined and cannot be tailored to individual classroom needs. Identifying core components of evidence-based SEL programs may make it possible to develop more feasible approaches to implementing SEL in schools. The purpose of this study was to systematically identify the core components in evidence based elementary school SEL programs, using the five interrelated sets of competencies identified by the Collaborative for Academic, Social, and Emotional Learning (CASEL) as an organizing framework. We present the components that were identified, and the rates at which each component was included in the sample of evidence-based SEL programs. The core components that occurred most frequently across programs were Social Skills (100% of programs), Identifying Others' Feelings (100% of programs), Identifying One's Own Feelings (92.3% of programs), and Behavioral Coping Skills/Relaxation (91.7% of programs). These findings illustrate the feasibility of systematically identifying core components from evidence-based SEL programs and suggest potential utility of developing and evaluating modularized SEL programs. PMID- 30443847 TI - Promising Practices for Promoting Health Equity Through Rigorous Intervention Science with Indigenous Communities. AB - Research in indigenous communities is at the forefront of innovation currently influencing several new perspectives in engaged intervention science. This is innovation born of necessity, involving efforts to create health equity complicated by a history of distrust of research. Immense diversity across indigenous cultures, accompanied by variation in associated explanatory models, health beliefs, and health behaviors, along with divergent structural inequities add further complexity to this challenge. The aim of this Supplemental Issue on Promoting Health Equity through Rigorous, Culturally Informed Intervention Science: Innovations with Indigenous Populations in the United States is to highlight the promising new approaches and perspectives implemented by a group of engaged researchers and their community partners, as they seek to move intervention research forward within indigenous communities. Case studies presented are from projects led by members of the National Institutes of Health Intervention Research to Improve Native American Health (IRINAH) consortioum, investigators who conduct health promotion and disease prevention research among American Indians, Alaska Natives, and Native Hawaiians. The promising practices profiled include new strategies in (a) community partnerships, engagement, and capacity building; (b) integration of indigenous and academic perspectives; (c) alignment of interventions with indigenous cultural values and practices; and (d) implementation and evaluation of multilevel interventions responsive to complex cultural contexts. The IRINAH projects illustrate the evolution of an intervention science responsive to the needs, realities, and promise of indigenous communities, with application to health research among other culturally distinct health inequity groups. PMID- 30443848 TI - Methodology in Research on the Rainbow Body: Anthropological and Psychological Reflections on Death and Dying. AB - The rainbow body research project, engaging claims of spiritual attainment and personal transformation, enables us to examine key features of anthropological research. Engagement with communities of discourse exposed aspects of the artificial emic-etic divide, allowing the anthropological study of religion to advance methods in religious studies. The study of paranormal phenomena cannot be isolated from societal contextualization. In this instance, a study of death and dying, contextualized in a traditional community, required unique features of engagement for the researcher who would be present to the social dynamics surrounding the death of a person of high repute. PMID- 30443849 TI - Correction to: PF-06438179/GP1111: An Infliximab Biosimilar. AB - The article PF-06438179/GP1111: An Infliximab Biosimilar, written by Zaina T. Al Salama. PMID- 30443850 TI - Analysis of miRNA-seq in the liver of common carp (Cyprinus carpio L.) in response to different environmental temperatures. AB - Water temperature affects the survival, growth, immunity, reproduction, and productivity of farmed fish. The temperature beyond suitable range will disrupt the normal physiological activity. Common carp (Cyprinus carpio L.) is a representative eurythermic fish; they are able to sense and respond to changes in water temperature by adjusting their physiology. To investigate the miRNAs in common carp at different temperatures, nine liver small-RNA libraries (5 degrees C, 17 degrees C, and 30 degrees C, each group have three biological repetitions) were constructed and sequenced using high-throughput sequencing. A total of 110 known miRNAs were identified. Twenty-nine known miRNAs were differentially expressed compared with in control group. GO and KEGG analysis indicated that the miRNAs may play important roles in metabolism and environment information processing. Specifically, we considered the insulin-signaling and glycerophospholipid metabolism pathway, and the results show that in 30 degrees C, miR-301a, miR-203b-5p, and miR-210-3p were upregulated; their target genes which are the mechanistic targets of the rapamycin kinase (mtor) gene and the protein kinase AMP-activated catalytic subunit alpha 1 (prkaa1) gene in the insulin-signaling pathway were downregulated. And miR-9-5p, miR-27d, miR-92b-3p, and miR-155 were upregulated; their target genes, 1-acylglycerol-3-phosphate O acyltransferase 3 (agpat3), CDP-diacylglycerol-inositol 3-phosphatidyltransferase (cdipt), glycerol-3-phosphate acyltransferase mitochondrial (gpam), and phosphatidylglycerophosphate synthase 1 (pgs1), in glycerophospholipid metabolism pathway were downregulated. But in 5 degrees C, the situation was opposite. These findings suggest that significant changes occur in energy metabolism and metabolic processes with components of the cell membrane in different temperatures, which significantly advance our understanding of the regulatory mechanisms underlying the physiological change of temperature stress-induced in liver, specifically with regard to miRNAs. These data provide a foundation for further studies of the role of miRNAs in environmental adaptation in fish. PMID- 30443851 TI - Comparative analysis of root transcriptome profiles between low- and high-cadmium accumulating genotypes of wheat in response to cadmium stress. AB - Wheat, one of the most broadly cultivated and consumed food crops worldwide, can accumulate high Cd contents in their edible parts, which poses a major hazard to human health. Cd accumulation ability differs among varieties in wheat, but the underlying molecular mechanism is largely unknown. Here, key genes responsible for Cd accumulation between two contrasting wheat genotypes (low-Cd accumulation one L17, high-Cd accumulation one H17) were investigated. Total 1269 were differentially expressed genes (DEGs) in L17 after Cd treatment, whereas, 399 Cd induced DEGs were found in H17. GO-GO network analysis showed that heme binding was the most active GO, and metal binding was the second one that associated with other GOs in response to Cd stress in both genotypes. Pathway-pathway network analysis showed that phenylpronanoid biosynthesis and glutathione metabolism were the top pathways in response to Cd stress in both genotypes. Furthermore, we found that DEGs related to ion binding, antioxidant defense mechanisms, sulfotransferase activity, and cysteine biosynthetic process were more enriched in L17. In conclusion, our results not only provide the foundation for further exploring the molecular mechanism of Cd accumulation in wheat but also supply new strategies for improving phytoremediation ability of wheat by genetic engineering. PMID- 30443852 TI - Effect of C-Terminus Modification in Salmonella typhimurium FliC on Protein Purification Efficacy and Bioactivity. AB - Recombinant flagellin (FliC) has shown low efficacy in purification because of inclusion bodies formation and aggregation. We hypothesized preserving TLR5 binding site of FliC and removing some amino acids could be responsible for aggregation and solubility improvement. Hence, a bioinformatics study was performed to find hotspots in aggregate formation. Protein modeling was carried out by SWISS-MODEL and I-TASSER servers and models were compared by MATRAS server and Chimera 1.11.2. Gene modification was carried out based on bioinformatics studies. Genes, (truncated modified fliC (tmFliC) and full-length fliC (flFliC)), were cloned and expressed in pET-21a vector. Protein purification was carried out using HIS-Tag method. Proliferation assay and also induction of IL-8 in HEK293 cells were performed to confirm bioactivity function of tmFliC. Bioinformatics results showed that partial deletion of C-terminus may increase solubility without unfavorable effect on TLR5 recognition. Also, model comparison showed that this protein may preserve 3D structure. In addition, GlobPlot server demonstrated that tmFliC formed its globular domains which were important in TLR5 recognition. As we expected, high purification efficacy for tmFliC compared with flFliC was also obtained in experimental studies and a proper function for tmFliC was observed. The tmFliC enhanced cell proliferation in HEK293 cells compare with control after 24 h. Also, IL-8 level was increased with stimulation by tmFliC after 24 h. In conclusion, reducing hydrophobicity in C-terminus and deleting necessary amino acids for filament formation may increase protein solubility. PMID- 30443853 TI - Sialic acids as cellular markers of immunomodulatory action of dexamethasone on glioma cells of different immunogenicity. AB - Glucocorticosteroids, including dexamethasone (Dex), are commonly used to control tumor-induced edema in the brain tumor patients. There are increasing evidences that immunosuppressive action of Dex interferes with immune surveillance resulting in lower patients overall survival; however, the mechanisms underlying these actions remain unclear. Changes in the expression of sialic acids are critical features of many cancers that reduce their immunogenicity and increase viability. Sialoglycans can be recognized by CD33-related Siglecs that negatively regulate the immune response and thereby impair immune surveillance. In this study, we analysed the effect of Dex on cell surface sialylation pattern and recognition of these structures by Siglec-F receptor in poorly immunogenic GL261 and immunogenic SMA560 glioma cells. Relative amount of alpha2.3-, alpha2.6- and alpha2.8-linked sialic acids were detected by Western blot with MAA (Maackia amurensis) and SNA (Sambucus nigra) lectins, and flow cytometry using monoclonal antibody anti-PSA-NCAM. In response to Dex, alpha2.8 sialylation in both, GL261 and SMA560 was increased, whereas the level of alpha2.3-linked sialic acids remained unchanged. Moreover, we found the opposite effects of Dex on alpha2.6 sialylation in poorly immunogenic and immunogenic glioma cells. Furthermore, changes in sialylation pattern were accompanied by dose-dependent effects of Dex on Siglec-F binding to glioma cell membranes as well as decreased alpha neuraminidase activity. These results suggest that glucocorticosteroid-induced alterations in cell surface sialylation and Siglecs recognition may dampen anti tumor immunity, and participate in glioma-promoting process by immune cells. Our study gives new view on corticosteroid therapy in glioma patients. PMID- 30443854 TI - Vascular endothelial growth factor-C promotes human mesenchymal stem cell migration via an ERK-and FAK-dependent mechanism. AB - Vascular endothelial cell growth factor-C (VEGF-C) is a member of the VEGF family and plays a role in various biological activities. VEGF-C enhances proliferation and migration of lymphatic endothelial cells and vascular endothelial cells through VEGF receptor 2 (VEGFR2) and/or receptor 3 (VEGFR3), and thereby induces lymphangiogenesis or angiogenesis. However, it remains unclear whether VEGF-C promotes the migration of mesenchymal stem cells (MSCs). Here, we investigated the effects of VEGF-C on the migration of MSCs and evaluated the underlying molecular mechanisms. VEGF-C treatment significantly induced the migration of MSCs, which is accompanied by the promotion of actin cytoskeletal reorganization and focal adhesion assembly. VEGF-C treatment enhanced the phosphorylation of VEGFR2 and VEGFR3 proteins in MSCs, and pretreatment with VEGFR2 and VEGFR3 kinase inhibitors effectively suppressed the VEGF-C-induced MSC migration. In addition, VEGF-C treatment promoted phosphorylation of ERK and FAK proteins in MSCs, and inhibition of VEGFR2 and VEGFR3 signaling pathways abolished the VEGF-C induced activation of ERK and FAK proteins. Furthermore, treatment with ERK and FAK inhibitors suppressed VEGF-C-induced actin cytoskeletal reorganization and focal adhesion assembly, and then significantly inhibited MSCs migration. These results suggest that VEGF-C-induced MSC migration is mediated via VEGFR2 and VEGFR3, and follows the activation of the ERK and FAK signaling pathway. Thus, VEGF-C may be valuable in tissue regeneration and repair in MSC-based therapy. PMID- 30443855 TI - Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs. AB - The anti-senescence activity of genistein is associated with inducing autophagy; however, the underlying mechanisms are not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein (1000 nM) for 30 min and then exposed to ox-LDL (50 mg/L) for another 12 h. The study found that genistein inhibited the ox-LDL-induced senescence (reducing the levels of P16 and P21 protein, and the activity of SA-beta-gal); meanwhile, the effect of genistein was bound up with enhancing autophagic flux (increasing LC3-II, and decreasing the level of P62, p-mTOR and p-P70S6K). Moreover, SIRT1/LKB1/AMPK pathway was involved in genistein accelerating autophagic flux and mitigating senescence in HUVECs. The present study illustrated that genistein was a promising therapeutic agent to delay aging process and extend longevity. PMID- 30443856 TI - Ultrasound-based detection of glucocorticoid-induced impairments of muscle mass and structure in Cushing's disease. AB - PURPOSE: To investigate the glucocorticoid-induced impairments of muscle mass and structure in patients presenting different stages of steroid myopathy progression. METHODS: Thirty-three patients (28 women) affected by active (N = 20) and remitted (N = 13) Cushing's disease were recruited and the following variables were assessed: walking speed, handgrip strength, total body and appendicular muscle mass by bioelectrical impedance analysis (BIA), thickness and echo intensity of lower limb muscles by ultrasonography. RESULTS: The two groups of patients showed comparable values of both handgrip strength [median (interquartile range) values: active disease: 27.4 (7.5) kg vs. remitted disease: 26.4 (9.4) kg; P = 0.58] and walking speed [active disease: 1.0 (0.2) m/s vs. remitted disease: 1.1 (0.3) m/s; P = 0.43]. Also, the thickness of the four muscles and all BIA-derived sarcopenic indices were comparable (P > 0.05 for all comparisons) between the two groups. On the contrary, the echo intensity of vastus lateralis, tibialis anterior (lower portion), and medial gastrocnemius was significantly (P < 0.05 for all comparisons) higher in patients with active disease compared to patients with remitted disease. Finally, significant negative correlations were found in the whole group of patients between muscle echo intensity and muscle function assessments. CONCLUSIONS: We provided preliminary evidence that the ultrasound-derived measurements of muscle thickness and echo intensity can be useful to detect and track the changes of muscle mass and structure in patients with steroid myopathy and we suggest that the combined assessment of muscle mass, strength, and performance should be systematically applied in the routine examination of steroid myopathy patients. PMID- 30443857 TI - The Italian Registry of GH Treatment: electronic Clinical Report Form (e-CRF) and web-based platform for the national database of GH prescriptions. AB - BACKGROUND: In Italy, the utilization and the reimbursement of Growth Hormone (rGH) therapy by the National Health System (Servizio Sanitario Nazionale) are regulated by the "Note #39" included in the "Notes for the use of drugs" by the Italian Medicines Agency (AIFA), which are published in the Official Gazette, thus having the force of law. The "Note #39" establishes the diagnosis for which the reimbursement is granted and confirms the assignment of the national health surveillance on the use of GH therapy to the Italian National Institute of Health, requesting its computerization. AIM: The aim of this work was to realize a dedicated electronic Clinical Report Form based on the mandatory data requested by the Note #39 and allowing the online reporting of the rGH prescriptions by the regional accredited centers. RESULTS AND CONCLUSIONS: This interface is at the base of the national database of the Italian Registry of GH Treatment, which allows obtaining and managing correct and complete data to provide public health surveillance on GH therapy, both at national and local levels, necessary for policymakers decisions. In addition, this national database could be a useful instrument for improving knowledge about aspects of this treatment still under discussion. PMID- 30443859 TI - Comparison of breast-conserving surgery and mastectomy in early breast cancer using observational data revisited: a propensity score-matched analysis. AB - Recent observational studies showed that breast-conserving surgery (BCS) resulted in superior survival compared to mastectomy in breast cancer patients. This study compared the clinical outcomes of BCS and mastectomy using propensity score (PS) matching analysis, which had advantages over conventional methods in reducing bias. Nonmetastatic breast cancer patients who underwent BCS and mastectomy were matched 1:1 based on their PS. We used the Kaplan-Meier method and Cox-regression model to estimate the treatment effects. A total of 2,866 patients with a median follow-up time of 67 months were included in the original study population. Although the mastectomy cohort (N=1,219) had more advanced disease compared to the BCS cohort (N=1,647), LRFS was similar between the two groups (93.8% vs. 92.4%, P>0.05). BCS (vs. mastectomy) was associated with improved DFS (73.8% vs. 58.7%, P<0.01) and CSS (91% vs. 78.2%, P<0.01) in the original population. In the PS-matched population (N=1,668), clinicopathological features were equally distributed between the two cohorts. BCS (vs. mastectomy) was not associated with improved DFS (70.7% vs. 66.9%, P>0.05) or CSS (87.5% vs. 84.9%, P>0.05). We found that PS methods reduce bias when estimating treatment effects using observational data. BCS and mastectomy show equivalent outcomes in nonmetastatic breast cancer patients. PMID- 30443860 TI - Characterization of H3 methylation in regulating oocyte development in cyprinid fish. AB - Histone post-modifications are important epigenetic markers involved in multiple cellular processes via regulation of gene transcription or remodeling of chromatin structure. Oocyte development is a critical process under rigorous control to prevent the generation of aberrant gametes. However, the regulatory mechanism of oocyte early development is not well-understood due to the tiny size and poor distinguishability of the gonad in juvenile stages. Here, two cyprinid hybrid fishes, a sterile allotriploid fish and a gynogenetic hybrid fish with delayed oocyte development, provided research models to investigate the mechanisms involved. We used cytogenetic and molecular methods to confirm the pachytene arrest of oocytes in allotriploid fish and gynogenetic hybrid fish. On the basis of these developmental differences, we screened 21 different histone H3 modifications by ELISA and found that four modifications (H3K4me3, H3K9me3, H3K79me, and H3K79me3) differed significantly in the two cyprinid hybrid fishes. Changes in histone methylation at the three residues (H3K4, K9, K79) were caused by specific methyltransferases and demethylases. Our results provide new insights into the epigenetic regulation of oocyte early development in fish, a process critical for understanding of reproductive biology and with practical applications in the aquacultural breeding industry. PMID- 30443858 TI - Delivery of pDNA Polyplexes to Bronchial and Alveolar Epithelial Cells Using a Mesh Nebulizer. AB - PURPOSE: In this study, a cell penetrating peptide was used as an uptake enhancer for pDNA delivery to the lungs. METHODS: Polyplexes were prepared between pDNA and CPP. Intracellular delivery of pDNA was assessed in both alveolar (A549) and bronchial (Calu-3) epithelial cells. Aerosol delivery was investigated using a mesh nebulizer. RESULTS: Efficient intracellular delivery of pDNA occurs in both A549 and Calu-3 cells when delivered as polyplexes. Protection against nucleases and endosomal escape mechanism occurs when pDNA is formulated within the polyplexes. For aerosol delivery, 1% (w/v) mannitol was able to protect naked DNA structure during nebulization with a significant increase in fine particle fraction (particles <5 MUm). The structure of polyplexes when delivered via a mesh nebulizer using 1% (w/v) mannitol could partially withstand the shear forces involved in aerosolization. Although some loss in functionality occurred after nebulization, membrane-associated fluorescence was observed in A549 cells. In Calu-3 cells mucus entrapment was a limiting factor for polyplex delivery. CONCLUSIONS: The presence of CPP is essential for efficient intracellular delivery of pDNA. The polyplexes can be delivered to lung epithelial cells using mesh nebulizer. The use of different excipients is essential for further optimization of these delivery systems. PMID- 30443861 TI - Diversity, evolutionary contribution and ecological roles of aquatic viruses. AB - Aquatic viruses include infected viruses in aquatic animals, plants and microorganisms, and free-floating viruses (virioplankton) in water environments. In the last three decades, a huge number of aquatic viruses, especially diverse free-floating viruses, including cyanophages, phycoviruses, archaea viruses, giant viruses, and even virophages, have been identified by virological experiments and metagenomic analyses. Based on a comprehensive introduction of aquatic virus classification and their morphological and genetic diversity, here, we summarize and outline main virus species, their evolutionary contribution to aquatic communities through horizontal gene transfer, and their ecological roles for cyanobacterial bloom termination and global biogeochemical cycling in freshwater and marine ecosystems. Thereby, some novel insights of aquatic viruses and virus-host interactions, especially their evolutionary contribution and ecological rolesin diverse aquatic communities and ecosystems, are highlighted in this review. PMID- 30443862 TI - Diverse and variable sex determination mechanisms in vertebrates. AB - Sex is prevalent in nature and sex determination is one of the most fundamental biological processes, while the way of initiating female and male development exhibits remarkable diversity and variability across vertebrates. The knowledge on why and how sex determination mechanisms evolve unusual plasticity remains limited. Here, we summarize sex determination systems, master sex-determining genes and gene-regulatory networks among vertebrates. Recent research advancements on sex determination system transition are also introduced and discussed in some non-model animals with multiple sex determination mechanisms. This review will provide insights into the origin, transition and evolutionary adaption of different sex determination strategies in vertebrates, as well as clues for future perspectives in this field. PMID- 30443863 TI - [The impact of neighbourhood-based work on helping older migrants gain access to care : Older migrants and neighbourhood-based work in care and social services]. AB - This article studies how older migrants gain access to care through neighbourhood based forms of working. In the Netherlands, the neighbourhood is increasingly viewed as an ideal place to organize care and social services, close to citizens. To this end, municipalities are developing neighbourhood structures and facilities in which local providers cooperate. In our qualitative research we studied the developments in crafting practices relevant to access to care of older migrants in the city of Nijmegen, the Netherlands. In Nijmegen the new neighbourhood structures are only partly successful in helping older migrants gain access to care. Older migrants visit neighbourhood facilities not for the services these facilities provide, but because of the presence of care professionals who speak the same language, or share the same cultural background as do these older migrants. These caregivers are able to bridge the mental distance between the health care system and the lifeworld of older migrants. Relations also arise outside the neighbourhood structures, for instance at culture-specific day care facilities. To prevent too great a claim on professionals with a migration background, agreements between the city of Nijmegen and local providers to enhance cultural sensitivity should be better monitored. PMID- 30443864 TI - Impact of Experience-Based, Longitudinal Psychiatry Training on Family Medicine Residents' Attitudes Toward Depression and Psychiatry in Singapore: a Prospective Study. AB - OBJECTIVES: The primary aim of this study was to evaluate the impact of an experience-based, longitudinal psychiatry training program in a Family Medicine residency on residents' attitudes toward depression and psychiatry. The secondary aim was to identify background predictor variables of changes in attitudes. METHODS: Pre- and post-training surveys were prospectively conducted on attitudes toward depression and psychiatry on Family Medicine residents undergoing an experience-based, longitudinal psychiatry training program. The primary outcome measures were pre- and post-training Depression Attitude Questionnaire (DAQ) and Modified Attitudes to Psychiatry Scale (mAPS) scores. Regression analysis was carried out to determine background variables predictive of improvement in DAQ and/or mAPS scores post-training. RESULTS: Sixty-three Family Medicine residents (100% response rate) responded to the pre-training surveys. All 63 subjects completed the post-training surveys (100% retention rate). There was significant improvement in DAQ and mAPS scores post-training, indicating better attitudes toward depression and psychiatry. Significant improvement was observed in 8 out of 13 DAQ items and 3 out of 4 mAPS domains. Regression models showed having a previous 3-month elective psychiatry inpatient posting was a predictor of less improvement in mAPS scores. CONCLUSIONS: Our experience-based, longitudinal psychiatry training program significantly improved Family Medicine residents' attitudes toward depression and psychiatry. Experiential and situated learning in communities of practice, as well as educational continuity with longitudinal supervision, coaching, and modeling may have contributed to this improvement. PMID- 30443865 TI - Do we need CBCTs for sufficient diagnostics?-dentist-related factors. AB - BACKGROUND: The aim of this study was to assess the diagnostic accuracy of various dentoalveolar pathologies based on panoramic radiography (OPG), cone beam computed tomography (CBCT) and printed 3D models in consecutive order; and to evaluate the impact of specialisation of residents in oral surgery (OS) versus residents in orthodontics (ORTH). METHODS: Fourteen residents were recruited to evaluate nine selected cases with different dentoalveolar pathologies. The residents were given for each case an OPG, a CBCT and a printed 3D model. For each case and imaging modality, the residents were asked several questions relating to (i) diagnosis, and (ii) the request for consecutive imaging in order to enable treatment. Further, aspects like impact of specialisation (OS versus ORTH), gender and years of experience were analysed. RESULTS: In this study, diagnostic accuracy (i) improved for OS from OPG to CBCT (OPG 66.3%, CBCT 83.4%) and likewise for ORTH (OPG 63.7%, CBCT 78.0%). 3D models generally did not seem more useful than CBCTs. For treatment planning (ii), residents in orthodontics considered OPGs significantly more often as sufficient compared to residents in oral surgery (OR 6.3, p < 0.001). Further, the odds to request a CBCT after OPG for treatment planning is influenced by dentist-related factors: female dentists (OR 3.8) or residents with limited professional experience as dentists (OR 3.0) asked more frequently for a CBCT. CONCLUSIONS: Overall diagnostic accuracy is decent with OPG and can be improved with CBCT. Specialisation seems to have a moderate impact on diagnostic accuracy, but influences whether a CBCT was requested for treatment planning. Based on these findings, future studies shall analyse the diagnostic accuracy of specific pathologies in higher number in order to substantiate the present findings with regard to specific pathologies. PMID- 30443866 TI - Synthesis and antitumor activities of 3-substituted-analine derivatives: structure modifications of Tuv part of tubulysins. AB - BACKGROUND: Tubulysins family is a kind of natural compound with potent, antitumor activity. To simplify the synthesis route and find new antitumor compounds is becoming a hotspot of research recent years. RESULTS: Starting from 3-nitrobenzoic acid, after 7 steps transformations, 12 new tubulysin analogues were synthesized by the conformational restraint and bioisostere principle. These structures are featuring 3-substituted analine moieties. All these compounds are new compounds, and the structures were characterized by 1H NMR, 13C NMR, and HRMS. The antitumor activities were screened by the MTT method using MDA-MB 231and MCF7 cells. CONCLUSIONS: Compound IIb exhibited certain antitumor activity with the IC50 value of 7.6 and 11.8 uM against MDA-MB-231 and MCF7 cells respectively. Compounds IIa-IIe had moderate antitumor activities suggested that the thiazole ring in the Tuv could be replaced by the phenyl ring. However, Compounds Ia-Ie lose antitumor activity dramatically suggested that the conformation of the Tuv was crucial for the tubulysin analogues to maintain the biological activity. PMID- 30443867 TI - Lung aeration and ventilation after percutaneous tracheotomy measured by electrical impedance tomography in non-hypoxemic critically ill patients: a prospective observational study. AB - BACKGROUND: Percutaneous dilatational tracheotomy (PDT) may lead to transient impairment of pulmonary function due to suboptimal ventilation, loss of positive end-expiratory pressure (PEEP) and repetitive suction maneuvers during the procedure. Possible changes in regional lung aeration were investigated using electrical impedance tomography (EIT), an increasingly implied instrument for bedside monitoring of pulmonary aeration. METHODS: With local ethics committee approval, after obtaining written informed consent 29 patients scheduled for elective PDT under bronchoscopic control were studied during mechanical ventilation in supine position. Anesthetized patients were monitored with a 16 electrode EIT monitor for 2 min at four time points: (a) before and (b) after initiation of neuromuscular blockade (NMB), (c) after dilatational tracheostomy (PDT) and (d) after a standardized recruitment maneuver (RM) following surgery, respectively. Possible changes in lung aeration were detected by changes in end expiratory lung impedance (Delta EELI). Global and regional ventilation was characterized by analysis of tidal impedance variation. RESULTS: While NMB had no detectable effect on EELI, PDT led to significantly reduced EELI in dorsal lung regions as compared to baseline, suggesting reduced regional aeration. This effect could be reversed by a standardized RM. Mean delta EELI from baseline (SE) was: NMB - 47 +/- 62; PDT - 490 +/- 180; RM - 89 +/- 176, values shown as arbitrary units (a.u.). Analysis of regional tidal impedance variation, a robust measure of regional ventilation, did not show significant changes in ventilation distribution. CONCLUSION: Though changes of EELI might suggest temporary loss of aeration in dorsal lung regions, PDT does not lead to significant changes in either regional ventilation distribution or oxygenation. PMID- 30443869 TI - Oncologic outcomes of nephron-sparing surgery in patients with T1 multifocal renal cell carcinoma. AB - OBJECTIVE: This study is performed to explore the pathological characteristics and oncologic outcomes of T1 multifocal renal cell carcinoma (RCC). METHODS: The clinical data of 600 patients (442 males and 158 females) between the age of 29 and 73 years, diagnosed with T1 RCC were collected from three hospitals in China, out of which 421 cases had undergone nephron-sparing surgery (NSS) and 179 cases had undergone radical nephrectomy (RN) between December 2010 and January 2015. RESULTS: Tumor was identified with multifocality in 32 patients (5.33%), out of which 21 were set to receive NSS, and 11 to receive RN, respectively; 21 cases of clear cell tumor, 8 cases of papillary tumor, 1 case of chromophobe tumor and 2 cases of Xp.11.2 translocation RCC. Among 568 cases of monofocal tumors, 400 patients underwent NSS, and the remaining 168 patients underwent RN, respectively. After a median follow-up of 5 years, 13 patients were found with recurrent tumors out of those who had undergone NSS, 11 with monofocal tumors and 2 with multifocal tumors containing satellite tumor nodules (p = 0.13). Out of the 32 individuals with multifocal RCC, 4 cases were reported to have died of cancer, 2 of NSS and 2 of RN. From these findings, the cancer-specific survival for NSS and RN was estimated to be 90.48% and 81.82%, respectively (p = 0.48). CONCLUSION: The findings from the study suggested that there were pathological differences in multifocal renal tumors, and that papillary carcinoma may be more common than clear cell carcinoma. The recurrence rate and survival rate of multifocal RCC were similar to monofocal tumors. Tumor recurrence may be related to satellite tumor nodules, which can only be detected once surgery is performed. PMID- 30443868 TI - SEOM clinical guidelines in early stage breast cancer (2018). AB - Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20 30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy. PMID- 30443870 TI - Understanding modern, technological medicine: enchanted, disenchanted, or other? PMID- 30443871 TI - Drugs that Can Kill a Toddler with One Tablet or Teaspoonful: A 2018 Updated List. AB - BACKGROUND AND OBJECTIVE: Young children may be accidentally exposed to adult dose forms of medications, some of which can be fatal, even with a single dose. As numerous new medications have been introduced, we herein update a 2004 list of potentially toxic drugs that can be lethal for toddlers when taking one adult dose unit. METHODS: We reviewed all medications available in North America and identified their reported fatal doses per kilogram in children, or in adults if no pediatric data were available. For each drug we identified the largest dose unit available on the market and calculated how many dose units would be fatal to a 10 kg toddler. RESULTS: Since 2004, the list of potentially fatal drugs for toddlers has doubled and now includes new anticoagulants, a phosphodiesterase-5 inhibitor, new antiepileptic drugs, antidiabetic medications, drugs for multiple sclerosis, and second-generation antipsychotic drugs, among others. CONCLUSION: With the development of potent new medications, an increasing number of drugs are dangerous upon accidental exposure to toddlers and young children. The present 2018 list of documented fatal drugs has doubled compared with 2004, and special labeling of these medications is urgently needed to avoid such calamities. PMID- 30443872 TI - Correction to: Eyes, More Than Other Facial Features, Enhance Real-World Donation Behavior. AB - In Fig. 2 of the aforementioned article the mean value of the "chair" condition is incorrectly displayed as 0.011 when it should be 0.008. All statistics in the text are correct, and the conclusions remain the same. PMID- 30443873 TI - Utility of strain imaging in conjunction with heart failure stage classification for heart failure patient management. AB - The American College of Cardiology Foundation/American Heart Association (ACCF/AHA) classification, based on structural changes and symptoms, classifies stages of heart failure (HF) development as Stages A-D. This HF classification emphasizes the development and progression of the disease and can be used to describe individuals and populations. Since HF is considered a progressive disorder that can be represented as a clinical continuum, individuals at a particular HF stage require specific management with the long-term goal of avoiding HF development and progression. Although early detection of subclinical left ventricular (LV) dysfunction is essential for delaying progression to HF, the assessment of such dysfunction can be challenging. While echocardiography plays a pivotal role in the quantification and early detection of LV structural findings, two-dimensional speckle-tracking echocardiographic parameters, especially global longitudinal strain (GLS), have recently been reported to be sensitive markers of early subtle abnormalities of LV myocardial performance. They are thus helpful for prediction of outcomes for various cardiac diseases, and superior to conventional echocardiographic indices such as LV ejection fraction, mitral inflow E and mitral e' annular velocities ratio. Strain imaging, especially GLS-guided management for patients at a particular stage of HF, may therefore have the potential to prevent progression to later HF stages and may offer new insights into the management of HF patients. This article reviews the utility of strain imaging, especially GLS in conjunction with HF stage classification, and future perspectives for HF patient management. PMID- 30443874 TI - Identification of Peptides Implicated in Antibacterial Activity of Snow Crab Hepatopancreas Hydrolysates by a Bioassay-Guided Fractionation Approach Combined with Mass Spectrometry. AB - Snow crab (Chionoecetes opilio) by-products are a rich source of biomolecules, such as lipids, proteins, and chitin, which have not been extensively investigated. This study aims to identify antibacterial peptides to enhance the value of C. opilio by-products. After hydrolysis of different component parts using Protamex(r), and concentration by solid-phase extraction, the resulting fractions were tested for antibacterial activity against Escherichia coli, Listeria innocua, and Vibrio parahaemolyticus. Hepatopancreas was the only tissue to display antibacterial activity detected using this protocol. Four fractions obtained with and without enzymatic hydrolysis of hepatopancreas followed by SPE C18 fractionation and elution with 50 and 80% acetonitrile demonstrated bacteriostatic activity against L. innocua HPB13, from concentrations of 0.30 to 43.05 mg/mL of peptides/proteins. Eleven peptides sharing at least 80% amino acid homology with four antimicrobial peptides were identified by mass spectrometry. Two peptides had homology to crustin-like and yellowfin tuna GAPDH antimicrobial peptides belonging to the marine organisms Penaeus monodon and Thunnus albacares, respectively. Other peptide sequence homologies were also identified: Odorranain C7 from the frog Odorrana grahami and a predicted antibacterial peptide in the Asian ladybeetle Harmonia axyridis. These active peptides may represent a novel group of bioactive peptides deserving further investigation as food preservatives. PMID- 30443876 TI - Female Genital Cutting: Clinical knowledge, Attitudes, and Practices from a Provider survey in the US. AB - Migration from countries where female genital cutting (FGC) is practiced means women's healthcare providers need to meet this population's unique healthcare needs. We explored providers' FGC-related experience, knowledge of the cultural practice, prior training, attitudes towards medicalization, including reinfibulation, and clinical practice. An online, 53-question survey to a multidisciplinary sample of women's health providers in the US were recruited by email via professional organizations, medical departments, and the authors' professional networks. From a total of 508 usable surveys, nearly half of respondents did not receive formal FGC training, but a majority had cared for FGC affected women in their practice. A 'know-do' gap existed with managing infibulated patients; and surgical defibulation procedures were not routinely offered. Most respondents (79%, n = 402) reported a desire for additional education. Women's healthcare providers in the US, regardless of disciplinary backgrounds, are inadequately prepared to meet the needs of FGC-affected women. To address these, FGC content needs to be embedded in educational and training curricula, and ongoing clinical mentorship made available. PMID- 30443877 TI - Health Care Decisions and Delay of Treatment in Companion Animal Owners. AB - Previous research has indicated that companion animal ownership may confer health benefits; however, no studies have considered how companion animal ownership impacts key health decisions. The purpose of the current studies was to examine the extent to which animal-related factors influence health care decision making, specifically, owners' willingness to proceed with necessary medical treatments. In Study 1, a sample of 162 companion animal owners was recruited via Amazon Mechanical Turk to complete an online survey which included measures of social support, quality of relationship with the companion animal and two vignettes describing needed hospitalization. Results suggest that nearly half of companion animal owners would consider delaying a hospitalization due to reasons related to ownership. Similarly, in Study 2, dog owners were compared to a group of non-pet owners. Dog owners were more likely to report willingness to delay medical procedures due to their pets than non-pet owners were to consider delay due to friends or family members. Owners' health care decisions may be influenced by their relationship with their companion animal. Particularly at risk for delaying health procedures are those with lower levels of social support. While further study is needed, opportunities for intervention are considered. PMID- 30443878 TI - Induced expression of small heat shock proteins is associated with thermotolerance in female Laodelphax striatellus planthoppers. AB - Insects are often exposed to high temperature stress in natural environments, but the mechanisms involved in thermotolerance in many insect groups like Hemiptera are not well known. To explore possible mechanisms of thermotolerance in the hemipteran pest Laodelphax striatellus, which damages rice through direct feeding and viral transmission, small heat shock proteins (sHsps) implicated in thermotolerance in other insect groups were identified. The seven sHsps identified have a conserved alpha crystallin domain, a variable N-terminal region, and shared relative low identities to each other. Three of the sHsp genes (LsHsp20.5, LsHsp21.5, and LsHsp21.6) exhibited higher basal expression than the other four genes but showed weak or no heat-induced expression. The other four genes (LsHsp20.1, LsHsp21.2, LsHsp21.4, and LsHsp22.0) were induced up to 3306 fold by heat. Injection of dsRNA indicated that expression of these sHsps was associated with thermotolerance, and Escherichia coli transformed with LsHsp21.2 and LsHsp20.1 showed relatively higher thermotolerance. These results point to an important functional role of these sHsps for thermotolerance in L. striatellus. PMID- 30443879 TI - Application of microbial fuel cell technology for vinasse treatment and bioelectricity generation. AB - OBJECTIVE: Our study evaluated the performance of different two-chambered microbial fuel cell (MFC) prototypes, operated with variable distance between electrodes and Nafion membrane and specific inoculum concentration, applied for vinasse treatment. RESULTS: The performance of the developed MFC resulted in a maximum current density of 1200 mA m-2 and power density of 800 mW m-2 in a period of 61 days. MFC performed a chemical oxygen demand removal at a rate ranging from 51 to 60%. CONCLUSIONS: Taking our preliminary results into consideration, we concluded that the MFC technology presents itself as highly promising for the treatment of vinasse. PMID- 30443880 TI - YouTube English videos as a source of information on breast self-examination. AB - OBJECTIVE: To examine the content, quality and reliability of YouTube videos related to breast self-examination. DESIGN: A search of YouTube was made on 21.06.2018 using the keyword of "breast self-examination". The videos were categorised by two doctors as useful information or misleading information. To evaluate the quality of the videos, a 5-point global quality scale was used (GQS: 1 = poor quality, 5 = excellent quality), for reliability a 5-point DISCERN scale was used, and for content an 8-point scale (higher points indicated greater reliability and better content). RESULTS: Of the 200 videos initially included in the study, 33 (37.9%) were classified as useful and 54 (62%) as misleading information. The reliability, content and quality scores of the videos in the useful information group were higher. The length (in seconds) of the videos in the useful information group (median 301, IQR 231-512) was longer than that of those in the misleading information group (median 163, IQR 94.8-231) (p = 0.003). The majority (70.6%) of the videos in the misleading information group had been uploaded by an individual user. The number of views per day of the videos in the misleading information group (median 58.6, IQR 18.5-298) was greater than that of the videos in the useful information group (median 49.7, IQR 16.3-268) (p = 0.276). The number of total views was higher for the misleading information group (median 83807 vs. 80237) but not at a level of statistical significance (p = 0.153). There were more videos explaining breast self-examination directed at women only, and there were determined to be few videos including men only or both genders. CONCLUSION: Although there are many videos in English related to breast self-examination on YouTube, a great many of these contain misleading information. Therefore, for public information, there is a need for videos with full and accurate information to be made by universities, healthcare organisations and doctors not benefitting from the outcomes, to be uploaded to YouTube, which is a currently important source of information for the general population. PMID- 30443881 TI - Treatment delays from transfers of care and their impact on breast cancer quality measures. AB - PURPOSE: Despite delays between diagnosis and surgery adversely affecting survival, patients frequently transfer their breast cancer care between institutions. This study was performed to assess the prevalence and effect of such transfers of care (TsOC) on the time to surgery, and its impact on current time-dependent breast cancer quality metrics at Commission on Cancer (CoC) and National Accreditation Program for Breast Centers (NAPBC)-accredited institutions. METHODS: Patients having non-metastatic invasive breast cancer diagnosed between 2006 and 2015 at CoC and NAPBC centers ("reporting facilities") in the National Cancer Database were reviewed. TsOC refer to transferring into or out of a reporting facility between diagnosis and surgery. RESULTS: Among 622,793 patients, 36.6% of patients transferred care. TsOC add 7.3, 7.8, 8.7, and 9.8 days in time to surgery, chemotherapy, radiotherapy, and endocrine therapy, respectively (p's < 0.0001). On multivariable analysis, the odds of surgery occurring > 90 days from diagnosis were greatest for patients undergoing unilateral or bilateral mastectomy, Black or Hispanic patients, and those having TsOC (ORs > 1.73, p's < 0.0001). TsOC increase the odds of non-compliance, per patient, for chemotherapy, radiotherapy and endocrine therapy time-dependent measures by 65.4%, 25.6%, and 56.5%, respectively (p < 0.0001). CONCLUSIONS: TsOC for newly diagnosed breast cancers to or from an accredited facility result in delays in time to surgery which can affect compliance with time-dependent quality measures. Facilities frequently receiving transferred patients may be most adversely affected. Although non-compliance with these quality measures is low, institutions and accrediting bodies should be aware of these associations in order to comply with time-dependent standards. PMID- 30443882 TI - Photobiomodulation modulates the resolution of inflammation during acute lung injury induced by sepsis. AB - Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI. PMID- 30443883 TI - Comparison of high-intensity laser therapy and combination of ultrasound treatment and transcutaneous nerve stimulation in patients with cervical spondylosis: a randomized controlled trial. AB - The aim of the study was to compare the effect of high-intensity laser therapy (HILT) and a combination of ultrasound (US) treatment and transcutaneous nerve stimulation (TENS) on pain, range of motion (ROM), and functional activity in patients with cervical spondylosis (CS). A total of 84 patients with a mean age of 51.54 years (52 women and 32 men) affected by CS were enrolled in this study. Patients were randomly divided into two groups. In group A (42 subjects), patients received 12 sessions of HILT plus exercise, while in group B (42 subjects), they received a combination of US, TENS, and exercise. The outcomes measured were cervical segment ROM, pain level measured by visual analogue scale (VAS), and functional activity measured by neck disability index (NDI) at the end of the therapy. The level of statistical significance was set as p < 0.05. In the two groups, cervical ROM, VAS, and functional scores showed significant changes. Both HILT plus exercise and US/TENS plus exercise effectively increased cervical ROM and reduced pain (with a significant greater decrease in group A). Statistically significant differences in NDI scores were observed after treatment sessions with better results for participants enrolled in group A (HILT plus exercise) Both therapeutic modalities demonstrated analgesic efficacy and improved function in patients affected by cervical spondylosis 4 weeks after the therapy. HILT plus exercise was more effective than US/TENS plus exercise. HILT can be promoted and used in this pathology with positive outcomes. However, further studies are needed to optimize the dose and duration of HILT therapy. PMID- 30443884 TI - Malignant transformation of oral leukoplakia treated with carbon dioxide laser: a meta-analysis. AB - A series of studies are dedicated to research the clinical outcomes of oral leukoplakia (OLK) treated with carbon dioxide laser (CO2 laser); however, the results vary from studies especially related to recurrence and malignant transformation. Hence, we performed this meta-analysis to precisely evaluate the malignant transformation of OLK dealt with CO2 laser and investigate the association between its malignant transformation and kinds of related risk factors, such as gender, clinical classification, long duration of leukoplakia, and degree of epithelial dysplasia and lesion regions. We performed a systematic search of the Cochrane Library, EMBASE, Pubmed, Web of Science, and SCOPUS. Single-arm rate of the overall risk of malignant transformation in OLK treated with CO2 laser was calculated using the Der-Simonian Liard method. We applied subgroup analysis to compare the risk of malignant transformation according to the degree of epithelial dysplasia, clinical type, and region of OLK. Moreover, a pooled odds ratio (OR) is calculated, along with its 95% confidence interval (CI), to compare the risk of malignant transformation according to patients' gender, tobacco, and alcohol consumption. We used the meta package of R software for quantitative data synthesis and analysis. The rate of malignant transformation of OLK treated with carbon dioxide laser ranged from 0 to 15.38% in included studies. The overall rate of malignant transformation of OLK treated with CO2 laser is 4.50% under the random effect model [95% CI 0.0305-0.0659]. A systematic review of observational studies of OLK reported that the estimated overall (mean) malignant transformation rate was 3.5%, with a wide range between 0.13 and 34.0%. Interestingly, our result revealed that it was the male, homogeneous type, no tobacco consumption, and without alcohol-use who had a higher tendency of malignancy after laser surgery. However, this result lack statistically significant data. Generally speaking, whether oral leukoplakia patients underwent laser surgical treatment or not, it may have little effect on malignant transformation. In addition, we strongly advise that it had better not to perform CO2 laser intervention on OLK patients with the following clinical characteristics: homogeneous type, male, no tobacco consumption, and without alcohol-use. Evidence is still lacking in terms of relationship between malignant transformation and risk factors among OLK patients managed with CO2 laser. Thus, these associations should be further investigated. PMID- 30443885 TI - The Acute Phase of Experimental Subarachnoid Hemorrhage: Intracranial Pressure Dynamics and Their Effect on Cerebral Blood Flow and Autoregulation. AB - Clinical presentation and neurological outcome in subarachnoid hemorrhage (SAH) is highly variable. Aneurysmal SAH (aSAH) is hallmarked by sudden increase of intracranial pressure (ICP) and acute hypoperfusion contributing to early brain injury (EBI) and worse outcome, while milder or non-aneurysmal SAH with comparable amount of blood are associated with better neurological outcome, possibly due to less dramatic changes in ICP. Acute pressure dynamics may therefore be an important pathophysiological aspect determining neurological complications and outcome. We investigated the influence of ICP variability on acute changes after SAH by modulating injection velocity and composition in an experimental model of SAH. Five hundred microliters of arterial blood (AB) or normal saline (NS) were injected intracisternally over 1 (AB1, NS1), 10 (AB10, NS10), or 30 min (AB30) with monitoring for 6 h (n = 68). Rapid blood injection resulted in highest ICP peaks (AB1 median 142.7 mmHg [1.Q 116.7-3.Q 230.6], AB30 33.42 mmHg [18.8-38.3], p < 0.001) and most severe hypoperfusion (AB1 16.6% [11.3 30.6], AB30 44.2% [34.8-59.8]; p < 0.05). However, after 30 min, all blood groups showed comparable ICP elevation and prolonged hypoperfusion. Cerebral autoregulation was disrupted initially due to the immediate ICP increase in all groups except NS10; only AB1, however, resulted in sustained impairment of autoregulation, as well as early neuronal cell loss. Rapidity and composition of hemorrhage resulted in characteristic hyperacute hemodynamic changes, with comparable hypoperfusion despite different ICP ranges. Only rapid ICP increase was associated with pronounced and early, but sustained disruption of cerebral autoregulation, possibly contributing to EBI. PMID- 30443886 TI - Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and Vascular Cognitive Impairment. AB - White matter hyperintensities (WMH) are presumed to indicate subcortical ischemic vascular disease but their underlying pathobiology remains incompletely understood. The soluble epoxide hydrolase (sEH) enzyme converts anti-inflammatory and vasoactive cytochrome p450-derived polyunsaturated fatty acid epoxides into their less active corresponding diol species. Under the hypothesis that the activity of sEH might be associated with subcortical ischemic vascular disease and vascular cognitive impairment, this study aimed to compare the relative abundance of sEH substrates and products in peripheral blood between patients with extensive WMH (discovered due to transient ischemic attack; n = 29) and healthy elderly with minimal WMH (n = 25). The concentration of 12,13-DiHOME (a sEH-derived linoleic acid metabolite), and the ratio of 12,13-DiHOME to its sEH substrate, 12,13-EpOME, were elevated in the extensive WMH group (F1,53 = 5.9, p = 0.019), as was the 9,10-DiHOME/9,10-EpOME ratio (F1,53 = 5.4, p = 0.024). The 12,13-DiHOME/12,13-EpOME ratio was associated with poorer performance on a composite score derived from tests of psychomotor processing speed, attention, and executive function (beta = - 0.473, p = 0.001, adjusted r2 = 0.213), but not with a composite verbal memory score. In a mediation model, periventricular WMH (but not deep WMH), explained 37% of the effect of the 12,13-DiHOME/12,13-EpOME ratio on the speed/attention/executive function composite score (indirect effect = - 0.50, 95% bootstrap confidence interval [- 0.99, - 0.17] Z-score units). Serum oxylipin changes consistent with higher sEH activity were markers of vascular cognitive impairment, and this association was partly explained by injury to the periventricular subcortical white matter. PMID- 30443887 TI - Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale. AB - Immunotherapy of multiple sclerosis (MS) and other neuroimmune diseases is rapidly evolving. For the past 25 years, there has been an accelerating inclusion of new immunomodulating drugs. Based on their molecular construction and their basic mechanism of action, immunotherapeutic agents belong to the following categories: (1) cytotoxic drugs, (2) synthetic immunomodulators, (3) monoclonal antibodies, (4) vaccines (T cell vaccines, antigen vaccines), (5) oral tolerizing agents, (6) modalities that act as indirect immunosuppressants (plasmapheresis, intravenous immunoglobulins [IVIG]), and (7) cellular therapies. MS immunotherapies may also be classified in a different way, into treatments that are given continuously (chronic treatments) and medications that are applied intermittently (IRTs). The principle behind the latter is depletion of the immune system that allows it to rebuild itself. Upon its reconstitution/resetting, the immune system regains the ability to respond to infections and survey the periphery for cancer. An IRT by definition is given at short intermittent courses and not continuously. IRT modalities were shown to induce long-term remission of MS that, in some cases, is close to the definition of a "cure." There are cohorts of patients having been treated with the IRTs, alemtuzumab, and HSCT, who experience-under these modalities-no evidence of disease activity (NEDA) for over 10 years. Most importantly, IRTs cause radical changes in the lymphocyte repertoire after the reconstitution phase that may explain the long-term beneficial effects of IRT and the possibility of re-induction of self-tolerance to self/myelin antigens. In comparison, a chronic treatment cannot result in cure of the autoimmune reactivity, because it only blocks the immune system, as long as it is given; it cannot therefore radically affect the immunopathogenesis of the disease. The risks of adverse events related to immune suppression (such as opportunistic infections and secondary malignancies) with IRTs are lower and front-loaded, whereas the common side effects of chronic immunomodulation are higher and accumulate with time. In conclusion, IRT provides a novel concept for MS therapy with substantial advantages over chronic immunosuppression. IRT therapies have shown a significantly higher level of efficacy in MS. The "Holy grail" of the treatment of autoimmunity, which is to re-induce the disrupted self tolerance, seems to be achievable-at least in part-with this approach. Moreover, the benefits of IRT, administered in short pulses, include significantly higher adherence to treatment and lower risks for accumulative side effects that are typically associated with chronic immunosuppression. PMID- 30443888 TI - Frequency and intensity of pulmonary bone marrow and fat embolism due to manual or automated chest compressions during cardiopulmonary resuscitation. AB - Iatrogenic consequences of cardiopulmonary resuscitation (CPR) include sternal or rib fractures, pulmonary bone marrow embolisms (BME) and fat embolisms (FE). This report aimed to analyze the frequency and intensity of pulmonary BME and FE in fatal cases receiving final CPR efforts with the use of automated chest compression devices (ACCD) or manual chest compressions (mCC). The study cohort (all cardiac causes of death, no ante-mortem fractures) consisted of 15 cases for each group 'ACCD', 'mCC' and 'no CPR'. Lung tissue samples were retrieved and stained with hematoxylin eosin (n = 4 each) and Sudan III (n = 2 each). Evaluation was conducted microscopically for any existence of BME or FE, the frequency of BME-positive vessels, vessel size for BME and the graduation according to Falzi for FE. The data were compared statistically using non parametric analyses. All groups were matched except for CPR duration (ACCD > mCC) but this time interval was linked to the existence of pulmonary BME (p = 0.031). Both entities occur in less than 25% of all cases following unsuccessful CPR. BME was only detectable in CPR cases, but was similar between ACCD and mCC cases for BME frequency (p = 0.666), BME intensity (p = 0.857) and the size of BME-affected pulmonary vessels (p = 0.075). If any, only mild pulmonary FE (grade I) was diagnosed without differences in the CPR method (p = 0.624). There was a significant correlation between existence of BME and FE (p = 0.043). Given the frequency, intensity and size of pulmonary BME and FE following CPR, these conditions may unlikely be considered as causative for death in case of initial survival but can be found in lower frequencies in autopsy histology. PMID- 30443889 TI - "Deep-Onto" network for surgical workflow and context recognition. AB - PURPOSE: Surgical workflow recognition and context-aware systems could allow better decision making and surgical planning by providing the focused information, which may eventually enhance surgical outcomes. While current developments in computer-assisted surgical systems are mostly focused on recognizing surgical phases, they lack recognition of surgical workflow sequence and other contextual element, e.g., "Instruments." Our study proposes a hybrid approach, i.e., using deep learning and knowledge representation, to facilitate recognition of the surgical workflow. METHODS: We implemented "Deep-Onto" network, which is an ensemble of deep learning models and knowledge management tools, ontology and production rules. As a prototypical scenario, we chose robot assisted partial nephrectomy (RAPN). We annotated RAPN videos with surgical entities, e.g., "Step" and so forth. We performed different experiments, including the inter-subject variability, to recognize surgical steps. The corresponding subsequent steps along with other surgical contexts, i.e., "Actions," "Phase" and "Instruments," were also recognized. RESULTS: The system was able to recognize 10 RAPN steps with the prevalence-weighted macro-average (PWMA) recall of 0.83, PWMA precision of 0.74, PWMA F1 score of 0.76, and the accuracy of 74.29% on 9 videos of RAPN. CONCLUSION: We found that the combined use of deep learning and knowledge representation techniques is a promising approach for the multi-level recognition of RAPN surgical workflow. PMID- 30443890 TI - Delayed Application of Binding Condition C During Cataphoric Pronoun Resolution. AB - Previous research has shown that during cataphoric pronoun resolution, the predictive search for an antecedent is restricted by a structure-sensitive constraint known as 'Condition C', such that an antecedent is only considered when the constraint does not apply. Evidence has mainly come from self-paced reading (SPR), a method which may not be able to pick up on short-lived effects over the timecourse of processing. This study investigates whether or not the active search mechanism is constrained by Condition C at all points in time during cataphoric processing. We carried out one eye-tracking during reading and a parallel SPR experiment, accompanied by offline coreference judgment tasks. Although offline judgments about coreference were constrained by Condition C, the eye-tracking experiment revealed temporary consideration of antecedents that should be ruled out by Condition C. The SPR experiment using exactly the same materials indicated, conversely, that only structurally appropriate antecedents were considered. Taken together, our results suggest that the application of Condition C may be delayed during naturalistic reading. PMID- 30443891 TI - Lipid Production by Arctic Microalga Chlamydomonas sp. KNF0008 at Low Temperatures. AB - A lipid-producing microalga, Chlamydomonas sp. KNF0008, collected from the Arctic was capable of growing at temperatures ranging from 4 to 20 degrees C, and the highest cell density was measured at 15 degrees C and 100 MUmol photons m-2 s-1 light intensity under continuous shaking and external aeration. KNF0008 showed the elevated accumulation of lipid bodies under nitrogen-deficient conditions, rather than under nitrogen-sufficient conditions. Fatty acid production of KNF0008 was 4.2-fold (104 mg L-1) higher than that of C. reinhardtii CC-125 at 15 degrees C in Bold's Basal Medium. The dominant fatty acids were C16:0, C16:4, C18:1, and C18:3, and unsaturated fatty acids (65.69%) were higher than saturated fatty acids (13.65%) at 15 degrees C. These results suggested that Arctic Chlamydomonas sp. KNF0008 could possibly be utilized for production of biodiesel during periods of cold weather because of its psychrophilic characteristics. PMID- 30443892 TI - Visual search task immediate training effects on task-related functional connectivity. AB - Brain plasticity occurs over the course of the human lifetime. Learning and training modify our neuronal synapses and adapt our brain activity, from priming effects in modal areas to higher-order changes in the association cortex. The current state of the art suggests that learning and training effects might induce large-scale brain connectivity changes. Here, we used task-fMRI data and graph based approaches to study the immediate brain changes in functional connections associated with training on a visual search task, and the individual differences in learning were studied by means of brain-behavior correlations. In a previous work, we found that trained participants improved their response speed on a visual search task by 31%, whereas the control group hardly changed. In the present study, we showed that trained individuals changed regional connections (local links) in cortical areas devoted to the specific visual search processes and to areas that support information integration, and largely modified distributed connections (distant links) linking primary visual areas to specific attentional and cognitive control areas. In addition, we found that the individuals with the most enhanced connectivity in the dorsolateral prefrontal cortex performed the task faster after training. The observed behavioral and brain connectivity findings expand our understanding of large-scale dynamic readjustment of the human brain after learning experiences. PMID- 30443893 TI - Effective connectivity analysis of inter- and intramodular hubs in phantom sound perception - identifying the core distress network. AB - Tinnitus, the perception of a phantom sound, is accompanied by loudness and distress components. Distress however accompanies not just tinnitus, but several disorders. Several functional connectivity studies show that distress is characterized by disconnectivity of fronto-limbic circuits or hyperconnectivity of default mode/salience networks. The drawback, however, is that it considers only the magnitude of connectivity, not the direction. Thus, the current study aims to identify the core network of the domain-general distress component in tinnitus by comparing whole brain directed functional networks calculated from 5 min of resting state EEG data collected from 310 tinnitus patients and 256 non tinnitus controls. We observe a reorganization of the overall tinnitus network, reflected by a decrease in strength and efficiency of information transfer between fronto-limbic and medial temporal regions, forming the main hubs of the tinnitus network. Further, a disconnection amongst a subset of these connections was observed to correlate with distress, forming a core distress network. The core distress network showed a decrease in strength of connections specifically going from the left hippocampus/parahippocampus to the subgenual anterior cingulate cortex. Such a disconnection suggests that the parahippocampal contextual memory has little influence on the (paradoxical) value that is attached to the phantom sound and that distress is the consequence of the absence of modulation of the phantom sound. PMID- 30443895 TI - Myosin-X is essential to the intercellular spread of HIV-1 Nef through tunneling nanotubes. AB - Tunneling nanotubes (TNTs) are intercellular structures that allow for the passage of vesicles, organelles, genomic material, pathogenic proteins and pathogens. The unconventional actin molecular motor protein Myosin-X (Myo10) is a known inducer of TNTs in neuronal cells, yet its role in other cell types has not been examined. The Nef HIV-1 accessory protein is critical for HIV-1 pathogenesis and can self-disseminate in culture via TNTs. Understanding its intercellular spreading mechanism could reveal ways to control its damaging effects during HIV 1 infection. Our goal in this study was to characterize the intercellular transport mechanism of Nef from macrophages to T cells. We demonstrate that Nef increases TNTs in a Myo10-dependent manner in macrophages and observed the transfer of Nef via TNTs from macrophages to T cells. To quantify this transfer mechanism, we established an indirect flow cytometry assay. Since Nef expression in T cells down-regulates the surface receptor CD4, we correlated the decrease in CD4 to the transfer of Nef between these cells. Thus, we co-cultured macrophages expressing varying levels of Nef with a T cell line expressing high levels of CD4 and quantified the changes in CD4 surface expression resulting from Nef transfer. We demonstrate that Nef transfer occurs via a cell-to-cell dependent mechanism that directly correlates with the presence of Myo10-dependent TNTs. Thus, we show that Nef can regulate Myo10 expression, thereby inducing TNT formation, resulting in its own transfer from macrophages to T cells. In addition, we demonstrate that up-regulation of Myo10 induced by Nef also occurs in human monocyte derived macrophages during HIV-1 infection. PMID- 30443896 TI - An evaluation score of the difficulty of thyroidectomy considering operating time and preservation of recurrent laryngeal nerve. AB - The purpose of this study was to edit a renovated thyroidectomy difficulty scale (rTDS) in order to identify underlying thyroid diseases with a longer operative time and higher technical difficulty, also considering preservation of recurrent laryngeal nerve. We developed a renovated scale with a maximum score of 20 points by creating a form in which five variables were considered: vascularity, friability, mobility/fibrosis, gland size and difficulty in preservation of the recurrent laryngeal nerve. Two surgeons separately evaluated each of these. Through a simple linear regression analysis, we have analyzed the relationship between rTDS score and operative times, and between rTDS score and preservation of recurrent nerve. Eventually, Spearman's rank correlation coefficient has been used in order to evaluate our double-blind study. Our cohort included 131 patients undergoing total thyroidectomy. The mean of the rTDS was 9.00 +/- 3.67 for Surgeon A and 8.31 +/- 3.42 for Surgeon B, with Spearman's rank correlation coefficient between surgeons of 0.85 (p < 0.0001). We have shown that the rTDS score significantly influences the operating times (R2 = 0.44 for surgeon A, R2 = 0.46 for B, p < 0.0001 for both). Moreover, we can say that the rTDS score significantly influences preservation of the recurrent nerve (R2 = 0.37, Beta 0.61, 8.84 t test, p < 0.0001). Our rTDS is a useful tool and, thanks to it, we identified hyperthyroidism and goiter as the hardest underlying disease for surgery. Thus our scale could change operative approach, resulting in better surgeries' scheduling and identification of pathologies that require higher attention. PMID- 30443897 TI - Patient Perspectives on the Value of Patient Preference Information in Regulatory Decision Making: A Qualitative Study in Swedish Patients with Rheumatoid Arthritis. AB - BACKGROUND: There is increasing interest in involving patient preferences for benefits and risks in regulatory decision making. Therefore, it is essential to identify patient perspectives regarding the value of patient preference information (PPI). OBJECTIVES: The aim of this study was to explore how patients with rheumatoid arthritis (RA) value the use of PPI in regulatory decision making regarding medical products. METHODS: Regulators and patients with RA were interviewed to gather initial insights into opinions on the use of PPI in regulatory decisions regarding medical products. The interviews were used to draft and validate the interview guide for focus groups with patients with RA. Participants were purposively sampled in collaboration with the Swedish Rheumatism Association in Stockholm and Uppsala. Each focus group consisted of three to six patients (18 in total). All interviews were audio-recorded, transcribed verbatim, and analysed using content analysis. RESULTS: According to the participants, PPI could lead to regulators considering patients' needs, lifestyles and well-being when making decisions. PPI was important in all stages of the medical product lifecycle. Participants reported that, when participating in a preference study, it is important to be well-informed about the use of the study and the development, components, administration, and risks related to the medical products. CONCLUSIONS: Patients thought PPI could be valuable to consider in regulatory decisions. It is essential for patients to be well-informed when asked for their preferences. Research on information materials to inform patients in preference studies is needed to increase the value of PPI in regulatory decision making. PMID- 30443899 TI - Potential of bacterial culture media in biofabrication of metal nanoparticles and the therapeutic potential of the as-synthesized nanoparticles in conjunction with artemisinin against MDA-MB-231 breast cancer cells. AB - In the recent past, various groups have proposed diverse biocompatible methods for the synthesis of metal nanoparticles (NPs). Besides culture biomass, culture supernatants (CS) are increasingly being explored for the synthesis of NPs; however, with the ever-increasing exploration of various CS in the biofabrication of NPs, it is equally important to explore the potential of various culture media (CMs) in the synthesis of metal NPs. Considering these aspects, in the present investigation, we explore the possible applicability of various CMs in the biofabrication of metal NPs. The synthesis of NPs was primarily followed by UV/VIS spectroscopy, and, thereafter, the NPs were characterized by various physiochemical techniques, including EM, EDX, FT_IR, X-ray diffraction, and DLS measurements, and finally, their anticancer potentialities were investigated against breast cancer. In addition, the NPs were examined in conjunction with artemisinin for therapeutic benefits against aggressive and highly metastatic MDA MB-231 breast cancer cells. Cumulatively, the results of the present study collated the potentials of various bacterial CMs in the biofabrication of metal NPs and ascertained the efficacy of the as-synthesized silver nanoparticles, especially the combinatorial entity as intriguing breast cancer therapeutics. The data of the present study plausibly assist in advancing the therapeutic applicability of the combinatorial amalgam against aggressive and highly metastatic MDA-MB-231 breast cancer cells. PMID- 30443898 TI - SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia. AB - Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETalpha and SETbeta), significantly correlate with disease severity (overall survival and time-to-first-treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence in situ hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes. PMID- 30443900 TI - A Bayesian Hidden Markov Model for Detecting Differentially Methylated Regions. AB - Alterations in DNA methylation have been linked to the development and progression of many diseases. The bisulfite sequencing technique presents methylation profiles at base resolution. Count data on methylated and unmethylated reads provide information on the methylation level at each CpG site. As more bisulfite sequencing data become available, these data are increasingly needed to infer methylation aberrations in diseases. Automated and powerful algorithms also need to be developed to accurately identify differentially methylated regions between treatment groups. This study adopts a Bayesian approach using the hidden Markov model to account for inherent dependence in read count data. Given the expense of sequencing experiments, few replicates are available for each treatment group. A Bayesian approach that borrows information across an entire chromosome improves the reliability of statistical inferences. The proposed hidden Markov model considers location dependence among genomic loci by incorporating correlation structures as a function of genomic distance. An iterative algorithm based on expectation-maximization is designed for parameter estimation. Methylation states are inferred by identifying the optimal sequence of latent states from observations. Real datasets and simulation studies that mimic the real datasets are used to illustrate the reliability and success of the proposed method. This article is protected by copyright. All rights reserved. PMID- 30443901 TI - Open niche regulation of mouse spermatogenic stem cells. AB - In mammalian testes, robust stem cell functions ensure the continual production of sperm. In testicular seminiferous tubules, spermatogenic stem cells (SSCs) are highly motile and are interspersed between their differentiating progeny, while undergoing self-renewal and differentiation. In such an "open niche" microenvironment, some SSCs proliferate, while others exit the stem cell compartment through differentiation; therefore, self-renewal and differentiation are perfectly balanced at the population (or tissue) level, a dynamics termed "population asymmetry." This is in stark contrast to the classical perception of tissue stem cells being cells that are clustered in a specialized "closed niche" region and that invariantly undergo asymmetric divisions. However, despite its importance, how the self-renewal and differentiation of SSCs are balanced in an open niche environment is poorly understood. Recent studies have thrown light on the key mechanism that enables SSCs to follow heterogeneous fates, although they are equally exposed to signaling molecules controlling self-renewal and differentiation. In particular, SSCs show heterogeneous susceptibilities to differentiation-promoting signals such as Wnt and retinoic acid. Heterogeneous susceptibility to the ubiquitously distributed fate-controlling extracellular signal might be a key generic mechanism for the heterogeneous fate of tissue stem cells in open niche microenvironments. PMID- 30443902 TI - Benzo(a)pyrene inhibits endometrial cell apoptosis in early pregnant mice via the WNT5A pathway. AB - Benzo(a)pyrene (BaP) is an endocrine-disrupting pollutant present in various aspects of daily life, and studies have demonstrated that BaP exerts reproductive toxicity. We previously showed that BaP damages endometrial morphology and decreases the number of implantation sites in early pregnant mice, but the mechanisms underlying these effects remain unclear. The endometrial function is crucial for implantation, which is associated with endometrial cell apoptosis. In this study, we focused on the effect of BaP on endometrial cell apoptosis and the role of WNT signaling during this process. Pregnant mice were gavaged with corn oil (control group) or 0.2 mg.kg-1 .day -1 BaP (treatment group) from Days 1 to 6 of pregnancy. BaP impaired endometrial function by decreasing the expression of HOXA10 and BMP2, two markers of receptivity and decidualization. WNT5A and beta catenin were activated in the BaP group. BaP affected the expression of apoptosis related proteins and inhibited the apoptosis of endometrial stromal cells. In vitro, human endometrial stromal cells (HESCs) were treated with different concentrations of BaP (dimethyl sulfoxide (DMSO); 5, 10 uM). WNT5A and beta catenin were also upregulated in the BaP treatment group. HESC apoptosis was restrained by BaP. Inhibiting WNT5A by SFRP5 partially restored the effect of BaP on apoptosis. In summary, these results suggested that BaP exposure during early pregnancy activates WNT5A/beta-catenin signaling pathway, which inhibits the endometrial cell apoptosis and potentially destroys endometrial function. PMID- 30443903 TI - L-selectin expression is regulated by CXCL8-induced reactive oxygen species produced during human neutrophil rolling. AB - Neutrophils destroy invading microorganisms by phagocytosis by bringing them into contact with bactericidal substances, among which ROS are the most important. However, ROS also function as important physiological regulators of cellular signaling pathways. Here, we addressed the involvement of oxygen derivatives in the regulation of human neutrophil rolling, an essential component of the inflammatory response. Flow experiments using dihydroethidium-preloaded human neutrophils showed that these cells initiate an early production of intracellular ROS during the rolling phase of the adhesion cascade, a phenomenon that required cell rolling, and the interaction of the chemokine receptor CXCR2 with their ligand CXCL8. Flow cytometry experiments demonstrated that L-selectin shedding in neutrophils is triggered by ROS through an autocrine-paracrine mechanism. Preincubation of neutrophils with the NADPH oxidase complex inhibitor diphenyleniodonium chloride significantly increased the number of rolling neutrophils on endothelial cells. Interestingly, the same effect was observed when CXCL8 signaling was interfered using either a blocking monoclonal antibody or an inhibitor of its receptor. These findings indicate that, in response to CXCL8, neutrophils initiate ROS production during the rolling phase of the inflammatory response. This very early ROS production might participate in the modulation of the inflammatory response by inducing L-selectin shedding in neutrophils. PMID- 30443904 TI - Organ-on-chip models: Implications in drug discovery and clinical applications. AB - Before a lead compound goes through a clinical trial, preclinical studies utilize two-dimensional (2D) in vitro models and animal models to study the pharmacodynamics and pharmacokinetics of that lead compound. However, these current preclinical studies may not accurately represent the efficacy and safety of a lead compound in humans, as there has been a high failure rate of drugs that enter clinical trials. All of these failures and the associated costs demonstrate a need for more representative models of human organ systems for screening in the preclinical phase of drug development. In this study, we review the recent advances in in vitro modeling including three-dimensional (3D) organoids, 3D microfabrication, and 3D bioprinting for various organs including the heart, kidney, lung, gastrointestinal tract (intestine-gut-stomach), liver, placenta, adipose, retina, bone, and brain as well as multiorgan models. The availability of organ-on-chip models provides a wealth of opportunities to understand the pathogenesis of human diseases and provide a potentially better model to screen a drug, as these models utilize a dynamic 3D environment similar to the human body. Although there are limitations of organ-on-chip models, the emergence of new technologies have refined their capability for translational research as well as precision medicine. PMID- 30443905 TI - Utility of the DASH score after unprovoked venous thromboembolism; a single centre study. PMID- 30443906 TI - Sex bias: Is it pervasive in otolaryngology clinical research? AB - OBJECTIVES/HYPOTHESIS: Recent initiatives highlight substantial sex bias in biomedical research. The objective was to determine whether sex bias is present in otolaryngology and whether sex is appropriately analyzed as an independent variable in otolaryngology clinical research. STUDY DESIGN: Literature review. METHODS: We systematically reviewed all 2016 articles in three major otolaryngology journals: The Laryngoscope, JAMA Otolaryngology-Head and Neck Surgery, and Otolaryngology-Head and Neck Surgery. Extracted data included study origin, location, subspecialty, number/sex of subjects, >=50% sex matching (SM>=50 ), and sex-based statistical analysis. RESULTS: Six hundred of 1,209 articles comprising original clinical research were reviewed including 8,997,345,495 subjects (males: 3,898,559,264 [43.3%]; females: 5,095,592,583 [56.6%]; and unknown: 3,193,648 [0.04%]). There were 533/600 (88.8%) studies that included both sexes, eight (1.3%) included females only, five (0.8%) included males only, and 56 (9.3%) did not document participant sex. Only 280 studies (46.7%) analyzed data by sex, and 330 studies (60.7%) had SM>= 50 . Sex-based statistical analysis and SM>= 50 were similar in domestic and international studies (48.7% vs. 42.8% and 60.9% vs. 62%, respectively). Database studies performed sex-based statistical analysis more frequently than single and multi institutional studies (79.1% vs. 40.4% and 43.4%, P < .00001). Analysis by sex was more frequently performed in head and neck surgery (53.6%) and pediatric otolaryngology (51.3%), whereas SM>=50 was highest in pediatric otolaryngology (86.8%) and otology (82.4%). CONCLUSIONS: Sex bias exists in the clinical otolaryngology literature, with less than half the studies analyzing sex. Acknowledging the intertwinement of sex with disease pathophysiology and outcomes is important. Eliminating sex bias in research and clinical care should become a major focus for otolaryngologists. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30443907 TI - A case of recalcitrant face eczema. AB - A 37-year-old woman with a history of mild atopic dermatitis involving her antecubital flexures and sporadically her face presented with face eczema of one year duration. Due to acne and solar brown spots, she had applied a retinoic acid containing cream for one year and she had slowly developed recalcitrant face eczema that was unsuccessfully treated with different moisturizing creams, corticosteroid creams and sunscreens. As her face eczema further worsened the patient was referred for patch testing. PMID- 30443908 TI - The prevalence, alloimmunization risk factors, antigenic exposure, and evaluation of antigen-matched red blood cells for thalassemia transfusions: a 10-year experience at a tertiary care hospital. AB - BACKGROUND: Hemoglobin E-beta0 thalassemia and homozygous beta0 -thalassemia are the most common chronic transfusion-dependent thalassemias in Thailand. Patients with these conditions can experience clinical complications such as RBC alloimmunization. In this study we aimed to determine the prevalence, alloimmunization risk factors, antigenic exposure, and evaluation of antigen- (C, c, E, e, Mia ) matched RBC transfusion. STUDY DESIGN AND METHODS: Thalassemia patients were recruited from a tertiary care hospital for 10 years from 2008 to 2017. The medical records of transfusion history were reviewed for red cell phenotype both of patients and donors, number of units transfused, and type of alloantibodies. RESULTS: A total of 383 thalassemia patients were identified (178 males and 205 females). The frequency of RBC alloantibodies was 19.3%. Some patients tested positive for more than one antibody type. Autoantibodies were detected in nine individuals. Anti-E (49 [39.5%]), anti-Mia (24 [19.4%]), and anti-c (19 [15.3%]) were the most common antibodies detected. A high rate of alloimmunization was found in splenectomized patients. Risk of alloimmunization increased when more total units of blood had been transfused. A trend toward low alloimmunization rates was noted in the antigen-matched RBC group, where 3.5% (5/143) of patients were alloimmunized. Anti-E and anti-Mia , which may be naturally occurring, were identified in this group. CONCLUSION: Thai patients are more prone to develop antibodies against the Rh and Mia than to the Kell blood group antigens. Provision of at least antigen-matched (C, c, E, e, Mia ) RBCs appears to improve the efficacy of transfusion in thalassemia patients. PMID- 30443909 TI - Long-term swallowing performance following transoral robotic surgery for obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: This study aimed to evaluate the long-term swallowing performance following transoral robotic surgery (TORS) to the base of tongue (BOT) in the treatment of obstructive sleep apnea (OSA). STUDY DESIGN: Retrospective and prospective cohort study. METHODS: Data analysis of 39 patients who underwent BOT reduction via TORS to treat OSA at our center from September 2013 to April 2016. Long-term swallowing functions were assessed using subjective self-evaluated swallowing disturbances questionnaire (SDQ) and objective fiberoptic endoscopic evaluation of swallowing (FEES). RESULTS: Seven patients underwent TORS BOT reduction alone, whereas 32 had also uvulopalatoplasty +/- tonsillectomy, with a surgical success rate of 71.4%. Mean time for swallowing evaluation was 27.4 +/- 9.43 months. Twenty-five patients completed the SDQ with an average score of 9.26 +/- 10.05. In 32%, the SDQ was positive for dysphagia. In 10 out of 14 patients who underwent FEES, swallowing problems were noticed. The most common pathological findings were food residue in the vallecula followed by early spillage of food into the hypopharynx, penetration of solid food and liquid on the vocal folds surface, and aspiration. CONCLUSIONS: BOT reduction via TORS has a negative effect on long-term swallowing function. A self-assessment questionnaire can help detect patients who suffer from swallowing impairment. Postoperative objective swallowing tests are essential not only in the immediate postoperative period but also during late routine follow-up. Proper patient selection and detailed information about surgery and possible late-swallowing effect are important factors before scheduling BOT reduction via TORS for OSA treatment. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30443910 TI - Spawning and emergence phenology of bull trout Salvelinus confluentus under differing thermal regimes. AB - Median bull trout Salvelinus confluentus breeding was 2 weeks earlier in a cool stream than in a proximate warmer stream, aligning with expectations for salmonids, followed by emergence timing calculated to be six weeks later in the cool stream than the warm stream. This pattern is consistent with both site specific adaptation and thermal spawning threshold hypotheses for life-history event timing in this threatened species. PMID- 30443911 TI - Evolving phenotype of the head and neck surgeon. AB - OBJECTIVE: Characterize the evolution of head and neck (H&N) surgical practices in the United States over two decades by using resident case log data as a surrogate. METHODS: National residency case log data from all Accreditation Council for Graduate Medical Education-accredited otolaryngology residency programs was reviewed for the past 20 academic years (1996-2015). Key indicator procedures in each subcategory of H&N were analyzed to characterize standard ablative H&N surgical practices. Mean number of cases completed per resident each year was calculated. RESULTS: The proportion of H&N surgeries contributing to the total number of otolaryngology cases performed yearly remained relatively stable during the study period, ranging from 6.4% to 8.7%, indicating concurrent growth of H&N cases with all otolaryngology surgeries. Although each subcategory within H&N demonstrated modest increases in the number of cases performed per resident each year over the study period, the most significant growth occurred in the endocrine surgery subcategory: a 288% increase from 18.4 in 1996 to 71.5 in 2015. The proportion of H&N cases represented by each subcategory decreased, except for endocrine, which more than doubled in proportion from 21% in 1996 to 43% in 2015. CONCLUSION: Our findings suggest that the modern H&N surgeon is increasingly becoming an endocrine and H&N surgeon. The proportion of endocrine surgeries performed in residency, which serves as a surrogate for H&N practices, has more than doubled over the past 20 years and now represents the largest subcategory of H&N surgery. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30443912 TI - A rare complication of mitral valve replacement: Iatrogenic aortic valve perforation. AB - Iatrogenic aortic valve injury after mitral valve surgery is a well-known but rare complication. Herein, we report a 62-year-old male patient who underwent mitral valve replacement surgery 12 years ago and developed moderate to severe aortic regurgitation immediately after surgery. PMID- 30443913 TI - Lipoid pneumonia in an orangutan (Pongo abelii) with chronic respiratory problems. AB - An orangutan (Pongo abelii) presented with chronic respiratory problems. Cytological evaluation of the bronchoalveolar lavage fluids revealed macrophages with well-circumscribed intracytoplasmic clear vacuoles and lipid droplets in the background, confirmed by Oil Red O staining. The findings were indicative of lipoid pneumonia. This is the first report of lipoid pneumonia in an orangutan. PMID- 30443914 TI - Are chronic cough and laryngopharyngeal reflux more common in obstructive sleep apnea patients? AB - OBJECTIVES/HYPOTHESIS: To assess if there is a significant difference in the prevalence and severity of chronic cough symptoms in obstructive sleep apnea (OSA) patients versus non-OSA patients and examine this relationship in regard to laryngopharyngeal reflux (LPR) symptoms. STUDY DESIGN: Prospective cohort study. METHODS: Patients referred to Northwestern Medicine Sleep Lab for home sleep testing were enrolled. Patients filled out the Leicester Cough Questionnaire (LCQ) and Reflux Symptom Index (RSI) before completing sleep testing. Home sleep testing results were reviewed, and patients were separated into non-OSA and OSA groups by standard Apnea-Hypopnea Index (AHI) criteria. Demographic characteristics and questionnaire scores of the two groups were compared. The relationship between OSA severity, as determined by AHI, and LCQ and RSI scores was assessed. RESULTS: Of the 52 patients enrolled, 33 patients met criteria for OSA and 19 patients did not. Comparing patients without OSA versus those with OSA, there was a significant difference in mean LCQ score (129.9 vs. 120.0, respectively; P = .02), implying worse cough symptoms among OSA patients, and mean RSI score (3.2 vs. 11.2, respectively; P = .0013), implying worse upper airway reflux symptoms among OSA patients. There was a significant correlation between LCQ score and AHI (r = -0.39, P = .0061) and between RSI score and AHI (r = 0.37, P = .0078). CONCLUSIONS: OSA patients demonstrate worse chronic cough and LPR-related quality of life versus non-OSA patients. Furthermore, the severity of these quality-of-life measures was correlated with the severity of the AHI. Chronic cough and particularly the pharyngeal LPR symptoms may be associated with the presence and severity of OSA. LEVEL OF EVIDENCE: 2 . Laryngoscope, 2018. PMID- 30443915 TI - Tracheostomy demographics and outcomes among pediatric patients ages 18 years or younger-United States 2012. AB - OBJECTIVES/HYPOTHESIS: To estimate the number, demographics, and outcomes of pediatric patients who underwent tracheostomy in 2012 and to contrast those outcomes by age, race, and gender. STUDY DESIGN: Cross-sectional study. METHODS: The 2012 Kids Inpatient Database was queried to identify tracheostomy patients using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedural codes 311, 3121, and 3129. All patients <=18 years of age at the time of admission were included and categorized as neonates (<=28 days), infants (>28 days <=1 year), toddler (1 to 3 years), children (4 to 12 years), adolescents (13 to 17 years), and adults (=18 years). We recorded age, gender, race, insurance status, and zip code of primary residence. We used these variables to contrast the following outcomes: length of stay, total charges, complications of care, and mortality using multiple regression analysis. RESULTS: An estimated 4,424 pediatric tracheostomies occurred during 2012. Fifty-one percent of the patients were <=3 years old, and 62% were male. Forty-eight percentwere white followed by black (21%), Hispanic (20%), and Asian (3%). The median length of stay was 42 days, and the median total charges were $472,738. The complication rate was 29% and the mortality rate was 8.0%. The length of stay and total charges was predicted by age, with neonates having significantly longer hospitalizations. The complication rate was not associated with age, gender, or ethnicity. However, the mortality rate was associated with younger age. CONCLUSIONS: Pediatric tracheostomies are associated with significant hospital utilizations, complications, and mortality. Increased risk of mortality is observed among neonates and infants. Continued study of tracheostomy outcomes among these subsets of the pediatric population are warranted. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30443916 TI - Predictors of all-cause mortality and ischemic events within and beyond 1 year after an acute coronary syndrome: results from the EPICOR registry. AB - BACKGROUND: Patients discharged after an acute coronary syndrome (ACS) have substantial risk of recurrent ischemic events or dying. Hypothesis A difference may exist in risk predictors for all-cause mortality and ischemic events between year-1 and year-2 of follow up post-ACS. METHODS: EPICOR (NCT01171404) was a prospective, international, real-world cohort study of consecutive patients hospitalized for ACS within 24 hours of symptom onset and surviving to discharge. 10,568 patients were enrolled (555 hospitals; 20 countries) and followed-up for 2 years. From these, 4943 were admitted with ST-elevation myocardial infarction (STEMI) and 5625 with non-ST-elevation ACS (NSTE-ACS). Potential baseline predictors of major adverse cardiac and cerebrovascular events (MACCE; death, non fatal myocardial infarction [MI], non-fatal stroke) were evaluated in year 1 and 2 post-discharge. RESULTS: MACCE incidence per 100 person-years at risk within and after 1 year was 5.3 vs 3.6, primarily death (4.1 vs 2.3), with no significant differences for MI or stroke. Older age, lack of coronary revascularization, raised creatinine, low hemoglobin, previous cardiac disease, previous chronic obstructive pulmonary disease, raised glucose, male sex, and geographic region were risk factors for MACCE in both year 1 and 2. By contrast, low ejection fraction, poorer quality of life, low body mass index (BMI) <20 kg/m2 , in-hospital cardiac complications, and Killip class lost predictive power after 1 year. CONCLUSION: We observed continuous MACCE risk during 2 years of follow-up after discharge for ACS, with greater mortality within the first year. Specific predictors at discharge for events after 1 year could not be identified. PMID- 30443917 TI - Subjective well-being among left-behind children in rural China: The role of ecological assets and individual strength. AB - BACKGROUND: The plight of left-behind children affected by parental migration has aroused widespread public concern in China. However, limited research has been conducted on the positive aspects of the development (e.g., subjective well being) among left-behind children. Recently, a new means to investigating the mechanisms of positive development in left-behind children emerged from the positive youth development (PYD) approach. Grounded in the framework of PYD, this study was designed to examine how ecological assets (i.e., neighborhood social cohesion and trusting relationships with caregivers) and individual strength (i.e., resilience) predict subjective well-being among left-behind children. METHODS: Altogether 1,449 left-behind children (50.70% boys; Mage = 12.11 years, SD = 1.84) were recruited to complete questionnaires designed to assess perceived neighborhood social cohesion, trusting relationships with caregivers, resilience, and subjective well-being. RESULTS: The results show that neighborhood social cohesion and trusting relationships with caregivers positively predicted left behind children's subjective well-being. Moreover, structural equation modeling results reveal that resilience partially mediated the effect of neighborhood social cohesion and trusting relationships with caregivers on subjective well being. CONCLUSIONS: In this research we identified key contextual and personal enablers for subjective well-being among left-behind children. The results provide some important implications regarding the manner in which subjective well being can be promoted among left-behind children by increasing neighborhood and family ecological assets and enhancing resilience. PMID- 30443918 TI - Severe allergic contact dermatitis in a detergent production worker caused by exposure to methylisothiazolinone. AB - Methylisothiazolinone (MI) is a preservative commonly used in paints, detergents and cosmetics. It has been found to be a potent sensitizer. During the recent years there has been an epidemic increase in allergic contact dermatitis caused by MI (1). We present the case of a worker in the detergent production industry who developed severe allergic contact dermatitis following occupational exposure to MI, illustrating the need for attention to occupational exposure to MI in the production setting, where high concentrations of MI are used. PMID- 30443919 TI - Tools and Resources for Metabolomics Research Community: A 2017-2018 update. AB - The veracity at which mass spectrometry (MS) and nuclear magnetic resonance (NMR) based platforms generate metabolomics datasets for both research and clinical facilities to address challenges in biomedical to agricultural sciences is under appreciated. Thus, metabolomics efforts spanning microbe, environment, plant, animal and human systems, have led to a continual and concomitant growth of the in silico resources for analysis and interpretation of these datasets. These software tools, resources, and databases drive the field forward to help keep pace with the amount of data being generated and the sophisticated and diverse analytical platforms that are being used to generate metabolomics data. To address challenges in data pre-processing, metabolite annotation, statistical interrogation, visualization, interpretation, and integration, the metabolomics and informatics community comes up with hundreds of tools every year to tackle these challenges. The purpose of the present review is to provide a brief and useful summary of more than 95 metabolomics tools, software, and databases that were either developed or significantly improved during 2017-2018. We see this review help readers, developers, and researchers to obtain an informed access to these thorough list of resources for further improvisation, implementation, and application in due course of time. This article is protected by copyright. All rights reserved. PMID- 30443920 TI - Urine protein quantification in stacking gel by SDS-PAGE. AB - Urine total protein concentration is usually measured by the pyrogallol red molybdate (PRM) assay in clinical laboratories, but it is often subject to sample interference. Here, we introduce a stacking gel-based method for accurate protein quantitation. In this method, the urine protein samples are run into the stacking gel by SDS-PAGE where it is concentrated into a single band, and then quickly stained by 0.001% Coomassie at high temperature. High correlations were found between the BSA and urine protein standards (R2 = 0.997 and 0.990, respectively). Addition of 80 ng urine protein standard into each of the ten clinical urine specimens with questionable PRM results yielded the expected increase in the results by this method. Comparison of the PRM method and with the gel quantitation approach on about 60 clinical urine samples demonstrated a general consistency between the results (R2 = 0.825), but in PRM samples with lower protein concentration showed more variations. Overall, the stacking gel method might be a good alternative for clinical urine samples with suspicious protein concentration results. PMID- 30443921 TI - Are Aromatase Inhibitors Associated with Higher Myocardial Infarction Risk in Breast Cancer Patients? A Medicare Population-Based Study. AB - PURPOSE: Theoretically, the estrogen deprivation induced by aromatase inhibitors (AIs) might cause ischemic heart disease, but empiric studies have shown mixed results. We aimed to compare AIs and tamoxifen with regard to cardiovascular events among older breast cancer patients outside of clinical trials. PATIENTS AND METHODS: We identified women age >= 67 years diagnosed with breast cancer from 6/30/2006 to 6/01/2008 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, treated with either tamoxifen or an AI, and followed through 12/31/2012. To compare myocardial infarction (MI) risk for the treatment groups of AIs vs. tamoxifen, we developed and assigned stabilized probability of treatment weights and used the Fine and Gray model for time to MI with death not related to MI as a competing risk. RESULTS: Of the cohort of 5,648 women, 4,690 were treated with AIs and 958 with tamoxifen; a total of 251 patients developed MI, and 22 patients died of MI during the study period while 476 died of other causes. The hazard for MI was not significantly different between AI vs. Tamoxifen groups (HR=1.01, 95% C.I. 0.72-1.42), after adjusting for the following known MI risk factors at the start of adjuvant therapy: diabetes, ischemic heart disease, congestive heart failure, MI, and peripheral vascular disease. CONCLUSIONS: In this SEER-Medicare based population study, there were no significant differences in the risk of MI between AI and tamoxifen users after adjustment for known risk factors. PMID- 30443922 TI - Cell competition: Emerging mechanisms to eliminate neighbors. AB - Cell competition is a context-dependent cell elimination through short-range cell cell interaction, in which cells with higher fitness eliminate neighboring less fit or oncogenic cells within the growing tissue. Cell competition can be triggered by many different factors such as heterozygous mutations in the ribosomal protein genes (which are called "Minute" mutations), elevated Myc, Yorkie/YAP, Wg/Wnt, JAK-STAT, Ras, or Src activity, and loss of Mahjong/VprBP, endocytic pathway components, or apicobasal cell polarity. Studies on the mechanisms and roles of cell competition have suggested that cell competition can be divided into two types: selection of fitter cells or elimination of oncogenic cells. The former type of cell competition includes Minute or Myc-induced cell competition that is considered to be dependent on the relative level of protein synthesis. The later type of cell competition includes tumor-suppressive cell competition triggered by loss of cell polarity genes such as scribble (scrib) or discs large (dlg). Genetic studies in Drosophila during the past decade have provided significant progress in understanding the mechanisms of these phenomena. At the same time, these studies have now raised new questions; how do different mechanisms contribute or cooperate to drive cell competition, do common mechanisms exist in different types of cell competition, and what are the physiological roles of these cell competition phenomena? PMID- 30443923 TI - Aggravation of vitiligo by an electric heating pad: A possible case of heat triggered Koebnerization in vitiligo. PMID- 30443924 TI - Treatment adherence as a mediator of blood pressure control in Chinese older adults with depression. AB - OBJECTIVES: Both depression and hypertension (HTN) are prevalent, costly, and destructive, and frequently coexist among the aging population of China. This study aimed to examine the role that treatment adherence plays in blood pressure control in older adult Chinese with depression. METHODS: Data for these analyses were taken from a randomized control trial of a collaborative depression care management intervention conducted in rural villages of Zhejiang Province, China with older adults who had comorbid depression and HTN. They included baseline assessments of 2362 subjects ages >=60 years, whose blood pressure and depression were measured using a calibrated manual sphygmomanometer and the Chinese version of the 17-item Hamilton Depression Rating Scale (HDRS-17), respectively. Treatment adherence was identified by a single question asking whether patients on occasion did not take their medicine. RESULTS: Uncontrolled HTN was associated with older age (t = 3.10, P<0.01), higher HDRS-17 score (t = 5.76, P<0.01), and higher rates of non-adherence to HTN treatment (chi2 = 21.34, P<0.01). Logistic regression models indicated that adherence accounted for 39.4% of the total effect between depression and HTN. Specifically, those with poor adherence were at 1.417 greater odds of having their HTN uncontrolled compared with those with good adherence. CONCLUSIONS: Hypertension control in older adults with depression is complicated by nonadherence to treatment. In addition to diagnosing and treating depression in their older adult patients, primary care physicians can optimize blood pressure control by identifying and addressing their patients' adherence to recommendations for HTN management. PMID- 30443925 TI - Whole knee joint T1 values measured in vivo at 3T by combined 3D ultrashort echo time cones actual flip angle and variable flip angle methods. AB - PURPOSE: To measure T1 relaxations for the major tissues in whole knee joints on a clinical 3T scanner. METHODS: The 3D UTE-Cones actual flip angle imaging (AFI) method was used to map the transmission radiofrequency field (B1 ) in both short and long T2 tissues, which was then used to correct the 3D UTE-Cones variable flip angle (VFA) fitting to generate accurate T1 maps. Numerical simulation was carried out to investigate the accuracy of T1 measurement for a range of T2 values, excitation pulse durations, and B1 errors. Then, the 3D UTE-Cones AFI-VFA method was applied to healthy volunteers (N = 16) to quantify the T1 of knee tissues including cartilage, meniscus, quadriceps tendon, patellar tendon, anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), marrow, and muscles at 3T. RESULTS: Numerical simulation showed that the 3D UTE-Cones AFI-VFA technique can provide accurate T1 measurements (error <1%) when the tissue T2 is longer than 1 ms and a 150 MUs excitation RF pulse is used and therefore is suitable for most knee joint tissues. The proposed 3D UTE-Cones AFI-VFA method showed an average T1 of 1098 +/- 67 ms for cartilage, 833 +/- 47 ms for meniscus, 800 +/- 66 ms for quadriceps tendon, 656 +/- 43 ms for patellar tendon, 873 +/- 38 ms for ACL, 832 +/- 49 ms for PCL, 379 +/- 18 ms for marrow, and 1393 +/- 46 ms for muscles. CONCLUSION: The 3D UTE-Cones AFI-VFA method allows volumetric T1 measurement of the major tissues in whole knee joints on a clinical 3T scanner. PMID- 30443926 TI - Lost in translation? Paradigm conflict at the primary-secondary care interface. AB - CONTEXT: Historically, primary care (community and family) medicine has often been viewed as lower status than secondary care (hospital) practice. Current evidence suggests this pattern continues to impact medical practice and education. Medical education has however, yet to fully reflect this power dynamic, with undergraduate training in many institutions maintaining the hegemonic position of secondary care as the prime context for learning. METHODS: In this paper, we present primary and secondary care as conflicting paradigms of medical practice. Using a sociocultural lens drawing on Figured Worlds theory, implications for medical education are explored. CONCLUSIONS: We outline the two paradigms as having distinct epistemologies, identities and practices. Tensions at the primary-secondary care interface can, from a sociocultural perspective, be seen to impact developing identity and day-to-day clinical practice issues such as patient safety. We offer possibilities for engaging with paradigm conflict in meaningful ways and suggest potential changes for future educational policy and practice. PMID- 30443927 TI - Morphology and topography of internal reproductive organs in the female cat during prenatal and postnatal development: Scanning electron microscope and three dimensional reconstruction study. AB - The study describes the morphology and topography of internal reproductive organs in the domestic cat from the early prenatal period to maturity, using macroscopic and scanning electron microscope (SEM) observations with three-dimensional (3D) reconstructions. Fifty-seven female cat fetuses aged between the 27th and 63rd day postconception (p.c.), two newborn cats, three juveniles (3-month-old) cats, and three mature (12-month-old) cats were used in the study. The age of fetuses was determined on the basis of the growth curve for the domestic cat. The rudiments of cat ovaries develop on the ventral surface of the mesonephroi and within 30 days p.c. move to the sides of the abdominal cavity, which is similar to the position of the ovaries in the adult cat. The mesonephroi regress at about the 50th day p.c., when the residual mesonephric ducts are still found in the lower part of the body of the uterus. The paramesonephric ducts develop on the lateral surface of the mesonephroi and by the 45th day p.c., differentiate into the uterine tubes and the uterus. The arrangement of the paramesonephric ducts in the abdominal cavity changes from the U- to the V-shaped system. The final topography of the uterine tubes is established between the 54th and 60th day p.c., as the uterine tubes become convoluted. Before the 54th day p.c., the uterine horns undergo rapid elongation and convolution, forming the W-shaped system. By the third month of postnatal life, the uterine horns become straight, as in the adult cat. PMID- 30443928 TI - The influence of the Community-based Health Planning and Services (CHPS) program on community health sustainability in the Upper West Region of Ghana. AB - Ghana introduced Community-based Health Planning and Services (CHPS) to improve primary health care in rural areas. The extension of health care services to rural areas has the potential to increase sustainability of community health. Drawing on the capitals framework, this study aims to understand the contribution of CHPS to the sustainability of community health in the Upper West Region of Ghana-the poorest region in the country. We conducted in-depth interviews with community members (n = 25), key informant interviews with health officials (n = 8), and focus group discussions (n = 12: made up of six to eight participants per group) in six communities from two districts. Findings show that through their mandate of primary health care provision, CHPS contributed directly to improvement in community health (eg, access to family planning services) and indirectly through strengthening social, human, and economic capital and thereby improving social cohesion, awareness of health care needs, and willingness to take action at the community level. Despite the current contributions of CHPS in improving the sustainability of community health, there are several challenges, based on which we recommend, that government should increase staffing and infrastructure in order to strengthen and maintain the functionality of CHPS. PMID- 30443929 TI - Motion-robust diffusion compartment imaging using simultaneous multi-slice acquisition. AB - PURPOSE: To achieve motion-robust diffusion compartment imaging (DCI) in near continuously moving subjects based on simultaneous multi-slice, diffusion weighted brain MRI. METHODS: Simultaneous multi-slice (SMS) acquisition enables fast and dense sampling of k- and q-space. We propose to achieve motion-robust DCI via slice-level motion correction by exploiting the rigid coupling between simultaneously acquired slices. This coupling provides 3D coverage of the anatomy that substantially constraints the slice-to-volume alignment problem. This is incorporated into an explicit model of motion dynamics that handles continuous and large subject motion in robust DCI reconstruction. RESULTS: We applied the proposed technique, called Motion Tracking based on Simultanous Multislice Registration (MT-SMR) to multi b-value SMS diffusion-weighted brain MRI of healthy volunteers and motion-corrupted scans of 20 pediatric subjects. Quantitative and qualitative evaluation based on fractional anisotropy in unidirectional fiber regions, and DCI in crossing-fiber regions show robust reconstruction in the presence of motion. CONCLUSION: The proposed approach has the potential to extend routine use of SMS DCI in very challenging populations, such as young children, newborns, and non-cooperative patients. PMID- 30443930 TI - Cancer risk in 892 089 patients with psoriasis in Korea: A nationwide population based cohort study. AB - The relationship between psoriasis and cancer has not yet been established. The aim of this study was to evaluate the association of psoriasis with certain cancers using national statistics. All patients with psoriasis (n = 892 089; 51.7% male) and age- and sex-matched control subjects (n = 4 460 445) at a 5:1 ratio were enrolled using data from the National Health Insurance Service between 2007 and 2014 in Korea. In psoriatic subjects, overall cancer risk was higher than for subjects without psoriasis after adjusting for income level, diabetes, hypertension, dyslipidemia and place of residence (hazard ratio, 1.065; 95% CI, 1.049-1.081). The risk of cancer increased in the following order: prostate, thyroid, liver, ovarian, lung, leukemia, skin, multiple myeloma, lymphoma and testicular. The severity and sex of psoriatic patients also had different cancer risks. In psoriatic patients, a slightly increased risk for specific malignant neoplasms was shown. Therefore, periodic screening for cancer risk is recommended in patients with psoriasis. PMID- 30443931 TI - Relative size variation of the otoliths, swim bladder, and Weberian apparatus structures in piranhas and pacus (Characiformes: Serrasalmidae) with different ecologies and its implications for the detection of sound stimuli. AB - The Weberian apparatus of otophysan fishes confers acute hearing that is hypothesized to allow these fishes to assess the environment and to find food resources. The otophysan family Serrasalmidae (piranhas and pacus) includes species known to feed on falling fruits and seeds (frugivore/granivores) that splash in rivers, herbivorous species associated with torrents and rapids (rheophiles), and carnivores that feed aggressively within shoals. Relevant sound stimuli may vary among these ecological groups and hearing may be tuned to different cues among species. In this context, we examined size variation of the Weberian ossicles, swim bladder chambers, and otoliths of 20 serrasalmid species from three broad feeding ecologies: frugivore/granivores, rheophiles, and carnivores. We performed 3D-reconstructions of high resolution tomographic data (MUCT) from 54 museum specimens to estimate the size of these elements. We then tested for an ecology effect on covariation of auditory structure size and body size and accounted for phylogeny with phylogenetic generalized least squares analyses. Among ecological groups, we observed differences in relative sizes of otoliths associated with sound pressure and particle motion detection, and variation in Weberian ossicle size that may impact sound transmission. Rheophiles, which live in noisy environments, possess the strongest modifications of these structures. PMID- 30443932 TI - Interaction of gut microbiota with dysregulation of bile acids in the pathogenesis of nonalcoholic fatty liver disease and potential therapeutic implications of probiotics. AB - The intestinal microbiota is now recognised to play key roles in health due to its involvement in many aspects of human physiology. Disturbance in gut microbiota (dysbiosis) is thus associated with many diseases including nonalcoholic fatty liver disease (NAFLD) which includes nonalcoholic fatty liver and nonalcoholic steatohepatitis. The mechanisms for the effect of dysbiosis in NAFLD pathogenesis are not completely elucidated. Many explanations have been proposed to trigger dysbiosis, leading to NAFLD including inflammation, ethanol produced by the gut bacteria and lipotoxicity. Recently the roles of bile acids and nuclear receptors are highly regarded. It is well known that gut microbes produce enzymes that convert primary bile acids into secondary bile acids in the intestines. Several studies have demonstrated that disturbance of the intestinal microbiota leads to decreased synthesis of secondary bile acids, which in turn decreases activation of nuclear receptors such as farnesoid X receptor (FXR), pregnane X receptor, Takeda G-protein-coupled bile acid protein 5 and vitamin D receptor. These receptors are important in energy regulation and their dysregulation can cause NAFLD. Therefore, stimulation of nuclear receptors especially FXR has been extensively explored for the amelioration of NAFLD. However, paradoxical effects of nuclear receptor activation are a major problem for the clinical application of nuclear receptor stimuli. We further posit that microbiome restoration could be an alternative approach for the treatment of NAFLD. Several gut bacteria are now known to be involved in bile acid metabolism. It will be necessary to identify which one/ones is/are feasible. Careful selection of commensal bacteria for probiotics may lead to an effective therapy for NAFLD. PMID- 30443933 TI - Real-time robotic airway measurement: An additional benefit of a novel steady hand robotic platform. AB - OBJECTIVE: Describe the secondary capability of a robotic system to provide real time measurements of airway dimensions with high fidelity. METHODS: Seven unique phantoms of laryngotracheal stenosis (LTS) were modeled using a computer-aided design tool and were three dimensionally printed. These stenoses were of different dimensions and orientations, and some were purposefully oblique. The dimensions of the stenoses were then measured with the novel Robotic ENT (Ear, Nose, and Throat) Microsurgery System (REMS; Galen Robotics, Inc., Sunnyvale, CA) because it is capable of tool position memory in three dimensional (3D) space. Five participants (two laryngologists, two otolaryngology-head and neck surgery residents, one neurotology fellow) measured each axis of stenosis (anteroposterior, lateral, and craniocaudal) three times for each of the seven stenosis phantoms. These measurements were then compared to the known design dimensions. Mean magnitude of error (MOE) and interrater reliability (IRR) using an intraclass correlation coefficient (ICC) were then calculated. RESULTS: Mean MOE and standard deviation for all measurements was 0.306 +/- 0.247 mm. Mean MOE was 0.374 +/- 0.292 mm, 0.300 +/- 0.237 mm, and 0.244 +/- 0.185 mm for the anteroposterior, lateral, and craniocaudal dimensions of stenosis, respectively. Eighty-two percent of all measurements had MOE < 0.5 mm. ICC was 0.945 (95% confidence interval [CI]: 0.847-0.989), 0.995 (95% CI: 0.984-0.999), and 0.993 (95% CI: 0.987-0.999) for anteroposterior, lateral, and craniocaudal dimensions, respectively, indicating excellent agreement among participants. CONCLUSION: The REMS can be used to reliably and accurately measure airway dimensions in 3D regardless of the orientation of stenosis. This ability may be easily extrapolated to the measurement of any airway lesion during laryngotracheal surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30443934 TI - Drosophila glia: Few cell types and many conserved functions. AB - Glial cells constitute without any dispute an essential element in providing an efficiently operating nervous system. Work in many labs over the last decades has demonstrated that neuronal function, from action potential generation to its propagation, from eliciting synaptic responses to the subsequent postsynaptic integration, is evolutionarily highly conserved. Likewise, the biology of glial cells appears conserved in its core elements and therefore, a deeper understanding of glial cells is expected to benefit from analyzing model organisms such as Drosophila melanogaster. Drosophila is particularly well suited for studying glial biology since in the fly nervous system only a limited number of glial cells exists, which can be individually identified based on position and a set of molecular markers. In combination with the well-known genetic tool box an unprecedented level of analysis is feasible, that not only can help to identify novel molecules and principles governing glial cell function but also will help to better understand glial functions first identified in the mammalian nervous system. Here we review the current knowledge on Drosophila glia to spark interest in using this system to analyze complex glial traits in the future. PMID- 30443935 TI - Impact of a Formal Patient Safety and Quality Improvement Curriculum: A Prospective, Controlled Trial. AB - OBJECTIVE: To assess the impact of implementing a dedicated Patient Safety and Quality Improvement (PSQI) curriculum for otolaryngology residents. METHODS: Residents in two otolaryngology residency programs were recruited to participate in the study. Residents at institution A (intervention group) participated in a formal, newly developed, year-long PSQI curriculum. Residents at institution B (control group) participated in traditional, morbidity, and mortality conference based PSQI education, with no formal curriculum in place. Curriculum participants completed anonymous surveys to assess learner satisfaction. Validated instruments were administered to assess for changes in resident confidence in the ability to develop PSQI projects, their attitudes toward patient safety, and PSQI-related knowledge. The number and quality of PSQI-related resident projects were also assessed. RESULTS: Survey responses demonstrated excellent learner satisfaction with the curriculum. Based on validated instrument-based responses, both programs demonstrated similar confidence scores (P = 0.05), safety attitudes (P = 0.82), and PSQI knowledge (P = 0.29) at the beginning of the year. The residents of institution A demonstrated significant improvement in confidence (P = 0.00009) and knowledge (P = 0.0006) after completing the curriculum, with no improvement noted for residents at institution B in either confidence (P = 0.06) or knowledge (P = 0.79). Neither program demonstrated improvement in attitudes toward patient safety at the end of the year-long curriculum. CONCLUSION: Implementing a formal curriculum dedicated to PSQI led to an improvement in PSQI-related project development confidence and PSQI knowledge. Attitudes toward safety did not improve over the course of a year. Longer-term studies involving multiple institutions and other interventions are needed to evaluate the impact and duration of changes that occur. LEVEL OF EVIDENCE: 1b. Laryngoscope, 2018. PMID- 30443936 TI - Sodium-glucose cotransporter inhibitors and oxidative stress: An update. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are therapeutic agents that have been used recently to reduce tubular absorption of glucose, leading to enhanced glycosuria, resulting in the reduction of blood glucose and improved diabetes control. Recent data suggest that SGLT2 inhibitors have antioxidant properties that may be key to the reduction in cardiovascular death found in clinical trials. Oxidative stress is involved in the development and progression of atherosclerosis, as well as underlying diabetes complications, and may result from either increased free-radical production, a reduction in antioxidative capacity, or a combination of both. In this report, we have reviewed the recent evidence of the impact that SGLT2 inhibition may have on improved oxidative stress by either amelioration of free-radical generation or potentiation of cellular antioxidative capacity, and its importance in the prevention of cardiovascular and diabetes complications. PMID- 30443937 TI - Direct CVD Growth of Graphene on Traditional Glass: Methods and Mechanisms. AB - Chemical vapor deposition (CVD) on catalytic metal surfaces is considered to be the most effective way to obtain large-area, high-quality graphene films. For practical applications, a transfer process from metal catalysts to target substrates (e.g., poly(ethylene terephthalate) (PET), glass, and SiO2 /Si) is unavoidable and severely degrades the quality of graphene. In particular, the direct growth of graphene on glass can avoid the tedious transfer process and endow traditional glass with prominent electrical and thermal conductivities. Such a combination of graphene and glass creates a new type of glass, the so called "super graphene glass," which has attracted great interest from the viewpoints of both fundamental research and daily-life applications. In the last few years, great progress has been achieved in pursuit of this goal. Here, these growth methods as well as the specific growth mechanisms of graphene on glass surfaces are summarized. The typical techniques developed include direct thermal CVD growth, molten-bed CVD growth, metal-catalyst-assisted growth, and plasma enhanced growth. Emphasis is placed on the strategy of growth corresponding to the different natures of glass substrates. A comprehensive understanding of graphene growth on nonmetal glass substrates and the latest status of "super graphene glass" production are provided. PMID- 30443938 TI - The Role of the Memory Service in Helping Carers to Prepare for End of Life: A Mixed Methods Study. AB - OBJECTIVES: To explore current practice and the role taken by UK memory services in helping carers of people with dementia prepare for the end of life. METHODS: Mixed methods including a survey (48 responses/51% response rate) and semi structured interviews (n=12) with clinicians working in UK memory services accredited by the Memory Services National Accreditation Programme. We used descriptive statistics to report survey findings and thematically analysed interview and survey qualitative data. RESULTS: Surveys: services routinely discussed with carers the progressive nature of dementia (89%), legal arrangements (health: 72%; finances: 74%), advance care planning (63%) and implications of loss of capacity (61%). Fewer services routinely discussed the terminal nature of dementia (41%) and meaning of death (11%) with carers. Most (89%) agreed these conversations were in line with their role. Interview findings corresponded with survey findings. Themes included: diagnosis considered too early to discuss end of life; discussions being inconsistent with a 'living well' approach; people with dementia being resistant to conversations; and discussions of spirituality crossing professional boundaries. Services' capacity for follow up with carers impacted on ability to broach these topics. CONCLUSIONS: More in depth and distressing topics such as end of life and advance care planning require longer follow-up to establish relationships to broach difficult topics. Variability in follow-up practices between services created inequity in the extent to which memory services could address these topics. More research is required to investigate the best method for broaching these topics with carers and the person with mild dementia within different healthcare contexts. PMID- 30443939 TI - Pathophysiological changes in experimental polycystic ovary syndrome in female albino rats: Using either hemin or L-arginine. AB - Polycystic ovary syndrome (PCOS), one of the important endocrine disorders affecting females in the reproductive age, is caused mainly by an abnormal oxidation status that subsequently causes inflammatory conditions. Thus, this study aims to examine the possible individual prophylactic effects of gasotransmitters, hemin, or L-arginine in letrozole-induced PCOS. Fifty adult female albino rats were used and separated into a control group, which received the vehicle; a letrozole-induced PCOS group (L), which received letrozole orally at a dose level of 1 mg/kg for 21 days; a letrozole+hemin (L+H) group, which received letrozole plus hemin at a dose level of 25 mg/kg injected IP twice per week for 21 days; and a letrozole+L-arginine (L+A) group, which received letrozole plus L-arginine at a dose level of 200 mg/kg orally for 21 days. During PCO induction, the body weight and Lee index were measured. Serum glucose, insulin, lipid profile, gonadotrophic hormones, testosterone, estrogen, and tumor necrosis factor alpha were assayed, while ovarian tissues were analyzed to measure the oxidative state and histopathological changes. Our results proved that either hemin or L-arginine administration could improve the oxidative state, the inflammatory reaction, the hormonal imbalance, and the metabolic disturbances in PCO rats, which was confirmed by a histopathological examination of the rats' ovaries. In conclusion, either hemin or L-arginine had protective effects against PCOS with better pathophysiological changes with hemin. PMID- 30443940 TI - Precision and accuracy of Dahl-Lea back-calculated smolt lengths from adult scales of Atlantic salmon Salmo salar. AB - Using tagged and recaptured Atlantic salmon Salmo salar (n = 106) the present analysis shows that the most commonly applied linear back-calculation method for estimating past length, the Dahl-Lea method, resulted in overestimation of the length of large smolts and underestimation of small smolts. A correction equation (y = 0.53x + 6.23) for estimating true smolt length (y) from lengths back calculated from adult scale measures (x) to account for these systematic discrepancies is proposed. PMID- 30443941 TI - Incarceration of iodine in a pyrene-based metal-organic framework. AB - A pyrene-based metal-organic framework (MOF) SION-8 captures iodine (I2) vapour with a capacity of 460 mg g-1MOF and 250 mg g-1MOF at room temperature and at 75 degrees C, respectively. Single-crystal X-ray diffraction analysis and van der Waals-corrected density functional theory calculations confirm the presence of I2 molecules within the pores of SION-8 and their interaction with the pyrene-based ligands. The I2-pyrene interactions in the I2-loaded SION-8 lead to a 104-fold increase of its electrical conductivity compared to the bare SION-8. Upon adsorption, >=95% of I2 molecules are incarcerated and cannot be washed out, signifying the potential of SION-8 towards the permanent capture of radioactive I2 at room temperature. PMID- 30443942 TI - An air-assisted flow-gating interface for capillary electrophoresis. AB - A new kind of flow gating interface (FGI) has been designed for online connection of CE with flow-through analytical techniques. The sample is injected into the separation capillary from a space from which the BGE was forced out by compressed air. A drop of sample solution with a volume of 75 nL is formed between the outlet of the delivery capillary supplying the solution from the flow-through apparatus and the entrance to the CE capillary; the sample is hydrodynamically injected into the CE capillary from this drop. The sample is not mixed with the surrounding BGE solution during injection. The functioning of the proposed FGI is fully automated and the individual steps of the injection process are controlled by a computer. The injection sequence lasts several seconds and thus permits performance of rapid sequential analyses of the collected sample. FGI was tested for the separation of equimolar 50 MUM mixture of the inorganic cations K+ , Ba2+ , Na+ , Mg2+ , and Li+ in 50 mM acetic acid/20 mM Tris (pH 4.5) as BGE. The obtained RSD values for the migration times varied in the range 0.7-1.0% and the values for the peak area were 0.7-1.4%; RSD were determined for ten repeated measurements. PMID- 30443943 TI - Agomelatine modulates calcium signaling through protein kinase C and phospholipase C-mediated mechanisms in rat sensory neurons. AB - Agomelatine, a novel antidepressant exerting its effects through melatonergic and serotonergic systems, implicated to be effective against pain including neuropathic pain but without any knowledge of mechanism of action. To explore the possible role of agomelatine on nociceptive transmission at the peripheral level, the effects of agomelatine on intracellular calcium ([Ca2+ ]i ) signaling in peripheral neurons were investigated in cultured rat dorsal root ganglion (DRG) neurons. Using the fura-2-based calcium imaging technique, the effects of agomelatine on [Ca2+ ]i and roles of the second messenger-mediated pathways were assessed. Agomelatine caused [Ca2+ ]i signaling in a dose-dependent manner when tested at 10 and 100 MUM concentration. Luzindole, a selective melatonin receptor antagonist, almost completely blocked the agomelatine-induced calcium signals. The agomelatine-induced calcium transients were also nearly abolished following pretreatment with the 100 ng/ml pertussis toxin, a Gi/o protein inhibitor. The stimulatory effects of agomelatine on [Ca2+ ]i transients were significantly reduced by applications of phospholipase C (PLC) and protein kinase C (PKC) blockers, 10 MUM U73122, and 10 MUM chelerythrine chloride, respectively. The obtained results of agomelatine-induced [Ca2+ ]i signals indicates that peripheral mechanisms are involved in analgesic effects of agomelatine. These mechanisms seems to involve G-protein-coupled receptor activation and PLC and PKC mediated mechanisms. PMID- 30443944 TI - Direct oral anticoagulant use and subsequent start of proton pump inhibitors as proxy for gastric complaints. AB - PURPOSE: Dabigatran use has been linked to gastrointestinal complaints, but it is unknown if this leads to more use of proton pump inhibitors (PPI). Furthermore, it is unknown whether gastrointestinal complaints occur more frequently in dabigatran users compared with other direct oral anticoagulant (DOACs) users. We investigated the association between DOAC use (dabigatran, rivaroxaban, or apixaban) and subsequent PPI initiation as a proxy for gastrointestinal complaints. METHODS: In this population-based observational study with an active comparator new user study design, anonymised dispensing data from Community Pharmacies in the Netherlands from 2012 to 2016 were used. Patients initiating DOAC for the treatment of atrial fibrillation without any PPI use before or at time of DOAC initiation were included. The outcome measure, subsequent PPI initiation, was determined in 28553 DOAC users. RESULTS: The patients initiating dabigatran (10 942), apixaban (4897), or rivaroxaban (12714) were comparable for age (mean 69 years), sex (62% men), socioeconomic class, and concomitant medication use. The risk of PPI initiation in apixaban versus rivaroxaban users was similar (adjusted hazard ratio 1.06; 95% confidence interval 0.96-1.31) The adjusted hazard ratio of initiating PPI for dabigatran users was 1.21 (95% confidence interval 1.14-1.29) compared with rivaroxaban/apixaban users. The cumulative incidence of PPI initiation at 6 months of follow-up for patients using dabigatran was 13.0%, and 10.0% for those using rivaroxaban/apixaban, yielding a number needing treatment of 33. CONCLUSIONS: Proton pump inhibitor initiation occurred frequently in incident DOAC users but more often in patients treated with dabigatran than in those treated with rivaroxaban or apixaban. PMID- 30443945 TI - Test-retest multisite reproducibility of neurovascular 4D flow MRI. AB - BACKGROUND: 4D flow MRI shows great potential in neurovascular disorders such as stenosis, atherosclerotic disease, aneurysms, and vascular malformations. Its widespread application in the neurovascular system requires evidence of good test retest multicenter reproducibility. PURPOSE: To assess the multicenter reproducibility, test-retest reliability and interobserver dependence of 4D flow MRI in measurements of cerebral blood flow/velocity in main intracranial vessels. STUDY TYPE: Prospective study. SUBJECTS: Ten healthy subjects underwent 4D flow scans at three different centers. All subjects were scanned twice at 2 different days at each center. FIELD STRENGTH/SEQUENCE: 3.0 T; 4D flow sequence. ASSESSMENT: Multicenter reproducibility, test-retest reliability and interobserver agreement for measurements of the blood flow and peak velocity from five regions of interest were assessed (bilateral internal carotid arteries, bilateral medial cerebral arteries, and sagittal sinus). STATISTICAL TEST: A Shapiro-Wilks test was conducted to assess normality of measurements in each scan. Coefficient of variances (CVs) was computed to evaluate intra- and intersite variances of all measurements. The multicenter reproducibility was assessed by two-way mixed intraclass correlation coefficient (ICC). A Bland Altman plot and Pearson correlation were used to evaluate test-retest reliability. ICC was calculated to assess interobserver agreements. RESULTS: All P-values for Shapiro-Wilks tests were greater than 0.05, which indicated the normality of all measurements. Both intra- and intersite CVs were lower than 12%. There was good test-retest reliability for both blood flow and peak velocity of all ROIs (r = 0.75-0.94). In addition, high multicenter reproducibility was detected (ICC = 0.77-0.96, all P < 0.001). The results of these measurements also showed great interobserver agreement (all ICC > 0.9 and all P < 0.001). DATA CONCLUSION: High multicenter reproducibility and test-retest reliability was shown for 4D flow in the measurements of blood flow and peak velocity of intracranial vessels. In addition, these measurements showed great interobserver agreement. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 30443946 TI - MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. AB - In this study, we aimed to explore the association between miR-99a-5p and CDC25A in breast cancer and the regulatory mechanisms of miR-99a-5p on breast cancer. The expressions of messenger RNA and microRNAs in breast cancer tissues and adjacent tissues were analyzed by the Cancer Genome Atlas microarray analysis. Quantitative real-time polymerase chain reaction was conducted to find out the expression levels of miR-99a-5p and CDC25A. The expression levels of proteins (CDC25A, ki67, cyclin D1, p21, BAX, BCL-2, BCL-XL, MMP2, and MMP9) were determined by Western blot analysis. The relationship between miR-99a-5p and CDC25A was predicted and verified by bioinformatics analysis and dual luciferase assay. After transfection, cell proliferation, invasion, and apoptosis of breast cancer tissues were, respectively, observed by cell counting kit-8 assay, transwell assay, and flow cytometry (FCM). Furthermore, the relationship among miR-99a-5p, CDC25A, and cell-cycle progression was determined by FCM assay. The nude mouse transplantation tumor experiment was performed to verify the influence of miR-99a-5p on breast cancer cell in vivo. The expression of miR-99a-5p in breast cancer tissues and cells was significantly downregulated, whereas CDC25A expression was upregulated. MiR-99a-5p targeted CDC25A and suppressed its expression in breast cancer cells. Overexpression of miR-99a-5p and decreased expression of CDC25A could suppress breast cancer cell proliferation and invasion and facilitate apoptosis. Cell-cycle progression was significantly activated by downregulated miR-99a-5p and upregulated CDC25A. Moreover, miR-99a-5p overexpression repressed the expressions of CDC25A, marker ki67, and Cyclin D1 proteins, whereas it upregulated the expression of p21 protein. MicroRNA-99a-5p suppresses breast cancer progression and cell-cycle pathway through downregulating CDC25A. PMID- 30443947 TI - Roles and activities of community nurses in China: A descriptive study. AB - AIMS: To collect information about the current status of community nurses in China and explore the roles and activities that they perform in their daily community setting. BACKGROUND: Community health services are central to efforts to improve public health in China. Clarifying who performs which community nursing services can help assess the contributions of community nursing and guide future practices. However, specific information is limited in China. METHODS: A descriptive, cross-sectional survey was conducted from March to November 2014. Information was collected on demographics, work roles, and activities of community nurses. RESULTS: Most community nurses in our survey were young with a low educational level. Their daily routine most frequently involved immunization and basic medical services, while their main roles were caregiver, educator, organiser and manager. CONCLUSION: Although community nurses cover nearly all areas of service that the national government requires, some roles and their associated activities are neglected. The quantity and quality of community nurses may be hindering their ability to fulfill all roles and activities envisioned by the national government. IMPLICATIONS FOR NURSING MANAGEMENT: Further training should be provided to increase the ability of community nurses to perform frequent functions as well as activities that are currently neglected. PMID- 30443948 TI - Omega-6 fatty acids down-regulate matrix metalloproteinase expression in a coronary heart disease-induced rat model. AB - The present study investigated the therapeutic potential of omega-6 fatty acids, according to their effects on antioxidant markers and matrix metalloproteinases (MMPs), in coronary heart disease-induced rats. Rats were grouped into group I (sham control), group II (control), group III (0.5 g/kg bwt of omega-6 fatty acids) and group IV (1 g/kg bwt of omega-6 fatty acids). Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), catalase, glutathione peroxidase (Gpx) and acetylcholinesterase (AChE) enzyme activities were determined. ROS and MDA were substantially reduced, whereas SOD, catalase, Gpx and AChE were significantly increased, following supplementation with omega-6 fatty acids. MMP-2 mRNA expression was drastically increased by 95% in group II. Treatment significantly reduced MMP-2 mRNA expression by 12.3% and 26.7% in groups III and IV respectively. MMP-9 mRNA expression drastically increased, by 121%, in group II. Treatment significantly reduced MMP-9 mRNA expression by 22.6% and 29.4% in groups III and IV respectively. MMP-2 protein expression was drastically increased, by 81%, in group II. Treatment significantly reduced MMP-2 protein expression by 9.4% and 26% in groups III and IV respectively. MMP-9 protein expression was drastically increased, by 100%, in group II. Treatment significantly reduced MMP-9 protein expression by 18.9% and 26.9% in groups III and IV respectively. In summary, the consumption of omega-6 fatty acids significantly decreased MDA and ROS, while SOD, catalase, GHS, Gpx and AChE were increased. Furthermore, omega-6 fatty acids significantly downregulated MMP-2 and MMP-9 expression in our coronary heart disease-induced rat model. PMID- 30443949 TI - MiRNA-548c-5p downregulates inflammatory response in preeclampsia via targeting PTPRO. AB - Preeclampsia is a serious complication of pregnancy and leads to maternal hypertension and proteinuria. It remains a major health problem for mothers and babies across the world due to high maternal and fetal morbidity and mortality. Accumulated data have implicated the critical role of microRNA in preeclampsia. However, to date, the role of miR-548c-5p in preeclampsia remains vaguely understood. In this study, we first elucidate the role of miR-548c-5p and its underlying molecular mechanism in preeclampsia. Compared with healthy controls, miR-548c-5p was obviously downregulated in serum exosomes and placental mononuclear cells in patients with preeclampsia. Nonetheless, PTPRO was significantly upregulated and negatively associated with miR-548c-5p in placental mononuclear cells in patients with preeclampsia. PTPRO was a target of miR-548c 5p. PTPRO was downregulated in the miR-548c-5p-overexpressed macrophages. In addition, miR-548c-5p could inhibit the proliferation and activation of LPS stimulated macrophages, as evidenced by decreased levels of inflammatory cytokines (IL-12 and TNF-alpha) and less nuclear translocation of pNF-kappaB in pTHP1 cells. MiR-548c-5p acts as an anti-inflammatory factor in preeclampsia. The axis of miR-548c-5p/PTPRO/NF-kappaB may provide novel targets for the diagnosis and treatment of preeclampsia. PMID- 30443950 TI - High PD-L1 expression in the tumour cells did not correlate with poor prognosis of patients suffering for oral squamous cells carcinoma: A meta-analysis of the literature. AB - OBJECTIVES: Oral cancer represents one of the most common malignancies in humans. Its prognosis is still poor, despite the most recent improvements in therapies. An increasing attention is placed on the role of programmed death ligand 1 (PD L1) in the tumour immunity and its potential function as a marker for tumour prognosis. Whether PD-L1 expression is a prognostic factor for the poor outcomes in oral squamous cell carcinoma is still controversial. This study aimed to investigate, through a meta-analysis, a potential correlation between PD-L1 expression and the prognostic outcomes in patients with oral squamous cell carcinoma. MATERIALS AND METHODS: The studies were identified by searching PubMed, SCOPUS, Web of Science and were assessed by two of the authors. After the selection process, 11 articles met eligibility criteria and were included in the meta-analysis. Quality assessment of studies was performed according to the REMARK guidelines, and the risk of biases across studies was investigated through Q and I2 tests. Meta-analysis was performed to investigate the association between the PD-L1 expression either overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), gender and lymph node metastasis. RESULTS: A total of 1060 patients were analysed in the 11 studies included in the meta-analysis. Pooled analysis revealed that the expression of PD-L1 did not correlate with poor OS (HR, 0.60; 95% CI: [0.33, 1.10]; P = 0.10), DFS (HR, 0.62; 95% CI: [0.21, 1.88]; P = 0.40), DSS (HR, 2.05; 95% CI: [0.53, 7.86]; P = 0.29 and lymph node metastasis (HR, 1.15; 95% CI: [0.74, 1.81]; P = 0.53). Furthermore, results of the meta-analysis showed that high expression of PD-L1 is two times more frequent in female patients (OR, 0.5; 95% CI: [0.36, 0.69]; P < 0.0001) compared to males. For all the three outcomes analysed, a high rate of heterogeneity was detected (I2 > 50%). DISCUSSION: High PD-L1 expression did not correlate with poor prognosis of patients suffering for oral squamous cell carcinoma. Studies published on the topic showed a significant variation in results, limiting the use of PD-L1 expression by immunohistochemistry as prognostic biomarker in clinical practice. PMID- 30443951 TI - Sudden Unexpected Death in Epilepsy: Risk Factors, Biomarkers and Prevention. AB - Sudden unexpected death in epilepsy (SUDEP) is one of the most important direct epilepsy-related causes of death, with an incidence in adults of 1.2 per 1000 person years. Generalized tonic-clonic seizures have consistently emerged as the leading risk factor for SUDEP, particularly when such seizures are uncontrolled. High seizure burden, lack of antiepileptic drug (AED) treatment, polytherapy, intellectual disability, and prone position at the time of death are other key risk factors. Unfortunately, despite advances in treatment, overall mortality rates in epilepsy are rising. It is imperative that we learn more about SUDEP so that effective prevention strategies can be implemented. To help identify persons at greater risk of SUDEP and in need of closer monitoring, biomarkers are needed. Candidate biomarkers include electrocardiographic, electroencephalographic, and imaging abnormalities observed more frequently in those who have died suddenly and unexpectedly. As our knowledge of the pathophysiologic mechanisms behind SUDEP have increased, various preventative measures have been proposed. These include lattice pillows, postictal oxygen therapy, selective serotonin reuptake inhibitors, and inhibitors of opiate and adenosine receptors. Unfortunately, no randomized clinical trials are available to definitively conclude these measures are effective. Rather, gaining the best control of seizures possible (with AEDs, devices, and resective surgery) still remains the intervention with the best evidence to reduce the risk of SUDEP. In this evidenced-based review, we explore the incidence of SUDEP and review the risk factors, biomarkers, and latest prevention strategies. This article is protected by copyright. All rights reserved. PMID- 30443952 TI - Morphology of the clasper musculature in rays (Chondrichthyes; Elasmobranchii: Batoidea), with comments on their phylogenetic interrelationships. AB - The subclass Batoidea comprise skates, electric rays, stingrays, guitarfishes, and sawfishes, and their interrelationships are still problematical despite recent morphological and molecular phylogenetic studies. The most recent morphological phylogeny indicates that guitarfishes are a polyphyletic group, and that the phylogenetic placement of Platyrhina and Platyrhinoidis is still unclear. Several molecular studies suggest that guitarfishes (except Zanobatus) and sawfishes comprise the monophyletic order Rhinopristiformes, and that thornback rays (Platyrhinidae, Platyrhina, and Platyrhinoidis) are more closely related to the electric rays (Torpediniformes); rhinopristiforms have recently been supported by morphological data as well. The clasper musculature of batoids suggests an alternative pattern of interrelationships for thornback rays, with the m. dilatator attached to the dorsal terminal 1 cartilage by a series of tendons found only in Rhinopristiformes and Platyrhinidae, suggesting that they are closely related. Furthermore, Rajiformes, Rhinopristiformes, and Platyrhinidae exclusively share a reduced m. extensor lateralis, suggesting that these taxa form a monophyletic group. This study identifies new synapomorphies that corroborate the separate monophyly of Rajiformes, Torpediniformes, and Myliobatiformes: the m. dilatator divided into dorsal and ventral bundles and the presence of a single m. flexor are found only in Rajiformes; the extensor lateralis with a laminar shape is a derived character of Torpediniformes; and the exclusive m. flexor medialis arising on the puboischiadic bar is derived for Myliobatiformes. PMID- 30443953 TI - Differential modulations of reward expectation on implicit facial emotion processing: ERP evidence. AB - Implicit emotional processing refers to the preferential processing of emotional content even if it is task irrelevant. Given that motivation enhances executive control by biasing attentional resources toward target stimuli, here we investigated the effects of reward expectation on implicit facial emotional processing in two experiments using ERPs. A precue signaling additional monetary reward for fast and accurate response for the upcoming trial (incentive condition; relative to a cue indicating no such additional reward, i.e., nonincentive condition) was followed by the presentation of a happy, angry, or neutral face. Participants had to determine the gender of the face in Experiment 1 and decide whether a number superimposed on the face was even or odd in Experiment 2. In both experiments, incentive cues elicited larger P3 and contingent negative variation responses, and the targets following incentive cues elicited more positive-going ERPs (200-700 ms), compared with the nonincentive condition. Importantly, the N2 responses (200-280 ms) to the target exhibited differential patterns of Reward * Emotion interaction: relative to the nonincentive condition, the N2 amplitude differences between emotional (i.e., happy and/or angry) and neutral faces increased in the incentive condition in Experiment 1, but diminished in Experiment 2. These results indicate that reward expectation can differentially modulate implicit processing of facial expressions, with increased sensitivity to emotions when the processing of whole faces is required, but with reduced sensitivity when the processing of faces is distractive. This study enriches the evidence for interactions between reward related executive control and implicit emotional processing. PMID- 30443954 TI - Temporal changes in chromium allergy in Denmark between 2002 and 2017. AB - BACKGROUND: In 2012, Danish authorities submitted a proposal to the European Chemical Agency (ECHA) restricting the content of hexavalent chromium to a maximum of 3 ppm in leather goods. Following its adoption, this proposal was implemented in 2015 as a directive in the European Union (EU). OBJECTIVES: We examined the temporal trend of chromium contact allergy in adult dermatitis patients patch tested between 2002 and 2017. Furthermore, we determined clinical characteristics and causative exposures in these patients. METHODS: All adult dermatitis patients patch tested between 2002 and 2017 were included. Patch test data was reviewed retrospectively. Comparisons were done using chi2 -test and logistic regression analysis. RESULTS: A total of 13379 adults aged 18-99 were patch tested 2002 to 2017. The overall prevalence of chromium allergy was 2.2%. An overall decreasing trend of the prevalence of chromium allergy was found (Ptrend =0.00002). Specifically, a significant difference was found for the study periods 2010-2013 (Ptrend =0.002) and 2014-2017 (Ptrend <0.0001) when compared to 2002-2005. Leather remained the most important single cause of allergic contact dermatitis to chromium. The proportion of clinically relevant leather exposure increased from 42.3% during 2002-2009 to 54.8% during 2010-2017 (P=0.04). CONCLUSIONS: The prevalence of chromium allergy is decreasing. The EU Directive restricting the use of hexavalent chromium in leather goods is thought to play a central role in this change. PMID- 30443955 TI - Human Neonatal Stem Cell Derived Skin Substitute Improve Healing of Severe Burn Wounds in a Rat Model. AB - Conventional approaches can repair minor skin injuries; however, severe burn injuries require innovative approaches for efficient and better wound repair. Recent studies indicate that stem-cell-based regenerative therapies can restore severe damaged skin both structurally and functionally. The current study aims to evaluate the wound healing potential of skin substitute derived from human neonatal stem cells (hNSCs) using a severe burn injury rat model. AECs (Amniotic epithelial cells) and MSCs (mesenchymal stem cells) were isolated from placenta (a source of neonatal stem cells) by explant culture method. After characterization, AECs and UC-MSCs were differentiated into keratinocyte and fibroblasts, respectively. Morphological changes and, expression of corresponding keratinocyte and fibroblast specific markers were used to verify differentiation into respective lineage. A skin substitute was developed by mixing hNSCs derived skin cells (hNSCs-SCs) in plasma for transplantation in a rat model of severe burn injury. Results indicated that placenta derived AECs and MSCs were efficiently differentiated into skin cells i.e. keratinocytes and fibroblasts, respectively as indicated by morphological changes, immunostaining and PCR (polymerase chain reaction) analysis. Further, transplantation of hNSCs-SCs seeded in plasma significantly improved basic skin architecture, re epithelization rate and wound healing concurrent with reduced apoptosis. In conclusion, neonatal stem cell derived skin substitute efficiently improved severe burn wounds in a rat model of burn injury. Unique properties of placenta derived stem cells make them superlative candidates for the development of "off the-shelf" artificial skin substitutes for future use. PMID- 30443956 TI - Nursing perspectives on Integral Theory in nursing practice and education: An interpretive descriptive study. AB - While for decades nursing has advocated for theory-informed practice, more recent attention has tended to focus on mid-range theory rather than the earlier focus on developing grand theory to encompass all of nursing practice. However, there has been continued interest in the holistic nursing community on grand theory and, in particular, on Integral Theory. Although Integral Theory's four-quadrant (AQAL) perspective is familiar in nursing, little is known about how it is being used by nurses in direct practice. The purpose of this interpretive descriptive study was to provide a practice-based perspective on Ken Wilber's Integral Theory in professional nursing practice. The following research question was investigated: How does Integral Theory assist nurses in describing and understanding their professional work? Nurses participating in this study used Integral Theory as a map or heuristic that gave structure to an inquiry process in professional nursing practice and in nursing education in a manner that was holonic, multiperspectival, and self-reflective. Challenges constraining nurses' use of Integral Theory included its intricacy, as well as contextual factors in practice environments. Implications for nursing practice and education for the use of Integral Theory's meta-framework are described. PMID- 30443958 TI - CDC25A pathway toward tumorigenesis: Molecular targets of CDC25A in cell-cycle regulation. AB - The cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell-cycle phases during normal cell division, and in the case of DNA damage, they are key targets of the checkpoint machinery that ensure genetic stability. Little is known about the mechanisms underlying dysregulation and downstream targets of CDC25. To understand these mechanisms, we silenced the CDC25A gene in breast cancer cell line MDA-MB-231 and studied downstream targets of CDC25A gene. MDA-MB-231 breast cancer cells were transfected and silenced by CDC25A small interfering RNA. Total messenger RNA (mRNA) was extracted and analyzed by quantitative real-time polymerase chain reaction. CDC25A phosphatase level was visualized by Western blot analysis and was analyzed by 2D electrophoresis and LC ESI-MS/MS. After CDC25A silencing, cell proliferation reduced, and the expression of 12 proteins changed. These proteins are involved in cell-cycle regulation, programmed cell death, cell differentiation, regulation of gene expression, mRNA editing, protein folding, and cell signaling pathways. Five of these proteins, including ribosomal protein lateral stalk subunit P0, growth factor receptor bound protein 2, pyruvate kinase muscle 2, eukaryotic translation elongation factor 2, and calpain small subunit 1 increase the activity of cyclin D1. Our results suggest that CDC25A controls the cell proliferation and tumorigenesis by a change in expression of proteins involved in cyclin D1 regulation and G1/S transition. PMID- 30443957 TI - Hypomania and depression associated with distinct neural activity for immediate and future rewards. AB - Bipolar spectrum and unipolar depressive disorders have been associated with distinct and opposite profiles of reward-related neural activity. These opposite profiles may reflect a differential preexisting vulnerability for both types of disorders. In support, recent ERP studies find that, following reward feedback, a larger reward positivity (RewP) is associated with greater vulnerability for bipolar spectrum disorders, whereas a smaller RewP is associated with greater vulnerability for depression. However, prior studies have investigated only immediate rewards and have not examined dimensions of both bipolar disorder and unipolar depression within the same sample. The present study is the first to investigate feedback-related ERP correlates of proneness to hypomania and unipolar depressive tendencies within the same sample and to expand our scope to include future rewards. Participants completed a modified time estimation task where the same monetary reward was available immediately or at one of five different future dates. Results revealed proneness to hypomania and unipolar depressive tendencies were related to an elevated and blunted RewP, respectively, but only following immediate rewards (i.e., today). Following rewards in the distant future (e.g., 8 months), proneness to hypomania and depressive tendencies were associated with elevated and blunted amplitudes for the P3, respectively, a subsequent ERP component reflecting motivational salience during extended feedback processing. Furthermore, these opposing profiles were independent of, and significantly different from, one another. These results suggest that feedback-related ERPs following immediate and future rewards are candidate biomarkers that can physiologically separate vulnerability for bipolar spectrum from unipolar depressive disorders. PMID- 30443959 TI - Downregulation of lncRNA OIP5-AS1 inhibits breast cancer progression by targeting SOX2 via miRNA-129-5p upregulation. AB - Several studies have demonstrated an important role for long non-coding RNA (lncRNA) in breast cancer progression. This study investigated the role of the lncRNA OIP5-AS1 in the progression of breast cancer. OIP5-AS1 was significantly upregulated in breast cancer tissues and breast cancer cell lines, and OIP5-AS1 downregulation inhibited the malignant behaviors of breast cancer in vitro and in vivo. For the depth exploration of mechanism of OIP5-AS1 in breast cancer, we found that miR-129-5p which was found had bind sites in the sequence of OIP5-AS1, expression in breast cancer tissues was negatively correlated with OIP5-AS1 and luciferase assays indicated that OIP5-AS1 acted as miR-129-5p sponge, resulting in upregulated expression of the SOX2 transcription factor. Our study revealed that OIP5-AS1 plays a critical role in promoting breast cancer progression and that OIP5-AS1 downregulation targets SOX2 via miR-129-5p upregulation. This article is protected by copyright. All rights reserved. PMID- 30443960 TI - Ascitic cholesterol is superior to serum-ascites albumin gradient in the detection of non-portal hypertensive ascites and the diagnosis of mixed ascites. AB - BACKGROUND: The diagnostic value of ascitic cholesterol in the differential diagnosis of ascites is controversial. AIM: To investigate the diagnostic performance of ascitic cholesterol in the differential diagnosis of ascites. METHODS: Consecutive patients with new-onset ascites were enrolled prospectively. The pertinent data were collected from 629 patients with all forms of ascites. RESULTS: In the training cohort, determination of the ascitic cholesterol level was a highly effective method of distinguishing non-portal hypertension (NPH) from portal hypertension (PH). At the pre-determined cut-off value of 45 mg/dL, the sensitivity of ascitic cholesterol was superior to the serum-ascites albumin gradient (SAAG) in identifying NPH-related ascites; the area under the receiver operating characteristic curve was 0.945. In the patients misdiagnosed based on SAAG classification, the diagnostic accuracy of ascitic cholesterol was 69%. The ascitic cholesterol level showed excellent performance in identifying peritoneal lesions in patients with mixed ascites. CONCLUSION: Ascitic cholesterol is an excellent measure for detecting NPH ascites and for identifying peritoneal lesions in mixed ascites. Thus, this simple and cost-effective measure should be determined in patients with new-onset ascites (www.chictr.org.cn; ChiCTR-DCD 15006907). PMID- 30443961 TI - The lncRNA SCARNA2 mediates colorectal cancer chemoresistance through a conserved microRNA-342-3p target sequence. AB - Long noncoding RNAs (lncRNAs) have been implicated in numerous physiological and pathological processes, including cancer development and progression. However, the role and molecular mechanism of lncRNAs in resistance to chemotherapy of colorectal cancer (CRC) remain enigmatic. Here, we found that lncRNA small Cajal body-specific RNA 2 (SCARNA2) is expressed higher in CRC tissues than in adjacent normal tissues, and a robust expression of SCARNA2 is correlated with a bad prognosis of CRC patients after surgery. SCARNA2 overexpression significantly promoted chemoresistance in CRC cells, and downregulation of SCARNA2 obviously inhibited chemoresistance in vitro. SCARNA2 promotes chemotherapy resistance via competitively binding miR-342-3p to facilitate epidermal growth factor receptor (EGFR) and B-cell lymphoma 2 (BCL2) expression in CRC cells. Together, our results reveal a novel pathway that SCARNA2 regulates CRC chemoresistance through targeting miR-342-3p-EGFR/BCL2 pathway, providing a promising therapeutic target for CRC. PMID- 30443962 TI - Hospital responses to price shocks under the prospective payment system. AB - Under the prospective payment system (PPS), hospitals receive a bundled payment for an entire episode of treatment based on diagnosis-related groups (DRG). Although there is ample evidence regarding the impact of the introduction of the PPS, there is little research on the effects of the ensuing changes in payment levels under the PPS. In 2005, the Medicare PPS changed its definition of payment areas from the Metropolitan Statistical Areas to the Core-Based Statistical Areas, generating substantial area-specific price shocks. Using these exogenous price variations, this study examines hospital responses to price changes under the PPS. The results demonstrate that, while the average payment amount significantly increases in the affected areas, no parallel trend is observed in admission volume, treatment intensity, and quality of services. Conversely, hospitals facing a price increase are more liable to the perverse incentives that the PPS is known to encourage, namely, selecting or shifting patients into higher paying DRGs. These results suggest that paying a higher price for a given service may not induce hospitals to offer services of better quality, but can rather prompt even higher payments through other behavioral responses. PMID- 30443963 TI - Antibiotics Suppress Colon Tumorigenesis Through Inhibition of Aberrant DNA Methylation in an AOM/DSS Colitis Model. AB - Chronic inflammation is involved in the development of colon cancer by inducing mutations and aberrant DNA methylation in colon epithelial cells. Furthermore, there is growing evidence showing that the colonic microbiota modulates the inflammation response in the host and influences colon tumorigenesis. However, the influence of the colonic microbiota on aberrant DNA methylation remains unknown. Here, we show the effect of colonic microbes on DNA methylation and tumorigenicity using a mouse model of human ulcerative colitis. Mice treated with azoxymethane (AOM) and dextran sulfate sodium (DSS) showed an increase in degree of colitis, as estimated by body weight, occult blood, and stool consistency/diarrhea at 2 weeks after treatment, but treatment with antibiotics markedly reduced the severity of the colitis. Although mucosal hyperplasia and increased inflammation-related genes were observed in the colonic epithelial cells of the AOM/DSS-treated mice, treatment with antibiotics abrogated these changes. In addition, treatment with antibiotics significantly decreased the number of mucosal nodules from 5.9 +/- 5.3 to 0.2 +/- 0.6 (P < 0.01) and area of occupancy from 50.1 +/- 57.4 to 0.5 +/- 1.4 mm2 (P < 0.01). Aberrant DNA methylation of three marker CpG islands (Cbln4, Fosb and Msx1) was induced by AOM/DSS treatment in colonic mucosae, but this increase was suppressed by 50% to 92% (P < 0.05) with antibiotic treatment. Microbiome analysis showed that this change was associated with a decrease of the Clostridium leptum subgroup. These data demonstrate that antibiotics suppressed tumorigenesis through inhibition of aberrant DNA methylation induced by chronic inflammation. This article is protected by copyright. All rights reserved. PMID- 30443965 TI - An unusual pelvic mass: Contrast enhanced sonographic diagnosis of pelvic splenosis. AB - Splenosis is an unusual condition representing auto-transplantation of splenic tissue following splenic trauma or surgery. When detected on imaging studies, the splenosis deposits are usually misinterpreted as pathological masses. We present a case where a pelvic mass incidentally visualized on an MRI examination, was proven to represent a deposit of splenosis by contrast enhanced ultrasound (CEUS). CEUS demonstrated persistent late-phase enhancement characteristic of splenic tissue. Ultrasound practitioners should be aware of this condition when an unusual abdominal or pelvic mass is encountered in a patient with a history of splenic trauma or surgery. CEUS is ideally suited to confirming the diagnosis. PMID- 30443964 TI - Clinical features and long-term outcomes of lower esophageal sphincter-dependent and lower esophageal sphincter-independent jackhammer esophagus. AB - BACKGROUND: The most recent Chicago Classification expanded the criteria for diagnosis of jackhammer esophagus (JHE) to include the distal contractile integral (DCI) of the lower esophageal sphincter (LES). The clinical impact of the manometric inclusion of LES hypercontractility remains unclear. We aimed to analyze the clinical features and long-term outcomes of measured LES-dependent (LD-JHE) and LES-independent (LI-JHE) jackhammer esophagus. METHODS: Patients meeting diagnostic criteria for JHE were identified at two academic medical centers. High-resolution esophageal manometry data were re-analyzed with inclusion and exclusion of the LES DCI. LD-JHE was defined by falling outside JHE diagnostic criteria with exclusion of the LES. A telephone survey was conducted for follow-up utilizing the impact dysphagia (IDQ-10) questionnaire. KEY RESULTS: Eighty-one patients met study inclusion criteria, with 12 (14.8%) classified as LD-JHE. LD-JHE patients had a significantly lower mean DCI and fewer swallows with DCI >8000 mm Hg-s-cm. Basal LES pressure was higher in patients with dysphagia to solids than those with dysphagia to solids and liquids. Clinical and manometric parameters were otherwise similar between groups. Sixty-six patients had clinical or phone follow-up at a median of 46.6 months. Forty-one patients (62.1%) received therapies directed at JHE. There was no difference in symptom improvement for treated vs untreated patients or for JHE subtype. CONCLUSIONS AND INFERENCES: Our findings suggest that LD-JHE and LI-JHE are clinically indistinguishable and thus support existing diagnostic criteria. Furthermore, our long-term follow-up data suggest that JHE, irrespective of LES involvement, may improve without treatment. Further study is needed to clarify which patients merit therapeutic intervention. PMID- 30443966 TI - Effects of environmental enrichment on survivorship, growth, sex ratio and behaviour in laboratory maintained zebrafish Danio rerio. AB - Environmental enrichment involves increasing the complexity of a fish's environment in order to improve welfare. Researchers are legally obliged to consider the welfare of laboratory animals and poor welfare may result in less robust data in experimental science. Laboratory zebrafish Danio rerio are usually kept in bare aquaria for ease of husbandry and, despite being a well-studied species, little is known about how laboratory housing affects their welfare. This study shows that environmental enrichment, in the form of the addition of gravel substratum and plants into the tank, affects survivorship, growth and behaviour in laboratory-maintained D. rerio. Larvae reared in enriched tanks had significantly higher survivorship compared with larvae reared in bare tanks. Effects of the tank conditions on growth were more variable. Females from enriched tanks had a higher body condition than females maintained in bare tanks, but intriguingly this was not the case for males, where the only difference was a more variable body condition in males maintained in bare tanks. Sex ratio in the rearing tanks did not differ between treatments. Resource monopolisation was higher for fish in enriched tanks than for those in bare tanks. Fish from enriched tanks displayed lower levels of behaviours associated with anxiety compared with fish from bare tanks when placed into a novel environment. Thus, this study demonstrates differences in welfare for D. rerio maintained under different environmental conditions with enhancements in welfare more commonly associated with tank enrichment. PMID- 30443967 TI - Amino acid and lipid profiles following pig-to-primate liver xenotransplantation. AB - As outcomes in clinical liver transplantation steadily improve, demand continues to exceed supply, leading to a substantial disparity in organ availability. The translation of porcine liver xenotransplantation (LXT) into a clinical reality aims to address this dilemma. Our laboratory has previously established an applicable model of alpha-1,3-galactosyltransferase knockout (GalT-KO) pig-to primate LXT with continuous human coagulation factor infusion and costimulation blockade. This report aims to further investigate the post-LXT lipid and amino acid metabolism profile in our longest surviving recipients (25 and 29 days). Experimental samples and control samples, consisting of pre-transplant porcine and baboon serum and plasma, were analyzed for standard lipid profiles and for amino acid levels. Lipid profiles of LXT recipients remained stable following xenotransplantation compared to donor porcine baseline levels. Amino acid concentrations also remained similar to baseline controls, with the exception of a 3-fold increase in l-ornithine and more than a 10-fold decrease in l-arginine post-transplant when compared to both porcine and baboon baseline levels. The observed changes in l-arginine are consistent with prior studies investigating the effects of graft preservation injury following liver transplantation. These results indicate that the porcine liver can maintain most biochemical profiles stably post-operatively in baboons and suggest that arginine supplementation post LXT may potentially be useful for further prolongation of xenograft survival. PMID- 30443968 TI - Effect of phosphodiesterase type 5 inhibitors on prostate cancer risk and biochemical recurrence after prostate cancer treatment: A systematic review and meta-analysis. AB - Recent studies have examined the impact of phosphodiesterase type 5 inhibitors (PDE5-Is) use on the risk of prostate cancer, and biochemical recurrence (BCR) in prostate cancer patients, but the results were inconsistent. A meta-analysis was conducted to assess the associations with all published studies. Databases (PubMed, Web of Science and MEDLINE) were retrieved to identify relevant studies which explored the impact of PDE5-Is use on the risk of prostate cancer, and BCR in prostate cancer patients. The summary results along with 95% confidence intervals (CIs) were calculated. Nine articles were eligible for the inclusion criteria. The pooled analysis showed that PDE5-Is use was not related to the increased risk of prostate cancer (odds ratio (OR), 0.71; 95% CI, 0.40-1.29). Moreover, PDE5-Is use was not linked to BCR risk in prostate cancer patients with erectile dysfunction (ED) following radical prostatectomy or radiation therapy (relative risk (RR), 1.09; 95% CI, 0.89-1.34). The heterogeneity test suggested moderate heterogeneity across studies. PDE5-Is use does not influence the risk of prostate cancer, and BCR in prostate cancer patients. More well-designed studies are warranted to confirm the findings of our analyses. PMID- 30443969 TI - Side effects of tango: connubial contact dermatitis. AB - The term "Connubial or Consort allergic contact dermatitis" defines a peculiar dermatitis caused by sensitization towards substances used by people in close contact with the patient. A connubial allergic contact dermatitis in a tango dancer is reported. PMID- 30443970 TI - Simulation-based education for novices: complex learning tasks promote reflective practice. AB - CONTEXT: Simulated clinical immersion (SCI), in which clinical situations are simulated in a realistic environment, safely and gradually exposes novices to complex problems. Given their limited experience, undergraduate students can potentially be quite overwhelmed by SCI learning tasks, which may result in misleading learning outcomes. Although task complexity should be adapted to the learner's level of expertise, many factors, both intrinsic and extraneous to the learning task, can influence perceived task complexity and its impact on cognitive processes. OBJECTIVES: The purpose of this mixed-methods study was to understand the effects of task complexity on undergraduate pharmacy students' cognitive load, task performance and perception of learning in SCI. METHODS: A total of 167 second-year pharmacy students were randomly assigned to undertake one simple and one complex learning task in SCI consecutively. Participants' cognitive load was measured after each task and debriefing. Task performance and time on task were also assessed. As part of a sequential explanatory design, semi structured interviews were conducted with students showing maximal variations in intrinsic cognitive load to elucidate their perceptions of learning when dealing with complexity. RESULTS: Although the complex task generated significantly higher cognitive load and time on task than the simple task, performance was high for both tasks. Qualitative results revealed that a lack of clinical experience, an unfamiliar resource in the environment and the constraints inherent to SCI, such as time limitations, hindered the clinical reasoning process and led to poorer self-evaluation of performance. Simple tasks helped students gain more self-confidence, whereas complex tasks further encouraged reflective practice during debriefings. CONCLUSIONS: Although complex tasks in SCI were more cognitively demanding and took longer to execute, students indicated that they learned more from them than they did from simple tasks. Complex tasks constitute an additional challenge in terms of clinical reasoning and thus provide a more valuable learning experience from the student's perspective. PMID- 30443971 TI - Induction of Nectriapyrone Biosynthesis in the Rice Blast Fungus Pyricularia oryzae by Disturbance of the Two-Component Signal Transduction System. AB - Most fungal secondary metabolism genes are poorly expressed under laboratory conditions. Nectriapyrones are known as secondary metabolites produced mainly by symbiotic fungi, including endophytes and plant pathogens. Here, we show the induction of nectriapyrone production in the rice blast fungus Pyricularia oryzae. The two-component signal transduction system was disturbed by disrupting OSM1 and PoYPD1, encoding a HOG MAP kinase and a His-containing phosphotransfer (HPt) protein, respectively. This induced the production of two polyketide compounds, nectriapyrone and its hydroxylated analog. The nectriapyrone biosynthetic gene cluster consists of a polyketide synthase gene (NEC1) and an O methyltransferase gene (NEC2). Overexpression of the two genes induced overproduction of nectriapyrone and five nectriapyrone analogs, including a new derivative. Nectriapyrone production was not required for infection of rice. The structure of nectriapyrone is similar to that of the germicidins produced by Streptomyces spp., and nectriapyrone inhibited the growth of Streptomyces griseus. PMID- 30443972 TI - High prevalence of toothache among Great East Japan Earthquake survivors living in temporary housing. AB - OBJECTIVES: The Great East Japan Earthquake and subsequent tsunami cause large scale destruction in the north-eastern coastal areas in Japan, and forced many survivors to relocate to prefabricated temporary housing, a typical emergency accommodation. Based on the hypothesis that higher toothache prevalence among the disaster survivors is associated with postdisaster distress, we determined the impact of temporary residential environment as potential stressor on the subjective toothache prevalence. METHODS: A repeated cross-sectional health survey based on self-reported questionnaire was conducted in 2776 disaster survivors, of whom 1446 participants underwent dental examination by dentists. Housing type was categorized into three groups including the same housing as before the earthquake, temporary housing and rented/new housing. The association of housing type with subjective toothache prevalence was examined using multivariate logistic regression analysis in all subjects and subgroup analysis in dental examination applicants. Stratified analysis by survey wave was applied with inclusion of covariates such as the socio-demographic factors, and presence of insomnia and psychological distress. In subgroup analysis, presence of dental caries and gum problems in dental examination were included as factors of direct exposure to subjective toothache. RESULTS: In the first survey wave, the participants living in the temporary housing had significantly higher odds ratio (OR) for toothache prevalence compared to the participants living in the same housing (OR: 3.76, 95% confidence interval [CI]: 1.85-7.65, P < 0.001); whereas in all other survey waves, there was no significant difference. Subgroup analysis of dental examination applicants confirmed the presence of significant association of subjective toothache prevalence in the temporary housing group alone (OR: 3.27, 95% CI: 1.38-7.76, P = 0.004), but not in the rented/new housing group (OR: 1.50, 95% CI: 0.57-3.91, P = 0.411), even after adjusting for covariates related to oral findings. CONCLUSION: Temporary housing may be a factor to increase the risk of subjective toothache among disaster survivors only at postdisaster acute phase. PMID- 30443973 TI - MiR-130b promotes the progression of oesophageal squamous cell carcinoma by targeting SASH1. AB - MiR-130b and SAM and SH3 domain containing 1 (SASH1) play an important role in many types of human cancers. The aim of our research was to study their interactions in the process of the proliferation and aggressiveness of oesophageal squamous cell carcinoma (ESCC) cells. Microarray analysis was done to screen the differentially expressed genes in the ESCC tissues. miR-130b and SASH1 mRNA levels in the ESCC tissues and cells were detected by qRT-PCR. Dual luciferase reporter system was used to verify the target relationship between miR 130b and SASH1. The effects of miR-130b on SASH1 expression were explored by western blot in KYSE30 and TE1 cell lines. CCK-8 assay, flow cytometry, Transwell, and wound healing assays were conducted to explore the effects of miR 130b and SASH1 in vitro. In addition, in vivo experiments were conducted to study the roles of miR-130b and SASH1. miR-130b was highly expressed, while SASH1 was the opposite in both the ESCC tissues and cells. The expression of SASH1 was inhibited by the direct binding of miR-130b. The inhibition of miR-130b reduced the proliferation and aggressiveness of ESCC cells, while it also induced apoptosis and cell cycle arrest in the ESCC cells by suppressing SASH1. The in vivo assay suggested that the overexpression of miR-130b promoted the growth of ESCC tumours. MiR-130b was up-regulated in the ESCC tumour tissues and cells, acting as a tumour promoter. A stimulating effect was demonstrated on ESCC cell growth and aggressiveness by suppressing SASH1, which is an anti-oncogene. PMID- 30443974 TI - Knockdown of TMPRSS3 inhibits cell proliferation, migration/invasion and induces apoptosis of glioma cells. AB - Transmembrane protease serine 3 (TMPRSS3) is a member of type II transmembrane serine proteases (TTSP) family, which play important roles in the development and progression of various cancers. However, the role of TMPRSS3 in glioma remains unclear. In the present study, we evaluated the expression patterns of TMPRSS3 in clinical tumor samples and glioma cell lines. The results showed that TMPRSS3 was highly expressed in both human glioma tissues and cell lines. Knockdown of TMPRSS3 in glioma cells by transfection with small interfering RNA targeting TMPRSS3 (si-TMPRSS3) significantly suppressed cell proliferation and migration/invasion. Moreover, knockdown of TMPRSS3 markedly elevated the apoptotic rate of glioma cells. Si-TMPRSS3 transfection also resulted in a remarkable increase in bax expression and a notable decrease in bcl-2 expression in glioma cells. Furthermore, TMPRSS3 knockdown markedly suppressed the expressions of Notch1 and Hes1. The results indicated that knockdown of TMPRSS3 exhibited antiglioma effect, which is associated with the inactivation of the Notch signaling pathway. These findings suggested that TMPRSS3 might be used as a therapeutic target for glioma treatment. PMID- 30443975 TI - Single-donor spray-dried plasma. AB - BACKGROUND: Dried plasma is logistically superior for hemostasis management because it can be transported and stored under nonfrozen conditions and quickly reconstituted at the point of care, enabling prehospital administration. Velico Medical has developed a spray-drying system to be integrated into routine blood center work streams for spray drying single donor plasma units. This study compared the quality of the spray-dried plasma (on-demand plasma [ODP]) with fresh frozen plasma (FFP). STUDY DESIGN AND METHODS: ODP units (n = 60) were manufactured from never frozen fresh plasma, which was pretreated with glycine hydrochloric acid and stored at 1to 6 degrees C. Paired aliquots were frozen and stored at -18 degrees C or less. After 31 to 33 days, ODP samples were reconstituted with water for injection and comprehensively characterized in parallel with paired FFP. The quantities of plasma dried and rehydration fluid were predetermined, ensuring comparable total protein concentration in ODP and paired FFP. RESULTS: ODP is comparable to FFP in global coagulation function as assessed by activated partial thromboplastin time and prothrombin time and in clot formation evaluated by thrombelastography. Compared to FFP, ODP had greater than 80% levels of functional coagulation factors and related proteins and chemistry analytes except for Factor XIII (74%). Pretreatment mitigated cleavage of high-molecular-weight von Willebrand factor multimers by spray drying and resulted in 60% vWF:ristocetin cofactor activity in ODP compared to FFP. CONCLUSIONS: ODP demonstrates coagulation function comparable to that of FFP. The spray drying system can be implemented in blood centers and is capable of producing units of ODP. PMID- 30443976 TI - A novel user-friendly transcatheter edge-to-edge mitral valve repair device in a porcine model. AB - OBJECTIVES: The present study was performed to evaluate the feasibility and safety of the ValveClamp system for transcatheter edge-to-edge mitral valve repair in a porcine model. BACKGROUND: The ValveClamp system is a novel, transapically delivered edge-to-edge mitral valve repair system designed for ease of operation. METHODS: Thirteen young adult swine were enrolled in the study. The procedure was performed via the transapical approach under epicardial echocardiography guidance. RESULTS: The acute procedure success rate was 92.3% (12/13). The catheter manipulation time was just 18.5 +/- 8.2 min. Four pigs were explanted on the 14th day after the procedure. One pig died at the 20th day because of pneumonia. The other eight pigs lived to the study endpoint (140 days). No pig had severe mitral valve dysfunction. The gross observation showed that the clamp device was securely attached and created a double-orifice mitral valve in all pigs except the failed one. In the eight pigs living to the endpoint, the clamp device was noted to be completely endothelialized. None of the 13 pigs developed infective endocarditis, thrombosis, thromboembolism, or valve impairment. In two pigs for which mitral regurgitation (MR) was created, the degree of MR was reduced from severe to trace after the device implantation. CONCLUSIONS: It was feasible and safe to use ValveClamp to perform a catheter mediated edge-to-edge mitral valve repair in a porcine model. This system is potentially applicable as a novel user-friendly system for the treatment of MR. PMID- 30443977 TI - Ethyl acetate and n-butanol fraction of Cissus quadrangularis promotes the mineralization potential of murine pre-osteoblast cell line MC3T3-E1 (sub-clone 4). AB - In a sequel to investigate osteogenic potential of ethanolic extract of Cissus quadrangularis (CQ), the present study reports the osteoblast differentiation and mineralization potential of ethyl acetate (CQ-EA) and butanol (CQ-B) extracts of CQ on mouse pre-osteoblast cell line MC3T3-E1 (sub-clone 4) with an objective to isolate an antiosteoporotic compound. Growth curve, proliferation, and viability assays showed that both the extracts were nontoxic to the cells even at high concentration (100 ug/ml). The cell proliferation was enhanced at low concentrations (0.1 ug/ml and 1 ug/ml) of both the extracts. They also upregulated the osteoblast differentiation and mineralization processes in MC3T3 E1 cells as reflected by expression profile of osteoblast marker genes such as RUNX2, Osterix, Collagen (COL1A1), Alkaline Phosphatase (ALP), Integrin-related Bone Sialoprotein (IBSP), Osteopontin (OPN), and Osteocalcin (OCN). CQ-EA treatment resulted in early differentiation and mineralization as compared with the CQ-B treatment. These findings suggest that low concentrations of CQ-EA and CQ-B have proliferative and osteogenic properties. CQ-EA, however, is more potent osteogenic than CQ-B. PMID- 30443978 TI - SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. AB - Lactate dehydrogenase B (LDHB) is a glycolytic enzyme that catalyses the conversion of lactate and NAD+ to pyruvate, NADH and H+ . Protons (H+ ) generated by LDHB promote lysosomal acidification and autophagy in cancer, but how this role is regulated has not been defined. In this study, we identified an important post-translational mechanism by which LDHB is regulated during autophagy in cancer cells. Mass spectrometry revealed that protein sirtuin 5 (SIRT5) is a binding partner of LDHB that deacetylated LDHB at lysine-329, thereby promoting its enzymatic activity. Deacetylated LDHB increased autophagy and accelerated the growth of colorectal cancer (CRC) cells. Notably, SIRT5 knockout or inhibition by GW5074 increased LDHB acetylation at K329 and inhibited LDHB activity, which downregulated autophagy and CRC cell growth in vitro and in vivo. Clinically, the LDHB-Ac-K329 staining score in CRC tissues was lower than that in corresponding peritumour tissues. Low LDHB-Ac-K329 status was associated with malignant progression of human CRC and served as a potential prognostic indicator for patients with CRC. Altogether, we conclude that SIRT5-induced deacetylation of LDHB triggers hyperactivation of autophagy, a key event in tumorigenesis. Thus, the SIRT5/LDHB pathway may represent a novel target for treating CRC. PMID- 30443979 TI - In vivo transcriptomic analysis of Beauveria bassiana reveals differences in infection strategies in Galleria mellonella and Plutella xylostella. AB - BACKGROUND: Insect pests have evolved various defense mechanisms to combat fungal infection, fungi have developed multiple strategies to overcome the immune defense responses of insect. However, transcriptomic analysis of fungal strategies for infecting different pests has not been reported. RESULTS: Transcriptomic profiling of Beauveria bassiana was performed at 12, 24 and 48 h after infecting Galleria mellonella and Plutella xylostella, and 540, 847 and 932 differential expressed genes were detected, respectively. Functional categorization showed that most of these genes are involved in the ribosome, nitrogen metabolism and oxidative phosphorylation pathways. Thirty-one differentially expressed virulence genes (including genes involved in adhesion, degradation, host colonization and killing and secondary metabolism) were found, suggesting that different molecular mechanisms were used by the fungus during infection of the different pests, which was further confirmed by disrupting creA and fkh2. Virulence assay results showed that DeltacreA and Deltafkh2 strains of B. bassiana had distinct fold changes in their LT50 values (compared with the control stains) during their infection of G. mellonella (DeltacreA: 1.38-fold > Deltafkh2: 1.18-fold) and P. xylostella (DeltacreA: 1.44-fold < Deltafkh2: 2.25 fold). During infection progress, creA was expressed at higher levels during the infection of G. mellonella compared to P. xylostella, while fkh2 showed the opposite expression pattern, demonstrated that creA and Fkh2 play different roles in B. bassiana during the infection of G. mellonella and P. xylostella. CONCLUSION: These findings demonstrate that B. bassiana regulates different genes to infect different insects, advancing knowledge of the molecular mechanisms of Beauveria-pest interactions. This article is protected by copyright. All rights reserved. PMID- 30443980 TI - A Robust and Cost-Efficient Scheme for Accurate Conformational Energies of Organic Molecules. AB - Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO-CCSD(T)/cc-pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two-step strategy for reliable yet feasible conformational search and sampling in realistic-size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single-point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods. PMID- 30443981 TI - Considerations for community engagement when conducting clinical trials during infectious disease emergencies in West Africa. AB - Community engagement in research, including public health related research, is acknowledged as an ethical imperative. While medical care and public health action take priority over research during infectious disease outbreaks, research is still required in order to learn from epidemic responses. The World Health Organisation developed a guide for community engagement during infectious disease epidemics called the Good Participatory Practice for Trials of Emerging (and Re emerging) Pathogens that are Likely to Cause Severe Outbreaks in the Near Future and for which Few or No Medical Counter-Measures Exist (GPP-EP). This paper identified priorities for community engagement for research conducted during infectious disease outbreaks drawing on discussions held with a purposive sample of bioethicists, social scientists, researchers, policy makers and laypersons who work with ethics committees in West Africa. These perspectives were considered in the light of the GPP-EP, which adds further depth and dimension to discussions on community engagement frameworks. It concludes that there is no presumptive justification for the exclusion of communities in the design, implementation and monitoring of clinical trials conducted during an infectious disease outbreak. Engagement that facilitates collaboration rather than partnership between researchers and the community during epidemics is acceptable. PMID- 30443982 TI - Allergic contact dermatitis to Finn Chambers AQUA in two patients. AB - Adhesives are widely used in medical material and my cause allergic contact dermatitis (ACD). It is important to know the full composition of medical material to avoid iatrogenic ACD in sensitised patients. Over time, colophonium and rubber components have been replaced by other adhesives to avoid ACD.1. PMID- 30443983 TI - An intravenous insulin protocol designed for pregnancy reduces neonatal hypoglycaemia following betamethasone administration in women with gestational diabetes. AB - AIMS: Marked hyperglycaemia is common following betamethasone administration in women with gestational diabetes (GDM), and may contribute to neonatal hypoglycaemia. Validated protocols to deliver glycaemic stability following betamethasone are lacking. We hypothesized that an intravenous insulin (IVI) protocol for pregnancy-specific glycaemic targets (Pregnancy-IVI) would achieve greater at-target glycaemic control than a generic adult intravenous insulin protocol (Adult-IVI), and may reduce neonatal hypoglycaemia. METHODS: A retrospective cohort study of the performance Adult-IVI and Pregnancy-IVI following betamethasone in GDM, sequentially implemented at a tertiary hospital, without change in indication for IVI. Cases were identified by electronic record search. Primary outcome was percentage of on-IVI time with at-target glycaemia [blood glucose level (BGL) 3.8-7 mmol/l]. Secondary outcomes were time with critical hyperglycaemia (BGL > 10 mmol/l), occurrence of maternal hypoglycaemia (BGL < 3.8 mmol/l) and incidence of neonatal hypoglycaemia (BGL <= 2.5 mmol/l) if betamethasone was administered within 48 h of birth. RESULTS: The cohorts comprised 151 women (Adult-IVI n = 86; Pregnancy-IVI n = 65). The primary outcome was 68% time-at-target [95% confidence interval (CI) 64-71%) for Pregnancy-IVI compared with 55% (95% CI 50-60%) for Adult-IVI (P = 0.0002). Critical maternal hyperglycaemia (0% vs. 2%, P = 0.02) and hypoglycaemia (2% vs. 12%, P = 0.02) were both lower with Pregnancy-IVI than Adult-IVI. Neonatal hypoglycaemia was less common after Pregnancy-IVI (29%) than after Adult-IVI (54%, P = 0.03). A multiple logistic regression model adjusting for potential confounders gave an odds ratio for neonatal hypoglycaemia with Pregnancy-IVI of 0.27 (95% CI 0.10 0.76, P = 0.01). CONCLUSIONS: An IVI protocol designed for pregnancy effectively controlled maternal hyperglycaemia following betamethasone administration in GDM. This is the first intervention to show a reduction in betamethasone-associated neonatal hypoglycaemia, linked with optimum maternal glycaemic control. This article is protected by copyright. All rights reserved. PMID- 30443984 TI - An online investigation of the relationship between the frequency of word puzzle use and cognitive function in a large sample of older adults. AB - OBJECTIVE: The identification of modifiable lifestyle factors to preserve cognitive function in older individuals becomes increasingly of importance. This study examines whether word puzzle use is related to cognitive function in older adults. METHODS: Cognitive data from 19,078 cognitively healthy individuals aged 50 to 93 years enrolled into the online PROTECT study were evaluated for self reported frequency of performing word puzzles on a six-point scale, ranging from 'More than once per day' to 'Never'. Nine cognitive tests covered a range of domains including focussed and sustained attention, information processing, executive function, working memory and episodic memory. Analyses of covariance were used to determine any differences between the six response groups. RESULTS: Each of the 14 cognitive measures analysed showed highly statistically significant main effects of the frequency of performing word puzzles. For each measure, the group who never performed word puzzles performed most poorly, with the group who reported occasional puzzle use also performing more poorly than virtually every other group. Measures of speed provided the greatest discriminations, with a grammatical reasoning score differentiating the two highest frequency groups, performing word puzzles daily or more than once daily. CONCLUSIONS: The frequency of word puzzle use is directly related to cognitive function in adults aged 50 and over. Future work needs to determine whether engaging in such puzzles can favourably influence cognitive trajectory with age. PMID- 30443985 TI - Polyphenols and Tryptophan Metabolites Activate the Aryl Hydrocarbon Receptor in an in vitro Model of Colonic Fermentation. AB - SCOPE: Many dietary phytochemicals have been reported to promote gut health. Specific dietary phytochemicals, such as luteolin, as well as specific microbial metabolites of tryptophan are ligands of the aryl hydrocarbon receptor (AhR), which plays a role in immunity and homeostasis of the gut barrier. Here, the fate of luteolin during colonic fermentation and the contribution of tryptophan metabolites to AhR activity in different parts of the colon are investigated. METHODS AND RESULTS: Several polyphenols are screened for AhR activation and oregano, containing the ligand luteolin, is added to batch cultures of human microbiota from the distal colon. Luteolin is rapidly metabolized, with no measurable increase in AhR activity. In the second experiment, using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME), not all luteolin is metabolized in the ascending colon, but disappear rapidly in the transverse colon. The greatest AhR activity is due to microbiota-derived metabolites of tryptophan, particularly in the descending colon. CONCLUSIONS: Luteolin in food is rapidly metabolized in the transverse colon. Tryptophan metabolism by the microbiota in the colon contributes substantially to the pool of lumen metabolites that can activate the AhR. PMID- 30443987 TI - Retraction: "Identification of Novel Biomarkers for Pancreatic Cancer Using Integrated Transcriptomics With Functional Pathways Analysis" by Zhang, X., Tong, P., Chen, J., Pei, Z., Zhang, X., Chen, W., Xu, J., and Wang, J. AB - The above article from the Journal of Cellular Physiology, published online on 10 March 2016 in Wiley Online Library as Early View (http://onlinelibrary.wiley.com/enhanced/doi/10.1002/jcp.25353/), has been retracted by agreement between Gary Stein, the journal's Editor-in-Chief, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation at the University of Texas, MD Anderson Cancer Center, which confirmed that the article was submitted and approved for publication by Dr. Jin Wang without acknowledgement of NIH funding received or the consent and authorship of Dr. Ann Killary and Dr. Subrata Sen, with whom the manuscript was originally drafted. PMID- 30443986 TI - The intrinsically disordered nature of the peroxisomal protein translocation machinery. AB - Despite having a membrane that is impermeable to all but the smallest of metabolites, peroxisomes acquire their newly synthesized (cytosolic) matrix proteins in an already folded conformation. In some cases, even oligomeric proteins have been reported to translocate the organelle membrane. The protein sorting machinery that accomplishes this feat must be rather flexible and, unsurprisingly, several of its key components have large intrinsically disordered domains. Here, we provide an overview on these domains and their interactions trying to infer their functional roles in this protein sorting pathway. PMID- 30443988 TI - Circular RNA CCDC66 targets DCX to regulate cell proliferation and migration by sponging miR-488-3p in Hirschsprung's disease. AB - It has been suggested that circular RNAs play critical roles in natural growth and disease development. Nevertheless, whether the circular RNAs were related in Hirschsprung's disease (HSCR) remains unknown. Thus, we discovered the cir-CCDC66 was downregulated in HSCR compared with the normal gut tissues. The cir-CCDC66 reduction might inhibit cells' proliferation and migration in vitro. Then, we found that DCX transcript was putative cir-CCDC66 competing endogenous RNA. Furthermore, the function of cir-CCDC66 as a sponge for miR-488-3p to regulate DCX RNA expression was demonstrated by immunoprecipitation and luciferase reporter assays. In conclusion, this is the first report revealing that cir CCDC66 modulates DCX expression through sponging miR-488-3p and thus participates in the onset of HSCR. PMID- 30443989 TI - AP2a enhanced the osteogenic differentiation of mesenchymal stem cells by inhibiting the formation of YAP/RUNX2 complex and BARX1 transcription. AB - OBJECTIVES: Bone regeneration by bone tissue engineering is a therapeutic option for bone defects. Improving the osteogenic differentiation of mesenchymal stem cells (MSCs) is essential for successful bone regeneration. We previously showed that AP2a enhances the osteogenic differentiation in MSCs. The present study investigated the mechanism of how AP2a regulates the direct differentiation. MATERIALS AND METHODS: Co-immunoprecipitation and ChIP assays were carried out to investigate the underlying mechanism in MSCs differentiation. The osteogenic differentiation potential was determined by mineralization ability and the expression of osteogenic marker in vitro and the in vivo bone-like tissue generation in nude mice. RESULTS: We show that AP2a can compete with RUNX2, a key transcription factor in osteogenic differentiation, to recruit YAP and release the inhibition of RUNX2 activity from YAP by forming YAP-AP2a protein complex. YAP-AP2a protein complex also interacts with the BARX1 promoter through AP2a, inhibit the transcription of BARX1. Moreover, BARX1 inhibits osteogenic differentiation of MSCs. CONCLUSIONS: Our discoveries revealed that AP2a may regulate the osteogenic differentiation in an indirect way through competing with RUNX2 to relieve the RUNX2 activity which inhibited by YAP, and also in a direct way via targeting the BARX1 and directly repressed its transcription. Thus, our discoveries shed new light on the mechanism of direct differentiation of MSCs and provide candidate targets for improving the osteogenic differentiation and enhancing bone tissue regeneration. PMID- 30443990 TI - Combination of procalcitonin and C-reactive protein levels in the early diagnosis of bacterial co-infections in children with H1N1 influenza. AB - OBJECTIVE: This study evaluated the diagnostic value of measuring the levels of procalcitonin (PCT) and C-reactive protein (CRP) to differentiate children co infected with H1N1 influenza and bacteria from children infected with H1N1 influenza alone. METHODS: Consecutive patients (children aged < 5 years) with laboratory-confirmed H1N1 influenza who were hospitalized or received outpatient care from a tertiary-care hospital in Canton, China, between January 1, 2012, and September 1, 2017, were included in the present study. Laboratory results, including serum PCT and CRP levels, white blood cell (WBC) counts, and bacterial cultures, were analyzed. The predictive value of the combination of biomarkers versus any of the biomarkers alone for diagnosing bacterial co-infections was evaluated using logistic regression analyses. RESULTS: Significantly higher PCT (1.46 vs 0.21 ng/mL, P < 0.001) and CRP (19.20 vs 5.10 mg/dL, P < 0.001) levels were detected in the bacterial co-infection group than in the H1N1 infection alone group. Using PCT or CRP levels alone, the areas under the curves (AUCs) for predicting bacterial co-infections were 0.801 (95% CI, 0.772-0.855) and 0.762 (95% CI, 0.722-0.803), respectively. Using a combination of PCT and CRP, the logistic regression-based model, Logit(P) = -1.912 + 0.546 PCT + 0.087 CRP, showed significantly greater accuracy (AUC: 0.893, 95% CI: 0.842-0.934) than did the other three biomarkers. CONCLUSIONS: The combination of PCT and CRP levels could provide a useful method of distinguishing bacterial co-infections from an H1N1 influenza infection alone in children during the early disease phase. After further validation, the flexible model derived here could assist clinicians in decision-making processes. PMID- 30443991 TI - Sulfate is transported at significant rates through the symbiosome membrane and is crucial for nitrogenase biosynthesis. AB - Legume-rhizobia symbioses play a major role in food production for an ever growing human population. In this symbiosis, dinitrogen is reduced ('fixed') to ammonia by the rhizobial nitrogenase enzyme complex and is secreted to the plant host cells, while dicarboxylic acids derived from photosynthetically-produced sucrose are transported into the symbiosomes and serve as respiratory substrates for the bacteroids. The symbiosome membrane contains high levels of SST1 protein, a sulfate transporter. Sulfate is an essential nutrient for all living organisms, but its importance for symbiotic nitrogen fixation and nodule metabolism has long been underestimated. Using chemical imaging, we demonstrate that the bacteroids take up 20-fold more sulfate than the nodule host cells. Furthermore, we show that nitrogenase biosynthesis relies on high levels of imported sulfate, making sulfur as essential as carbon for the regulation and functioning of symbiotic nitrogen fixation. Our findings thus establish the importance of sulfate and its active transport for the plant-microbe interaction that is most relevant for agriculture and soil fertility. This article provides a comprehensive explanation for the importance of the nodule specific sulfate transporter (SST1) and the role of sulfate by dissecting the sulfur distribution across the nodule tissue and directly linking sulfate incorporation to nitrogenase biosynthesis. PMID- 30443993 TI - Awareness of clinical trial registration among healthcare professionals: An observational study. AB - AIM: Prospective registration in a freely accessible public platform is a key step in the ethical conduct of clinical trials. Little is known of the awareness of clinical trial registration among the scientific community. This study aimed to assess awareness of clinical trial registration among participants attending a medical congress in Sri Lanka. METHODS: Knowledge of trial registration was assessed using a self-administered questionnaire, which spanned domains such as involvement in research, and knowledge and perceptions regarding trial registration. A knowledge score was calculated and correlated with demographic variables. RESULTS: Of 251 survey respondents, 53.4% were male, 74.9% were below the age of 40 years, and 56.6% were currently engaged in research. Registration was considered necessary for trial publication by 73.3%, and 70.5% agreed that trials should be registered prospectively. Most achieved a knowledge score of 'Acceptable' (41%) or 'Good' (19.9%). Mid- or advanced career stages, postgraduate training, current involvement in research, and recent research publications/presentations were correlated with higher knowledge scores (P < 0.05). Beneficial effects considered to be associated with trial registration were access to findings of all trials (61.4%), access to negative results (47.8%), preventing trial duplication (69.3%), and preventing multiple publications (70.1%). Increasing research workload (49.8%), additional restrictions on research conduct (52.2%), and the possibility of 'intellectual theft' (56.2%) were seen as potential negative effects. CONCLUSIONS: Most participants were aware of the need for prospective registration as a requirement for publication of clinical trials. Concerns were expressed regarding several perceived negative effects of trial registration. PMID- 30443992 TI - Hepatitis E virus infection in Thai blood donors. AB - BACKGROUND: Hepatitis E virus (HEV) infection in several industrialized and developing countries is associated with the consumption of pork and other meat products, an exposure risk among the majority of blood donors. We aimed to evaluate the prevalence of HEV in plasma from healthy blood donors in Thailand. STUDY DESIGN AND METHODS: We screened blood samples collected between October and December 2015, from 30,115 individual blood donors in 5020 pools of six, for HEV RNA using in-house real-time reverse-transcription polymerase chain reaction (RT PCR). Thrice-reactive samples were subjected to a commercial real-time RT-PCR (cobas HEV test) and evaluated for anti-HEV immunoglobulin M and immunoglobulin G antibodies. Genotyping using nested RT-PCR, nucleotide sequencing, and phylogenetic analysis was performed. RESULTS: Twenty-six donors were positive for HEV RNA by the in-house assay, nine of whom were also positive by cobas test. None of the latter were reactive for anti-HEV immunoglobulin M or immunoglobulin G antibodies. Six samples were successfully genotyped and found to be HEV genotype 3. Thus, the frequency of HEV infection among healthy Thai blood donors is 1 in 1158. CONCLUSION: The presence of HEV RNA in the Thai blood supply was comparable to the rates reported in western European countries, but higher than in North America and Australia. PMID- 30443994 TI - MRI diagnosis and follow-up of chest wall and breast desmoid tumours in patients with a history of oncologic breast surgery and silicone implants: A pictorial report. AB - INTRODUCTION: Breast and chest wall desmoid tumours can cause debilitating symptoms and deformity. The mutilating effects of surgical treatment have prompted a shift to medical treatments and even to a wait-and-see approach. This study sought to highlight specific characteristics of breast and chest wall desmoid tumours on long-term follow-up by sequential MRI scans. METHODS: Thirty two breast MRI scans from six patients with chest wall or breast desmoid tumours followed up for up to 6 years were retrospectively reviewed. RESULTS: All patients underwent breast surgery prior to the development of the desmoid tumour. Five of the patients had reconstruction or augmentation using silicone implants. Two desmoids were treated primarily with surgery, three with medical means and one is under wait-and-see approach. On MRI, tumours appeared either oval and lobulated (chest wall) or spiculated with architectural distortion (breast). Chest wall desmoids demonstrated both an enhancing high-T2-signal component and a non-enhancing low-T2- signal component. The histologically defined phases during the course of desmoid tumours (progression, regression, residual disease) could be demonstrated by corresponding MRI changes in each of the components. CONCLUSIONS: Magnetic resonance imaging delineates the complex infiltrative features of chest wall and breast desmoid tumours. In tumours with a bright cellular enhancing and dark collagenous non-enhancing component, treatment response may be predicted by changes on serial T2-weighted sequences, beyond the tumour-dimension-based RECIST assessment alone. PMID- 30443995 TI - Enhancing signal to noise ratio and resolution in low-field NMR relaxation measurements using post-acquisition digital filters. AB - The traditional way to enhance signals to noise ratio (SNR) of Nuclear Magnetic Resonance (NMR) signals is to increase the number of scans. However, this procedure increases the measuring time that can be prohibitive for some applications. Therefore, we have tested the use of several post acquisition digital filters to enhance SNR up to one order of magnitude in time domain NMR (TD-NMR) relaxation measurements. The procedures were studied using continuous wave free precession (CWFP-T1 ) signals, acquired with very low flip angles that contain six times more noise than the Carr-Purcell-Meiboom-Gill (CPMG) signal of the same sample, and experimental time. Linear (LI) and Logarithmic (LO) data compression, Low-Pass infinity impulse response (LP), Savitzky-Golay (SG), and Wavelet transform (WA) post acquisition filters enhanced the SNR of the CWFP-T1 signals by at least six times. The best filters were LO, SG, and WA that have high enhancement in SNR without significant distortions in the ILT relaxation distribution data. Therefore, it was demonstrated that these post acquisition digital filters could be a useful way to denoise CWFP-T1 , as well as CPMG noisy signals, and consequently reducing the experimental time. It was also demonstrated that filtered CWFP-T1 method has the potential to be a rapid and non destructive method to measure fat content in beef, and certainly in other meat samples. PMID- 30443996 TI - Assessing student academic time use: assumptions, predictions and realities. AB - CONTEXT: In an era of medical education reform and increasing accountability at all levels of higher education, there is a need to understand how the time in which students engage in academic activities can inform evidence-based quality improvement of the curriculum. Time logging provides an opportunity to quantify student use of academic time and guide data-informed decision making in curriculum design. OBJECTIVES: This study aimed to evaluate faculty staff and student predictions of students' academic time use and to assess students' reported academic time use. METHODS: Graduate-level professional students engaged in a time use exercise during the first semester of Year 1 (autumn 2015) and second semester of Year 2 (spring 2017) of a redesigned curriculum launched in autumn 2015. This exercise involved three key activities: (i) prediction of time use; (ii) time logging, and (iii) reflection on time use. Key faculty staff predicted students' weekday time use in both semesters. RESULTS: Students' predictions of academic time use strongly correlated with their reported academic time use during both the first semester of Year 1 and second semester of Year 2 (r = 0.55 and r = 0.53, respectively). Faculty members' predictions of academic time use did not correlate with student academic time use during either semester. Although 63.8% of Year-1 students reported the time use exercise motivated them to change their time use, students reported spending similar amounts of time on academic activities during the first semester of Year 1 (7.8 +/- 1.5 hours per weekday) and the second semester of Year 2 (7.9 +/- 2.0 hours per weekday). Most students reported that the exercise had been useful and indicated that their logged time accurately reflected their actual time use. CONCLUSIONS: Although curriculum reform efforts may always require that some assumptions be made, time logging can quantify students' academic use of time. Although students predict their use of time more accurately than do faculty staff, negligible changes in students' academic time use despite reported desires to make changes indicate that students' academic time use may remain inelastic. Educators must consider these findings as they design curricula, identify academic rigour, and establish student expectations of academic time use. PMID- 30443997 TI - Minimally Invasive Left Ventricular Assist Device Implantation: A Comparative Study. AB - Left ventricular assist device (LVAD) is now a routine therapy for advanced heart failure. Minimally invasive approach via thoracotomy for LVAD implantation is getting popular due to its potential advantage over the conventional sternotomy approach in terms of reduced risk at re-operation due to sternal sparing. We compared the approaches (thoracotomy and sternotomy) to determine the superiority. Minimally invasive approach involved fitting of the LVAD inflow cannula into left ventricle apex via left anterior thoracotomy and anastomosis of outflow graft to ascending aorta via right anterior thoracotomy. In the sternotomy approach, both the procedures were performed via sternotomy. Outcomes in patients after LVAD implantation were compared depending on these approaches for the surgery. Two hundred and five continuous flow LVAD implantations performed between July 2006 and June 2015 at a single center were divided based on surgical approach, that is, sternotomy (n = 180) and thoracotomy (n = 25) groups. There was no significant difference between the groups in relation to patient demographics, preoperative hemodynamic parameters, laboratory markers, or risk factors. There was no significant difference between the groups in terms of postoperative hemodynamic parameters, laboratory markers, bleeding and requirement of blood products, intensive care unit, and hospital stay or complications of LVAD surgery. There were no significant differences in terms of long-term survival (Log-Rank P = 0.953), however, thoracotomy, compared to sternotomy approach, incurred significantly less requirement of temporary right ventricular assist (4 vs. 19.4%, P = 0.041). Minimally invasive bilateral thoracotomy approach for LVAD implantation in addition to benefits of sternal sparing avoids dilatation of right ventricle and reduces chances of right ventricular failure requiring temporary right ventricular assist. PMID- 30443998 TI - Hepatobiliary and Pancreatic: Glycogenic hepatopathy in a patient with poorly controlled diabetes mellitus mimics a hepatic neoplasm. PMID- 30443999 TI - Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study. AB - Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso-occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18-30 years) 1:1:1 to twice-daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient-reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non-major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary-reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study. PMID- 30444000 TI - Intensity expectation modifies gustatory evoked potentials to sweet taste: Evidence of bidirectional assimilation in early perceptual processing. AB - Expectations can affect subjective sensory and hedonic ratings of tastes, but it is unclear whether they also shape sensory experience at a perceptual level. The neural correlates of the taste-expectancy relationship were explored through EEG analysis. Using a trial-by-trial cueing paradigm, lingual delivery of 0.05 M or 0.3 M sucrose solutions was preceded by congruent or incongruent visual cues designed to promote anticipation of either a low-sweet or high-sweet solution. When participants were cued to expect low-sweet, but received high-sweet (incongruent cue), intensity ratings for high-sweet decreased. Likewise, expectation of high-sweet increased intensity ratings of low-sweet solutions. Taste-dependent, right central-parietal gustatory ERPs were detected, with greater P1 (associated with greater right insula activation) and P2 peak amplitudes for high-sweet tastes. Valid cue-taste pairings led to specific reduced right-lateralized N400 responses (associated with an attenuation in right insula activation) compared with invalid cue-taste pairings. Finally, P1 amplitudes following invalidly cued low-sweet tastes closely matched those generated by expected high-sweet tastes, and P1 amplitudes for invalidly cued high-sweet tastes resembled those generated by low-sweet tastes. We conclude that, as well as modifying subjective ratings toward the anticipated intensity level, expectations affect cortical activity in a top-down manner to induce bidirectional assimilation in the early perceptual processing of sweet taste and modulate N400 ERP components not previously associated with gustatory stimulation. PMID- 30444001 TI - Coupling function of CDK2 and SEPT2 in the promotion of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common and aggressive malignant tumor with poorly defined molecular mechanism. Cyclin-dependent kinase 2 (CDK2) and Septin2 (SEPT2) are two known oncogenic molecules but the mechanism of functional interactions remains unclear. Here, we interestingly found that CDK2 and SEPT2 show very similar dynamic expression during cell cycle. Both CDK2 and SEPT2 show highest protein level in G2/M phase, resulting in the fact that CDK2 interacts with SEPT2 and stabilizes SEPT2 in HCCs. In a panel of eight pairs of fresh HCC tissues and corresponding adjacent tissues, both WB and IHC assays demonstrate that CDK2 expression is highly correlated with SEPT2. HCCs with high expression of both CDK2 and SEPT2 are more likely to relapse. This observation is further demonstrated by a large panel of 100 HCC patients. In such large panel, high expression of both CDK2 and SEPT2 significantly correlates with tumor differentiation and microvascular invasion, which is an independent prognostic factor in HCC patients. In summary, our results reveal a cooperative function between CDK2 and SEPT2. HCCs with high expression of CDK2 and SEPT2 might be more aggressive and response poorly to current therapy. This article is protected by copyright. All rights reserved. PMID- 30444002 TI - Variations in contents of hyaluronan in the peritumoral micro-environment of human chondrosarcoma. AB - A concept consolidated in recent years is that tumor growth depends to a great extent on the micro-environment surrounding the tumor, which has a fundamental role in tumor progression and in determining the effectiveness of therapies. Our analysis focuses on chondrosarcoma, the second primary malignant bone tumor, resistant to both chemotherapeutic and radiation therapy. We quantified hyaluronan, one of the main components of the extracellular matrix, with the aim of comparing its amount in the connective tissue surrounding the tumor with intra tumoral tissue and healthy fascia of the same anatomic district, viewed as a health control. We demonstrate that hyaluronan increased significantly in the peritumoral stroma compared with the healthy fascia, which showed an average amount according to the physical characteristics of body districts by a mean value of 26.9 MUg/g. In the peritumoral stroma, the mean hyaluronan content reached 132.6 MUg/g (mean value of 63.2 MUg/g). The p-value was less than 0.01, showing a highly significant statistical difference. Surprisingly, no significant differences were detected as a function of age, gender, or tumor grade. The levels of hyaluronan were comparable in peritumoral and tumor tissues, although there were differences depending on the state of necrosis. In addition, data on the expression of hyaluronic acid synthetase showed a decrease of about 50% in peritumoral and tumor tissues, indicating alterations in hyaluronan turnover and synthesis. This work demonstrates a variation in hyaluronan contents around the chondrosarcoma, likely correlated with the aggressiveness and resistance to chemotherapy of this tumors. Statement of Clinical Significance: Deeper knowledge about the composition of the peritumoral stroma, rich in extracellular matrix, will enhance better study and understanding of the metastatic potential of tumors and their prognostic indices. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res. PMID- 30444003 TI - A study of quiet eye's phenomenon in the shooting section of "laser run" of modern pentathlon. AB - The aim of the study was to evaluate the effects of the Quiet eye (QE) phenomenon on performances during the shooting section of "Laser Run" of Modern Pentathlon, in two samples of athletes (novices and experts). The "Laser Run" consists of running and shooting activities. The study involved 18 experienced athletes of the Italian National Team of Modern Pentathlon (i.e., "elite" group) and 18 young and nonexpert athletes of a local Pentathlon club (i.e., "novice" group). Participants performed, in ecological conditions, five trials of four series of shootings (as it occurs in the real competitions), for a total of 20 series. During the shooting trials, athletes wore a mobile Eye Tracking System to record eye movements (saccades, blinks, and fixations). Key measures of the study were QE parameters (QE Duration [QED], Relative QED [RQED], and QE Onset), as well as the performance (accuracy and time to perform the event). The results revealed that both groups of athletes had a longer QED, RQED, and an earlier onset during their best shots than during the worse ones. Furthermore, differences between the groups showed that elite athletes had an earlier onset and a shorter QED than the novice group of athletes. These results provide insightful information about different cognitive and perceptual processes involved in Modern Pentathlon's athletes' performances at both the elite and non-elite level. PMID- 30444004 TI - Correction of B0 eddy current effects in spiral MRI. AB - PURPOSE: B0 eddy currents are a subtle but important source of artifacts in spiral MRI. This study illustrates the importance of addressing these artifacts and presents a system response-based eddy current correction strategy using B0 eddy current phase measurements on a phantom. METHODS: B0 and linear eddy current system response measurements were estimated from phantom-based measurement and used to predict residual eddy current effects in spiral acquisitions. The measurements were evaluated across multiple systems and gradient sets. The corresponding eddy current corrections were studied in both axial spiral-in/out TSE and sagittal spiral-out MPRAGE volunteer data. RESULTS: Correction of B0 eddy currents using the proposed method mitigated blurriness in the axial spiral in/out images and artifacts in the sagittal spiral-out images. The system response measurement was found to yield repeatable results over time with some variation in the B0 eddy current responses measured between different systems. CONCLUSIONS: The proposed eddy current correction framework was effective in mitigating the effects of residual B0 and linear eddy currents. Any spiral acquisition should take residual eddy currents into account. This is particularly important in spiral-in/out acquisitions. PMID- 30444006 TI - When I say ... team reflexivity. PMID- 30444005 TI - Surgeon peer network characteristics and adoption of new imaging techniques in breast cancer: A study of perioperative MRI. AB - BACKGROUND: Perioperative MRI has disseminated into breast cancer practice despite equivocal evidence. We used a novel social network approach to assess the relationship between the characteristics of surgeons' patient-sharing networks and subsequent use of MRI. METHODS: We identified a cohort of female patients with stage 0-III breast cancer from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. We used claims data from these patients and non cancer patients from the 5% Medicare sample to identify peer groups of physicians who shared patients during 2004-2006 (T1). We used a multivariable hierarchical model to identify peer group characteristics associated with uptake of MRI in T2 (2007-2009) by surgeons who had not used MRI in T1. RESULTS: Our T1 sample included 15 149 patients with breast cancer, treated by 2439 surgeons in 390 physician groups. During T1, 9.1% of patients received an MRI; the use of MRI varied from 0% to 100% (IQR 0%, 8.5%) across peer groups. After adjusting for clinical characteristics, patients treated by surgeons in groups with a higher proportion of primary care physicians (PCPs) in T1 were less likely to receive MRI in T2 (OR = 0.81 for 10% increase in PCPs, 95% CI = 0.71, 0.93). Surgeon transitivity (ie, clustering of surgeons) was significantly associated with MRI receipt (P = 0.013); patients whose surgeons were in groups with higher transitivity in T1 were more likely to receive MRI in T2 (OR = 1.29 for 10% increase in clustering, 95% CI = 1.06, 1.58). CONCLUSION: The characteristics of a surgeon's peer network are associated with their patients' subsequent receipt of perioperative MRI. PMID- 30444007 TI - Impacts of the ACA Medicaid expansion on health behaviors: Evidence from household panel data. AB - A motivation for increasing health insurance coverage is to improve health outcomes for impacted populations. However, health insurance coverage may alternatively increase risky health behaviors due to ex ante moral hazard, and past research on this issue has led to mixed conclusions. This paper uses a panel of household purchases to estimate the effects of the recent state-level Medicaid expansions resulting from the Affordable Care Act (ACA) on consumption goods that present adverse health risks. We utilize within-household variation to identify whether increases in Medicaid availability impacted household purchase patterns of alcohol, nicotine-related, snack food, and carbonated beverage products. Overall, we find little evidence that the ACA Medicaid expansion led to ex ante moral hazard across any of these products, but we find compelling evidence that the Medicaid expansions reduced cigarette consumption and increased smoking cessation product use among the Medicaid-eligible population. PMID- 30444008 TI - Association of age and gender with anxiety disorders in older adults: A systematic review and meta-analysis. AB - OBJECTIVES: To provide an estimate of 12-month and lifetime prevalence of DSM-IV anxiety disorders in older adults based on published studies on this topic, and to identify the impact of gender and age. METHODS/DESIGN: A systematic review and meta-analysis was performed. Six databases were searched and manual searches through reference lists of selected articles and reviews were performed. When the information was available, summary effects were calculated for the prevalence of each anxiety disorder and for every age and gender subgroups. Summary odd ratios (OR) were calculated to compare the prevalence of an anxiety disorder according to age and gender. RESULTS: A total of 6464 studies were identified and sixteen studies were included in the meta-analyses. Prevalence was significantly higher in women than men for generalized anxiety disorder (12-month OR=6.10, p=.001; lifetime OR=1.96, p=.001), 12-month social anxiety disorder (OR=2.07, p=.01), and lifetime posttraumatic stress disorder (OR=1.93, p=.002). The prevalence of specific phobia was significantly lower in both the 75-84 and 85+ age groups when compared to the 65-74 age group (OR=0.70, p=.004 and OR=0.63, p=.01, respectively). CONCLUSIONS: Our results suggest that the tendency for women to experience a greater prevalence of anxiety disorders remains present in older adults. Specific phobia was the only disorder to be less frequent with advancing age. This is likely to change with the DSM-5 criteria because the diagnostic manual now indicates that fear of falling is a possible type of specific phobia and fear of falling is generally more frequent in the oldest age groups. PMID- 30444009 TI - Phase II trial of neoadjuvant chemotherapy with intraperitoneal paclitaxel, S-1, and intravenous cisplatin and paclitaxel for stage IIIA or IIIB gastric cancer. AB - BACKGROUND: We carried out a phase II trial to evaluate the feasibility and efficacy of neoadjuvant chemotherapy comprising a single intraperitoneal administration of paclitaxel, followed by intravenous administrations of paclitaxel and cisplatin with S-1 for clinical stage III gastric cancer. METHODS: Patients with potentially resectable gastric cancer were eligible. A laparoscopic survey was performed to confirm CY0 and P0. Intraperitoneal paclitaxel (60 mg/m 2 ) was administered, followed by systemic chemotherapy. Surgery was performed after two cycles of chemotherapy. The primary endpoint was the response rate of chemotherapy. Secondary endpoints were adverse events, pathological response rate, and overall survival rate. RESULTS: Twenty patients were enrolled. Planned cycles were completed in all patients. Grade 3/4 leukopenia and grade 3/4 neutropenia were observed in four (20%) and seven (35%) patients, respectively. The overall response rate was 70% (partial response: 14, stable disease: 5, progressive disease: 1). All patients underwent R0 gastrectomy with D2 lymph-node dissection, with no surgery-related deaths. The pathological response rate was 65% (13 of 20). The 3- and 5-year overall survival rates were 90.0% and 77.1%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy including intraperitoneal paclitaxel followed by sequential intravenous paclitaxel and cisplatin with S-1 for resectable advanced gastric cancer is feasible and effective. PMID- 30444010 TI - Chronic wet cough in Aboriginal children: It's not just a cough. AB - AIM: Chronic respiratory disease is common among Aboriginal Australians. Chronic wet cough is an early marker of chronic disease in children but often goes undetected due, in part, to delayed health seeking by families. Currently, no studies have examined the reasons for delayed health seeking for children's chronic cough. To identify the barriers to, and enablers for, seeking medical help for chronic wet cough in Aboriginal children. METHODS: This was a qualitative study, gathering data through individual semi-structured, in-depth interviews and focus groups to ascertain Aboriginal family knowledge, attitudes and beliefs about seeking health care for chronic wet cough in children in a regional Kimberley town, Western Australia between October 2017 and March 2018. RESULTS: Forty Aboriginal community members participated. The three key barriers identified were: 'Cough normalisation', that is, 70% of participants considered chronic cough normal (with 53% of participants' previous interactions with doctors informing their understanding of chronic cough); the lack of health literacy information; and a sense of disempowerment (belief that no medical action would be taken and inability to challenge doctors). The key expressed enablers were provision of health literacy information and health practitioner training to assess and treat chronic wet cough in children. All participants reported that they would seek help for chronic wet cough once they were informed that it could signify underlying disease. CONCLUSION: Results highlight the need for a culturally appropriate information and education to inform Aboriginal families and their health practitioners of the importance of chronic wet cough in children. PMID- 30444011 TI - Synthesis and Ring Strain of a Benzoborirene-N-Heterocyclic Carbene Adduct. AB - The reduction of an N-heterocyclic carbene (1,3-diisopropyl-4,5 dimethylimidazolin-2-ylidene, IiPr Me2 ) adduct of dichloro(ortho bromophenyl)borane by tert-butyl lithium at low temperature yields the IiPr Me2 adduct A of parent benzoborirene, a highly strained boron-containing bicyclic compound. A is unstable at room temperature and dimerizes at low temperature to the bis-IiPr Me2 adduct of 9,10-dihydro-9,10-diboraanthracene, characterized by single-crystal X-ray crystallography. PMID- 30444012 TI - Dysfunctional hypoglossal nerve stimulator after electrical cardioversion: A case series. AB - OBJECTIVES/HYPOTHESIS: Upper airway stimulation has demonstrated marked improvements in apnea-hypopnea index, oxygen desaturation index, and quality-of life measures in patients with moderate to severe obstructive sleep apnea (OSA) who cannot tolerate continuous positive airway pressure. Cardiac arrhythmias are common in patients with OSA and can require electrical cardioversion. We describe the first four reported cases of hypoglossal nerve stimulator (HGNS) dysfunction after electrical cardioversion and illustrate our operative approach to device troubleshooting and repair. STUDY DESIGN: Retrospective case series. METHODS: A retrospective review of 201 HGNS implantations performed at two academic institutions revealed four cases of HGNS device dysfunction after electrical cardioversion requiring surgical revision. Preoperative and postoperative device performance metrics and electrical cardioversion specifications were retrospectively assessed and compiled for this case series. The senior authors (R.J.S., M.S.B.) detail operative planning and approach for HGNS implantable pulse generator (IPG) replacement. RESULTS: At least two patients with HGNS device dysfunction had received cardioversion via anterolateral electrode pad placement. Three patients had received multiple shocks. All four patients experienced a change in device functionality or complete cessation of functionality after electrocardioversion. Operatively, each patient required replacement of the IPG, with subsequent intraoperative interrogation revealing proper device functionality. CONCLUSION: Counseling for patients with HGNS undergoing external electrical cardioversion should include possible device damage and need for operative replacement. Anteroposterior electrode pad placement should be considered for patients with HGNS who require electrocardioversion. Operative replacement of an HGNS system damaged by electrocardioversion begins with IPG replacement and intraoperative device interrogation. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30444013 TI - Effects of genomic selection for intramuscular fat content in breast muscle in Chinese local chickens. AB - Improvements in living standards have resulted in consumers having higher expectations for chicken meat quality. This is particularly true in Asia, where there is high consumer preference for local breeds. Nothing is presently known about the effectiveness of using genomic selection (GS) strategies in chickens to genetically improve meat quality traits that cannot be measured in living potential parents. In this study, 724 Beijing-You chickens were used as a training population; all were genotyped using Illumina 60K SNP chips, and intramuscular fat content in breast muscle (IMFbr ) was measured. Birds in the GS line were selected based on genomic estimated breeding values, IMFbr being the sole trait. Genetic progress in one generation was compared to that from conventional family-based selection, and both were evaluated against random-bred controls. Results showed that relative to the random-bred controls, IMF percentage was improved 9.62% using GS, comparable to the 10.38% improvement using family-based selection. We quantified the effectiveness of GS when applied to a meat quality trait with low heritability in chickens. We plan to introduce custom SNP chips, appropriate for native chicken breeds in China, to assist in applying GS in local breeding and accelerate genetic gain. PMID- 30444015 TI - Safety and efficacy of patiromer use with tacrolimus in kidney transplant recipients. PMID- 30444016 TI - Cross-linked hemoglobin bis-tetramers from bioorthogonal coupling do not induce vasoconstriction in the circulation. AB - BACKGROUND: Hemoglobin-based oxygen carriers (HBOCs) are potential alternatives to red blood cells in transfusions. Clinical trials using early versions of HBOCs noted adverse effects that appeared to result from removal of the vasodilator nitric oxide (NO). Previous reports suggest that size-enlarged HBOCs may avoid NO rich regions along the vasculature and therefore not cause vasoconstriction and hypertension. STUDY DESIGN AND METHODS: Hemoglobin (Hb) bis-tetramers (bis tetramers of hemoglobin that are prepared using CuAAC chemistry [BT-Hb] and bis tetramers of hemoglobin that are specifically acetylated and prepared using CuAAC chemistry [BT-acHb]) can be reliably produced by a bio-orthogonal cyclo-addition approach. We considered that an HBOC derived from chemical coupling of two Hbs would be sufficiently large to avoid NO scavenging and related side effects. The ability of intravenously infused BT-Hb and BT-acHb to remain in the circulation without causing hypertension were determined in wild-type (WT) and diabetic (db/db) mouse models. RESULTS: In WT mice, the coupled oxygen-carrying proteins retained their function over several hours after administration. No significant changes in systolic blood pressure from baseline were observed after intravenous infusion of BT-Hb or BT-acHb in awake WT and db/db mice. In contrast, infusion of native Hb or cross-linked Hb tetramers in both animal models induced systemic hypertension. CONCLUSION: The results of this study indicate that bis-tetrameric HBOCs derived from the bio-orthogonal cyclo-addition process are likely to overcome clinical issues that arise from NO scavenging by Hb derivatives. PMID- 30444017 TI - A Bayesian-weighted approach to predicting the number of newly discovered rare species. AB - In natural ecological communities, most species are rare and thus susceptible to extinction. Consequently, the prediction and identification of rare species are of enormous value for conservation purposes. How many newly found species will be rare in the next field survey? We took a Bayesian viewpoint and used observed species abundance information in an ecological sample to develop an accurate way to estimate the number of new rare species (e.g., singletons, doubletons, and tripletons) in an additional unknown sample. A similar method has been developed for incidence-based data sets. Five seminumerical tests (3 abundance cases and 2 incidence cases) showed that our proposed Bayesian-weight estimator accurately predicted the number of new rare species with low relative bias and low relative root mean squared error and, accordingly, high accuracy. Finally, we applied the proposed estimator to 6 conservation-directed empirical data sets (3 abundance cases and 3 incidence cases) and found the prediction of new rare species was quite accurate; the 95% CI covered the true observed value very well in most cases. Our estimator performed similarly to or better than an unweighted estimator derived from Chao et al. and performed consistently better than the naive unweighted estimator. We recommend our Bayesian-weight estimator for conservation applications, although the unweighted estimator of Chao et al. may be better under some circumstances. We provide an R package RSE (rare species estimation) at https://github.com/ecomol/RSE for implementation of the estimators. PMID- 30444018 TI - Rollable, Stretchable, and Reconfigurable Graphene Hygroelectric Generators. AB - Moisture-triggered electricity generation has attracted much attention because of the effective utilization of the water-molecule diffusion process widely existing in atmosphere. However, the monotonous and rigid structures of previously developed generators have heavily restricted their applications in complex and highly deformable working conditions. Herein, by a rational configuration design with a versatile laser processing strategy, graphene-based hygroelectric generators (GHEGs) of sophisticated architectures with diversified functions such as rollable, stretchable, and even multidimensional transformation are achieved for the first time. More importantly, a wide range of 3D deformable generators that can automatically assemble and transform from planar geometries into spacial architectures are also successfully fabricated, including cubic boxes, pyramids, Miura-ori, and footballs. These GHEGs demonstrate excellent electricity generation performance in curling and elongating states. The generated voltages are easily up to 1.5 V under humidity variation in atmosphere, powering a variety of commercial electronic components. These deformable GHEGs can be applied on complicated surfaces, human bodies, and many more beyond those demonstrated in this work. PMID- 30444019 TI - A new analysis approach for T2 quantification: Orthogonal Matching Pursuit. AB - PURPOSE: In vivo myelin quantification can provide valuable noninvasive information on neuronal maturation and development, as well as insights into neurological disorders. Multiexponential analysis of multiecho T2 relaxation is a powerful and widely applied method for the quantification of the myelin water fraction (MWF). In recent literature, the MWF is most commonly estimated using a regularized nonnegative least squares algorithm. METHODS: The orthogonal matching pursuit algorithm is proposed as an alternative method for the estimation of the MWF. The orthogonal matching pursuit is a greedy sparse reconstruction algorithm with a low computation complexity. For validation, both methods are compared to a ground truth using numerical simulations and a phantom model using comparable computation times. The numerical simulations were used to measure the theoretical errors, as well as the effects of varying the SNR, strength of the regularization, and resolution of the basis set. Additionally, a phantom model was used to estimate the performance of the 2 methods while including errors occurring due to the MR measurement. Lastly, 4 healthy subjects were scanned to evaluate the in vivo performance. RESULTS: The results in simulations and phantoms demonstrate that the MWFs determined with the orthogonal matching pursuit are 1.7 times more accurate as compared to the nonnegative least squares, with a comparable precision. The remaining bias of the MWF is shown to be related to the regularization of the nonnegative least squares algorithm and the Rician noise present in magnitude MR images. CONCLUSION: The orthogonal matching pursuit algorithm provides a more accurate alternative for T2 relaxometry myelin water quantification. PMID- 30444020 TI - White matter myelin profiles linked to clinical subtypes of Parkinson's disease. AB - BACKGROUND: White matter (WM) microstructural integrity is important for effective brain functioning and alterations have been shown in many neurodegenerative diseases. PURPOSE: To investigate WM myelin profiles and their relation to clinical features of Parkinson's disease (PD). STUDY TYPE: Retrospective cross-sectional. POPULATION: In all, 29 PD subjects and 15 healthy controls. FIELD STRENGTH/SEQUENCE: Multiecho GRASE with 10 msec echo spacing and echo planar imaging (EPI) diffusion-weighted (b-value = 700 with 32 gradient directions) on a 3T scanner. ASSESSMENT: Myelin water fraction (MWF) and fractional anisotropy (FA) across 20 WM regions of interest (ROIs) were compared between groups. Partial least squares (PLS) was used to associate MWF and FA with clinical and behavioral measures. STATISTICAL TESTS: Group comparisons were done using two-sample t-tests. PLS was assessed with permutation tests. Bootstrapping was used to investigate the robustness of imaging features. RESULTS: No group differences in myelin content could be detected with univariate tests. A three component PLS model linked MWF profiles to clinical phenotypes but no FA profiles. The three components appeared to follow along broad motor/nonmotor subtypes of "akinetic-rigid," "tremor-predominant," and "depression/apathy" subtypes, respectively. The first component showed associations between overall motor scores (r = -0.43, P = 0.0196) and cognitive performance (r = 0.44, P = 0.0171) with interhemispheric and long-range association fibers. A second component linked overall motor scores (r = -0.58, P = 0.0009) and tremor scores (r = -0.48, P = 0.0091) to predominantly projection fibers. The last component related depression (r = -0.60, P = 0.0006) and apathy scores (r = -0.66, P = 0.0001 and r = -49, P = 0.0072) to a mixture of association and projection fibers. DATA CONCLUSION: MWF was robustly linked to distinct clinical subtypes of PD and may serve as an additional tool to characterize the disease. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018. PMID- 30444021 TI - Self-Assembly of Nanoparticles into Two Dimensional Arrays for Catalytic Applications. AB - Self-assembly of nanoparticles (NPs) is at the heart of nanotechnology, and has shown many potential applications in fabricating nanodevices with highly controlled functionality. Two-dimensional (2D) arrays of NPs can provide a thin and uniform NP array with each NP being exposed on the surface to maximize NP catalysis. This minireview summarizes the recent progress on the fabrication and application of 2D NP arrays. It conveys the important message to readers that creation of libraries of NP arrays with varying catalytic strengths is an exciting direction in catalysis. This approach can be used to solve complicated catalytic problems in which multiple chemical reactions need to be catalyzed in a single reaction vessel. PMID- 30444022 TI - Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy. AB - Inner and outer blood-retinal barriers (BRBs), mainly composed of retinal endothelial cells and retinal pigment epithelial (RPE) cells, respectively, maintain the integrity of the retinal tissues. In this study, we aimed to investigate the mechanisms of the outer BRB disruption regarding the interaction between RPE and microglia. In mice with high-fat diet-induced obesity and streptozotocin-induced hyperglycemia, microglia accumulated on the RPE layer, as in those after intravitreal injection of interleukin (IL)-6, which is elevated in ocular fluids of patients with diabetic retinopathy. Although IL-6 did not directly affect the levels of zonula occludens (ZO)-1 and occludin in RPE cells, IL-6 increased VEGFA mRNA in RPE cells to recruit microglial cells. In microglial cells, IL-6 upregulated the mRNA levels of MCP1, MIP1A, and MIP1B, to amplify the recruitment of microglial cells. In this manner, IL-6 modulated RPE and microglial cells to attract microglial cells on RPE cells. Furthermore, IL-6 treated microglial cells produced and secreted tumor necrosis factor (TNF)-alpha, which activated NF-kappaB and decreased the levels of ZO-1 in RPE cells. As STAT3 inhibition reversed the effects of IL-6-treated microglial cells on the RPE monolayer in vitro, it reduced the recruitment of microglial cells and the production of TNF-alpha in RPE tissues in streptozotocin-treated mice. Taken together, IL-6-treated RPE and microglial cells amplified the recruitment of microglial cells and IL-6-treated microglial cells produced TNF-alpha to disrupt the outer BRB in diabetic retinopathy. PMID- 30444023 TI - Mass-forming intrahepatic cholangiocarcinoma: Can diffusion-weighted imaging predict microvascular invasion? AB - BACKGROUND: Microvascular invasion (MVI) is a risk factor influencing the survival rate of patients with mass-forming intrahepatic cholangiocarcinoma (IMCC). PURPOSE: To investigate whether diffusion-weighted imaging (DWI) could be useful in predicting MVI of IMCC. STUDY TYPE: Retrospective. SUBJECTS: Eighty patients with surgically resected single IMCC (21 MVI-positive lesions and 59 MVI negative lesions). FIELD STRENGTH/SEQUENCE: Preoperative hepatic MRI (1.5T), including T1 - and T2 -weighted images (T1 WI, T2 WI), DWI, and dynamic enhancement imaging. ASSESSMENT: Morphologic characteristics including contour of the lesion, biliary dilation and hepatic capsule retraction, signal features on T1 WI, T2 WI, and DWI, and dynamic enhancement patterns were qualitatively evaluated. The quantitative analysis was performed for the size and apparent diffusion coefficient (ADC) values. STATISTICAL TESTS: Chi-square test, Fisher's exact test, and the independent t-test were used for univariate analysis to determine the relationships between these radiological parameters and the presence of MVI. Logistic regression analysis was used to identify the independent predictors of MVI among these radiological parameters. Receiver operating characteristic curve analysis was performed to evaluate their diagnostic performance. RESULTS: Larger tumor size (P = 0.006) and higher ADC values (P < 0.001) were positively correlated with MVI. Multivariate logistic regression analysis demonstrated that the ADC value (odds ratio, 3.099; P = 0.001) was an independent predictor for MVI of IMCC. The ADC value for MVI of IMCC showed an area under the receiver operating characteristic curve of 0.782 (optimal cutoff value was 1.59 * 10-3 mm2 /s). DATA CONCLUSION: Larger tumor size was associated with MVI and higher ADC values can be a useful predictor of MVI during the preoperative evaluation of IMCC. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30444024 TI - Trends in low-density lipoprotein-cholesterol blood values between 2012 and 2017 suggest sluggish adoption of the recent 2013 treatment guidelines. AB - BACKGROUND: Over a 14-year period, age-adjusted high total cholesterol (>=240 mg/dL) in the United States declined from 18.3% in 1999 to 2000 to 11.0% in 2013 to 2014, coinciding with the 2001 National Cholesterol Education Program Adult Treatment Panel (ATP)-III guidelines that endorsed low-density lipoprotein (LDL) cholesterol blood value goals. Statin treatment recommendations were revised by the American College of Cardiology and the American Heart Association (ACC/AHA) in November 2013 to a "risk-based prescription" approach that did not utilize blood cholesterol values. This increased dosage and expanded the statin-eligible population by an estimated 12.8 million US adults. These changes should further lower total and LDL cholesterol concentrations nationally. METHODS: We examined data from 507 752 patients nationally aged >=16 years whose fasting bloods were sent to Boston Heart Diagnostics for direct LDL-cholesterol measurements. Between 2012 and 2017, age-adjusted concentrations were examined by analysis of covariance and LDL-cholesterol >=160 mg/dL by logistic regression. RESULTS: Contrary to expectations, age-adjusted mean LDL-cholesterol concentrations (+/ SE, mg/dL) increased significantly (P < 10-16 ) in men (2012:113.8 +/- 0.3; 2013:115.3 +/- 0.2; 2014:114.7 +/- 0.2; 2015:116.0 +/- 0.2; 2016:117.6 +/- 0.2; and 2017:117.1 +/- 0.2 mg/dL) and women (2012:119.5 +/- 0.3; 2013:120.7 +/- 0.2; 2014:119.8 +/- 0.02; 2015:120.8 +/- 0.2; 2016:122.7 +/- 0.1; and 2017:123.8 +/- 0.2 mg/dL). The percentage with LDL-cholesterol >=160 mg/dL also increased significantly (P < 10-9 ) in men and women. Similar results were obtained for ages 40 to 75 years olds (corresponding to ACC/AHA guidelines). CONCLUSION: These results provide additional evidence that declining blood LDL-cholesterol levels observed following the ATP-III recommendations, did not further decline (actually increased) following the 2013 ACC/AHA recommendations. PMID- 30444025 TI - Three-dimensional echocardiography in the evaluation and management of paravalvular regurgitation. AB - Paravalvular regurgitation is an uncommon but serious complication that can be encountered after either surgical or percutaneous valve replacement and is associated with increased morbidity and mortality. Early detection and accurate assessment of paravalvular regurgitation are crucial to identify those who would benefit from intervention. Recent advances in 3-dimensional echocardiography have increased the feasibility of percutaneous approaches for the management of paravalvular regurgitation. Percutaneous closure of paravalvular regurgitation has emerged as a favorable alternative for redo surgery in selected cases. This article will review the role of 3-dimensional echocardiography in the assessment and management of paravalvular regurgitation. PMID- 30444026 TI - Overexpression of the lncRNA FER1L4 inhibits paclitaxel tolerance of ovarian cancer cells via the regulation of the MAPK signaling pathway. AB - To determine how the lncRNA FER1L4 in ovarian cancer cells influences paclitaxel (PTX) resistance, we examined the expression level of FER1L4 in human ovarian epithelial cell lines IOSE80 and HOSEpiC and human ovarian cancer cell lines OVCAR-3, Caov-3, and SKOV3 through RNA isolation and quantitative polymerase chain reaction (qRT-PCR). SKOV3 cell lines were treated with PTX. The cell survival rate and apoptosis rate of SKOV3 and SKOV3-PR at different PTX dose levels were evaluated. Next, qRT-PCR was performed to detect the expression of FER1L4 in SKOV3 and SKOV3-PR cell lines. SKOV3-PR cell lines were transfected with pcDNA3.1 as the control group (SKOV3-PR/pcDNA3.1) or pcDNA3.1-FER1L4 to upregulate the expression level of FER1L4 (SKOV3-PR/pcDNA3.1-FER1L4). The level of cell survival, apoptosis, and colony formation were compared between the two groups using MTT, flow cytometry analysis, and colony formation assay. To reveal the molecular mechanism, we measured the relative protein phosphorylation level of ERK and MAPK in SKOV3, SKOV3-PR, SKOV3-PR/pcDNA3.1, and SKOV3-PR/pcDNA3.1 FER1L4 groups using an enzyme-linked immunosorbent assay. The effects of SB203580 (a p38 MAPK inhibitor) on PTX were also investigated to reveal the function of the MAPK pathway on the PTX tolerance of SKOV3. In comparison with normal ovarian epithelial cells, FER1L4 was downregulated. The FER1L4 level was decreased in human ovarian cancer cells with drug resistance than in common ovarian cancer cells. The upregulation of FER1L4 could promote the PTX sensitivity of ovarian cancer cells. The increased level of FER1L4 could suppress the PTX resistance of ovarian cancer cells through the inhibition of the MAPK signaling pathway. PMID- 30444027 TI - A second KRT71 allele in curly coated dogs. AB - Major characteristics of coat variation in dogs can be explained by variants in only a few genes. Until now, only one missense variant in the KRT71 gene, p.Arg151Trp, has been reported to cause curly hair in dogs. However, this variant does not explain the curly coat in all breeds as the mutant 151 Trp allele, for example, is absent in Curly Coated Retrievers. We sequenced the genome of a Curly Coated Retriever at 22* coverage and searched for variants in the KRT71 gene. Only one protein-changing variant was present in a homozygous state in the Curly Coated Retriever and absent or present in a heterozygous state in 221 control dogs from different dog breeds. This variant, NM_001197029.1:c.1266_1273delinsACA, was an indel variant in exon 7 that caused a frameshift and an altered and probably extended C-terminus of the KRT71 protein NP_001183958.1:p.(Ser422ArgfsTer?). Using Sanger sequencing, we found that the variant was fixed in a cohort of 125 Curly Coated Retrievers and segregating in five of 14 additionally tested breeds with a curly or wavy coat. KRT71 variants cause curly hair in humans, mice, rats, cats and dogs. Specific KRT71 variants were further shown to cause alopecia. Based on this knowledge from other species and the predicted molecular consequence of the newly identified canine KRT71 variant, it is a compelling candidate causing a second curly hair allele in dogs. It might cause a slightly different coat phenotype than the previously published p.Arg151Trp variant and could potentially be associated with follicular dysplasia in dogs. PMID- 30444028 TI - The role of dietary factors in inflammatory bowel diseases: New perspectives. AB - The current review aimed to elucidate the role of diet in every stage of inflammatory bowel diseases, from aspects of prevention, treatment and rehabilitation. Western diet, characterized by overconsumption of refined sugar and saturated fat and low consumption of dietary fiber, may partly be blamed for its pathogenesis. Some immune-modulated nutrients (fibers, monounsaturated fatty acids, n-3 polyunsaturated fatty acids and vitamin D) exert their potential beneficial effects on gut microbiota and immune function, resulting in clinical remission and/or preventing relapse. However, data is limited to conclude optimal micronutrient levels and therapeutic implications. Further, diet itself is complex; therefore, it is reasonable to evaluate diet as a whole rather than a single type of food. Some specific dietary patterns are generated for the management of inflammatory bowel diseases with controversial results. Only exclusive enteral nutrition has been widely recommended for pediatric patients with non-stricturing active Crohn's disease. Self-monitoring, avoidance of certain types of foods, limited intake of alcohol and smoking, supplementation of minerals and vitamins if deficiency is confirmed, and adherence to the diet enriched in vegetables and fruits and low in animal food and un-digested fiber during flares are the most common dietary recommendation. Further clinical trials with a high evidence rank are warranted. PMID- 30444029 TI - Diazirine-Based Proteomic Profiling. AB - The elucidation of substrate-protein interactions is an important component of the drug development process. Due to the complexity of native cellular environments, elucidating these fundamental biochemical interactions remains challenging. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand-target interactions. By judicious modification of substrates with a photoreactive group, PAL creates a covalent crosslink between a substrate and its biolgical target following UV-irradiation. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine-based photoaffinity labeling will be discussed, with emphasis being placed on their applications in proteomic studies. PMID- 30444030 TI - Influence of Pre-organized N-Donor Group on the Coordination of Trivalent Actinides and Lanthanides by Aminopolycarboxylate Complexant. AB - Thermodynamic influence of a pre-organized N-donor group on the coordination of trivalent actinides and lanthanides by an aminopolycarboxylate aqueous complexant was investigated. The synthesized reagent N-2-methylpicolinate-ethylenediamine N,N',N'-triacetic acid, EDTA-Mpic, resembles ethylenediamine-N,N,N',N' tetraacetic acid, EDTA, with a single acetate pendant arm replaced for a 6 carboxypyridin-2-yl-methyl group. The rigidified N-donor picolinate functionality shows a profound impact on ligand protonation and trivalent f-element complexation equilibria as demonstrated using potentiometric, spectroscopic, liquid-liquid metal partitioning studies and molecular dynamics calculations. Relative to DTPA, the ability to preferentially bind trivalent actinides over trivalent lanthanides was moderately lowered due to the presence of N-2 methylpicolinate substitutent. The structural modification substantially amplifies the total ligand acidity of EDTA-Mpic. As a result the complexant sustains the metal complexation, and efficient An3+/Ln3+ differentiation in aqueous mixtures of unprecedented acidity for this class of reagents. PMID- 30444031 TI - Design for Highly Piezoelectric and Visible/Near-Infrared Photoresponsive Perovskite Oxides. AB - Defect-engineered perovskite oxides that exhibit ferroelectric and photovoltaic properties are promising multifunctional materials. Though introducing gap states by transition metal doping on the perovskite B-site can obtain low bandgap (i.e., 1.1-3.8 eV), the electrically leaky perovskite oxides generally lose piezoelectricity mainly due to oxygen vacancies. Therefore, the development of highly piezoelectric ferroelectric semiconductor remains challenging. Here, inspired by point-defect-mediated large piezoelectricity in ferroelectrics especially at the morphotropic phase boundary (MPB) region, an efficient strategy is proposed by judiciously introducing the gap states at the MPB where defect induced local polar heterogeneities are thermodynamically coupled with the host polarization to simultaneously achieve high piezoelectricity and low bandgap. A concrete example, Ni2+ -mediated (1-x)Na0.5 Bi0.5 TiO3 -xBa(Ti0.5 Ni0.5 )O3-delta (x = 0.02-0.08) composition is presented, which can show excellent piezoelectricity and unprecedented visible/near-infrared light absorption with a lowest ever bandgap ~0.9 eV at room temperature. In particular, the MPB composition x = 0.05 shows the best ferroelectricity/piezoelectricity (d33 = 151 pC N-1 , Pr = 31.2 MUC cm-2 ) and a largely enhanced photocurrent density approximately two orders of magnitude higher compared with classic ferroelectric (Pb,La)(Zr,Ti)O3 . This research provides a new paradigm for designing highly piezoelectric and visible/near-infrared photoresponsive perovskite oxides for solar energy conversion, near-infrared detection, and other multifunctional applications. PMID- 30444032 TI - Depression diagnoses, but not individual differences in depression symptoms, are associated with reduced autobiographical memory specificity. AB - OBJECTIVES: Difficulties recalling specific events from one's autobiographical past have been associated with a range of emotional disorders. We present the first examination of whether diagnoses of depression or individual differences in depression severity explain the most variance in autobiographical memory specificity. We also examine the contribution of other key cognitive factors associated with reduced memory specificity - rumination and verbal fluency - to these effects. METHODS: Participants with (n = 21) and without (n = 25) major depressive disorder completed self-report measures of depression severity (Beck Depression Inventory version II; BDI-II) and ruminative tendency (Ruminative Response Scale), a measure of verbal fluency, and the Autobiographical Memory Test (AMT) to assess memory specificity. RESULTS: People diagnosed with depression recalled significantly fewer specific memories in the AMT relative to healthy controls. In a linear regression, diagnostic status explained a significant amount of unique variance in specificity whereas BDI-II scores did not. Diagnostic group differences in verbal fluency also explained a significant amount of variance in specificity. CONCLUSIONS: Our findings extend our understanding of the mechanisms involved in reduced memory specificity but future research must explore the causal contribution of weak executive functioning to reduced memory specificity. PRACTITIONERS POINTS: Diagnoses of depression were associated with problems recalling specific events from one's past. Problems with memory specificity amongst depressed people were associated with executive functioning difficulties. Problems with specificity were not associated with individual differences in depression severity or ruminative tendencies. PMID- 30444033 TI - Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission. AB - The dipeptidyl peptidase 4 inhibitor vildagliptin (VLD), a widely used anti diabetic drug, exerts favourable effects on vascular endothelium in diabetes. We determined for the first time the improving effects of VLD on mitochondrial dysfunction in diabetic mice and human umbilical vein endothelial cells (HUVECs) cultured under hyperglycaemic conditions, and further explored the mechanism behind the anti-diabetic activity. Mitochondrial ROS (mtROS) production was detected by fluorescent microscope and flow cytometry. Mitochondrial DNA damage and ATP synthesis were analysed by real time PCR and ATPlite assay, respectively. Mitochondrial network stained with MitoTracker Red to identify mitochondrial fragmentation was visualized under confocal microscopy. The expression levels of dynamin-related proteins (Drp1 and Fis1) were determined by immunoblotting. We found that VLD significantly reduced mtROS production and mitochondrial DNA damage, but enhanced ATP synthesis in endothelium under diabetic conditions. Moreover, VLD reduced the expression of Drp1 and Fis1, blocked Drp1 translocation into mitochondria, and blunted mitochondrial fragmentation induced by hyperglycaemia. As a result, mitochondrial dysfunction was alleviated and mitochondrial morphology was restored by VLD. Additionally, VLD promoted the phosphorylation of AMPK and its target acetyl-CoA carboxylase in the setting of high glucose, and AMPK activation led to a decreased expression and activation of Drp1. In conclusion, VLD improves endothelial mitochondrial dysfunction in diabetes, possibly through inhibiting Drp1-mediated mitochondrial fission in an AMPK-dependent manner. PMID- 30444034 TI - Comparison of Dynamic Water Distribution and Microstructure Formation of Shiitake Mushrooms during Hot Air and Far Infrared Radiation Drying by LF-NMR and SEM. AB - BACKGROUND: A large number of shiitake mushrooms are consumed in dried form around the world. In this work, the changes in water state, water distribution and microstructure of shiitake mushrooms during hot-air drying (HAD) and far infrared radiation drying (FIRD) processes were investigated using low-field nuclear magnetic resonance (LF-NMR) and scanning electron microscopy (SEM). Quality attributes of the dried products were compared in terms of drying property, appearance, rehydration behavior, texture and storage stability. RESULTS: As compared with HAD, the rate of water diffusion and evaporation of the shiitake mushrooms dried by FIRD was higher, thus resulting in shorter drying time (630 min), lower water content (0.07 g/g w.b.) and higher Tg (7.88 degrees C) of dried products. Moreover, homogenous and porous microstructure with less shrinkage and case hardening was owned by the FIRD samples, indicating superior texture, for instance, larger pileus diameter (3.4 cm), higher rehydration ratio (7.31), lower hardness (37.93 N), and higher crispness (1.41 mm) of the FIRD shiitake mushrooms. CONCLUSION: High-quality shiitake mushrooms with desirable texture could be produced by FIRD through enhancing the diffusion of internal water and alleviating the case hardening during a relatively short drying process. This article is protected by copyright. All rights reserved. PMID- 30444035 TI - Zinc-mediated Intermolecular Reductive Radical Fluoroalkylfluorosulfonylation of Unsaturated Carbon-Carbon Bonds with Perfluoroalkyl bromides, DABSO and N Fluorobenzenesulfonimide. AB - A versatile and general Zinc-mediated intermolecular reductive radical fluoroalkylfluorosulfonylation of unsaturated C-C bonds has been developed using readily available perfluoroalkylbromides, 1,4-dizazbicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) and N-fluorobenzenesulfonimide (NFSI) with wide substrate scope and excellent functional group tolerance. Sulfur dioxide anion radical generated from the reduction of sulfur dioxide with zinc may be involved in the reaction mechanism. PMID- 30444037 TI - Ovarian germinal epithelium, oocyte development and the secretory epithelium in monkfish (Lophius americanus Valenciennes). AB - Histological examination of ovarian morphology was conducted on the monkfish, Lophius americanus. The ovary is of the cystovarian type, that is, with a lumen. However, ovarian morphology is quite unique, compared to other fishes, in that ovarian lamellae only originate along the ventral ovarian wall rather than around the periphery. They may branch at their base, but are otherwise unbranching. Furthermore, the germinal epithelium that is, the site of germ cell production, is described for the first time in L. americanus. The germinal epithelium is uniquely restricted around the base of each lamellae rather than being distributed along lamellar epithelia. Folliculogenesis, the process whereby ovarian follicles are formed, is completed in the Perinucleolar Step of the Primary Growth Stage. As oocytes grow and mature, they are increasingly observed towards the apex of the unbranched lamellae where ovulation occurs. The appearance of small vesicles within yolk at the vegetal pole was observed in oocytes during maturation. Prior to ovulation, cells of the ovarian epithelium produce a mucogelatinous matrix that forms the veil in which eggs, after fertilization, become suspended in the water column until hatching. PMID- 30444036 TI - O-GlcNAc-induced nuclear translocation of hnRNP-K is associated with progression and metastasis of cholangiocarcinoma. AB - O-GlcNAcylation is a key post-translational modification that modifies the functions of proteins. Associations between O-GlcNAcylation, shorter survival of cholangiocarcinoma (CCA) patients and increased migration/invasion of CCA cell lines have been reported. However, the specific O-GlcNAcylated proteins (OGPs) that participate in promotion of CCA progression are poorly understood. OGPs were isolated from human CCA cell lines, KKU-213 and KKU-214, using a click chemistry based enzymatic labeling system, identified using LC-MS/MS, and searched against an OGP database. From the proteomic analysis, a total of 21 OGPs related to cancer progression were identified, of which 12 have not been previously reported. Among these, hnRNP-K, a multi-faceted RNA and DNA binding protein known as a pre-mRNA-binding protein, was one of the most abundantly expressed, suggesting its involvement in CCA progression. O-GlcNAcylation of hnRNP-K was further verified by anti-OGP/anti-hnRNP-K immunoprecipitations and sWGA pull-down assays. The perpetuation of CCA by hnRNP-K was evaluated using siRNA, which revealed modulation of cyclin D1, XIAP, EMT markers, MMP2 and MMP7 expression. In native CCA cells, hnRNP-K was primarily localized in the nucleus; however, when O GlcNAcylation was suppressed hnRNP-K was retained in the cytoplasm. These data signify an association between nuclear accumulation of hnRNP-K and the migratory capabilities of CCA cells. In human CCA tissues, expression of nuclear hnRNP-K was positively correlated with high O-GlcNAcylation levels, metastatic stage, and shorter survival of CCA patients. This study demonstrates the significance of O GlcNAcylation on the nuclear translocation of hnRNP-K and its impact on the progression of CCA. This article is protected by copyright. All rights reserved. PMID- 30444038 TI - Pirin: a potential novel therapeutic target for castration-resistant prostate cancer regulated by miR-455-5p. AB - Androgen deprivation therapy is frequently used to treat prostate cancer (PCa) but resistance can occur, a condition known as castration-resistant prostate cancer (CRPC). Thus, novel approaches for identification of CRPC are important for designing effective prostate cancer (PCa) treatments. Analysis of microRNA (miRNA) expression signatures by RNA sequencing showed that both passenger and guide strands of the miR-455 duplex (miR-455-5p and miR-455-3p, respectively) acted as anti-tumor miRNAs in PCa cells. The involvement of miRNA passenger strands in cancer pathogenesis is a novel concept for miRNA functionality. Based on a large patient cohort in The Cancer Genome Atlas (TCGA), expression of eight miR-455-5p/-3p target genes (PIR: p = 0.0137, LRP8: p = 0.0495, IGFBP3: p = 0.0172, DMBX1: p = 0.0175, CCDC64: p = 0.0446, TUBB1: p = 0.01497, KIF21B: p = 0.0336 and NFAM1: p = 0.0013) was significantly associated with poor prognosis of PCa patients. Here we focused on PIR (pirin), a highly conserved member of the cupin superfamily. PIR expression was directly regulated by miR-455-5p and PIR overexpression was detected in hormone-sensitive PCa (HSPC) surgical specimens and CRPC autopsy specimens. Loss-of-function assays using siRNA or an inhibitor (bisamide) showed that downregulation of PIR expression blocked cancer cell migration and invasion. Moreover, the miR-455-5p/PIR axis contributed to cancer cell aggressiveness. These results suggest that PIR might be a promising diagnostic marker for HSPC and CRPC. Furthermore, CRPC treatment strategies targeting PIR may be possible in the future. Identification of anti-tumor miRNAs, including miRNA passenger strands, may contribute to the development of new diagnostic markers and therapeutic strategies for CRPC. PMID- 30444039 TI - Translocation and activation of sphingosine kinase 1 by ceramide-1-phosphate. AB - Sphingosine kinases (SphKs) and ceramide kinase (CerK) phosphorylate sphingosine to sphingosine-1-phosphate (S1P) and ceramide to ceramide-1-phosphate (C1P), respectively. S1P and C1P are bioactive lipids that regulate cell fate/function and human health/diseases. The translocation and activity of SphK1 are regulated by its phosphorylation of Ser 225 and by anionic lipids such as phosphatidic acid and phosphatidylserine. However, the roles of another anionic lipid C1P on SphK1 functions have not yet been elucidated, thus, we here investigated the regulation of SphK1 by CerK/C1P. C1P concentration dependently bound with and activated recombinant human SphK1. The inhibition of CerK reduced the phorbol 12-myristate 13-acetate-induced translocation of SphK1 to the plasma membrane (PM) and activation of the enzyme in membrane fractions of cells. A treatment with C1P translocated wild-type SphK1, but not the SphK1-S225A mutant, to the PM without affecting phosphorylation signaling. A cationic RxRH sequence is proposed to be a C1P-binding motif in alpha-type cytosolic phospholipase A 2 and tumor necrosis factor alpha-converting enzyme. The mutation of four cationic amino acids to Ala in the 56-RRNHAR-61 domain in SphK1 reduced the phorbol 12-myristate 13-acetate- and C1P-induced translocation of SphK1 to the PM, however, the capacity of C1P to bind with and activate SphK1 was not affected by this mutation. In conclusion, C1P modulates SphK1 functions by interacting with multiple sites in SphK1. PMID- 30444040 TI - A novel soft tissue thickness measuring method using cone beam computed tomography. AB - OBJECTIVE: The aim of this study was to introduce a novel soft tissue thickness measurement method using cone beam computed tomography (CBCT) and to compare the new method with ultrasonic device applications and transgingival probing measurements. METHODS: Twenty-five participants (12 female, 13 male, age range, 25-51 years) were included the study. Soft tissue thickness in lateral incisor, canine, premolar, and molar regions were measured using transgingival probing (group T), ultrasonic device (group U), and CBCT scan measurements (group C). Differences and correlations between groups and agreement between measurement methods were evaluated. RESULTS: Soft tissue thickness was significantly lower in group U in premolar region, but was significantly higher in molar region compared with group C and group T (P < .05). There were significant positive correlations in lateral incisor and canine region, between group U and group C, in premolar region between group T and group C, and in molar region between group U and group C, and between group C and group T (P < .05). The highest agreement between measurement methods was evident between group T and group C. CONCLUSION: Soft tissue thickness values in maxilla may differ depending on the measurement method and location of the measurement. Ultrasonic device, transgingival probing, and CBCT measures may not necessarily correlate in all locations. The high agreement between CBCT measurements and transgingival probing may suggest the newly introduced method as a promising technique for soft tissue thickness evaluation. CLINICAL SIGNIFICANCE: This study evaluated the relation between different soft tissue thickness measurement methods and demonstrated a novel method which can be used in any part of the mouth. The outcome also suggested that the measurement method and the location might affect the soft tissue thickness value obtained, and therefore might be important in clinical decision making. PMID- 30444041 TI - Subtractive non-contrast-enhanced MRI of lower limb veins using multiple flow dependent preparation strategies. AB - PURPOSE: To evaluate the performance of acceleration-dependent vascular anatomy for non-contrast-enhanced MR venography (ADVANCE-MRV) in femoral veins and to investigate whether venous signal uniformity can be improved by applying multiple acquisitions with different flow suppressions or multiple flow suppressions in 1 acquisition. METHODS: The ADVANCE-MRV method uses flow-sensitized modules to acquire a dark-artery image set and a dark-artery vein set, which are subsequently subtracted. Ten healthy volunteers were imaged using the ADVANCE-MRV sequence with improved venous suppression uniformity in the dark-artery vein images achieved by applying multiple flow suppressions in the same acquisition or by combining multiple images acquired with different flow suppressions. The performance of the improved technique was also evaluated in 13 patients with lower-limb deep venous thrombosis. RESULTS: Multiple-preparation and multiple acquisition approaches all improved venous signal uniformity and reduced the signal void artifacts observed in the original ADVANCE-MRV images. The multiple acquisition approaches achieved excellent blood signal uniformity and intensity, albeit at the cost of an increase in the total acquisition time. The double preparation approach demonstrated good performance in all measurements, providing a good compromise between signal uniformity and acquisition time. The blood signal spatial variation and its variation using different gradient amplitudes were reduced by 20% and 29%. All patient images showed uniform and bright venous signal in nonoccluded sections of vein. CONCLUSION: The enhanced ADVANCE-MRV methods substantially improved signal uniformity in healthy volunteers and patients with known deep venous thrombosis. The double-preparation approach gave good-quality femoral vein images, providing improved venous signal uniformity without increasing acquisition time in comparison to the original sequence. PMID- 30444042 TI - Near-future forest vulnerability to drought and fire varies across the western United States. AB - Recent prolonged droughts and catastrophic wildfires in the western United States have raised concerns about the potential for forest mortality to impact forest structure, forest ecosystem services, and the economic vitality of communities in the coming decades. We used the Community Land Model (CLM) to determine forest vulnerability to mortality from drought and fire by the year 2049. We modified CLM to represent 13 major forest types in the western United States and ran simulations at a 4-km grid resolution, driven with climate projections from two general circulation models under one emissions scenario (RCP 8.5). We developed metrics of vulnerability to short-term extreme and prolonged drought based on annual allocation to stem growth and net primary productivity. We calculated fire vulnerability based on changes in simulated future area burned relative to historical area burned. Simulated historical drought vulnerability was medium to high in areas with observations of recent drought-related mortality. Comparisons of observed and simulated historical area burned indicate simulated future fire vulnerability could be underestimated by 3% in the Sierra Nevada and overestimated by 3% in the Rocky Mountains. Projections show that water-limited forests in the Rocky Mountains, Southwest, and Great Basin regions will be the most vulnerable to future drought-related mortality, and vulnerability to future fire will be highest in the Sierra Nevada and portions of the Rocky Mountains. High carbon-density forests in the Pacific coast and western Cascades regions are projected to be the least vulnerable to either drought or fire. Importantly, differences in climate projections lead to only 1% of the domain with conflicting low and high vulnerability to fire and no area with conflicting drought vulnerability. Our drought vulnerability metrics could be incorporated as probabilistic mortality rates in earth system models, enabling more robust estimates of the feedbacks between the land and atmosphere over the 21st century. PMID- 30444043 TI - miR-381 overcomes cisplatin resistance in breast cancer by targeting MDR1. AB - Increasing evidence suggests the involvement of microRNA-381 (miR-381) in chemoresistance of cancer treatment. However, its function and molecular mechanisms in breast cancer chemoresistance are still not well elucidated. In the present study, we aimed to investigate the functional role of miR-381 in cisplatin (DDP) resistance of breast cancer and discover the underlying molecular mechanism. The expression levels of miR-381 and MDR1 were detected by quantitative real-time PCR (qRT-PCR) and western blot analysis in breast cancer tissues and cell lines. The DDP sensitivity and cell apoptosis of breast cancer cells were determined by MTT assay and flow cytometric analysis, respectively. The relationship between miR-381 and MDR1 was explored by target prediction and luciferase reporter analysis. miR-381 was decreased in DDP-resistant breast cancer tissues and cell lines. Low miR-381 expression was correlated with poor prognosis of breast cancer patients. miR-381 overexpression improved DDP sensitivity of MCF-7/DDP and MDA-MB-231/DDP cells. Conversely, miR-381 inhibition lowered the response of MCF-7 and MDA-MB-231 to DPP. Moreover, miR-381 could directly suppress multidrug resistance 1 (MDR1) expression. MDR1 knockdown could overcome DDP resistance in MCF-7/DDP and MDA-MB-231/DDP cells, while MDR1 overexpression led to DDP resistance in MCF-7 and MDA-MB-231 cells. Notably, MDR1 overexpression counteracted the inductive effect of miR-381 mimics on DDP sensitivity of MCF-7/DDP and MDA-MB-231/DDP cells. On the contrary, miR-381 inhibition-mediated DDP resistance in MCF-7 and MDA-MB-231 cells was reversed by MDR1 knockdown. In summary, miR-381 could overcome DDP resistance of breast cancer by directly targeting MDR1, providing a novel therapeutic target for breast cancer chemoresistance. PMID- 30444044 TI - Discourse macrolinguistic impairment as a marker of linguistic and extralinguistic functions decline in early Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease is characterized by macrolinguistic changes. This decline is often analyzed with quantitative scales. AIMS: To analyze discourse production in early Alzheimer's disease (AD) and to identify qualitative markers of macrolinguistic decline. METHODS & PROCEDURES: We analyzed macrolinguistic features of a clinical narrative task along with patients' cognitive changes. To do so, 17 early AD participants and 17 healthy controls were recruited and given a full neuropsychological and language assessment. Narrative discourses produced during the language assessment were transcribed and macrolinguistic features were qualitatively analyzed (i.e., local and global coherence marks and discourse informativeness). Inter-group comparison was complemented by intra-group correlation. As some inter-group comparisons revealed the existence of subgroups of patients, permutation tests were used to investigate how these subgroups differed vis-a-vis cognitive measures. OUTCOMES & RESULTS: Overall, the results indicate that AD participants presented declines in informativeness and global coherence, correlated with declines in memory and executive functions. Permutation tests showed that participants with AD producing referential errors or misinterpretations had a deeper lexical-executive decline and a lower Mini Mental State Evaluation (MMSE). CONCLUSIONS & IMPLICATIONS: This study shows that two clinically relevant, qualitative signs differ in discourse production between typical ageing and early AD, namely information units and modalizing discourse. It also shows that macrolinguistic assessment is a useful tool for revealing impaired communication and cognition in early AD. Although lexical processing decline probably contributes to patients' macrolinguistic impairment, implications of extralinguistic functioning should be further investigated. PMID- 30444045 TI - Changes to Editorial Team. PMID- 30444046 TI - The expression signature of cancer-associated KRAB-ZNF factors identified in TCGA pan-cancer transcriptomic data. AB - The KRAB-ZNF (Kruppel-associated box domain zinc finger) gene family is composed of a large number of highly homologous genes, gene isoforms, and pseudogenes. The proteins encoded by these genes, whose expression is often tissue-specific, act as epigenetic suppressors contributing to the addition of repressive chromatin marks and DNA methylation. Due to its high complexity, the KRAB-ZNF family has not been studied in sufficient detail, and the involvement of its members in carcinogenesis remains mostly unexplored. In this study, we aimed to provide a comprehensive description of cancer-associated KRAB-ZNFs using publicly available TCGA pan-cancer datasets. We analyzed 6727 tumor and normal tissue samples from 16 cancer types. Here, we showed that a small but distinctive cluster of 16 KRAB ZNFs is commonly upregulated across multiple cancer cohorts in comparison to normal samples. We confirmed these observations in the independent panels of lung and breast cancer cell lines and tissues. This upregulation was also observed for most of the KRAB-ZNF splicing variants, whose expression is simultaneously upregulated in tumors compared to normal tissues. Finally, by analyzing the clinicopathological data for breast and lung cancers, we demonstrated that the expression of cancer-associated KRAB-ZNFs correlates with patient survival, tumor histology, and molecular subtyping. Altogether, our study allowed the identification and characterization of KRAB-ZNF factors that may have an essential function in cancer biology and thus, potential to become novel oncologic biomarkers and treatment targets. PMID- 30444047 TI - Three-Dimensional Numerical Simulations of Aspiration Process: Evaluation of Two Penumbra Aspiration Catheters Performance. AB - Acute ischemic stroke (AIS) is the leading cause of mortality and disability worldwide. AIS occur while cerebral arteries become blocked by embolism or thrombosis. Aspiration thrombectomy is a promising interventional device to extract massive clots from occluded cerebral arteries. The aim of this article is to develop a computer-aided method to clarify the performance of aspiration catheter and identify the risks of aspiration for each specific AIS patient. In order to simulate the aspiration process, a three-dimensional fluid-structure interaction (FSI) method was developed. The blood clot was modeled as a porous media which composed of viscoelastic fibrin networks. The finite element method (FEM) was implemented to compute the blood flow dynamics in the simplified cerebral vessel. The introduced clot model was validated by comparing the numerical results with experimental data. Furthermore, the analytical solution of the flow through the partially porous pipe was considered to validate FEM. In this research, the performance of two model of the Penumbra aspiration catheter 4MAX and 5MAX-were were compared at three distinct suction pressures. The aspiration ratio of the clot, aspiration time, amount of free fragments, wall shear stress (WSS), and extracted volume of the blood were calculated to evaluate catheters performance. At suction pressure -50 kPa, the aspiration ratio of 5MAX catheter reached 86.58% within 1.36 s. However, in 4MAX case, aspiration ratio of 76.41% was achieved within 1.39. Also, 5MAX catheter created 6.11% fewer free fragments in comparison to 4MAX. Hence, the possibility of distal embolization of 4MAX model was greater. However, the risk of vessel wall rupture was higher in 5MAX by considering mean WSS. PMID- 30444048 TI - Promoting Li-O2 batteries with redox mediators. AB - Lithium O2 battery has a high theoretical specific energy, 3500 Wh kg-1, however its practical capacity is far below this value and it is limited by the passivation of insulating discharge product. The nonconductive nature of Li2O2 also impedes the charging process, leading to low coulombic efficiency and high over-potential on charge even at a moderate rate. To address these challenges, redox mediators could be used both on discharge and charge to transfer the electron between O2/electrode surface or Li2O2/electrode surface to overcome the passivation of Li2O2, and thus facilitate the discharge and charge process. The capacity and current density were significantly improved by using the redox mediators. It demonstrated a promising strategy to deliver a high energy density lithium-O2 battery. PMID- 30444049 TI - Experiences and coping strategies related to food and eating up to two years after the termination of treatment in patients with head and neck cancer. AB - The purpose was to describe how patients with head and neck cancer experience and cope with difficulties related to food and eating up to two years after the termination of treatment. One hundred and thirty-five patients were followed with thematically structured interviews. The patients' responses of nutritional issues were categorised using similarities and differences technique. In the analysis, six categories emerged describing the process of eating and drinking from the end of treatment up to two years after treatment: The constant battle-eating and drinking over time, Food alterations and nutritional support-both pros and cons, Standing aside and not joining in when eating together with others, Finding ways to cope and to make the new a part of everyday life, Relationships and social support-hindrances and facilitators, and Longing for "normality." Results imply that patients struggle with physiological, psychological and social aspects related to food and eating, and use coping mechanisms to facilitate their eating problems. The best practice for rehabilitation and follow-up must be established in order to meet the multifaceted needs of head and neck cancer survivors. PMID- 30444050 TI - Molecular basis for Poria cocos mushroom polysaccharide used as an antitumour drug in China. AB - Poria cocos is an edible medicinal fungus known as "Fuling" in Chinese and has been used as a Chinese traditional medicine for more than two thousand years. Pharmacological studies reveal that polysaccharide is the most abundant substance in Poria cocos and has a wide range of biological activities including antitumour, immunomodulation, anti-inflammation, antioxidation, anti-ageing, antihepatitis, antidiabetics and anti-haemorrhagic fever effects. As a result, "Poria cocos polysaccharide oral solution" was developed and sold as an over-the counter health supplement since 1970s. In 2015, "Polysaccharidum of Poria cocos oral solution" was approved as a drug by Chinese Food and Drug Administration for treating multiple types of cancers, hepatitis and other diseases alone or during chemo- or radiation therapy for patients with cancer. In this article, biochemical, preclinical and clinical studies of Poria cocos polysaccharide from 72 independent studies during the past 46 years (1970-2016) based on PubMed, VIP (Chongqing VIP Chinese Scientific Journals Database), CNKI (China National Knowledge Infrastructure) and Wanfang database searches are summarized. The structure, pharmacological effects, clinical efficacy, immunobalancing molecular mechanism and toxicity of Poria cocos polysaccharide are deliberated to provide a general picture of Poria cocos polysaccharide as a clinically used antitumour drug. PMID- 30444051 TI - Advances in evidence-based medicine for immunotherapy of non-small cell lung cancer. AB - Tumor immunotherapy is praised as "green therapy," which can attack tumor by mobilizing immune system. By removing the inhibition of immune cells, checkpoint inhibitors help T cells to identify and kill tumor cells. In recent years, more and more attention has been paid to its effectiveness as a tumor therapy with a large number of clinical data. Currently, inhibitors of 2 checkpoints, CTLA-4 and PD-1/PD-L1, have been approved to be listed. In particular, the latter has achieved breakthrough progress in non-small cell lung cancer in recent years, bringing about changes in the therapeutic strategy of lung cancer, as well as challenges to the evaluation criteria. This article focuses on the latest immunotherapy methods for lung cancer. The purpose of this article is to summarize the development of evidence-based medicine for lung cancer immunotherapy and to provide help for further understanding of lung cancer immunotherapy. PMID- 30444052 TI - The Absence and Importance of Operando Techniques for Metal-Free Catalysts. AB - Operando characterization techniques have played a crucial role in modern technological developments. In contrast to the experimental uncertainties introduced by ex situ techniques, the simultaneous measurement of desired sample characteristics and near-realistic electrochemical testing provides a representative picture of the underlying physics. From Li-ion batteries to metal based electrocatalysts, the insights offered by real-time characterization data have enabled more efficient research programs. As an emerging class of catalyst, much of the mechanistic understanding of metal-free electrocatalysts continues to be elusive in comparison to their metal-based counterparts. However, there is a clear absence of operando characterization performed on metal-free catalysts. Through the proper execution of operando techniques, it can be expected that metal-free catalysts can achieve exceptional technological progress. Here, the motivation of using operando characterization techniques for metal-free carbon based catalyst system is considered, followed by a discussion of the possibilities, difficulties and benefits of their applications. PMID- 30444053 TI - Toward predictive modeling of catheter-based pulmonary valve replacement into native right ventricular outflow tracts. AB - BACKGROUND: Pulmonary insufficiency is a consequence of transannular patch repair in Tetralogy of Fallot (ToF) leading to late morbidity and mortality. Transcatheter native outflow tract pulmonary valve replacement has become a reality. However, predicting a secure, atraumatic implantation of a catheter based device remains a significant challenge due to the complex and dynamic nature of the right ventricular outflow tract (RVOT). We sought to quantify the differences in compression and volume for actual implants, and those predicted by pre-implant modeling. METHODS: We used custom software to interactively place virtual transcatheter pulmonary valves (TPVs) into RVOT models created from pre implant and post Harmony valve implant CT scans of 5 ovine surgical models of TOF to quantify and visualize device volume and compression. RESULTS: Virtual device placement visually mimicked actual device placement and allowed for quantification of device volume and radius. On average, simulated proximal and distal device volumes and compression did not vary statistically throughout the cardiac cycle (P = 0.11) but assessment was limited by small sample size. In comparison to actual implants, there was no significant pairwise difference in the proximal third of the device (P > 0.80), but the simulated distal device volume was significantly underestimated relative to actual device implant volume (P = 0.06). CONCLUSIONS: This study demonstrates that pre-implant modeling which assumes a rigid vessel wall may not accurately predict the degree of distal RVOT expansion following actual device placement. We suggest the potential for virtual modeling of TPVR to be a useful adjunct to procedural planning, but further development is needed. PMID- 30444054 TI - A doxycycline-treated hydroxyapatite implant surface attenuates the progression of peri-implantitis: A radiographic and histological study in mice. AB - BACKGROUND: Oral rehabilitation with dental implants has become increasingly common; however, the increase of peri-implantitis is a great concern. Doxycycline (DOX) is a widely used antibiotic that inhibits bacteria growth, inflammation, and bone resorption. OBJECTIVES: To evaluate the progression of peri-implantitis of hydroxyapatite (HA)-coated implants with (5 mg/mL, DOX group) or without (HA group) DOX treatment on the surface. MATERIALS AND METHODS: The maxillary first molars of 20 male mice were extracted. Eight weeks later, small titanium screw implants coated with thin HA and treated with or without DOX were placed at the extracted sites. Four weeks after implant placement, half of the animals in both groups were sacrificed, and ligatures were placed around the implant necks in the other half. These mice were sacrificed 4 weeks later. The bone around the implants was examined radiologically and histologically. RESULTS: Four weeks after the ligature placement, the radiographic measurements revealed that peri implant bone levels of palatal and mesial sites, and histological measurements showed that bone levels of mesial and distal sites in the DOX group were significantly higher than those in the HA group. CONCLUSIONS: The present results indicating that the DOX-treated HA implant surface attenuates the progression of peri-implantitis. PMID- 30444055 TI - Eye of the beholder: Rare eye diseases in focus. PMID- 30444056 TI - Biopsy of abnormal intramammary and axillary lymph nodes in patients without breast cancer. PMID- 30444057 TI - TGF-beta1 promotes gap junctions formation in chondrocytes via Smad3/Smad4 signalling. AB - OBJECTIVES: Connexin-mediated functional gap junction intercellular communication (GJIC) has a vital role in development, homeostasis and pathology. Transforming growth factor-beta1 (TGF-beta1), as one of the most vital factors in chondrocytes, promotes cartilage precursor cell differentiation and chondrocyte proliferation, migration and metabolism. However, how TGF-beta1 mediates GJIC in chondrocytes remains unclear. This study aims to determine the influence of TGF beta1 on GJIC in mouse chondrocytes and its underlying mechanism. METHODS: qPCR and mRNA microarray were used to verify the expression of genes in the TGF-beta and connexin families in cartilage and chondrocytes. A scrape loading/dye transfer assay was performed to explore GJIC. Western blot analysis was used to detect connexin43 (Cx43) and Smad signalling components. Immunofluorescence staining was performed to characterize protein distribution. RESULTS: The TGF beta1 mRNA was the highest expressed member of the TGFbeta super family in cartilage. TGF-beta1 promoted functional GJIC through increased expression of Cx43. TGF-beta1-mediated GJIC required the participation of TGF-beta type I receptor. TGF-beta1 activated Smad3 and Smad4 signalling to facilitate their nuclear translocation. The Smad3 and Smad4 signalling proteins bound to the promoter of Gja1 and thus initiated Cx43 gene expression. CONCLUSIONS: For the first time, these results revealed a vital role of TGF-beta1 in cell-cell communication in chondrocytes via gap junction formation. We describe the regulatory mechanism, the involvement of TGF-beta type I receptor and the nuclear translocation of Smad3/4. PMID- 30444059 TI - The Human Metabolism of Nuts Proanthocyanidins does not Reveal Urinary Metabolites Consistent with Distinctive Gut Microbiota Metabotypes. AB - SCOPE: The stratification of individuals according to their gut microbiota metabotypes is crucial to understand the polyphenols health effects as reported for isoflavones and ellagitannins. To date, the existence of human gut microbiota metabotypes associated with proanthocyanidins (PAs) catabolism remains unclear. METHODS & RESULTS: Sixty-eight healthy volunteers (40 adolescents and 28 adults) consumed a mixture of walnuts, almonds, and hazelnuts for 3 days, providing 163.65 +/- 11.74 mg of PAs. Urine samples were analyzed by ultra-performance LC ESI-quadrupole time-of-flight. Twenty-one isomers of conjugated valerolactones and valeric acids were identified, which derived from six valerolactone and valeric acid precursors after analysis of hydrolyzed urine. This combined approach allowed discrimination between the inter-individual variability related to phase-II enzymes polymorphisms and the metabolism of PAs by the gut microbiota. No associations of PAs metabolism with gender, age, BMI, or ellagitannin metabotypes were found. Different quantitative excretion was observed after multivariate analysis but not true gut microbiota metabotypes associated with PAs catabolism. CONCLUSIONS: The metabolism of PAs does not reveal urinary metabolites consistent with distinctive gut microbiota metabotypes. The quantitative excretion of metabolites is inadequate to stratify individuals due to the strong influence of external factors (source, quantity, and time of the last intake of PAs, etc.). PMID- 30444058 TI - Atrial fibrillation following heart transplantation: A systematic review and meta analysis of observational studies. AB - OBJECTIVE: Previous studies have suggested a high incidence of atrial fibrillation (AF) in heart transplant recipients. However, incidence trends of AF in heart transplant recipients remain unclear. The study's aims were (1) to investigate the pooled incidence/incidence trends of AF following heart transplantation and (2) to assess the mortality risk of heart transplant recipients with AF. METHODS: A literature search for studies that reported the incidence of AF following heart transplantation was conducted using MEDLINE, EMBASE, and The Cochrane Database from inception through March 2018. Pooled incidence and odds ratios (OR) with 95%CI were calculated using a random-effects model. RESULTS: Eighteen studies (2 cohorts from clinical trials and 16 cohort studies) with 5393 heart transplant recipients were enrolled. The pooled estimated incidence of AF in heart transplant was 10.1% (95%CI: 7.6%-13.2%). Meta analysis based on the type of anastomotic technique demonstrated a pooled estimated incidence of AF following heart transplantation of 18.7% (95%CI: 10.3% 31.5%) and 11.1% (95%CI: 6.5%-18.4%) by biatrial and bicaval techniques, respectively. There was a significant association between AF following a heart transplant and increased mortality risk with a pooled OR of 2.86 (95%CI: 2.08 3.93). Meta-regression analyses showed no significant correlations between the year of study and incidence of AF (P = 0.47) or mortality risk of AF after heart transplantation (P = 0.99). CONCLUSIONS: The overall estimated incidence of AF following heart transplantation is 10.1%. There is a significant association between AF and increased mortality after transplantation. Furthermore, incidence and mortality risk of AF following heart transplant does not seem to decrease over time. PMID- 30444060 TI - Cytotoxic neoclerodane diterpenoids from scutellaria barbata D. Don. AB - A new neoclerodane diterpenoid, barbatin H (1) together with fifteen known analogues (2-16) were isolated from Scutellaria barbata D. Don. Their structures were determined on the basis of NMR and HRMS spectral analysis and comparison with the reported data. All of those compounds were comparatively predicted for their cytotoxic activities against four human tumor cell lines LoVo (colon cancer), MCF-7 (breast cancer), SMMC-7721 (hepatoma cancer), and HCT-116 (colon cancer) cells by MTT method in vitro. The results turned out that the series of neoclerodane diterpenoids exhibited varying degrees of cytotoxic activities against the growth of the tested tumor cell lines, and most of them exhibited selective cytotoxicity against LoVo cell lines. Compound 14 showed significant cytotoxic activities against four tested tumor cells among those compounds with IC50 values of 4.57, 7.68, 5.31 and 6.23 MUM, respectively, which indicated it might be a potential chemotherapeutic agents. PMID- 30444061 TI - Alkyl Sulfides as Promising Sulfur Sources: Metal-Free Synthesis of Aryl Alkyl Sulfides and Dialkyl Sulfides by Transalkylation of Simple Sulfides with Alkyl Halides. AB - A site-selective metal-free dealkylative approach to synthesize aryl alkyl and symmetrical dialkyl sulfides has been developed. This procedure is convenient and has wide functional group tolerance giving rise to sulfides carrying various alkyl chains from simple alkyl sulfides and alkyl halides in good to excellent yields. This transalkylation proceeds by an ionic mechanism via sulfonium intermediates and it was proposed that dimethylacetamide (DMAC) may participate in part to promote the reaction. PMID- 30444062 TI - Net energy of oat bran, wheat bran, and palm kernel expellers fed to growing pigs using indirect calorimetry. AB - The objectives of this experiment were to (a) determine the effects of fiber increase in diets on heat production (HP), (b) determine the net energy (NE) of oat bran (OB), wheat bran (WB), and palm kernel expellers (PKE) fed to growing pigs using indirect calorimetry (IC). Twenty-four growing barrows (29.2 +/- 2.6 kg) were randomly allotted to one of four diets with six replicate pigs per diet. Diets included a corn-soybean meal basal diet and three test diets containing 30% OB, WB or PKE, respectively. During each period, pigs were individually housed in metabolism crates for 20 days, including 14 days to adapt to the diets. On day (d) 15, pigs were transferred to the open-circuit respiration chambers for determination of daily total HP and were fed one of the four diets at 2.3MJ ME/kg body weight (BW)0.6 /day. Total feces and urine were collected for the determination of digestible energy (DE) and metabolizable energy (ME) and daily total HP was measured from d 15 to d 19 and fasted on day 20 for the measurement of fasting heat production (FHP). The apparent total tract digestibility (ATTD) of dry matter (DM), gross energy (GE), and organic matter (OM) were greater (p < 0.01) in pigs fed the basal diet compared with those fed the test diets. The ATTD of neutral detergent fiber (NDF) was lower (p < 0.01) in pigs fed the WB diet compared with those fed the basal, OB, or PKE diets. The ATTD of ether extract (EE) in pigs fed the PKE diet was greater (p < 0.01) compared with those fed the other diets. The average total HP and FHP in pigs fed the four diets were 1261 and 787 kJ/kg BW0.6 /d, respectively, and were not significantly affected by diet characteristics. The NE:ME ratio for diets ranged from 78.1 to 80.9%. The NE contents of OB, WB, and PKE were 10.93, 7.47, and 8.71 MJ/kg DM, respectively. PMID- 30444063 TI - Rediscovery of Black Phosphorus: Bioactive Nanomaterials with Inherent and Selective Chemotherapeutic Effects. AB - Black phosphorus nanosheets (BPs) are demonstrated to be highly bioactive anti cancer agents because of their inherent and selective chemotherapeutic effects. Fast intracellular biodegradation of BPs and acute elevation of phosphate anions are observed from different types of cancer cells due to the stronger intracellular oxidative stress and accelerated energy metabolism but normal cells are not affected. Selective biodegradation of BPs induces G2/M phase arrest and subsequent apoptosis- and autophagy-mediated cell death in cancer cells but not normal cells. The selectivity is superior to that of the traditional chemotherapeutic agent, doxorubicin (DOX). In vivo assessment confirms the efficiency of BPs in suppressing tumor growth. This study provides insights into nanostructured bioactive anti-cancer agents and reveals a new direction for nanomedicine research. PMID- 30444064 TI - Helper CD4 T cells expressing granzyme B cause glial fibrillary acidic protein fragmentation in astrocytes in an MHCII-independent manner. AB - During inflammatory processes of the central nervous system, helper T cells have the capacity to cross the blood-brain barrier and injure or kill neural cells through cytotoxic mechanisms. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is part of the astrocyte cytoskeleton that can become fragmented in neuroinflammatory conditions. The mechanism of action by which helper T cells with cytotoxic properties injure astrocytes is not completely understood. Primary human astrocytes were obtained from fetal brain tissue. Human helper (CD4+ ) T cells were isolated from peripheral blood mononuclear cells and activated with the superantigen staphylococcal enterotoxin E (SEE). Granzyme B was detected by enzyme linked immunosorbent assay and intracellular flow cytometry. GFAP fragmentation was monitored by western blotting. Cell death was monitored by lactic acid dehydrogenase release and terminal biotin-dUTP nick labeling (TUNEL). Astrocyte migration was monitored by scratch assay. Adult human oligodendrocytes were cultured with sublethally injured astrocytes to determine support function. Helper T cells activated with SEE expressed granzyme B but not perforin. Helper T cells released granzyme B upon contact with astrocytes and caused GFAP fragmentation in a caspase dependent, MHCII-independent manner. Sublethally injured astrocytes were not apoptotic; however, their processes were thin and elongated, their migration was attenuated, and their ability to support oligodendrocytes was reduced in vitro. Helper T cells can release granzyme B causing sublethal injury to astrocytes, which compromises the supportive functions of astrocytes. Blocking these pathways may lead to improved resolution of neuroinflammatory lesions. PMID- 30444065 TI - Intradermal injection of Fluorouracil versus triamcinolone in localized vitiligo treatment. AB - BACKGROUND: Vitiligo is an autoimmune disease with a prevalence of 1.22% in Egypt. Intralesional steroids use in localized vitiligo treatment still a matter of debate. Fluorouracil was tried in vitiligo treatment after lesion dermabrasion, ablative laser, or micro-needling. The study aimed to compare the efficacy of intradermal fluorouracil and triamcinolone acetonide without any adjuvant therapy in localized vitiligo treatment. PATIENTS AND METHODS: Sixty patients with localized non-segmental stable vitiligo were assigned randomly and equally into groups. Patients subjected to intradermal injection of either fluorouracil (50 mg/mL), triamcinolone acetonide (3 mg/mL) or an equal mixture of both drugs. All patients had four treatment sessions every 2 weeks were followed up for 6 months. RESULTS: Intradermal fluorouracil showed the best overall improvement (median 52.27, IQR 36.25-68.18) when compared with triamcinolone (median 13.86, IQR 3.83-33.32) and the drug mixture (median 17.15, IQR 7.48 41.67). During follow-up, the vitiliginous patches continued to repigment for 6 months in fluorouracil and the drug mixture groups. The improvement stopped 1 month after the last session in the triamcinolone group. CONCLUSION: The intradermal fluorouracil injection is an effective treatment of localized vitiligo. The intradermal steroid has a short-acting therapeutic effect, but the mixture of drugs added no therapeutic effect. PMID- 30444066 TI - Musical auditory processing, cognition, and psychopathology in 22q11.2 deletion syndrome. AB - Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with impairment in multiple domains of cognition and risk for several psychiatric disorders. Musical auditory processing is highly heritable, and is impaired in individuals with schizophrenia and other neurodevelopmental disorders, but has never been studied in 22q11DS, notwithstanding anecdotal evidence of its sparing. We aimed to characterize musical auditory processing in 22q11DS and explore potential relationships with other cognitive domains, musical engagement, and psychiatric disorders. The Distorted Tunes Task and Global Musical Sophistication Index were used to assess pitch discrimination and general musical engagement in 58 individuals with 22q11DS aged 8-29 years. Psychopathology was assessed with sections from the modified Schedule for Affective Disorders and Schizophrenia for School-Age Children and the Structured Interview for Prodromal Syndromes. The Penn computerized neurocognitive battery (CNB) examined four domains of cognition (executive functioning, episodic memory, complex cognition, and social cognition). Significant musical auditory processing impairment and reduced musical engagement were found in individuals with 22q11DS. However, deficits in musical auditory processing were not associated with reduced musical engagement. After covarying for age and sex, episodic memory and overall CNB performance accuracy were significantly related to performance in musical auditory processing. There were no relationships between musical auditory processing and presence of any psychiatric diagnoses. Individuals with 22q11DS experience significant deficits in musical auditory processing and reduced musical engagement. Pitch discrimination is associated with overall cognitive ability, but appears to be largely independent of psychiatric illness. PMID- 30444067 TI - Irritable bowel syndrome, mental health, and quality of life: Data from a population-based survey in Germany (SHIP-Trend-0). AB - BACKGROUND: Irritable bowel syndrome (IBS) is associated with reduced quality of life and high healthcare costs. This study aimed to assess the prevalence and risk factors for IBS in a general adult population. METHODS: The Study of Health in Pomerania (SHIP) is a population-based cohort study in northeastern Germany. SHIP-Trend-0 participants enrolled from 2008 to 2012 were grouped according to Rome III criteria (main criteria: abdominal discomfort or crampy or bloating pain for at least six months plus 2/3 additional criteria). Factors associated with IBS were assessed using survey-weighted backward stepwise logistic regression. KEY RESULTS: The final data set included 4194 records. IBS prevalence was 3.5% (3.0%-4.2%). Unemployment (OR: 2.02, 1.26-3.21), headaches (OR: 2.37, 1.59-3.52), mental quality of life (OR: 0.95 per unit increase, 0.93-0.97), and interactions between gender and physical quality of life (P = 0.004) and gender and alexithymia (P = 0.002) predicted IBS probability. The model resulted in a good discrimination (area under the curve = 75.4%) and model fit (F = 0.72, P = 0.69). History of depression (OR: 2.77, 1.94-3.95), back pain (OR: 2.38, 1.69-3.35), early trauma (OR: 1.03, 1.02-1.04), and duration of inpatient treatment within the last twelve months (OR: 1.02, 1.01-1.04) lost their significance in multivariable analysis. CONCLUSIONS & INFERENCES: IBS prevalence was relatively low compared to other studies. Factors predicting IBS were of biological, psychological, and social nature. The association between IBS and pain in different areas of the body indicates a potential underlying complex somatic symptom disorder. PMID- 30444068 TI - Interpretation of non-verbal cues by people with and without TBI: understanding relationship intentions. AB - BACKGROUND: Although long-term social challenges following traumatic brain injury (TBI) are well documented, the challenges of establishing new relationships following TBI are less understood. AIMS: To examine how the type of non-verbal cues produced by an unfamiliar communication partner impacts feelings of relationship closeness by people with and without TBI. METHODS & PROCEDURES: In this quasi-experimental comparative mixed-group design, participants included 12 male heterosexual adults with moderate/severe TBI and 10 typical comparison peers. An adaptation of the Relationship Closeness Induction Task (RCIT), a 29 item questionnaire, was completed by all participants to induce relationship closeness through reciprocal self-disclosure during conversation. Participants completed the RCIT three separate times in counterbalanced order. Conversational partners for the RCIT were three female actors trained to convey similar verbal answers to the RCIT questions, but to produce different non-verbal cues: solicitation (i.e., flirting), neutral and rejecting. Following each conversation, the participants completed a 10-item Likert-type questionnaire about the experience. OUTCOMES & RESULTS: Between- and within-group non parametric statistical analysis of Likert questions showed non-significant differences between the two participant groups such that both groups consistently rated the female actor who used flirting non-verbal cues higher than the actor who used rejecting non-verbal cues. CONCLUSIONS & IMPLICATIONS: These results suggest a small sample of heterosexual males with TBI interpret non-verbal relationship cues in real-time conversations with unfamiliar partners as well as comparison peers. Clinical implications include the need to consider real-time conversation in assessment and treatment planning for social communication goals related to cognitive-communication impairment. PMID- 30444069 TI - Elevated EGFL6 modulates cell metastasis and growth via AKT pathway in nasopharyngeal carcinoma. AB - Epidermal growth factor-like domain multiple 6 (EGFL6) is a secreted protein, regulates maintenance and metastasis of cancer cells. Nevertheless, how EGFL6 participates in the progression and tumorigenesis of nasopharyngeal carcinoma (NPC) remains unclear. In our study, EGFL6 was detected highly expressed in 20 NPC tissues compared with normal tissues by IHC assay. Then, the level of EGFL6 in NPC serum and NPC cells was explored through enzyme-linked immunosorbent assay and western blot, the results consistent with IHC. More interestingly, EGFL6 accelerated the migration and growth of NPC in vitro assays. Considering the mechanism of migration, NPC cells were cultured with AKT activator, revealing EGFL6 facilitated the progression of NPC via AKT. Moreover, the same effect of EGFL6 in promoting NPC growth was proved in nude mice. Furthermore, heat-shock zebrafish model was established with EGFL6 overexpression. Then, CNE2 cells were injected into the model and cells mass was observed, showing that EGFL6 enhanced the migration and metastasis of NPC. Currently, as the prognosis of NPC is severely affected by distant metastasis, it might be a new therapeutic target toward EGFL6. Taken together, our results suggested that EGFL6 acts as a potential positive regulator in the migration and proliferation of NPC. PMID- 30444070 TI - Dedifferentiated Schwann cells secrete progranulin that enhances the survival and axon growth of motor neurons. AB - Schwann cells (SCs), the primary glia in the peripheral nervous system (PNS), display remarkable plasticity in that fully mature SCs undergo dedifferentiation and convert to repair SCs upon nerve injury. Dedifferentiated SCs provide essential support for PNS regeneration by producing signals that enhance the survival and axon regrowth of damaged neurons, but the identities of neurotrophic factors remain incompletely understood. Here we show that SCs express and secrete progranulin (PGRN), depending on the differentiation status of SCs. PGRN expression and secretion markedly increased as primary SCs underwent dedifferentiation, while PGRN secretion was prevented by administration of cAMP, which induced SC differentiation. We also found that sciatic nerve injury, a physiological trigger of SC dedifferentiation, induced PGRN expression in SCs in vivo. These results suggest that dedifferentiated SCs express and secrete PGRN that functions as a paracrine factor to support the survival and axon growth of neighboring neurons after injury. PMID- 30444071 TI - Competence-based training needs assessment for basic life support instructors. AB - Basic life support instructors play an important role in the planning, implementation, and evaluation of basic life support education. However, little is known about basic life support instructors' competence. The aim of the present study was to identify basic life support instructors' competence attributes and assess their competence-based training needs according to their expertise. This was a descriptive survey study to identify the educational needs of basic life support instructors using importance and performance analysis. A Web-based survey with a 29 item Competence Importance-Performance scale was undertaken with a convenience sample of 213 Korean instructors. Factor analysis identified several important factors for the competence of instructors: assessment, professional foundations, planning and preparation, educational method and strategies and evaluation. The importance and performance analysis matrix showed that training priorities for novice instructors were communication with learners and instructors, learner motivation, educational design, and qualifications of instructors, whereas checking equipment status and educational environment had the highest training priority for experienced instructors. Assessment was the most important factor in basic life support instructor's competence. A competence based training program is needed according to basic life support instructors' expertise. PMID- 30444072 TI - Simply Structured Near-Infrared Emitters with a Multi-cyano Linear Acceptor for Solution Processed Organic Light-Emitting Diodes. AB - Near-infrared (NIR) organic light emitting diodes (OLEDs) show great potential in variety of applications including sensors, night vision and information security. Despite the superiority of thermally activated delayed fluorescence (TADF) in 100% exciton harvesting, the development of NIR TADF OLEDs is still great challenge, especially based on solution processing technology. In this work, a multi-cyano acceptor of 2-dicyanomethylene-3-cyano-4,5,5-trimethyl-2,5 dihydrofurance (TCF) with strong electron-withdrawing ability was employed to construct solution processible NIR emitters CzTCF and tBCzTCF with the feature of donor-pi-acceptor (D-pi-A) structure. The significantly enhanced intermolecular charge transfer effects not only render the deep red and NIR emissions for CzTCF and tBCzTCF films, respectively, but also lead to their typical TADF characteristics. Consequently, the nondoped solution-processed NIR OLED based on tBCzTCF was successfully demonstrated with the peak wavelength of 715 nm, which paves the way for developing NIR emitters without polycyclic aromatic cores and heavy-metal ions. PMID- 30444073 TI - The "architect analogy" of evidence-based practice: Reconsidering the role of clinical expertise and clinician experience in evidence-based health care. AB - The role of expertise in evidence-based medicine (EBM) and practice (EBP) has long been debated. In the early years of the EBP movement, the role of expertise and experience were diminished in clinical decision-making. However, the concepts of EBP are evolving. A more nuanced view of the value of clinician expertise, based on experience and clinical judgement, has emerged. This article proposes that clinical expertise does not belong within the evidence hierarchy's decision making pyramid as the lowest form of evidence, but rather alongside it, representing a complementary source of knowledge that supports the processes of EBP. An "Architect Analogy of EBP" is proposed as a new model by which to describe this relationship. In this analogy, the clinician's use of expertise is likened to the role of an architect, using evidence as building blocks in the construction of the client's edifice, representing the patients' health and wellbeing. Much as an architect carefully designs the edifice in consultation with the client's needs and preferences, choosing appropriate material (evidence), rejecting faulty material, and ensuring construction stays on course, the clinician must sort through a plethora of sometimes contradictory evidence, evaluate its merits and appropriateness for the patients' unique biopsychosocial circumstances and values, and monitor the effects of interventions on patients' health and wellbeing. The expertise of practitioners, as the architects of EBP, is an important supporting source of knowledge that facilitates the "Five Steps of EBP," informs and facilitates EBP, and supports patient-centred care. PMID- 30444074 TI - Injectable profiloplasty: Forehead, nose, lips, and chin filler treatment. AB - INTRODUCTION: We propose a medical filler treatment algorithm of the profile which includes forehead, nose, and chin and to evaluate profilometric results and complications. MATERIALS AND METHODS: 83 case reviews of associated liquid forehead, nose, and chin plasty performed consecutively from 2014 to 2016. We monitored the horizontal and vertical sagittal stability into two age group: <40 y.o. and >40 y.o. using profilometric Arnett analysis measurements on the F, Gb, Na, Nd, Nt, Sn, ULA, LLA, B, Pg, and Gn soft-tissue points. RESULTS: The results at both 3 and 6 months were consistent with the normal ranges indicated by Arnett, with a 0.8 mm maximum of defect/excess. Forehead treatment was performed in 51 (61.4%) patient. Patients >40 y.o. always needed a global correction of the forehead profile. We performed nasal treatment in 83 (100%) patient, acute nasolabial angles was the more frequent nasal defect. The lips were injected in 59 patients (71.1) more frequently >40 y.o. In 83 (100%) patients we perform a chin augmentation. The average advancement of the chin was 3 mm. CONCLUSIONS: The correction of the projection of the forehead, of the profile and shape of the nose, of the lips and chin as well as an overall improvement in face aesthetics and harmony gives a good solution in patients avoiding the need for a surgical intervention, scars and cost of general anesthesia, thus providing the optimum in patient satisfaction. PMID- 30444075 TI - Evaluation of 0.2% delmopinol mouth rinse for prevention of peri-implant mucositis and peri-implantitis: A randomized controlled canine study. AB - OBJECTIVES: To evaluate the effectiveness of 0.2% delmopinol mouth rinse in maintenance of peri-implant tissue health and prevention or inhibition of peri implant mucositis and peri-implantitis. MATERIALS AND METHODS: Four weeks following tooth extraction, eight titanium dental implants, were placed in six dogs' mandibles. Three dogs were assigned to the test or placebo mouth rinse. Eight weeks following implant installation (T2) ligature was placed to induce peri-implant disease. Clinical and radiographic assessment was performed during the study period as well as micro-CT analysis and histologic assessment to evaluate Bone-Implant Contact at the end of the follow-up (T4). RESULTS: Plaque at implant sites before ligature placement (T2) was lower for the test group (0.7 +/- 1.0 vs 1.5 +/- 1.3, P < .05). The ratio of affected implant (PD ?4 mm) at T2 and T4 in the test group was significantly smaller than that of the placebo group (T2, 17% vs 47%, P < .01; T4, 67% vs 83%, P < .05). The test agent also seemed to be effective in partially preventing bone loss induced by ligature placement according to the Computed Tomography and histologic analysis (test, 1.1 +/- 0.8 mm; placebo, 1.5 +/- 0.9 mm). CONCLUSIONS: Within the limits of this animal model study, the results of the study indicate that the 0.2% delmopinol rinse might play a role in prevention of peri-implant disease development. PMID- 30444076 TI - Invisible cornerstones. A hermeneutic study of the experience of care partners of older people with mental health problems in home care services. AB - OBJECTIVES: To explore the lived experiences and support needs of the care partners of older people with mental health problems living at home with assistance from home care services. Care partners face significant challenges in their care role and they often feel unsupported. An understanding of their experiences may help improve home care to support their needs. METHOD: An exploratory qualitative approach was used. The study is based on the SRQR and COREQ reporting guidelines. In-depth interviews were conducted with six Norwegian care partners from two municipalities. Data were collected during 2012-2013 and 2016. The data were analysed using Gadamer's hermeneutics. RESULTS: Three themes were identified: "invisible cornerstones," "dimensions of collaboration" and "unwanted roles." CONCLUSION: Few or no routines for collaboration exist between care partners and home care, and the care partners seem to have little knowledge of legal rights. They request more information, spare time and the opportunity to remain in their original family role. However, their main focus is for the patient to receive the necessary help from home care. Home care have restricted resources for meeting these needs and share a sense of powerlessness and lack of influence over their own everyday life with the care partners. There is a need for a systematic, person-centred approach to collaboration. A correlation is necessary between what is communicated at the system level and the means of realising this in practice for home care to meet care partners' needs. PMID- 30444077 TI - H2 Activation by Non-Transition Metal Systems: Hydrogenation of Aldimines and Ketimines with LiN(SiMe3)2. AB - In recent years, H2 activation at non-transition metal centers has met with increasing attention. Here, we report a system in which H2 is activated and transferred to aldimines and ketimines using substoichiometric amounts of lithium bis(trimethylsilyl)amide. Notably, the reaction tolerates the presence of acidic protons in the alpha-position. Mechanistic investigations indicate that the reaction proceeds via a lithium hydride intermediate as the actual reductant. PMID- 30444078 TI - Phenotypic stability of the human MG-63 osteoblastic cell line at different passages. AB - One of the most popular cell lines in osteogenesis studies is the human osteoblastic line MG-63. For cell biological investigation, it is important that the cells remain stable in their phenotype over several passages in cell culture. MG-63 cells can be used to provide fundamental insights into cell-material interaction. The aim of this study is to present a systematic characterization of the physiological behavior of MG-63 cells in the range of passages five to thirty. Significant cell physiology processes during the first 24 h, including cell morphology, availability of adhesion receptors, cell cycle phases, as well as the expression of the signaling proteins Akt, GSK3a/b, IkB-alpha, ERK1/2, p38 MAPK, and intracellular calcium ion mobilization, remained stable over the entire range of passages P5-P30. Due to these stable characteristics in a wide range of cell culture passages, MG-63 cells can be considered as a suitable in vitro-model to analyze the biocompatibility and biofunctionality of implant materials. PMID- 30444079 TI - IL-2mAb reduces demyelination after focal cerebral ischemia by suppressing CD8+ T cells. AB - AIMS: Demyelination, one of the major pathological changes of white matter injury, is closely related to T-cell-mediated immune responses. Thus, we investigate the role of an IL-2 monoclonal antibody (IL-2mAb, JES6-1) in combatting demyelination during the late phase of stroke. METHODS: IL-2mAb or IgG isotype antibody (0.25 mg/kg) was injected intraperitoneally 2 and 48 hours after middle cerebral artery occlusion (MCAO) surgery. Infarct volume, peripheral immune cell infiltration, microglia activation, and myelin loss were measured by 2,3,5-triphenyte trazoliumchloride staining, immunofluorescence staining, flow cytometry, and Western blot. Intraperitoneal CD8 neutralizing antibody (15 mg/kg) was injected 1 day before MCAO surgery to determine the role of CD8+ T cells on demyelinating lesions. RESULTS: IL-2mAb treatment reduced brain infarct volume, attenuated demyelination, and improved long-term sensorimotor functions up to 28 days after dMCAO. Brain infiltration of CD8+ T cells and peripheral activation of CD8+ T cells were both attenuated in IL-2 mAb-treated mice. The protection of IL 2mAb on demyelination was abolished in mice depleted of CD8+ T cell 1 week after stroke. CONCLUSIONS: IL-2mAb preserved white matter integrity and improved long term sensorimotor functions following cerebral ischemic injury. The activation and brain infiltration of CD8+ T cells are detrimental for demyelination after stroke and may be the major target of IL-2mAb posttreatment in the protection of white matter integrity after stroke. PMID- 30444081 TI - 2018 Peripheral Nerve Society Annual Meeting 21-25 July, 2018 Baltimore, Maryland. PMID- 30444080 TI - Capn4 promotes esophageal squamous cell carcinoma metastasis by regulating ZEB1 through the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Capn4 and ZEB1 play important roles in the metastasis of several types of cancer. However, the roles and relationship of Capn4 and ZEB1 in esophageal squamous cell carcinoma (ESCC) remain unclear. METHODS: ESCC tumor tissues and corresponding normal esophageal epithelial tissues were obtained from 86 patients undergoing resection surgery at the Department of General Surgery, First Affiliated Hospital of Chinese PLA General Hospital from 2012 to 2017. Cell migration and invasion were examined via quantitative real-time PCR and Western blot assay. RESULTS: Our results indicate that both Capn4 and ZEB1 are significantly upregulated in ESCC tissues compared to corresponding adjacent tissues, and a positive correlation between expression and associated malignant characteristics was found. Silencing of Capn4 expression markedly inhibited ESCC invasion and metastasis in vitro and in vivo, and was accompanied by decreased ZEB1 expression. Furthermore, the anti-metastasis role of Capn4 silencing was reversed by ZEB1 overexpression, whereas knockdown of ZEB1 decreased ESCC metastasis driven by the upregulation of Capn4. Mechanistically, Capn4 regulated ZEB1 expression via activation of the Wnt/beta-catenin signaling pathway in ESCC cells. CONCLUSION: Overall, our results show that enhanced Capn4 expression activates the Wnt/beta-catenin signaling pathway, resulting in increased ZEB1 expression and the promotion of ESCC cell metastasis. PMID- 30444082 TI - A Quantitative Chemical Proteomics Approach for Site-specific Stoichiometry Analysis of Ubiquitination. AB - Stoichiometric analysis of post-translational modifications is an emerging strategy for absolute quantification of the fractional abundance of the modification. Herein, a quantitative chemical proteomic workflow for stoichiometric analysis of ubiquitination is reported, named isotopically balanced quantification of ubiquitination (IBAQ-Ub). The strategy utilizes a new amine-reactive chemical tag (AcGG-NHS) that is structurally homologous to the GG remnant of ubiquitin on modified lysine after trypsin cleavage and therefore enables the generation of structurally identical peptides from ubiquitinated and unmodified lysine residues following trypsin digestion and secondary stable isotopic labeling. The strategy is highly robust, sensitive, and accurate with a wide dynamic range using either protein standards or complex cell lysates. Thus, this work provides an efficient chemical proteomics tool for quantitative stoichiometric analysis of ubiquitination signaling pathways. PMID- 30444083 TI - Simultaneous screening and isolation of activated constituents from Puerariae Flos by ultrafiltration-liquid chromatography-mass spectrometry combined with high-speed counter-current chromatography. AB - Puerariae Flos is the flower of Puerariae Radix, which is a common Chinese herb containing numerous isoflavones in all parts of the flower. Standard methods for screening and isolating isoflavones are typically labor-intensive and time consuming. In this study, a new assay based on ultrafiltration-liquid chromatography-mass spectrometry was developed for the rapid screening and identification of ligands for alpha-glucosidase, xanthine oxidase and lactate dehydrogenase in the extract of Puerariae Flos. Three isoflavones were identified as alpha-glucosidase inhibitors, three isoflavones were identified as lactate dehydrogenase inhibitors, and no specific binding ligands were identified for xanthine oxidase in the extract. Subsequently, specific binding ligands, puerarin, genistin, and tectorigenin (purities were 90.60%, 99.00%, and 91.73%, respectively), were separated by high-speed counter-current chromatography. The partition coefficient values of the target compounds and resolutions of peaks were employed as indicators and the solvent system and mobile phase flow rate were optimized for two-stage separation. An optimized two-phase solvent system comprised of ethyl acetate-ethanol-water (4.0:0.5:3.0, v/v/v) was successfully used to isolate the three compounds from Puerariae Flos. The monomer compounds isolated, collected, and purified by high-speed counter-current chromatography were analyzed by high-performance liquid chromatography, resulting in the isolation of three targeted compounds. The chemical structures of all three targeted compounds were individually identified by ultra-high-performance liquid chromatography -high-resolution mass spectrometry. The results demonstrate that ultrafiltration-liquid chromatography-mass spectrometry combined with high-speed counter-current chromatography is not only a powerful tool for screening and isolating alpha-glucosidase and lactate dehydrogenase inhibitors in complex samples, but also a useful platform for identifying bioactive compounds for preventing and treating diabetes and stroke. This article is protected by copyright. All rights reserved. PMID- 30444084 TI - Depth dependence of coherent hemodynamics in the human head. AB - We report a near-infrared spectroscopy (NIRS) study of coherent hemodynamic oscillations measured on the human forehead at multiple source-detector distances (1 to 4 cm). The physiological source of the coherent hemodynamics is arterial blood pressure oscillations at a frequency of 0.1 Hz, induced by cyclic inflation (to a pressure of 200 mmHg) and deflation of two thigh cuffs wrapped around the subject's thighs. To interpret our results, we use a recently developed hemodynamic model and a phasor representation of the oscillations of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations in the tissue (phasors O, D, and T, respectively). The increase in the phase angle between D and O at larger source-detector separations is assigned to greater flow versus volume contributions and to a stronger blood flow autoregulation in deeper tissue (brain cortex) with respect to superficial tissue (scalp and skull). The relatively constant phase lag of T versus arterial blood pressure oscillations at all source-detector distances was assigned to competing effects from stronger autoregulation and smaller arterial-to-venous contributions in deeper tissue with respect to superficial tissue. We demonstrate the application of a hemodynamic model to interpret coherent hemodynamics measured with NIRS and to assess the different nature of shallow (extracerebral) versus deep (cerebral) tissue hemodynamics. PMID- 30444085 TI - Fast and improved bioimaging via temporal focusing multiphoton excitation microscopy with binary digital-micromirror-device holography. AB - Conventional temporal focusing-based multiphoton excitation microscopy (TFMPEM) can offer widefield optical sectioning with an axial excitation confinement of a few microns. To improve the axial confinement of TFMPEM, a binary computer generated Fourier hologram (CGFH) via a digital-micromirror-device (DMD) was implemented to intrinsically improve the axial confinement by filling the back focal aperture of the objective lens. Experimental results show that the excitation focal volume can be condensed and the axial confinement improved about 24% according to the DMD holography. In addition, pseudouniform MPE can be achieved using two complementary CGFHs with rapid pulse-width modulation switching via the DMD. Furthermore, bioimaging of CV-1 in origin with SV40 genes 7 cells demonstrates that the TFMPEM with binary DMD holography can improve image quality by enhancing axial excitation confinement and rejecting out-of-focus excitation. PMID- 30444086 TI - Intraocular pressure remote photonic biomonitoring based on temporally encoded external sound wave stimulation. AB - Continuous noninvasive measurement of intraocular pressure (IOP) is an important tool in the evaluation process for glaucoma. We present a methodology enabling high-precision, noncontact, reproducible, and continuous monitoring of IOP based on the value of the damping factor of transitional oscillations obtained at the surface of the eye after terminating its stimulation by a sound wave. The proposed configuration includes projection of a laser beam and usage of a fast camera for analyzing the temporal-spatial variations of the speckle patterns backscattered from the iris or the sclera following the above-mentioned sound waves external stimulation. The methodology was tested on an artificial eye and a carp fish eye under varying pressure as well as on human eyes. PMID- 30444087 TI - Characteristics of virophages and giant viruses. AB - Five years after being discovered in 2003, some giant viruses were demonstrated to play a role of the hosts for virophages, their parasites, setting out a novel and yet unknown regulatory mechanism of the giant viruses presence in an aqueous. So far, 20 virophages have been registered and 13 of them have been described as a metagenomic material, which indirectly impacts the number of single- and multi cell organisms, the environment where giant viruses replicate. PMID- 30444088 TI - Effects of kinesiotherapy on muscle strengthening in patients with Parkinson disease. AB - Aim To investigate the effect of kinesiotherapy on muscle strengthening in patients with Parkinon's disease. Methods This clinical retrospective - prospective study was based on collected data from medical histories and included 40 patients, who, beside medicaments, had undergone kinesiotherapy. This study analysed age, gender, duration of the rehabilitation and estimation of the gross muscle strength at admittance and discharge using Manual Muscle Test (MMT). Results Females was slightly more represented in the total sample without significant statistical difference. After kinesiotherapy significant statistical difference in muscle strength was observed, average MMT of the upper extremities increased from 3.25+/-0.6 to 3.53+/-0.8 and on the lower extremities from 2.9+/ 0.8 to 3.3+/-0.9. The analysis of the gender on the higher score of MMT showed that gender does not affect the score of MMT. Correlational analysis of the age and duration of hospitalization on the score of MMT showed that patients with longer hospitalization had better improvement. Conclusion Results of the study showed that kinesiotherapy has positive effect on muscle strength in patients with Parkinson's disease. PMID- 30444089 TI - METHOD OF FIXATION OF TENDINOUS TRANSPLANT IN TENDOPLASTY OF DEEP FLEXOR MUSCLE OF FINGERS. AB - The authors supposed the method of tendinous transplant application in tendoplasty of deep flexor muscle of fingers based on usage of a new variant of tendon suture and modified device for its external cutaneous fixation. Firm and safe junction of transplant with tendon parts of the deep flexor muscle allowed an early activation of the hand function and high efficacy of operative treatment. PMID- 30444090 TI - MODERN ANTICEPTIC HYDROGEL IN TREATMENT OF INFECTIOUS COMPLICATIONS OF WOUNDS IN SURGERY. AB - Treatment and prevention of infectious complications remain the actual problems of surgery. Purulent complications very often arise in operative interventions with an application of various fixing devices. A study of the adhesive surgical antiseptic (ASA) "ARGAKOL" (Registration certificate No FS 012b2005/1878-05) was completed. The results of the preliminary antimicrobial activity of the developed composition showed that ASA "ARGAKOL" had a broad spectrum of antimicrobial action. There was used the method of twofold serial dilutions in a liquid medium and Cup-suspension. The study of the influence of the ASA "ARGAKOL" on the wound healing was made in the experiment on white outbred rats. There were carried out two series of experiments with 10 rats in each group: on the model of just contaminated wound (the first series) and on the model of infected wound with delayed application of the glue (after 3 days) after trauma (the second series). PMID- 30444091 TI - RESULTS OF HIP ARTHROPLASTY AFTER OSTEOSYNTHESIS OF PROXIMAL FEMUR. AB - The hip arthroplasty in case of destructive - dystrophic affection is considered as the most effective method, which provided social and home reintegration. A modern science development facilitates to this technique. However, specialists noted that the rate of endoprosthesis complication increased in the patients after osteosynthesis of proximal femur. The authors compared the results of patient's treatment that applied hip arthroplasty methods after osteosynthesis of proximal femur. The main group consisted of 38 patients who underwent hip arthroplasty after osteosynthesis of proximal femur. The control group had 43 patients with hip idiopathic osteoarthrosis, who underwent primary arthroplasty. The endoprothesis replacement was associated with increase of the rate of intraoperative and postoperative complications in the main group of patients. According to the results, given group of patients requires a special approach to diagnostics and treatment. PMID- 30444092 TI - ASSESSMENT OF EFFICACY OF THE METHOD OF PROGRAMMED IRRIGATION ASPIRATION SANATION IN COMPLEX TREATMENT OF PATIENTS WITH CHRONIC POSTTRAUMATIC OSTEOMYELITIS OF THE LONG BONES. AB - The analysis of treatment results of 128 patients aged from 21 to 62 years old with chronic posttraumatic osteomyelitis of the long bones was made at the period from 2006 to 2013. The main group included 67 patients and the method of programmed irrigation aspiration sanation was applied for them. The comparison group consisted of 61 patients and drainage was performed for these patients using the conventional ways. The authors noted good immediate results in the main group in 56 (83,58%) out of 67 patients and in the comparison group - in 43 (70,49%) out of 61 patients. The long-term results were analyzed in 116 (90,6%) out of 128 patients in terms from two to five years after treatment. The rate of recurrences such as formation of purulent fistula were twice less in patients of the main group, than in the comparison group. According to the results of questionnaire SF-36, there was noticed, that patients of the main group got better mean indices of quality of life on all 8 scales compared with the other group. PMID- 30444093 TI - THERAPEUTIC APPROACH IN RECURRENT INTUSSUSCEPTION OF BOWELS IN CHILDREN. AB - An analysis of treatment results was made in 216 patients with intussusception of bowels at the period from 2000 to 2015. The authors showed that it would be reasonable to carry out a conservative therapy in the cases of recurrent intussusception in absence of peritonitis symptoms. PMID- 30444094 TI - BLOOD TRANSFUSION IN LUNG OPERATIONS. AB - The authors admit the risks of blood transfusion, as well as the fact that the blood is a limited resource. These conclusions became the basis of the research in order to make an analysis and develop transfusion strategies in the hospital. An assessment of blood components application was performed in specific cases. There was changed the management of blood transfusion and further monitoring was continued. It was shown that the efficacy of an introduction of a new transfusion strategy confirmed the decrease of the rate of inappropriate blood transfusions, the quantity of patients who obtained transfusion of allogenic blood components and as a result, the new methods reduced the number of blood transfusions. PMID- 30444095 TI - URGENT X-RAY DIAGNOSTICS OF INTRACRANIAL PYOINFLAMMATORY OTORHINOSINUSOGENIC COMPLICATIONS. AB - An analysis of the results of X-ray CT and MR-imaging was made in 46 patients aged from 13 to 78 years old. The patients were admitted to multifield hospitals in Kursk at the period from 2005 to 2015. The research included the nasal cavity, paranasal sinuses, mastoid and pyramid of the temporal bones and the brain. The study could be repeated with bolus contrast medium infusion. The condition of the patients was evaluated in dynamics at intervals of 5-7 days and these data was associated with clinical picture. The authors presents a complex of symptoms and an algorithm of differentiated X-ray diagnostics of diseases of the ENT organs and the main nosological forms of pyoinflammatory diseases of arachnoid membrane and substances of the brain. PMID- 30444097 TI - MR-IMAGING IN DIAGNOSTICS OF FOCAL LIVER LESIONS. AB - The authors determined the efficacy of main methods of MR-imaging and their part in differentiated diagnostics of focal liver lesions. There were examined 256 patients and 414 liver lesions were analyzed. It was shown that the efficacy of conventional research without application of contrast medium was very limited (efficacy of mathematical model 58%). The data obtained during dynamic contrast enchancement (efficacy of the model 67%) were the basis for differentiated diagnostics for majority of nosological forms. The investigation using hepatotropic contrast medium had the greatest possibilities (efficacy of the model 80%). MR-diffusion is the effective procedure for visualization of focal liver lesions, but its possibilities in differentiated diagnostics is limited PMID- 30444096 TI - DIAGNOSTICS AND TREATMENT OF PATIENTS WITH TOOL ESOPHAGEAL PERFORATION. AB - The article presents an experience of diagnostics and treatment in 21 patients with esophageal perforation at the period from 1995 to 2015. The perforation was often (13 patients) the complication of interventional surgery which was directed to reconstruction of esophagus passing (scarry stricture of the esophagus, esophageal cancer, achalasia of esophagus). There was noted an esophageal rupture of lower third part of esophagus in 14 cases. These complications were diagnosed in all cases and the patients underwent an operation. There was performed the opening and drainage of the mediastinum in order to prevent mediastinitis. Complications had one patient in postoperative period. There wasn't observed lethal outcome. PMID- 30444099 TI - DIAGNOSTIC TRENDS IN ACUTE APPENDICITIS. AB - The authors presents the results of application of ultrasound investigation, diagnostic laparoscopy and multi-helical computer tomography in diagnostics of acute appendicitis. The research was applied on 139 patients whom clinical diagnosis was hard to establish using clinical - laboratory criteria. Ultrasound signs of acute appendicitis were revealed in 44 patients out of 139 (31,6%). Diagnostic laparoscopy was performed in 37 (26,6%) patients. According to the results of laparoscopy, the diagnosis of acute appendicitis was sonfirmed in 22 (70,2%) cases. The application of CT allowed the authors to confirm or reject the supposed diagnosis in 90,8% patients. The authors came to conclusion that this non-invasive method facilitated to diagnostics of vermiform appendix inflammation and had a high diagnostic accuracy. PMID- 30444098 TI - TREATMENT OF PATIENTS WITH COMPLICATIONS OF COLON CANCER IN CONDITIONS OF MULTIFIELD GERONTOLOGICAL HOSPITAL. AB - The article analyzes treatment results of 482 patients of elderly and senile age with complicated colon cancer forms who were in the hospital for war veterans at the period from 2008 to 2014. The more frequent complication of colon cancer was an acute intestinal obstruction (76,8%). Peritumorous inflammation with abscess formation was noted in 13,5% cases, hemorrhage - in 5,6% tumor perforation - in 4,1% cases. The operations were performed by conventional methods and using endovideosurgical technologies in case of complication of colon cancer. Laparoscopic operations had less volume of intraoperative hemorrhage, lower rate of postoperative complications and reduction of the level of postoperative lethality. The rate of lethality was 31,18% after conventional operations and it consisted of 1,81% after laparoscopic surgery. Total postoperative lethality was 24,5%. The maximal level of postoperative lethality was noted in cases of colon cancer complications and it had an ultimate rate (100%) in cases of perforation of locally advanced tumor. PMID- 30444101 TI - Cyst of round ligament of liver as a cause of pain syndrome in the right hypochondrium. PMID- 30444100 TI - Surgical treatment of iatrogenic damage of bile-excreting ducts. PMID- 30444102 TI - PREVENTION OF VENOUS THROMBOEMBOLIC COMPLICATIONS IN REPLACEMENT ARTHROPLASTY PERFORMANCE IN PATIENTS WITH ASSOCIATED CHRONIC DISEASES OF LOWER EXTREMITIES VEINS. AB - A number of patients with problems of major joints increases every year. These patients need the replacement arthroplasty. The rate of thrombotic complications rises in given category of patients simultaneously with the increase of the number of performed operations. There weren't well-defined instructions of management of the patients with associated chronic vein diseases at the preparation period for arthroplasty performance in spite of the presence of clinical recommendations for prevention of thromboembolic complications. The authors analyzed the experience of management of such patients and presented these data for doctors from polyclinic and hospitals in order to apply the common treatment strategy. PMID- 30444103 TI - ECONOMIC ANALYSIS OF TREATMENT OF THE PATIENTS WITH CHRONIC POSTTRAUMATIC OSTEOMYELITIS OF THE SHOULDER BY THE METHOD OF TRANSOSSEOUS OSTEOSYNTHESIS BY ILIZAROV'S APPARATUS. AB - An analysis of the terms of hospitalization, cost of treatment was made. There were matched the real medical costs of treatment of the patients with chronic posttraumatic osteomyelitis of the shoulder using the method of transosseous osteosynthesis with application of Ilizarov's apparatus and medical costs according to the medical standards of treatment for patients with osteomyelitis. It was shown that actual expenses on drug therapy and expendable materials on one patients were approximately three times higher, than planned expenses according to standard. The presence of different microflora was revealed throughout the bacteriological research of suppurative focus in 25(96%) patients. There was detected an excess of actual expenses on one patient with given nosology compared with standard of financial expenditure from the funds for high-technology medical care from 6 % (average case) to 58% (Bassilus pynocyaneus). The excess of actual expenses from the funds of local program of obligatory medical insurance achieved from 48% (average patient) to 100% (Bassilus pynocyaneus case). PMID- 30444104 TI - SOCIAL AND ECONOMIC ASPECTS OF SIMULTANEOUS OPERATIONS ON ABDOMINAL ORGANS. AB - The article presents an analysis of 107 cases of simultaneous operations of big volume with main stage as gastric resections (gastrectomy) or large intestine resections and mean volume interferences as cholecystectomy and removal of abdominal hernias. It was stated, that simultaneous operations compared with two steps treatment of combined surgical diseases obtained the high economical efficacy. This efficacy was determined by a single - stage routine presurgical examination, single anesthetic management, less medical expenses for medication and laboratory - instrumental studies in postoperative period, significant shortening the terms of hospitalization and disability terms. The authors proposed formulas to evaluate the economis efficacy of simultaneous operations in system of paid medical service and system of rendering medical aid using paid medical insurance. The efficacy of large operations was 40 766 rubles and in case of mean volume interventions - 25 382 rubles for the paid medical system. The economical efficacy of simultaneous operations of large and mean volume was the same in the system of obligatory medical insurance. It consisted of 19 737,5 or 22 920,1 rubles and depended on the degree of operative anaesthetic risk of the second intervention in two steps treatment of patients. PMID- 30444105 TI - Philosophy of surgery of multiple and float rib fractures. PMID- 30444106 TI - Resection and reconstruction of trachea picture in oncosurgery: technical aspects and results. PMID- 30444107 TI - Antireflective Transparent Oleophobic Surfaces by Noninteracting Cavities. AB - Oleophobic surfaces have been so far realized using complex microscale and nanoscale re-entrant geometries, where primary and secondary structures or overhang geometries are typically required. Here, we propose a new design to create them with noninteracting cavities. The suspension of liquid droplets relies on the mechanism of compression of air under the meniscus leading to stable composite oil-air-solid interfaces. To demonstrate the concept, we make oleophobic surfaces, with contact angle for oleic acid of about 130 degrees (and hexadecane about 110 degrees ), using both microholes in silicon and nanoholes in glass. Thanks to the subwavelength dimensions and antireflection effect of the nanoholes, the glass substrate also shows a high degree of optical transparency with optical transmission exceeding that of the initial bare substrate. Crockmeter tests without any significant change in morphology, optical and wetting properties after more than 500 passes also confirm the high mechanical durability of the nanohole surface. The results indicate the possibility of using the proposed oleophobic surfaces for a wide range of applications, including self cleaning transparent windows and windshields for automobiles and aircrafts. PMID- 30444108 TI - Synthesis, Characterization, and Applications of Polymer-Silica Core-Shell Microparticle Capsules. AB - Encapsulation is a powerful method for the targeted delivery of concentrated reagents and capture of valuable materials in dilute systems. To this end, many encapsulation schemes for specific scenarios have been devised that incorporate chemospecificity or stimulus response in terms of uptake or release. However, an encapsulation platform that enables highly tailorable surface chemistry for targeting, stimulus response, and core chemistry for capture and release of reagents remains elusive. Here, we present such a system comprising composite core-shell capsule particles of hydrophilic polymers coated with thin silica layers synthesized via straightforward one-pot syntheses. Silica is found to encapsulate a range of polymer hydrogels through a mechanism independent of the specific core chemistry. The hybrid materials possess significantly enhanced rigidity while allowing surface modification through simple yet versatile silane coupling reactions without a reduction in the functionality of the core. They are shown to have applications as diverse as recyclable catalysis and controlled delivery vehicles for agrochemicals. The successful synthesis and utilization of this catalog of materials indicate the broader capability of simple composite structures in an array of high-value applications. PMID- 30444109 TI - Transparent Urethane-Siloxane Hybrid Materials for Flexible Cover Windows with Ceramic-Like Strength, yet Polymer-Like Modulus. AB - Any transition toward an era of flexible electronics will have to overcome the mechanical limitations of materials. Specifically, the attainment of both strength and flexibility, which are generally mutually exclusive, is required including glass-like wear resistance, plastic-like compliance, and a high level of strain. Here, we fabricate a urethane-methacrylate-siloxane hybrid (UMSH) material. It is found that UMSH, with molecule-level hybridization of urethane linkage and methacrylate-siloxane conetworks, demonstrates ceramic-like high strength (574 MPa), yet polymer-like low modulus (8.42 GPa), and even high strain (6.3%) at fracture with excellent optical transparency. This combination of high strength, flexibility, and optical transparency indicates that this is a suitable material for glass substitution and can be used as a transparent flexible cover window for foldable display. PMID- 30444110 TI - Detection of Neurotransmitters by Three-Dimensional Laser-Scribed Graphene Grass Electrodes. AB - Carbon nanomaterials possess superb properties and have contributed considerably to the advancement of integrated point-of-care chemical and biological sensing devices. Graphene has been widely researched as a signal transducing and sensing material. Here, a grass-like laser-scribed graphene (LSG) was synthesized by direct laser induction on common polyimide plastics. The resulting LSG grass was employed as a disposable electrochemical sensor for the detection of three neurotransmitters, dopamine (DA), epinephrine (EP), and norepinephrine (NE), and in the presence of uric acid and ascorbic acid as potential interferants, using differential pulse voltammetry and cyclic voltammetry. The LSG grass sensor achieved sensitivities of 0.243, 0.067, and 0.110 MUA MUM-1 for DA, EP, and NE, respectively, whereas the limits of detection were 0.43, 1.1, and 1.3 MUM, respectively. The selectivity of LSG grass was excellent for competing biomarkers with high structural similarity (EP vs NE and EP vs DA). The exceptional performance of LSG grass for DA, EP, and NE detection holds a promising future for carbon nanomaterial sensors with unique surface morphologies. PMID- 30444111 TI - Tunable Nonlinear Acoustic Reporters Using Micro- and Nanosized Air Bubbles with Porous Polymeric Hard Shells. AB - The ability to tailor acoustic cavitation of contrast agents is pivotal for ultrasound applications in enhanced imaging, drug delivery, and cancer therapy, etc. A biopolymer-based system of microbubbles and nanobubbles was developed as acoustic reporters that consist of extremely porous hard shells. Despite the existence of an incompressible shell, these porous contrast agents exhibited strong nonlinear acoustic response under very low acoustic pressure, e.g, harmonics, characteristic of free gas bubbles. The large air/water surface area within the transmural capillaries are believed to facilitate oscillation of the inner gas core. Furthermore, the acoustic cavitation can be tailored by variation in polymer structures. This synthetically based platform offers insight for the rational design of advanced acoustic biomaterials. PMID- 30444112 TI - Synthesis and Formation Mechanism of All-Organic Block Copolymer-Directed Templating of Laser-Induced Crystalline Silicon Nanostructures. AB - This report describes the generation of three-dimensional (3D) crystalline silicon continuous network nanostructures by coupling all-organic block copolymer self-assembly-directed resin templates with low temperature silicon chemical vapor deposition and pulsed excimer laser annealing. Organic 3D mesoporous continuous network resin templates were synthesized from the all-organic self assembly of an ABC triblock terpolymer and resorcinol-formaldehyde resols. Nanosecond pulsed excimer laser irradiation induced the transient melt transformation of amorphous silicon precursors backfilled in the organic template into complimentary 3D mesoporous crystalline silicon nanostructures with high pattern fidelity. Mechanistic studies on laser-induced crystalline silicon nanostructure formation revealed the resin template was carbonized during transient laser-induced heating in the milli- to nanosecond timescales, thereby imparting enhanced thermal and structural stability to support the silicon melt crystallization process at temperatures above 1250 degrees C. Photoablation of the resin material under pulsed excimer laser irradiation was mitigated by depositing an amorphous silicon overlayer on the resin template. This approach represents a potential pathway from organic block copolymer self-assembly to alternative functional hard materials with well ordered 3D morphologies for potential hybrid photovoltaics, photonic, and energy storage applications. PMID- 30444113 TI - Preparation of Hollow Cu and CuO x Microspheres with a Hierarchical Structure for Heterogeneous Catalysis. AB - Diffusion is one of the most critical factors which affect the performance of porous catalysts in heterogeneous reactions. Hollow spheres with a hierarchical structure could significantly improve the mass transfer in the spherical catalyst. Therefore, preparation of such kind of microspheres is an important work in the field of inorganic synthesis. Herein, we combine microfluidic technology and electroless deposition to prepare hollow Cu and CuO x microspheres with a hierarchically porous structure. These microspheres have a controllable diameter (100-500 MUm) and shell thickness (10-60 MUm). Numerical simulation and experimental results indicate that the hollow structure is beneficial for the diffusion and utilization of the catalyst in heterogeneous reactions. The Cu and CuO x microspheres were used to catalyze the hydrogenation and Fenton-like reactions in a flow reactor, respectively. The conversion of all reactants can reach more than 95%, and catalysts can maintain their reactivity in long reaction times. Thus, the strategy in the present research should apply in the construction of other porous catalysts with high performance. PMID- 30444114 TI - Biochemical Methods to Image and Analyze RNA Localization: from One to Many. AB - Recent analysis of transcriptomes has revealed that RNAs perform a myriad of functions beyond coding for proteins. Critical to RNA function is its transport to unique subcellular locations, where it can be spatially regulated to perform its biological function. Within this perspective we highlight the techniques developed to image and discover RNAs within their subcellular compartments, and discuss the utility of these techniques in understanding RNA localization. PMID- 30444115 TI - Metabolite Identification and Pharmacokinetic Profiling of Isoflavones from Black Soybean in Rats Using Ultrahigh-Performance Liquid Chromatography with Linear-Ion Trap-Orbitrap and Triple-Quadrupole Tandem Mass Spectrometry. AB - Black soybeans are rich in isoflavones, which have several beneficial health effects. In this study, a validated method based on UHPLC-MS/MS was developed to screen black-soybean metabolites in rat urine, bile, and plasma and to quantify the compounds (daidzein, genistein, glycitein, and daidzin) and their metabolites (daidzein-4'-beta-d-glucuronide, genistein-7-beta-d-glucuronide, and genistein-4' beta-d-glucuronide) in plasma. Thirty-seven compounds were tentatively detected in the biological samples. The method was fully validated in quantitative experiments, including in assessments of linearity (2.5-100 ng/mL for daidzein, genistein, and glycitein; 10-100 ng/mL for daidzin; 5-3125 ng/mL for genistein-7 beta-d-glucuronide; and 5-1562.5 ng/mL for daidzein-4'-beta-d-glucuronide and genistein-4'-beta-d-glucuronide), matrix effects (85-115%), recovery (80-105%), precision (<10%), and accuracy (<10%). The compounds were stable throughout sample storage, treatment, and analysis. The method was first applied to detect IFs and metabolites in rats after oral administration of black-soybean extract. These results support the potential of this method for successful application in pharmacokinetic studies. PMID- 30444116 TI - Advances in Optical Sensing and Bioanalysis Enabled by 3D Printing. AB - The recent explosion of 3D printing applications in scientific literature has expanded the speed and effectiveness of analytical technological development. 3D printing allows for manufacture that is simply designed in software and printed in-house with nearly no constraints on geometry, and analytical methodologies can thus be prototyped and optimized with little difficulty. The versatility of methods and materials available allows the analytical chemist or biologist to fine-tune both the structural and functional portions of their apparatus. This flexibility has more recently been extended to optical-based bioanalysis, with higher resolution techniques and new printing materials opening the door for a wider variety of optical components, plasmonic surfaces, optical interfaces, and biomimetic systems that can be made in the laboratory. There have been discussions and reviews of various aspects of 3D printing technologies in analytical chemistry; this Review highlights recent literature and trends in their applications to optical sensing and bioanalysis. PMID- 30444117 TI - Highly Erbium-Doped Nanoplatform with Enhanced Red Emission for Dual-Modal Optical-Imaging-Guided Photodynamic Therapy. AB - Generally, luminescence quenching at high doping concentrations typically limits the concentration of doped ions in the lanthanide material to less than 0.05-20 mol %, and this is still a major hindrance in designing nanoplatforms with improved brightness. In this research, a nanoplatform capable of dual-modal imaging and synergetic antitumor cells therapy was designed. NaYF4: x%Er@NaXF4 ( x = 5, 25, 50, and 100; X = Lu and Y) core@shell nanoparticles with Er3+ ion concentration up to 100 mol % were synthesized, and the luminescence properties under near-infrared (NIR) excitation were detected. The results show the strong coupled of surface and concentration quenching effects in upconversion nanoparticles (UCNP). Upconversion luminescence (UCL) and NIR-II emission intensity increased with negligible concentration quenching effect under 980 and 800 nm NIR lasers because of the growth of epitaxial shells. Therefore, the enhanced red luminescence transfers energy to photosensitizer ZnPc as the photodynamic therapy (PDT) agent for tumor inhibition efficacy. PMID- 30444118 TI - Structures, Phase Fields, and Mixed Protonic-Electronic Conductivity of Ba Deficient, Pr-Substituted BaZr0.7Ce0.2Y0.1O3-delta. AB - The BaZr0.7Ce0.2Y0.1O3-delta-BaPrO3-delta perovskite system, of interest for high temperature electrochemical applications involving mixed protonic-electronic conductivity, forms a solid-solution with a wide interval of Ba substoichiometry in the range Ba(Ce0.2Zr0.7)1- xPr xY0.1O3-delta, 0 <= x <= 1. Structural phase transitions mapped as a function of temperature and composition by high resolution neutron powder diffraction and synchrotron X-ray diffraction reveal higher symmetry for lower Pr content and higher temperatures, with the largest stability field observed for rhombohedral symmetry (space group, R3 c). Rietveld refinement, supported by magnetic-susceptibility measurements, indicates that partitioning of the B-site cations over the A and B perovskite sites compensates Ba substoichiometry in preference to A-site vacancy formation and that multiple cations are distributed over both sites. Electron-hole transport dominates electrical conductivity in both wet and dry oxidizing conditions, with total conductivity reaching a value of ~0.5 S cm-1 for the x = 1 end-member in dry air at 1173 K. Higher electrical conductivity and the displacement of oxygen loss to higher temperatures with increasing Pr content both reflect the role of Pr in promoting hole formation at the expense of oxygen vacancies. In more reducing conditions (N2) and at low Pr contents, conductivity is higher in humidified atmospheres (~0.023 atm pH2O) indicating a protonic contribution to transport, whereas the greater electron-hole conductivity with increasing Pr content results in lower conductivity in humidified N2 due to the creation of protonic defects and the consumption of holes. PMID- 30444119 TI - Nature-Inspired and "Water-Skating" Paper and Polyester Substrates Enabled by the Molecular Structure of Poly(gamma-stearyl-alpha,l-glutamate) Homopolypeptide. AB - We demonstrate that the molecular structure of a synthetic homopolypeptide that resembles the leg architecture of water strider insects is effective to impart flexible polymeric surfaces with superhydrophobic behavior. Filter paper (FP) and polyester (PET) were modified with a coating consisting of low-molecular weight alpha-helical poly(gamma-stearyl-alpha,l-glutamate) (PSLG, Mw = 4500 Da) homopolypeptide. PSLG-coated substrates displayed near to and superhydrophobic behavior (>=150 degrees ) as reflected by the contact angle values. Despite being physically adsorbed, the PSLG coating uniformly covered and was strongly adhered to the substrate surfaces. The thin coating layer displayed remarkable mechanical abrasion resistance and was insensitive to long-time exposure to ambient conditions. PLSG-coated textile fibers exhibited useful and interesting properties. Under an iron-containing load, PSLG-coated PET was able to float and "walk" on water when exposed to a magnet. The PSLG coating was able to reduce the adhesion of Escherichia coli, model Gram-negative bacteria. The results indicated that the molecular geometry of PSLG homopolypeptide, which possesses a alpha helical backbone sprouting out of highly hydrophobic stearyl side chains, was the key feature responsible for the observed behaviors. This study is relevant for a broad range of potential applications: from crop and drinking water management in arid geographic areas to biomedical devices and implants. PMID- 30444120 TI - Emissive Azobenzenes Delivered on a Silver Coordination Polymer. AB - Azobenzene has become a ubiquitous component of functional molecules and polymeric materials because of the light-induced trans -> cis isomerization of the diazene group. In contrast, there are very few applications utilizing azobenzene luminescence, since the excitation energy typically dissipates via nonradiative pathways. Inspired by our earlier studies with 2,2'-bis[ N,N'-(2 pyridyl)methyl]diaminoazobenzene (AzoAM oP) and related compounds, we investigated a series of five aminoazobenzene derivatives and their corresponding silver complexes. Four of the aminoazobenzene ligands, which exhibit no emission under ambient conditions, form silver coordination polymers that are luminescent at room temperature. AzoAE pP (2,2'-bis[ N,N'-(4-pyridyl)ethyl]diaminoazobenzene) assembles into a three-dimensional coordination polymer (AgAAE pP) that undergoes a reversible loss of emission upon the addition of metal-coordinating analytes such as pyridine. The switching behavior is consistent with the disassembly and reassembly of the coordination polymer driven by displacement of the aminoazobenzene ligands by coordinating analytes. PMID- 30444121 TI - Preparation and Properties of Chlorosulfuryl Chloroformate, ClC(O)OSO2Cl. AB - The novel chlorosulfuryl chloroformate, ClC(O)OSO2Cl, was prepared by the reaction of CCl4 and SO3. Alternatively, the compound was obtained from the direct insertion reaction of SO3 to Cl2C?O. The latter reaction constitutes also a confirmation of the proposed mechanism for the former one. Density functional theory and MP2 theoretical approximations predict the existence of two conformers, syn-gauche and syn-anti, depending on the value adopted by the dihedral angles phi(Cl-C-O-S) and phi(C-O-S-Cl). The structure of the syn-gauche conformer was determined by gas-phase electron diffraction (GED). The existence of the syn-anti conformer can be neither confirmed nor excluded by the GED experiment. Vibrational spectra (vapor-phase and argon-matrix Fourier transform infrared and liquid Fourier transform Raman) were interpreted by an equilibrium mixture between both conformers. PMID- 30444122 TI - Oxidative Cyclization of beta-Aminoacrylamides Mediated by PhIO: Chemoselective Synthesis of Isoxazoles and 2 H-Azirines. AB - Cyclization of a variety of beta-aminoacrylamides in the presence of iodosobenzene (PhIO) is described. This process features mild reaction conditions, simple execution, and high chemoselectivity and thereby provides an efficient protocol for the divergent synthesis of substituted isoxazoles and 2 H azirines via switchable N-O and N-C bond formation controlled by simply varying the beta-substituent R3 of the readily available substrates. PMID- 30444123 TI - Band Structures of Quasi-One-Dimensional Incommensurate Helical Systems: A Case Study of Infinite Chromium Extended Metal Atom Chain. AB - Extended metal atom chains (EMACs) are promising candidates for molecular wires but their band structures remain to be explored. As a quasi-one-dimensional (Q1D) system, the incommensurate helical nature of EMACs hinders such calculations. In this work, we resolved this issue via explicit implementation of helical symmetry. Moreover, the pattern of metal d bands was rationalized by a systematic investigation on a series of related Q1D helical systems. Two critical factors, helical ligand field and chemically asymmetric ligand field, are proposed and identified. We found that the symmetry and ligand fields of the system dominate the pattern of the metal d bands, instead of specific chemical composition of ligands. The presented method and rationale are applicable to not only EMACs but also related Q1D helical systems. PMID- 30444124 TI - Ultrafast Nonadiabatic Cascade and Subsequent Photofragmentation of Extreme Ultraviolet Excited Caffeine Molecule. AB - Ultrafast XUV chemistry is offering new opportunities to decipher the complex dynamics taking place in highly excited molecular states and thus better understand fundamental natural phenomena as molecule formation in interstellar media. We used ultrashort XUV light pulses to perform XUV pump-IR probe experiments in caffeine as a model of prebiotic molecule. We observed a 40 fs decay of excited cationic states. Guided by quantum calculations, this time scale is interpreted in terms of a nonadiabatic cascade through a large number of highly correlated states. This shows that the correlation driven nonadiabatic relaxation seems to be a general process for highly excited states, which might impact our understanding of molecular processing in interstellar media. PMID- 30444125 TI - Size Distributions and Yields of Giant Vesicles Assembled on Cellulose Papers and Cotton Fabric. AB - Lamellar phospholipid stacks on cellulose paper vesiculate to form cell-like giant unilamellar vesicles (GUVs) in aqueous solutions. The sizes and yields of the GUVs that result and their relationship to the properties of the cellulose fibers are unknown. Here, we report the characteristics of GUVs produced on four different cellulose substrates, three disordered porous media consisting of randomly entangled cellulose fibers (high-purity cellulose filter papers of different effective porosities), and an ordered network of weaved cellulose fibers (cotton fabric). Large numbers of GUVs formed on all four substrates. This result demonstrates for the first time that GUVs form on cotton fabric. Despite differences in the effective porosities and the configuration of the cellulose fibers, all four substrates yielded populations of GUVs with similar distribution of diameters. The distribution of diameters of the GUVs had a single well-defined peak and a right tail. Ninety-eight percent of the GUVs had diameters less than the average diameter of the cellulose fibers (~20 micrometers). Cotton fabric produced the highest yield of GUVs with the lowest sample-to-sample variation. Moreover, cotton fabric is reusable. Fabric used sequentially produced similar crops of GUVs at each cycle. At the end of the sequence, there was no apparent change in the cellulose fibers. Cellulose fibers thus promote the vesiculation of lamellar phospholipid stacks in aqueous solutions. PMID- 30444126 TI - Equilibrium Acidities of Nitroalkanes in an Ionic Liquid. AB - The acidity ladder scale in [BMPY][NTf2] was successfully expanded toward the weak acidity region for about five more p K units compared to the previously established one. This allows the acidities of a series of 13 aliphatic and aromatic nitroalkanes to be determined accurately by the UV-vis spectroscopic method. The acidity of nitroalkane in [BMPY][NTf2] covers ~8 p K units and is significantly weaker than those in DMSO and water. The Hammett plot for 4 substituted phenylnitromethanes shows an excellent linearity with a slope of 2.06, which is rather close to that in DMSO but significantly larger than that in water (0.80). The regression analyses reveal that the solvation behavior of [BMPY][NTf2] on the acidic dissociations of C-H acids is similar to that of DMSO. PMID- 30444128 TI - Interaction of neuropeptide Y receptors (NPY1, NPY2 and NPY5) with somatostatin on somatostatin- induced feeding behaviour in broiler chicken. AB - 1 The present study was conducted to investigate whether brain somatostatin increases feed intake in neonatal chickens. The mediating role of neuropeptide Y receptors on feed intake induced by somatostatin was investigated. 2. In this study, seven experiments were designed, each with four treatment groups (n=44 in each experiment). In Experiment 1, chicks received control solution and 0.5, 1, and 2 nmol of somatostatin through intracerebroventricular (ICV) injection. In experiments 2, 3 and 4, chickens were ICV injected with control solution and 1.25, 2.5 and 5 MUg of B5063 (NPY1 receptor antagonist), SF22 (NPY2 receptor antagonist) and SML0891 (NPY5 receptor antagonist), respectively. In experiment 5, 6 and 7 chickens received ICV injection of B5063, SF22, SML0891, with a co injection of +somatostatin, control solution and somatostatin. The cumulative feed intake was measured until 120 minutes post injection. 3. Somatostatin significantly increased feed intake in FD3 chicks. Both B5063 and SML0891 dose dependently decreased feed intake compared with the control group, while SF22 led to a dose-dependent increase in feed intake. In addition, the hyperphagic effect of somatostatin significantly decreased with co-injection of B560 plus somatostatin (P<0.05), but SF22 and SML0891 had no effect on feed intake induced by somatostatin in chicks (P>0.05). 4. Based on the results of this study, it is likely that somatostatin increased feed intake and NPY1 receptor acts as a mediator in hyperphagic effect of somatostatin in neonatal chicks. PMID- 30444127 TI - A proposal for a kinetic summary measure: the Gait Kinetic Index. AB - A new summary index for kinetic gait data is proposed (Gait Kinetic Index - GKI), BASED on six kinetic selected variables: hip, knee and ankle moments and powers on the sagittal plane. This method was applied on a control group (CG) of 18 subjects and on 57 patients with diplegic Cerebral Palsy (CP). CP showed statistical different GKI value in comparison with CG. The same is for the sub GKI with the exclusion of GKI Knee Power. The GKI seems to be a promising tool useful to measure extensively the gait pathology taking into consideration kinetic aspects of gait pattern. PMID- 30444129 TI - Conditional estimation and inference to address observed covariate imbalance in randomized clinical trials. AB - BACKGROUND: Baseline covariate imbalance (between treatment groups) is a common problem in randomized clinical trials which often raises questions about the validity of trial results. Answering these questions requires careful consideration of the statistical implications of covariate imbalance. The possibil ity of having covariate imbalance contributes to the marginal variance of an unadjusted treatment difference estimator, which can be reduced by making appropriate adjustments. Actual observed imbalance introduces a conditional bias into an unadjusted estimator, which may increase the conditional size of an unadjusted test. METHODS: This article provides conditional estimation and inference procedures to address the conditional bias due to observed imbalance. Interestingly, it is possible to use the same adjusted treatment difference estimator to address the marginal variance issue and the conditional bias issue associated with covariate imbalance. Its marginal variance estimator tends to be conservative for conditional inference, and we propose a conditionally appropriate variance estimator. We also provide an estimator of the conditional bias in an unadjusted treatment difference estimator, together with a conditional variance estimator. RESULTS: The proposed methodology is illustrated with real data from a stroke trial and evaluated in simulation experiments based on the same trial. The simulation results show that covariate imbalance can result in a substantial conditional bias and that the proposed methods deal with the conditional bias quite effectively. DISCUSSION: We recommend that the proposed methodology be used routinely to address the observed covariate imbalance in randomized clinical trials. PMID- 30444130 TI - Contextual compatibility of three empirically supported behavior therapies for cART adherence among patients with substance use disorders. AB - Though substance use disorders complicate adherence to combination antiretroviral therapy (cART), cognitive-behavioral therapy (CBT), contingency management (CM), and motivational interviewing (MI) each demonstrate efficacy to improve cART adherence among substance-using patients. To inform dissemination of these therapies, this mixed-method study was undertaken involving a full-day site visit to each of four HIV care settings. At each setting, an initial administrator interview elicited setting data. Paired focus groups with setting staff and patients then served as forums for open discussion and live polling of the therapies' respective contextual compatibility. Focus group recordings were subjected to a phenomenological narrative analysis by multidisciplinary investigators, and staff/patient compatibility ratings were analyzed via generalized linear models. Findings include: (1) emergent themes among staff of adaptability, patient-centeredness, and mission-congruence as desired therapy attributes, (2) emergent themes among patients of intrinsic motivation, respect for patient autonomy in illness management, and fairness among service recipients as desired therapy attributes; and (3) comparatively stronger staff perception of compatibility for MI than CBT or CM, and a similar albeit less robust or reliable pattern among patients. Collective findings support MI as a behavior therapy of choice for broad dissemination to HIV care settings to improve cART adherence of patients with substance use disorders. PMID- 30444131 TI - A salutogenic inquiry into positive aging - a longitudinal analysis. AB - OBJECTIVES: Based on a gero-salutogenic approach, we investigated the stability of the sense of coherence over a time span of four years in active older individuals and long-term effects of this life orientation on three different indicators of positive aging-subjective well-being, psychological health and physical health. This is the first study to explore associations between gain in sense of coherence and future positive aging. METHODS: Our longitudinal sample consisted of 125 physically active individuals (73.5% women) at the mean age of 71 years at follow-up (range: 64 to 87 years; response rate: 73.5%), who completed our questionnaire twice. There were no systematic differences between the follow-up responders and non-responders. RESULTS: The sense of coherence increased over four years, disclosing a small effect size. The baseline sense of coherence had a substantial predictive value for future subjective well-being and psychological health, but not for physical health. Stepwise hierarchical regression analyses showed that both the baseline sense of coherence and gain in sense of coherence predicted future subjective well-being and psychological health. With respect to future physical health, only gain in sense of coherence was significant. CONCLUSION: Consistent with gero-salutogenic theory, the baseline sense of coherence is an effective predictor of future positive aging, and growth in sense of coherence within a time span of four years is reflected in improved positive aging. It is important to encourage experiences in older age that cultivate the three components of the sense of coherence-feelings of comprehensibility, manageability and meaningfulness. PMID- 30444132 TI - Progress in nano-drug delivery of artemisinin and its derivatives: towards to use in immunomodulatory approaches. AB - In recent years, artemisinin (ART) and its derivatives have highlighted according to their effects on highly aggressive cancers, as well as treatment of malaria and leishmaniasis, besides presenting anti-inflammatory and antibacterial activity. It has also been shown that ART compounds have the ability to modulate the immune response by regulating cell proliferation and cytokine release. These effects may be beneficial and improve the treatment of cancer and parasitic diseases by increasing therapeutic success, but it has some pharmacological limitations such as low bioavailability, short half-life and limited tissue access. Nanotechnology has been explored during the last decades, notably in the design of drug carrier systems which includes polymeric, lipid and inorganic nanoparticles, cyclodextrins inclusion complexes, liposomes, carbon nanotubes, among others. These nanostructured drug delivery systems bring benefits both increased therapeutic efficacy and reduced toxicity. This review article aims to give an overview of the current progress in nanostructured drug carriers used for encapsulation of ART and its derivatives yielding examples of successful outcomes. The data collection suggests future applications of ART and derivatives encapsulated in nano delivery systems in clinical trials and prospects for use of ART loaded nanosystems in immunomodulatory responses. PMID- 30444133 TI - Cognitive stimulation therapy for brazilian people with dementia: examination of implementation' issues and cultural adaptation. AB - OBJECTIVES: The prevalence of dementia has been increasing particularly in developing countries. However, people with dementia (PwD) in Brazil are currently offered no psychosocial treatment upon diagnosis. Cognitive stimulation therapy (CST) that originated in the UK has proven benefits on cognition and quality of life in PwD. We investigate the possible issues for the implementation of CST for the Brazilian population and its cultural appropriateness. METHOD: Individual interviews and focus groups were conducted with PwD, their caregivers and health professionals (n = 37). Data were recorded and transcribed, before being analyzed using Framework Analysis. RESULTS: Regarding the issues for implementation of CST in the Brazilian population, two main themes emerged, 'Barriers' and 'Facilitators', along with nine subthemes. Overall, the activities and materials were seen as being appropriate for use with the Brazilian population, some minor changes were suggested. CONCLUSIONS: The results indicate that CST is appropriate for use in the Brazilian population, only some cultural adaptations are necessary. In the stakeholders' opinions, CTS intervention is needed in Brazil, due to the lack of treatment options for PwD in developing countries. PMID- 30444134 TI - How our understanding of the microbiome has changed the way we look at liver diseases. PMID- 30444135 TI - APACPH Sabah Declaration: Improving Regional Health. PMID- 30444136 TI - Future of Public Health Training: What Are the Challenges? What Might the Solutions Look Like? AB - The Asia-Pacific region has rapidly changing health needs. This reshaping of health priorities is directly affecting current and future public health education. This brief review focuses on foundational public health skills including epidemiology, biostatistics, and health informatics. Epidemiological skills, in particular, are essential for policymakers and practitioners to identify the emergence of problems and to inform priority setting of public health efforts. Training needs to move beyond didactic, passive learning methods in class settings to approaches that engage and challenge students and academics in active, flexible learning and realistic problem-solving. We provide an overview of future trends in public health training in the Asia-Pacific region and illustrate the diversity of online training resources globally that can enrich staff and student skills and complement our active, class-based teaching. PMID- 30444137 TI - The clinical efficacy of angiotensin II type1 receptor blockers on inflammatory markers in patients with hypertension: a multicenter randomized-controlled trial; MUSCAT-3 study. AB - PURPOSE: The purpose of present study was to evaluate the clinical efficacy of irbesartan on the anti-inflammatory and anti-oxidative stress effect in patients with hypertension compared to other ARBs. Further, we assessed the effect of the ARBs on kidney function and urinary albumin excretion. METHODS: Eighty-five outpatients with hypertension who took an ARB except irbesartan more than 3 months were assigned into two groups, one continued the same ARB and the other switched the ARB to irbesartan for 6 months. RESULTS: Although blood pressures were equally controlled (continue group: 148 +/- 2/79 +/- 2 mmHg to 131 +/- 2/74 +/- 2 mmHg; switch group: 152 +/- 2/81 +/- 2 mmHg to 132 +/- 2/74 +/- 2 mmHg; p < 0.001 each), the inflammatory markers (hsCRP, PTX3, MCP-1) and oxidative stress marker (MDA-LDL) did not change after 6 months in both groups. Urinary albumin excretion was significantly reduced only in the switch group without renal function deterioration (switch group 292.4 +/- 857.9 mg/gCr to 250.6 +/- 906.5 mg/gCr, p = 0.012). CONCLUSION: These results provide knowledge of the characteristics of irbesartan, suggesting appropriate choice of ARBs in the treatment for hypertension should be considered. PMID- 30444139 TI - Families' Adherence to a Family-Based Childhood Obesity Intervention: A Qualitative Study on Perceptions of Communicative Authenticity. AB - Childhood obesity is associated with severe physical and psychological health problems. Interventions are often directed at the whole family, but the literature provides no clear indication of the characteristics of an effective family-based intervention. The objective of the present paper is to study whether and how an analytical framework focusing on communicative authenticity can be used to observe and elaborate upon aspects of adherence in relation to health behavior change in a concrete family-based intervention. We do this by focusing on the families' experiences with a Shared-care health education intervention and thus explore the association between families' self-reported experience and their adherence to the intervention. The dataset consists of 21 in-depth semi structured family interviews. The study shows that the Shared-care model has potential, but that this potential is rarely fulfilled in the intervention form under study. The sharing of care adds potential for several kinds of communicative authenticity because families are met by both the medical knowledge authority at the hospital and the local nurses in their municipality. It is, however, a significant finding that the families rarely benefit from this potential authenticity. Using theories of authenticity in this context adds theoretical and analytical potential and manages to incorporate elements of participation in tasks and practices of value, a sense of who we are and what we know, negotiation of meaning, emphatic caring, consistency between values and actions, and horizons of significance. The article brings new perspectives on how family-based interventions could be tailored to communicatively suit individual families. PMID- 30444138 TI - Strategic inclusion of regions in multiregional clinical trials. AB - BACKGROUND: With the recent publication of the International Conference on Harmonisation E17 guideline and major reforms in China underway, the platform for clinical trial conduct is expected to change. This study aims to assess the strategic inclusion of regions in clinical trials and its change in trends over the past decade. METHODS: The ClinicalTrials.gov registry was searched for clinical trials registered by the top 10 pharmaceutical companies between 1 January 2008 and 31 December 2017. Extracted data included phase, disease type, intervention, study start year, and region. Trial type was classified as either a local study or a multiregional clinical trial as per the International Conference on Harmonisation E17 guideline. RESULTS: Of 2488 phase I, 1855 phase II, and 1999 phase III trials included, the majority of phase I trials were local studies (76.8%), while the majority of phase II (66.0%) and phase III (72.2%) trials were multiregional clinical trials. The proportion of multiregional clinical trials showed an increasing trend for all phases ( p < 0.01). Although North America and Europe remained the main locations, increasing trends of inclusion of other regions, such as East Asia, were noted. CONCLUSION: Globalization of drug development is evident with the increasing trend of multiregional clinical trial. Regulatory authorities as well as the pharmaceutical industry should prepare for the evolving setting of clinical research and problems that can arise from these changes. PMID- 30444140 TI - Beyond viral suppression: the quality of life of people living with HIV in Sweden. AB - Sweden has one of the best HIV treatment outcomes in the world and an estimated 95% of all diagnosed people living with HIV are virally suppressed, but the quality of life (QoL) is understudied. The aim of this study was to examine the associations between variables within sociodemographic, behavioural, clinical, psychological, sexual life, social support and personal resource component and the QoL of people living with HIV in Sweden. Data were derived from a cross sectional, nation-wide survey completed by 15% (n = 1096) of all people living with HIV and collected at 15 infectious disease clinics and 2 needle exchange sites during 2014. Ordinal univariate and multivariate logistic regression analyses were used to examine associations between potential contributors and QoL. Respondents reported high QoL: 63% rated their QoL 7 or higher on a scale ranging from 0 to 10. QoL was independent of gender, age, mode of HIV transmission and country of origin. Lower QoL was associated with recent homelessness, hazardous alcohol consumption, comorbidities, treatment side effects, HIV-related physical symptoms, hopelessness, negative self-image, sexual dissatisfaction, and negative changes in sex life after HIV. The QoL of people living with HIV in Sweden was high overall, but still significantly influenced by HIV. PMID- 30444141 TI - Molecular insight to influential role of Hha-TomB toxin-antitoxin system for antibacterial activity of biogenic silver nanoparticles. AB - Emergence of silver nanoparticles (AgNPs) as a potent antibacterial agent for clinical application has raised attention towards its mode of action and needs detailed understanding of the mechanism. The current study investigates the influential role of Hha-TomB toxin-antitoxin system in determination of AgNPs antibacterial activity. AgNPs were synthesized by biogenic process using bacterial supernatant and were characterized for their physiochemical properties. Microbiological and computational assays like molecular docking, growth curve analysis, live/dead assay, oxidative stress and apoptosis assay were performed with wild type (WT) and mutants (Deltahha, DeltatomB) strains treated with AgNPs for elucidation of mechanism. Stable AgNPs having size 30-40 nm and zeta potential -32 +/- 09 mV were synthesized. AgNPs have shown significant antibacterial activity against S. typhimurium. Influential role of Hha-TomB TA proteins was observed in antibacterial effect by their altered expression level change in ROS level and programmed cell death. Molecular investigation elucidated the effect of AgNPs as consequence of their interaction with cellular proteins with different amino acids via hydrophobic interaction leading to alteration of cellular metabolic processes like ROS induction and apoptosis causing ultimate death. The study provided a detail illustration of Hha-TomB TA system influence on antibacterial mechanism of AgNPs for wide spectrum clinical application. PMID- 30444142 TI - The acute toxicity profile of a teething gel containing salicylamide in toddlers: an observational poisons centre-based study. PMID- 30444143 TI - The leaky lung test: A pilot study using inhaled mannitol to measure airway barrier function in asthma. AB - OBJECTIVE: Airway epithelial barrier dysfunction is emerging as an important feature of asthma pathogenesis, but this is difficult to measure in individual subjects. We aimed to develop a noninvasive way to measure airway permeability in asthma. METHODS: Healthy controls and subjects with mild asthma inhaled dry powder mannitol in a dose-escalating manner on two separate occasions, stopping at 155 mg or 315 mg. Serum mannitol levels were measured at baseline and then 30, 90, and 150 min after mannitol inhalation. Mannitol absorption was compared with measurements of airflow obstruction (FEV1) and airway inflammation (FeNO). RESULTS: Serum mannitol levels increased in a time- and dose-dependent manner in both healthy control and subjects with asthma. There were no significant differences in mannitol absorption when comparing healthy controls and subjects with asthma. Mannitol absorption did not correlate with markers of airway obstruction or inflammation. CONCLUSIONS: Measuring serum concentrations of mannitol after inhalation challenge can potentially provide insights into airway barrier function in asthma. PMID- 30444144 TI - EXPRESS: Laser Tweezers Raman Spectroscopy to Detect Effects of Chlorine Dioxide on Individual Nosema bombycis Spores. PMID- 30444145 TI - A randomised controlled trial comparing tapentadol with oxycodone in non breastfeeding women post elective caesarean section. AB - BACKGROUND: Tapentadol may allow greater pain relief with reduced 'opioid load' compared to oxycodone. Its use has not been studied in the obstetric population. The objective of this study was to compare the efficacy and side effect profile of tapentadol with oxycodone in patients who received spinal anaesthesia for elective caesarean section. The trial was registered with EU Clinical Trials Register with CT number 2016-001621-33. METHODS: This was a multicentre, randomised controlled trial. Randomised patients (n = 68) received either 50 mg tapentadol or oxycodone 10 mg 12 hourly postoperatively. The primary endpoint was the sum of pain intensity difference over the first 48 hours of treatment (SPID48). Secondary outcomes included time to rescue medications, SPID36, total pain relief scores (TOTPAR), patient satisfaction scores, sum of total pain relief and pain intensity difference (SPRID) scores, time to rescue medications and side effects experienced. An analysis of covariance model with baseline pain intensity score as a covariate was used for statistical analysis. RESULTS: There was no significant difference in the primary endpoint of SPID48 with adjusted mean difference -11.45 (95% CI -35.35, 12.45) p = 0.34). Oxycodone showed a significant reduction in SPID36 compared to tapentadol with significantly increased time to rescue medication. Side effects experienced were similar between groups. CONCLUSION: Tapentadol did not provide superior pain control or improved tolerability compared to oxycodone post caesarean section. Results should be interpreted however with consideration of administration of intrathecal opioids to all patients in this study and debate over the optimal dose of tapentadol for acute pain. PMID- 30444146 TI - Is more frequent physical therapy associated with increased gross motor improvement in children with cerebral palsy? A national prospective cohort study. AB - PURPOSE: To investigate the association between physical therapy frequency and gross motor improvement in children with cerebral palsy (CP). MATERIALS AND METHODS: This is a prospective cohort study of 442 children aged 2-12 years, Gross Motor Function Classification System levels I-V, from the Cerebral Palsy Follow-up Program and the Cerebral Palsy Register of Norway. Outcome was change in reference percentiles for the Gross Motor Function Measure (GMFM-66) between two subsequent assessments (N = 1056) analyzed in a linear mixed model. RESULTS: It was a dose response association between physical therapy frequency and gross motor improvement. Mean change was 4.2 (95% CI: 1.4-7.1) percentiles larger for physical therapy 1-2 times per week and 7.1 (95% CI: 2.6-11.6) percentiles larger for physical therapy >2 times per week, compared to less frequent physical therapy when analyzed in a multivariable model including multiple child and intervention factors. The only statistically significant confounder was number of contractures which was negatively associated with gross motor improvement. CONCLUSIONS: When gross motor improvement is a goal for children with CP, more frequent physical therapy should be considered. Implications for rehabilitation In general, the gross motor development of Norwegian children with cerebral palsy was as expected according to the reference percentiles for the GMFM-66. When gross motor improvement is a goal for children with cerebral palsy, high frequency physical therapy should be considered. Contractures should be addressed in order to optimize gross motor improvement for children with cerebral palsy. PMID- 30444147 TI - Recent advances in the pharmacological management of infections due to multidrug resistant gram-negative bacteria. AB - INTRODUCTION: The emergence and diffusion of multidrug resistant Gram-negative bacteria (MDR-GNB) is an unprecedented threat, with prevalences as high as 10-50% being reported in many countries. Areas covered: In the present review we discuss the management of infections due to MDR-GNB, focusing in particular on current strategies and novel agents with already available results from phase 3 randomized controlled trials. Expert commentary: Some new drugs, such as ceftolozane/tazobactam, ceftazidime/avibactam, and meropenem/vaborbactam, which have become available in the past months, have increased our chance of improving survival in severe carbapenem-resistant Pseudomonas aeruginosa and carbapenem resistant Enterobacteriaceae infections; while others, with potent activity against carbapenem-resistant Acinetobacter baumannii which is currently the highest priority regarding the need for novel agents, will become available in the near future. In the meantime, the focus of both clinical practice and research is slowly but steadily widening from efficacy and tolerability of new treatment options to also future preservation of their antimicrobial activity. This is reflected in clinical practice by more attention paid to antimicrobial stewardship initiatives, and in clinical research by growing interest in exploring resistance development as a major endpoint in both pre-clinical and clinical studies. PMID- 30444148 TI - Prevalence of asthma symptoms and association with obesity, sedentary lifestyle and sociodemographic factors: data from the Hellenic National Action Plan for the assessment, prevention and treatment of childhood obesity (MIS301205). AB - OBJECTIVES: To evaluate the prevalence of asthma symptoms in a representative sample of Greek schoolchildren and to evaluate its association with overweight/obesity as well as other socioeconomic, demographic, and lifestyle factors. METHODS: This is a cross-sectional study conducted from 10/2012 to 12/2013 on a pre-selected, representative elementary school cohort. Parents completed standardized questionnaires evaluating among others socioeconomic and sedentary activity habits. Students were measured with high sensitivity methods. Socioeconomic status (SES) index (range: 0-13) was calculated on years of parental education, rented versus owned residence, size of residence evaluated as meters squared per person (m2/person), and number of vehicles. Asthma was defined according to the approved Greek version of the International Study on Allergies and Asthma in Childhood (ISAAC) criteria. RESULTS: The prevalence of any asthma symptoms was documented in 31% of population. The odds of presenting any asthma symptoms decreased with increase in age (odds ratio: 0.96, 95% CI: 0.94-0.98) and increased with overweight (odds ratio: 1.13, 95% CI: 1.03-1.25), obesity (odds ratio: 1.27, 95% CI: 1.11-1.46) and sedentary lifestyle. CONCLUSION: This is the first representative survey of prevalence of asthma symptoms in children and adolescents in Greece indicating its continuous increase. A strong association between presence of asthma symptoms and obesity and sedentary activities was documented irrespectively of socioeconomic and regional factors. The findings stress the importance of public health policies toward obesity prevention and enhancement of physical activities in pediatric populations. PMID- 30444149 TI - Anti-interleukin (IL)-5 as a steroid-sparing agent in chronic eosinophilic pneumonia. AB - INTRODUCTION: Anti-interleukin (IL)-5 therapy is a novel drug class clinically effective in patients with diverse eosinophil-related disorders such as allergic eosinophilic asthma, eosinophilic granulomatosis with polyangiitis (EGPA), nasal polyposis, eosinophilic COPD, and other non-pulmonary disorders such as eosinophilic esophagitis. Chronic eosinophilic pneumonia (CEP) is a steroid responsive disorder, however, relapses are common following corticosteroid tapering. CASE STUDY: We present the case of a 42-year-old woman with steroid dependent relapsing CEP successfully treated with anti-IL-5 antibody. RESULTS: Treatment with anti-IL-5 antibody resulted in remission with the ability to taper off the steroids, and no recurrence of the disease for 6 months. CONCLUSION: Our case report supports the potential use of anti-IL-5 therapy for remission of patients with CEP with recurrent relapses. Whether, it would also be an effective initial therapy might also be an area that deserves future investigation. PMID- 30444150 TI - Safety profile of the SQ house dust mite sublingual immunotherapy-tablet in Japanese adult patients with house dust mite-induced allergic asthma: a randomized, double-blind, placebo-controlled phase I study. AB - OBJECTIVE: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet has demonstrated effective treatment of HDM-induced allergic asthma in patients 18 years or older in European trials. This study investigated its safety and immunology profile in Japanese adult patients with mild-to-moderate HDM-induced allergic asthma. METHODS: In this randomized, double-blind, placebo-controlled study, 48 Japanese patients were randomly assigned to a daily treatment of SQ HDM SLIT-tablet or placebo (3:1) for 14 d with or without an up-dosing regimen. Active groups comprised 5000, 10,000 or 20,000 Japanese Allergy Unit (JAU) for 14 d, and the up-dosing group comprised 5,000 JAU in day 1-3, 10,000 JAU in day 4-7 and 20,000 JAU in day 8-14. RESULTS: No marked differences were observed in the incidence rate of adverse events (AEs) and their severity among active groups. The five most common investigational medicinal product (IMP)-related AEs were local events at the application site observed within 30 min after the intake of the SQ HDM SLIT-tablet. Although most events recovered within 1 h, mouth edema indicated a different profile of duration with more than 25% of the events lasting for more than 1 h. CONCLUSIONS: The SQ HDM SLIT-tablet of up to 20,000 JAU was well tolerated, and safety profile was acceptable for Japanese subjects with HDM-induced allergic asthma. PMID- 30444151 TI - Mixed methods study: a one-week international service project enhances healthcare competencies. AB - Interprofessional Education Collaborative (IPEC) core competencies are widely accepted as a guide to prepare healthcare professionals. Two competency domains, values/ethics and roles and responsibilities, have specific relevance when investigating the effectiveness of a transcultural interprofessional experience. Participants were University of South Alabama students from the Colleges of Allied Health Professions, Medicine, and Nursing, who volunteered for a 7-day service learning experience in Trinidad. A convergent mixed methods research design was used. Students completed two Likert scale surveys, the Interprofessional Education Collaborative Competency Survey (IPECC) and the Transcultural Self-Efficacy Tool- Multidisciplinary Healthcare Provider Version (TSET-MHP), prior to and following the experience. A Wilcoxon Sign Test was used to analyze quantitative data. Qualitative data, guided by the Critical Incident Technique, was obtained from diary entries during the trip and a selected member focus group post-trip. There was a significant improvement in all three cultural competency domains of the TSET-MHP (p < .001). The most frequently reported IPEC sub-competencies were the ability to work in cooperation with those who receive, provide, and support care; and the ability to engage diverse healthcare providers to complement one's own professional expertise. Based on participant report, an international interprofessional clinical experience appears to be effective in enhancing health care competencies. PMID- 30444152 TI - Weight-management in children living with asthma: a qualitative study of the experiences of paediatric healthcare professionals. AB - OBJECTIVE: Weight loss has been found to improve the symptoms of asthma in children who are overweight. However, many paediatric weight management programmes do not address the challenges associated with living with asthma. The aim of this study was to explore the views and experiences of paediatric healthcare professionals concerning weight management advice and support offered to families of children living with asthma. METHODS: In-depth individual interviews with 10 healthcare professionals who work with a paediatric asthma population (n = 4 Respiratory Consultants, 3 Respiratory Nurses, 3 General Paediatricians). Data were analysed using a Framework approach. RESULTS: Healthcare professionals highlighted that families' perceptions of weight, their approach to physical activity and nutrition, the family's social context and perceptions of asthma and asthma treatment all influence weight management in children living with asthma. Initiating weight management conversations and referring to weight management support were perceived as challenging. It was thought that tailoring weight management to the needs of children living with asthma and locating support within the community were important to the success of a family-centred intervention. CONCLUSIONS: The results highlight the added complexity of responding to excessive weight in a paediatric population with asthma. Training and referral guidance for healthcare professionals may help overcome weight management support challenges. Addressing family beliefs about the factors influencing paediatric asthma and exploring families' motivations for behaviour change may enhance engagement with weight management. PMID- 30444153 TI - Launching into interprofessional education: graduate students learning and growing together. AB - Interprofessional education (IPE) is vital in university clinical settings to prepare graduate students to engage in today's health care system. However, few university programs have successfully implemented IPE into existing clinical programs. The purpose of this pilot study was to evaluate the effectiveness of an interprofessional (IP) training and clinical experience on graduate students' and caregivers perceptions on quality of care in a pre-existing clinical program. Speech-language pathology (SLP) and Physical Therapy (PT) faculty, worked to coordinate and develop an IP training and clinical experience. Graduate students from both disciplines participated in the IP training and completed a pre-post training questionnaire. Students then participated in an IP clinical experience with three preschool-age children with complex sensory motor needs and completed the questionnaire again following this experience. Students' attitudes and perceptions of readiness for IP engagement following IPE training showed a positive trend but not following an IP clinical experience. Subjective feedback from students and caregivers was highly favorable. The results provide further evidence of the benefits of IP training and clinical experience. More effective qualitative and quantitative tools must be developed to capture the effectiveness of direct IP clinical collaboration. PMID- 30444154 TI - The effects of education and clinical specialization on nurses' status affirmation by physicians: A quantitative analysis. AB - Research has demonstrated a status gap between members of healthcare delivery teams. However, it is unclear which factors mitigate or exacerbate the status gap between healthcare providers. This paper examines the concept of status affirmation, the belief that others affirm the individual's social standing, as one factor that can affect the status gap between healthcare professionals. The aim of this exploratory study was to investigate two factors that affect nurses' status affirmation: nurses' educational backgrounds and clinical specializations. A close-ended survey was administered to registered nurses in Indiana, a midwestern American state 1 (N = 1262) to identify which nurses are likely to have their status affirmed by physicians, in general. Results of multinomial logistic regression analyses suggest that highly educated nurses are unlikely to receive status affirmation, and there are differences in status affirmation across clinical specialties. In addition, nurses with advanced degrees often do not work in specialties that receive status affirmation. These results suggest that conflict among nurses and doctors is as likely to exist across divisions in nurses' educational attainment as across work specializations. Status affirmation is posited as a theoretical antecedent to interprofessional collaboration. PMID- 30444155 TI - Thrombotic microangiopathy following Bothrops jararaca snakebite: case report. AB - CONTEXT: Thrombotic microangiopathy (TMA) is an uncommon and severe complication of snakebites, and is similar, in general, to hemolytic-uremic syndrome (HUS). We describe a case of TMA following envenomation by Bothrops jararaca. CASE DETAILS: A 56-y-old-woman with controlled hypertension was transferred from a primary hospital to our ER ~7 h after being bitten by B. jararaca in the distal left leg. She developed edema extending from the bite site to the proximal thigh, associated with intense radiating local pain, local paresthesia and ecchymosis at the bite site. Laboratory features upon admission revealed coagulopathy (20 min whole blood clotting time - WBCT20 > 20 min), thrombocytopenia (76,000 platelets/mm3) and slight increase in serum creatinine (1.58 mg/dL; RV < 1.2 mg/dL). Upon admission, the patient was treated with bothropic antivenom and fluids replacement. During evolution, her thrombocytopenia and anemia worsened, with blood films showing fragmented red cells, haptoglobin consumption, increase in serum lactate dehydrogenase, and progressive increase of serum creatinine (KDIGO stage = 3). No RBC transfusion, renal replacement therapy or plasmapheresis was done. The patient showed progressive improvement from day nine (D9) onwards and was discharged on D20; there was complete recovery of hemoglobin levels at follow-up (D50). ADAMTS-13 activity, assayed 10 months post-bite, was within reference values. DISCUSSION: TMA following snakebite has been reported mainly in India, Sri Lanka and Australia, with several patients needing renal replacement therapy. Although controversial, plasmapheresis has also been used in some cases. Our patient developed microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury, a triad of features compatible with TMA similar to HUS. Despite the severity, the outcome following conservative treatment was good, with complete recovery. PMID- 30444156 TI - Community Organization Membership, Financial Security, and Social Protection among Female Sex Workers in India. AB - The purpose of this study is to examine the female sex workers' (FSWs) community organization (CO) membership, their financial and social protection security, and the relationship between these factors among FSWs in India. Data from 4098 FSWs collected under the Avahan-III baseline evaluation survey-2015 in 5 high HIV prevalence states (Maharashtra, Tamil Nadu, Karnataka, Telangana, and Andhra Pradesh) in India were used here. More than three-fifths (77%) were registered CO members, of whom 79% had been CO members for more than 1 year. The likelihood of having high financial security (19% versus 10%; adjusted odds ratio [AOR]: 1.7; 95% confidence interval [CI]: 1.3-2.1) and social protection security (13% versus 6%; AOR: 1.6; 95% CI: 1.2-2.0) was 2 times higher among FSWs who were CO members compared to those who were not. The study offers important insights into furthering CO membership to address financial and social vulnerability as a path to a sustainable reduction of HIV risk. PMID- 30444157 TI - Self-reported treatment adherence among psychiatric in- and outpatients. AB - BACKGROUND: Poor adherence to psychiatric treatment is a common clinical problem, leading to unfavourable treatment outcome and increased healthcare costs. AIM: The aim of this study was to investigate the self-reported adherence and attitudes to outpatient visits and pharmacotherapy in specialized care psychiatric patients. METHODS: Within the Helsinki University Psychiatric Consortium (HUPC) pilot study, in- and outpatients with schizophrenia or schizoaffective disorder (SSA, n = 113), bipolar disorder (BD, n = 99), or depressive disorder (DD, n = 188) were surveyed about their adherence and attitudes towards outpatient visits and pharmacotherapy. Correlates of self reported adherence to outpatient and drug treatment were investigated using regression analysis. RESULTS: The majority (78.5%) of patients reported having attended outpatient visits regularly or only partly irregularly. Most patients (79.2%) also reported regular use of pharmacotherapy. Self-reported non-adherence to preceding outpatient visits was consistently and significantly more common among inpatients than outpatients across all diagnostic groups (p < .001). Across all groups, hospital setting was the strongest independent correlate of poor adherence to outpatient visits (SSA beta = -2.418, BD beta = -3.417, DD beta = 2.766; p < .001 in all). Another independent correlate of non-adherence was substance use disorder (SSA beta = -1.555, p = .001; BD beta = -1.535, p = .006; DD beta = -2.258, p < .000). No other socio-demographic or clinical factor was significantly associated with poor adherence in multivariate regression models. CONCLUSIONS: Irrespective of diagnosis, self-reported adherence to outpatient care among patients with schizophrenia or schizoaffective disorder, bipolar disorder, and depression is associated strongly with two factors: hospital setting and substance use disorders. Thus, detection of adherence problems among former inpatients and recognition and treatment of substance misuse are important to ensure proper outpatient care. PMID- 30444158 TI - Decreased serum magnesium levels in depression: a systematic review and meta analysis. AB - BACKGROUND: Magnesium (Mg2+), an endogenous N-methyl-D-aspartate receptor antagonist, has received increased attention recently because of its role in the pathophysiology of and treatment response in depression. However, whether Mg2+ level is decreased in depression is not firmly established. We aimed to conduct a systematic review and meta-analysis to help making consensus for the association between Mg2+ levels and depression. METHODS: A systematic search was conducted in the electronic database resources PubMed and Embase. After a careful selection of relevant studies, a meta-analysis using the random effects model was conducted in each measuring source, such as serum, plasma, and cerebrospinal fluid (CSF). RESULTS: A total of 18 studies were included in this study. Among 11 studies that measured Mg2+ in the serum, Mg2+ level was lower in patients with depression than in controls (weighted mean difference = -.088, 95% confidence interval = -.164 to -.012). In the sensitivity analysis by removing studies one by one, 2 out of the 11 studies obliterated such significant differences. There were no significant differences in the Mg2+ levels in the studies for plasma and CSF. CONCLUSIONS: Despite some evidence supporting an association between decreased Mg2+ levels and depression from studies with serum, the results of our meta analysis urge to use caution when associating Mg2+ levels and depression. Future studies are needed to establish a consensus for the role of low Mg2+ levels in depression. PMID- 30444159 TI - Dose reduction of biological therapies for inflammatory rheumatic diseases: what do patients think? PMID- 30444160 TI - Clinical and imaging characteristics of posterior column ataxia with retinitis pigmentosa with a specific FLVCR1 mutation. AB - BACKGROUND: Posterior column ataxia retinitis pigmentosa (PCARP) with feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) gene mutation is a rare disorder with significant ophthalmic features. MATERIALS AND METHODS: We conducted a retrospective case series study of patients diagnosed with PCARP and genetic testing positive for FLVCR1 mutation between 1 January 2015 and 1 October 2017 at the Children's Hospital of Pittsburgh. Clinical charts, visual fields, fundus autofluorescence, and spectral-domain optical coherence tomography (SD OCT) were reviewed. RESULTS: Seven patients from three families were identified to have PCARP and FLVCR1 mutation. The median age at presentation was 13 years (range, 7-28 years). Common clinical exam findings were astigmatism, cataracts, and vitreous syneresis. Funduscopy on all patients revealed bull's eye maculopathy, retinal vessels attenuation, and bone spicule changes in the peripheral retina. Fundus autofluorescence showed bilateral hyperautofluorescent rings. SD-OCT demonstrated morphological changes, which differed based on age. The youngest sibling family exhibited peripheral loss, but subfoveal preservation of the outer retinal layers. These layers were lost in the oldest sibling family. Visual fields loss paralleled SD-OCT findings. CONCLUSION: There is limited published ophthalmic data on FLVCR1-related PCARP. We describe clinical and retinal imaging features in the one of the largest cohorts of affected patients in the literature. Given the availability of genetic testing for this phenotype, testing for FLVCR1 mutations should be considered in pediatric and adult patients with sensory ataxia and retinitis pigmentosa. PMID- 30444161 TI - MRI-based tumor inter-fraction motion statistics for rectal cancer boost radiotherapy. AB - BACKGROUND: In patients diagnosed with rectal cancer, dose escalation is currently being investigated in a large number of studies. Since there is little known on gross tumor volume (GTV) inter-fraction motion for rectal cancer, a wide variety in margins is used. Purpose of this study is to quantify GTV inter fraction motion statistics on different timescales and to give estimates of planning target volume (PTV) margins. MATERIAL AND METHODS: Thirty-two patients, diagnosed with rectal cancer, were included. To investigate motion from week-to week, 16 patients underwent a pretreatment and five weekly MRIs, prior to a radiotherapy (RT) fraction of the chemoradiotherapy treatment. To investigate motion from day-to-day, the remaining 16 patients underwent five daily MRIs before each fraction in one week of RT. GTV was delineated on all scans according to guidelines. Scans were aligned on bony anatomy with the first MRI. For both datasets separately, GTV inter-fraction motion was determined based on center-of gravity displacement. Therefrom, systematic and random errors were determined in left/right (LR), anterior/posterior and cranial/caudal (CC) direction. PTV margin estimates were calculated and evaluated on GTV coverage. RESULTS: Systematic and random errors were found in the range of 2.3-4.8 mm and 1.5-3.3 mm from week-to week, and 1.8-4.5 mm and 1.8-4.0 mm from day-to-day, respectively. On both timescales, similar motion patterns were found; the most motion was observed in CC whilst the least motion was observed in LR. On the week-to-week data more systematic and less random motion was observed compared to the day-to-day data. Overall, only slight differences in margin estimates were found. Derived PTV margin estimates were found to give adequate GTV coverage. CONCLUSION: GTV inter fraction motion, on a week-to-week and day-to-day timescale, can be accounted for using motion statistics presented in this study. PMID- 30444162 TI - Application of the pathogen Trojan horse approach in maize (Zea mays). AB - Maize, Zea mays, the second-most-widely-grown crop, yields 20 % of all consumed calories worldwide.1 Despite its agronomic importance, research progress is limited by costly transformation. We recently described the Trojan horse method as a useful tool to study maize proteins in situ that circumvents time- and space consuming whole plant transformation. The Trojan horse approach uses the protein folding and secretory properties of the corn smut fungus Ustilago maydis to secrete maize proteins from fungal cells into the maize apoplast. Here, we discuss the timing and location of U. maydis during infection and the protein secretion site in relation to anther anatomy. This spatiotemporal analysis enables the study of apoplastic anther proteins in various premeiotic anther developmental stages, and could be adapted for larger screens. PMID- 30444163 TI - Passing experiences on to future generations: endocrine disruptors and transgenerational inheritance of epimutations in brain and sperm. AB - All animals have body burdens of polychlorinated biphenyls (PCBs) despite their ban decades ago. These and modern endocrine-disrupting chemicals (EDCs) such as the fungicide vinclozolin (VIN) perturb hormone signaling and lead to dysfunctions following prenatal exposures. Beyond direct exposures, transgenerational disease phenotypes can persist for multiple generations without subsequent exposure. The mechanisms of action of these EDCs differ: VIN is anti androgenic while the PCB mixture Aroclor 1221 (A1221) is weakly estrogenic. Based on limited evidence for the inheritance of epimutations in germline, we measured DNA methylation in brain and sperm of rats. Pregnant dams were exposed from day 8 18 of gestation to low dosages of VIN, A1221, or the vehicle. To produce paternal lineages, exposed F1 males were bred with untreated females, creating the F2 and subsequently F3 generations. In adult F1 and F3 males, mature sperm was collected, and brain nuclei involved in anxiety and social behaviors (CA3 of the hippocampus; central amygdala) were selected for assays of epimutations in CpG islands using reduced representation bisulfite sequencing. In F1 sperm, VIN and PCBs induced differential methylation in 215 and 284 CpG islands, respectively, compared to vehicle. The majority of effects were associated with hypermethylation. Fewer epimutations were detected in the brain. A subset of differentially methylated regions were retained from the F1 to the F3 generation, suggesting a common mechanism of EDC and germline epigenome interaction. Thus, EDCs can cause heritable epimutations in the sperm that may embody the future phenotype of brain-behavior disorders caused by direct or transgenerational exposures. PMID- 30444164 TI - What does the future hold? No one knows for sure.... PMID- 30444165 TI - HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. AB - Cancer stem-like cells (CSCs), a small population of pluripotent cells residing within heterogeneous tumor mass, remain highly resistant to various chemotherapies as compared to the differentiated cancer cells. It is being postulated that CSCs possess unique molecular mechanisms, such as autophagic homeostasis, that allow CSCs to withstand the therapeutic assaults. Here we demonstrate that HDAC6 inhibition differentially modulates macroautophagy/autophagy in CSCs as compared to that of differentiated cancer cells. Using human and murine CSC models and differentiated cells, we show that the inhibition or knockdown (KD) of HDAC6 decreases CSC pluripotency by downregulating major pluripotency factors POU5F1, NANOG and SOX2. This decreased HDAC6 expression increases ACTB, TUBB3 and CSN2 expression and promotes differentiation in CSCs in an apoptosis-independent manner. Mechanistically, HDAC6 KD in CSCs decreases pluripotency by promoting autophagy, whereas the inhibition of pluripotency via retinoic acid treatment, POU5F1 or autophagy related gene (ATG7 and ATG12) KD in CSCs decreases HDAC6 expression and promotes differentiation. Interestingly, HDAC6 KD-mediated CSC growth inhibition is further enhanced in the presence of autophagy inducers Tat-Beclin 1 peptide and rapamycin. In contrast to the results observed in CSCs, HDAC6 KD in differentiated breast cancer cells downregulates autophagy and increases apoptosis. Furthermore, the autophagy regulator p-MTOR, upstream negative regulators of p-MTOR (TSC1 and TSC2) and downstream effectors of p-MTOR (p-RPS6KB and p-EIF4EBP1) are differentially regulated in CSCs versus differentiated cancer cells following HDAC6 KD. Overall these data identify the differential regulation of autophagy as a molecular link behind the differing chemo-susceptibility of CSCs and differentiated cancer cells. PMID- 30444166 TI - Color-encoding visualizations as a tool to assist a nonliterate population in completing health survey responses. AB - Visual representations of data have increasingly included color-encodings to help engage participants in health research. However, there is limited information on the way in which participants interpret color or on the influence of embedded cultural interpretations of color on survey responses. This study examines the interpretation of color-encodings used to indicate survey response options and their impact on participants' responses. Using a descriptive, cross-sectional design, interviews were conducted with 30 older Hmong adults from one Midwestern city in the United States. A survey data collection method was developed using: (a) an Audio-Computer-Assisted Self-Interviewing tool with (b) text-based and color-encoded response options and (c) assistance from a familiar helper. We analyzed the responses using directed content analysis. Findings reveal that some colors (red, black, and white) have strong cultural connotations; such colors were strongly correlated with specific emotions, while others (green, blue, purple, and pink) had no cultural meaning. Early in the survey, some older Hmong were distracted by response options indicated in red and black, influencing their response choices. However, with repeated instructions from the helpers, all participants overcame the color-related distractions and completed the survey. The findings highlight the importance of using colors cautiously and purposively in visualization development. PMID- 30444167 TI - Outcome of endovascular salvage of immature hemodialysis arteriovenous fistulas. AB - PURPOSE:: To assess the causes of immature hemodialysis arteriovenous fistula and the outcome of endovascular salvage. METHODS:: The outcome of 207 endovascular salvage procedures in 139 patients after the first successful cannulation was analyzed retrospectively from January 2011 to December 2017 in the Catholic University of Korea, Seoul St. Mary's Hospital. RESULTS:: Of the 139 patients aged 62 +/- 13 years, 45% were women, 59% had diabetes, and 71% were maintained on hemodialysis using central venous catheters. Mean interval between arteriovenous fistula creation and referral to angiography was 87 +/- 63 days. While inflow stenosis (54.4%) was the most common cause of immature forearm fistulas (n = 76), both inflow (38.6%) and mixed stenosis (35.1%) were the main causes of immature upper arm fistulas (n = 63). Endovascular salvage procedures included percutaneous transluminal angioplasty (n = 174) and accessory vein obliteration (n = 30). The overall technical and clinical success rates were 97% and 93.4%, respectively. Mean interval between endovascular procedure and the first successful cannulation of the fistula was 28 +/- 35 days. At 3, 6, and 12 months following the first successful cannulation, the primary patency rates were 81%, 69.5%, and 57.6%, respectively, and the secondary patency rates were 97.2%, 96%, and 94.8%, respectively. Mixed stenosis was the only determinant of secondary patency rate of immature arteriovenous fistula (hazard ratio = 6.334, confidence interval = 1.364-29.423, p = 0.018), and patients with mixed stenosis had poorer access outcomes ( p = 0.016). CONCLUSION:: Immature arteriovenous fistulas can be successfully salvaged by aggressive and timely endovascular intervention. Mixed stenosis is associated with poor access outcomes. PMID- 30444168 TI - Comparing patient-reported outcomes entered at home versus at hospital, and testing touch screens for initial recruitment to scientific trials in arthritis patients. AB - OBJECTIVES: Touch screens for entering patient-reported outcomes (PROs) are available at all Danish departments of rheumatology reporting to the nationwide DANBIO registry. This project comprises two substudies in patients with rheumatoid arthritis (RA) or axial spondyloarthritis (AxSpA), aiming to (A) investigate the feasibility of first line patient recruitment for research via touch screens, and (B) compare PROs collected at hospital versus at home, including patient preferences. METHOD: Substudy A: using a touch screen, patients answered whether we could contact them about a clinical research project (yes/no). Characteristics of patients who accepted/declined were explored using chi-squared and Mann-Whitney U-tests. Substudy B (randomized crossover agreement study): a random sample of patients from the accepting group in substudy A was contacted by telephone. According to prespecified power and sample size estimation, 56 patients were included. After randomization, 50% of patients entered PROs and information on comorbidities and lifestyle from home and then at hospital, and 50% first from hospital and then at home. Finally, they stated their preference for data entry (hospital/home/equally good). Differences in PROs entered from home and in the hospital were compared (limits of agreement, 95% confidence intervals, and intraclass correlation coefficients). RESULTS: The touch-screen invitation was accepted by 428/952 patients (45%). Patients who accepted and those who declined had similar PROs and demographics. Substudy B was completed by 42 patients (22 RA, 20 AxSpA). They had no significant differences between PROs and lifestyle/comorbidity data entered from home and hospital, except for AxSpA patients on the Bath Ankylosing Spondylitis Functional Index and Bath Ankylosing Spondylitis Disease Activity Index item 5. The preferred method of data entry was hospital (10%), home (50%), and equally good (40%). CONCLUSION: Touch screens seem feasible for first line research recruitment. PROs collected from home were similar to the touch-screen solution. Patients preferred data entry from home. PMID- 30444170 TI - Health literacy and social change: exploring networks and interests groups shaping the rising global health literacy movement. AB - Limited health literacy is a neglected public health challenge in many countries. To bridge the gap, various interest groups, coalitions and networks have increasingly been formed. This study aimed to scope the formation of health literacy groups, coalitions and networks to map their existence and to discuss whether an actual global health literacy movement is under development. The internet was searched, particularly using Google, LinkedIn and Twitter. The 60 identified entities were categorised and analysed according to their target group, geographical origin, member profile, aim, year of establishment and communication platform. The study revealed a vibrant worldwide health literacy community driving the rise of an emerging global health literacy movement for social change towards empowerment and health equity. Time will show whether health literacy will successfully become mainstream or fade out without impact. PMID- 30444169 TI - Is primary optic nerve sheath schwannoma a misnomer? Report of two cases and literature review. AB - AIMS: To report clinicopathological characteristics of two patients with optic nerve sheath schwannoma (ONSS) and review the literature. METHOD: The first patient (22-year-old man) presented with left eye proptosis and decreased vision in 2012 whose orbital imaging showed a large cystic lesion around the optic nerve. The second patient (52-year-old man) presented with decreased vision in the left eye (without proptosis) in the 2006. His imaging showed a small orbital apex lesion between the medial rectus and optic nerve. Both lesions were histopathologically consistent with ONSS. ONSS has previously been reported in 12 patients. RESULTS: Orbital biopsy and subsequently external beam radiotherapy were performed for the first patient who showed a temporary improvement of vision. However, his proptosis progressed and vision decreased to light perception (LP) a few months after radiotherapy when the lesion was resected in April 2013. Second patient declined any procedure until his vision gradually decreased to LP in October 2007. It was then removed through a combined medial and lateral orbitotomy procedure. Both patients ended up with visual acuity of no LP and no recurrence in their last follow up visits in April 2018. No histopathological evidence was found to show that optic nerve sheath could be the origin for presenting and previously reported cases in the literature. CONCLUSION: Presenting cases and literature review imply that ONSS is a misnomer and all the lesions are different types of orbital schwannomas with optic nerve sheath attachment. PMID- 30444171 TI - Kiss1 and its receptor: molecular characterization and immunolocalization in the hypothalamus and corpus luteum of the buffalo. AB - ABSTARCT The neuropeptide kisspeptin (Kp) through its receptor Kiss1r regulates the HPG axis by controlling GnRH release. Since buffalo is a seasonal breeder with problems of delayed puberty and postpartum anestrus, we characterized the Kiss1 and Kiss1r and investigated the immunolocalization in the hypothalamus and corpus luteum (CL). Kiss1 and Kiss1r genes were amplified from gDNA covering the coding region, cloned and sequenced with accession numbers MF168937 and MG820539, respectively. The Kiss1 DNA sequence had two exonic segment contained coding sequence (cds); 408 bp encoding a predicted protein of 136 aa with conservation of Kp-10 and shared 94.5-98.3% identity with ruminants. Kiss1r DNA sequence consisted of five exons with a cds of 1134 bp encoding a protein of 378 aa. Phylogenetic analysis of Kiss1 and Kiss1r revealed that it formed a monophyletic clade with cattle, which branched from sheep and goat. Immunofluorescence study revealed the presence of Kiss1 and Kiss1r in the neuronal soma and perinuclear area of preoptic and arcuate regions of the hypothalamus and luteal cells of the CL. This is the first report on molecular characterization of bubaline Kiss1 and Kiss1r genes that confirmed the presence of conserved Kp-10 like other ruminants and kisspeptinergic system is present in the hypothalamus and CL. PMID- 30444172 TI - Response to: Gaining an advantage by sitting an OSCE after your peers: A retrospective study. PMID- 30444173 TI - Prognostic impact of blood product transfusion in VA and VV ECMO. AB - BACKGROUND:: Extracorporeal membrane oxygenation (ECMO) is an accepted and reliable technique to provide temporary circulatory and/or respiratory support. Our objective was to describe the transfusion requirements in ECMO recipients. Secondarily, we addressed the effect of indications for ECMO on transfusion requirements and the baseline factors associated with worse survival. METHODS:: We reviewed the prospectively collected data of 509 patients receiving venoarterial (VA) or venovenous (VV) ECMO therapy (2005-2016). Follow-up was prospectively conducted. Data were prospectively entered in the Rennes ECMO database. RESULTS:: VA ECMO was employed in 81% of cases; indications were post cardiotomy myocardial failure in 28% of cases, post-heart transplantation (early graft failure) in 13.2% and cardiogenic shock in 149 (36.4%). VV ECMO was employed in the remaining patients. Average follow-up was 80.25 +/- 85.13 days and was 100% complete. In the VA and VV groups, survival at the 30th post implantation day was 58.3% and 71.1%, respectively, and survival at 6 months was 40.5% and 50.5%, respectively. Platelets and prothrombin time (PT) levels were significantly lower in the VA ECMO group at implantation (p<0.001). VA ECMO patients had a higher rate of thrombotic/haemorrhagic complications (p<0.001) and received both fresh frozen plasma (FFP) (60.5% vs. 31.8% p<0.001) and platelet units (Plt) (61.7% vs. 34.1% p<0.001) more frequently than VV ECMO patients. Post cardiotomy and post-transplantation patients had significantly higher rates of transfusion of packed red blood cells (pRBC), FFP and Plt than other VA ECMO cases (p<0.001, all). Mortality was equal or greater than 80% among patient subgroups who received more than 19 pRBC, 5 Plt and/or 12 FFP. CONCLUSIONS:: An ECMO program is associated with important consumption of blood products. VA ECMO patients have a greater transfusion burden than VV ECMO patients. Mortality is greater in the case of extreme transfusion requirements. PMID- 30444174 TI - A flexible criterion of response selection: When is it needed? Comment on Nozari and Hepner (2018). PMID- 30444175 TI - Matrix metalloproteinase 9 and osteopontin interact to support synaptogenesis in the olfactory bulb following mild traumatic brain injury. AB - Olfactory receptor axons re-innervate the olfactory bulb (OB) after chemical or transection lesion. Diffuse brain injury damages the same axons, but the time course and regulators of OB re-innervation are unknown. Gelatinases (MMP2, 9) and their substrate osteopontin (OPN) are candidate mediators of synaptogenesis following CNS insult, including olfactory axon damage. Here we examined the time course of MMP9, OPN and OPN receptor CD44 response to diffuse OB injury. FVBV/NJ mice received mild midline fluid percussion insult (mFPI), after which MMP9 activity and both OPN, CD44 protein expression were measured. Diffuse mFPI induced time-dependent increase in OB MMP9 activity and elevated the cell signaling 48kD OPN fragment. This response was bimodal at 1 and 7d postinjury. MMP9 activity was also correlated with 7d reduction in a second, 32kD OPN peptide. CD44 increase peaked at 3d, delayed relative to MMP9/OPN response. MMP9 and OPN immunohistochemistry suggested that deafferented tufted and mitral neurons were the principal sites for these molecular interactions. Analysis of injured MMP9KO mice showed that 48kD OPN production was dependent on OB MMP9 activity, but with no KO effect on CD44 induction. Olfactory marker protein (OMP), used to identify injured olfactory axons, revealed persistent axon damage in the absence of MMP9. MMP9KO ultrastructure at 21d postinjury indicated that persistent OMP reduction was paired with delayed removal of degenerated axons. These results provide evidence that diffuse, concussive brain trauma induces a postinjury interaction between MMP9, OPN and CD44 which mediates synaptic plasticity and reinnervation within the OB. PMID- 30444176 TI - Neural Correlates of Hypokinetic Dysarthria and Mechanisms of Effective Voice Treatment in Parkinson Disease. AB - BACKGROUND: Hypokinetic dysarthria is highly prevalent in idiopathic Parkinson disease (PD), and effectiveness of high-intensity voice treatment is well established. However, the neural correlates remain largely unknown. OBJECTIVE: We aimed to specify cerebral pathophysiology of hypokinetic dysarthria and treatment induced changes using functional magnetic resonance imaging (fMRI). METHODS: We used fMRI to investigate healthy controls (HCs) and patients with idiopathic PD associated dysarthria before and after treatment according to the Lee Silverman Voice Treatment LOUD (LSVT). During fMRI, participants covertly read sentences with normal (eg, conversation in a quiet room) or high (eg, shouting on a windy beach) intensity. In addition, we tested LSVT effects on intelligibility and different speech features (intensity, pitch, articulation). RESULTS: LSVT effectively improved intelligibility, articulation, and pitch in patients. Covert high-intensity speech compared with covert normal-intensity speech led to increased activation of mainly secondary motor areas and bilateral superior and medial temporal regions. Prior to LSVT, patients showed less activity in several speech-associated areas compared with HCs. As a neural correlate of effective LSVT, increased right-sided superior temporal activity correlated with improved intelligibility. CONCLUSION: This is the first brain imaging study using a covert speech paradigm in PD, which revealed cortical hypoactivation as correlate of hypokinetic dysarthria. Furthermore, cortical correlates of effective LSVT treatment colocalized with the neuronal network, showing increased activation during high- versus normal-intensity speech generation. PMID- 30444177 TI - [EXPRESS] The Involvement of mGluR5 and TRPV1 in Visceral Nociception In A Rat Model of Uterine Cervical Distension. AB - Metabotropic glutamate receptor 5 (mGluR5) and transient receptor potential vanilloid subtype 1 (TRPV1) have been shown to play critical roles in the transduction and modulation of cutaneous nociception in the central nervous system. However, little is known regarding the possible involvement of mGluR5 and TRPV1 in regulating visceral nociception from the uterine cervix. In this study, we used a rat model of uterine cervical distension (UCD) to examine the effects of noxious stimuli to the uterine cervix on expression of spinal mGluR5 and TRPV1. Our findings included: (1) UCD resulted in a stimulus-dependent increase in EMG, spinal c-Fos signal, and expression of mGluR5 and TRPV1 in the spinal cord; (2) intrathecal administration of the mGluR5 antagonist 2-methyl-6- (phenylethynyl)-pyri-dine (MPEP) significantly reduced the increased TRPV1 and c Fos expression induced by UCD; and, (3) The TRPV1 inhibitor SB-366791 inhibited increased spinal c-Fos expression, but had no effect on the expression of mGluR5 in response to UCD. Our findings indicate that the spinal mGluR5-TRPV1 pathway modulates nociceptive transmission in UCD-induced pathological visceral pain. PMID- 30444178 TI - Measurement of everyday dysexecutive symptoms in normal aging with the Greek version of the dysexecutive questionnaire-revised. AB - The Dysexecutive Questionnaire is a sensitive and ecologically valid measure of everyday dysexecutive symptoms. Recently, a revised version of the tool has been proposed (DEX-R). The current study aimed to examine the factorial validity of the Greek DEX-R, the level of agreement between the self and informant rating versions and the effect of age on each dysexecutive symptoms component. The questionnaire was administered to a sample of older adults (n = 235) and to a sample of informants (n = 187) in the context of the Neurocognitive Study for the Aging in Cyprus. Confirmatory Factor Analysis results showed that dysexecutive symptoms can be grouped into three underlying components or factors: (a) Motivation and Attention, (b) Flexibility, Fluency and Working Memory, and (c) Social Self-Regulation. Overall, the elderly reported more symptoms than their relatives, however the difference was significant only for the Flexibility, Fluency and Working memory factor. In a structural equation model, a weak positive effect of age was observed on the Flexibility, Fluency and Working Memory factor, based on the informant ratings. This study provides empirical evidence about the use of the DEX-R questionnaire in the Greek-speaking elderly population as a valid and reliable measure of everyday dysexecutive symptoms. PMID- 30444179 TI - Organism-derived phthalate derivatives as bioactive natural products. AB - Phthalates are widely used in polymer materials as a plasticizer. These compounds possess potent toxic variations depending on their chemical structures. However, a growing body of evidence indicates that phthalate compounds are undoubtedly discovered in secondary metabolites of organisms, including plants, animals and microorganisms. This review firstly summarizes biological sources of various phthalates and their bioactivities reported during the past few decades as well as their environmental toxicities and public health risks. It suggests that these organisms are one of important sources of natural phthalates with diverse profiles of bioactivity and toxicity. PMID- 30444180 TI - Long-term impact of critical silent cerebrovascular disease in patients undergoing coronary artery bypass surgery: a propensity score and multivariate analyses. AB - BACKGROUND:: Cerebrovascular disease (CVD) with brain hypoperfusion is a strong risk factor for stroke. However, how this pathology influences long-term outcomes after coronary artery bypass graft (CABG) surgery is not known. METHODS:: Magnetic resonance imaging/angiography (MRI/A) of the neck and brain was performed in 318 out of 575 consecutive CABG patients between May 2005 and April 2018. Critical CVD with chronic hypoperfusion was defined as multiple severe stenoses (?70%) and/or occlusion in the carotid and/or vertebral systems associated with reduced collateral flow due to severe contralateral and/or circle of Willis lesion. Fifty patients were identified to have this pathology (early results were previously reported). The entire cohort was followed up for 83.6 +/- 53.7 months. Carotid endarterectomy was considered for symptomatic patients. Propensity matching was performed to compare long-term outcomes between patients with and without critical CVD. RESULTS:: Patients with critical CVD at follow-up displayed significantly higher incidences of stroke than those without critical CVD (p=0.007), with an extremely high final incidence (approximately 40% at 8 years). However, survival (p=0.623) and incidences of major adverse cardiac events (MACE: myocardial infarction, coronary revascularization and all causes of death) (p=0.881) were similar. The Cox hazard model revealed that critical CVD was the strongest risk factor for stroke (p=0.000; hazard ratio 6.572; 95% confidence interval 2.657-16.258) while not affecting survival and MACE. CONCLUSION:: Critical CVD was the strongest risk factor for long-term stroke after CABG. However, survival and MACE-free rates were equivalent in patients with critical CVD and those without critical CVD. PMID- 30444181 TI - Inserting cycads into global nutrient relations data sets. AB - Global research agendas on plant nutrient relations attempt to illuminate biotic and abiotic factors that mediate nutrient relations. We contend that cycad species are not adequately represented in these global agendas. Little is known about how various cycad traits such as phylogenetics, growth form, latitudinal range, or ecological niche influence concentration, stoichiometry, and resorption dynamics of leaf nutrients. The addition of cycad species data to the global research dataset will address a critical knowledge gap and benefit global research needs to improve our systemic understanding of biotic and abiotic influences on plant nutrition. PMID- 30444182 TI - Differences over time in head orientation in European portrait paintings. AB - There is evidence for a tendency for European portrait paintings to have the head oriented so that the left side of the face is visible more than the right side. This is particularly the case for female sitters. There is evidence that the left side of the face shows emotion more than the right side does, so it has been proposed that there is a tendency for artists or sitters to want to show more of the emotionality of the sitter. It is shown here that the left-side tendency varies by date. In two studies, large samples were drawn from European gallery collections (study 1) and the National Portrait Gallery in London (study 2). The studies showed a strong left side tendency before 1600, absence of the tendency in the seventeenth and eighteenth centuries, and some recurrence of it in the nineteenth and twentieth centuries, modulated by changing gender differences. These findings show that cultural, historical, or art-historical factors are likely to be involved in determining tendencies in head orientation as well as psychological ones. PMID- 30444183 TI - Population structure and admixture analysis in Frieswal crossbred cattle of India - a pilot study. AB - The present study was aimed to assess parameters related to genetic diversity, population structure and admixture in the Frieswal crossbred cattle of India. A total of three datasets were analyzed during this study. Dataset A (n = 80) consisted of data on two purebred populations, i.e., Shorthorn (n = 35) and Brahman (n = 25) and one crossbred strain Santa Gertrudis (n = 20). The dataset B (n = 71) consisted of data on three populations that included Holstein-Friesian (n = 30), Sahiwal (n = 27) and Frieswal (n = 14) cattle. The dataset C included data on all the six breeds under study. Dataset C was used to assess the indices of population structure and genetic diversity of different breeds prior to and after LD pruning. For Frieswal cattle strain, the proportion of polymorphic SNPs and MAF levels was 84.54% and 0.24, respectively. Frieswal strain maintained appreciable genetic diversity with observed heterozygosity measure of 0.414. PCA plots for three datasets depicted effective stratification of different breeds in the respective datasets. The genomic clustering levels of Sahiwal and Holstein Friesian were found to be 98.45 and 99.89%, respectively, while the admixture of Frieswal was estimated to be about 61.5 and 38.5% from Holstein-Friesian and Sahiwal breeds, respectively. PMID- 30444185 TI - Journal of Agromedicine "Peer Reviewer of the Year" 2019: Dennis J. Murphy, PhD. PMID- 30444184 TI - Explaining Cross-Language Asymmetries in Prosodic Processing: The Cue-Driven Window Length Hypothesis. AB - Cross-language studies have shown that English speakers use suprasegmental cues to lexical stress less consistently than speakers of Spanish and other Germanic languages ; accordingly, these studies have attributed this asymmetry to a possible trade-off between the use of vowel reduction and suprasegmental cues in lexical access. We put forward the hypothesis that this "cue trade-off" modulates intonation processing as well, so that English speakers make less use of suprasegmental cues in comparison to Spanish speakers when processing intonation in utterances causing processing asymmetries between these two languages. In three cross-language experiments comparing English and Spanish speakers' prediction of hypo-articulated utterances in focal sentences and reporting speech, we have provided evidence for our hypothesis and proposed a mechanism, the Cue-Driven Window Length model, which accounts for the observed cross language processing asymmetries between English and Spanish at both lexical and utterance levels. Altogether, results from these experiments illustrated in detail how different types of low-level acoustic information (e.g., vowel reduction versus duration) interacted with higher-level expectations based on the speakers' knowledge of intonation providing support for our hypothesis. These interactions were coherent with an active model of speech perception that entailed real-time adjusting to feedback and to information from the context, challenging more traditional models that consider speech perception as a passive, bottom-up pattern-matching process. PMID- 30444186 TI - Differences in Diagnostic Criteria Mask the True Prevalence of Thyroid Disease in Pregnancy - A Systematic Review and Meta-Analysis. AB - BACKGROUND: The reported prevalence of thyroid disease in pregnancy varies widely through the published literature. These discrepancies are due to differences in criteria for euthyroidism, nationality, iodine status and gestational age at screening. As a result, there does not currently exist an accepted rate of prevalence for the various thyroid diseases in pregnancy. Understanding the true prevalence rates of these disorders has important implications for clinical management and the ongoing discussion regarding universal screening. The aims of this study were to assess (i) the true prevalence of thyroid disorders in pregnancy and (ii) the impact of diagnostic methodology on these rates. METHODS: A systematic review was conducted of the existing literature, including the Pubmed database and references from relevant review articles. Sixty-three studies reporting prevalence of overt hypothyroidism, subclinical hypothyroidism, isolated hypothyroxinemia, subclinical hyperthyroidism and overt hyperthyroidism in pregnant women were included. Studies were further classified by TSH cutoff for diagnosis in hypothyroid disease and timing of screening for hyperthyroid disease. Meta-analysis yielded pooled-prevalence rates, with subgroup analyses for TSH cutoff and timing of screening. Analysis of studies using the 97.5th percentile TSH cutoff was assessed to yield the most accurate prevalence rates for hypothyroidism. RESULTS: Pooled-prevalence rates for hypothyroidism calculated from studies using the 97.5th percentile as an upper limit for TSH were 0.50% for overt hypothyroidism, 3.47% for subclinical hypothyroidism and 2.05% for isolated hypothyroxinemia. Pooled-prevalence rates in the first and second trimesters for hyperthyroidism were 0.91% and 0.65% respectively for overt hyperthyroidism and 2.18% and 0.98% respectively for subclinical hyperthyroidism. CONCLUSION: Population-based, trimester-specific TSH cutoffs for diagnosis of hypothyroid disease in pregnancy result in more accurate diagnosis and better estimates for prevalence of disease. Prevalence of hyperthyroidism in pregnancy varies depending on timing of screening. The prevalence rates reported in this study represent the best estimate to date of the true rates of thyroid disease in pregnancy. PMID- 30444187 TI - Distributed corporeality: Anatomy, knowledge and the technological reconfiguration of bodies in ballet. AB - Various specialist cultures configure bodies as complex technological devices. We know little about how exactly this is done. I focus on one of these cultures, classical ballet, to praxeologically reconstruct the conceptual, situational and material configuration of bodies as particular instruments. The technologization of the body is closely intertwined with the scientification of the practice - its ladenness with scientific knowledge about the body and an elaborate apparatus for the production of bodies. When anatomical knowledge and didactics intertwine in ballet class, this facilitates an opening of the black box 'body' for technical improvement. 'A body' becomes a plurality of (in this case, anatomically distinguished) actants. This distributed corporeality suggests that 'the body' is an assemblage that becomes apparent as such in moments of its modification. The empirical case as well as the analytical approach here give reason to reconsider the distinction between humans and non-humans that still prevails in actor network theory and elsewhere. PMID- 30444188 TI - Gender and intraoperative blood transfusion: analysis of 54,122 non-reoperative coronary revascularization procedures. AB - BACKGROUND:: Previous studies have shown that women undergoing isolated coronary artery bypass graft (CABG) surgery have an increased risk for postoperative morbidity and mortality when compared to men. Additionally, recent evidence suggests that blood transfusions are independently associated with an increased risk of adverse outcome. METHODS:: We evaluated gender differences in the risk of intraoperative red blood cell (RBC) transfusion during CABG surgery. Consecutive, non-reoperative CABG procedures performed across 196 institutions between April 2012 and May 2015 were retrospectively reviewed. Gender differences for intraoperative transfusion were evaluated with a multi-variable binary logistic regression model, adjusting for age, blood volume (Nadler formula to normalize for height and weight), body mass index, procedure acuity, net extracorporeal circuit prime volume, use of autologous priming, first hematocrit (Hct) in the operating room (OR), nadir Hct on cardiopulmonary bypass (CPB), volume added on CPB, ultrafiltration volume, urine output on CPB and procedure duration. RESULTS:: Among 54,122 patients (25.3% female), 21.6% (n = 11,701) received a RBC transfusion. Compared to men, female patients were older (66 years vs. 64 years, p<0.001), had lower blood volumes (4.3L vs. 5.6L, p<0.001) and a lower preoperative Hct (32.9% vs. 37.2%, p<0.001). Transfusion rates were three-fold higher in women versus men (45.1% vs. 13.7%, p<0.001). After adjustment for independent predictors of intraoperative transfusion, women remained at increased risk versus men (OR = 1.30, 95%CI = 1.19-1.43). CONCLUSIONS:: Women have an increased risk of intraoperative RBC transfusion versus men. After adjusting for height and weight, much of this risk is due to gender differences in preoperative Hct and blood volume; however, a residual significant risk remained after adjustment. Perfusion strategies aimed at gender differences may minimize unnecessary transfusions. Future study on the impact of gender on transfusion practice in cardiac surgery is warranted. PMID- 30444189 TI - Polysubstance Use Among Veterans in Intensive PTSD Programs: Association With Symptoms and Outcomes Following Treatment. AB - OBJECTIVE: A distinct group of patients has recently been described who experience polysubstance use disorder characterized by use of multiple addictive substances. This study examines baseline characteristics and longitudinal outcomes of a group of such patients in specialized intensive Veterans Health Administration posttraumatic stress disorder (PTSD) programs and followed 4 months after discharge. METHODS: Patients with diagnosed PTSD or subsyndromal PTSD and who used a single substance at baseline were compared to those who used two or three and more than three different addictive substances on measures of PTSD symptom severity and functioning. Comparisons were also adjusted for differences in total days of any substance use and other potentially confounding factors. Patients were reclassified according to the number of substances used at follow-up and again compared on symptoms and functioning. RESULTS: Bivariate analysis of baseline data (N = 8,240) showed frequent polysubstance use (n = 3,695, 44.8% of the sample) and that use of greater numbers of substances was associated with more severe PTSD symptoms as well as more total days of substance use. At follow-up after treatment, 58.2% of the original sample (n = 4,797) was assessed. Polysubstance use was less frequent (n = 756, 15.8% of the follow-up sample), but showed a similar association with more severe symptoms, although differences were attenuated after adjusting for total days of substance use. CONCLUSIONS: Polysubstance use, conceptualized within the multimorbidity perspective, is associated with increased severity of PTSD symptoms among veterans with dual diagnoses requiring complex interventions, the evaluation of which will require innovative trial designs. PMID- 30444191 TI - Combination of grid laser photocoagulation and a single intravitreal ranibizumab as an efficient and cost-effective treatment option for macular edema secondary to branch retinal vein occlusion. AB - Purpose Our prospective, comparative study of 60 patients aimed to compare the efficacy and feasibility of a single injection ranibizumab vs a single grid laser photocoagulation and vs. a combined treatment in macular edema secondary to branch retinal vein occlusion in Asian population. Methods Patients were randomized 1:1:1 (n=20/group) into laser (LAS), the ranibizumab (RAN) and the combination (COM) group. Outcomes were measured as best-corrected visual acuity (BCVA) and central macular thickness (CMT). Results There were significant differences in mean BCVA between the three groups at 1 week and 1 month (P<0.05), and in mean CMT at 1 week and 1, 3, 6, 12 months (P<0.05). Overall, best results were observed in the combination group. However, the RAS and COM groups achieved very similar results. At 12 months, the CMT in all three groups was decreased compared with baseline (P<0.05). Conclusions Our results allow to conclude that the effect of early treatment with a single injection of intravitreal ranibizumab (cost reduction) and the stabilizing effect of grid laser photocoagulation is indeed an effective, feasible and safe regiment for of macular edema secondary to BRVO in Chinese patients, allowing to obviate the need for repeated intravitreal injections and thus reduce the adverse events, therapy duration, patients' malcompliance and adverse events. A single ranibuzumab therapy however is a comparable alternative. PMID- 30444192 TI - Methicillin-resistant staphylococcus aureus pneumonia in older people: a diagnostic and therapeutic challenge. AB - Pneumonia is one of the leading causes of death in older people, with high mortality rates (> 80%). One of the bacterial pathogens causing pneumonia is Staphylococcus aureus. The unique adaptive ability of S. aureus to a broad range of antibiotics has led to the emergence of methicillin-resistant S. aureus (MRSA) strain. MRSA pneumonia remains a relatively uncommon infection in older people, but it is associated with a very high mortality rate. We report two cases of MRSA pneumonia that highlight the severe clinical presentation and virulence of MRSA infections in geriatric population. MRSA pneumonia can present with mostly an uncontrollable clinical evolution and an infaust prognosis. Therefore, clinicians should be aware of MRSA pneumonia in patients with comorbidities, recent hospitalization with antibiotic treatment, previous MRSA infections and also in patients residing in nursing homes/revalidation centers. Low prevalence of MRSA combined with a lack of highly distinctive clinical features makes accurate targeting of empirical treatment with antibiotics very difficult. Currently, monotherapy with linezolid or vancomycin remain the first choice, in adult patients with proven MRSA infection. Despite the higher age related mortality rates, there are no specific treatment guidelines for older patients. PMID- 30444190 TI - MicroRNA Regulation of Energy Metabolism to Induce Chemoresistance in Cancers. AB - Since "Warburg effect" has been firstly uncovered in cancer cells in 1956, mounting evidence has supported the molecular mechanism underlying the energy metabolism in induced chemoresistance in cancers. MicroRNAs can mediate fine tuning of genes in physiological process. MicroRNAs' energy metabolic role in chemoresistance has been probed recently. In this review, we summarize 5 microRNAs in regulating glucose and lipid metabolism and other energy metabolism. They partially modulate chemoresistance to cancer treatments. Furthermore, we discuss the great therapeutic potential of metabolism-related microRNAs in novel combinatorial means to treat human cancers. PMID- 30444193 TI - Effect of dentin matrix components on the mineralization of human mesenchymal stromal cells. AB - In teeth with an injured pulp, dentin matrix orchestrates hard tissue repair through the release of dentin extracellular matrix components (dEMCs). dEMCs regulate the differentiation of resident mesenchymal stromal cells (MSCs), thereby affecting mineral deposition. Here, we show that low concentration solubilized dEMCs in osteogenic cultures of human umbilical cord mesenchymal stromal cells (UC-MSCs) and dental pulp stromal cells (DPSCs) enhanced mineral deposition, while adipose stromal cells (ASCs) were barely affected. Interestingly, UC-MSCs displayed significantly greater hydroxyapatite formation compared to DPSCs. UC-MSCs and DPSCs showed a dose-dependent viability and proliferation, whereas proliferation of ASCs remained unaffected. Qualitative analysis of the dEMCs-supplemented osteogenic cultures through scanning electron microscopy demonstrated differences in the architecture of the deposited mineralized structures. Large-sized mineral accretions upon a poorly organized collagen network was the prominent feature of UC-MSCs cultures, while mineral nodules interspersed throughout a collagen mesh were observed in the respective DPSCs cultures. The ability of dEMCs to induce mineralization varies between different human MSCs types in terms of total mineral formation and its architecture. Mineral formation by UC-MSCs exposed to low concentration dEMCs proved to be the most efficient and therefore could be considered as a promising combination for mineralized tissue engineering. PMID- 30444194 TI - Development of topical nanocarriers for skin cancer treatment using Quality by Design approach. AB - BACKGROUND: One of the most compelling medical challenges of this century is the treatment of cancer and among them, skin cancer is the most common type. Thus, current treatments need to be renewed continuously to handle this challenge. OBJECTIVE: This review presents considerations which can be employed during the development of nanosized formulations dedicated to the topical treatment of skin cancer. We aimed to collect and organize literature data on the treatment options for skin cancer in order to determine the required quality attributes of an effective dermal anticancer formulation. METHOD: With the consideration of the Quality by Design (QbD) approach related to the development of new pharmaceutical formulations, a cost-saving process ensuring a high-quality product taking into account patient expectations, industrial and regulatory aspects can be achieved. Furthermore, this concept is highly recommended by regulatory agencies. RESULTS: Our work discusses the current therapies, active agents, drug carrier systems, evaluation methods in connection with the treatment of skin cancer and outlines Critical Quality Attributes which need to be considered during the development of a nanosized dermal anticancer formulation. CONCLUSION: The first part of this review summarizes the most important topical treatment therapies for skin cancer and highlights the future therapeutic perspectives, focusing on the benefits of nanotechnology and dermal administration. The second part outlines the critical points of nanosized dermal anticancer formulation development in the view of QbD approach. Our research emphasizes the application of QbD method for a rationalized and more effective anticancer formulation development process. PMID- 30444195 TI - Small Molecules Targeting Mutant P53: A Promising Approach For Cancer Treatment. AB - More than half of all human tumors express mutant forms of p53, with ovary, lung, pancreas, and colorectal cancers among the tumor types that display the highest prevalence of p53 mutations. In addition, the expression of mutant forms of p53 in tumors is associated with poor prognosis due to increased chemoresistance and invasiveness. Therefore, the pharmacological restoration of wild-type-like activity to mutant p53 arises as a promising therapeutic strategy against cancer. This review is focused on the most relevant mutant p53 small molecule reactivators described to date. Despite some of them have entered into clinical trials, none has reached the clinic, which emphasizes that new pharmacological alternatives, particularly with higher selectivity and lower adverse toxic side effects, are still required. PMID- 30444196 TI - Preface. PMID- 30444198 TI - COMMENTARY: Calreticulin - Oncogene, Anti-oncogene, or Both? PMID- 30444197 TI - Binding and Elution Properties of Mixed-Mode Chromatography and Its Applications for Purification. PMID- 30444199 TI - Molecular targets, anti-cancer properties and potency of synthetic indole-3 carbinol derivatives. AB - The indole-3-carbinol (I3C) displays anti-proliferative and anti-cancer activities against human cancer cells. Cellular proliferation is an important event associated with cancer development and continued progression. This manifest is described by altered expression and/or functions of cell cycle related proteins. The constitutive activation of many signal transduction pathways also stimulates cell growth. The immediate stages in tumor development are accompanied by a fibrogenic response and the progression of a hypoxic environment, is in favor of the survival and proliferatory functions of cancer stem cells. The main part for the survival strategy in cancer cells may manifest through altering cell metabolism. The growth and metastasis may be supported by increased generation of appropriate hormones (in hormone dependent cancers), by promoting the development of angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as by taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in combination with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may provide early diagnostic markers and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. Very particularly, I3C and its dimeric product, 3, 3' diindolylmethane (DIM), have been widely in vestigated for their importance against a number of human cancers both in vitro and in vivo. We aimed the present manuscript, to review an in-depth study of the anticancer properties and the miscellaneous mechanisms underlying the anticarcinogenicity, thereby broadening I3C therapeutic marvel. PMID- 30444201 TI - The Ascent of Mineralocorticoid Receptor Antagonists in Diabetic Nephropathy. AB - Diabetic nephropathy (DN) is defined as a decline in the renal function and an increase in the amount of albuminuria (>300 mg/day). The well-established first line drug therapies for DN include angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) and the second line drug therapies include calcium channel blockers or diuretics. The interruption of the renin angiotensin-aldosterone system (RAAS) by ACEi and ARBs has been beneficial in reducing the progression of renal diseases; however, there is an increase in the levels of aldosterone due to the aldosterone escape phenomenon. Newer and novel approaches to counteract this aldosterone breakthrough while accentuating the anti-hypertensive and anti-proteinuric effects of these agents would be ideal and mineralocorticoid receptor antagonists (MRAs) fit in this slot perfectly. This review attempted to evaluate the safety and efficacy of MRAs for DN. Presently MRAs such as spironolactone, eplerenone and finerenone are being investigated as both monotherapies and as an additional therapy. Clinical studies have shown that these drugs have been effective in the reduction of blood pressure (BP), urinary albumin-excretion (UAE) and estimated glomerular filtration rate (eGFR). The adverse effects of hyperkalaemia, gynaecomastia and vaginal bleeding that are bothersome with spironolactone seem to be avoidable if these patients are switched over to non-steroidal MRAs such as finerenone and eplerenone. Most of the studies have only evaluated the short-term effects of MRAs on DN. Hard outcomes such as cardiovascular events, creatinine doubling, progression to ESRD, mortality, and need for temporary or permanent dialysis needs to be studied with these molecules. PMID- 30444200 TI - Functional Improvement of Chimeric Antigen Receptor Through Intrinsic Interleukin 15Ralpha Signaling. AB - Recent studies of CD19-specific chimeric antigen receptor (CAR)-modified T cells (CARTs) have demonstrated unprecedented successes in treating refractory and relapsed B cell malignancies. The key to the latest CART therapy advances can be attributed to the improved co-stimulatory signals in the CAR design. Here we established several novel CARs by incorporating T cell signaling domains of CD28 in conjunction with intracellular signaling motif of 4-1BB, CD27, OX40, ICOS, and IL-15Ralpha. These novel CARs were functionally assessed based on a simple target cell killing assay. The results showed that the CD28/IL-15Ralpha co-signaling (153z) CAR demonstrated the fastest T cell expansion potential and cytotoxic activities. IL-15 is a key cytokine that mediates immune effector activities. The 153z CARTs maintained prolonged killing activities after repetitive rounds of target cell engagement. Consistent with the enhanced target killing function, the 153z CARTs produced increased amount of effector cytokines including IFN-?, TNF? and IL-2 upon interaction with the target cells. In a follow-up clinical study, an acute lymphoblastic leukemia patient, who had experienced repetitively relapsed central nervous system leukemia (CNSL) and failed all conventional therapies, was enrolled to receive the CD19-specific 153z CART treatment. The patient achieved complete remission after the 153z CART cell infusion. The translational outcome supports further investigation into the safety and enhanced therapeutic efficacy of the IL-15Ralpha-modified CART cells in cancer patients. PMID- 30444202 TI - Pibrentasvir / Glecaprevir - induced cholestatic jaundice in a HCV patient with renal failure. A case presentation. AB - Direct-acting a antiviral (DAA) are currently used in the treatment of chronic HCV infection. In patients with renal failure with Elbasvir/Grazoprevir (genotype 1 and 4) or Pibrentasvir/Glecaprevir (genotype 1-6) is advised and these documented both good safety and efficacy. In this manuscript we reported the development of cholestatic jaundice, during Pibrentasvir/Glecaprevir treatment, in a 86-year-old male with chronic HCV (genotype 2) infection and renal failure. At examination patient was jaundiced and suffered of a severe itch. Ultrasound and laboratory findings excluded a liver failure (e.g. liver or pancreatic cancer, liver lithiasis) while Naranjo probability scale suggested a probable (score 6) association between cholestatic janduice and Pibrentasvir/Glecaprevir. About 4 weeks after drug discontinuation we documented an improvement in both jaundice and itch, with a normalization in bilirubin values (total bilirubin: 0.96). HCV-RNA was undetected (ND) as also documented from a new analysis performed on June 15,2018. It is worth mentioning that although we reported the development of cholestatic jaundice upon treatment with Glecaprevir/Pibrentasvir we recorded a clinical efficacy (HCV-RNA <15 IU/L) 4 weeks after the beginning of the treatment with a complete remission of clinical symptoms lasting until 6 months after drug discontinuation, supporting the data on the clinical efficacy of Glecaprevir/Pibrentasvir association in elderly patients, despite the sub optimal period of treatment. PMID- 30444203 TI - In vivo, Extract from Withania somnifera root ameliorates arthritis via regulation of key immune mediators of inflammation in experimental model of arthritis. AB - Rheumatoid arthritis (RA) is a devastating disease characterized by continual addition of leukocytes and T cells within the articular cavity causing inflammation. Withania somnifera is reported to have antioxidant, anti inflammatory, immunomodulatory properties. The purpose of this study was to evaluate anti-inflammatory activity of aqueous extract of Withania somnifera roots (WSAq) in collagen induced arthritic (CIA) rats. To achieve this, we assess the level of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, IL 1beta, IL-6 and IL-10 in CIA rats. Further, transcription factor, oxidative stress parameters and CD+8 expressions was also analyzed in CIA rats. Arthritic rats shows a greater increased in the levels of pro inflammatory cytokinees such as TNF-alpha, IL-1beta, IL-6, NF-kappaB and decrease in IL-10 concentration than controls rats. Oral administration of WSAq at a dose of 300mg/kg.wt. (WSAq300) appreciably attenuates the production of these pro inflammatory cytokines. This anti-inflammatory activity of WSAq300 might be partly mediated through increase in secretion of IL-10 and inhibition of NF-kappaB activity. Further, arthritic rats also show increased oxidative stress as compared to control rats. This increased oxidative stress in the arthritic rats appears to be the outcome of both an activated pro-oxidant and a poor antioxidant defense system. Treatment with WSAq300 strongly ameliorates all these ROS parameters significantly to near normal. Additional, metalloproteinase MMP-8 were also measured and found to be increased in CIA rats which after treatment with WSAq300 come down to near normal. From the above results it can be concluded that use of WSAq300 may be a valuable supplement which can improve human arthritis. PMID- 30444205 TI - Review. Strategies for rot control of soybean sprouts. AB - Soybean sprouts are nutrient-rich, containing plentiful protein, vitamin C, and minerals and are packed in small numbers after production. As soybean sprouts were mass produced in a factory, the occurrence of rotting in soybean sprouts has become a serious problem. To overcome these problems, many efforts have been made to provide healthy soybean sprouts in Korea. This paper reviewed the physicochemical techniques used for supplying water with antibacterial properties and the natural antimicrobial materials developed for soybean sprout cultivation. On the basis of this review, 11 of the antimicrobial agents and/or techniques currently used originated from mineral, non-metal ions, and metal ions, 4 from antagonistic microorganisms, 7 from agents originating from animals, 31 from medicinal and herbal plants, and 11 from physicochemical agents and/or techniques. In addition, these agents and/or techniques showed potential not only for the inhibition of spoilage and rot of soybean sprouts but also for the extension of product shelf life, the enhancement of taste and aroma, the enhancement of nutrition and functional components, growth promotion, and/or the reduction of production costs. Continuous scientific innovations and improved processing technology will aid in further advancements and improvements in this area. Therefore, this study offers useful insights suggesting direction for future research and provides information on the different anti-rotting agents and/or techniques for soybean sprouts developed to date, also as discussed in various patents. PMID- 30444204 TI - Diabetes association with liver diseases: an overview for clinicians. AB - BACKGROUND: There is strong association between liver diseases and diabetes (DM) which is higher than expected by a correlation between two very common diseases. Liver diseases may occur as a result of diabetes, and the reverse is true as well. AIM: To review the etiology of this association between liver diseases and diabetes and how to diagnose it. METHODS: Studies that identified this association between liver diseases and diabetes and how to diagnose it were reviewed. RESULTS: This association can be divided into the following categories: liver disease related to diabetes (Diabetic hepatopathy), hepatogenous diabetes (HD), and liver diseases that occur in conjunction with Diabetes mellitus. Two hours after glucose loading is the best screening test for HD. HbA1c may not be suitable for neither diagnosis nor monitoring of diabetes that links liver disease. CONCLUSIONS: NAFLD, hepatogenous diabetes, glycogenic hepatopathy and diabetic hepatosclerosis are the most important association between liver diseases and diabetes. The criteria for the diagnosis of diabetes associating liver disease are the same for the primary diabetes. Two hours post glucose load is the best screening test for HD due to the fact that fasting glucose can be normal early in the disease. The tool used for diabetes monitoring depends on stage and severity of liver condition. PMID- 30444206 TI - Fat mass estimation in neonates: anthropometric models compared with air displacement plethysmography. PMID- 30444207 TI - The cross-sectional relationships between consumption of takeaway food, eating meals outside the home and diet quality in British adolescents. AB - OBJECTIVE: The present study aimed to evaluate the association of frequency of consuming takeaway meals and meals out with diet quality of UK adolescents. DESIGN: The Diet Quality Index for Adolescents (DQI-A) tool was used to assess diet quality, where adolescents' food intake was based on 4d diary records obtained from the UK cross-sectional National Diet and Nutrition Survey (NDNS) rolling programme Years 1-6. Models included confounders. SETTING: The DQI-A relies on three components, specifically diet quality, diversity and equilibrium, which reflect the degree of adherence of an adolescent's diet with food-based dietary guidelines.ParticipantsBritish (n 2045) adolescents aged 11-18 years. RESULTS: Mean diet quality score for all adolescents was 20.4 % (overall DQI-A score range: -33 to 100 %). After adjusting for age, gender and equivalised household income, DQI-A% score was higher for low and moderate takeaway consumers by 7.4 % (95 % CI 5.5, 9.2; P<0.01) and 3.5 % (95 % CI 1.9, 5.1; P<0.01), respectively, v. frequent consumers. Significant differences were also observed between low, moderate and frequent takeaway consumers among all DQI-A components and sub-components (P<0.05), except for the diet adequacy sub-component (DAx). Results for frequent consumption of meals out were similar but attenuated and not statistically significant for individual components before or after adjusting for confounders. CONCLUSIONS: Frequent consumption of takeaway meals may have a negative impact on adolescents' diet quality and therefore policies to reduce the intake of takeaways should be considered in this age group. PMID- 30444209 TI - The potential use of probiotic and beneficial bacteria in the Brazilian dairy industry. AB - Scientific studies demonstrate the importance of intestinal microbiota to human health and how probiotic microorganisms can positively affect health when administered regularly and in adequate amounts. Probiotic bacteria can be part of fermented products and their functional importance is associated mainly with their metabolism. They are thought to benefit individuals to maintain their health and also to strengthen resistance against various types of diseases. The acceptance of probiotic cultures and products by consumers increased when these bacteria were marketed as natural cultures that help in digestion and health. Considering this, the food industry has an increasing demand for new candidates as probiotic cultures, and the dairy industry has a particular interest for fermented milks and other dairy products, since these are the most common food vehicles for probiotic cultures. Therefore, the dairy industries are increasingly seeking to improve their products with these beneficial bacteria. However, the legal peculiarities and excess of control agencies in Brazil makes the registration of these products and the collection of data very complex. Prospective analysis suggests that probiotic foods have the potential to effect a considerable expansion of the dairy industry, allowing the dairy sector to grow and for these products to be increasingly sought by consumers globally. For this, not only actions on research and innovation are necessary, but also official clarifications on the claims for considerations of microbiological security and functionality of these products. This review aims to elucidate important probiotic research regarding the isolation and characterization of beneficial cultures in Brazil, and to demonstrate the relevance of the dairy chain as a potential source of novel cultures for the development of new probiotic products to expand the Brazilian dairy industry. PMID- 30444208 TI - Mild Traumatic Brain Injury Burden Moderates the Relationship Between Cognitive Functioning and Suicidality in Iraq/Afghanistan-Era Veterans. AB - OBJECTIVES: Suicidal ideation (SI) is highly prevalent in Iraq/Afghanistan-era veterans with a history of mild traumatic brain injury (mTBI), and multiple mTBIs impart even greater risk for poorer neuropsychological functioning and suicidality. However, little is known about the cognitive mechanisms that may confer increased risk of suicidality in this population. Thus, we examined relationships between neuropsychological functioning and suicidality and specifically whether lifetime mTBI burden would moderate relationships between cognitive functioning and suicidal ideation. METHODS: Iraq/Afghanistan-era Veterans with a history of mTBI seeking outpatient services (N = 282) completed a clinical neuropsychological assessment and psychiatric and postconcussive symptom questionnaires. RESULTS: Individuals who endorsed SI reported more severe post traumatic stress disorder (PTSD), depression, and postconcussive symptoms and exhibited significantly worse memory performance compared to those who denied SI. Furthermore, mTBI burden interacted with both attention/processing speed and memory, such that poorer performance in these domains was associated with greater likelihood of SI in individuals with a history of three or more mTBIs. The pattern of results remained consistent when controlling for PTSD, depression, and postconcussive symptoms. CONCLUSIONS: Slowed processing speed and/or memory difficulties may make it challenging to access and use past experiences to solve current problems and imagine future outcomes, leading to increases in hopelessness and SI in veterans with three or more mTBIs. Results have the potential to better inform treatment decisions for veterans with history of multiple mTBIs. (JINS, 2018, 00, 1-11). PMID- 30444210 TI - Assessing risk of neurodevelopmental disorders after birth with oxytocin: a systematic review and meta-analysis. AB - Experts have raised concerns that oxytocin for labor induction and augmentation may have detrimental effects on the neurodevelopment of children. To investigate whether there is the reason for concern, we reviewed and evaluated the available evidence by searching databases with no language or date restrictions up to 9 September 2018. We included English-language studies reporting results on the association between perinatal oxytocin exposure and any cognitive impairment, psychiatric symptoms or disorders in childhood. We assessed the quality of studies using the Newcastle-Ottawa Quality Assessment Scales. Independent risk estimates were pooled using random-effects meta-analyses when at least two independent datasets provided data on the same symptom or disorder. Otherwise, we provided narrative summaries. Two studies examined cognitive impairment, one examined problem behavior, three examined attention-deficit/hyperactivity disorder (ADHD) and seven focused on autism spectrum disorders (ASD). We provided narrative summaries of the studies on cognitive impairment. For ADHD, the pooled risk estimate was 1.17; 95% confidence interval (CI) 0.77-1.78, based on a pooled sample size of 5 47 278 offspring. For ASD, the pooled risk estimate was 1.10; 95% CI 1.04-1.17, based on 8 87 470 offspring. Conclusions that perinatal oxytocin increases the risks of neurodevelopmental problems are premature. Observational studies of low to high quality comprise the evidence-base, and confounding, especially by the genetic or environmental vulnerability, remains an issue. Current evidence is insufficient to justify modifying obstetric guidelines for the use of oxytocin, which state that it should only be used when clinically indicated. PMID- 30444211 TI - Community-based care of children affected by AIDS in Swaziland: a gender-aware analysis. AB - BACKGROUND: Care of children affected by AIDS in Swaziland is predominately provided by families, with support from 'community-based responses'. This approach is consistent with United Nations International Children's Fund's (UNICEF) framework for the protection, care and support of children affected by AIDS. However, the framework relies heavily on voluntary caregiving which is highly gendered. It pays limited attention to caregivers' well-being or sustainable community development which enables more effective caregiving. As a result, the framework is incompatible with the social justice principles of primary health care, and the sustainable development goals (SDGs).AimOur aim was to examine the effects and gender dimensions of providing voluntary, community based, care-related labour for children affected by AIDS. METHODS: We conducted multiple-methods research involving an ethnography and participatory health research, in a rural Swazi community. We analysed data related to community-based responses using an abductive, mixed-methods technique, informed by the capabilities approach to human development and a gender analysis framework.FindingsTwo community-based responses, 'neighbourhood care points' (facilities that provide children meals) and the 'lihlombe lekukhalela' (child protector) program were being implemented. The unpaid women workers at neighbourhood care points reported working in challenging conditions (eg, lacking labour-saving technologies), insufficient and diminishing material support (eg, no food), and receiving limited support from the broader community. Child protectors indicated their effectiveness was limited by lack of social power, relative to the perpetrators of child abuse. The results indicate that support for community-based responses will be enhanced by acknowledging and addressing the highly gendered nature of care-related labour and social power, and that increasing access to material resources including food, caregiver stipends and labour-saving technologies, is essential. These strategies will simultaneously contribute to the social and economic development of communities central to primary health care, and achieving the poverty, hunger, gender and work-related SDGs. PMID- 30444212 TI - Opioid prescribing after hysterectomy and route of hysterectomy-opportunities to improve care. PMID- 30444213 TI - Novel Compound Heterozygous Variants in the LHCGR Gene in a Genetically Male Patient with Female External Genitalia. AB - OBJECTIVES: The LHCGR gene encodes a G-protein coupled receptor that plays a pivotal role in sexual differentiation in males, ovarian development in females, and in fertility via its interaction with luteinizing hormone (LH) and chorionic gonadotropin (CG). Inactive variants of the LHCGR gene cause Leydig cell hypoplasia (LCH), which is a rare disease and one of the causes of disorder of sexual differentiation (DSD) in males. The aim of this work is to study the clinical and molecular characteristics of a 2-year-9-month old patient with type 1 LCH. METHODS: Whole-exome sequencing was performed for the patient family, and variants in the LHCGR gene were validated by Sanger sequencing. Pathogenicity of the missense variant was evaluated by multiple in silico tools. RESULTS: The Chinese patient, who exhibits DSD, has female external genitalia (normal labia majora and minora, external opening of urethra under the clitoris and blind-ended vagina) and bilateral testis tissues in the inguinal region. Genetic sequencing revealed compound heterozygous variants in the LHCGR gene in the patient, including a novel missense variant in exon 4 (c.349G>A, p.Gly117Arg) and a novel nonsense variant in exon 10 (c.878C>A, p.Ser293*). The missense variant is in the first leucine-rich repeat (LRR) domain of the LHCGR protein, which is predicted to affect ligand recognition and binding affinity and thus protein function. CONCLUSIONS: The patient is molecularly and clinically diagnosed with type 1 LCH, which is caused by novel, compound heterozygous variants of the LHCGR gene. This report expanded the genotypic spectrum of LHCGR variants. PMID- 30444214 TI - Management of fibroids prior to in vitro fertilization/intracytoplasmic sperm injection: A pragmatic approach. AB - Fibroids are relatively common in women undergoing in vitro fertilization (IVF) treatment due to their high prevalence in women. It is generally accepted that submucosal fibroids are deleterious to the IVF outcome and their removal is beneficial. Evidence from relatively low quality studies on the impact of intramural fibroids on IVF outcome is also suggestive of a detrimental impact. The majority of published studies included women with relatively small intramural fibroids and women with cavity distorting fibroids were usually excluded, hence it is quite likely that the detected impact in the systematic reviews is an underestimation. Evidence of benefit is scarce for the removal of noncavity distorting intramural fibroids. It is quite likely that numbers needed to treat (NNT) for this purpose would be very high for small fibroids but lower for larger fibroids. This would need to be taken into account when decisions are made on myomectomy and potential benefits should be weighed against the associated morbidity, cost and delay in fertility treatment. Whilst there is a need to perform prospective randomised studies in this field, a pragmatic approach which takes prognostic factors into account to estimate the magnitude of possible impact of the fibroid(s) and potential benefit of removal is likely to lead to better reproductive outcomes. PMID- 30444215 TI - Electrode fabrication and interface optimization for imaging of evoked peripheral nervous system activity with electrical impedance tomography (EIT). AB - OBJECTIVE: Non-invasive imaging techniques are undoubtedly the ideal methods for continuous monitoring of neural activity. One such method, fast neural electrical impedance tomography (EIT) has been developed over the past decade in order to image neural action potentials with non-penetrating electrode arrays. APPROACH: The goal of this study is two-fold. First, we present a detailed fabrication method for silicone-based multiple electrode arrays which can be used for epicortical or neural cuff applications. Secondly, we optimize electrode material coatings in order to achieve the best accuracy in EIT reconstructions. MAIN RESULTS: The testing of nanostructured electrode interface materials consisting of platinum, iridium oxide, and PEDOT:pTS in saline tank experiments demonstrated that the PEDOT:pTS coating used in this study leads to more accurate reconstruction dimensions along with reduced phase separation between recording channels. The PEDOT:pTS electrodes were then used in vivo to successfully image and localize the evoked activity of the recurrent laryngeal fascicle from within the cervical vagus nerve. SIGNIFICANCE: These results alongside the simple fabrication method presented here position EIT as an effective method to image neural activity. PMID- 30444216 TI - Neural tracking of the speech envelope in cochlear implant users. AB - OBJECTIVE: When listening to speech, the brain tracks the speech envelope. It is possible to reconstruct this envelope from EEG recordings. However, in people who hear using a cochlear implant (CI), the artifacts caused by electrical stimulation of the auditory nerve contaminate the EEG. The objective of this study is to develop and validate a method for assessing the neural tracking of speech envelope in CI users. APPROACH: To obtain EEG recordings free of stimulus artifacts, the electrical stimulation is periodically interrupted. During these stimulation gaps, artifact-free EEG can be sampled and used to train a linear envelope decoder. EEG recordings obtained during audible and inaudible (i.e. sub threshold) stimulation were used to characterize the artifacts and their influence on the envelope reconstruction. MAIN RESULTS: The present study demonstrates for the first time that neural tracking of the speech envelope can be measured in response to ongoing electrical stimulation. The responses were validated to be truly neural and not affected by stimulus artifact. SIGNIFICANCE: Besides applications in audiology and neuroscience, the characterization and elimination of stimulus artifacts will enable future EEG studies involving continuous speech in CI users. Measures of neural tracking of the speech envelope reflect interesting properties of the listener's perception of speech, such as speech intelligibility or attentional state. Successful decoding of neural envelope tracking will open new possibilities to investigate the neural mechanisms of speech perception with a CI. PMID- 30444217 TI - Artifact-free recordings in human bidirectional brain-computer interfaces. AB - OBJECTIVE: Intracortical microstimulation has shown promise as a means of evoking somatosensory percepts as part of a bidirectional brain-computer interface (BCI). However, microstimulation generates large electrical artifacts that dominate the recordings necessary for BCI control. These artifacts must be eliminated from the signal in real-time to allow for uninterrupted BCI decoding. APPROACH: We present a simple, robust modification to an existing clinical BCI system to allow for simultaneous recording and stimulation using a combination of signal blanking and digital filtering, without needing to explicitly account for varying parameters such as electrode locations or amplitudes. We validated our artifact rejection scheme by recording from microelectrodes in primary motor cortex (M1) while stimulating in somatosensory cortex of a person with a spinal cord injury. MAIN RESULTS: M1 recordings were digitally blanked using a sample-and-hold circuit triggered just prior to stimulus onset and a first-order 750 Hz high-pass Butterworth filter was used to reduce distortion of the remaining artifact. This scheme enabled spike detection in M1 to resume as soon as 740 us after each stimulus pulse. We demonstrated the effectiveness of the complete bidirectional BCI system by comparing functional performance during a 5 degree of freedom robotic arm control task, with and without stimulation. When stimulation was delivered without this artifact rejection scheme, the number of objects the subject was able to move across a table in 2 min under BCI control declined significantly compared to trials without stimulation (p < 0.01). When artifact rejection was implemented, performance was no different than in trials that did not include stimulation (p = 0.621). SIGNIFICANCE: The proposed technique uses simple changes in filtering and digital signal blanking with FDA-cleared hardware and enables artifact-free recordings during bidirectional BCI control. PMID- 30444218 TI - A machine-learning approach to volitional control of a closed-loop deep brain stimulation system. AB - OBJECTIVE: Deep brain stimulation (DBS) is a well-established treatment for essential tremor, but may not be an optimal therapy, as it is always on, regardless of symptoms. A closed-loop (CL) DBS, which uses a biosignal to determine when stimulation should be given, may be better. Cortical activity is a promising biosignal for use in a closed-loop system because it contains features that are correlated with pathological and normal movements. However, neural signals are different across individuals, making it difficult to create a 'one size fits all' closed-loop system. APPROACH: We used machine learning to create a patient-specific, CL DBS system. In this system, binary classifiers are used to extract patient-specific features from cortical signals and determine when volitional, tremor-evoking movement is occurring to alter stimulation voltage in real time. MAIN RESULTS: This system is able to deliver stimulation up to 87% 100% of the time that subjects are moving. Additionally, we show that the therapeutic effect of the system is at least as good as that of current, continuous-stimulation paradigms. SIGNIFICANCE: These findings demonstrate the promise of CL DBS therapy and highlight the importance of using subject-specific models in these systems. PMID- 30444219 TI - Increased Expression of c-Met is Associated with Chemotherapy-Resistant Breast Cancer and Poor Clinical Outcome. AB - BACKGROUND The relevance of c-Met expression as a prognostic or predictive clinical indicator in chemotherapy-resistant breast cancer remains unknown. The aims of this study were to investigate the expression of c-Met in breast cancer tissues and its association with expression of type II topoisomerase (TOPO II), including in patients who received neoadjuvant chemotherapy (NAC), and to investigate chemotherapy resistance in vitro in breast cancer cell lines. MATERIAL AND METHODS Tissue samples from 255 patients with breast cancer, with matched adjacent normal breast tissue, were used in tissue microarrays (TMAs). c Met protein expression levels were determined using immunohistochemistry. Forty five cases of breast cancer treated with NAC were studied to investigate the association between c-Met and TOPO II expression and clinical outcome. Chemotherapy resistance was evaluated in vitro in the MCF-7 and MDA-MB-231 breast cancer cell lines. RESULTS Expression of c-Met protein was increased in breast cancer tissue compared with normal breast tissue. In breast cancer tissue samples, increased c-Met expression was significantly associated with increased Ki-67 expression, tumor size, tumor stage, and TOPO II expression, and with reduced overall survival (OS) rates. Increased c-Met expression and reduced TOPO II expression were associated with chemotherapy resistance. In breast cancer cell lines, knockdown of c-Met expression induced TOPO II expression and increased tumor cell sensitivity to chemotherapy. CONCLUSIONS The findings of this study support a role for c-Met as a clinical prognostic marker and for c-Met and TOPO II as predictive markers for response to chemotherapy in patients with breast cancer. PMID- 30444220 TI - Endometriosis - The challenge for occupational life of diagnosed women: A review of quantitative studies. AB - The aim of the article was to summarize the results offered in the research on occupational functioning of women with endometriosis. We followed PRISMA guidelines. Database search was done in November 2017 using EBSCO. In the review were included the articles clearly referring to the relationships between endometriosis and work or any aspect of work (e.g., work productivity, work ability, absenteeism). Eight papers were included in the final review. Seven studies were cross-sectional, one retrospective. The majority of researchers used standardized research measures, such as Work Ability Index, Work Productivity and Activity Impairment Questionnaire or Health Related Productivity Questionnaire. Only in two studies the reference group was considered, one of them consisted of healthy women. The results clearly indicate that endometriosis is a disease that causes major disturbance in occupational functioning of the suffering women. In the future the researchers should search for individual and organizational correlates of the improvement of occupational functioning in this group of patients. The methodology of the existing studies has been evaluated and the methodological cues for future research has been given. Med Pr 2018;69(6). PMID- 30444221 TI - [Occupational diseases in Poland in 2016]. AB - BACKGROUND: The aim of the work is to present the epidemiological situation in the field of occupational diseases in Poland in 2016. MATERIAL AND METHODS: The cases of occupational diseases identified in accordance with the applicable case law system in Poland and reported to the Central Register of Occupational Diseases in 2016 were analyzed. The analysis includes nosologic units, their causative factors as well as gender and age of patients. Absolute numbers and incidence rates per 100 thousand employees were presented. RESULTS: In 2016, 2119 cases of occupational diseases were recorded in Poland, i.e. 14.3 cases per 100 thousand employed persons. The incidence rate was mainly caused by pneumoconioses (28.5%), infectious or parasitic diseases (27.2%), chronic voice disorders (9.7%), chronic diseases of the peripheral nervous system (8.6%) and hearing loss (6.3%). The highest incidence was recorded in the mining and quarrying (329.7 cases), agriculture and forestry (23.8 cases), manufacturing (20 cases) and education (17.9 cases) and healthcare and social work activities (17.7 cases). CONCLUSIONS: In comparison with 2015, there was an increase in the number of cases of occupational diseases by 1.2%, which was influenced mainly by a larger (by 181 cases) number of pneumoconiosis. The epidemiological situation resulting from occupational diseases in our country, although it covers all identified cases, should be assessed with caution because the suspicion arises underestimation of certain diseases, especially cancer. Med Pr 2018;69(6). PMID- 30444222 TI - Biomedical applications of mid-infrared quantum cascade lasers - a review. AB - Mid-infrared spectroscopy has been applied to research in biology and medicine for more than 20 years and conceivable applications have been identified. More recently, these applications have been shown to benefit from the use of quantum cascade lasers due to their specific properties, namely high spectral power density, small beam parameter product, narrow emission spectrum and, if needed, tuning capabilities. This review provides an overview of the achievements and illustrates some applications which benefit from the key characteristics of quantum cascade laser-based mid-infrared spectroscopy using examples such as breath analysis, the investigation of serum, non-invasive glucose monitoring in bulk tissue and the combination of spectroscopy and microscopy of tissue thin sections for rapid histopathology. PMID- 30444223 TI - A separation voltage polarity switching method for higher sample loading capacity and better separation resolution in transient capillary isotachophoresis separation. AB - A separation voltage polarity switching transient capillary isotachophoresis (PS tCITP) was developed to overcome a major sample loading volume limitation in transient capillary isotachophoresis (tCITP). The fundamental idea of PS-tCITP is to let sample ions move back and forth in a separation capillary during their initial isotachophoresis focusing stage by switching the polarity of the separation voltage, in order to both increase the sample loading volume and improve the separation efficiency as compared to the conventional tCITP method. The experimental evaluation of the novel PS-tCITP method by using two peptide standards at 2 MUM concentration showed that the maximum sample loading volume could be increased from 45% of the total separation capillary volume in tCITP to 70% in PS-tCITP, which resulted in a more than 1.5 fold increase in the peptide peak intensity at a given length/volume of the separation capillary. Due to the consecutive focusing of sample volume from each polarity switching of the separation voltage, the separation time window at a given sample loading volume was also increased significantly in PS-tCITP as compared to tCITP. Experiment comparison between tCITP and PS-tCITP at 45% sample loading volume using the same setup showed that the migration time difference between the two peptide peaks increased from 0.3 min in tCITP to 0.363 min in PS-tCITP with similar peak widths and heights, resulting in roughly a 21% improvement in separation resolution. The performance advantages of PS-tCITP separation over tCITP separation were further verified by using a mixture of six peptide standards. PMID- 30444224 TI - Molecular genetic and biochemical characterization of a putative family of zinc metalloproteins in Caenorhabditis elegans. AB - Four highly similar genes (W08E12.2, W08E12.3, W08E12.4 and W08E12.5) which are consecutively aligned on chromosome IV of the C. elegans genome are predicted to code for small (120-141aa) yet cysteine rich (18-19 cysteines) proteins. Cloning and sequencing of the genomic regions of the isoforms confirmed the presence and order of all genes. The generation of transgenic worms strains with an integrated single copy or extrachromosomal multi-copy PW08E12.3;W08E12.4::GFP uncovered that W08E12.3 and W08E12.4 are constitutively expressed in the pharynx and significantly induced in worms exposed to 100 MUM Zn. Knockdown by RNAi did not have a marked consequence on reproductive performance nor was a Zn-dependent effect on nematode growth observed. However, RNAi of these genes led to an accumulation of Zn in the intestinal cells. W08E12.3 was recombinantly expressed in E. coli and the purified protein was shown to be able to bind up to 6.5 Zn molecules at neutral pH. Zn-binding was acid-labile and the apo protein was observed at pH < 4.3. This characterization suggests W08E12.2, W08E12.3, W08E12.4 and W08E12.5 belong to a family of putative Metalloproteins which, akin to metallothioneins, may play an important role in Zn-sensing, homeostasis and/or detoxification. PMID- 30444225 TI - Crystallographic plane and topography-dependent growth of semipolar InGaN nanorods on patterned sapphire substrates by molecular beam epitaxy. AB - A low-cost, high-efficiency, and catalyst-free method for fabricating well aligned and uniform semipolar InGaN nanorods (NRs) by molecular beam epitaxy (MBE) is proposed using an optimized patterned sapphire substrate (PSS) with high Miller index crystallographic planes. The dense, obliquely aligned, and high quality semipolar (11[combining macron]02) InGaN NRs are fabricated on hexagonal pyramid arrays of the PSS for the first time in this work. A unique semipolar (11[combining macron]02) and polar (0001) InGaN NR array composite structure is thus achieved on a hexagonal pyramid PSS. The connected, uniform, and obliquely aligned NRs are formed on the PSS with cylindrical arrays. The cylindrical and hexagonal pyramid arrays of PSSs are structured by the standard photolithography process and etching techniques. Both pattern topography and crystallographic plane of the PSS significantly affect the morphology, dimension, and crystallographic orientation of InGaN NRs. It is clearly demonstrated that the PSS with exposed high Miller index crystallographic planes, with well-organized step-terrace structures, facilitates the growth of ordered and dense semipolar InGaN NRs. This work contributes to the thorough understanding of the nucleation and growth mechanisms of InGaN NRs on a high Miller index plane of the PSS with different topographies, as well as of those of controllably fabricating dense and uniform semipolar NRs, thus facilitating the fabrication of NR-based optoelectronic devices with enhanced performance. PMID- 30444226 TI - Microwave-assisted rapid preparation of hollow carbon nanospheres@TiN nanoparticles for lithium-sulfur batteries. AB - Highly conductive titanium nitride (TiN) has a strong anchoring ability for lithium polysulfides (LiPSs). However, the complexity and high cost of fabrication limit their practical applications. Herein, a typical structure of hollow carbon nanospheres@TiN nanoparticles (HCNs@TiN) was designed and successfully synthesized via a microwave reduction method with the advantages of economy and efficiency. With unique structural and outstanding functional behavior, HCN@TiN-S hybrid electrodes display not only a high initial discharge capacity of 1097.8 mA h g-1 at 0.1C, but also excellent rate performance and cycling stability. After 200 cycles, a reversible capacity of 812.6 mA h g-1 is still retained, corresponding to 74% capacity retention of the original capacity and 0.13% decay rate per cycle, which are much better than those of HCNs-S electrodes. PMID- 30444227 TI - Conductive diamond: synthesis, properties, and electrochemical applications. AB - Conductive diamond possesses unique features as compared to other solid electrodes, such as a wide electrochemical potential window, a low and stable background current, relatively rapid rates of electron-transfer for soluble redox systems without conventional pretreatment, long-term responses, stability, biocompatibility, and a rich surface chemistry. Conductive diamond microcrystalline and nanocrystalline films, structures and particles have been prepared using a variety of approaches. Given these highly desirable attributes, conductive diamond has found extensive use as an enabling electrode across a variety of fields encompassing chemical and biochemical sensing, environmental degradation, electrosynthesis, electrocatalysis, and energy storage and conversion. This review provides an overview of the fundamental properties and highlights recent progress and achievements in the growth of boron-doped (metal like) and nitrogen and phosphorus-doped (semi-conducting) diamond and hydrogen terminated undoped diamond electrodes. Applications in electroanalysis, environmental degradation, electrosynthesis electrocatalysis, and electrochemical energy storage are also discussed. Diamond electrochemical devices utilizing micro-scale, ultramicro-scale, and nano-scale electrodes as well as their counterpart arrays are viewed. The challenges and future research directions of conductive diamond are discussed and outlined. This review will be important and informative for chemists, biochemists, physicists, materials scientists, and engineers engaged in the use of these novel forms of carbon. PMID- 30444228 TI - Mechanisms of (photo)toxicity of TiO2 nanomaterials (NM103, NM104, NM105): using high-throughput gene expression in Enchytraeus crypticus. AB - Titanium dioxide (TiO2) based nanomaterials (NMs) are among the most produced NMs worldwide. When irradiated with light, particularly UV, TiO2 is photoactive, a property that is explored for several purposes. There are an increasing number of reports on the negative effects of photoactivated TiO2 on non-target organisms. We have here studied the effect of a suite of reference type TiO2 NMs (i.e. NM103, NM104, and NM105 and compared these to the bulk) with and without UV radiation to the oligochaete Enchytraeus crypticus. High-throughput gene expression was used to assess the molecular mechanisms, while also anchoring it to the known effects at the organism level (i.e., reproduction). Results showed that the photoactivity of TiO2 (UV exposed) played a major role in enhancing TiO2 toxicity, activating the transcription of oxidative stress, lysosome damage and apoptosis mechanisms. For non-UV activated TiO2, where toxicity at the organism level (reproduction) was lower, results showed potential for long-term effects (i.e., mutagenic and epigenetic). NM specific mechanisms were identified: NM103 affected transcription and translation, NM104_UV negatively affected the reproductive system/organs, and NM105_UV activated superoxide anion response. Results provided mechanistic information on UV-related phototoxicity of TiO2 materials and evidence for the potential long-term effects. PMID- 30444229 TI - Molybdenum carbide promotion on Fe-N-doped carbon nanolayers facilely prepared for enhanced oxygen reduction. AB - The catalysts towards the oxygen reduction reaction (ORR) are the key materials for fuel cells and have stimulated continuous investigations on rational designs. Apart from the popular strategies reported, we demonstrate here a facile method resulting in a nanocomposite composed of molybdenum carbide (Mo2C) nanoparticles embedded and buried in Fe-N-doped carbon nanolayers by directly pyrolyzing the mixture of Fe2(MoO4)3 and dicyandiamide. The underlying Mo2C donates electrons of higher energy to the exterior N-containing carbon nanolayers (NC) and strongly couples with the active sites induced by Fe in the NC layer, leading to significant improvement at half-wave potential with respect to the control sample without Mo2C. The catalyst as a whole exhibits a fairly good ORR performance comparable to commercial Pt/C. Moreover, the method is extremely simplified and the material shows better long-term stability and tolerance to the methanol crossover in comparison with Pt/C. PMID- 30444230 TI - High-yield paper-based quantitative blood separation system. AB - Interest in developing paper-based devices for point-of-care diagnostics in resource-limited settings has risen remarkably in recent decades. In this paper, we demonstrate what we refer to as "high yield passive rrythrocyte removal" (HYPER) technology, which utilizes capillary forces in a unique cross-flow filtration for the separation of whole blood with performance comparable to centrifuges. As we will demonstrate, state-of-the-art passive blood separation methods implemented in paper-based systems exhibit rapid blood cell clogging on the filtration media or serum outlet and yield only about 10-30% of the total serum present in the sample. Our innovation results from the inclusion of a differentiation pad, which exploits hydrodynamic effects to reduce the formation of a fouling layer on the blood filtration membrane resulting in more than 60% serum yield with undiluted whole blood as direct input. To demonstrate the effectiveness of the HYPER technology we implement it in a lateral flow system and demonstrate the accurate quantification of vitamin A and iron levels in whole blood samples in 15 minutes. PMID- 30444231 TI - An ultra-sensitive and selective nitrogen dioxide sensor based on a novel P2C2 monolayer from a theoretical perspective. AB - The sensing properties of an alpha phase black phosphorus carbide (P2C2) monolayer for the adsorption of CO2, H2, H2O, N2, H2S, NH3, O2 and NO2 gases are theoretically investigated using first-principles calculations. We calculate the adsorption energy, equilibrium distance, Mulliken charge transfer, electron localization function, and work function to explore whether P2C2 is suitable for detecting NO2 gas. The results demonstrate that the P2C2 monolayer is highly sensitive and selective to NO2 gas molecules with robust adsorption energy and superior charge transfer due to the existence of strong orbital hybridization between the NO2 molecule and monolayer P2C2. In addition, the results of the work function calculations indicate that field effect transistor type NO2 gas sensors based on P2C2 monolayers are also feasible. Furthermore, the current-voltage curves reveal that the adsorption of NO2 can greatly modify the resistance of the P2C2 monolayer. Our results show that gas sensors based on P2C2 monolayers could be better than those based on black phosphorene (BP) for detecting NO2 molecules in an air mixture. In addition, the recovery time of the P2C2 sensor at T = 300 K was estimated to be short (and even shorter at higher temperatures) for NO2 which satisfies the demands for sustainable use. PMID- 30444232 TI - Analysis of bacteria stress responses to contaminants derived from shale energy extraction. AB - In order to survive environmental changes, bacteria have stress responses, which protect them from adverse and variable conditions. Contamination can be a source of stress and bacterial responses can serve as an indicator of environmental abnormality. In this work, the biochemical effects of toxic compounds that stem from hydraulic fracturing were measured on the whole cell-derived fatty acid and protein compositions of Escherichia coli, Klebsiella oxytoca, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Aeromonas hydrophila, Bacillus cereus, and Bacillus subtilis. These microorganisms were exposed to elevated levels of benzene, ethanol, propanol, toluene, and salt. These were chosen to represent significant subsurface contamination or a surface spill. The fatty acid and protein profiles for the bacteria were analyzed using gas chromatography - vacuum ultraviolet spectroscopy and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, respectively. Overall, different fatty acid and protein profiles were observed when the microorganisms were grown in the presence of the toxic compounds. The cells exhibited an increase in the saturated/unsaturated ratio and displayed the presence of branched and cyclopropane fatty acids when in the presence of common fracture fluid constituents to decrease membrane permeability which was confirmed by the analysis of produced water. This approach provides a potentially useful tool for environmental diagnosis, since proteins and fatty acids can act as a harbinger of ecological health. PMID- 30444233 TI - Transparent rutile TiO2 films prepared by thermal oxidation of sputtered Ti on FTO glass. AB - TiO2 films were prepared via a two-step fabrication process, i.e. deposition of Ti films by magnetron sputtering on an FTO glass substrate followed by thermal oxidation at 600-725 degrees C. The investigated parameters were Ti layer thickness, temperature of oxidation and deposition conditions (pre-treatment and substrate heating). Such TiO2 films have a rutile structure and contain metallic Sn which is the result of a thermal reaction at the interface between SnO2 and Ti at temperatures above 500 degrees C. A calcination temperature of 600 degrees C is optimal for fabricating TiO2 films with significant photoelectrochemical response. Heating of the FTO substrate during magnetron sputtering deposition of Ti films results in a significant improvement of the compactness of the TiO2 films. A similar but not so pronounced improvement was observed for the TiO2 films deposited on the FTO substrate pre-treated with radio-frequency plasma under Ar-O2 and N2-H2 atmosphere. The observed correlation between the increased content of Sn in the TiO2 films and compactness of the TiO2 films supports the explanation of both positive effects by better adhesion of the Ti films to the FTO substrate. PMID- 30444234 TI - Taiwanoids A-D, four dimeric diterpenoids featuring tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane from Taiwania cryptomerioidesim. AB - Biogenesis-inspired chemical research of the leaves of Taiwania cryptomerioides afforded four unprecedented dimeric diterpenes, featuring a tetracyclic [7. 75, 9. 4. 05, 10. 08, 9] octodecane core: taiwanoids A-D (1-4). The structures of these compounds were determined on the basis of comprehensive spectral analysis, chemical conversions and X-ray crystallography. A possible biosynthetic pathway for compounds 1-4 was proposed. Compounds 2 and 3 exerted a 5.37 and 6.26-fold potentiation effect on bortezmib (BTZ) susceptibility at a tested concentration of 20 MUM, respectively. PMID- 30444235 TI - Electrokinetic droplet transport from electroosmosis to electrophoresis. AB - Droplet transport in microfluidic channels by electrically induced flows often entails the simultaneous presence of electroosmosis and electrophoresis. Here we make use of coupled lattice-Boltzmann/molecular dynamics simulations to compute the mobility of a droplet in a microchannel under the effect of an external electric field. By varying the droplet solvation free energy of the counterions released at the channel walls, we observe the continuous transition between the electroosmotic and electrophoretic regime. We show that it is possible to describe the mobility of a droplet in a unified, consistent way, by combining the theoretical description of the electroosmotic flow with, in this case, the Huckel limit of electrophoresis, modified in order to take into account the Hadamard Rybczynski droplet drag. PMID- 30444236 TI - Do the properties of gels constructed by interlinking triply-responsive microgels follow from those of the building blocks? AB - Microgels (MGs) are swellable crosslinked polymer colloids. They can also be used as the only building block to construct nanostructured hydrogels which are denoted as doubly crosslinked microgels (DX MGs). Here, new triply responsive DX MGs comprised of interlinked MGs of oligo(ethylene glycol)methacrylate (OEGMA), 2 (2-methoxyethoxy)ethyl methacrylate (MEO2MA), methacrylic acid (MAA) and a o nitrobenzyl-based UV photocleavable crosslinker are investigated. The MGs swelled or collapsed in response to temperature and pH changes. These behaviours were rationalised with a generic model using Monte Carlo simulations. The MGs also degraded when UV irradiated due to photocleavage of nPh. DX MGs were assembled from the MGs to give injectable gels that were not cytotoxic to nucleus pulposus cells. Comparison of the responsive properties of the DX MGs and MGs showed that the temperature and pH responses of the former were mostly governed by the latter. However, two key differences were found. Firstly, whilst increasing the crosslinker mol% in the MG building blocks (x) did not change MG particle swelling, the compression modulus (E) and swelling of the DX MG gels were strongly affected by x. The E value for the gels was tuneable using x which is a potentially useful new observation for DX MGs. Secondly, UV irradiation of the DX MGs enhanced gel mechanical photostability in contrast to the behaviour of the MGs. We find that the properties of the DX MGs do not simply follow those of the parent MGs and propose mechanisms to account for the differences. The new family of multi-responsive DX MGs presented in this study have potential application for soft tissue repair as injectable gels or as gel implants which report sterilisation. PMID- 30444237 TI - Influence of polymer flexibility on nanoparticle dynamics in semidilute solutions. AB - The hierarchical structure and dynamics of polymer solutions control the transport of nanoparticles (NPs) through them. Here, we perform multi-particle collision dynamics simulations of solutions of semiflexible polymer chains with tunable persistence length lp to investigate the effect of chain stiffness on NP transport. The NPs exhibit two distinct dynamical regimes - subdiffusion on short time scales and diffusion on long time scales. The long-time NP diffusivities are compared with predictions from the Stokes-Einstein relation (SER), mode-coupling theory (MCT), and a recent polymer coupling theory (PCT). Increasing deviations from the SER as the polymer chains become more rigid (i.e. as lp increases) indicate that the NP motions become decoupled from the bulk viscosity of the polymer solution. Likewise, polymer stiffness leads to deviations from PCT, which was developed for fully flexible chains. Independent of lp, however, the long time diffusion behavior is well-described by MCT, particularly at high polymer concentration. We also observed that the short-time subdiffusive dynamics are strongly dependent on polymer flexibility. As lp is increased, the NP dynamics become more subdiffusive and decouple from the dynamics of the polymer chain center-of-mass. We posit that these effects are due to differences in the segmental mobility of the semiflexible chains. PMID- 30444238 TI - Encapsulating [Mo3S13]2- clusters in cationic covalent organic frameworks: enhancing stability and recyclability by converting a homogeneous photocatalyst to a heterogeneous photocatalyst. AB - We encapsulated anionic [Mo3S13]2- clusters in cationic COFs (EB-COF) to obtain the novel composite photocatalytic material Mo3S13@EB-COF. Comprehensive studies indicated that the Mo3S13@EB-COF was the product of a successful conversion of a homogeneous to a heterogeneous catalyst, and exhibited excellent stability and recyclability as well as a remarkable photocatalytic hydrogen evolution rate of 13 215 MUmol g-1 h-1 under visible-light irradiation over the course of 18 hours. PMID- 30444239 TI - A fumed alumina induced gel-like electrolyte for great performance improvement of lithium-sulfur batteries. AB - The practical application of high energy lithium-sulfur batteries is still limited by unstable lithium anodes and the shuttle effect of polysulfides. Herein, a gel-like electrolyte induced by fumed alumina is proposed for dendrite free Li deposition, lower over-potential and better cycle stability. Li-S@pPAN cells with the proposed electrolyte exhibit outstanding cycle stability and rate performance with capacity retentions of 95.1% after 300 cycles and 76.5% at 10C against 1C, respectively. PMID- 30444240 TI - Transformation of amorphous carbon to graphene on low-index Ni surfaces during rapid thermal processing: a reactive molecular dynamics study. AB - The transformation of amorphous carbon to graphene on different Ni surfaces during rapid thermal processing was explored using reactive molecular dynamics simulation. Due to the difference in activation energy, Ni surfaces affected the diffusion behavior of C into Ni and thus modulated the remnant number of C atoms, dominating the formation and quality of graphene, which accorded with the developed empirical equation. PMID- 30444241 TI - Tuning the electronic properties of van der Waals heterostructures composed of black phosphorus and graphitic SiC. AB - This study presents a new van der Waals (vdW) heterostructure composed of monolayer black phosphorus (BP) and monolayer graphitic SiC (g-SiC). Using first principles calculations, the structural and electronic properties of the BP/SiC heterostructure were investigated. It was found that by stacking BP with SiC, weak type-I band alignment can be achieved with a band gap of 0.705 eV, where the direct band gap as well as linear dichroism features were well preserved. The electrostatic potential drop in the heterojunction was calculated to be 4.044 eV. By applying perpendicular electric field, the band alignment can be altered to either type-I or type-II, and the band gap can be effectively controlled by field intensity, hence making the heterostructure suitable for various applications. PMID- 30444242 TI - Differential steric effects in the inelastic scattering of NO(X) + Ar: spin-orbit changing transitions. AB - Spin-orbit changing transitions for bond-axis oriented collisions of NO(X) with Ar have been investigated with full quantum state selection via a crossed molecular beam experiment at collision energies of 532 cm-1 and 651 cm-1. NO(X) molecules were selected in their ground rotational state (Omega = 0.5, j = 0.5, f) before being adiabatically oriented using a static electric field, such that either the N- or O-end of the molecule was directed towards the incoming Ar atom. After collision, NO(X, Omega' = 1.5, j', e) molecules were probed quantum state specifically using velocity-map ion imaging, coupled with resonantly enhanced multi-photon ionization. Differences were observed between the experimental ion images and differential cross sections for collisions occurring at the two ends of the molecule, with results that could largely be accounted for by quantum mechanical scattering calculations. The bond-axis oriented data for the spin orbit changing collisions are compared with similar results obtained previously for spin-orbit conserving transitions, and for field free scattering of NO(X) with Ar. PMID- 30444243 TI - Expanding the chemistry of ring-fused 1,4-diphosphinines by stable mono anion formation. AB - A new sulfur-enriched tricyclic 1,4-diphosphinine (2) was synthesized and novel reactivity studies on the phosphorus heterocycle were performed: a weak anionic nucleophile (KHMDS) adds selectively thus forming a stable anionic 1,4 diphosphinine derivative (3b) which was fully characterized. The substitution potential of 3b was demonstrated using Ph2PCl to give 4b, while oxidation of 3b using elemental iodine furnished cleanly the P-P coupling product 5. PMID- 30444244 TI - A molecular dynamics model for glycosylphosphatidyl-inositol anchors: "flop down" or "lollipop"? AB - We present a computational model of glycosylphosphatidyl-inositol (GPI) anchors for molecular dynamics studies. The model is based on state-of-the-art biomolecular force fields from the AMBER family, employing GLYCAM06 for carbohydrates and Lipid14 to represent fatty acid tails. We construct an adapted glycero-phosphatidyl-inositol unit to establish a seamless transition between the two domains of atom types. This link can readily be extended into a broad variety of GPI variants by applying either domain's building block scheme. As test cases, selected GPI fragments inserted into DMPC and POPC bilayer patches are considered. Our results suggest that the glycan part of the GPI anchor interacts strongly with the lipid head groups, partially embedding the carbohydrate moieties. This behaviour is supported by the conformational preferences of the GPI anchor, which in particular are conveyed by the strong interactions between the proximal amine and phosphate groups. In a similar way we can conclude that the extension of the anchor away from the lipid bilayer surface that could prevent the contact of the membrane with an attached protein ("lollipop picture") is quite unfavorable. Indeed, when attaching green fluorescent protein to the GPI anchor, it is found to reside close to bilayer surface all the time, and the rather flexible phosphoethanolamine linker governs the extent to which the protein directly interacts not only with the head groups, but also with its own GPI core. PMID- 30444245 TI - Retro-metal-ene versus retro-Aldol: mechanistic insight into Rh-catalysed formal [3+2] cycloaddition. AB - Theoretical calculations have been performed to investigate the mechanism and stereoselectivity of rhodium-catalysed intramolecular [3+2] cycloaddition for construction of a substituted hexahydropentalene complex. A new C-C bond cleavage mechanism, retro-Aldol-type, is proposed and verified for this Rh-catalysed [3+2] cycloaddition reaction. PMID- 30444246 TI - Symmetrical and unsymmetrical diphosphanes with diversified alkyl, aryl, and amino substituents. AB - We present the comprehensive study of diphosphanes with diversified substituents regarding their syntheses, structures, and properties. To this end, we have synthesized a series of novel unsymmetrical alkyl, aryl and amino-substituted diphosphanes of the general formula R1R2P-PR3R4 (where R1, R2, R3, R4 = tBu, Ph, Et2N or iPr2N) via a salt metathesis reaction of halophosphanes with metal phosphides in high yield. We vastly expanded this group of compounds by obtaining the first mono- and tri-amino-substituted systems. The structures of the isolated compounds were characterized by NMR spectroscopy and X-ray diffraction. The isolated unsymmetrical diphosphanes have no tendency to rearrange to the corresponding symmetrical species. Additionally, we proposed the general classification of diphosphanes based on the number of different groups attached to phosphorus atoms and their distribution within a molecule. To investigate the impact of substituents on the properties of P-centers and a molecule as a whole, we conducted a DFT study on the electronic and steric properties of the obtained systems. The experimental and theoretical results can be very useful for designing P-P systems with desired properties. PMID- 30444247 TI - Alumina: discriminative analysis using 3D correlation of solid-state NMR parameters. AB - Synthetic transition aluminas (chi, kappa, theta, gamma, delta, eta, rho) exhibit unique adsorptive and catalytic properties leading to numerous practical applications. Generated by thermal transformation of aluminium (oxy)hydroxides, structural differences between them arise from the variability of aluminium coordination numbers and degree of dehydroxylation. Unequivocal identification of these phases using X-ray diffraction has proven to be very difficult. Quadrupolar interactions of 27Al nuclei, highly sensitive to each site symmetry, render advanced 27Al solid-state NMR a unique spectroscopic tool to fingerprint and identify the different phases. In this paper, 27Al NMR spectroscopic data on alumina reported in literature are collected in a comprehensive library. Based on this dataset, a new 3D correlative method of NMR parameters is presented, enabling fingerprinting and identification of such phases. Providing a gold standard from crystalline samples, this approach demonstrates that any sort of crystalline, ill crystallized or amorphous, mixed periodic or aperiodically ordered transition alumina can now be assessed beyond the current limitations of characterisation. Adopting the presented approach as a standard characterisation of alumina samples will readily reveal NMR parameter-structure-property relations suitable to develop new or improved applications of alumina. Methodological guidance is provided to assist consistent implementation of this characterisation throughout the fields involved. PMID- 30444248 TI - Inducing the distinctly different fluorescence properties of a tetraphenylethene (TPE) derivative modified lanthanide nanowire upon the addition of a pair of cis- and trans-isomers of fatty acids. AB - A simple layer-by-layer approach has been developed to introduce a 3,5 dicarboxylphenoxy decorated tetraphenylethene derivative (denoted as TPE-2COOH) into a lanthanide nanowire. Interestingly, the aggregation-induced emission (AIE) was turned on by loading the negative TPE-2COOH on the positive surface of the nanowire via electrostatic interactions. More excitingly, these synthesized composite nanowires exhibit significantly different fluorescence properties in the presence of a pair of cis- and trans-isomers of fatty acids (oleic acid and elaidic acid). The obvious emission peak (382 nm) upon the addition of oleic acid (cis-configuration) was observed, which was consistent with that of the frozen diluted TPE-2COOH solution (1.95 * 10-10 mol L-1), demonstrating the occurrence of the monomer emission of TPE-2COOH. When the oleic acid with a special cis configuration got close to the nanowire, it substituted some TPE-2COOH and arranged as cages on the surface to isolate the TPE-2COOH molecule, leading to the monomer emission. Different from such monomer emission induced by oleic acid, an attenuated aggregate emission was detected by the addition of its trans isomer elaidic acid, because it is almost impossible for the elaidic acid with a linear structure to form the cage-like shape on the surface during the substitution process. It was found for the first time that the fluorescence of such a TPE based material can be controlled by the configuration of isomers. This discovery may provide a facile strategy to design and synthesize more promising candidates for TPE-based fluorescent sensors. PMID- 30444249 TI - Cation-specific interactions of protein surface charges in dilute aqueous salt solutions: a combined study using dielectric relaxation spectroscopy and Raman spectroscopy. AB - We exploited glycine as a zwitterionic model system to experimentally probe the cation specific interaction of protein surface charges in dilute (<=0.25 mol L-1) aqueous solutions of four biologically relevant inorganic salts, NaCl, KCl, MgCl2 and CaCl2, via dielectric relaxation spectroscopy (DRS) and Raman spectroscopy. Glycine is the simplest building block of proteins and it exposes the same charged groups (carboxylate and ammonium) to the solvent that dominate the protein-water interface. As a counter ion, we selected Cl- due to its biological importance. For all systems, we performed simultaneous fitting of the real (epsilon') and imaginary (epsilon") parts of the dielectric functions, assuming a multimodal relaxation model, obtained from concentration dependent dielectric measurements at ~293 K. We observe a reduction of the dielectric amplitude for the glycine relaxation while the corresponding time constant shows only small (<7%) deviations compared to aqueous glycine solutions. We propose that the observed reduction in dielectric amplitude is due to a reduction of the effective dipole moment (ueff) of zwitterionic glycine caused by the interaction of glycine with the ion even at very low (0.05 M) salt concentrations. The interaction between divalent metal ions and zwitterionic glycine is increased compared to the monovalent cation-zwitterion interaction; a finding that is also supported by Raman spectroscopy. Our combined dielectric relaxation and Raman spectroscopic study indicates that ion-glycine interactions are weak and mediated by the solvent. Cation-specificity of protein surface charges is also observed in dilute salt solutions (<=0.25 mol L-1), where electrostatic interactions dominate. PMID- 30444250 TI - Recent advances in one-dimensional assembly of nanoparticles. AB - Compared with 2D or 3D assembly models, 1D assembly of functional nanoparticles (NPs) is more difficult to prepare due to its higher surface energy. Despite the fabrication difficulty, 1D assembly of NPs exhibits many unique properties, and can directionally transport excitons, photons, phonons, etc., which generate great interest in considerable applications in biomedicine, data storage, waveguiding, highly sensitive sensors, color displays, microcircuits and others. The unique features of 1D assembly of NPs can bridge fabrication of NPs with their practical device applications. The aim of this Tutorial Review is to introduce the general mechanisms to assemble NPs in one direction. To achieve 1D assembly of NPs, different kinds of traditional and newly developed assembly strategies will be discussed. Finally, some examples will be demonstrated to illustrate the applications of NP 1D assemblies in the fields of optics, electronics and magnetics. PMID- 30444252 TI - From CO2 methanation to ambitious long-chain hydrocarbons: alternative fuels paving the path to sustainability. AB - The clean and sustainable CO2 reutilization toward products of higher value is of great interest in a background of established environmental concerns and reducing the use of fossil fuels. As promising alternative fuels, hydrocarbons are more valuable than CO, alcohols or formate and can be directly used in existing infrastructures with high energy densities. The prominent development of catalysts capable of selectively converting CO2 into hydrocarbons, from methane to short olefins and long carbon-chains, has been reflected in an expanding volume of exploratory works, which suitably demand interpretive and continuous revision. In the past decades, conventional studies on the thermochemical conversion of CO2 have consistently unlocked meaningful pathways toward the synthesis of hydrocarbons covering a fairly wide range of molecular weights. Conversely, both electrochemically and photochemically driven reactions have only now started to unveil encouraging results, with an extensive number of critical citations outlining the continuous emergence of very recently published reports. In a field in need of urgent development, the authors provide, in a clear form, a detailed retrospective on benchmark catalysts, pioneering approaches and competitive developments in this subject, mechanistic difficulties, emerging stability issues, and reactor design, while highlighting the latest noteworthy reports. Most importantly, this review highlights the advances toward an increase in the hydrocarbon chain-length in the synthesis of highly competitive alternative fuels. Comparisons of valuable thermochemical, electrochemical and photochemically driven strategies in the conversion of CO2 to hydrocarbons are expected to serve as guidelines to disclose promising pathways in a field where mechanistic uncertainties remain a bottleneck for determining the product selectivity. The authors summarize leading and inquisitive perspectives with a focus on the viability and practicability of each approach at a larger scale, while tentatively paving the way to stimulate progress in this field. PMID- 30444253 TI - Nature of cucurbituril-halogen encapsulation. Structural and interaction energy consideration in the X2@CB[n] (X = Cl, Br, I, n = 6, 7, 8) from relativistic DFT calculations. AB - The formation of host-guest species is a relevant issue in the obtaining of supramolecular arrays. In this work, the encapsulation of dihalogen molecules into different cucurbituril hosts allows further evaluation of the role of size and interaction energy for the stabilization of host-guest species. Our results for the X2@CB[n] (X = Cl, Br, I, n = 6, 7, 8) series, allow exploration of the hosts providing increasing cavity sizes, resulting in different host-guest scenarios. It is found that the interaction is mostly given by London type interactions (59% to 65%), followed by the electrostatic character of the interaction (31-27%). For species with a packing coefficient (PC) within the suggested favorable range (PC = 55-68%), and lower, the strength of the stabilizing electrostatic interaction and covalent character, and the repulsive Pauli term, remain similar. Moreover, the dispersion term varies to a large extent, owing to its relation to the available interacting internal face of CB[n], which is less in n = 7 and 8 counterparts. Hence, greater host flexibility is able to maximize the host-guest interactions, where this feature can be viewed as an interesting characteristic towards molecular recognition capabilities, which can be further studied in other related species such as cyclodextrins, pillararenes and other supramolecular hosts. PMID- 30444251 TI - Targeting small molecule drugs to T cells with antibody-directed cell-penetrating gold nanoparticles. AB - We sought to develop a nanoparticle vehicle that could efficiently deliver small molecule drugs to target lymphocyte populations. The synthesized amphiphilic organic ligand-protected gold nanoparticles (amph-NPs) were capable of sequestering large payloads of small molecule drugs within hydrophobic pockets of their ligand shells. These particles exhibit membrane-penetrating activity in mammalian cells, and thus enhanced uptake of a small molecule TGF-beta inhibitor in T cells in cell culture. By conjugating amph-NPs with targeting antibodies or camelid-derived nanobodies, the particles' cell-penetrating properties could be temporarily suppressed, allowing targeted uptake in specific lymphocyte subpopulations. Degradation of the protein targeting moieties following particle endocytosis allowed the NPs to recover their cell-penetrating activity in situ to enter the cytoplasm of T cells. In vivo, targeted amph-NPs showed 40-fold enhanced uptake in CD8+ T cells relative to untargeted particles, and delivery of TGF-beta inhibitor-loaded particles to T cells enhanced their cytokine polyfunctionality in a cancer vaccine model. Thus, this system provides a facile approach to concentrate small molecule compounds in target lymphocyte populations of interest for immunotherapy in cancer and other diseases. PMID- 30444254 TI - Facile in situ generation of highly active (arylimido)vanadium(v)-alkylidene catalysts for the ring-opening metathesis polymerization (ROMP) of cyclic olefins by immediate phenoxy ligand exchange. AB - Highly active catalysts for the ring-opening metathesis polymerization (ROMP) of cyclic olefins (norbornene, cyclopentene, cycloheptene) can be generated in situ by premixing V(CHSiMe3)(NC6F5)(O-2,6-iPr2C6H3)(PMe3)2 (1) with 1.0 equiv. of C6F5OH or C6Cl5OH via the immediate phenoxy exchange; the activity was affected by the kind of phenol added [activity (TOF) in the ROMPs of norbornene: 46 200 min-1 (upon addition of C6F5OH) vs. 37.3 min-1 (by 1)]. PMID- 30444255 TI - Cu(i) coordination polymers (CPs) as tandem catalysts for three-component sequential click/alkynylation cycloaddition reaction with regiocontrol. AB - To expand coordination polymers (CPs) as solid catalysts to selectively catalyze the three-component tandem click/alkynylation reaction for their fully substituted triazole skeletons, two Cu(i)-based CPs (CuI-CPs), [CuBr(aas-TPB)]n (1) and [Cu3I3(aas-TPB)2]n (2) (TPB = N,N,N-tri(3-pyridinyl)-1,3,5 benzenetricarboxamine), have been prepared. Because of the template effect of anions (Br- and I-), the structure of compounds is regulated under solvothermal conditions. CP 1 exhibited a one-dimensional (1D) chain, while the double strand framework with the Cu3I3 cluster platform was observed in 2. Furthermore, the different product selectivities of catalyzing terminal alkynes, benzyl azide and bromoalkyne to synthesize triazole skeletons have been caused by the significantly structural diversity of 1 and 2. The distinct structural feature of 2 endows it with unique multinuclear platforms (Cu3I3) and reaction pathways to promote the three-component tandem click/alkynylation cycloaddition reaction. As a result, 2 can be an outstanding catalyst candidate for sequential click/alkynylation cycloaddition, while 1 can efficiently catalyze the generation of click products. PMID- 30444256 TI - Self-healing cellulose nanocrystal-stabilized droplets for water collection under oil. AB - The removal of small water droplets from oils is imperative because oils can easily be contaminated or deteriorated by water during transportation, storage and usage. Here, we report superhydrophobic magnetic cellulose nanocrystal (CNC) nanoparticles, which are capable of removing tiny water droplets from oil by forming under oil particle-stabilized droplets. These particle-stabilized droplets can be collected and moved by a magnetic force, and self-healed upon damage by an external force. PMID- 30444257 TI - The Silesian Registry of Out-of-Hospital Cardiac Arrest: Study design and results of a three-month pilot study. AB - BACKGROUND: Despite the introduction of the concept known as "Chain of Survival" has significantly increased survival rates in patients with out-of-hospital cardiac arrest (OHCA), short-term mortality in this group of patients is still very high. Epidemiological data on OHCA in Poland are limited. The aim of this study was to create a prospective registry on OHCA covering a population of 2.7 million inhabitants of Upper Silesia in Poland. Presented herein is the study design and results of a three-month pilot study. METHODS: The Silesian Registry of Out-of-Hospital Cardiac Arrest (SIL-OHCA) is a prospective, population-based registry of OHCA, of minimum duration which took 12 months; from January 1st ,2018 to December 31st ,2018. The first 3 months of the study constituted the pilot phase. The inclusion criterion is the occurrence of OHCA in the course of activity of the Voivodeship Rescue Service in the city of Katowice, Poland. RESULTS: During the 3-month pilot phase of the study there were 390 cases of OHCA in which cardiopulmonary resuscitation was undertaken. Estimated frequency of OHCA in the population analyzed was 57 per 100,000 population per year. Shockable rhythm was present in 25.8% of cases. Return of spontaneous circulation was achieved in 35.1% of the whole cohort. 28.7% of patients were admitted to the hospital, including 2.8% of patients, who were admitted during an ongoing cardiopulmonary resuscitation. CONCLUSIONS: Prehospital survival of patients with OHCA in Poland is still unsatisfactory. It is believed that data collected in SIL OHCA registry will allow identification factors, which require improvement in order to reduce short- and long-term mortality of patients with OHCA. PMID- 30444258 TI - Reproducibility of optical coherence tomography in vein grafts used for coronary revascularization. AB - BACKGROUND: Optical coherence tomography (OCT) is a high-resolution imaging modality able to provide near-histological images of vessel walls making it possible to distinguish intima and media layers of the vessel wall separately. The use of this imaging technique is increasing while data on the variability and reliability is lacking. The aim of this study was to investigate the reproducibility of frequency-domain OCT in vein grafts used for coronary revascularization. METHODS: Five pullbacks were analyzed by the same analyst with a 1-month delay (intraobserver) and by two different analysts (interobserver). Five pairs of pullbacks from the same catheters and vein graft were also analyzed (inter pullback). RESULTS: Optical coherence tomography showed low variability in intra- and interobserver analysis with relative differences of mean media and intima thicknesses and areas of less than 5% for most parameters. Relative differences of the same parameters in the inter pullback analysis were in the 5 15% range. Intra- and interobserver reliability was excellent (intraclass correlation coefficient [ICC] > 0.90) for intima thickness and intima, media and intima-media area measurements. Inter pullback reliability was good (ICC: 0.75 0.90) for intima and intima-media area measurements, and moderate to good for mean intima thickness measurements (ICC: 0.79; 0.7338-0.8284). CONCLUSIONS: Optical coherence tomography provides good reproducibility for the measurements of parameters relevant for the development of atherosclerosis in vein grafts. CLINICAL TRIAL REGISTRATION: ID NCT01834846. PMID- 30444259 TI - Influence of QRS duration and axis on response to cardiac resynchronization therapy in chronic heart failure with reduced left ventricular ejection fraction: A single center study including patients with left bundle branch block. AB - BACKGROUND: The aim of the study was to evaluate QRS duration and axis as predictors of response to cardiac resynchronization therapy (CRT) in order to reduce the proportion of non-responders. METHODS: Retrospective single-center study including 42 CRT recipients, with left bundle branch block (LBBB), left ventricular ejection fraction (LVEF) < 40%, in New York Heart Association (NYHA) class >= II. Response to CRT was declared as NYHA class improvement >= 1 (symptomatic) and LVEF improvement by >= 10% (echocardiographic) > 6 months post implantation. RESULTS: Symptomatic responders had longer pre- (172.3 +/- 17.9 vs. 159.0 +/- 18.3 ms; p = 0.027) and postimplantation (157.2 +/- 24.1 vs. 136.7 +/- 23.2 ms; p = 0.009) QRS duration. Preimplantation QRS < 150 ms predicted poor response (OR for response vs. lack of response 0.04; 95% CI 0.001-0.74). Predictors of symptomatic response included: postimplantation QRS > 160 ms (OR 7.2; 95% CI 1.24-41.94), longer QRS duration before (OR for a 1 ms increase 1.04, 95% CI 1.00-1.08) and post implantation (OR for a 1 ms increase 1.04; 95% CI 1.01 1.07). Area under the curve (AUC) for pre- and postimplantation QRS duration was 0.672 (95% CI 0.51-0.84) and 0.727 (95% CI 0.57-0.89), respectively, with cut-off points of 178.5 ms and 157 ms. For post implantation QRS axis, AUC was 0.689 (95% CI 0.53-0.85), with cut-off points of -60.5 degrees or -38.5 degrees . Preimplantation QRS axis was the only predictor of echocardiographic response (OR 0.98; 95% CI 0.96-1.00), with AUC of 0.693 (95% CI 0.54-0.85) and a threshold of 36 degrees . CONCLUSIONS: Marked pre- and postimplantation QRS prolongation and preimplantation negative QRS axis deviation are moderate predictors of response to CRT. PMID- 30444261 TI - Cutaneous squamous cell carcinoma metastasis to the parotid region lymph nodes. AB - OBJECTIVE: To determine the effect on survival of periauricular region cutaneous squamous cell carcinomas (cSCC) metastasizing to parotid region and cervical lymph nodes. METHODS: From May 1995 to October 2013, consecutive patients with cSCC undergoing parotidectomy/neck dissection >= 18 years without distant metastasis were included. Demographic, clinical, and pathologic data were analyzed. Uni- and multivariate analyses of disease-specific survival and overall survival were performed. Statistical significance was set at P < 0.05. RESULTS: We evaluated 137 patients. Most patients were Caucasian males with an average age of 71.6 years. The median follow-up time was 29.4 months. Thirty-six percent of patients had pathological evidence of cervical metastasis (N+). Seven percent had metastasis to level I, 21.9% to level II, 14.6% to level III, 8% to level IV, and 9.5% to level V. Thirty-nine percent of patients had metastasis to parotid region (P+). The average number of positive:total nodes from parotidectomy was 1.9:4.6. The median overall and disease-specific survival times were 2.81 and 1.96 years, respectively. Patients with either neck or parotid metastasis (N + or P+) had significantly decreased survival, hazard ratio 2.298 (1.2739, 4.1445), compared to patients without metastasis (N0P0), P < 0.0057. CONCLUSION: Patients with periauricular region cSCC metastasizing to parotid and cervical regions lymph nodes have significantly decreased survival compared with patients without cervical and/or parotid metastasis. Metastasis to parotid region should be considered as a distinct head and neck level when staging periauricular cancers. This study provides a basis for further studies to validate these findings. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30444260 TI - Comparison of outcome in dogs undergoing single-incision laparoscopic-assisted intestinal surgery and open laparotomy for simple small intestinal foreign body removal. AB - OBJECTIVE: To evaluate and compare outcome in dogs that underwent single-incision laparoscopic-assisted intestinal surgery (SILAIS) and open laparotomy (OL) for simple foreign body removal. STUDY DESIGN: Retrospective study. ANIMALS: Twenty eight client-owned dogs that underwent SILAIS (n = 13) or OL (n = 15). METHODS: Foreign body removal via SILAIS was performed with a commercially available single-port device. After laparoscopic evaluation, a wound retraction device (WRD) was inserted. The small intestine was extracorporeally explored, and foreign body removal was performed. The surgeon's hand was inserted through the WRD to palpate portions of the gastrointestinal tract not able to be extracorporeally evaluated. Open laparotomy with foreign body removal was performed via a ventral midline approach. Medical records were retrospectively reviewed, and perioperative data were collected. Follow-up data were collected with a standardized questionnaire with the referring veterinarian and/or owner via telephone interview. RESULTS: No postoperative complications were encountered in either the SILAIS or the OL group, and all dogs were successfully discharged from the hospital. Conversion from SILAIS to OL occurred in 3/13 cases. There was no significant difference in duration of hospitalization, duration of time to recovery, or surgical time between surgical approaches (SILAIS vs OL). CONCLUSION: Single-incision laparoscopic-assisted intestinal surgery for foreign body removal was not significantly different from OL in a variety of outcome measures in this cohort of dogs. Diagnostic imaging including ultrasonography or computed tomography may improve appropriate case selection for SILAIS for simple foreign body removal. CLINICAL SIGNIFICANCE: Single-incision laparoscopic assisted intestinal surgery offers a minimally invasive technique for simple small intestinal foreign body removal. Additional study is required to compare SILAIS with OL. PMID- 30444262 TI - Minimally invasive percutaneous medial plate-rod osteosynthesis for treatment of humeral shaft fractures in dog and cats: Surgical technique and prospective evaluation. AB - OBJECTIVE: To describe and prospectively report outcomes associated with a novel minimally invasive percutaneous osteosynthesis (MIPO) technique for the treatment of humeral fractures in dogs and cats. STUDY DESIGN: Prospective clinical case series. ANIMALS: Eleven dogs and 4 cats with traumatic nonarticular humeral fractures. METHODS: Dogs and cats that presented with traumatic humeral fractures were enrolled in the study. After closed reduction, the fracture was stabilized by using a plate-rod combination applied via remote medial incisions. Postoperative alignment in the frontal and sagittal planes was statistically compared with the contralateral limbs. Time to clinical union and complications were also recorded. RESULTS: Eleven dogs and 4 cats were included in this study. Body weight ranged from 4.5 to 33.6 kg in dogs and from 2.2 to 3.6 kg in cats. A veterinary cuttable plate (6/11 dogs and 3/4 cats) or locking compression plate was used in a plate-rod configuration (11/11 dogs and 2/4 cats) or alone (2/4 cats). Rod-to-medullary-cavity ratio was 30%. Plate-span ratio was 5.8 (range, 2 13.5). No significant differences were found in frontal or sagittal plane alignment. Healing time in cases that completed on-time follow-up (12/15) was 36 +/- 14 days (range, 20-69). No major complications were recorded. CONCLUSION: The reported technique was associated with good outcomes in a large variety of fracture configurations and animal sizes, with no complications. CLINICAL SIGNIFICANCE: This report provides evidence that MIPO is a compelling alternative to open reduction and internal fixation in the treatment of various humeral fractures. PMID- 30444263 TI - Mitogen-Activated Protein Kinase Signaling Mediates Opioid-induced Presynaptic NMDA Receptor Activation and Analgesic Tolerance. AB - Opioid-induced hyperalgesia and analgesic tolerance can lead to dose escalation and inadequate pain treatment with MU-opioid receptor agonists. Opioids cause tonic activation of glutamate NMDA receptors (NMDARs) at primary afferent terminals, increasing nociceptive input. However, the signaling mechanisms responsible for opioid-induced activation of presynaptic NMDARs in the spinal dorsal horn remain unclear. In the present study, we determined the role of mitogen-activated protein kinase (MAPK) signaling in opioid-induced presynaptic NMDAR activation caused by chronic morphine administration. Whole-cell recordings of excitatory postsynaptic currents (EPSCs) were performed on dorsal horn neurons in rat spinal cord slices. Chronic morphine administration markedly increased the frequency of miniature EPSCs, increased the amplitude of monosynaptic EPSCs evoked from the dorsal root, and reduced the paired-pulse ratio of evoked EPSCs. These changes were fully reversed by an NMDAR antagonist and normalized by inhibiting extracellular signal-regulated kinase 1/2 (ERK1/2), p38, or c-Jun N terminal kinase (JNK). Furthermore, intrathecal injection of a selective ERK1/2, p38, or JNK inhibitor blocked pain hypersensitivity induced by chronic morphine treatment. These inhibitors also similarly attenuated a reduction in morphine's analgesic effect in rats. In addition, co-immunoprecipitation assays revealed that NMDARs formed a protein complex with ERK1/2, p38, and JNK in the spinal cord and that chronic morphine treatment increased physical interactions of NMDARs with these three MAPKs. Our findings suggest that opioid-induced hyperalgesia and analgesic tolerance are mediated by tonic activation of presynaptic NMDARs via three functionally interrelated MAPKs at the spinal cord level. This article is protected by copyright. All rights reserved. PMID- 30444264 TI - Voice therapy associated with a decrease in the reflux symptoms index in patients with voice complaints. AB - OBJECTIVES/HYPOTHESIS: Patients with muscle tension dysphonia often demonstrate an elevation in Reflux Symptom Index (RSI) and 10-item Voice Handicap Index (VHI 10) scores, and may be erroneously diagnosed with laryngopharyngeal reflux disease. In this study we assessed the effects of voice therapy on RSI and VHI-10 scores in patients with voice complaints not responsive to antireflux medications. STUDY DESIGN: Retrospective cohort study. METHODS: A study of patients was conducted at a single tertiary-care center over 1 year (January 2012 January 2013). Patients were included if they had dysphonia not responsive to proton pump inhibition, did not have neurologic or neoplastic disease, and participated in at least three voice-therapy sessions in the absence of antireflux therapy. Primary analysis assessed change in RSI scores between the initial and follow-up visits with a laryngologist. RESULTS: A total of 18 patients were included (mean age = 49.9 +/- 14.5 years, 89% female, 83% with a primary complaint of dysphonia). From initial to follow-up visit, the median RSI score (18.5 [interquartile range {IQR}, 9.5-22.8] vs. 10.5 [IQR, 4.5-14]; P = .02) and median VHI-10 score (25.5 [IQR, 11.3-30.0] vs. 13.5 [IQR, 9.5-20.8]; P = .03) significantly decreased. A significant inverse correlation was found between the number of voice therapy sessions/month and change in RSI score (r = -0.4; P = .05). CONCLUSIONS: In this study of patients with muscle tension dysphonia or vocal hyperfunction not responsive to antireflux therapy, RSI and VHI-10 scores improved following voice therapy. Results suggest that self-reported symptoms typically attributed to laryngopharyngeal reflux disease may actually be secondary to inefficient voice use patterns or anxiety about dysphonia that are responsive to voice therapy. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30444265 TI - A Density Functional Theory Study on Nonlinear Optical Properties of Double Cage Excess Electron Compounds: Theoretically Design M[Cu(Ag)@(NH3 )n ](M = Be, Mg and Ca; n = 1-3). AB - In this work, we investigated the nonlinear optical (NLO) properties of excess electron electride molecules of M[Cu(Ag)@(NH3 )n ](M = Be, Mg and Ca; n = 1-3) using density functional theory (DFT). This electride molecules consist of an alkaline-earth (Be, Mg and Ca) together with transition metal (Cu and Ag) doped in NH3 cluster. The natural population analysis of charge and their highest occupied molecular orbital suggests that the M[Cu(Ag)@(NH3 )n ] compound has excess electron like alkaline-earth metal form double cage electrides molecules, which exhibit a large static first hyperpolarizability ( beta0e ) (electron contribution part) and one of which owns a peak value of beta0e 216,938 (a.u.) for Be[Ag@(NH3 )2 ] and vibrational harmonic first hyperpolarizability ( betazzznr ) (nuclear contribution part) values and the ratio of betazzznr / betazzze , namely, eta values from 0.02 for Be[Ag@(NH3 )] to 0.757 for Mg[Ag@(NH3 )3 ]. The electron density contribution in different regions on betazzze values mainly come from alkaline-earth and transition metal atoms by first hyperpolarizability density analysis, and also explains the reason why betazzze values are positive and negative. Moreover, the frequency-dependent values beta( 2omega,omega,omega) are also estimated to make a comparison with experimental measures. (c) 2018 Wiley Periodicals, Inc. PMID- 30444266 TI - Assessment of Peripheral Nerves With Shear Wave Elastography in Type 1 Diabetic Adolescents Without Diabetic Peripheral Neuropathy. AB - OBJECTIVES: To investigate the utility of shear wave elastography (SWE) in detecting morphologic abnormalities of the median nerve and posterior tibial nerve in transverse and longitudinal axes in adolescents with type 1 diabetes mellitus (DM) without diabetic peripheral neuropathy (DPN). METHODS: The median nerves and posterior tibial nerves of 25 adolescents with diagnosis and follow-up of type 1 DM without DPN and 32 healthy volunteers were evaluated with SWE by 2 observers on the transverse and longitudinal axes. The cross-sectional area and thickness of the nerves and disease duration were noted, and probable associations of these parameters with SWE features were analyzed. Interobserver and intraobserver correlations were also examined. The statistical significance level was set at P < .05. RESULTS: Both the median nerve and posterior tibial nerve were smaller, thinner, and stiffer in the patient group for both observers on both axes. The disease duration weakly correlated with median nerve SWE features (r = 0.245-0391). The thickness and cross-sectional area had no correlations with SWE features. CONCLUSIONS: The median nerve and posterior tibial nerve in adolescents with type 1 DM without DPN have morphologic abnormalities that can be displayed by SWE regardless of the imaging axis. Shear wave elastography may have a potential role in subclinical DPN, but the reliability of the findings is not as high as desirable. PMID- 30444267 TI - Shaved hair style scalp medical tattooing technique for treatment of advanced male pattern baldness patients. AB - BACKGROUND: The most infallible approach to male pattern baldness (MPB) is hair transplantation in the thinning area in parallel to medical treatment to prevent further alopecia progression. For an individual with advanced stage hair loss, a megasession surgery is recommended to meet the high donor hair requirement. Yet a most effective therapeutic regimen for alopecia, hair transplantation inevitably has its advantages and disadvantages for it is done with the expense of donor hair sacrifice, intraoperative and postoperative pain, and unavoidable scars. Also, with poor donor condition, surgery may not even be an option. Nowadays, more patients with such limitations are undergoing shaved style scalp medical tattoo (SMT). OBJECTIVE: To assess the effectiveness of SMT technique for shaved hair style. METHODS AND MATERIALS: A total of 80 patients who were included in the study underwent SMT for shaved hair style between June 2014 and June 2017 and were followed for at least 6 months afterward. Patients and the surgeon completed a survey about donor and recipient site surgical results using a 5-point Likert scale. RESULTS: The average satisfaction scores of patients and surgeon were 4.8 and 4.9, respectively. CONCLUSION: Shaved style SMT can be considered one of the most effective treatment methods for patients with advanced stage hair loss. LEVEL OF EVIDENCE: IV. PMID- 30444268 TI - Missed outpatient appointments and unplanned healthcare: the real question is 'why'? PMID- 30444269 TI - Cognitive Behavioral Therapy for Pediatric Headache and Migraine: Why to Prescribe and What New Research Is Critical for Advancing Integrated Biobehavioral Care. AB - PURPOSE OF REVIEW: To highlight current evidence supporting the prescription of cognitive behavioral therapy (CBT) as part of first-line preventive treatment for children and adolescents with headache and discuss a research strategy aimed at: (1) understanding how and why CBT works, and (2) developing effective and efficient approaches for integrating CBT into headache specialty, neurology, and primary care settings. RECENT FINDINGS: Although preventive medications for pediatric headache and migraine are commonly prescribed, recent meta-analyses and an NIH-funded, multi-center clinical trial suggests that the effect of pill taking therapies may be mostly due to a placebo effect. These findings have led to greater consideration of prescription of non-pharmacological therapies as first-line interventions (either alone or in combination with pill-based therapy). A literature that extends back to the 1980s and includes recent clinical trials and meta-analyses demonstrates that CBT decreases headache frequency and related disability in youth with headache and migraine and has a favorable benefit to risk profile with almost no negative side effects. SUMMARY: CBT has been repeatedly demonstrated as effective in treating pediatric headache and migraine. As such, it should be considered as part of first-line preventive treatment for pediatric headache (either alone or in combination with a pill based therapy). We need to better understand how this therapy works and what makes it distinct (if anything) from the placebo effect. What we need to achieve is empirical support for efficient access to this evidence-based treatment and clarity on how to match the intensity of non-pharmacological intervention to the needs of our patients at the time they present for care. PMID- 30444270 TI - How socio-economic disadvantage modifies health outcomes in children with cerebral palsy. PMID- 30444271 TI - Proanthocyanidins with a Low Degree of Polymerization are Good Inhibitors of Digestive Enzymes Because of their Ability to form Specific Interactions: A Hypothesis. AB - Inhibition of target digestive enzymes is an accepted strategy to prevent diseases such as obesity and diabetes. Proanthocyanidins (PACs) are known for their ability to bind, inhibit, and precipitate enzymes, which makes them potential bioDrugs with an impact on the digestive process. PAC degree of polymerization (DP) is one of the structural features responsible for their differential inhibitory potency but the explanation for this phenomenon is still unclear. Pecan nut (Carya illinoinensis L.) kernels and nutshells are rich in oligomeric and polymeric PACs. We have used thiolysis and HPLC analyses to propose four theoretical model structures of PACs representative of four semipurified fractions obtained from pecan kernel and shell, which showed different inhibitory activity against intestinal lipases, amylases, and proteases. The noncovalent interactions between PACs and digestive enzymes were predicted by in silico methods through computational software. These observations are discussed in view of current literature on the biological effects of PACs with different DPs and allowed us to propose the hypothesis that "small oligomeric PACs could be digestive enzyme inhibitors due to their capacity to enter and bind the enzymes' specific cavities better than polymers and oligomers of medium and high molecular weight." PMID- 30444272 TI - A stochastic microstructure model for particle reinforced aluminium matrix composites. AB - Metal matrix composites are complex materials consisting of various phases which can display largely different mechanical properties. The deformation behaviour of these composites cannot be sufficiently modelled by averages or simple particle shapes due to the local stresses that occur on the particle edges. Therefore, a sophisticated model of the microstructure is needed. We introduce a method for stochastic modelling of a silicon carbide (SiC) particle reinforced aluminium matrix composite. The SiC particles are modelled by Laguerre polyhedra generated by densely packed spheres. The shape factors of the polyhedra have been fitted to the particle shapes observed in three-dimensional images. Particle elongation in extrusion direction and the observed log-normal volume distribution of the particles are included in the model by suitable scaling. An outlook is presented on how to model the grains of the polycrystalline aluminium matrix and intermetallic precipitates, which result from the strengthening mechanism of the matrix. LAY DESCRIPTION: Metal matrix composites are complex materials consisting of different phases which can display largely different mechanical properties. The deformation behaviour of these composites cannot be sufficiently modelled by averages or simple particle shapes due to the local stresses that occur on the particle edges. Therefore, a sophisticated model of the microstructure is needed. We introduce a method of stochastic modelling of a silicon carbide (SiC) particle reinforced aluminium matrix composite. The SiC particles are modelled by Laguerre polyhedra generated by densely packed spheres. The shape factors of the polyhedra have been fitted to the SiC shapes observed in three-dimensional images. Additionally, the polyhedra are scaled anisotropically to account for orientation anisotropy and to obtain a log-normal volume distribution. An outlook is presented on how to model the aluminium phase's grains and intermetallic precipitates, which result from the strengthening mechanism of the aluminium matrix alloy. PMID- 30444274 TI - Review of Liver Elastography Guidelines. AB - Nowadays, shear wave elastographic techniques have brought a substantial reduction of liver biopsies performed to stage liver fibrosis in patients with chronic hepatitis. The availability of accurate noninvasive methods for the assessment of liver fibrosis was an important breakthrough and prompted ultrasound federations of societies as well as clinical and radiologic societies to issue international guidelines or consensus statements on the clinical applications of shear wave elastographic techniques. This article reviews the guidelines that have been published as of today. PMID- 30444273 TI - A New Perspective of Migraine Symptoms in Patients With Congenital Heart Defect. AB - OBJECTIVE: To investigate the association between congenital heart defects (CHDs) and migraine and evaluate the efficacy of transcatheter defect closure from a new perspective. METHODS: The patients with CHDs who underwent transcatheter defect closure were screened in the medical database of Chinese PLA General Hospital from January 2006 to January 2017. The assessment included basic admission information, the 3-item ID Migraine Screener, and a detailed questionnaire administered by telephone or in an outpatient clinic. Patients were divided into ventricular septal defect (VSD) group and AP group (ie, patients with ASD or PFO) based on the type of defects. The latter group could be further divided into right-to-left shunt (RLS) group and left-to-right (LRS) shunt group. Each group contained 4 subgroups according to their migraine diagnosis before and after defect closure: persistent migraine (PM), relieved migraine (RM), without migraine (WM), and new-onset migraine (NM). RESULTS: The study recruited total 441 CHDs patients. Most patients in RLS group had migraine before and/or after surgery (76.4%, 42/55) and the proportion of them in NM group was higher than that of in LRS group (23.5%, 4/17 vs 6.8%, 18/266, P = .0418). Although the size of closure device or defect did not show significant differences, the ratios (R = size of closure/size of defect) were significantly higher in NM group than those in WM group (1.40 [1.26, 1.80] vs 1.22 [1.13, 1.38] in AP group, P = .00238; 1.38 [1.23, 1.50] vs 1.22 [1.13, 1.37] in LRS group, P = .024934, respectively). Further logistic regression analysis illustrated that larger R value was a risk factor for NM in AP group (OR 1.48, 95% CI 1.07-2.05, P = .0188). Besides, migraine symptoms decreased significantly after defect closure in PM group among patients with ASD and PFO. CONCLUSION: This study revealed several associations between migraine and CHDs, especially the large ratio of closure device size to defect size. High-quality randomized controlled trials and animal studies are needed to further investigate and clarify the underlying association between CHDs and migraine. PMID- 30444275 TI - A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumour and its microenvironment: iBD score. AB - AIMS: Tumour budding and invasive depth can predict survival of patients with tongue squamous cell carcinoma (TSCC), while the prognostic value of tumour microenvironment (TME) remains unknown. Here, both characteristics of tumour and its microenvironment were examined and a novel prognostic model has been proposed. METHODS: A total of 246 patients with TSCC were included. Using H&E stained sections, pathological parameters of tumour and the TME were assessed. Inflammatory response (i), tumour budding (B), and invasive depth (D) were combined as iBD score. The association between these variables and the patient survival was determined. RESULTS: Both tumour budding and inflammatory status were independent variables for predicting overall survival (OS) and disease-free survival (DFS) of TSCC patients. Invasive depth was correlated with differentiation, T classification, lymph node metastasis, clinical stage, and recurrence (P < 0.05). The novel iBD model was strongly correlated with T classification, lymph node metastasis, clinical stage, and recurrence, and showed clear distinction of score 0, 1 and 2. High iBD score had a strong association with reduced OS and DFS (P < 0.01). CONCLUSIONS: iBD scoring model is strongly associated with lymph node metastasis and recurrence in TSCC and could be a promising survival predictor for TSCC patients. This article is protected by copyright. All rights reserved. PMID- 30444276 TI - High-Frequency (10 kHz) Electrical Stimulation of Peripheral Nerves for Treating Chronic Pain: A Double-Blind Trial of Presence vs Absence of Stimulation. AB - OBJECTIVES: The study objectives were to perform a clinical audit of patients implanted with 10 kHz spinal cord (SCS) and peripheral nerve (PNS) stimulators for treating chronic pain and to investigate the effect of 10 kHz PNS on pain and other sensory modalities in a double-blind cross-over trial. METHODS: Pain, disability, and medication status were audited for 12 months after stimulator implantation in 58 SCS patients and in 11 PNS patients with an electrode positioned along a branch of the occipital or trigeminal nerve (four patients), a limb nerve trunk (four patients), or the S1 nerve root, genito-femoral nerve or ileo-inguinal nerve (one patient each). In PNS patients, pain and other sensory modalities were also assessed double-blind before and after the stimulator was switched either ON or OFF for two hours (protocol 1) or four hours (protocol 2). RESULTS: Decreases in pain and disability after stimulator implantation were maintained in both groups at 3-6 months, but these decreases were greater in PNS than SCS patients. In PNS trial patients, pain increased after the system had been turned OFF overnight for at least 12 hours before testing. Pain did not change after two hours of PNS but had decreased significantly after four hours. Other sensory modalities were minimally affected either by two or four hours of stimulation. CONCLUSIONS: These findings suggest that PNS at 10 kHz decreases pain when conducted for at least four hours. Stimulation analgesia does not appear to be due to sensory conduction block. PMID- 30444277 TI - pouC regulates expression of bmp4 during atrioventricular canal formation in zebrafish. AB - BACKGROUND: Many human gene mutations have been linked to congenital heart disease (CHD), yet CHD remains a major health issue worldwide due in part to an incomplete understanding of the molecular basis for cardiac malformation. RESULTS: Here we identify the orthologous mouse Pou6f1 and zebrafish pouC as POU homeodomain transcription factors enriched in the developing heart. We find that pouC is a multi-functional transcriptional regulator containing separable activation, repression, protein-protein interaction, and DNA binding domains. Using zebrafish heart development as a model system, we demonstrate that pouC knockdown impairs cardiac morphogenesis and affects cardiovascular function. We also find that levels of pouC expression must be fine-tuned to enable proper heart formation. At the cellular level, we demonstrate that pouC knockdown disrupts atrioventricular canal (AVC) cardiomyocyte maintenance, although chamber myocyte specification remains intact. Mechanistically, we show that pouC binds a bmp4 intronic regulatory element to mediate transcriptional activation. CONCLUSIONS: Taken together, our study establishes pouC as a novel transcriptional input into the regulatory hierarchy that drives AVC morphogenesis in zebrafish. We anticipate that these findings will inform future efforts to explore functional conservation in mammals and potential association with atrioventricular septal defects (AVSDs) in humans. This article is protected by copyright. All rights reserved. PMID- 30444278 TI - Developmental roles of microglia: a window into mechanisms of disease. AB - Microglia are engineers of the CNS both in health and disease. In addition to the canonical immunological roles of clearing damaging entities and limiting the spread of toxicity and death, microglia remodel the CNS throughout life. While they have been extensively studied in disease and injury, due to their highly variable functions, their precise role in these contexts still remains uncertain. Over the last decade we have greatly expanded our understanding of microglial function, including their essential homeostatic roles during development. Here, we review these developmental roles, identify parallels in disease, and speculate whether developmental mechanisms reemerge in disease and injury. This article is protected by copyright. All rights reserved. PMID- 30444279 TI - Medical emergencies in rural North Queensland: Doctors perceptions of the training needs. AB - OBJECTIVE: This study aimed to explore doctors' perceptions of the training needs of rural doctors in the context of managing emergencies in rural North Queensland. DESIGN: Using a qualitative approach, 20 semistructured interviews were conducted via telephone, video conference and in-person. Using an interview guide, areas such as preparedness of junior doctors for rural practice, areas for further training and confidence with managing emergencies were discussed. Interviews were analysed using the principles of grounded theory. Participant recruitment continued until data saturation was achieved. SETTING: Multiple health facilities across three hospital and health services in North Queensland. PARTICIPANTS: (i) Doctors with current or recent work in rural North Queensland; (ii) doctors involved with rural medical training; and (iii) emergency medicine specialists working in a tertiary referral centre. MAIN OUTCOME MEASURE: Perspectives of doctors on the training needs of rural doctors in North Queensland. RESULTS: Rural doctors were found to be as prepared as they could be to take up rural practice; however, they still had training needs. Region specific emergencies, access to regular in-house simulations and non-medical challenges, including understanding local team dynamics and taking on a team leader role, were seen as key training needs. Senior doctors indicated that further formal and informal on-the-job training were required for provisional fellows with limited experience in the emergency department. CONCLUSION: Certain training needs of rural doctors still remain unmet. Further access to in-house simulations and tele-training could be useful strategies to meet these training needs to further support rural doctors. PMID- 30444280 TI - Intermediate and long-term outcomes of fibroadenoma excision in adolescent and young adult patients. AB - Fibroadenomas are benign breast masses that often occur in adolescence and young adulthood. Primary management options include observation or surgical excision, but little is known about long-term outcomes after fibroadenoma excision in adolescents. In the present study, we reviewed the medical records of females aged 13-35 years who underwent fibroadenoma excision at our institution from 1986 through 2010. Patients were included if they had excision of at least 1 fibroadenoma (confirmed by histopathology) smaller than 5 cm in maximal diameter. We collected information pertaining to clinical presentation, management, and outcomes. In addition, an investigator-designed long-term outcome survey was sent to 138 eligible participants to assess patient satisfaction, as well as the recurrence of fibroadenoma, and the need or desire for further surgical intervention. Most patients (126 of 138) underwent 1 operation for fibroadenoma excision. Three women underwent immediate breast reconstruction at fibroadenoma excision. Fifty-seven patients completed the investigator-designed survey (response rate, 41.3%) with a median follow-up time of 13.5 (range, 2.0-26.7) years. Nine of 55 patients (16.4%) reported postoperative breast asymmetry and the desire to pursue reconstructive surgery. Three survey responders reported breast pain. Fourteen of 56 women (25.0%) reported the diagnosis of 1 or more additional fibroadenomas after the initial excision; another 7 reported recurrence of the mass at the site of excision. Most survey participants were satisfied with the aesthetic outcome of their fibroadenoma excision; however, a small proportion believed that they would benefit from reconstructive breast surgery. The recurrence and development of additional fibroadenomas should be addressed by providers during counseling for treatment options and postoperative follow-up. PMID- 30444282 TI - Special Issue on Stem cell and Tissue Engineering in Development, Disease and Repair. PMID- 30444281 TI - Comparing morbidity rates between wise pattern and standard horizontal elliptical mastectomy incisions in patients undergoing immediate breast reconstruction. AB - BACKGROUND: Breast cancer patients with ptotic breasts pursuing mastectomy with immediate reconstruction can present challenges. A wise pattern (inverted-T) mastectomy incision (WPM) has been suggested as an alternative to the standard horizontal elliptical mastectomy (EM) to reduce redundant skin and correct ptosis. Herein, we sought to examine the differences in morbidity between the two techniques. METHODS: We performed a retrospective review of women undergoing mastectomy with immediate reconstruction at our institution from June 2007 to January 2016. We compared those undergoing WPM to a control population undergoing EM. Statistical analysis was performed evaluating clinical, pathological, and surgical outcome variables according to patient and per breast. All tests were two-sided with alpha level set at 0.05 for statistical significance. RESULTS: A total of 241 women underwent mastectomy and reconstruction in 421 breasts; 78/241 (32%) had WPM (149 breasts), 163/241 (68%) had EM (272 breasts). Both groups were similar in age, smoking status, diabetes, race, tumor type, and pathologic stage (all P > 0.07). Skin flap necrosis was the most frequently encountered complication, occurring in 58/149 (38.9%) of WPM breasts and in 24/272 (8.9%) of EM breasts (P < 0.0001). There was no difference in the need for revisional procedures between the groups (WPM: 24.1% vs EM: 17.6%, P = 0.207). CONCLUSION: Patients should be counseled WPM is associated with higher rates of skin flap necrosis. However, this does not translate into higher rates of revisional procedures or return to OR. PMID- 30444283 TI - Effect of CPAP on airway reactivity and airway inflammation in children with moderate-severe asthma. AB - BACKGROUND AND OBJECTIVE: Asthma is characterized by airway hyperreactivity and airway inflammation. We previously demonstrated that adults with mild well controlled asthma exhibited a marked decrease in airway reactivity (PC20 increased >2-fold) after using nocturnal continuous positive airway pressure (CPAP) for 1 week. If CPAP produces a similar suppression of airway reactivity in children with moderate-severe asthma, who require chronic use of corticosteroids, then this non-pharmacological therapy might provide a beneficial alternative or supplemental therapy in these subjects. METHODS: Children aged 8-17 years with moderate-severe asthma were treated with 4 weeks of nocturnal CPAP (8-10 cm H2 O) or sham CPAP (<2 cm H2 O). Adherence was monitored with a modem installed in the equipment or by memory cards. Airway reactivity, assessed by methacholine bronchial challenge, was measured prior to and following treatment. RESULTS: The percentage of subjects adherent to treatment was similar in both groups (19/27 CPAP vs 19/28 sham, ~70%). There was a tendency for PC20 to increase with treatment in both groups (3.0-5.3 mg/mL CPAP vs 3.2 to 4.3 mg/mL sham, P = 0.083); however, the change did not differ significantly between groups (P = 0.569). CONCLUSION: We found that the 4-week treatment with nocturnal CPAP did not produce a twofold suppression of airway reactivity in children with moderate severe asthma. PMID- 30444284 TI - Intraoperative Neuromonitoring in Percutaneous Spinal Cord Stimulator Placement. AB - INTRODUCTION: Placement of spinal cord stimulation (SCS) paddles under general anesthesia using intraoperative neuromonitoring (IONM) has been shown to be associated with equivocal or superior clinical outcomes in comparative studies. The value of IONM in percutaneous permanent SCS placement has not been demonstrated. METHODS: Outcomes for patients under percutaneous SCS placement performed with IONM were prospectively collected. Descriptive outcomes included numerical rating scale (NRS), the Oswestry disability index (ODI), McGill pain questionnaire, pain catastrophizing scale score (PCS), and Beck Depression Inventory. We also assessed satisfaction, willingness to repeat surgery, complication rates, and opioid use at baseline and follow-up using chart data and the New York Internet System for Tracking Over-Prescribing data base. RESULTS: The mean follow-up for our 46 patients was 22.04 +/- 15.03 months (range 6-52 months). There were 10 patients (21.3%) who underwent revisions or removals with a mean time to revision/explant of 11.4 +/- 11.7 months. About 85% of patients were satisfied with surgery. A total of 24 of 46 patients were on opioids at baseline. Following surgery, 17 of 24 (70.83%) patients demonstrated decreased opioid use in Morphine Milligram Equivalents. Of the 17 patients that reduced opioid use, 14 (82.35%) ceased opioid use entirely. Improvement from baseline was noted in NRS, ODI, and PCS (p < .05). CONCLUSIONS: Permanent percutaneous implantation of a SCS system using IONM with general anesthesia demonstrates results within range to those in the literature. Patients demonstrated statistically significant improvement in outcomes and opioid use was reduced in 71% of patients who were using opioids at baseline. We recommend its use in patients with morbid obesity, sleep apnea, and considerable anxiety. Further research is warranted to define the possible future role for percutaneous SCS implantation under IONM. PMID- 30444285 TI - Investigation on the use and acceptability of the Edmonton Frail Scale in a rural primary care setting. PMID- 30444286 TI - Diffusion-weighted MR imaging increases diagnostic accuracy of breast MR imaging for predicting axillary metastases in breast cancer patients. AB - PURPOSE: To evaluate the incremental value of diffusion-weighted imaging (DWI) to conventional MR imaging (CMRI) to predict ipsilateral metastatic axillary lymphadenopathy in patients with newly diagnosed breast cancer. SUBJECTS AND METHODS: In an IRB approved retrospective single-institution study, newly diagnosed consecutive breast cancer patients with pathological verification of axillary lymph node (LN) status who had undergone breast MR imaging, including DWI as part of their standard MRI between August 1, 2010, and December 31, 2010, were reviewed. Lesion size, tumor grade, and tissue prognostic factors were noted. Ipsilateral axillary LNs were evaluated using morphological criteria on CMRI. Apparent diffusion coefficient (ADC) values of suspicious ipsilateral LNs were obtained and compared with ADC values of contralateral benign axillary LNs. Receiver operating characteristic curves and multivariate logistic regression analyses were used using pathology as the gold standard. RESULTS: Eighty-five eligible patients were identified, with surgical pathology revealing 34 patients (40%) who had malignant and 51 (60%) had benign ipsilateral axillae. The sensitivity of CMRI was 79%, with a specificity of 81%, a positive predictive value (PPV) of 65%, and a negative predictive value (NPV) of 89%. On DWI, the mean ADC value was significantly lower for metastatic LNs (0.89 +/- 0.18 * 10-3 mm2 /s) than for benign ipsilateral LNs (1.41 +/- 0.21 * 10-3 mm2 /s; P < 0.0001). Using a cutoff ADC value of 0.985 * 10-3 mm2 /s, yielded improved sensitivity, specificity, PPV, and NPV of 83%, 98%, 95%, and 93%, respectively. CONCLUSION: Apparent diffusion coefficient values increase the specificity of CMRI for predicting ipsilateral axillary LN metastases in patients with newly diagnosed breast cancer. PMID- 30444287 TI - Trauma Memory Processing in Posttraumatic Stress Disorder Psychotherapy: A Unifying Framework. AB - Trauma memory processing (TMP) is an empirically supported approach to psychotherapy for posttraumatic stress disorder (PTSD). However, TMP is not a single, uniform intervention but instead a paradigm that can be operationalized through a variety of component procedures that have not been systematically elucidated and formally tested. Based on findings from phenomenological/structural and neuroimaging research, a central feature of PTSD is theorized to be the involuntary immersion in trauma memories with diminished awareness or negative appraisals of self and current context. Such intrusive reexperiencing-which is epitomized by, but not limited to, flashbacks-is postulated to underlie PTSD's avoidance, altered emotions and cognitions, dissociative, and hyperarousal/hypervigilance symptoms; it is thus a logical target for TMP. The varied approaches to TMP for PTSD are conceptualized as having the common goal of activation of the neural networks in the brain that underlie two key capacities disrupted by intrusive reexperiencing in PTSD: intentional self-referential retrieval of memories and suppression of memory retrieval. Therefore, TMP is postulated to involve two core functions (purposeful reflective remembering and memory awareness in situ) and three essential types (in vivo, imaginal, and cognitive reappraisal). Several implications of this framework for clinical practice and research on TMP for PTSD are discussed. PMID- 30444288 TI - Reactivity of CK 7 across the spectrum of renal cell carcinomas with clear cells. AB - AIMS: Current available data on cytokeratin 7 immunostaining pattern in the clear cell renal cell carcinoma (RCC) spectrum is conflicting. The aim of this study was to assess CK7 immunoreactivity within the spectrum of clear cell renal neoplasms, including clear cell RCC, multicystic renal neoplasm of low malignant potential, and clear cell papillary RCC-like tumors. METHODS AND RESULTS: We analyzed two clones of CK7 and two tumor blocks for a total of 75 cases divided into five distinct groups: 1) low grade clear cell RCC, 2) high grade clear cell RCC, 3) multicystic renal neoplasm of low malignant potential, 4) clear cell RCC with cystic changes and 5) clear cell papillary RCC-like tumors. We found the highest CK7 reactivity in low grade clear cell RCC, multicystic renal neoplasm and clear cell papillary RCC-like groups, ranging from 60-93%. CONCLUSIONS: Our findings show that CK7 immunoreactivity in clear cell RCC is variable and the extent of staining depends on the grade and architectural growth patterns of the tumors. This article is protected by copyright. All rights reserved. PMID- 30444289 TI - Effects of an intervention program for reducing severe perineal trauma during the second stage of labor. AB - BACKGROUND: Obstetric anal sphincter injuries lead frequently to short- and long term consequences for the mother, including perineal pain, genital prolapse, and sexual problems. The aim of the study was to evaluate whether the implementation of an intervention program in the second stage of labor involving altered perineal support techniques reduced severe perineal trauma. METHODS: All women reaching the second stage of labor and giving birth vaginally to singleton babies at Landspitali University Hospital (comprising 76% of births in Iceland in 2013) were enrolled in a cohort study. Data were recorded retrospectively for 2008-2010 and prospectively in 2012-2014, for a total of 16 336 births. During 2011, an intervention program was implemented, involving all midwives and obstetricians working in the labor wards. Two professionals assessed and agreed on classification of every perineal tear. RESULTS: The prevalence of obstetric anal sphincter injuries decreased from 5.9% to 3.7% after the implementation (P < 0.001). Third-degree tears decreased by 40%, and fourth-degree tears decreased by 56% (P < 0.001). The prevalence of first-degree tears increased from 25.8% to 33.1%, whereas second-degree tears decreased from 44.7% to 36.6% between the before and after study periods. Severe perineal trauma was linked to birthweight, and this did not change despite the new intervention. CONCLUSIONS: Active intervention to reduce perineal trauma was associated with an overall significant decrease in obstetric anal sphincter injuries. Good perineal visualization, manual perineal support, and controlled delivery of the fetal head were essential components for reducing perineal trauma. PMID- 30444290 TI - 'One tooth one child': evaluating the effects of diet and fertility on the oral health of women from archaeological sites in South America. AB - Women from ancient societies have shown a higher prevalence of dental caries in comparison with men. Recent research has shown that the relationship between increased oestrogen production during pregnancy and decreased salivary flow is a possible cause for the higher levels of caries in women, which is in contrast to the traditional view of sexual division of labour resulting in unequal access to cariogenic food. In order to test these two hypotheses, individuals exhumed from 12 South American archaeological sites were examined for markers of oral health (caries, ante mortem tooth loss, deep caries, and enamel hypoplasia) and compared in terms of fertility (Crude Birth Rate) and subsistence systems. Our results suggest that diet and other cultural practices remain the most important factors affecting oral health and that the effects of hormones can be masked by them. Such findings add to the discussion regarding the availability of micronutrients in such societies affecting caries experience in pregnant women, because of their special nutritional requirements. PMID- 30444291 TI - Endocrine regulation of gut function - a role for glucagon-like peptide-1 in the pathophysiology of irritable bowel syndrome. AB - NEW FINDINGS: Pathophysiological changes linked to Irritable Bowel Syndrome (IBS) include stress and immune activation, changes in gastrointestinal microbial and bile acids profiles and sensitisation of extrinsic and intrinsic gut neurons. This review explores the potential role for L-cells in these pathophysiological changes. L-cells, which secrete glucagon-like peptide-1 (GLP-1) in response to nutrients, microbial factors, bile acids and short-chain fatty acids, may sense IBS-related changes in the luminal environment. Glucagon-like peptide 1 can act as a hormone, a paracrine factor or a neuromodulatory factor and through its actions on central or peripheral neurons, may play a role in gastrointestinal dysfunction. ABSTRACT: The prevalent and debilitating functional bowel disorder Irritable Bowel Syndrome (IBS), is characterized by symptoms which include abdominal pain, bloating, diarrhoea and/or constipation. The heterogeneity of IBS underscores a complex multifactorial pathophysiology, which is not completely understood, but involves dysfunction of the bidirectional signalling axis between the brain and the gut. This axis incorporates efferent and afferent branches of the autonomic nervous system, circulating endocrine hormones and immune factors, local paracrine and neurocrine factors and microbial metabolites. L-cells, which are electrically excitable biosensors embedded in the gastrointestinal epithelium, secrete glucagon-like peptide-1 (GLP-1) in response to nutrients in the small intestine. However, they appear to function differently more distally in the gastrointestinal tract, where they are activated by luminal factors including short-chain fatty acids, bile acids and microbial metabolic products, all of which are altered in IBS patients. GLP-1 can also interact with the hypothalamic-pituitary-adrenal stress axis and immune system, both of which are activated in IBS. Given that a GLP-1 mimetic has been found to alleviate acute pain symptoms in IBS patients, GLP-1 may be important in the manifestation of IBS symptoms. This review assessed the current knowledge on the role of GLP-1 in IBS pathophysiology and its potential role as a signal transducer in the microbiome gut-brain signalling axis. This article is protected by copyright. All rights reserved. PMID- 30444292 TI - Spatial avoidance as a response to contamination by aquatic organisms in non forced, multi-compartmented exposure systems: a complementary approach to the behavioral response. AB - The idea that the hazard of contaminants is exclusively related to their toxic effects does not consider the fact that some organisms can avoid contamination, preventing toxicity. Although in the majority of behavioral ecotoxicology studies inferences about avoidance are made, assessment of the real spatial displacement (organisms moving towards another habitat to escape from contamination) is difficult due to the type of exposure (confined and mandatory) used in the bioassays: a forced exposure approach. A complementary approach using non-forced exposure systems to assess how contaminants affect the spatial distribution of organisms in a bi-compartmented (toxic or non-toxic) environment has been described for a long time. Recently, this non-forced approach has been developed to include a multi-compartmented system in which different samples can be simultaneously tested. The aim of this review is to describe the importance of the non-forced, multi-compartmented exposure approach to simulate a gradient or patches of contamination, to describe the two main exposure systems and to highlight the ecological relevance of including spatial avoidance and habitat preference to ecotoxicological studies. The multi-compartmentalization of the system makes it possible to simulate more complex scenarios and, therefore, include new ecological concepts to bioassays. We also contrasted spatial avoidance in the non-forced exposure systems with the behavioral endpoints measured under other exposure systems. Finally, we showed that the non-forced, multi-compartmented exposure approach makes it possible (i) to improve environmental risk assessments by adding the dispersion pattern of organisms in a multi-habitat scenario and (ii) to integrate ecological concepts, such as recolonization of recovering habitats, loss of habitat connectivity, habitat fragmentation and contamination-driven metapopulation, which have received limited attention in ecotoxicological studies. This article is protected by copyright. All rights reserved. PMID- 30444293 TI - The bZIP transcription factor SPA Heterodimerizing Protein represses glutenin synthesis in Triticum aestivum. AB - The quality of wheat grain is mainly determined by the quantity and composition of its grain storage proteins (GSPs). GSPs consist of the low (LMW-GS) and high (HMW-GS) molecular-weight glutenins and gliadins. The synthesis of these proteins is essentially regulated at the transcriptional level and by the availability of nitrogen and sulfur. The regulation network has been extensively studied in barley where BLZ1 and BLZ2, members of the basic leucine zipper (bZIP) family, activate the synthesis of hordeins. To date, in wheat, only the ortholog of BLZ2, Storage Protein Activator (SPA), has been identified as playing a major role in the regulation of GSP synthesis. Here, the ortholog of BLZ1 named SPA Heterodimerizing Protein (SHP) was identified and its involvement in the transcriptional regulation of the genes coding for GSPs was analyzed. In gel mobility shift assays, SHP binds cis-motifs known to bind to bZIP family TFs in HMW-GS and LMW-GS promoters. Moreover, we showed by transient expression assays in wheat endosperms that SHP acts as a repressor of the activity of these gene promoters. This result was confirmed in transgenic lines overexpressing SHP, which were grown with low and high nitrogen supply. The phenotype of SHP overexpressing lines showed a lower quantity of both LMW-GS and HMW-GS, while the quantity of gliadin was unchanged, whatever the availability in nitrogen. Thus, the gliadin/glutenin ratio was increased, which suggests that gliadin genes may be differently regulated than glutenin genes. This article is protected by copyright. All rights reserved. PMID- 30444294 TI - Ultrafast 3D Bloch-Siegert B 1+ -mapping using variational modeling. AB - PURPOSE: Highly accelerated B THEORY AND METHODS: The B RESULTS: The reconstructed B CONCLUSIONS: The proposed variational approach enables highly accelerated 3D acquisitions of Bloch-Siegert data and thus full liver coverage in a single breath hold. PMID- 30444295 TI - Oligodendroglial A-synucleinopathy driven neuroinflammation in multiple system atrophy. AB - Neuroinflammation and oligodendroglial cytoplasmic alpha-synuclein (alpha-syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood. Here, we demonstrate MSA-associated neuroinflammation being restricted to myeloid cells and tightly linked to oligodendroglial alpha-syncleinopathy. In human putaminal post-mortem tissue of MSA patients, neuroinflammation was observed in white matter regions only. This locally restricted neuroinflammation coincided with elevated numbers of alpha-syn inclusions, while gray matter with less alpha synucleinopathy remained unaffected. In order to analyze the temporal pattern of neuroinflammation, a transgenic mouse model overexpressing human alpha-syn under the control of an oligodendrocyte-specific myelin basic protein (MBP) promoter (MBP29-halpha-syn mice) was assessed in a pre-symptomatic and symptomatic disease stage. Strikingly, we detected an increased neuroinflammation in regions with a high alpha-syn load, i.e. corpus callosum and striatum, of MBP29-halpha-syn mice, already at a pre-symptomatic stage. Furthermore, this inflammatory response was restricted to myeloid cells being highly proliferative and showing an activated, phagocytic phenotype. In contrast, severe astrogliosis was observed only in gray matter regions of MSA patients as well as MBP29-halpha-syn mice. To further characterize the influence of oligodendrocytes on initiation of the myeloid immune response we performed RNA sequencing analysis of alpha-syn overexpressing primary oligodendrocytes. A distinct gene expression profile including upregulation of cytokines important for myeloid cell attraction and proliferation was detected in alpha-syn overexpressing oligodendrocytes. Additionally, microdissected tissue of MBP29-halpha-syn mice exhibited a similar cellular gene expression profile in white matter regions even pre-symptomatically. Collectively, these results imply an early crosstalk between neuroinflammation and oligodendrocytes containing alpha-syn inclusions leading to an immune response locally restricted to white matter regions in MSA. This article is protected by copyright. All rights reserved. PMID- 30444296 TI - The medicinal plant Andrographis paniculata genome provides insight into biosynthesis of the bioactive diterpenoid neoandrographolide. AB - Andrographis paniculata is a herbaceous dicot plant widely used for its anti inflammatory and anti-viral properties across its distribution in China, India and other Southeast Asia countries. A. paniculata was used as a crucial therapeutic treatment during the influenza epidemic of 1919 in India and is still used for the treatment of infectious disease in China. A. paniculata produces large quantities of the anti-inflammatory diterpenoid lactones andrographolide, neoandrographolide and their analogs; touted to be the next generation of natural anti-inflammatory medicines for lung diseases, hepatitis, neurodegenerative disorders, autoimmune disorders and inflammatory skin diseases. Here, we report a chromosome-scale A. paniculata genome sequence of 269 Mb that was assembled by Illumina short reads, PacBio long reads and Hi-C data. Gene annotation predicted 25,428 protein-coding genes. To decipher the genetic underpinning of diterpenoid biosynthesis, transcriptome data from seedlings elicited with methyl jasmonate also was obtained, which enabled identification of genes encoding diterpenoid synthases, cytochrome P450 monooxygenases, 2-oxoglutarate-dependent dioxygenases and UDP-dependent glycosyltransferases potentially involved in diterpenoid lactone biosynthesis. We further carried out functional characterization of pairs of classes I and II diterpene synthases, revealing the ability to produce diversified labdane-related diterpene scaffolds. In addition, a glycosyltransferase able to catalyze O-linked glucosylation of andrograpanin, yielding the major active product neoandrographolide, was identified as well. Thus, our results demonstrate the utility of the combined genomic and transcriptomic dataset generated here for investigation of the production of the bioactive diterpenoid lactone constituents of the important medicinal herb A. paniculata. This article is protected by copyright. All rights reserved. PMID- 30444297 TI - Dental anxiety in relation to torture experiences and symptoms of post-traumatic stress disorder. AB - Torture victims often show symptoms of dental anxiety when receiving dental care, but little systematic research is available. The purpose of this study was to explore torture experiences, symptoms of post-traumatic stress disorder (PTSD), and dental anxiety in refugees in Norway and to test the hypothesis that refugees with torture experiences are more prone to dental anxiety than refugees with no such experiences. A total of 173 refugees were interviewed shortly after an oral examination. The Modified Dental Anxiety Scale (MDAS) and the Harvard Trauma Questionnaire-PTSS16 were administered verbally through attending interpreters. Among torture victims (47%, n = 81), the prevalence of torture experiences involving mouth or teeth was 35% and 23%, respectively. Harvard Trauma Questionnaire mean sum scores were statistically significantly higher in torture victims (34.3 vs. 24.8). Torture survivors report a larger number of symptoms of PTSD, and dental anxiety shows a higher prevalence in refugees reporting PTSD symptoms than in refugees who do not report such symptoms. When analysed using logistic regression models, the data showed the odds of high levels of dental anxiety being 6.1 times higher in refugees with torture experiences compared with other refugees and 9.3 times higher in torture victims with PTSD symptoms. Oral health professionals should be aware of these associations when providing dental care to refugees. The hypothesis that tortured refugees are more prone to dental anxiety is supported. PMID- 30444298 TI - Joint status in Spanish haemophilia B patients assessed using the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score. AB - AIM: The use of musculoskeletal ultrasound (MSK-US) following protocols for haemophilic arthropathy and the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) score can help standardize monitoring in haemophilia. This study evaluated the joint status (elbows, knees and ankles) of patients with haemophilia B (HB) in Spain using MSK-US and the HEAD-US score. METHODS: Haemophilia B patients >=14 years old were included in this observational, multicentre, cross-sectional study, regardless of their clinical condition, HB severity and treatment received. Two blinded observers were involved in image acquisition and scoring in each centre. RESULTS: Eighty-two patients from 12 centres were enrolled: 27% mild HB, 23% moderate, 50% severe HB. Mean age was 38.9 +/- 16.4 years, 60% were treated on demand (OD) and 40% were on prophylaxis. HEAD-US was zero in all joints in 28.6% OD patients and 36.4% on prophylaxis. Mean scores significantly worsened with HB severity, except for the left knee. Patients on primary and secondary prophylaxis had significantly better joint health vs OD patients in all joints, except the right ankle. Among OD patients, those with severe disease presented significantly worse scores in all HEAD-US items related to permanent damage. CONCLUSION: Joint status of HB patients in Spain is influenced by severity and treatment modality, related to the development of arthropathy, which appears prevalent in OD patients with severe HB. Routine assessment with an imaging tool such as ultrasound and HEAD-US system may help to improve joint health by personalizing and adjusting treatment in this population. PMID- 30444299 TI - Neural signatures of the risk for Bipolar Disorder: a meta-analysis of structural and functional neuroimaging studies. AB - OBJECTIVE: Widespread functional and structural alterations in the brain have been extensively reported in unaffected relatives (RELs) of patients with bipolar disorder (BD) that are at genetic risk for BD. A sufficiently powered meta analysis of structural (sMRI) and functional magnetic resonance imaging (fMRI) alterations in RELs is still lacking. METHODS: Functional and structural magnetic resonance imaging studies investigating RELs and healthy controls (HCs) published by July 2017 were included in the meta-analyses. Study procedures were conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. Random-effects coordinate-based meta-analyses were performed across all the studies per imaging modality using Seed-based d Mapping (SDM). For fMRI studies, meta-analyses were calculated for each task-type. For sMRI studies, regional volumetric changes-analyses were estimated using R. Finally, multimodal meta-analyses of structural and functional abnormalities were performed. RESULTS: 69 imaging studies (2195 RELs and 3169 HCs) were included in the meta-analyses. RELs showed hyperactivation in the fronto-striatal regions as well as parietal hypoactivation during cognition. Also, activation was increased in the amygdala during emotional processing and in the orbitofrontal cortex during reward, respectively. Frontal and superior temporal cortex were hypertrophic in RELs. The right inferior frontal gyrus (rIFG) showed both increased activation during cognitive tasks and greater volume in RELs. CONCLUSIONS: Our findings demonstrate that increased brain volume and activation are present in RELs and may represent intermediate phenotypes for the disorder. Furthermore, some neural changes including increased rIFG volume may be associated with the resilience to BD. This article is protected by copyright. All rights reserved. PMID- 30444300 TI - Pressure and temperature effects on deep-sea hydrocarbon-degrading microbial communities in subarctic sediments. AB - The Hatton-Rockall Basin (North-East Atlantic) is an area with potential for deep sea (2,900 m) hydrocarbon exploration. Following the Deepwater Horizon oil spill, many investigations into the responses of sediment microbial communities to oil pollution have been undertaken. However, hydrostatic pressure is a parameter that is often omitted due to the technical difficulties associated with conducting experiments at high pressure (>10 MPa). In this study, sediments from 2,900 m in the Hatton-Rockall Basin, following a one-week decompression period in a temperature-controlled room at 5 degrees C, were incubated in factorial combinations of 0.1 and 30 MPa, 5 and 20 degrees C, and contamination with a hydrocarbon mixture or uncontaminated controls to evaluate the effect of these environmental variables on the bacterial community composition. Our results revealed varying effects of pressure, temperature, and oil contamination on the composition of the bacterial community within the sediment. Temperature was the strongest determinant of differences in the bacterial community structure between samples followed by pressure. Oil contamination did not exert a strong change in the sediment bacterial community structure when pressure and temperature conditions were held at in situ levels (30 MPa and 5 degrees C). The gamma proteobacteria Pseudomonas and Colwellia, and several Bacteroidetes dominated communities at 30 MPa. In contrast, hydrocarbon degraders such as Halomonas, Alcanivorax, and Marinobacter decreased in relative abundance at the same pressure. This study highlights the importance of considering hydrostatic pressure in ex situ investigations into hydrocarbon-degrading deepwater microbial communities. PMID- 30444301 TI - Autochthonous Bacillus licheniformis: Probiotic potential and survival ability in low-fishmeal extruded pellet aquafeed. AB - In recent years, Bacillus spp. have garnered attention as probiotic supplements in aquafeed owing to the production of heat stable and low pH resistant spores. Herein, we isolated and characterized an autochthonous Bacillus licheniformis KCCM 43270 from the intestine of olive flounder (Paralichthys olivaceus) for supplementation in low-fishmeal extruded aquafeeds. The KCCM 43270 was screened based on amylase, protease, cellulase, and lipase as well as non-hemolytic activities. The isolate was able to grow in carboxymethyl cellulose (CMC), xylan, and soybean meal (SBM) when used as a single carbon source in the minimal nutrient M9 medium. The KCCM 43270 spores displayed complete survival in acid (pH 2.5) and bile (0.3%, w/v) for 3 hr, strong biofilm formation, and nearly 50% adhesion with intestinal mucus. The spores of the isolate also showed significant survival ability at 80, 90, 100 degrees C for 60, 30, and 1 min, respectively. In addition, the spores in a blend of SBM complex carrier showed significant heat stability at 120 degrees C for 5 min and under different drying conditions. Furthermore, the spores also survived the extrusion process during low-fishmeal aquafeed manufacturing, implying the potential application of B. licheniformis KCCM 43270 in aquafeed industry. PMID- 30444302 TI - Design of Thermochromic Luminescent Dyes Based on the Bis(ortho-carborane) Substituted Benzobithiophene Structure. AB - To obtain solid-state emissive materials having stimuli-responsive luminescent chromic properties without phase transition, benzobithiophenes modified with two o-carborane units having various substituents in the adjacent phenyl ring in o carborane were designed and synthesized. Their emission colors were strongly affected not only by the substituents at the para-position of the phenyl ring but also by molecular distribution in the solid state. In particular, the emission colors were changed by heating without crystal phase transition. It was proposed that their thermochromic properties were correlated not with isomerization but with the molecular motion at the distorted benzobithiophene moiety. PMID- 30444303 TI - Effect of the Folate Ligand Density on the Targeting Property of Folated Conjugated Polymeric Nanoparticles. AB - Targeted drug delivery systems have attracted increasing attention due to their ability for delivering anticancer drugs selectively to tumor cells. Folic acid (FA)-conjugated targeted block copolymers, FA-Pluronic-polycaprolactone (FA Pluronic-PCL) are synthesized in this study. The anticancer drug paclitaxel (PTX) is loaded in FA-Pluronic-PCL nanoparticles by nanoprecipitation method. The in vitro release of PTX from FA-Pluronic-PCL nanoparticles shows slow and sustained release behaviors. The effect of FA ligand density of FA-Pluronic-PCL nanoparticles on their targeting properties is examined by both cytotoxicity and fluorescence methods. It is shown that FA-Pluronic-PCL nanoparticles indicated better targeting ability than non-targeted PCL-Pluronic-PCL nanoparticles. Furthermore, FA-F127-PCL nanoparticle with 10% FA molar content has more effective antitumor activity and higher cellular uptake than those with 50% and 91% FA molar content. These results prove that FA-F127-PCL nanoparticle with 10% FA molar content can be a better candidate as the drug carrier in targeted drug delivery systems. PMID- 30444304 TI - Natural history of untreated squamous cell carcinoma of the head and neck. AB - The natural history of untreated head and neck squamous cell carcinoma (SCC) was not well defined. A total of 206 patients with untreated head and neck SCC were retrospectively enrolled. The 1-year survival rate for cancers arising in oral cavity, oropharynx, throat, and hypopharynx was 31%, 20%, 0%, and 3%, respectively, the difference was significant (p<0.001). 57.2% of the patients died within 12 months, median survival time was 11 months. The prognosis of untreated head and neck SCC patients is extremely unfavorable. T stage is the strongest predictors for the survival time. This article is protected by copyright. All rights reserved. PMID- 30444305 TI - Selective Separation of Isomeric Dicarboxylic Acid by the Preferable Crystallization of Metal-Organic Frameworks. AB - Simple and effective separation of isomeric organic molecules is an important but challenging task. Herein, we successfully developed a selective crystallization strategy to separate the mixtures of isomeric dicarboxylic acids (DCAs) for the first time. The target DCAs could be preferably combined with crystallization inducer of Zr4+ ions to form a pre-designed metal-organic frameworks (MOFs) crystal structure whereas the entry of non-target isomeric DACs into the MOFs lattice could be exclusively inhibited. Several isomeric pairs were exemplified to verify the extensibility and validity of the developed strategy. PMID- 30444306 TI - A rare case report of cutaneous endometriosis over arm diagnosed by fine needle aspiration cytology. PMID- 30444308 TI - Infection and Propagation of Astrovirus VA1 in Cell Culture. AB - Astrovirus VA1/HMO-C (VA1) is the representative genotype of mamastrovirus 9, a species of the single-stranded, positive-sense RNA viral family, Astroviridae. Astroviruses have been traditionally considered pathogens of the gastrointestinal tract but they have been recently associated with neurological diseases in humans, cattle, mink, sheep, and pigs. VA1 is the astrovirus genotype most commonly identified from human cases of meningoencephalitis and has been recently propagated in cell culture. VA1 can now be used as a model system to study pathogenesis of the neurological diseases associated with astrovirus infection. In this article, we describe two fundamental assays to quantify replication and propagation of VA1, a quantitative reverse transcription-PCR (qRT-PCR) to measure viral RNA and a 50% tissue culture infectious dose (TCID50 ) assay to measure infectious viral particles. (c) 2018 by John Wiley & Sons, Inc. PMID- 30444307 TI - Population-based birth defects data in the United States, 2011-2015: A focus on eye and ear defects. AB - BACKGROUND/OBJECTIVES: In this data brief, we examine major eye and ear anomalies (anophthalmia/microphthalmia, anotia/microtia, and congenital cataract) for a recent 5-year birth cohort using data from 30 population-based birth defects surveillance programs in the United States. METHODS: As a special call for data for the 2018 NBDPN Annual Report, state programs reported expanded data on eye/ear anomalies for birth years 2011-2015. We calculated the combined overall prevalence (per 10,000 live births) and 95% confidence intervals (CI), for the three anomalies as well as by maternal age, maternal race/ethnicity, infant sex, laterality, presence/absence of other major birth defects, and case ascertainment methodology utilized by the program (active vs. passive). RESULTS: The overall prevalence estimate (per 10,000 live births) was 1.5 (95% CI: 1.4-1.5) for anophthalmia/microphthalmia, 1.5 (95% CI: 1.4-1.6) for congenital cataract, and 1.8 (95% CI: 1.7-1.8) for anotia/microtia. Congenital cataract prevalence varied little by maternal race/ethnicity, infant sex, or case ascertainment methodology; prevalence differences were more apparent across strata for anophthalmia/microphthalmia and anotia/microtia. Prevalence among active vs. passive ascertainment programs was 50% higher for anophthalmia/microphthalmia (1.9 vs. 1.2) and two-fold higher for anotia/microtia (2.6 vs. 1.2). Anophthalmia/microphthalmia was more likely than other conditions to co-occur with other birth defects. All conditions were more frequent among older mothers (40+ years). CONCLUSIONS: This data brief provides recent prevalence estimates for anophthalmia/microphthalmia, congenital cataract, and anotia/microtia that address a data gap by examining pooled data from 30 population-based surveillance systems, covering a five-year birth cohort of about 12.4 million births. PMID- 30444309 TI - Prenatal heart block screening in mothers with SSA/SSB autoantibodies: Targeted screening protocol is a cost-effective strategy. AB - OBJECTIVE: Maternal anti-Ro/SSA and anti-La/SSB antibodies can lead to fetal complete heart block (CHB). Current guidelines recommend weekly echocardiographic screening between 16 and 28 weeks gestation. Given the cost of screening and the rarity of conduction abnormalities in fetuses of mothers with low anti-Ro levels (<50 U/mL), we sought to identify a strategy that optimizes resource utilization. DESIGN: Decision analysis cost-utility modeling was performed for three screening paradigms: "standard screening" (SS) in which mid-gestation mothers are screened weekly, "limited screening" (LS) in which fetal echocardiograms are avoided unless the fetus develops bradycardia, and "targeted screening by maternal antibody level" (TS) in which only high anti-Ro values warrant weekly screening. A systematic review of existing literature and institutional cost data were used to define model inputs. RESULTS: The average cost of LS, TS, and SS was $8566, $11 038, and $23 279, respectively. SS was cost-ineffective with an incremental cost-effectiveness ratio (ICER) of $322 756 while TS was cost-effective with an ICER of $43 445. CONCLUSION: While the efficacy of fetal intervention for first or second degree AV block remains unclear, this analysis supports utilizing antibody levels to stratify this population for optimized surveillance for CHB. SS is cost-ineffective and results in resource overutilization. PMID- 30444310 TI - Catalytic Enantioselective alpha-Ketol Rearrangement. AB - A highly enantioselective alpha-ketol rearrangement has been developed. In the presence of a chiral Cu-bisoxazoline complex, achiral beta-hydroxy-alpha dicarbonyls were isomerized to chiral alpha-hydroxy-beta-dicarbonyls and their bicyclic derivatives in excellent yields and enantioselectivities. Enantioenriched 2-acyl-2-hydroxy cyclohexan-1-ones, dihydroxyhexahydrobenzofuranones, and dihydroxyhexahydro-cycloheptafuranones, with up to three stereocenters, were readily prepared from achiral starting materials in one operation. The reaction is applicable to the desymmetrization of meso substrates and kinetic resolution of racemic alcohols. PMID- 30444311 TI - Molecular dynamics simulations of water-mediated cholesterol capture within an open-ended single-walled carbon nanotube. AB - The excess concentration of cholesterol in the bloodstream can be brought down to safer level by utilizing a potential cholesterol-binding agent such as a carbon nanotube (CNT). Here, we have probed solvent-mediated interactions between cholesterol and CNT by performing molecular dynamics simulations and potential-of mean force (PMF) calculations. Simulations predict favorable interactions between water-mediated cholesterol and CNT due to strong mutual interactions between them, whereas water plays opposing role in the association. The further breakdown of PMF into its enthalpic and entropic contributions indicates that contrary to traditional entropy-driven hydrophobic association, the cholesterol encapsulation within CNT is primarily driven by enthalpy. PMID- 30444312 TI - Resistive pulse sensing as particle counting and sizing method in microfluidic systems: Designs and applications review. AB - Resistive pulse sensing is a well-known and established method for counting and sizing particles in ionic solutions. Throughout its development the technique has been expanded from detection of biological cells to counting nanoparticles and viruses, and even registering individual molecules, e.g., nucleotides in nucleic acids. This technique combined with microfluidic or nanofluidic systems shows great potential for various bioanalytical applications, which were hardly possible before microfabrication gained the present broad adoption. In this review, we provide a comprehensive overview of microfluidic designs along with electrode arrangements with emphasis on applications focusing on bioanalysis and analysis of single cells that were reported within the past five years. PMID- 30444313 TI - Facile Cleavage of the P=P Double Bond in Vinyl-Substituted Diphosphenes. AB - The reactions of the cyclic alkyl amino carbene (CAAC) 1 with phosphaalkynes generate the kinetically unstable CAAC-derived phosphirenes 4 and 5, which undergo rearrangement/dimerization reactions to give the vinyl-substituted diphosphenes 2, 3, and 6. The P=P double bond scission of 2 or 3 is unprecedentedly effected by S8 , [AuCl(tht)], or MeOTf at room temperature, which affords a dithiophosphorane 7, a phosphepine Au complex 8, or phosphepinium cations 9 and 10, respectively. The cationic species feature little homoaromaticity while representing the first examples of the phosphorus containing analogue of the tropylium ion. PMID- 30444314 TI - Applications of solid-phase micro-extraction with mass spectrometry in pesticide analysis. AB - Pesticides, widely applied in agriculture, can produce a variety of transformation products and their continuous use causes deleterious effects to ecosystem. Efficient and sensitive analytical techniques for enrichment and analysis of pesticides samples are highly required. Compared with other extraction methods, solid-phase micro extraction is a solvent free, cost effective, robust, versatile, and high throughput sample preparation technique, especially for the analysis of pesticides from complicated matrices. Coupling of solid-phase micro extraction with gas chromatography and mass spectrometry and liquid chromatography-mass spectrometry has been extensively applied in pesticide analysis. On the other hand, in recent years, combination of fast separation using solid-phase micro extraction and rapid detection using ambient mass spectrometry is providing highly efficient pesticide screening. This article summarizes the applications of solid-phase micro extraction coupled to mass spectrometry for pesticides analysis. PMID- 30444316 TI - Emergency general surgeons, subspeciality surgeons and the future management of emergency surgery: results of a national survey. AB - AIM: This study aimed to survey consultants' experience of working as or with emergency general surgery (EGS) surgeons and to investigate the role they fulfil in the management of general and subspeciality emergencies. METHOD: An electronic survey, designed to capture both quantitative and qualitative data, was piloted and then circulated to members of the Association of Coloproctology of Great Britain and Ireland. RESULTS: Two hundred and forty-two responses were received from 848 recipients (a 29% response rate) covering 104 of 135 (77%) acute NHS Trusts in England. EGS surgeons were in post in 43/141 (30%) hospitals overall and 12/24 (50%) of hospitals in London. Most respondents working in units with EGS surgeons found them to be advantageous (46/63, 73%). Consultants working with EGS surgeons were significantly more likely to support their use (49/63, 78%) than those without them (83/178, 47%) (chi2 = 16.9, P < 0.001). EGS surgeons were considered to improve the delivery of EGS (78%), create time for subspecialists (70%) and provide service (73%). However, there were concerns about the quality of surgery (43%), an insufficient standard of specialist care (54%) and compromise in the training of juniors (25%). Respondents commented on a lack of job structure with a high attrition rate (21%), the insufficient quality of applicants (18%) and that subspecialization and split on-call was preferable (17%). CONCLUSION: Respondents were supportive of the ability of EGS surgeons to relieve pressure on subspecialists; however, there were significant concerns about the sustainability and quality of the EGS surgeon role. Emergency colorectal resections should have the input of a surgeon who performs elective colorectal resections. PMID- 30444315 TI - Home blood pressure control status in 2017-2018 for hypertension specialist centers in Asia: Results of the Asia BP@Home study. AB - A self-measured home blood pressure (BP)-guided strategy is an effective practical approach to hypertension management. The Asia BP@Home study is the first designed to investigate current home BP control status in different Asian countries/regions using standardized home BP measurements taken with the same validated home BP monitoring device with data memory. We enrolled 1443 medicated hypertensive patients from 15 Asian specialist centers in 11 countries/regions between April 2017 and March 2018. BP was relatively well controlled in 68.2% of patients using a morning home systolic BP (SBP) cutoff of <135 mm Hg, and in 55.1% of patients using a clinic SBP cutoff of <140 mm Hg. When cutoff values were changed to the 2017 AHA/ACC threshold (SBP <130 mm Hg), 53.6% of patients were well controlled for morning home SBP. Using clinic 140 mm Hg and morning home 135 mm Hg SBP thresholds, the proportion of patients with well-controlled hypertension (46%) was higher than for uncontrolled sustained (22%), white-coat (23%), and masked uncontrolled (9%) hypertension, with significant country/regional differences. Home BP variability in Asian countries was high, and varied by country/region. In conclusion, the Asia BP@Home study demonstrated that home BP is relatively well controlled at hypertension specialist centers in Asia. However, almost half of patients remain uncontrolled for morning BP according to new guidelines, with significant country/regional differences. Strict home BP control should be beneficial in Asian populations. The findings of this study are important to facilitate development of health policies focused on reducing cardiovascular complications in Asia. PMID- 30444317 TI - Injectable Biodegradable Chitosan-Alginate 3D Porous Gel Scaffold for mRNA Vaccine Delivery. AB - mRNA vaccines have proven to be more stable, effective, and specific than protein/peptide-based vaccines in stimulating both humoral and cellular immune response. However, mRNA's fast degradation rate and low-transfection efficiency in vivo impede its potential in vaccination. Recent research in gene delivery has focused on nonviral vaccine carriers and either implantable or injectable delivery systems to improve transgene expression in vivo. Here, an injectable chitosan-alginate gel scaffold for the local delivery of mRNA vaccines is reported. Gel scaffold biodegradation rates and biocompatibility are quantified. Scaffold-mediated mRNA in vivo transgene expression as well as ovalbumin antigen specific cellular and humoral immune responses are evaluated in vivo. Luciferase reporter protein expression resulting from mRNA lipoplex-loaded gel scaffolds is five times higher than systemic injection. Compared to systemic injections of naked mRNA or mRNA:lipoplexes, elevated levels of T cell proliferation and IFN gamma secretion are seen with in vivo scaffold-mediated mRNA lipoplex delivery. Furthermore, a humoral response (ovalbumin antigen specific IgG levels) is observed as early as week 1 for scaffold-mediated mRNA lipoplex delivery, while protein-based immunization did not elicit IgG production until 2 weeks post injection. Results suggest that injectable scaffold mRNA vaccine delivery maybe a viable alternative to traditional nucleic acid immunization methods. PMID- 30444318 TI - Preparation of a Monolithic Column with Mixed-Mode Stationary Phase of Reversed Phase/Hydrophilic-Interaction for Capillary Liquid Chromatography. AB - A monolithic capillary column with a mixed-mode stationary phase of reversed phase/hydrophilic-interaction chromatography was prepared for capillary liquid chromatography. The monolith was created by an in-situ copolymerization of a home made monomer N,N-dimethyl-N-acryloxyundecyl-N-(3-sulfopropyl) ammonium betaine and a cross-linker pentaerythritol triacrylate in a binary porogen agent consisting of methanol and isopropanol. The functional monomer was designed to have a highly polar zwitterionic sulfobetaine terminal group and a hydrophobic long alkyl chain moiety. The composition of the polymerization solution was systematically optimized to permit the best column performance. The columns were evaluated by using acidic, basic, polar neutral analytes, as well as a set of alkylbenzenes and Triton X100. Very good separations were obtained on the column with the mixed-mode stationary phase. It was demonstrated that the mixed-mode stationary phase displayed a typic dual retention mechanisms of reversed phase/hydrophilic-interaction liquid chromatography depending on the content of acetonitrile in the mobile phase. The method for column preparation is reproducible. This article is protected by copyright. All rights reserved. PMID- 30444319 TI - Extraction and Antioxidant Activities of Magnolia kwangsiensis Figlar & Noot. Leaf Polyphenols. AB - Microwave-assisted extraction was employed to extract polyphenols from the leaf of Magnolia kwangsiensis Figlar & Noot.. The polyphenols yield was 2.44+/-0.02% under the optimal conditions of RSM: acetone concentration of 70%, ratio of solvent to material of 21 mL.g -1 and extraction time of 16 min. The antioxidant activities were evaluated in terms of total antioxidant ability, reducing power, DPPH. and .OH scavenging activity. Results showed the polyphenols presented potential antioxidant activities, especially the stronger scavenging activity on .OH. In term of .OH scavenging activity, the IC50 value of NKA-9 purification was 0.335 mg.mL-1, equivalent to 35.23% of VC. And the IC50 values of crude extract and ethyl acetate extract were 0.580 and 0.828 mg.mL-1, equivalent to 60.99% and 87.07% of VC. Results indicated that M. kwangsiensis leaf polyphenols present potential antioxidant activities that make it beneficial for human health by preventing or reducing oxidative damage. PMID- 30444320 TI - Does the 'equal management of equal risks' model cause overtreatment in patients with positive cervical cytology results for ASCUS/non-HPV16/18 oncogenic types? AB - OBJECTIVES: According to the American Society of Colposcopy and Cervical Pathology (ASCCP), cervical cytology patients who test positive for atypical squamous cells of undetermined significance (ASCUS) and the human papilloma virus (HPV) positive are recommended to undergo colposcopies. This study compared the colposcopic biopsy evaluation results of patients with positive cervical cytology results for ASCUS and HPV with regards to their HPV genotypes. METHODS: This study included 179 patients who underwent cervical cancer screening tests between June 2015 and June 2017 and whose results displayed positive cervical cervical cytology results for ASCUS and HPV. Cytological samples were classified using the Bethesda system in liquid-based specimens. The Hybrid Capture II system was used to define the HPV-DNA. Colposcopic diagnoses and biopsy results were compared in terms of the outcomes of the Pap test and HPV genotypes. RESULTS: There were 107 ASCUS/HPV16/18-positive patients. Of the HPV 16/18 positive patients; 28 (26.1%) patients were detected with CIN1, 8 (7.5%) patients were detected with CIN2, 6 (6%) patients were detected with CIN3, and 1 (0.9%) patient was detected with cervical cancer. Of the 72 non-HPV 16-18 positive patients; 8 (11%) patients were detected with CIN1 and 2 (2.7%) patients were detected with CIN2. CONCLUSION: This study believes that the ASCCP recommendations, which state that a 'colposcopy should be performed on all women with positive cytology for ASCUS/non HPV16/18 oncogenic types', is required to be revised. This will reduce the rate of the colposcopy procedures by 40% in women with ASCUS/HPV positivity. PMID- 30444321 TI - Rapid determination of nosiheptide in feed based on dispersive SPE coupled with HPLC. AB - A novel, simple and reliable method based on high-performance liquid chromatography coupled with fluorescence detection has been developed for the determination of nosiheptide in feed. The feed samples were extracted with acetonitrile-0.1% formic acid aqueous solution and then purified via a dispersive SPE procedure using silica gel powder as the sorbent. Using a mixture of acetonitrile and 5 mM ammonium acetate solution (containing 0.1% formic acid) as the mobile phase, good separation and peak shape were obtained for nosiheptide on a Poroshell C8 column (250 mm * 4.6 mm id, 4 MUm) via the isocratic elution program. The resulting calibration curve shows high levels of linearity (r2 > 0.999) for nosiheptide concentrations of 50.0-1000 MUg/L. At three spiked levels, i.e., 0.500, 2.50 and 5.00 mg/kg, the intraday and interday recoveries of nosiheptide in five types of feed ranged from 78.5-96.8% and from 84.9-94.2%, respectively. The intraday and interday relative standard deviations were less than 10.8%. The limits of quantification for nosiheptide in complete feed and premixes were measured as 50.0 and 100 MUg/kg, respectively. Compared with other common adsorbents, silica gel presents stronger recovery and purification results for feed samples during the dispersive SPE process. This article is protected by copyright. All rights reserved. PMID- 30444322 TI - Use of an Evidence-Based Guideline for Management of Side Effects from Long Acting Reversible Contraceptives: A Quality Improvement Report. AB - INTRODUCTION: Many health care providers believe that women who initiate long acting reversible contraceptives (LARC) discontinue the method because of side effects too soon for the method to be economical. The purpose of this quality improvement project was to implement and evaluate an evidence-based telephone triage nursing guideline for management of side effects of LARC with an ultimate goal of reducing the number of early discontinuations. PROCESS: A telephone triage guideline was adapted from the Contraceptive Choice Project's Clinician Call Back System, supplemented with evidence-based resources, and approved by clinicians at 2 community women's health and midwifery offices. Baseline retrospective data were collected on all women over the age of 18 who had LARC inserted at the 2 sites in the year prior to guideline implementation and in the 3 months after implementation. Rates of LARC removal at or before 3 months postinsertion, before and after guideline implementation, were evaluated. OUTCOMES: Approximately 1 in 5 women called for help managing LARC side effects. Of the callers, 3 of 32 (9.4%) women receiving standard care discontinued their LARC prior to 3 months, whereas 0 of 24 women who were triaged using the guideline discontinued their LARC prior to 3 months (P = .12). Cramping, bleeding, and malposition or expulsion were the most common concerns and reasons for discontinuation. DISCUSSION: Fewer women than anticipated called to report side effects, and even fewer chose to discontinue their LARC early. There were fewer discontinuations with guideline use, but this was not a statistically significant difference. Most women did not discontinue their LARC early for any reason, including side effects. PMID- 30444323 TI - Ileal pouch revision vs. excision: short-term (30-day) outcomes from the National Surgical Quality Improvement Program. AB - AIM: Ileal pouch-anal anastomosis failure occurs in approximately 5 - 10% of patients. We aimed to compare short-term (30-day) post-operative outcomes associated with pouch revision and with pouch excision using a large international database. Our null hypothesis was that there is no statistically significant difference in overall post-operative complications between patients selected for pouch revision vs. pouch excision. METHODS: Using the American College of Surgeons National Quality Improvement Program (NSQIP) Participant User File from 2005 - 2016 we identified patients who underwent either IPAA revision via combined abdominoperineal (AP) approach (CPT 46712) or IPAA excision (CPT 45136). Differences in baseline characteristics and short-term outcomes between groups were assessed with univariate and matched analyses. RESULTS: We identified 593 re-operative IPAA procedures: revision group 78 (13%) and excision group 515 (86%). The groups had similar age and BMI (kg/m2), but the revision group had more women (65.4% vs. 51.8%, p=0.02) and fewer were on chronic steroids (3.9% vs. 17.9%, p=0.0008) relative to the excision group. Revision IPAA patients were more likely to have received a preoperative transfusion (5.1% vs. 0.97%, p=0.02). Revision and excision were associated with similar post-operative length of stay (9.3 vs. 8.6 days, 0.44), mortality (nil vs. 0.58%, respectively: p=0.99) and short-term morbidity (34.6% vs. 40.2%, respectively, p=0.88) at 30-days. CONCLUSIONS: Pouch revision and excision have comparable short-term post operative outcomes, but pouch excision is appears to be more commonly utilized. Increased awareness of the indications for pouch revision or referral to specialized centers may improve pouch excision rates. This article is protected by copyright. All rights reserved. PMID- 30444324 TI - The influence of the manufacturing process of rotary files on the shaping of L shaped canals. AB - BACKGROUND: The nickel-titanium alloy used in the production of nickel-titanium files contains approx. 56% nickel and 44% titanium by weight. To improve the properties of nickel-titanium files, the manufacturers introduce some innovations in the production process. Their purpose is primarily to decrease the stiffness of the instruments while increasing the resistance to cyclic fatigue, which reduces the risk of file separation. One of the most popular processes is the heat treatment of the nickel-titanium alloy. OBJECTIVES: The aim of the research was to determine the influence of the manufacturing process of rotary files on the shaping of L-shaped canals. MATERIAL AND METHODS: Fifty L-shaped resin canals were instrumented (10/group) with ProTaper Universal (r), ProTaper Next(r), Hyflex CM(r), Hyflex EDM(r), or WaveOne Gold(r) files, with the same apical size of 25. Each L-shaped resin canal was photographed both before and after instrumentation. Differences between the change of the working length and apical transportation were analyzed statistically. RESULTS: The smallest mean loss of the working length was observed after instrumentation with Hyflex CM files. Statistically significant differences in the working length were found between ProTaper Universal and Hyflex CM (p = 0.0032), ProTaper Universal and Hyflex EDM (p = 0.021), and ProTaper Universal and WaveOne Gold (p = 0.0112) files. The lowest apical transportation was noted in the case of WaveOne Gold files. In terms of apical transportation, statistically significant differences were observed between ProTaper Universal and WaveOne Gold files (p = 0.0254). Shaping Lshaped canals with the ProTaper Universal file system resulted in the greatest changes in the working length (x = 0.35 mm) and apical transportation (x = 0.034 mm). CONCLUSIONS: The study, with its limitations, shows that in the files whose nickel-titanium alloy was subjected to a thermal treatment process, a smaller loss of the working length and lower values of apical transportation were observed. PMID- 30444325 TI - ONJ UPDATE 2018 CONGRESS ABSTRACTS Osteonecrosi delle ossa mascellari (ONJ) da bifosfonati e altri farmaci: prevenzione, diagnosi, farmacovigilanza, trattamento. Alessandria, 5 maggio 2018. PMID- 30444326 TI - [Methods for evaluating the economic efficiency of the project of PET-center's creation in conditions of a specialized medical institution]. AB - This study evaluates the cost-effectiveness of the project of PET center's creation in the structure of specialized institution. To analyze the effectiveness and stability of obtained results there are used estimations of discounted factors, the flow and the amount of investments and the income at different discount rates. The figures revealed that the project should generate revenue as at zero discount rate it pays off. PMID- 30444327 TI - [Cancer stem cells as a possible source of tumor initiation and progression]. AB - Cancer stem cells may be a source of malignant tumors as well as their relapses after treatment and metastases. They share many features with normal tissue stem cells but also possess mutations and other genetic and epigenetic changes that make them tumorigenic and resistant to conventional cancer therapies. The source of cancer stem cells is discussed: they may originate from normal tissue stem cells as a result of their mutations or deregulation of signaling pathways or alternatively from differentiated tumor cells as a result of dedifferentiation during tumor development. Cancer stem cells reside in a special tumor microenvironment (niche) that regulates their functions. A number of signaling pathways and molecules participate in regulating cancer stem cells features. And although there are some inconsistencies concerning cancer stem cells, their existence may change our view on cancer progression and help to develop new strategies of cancer treatment. PMID- 30444328 TI - [Radioimmunotherapy: current state of the problem]. AB - This review presents modern data about one of the promising direction in treatment of malignancies, which is called radioimmunotherapy. The special attention is paid to search of new targets and development of radiopharmaceuticals that will allow improving quality and accuracy of the directed impact on tumors of various localizations. PMID- 30444330 TI - [Neutrophils as tumor microenviroment member]. AB - Conception of the neutrophils role in the immune system has been changed significantly in the recent time. Many studies prove important and diversified role of this cells in the cancer biology in the last few years. It was shown that their presence in tumor microenvironment has mixed role on cancer growth. This review summaries evidence of neutrophils heterogeneity, plasticity and ability to differentiate into other myeloid types of cells despite formed proinflammatory potential. Prognostic value of tumor-associated neutrophils and high neutrophil level in peripheral blood in patients with different type of malignancies (i.e. renal cell cancer, melanoma, colorectal cancer, hepatocellular cancer, cholangiocarcinoma, glioblastoma, gastrointestinal stromal tumors, gastric cancer, lung cancer, ovarian cancer, head and neck cancer) is discussed. More sophisticated study of existence and functional activity of pro- and antitumor abilities of neutrophils is needed for finding new diagnostic and therapeutic approaches in oncology. PMID- 30444329 TI - [Current possibilities of clinical applications of breast tumors typing expression]. AB - Whole-genome expression analysis methods significantly clarified contemporary breast cancer classification. Besides today clinical practice lacks the use of expression methods due to complexity of conduction, analysis and lack of clinical application. Further studies of breast cancer expression characteristics and clinical trials with stratification based of phonotypical features may improve the results of existing anticancer agents. Creation of limited clinically applicable test system, which incorporates all the specific breast cancer subtypes is currently needed. PMID- 30444331 TI - [Clinical studies of ABC-transporters contribution to the multidrug resistance of breast cancer]. AB - This review summarizes the clinical trials of the relationship of gene expression and protein ABC-transporters in breast cancer with the response to neoadjuvant chemotherapy (NAC) and survival of patients. In a large clinical material is considered the pre-treatment multidrug resistance (MDR) and adaptive MDR, that occurs in tumor cells during chemotherapy. Association pre-treatment MDR with NAC efficiency and survival is highly variable and not well-established. In all clinical trials, adaptive MDR showed a good association with NAC efficiency and survival of patients. The own results showed that 5-year distant metastasis-free survival was 73-78% and good response to NAC in patients with a decrease in ABC- expression. The up-regulation of these genes during NAC was related to a significant decrease (up to 50-55%) in metastasis-free survival and poor response to NAC. In the development of strategies to overcome MDR phenotype it is concluded based on the submitted clinical data. PMID- 30444332 TI - [Epidemiological characteristics of malignant tumor incidence of the population of the Perm region]. AB - The article presents the results of an epidemiological descriptive and retrospective study of the malignant tumor incidence in the Perm region according to official statistics for the 2002-2014. Through the use of standardized rates it was revealed that the incidence of growth mainly due to an increased risk of illness because of the intensification of epidemiological factors (13,1%). Changes in the total extent and structure of population resulted in growth of number of cases by 3,5% of the total increase. Over 80% of the total incidence was recorded among persons older than 50 years. Cancer of the breast, skin, colon and rectum and lung were characterized by the greatest intensity of oncoepidemiological process. The highest growth rate of incidence had ovarian cancer, cervical cancer, endometrial cancer and prostate cancer. PMID- 30444334 TI - [Technology of puncture cryosurgery for soft tissue tumors]. AB - The technology and the first experience of the local cryotherapy for tumors of the breast, lateral triangle of the neck and lumbar area using ultrasound navigation of cryoprobes and new medical equipment are presented. PMID- 30444333 TI - [25-year trends of incidence and mortality from liver cancer and viral hepatitis in Novosibirsk]. AB - The article presents data of Cancer Registry in Novosibirsk for the period 1988 2012 concerning primary liver cancer. Over the period studied the incidence and mortality have declined significantly (2,5 and 2,1 times, respectively). Both figures fall in line for men and women being generally twice as high in men. The long-term trends of main etiologic risk factor for liver cancer (prevalence of hepatitis viruses B and C in the population) are shown. The issues of screening and prevention are discussed. PMID- 30444335 TI - [Quantitative estimation of tumor size and density by computed tomography images during adaptive radiation therapy]. AB - The purpose of this study is to demonstrate clinically available quantitative method (special program) of estimation dynamics of tumor size and physical density (g/cm3) during adaptive radiation therapy of cancer patients for any occasion of visualization of tumor borders including the cases when tumor border is not clearly visualized. It has been showed quantitative information content of this method that could be used in clinical practice. PMID- 30444336 TI - [Results of surgical and combined treatment for nonsmall cell lung cancer with postoperative radiation therapy in a mode of hypofranctionation. Post II. Relapse free survival and survival without locoregional recurrence]. AB - Conducting postoperative radiotherapy in a mode of hypofranctionation with SFD 3Gy to TFD-36-39Gy (EQD2 = 43,246,8Gy) in combined treatment of patients with non small cell lung cancer allows significantly increasing a 5-year disease-free survival at IIB-IIIB stages of the disease (pN1-2) as well as the central cancer, squamous cell morphological type of tumor after surgery in a volume of lob bilobectomy. The clearest effect of postoperative radiotherapy is assessed by survival without locoregional recurrence where radiation therapy in the adjuvant setting allows achieving a statistically significant increase in local control of the disease to the level of 85-95% regardless of stage of the disease, tumor size, regional lymph nodes lesion and the surgical treatment. PMID- 30444337 TI - [Hormone-associated properties and plasticity of omental fat: the relation with clinical-morphological features of endometrial cancer in patients with different obesity phenotypes]. AB - The authors aimed to compare expression of UCP1, aromatase (CYP19), markers of macrophage infiltration (CD68, CD163), omentin and PTEN in omental fat of endometrioid or non-endometrioid endometrial cancer (EC) patients with signs of standard (SO) or metabolically healthy obesity (MHO) by immunohistochemical (IHC) or real-time PCR methods. Totally 57 omental fat samples collected during surgery in EC pts (average age 60.1) were studied. According to IHC data, statistically significant decrease in expression of aromatase and CD68 was revealed in omental fat of MHO patients. Expression of UCP1 demonstrated an inclination to decrease in the same group, simultaneously showing correlation with clinical stage of EC. According to real time PCR data, omentin expression displayed tendency to an increase with increase in body mass index (whole group), clinical stage of EC (in SO subgroup) and serum omentin level (MHO subgroup). No any difference in studied omental fat parameters was discovered between patients with endometrioid and non endometrioid EC. Thus, omental fat properties in EC patients are associated with obesity phenotype and not with histologic subtype of this cancer. Apparently, the features of omental fat depot characteristic for visceral adipose tissue at least are equal to its attributes as a brown fat compartment. Decrease, according to IHC info, of the estrogen biosynthesis and macrophagal infiltration in omental fat of EC patients with MHO phenotype may indicate additional mechanisms for more favorable in this case clinical course of uterine body cancer. Supported by RFBR grant 15-04-00384. PMID- 30444338 TI - [Results of palliative thermochemotherapy for colorectal cancer metastases to the liver]. AB - The purpose of the study is to investigate the effectiveness of thermochemotherapy in patients with colorectal cancer metastases to the liver in palliative mode. Loco-regional hyperthermia in combination with chemotherapy was applied to 33 patients. The comparison group was of 40 patients who underwent only chemotherapy. 5-fluorouracil (5-FU) or capecitabine over standard regimens were used for chemotherapy in both groups. Loco-regional hyperthermia was carried out by capacitive method for 40-90 minutes at a maximum temperature within 41-44 degrees C in tumor. No significant differences in dynamics of the overall status, clinical symptoms of the disease and biochemical parameters between the groups were revealed. In the group of patients with thermochemotherapy there were received a complete response in 3 patients (9%), partial response - in 14 patients (44%) while in the group of patients with chemotherapy - in 1 patient (3%) and 11 patients (28%), respectively. The significant difference was found in terms of objective response, i.e. summarized parameters of complete and partial regression (p=0.04). Thermochemotherapy compared with chemotherapy significantly increased survival rates of patients. PMID- 30444339 TI - Recyclable Visible Light-Driven O-g-C3N4/Graphene Oxide/N-Carbon Nanotube Membrane for Efficient Removal of Organic Pollutants. AB - Organic pollutants are harmful to human health, which creates a global need for the development of novel and effective materials for efficiently removing contaminants. Accordingly, an efficient visible light-driven heterostructured membrane combined with oxygen-modified monolayer g-C3N4, graphene oxide, and nitrogen-doped carbon nanotubes (CNTs) (O-g-C3N4/GO/N-CNT) was successfully fabricated through electrostatic interactions and subsequent vacuum filtration. The results suggested that the O-g-C3N4/GO/N-CNT membrane exhibited higher degradation rate than those of O-g-C3N4/GO and pure O-g-C3N4 under visible light exposure. This enhanced photocatalytic performance was attributed to the introduction of GO and N-CNT, which acted as electronic acceptors for monolayer O g-C3N4 that effectively inhibited recombination of photogenerated electron-hole pairs, thus enhancing visible light photocatalytic activity. Furthermore, the enrichment and degradation rates of O-g-C3N4/GO/N-CNT membranes were demonstrated for tetracycline hydrochloride, which were found to be 96.64 and 94.30%, respectively, and no distinct enrichment or catalytic activity reduction was observed when their reusability was measured. These results suggested that these recyclable O-g-C3N4/GO/N-CNT membranes provide a new strategy for the highly efficient removal of environmental pollutants. PMID- 30444340 TI - Disulfiram Copper Nanoparticles Prepared with a Stabilized Metal Ion Ligand Complex Method for Treating Drug-Resistant Prostate Cancers. AB - Disulfiram (DSF), an alcohol-aversion drug, has been explored for cancer treatment. Copper diethyldithiocarbamate (Cu(DDC)2) complex formed by DSF and copper ions is a major active ingredient for its anticancer activity. Direct administration of Cu(DDC)2 is a promising strategy to enhance the anticancer efficacy of DSF. However, efficient drug delivery remains a significant challenge for Cu(DDC)2 and hinders its clinical use. In this study, we developed a facile stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)2 nanoparticles (NPs). The SMILE method could prepare Cu(DDC)2 NPs with different types of stabilizers including 1,2-distearoyl- sn-glycerol-3-phosphoethanolamine poly(ethylene glycol) (PEG) 2000, d-alpha-tocopherol PEG 1000 succinate, methoxy PEG 5000- b-poly(l-lactide) 5000, and other generally recognized as safe excipients approved by the US Food and Drug Administration. The optimized formulations demonstrated excellent drug-loading efficiency (close to 100%), high drug concentrations (increased drug concentration by over 200-fold compared to the traditional micelle formulation), and an optimal particle size in the sub-100 nm range. Cu(DDC)2 NPs exhibited outstanding stability in serum for 72 h and can also be stored at room temperature for at least 1 month. The anticancer effects of Cu(DDC)2 NP formulations were determined by multiple assays including 3-(4,5 dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, colony-forming assay, calcein-AM/propidium iodide staining, and others. Cu(DDC)2 NPs showed excellent activity against drug-resistant prostate cancer cells and other cancer cells with a half-maximal inhibitory concentration (IC50) of around 100 nM. Our study also demonstrated that Cu(DDC)2 NPs induced cell death in drug-resistant prostate cancer cells (DU145-TXR) through paraptosis, which is a nonapoptotic cell death. To our best knowledge, the SMILE method provides, for the first time, a simple yet efficient process for generating Cu(DDC)2 NPs with high drug concentration, excellent loading efficiency, and desirable physicochemical properties. This method could potentially address drug delivery challenges of DSF/copper-based chemotherapy and facilitate its clinical translation. PMID- 30444341 TI - Plasma Functionalization of Polycaprolactone Nanofibers Changes Protein Interactions with Cells, Resulting in Increased Cell Viability. AB - The surface properties of electrospun scaffolds can greatly influence protein adsorption and, thus, strongly dictate cell-material interactions. In this study, we aim to investigate possible correlations between the surface properties of argon, nitrogen, and ammonia and helium plasma-functionalized polycaprolactone (PCL) nanofibers (NFs) and their cellular interactions by examining the protein corona patterns of the plasma-treated NFs as well as the cell membrane proteins involved in cell proliferation. As a result of the performed plasma treatments, PCL NFs morphology was preserved, while wettability was improved profoundly after all treatments because of the incorporation of polar surface groups. Depending on the discharge gas, different types of groups are incorporated, which influenced the resultant cell-material interactions. Argon plasma-functionalized PCL NFs, only enriched by oxygen-containing functional groups, were found to show the best cell-material interactions, followed by N2 and He/NH3 plasma-treated samples. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and liquid chromatography-mass spectrometry clearly indicated an increased protein retention compared with non-treated PCL NFs. The nine proteins retained best on plasma treated NF are important mediators of extracellular matrix interaction, illustrating the importance thereof for cell proliferation and the viability of cells. Finally, 92 proteins that can be used to differentiate how the different plasma treatments are clustered and subjected to a gene ontology study, illustrating the importance of keratinization and extracellular matrix organization. PMID- 30444342 TI - Extreme Temperature-Tolerant Organohydrogel Electrolytes for Laminated Assembly of Biaxially Stretchable Pseudocapacitors. AB - Polymer gel electrolytes (PGEs) have been considered as one of the most promising candidates to solve safety and flexibility issues in wearable devices. To supply energy for the daily-used epidermal electronic systems, biaxial stretchability and temperature tolerance are essential for energy storage units. However, the limited choices of PGEs, including fragile poly(vinyl alcohol) and uniaxial stretchable polyacrylamide hydrogel, lag far behind the requirement of wearable supercapacitors. Herein, an adhesive organohydrogel with a water/ethylene glycol binary solvent is tailored as the electrolyte of an all-climate, biaxially stretchable pseudocapacitor. The adhesive organohydrogel electrolyte facilitates the device assembly with carbon nanotube (CNT) paper electrodes and electroactive 2-pyridinethiol. The final pseudocapacitor has the highest specific capacitance 364 F/g and all-climate stability ranging from -40 to 80 degrees C. More importantly, this pseudocapacitor can be biaxially stretched up to 400% of its area. This work provides the first example of using organohydrogel electrolytes in biaxially stretchable and all-climate pseudocapacitors and a platform to design stretchable electronics and devices with high performance and all-climate tolerance. PMID- 30444343 TI - Microneedle-Assisted Topical Delivery of Photodynamically Active Mesoporous Formulation for Combination Therapy of Deep-Seated Melanoma. AB - Topical treatment using photodynamic therapy (PDT) for many types of skin cancers has largely been limited by the inability of existing photosensitizers to penetrate into the deep skin tissue. To overcome these problems, we developed a mesoporous nanovehicle with dual loading of photosensitizers and clinically relevant drugs for combination therapy, while utilizing microneedle technology to facilitate their penetration into deep skin tissue. Sub-50 nm photodynamically active mesoporous organosilica nanoparticles were synthesized with photosensitizers covalently bonded to the silica matrix, which dramatically increased the quantum yield and photostability of these photosensitizers. The mesopores of the nanoparticles were further loaded with small-molecule inhibitors, i. e., dabrafenib and trametinib, that target the hyperactive mitogen activated protein kinase (MAPK) pathway for melanoma treatment. As-prepared empty nanovehicle was cytocompatible with normal skin cells in the dark, while NIR irradiated drug-loaded nanovehicle showed a synergistic killing effect on skin cancer cells mainly through reactive oxygen species and caspase-activated apoptosis. The nanovehicle could significantly inhibit the proliferation of tumor cells in a 3D spheroid model in vitro. Porcine skin fluorescence imaging demonstrated that microneedles could facilitate the penetration of nanovehicle across the epidermis layer of skin to reach deep-seated melanoma sites. Tumor regression studies in a xenografted melanoma mouse model confirmed superior therapeutic efficacy of the nanovehicle through combinational PDT and targeted therapy. PMID- 30444344 TI - Implanted Battery-Free Direct-Current Micro-Power Supply from in Vivo Breath Energy Harvesting. AB - In vivo biomechanical energy harvesting by implanted nanogenerators (i-NGs) is promising for self-powered implantable medical devices (IMDs). One critical challenge to reach practical applications is the requirement of continuous direct current (dc) output, while the low-frequency body activities typically generate discrete electrical pulses. Here, we developed an ultrastretchable micrograting i NG system that could function as a battery-free dc micro-power supply. Packaged by a soft silicone elastomer with a cavity design, the i-NG exhibited an ultralow Young's modulus of ~45 kPa and a high biocompatibility to soft biological tissues. The i-NG was implanted inside the abdominal cavity of Sprague Dawley adult rats and directly converted the slow diaphragm movement during normal respiration into a high-frequency alternative current electrical output, which was readily transmitted into a continuous ~2.2 V dc output after being integrated with a basic electrical circuit. A light-emitting diode was constantly operated by the breath-driven i-NG without the aid of any battery component. This solely biomechanical energy-driven dc micro-power supply offers a promising solution for the development of self-powered IMDs. PMID- 30444345 TI - Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa. AB - A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection. PMID- 30444347 TI - Flow-Assisted Switchable Catalysis of Metal Ions in a Microenvelope System Embedded with Core-Shell Polymers. AB - Many efforts have been made on stimuli-responsive switchable catalysis to trigger catalytic activity over various chemical reactions. However, the reported light-, pH- or chemically responsive organocatalysts are mostly incomplete in the aspects of shielding efficiency and long-term performance. Here, we advance the flow assisted switchable catalysis of metal ions in a microenvelope system that allows the on-off catalysis mode on demand for long-lasting catalytic activity. Various metal-ion catalysts can be selectively embedded in a novel polymeric core-shell of the heteroarm star copolymer of poly(styrene) and poly(4-vinylpyridine) emanated from a polyhedral oligomeric silsesquioxane center. The immobilized core shell polymer on the inner wall of a poly(dimethylsiloxane) envelope microreactor shows on-off switching catalysis between the expanded active mode and contracted protective mode under continuous flow of solvents or subsequent dry conditions. In particular, the preserved catalytic activity of toxic Hg2+ for oxymercuration was demonstrated even for 2 weeks without leaching, whereas the activity of moisture-sensitive Ru3+ ions for polymerization of methyl methacrylate was maintained even after 5 days from an open atmosphere. It is practical that the tight environment of the enveloped microfluidic system facilitates cyclic switching between the reaction-"on" and -"off" modes of such toxic, sensitive/expensive catalysts for long-term prevention and preservation. PMID- 30444346 TI - Guided Assembly of Block Copolymers in Three-Dimensional Woodpile Scaffolds. AB - Three-dimensional (3D) nanofabrication using the directed self-assembly of block copolymers (BCPs) holds great promise for the nanoscale device fabrication and integration into 3D architectures over large areas with high element densities. In this work, a robust platform is developed for building 3D BCP architectures with tailored functionality using 3D micron-scale woodpile structures (WPSs), fabricated by a multiphoton polymerization technique. By completely filling the spaces of the WPSs and using the interactions of the blocks of the BCPs with the struts of the WPS, well-developed 3D nanoscopic morphologies are produced. Metal ion complexation with one block of the copolymer affords a convenient stain to highlight one of the microdomains of the copolymer for electron microscopy studies but also, with the reduction of the complexing salt to the corresponding metal, a simple strategy is shown to produce 3D constructs with nanoscopic domain resolution. PMID- 30444348 TI - Monitoring metabolite production of aflatoxin biosynthesis by Orbitrap Fusion mass spectrometry and D-optimal mixture design method. AB - Aflatoxins, highly toxic and carcinogenic to humans, are synthesized via multiple intermediates by a complex pathway in several Aspergilli including Aspergillus flavus. Few analytical methods are available for monitoring the changes in metabolite profiles of the aflatoxin biosynthesis pathway under different growth and environmental conditions. In the present study, we developed by D-optimal mixture design a solvent system, methanol/dichloromethane/ethyl acetate/formic acid (0.36/0.31/0.32/0.01), that was suitable for extracting the pathway metabolites. Matrix effect from dilution of cell extracts was negligible. To facilitate the identification of these metabolites, we constructed a fragmentation ion library. We further employed liquid chromatography coupled with high-resolution mass spectroscopy (UHPLC-HRMS) for simultaneous quantification of the metabolites. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.002-0.016 MUg/kg and 0.008-0.05 MUg/kg, respectively. The spiked recovery rates ranged from 81.3% to 100.3% with intra-day and inter-day precision to be less than 7.6%. Using the method developed to investigate time-course aflatoxin biosynthesis, we found that precursors, including several possible toxins (with a carcinogenic group similar to aflatoxin B1) occurred together with aflatoxin, production increased rapidly at the early growth stage, peaked on day four and then decreased substantially. The maximum production of aflatoxin B1 and aflatoxin B2 occurred one day later. Moreover, the dominant branch pathway was the one for aflatoxin B1 formation. We revealed that the anti-aflatoxigenicity mechanism of Leclercia adecarboxylata WT16 was associated with a factor upstream of the aflatoxin biosynthesis pathway. The design strategies can be applied to characterize or detect other secondary metabolites to provide a snapshot of the dynamic changes during their biosynthesis. PMID- 30444349 TI - Ketoreductase domain dysfunction expands chemodiversity: malyngamide biosynthesis in the cyanobacterium Okeania hirsuta. AB - Dozens of type A malyngamides, principally identified by a decorated six-membered cyclohexanone head group and methoxylated lyngbic acid tail, have been isolated over several decades. Their environmental sources include macro- and microbiotic organisms, including sea hares, red alga, and cyanobacterial assemblages but their true producing organism has remained enigmatic. Many type A analogs display potent bioactivity in human-health related assays, spurring an interest in this molecular class and its biosynthetic pathway. Here we present the discovery of the type A malyngamide biosynthetic pathway in the first sequenced genome of the cyanobacterial genus Okeania. Bioinformatic analysis of two cultured Okeania genome assemblies identified 62 and 68 kb polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) pathways with unusual loading and termination genes. NMR data of malyngamide C acetate derived from 13C-substrate-fed cultures provided evidence that an intact octanoate moiety is transferred to the first KS module via a LipM homolog originally associated with lipoic acid metabolism and implicated an inactive ketoreductase (KR0) as critical for six-membered ring formation, a hallmark of the malyngamide family. Phylogenetic analysis and homology modeling of the penultimate KR0 domain inferred structural cofactor binding and active site alterations as contributory to domain dysfunction, which was confirmed by recombinant protein expression and NADPH binding assay. The carbonyl retained from this KR0 ultimately enables an intramolecular Knoevenagel condensation to form the characteristic cyclohexanone ring. Understanding this critical step allows assignment of a biosynthetic model for all type A malyngamides, whereby well-characterized tailoring modifications explain the surprising proliferation and diversity of analogs. PMID- 30444350 TI - Ultrasensitive Photoelectrochemical Assay with PTB7-Th/CdTe Quantum Dots Sensitized Structure as Signal Tag and Benzo-4-chlorohexadienone Precipitate as Efficient Quencher. AB - Herein, an ultrasensitive photoelectrochemical (PEC) assay was developed for the monitoring of microRNA-141 (miRNA-141) based on poly{4,8-bis[5-(2 ethylhexyl)thiophen-2-yl]benzo[1,2- b:4,5- b']dithiophene-2,6-diyl- alt-3-fluoro 2-[(2-ethylhexyl)carbonyl]thieno[3,4- b]thiophene-4,6-diyl}/CdTe quantum dots ( PTB7-Th/CdTe QDs) sensitized structure as signal tag and the benzo-4 chlorohexadienone (4-CD) precipitate as efficient quencher. PTB7-Th and CdTe QDs were successively modified on the electrode surface to form a novel sensitized structure with eminent photovoltaic performances and surpassing film-forming ability. The PTB7-Th/CdTe QDs sensitized structure served as signal tag for achieving a strong initial PEC signal. Besides, a tiny amount of target (miRNA 141) could be transformed into numerous DNA products via enzyme-assisted target cycling procedure, which further triggered the formation of a DNA supersandwich structure on the electrode surface for loading abundant manganese porphyrin (MnPP). Thereafter, MnPP as mimetic enzyme could catalyze 4-chloro-1-naphthol (4 CN) to generate 4-CD precipitate on the sensing interface in the presence of H2O2, which could efficiently block electron transfer, leading to a significantly quenched PEC signal for determination of miRNA-141. The designed PEC biosensor performed a wide detection range from 0.1 fM to 1 nM with a low detection limit of 33 aM for miRNA-141, which paved a new avenue for highly accurate and ultrasensitive monitoring of multifarious analytes in bioanalysis and clinical diagnosis. PMID- 30444351 TI - Cell-Membrane Immunotherapy Based on Natural Killer Cell Membrane Coated Nanoparticles for the Effective Inhibition of Primary and Abscopal Tumor Growth. AB - Developing effective immunotherapies with low toxicity and high tumor specificity is the ultimate goal in the battle against cancer. Here, we reported a cell membrane immunotherapy strategy that was able to eliminate primary tumors and inhibited distant tumors by using natural killer (NK) cell membrane cloaked photosensitizer 4,4',4'',4'''-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP)-loaded nanoparticles (NK-NPs). The proteomic profiling of NK cell membranes was performed through shotgun proteomics, and we found that NK cell membranes enabled the NK-NPs to target tumors and could induce or enhance pro inflammatory M1-macrophages polarization to produce antitumor immunity. The TCPP loaded in NK-NPs could induce cancer cell death through photodynamic therapy and consequently enhanced the antitumor immunity efficiency of the NK cell membranes. The results confirmed that NK-NPs selectively accumulated in the tumor and were able to eliminate primary tumor growth and produce an abscopal effect to inhibit distant tumors. This cell-membrane immunotherapeutic approach offers a strategy for tumor immunotherapy. PMID- 30444352 TI - Toward Automated Identification of Glycan Branching Patterns Using Multistage Mass Spectrometry with Intelligent Precursor Selection. AB - Glycans play important roles in a variety of biological processes. Their activities are closely related to the fine details of their structures. Unlike the simple linear chains of proteins, branching is a unique feature of glycan structures, making their identification extremely challenging. Multistage mass spectrometry (MS n) has become the primary method for glycan structural identification. The major difficulty for MS n is the selection of fragment ions as precursors for the next stage of scanning. Widely used strategies are either manual selection by experienced experts, which requires considerable expertise and time, or simply selecting the most intense peaks by which the product-ion spectrum generated may not be structurally informative and therefore fail to make the assignment. We here report a glycan "intelligent precursor selection" strategy (GIPS) to guide MS n experiments. Our approach consists of two key elements, an empirical model to calculate candidate glycan's probability and a statistical model to calculate fragment ion's distinguishing power in order to select the structurally most informative peak as the precursor for next-stage scanning. Using 15 glycan standards, including three pairs with isomeric sequences and eight variously fucosylated oligosaccharides on linear or branched hexasaccharide backbones isolated from a human milk oligosaccharide fraction by HPLC, we demonstrate its successful application to branching pattern analysis with improved efficiency and sensitivity and also the potential for automated operation. PMID- 30444353 TI - Exposure to Freeze-Thaw Conditions Increases Virulence of Pseudomonas aeruginosa to Drosophila melanogaster. AB - Groundwater contamination by pathogenic bacteria present in land-applied manure poses a threat to public health. In cold climate regions, surface soil layers experience repeated temperature fluctuations around the freezing point known as freeze-thaw (FT) cycles. With global climate change, annual soil FT cycles have increased, and this trend is expected to continue. It is therefore of interest to understand how FT cycles impact soil microbial communities. This study investigates the influence of FT cycles on the growth, culturability, biofilm formation, and virulence of the bacterial opportunistic pathogen Pseudomonas aeruginosa, a ubiquitous bacterium found in soil and water, responsible for infections in immunocompromised hosts. Our findings demonstrate that exposure to FT had no significant effect on growth or culturability of the bacteria. However, FT treatment significantly increased biofilm formation and delayed the onset of swimming motility, factors that are important for the pathogenicity of P. aeruginosa. An in vivo study using a chronic infection model revealed an increase in the virulence of P. aeruginosa after FT exposure. These results suggest that the impact of climate change on natural FT cycles may be affecting the ecology of soil-borne pathogens and host-pathogen interactions in unexpected ways. PMID- 30444354 TI - Sum Frequency Generation Vibrational Spectroscopy Using Evanescent Waves-Toward Probing Irregular and Complex Surfaces of Mesoscopic-Scale Materials. AB - With the rapid development of materials science, on-demand techniques are highly needed with the capability to characterize materials in the micrometer and nanometer scales. In this work, we show that, by employing a prism geometry, total internal reflection sum frequency generation (SFG) vibrational spectroscopy allows for characterizing mesoscopic materials with irregular or complex surfaces. Four representative examples were presented. First, we reveal that mechanical grinding can subtly alter the surface molecular structures of original materials. Second, spin coating can substantially change the surface molecular structures of particle samples. Third, surface restructuring of carboxylated multiwalled carbon nanotubes can happen in response to the surrounding environment. Fourth, surface adsorption and desorption dynamics of toluene on activated charcoal can be traced. Such experiments demonstrate that there are still a broad range of research fields ahead SFG can be directed to, where materials in mesoscopic scales with irregular or complex surfaces can be studied. PMID- 30444355 TI - Application of a Novel Coarse-Grained Soil Organic Matter Model in the Environment. AB - Soil organic matter (SOM) is ubiquitous in the environment. Intensive efforts have been made to find effective ways to assess the interaction of SOM with contaminants since such interactions are one of the important criteria used to evaluate the migration, persistency and bioavailability of chemicals in the environment. This study aims to extend the application of coarse-grained (CG) dissipative particle dynamics (DPD) to the water/SOM system and predict contaminant mobility in the system. The CG model was based on the Vienna Soil Organic-Matter Modeler, which can generate flexible condensed-phase models of SOM. A series of DPD simulations was performed to investigate the mobility of perfluorinated sulfonic acids (PFSAs) and hexachlorobutadiene (HCBD). The results indicated that the mobility of PFSAs decreased with increasing length in the carbon chain. In addition, HCBD and hexachlorobenzene (HCB) have similar diffusion coefficients, indicating analogous behavior in SOM. Moreover, water containing SOM layers may reflect a more realistic situation. This work, coupling the CG method with DPD simulation, provides a new high-efficiency tool to assess the behavior of contaminants in the environment. PMID- 30444356 TI - Boron Can Be Used to Predict Trace Organic Rejection through Reverse Osmosis Membranes for Potable Reuse. AB - Potable water reuse is a viable option for communities with extreme water scarcity. Improvements in measurement capabilities and greater occurrence of contaminants of emerging concern (CECs) have made the investigation of the removal of CECs through advanced treatment facilities essential for further reuse considerations. Reverse osmosis (RO) has been demonstrated to remove many CECs, but poor removal has been observed for many low molecular weight (MW), neutral organic compounds. With the availability of many RO membrane products on the market, it is increasingly important to be able to predict organics rejection through different products without detailed information about the RO membrane's properties or structure. This laboratory-scale study investigated the rejection of low-MW, neutral organics, boron, and sodium chloride by six RO membrane products. The experimental results were used to develop a correlation between the removal of organics and boron. If the rejection of boron and a neutral organic through one reference membrane is available, then the rejection of that organic through any other membrane product can be estimated using the rejection of boron through that membrane. PMID- 30444357 TI - Intelligent Micro/nanomotors with Taxis. AB - Micro/nanomotors (MNMs) are micro/nanoscale devices that can convert energy from their surroundings into autonomous motion. With this unique ability, they may revolutionize application fields ranging from active drug delivery to biological surgeries, environmental remediation, and micro/nanoengineering. To complete these applications, MNMs are required to have a vital capability to reach their destinations. Employing external fields to guide MNMs to the targets is common and effective way. However, in application scenarios where targets are generally unknown or dynamically change, MNMs must possess the capability of self navigation or self-targeting. Taking advantage of tactic movements toward or away from signal sources, numerous intelligent MNMs with self-navigation or self targeting have been demonstrated and attracted much attention during the past few years. In this Account, we elucidate the intelligent response mechanisms of such tactic MNMs, which are summarized as two main models. One is that local vector fields, including those of chemical concentration gradients, gravity, flows, and magnetic fields existing in systems, achieve the overall alignment of asymmetric MNMs via aligning torques, directing the MNMs to swim toward or away from the signal sources. Another is that isotropic MNMs may produce propulsion forces with direction solely determined by the local vector field regardless of their Brownian rotations. Then we discuss and highlight the recent progress in tactic MNMs, including chemotactic, phototactic, rheotactic, gravitactic, and magnetotactic motors. Artificial chemotactic MNMs can be designed with different morphologies and compositions if asymmetric reactions are associated with chemical concentration gradients. In these systems, asymmetric phoretic slip flows are induced, leading to torques that enable the anisotropic particles to align and exhibit chemotaxis. For phototactic MNMs, light irradiation establishes asymmetric fields surrounding the motors via light-induced chemical reactions or physical effects to generate phototactic motion. Shape-asymmetric MNMs reorient in natural fluid flows because of torques applied by the flows, inducing rheotactic movements. MNMs with either the centroid or magnetic components distributed asymmetrically maintain orientation under the torque triggered by gravity or magnetic forces, generating tactic motions. In the end, we envision the future development of synthetic tactic MNMs, including enhancement of the sensitivity of motors to target signals, increasing the diversity of chemical motor systems, and combining multiple mechanisms to endow the tactic motors with multiple functionality. By highlighting the current achievements and offering our perspective on tactic MNMs, we look forward to inspiring the emergence of the next generation of intelligent MNMs with taxis. PMID- 30444358 TI - SN2"-Selective and Enantioselective Substitution with Unsaturated Organoboron Compounds and Catalyzed by a Sulfonate-Containing NHC-Cu Complex. AB - The first broadly applicable strategy for SN2"-selective and enantioselective catalytic substitution is disclosed. Transformations are promoted by 5.0 mol% of a sulfonate-containing NHC-Cu complex (NHC = N-heterocyclic carbene), and are carried out in the presence of commercially available allenyl-B(pin) (pin = pinacolato) or a readily accessible silyl-protected propargyl-B(pin). Acyclic, or aryl-, heteroaryl-, and alkyl-substituted penta-2,4-dienyl phosphates, as well as those bearing either only 1,2-disubstituted olefins or a 1,2-disubstituted and a trisubstituted alkene were found to be suitable starting materials. Cyclic dienyl phosphates may also serve as substrates. The products containing, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moiety (from reactions with allenyl-B(pin)) were obtained in 51-82% yield, 84-97% SN2" selectivity, 89:11-97:3 E: Z ratio, and 86:14-98:2 enantiomeric ratio (er). Reactions with a silyl-protected propargyl-B(pin) compound led to the formation of the corresponding silyl-allenyl products in 53-89% yield, 69-96% SN2" selectivity, 98:2 to >98:2 E: Z ratio, and 94:6-98:2 er. Insight regarding several of the unique mechanistic attributes of the catalytic process was obtained on the basis of kinetic isotope effect measurements and DFT studies. These investigations indicate that cationic pi-allyl-Cu complexes are likely intermediates, clarifying the role of the s-cis and s-trans conformers of the intermediate organocopper species and their impact on E: Z selectivity and enantioselectivity. The utility of the approach is demonstrated by chemoselective functionalization of various product types, through which the propargyl, allenyl, or 1,3-dienyl sites within the products have been converted catalytically and chemoselectively to several useful derivatives. PMID- 30444359 TI - Theoretical Model of Exciton States and Ultrafast Energy Transfer in Heliobacterial Type I Homodimeric Reaction Center. AB - A simple theoretical model of exciton dynamics was proposed to interpret the fast excitation energy-transfer process in the type I homodimeric reaction center of Heliobacterium modesticaldum (hRC); this structure was recently identified and shown to resemble that of the plant/cyanobacterial photosystem I (PSI) reaction center. The exciton state model, which mainly relies on the geometries of 54 bacteriochlorophyll (BChl) g, 4 BChl- g', and 2 chlorophyll (Chl) a on hRC and assumes constant site energy values for the pigments, reproduced the absorption spectrum of hRC rather well. The model also enabled numerical analysis of the exciton dynamics on hRC, which can be compared with the decay-associated spectra obtained by the laser spectroscopy experiments. The model indicates that the stronger transition-dipole moment on BChl- g contributes to the faster energy transfer due to the higher coherency of the delocalized exciton states on hRC compared to that on PSI that arranges Chl- a at almost homologous locations. PMID- 30444360 TI - Synthesis and Biological Evaluation of Cajaninstilbene Acid and Amorfrutins A and B as Inhibitors of the Pseudomonas aeruginosa Quorum Sensing System. AB - The quorum sensing (QS) system inhibitors of Pseudomonas aeruginosa are thought to attenuate bacterial pathogenicity and drug resistance by inhibiting biofilm formation and the production of virulence factors. In this study, a synthetic approach to the natural products cajaninstilbene acid (1) and amorfrutins A (2) and B (3) has been developed and was characterized by the Heck reaction, which was used to obtain the stilbene core and a Pinick oxidation to give the O hydroxybenzoic acid. The biological activities of these compounds against the P. aeruginosa quorum sensing systems were evaluated. Amorfrutin B (3) showed promising antibiofilm activity against P. aeruginosa PAO1 with a biofilm inhibition ratio of 50.3 +/- 2.7. Three lacZ reporter strains were constructed to identify the effects of compound 3 on different QS systems. Suppression efficacy of compound 3 on the expression of lasB-lacZ and pqsA-lacZ as well as on the production of their corresponding virulence factors elastase and pyocyanin was observed. PMID- 30444361 TI - Nucleophilicity and Electrophilicity Parameters for Predicting Absolute Rate Constants of Highly Asynchronous 1,3-Dipolar Cycloadditions of Aryldiazomethanes. AB - Kinetics of the reactions of aryldiazomethanes (ArCHN2) with benzhydrylium ions (Ar2CH+) have been measured photometrically in dichloromethane. The resulting second-order rate constants correlate linearly with the electrophilicities E of the benzhydrylium ions which allowed us to use the correlation lg k = sN( N + E) (eq 1) for determining the nucleophile-specific parameters N and sN of the diazo compounds. UV-vis spectroscopy was analogously employed to measure the rates of the 1,3-dipolar cycloadditions of these aryldiazomethanes with acceptor substituted ethylenes of known electrophilicities E. The measured rate constants for the reactions of the diazoalkanes with highly electrophilic Michael acceptors ( E > -11, for example 2-benzylidene Meldrum's acid or 1,1 bis(phenylsulfonyl)ethylene) agreed with those calculated by eq 1 from the one bond nucleophilicities N and sN of the diazo compounds and the one-bond electrophilicities of the dipolarophiles, indicating that the incremental approach of eq 1 may also be applied to predict the rates of highly asynchronous cycloadditions. Weaker electrophiles, e.g., methyl acrylate, react faster than calculated from E, N, and sN, and the ratio of experimental to calculated rate constants was suggested to be a measure for the energy of concert Delta G?concert = RT ln( k2exptl/ k2calcd). Quantum chemical calculations indicated that all products isolated from the reactions of the aryldiazomethanes with acceptor substituted ethylenes (Delta2-pyrazolines, cyclopropanes, and substituted ethylenes) arise from intermediate Delta1-pyrazolines, which are formed through concerted 1,3-dipolar cycloadditions with transition states, in which the C-N bond formation lags behind the C-C bond formation. The Gibbs activation energies for these cycloadditions calculated at the PCM(UA0,CH2Cl2)/(U)B3LYP-D3/6 31+G(d,p) level of theory agree within 5 kJ mol-1 with the experimental numbers showing the suitability of the applied polarizable continuum model (PCM) for considering solvation. PMID- 30444362 TI - A Survey of the Structures of US FDA Approved Combination Drugs. AB - Combination drugs are an important class of US FDA approved pharmaceuticals. These drugs have been on a continuous growth trajectory since the first combination drugs were approved in the 1940s. In this Perspective, we report the first comprehensive compilation and analysis of US FDA approved combination drugs, from the first approval in 1943 through 2018. Our database contains 419 combination drugs, which are represented by 328 unique small molecule structures. Breakdown of these drugs according to disease category, structure, combination composition, and year of approval is presented as well as the top 24 most commonly used small molecule combination drug components. For frequently used small molecule components, we present "relationship diagrams" to aid in the visualization of the many drug combinations these structures are part of. The main body contains 10 disease-focused sections wherein every small molecule component utilized as part of a combination for each disease category is displayed. PMID- 30444363 TI - Charge-Assisted Self-Assembly of ZIF-8 and Laponite Clay toward a Functional Hydrogel Nanocomposite. AB - The fabrication of a gel through the self-assembly of a nanoscale metal-organic framework is extremely rare. Here we report the facile synthesis of new hydrogel nanocomposites by the surface coating of ZIF-8 nanoparticles with laponite (LP) nanoclay through electrostatic interaction. The hydrogel exhibits a pH-controlled release of encapsulated guest molecules. Also, a luminescent hydrogel nanocomposite is prepared by encapsulating dye into ZIF-8, followed by gelation with LP. PMID- 30444365 TI - Fundamental Gaps of Condensed-Phase Organic Semiconductors from Single-Molecule Calculations using Polarization-Consistent Optimally Tuned Screened Range Separated Hybrid Functionals. AB - Range-separated hybrid (RSH) functionals have been shown to overcome the tendency of traditional density functional theory to underestimate the fundamental orbital gap. More recently, the screened RSH (SRSH) approach has been developed as a means to extend these functionals to address the effect of the electrostatic environment on the fundamental gap. Here, we report a scheme that combines the SRSH formulation with the polarized continuum model (PCM) within a consistent framework for addressing long-range screened electrostatic interactions, which is further improved by optimal tuning (OT). The quantitative predictive power of the new OT-SRSH-PCM scheme is demonstrated by addressing fundamental gaps in thin films of organic semiconducting materials. This is especially impressive as the approach is based on single molecule calculations. We also discuss the advantages of this approach over alternative schemes combining PCM with RSH. In particular, we show that it avoids the well-documented tendency of standard OT to collapse the range separation parameter when performed within a dielectric continuum. PMID- 30444364 TI - Stabilization of SF5- with Glyme-Coordinated Alkali Metal Cations. AB - The stabilization of complex fluoroanions derived from weakly acidic parent fluorides is a significant and ongoing challenge. The [SF5]- anion is recognized as one such case, and only a limited number of [SF5]- salts are known to be stable at room temperature. In the present study, glyme-coordinated alkali metal cations (K+, Rb+, and Cs+) are employed to stabilize [SF5]-, which provides a simple synthetic route to a [SF5]- salt. The reactivities of KF and RbF with SF4 are significantly enhanced by complexation with G4, based on Raman spectroscopic analyses. A new room-temperature stable salt, [Cs(G4)2][SF5] (G4 = tetraglyme), was synthesized by stoichiometric reaction of CsF, G4, and SF4. The vibrational frequencies of [SF5]- were assigned based on quantum chemical calculations, and the shift of the G4 breathing mode accompanying coordination to metal cations was confirmed by Raman spectroscopy. Single-crystal X-ray diffraction revealed that Cs+ is completely isolated from [SF5]- by two G4 ligands and [SF5]- is disordered along the crystallographic two-fold axis. Hirshfeld surface analysis reveals that the H...H interaction between two neighboring [Cs(G4)2]+ moieties is more dominant on the Hirshfeld surface than the interaction between the H atom in glyme molecules and the F atom in [SF5]-, providing a CsCl-type structural model where the large and spherical [Cs(G4)2]+ cations contact each other and the [SF5] anions occupy interstitial spaces in the crystal lattice. The [SF5]- anion, combined with [Cs(G4)2]+, exhibits a very limited deoxofluorinating ability toward hydroxyl groups in both neat conditions and THF solutions. PMID- 30444366 TI - Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Inhibition: An Emerging Strategy in Cancer Therapy. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a pleiotropic transcription factor, especially for its complex and dual effects in cancer. With the continuous growing research, new regulatory modes and new functions of Nrf2 and tumor-promoting effects of Nrf2 in malignant transformed tumors have become increasingly clear. Accumulating evidence has established that Nrf2 contributes to the whole process of pathogenesis, progression, metastasis, and prognosis of cancer, and Nrf2 could be a promising target in cancer therapy. However, the development of Nrf2 inhibitor is still limited. In this perspective, we will briefly describe the biological function and modulating network of Nrf2, stress its oncogenic role, and point out possible ways to inhibit Nrf2, as well as summarize the reported Nrf2 inhibitors. PMID- 30444367 TI - Probabilistic Lifecycle Assessment of Butanol Production from Corn Stover Using Different Pretreatment Methods. AB - The recalcitrant nature of lignocelluloses requires a pretreatment process before the fermentative butanol production. The commonly used pretreatment processes, such as steam explosion, sulfuric acid, ammonia fiber explosion, ionic liquid (IL), and biological, require different quantities and types of process chemicals, and produce different quality and quantity of fermentable sugars. This study determines life-cycle greenhouse gas emissions (GHG) these pretreatment methods by developing a system-level process model including corn stover feedstock supply system and the downstream butanol production process. This study further evaluates the uncertainty associated with energy use and GHG emissions for each stage of the entire butanol production chain and provide the future optimization opportunities. Probabilistic results of these analyses describe a distribution of GHG emissions with an average of 18.09-1056.12 gCO2e/MJ and a 95% certainty to be less than 33.3-1888.3 gCO2e /MJ. The highest GHG emissions of IL pretreatment of 1056.12 gCO2e/MJ reaches to 89.8 gCO2e/MJ by switching IL recovery from 80 to 99 wt %, which is the most influential parameter for IL pretreatment. Additionally, credits from excess electricity, butanol yield, nitrogen replacement, and diesel fuel for transportation and harvesting were the most influential parameters. Based on the current state of technologies, apart from ionic liquid and biological pretreatments, other pretreatment processes have similar metrics of sustainability. PMID- 30444368 TI - Quaternary Structure Analysis of a Hemoglobin Core in Hemoglobin-Albumin Cluster. AB - A core-shell ensemble of bovine hemoglobin (Hb) and human serum albumin (HSA) is an artificial O2 carrier as a red blood cell substitute. This protein particle is created by covalent wrapping of a carbonyl Hb with HSAs: HbR-HSA3 cluster, where HbR signifies the use of carbonyl Hb [relaxed(R)-state conformation] as a starting material. The HbR-HSA3 cluster exhibits high O2 affinity and low cooperativity. Analysis of the quaternary structure of the central HbR in the cluster revealed that its high O2 affinity is attributed to the physically immobile HbR nucleus. Circular dichroism and UV-vis absorption spectroscopy showed that the structure of deoxy HbR core closely resembles the R-state. The crystal structure of Lys-modified carbonyl HbR was superimposed to that of carbonyl Hb. These results imply that chemical modifications of the surface Lys groups and Cys-93(beta) of the carbonyl Hb with crosslinking agent interfered in the quaternary structure movement from the R-state to Tense(T)-state. As expected, coupling of deoxy Hb (T-state) with HSAs yielded HbT-HSA3 cluster having low O2 affinity. The mixing of HbR-HSA3 and HbT-HSA3 clusters conferred a tailor-made formulation of artificial O2 carrier with a desired O2 affinity (P50). PMID- 30444369 TI - Amyloid-Binding Alcohol Dehydrogenase (ABAD) Inhibitors for the Treatment of Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most common dementia. No cure exists, and current treatment only manages early symptoms. Mitochondrial dysfunction is a hallmark of amyloid-beta (Abeta) neurotoxicity, the pathogenic protein implicated in AD. This is due in part to the interaction between Abeta and amyloid-binding alcohol dehydrogenase (ABAD). This mitochondrial protein is a vital energy regulator that, following Abeta binding, activates signaling cascades that lead to neuronal death. One of the most significant roles of ABAD is to maintain the balance of estradiol/estrone in neurons. However, the Abeta-ABAD interaction disrupts this balance and leads to a reduction in levels of estradiol, thus leading to an increase in reactive oxygen species levels and to apoptosis. Two additional proteins, peroxiredoxin-2 and endophilin-1, are implicated in Abeta-ABAD complex mediated toxicity. Targeting the Abeta-ABAD interaction has emerged as a novel therapeutic strategy for AD. Herein, we review the chemistry and pharmacology of reported ABAD inhibitors. PMID- 30444370 TI - Dynamics and wetting behavior of core-shell soft particles at a fluid-fluid interface. AB - We investigate the conformation, position, and dynamics of core-shell nanoparticles (CSNPs) composed of a silica core encapsulated in a cross-linked poly-N-isopropylacrylamide shell at a water-oil interface for a systematic range of core sizes and shell thicknesses. We first present a free-energy model that we use to predict the CSNP wetting behavior at the interface as a function of its geometrical and compositional properties in the bulk phases, which gives good agreement with our experimental data. Remarkably, upon knowledge of the polymer shell deformability, the equilibrium particle position relative to the interface plane, an often elusive experimental quantity, can be extracted by measuring its radial dimensions after adsorption. For all the systems studied here, the interfacial dimensions are always larger than in bulk and the particle core resides in a configuration wherein it just touches the interface or is fully immersed in water. Moreover, the stretched shell induces a larger viscous drag at the interface, which appears to depend solely on the interfacial dimensions, irrespective of the portion of the CSNP surface exposed to the two fluids. Our findings indicate that tailoring the architecture of CSNPs can be used to control their properties at the interface, as of interest for applications including emulsion stabilization and nanopatterning. PMID- 30444371 TI - In Vivo Stability Profiles of Anti-Factor D Molecules Support Long-Acting Delivery Approaches. AB - The collection of aqueous humor (phase 1b/2 Mahalo study) from patients dosed intravitreally with anti-factor D (AFD; FCFD4514S, lampalizumab), a humanized antibody fragment previously under investigation to treat geographic atrophy (GA) secondary to age-related macular degeneration, presented a unique opportunity to examine AFD properties in clinical samples. We investigated AFD stability and target-binding characteristics to set up strategies for engineering and evaluating optimized molecules that enable less frequent dosing. Two variants, AFD.v8 and AFD.v14, were evaluated as alternatives to AFD for longer-acting treatments. Mass spectrometry, surface plasmon resonance, and immunoassay were used to assess AFD stability and binding activity in aqueous humor samples from Mahalo patients. In vitro stability and binding activity of AFD, AFD.v8, and AFD.v14 were assessed in human vitreous humor versus buffer at 37 degrees C over 16 weeks and in vivo in rabbits over 28 days along with pharmacokinetic determinations. In human aqueous humor, AFD specific binding was >85% through 30 days and deamidation was <3% through 60 days, consistent with AFD stability and binding activity in vitreous humor from humans in vitro and rabbits in vivo. Target binding, stability, and rabbit pharmacokinetic parameters of AFD.v8 and AFD.v14 were similar to those of AFD. Physiological stability and activity of AFD translated across in vitro and in vivo studies in humans and rabbits. The two variants AFD.v8 and AFD.v14 demonstrated comparable potency and pharmacokinetics. These findings, along with previously demonstrated improved solubility of AFD.v8 and AFD.v14, provide proof-of-concept for developing other similar long-acting therapeutic variants. PMID- 30444372 TI - Nanocomposites Inhibit the Formation, Mitigate the Neurotoxicity, and Facilitate the Removal of beta-Amyloid Aggregates in Alzheimer's Disease Mice. AB - Alzheimer's disease (AD) is a progressive and irreversible brain disorder. Recent studies revealed the pivotal role of beta-amyloid (Abeta) in AD. However, there is no conclusive indication that the existing therapeutic strategies exerted any effect on the mitigation of Abeta-induced neurotoxicity and the elimination of Abeta aggregates simultaneously in vivo. Herein, we developed a novel nanocomposite that can eliminate toxic Abeta aggregates and mitigate Abeta induced neurotoxicity in AD mice. This nanocomposite was designed to be a small sized particle (14 +/- 4 nm) with Abeta-binding peptides (KLVFF) integrated on the surface. The nanocomposite was prepared by wrapping a protein molecule with a cross-linked KLVFF-containing polymer layer synthesized by in situ polymerization. The presence of the nanocomposite remarkably changed the morphology of Abeta aggregates, which led to the formation of Abeta/nanocomposite coassembled nanoclusters instead of Abeta oligomers. With the reduction of the pathological Abeta oligomers, the nanocomposites attenuated the Abeta-induced neuron damages, regained endocranial microglia's capability to phagocytose Abeta, and eventually protected hippocampal neurons against apoptosis. Thus, we anticipate that the small-sized nanocomposite will potentially offer a feasible strategy in the development of novel AD treatments. PMID- 30444373 TI - Mixed Diboration of Alkynes Catalyzed by LiOH: Regio- and Stereoselective Synthesis of cis-1,2-Diborylalkenes. AB - A diboration of terminal alkynes with an unsymmetrical diboron reagent pinBBdan has been achieved using LiOH as the catalyst in the presence of stoichiometric amounts of MeOH, affording 1,2-diborylalkenes with different boryl groups. The reaction proceeds in a highly regio- and stereoselective manner through cis addition of pinBBdan to the C-C triple bond, with the Bdan moiety being incorporated at the internal position. By taking advantage of the different reactivities of the two boryl groups, the mixed diboration product can undergo the sequential, chemoselective cross-couplings with aryl bromides to form trisubstituted alkenes. PMID- 30444374 TI - Catalyst-Free Phosphorylation of Acridine with Secondary Phosphine Chalcogenides: Nucleophilic Addition vs SNHAr Reaction. AB - Acridine adds secondary phosphine chalcogenides HP(X)R2 (X = O, S, Se; R = Ar, ArAlk) under catalyst-free conditions at 70-75 degrees C (both in the presence and absence of the electron-deficient acetylenes) to give 9-chalcogenophosphoryl 9,10-dihydroacridines in 61-94% yields. This contrasts with pyridines, which under similar conditions undergo an SNHAr reaction, wherein electron-deficient acetylenes play the role of oxidants. For acridine, the SNHAr step has been accomplished by the oxidation of the intermediate 9-phosphoryl-9,10 dihydroacridines (X = O) with chloranil. PMID- 30444375 TI - Synthesis of Isothiochroman-3-ones via Metal-Free Oxidative Cyclization of Alkynyl Thioethers. AB - A novel Bronsted acid-catalyzed oxidative C-H functionalization of alkynyl thioethers has been developed. This method allows the practical synthesis of valuable isothiochroman-3-ones in mostly moderate to good yields under mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, this metal-free oxidation can also be used to promote formal N-H insertion involving an unexpected 1,2-sulfur migration, affording useful 1,4-benzothiazin-3-ones. PMID- 30444376 TI - Modification of [5]Helicene with Dimesitylboryl: One Way To Enhance the Fluorescence Efficiency. AB - The efficient synthetic route was disclosed to prepare structurally asymmetric [5]helicenes, which are substituted with either BMes2 (7B-HC) or both BMes2 and NMe2 (8B5NMe2-HC, 7B5NMe2-HC). Compared with the parent [5]helicene, these compounds show greatly enhanced fluorescence. In addition, they still retain fairly strong fluorescence in the solid state. Moreover, the complexation of 8B5NMe2-HC and 7B5NMe2-HC with fluoride can induce significant blue shift in fluorescence and the formed complexes are also highly fluorescent. PMID- 30444377 TI - Observation of a Space-Time Crystal in a Superfluid Quantum Gas. AB - Time crystals are a phase of matter, for which the discrete time symmetry of the driving Hamiltonian is spontaneously broken. The breaking of discrete time symmetry has been observed in several experiments in driven spin systems. Here, we show the observation of a space-time crystal using ultracold atoms, where the periodic structure in both space and time is directly visible in the experimental images. The underlying physics in our superfluid can be described ab initio and allows for a clear identification of the mechanism that causes the spontaneous symmetry breaking. Our results pave the way for the usage of space-time crystals for the discovery of novel nonequilibrium phases of matter. PMID- 30444378 TI - Frustrated Structural Instability in Superconducting Quasi-One-Dimensional K_{2}Cr_{3}As_{3}. AB - We present density functional theory and neutron total scattering studies on quasi-one-dimensional superconducting K_{2}Cr_{3}As_{3} revealing a frustrated structural instability. Our first principles calculations find a significant phonon instability, which, under energy minimization, corresponds to a frustrated orthorhombic distortion. In neutron diffraction studies we find large atomic displacement parameters with anomalous temperature dependencies, which result from highly localized orthorhombic distortions of the CrAs sublattice and coupled K displacements. These results suggest a more complex phase diagram than previously assumed for K_{2}Cr_{3}As_{3} with subtle interplays of structure, electron-phonon, and magnetic interactions. PMID- 30444379 TI - Optically Addressing Single Rare-Earth Ions in a Nanophotonic Cavity. AB - We demonstrate optical probing of spectrally resolved single Nd^{3+} rare-earth ions in yttrium orthovanadate. The ions are coupled to a photonic crystal resonator and show strong enhancement of the optical emission rate via the Purcell effect, resulting in near radiatively limited single photon emission. The measured high coupling cooperativity between a single photon and the ion allows for the observation of coherent optical Rabi oscillations. This could enable optically controlled spin qubits, quantum logic gates, and spin-photon interfaces for future quantum networks. PMID- 30444380 TI - Transition Radiation as a Probe of the Chiral Anomaly. AB - A fast charged particle crossing the boundary between chiral matter and vacuum radiates transition radiation. Its most remarkable features-the resonant behavior at a certain emission angle and the circular polarization of the spectrum-depend on the parameters of the chiral anomaly in a particular material or matter. Chiral transition radiation can be used to investigate the chiral anomaly in such diverse media as the quark-gluon plasma, Weyl semimetals, and axionic dark matter. PMID- 30444381 TI - Boson Peak Decouples from Elasticity in Glasses with Low Connectivity. AB - We perform molecular-dynamics simulations of the vibrational and elastoplastic properties of polymeric glasses and crystals and the corresponding atomic systems. We evidence that the elastic scaling of the density of states in the low frequency boson peak (BP) region is different in crystals and glasses. Also, we see that the BP of the polymeric glass is nearly coincident with the one of the atomic glasses, thus revealing that the former-unlike the elasticity-is controlled by nonbonding interactions only. Our results suggest that the interpretation of the BP in terms of the macroscopic elasticity, discussed in highly connected systems, does not hold for systems with low connectivity. PMID- 30444382 TI - Oscillating Electric Fields in Liquids Create a Long-Range Steady Field. AB - We demonstrate that application of an oscillatory electric field to a liquid yields a long-range steady field, provided the ions present have unequal mobilities. The main physics is illustrated by a two-ion harmonic oscillator, yielding an asymmetric rectified field whose time average scales as the square of the applied field strength. Computations of the fully nonlinear electrokinetic model corroborate the two-ion model and further demonstrate that steady fields extend over large distances between two electrodes. Experimental measurements of the levitation height of micron-scale colloids versus applied frequency accord with the numerical predictions. The heretofore unsuspected existence of a long range steady field helps explain several long-standing questions regarding the behavior of particles and electrically induced fluid flows in response to oscillatory potentials. PMID- 30444383 TI - Quantum Limited Superresolution of an Incoherent Source Pair in Three Dimensions. AB - The error in estimating the separation of a pair of incoherent sources from radiation emitted by them and subsequently captured by an imager is fundamentally bounded below by the inverse of the corresponding quantum Fisher information (QFI) matrix. We calculate the QFI for estimating the full three-dimensional pair separation vector, extending previous work on pair separation in one and two dimensions. We also show that the pair-separation QFI is, in fact, identical to source localization QFI, which underscores the fundamental importance of photon state localization in determining the ultimate estimation-theoretic bound for both problems. We also propose general coherent-projection bases that can attain the QFI in two special cases. We present simulations of an approximate experimental realization of such quantum limited pair superresolution using the Zernike basis, confirming the achievability of the QFI bounds. PMID- 30444384 TI - Random-Length Random Walks and Finite-Size Scaling in High Dimensions. AB - We address a long-standing debate regarding the finite-size scaling (FSS) of the Ising model in high dimensions, by introducing a random-length random walk model, which we then study rigorously. We prove that this model exhibits the same universal FSS behavior previously conjectured for the self-avoiding walk and Ising model on finite boxes in high-dimensional lattices. Our results show that the mean walk length of the random walk model controls the scaling behavior of the corresponding Green's function. We numerically demonstrate the universality of our rigorous findings by extensive Monte Carlo simulations of the Ising model and self-avoiding walk on five-dimensional hypercubic lattices with free and periodic boundaries. PMID- 30444385 TI - Assessing Near-Future Direct Dark Matter Searches with Benchmark-Free Forecasting. AB - Forecasting the signal discrimination power of dark matter (DM) searches is commonly limited to a set of arbitrary benchmark points. We introduce new methods for benchmark-free forecasting that instead allow an exhaustive exploration and visualization of the phenomenological distinctiveness of DM models, based on standard hypothesis testing. Using this method, we reassess the signal discrimination power of future liquid xenon and argon direct DM searches. We quantify the parameter regions where various nonrelativistic effective operators, millicharged DM, and magnetic dipole DM can be discriminated, and where upper limits on the DM mass can be found. We find that including an argon target substantially improves the prospects for reconstructing the DM properties. We also show that only in a small region with DM masses in the range 20-100 GeV and DM-nucleon cross sections a factor of a few below current bounds can near-future xenon and argon detectors discriminate both the DM-nucleon interaction and the DM mass simultaneously. In all other regions only one or the other can be obtained. PMID- 30444386 TI - Understanding the Enhancement of Surface Diffusivity by Dimerization. AB - Beyond dilute coverage, the collective diffusion of molecules might enhance material transport. We reveal an enhanced mobility of molecular dimers by separating two motions, diffusion and rotation, of CO dimers on elemental Ag(100) as well as on a dilute Cu alloy of Ag(100). From time-lapsed scanning tunneling microscopy movies recorded between 15 and 25 K, we determine the activation energy of dimer diffusion on elemental Ag(100) to be, at (40+/-2) meV, considerably smaller than the one for monomer diffusion, at (72+/-1) meV. The alloyed Cu atoms reduce the dimer mobility facilitating to determine their rotational barrier separately to be (39+/-3) meV. Disentangling different degrees of freedom suggests that a rotational motion is at the origin of enhanced dimer diffusivity. PMID- 30444387 TI - Thermal Expansion of Single-Crystal H_{2}O and D_{2}O Ice Ih. AB - Thermal expansion of H_{2}O and D_{2}O ice Ih with relative resolution of 1 ppb is reported. A large transition in the thermal expansion coefficient at 101 K in H_{2}O moves to 125 K in D_{2}O, revealing one of the largest-known isotope effects. Rotational oscillatory modes that couple poorly to phonons, i.e., lattice solitons, may be responsible. PMID- 30444388 TI - Certifying the Building Blocks of Quantum Computers from Bell's Theorem. AB - Bell's theorem has been proposed to certify, in a device-independent and robust way, blocks either producing or measuring quantum states. In this Letter, we provide a method based on Bell's theorem to certify coherent operations for the storage, processing, and transfer of quantum information. This completes the set of tools needed to certify all building blocks of a quantum computer. Our method distinguishes itself by its robustness to experimental imperfections, and so could be used to certify that today's quantum devices are qualified for usage in future quantum computers. PMID- 30444389 TI - Electron Doping of Proposed Kagome Quantum Spin Liquid Produces Localized States in the Band Gap. AB - Carrier doping of quantum spin liquids is a long-proposed route to the emergence of high-temperature superconductivity. Electrochemical intercalation in kagome hydroxyl halide materials shows that samples remain insulating across a wide range of electron counts. Here we demonstrate through first-principles density functional calculations, corrected for self-interaction, the mechanism by which electrons remain localized in various Zn-Cu hydroxyl halides, independent of the chemical identity of the dopant-the formation of polaronic states with attendant lattice displacements and a dramatic narrowing of bandwidth upon electron addition. The same theoretical method applied to electron doping in cuprate Nd_{2}CuO_{4} correctly produces a metallic state when the initially formed polaron dissolves into an extended state. Our general findings explain the insulating behavior in a wide range of "doped" quantum magnets and demonstrate that new quantum spin liquid host materials are needed to realize metallicity borne of a spin liquid. PMID- 30444391 TI - Coherent Superconductivity with a Large Gap Ratio from Incoherent Metals. AB - A mysterious incoherent metallic (IM) normal state with T-linear resistivity is ubiquitous among strongly correlated superconductors. Recent progress with microscopic models exhibiting IM transport has presented the opportunity for us to study new models that exhibit direct transitions into a superconducting state out of IM states within the framework of connected Sachdev-Ye-Kitaev "quantum dots." Here, local Sachdev-Ye-Kitaev interactions within a dot produce IM transport in the normal state, while local attractive interactions drive superconductivity. Through explicit calculations, we find two features of superconductivity arising from an IM normal state. First, despite the absence of quasiparticles in the normal state, the superconducting state still exhibits coherent superfluid transport. Second, the nonquasiparticle nature of the IM Green's functions produces a large enhancement in the ratio of the zero temperature superconducting gap Delta and transition temperature T_{SC}, 2Delta/T_{SC}, with respect to its BCS value of 3.53. PMID- 30444390 TI - Superallowed alpha Decay to Doubly Magic ^{100}Sn. AB - We report the first observation of the ^{108}Xe->^{104}Te->^{100}Sn alpha-decay chain. The alpha emitters, ^{108}Xe [E_{alpha}=4.4(2) MeV, T_{1/2}=58_{ 23}^{+106} MUs] and ^{104}Te [E_{alpha}=4.9(2) MeV, T_{1/2}<18 ns], decaying into doubly magic ^{100}Sn were produced using a fusion-evaporation reaction ^{54}Fe(^{58}Ni,4n)^{108}Xe, and identified with a recoil mass separator and an implantation-decay correlation technique. This is the first time alpha radioactivity has been observed to a heavy self-conjugate nucleus. A previous benchmark for study of this fundamental decay mode has been the decay of ^{212}Po into doubly magic ^{208}Pb. Enhanced proton-neutron interactions in the N=Z parent nuclei may result in superallowed alpha decays with reduced alpha-decay widths significantly greater than that for ^{212}Po. From the decay chain, we deduce that the alpha-reduced width for ^{108}Xe or ^{104}Te is more than a factor of 5 larger than that for ^{212}Po. PMID- 30444392 TI - Density-Driven Flows in Evaporating Binary Liquid Droplets. AB - In the evaporation of microlitre liquid droplets, the accepted view is that surface tension dominates and the effect of gravity is negligible. We report, through the first use of rotating optical coherence tomography, that a change in the flow pattern and speed occurs when evaporating binary liquid droplets are tilted, conclusively showing that gravitational effects dominate the flow. We use gas chromatography to show that these flows are solutal in nature, and we establish a flow phase diagram demonstrating the conditions under which different flow mechanisms occur. PMID- 30444393 TI - Experimental Realization of an Information Machine with Tunable Temporal Correlations. AB - We experimentally realize a Maxwell's demon that converts information gained by measurements to work. Our setup is composed of a colloidal particle in a channel filled with a flowing fluid. A barrier made by light prevents the particle from being carried away by the flow. The colloidal particle then performs biased Brownian motion in the vicinity of the barrier. The particle's position is measured periodically. When the particle is found to be far enough from the barrier, feedback is applied by moving the barrier upstream while maintaining a given minimal distance from the particle. At steady state, the net effect of this measurement and feedback loop is to steer the particle upstream while applying very little direct work on it. This clean example of a Maxwell's demon is also naturally operated in a parameter regime where correlations between outcomes of consecutive measurements are important. Interestingly, we find a tradeoff between output power and efficiency. The efficiency is maximal at quasistatic operating conditions, whereas both the power output and rate of information gain are maximal for very frequent measurements. PMID- 30444394 TI - Moire Valleytronics: Realizing Dense Arrays of Topological Helical Channels. AB - We propose a general and robust platform, the moire valleytronics, to realize high-density arrays of 1D topological helical channels in real materials at room temperature. We demonstrate the idea using a long-period 1D moire pattern of graphene on hBN by first-principles calculation. Through calculating the Berry curvature and topological charge of the electronic structure associated with various local graphene/hBN stackings in the moire pattern, it is revealed that the helical channel arrays originate intrinsically from the periodic modulation of the local topological orders by the moire pattern. For a freestanding wavelike moire pattern, two groups of helical channel arrays are spatially separated out of plane, validating the structural robustness of the moire topology. The generality and experimental feasibility of moire valleytronics are demonstrated by investigating a broad range of moire systems. PMID- 30444395 TI - Sticky Matters: Jamming and Rigid Cluster Statistics with Attractive Particle Interactions. AB - While the large majority of theoretical and numerical studies of the jamming transition consider athermal packings of purely repulsive spheres, real complex fluids and soft solids generically display attraction between particles. By studying the statistics of rigid clusters in simulations of soft particles with an attractive shell, we present evidence for two distinct jamming scenarios. Strongly attractive systems undergo a continuous transition in which rigid clusters grow and ultimately diverge in size at a critical packing fraction. Purely repulsive and weakly attractive systems jam via a first-order transition, with no growing cluster size. We further show that the weakly attractive scenario is a finite size effect, so that for any nonzero attraction strength, a sufficiently large system will fall in the strongly attractive universality class. We therefore expect attractive jamming to be generic in the laboratory and in nature. PMID- 30444396 TI - Collective Effects in Casimir-Polder Forces. AB - We study cooperative phenomena in the fluctuation-induced forces between a surface and a system of neutral two-level quantum emitters prepared in a coherent collective state, showing that the total Casimir-Polder force on the emitters can be modified via their mutual correlations. Particularly, we find that a one dimensional chain of emitters prepared in a super- or subradiant state experiences an enhanced or suppressed collective vacuum-induced force, respectively. The collective nature of dispersion forces can be understood as resulting from the interference between the different processes contributing to the surface-modified resonant dipole-dipole interaction. Such cooperative fluctuation forces depend singularly on the surface response at the resonance frequency of the emitters, thus being easily maneuverable. Our results demonstrate the potential of collective phenomena as a new tool to selectively tailor vacuum forces. PMID- 30444397 TI - Pairing Mechanism in Hund's Metal Superconductors and the Universality of the Superconducting Gap to Critical Temperature Ratio. AB - We analyze a simple model containing the physical ingredients of a Hund's metal, the local spin fluctuations with power-law correlators, (Omega_{0}/|Omega|)^{gamma}, with gamma greater than one, interacting with electronic quasiparticles. While the critical temperature and the gap change significantly with varying parameters, the 2Delta_{max}/k_{B}T_{c} remains close to twice the BCS value in agreement with experimental observations in the iron based superconductors (FeSC). PMID- 30444399 TI - Static Hopf Solitons and Knotted Emergent Fields in Solid-State Noncentrosymmetric Magnetic Nanostructures. AB - Two-dimensional topological solitons, commonly called Skyrmions, are extensively studied in solid-state magnetic nanostructures and promise many spintronics applications. However, three-dimensional topological solitons dubbed hopfions have not been demonstrated as stable spatially localized structures in solid state magnetic materials. Here we model the existence of such static solitons with different Hopf index values in noncentrosymmetric solid magnetic nanostructures with a perpendicular interfacial magnetic anisotropy. We show how this surface anisotropy, along with the Dzyaloshinskii-Moriya interactions and the geometry of nanostructures, stabilize hopfions. We demonstrate knots in emergent field lines and computer simulate Lorentz transmission electron microscopy images of such solitonic configurations to guide their experimental discovery in magnetic solids. PMID- 30444398 TI - Beliaev Damping of a Spin-Orbit-Coupled Bose-Einstein Condensate. AB - Beliaev damping provides a fundamental mechanism for dissipation of quasiparticles. Previous research has shown that the two-component internal degrees of freedom has no nontrivial effect on Beliaev damping. Here we provide the first example where the spinor nature of Bose gases can manifest itself in the Beliaev damping by way of spin-obit coupling. We identify novel features of the Beliaev decay rate due to spin-orbit coupling; in particular, it shows an explicit dependence on the spin-density interaction and diverges at the interaction-modified phase boundary between the zero-momentum and plane wave phases. This represents a manifestation of the effect of spin-orbit coupling in the beyond-mean-field regime, which by breaking Galilean invariance couples excitations in the density and spin channels. We further show that the measurement of the Beliaev damping rate is experimentally feasible through the measurement of spin polarizability susceptibility, which has been already achieved in spin-orbit-coupled Bose gases. PMID- 30444400 TI - Fractional Quantum Hall Effect at nu=2+6/13: The Parton Paradigm for the Second Landau Level. AB - The unexpected appearance of a fractional quantum Hall effect (FQHE) plateau at nu=2+6/13 [A. Kumar et al., Phys. Rev. Lett. 105, 246808 (2010)PRLTAO0031 900710.1103/PhysRevLett.105.246808] offers a clue into the physical mechanism of the FQHE in the second Landau level (SLL). Here we propose a "3[over -]2[over ]111" parton wave function, which is topologically distinct from the 6/13 state in the lowest Landau level. We demonstrate the 3[over -]2[over -]111 state to be a good candidate for the nu=2+6/13 FQHE, and make predictions for experimentally measurable properties that can reveal the nature of this state. Furthermore, we propose that the "n[over -]2[over -]111" family of parton states naturally describes many observed SLL FQHE plateaus. PMID- 30444401 TI - Observation of the Bogoliubov Dispersion in a Fluid of Light. AB - Quantum fluids of light are a photonic counterpart to atomic Bose gases and are attracting increasing interest for probing many-body physics quantum phenomena such as superfluidity. Two different configurations are commonly used: the confined geometry where a nonlinear material is fixed inside an optical cavity and the propagating geometry where the propagation direction plays the role of an effective time for the system. The observation of the dispersion relation for elementary excitations in a photon fluid has proved to be a difficult task in both configurations with few experimental realizations. Here, we propose and implement a general method for measuring the excitations spectrum in a fluid of light, based on a group velocity measurement. We observe a Bogoliubov-like dispersion with a speed of sound scaling as the square root of the fluid density. This Letter demonstrates that a nonlinear system based on an atomic vapor pumped near resonance is a versatile and highly tunable platform to study quantum fluids of light. PMID- 30444402 TI - Multiscale Energy Dissipation Mechanism in Tough and Self-Healing Hydrogels. AB - Understanding the energy dissipation mechanism during deformation is essential for the design and application of tough soft materials. We show that, in a class of tough and self-healing polyampholyte hydrogels, a bicontinuous network structure, consisting of a hard network and a soft network, is formed, independently of the chemical details of the hydrogels. Multiscale internal rupture processes, in which the double-network effect plays an important role, are found to be responsible for the large energy dissipation of these hydrogels. PMID- 30444403 TI - Stabilizing Mechanism for Bose-Einstein Condensation of Interacting Magnons in Ferrimagnets and Ferromagnets. AB - We propose a stabilizing mechanism for the Bose-Einstein condensation (BEC) of interacting magnons in ferrimagnets and ferromagnets. By studying the effects of the magnon-magnon interaction on the stability of the magnon BEC in a ferrimagnet and two ferromagnets, we show that the magnon BEC remains stable even in the presence of the magnon-magnon interaction in the ferrimagnet and ferromagnet with a sublattice structure, while it becomes unstable in the ferromagnet without a sublattice structure. This indicates that the existence of a sublattice structure is the key to stabilizing the BEC of interacting magnons, and the difference between the spin alignments of a ferrimagnet and a ferromagnet is irrelevant. Our result can resolve a contradiction between experiment and theory in the magnon BEC of yttrium iron garnet. Our theoretical framework may provide a starting point for understanding the physics of the magnon BEC including the interaction effects. PMID- 30444404 TI - Majorana Doublets, Flat Bands, and Dirac Nodes in s-Wave Superfluids. AB - Topological superfluids protected by mirror and time-reversal symmetries are exotic states of matter possessing Majorana Kramers pairs (MKPs), yet their realizations have long been hindered by the requirement of unconventional pairing. We propose to realize such a topological superfluid by utilizing s-wave pairing and emergent mirror and time-reversal symmetries in two coupled 1D ultracold atomic Fermi gases with spin-orbit coupling. By stacking such systems into 2D, we discover topological and Dirac-nodal superfluids hosting distinct MKP flat bands. We show that the emergent symmetries make the MKPs and their flat bands stable against pairing fluctuations that otherwise annihilate Majorana pairs. Exploiting new experimental developments, our scheme provides a unique platform for exploring MKPs and their applications in quantum computation. PMID- 30444405 TI - Nonlocal Spin Transport Mediated by a Vortex Liquid in Superconductors. AB - Departing from the conventional view on superconducting vortices as a parasitic source of dissipation for charge transport, we propose to use mobile vortices as topologically stable information carriers. To this end, we start by constructing a phenomenological theory for the interconversion between spin and vorticity, a topological charge carried by vortices, at the interface between a magnetic insulator and a superconductor, by invoking the interfacial spin Hall effect therein. We then show that a vortex liquid in superconductors can serve as a spin transport channel between two magnetic insulators by encoding spin information in the vorticity. The vortex-mediated nonlocal signal between the two magnetic insulators is shown to decay algebraically as a function of their separation, contrasting with the exponential decay of the quasiparticle-mediated spin transport. We envision that hydrodynamics of topological excitations, such as vortices in superconductors and domain walls in magnets, may serve as a universal framework to discuss long-range transport properties of ordered materials. PMID- 30444406 TI - Stimulated Excitation of an Optical Cavity by a Multibunch Electron Beam via Coherent-Diffraction-Radiation Process. AB - With a low emittance and short-bunch electron beam at a high repetition rate realized by a superconducting linac, stimulated excitation of an optical cavity at the terahertz spectrum range is shown. The electron beam passes through small holes in the cavity mirrors without being destroyed. A sharp resonance structure which indicates wideband stimulated emission via coherent diffraction radiation is observed while scanning the round-trip length of the cavity. PMID- 30444407 TI - Phonon-Number-Sensitive Electromechanics. AB - We use the strong intrinsic nonlinearity of a microwave superconducting qubit with a 4 GHz transition frequency to directly detect and control the energy of a micromechanical oscillator vibrating at 25 MHz. The qubit and the oscillator are coupled electrostatically at a rate of approximately 2pi*22 MHz. In this far off resonant regime, the qubit frequency is shifted by 0.52 MHz per oscillator phonon, or about 14% of the 3.7 MHz qubit linewidth. The qubit behaves as a vibrational energy detector and from its line shape we extract the phonon number distribution of the oscillator. We manipulate this distribution by driving number state sensitive sideband transitions and creating profoundly nonthermal states. Finally, by driving the lower frequency sideband transition, we cool the oscillator and increase its ground state population up to 0.48+/-0.13, close to a factor of 8 above its value at thermal equilibrium. These results demonstrate a new class of electromechanics experiments that are a promising strategy for quantum nondemolition measurements and nonclassical state preparation. PMID- 30444408 TI - Generation of a Lattice of Spin-Orbit Beams via Coherent Averaging. AB - We describe a highly robust method, applicable to both electromagnetic and matter wave beams, that can produce a beam consisting of a lattice of orbital angular momentum (OAM) states coupled to a two-level system. We also define efficient protocols for controlling and manipulating the lattice characteristics. These protocols are applied in an experimental realization of a lattice of optical spin orbit beams. The novel passive devices we demonstrate here are also a natural alternative to existing methods for producing single-axis OAM and spin-orbit beams. Our techniques provide new tools for investigations of chiral and topological materials with light and particle beams. PMID- 30444409 TI - Experimental Observation of Hidden Berry Curvature in Inversion-Symmetric Bulk 2H WSe_{2}. AB - We investigate the hidden Berry curvature in bulk 2H-WSe_{2} by utilizing the surface sensitivity of angle resolved photoemission (ARPES). The symmetry in the electronic structure of transition metal dichalcogenides is used to uniquely determine the local orbital angular momentum (OAM) contribution to the circular dichroism (CD) in ARPES. The extracted CD signals for the K and K^{'} valleys are almost identical, but their signs, which should be determined by the valley index, are opposite. In addition, the sign is found to be the same for the two spin-split bands, indicating that it is independent of spin state. These observed CD behaviors are what are expected from Berry curvature of a monolayer of WSe_{2}. In order to see if CD-ARPES is indeed representative of hidden Berry curvature within a layer, we use tight binding analysis as well as density functional calculation to calculate the Berry curvature and local OAM of a monolayer WSe_{2}. We find that measured CD-ARPES is approximately proportional to the calculated Berry curvature as well as local OAM, further supporting our interpretation. PMID- 30444411 TI - Response of the Skyrmion Lattice in MnSi to Cubic Magnetocrystalline Anisotropies. AB - We report high-precision small-angle neutron scattering of the orientation of the Skyrmion lattice in a spherical sample of MnSi under systematic changes of the magnetic field direction. For all field directions the Skyrmion lattice may be accurately described as a triple-Q[over ->] state, where the modulus |Q[over ->]| is constant and the wave vectors enclose rigid angles of 120 degrees . Along a great circle across ?100?, ?110?, and ?111? the normal to the Skyrmion-lattice plane varies systematically by +/-3 degrees with respect to the field direction, while the in-plane alignment displays a reorientation by 15 degrees for magnetic field along ?100?. Our observations are qualitatively and quantitatively in excellent agreement with an effective potential, which is determined by the symmetries of the tetrahedral point group T and includes contributions up to sixth order in spin-orbit coupling, providing a full account of the effect of cubic magnetocrystalline anisotropies on the Skyrmion lattice in MnSi. PMID- 30444410 TI - Device-Independent Entanglement Certification of All Entangled States. AB - We present a method to certify the entanglement of all entangled quantum states in a device-independent way. This is achieved by placing the state in a quantum network and constructing a correlation inequality based on an entanglement witness for the state. Our method is device independent, in the sense that entanglement can be certified from the observed statistics alone, under minimal assumptions on the underlying physics. Conceptually, our results borrow ideas from the field of self-testing to bring the recently introduced measurement device-independent entanglement witnesses into the fully device-independent regime. PMID- 30444412 TI - Hydrodynamic Interactions, Hidden Order, and Emergent Collective Behavior in an Active Bacterial Suspension. AB - Spontaneous self-organization (clustering) in magnetically oriented bacteria arises from attractive pairwise hydrodynamics, which are directly determined through experiment and corroborated by a simple analytical model. Lossless compression algorithms are used to identify the onset of many-body self organization as a function of experimental tuning parameters. Cluster growth is governed by the interplay between hydrodynamic attraction and magnetic dipole repulsion, leading to logarithmic time dependence of the cluster size. The dynamics of these complex, far-from-equilibrium structures are relevant to broader phenomena in condensed matter, statistical mechanics, and biology. PMID- 30444413 TI - Quantum-Impurity Relaxometry of Magnetization Dynamics. AB - Prototypes of quantum impurities, such as NV and SiV color centers in diamond, have garnered much attention due to their minimally invasive and high-resolution magnetic field and thermal sensing. Here, we investigate quantum-impurity relaxometry as a method for probing collective excitations in magnetic insulators. We develop a general framework to relate the measurable quantum impurity relaxation rates to the intrinsic dynamic properties of a magnetic system via the noise emitted by the latter. We suggest, in particular, that the quantum-impurity relaxometry is sensitive to dynamic phase transitions, such as magnon condensation, and can be deployed to detect signatures of the associated coherent spin dynamics, both in ferromagnetic and antiferromagnetic systems. Finally, we discuss prospects to nonintrusively probe spin-transport regimes and measure the associated transport coefficients in magnetic insulators. PMID- 30444414 TI - Manipulation of the Vacuum to Control Its Field-Induced Decay. AB - It has long been predicted that permanent electron-positron pairs can be created from the quantum vacuum at those spatial regions where an external electric field exceeds a supercritical value. By solving the Dirac equation numerically, we show that the yield of the created positrons at targeted energies can be controlled via a second (subcritical) electric field that is placed far outside the creation zone. This is a clear indication of the nonlocal character of the pair-creation process, as the second field can be placed at distant spatial regions that are never visited by the created positrons. This counterintuitive phenomenon can be understood in terms of a dressing of the vacuum state long before the particles are actually created. We present an analytical expression for the spectrum of the created particles that describes all quantitative features of this dressing and predicts how the second field can be used to increase as well as decrease the electron-positron yield for desired energies. PMID- 30444415 TI - Experimental Measurements of Ion Heating in Collisional Plasma Shocks and Interpenetrating Supersonic Plasma Flows. AB - We present time-resolved measurements of ion heating due to collisional plasma shocks and interpenetrating supersonic plasma flows, which are formed by the oblique merging of two coaxial-gun-formed plasma jets. Our study is repeated using four jet species: N, Ar, Kr, and Xe. In conditions with small interpenetration between jets, the observed peak ion temperature T_{i} is consistent with the predictions of collisional plasma-shock theory showing a substantial elevation of T_{i} above the electron temperature T_{e} and also the subsequent decrease of T_{i} on the classical ion-electron temperature equilibration timescale. In conditions of significant interpenetration between jets, such that shocks do not apparently form, the observed peak T_{i} is still appreciable and greater than T_{e} but much lower than that predicted by collisional plasma-shock theory. Experimental results are compared with multifluid plasma simulations. PMID- 30444416 TI - Robust Entanglement Gates for Trapped-Ion Qubits. AB - High-fidelity two-qubit entangling gates play an important role in many quantum information processing tasks and are a necessary building block for constructing a universal quantum computer. Such high-fidelity gates have been demonstrated on trapped-ion qubits; however, control errors and noise in gate parameters may still lead to reduced fidelity. Here we propose and demonstrate a general family of two-qubit entangling gates which are robust to different sources of noise and control errors. These gates generalize the renowned Molmer-Sorensen gate by using multitone drives. We experimentally implemented several of the proposed gates on ^{88}Sr^{+} ions trapped in a linear Paul trap and verified their resilience. PMID- 30444417 TI - High-Temperature Majorana Corner States. AB - Majorana bound states often occur at the end of a 1D topological superconductor. Validated by a new bulk invariant and an intuitive edge argument, we show the emergence of one Majorana Kramers pair at each corner of a square-shaped 2D topological insulator proximitized by an s_{+/-}-wave (e.g., Fe-based) superconductor. We obtain a phase diagram that addresses the relaxation of crystal symmetry and edge orientation. We propose two experimental realizations in candidate materials. Our scheme offers a higher-order and higher-temperature route for exploring non-Abelian quasiparticles. PMID- 30444418 TI - Temperature-Driven Topological Phase Transition and Intermediate Dirac Semimetal Phase in ZrTe_{5}. AB - We present an infrared spectroscopy study of ZrTe_{5}, which confirms a recent theoretical proposal that this material exhibits a temperature-driven topological quantum phase transition from a weak to a strong topological insulating state with an intermediate Dirac semimetal state around T_{p}?138 K. Our study details the temperature evolution of the energy gap in the bulk electronic structure. We found that the energy gap closes around T_{p}, where the optical response exhibits characteristic signatures of a Dirac semimetal state, i.e., a linear frequency-dependent optical conductivity extrapolating to the origin (after subtracting a weak Drude response). This finding allows us to reconcile previous diverging reports about the topological nature of ZrTe_{5} in terms of a variation of T_{p} that depends on the crystal growth condition. PMID- 30444419 TI - Self-Similar Multimode Bubble-Front Evolution of the Ablative Rayleigh-Taylor Instability in Two and Three Dimensions. AB - The self-similar nonlinear evolution of the multimode ablative Rayleigh-Taylor instability (ARTI) is studied numerically in both two and three dimensions. It is shown that the nonlinear multimode bubble-front penetration follows the alpha_{b}A_{T}(?sqrt[g]dt)^{2} scaling law with alpha_{b} dependent on the initial conditions and ablation velocity. The value of alpha_{b} is determined by the bubble competition theory, indicating that mass ablation reduces alpha_{b} with respect to the classical value for the same initial perturbation amplitude. It is also shown that ablation-driven vorticity accelerates the bubble velocity and prevents the transition from the bubble competition to the bubble merger regime at large initial amplitudes leading to higher alpha_{b} than in the classical case. Because of the dependence of alpha_{b} on initial perturbation and vorticity generation, ablative stabilization of the nonlinear ARTI is not as effective as previously anticipated for large initial perturbations. PMID- 30444420 TI - Microscopic Theory of Two-Step Yielding in Attractive Colloids. AB - Attractive colloids display two distinct amorphous solid phases: the attractive glass due to particle bonding and the repulsive glass due to the hard-core repulsion. By means of a microscopic mean field approach, we analyze their response to a quasistatic shear strain. We find that the presence of two distinct interaction length scales may result in a sharp two-step yielding process, which can be associated with a hysteretic stress response or with a reversible but nonmonotonic stress-strain curve. We derive a generic phase diagram characterized by two distinct yielding lines, an inverse yielding and a critical point separating the hysteretic and reversible regimes. Our results should be applicable to a large class of glassy materials characterized by two distinct interaction length scales. PMID- 30444421 TI - Quantum-Mechanical Relation between Atomic Dipole Polarizability and the van der Waals Radius. AB - The atomic dipole polarizability alpha and the van der Waals (vdW) radius R_{vdW} are two key quantities to describe vdW interactions between atoms in molecules and materials. Until now, they have been determined independently and separately from each other. Here, we derive the quantum-mechanical relation R_{vdW}=const*alpha^{1/7}, which is markedly different from the common assumption R_{vdW}?alpha^{1/3} based on a classical picture of hard-sphere atoms. As shown for 72 chemical elements between hydrogen and uranium, the obtained formula can be used as a unified definition of the vdW radius solely in terms of the atomic polarizability. For vdW-bonded heteronuclear dimers consisting of atoms A and B, the combination rule alpha=(alpha_{A}+alpha_{B})/2 provides a remarkably accurate way to calculate their equilibrium interatomic distance. The revealed scaling law allows us to reduce the empiricism and improve the accuracy of interatomic vdW potentials, at the same time suggesting the existence of a nontrivial relation between length and volume in quantum systems. PMID- 30444422 TI - Resilient Entangling Gates for Trapped Ions. AB - Constructing a large-scale ion trap quantum processor will require entangling gate operations that are robust in the presence of noise and experimental imperfection. We experimentally demonstrate how a new type of Molmer-Sorensen gate protects against infidelity caused by heating of the motional mode used during the gate. Furthermore, we show how the same technique simultaneously provides significant protection against slow fluctuations and mis-sets in the secular frequency. Since this parameter sensitivity is worsened in cases where the ions are not ground-state cooled, our method provides a path towards relaxing ion cooling requirements in practical realizations of quantum computing and simulation. PMID- 30444423 TI - Circular RNA circRHOT1 is upregulated and promotes cell proliferation and invasion in pancreatic cancer. AB - AIM: We aimed to identify the roles of circRHOT1 in pancreatic cancer. MATERIALS & METHODS: The circRHOT1 was acquired from our previous study followed by quantitative real-time PCR and fluorescence in situ hybridization validation in pancreatic cancer. We used siRNA and shRNA to explore the function of circRHOT1 in pancreatic cancer cells. Bioinformatic analyses were applied to study the potential mechanism of circRHOT1. RESULTS: The circRHOT1 was upregulated in pancreatic cancer and predominantly located in the cytoplasm. Reducing the circRHOT1 expression may inhibit the pancreatic cancer cell proliferation, invasion and migration. The circRHOT1 may play a role in pancreatic cancer through binding miR-26b, miR-125a, miR-330 and miR-382 to regulate multiple tumor associated pathways. CONCLUSION: This study demonstrated that circRHOT1 may serve as an oncogenic circRNA that promotes tumor progression. PMID- 30444424 TI - A review discussing the use of polyethylene glycol microspheres in the treatment of hepatocellular carcinoma. AB - Transarterial chemoembolization (TACE) is indicated in unresectable hepatocellular carcinoma and allows the delivery of embolics inside tumor vascularization to reduce blood supply and release gradually the drug. This lowers the systemic exposure to chemotherapeutics, while increasing their local concentration and tissue necrosis that is higher than conventional TACE. The technology of TACE has seen the introduction of several types of embolics that are made of different materials. Available embolics for TACE include: drug eluting beads (DC beads), acrylic copolymer, tris-acrylic microspheres and polyethylene glycol (PEG) microspheres. Few studies are available on PEG embolics and their use for TACE. This review focuses on the efficacy and safety of TACE performed with PEG microspheres for the treatment of hepatocellular carcinoma and discusses future therapeutic advantages. PMID- 30444425 TI - Getting Ready For Health Reform 2020: Republicans' Options For Improving Upon The State Innovation Approach. AB - The 2020 presidential election will be consequential for the future of health reform, with the two major-party nominees taking very different views on the future of the Affordable Care Act (ACA), as well as the policies needed to lower health costs and continue to expand access to coverage. The Republican nominee will likely signal broad opposition to the ACA and a desire to replace it with a state innovation-based approach to reform, based on the Graham-Cassidy-Heller Johnson legislation considered by the Senate in the fall of 2017. This article takes that legislation as a starting point, contextualizes it within the broader health reform discussion, and suggests ways to improve upon it to enhance the affordability of and access to coverage and to ensure that states have adequate flexibility to implement their policy goals. PMID- 30444426 TI - Tissue transglutaminase autoantibodies in children with newly diagnosed type 1 diabetes are related to human leukocyte antigen but not to islet autoantibodies: A Swedish nationwide prospective population-based cohort study. AB - OBJECTIVES: This study explored the association between tissue transglutaminase autoantibody (tTGA), high-risk human leucocyte antigen (HLA) genotypes and islet autoantibodies in children with newly diagnosed type 1 diabetes (T1D). PATIENTS AND METHODS: Dried blood spots and serum samples were taken at diagnosis from children <18 years of age participating in Better Diabetes Diagnosis (BDD), a Swedish nationwide prospective cohort study of children newly diagnosed with T1D. We analyzed tTGA, high-risk HLA DQ2 and DQ8 (DQX is neither DQ2 nor DQ8) and islet auto-antibodies (GADA, IA-2A, IAA, and three variants of Zinc transporter; ZnT8W, ZnT8R, and ZnT8QA). RESULTS: Out of 2705 children diagnosed with T1D, 85 (3.1%) had positive tTGA and 63 (2.3%) had borderline values. The prevalence of tTGA was higher in children with the HLA genotypes DQ2/2, DQ2/X or DQ2/8 compared to those with DQ8/8 or DQ8/X (p = .00001) and those with DQX/X (p <= .00001). No significant differences were found in relation to islet autoantibodies or age at diagnosis, but the presence of tTGA was more common in girls than in boys (p = .018). CONCLUSION: tTGA at T1D diagnosis (both positive and borderline values 5.4%) was higher in girls and in children homozygous for DQ2/2, followed by children heterozygous for DQ2. Only children with DQ2 and/or DQ8 had tTGA. HLA typing at the diagnosis of T1D can help to identify those without risk for CD. PMID- 30444427 TI - How Democratic Candidates For The Presidency In 2020 Could Choose Among Public Health Insurance Plans. AB - Democratic candidates for president in 2020 will likely include some type of public plan in their health care reform platforms. Existing public plans take many forms and often incorporate private elements, as do most proposals to extend such plans. We review the types of public plans in the current system. We describe and assess the range of proposals to extend these plans or elements of them to additional populations. We suggest questions that candidates could use to guide their decisions about the scope and content of their health policy proposals. Developmental work during campaigns will contribute to success in turning candidates' promises into accomplishments. PMID- 30444429 TI - Corneal Involvement of Patients with Polymyositis and Dermatomyositis. AB - PURPOSE: To evaluate corneal parameters in patients with polymyositis (PM) and dermatomyositis (DM) and compare them with those of healthy controls. METHODS: A total of 43 PM and 32 DM patients and 93 controls were enrolled in this cross sectional, observational, case-control study. Corneal parameters were evaluated by Pentacam. Objective clinical tests of dry eye disease (DED) were also performed. RESULTS: All pachymetric measurements and corneal volumes (CVs) proved to be significantly lower both in PM and DM patients. The values of DM patients were closer to control values than those of the PM patients. For tear break-up time and Schirmer-I test values significant differences were observed between patients and controls, with values decreased both in PM and DM patients. CONCLUSIONS: PM patients rather than DM patients tend to develop thinner and low volume corneas as compared to controls. Additionally, a high prevalence of DED among both PM and DM patients was also detected. PMID- 30444428 TI - Three-dimensional contrast-enhanced ultrasound fusion imaging predicts local tumor progression by evaluating ablative margin of radiofrequency ablation for hepatocellular carcinoma: a preliminary report. AB - PURPOSE: To investigate the feasibility of three-dimensional contrast-enhanced ultrasound (3DCEUS) fusion in evaluating ablative margin (AM) after radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) and compare with those of computed tomography (CT) fusion. PATIENTS AND METHODS: In total, 55 patients (47 men, 8 women; mean age, 56.0 +/- 10.6 years) with 55 HCCs were included. Pre- and post-RFA 3DCEUS images were fused to assess AM immediately after RFA. The AM measured on fusion imaging was categorized into two groups: (A) AM <5 mm, and (B) AM >=5 mm. The agreement of AM evaluation was compared between 3DCEUS and CT fusion. The influence of AMs evaluated by 3DCEUS fusion on the risk of local tumor progression (LTP) was assessed. RESULTS: For 3DCEUS fusion, registration success rate was 96.4% (53/55). AM evaluation resulted in 28 tumors in group A and 25 tumors in group B. For CT fusion, AM evaluation resulted in 31 tumors with AM <5 mm and 23 tumors with AM >=5 mm. AM was successful evaluated by both technique in 53 (96.4%) tumors. The agreement between 3DCEUS and CT fusion was excellent (kappa coefficient = 0.924, p < .001). LTP was identified in 5 tumors (9.4%, 5/53). LTPs all occurred in the area where unachieved 5 mm AM was evaluated by 3DCEUS fusion. Cumulative rate of LTP was significantly higher in group A than in group B (28% versus 0%; p = .033, log-rank test). CONCLUSIONS: 3DCEUS fusion enables AM evaluation for HCC immediately after RFA with comparable accuracy to CT fusion. AM <5 mm evaluated by 3DCEUS fusion has high predictive value for LTP. PMID- 30444430 TI - Pharmacological treatment of pediatric Gaucher disease. AB - INTRODUCTION: Gaucher disease is an autosomal recessive disorder resulting from the deficiency of the lysosomal enzyme glucocerebrosidase (b-glucosidase), associated with varying degrees of visceral, bone and central nervous system pathology, leading to wide phenotypic diversity. Response to therapy and clinical outcomes are very different between the three clinical subtypes - non neuronopathic, acute neuronopathic and chronic neuronopathic forms; hence a definitive clinical diagnosis is essential. The availability of two therapeutic options, i.e., enzyme replacement and substrate reduction, has transformed the natural course of the disease. As pre-treatment disease severity clearly impacts results of therapy, early diagnosis and initiation of treatment especially in the pediatric population are keys to achieving an optimal outcome. Areas Covered: We reviewed the literature concerning the treatment of Gaucher disease focusing on pediatric presentations, various pharmacological treatment options and recommendations for management goals. A PubMed literature search was performed for relevant publications between 1991 to September 2018. Expert Commentary: The approval of enzyme replacement therapy(ERT) for Gaucher disease in the pediatric age group has significantly altered the course of the disease, especially for non neuronopathic and chronic neuronopathic forms, as ERT does not cross the blood brain barrier. Early diagnosis, regular follow up and early initiation of treatment can thus prevent some irreversible complications and improve patient quality of life. PMID- 30444431 TI - Contribution of Bipolar Cells of Cone ON and OFF Pathways to Electroretinograms Elicited by Ultraviolet and Middle Wavelength Stimuli. AB - PURPOSE: To determine the contribution of the ON and OFF cone bipolar cell pathways to the electroretinograms (ERGs) elicited by ultraviolet (UV) and middle wavelength light in mice. MATERIALS AND METHODS: The experiments were performed on 8- to 10-week-old C57BL/6J mice. The ERGs elicited by single-flash and flickering UV-light stimuli were compared to those elicited by green light stimuli under photopic conditions. Pharmacological agents were used to selectively block the ON and OFF pathways contributing to the ERGs. Saline was used as a control. The flicker ERGs elicited by UV light were compared to the ERGs elicited by green light after the injection of the pharmacological agents to determine the contribution of the cone ON and OFF pathways to the ERGs. RESULTS: The photopic single flash and flicker ERGs were more sensitive to the UV light stimuli than to those elicited by green light stimuli. The flicker ERG responses elicited by both UV and green light stimuli at stimulus frequencies lower than 15 Hz decreased after L-2-amino-4-phosphobutyric acid was injected. The ERGs elicited by UV light at 30-Hz and by green light at frequencies lower than 15-Hz decreased significantly after the intravitreal injection of cis-2, 3-piperidine dicarboxylic acid. An analysis of the ON and OFF components of the flicker ERGs showed that there might be pharmacological differences between the UV light sensitive responses and the green light-sensitive responses. CONCLUSIONS: These results suggest that the UV light sensitive cones connect to both the ON and OFF bipolar cells differently than that of the green light sensitive cones. PMID- 30444432 TI - Where phonology meets morphology in the context of rapid language change and universal bilingualism: Irish initial mutations in child language. AB - As one of the Celtic languages, Irish is among the few languages in the world that employ word initial mutations (IMs) in order to express grammatical functions. IMs express grammatical information by a way of systematic alternation of minimal phonological contrasts, which closely links segmental phonology to grammatical morphology (Irish also employs final consonant palatalization as a grammatical marker, but this will not be the focus of our paper). The overwhelming majority of Irish speakers are bilingual (with English), and virtually all Irish-speaking children grow up with varying degrees of exposure to and use of English in the home. Irish is undergoing rapid language change at present, and the system of IM is affected by this process of shift such that many fluent Irish speakers show inconsistent use of IM in their spoken language. Given inconsistency in the use of a grammatical system in the adult language, the question arises whether it will be possible to identify developmental norms for the use of IM in child language. This in turn has clinical implications, in terms of the presence (or absence) of clinical markers of language delay or disorder. The data we report on consist of narrative samples from typically developing children (aged between 3 and 6) and a group of parents, who completed the same task (telling a story from a wordless picture book). We plot consistency and accuracy IM use in the language of children and parents. A key finding is that inconsistent IM use by parents is mirrored by inconsistent use by children. We discuss clinical implications for language sampling for diagnostic purposes, and the importance of individualized assessment. PMID- 30444433 TI - Health-related quality of life in adult primary immune thrombocytopenia. AB - INTRODUCTION: Immune thrombocytopenia (ITP) and the associated biologic and psychological effects can lead to reduced health-related quality of life (HRQoL). Areas covered: This review focuses on the impact of ITP itself and its treatment on patients' HRQoL. The findings show that the HRQoL is uniformly reduced amongst ITP patients, both with and without interventions. ITP significantly affects many aspects of patient HRQoL, which is comparable to that of patients with other chronic diseases. However, there is a lack of longitudinal studies among unselected ITP populations and the majority of studies focus on statistical differences between groups or between measures at different time points rather than quality of life (QoL) changes that are perceived as clinically relevant in patients. Expert commentary: Due to ITP being a chronic disease with an ongoing risk of bleeding, many treatments, and a good prognosis for survival, patients deal with their symptoms over prolonged time periods and good HRQoL is very important. In this review of HRQoL in ITP, we provide data on the current understanding, how HRQoL may be modified by treatment, and why it needs to be included as an outcome in future studies to optimize management of HRQoL issues in clinical practice. PMID- 30444434 TI - Herpetic Panophthalmitis: A Diagnostic Dilemma. AB - PURPOSE: To describe an uncommon presentation of ocular infection caused by human herpes simplex virus 2 (HSV-2). METHODS: Case report. RESULTS: A 32-year-old female with no prior history of mucocutaneous herpesvirus infection presented with a minimally painful hypertensive granulomatous panophthalmitis and optic neuropathy that was initially suspected to be orbital cellulitis. Her disease progressed despite antibiotic and steroid treatment, and HSV-2 was ultimately identified in the vitreous. CONCLUSION: Although rare, ocular infection by human herpesvirus can present as a panophthalmitis. The case is discussed in the context of two previously reported cases of herpes simplex panophthalmitis, as well panophthalmitis caused by varicella zoster virus. PMID- 30444435 TI - Development of a Solid Supersaturated Self-Nanoemulsifying preconcentrate (S superSNEP) of Fenofibrate using Dimethylacetamide and a Novel Co-processed Excipient. AB - BACKGROUND: Recrystallization of drug and incomplete drug release from liquisolid formulation are two major hurdles in the development of a supersaturated self nanoemulsifying drug delivery system. The aim of this research work was to develop a solid supersaturated self-nanoemulsifying drug delivery system of fenofibrate (FB) for enhanced dissolution. METHODS: FB loaded supersaturated self nanoemulsifying preconcentrate (superSNEP) was prepared using dimethyl acetamide (DMA), medium chain triglycerides (MCT) and kolliphor EL. Co-processed excipients (CPE) prepared using inorganic microporous silica (Neusilin US2, Florite 100 or Aerosil 200) and hydrophilic polymers (Polyvinyl alcohol, HPMC and Kollidon VA64) were evaluated for flow property, BET surface area and adsorption capacity. Lipophilic fluorescent probe (coumarin-6) was used to investigate the extent of self-emulsification. The formulation was further characterized for solid state, in-vitro cytotoxicity in caco-2 cell line and in-vitro dissolution in a sink and non-sink conditions. RESULTS: Optimized superSNEP with 20% w/v FB loading spontaneously formed nanoglobules of 40 +/- 2.7 nm. DMA based self nanoemulsifying system was found to be non-toxic to Caco-2 cell even at a very high concentration. CPE prepared using PVA and Florite 100 (1:1 weight ratio) showed the highest adsorption capacity (1 mL/g) and complete release of oil as depicted by fluorescence study. DSC thermogram and PXRD of S-superSNEP confirmed that FB remained in a solubilized state. S-superSNEP showed significantly faster and higher dissolution of FB in sink and non-sink conditions compared to the plain API. CONCLUSION: DMA and PVA-F100 based novel co-processed excipient could be potentially useful for the development of solid supersaturated self nanoemulsifying drug delivery system for enhancing dissolution of lipophilic drugs. PMID- 30444436 TI - The Clinical Significance of Crohn Disease Activity at Resection Margins. AB - CONTEXT.-: Conflicting data about the clinical significance of microscopic Crohn disease (CD) activity at resection margins have led to varying practice patterns for routine reporting by pathologists. OBJECTIVE.-: To characterize the association between active disease at resection margins with postoperative CD recurrence and time-to-recurrence in the era of anti-tumor necrosis factor therapy. DESIGN.-: We performed a multicenter retrospective cohort study of 101 consecutive CD bowel resections during 10 years. Margin slides were reviewed, and CD activity at the margins was graded as none, mild, moderate, or severe. The association between microscopic CD activity at the margin with postoperative recurrence and time-to-recurrence were evaluated with logistic regression and Cox regression analyses, respectively. RESULTS.-: Crohn disease activity at resection margins was reported in 43% of pathology reports. Resection margins had CD involvement in 39.6% of cases, 20 of which were classified as mild, 6 as moderate, and 12 with severe CD activity. Although patients with mild (odds ratio, 1.14; 95% CI, 0.40-3.20) and moderate to severe (odds ratio, 1.97; 95% CI, 0.62-6.35) activity were at increased risk of disease recurrence, the differences were not statistically significant. Patients with mild (hazard ratio, 0.97; 95% CI, 0.50-1.91) and moderate to severe (hazard ratio, 1.29; 95% CI, 0.65-2.55) disease activity at margins did not have significantly different time-to recurrence compared with those without disease activity. CONCLUSIONS.-: Our study suggests CD activity at resection margins is not significantly associated with postoperative CD recurrence. PMID- 30444437 TI - Gastrointestinal Presentations of Common Variable Immunodeficiency: Hiding in Plain Sight. AB - Primary immunodeficiency disorders typically have an onset in childhood. The suspicion for these conditions usually arises from a history of recurrent respiratory, gastrointestinal, or cutaneous infections with a history often dating back to infancy or early childhood. However, adults can also be affected. Common variable immunodeficiency, which usually has an onset/diagnosis in adulthood, is the most common symptomatic primary immunodeficiency. However, as its presentation could be manifold, its diagnosis is often delayed. The gastrointestinal tract is the second most affected system after the respiratory tract; symptoms associated with the gastrointestinal tract are often intractable. As patients with common variable immunodeficiency are often misdiagnosed, a high index of suspicion and clinical correlation is required for the appropriate diagnosis of this potentially debilitating condition. PMID- 30444438 TI - Metastases to the Thyroid: Potential Cytologic Mimics of Primary Thyroid Neoplasms. AB - Secondary tumors of the thyroid gland, although uncommon, can sometimes pose as diagnostic dilemmas on fine-needle aspiration cytology, frequently mimicking primary thyroid neoplasms. An accurate diagnosis of such lesions, however, is critical for patient management and prognosis. The present study reviews the cytologic aspects of secondary involvement of the thyroid, listing the most common primary malignancies that metastasize to this gland. Knowledge of such morphologic aspects, combined with prompt clinical correlation, is essential for the cytopathologist to achieve a proper, definite diagnosis. PMID- 30444439 TI - High Frequency of MYD88 L265P Mutation in Primary Ocular Adnexal Marginal Zone Lymphoma and Its Clinicopathologic Correlation: A Study From a Single Institution. AB - CONTEXT.-: The pathogenesis of primary ocular adnexal marginal zone lymphoma (POAMZL) remains unclear. The reported associations with Chlamydia psittaci infection and MYD88 mutations are highly variable. OBJECTIVE.-: To examine MYD88 L265P mutation in ocular marginal zone lymphomas and correlate with clinicopathologic features and Chlamydia infection. DESIGN.-: Presence of MYD88 L265P mutation and Chlamydia infection in lymphoma was analyzed by using sensitive polymerase chain reaction (PCR) methods. RESULTS.-: The MYD88 L265P mutation was identified in 8 of 22 POAMZLs (36%), including 2 of 3 cases in which PCR failed to detect clonal IGH gene rearrangement; none of the 4 secondary marginal zone lymphomas were positive. Test results for Chlamydia were negative in all cases. Patients with and without the MYD88 mutation had similar clinicopathologic features. CONCLUSIONS.-: The MYD88 mutational analysis provides important information in diagnostic workup of POAMZL. The frequent MYD88 mutation suggests a critical role of this aberration in the pathogenesis of POAMZL and may serve as a therapeutic target for patients with progressive disease. PMID- 30444440 TI - A book review of Laboratory Imaging and Photography: Best Practices for Photomicrography and More. PMID- 30444441 TI - Scott Camazine: Memento Mori. PMID- 30444442 TI - The objective CORE score allows early rule out in acute chest pain patients. AB - OBJECTIVES: Chest pain is a common complaint in the emergency department (ED), and it is a challenge to identify low-risk chest pain patients eligible for early discharge. We aimed to develop a simple objective decision rule to exclude 30-day major adverse cardiac events (MACE) in ED chest pain patients. DESIGN: We analyzed prospectively included patients presenting with chest pain. Low risk patients were identified with the clinical objective rule-out evaluation (CORE). CORE was based on high sensitivity cardiac troponin T (hs-cTnT) tests at ED presentation (0h) and 2h later together with a simplified risk score consisting of four objective variables: age >=65 years and a history of arterial disease, hypertension or diabetes. For the patient to be classified as low risk in the CORE rule, hs-cTnT had to be <=14 ng/l both at 0 and 2h, and the sum of the risk score had to be 0. The primary outcome was MACE within 30 days. RESULTS: Among the 751 patients in the final analysis, 90 (11.9%) had a MACE. CORE identified 248 (33%) of patients as low risk with a sensitivity of 98.9% (CI 93.1-99.9) and a negative predictive value of 99.6% (95% CI 97.4-100) for 30-day MACE. Adding the ED physician's interpretation of the ECG to CORE did not improve diagnostic performance. CONCLUSION: A simple objective decision rule (CORE) identified one third of all patients as having a very low 30-day risk of MACE. These patients may potentially be discharged without additional investigations for acute coronary syndrome. PMID- 30444443 TI - Study on the transdermal penetration mechanism of ibuprofen nanoemulsions. AB - OBJECTIVE: The purpose of this study was to research the mechanism of percutaneous penetration of Ibuprofen (IBU) nanoemulsion. METHOD: Transdermal penetration mechanism of IBU nanoemulsion was investigated by using Fourier transform infra-red spectral analysis (FTIR), differential scanning calorimeter thermogram (DSC), and activation energy (Ea) measurement. The in vivo skin penetration test of rats was carried out using Rhodamine B nanoemulsion to simulate the process of drug penetration into the skin, and the frozen section of the skin was observed by confocal laser scanning microscopy (CLSM). RESULT: FTIR spectra and DSC thermogram of rat skin treated with IBU nanoemulsion showed that infiltration occurred due to disruption of the stratum corneum (SC) protein-lipid structure and increasing of fluidity, hydration, and disruption of the lipid bilayer structure of the SC. The significant reduce in Ea (1.255 kcal/mol) for IBU permeating rat skin suggested crucial disruption of the SC lipid bilayers (P < 0.05), which is speculated that nanoemulsion may create new pathways to promote drug penetration. CLSM revealed that Rhodamine B penetrated into the SC in a shorter period of time and it accumulated around the sebaceous glands. CONCLUSION: The study of skin penetration mechanism indicated that nanoemulsion can be perfectly well used as the transdermal penetration of poorly soluble drugs. PMID- 30444444 TI - Special Issue in Honor of Gordon H. Dixon. PMID- 30444445 TI - Improved corrosion resistance of commercially pure magnesium after its modification by plasma electrolytic oxidation with organic additives. AB - The optimal mechanical properties render magnesium widely used in industrial and biomedical applications. However, magnesium is highly reactive and unstable in aqueous solutions, which can be modulated to increase stability of reactive metals that include the use of alloys or by altering the surface with coatings. Plasma electrolytic oxidation is an efficient and tuneable method to apply a surface coating. By varying the plasma electrolytic oxidation parameters voltage, current density, time and (additives in the) electrolytic solution, the morphology, composition and surface energy of surface coatings are set. In the present study, we evaluated the influence on surface coatings of two solute additives, i.e. hexamethylenetetramine and mannitol, to base solutes silicate and potassium hydroxide. Results from in vitro studies in NaCl demonstrated an improvement in the corrosion resistance. In addition, coatings were obtained by a two-step anodization procedure, firstly anodizing in an electrolyte solution containing sodium fluoride and secondly in an electrolyte solution with hexamethylenetetramine and mannitol, respectively. Results showed that the first layer acts as a protective layer which improves the corrosion resistance in comparison with the samples with a single anodizing step. In conclusion, these coatings are promising candidates to be used in biomedical applications in particular because the components are non-toxic for the body and the rate of degradation of the surface coating is lower than that of pure magnesium. PMID- 30444446 TI - Becoming a "Science Person": Faculty Recognition and the Development of Cultural Capital in the Context of Undergraduate Biology Research. AB - We argue that cultural capital plays an underexamined role in students' recognition as budding scientists by faculty. By triangulating interview data from undergraduates and faculty mentors in a multi-institutional biology research network, we identified a set of intersecting domains of capital that help render students recognizable to faculty. We argue that faculty recognition often reflects a (mis)alignment between the cultural capital that students possess and display and what faculty expect to see. To understand why mis- or underrecognition occurs, and how this influenced students' opportunities to further develop cultural capital, we explored our data set for patterns of explanation. Several key themes cut across students' experiences and influenced their recognition by faculty: Faculty more easily recognized students interested in research science trajectories and those involved in institutional programs to support science, technology, engineering, and mathematics success. Students with competing family responsibilities struggled to maintain faculty recognition. Finally, faculty who broadened their scopes of recognition were able to affirm the science identities of students with fewer incoming cultural resources in science and support their development of capital. Students can and do develop scientific cultural capital through practice, but this requires access to research and mentorship that explicitly teaches students the implicit "rules of the game." PMID- 30444447 TI - Student Learning Outcomes and Attitudes Using Three Methods of Group Formation in a Nonmajors Biology Class. AB - Group work is often a key component of student-centered pedagogies, but there is conflicting evidence about what types of groups provide the most benefit for undergraduate students. We investigated student learning outcomes and attitudes toward working in groups when students were assigned to groups using different methods in a large-enrollment, student-centered class. We were particularly interested in how students entering the class with different levels of competence in biology performed in homogeneous or heterogeneous groups, and what types of group compositions were formed using different methods of group formation. We found that low-competence students had higher learning outcomes when they were in heterogeneous groups, while mid- and high-competence students performed equally well in both group types. Students of all competence types had better attitudes toward group work in heterogeneous groups. The use of student demographic variables to preemptively form groups and allowing students to self-select their group mates both yielded heterogeneous competence groups. Students in the instructor-formed, demographic groups had higher learning outcomes compared with students allowed to self-select. Thus, heterogeneous groupings provided the most benefit for students in our nonmajors, large-enrollment class. PMID- 30444448 TI - Structuring and Supporting Excellence in Undergraduate Biochemistry and Molecular Biology Education: The ASBMB Degree Accreditation Program. PMID- 30444449 TI - Representation of Industry in Introductory Biology Textbooks: A Missed Opportunity to Advance STEM Learning. AB - The majority of students who enroll in undergraduate biology courses will eventually be employed in non-STEM (science, technology, engineering, and mathematics) business occupations. This work explores how representations of industry in undergraduate biology textbooks could impact STEM learning for these students and their ability to apply this learning in their chosen work. We used text analysis to identify passages with references to industry in 29 textbooks. Each passage was categorized for relevance to health or environment, for implied positive or negative connotations, and for descriptions of synergy or conflict between science and industry. We found few passages describing applications of STEM learning in non-STEM business occupations and a paucity of content to support context-based learning for students aiming at business careers. A significant number of passages embodied negative connotations regarding industry. Notable passages highlighted irregular or fraudulent business practices or included simplistic caricatures of business practice. We discuss how the representation of industry in these textbooks may impact student engagement, context-based learning, the ability of students to critically apply STEM learning in industry or business occupations, and heuristics that guide intuitive perceptions about the intersection between science and industry. PMID- 30444450 TI - Survival now versus survival later: immediate and delayed HIV risk assessment among young Jamaican men who have transactional sex with men. AB - This study explored the experiences of young Jamaican men who have sex with men who engaged in transactional sex as a result of homelessness, family neglect or limited financial resources. It further examined the circumstances that affect their immediate or delayed decisions around sexual risk and increased vulnerability for HIV infection. Barriers experienced when accessing condoms, healthcare, HIV testing and other prevention services are also described. Twenty in-depth interviews and one focus group with 10 participants in various parishes in Jamaica were conducted. Findings from this study reveal how stigma and discrimination in the form of pervasive homophobia-influenced participation in the street economy via transactional sex. Socio-structural factors at family and commity level led to diminished social/economic prospects, which extended into adulthood. Sexual decision making was based on immediate needs for protection, food or shelter; concerns about acquiring HIV were considered only after meeting those immediate needs. Future HIV prevention strategies must take seriously the socio-structural factors that influence HIV risk behaviours among young men who have sex with men in Jamaica. PMID- 30444451 TI - [The immediate results of bronchoplastic surgical operations in surgery for lung malignant tumors]. AB - Bronchoplastic surgical operations by means of invaginated method on 1 semicircle in lung malignant tumors were performed in 124 patients. Of them 116 patients (93,5%) had primary and 8 patients (6,5%) metastatic tumors. There were 94 men (75,8%) and 30 women (24,2%). The average age of patients was 56,4. The lesion of the right lung was observed in 78 patients (62,9%), of the left one in 46 patients (37,1%). Bronchoplastic lobectomies were performed in 98 patients (79%), bilobectomies - 17 patients (13,7%), segmentectomy - 4 patients (3.3%), isolated resections of bronchi - 5 patients (4,0%). All operations were radical. In all cases of lung cancer there was carried out extended inpsilateral lymph node dissection. Complications of different severity were observed in 24 patients (19,4%): pneumonia (4,8%), atelectasis (0,8%), insufficiency of bronchial sutures (3.2%), granulation stenosis of the bronchial anastomosis (1,6 %), chylothorax (0,8%), recurrent nerve palsy (2,4%), heart rhythm disorders (2,4%). Postoperative lethality was 4.8%. PMID- 30444452 TI - Generational Changes in Personality: The Evidence From Corpus Linguistics. AB - According to theory, social change is interconnected with changes in mental phenomena and language. In the present study, secular change in the usage frequencies of common English personality adjectives ( n = 336) qualifying the word person was analyzed over the period 1900 to 2002. It was hypothesized that words that represent those personality traits that are advantageous in occupations typical for modern societies have increased in frequency. The results show changes in the frequencies of individual words but stability across the five major categories of trait adjectives in the Google Books English fiction corpus. A modest increase for Extraversion-, Agreeableness-, and Stability-related adjectives was observed in the Google Books English 2012 corpus. Frequency of Intellect-related words increased up to 1960 and then declined. The results suggest that (a) human nature has changed little over the 20th century, (b) generational changes in personality are not strongly reflected in language, or (c) the corpus linguistic method used is not reliable for studying generational changes in personality. PMID- 30444453 TI - Aging, Melatonin Biosynthesis and Circadian Clockworks in the Gastrointestinal System of the Laboratory Mouse. AB - The gastrointestinal (GI) system is vital in its capacities for nutrient and water uptake, immune function, metabolism and detoxification, and stem-cell derived regeneration. Of significance to human health are a myriad of gastrointestinal disorders associated with aging that integrate with the circadian clock. Here we present data from three groups of mice: young (3 months old), middle-aged (12 months old), and old-aged (24 months old). Small intestine and colon samples taken every 4 hours under light:dark (LD) conditions were assayed for gene expression related to molecular circadian rhythmicity, transcription, cell-signaling, and immune function. Transcripts related to melatonin biosynthesis and signaling - as well as melatonin content from stool - were also included, as gastrointestinal melatonin and aging have been associated in contexts outside of the circadian clock. With respect to circadian genes, the data here are congruent with data from other peripheral tissues: age does not affect the rhythmic expression of core clock genes in the gut. The same can be said for several clock-controlled transcripts. In contrast, diurnal patterns in the expression of nitric oxide synthase 1 (nos1) and of immune factors irak4 and interleukin-8 were observed in the colon of young mice that were lost in middle aged and aged animals. Further, the diurnal pattern of melatonin synthesis genes were altered by age, and stool melatonin levels showed significant decline between young mice and aged cohorts. These data expand the evidence for the persistence of the circadian clock throughout the aging process and highlight its importance to health. PMID- 30444454 TI - Stabilizing supersaturated drug-delivery system through mechanism of nucleation and crystal growth inhibition of drugs. AB - A supersaturated drug-delivery system is capable of enhancing oral bioavailability of hydrophobic drugs. Maintenance of the supersaturated system both in vitro and in vivo is one of the most challenging parts, for that it is required to keenly understand the nucleation and crystal growth behavior. Polymers are widely used to stabilize supersaturated solutions; screening of polymers is done on the basis of their interaction with drug. Nucleation and crystal growth inhibition and drug-polymer interactions can be investigated by using various spectroscopic methods. Various formulations are prepared as supersaturated systems using different drug-delivery systems utilizing different polymers, which illustrates that supersaturation is worthwhile to increase the solubility and hence oral bioavailability of poorly soluble drugs. PMID- 30444455 TI - Long circulating liposomes: challenges and opportunities. AB - The poor pharmacokinetic parameters and low solubility of many anticancer therapeutics have warranted the use of drug-delivery systems such as liposomes. Overcoming some drawbacks of the conventional liposomes, targeted liposomal delivery by longer circulation time by addition of poly(ethylene glycol) to the liposomal surface and further adding specific ligands to achieve ligand selective retention and uptake has been introduced. PEGylated liposomes are the only second generation liposomal formulations in clinical use and are now being challenged with the allergenic response they pose even in the treatment of naive patients. This article will review the challenges and hindrances in the use of long circulating liposomes and explore the opportunities to overcome this issue. PMID- 30444456 TI - Industry update covering August 2018. PMID- 30444457 TI - Does moderate-intensity continuous training result in greater total energy expenditure compared to high-intensity interval training? AB - Recently in the Journal of Sports Sciences, Schaun et al. published a study on the comparison of energy expenditure between high-intensity interval training and moderate continuous training performed in water. With this Letter to the Editor, we would like to comment on the methodological aspects that should be considered to analyze the results presented, as well as the conclusions. Abbreviations: CONT, moderate-intensity continuous training; EPOC, excess post-exercise oxygen consumption; HIIT, high-intensity interval training; VO2max, maximal oxygen consumption. PMID- 30444458 TI - A Cross-Cultural Comparison of Climacteric Symptoms, Health-Seeking Behavior, and Attitudes towards Menopause Among Mosuo Women and Han Chinese Women in Yunnan, China. AB - Cultural background has been shown to influence climacteric symptoms of women. This study compares various characteristics of climacteric symptoms, illness conception, health-seeking behavior, and attitude towards menopause of Mosuo women, a Chinese ethnic minority with a matriarchal structure, and Han Chinese women, the majority ethnic group of China with a patriarchal structure. Through convenience sampling, 51 Mosuo and 47 Han women ages 40 to 60 completed a sociodemographic questionnaire, the modified Kupperman Menopause Index (KMI), the Self-Rating Scale of Illness Conception and Health Seeking Behavior (SSICHSB) and the Menopause Attitude Questionnaire (MAQ). The Mosuo and Han Chinese women are comparable with regard to their age, educational levels and menstrual status. During climacteric, Mosuo women showed less severe melancholia ( p = .009), reported less health-seeking behavior ( p = .009), and displayed more positive attitudes towards menopause than their Han Chinese counterparts ( p < .001). One predictive variable of the melancholia severity in Mosuo was "menarche age", while that in the Han group was "social view on the menopause". Future research with a larger sample is needed to deepen our understanding about the interaction between culture and climacteric symptoms. PMID- 30444459 TI - Photodynamic therapy of cancer with liposomal photosensitizers. AB - The photodynamic reaction involves the light-induced generation of an excited state in a photosensitizer molecule (PS), which then results in the formation of reactive oxygen species in the presence of oxygen, or a direct modification of a cellular molecule. Most PSs are porphyrinoids, which are highly lipophilic, and are administered usually in liposomes to facilitate their effective delivery to target cells. The currently available liposomal formulations are Visudyne(r) and Fospeg(r). Novel PSs were developed and tested for their photodynamic activity against cancer cells. Several compounds were highly phototoxic to oral cancer cells both in free and liposome-encapsulated form, with nanomolar IC50 values. The lowest IC50s (7-13 nM) were obtained with a PS encapsulated in cationic liposomes. PMID- 30444460 TI - Industry update: the latest developments in the field of therapeutic delivery, July 2018. PMID- 30444461 TI - Eudragit(r)-based microcapsules of probucol with a gut-bacterial processed secondary bile acid. AB - AIM: Deoxycholic acid (DCA) has improved gliclazide oral absorption, while Eudragit(r) (ED) polymers have improved formulation stability of antidiabetic drugs. The aim of the study is to test if DCA and ED encapsulation will optimize the release and stability of the potential antidiabetic drug probucol (PB). MATERIALS & METHODS: The PB formulations were prepared using ED polymers and DCA, and formulations were analyzed for their rheological and biological properties. RESULTS: Rheological properties and size distribution were similar among all groups. beta-cell survival and biological activities were best with NM30D microcapsules. The inflammatory profile and oxidative stress effects of microcapsules remained similar among all groups. CONCLUSION: ED NM30D and DCA incorporation can exert positive and stabilizing effects on PB oral microcapsules. PMID- 30444462 TI - Spray congealing: a versatile technology for advanced drug-delivery systems. AB - Spray congealing is a low cost, simple and versatile method to produce microparticles without the use of organic or aqueous solvent. This review provides a detailed picture of the pharmaceutical applications of this technology, with an overview of the spray-congealed-based drug-delivery systems. First, the basic principles and equipment of spray congealing technology are presented. Then, representative examples of the drug-delivery systems are examined and critically discussed. Emphasis is given on the role of formulation variables, together with practical considerations for formulation design. In addition, the current status of the industrial applications of this technology within the pharmaceutical field is examined. The final part points out benefits, limitations and future perspectives of this technology in drug delivery. PMID- 30444463 TI - Age-associated changes in GSH S-transferase gene/proteins in livers of rats. AB - OBJECTIVES: Glutathione S-transferases (GSTs) are phase-II metabolic enzymes playing important roles in drug metabolism, anti-oxidative stress and anti-aging. Age is a key factor influencing GSTs expression. Thus, age-related changes of 10 GSTs were examined. METHODS: Livers from male Sprague-Dawley rats at fetus (-2 d), neonates (1, 7, 14 and 21 d), puberty (28 and 35 d), adulthood (60 and 180 d), and aging (540 and 800 d), were collected and subjected to qPCR analysis. Liver proteins from 14, 28, 60, 180, 540 and 800 d were also extracted for selected protein analysis by Western-blot. RESULTS: The expression of GSTA1 and GSTP1 increased over the life span and the expression of GSTA4, GSTO1 and GSTZ1 gradually increased until adulthood, and slightly decreased at 800 days. The expression of GSTM1, GSTM3, GSTT1, GSTT2 and GSTK1 gradually increased until adulthood, but significantly decreased during aging of 540 and 800 days. There is a small peak at 7-14 d for GSTA1, GSTP1 and GSTZ1. The protein expression of GSTA1, GSTM1 and GSTP1 followed the trend of mRNA changes. DISCUSSION: This study characterized three expression patterns of 10 GSTs during development and aging in rat liver, adding to our understanding of anti-aging role of GSTs. PMID- 30444464 TI - Variability in peripheral rewarming after cold stress among 255 healthy Norwegian army conscripts assessed by dynamic infrared thermography. AB - Exposure to cold climate is an inevitable consequence of military training in Norway. Adequate peripheral microcirculation in the extremities is important to maintain temperature, and to protect against freezing cold injuries. The aim of this study was to investigate the variability in skin rewarming ability. The study subjects consisted of 260 healthy Norwegian army conscripts, following a mild cold provocation test (hands immersed in 20 degrees C water for 1 min) using dynamic infrared thermography (DIRT). Thermal images were obtained to investigate any differences in skin rewarming ability of the hand (fingers). DIRT took place under standardised and stable study conditions. Conscripts were characterised as either slow, intermediate or rapid rewarmers. While 90% could recover, partially or completely, within 4 min to the skin temperature values before the provocation test, 10% showed a slow rewarming pattern. In the slow rewarmers, the rewarming ability was correlated with a low average temperature of the hands prior to the cooling test. The healthy young army conscripts in this study showed a large variability in their rewarming ability following a standardised mild cold provocation test. PMID- 30444465 TI - Biotreatment of petroleum refinery wastewater in vertical surface-flow constructed wetland vegetated with Eichhornia crassipes: lab-scale experimental and kinetic modelling. AB - The objectives of this study were to evaluate the potential of vertical surface flow constructed wetland (VSF-CW) vegetated with Eichhornia crassipes to treat petroleum refinery secondary wastewater under tropical conditions. Also, to provide a comparative evaluation of biotreatment kinetic models (traditional first order and other alternative kinetic models) proposed to describe the removal kinetics of organics (biochemical oxygen demand (BOD) and chemical oxygen demand (COD)), nitrate-nitrogen and total petroleum hydrocarbons (TPH) in wetland systems. The refinery secondary wastewater was characterized and treated in five VSF-CWs. Eichhornia crassipes were planted in three VSF-CWs and the remaining two VSF-CWs served as the unvegetated control. The wastewater relatively had high levels of turbidity (18.30 +/- 3.88 NTU), BOD (20.40 +/- 2.20 mg/L), COD (86 +/- 6.0 mg/L), TPH (16.6 +/- 1.76 mg/L), oil and grease (18.4 +/- 2.00 mg/L), heavy metals (Cadmium (0.034 +/- 0.01 mg/L), Lead (0.12 +/- 0.05 mg/L), Chromium (0.47 +/- 0.01 mg/L), Iron (1.54 +/- 0.25 mg/L) and Nickel (0.09 +/- 0.01 mg/L)) and Chloride (1412 +/- 9.6 mg/L). The vegetated VSF-CWs significantly performed better than the unvegetated control and resulted in the removal efficiencies of 91.5% turbidity, 94.6% BOD5, 80.2% COD, 92.6% TPH, 90.4% oil and grease, 94% cadmium, 92.5% lead, 93% chromium, 94.8% iron, 92.2% nickel, and 57.7% chloride. The results suggested that the proposed kinetic models were applicable for understanding the removal mechanisms of organics, nitrate-nitrogen and hydrocarbons in VSF-CW systems. Thus, Eichhornia crassipes planted VSF-CW has the potential of treating refinery secondary wastewater to discharge permissible limits. PMID- 30444466 TI - Identification of Dialeurodes citri as a Vector of Citrus yellow vein clearing virus in China. AB - In 2009, a new citrus viral disease caused by Citrus yellow vein clearing virus (CYVCV) was first discovered in China and now CYVCV is widely distributed in the field. CYVCV is transmissible by grafting and is spread by aphids from lemon to bean, and from bean to bean. However, until now, no vector has been shown to transmit CYVCV from citrus to citrus. In this study, after a 24-h acquisition access period (AAP), CYVCV was tested for in Dialeurodes citri (Ashmead), Panonychus citri McGregor, and Aphis citricidus (Kirkaldy) by quantitative RT PCR. After an AAP of 48 h, groups of adults of D. citri, P. citri, and A. citricidus were given a 48 h inoculation access period on cultivar Daidai sour orange seedlings. Three, 6, and 12 months post-transmission by D. citri, CYVCV was detected in the receptor plants, and the mean incidence of infected trees was 31.9, 39.1, and 39.1%, respectively. CYVCV was not transmitted to citrus by P. citri or A. citricidus. This is the first report of the ability of D. citri to transmit CYVCV from infected to healthy citrus under laboratory conditions. PMID- 30444467 TI - Evaluation of Rice Responses to the Blast Fungus Magnaporthe oryzae at Different Growth Stages. AB - Rice blast, caused by the fungus Magnaporthe oryzae, is the most damaging disease for rice worldwide. However, the reactions of rice to M. oryzae at different growth stages are largely unknown. In the present study, two temperate japonica rice cultivars, M-202 and Nipponbare, were inoculated synchronously at different vegetative growth stages, V1 to V10. Plants of M-202 at each stage from V1 to reproductive stage R8 were inoculated with M. oryzae race (isolate) IB-49 (ZN61) under controlled conditions. Disease reactions were recorded 7 days postinoculation by measuring the percentage of diseased area of all leaves, excluding the youngest leaf. The results showed that the plants were significantly susceptible at the V1 to V4 stages with a disease severity of 26.7 to 46.8% and disease index of 18.62 to 37.76 for M-202. At the V1 to V2 stages, the plants were significantly susceptible with a disease a severity of 28.6 to 39.3% and disease index of 23.65 to 29.82 for Nipponbare. Similar results were observed when plants of M-202 were inoculated at each growth stage with a disease severity of 29.7 to 60.6% and disease index of 21.93 to 59.25 from V1 to V4. Susceptibility decreased after the V5 stage (severity 4.6% and index 2.17) and became completely resistant at the V9 to V10 stages and after the reproductive stages, suggesting that plants have enhanced disease resistance at later growth stages. These findings are useful for managing rice blast disease in commercial rice production worldwide. PMID- 30444468 TI - Paecilomyces niveus: Pathogenicity in the Orchard and Sensitivity to Three Fungicides. AB - Paecilomyces rot of apples is a postharvest disease caused by the thermotolerant fungus Paecilomyces niveus (Byssochlamys nivea). The etiology of disease and the activity of fungicides against P. niveus are not yet well understood. This study evaluated the ability of P. niveus to infect 'Gala' apples growing in a conventionally managed orchard. In addition, the sensitivity of P. niveus isolates to postharvest fungicides difenoconazole, fludioxonil, and pyrimethanil was characterized for isolates from both agricultural and nonagricultural environments. Apples were wounded and mock-inoculated or inoculated with P. niveus in early July. At the time of harvest, 8 weeks after wounding, the inoculated apples had significantly larger lesions than mock-inoculated apples (P < 0.005). The average diameter of lesions on wound-inoculated apples was 11.17 mm +/- 6.82 SD, while the average diameter of mock-inoculated lesions was 3.34 mm +/ 1.85 SD. Disease symptoms in the orchard were similar to postharvest symptoms of Paecilomyces rot. Symptoms included a brown, flattened, circular lesion with faint concentric rings. The necrosis of mesocarp was firm and roughly U-shaped. Baseline isolates of P. niveus, from nonagricultural environments, were used to determine the effective fungicide dose at which growth was inhibited by 50% (EC50). Furthermore, fungicide sensitivity of P. niveus isolates was examined using relative growth assays at the mean baseline EC50 values to compare baseline isolates with isolates obtained from commercial apple orchards where they were likely exposed to fungicides. Among the exposed isolates, reduced sensitivity to all fungicides was observed, but significant differences between baseline and exposed isolates were only observed with fludioxonil (P < 0.0001). This is the first report demonstrating that P. niveus can infect apples that are wound inoculated in the orchard and that isolates from agricultural environments are less sensitive to common fungicides, especially fludioxonil. This finding may have implications for the control of this postharvest diseases. Whether natural infections of apples by P. niveus is initiated in the orchard or during postharvest has yet to be determined. PMID- 30444469 TI - Post-transcriptional regulation of cholera toxin production in Vibrio cholerae by the stringent response regulator DksA. AB - Expression of cholera toxin (CT), the principal virulence factor of the cholera pathogen Vibrio cholerae, is positively modulated by the RNA polymerase binding unusual transcription factor DksA (DksAVc) of the stringent response pathway. Here we report that even though CT (encoded by the genes ctxAB) production is downregulated in the V. cholerae DeltadksA (DeltadksAVc) mutant, the expression of the ctxA gene as well as the genes encoding different virulence regulators, namely, AphA, TcpP and ToxT, were also upregulated. Since DksAVc positively regulates HapR, a known negative regulator of CT production, the increased expression of different virulence genes in DeltadksAVc was due most probably to downregulation of HapR. There was no secretion/transport-related defect in DeltadksAVc cells because whole cell lysates of the mutant showed a negligible amount of CT accumulation similar to WT cells. To understand further, the hapR gene was deleted in DeltadksAVc background, however, the double mutant failed to rescue the CT production defect suggesting strongly towards post transcriptional/translational regulation by DksAVc. This hypothesis was further confirmed when the site-directed mutagenesis of each or both of the conserved aspartic acid residues at positions 68 and 71 of DksAVc, which are essential for transcription initiation during the stringent response, had no effect in the regulation of CT expression. Interestingly, progressive deletion analysis indicated that the C4-type Zn finger motif present in the C-terminus of DksAVc is essential for optimal CT production. Since this motif plays important roles in DNA/RNA binding, the present study indicates a novel complex post-transcriptional regulation of CT expression by DksAVc. PMID- 30444470 TI - Thermocatellispora soli sp. nov., isolated from hot spring soil. AB - An aerobic, spore-forming, actinomycete, designated strain CHM3-46T, was isolated from soil in a hot spring pond located in Chiangmai province, Thailand. The strain exhibited taxonomic characteristics consistent with the genus Thermocatellispora. Strain CHM3-46T produced short, straight chains of warty spores on aerial mycelia. The presence of meso-diaminopimelic acid was observed in the cell-wall peptidoglycan. The whole-cell reducing sugars were glucose, mannose, galacose and ribose. The phospholipids comprised phosphatidylmethylethanolamine, hydroxyphosphatidylmethylethanolamine, phosphatidylethanolamine, hydroxyphosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, four phosphoglycolipids and three unidentified phospholipids. The predominant menaquinones were MK-9(H4), MK-9(H6) and MK-9(H8). 10-methyl C17 : 0, C16 : 0, C17 : 0 and iso-C16 : 0 were identified as the main cellular fatty acids. The G+C content of the genomic DNA was 73.2 mol%. Analysis of the 16S rRNA gene sequence showed that strain CHM3-46T belonged to the genus Thermocatellispora, exhibiting the highest similarity to Thermocatellispora tengchongensis YIM 77521T (98.5 %). Furthermore, a low DNA relatedness value (23.4 %+/-0.8) and several physiological and biochemical characteristic differences were detected between strain CHM3-46T and its closest relative. Based on the taxonomic data, strain CHM3-46T could be readily distinguished from its closest phylogenetic relative and represents a novel species, for which the name Thermocatellisporasoli sp. nov. is proposed. The type strain is CHM3-46T (=TBRC 7649T=NBRC 113148T). PMID- 30444472 TI - Preparation of the Validation Lists and the role of the List Editors. AB - Recently a number of queries were received about the ways in which requests for validation of names of taxa effectively published in journals other than the IJSEM are approved or denied and about the criteria used by the List Editors of the journal when deciding whether or not a validation request can be approved. As this process may be unclear to some authors of proposals, we would like to clarify the nature of the validation process and the role of the List Editors. PMID- 30444471 TI - Detection and molecular characteristics of neboviruses in dairy cows in China. AB - In this study, 98 diarrhoeic and 70 non-diarrhoeic samples were collected from 13 dairy farms located across 5 provinces in China from April 2017 to May 2018. Approximately 41.8 % (41/98) of diarrhoeic samples and 5.7 % (4/70) of non diarrhoeic samples were nebovirus-positive based on RT-PCR results, and some diarrhoeic samples were co-infected with bovine rotavirus (73.2 %), bovine coronavirus (36.6 %) and/or bovine viral diarrhoea virus (31.7 %). A phylogenetic analysis of 23 nebovirus RdRp fragments showed that these strains were closely related to Nebraska-like (NB-like) strains but were all located in a unique large branch. Moreover, a phylogenetic analysis of the 18 complete VP1 sequences from this study revealed that 14 strains belonged to lineage 1 and 4 strains belonged to lineage 3. Notably, all four lineage 3 strains shared the same recombination event, with a breakpoint located within the P1A domain. The complete genome of one nebovirus strain, Bo/YLA-2/17/CH, which had a recombination event within the P1A domain of its VP1, was successfully sequenced and was found to be 7453 nt in length, and this may represent a novel nebovirus strain based on the phylogenetic analysis of its complete genome sequence. In conclusion, this study reveals that neboviruses circulate widely in dairy cows in China and exhibit a unique evolution of RdRp. To the best of our knowledge, this is the first reported recombination event located within the P1A domain of nebovirus VP1. PMID- 30444473 TI - Allorhizocola rhizosphaerae gen. nov., sp. nov., a new member of Micromonosporaceae isolated from rhizosphere soil of the plant Calligonum mongolicum. AB - The taxonomic position of an actinobacterium, designated CPCC 204380T, which was isolated from a rhizosphere soil sample of the plant Calligonum mongolicum collected from Xinjiang Province, China, was established using a polyphasic approach. Vegetative hyphae developed well and globose bodies formed from aged hyphae. Spore chains that differentiated from the vegetative hyphae contained non motile rod-shaped spores. The peptidoglycan contained meso-diaminopimelic acid and 3-hydroxydiaminopimelic acid as the diagnostic amino acids. The acyl type of the peptidoglycan was glycolyl. Glucose, mannose, ribose and xylose were detected in whole-cell hydrolysates. The predominant menaquinone was MK-10(H8), followed by MK-10(H6) and MK-10(H4). The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The major fatty acids were iso-C15 : 0, iso-C16 : 0 and C17 : 1omega9c. The genomic G+C content was 64.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain CPCC 204380T should be placed in the family Micromonosporaceae, in which it formed a distinct lineage next to the genera Rhizocola, Catellatospora, Catelliglobosispora, Hamadaea and Allocatelliglobosispora. It shared the highest 16S rRNA gene sequence similarities with Rhizocola hellebori K12-0602T (96.1 %), Catellatospora chokoriensis 2-25/1T (95.9 %), Catelliglobosispora koreensis DSM 44566T (95.9 %), Hamadaea tsunoensis DSM 44101T (95.3 %) and Allocatelliglobosispora scoriae Sco B14 T (94.2 %), and less than 94.0 % sequence similarity with other validly described species. The combination of phylogenetic analysis and phenotypic characteristics supported the proposal of strain CPCC 204380T as representing a novel species of a new genus in the family Micromonosporaceae, for which the name Allorhizocola rhizosphaerae gen. nov., sp. nov. is proposed. CPCC 204380T (=DSM 102292T=KCTC 39746 T) is the type strain of the type species. PMID- 30444475 TI - A probable case of doping in an Olympic athlete coming back from ancient Greece (V cent. B.C.). AB - We present here the hypothesis of doping in an athlete coming back from the ancient Greece, dating back to V century B.C. There are some bone alterations due to the sports that he probably practiced, and that are represented on the amphorae (prices of his victories) found near his sepulchre. The skeleton shows a considerable mass and bone density. The chemical analyses performed on the bone emphasized the presence of arsenic, while the X-ray and CAT scan examinations revealed a quite big sella turcica. These two aspects might have influenced the performances of this athlete, and in the same time might have provoked his death at the age of about 30 years. PMID- 30444474 TI - Hospital doors under pressure; policies and trends in the major tertiary care hospital in Albania. AB - OBJECTIVES: Quantification of elective and emergency hospital admissions as a resultant of patients' diagnostic and therapeutic pathways (referral system) and patients' preferences to choose the health-care provider. DESIGN: Retrospective analysis of routine hospital discharge data. Findings were analyzed with descriptive statistical methods. SETTING: University Hospital Center, "Mother Teresa", Albania, a secondary and tertiary health care provider to the capital Tirana and tertiary health care provider for the rest of Albania. SUBJECTS: 692,284 hospital admissions during eleven years period, 2006-2016. MAIN OUTCOME MEASURES: Hospital admission trends measured as Average Annual Percentage Change and standardized admissions by district per 100,000 inhabitants. RESULTS: Number of hospital admissions increased from 55,528 in the baseline year to 78,130 in the last year of our study. During eleven years ALOS changed from 7.60 to 5.80 days and BOR increased from 83.2% to 91.6%. AAPC total, Average Annual Percentage Change was 3.2% at the ending year, 2006 to 2016. Cramer's V between variables 'year of admission' and 'prefecture' was 0.024, p < 0.001 and between 'year of admission' and 'Tirana University Hospital Center administrative units' was 0.055, p < 0.001. Both relationships are weak but significant. Maps show the exaggerated flow from other districts towards Tirana. CONCLUSIONS: Patient satisfaction, as a health care quality metric, is a driving force towards the choice of health provider. The satisfied patient chooses again or tells the next patient the preferred provider. The perceived professional difference among health care providers has built a competitive environment. The referral system puts strict rules over patient pathway which in his turn finds ways to bypass it if preferences are not taken in consideration. Commitment to such rules is accepted till forces considered as expression of free choice overcome them, jeopardizing the performance of the whole system. Patient's preferences deserve to be evaluated and incorporated in the patient pathway design. PMID- 30444476 TI - Multidrug-resistant Gram-negative osteomyelitis: a 10-year study. AB - AIM: Few series of osteomyelitis due to multi-drug (MDR) or extensively-drug resistant (XDR) gram-negative bacteria exist. A retrospective study of MDR and XDR gram-negative osteomyelitis cases was performed, aiming to investigate causative organisms, proper surgical and medical management, as well as outcome. PATIENTS AND METHODS: All patients, treated at the University hospital of Crete between 2007 and 2016 for acute osteomyelitis, due to MDR or XDR gram-negative pathogens were evaluated. RESULTS: A total of 14 patients (8 males) were identified with a mean age of 50.6 years. Five Acinetobacter baumanii cases, 3 XDR and 2 MDR, were found. Furthermore, 3 MDR Klebsiella pneumoniae and 3 MDR Enterobacter cloacae isolates were identified. Additionally, 2 MDR Escherichia coli, as well as 2 Pseudomonas aeruginosa, 1 XDR and 1 MDR, were isolated. One case of Roseomonas gilardii was also identified. In 5 cases the same pathogen was also isolated from blood. Five out of the 14 patients were smokers, 6 were suffering severe injury, 4 had diabetes-mellitus, 2 chronic renal disease and 2 were obese. Most causative organisms had hospital origin. All patients received first line empirical combination antimicrobial treatment, proven effective in 4. Thirteen patients were also subjected to surgical treatment. The study included mainly young individuals, most likely due to the high incidence of traffic accidents involving young adults in Crete. CONCLUSIONS: Antimicrobial regimens are important supplements to surgical treatment of acute osteomyelitis. However, due to emergence of resistant microorganisms, compliance with strict rules of antimicrobial strategy is of utmost importance. PMID- 30444479 TI - Transanal repair of rectocele with high frequency radio scalpel. AB - AIM: This is a prospective randomized study to analyze results obtained in two groups of patients, affected by stage 2 rectocele and treated with rectum anterior wall repair and strength, performed with standard or modified Khubchandani technique, using High Frequency (HF) Radio Scalpel. MATERIALS AND METHODS: A cohort of 24 patients with stage 2 rectocele (Mellgren's classification) have been included. Twelve (group A) underwent surgery with standard technique and twelve (group B) underwent surgery using the HF Radio Scalpel, which cuts and coagulates tissues without damage thanks to its low working temperature (45-70 degrees C). Each patient underwent proctolo-gical examination and anoscopy in 7th, 15th, 45th POD and after 6 and 12 months. RESULTS: During post-operative follow-up 5 patients from group A and 1 from group B didn't show up so that they drop out the study. As a result, group A is composed by 7 patients and group B by 11 patients. Mean operating time was significantly favourable in group B (51 vs 33 minutes, p< 0.01). The differences between other parameters weren't statistically significant, even if post operative course was less difficult in HF Radio Scalpel group. CONCLUSIONS: The surgical technique to repair and reinforce anterior rectal wall is easier and faster if performed with HF Radio Scalpel respect to the standard procedure described by Khubchandani. Post-operative course was less painful and, even more importantly considering the patient age, surgical time was shorter. Therefore, the results obtained cast positive light on using this technique to treat uncomplicated grade 2 rectocele. PMID- 30444477 TI - IONM and minimally invasive videoassisted thyroidectomy. AB - BACKGROUND: We know that benefits of MIVAT are related to a better cosmetic result and lower post-operative pain in comparison to CT. The incidence of nerve cold palsy is related to a correct identification of the recurrent laringeal nerve (RLN) as standard procedure in thyroid surgery. From September 2014 we have introduced the use of intraoperative neural monitoring(I-IONM) in all thyroidectomies in the Unit of General Surgery of University Hospital of Parma, including in MIVAT. PATIENTS AND METHODS: We have considered all patients treated from September 2014 to September 2017 for thyroid diseases using MIVAT and IONM. Intermittent neuromonitoring with NIM-3.0 equipment (Medtronic, Jacksonville, FL, USA) was used during all operations. We have recorded all data about age, sex, diagnosis, surgical time, i-IONM signal, postoperative pain, postoperative hypocalcemia after 24 hours, haematoma and vocal cord palsy. The mean hospital stay was collected from surgical procedure to hospital discharge. We have considered vocal dysfunctions that persist six months after surgery as permanent. RESULTS: From September 2014 to September 2017 we treated consecutively with both MIVAT and i-IONM 100 patients. Considering the extent of surgery, 26 pts underwent to hemithyroidectomy and 74 pts to total thyroidectomy. The mean surgical time was 61.8 minutes. In 7 cases the patients were affected by preoperative clinical dysphonia. Using I-IONM during thyroidectomy, we recorded in 5 cases (5%) a loss of signal; in two cases (2%) we experienced a temporary postoperative vocal cord palsy. DISCUSSION: In our experience the use of IONM has improved the safety during thyroidectomy because precision that can be achieved by endoscopic procedures is further improved by complementary use of IONM. The costs associated to a potential reduction of medical litigation have not been investigated. PMID- 30444478 TI - The management of the slow transit constipation in the laparoscopic era. AB - The slow transit constipation (STC) is a functional bowel pathology with slow total gut transit time with normal calibre colon in addition to a variety of other systemic symptoms. Patients with an abnormal colonic motility refractory to conservative treatment are regarded as appropriate candidates for surgery. Laparoscopic total colectomy with ileum-rectum anastomosis represents the commonest surgical operation in the treatment of STC, in well selected patients, after failure of conservative treatment. From 2012 to 2016, 8 patients suffering constipation according to Roma III criteria and diagnosed as STC were submitted to a total colectomy in our O.U. We evaluated the long-term post-operative quality of life and the bowel function, specifically the persistence of constipation and the number of daily bowel movements. Based on our results, we consider that the use of minimally invasive total colectomy with an ileum-rectal anastomosis is the procedure of choice in patients with colonic inertia, and should be performed by experts in laparoscopic colorectal surgery offering a satisfying post-operative quality of life with low morbidity and mortality rates. PMID- 30444480 TI - Is human fibrin sealant a possible choice for the fixation of laparoscopic inguinal hernia repair? A single center experience and the analysis of the results after 326 TAPP in two years. AB - BACKGROUND: Groin hernioplasty is most intervention performed in the worldwide. The present study aimed to evaluate a combination between ultralight mesh and fibrin human sealant in the laparoscopic treatment of inguinal hernia. PATIENTS AND METHODS: This retrospective study included consecutive patients who underwent laparoscopic transabdominal preperitoneal hernioplasty (TAPP) from 1st of January 2015 to 31st of December 2016. Demographics, surgical data and postoperative outcomes were entered in an anonymized prospective database. Prospective longterm follow-up carried out in all patients. RESULTS: One hundred eighty-four patients with a median age 57.5 (range 19-84) and median BMI (Body Mass Index) of 28.5 (range 18.5-31.5) were included. A median follow-up of 25 months (median 13-35) was carried out. Five recurrences (1.5%) and two cases of missed lipoma were observed and operated. Chronic pain (CP) was observed in eleven (9%) patients but in 9 patients it decreased spontaneously. CONCLUSIONS: Combination of ultralight mesh and Evicel(r) in TAPP operation is a safe solution for the treatment of groin hernia. Recurrences and chronic pain are similar to other combination of fibrin sealant and meshes. Moreover action of Evicel(r) may provide to improve the hemostasis and consequently hematoma of the cord. PMID- 30444482 TI - Acute diverticulitis in patients under 50 years of age. AB - : Acute diverticulitis typically occurs in patients over 80 years old. The last five years we observed an increased incidence of acute diverticulitis in patients under 50 years. The aim of this study is to evaluate the increased rate of patients under 50 years that are hospitalized due to acute diverticulitis. Also, we aim to confirm the common symptoms for this disease and the laboratory data, the changes in dietary history (Mediterranean diet) and lifestyle and to calculate the differences in the treatment and the severity in the course of the disease, between younger (<50) and older (>50) patients. PATIENTS AND METHODS: From 2003 to 2008, 118 patients were admitted to our Surgical Department for acute diverticulitis. 32 patients were under 50 years old. In the next five year period (2008-2013) the number of patients under 50 that were admitted due to acute diverticulitis doubled to 183 with 102 patients being over 50 years and 61 patients under 50. For all these patients, the medical and dietary history, laboratory and clinical examinations, radiographic and endoscopic findings were recorded. RESULTS: For patients aged over 50 years there is a predominance in male sex. Symptoms were the same in both groups and no difference in treatment was noted. Furthermore, readmission and recurrence rates were the same for both groups. The condition was equally aggressive in both groups. The only difference observed was increased obesity rate for patients under 50 and variation from the traditional Mediterranean diet to western diet habits. CONCLUSIONS: Although our study has limitations it seems that new cases of diverticular disease in patients have increased due to dietary changes, but treatment and severity have remained the same. PMID- 30444481 TI - Spontaneous bladder rupture mimicking a jejuno-ileal perforation. AB - Spontaneous urinary bladder perforation is a very rare disease. The main cause of urinary perforation, indeed, is a damage to the urinary bladder wall by blunt or penetrating trauma. There are only few idiopathic spontaneous rupture of urinary bladder (ISRUB) cases reported in the literature. Pre-operative diagnosis is very difficult due to similar symptoms, laboratory and imaging findings of a gastrointestinal perforation that is usually excluded intraoperatively. Herein we report a case of a 91-year-old man presented to the emergency department with a spontaneous bladder perforation mimicking an ileal perforation. PMID- 30444483 TI - Mesothelial cyst of the round ligament. AB - Mesothelial cyst of the round ligament is a rare finding in females, with only a few cases reported so far. A case of a 25 year old female patient presenting with a palpable mass in her right inguinal region is presented. The preoperative investigation through ultrasound (U/S), computed tomography (CT) and magnetic resonance imaging (MRI) revealed the presence of an intraabdominal cystic lobular mass in the inguinal canal, in contact with the femoral vessels. The mass was excised and the diagnosis of a benign mesothelial cyst was made through pathological examination. Even though it is a rare condition, it is advisable that clinicians consider in the differential diagnosis when evaluating a non reducible mass in the inguinal region of a female patient. PMID- 30444485 TI - Sindrome del tunnel carpale, neuroprotezione e attivita antalgica con L-acetil carnitina. PMID- 30444484 TI - Fibrin sealant agents: clinical application of TachoSil(r) in abdominal surgery. Six years experience in an emergency surgery department and review of the literature. AB - BACKGROUND: The success of every surgical procedure depends on an appropriate hemostatis. Topical haemostatic agents, like fibrin sealants, are an option for providing haemostasis and may be particularly useful for complex injuries. AIM: The aim of the study is to evaluate the use of TachoSil(r) in abdominal surgery and its benefits to prevent bleedings, and to establish its fields of use. METHODS: A retrospective observational study was performed on 308 patients underwent to emergency surgery with TachoSil(r)'s application into our department between January 2012 and March 2018. RESULTS: After the application of the hemostatic device there have been no haemorrhagic complications that have needed a second surgical intervention. Most frequently use of TachoSil(r) was in the gallbladder bed after cholecystectomy for an acute cholecystitis. CONCLUSIONS: Our experience, supported by other reports in the literature, suggests the use of TachoSil(r) may provide an effective option in helping to control bleedings. PMID- 30444486 TI - Effectiveness of the new integrated strategy to control the transmission of Schistosoma japonicum in China: a systematic review and meta-analysis. AB - Since 2004, the national schistosomiasis control strategy in China has shifted from the morbidity control strategy (conventional strategy) to an integrated strategy (new strategy). We investigated the effectiveness of the new strategy and compared it against the conventional strategy. We retrieved from electronic databases the literature regarding the new strategy published from 2000 to 2017. The effect of the new or conventional strategy on infection by Schistosoma japonicum of humans and snails (Oncomelania hupensis) was evaluated with pooled log relative risk (logRR). A total of only eight eligible publications were included in the final meta-analysis. The results showed that implementation of the new strategy reduced the infection risk by 3-4 times relative to the conventional strategy. More specifically, the conventional strategy caused a reduction in both human (logRR = 0.56, 95% CI: 0.12-0.99) and snail infections (logRR = 0.34, 95% CI: -0.69-1.37), while the new strategy also significantly reduced both human (logRR = 1.89, 95% CI: 1.33-2.46) and snail infections (logRR = 1.61, 95% CI: 1.06-2.15). In contrast to the conventional strategy, the new strategy appeared more effective to control both human (logRR difference = 1.32, 95% CI: 0.78-1.86) and snail infections (logRR difference = 1.53, 95% CI: 0.76 2.31). Our data demonstrate that the new integrated strategy is highly effective to control the transmission of S. japonicum in China, and this strategy is recommended for schistosomiasis elimination in other affected regions across the world, with adaptation to local conditions. PMID- 30444487 TI - New species of Paracolpenteron n. gen. and Ancyrocephalus (Monogenea, Dactylogyridae) inhabiting the urinary bladder and gills of the Maya needlefish Strongylura hubbsi (Beloniformes, Belonidae) from Chiapas, Mexico. AB - Parasitological examination of the maya needlefish Strongylura hubbsi Collette (Belonidae) from the Rio Lacantun basin in the Montes Azules Biosphere Reserve, Chiapas, Mexico showed that specimens were parasitized by two monogenean species in two different sites: Paracolpenteron hubbsii n. gen., n. sp in the urinary bladder and Ancyrocephalus chiapanensis n. sp in the gill lamellae. Paracolpenteron hubbsii differs from other dactylogyrid species without a haptoral anchor/bar complex infecting the urinary systems, gills and nasal cavities by the general morphology of hooks, a dextral vaginal opening, a tubular male copulatory organ comprising a base from which a coiled shaft arises in counterclockwise direction, and an unarticulated Y-shaped accessory piece. Ancyrocephalus chiapanensis n. sp. resembles Ancyrocephalus cornutus William & Rogers, 1972 from the gills of Strongylura marina from Florida from which it differs in possessing a twisted tube of the male copulatory organ (curved in A. cornutus), ventral bar with cavities on the ends (cavities absent in A. cornutus) and by the size of the ventral (length 31-34 MUm vs. 24-27 MUm in A. cornutus) and dorsal (length 25-28 MUm vs. 18-22 MUm in A. cornutus) anchors. These new monogeneans are described herein and their biogeography is briefly discussed based on the previous phylogenetic hypotheses concerning the host family. PMID- 30444489 TI - Correction: Multiplexed genetic engineering of human hematopoietic stem and progenitor cells using CRISPR/Cas9 and AAV6. PMID- 30444490 TI - Mycobacterium tuberculosis induces decelerated bioenergetic metabolism in human macrophages. AB - How Mycobacterium tuberculosis (Mtb) rewires macrophage energy metabolism to facilitate survival is poorly characterized. Here, we used extracellular flux analysis to simultaneously measure the rates of glycolysis and respiration in real-time. Mtb infection induced a quiescent energy phenotype in human monocyte derived macrophages and decelerated flux through glycolysis and the TCA cycle. In contrast, infection with the vaccine strain, M. bovis BCG, or dead Mtb induced glycolytic phenotypes with greater flux. Furthermore, Mtb reduced the mitochondrial dependency on glucose and increased the mitochondrial dependency on fatty acids, shifting this dependency from endogenous fatty acids in uninfected cells to exogenous fatty acids in infected macrophages. We demonstrate how quantifiable bioenergetic parameters of the host can be used to accurately measure and track disease, which will enable rapid quantifiable assessment of drug and vaccine efficacy. Our findings uncovered new paradigms for understanding the bioenergetic basis of host metabolic reprogramming by Mtb. PMID- 30444488 TI - Hedonic processing in humans is mediated by an opioidergic mechanism in a mesocorticolimbic system. AB - : It has been hypothesized that the pleasure of a reward in humans is mediated by an opioidergic system involving the hypothalamus, nucleus accumbens and the amygdala. Importantly, enjoying the pleasure of a reward is distinct from incentive salience induced by cues predicting the reward. We investigated this issue using a within subject, pharmacological challenge design with the opioid receptor antagonist naloxone and fMRI. Our data show that blocking opioid receptors reduced pleasure associated with viewing erotic pictures more than viewing symbols of reward such as money. This was paralleled by a reduction of activation in the ventral striatum, lateral orbitofrontal cortex, amygdala, hypothalamus and medial prefrontal cortex. Crucially, the naloxone induced activation decrease was observed at reward delivery, but not during reward anticipation, indicating that blocking opioid receptors decreases the pleasure of rewards in humans. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). PMID- 30444492 TI - Erratum. The second-generation eCLIPs Endovascular Clip System: initial experience. PMID- 30444493 TI - Erratum. A meta-analysis of outcomes and complications of magnetic resonance guided focused ultrasound in the treatment of essential tremor. PMID- 30444494 TI - Rebuttal Letter to the Editor Kloosterboer et al., Ther Drug Monit 2018;40: 344 350. PMID- 30444495 TI - Preparation is the Only Shortcut You Need in Surgery: A Guide to Surgical Rehearsals for Hand and Upper Extremity Transplantation. AB - As upper extremity transplantation is becoming more accepted worldwide, the demand for a fresh tissue cadaveric training model for this procedure is increasing and necessary to assure surgical success. Surgical rehearsals can decrease operative time, improve technique, and reduce errors made on the actual day of surgery. The purpose of this article is to describe a method for surgical rehearsal of upper extremity transplantation using cadaveric specimens based on the clinical experience of an academic institution with an active transplantation program. The logistics of rehearsal setup, equipment, and modified version of procedural checklists are described. PMID- 30444491 TI - Angiopoietin-4-dependent venous maturation and fluid drainage in the peripheral retina. AB - The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using genetic reporter, fate mapping, and in situ hybridization, we found Angpt4 expression in a specific sub-population of astrocytes at the site where venous morphogenesis occurs and that lower oxygen tension, which distinguishes peripheral and venous locations, enhances Angpt4 expression. Correlating with its spatiotemporal expression, deletion of Angpt4 resulted in defective venous development causing impaired venous drainage and defects in neuronal cells. In vitro characterization of angiopoietin-4 proteins revealed both ligand-specific and redundant functions among the angiopoietins. Our study identifies Angpt4 as the first growth factor for venous-specific development and its importance in venous remodeling, retinal fluid clearance and neuronal function. PMID- 30444497 TI - An overlapping case of Bickerstaff brainstem encephalitis and acute motor axonal neuropathy variant of Guillain-Barre syndrome associated with Systemic Lupus Erythematosus. PMID- 30444496 TI - A gallstone impaction at the ampulla of Vater. PMID- 30444498 TI - Molecular and living cell dynamic assays with optical microscopy imaging techniques. AB - Generally, the message elucidated by the conventional analytical methods overlooks the heterogeneity of single objects, where the behavior of individual molecules is shielded. With the advent of optical microscopy imaging techniques, it is possible to identify, visualize and track individual molecules or nanoparticles under a biological environment with high temporal and spatial resolution. In this work, we summarize the commonly adopted optical microscopy techniques for bio-analytical assays in living cells, including total internal reflection fluorescence microscopy (TIRFM), super-resolution optical microscopy (SRM), and dark-field optical microscopy (DFM). The basic principles of these methods and some recent interesting applications in molecular detection and single-particle tracking are introduced. Moreover, the development in high dimensional optical microscopy to achieve three-dimensional (3-D) as well as sub diffraction localization and tracking of biomolecules is also highlighted. PMID- 30444499 TI - Growth and shape stability of Cu-Ni core-shell nanoparticles: an atomistic perspective. AB - The growth and shape stability of bi-metallic cubic Cu-Ni nanoparticles are studied using atomic-level simulations. Cubic nano-crystals coated with an ultra thin Cu layer can be readily obtained when Ni cubic nanoparticles are used as the seeds. At elevated temperatures, the Cu seed with extending Ni branches preserves its shape compared to the Ni seed with extending Cu branches. PMID- 30444500 TI - An efficient protocol for computing the pKa of Zn-bound water. AB - At a given pH, whether a metal-bound water molecule is deprotonated or not can be determined if the pKa of the metal-bound water molecule (denoted pKw) is known. Although protocols/tools to predict the protonation states of titratable amino acid residues and small molecules have been developed, an efficient and accurate method to predict the absolute pKw values of metal complexes is lacking. Here, we present calibrated methods for optimizing the geometries and computing the absolute pKw values of a wide range of Zn2+-complexes containing protein-like ligating groups. We tested 18 different geometry-optimization methods on 19 ultra high-resolution structures of Zn2+ complexes of varying coordination numbers and ligating atoms and 98 methods in reproducing 36 experimental pKw values of diverse Zn2+ complexes in the absence and presence of explicit water molecules. The results underscore the importance of estimating the Zn2+-bound water/hydroxide solvation properly, whereas correcting for the basis set superposition error was not found to be important. The protocol presented can be used to (i) evaluate the geometries of the different Zn2+-sites found in proteins and (ii) to dissect the individual contributions of the various factors modulating the pKw in Zn2+-sites found in proteins. Predicting absolute pKw values in various environments with efficiency and accuracy will indicate when a Zn2+-bound water molecule is deprotonated, thus providing physical insight into the mechanisms of enzyme-catalyzed reactions and the design of drug candidates that can displace a metal-bound water molecule. PMID- 30444501 TI - Reactive molecular dynamics simulation of thermal decomposition for nano aluminized explosives. AB - Aluminized explosives have important applications in civil construction and military armaments, but their thermal decomposition mechanisms are not well characterized. Here, the thermal decomposition of TNT, RDX, HMX and CL-20 on Al nanoparticles is examined by reactive dynamics simulations using a newly parameterized reactive force field with low gradient correction (ReaxFF-lg). Partially passivated Al nanoparticles were constructed and mixed with TNT, RDX, HMX and CL-20 crystals and then the mixed systems are heated to a high temperature in which the explosives are fully decomposed. The simulation results show that the aluminized explosives undergo three main steps of thermal decomposition, which were denoted "adsorption period" (0-20 ps), "diffusion period" (20-80 ps) and "formation period" (80-210 ps). These stages in sequence are the chemical adsorption between Al and surrounding explosive molecules (R-NO2 Al bonding), the decomposition of the explosives and the diffusion of O atoms into the Al nanoparticles, and the formation of final products. In the first stage, the Al nanoparticles decrease the decomposition reaction barriers of RDX (1.90 kJ g-1), HMX (1.95 kJ g-1) and CL-20 (1.18 kJ g-1), respectively, and decrease the decomposition reaction barrier of TNT from 2.99 to 0.29 kJ g-1. Comparing with the crystalline RDX, HMX and CL-20, the energy releases are increased by 4.73-4.96 kJ g-1 in the second stage. The number of produced H2O molecules increased by 25.27-27.81% and the number of CO2 molecules decreased by 47.73-68.01% in the third stage. These three stages are further confirmed by the evolutive diagram of the structure and temperature distribution for the CL-20/Al system. The onset temperatures (To) of generating H2O for all the aluminized explosives decrease, while those of generating CO2 for aluminized HMX and CL-20 increase, which are in accord with the experiment of aluminized RDX. PMID- 30444502 TI - Ruthenium mediated halogenation of white phosphorus: synthesis and reactivity of the unprecedented P4Cl2 moiety. AB - The transition metal mediated functionalization of P4 is an approach to develop a more sustainable production of organophosphorus compounds. In this paper a ruthenium complex is presented, in which the P4 unit can be selectively converted into new P4R2 molecules in a two-step synthesis. The unsaturated 16 electron species [RuX(Cp*)(PCy3)] (Cp* = C5Me5, X = Cl, Br) reacts with a half equivalent of P4 affording a bimetallic complex bearing a planar P4X2 moiety as a ligand. The latter eliminates chloride anions under reduction with magnesium. In this process the butadiene-like P4Cl2 ligand is converted into two weakly bound P2 units which bridge the ruthenium centers. In the presence of n-BuLi, the P4Cl2 unit can be selectively alkylated, yielding the planar organophosphorus ligand P4nBu2. A detailed analysis of the electronic properties and solid state structures of the compounds combined with DFT calculations and AIM analyses demonstrate that the P4 unit in all complexes acts as an electronically highly flexible, non-innocent ligand. PMID- 30444503 TI - Full compositional control of PbSxSe1-x thin films by the use of acylchalcogourato lead(ii) complexes as precursors for AACVD. AB - Selenium and sulfur derivatives of lead(ii) acylchalcogourato complexes have been used to deposit PbSxSe1-x thin films by AACVD. By variation of the mole ratio of sulfur and selenium precursors in the aerosol feed solution the full range of compositions of PbSxSe1-x was obtained, i.e. 0 >= x >= 1. The films showed no contaminant phases demonstrating the potential for acylchalcogourato metal complexes as precursors for metal chalcogenide thin films. The crystal structure for bis[N,N-diethyl-N'-2-naphthoylthioureato]lead(ii) was solved and displayed the expected decreases in Pb-E bond lengths from the previously reported selenium variant. PMID- 30444504 TI - Supramolecular delivery systems based on pillararenes. AB - Supramolecular delivery systems (SDSs) fabricated via molecular assembly, which conveniently allow integration of multiple functions in a single system and structural diversity of systems, are a very active research area due to their enormous potential in biomedical applications, including drug delivery, cell imaging, diagnosis, and release monitoring. Pillararenes, a novel type of macrocyclic molecule, are gaining increasing interest as an important component in the construction of SDSs due to their unique structural and chemical properties. This feature article summarizes pillararene-based SDSs constructed via host-guest interactions via four strategies: (1) supramolecular host-guest complexation; (2) self-assembly of supramolecular amphiphiles; (3) self-assembly of amphiphilic supramolecular polymer conjugates; (4) hybridization with other porous materials, such as inorganic materials and metal-organic frameworks (MOFs). The various SDSs based on pillararenes for the delivery of different cargoes from anti-cancer drugs, fluorescent molecules, siRNAs, and insulin to antibiotics are reviewed. Furthermore, future challenges for advanced SDSs based on pillararenes and their broader applications are outlined. PMID- 30444505 TI - Optical nano-agents in the second near-infrared window for biomedical applications. AB - The optical technology presents non-invasive, non-destructive, and non-ionizing features and has the ability to display various chemical components in tissues to provide useful information for various biomedical applications. Regarding selection of light wavelengths, second near-infrared (NIR-II, 900-1700 nm) light is a much better choice compared to both visible (380-780 nm) and traditional near-infrared (780-900 nm) light, because of its advantages including deeper penetration into biological tissues, less tissue scattering or absorption, and decreased interference by fluorescent proteins. Thus, using optical nano-agents that absorb or emit light in the NIR-II window can achieve deeper tissue optical imaging with higher signal-to-background ratios and better spatial resolution for diagnosis. What's more, some of these nano-agents can be further applied for imaging guided surgical removal, real-time monitoring of drug delivery, labeling lymphatic metastasis, biosensing, and imaging guided phototherapy. In this review, we attempt to summarize the recent advances of various NIR-II nano-agents (including single-walled carbon nanotubes, quantum dots, rare-earth doped nanoparticles, other inorganic nanomaterials, small organic molecule-based nanoparticles, and semiconducting polymer nanoparticles) in both bioimaging and therapeutic applications, and discuss the challenges and perspectives of these nano-agents for clinical practice in the near future. PMID- 30444506 TI - Distribution of water in the pores of periodic mesoporous organosilicates - a proton solid state MAS NMR study. AB - Solid state proton (1H) magic angle spinning (MAS) NMR has been employed to study the distribution of confined water in ethane substituted periodic mesoporous organosilicate (PMOE) materials. Proton spectra acquired at different hydration levels are analysed and interpreted in terms of water clusters of various sizes and distributions of water layers on the pore surface. For comparison, we also performed similar experiments on SBA-15. The formation of larger clusters at lower hydration suggests that the pores of PMOE are getting filled with water at lower hydration levels than those in SBA-15. For PMOE, the simultaneous presence of two major resonances in the ranges 3.6-4.1 ppm and 4.4-5.2 ppm and their behaviour upon hydration imply a water layer distribution that is the sum of two contributions, corresponding to fully filled and partially filled pores or pore segments. Furthermore, the behaviour mentioned above suggests that both radial and axial filling mechanisms play a significant role in the hydration process. For SBA-15, as a function of hydration, we observed a smooth variation in the proton chemical shift of the main dynamic resonance. In accordance with previous studies, this is attributed to the gradual increase in the average thickness of water layers with an increase in hydration, and to a pore filling mechanism that is predominantly radial. PMID- 30444507 TI - Synthesis of chiral chromanols via a RuPHOX-Ru catalyzed asymmetric hydrogenation of chromones. AB - Chiral chromanols and their derivatives have been synthesized via a RuPHOX-Ru catalyzed asymmetric hydrogenation of chromones in high yields, >20 : 1 drs and with up to 99.9% ee. Control experiments show that the reaction undergoes two sequential asymmetric hydrogenation steps of the C[double bond, length as m dash]C and C[double bond, length as m-dash]O double bonds. The reaction could be performed on a gram-scale with a relatively low catalyst loading (up to 1000 S/C), and the resulting products can be transformed to several biologically active compounds. PMID- 30444508 TI - Photocontrolled reversible conversion of a lamellar supramolecular assembly based on cucurbiturils and a naphthalenediimide derivative. AB - Lamellar and helical supramolecular assemblies were constructed using cucurbiturils and a naphthalenediimide derivative. More interestingly, the formation of the lamellar assembly could be reversibly photocontrolled via competitive binding with alpha-cyclodextrin and water-soluble azobenzene. PMID- 30444509 TI - Fewer-layer conductive metal-organic nanosheets enable ultrahigh mass activity for the oxygen evolution reaction. AB - A new class of 2D fewer-layer pi-conjugated conductive metal-organic nanosheets was developed via the Langmuir-Blodgett method, exhibiting ultrahigh mass activity (64.63 A mg-1, 1.7 V vs. RHE) and stability for electrochemical oxygen evolution reactions (OER). PMID- 30444510 TI - A recyclable self-assembled composite catalyst consisting of Fe3O4-rose bengal layered double hydroxides for highly efficient visible light photocatalysis in water. AB - The first case of a highly efficient layered double hydroxide (LDH) supported organic visible light photocatalyst is reported and it can catalyze various organic transformations with high efficiency in water under visible light irradiation. PMID- 30444512 TI - A facile two-photon fluorescent probe: an endoplasmic reticulum tracker monitoring ER stress and vesicular transport to lysosomes. AB - The morphological divergence of the Endoplasmic Reticulum (ER) during stress is a powerful indicator of several diseases. A new two-photon, non-cytotoxic, fluorescent probe (ERLp) was designed and synthesized in a facile manner for selective tracking of the Endoplasmic Reticulum (ER) with a high Pearson co localization coefficient (0.91) in live cells and tumor spheroids. Further, ER stress during cell apoptosis and vesicular transport from the ER to the lysosomal compartment were also explored by employing ERLp. Therefore, ERLp can be used as a potent tool for examining vesicle transport or ER stress associated diseases in real time. PMID- 30444511 TI - Spiro-fused bis-hexa-peri-hexabenzocoronene. AB - A spiro-fused hexa-peri-hexabenzocoronene dimer was synthesized, and its physicochemical properties were studied by UV-Vis absorption and emission spectroscopy as well as cyclic voltammetry. Chemical oxidation of SB-HBC afforded its radical cation and dication derivatives, which could be reversibly reduced to the neutral state. PMID- 30444513 TI - Quantitative determination of a model organic/insulator/metal interface structure. AB - By combining X-ray photoelectron spectroscopy, X-ray standing waves and scanning tunneling microscopy, we investigate the geometric and electronic structure of a prototypical organic/insulator/metal interface, namely cobalt porphine on monolayer hexagonal boron nitride (h-BN) on Cu(111). Specifically, we determine the adsorption height of the organic molecule and show that the original planar molecular conformation is preserved in contrast to the adsorption on Cu(111). In addition, we highlight the electronic decoupling provided by the h-BN spacer layer and find that the h-BN-metal separation is not significantly modified by the molecular adsorption. Finally, we find indication of a temperature dependence of the adsorption height, which might be a signature of strongly-anisotropic thermal vibrations of the weakly bonded molecules. PMID- 30444514 TI - Cyanoferrocenes as redox-active metalloligands for coordination-driven self assembly. AB - Ferrocene-based Lewis bases have found utility as metalloligands in a wide variety of applications. The coordination chemistry of cyanoferrocenes however, is underexplored. Herein, we describe a new synthetic protocol for the generation of cyanoferrocenes. The coordination chemistry of these metalloligands to [Cu(NCMe)4][PF6], [(PPh3)2Cu(NCMe)2][PF6] and [(dppf)Cu(NCMe)2][PF6] salts has been explored, providing crystallographic evidence of cluster and polymeric forms of 1,1'- and 1,2-dicyanoferrocene complexes. The stability of the complexes and ligand dissociation were found to be strongly solvent-dependent. PMID- 30444515 TI - Genetic, structural, and functional diversity of low and high-affinity siderophores in strains of nitrogen fixing Azotobacter chroococcum. AB - To increase iron (Fe) bioavailability in surface soils, microbes secrete siderophores, chelators with widely varying Fe affinities. Strains of the soil bacterium Azotobacter chroococcum (AC), plant-growth promoting rhizobacteria used as agricultural inoculants, require high Fe concentrations for aerobic respiration and nitrogen fixation. Recently, A. chroococcum str. NCIMB 8003 was shown to synthesize three siderophore classes: (1) vibrioferrin, a low-affinity alpha-hydroxy carboxylate (pFe = 18.4), (2) amphibactins, high-affinity tris hydroxamates, and (3) crochelin A, a high-affinity siderophore with mixed Fe chelating groups (pFe = 23.9). The relevance and specific functions of these siderophores in AC strains remain unclear. We analyzed the genome and siderophores of a second AC strain, A. chroococcum str. B3, and found that it also produces vibrioferrin and amphibactins, but not crochelin A. Genome comparisons indicate that vibrioferrin production is a vertically inherited, conserved strategy for Fe uptake in A. chroococcum and other species of Azotobacter. Amphibactin and crochelin biosynthesis reflects a more complex evolutionary history, shaped by vertical gene transfer, gene gain and loss through recombination at a genomic hotspot. We found conserved patterns of low vs. high-affinity siderophore production across strains: the low-affinity vibrioferrin was produced by mildly Fe limited cultures. As cells became more severely Fe starved, vibrioferrin production decreased in favor of high-affinity amphibactins (str. B3, NCIMB 8003) and crochelin A (str. NCIMB 8003). Our results show the evolution of low and high-affinity siderophore families and conserved patterns for their production in response to Fe bioavailability in a common soil diazotroph. PMID- 30444516 TI - In-line whole blood fractionation for Raman analysis of blood plasma. AB - Blood plasma evaluation has high significance in clinical diagnostics. Current schemes involve the preparation of blood plasma by centrifugation of whole blood followed by electrochemical or spectroscopic analysis. However, centrifugation is often too time-consuming for application in clinical emergency and point-of-care settings. We propose to combine microfluidic, instantaneous plasma fractionation with localized spectroscopic methods for in-line analysis. As an example, we present confocal Raman spectroscopy in fractionated plasma domains at two different Raman excitation wavelengths. Resonance Raman spectroscopy with laser excitation at 408 nm allows the specific detection of free hemoglobin in blood plasma at concentrations above 22 mg dl-1 (level of detection). Consequently, we are able to accurately resolve the range of clinical relevance regarding hemolysis. At near-infrared excitation (785 nm) we furthermore demonstrate the acquisition of characteristic Raman spectra of fractionated blood plasma in the microfluidic setting. These spectra can serve as starting point for a multi parameter regression analysis to quantify a set of blood plasma parameters from a single Raman spectrum. The combined microfluidics and Raman spectroscopy method is non-destructive and has a whole blood consumption of less than 100 MUl per hour. It thus allows for continuous in-line blood plasma monitoring. PMID- 30444517 TI - The Gigahertz and Terahertz spectrum of monodeutero-oxirane (c-C2H3DO). AB - The rotational spectrum of monodeutero-oxirane was analysed as measured using the Zurich Gigahertz (GHz) spectrometer and our highest resolution Fourier Transform Infrared (FTIR) spectrometer system coupled to synchrotron radiation at the Swiss Light Source (SLS). 112 distinct line frequencies have been newly assigned in the GHz range (extended to 120 GHz, compared to previous work extending to only 59 GHz) including rotational states up to J = 23. We have furthermore assigned 398 lines in the far infrared or Terahertz range (0.75-2.10 THz or 25-70 cm-1) including transitions with rotational quantum numbers up to J = 59. The results are discussed in relation to the possible first astrophysical observation of an isotopically chiral molecule and in relation to molecular parity violation. PMID- 30444518 TI - Stapling of two PEGylated side chains increases the conformational stability of the WW domain via an entropic effect. AB - Hydrocarbon stapling and PEGylation are distinct strategies for enhancing the conformational stability and/or pharmacokinetic properties of peptide and protein drugs. Here we combine these approaches by incorporating asparagine-linked O allyl PEG oligomers at two positions within the beta-sheet protein WW, followed by stapling of the PEGs via olefin metathesis. The impact of stapling two sites that are close in primary sequence is small relative to the impact of PEGylation alone and depends strongly on PEG length. In contrast, stapling of two PEGs that are far apart in primary sequence but close in tertiary structure provides substantially more stabilization, derived mostly from an entropic effect. Comparison of PEGylation + stapling vs. alkylation + stapling at the same positions in WW reveals that both approaches provide similar overall levels of conformational stability. PMID- 30444519 TI - Dynamic surface antifouling: mechanism and systems. AB - Marine biofouling is a global problem today. High efficiency and eco-friendly antifouling systems are in pressing need. In recent years, we have proposed the concept of dynamic surface antifouling (DSA). That is, a continuously changing surface can effectively prevent marine fouling organisms from landing and adhesion. Based on this strategy, we developed coatings with dynamic surfaces by using degradable polymers including polyester-polyurethane, modified polyester and poly(ester-co-acrylate). They exhibit tunable renewability, and excellent antifouling and mechanical performance. Moreover, the polymers can serve as carrier and controlled release systems of antifoulants so that they have long service life. This paper reviews the progress and trends in marine anti biofouling, and presents the mechanism and systems of DSA. PMID- 30444520 TI - Dietary supplementation of vitamin C: an effective measure for protection against UV-B irradiation using fish as a model organism. AB - The development of UV-B protective mechanisms in aquacultural species is essential for the sustainable production of healthy aqua crop. Freshwater carp Catla catla larvae (13.5 +/- 1.12 mg) were fed with a diet containing 0.5% vitamin C (D1) and a control diet (D2) for 40 days. Each group was exposed to two doses of UV-B irradiation: 360 (5 min, D15 min and D25 min) and 720 mJ cm-2 (10 min, D110 min and D210 min) for 15 days. Significantly (p < 0.05) higher survival and average weight were recorded in D1 compared to D2 exposed to the same dose. Also, significantly (p < 0.001) higher nitric oxide synthase and lower thiobarbituric acid reactive substances and heat shock protein 70 levels were recorded in D15 min compared to the other groups. A direct relationship was found between the dose of UV-B and DNA fragmentation in muscles. DNA damage indices such as tail DNA, tail extent moment and olive tail moment were significantly (p < 0.01) lower in D15 min. Thus, supplementation of vitamin C in the diet provides UV-B protection to larvae. PMID- 30444521 TI - Single-molecule magnet behaviour in a Dy(iii) pentagonal bipyramidal complex with a quasi-linear Cl-Dy-Cl sequence. AB - We report the synthesis and magnetic investigation of a dysprosium pentagonal bipyramidal complex [Dy(THF)5Cl2][BPh4] (1) exhibiting a linear Cl-Dy-Cl sequence suitable for providing a coordination environment allowing a zero-field slow relaxation of the magnetization. Besides, the complex also shows dual luminescence originating from [BPh4]- and Dy3+. PMID- 30444523 TI - Melatonin promotes self-renewal and nestin expression in neural stem cells from the retina. AB - Although melatonin has been shown to exhibit a wide variety of biological functions, its effects on promoting self-renewal in retinal stem cells remain unknown. We found that melatonin can significantly increase proliferation and enhance expression of a stem cell marker, nestin, in retinal neural stem cells (NSCs) via melatonin receptor 1 (MT1). The ERK pathway inhibitor SCH772984 and TGF-beta pathway inhibitor SB431542 were used to study the melatonin-mediated molecular mechanisms of cell proliferation in NSCs. The results revealed a novel molecular mechanism of melatonin promotion of self-renewal of NSCs in which a chain reaction in the ERK and TGF-beta/Smad pathways promotes self-renewal and transcription of nestin. In addition, dual-luciferase assays revealed that Smad4 directly regulated nestin transcription after melatonin treatment in NSCs. These findings revealed novel mechanisms through which the ERK pathway cooperates with the Smad pathway to regulate self-renewal in NSCs to enhance nestin expression. PMID- 30444522 TI - Ligand exchange processes in zirconocene dichloride-trimethylaluminum bimetallic systems and their catalytic properties in reaction with alkenes. AB - Ligand exchange processes in the systems L2ZrCl2-AlMe3 (L2ZrCl2: Cp2ZrCl2, (CpMe)2ZrCl2, (C5Me5)2ZrCl2, Me2SiCp2ZrCl2, Me2Si(C5Me4)2ZrCl2, rac-Me2C(2-Me-4 But-Cp)2ZrCl2, meso-Me2C(2-Me-4-But-Cp)2ZrCl2, rac-Me2C(3-But-Cp)2ZrCl2, Ind2ZrCl2, rac-H2C(Ind)2ZrCl2, rac-Me2C(Ind)2ZrCl2, rac-Me2Si(Ind)2ZrCl2, rac C2H4(Ind)2ZrCl2, rac-C2H4(THInd)2ZrCl2, rac-Me2Si(THInd)2ZrCl2) and Cp2ZrMeCl2-n AlMe3 (n = 1, 2) were studied by NMR spectroscopy with the goal to establish the structures and dynamic features of probable intermediates in the zirconocene catalyzed reactions of alkenes with AlMe3. The effect of solvent, the organoaluminum compound concentration and the addition of (ClAlMe2)2 on the activation parameters of the alkyl exchange in the trimethylaluminum dimer was studied as well. The constants and activation parameters of the methyl group exchange in the monoalkyl-substituted ansa-complexes L2ZrMeCl (L2 = rac-Me2C(2-Me 4-But-Cp)2, rac-Me2C(3-But-Cp)2, rac-H2CInd2, rac-Me2CInd2, rac-Me2SiInd2, rac H4C2Ind2) were established for the first time. The catalytic activity and chemoselectivity of zirconocenes in the reaction of alkenes with AlMe3 were evaluated and compared with the exchange and equilibrium constants of ligand exchange processes. A mechanism of the reaction was proposed. PMID- 30444524 TI - Volumetric and three-dimensional examination of sella turcica by cone-beam computed tomography: reference data for guidance to pathologic pituitary morphology. AB - BACKGROUND: To assess the dimensions and volume of sella turcica in healthy Caucasian adults with normal occlusion and facial appearance from cone-beam computerized tomography (CBCT) images. MATERIALS AND METHODS: CBCT images of 80 Caucasian adult patients (40 males, 40 females) with normal facial appearance and occlusion taken previously for diagnostic purposes were evaluated. Two groups were constructed in accordance to gender. The volume, length, diameter, and depth of the sella turcica were measured by Romexis software program. Mann Whitney U test and Independent t-tests were used for statistical analysis. RESULTS: The mean lengths of the sella were 9.9mm and 10.2mm, depths were 9.2mm and 8.8mm and diameters were 12.3mm and 12.1mm in female and male groups, respectively. Between the genders, no statistically significant differences were found for any of the measurements. There were significantly higher values for the volume of sella turcica in males than in females (1102+/-285.3mm3 and 951.3+/-278.5mm3 respectively). CONCLUSION: The dimensions of sella turcica in healthy caucasian adults with normal occlusion and facial appearance revealed nonsignificant interdifferences of the genders. Individual variability in dimensions and gender differences in the volume are of importance in comparison of patients with craniofacial syndromes and aberrations. Knowledge concerning the dimensions and volume of sella turcica will be clinically relevant for a guidance to consciously realize pituitary disorders. PMID- 30444525 TI - Complement component 5 does not interfere with physiologic hemostasis but is essential for Escherichia coli-induced coagulation accompanied by Toll-like receptor 4. AB - There is a close cross-talk between complement, Toll-like receptors (TLRs) and coagulation. The role of the central complement component 5 (C5) in physiologic and pathophysiologic hemostasis has however not been fully elucidated. This study examined the effects of C5 in normal hemostasis and in Escherichia coli (E.coli) induced coagulation and tissue factor (TF) upregulation. Fresh whole blood obtained from six healthy donors and one C5-deficient individual (C5D) was anticoagulated with the thrombin inhibitor lepirudin. Blood was incubated with or without E.coli in the presence of the C5 inhibitor eculizumab, a blocking anti CD14 monoclonal antibody (anti-CD14) or the TLR4 inhibitor eritoran. C5D blood was reconstituted with purified human C5. TF mRNA was measured by qPCR, and monocyte TF and CD11b surface expression by flow cytometry. Prothrombin fragment 1+2 (PTF1.2) in plasma and microparticles exposing TF (TF-MP) was measured by ELISA. Coagulation kinetics were analyzed by rotational thromboelastometry and platelet function by PFA-200. Normal blood with eculizumab as well as C5D blood with or without reconstitution with C5 displayed completely normal biochemical hemostatic patterns. In contrast, E.coli-induced TF mRNA and TF-MP were significantly reduced by C5 inhibition. C5 inhibition combined with anti-CD14 or eritoran completely inhibited the E.coli-induced monocyte TF, TF-MP and plasma PTF1.2. Addition of C5a alone did not induce TF expression on monocytes. In conclusion, C5 showed no impact on physiological hemostasis, but substantially contributed to E.coli-induced procoagulant events, which were abolished by the combined inhibition of C5 and CD14 or TLR4. This article is protected by copyright. All rights reserved. PMID- 30444527 TI - Prevalence of comorbidities and effect on survival in survivors of human papillomavirus-related and human papillomavirus-unrelated head and neck cancer in the United States. AB - BACKGROUND: The increasing incidence of human papillomavirus (HPV)-related head and neck cancer (HNC) has led to the increasing prevalence of survivors, yet to the best of the authors' knowledge the prevalence of comorbidities during the survivorship period and their effects on survival are relatively unknown. METHODS: In this retrospective cross-sectional study, individuals with a first incident primary diagnosis of HNC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases were included in the analysis and classified as patients with HPV-related or HPV-unrelated HNC. The presence of 30 comorbid conditions of interest was identified. Associations between comorbidity and treatment group as well as overall survival were evaluated. RESULTS: The study population consisted of 8025 patients with HPV unrelated HNC and 2499 patients with HPV-related HNC. Hypertension, congestive heart failure, cerebrovascular disease, and chronic obstructive pulmonary disease all were found to be highly prevalent at the time of the cancer diagnosis and increased over time for both groups. These comorbidities were found at significantly lower rates in the HPV-related HNC population, yet were associated with an increased risk of death in both groups. The probabilities of developing cancer-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in both groups after treatment but were more likely in patients with HPV-related HNC. In both groups of patients, the presence of each comorbidity either at the time of diagnosis or during survivorship was associated with a significantly increased risk of death. CONCLUSIONS: There is a large burden of comorbidities in both patients with HPV related and HPV-unrelated HNC, both of which are associated with decreased survival. Oncologic surveillance should not be limited to the evaluation of disease status, but also should include screening for the highly prevalent conditions associated with the risk of death. PMID- 30444526 TI - Differential use of medical versus surgical androgen deprivation therapy for patients with metastatic prostate cancer. AB - BACKGROUND: Surgical and medical androgen deprivation therapy (ADT) strategies are comparable in their ability to suppress serum testosterone levels as treatment in patients with metastatic prostate cancer but differ with regard to cost and impact on quality of life. Medical ADT is associated with better long term quality of life due to the flexibility of possible therapy interruption but comes with a higher cumulative cost. In the current study, the authors examined whether surgical ADT (ie, bilateral orchiectomy) was used differentially by race/ethnicity and other social factors. METHODS: The authors identified patients with metastatic disease at the time of diagnosis through the California Cancer Registry. The association between race/ethnicity and receipt of surgical ADT was modeled using multivariable Firth logistic regression adjusting for age, Gleason score, prostate-specific antigen level, clinical tumor and lymph node classification, neighborhood socioeconomic status (SES), insurance, marital status, comorbidities, initial treatment (radiotherapy, chemotherapy), location of care, rural/urban area of residence, and year of diagnosis. RESULTS: The authors examined a total of 10,675 patients with metastatic prostate cancer, 11.4% of whom were non-Hispanic black, 8.4% of whom were Asian/Pacific Islander, 18.5% of whom were Hispanic/Latino, and 60.5% of whom were non-Hispanic white. In the multivariable model, patients found to be more likely to receive surgical ADT were Hispanic/Latino (odds ratio [OR], 1.32; 95% confidence interval [95% CI], 1.01-1.72), were from a low neighborhood SES (OR, 1.96; 95% CI, 1.34-2.89) or rural area (OR, 1.49; 95% CI, 1.15-1.92), and had Medicaid/public insurance (OR, 2.21; 95% CI, 1.58-3.10). Patients with military/Veterans Affairs insurance were significantly less likely to receive surgical ADT compared with patients with private insurance (OR, 0.34; 95% CI, 0.13-0.88). CONCLUSIONS: Race/ethnicity, neighborhood SES, and insurance status appear to be significantly associated with receipt of surgical ADT. Future research will need to characterize other differences in initial treatments among men with advanced prostate cancer based on race/ethnicity and aim to better understand what factors drive the association between surgical ADT among men of Hispanic origin or those from areas with low neighborhood SES. PMID- 30444528 TI - Evaluation of in vitro culture systems for goat preantral follicles using reused ovaries from reproductive biotechniques: an alternative to maximize the potential of reproduction. AB - This study aimed to examine the in vitro culture of secondary preantral follicles, using reused ovaries, to compare both the 2D and 3D methods of in vitro culture of preantral follicles, and the system of medium replacement. Twenty-five pairs of ovaries from mixed-breed goats were used for the experiment. Follicular puncture of antral follicles was performed for in vitro production. After this procedure, the secondary preantral follicles were submitted to a microdissection procedure. The isolated preantral follicles were randomly divided into 3 treatments: 1) Two-dimensional culture with partial replacement of medium during culture (2D PR), 2) Three-dimensional culture with addition of medium during culture (3D AD), and 3) Three-dimensional culture with partial replacement of medium (3D PR). The culture period was 18 days. All treatments at the end of the in vitro culture period (18 days) presented a follicular survival rate which ranged from 59 to 70%, demonstrating that it was possible to perform an experiment with preantral follicles using ovaries that had previously been used in another reproductive biotechnique. The 3D AD treatment showed a survival percentage and follicular diameter higher than the 2D PR treatment, however, it did not differ from the 3D PR treatment. In conclusion, experiments employing the use of preantral follicles can be performed with success after the ovaries have been used for experiments with antral follicles. Moreover, the three-dimensional system with the addition of medium is recommended for in vitro culture of preantral follicles, since this system is more practical and financially feasible. This article is protected by copyright. All rights reserved. PMID- 30444529 TI - A population of descending tyraminergic/octopaminergic projection neurons of the insect deutocerebrum. AB - In this study we describe a cluster of tyraminergic/octopaminergic neurons in the lateral dorsal deutocerebrum of desert locusts (Schistocerca gregaria) with descending axons to the abdominal ganglia. In the locust these neurons synthesize octopamine from tyramine stress-dependently. Electrophysiological recordings in locusts reveal that they respond to mechanosensory touch stimuli delivered to various parts of the body including the antennae. A similar cluster of tyraminergic/octopaminergic neurons was also identified in the American cockroach (Periplaneta americana) and the pink winged stick insect (Sipyloidea sipylus). It is suggested that these neurons release octopamine in the ventral nerve cord ganglia and, most likely, convey information on arousal and/or stressful stimuli to neuronal circuits thus contributing to the many actions of octopamine in the central nervous system This article is protected by copyright. All rights reserved. PMID- 30444530 TI - A home-based tele-rehabilitation protocol for patients with hip fracture called @ctivehip. AB - Home-based tele-rehabilitation programs are under development and may be a future option for some patients. The objectives of this non-randomized clinical trial are to design a home-based multidisciplinary tele-rehabilitation protocol for patients with hip fracture, and to compare this protocol versus the home-based usual outpatient rehabilitation protocol. Seventy patients treated for an acute hip fracture, aged 65 years or older, with a high pre-fracture functional level (Functional Independence Measure score >90), without severe cognitive impairment, absence of terminal disease, discharged to their own home or a relatives home postoperatively, allowed weight-bearing, and with signed informed consent, will be allocated into a tele-rehabilitation group (n = 35) or a control group (n = 35). The inclusion criterion for the intervention group will be to have a caregiver with the ability to access the Internet who is willing to perform exercises and activities with the patient at home. The intervention includes a program of physical exercise and occupational therapy (five weekly sessions during 12 weeks), and recommendations for patients and their caregivers, all delivered through a website. The patient's functional level (Functional Independence Measure), quality of life (Euro-Qol), physical performance (Timed Up and Go), caregiver burden (Zarit Interview), and other descriptive data will be assessed at hospital discharge, 4 weeks, and 12 weeks. This project will add to the knowledge concerning the feasibility of tele-rehabilitation as an option to promote recovery of the pre-fracture functional level for some patients with a hip fracture. ClinicalTrials.gov Identifier: NCT02968589NCT. PMID- 30444531 TI - Measurement of torque generated during intracanal instrumentation in vivo. AB - AIM: To compare two different clinical techniques when using endodontic rotary instruments by monitoring the torque in vivo. METHODOLOGY: Ten single-rooted maxillary anterior teeth were prepared by an endodontist using size 25, .06 taper TF rotary instruments (KerrEndo, Orange, CA, USA). All instruments were rotated at 500 rpm with maximum torque set at 2.5 N cm using an endodontic motor (Kavo, Biberach, Germany), which automatically recorded the torque values every 1/10 of a second. Instruments were used with two modi operandi: (i) Inward action: short length intermittent progression with slight apical pressure aiming to reach the working length (also known as pecking motion), followed by (ii) Outward action: lateral brushing action selectively directed to address the canal circumference whilst removing instruments in the coronal direction. The mean, maximum and accumulated torque values were recorded and analysed statistically (t-test and Wilcoxon test) with a significance level set at 5%. None of the recorded values exceeded the selected torque limit. RESULTS: A significant difference between inward and outward actions was found regarding the evaluated parameters (P < 0.05). The outward action (brushing) was significantly safer (requiring less torque) compared to the inward action (pecking). CONCLUSIONS: Torque measurements during in vivo instrumentation provided useful information regarding the techniques evaluated. Although the torque limit was not reached by any of the two actions, the technique impacted significantly on the torque applied to the instrument. PMID- 30444532 TI - Isolation and characterization of soil bacteria able to rapidly degrade the organophosphorus nematicide fosthiazate. AB - Foshtiazate is an organophosphorus nematicide commonly used in protected crops and potato plantations. It is toxic to mammals, birds and honeybees, it is persistent in certain soils and can be transported to water resources. Recent studies by our group demonstrated, for the first time, the development of enhanced biodegradation of fosthiazate in agricultural soils. However the microorganisms driving this process are still unknown. We aimed to isolate soil bacteria responsible for the enhanced biodegradation of fosthiazate and assess their degradation potential against high concentrations of the nematicide. Enrichment cultures led to the isolation of two bacterial cultures actively degrading fosthiazate. Denaturating Gradient Gel Electrophoresis (DGGE) analysis revealed that they were composed of a single phylotype, identified via 16S rRNA cloning and phylogenetic analysis as Variovorax boronicumulans. This strain showed high degradation potential against fosthiazate. It degraded up to 100 mg L 1 in liquid cultures (DT50 = 11.2 d), while its degrading capacity was reduced at higher concentration levels (500 mg L-1 , DT50 = 20 d). This is the first report for the isolation of a fosthiazate-degrading bacterium, which showed high potential for use in future biodepuration and bioremediation applications. This article is protected by copyright. All rights reserved. PMID- 30444533 TI - A review of inorganic UV filters zinc oxide (ZnO) and titanium dioxide (TiO2 ). AB - Photoprotection has become integral in the prevention of keratinocyte cancer and photoaging. Organic UV filters such as oxybenzone and octinoxate have become controversial due to their potential impact on the environmental and their potential human health risks. As such, inorganic UV filters, ZnO and TiO2, have become paramount in discussions about photoprotection. ZnO and TiO2 are used in sunscreens as nanoparticles, which denotes a size less than 100nm. The smaller size of these mineral particles increases their cosmetic acceptability by users as they are much less visible after application. ZnO has a broad UVA-UVB absorption curve, while TiO2 provides better UVB protection. Overall, the human health risks with inorganic filters are extremely low given a lack of percutaneous absorption; however, there is potential risk when exposed via inhalation, prompting recommendations against spray sunscreen products with nanoparticles. At this time, the known risk to the environment is low though the risk stratification may evolve with increasing usage of these filters and higher environmental concentrations. The continued practice of photoprotection is critical. The public should be counseled to seek shade, use photoprotective clothing including hats and glasses in addition to sunscreens on sun-exposed skin. For those concerned about emerging evidence of environmental impact of organic UV filters, based on current evidence, ZnO and TiO2 -containing sunscreens are safe alternatives. This article is protected by copyright. All rights reserved. PMID- 30444534 TI - Arabinoxylan from Argentinian whole wheat flour promote the growth of Lactobacillus reuteri and Bifidobacterium breve. AB - Arabinoxylans are part of dietary fiber and have received attention given their emergent prebiotic character. Four arabinoxylans extracts were obtained from Argentinian soft and hard wheat. In vitro assays were performed to describe the extent to which the extracts from whole wheat flour support selective growth of Bifidobacterium breve and probiotic Lactobacillus reuteri ATCC23272 in a defined media. The prebiotic effect was evaluated by three quantitative scores: relative growth, prebiotic activity score and prebiotic index. For prebiotic index equation the growth of Bacteroides and Clostridium strains was compared to that of bifidobacteria and lactic acid bacteria. All the arabinoxylans extracts supported the growth of Lactobacillus and Bifidobacterium, reaching higher prebiotic activity score values than inulin (0.37 and 0.36 for Lactobacillus and Bifidobacterium, respectively). AX2 from soft wheat and AX4 from hard showed similar prebiotic index value to commercial inulin (2.64, 2.52 and 2.22, respectively), and AX3 extract presented higher prebiotic index value (4.09) than the positive control and other prebiotic index reported for arabinoxylans. These extracts could be used as prebiotic, synbiotic compositions or novel food prototypes to treat dysbiosis associated with many diseases. This article is protected by copyright. All rights reserved. PMID- 30444535 TI - Technical Note: Design of a handheld dipole antenna for a compact thermoacoustic imaging system. AB - PURPOSE: Conventional antenna used in thermoacoustic imaging (TAI) is often bulky, making it difficult to translate TAI from the bench to the clinic. In this paper, we proposed a handheld dipole antenna which will be a good candidate for the construction of a compact TAI system. METHODS: Here, we propose a TAI system based on a handheld dipole antenna with an aperture of 6 cm and a weight of 230 g. Compensation of the electric field attenuation for such a system was also investigated. RESULTS: Compared to the conventional open-ended waveguide and pyramidal horn antenna used in TAI, our results reveal that the electric field attenuation induced distortion is effectively reduced by using the attenuation factor 1/r2 for compensation and that the handheld dipole antenna provides the highest efficiency of microwave delivery. CONCLUSIONS: This study suggests that the handheld dipole antenna has the potential to be utilized for the construction of a compact TAI system, making TAI more suitable for preclinical and clinical applications. PMID- 30444536 TI - How flower colour signals allure bees and hummingbirds: a community-level test of the bee avoidance hypothesis. AB - Colour signals are the main floral trait for plant-pollinator communication. Due to visual specificities, flower visitors exert different selective pressures on flower colour signals of plant communities. Although it evolved to attract pollinators, matching their visual sensitivity and colour preferences, floral signals may also evolve to avoid less efficient pollinators and antagonistic flower visitors. We evaluated evidence for the bee avoidance hypothesis in a Neotropical community pollinated mainly by bees and hummingbirds, the campo rupestre. We analysed flower reflectance spectra, compared colour variables of bee- (bee-flowers; 244 species) and hummingbird-pollinated flowers (hummingbird flowers; 39 species), and looked for evidence of bee sensorial exclusion in hummingbird-flowers. Flowers were equally contrasting for hummingbirds. Hummingbird-flowers were less conspicuous to bees, reflecting mainly long wavelengths and avoiding red-blind visitors. Bee-flowers reflected more short wavelengths, were more conspicuous to bees (higher contrasts and spectral purity) than hummingbird-flowers and displayed floral guides more frequently, favouring flower attractiveness, discrimination and handling by bees. Along with no phylogenetic signal, the differences in signal strategies between bee- and hummingbird-flowers are the first evidence of the bee avoidance hypothesis at a community level and reinforce the role of pollinators as a selective pressure driving flower colour diversity. This article is protected by copyright. All rights reserved. PMID- 30444537 TI - The effect of repeated stimulated granulocyte donations on hematopoietic indexes in donors: a 24-year donor center experience. AB - BACKGROUND: Short- and long-term effects of mobilization regimens in hematopoietic stem cell and granulocyte donors have been well characterized. In this study, we examined the longitudinal hematopoietic changes related to repeat stimulated granulocyte donation. STUDY DESIGN AND METHODS: Complete blood counts for consecutive granulocyte donors between October 1994 and May 2017 were compared to unstimulated granulocyte donors. Plateletpheresis donors served as controls. The longitudinal change in precollection white blood cell (WBC) counts for these donor groups were modeled using a linear mixed-effects model. The investigated variables were granulocyte, lymphocyte, and monocyte counts and the granulocyte collection yield. Contrasts were performed to explore the effect of donation number on precollection counts. RESULTS: For the granulocyte-colony stimulating factor plus dexamethasone (G-CSF/Dex)-stimulated group, both the granulocyte and the lymphocyte counts decreased 6.51 * 109 /L (-23.1%, p < 0.001) and 0.21 * 109 /L (-20.4%, p < 0.001), respectively, between Donation 1 and Donation 20. This effect was still present at the 3- to 4-year interval (b = 0.0008313, SE = 0.00029, p = 0.004). For the unstimulated donor group between Donation 1 and Donation 20, the lymphocyte count decreased by 0.62 * 109 /L ( 51.5%, p < 0.001). This effect was only significant up to Year 2 (b = -0.0026, SE = 0.0010, p = 0.013). CONCLUSIONS: Past granulocyte donations were found to have a statistically strong negative effect on precollection granulocyte counts and lymphocyte counts and decreased granulocyte yield both in the G-CSF/Dex stimulated donors and the unstimulated donors. In this statistical model, for both these groups, the effect of past donations on granulocyte and WBC counts were still detectable 2 years later. PMID- 30444538 TI - Does Poverty Cause Dental Caries? AB - Dental caries generates significant health, financial and social costs to individuals and communities, but risk factors are not spread randomly and evenly throughout populations. People from lower socioeconomic status (SES) and disadvantaged groups suffer a disproportionately greater disease burden. Clinicians and public health experts view this problem through a different lens. Dentists at the clinical coalface consider individual risk factors and behaviours, for example sugar consumption, cariogenic bacteria and poor oral hygiene, as major causes of dental caries. However, considerable evidence suggests that low SES, via traditional individual risk factors as mediators and through additional independent pathways, is another significant cause. Progressive clinical practice uses education, prevention and treatment to reduce the impact of individual risk factors. Policy makers and health administrators use population-based approaches to improve the health of societies. The authors use literature review to argue for both a greater awareness of the upstream socioeconomic determinants of dental caries, and action from key community sectors to redress the societal inequalities contributing to dental health inequalities. This article is protected by copyright. All rights reserved. PMID- 30444539 TI - Plant traits inform predictions of tundra responses to global change. AB - In the rapidly warming tundra biome, plant traits provide an essential link between ongoing vegetation change and feedbacks to key ecosystem functions. However, only recently have comprehensive trait data been compiled for tundra species and sites, allowing us to assess key elements of functional responses to global change. In this review, we summarize trait-based research in tundra ecosystems, with a focus on three components: plant trait variation and how it compares with global patterns; shifts in community-level traits in response to environmental change; and the use of traits to understand and predict ecosystem function. Quantifying patterns and trends in plant traits will allow us to better project the consequences of environmental change for the ecology and functioning of tundra ecosystems. This article is protected by copyright. All rights reserved. PMID- 30444540 TI - Heteroatom-Doped Carbon Materials for Hydrazine Oxidation. AB - The key in designing efficient direct liquid fuel cells (DLFCs), which can offer some solutions to society's grand challenges associated with sustainability and energy future, currently lies in the development of cost-effective electrocatalysts. Among the many types of fuel cells, direct hydrazine fuel cells (DHFCs) are of particular interest, especially due to their high theoretical cell voltages and clean emission. However, DHFCs currently use noble-metal-based electrocatalysts, and the scarcity and high cost of noble metals are hindering these fuel cells from finding large-scale practical applications. In order to replace noble-metal-based electrocatalysts with sustainable ones and help DHFCs become widely usable, great efforts are being made to develop stable heteroatom (e.g., B, N, O, P and S)-doped carbon electrocatalysts, the activities of which are comparable to, or better than, those of noble metals. Here, the recent research progress and the advancements made on the development of heteroatom doped carbon materials, their general properties, their electrocatalytic activities toward the HzOR, and their dopant- and structure-related electrocatalytic properties for the HzOR are summarized. Perspectives on the different directions that the research endeavors in this field need to take in the future and the challenges associated with DHFCs are included. PMID- 30444541 TI - On the origins of osmotically-driven stomatal movements. AB - Stomatal pores with aperture that can be adjusted by changes in guard cell turgor have facilitated plant success in dry environments. We explore their evolutionary origins, considering recent findings from bryophytes. Unlike vascular plant stomata, which close to prevent water loss, bryophyte stomata become locked open to promote spore desiccation. We find that the families of ion channels, known to control stomatal movements in angiosperms, are ancient and represented across extant land plants. However, while angiosperm guard cells express specific ion channel genes, none are specifically expressed in stomata-bearing moss tissues. Given the evolutionary shift in stomatal function from promotion to prevention of water loss, we postulate that ion channels adopted guard cell-specific functions after the divergence of bryophytes. This article is protected by copyright. All rights reserved. PMID- 30444542 TI - Alterations in cortical and thalamic connections of somatosensory cortex following early loss of vision. AB - Early loss of vision produces dramatic changes in the functional organization and connectivity of the neocortex in cortical areas that normally process visual inputs, such as the primary and second visual area. This loss also results in alterations in the size, functional organization and neural response properties of the primary somatosensory area, S1. However, the anatomical substrate for these functional changes in S1 have never been described. In the present investigation, we quantified the cortical and subcortical connections of S1 in animals that were bilaterally enucleated very early in development, prior to the formation of retino-geniculate and thalamocortical pathways. We found that S1 receives dense inputs from novel cortical fields, and that the density of existing cortical and thalamocortical connections was altered. Our results demonstrate that sensory systems develop in tandem and that alterations in sensory input in one system can affect the connections and organization of other sensory systems. Thus, therapeutic intervention following early loss of vision should focus not only on restoring vision, but also on augmenting the natural plasticity of the spared systems. This article is protected by copyright. All rights reserved. PMID- 30444543 TI - Endoscopic ultrasound-guided choledochoduodenostomy using a thin stent delivery system in patients with unresectable malignant distal biliary obstruction: a prospective multicenter study. AB - OBJECTIVES: When endoscopic retrograde cholangiopancreatography (ERCP) fails in patients with malignant distal biliary obstruction, endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) is an alternative. It associates with high technical and clinical success rates but also high adverse events rates. This prospective cohort study was aimed to evaluate the clinical efficacy and safety of EUS-CDS with our newly developed partially-covered self-expandable metal stent with a thin delivery system. METHODS: The patients consisted of all consecutive patients in three tertiary referral centers with unresectable malignant distal obstruction in whom ERCP failed and in whom EUS-CDS with the thin delivery system was selected as the second-line approach. The rates of clinical success, technical success, technical success in cases not requiring fistulous tract dilation, adverse events, and stent dysfunction were determined. RESULTS: In the 20 patients, the technical and clinical success rates were 95.0% (19/20) and 100% (19/19), respectively. In 31.6% (6/19), the delivery system was successfully inserted into the bile duct without requiring a fistulous-tract dilatation device. These patients had significantly shorter procedure times than patients requiring fistulous-tract dilatation (12.7+/-3.1 vs. 23.2+/-2.1 min; P<0.01). One patient (5.0%) who required fistulous dilation had an adverse event, which was managed conservatively. There were no procedure-related deaths. During follow-up, four patients (21.1%) developed stent dysfunction. Re-intervention was successful in all cases. CONCLUSIONS: The EUS-CDS approach was associated with 95% technical and 100% clinical success rates, with adverse events reported in 5% of cases. EUS CDS may become safer if efforts are made to avoid the dilation step (UMIN 000023938). This article is protected by copyright. All rights reserved. PMID- 30444545 TI - Enzyme-Instructed Supramolecular Self-Assembly with Anticancer Activity. AB - Cancer remains one of the leading causes of death, which has continuously stimulated the development of numerous functional biomaterials with anticancer activities. Herein is reviewed one recent trend of biomaterials focusing on the advances in enzyme-instructed supramolecular self-assembly (EISA) with anticancer activity. EISA relies on enzymatic transformations to convert designed small molecular precursors into corresponding amphiphilic residues that can form assemblies in living systems. EISA has shown some advantages in controlling cell fate from three aspects. 1) Based on the abnormal activity of specific enzymes, EISA can differentiate cancer cells from normal cells. In contrast to the classical ligand-receptor recognition, the targeting capability of EISA relies on dynamic control of the self-assembly process. 2) The interactions between EISA and cellular components directly disrupt cellular processes or pathways, resulting in cell death phenotypes. 3) EISA spatiotemporally controls the distribution of therapeutic agents, which boosts drug delivery efficiency. Therefore, with regard to the development of EISA, the aim is to provide a perspective on the future directions of research into EISA as anticancer theranostics. PMID- 30444544 TI - Organic Photovoltaics with Multiple Donor-Acceptor Pairs. AB - Compared with conventional organic solar cells (OSCs) based on single donor acceptor pairs, terpolymer- and ternary-based OSCs featuring multiple donor acceptor pairs are promising strategies for enhancing the performance while maintaining an easy and simple synthetic process. Using multiple donor-acceptor pairs in the active layer, the key photovoltaic parameters (i.e., short-circuit current density, open-circuit voltage, and fill factor) governing the OSC characteristics can be simultaneously or individually improved by positive changes in light-harvesting ability, molecular energy levels, and blend morphology. Here, these three major contributions are discussed with the aim of offering in-depth insights in combined terpolymers and ternary systems. Recent exemplary cases of OSCs with multiple donor-acceptor pairs are summarized and more advanced research and perspectives for further developments in this field are highlighted. PMID- 30444546 TI - Enhancement of immune response mediated by oropharyngeal colostrum administration in preterm neonates. AB - BACKGROUND: The immune system of preterm infants is immature, being a significant cause of morbidity and mortality, particularly in the preterm infant. Oropharyngeal colostrum administration could be an immunomodulatory aid. Our aim was to evaluate the effect of oropharyngeal colostrum on the serum levels of immunoglobulins, lactoferrin and resistin during the first month of life and to track the clinical outcome of the neonates. METHODS: 100 preterm neonates born at < 32 weeks of gestation and/or weighing less than 1,500g and assisted in the Neonatal Intensive Care Unit were enrolled and divided into two groups: colostrum (n=48) and control (n=52). The subjects assigned to the colostrum group received 0.2 ml of colostrum (oropharyngeal route) every 4 hours for the first 15 days of life and if mothers have inability to breastfeed, they were included in the control group (no oropharyngeal colostrum). Serum concentrations of IgA, IgM and IgG1, lactoferrin and resistin were assessed in both groups at 1, 3, 15 and 30 days of life. Clinical data during hospitalization were collected. RESULTS: IgA and IgM increased in preterm neonates who were administered colostrum for 15 and 30 days. Lactoferrin increased after 30 days and resistin increased after 15 days of supplying oropharyngeal colostrum. The colostrum group underwent full enteral nutrition before and no differences were observed in the common neonatal morbidities. CONCLUSION: Oropharyngeal colostrum administration is safe in preterm neonates and improves their immunological profile, showing a potential role as an immunomodulatory agent. This article is protected by copyright. All rights reserved. PMID- 30444547 TI - Endoscopic radiofrequency biliary ablation treatment: a comprehensive review. AB - Radiofrequency ablation (RFA) acts by delivering thermal energy within the tissue, the result of a high-frequency alternating current released from an active electrode, leading to coagulative necrosis and cellular death. Recently, a biliary catheter working on a guide-wire has been developed and a number of studies have been performed so far. The present paper provides a comprehensive review of the literature on the results of the use of RFA for the clinical management of patients with unresectable malignant biliary strictures, benign biliary strictures, and residual adenomatous tissue in the bile duct after endoscopic papillectomy. The available data show that biliary RFA treatment is a promising adjuvant therapy in patients with unresectable malignant biliary obstruction. The procedure is safe, well tolerated and improves stent patency and survival, even though more studies are warranted. In patients with residual endobiliary adenomatous tissue after endoscopic papillectomy, a significant rate of neoplasia eradication after a single RFA session has been reported, thus favoring this treatment over surgical intervention. In these patients, as well as, in those with benign biliary strictures, dedicated probes with a short electrode able to focus the RF current on the short stenosis are needed to expand RFA treatment for these indications. This article is protected by copyright. All rights reserved. PMID- 30444548 TI - Endobronchial ultrasound guided transbronchial needle aspiration cytology in patients with known or suspected extra-pulmonary malignancies: A cytopathology based study. AB - BACKGROUND: Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is the primary modality for mediastinal lymph node staging in lung carcinoma. We aimed to evaluate its utility in extra-pulmonary malignancies (EPM). METHODS: Database search of EBUS-TBNA aspirations (2013-2017) done in patients with known/suspected EPMs and mediastinal lymphadenopathy/masses was performed. All archived cytology/histology material was reviewed and categorized as positive, negative and unsatisfactory. RESULTS: The selected 139 patients included 100 patients with known EPMs, 11 patients with known lymphoma, and 28 patients with suspected EPM of unknown primary. EBUS-TBNA was adequate in 110 patients (79%), including 21 patients who yielded only reactive lymphoid tissue. Satisfactory blood clot cores were obtained in 34 patients and contributed significantly to diagnosis and ancillary testing. Metastasis was detected in 45 patients with known EPM, predominantly originating from a known primary in the breast in females (56%) and squamous cell carcinomas of head and neck in males (60%). Granulomatous lymphadenopathy was identified in 16 patients with known EPM (16%). Lymphoma relapse and granulomatous lymphadenopathy was identified in 3 and 4 patients with known lymphoma, respectively. In patients with suspected EPM of unknown primary site, malignancy was confirmed in 21 patients, predominantly representing metastatic adenocarcinomas (n=5) and neuroendocrine neoplasms (n=5). Immunocytochemistry was performed in 16 of these cases and aided in characterization of primary site/type of tumor in 12 cases. CONCLUSION: EBUS-TBNA is efficient for screening mediastinal lymph nodes/masses for malignancy in EPMs. Procuring sufficient material for ancillary testing would improve diagnostic accuracy and reduce need for resampling. This article is protected by copyright. All rights reserved. PMID- 30444549 TI - A FRET sensor for live-cell imaging of MAP kinase activity in Arabidopsis. AB - The catalytic activity of mitogen activated protein kinases (MAPKs) is dynamically modified in plants. Since MAPKs have been shown to play important roles in a wide range of signaling pathways, the ability to monitor MAPK activity in living plant cells would be valuable. Here we report the development of a genetically encoded MAPK activity sensor for use in Arabidopsis thaliana. The sensor is composed of yellow and blue fluorescent proteins, a phosphopeptide binding domain, a MAPK substrate domain, and a flexible linker. Using in vitro testing, we demonstrated that phosphorylation causes an increase in the Forster resonance energy transfer (FRET) efficiency of the sensor. FRET efficiency can therefore serve as a readout of kinase activity. We also produced transgenic Arabidopsis lines expressing this sensor of MAPK activity (SOMA) and performed live-cell imaging experiments using detached cotyledons. Treatment with NaCl, the synthetic flagellin peptide flg22, and chitin all led to rapid gains in FRET efficiency. Control lines expressing a version of SOMA in which the phosphosite was mutated to an alanine did not show any substantial FRET changes. We also expressed the sensor in a conditional loss-of function double-mutant line for the Arabidopsis MAPK genes MPK3 and MPK6. These experiments demonstrated that MPK3/6 are necessary for the sensor's NaCl-induced FRET gain, while other MAPKs are likely contributing to the chitin and flg22-induced FRET increases. Taken together, our results suggest that SOMA is able to dynamically report MAPK activity in living plant cells. This article is protected by copyright. All rights reserved. PMID- 30444550 TI - Synthesis of Cyclic Alkyl(amino) Carbene Stabilized Silylenes with Small N donating Substituents. AB - Lewis base cAACs stabilized monomeric silylenes with halogen or methyl substitutents at the silicon center have not been reported due to the strong sigma-donor and pi-acceptor character of cAAC. To prepare these monomeric silylenes, we used the silicon(IV) precursors 5 and 6 with a nitrogen donor group L (L = o-C6H4NMe2). The cAAC-stabilized (cAAC = C(CH2)(CMe2)2N-Ar, Ar = 2,6 iPr2C6H3) silylenes LSiCl(cAAC) (7) and LSiMe(cAAC) (8) were synthesized by reduction of LSiCl3 and LSiMeCl2 with two equivalents of KC8 in the presence of one equivalent of cAAC, respectively. Compounds 7 and 8 were characterized by single crzstal X-ray crystallography, NMR spectroscopy, and elemental analyses. Compounds 7 and 8 are stable in the solid state as well as in solution at room temperature for at least four months under inert conditions. PMID- 30444551 TI - Effects of melatonin on oocyte developmental competence and the role of melatonin receptor 1 in juvenile goats. AB - Melatonin enhances in vitro embryo development in several species by improving the oocyte developmental competence during in vitro maturation (IVM). Melatonin has a wide range of actions, from scavenging reactive oxygen species (ROS) to regulating gene expression, and it can also act by way of melatonin receptors. The aim of this study was to determine the mechanism of action of melatonin during the IVM of juvenile goat oocytes and the role of the membrane receptors. Melatonin receptor 1 was immunolocalized in cumulus cells and oocytes before and after 24 hr of IVM. The effect of melatonin on oocyte developmental competence was tested in three experimental IVM groups: (a) control, (b) 10-7 M melatonin, and (c) 10-7 M melatonin +10-7 M luzindole (an inhibitor of both melatonin receptors). After IVM oocytes were assessed for ROS levels, mitochondrial activity, adenosine 5'-triphosphate (ATP) concentration and relative gene expression (ACTB, SLC1A1, SOD1, GPx1, BAX, DNMT1, GCLC and GDF9). IVM-oocytes were in vitro fertilized and cultured under conventional conditions. Blastocyst rate and quality (differential cell count) were assessed at 8 days post fertilization. Melatonin decreased ROS levels, increased mitochondrial activity and ATP content and increased blastocyst quality compared to control group (55.8 vs. 30.4 inner cell mass ICM, p < 0.05). There was no effect on the relative gene expression due to treatment with melatonin. In conclusion, we have showed that melatonin improves oocyte developmental competence in juvenile goats by reducing ROS levels and improving mitochondrial activity. PMID- 30444552 TI - Clarity reveals a more protracted temporal course of axon swelling and disconnection than previously described following traumatic brain injury. AB - Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal "axon bulb" at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue-sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue-clearing technology, CLARITY, permits three-dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6h, 24h, 1-week and 1-month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8MUm thick regions of tissue, were instead revealed to be varicose swellings along intact axons when three-dimensions were fully-visible. Moreover, the percentage of these potentially-viable axon swellings differed with survival from injury and may represent the delayed-onset of distinct mechanisms of degeneration. Even at 1 month post-CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard-thickness tissue sections overestimates axon disconnection, particularly acutely post injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery. This article is protected by copyright. All rights reserved. PMID- 30444553 TI - Bioinspired 3D Printed Locomotion Devices Based on Anisotropic Friction. AB - Anisotropic friction plays a key role in natural systems, particularly for realizing the purpose of locomotion and strong attachment for the survival of organisms. Of particular interest, here, is the observation that friction anisotropy is promoted numerous times by nature, for example, by wild wheat awn for its targeted and successful seed anchorage and dispersal. Such feature is, however, not fully exploited in man-made systems, such as microbots, due to technical limitations and lack of full understanding of the mechanisms. To unravel the complex dynamics occurring in the sliding interaction between anisotropic microstructured surfaces, the friction induced by asymmetric plant microstructures is first systematically investigated. Inspired by this, anisotropic polymer microactuators with three-dimensional (3D) printed microrelieves are then prepared. By varying geometric parameters, the capability of microactuators to generate strong friction anisotropy and controllable motion in remotely stretched cylindrical tubes is investigated. Advanced theoretical models are proposed to understand and predict the dynamic behavior of these synthetic systems and to shed light on the parameters and mechanisms governing their behavior. Finally, a microbot prototype is developed and cargo transportation functions are successfully realized. This research provides both in-depth understanding of anisotropic friction in nature and new avenues for developing intelligent actuators and microbots. PMID- 30444554 TI - Spray-Assisted Coil-Globule Transition for Scalable Preparation of Water Resistant CsPbBr3 @PMMA Perovskite Nanospheres with Application in Live Cell Imaging. AB - Despite their impressive optical properties, lead halide perovskite quantum dots (PQDs) have not realized their potential, especially in bioimaging applications, as they suffer from poor moisture and thermal stability, solvent incompatibility, and significant toxicity. Here, a spray-assisted coil-globule transition method for encapsulating CsPbBr3 (CPB) PQDs into poly(methyl methacrylate) (PMMA) polymer nanospheres is reported. Polyvinylpyrrolidone-capped CPB PQDs are synthesized via the ligand assisted reprecipitation method in dichloromethane. After dissolving PMMA, the above precursor solution is sprayed into petroleum ether under high pressure N2 . High-pressure nebulization restricts the interactions between PMMA polymer chains, resulting in the formation of ~112 nm nanoscale composite spheres after a coil-globule transition. The CPB@PMMA nanospheres not only possess 73% quantum yields but retain 81% of fluorescence intensity after the exposure to water for over 80 days. Due to their confined size and biocompatible encapsulation, they are readily available for cellular uptake and exhibit no toxicity on live HeLa cells. Furthermore, the PMMA surface allows for functional surface modification, carrying the possibility of targeting specific biological species and processes. PMID- 30444555 TI - Semiconducting Polymer Spherulites-From Fundamentals to Polymer Electronics. AB - The control of the morphology of semiconducting semicrystalline polymers is crucial to the performance of various electronic devices. Among other superstructures in semicrystalline polymers, spherulites stand out for various reasons. They are highly ordered, relatively easy to grow, and their underlying molecular structure provides anisotropic optical and electronic properties of the resulting polymeric material. In this feature article, a short overview of classical crystallization theory is given as well as a brief introduction to spherulites as supermolecular structures. The article then focuses on semicrystalline polymers with semiconducting properties. From classical melt crystallization toward solvent vapor annealing, different strategies of growing spherulites of these types of polymers are presented and examples of the corresponding polymers and their resulting morphology are given. Eventually, the potential application of spherulitic thin films in organic electronics such as field-effect transistors is demonstrated. Conductivity and mobility measurements are shown, particularly focusing on the anisotropy of the latter. PMID- 30444556 TI - Factors associated with a cervical high-grade lesion on cytology or a positive visual inspection with acetic acid among more than 3300 Tanzanian women. AB - OBJECTIVES: Cervical cancer screening by visual inspection with acetic acid (VIA) is a widely used alternative to cytology in developing countries. This study aimed to evaluate risk factors associated with a positive VIA test and with cervical high-grade lesions on cytology. METHODS: We conducted a large cross sectional study among 3339 women from urban and rural Tanzania. Study participants were interviewed about socio-demographic, reproductive and lifestyle factors. Blood samples were tested for HIV, and a gynaecological examination was performed. Human papillomavirus (HPV) status was determined by Hybrid Capture 2, and HPV genotyping was done using the LiPA Extra test. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and confidence intervals (CIs). RESULTS: The strongest risk factors for VIA positivity were positivity to HIV (OR = 3.48; 95% CI: 2.34-5.17) or to high-risk HPV (HrHPV) (OR = 1.97; 95% CI: 1.37-2.85). HrHPV was by far the strongest predictor of high grade cytology (OR = 110.1; 95% CI: 50.4-240.4), while there was no significant association with HIV in the multivariable analysis (OR = 1.27; 95% CI: 0.78 2.08). After adjustment for HrHPV, HIV and age, the risk of high-grade cytology also increased with increasing age, number of births and low body mass index (BMI), while high BMI decreased the risk of VIA positivity. CONCLUSIONS: Infection with HrHPV is a major risk factor for high-grade cytology, while VIA positivity is associated with HIV and to a lesser extent with HrHPV. PMID- 30444557 TI - Locals get travellers' diarrhoea too: risk factors for diarrhoeal illness and pathogenic Escherichia coli infection across an urban-rural gradient in Ecuador. AB - OBJECTIVES: Diarrhoea is a common and well-studied cause of illness afflicting international travellers. However, traveller's diarrhoea can also result from travel between high and low disease transmission regions within a country, which is the focus of this study. METHODS: We recruited participants for a case-control study of diarrhoea at four sites along an urban-rural gradient in Northern Ecuador: Quito, Esmeraldas, Borbon and rural communities outside of Borbon. At each of these sites, approximately 100 subjects with diarrhoea (cases) were recruited from Ministry of Health clinics and were age-matched with subjects visiting the same clinics for other complaints (controls). RESULTS: Travellers to urban destinations had higher risk of diarrhoea and diarrhoeagenic Escherichia coli (DEC) infections. Travel to Quito was associated with diarrhoea (aOR = 2.01, 95% CI = 1.10-3.68) and travel to Guayaquil (another urban centre in Ecuador) was associated with Diffuse Adherent E. coli infection (OR = 2.09, 95% CI = 1.01 4.33). Compared to those not travelling, urban origins were also associated with greater risk of diarrhoea in Esmeraldas (aOR = 2.28, 95% CI = 1.20-4.41), and with higher risk of diarrhoeagenic E. coli infections in Quito (aOR = 2.61, 95% CI = 1.16-5.86), with >50% of travel from Quito and Esmeraldas specified to another urban destination. CONCLUSIONS: This study suggests that individuals travelling from lower-transmission regions (rural areas) to higher transmission regions (urban centres) within a single country are at a greater risk of acquiring a diarrhoea-related illness. Investments to improve water, sanitation and hygiene conditions in urban areas could have impacts on outlying rural areas within a given country. PMID- 30444558 TI - Pain Relief in the Palm of Your Hand: Harnessing Mobile Health to Manage Pediatric Pain. AB - The development and implementation of mobile health (mHealth) interventions provide an opportunity for more optimal management of pediatric pain in the home setting. Leveraging the popularity, mobility, and technological capabilities of digital mobile devices may reduce pediatric pain. Several mHealth applications have already been developed that target the reduction of acute and chronic pediatric pain by digitally delivering intervention strategies in an engaging manner, accumulating pain assessment data, facilitating patient provider communication, and providing interactive training. Although several mHealth programs have begun to make strides in the management of pediatric pain, there are still many more possibilities for improvement as greater development and adoption of mHealth practices is on the horizon. Recommendations are provided that advocate for continued advancement of pediatric pain mHealth implementation with an emphasis on robust scientific evaluation, a structured approach to development and design elements that enhance engagement. Increased awareness about the positive influence of mHealth along with the encouragement of researchers and healthcare providers to promote and develop mHealth programs has the potential to transform pediatric pain management. This merger of evidence based pain management strategies and digital technology positions pediatric mHealth to have a profound impact by effectively augmenting standard of care and benefiting healthcare providers, parents, and especially children in need. This article is protected by copyright. All rights reserved. PMID- 30444560 TI - Reactivity of the Major Product of C5'-Oxidative DNA Damage in Nucleosome Core Particles. AB - The major pathway for DNA damage following hydrogen atom abstraction from the C5' position results in direct strand scission and concomitant formation of a 5' aldehyde containing nucleotide (e.g. T-al). We determined that the half-life for alkali-labile T-al in free DNA under physiological conditions varies from 5 - 12 days. T-al reactivity was examined at 3 positions within nucleosome core particles (NCPs). beta-Elimination increased >2.5-fold when T-al was proximal to the lysine rich histone H4 tail. No difference in reactivity between free DNA and NCPs was observed when T-al was distal from the histone tails. Position dependent involvement of histone tails in T-al elimination was gleaned from experiments using sodium cyanoborohydride and histone protein variants. The enhancement of T al elimination in NCPs is significantly smaller than previously observed for abasic sites. Computational studies comparing elimination from T-al and abasic sites indicate that the barrier for the rate determining step in the latter is 2.6 kcal/mol lower in energy and is stabilized by a hydrogen bond between C4 hydroxyl group and phosphate leaving group. The long lifetime for T-al in NCPs, combined with what is known about its repair suggests that this DNA lesion may pose significant challenges within cells. PMID- 30444559 TI - Leaving Group Assisted Strategy for Photoinduced Fluoroalkylations Using N Hydroxybenzimidoyl Chloride Esters. AB - Redox-active esters (RAEs) as alkyl radical precursors have been extensively developed for C-C bond formations. However, the analogous transformations of fluoroalkyl radicals from the corresponding acid or ester precursors remain challenging because of the high oxidation potential of the fluoroalkyl carboxylate anions. The newly developed N-hydroxybenzimidoylchloride (NHBC) ester provides a general leaving group assisted strategy to generate a portfolio of fluoroalkyl radicals, and can be successfully applied in photoinduced decarboxylative hydrofluoroalkylation and heteroarylation of unactivated olefins. In addition, DFT calculations revealed that the NHBC ester proceeds by the fluorocarbon radical pathway, whereas other well-known RAEs proceed by the nitrogen radical pathway. PMID- 30444562 TI - Systematic review of factors associated with the development of guillain-barre syndrome 2007 to 2017: what has changed? AB - OBJECTIVE: To describe the factors associated with the development of Guillain Barre syndrome, both infectious and non-infectious, during and after the A(H1N1) influenza pandemic in 2009 and the recent Zika virus epidemic in the Americas. METHOD: Systematic review of literature on factors associated with the development of the Guillain-Barre syndrome published between 2007 and 2017 listed in EBSCO, MEDLINE, and LILACS databases. The quality of the studies was evaluated using the Newcastle Ottawa Scale. RESULTS: 34 articles met inclusion criteria and were selected for analysis. Their quality was considered good in relation to most of the items evaluated. Many etiological agents had results of association with Guillain-Barre syndrome, among them Campylobacter jejuni, influenza vaccine - both pandemic and seasonal vaccines, respiratory infection, gastrointestinal infection among others. The etiological agents found are in most part the same reported prior to the study period. The association with surgeries, chikungunya virus (CHIKV), Zika virus and quadrivalent human papillomavirus vaccine stand out as new etiological agents in the list of the various possible agents that trigger Guillain-Barre syndrome reported in the study period. There were no Brazilian studies identified during this period. CONCLUSIONS: The results of the review reaffirmed Campylobacter jejuni as the major trigger of GBS, whereas the association of influenza vaccines and GBS is less clear: Zika virus infection in association with GBS was found in only one study. This article is protected by copyright. All rights reserved. PMID- 30444561 TI - Modafinil for post-stroke patients: a systematic review. AB - INTRODUCTION: Stroke is a major cause of death and disability worldwide. The use of modafinil, a wakefulness-promoting agent, is hypothesized to benefit stroke patients. METHODS: We performed a systematic review in accordance with the Cochrane Handbook for Systematic Reviews of Interventions recommendations to assess the efficacy and safety of modafinil in post stroke patients. We prospectively registered the review protocol in PROSPERO (CRD42017078465) and reported the systematic review following the PRISMA statement. RESULTS: Two published studies (77 participants) and one ongoing randomized controlled trial, with limited methodological quality, assessed the effects of modafinil (200mg or 400mg) for adults from 14 days post-stroke up to 3 months pos-stroke and fulfilled our inclusion criteria and. The clinical and methodological variability between studies precluded meta-analyses. Overall, these studies showed some benefit of modafinil for fatigue, but no benefit for disability, cognition and for subscores of stroke-specific quality of life. Data for adverse events were scarce and mortality was not considered by studies. Due to very low quality related to the evidence, we are uncertain about the effects of modafinil for all outcomes assessed by our systematic review. CONCLUSION: Based on two small randomized controlled trial, which provided very low quality evidence, the effects (benefits and harms) of modafinil for stroke patients are unclear and do not support its routinely use in clinical practice for this clinical situation. This article is protected by copyright. All rights reserved. PMID- 30444563 TI - Why evolutionary biology needs anthropology: Evaluating core assumptions of the extended evolutionary synthesis. AB - Anthropologists have a long history of applying concepts from evolutionary biology to cultural evolution. Evolutionary biologists, however, have been slow to turn to anthropology for insights about evolution. Recently, evolutionary biology has been engaged in a debate over the need to revise evolutionary theory to account for developments made in 60 years since the Modern Synthesis, the standard evolutionary paradigm, was framed. Revision proponents maintain these developments challenge central tenets of standard theory that can only be accounted for in an extended evolutionary synthesis (EES). Anthropology has much to offer to this debate. One important transition in human cultural evolution, the domestication of plants and animals, provides an ideal model system assessing core EES assumptions about directionality, causality, targets of selection, modes of inheritance, and pace of evolution. In so doing, anthropologists contribute to an overarching framework that brings together cultural and biological evolution. PMID- 30444564 TI - A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells. AB - Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determine MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the TGF-beta signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal (NLS). Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-Runx2 interactions in the C3H10T1/2 MSC cell line and pre-osteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-PPARgamma interaction in C3H10T1/2 and pre-adipogenic 3 T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARgamma, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. (c) AlphaMed Press 2018. PMID- 30444565 TI - Phylogeny, Evidence for a Cryptic Plastid, and Distribution of Chytriodinium Parasites (Dinophyceae) Infecting Copepods. AB - Spores of the dinoflagellate Chytriodinium are known to infest copepod eggs causing their lethality. Despite the potential to control the population of such an ecologically important host, knowledge about Chytriodinium parasites is limited: we know little about phylogeny, parasitism, abundance, or geographical distribution. We carried out genome sequence surveys on four manually isolated sporocytes from the same sporangium, which seemed to be attached to a copepod nauplius, to analyse the phylogenetic position of Chytriodinium based on SSU and concatenated SSU/LSU rRNA gene sequences, and also characterize two genes related to the plastidial heme pathway, hemL and hemY. The results suggest the presence of a cryptic plastid in Chytriodinium and a photosynthetic ancestral state of the parasitic Chytriodinium/Dissodinium clade. Finally, by mapping Tara Oceans V9 SSU amplicon data to the recovered SSU rRNA gene sequences from the sporocytes, we show that globally, Chytriodinium parasites are most abundant within the pico/nano- and mesoplankton of the surface ocean and almost absent within microplankton, a distribution indicating that they generally exist either as free living spores or host-associated sporangia. This article is protected by copyright. All rights reserved. PMID- 30444566 TI - Relationship between body image and health-related quality of life in Chinese cancer survivors during the transitional cancer survivorship. AB - BACKGROUND: Previous research has documented the negative impact of cancer treatment on body image and health-related quality of life among survivors, and the positive relationship between those factors. However, existing evidence is mainly based on Western studies of female survivors, and there is thus a huge knowledge gap in research on non-Western cancer survivors. OBJECTIVES: The aim of the study was to assess body image and health-related quality of life, and explore their relationship, among Chinese cancer survivors during transitional survivorship. METHODS: Chinese cancer survivors with various diagnoses at the oncology outpatient clinic of a regional hospital in Hong Kong were invited to complete a self-reported survey on socio-demographic and clinical data, the instrument of Quality of Life in Adult Cancer Survivors and Body Image Scale. RESULTS: A convenience sample of 402 Chinese cancer survivors was recruited, with a mean age of 54.4 years, the majority female (70.4%). In general, participants reported satisfactory body image but only fair health-related quality of life. Hierarchical multiple regression showed that body image was independently associated with both generic and cancer-specific health-related quality of life after controlling for socio-demographic and clinical characteristics (B = 9.572, P < 0.001; B = 5.165, P < 0.001). CONCLUSIONS: Addressing body image may be an effective approach to enhancing Chinese cancer survivors' health-related quality of life during their transitional survivorship. Since there is a lack of attention given to body image in local clinical settings, early assessment and appropriate interventions should be considered. PMID- 30444567 TI - Varroa chemosensory proteins: Some conserved across Arthropoda but others are Arachnid specific. AB - The tight synchronization between the life cycle of the obligatory parasitic mite Varroa destructor (Varroa) and its host, the honeybee, is mediated by honeybee chemical stimuli. These stimuli are mainly perceived by a pit organ located at the distal part of the mite's foreleg. In the present study, we searched for Varroa chemosensory molecular components by comparing transcriptomic and proteomic profiles between forelegs from different physiological stages, and rear legs. In general, a comparative transcriptomic analysis showed a clear separation of the expression profiles between the rear legs and the three groups of forelegs (phoretic, reproductive and tray-collected mites). Most of the differentially expressed transcripts and proteins in the mite's foreleg were previously uncharacterized. Using a conserved domain approach, we identified 45 transcripts with known chemosensory domains belonging to seven chemosensory protein families, of which 16 were significantly up regulated in the mite's forelegs when compared to rear legs. These are soluble and membrane bound proteins, including the somewhat ignored receptors of degenerin/epithelial Na+ channels (ENaCs) and transient receptor potentials (TRPs). Phylogenetic clustering and expression profiles of the putative chemosensory proteins, suggest their role in chemosensation and shed light on the evolution of these proteins in Chelicerata. This article is protected by copyright. All rights reserved. PMID- 30444568 TI - Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, potentiates coagulation function in factor XI-deficient plasma in vitro. AB - BACKGROUND: Patients with factor (F)XI-deficiency commonly present with markedly prolonged activated partial thromboplastin times (aPTT), although bleeding phenotypes are heterogeneous. Emicizumab, a bispecific monoclonal antibody to FIX/FIXa and FX/FXa, mimics FVIIIa cofactor function on phospholipid (PL) surfaces. Antibody reactions were designed, therefore, to augment mechanisms during the propagation phase of blood coagulation. AIM: To assess emicizumab driven hemostatic function in FXI-deficient plasmas. METHODS AND RESULTS: Standard ellagic acid (Elg)/PL-based aPTTs of different FXI-deficient plasmas (n=13; FXI activity; <1 IU/dl) were markedly shortened dose-dependently by the presence of emicizumab. To further analyze the effects of emicizumab, clot waveform analysis (CWA) in FXI-deficient plasmas with emicizumab, triggered by tissue factor (TF)/Elg demonstrated both improvements in clot times reflecting the initiation phase and coagulation velocity that represents the propagation phase. Emicizumab also enhanced the TF/Elg-triggered thrombin generation in FXI deficient plasmas dose-dependently although the degree of enhancement varied in individual cases. Thrombin generation with either FVII-deficient plasma or FIX deficient plasma treated with anti-FXI antibody showed little or no increase by the co-presence of emicizumab, suggesting that the accelerated thrombin generation in FXI-deficient plasmas by emicizumab should depend on the FIXa involved coagulation propagation initially triggered by FVIIa/TF. The ex vivo addition of emicizumab to whole blood from 3 patients with severe FXI deficiency demonstrated modest, dose-dependent improvements in Ca2+ -triggered thromboelastograms (NATEM mode). CONCLUSION: Emicizumab appeared to improve coagulation function in severe FXI-deficient plasma, and might provide possibilities for clinical application in the patients with FXI deficiency. This article is protected by copyright. All rights reserved. PMID- 30444569 TI - Genetic determinants of steatosis and fibrosis progression in pediatric non alcoholic fatty liver disease. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison to adult disease, pediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histologic disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n=200) and analyzed in relation to histologic disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with pediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P=2.80*10-06 ), rs1044498 (ENPP1, P=0.0091) and rs780094 (GCKR, P=0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR adjusted P=0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and down-regulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism. This article is protected by copyright. All rights reserved. PMID- 30444570 TI - Platelet Shp2 negatively regulates thrombus stability under high shear stress. AB - BACKGROUND: Perpetuation is the final phase of thrombus formation, however it's mechanisms and regulation are poorly understood. OBJECTIVE: To investigate the mechanism of Shp2 in platelet function and thrombosis. METHODS AND RESULTS: We demonstrate that the platelet-expressed SH2 domain-containing protein-tyrosine phosphatase Shp2 is a negative regulator of thrombus stability under high shear stress. In a ferric chloride-induced mesenteric arteriole thrombosis model, megakaryocyte/platelet-specific Shp2-deficient mice showed less thrombi shedding than wild type mice, although their occlusion times were comparable. In accordance with this in vivo phenotype, a microfluidic whole-blood perfusion assay revealed that the thrombi formed on collagen surfaces by Shp2-deficient platelets were more stable under high shear rates than those produced by wild type platelets. While Shp2 deficiency did not alter the platelet responsiveness towards thrombin-, ADP-, and collagen-stimulation, Shp2-deficient platelets displayed increased dense granule secretion when stimulated by the TXA2 analogue U46619. Shp2 appears to act downstream of integrin alphaIIbbeta3 outside-in signaling, inhibiting the phosphorylation of Akt (Ser473 , Thr308 ) and dense granule secretion. Calmodulin was also shown to bind both Shp2 and Akt, linking Shp2 to Akt activation. CONCLUSIONS: Platelet Shp2 negatively regulates thrombus perpetuation under high shear stress. This signaling pathway may constitute an important mechanism for the prevention of unwanted occlusive thrombus formation, without dramatically interfering with hemostasis. This article is protected by copyright. All rights reserved. PMID- 30444571 TI - Periodontal disease in adults with diabetes, prevalence and risk factors. Results of an observational study. AB - AIM: We sought (a) to assess the association between periodontal disease and diabetes, controlling for socio-demographic characteristics, comorbidities, oral health status and lifestyle variables; (b) to identify which of these variables are independently associated with periodontal disease among diabetes sufferers. METHODS: We conducted a case-control study using data from the National/European Health Interview Surveys, conducted from 2003 to 2014 in Spain. We included 65 295 subjects >=40 years. Diabetes status was self-reported. One non-diabetic control was matched by the year-of-survey, age and sex for each diabetic patient. The presence of periodontal disease was defined using the answer "my teeth bleed spontaneously or while brushing" or/and "my teeth move" to the following question: "Do you suffer of any of these dental and oral disorders or disease?". Independent variables included demographic, socio-economic and healthcare related variables, oral health status and comorbidities. RESULTS: The prevalence of periodontal disease was higher among those suffering from diabetes than their non diabetes controls (23.8% vs 19.5%; P < 0.001). Adjusted OR of periodontal disease for subjects with diabetes was 1.22 (95% CI; 1.03-1.45). Among diabetes sufferers, missing teeth status (OR 2.08, 95% CI; 1.70-2.53), suffering osteoporosis (OR 1.41, 95% CI; 1.07-1.63) and suffering depression (OR 1.39, 95% CI; 1.12-1.71) were positively associated with higher risk of periodontal disease. Older ages, using private insurance and university education level were associated with lower rates of periodontitis. CONCLUSIONS: Diabetes subjects have an increased likelihood of periodontal disease. Dentists and physicians should increase their awareness with their diabetic patients, especially those with lower educational level, with missing teeth, osteoporosis and depression. PMID- 30444572 TI - Improving Drug Delivery of Micellar Paclitaxel against Non-Small Cell Lung Cancer by Coloading Itraconazole as a Micelle Stabilizer and a Tumor Vascular Manipulator. AB - Although polymeric micelles of paclitaxel (PTX) significantly reduce excipient induced toxicity compared with Taxol, they exhibit few clinical advantages in tumor inhibition and overall survival. To improve, itraconazole (ITA), an antifungal drug with potent anti-angiogenesis activity, is co-encapsulated together with PTX within the PEG-PLA micelles. The strong intermolecular interactions between the payloads inhibit drug crystallization and prevent drugs from binding with external proteins, render super-stable micelles upon dilution and exposure to biological environment, and enter the tumor cells through endocytosis. The co-encapsulated micelles show strong anti-proliferation potency against non-small-cell lung cancer (NSCLC) and even PTX resistant NSCLC cells in vitro and significantly improve the drug accumulation within the tumor in vivo. Compared with PTX monotherapy or combination therapy using individual PTX and ITA micelles, the co-encapsulated micelle demonstrates strikingly superior efficacy in tumor growth inhibition, recurrence prevention, and reversion of PTX resistance, in Kras mutant patient derived xenografts, orthotropic models, and paclitaxel-resistance subcutaneous models. Besides the pharmacokinetic improvement, therapeutic benefits are also contributed by angiogenesis inhibition and blood vessel normalization by ITA. Utilizing the pharmaceutical and pharmacological synergies between the therapeutic agents, a simple yet effective design of a combination cancer nanomedicine that is industrially scalable and clinically translatable is achieved. PMID- 30444573 TI - Evolutionary and ecological functional genomics, from lab to the wild. AB - Plant phenotypes are the result of both genetic and environmental forces that act to modulate trait expression. Over the least few years, numerous approaches in functional genomics and systems biology have led to a greater understanding of plant phenotypic variation and plant responses to the environment. These approaches, and the questions that they can address, have been loosely termed evolutionary and ecological functional genomics (EEFG), and have been providing key insights on how plants adapt and evolve. In particular, by bringing these studies from the laboratory to the field, EEFG studies allow us to gain greater knowledge of how plants function in their natural contexts. This article is protected by copyright. All rights reserved. PMID- 30444575 TI - Microsecond Protein Dynamics from Combined Bloch-McConnell and Near-Rotary Resonance R1rho Relaxation-Dispersion MAS NMR. AB - Studying protein dynamics on microsecond-to-millisecond time scales can provide important insight into protein function. In magic-angle-spinning (MAS) NMR, microsecond dynamics can be visualized by R1rho rotating-frame relaxation dispersion experiments in different regimes of radio-frequency field strengths: at low RF field strength, isotropic-chemical-shift fluctuation leads to "Bloch McConnell-type" relaxation dispersion, while when the RF field approaches resonance conditions with the MAS frequency ("Near-Rotary-Resonance Relaxation Dispersion", NERRD), bond angle fluctuations become visible through the dipolar/CSA reorientation. Here we explore the joint analysis of both regimes to gain comprehensive insight into motion in terms of geometric amplitudes, chemical shift changes, populations and exchange kinetics. We use a numerical simulation procedure to illustrate these effects and apply the methodology to gain insight into a previously described conformational exchange process in microcrystalline ubiquitin. PMID- 30444574 TI - Circular Dichroism and Isotropy - Polarity Reversal of Ellipticity in Molecular Films of 1,1'-Bi-2-Naphtol. AB - We have studied the circular dichroism (CD), in the ultraviolet and visible regions, of the transparent, chiral molecule 1,1'-Bi-2-naphtol (BINOL) in 1.5 MUm thick films. The initial transparent film shows an additional negative cotton effect in the CD compared to solution. With time under room temperature the film undergoes a structural phase transition. This goes hand in hand with a cotton effect at the low energy absorption band which inverts with opposite propagation direction of light through the film which is revealed as a polarity reversal of ellipticity (PRE). After completion of the phase transition the film exhibits circular differential scattering throughout the visible range which also shows PRE. The structure change was studied with Raman, microscopy under cross polarization conditions and nonlinear second-harmonic generation circular dichroism (SHG-CD). The superposition of the optical activity of individual molecules and isotropy effects makes an interpretation challenging. Yet overcoming this challenge by finding a suitable model structural information can be derived from CD measurements. PMID- 30444576 TI - A Nanofibrillated Cellulose/Polyacrylamide Electrolyte-Based Flexible and Sewable High-Performance Zn-MnO2 Battery with Superior Shear Resistance. AB - There is a growing demand for flexible and wearable energy devices. How to enhance their tolerance to various mechanical stresses is a key issue. Bending, stretching, or twisting of flexible batteries has been widely researched. However, shear force is inevitably applied on the batteries during stretching, bending, and twisting. Unfortunately, thus far, research on analyzing shear resistance of solid batteries or even enhancing the shear tolerance has never been reported. Herein, a sewable Zn-MnO2 battery based on a nanofibrillated cellulose (NFC)/ployacrylamide (PAM) hydrogel, electrodeposited Zn nanoplates anode, and carbon nanotube (CNT)/alpha-MnO2 cathode is reported. The designed NFC/PAM hydrogel exhibits a relatively high mechanical strength with a large stretchability; the preformed NFC bone network stabilizes the large pores as channels for electrolyte diffusion. Furthermore, the effect of sewing on enhancing the shear resistance of the solid batteries is analyzed. The sewed Zn MnO2 battery retains 88.5% of its capacity after 120 stitches, and withstands a large shear force of 43 N. The sewable and safe Zn-MnO2 is also able to be designed into a skirt and put on a toy as an energy source to power a red light emitting diode. PMID- 30444577 TI - Fluctuations in the Emission Polarization and Spectrum in Single Chains of a Common Conjugated Polymer for Organic Photovoltaics. AB - Measuring the nanoscale organization of conjugated polymer chains used in organic photovoltaic (OPV) blends is vital if one wants to understand the materials. This is made very difficult with high efficiency OPV polymers such as PTB7 that form aggregates, as a lack of periodicity and a high degree of disorder make understanding of the nanoscale organization challenging. Here, single molecule spectroscopy is used to observe single chains and aggregates of PTB7. Using four detectors the photoluminescence intensity, wavelength, polarization, and lifetime are simultaneously monitored. Fast (milliseconds) and slow (seconds) fluctuations are observed over a time window of 30 s in all of these observables from single aggregates and chains as individual chromophores activate and deactivate, leading to dynamical changes in the emission spectrum and dipole orientation. This information can be used to help reconstruct the spatial and spectral organization of disordered aggregates of PTB7, thereby adding valuable new information on how the chains are arranged in space. PMID- 30444578 TI - A New Class of Zn1 -x Fex -Oxyselenide and Zn1- x Fex -LDH Nanostructured Material with Remarkable Bifunctional Oxygen and Hydrogen Evolution Electrocatalytic Activities for Overall Water Splitting. AB - The scalable and cost-effective H2 fuel production via electrolysis demands an efficient earth-abundant oxygen and hydrogen evolution reaction (OER, and HER, respectively) catalysts. In this work, for the first time, the synthesis of a sheet-like Zn1- x Fex -oxyselenide and Zn1- x Fex -LDH on Ni-foam is reported. The hydrothermally synthesized Zn1- x Fex -LDH/Ni-foam is successfully converted into Zn1- x Fex -oxyselenide/Ni-foam through an ethylene glycol-assisted solvothermal method. The anionic regulation of electrocatalysts modulates the electronic properties, and thereby augments the electrocatalytic activities. The as-prepared Zn1- x Fex -LDH/Ni-foam shows very low OER and HER overpotentials of 263 mV at a current density of 20 mA cm-2 and 221 mV at 10 mA cm-2 , respectively. Interestingly, this OER overpotential is decreased to 256 mV after selenization and the HER overpotential of Zn1- x Fex -oxyselenide/Ni-foam is decreased from 238 to 202 mV at 10 mA cm-2 after a stability test. Thus, the Zn1- x Fex -oxyselenide/Ni-foam shows superior bifunctional catalytic activities and excellent durability at a very high current density of 50 mA cm-2 . More importantly, when the Zn1- x Fex -oxyselenide/Ni-foam is used as the anode and cathode in an electrolyzer for overall water splitting, Zn1- x Fex oxyselenide/Ni-foam(+)||Zn1- x Fex -oxyselenide/Ni-foam(-) shows an appealing potential of 1.62 V at 10 mA cm-2 . The anionic doping/substitution methodology is new and serves as an effective strategy to develop highly efficient bifunctional electrocatalysts. PMID- 30444579 TI - Transparent Electronics Using One Binary Oxide for All Transistor Layers. AB - A novel process is developed in which thin film transistors (TFTs) comprising one binary oxide for all transistor layers (gate, source/drain, semiconductor channel, and dielectric) are fabricated in a single deposition system at low temperature. By simply changing the flow ratio of two chemical precursors, C8 H24 HfN4 and (C2 H5 )2 Zn, in an atomic layer deposition system, the electronic properties of the binary oxide (Hf x Zn1- x O2- delta or HZO) are tuned from conducting, to semiconducting, to insulating. Furthermore, by carefully optimizing the properties of the various transistor HZO layers, all-HZO thin film transistors are achieved with excellent performance on both glass and plastic substrates. Specifically, the optimized all-HZO TFTs show a saturation mobility of ~17.9 cm2 V-1 s-1 , low subthreshold swing of ~480 mV dec-1 , high Ion /Ioff ratio of >109 , and excellent gate bias stability at elevated temperatures. In addition, all-HZO inverters with high DC voltage gain (~470), and all-HZO ring oscillators with low stage delay (~408 ns) and high oscillation frequency of 245 kHz are demonstrated. This approach presents a novel, simple, high performance, and cost-effective process for the fabrication of indium-free transparent electronics. PMID- 30444580 TI - Immunogenicity of a bivalent protein as a vaccine against Edwardsiella anguillarum and Vibrio vulnificus in Japanese eel (Anguilla japonica). AB - The OMPs A (OmpA)-of Edwardsiella anguillarum and OmpU of V. vulnificus have been proven to be good antigens. In this study, after construction of a vector, a new recombinant Omp (rOMP) containing both OmpA and OmpU was expressed and purified. Then, the Japanese eels (Anguilla japonica) were intraperitoneally (i.p.) injected with the phosphate-buffered saline (PBS group), formalin-killed-cell (FKC group) or the recombinant Omp (rOMP group). The stimulation index of the whole blood cells in eels from FKC group was significantly higher than the eels from PBS and rOMP groups at 28 dpi; serum titers of anti-E. anguillarum and anti V. vulnificus antibody of eels from FKC and rOMP group increased significantly at 21 and 28 dpi; in the rOMP group, eels serum titer stayed at a high level on 42 dpi. The activities of lysozyme in skin mucus, liver, kidney, and serum in three groups exhibited considerable changes. The relative percent survival (RPS) rate of eels from rOMP group were 100% and 83% when challenged with V. vulnificus or E. anguillarum. These results indicated that inoculation of rOMP would protect Japanese eels against the infection by E. anguillarum and V. vulnificus. PMID- 30444581 TI - A Fluorescent Silver(I) Carbene Complex with Anticancer Properties: Synthesis, Characterization and Biological Studies. AB - The silver(I) NHC (N-heterocyclic carbene) complex bis(1-(anthracen-9-ylmethyl)-3 ethylimidazol-2-ylidene) silver chloride, ([Ag(EIA)2]Cl) hereafter, bearing two anthracenyl fluorescent probes has been synthesized and characterised. [Ag(EIA)2]Cl is stable in organic solvents and under physiological-like conditions, and shows potent cytotoxic effects in vitro toward human SH-SY5Y neuroblastoma cells. The interactions of [Ag(EIA)2]Cl with a few model biological targets have been studied here as well as its ability to be internalized in cells. The in vitro anticancer activity is apparently related to the level of drug internalisation. Notably, [Ag(EIA)2]Cl does not react with a few model proteins, but is capable to bind the C-terminal dodecapeptide of thioredoxin reductase hTrxR(488-499). Binding occurs through an unconventional process leading to covalent binding of one or two carbene ligands to the C-terminal dodecapeptide with concomitant release of the silver cation. This mode of interaction, to the best of our knowledge, is reported here for the first time for Ag(NHC)2 complexes; consequently, a potent enzyme inhibition is measured. PMID- 30444583 TI - Flow Cytometry Instrumentation - An Overview. AB - The term flow cytometry, used since the seventies, describes a technology employed mainly in biology and medicine to measure and classify suspended particles, e.g., cells or microspheres. Measurable cell parameters include: geometric properties, such as cell size (diameter, surface area, volume); physiological properties (membrane potential, integrity, vitality); and quantities of DNA, RNA, cytokines, surface antigens, nuclear antigens, enzymes, and proteins. PMID- 30444582 TI - Encephalitozoon: Tissue Culture, Cryopreservation, and Murine Infection. AB - Microsporidia are eukaryotic unicellular parasites that have been studied for more than 150 years. They are found throughout the world and are capable of infecting various invertebrate and vertebrate hosts. They can cause disease in both immune-compromised and immune-competent humans. In immune-compromised individuals, infections can be severe and often fatal. Microsporidia possess a unique, highly specialized invasion mechanism that involves a structure known as the polar tube as well as the spore wall. During spore germination, the polar tube rapidly discharges from the spore and deliver the sporoplasm into the host cell. Spores are the only stage of microsporidia that can survive outside of host cells. Since the first attempt to culture microsporidia in vitro in 1930s, their cultivation has served a critical role in the study and diagnosis of these parasites. In this chapter, we include methods on the cultivation, isolation, and cryopreservation of Encephalitozoon cuniculi, which can infect humans and provides a useful model for other microsporidia. These methods can also be utilized for the culture of Encephalitozoon hellem or Encephalitozoon intestinalis. (c) 2018 by John Wiley & Sons, Inc. PMID- 30444584 TI - Guideline of prevention and treatment of nonalcoholic fatty liver disease (2018, China). AB - Non-alcoholic fatty liver disease (NAFLD) is an acquired metabolic stress-induced liver disease associated closely with genetic susceptibility and insulin resistance (IR), the spectrum of the disease includes non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH) and related liver cirrhosis, and hepatocellular carcinoma (HCC).1,2 This article is protected by copyright. All rights reserved. PMID- 30444585 TI - [Circulating regulatory T-cells and changes in the subpopulation composition of lymphocytes in colorectal cancer patients]. AB - Data on the frequency of peripheral Treg cells, their functional activity, as well as their relationship to changes in characteristics of cellular immunity in patients with colorectal cancer (CRC, n=42) and healthy donors (n=34) are presented in the article. Assessment of the expression of molecular markers of lymphocytes was performed by multicolor flow cytometry. It was shown that the number of these cells is significantly increased in CRC patients (p<0,05). Probably CD4+CD25+FOXP3+ Treg cells may play a more substantial role in the periphery during the initial period of tumor formation, whereas CD8+FOXP3+ Treg cells are important in the later stages of the disease. In CRC patients, the increase of the functional activity of Treg cells (CD4+CD25+CD127lo/') on the expression of inhibitory molecules CTLA-4 and the marker of cell proliferation Ki 67 was observed. In patients with CRC, the frequency of peripheral Treg cells and the expression level of CTLA-4 were inversely correlated with the number of CD3+CD4+ T-helper cells. PMID- 30444586 TI - [Matrix metalloproteinase-9 in plasma of bone marrow aspirates of patients with acute myeloid leukemia and myelodysplastic syndrome]. AB - There was studied the level of matrix metalloproteinase-9 (MMP-9) in plasma of bone marrow aspirates in 87 patients: 39 with acute myeloid leukemia (AML) and 48 myelodysplastic syndrome (MDS). It has been found out an association of the level of MMP-9 in plasma of bone marrow aspirates in patients with AML and MDS with a volume of leukemic mass. PMID- 30444587 TI - [Determination of a vector of therapy for weakness in incurable breast cancer patients based on the level of inflammatory response]. AB - The weakness is one of the negative factors that degrade cancer patients' quality of life. The nature of weakness may be multifactorial but among mechanisms of development of weakness a syndrome of chronic inflammation plays a crucial role. Therapy aimed at reducing of inflammation degree allows correcting other cancer related symptoms and improving the quality of life of incurable patients. PMID- 30444588 TI - [Pilot clinical and genetic study of Russian patients with Peutz-Jeghers syndrome]. AB - Peutz-Jeghers syndrome is a rare hereditary syndrome characterized by presence of hamartoma polyps in intestinal tract and usually by mucocutaneous pigmentation. Clinical-genetic characteristics of Russian patients with Peutz-Jeghers syndrome were studied for the first time. Four germline mutations in STK11gene were found in probands from six families and three of them had not been described previously. Clinical pattern of disease in Russian patients included: frequent polyposis of colon and stomach (62,5% and 75%, respectively) along with small bowel; frequent presence of malignant tumors (62,5%). These clinical aspects can help physicians to find out Peutz-Jeghers syndrome. Molecular-genetic testing of individuals should be recommended. PMID- 30444589 TI - [Application of GLAD-PCR analysis for the methylation sites detection in the regulatory areas of tumor-suppressor genes ELMo1 and EsR1 in colorectal cancer]. AB - Aberrant methylation of regulation regions of tumorsuppressor genes is showed for many cancer diseases. In course of this modification an enzyme DNMT3 methylates RCGY sites in CpG-islands of regulation regions producing R(5mC)GY sites. Earlier we developed GLAD-PCR assay to determine R(5mC)GY site in a definite position of human genome. In this work we have applied GLAD-PCR assay to determine R(5mC)GY sites in regulation regions of ESR1 and ELMO1 tumor-suppressor genes. We have studied a fragment of first exon of ELMO1 gene and a part of ESR1 promoter region in DNA preparations from malignant cell line SW837 and colorectal tumor samples. We have checked four sites in each region and found two highly methylated sites: GCGC in first exon of ELMO1 gene and GCGT in promoter region of ESR1 gene. Site GCGT is weakly methylated in healthy tissues and more methylated in the most of colorectal samples. Site GCGC is not methylated in healthy tissues and significantly methylated in 60% of colorectal samples. A possibility to use GLAD PCR assay for cancer diagnostics is discussed. PMID- 30444590 TI - [Genome-wide analysis of DNA methylation in prostate cancer using the technology of Infinium HumanMethylation450 BeadChip (HM450)]. AB - Using the technology of DNA chips Infinium HumanMethylation 450 BeadChip it was analyzed quantitative DNA methylation status in 12 paired samples of prostate adenocarcinoma, and morphologically altered tissues. Analysis of differentially methylated regions of the genome showed an association with abnormal status for 21610 and 3852 hypomethylated hyper-methylated CpG sites. Dominance in the cancer genome hypermethylated sites and their predominant localization in the regulatory regions of genes indicate their possible role in the implementation of mechanisms of gene suppression in the pathogenesis of prostate cancer (PCa). For 14 genes studied were characterized array maximum values hypermethylation in promoter region (> 50% CpG sites) in combination with a high level of methylation differences between treatment groups (> 40%). Role of hypermethylation in some of them: AOX1, KLF8, ZNF154, TMEM106A in the pathogenesis of prostate cancer has been showed previously. Hypermethylation of genes ACSS3, TAC1, TUBA4B, ZSCAN12 not previously been shown for prostate cancer, but is characterized by the association with other cancers. In turn, the differences in the levels of methylation in genes GPRASP1, NKX2-6, ARX, CYBA, EPSTI1, RHCG been documented as a result of a number of genome-research oncology, but has not been studied in detail. To assess the diagnostic potential of epigenetic markers of prostate cancer there was carried out unbiased selection of individual CpG sites most reliably discriminate against tumor samples from a group of no tumor samples. In selected diagnostic model based on logistic regression included 9 CpG sites. Validation of the model was carried out on an independent dataset of methylation of 40 paired samples from the prostate cancer project Atlas of Cancer Genome (TCGA) analyzed on the same version of the DNA chip. Summarized rates of diagnostic informativeness of a model (specificity 95%, sensitivity of 97%, the area under the curve of the diagnostic test (ROC) - 0,96), obtained after validation, allow us to consider these CpG Sites as potential markers for molecular diagnosis of prostate cancer. PMID- 30444591 TI - [Creation of a model of HER2/neu-positive transplantable tumor on the immunocompetent mice]. AB - In this study we established a HER2/neu expressing mouse tumor model using hepatoma MH-22a cell line tumorigenic in DBA mice. G10 clone with high level of HER2/neu expression was obtained by stable transfection and cloning. Solid tumors induced by subcutaneous injection of G10 cells into immunocompetent mice retain the expression of human receptor for at least three weeks. Treatment with trastuzumab results in statistically significant inhibition of tumor growth. This model can be used to evaluate in vivo efficiency of novel anti-HER2/neu antibodies and to test antibody-based conjugates for diagnostics. PMID- 30444592 TI - [Oncolytic potential of recombinant influenza A virus vectors on a model of malignant glioma in vivo]. AB - Malignant glioma is the most frequently occurring primary brain tumor. Despite significant progress in the diagnostics and treatment of neoplastic diseases the prognosis for patients with III-IV grade gliomas, remains extremely unfavorable. Rapidly developing area in oncology is the employment of therapeutic viruses with natural or genetically engineered oncolytic activity. In the present study we demonstrated the oncolytic potential of a recombinant influenza A virus vector with impaired interferon antagonism function of NS1 protein in treatment of malignant glioma. Recombinant influenza A virus (HA-DS-GFP) expressing green fluorescent protein from the NS1 open reading frame was used as a model vector. HA-DS-GFP virus has shown infectivity towards glioma cells both in vitro, and in vivo (experimental glioma model in rats). Intratumoral inoculation of HA-DS-GFP resulted in a substantial inhibition or complete regression of tumor growth. Our data demonstrate that recombinant influenza vectors have promising potential in therapy of malignant gliomas. PMID- 30444593 TI - [Melatonin enhances antitumor effect of doxorubicin on a model of transplantable Ehrlich tumor in female sHR mice]. AB - A combined antitumor effect of a single injection of doxorubicin and the indole hormone melatonin was investigated in the model of transplantable Ehrlich carcinoma in female SHR mice. Animals received melatonin either subcutaneous 10 mg/ kg in the evening or with water 10 mg/l at night (from 20 pm to 8 am) for 3 weeks. The results of an experiment showed that combined use of doxorubicin and melatonin both subcutaneous and with water leads to statistically significant inhibition of tumor growth compared with control and doxorubicin alone. PMID- 30444594 TI - [Case of restoration of reproductive function using the method of cryopreservation and autotransplantation of ovarian tissue in a Hodgkin's lymphoma patient]. AB - Recent advances of cancer treatment resulted in the increase of patient survival rate. Treatment for Hodgkin's lymphoma (HL) may impair reproductive function, which leads to a decrease of the quality of life of cancer survival. Today different approaches have been developed for fertility preservation, one of which is the cryopreservation of ovarian tissue with subsequent orthotopic transplantation. We have described a recovery of reproductive function in patient of 28 years with acute ovarian failure, which was induced after cancer treatment. After the orthotopic transplantation cryopreserved ovarian tissue ongoing pregnancy was achieved in the natural cycle after IVF insemination. We have described the first live birth in Russia after the orthotopic transplantation cryopreserved ovarian tissue in cancer patient. This approach has resulted in the recovery of endocrine function without replacement hormonal therapy and possibility for a woman to have her own biological baby. It suggests that cryopreservation of ovarian tissue should be offered to all young women diagnosed with cancer. PMID- 30444595 TI - [Factors affecting survival of radically operated nonsmall cell lung cancer patients of 70 years and older]. AB - It is performed univariate and multivariate analysis of factors affecting the overall cancer survival of 613 patients of 70 years or older radically operated for non-small cell lung cancer. It is found that the main independent predictors of survival are T and N categories. These variables retain their importance in the overall multivariate model both types of survival, and the variable T - in separate multivariate models for samples stratified by category N. The presence of diabetes dramatically reduced both types of survival. Among patients without regional metastases women had a higher survival rate. The age of the operated patients older than 70 years had no significant independent effect on survival. PMID- 30444596 TI - Enhanced Charge Transfer between Fullerene and Non-Fullerene Acceptors Enables Highly Efficient Ternary Organic Solar Cells. AB - Insufficient driving forces defined as the energetic offsets of the frontier molecular orbitals between a donor and an acceptor influence the charge separation in organic solar cells (OSCs), thus restricting the improvement of quantum efficiencies. Herein, we demonstrate that enhancing charge transfer between fullerene and non-fullerene acceptors via ternary strategy is an effective method to address this problem. By introducing an electron acceptor [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as the third component to the binary blends based on the polymer donor of poly[(2,6-(4,8-bis(5-(2-ethylhexyl)-4 fluorothiophen-2-yl)-benzo[1,2- b:4,5- b']dithiophene))- alt-(5,5-(1',3'-di-2 thienyl-5',7'-bis(2-ethylhexyl)benzo[1',2'- c:4',5'- c']dithiophene-4,8-dione)] (PBDB-TF) and the small-molecule acceptor of 2,2'-((2 Z,2' Z)-(((2,5-difluoro-1,4 phenylene)bis(4,4-bis(2-ethylhexyl)-4 H-cyclopenta[2,1- b:3,4- b']dithiophene-6,2 diyl))bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1 H-indene-2,1 diylidene))dimalononitrile (HF-PCIC) or 2,2'-((2 Z,2' Z)-(((2,5-difluoro-1,4 phenylene)bis(4,4-bis(2-ethylhexyl)-4 H-cyclopenta[2,1- b:3,4- b']dithiophene-6,2 diyl))bis(methanylylidene))bis(5,6-dichloro-3-oxo-2,3-dihydro-1 H-indene-2,1 diylidene))dimalononitrile (HC-PCIC) with unfused cores, the quantum efficiencies can be boosted from ~70% for binary blends to over 80% for ternary blends in the longer wavelength ranges. PC71BM shows lower energy levels and higher electron mobility, benefiting the charge transfer and transport in ternary OSCs and resulting in an enhanced quantum efficiency. As a result, ternary OSCs based on PBDB-TF/HF-PCIC/PC71BM and PBDB-TF/HC-PCIC/PC71BM exhibit high power conversion efficiencies (PCEs) of 11.55 and 12.36%, respectively. In addition, excellent thermal stabilities are realized for both ternary OSCs, which retained ~80% initial PCEs after thermal treatment at 130 degrees C for 12 h, indicating that the active layer morphology containing fullerene/non-fullerene acceptors is stabilized. This work demonstrates efficient and thermally stable ternary OSCs with enhanced charge transfer between fullerene and non-fullerene acceptors via the modulation of energy levels, which helps to better understand the working mechanism of ternary OSCs. PMID- 30444597 TI - Fabrication of Morphologically Controlled Composites with High Thermal Conductivity and Dielectric Performance from Aluminum Nanoflake and Recycled Plastic Package. AB - Polymer composites with high thermal conductivity are highly desirable for modern electronic and electrical industry because of their wide range of application. However, conventional polymer composites with high thermal conductivity usually suffer from the deterioration of electrical insulating and high dielectric loss, while on the other hand, polymer composite materials with excellent electrical insulating and dielectric properties usually possess low thermal conductivity. In this study, combining surface oxidized aluminum (Al) nanoflake and multilayer plastic package waste (MPW) by powder mixing technique, a novel strategy for highly thermally conductive, electrically insulating and low dielectric loss polymer composites is reported. The resultant MPW/Al, MPW/Al400 and MPW/Al500 composite exhibited the maximum thermal conductivity of 4.8 W/mK, 3.5 W/mK and 1.4 W/mK respectively, which exceeds most corresponding composites reported previously. In addition, all composite is still highly insulating (<10-13 S/cm) and the dielectric loss maintains at a relatively low level (< 0.025). Such a result is ascribed to the formation of insulating Al2O3 shell and the continuous 3D filler network which revealed by Agari model fitting coefficient. The model of effective medium theory qualitatively demonstrates that the lower interfacial thermal resistances of MPW/Al composite can also benefit the high thermally conductive. This interfacial engineering strategy provides an effectively method for the fabrication of high-performance thermal management polymer materials. PMID- 30444598 TI - Electronic and Geometric Structure, Optical Properties, and Excited State Behavior in Atomically Precise Thiolate-Stabilized Noble Metal Nanoclusters. AB - Ligand-protected noble metal nanoclusters are of interest for their potential applications in areas such as bioimaging, catalysis, photocatalysis, and solar energy harvesting. These nanoclusters can be prepared with atomic precision, which means that their stoichiometries can be ascertained; the properties of these nanoclusters can vary significantly depending on the exact stoichiometry and geometric structure of the system. This leads to important questions such as: What are the general principles that underlie the physical properties of these nanoclusters? Do these principles hold for all systems? What properties can be "tuned" by varying the size and composition of the system? In this Account, we describe research that has been performed to analyze the electronic structure, linear optical absorption, and excited state dynamics of thiolate-stabilized noble metal nanoclusters. We focus primarily on two systems, Au25(SR)18- and Au38(SR)24, as models for understanding the principles underlying the electronic structure, optical properties, luminescence, and transient absorption in these systems. In these nanoclusters, the orbitals near the HOMO-LUMO gap primarily arise from atomic 6sp orbitals located on Au atoms in the gold core. The resulting nanocluster orbitals are delocalized throughout the core of these systems. Below the core-based orbitals lies a set of orbitals that are primarily composed of Au 5d and S 3p atomic orbitals from atoms located around the exterior gold-thiolate oligomer motifs. This set of orbitals has a higher density of states than the set arising from the core 6sp orbitals. Optical absorption peaks in the near-infrared and visible regions of the absorption spectrum arise from excitations between core orbitals (lowest energy peaks) and excitations from oligomer-based orbitals to core-based orbitals (higher energy peaks). Nanoclusters with different stoichiometries have varying gaps between the core orbitals themselves as well as between the band of oligomer-based orbitals and the band of core orbitals. These gaps can slow down nonradiative electron transfer between excited states that have different character; the excited state electron and hole dynamics depend on these gaps. Nanoclusters with different stoichiometries also exhibit different luminescence properties. Depending on factors that may include the symmetry of the system and the rigidity of the core, the nanocluster can undergo large or small nuclear changes upon photoexcitation, which affects the observed Stokes shift in these systems. This dependence on stoichiometry and composition suggests that the size and the corresponding geometry of the nanocluster is an important variable that can be used to tune the properties of interest. How does doping affect these principles? Replacement of gold atoms with silver atoms changes the energetics of the sp and d atomic orbitals that make up the nanocluster orbitals. Silver atoms have higher energy sp orbitals, and the resulting nanocluster orbitals are shifted in energy as well. This affects the HOMO-LUMO gap, the oscillator strength for transitions, the spacings between the different bands of orbitals, and, as a consequence, the Stokes shift and excited state dynamics of these systems. This suggests that nanocluster doping is one way to control and tune properties for use in potential applications. PMID- 30444599 TI - Tandem Analysis by a Dual-Trap Miniature Mass Spectrometer. AB - Miniature mass spectrometers are of an increasing interest for in-situ analyses, and their coupling with the ambient ionization sources is a valid path for direct analysis of complex samples. In this study, a miniature mass spectrometer using discontinuous atmospheric pressure interface was developed with a dual-LIT (linear ion trap) configuration. The comprehensive scan modes were enabled for tandem mass spectrometry analysis, which are critical for high-quality qualitative and quantitative analysis. A real-time pressure control was implemented to facilitate the ion transfer and collision induced dissociation (CID). Beam-type CID could be performed for tandem analysis at a high number of stages. In-trap CID at high q could also be performed with the fragment ions accumulated in a second trap. A precursor ion scan mode for analyzing target analytes has also been demonstrated. PMID- 30444600 TI - Prismatic Deflection of Live Tumor Cells and Cell Clusters. AB - The analysis of heterogeneous subpopulations of circulating tumor cells (CTCs) is critical to enhance our understanding of cancer metastasis and enable noninvasive cancer diagnosis and monitoring. The phenotypic variability and plasticity of these cells-properties closely linked to their clinical behavior-demand techniques that isolate viable, discrete fractions of tumor cells for functional assays of their behavior and detailed analysis of biochemical properties. Here, we introduce the Prism Chip, a high-resolution immunomagnetic profiling and separation chip which harnesses a cobalt-based alloy to separate a flowing stream of nanoparticle-bound tumor cells with differential magnetic loading into 10 discrete streams. Using this approach, we achieve exceptional purity (5.7 log white blood cell depletion) of isolated cells. We test the differential profiling function of the integrated device using prostate cancer blood samples from a mouse xenograft model. Using integrated graphene Hall sensors, we demonstrate concurrent automated profiling of single cells and CTC clusters that belong to distinct subpopulations based on protein surface expression. PMID- 30444601 TI - Hydrogen-Bonded Tannic Acid-Based Anticancer Nanoparticle for Enhancement of Oral Chemotherapy. AB - Oral chemotherapy has been emerging as a hopeful therapeutic regimen for the treatment of various cancers because of its high safety and convenience, lower costs, and high patient compliance. Currently, nanoparticulate drug delivery systems (NDDS) exhibit many unique advantages in mediating oral drug delivery; however, many anticancer drugs that were susceptible in hostile gastrointestinal (GI) environment showed poor permeability across intestinal epithelium, and most materials used as drug carriers are nonactive excipients and displayed no therapeutically relevant function, which leads to low oral bioavailability and therapeutic efficacy of anticancer drugs (e.g., paclitaxel). Inspired by these, in this study, paclitaxel (PTX) was used as a model drug, depending on intermolecular hydrogen-bonded interactions, PTX-loaded tannic acid/poly( N vinylpyrrolidone) nanoparticles (PTX-NP) were produced by a flash nanoprecipitation (FNP) process. The optimized PTX-NP showed an average diameter of 54 nm with a drug encapsulation efficiency of 80% and loading capacity of 14.5%. Molecular dynamics simulations were carried out to illuminate the assembling mechanism of hydrogen-bonded PTX-NP. In vitro and in vivo results confirmed that PTX-NP showed pH-dependent intestinal site-specific drug release, P-gp inhibitory function by tannic acid (TA), prolonged intestinal retention, and improved trans-epithelial transport properties. Oral administration of PTX-NP generated a high oral delivery efficiency and relative oral bioavailability of 25.6% in rats, and further displayed a significant tumor-inhibition effect in a xenograft breast tumor model. These findings confirmed that our PTX-NP might be a promising oral drug formulation for chemotherapy. PMID- 30444602 TI - Zwitterionic Skins with a Wide Scope of Customizable Functionalities. AB - With growing interest in the fields of wearable devices, it is crucial yet rather challenging to develop skinlike soft conductive materials with customizable functionalities and human tissue-compatible mechanical properties. Previously reported electronic skins struggle to meet the demands for transparence, mechanical adaptability, and stable conductivity during deformation. The recent rise of ionic skins with inorganic salts or ionic liquids doping provides the intrinsic stretchability, however, dilemmas remain for their limited functionalities such as a monotonous appearance and a narrow scope of mechanical and sensory properties. Herein, we design a type of zwitterionic hydrogels from the perspective of molecular interactions, which successfully combines ultrastretchability (>10000% strain), high strength (~300 kPa), self-healability (at room temperature within 12 h), 3D printability, distinct stimuli responsibility, biocompatibility, and antibacterial activity. The wide spectrum of such excellent properties has been rarely reported before and along with the ability to fabricate bioinspired intelligent skins recreating multiple sensations and mechanical properties of human skin, covering a broad range of sensitivity, and displaying tunable visual effect. We believe this work will inspire the programming of stimuli-responsive skinlike materials and contribute to the smart devices for information transformation between natural and artificial interfaces. PMID- 30444603 TI - Small, Thin Graphene Oxide Is Anti-inflammatory Activating Nuclear Factor Erythroid 2-Related Factor 2 via Metabolic Reprogramming. AB - Graphene oxide (GO), an oxidized form of graphene, has potential applications in biomedical research. However, how GO interacts with biological systems, including the innate immune system, is poorly understood. Here, we elucidate the effects of GO sheets on macrophages, identifying distinctive effects of GO on the inflammatory phenotype. Small, thin (s)-GO dose-dependently inhibited release of interleukin (IL)-1beta and IL-6 but not tumor necrosis factor alpha. NLRP3 inflammasome and caspase-1 activation was not affected. The effect of s-GO was pretranslational, as s-GO blocked Toll-like receptor 4-dependent expression of Il1b and Il6 but not Nlrp3 or Tnf mRNA transcripts. s-GO was internalized by immortalized bone-marrow-derived macrophages, suggesting a potential intracellular action. Uptake of polystyrene beads with similar lateral dimensions and surface charge did not phenocopy the effects of s-GO, suggesting that s-GO mediated inhibition of interleukin expression was not simply due to particle phagocytosis. RNA-Seq analysis established that s-GO had profound effects on the immunometabolism of the cells, leading to activation of the transcription factor nuclear factor erythroid 2-related factor 2, which inhibited expression of cytokines such as IL-1beta and IL-6. Thus, we have identified immunometabolic effects of GO that reveal another dimension to its effects on cells. These findings suggest that s-GO may be used as a valuable tool to generate further insights into inflammatory mechanisms and indicate its potential applications in biomedicine. PMID- 30444604 TI - Manifestations of Weak O-H...F Hydrogen Bonding in M(H2O) n(B12F12) Salt Hydrates: Unusually Sharp Fourier Transform Infrared nu(OH) Bands and Latent Porosity (M = Mg-Ba, Co, Ni, Zn). AB - Eight M(H2O) n(Z) salt hydrates were characterized by single-crystal X-ray diffraction (Z2- = B12F122-): M = Ca, Sr, n = 7; M = Mg, Co, Ni, Zn, n = 6; M = Ba, n = 4, 5. Weak O-H...F hydrogen bonding between the M(H2O) n2+ cations and Z2 resulted in room-temperature Fourier transform infrared (FTIR) spectra having sharp nu(OH) bands, with full widths at half max of 10-30 cm-1, which are much more narrow than nu(OH) bands in room temperature FTIR spectra of most salt hydrates. Clearly resolved nuasym(OH/OD) and nusym(OH/OD) bands with Deltanu(OH) as small as 17 cm-1 and Deltanu(OD) as small as 11 cm-1 were observed (Deltanu(OX) = nuasym(OX) - nusym(OX)). The isomorphic hexahydrates ( R3) have two fac-(H2O)3 sets of H2O ligands and nearly octahedral coordination spheres. They exhibited four resolvable nu(OH) bands, one nuasym(OH)/nusym(OH) pair for H2O ligands with longer O(H)...F distances and one nuasym(OH)/nusym(OH) pair for H2O ligands with shorter O(H)...F distances. The nu(OH) bands for the three H2O molecules with shorter, slightly stronger O(H)...F hydrogen bonds were broader, more intense, and red-shifted by ca. 25 cm-1 relative to the bands for the three other H2O molecules, the first time that such small differences in relatively weak O(H)...F hydrogen bonds in the same crystalline hexahydrate have resulted in observable IR spectroscopic differences at room temperature. For the first time room temperature nu(OH) values for salt hexahydrates showed the monotonic progression Mg2+ > Co2+ > Ni2+ > Zn2+, essentially the same progression as the p Ka values for these metal ions in aqueous solution. A further manifestation of the weak O-H...F hydrogen bonding in these hydrates is the latent porosity exhibited by Ba(H2O)5,8(Z), Sr(H2O) n,m(Z), and Ca(H2O)4,6(Z). Finally, the H2O/D2O exchange reaction Co(D2O)6(Z) -> Co(H2O)6(Z) was ca. 50% complete in 1 h at 50 degrees C in N2/17 Torr H2O( g). PMID- 30444605 TI - Reversible Switching of the Magnetic Orientation of Titanate Nanosheets by Photochemical Reduction and Autoxidation. AB - Optical properties of aqueous colloidal dispersions of 2D electrolytes, if their aspect ratios are extra-large, can be determined by their orientation preferences. Recently, we reported that a colloidal dispersion of diamagnetic titanate(IV) nanosheets (TiIVNSs), when placed in a magnetic field, is highly anisotropic because TiIVNS anomalously orients its 2D plane orthogonal to the magnetic flux lines due to its large anisotropic magnetic susceptibility. Herein, we report a serendipitous finding that TiIVNSs can be in situ photochemically reduced into a paramagnetic species (TiIV/IIINSs), so that their preference of magnetic orientation changes from orthogonal to parallel. This transition distinctly alters the structural anisotropy and therefore optical appearance of the colloidal dispersion in a magnetic field. We also found that TiIV/IIINSs is autoxidized back to TiIVNSs under non-deaerated conditions. By using an elaborate setup, the dispersion of TiIVNSs serves as an optical switch remotely operable by magnet and light. PMID- 30444606 TI - Searching for Hidden Descriptors in the Metal-Ligand Bond through Statistical Analysis of Density Functional Theory (DFT) Results. AB - A statistical treatment of the DFT-computed heterolytic bond dissociation energies (BDE) between a diverse variety of metal fragments and ligands leads to the identification of five hidden descriptors that best characterize the bonding ability per moiety, and of a simple mathematical formula able to obtain from these hidden descriptors a BDE estimation within a few kcal/mol from the DFT value. A simple extension of this treatment beyond the original set of metal fragments and ligands is also presented. The first two hidden descriptors can be associated with the well-known concepts of sigma-donation and pi-effects, with the next two associated with cis influence and degree of covalency. The procedure can be easily extended to additional ligands and metal fragments, and it opens the way to an improved understanding of fundamental concepts of chemical bonding. PMID- 30444607 TI - Temporal and Reversible Control of a DNAzyme by Orthogonal Photoswitching. AB - The reversible switching of catalytic systems capable of performing complex DNA computing operations using the temporal control of two orthogonal photoswitches is described. Two distinct photoresponsive molecules have been separately incorporated into a split horseradish peroxidase-mimicking DNAzyme. We show that its catalytic function can be turned on and off reversibly upon irradiation with specific wavelengths of light. The system responds orthogonally to a selection of irradiation wavelengths and durations of irradiation. Furthermore, the DNAzyme exhibits reversible switching and retains this ability throughout multiple switching cycles. We apply our system as a light-controlled 4:2 multiplexer. Orthogonally photoswitchable DNAzyme-based catalysts as introduced here have potential use for controlling complex logical operations and for future applications in DNA nanodevices. PMID- 30444608 TI - Aliphatic Azides as Selective Cysteine Labeling Reagents for Integral Membrane Proteins. AB - Upon ultraviolet activation, cannabinergic aliphatic azido (N3) ligands covalently label cannabinoid receptors, prominent G-protein coupled receptor (GPCR) drug targets. We report here the mechanism of covalent attachment to selected substrates of the high-affinity CBR inverse agonist AM1335 and its deuterated analog, AM1335(d10), arylpyrazole compounds with an azide moiety at their n-pentyl side chain. To model the receptor interaction, we synthesized the human cannabinoid 2 receptor (hCB2R) transmembrane helix 6 (TMH6) peptide and an N-acyl-protected cysteine (NAC). The photochemical reaction products of model substrates with AM1335 and AM1335(d10) were analyzed with tandem electrospray ionization-mass spectrometry fragmentation and deuterium exchange mass spectrometry. The nitrene initially formed after photoreaction undergoes rearrangement to an imine which then interacts with the cysteine sulfhydryl group, resulting in ligand attachment. Our results demonstrate that covalent probes carrying aliphatic azides behave more selectively than originally thought and can be used to label protein cysteine residues preferentially. PMID- 30444609 TI - Understanding Degradation Mechanisms and Improving Stability of Perovskite Photovoltaics. AB - This review article examines the current state of understanding in how metal halide perovskite solar cells can degrade when exposed to moisture, oxygen, heat, light, mechanical stress, and reverse bias. It also highlights strategies for improving stability, such as tuning the composition of the perovskite, introducing hydrophobic coatings, replacing metal electrodes with carbon or transparent conducting oxides, and packaging. The article concludes with recommendations on how accelerated testing should be performed to rapidly develop solar cells that are both extraordinarily efficient and stable. PMID- 30444610 TI - Imaging of Receptor Dimers in Zebrafish and Living Cells via Aptamer Recognition and Proximity-Induced Hybridization Chain Reaction. AB - On cell-membrane surfaces, receptor-protein dimers play fundamental roles in many signaling pathways that are crucial for normal biological processes and cancer development. Efficient and sensitive analysis of receptor dimers in the native environment is highly desirable. Herein, we present a strategy for amplified imaging of receptor dimers in zebrafish and living cells that relies on aptamer recognition and proximity-induced hybridization chain reaction. Taking advantage of specific aptamer recognition and enzyme-free signal amplification, this strategy is successfully applied to the visualization of c-Met-receptor dimers in an HGF-independent or -dependent manner. Therefore, the developed imaging strategy paves the way for further investigation of the dimerization or oligomerization states of cell-surface receptors and their corresponding activation processes in zebrafish and living cells. PMID- 30444611 TI - DRomics: a turnkey tool to support the use of the dose-response framework for omics data in ecological risk assessment. AB - Omics approaches (e.g. transcriptomics, metabolomics) are promising for ecological risk assessment (ERA) since they provide mechanistic information and early warning signals. A crucial step in the analysis of omics data is the modelling of concentration-dependency which may have different trends including monotonic (e.g. linear, exponential) or biphasic (e.g. U shape, bell shape) forms. The diversity of responses raises challenges concerning detection and modelling of significant responses and effect concentration (EC) derivation. Furthermore, handling high-throughput datasets is time-consuming and requires effective and automated processing routines. Thus, we developed an open source tool (DRomics, available as an R-package and as a web-based service) which, after elimination of molecular responses (e.g. gene expressions from microarrays) with no concentration-dependency and/or high variability, identifies the best model for concentration-response curve description. Subsequently, an EC (e.g. a benchmark dose) is estimated from each curve and curves are classified based on their model parameters. This tool is especially dedicated to manage data obtained from an experimental design favoring a great number of tested doses rather than a great number of replicates and also to handle properly monotonic and biphasic trends. The tool finally restitutes a table of results that can be directly used to perform ERA approaches. PMID- 30444612 TI - Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation. AB - Enzymatic inhibition has proven to be a successful modality for the development of many small-molecule drugs. In recent years, small-molecule-induced protein degradation has emerged as an orthogonal therapeutic strategy that has the potential to expand the druggable target space. Focal adhesion kinase (Fak) is a key player in tumor invasion and metastasis, acting simultaneously as a kinase and a scaffold for several signaling proteins. While previous efforts to modulate Fak activity were limited to kinase inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously block Fak's kinase signaling and scaffolding capabilities. Here, we report the development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect to Fak activation as well as Fak-mediated cell migration and invasion. These results underline the potential that PROTACs offer in expanding the druggable space and controlling protein functions that are not easily addressed by traditional small-molecule therapeutics. PMID- 30444613 TI - Metal-Rich Oxametallaboranes of Group 5 Metals: Synthesis and Structure of a Face Fused MU7-Boride Cluster. AB - Aerobic oxidation of metallaborane compounds is an unexplored field apart from the few reports on accidental oxidation leading to oxametallaboranes. An effective method for the synthesis of group 5 oxametallaboranes has been developed by the oxidation of [(Cp*M)2(B2H6)2] (M = Ta/Nb) (Cp* = eta5-C5Me5). The reaction of [(Cp*M)2(B2H6)2] (M = Ta/Nb) with O2 gas at room temperature yielded oxametallaboranes [(Cp*M)2(B4H10O)] (for 1, M = Nb; for 2, M = Ta). Density functional theory calculations signify an increase in the HOMO-LUMO energy gap for 1 and 2 as compared to that for the parent metallaboranes, [(Cp*M)2(B2H6)2] (M = Ta/Nb). Reaction of 1 and 2 with [Ru3(CO)12] led to the isolation of fused metallaborane clusters [(Cp*Nb)2(B2H4O){Ru(CO)2}2(B2H4){Ru(CO)3}2{MU-H}4] (3) and [(Cp*Ta)2(B3H4O){Ru(CO)2}3{MU7-B}{MU-CO}2{MU-H}4] (4). The structure of 3 may be considered as a fusion of five subunits [two tetrahedra (Td), two square pyramids (sqp), and one trigonal bipyramid (tbp)]. One of the key features of cluster 4 is the presence of a MU7-boride atom that shares three cluster units (one monocapped trigonal prism and two Td). All the compounds have been characterized by mass spectrometry, infrared spectroscopy, and 1H, 13C, and 11B nuclear magnetic resonance spectroscopy, and the structural types were unequivocally established by crystallographic analysis of compounds 1, 3, and 4. PMID- 30444614 TI - Response to "Determining Allele-Specific Protein Expression (ASPE) Using a Novel Quantitative Concatamer Based Proteomics Method". AB - A recent publication in this journal reported the application of a targeted proteomic strategy using a quantitative concatemer (QconCAT) standard to the assessment of allele-specific expression of UGT2B15 claiming this methodology to be a "novel" approach ( J. Proteome Res. 2018, 17 (10), 3606-3612, DOI: 10.1021/acs.jproteome.8b00620). While the application is not common, the method was previously described and reported by our group in relation to the quantification of CYP2B6 alleles ( J. Proteome Res. 2013, 12 (12), 5934-5942, DOI: 10.1021/pr400279u) to assess the expression of a prevalent polymorphism in a Caucasian population. PMID- 30444615 TI - Gigantic Magnetic Field Effect on the Long-Lived Intermolecular Charge-Separated State Created at the Nonionic Bilayer Membrane. AB - For realization of low-cost organic photon-energy conversion, the supramolecular approach has been a focus of attention as a counter approach to precise synthesis of covalently linked donor (D)-acceptor (A) molecules. Here we report photogeneration of a long-lived (~3 MUs) intermolecular charge-separated (CS) state of metal porphyrins (D) and an alkyl viologen (A) at an interface of a vesicle membrane formed by self-assembly of nonionic surfactant and cholesterol molecules. The yield of escaped free radicals is negligibly low as in the case of CS states in covalently linked D-A systems. Furthermore, the transient concentration of the CS state dramatically increases by ~100% upon application of a magnetic field of 250 mT at room temperature. The simulation of the spin dynamics of the CS state indicates that fast (~107 s-1) spin-selective recombination and slow (105-106 s-1) dissociation-re-encounter dynamics are the key processes for the long CS-state lifetime and the gigantic magnetic field effect. It has turned out that such dynamics are sharply dependent on temperature and alkyl chain length of the viologen. The present results would lead to the development of future materials for light energy conversion, drug delivery, and microscopic bioprobes. PMID- 30444616 TI - Temperature Dependence in the NEXAFS Spectra of n-Alkanes. AB - The near edge X-ray absorption fine structure (NEXAFS) spectra of orthorhombic single crystals of n-octacosane ( n-C28H58), recorded at room temperature (298 K) and at cryogenic temperatures (93 K), show distinct differences. The characteristic carbon 1s -> sigma*C-H band in the NEXAFS spectrum of n-C28H58 is broader and has a lower-energy onset in its room temperature spectrum than in its NEXAFS spectrum recorded at cryogenic temperatures. Density functional theory simulations show that nuclear motion and molecular disorder contribute to the observed spectral broadness and are the origin of the low-energy onset of the C-H band in the room temperature spectrum. PMID- 30444617 TI - The Self-Reaction of ortho-Benzyne at High Temperatures Investigated by Infrared and Photoelectron Spectroscopy. AB - Ortho-benzyne, a Kekule-type biradical is considered to be a key intermediate in the formation of polycyclic aromatic hydrocarbons (PAH) and soot. In the present work we study the ortho-benzyne self-reactions in a hot micro-reactor and identify the high-temperature products by IR/UV spectroscopy and by photoion mass selected threshold photoelectron spectroscopy (ms-TPES) in a free jet. Ms-TPES confirms formation of ortho-benzyne as generated from benzocyclobutendione, as well as benzene, biphenylene, diacetylene and acetylene, originating from the reaction o-C6H4 ? HCC-CCH + C2H2 , and CH3. PAH molecules like naphthalene, 2 ethynylnaphthalene, fluorene, phenanthrene and triphenylene are identified based on their IR/UV spectra. By comparison with recent computations their formation starting from ortho-benzyne can be readily understood and supports the importance of the biradical addition (1,4-cycloaddition followed by fargmenation) pathway to PAH molecules, recently proposed by Comandini et al. PMID- 30444618 TI - Revealing Electron-Phonon Interactions and Lattice Dynamics in Nanocrystal Films by Combining in Situ Thermal Heating and Femtosecond Laser Excitations in 4D Transmission Electron Microscopy. AB - We present a comparative investigation on static equilibrium and transient structural dynamics of nanocrystalline gold films on silicon nitride supports performed at various in situ temperatures and by ultrafast laser excitations in a four-dimensional ultrafast transmission electron microscope (4D-UTEM). The change of relative diffraction intensity and lattice spacing with rising temperatures was systematically measured for {220} Debye-Scherrer rings via the in situ heating technique, which leads to a precise determination of the actual Debye temperature and a finding of significant depression of lattice expansions in the films. The diffraction intensity/lattice spacing-temperature relationship calibrated by the static, thermally equilibrium observations was then employed for investigating ultrafast transient dynamics on the same specimen region. The electron-phonon coupling constant g was determined to be 7.2 * 1015 W/m3 K in combination with simple two-temperature model analysis. We found a marked variation of temperature rise maximum (at quasi-equilibrium states) in between the temporal evolutions of lattice spacing and diffraction intensity, a phenomenon which may only be explained by the effect of nonthermal equilibrium relaxation dynamics following femtosecond laser excitations. The method demonstrated here can thus be applied to quantitative evaluations of nonthermal equilibrium contributions during the electron-lattice thermalization. PMID- 30444619 TI - Nickel/Briphos-Catalyzed Direct Transamidation of Unactivated Secondary Amides Using Trimethylsilyl Chloride. AB - Direct transamidation of secondary amides was developed via nickel catalysis. In the presence of trimethylsilyl chloride and manganese, Ni(diglyme)Cl2 with a Briphos ligand efficiently promoted the transamidation of N-aryl benzamide derivatives with primary amines to afford the corresponding secondary amides in moderate to good yields. Primary amines bearing electron-donating groups gave higher yields of the transamidation products. PMID- 30444620 TI - Competition of F/OH-Induced SN2 and Proton-Transfer Reactions with Increased Solvation. AB - The potential energy profiles of F/OH-induced nucleophilic substitution (SN2) and proton-transfer (PT) channels evolving with solvation for reactions of F-(H2O) n=1-2 + CH3I were characterized using B3LYP/ECP/d method. The hydrogen-bonded F (H2O) n---HCH2I prereaction complex at the entrance of potential energy surface (PES) has a significant role on the reaction dynamics for each channel. Among the above three channels, the F-SN2 channel is the most preferred and OH-SN2 could be competitive. In contrast, the PT channel will occur at much higher collision energy. Importantly, for each channel, the central barrier is gradually increased with the addition of water molecules. This phenomenon indicates that the reactivity will decrease with degrees of solvation and this has been confirmed by experiment and direct dynamics simulations. Moreover, compared with the previous trajectory simulations, a non-IRC behavior has been uncovered. The water delivering process from fluorine to iodine side as illustrated on PES is barely observed, and instead, the reaction tends to dehydrate before passing through the SN2 barrier and proceeds with the less hydrated pathway in order to weaken the steric effect. The work presented here shows the comprehensive potential energy surfaces and structures information on the F-SN2, PT, and OH-SN2 channels, and predict their competitive relationship, which would be helpful for better understanding the dynamics behavior of the title and analogous reactions. PMID- 30444621 TI - Mechanical stability of surface nanobubbles. AB - Bubble cavitation is important in technologies such as non-invasive cancer treatment and diagnosis, surface cleaning, and waste-water treatment. The cavitation threshold is the critical external tensile pressure that induces unstable growth of the bubble. Surface nanobubbles have been previously shown experimentally to be stable down to -6 MPa, in disagreement with the Blake threshold, which is the classical cavitation model that predicts bulk bubbles with radii ?100 nm should be unstable below -0.6 MPa. Here we use Molecular Dynamics to simulate quasi-2D and 3D nitrogen surface nanobubbles immersed in water, subject to a range of pressure drops until unstable growth is observed. We propose and assess new cavitation threshold models, derived from mechanical equilibrium analyses for both the quasi-2D and 3D cavitating bubbles. The discrepancies from the Blake threshold are attributed to the pinned contact line, within which the surface nanobubbles grow with constant lateral contact diameter, and consequently a reduced radius of curvature. We conclude with discussion of previous experimental results on the cavitation of relatively large surface nanobubbles. PMID- 30444622 TI - Bandgap Engineered Polypyrrole-Polydopamine Hybrid with Intrinsic Raman and Photoacoustic Imaging Contrasts. AB - Intrinsically multimodal nanomaterials have revealed their great potential as a new class of contrast agents. We herein report a bandgap engineering strategy to develop an intrinsically Raman-photoacoustic (PA) active probe that is based on semiconducting conjugated polymers. This dual modal probe is prepared by doping a semiconducting conjugated polymer with polydopamine (PDA) through a one-pot reaction. When applied in the polypyrrole (PPy), this strategy can enhance Raman scattering and the PA amplitude of PPy-PDA hybrid by 3.2 and 2.4 times, respectively, so that both signals can be further applied in bioimaging. In the hybrid, such a dual-enhancement effect is achieved by infusing these two macromolecules at the nanoscale to reduce the optical bandgap energy. This work not only introduces a dual modal contrast agent but also provides a new method of manipulating semiconducting polymer's inherent optical features for bioimaging. PMID- 30444623 TI - Reconciling Structural and Spectroscopic Fingerprints of the Oxygen-Evolving Complex of Photosystem II: A Computational Study of the S2 State. AB - The catalytic cycle of photosynthetic water oxidation occurs at the Mn4CaO5 oxygen-evolving complex (OEC) of photosystem II. Extensive spectroscopic data have been collected on the intermediates, especially the S2 (Kok) state, although the proton and electron inventories (Mn oxidation states) are still uncertain. The "high oxidation" paradigm assigns S2 Mn oxidation level (III, IV, IV, IV) or (IV, IV, IV, III), whereas a "low oxidation" paradigm posits two additional electrons. Here, we investigate the geometric (X-ray diffraction, extended X-ray absorption fine structure) and spectroscopic (electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR)) properties of the S2 state using quantum chemical density functional theory calculations, focusing on the neglected low paradigm. Two interconvertible electronic spin configurations are predicted as ground states, producing multiline ( S = 1/2) and broad ( S = 5/2) EPR signals in the low paradigm oxidation state (III, IV, III, III) and with W2 as OH- and O5 as OH-. They have "open" ( S = 5/2) and "closed" ( S = 1/2) Mn3CaO4 cubane geometries. Other energetically accessible isomers with ground spin states 1/2, 7/2, 9/2, or 11/2 can be obtained through perturbations of hydrogen-bonding networks (e.g., H+ from His337 to O3 or W2), consistent with experimental observations. Conformers with the low oxidation state configuration (III, IV, IV, II) also become energetically accessible when the protonation states are O5 (OH ), W2 (H2O), and neutral His337. The configuration with (III, IV, III, III) agrees well with earlier low-temperature EPR and ENDOR interpretations, whereas the MnII-containing configuration agrees partially with recent ENDOR data. However, the low oxidation paradigm does not yield isotropic ligand hyperfine interactions in good agreement with observed values. We conclude that the low Mn oxidation state proposal for the OEC can closely fit most of the available structural and electronic data for S2 at accessible energies. PMID- 30444624 TI - Nanoparticle-Induced Controlled Drug Delivery Using Chitosan-Based Hydrogel and Scaffold: Application to Bone Regeneration. AB - The novel chitosan nanohybrid hydrogel and scaffold have been developed with high mechanical strength and tailor the drug release ability for their applications in the biomedical arena. Nanohybrid hydrogels are prepared in dilute acetic acid medium using two different types of two-dimensional-layered nanoparticles. Scaffolds are prepared through lyophilization of hydrogels. Highly porous, open, and 3D interconnected morphologies are observed in the nanohybrid scaffolds, as opposed to the thick wall, smaller pore dimension in pure chitosan. The interaction between the nanoparticles and chitosan chains are elucidated using different spectroscopic techniques, which in turn are responsible for the uniform distribution of the nanoparticle in the chitosan matrix. Nanohybrids are found to be highly mechanically stable in both states (hydrogel and scaffold), as compared to pure chitosan because of the good reinforcing ability of 2D nanoparticles. Sustained drug release has been achieved in nanohybrid in vitro, as compared to the pure chitosan hydrogel/scaffold, mainly due to greater interactions between the components and the better barrier effect of 2D nanoparticles. Cytotoxicity of the nanohybrids is verified using NIH 3T3 mouse embryonic fibroblast cells for their possible use as controlled drug delivery vehicles. Nanohybrids are found to be nontoxic in nature and more biocompatible as compared to pure chitosan, as observed through cell viability and cell imaging studies. Interestingly, cell growth occurs within the pores of the nanohybrid scaffold, vis-a-vis the surface proliferation noticed in the pure chitosan scaffold. Better biocompatibility, hydrophilic nature, and sustained delivery with location specific cell growth make this nanohybrid hydrogel unique for biomedical uses. The bone regeneration rate is found to be significantly higher for the nanohybrid scaffold as compared to blank/pure chitosan without any side effect, suggesting nanohybrid systems are superior biomaterials. PMID- 30444625 TI - Exploring the Reactivity of Hydrofluoropolyethers Towards OH Through a Cost Effective Protocol for Calculating Multiconformer Transition State Theory Rate Constants. AB - In this work we propose a cost-effective protocol for the calculation of rate constants within the framework of multiconformer transition state theory. We have developed this methodology while calculating for the first time on a theoretical level rate constants for a series of six reactions between the OH radical and hydrofluoropolyethers: the latter are promising third-generation CFC replacements whose atmospheric impact is still widely unknown. Our investigation, which is based on computationally accessible M08-HX/apcseg-2//M08-HX/pcseg-1 calculations, shows that two of our rate constants are within a factor of 0.6 and 1.4 of experimental data, a good result that probably benefits from some error cancellation. It also exhibits a reactivity trend, for which we provide detailed insights that could be used to shed new light on the general reactivity of ethers towards OH. Finally, because the studied reactions share an ubiquitous mechanism in atmospheric chemistry, we hope that our protocol can be routinely applied to explore the reactivity of computationally challenging reactions and to pave new ways in the development of greener CFC replacements. PMID- 30444626 TI - A Quantum Impurity Rotator in a Matrix of Quantum Rotors: EPR Dynamics of CH3 in Solid CD4 Matrix. AB - The rotational dynamics and the geometry of a light and flexible impurity molecule like methyl, matrix isolated in van-der-Waals solid, are supposed to be sensitive to the host molecule dynamics and order alterations of the matrix. In addition, the location of the impurity and its interaction with the matrix molecules is of prime importance. Large energy gaps between rotation levels of quantum rotators allow precise investigation of temperature assisted quantum tunneling effects. The molecular rotation of methyl radicals isolated in the deuteriated solid methane isotopomer, CD4, was investigated both by experimental and theoretical EPR methods. The reduction of the quantum rotation frequency evident from the EPR spectrum of methyl radical at liquid-He temperatures was explained and connected to the irregular ratio between the central doublet to the outer quartet hf transitions. The involvement of temperature in the alteration of methyl symmetry between the C3 and D3 groups and the molecular host-host and guest -host interaction strengths were also examined by constructing temperature profiles of the rotation correlation times in the three phases of solid methane. The present study proves the deep impact that a van-der-Waals matrix may have on the geometry and the rotation levels of a substitutionally trapped quantum impurity rotor, effects that are yet very little known. This close correlation between dynamics of an impurity particle and the matrix molecules has great potential in developing sensitive physicochemical probes for van-der-Waals solids. PMID- 30444627 TI - Construction of Azepino[2,3- b]indole Core via Sulfur Ylide Mediated Annulations. AB - A novel [4 + 3] annulation of indoline-based aza-dienes and crotonate-derived sulfur ylides is described. This method could be further expanded by using more efficient synthetic strategies, including three-component [3 + 1 + 3] cascade and the direct sulfide-catalyzed [4 + 3] cyclization. These protocols enable the rapid construction of azepino[2,3- b]indole cores, and a broad spectrum of the desired products with diverse substituents was facilely accessed in generally high yield. PMID- 30444628 TI - Synthesis of Functionalized Diaryl Sulfides by Cobalt-Catalyzed Coupling between Arylzinc Pivalates and Diaryl Disulfides. AB - An efficient protocol for the cobalt-catalyzed preparation of diaryl sulfides from solid organozinc pivalates and commercially available diaryl disulfides is reported. This cross-coupling proceeds at room temperature and displays a good functional group tolerance, allowing the preparation of a diversity of symmetrical or asymmetrical diaryl sulfides in 60-95% yield. PMID- 30444629 TI - Silver-Catalyzed tert-Butyl 3-Oxopent-4-ynoate pi-Cyclizations: Controlling the Ring Size-Hydroxypyrone or Pulvinone Formation-by Counterion and Additive Optimization. AB - tert-Butyl 2,5-diaryl-3-oxopent-4-ynoates, obtained from arylacetylenes and the acid chloride of tert-butyl 2-phenylmalonate, represent strongly enolized beta ketoesters. Their C=C bonds were activated by Ag(I) salts so that de- tert butylating pi-cyclizations occurred. The latter followed a 6- endo- dig mode giving 3,6-diaryl-4-hydroxy-2-pyrones, or a 5- exo- dig mode giving ( Z) configured 2-aryl-4-(arylmethylidene)tetronic acids ("pulvinones"). Perfectly selective pyrone formations were induced by AgSbF6 in methanol and equally selective pulvinone formations by Ag2CO3 and DABCO in acetonitrile. PMID- 30444630 TI - Highly Cytotoxic Ruthenium(II)-Arene Complexes from Bulky 1-Pyrenylphosphane Ligands. AB - In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(eta6-arene)Cl2(PR1R2(1 pyrenyl))] (eta6-arene = p-cymene and R1 = R2 = methyl for 1; eta6-arene = methylbenzoate and R1 = R2 = methyl for 2; eta6-arene = p-cymene and R1 = R2 = phenyl for 3; eta6-arene = methylbenzoate and R1 = R2 = phenyl for 4; eta6-arene = p-cymene, R1 = methyl and R2 = phenyl for 5; eta6-arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC50 values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1-6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G2/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells. PMID- 30444631 TI - Three Weaknesses for Three Perturbations: Comparing Protein Unfolding under Shear, Force and Thermal Stresses. AB - The perturbation of a protein conformation by a physiological fluid flow is crucial in various biological processes including blood clotting and bacterial adhesion to human tissues. Investigating such mechanisms by computer simulations is thus of great interest but it requires to develop ad hoc strategies to mimic the complex hydrodynamic interactions acting on the protein from the surrounding flow. In this study, we apply the Lattice Boltzmann Molecular Dynamics (LBMD) technique built on the implicit solvent coarse-grained model for protein OPEP and a mesoscopic representation of the fluid solvent, to simulate the unfolding of a small globular cold shock protein in shear flow, and to compare it to the unfolding mechanisms caused either by mechanical or thermal perturbations. We show that each perturbation probes a specific weakness of the protein, and causes the disruption of the native fold along different unfolding pathways. Notably, the shear flow and the thermal unfolding exhibit very similar pathways, while because of the directionality of the perturbation, the unfolding under force is quite different. For force and thermal disruption of the native state, the coarse grained simulations are compared to all-atom simulations in explicit solvent, showing an excellent agreement in the explored unfolding mechanisms. These findings encourages the use of LBMD based on the OPEP model to investigate how a flow can affect the function of larger proteins, e.g. in catch-bond systems. PMID- 30444632 TI - CORRIGENDUM. PMID- 30444633 TI - Corrigendum. PMID- 30444634 TI - CORRIGENDUM. PMID- 30444635 TI - A comparison of student performance and satisfaction between a traditional and integrative approach to teaching an introductory radiology course on the extremities. AB - OBJECTIVE:: The purpose of the study was to compare student performance and student satisfaction ratings for an introductory extremities radiology course taught using 2 different educational methods. METHODS:: One group of students was taught using a traditional face-to-face instruction method, and the other group received an integrative blended-learning approach. A multivariate analysis of scores on lecture and laboratory examinations was performed to detect differences in student performance between the 2 methods. An independent t test was performed to compare the final course averages between the 2 methods. chi2 Analysis was used to compare the distribution of letter grades and levels of satisfaction between the 2 groups. RESULTS:: Test scores were higher for the integrative approach than for the traditional face-to-face method ( p < .05). However, the differences were not meaningful, as the greatest improvement in correct responses was only for 2 questions. Students appeared to be more satisfied with the integrative approach when compared to the traditional method ( p < .05). CONCLUSION:: Student satisfaction with the educational delivery methods in an introductory extremities radiology course using an integrative approach was greater than for the traditional face-to-face instruction method. Student performance was similar between the 2 cohorts. PMID- 30444636 TI - A mixed-method study of chiropractic student clinical immersion placements in nonmetropolitan Western Australia: Influence on student experience, professional attributes, and practice destination. AB - OBJECTIVE:: To explore the influence of nonmetropolitan clinical immersion placements (CIPs) on undergraduate chiropractic student experience, professional attributes, and practice destination. METHODS:: Students enrolled in an Australian undergraduate chiropractic program were invited to complete a service experience questionnaire and an open-ended reflective feedback form following a nonmetropolitan CIP (Part A). Online searches were performed to gather data on graduate practice location (Part B). RESULTS:: Sixty-four students participated in Part A. All agreed that the placement was educational and should be retained in the program. Students agreed that the placement enhanced respect for individuals and awareness of others in need, highlighted the importance of respect for all people, improved empathy for the disadvantaged, and provided an opportunity to improve communication skills. Most indicated that they were more likely to practice in a country setting as a result of their placement, with those participating in a country placement more likely to practice in nonmetropolitan regions after graduation. CONCLUSION:: Many chiropractic programs around the world are adopting CIPs. This study is the 1st to investigate the possible influence of nonmetropolitan CIPs on the development of desirable attributes in Australian chiropractic students. It also discusses the potential influence of nonmetropolitan CIPs on future practice location decisions. These results support the utility of CIPs to help meet the educational objectives of chiropractic programs and possibly address the maldistribution of the chiropractic workforce in Australia. PMID- 30444638 TI - CORRIGENDUM. PMID- 30444637 TI - Quantum Mechanical Tunnelling Through the Catalytic Effects of A2451 Ribosomal Residue During a Stepwise Peptide Bond Formation. AB - The search for the mechanism of ribosomal peptide bond formation is still ongoing. Even though the actual mechanism of peptide bod formation is still a dilemma, the dominance of proton transfer in this reaction is known for certain. Therefore, it is vital to take the quantum mechanical effects on proton transfer reaction into consideration, the effects of which were neglected in all previous studies. In this study, we have taken such effects into consideration using a semi-classical approach to the overall reaction mechanism. The DFT functional M06 2X/6-31++G(d,p) is used to calculate the energies of the critical points on the potential energy surface of the reaction mechanism, which are then used in transition state theory to calculate the classical reaction rate. The tunnelling contribution is then added to the classical part by calculating the transmission permeability and tunnelling constant of the reaction barrier using the numerical integration over the Boltzmann distribution for the symmetrical Eckart potential. The results of this study which accounts for quantum effects indicates that the A2451 ribosomal residue induces proton tunnelling in a stepwise peptide bond formation. PMID- 30444639 TI - Corrigendum. PMID- 30444640 TI - CORRIGENDUM. PMID- 30444641 TI - Biomedical Explanations of Psychopathology and Their Implications for Attitudes and Beliefs About Mental Disorders. AB - Mental disorders are increasingly conceptualized as biomedical diseases, explained as manifestations of genetic and neurobiological abnormalities. Here, we discuss changes in the dominant explanatory accounts of psychopathology that have occurred over time and the driving forces behind these shifts, lay out some real-world evidence for the increasing ascendancy of biomedical explanations, and provide an overview of the types of attitudes and beliefs that may be affected by them. We examine theoretical and conceptual models that are relevant to understanding how biomedical conceptualizations might affect attitudes and beliefs about mental disorders, and we review some empirical evidence that bears on this question. Finally, we examine possible strategies for combatting potential negative effects of biomedical explanations and discuss important conclusions and directions for future research. Expected final online publication date for the Annual Review of Clinical Psychology Volume 15 is May 7, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30444642 TI - Blood Pressure Levels Among Indigenous Children Living at Different Altitudes. AB - OBJECTIVE: To compare blood pressure (BP) levels in two groups of indigenous Argentine school children from similar ethnic backgrounds but living at different altitudes. METHODS: 152 (46.3%) children (age 4-14 years) from San Antonio de los Cobres (SAC), at 3750 m above sea level, and 176 children (53.7%) from Chicoana (CH), at 1400 m, participated in this cross-sectional study. Data for children's anthropometry, BP, glucose, lipids, vitamin D, and insulin, as well as mothers' height and weight, were assessed. Hypertension was defined as BP >=95th percentile. RESULTS: The prevalence of overweight/obesity among children was significantly lower in SAC (n=17, 11.2%) than in CH (n=74, 42%) (BMI >85th percentile per US Centers for Disease Control and Prevention norms). However, the prevalence of hypertension was significantly higher among children in SAC (n=15, 9.9%) than among those in CH (n=2, 1.1%). Children were divided into 4 groups by mean arterial BP quartiles for comparison by analysis of variance. As mean arterial BP increased, age, BMI, glucose, triglycerides, triglycerides/ HDL-C, and insulin levels increased significantly. Multiple linear regression analyses showed that children's mean arterial BP was significantly associated with altitude adjusted for confounding variables (R2=0.42). Furthermore, when mean arterial BP was replaced by systolic BP (R2=0.51) or diastolic BP (R2=0.33), similar results were obtained. CONCLUSIONS: Our results suggest that indigenous children who live permanently at high altitude have higher levels of BP, adjusted for confounding variables. Routine BP measurements conducted in the SAC community could be essential for the prevention of cardiovascular disease. PMID- 30444643 TI - CORRIGENDUM. PMID- 30444644 TI - Higher energy and carbohydrate demand of interval training at a given average velocity on track vs. treadmill. AB - We tested the hypothesis that due to acceleration and deceleration the energy and carbohydrate demand are higher in interval training on a track than on a treadmill. Ten male subjects performed the same interval training on a treadmill and an outdoor track. A higher energy and carbohydrate demand on the track, emphasizes that treadmill interval studies analyzing high numbers of short lasting interval bouts are not transferable to interval running on a track. PMID- 30444645 TI - Corrigendum. PMID- 30444646 TI - A SGLT2 inhibitor dapagliflozin comparison with insulin exerts important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress. AB - Sodium-glucose cotransporter 2 (SGLT2)-inhibitors showed significant effect in patients with diabetes or metabolic syndrome, MetS with high cardiovascular-risk. Although the increased intracellular Zn2+ level ([Zn2+]i), oxidative stress and alterated cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important role in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2-inhibitor dapagliflozin (DAP) on cardiac Zn2+-transporters responsible from [Zn2+]i-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative stress-status in MetS-rats. High-carbohydrated diet-induced MetS-rats received DAP or INS for two weeks. DAP but not INS in MetS-rats significantly decreased high blood-glucose level, while both treatments exerted benefits on increased total-oxidative-status and decreased total-antioxidant-status in MetS-rat plasma as well as in heart tissue. Protein levels of Zn2+-transporters, responsible from Zn2+-influx into cytosol, ZIP7 and ZIP14 were decreased with no change in ZIP8 of MetS-rat cardiomyoctes, while Zn2+-transporters, responsible from cytosolic Zn2+ efflux, ZnT7 was decreased. Both treatments induced significant beneficial effects on altered ZIP14, ZIP8 and ZnT7 levels. Furthermore, both treatments exerted also benefits on depressed gelatin-zymography and protein expression levels of MMP-2 and MMP-9 in MetS-rat ventricular cardiomyocytes. The direct effect of DAP on heart was also confirmed with measurement of left ventricular developed pressure. Overall, we showed that DAP has important antioxidant-like cardio-protective effect in MetS-rats, similar to INS-effect, affecting Zn2+ regulation via Zn2+-transporters, MMPs and oxidative-stress. Therefore one can suggest that SGLT2-inhibitors can be new therapeutic agents for cardio-protection not only in hyperglycemia but also in failing heart. PMID- 30444647 TI - Oxidized Lipids: Not just another brick in the wall. AB - Over the past decade there has been intense investigation in trying to understand the pathological role that oxidized phospholipids play in cardiovascular disease. Phospholipids are targets for oxidation, particularly during conditions of excess free radical generation. Once oxidized, they acquire novel roles uncharacteristic of their precursors. Oxidized phosphatidylcholines have an important role in multiple physiological and pathophysiological conditions including atherosclerosis, neurodegenerative diseases, lung disease, inflammation, and chronic alcohol consumption. Circulating oxidized phosphatidylcholine may also serve as a clinical biomarker. The focus of this review, therefore, will be to summarize existing evidence that oxidized phosphatidylcholine molecules play an important role in cardiovascular pathology. PMID- 30444649 TI - Corrigendum. PMID- 30444648 TI - CircRNAs constitute an inherent gene-regulatory axis in the mammalian eye and brain. AB - CircRNAs are a new class of covalently closed transcripts that are produced via back-splicing. These molecules have been identified in organisms ranging from worm to plants. Research on circRNAs is an active area because of their diverse roles in health and in diseases. Their circularity makes them resistant to degradation thus they hold great promise as unique biomarkers. We believe that further work on their applications could help in developing them as "first-in class" diagnostics, therapeutics, and prognostic targets for eye conditions. Many circRNAs play roles in transcriptional regulation by acting as miRNAs sponges. Since retina is an extension of brain and is part of CNS, we highlight the current state of circRNA biogenesis, properties and function and we review the crucial roles they play in the eye and brain. We also discuss their roles as miRNA sponges, regulation of genes or linear mRNAs, translation into micro peptides/proteins, and responses to cellular stress. We posit that future advances will provide newer insights in the fields of RNA metabolism in general and diseases of the aging eye and brain. Furthermore, in keeping pace with the rapidly evolving discipline of RNA'omics'-centered metabolism and to achieve uniformity among researchers, we recently introduced the term "cromics". PMID- 30444650 TI - Evolutionary Responses to Conditionality in Species Interactions across Environmental Gradients. AB - The outcomes of many species interactions are conditional on the environments in which they occur. Often, interactions grade from being more positive under stressful or low-resource conditions to more antagonistic or neutral under benign conditions. Here, we take predictions about two well-supported ecological theories on conditionality-limiting resource models and the stress-gradient hypothesis-and combine them with those from the geographic mosaic theory of coevolution (GMTC) to generate predictions for systematic patterns of adaptation and coadaptation between partners along abiotic gradients. When interactions become more positive in stressful environments, mutations that increase fitness in one partner may also increase fitness in the other; because fitnesses are aligned, selection should favor greater mutualistic adaptation and coadaptation between interacting species in stressful ends of environmental gradients. As a corollary, in benign environments antagonistic coadaptation could result in Red Queen or arms-race dynamics or the reduction of antagonism through character displacement and niche partitioning. Here, we distinguish between generally mutualistic or antagonistic adaptation (i.e., mutations in one partner that have similar effects across multiple populations of the other) and specific adaptations to sympatric partners (local adaptation), which can occur either alone or simultaneously. We then outline the kinds of data required to test these predictions, develop experimental designs and statistical methods, and demonstrate these using simulations based on GMTC models. Our methods can be applied to a range of conditional outcomes and may also be useful in assisted translocation approaches in the face of climate change. PMID- 30444651 TI - Secretary's Report, 2018: American Society of Naturalists. PMID- 30444652 TI - "Her Joyous Enthusiasm for Her Life-Work ...": Early Women Authors in The American Naturalist. AB - Women have long been underrepresented in the natural sciences, and although great progress has been made in recent decades, many subtle and not-so-subtle barriers persist. In this context, it is easy to get the impression that the early history of ecology and evolutionary biology was exclusively the domain of male researchers. In fact, a number of women made very substantial contributions to The American Naturalist in its first decades. In a follow-up to a series of retrospective essays celebrating 150 years of this journal, we highlight the scientific contributions of the women published in it during its first 50 years (1867-1916). We also discuss the diverse paths that their scientific careers took and the barriers they faced along the way. PMID- 30444653 TI - Purring Crickets: The Evolution of a Novel Sexual Signal. AB - Opportunities to observe contemporary signal change are incredibly rare but critical for understanding how diversity is created and maintained. We discovered a population of the Pacific field cricket (Teleogryllus oceanicus) with a newly evolved song (purring), different from any known cricket. Male crickets use song to attract females from afar and to court females once near. Teleogryllus oceanicus is well known for sexual signal evolution, as exemplified by a recent signal loss. In this study, we characterized the new purring sound and investigated the role of the purr in long-distance and short-distance communication. The purring sound differed from typical ancestral calls in peak frequency, amplitude, and bandwidth. Further, the long-distance purring song facilitated mate location, though the role of courtship purring song is less clear. Our discovery of purring male crickets is an unprecedented opportunity to watch the emergence of a newly evolved sexual signal unfold in real time and has potential to illuminate the mechanisms by which evolutionary novelties arise and coevolve between the sexes. PMID- 30444655 TI - Treasurer's Report, 2017: Statement of Activities For the year ending December 31, 2017. PMID- 30444654 TI - Genetic Quality Affects the Rate of Male and Female Reproductive Aging Differently in Drosophila melanogaster. AB - Males and females often maximize fitness by pursuing different reproductive strategies, with males commonly assumed to benefit more from increased resource allocation into current reproduction. Such investment should trade off with somatic maintenance and may explain why males frequently live shorter than females. It also predicts that males should experience faster reproductive aging. Here we investigate whether reproductive aging and life span respond to condition differently in male and female Drosophila melanogaster, as predicted if sexual selection has shaped male and female resource-allocation patterns. We manipulate condition through genetic quality by comparing individuals inbred or outbred for a major autosome. While genetic quality had a similar effect on condition in both sexes, condition had a much larger general effect on male reproductive output than on female reproductive output, as expected when sexual selection on vigor acts more strongly on males. We find no differences in reproductive aging between the sexes in low condition, but in high condition reproductive aging is relatively faster in males. No corresponding sex-specific change was found for life span. The sex difference in reproductive aging appearing in high condition was specifically due to a decreased aging rate in females rather than any change in males. Our results suggest that females age slower than males in high condition primarily because sexual selection has favored sex differences in resource allocation under high condition, with females allocating relatively more toward somatic maintenance than males. PMID- 30444656 TI - Metabolic Theory and the Temperature-Size Rule Explain the Temperature Dependence of Population Carrying Capacity. AB - The temperature dependence of highly conserved subcellular metabolic systems affects ecological patterns and processes across scales, from organisms to ecosystems. Population density at carrying capacity plays an important role in evolutionary processes, biodiversity, and ecosystem function, yet how it varies with temperature-dependent metabolism remains unclear. Though the exponential effect of temperature on intrinsic population growth rate, r, is well known, we still lack clear evidence that population density at carrying capacity, K, declines with increasing per capita metabolic rate, as predicted by the metabolic theory of ecology (MTE). We experimentally tested whether temperature effects on photosynthesis propagate directly to population carrying capacity in a model species, the mobile phytoplankton Tetraselmis tetrahele. After maintaining populations at a fixed resource supply and fixed temperatures for 43 days, we found that carrying capacity declined with increasing temperature. This decline was predicted quantitatively when models included temperature-dependent metabolic rates and temperature-associated body-size shifts. Our results demonstrate that warming reduces carrying capacity and that temperature effects on body size and metabolic rate interact to determine how temperature affects population dynamics. These findings bolster efforts to relate metabolic temperature dependence to population and ecosystem patterns via MTE. PMID- 30444657 TI - Natural Selection on Antihelminth Antibodies in a Wild Mammal Population. AB - An effective immune response is expected to confer fitness benefits through improved resistance to parasites but also incur energetic costs that negatively impact fitness-related traits, such as reproduction. The fitness costs and benefits of an immune response are likely to depend on host age, sex, and levels of parasite exposure. Few studies have examined the full extent to which patterns of natural selection on immune phenotypes vary across demographic groups and environments in the wild. Here, we assessed natural selection on plasma levels of three functionally distinct isotypes (IgA, IgE, and IgG) of antibodies against a prevalent nematode parasite measured in a wild Soay sheep population over 26 years. We found little support for environment-dependent selection or reproductive costs. However, antibody levels were negatively associated with parasite egg counts and positively associated with subsequent survival, albeit in a highly age- and isotype-dependent manner. Raised levels of antiparasite IgA best predicted reduced egg counts, but this did not predict survival in lambs. In adults increased antiparasite IgG predicted reduced egg counts, and in adult females IgG levels also positively predicted overwinter survival. Our results highlight the potential importance of age- and sex-dependent selection on immune phenotypes in nature and show that patterns of selection can vary even among functionally related immune markers. PMID- 30444659 TI - The Cost of Being Big: Local Competition, Importance of Dispersal, and Experimental Evolution of Reversal to Unicellularity. AB - Multicellularity provides multiple benefits. Nonetheless, unicellularity is ubiquitous, and there have been multiple cases of evolutionary reversal to a unicellular organization. In this article, we explore some of the costs of multicellularity as well as the possibility and dynamics of evolutionary reversals to unicellularity. We hypothesize that recently evolved multicellular organisms would face a high cost of increased competition for local resources in spatially structured environments because of larger size and increased cell densities. To test this hypothesis we conducted competition assays, computer simulations, and selection experiments using isolates of Saccharomyces cerevisiae that recently evolved multicellularity. In well-mixed environments, multicellular isolates had lower growth rates relative to their unicellular ancestor because of limitations of space and resource acquisition. In structured environments with localized resources, cells in both multicellular and unicellular isolates grew at a similar rate. Despite similar growth, higher local density of cells in multicellular groups led to increased competition and higher fitness costs in spatially structured environments. In structured environments all of the multicellular isolates rapidly evolved a predominantly unicellular life cycle, while in well-mixed environments reversal was more gradual. Taken together, these results suggest that a lack of dispersal, leading to higher local competition, might have been one of the main constraints in the evolution of early multicellular forms. PMID- 30444658 TI - Transgenerational and Within-Generation Plasticity in Response to Climate Change: Insights from a Manipulative Field Experiment across an Elevational Gradient. AB - Parental environmental effects-or transgenerational plasticity-can influence an individual's phenotype or fitness yet remain underexplored in the context of global change. Using the perennial self-pollinating plant Boechera stricta, we explored the effects of climate change on transgenerational and within-generation plasticity in dormancy, germination, growth, and survival. We first conducted a snow removal experiment in the field, in which we transplanted 16 families of known origin into three common gardens at different elevations and exposed half of the siblings to contemporary snow dynamics and half to early snow removal. We planted the offspring of these individuals in a factorial manipulation of temperature and water level in the growth chamber and reciprocally transplanted them across all parental environments in the field. The growth chamber experiment revealed that the effects of transgenerational plasticity persist in traits expressed after establishment, even when accounting for parental effects on seed mass. The field experiment showed that transgenerational and within-generation plasticity can interact and that plasticity varies clinally in populations distributed across elevations. These findings demonstrate that transgenerational plasticity can influence fitness-related traits and should be incorporated in studies of biological responses to climate change. PMID- 30444660 TI - A Comparative Study of the Role of Sex-Specific Condition Dependence in the Evolution of Sexually Dimorphic Traits. AB - Sexual selection can displace traits acting as ornaments or armaments from their viability optimum in one sex, ultimately giving rise to sexual dimorphism. The degree of dimorphism should not only mirror the strength of sexual selection but also the net viability costs of trait maintenance at equilibrium. As the ability of organisms to bear exaggerated traits will depend on their condition, more sexually dimorphic traits should also exhibit greater sex differences in condition dependence. While this has been demonstrated among traits within species, similar patterns are expected across the phylogeny. We investigated this prediction within and across 11 (sub)species of sepsid flies with varying mating systems. When estimating condition dependence for seven sexual and nonsexual traits that vary in their sexual dimorphism, we not only found a positive relationship between the sex difference in allometric slopes (our measure of condition dependence) and relative trait exaggeration within species but also across species for those traits expected to be under sexual selection. Species with more pronounced male aggression further had relatively larger and more condition-dependent male fore- and midlegs. Our comparative study suggests a common genetic/developmental basis of sexual dimorphism and sex-specific plasticity that evolves across the phylogeny-and that the evolution of size consistently alters scaling relationships and thus contributes to the allometric variation of sexual armaments or ornaments in animals. PMID- 30444661 TI - Multiscale Immune Selection and the Transmission-Diversity Feedback in Antigenically Diverse Pathogen Systems. AB - Antigenic diversity is commonly used by pathogens to enhance their transmission success. Within-host clonal antigenic variation helps to maintain long infectious periods, whereas high levels of allelic diversity at the population level significantly expand the pool of susceptible individuals. Diversity, however, is not necessarily a static property of a pathogen population but in many cases is generated by the very act of infection and transmission, and it is therefore expected to respond dynamically to changes in transmission and immune selection. We hypothesized that this coupling creates a positive feedback whereby infection and disease transmission promote the generation of diversity, which itself facilitates immune evasion and further infections. To investigate this link in more detail, we considered the human malaria parasite Plasmodium falciparum, one of the most important antigenically diverse pathogens. We developed an individual based model in which antigenic diversity emerges as a dynamic property from the underlying transmission processes. Our results show that the balance between stochastic extinction and the generation of new antigenic variants is intrinsically linked to within-host and between-host immune selection. This in turn determines the level of diversity that can be maintained in a given population. Furthermore, the transmission-diversity feedback can lead to temporal lags in the response to natural or intervention-induced perturbations in transmission rates. Our results therefore have important implications for monitoring and assessing the effectiveness of disease control efforts. PMID- 30444662 TI - Eco-Evolutionary Dynamics in Metacommunities: Ecological Inheritance, Helping within Species, and Harming between Species. AB - Understanding selection on intra- and interspecific interactions that take place in dispersal-limited communities is a challenge for ecology and evolutionary biology. The problem is that local demographic stochasticity generates eco evolutionary dynamics that are generally too complicated to make tractable analytical investigations. Here we circumvent this problem by approximating the selection gradient on a quantitative trait that influences local community dynamics, assuming that such dynamics are deterministic with a stable fixed point. The model nonetheless captures unavoidable kin selection effects arising from demographic stochasticity. Our approximation reveals that selection depends on how an individual expressing a trait change influences (1) its own fitness and the fitness of its current relatives and (2) the fitness of its downstream relatives through modifications of local ecological conditions (i.e., through ecological inheritance). Mathematically, the effects of ecological inheritance on selection are captured by dispersal-limited versions of press perturbations of community ecology. We use our approximation to investigate the evolution of helping within species and harming between species when these behaviors influence demography. We find that altruistic helping evolves more readily when intraspecific competition is for material resources rather than for space, because in this case the costs of kin competition tend to be paid by downstream relatives. Similarly, altruistic harming between species evolves when it alleviates downstream relatives from interspecific competition. Beyond these examples, our approximation can help better understand the influence of ecological inheritance on a variety of eco-evolutionary dynamics in metacommunities, from consumer-resource and predator-prey coevolution to selection on mating systems with demographic feedbacks. PMID- 30444663 TI - Corrigendum. PMID- 30444664 TI - Enhanced nitric oxide signaling amplifies vasorelaxation of human colon cancer feed arteries. AB - Inadequate perfusion of solid cancer tissue results in low local nutrient and O2 levels and accumulation of acidic waste products. Previous investigations focused primarily on tumor blood vessel architecture and we lack information concerning functional differences between arteries that deliver blood to solid cancer tissue versus normal tissue. Here, we use isometric myography to study resistance-sized arteries from human primary colon adenocarcinomas and matched normal colon tissue. Vasocontraction of colon cancer feed arteries in response to endothelin-1 and thromboxane stimulation is attenuated compared to normal colon arteries despite similar wall dimensions and comparable contractions to arginine vasopressin and K+-induced depolarization. Acetylcholine-induced vasorelaxation and endothelial NO-synthase expression are increased in colon cancer feed arteries compared to normal colon arteries, whereas vasorelaxation to exogenous NO-donors is unaffected. In congruence, the differences in vasorelaxant and vasocontractile function between colon cancer feed arteries and normal colon arteries decrease after NO-synthase inhibition. Rhythmic oscillations in vascular tone-known as vasomotion-are of lower amplitude but similar frequency in colon cancer feed arteries compared with normal colon arteries. In conclusion, higher NO-synthase expression and elevated NO signaling amplify vasorelaxation and attenuate vasocontraction of human colon cancer feed arteries. We propose that enhanced endothelial function augments tumor perfusion and represents a potential therapeutic target. PMID- 30444665 TI - Pulmonary Hemodynamic and Right Ventricular Responses to Brief and Prolonged Exercise in Middle-Aged Endurance Athletes. AB - AIMS: Right ventricular (RV) function is closely coupled to pulmonary arterial (PA) hemodynamics and is believed to decline with prolonged exercise. A linear pressure-flow relationship is thought to exist between PA pressures and increasing exercise intensity in athletes, yet a paucity of directly-measured pulmonary hemodynamic data exists supporting this contention. We sought to describe the PA, PA wedge pressure (PAWP), and RV functional response to brief and prolonged exercise in endurance-trained athletes. METHODS AND RESULTS: Twenty one healthy athletes (54+/-5 years) underwent right heart catheterization to assess pulmonary hemodynamics during graded, submaximal exercise. Measurements were made at rest and during three stages of steady-state semi-upright cycle ergometry at heart rates of 100 bpm (EX1), 130 bpm (EX2) and 150 bpm (EX3). Five athletes completed an additional 34 minutes at 130 bpm for a total exercise time of 60 minutes (PLG). PA pressures and PAWP increased significantly at EX1, without further rise at EX2, EX3 or PLG. PAWP adjusted for absolute workrate demonstrated a significant decline as exercise intensity increased from EX1 to EX2. RpCp-time decreased at EX1 without further change at EX2, EX3 and PLG. RV function did not decline during prolonged exercise. CONCLUSION: Following an initial rise in PA and PAWP during early, non-steady state exercise, values remain constant despite increases in exercise intensity and duration. These data indicate that in healthy, middle-aged endurance athletes, the PA and pulmonary venous/left atrial compartments rapidly accommodate high conduit flows produced during intensive and prolonged exercise while maintaining RV function. PMID- 30444666 TI - Perspectives of Health Care Payer Organizations on Cancer Care Delivery Redesign: A National Study. AB - INTRODUCTION:: Despite advancements in cancer care, persistent gaps remain in the delivery of high-value end-of-life cancer care. The aim of this study was to examine views of health care payer organization stakeholders on approaches to the redesign of end-of-life cancer care delivery strategies to improve care. METHODS:: We conducted semistructured interviews with 34 key stakeholders (eg, chief medical officers, medical directors) in 12 health plans and 22 medical group organizations across the United States. We recorded, transcribed, and analyzed interviews using the constant comparative method of qualitative analysis. RESULTS:: Participants endorsed strategies to redesign end-of-life cancer care delivery to improve end-of-life care. Participants supported the use of nonprofessionals to deliver some cancer services through alternative formats (eg, telephone, Internet) and delivery of services in nonclinical settings. Participants reported that using nonprofessional providers to offer some services, such as goals of care discussions and symptom assessments, via telephone in community-based settings or in patients' homes, may be more effective and efficient ways to deliver high-value cancer care services. Participants described challenges to redesign, including coordination with and acceptance by oncology providers and payment models required to financially support clinical changes. Some participants suggested solutions, including providing funding and logistic support to encourage implementation of care delivery innovations and to financially reward practices for delivery of high value end-of-life cancer care services. CONCLUSION:: Stakeholders from payer organizations endorsed opportunities to redesign cancer care delivery, and some are willing to provide logistic, design, and financial support to practices interested in improving end-of-life cancer care. PMID- 30444667 TI - Corrigendum. PMID- 30444668 TI - QOPI Certification Roadmap. PMID- 30444669 TI - Corrigendum. PMID- 30444670 TI - Corrigendum. PMID- 30444671 TI - Pupillary Contagion in Autism. AB - Pupillary contagion is an involuntary change in the observer's pupil size in response to the pupil size of another person. This effect, presumed to be an important adaption for individuals living in groups, has been documented in both typical infants and adults. Here, for the first time, we report pupillary contagion in individuals with autism, a disorder of social communication. We found that, compared with a typical group ( n = 63), individuals with autism ( n = 54) exhibited comparable pupillary contagion when observing pictures of emotional faces, despite less spontaneous attention toward the eye region. Furthermore, the magnitude of the pupillary response in the autism group was negatively correlated with time spent fixating the eye region. The results suggest that even with less looking toward the eyes, individuals with autism respond to the affective and arousal levels transmitted from other individuals. These results are discussed in the context of an overarousal account of socioaffective-processing differences in autism. PMID- 30444672 TI - Safety evaluation of Adalimumab in immune-mediated inflammatory disorders: a rheumatological point of view. AB - INTRODUCTION: Immune-Mediated Inflammatory Disorders (IMIDs) are systemic conditions which arise secondary to complex immune mechanism defects and can affect many organs. While previous therapies based on steroids and immunosuppressive agents had a poor risk/benefit balance, TNFalpha specific inhibitors such as adalimumab have revolutionised the course of many diseases and patient outcomes. However, concerns were raised regarding the increased risk of infectious diseases and neoplasia due to potential prospective loss of immune control. This is especially true when considering that IMIDs concerns elderly/frail populations, with multiple co-morbidities, organ damage and often long-term steroid therapy. Areas covered: Now prescribed for more than 15 years for a diverse range of indications, long-term data highlighting the efficacy and safety are available and led to recommendations for the daily practice that will be discussed. Expert opinion: The efficacy of adalimumab changed the therapeutic paradigm of many diseases. Its tolerance is good and it is the most widely prescribed therapy in many IMIDs. It is now the standard of care arm in head to head trials. In the long term, adalimumab dominant role might be weakened by more targeted therapies but its varied indications among IMIDs should secure its position as an important tool in our practice for years to come. PMID- 30444673 TI - Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States. AB - Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (>= 94.8%), DTaP-HBV-IPV+ HibA (>= 98.1%) or DTaP-IPV/Hib+ HBV (>= 97.8%) groups. We observed robust immune responses post booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines. PMID- 30444674 TI - KOOS-JR Demonstrates Psychometric Limitations in Measuring Knee Health in Individuals After ACL Reconstruction. AB - BACKGROUND:: Measurement properties of the short form of the Knee injury and Osteoarthritis Outcome Score (KOOS-JR) are not established in individuals after anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to determine the extent to which the KOOS-JR measures the construct of knee health in individuals post-ACLR using Rasch analysis. HYPOTHESIS:: The KOOS-JR will fit the Rasch model, but significant ceiling effects will be present. STUDY DESIGN:: Cross-sectional study. LEVEL OF EVIDENCE:: Level 3. METHODS:: Rasch analysis of the KOOS-JR from 166 individuals 10 months post-ACLR was conducted. Unidimensionality, a key criterion of the Rasch model, was evaluated using confirmatory factor analysis. Model fit of the rating scale, items, and persons were evaluated. Mean square fit statistics >=1.6 and standardized z-scores >=2.0 were indicative of person or item misfit. Additionally, reliability indicators including person reliability and separation indices were examined. RESULTS:: The KOOS-JR fit the criteria of unidimensionality. All items demonstrated model fit; however, ceiling effects were noted (n = 36; 22%). Person reliability was low (0.47). Calculation of person strata revealed that the KOOS-JR did not separate participants into more than 1 stratum. The mean person measure was 3.56 logits higher than the mean item measure, indicating that this sample is skewed toward increased knee health. CONCLUSION:: Although the KOOS-JR represented a unidimensional construct with items and persons fitting the Rasch model, several limitations were noted: ceiling effects, low person reliability, and poor person differentiation. Ceiling effects indicate that many individuals in this sample experienced better knee health than the KOOS-JR items were able to measure. CLINICAL RELEVANCE:: Evaluating the measurement properties of the KOOS-JR is necessary to determine its clinical value in sports medicine. In later stages after ACLR recovery, administration of the KOOS-JR may not be adequate. PMID- 30444676 TI - Corrigendum. PMID- 30444675 TI - Vaccination and risk of lone atrial fibrillation in the active component United States military. AB - PURPOSE: To evaluate the hypothesis that receipt of anthrax vaccine adsorbed (AVA) increases the risk of atrial fibrillation in the absence of identifiable underlying risk factors or structural heart disease (lone atrial fibrillation). METHODS: We conducted a retrospective population-based cohort study among U.S. military personnel who were on active duty during the period from January 1, 1998 through December 31, 2006. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify individuals diagnosed with atrial fibrillation in the Defense Medical Surveillance System, and electronic records were screened to include only individuals without evidence of predisposing medical conditions. We used multivariable Poisson regression to estimate the risk of lone atrial fibrillation after exposure to AVA. We also evaluated possible associations with influenza and smallpox vaccines. RESULTS: Our study population consisted of 2,957,091individuals followed for 11,329,746 person-years of service. Of these, 2,435 met our case definition for lone atrial fibrillation, contributing approximately 8,383 person-years of service. 1,062,176 (36%) individuals received at least one dose of AVA; the median person time observed post-exposure was 3.6 years. We found no elevated risk of diagnosed lone atrial fibrillation associated with AVA (adjusted risk ratio = 0.99; 95% confidence interval = 0.90, 1.09; p = 0.84). No elevated risk was observed for lone atrial fibrillation associated with influenza or smallpox vaccines given during military service. CONCLUSIONS: We did not find an increased risk of lone atrial fibrillation after AVA, influenza or smallpox vaccine. These findings may be helpful in planning future vaccine safety research. PMID- 30444677 TI - Incidence of Concussion and Head Impacts in Australian Elite-Level Male and Female Cricketers After Head Impact Protocol Modifications. AB - BACKGROUND:: Concussion in sport is a topic of growing interest in Australia and worldwide. To date, relatively few studies have examined the true incidence of concussion in cricket. HYPOTHESIS:: Concussion in cricket is more common than current literature suggests. STUDY DESIGN:: Descriptive epidemiology study. LEVEL OF EVIDENCE:: Level 4. METHODS:: This is a prospective registry and subsequent analysis of head impacts and concussions in elite-level male and female cricketers in Australia over 2 seasons (2015-2016 and 2016-2017). A total of 172 male and 106 female domestic and international players in 2015-2016 and 179 males and 98 females in 2016-2017 were included. RESULTS:: There were 92 head impacts (29 concussions) in men's matches and 15 head impacts (8 concussions) in women's matches. Match incidence rates per 1000 player days were 7.2 head impacts (2.3 concussions) in elite male cricket and 3.7 head impacts (2.0 concussions) in elite female cricket. This equates to a head impact every 2000 balls and concussion every 9000 balls in male domestic cricket. Concussion rates per 1000 player-match hours were 0.4 for elite males and 0.5 for elite females; 53% of head impacts in females were diagnosed as concussions compared with 32% in males, and 83% of concussions resulted in missing no more than 1 game. CONCLUSION:: The rate of concussion in cricket is higher than previously appreciated; however, the majority of patients recovered quickly, and players generally did not miss much playing time as a result. The institution of concussion policies after head impact, including player substitution, appears to have had an effect on increasing reporting of symptoms, resulting in an increase in diagnosis of concussion. CLINICAL RELEVANCE:: Concussion in cricket is not as infrequent as previously assumed. Ongoing review of the rules and regulations is required to ensure that protection of player welfare lies in parallel with other sporting codes. PMID- 30444678 TI - Corrigendum. PMID- 30444680 TI - Corrigendum. PMID- 30444679 TI - Corrigendum. PMID- 30444682 TI - FISHing for the Miracle of Eicosapentaenoic Acid. PMID- 30444681 TI - Tracking Colisteners' Knowledge States During Language Comprehension. AB - When we receive information in the presence of other people, are we sensitive to what they do or do not understand? In two event-related-potential experiments, participants read implausible sentences (e.g., "The girl had a little beak") in contexts that rendered them plausible (e.g., "The girl dressed up as a canary for Halloween"). No semantic-processing difficulty (no N400 effect) ensued when they read the sentences while alone in the room. However, when a confederate was present who did not receive the contexts so that the critical sentences were implausible for him or her, participants exhibited processing difficulty: the social-N400 effect. This effect was obtained when participants were instructed to adopt the confederate's perspective-and critically, even without such instructions-but not when performing a demanding comprehension task. Thus, unless mental resources are limited, comprehenders engage in modeling the minds not only of those individuals with whom they directly interact but also of those individuals who are merely present during the linguistic exchange. PMID- 30444683 TI - alpha4beta7 integrin inhibitors: a patent review. AB - INTRODUCTION: The alpha4beta7 integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM 1) is an exclusive ligand for alpha4beta7 integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of alpha4beta7 integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: alpha4beta7 integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of alpha4-subunit blocking both alpha4beta1 and alpha4beta7 integrin. Vedolizumab selectively targets the alpha4beta7 integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the beta7-subunit and AMG-181 specifically against the alpha4beta7 integrin are the most promising anti-alpha4beta7 integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective alpha4beta7 integrin inhibitors. PMID- 30444684 TI - Aligning Programs and Policies to Support Food Security and Public Health Goals in the United States. AB - Food insecurity affects 1 in 8 US households and has clear implications for population health disparities.We present a person-centered, multilevel framework for understanding how individuals living in food-insecure households cope with inadequate access to food themselves and within their households, communities, and broader food system. Many of these coping strategies can have an adverse impact on health, particularly when the coping strategies are sustained over time; others may be salutary for health. There exist multiple opportunities for aligning programs and policies so that they simultaneously support food security and improved diet quality in the interest of supporting improved health outcomes. Improved access to these programs and policies may reduce the need to rely on individual- and household-level strategies that may have negative implications for health across the life course. Expected final online publication date for the Annual Review of Public Health Volume 40 is April 1, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. PMID- 30444685 TI - SELECT: A Phase II Trial of Adjuvant Erlotinib in Patients With Resected Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer. AB - PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC. MATERIALS AND METHODS: In this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2 year disease-free survival (DFS) greater than 85%, improving on historic data of 76%. RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months. CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit. PMID- 30444686 TI - Defining Risk Factors for Chemotherapeutic Intervention in Infants With Stage 4S Neuroblastoma: A Report From Children's Oncology Group Study ANBL0531. AB - PURPOSE: Infants with stage 4S neuroblastoma usually have favorable outcomes with observation or minimal chemotherapy. However, young infants with symptoms secondary to massive hepatomegaly or with unfavorable tumor biology are at high risk of death. Our aim was to improve outcomes for patients with symptomatic and/or unfavorable biology 4S neuroblastoma with a uniform treatment approach using a biology- and response-based algorithm. PATIENTS AND METHODS: The subset of patients with 4S disease with MYCN-not amplified tumors with impaired or impending organ dysfunction, or with unfavorable histology and/or diploid DNA index, were eligible. Patients were assigned to receive two, four, or eight cycles of chemotherapy on the basis of histology, diploid DNA index, chromosome arm 1p or 11q loss of heterozygosity (LOH) status, and symptoms. RESULTS: Forty nine eligible patients were enrolled: 41 were symptomatic and 28 had unfavorable biology. Seventeen patients (symptomatic, favorable biology) were assigned two cycles, 21 patients (any unfavorable biologic feature without 1p or 11q LOH) were assigned four cycles, and 11 patients (unfavorable biology including 1p and/or 11q LOH [n = 7] or symptomatic with unknown biology [n = 4]), were assigned eight cycles. The 3-year overall survival was 81.4% +/- 5.8%. Eight of nine deaths were in patients younger than 2 months of age at diagnosis (median, 9 days [range, 1 to 68 days]): five acute deaths were a result of hepatomegaly and associated toxicities; two were a result of late relapse in patients with unfavorable biology; and two were a result of treatment complications. No deaths occurred after protocol-mandated pre-emptive treatment of infants younger than 2 months with hepatomegaly, regardless of symptoms. A new scoring algorithm for emergent chemotherapy in patients with 4S disease was developed on the basis of this experience. CONCLUSION: The outcome for 4S neuroblastoma can be improved with pre emptive chemotherapy for evolving hepatomegaly or other baseline comorbidities in infants younger than 2 months of age. PMID- 30444687 TI - Effect of Simulated Pulpal Microcirculation on Temperature When Light Curing Bulk Fill Composites. AB - OBJECTIVES:: To evaluate the effect of light curing bulk fill resin composite restorations on the increase in the temperature of the pulp chamber both with and without a simulated pulpal fluid flow. METHODS AND MATERIALS:: Forty extracted human molars received a flat occlusal cavity, leaving approximately 2 mm of dentin over the pulp. The teeth were restored using a self-etch adhesive system (Clearfil SE Bond, Kuraray) and two different bulk fill resin composites: a flowable (SDR, Dentsply) and a regular paste (AURA, SDI) bulk fill. The adhesive was light cured for 20 seconds, SDR was light cured for 20 seconds, and AURA was light cured for 40 seconds using the Bluephase G2 (Ivoclar Vivadent) or the VALO Cordless (Ultradent) in the standard output power mode. The degree of conversion (DC) at the top and bottom of the bulk fill resin composite was assessed using Fourier-Transform Infra Red spectroscopy. The temperature in the pulp chamber when light curing the adhesive system and resin composite was measured using a J type thermocouple both with and without the presence of a simulated microcirculation of 1.0-1.4 mL/min. Data were analyzed using Student t-tests and two-way and three-way analyses of variance (alpha=0.05 significance level). RESULTS:: The irradiance delivered by the light-curing units (LCUs) was greatest close to the top sensor of the MARC resin calibrator (BlueLight Analytics) and lowest after passing through the 4.0 mm of resin composite plus 2.0 mm of dentin. In general, the Bluephase G2 delivered a higher irradiance than did the VALO Cordless. The resin composite, LCU, and region all influenced the degree of cure. The simulated pulpal microcirculation significantly reduced the temperature increase. The greatest temperature rise occurred when the adhesive system was light cured. The Bluephase G2 produced a rise of 6 degrees C, and the VALO Cordless produced a lower temperature change (4 degrees C) when light curing the adhesive system for 20 seconds without pulpal microcirculation. Light curing SDR produced the greatest exothermic reaction. CONCLUSIONS:: Using simulated pulpal microcirculation resulted in lower temperature increases. The flowable composite (SDR) allowed more light transmission and had a higher degree of conversion than did the regular paste (AURA). The greatest temperature rise occurred when light curing the adhesive system alone. PMID- 30444688 TI - Effects of Enzymatic Activation of Bleaching Gels on Hydrogen Peroxide Degradation Rates, Bleaching Effectiveness, and Cytotoxicity. AB - OBJECTIVES:: The aim of this study was to evaluate the effect of horseradish peroxidase (HRP) on the release of free radicals, bleaching effectiveness, and indirect cytotoxicity of a 35% hydrogen peroxide (HP) bleaching gel. METHODS AND MATERIALS:: First, HP degradation rates and free radical release were evaluated for 35% HP in contact or not with HRP (10 mg/mL). The bleaching gel associated or not with HRP was then applied (3 * 15 minutes) to enamel/dentin discs adapted to artificial pulp chambers, and the culture medium in contact with dentin surfaces (extract) was collected and exposed to cultured odontoblast-like cells. Membrane damage and viability of cells as well as oxidative stress were evaluated. Residual HP/free radical diffusion was quantified, and bleaching effectiveness (DeltaE) was assessed. Unbleached discs served as negative controls. RESULTS:: The addition of HRP to the 35% HP bleaching gel enhanced the release of free radicals in comparison with plain HP gel. The 35% HP-mediated cytotoxicity significantly decreased with HRP in the bleaching gel and was associated with reduced HP/free radical diffusion through the enamel/dentin discs. DeltaE values increased every bleaching session for HRP-containing gel relative to positive control, accelerating the whitening outcome. CONCLUSION:: The enzymatic activation of a 35% HP bleaching gel with HRP accelerated HP degradation mediated by intensification of free radical release. This effect optimized whitening outcome as well as minimized residual HP and free radical diffusion through enamel and dentin, decreasing the harmful effects on odontoblast-like cells. PMID- 30444689 TI - Controlling In Vivo, Human Pulp Temperature Rise Caused by LED Curing Light Exposure. AB - OBJECTIVE:: The objective of this study was to evaluate the in vivo effectiveness of air spray to reduce pulp temperature rise during exposure of intact premolars to light emitted by a high-power LED light-curing unit (LCU). METHODS AND MATERIALS:: After local Ethics Committee approval (#255945), intact, upper first premolars requiring extraction for orthodontic reasons from five volunteers received infiltrative and intraligamental anesthesia. The teeth (n=9) were isolated using rubber dam, and a minute pulp exposure was attained. The sterile probe from a wireless, NIST-traceable, temperature acquisition system was inserted directly into the coronal pulp chamber. Real-time pulp temperature (PT) ( degrees C) was continuously monitored, while the buccal surface was exposed to a polywave LED LCU (Bluephase 20i, Ivoclar Vivadent) for 30 seconds with simultaneous application of a lingually directed air spray (30s-H/AIR) or without (30s-H), with a seven-minute span between each exposure. Peak PT values were subjected to one-way, repeated-measures analysis of variance, and PT change from baseline (DeltaT) during exposure was subjected to paired Student's t-test ( alpha=0.05). RESULTS:: Peak PT values of the 30s-H group were significantly higher than those of 30s-H/AIR group and those from baseline temperature ( p<0.001), whereas peak PT values in the 30s-H/AIR group were significantly lower than the baseline temperature ( p=0.003). The 30s-H/AIR group showed significantly lower DeltaT values than did the 30s-H group ( p<0.001). CONCLUSION:: Applying air flow simultaneously with LED exposure prevents in vivo pulp temperature rise. PMID- 30444690 TI - Structural Integrity Evaluation of Large MOD Restorations Fabricated With a Bulk Fill and a CAD/CAM Resin Composite Material. AB - AIMS:: To evaluate the effect of two composite restorative techniques (direct bulk fill vs indirect CAD/CAM) on the fracture resistance and mode of fracture of extended mesio-occlusal-distal (MOD) cavity preparations. METHODS:: Fifty-one sound human mandibular third molars were divided into three groups (n=17). Extended bucco-lingual MOD cavities were prepared. Teeth in group 1 were restored with a bulk-fill resin composite (Filtek Bulk-Fill Posterior Restorative), teeth in group 2 were restored with composite computer-aided design/computer-aided manufacturing (CAD/CAM) inlays (Lava Ultimate), and teeth in group 3 served as control and remained intact. All specimens were submitted to thermocycling, and a fracture resistance test was performed using a Universal testing machine (0.5 mm/min). Mode of fracture was classified into five types. One-way analysis of variance and the Duncan test were used to analyze the fracture load data at a significance level of alpha = 0.05. A chi-square test was used for the analysis of fracture mode between the restorative groups. RESULTS:: Statistical analysis showed significant differences in fracture resistance among the experimental groups. The teeth restored with the bulk-fill composite exhibited lower fracture resistance (1285.3+/-655.0 N) when compared to the teeth restored with the composite CAD/CAM inlays (1869.8+/-529.4 N) ( p<0.05). Mode of fracture showed the same distribution between the restorative groups. CONCLUSIONS:: Although both types of restorations failed at loads larger than those found in the oral cavity, the CAD/CAM composite inlays increased the fracture resistance of teeth with large MOD cavities when compared to direct bulk-fill composite restorations. The majority of fracture types were intraorally repairable for both restorative techniques. PMID- 30444691 TI - Clinical and Histological Study on Direct Pulp Capping With CO2 Laser Irradiation in Human Teeth. AB - The study aimed to histologically evaluate wound healing of exposed human pulp on direct pulp capping using super-pulsed CO2 laser preirradiation. In this single blind clinical trial, 28 third molar teeth of 17 volunteers were randomly capped with either CO2 laser irradiation (n=14) or Dycal (calcium hydroxide cement; n=14) and restored using resin composite. The laser was operated in super-pulsed mode (pulse duration, 0.2 ms; interval, 5.8 ms; 0.003 J/pulse). The irradiation conditions were a power output of 0.5 W, an irradiation time of 15 seconds, repeat mode (10-ms irradiation and 10-ms intervals, for a total beam exposure time of 7.5 seconds), total applied energy of 3.75 J, and an activated air cooling system. Each tooth was extracted at six or 12 months posttreatment and prepared for histological evaluation. We evaluated the parameters of pulp tissue disorganization, inflammatory cell infiltration, reparative dentin formation (RDF), and bacterial penetration. There were no significant differences between groups for all parameters at each postoperative period (Mann-Whitney U-test, p>0.05). CO2 laser irradiation completely controlled bleeding and exudate from the exposed pulp. The CO2 laser group had a tendency to delay RDF compared with the Dycal group, but 4 of 7 teeth from the CO2 laser group showed a complete dentin bridge at 12 months posttreatment. PMID- 30444692 TI - Impact of Modifiable Risk Factors on Bone Loss During Periodontal Maintenance. AB - OBJECTIVES: The aim of this study was to analyze modifiable patient risk factors from dental chart histories and radiographs for progressive mild-moderate periodontitis during periodontal maintenance (PM). METHODS AND MATERIALS: Bitewing radiographs of 442 elderly periodontal maintenance patients were taken before and after two years of periodontal maintenance. Each progressive periodontitis (PP) patient (with at least one site of posterior interproximal bone loss of >=2 mm, n=71) was matched to a periodontitis stable (PS) patient (no sites with bone loss, n=71) of the same gender and age (+/-five years) to control for these variables and was compared for measurements of general patient (medical history, smoking, hygiene and compliance habits) and tooth-related (bone loss, overhangs, interproximal dimensions) factors at baseline. Fisher exact and t tests were used to compare groups. RESULTS: While the elderly PM patients with mild-moderate periodontitis were generally stable, 71 of 442 were PP patients. No significant differences from PS patients were observed at baseline with regard to the systemic factors measured. However, the PP group had less cementoenamel junction to bone length (bone loss p<0.0001) and more interproximal width (2.3+/ 1.0 mm) than did the PS group (1.7+/-0.6 mm, p=0.0016). This was reflected in more open sites without adjacent tooth contact in PP (42% vs 15%, p=0.0006). CONCLUSIONS: In the short term, systemic and behavior factors are of limited value in identifying mild-moderate periodontitis patients on PM at increased risk of bone loss. However, interproximal width and lack of adjacent tooth contacts are related to the likelihood of losing interproximal bone during periodontal maintenance, suggesting the need for restorative therapy. PMID- 30444693 TI - Composite-composite Adhesion as a Function of Adhesive-composite Material and Surface Treatment. AB - OBJECTIVE:: To evaluate the composite-to-composite repair interfacial fracture toughness (iFT) as a function of adhesive and composite repair material. METHODS AND MATERIALS:: Beam-shaped composite specimens (21*4*3+/-0.2 mm) were prepared for each substrate material (Filtek Supreme Ultra [FSU] or Clearfil Majesty ES-2 [CME]) and artificially aged for 50,000 thermocycles (5-55 degrees C, 20-second dwell time). Aged specimens were sectioned in half, and the resulting hemispecimens were randomly assigned to one of the different repair methods (n=10) based on the following variables: type of substrate composite (FSU or CME), acid etch (yes or no), adhesive type (Scotchbond Universal or Clearfil SE Bond 2), and type of repair composite (FSU or CME). The repair surface was prepared with a course diamond bur (Midwest #471271). When used, 37% phosphoric acid was applied for 20 seconds, rinsed, and dried. All adhesives and composites were applied according to manufacturers' instructions. After postrepair storage (100% humidity, 37 degrees C, 24 hours), iFT was measured and expressed as MPa. Data were analyzed for statistical significance using a three-way analysis of variance and Tukey post hoc tests (alpha=0.05). RESULTS:: iFT values ranged from 0.64 +/- 0.19 MPa to 1.28 +/- 013 MPa. Significantly higher iFT values were achieved when FSU was used as the repair composite resin regardless of the substrate composite resin ( p<0.001). Clearfil SE Bond 2 adhesive was associated with significantly higher iFT values for FSU substrate ( p<0.001). The etching procedure had no significant effect on the iFT values of the repair procedures ( p>0.05). CONCLUSIONS:: Composite repair strength is adhesive and composite dependent. Repair strength appears to be higher when FSU is the repair composite regardless of the adhesive used. PMID- 30444694 TI - The Role of Occlusal Factors in the Presence of Noncarious Cervical Lesions in Young People: A Case-Control Study. AB - OBJECTIVE:: The aim of this retrospective case-control study was to evaluate the influence of different occlusal characteristics and self-referred bruxism in the presence of noncarious cervical lesions (NCCLs). METHODS AND MATERIALS:: The participants were 280 students (140 cases and 140 controls), with an average age of 24.5 years, from six schools of dentistry in Spain. Clinical examination was carried out to record the NCCLs and the static and dynamic occlusal characteristics. The side of mastication and bruxism was collected by questionnaire. Data variables were analyzed by means of univariate and multivariate logistic regression. Odds ratios and the respective 95% confidence intervals were calculated ( p<0.05). RESULTS:: The presence of NCCLs was significantly more likely in subjects with protrusive interferences (odds ratio [OR]=1.82); with lateral interferences, especially on the nonworking side (OR= 1.77); or who were self-reported bruxists (OR=1.72). In the multivariate analysis, protrusive interferences, bruxism, age, and the presence of attrition were risk factors for the development of NCCLs. These factors resulted in a model with an area under the receiver-operating characteristic curve of 0.667 and a positive predictive value of 61.43%. CONCLUSIONS:: There was no significant relationship between most occlusal factors and the presence of NCCLs. Only bruxism, protrusive interferences, age, and occlusal wear were risk factors. The predictive model was not sufficiently explanatory. Occlusal factors alone do not appear to be sufficient to explain the presence of NCCLs. PMID- 30444695 TI - Surface Sealant Effect on the Color Stability of a Composite Resin Following Ultraviolet Light Artificial Aging. AB - OBJECTIVE:: To examine how exposure to accelerated artificial aging (AAA) stimuli (ultraviolet [UV] light) affects the color stability of a composite resin following surface sealant (SS) application. METHODS AND MATERIALS:: A total of 30 cylindrical composite resin (Esthet-X) discs were prepared using Teflon-coated rings. The treatment groups, defined by different SS (Seal-N-Sine, PermaSeal, OptiGuard, Biscover LV, and DuraFinish) use, were divided into five groups of six discs each. The discs were subjected to baseline color measurements followed by measurements after surface sealant application (specular included component [SCI] and specular excluded component [SCE]) using a spectrophotometer. Three measurements (SCI and SCE) were performed for a total of 18 readings (test surface) per specimen group. All specimens were then exposed to a UV light source for a total of 382 hours. Color readings of the specimens were again recorded for each group. Quantitative color measurements were executed using Commission Internationale de l'Eclairage L*a*b* calculations. RESULTS:: Baseline color measurements of the composite resin discs, following the AAA exposure protocol, revealed no significant differences. A comparison of the composite resin discs before and after SS application (without UV light exposure) showed statistically significant differences using both SCI and SCE measurement criteria. Although significant differences were encountered between the DeltaL*, Deltaa*, Deltab*, and DeltaE parameters, all specimens (groups) were within the clinically acceptable range (1.0=13, indicating risk of developing postpartum depression. Data analysis revealed five themes. The themes were integrated under the holistic concept of community and included 1) social support; 2) anonymity; 3) in-groups; 4) drama; and 5) entertainment/pastime. CLINICAL IMPLICATIONS: Findings suggest online forums can provide social support for new mothers. They can facilitate sharing of information, act as a source of entertainment, and provide a sense of community for participants who might otherwise feel isolated due to the demands of new motherhood. Nurses working with childbearing women should be aware of the positive and negative aspects of online forums so they can support new mothers who choose to participate. PMID- 30444740 TI - Normal Complications and Abnormal Assumptions After Perinatal Death. AB - There are several ways, clinically, to approach grief after perinatal death, including from a humanistic or a medicalized perspective. The death of a baby is complicated. The loss is an embodied one that incites deep psychological wounds and can be isolating for many parents. Parents process their grief experiences within a sometimes oppressive social context that either sees their expressions of loss as a normal response to an abnormal tragedy or as pathology. Several diagnostic categories have been proposed relative to the traumatic grief experiences of grieving parents that potentially affect them. We explore this nomenclature and, through the lens of a Social-Cognitive Processing Model, examine social support, attitudes, context, and oppressive interpersonal and social structures that affect parents. Clinical implications are discussed. PMID- 30444741 TI - Support for Young Black Urban Women After Perinatal Loss. AB - PURPOSE: To describe the bereavement support needs of black urban women in late adolescence after perinatal loss. STUDY DESIGN AND METHODS: Eight black women aged 18 to 21 years who had experienced recent perinatal loss were interviewed in person or by telephone at three points in the 12 weeks that followed their loss to describe their perinatal bereavement experience and support needs. Data from the interviews were analyzed using constant comparative analysis. RESULTS: Black adolescent women need culturally appropriate bereavement support targeted at key transition points along the bereavement trajectory. They need accurate information, compassionate and respectful communication, and support from their mothers, grandmothers, and other women from their community of faith who have experienced perinatal loss. They value mementos, such as photographs and footprints. CLINICAL IMPLICATIONS: Nurses are well-positioned to be consistent caregivers and to provide clear, compassionate communication and anticipatory guidance to young black women experiencing perinatal loss. Attending to spiritual needs, harnessing family support, providing mementos, and encouraging reflection through journaling may help adolescent women find meaning and new perspectives on their bereavement experience. PMID- 30444742 TI - Anonymity Decreases the Punitive Nature of a Departmental Morbidity and Mortality Conference. AB - OBJECTIVES: We sought to analyze the effect of an anonymous morbidity and mortality (M&M) conference on participants' attitudes toward the educational and punitive nature of the conference. We theorized that an anonymous conference might be more educational, less punitive, and would shift analysis of cases toward systems-based analysis and away from individual cognitive errors. METHODS: We implemented an anonymous M&M conference at an academic emergency medicine program. Using a pre-post design, we assessed attitudes toward the educational and punitive nature of the conference as well as the perceived focus on systems versus individual errors analyzed during the conference. Means and standard deviations were compared using a paired t test. RESULTS: Fifteen conferences were held during the study period and 53 cases were presented. Sixty percent of eligible participants (n = 38) completed both the pretest and posttest assessments. There was no difference in the perceived educational value of the conference (4.42 versus 4.37, P = 0.661), but the conference was perceived to be less punitive (2.08 versus 1.76, P = 0.017). There was no difference between the perceived focus of the conference on systems (2.76 versus 2.76, P = 1.00) versus individual (4.21 versus 4.16, P = 0.644) errors. Most participants (59.5%) preferred that the conference remain anonymous. CONCLUSIONS: We assessed the effect of anonymity in our departmental M&M conference for a 7-month period and found no difference in the perceived effect of M&M on the educational nature of the conference but found a small improvement in the punitive nature of the conference. PMID- 30444743 TI - Risk Factors for 1-Year Mortality and Hospital Utilization Patterns in Critical Care Survivors: A Retrospective, Observational, Population-Based Data Linkage Study. AB - OBJECTIVES: Clear understanding of the long-term consequences of critical care survivorship is essential. We investigated the care process and individual factors associated with long-term mortality among ICU survivors and explored hospital use in this group. DESIGN: Population-based data linkage study using the Secure Anonymised Information Linkage databank. SETTING: All ICUs between 2006 and 2013 in Wales, United Kingdom. PATIENTS: We identified 40,631 patients discharged alive from Welsh adult ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 365-day survival. The secondary outcomes were 30- and 90-day survival and hospital utilization in the 365 days following ICU discharge. Kaplan-Meier curves were plotted to compare survival rates. Cox proportional hazards regression models were used to determine risk factors of mortality. Seven-thousand eight-hundred eighty-three patients (19.4%) died during the 1-year follow-up period. In the multivariable Cox regression analysis, advanced age and comorbidities were significant determinants of long-term mortality. Expedited discharge due to ICU bed shortage was associated with higher risk. The rate of hospitalization in the year prior to the critical care admission was 28 hospitalized days/1,000 d; post critical care was 88 hospitalized days/1,000 d for those who were still alive; and 57 hospitalized days/1,000 d and 412 hospitalized days/1,000 d for those who died by the end of the study, respectively. CONCLUSIONS: One in five ICU survivors die within 1 year, with advanced age and comorbidity being significant predictors of outcome, leading to high resource use. Care process factors indicating high system stress were associated with increased risk. More detailed understanding is needed on the effects of the potentially modifiable factors to optimize service delivery and improve long-term outcomes of the critically ill. PMID- 30444744 TI - Randomized-controlled trial of methocarbamol as a novel treatment for muscle cramps in cirrhotic patients. AB - BACKGROUND: Muscle cramps occur in 29-88% of patients with liver cirrhosis. They adversely affect quality of life. This study aimed to evaluate the efficacy and safety of methocarbamol as a novel therapy in controlling muscle cramps in cirrhotic patients. PATIENTS AND METHODS: This study was carried on 100 patients with liver cirrhosis in addition to chronic hepatitis C who presented with frequent muscle cramps (>=three cramps per week). Half of these patients received methocarbamol and the other half received placebo. This was done through equal randomization. Questionnaires on muscle cramp were answered. Patients were evaluated before, after 1 month of treatment, and 2 weeks after washout of treatment in terms of severity, duration, and frequency of cramps. Liver, renal functions, and electrolytes were analyzed. Also, any side effect was detected. RESULTS: Patients who were treated with methocarbamol showed a significant decrease in the frequency and duration of cramps. Also, the pain score improved significantly. However, no significant changes were observed in the placebo group. Few side effects of methocarbamol were recorded, including dry mouth and drowsiness. CONCLUSION: Methocarbamol seems to be a promising safe and well tolerated medication, and plays a role in the treatment of muscle cramps in patients with liver cirrhosis. PMID- 30444745 TI - Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence. AB - A consolidated overview of evidence for the effectiveness and safety/tolerability of hepatic encephalopathy (HE) treatment over the long term is currently lacking. We identified and assessed published evidence for the long-term (>=6 months) pharmacological management of HE with lactulose and/or rifaximin. A literature search was conducted in PubMed (cutoff date 05 March 2018) using the search terms 'hepatic encephalopathy+rifaximin' and 'hepatic encephalopathy+lactulose'. All articles containing primary clinical data were manually assessed to identify studies in which long-term (>=6 months) effectiveness and/or safety/tolerability end points were reported for lactulose and/or rifaximin. Long-term effectiveness outcomes were reported in eight articles for treatment with lactulose alone and 19 articles for treatment with rifaximin, alone or in combination with lactulose. Long-term safety/tolerability outcomes were reported in six articles for treatment with lactulose alone and nine articles for treatment with rifaximin, alone or in combination with lactulose. These studies showed that lactulose is effective for the prevention of overt HE recurrence over the long term and that the addition of rifaximin to lactulose significantly reduces the risk of overt HE recurrence and HE-related hospitalization, compared with lactulose therapy alone, without compromising tolerability. Current evidence therefore supports recommendations for the use of lactulose therapy for the prevention of overt HE recurrence over the long term, and for the additional benefit of adding rifaximin to lactulose therapy. Addition of rifaximin to standard lactulose therapy may result in substantial reductions in healthcare resource utilization over the long term, by reducing overt HE recurrence and associated rehospitalization. PMID- 30444746 TI - Impact of direct-acting antivirals on leukocytic DNA telomere length in hepatitis C virus-related hepatic cirrhosis. AB - BACKGROUND: Direct-acting antiviral (DAAs) represent advancement in the management of hepatitis C virus (HCV)-related hepatic cirrhosis. A high proportion of patients achieve a sustained virologic response; eradication of HCV is coupled with a decreased risk of hepatocellular carcinoma. Recent evidence suggests that shortening of the DNA telomere may be linked to cellular senescence as well as predisposition to malignant transformation. OBJECTIVE: This study aimed to assess pretreatment leukocytic DNA telomere length in HCV-related cirrhosis and post viral eradication using DAAs. PATIENTS AND METHODS: This study included 24 patients with HCV-related cirrhosis, Child-Pugh A. Whole-blood samples were obtained from patients before treatment and 12 weeks after the end of treatment, as well as from 24 healthy controls. Terminal restriction fragment, corresponding to telomere length, was measured using a nonradioactive Southern blot technique, detected by chemiluminescence. RESULTS: DNA telomere length was significantly shorter before treatment compared with 12 weeks after end of treatment in HCV-related cirrhotic patients. Also, it was significantly shorter in patients before treatment compared with healthy individuals. CONCLUSION: Telomere elongation in blood leukocytes can be considered a marker of recovery of inflammation after DAAs-induced HCV eradication. Still, the possibility of activation by cancer initiation cannot be excluded. PMID- 30444747 TI - Neoadjuvant Vismodegib and Mohs Micrographic Surgery for Locally Advanced Periocular Basal Cell Carcinoma. AB - INTRODUCTION: Vismodegib has shown a significant response rate in locally advanced periocular basal cell carcinoma. Long-term monotherapy is very difficult to accomplish due to primary or secondary resistance and side effects that limit the length of treatment. The use of Vismodegib as neoadjuvant followed by Mohs micrographic surgery is an option. PURPOSE: To report the use of neoadjuvant Vismodegib as an option for operable locally advanced basal cell carcinoma followed by Mohs surgery. PATIENTS AND METHODS: The authors treated 8 locally advanced periocular basal cell carcinomas. Mean age was 76, and 6 of 8 were women. Mean size was 18 mm (12-30). Three were recurrent after surgery. Maximal clinical response was obtained at 4.8 months. Patients were operated at the mean time of 7.3 months. RESULTS: Seven patients (87.5%) had a complete response and 1 (12.5%) progressed. Mohs micrographic surgery allowed to confirm a complete histologic response in 5 of 6 (83.3%) cases, and 1 patient refused surgery. All 7 patients are disease free after a mean follow-up of 12.4 months. All patients experienced adverse events. The most common included dysgeusia (100%) and muscle spasms (100%). Weight loss was present in 75% of the patients with a mean loss of 12.6 pounds and hair loss was seen in 50%. Only 1 (12.5%) patient withdraw from treatment because of intolerable muscle spasms. CONCLUSIONS: The authors believe there is a clear role for Vismodegib as neoadjuvant in locally advanced periocular basal cell carcinoma, even in operable cases. Specific indications beyond those already approved should be further discussed. Prospective studies to assess the combination of neoadjuvant Vismodegib followed by Mohs micrographic surgery in locally advanced periocular basal cell carcinoma with long-term follow up are needed. PMID- 30444748 TI - Fluorine-18-fluorodeoxyglucose positron emission tomography in thyroid nodules with indeterminate cytology: a prospective study. AB - BACKGROUND: Up to 20% of thyroid nodules subjected to fine-needle aspiration exhibit indeterminate cytology. The rate of malignancy in these nodules ranges from 10 to 40%. The objective of this prospective study was to evaluate the utility of fluorine-18-fluorodeoxyglucose (F-FDG) PET in nonautonomous thyroid nodules of more than 1 cm whose cytology is indeterminate (Bethesda categories III or IV) and that are not highly suspicious on ultrasonography. PATIENTS AND METHODS: Fifty-nine patients with 63 nodules were studied. RESULTS: F-FDG PET result was positive in 31 nodules. Of these, 22.6% were malignant, 25.8% were noninvasive follicular thyroid neoplasm with papillary-like nuclear features, 6.5% were tumors of uncertain malignant potential, and 45.1% were benign. F-FDG PET result was negative in 32 nodules. Of these, 3.1% were neoplasm with papillary-like nuclear features, 3.1% were tumors of uncertain malignant potential, and 93.8% were benign. CONCLUSION: This study suggests a high negative predictive value of F-FDG PET in thyroid nodules of more than 1 cm whose cytology is indeterminate and that are not highly suspicious on ultrasonography. PMID- 30444749 TI - Choline PET/CT in parathyroid imaging: a systematic review. AB - One of the most promising imaging techniques in primary hyperparathyroidism is PET/CT with choline-based tracers. To investigate the current evidence of these tracers in localizing parathyroid adenoma, a systematic review was performed. A comprehensive literature search was carried out and eligible studies were analyzed. Data were extracted, the level of evidence was scored, and performance data were pooled to calculate the weighted detection rate. Eleven articles were included in this study. The pooled detection rate was 97 and 94% on per patient based and per lesion-based analysis, respectively. There was considerable heterogeneity between studies and the level of evidence was determined to be 3a-, following Oxford criteria. Choline PET/CT has shown favorable results in detection of hyperfunctioning parathyroid tissue and may replace conventional technetium-99m-sestamibi scintigraphy in preoperative planning of parathyroid surgery. However, the quality of current evidence is moderate, and additional high-quality studies are needed to confirm these numbers. PMID- 30444750 TI - Spontaneous resolution of focal fibrocartilaginous dysplasia of femur on long term follow-up: case report and review of literature. AB - Focal fibrocartilaginous dysplasia (FFCD) is a rare developmental disorder frequently leading to angular deformities in young children. It most commonly affects the proximal tibia followed by distal femur. There are totally 22 reported cases of FFCD of femur. We report a case of FFCD of distal femur as a cause of varus deformity that was managed nonoperatively. The deformity resolved spontaneously over a period of 8 years. This is the second reported case of spontaneous resolution of angular deformity secondary to FFCD of distal femur. We strongly recommend to observe the behavior of deformity over a period of 24 months before any surgical intervention is planned. PMID- 30444751 TI - Mesenchymal stem cells as adjuvant therapy for limb lengthening in achondroplasia. AB - Staged leg lengthening allows achondroplastic dwarfs to reach nearly normal height, but it takes long periods of external fixation and it can be burdened by delayed unions. Between 2009 and 2013, eight achondroplastic dwarfs showed delayed unions in the callus formation during femoral lengthening stages in our institute. We performed in-situ injections of bone marrow-derived stem cell concentrates. Patients underwent monthly clinical and radiographic assessment for determination of the healing rate. All eight patients showed an improvement in the regenerated bone, with an average healing index of 23.1 days/cm (range: 18.7 23.8 days/cm). The complete recovery of the delayed consolidation took on an average of 5.2 months (range: 2-10 months). The use of cellular therapy in these patients could represent an innovative application. PMID- 30444752 TI - Lifestyle behaviours and health measures of women at increased risk of breast cancer taking chemoprevention. AB - Women at increased breast cancer (BC) risk are eligible for chemoprevention. Healthy lifestyles are potentially important for these women to improve efficacy and minimise side effects of chemoprevention and reduce the risk of BC and other lifestyle-related conditions. We investigated whether women taking chemoprevention adhere to healthy lifestyle recommendations, how their lifestyle risk factors and health measures compare to women in the general population, and whether these change whilst taking chemoprevention. Lifestyle risk factors and health measures in 136 premenopausal women taking tamoxifen for prevention of BC (Tam-Prev study) were compared to both national recommendations and an age matched female population from the Health Survey for England 2012. The Tam-Prev population had high rates of overweight and obesity (59.2%) and low adherence to physical activity recommendations (30.6%) which were comparable to the general population (55.2 and 35.1%, respectively). Fewer Tam-Prev participants were current smokers (10.5 vs. 18.2%, P=0.032), but more exceeded alcohol recommendations (45.0 vs. 18.7%, P<0.001). Tam-Prev participants had suboptimal diets; proportions not meeting fibre, saturated fat and non-milk extrinsic sugar recommendations were 87.8, 64.9 and 21.4% respectively. Many Tam-Prev participants had markers of cardiovascular disease risk and the metabolic syndrome. Health behaviours did not change during the first year on tamoxifen. Women taking chemoprevention had a high prevalence of unhealthy lifestyle behaviours and health measures, similar to an age-matched English cohort. Improving these measures in women at increased BC risk could significantly decrease rates of BC and other noncommunicable diseases. PMID- 30444753 TI - Integration rates of human papilloma virus genome in a molecular survey on cervical specimens among Iranian patients. AB - The human papilloma virus (HPV) as a major causative agent of different cancers is under investigation globally. In this study, we aim to investigate HPV infection in different cytological and pathological stages by different molecular methods, and then the viral genome integration of HPV-16 and -18 is determined by a specific real-time PCR method. The study included women who underwent liquid based cytology. HPV PCR was conducted by MY09/11 universal primers, HPV genotyping was performed by INNO-LiPA HPV genotyping assay, and the viral genome status was defined by two real-time PCR assays. The statistics were calculated by SPSS v.22 software. In 1668 women included in the study with mean age+/-std. deviation of 35.6+/-0.7, HPV was detected in 632 (38%) participants. Following genotyping analyses, 16 HPV types and 713 strains were detected. HPV-16 and HPV 18 from high-risk types and HPV-6 and HPV-11 from low-risk types were the dominant types. We found HPV-16 strains in mixed form (58.8%), and of the HPV-18 strains, the episomal form was prevalent (92.9%). The statistics revealed significant presence of HPV-6 and within normal limits cases; HPV-16 and atypical squamous cells of undetermined significance; HPV-33 as well as HPV-39 and low grade squamous intraepithelial lesion; HPV-6 and atypical squamous cells of undetermined significance; and HPV-35 as well as HPV-56 and squamous cell carcinoma. Our study showed high prevalence of HPV in low-grade cervical lesions, although it is associated with higher grades. The HPV molecular testing extra to cytology is recommended. HPV-16 and HPV-18 have different programs in genome integration in infected cells. PMID- 30444754 TI - Colorectal cancer screening in hospitalized patients: results from the Nationwide Inpatient Sample. AB - Colorectal cancer (CRC) is preventable with regular screening. This study aims to determine estimates and predictors of inpatient CRC screening during hospitalization in the USA. This nationwide population-based study utilized data from the National Inpatient Sample database from 2005 to 2014 to examine rates of CRC screening among hospitalized patients. There were 6470 inpatient CRC screening nationwide from 129 645 394 inpatient hospitalizations. Multivariable analysis showed that higher rates of inpatient CRC screening were associated with: females compared to males [odds ratio (OR): 0.87; 95% confidence interval (CI): 0.78-0.97]; 50-59 years age group compared to 70-79 years (OR: 0.76; 95% CI: 0.62-0.94) and more than 80 years (OR: 0.47; 95% CI: 0.35-0.64); Charlson Comorbidity Index score of 0 compared to scores of 1-2 (OR: 0.79; 95% CI: 0.64 0.98), 3-4 (OR: 0.61; 95% CI: 0.49-0.76), more than 5 (OR: 0.61; 95% CI: 0.47 0.79); rural hospitals rather than urban teaching hospital (OR: 0.50; 95% CI: 0.39-0.63) and urban nonteaching hospitals (OR: 0.64; 95% CI: 0.49-0.82); hospitals in the Midwest region (OR: 1.56; 95% CI: 1.14-2.12) compared to the Northeast region; recent years of 2011/2012 (OR: 1.89; 95% CI: 1.44-2.49) and 2013/2014 (OR: 2.70; 95% CI: 2.14-3.41) compared to the period 2005/2006. The CRC screening rate among hospitalized patients admitted in US hospitals is low. There were no association of differences in racial, household income or health insurance status with inpatient CRC screening. Noninvasive screening methods in hospitalized patients like stool-based fecal immunochemical test provide a unique method of increasing cancer screening rates. PMID- 30444755 TI - The Need and Desire for Mental Health and Substance Use-Related Services Among Clients of Publicly Funded Sexually Transmitted Infection Clinics in Vancouver, Canada. AB - CONTEXT: Sexually transmitted infections (STI) and mental health and substance use (MHSU) disorders all occur at elevated rates in sexual and gender minorities. These overlapping epidemics, or syndemics, are exacerbated by challenges these same populations face in accessing sexual/gender minority-affirming services. Many publicly funded STI clinics are a low barrier and provide sexual minority competent care. These sites therefore may be uniquely situated to address clients' MHSU-related needs. OBJECTIVE: We characterize the need and desire for MHSU services among STI clinic clients. DESIGN, SETTING, PARTICIPANTS: We conducted a waiting room survey at 6 STI clinics in Metro Vancouver, Canada. MAIN OUTCOME MEASURES: We calculated the proportion of clients with self-reported unmet MHSU needs in the previous 12 months and, among these clients, barriers to accessing MHSU services and desire for MHSU services within the STI clinic. We also examined social disparities in barriers to accessing MHSU services. RESULTS: Among 1115 respondents-65% of whom were sexual minorities-39% reported a recent need for MHSU-related care, most frequently in relation to anxiety (29%), depression (26%), substance use (10%), or suicide ideation (7%). Seventy-two percent of this group had not yet talked to a provider about their concern. Common barriers included shame (26%) and inability to afford the service (24%). Eighty-three percent of clients with unmet MHSU needs indicated that they were comfortable discussing MHSU concerns with an STI clinic provider, and 94% expressed desire to receive MHSU assessments, referrals, or counseling in the STI clinic. Sexual and gender minorities and those attending a suburban clinic were more likely to report barriers to accessing MHSU services. CONCLUSIONS: More than a quarter of STI clinic clients report unmet MHSU health care needs; moreover, these clients report high levels of comfort with and desire to discuss MHSU concerns with STI clinic providers. Sexually transmitted infections clinics are thus opportune sites for syndemic service integration. PMID- 30444756 TI - Acetabular Labral Tears Are Common in Asymptomatic Contralateral Hips With Femoroacetabular Impingement. AB - BACKGROUND: The number of patients undergoing hip arthroscopy for labral tears has increased, but labral tears are sometimes seen in asymptomatic patients with femoroacetabular impingement (FAI). The frequency of this finding, however, has not been well characterized nor is the proportion of patients with previously asymptomatic labral tears who may later become symptomatic. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) the prevalence of labral tears and other intraarticular pathology in the asymptomatic contralateral hip of patients undergoing surgery for symptomatic FAI; (2) the likelihood that the asymptomatic hip had become symptomatic at latest followup; and (3) any association between MRI findings and age, sex, and body mass index (BMI) in both symptomatic and asymptomatic sides. METHODS: This study included patients who were diagnosed with unilateral symptomatic FAI between 2013 and 2015 and who had an available MRI of both hips. The study included 100 patients (47 females, 53 males) with a mean age of 33 years (range, 17-57 years). Patients with a symptomatic contralateral hip (n = 56) or an unsuitable MRI for review based on both reviewers' consensus (n = 344) were excluded. The MRI of both hips was independently evaluated by two orthopaedic surgeons and interobserver reliability tested. The interobserver reliability for the two surgeons' MRI ratings was almost perfect (kappa >= 0.85). The presence of a labral tear, an acetabular chondral lesion, subchondral acetabular cysts, and fibrocystic changes in the femoral head-neck junction was documented for both hips. At latest followup, asymptomatic hips were investigated for any symptomatic labral tears or surgical procedures resulting from FAI. RESULTS: A labral tear was recorded in 97 (97%) and 96 (96%) of symptomatic hips, respectively, for each surgeon's evaluation. A labral tear was also detected in 41 (41%) and 43 (43%) of asymptomatic hips. In addition, an acetabular chondral lesion was detected in 32 (32%) and 35 (35%) of the symptomatic hips and 15 (15%) and 17 (17%) of the asymptomatic hips. At latest followup, nine of the patients were diagnosed with symptomatic labral tears in the contralateral asymptomatic hip and were treated. None of the radiologic parameters examined demonstrated an association with patient age, sex, or BMI in either symptomatic or asymptomatic hips. CONCLUSIONS: Labral tears and acetabular chondral lesions are common in the asymptomatic contralateral hip of patients undergoing surgery for FAI. The incidence of a symptomatic labral tear in these asymptomatic hips was 9% during 2 years of followup. We suggest that the decision to perform chondral or labral surgery in patients with FAI should be made with caution considering the relatively high prevalence of labral tears in asymptomatic hips and the low chance of development of symptoms. LEVEL OF EVIDENCE: Level IV, case-series study. PMID- 30444757 TI - How to Avoid Posterior Interosseous Nerve Injury During Single-Incision Distal Biceps Repair Drilling. AB - BACKGROUND: The posterior interosseous nerve (PIN) is occasionally damaged during distal biceps tendon repair. But to our knowledge, no studies have examined the position of the PIN in relation to the bicipital tuberosity in full supination, which is the recommended position during single-incision distal biceps repair or reconstruction QUESTIONS/PURPOSES: (1) What is the anterior safe zone when exposing the anterior tuberosity with the arm in supination? (2) When drilling the radial tuberosity for bicortical button placement in full supination, how should the drill be angled to avoid PIN injury? METHODS: Fifteen adult cadaver elbows had the PIN dissected around the proximal radius. The position of the PIN was measured relative to the most ulnar aspect of the radius at three sites in full supination: at the bicipital tuberosity (bicipital tuberosity-PIN), 10 mm proximal to the bicipital tuberosity (bicipital tuberosity-proximal), and 10 mm distal to the bicipital tuberosity (bicipital tuberosity-distal). We made another measurement by drawing a line from the lateral humeral epicondyle to the radial styloid. The point where the PIN intersects this line, when viewed laterally and measured from the lateral humeral epicondyle, was marked and measured to indicate where it wraps around the radius laterally (PIN-lateral). The last measurement (bicipital tuberosity-lateral) was made where the line from the lateral humeral epicondyle to the radial styloid intersected the position of the bicipital tuberosity. This was determined by the point where a perpendicular line from the bicipital tuberosity was drawn laterally to meet with the lateral line. We did this to establish if the PIN adopts its most lateral position on the radius at the same level as the bicipital tuberosity. RESULTS: The anterior safe zone in the approach to the biceps tuberosity extends approximately 15 mm from its prominence (mean, 20.7 mm; range, 16.0-24.1 mm). The PIN crosses the lateral midline from anterior to posterior at 46.0 mm (range, 31.2-67.0 mm) from the lateral epicondyle (lying directly opposite the bicipital tuberosity at nearly the same level); therefore, the drill exit should be posterior to lateral midline while aiming proximally to the bicipital tuberosity. CONCLUSION: Our anterior safe zone found that the PIN travels from an anterior position on the radius, when measuring 1 cm proximal to the bicipital tuberosity to a lateral position on the radius at the level of the bicipital tuberosity prominence (on the contralateral cortex), to a slightly more posterior position on the radius 1 cm distal to the bicipital tuberosity. Typically, the PIN sits directly opposite the biceps tuberosity, often directly on the cortex of the radius when the forearm is in full supination. CLINICAL RELEVANCE: Because of these findings, perpendicular bicortical drilling starting at the bicipital tuberosity should be avoided. A more proximal and ulnar drilling angle is recommended. Defining a safe zone for an anterior approach seems to be clinically unhelpful due to the high anatomical variability that exists for the position of the PIN around the proximal radius. Future studies could attempt to confirm our findings with the analysis of noncadaveric imaging in three different planes using such modalities as MRI to avoid the effects of tissue distortion during cadaveric preparation and dissection. PMID- 30444758 TI - Imaging the itis: endocarditis, myocarditis, and pericarditis. AB - PURPOSE OF REVIEW: Inflammatory and/or infectious conditions affecting the heart and pericardium in children are primarily diagnosed via noninvasive imaging modalities. In addition, the use of multiple imaging modalities (multimodality imaging) is becoming increasingly common to assist in diagnosis, management, and prognosis. This review focuses on the use of noninvasive imaging in endocarditis, myocarditis, and pericarditis, with emphasis placed on the use of echocardiography and cardiac MRI in these conditions. RECENT FINDINGS: Echocardiography remains the most commonly employed imaging modality for all of the above diagnoses. However, echocardiography has several important limitations, foremost of which is a limited ability to characterize myocardial tissue abnormalities, such as inflammation and fibrosis. Quantitative assessment of cardiac output and valve function is also limited with echocardiography. Cardiac MRI is superior to echocardiography in these domains and provides useful complementary information. SUMMARY: Echocardiography and cardiac MRI play crucial roles in the diagnosis, management, and forecasting of prognosis in inflammatory and/or infectious conditions affecting the heart in children. New advances, particularly in MRI imaging, have allowed clinicians to provide more accurate diagnoses and information regarding prognosis. PMID- 30444759 TI - Cryoballoon ablation beyond paroxysmal atrial fibrillation. AB - PURPOSE OF REVIEW: Although radiofrequency-based pulmonary vein isolation (PVI) was considered the 'gold standard' for the treatment of atrial fibrillation for a long time, the cryoballoon has turned out to be a common alternative tool for atrial fibrillation ablation. Most of the data regarding cryoballoon-based ablation relate to patients with paroxysmal atrial fibrillation (PAF). In this review, we summarize recent knowledge on the usage of cryoballoon ablation for other conditions, especially persistent atrial fibrillation. RECENT FINDINGS: The cryoballoon is an effective ablation tool for PVI. As PVI is the first-line recommended procedural endpoint in atrial fibrillation ablation, it can be recommended not only for the treatment of PAF but also persistent atrial fibrillation and results in satisfying clinical outcomes. Recently, smaller studies and case reports were published reporting on cryoballoon ablation strategies beyond stand-alone PVI. These studies report a wide application spectrum of the cryoballoon and therefore potentially increase clinical success as well as the patient collective amenable to cryoballoon ablation. SUMMARY: Cryoballoon-based PVI can be recommended not only for patients with PAF but also for patients with persistent atrial fibrillation. Ablation strategies going beyond PVI need further evaluation, but might expand the use of the cryoballoon. PMID- 30444760 TI - Long-lasting benefits of exercise for those living with a Fontan circulation. AB - PURPOSE OF REVIEW: In recent decades, the physiology and late outcomes of the Fontan circulation have become better characterized and interest has turned to interventions that might improve exercise capacity and clinical sequelae. No therapy has currently been shown to be more effective for improving exercise capacity in the setting of a Fontan circulation than exercise. This review examines the current evidence supporting exercise as therapy for this group. RECENT FINDINGS: People living with a Fontan circulation are at increased risk for reduced skeletal muscle mass and exercise capacity with important implications for clinical outcomes. Small studies suggest that performing moderate-to-vigorous aerobic and resistance exercise improves exercise capacity through unique mechanisms such as superior respiratory and skeletal muscle function and venous return. SUMMARY: Despite traditional concerns about moderate to-vigorous physical activity, current evidence suggests that exercise is beneficial for the Fontan circulation and that, after appropriate screening, we should be encouraging regular moderate-to-vigorous physical activity. Multicentre randomized controlled trials are needed that further explore mechanisms, late impact for end-organ function and strategies to optimize long-term moderate-to vigorous physical activity levels. PMID- 30444761 TI - Advances in fetal echocardiography: myocardial deformation analysis, cardiac MRI and three-dimensional printing. AB - PURPOSE OF REVIEW: Advances in ultrasound technology have led to new ways of evaluating cardiac function and structure, including myocardial deformation imaging (strain and strain rate), cardiac MRI and three-dimensional (3D) printing. As ultrasound technology has improved, it has become possible to use these modalities to evaluate the fetal heart. This article will review some of the more recent developments in applying these techniques to the evaluation of fetal cardiac structure and function. RECENT FINDINGS: Myocardial deformation analyses have led to the establishment of normative values for strain and strain rate in the fetal heart and have also been used to evaluate fetal heart function in both fetal disease states and maternal disease states. Technological advances in MRI technology, 3D imaging and 3D printing have opened up new methods of evaluating fetal structural heart disease. SUMMARY: A deeper understanding of the subtleties of myocardial dysfunction in various fetal and maternal disease states may elucidate the pathophysiology involved and lead to new treatment and/or counseling paradigms that may ultimately affect outcome. Similarly, the ability to image the fetal heart in new ways, including fetal MRI and 3D printing, could potentially change fetal counseling techniques and prenatal planning. PMID- 30444762 TI - Talent alone is not enough: lessons learned in a decade as chief. AB - PURPOSE OF REVIEW: In this review, we explore the change in what is required for outstanding and successful clinical practice and the challenges of putting our teams in positions to succeed. RECENT FINDINGS: We review the benefits of sleep in the training of physicians, acknowledge the science and practice of quality, safety, professionalism and communication in clinical practice. SUMMARY: The talented physician has more than scientific knowledge and technical expertise; they must incorporate a commitment to patient safety, personal and colleague well being and a culture that is built on values of professional behavior. PMID- 30444763 TI - Comparing radiofrequency and cryoballoon technology for the ablation of atrial fibrillation. AB - PURPOSE OF REVIEW: With the growing popularity of the cryoballoon tool for catheter ablation of atrial fibrillation, there has been discussion of whether cryothermal energy is just as or more effective than traditional radiofrequency. This review will compare both thermal energies for the treatment of atrial fibrillation. RECENT FINDINGS: Although the FIRE and ICE trial established that cryoballoon technology is noninferior to radiofrequency ablation for the treatment of atrial fibrillation, both thermal technologies have undergone advancement. This review intends to explore recent changes in technology and catheter ablation technique to improve outcomes for patients with atrial fibrillation. SUMMARY: Catheter ablation is standard treatment for patients with atrial fibrillation, which primarily focuses on electrical isolation of the pulmonary veins. Radiofrequency is the most common approach at present times; however, over time, new technology has developed. Most successful among these is the cryoballoon tool. Although the FIRE and ICE trial indicated radiofrequency and cryothermal energy to be approximately equal in efficacy and safety, there are advantages and disadvantages to both. This review seeks to address the value of each tool, as well as further development needed to better address atrial fibrillation while improving procedural safety. PMID- 30444764 TI - Catheter ablation in elderly patients: a review of current studies and pending questions. AB - PURPOSE OF REVIEW: Catheter ablations are established treatment options for cardiac arrhythmias. Despite the fact that they are increasingly performed in elderly patients, publications focusing on procedural safety and success concerning this patient subgroup are sparse. The purpose of this review is to inform about current and upcoming studies regarding catheter ablations in the elderly. RECENT FINDINGS: The overall pattern of available studies is indistinct because of varying age limits and scant patient populations. Most studies do not identify advanced patient age as a promoting factor for peri-procedural complications and recurrence rates. There are a few upcoming publications with regards to catheter ablations in the elderly, some of which might produce new insight. SUMMARY: The results at hand might implicate, that in most cases individual patient health could be decisive instead of mere patient age to promise well-tolerated and effective catheter ablation in aged patients. Nevertheless, further studies with larger patient populations are needed to clarify the role of catheter ablation in aged patients. PMID- 30444765 TI - Body Mass Index and Parotidectomy Outcomes. AB - Multiple specialties have demonstrated increased risk of certain postoperative complications in patients with an increased body mass index (BMI). The goal of this study was to understand the outcomes of patients undergoing parotidectomy with an increased BMI and to identify any other patient risk factors for postoperative complications. This study was a retrospective chart review of 432 patients. Patient variables collected included BMI, age, gender, history of diabetes mellitus, type of parotidectomy, and pathology. Outcomes reviewed included facial nerve weakness, hematoma or seroma formation, and wound infection. The results showed that BMI had no statistically significant effect on complications. However, patients undergoing a total parotidectomy, malignant pathology, and patients with a history of diabetes mellitus had significantly more postoperative facial weakness. In conclusion, BMI does not influence postoperative complications in patients undergoing parotidectomy. Patients with diabetes, those undergoing total parotidectomies, and patients with malignant pathology have significantly more facial weakness and should be counseled accordingly. PMID- 30444766 TI - Preliminary Analysis on Characteristics of Rib Cartilage Calcification in Patients With Congenital Microtia. AB - Autogenous rib cartilage graft procedure for microtia reconstruction has been adopted as the most standardized current method. But calcification would make it difficult for cartilage harvesting and ear framework sculpting. The objective of this study was to explore the rate, degree, and pattern of rib cartilage calcification in microtia and to guide rib cartilage harvesting and the optimal timing of auricular reconstruction. A retrospective study was performed with the imaging data from 320 consecutive patients who received a preoperative 3 dimensional chest computed tomography (CT). Overall, calcification rate of cartilages in female patients was higher than male's (P < 0.05). In 6 to 15 years group, calcification rates of male and female had a similar rate, while female's were higher than male's in other 3 groups. Furthermore, the moderate-to-severe calcification rate was higher in female than in male patients (P < 0.001). Therefore, girls who are over 15 years should be paid more attention regarding the possibility of moderate-to-severe calcification; these patients should take CT examinations if necessary. Calcification rate of the youngest group (6-15 years) was the lowest of all groups, while other 3 groups showed no statistical significance (P > 0.05). So merely the age increasing is not the contradiction for cartilage harvesting, as long as the authors effectively evaluate the condition of rib cartilage before operation. Rib cartilages serve as the key material in auricular framework sculpting and determine the feasibility and outcomes of the surgery. So CT examinations for preoperative evaluation of rib cartilage could be a useful method for planning microtia reconstruction. PMID- 30444767 TI - Evaluation of Temporomandibular Joint Movement After Mandibular Reconstruction. AB - Mandibular head dislocation and problems with mouth opening may develop after mandibular reconstruction. The authors investigated dislocation of the mandibular head and amount of protrusive sliding (excursion) and their effect on mouth opening. The authors divided 55 mandibular reconstruction patients into 3 groups on the basis of the extent of masticatory muscle and mandibular resection and investigated mandibular head dislocation. On the other hand, the authors focused on mandibular head protrusive excursion as a function of a reconstructed mandible. Protrusive excursion was measured by plain radiography in 29 patients. The extent of mouth opening was measured between the central incisors. Fluoroscopy was performed in 9 patients and the motions of the mandible were analyzed with video-analysis software. Mandibular head dislocation was observed in 15 patients (27.2%) who underwent resection of the mandibular ramus and coronoid process. The extent of mouth opening did not vary significantly among the 3 groups but was lower than that in healthy persons. Mandibular excursion was restricted in patients with conserved temporalis and lateral pterygoid muscles. Protrusive excursion was correlated with the extent of mouth opening. Structural problems involving dislocation of the mandibular head are caused by severing the coronoid process and protrusive excursion disorders are important factors causing mouth opening problems. Physiological sliding and other motions were observed in reconstructed models. The authors believe that when the ramus is resected, there is a greater chance of articular head dislocation. These findings suggest that dislocation of the mandibular head and protrusive excursion disorders arise from imbalances of the remaining masticatory muscles. PMID- 30444768 TI - Dacryocystitis and Rhinosinusitis Secondary to Sarcoidosis. AB - Sarcoidosis rarely develops in the lacrimal sac. Lacrimal sac sarcoidosis may be associated with sarcoidosis-related rhinosinusitis. The anatomical and histological relationship between the lacrimal drainage system and nasal mucosa has been indicated as a predisposing factor for this concomitance. However, the characteristics of this condition are not fully understood. Herein, the authors report a case where dacryocystitis and rhinosinusitis developed secondary to sarcoidosis. Pathological examination of the lacrimal sac wall revealed noncaseating epithelioid granulomas in the subepithelial layer, which contains the lacrimal-drainage-associated lymphoid tissue. The lacrimal-drainage associated lymphoid tissue comprises the main immune mechanism of the lacrimal system and forms a functional unit with the lacrimal gland, conjunctiva, and nasal mucosa to maintain ocular surface integrity through lymphocyte recirculation. Because sarcoidosis is an autoimmune disorder, this lymphocyte recirculation may be associated with the concurrent nasal lesions in the authors' case. PMID- 30444769 TI - Gingival Neurofibroma With Teardrop-Shaped Defects of the Interdental Alveolar Bone: An Unusual Oral Manifestation of Neurofibromatosis Type 1. AB - Gingival enlargement, although frequently encountered in clinical settings, is rarely associated with systemic diseases or syndromes. Among the diverse pathological conditions of neurofibromatosis type 1 (NF-1), minor manifestations in the orofacial region are occasionally overlooked. Herein, the authors present an unusual case of gingival neurofibroma in a patient with NF-1 associated with characteristic osseous defects in the alveolus in the long-term course of 17 years from the first examination.A 5-year-old boy with NF-1 was referred for the evaluation of gingival enlargement in the posterior left maxilla. An incisal biopsy led to the diagnosis of neurofibroma. At 22 years of age, the patient was referred again with a complaint of bleeding and pain in the same region refractory to periodontal therapy. The gingiva and tuberosity were swollen, and the second molar was affected by the tumor. Radiography revealed a low level of the interdental septum beneath the tumor with a relatively intact periodontal cortical bone, exhibiting a teardrop-shaped bone defect. The lesion was completely resected with the periosteum.Gingival neurofibroma in NF-1 may be associated with osseous and dental abnormalities and can be mistaken for periodontitis. Raising awareness of this clinical entity can lead to proper management of the esthetic and functional problems in the oral and maxillofacial region. PMID- 30444770 TI - Modified Posterolateral Approach for Pterygium Colli. AB - Pterygium colli is a congenital deformity associated with malformation syndromes. Various surgical procedures have been reported, but these procedures have advantages and disadvantages. The modified posterolateral approach has been reported as a new surgical procedure for pterygium colli. However, there has been no confirmatory report. In this study, a case of pterygium colli that was treated with the modified posterolateral approach was reported.An 11-year-old girl with Turner syndrome was referred with chief complaints of web neck deformity and an abnormal hairline. The modified posterolateral approach was selected. Hairy excessive skin was excised at the posterolateral and posterior neck. An inferior skin incision was made parallel to the hairline, and a superior skin incision was made along the desired hairline. Hairless excessive skin was excised along the posterior midline of the neck. Undermining was extended over the sternocleidomastoid muscle, and flaps were rotated upward and inward. Z-plasty was performed at the posterior midline of the neck to prevent hypertrophic scar formation. The web neck deformity disappeared, but the patient expressed concern for excessive skin at the posterior midline. Thus, secondary surgery was performed 12 months later. The operative scar was opened 2 months after secondary surgery owing to suture abscess, and the wound was closed directly. The web neck deformity had not recurred, and the natural hairline was maintained at 65 months after the primary surgery.The modified posterolateral approach is beneficial for pterygium colli, because it allows the correction of the web neck deformity and abnormal hairline without a noticeable scar. PMID- 30444771 TI - Reliability of Ultrasound-Guided One-Point Fixation for Zygomaticomaxillary Complex Fractures. AB - This study aimed to analyze the precision and postoperative stability of ultrasound guided 1-point fixation on the zygomaticomaxillary buttress for the treatment of zygomaticomaxillary complex (ZMC) fractures. The authors analyzed 24 consecutive patients who underwent ultrasound-guided 1-point fixation for ZMC fractures without separation of the fracture at the frontal process of the zygomatic bone. The authors used titanium plates in the first 6 cases, and biodegradable plates in the remaining 18 cases. The authors obtained computed tomography images preoperatively, and again the first day after surgery (T1) and 6 months after the surgery (T2). The authors calculated vertical change (VC) and horizontal change (HC) of the zygoma on computed tomography. Precision was evaluated with T1 images. Stability was evaluated from T1 to T2, and titanium and biodegradable plates were compared. From T1 images, the mean VC and HC was 0.22 degrees (range, 1.60 degrees -1.08 degrees ) and 0.33 degrees (range, 1.86 degrees -1.03 degrees ), respectively. From T1 to T2, the mean VC and HC was 0.08 degrees and 0.28 degrees , respectively. Comparing the types of plates, the mean HC in the biodegradable plate group was 0.39 degrees , which was significantly greater than that in the titanium plate group (mean -0.10 degrees ). However, as the degree of change was relatively small, this did not pose any clinical problems. Our findings suggest that ultrasound-guided 1-point fixation on the zygomaticomaxillary buttress provides accurate reduction on ZMC fractures without the separation of the frontal process of the zygomatic bone fracture. Sufficient stability was obtained, even with the use of biodegradable plates. PMID- 30444772 TI - Assessment of Simultaneous Surgery for Odontogenic Sinusitis: Endoscopic Sinus Surgery With Endoscopic Apicoectomy. AB - Odontogenic sinusitis (OS) is a disease commonly encountered by otolaryngologists and oral surgeons. There is currently no standard consensus for the management of the causative teeth of OS, and the therapeutic outcomes of endodontic surgery remain unclear. The authors herein report the outcomes of simultaneous surgery for OS, endoscopic sinus surgery (ESS) with endoscopic apicoectomy. Twenty-one OS patients who underwent ESS were included in the intent-to-treat population. Eleven patients who simultaneously underwent endoscopic apicoectomy were included as the study group, and another 10 patients who were subjected to the extraction of the causative teeth preceding or during surgery were included as the control group. The postoperative tooth course after surgery in the study group was assessed as the primary outcome by periodic radiographs. The postoperative sinus course was compared between the 2 groups as the secondary outcome. Seventeen teeth were subjected to endoscopic apicoectomy concurrently with ESS, and the treatment success rate for periapical lesions was 94.1% (16 out of 17 teeth), which was consistent with previously reported outcomes for endodontic microsurgery. Ten of 11 patients (90.9%) had good postoperative sinus courses, and the mean wound-healing period of the sinus mucosa was 6.9 +/- 3.5 weeks. These results were not significantly different from those obtained for the control group (90% and 6.1 +/- 3.2 weeks). This surgical procedure may contribute to the preservation of causative teeth without having an impact on the successful treatment of sinusitis. A comprehensive surgical approach by otolaryngologists and oral surgeons is desirable for the treatment of OS. PMID- 30444773 TI - Zygomatic Nonunion: A Misunderstood Complication of Reduction Malarplasty. AB - Reduction malarplasty is a popular facial skeletal contour surgery in East Asia. Zygomatic nonunion is a reported complication. However, it is often misunderstood and misdiagnosed. Here we present typical misdiagnosed zygomatic nonunion cases, propose and preliminarily clarify 4 major misunderstandings of zygomatic nonunion: diagnostic standard, the cause, the incidence, and the prognosis of zygomatic nonunion. PMID- 30444774 TI - Surgical Treatment of Growing Skull Fracture: Technical Aspects of Cranial Bone Reconstruction. AB - BACKGROUND: Growing skull fracture (GSF) is a rare, posttraumatic complication observed mainly in young infants. In GSF, the skull fracture associated with an underlying dural tear gradually expands due to herniation of the intracranial tissue into the fracture site. Many reports have discussed GSF from various points of view. However, only a few studies have focused on the details of cranial reconstruction. The present study aims to redress this omission by shedding some light on bone work in GSF surgery. METHODS: Patients registered in the institutional database who underwent surgical repair of GSF were retrospectively reviewed. RESULTS: Four patients underwent surgical repair for GSF. The site of injury was parietal in 3 patients and occipital in 1 patient . Age at the time of injury ranged from 3 months to 1 year 5 months (mean: 7 months). The duration from injury to surgery ranged from 5 to 7 months (mean: 5 months). In all patients, dural reconstruction was performed with autologous periosteum and cranial reconstruction was performed with an autologous calvarial bone graft. Regardless of the age distribution, split bone grafting was possible for all patients. CONCLUSION: To diagnose GSF promptly and thereby reduce the risk of neurologic sequelae, careful observation of the course, and education of the patients' parents are desirable. Although most children with GSF are under 3 years old, the age before the formation of the diploic layer, split bone grafts should be considered for the treatment of GSF to reduce the risk of residual cranial bone defects. PMID- 30444775 TI - Bony Orbital Decompression Following Lateral Canthotomy and Cantholysis for Traumatic Orbital Compartment Syndrome. AB - PURPOSE: To describe the clinical course of patients with traumatic orbital compartment syndrome who underwent bony orbital decompression due to persistently abnormal pupillary light reflex after lateral canthotomy and cantholysis. METHODS: Four consecutive patients were retrospectively reviewed. The authors performed bony orbital decompression as there was no improvement in the pupillary light reflex and a tight orbit persisted even after lateral canthotomy and cantholysis. RESULTS: The median interval between injury and bony decompression was 8.8 hours (range, 7-12 hours). All patients showed a preoperative intraocular pressure of 40 mm Hg or greater, which decreased to 20 mm Hg or less the next day. Two patients showed globe tenting with a posterior globe angle of 110 degrees or less, which was resolved on the following day. Two patients with initial visual acuity of counting fingers or better showed complete visual recovery. By contrast, only 1 of the 2 patients with no light perception slightly improved to light perception while the other showed no improvement after surgery. CONCLUSIONS: Bony orbital decompression is effective for the treatment of traumatic orbital compartment syndrome in patients whose preoperative visual acuity is counting fingers or better. PMID- 30444776 TI - Comparison of Nasal Symmetry Between Presurgical Nasal Stenting and Postsurgical Nasal Retainer Placement in Unilateral Clefts. AB - The timing of cleft lip nose surgery remains controversial. The less invasive the procedure at the time of primary cleft lip repair, the less the growth and development of the nose is affected. Therefore, the nasal-stenting component of presurgical nasoalveolar molding has increasingly been used. However, not all cleft centers use such treatment. Conventional postsurgical placement of silicone nasal retainers remains popular. No report has yet compared presurgical nasal stenting (preNS) and postsurgical nasal retainer placement (postNR). In this study, postoperative nasal form outcomes after primary lip repair using preNS or postNR in patients with complete unilateral cleft lips, alveoli, and palates were compared. Patients in whom preNS alone was used for 6 months (group I) were compared with those receiving postNR (no preNS) for 6 months after primary nasal cartilage dissection (group II) and controls with no appliance (group III). Nasal anthropometric distances and angular relationships were measured photographically to assess nasal symmetry at 4 years of age in all groups. Compared to group III, groups I and II exhibited significantly greater nostril heights (P = 0.0075, P = 0.0015 respectively) and columellar deviation angles (P = 0.0020, P = 0.0221). Groups I and II did not differ significantly. No significant between-treatment difference in terms of nasal symmetry between preNS and postNR was observed. However, both treatments afforded significantly better results than no treatment. Since older infants tend to resist the placement of nasal devices, preNS is more feasible in this age group. PMID- 30444777 TI - Overcorrected Midface Advancement to Improve Airway Problems in Severe Pfeiffer Syndrome Types II and III. AB - INTRODUCTION: Treatment of patients with severe Pfeiffer syndrome types II and III is difficult. The purpose of this article is to present our method of overcorrecting midface advancement to improve airway problems in such patients. MATERIALS AND METHODS: One boy and two girls with types II and III Pfeiffer syndrome and who underwent Le Fort III midface advancement using our previously described corrected cephalometric analysis and distraction system were included in the study. RESULTS: The authors overcorrected by advancing the midface to make it look as similar as possible to an adult face. While the overcorrected midface advancement widened the upper airway spaces in the 3 patients, the tracheostomy that had already been placed during infancy could not be closed, probably because of an underlying tracheal abnormality or tracheomalacia. DISCUSSION: Overcorrected midface advancement cannot enable tracheostomy closure, probably because of severe tracheal anomalies, such as tracheomalacia, below the tracheostomy. However, with the possibility of gradual improvement of the tracheomalacia with age, closure of the tracheostomy can eventually be expected. Therefore, efforts to close a tracheostomy should be pursued even if the probability of its removal is low. CONCLUSION: Overcorrected midface advancement did not enable tracheostomy closure, probably because of severe tracheal anomalies such as tracheomalacia. However, the severe exophthalmos and angle III malocclusion were improved, and with the possibility of gradual improvement of the tracheomalacia with age, closure of the tracheostomy can eventually be expected. Therefore, efforts to close a tracheostomy should be pursued even if the probability of its removal is low. PMID- 30444778 TI - Mandibular Regeneration With Autologous Human Bone Marrow Derived Mesenchymal Stem Cells to Treat Unicystic Ameloblastoma: a Clinical Report. AB - Ameloblastoma is a rare, benign tumor found in the jaw. These tumors have a tendency for locally aggressive expansion, and thus require surgical removal. For the previous 3 decades, autologous bone grafting and free flap surgeries have been most commonly used to correct bone defects after surgical removal of the lesion. In this report, the authors describe a case of unicystic ameloblastoma in a 14-year-old girl who was successfully treated with mandibular regeneration, attained by autologous human bone marrow mesenchymal stem cells without any autologous bone graft and free flap transfer. This case shows that autologous human bone marrow mesenchymal stem cells can be used as an alternative method to autologous bone graft and free flap transfer in a large bone defect of the jaw. PMID- 30444779 TI - Modification of the Lazy-T Procedure for Correction of Punctal Ectropion. AB - The Lazy-T procedure is used to correct moderate-to-severe punctal ectropion in the lower eyelid. It includes full-thickness wedge resection of the medial lower eyelid and horizontal tarso-conjunctival diamond excision inferior to the lower punctum. However, the skin wound vertical to the relaxed skin tension lines is often conspicuous and horizontal excision of a part of the tarsus may impair function of the meibomian gland. In this study, the authors developed a modified Lazy-T procedure, which includes subciliary incision, pentagonal tarso conjunctival resection, and medial spindle excision for submerging the vertical wound after suturing the pentagonal tarso-conjunctival resection under the skin flap and minimizing damage to the tarsus. The modified Lazy-T procedure was applied in 4 eyelids of 3 patients and achieved good anatomical results with cosmetically acceptable postoperative appearances and no remarkable complication. PMID- 30444780 TI - Assessing the Compliance of Randomized Controlled Trials Published in Craniofacial Surgery Journals With the CONSORT Statement. AB - BACKGROUND: Randomized controlled trials (RCTs) are gold standard assessments for healthcare interventions. The Consolidated Standards of Reporting Trials (CONSORT) statement was published to maximize RCT reporting transparency. The authors conducted a systematic review to assess current compliance of RCTs published within craniofacial surgery with the CONSORT statement. METHODS: The Thomson Reuters Impact Factor Report 2016 was consulted to identify craniofacial surgery journals. PubMed was used to search for recent RCTs published within the 5 journals identified. Two independent researchers assessed each study for inclusion and performed data extraction. The primary outcome was compliance of each RCT with the CONSORT statement. Secondary outcomes were the pathology and interventions examined, impact factor, multi-versus-single center, number of authors, and publication date. RESULTS: Eighty-six studies met the inclusion criteria, across which a median of 56% (range 33%-94%) applicable CONSORT items were reported. The 5 least reported items were: trial design (3a); registration number and name of trial registry (23); who generated random allocation sequences, enrolled participants, and assigned participants to interventions (10); sample size determination (7a); mentioning "randomized trial" in the title (1a). CONCLUSION: The compliance of craniofacial surgery RCTs with the CONSORT statement requires improvement. Areas in need are identified, and methods to improve reporting transparency, are discussed. PMID- 30444781 TI - Effects of Ultraviolet Irradiation on Cellular Senescence in Keratinocytes Versus Fibroblasts. AB - Aging is a biologic process characterized by time-dependent functional declines that are influenced by oxidative stress-induced inflammatory reactions. In particular, ultraviolet (UV) irradiation plays a key role in cellular senescence in photo-aged skin. However, the cellular senescence of epidermal keratinocytes and dermal fibroblasts by UV irradiation may differ depending on the exposure time and dosage of UV irradiation. Therefore, the purpose of the study was to evaluate and compare the effects of UV irradiation on cellular senescence in human epidermal keratinocytes (HaCaT) and human dermal fibroblasts (HDFs). After cell viability test, 200 mJ/cm UV irradiation was used in this study. To evaluate the reactive oxygen species and reactive nitrogen species production, the levels of glutathione (GSH) and nitrite (NO2) were measured. We also performed reverse transcription-polymerase chain reaction, Western blot analysis, and senescence associated beta-galactosidase assay. An overall decrease in GSH and an increase in NO2 were observed in the HaCaT and HDF cells. However, the time-line and dose dependent effects varied. Higher expressions of tumor necrosis factor-alpha, inducible nitric oxide synthase, and interleukin-1beta than that of the control group were observed in both cells. The HDF cells showed high levels of matrix metallopeptidase 9 and neutral endopeptidase protein but low levels of SIRT1 and procollagen I. The expression of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB) was increased in the HaCaT cells, but not in the HDF cells. The NF-kappaB peaked at 1 hour after UV irradiation in the HaCaT cells. The "turning-on" signal was faster in the irradiated HaCaT cells. PMID- 30444782 TI - Introduction to the Craniofacial Collaboration UK: A Developmental Screening Protocol at the United Kingdom's Four Highly Specialized Craniofacial Centers. AB - The clinical psychologists at the 4 highly specialized craniofacial centers in the United Kingdom have developed a systematic, developmental screening protocol, called the Craniofacial Collaboration UK (CC-UK). Previous systematic reviews of the literature into the developmental sequelae of single-suture craniosynostosis have identified a number of methodological flaws which the CC-UK seeks to avoid. This study presents an introduction to the rationale for its development, as well as the methodology of the CC-UK. PMID- 30444783 TI - Fibromyxoma of the Orbit. AB - Fibromyxomas are rare tumors that are not commonly seen in the orbit. The authors present a case of orbital fibromyxoma. A 42-year-old male presented with proptosis of the right eye that began 1 month prior. Magnetic resonance imaging revealed the presence of an orbital mass in the right eye, with low signal intensity on T1-weighted images and heterogeneous high-signal intensity on T2 weighted images. The patient underwent excisional biopsy of the orbital tumor through a Kronlein approach. The tumor originated from the inferior rectus muscle. Histopathologic analysis demonstrated scattered spindle cells, with both fibrous and myxoid stroma. Immunohistochemical staining was positive for Vimentin and negative for S-100 protein and CD34. The tumor was diagnosed as orbital fibromyxoma. The patient showed no evidence of recurrence over 18 months of follow-up after operation. PMID- 30444784 TI - Assessment of Bioabsorbable Hydroxyapatite for Cranial Defect in Children. AB - PURPOSE: To evaluate the utility and efficacy of bioabsorbable hydroxyapatite and collagen complex (HA/Col) for cranioplasty repair of cranial bone defects in children. METHODS: Two patients (a 6-year-old male and 11-year-old female) with Treacher Collins syndrome received zygoma and orbital floor reconstruction using a full thickness of parietal bone. The bone grafts were taken from each patient's parietal cranium. The right parietal cranial defect was repaired with autologous bone dust, and the left side was repaired with HA/Col in each patient. Computed tomography scans were taken immediately after and at 12 months following surgery. The osteosynthesis areas and thicknesses were measured using computer-aided engineering. RESULTS: Both patients experienced no complications, including infection. In the 6- and 11-year-old patients, the extent of osteosynthesis for HA/Col was 92.2% and 89.4%, respectively; and for the autologous bone dust was 78.5% and 53.2%, respectively. Because of the small sample size, a significant difference could not be calculated; however, the percentage of osteosynthesis for HA/Col was higher than for the autologous bone dust. CONCLUSION: This study showed that HA/Col can be effectively used in cranial defects and can be considered an alternative graft material for cranial reconstruction. PMID- 30444785 TI - Primary Reconstruction After Maxillectomy Defects Using Ultra Flex Mesh Plate and Rectus Abdominis Myocutaneous Free Flap Including Aponeurosis of External Abdominal Oblique Muscle. AB - BACKGROUND: In primary reconstruction after maxillectomy for cancer, simple and less invasive surgical techniques considering functionality and aesthetics are necessary. The authors performed reconstruction for tissue defects after maxillectomy using an Ultra flex mesh plate and a free rectus abdominis myocutaneous flap including the aponeurosis of the external abdominal oblique muscle. METHOD: A 72-year-old male with a maxillary squamous cell carcinoma underwent subtotal maxillectomy. For maxillary defects, including those in the orbital floor and hard palate, the authors performed rigid reconstruction using an Ultra flex mesh plate produced after simulation surgery using a 3-dimensional solid model, and palatal and soft tissue reconstruction using a free rectus abdominis myocutaneous flap including the aponeurosis of the external abdominal oblique muscle. After screw fixation of the mesh plate at the surrounding normal bone, the skinpaddle of the rectus abdominis flap was transferred to the oral defect. The surface of the mesh plate was completely covered with the aponeurosis of the external abdominal oblique muscle, and the remaining rectus abdominis flap was inserted into the maxillary sinus. RESULTS: At present, 1 year after the operation, there is no recurrence, complications, such as infection, or titanium mesh breakage/exposure, and his facial shape is favorably maintained. CONCLUSION: Reconstruction using this method is simple and less invasive. Postoperative infection and plate exposure were prevented by the complete coverage of the mesh plate with the aponeurosis of the external abdominal oblique muscle and flap. Mesh plates, when properly used, are useful reconstruction materials, but are susceptible to infection compared with autologous tissue, requiring long-term follow-up. PMID- 30444787 TI - Ulnar Artery Thrombosis Following Tranexamic Acid Administration for Craniosynostosis Repair. AB - Pediatric craniosynostosis repair with cranial vault reconstructive surgery can be associated with significant blood loss. Tranexamic acid (TXA), an antifibrinolytic agent, has been shown to decrease blood loss and transfusion volume in craniofacial surgery. Nonetheless data regarding the safety of TXA remains limited. The authors describe a case of ulnar artery thrombosis following ulnar arterial line placement in a patient who received TXA for cranial vault reconstructive surgery. PMID- 30444786 TI - Development of Multidirectional Cranial Distraction Osteogenesis for the Treatment of Craniosynostosis. AB - BACKGROUND: Previously, the authors developed a new method of distraction osteogenesis for the treatment of craniosynostosis, multidirectional cranial distraction osteogenesis (MCDO). The purpose of this study is to review the authors' experience of MCDO for remodeling of the anterior cranium in the patients of craniosynostosis. METHODS: Forty-five patients with craniosynostosis underwent MCDO for anterior cranial remodeling from 2003 to 2017. The ages of the patients ranged from 8 to 72 months (mean: 23.9 months, median: 13 months). The involved sutures included the bicoronal suture in 14 patients, unicoronal suture in 4 patients, sagittal suture in 14 patients, metopic suture in 2 patient, and multiple sutures in 10 patients. RESULTS: An improvement of in cranial shape was achieved in 40 patients. In 1 patient, intraoperative massive bleeding forced us finishing the procedure before completing the planned osteotomy. Transient cerebrospinal fluid leakage occurred in 3 patients during the activation phase but recovered with conservative therapy. The mean blood transfusion was 25.5 mL/kg. The phase of activation ranged from 7 to 17 days (mean, 10.6 days) and the consolidation period ranged from 16 to 67 days (mean, 32.4 days). Loosening of traction pins occurred in 7 patients, resulting in undercorrection in 2 patients, and loosening of anchor pins occurred in 19 patients, resulting in acceleration of removal of the devices in 7 patients. CONCLUSIONS: Multidirectional cranial distraction osteogenesis was effective and has several advantages over the conventional procedures. Therefore, the authors conclude that MCDO will be a useful alternative for all phenotypes of craniosynostosis. PMID- 30444788 TI - Modified Upper Blepharoplasty Using Combination of Incision and Nonincision Surgical Approaches. AB - Upper blepharoplasty can be divided into incision and nonincision technique. Each has its advantages and disadvantages. The author innovated a method of modified upper blepharoplasty by taking advantage of both procedures' strengths. This method involves redundant skin excision followed by double fold formation using the buried suture method. Orbicularis oculi muscle (OOM) excision or orbital fat excision may be performed if necessary, and ptosis can be corrected using Muller tucking. Lateral double fold reinforcement may be performed in older patients, where the OOM is sutured and fixed on to the levator aponeurosis in the lateral canthal area to prevent the lateral double fold from fading. This procedure was performed in 30 patients from March 2017 to February 2018, with satisfactory outcomes in most patients. Modified upper blepharoplasty is simple to perform, has fast recovery time as swelling rapidly disappears, and creates a dynamic fold. PMID- 30444789 TI - Soft Palate Dysfunction in Children With Microtia. AB - BACKGROUND: Speech issues in microtia patients have been historically attributed to poor hearing. However, the authors have noted that almost all patients with microtia have palatal dysfunction. The aim of this study is to determine the prevalence of soft palate dysfunction (SPD) and velopharyngeal insufficiency (VPI) in microtia patients. METHODS: A prospective cohort study was performed on consecutive microtia patients from March to June 2017. Clinical characteristics were collected. Palate movement was rated by oral examination and degree of nasal escape by the mirror-fogging test. Correlations between clinical characteristics of microtia and SPD were determined. RESULTS: Ninety-seven (40 unilateral, 27 bilateral, and 30 control) children met inclusion criteria. Among all 67 patients with microtia, 96% (64 patients) showed SPD. Twenty-four unilaterals (60%) and 23 bilaterals (85%) had observable VPI by mirror examination. Of these patients, nasality was noticeable to the examiners in 14 unilaterals (58%) and 21 bilaterals (91%). Sixteen of the 27 bilaterals (59%) showed almost no movement of the soft palate. There was a significant correlation between SPD and mirror fogging. A less developed middle ear as determined by computed tomography scan was associated with palatal dysfunction (P = 0.007). The severity of mandibular shift (P = 0.048) and presence of a syndrome (P = 0.045) were associated with grade of VPI. The severity of the ear deformity (P = 0.007) and presence of a syndrome (P = 0.034) were also correlated with the presence of SPD. CONCLUSIONS: This is the first study that documents the presence of VPI due to soft palate dysfunction in patients with isolated and nonisolated microtia. PMID- 30444790 TI - The Diffuse and Severe Traumatic Subarachnoid Hemorrhage Being Hard to Distinguish to Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: In primary intracerebral hemorrhage, several studies showed that contrast extravasation (CEV) is reported to be an indicator of delayed hematoma expansion, emergent hematoma removal and poor prognosis. On the contrary in head trauma, few researches validated the effectiveness of CEV because of other influences such as subarachnoid hemorrhage (SAH), contusion or brain swelling. The authors experienced a patient showing diffuse SAH caused by traumatic mechanism with acute subdural hematoma (ASDH). In the angiography, a notable rare image of CEV was found and emergency operation mainly to cease the bleeding points was performed. PATIENT PRESENTATION: A 70-year-old man was found being comatose and brought to emergency room. Computed tomography (CT) revealed diffuse SAH with left ASDH. Computed tomography angiography (CTA) also did not clarify any abnormal vessel structure except for slightly dilatation at the part of internal carotid artery, suggesting tiny ruptured aneurysm. The authors performed a cerebral angiography and resulted in no aneurysm or arteriovenous shunt detection but revealed the extravasation from middle cerebral artery and middle meningeal artery. Follow-up CT revealed increased left ASDH though 5 hours have already elapsed. The authors performed surgical intervention to halt the bleeding. CONCLUSION: The authors experienced a notably rare image of the extravasation from middle cerebral artery and middle meningeal artery in the cerebral angiography. When an obscure arterial abnormality is suspected on CTA for the unknown origin SAH with ASDH, the authors may have an affirmative attitude toward performing conventional cerebral angiography, which is most promising modality to detect the source of bleeding including CEV. PMID- 30444791 TI - An Application of Craniofacial Surgery to Aesthetic Surgery: Following the Path of Legendary Professor John Marquis Converse. PMID- 30444792 TI - C-terminal fragments of amyloid precursor proteins increase cofilin phosphorylation by LIM kinase in cultured rat primary neurons. AB - Amyloid precursor proteins (APPs) are processed by beta-, gamma-, and epsilon secretases and caspase-3 to generate C-terminal fragments of APP (APP-CTFs), which may contribute to the pathology of Alzheimer's disease (AD). In addition to amyloid plaques and neurofibrillary tangles, AD brains contain Hirano bodies, which are rod-like structures mostly composed of actin and the actin-binding protein, cofilin. However, the mechanisms underlying the formation of cofilin actin rods are still unknown. In this study, we aim to elucidate the effects of APP-CTFs on the actin-depolymerizing factor [(ADF)/cofilin]. Our data indicate that transfection with APP-CT99 and APP-CT57 may increase the phosphorylation level of Ser3 of ADF/cofilin and Thr508 of LIM-kinase 1 in rat primary cortical neuronal cultures. S3 peptide, a synthetic peptide competitor of LIM-kinase 1 for ADF/cofilin phosphorylation and an inhibitor of APP-CTFs, induced ADF/cofilin phosphorylation. In comparison with the wild-type mouse, the APP-CT transgenic mouse showed increased immunoreactivity of phosphorylated cofilin (p-cofilin) in the brain. Treatment with DAPT, an inhibitor of gamma-secretase, resulted in a decrease in p-cofilin protein level in the group transfected with full-length APP 695. Transfection with the mutant APP-CTF with a deleted YENPTY domain resulted in no significant increase in p-cofilin level. Thus, APP-CTFs induced cofilin phosphorylation to facilitate nuclear translocation. These results suggest a relationship between APP-CTFs and ADF/cofilin that may be suggestive of a new toxic pathway in the pathology of AD. PMID- 30444793 TI - Noninvasive Ventilation During Pediatric and Neonatal Critical Care Transport: A Systematic Review. AB - OBJECTIVES: Noninvasive ventilation is increasingly used in neonatal and pediatric patients, but the intensive care transport setting is lagging in terms of availability of noninvasive ventilation for children. The objective of this systematic review of the literature was to answer the question: In children 0 days to 18 years old, who are hospitalized with acute respiratory distress and require critical care transport, is noninvasive ventilation effective and safe during transport? DATA SOURCES: MEDLINE via PubMed, EMBASE (via Scopus), Cochrane Central Register of Controlled Trials, African Index Medicus, Web of Science Citation Index, and the World Health Organization Trials Registry. STUDY SELECTION: Two reviewers independently reviewed all identified studies for eligibility and quality. DATA EXTRACTION: Data were extracted independently by two reviewers using piloted data extraction forms. DATA SYNTHESIS: Data were not synthesized due to nature of studies included. RESULTS: A total of 1,287 records were identified; no randomized or quasi-randomized controlled trials were found. Eight observational studies, enrolling 858 patients were included, of these 60.4% were neonatal ICU and 39.6% were nonneonatal ICU patient transports. The mode of noninvasive ventilation during transport was continuous positive airway pressure in seven studies (708 patients) and high-flow nasal cannula in one study (150 patients). During transport on noninvasive ventilation, three of 858 patients (0.4%) required either intubation or escalation of noninvasive ventilation. In the 24 hours following transfer, 63 of 650 children (10%) transferred on noninvasive ventilation were intubated. The odds of intubation within 24 hours were significantly higher for continuous positive airway pressure transfer 60 of 500 (12%) compared with high-flow nasal cannula three of 150 (2%): odds ratio (95% CI) 6.68 (2.40-18.63), p value equals to 0.00003. Minor adverse events occurred in 1-4% of noninvasive ventilation transports. CONCLUSIONS: This review found observational study evidence of a rate of intubation or escalation of 0.4% during noninvasive ventilation transport of children 0-18 years old, with an in transport adverse event rate of 1-4%. Further studies are required. If randomized trials are not possible, it is suggested that well-conducted observational studies are reported in a more standardized manner. PMID- 30444794 TI - T1- and T2*-Mapping for Assessment of Tendon Tissue Biophysical Properties: A Phantom MRI Study. AB - OBJECTIVES: The aim of this study was to quantitatively assess changes in collagen structure using MR T1- and T2*-mapping in a novel controlled ex vivo tendon model setup. MATERIALS AND METHODS: Twenty-four cadaveric bovine flexor tendons underwent MRI at 3 T before and after chemical modifications, representing mechanical degeneration and augmentation. Collagen degradation (COL), augmenting collagen fiber cross-linking (CXL), and a control (phosphate buffered saline [PBS]) were examined in experimental groups, using histopathology as standard of reference. Variable echo-time and variable-flip angle gradient echo sequences were used for T2*- and T1-mapping, respectively. Standard T1- and T2-weighted spin-echo sequences were acquired for visual assessment of tendon texture. Tendons were assessed subsequently for their biomechanical properties and compared with quantitative MRI analysis. RESULTS: T1- and T2*-mapping was feasible and repeatable for untreated (mean, 545 milliseconds, 2.0 milliseconds) and treated tendons. Mean T1 and T2* values of COL, CXL, and PBS tendons were 1459, 934, and 1017 milliseconds, and 5.5, 3.6, and 2.5 milliseconds, respectively. T2* values were significantly different between enzymatically degraded tendons, cross-linked tendons, and controls, and were significantly correlated with mechanical tendon properties (r = -0.74, P < 0.01). T1 values and visual assessment could not differentiate CXL from PBS tendons. Photo spectroscopy showed increased autofluorescence of cross-linked tendons, whereas histopathology verified degenerative lesions of enzymatically degraded tendons. CONCLUSIONS: T2*-mapping has the potential to detect and quantify subtle changes in tendon collagen structure not visible on conventional clinical MRI. Tendon T2* values might serve as a biomarker for biochemical alterations associated with tendon pathology. PMID- 30444795 TI - Advanced Robotic Angiography Systems for Image Guidance During Conventional Transarterial Chemoembolization: Impact on Radiation Dose and Image Quality. AB - OBJECTIVES: The aim of this study was to compare 2 advanced robotic angiography systems for real-time image guidance in terms of radiation dose and image quality (IQ) during conventional transarterial chemoembolization (C-TACE) of hepatic malignant tumors. MATERIALS AND METHODS: One hundred six patients (57 women/49 men; mean age, 60 +/- 11 years) who had undergone C-TACE using 2 generations of robotic angiography platforms for image guidance were included in this retrospective study. Patients were divided into 2 groups (n = 53, respectively): group 1 (first generation) and group 2 (second generation). Radiation dose for fluoroscopy and digital subtraction angiography (DSA) was compared between first generation and second-generation angiography equipment, respectively. Among several features of the second-generation compared with the first-generation system, improvements included a refined crystalline detector system for enhanced noise reduction and advanced CARE filter software for lowering radiation dose. Radiation dose was measured using an ionization chamber. Image quality was assessed by 3 radiologists using 5-point Likert scales. RESULTS: Both groups were comparable in terms of number and location of lesions, as well as body weight, body mass index, and anatomical variants of feeding hepatic arteries (all P > 0.05). Dose-area product (DAP) for fluoroscopy was significantly lower in group 2 (1.4 +/- 1.1 Gy.cm) compared with group 1 (2.8 +/- 3.4 Gy.cm; P = 0.001). For DSA, DAP was significantly lower (P = 0.003) in group 2 (2.2 +/- 1.2 Gy.cm) versus group 1 (4.7 +/- 2.3 Gy.cm). Scores for DSA IQ indicated significant improvements for group 2 by 30% compared with group 1 (P = 0.004). Regarding fluoroscopy, scores for IQ were 76% higher in group 2 compared with group 1 (P = 0.001). Good to excellent interrater agreement with Fleiss kappa coefficients of kappa = 0.75 for group 1 and kappa = 0.74 for group 2 were achieved. CONCLUSIONS: Most recent generation robotic angiography equipment allows for considerable radiation dose reductions while improving IQ in fluoroscopy and DSA image guidance during C-TACE treatment. PMID- 30444796 TI - Tomoelastography for the Evaluation of Pediatric Nonalcoholic Fatty Liver Disease. AB - OBJECTIVES: Today, nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adults alike. Yet, the noninvasive evaluation of disease severity remains a diagnostic challenge. In this study, we apply multifrequency magnetic resonance elastography (mMRE) for the quantification of liver steatosis and fibrosis in adolescents with NAFLD. METHODS: Fifty adolescents (age range, 10-17 years; mean BMI, 33.9 kg/m; range, 21.4-42.1 kg/m) with biopsy-proven NAFLD were included in this prospective study. Multifrequency magnetic resonance elastography was performed using external multifrequency vibrations of 30 to 60 Hz and tomoelastography postprocessing, resulting in penetration rate (a) and shear wave speed (c). Hepatic fat fraction was determined using Dixon method. The diagnostic accuracy of mMRE in grading liver steatosis and staging liver fibrosis was assessed by receiver operating characteristic curve analysis. RESULTS: Multifrequency magnetic resonance elastography parameters c and a were independently sensitive to fibrosis and steatosis, respectively, providing area under the receiver operating characteristic values of 0.79 (95% confidence interval [CI], 0.66-0.92), 0.91 (95% CI, 0.83-0.99), and 0.90 (95% CI, 0.80-0.99) for the detection of any (>=F1), moderate (>=F2), and advanced (>=F3) fibrosis, and 0.87 (95% CI, 0.76 0.97) and 0.87 (95% CI, 0.77-0.96) for the detection of moderate (>=S2) and severe (S3) steatosis. CONCLUSIONS: One mMRE measurement provides 2 independent parameters with very good diagnostic accuracy in detecting moderate and advanced fibrosis as well as moderate and severe steatosis in pediatric NAFLD. PMID- 30444797 TI - Gait Mechanics and T1rho MRI of Tibiofemoral Cartilage 6 Months Post ACL Reconstruction. AB - PURPOSE: Aberrant walking biomechanics following anterior cruciate ligament reconstruction (ACLR) are hypothesized to associate with deleterious changes in knee cartilage. T1rho magnetic resonance imaging (MRI) is sensitive to decreased proteoglycan density of cartilage. Our purpose was to determine associations between T1rho MRI inter-limb ratios (ILR) and walking biomechanics 6-months post ACLR. METHODS: Walking biomechanics (peak vertical ground reaction force [vGRF], vGRF loading rate [vGRF-LR], knee extension moment [KEM], knee abduction moment [KAM]) were extracted from the first 50% of stance phase in 29 individuals with unilateral ACLR. T1rho MRI ILR (ACLR limb/uninjured limb) were calculated for regions of interest in both medial and lateral femoral (MFC and LFC) and tibial (MTC & LTC) condyles. Separate, stepwise linear regressions were used to determine associations between biomechanical outcomes and T1rho MRI ILR after accounting for walking speed and meniscal/chondral injury (P<=0.05). RESULTS: Lesser peak vGRF in the ACLR limb associated with greater T1rho MRI ILR for the LFC (Posterior DeltaR=0.14 P=0.05; Central DeltaR=0.15, P=0.05) and MFC (Central DeltaR=0.24, P=0.01). Lesser peak vGRF-LR in the ACLR limb (DeltaR=0.21, P=0.02) and the uninjured limb (DeltaR=0.27, P=0.01) associated with greater T1rho MRI ILR for the Anterior LFC. Lesser KAM for the injured limb associated with greater T1rho MRI ILR for the Anterior LFC (DeltaR=0.16, P=0.04) as well as the Posterior MTC (DeltaR=0.13, P=0.04). CONCLUSION: Associations between outcomes related to lesser mechanical loading during walking and greater T1rho MRI ILR were found 6 months post-ACLR. While preliminary, our results suggest under-loading of the ACLR limb at 6 months post-ACLR may be associated with lesser proteoglycan density in the ACLR limb compared to the uninjured limb. PMID- 30444798 TI - Hepatitis B vaccination induces mucosal antibody responses in the female genital tract, indicating potential mechanisms of protection against infection. AB - Vaccines against hepatitis B virus confer effective protection. ELISA was developed to test for specific antibodies in female genital tract secretions. Anti-HBs IgG and IgA were detected in the cervico-vaginal secretions of women following Hepatitis B vaccination, indicating a potential genital tract role for neutralising antibodies against sexually transmitted HBV. PMID- 30444799 TI - Invited Commentary Related to: Delay in Hip Fracture Surgery Prolongs Postoperative Hospital Length of Stay but Does Not Adversely Affect Outcomes at 30 Days. PMID- 30444800 TI - Varus Posteromedial Rotatory Instability of the Elbow: Injury Pattern and Surgical Experience of 27 Acute Consecutive Surgical Patients. AB - OBJECTIVES: To identify associated injuries that occur in varus posteromedial rotatory instability (VPMRI) of the elbow and present their surgical management. DESIGN: Level II retrospective study. SETTING: Tertiary referral center. PATIENT/PARTICIPANTS: Twenty-seven patients with VPMRI injuries treated surgically over an 8-year period. INTERVENTION: Open reduction and internal fixation of anteromedial coronoid facet fracture, lateral collateral ligament repair, and associated injured soft-tissue repairs. MAIN OUTCOME MEASURED: Radiographic classification, associated medial and lateral bony and soft-tissue injuries, surgical fixation method, and complications were recorded. RESULTS: According to the O'Driscoll classification, there were 15 (55%) type 2-2, 11 (41%) type 2-3, and 1 (4%) type 3-1 fractures. Lateral and medial collateral ligament tears were found in 100% and 63%, respectively. Common extensor and flexor origin injuries occurred in 19 (70%) and 2 (7%) elbows, respectively. A marginal radial head fracture was found in 1 patient. Most patients were treated with a combination of fixation methods. Complications occurred in 7 (26%) patients. CONCLUSIONS: This study documents both associated findings and surgical fixation methods. In all cases, the lateral collateral ligament was disrupted, often in association with an injured common extensor origin. Medial collateral ligament injuries are commonly involved. Radial head fractures are rarely associated. The surgeon should have a high index of suspicion if an isolated coronoid fracture is encountered. Clinical and functional outcome scores are needed in future studies to further inform treatment of VPMRI of the elbow. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 30444801 TI - The Effect of Foot Massage on Pain Intensity and Anxiety in Patients Having Undergone a Tibial Shaft Fracture Surgery: A Randomized Clinical Trial. AB - OBJECTIVE: To determine the effect of massage therapy on pain intensity and anxiety in patients who have undergone tibial shaft fracture surgery. DESIGN: This study was a randomized clinical trial with a pre-post design. As the study included 2 treatment groups, it was a parallel study. SETTING: Khatam-Al-Anbia Hospital in Zahedan, Iran, between July and August 2017. PATIENTS: In all, 66 patients who underwent a tibial shaft fracture surgery were enrolled and randomly assigned to intervention and control groups (33 patients each). INTERVENTION: The intervention included a 10-minute foot massage (5 minutes per leg) using sweet almond oil, the most common lubricant used in massage therapy. MAIN OUTCOME MEASUREMENTS: Data were collected using pain numeric rating scale and Spielberger State-Trait Anxiety Inventory before and after intervention. RESULTS: After intervention, the mean scores for pain intensity, and anxiety in the intervention and control groups were 4.72 (0.97) and 5.72 (0.91), and 42.84 (6.50) and 58.36 (10.37), respectively. A significant difference was noted between the intervention and control groups concerning pain intensity and anxiety. CONCLUSIONS: The results indicated that massage therapy reduced pain intensity and anxiety in patients who underwent tibial shaft fracture surgery. Therefore, using massage as a noninvasive and acceptable intervention is suggested in orthopaedic surgery, especially after tibial shaft fracture surgeries. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 30444802 TI - Deceased brain dead donor liver transplantation and utilization in the United States: nighttime and weekend effects. AB - BACKGROUND: Understanding factors that contribute to liver discards and non-usage is urgently needed to improve organ utilization. METHODS: With SRTR data, we studied a national cohort of all U.S. adult, deceased brain dead donor, isolated livers available for transplantation from 2003-2016, including organ-specific and system-wide factors that may affect organ procurement and discard rates. RESULTS: Of 73,686 available livers, 65,316 (88.64%) were recovered for transplant, of which 6,454 (9.88%) were ultimately discarded. Livers that were not procured or, upon recovery, discarded were more frequently from older, heavier, HCV+, and more comorbid donors (p<0.001). However, even after adjustment for organ quality, the odds of liver non-usage were 11% higher on the weekend (defined as donor procurements with cross-clamping occurring from 17:00 Friday until 23:59 Sunday) compared to weekdays (p<0.001). Non-use rates were also higher at night (p<0.001), defined as donor procurements with cross-clamping occurring from 17:00 to 05:00; however, weekend nights had significantly higher non-use rates compared to weekday nights (p=0.005). After Share 35, weekend non-usage rates decreased from 21.77% to 19.51% but were still higher than weekday non-usage rates (p=0.065). Weekend liver non-usage was higher in all 11 UNOS regions, with an absolute average of 2.00% fewer available livers being used on the weekend compared to weekdays. CONCLUSIONS: While unused livers frequently have unfavorable donor characteristics, there are also systemic and operational factors, including time of day and day of the week a liver becomes available, that impact the chance of liver non-procurement and discard. PMID- 30444803 TI - Modified technique of total hepatectomy in polycystic liver disease with caval flow preservation: the exposure left lateral sectionectomy. AB - BACKGROUND: Liver transplantation (LT) for polycystic liver disease (PLD) is rare, extremely challenging and hemorrhagic, without standard approach. Moreover, LT for PLD presents the highest mortality rate (12 to 18%) among all causes of LT. In this setting, the combination of difficult mobilization of a heavy polycystic native liver with narrow access to inferior vena cava (IVC) and fragile venous wall may lead to venous tearing and cataclysmic bleeding during dissection. The aim of this study was to evaluate a modified technique of total hepatectomy in order to limit hazardous liver manipulation and improve exposure of IVC in patients with massive hepatomegaly related to PLD: the exposure left lateral sectionectomy (ELLS). METHODS: From 2011 to 2018, ELLS was performed during LT for PLD. Key technical points for safe and fast ELLS include avoidance of left triangular ligament section and placement of a tape behind the left lateral section allowing its ascension and prior dissection of the hepatic pedicle to limit bleeding. The transection plane is mainly composed of cysts, with limited parenchyma, this allows for rapid and bloodless transection using electric scalpel. RESULTS: Fifteen patients had ELLS with no postoperative death or intraoperative complication. Median ELLS duration was 16 min and no massive bleeding occurred during this step. During total hepatectomy, median blood loss was 500 ml and no patient required total caval clamping. All patients were alive at the end of the follow-up. CONCLUSIONS: ELLS during LT for PLD facilitates total hepatectomy with vena cava and caval flow preservation. PMID- 30444804 TI - ENDOTHELIAL GLYCOCALYX SHEDDING PREDICTS DONOR ORGAN ACCEPTABILITY AND IS ASSOCIATED WITH PRIMARY GRAFT DYSFUNCTION IN LUNG TRANSPLANT RECIPIENTS. AB - BACKGROUND: The endothelial glycocalyx, a sieve-like structure located on the luminal surface of all blood vessels, has been found to be integral to regulation of capillary permeability and mechanotransduction. Given this, we investigated the role of endothelial glycocalyx breakdown products in organ donors and recipients in terms of acceptability for transplant and risk of primary graft dysfunction (PGD). METHODS: Endothelial glycocalyx breakdown products were measured in the peripheral blood of 135 intended and actual organ donors. Breakdown product levels were tested for association with donor demographic and clinical data, organ acceptability for transplant along with lung recipient outcomes (n=35). Liquid chromatography mass-spectrometry analysis was performed to confirm glycosaminoglycan levels and sulphation patterns on donor samples (n=15). In transplant recipients (n=50), levels were measured pre-transplant and daily for 4 days post-transplant. Levels were correlated with PGD severity and intubation time. RESULTS: Decreased hyaluronan levels in peripheral blood independently predicted organ acceptability in intended and actual donors (OR 0.96; (95%CI: 0.93-0.99) p=0.026). Furthermore, high donor syndecan-1 levels were associated with PGD in recipients (3142(1575-4829) vs 6229(4009-8093)pg/ml; p=0.045). In recipient blood, levels of syndecan-1 were correlated with severe (Grade 2-3) PGD at 72 hrs post-transplant (5982((3016-17191) vs 3060(2005 4824))pg/ml; p=0.01). CONCLUSIONS: Endothelial glycocalyx breakdown occurs in lung transplant donors and recipients and predicts organ acceptability and development of PGD. Glycocalyx breakdown products may be useful biomarkers in transplantation, and interventions to protect the glycocalyx could improve transplant outcomes. PMID- 30444805 TI - A Propensity Matched Survival Analysis: Do Simultaneous Liver-Lung Transplant Recipients Need a Liver? AB - BACKGROUND: There is debate whether simultaneous lung-liver transplant (LLT) long term outcomes warrant allocation of 2 organs to a single recipient. We hypothesized that LLT recipients would have improved posttransplant survival compared to matched single-organ lung recipients with an equivalent degree of liver dysfunction. METHODS: The OPTN/UNOS STAR file was queried for adult candidates for LLT and isolated lung transplantation from 2006-2016. Waitlist mortality and transplant odds were calculated for all candidates. Donor and recipient demographic characteristics were compiled and compared. LLT recipients were matched 1:2 with a nearest neighbor method to single-organ lung recipients. Kaplan-Meier methods with log-rank test compared long-term survival between groups. Univariate regression was used to calculate the association of LLT and mortality within 6-months of transplant. A proportional hazards model was used to calculate risk-adjusted mortality after 6-months posttransplantation. RESULTS: Thirty-eight LLT patients were matched to 75 single-organ lung recipients. After matching, no differences in baseline demographics or liver function were observed between cohorts. Length of stay was significantly longer in LLT recipients compared to isolated lung recipients (45.89 days vs. 22.44 days, p<0.001). There was no significant difference in survival probability between LLT and isolated lung transplant (1-year 89.5% vs. 86.7%, 5-year 67.0% vs. 64.6, p=0.20). CONCLUSIONS: After matching for patient characteristics and level of liver dysfunction, survival in simultaneous LLT was comparable to isolated lung transplantation. While this population is unique, the clinical picture prompting liver transplant is not clear. National guidelines to better elucidate patient selection are needed. PMID- 30444806 TI - Cell-free microRNA miR-505-3p in graft preservation fluid is an independent predictor of delayed graft function after kidney transplantation. AB - BACKGROUND: Delayed graft function (DGF), a common complication after transplantation of deceased donor kidneys, affects both short- and long-term outcomes. Currently available biomarkers during graft preservation lack sensitivity in predicting risk for DGF. The aim of this study is to identify cell free microRNA biomarkers in graft preservation fluid predictive of DGF after kidney transplantation. METHODS: Vascular bed preservation fluid was collected from 48 kidney grafts from DCD or DBD (donation after circulatory death or brain death) donors. MiRNA profiles were determined by PCR array (n=8) and validated by RT-qPCR (n=40). Graft function post-transplantation was defined as immediate good function (IF) or DGF. RESULTS: A total of 223 miRNAs fulfilled the pre-set parameters (Ct<40 in 3 or more samples) and were included in the analysis. Thirty two miRNAs were significantly different between DGF and IF kidney grafts (p<0.05) but, after correction for multiple testing, only miR-505-3p remained significant. The significant association of high miR-505-3p levels with DGF was confirmed in an independent validation cohort using conventional RT-qPCR detection. Multivariate analyses showed miR-505-3p as an independent predictor for DGF (OR 1.12, p=0.028). If stratified for donor type, miR-505-3p levels remained significantly different between IF and DGF in DCD grafts (p<0.01), but not in DBD grafts. ROC curve analysis showed a high sensitivity and specificity (AUC: 0.833). CONCLUSIONS: In DCD grafts, high levels of miR-505-3p in preservation fluid is associated with increased risk of DGF after kidney transplantation. Further study is required to confirm the utility of cell-free miR-505-3p as prognostic biomarker for DGF. PMID- 30444807 TI - Severity and Timing of Onset Drive Economic Costs and Clinical Outcomes With Sepsis. PMID- 30444808 TI - Is Teamwork Observation in the Eye of the Beholder? PMID- 30444809 TI - Can Serial Quick Sequential (Sepsis-Related) Organ Failure Assessment Measurement Aid in Sepsis Identification and Triage Decisions? PMID- 30444810 TI - Remembering the Unforgettable: Trialing ICU Diaries in North America. PMID- 30444811 TI - When Using Biomarkers in Alerts, Timing Is Everything. PMID- 30444812 TI - What Do ICU Clinicians Really Need to Know About Statistics: Time to Give Up or Time to Bridge the Gap Between the Evidence and the Reader? PMID- 30444814 TI - Did God Shape Humans to Be Long-Term Intubated and if Not-Does it Matter? PMID- 30444813 TI - Central Venous Catheter Failures: Nowhere Near Zero. PMID- 30444815 TI - Subtypes of Delirium: A Step Toward Precision Medicine. PMID- 30444816 TI - Burn Resuscitation: Don't Forget the Feeds. PMID- 30444817 TI - Keys, the Streetlamp, and Tidbits. PMID- 30444818 TI - Vitamin D for Acute Respiratory Distress Syndrome: Sunshine or Shade? PMID- 30444819 TI - ICU Readmission Is a More Complex Metric Than We First Imagined. PMID- 30444820 TI - Timing of Antibiotic Administration and Mortality in Septic Patients Presenting With Vague Symptoms. PMID- 30444821 TI - The authors reply. PMID- 30444822 TI - Half-Dose Versus Full-Dose Alteplase Therapy in Pulmonary Embolism: Does Half Dose Really Lose? PMID- 30444823 TI - The authors reply. PMID- 30444824 TI - Sleep, the Missing Link? PMID- 30444825 TI - The authors reply. PMID- 30444826 TI - Will This Patient Need to Be Admitted to the ICU After Supratentoral Brain Tumor Resection? A Hard Nut to Crack. PMID- 30444827 TI - The authors reply. PMID- 30444828 TI - The End of Corticosteroid in Sepsis: Fragile Results From Fragile Trials. PMID- 30444829 TI - The authors reply. PMID- 30444830 TI - In-Hospital Mortality After Rapid Response Team Calls in a 274 Hospital Nationwide Sample: Does Telemetry Monitoring Have a Role to Play? PMID- 30444831 TI - The authors reply. PMID- 30444832 TI - Inhaled Nitric Oxide in Children: Is There a Varying Effect by Severity? PMID- 30444833 TI - The authors reply. PMID- 30444834 TI - Neurostimulation-Guided Anal Intrasphincteric Botulinum Toxin Injection in Children with Hirschsprung's Disease. AB - OBJECTIVES: In Hirschsprung's disease (HD), despite successful surgical treatment, 50% of children experience long-term functional gastrointestinal problems, particularly chronic functional obstructive symptoms. We report our experience regarding clinical effects of neurostimulation-guided anal intrasphincteric botulinum toxin (BT) injections on postoperative obstructive symptoms attributed to a non-relaxing anal sphincter complex in HD patients. METHODS: In this monocenter cohort study, 15 HD patients with postoperative functional intestinal obstructive symptoms received neurostimulation-guided anal intrasphincteric BT injections. Short, medium and long-term effects were evaluated. The Bristol stool form scale was used to assess stool consistency, and the Jorge-Wexner (JW) score to assess fecal continence. RESULTS: The median age at first injection was 4 years. In the short-term, a significant improvement in stool consistency was noted in 12/14 patients (p = 0.0001) and JW score decreased for 14/15 patients (p = 0.001). In the medium-term, JW score significantly decreased for all patients (p = 0.0001), with an improvement of 50% or more for 10 patients (66.7%). In the long-term, 83.3% of patients had normal stool consistency and JW score was less than 3 for all. Recurrent enterocolitis decreased from 86.7% to 8.3%. A complete resolution of all symptoms without further medication was observed in 66.7% of patients in the long-term. CONCLUSIONS: Intrasphincteric BT injection was a safe, effective and durable option for the management of postoperative functional intestinal obstructive symptoms in HD. The use of neurostimulator guidance for specific delivery of BT to muscular fibers of non-relaxing anal sphincter complex takes into consideration the variability of patient's anatomy secondary to curative surgery. PMID- 30444835 TI - Clinical Safety and Utility of Pediatric Balloon Assisted Enteroscopy; A Multicenter Prospective Study in Japan. AB - OBJECTIVES: The benefit of balloon-assisted enteroscopy (BAE) had been recently documented in pediatric patients, but previous reports are based on single institution experiences. We evaluated the feasibility of pediatric BAE in 8 tertiary referral hospitals throughout Japan. METHODS: This was a prospective, multi-institutional study. Patients under 18 years were enrolled between April 2014 and March 2017 to undergo double-balloon or single-balloon enteroscopy. Data were collected prospectively using a standardized questionnaire. RESULTS: We enrolled 79 pediatric patients (96 procedures, 70 boys, 26 girls; median age 12.7 years, range 1-17 years). Antegrade (oral-route) BAE was performed in 20 procedures (lowest body weight 12.9 kg, youngest age 3.7 years), and retrograde (anal-route) BAE in 76 (lowest body weight 10.8 kg, youngest age 1.6 years). Severe adverse events were associated with BAE in two patients: one with hemorrhage due to polypectomy, and one with pancreatitis after double balloon endoscopic retrograde cholangioscopy. No intestinal perforation was reported. Procedure duration of oral-route BAE for diagnosis was significantly longer than anal-route for diagnosis (p < 0.001). The overall diagnostic yield for rectal bleeding/positive fecal occult blood test and abdominal pain was 48%. Among 40 patients referred for diagnosis who did not undergo capsule endoscopy, diagnoses were confirmed in 17 (42.5%) patients after BAE. CONCLUSIONS: This prospective multicenter observational study documents the efficacy of BAE in pediatric patients. PMID- 30444836 TI - Association Between Obesity/Overweight and Functional Gastrointestinal Disorders in Children. AB - OBJECTIVE: Although emerging data indicate that obese/overweight children are more likely to develop functional gastrointestinal disorders (FGIDs) than normal weight peers, contrasting results have been reported. The present observational, case-control study aimed at estimating the prevalence of FGIDs in obese/overweight children compared to normal-weight peers. METHODS: Consecutive obese and overweight children aged 4-18 years attending the obesity outpatient clinic were enrolled as study cases. Normal-weight children were enrolled as comparison group. All the enrolled patients received a thorough health examination from both a pediatric endocrinologist and gastroenterologist. Moreover, they were asked to fill out the Rome III questionnaire for the diagnosis of FGIDs. Data were analyzed to compare the prevalence of FGIDs between cases and controls. RESULTS: Throughout the study period we enrolled 103 cases and 115 controls. No significant age and gender differences were found between the 2 groups. FGIDs were significantly more prevalent in obese/overweight compared to normal-weight children (47.57% vs 17.39%; p < 0.0001). Increased prevalence was observed for functional constipation (18.44% vs 7.82%; p = 0.025), functional dyspepsia (23.33% vs 6.95%; p = 0.001), and irritable bowel syndrome (10.67% vs 2.60%; p = 0.024) while no difference was observed for functional abdominal pain (1.94% vs 2.60%; p = 1.00). CONCLUSIONS: Our data suggest that there is a link between excess body fat and FGIDs in children. This finding might offer a model of patients where the effects of food and nutritional substances, the gut microbial environment, as well as psychosocial factors are fitting well with the emerging biopsychosocial conceptual model for FGIDs. PMID- 30444837 TI - Noninvasive peripheral vascular function and atrial fibrillation in the general population. AB - BACKGROUND: Arterial stiffness is a strong predictor of atrial fibrillation in the community. Whether noninvasively measured conduit artery function and peripheral vascular reactivity are related to atrial fibrillation remains unknown. METHODS AND RESULTS: In 15 010 individuals of the population-based Gutenberg Health Study, mean age 55 +/- 11 years, 50.5% men, we determined noninvasive vascular function by flow-mediated dilation (FMD) and peripheral arterial tonometry (PAT) in relation to manifest atrial fibrillation (N = 466). Patients with atrial fibrillation exhibited a higher mean brachial artery diameter [4.81 mm (4.17, 5.33) in atrial fibrillation vs. 4.31 mm (3.67, 4.93)] and baseline pulse amplitude in arbitrary units [6.35 (5.76, 6.78) in atrial fibrillation vs. 6.09 (5.36, 6.71)] as well as a reduced FMD in arbitrary units [1.29 (1.26, 1.33) in atrial fibrillation vs. (1.31 (1.26, 1.37)] and PAT ratio [0.42 (0.19, 0.77) in atrial fibrillation vs. 0.67 (0.33, 0.94)] compared with individuals without atrial fibrillation (all PWilcoxon rank-sum test). In age adjusted and sex-adjusted logistic regression analyses, only baseline brachial artery diameter [odds ratio (OR) per standard deviation 1.19; 95% confidence interval (CI), 1.04-1.37; P = 0.012] and PAT ratio (OR 0.83; 0.74-0.94; P = 0.0029) were associated with atrial fibrillation. In risk factor and heart rate adjusted models, there was no statistically significant correlation of atrial fibrillation and brachial artery diameter, FMD and PAT ratio while baseline pulse amplitude was reduced in individuals with atrial fibrillation (OR 0.81; 95% CI 0.71-0.93; P = 0.0034). CONCLUSION: In our large contemporary cohort, peripheral vascular function was compromised in individuals with atrial fibrillation. However, observed associations were mediated by age and classical risk factors. Noninvasive vascular function measures did not improve discriminatory ability for atrial fibrillation.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30444838 TI - Impact of cumulative SBP and serious adverse events on efficacy of intensive blood pressure treatment: a randomized clinical trial. AB - BACKGROUND: Intensive blood pressure lowering is increasingly gaining attention. In addition to higher baseline blood pressure, cumulative SBP, visit-to-visit variability, and treatment-induced serious adverse events (SAEs) could impact treatment efficacy over time. Our aim was to assess the impact of cumulative SBP and SAEs on intensive hypertension treatment efficacy in the Systolic Blood Pressure Intervention Trial (SPRINT) population during follow-up. METHODS: Secondary analysis of the SPRINT study: a randomized, controlled, open-label trial including 102 clinical sites in the United States. We included 9068 SPRINT participants with 128 139 repeated SBP measurements. Participants were randomly assigned to intensive (target SBP < 120 mmHg) versus standard treatment (target SBP between 135 and 139 mmHg). We used cumulative joint models for longitudinal and survival data analysis. Primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, acute decompensated heart failure, stroke, and cardiovascular mortality. RESULTS: Although intensive treatment decreased the risk for the primary SPRINT outcome at the start of follow-up, its effect lost significance after 3.4 years of follow-up in the total SPRINT population and after 1.3, 1.3, 1.1, 1.8, 2.1, 1.8, and 3.4 years among participants with prevalent chronic kidney disease, prevalent cardiovascular disease, women, black individuals, participants less than 75 years, those with baseline SBP more than 132 mmHg, and individuals who suffered SAEs during follow up, respectively. CONCLUSION: The initial beneficial impact of intensive hypertension treatment might be offset by cumulative SBP and development of SAEs during follow-up.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc nd/4.0. PMID- 30444839 TI - Feasibility Study of a Mechanical Real-Time Feedback System for Optimizing the Sound Transfer in the Reconstructed Middle Ear. AB - OBJECTIVE: To evaluate electromechanical excitation as an alternative excitation mode for middle ear transfer function (METF) measurements as well as real-time feedback in prosthetic ossicular reconstruction. METHOD: In eight human cadaveric temporal bones, the ossicular chain was excited using acoustic and mechanical (floating mass transducer, FMT) stimulation to determine the METF. After disconnecting the ossicular chain and reconstruction with partial or total prosthesis the METFs were measured again. Continuous FMT stimulation was then applied to improve the prosthesis' position using real-time feedback of the METF. RESULTS: Mechanical stimulation of ossicular vibration showed characteristic differences to acoustic excitation resulting from the force characteristics of the FMT. Furthermore, the interspecimen METF variability was greater with electromechanical than acoustic stimulation because of interspecimen variability in the FMT coupling conditions. When the METF with FMT excitation was used as a real-time feedback tool, a measurable improvement in the quality of ossicular reconstruction could be achieved. CONCLUSIONS: Mechanical excitation is an effective and suitable alternative stimulation method in experimental METF measurements. The system provides real-time feedback for ossicular reconstruction in the experimental setting. Some influencing factors still need to be distinguished for reliable measurements. However, the method does not yet meet the requirements for clinical application as an intraoperative, real-time monitoring tool. However, the system could be an excellent model for high-end cadaveric temporal bone training in ossiculoplasty. PMID- 30444840 TI - Vestibular Testing: Patient Perceptions, Morbidity, and Opportunity Costs. AB - OBJECTIVE: To characterize patient tolerance and nonmonetary cost burdens of vestibular testing. Rigorously acquired data are essential for patient counseling and to determine if proposed additions/modifications to current protocols improve quality, experience, and efficiencies of care. STUDY DESIGN: Prospective observational study. SETTING: Tertiary center. PATIENTS: 130 adults (67% women, mean age 55 yr), referred to audiology clinic for vestibular testing. INTERVENTION(S): Surveys administered to patients and audiologists immediately and 1 week following videonystagmography (VNG) with caloric and/or rotary chair (RC) testing. MAIN OUTCOME MEASURE(S): Symptoms, visual analog scale ratings of dizziness, distress, and nausea during testing; test completion; and opportunity costs (time, missed work). RESULTS: Seventy-five patients (58%) experienced undesirable symptoms during testing, including nausea (50%), vomiting (5%), and headaches (12%). Distress and nausea ratings during testing were low (<3/10), with RC ratings lower than VNG. Nineteen patients (15%) discontinued testing early, rating distress and nausea two to three times higher than those who completed testing (p < 0.05). Greater dizziness was associated with younger age and female sex, not migraine and total eye speed. Women had increased distress. Test times were 71 [23] and 26 [13] minutes for VNG with calorics and RC, respectively. Testing required 48% to miss work (range 2-120 h) and 78% obtained assistance to/from testing. Posttest symptoms included drowsiness/fatigue (44%), nausea (31%), and headache (33%). CONCLUSIONS: This work provides baseline patient tolerance data for vestibular testing. While eliciting distress ratings comparable to other in-office otolaryngology procedures, there are high frequencies of undesirable symptoms, posttest morbidity, and opportunity costs. PMID- 30444841 TI - Significance of 1 kHz Pure-tone Threshold in Acute Low-frequency Sensorineural Hearing Loss. AB - OBJECTIVES: To analyze risk factors for acute low-frequency hearing loss (ALFHL), and compare treatment outcomes in the presence or absence of such risk factors. STUDY DESIGN: A case series featuring retrospective chart review. SETTING: An academic university hospital. PATIENTS: We included 170 ALFHL patients without vertigo. All of the patients received one of four treatments: low-dose steroid (LD-steroid), high-dose steroid (HD-steroid), LD-steroid and diuretics (LD combination therapy), and ITDI (intratympanic dexamethasone injection) and diuretics (ITDI-combination therapy). To identify risk factors, we reviewed the clinical features of patients such as age, sex, chief complaint, accompanying symptoms, diabetes, hypertension, time from disease onset, the extent of hearing loss, treatment methods, and 1 kHz involvement. INTERVENTIONS: ALFHL was diagnosed based on the average hearing loss >30 dB at 250 and 500 Hz. RESULTS: The overall rates of hearing recovery were 70-80% in the four treatment groups. In terms of the prognosis of ALFHL patients, we found that a longer time from disease onset and 1 kHz involvement were independent risk factors for poor prognosis. In addition, we compared treatment outcomes of four treatment methods in the presence or absence of risk factors. In ALFHL patients with risk factors, we found statistically significant differences (p = 0.042) among treatment methods; effectiveness ranged in the order if ITDI-combination therapy, LD combination therapy, HD-steroid, and LD-steroid. CONCLUSIONS: Risk factors for poor hearing recovery in ALFHL included longer symptom duration and 1 kHz involvement. In ALFHL with such risk factors, combination therapy was more effective than oral steroid therapy. PMID- 30444842 TI - Language Outcomes Improved Through Early Hearing Detection and Earlier Cochlear Implantation. AB - HYPOTHESIS: Early identification and intervention, earlier cochlear implantation, and mother's level of education will directly and/or indirectly impact the language outcomes of children with cochlear implants (CIs). BACKGROUND: Identifying factors that contribute to the wide range of language outcomes in children who use CIs will assist healthcare and rehabilitation professionals in optimizing service delivery for this population. Universal newborn hearing screening provides an opportunity to examine the relationship between meeting the early hearing detection and intervention (EHDI) 1-3-6 guidelines and child language outcomes. These guidelines recommend screening by 1 month, confirmation of hearing loss by 3 months, and intervention by 6 months of age. METHODS: Participants were 125 children with CIs ranging from 13 to 39 months of age. Language ability was measured using the Child Development Inventory and MacArthur Bates Communicative Development Inventories. RESULTS: Meeting EHDI 1-3-6, higher levels of maternal education and earlier cochlear implant activation had a direct, positive impact on language outcomes. Meeting the EHDI 1-3-6 guidelines also had an indirect positive effect on language outcomes via increasing the probability that the children's CIs would be activated earlier. Maternal education did not significantly predict age of cochlear implant activation nor whether a child met EHDI 1-3-6. CONCLUSION: Ensuring families meet the EHDI 1-3-6 guidelines is an early step that can lead to higher language outcomes and also earlier cochlear implantation. PMID- 30444843 TI - Nonverbal Reasoning as a Contributor to Sentence Recognition Outcomes in Adults With Cochlear Implants. AB - HYPOTHESIS: Significant variability in speech recognition persists among postlingually deafened adults with cochlear implants (CIs). We hypothesize that scores of nonverbal reasoning predict sentence recognition in adult CI users. BACKGROUND: Cognitive functions contribute to speech recognition outcomes in adults with hearing loss. These functions may be particularly important for CI users who must interpret highly degraded speech signals through their devices. This study used a visual measure of reasoning (the ability to solve novel problems), the Raven's Progressive Matrices (RPM), to predict sentence recognition in CI users. METHODS: Participants were 39 postlingually deafened adults with CIs and 43 age-matched normal-hearing (NH) controls. CI users were assessed for recognition of words in sentences in quiet, and NH controls listened to eight-channel vocoded versions to simulate the degraded signal delivered by a CI. A computerized visual task of the RPM, requiring participants to identify the correct missing piece in a 3*3 matrix of geometric designs, was also performed. Particular items from the RPM were examined for their associations with sentence recognition abilities, and a subset of items on the RPM was tested for the ability to predict degraded sentence recognition in the NH controls. RESULTS: The overall number of items answered correctly on the 48-item RPM significantly correlated with sentence recognition in CI users (r = 0.35-0.47) and NH controls (r = 0.36-0.57). An abbreviated 12-item version of the RPM was created and performance also correlated with sentence recognition in CI users (r = 0.40-0.48) and NH controls (r = 0.49-0.56). CONCLUSIONS: Nonverbal reasoning skills correlated with sentence recognition in both CI and NH subjects. Our findings provide further converging evidence that cognitive factors contribute to speech processing by adult CI users and can help explain variability in outcomes. Our abbreviated version of the RPM may serve as a clinically meaningful assessment for predicting sentence recognition outcomes in CI users. PMID- 30444844 TI - Facial Nerve Stimulation Patterns Associated With Cochlear Implantation in Labyrinthitis Ossificans. AB - OBJECTIVE: To describe and characterize facial nerve stimulation (FNS) patterns in patients with labyrinthitis ossificans who underwent cochlear implantation (CI) for sensorineural hearing loss. PATIENTS: Five ears in four patients with labyrinthitis ossificans who underwent CI and subsequently developed FNS. INTERVENTIONS: CI, electrode mapping, and/or explantation to resolve FNS. MAIN OUTCOME MEASURES: FNS, postoperative computed tomography imaging, and resolution of FNS. RESULTS: Fourteen ears with labyrinthitis ossificans underwent CI over an 11-year period at a single institution; 5 of these ears exhibited postoperative FNS (35.7% incidence). Four cases had involvement of basal electrodes, while all five cases had middle and/or apical electrode stimulation. All cases had resolution of FNS with CI reprogramming, however, the resultant map in two cases provided minimal audiologic benefit and patients became nonusers in that ear. CONCLUSIONS: FNS arising from all cochlear regions is possible in patients with labyrinthitis ossificans who undergo CI. Mapping and electrode deactivation can resolve symptoms, but resultant audiologic benefit is variable and may lead to explantation. PMID- 30444845 TI - Single Intravenous High Dose Administration of Prednisolone Has No Influence on Postoperative Impedances in the Majority of Cochlear Implant Patients. AB - OBJECTIVE: To evaluate effect of prednisolone on the impedances after cochlear implantation. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS AND INTERVENTION: A total of 130 patients underwent cochlear implantation with a Med-El Flex28 synchrony device between 2012 and 2016 and met the inclusion criteria. Only patients with full datasets regarding impedance measurements perioperatively, at first fitting (before and after chronic electric stimulation) and at 3 and 12 months appointments afterward were included. Patients (n = 101) received a single intravenous administration of at least 200 mg prednisolone intraoperatively and control patients (n = 29) did not receive any steroids at all. Patients receiving low dose steroids during surgery were excluded. MAIN OUTCOME MEASURES: Mean values for impedances were calculated over all electrode contacts and separately for basal, medial, and apical regions. RESULTS: Impedances increased significantly from perioperative measures to first fitting in both groups. Mainly at the basal region of the electrode array, impedances were slightly lower in the steroid group compared with controls. However, the majority of the patients showed increased impedances whether they received steroid treatment or not. CONCLUSION: The present study shows a slight but statistically significant reduction of the mean value of postoperative impedances at the basal electrode contacts in patients receiving a single systemic high dose application of prednisolone. Less than half of the patients showed a decrease in impedances and whether this decrease is clinically relevant remains to be elucidated. PMID- 30444846 TI - Neurocognitive Factors Contributing to Cochlear Implant Candidacy. AB - HYPOTHESIS: Clinical adult cochlear implant (CI) candidacy evaluations rely heavily on measures of sentence recognition under the best-aided listening conditions. The hypothesis tested in this study was that nonauditory measures of neurocognitive processes would contribute to scores on preoperative sentence recognition for CI candidates, above and beyond hearing ability as assessed using pure-tone average (PTA). Support for this hypothesis would suggest that best aided sentence recognition is not simply a measure of hearing ability; rather, neurocognitive functions contribute to performance and should be considered while counseling patients during CI candidacy evaluation about postoperative rehabilitative and outcome expectations. BACKGROUND: Neurocognitive functions, such as working memory capacity, inhibition-concentration, information processing speed, and nonverbal reasoning contribute to aided speech recognition outcomes in adults with hearing loss. This study examined the roles of these neurocognitive factors on preoperative speech recognition performance in adults evaluated for CI candidacy. METHODS: Thirty-one postlingually deafened adult CI candidates were enrolled. Participants were assessed using nonauditory measures of working memory capacity, inhibition-concentration, information processing speed, and nonverbal reasoning. Measures of sentence recognition in quiet and in multitalker babble (AzBio sentences) as well as sentences from the City University of New York in quiet were collected under best-aided conditions. RESULTS: AzBio sentence recognition scores in babble were predicted significantly by scores of working memory capacity after accounting for PTA. Similarly, the City University of New York sentence recognition scores were predicted significantly by nonverbal reasoning after accounting for PTA. CONCLUSIONS: Findings support the idea that clinical measures of sentence recognition may be affected to varying degrees by neurocognitive functions, and these functions should be considered during evaluation for CI candidacy. PMID- 30444847 TI - The Insertion Results of a Mid-scala Electrode Assessed by MRI and CBCT Image Fusion. AB - OBJECTIVES: To investigate the results of clinical surgical insertions with a Mid scala array (HIFocus Mid-Scala Electrode, HFms). STUDY DESIGN: Consecutive retrospective case study. SETTINGS: Tertiary referral center. PATIENTS: Analyses of imaging data of 26 consecutive patients (31 insertions) implanted with the HFms. INTERVENTION (S): The evaluation of insertion trauma evoked by a previously validated image fusion technique. Electrode reconstructions from postoperative cone-beam computed tomography (CBCT) were overlaid onto preoperative magnetic resonance imaging (MRI) scans to create artifact-free images. MAIN OUTCOME MEASURES: The electrode position was quantified in relation to the basilar membrane. Trauma scaling adopted from Eshraghi was used for evaluating insertion trauma. The results of the visual assessment of the postoperative CBCT were compared to those obtained with the fusion technique. RESULTS: Three insertions had to be excluded due to incompatibility of the imaging data with the fusion software. We found consistent peri- to mid-modiolar placement of the HFms with a mean insertion depth angle of 376 degrees . According to the medical records, a visual examination of the postoperative CBCT indicated that there had been no scala dislocations but when assessed by the image fusion technique, five scala dislocations (17.8%) were found. Additionally, one tip fold-over was detected in the postoperative CBCT even though this was not evident in any intraoperative measurements. CONCLUSION: HFms showed atraumatic surgical insertion results with consistent mid-modiolar placement. Image fusion enhances the accuracy of the insertion trauma assessment. Routine postoperative imaging is recommended for identifying tip fold-over as well as for quality control and documentation. PMID- 30444849 TI - A Cohort Study of Hearing Outcomes Between Middle Fossa Craniotomy and Transmastoid Approach for Surgical Repair of Superior Semicircular Canal Dehiscence Syndrome. AB - OBJECTIVE: To compare postoperative hearing outcomes between transmastoid and middle fossa craniotomy (MFC) approaches for surgical repair of superior semicircular canal dehiscence syndrome (SCDS) in a tertiary referral center. STUDY DESIGN: Historical cohort study. SETTING: Tertiary referral center. PATIENTS: Twelve consecutive SCDS cases who underwent transmastoid plugging of the superior canal; "controls" were 18 audiogram-matched patients who underwent MFC plugging and resurfacing. MAIN OUTCOME MEASURES: Differences between preoperative, 7-day postoperative, and long-term (>6 wk) postoperative air and bone conduction, speech discrimination scores (SDS), and pure-tone averages (PTA) in TM cases versus MFC controls. METHODS: MFC controls were selected by matching preoperative bone conduction (BC) pure-tone thresholds from the TM cases within 10-dBs NHL in >=80% of recorded frequencies. Wilcoxon signed-rank tests were performed to compare primary outcomes between matches, with a Bonferroni corrected p value of 0.004 (n = 13 variables measured at each time period). RESULTS: No statistically significant differences were found in long-term postoperative air conduction and BC thresholds at any frequency both during the immediate postoperative period as well as at long-term follow-up (p > 0.004). Similarly, there were no differences in long-term SDS or PTA (p > 0.004). CONCLUSIONS: In this pilot study, there were no long-term significant differences in hearing outcomes between the two repair techniques for SCDS. We recommend continuing with the established practice for recommending surgical repair based on individual patient characteristics and preferences in managing both vestibular and auditory function. PMID- 30444850 TI - CASE-CONTROL STUDY IS BEST FOR BASIC FIBROBLAST GROWTH FACTOR REPAIRING HUMAN CHRONIC TYMPANIC MEMBRANE PERFORATION. PMID- 30444851 TI - STRATEGY FOR REGENERATION OF CHRONIC TYMPANIC MEMBRANE PERFORATION WITH CHOLESTEATOMA TUMOR OR SEVERE CALCIFICATION. PMID- 30444848 TI - Mouse Magnetic-field Nystagmus in Strong Static Magnetic Fields Is Dependent on the Presence of Nox3. AB - HYPOTHESIS: Magnetic vestibular stimulation (MVS) elicits nystagmus in C57BL/6J mice but not head tilt mice lacking Nox3, which is required for normal otoconial development. BACKGROUND: Humans have vertigo and nystagmus in strong magnetic fields within magnetic resonance imaging machines. The hypothesized mechanism is a Lorentz force driven by electrical current entering the utricular neuroepithelium, acting indirectly on crista hair cells via endolymph movement deflecting cupulae. We tested an alternate hypothesized mechanism: Lorentz action directly on crista hair cell stereocilia, driven by their currents independent of the utricle. METHODS: Before MVS, vestibulo-ocular reflex responses of eight C57BL/6J mice and six head tilt mice were measured during whole-body sinusoidal rotations and tilts using video-oculography. Mice were then placed within a 4.7 Tesla magnetic field with the horizontal semicircular canals approximately Earth horizontal for >=1 minute in several head orientations, while eye movements were recorded via infrared video in darkness. RESULTS: Outside the magnet, both C57BL/6J and head tilt mice had intact horizontal vestibulo-ocular reflex, but only C57BL/6J mice exhibited static counter-roll responses to tilt (normal utiruclo-ocular reflex). When placed in the magnet nose-first, C57BL/6J mice had left-beating nystagmus, lasting a median of 32.8 seconds. When tail-first, nystagmus was right-beating and similar duration (median 28.0 s, p > 0.05). In contrast, head tilt mice lacked magnetic field-induced nystagmus (p < 0.001). CONCLUSIONS: C57BL/6J mice generate nystagmus in response to MVS, while mice deficient in Nox3 do not. This suggests 1) a normal utricle is necessary, and 2) functioning semicircular canals are insufficient, to generate MVS-induced nystagmus in mice. PMID- 30444852 TI - Sudden Severe Unilateral Vestibulo-Cochlear Loss Due to Acute Staphylococcal Otitis Media. PMID- 30444853 TI - An Unusual Case of Perforating Injury to the Middle Ear and Temporal Bone. PMID- 30444854 TI - To the Editor. PMID- 30444855 TI - Emergency General Surgery in Geriatric Patients: How Should We Evaluate Hospital Experience? AB - INTRODUCTION: As the aging American population poses unique challenges to acute care services, we determined if either hospital proportion or annual volume of geriatric patients undergoing emergency general surgery (EGS) procedures is associated with outcomes. METHODS: Using criteria from the American Association of the Surgery of Trauma, we identified five EGS procedures in the 2012-2015 Nationwide Inpatient Sample common in geriatric patients (65+ years). We defined hospital proportion as the fraction of geriatric EGS patients divided by all EGS patients, where volume was the raw number of geriatric EGS patients. We then divided hospitals into quartiles both by proportion and then by volume of geriatric patients. Multivariable logistic regressions compared four outcomes between these quartiles: mortality, complications, failure-to-rescue (FTR, death after a complication), and extended length of stay (LOS, procedure-specific top decile of patients). RESULTS: We identified 25,084 complex EGS procedures in geriatric patients at 3528 hospitals (mortality: 10.6%, complications: 30.5%, FTR: 27.7%, extended LOS: 9.1%). The median hospital proportion of geriatric patients among EGS procedures was 42.8% (IQR: 33.3% to 52.2%), whereas the median hospital geriatric EGS volume after nationwide weighting was 40/year (IQR: 20/year to 70/year). After adjustment, the lowest hospital proportion quartile relative to the highest was associated with adverse outcomes: mortality (OR 1.21 [95%-CI 1.03-1.44]), complications (1.16 [1.05-1.29]), FTR (1.32 [1.08-1.63]), and extended LOS (1.30 [1.12-1.50]). The lowest volume quartile relative to the highest was not associated with adverse outcomes. As the hospital proportion of geriatric patients increased by 10%, the odds of all adverse outcomes decreased: mortality by 7%, complications by 4%, FTR by 9%, and extended LOS by 8%. CONCLUSION: When accounting for both, hospital proportion of geriatric EGS patients but not hospital volume is associated with postoperative outcomes, having important implications for quality improvement initiatives, benchmarking endeavors, and health services research. EVIDENCE: Level III, Prognostic and Epidemiologic. PMID- 30444856 TI - THE IMPACT OF HYPOTHERMIA ON OUTCOMES IN MASSIVELY TRANSFUSED PATIENTS. AB - BACKGROUND: Hypothermia is associated with poor outcomes after injury. The relationship between hypothermia during contemporary large volume resuscitation and blood product consumption is unknown. We evaluated this association, and the predictive value of hypothermia on mortality. METHODS: Patients predicted to receive massive transfusion at 12 Level-1 trauma centers, randomized in the PROPPR trial, were grouped into those who were hypothermic (<36 degrees Celsius) or normothermic (36-38.5 degrees Celsius) within the first 6 hours of Emergency department arrival. The impact of hypothermia or normothermia on the volume of blood product required during the first 24 hours was determined via negative binomial regression, adjusting for treatment arm, injury severity score, mechanism, demographics, pre-emergency department fluid volume, blood administered prior to becoming hypothermic, pulse and systolic blood pressure on arrival and the time exposed to hypothermic or normothermic temperatures. RESULTS: Of 680 patients, 590 had a temperature measured during the first 6 hours in hospital, and 399 experienced hypothermia. The mean number of red blood cell units given to all patients in the first 24 hours of admission was 8.8 (95% CI 7.9-9.6). In multivariable analysis, every one-degree decrease in temperature below 36.0 degrees was associated with a 10% increase (incidence rate ratio [IRR] 0.90; 95% CI 0.89-0.92; p<0.00) in consumption of red blood cells during the first 24 hours of admission. There was no association between red blood cell administration and a temperature above 36 degrees. Hypothermia on arrival was an independent predictor of mortality, with an adjusted odds ratio of 2.7 (95% CI 1.7-4.5; p<0.00) for 24-hour and 1.8 (95% CI 1.3-2.4; p<0.00) for 30-day mortality. CONCLUSION: Hypothermia is associated with increased in blood product consumption and mortality. These findings support the maintenance of normothermia in trauma patients, and suggests that further investigation on the impact of cooling or rewarming during massive transfusion is warranted. LEVEL OF EVIDENCE: III Prognostic. PMID- 30444857 TI - Near-Hangings: Epidemiology, Injuries, and Investigations. AB - BACKGROUND: Near-hangings are an infrequent cause of trauma and the optimal work up for these patients is unclear. The study objectives were to define the epidemiology, injury patterns, and use of investigations, including CTA neck, after near-hangings. METHODS: All patients presenting to LAC+USC Medical Center (2008-2015) after near-hanging (ICD-9 E913.8, E953.0, E963, or E983.0) were screened for inclusion. Transferred patients were excluded. Patient demographics, clinical data, injury data, investigations performed, and outcomes were collected. RESULTS: Over the study period, 71 patients were identified. Mean age was 37 (range 17-89) and 85% (n=64) were male. Average GCS was 10 (range 3-15) and mean ISS was 5 (range 1-35). Mortality rate was 14% (n=10). The most common finding on physical examination was a ligature mark (n=38, 54%). Cervical injuries after near-hangings occurred infrequently (5 injuries in 4 patients [6%]: 3 [4%] arterial injuries and 2 [3%] laryngotracheal injuries). Only one patient (1%) required surgical and/or endovascular intervention. Two (3%) arrived in cardiac arrest, underwent resuscitative thoracotomy, and were pronounced dead. All others (n=69, 97%) underwent CTA of the neck. No patient in this series manifested signs or symptoms of cervical injury during hospitalization after a normal CTA neck on presentation. CONCLUSIONS: Near-hangings infrequently result in cervical injury and intervention is rarely needed. When injuries are sustained, they occur to critical structures such as the larynx, trachea, and cervical vasculature. Therefore, effective injury screening is important. We recommend CTA of the neck as the optimal initial imaging investigation after near hangings. LEVEL OF EVIDENCE: IV: Study Type: Descriptive case series. PMID- 30444858 TI - Guidelines for a system-wide multi-disciplinary approach to institutional REBOA implementation. PMID- 30444859 TI - Re: Use of an evidence-based algorithm for patients with traumatic hemothorax reduces need for additional interventions. PMID- 30444860 TI - Authors Response to Commentary on our Manuscript. PMID- 30444861 TI - CHANGE IN FUNCTIONAL STATUS AMONG CHILDREN TREATED IN THE INTENSIVE CARE UNIT AFTER INJURY. AB - BACKGROUND: Because pediatric trauma-related mortality continue to decline, metrics assessing morbidity are needed to evaluate the impact of treatment after injury. Based of its value for assessing children with traumatic brain injuries and other critical illnesses, Functional Status Scale (FSS), a tool that measures function in six domains (communication, feeding, mental, motor, sensory and respiratory), was evaluated as an outcome measure for the overall population of injured children. METHODS: Children with at least one injury (Abbreviated Injury Scale [AIS] severity >=1) surviving to discharge between December 2011 and April 2013 were identified in a previous study of intensive care unit admissions. Morbidity was defined as additional morbidity in any domain (domain FSS change >=2) and additional overall morbidity (total FSS change >=3 or 'new domain morbidity') between preinjury status and discharge. Associations between injury profiles and the development of morbidity were analyzed. RESULTS: We identified 553 injured children, with an average of 2.0 +/- 1.9 injuries. New domain and overall morbidity were observed in 17.0% and 11.0% of patients, respectively. New domain morbidity was associated with an increasing number of body regions with an injury with AIS>= 2 (P<0.001), with severe (AIS >= 4) head (P=0.04) and spine (P=0.01) injuries and with at moderately severe (AIS >= 2) lower extremity injuries (P=0.01). New domain morbidity was more common among patients with severe spine and lower extremity injuries (55.6% and 48.7%, respectively), with greatest impact in the motor domain (55.6% and 43.6%, respectively). New domain morbidity was associated with increasing ISS, number of moderately severe injuries and number of body regions with more than a moderately severe injury (P<0.001 for all). CONCLUSIONS: Higher morbidity measured by the FSS is associated with increasing injury severity. These findings support the use of the FSS as a metric for assessing outcome after pediatric injury. LEVEL OF EVIDENCE: III: Study type: Prognostic. PMID- 30444862 TI - Functional Long Noncoding RNAs (lncRNAs) in Clear Cell Kidney Carcinoma Revealed by Reconstruction and Comprehensive Analysis of the lncRNA-miRNA-mRNA Regulatory Network. AB - BACKGROUND A variety of treatment strategies have been developed for clear cell kidney carcinoma (KIRC); however, there is still a need for effective therapeutic targets and prognostic molecular biomarkers. Given that long noncoding RNAs (lncRNAs) has been emerging as an important regulator in tumorigenesis, we explored potential functional lncRNAs in KIRC by comprehensively analyzing the lncRNA-miRNA-mRNA regulatory network with bioinformatics processing tools. MATERIAL AND METHODS RNA-seq/miRNA-seq data of KIRC in The Cancer Genome Atlas (TCGA) were obtained and analyzed. The "edgeR" package in R software was used to identify differentially expressed lncRNAs (DElncRNAs, differentially expressed long noncoding RNAs), miRNAs (DEmiRNAs, differentially expressed micro RNAs), and mRNAs (DEmRNAs, differentially expressed messenger RNAs) in KIRC and normal samples. A global triple network was conducted based on the competing endogenous RNA (ceRNA) theory, and survival analysis was conducted by "survival" package in R software. RESULTS A total of 4246 DElncRNAs, 179 DEmiRNAs, and 5758 DEmRNAs were identified, among which a subset of them (321 lncRNAs, 26 miRNAs, and 1068 mRNAs) were found to constitute a global ceRNA network in KIRC. Four lncRNAs (ENTPD3-AS1, FGD5-AS1, LIFR-AS1, and UBAC2-AS1) were revealed to be potential therapeutic targets as well as prognostic biomarkers of KIRC by our extensive functional analysis. CONCLUSIONS We reported here the identification of functional lncRNAs in KIRC via a TCGA data-based bioinformatics analysis. We believe that this study might contribute to improving the comprehension of the lncRNA-mediated ceRNA regulatory mechanisms in the tumorigenesis of KIRC. Meanwhile, our results suggested that 4 lncRNAs might act as potential therapeutic targets or candidate prognostic biomarkers in KIRC. PMID- 30444863 TI - Metabolic models and gene essentiality data reveal essential and conserved metabolism in prokaryotes. AB - Essential metabolic reactions are shaping constituents of metabolic networks, enabling viable and distinct phenotypes across diverse life forms. Here we analyse and compare modelling predictions of essential metabolic functions with experimental data and thereby identify core metabolic pathways in prokaryotes. Simulations of 15 manually curated genome-scale metabolic models were integrated with 36 large-scale gene essentiality datasets encompassing a wide variety of species of bacteria and archaea. Conservation of metabolic genes was estimated by analysing 79 representative genomes from all the branches of the prokaryotic tree of life. We find that essentiality patterns reflect phylogenetic relations both for modelling and experimental data, which correlate highly at the pathway level. Genes that are essential for several species tend to be highly conserved as opposed to non-essential genes which may be conserved or not. The tRNA-charging module is highlighted as ancestral and with high centrality in the networks, followed closely by cofactor metabolism, pointing to an early information processing system supplied by organic cofactors. The results, which point to model improvements and also indicate faults in the experimental data, should be relevant to the study of centrality in metabolic networks and ancient metabolism but also to metabolic engineering with prokaryotes. PMID- 30444864 TI - Towards a molecular basis of ubiquitin signaling: A dual-scale simulation study of ubiquitin dimers. AB - Covalent modification of proteins by ubiquitin or ubiquitin chains is one of the most prevalent post-translational modifications in eukaryotes. Different types of ubiquitin chains are assumed to selectively signal respectively modified proteins for different fates. In support of this hypothesis, structural studies have shown that the eight possible ubiquitin dimers adopt different conformations. However, at least in some cases, these structures cannot sufficiently explain the molecular basis of the selective signaling mechanisms. This indicates that the available structures represent only a few distinct conformations within the entire conformational space adopted by a ubiquitin dimer. Here, molecular simulations on different levels of resolution can complement the structural information. We have combined exhaustive coarse grained and atomistic simulations of all eight possible ubiquitin dimers with a suitable dimensionality reduction technique and a new method to characterize protein-protein interfaces and the conformational landscape of protein conjugates. We found that ubiquitin dimers exhibit characteristic linkage type-dependent properties in solution, such as interface stability and the character of contacts between the subunits, which can be directly correlated with experimentally observed linkage-specific properties. PMID- 30444865 TI - Ribosome display for the rapid generation of high-affinity Zika-neutralizing single-chain antibodies. AB - BACKGROUND: Zika virus (ZIKV) is an emerging pathogen with no approved therapeutics and only limited diagnostics available. To address this gap, six mouse single-chain antibodies (scFvs) to ZIKV envelope (E) protein were isolated rapidly and efficiently from a ribosome-displayed antibody library constructed from the spleens of five immunized mice. METHODOLOGY/RESULTS: In this report, we have generated a panel of mouse scFvs to ZIKV E protein using ribosome display. The six scFvs demonstrated no cross-reactivity with DENV2 NGC envelope protein, suggesting specificity for ZIKV E protein. These scFvs showed differences in their affinity: two (scFv45-3, scFv63-1) of them were dominant after four rounds of panning, and showed higher affinity (an apparent Kd values from 19 to 27 nM) than the other four (scFv5-1, scFv7-2, scFv38-1, and scFv51-2). All six scFvs showed ZIKV-neutralizing activity in the plaque reduction neutralization test (PRNT) assay and their neutralizing activity was positively correlated with their affinities. CONCLUSIONS/SIGNIFICANCE: The scFvs (45-3 and 63-1) with highest affinity may have dual utility as diagnostics capable of recognizing ZIKV E subtypes and may be further developed to treat ZIKV infection. Our approach has the added advantage of generating Fc receptor-deficient antibodies, minimizing concern of antibody-dependent enhancement (ADE) of infection. PMID- 30444866 TI - Identification and characterization of Loa loa antigens responsible for cross reactivity with rapid diagnostic tests for lymphatic filariasis. AB - The Global Program to Eliminate Lymphatic Filariasis (LF) relies on rapid diagnostic tests (RDTs) to determine where annual mass drug administration for LF is required and when it can be stopped. These tests detect a Wuchereria bancrofti glycoprotein in the blood of infected persons via a carbohydrate moiety recognized by the monoclonal antibodies AD12 and DH6.5. Loiasis cross-reactivity with LF RDTs has recently been recognized as a serious obstacle to LF elimination in loiasis-endemic areas. To better understand the nature of this cross reactivity, we used the DH6.5 antibody to immunoaffinity purify Loa loa antigens from the sera of individuals with a positive RDT due to loiasis. Immunoblot analysis revealed many circulating AD12/DH6.5-reactive antigens, and proteomic analysis identified multiple L. loa proteins in LF RDT-positive loiasis sera. These included both secreted and somatic proteins, suggesting that they may be released by dying L. loa adult worms and/or microfilariae. Unlike the single high molecular weight W. bancrofti circulating filarial antigen that is reliably present in the blood of persons with bancroftian filariasis, reactive L. loa antigens appeared to be only transiently present in the blood of a subset of persons with loiasis. These key differences between the circulating antigens of W. bancrofti and L. loa can be used to differentiate positive results generated by both species and may lead to improved diagnostic tests for LF and loiasis. PMID- 30444867 TI - Correction: Plasma Membrane Is the Site of Productive HIV-1 Particle Assembly. AB - [This corrects the article DOI: 10.1371/journal.pbio.0040435.]. PMID- 30444869 TI - A glimpse into the genetic diversity of the Peruvian seafood sector: Unveiling species substitution, mislabeling and trade of threatened species. AB - Peru is one of the world's leading fishing nations and its seafood industry relies on the trade of a vast variety of aquatic resources, playing a key role in the country's socio-economic development. DNA barcoding has become of paramount importance for systematics, conservation, and seafood traceability, complementing or even surpassing conventional identification methods when target organisms show similar morphology during the early life stages, have recently diverged, or have undergone processing. Aiming to increase our knowledge of the species diversity available across the Peruvian supply chain (from fish landing sites to markets and restaurants), we applied full and mini-barcoding approaches targeting three mitochondrial genes (COI, 16S, and 12S) and the control region to identify samples purchased at retailers from six departments along the north-central Peruvian coast. DNA barcodes from 131 samples were assigned to 55 species (plus five genus-level taxa) comprising 47 families, 24 orders, and six classes including Actinopterygii (45.03%), Chondrichthyes (36.64%), Bivalvia (6.87%), Cephalopoda (6.11%), Malacostraca (3.82%), and Gastropoda (1.53%). The identified samples included commercially important pelagic (anchovy, bonito, dolphinfish) and demersal (hake, smooth-hound, Peruvian rock seabass, croaker) fish species. Our results unveiled the marketing of protected and threatened species such as whale shark, Atlantic white marlin, smooth hammerhead (some specimens collected during closed season), shortfin mako, and pelagic thresher sharks. A total of 35 samples (26.72%) were mislabeled, including tilapia labeled as wild marine fish, dolphinfish and hake labeled as grouper, and different shark species sold as "smooth-hounds". The present study highlights the necessity of implementing traceability and monitoring programs along the entire seafood supply chain using molecular tools to enhance sustainability efforts and ensure consumer choice. PMID- 30444870 TI - Genome-wide detection of terpene synthase genes in holy basil (Ocimum sanctum L.). AB - Holy basil (Ocimum sanctum L.) and sweet basil (Ocimum basilicum L.) are the most commonly grown basil species in India for essential oil production and biosynthesis of potentially volatile and non-volatile phytomolecules with commercial significance. The aroma, flavor and pharmaceutical value of Ocimum species is a significance of its essential oil, which contains most of the monoterpenes and sesquiterpenes. A large number of plants have been studied for characterization and identification of terpene synthase genes, involved in terpenoids biosynthesis. The goal of this study is to discover and identify the putative functional terpene synthase genes in O. sanctum. HMMER search was performed by using a set of 13 well sequenced and annotated plant genomes including the newly sequenced genome of O. sanctum with Pfam-A database locally, using HMMER 3.0 hmmsearch for the two Pfam domains (PF01397 and PF03936). Using this search method 81 putative terpene synthases genes (OsaTPS) were identified in O. sanctum; the study further reveals 47 OsaTPS were putatively functional genes, 19 partial OsaTPS, and 15 OsaTPS as probably pseudogenes. All these identified OsaTPS genes were compared with other plant species, and phylogenetic analysis reveals the subfamily classification of OsaTPS in TPS-a, -b, -c, -e, -f and TPS-g subfamilies clusters. This genome-wide identification of OsaTPS genes, their phylogenetic analysis and secondary metabolite pathway mapping predictions together provide a comprehensive understanding of the TPS gene family in Ocimum sanctum and offer opportunities for the characterization and functional validation of numbers of terpene synthase genes. PMID- 30444868 TI - Exploring patient information needs in type 2 diabetes: A cross sectional study of questions. AB - This study set out to analyze questions about type 2 diabetes mellitus (T2DM) from patients and the public. The aim was to better understand people's information needs by starting with what they do not know, discovered through their own questions, rather than starting with what we know about T2DM and subsequently finding ways to communicate that information to people affected by or at risk of the disease. One hundred and sixty-four questions were collected from 120 patients attending outpatient diabetes clinics and 300 questions from 100 members of the public through the Amazon Mechanical Turk crowdsourcing platform. Twenty-three general and diabetes-specific topics and five phases of disease progression were identified; these were used to manually categorize the questions. Analyses were performed to determine which topics, if any, were significant predictors of a question's being asked by a patient or the public, and similarly for questions from a woman or a man. Further analysis identified the individual topics that were assigned significantly more often to the crowdsourced or clinic questions. These were Causes (CI: [-0.07, -0.03], p < .001), Risk Factors ([-0.08, -0.03], p < .001), Prevention ([-0.06, -0.02], p < .001), Diagnosis ([-0.05, -0.02], p < .001), and Distribution of a Disease in a Population ([-0.05,-0.01], p = .0016) for the crowdsourced questions and Treatment ([0.03, 0.01], p = .0019), Disease Complications ([0.02, 0.07], p < .001), and Psychosocial ([0.05, 0.1], p < .001) for the clinic questions. No highly significant gender-specific topics emerged in our study, but questions about Weight were more likely to come from women and Psychosocial questions from men. There were significantly more crowdsourced questions about the time Prior to any Diagnosis ([(-0.11, -0.04], p = .0013) and significantly more clinic questions about Health Maintenance and Prevention after diagnosis ([0.07. 0.17], p < .001). A descriptive analysis pointed to the value provided by the specificity of questions, their potential to disclose emotions behind questions, and the as-yet unrecognized information needs they can reveal. Large-scale collection of questions from patients across the spectrum of T2DM progression and from the public-a significant percentage of whom are likely to be as yet undiagnosed-is expected to yield further valuable insights. PMID- 30444871 TI - Knowledge, attitudes and practices towards dog-bite related rabies in para medical staff at rural primary health centres in Baramati, western India. AB - The lack of awareness regarding rabies amongst rural primary care health staff and their adverse practices towards the management of dog-bite wounds is a major contributor to the high incidence of rabies infection and subsequent human mortality in India. A Knowledge, Attitudes and Practices survey was carried out involving 54 nursing and non-nursing staff working in 18 rural Primary Health centres and sub-centres around Baramati town of Pune district in Western India. Multivariable logistic regression models were constructed to assess factors that influenced knowledge of rabies and practices towards management of dog-bite related wounds. The more experienced and better-educated workers were found to have a good awareness of rabies (OR 3.4, 95%CI 1.0-12.1) and good practices towards dog-bite wound management (OR 5.6, 95%CI 1.2-27.0). Surprisingly, non nursing staff were significantly more knowledgeable about rabies (OR 3.5, 95%CI 1.0-12.3), but their practices towards dog-bite wound management were inadequate (OR 0.18, 95%CI 0.04-0.8) compared to the nursing staff. It is recommended that a mandatory training module for primary care health staff be developed and implemented to improve their knowledge regarding rabies and management of dog bite wounds to reduce the incidence of human rabies in rural India. PMID- 30444872 TI - A novel sensor design for accurate measurement of facial somatosensation in pre term infants. AB - Facial somatosensory feedback is critical for breastfeeding in the first days of life. However, its development has never been investigated in humans. Here we develop a new interface to measure facial somatosensation in newborn infants. The novel system allows to measure neuronal responses to touching the face of the subject by synchronously recording scalp electroencephalography (EEG) and the force applied by the experimenter. This is based on a dedicated force transducer that can be worn on the finger underneath a clinical nitrile glove and linked to a commercial EEG acquisition system. The calibrated device measures the pressure applied by the investigator when tapping the skin concurrently with the resulting brain response. With this system, we were able to demonstrate that taps of 192 mN (mean) reliably elicited facial somatosensory responses in 7 pre-term infants. These responses had a time course similar to those following limbs stimulation, but more lateral topographical distribution consistent with body representations in primary somatosensory areas. The method introduced can therefore be used to reliably measure facial somatosensory responses in vulnerable infants. PMID- 30444873 TI - Scan, dwell, decide: Strategies for detecting abnormalities in diabetic retinopathy. AB - Diabetic retinopathy (DR) is a disease which is widely diagnosed using (colour fundus) images. Efficiency and accuracy are critical in diagnosing DR as lack of timely intervention can lead to irreversible visual impairment. In this paper, we examine strategies for scrutinizing images which affect diagnostic performance of medical practitioners via an eye-tracking study. A total of 56 subjects with 0 to 18 years of experience participated in the study. Every subject was asked to detect DR from 40 images. The findings indicate that practitioners use mainly two types of strategies characterized by either higher dwell duration or longer track length. The main findings of the study are that higher dwell-based strategy led to higher average accuracy (> 85%) in diagnosis, irrespective of the expertise of practitioner; whereas, the average obtained accuracy with a long-track length based strategy was dependent on the expertise of the practitioner. In the second part of the paper, we use the experimental findings to recommend a scanning strategy for fast and accurate diagnosis of DR that can be potentially used by image readers. This is derived by combining the eye-tracking gaze maps of medical experts in a novel manner based on a set of rules. This strategy requires scrutiny of images in a manner which is consistent with spatial preferences found in human perception in general and in the domain of fundus images in particular. The Levenshtein distance-based assessment of gaze patterns also establish the effectiveness of the derived scanning pattern and is thus recommended for image readers. PMID- 30444874 TI - Same but different: Comparison of two system-specific molecular chaperones for the maturation of formate dehydrogenases. AB - The maturation of bacterial molybdoenzymes is a complex process leading to the insertion of the bulky bis-molybdopterin guanine dinucleotide (bis-MGD) cofactor into the apo-enzyme. Most molybdoenzymes were shown to contain a specific chaperone for the insertion of the bis-MGD cofactor. Formate dehydrogenases (FDH) together with their molecular chaperone partner seem to display an exception to this specificity rule, since the chaperone FdhD has been proven to be involved in the maturation of all three FDH enzymes present in Escherichia coli. Multiple roles have been suggested for FdhD-like chaperones in the past, including the involvement in a sulfur transfer reaction from the l-cysteine desulfurase IscS to bis-MGD by the action of two cysteine residues present in a conserved CXXC motif of the chaperones. However, in this study we show by phylogenetic analyses that the CXXC motif is not conserved among FdhD-like chaperones. We compared in detail the FdhD-like homologues from Rhodobacter capsulatus and E. coli and show that their roles in the maturation of FDH enzymes from different subgroups can be exchanged. We reveal that bis-MGD-binding is a common characteristic of FdhD-like proteins and that the cofactor is bound with a sulfido-ligand at the molybdenum atom to the chaperone. Generally, we reveal that the cysteine residues in the motif CXXC of the chaperone are not essential for the production of active FDH enzymes. PMID- 30444876 TI - A minimal power model for human running performance. AB - Models for human running performances of various complexities and underlying principles have been proposed, often combining data from world record performances and bio-energetic facts of human physiology. The purpose of this work is to develop a novel, minimal and universal model for human running performance that employs a relative metabolic power scale. The main component is a self-consistency relation for the time dependent maximal power output. The analytic approach presented here is the first to derive the observed logarithmic scaling between world (and other) record running speeds and times from basic principles of metabolic power supply. Our hypothesis is that various female and male record performances (world, national) and also personal best performances of individual runners for distances from 800m to the marathon are excellently described by this model. Indeed, we confirm this hypothesis with mean errors of (often much) less than 1%. The model defines endurance in a way that demonstrates symmetry between long and short racing events that are separated by a characteristic time scale comparable to the time over which a runner can sustain maximal oxygen uptake. As an application of our model, we derive personalized characteristic race speeds for different durations and distances. PMID- 30444875 TI - Mutational monitoring of EGFR T790M in cfDNA for clinical outcome prediction in EGFR-mutant lung adenocarcinoma. AB - Several ultra-sensitive methods for T790M in plasma cell-free DNA (cfDNA) have been developed for lung cancer. The correlation between mutation-allele frequency (MAF) cut-off, drug responsiveness, and outcome prediction is an unmet needs and not fully addressed. An innovative combination of peptide nucleic acid (PNA) and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) was used to proof of concept for monitoring cfDNA T790M in EGFR mutant patients. Mutant enrichment by PNA was optimized and the detection limit was evaluated through serial dilutions. The cut-off value was identified by receiver-operating-characteristic (ROC) curve analysis utilizing serial sampled plasmas of patients from EGFR-tyrosine kinase inhibitor (TKI) pretreatment to progressive-disease (PD). Results, comparisons, and objective response rate (ORR) were analyzed in 103 patients' tumor and cfDNA T790M, with 20 of them receiving an additional COBAS test. The detection limit was 0.1% MAF. The cut-off for PD and imminent PD was 15% and 5% with an ROC area under the curve (AUC) of 0.96 and 0.82 in 2 ml plasma. Detection sensitivity of cfDNA T790M was 67.4% and overall concordance was 78.6%. ORR was similar in T790M-positive cfDNA (69.6%) and tumor samples (70.6%) treated with osimertinib. Among 65 T790M-positive tumors, 15 were negative in cfDNA (23.1%). Seven of 38 T790M-positive cfDNA samples were negative in the tumors (18.4%). PNA-MALDI-TOF MS had a higher detection rate than COBAS. In conclusion, identification of T790M cut-off value in cfDNA improves cancer managements. We provide a strategy for optimizing testing utility, flexibility, quality, and cost in the clinical practice. PMID- 30444877 TI - Modeling physiological responses induced by an emotion recognition task using latent class mixed models. AB - Correctly recognizing emotions is an essential skill to manage interpersonal relationships in everyday life. Facial expression represents the most powerful mean to convey important information on emotional and cognitive states during interactions with others. In this paper, we analyze physiological responses triggered by an emotion recognition test, which requires the processing of facial cues. In particular, we evaluate the modulation of several Heart Rate Variability indices, collected during the Reading the Mind in the Eyes Test, accounting for test difficulty (derived from a Rasch analysis), test performances, demographic and psychological characteristics of the participants. The main idea is that emotion recognition is associated with the Autonomic Nervous System and, as a consequence, with the Heart Rate Variability. The principal goal of our study was to explore the complexity of the collected measures and their possible interactions by applying a class of flexible models, i.e., the latent class mixed models. Actually, this modelling strategy allows for the identification of clusters of subjects characterized by similar longitudinal trajectories. Both univariate and multivariate latent class mixed models were used. In fact, while the interpretation of the Heart Rate Variability indices is very difficult when considered individually, a joint evaluation provides a better description of the Autonomic Nervous System state. PMID- 30444878 TI - Functional regulatory mechanism of smooth muscle cell-restricted LMOD1 coronary artery disease locus. AB - Recent genome-wide association studies (GWAS) have identified multiple new loci which appear to alter coronary artery disease (CAD) risk via arterial wall specific mechanisms. One of the annotated genes encodes LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle-containing tissues such as the artery wall. However, it is still unknown whether LMOD1 is the causal gene at this locus and also how the associated variants alter LMOD1 expression/function and CAD risk. Using epigenomic profiling we recently identified a non-coding regulatory variant, rs34091558, which is in tight linkage disequilibrium (LD) with the lead CAD GWAS variant, rs2820315. Herein we demonstrate through expression quantitative trait loci (eQTL) and statistical fine-mapping in GTEx, STARNET, and human coronary artery smooth muscle cell (HCASMC) datasets, rs34091558 is the top regulatory variant for LMOD1 in vascular tissues. Position weight matrix (PWM) analyses identify the protective allele rs34091558-TA to form a conserved Forkhead box O3 (FOXO3) binding motif, which is disrupted by the risk allele rs34091558-A. FOXO3 chromatin immunoprecipitation and reporter assays show reduced FOXO3 binding and LMOD1 transcriptional activity by the risk allele, consistent with effects of FOXO3 downregulation on LMOD1. LMOD1 knockdown results in increased proliferation and migration and decreased cell contraction in HCASMC, and immunostaining in atherosclerotic lesions in the SMC lineage tracing reporter mouse support a key role for LMOD1 in maintaining the differentiated SMC phenotype. These results provide compelling functional evidence that genetic variation is associated with dysregulated LMOD1 expression/function in SMCs, together contributing to the heritable risk for CAD. PMID- 30444880 TI - Identification of molecular determinants that govern distinct STIM2 activation dynamics. AB - The endoplasmic reticulum (ER) Ca2+ sensors stromal interaction molecule 1 (STIM1) and STIM2, which connect ER Ca2+ depletion with extracellular Ca2+ influx, are crucial for the maintenance of Ca2+ homeostasis in mammalian cells. Despite the recent progress in unraveling the role of STIM2 in Ca2+ signaling, the mechanistic underpinnings of its activation remain underexplored. We use an engineering approach to direct ER-resident STIMs to the plasma membrane (PM) while maintaining their correct membrane topology, as well as Forster resonance energy transfer (FRET) sensors that enabled in cellulo real-time monitoring of STIM activities. This allowed us to determine the calcium affinities of STIM1 and STIM2 both in cellulo and in situ, explaining the current discrepancies in the literature. We also identified the key structural determinants, especially the corresponding G residue in STIM1, which define the distinct activation dynamics of STIM2. The chimeric E470G mutation could switch STIM2 from a slow and weak Orai channel activator into a fast and potent one like STIM1 and vice versa. The systemic dissection of STIM2 activation by protein engineering sets the stage for the elucidation of the regulation and function of STIM2-mediated signaling in mammals. PMID- 30444879 TI - Experimental co-transmission of Simian Immunodeficiency Virus (SIV) and the macaque homologs of the Kaposi Sarcoma-Associated Herpesvirus (KSHV) and Epstein Barr Virus (EBV). AB - Macaque RFHV and LCV are close homologs of human KSHV and EBV, respectively. No experimental model of RFHV has been developed due to the lack of a source of culturable infectious virus. Screening of macaques at the Washington National Primate Research Center detected RFHV in saliva of SIV-infected macaques from previous vaccine studies. A pilot experimental infection of two naive juvenile pig-tailed macaques was initiated by inoculation of saliva from SIV-infected pig tailed and cynomolgus macaque donors, which contained high levels of DNA (> 106 genomes/ml) of the respective species-specific RFHV strain. Both juvenile recipients developed SIV and RFHV infections with RFHV DNA detected transiently in saliva and/or PBMC around week 16 post-infection. One juvenile macaque was infected with the homologous RFHVMn from whole saliva of a pig-tailed donor, which had been inoculated into the cheek pouch. This animal became immunosuppressed, developing simian AIDS and was euthanized 23 weeks after inoculation. The levels of RFHV DNA in saliva and PBMC remained below the level of detection after week 17, showing no reactivation of the RFHVMn infection during the rapid development of AIDS. The other juvenile macaque was infected with the heterologous RFHVMf from i.v. inoculation of purified virions from saliva of a cynomolgus donor. The juvenile recipient remained immunocompetent, developing high levels of persistent anti-RFHV and -SIV antibodies. After the initial presence of RFHVMf DNA in saliva and PBMC decreased to undetectable levels by week 19, all attempts to reactivate the infection through additional inoculations, experimental infection with purified SRV-2 or SIV, or immunosuppressive treatments with cyclosporine or dexamethasone were unsuccessful. An heterologous LCV transmission was also detected in this recipient, characterized by continual high levels of LCVMf DNA from the cynomolgus donor in both saliva (> 106 genomes/ml) and PBMC (> 104 genomes/million cells), coupled with high levels of anti-LCV antibodies. The macaque was sacrificed 209 weeks after the initial inoculation. Low levels of LCVMf DNA were detected in salivary glands, tonsils and other lymphoid organs, while RFHVMf DNA was below the level of detection. These results show successful co-transmission of RFHV and LCV from saliva and demonstrate differential lytic activation of the different gammaherpesvirus lineages due to presumed differences in biology and tropism and control by the host immune system. Although this initial pilot transmission study utilized only two macaques, it provides the first evidence for experimental transmission of the macaque homolog of KSHV, setting the stage for larger transmission studies to examine the differential activation of rhadinovirus and lymphocryptovirus infections and the pathological effects of immunosuppression. PMID- 30444881 TI - Fatty acid, physicochemical composition and sensory attributes of meat from lambs fed diets containing licuri cake. AB - The aim of this study was to determine the effect of feeding licuri cake to lambs on the sensory characteristics, physicochemical characteristics and fatty acid (FA) profile of meat from lambs. Forty-four crossbred Santa Ines lambs (21.2 +/- 2.70 kg body weight; 6 months old) were housed in individual pens and fed 4 experimental diets, containing 0, 8, 16 or 24% licuri cake (DM basis). The averages concentrations of ash (11.4), pH (5.82), lightness (38.1), cooking loss (26.8) or shear-force resistance (2.48) of lamb meat were not affected by the licuri cake diets. However, there was a linear decrease (P < 0.01) of redness and chroma indexes, lipid and protein contents, whereas the moisture content of the meat (P < 0.001) increased linearly due to the inclusion of licuri cake in lambs' diets. The licuri cake inclusion in the lambs feed linearly increased (P < 0.05) the fatty acids concentrations of C12:0, C17:0, C20:0, C20:1, C18:3, C20:3, C20:4 and SigmaPUFA/SigmaMUFA ratio, Sigmaomega-3 and atherogenicity index (AI). However, C18:1 cis, C20:2, C20:5, SigmaMUFA, SigmaMUFA/SigmaSFA and Sigmaomega 6:Sigmaomega-3 ratios in the longissimus lumborum of lambs linearly decreased by licuri cake inclusion. There was a quadratic increase (P < 0.05) on C14:0 (maximum point 4.94 g/100 g FAME to 14.5% licuri inclusion), C16:1 (maximum point 8.59 g/100 g FAME to 10.7% licuri inclusion) and enzymatic activities of Delta9 desaturase C16 (maximum point 27.5 g/100 g FAME to 10.6% licuri inclusion) in the longissimus lumborum of lambs fed due to increased concentrations of licuri cake. However, there was a quadratic decrease (P = 0.04) in SigmaPUFA/SigmaSFA ratio with minimum concentration of 0.63 g/100 g FAME to 11.1% inclusion. The inclusion of licuri cake in the lambs diet did not change (P > 0.05) the concentrations of SFA C10:0, C15:0, C16:0, C18:0, C14:1, MUFA C18:1 trans, PUFA C18:2 cis, CLA, total sum of SigmaSFA and SigmaPUFA, desirable fatty acids (DFA), hypocholesterolemic:hypercholesterolemic index, and elongase and Delta9 desaturase C18 enzymes. Licuri cake in the lamb diet improved (P < 0.05) meat aroma, flavor and overall acceptance by consumers. Licuri cake inclusion in the diet of lambs improves sensory attributes of meat and the meat fatty acid profile becomes nutritionally healthier for the human diet because do not affect major FA of meat; however, the growth performance of finishing lambs is reduced. PMID- 30444882 TI - Effects of hot air treatment and chitosan coating on citric acid metabolism in ponkan fruit during cold storage. AB - In citrus fruit, citric acid is the predominant organic acid which influence fruit taste, flavor and quality. The effect of hot air treatment (HAT 40 degrees C, 48 h) and 1.0% chitosan coating on the change of organic acids and the related gene expression of citric acid synthesis and degradation in ponkan (Citrus reticulata Blanco) fruit during cold storage have been studied. The results showed that citric acid was the main organic acid in fruit, the trend change of citric acid content was consistent with total organic acids and titratable acidity (TA) content, which decreased with the prolongation of storage time, hot air treatment significantly promoted but chitosan coating treatment significantly delayed citric acid degradation in Ponkan fruit. Hot air treatment could induced CitAco2/3, CitIDH2/3, CitGAD4, CitACLs, CitPEPCKs and CitFBPases expression during fruit storage period, but had no significant effect on CitGSs expression, The enhanced expression of degradation-related genes was closely related to the degradation of citric acid. The expressions of CitAco3, CitGAD4 CitACLalpha2/beta, CitPEPCKs and CitFBPases were inhibited, which leading to the degradation rate of citric acid was slowed by chitosan coating during storage. These results showed that the degradation of citric acid in fruit was regulated by ATP citrate lyase (ACL) pathway and gamma-aminobutyric acid (GABA) pathway. PMID- 30444883 TI - Home is home-Botswana's return migrant health workers. AB - The shortage of skilled healthcare workers in Sub-Saharan Africa is aggravated by their emigration to high resource countries. There is evidence that a small number of healthcare workers return to their home countries. It is important to understand the factors that influence decisions to return in order to develop appropriate strategies to attract more back. This study sought to investigate the perspectives of healthcare workers who returned to Botswana after working in the diaspora. We conducted semi-structured interviews of 8 healthcare workers. Using the thematic analysis method we developed a thematic index to code the data. The main reasons for returning were family ties and missing home whilst the key reasons for emigration were concerns about the quality of health care, lack of professional progression opportunities and feeling under-valued. Difficulties reintegrating into the Botswana health care system are a potential push factors for those who return. Policies that aim to attract back healthcare workers should address professional progression, reintegration and improvement of the healthcare system. PMID- 30444885 TI - Liver ultrasound elastography for the evaluation of periportal fibrosis in schistosomiasis mansoni: A cross-sectional study. AB - BACKGROUND: ARFI elastrography has been used as a noninvasive method to assess the severity of liver fibrosis in viral hepatitis, although with few studies in schistosomiasis mansoni. We aimed to evaluate the performance of point shear wave elastography (pSWE) for predicting significant periportal fibrosis (PPF) in schistosomotic patients and to determine its best cutoff point. METHODOLOGY/PRINCIPAL FINDINGS: This cross-sectional study included 358 adult schistosomotic patients subjected to US and pSWE on the right lobe. Two hundred two patients (62.0%) were women, with a median age of 54 (ranging 18-92) years. The pSWE measurements were compared to the US patterns of PPF, as gold standard, according to the Niamey classification. The performance of pSWE was calculated as the area under the ROC curve (AUC). Patients were further classified into two groups: 86 patients with mild PPF and 272 patients with significant PPF. The median pSWE of the significant fibrosis group was higher (1.40 m/s) than that of mild fibrosis group (1.14 m/s, p<0.001). AUC was 0.719 with <=1.11 m/s as the best cutoff value for excluding significant PPF. Sensitivity and negative predictive values were 80.5% and 40.5%, respectively. Whereas, for confirming significant PPF, the best cutoff value was >1.39 m/s, with specificity of 86.1% and positive predictive value of 92.0%. CONCLUSIONS/SIGNIFICANCE: pSWE was able to differentiate significant from mild PPF, with better performance to predict significant PPF. PMID- 30444886 TI - Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis. AB - CFTR modulators have revolutionized the treatment of individuals with cystic fibrosis (CF) by improving the function of existing protein. Unfortunately, almost half of the disease-causing variants in CFTR are predicted to introduce premature termination codons (PTC) thereby causing absence of full-length CFTR protein. We hypothesized that a subset of nonsense and frameshift variants in CFTR allow expression of truncated protein that might respond to FDA-approved CFTR modulators. To address this concept, we selected 26 PTC-generating variants from four regions of CFTR and determined their consequences on CFTR mRNA, protein and function using intron-containing minigenes expressed in 3 cell lines (HEK293, MDCK and CFBE41o-) and patient-derived conditionally reprogrammed primary nasal epithelial cells. The PTC-generating variants fell into five groups based on RNA and protein effects. Group A (reduced mRNA, immature (core glycosylated) protein, function <1% (n = 5)) and Group B (normal mRNA, immature protein, function <1% (n = 10)) variants were unresponsive to modulator treatment. However, Group C (normal mRNA, mature (fully glycosylated) protein, function >1% (n = 5)), Group D (reduced mRNA, mature protein, function >1% (n = 5)) and Group E (aberrant RNA splicing, mature protein, function > 1% (n = 1)) variants responded to modulators. Increasing mRNA level by inhibition of NMD led to a significant amplification of modulator effect upon a Group D variant while response of a Group A variant was unaltered. Our work shows that PTC-generating variants should not be generalized as genetic 'nulls' as some may allow generation of protein that can be targeted to achieve clinical benefit. PMID- 30444884 TI - Knowledge, attitudes and practices related to stroke in Ghana and Nigeria: A SIREN call to action. AB - INTRODUCTION: Stroke is a prominent cause of death, disability, and dementia in sub-Saharan Africa (SSA). The Stroke Investigative Research and Education Network works collaboratively with stroke survivors and individuals serving as community controls to comprehensively characterize the genomic, sociocultural, economic and behavioral risk factors for stroke in SSA. PURPOSE: In this paper, we aim to: i) explore the attitudes, beliefs, and practices related to stroke in Ghana and Nigeria using the process of qualitative description; and ii) propose actions for future research and community-based participation and education. METHODS: Stroke survivors, their caregivers, health care professionals, and community representatives and faith-based leaders participated in one of twenty-six focus groups, which qualitatively explored community beliefs, attitudes and practices related to stroke in Ghana and Nigeria. Arthur Kleinman's Explanatory Model of Illness and the Social Ecological Model guided the questions and/or thematic analysis of the qualitative data. We hereby describe our focus group methods and analyses of qualitative data, as well as the findings and suggestions for improving stroke outcomes. RESULTS AND DISCUSSION: The major findings illustrate the fears, causes, chief problems, treatment, and recommendations related to stroke through the views of the participants, as well as recommendations for working effectively with the SIREN communities. Findings are compared to SIREN quantitative data and other qualitative studies in Africa. As far as we are aware, this is the first paper to qualitatively explore and contrast community beliefs, attitudes, and practices among stroke survivors and their caregivers, community and faith-based leaders, and health professionals in multiple communities within Nigeria and Ghana. PMID- 30444887 TI - Radiation-induced lung toxicity in mice irradiated in a strong magnetic field. AB - Strong magnetic fields affect radiation dose deposition in MRI-guided radiation therapy systems, particularly at interfaces between tissues of differing densities such as those in the thorax. In this study, we evaluated the impact of a 1.5 T magnetic field on radiation-induced lung damage in C57L/J mice. We irradiated 140 mice to the whole thorax with parallel-opposed Co-60 beams to doses of 0, 9.0, 10.0, 10.5, 11.0, 12.0, or 13.0 Gy (20 mice per dose group). Ten mice per dose group were irradiated while a 1.5 T magnetic field was applied transverse to the radiation beam and ten mice were irradiated with the magnetic field set to 0 T. We compared survival and noninvasive assays of radiation induced lung damage, namely respiratory rate and metrics derived from thoracic cone-beam CTs, between the two sets of mice. We report two main results. First, the presence of a transverse 1.5 T field during irradiation had no impact on survival of C57L/J mice. Second, there was a small but statistically significant effect on noninvasive assays of radiation-induced lung damage. These results provide critical safety data for the clinical introduction of MRI-guided radiation therapy systems. PMID- 30444889 TI - Protective effects of Phyllanthus phillyreifolius extracts against hydrogen peroxide induced oxidative stress in HEK293 cells. AB - Phyllanthus phillyreifolius, a plant species indigenous to Reunion Island, is used in folk medicine for treating diarrhea and as a diuretic. In the present study acetone and hydroethanol extracts of P. phillyreifolius were evaluated for their cytotoxicity and antioxidant effects using in vitro (TPC, ABTS, DPPH, FRAP, ORAC) and in cellulo (MTT, DCFH-DA, RT-qPCR) assays. Major compounds were evaluated using UPLC-QTOF-MS. MTT cell viability assay showed low cytotoxicity of extracts towards human embryonic kidney 293 (HEK293) cell line. Both extracts were rich in polyphenols (mainly ellagitannins) and showed high antioxidant potential and intracellular ROS decreasing effect. Preconditioning of HEK293 cells with extracts influenced gene expression of antioxidant enzymes, however ROS level decreasing effect was more related to their capacity to scavenge free radicals and with their reducing power. Strong antioxidant activity of extracts as well as the presence of geraniin supports the use of P. phillyreifolius in traditional medicine. PMID- 30444891 TI - The influence of gender ratios on academic careers: Combining social networks with tokenism. AB - This paper examines how gender proportions at the workplace affect the extent to which individual networks support the career progress (i.e. time to promotion). Previous studies have argued that men and women benefit from different network structures. However, the empirical evidence about these differences has been contradictory or inconclusive at best. Combining social networks with tokenism, we show in a longitudinal academic study that gender-related differences in the way that networks affect career progress exist only in situations where women are in a token position. Our empirical results further show that women not in severely underrepresented situations benefit from the same network structure as men. PMID- 30444888 TI - OsTGA2 confers disease resistance to rice against leaf blight by regulating expression levels of disease related genes via interaction with NH1. AB - How plants defend themselves from microbial infection is one of the most critical issues for sustainable crop production. Some TGA transcription factors belonging to bZIP superfamily can regulate disease resistance through NPR1-mediated immunity mechanisms in Arabidopsis. Here, we examined biological roles of OsTGA2 (grouped into the same subclade as Arabidopsis TGAs) in bacterial leaf blight resistance. Transcriptional level of OsTGA2 was accumulated after treatment with salicylic acid, methyl jasmonate, and Xathomonas oryzae pv. Oryzae (Xoo), a bacterium causing serious blight of rice. OsTGA2 formed homo- and hetero-dimer with OsTGA3 and OsTGA5 and interacted with rice NPR1 homologs 1 (NH1) in rice. Results of quadruple 9-mer protein-binding microarray analysis indicated that OsTGA2 could bind to TGACGT DNA sequence. Overexpression of OsTGA2 increased resistance of rice to bacterial leaf blight, although overexpression of OsTGA3 resulted in disease symptoms similar to wild type plant upon Xoo infection. Overexpression of OsTGA2 enhanced the expression of defense related genes containing TGA binding cis-element in the promoter such as AP2/EREBP 129, ERD1, and HOP1. These results suggest that OsTGA2 can directly regulate the expression of defense related genes and increase the resistance of rice against bacterial leaf blight disease. PMID- 30444890 TI - Restoring oysters to urban estuaries: Redefining habitat quality for eastern oyster performance near New York City. AB - Restoring and conserving coastal resilience faces increasing challenges under current climate change predictions. Oyster restoration, in particular, faces threats from alterations in precipitation, warming water temperatures, and urbanization of coastlines that dramatically change salinity patterns, foster the proliferation and spread disease, and disrupt habitat connectivity, respectively. New York City (NYC) coastal waters, once home to a booming oyster fishery for eastern oysters (Crassostrea virginica), are now nearly devoid of live oyster reefs. Oyster restoration in urban estuaries is motivated by the synergistic ecosystem benefits this native keystone species can deliver. Recent surveys have documented substantial remnant populations of adult oysters in the upper low salinity zone of the Hudson/Raritan Estuary (HRE) near Tarrytown, NY. This study assessed fitness-related performance across the HRE salinity gradient to evaluate habitat suitability on an estuarine scale. Oysters were hatchery-produced from wild, moderate-salinity broodstock, then outplanted for measurement of growth, survival, reproduction and disease prevalence over two years. Survival was generally higher in the lower salinity river sites and in the higher salinity Jamaica Bay sites relative to mesohaline NYC harbor sites. Growth rate was highest in Jamaica Bay and had high variation among other sites. Surprisingly, the highest proportion of individuals with sex-differentiated gametes and the highest average gonad maturation index was found at a low salinity site. Consistent with the advanced gametogenesis measured in experimental animals at low salinity, annual wild recruitment was documented near the low salinity remnant population in each of five monitored years. These results suggest that the remnant HRE oyster population is a robust, self-sustaining population that can be leveraged to support restoration of subpopulations in other parts of the estuary, but further research is required to determine if the mesohaline and near ocean reaches of the HRE can support the full oyster life cycle. PMID- 30444892 TI - Estimating the age of the p.Cys433Arg variant in the MYOC gene in patients with primary open-angle glaucoma. AB - The aim of this study was to estimate the age of the Cys433Arg (c.1297T>C, p.Cys433Arg) variant by comparing the genotypes of individuals affected and not affected by primary open angle glaucoma juvenile onset (JOAG). Our sample consisted of 35 JOAG-affected individuals from three families, 16 unrelated patients with the MYOC p.Cys433Arg variant and 16 unaffected individuals. Genomic DNA was amplified by PCR; nine short tandem repeats were genotyped through automated electrophoresis and three single nucleotide polymorphisms through Sanger sequencing. The determination of haplotypes was performed using Arlequin software and age estimation was performed using DMLE+ 2.3 and BDMC21 softwares. Four markers constituted the haplotypes associated with the p.Cys433Arg variant. The software DMLE+2.3 predicted an age of 43 generations for this variant with a 95% confidence interval ranging from 28 to 76 generations (560-1520 years) and BDMC21 predicted an age of 59 generations (1180 years) (95% CI: 40 to 100). PMID- 30444893 TI - Association between body mass index and mortality in the Korean elderly: A nationwide cohort study. AB - The objective of this study was to investigate the relationship between body mass index (BMI) and mortality in the elderly. This study was a nation-wide population based retrospective cohort study of the National Health Insurance System-Senior Database (NHIS-SD). In this study, a total of 75,856 subjects were identified and selected from among 251,593 individuals aged >= 65 years who underwent health screening at least once between 2009 and 2012 and who had no history of diabetes, cardiovascular disease, stroke, cancer, or chronic obstructive pulmonary disease (COPD). The subjects of this study were followed-up until 2013 to identify the total mortality and the cause-specific mortality of 6 groups divided according to BMI. The hazard ratio (HR) by reference group (23 <= BMI < 25 kg/m2) of each group was calculated. A significant increase in the HR with a decreased BMI was observed in the group with a BMI < 23 kg/m2, whereas the HR in the group with a BMI >= 25 kg/m2 was not significantly different than that of the reference group (23 <= BMI < 25 kg/m2). This pattern was also seen in the subgroup analyses in relation to age, smoking history, alcohol use, exercise level, and socioeconomic status. In this study, we found that a low BMI was a risk factor for death in the elderly and that no significant difference in mortality was seen in the elderly with a BMI of 25 or over. In terms of an optimal BMI in the elderly, it is important to maintain an appropriately healthy range of BMI with the aim of preventing weight loss. PMID- 30444894 TI - The impact of computerised physician order entry and clinical decision support on pharmacist-physician communication in the hospital setting: A qualitative study. AB - BACKGROUND: The implementation of Computerised Physician Order Entry (CPOE) and Clinical Decision Support (CDS) has been found to have some unintended consequences. The aim of this study is to explore pharmacists and physicians perceptions of their interprofessional communication in the context of the technology and whether electronic messaging and CDS has an impact on this. METHOD: This qualitative study was conducted in two acute hospitals: the University Hospitals Birmingham NHS Foundation Trust (UHBFT) and Guy's and St Thomas' NHS Foundation Trust (GSTH). UHBFT use an established locally developed CPOE system that can facilitate pharmacist-physician communication with the ability to assign a message directly to an electronic prescription. In contrast, GSTH use a more recently implemented commercial system where such communication is not possible. Focus groups were conducted with pharmacists and physicians of varying grades at both hospitals. Focus group data were transcribed and analysed thematically using deductive and inductive approaches, facilitated by NVivo 10. RESULTS: Three prominent themes emerged during the study: increased communication load; impaired decision-making; and improved workflow. CPOE and CDS were found to increase the communication load for the pharmacist owing to a reduced ability to amend electronic prescriptions, new types of prescribing errors, and the provision of technical advice relating to the use of the system. Decision-making was found to be affected, owing to the difficulties faced by pharmacists and physicians when trying to determine the context of prescribing decisions and knowledge of the patient. The capability to communicate electronically facilitated a non-interruptive workflow, which was found to be beneficial for staff time, coordination of work and for limiting distractions. CONCLUSION: The increased communication load for the pharmacist, and consequent workload for the physician, has the potential to impact on the quality and coordination of care in the hospital setting. The ability to communicate electronically has some benefits, but functions need to be designed to facilitate collaborative working, and for this to be optimised through interprofessional training. PMID- 30444895 TI - Pulling strength, muscular fatigue, and prediction of maximum endurance time for simulated pulling tasks. AB - Truck pulling is one of the common manual materials handling tasks which contribute to musculoskeletal disorders. The maximum endurance time (MET) for two handed truck pulling tasks has been rarely discussed in the literature. The objectives of this study were to explore the development of muscular fatigue when performing two-handed pulling task and to establish models to predict the MET. A simulated pallet truck pulling experiment was conducted. Sixteen healthy adults including eight females and eight males participated. The participants pulled a handle simulating that of a pallet truck using two hands until they could not pull any longer under two postures. The forces applied for females and males were 139.65 N and 170.03 N, respectively. The maximum voluntary contractions (MVC) of the pulling strength both before and after the simulated pull were measured. After each trial, both the MET and subjective ratings of muscular fatigue on body segments were recorded. The results showed that posture significantly affected MVC of pull both before and after the trial. It was found that foot/shank of the front leg had higher subjective ratings of muscular fatigue than the other body segments. The MET equations employing both power and logarithmic functions were developed to predict the MET of the two-handed pulling tasks. Predictive models established in this study may be used to assess the MET for two-handed pulling tasks. PMID- 30444897 TI - Development of a multichannel current-EMG system for coherence modulation with visual biofeedback. AB - By means of biofeedback, neuromotor control can be modified. Recent biofeedback experiments have used the power of the electromyogram of one muscle in different frequency bands to control a two-dimensional cursor. However, the human body usually requires coherent activation of multiple muscles to achieve daily life tasks. Additionally, electromyography (EMG) instrumentation has remained the same for decades, and might not be the most suitable to measure coherent activations from pennated muscles according to recent experiments by von Tscharner and colleagues. In this study, we propose the development of a multichannel current based EMG amplifier to use intermuscular coherence as the control feature of a visual biofeedback system. The system was used in a leg extension protocol to voluntarily increase intermuscular coherence between the vastii muscles. Results from ten subjects show that it is possible to increase intermuscular coherence through visual biofeedback. Such a system can have applications in endurance training and rehabilitation. PMID- 30444896 TI - Akt2 causes TGFbeta-induced deptor downregulation facilitating mTOR to drive podocyte hypertrophy and matrix protein expression. AB - TGFbeta promotes podocyte hypertrophy and expression of matrix proteins in fibrotic kidney diseases such as diabetic nephropathy. Both mTORC1 and mTORC2 are hyperactive in response to TGFbeta in various renal diseases. Deptor is a component of mTOR complexes and a constitutive inhibitor of their activities. We identified that deptor downregulation by TGFbeta maintains hyperactive mTOR in podocytes. To unravel the mechanism, we found that TGFbeta -initiated noncanonical signaling controls deptor inhibition. Pharmacological inhibitor of PI 3 kinase, Ly 294002 and pan Akt kinase inhibitor MK 2206 prevented the TGFbeta induced downregulation of deptor, resulting in suppression of both mTORC1 and mTORC2 activities. However, specific isoform of Akt involved in this process is not known. We identified Akt2 as predominant isoform expressed in kidney cortex, glomeruli and podocytes. TGFbeta time-dependently increased the activating phosphorylation of Akt2. Expression of dominant negative PI 3 kinase and its signaling inhibitor PTEN blocked Akt2 phosphorylation by TGFbeta. Inhibition of Akt2 using a phospho-deficient mutant that inactivates its kinase activity, as well as siRNA against the kinase markedly diminished TGFbeta -mediated deptor suppression, its association with mTOR and activation of mTORC1 and mTORC2. Importantly, inhibition of Akt2 blocked TGFbeta -induced podocyte hypertrophy and expression of the matrix protein fibronectin. This inhibition was reversed by the downregulation of deptor. Interestingly, we detected increased phosphorylation of Akt2 concomitant with TGFbeta expression in the kidneys of diabetic rats. Thus, our data identify previously unrecognized Akt2 kinase as a driver of TGFbeta induced deptor downregulation and sustained mTORC1 and mTORC2 activation. Furthermore, we provide the first evidence that deptor downstream of Akt2 contributes to podocyte hypertrophy and matrix protein expression found in glomerulosclerosis in different renal diseases. PMID- 30444898 TI - Detection of central nervous system viral infections in adults in Manado, North Sulawesi, Indonesia. AB - Central nervous system (CNS) viral infections are important causes of morbidity and mortality worldwide but the systematic survey of patients admitted to hospitals with CNS infections in many countries, including Indonesia, is limited. To obtain more information regarding the causes of CNS infections in Indonesia, this study was performed to detect and identify viral agents associated with CNS infections amongst in-patients at a referral hospital in Manado, North Sulawesi, Indonesia. Adult patients admitted to R.D. Kandou General Hospital with presumed CNS infection were enrolled. Cerebrospinal fluid, serum, and throat swab samples were collected and tested using molecular, serological, and virus isolation assays. A confirmed viral etiology was established in three and a probable/possible in 11 out of 74 patients. The most common was herpes simplex virus 1 (7/74, 9.5%), followed by Epstein-Barr virus (2/74, 2.7%), cytomegalovirus (1/74, 1.4%), enterovirus D68 (1/74, 1.4%), rhinovirus A (1/74, 1.4%), dengue virus (1/64, 1.6%), and Japanese encephalitis virus (1/64, 1.6%). There were 20 fatal cases (27.0%) during hospitalization in which eight were associated with viral causes. We identified herpes simplex virus 1 as the most common cause of CNS infection among adults in North Sulawesi with most of the cases remaining undiagnosed. Our study highlights the challenges in establishing the etiology of viral CNS infections and the importance of using a wide range of molecular and serological detection methods to identify CNS viruses. PMID- 30444899 TI - Access to environmental health assets across wealth strata: Evidence from 41 low- and middle-income countries. AB - INTRODUCTION: Low levels of household access to basic environmental health assets (EHAs)-including technologies such as clean cookstoves and bed nets or infrastructure such as piped water and electricity-in low- and middle-income countries (LMICs) are known to contribute significantly to the global burden of disease. This low access persists despite decades of promotion of many low-cost, life-saving technologies, and is particularly pronounced among poor households. This study aims to characterize variation in access to EHAs among LMIC households as a function of wealth, as defined by ownership of various assets. METHODS: Demographic and Health Survey (DHS) data from 41 low- and middle-income countries were used to assess household-level access to the following EHAs: 1) improved water supply; 2) piped water supply; 3) improved sanitation; 4) modern cooking fuels; 5) electricity; and 6) bed nets. For comparison, we included access to mobile phones, which is considered a highly successful technology in terms of its penetration into poor households within LMICs. Ownership levels were compared across country-specific wealth quintiles constructed from household assets using bivariate analysis and multivariable linear regression models. RESULTS: Access to EHAs was low among the households in the bottom three quintiles of wealth. Access to piped water, modern cooking fuels, electricity and improved sanitation, for example, were all below 50% for households in the bottom three wealth quintiles. Access to certain EHAs such as improved water supply and bed nets increased only slowly with concomitant increases in wealth, while gaps in access to other EHAs varied to a greater degree by wealth quintile. For example, disparities in access between the richest and poorest quintiles were greatest for electricity and improved sanitation. Rural households in all wealth quintiles had much lower levels of access to EHAs, except for bed nets, relative to urban households. CONCLUSIONS: The findings of this study provide a basis for understanding how EHAs are distributed among poor households in LMICs, elucidate where inequalities in access are particularly pronounced, and point to a need for strategies that better reach the poor, if the global environmental burden of disease is to be reduced. PMID- 30444900 TI - The effect of the optical design of multifocal contact lenses on choroidal thickness. AB - Studies have found reduced myopia progression with multifocal contact lenses, albeit with an unclear mechanism behind their protective effect. It is hypothesized that the induced myopic defocus of the addition zones of the multifocal contact lenses leads to choroidal thickening and therefore inhibits eye growth. In the current study, the effect of the optical design of multifocal contact lenses on choroidal thickness was investigated. Eighteen myopic participants wore four different contact lenses ((1) single-vision lenses corrected for distance, (2) single-vision lenses with +2.50 D full-field defocus, (3) Multifocal center-distance design, (4) Multifocal center-near design, both with addition power +2.50 D) for 30 min each on their right eye. Automated analysis of the macular choroidal thickness and vitreous chamber depth were performed before and after the wear of each of the contact lenses. Peripheral refraction profiles in primary gaze were obtained using eccentric photorefraction prior to contact lens wear. Choroidal thickness and vitreous chamber depth showed no significant differences to baseline with any of the contact lenses (all p > 0.05). Choroidal thickness increased by +2.1 +/- 11.1 MUm with the Multifocal center-distance design, by +2.0 +/- 11.1 MUm with the full-field defocus lens, followed by the Multifocal center-near design with +1.6 +/- 11.3 MUm and the single-vision contact lens correcting for distance with +0.9 +/- 11.2 MUm. Multifocal contact lenses have no significant influence on choroidal thickness after short-term wear. Therefore, changes in choroidal thickness might not be the main contributor to the protective effect of multifocal contact lenses in myopia control. PMID- 30444901 TI - Differences in multiple immune parameters between Indian and U.S. infants. AB - To compare immune phenotypes across two geographic and ethnic communities, we examined umbilical cord blood by flow cytometry and Luminex in parallel cohorts of 53 newborns from New Delhi, India, and 46 newborns from Stanford, California. We found that frequencies of a B cell subset suggested to be B-1-like, and serum IgM concentration were both significantly higher in the Stanford cohort, independent of differences in maternal age. While serum IgA levels were also significantly higher in the Stanford cohort, IgG1, IgG2, and IgG4 were significantly higher in the New Delhi samples. We found that neutrophils, plasmacytoid dendritic cells, CD8+ T cells, and total T cells were higher in the U.S. cohort, while dendritic cells, patrolling monocytes (CD14dimCD16+), natural killer cells, CD4+ T cells, and naive B cells were higher in the India cohort. Within the India cohort, we also identified cell types whose frequency was positively or negatively predictive of occurrence of infection(s) in the first six months of life. Monocytes, total T cells, and memory CD4+ T cells were most prominent in having an inverse relationship with infection. We suggest that these data provide impetus for follow-up studies linking phenotypic differences to environmental versus genetic factors, and to infection outcomes. PMID- 30444902 TI - Understanding the sexual recruitment of one of the oldest and largest organisms on Earth, the seagrass Posidonia oceanica. AB - The seagrass Posidonia oceanica is considered one of the oldest and largest living organisms on Earth. Notwithstanding, given the difficulty of monitoring its fruits and seeds in the field, the development of P. oceanica during its sexual recruitment is not completely understood. We studied the stages of development of P. oceanica seeds from their dispersion in the fruit interior to their settlement in sediment through histological, ultrastructural and mesocosm experiments. P. oceanica sexual recruitment can be divided into three main stages that focus on maximising photosynthesis and anchoring the seedlings to the sediment. In the first stage (fruit dispersion), seeds perform photosynthesis while being transported inside the fruit along the sea surface. In the second stage (seed adhesion), seeds develop adhesive microscopic hairs that cover the primary and secondary roots and favour seed adhesion to the substrate. In the last stage (seedling anchorage), roots attach the seedlings to the substrate by orienting them towards the direction of light to maximise photosynthesis. The adaptations observed in P. oceanica are similar to those in other seagrasses with non-dormant seeds and fruits with membranous pericarps, such as Thalassia sp. and Enhalus sp. These common strategies suggest a convergent evolution in such seagrasses in terms of sexual recruitment. Understanding the sexual recruitment of habitat-forming species such as seagrasses is necessary to adequately manage the ecosystems that they inhabit. PMID- 30444903 TI - Serodiscordant partnerships and opportunities for pre-exposure prophylaxis among partners of women and men living with HIV in St. Petersburg, Russia. AB - OBJECTIVE: To describe the frequency of being partnered and having an HIV negative partner, and whether this differed by gender, among a cohort of persons living with HIV (PLWH) who have ever injected drugs; to describe awareness of HIV pre-exposure prophylaxis (PrEP) and perceived partner interest in PrEP. SETTING: Secondary analyses of an observational cohort study of PLWH who have ever injected drugs in St. Petersburg, Russia. METHODS: Primary outcomes were 1) being partnered and 2) being in a serodiscordant partnership. The main independent variable was gender. Multivariable GEE logistic regression models were fit for binary outcomes, adjusted for age, income, education, and recent opioid use. Descriptive analyses were performed for partners' HIV status, substance use, sex risk behaviors, and awareness of PrEP for a subset of participants. RESULTS: At baseline, 50% (147/296) reported being in a partnership, and of those, 35% were in a serodiscordant partnership. After adjustment, women had significantly higher odds of being partnered compared to men (aOR = 3.12; 95% CI: 1.77, 5.51), but there were no significant gender differences in the odds of being in a serodiscordant partnership (aOR = 0.58; 95% CI: 0.27, 1.24). Among a sub-sample of participants queried (n = 56), 25% were aware of PrEP for prevention of sexual HIV transmission and 14% for prevention of injection-related transmission. CONCLUSION: Although half of our sample were partnered and one third of these partnerships were serodiscordant, PrEP awareness was low. Substantial opportunities for HIV prevention exist among PLWH who have ever injected drugs in Russia and their HIV-negative partners. Given the high proportion of HIV-negative partners among this ART-naive sample, efforts to address the associated inherent risks, such as couples-based interventions, are needed to increase condom use, PrEP awareness, or uptake of other HIV-prevention modalities (e.g., ART for the HIV-positive partner). PMID- 30444905 TI - Postoperative pulmonary complications following posterior spinal instrumentation and fusion for congenital scoliosis. AB - BACKGROUND: Congenital scoliosis (CS) may lead to more serious pulmonary complications compared with idiopathic scoliosis after spinal fusion surgery. However, little has been reported about postoperative pulmonary complication events in patients with CS after spinal fusion surgery. OBJECTIVE: To investigate the incidence of and predictive factors of postoperative pulmonary complications following posterior spinal instrumentation and fusion surgery for the treatment of CS. METHODS: We retrospectively reviewed the records of 174 patients with CS (128 females and 46 males, mean age 16.4 years) treated with posterior spinal instrumentation and fusion surgery between January 2012 and April 2017. We extracted demographic, medical history, and clinical data, and investigated the major predictive factors for postoperative pulmonary complications by logistic regression and receiver-operating characteristic curves analyses. RESULTS: A total of 26 (14.9%) patients developed postoperative pulmonary complications, consisting of pleural effusion (10.9%), pneumonia (6.9%), pneumothorax (1.1%), atelectasis (2.3%), hypoxemia (6.3%), and respiratory failure (1.1%). Logistic regression analysis revealed that the predictive factors for postoperative pulmonary complications were age > 18.1 years (P = 0.039), a Cobb angle of > 77 degrees (P = 0.011), operation time of > 430 min (P = 0.032), and blood transfusion volume > 1500 ml (P = 0.015). CONCLUSIONS: Postoperative pulmonary complications are among the main complications following posterior spinal instrumentation and fusion surgery in patients with CS. Such patients aged >18.1 years, with Cobb angles > 77 degrees , operation times > 430 min, and/or blood transfusion volume of > 1500 ml may be more likely to develop postoperative pulmonary complications. PMID- 30444904 TI - Combination of triapine, olaparib, and cediranib suppresses progression of BRCA wild type and PARP inhibitor-resistant epithelial ovarian cancer. AB - PARP inhibitors target BRCA mutations and defective homologous recombination repair (HRR) for the treatment of epithelial ovarian cancer (EOC). However, the treatment of HRR-proficient EOC with PARP inhibitors remains challenging. The objective of this study was to determine whether the combination of triapine (ribonucleotide reductase inhibitor), cediranib (vascular endothelial growth factor receptor tyrosine kinase inhibitor), and the PARP inhibitor olaparib synergized against BRCA wild-type and HRR-proficient EOC in xenograft mouse models. In addition, the mechanisms by which cediranib augmented the efficacy of triapine and olaparib were investigated. BRCA-wild type and PARP inhibitor resistant EOC cell lines were implanted subcutaneously (s.c.) into nude mice or injected intraperitoneally (i.p.) into SCID-Beige mice. Mice were then treated i.p. with olaparib, cediranib, triapine, various double and triple combinations. The volume of s.c tumor in nude mice and the abdominal circumference of SCID Beige mice were measured to evaluate the effectiveness of the treatment to delay tumor growth and prolong the survival time of mice. In both xenograft mouse models, the combination of triapine, olaparib and cediranib resulted in marked suppression of BRCA-wild type EOC growth and significant prolongation of the survival time of mice, with efficacy greater than any double combinations and single drugs. Furthermore, we identified that cediranib abrogated pro-survival and anti-apoptotic AKT signaling, thereby enhancing the efficacy of triapine and olaparib against BRCA-wild type EOC cells. Taken together, our results demonstrate a proof-of-principle approach and the combination regiment holds promise in treating BRCA-wild type and PARP inhibitor-resistant EOC. PMID- 30444906 TI - Ossification area localization in pediatric hand radiographs using deep neural networks for object detection. AB - BACKGROUND: Detection of ossification areas of hand bones in X-ray images is an important task, e.g. as a preprocessing step in automated bone age estimation. Deep neural networks have emerged recently as de facto standard detection methods, but their drawback is the need of large annotated datasets. Finetuning pre-trained networks is a viable alternative, but it is not clear a priori if training with small annotated datasets will be successful, as it depends on the problem at hand. In this paper, we show that pre-trained networks can be utilized to produce an effective detector of ossification areas in pediatric X-ray images of hands. METHODS AND FINDINGS: A publicly available Faster R-CNN network, pre trained on the COCO dataset, was utilized and finetuned with 240 manually annotated radiographs from the RSNA Pediatric Bone Age Challenge, which comprises over 14.000 pediatric radiographs. The validation is done on another 89 radiographs from the dataset and the performance is measured by Intersection-over Union (IoU). To understand the effect of the data size on the pre-trained network, subsampling was applied to the training data and the training was repeated. Additionally, the network was trained from scratch without any pre trained weights. Finally, to understand whether the trained model could be useful, we compared the inference of the network to an annotation of an expert radiologist. The finetuned network was able to achieve an average precision (mAP@0.5IoU) of 92.92 +/- 1.93. Apart from the wrist region, all ossification areas were able to benefit from more data. In contrast, the network trained from scratch was not able to produce any correct results. When compared to the annotations of the expert radiologist, the network was able to localize the regions quite well, as the F1-Score was on average 91.85 +/- 1.06. CONCLUSIONS: By finetuning a pre-trained deep neural network, with 240 annotated radiographs, we were able to successfully detect ossification areas in prediatric hand radiographs. PMID- 30444907 TI - Automatic inference model construction for computer-aided diagnosis of lung nodule: Explanation adequacy, inference accuracy, and experts' knowledge. AB - We aimed to describe the development of an inference model for computer-aided diagnosis of lung nodules that could provide valid reasoning for any inferences, thereby improving the interpretability and performance of the system. An automatic construction method was used that considered explanation adequacy and inference accuracy. In addition, we evaluated the usefulness of prior experts' (radiologists') knowledge while constructing the models. In total, 179 patients with lung nodules were included and divided into 79 and 100 cases for training and test data, respectively. F-measure and accuracy were used to assess explanation adequacy and inference accuracy, respectively. For F-measure, reasons were defined as proper subsets of Evidence that had a strong influence on the inference result. The inference models were automatically constructed using the Bayesian network and Markov chain Monte Carlo methods, selecting only those models that met the predefined criteria. During model constructions, we examined the effect of including radiologist's knowledge in the initial Bayesian network models. Performance of the best models in terms of F-measure, accuracy, and evaluation metric were as follows: 0.411, 72.0%, and 0.566, respectively, with prior knowledge, and 0.274, 65.0%, and 0.462, respectively, without prior knowledge. The best models with prior knowledge were then subjectively and independently evaluated by two radiologists using a 5-point scale, with 5, 3, and 1 representing beneficial, appropriate, and detrimental, respectively. The average scores by the two radiologists were 3.97 and 3.76 for the test data, indicating that the proposed computer-aided diagnosis system was acceptable to them. In conclusion, the proposed method incorporating radiologists' knowledge could help in eliminating radiologists' distrust of computer-aided diagnosis and improving its performance. PMID- 30444908 TI - Predicting osmotic potential from measurements of refractive index in cherries, grapes and plums. AB - Studies of fruit tree water relations often require data on water potentials of fruit. However, this is sometimes difficult because the fruit stalks are not sufficiently long for use in a pressure bomb. Also, because fruit xylem function is often lost during maturation. In the absence of significant turgor, the osmotic potential of the expressed juice is a useful proxy for a fruit's water potential. The osmotic potential of most fleshy fruit is determined largely by the concentration of soluble carbohydrates and this can be quantified by osmometry. Soluble solids may also be quantified by refractometry. Compared with osmometry, refractometry is markedly less expensive and also much faster. Hence, it is better suited to high-throughput analyses. The objective of this study was to establish relationships between the osmotic potentials of juices expressed from sweet cherries and sour cherries, grapes and plums as determined using a vapor pressure osmometer and their soluble solids concentrations as determined using a refractometer. The data reveal close relationships within all these species. Except for plums, the relationships between species were almost identical. This is due to similarity among cultivars and species in the relative abundances of the same set of major osmolytes-i.e. the carbohydrates glucose, fructose and sorbitol and the potassium salts of the organic acids malate or tartrate. For plums, the relationship between osmotic potential and soluble solids concentration was slightly displaced. Our findings indicate osmotic potentials may be reliably predicted from soluble solids concentrations determined by refractometry. PMID- 30444909 TI - Sensitivity of nasal airflow variables computed via computational fluid dynamics to the computed tomography segmentation threshold. AB - Computational fluid dynamics (CFD) allows quantitative assessment of transport phenomena in the human nasal cavity, including heat exchange, moisture transport, odorant uptake in the olfactory cleft, and regional delivery of pharmaceutical aerosols. The first step when applying CFD to investigate nasal airflow is to create a 3-dimensional reconstruction of the nasal anatomy from computed tomography (CT) scans or magnetic resonance images (MRI). However, a method to identify the exact location of the air-tissue boundary from CT scans or MRI is currently lacking. This introduces some uncertainty in the nasal cavity geometry. The radiodensity threshold for segmentation of the nasal airways has received little attention in the CFD literature. The goal of this study is to quantify how uncertainty in the segmentation threshold impacts CFD simulations of transport phenomena in the human nasal cavity. Three patients with nasal airway obstruction were included in the analysis. Pre-surgery CT scans were obtained after mucosal decongestion with oxymetazoline. For each patient, the nasal anatomy was reconstructed using three different thresholds in Hounsfield units (-800HU, 550HU, and -300HU). Our results demonstrate that some CFD variables (pressure drop, flowrate, airflow resistance) and anatomic variables (airspace cross sectional area and volume) are strongly dependent on the segmentation threshold, while other CFD variables (intranasal flow distribution, surface area) are less sensitive to the segmentation threshold. These findings suggest that identification of an optimal threshold for segmentation of the nasal airway from CT scans will be important for good agreement between in vivo measurements and patient-specific CFD simulations of transport phenomena in the nasal cavity, particularly for processes sensitive to the transnasal pressure drop. We recommend that future CFD studies should always report the segmentation threshold used to reconstruct the nasal anatomy. PMID- 30444910 TI - Toxicity to, oviposition and population growth impairments of Callosobruchus maculatus exposed to clove and cinnamon essential oils. AB - The use of plant essential oils has been shown to efficiently control insect pests of stored beans, significantly reducing the threats associated with synthetic insecticides. Here, we evaluated the potential of applications of essential oils of clove, Syzygium aromaticum L., and cinnamon, Cinnamomum zeylanicum L., to control Callosobruchus maculatus, considered as one of the most cosmopolitan pests of stored beans. Using four combinations of couples (i.e., unexposed couples, exposed females, exposed males, and exposed couples), we also evaluated how sublethal exposure to these essential oils impacted C. maculatus oviposition. Bioassays results revealed that both essential oils exhibited insecticidal activities similar to the synthetic pyrethroid insecticide deltamethrin. Furthermore, oil dosage increments proportionately decreased the growth rate and reduced the losses in bean weight caused by cowpea weevils, and offspring emergence was almost abolished when parents were exposed to the LD20 of each essential oil. Finally, significant oviposition impairments were perceived only in couples where females were exposed (i.e., females exposed and exposed couples) to the LD20 of cinnamon and clove essential oils. Thus, by exhibiting similar insecticidal activities as synthetic insecticides and by significantly affecting the oviposition of sublethally exposed C. maculatus females, the cinnamon and clove essential oils represent valuable tools with potential of integration into the management of C. maculatus infestations. PMID- 30444911 TI - Indole primes plant defense against necrotrophic fungal pathogen infection. AB - Indole is a volatile compound and emitted from plants challenged by insect infestation or mechanic wounding. It has been shown to prime defense against herbivory. Here we identified that indole induced defense either directly or as a priming agent against necrotrophic pathogens Fusarium graminearum and F. moniliforme in maize and Magnaporthe oryzae in rice. With indole pretreatment, smaller lesions were developed in infected leaves, as well as less fungal growth. Indole induced H2O2 burst in the priming stage like other priming substances did. Such priming relied on mitogen-activated protein kinase (MAPK) cascade, which potentially activated downstream defense signaling. In addition, indole priming resulted in earlier and stronger defensive gene expression upon pathogen infection, including genes of jasmonate and phytoalexin biosynthesis, pathogenesis-related proteins (PRs) and anti-oxidant enzymes, which enhanced plant resistance. Meanwhile, H2O2 was also identified as the priming agent to induce plant defense. Taken together, indole exhibited priming function not only against herbivory but also necrotrophic pathogens. The common emission of indole in plants suggests that it plays important roles as the universal and endogenous priming substance in plant defense. PMID- 30444912 TI - Probing inhibition mechanisms of adenosine deaminase by using molecular dynamics simulations. AB - Adenosine deaminase (ADA) catalyzes the deamination of adenosine, which is important in purine metabolism. ADA is ubiquitous to almost all human tissues, and ADA abnormalities have been reported in various diseases, including rheumatoid arthritis. ADA can be divided into two conformations based on the inhibitor that it binds to: open and closed forms. Here, we chose three ligands, namely, FR117016 (FR0), FR221647 (FR2) (open form), and HDPR (PRH, closed form), to investigate the inhibition mechanism of ADA and its effect on ADA through molecular dynamics simulations. In open forms, Egap and electrostatic potential (ESP) indicated that electron transfer might occur more easily in FR0 than in FR2. Binding free energy and hydrogen bond occupation revealed that the ADA-FR0 complex had a more stable structure than ADA-FR2. The probability of residues Pro159 to Lys171 of ADA-FR0 and ADA-FR2 to form a helix moderately increased compared with that in nonligated ADA. In comparison with FR0 and FR2 PRH could maintain ADA in a closed form to inhibit the function of ADA. The alpha7 helix (residues Thr57 to Ala73) of ADA in the closed form was mostly unfastened because of the effect of PRH. The number of H bonds and the relative superiority of the binding free energy indicated that the binding strength of PRH to ADA was significantly lower than that of an open inhibitor, thereby supporting the comparison of the inhibitory activities of the three ligands. Alanine scanning results showed that His17, Gly184, Asp295, and Asp296 exerted the greatest effects on protein energy, suggesting that they played crucial roles in binding to inhibitors. This study served as a theoretical basis for the development of new ADA inhibitors. PMID- 30444913 TI - Neo4j graph database realizes efficient storage performance of oilfield ontology. AB - The integration of oilfield multidisciplinary ontology is increasingly important for the growth of the Semantic Web. However, current methods encounter performance bottlenecks either in storing data and searching for information when processing large amounts of data. To overcome these challenges, we propose a domain-ontology process based on the Neo4j graph database. In this paper, we focus on data storage and information retrieval of oilfield ontology. We have designed mapping rules from ontology files to regulate the Neo4j database, which can greatly reduce the required storage space. A two-tier index architecture, including object and triad indexing, is used to keep loading times low and match with different patterns for accurate retrieval. Therefore, we propose a retrieval method based on this architecture. Based on our evaluation, the retrieval method can save 13.04% of the storage space and improve retrieval efficiency by more than 30 times compared with the methods of relational databases. PMID- 30444914 TI - Muscle Dysmorphic Disorder Inventory (MDDI): Validation of a German version with a focus on gender. AB - Muscle dysmorphia (MD) is a condition that is characterized by body image disturbance, a drive for muscularity and excessive exercising. It leads to considerable functional impairment. Most previous studies focused on male samples. The study aimed to validate a German version of the Muscle Dysmorphic Disorder Inventory (MDDI) in order to make the instrument available in German speaking countries. We further aimed to explore for gender differences in the MDDI factors (measurement invariance) and to assess the relationship between MD and positive dimensions of body experience as well as exercise dependence. 394 participants (53% females, mean age 24.3 years) took part in an internet-based survey. The three-factor structure of the English version of the MDDI was replicated, independent of gender (multi group CFA; Base model TLI = .961; CFI = .970). Cronbach's alpha was .81-.84 for the subscales and .75 for the MDDI total score. MD was associated with exercise dependence and negatively correlated with dimensions of positive body experience, which can be considered relevant for satisfying relationships and a positive sense of self: e.g. body contact and sexual fulfillment. Men and women showed differences in two subscales of the MDDI (appearance intolerance, drive for size). Testing for measurement invariance resulted in weak invariance: Equivalent factor structure for men and women, but significantly different loadings and coefficients. No statistically significant difference in the MDDI total score was found. The findings suggest good psychometric properties of the German version of the MDDI. Future studies should address the question of cut-off scores and norms for different samples as well as a possible overlap between MD and eating disorder psychopathology in women. PMID- 30444916 TI - Effect of anaesthetic technique on neonatal morbidity in emergency caesarean section for foetal distress. AB - BACKGROUND: While foetal distress is typically associated with ischaemic injury, few studies have assessed neonatal morbidity for emergency caesarean section. Moreover, the decision of the anaesthetic technique may be of paramount importance in emergency caesareans, because of the limited time and increased risk. We aimed to evaluate the effect of the anaesthetic technique on neonatal morbidity in emergency caesarean indicated for foetal distress. METHODS: This was a single-centre, prospective observational study, conducted between July-2015 and December-2015. The study enrolled parturient with indication for emergency caesarean section after diagnosis of foetal distress, who received either regional or general anaesthesia. The outcome measures were: 1, 5-minute Apgar scores; umbilical blood pH; length of hospitalization; and morbidity, defined as a 5-minute Apgar score <7, need for mechanical ventilation, admittance to a neonatal intensive care unit, or respiratory insufficiency symptoms. RESULTS: 61 patients were included in the study, of whom 31 received regional anaesthesia. Neonatal morbidity was noted in 5 and 9 cases with regional and general anaesthesia, respectively. The 1-minute Apgar score was significantly lower(p = 0,045) for cases with general anaesthesia, which was not true for the 5-minute Apgar score. Regional anaesthesia was non-significantly associated with shorter length of hospitalization, lower incidence of morbidity, and higher umbilical blood pH. When we take regional anaesthesia cases as a reference point, we detected that general anaesthesia cases are showing 2,2 times more morbidity risk. But these results did not reach any statistically significant levels. CONCLUSIONS: While we did find some improved results for regional anaesthesia group, we found no statistical evidence that neither anaesthesia technique is superior regarding neonatal morbidity. We think that regional anaesthesia should be preferred whenever possible because of our improved results of length of hospital stay, APGAR and morbidity and we think that general anaesthesia is indicated for very urgent cases or regional anaesthesia contraindicated patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN15181117. PMID- 30444917 TI - MAIA-A machine learning assisted image annotation method for environmental monitoring and exploration. AB - Digital imaging has become one of the most important techniques in environmental monitoring and exploration. In the case of the marine environment, mobile platforms such as autonomous underwater vehicles (AUVs) are now equipped with high-resolution cameras to capture huge collections of images from the seabed. However, the timely evaluation of all these images presents a bottleneck problem as tens of thousands or more images can be collected during a single dive. This makes computational support for marine image analysis essential. Computer-aided analysis of environmental images (and marine images in particular) with machine learning algorithms is promising, but challenging and different to other imaging domains because training data and class labels cannot be collected as efficiently and comprehensively as in other areas. In this paper, we present Machine learning Assisted Image Annotation (MAIA), a new image annotation method for environmental monitoring and exploration that overcomes the obstacle of missing training data. The method uses a combination of autoencoder networks and Mask Region-based Convolutional Neural Network (Mask R-CNN), which allows human observers to annotate large image collections much faster than before. We evaluated the method with three marine image datasets featuring different types of background, imaging equipment and object classes. Using MAIA, we were able to annotate objects of interest with an average recall of 84.1% more than twice as fast as compared to "traditional" annotation methods, which are purely based on software-supported direct visual inspection and manual annotation. The speed gain increases proportionally with the size of a dataset. The MAIA approach represents a substantial improvement on the path to greater efficiency in the annotation of large benthic image collections. PMID- 30444915 TI - Metabolite normalization with local radiotherapy following breast tumor resection. AB - The aims of this study were to investigate changes in energy balance-associated metabolites associated with radiotherapy in patients with breast cancer, and to relate these changes to the clinical and pathological response-to-treatment. We studied 151 women with breast cancer who received radiotherapy following surgical excision of the tumor. Blood was obtained before and after the irradiation procedure. The control group was composed of 44 healthy women with a similar age distribution to that of the patients. We analyzed the concentrations of metabolites involved in glycolysis, citric acid cycle and amino acid metabolism using targeted quantitative metabolomics. Post-surgery, pre-radiotherapy, patients had major alterations in the serum concentrations of products of glycolysis, citric acid cycle and amino acid metabolism. The strongest alterations were decreases in serine, leucine and isoleucine concentrations. Alterations in metabolite levels were partially, or totally, reversed after irradiation; the concentrations of serine, leucine and isoleucine approached equivalence to those of the control group. Estrogen receptor-positive patients were those with lower concentrations, while triple negative patients had higher concentrations of these amino acids. The normalization of the amino acids serine, leucine and isoleucine concentrations could be clinically relevant because the normalization of these energy-balance metabolites would suggest that residual micro-metastatic disease had been effectively diminished by the radiotherapy, and may be an indicator of its efficacy. PMID- 30444918 TI - Correction: Hepatitis C virus NS4B induces the degradation of TRIF to inhibit TLR3-mediated interferon signaling pathway. AB - [This corrects the article DOI: 10.1371/journal.ppat.1007075.]. PMID- 30444919 TI - Sequential organ failure assessment in predicting mortality after paraquat poisoning: A meta-analysis. AB - Sequential organ failure assessment (SOFA) score is commonly used to determine disease severity and predict prognosis in critically ill patients. However, the prognostic value of SOFA after acute paraquat (PQ) poisoning remains unclear. This meta-analysis aimed to study the capability of SOFA to predict mortality in patients with PQ poisoning. Databases that included PubMed, Embase, Web of Science, ScienceDirect, Embase, and Cochrane Library were searched through May 2018. Six studies involving 946 patients were included in the meta-analysis. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and then ORs with 95% CIs were pooled for the estimation of the prognostic role of SOFA in patients with PQ poisoning. Results showed that higher SOFA in patients with PQ poisoning was related to severe mortality (OR = 8.14, 95%CI 4.26-15.58, p<0.001). The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic OR, and area under the curve were 72% (95%CI 0.65-0.79), 75% (95%CI 0.65-0.83), 2.9 (95%CI 2.0-4.1), 0.37 (95%CI 0.28-0.41), 8 (95%CI 4-14), and 0.79 (95%CI 0.76-0.83), respectively. No evidence of publication bias was detected by funnel plot analysis and formal statistical tests. Sensitivity analyses showed no important differences in the estimates of effects. The high SOFA score (8.1-fold) was associated with severe mortality in patients with PQ poisoning. PMID- 30444920 TI - Assessment and application of host-specific Bacteroidales genetic markers for microbial source tracking of river water in Japan. AB - Microbial source tracking using host-specific microbial genetic markers is considered a promising approach to determine fecal contamination sources of aquatic environments. This study aimed to assess the application of previously developed host-specific Bacteroidales quantitative PCR assays to microbial source tracking of river water samples in Yamanashi Prefecture, Japan. Various types of fecal-source samples, such as raw sewage, secondary-treated sewage of a wastewater treatment plant, and cattle feces, were used for three human-, two ruminant- and two pig-specific Bacteroidales quantitative PCR assays. Our results demonstrated that BacHum, BacR and Pig2Bac assays as suitable human-, ruminant- and pig-specific assays, with an accuracy of 86%, 94% and 77%, respectively. These selected assays were used for microbial source tracking of 63 river water samples collected at nine sites in two river basins. From these sites, there were 48 (76%), 34 (54%) and 9 (14%) positive samples using the BacHum, BacR and Pig2Bac assays, respectively. These assays revealed the effects of humans and animals on fecal contamination of river water. PMID- 30444921 TI - Correction: Potential use of text classification tools as signatures of suicidal behavior: A proof-of-concept study using Virginia Woolf's personal writings. AB - [This corrects the article DOI: 10.1371/journal.pone.0204820.]. PMID- 30444922 TI - Correction: Herring supports Northeast Pacific predators and fisheries: Insights from ecosystem modelling and management strategy evaluation. AB - [This corrects the article DOI: 10.1371/journal.pone.0196307.]. PMID- 30444923 TI - Correction: Effectiveness of robot therapy on body function and structure in people with limited upper limb function: A systematic review and meta-analysis. AB - [This corrects the article DOI: 10.1371/journal.pone.0200330.]. PMID- 30444924 TI - Using the RIGHT statement to evaluate the reporting quality of clinical practice guidelines in traditional Chinese medicine. AB - OBJECTIVE: To evaluate the reporting quality of clinical practice guidelines (CPGs) in traditional Chinese medicine (TCM). METHODS: A systematic search was undertaken to extract CPGs for TCM. The RIGHT (Reporting Items for practice Guidelines in Healthcare) statement was used to calculate scores for the reporting quality in terms of domains and items, followed by a subgroup analysis of the results and determination of the correlation between the RIGHT and AGREE II (Appraisal of Guidelines for Research and Evaluation II) scores. RESULTS: Overall, 539 TCM CPGs were included. (1) The mean scores (Med, IQR) for each RIGHT domain were as follows: basic information (4, 1), background (3, 2), evidence (0, 0), recommendations (2, 2), review and quality assurance (0, 0), funding and declaration and management of interests (0, 0.5), and other information (0, 0). (2) The items with a low reporting rate (<10%) included 2, 5, 8b, 9a, 10a, 10b, 11a, 11b, 14a, 14b, 14c, 16, 17, 19b, 20, 21, and 22, and those with a high reporting rate (> 90%) included 1a, 1b, 1c, 7b, 13a, and 13b. (3) In recent years, the reporting quality of TCM CPGs has improved, and there was a significant difference among the organizations (P = 0.000), where that of the updated versions was greater than that of the historical versions (P = 0.047). (4) The RIGHT and AGREE II scores were positively correlated (P = 0.014). CONCLUSIONS: At present, although the reporting quality of TCM CPGs is improving, the overall quality remains suboptimal. Guideline developers should strictly follow the evidence-based process of developing guidelines and should follow the RIGHT statement to produce a standardized report when writing guidelines. PMID- 30444925 TI - Correction: Aqueous humor cytokine levels in patients with diabetic macular edema refractory to anti-VEGF treatment. AB - [This corrects the article DOI: 10.1371/journal.pone.0203408.]. PMID- 30444927 TI - Estimating duration-distance relations in cycle commuting in the general population. AB - It is important to estimate the duration-distance relation in cycle commuting in the general population since this enables analyses of the potential for various public health outcomes. Therefore, the aim is to estimate this relation in the Swedish adult population of 2015. For that purpose, the first step was to establishit for adult male and female cycle commuters in Greater Stockholm, Sweden. Whether or not the slopes of these relations needed to be altered in order to make them representative of the general population was evaluated by comparing the levels of maximal oxygen uptake in samples of commuter cyclists and the population. The measure used was the maximal oxygen uptake divided by both the body weight and a cycle weight of 18.5 kg. The body weights in the population samples were adjusted to mirror relevant levels in 2015. Age adjustments for the duration-distance relations were calculated on the basis of the maximal oxygen uptake in the population samples aged 20-65 years. The duration-distance relations of the cycle commuters were downscaled by about 24-28% to mirror levels in the general population. The empirical formula for the distance (D, km) was based on duration (T, minutes) . speed (km/min) . a correction factor from cycle commuter to the general population . age adjustment (A, years). For the males in the general population the formula was: D = T . 20.76 km/h . 0.719 . (1.676 0.0147 . A). For females, the formula was: D = T . 16.14 km/h . 0.763 . (1.604 0.0129 . A). These formulas, combined with distributions of route distances between home and work in the population, enable realistic evaluations of the potential for different public health outcomes through cycle commuting. PMID- 30444926 TI - Distal radius fractures-Regional variation in treatment regimens. AB - OBJECTIVES: After recent technical innovations of fracture surgery implants, treatment traditions are changing for distal radius fractures, the most common orthopaedic injury. The aim of this study was to determine if the choice of surgical method for treatment of distal radius fractures differ between healthcare regions in Sweden. METHOD: The study was based on all (n = 22 378) adult patients who were registered with a surgical procedure due to a distal radius fracture during 2010-2013 in Sweden. Consecutive data was collected from the Swedish National Patient Registry. RESULTS: The proportions of use of surgical method varied among the 21 healthcare regions between 41% and 95% for internal fixation, between 2.3% and 44% for percutaneous fixation and between 0.6% and 19% for external fixation. Differences between regions were statistically significant in all but 6 comparisons when controlled for age and gender. Incidence rates of surgical treatment of a distal radius fracture varied between 4.2 and 9.2/10 000 person-years. CONCLUSION: We conclude that there is a large variation in operative management of distal radius fractures between Swedish healthcare regions. PMID- 30444928 TI - Declining racial and ethnic representation in clinical academic medicine: A longitudinal study of 16 US medical specialties. AB - OBJECTIVE: To evaluate trends in racial, ethnic, and sex representation at US medical schools across 16 specialties: internal medicine, pediatrics, surgery, psychiatry, radiology, anesthesiology, obstetrics and gynecology, neurology, family practice, pathology, emergency medicine, orthopedic surgery, ophthalmology, otolaryngology, physical medicine and rehabilitation, and dermatology. Using a novel, Census-derived statistical measure of diversity, the S-score, we quantified the degree of underrepresentation for racial minority groups and female faculty by rank for assistant, associate, and full professors from 1990-2016. METHODS: This longitudinal study of faculty diversity uses data obtained from the American Association of Medical Colleges (AAMC) Faculty Roster from US allopathic medical schools. The proportion of professors of racial minority groups and female faculty by rank was compared to the US population based on data from the US Census Bureau. The Roster includes data on 52,939 clinical medical faculty in 1990, and 129,545 in 2016, at the assistant professor level or higher. The primary measure used in this study was the S-score, a measure of representation based on the probability of the observed frequency of faculty from a racial/ethnic group and sex, given the racial and ethnic distribution of the US. Pearson correlations and 95% confidence intervals for S score with time were used to measure trends. RESULTS: Blacks and Hispanics showed statistically significant trends (p<0.05) towards increasing underrepresentation in most specialties and are more underrepresented in 2016 than in 1990 across all ranks and specialties analyzed, except for Black females in obstetrics & gynecology. White females were also underrepresented in many specialties and in a subset of specialties trended toward greater underrepresentation. CONCLUSIONS: Current efforts to improve faculty diversity are inadequate in generating an academic physician workforce that represents the diversity of the US. More aggressive measures for faculty recruitment, retention, and promotion are necessary to reach equity in academia and healthcare. PMID- 30444929 TI - Climate change impacts on crop yield, soil water balance and nitrate leaching in the semiarid and humid regions of Canada. AB - The impact of climate change on agricultural systems is a major concern as it can have a significant effect on the world food supply. The objective of this study was to evaluate climate change impacts on crop production and nitrate leaching in two distinct climatic zones in Canada. Spring wheat (Triticum aestivum L.) was selected for the semiarid regions of Western Canada (Swift Current, SK) and maize (Zea mays L.) was chosen for the more humid regions of central Canada (Woodslee, ON). Climate scenarios were based upon simulations from a Canadian Regional Climate Model (CanRCM4) under two Representative Concentration Pathways (RCP4.5 and RCP8.5) and crop simulations were conducted using the Decision Support System for Agrotechnology Transfer (DSSAT) model. Compared to the baseline climate scenario, wheat yields increased by 8, 8, 11, 15%, whereas maize yields decreased by 15, 25, 22, 41% under RCP4.5 2050s (2041-2070), RCP4.5 2080s (2071-2100), RCP8.5 2050s and RCP8.5 2080s scenarios, respectively. Annual nitrate leaching increased by 19, 57, 73, 129% at Swift Current and by 84, 117, 208, 317% at Woodslee under the four scenarios, respectively. Adaptation measures suggested that fertilizer N rate for spring wheat should be increased to 80-100 kg N ha-1 to obtain optimal yields although this will result in an additional risk of 5-8 kg N ha-1 nitrate leaching at Swift Current. The fertilizer N rate of 150 kg N ha 1 was found to be suitable for high maize yields at Woodslee. New wheat and maize cultivars with long growing seasons would enable crop growth to match the phenological stage and hence maintain high crop yields to adapt to increased temperatures in the future. PMID- 30444930 TI - Soluble transforming growth factor beta-1 enhances murine mast cell release of Interleukin 6 in IgE-independent and Interleukin 13 in IgE-dependent settings in vitro. AB - INTRODUCTION: For immune cells transforming growth factor beta-1 (TGF-beta1) can enhance or repress effector functions. Here, we characterize the effects of TGF beta1 on IgE-mediated and IL-33-mediated activation of primary murine mast cells derived from hematopoietic stem cells (bone marrow derived mast cells; BMMC). We also investigated potential interactions between TGF-beta1 and stem cell factor (SCF). We conclude TGF-beta1 plays a selectively stimulatory role for mast cell cultures in vitro. METHODS: BMMCs from C57BL/6 mice were differentiated with IL-3 and then treated with TGF-beta1. BMMCs were exposed to TGF-beta1, primed with IgE, activated with antigen, and then IL-6 and IL-13 cytokine release was quantified using ELISA. Additionally, the effects of TGF-beta1 on both IgE and IL 33-mediated short term activation were observed via flow cytometric analysis of both surface LAMP-1 expression and intracellular IL-6. Receptor colocalization was visualized using fluorescence confocal microscopy and individual receptor expression levels were also quantified. RESULTS: Resting IL-6 production increased with TGF-beta1 but significance was lost following BMMC activation via IgE receptor (FcepsilonRI) crosslinking. This was similar to a comparison effect due to SCF treatment alone, which also enhanced resting levels of IL-6. TGF-beta1 treatment enhanced release of IL-13 only with FcepsilonRI-IgE-mediated activation. TGF-beta1 suppressed mobilization of IL-6 with short-term BMMC activation when stimulated with IL-33. Lastly, colocalization patterns of the SCF receptor (CD117) and FcepsilonRI with IgE crosslinking were unaffected by TGF beta1 treatment, but individual expression levels for FcepsilonRI, CD117, and TGFbetaRII were all reduced following either IgE activation or TGF-beta1 treatment; this reduction was partially recovered in BMMCs that were both activated by IgE and treated with TGF-beta1. DISCUSSION: These data reveal a novel positive effect of soluble TGF-beta1 on mast cell activation in vitro, suggesting mast cells may be activated through a non-canonical pathway by TGF beta1. Understanding this interaction will provide insight into the potential role of mast cells in settings where TGF-beta1 is produced in an aberrant manner, such as in and around high grade tumors. PMID- 30444932 TI - Resurrection and Reactivation of Acetylcholinesterase and Butyrylcholinesterase. AB - Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical nerve agents, but more commonly, civilians are exposed to less toxic OP pesticides, while resulting in the same negative toxicological effects and thousands of deaths on an annual basis. After decades of research, no new therapeutics have been realized since the mid-1900s. Upon phosphylation of the catalytic serine residue, known as inhibition, there is an accumulation of acetylcholine (ACh) in the brain synapses and neuromuscular junctions, leading to a cholinergic crisis and eventually death. Oxime nucleophiles can reactivate select OP-inhibited acetylcholinesterase (AChE). Yet, the fields of reactivation of AChE and butyrylcholinesterase encounter additional challenges as broad spectrum reactivation of either enzyme is difficult. Additional problems include the ability to cross the blood brain barrier (BBB) and to provide therapy in the central nervous system. Yet another complication arises in a competitive reaction, known as aging, whereby OP-inhibited AChE is converted to an inactive form, that until very recently, had been impossible to reverse to an active, functional form. Evaluations of uncharged oximes and other neutral nucleophiles have been made. Non-oxime reactivators, such as aromatic general bases and Mannich bases, have been developed. The issue of aging, which generates an anionic phosphylated serine residue, has been historically recalcitrant to recovery by any therapeutic approach - that is, until earlier this year. Mannich bases not only serve as reactivators of OP-inhibited AChE, but this class of compounds can also recover activity from the aged form of AChE, a process referred to as resurrection. This review covers the modern efforts to address all of these issues and notes the complexities of therapeutic development along these different lines of research. PMID- 30444933 TI - Gamma-delta T cell large granular lymphocyte leukaemia with multiple cutaneous nodules that showed spontaneous regression. PMID- 30444931 TI - Impact of asymptomatic genital tract infections on in vitro Fertilization (IVF) outcome. AB - BACKGROUND: Infertility is estimated to affect approximately 9-30% of reproductive-aged couples. Several conditions involving one or both partners may contribute to infertility. The aim of this study is to evaluate the role of asymptomatic genital tract infections in the outcome of In Vitro Fertilization (IVF) in couples with infertility. METHODS: A total of 285 infertile couples were enrolled in the study. Vaginal/endocervical swabs and semen samples were collected and subjected to microbiological analysis. Spermiograms were carried out on semen specimens, and lactobacilli were quantified in vaginal swabs. Data were associated with IVF results and analysed by using non parametric tests and multivariate analysis. RESULTS: Microbiological analysis showed that 46.3% of couples presented with an asymptomatic genital tract infection. Spermiogram results showed a significantly diminished motility of sperm cells in samples positive to microbiological testing compared to negative specimens. Enterococcus faecalis was the most prevalent species (11.6%) in positive semen samples and was found to negatively affect both sperm morphology (p = 0.026) and motility (p = 0.003). Analysis of genital swabs from females showed that the presence of E. faecalis (p<0.0001), Escherichia coli (p = 0.0123), Streptococcus agalactiae (p<0.0001), and Gardnerella vaginalis (p = 0.0003) was significantly associated to reduced levels of vaginal lactobacilli. Association of microbiological data with IVF outcome showed that 85.7% of IVF+ couples was microbiologically negative, while IVF was successful in just 7.5% of couples infected with E. faecalis and/or U. urealyticum and/or M. hominis (p = 0.02). CONCLUSIONS: The results show the negative impact of E. faecalis on sperm quality and the association of definite bacterial pathogens with reduced levels of vaginal lactobacilli. The presence of E. faecalis and/or U. urealyticum and/or M. hominis in genital samples of infertile couples is predictive for a negative outcome of IVF. PMID- 30444934 TI - Medical Emergencies in Farmers. AB - BACKGROUND: Agricultural work involves hazards that may harm long-term well being. We evaluated the risk of long-term disability and death for agricultural workers compared to construction workers with similar demographics. We hypothesized that delays to emergency care and subsequent long-term disability following injury might be worse for agricultural workers compared to those injured in construction. METHODS: We evaluated all adults severely injured on farms or on construction sites in Ontario, Canada, between April 1, 2009, and March 31, 2012, according to the Ontario Trauma Registry. We excluded individuals living outside of the province, those missing a valid health card number, or youth less than 17 years old. Our primary outcome was death or the subsequent application for disability support. RESULTS: In total, 353 patients were injured on a farm or construction site during the study period. Delays to emergency care exceeding 12 hours were more frequent for agricultural workers compared to construction workers (43% vs 23%, P <.001). After a 5-year follow-up, agricultural workers had a death or disability rate marginally higher than construction workers (23% vs 14%, P = .068), equivalent to a hazard ratio of 1.62 that was marginally statistically significant (95% confidence interval 0.96-2.75, P = .072). The risk of death and disability was greatest for patients who had the longest delays to emergency care. INTERPRETATION: Agricultural workers experience a substantial delay in receiving emergency care and a marginally higher risk of death or disability in the years following injury compared to construction workers. PMID- 30444935 TI - Differences in Rural and Urban Health Information Access and Use. AB - PURPOSE: Rural residents may have lower access to and use of certain health information sources relative to urban residents. We investigated differences in information source access and use between rural and urban US adults and whether having low health literacy might exacerbate rural disparities in access to and use of health information. METHODS: Six hundred participants (50% rural) completed an online survey about access and use of 25 health information sources. We used logistic regression models to test associations between rurality and access to and use of health information sources and whether rurality interacted with health literacy to predict the access and use. FINDINGS: Compared to urban residents, rural residents had lower access to health information from sources including primary care providers, specialist doctors, blogs, and magazines, and less use of search engines. After accounting for sociodemographics, rural residents only had lower access to specialist doctors than urban residents. Rural residents with limited health literacy had lower access to mass media and scientific literature but higher use of corporations/companies than rural residents with adequate health literacy and urban residents regardless of health literacy level. CONCLUSIONS: Some differences in access to and use of health information sources may be accounted for by sociodemographic differences between rural and urban populations. There may be structural barriers such as shortage of specialist doctors and limited media exposure that make it harder for rural residents to access health information, especially those with limited health literacy. PMID- 30444937 TI - 2018 Annual Meeting of the American Society for Bone and Mineral Research Palais des congres de Montreal in Montreal, Quebec, Canada September 28 - October 1, 2018. PMID- 30444936 TI - Metabolites identification of Tanshinol Borneol Ester in rats by high performance liquid chromatography combined with electrospray ionization quadrupole time-of flight mass spectrometry. AB - Tanshinol borneol ester (DBZ), a potential drug candidate composed of danshensu and borneol. It shows efficiency on anti-ischemic and anti-atherosclerosis. However, little is known about its metabolism in vivo. This research aims to elucidate the metabolic profile of DBZ through analyzing its metabolites by high performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight mass spectrometry (HPLC-ESI-Q-TOF-MS). Chromatographic separation was performed on an Agilent TC-C18 column (150*4.6 mm, 5.0 MUm) with gradient elution using methanol and water containing 0.2% (V:V) formic acid as the mobile phase. Metabolites identification involved analyzing the retention behaviors, changes of molecular weights and MS/MS fragment patterns of DBZ and its metabolites. As a result, 20 potential metabolites were detected and tentatively identified in rat plasma, urine and feces after administration of DBZ. DBZ could be metabolized to O-methylated DBZ, DBZ-O-glucuronide, O methylated DBZ-O-glucuronide, hydroxylated DBZ and danshensu (DSS). DSS, a hydrolysis product of DBZ, could further be transformed into 12 metabolites. The proposed method was confirmed to be a reliable and sensitive alternative for characterizing metabolic pathways of DBZ and providing valuable information of its druggability. PMID- 30444938 TI - MiRNA-218 regulates osteoclast differentiation and inflammation response in periodontitis rats through Mmp9. AB - Periodontitis a multiple infection and inflammatory disease featured by connective tissue homeostasis loss, periodontal inflammation and alveolar bone resorption. MicroRNAs (miRNAs) are involved in the mediation of a large-scale of pathological processes. Here we show that miRNA-218 provides protective effect on periodontitis via regulation of matrix metalloproteinase-9 (Mmp9). This pathway is aberrant in periodontium from rats with periodontitis and HPLPCs stimulated by LPS, with downregulation of miR-218 and higher levels of Mmp9 compared to periodontium from healthy rats and cells without stimulation. Overexpression of miR-218 can suppress the degradation of collagen types I, IV and Dentin Sialoprotein (DSP), attenuate osteoclast formation, and inhibit the secretion of pro-inflammatory cytokines. On the other hand, overexpression of Mmp9 promotes the degradation of collagen types I, IV and DSP as well as RANKL-induced osteoclast formation, and elevates inflammatory factors levels. Furthermore, the inhibitory effect of miR-218 was prevented by rescued the Mmp9 expression. In addition, we also have showed that miR-218 was able to attenuate bone resorption and inflammation in a periodontitis rat model. Collectively, our findings therefore suggest that miR-218 acts as a protective role in periodontitis through the regulation of Mmp9. PMID- 30444939 TI - New perspectives of childhood asthma treatment with biologics. AB - Asthma is no longer considered as a single disease but rather as a syndrome corresponding to different entities and pathophysiological pathways. A targeted strategy is part of personalized medicine which aims to better define each patient's phenotype and endotype so as to prescribe the most suitable treatment at an individual level. Omalizumab, and more recently mepolizumab, are the first biologics approved for children (6-18 years). Omalizumab is now widely used to treat severe allergic asthma in children and is highly effective for asthma exacerbations and asthma control with a good safety profile. Moreover, several other drugs -lebrikizumab, dupimumab, tezepelumab, mepolizumab, reslizumab, benralizumab- are used or are being studied in both teenagers and adults, and could benefit younger children in the near future. We hypothesize that defining the asthma phenotype/endotype regarding the type and intensity of inflammation, association with allergic or non-allergic comorbidities, and airway remodeling should contribute to the choice of a specific biologic. Pediatric specificities have to be addressed and validated by studies in children. Long-term effectiveness and particularly the impact on the natural history of asthma should also be investigated. Severe asthma in children is a complex disease and patients have to be referred to a specialized pediatric asthma center to confirm diagnosis and initiate the best treatment strategy which could include biologics whilst taking into account their high cost. This article is protected by copyright. All rights reserved. PMID- 30444940 TI - Adapting the Chumbley Score to Match Striae on Land Engraved Areas (LEAs) of Bullets. AB - The same-source problem remains a major challenge in forensic toolmark and firearm examination. Here, we investigate the applicability of the Chumbley method (J Forensic Sci, 2018, 63, 849; J Forensic Sci, 2010, 55, 953) (10,12), developed for screwdriver markings, for same-source identification of striations on bullet LEAs. The Hamby datasets 44 and 252 measured by NIST and CSAFE (high resolution scans) are used here. We provide methods to identify parameters that minimize error rates for matching of LEAs, and a remedial algorithm to alleviate the problem of failed tests, while increasing the power of the test and reducing error rates. For 85,491 land-to-land comparisons (84,235 known nonmatches and 1256 known matches), the adapted test does not provide a result in 176 situations (originally more than 500). The Type I and Type II error rates are 7.2% (6105 out of 84,235) and 21.4% (271 out of 1256), respectively. This puts the proposed method on similar footing as other single-feature matching approaches in the literature. PMID- 30444941 TI - Evaluation of Nile Red-Loaded Mesoporous Silica Nanoparticles for Developing Water-Soaked Fingerprints on Thermal Paper. AB - Nile red has been an alternative reagent for detecting latent fingerprints on wetted substrates. However, the presence of methanol in nile red solution could make injury to handlers and destroy the traces on surfaces, such as texts on thermal papers. A novel small particle reagent formulation constituting of mesoporous silica nanoparticles (MSNs) based on nile red was prepared to overcome the problem. Compared with the conventional reagents Oil Red O or nile red solution, the nile red-loaded MSNs are highly selective to lipid residues of fingerprints and showed a greater ability to develop clear, sharp, and detailed fingerprints on thermal papers after these were immersed in water. In addition, it can retain texts on the thermal papers well and use only water as a solvent. These suggested that nile red-loaded MSNs are a safe, efficient, and convenient method to develop latent fingerprints on wide range of substrates of forensic importance. PMID- 30444942 TI - Harnessing stem cells and biomaterials to promote neural repair. AB - With the limited capacity for self-repair in the adult central nervous system, efforts to stimulate quiescent stem cell populations within discrete brain regions, as well as harness the potential of stem cell transplants, offers significant hope for neural repair. These new cells are capable of providing trophic cues to support residual host populations and/or replace those cells lost to the primary insult. However, issues with low level adult neurogenesis, cell survival, directed differentiation, and inadequate reinnervation of host tissue have impeded the full potential of these therapeutic approaches and their clinical advancement. Biomaterials offer novel approaches to stimulate endogenous neurogenesis, as well as for the delivery and support of neural progenitor transplants, providing a tissue-appropriate physical and trophic milieu for the newly integrating cells. In this review we will discuss the various approaches by which bioengineered scaffolds may improve stem cell-based therapies for repair of the central nervous system. PMID- 30444943 TI - A Fatal Mediastinitis Due to a Neck Trauma from an Undeclared Assault. AB - History of neck trauma should be promptly investigated in patients with severe infections of the chest as mediastinitis. We present a forensic case of a death due to a mediastinitis in a patient with an undetected fracture of the superior horn of the thyroid cartilage that was exclusively revealed at autopsy examination. Histological analyses of the neck tissues showed signs of pharyngeal mucosal microperforation caused by the fracture and surrounded by an inflammatory reaction. The fracture was caused by a not declared manual strangulation attempt, happened several days before medical evaluations. We share our experience to emphasize the importance of revealing the etiologies of fatal infections of the mediastinum both for clinical and forensic purposes. PMID- 30444944 TI - Mild Cognitive Impairment that Does Not Progress to Dementia: A Population-Based Study. AB - BACKGROUND/OBJECTIVE: In population studies, most individuals with mild cognitive impairment (MCI) do not progress to dementia in the near term, but rather remain stable MCI or revert to normal cognition. Here, we characterized MCI subgroups with different outcomes over 5 years. SETTING/PARTICIPANTS: A population-based cohort (N=1603). MEASUREMENTS: Clinical Dementia Rating (CDR); self-reported medical conditions, subjective cognitive concerns, self-rated health, depressive symptoms, blood pressure, medications, blood pressure, APOE genotype, cognitive domain composite scores. DESIGN: We compared 3 MCI subgroups who progressed to dementia (n=86), stabilized at MCI (n=384), or reverted to normal (n=252), to those who remained consistently normal (n=881), defining MCI as CDR = 0.5 and dementia as CDR>=1. Using multinomial logistic regression models adjusted for demographics, we examined the associations of each group with selected baseline characteristics. RESULTS: With the normal group for reference, worse subjective cognitive concerns, functional impairments, self-rated health, and depressive symptoms were associated with being in any MCI group. Taking more prescription medications was associated with being in the stable MCI and reverter groups; diabetes and low diastolic blood pressure were associated with stable MCI. The APOE4 genotype was associated with stable and progressive MCI; stroke was associated with progressive MCI. All MCI subgroups were likely to have lower mean composite scores in all cognitive domains and more operationally defined impairments in attention, language, and executive function; reverters were more likely to lack memory and visuospatial impairments. CONCLUSIONS: MCI subgroups with different 5-year outcomes had some distinct characteristics suggesting different underlying causes. The progressors, unlike the reverters, had a profile broadly typical of Alzheimer's disease; the stable MCIs had other, including vascular, morbidity. These data shed light on the heterogeneity of MCI in the population. PMID- 30444945 TI - Boron deficiency alters cytosolic Ca2+ concentration and affects the cell wall components of pollen tubes in Malus domestica. AB - Boron (B) is essential for plant normal growth including pollen tube growth. B deficiency influences various physiological and metabolic processes of plants. However, the underlying mechanism of B deficiency in pollen tube growth is insufficiently understood. In the present research, the influence of B deficiency on apple (Malus domestica) pollen tube growth was studied and the possible regulatory mechanism was evaluated. Apple pollen grains were cultured under different concentrations of B. Scanning ion-selective electrode technique, fluorescent labeling and Fourier-transform infrared analysis (FTIR) were used to detect calcium ion flux, cytosolic Ca2+ concentration ([Ca2+ ]cyt), actin filaments and cell wall components of pollen tubes. The results illustrated that B deficiency inhibited apple pollen germination and induced retardation of tube growth. B deficiency increased extracellular Ca2+ influx and thus led to increased [Ca2+ ]cyt in pollen tube tip. In addition, B deficiency modified actin filament arrangement at the pollen tube apex. B deficiency also altered deposition of pollen tube wall components. Clear differences were not observed concerning the distributive patterns of cellulose and callose between control and B deficiency treated pollen tubes. However, B deficiency affected pectin and arabinogalactan proteins (AGPs) distributive patterns. Clear ring-like signals of pectins and AGPs on control pollen tube were varied by B deficiency. B deficiency further decreased acid pectins, esterified pectins and AGPs content at the tip of pollen tube, which were supported by the changes in the chemical composition of tube walls. In a word, B might take an active part in pollen tube growth through affecting [Ca2+ ]cyt, actin filament assembly, pectins and AGP deposition at the pollen tube. These findings provide valuable information which enhances our current understanding of the mechanism regulating pollen tube growth. This article is protected by copyright. All rights reserved. PMID- 30444946 TI - Vinylidenation of Organoboronic Esters Enabled by a Pd-Catalyzed Metallate Shift. AB - Organoboron 'ate' complexes undergo a net vinyl insertion reaction to give 1,1 disubstituted alkenyl boronic esters when treated with stoichiometric allyl acetate and a palladium catalyst. Reactions that employ vinyllithium afforded good to excellent yields after one hour, while reactions that employ vinylmagnesium chloride furnished modest to good yields after 18 hours. PMID- 30444947 TI - Leprosy services in primary health care in India: comparative economic cost analysis of two public-health settings. AB - OBJECTIVES: The WHO recommends inclusion of post-exposure chemoprophylaxis with single-dose rifampicin in national leprosy control programmes. The objective was to estimate the cost of leprosy services at primary care level in two different public-health settings. METHODS: Ingredient-based costing was performed in eight primary health centres (PHCs) purposively selected in the Union Territory of Dadra and Nagar Haveli (DNH) and the Umbergaon block of Valsad district, Gujarat, India. All costs were bootstrapped, and to estimate the variation in total cost under uncertainty, a univariate sensitivity analysis was performed. RESULTS: The mean annual cost of providing leprosy services was USD 29 072 in the DNH PHC (95% CI: 22 125-36 020) and USD 11 082 in Umbergaon (95% CI: 8334-13 830). The single largest cost component was human resources: 79% in DNH and 83% in Umbergaon. The unit cost for screening the contact of a leprosy patient was USD 1 in DNH (95% CI: 0.8-1.2) and USD 0.3 in Umbergaon (95% CI: 0.2-0.4). In DNH, the unit cost of delivering single-dose of rifampicin (SDR) as chemoprophylaxis for contacts was USD 2.9 (95% CI: 2.5-3.7). CONCLUSIONS: The setting with an enhanced public health financing system invests more in leprosy services than a setting with fewer financial resources. In terms of leprosy visits, the enhanced public-health system is hardly more expensive than the non-enhanced public-health system. The unit cost of contact screening is not high, favouring its sustainability in the programme. PMID- 30444948 TI - A genomic survey of nitrogen assimilation pathways in budding yeasts (sub-phylum Saccharomycotina). AB - Sequenced genomes of 149 species of budding yeast (including 62 species with draft genomes that currently lack gene annotations) were surveyed for the presence of 24 genes associated with the assimilation of amines, uracil, dihydropyrimidines, purines, uric acid, allantoin, and nitrate as nitrogen sources. Genes for the assimilation of primary amines were distributed broadly across the Saccharomycotina while choline assimilation appeared to be mostly restricted to the families Debaryomycetaceae, Metschnikowiaceae, and Pichiaceae. Conversely, the uracil catabolic pathway was completely absent in Debaryomycetaceae and Metschnikowiaceae but present in the majority of the remaining Saccharomycotina. The super-pathway for assimilation of purines, uric acid, and allantoin was present in the majority of surveyed species. Genes for the assimilation of nitrate were restricted to a minority of species in families Phaffomycetaceae, Pichiaceae, and Trichomonascaceae as well as some currently unassigned genera. This study also successfully identified yeast homologs of all six previously known eukaryotic genes involved in the biosynthesis of the molybdenum cofactor, which is required for the activity of the nitrogen assimilation-associated enzymes nitrate reductase and xanthine oxidoreductase. Analysis of 1,187 upstream intergenic regions identified three novel putative regulatory motifs for the assimilation of uracil, purines, and uric acid as well as a possible role for the MADS-box transcription factor Mcm1 in the regulation of amine assimilation genes. PMID- 30444950 TI - Lateral adsorbate interactions inhibit HCOO- while promoting CO selectivity for CO2 electrocatalysis on Ag. AB - Elucidating the pathways involved in the electrochemical reduction of carbon dioxide (CO2ER) is crucial for the advancement of sustainable chemical and fuel manufacturing processes. Ag is an appealing CO2ER catalyst due to its promising performance for carbon monoxide (CO) production and relatively low cost. In this report, we study the role of the formate (HCOO-) intermediate *OCHO, aiming to resolve the discrepancy between the current theoretical understanding and experimental performance of Ag catalysts. We demonstrate that the first coupled proton-electron transfer (CPET) step in the pathway for CO production to form *COOH competes with the Volmer step for formation of *H, whereas this Volmer step is a prerequisite for the formation of the *OCHO species. We show that *OCHO should form readily on the Ag surface owing to substantial stabilization of the transition state due to solvation and favorable binding strength. In addition, we use in-situ surface-enhanced Raman spectroscopy (SERS) experiments to provide preliminary evidence of the presence of O-bound bidentate species on polycrystalline Ag catalyst during CO2ER at low overpotentials which we attribute to *OCHO. Lateral adsorbate-adsorbate interactions in the presence of *OCHO have a significant influence on the surface coverage of *H, resulting in the inhibition of HCOO- and H2 production and a higher selectivity towards CO. We argue that the species *OCHO plays an important role in determining the activity and selectivity for not only formate-producing catalysts but also for catalysts such as Ag that predominantly produce CO. PMID- 30444949 TI - The challenges on the family unit faced by younger couples affected by prostate cancer: A qualitative study. AB - OBJECTIVE: The number of younger men being diagnosed with prostate cancer (PCa; aged <=65) is increasing. It is recognised that PCa and treatment side effects can have a significant impact on quality of life. This study explores the challenges faced by younger couples affected by PCa with dependent children (under 18 years) or young adults (18-29 years) in their families. METHODS: Twenty three men with PCa and their partners were interviewed (separately) by telephone. Participants were recruited from respondents to the life after prostate cancer diagnosis (LAPCD) national survey. Men were 3 to 5 years postdiagnosis, and following a range of treatment pathways. Data were analysed using the Framework Approach. RESULTS: Younger couples affected by PCa felt challenged by issues relating to their parental role and the dynamics within the family. Five main themes emerged: difficult conversations about PCa diagnosis; parental perceptions of the impact of diagnosis on children; parental responses to the impact of PCa on the family; shielding, coping, and normalising strategies; and levels of support. CONCLUSIONS: A diagnosis of PCa can cause significant disruption to the family unit and the quality of life of its members. Support programmes offering guidance to children/young adults affected by PCa in their family, and addressing the concerns of parents may help families to better adapt. Encouraging clinical professionals to initiate conversations with younger couples about their children may be a way forward in directing appropriate support. Further research is needed to elucidate appropriate, effective supportive interventions. PMID- 30444951 TI - Surrogate analyte-based quantification of main endocannabinoids in whole blood using liquid chromatography-tandem mass spectrometry. AB - Endocannabinoids (eCBs) are endogenous ligands of endocannabinoid system (ECS) that are known to regulate several physiological and behavioral processes. Previous studies have developed methods for detection of main eCBs including arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), mostly in serum or plasma. Whole blood is a superior biomaterial for eCBs analysis due to the nature of shortened isolation procedure and decreased risk of 2-AG isomerization during preparing. In this study, a surrogate analyte-based liquid chromatography tandem mass spectrometry assay was developed for the measurement of AEA, 2-AG and its isomer 1-arachidonoylglycerol (1-AG) using a maximum of 100 MUL whole blood. Chromatographic separation was achieved using reverse-phase column and a gradient elution. Detection was performed in selected reaction monitoring mode with an electrospray ionization source. The limits of detection of three eCBs were 0.05 0.1 ng/mL. Good linearity was observed over the concentration range. Intra-assay and inter-assay accuracy and precision were <=10.9% and <=8.7% at four QC levels. The response factor and parallelism experiment illustrated that the surrogate analytes were suitable for accurate quantification of main eCBs in whole blood. This surrogate analyte approach was successfully applied to authentic blood samples obtained from alcohol negative drivers and those under the influence of alcohol. PMID- 30444953 TI - Development of Latent Fingermarks on Surfaces of Food-A More Realistic Approach. AB - Latent fingermark developing methods from food (mandarin, egg, banana, apple, potato, carrot, eggplant, onion, bell pepper, and tomato) surface has been studied by 10 methods, including powdering method, small particle reagent method, and cyanoacrylate fuming method. The foods were stored under two conditions (room temperature and refrigerator) before fingermark deposition and aged for 2, 24, 48, and 72 h before fingermark development. In most of the food surfaces used in this study, cyanoacrylate fuming with 80% relative humidity was superior to the powder or small particle reagent methods. The quality of the fingermarks varied depending on the storage conditions before the fingermark deposition (in the refrigerator or at ambient temperature) and the time elapsed since the fingermark deposition. However, the storage conditions before the fingermark deposition and the time elapsed since the fingermark deposition did not show any correlation with the quality of the fingermark. PMID- 30444954 TI - The prevalence and risk predictors of cesarean scar defect at 6 weeks postpartum in Shanghai, China: a prospective cohort study. AB - INTRODUCTION: The aim of this study was to explore the prevalence and predictors of cesarean scar defect (CSD) at 6 weeks postpartum in Shanghai, China. MATERIAL AND METHODS: Women scheduled to receive a cesarean section were recruited from a university hospital. Surgery related factors, pregnancy complications, routine examinations, perioperative medications and physical signs were collected and transvaginal ultrasonography was done to assess the presence of a CSD at 6 weeks postpartum. Multivariate logistic regression was applied to identify the predictors for CSD. RESULTS: CSD were detected in 223 of 514 women (43.4%, 95% CI; 39.1% to 47.7%) by transvaginal ultrasonography. Of the women who with normal temperature (T<37.5 degrees C, CSD prevalence 33.9%, 95% CI; 28.4 to 39.5%), women with postpartum fever (T>=38 degrees C, CSD 44.1%, 95% CI; 31.0 to 57.1%) and whose who were subfebrile in the postpartum (37.5<=T<=38.0 degrees C, CSD 58.3%, 95% CI; 50.9 to 65.7%), the latter two had significantly increased risk for CSD (aOR 2.7, 95% CI; 1.3 to 5.2 and aOR 3.3, 95% CI; 2.1 to 5.3; respectively). In comparison to single dose antibiotic administration (CSD 49.0%, 95% CI; 43.8 to 54.3%), multi-dose antibiotic administration (CSD 31.1%, 95% CI; 23.8 to 38.3%) had a protective effect (aOR 0.4, 95% CI; 0.3 to 0.7). Postpartum fever, intrapartum infection, emergency CS, and cervical dilation>=3 cm were found to be the main predictors of multi-dose antibiotics management. Low platelet count postpartum (defined as <=150*109 /L) and high fibrinogen pre-CS (defined as >=4.5g/L) increased CSD risk (aOR 2.0, 95% CI; 1.1 to 3.6 and 1.7, 95% CI; 1.1 to 2.5; respectively). CONCLUSIONS: The prevalence of CSD in Chinese population is high enough to be concerned. Perioperative infection and hypercoagulability should be considered CSD predictors, while multi-doses antibiotics have a protective effect. This article is protected by copyright. All rights reserved. PMID- 30444952 TI - Suggestive association between OPRM1 and impulse control disorders in Parkinson's disease. AB - BACKGROUND: Impulse control disorders are frequently associated with dopaminergic therapy in Parkinson's disease. Genetic studies have suggested a high heritability of impulse control disorders in the general population and in PD. The aim of this study was to identify candidate gene variants associated with impulse control disorders and related behaviors in PD. METHODS: We performed a multicenter case-control study in PD patients with (cases) or without impulse control disorders and related behaviors despite significant dopamine agonist exposure of >300 mg levodopa-equivalent daily dose during 12 months (controls). Behavioral disorders were assessed using the Ardouin scale. We investigated 50 variants in 24 candidate genes by a multivariate logistic regression analysis adjusted for sex and age at PD onset. RESULTS: The analysis was performed on 172 cases and 132 controls. Cases were younger (60 +/- 8 vs 63 +/- 8 years; P < 0.001) and had a higher family history of pathological gambling (12% vs 5%, P = 0.03). No variant was significantly associated with impulse control disorders or related behaviors after correction for multiple testing, although the 2 top variants were close to significant (OPRM1 rs179991, OR, 0.49; 95%CI, 0.32-0.76; P = 0.0013; Bonferroni adjusted P = 0.065; DAT1 40-base pair variable number tandem repeat, OR, 1.82; 95%CI, 1.24-2.68; P = 0.0021; Bonferroni adjusted P = 0.105). CONCLUSIONS: Our results are suggestive of a novel association of the opioid receptor gene OPRM1 with impulse control disorders and related behaviors in PD and confirm a previous association with DAT1. Although replication in independent studies is needed, our results bring potential new insights to the understanding of molecular mechanisms of impulse control disorders. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 30444955 TI - Development of a Gulfweed-Based Edible Coating Using High-Pressure Homogenization and Its Application to Smoked Salmon. AB - Gulfweed-based edible materials were developed in forms of food film and coating. Gulfweed suspension was subjected to high-pressure homogenization (HPH) at 103, 138, and 193 MPa with 1, 2, and 3 passes, and mixed with 14, 30, 50, and 70% (w/w gulfweed) glycerol and 1% (w/w gulfweed) polysorbate 20 to produce a film-forming suspension. The particle size of the suspension decreased with increasing pressure from 103 to 193 MPa and pass number from 1 to 3. The HPH-treated gulfweed suspension behaved like a pseudo-plastic non-Newtonian fluid. High pressure and pass number generally decreased the suspension viscosity. Uniformity and compactness of the films increased with increasing pressure. The optimal conditions for forming a film with high stretchability, low water vapor permeability, low and water solubility, as well as for preparing bright-colored coated smoked salmon, were found to be 193 MPa, three passes of HPH, and a glycerol concentration of 70%. Coating smoked salmon with gulfweed suspension enhanced the redness without altering its texture and volatile properties. The method reported in this study may be useful for seaweed-based edible film production, increasing their potential application to various food products like red meats. PRACTICAL APPLICATION: Seaweeds have high nutritional and functional values, but they are not commonly used as food materials owing to their appearance and size. Therefore, it is important to develop methods to utilize seaweeds by overcoming appearance and size limitations. A self-standing film/coating using gulfweed was developed in this study, making use of commercially available high-pressure homogenization technology. The method developed herein might enable increased applications of gulfweed and possibly other seaweeds to food products such as films, rolls, or coatings. PMID- 30444956 TI - Mechanisms of lymphatic system-specific viral replication and its potential role in autoimmune disease. AB - Viral infections can be fatal because of the direct cytopathic effects of the virus or the induction of a strong, uncontrolled inflammatory response. Virus and host intrinsic characteristics strongly modulate the outcome of viral infection. Recently we determined the circumstances under which enhanced replication of virus within the lymphoid tissue is beneficial for the outcome of a disease. This enforced viral replication promotes antiviral immune activation and, counterintuitively, accelerates virus control. In this review we summarize the mechanisms that contribute to enforced viral replication. Antigen-presenting cells and CD169+ macrophages exhibit enforced viral replication after infection with the model viruses lymphocytic choriomeningitis virus (LCMV) and vesicular stomatitis virus (VSV). Ubiquitin specific proteases 18 (Usp18), an endogenous type I interferon blocker in CD169+ macrophages, has been identified as a proviral gene, as are B-cell activating factor and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). Lymphotoxins (LT) strongly enhance viral replication in the spleen and lymph nodes. All of these factors modulate splenic architecture and thereby promote the development of CD169+ macrophages. Tumor necrosis factor alpha (TNF-alpha) and nuclear factor kappa-light-chain enhancer of activated B cells signaling (NF-kappaB) have been found to promote the survival of infected CD169+ macrophages, thereby similarly promoting enforced viral replication. Association or autoimmune disease with infections is evident from 1) Autoimmune phenomena described during a chronic virus infection. 2) Onset of autoimmune disease simultaneous to viral infections 3) Experimental evidence. Involvement of virus infection during onset of type I diabetes is strongly evident. EBV infection was discussed to be involved in the pathogenesis of systemic lupus erythematosus. In conclusion, several mechanisms promote viral replication in secondary lymphatic organs. Identifying such factors in humans is a challenge for future studies. This article is protected by copyright. All rights reserved. PMID- 30444957 TI - From telling to sharing to silence: A longitudinal ethnography of professional patient communication about oral chemotherapy for colorectal cancer. AB - BACKGROUND: Healthcare professionals are encouraged to promote concordance, a shared agreement about prescription and administration of medications, in their communication with patients. However, there is a paucity of research regarding the impact of communication about self-administered oral chemotherapy. The aim of this study was to examine the changing dynamics of communication through the patient journey from diagnosis of colorectal cancer to posttreatment of chemotherapy. METHODS: Over 60 hours of observational data were digitally recorded from interactions between 15 healthcare professionals, eight patients with colorectal cancer prescribed capecitabine, and 11 family members over a 6 month period in outpatient departments within one hospital in the United Kingdom. Sixteen semi-structured interviews were conducted with patients during and after their treatment. Three focus groups were carried out with healthcare professionals. These data were analysed using thematic analysis. RESULTS: The patient journey followed a path of four distinct phases: autocracy, physiological concordance, holistic concordance, and silence. Initially, communication was medicalised with patients occupying a passive role. As patients continued their journey, they took a more active role in their treatment discussion by leading consultations and sharing their priorities of care. At the end of treatment, patients felt isolated and unsupported when they were discharged from their oncology team. CONCLUSIONS: Communication about oral chemotherapy is not a static process; it evolves to take account of changing clinical requirements and growing patient confidence in dealing with their cancer. Different stages in the treatment journey indicate the need for different approaches to communication. PMID- 30444958 TI - The Quest for Stable Silaaldehydes: Synthesis and Reactivity of a Masked Silacarbonyl. AB - First donor-acceptor complex of a silaaldehyde, compound with general formula (NHC)(Ar)Si(H)OGaCl3, was synthesized using the reaction of silyliumylidene-NHC complex [(NHC)2(Ar)Si]Cl with water in the presence of GaCl3. Conversion of this complex to the corresponding silacarboxylate dimer [(NHC)(Ar)SiO2GaCl2]2, free silaacetal ArSi(H)(OR)2, silaacyl chloride (NHC)(Ar)Si(Cl)OGaCl3, and phosphasilene-NHC adduct (NHC)(Ar)Si(H)PTMS unveil its true potential as a synthon in silacarbonyl chemistry. PMID- 30444959 TI - Factors That Impact Treatment Decisions: Results From an Online Survey of Individuals With Bipolar and Unipolar Depression. AB - Objective: To identify patient-reported factors that influence medication treatment decisions among individuals with bipolar and unipolar depression. Methods: The Depression and Bipolar Support Alliance (DBSA) conducted an online survey February 2016 to April 2016 asking participants about factors that influence treatment decisions (eg, starting and stopping specific medications). Results: In total, 896 participants completed the survey (49.9% unipolar depression [n = 447] and 50.1% bipolar depression [n = 449]). The majority of respondents reported several previous medication trials. The most frequently reported factors impacting treatment decisions were side effects, doctor recommendations, cost, and how quickly the treatment will begin to work. The most common reason for changing treatments was ineffectiveness in the unipolar depression group and side effects in the bipolar depression group. Weight gain was the side effect that most commonly led respondents to discontinue a medication. When respondents currently using medications versus respondents not using medications were compared, doctor recommendations were more likely to be influential for those taking medications (P < .0001). Conversely, cost (P = .008) and impact on pregnancy/lactation (P = .045) were more likely to impact treatment decisions in participants not currently taking medications. Current medication use was associated with increased rates of perceived treatment effectiveness (P < .0001). Conclusions: Side effects, doctor recommendations, cost, and rapidity of antidepressant effects were determined to be particularly important factors in making treatment decisions, with doctor recommendations being more influential for medication users and cost being more influential for participants not using medications. These findings highlight the importance of patient-centered factors in adjudicating treatment decisions. PMID- 30444960 TI - Mirtazapine-Induced Epistaxis in an Australian Indigenous Man. PMID- 30444961 TI - Psychotic Symptoms Associated With Superior Vena Cava Syndrome Following Methamphetamine Abuse. PMID- 30444962 TI - Development and Theoretical Approach to an Adaptive Text Message Program to Promote Well-Being and Health Behaviors in Primary Care Patients. AB - A majority of individuals with chronic medical conditions do not fully follow recommendations about health behaviors, and deficits in health education, motivation, support, and well-being all likely play a role. This report describes the theory, programming, development, and implementation process for a machine learning-based, adaptive, once-daily text message intervention to address this public health problem. The intervention aims to promote psychological well-being and provide education and support around health behaviors. The platform allows patients to provide real-time feedback about each message, and the machine learning algorithm then delivers subsequent messages that are increasingly tailored to individuals' preferred message content. PMID- 30444963 TI - Psoas Abscess as a Differential Diagnosis of Neuroleptic Malignant Syndrome in a Schizoaffective Disorder Patient With Catatonic Symptoms. PMID- 30444964 TI - Uncooled Photodetector at Short-Wavelength Infrared Using InAs Nanowire Photoabsorbers on InP with p- n Heterojunctions. AB - In this work, we demonstrate an InAs nanowire photodetector at short-wavelength infrared (SWIR) composed of vertically oriented selective-area InAs nanowire photoabsorber arrays on InP substrates, forming InAs-InP heterojunctions. We measure a rectification ratio greater than 300 at room temperature, which indicates a desirable diode performance. The dark current density, normalized to the area of nanowire heterojunctions, is 130 mA/cm2 at a temperature of 300 K and a reverse bias of 0.5 V, making it comparable to the state-of-the-art bulk InAs p i- n photodiodes. An analysis of the Arrhenius plot of the dark current at reverse bias yields an activation energy of 175 meV from 190 to 300 K, suggesting that the Shockley-Read-Hall (SRH) nonradiative current is the primary contributor to the dark current. By using three-dimensional electrical simulations, we determine that the SRH nonradiative current originates from the acceptor-like surface traps at the nanowire-passivation heterointerfaces. The spectral response at room temperature is also measured, with a clear photodetection signature observed at wavelengths up to 2.5 MUm. This study provides an understanding of dark current for small band gap selective-area nanowires and paves the way to integrate these improved nanostructured photoabsorbers on large band gap substrates for high-performance photodetectors at SWIR. PMID- 30444965 TI - Identification of Patients with Preeclampsia by Measuring Fluorescence of an Amyloid-Binding Aryl Cyano Amide in Human Urine Samples. AB - Preeclampsia (PE) is a hypertensive disorder of pregnancy and one of the leading contributors to both maternal and perinatal morbidity and mortality. Reliable diagnostic parameters unique to the disorder that accurately define and diagnose PE are currently unavailable. Recent studies have revealed that PE is accompanied by the accumulation of amyloidogenic deposits in the placenta and the presence of congophilic amyloid-like protein aggregates in the urine. Here, we evaluate the capability of an amyloid-targeting aryl cyano amide (ARCAM-1) fluorophore to identify PE patients from analysis of urine samples. Our results reveal that this probe can distinguish patients with PE from gestationally healthy patients and patients suffering from non-PE hypertension, highlighting the potential for amyloid-targeting fluorophores to help identify PE patients during pregnancy. PMID- 30444966 TI - Accelerated Barocycler Lysis and Extraction Sample Preparation for Clinical Proteomics by Mass Spectrometry. AB - We have developed a streamlined proteomic sample preparation protocol termed Accelerated Barocycler Lysis and Extraction (ABLE) that substantially reduces the time and cost of tissue sample processing. ABLE is based on pressure cycling technology (PCT) for rapid tissue solubilization and reliable, controlled proteolytic digestion. Here, a previously reported PCT based protocol was optimized using 1-4 mg biopsy punches from rat kidney. The tissue denaturant urea was substituted with a combination of sodium deoxycholate (SDC) and N-propanol. ABLE produced comparable numbers of protein identifications in half the sample preparation time, being ready for MS injection in 3 h compared with 6 h for the conventional urea based method. To validate ABLE, it was applied to a diverse range of rat tissues (kidney, lung, muscle, brain, testis), human HEK 293 cell lines, and human ovarian cancer samples, followed by SWATH-mass spectrometry (SWATH-MS). There were similar numbers of quantified proteins between ABLE-SWATH and the conventional method, with greater than 70% overlap for all sample types, except muscle (58%). The ABLE protocol offers a standardized, high-throughput, efficient, and reproducible proteomic preparation method that when coupled with SWATH-MS has the potential to accelerate proteomics analysis to achieve a clinically relevant turn-around time. PMID- 30444967 TI - Photochemical Homologation for the Preparation of Aliphatic Aldehydes in Flow. AB - Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with nonstabilized diazo compounds, enabled by UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No transition-metal catalyst or additive was required to affect the reaction, which proceeded at room temperature in 80 min. PMID- 30444968 TI - Managing antiretroviral therapy in the elderly HIV patient. AB - INTRODUCTION: Owing to more effective and less toxic antiretroviral therapy (ART), people living with HIV (PLWH) live longer, a phenomenon expected to grow in the next decades. With advancing age, effectively treated PLWH experience not only a heightened risk for non-infective comorbidities and multimorbidity, but also for geriatric syndromes and frailty. In addition, older adults living with HIV (OALWH) have a higher prevalence of so-called iatrogenic triad described as polypharmacy (PP), potentially inappropriate medication use, and drug-drug interactions. Areas covered: This review will focus the management of ART in OALWH. We will discuss iatrogenic triad and best way to address PP. Special focus will be given to pharmacokinetic and pharmacodynamic aspects of ART in the elderly, evaluation of ART toxicities, and specific ART strategies commonly used in this population. Expert commentary: Research should be focused on recruiting more OALWH, frail individuals in particular, into the clinical trials and specific geriatric outcome need to be considered together with traditional viroimmunological outcomes. PMID- 30444969 TI - ARHGEF10L contributes to liver tumorigenesis through RhoA-ROCK1 signaling and the epithelial-mesenchymal transition. AB - Aberrant activity of Rho small G-proteins and their regulators plays an important role in tumorigenesis. Rho guanine nucleotide exchange factor 10-Like (ARHGEF10L) is a member of the RhoGEF family that promotes the active GTP-bound state of Rho GTPases. This study used the Illumina GoldenGate microassay, Sequenom MassARRAY and TaqMan to analyze possible correlations between tag single nucleotide polymorphisms (tag SNPs) in the ARHGEF10L locus and various tumor risks. The genotyping analyses demonstrated a strong association of rs2244444 and rs12732894 with liver cancer. Western blotting and immunohistochemistry also revealed increased expression of ARHGEF10L in hepatocellular carcinoma tissues. Furthermore, increased cell proliferation, cell migration and RhoA activity; increased expression of Rho-associated coiled-coil kinase-1 (ROCK1), phospho- Ezrin/Radixin/Moesin (ERM), vimentin, N-cadherin and Slug, and decreased E cadherin expression were detected in hepatocellular carcinoma cell Bel-7402 and HepG2 cells with transfection of ARHGEF10L-expressing plasmids. Opposite results were obtained in the two cell lines with transfection of anti-ARHGEF10L siRNA. Tumor-bearing mice were generated with Bel-7402 cells transfected with lentivirus vectors packaging short hairpin ARHGEF10L RNA. The xenograft tumors with the inhibited ARHGEF10L expression showed decreased tumor growth and expression of vimentin, N-cadherin and Slug. Additionally, decreased phospho-ERM expression was detected in Bel-7402 and HepG2 cells with transfection of anti-ROCK1 siRNA and increased expression of ROCK1 was detected in hepatocellular carcinoma tissues. E cadherin, vimentin, N-cadherin and Slug are markers of the epithelial-to mesenchymal transition (EMT). ROCK1, phospho-ERM and EMT have been reported to promote tumor cell proliferation, metastasis and angiogenesis. Our study suggests that increased expression of ARHGEF10L stimulates hepatocellular tumorigenesis by activating the RhoA-ROCK1- phospho ERM pathway and EMT. PMID- 30444971 TI - Molecular epidemiology of dengue, yellow fever, Zika and Chikungunya arboviruses: An update. AB - Arboviruses are a group of viruses transmitted by arthropods. They are characterized by a wide geographic distribution, which is associated with the presence of the vector, and cause asymptomatic infections or febrile diseases in humans in both enzootic and urban cycles. Recent reports of human infections caused by viruses such as dengue, Zika, and chikungunya have raised concern regarding public health, and have led to the re-evaluation of surveillance mechanisms and measures to control the transmission of these arboviruses. Viruses such as Mayaro and Usutu are not currently responsible for a high number of symptomatic infections in humans, but should remain under epidemiological surveillance to avoid the emergence of new epidemics, as happened with Zika virus, that are associated with new or more severe symptoms. Additionally, significant variation has been observed in these viruses, giving rise to different lineages. Until recently, the emergence of new lineages has primarily been related to geographical distribution and dispersion, allowing us to ascertain the possible origins and direction of expansion of each virus type, and to make predictions regarding regions where active infections in humans are likely to occur. Therefore, this review is focused on untangling the molecular epidemiology of Dengue, Yellow fever, Zika and Chikungunya due to their recent epidemics in Latinamerica but provides an update on the geographical distribution globally of these viral variants, and outlines the need for further understanding of the genotypes/lineages assignment. PMID- 30444970 TI - Medical abortion in the late first trimester: a systematic review. AB - OBJECTIVE: To describe the efficacy, safety, and acceptability of medical abortion in the late first trimester. STUDY DESIGN: We searched PubMed and Cochrane databases for articles in any language that examined the success of medical abortion at gestational ages (>63 to<=84days gestation). We sought articles that compared: medical abortion with surgical abortion at this gestational age, combination mifepristone and misoprostol and/or misoprostol alone); different dosages of misoprostol; different routes of misoprostol administration; frequency of dosing; and location of medical abortion (in health care facility vs. outpatient management). Our primary outcome was complete abortion. Data was independently abstracted by two authors, graded for evidence quality, and assessed for risk of bias. RESULTS: The search strategy returned 3384 articles, 9 of which met inclusion criteria. Medical abortion, as compared with surgical abortion, was effective in the late first trimester (94.6% versus 97.9% complete abortion). A combined regimen of mifepristone and misoprostol was significantly more effective than misoprostol alone (90.4 versus 81.6% completed rates). Complete abortion rates for all regimens investigated ranged from 78.6% to 94.6%. Success rates were higher with repeat dosing of misoprostol both in combination regimens and alone, and with vaginal compared with oral administration for repeat dosing. CONCLUSION: A limited body of evidence indicates a range of efficacy of medical abortion in the late first trimester and highlights the need for well-designed trials in this gestational age range. IMPLICATIONS: This review highlights the need for research focused on the late first trimester to strengthen the body of evidence. The available evidence is limited but offers reassurance that adverse events are rare for later first trimester abortion. Importantly, new research demonstrates that efficacy remains unchanged in the 10th gestational week regardless of whether the medication is taken in a facility or at a woman's home. PMID- 30444972 TI - Broadening the tools for studying sand fly breeding habitats: A novel molecular approach for the detection of phlebotomine larval DNA in soil substrates. AB - Phlebotomine sand flies constitute a group of haematophagous insects of great medical and veterinary importance. Despite the significant knowledge on the biology and behavior of adult sand flies in the wild, there is little information available on the ecology of their larval stages due to difficulties of detecting them in the soil. So far, investigations on sand fly breeding sites have been based on methods to catch emerging adults or on microscopic examination of the soil for the presence of immatures, neither of which is very precise or efficient for studying immatures in the field. Thus, there is a need for a better method to detect, identify and quantify immatures in soil samples. To address this issue we developed a novel molecular genetic approach for the detection of sand fly larval DNA within soil samples. Different numbers of live larvae of Phlebotomus papatasi and P. tobbi (alone or in combination), were mixed with soil and analyzed to identify and quantify the sand flies. By modifying already existing soil DNA extraction protocols in combination with a real-time PCR using species-specific primers, we successfully detected as little as one larva/40 ml of soil. We could also distinguish the two species of sand flies. This method should be very useful for increasing our knowledge of sand fly larval ecology in the field, and thus help develop more efficient, targeted control strategies against Phlebotomus sand flies. PMID- 30444973 TI - BAmSA: Visualising transmembrane regions in protein complexes using biotinylated amphipols and electron microscopy. AB - Membrane protein (MP) complexes play key roles in all living cells. Their structural characterisation is hampered by difficulties in purifying and crystallising them. Recent progress in electron microscopy (EM) have revolutionised the field, not only by providing higher-resolution structures for previously characterised MPs but also by yielding first glimpses into the structure of larger and more challenging complexes, such as bacterial secretion systems. However, the resolution of pioneering EM structures may be difficult and their interpretation requires clues regarding the overall organisation of the complexes. In this context, we present BAmSA, a new method for localising transmembrane (TM) regions in MP complexes, using a general procedure that allows tagging them without resorting to neither genetic nor chemical modification. Labels bound to TM regions can be visualised directly on raw negative-stain EM images, on class averages, or on three-dimensional reconstructions, providing a novel strategy to explore the organisation of MP complexes. PMID- 30444974 TI - Characterization of N-glycosylations in Entamoeba histolytica ubiquitin. AB - Entamoeba histolytica harbors an extensive intracellular distribution of ubiquitin-proteasome systems important for numerous cellular processes. However, glycosylation studies of ubiquitin-proteasome components have not yet been elucidated. Here we report the partial characterization of N-linked glycosylation profile in E. histolytica ubiquitin by Fluorophore-Assisted Carbohydrate Electrophoresis (FACE), Nanoelectrospray Ionization-Tandem Mass Spectrometry (NSI MS), Matrix-Assisted Laser-Desorption time-of-flight Mass Spectrometry (MALDI-TOF MS) and Gas Chromatography-Mass Spectrometry (GC-MS) analysis. To our knowledge, the data presented in this report represents the first structural glycomics analysis of E. histolytica ubiquitin, while most of the reports are performed on whole parasitic glycan profiles. The glycan profile of E. histolytica ubiquitin has high mannose N-glycan structures. The N-linked glycan profile showed fragments from Hex3HexNAc2 to Hex9HexNAc2. Based in our findings and ubiquitin function, we hypothesize that the same ubiquitin Asn-Asp-Ser sequon carries heterogenic glycosylations, at different metabolic pathway stages according to ubiquitin functional requirements. Finally, we propose a set of possible high mannose N-glycan structures that will help to elucidate the ubiquitin biochemical composition and may well represent good targets for anti-amoebic drugs. PMID- 30444975 TI - Thermodynamic buffering, stable non-equilibrium and establishment of the computable structure of plant metabolism. AB - The equilibria of coenzyme nucleotides and substrates established in plant cells generate simple rules that govern the plant metabolome and provide optimal conditions for the non-equilibrium fluxes of major metabolic processes such as ATP synthesis, CO2 fixation, and mitochondrial respiration. Fast and abundant enzymes, such as adenylate kinase, carbonic anhydrase or malate dehydrogenase, provide constant substrate flux for these processes. These "buffering" enzymes follow the Michaelis-Menten (MM) kinetics and operate near equilibrium. The non equilibrium "engine" enzymes, such as ATP synthase, Rubisco or the respiratory complexes, follow the modified version of MM kinetics due to their high concentration and low concentration of their substrates. The equilibrium reactions serve as control gates for the non-equilibrium flux through the engine enzymes establishing the balance of the fluxes of load and consumption of metabolic components. Under the coordinated operation of buffering and engine enzymes, the concentrations of free and Mg-bound adenylates and of free Mg2+ are set, serving as feedback signals from the adenylate metabolome. Those are linked to various cell energetics parameters, including membrane potentials. Also, internal levels of reduced and oxidized pyridine nucleotides are established in the coordinated operation of malate dehydrogenase and respiratory components, with proton concentration as a feedback from pyridine nucleotide pools. Non coupled pathways of respiration serve to equilibrate the levels of pyridine nucleotides, adenylates, and as a pH stat. This stable non-equilibrium organizes the fluxes of energy spatially and temporally, controlling the rates of major metabolic fluxes that follow thermodynamically and kinetically defined computational principles. PMID- 30444976 TI - Recurrent short-term hypoglycemia and hyperglycemia induce apoptosis and oxidative stress via the ER stress response in immortalized adult mouse Schwann (IMS32) cells. AB - Hypoglycemia and fluctuating high or low glucose conditions are under-appreciated sources of oxidative stress contributing to diabetic neuropathy. We investigated the effects of recurrent short-term hypoglycemia and hyperglycemia, on apoptosis and oxidative stress in Schwann cells. Immortalized adult mouse Schwann (IMS32) cells were exposed to five different glucose treatments over 3 days: 1) normal glucose (NG), 2) constant low glucose (LG), 3) constant high glucose (HG), 4) intermittent low glucose (ILG; 1 h three times per day), 5) intermittent high glucose (IHG; 1 h three times per day). Cell viability was decreased by all treatment variants, in comparison to NG. Thiobarbituric acid reactive substance (TBARS) levels were increased by HG, LG, IHG, and ILG. High glucose (HG and IHG) and low glucose (LG and ILG) increased the expression of cleaved caspase-3 and reduced that of Bcl-2. In addition, endoplasmic reticulum (ER) stress-responsive transcription factor C/EBP homologous protein (CHOP) expression was increased under low and high glucose conditions. Cell death and oxidative stress induced by HG, LG, IHG, and ILG were significantly reduced by 4-phenyl butyric acid (4-PBA), an ER stress inhibitor. These findings indicate that recurrent short-term hypoglycemia and hyperglycemia induce apoptosis and oxidative stress via the ER stress response in Schwann cells. PMID- 30444977 TI - Trypanosoma brucei: beta2-selective proteasome inhibitors do not block the proteasomal trypsin-like activity but are trypanocidal. AB - Previous studies indicated that the proteasome of the protozoan parasite Trypanosoma brucei is particularly sensitive to inhibition of the trypsin-like activity. In this study, three newly developed beta2 subunit-specific inhibitor (LU-102, LU-002c and LU-002i) were tested for their ability to block the trypsin like activity of the trypanosomal proteasome. At 10 MUM, none of the compounds affected the proteasomal trypsin-like activity in cell lysates of bloodstream forms of T. brucei. On the other hand, leupeptin, a well-established beta2 inhibitor, supressed the proteasomal trypsin-like activity within trypanosome cell lysates with a 50% inhibitory concentration of 2 MUM demonstrating the inhibitability of the trypsin-like activity of the T. brucei proteasome under the experimental condition. Nevertheless, two compounds (LU-102 and LU-002i) displayed moderate trypanocidal activity with 50% growth inhibition values of 6.9 and 8.5 MUM, respectively. In the case of LU-102, it was shown that the trypanocidal activity of the compound was due to inhibition of the major lysosomal cysteine protease TbCATL. The main finding of this study indicate substantial inhibitor sensitivity differences between the trypsin-like sites of the human and trypanosomal proteasomes. Whether these differences can be exploited for the design of anti-trypanosomal drug therapies remains to be shown. PMID- 30444978 TI - A new reporter cell line for studies with proteasome inhibitors in Trypanosoma brucei. AB - A Trypanosoma brucei cell line is described that produces a visual readout of proteasome activity. The cell line contains an integrated transgene encoding an ubiquitin-green fluorescent protein (GFP) fusion polypeptide responsive to the addition of proteasome inhibitors. A modified version of T. brucei ubiquitin unable to be recognized by deubiquitinases (UbG76V) was fused to eGFP and constitutively expressed. The fusion protein is unstable but addition of the proteasome inhibitor lactacystin stabilizes it and leads to visually detectable GFP. This cell line can be widely used to monitor the efficiency of inhibitor treatment through detection of GFP accumulation in studies involving proteasome mediated proteolysis, screening of proteasome inhibitors or other events related to the ubiquitin-proteasome pathway. PMID- 30444979 TI - Cytotoxicity and molecular docking studies on phytosterols isolated from Polygonum hydropiper L. AB - Based on our previous studies on cytotoxic potentials of Polygonum hydropiper L, two steroidal compounds beta-sitosterol and stigmasterol were isolated from the most active fraction and were subjected to cell lines cytotoxicity. Isolated compounds were tested against HeLa, MCF-7 and NIH/3T3 cell lines following MTT assay. Furthermore, the compounds were also docked against tyrosine kinase enzyme to predict the binding mode of phytosterols in the active sites of the enzyme. Beta-sitosterol exhibited considerable cytotoxicity against NIH/3T3, HeLa and MCF 7 cell with 67.05 +/- 2.08, 79.63 +/- 2.34 and 71.50 +/- 1.57% lethality respectively at 1 mg/ml concentration. Median inhibitory concentrations calculated from dose response curve against NIH/3T3, HeLa and MCF-7 cells were 440, 170 and 200 ug/ml respectively. Stigmasterol was more effective against MCF 7 and NIH/3T3 cells by killing 87.50 and 81.45% cancerous cells respectively at 1 mg/ml concentration. Stigmasterol showed 77.25% cyctotoxicity against HeLA cells at 1 mg/ml concentration in MTT assay. The IC50 values for HeLA, MCF-7 and NIH/3T3 cells were 170, 60 and 140 ug/ml respectively. In docking studies, the docking score for beta-sitosterol and stigmasterol were -7.266 and -4.89 respectively. The binding energies for beta-sitosterol and stigmasterol were 41.21 and -41.04 respectively. Such lower binding energies indicate that the compounds fit into the active site more strongly. Binding affinities for both compounds were -7.76 and -7.68 respectively. Both phytosterols possess significant anticancer potentials and can be effective in the prevention and treatment of several malignancies. PMID- 30444980 TI - Interaction of the effects associated with auditory-motor integration and attention-engaging listening tasks. AB - A number of previous studies have implicated regions in posterior auditory cortex (AC) in auditory-motor integration during speech production. Other studies, in turn, have shown that activation in AC and adjacent regions in the inferior parietal lobule (IPL) is strongly modulated during active listening and depends on task requirements. The present fMRI study investigated whether auditory-motor effects interact with those related to active listening tasks in AC and IPL. In separate task blocks, our subjects performed either auditory discrimination or 2 back memory tasks on phonemic or nonphonemic vowels. They responded to targets by either overtly repeating the last vowel of a target pair, overtly producing a given response vowel, or by pressing a response button. We hypothesized that the requirements for auditory-motor integration, and the associated activation, would be stronger during repetition than production responses and during repetition of nonphonemic than phonemic vowels. We also hypothesized that if auditory-motor effects are independent of task-dependent modulations, then the auditory-motor effects should not differ during discrimination and 2-back tasks. We found that activation in AC and IPL was significantly modulated by task (discrimination vs. 2-back), vocal-response type (repetition vs. production), and motor-response type (vocal vs. button). Motor-response and task effects interacted in IPL but not in AC. Overall, the results support the view that regions in posterior AC are important in auditory-motor integration. However, the present study shows that activation in wide AC and IPL regions is modulated by the motor requirements of active listening tasks in a more general manner. Further, the results suggest that activation modulations in AC associated with attention-engaging listening tasks and those associated with auditory-motor performance are mediated by independent mechanisms. PMID- 30444981 TI - Rediscovering Ignaz Philipp Semmelweis (1818-1865). AB - Ignaz Semmelweis was a Hungarian obstetrician who discovered the cause of puerperal or childbed fever (CBF) in 1847 when he was a 29 year old Chief Resident ('first assistant') in the first clinic of the lying-in division of the Vienna General Hospital. Childbed fever was then the leading cause of maternal mortality, and so ravaged lying-in hospitals that they often had to be closed. The maternal mortality rate (MMR) from CBF at the first clinic where Semmelweis worked, and where only medical students were taught, was three times greater than at the second clinic, where only midwives were taught, and Semmelweis was determined to find out why. Semmelweis concluded that none of the purported causes of CBF could explain the difference in MMR between the two clinics, as they all affected both clinics equally. The clue to the real cause came after Semmelweis's beloved professor, Kolletschka, died after a student accidentally pricked his finger during an autopsy. Semmelweis reviewed Kolletschka's autopsy report, and noted that the findings were identical to those in mothers dying of CBF. He then made two groundbreaking inferences: that Kolletschka must have died of the same disease as mothers dying from CBF, and that the cause of CBF must be the same as the cause of Kolletschka's death, because if two diseases were the same, they must have the same cause. Semmelweis quickly realized why the MMR from CBF was higher on the first clinic: medical students, who assisted at autopsies, were transferring the causative agent from cadavers to the birth canal of mothers in labor with their hands, and soon discovered that it could also be transferred from living persons with purulent infections. Bacteria had not yet been discovered to cause infections, and Semmelweis called the agent 'decaying animal organic matter'. He implemented chlorine hand disinfection to remove this organic matter from the hands of the attendants, as soap and water alone had been ineffective. Hand disinfection reduced the MMR from CBF 3-10 fold, yet most leading obstetricians rejected Semmelweis's doctrine because it conflicted with all extant theories of the cause of CBF. His work was also used in the fight raging over academic freedom in the University of Vienna Medical School, which turned Semmelweis's chief against him, and forced Semmelweis to return to Budapest, where he was equally successful in reducing MMR from CBF. But Semmelweis never received the recognition his groundbreaking work deserved, and died an ignominious death in 1865 at the age of 47 in an asylum, where he was beaten by his attendants, and died of his injuries. Fifteen years later, his work was validated by the adoption of the germ theory, and honors were belatedly showered on Semmelweis from all over the world - but over the last 40 years, a myth has been created that has tarnished Semmelweis' reputation by blaming the rejection of his work on Semmelweis' character flaws. This myth is shown to be a genre of reality fiction that is inconsistent with historical facts. PMID- 30444983 TI - Development of a loop-mediated isothermal amplification assay for the detection and quantification of epizootic epitheliotropic disease virus (salmonid herpesvirus-3). AB - Epizootic Epitheliotropic Disease Virus (EEDV; Salmonid Herpesvirus-3) causes a serious disease hatchery-reared lake trout (Salvelinus namaycush), threatening restoration efforts of this species in North America. The current inability to replicate EEDV in vitro necessitates the search for a reproducible, sensitive, and specific assay that allows for its detection and quantitation in a time- and cost-effective manner. Herein, we describe a loop-mediated isothermal amplification (LAMP) assay that was developed for the quantitative detection of EEDV in infected fish tissues. The newly developed LAMP reaction was optimized in the presence of calcein, and the best results were produced using 2 mM MgCl2, 1.8 mM dNTPs and at an incubation temperature of 67.1 degrees C. This method was highly specific to EEDV, as it showed no cross-reactivity with several fish viruses, including Salmonid Herpesvirus-1, -2, -4, and -5, Infectious Pancreatic Necrosis Virus, Spring Viremia of Carp Virus, Infectious Hematopoietic Necrosis Virus, Golden Shiner Reovirus, Fathead Minnow Nidovirus, and Viral Hemorrhagic Septicemia Virus. The analytical sensitivity of the EEDV-LAMP method was estimated to be as low as 16 copies of plasmid per reaction. When infected fish tissue was used, a positive reaction could be obtained when an infected gill tissue sample that contained 430 viral copies/MUg was diluted up to five orders of magnitude. The sensitivity and specificity of the newly developed LAMP assay compared to the SYBR Green qPCR assay were 84.3% and 93.3%, respectively. The quantitative LAMP for EEDV had a correlation coefficient (R2 = 0.980), and did not differ significantly from the SYBR Green quantitative PCR assay (p > 0.05). Given its cost- and time-effectiveness, this quantitative LAMP assay is suitable for screening lake trout populations and for the initial diagnosis of clinical cases. PMID- 30444982 TI - Self-Administered Vaginal Lidocaine Gel for Pain Management with Intrauterine Device Insertion: A Blinded, Randomized Controlled Trial. AB - BACKGROUND: A major barrier to intrauterine device use is fear of pain during insertion. Trials exploring analgesic interventions for intrauterine device insertion have yielded mixed results, and no standardized pain management guidelines currently exist for this procedure. In an abortion-related study, self administered lidocaine gel over a prolonged time interval showed promise as a method of pain control. OBJECTIVE(S): To assess pain control with intrauterine device insertion after patient-administered lidocaine gel compared to placebo. STUDY DESIGN: We conducted a randomized, blinded trial of women undergoing levonorgestrel or copper intrauterine device insertion in an outpatient gynecology clinic between July 2016 and April 2017. Participants self administered either 20 mL of 2% lidocaine gel or placebo gel vaginally at least 15-minutes prior to intrauterine device insertion. No other analgesics were administered. The primary outcome was pain during intrauterine device insertion, measured on a 100-mm visual analog scale (VAS, 0 being "no pain" and 100 being "worst pain imaginable"). Secondary outcomes included anticipated and baseline pain and pain with speculum insertion and tenaculum placement. In a post procedure questionnaire, participants reported acceptability of vaginal gel and willingness to wait for pain control. Median values were assessed due to the non normal distribution of visual analog scale scores using the Mann-Whitney U test. Predictors of IUD insertion pain were assessed using a multiple linear regression. RESULTS: In total, 220 women were randomized and 215 were included in analysis (108 in lidocaine gel, 107 in placebo gel groups). Median (range) time from gel administration to speculum insertion was 21 (14-74) and 20 (12-43) minutes in the lidocaine and placebo groups, respectively (p=.13). The median pain scores during intrauterine device insertion were not significantly different: 65 (1-99) mm in the lidocaine group and 59 (5-100) mm in the placebo group (p=.09). Among secondary outcome time points, only median pain scores at speculum insertion were significantly different between the lidocaine and placebo groups (7 (0-81) mm versus 11 (0-80) mm, respectively; p=.046). Anticipated pain and menstrual pain were both predictors of pain with IUD insertion. The majority of women in both groups found the amount of vaginal leakage following gel insertion to be acceptable (>80%). Ninety-two percent (n= 194) of participants stated they would be willing to wait before intrauterine device placement for a potential analgesic effect. CONCLUSION(S): Self-administered lidocaine gel at least 15-minutes before intrauterine device insertion does not appear to reduce pain compared with placebo, but may help with speculum insertion. We found that women are willing to extend visit time to gain pain control. Self-administration of local anesthetic is acceptable to patients and should be considered in future research. PMID- 30444984 TI - Effect of microinjections of dopamine into the nucleus accumbens shell on emission of 50 kHz USV: Comparison with effects of d-amphetamine. AB - Systemic pharmacological manipulation of dopamine (DA) signaling has been central to many investigations of 50 kHz ultrasonic vocalizations (USVs) in the rat. In particular, the indirect DA releaser d-amphetamine (AMPH) has been used extensively in many such investigations. The possible unique character of the native transmitter relative to DA-stimulating drugs such as AMPH in inducing and modulating emission of 50 kHz USVs has not been investigated. Adult male Long Evans rats were tested with intracerebral application of DA into the nucleus accumbens shell at several doses (3.75 MUg-120 MUg) to determine its capacity to induce 50 kHz USV emission. Additionally, the call profile characteristics of intracerebral DA injections were compared with those of intracerebral application of AMPH. Results indicated that local increases in DA signaling within the nucleus accumbens shell are sufficient to increase 50 kHz call rate, reduce latency to call, and increase the degree of frequency modulation of emitted USVs. However, our results found that microinjections of DA were not as efficacious in either inducing 50 kHz USVs or increasing frequency modulation without antagonism of the dopamine reuptake transporter when compared with AMPH. In summary, these results support the notion that the native transmitter DA is driving the increase in frequency modulation seen after administration of DA stimulating drugs. These results also suggest that drugs affecting dopamine may be altering the 50 kHz call profile in a distinct manner from the native transmitter and thus caution should be used in interpreting their effects. PMID- 30444985 TI - The role of dopamine D1- and D2-like receptors related to muscarinic M1 receptors in impulsive choice in high-impulsive and low-impulsive rats. AB - The non-selective muscarinic receptor agonist oxotremorine-M has been found to decrease impulsive choice in high-impulsive (HI) rats and increase impulsive choice in low-impulsive (LI) rats, but little is known about the muscarinic M1 receptor agonist N-desmethylclozapine (NDMC). This study investigated effects of NDMC on impulsive choice, and the effect of co-administration of NDMC with the dopamine D1-like receptor antagonist SCH 23390 or D2-like receptor antagonist raclopride on impulsive choice in HI and LI rats, characterized by basal levels of impulsive choice in a delay-discounting task. The results revealed that NDMC (1 and 2 mg/kg) significantly increased impulsive choice in HI, but not LI rats. SCH 23390 significantly promoted impulsive choice in HI rats at 0.01 mg/kg, and in LI rats at 0.0075 and 0.01 mg/kg. Moreover, SCH 23390 (0.005 and 0.0075 mg/kg) significantly inhibited the increase in impulsive choice induced by NDMC (1 mg/kg) in HI rats, whereas the increase in impulsive choice produced by SCH 23390 (0.0075 mg/kg) was significantly reversed by NDMC (1 mg/kg) in LI rats. Raclopride (0.04, 0.08, and 0.12 mg/kg) did not affect choice in both HI and LI rats, but significantly antagonized the increase in impulsive choice induced by NDMC (1 mg/kg) in HI rats. These findings suggest that D1- and D2-like receptors might be involved in different effects of the M1 receptor agonist on impulsive choice between HI and LI rats. PMID- 30444986 TI - IGF-1 and somatocrinin trigger islet differentiation in human amniotic membrane derived mesenchymal stem cells. AB - AIM: To induce differentiation of human amniotic membrane derived mesenchymal stem cells (hAMMSCs) into insulin producing cells (IPCs) by treating with somatocrinin or growth hormone releasing hormone (GHRH) and Insulin-like growth factor-1 (IGF-1). MAIN METHOD: In this investigation, we cultivated and characterized hAMMSCs and then treated with IGF-1 and somatocrinin to find out whether this combination gives better yield of insulin producing cells. We showed that hAMMSCs can give rise to IPCs on exposure to serum-free defined media containing specific growth factors and differentiating agents in presence of IGF 1 and somatocrinin. KEY FINDING: A combination of IGF-1 and somatocrinin lead to differentiation of large number of IPCs from hAMMSCs. These IPCs were found to be positive for dithizone indicating their insulin secretory mechanism. Moreover these cells were also found to be positive for C-peptide. IPCs released insulin in response to glucose challenge. Gene expression analysis exhibited significant up-regulation of pancreatic transcription factor GLUT2 and Insulin. SIGNIFICANCE: Our data thus demonstrates for the first time that somatocrinin and IGF-1 synergistically enhance the differentiation of hAMMSCs into IPCs. PMID- 30444987 TI - Protective efficacy of crocetin and its nanoformulation against cyclosporine A mediated toxicity in human embryonic kidney cells. AB - AIM: This study is aimed to formulate crocetin-loaded lipid Nanoparticles (NPs) and to evaluate its antioxidant properties in a cyclosporine A-mediated toxicity in Human Embryonic Kidney (HEK-293) cells in vitro. MAIN METHODS: Crocetin-loaded NPs were prepared followed by physicochemical characterization. In vitro protective efficacy of crocetin and crocetin loaded NPs was investigated in cyclosporine A-mediated toxicity in HEK-293 cells by assessing free radical scavenging, DNA Nicking, cytotoxicity, intracellular Reactive oxygen species (ROS) inhibition, Mitochondrial membrane potential (MMPs) loss and evaluating the activity and expression of antioxidant enzymes and non-enzyme level. Further, we have studied the mechanism of protective activity of crocetin either native or in NPs by studying the expression of phase II detoxifying proteins (HO-1) via Nrf2 mediated regulation. KEY FINDINGS: Our results showed that pretreatment with crocetin and crocetin-loaded NPs attenuated the cyclosporine A-mediated toxicity, ROS production and exhibited enhance free radical scavenging ability and cytoprotective activity. Further, the treatment prevented MMPs loss by directly scavenging the ROS and restored the antioxidant enzyme network with normalization of HO-1 expression by inhibiting nuclear translocation of Nrf2. SIGNIFICANCE: Pretreatment of crocetin and crocetin-loaded NPs provided pronounce protective effect against cyclosporine A-mediated toxicity in HEK-293 cells by nullifying the ROS formation and restored antioxidant network through inhibition of Nrf2 translocation and followed by expression of HO-1. Such an approach may be anticipated to be beneficial for antioxidant therapy. PMID- 30444988 TI - Induction Radiation Therapy for Esophageal Cancer: Does Dose Affect Outcomes? AB - BACKGROUND: Wide variation is seen in dosage of preoperative induction radiation therapy for esophageal cancer. We investigated associations between outcomes following esophagectomy and dosage of induction radiation. METHODS: Patients undergoing induction radiation therapy (30-70Gy) followed by esophagectomy were identified from the National Cancer Database and classified as low- (<40Gy), standard- (40-50.4Gy), and high-dose (>50.4Gy). Perioperative outcomes and overall survival were compared. Subgroup analysis compared two common dosages: 45Gy and 50.4Gy. RESULTS: From 2004-2014, 10,738 patients (84.7%) received standard-dose radiation: increasing from 69.7% in 2004 to 93.6% in 2014 (p<0.001). Additionally, 1,329 (10.5%) received low-dose and 608 (4.8%) received high-dose radiation. Higher rates of pathologic complete response (pCR) (low: 11.7%, standard: 16.2%, high: 21.0%, p<0.001) and downstaging (low: 52.0%, standard: 56.4%, high: 63.1%, p=0.001) were observed as dosage increased. On multivariate analysis, compared to standard-dose, high-dose radiation was associated with higher 30-day mortality (OR 2.11, p<0.001) without a higher likelihood of downstaging or pCR. Low-dose radiation was associated with lower likelihood of downstaging (OR 0.85, p=0.04) and pCR (OR 0.67, p<0.001) without lowering the risk of 30-day mortality. 50.4Gy was associated with higher likelihood of pCR (OR 1.12, p=0.04) without impacting 30-day mortality, compared to 45Gy. CONCLUSIONS: High-dose induction radiation (>50.4Gy) is associated with increased perioperative mortality following esophagectomy without significant improvement in tumor response. Low-dose radiation (<30Gy) is associated with worse tumor response without lower risk of perioperative mortality. Within standard dosages, 50.4Gy is associated with higher likelihood of pCR without adversely impacting perioperative mortality compared to 45Gy. PMID- 30444989 TI - Complete sternal-sparing HeartMate 3 implantation: a case series of ten consecutive patients. AB - BACKGROUND: Left ventricular assist device (LVAD) therapy has been the standard of care for selected patients with advance heart failure. Even though considerable strides have been achieved with the introduction of the newest centrifugal pump, therapy is still burdened with significant perioperative complications. Smaller devices along with improved techniques and instruments have encouraged the adoption of minimally invasive cardiac surgery (MICS) techniques for LVAD implantation to improve perioperative outcomes. METHODS: We describe a technique for complete sternal-sparing (CSS) HeartMate 3 left ventricular assist device (LVAD) implantation using bilateral thoracotomies and discuss early clinical outcomes of the first ten consecutive patients who underwent CSS implantation of the HeartMate 3 LVAD at our institution. RESULTS: The median length of stay in the intensive care unit was 3.5 days. No patients required re-exploration for postoperative bleeding. There was no incidence of RV failure, stroke, renal failure, hepatic failure, or myocardial infarction. The median length of hospitalization after LVAD implantation was 14.5 days [IQR, 12 17]. CONCLUSIONS: Our early outcomes suggest that the CSS approach may reduce the incidence of right ventricular failure, bleeding, intubation time and ICU length of stay. Further studies are needed to fully elucidate the advantages of CSS LVAD implantation compared with median sternotomy. PMID- 30444990 TI - Management of patients with coronary artery malperfusion secondary to Type A aortic dissection. AB - BACKGROUND: To review our experience with coronary artery (CA) malperfusion secondary to Type A aortic dissection. METHODS: Between 2002 and 2017, 76 patients presented with CA malperfusion with a dissection flap limited to the aorta in the region of the coronary ostium (Type A lesion, n=26, 34%), with a dissection flap involving the CA itself (Type B lesion, n=32, 42%), or with complete avulsion of the CA (Type C lesion, n=18, 24%). RESULTS: Ostial repair was successfully performed in 23 (88%) Type A patients, in 20 (63%) Type B patients and in no (0%) Type C patient. CABG was performed when antegrade cardioplegia could not be applied in all 18 (100%) Type C patients and in 5 (16%) Type B patients because of a primary entry at the coronary ostium and in 6 patients (Type A: 3 (12%) patients, Type B: 4 (13%) patients) with evidence of CA disease (p<0.001). Perioperative mortality in patients with CA malperfusion is high (18 patients, 24%), but there is no difference in short (p=0.153) or long term survival (log rank: p=0.542). Also, a landmark analysis showed equal survival of discharged patients with CA malperfusion compared to patients without (log rank: p=0.645). CONCLUSIONS: We recommend CABG in patients with Type C lesions or in patients with underlying CA disease for optimal delivery of cardioplegia and ostial pledgetted suture repair in patients with Type A lesions or Type B lesions when the administration of antegrade cardioplegia is successful. PMID- 30444992 TI - Uniportal Thoracoscopic Thoracic Duct Clipping In Poirier's Triangle For Post operative Chylothorax. AB - Post-operative chylothorax is a rare but potentially life-threatening complication. Conservative treatment is usually unsuccessful in patients with high-output chylothorax, for whom early surgical thoracic duct ligation has advocated to minimize morbidity and mortality. Herein, we reported the left uniportal thoracoscopic closure of persistent high-output chylothorax via the Poirier's triangle in a patient undergoing thoracoscopic thymectomy. After resection of pleural adhesions, the mediastinal pleura was resected at the level of the arch of aorta, left subclavian artery, and vertebral column, anatomic limits of Poirier's triangle. The thoracic duct was then isolated from the esophagus and successfully clipped along its path. PMID- 30444991 TI - Clinical validation of a coronary surgery technique that minimizes aortic manipulation. AB - BACKGROUND: To minimize aortic manipulation and maximize use of arterial conduits are aims of modern coronary surgery. METHODS: From March 2012 to October 2016, 890 consecutive patients with multivessel coronary disease underwent isolated coronary surgery using both internal thoracic arteries (ITAs). In 205 (23%; mean age, 67.6+/-9.2 years), the right ITA was proximally transected and used as free graft, while its in situ stump was elongated with a saphenous vein graft. The new arteriovenous I-conduit was directed to the inferolateral cardiac wall. Operative data and early outcomes of these patients (I-group) were compared with the remaining 685 patients (C-group). Early and late outcomes were compared also in 184 pairs identified with the propensity score-matching. RESULTS: Between I and C group there was no significant difference on expected operative risk (European System for Cardiac Operative Risk Evaluation II, p=0.28), though diseased ascending aorta (p<0.0001) and critical preoperative state (p=0.027) were more frequent in I-group. Despite higher number of coronary anastomoses (mean, 4+/-0.9 vs. 3.7+/-1, p<0.0001), cardiopulmonary bypass time (minutes) was shorter in I group both in overall (86.7+/-23.7 vs. 105.7+/-34.2, p<0.0001) and matched series (86.8+/-24.1 vs. 108.8+/-31.9, p<0.0001). In-hospital mortality (1% vs. 1.9%, p=0.54) and the rates of postoperative complications were similar. During the follow-up period, in matched patients, no intergroup difference was found about the non-parametric estimates of freedom from all-cause death (p=0.39) and major adverse cardiac and cerebrovascular events (p=0.44). CONCLUSIONS: Surgery using this arteriovenous I-conduit is safe, minimizes aortic manipulation, makes shorter cardiopulmonary bypass time, and aids complete revascularization. PMID- 30444993 TI - Rare presentation of giant isolated enteric cyst in anterior mediastinum. AB - Mediastinal enteric cysts are extremely rare. In the published English literature, the majority of such cysts are reported in the right posterior mediastinal position; often with vertebral anomalies. Just 4 cases have been reported for enteric cysts in atypical mediastinal locations since 1997. Herein, we report an additional case of an atypically located giant isolated enteric cyst in the anterior mediastinum. PMID- 30444994 TI - The Impact of Donor and Recipient Age: Older Lung Transplant Recipients Do Not Require Younger Lungs. AB - BACKGROUND: Lung transplantation for patients with end-stage lung disease continues to grow worldwide. Increasing demand for this therapy generates significant waitlist mortality, indicating that alternative sources of donor lungs, such as older donors, are needed. The effect of the donor-recipient age relationship on outcomes remains unclear. METHODS: A retrospective review of the United Network for Organ Sharing Standard Transplant Analysis and Research database was performed for adult lung recipients from 2005 to 2015. Variables examined included donor age, recipient age, listing diagnosis, episodes of acute cellular rejection in the first year, and survival. Both donors and recipients were stratified according to age ranges. Survival was compared with the log-rank test. Propensity score matching was done stratifying donors < 60 years vs > 60 years for the recipient population of 60-69 years. RESULTS: From May 2005 to February 2015, 15,844 patients underwent lung transplantation. Unadjusted comparisons of donor-to-recipient age showed that older donor age appeared to be more relevant for recipients 60 to 69 years old (p=0.002). Nevertheless, when propensity matching was done based on relevant covariates for recipients in this age range by donors < or > 60 years, there were no differences in survival. CONCLUSIONS: Our results suggest that even though donor and recipient age may be important in lung transplantation, the interplay between donor and recipient age alone is not an independent determinant of survival. Careful selection of lungs from donors over 60 years old should be exercised, taking into consideration the totality of donor demographics and risk factors rather than dismissing lungs based on advanced age alone. PMID- 30444995 TI - Re-viewing the 3D Organization of mRNPs. AB - In this issue of Molecular Cell, using leading-edge technologies, Metkar et al. (2018) and Adivarahan et al. (2018) revisit the spatial organization of mRNPs, showing that they form flexible rod-like structures prior to translation that decompact during translation while the closed-loop conformation is rarely observed. PMID- 30444996 TI - To Build by Destruction. AB - In this issue of Molecular Cell, Weith et al. (2018) demonstrate that p97, together with a SEP adaptor, can catalyze ordered subunit exchange to facilitate the biogenesis of protein phosphatase-1 (PP1) holoenzyme, establishing a novel ubiquitin-independent "segregase" function for this versatile ATPase. PMID- 30444997 TI - If You'd Like to Stop a Type III CRISPR Ribonuclease, Then You Should Put a Ring (Nuclease) on It. AB - Athukoralage et al. (2018) identify a new class of nuclease that degrades cyclic oligoadenylate (cOA), a second messenger that activates non-specific RNA degradation by the type III CRISPR-Cas accessory RNase Csm6/Csx1. This discovery provides a mechanism for regulating the degradation of foreign transcripts during the type III CRISPR immune response. PMID- 30444998 TI - Chemical and Physiological Features of Mitochondrial Acylation. AB - Growing appreciation of the diversity of post-translational modifications (PTMs) in the mitochondria necessitates reevaluation of the roles these modifications play in both health and disease. Compared to the cytosol and nucleus, the mitochondrial proteome is highly acylated, and remodeling of the mitochondrial "acylome" is a key adaptive mechanism that regulates fundamental aspects of mitochondrial biology. It is clear that we need to understand the underlying chemistry that regulates mitochondrial acylation, as well as how chemical properties of the acyl chain impact biological functions. Here, we dissect the sources of PTMs in the mitochondria, review major mitochondrial pathways that control levels of PTMs, and highlight how sirtuin enzymes respond to the bioenergetic state of the cell via NAD+ availability to regulate mitochondrial biology. By providing a framework connecting the chemistry of these modifications, their biochemical consequences, and the pathways that regulate the levels of acyl PTMs, we will gain a deeper understanding of the physiological significance of mitochondrial acylation and its role in mitochondrial adaptation. PMID- 30444999 TI - Widespread Enhancer Dememorization and Promoter Priming during Parental-to Zygotic Transition. AB - The epigenome plays critical roles in controlling gene expression and development. However, how the parental epigenomes transit to the zygotic epigenome in early development remains elusive. Here we show that parental-to zygotic transition in zebrafish involves extensive erasure of parental epigenetic memory, starting with methylating gametic enhancers. Surprisingly, this occurs even prior to fertilization for sperm. Both parental enhancers lose histone marks by the 4-cell stage, and zygotic enhancers are not activated until around zygotic genome activation (ZGA). By contrast, many promoters remain hypomethylated and, unexpectedly, acquire histone acetylation before ZGA at as early as the 4-cell stage. They then resolve into either activated or repressed promoters upon ZGA. Maternal depletion of histone acetyltransferases results in aberrant ZGA and early embryonic lethality. Finally, such reprogramming is largely driven by maternal factors, with zygotic products mainly contributing to embryonic enhancer activation. These data reveal widespread enhancer dememorization and promoter priming during parental-to-zygotic transition. PMID- 30445000 TI - Analysis of a genetic-metabolic oscillator with piecewise linear models. AB - Interactions between gene regulatory networks and metabolism produce a diversity of dynamics, including multistability and oscillations. Here, we characterize a regulatory mechanism that drives the emergence of periodic oscillations in metabolic networks subject to genetic feedback regulation by pathway intermediates. We employ a qualitative formalism based on piecewise linear models to systematically analyze the behavior of gene-regulated metabolic pathways. For a pathway with two metabolites and three enzymes, we prove the existence of two co-existing oscillatory behaviors: damped oscillations towards a fixed point or sustained oscillations along a periodic orbit. We show that this mechanism closely resembles the "metabolator", a genetic-metabolic circuit engineered to produce autonomous oscillations in vivo. PMID- 30445002 TI - Reviewing two decades of nanomedicine implementations in targeted treatment and diagnosis of pancreatic cancer: An emphasis on state of art. AB - Pancreatic cancer is nowadays the most life-threatening cancer type worldwide. The problem of poor diagnosis, anti-neoplastics resistance and biopharmaceutical drawbacks of effective anti-cancer drugs lead to worsen disease state. Nanotechnology-based carrier systems used in both imaging and treatment procedures had solved many of these problems. It is critical to develop advanced detection method to save patients from being too late diagnosed. Targeting the pancreatic cancer cells as well helped in decreasing the side effects associated with normal cells destruction. Drug resistance is another challenge in pancreatic cancer management that can be solved by thorough understanding of the microenvironment associated with the disease to design creative nanocarriers. This is the first article to review multifaceted approaches of nanomedicine in pancreatic cancer detection and management. Additionally, mortality rates in selected Arab and European countries were illustrated herein. An emphasis was given on therapeutic and diagnostic challenges and different nanotechnologies adopted to overcome. The four main approaches encompassed nanomedicine for herbal treatment, nanomedicine of synthetic anti-cancer drugs, metal nanoparticles as a distinct treatment policy and nanotechnology for cancer diagnosis. Future research perspectives have been finally proposed. PMID- 30445001 TI - EUS-guided fiducial placement for GI malignancies: a systematic review and meta analysis. AB - BACKGROUND AND AIMS: Image-guided radiotherapy (IGRT) allows the delivery of radiation with high precision to a target lesion while minimizing toxicity to surrounding tissues. Endoscopic ultrasound (EUS) provides excellent visualization of GI tumors and consequently is being used for fiducial placement with increased frequency. Our goal was to perform a systematic review and meta-analysis of studies evaluating the technical aspects, safety and efficacy of EUS fiducial placement for IGRT in GI malignancies. METHODS: A systematic literature search was carried out in the following databases: Medline, Pubmed, Embase, Web of Science and Cochrane Library, using Medical Subject Headings terms combined with text words. A random effects model was used to determine pooled proportions of technical success, migration and adverse events rates. Heterogeneity was assessed using the I2 statistic. Publication bias was visually inspected by using a funnel plot and by the Begg's and Egger's tests. RESULTS: Nine full articles and 5 abstracts reporting on 1155 patients, 49% from a single study by Dhadham et al, were included in the meta-analysis. Pooled rate of technical success was 98% (95% CI, 96-99). Moderate heterogeneity (I2 = 34.18) was present, which appeared to be due to variable sample sizes. Publication bias was present suggesting that studies with less substantial outcomes may have not been reported (Begg's test p = 0.87, Egger's test p<0.01). Pooled rates for fiducial migration and adverse events were 3% (95% CI, 1.0-8.0) and 4% (95% CI, 3-7), respectively. CONCLUSIONS: Our meta-analysis showed that EUS-guided insertion of gold fiducials for IGRT is technically feasible and safe. Further controlled studies assessing its long-term effectiveness in gastrointestinal malignancies are needed. PMID- 30445004 TI - Editorial. PMID- 30445003 TI - Mitochondrial targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative for cancer treatment by inducing mitochondrial apoptosis pathways. AB - Mitochondria are ideal anti-tumor target due to mitochondria's central regulation role in cell apoptosis and tumor resistance to apoptosis. There are several challenges for mitochondrial targeting drug delivery, including complex multistep preparations, low drug- loading and systemic toxicity from the carriers. To address these issues, we firstly constructed mitochondria-targeting nanodrugs self-assembled from 9-O-octadecyl substituted berberine derivative (BD) using simple nano-precipitation approach. BD-based nanodrugs were modified by DSPE PEG2000 (distearylphosphatidylethanolamine- methoxypolyethylene glycol 2000) to increase stability. Negatively charged hyaluronic acid (HA) was further coated to conceal positive charges and achieve tumor targeting. PEG and HA dually modified BD NDs (HA/PEG/BD NDs) were prepared with surface charge of -25.8 mV and high drug loading >70%. The degradation of HA by hyaluronidase (HAase) at tumor tissue allowed the exposure of the positively charged PEG/BD NDs to the cells, which is beneficial for cell uptake and further lysosome escape and mitochondrial targeting. Then, HA/PEG/BD NDs were investigated to induce apoptosis through dissipating mitochondria membrane potential, releasing cytochrome C, increasing the activities of caspase 9/3, activating the pro-apoptotic Bax, suppressing the anti-apoptotic Bcl-2 and upregulating ROS levels. In the A549 xenografted tumor model, HA/PEG/BD NDs exhibited obvious tumor cell mitochondrial targeting and significant anti-tumor efficacy. Overall, comparing to conventional nanoparticles, mitochondrial targeting HA/PEG/BD NDs provide a new strategy for cancer treatment with enhanced drug-loading, relatively simplified preparation processes and reduced carrier toxicities. PMID- 30445005 TI - Roadmap to 3D printed oral pharmaceutical dosage forms: Feedstock filament properties and characterization for fused deposition modeling. AB - Application of additive manufacturing techniques (3D printing) for mass customized products has boomed in the recent years. In pharmaceutical industry and research, the interest has grown particularly with the future scenario of more personalized medicinal products. Understanding a broad range of material properties and process behavior of the drug-excipient combinations is necessary for successful 3D printing of dosage forms. This commentary reviews recent 3D printing studies by fused deposition modeling (FDM) technique in pharmaceutical sciences, extending into the fields of polymer processing and rapid prototyping, where more in-depth studies on the feedstock material properties, modeling and simulation of the FDM process have been performed. A case study of a model oral dosage form from custom-prepared indomethacin-polycaprolactone feedstock filament was used as an example in the pharmaceutical context. The printability was assessed in the different process steps: preparation of customized filaments for FDM, filament feeding, deposition, and solidification. These were linked with the rheological, thermal, and mechanical properties and their characterization, relevant for understanding the printability of drug products by FDM. PMID- 30445006 TI - Abdominal Septic Shock. An eye-popping case. PMID- 30445007 TI - NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice. AB - BACKGROUND & AIMS: Although there are associations among oxidative stress, NADPH oxidase (NOX) activation, and hepatocellular carcinoma (HCC) development, it is not clear how NOX contributes to hepatocarcinogenesis. We studied the functions of different NOX proteins in mice following administration of a liver carcinogen. METHODS: Fourteen-day-old Nox1-/- mice, Nox4-/- mice, Nox1-/-; Nox4-/- (double knockout) mice, and wild-type (WT) C57BL/6 mice were given a single intraperitoneal injection of diethylnitrosamine (DEN) and liver tumors were examined at 9 months. We also studied the effects of DEN in mice with disruption of Nox1 specifically in hepatocytes (Nox1DeltaHep), hepatic stellate cells (Nox1DeltaHep), or macrophage (Nox1DeltaMac). Some mice were also given injections of the NOX1 specific inhibitor ML171. To study the acute effects of DEN, 8-12 week old mice were given a single intraperitoneal injection, and liver and serum were collected at 72 hrs. Liver tissues were analyzed by histology, quantitative PCR, and immunoblots. Hepatocytes and macrophages were isolated from WT and knockout mice and analyzed by immunoblots. RESULTS: Nox4-/- mice and WT mice developed liver tumors within 9 months after administration of DEN, whereas Nox1-/- mice developed 80% fewer tumors, which were 50% smaller than those of WT mice. Nox1DeltaHep and Nox1DeltaHSC mice developed liver tumors of the same number and size as WT mice, whereas Nox1DeltaMac developed fewer, smaller tumors, similar to Nox1-/- mice. Following DEN injection, levels of tumor necrosis factor (TNF), interleukin 6 (IL6) and phosphorylated STAT3 were increased in livers from WT, but not Nox1-/- or Nox1DeltaMac mice. Conditioned medium from necrotic hepatocytes induced expression of NOX1 in cultured macrophages, followed by expression of TNF, IL6, and other inflammatory cytokines; this medium did not induce expression of IL6 or cytokines in Nox1DeltaMac macrophages. WT mice given DEN followed by ML171 developed fewer and smaller liver tumors than mice given DEN followed by vehicle. CONCLUSIONS: In mice given injections of a liver carcinogen (DEN), expression of NOX1 by macrophages promotes hepatic tumorigenesis by inducing the production of inflammatory cytokines. We propose that upon liver injury, damage-associated molecular patterns released from dying hepatocytes activate liver macrophages to produce cytokines that promote tumor development. Strategies to block NOX1 or these cytokines might be developed to slow HCC progression. PMID- 30445008 TI - Dexlansoprazole and Esomeprazole Do Not Affect Bone Homeostasis in Healthy Postmenopausal Women. AB - BACKGROUND & AIMS: Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. METHODS: We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomized to groups given dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n=30). RESULTS: Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the dexlansoprazole group (0.12 ng/mL). The esomeprazole and dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA. CONCLUSIONS: In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293. PMID- 30445009 TI - Direct-acting Antiviral Therapy for HCV Infection is Associated with a Reduced Risk of Cardiovascular Disease Events. AB - BACKGROUND & AIMS: Infection with hepatitis virus C (HCV) is associated with an increased risk of cardiovascular disease (CVD) events. It is not clear whether treatment with direct-acting antiviral (DAA) agents affects risk of CVD. METHODS: We searched the Electronically Retrieved Cohort of HCV-infected Veterans database for patients with chronic HCV infection (n=242,680), identifying patients who had been treated with a pegylated interferon and ribavirin regimen (n=4436) or a DAA containing regimen (12,667). Treated patients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection (controls). All subjects were free of any CVD event diagnosis of HCV infection at baseline. The primary outcome was incident CVD events, identified by ICD9/10 code, in the different groups and among patients with vs without a sustained virologic response (SVR) to therapy. RESULTS: There were 1239 (7.2%) incident CVD events in the treated and 2361 (13.8%) in the control group. The incidence rate was 30.9/1000 patient-years (95% CI, 29.6-32.1) in the control group and 20.3/1000 patient-years (95% CI, 19.2-21.5) in the treated groups (P<.0001). Treatment with pegylated interferon and ribavirin (hazard ratio, 0.78; 95% CI, 0.71-0.85) or a DAA regimen (0.57; 95% CI, 0.51-0.65) was associated with a significantly lower risk of a CVD event, compared with no treatment (controls). Incidence rates for CVD events were 23.5/1000 patient-years (95% CI, 21.8-25.3) in group treated with pegylated interferon and ribavirin regimen, 16.3/1000 patient-years (95% CI, 14.7-18.0) in the group treated with a DAA regimen, and 30.4 (95%, 29.2-31.7) in the control group. An SVR was associated with a lower risk of incident CVD events (hazard ratio, 0.87; 95% CI, 0.77-0.98). CONCLUSIONS: In an analysis of a cohort of HCV-infected Veterans, we found treatment of HCV infection to be associated with a significant reduction in risk of CVD events. Patients treated with a DAA regimen and patients who achieved SVRs had the lowest risk for CVD events. PMID- 30445010 TI - Long Non-coding RNA GMAN, Upregulated in Gastric Cancer Tissues, is Associated with Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS. AB - BACKGROUND & AIMS: We aimed to identify long non-coding RNAs (lncRNAs) that are upregulated in gastric cancer tissues from patients and study their function in gastric tumor metastasis. METHODS: We collected gastric tumor and non-tumor tissues from patients in China and analyzed levels of lncRNAs by microarray analysis, proteins by immunohistochemistry, and RNAs by quantitative reverse transcription-PCR; we compared these with survival times of patients and tumor progression. RNA levels were knocked down or knocked out in BGC-823, SGC-7901, and MKN45 cell lines using small interfering or hairpin RNAs or CRISPR/Cas9 vectors. Genes were overexpressed from transfected plasmids in HGC-27 cells. Cells were analyzed by Northern and immunoblots, polysome profiling assays, and cell invasion assays. Cells were injected into tail veins or spleens of nude mice or SCID mice; lung and liver tissues were collected and metastases were counted. LncRNAs were cloned using rapid amplification of cDNA ends. Their interactions with other genes were determined by RNA pull-down and mapping assays. RESULTS: In microarray analyses, we identified 151 lncRNAs expressed at significantly higher levels in gastric tumor vs non-tumor tissues. Levels of an lncRNA that we called gastric cancer metastasis associated long non-coding RNA (GMAN) were increased in gastric tumor tissues, compared with non-tumor tissues; its upregulation was associated with tumor metastasis and shorter survival times of patients. The GMAN gene overlaps with the ephrin A1 gene (EFNA1) and was highly expressed in BGC-823 and MKN45 cells. Knockdown of the GMAN in these cells did not affect proliferation, colony formation, or adhesion, but did reduce their invasive activity in transwell assays. Ectopic expression of GMAN increased the invasive activity of HGC-27 cells. BGC-823 and MKN45 cells with knockdown of GMAN formed fewer metastases following injection into tail veins of nude mice. Knockdown or knockout of GMAN also reduced levels of EFNA1 protein in cells. We found that GMAN promoted translation of EFNA1 mRNA into protein by binding to the antisense GMAN RNA (GMAN-AS)-this antisense sequence is also complementary to that of EFNA1 mRNA. Levels of EFNA1 protein were also increased in gastric tumors from patients with metastases, compared to that without metastases. Knockout of EFNA1 in BGC 823 cells reduced their invasive activity in transwell assays and ability to form metastases following injection into SCID mice. Ectopic expression of EFNA1 in BGC 823 cells with knockdown or knockout of GMAN restored their invasive activities and ability to form metastases in nude or SCID mice. A CRISPR/Cas9-based strategy to disrupt the GMAN gene significantly reduced the numbers of metastases formed from SGC-7901 cells in mice. CONCLUSIONS: We identified an lncRNA, which we call GMAN, that is increased in gastric tumors from patients and associated with survival and formation of metastases. It regulates translation of EFNA1 mRNA by binding competitively to GMAN-AS RNA. Knockdown or knockout of GMAN or EFNA1 in gastric cancer cell lines reduces their invasive activity and ability to form metastases following injection into mice. These genes might be targeted to prevent or reduce gastric cancer metastasis. PMID- 30445011 TI - What did we learn from the ADAPT trials? PMID- 30445012 TI - Propensity for Intra-abdominal and Hepatic Adiposity Varies Among Ethnic Groups. AB - BACKGROUND & AIMS: We compared fat storage in the abdominal region among individuals from 5 different ethnic/racial groups to determine whether fat storage is associated with disparities observed in the metabolic syndrome and other obesity-associated diseases. METHODS: We collected data from 1794 participants in the Multiethnic Cohort Study (60-77 years old; of African, European (white), Japanese, Latino, or Native Hawaiian ancestry) with body mass index values of 17.1-46.2 kg/m2. From May 2013 through April 2016, participants visited the study clinic to undergo body measurements, an interview, and a blood collection. Participants were evaluated by dual energy X-ray absorptiometry and abdominal magnetic resonance imaging. Among the ethnic groups, we compared adiposity of trunk, intra-abdominal visceral cavity, and liver, adjusting for total fat mass; we evaluated the association of adult weight change with abdominal adiposity; and we examined the prevalence of the metabolic syndrome mediated by abdominal adiposity. RESULTS: Relative amounts of trunk, visceral, and liver fat varied significantly with ethnicity-they were highest in Japanese Americans, lowest in African Americans, and intermediate in the other groups. Compared with African Americans, the mean visceral fat area was 45% and 73% greater in Japanese American men and women, respectively, and the mean measurements of liver fat were 61% and 122% greater in Japanese American men and women. The visceral and hepatic adiposity associated with weight gain since participants were 21 years old varied in a similar pattern among ethnic/racial groups. In the mediation analysis, visceral and liver fat jointly accounted for a statistically significant fraction of the difference in metabolic syndrome prevalence, in comparison to white persons, for African Americans, Japanese Americans, and Native Hawaiian women, independently of total fat mass. CONCLUSIONS: In an analysis of data from the participants in the Multiethnic Cohort Study, we found extensive differences among ethnic/racial groups in the propensity to store fat intra-abdominally. This observation should be considered by clinicians in the prevention and early detection of metabolic disorders. PMID- 30445014 TI - Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery. AB - BACKGROUND AND AIMS: Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, though parallel changes in body weight and other confounding variables limits this interpretation. METHODS: Global G protein coupled bile acid receptor-1 null (Tgr5-/-) and intestinal-specific farnesoid X receptor null (FxrDelta/E) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r-/-) mice on chow diet were characterized following bile diversion to the ileum (GB-IL). RESULTS: GB-IL induced weight loss and improved oral glucose tolerance in HFD-fed Tgr5-/-, but not FxrDelta/E mice, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with Ex-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole body Glp-1r-/- mice. CONCLUSIONS: Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes. PMID- 30445013 TI - Nuclear Translocation of RELB is Increased in Diseased Human Liver and Promotes Ductular Reaction and Biliary Fibrosis in Mice. AB - BACKGROUND: &Aims: Cholangiocyte proliferation and ductular reaction contribute to onset and progression of liver diseases. Little is known about the role of the transcription factor NF-kB in this process. We investigated the activities of the RELB proto-oncogene NF-kB subunit (RELB) in human cholangiocytes and in mouse models of liver disease characterized by a ductular reaction. METHODS: We obtained liver tissue samples from patients with primary sclerosing cholangitis, primary biliary cholangitis, hepatitis B or C virus infection, autoimmune hepatitis, alcoholic liver disease, or without these diseases (controls) from a tissue bank in Germany. Tissues were analyzed by immunohistochemistry for levels of RELB and lymphotoxin beta (LTB). We studied mice with liver parenchymal cell (LPC)-specific disruption of the CYLD lysine 63 deubiquitinase gene (Cyld), with or without disruption of Relb (CyldDeltaLPC mice and Cyld/RelbDeltaLPC mice) and compared them to C57BL/6 mice (controls). Mice were fed 5-diethoxycarbonyl-1,4 dihydrocollidine (DDC) or standard chow diets to induce biliary injury or given injections of CCl4 to induce non-cholestatic liver fibrosis. Liver tissues were analyzed by histology, immunohistochemistry, immunoblots, in situ hybridization, and quantitative real-time PCR. Cholangiocytes were isolated from normal human liver, incubated with LTB receptor agonist and transfected with small interfering RNAs to knock down RELB. RESULTS: In liver tissues from patients with primary sclerosing cholangitis, primary biliary cholangitis, chronic infection with hepatitis B or C viruses, autoimmune hepatitis, or alcoholic liver disease, we detected increased nuclear translocation of RELB and increased levels of LTB in cholangiocytes that formed reactive bile ducts, compared to control liver tissues. Human cholangiocytes, but not those with RELB knockdown, proliferated upon exposure to LTB. The phenotype of CyldDeltaLPC mice, which included ductular reaction, oval cell activation, and biliary fibrosis, was completely lost from Cyld/RelbDeltaLPC mice. Compared with livers from control mice, livers from CyldDeltaLPC mice (but not Cyld/RelbDeltaLPC mice) had increased levels of mRNAs encoding cytokines (LTB; CD40; and the TNF superfamily members [TNFSF] 11 [RANKL], TNFSF13B [BAFF], and TNFSF14 [LIGHT]), produced by reactive cholangiocytes. However, these strains of mice developed similar levels of liver fibrosis in response to CCl4 exposure. CyldDeltaLPC mice and Cyld/RelbDeltaLPC mice had improved liver function following the DDC diet, compared to control mice fed the DDC diet. CONCLUSION: Reactive bile ducts in patients with chronic liver diseases have increased levels of LTB and nuclear translocation of RELB. RELB is required for the ductular reaction and development of biliary fibrosis in CyldDeltaLPC mice. Deletion of RELB and CYLD from LPCs protects mice from DDC induced cholestatic liver fibrosis. PMID- 30445015 TI - Interleukin 6 receptor and inflammatory bowel disease: a Mendelian randomization study. PMID- 30445016 TI - Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review. AB - BACKGROUND & AIMS: The liver imaging reporting and data system (LI-RADS) categorizes observations from imaging analyses of high-risk patients based on level of suspicion for hepatocellular carcinoma (HCC) and overall malignancy. The categories range from definitely benign (LR-1) to definitely HCC (LR-5), malignancy (LR-M), or tumor in vein (LR-TIV), based on findings from computed tomography or magnetic resonance imaging. However, the actual percentage of HCC and overall malignancy within each LI-RADS category is not known. We performed a systematic review to determine the percentage of observations in each LI-RADS category for computed tomography and magnetic resonance imaging that are HCCs or malignancies. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014 through 2018 for studies that reported the percentage of observations in each of the LI-RADS v2014 and LI-RADS v2017 categories that were confirmed as HCCs or other malignancies, based on pathology, follow-up imaging analyses, or response to treatment (reference standard). Data were assessed on a per-observation basis. Random effects models were used to determine the pooled percentages of HCC and overall malignancy for each LI-RADs category. Differences between categories were compared by analysis of variance of logit transformed percentage of HCC and overall malignancy. Risk of bias and concerns about applicability were assessed with QUADAS-2. RESULTS: Of 454 studies identified, 17 (all retrospective studies) were included in the final analysis, comprising 2760 patients, 3556 observations, and 2482 HCCs. The pooled percentages of observations confirmed as HCC and overall malignancy, respectively, were: LR-5, 94% (95% CI, 92%-96%) and 97% (95% CI, 95%-99%); LR-4, 74% (95% CI, 67%-80%) and 80% (95% CI, 75%-85%); LR-3, 38% (95% CI, 31%-45%) and 40% (95% CI, 31%-50%); LR 2, 13% (95% CI, 8%-22%) and 14% (95% CI, 9%-21%); LR-TIV, 79% (95% CI, 63%-89%) and 92% (95% CI, 77%-98%); and LR-M, 36% (95% CI, 26%-48%) and 93% (95% CI, 87% 97%). No malignancies were found in the LR-1 group. The percentage of HCCs and overall malignancies confirmed differed significantly among the LI-RADS 2-5 groups (P<.00001). Patient selection was the most frequent factor that affected bias risk, due to verification bias and case-control study design. CONCLUSIONS: In a systematic review, we found increasing LI-RADS categories to contain increasing percentages of HCCs and overall malignancy, based on reference standard confirmation. Of observations categorized as LR-M, 93% were malignancies and 36% were confirmed as HCCs. The percentage of HCCs found in the LR-2 and LR-3 categories indicate the need for a more active management strategy than currently recommended. Prospective studies are needed to validate these findings. PROSPERO number: CRD42018087441. PMID- 30445018 TI - RhoA and Rho-kinase inhibitors modulate cervical resistance: The possible role of RhoA/Rho-kinase signalling pathway in cervical ripening and contractility. AB - Improper cervical function may lead premature or late-term birth. The RhoA/Rho kinase (ROCK) signalling pathway takes part in cellular functions including smooth muscle contraction. No information is available about the cervical expression of the RhoA/ROCK system during pregnancy. Our aim was to detect the mRNA and protein expression of ROCK enzymes in rat cervices and to evaluate the effects of RhoA/ROCK inhibitors on cervical resistance. The mRNA and protein expressions of RhoA, ROCK I and II were measured in non-pregnant, pregnant and postpartum rat cervices and during parturition by Real-time qPCR and Western blot. The cervical resistance modifying effects of RhoA (simvastatin) and ROCK (fasudil, Y-27632) (10-6M) were investigated in tissue bath experiments. RhoA mRNA was increased on post-partum day 3, while the RhoA protein expression was decreased near and during parturition. ROCK I mRNA and protein expressions were fluctuating with a decrease in protein expression during parturition. ROCK II mRNA and protein expressions were sharply reduced during parturition. Simvastatin increased the cervical resistance on pregnancy days 20 and 22 while Y-27632 and fasudil reduced the resistance on pregnancy days 20. The decrease in RhoA/ROCK expression near parturition may take part in cervical ripening, especially in the final processes leading to delivery. ROCK inhibitors might be potential drug candidates to treat insufficient cervical ripening late-term pregnancies. The effect of simvastatin possibly due to its unique smooth muscle contracting activity in pregnant cervix. Compounds with simvastatin-like action might be new drug candidates for preterm cervical ripening. PMID- 30445017 TI - Identification and regulation of the long non-coding RNA Heat2 in heart failure. AB - AIMS: Circulating immune cells have a significant impact on progression and outcome of heart failure. Long non-coding RNAs (lncRNAs) comprise novel epigenetic regulators which control cardiovascular diseases and inflammatory disorders. We aimed to identify lncRNAs regulated in circulating immune cells of the blood of heart failure patients. METHODS AND RESULTS: Next-generation sequencing revealed 110 potentially non-coding RNA transcripts differentially expressed in peripheral blood mononuclear cells of heart failure patients with reduced ejection fraction. The up-regulated lncRNA Heat2 was further functionally characterized. Heat2 expression was detected in whole blood, PBMNCs, eosinophil and basophil granulocytes. Heat2 regulates cell division, invasion, transmigration and immune cell adhesion on endothelial cells. CONCLUSION: Heat2 is an immune cell enriched lncRNA that is elevated in the blood of heart failure patients and controls cellular functions. PMID- 30445019 TI - Resveratrol protects cardiomyocytes against anoxia/reoxygenation via dephosphorylation of VDAC1 by Akt-GSK3 beta pathway. AB - Our previous studies showed that the effect of resveratrol preventing mitochondrial permeability transition pore (mPTP) opening in myocardial ischemia/reperfusion injury was achieved by regulating voltage-dependent anion channel 1 (VDAC1). However, the underlying mechanism remains unclear. Previous studies demonstrated that the activity and function of VDAC1 are highly regulated by post-translational modification. In present study, we investigated whether resveratrol modulates VDAC1 phosphorylation to achieve cardioprotection and explored the signaling pathways involved. Our findings demonstrated that anoxia/reoxygenation (A/R) treatment, an ischemia/reperfusion model in vitro, enhanced VDAC1 phosphorylation in cardiomyocytes. Moreover, we found phosphorylated VDAC1 showed increased affinity to Bax, whereas interaction with hexokinase 2 (HK2) was reduced. Accordingly, the generation of reactive oxygen species increased, the mitochondrial membrane potential collapsed, mPTP opening increased and cytochrome c released into cytoplasm, thereby leading to increased apoptosis. Moreover, our data showed that pretreatment with resveratrol prior to A/R injury inhibited VDAC1 phosphorylation. Dephosphorylated VDAC1 using pretreated resveratrol promoted dissociation with Bax and binding to HK2, which subsequently protected cardiomyocytes against A/R injury. In addition, Akt and its downstream glycogen synthase kinase 3 beta (GSK3beta) were phosphorylated by the action of resveratrol. Akt inhibitor IV abrogated Akt-GSK3beta phosphorylation and thereby abolished the dephosphorylation activity of resveratrol on VDAC1. Moreover, all resveratrol-mediated protective effects on A/R injured cardiomyocytes were abolished by Akt inhibitor IV. Taken together, our data indicated that A/R injury enhanced VDAC1 phosphorylation in cardiomyocytes, whereas pretreatment with resveratrol dephosphorylated VDAC1 through the Akt-GSK3beta pathway, thereby protecting cardiomyocytes against A/R injury. PMID- 30445020 TI - NOTCH inhibition enhances Graft-versus-leukemia while reducing Graft-versus-host disease. AB - Graft-versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dissociation of graft versus-leukemia (GVL) activity from GVHD has yet to be achieved. In this study, we used gamma-secretase inhibitor (GSIs, DAPT) to inhibit Notch signaling in GVHD and GVL murine model. We found that CD11c+CD80+ dendritic cells (DCs) were up-regulated but did not enhance GVHD. Regulatory T cells (Tregs) and central memory T cells that express high levels of CD62L and CD44 had an expansion after Notch inhibition. Reduced Tumor Necrosis Factor-alpha and increased Interferon-gamma production were found, which might be ascribed to the expansion of Tregs and central memory T cells, and result in increased sensitivity of tumor cells to cytotoxic T lymphocyte activity. Fas Receptor-Fas Ligand interaction plays a critical role in GVL instead of aGVHD. Fas Ligand expressions were similar in recipients with or without Notch inhibition, suggesting that GVL activity was maintained. We showed that Notch inhibition could enhances GVL while reducing GVHD via modulating host DCs and donor T cell activity, and the production of inflammatory cytokines. PMID- 30445021 TI - A phenanthroline derivative enhances radiosensitivity of hepatocellular carcinoma cells by inducing mitochondria-dependent apoptosis. AB - Combining radiosensitizers with ionizing radiation (IR) is an effective strategy to increase the radiation therapeutic effect for hepatocellular carcinoma (HCC) patients. A phenanthroline derivative, 2-phenyl-imidazo [4, 5f] [1, 10] phenanthroline (L02), had been synthesized. This study investigated the radiosensitization and mechanisms of L02 combined with IR against HCC. The radiosensitization of L02 combined with IR was evaluated by the sensitivity enhancement ratio (SER) and the isobolographic analysis. The toxicity of L02 and cisplatin were compared by the zebrafish model. The cell cycle and apoptosis were examined by flow cytometry. DNA damage was measured by comet assay and the expressions of apoptosis related proteins were analyzed by western blotting. L02 was effective in sensitizing HCC to IR. The SERs in HepG2 and BEL7402 were 1.41 and 1.28, respectively. The sensitization of L02 was comparable with cisplatin. L02 treatment with IR had synergistic anti-tumor effect. L02 enhanced the percentage of IR induced apoptosis cells. L02 increased comet tail in comet assay when combined with IR. L02 sensitized HCC to IR by the activation of P53 signaling, the decrease in Bcl-2, up-regulation of cytochrome c and the subsequent activation of caspase-3. L02 sensitizes HCC to IR, mostly likely by inhibiting cell proliferation, inducing DNA damage and mitochondria-dependent apoptosis. L02 may be a novel radiosensitizer for HCC. PMID- 30445022 TI - Physiology of crapemyrtle bark scale, Acanthococcus lagerstroemiae (Kuwana), associated with seasonally altered cold tolerance. AB - Temperature is one of the most important abiotic factors influencing the adaptation and diversification of insects. Diverse and complex physiological mechanisms have evolved to help insects adapt to seasonal changes in temperature and prevent cold injury. Although the mechanisms of seasonal adaptation to low temperatures have been studied for insects in different taxa, none of these mechanisms have been investigated in scale insects in the superfamily Coccoidea. The crapemyrtle bark scale, Acanthococcus lagerstroemiae (Kuwana) (Hemiptera: Eriococcidae), is a newly introduced scale pest of crapemyrtles, Lagerstroemia spp. (Myrtales: Lythraceae). Our previous study concerning the cold tolerance of this pest suggested that, from summer to winter, A. lagerstroemiae seasonally adapted to lower temperature with a 5 degrees C reduction of supercooling points. In addition, time required to achieve the same levels of mortality at lower temperatures also increased. In this study, we used A. lagerstroemiae as a model system to investigate the physiological mechanisms correlated with changes in cold tolerance in scale insects, by measuring water content, lipid content and fatty acid composition, and cryoprotective polyols and sugars every other month. Results suggested that water content was lower in winter and early spring than in summer and early fall (40.8% vs. 63.3%). The proportions of the fatty acids in PL were similar over seasons, but in TAG, shorter chain fatty acids (from C6:0 to C10:0) increased in winter as longer chain fatty acids (from C14:0 to C18:0) decreased. Among all measured polyols and sugars, including glycerol, d-mannitol, myo-inositol, and d-trehalose, the levels of d-mannitol were the highest in January 2016, which were 19-times of those in March 2016 and 4.5-times of those in September 2016. Results from this study provide a better understanding on how A. lagerstroemiae overwinters, which may give insights into the overwintering strategies of other scale insects. PMID- 30445023 TI - Aquaporins as a link between water relations and photosynthetic pathway in abiotic stress tolerance in plants. AB - Plant aquaporins constitute a large family of proteins involved in facilitating the transport of water and small neutral molecules across biological membranes. In higher plants they are divided into several sub-families, depending on membrane-type localization and permeability to specific solutes. They are abundantly expressed in the majority of plant organs and tissues, and play a function in primary biological processes. Many studies revealed the significant role of aquaporins in acquiring abiotic stresses' tolerance. This review focuses on aquaporins belonging to PIPs sub-family that are permeable to water and/or carbon dioxide. Isoforms transporting water are involved in hydraulic conductance regulation in the leaves and roots, whereas those transporting carbon dioxide control stomatal and mesophyll conductance in the leaves. Changes in PIP aquaporins abundance/activity in stress conditions allow to maintain the water balance and photosynthesis adjustment. Broad analyses showed that tight control between water and carbon dioxide supplementation mediated by aquaporins influences plant productivity, especially in stress conditions. Involvement of aquaporins in adaptation strategies to dehydrative stresses in different plant species are discussed in this review. PMID- 30445025 TI - Efficacy of Leukemia Inhibitory Factor as a Therapeutic for Permanent Large Vessel Stroke Differs among Aged Male and Female Rats. AB - Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. Although LIF increased neuronal LIFR expression in vitro, it did not increase LIFR in the aged brain. Levels of LIFR protein in brain tissue were significantly downregulated between young males and aged males/females at 72 h after stroke. These results demonstrated that low LIFR expression reduces the neuroprotective efficacy of LIF in aged rodents of both sexes. Furthermore, the ability of LIF to promote motor improvement is dependent upon sex in aged rodents. PMID- 30445024 TI - Early functional connectivity deficits and progressive microstructural alterations in the TgF344-AD rat model of Alzheimer's Disease: A longitudinal MRI study. AB - The development and characterization of new improved animal models is pivotal in Alzheimer's Disease (AD) research, since valid models enable the identification of early pathological processes, which are often not accessible in patients, as well as subsequent target discovery and evaluation. The TgF344-AD rat model of AD, bearing mutant human amyloid precursor protein (APPswe) and Presenilin 1 (PSEN1DeltaE9) genes, has been described to manifest the full spectrum of AD pathology similar to human AD, i.e. progressive cerebral amyloidosis, tauopathy, neuronal loss and age-dependent cognitive decline. Here, AD-related pathology in female TgF344-AD rats was examined longitudinally between 6 and 18 months by means of complementary translational MRI techniques: resting state functional MRI (rsfMRI) to evaluate functional connectivity (FC) and diffusion tensor imaging (DTI) to assess the microstructural integrity. Additionally, an evaluation of macroscopic changes (3D anatomical MRI) and an image-guided validation of ex vivo pathology were performed. We identified slightly decreased FC at 6 months followed by severe and widespread hypoconnectivity at 10 months of age as the earliest detectable pathological MRI hallmark. This initial effect was followed by age-dependent progressive microstructural deficits in parallel with age dependent ex vivo AD pathology, without signs of macroscopic alterations such as hippocampal atrophy. This longitudinal MRI study in the TgF344-AD rat model of AD revealed early rsfMRI and DTI abnormalities as seen in human AD patients. The characterization of AD pathology in this rat model using non-invasive MRI techniques further highlights the translational value of this model, as well as its use for potential treatment evaluation. PMID- 30445027 TI - The role of adenosine in up-regulation of p38 MAPK and ERK during limb ischemic preconditioning-induced brain ischemic tolerance. AB - Our previous studies have demonstrated that limb ischemic preconditioning (LIP) induced brain ischemic tolerance and up-regulated the expression of p38 MAPK and ERK in the hippocampal CA1 region in rats. The present study was undertaken to investigate the role of adenosine in brain protection and up-regulation of p38 MAPK and ERK induced by LIP. It was found that adenosine A1 receptor antagonist DPCPX dose-dependently inhibited the protective effect of LIP. The up-regulation of p38 MAPK and ERK induced by LIP could be blocked by DPCPX. Furthermore, we observed the effect of adenosine on the brain ischemia. The results showed that pre-administration of adenosine could partly mimic the neuroprotective effect on the brain, up-regulate the expression of p38 MAPK and ERK. Based on the above results, it can be concluded that adenosine participated in brain protection and up-regulation of the expression of p38 MAPK and ERK during the induction of brain ischemic tolerance after LIP. PMID- 30445026 TI - Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice. AB - Ischemic stroke is one of the most common diseases leading to death and is the primary cause of physical handicap. Recent studies have reported that chronic colitis increases the risk of ischemic stroke, but it is unknown whether chronic colitis participates in ischemic brain injury directly. A combined mouse model of chronic colitis induced by dextran sodium sulfate (DSS) and ischemic stroke induced by photochemical infarction was used in this study. We demonstrated that chronic colitis significantly increased the infarction volume, activated microglia/macrophage numbers, proliferation of M1 microglia/macrophage, non-gut derived CD4 + T lymphocyte penetration and decreased neuron numbers in the peri infarction at 7 d after stroke. Furthermore, gut-derived CD4 + T cell accumulation on the meninges was observed at 7 d after stroke. In addition, selective depletion of meningeal macrophages resulted in a reduction of infarction volume and the non-gut-derived CD4 + T lymphocyte penetration. We concluded that chronic colitis exacerbated ischemic stroke by promoting CD4 + T cell migration from the gut to the meninges and disequilibrium of M1 and M2 microglia/macrophages. We speculated that the gut-derived CD4+ T cells may interact with meningeal macrophages and result in non-gut-derived CD4 + T lymphocyte infiltration that aggravated brain injury in ischemic stroke. PMID- 30445028 TI - Event-Related Potential Correlates of Recognition Memory in Asymptomatic Individuals with CADASIL. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder and is caused by mutations of the NOTCH3 gene. Cognitive decline in CADASIL is characterized by early impairments of attention, memory, and executive functions. Studying asymptomatic individuals with CADASIL offers a unique genetic model to understand preclinical vascular cognitive impairment and dementia. This study aimed at examine whether early preclinical physiological changes could be observed in asymptomatic individuals with CADASIL, who will go on to develop vascular cognitive impairment and dementia later in life. Twenty-nine individuals (mean age: 54.1 years old) were included in the study; five CADASIL NOTCH3 mutation carriers and twenty-five age-matched non-carriers. Participants underwent a comprehensive clinical evaluation and neuropsychological testing. Event-related potentials (ERPs) were recorded during a picture recognition memory task. Analyses focused on the early frontal effect and parietal effect ERP components associated with familiarity and recollection memory. There were no differences between groups in behavioral performance during recognition memory discrimination or cognitive performance. Compared to non-carriers, CADASIL carriers had decreased amplitudes in both ERP components for hits and correct rejections. Among mutation carriers, lower amplitude at 500-600ms in the left parietal region of interest for correct rejections was correlated with worse performance on measures of semantic fluency and inhibitory control. We conclude that cognitively unimpaired CADASIL carriers showed abnormalities in the neural correlates of recognition memory, years before clinical onset. Early disruptions of fronto-subcortical networks may explain preclinical changes in brain function during recognition memory. This work also demonstrates the potential usefulness of ERP brain correlates as preclinical markers of vascular dementia. PMID- 30445029 TI - Comparison of the new and traditional CKD-EPI GFR estimation equations with urinary inulin clearance: A study of equation performance. AB - BACKGROUND: Diagnosis, prognostication and treatment in chronic kidney disease is often informed by an estimate of the glomerular filtration rate (GFR). Commonly used GFR estimation (eGFR) equations are based on serum creatinine (Cr) concentrations and display suboptimal precision and accuracy. Newer equations incorporating additional endogenous markers such as beta-Trace Protein (BTP), beta2-Microglobulin (B2M) and cystatin C (cysC) have been developed but require validation. METHODS: This prospective cohort study evaluated the performance of 6 eGFR equations developed by the chronic kidney disease - epidemiology collaboration group (CKD-EPI) against urinary inulin clearance GFR in patients recruited from outpatient nephrology clinics. RESULTS: Mean biases were negligible and similar between equations. The eGFR-EPI Cr/cysC had the best precision and accuracy of all the equations and the best agreement with inulin mGFR when classifying participants into GFR categories. The BTP and B2M equations displayed the worst precisions and accuracies and showed the least consistent performance across levels of GFR. Thus, the eGFR-EPI Cr/cysC is the least biased, most precise and has the highest accuracy as compared to other eGFR-EPI equations. CONCLUSIONS: The BTP and B2M equations are the worst performing of the eGFR-EPI equations, and no benefit is observed with the addition of BTP or B2M to Cr/cysC. PMID- 30445030 TI - Development of up-converting phosphor technology-based lateral flow assay for quantitative detection of serum PIVKA-II: Inception of a near-patient PIVKA-II detection tool. AB - BACKGROUND: Development of a test card based on up-conversion phosphor technology based immune lateral flow (UPT-LF) assay as a near-patient detection tool for serum Prothrombin induced by vitamin K absence or antagonist II (PIVKA-II). METHODS: Up-converted phosphor nanoparticles (UCPs) were used to bind to PIVKA-II monoclonal antibodies as labeled probes to develop the test card for detecting serum PIVKA-II. The UPT-LF test card was evaluated by the limit of detection, linearity, stability, recovery rate, precision and interference. Preliminary clinical validation was conducted by detection of 498 serum samples from 228 patients with hepatocellular carcinoma (HCC), 170 patients with liver benign lesion (LBL) and 100 healthy controls (HC). Additionally, the correlation of serum PIVKA-II detection between UPT-LF assay and Chemiluminescence enzyme immunoassay (CLEIA) assay were performed. RESULTS: Modified and activated UCPs bound to monoclonal antibodies powerfully to form the luminescent labeled probes. Limit of detection and linear range of UPT-LF test card for serum PIVKA-II were 2.66 and 4.8-20,000 ng/ml, respectively. Test card had good 25 degrees C thermal and 4 degrees C validity period stability, 93.1%-99.2% of recovery rate, 2.6 5.8% and 5.4-8.9% of intra-assay and inter-assay CVs, and strong anti interference ability for 8 common serum analytes. The sensitivity and specificity (vs LBL + HC group) of test card for HCC were 71.5% and 88.9%, respectively. The R2 between UPT-LF assay and CLEIA assay was 0.901. CONCLUSIONS: UPT-LF assay provides a reliable, rapid and convenient test for quantitative detection of serum PIVKA-II as well as diagnosis of HCC by a point of care testing way. PMID- 30445031 TI - Long interspersed nucleotide element-1 (LINE-1) methylation in colorectal cancer. AB - Colorectal cancer (CRC) represents a group of molecularly heterogeneous diseases characterized by genetic and epigenetic alterations. Long interspersed nuclear elements (LINEs) are a form of retrotransposable element found in many eukaryotic genomes. These LINEs, when active, can mobilize in the cell and steadily cause genomic rearrangement. Active LINE reorganization is a source of endogenous mutagenesis and polymorphism in the cell that brings about individual genomic variation. In normal somatic cells, these elements are heavily methylated and thus mostly suppressed, in turn, preventing their potential for bringing about genomic instability. When LINEs are inadequately controlled, they can play a role in the pathogenesis of several genetic diseases, such as cancer. In tumor cells, LINE hypomethylation can reactivate the mobilization of these elements and is associated with both an advanced stage and a poor prognosis. In this article, we summarize the current knowledge surrounding LINE methylation, its correlation to CRC and its application as a diagnostic, prognostic and predictive biomarker in colon cancer. PMID- 30445032 TI - A manifesto for the future of laboratory medicine professionals. AB - Laboratory medicine plays an increasingly essential role in modern healthcare systems, since it is integral to most care pathways and plays an essential role for optimizing patient flow, harmonizing procedures before and after analysis, improving harmonization and containing unnecessary testing. Nevertheless, recent changes in the nature of laboratory services, promoted by innovation and introduction of more complex tests in emerging diagnostic fields, more advanced diagnostics along with other "internal" and "external" drivers, will promote a paradigmatic transformation of current scenarios. The future of laboratory professionals remains hence uncertain, and is seems obvious that the role and figure of laboratory scientists and professionals shall evolve. We are hence proposing this 10-point "manifesto", which is aimed to encourage a new vision of the future of this discipline and should help supporting the development of a new generation of laboratory professionals and leaders, who shall be able to integrate specific technical and administrative skills with a broader vision of health care and patients needs. PMID- 30445033 TI - From Cellular Diversity to the Roots of Variability. PMID- 30445034 TI - Native American Genomic Diversity through Ancient DNA. AB - Ancient DNA is a powerful tool to understand the evolutionary dynamics of both current and ancestral populations. Posth et al. use ancient DNA to elucidate important questions surrounding the peopling of Central and South America, giving us greater insights into the ancestry of genetically understudied populations. PMID- 30445035 TI - Flaviviruses Hit a Moving Target. AB - The enteric nervous system (ENS) is central to intestinal motility and a candidate target for the heterogeneous spectrum of dysmotility diseases. White et al. reveal that relapsing intestinal dysmotility occurs when partial ENS depletion by enteric neurotropic viruses is followed by functional impairment due to intermittent nonspecific intestinal inflammation. PMID- 30445036 TI - Temporal Coding of Sleep. AB - In Drosophila, well-delineated circuits control circadian rhythms, but the electrophysiological patterns that occur within these circuits are not well understood. In this issue, Tabuchi et al. clarify the temporal coding within a circuit, linking patterns of neural activity to sleep behavior. PMID- 30445037 TI - Non-mendelian Inheritance in Mammals Is Highly Constrained. AB - In this issue, Kazachenka, Bertozzi, and colleagues identify elements in the mouse genome with epigenetic variability between littermates, a phenomenon linked to transmission of phenotypes over generations. This addresses two questions that remained unanswered despite intense speculation: how prevalent are these alleles, and what is their effect, within and across generations? PMID- 30445038 TI - Evolving to End a Toxic Relationship: ADP Ribosylation in Interbacterial Warfare. AB - Long before pathogenic interactions with eukaryotic cells evolved, bacteria were competing with one another for limited resources. In this issue, Ting et al. (2018) identify previously unappreciated players in the interbacterial arms race that may be the evolutionary ancestors of eukaryotic cell-targeting ADP ribosyltransferase toxins. PMID- 30445039 TI - Food Perception Primes Hepatic ER Homeostasis via Melanocortin-Dependent Control of mTOR Activation. AB - Adaptation of liver to the postprandial state requires coordinated regulation of protein synthesis and folding aligned with changes in lipid metabolism. Here we demonstrate that sensory food perception is sufficient to elicit early activation of hepatic mTOR signaling, Xbp1 splicing, increased expression of ER-stress genes, and phosphatidylcholine synthesis, which translate into a rapid morphological ER remodeling. These responses overlap with those activated during refeeding, where they are maintained and constantly increased upon nutrient supply. Sensory food perception activates POMC neurons in the hypothalamus, optogenetic activation of POMC neurons activates hepatic mTOR signaling and Xbp1 splicing, whereas lack of MC4R expression attenuates these responses to sensory food perception. Chemogenetic POMC-neuron activation promotes sympathetic nerve activity (SNA) subserving the liver, and norepinephrine evokes the same responses in hepatocytes in vitro and in liver in vivo as observed upon sensory food perception. Collectively, our experiments unravel that sensory food perception coordinately primes postprandial liver ER adaption through a melanocortin-SNA mTOR-Xbp1s axis. VIDEO ABSTRACT. PMID- 30445041 TI - High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy. PMID- 30445042 TI - Earthworm protease in anti-thrombosis and anti-fibrosis. AB - BACKGROUND: Earthworms are widely used in basic and applied research in medicine, food, environment and agriculture, in which for instance earthworm protease has its own biochemical features. SCOPE OF REVIEW: This review summarizes earthworm protease biochemical features in anti-thrombosis and anti-fibrosis, and provides new perspectives for earthworm to be used in biochemical and pharmaceutical studies. MAJOR CONCLUSIONS: Earthworm protease functions in anti-thrombosis by its fibrinolytic activity and inhibiting platelets aggregation, and anti-fibrosis by its decreasing fibronectin, collagen and laminin, showing a broad substrate specificity. The protease regulators (U3EE) from earthworm also has multiple functions acting as an activator and an inhibitor on different target proteins. Nonetheless, the protease improves the substrate selectivity through substrate induced changes in the protease active site conformation impact on subsequent reactions with substrates. GENERAL SIGNIFICANCE: It is predictable that both biochemical and applied studies of earthworm proteins including protease will be wider and deeper in the future. PMID- 30445043 TI - Early life exposure to extended general anesthesia with isoflurane and nitrous oxide reduces responsivity on a cognitive test battery in the nonhuman primate. AB - Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 h of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life. PMID- 30445044 TI - Pathogenic troponin T mutants with opposing effects on myofilament Ca2+ sensitivity attenuate cardiomyopathy phenotypes in mice. AB - Mutations in cardiac troponin T (TnT) associated with hypertrophic cardiomyopathy generally lead to an increase in the Ca2+ sensitivity of contraction and susceptibility to arrhythmias. In contrast, TnT mutations linked to dilated cardiomyopathy decrease the Ca2+ sensitivity of contraction. Here we tested the hypothesis that two TnT disease mutations with opposite effects on myofilament Ca2+ sensitivity can attenuate each other's phenotype. We crossed transgenic mice expressing the HCM TnT-I79N mutation (I79N) with a DCM knock-in mouse model carrying the heterozygous TnT-R141W mutation (HET). The results of the Ca2+ sensitivity in skinned cardiac muscle preparations ranked from highest to lowest were as follow: I79N > I79N/HET > NTg > HET. Echocardiographic measurements revealed an improvement in hemodynamic parameters in I79N/HET compared to I79N and normalization of left ventricular dimensions and volumes compared to both I79N and HET. Ex vivo testing showed that the I79N/HET mouse hearts had reduced arrhythmia susceptibility compared to I79N mice. These results suggest that two disease mutations in TnT that have opposite effects on the myofilament Ca2+ sensitivity can paradoxically ameliorate each other's disease phenotype. Normalizing myofilament Ca2+ sensitivity may be a promising new treatment approach for a variety of diseases. PMID- 30445040 TI - Structural Basis of Membrane Protein Chaperoning through the Mitochondrial Intermembrane Space. AB - The exchange of metabolites between the mitochondrial matrix and the cytosol depends on beta-barrel channels in the outer membrane and alpha-helical carrier proteins in the inner membrane. The essential translocase of the inner membrane (TIM) chaperones escort these proteins through the intermembrane space, but the structural and mechanistic details remain elusive. We have used an integrated structural biology approach to reveal the functional principle of TIM chaperones. Multiple clamp-like binding sites hold the mitochondrial membrane proteins in a translocation-competent elongated form, thus mimicking characteristics of co translational membrane insertion. The bound preprotein undergoes conformational dynamics within the chaperone binding clefts, pointing to a multitude of dynamic local binding events. Mutations in these binding sites cause cell death or growth defects associated with impairment of carrier and beta-barrel protein biogenesis. Our work reveals how a single mitochondrial "transfer-chaperone" system is able to guide alpha-helical and beta-barrel membrane proteins in a "nascent chain like" conformation through a ribosome-free compartment. PMID- 30445045 TI - Photoreceptor degeneration in a new Cacna1f mutant mouse model. AB - The Cacna1f gene encodes the alpha1F subunit of an L-type voltage-gated calcium channel, Cav1.4. In photoreceptor synaptic terminals, Cav1.4 channels mediate glutamate release and postsynaptic responses associated with visual signal transmission. We have discovered a new Cacna1f mutation in nob9 mice, which display more severe phenotypes than do nob2 mice. To characterize the nob9 phenotype at different ages, we examined the murine fundus, applied retinal optical coherence tomography, measured flash electroretinograms (ERGs) in vivo, and analyzed the retinal histology in vitro. After identifying the X-linked recessive inheritance trait, we sequenced Cacna1f as the candidate gene. Mutations in this gene were detected by polymerase chain reaction (PCR) and confirmed by restriction fragment length polymorphism. Morphologically, an early onset of retinal disorder was detected, and the degeneration of the outer plexiform layers progressed rapidly. Moreover, the mutant mice showed drastically reduced scotopic ERGs with increasing age. In 14-month-old nob9 retinas, immunostaining of cone opsins demonstrated a reduction in the number of short wavelength opsins (S-opsins) to 54% of wild-type levels, and almost no middle wavelength opsins (M-opsins) were observed. No cone ERGs could be detected from residual cones, in which S-opsins abnormally migrated to inner segments of the photoreceptors. The mutations of the Cacna1f gene in nob9 mice involved both a single nucleotide G to A transition and a 10-nucleotide insertion, the latter resulting in a frame-shift mutation in exon 14. PMID- 30445046 TI - The presence and distribution of G protein-coupled receptor 35 (GPR35) in the human cornea - Evidences from in silico gene expression analysis and immunodetection. AB - We provide the evidence for G protein-coupled receptor 35 (GPR35) presence and distribution in the human cornea. The initial data on GPR35 gene expression were retrieved from microarray repositories and were further confirmed by western blotting and immunohistochemical analysis. Immunoblotting suggested that GPR35 exists predominantly as a dimer in corneal tissue. Moreover, corneal tissues were significantly richer in GPR35 compared to the adjacent sclera. Immunoreactivity for GPR35 was detected in normal corneas, keratoconus and Fuchs' dystrophy, mainly in the corneal epithelium and endothelium. In corneas with Fuchs' dystrophy, less intensive immunoreactivity for GPR35 in endothelium was revealed. The physiological relevance of this phenomenon requires further investigation. PMID- 30445048 TI - Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice. AB - We sought to investigate the effects of diabetes and hyaluronidase on the thickness of the endothelial glycocalyx layer in the mouse retina. In our study, the retinal circulation of diabetic Ins2(Akita) mice and their nondiabetic littermates were observed via intravital microscopy. The endothelial glycocalyx thickness was determined from the infusion of two fluorescently labeled plasma markers, one of which was a high molecular weight rhodamine dextran (MW = 155,000) excluded from the glycocalyx, and the other a more permeable low molecular weight sodium fluorescein (MW = 376). In nondiabetic C57BL/6 mice, the glycocalyx thickness also was evaluated prior to and following infusion of hyaluronidase, an enzyme that can degrade hyaluronic acid on the endothelial surface. A leakage index was used to evaluate the influence of hyaluronidase on the transport of the fluorescent tracers from the plasma into the surrounding tissue, and plasma samples were obtained to measure levels of circulating hyaluronic acid. Both diabetes and hyaluronidase infusion significantly reduced the thickness of the glycocalyx in retinal arterioles (but not in venules), and hyaluronidase increased retinal microvascular leakage of both fluorescent tracers into the surrounding tissue. However, only hyaluronidase infusion (not diabetes) increased circulating plasma levels of hyaluronic acid. In summary, our findings demonstrate that diabetes and hyaluronidase reduce the thickness of the retinal endothelial glycocalyx, in which hyaluronic acid may play a significant role in barrier function. PMID- 30445047 TI - Attention, novelty preference and the visual paired comparison task. AB - The innate ability of humans to identify, process and ascribe greater attentional resources (attention bias) to novel stimuli is essential for exploring new opportunities and consequently adapt to changing environments. One of the most common tests to assess attention bias to novel stimuli (Novelty Preference - NP) is the visual paired comparison task (VPC). In the VPC task subjects are presented with novel and previously seen images (repeated images) and NP is measured by parameters that describe visual scanning patterns on these images. The main objective of this study is to evaluate the effects of divided attention on NP. NP was measured in 26 healthy young individuals under two test conditions. In the first condition, subjects performed the VPC task and an audio task simultaneously (divided attention test condition), while in the second condition subjects performed only the VPC task (undivided attention test condition). For each test condition, repeated images were presented after delays ranging from 1.0 to 219.5 s and NP was measured by the mean difference between the relative fixation times on novel and repeated images at each delay. In the divided attention test condition, there were significant differences (p < 0.037) between the magnitudes of NPs for long delays (>= 162 s) and short delays (<=12.5 s). Such differences were not detected in the undivided attention test condition. Analysis of variance revealed significant differences between the measured NPs during the divided and undivided attention test conditions (F(1, 25) = 18.38, p < 0.001, eta2 = 0.424) and significant interaction effects between delays and testing conditions (F(5,125) = 2.88, p = 0.017, eta2 = 0.103). Post-hoc t-tests showed significant differences between the measured NPs during the divided attention and undivided attention test conditions for long delays (162.0 and 219.5 s) but not for short delays (1.0 and 12.5 s). The results of the study are consistent with the hypothesis that for longer delays between the presentations of repeated images in the VPC task, NP is dependent on the recollection-based item recognition memory system, while for shorter delays NP is dependent on the automatic, familiarity-based item recognition memory system. PMID- 30445049 TI - Gaze behavior during navigation with reduced acuity. AB - Navigating unfamiliar indoor spaces while visually searching for objects of interest is a challenge faced by people with visual impairment. We asked how restricting visual acuity of normally sighted subjects would affect visual search and navigation in a real world environment, and how their performance would compare to subjects with naturally occurring low vision. Two experiments were conducted. In the first, 8 normally sighted subjects walked along an indoor path, looking for objects placed at unpredictable intervals to the left and right of the path, and identified single letters posted on the objects. A head-mounted eye tracker was used to assess their gaze direction in the environment. For half the trials, blur foils were used to restrict visual acuity to approximately logMAR 1.65. Gaze behavior, travel time, and letter recognition accuracy were compared between blurred and unrestricted conditions. In the second experiment, the same procedure was conducted, but performance was compared between acuity-restricted normally-sighted subjects and subjects with naturally occurring low vision (mean acuity 1.09 logMAR, range 0.48-1.85 logMAR). In Experiment 1, neither Blur nor the Letter Recognition Task individually had a statistically significant effect on travel time. However, when combined, there was an interaction between the two that increased travel time by approximately 63%, relative to baseline trials. Blur modified gaze behavior such that subjects spent more time looking down toward the floor while walking, at the expense of time spent looking in other directions. During Letter Recognition Task trials with Blur, subjects spent extra time examining objects, though more objects were missed altogether. In Experiment 2, low-vision subjects spent more time looking toward the boundary between the floor and the wall, but gaze patterns were otherwise similar to acuity-restricted subjects with normal vision. Low-vision subjects were also more likely to miss objects compared to acuity-restricted subjects. We conclude that under conditions of artificially restricted acuity, normally sighted subjects look downward toward the floor more frequently while navigating and take extra time to examine objects of interest, but are less likely to detect them. Low-vision subjects tend to direct their gaze toward the boundary between the wall and the floor, which may serve as a high contrast cue for navigation. PMID- 30445050 TI - High doses of sodium ascorbate act as a prooxidant and protect gnotobiotic brine shrimp larvae (Artemia franciscana) against Vibrio harveyi infection coinciding with heat shock protein 70 activation. AB - Ascorbate is an essential nutrient commonly regarded as an antioxidant. In this study, using axenic brine shrimp and pathogenic strain Vibrio harveyi as the host pathogen model, we confirmed that pretreatment of sodium ascorbate (NaAs), at an optimum concentration, was a prooxidant by generation of hydrogen peroxide, inducing protective effects in the brine shrimp against V. harveyi infection. Such a protective effect could be neutralized by the addition of an antioxidant enzyme catalase. We further showed that generation of oxygen radicals is linked to the induction of heat shock protein 70 (Hsp70), which is involved in eliciting the antioxidant protection system including superoxidase dismutase (SOD) and possibly many other immune responses. Furthermore, using RNA interference technique, we found that the pretreatment of sodium ascorbate increased the survival significantly in the control knockdown groups (using green fluorescent protein, GFP) but not in Hsp70 knockdown groups and the result directly suggested that the up-regulated Hsp70 induced by sodium ascorbate pretreatment induced the protective effect. These results provide a mechanistic rationale for exploring the further use of ascorbate for antimicrobial therapy in aquaculture. PMID- 30445051 TI - Oxygen Starvation Unmasks a Killer. AB - In this issue of Cell Chemical Biology, Jacobsen et al. (2018) investigate the hypoxia selectivity of two cyclolipodepsipeptide natural products bearing a 4 amido-2,4-pentadienoate warhead. A switch in the cell death pathway under hypoxic conditions is observed, suggesting these electrophilic natural products have potential as a prodrug-free approach for treating hypoxic tumors. PMID- 30445052 TI - Weighing up the Selenocysteome Uncovers New Sec-rets. AB - Challenging the paradigm of SECIS-dependent selenoprotein translation, in this issue of Cell Chemical BiologyGuo et al. (2018) introduce a new selenoprotein profiling platform with which they identify novel selenoproteins apparently lacking SECIS. With increased interest in covalent targeting of reactive Sec residues in drug discovery, their method adds a valuable contribution toward expanding the druggable human proteome. PMID- 30445053 TI - Role of estrogen receptors alpha and beta in the development of allergic airway inflammation in mice: A possible involvement of interleukin 33 and eosinophils. AB - Recent studies have shown that the estrogen receptor alpha (ERalpha), but not ERbeta, is involved in the proinflammatory and propruritic responses in cutaneous allergy. In addition, results from our recent study showed that while oral administration of the rather ERbeta-selective agonist bisphenol A exacerbated the respiratory allergic inflammation, the potential inflammatory reaction in the skin was decreased after administration of bisphenol A. This study aimed to elucidate whether ERalpha and ERbeta are involved in the progression of an allergic airway inflammation. We performed an in vivo experiment using an animal model of allergic airway inflammation using male BALB/c mice to confirm an increase in the proinflammatory response induced by propylpyrazoletriol (PPT), an ERalpha agonist, and diarylpropionitrile (DPN), an ERbeta agonist. Oral administration of PPT or DPN showed a significant increase in the inflammation of the lung and infiltration of eosinophils. While the expression of Th2 cytokines such as interleukin 4 (IL-4) and IL-13 was not affected by exposure to PPT or DPN, administration of these agonists significantly increased the expression of IL-33. The mechanism underlying the development of such allergic inflammatory responses was determined by an in vitro study using the human bronchial epithelial cell line (BEAS-2B) and the human eosinophilic leukemia cell line (EoL 1). Activated cells were exposed to PPT or DPN for 24 h, and the cytokine levels were measured. The IL-33 levels in BEAS-2B cells increased significantly after exposure to PPT or DPN. In addition, pretreatment with PPT or DPN increased the expression of IL-8 in activated EoL-1 cells. Our findings indicate that ERalpha and ERbeta are involved in the proinflammatory response in respiratory allergy, and their effects may be mediated by an increase in the expression of IL-33 and infiltration of eosinophils. PMID- 30445054 TI - Oxidative stress in the neurodegenerative brain following lifetime exposure to lead in rats: Changes in lifespan profiles. AB - A large number of studies have evidenced that developmental neurotoxicity induced by lead (Pb) is related to oxidative injury. Furthermore, recent studies have found that developmental Pb exposure can induce neurodegeneration in old age. Because of the common presence of Pb in the environment, humans are exposed to this metal throughout their lifetime. However, few studies have explored the changes in lifespan profiles of neurotoxicity, as well as oxidative stress following lifetime Pb exposure. In the present study, rats were exposed to lead acetate from their embryonic stage to old age. Dynamic changes in neurodegeneration, oxidative stress, and endoplasmic reticulum (ER) stress in the brains at postnatal week 3 (PNW3, weaning), 41 weeks (PNW41, adulthood) and 70 weeks (PNW70, old age) were investigated. Pb exposure resulted in neurodegeneration with decreased neuronal densities and brain volumes in PNW3 and PNW70 rats; however, no significant changes occurred in PNW41 rats based on thionine stain analysis and magnetic resonance imaging (MRI) scans. Expression of the ER stress protein glucose-regulated protein 78 (GRP78) increased in Pb exposed rats, which was associated with high levels of 8-hydroxy-2' deoxyguanosine (8-OHdG) in rat brains after Pb exposure in PNW3 and PNW70 rats. Our findings suggested that lifetime Pb exposure induced neurodegenerative injuries that began to occur in infancy, were relieved in adulthood, but intensified in old age. The critical periods for prevention or intervention in neurodegenerative diseases induced by Pb exposure occurred in early life. PMID- 30445055 TI - Morphological, cellular and molecular characterization of posterior regeneration in the marine annelid Platynereis dumerilii. AB - Regeneration, the ability to restore body parts after an injury or an amputation, is a widespread but highly variable and complex phenomenon in animals. While having fascinated scientists for centuries, fundamental questions about the cellular basis of animal regeneration as well as its evolutionary history remain largely unanswered. Here, we present a study of regeneration of the marine annelid Platynereis dumerilii, an emerging comparative developmental biology model, which, like many other annelids, displays important regenerative abilities. When P. dumerilii worms are amputated, they are able to regenerate the posteriormost differentiated part of their body and a stem cell-rich growth zone that allows the production of new segments replacing the amputated ones. We show that posterior regeneration is a rapid process that follows a well reproducible path and timeline, going through specific stages that we thoroughly defined. Wound healing is achieved one day after amputation and a regeneration blastema forms one day later. At this time point, some tissue specification already occurs, and a functional posterior growth zone is re-established as early as three days after amputation. Regeneration timing is only influenced, in a minor manner, by worm size. Comparable regenerative abilities are found for amputations performed at different positions along the antero-posterior axis of the worm, except when amputation planes are very close to the pharynx. Regenerative abilities persist upon repeated amputations without important alterations of the process. We also show that intense cell proliferation occurs during regeneration and that cell divisions are required for regeneration to proceed normally. Finally, 5-ethynyl-2'-deoxyuridine (EdU) pulse and chase experiments suggest that blastemal cells mostly derive from the segment immediately abutting the amputation plane. The detailed characterization of P. dumerilii posterior body regeneration presented in this article provides the foundation for future mechanistic and comparative studies of regeneration in this species. PMID- 30445056 TI - Histologic similarities in children with eosinophilic esophagitis and PPI responsive esophageal eosinophilia. AB - The EPX histologic scoring system can be used to differentiate children with EoE and PPI-REE relative to GERD, supporting the relationship between these 2 groups and enhancing current diagnostic and treatment approaches. PMID- 30445058 TI - The Expression and Function of the Ectopic Olfactory Receptor OR10G7 in Atopic Dermatitis. AB - BACKGROUND: Ectopic olfactory receptors (OR) are found in the skin but their expression and biological functions in normal skin and atopic dermatitis (AD) are unknown. OBJECTIVES: To characterize the expression of ORs in the skin and assess OR-mediated biological responses of primary human keratinocytes in the presence of odorant ligands. METHODS: OR expression was examined by whole transcriptome sequencing of skin tape strips collected from AD and healthy controls (NC). OR10G7 and FLG-1 expression were analyzed by RT-PCR and immunostaining in AD and NC skin biopsies and primary human keratinocytes. ATP and cyclic AMP production by control and OR10G7 siRNA transfected keratinocytes in response to odorant stimulation with acetophenone and eugenol were assessed. RESULTS: A total of 381 OR gene transcripts were detected in the skin samples, with the greatest OR expression detected in the skin tape strips, corresponding to the upper granular layer of the skin. OR10G7 expression was significantly increased in AD compared to NC skin biopsies (p=0.01) and inversely correlated with FLG-1 expression (p=0.009). OR10G7 expression was highest in undifferentiated AD keratinocytes and was down-regulated with progressive differentiation. Primary human keratinocytes produced ATP, an essential neurotransmitter in sensory pathways, in response to acetophenone and eugenol, odorants previously identified as potential ligands for this receptor. This response was abolished in OR10G7 siRNA-transfected keratinocytes. CONCLUSIONS: OR10G7 is expressed at significantly higher levels in undifferentiated AD keratinocytes compared to normal controls. OR10G7 is likely involved in the transmission of skin-induced chemosensory responses to odorant stimulation, which may modulate differential nociceptive responses in AD skin. PMID- 30445057 TI - Nasal Allergen Neutralising IgG4 Antibodies Block IgE-mediated Responses: Novel biomarker of Subcutaneous Grass Pollen Immunotherapy. AB - BACKGROUND: Grass pollen subcutaneous immunotherapy (SCIT) is associated with induction of serum IgG4-associated inhibitory antibodies that prevent IgE facilitated allergen binding to B cells. OBJECTIVE: To determine whether SCIT induces nasal allergen-specific IgG4 antibodies with inhibitory activity that correlate closely with clinical response. METHODS: In a cross-sectional, controlled study, nasal fluid and sera were collected during the grass pollen season from 10 SCIT-treated patients, 13 untreated allergics (SAR) and 12 non atopic controls (NA). Nasal and serum IgE and IgG4 to Phleum pratense (Phl p) components were measured by ISAC microarray. Inhibitory activity was measured by IgE-FAB assay. IL-10+Breg cells were quantified in peripheral blood by flow cytometry. RESULTS: Nasal and serum Phl p1 and Phl p5-specific IgE levels were elevated in SAR compared to NA (all, P < .001) and SCIT group. Nasal IgG4 levels were increased in SCIT compared to SAR group (P < .001) during the pollen season compared to out of season. IgG-associated inhibitory activity in nasal fluid and serum was significantly increased in SCIT compared to SAR group (both, P < .001). The magnitude of the inhibitory activity was 96% in the nasal fluid compared to 66% in serum and was reversed following depletion of IgG in nasal fluid (P = .03) and serum (P = .002). Both nasal fluid (r = -0.67, P = .0011) and serum (r = 0.59, P = .0097) blocking activity correlated global symptom improvement. IL 10+Breg cells were increased in season compared to out of season in SCIT group (P < .01). CONCLUSION: For the first time, we show that nasal IgG4-associated inhibitory activity correlate closely with the clinical response to allergen immunotherapy in allergic rhinitis with/without asthma. PMID- 30445059 TI - Cost-effectiveness of diagnostic algorithms for peanut allergy in children. AB - Incorporating component-resolved allergen diagnosis and peanut conjunctival allergen provocation test in the diagnostic algorithm appears to improve health related quality of life at an acceptable increase in costs, representing the optimal cost-effective diagnostic strategy. PMID- 30445061 TI - Shedding light on corticosteroid-resistant Type-2 high severe asthma. PMID- 30445060 TI - Immunologic reconstitution following hematopoietic stem cell transplantation despite lymph node paucity in NIK deficiency. AB - This case demonstrates successful immune reconstitution following hematopoietic stem cell transplantation in NIK deficiency. PMID- 30445062 TI - Transcriptional and Functional Diversity of Human Macrophage Repolarization. AB - BACKGROUND: Macrophage plasticity allows cells to adopt different phenotypes, a property with important implications in disorders such as cystic fibrosis (CF) and asthma. OBJECTIVE: To examine the transcriptional and functional significance of macrophage repolarization from an "M1" towards an "M2" phenotype, and assess the role of a common human genetic disorder (CF) and a prototypical allergic disease (asthma) in this transformation. METHODS: Monocyte-derived macrophages were collected from healthy and CF subjects and polarized to an M2 state using IL 4, IL-10, glucocorticoids, apoptotic PMNs, or azithromycin. We performed transcriptional profiling and pathway analysis for each stimulus. We assessed the ability of M2-repolarized macrophages to respond to LPS re-challenge and clear apoptotic neutrophils, and used murine models to determine conserved functional responses to IL-4 and IL-10. We investigated whether M2 signatures were associated with alveolar macrophage phenotypes in asthma. RESULTS: We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, IL-10 activated pro-inflammatory pathways and abrogated LPS tolerance allowing for rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS-tolerance, dampening pro-inflammatory responses after repeat LPS challenge. A common theme observed across all M2 stimuli was suppression of interferon-associated pathways. We found that CF macrophages had intact reparative and transcriptional responses, suggesting that macrophage contributions to CF lung disease are primarily shaped by their environment. Finally, we leveraged in vitro-derived signatures to show that allergen provocation induces distinct M2-state transcriptional patterns in alveolar macrophages. CONCLUSION: Our findings highlight the diversity of macrophage polarization, attribute functional consequences to different "M2" stimuli, and provide a framework to phenotype macrophages in disease states. PMID- 30445064 TI - Ordinary vibratory angioedema is not generally associated with ADGRE2-mutation. AB - Mild forms of vibratory angioedema/pruritus are more common than expected. As the ADGRE2-mutation causing familiar vibratory angioedema was not seen in the population investigated, at least two subtypes must exist. PMID- 30445063 TI - Selection of house dust mite allergic patients by molecular diagnosis may enhance success of specific immunotherapy. AB - AIT performed with HDM extracts inducing IgG antibodies only to Der p 1 and 2 was beneficial for patients sensitized exclusively to these allergens but not for patients with sensitization to other HDM allergens. PMID- 30445065 TI - Remission of persistent childhood asthma: early predictors of adult outcomes. AB - BACKGROUND: Few data exist on the predictors of asthma remission by early adulthood in North America. OBJECTIVE: The predictors of adult asthma remission were determined in a multiethnic population of mild-to-moderate persistent childhood asthmatics. METHODS: Asthma remission in early adulthood was measured using two definitions, a clinical and a strict definition. Both included normal lung function and the absence of symptoms, exacerbations, and medication use. The strict definition also included normal airways responsiveness. Predictors were identified from 23 baseline measures using multivariate logistic regression. The probability of remission was modeled using decision tree analysis. RESULTS: In 879 subjects, mean baseline age was 8.8 years (SD +/- 2.1), 59.4% were males, and 68.7% were Caucasian. By adulthood, 229 (26.0%) of 879 participants were in clinical remission and 111 (15.0%) of 741 participants were in strict remission. The degree of forced expiratory volume in one second to forced vital capacity (FEV1/FVC) impairment was the largest predictor of asthma remission. Over half of boys and two-thirds of girls with baseline FEV1/FVC >= 90% were in remission at adulthood. Decreased airways responsiveness was also a predictor for both remission definitions (clinical remission OR 1.23, 95% CI 1.09-1.39; strict remission OR 1.52, 95% CI 1.26-1.84). The combination of normal FEV1/FVC, airways responsiveness, and serum eosinophil count at baseline yielded > 80% probability of remission by adulthood. CONCLUSION: A considerable minority of persistent childhood asthmatics will develop disease remission by adulthood. Clinical prognostic indicators of asthma remission, including baseline lung function, can be seen from an early age. PMID- 30445066 TI - Relationship between hedonic hunger and serum levels of insulin, leptin and BDNF in the Iranian population. AB - BACKGROUND: The prevalence of obesity has led the scientific community to investigate the cause of this multifactorial metabolic disorder. Highly palatable foods can stimulate hedonic hunger and could be a cause of obesity. In the present study, for the first time, the relationships between insulin, leptin and BDNF levels and hedonic hunger were investigated. Ninety overweight and obese women were studied. The demographic characteristics and anthropometric indices were measured and the power of food scale (PFS) questionnaire was used to assess hedonic hunger. In addition, the serum levels of fasting blood sugar (FBS), insulin, leptin and brain-derived neurotrophic factor (BDNF) were determined. Regression analysis was used to predict hedonic hunger using age, body mass index (BMI) and body fat percentage (BFP) as covariates. The levels of insulin and leptin were found to be significantly correlated with the PFS total score and the scores of PFS-FA (food available), PFS-FP (food present), and PFS-FT (food taste). The BDNF level showed a significant negative correlation only with PFS FT. Multiple regression analysis showed statistically significant associations between hedonic hunger and levels of insulin [beta coefficient: 1.29 (SE: 0.32), p < .001], leptin [beta coefficient: 0.2 (SE: 0.09), p = .023] and BDNF [beta coefficient: -6.29 (SE: 2.81), p = .028]. These three values were found to be predictors of hedonic hunger. The findings provide further evidence in favor of the role of these hormones in hedonic hunger. PMID- 30445067 TI - Caffeine improves contrast sensitivity of freely moving rats. AB - Caffeine (1, 3, 7-trimethylxanthine) is a well-known central nervous system stimulant that affects various brain functions such as attention, memory and sensation. However, it remains unclear whether and how caffeine modulates visual ability such as contrast sensitivity (CS) and the CS-spatial frequency (SF) relationship. To investigate these points, we tested the effects of caffeine on the perceptual CS of rats under three SF conditions. CS was measured using a two alternative forced choice (2AFC) grating detection task combined with a staircase method. Intraperitoneal administration of caffeine 30 min prior to the task improved CS in an SF-dependent manner, in which the improving effect was observed at 0.1 cycles/degree (cpd) of the optimal SF for rats but not at 0.5 or 1 cpd. We concluded that caffeine, a representative ingredient contained in foods or drinks consumed daily, leads to an improvement of perceptual visual sensitivity. PMID- 30445068 TI - Emotional and electrophysiological measures correlate to flavour perception in the presence of music. AB - Research into the influence of auditory cues upon food perception has increased in the past decade. Mechanisms evoked to explain crossmodal interactions between the auditory and gustatory senses include attentional, emotional, and affective mediators. In this study, the Temporal Dominance of Sensations (TDS) method was utilised to document the changes in taste and flavour of chocolate gelato while participants listened to music. After each TDS trial, the participants rated their emotions using intensity scales. Additionally, electrophysiological measures including heart rate, respiration rate, and skin conductance were obtained. As anticipated, listening to liked music evoked positive emotions (enjoyment, happiness, love, and satisfaction), while disliked music elicited negative emotions (disappointment, and disgust). No significant difference in terms of respiration parameters were observed while listening to music differing in liking. When compared to neutral and liked music, listening to disliked music exhibited the greatest change in skin conductance. Additionally, neutrally liked music significantly decreased blood volume pulse amplitude, while listening to liked music significantly increased heart rate. Partial Least Square Regression (PLSR) analysis was employed to explore associations between electrophysiological and sensory measures. Skin conductance and cardiovascular measures were both linked to the perception of gelato. Partial Least Square Path Modelling (PLS-PM) was also utilised to investigate the relationships between the electrophysiological measures, subjective ratings of emotion, and perception. The PLS-PM model showed that changes in cardiac and skin conductance measures were correlated with subjectively-rated emotions. Furthermore, these self-reported emotions evoked by music were significantly correlated with flavour. PMID- 30445069 TI - Hot water extraction and artificial simulated gastrointestinal digestion of wheat germ polysaccharide. AB - The conditions of wheat germ polysaccharide extraction were determined using the water extraction method. The gastric and intestinal digestion of wheat germ polysaccharide was analyzed in vitro. According to a single factor experiment and response surface experiment, the optimal extraction conditions of wheat germ polysaccharide were the following: liquid-solid ratio, 5:1 mL/g; extraction temperature, 69 degrees C; repetition of the extracting procedure, 3 times; extraction time, 44 min. Under such conditions, wheat germ polysaccharide yield was 8.89% +/- 0.002%. In the in vitro gastrointestinal experiment, wheat germ polysaccharide was digested and the content of reducing sugar increased during the digestion period, indicating that this increase might be due to the breakdown of glycosidic bonds in the wheat germ polysaccharide. Furthermore, no monosaccharide was detected, demonstrating that the gastrointestinal digestion did not cause free monosaccharide released. These results show some preliminary characteristics of the wheat germ polysaccharide in vitro digestion, providing a theoretical basis for further understanding wheat germ polysaccharide properties. PMID- 30445070 TI - Endogenous calcium attenuates the immunomodulatory activity of a polysaccharide from Lycium barbarum L. leaves by altering the global molecular conformation. AB - A heteropolysaccharide, LP5, was purified from Lycium barbarum L. leaves. It was identified as a calcium-rich polysaccharide (8.6 mg calcium/g) with a molecular weight of 2.50 * 105 Da. The polysaccharide was composed of six kinds of monosaccharides, of which mannose and xylose are the main components. And it contains 16.37% glucuronic acid. Studies on RAW264.7 cells demonstrated that this polysaccharide exhibited potent immunomodulatory activity, including an increase in phagocytic activity, as well as the release of both nitric oxide and cytokines. However, after the depletion of calcium, the polysaccharide exhibited greater immunomodulatory activity (p < 0.05). Further conformation analysis confirmed that the polysaccharide changed from a compact spherical conformation to a random coil structure in aqueous solution after the depletion of calcium, which resulted in increased immunomodulatory activity by LP5. PMID- 30445071 TI - Microwave-assisted extraction releases the antioxidant polysaccharides from seabuckthorn (Hippophae rhamnoides L.) berries. AB - Seabuckthorn berries are rich in various bioactive components and used as a traditional medicine for a long time. Until now, little information is available for the extraction of polysaccharides from seabuckthorn berries (PSB) by linking antioxidant activity and microwave power. In this study, microwave-assisted extraction, characterization, in vitro and in vivo antioxidant activities of PSB were explored. The maximum PSB extraction yield of 0.264+/-0.005% was obtained under the optimal conditions as follows: microwave power 600W, extraction time 6min, liquid to material ratio 10: 1mL/g, and extraction temperature 85 degrees C. Meanwhile, effects of microwave power on antioxidant activity of PSB was investigated and found that microwave at power of 600W can facilitate the release of antioxidant PSB in a high yield. The main monosaccharides of PSB were Rha, Man, Glu, and Gal at a molar ratio of 1.00: 6.89: 1.62: 13.52, UV and FT-IR analysis coupled with molecular weight determination further indicated that PSB is a polydisperse polysaccharide. Moreover, PSB obtained under the optimal conditions equally exerted in vivo antioxidant activity through decreasing malonaldehyde and protein carbonyls and increasing superoxide dismutase and glutathione. PMID- 30445072 TI - Swelling behavior and satiating effect of the gel microparticles obtained from callus cultures pectins. AB - Gel microparticles were prepared from pectins of campion (SVCgel) and duckweed (LMCgel) callus cultures, as well as from commercial apple pectin (APgel) by emulsion dehydration techniques with successive ionotropic gelation. The morphology and swelling behavior of the microparticles were determined after successive incubation in simulated gastric (SGF), intestinal (SIF), and colonic (SCF) fluids. Both SVCgel and LMCgel microparticles were found to swell in SGF and SIF gradually, and at oral administration decreased food intake by laboratory mice during the first 5 h of free-feeding. The SVCgel microparticles demonstrated the higher stability in SCF within 24 h than LMCgel ones. Only the SVCgel microparticles were shown to decrease food intake by 24% during the 21 h of free feeding and decreased body weight of mice by 4% during 24 h after oral administration. The APgel microparticles lost their shape in SIF, then fully disintegrated after 0.5 h of incubation in SCF, and failed to affect food intake or mice body weight. The data obtained indicated that sustainability and swelling of the gel microparticles from the SVC pectin in the colonic fluid may provide the stronger satiating effect compared to that of the LMCgel microparticles. PMID- 30445073 TI - Mechanistic investigation on binding interaction of konjac glucomannan with Zanthoxylum armatum DC. seed glutelin in solution. AB - Interaction between konjac glucomannan (KGM) and Zanthoxylum armatum DC. seed glutelin (ZSG) was believed to influence the conformational and physicochemical properties of ZSG and impact the texture and shelf-life of food. We investigated changes in fluorescence, ultraviolet-visible (UV-Vis) and fourier transform infrared (FTIR) spectroscopies to explore the interaction of ZSG and KGM. The Stern-Volmer quenching constant (KSV) at three temperatures was evaluated in order to determine the quenching mechanism. The results showed that KGM quenches the fluorescence intensity of ZSG through a static quenching process. Thermodynamic parameters at different temperatures demonstrated that the interaction between ZSG and KGM was mainly favored by van der Waals forces and hydrogen bonding forces, and the binding process was spontaneous and exothermic. The fluorescence spectroscopy, UV-Vis absorption spectroscopy and FTIR spectroscopy data revealed the conformational changes of ZSG upon its interaction with KGM. According to the obtained results, the ZSG-KGM complex was formed. PMID- 30445074 TI - Effects of Cyclocarya paliurus polysaccharide on lipid metabolism-related genes DNA methylation in rats. AB - The present study was conducted to evaluate the effect of CPP on the DNA methylation and expressions of lipid metabolism-related genes (leptin and MTTP) in hyperlipidemic rats. After 8 weeks intervention of CPP, the abdominal wall fat index, liver weight, the serum concentrations of TC, TG and LDL-C were significantly decreased, while HDL was increased. In addition, DNA methylation was analyzed by bisulfite sequencing method, and the mRNA expression levels of leptin and MTTP were detected by Q-PCR. The results showed that CPP could considerably decrease DNA methylation levels of leptin (regions from -694 ~ -370 bp contains 14 CpGs and -324 ~ -29 bp contains 18 CpGs) and MTTP (region from 350 ~ -1 bp contains 11 CpGs) promoters in the liver with the maximum decrease rate of 43.2%, 40.2% and 7.7%, respectively. In parallel, the mRNA contents of leptin and MTTP were dramatically down-regulated. In conclusion, the present findings demonstrated that CPP can regulate the level of mRNA by controlling DNA methylation levels in the liver, thereby reducing blood lipids. PMID- 30445075 TI - Functional annotation of operome from Methanothermobacter thermautotrophicus DeltaH: An insight to metabolic gap filling. AB - Methanothermobacter thermautotrophicus DeltaH (MTH) is a potential methanogen known to reduce CO2 with H2 for producing methane biofuel in thermophilic digesters. The genome of this organism contains ~50.5% conserved hypothetical proteins (HPs; operome) whose function is still not determined precisely. Here, we employed a combined bioinformatics approach to annotate a precise function to HPs and categorize them as enzymes, binding proteins, and transport proteins. Results of our study show that 315 (35.6%) HPs have exhibited well-defined functions contributing imperative roles in diverse cellular metabolism. Some of them are responsible for stress-response mechanisms and cell cycle, membrane transport, and regulatory processes. The genome-neighborhood analysis found five important gene clusters (dsr, ehb, kaiC, cmr, and gas) involving in the energetic metabolism and defense systems. MTH operome contains 223 enzymes with 15 metabolic subsystems, 15 cell cycle proteins, 17 transcriptional regulators and 33 binding proteins. Functional annotation of its operome is thus more fundamental to a profound understanding of the molecular and cellular machinery at systems-level. PMID- 30445076 TI - Preparation and characterization of microcrystalline cellulose from waste cotton fabrics by using phosphotungstic acid. AB - Recycling of waste cotton fabrics (WCFs) and converting them into high value added products have not been developed. In this study, a novel and green process was developed for the preparation of microcrystalline cellulose (MCC) from WCFs by the catalytic hydrolysis of phosphotungstic acid (H3PW12O40, HPW). The effects of hydrolysis conditions such as HPW concentration, reaction temperature, reaction time, and solid/liquid ratio were investigated. The optimum process conditions were determined as follows: HPW concentration of 3.47 mmol/L, a solid/liquid ratio of 1:40, reaction temperature of 140 degrees C, and reaction time of 6 h. The yield of MCC prepared was as high as 83.4% and exhibited better performance than commercial MCC such as a higher crystallinity (85.2%), smaller particle size (20.37 MUm), and narrower particle size distribution (72.75%, 8.68 31.1 MUm). Furthermore, the HPW could be extracted and recycled easily with diethyl ether for five times and used to prepare MCC with a high yield and crystallinity index. PMID- 30445077 TI - Encapsulation of graphene quantum dot-crosslinked chitosan by carboxymethylcellulose hydrogel beads as a pH-responsive bio-nanocomposite for the oral delivery agent. AB - Oral delivery most commonly used due to the non-invasive nature and the fact that avoids patient pain and discomfort in compression with the intravenous administration. Herein, the obtained graphene quantum dots (GQDs) from citric acid were employed as a cross-linker for chitosan (CS). Sodium salicylate (SS) as a model drug was loaded in the prepared graphene quantum dots-crosslinked chitosan hybrid bio-nanocomposite beads (CS-GQD). SS-loaded CS-GQD (CS-GQD/SS) was protected with pH-sensitive biopolymeric carboxymethylcellulose (CMC) hydrogel beads. The CMC encapsulated CS-GQD/SS bio-nanocomposite hydrogel beads (CS-GQD/SS@CMC) were characterized using FT-IR, PL and SEM analysis. For determination of surficial charge of the carrier, pH point of zero charges (pHpzc) was measured. In-vitro drug delivery tests were carried out in simulating the gastrointestinal tract conditions for proving the efficiency of the prepared beads as a controlled oral drug delivery. The synergistic effects of CMC and CS enhanced the stability of drug dosing for a long time with controlling the drug releases in the gastrointestinal tract conditions. The MTT test confirmed that the bio-nanocomposite beads have low toxicity against human colon adenocarcinoma HT29 cells. The obtained results showed that the prepared novel CS-GQD/SS@CMC could potentially be used as a safe carrier for oral drug delivery. PMID- 30445078 TI - Alginate/PAMAM dendrimer - Halloysite beads for removal of cationic and anionic dyes. AB - The alginate beads have been widely used for dye removal. However, most of the systems described in literature refer to one type of dyes and the adsorbents of cationic ones are dominant. In this study, the composite alginate beads were prepared and characterized. The system was obtained by encapsulation of polyamidoamine - functionalized halloysite nanotubes in alginate (Alg/Hal_PAMAM beads). The adsorptive properties of the beads towards model dyes - cationic methyl green (MG) and anionic sunset yellow FCF (SY) - were investigated with reference to pH, adsorbent dose, time, dye concentration and temperature. The adsorption capacities were improved compared to pure alginate beads. The kinetic data were best correlated to the pseudo-second-order model. The intraparticle diffusion model showed two (MG) or one (SY) adsorptive steps of mass transport. The Freundlich isotherm model was suitable for describing the adsorption process thus the composite beads were characterized by heterogeneous sites. The thermodynamic parameters indicated the spontaneous and endothermic nature of the adsorption process. It was also found that the process was favorable. Additionally, the beads could be reused with satisfactory removal efficiency in several cycles. Therefore, Alg/Hal_PAMAM beads could be considered as promising material for simultaneous removal of cationic and anionic dyes. PMID- 30445079 TI - The effect of the stoichiometric ratio of zinc towards the fibrillation of Bovine Serum Albumin (BSA): A mechanistic insight. AB - Fibrillation of proteins is a major cause of various neurodegenerative diseases and its exact mechanism of formation is yet unclear instead of extensive research. However, the role of metal ions influencing fibrillation of proteins is gaining more attention recently. Herein, we have investigated the role of various concentrations of the transition metal, Zn(II), on the fibrillation of Bovine Serum Albumin (BSA) at the physiological pH 7.4. Several biophysical and simulation techniques were employed in order to analyze the same. Thioflavin T intensity and residual protein investigations revealed that fibrillation of BSA was significantly decelerated and accelerated at 1:3 and 1:4 ratios of BSA Zn(II), respectively; while it was found to be independent at other ratios (1:1 and 1:2). Fourier transform infrared spectroscopy analysis revealed that the transition of BSA from alpha-helical conformation to the beta-sheet rich structure is greatly resisted at 1:3 ratio, however, the same is promoted at 1:4 ratio. Similarly, dynamic light scattering and field emission transmission electron microscopy analyses further confirmed the above observations. Furthermore, Isothermal Titration Calorimetry revealed the interaction of Zn(II) towards four binding sites of BSA with preferential affinities. Molecular dynamics studies predicted that at 1:3 ratio, the C- and N-terminal zones of BSA were least flexible owing to more stable conformation. Moreover, the solvent accessible surface area and structural analyses showed increase in hydrophilicity and more conserved secondary structure, respectively at 1:3 ratio. We propose that BSA fibrillation is indeed dependent on particular Zn(II) concentration, the temperature of the microenvironment of BSA, the number of binding sites exposed due to unfolding and the conformation after metal binding. PMID- 30445080 TI - Glycation of hemoglobin leads to the immunogenicity as a result of neo-epitope generation. AB - Non-enzymatic glycation occurs rapidly which ultimately leads to the formation of advanced glycation endproducts (AGEs). These AGEs have shown to associated with the development of many diseases such as diabetes-mellitus. This study is focused on immunological characterization of glycated-Hb induced by d-ribose. Here, we analysed the immunogenicity of glycated-Hb by direct binding and competitive inhibition ELISA. Direct binding ELISA confirmed that glycated-Hb was highly immunogenic and induced high titre antibodies as compared to native-Hb. The antigen binding specificity and cross reactivity of these antibodies were also screened by competitive inhibition ELISA. The IgG from rabbit sera showed enhanced binding of glycated-Hb than native-Hb. Thus, it is possible that alterations in Hb induced by d-ribose could have generated highly immunogenic neoepitopes. Moreover, induced antibodies were also found to cross-react with other modified/native proteins. On the basis of the results of this study, we presume that this type of structural perturbations in Hb in vivo by d-ribose might take place in untreated diabetic condition that could induce such type of immunogenic auto-antibodies. Furthermore, increased level of these auto antibodies could serve as a biomarker in diabetes and its progression. PMID- 30445081 TI - Extraction, characterization and antioxidant activity analysis of the polysaccharide from the solid-state fermentation substrate of Inonotus hispidus. AB - A polysaccharide from Inonotus hispidus was prepared by solid-state fermentation (SSF), and an efficient ultrasound-assisted extraction method was used to optimize the extraction process of Inonotus hispidus solid-state fermentation polysaccharide (IHSFP). The optimal extraction parameters were as follows: solid liquid ratio of 1:40, ultrasound time of 34 min, ultrasound power of 350 W and ultrasound temperature of 70 degrees C. The yield of IHSFP was 51.06 +/- 0.34% under the optimal conditions. Two types of polysaccharide fractions (IHSFP-1 and IHSFP-2) were isolated by DEAE-52 and Sephadex G-200 columns. IHSFP-2 had stronger antioxidant activity than IHSFP-1, and it can reduce H2O2-induced oxidative damage to cells in vitro. Therefore, the properties of IHSFP-2 were further characterized. The results showed that the molecular weight of IHSFP-2 was 14.44 kDa, it was composed of glucose (Glc), mannose (Man), galactose (Gal), glucuronic acid (GlcUA), galactosamine (GalN), arabinose (Ara) and ribose (Rib), and the contents of these monosaccharides were 51%, 21%, 20%, 3%, 2%, 2% and 1%, respectively. The results of this study may contribute to the efficient production of the polysaccharide of Inonotus hispidus, and provide new ideas for its application in functional foods and cosmetics. PMID- 30445082 TI - Bio-barcode technology for detection of Staphylococcus aureus protein A based on gold and iron nanoparticles. AB - S. aureus is one of important causes of disease, food poisoning in humans and animals. The generally methods for detection of S. aureus is time consuming. Therefore, a new method is necessary for rapid, sensitive and specific diagnosis of S. aureus. In the present study, two probes and a Bio-barcode DNA were designed for detection of S. aureus (Protein A). Firstly, magnetic nanoparticle (MNPs) and gold nanoparticle (AuNPs) were synthesized at 80 degrees C and 100 degrees C, respectively. The AuNPs and the MNPs were functionalized with probe1, Bio-barcode DNA and probe2, respectively. Target DNA was added into the nanomaterial's system containing bio-barcode DNA-AuNPs-probe1 and probe2-MNPs to formed bio-barcode DNA-AuNPs-probe1-target DNA-probe2-MNPs complex. The bio barcode DNA-AuNPs-probe1-target DNA-probe2-MNPs complex was separated with magnetic field. Finally, the bio-barcode DNA was released from surface of complex using DTT (0.8 M) and there was isolated of nanoparticles by magnetic field and centrifuge. The fluorescence intensity of bio-barcode DNA was measured in different concentrations of S. aureus (101 to 108 CFU mL-1) by fluorescence spectrophotometry. The results showed that standard curve was linearly from 102 to 107 CFU mL-1. Limit of detection of bio-barcode assay for both PBS and real samples was 86 CFU mL-1. PMID- 30445083 TI - The polysaccharide from Inonotus obliquus protects mice from Toxoplasma gondii induced liver injury. AB - The study aimed to explore the protective effects and mechanism of Inonotus obliquus polysaccharide (IOP) on liver injury caused by Toxoplasma gondii (T. gondii) infection in mice. The results showed that treatment with IOP significantly decreased the liver coefficient, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and nitric oxide (NO), and increased the contents of antioxidant enzyme superoxide dismutase (SOD) and glutathione (GSH). IOP effectively decreased the expression of serum tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL 6), interleukin-1beta (IL-1beta), interferon-gamma (IFN-gamma) and interluekin-4 (IL-4) in T. gondii-infected mice. In agreement with these observations, IOP also alleviated hepatic pathological damages caused by T. gondii. Furthermore, we found that IOP down-regulated the levels of toll-like receptor 2 (TLR2) and toll like receptor 4 (TLR4), phosphorylations of nuclear factor-kappaappaB (NF-kappaB) p65 and inhibitor kappaBalpha (IkappaBalpha), whereas up-regulated the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). These findings suggest that IOP possesses hepatoprotective effects against T. gondii-induced liver injury in mice, and such protection is at least in part due to its anti-inflammatory effects through inhibiting the TLRs/NF kappaB signaling axis and the activation of an antioxidant response by inducing the Nrf2/HO-1 signaling. PMID- 30445084 TI - Isolation, structural characterization, and immunostimulatory activity of a new water-soluble polysaccharide and its sulfated derivative from Citrus medica L. var. sarcodactylis. AB - The homogeneous heteropolysaccharide CMSPW90-1 was first purified from bergamot by DEAE Sepharose Fast Flow and Sephadex G-75 column with a molecular weight of 18.8kDa. The structure of CMSPW90-1 was elucidated with high-performance gel permeation chromatography, gas chromatography-mass spectrometry, infrared spectrum, methylation, nuclear magnetic resonance (NMR), Congo red test, and circular dichroism. In comparison with CMSPW90-1, the sulfated derivative CMSPW90 M1 showed significant ultra-structural differences with a molecular weight of 75.4kDa. The antioxidant and immunomodulatory activities of CMSPW90-M1 were examined to determine the relationships of structure-bioactivity. CMSPW90-M1 exhibited stronger scavenging activities for DPPH and ABTS+ than those of CMSPW90 1. CMSPW90-M1 exhibited more immunomodulatory activity in vitro by promoting the proliferation of mouse splenocytes and the neutral red phagocytosis of RAW264.7 cells. The results demonstrated that CMSPW90-M1 could be developed as one of the potential free radical inhibitors and immunomodulators. PMID- 30445085 TI - Anti-hyperuricemic and anti-gouty arthritis activities of polysaccharide purified from Lonicera japonica in model rats. AB - In this present study, we investigated the anti-hyperuricemic and anti-gouty arthritis effect of a puried water-soluble polysaccharide (LJP-1) obtained from Lonicera japonica. A series of characterization of the purified polysaccharide were carried out in this paper. Monosaccharide analysis showed that LJP-1 composed of glucuronic acid, glucose, galactose, arabinose, and xylose at the ratio of 2.43:1:2.09:1.95:1.96, respectively. The estimated molecular weight of LJP-1 was 17.5 kDa. LJP-1 belonged to pyranose and possessed alpha- and beta glycosidic configurations. Congo red test showed that LJP-1 had a spatial triple helix structure. In pharmacodynamic experiments, the anti-hyperuricemic activity of LJP-1 was studied using hyperuricemic SD rat model induced via potassium oxonate and hypoxanthine. The result showed that LJP-1 could obviously decrease the serum uric acid level and suppress xanthine oxidase (XOD) activity. Moreover, in the gouty arthritis model established by sodium urate crystals, the degree of swelling of the ankle joint, IL-1beta, IL-6, TNF-alpha and COX-2-related inflammatory factors levels in murine serum all declined. Taken together, these results demonstrated that LJP-1 has anti-gouty arthritis effect. Therefore, LJP-1 could serve as a promising candidate for developing novel natural anti-gouty agent. PMID- 30445086 TI - Characterization and properties of biodegradable thermoplastic grafted starch films by different contents of methacrylic acid. AB - Due to poor mechanical and thermal properties of native starch (NS) film; in the present work; NS was modified by graft copolymerization. Thermoplastic starch (TPS) grafted by methacrylic acid (MAA) with different percentage of grafting, i.e., 0%, 18.3%, 36.3%, 52.1% and 89.7% were prepared and tested. The result demonstrated that the intensity of IR peak of acrylic group increased with the increasing percentage of grafting. The higher graft copolymerization with MAA also significantly reduced degree of crystallinity. The strain at maximum load of TPS film grafted by MAA increased with the increasing percentage of grafting. However, water uptake of TPS film grafted by MAA reduced with high percentage of grafting (52.1% and 89.7%). In addition, different TPS films grafted by MAA were also examined for morphology, water vapor permeability, thermal property and biodegradable property by soil buried test. PMID- 30445087 TI - Rheological characterization of cold water soluble rice (Oryza sativa) starch lactates and citrates prepared via alcoholic-alkaline method. AB - The present study prepared citrates and lactates from rice starch which were then given alcoholic-alkaline treatment to produce cold water soluble (CWS) starches. These chemically modified starches were then compared in terms of rheological parameters to their hot water soluble starches (without alcoholic-alkaline treatment). FTIR spectra showed characteristic peak between 1710-1727 cm-1 which confirmed esterification of starch via citrate and lactate groups. All samples demonstrated viscoelastic character i.e. storage moduli (G') exceeded loss moduli (G"). Both CWS and HWS starch citrates prepared by addition of 40 g citric acid to 100 g of starch exhibited highest G' and G" suggesting highly structured and strong gels. Dynamic frequency and temperature sweep clearly showed that alcoholic alkaline treatment disrupted the granular conformity due to gelatinization of starch and as a result CWS starches were more susceptible to break down. Steady shear flow test confirmed that all samples were non-Newtonian while results of In-shear structural recovery measurements indicated anti thixotropic behavior of CWS starch lactates. PMID- 30445088 TI - Studies on the effects of microencapsulated human mesenchymal stem cells in RGD modified alginate on cardiomyocytes under oxidative stress conditions using in vitro biomimetic co-culture system. AB - Stem cell therapy has been recognized as a promising approach for myocardium regeneration post myocardial infarction (MI); however, it unfortunately often remains a challenge because of poor survival of transplanted cells and a lack of clear understanding of their interactions with host cells. High oxidative stress at heart tissues post MI is considered one of the important factors damaging transplanted cells and native cells/tissues. Here, we employed an in vitro co culture system, capable of mimicking cases of stem cell transplantation into the myocardium presenting high oxidative stress, using human mesenchymal stem cells (hMSCs) encapsulated in alginate or cell interactive Arg-Gly-Asp (RGD) peptide modified alginate micro-hydrogels. Under H2O2-induced oxidative stress conditions, viabilities of hMSCs and CMs were significantly higher in their co culture than in their individual monolayer cultures. Expression of cardiac muscle markers remained high even with H2O2 treatment when cardiomyocytes (CMs) were co cultured with hMSCs in RGD-alginate. Higher levels of various growth factors (associated with angiogenesis, cardiac regeneration, and contractility) were found in co-culture (noticeably with RGD-alginate) compared to monolayer cultures of CMs or hMSCs. These results can benefit the study of in vivo MI progression with transplanted stem cells and the development of effective stem cell-based therapeutic strategies for various oxidative stress-related diseases. PMID- 30445089 TI - Polyhydroxyalkanoates as biomaterial for electrospun scaffolds. AB - Polyhydroxyalkanoates (PHA) are natural polyesters produced by microorganisms under carbon source excess and limiting nutrient conditions. However, these biopolymers possess low mechanical and thermal properties, decreasing their potential applications in the medical field. Electrospinning is a technique that forms fibers from different polymers. PHA electrospun fibers improve the mechanical properties and decrease the crystallinity of PHA, including poly-3 hydroxybutyrate and its copolymers, which is attributed to the metastable structure (beta-form) formation. Therefore, the mechanical properties of fibers are intrinsically related to their plane orientation. Aligned fibers present better mechanical properties than randomly oriented fibers. However, randomly oriented fibers promote cell-fiber interaction and cell infiltration. Fibers produced with PHA blended with other polymers have shown improved mechanical and biological properties. Gelatin, zein and cellulose acetate are the main natural polymers that have been blended with PHA for electrospun scaffolds. For scaffold production by coaxial electrospinning, gelatin has been used as a shell and PHA as the core. PHA have been combined with different synthetic polymers and plasticizers resulting in an increase in the PHA miscibility. Therefore, the use of electrospinning in the development of PHA-based scaffolds seems to be an attractive method to change the intrinsic polymer features, increasing and enhancing PHA applications in tissue engineering. PMID- 30445090 TI - Multiple fingerprint profiles and chemometrics analysis of polysaccharides from Sarcandra glabra. AB - Multiple techniques including high performance size-exclusion chromatography (HPSEC), Fourier-transform infrared spectroscopy (FT-IR) and pre-column derivatization high-performance liquid chromatography (PCD-HPLC) were applied to the fingerprint analysis of the polysaccharides from Sarcandra glabra (SGPs) in different regions. Chemometrics was used to evaluate the similarity and differences of SGPs from different regions based on their fingerprints. The results of the present study showed that polysaccharides from 18 batches of Sarcandra glabra had a high degree of similarity based on the HPSEC, PCD-HPLC, and FT-IR fingerprints. The samples from different regions could be classified by clustering analysis based on their nuances. The five monosaccharides (Gal, Rha, Xyl, GlcA, and Glc) and the wavelengths of FT-IR (3371 cm-1 and 1411 cm-1) could be selected as herb markers for the quality control of Sarcandra glabra. PMID- 30445091 TI - Metal ions driven production, characterization and bioactivity of extracellular melanin from Streptomyces sp. ZL-24. AB - A melanin-producing strain was identified as Streptomyces sp. ZL-24 by phylogenetic analysis of 16S rRNA gene sequences. Based on single factor experiment, NiCl2, FeSO4 and soy peptone were selected as significant variables of melanin production. Subsequent biochemical and RT-qPCR analyses revealed that melanin production was markedly driven by moderate levels of ferrous and nickel ions. The central composite design indicated that the optimal medium was composed of 3.05 mM NiCl2, 1.33 g/L FeSO4 and 20.31 g/L soy peptone. The maximum production of the insoluble melanin (189.90 mg/L) was obtained using 3% (v/v) inoculation size in the medium of pH 7.0 at 30 degrees C for 5 days. Under this optimal condition, an indigenous plate culture system was standardized and used to produce soluble melanin. The resulting pure melanin pigment was up to 4.24 g/L, which set a new record of soluble melanin production. Bioactivity assay in vitro showed that both melanin pigments had strong antimicrobial, anti-biofilm and antioxidant activity. To our best knowledge, the results provide novel data on soluble melanin production, and identify an excellent candidate for anti biofilm application. PMID- 30445092 TI - Apios americana Medik flowers polysaccharide (AFP-2) attenuates H2O2 induced neurotoxicity in PC12 cells. AB - Oxidative stress is a critical cause for the progression of neurodegenerative diseases, indicating that screening natural antioxidant and pharmacological targeting of mechanism need more attention. Natural plant polysaccharides are the primary group of natural antioxidants showing mighty antioxidant activity. Therefore, a polysaccharide (AFP-2) from flowers of Apios americana Medik was isolated, purified and characterized. Then, a H2O2-induced PC12 cells oxidative stress model was established to investigate the neuroprotective role of AFP-2 and to clarify the potential mechanism of action against H2O2-induced neurotoxicity. It was found that AFP-2 reduced ROS production and mitochondrial damage caused by hydrogen peroxide in PC12 cells. In addition, data from transmission electron microscope and western blot displayed that AFP-2 significantly activated autophagy in PC12 cells via Akt-mTOR pathway. These results together qualify AFP 2 as an interesting natural polysaccharide worth further investigation as a neuroprotective agent. PMID- 30445093 TI - Interactions of oligochitosan with blood components. AB - Oligochitosan (OCHI) is known to have some specific biological activities. However, its interactions with blood components and related correlation with molecular structures remains to be clarified due to its growing use in biomedical areas. Herein, a series of OCHI were prepared by hydrogen peroxide induced degradation combined fractionation in ethanol solutions and their molecular structures were characterized by GPC, FTIR, 1H and 13C NMR, and then the interactions of the prepared OCHI with blood components, including red blood cells (hemolysis, deformability, and aggregation), coagulation system, complement (C3a, and C5a activation), and platelet (activation, and aggregation), were investigated. For red blood cells, OCHI has a quite low risk of hemolysis in a dose- and MW-dependent manner and the deformability and aggregation were observed in its high MW fraction. The coagulation tests revealed that OCHI is capable of a mild anticoagulation through blocking the intrinsic pathway and the anticoagulation corresponding MW was identified. In terms of complement, OCHI could inhibit C3a in a dose-dependent manner and activate C5a with its high MW fraction. In addition, there is no significant effect of OCHI on platelet activation and aggregation. Based on above results, the interactions related mechanism was discussed and proposed. PMID- 30445094 TI - Attenuation of oxidative stress induced mitochondrial dysfunction and cytotoxicity in fibroblast cells by sulfated polysaccharide from Padina gymnospora. AB - In this present study, isolation, characterization and protective effect of sulfated polysaccharide (SP) isolated from the brown algae Padina gymnospora was investigated. SP was isolated and characterized through FT-IR, 1H NMR, TGA, GC-MS and CHN analysis. The molecular weight of SP was found to be 16 kDa. The isolated SP contains 29.4 +/- 0.35% of sulfate, 27 +/- 0.11% of fucose, 0.05 +/- 0.12% of protein, respectively. Furthermore, SP exhibits its excellent radical scavenging effects were evaluated by DPPH, ABTS radical scavenging and reducing power assays. Moreover, pretreatment with SP significantly mitigates H2O2 induced cytotoxicity in L-929 cells in a dose dependent manner. Furthermore, SP pretreatment ameliorates oxidative stress induced apoptosis and DNA damage, alleviates the generation of intracellular reactive oxygen species (ROS) and restores mitochondrial membrane potential (MMP) in L-929 cells through its antioxidant potential. Together, these results suggest that SP can be exploited as a natural antioxidant in the food and pharmaceutical industries. PMID- 30445095 TI - Hyaluronic acid conjugated multi-walled carbon nanotubes for colon cancer targeting. AB - Purpose of the present research was to evaluate in vitro and in vivo potential of gemcitabine (GEM) loaded hyaluronic acid (HA) conjugated PEGylated multi-walled carbon nanotubes (GEM/HA-PEG-MWCNTs) for effective colon cancer targeting. HA was conjugated onto the surface of aminated or PEGylated MWCNTs which were evaluated for size, surface morphology, entrapment efficiency (~90%), in vitro drug release, in vitro cytotoxicity and in vivo performance in Sprague Dawley rats. In vitro release showed that the release rate of GEM in acidic conditions (pH 5.3) was faster than physiological conditions (PBS, pH 7.4) followed by a sustained release pattern. The developed GEM/HA-PEG-MWCNTs indicated significantly less hemolytic toxicity (7.73 +/- 0.4%) paralleled to free GEM (18.71 +/- 0.44%) and showed higher cytotoxicity against HT-29 colon cancer cell line. The antitumor study assured that GEM/HA-PEG-MWCNTs significantly reduced tumor volume as compared to free GEM and increased survival rate without noticeable loss in body weight. In vivo studies showed an improvement in pharmacokinetics in terms of remarkable escalation in mean residence time, half-life, AUC, AUMC, median survival time in tumor bearing rats treated with GEM/HA-MWCNTs and GEM/HA-PEG MWCNTs as compared to free GEM (p ? 0.001). These outcomes proved engineered MWCNTs as a safe and effective nanomedicine in colon cancer targeting. PMID- 30445096 TI - Drug supersaturation during formulation digestion, including real-time analytical approaches. AB - Self-emulsifying and other lipid-based drug delivery systems have drawn considerable interest from pharmaceutical scientists for managing oral delivery of poorly water-soluble compounds. Following administration, self-emulsifying systems exhibit complex aqueous dispersion and digestion in the gastro-intestinal tract. These processes generally result in drug supersaturation, which leads to enhanced absorption or the high drug concentrations may cause precipitation with erratic and variable oral bioavailability. This review briefly outlines drug supersaturation obtained from self-emulsifying and other lipid-based formulations; recent advancements of in vitro lipolysis testing are also discussed. Further, a main focus is mechanisms by which supersaturation is triggered from gastro-intestinal processes, as well as analytical techniques that are promising from a research and development perspective. Comparatively simple approaches are presented together with more sophisticated process analytics to enable direct examination of kinetic changes. The analytical methods together with their sensor probes are discussed in detail to clarify opportunities as well as technical limitations. Some of the more sophisticated methods, including those based on synchrotron radiation, are primarily research oriented despite interesting experimental findings from an industrial viewpoint. The availability of kinetic data further opens the door to mathematical modeling of supersaturation and precipitation versus permeation, which lays the groundwork for better in vitro to in vivo correlations as well as for physiologically-based modeling of lipid-based systems. PMID- 30445097 TI - An engineered Staphylococcal Protein A based ligand: Production, characterization and potential application for the capture of Immunoglobulin and Fc-fusion proteins. AB - In antibody purification processes, affinity chromatography has been used with Staphylococcus aureus protein A (SpA) as the main ligand. In this work, we present a novel Staphylococcal Protein A (AviPure thereafter), a synthetic ligand analogue based on native SpA B domain, with a molecular weight of approximately 14 kDa. The binding affinity of mAbs to AviPure was evaluated using Surface Plasmon Resonance (SPR) and affinity chromatography methods. The equilibrium dissociation constant (KD) between the AviPure and mAbs was systematically measured using 1:1 (Langmuir) model and found to be 4.7 * 10-8 M, with constant of dissociation at kd <= 1.0 * 10-3 s-1 and ka being 3.1 * 104 M-1 s-1. When immobilized on Sepharose, the AviPure ligand density was 429 nmol/g moist weight resin and was able to effectively bind immunoglobulin and Fc fragment samples with higher affinity and the most effective flow rate when using ligand - Sepharose beads was at 75 cm/h giving the dynamic binding capacity of 53 mg/mL and 91% recovery of IgG. Suitable ligands used in affinity purification should have a KD <= 10-6 M and a dissociation rate (ka) averaging 10-3 M-1 s-1 with the kd ranging between 103 - 108 M-1. Therefore, the AviPure ligand can be used as an alternative to the standard protein A ligand in the purification of mAbs and Fc fused proteins. PMID- 30445098 TI - HLA in Uros from Peru Titikaka Lake: Tiwanaku, Easter and Pacific Islanders. AB - Uros people live in floating reed islands in Titikaka Lake in front of Puno town (Peru). They could have started Tiwanaku culture and shared genes and culture with Pacific Islanders; it is particularly relevant the giant hat covered men statues found in both Tiwanaku at Titikaka Lake shore and Easter Island (3700 km far from Chile in Pacific Ocean). These giants monoliths are very similar one another and unique in America and Pacific Islands. The following HLA alleles are shared in a specifically high frequency between Uros and Pacific Islanders : HLA A*24:02, HLA-B*35:05, HLA-B*48:01, HLA-DRB1*04:03, HLA-DRB1*08:02 and HLA DRB1*09:01. Uros also have 3 unique HLA haplotypes: A*24:02-B*15:04 - DRB1*14:02 DQB1*03:01, A*68:01:02-B*35:05-DRB1*04:03-DQB1*03:02, A*24:02-B*48:01-DRB1*04:03 DQB1*03:02. Also Uros seem to be one of the most ancient population in Titikaka Lake that could have started Tiwanaku culture. Prehistoric contacts between Amerindians and Pacific Islanders are strongly suggested by genetic and cultural traits. It is not discarded that Uros could have come from Pacific Islands: Uros show melanic skin and are dolichocephalic; in contrast, surrounding Aymara people have a clear skin and are brachicephalic. The Kon-Tiki project led by Thor Heyerdahl showed that a simple sailing is possible between Peru and Polynesia Islands; also, the most ancient skull found in America is of black origin: Luzia, suggesting that first America peopling was also carried out by Black/coloured people. PMID- 30445099 TI - Association of Pro-Inflammatory Cytokines and Monocyte Subtypes in Older and Younger Patients on Clinical Outcomes after Mechanical Circulatory Support Device Implantation. AB - Noninvasive immunologic analysis of peripheral blood holds promise for explaining the mechanism of development of adverse clinical outcomes, and may also become a method for patient risk stratification before or after mechanical circulatory support device (MCSD) implantation. Dysregulation of the innate immune system is associated with increased patient age but has yet to be evaluated in the older patient with advanced heart failure undergoing MCSD surgery. Patients pre- and post-MCSD implantation had peripheral blood mononuclear cells (PBMC) and serum isolated. Multiparameter flow cytometry was used to analyze markers of innate cell function, including monocyte subtypes. Multiplex cytokine analysis was performed. MELD-XI and SOFA scores were utilized as surrogate markers of outcomes. Increased levels of pro-inflammatory cytokines including IL-15, TNF alpha, and IL-10 were associated with increased MELD-XI and SOFA scores. IL-8, TNF- alpha, and IL-10 were associated with risk of death after MCSD implantation, even with correction for patient age. Increased frequency of 'classical' monocytes (CD14+CD16-) were associated with increased MELD-XI and SOFA scores. This suggests that inflammation and innate immune system activation contribute to progression to multiorgan system failure and death after MCSD surgery. Development of noninvasive monitoring of peripheral blood holds promise for biomarker development for candidate selection and patient risk stratification. PMID- 30445100 TI - Ultrasonic vocalizations as a tool in studying emotional states in rodent models of social behavior and brain disease. AB - Rodents emit ultrasonic vocalizations (USVs) to communicate the presence of positive or negative emotional states and to coordinate social interactions. On this basis, USVs are increasingly being used as a behavioral readout in rodent studies of affect, motivation and social behavior. Notably, several investigations have demonstrated that rodents emit USVs when tested in experimental paradigms that are used in preclinical studies of psychiatric and neurological diseases. Moreover, it has been shown that calling behavior may be influenced by genetic and/or environmental factors (i.e., stress), early rearing conditions that have been implicated in brain disease, as well as psychoactive drugs. Hence, measuring USV emissions has emerged as a useful tool in studying the mechanisms that underlie the emotional disturbances featuring certain brain diseases, as well as in the development of suited pharmacological therapies. This review provides an overview of the behavioral significance of USV emissions and describes the contexts that promote calling behavior in rats and mice. Moreover, the review summarizes the current evidence concerning the use of USVs as a marker of affect in rat and mouse models of sociability, psychiatric diseases and neurological diseases, and discusses the strengths and current limitations of using USVs as a behavioral readout in rodent studies of emotional behavior. PMID- 30445101 TI - Crosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) in the brain: Focus on heteroreceptor complexes and related functional neurotrophic effects. AB - Neuronal events are regulated by the integration of several complex signaling networks in which G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) are considered key players of an intense bidirectional cross communication in the cell, generating signaling mechanisms that, at the same time, connect and diversify the traditional signal transduction pathways activated by the single receptor. For this receptor-receptor crosstalk, the two classes of receptors form heteroreceptor complexes resulting in RTKs transactivation and in growth-promoting signals. In this review, we describe heteroreceptor complexes between GPCR and RTKs in the central nervous system (CNS) and their functional effects in controlling a variety of neuronal effects, ranging from development, proliferation, differentiation and migration, to survival, repair, synaptic transmission and plasticity. In this interaction, RTKs can also recruit components of the G protein signaling cascade, creating a bidirectional intricate interplay that provides complex control over multiple cellular events. These heteroreceptor complexes, by the integration of different signals, have recently attracted a growing interest as novel molecular target for depressive disorders. PMID- 30445102 TI - Sofosbuvir/velpatasvir for patients with chronic genotype 3 HCV infection with compensated cirrhosis: Response to EASL Recommendations on Treatment of Hepatitis C 2018. PMID- 30445103 TI - Is malnutrition associated with orthopaedic infections? A single-centre pilot evaluation. PMID- 30445104 TI - Chemical composition and evaluation of the anti-inflammatory and antinociceptive activities of Duguetia furfuracea essential oil: Effect on edema, leukocyte recruitment, tumor necrosis factor alpha production, iNOS expression, and adenosinergic and opioidergic systems. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Duguetia furfuracea (A. St. -Hil.) Saff. (Annonaceae) is commonly known in Brazil as "araticum-seco," and its root is used in folk medicine to treat inflammatory and painful disorders. However, no studies have been performed to evaluate these therapeutic activities. AIM OF THE STUDY: Investigate the chemical composition, anti-inflammatory and antinociceptive effects, and elucidate the possible antinociceptive mechanisms of action from the essential oil of D. furfuracea (EODf) underground stem bark. MATERIALS AND METHODS: Chemical composition was determined by gas chromatography and mass spectrometry (GC/MS). The paw edema induced by LPS, formalin-induced nociception, LPS-induced thermal hyperalgesia and rota-rod tests in vivo were used to evaluate the anti-inflammatory and antinociceptive effects in addition to the alteration on motor coordination. Histological analyses and an immunohistochemistry assay for iNOS were performed on mouse footpads of naive, control, 10mg/kg EODf, and 10mg/kg indomethacin (Ind) groups. The samples were removed at 1, 3, and 6h after subplantar injection of LPS. In addition, the involvement of the adenosinergic, opioidergic, serotonergic, and cholinergic systems were investigated, in order to elucidate possible antinociceptive mechanisms. RESULTS: Twenty-four volatile constituents were detected and identified. (E)-asarone (21.9%), bicyclogermacrene (16.7%), 2,4,5-trimethoxystyrene (16.1%), alpha-gurjunene (15%), cyperene (7.8%), and (E)-caryophyllene (4.6%) were major compounds found in EODf. Oral treatment (p.o.) with EODf (1, 3, and 10mg/kg) significantly inhibited the paw edema induced by LPS. At 10mg/kg EODf promoted inhibition of tumor necrosis factor alpha (TNF-alpha) production, recruitment of polymorphonuclear (PMN) leukocytes and inducible nitric oxide synthase (iNOS) expression in paw tissue. EODf (10 and 30mg/kg, p.o.) also reduced licking time in both phases of the formalin test and it had a significant effect on the LPS-induced thermal hyperalgesia model. The administration of caffeine (Caf) and naloxone (Nal) reversed the antinociceptive activity of EODf, in the first phase of the formalin test and in the LPS-induced thermal hyperalgesia model. Moreover, Nal was also able to abolish the antinociception caused by EODf, in the second phase of formalin test. In the rota rod test, EODf-treated animals did not show any alteration of motor coordination. CONCLUSIONS: Our findings indicate that EODf underground stem bark produces anti inflammatory and both central and peripheral antinociceptive effects. Furthermore, the antinociceptive activity of EODf underground stem bark is possibly mediated by adenosinergic and opioidergic pathways, and its properties do not induce effects on motor coordination. These results support the use of the folk medicine, D. furfuracea root, to treat inflammation and painful conditions. PMID- 30445105 TI - Chemical composition, antioxidant and gastrointestinal properties of Sedum dendroideum Moc & Sesse ex DC leaves tea infusion. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sedum dendroideum Moc & Sesse ex DC (Crassulaceae) is a medicinal plant employed in Mexican and Brasilian folk medicine as juice or infusion, as remedy for the treatment of different diseases, including gastric disorders. AIM OF THE STUDY: Although some studies carried out with Sedum dendroideum have demonstrated its gastroprotective effect, the purpose of this study was to elucidate the chemical constituents, antioxidant, cytotoxic and mechanisms underlying the gastrointestinal properties of Sedum dendroideum accordingly its traditional use, as fresh leaves tea infusion (SDI). MATERIALS AND METHODS: Chemical constituents were analyzed using high performance liquid chromatography and mass spectrometry (HPLC-MS). Antioxidant and cytotoxicity were evaluated in in vitro assays. The efficacy of the SDI on macroscopic ulcer appearance, mucus and GSH maintenance on ethanol- and indomethacin-induced ulcer models, gastric acid secretion and gastrointestinal motility were investigated. RESULTS: Phytochemical analysis by HPLC-MS revealed the presence of different flavonol glycosides, containing myricetin and quercetin, along with the kaempferol as aglycones. In vitro pharmacological investigation of SDI demonstrated potent antioxidant activity in DPPH assay (IC50: 13.25 +/- 3.37 ug/mL) and absence of cytotoxicity in Caco-2 cells by MTT method. Oral administration of SDI (ED50 of 191.00 +/- 0.08 mg/kg) in rats promoted gastroprotection against ethanol or indomethacin in rats through reinforcement of gastric wall mucus, GSH content and nitric oxide release, without present antisecretory properties. The gastroprotective effect was maintained when SDI (19 mg/kg) was administrated by intraperitoneal route. Furthermore, SDI (150 mg/kg) unchanged the gastric emptying but increase small bowel transit in mice through cholinergic pathways. CONCLUSIONS: Collectively, this study confirmed that Sedum dendroideum promotes gastroprotection through preventing of endogenous defense mechanisms, represented by mucus and GSH without changes gastric acid secretion. Sedum dendroideum tea infusion features a chemical profile that contributes to the antioxidant and gastric health-promoting effects, supporting the use in folk medicine for the treatment of gastrointestinal disorders. PMID- 30445107 TI - Quantitative proteomics reveal antidepressant potential protein targets of xiaochaihutang in corticosterone induced model of depression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xiaochaihutang (XCHT), one of famous Chinese herbal prescription for treating Shaoyang symptom, has been used successfully in depressive disorders for many years. Our laboratory has demonstrated that XCHT remarkably alleviated various depressive behaviors induced by several depressive animal models, but previous studies only focused on one or several protein targets, lacked dynamic change and interrelation of proteins. Therefore, potential protein targets and mechanisms are required further systematic investigation. AIM OF THE STUDY: To discover and assess the differentially expressed proteins (DEPs) of hippocampus after oral administration of XCHT in corticosterone (CORT) induced model of depression by using isobaric tags for relative and absolute quantification (iTRAQ) analysis. MATERIALS AND METHODS: The antidepressant effects of XCHT were assessed by two behavioral despair models (forced swimming test and tail suspension test) in CORT induced model of depression. The DEPs of hippocampus after XCHT treatment were investigated by iTRAQ analysis. Potential protein targets and mechanisms were assessed by gene ontology (GO), Kyoto encyclopedia of gene and genomes (KEGG) and protein-protein interaction (PPI) network. RESULTS: Our data demonstrated XCHT could significantly improve depressive behaviors. A total of 241 DEPs were identified after XCHT treatment, including 68 up regulation and 173 down regulation proteins. GO enrichment results indicated that XCHT mainly regulated intracellular structural proteins involved in cellular response to stress, transferase activity and steroid hormone. KEGG enrichment analysis showed that endocytosis might be the principal pathway of XCHT on depression. PPI analysis predicted cell division cycle and apoptosis regulator protein 1 (Ccar1) and Calretinin (Calb2) might play the central roles in XCHT's antidepressant network. CONCLUSION: Our results indicate that XCHT plays the important roles in antidepressant action by restoring DEPs, which results in the dysregulation of hippocampal neurogenesis, neurotransmitter and steroid hormone. The current results wish to provide novel perspectives for revealing the potential protein targets of XCHT on depression. PMID- 30445106 TI - Tabernaemontana catharinensis leaves exhibit topical anti-inflammatory activity without causing toxicity. AB - BACKGROUND: Tabernaemontana catharinensis, popularly known as snake skin, has been empirically used as an anti-inflammatory to treat cutaneous skin disorders. However, no study proves its effectiveness as a topical anti-inflammatory. STUDY DESIGN: We investigated the topical anti-inflammatory effect of T.catharinensis leaves crude extract (TcE) in irritant contact dermatitis models in mice and its preliminary toxicity profile. METHODS: The topical anti-inflammatory effect was evaluated by ear thickness measurement, inflammatory cell infiltration (MPO activity measurement and histological procedure) and cytokines levels. TcE qualitative phytochemical analysis was performed by UHPLC-ESI-HRMS and the TcE effect (therapeutic dose; 10 ug/ear) on preliminary toxicological parameters was also evaluated (on the 14 degrees day of experiment). RESULTS: TcE (10 MUg/ear) prevented the development of ear edema induced by cinnamaldehyde, capsaicin, arachidonic acid, phenol, and croton oil with maximum inhibition of 100% to cinnamaldehyde, arachidonic acid, phenol, and croton oil and 75 +/- 6% to capsaicin. Besides, the TcE (10 MUg/ear) also prevented the increase of MPO activity by 96 +/- 2%, 48 +/- 7%, 100%, 87 +/- 8%, and 93 +/- 4%, respectively, to the same irritant agents. The positive controls also prevented both ear edema and the increased of MPO activity by 100% and 42 +/- 8% (HC-030031), 54 +/- 6% and 80 +/- 4% (SB-366791), 100% and 54 +/- 5% (indomethacin), 100% and 80 +/- 4% (dexamethasone in skin inflammation model induced by phenol) and 100% and 97 +/- 3% (dexamethasone in inflammation model induced by croton oil), respectively. TcE also prevented the inflammatory cells infiltration and the increase of MIP-2, IL 1beta and TNF-alpha levels irritant agents-induced. TcE topical anti-inflammatory effect may be attributed to the combined effect of indole alkaloids, terpenes, and phenolic compounds found in the extract and identified by dereplication method. The TcE' therapeutic dose proved to be safe in preliminary toxicological tests. CONCLUSION: Our results suggest that TcE could be an interesting strategy for the treatment of inflammatory diseases. PMID- 30445109 TI - In vitro and in vivo anti-leukemia activity of the stem bark of Salacia impressifolia (Miers) A. C. Smith (Celastraceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Salacia impressifolia (Miers) A. C. Smith (family Celastraceae) is a traditional medicinal plant found in the Amazon Rainforest known as "miraruira", "cipo-miraruira" or "panu" and is traditionally used to treat dengue, flu, inflammation, pain, diabetes, male impotency, renal affections, rheumatism and cancer. AIM OF THE STUDY: The aim of this study was to investigate in vitro and in vivo anti-leukemia activity of the stem bark of S. impressifolia in experimental models. MATERIALS AND METHODS: The in vitro cytotoxic activity of extracts, fractions and quinonemethide triterpenes (22 hydroxytingenone, tingenone and pristimerin) from the stem bark of S. impressifolia in cultured cancer cells was determined. The in vivo antitumor activity of the ethyl acetate extract (EAE) and of its fraction (FEAE.3) from the stem bark of S. impressifolia was assessed in C.B-17 severe combined immunodeficient (SCID) mice engrafted with human promyelocytic leukemia HL-60 cells. RESULTS: The extract EAE, its fraction FEAE.3, and quinonemethide triterpenes exhibited potent cytotoxicity against cancer cell lines, including in vitro anti-leukemia activity against HL-60 and K-562 cells. Moreover, extract EAE and its fraction FEAE.3 inhibited the in vivo development of HL-60 cells engrafted in C.B-17 SCID mice. Tumor mass inhibition rates were measured as 40.4 and 81.5% for the extract EAE (20mg/kg) and for its fraction FEAE.3 (20mg/kg), respectively. CONCLUSIONS: Ethyl acetate extract and its fraction from the stem bark of S. impressifolia exhibit in vitro and in vivo anti-leukemia activity that can be attributed to their quinonemethide triterpenes. These data confirm the ethnopharmacological use of this species and may contribute to the development of a novel anticancer herbal medicine. PMID- 30445108 TI - Discovery of anti-inflammatory terpenoids from Mallotus conspurcatus croizat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mallotus conspurcatus croizat (Euphorbiaceae), a plant native to Jinxiu in Guangxi, is popularly used in folk medicine to treat pelvic inflammatory disease. The anti-inflammatory activities of the compounds obtained from M. conspurcatus root were evaluated in this study. AIM OF THE STUDY: This study explored the major anti-inflammatory components of this plant. MATERIALS AND METHODS: The ethyl acetate fraction of the ethanol extract from M. conspurcatus was separated using chromatographic techniques. The structures of the isolates were elucidated from NMR, MS and X-ray data as well as from ECD. The anti-inflammatory activities of the isolates from M. conspurcatus were evaluated using LPS-stimulated RAW 264.7 cell models. The production of NO, TNF-alpha and PGE-2 was determined by ELISA and Griess tests. The expression levels of COX-2, NF-kappaB/p65 and iNOS were measured by western blotting. RESULTS: Two new diterpenoids, malloconspur A (1) and malloconspur B (2), and sixteen known terpenoids (3-18) were identified by comprehensive spectroscopic analyses and comparison with literature data. Malloconspur B (2) and 17-hydroxycleistantha 12,15-dien-3-one (3) substantially inhibited the release of NO with IC50 values of 10.47 MUM and 9.32 MUM, respectively. Compounds 1, 2 and 3 markedly decreased the secretion of PGE2 and TNF-alpha (P < 0.01) by LPS-induced RAW264.7 cells. Compounds 2 and 3 markedly decreased iNOS, NF-kappaB/p65 and COX-2 protein expression. CONCLUSIONS: Our identification of these diterpenoids provides strong evidence for the use of M. conspurcatus among the Yao people as a medicinal plant for the treatment of inflammation. The dramatic differences in the chemical structures of the active diterpenoids of this plant from those on the market suggest these compounds have potential as anti-inflammatory lead compounds for follow-up research. PMID- 30445110 TI - Danggui Buxue Tang promotes the adhesion and migration of bone marrow stromal cells via the focal adhesion pathway in vitro. AB - ETHNOPHARMACOLOGY RELEVANCE: Danggui Buxue Tang has been used in China to treat clinical anemia for more than 800 years. However, there is no scientific report on its effect on bone marrow stromal cells. AIM OF THE STUDY: Here, we aimed to explore the effect of Danggui Buxue Tang on bone marrow stromal cell adhesion and migration. MATERIALS AND METHODS: Bone marrow stromal cells were used as a model to evaluate the effect of Danggui Buxue Tang on the adhesion and migration of bone marrow stromal cells. RNA-sequencing, quantitative polymerase chain reaction, and western blotting were used to detect and confirm the expression of genes related to the focal adhesion pathway before and after drug delivery. RESULTS: Danggui Buxue Tang significantly increased the number of bone marrow stromal cells. After 12 days of 16 mg/mL Danggui Buxue Tang treatment, bone marrow stromal cells were significantly increased (by 0.527 +/- 0.008 fold; p < 0.001) as compared to the control group (0.180 +/- 0.019). The effect was not due to enhanced cell proliferation, as there was no difference in the cell cycle (p > 0.05). The adhesion area of a single cell was doubled by Danggui Buxue Tang treatment (p < 0.001), and the time required for cell adhesion to a Petri dish was shortened. Thus, Danggui Buxue Tang increases the number of bone marrow stromal cells by promoting adhesion. Danggui Buxue Tang also significantly promoted bone marrow stromal cell migration (p < 0.001). Transcript analysis revealed that the focal adhesion and PI3K-Akt signaling pathways were activated. Expression analysis confirmed that the gene and protein expression of focal adhesion-related factors were upregulated. CONCLUSION: Danggui Buxue Tangaffects bone marrow stromal cell adhesion and migration by enhancing the focal adhesion pathway in vitro, and bone marrow stromal cells are a target of DBT-regulated hematopoiesis, and the active ingredients of DBT involved in the effects require further investigation. PMID- 30445111 TI - Method for functional analysis of a gene of interest in Streptococcus mutans: gene disruption followed by purification of a polyhistidine-tagged gene product. AB - Typical methods for elucidating the function of a particular gene involve comparative phenotypic analysis of the wild-type strain and a strain in which the gene of interest has been disrupted. We previously described a simple method for the generation of a gene-disrupted strain in Streptococcus mutans by replacing the gene of interest with an antibiotic resistance marker gene. It is also crucial that the function lost following the gene disruption is restored by exogenous addition of the gene product, but purification of this product can be difficult and involve a complex series of steps. In this study, we describe a simple method for the purification of gene products following gene disruption in S. mutans. The method involves the expression of an additional polyhistidine tag at the C-terminus of the gene product. The target protein can be simply purified by immobilized metal affinity chromatography and applied to a restoration assay. This method utilizes the genomes of both the wild-type strain and the gene disrupted strain as PCR templates to generate the DNA construct. Therefore, generation of the gene-disrupted strain is a prerequisite for the present procedure. The combination of gene disruption and gene product purification results in an efficient method for the analysis of gene function that could be further adapted to various other bacterial species. PMID- 30445113 TI - Association of non-tuberculous mycobacteria with Mycobacterium leprae in environment of leprosy endemic regions in India. AB - Non-tuberculous mycobacteria (NTM) are environmental mycobacteria found ubiquitously in nature. The present study was conducted to find out the presence of various species of NTM in leprosy endemic region along with Mycobacterium (M) leprae. Water and wet soil samples from the periphery of ponds used by the community were collected from districts of Purulia of West Bengal and Champa of Chhattisgarh, India. Samples were processed and decontaminated followed by culturing on Lowenstein Jensen (LJ) media. Polymerase chain reaction (PCR) was performed using 16S rRNA gene target of mycobacteria and species was confirmed by sequencing method. Indirect immune-fluorescent staining of M. leprae from soil was performed using M. leprae-PGL-1 rabbit polyclonal antibody. The phylogenetic tree was constructed by using MEGA-X software. From 380 soil samples 86 NTM were isolated, out of which 34(40%) isolates were rapid growing mycobacteria (RGM) and 52(60%) isolates were slow growing mycobacteria (SGM). Seventy-seven NTM isolates were obtained from 250 water samples, out of which 35(45%) were RGM and 42(55%) were SGM. Amongst all the RGM, we isolated M. porcinum, M. psychrotolerans, M. alsenase, M. arabiense and M. asiaticum from Indian environmental samples. M. fortuitum was the most commonly isolated species of all RGM. Out of all SGM, M. holsaticum, M. yongonense, M. seoulense, M. szulgai, M. europaeum, M. simiae and M. chimaera were isolated for the first time from Indian environment. M. intracellulare was the commonest of all isolated SGM. Presence of M. leprae was confirmed by indirect immunofluorescent microcopy and PCR method from the same environmental samples. Phylogenetic tree was showing a close association between these NTMs and M. leprae in these samples. Several NTM species of pathogenic and nonpathogenic in nature along with M. leprae were isolated from soil and pond water samples from leprosy endemic regions and these might be playing a role in causing disease and maintaining leprosy endemicity in India. PMID- 30445112 TI - Loop-mediated isothermal amplification assay for detection of Coxiella burnetii targeting the com1 gene. AB - We developed the com1 gene based loop-mediated isothermal amplification (LAMP) assay for the detection of Coxiella burnetii and validated it by screening DNA isolated from serum samples collected from animals and humans. The detection of Coxiella by LAMP assay was comparable with the com1 based-PCR. PMID- 30445114 TI - Herpesvirus infection in marine mammals: A retrospective molecular survey of stranded cetaceans in the Portuguese coastline. AB - Herpesvirus (HVs) infection has already been reported in cetaceans, but available information on its epidemiology is scarce. In this study we surveyed a total of 179 cetaceans belonging to 6 different species. Samples were obtained from cetaceans stranded along the Portuguese coastline, belonging to populations that roam the north-east region of the Atlantic Ocean. Detection of HVs was performed by conventional nested PCR. Amplicons were sequenced by Sanger's method and sequences used to construct phylogenetic trees by Maximum Likelihood method. Our results show that prevalence of positive samples, among fresh carcasses, reached 14.3% (10/70) and both alpha and gammaherpesvirus were detected. Histopathology showed that herpesvirus infection varied from absence of signs compatible with disease, localized genital lesions and systemic disease. Phylogenetic analysis revealed three clusters within the alphaherpesvirus family; within the gammaherpesvirus no subdivision was detected. All clusters included animals from different species and geographic origins. In seven of the positive HVs samples, co-infections with other agents such as morbillivirus and toxoplasma gondii were detected. The viral nucleotide sequences were not assigned to a specific animal species, nor presented a given geographic distribution, which may imply a wider distribution of herpesvirus in these animal populations. Our results are also the first report of herpesvirus infection in common dolphins (Delphinus delphis), with both alpha and gammaherpesvirus detected. PMID- 30445115 TI - The peculiar structure of the flagellar axoneme in Coccinellidae (Insecta Coleoptera). AB - The ultrastructure of the complex organisation of the spermatozoa in Harmonia axyridis and Adalia decempunctata (Coccinellidae) was studied, with particular emphasis on the origin of the anterior shifting of the axonemal structure, which becomes parallel to the nucleus in the sperm flagellum. In studying the spermiogenesis, a centriolar remodelling was observed with the long centriole, present in the early spermatids, transformed in the spermatozoa into an exceptional long and narrowed basal body (about 0.16 * 3.5-4.0 MUm long) displaying a 9+0 microtubular pattern in the proximal part and a 9+2 pattern in the following part; this is a characteristic not observed in any other pterygotan insects. The sperm also have a very long acrosome surrounded by a dense layer of material extending along the whole basal body. These two uncommon features were discussed in the light of sperm movement. PMID- 30445116 TI - Morphogenesis of serial abdominal outgrowths during development of the viviparous dermapteran, Arixenia esau (Insecta, Dermaptera). AB - The embryos and first instar larvae of the epizoic earwig, Arixenia esau, develop sequentially in two different compartments of the female reproductive system, that is ovarian follicles and the lateral oviducts (the uterus). Here we show that the second (intrauterine) phase of development consists of three physiologically disparate stages: early embryos (before dorsal closure, surrounded by an egg envelope), late embryos (after dorsal closure, surrounded by an egg envelope) and the first instar larvae (after "hatching" from an egg envelope). Early and late embryos float in the fluid filling the uterus, whereas the first instar larvae develop attached to the uterus wall. Our analyses revealed also that in Arixenia serial multilobed outgrowths develop on dorso lateral aspects of all abdominal segments. At the onset of the third developmental stage and after liberation from an egg envelope, these outgrowths (or more precisely their lobes) adhere to the epithelium lining the uterus, forming a series of small contact sites, where the mother and embryo tissues are separated only by a thin, presumably permeable, embryonic cuticle. We suggest that all these contact sites collectively constitute a dispersed placenta-like organ involved in the nourishment of the embryo. PMID- 30445117 TI - Was the ancestral panarthropod mouth ventral or terminal? AB - It has recently been suggested that the panarthropod mouth was ancestrally terminal, based on the assumption that the ancestral tardigrade had a terminal mouth and on the observations of a terminal mouth in adults of some stem-group fossils. This is shown to be unlikely, and it is concluded that the ancestral panarthropod had a ventral mouth. PMID- 30445118 TI - The social network structure of a semi-free roaming European bison herd (Bison bonasus). AB - The use of social network analysis to better understand animal behaviour has led to an increase in the number of studies on this topic, particularly for species management and conservation as well as the welfare of captive animals. The current knowledge of social organization in the European bison (Bison bonasus) is still largely based on descriptions of group compositions, most of which were obtained during opportunistic field observations. However, the numerous conservation programs for this species can only implement effective management decisions after the analysis of its social structures. For instance, the removal of a key individual can disturb the social stability of a group and thus indirectly affect the fitness of group members. This is the first study that uses social network analysis to examine the social structure of a semi-free ranging bison herd (N = 14). Closest neighbour associations are used to calculate the eigenvector centrality and individual social strength of each animal. These two indices are combined after a principal component analysis (PCA) to form the Sociability variable, which was then tested for correlations with age, dominance rank, number of matrilines and reproductive status (lactating vs non-lactating). Results reveal strong group cohesion, with a close association of individuals belonging to the same matriline within the herd. The cumulative distribution of the eigenvector centralities follows a linear function, meaning that no individual has a highly central position compared to its congeners. Finally, a high Sociability value was not correlated to age, dominance rank or number of matrilines, but was dependent on the reproductive status of females. These results indicate the necessity to consider the social welfare of animals, for instance by taking matrilineal relationships into account when making bison groups management decisions. PMID- 30445119 TI - Can the discriminative stimulus effects of nicotine function concurrently as modulatory opponents in operant and pavlovian occasion setting paradigms in rats? AB - Nicotine promotes interoceptive changes in the nervous system. Such interoceptive stimuli play important roles in modulating addictive behavior. Operant and Pavlovian stimulus control modulate responsiveness to environmental stimuli related to drug-seeking and self-administration. Nicotine functions as a discriminative stimulus in modulating operant behavior as well as Pavlovian feature stimuli in modulating the conditional responding (CR) to exteroceptive CS >US contingencies. Elucidation of the interaction of these interoceptive stimulus control functions is vital for a comprehensive understanding of nicotine use/abuse, which might lead to better behavioral treatment strategies. This experiment evaluated the interaction among Pavlovian feature positive (FP) and feature negative (FN) effects of nicotine on concurrently occurring operant SD and SDelta effects. Sixteen rats were trained in a Pavlovian and operant bidirectional contingency paradigm, using nicotine (0.3 mg/kg) and non-drug (saline) states as interoceptive cues for operant discriminative stimulus conditions (SD and SDelta) as well as Pavlovian FP and FN for a light-CS, either leading to a shared food pellet outcome or non-outcome. Nicotine and saline sessions were intermixed. For one group of rats (n = 8), nicotine served as an SD for lever pressing (variable interval 60 s) and simultaneously functioned as an FN for CS-light->noUS relation on the same sessions. On intermixed sessions, saline served as the SDelta for lever pressing (non-reinforced) and FP, during which the 8-sec light preceded delivery of the food pellet (variable time ITI = 60 s). For the other group (n = 8) nicotine served as the SDelta (lever pressing non-reinforced) and FP for the CS, with saline serving in the reverse roles. Consecutive brief non-reinforcement tests revealed that: A) rates of lever pressing were significantly greater in SD than SDelta with nicotine and saline suggesting strong operant discriminative stimulus control; B) FP responding to the light CS with nicotine and saline was evident; and C) FN suppression of the CR with nicotine was not evident but weak under saline. These data suggest that nicotine can function as an interoceptive context that hierarchically can enter into concurrently opposing modulatory relations in Pavlovian and operant drug discrimination procedures. PMID- 30445120 TI - Dominance hierarchy establishment in the invasive round goby, Neogobius melanostomus. AB - Organisms living at high densities may be forced to engage in conflict for access to resources such as food or shelter. When these resources are limited, the outcome of interactions may have important fitness implications. We investigated the behavioural interactions of the invasive Round Goby (Neogobius melanostomus) in a shelter-limited environment. Round Goby are benthic fish that utilize rocky shelters for predator avoidance and as reproductive sites in which territorial males defend clutches of eggs. Previous work on this and other species has shown that larger individuals have greater resource holding potential in dyadic interactions. In order to understand the outcome of agonistic interactions in more complex social environments, we observed groups of three goby of the same sex which varied in relative size in an aquarium in which individuals had the opportunity to compete for access to shelters. We predicted that larger goby would behave aggressively towards smaller goby, and outcompete smaller goby for access to shelters. Because males defend shelters while breeding, we also predicted that male goby would compete more aggressively than females over dominance status. We found that larger goby in groups were socially dominant to smaller goby, regardless of sex. Additionally, we found that the largest goby in each group was involved in more aggressive interactions than the second or third largest goby in each group. We found no effect of relative size or sex on aggressive interaction or the emergent dominance relationships. Our findings highlight that aspects of the social environment may limit the opportunity for individuals to establish dominance or establish ownership of resources. PMID- 30445121 TI - Vaccinating against monkeypox in the Democratic Republic of the Congo. AB - Healthcare-associated transmission of monkeypox has been observed on multiple occasions in areas where the disease is endemic. Data collected by the US Centers for Disease Control and Prevention (CDC) from an ongoing CDC-supported program of enhanced surveillance in the Tshuapa Province of the Democratic Republic of the Congo, where the annual incidence of human monkeypox is estimated to be 3.5 5/10,000, suggests that there is approximately one healthcare worker infection for every 100 confirmed monkeypox cases. Herein, we describe a study that commenced in February 2017, the intent of which is to evaluate the effectiveness, immunogenicity, and safety of a third-generation smallpox vaccine, IMVAMUNE(r), in healthcare personnel at risk of monkeypox virus (MPXV) infection. We describe procedures for documenting exposures to monkeypox virus infection in study participants, and outline lessons learned that may be of relevance for studies of other investigational countermeasures in hard to reach, under-resourced populations. PMID- 30445122 TI - The Feasibility and Safety of Reproductive Organ Preserving Radical Cystectomy for Elderly Female Patients With Muscle-Invasive Bladder Cancer: A Retrospective Propensity Score-matched Study. AB - OBJECTIVE: To evaluate the feasibility and safety of reproductive organ preserving radical cystectomy (ROPRC) compared to radical cystectomy (RC) for elderly female patients with muscle-invasive bladder cancer. METHODS: We retrospectively studied 135 elderly female patients (aged >=75 years) who underwent RC followed by cutaneous ureterostomies at our center between January 1, 2007 and December 31, 2017. Eighty-four patients treated with RC, and 51 patients treated with ROPRC, were grouped into 45 pairs. Patient demographics, extensive peri-operative, and oncological data were then recorded and evaluated. RESULTS: In the matched group, the incidence of short-term and long-term complications in the ROPRC group were lower than the RC group (18.0% vs 28.0%, P = .035; 12.0% vs 22.0%, P = .030). Furthermore, operative time was shorter, estimated blood loss was lower, and bowel recovery was quicker in the ROPRC group (207.5 minutes vs 267.9 minutes, P < .001; 500 mL vs 600 mL, P = .024; 3.0 days vs 4.0 days, P < .001, respectively) compared to the RC group. The recurrence free survival (P = .658), overall survival (P = .604), and cancer-specific survival (P = .361) were all equivalent when compared between the 2 groups with a median follow-up period of 34.0 and 38.0 months, respectively. The surgical approach (RC vs ROPRC) was an independent risk factor for short-term complications (P = .045), duration of operative time (P < .001), estimated blood loss (P = .004), and bowel recovery (P < .001). CONCLUSION: This propensity score matched cohort study showed that ROPRC was both feasible and safe for elderly female patients with muscle-invasive bladder cancer compared to RC, and also had comparable oncological outcomes after a lengthy follow-up period. PMID- 30445123 TI - The anatomical structure of a fused renal pyramid and its clinical significance in the establishment of percutaneous renal access. AB - OBJECTIVE: To explore the clinical significance of the fused renal pyramid(FRP) in establishing percutaneous renal access, and the anatomical basis for avoiding vascular injury caused by puncturing through this renal pyramid with the aim of achieving accurate puncture in PCNL. MATERIALS AND METHODS: Sixty-two cadaveric kidneys and 105 porcine kidneys were selected for the assessment of regional anatomy, to explore the anatomical structure of the FRP and determine its frequency. Then, we compared the effects of four different puncture paths on the occurrence of renal vascular injury when respectively punctured through the normal renal pyramid (group A), the centreline of one side pyramid of the FRP (group B), the centre of the entire FRP (group C) and the renal column (group D). RESULTS: The incidence of FRP in human kidneys is not low. The artery in the kidney can be divided into six grades. The grade IV branch-interlobar artery courses through the FRP. There was significant difference in the degree of arterial injury between the group A and C (P=0.003), while no significant difference between the group A and B (P=0.151). There was significant difference in the proportion of interlolar artery injury between group A and C (P < 0.001), while no significant difference between group A and B (P = 0.239). CONCLUSIONS: It is necessary to carefully identify and bypass the FRP when establishing a percutaneous renal access. If unavoidable, the puncture path should be on the centreline of one side pyramid of the FRP. PMID- 30445124 TI - Is chronodisruption a vulnerability factor to stress? AB - Since the circadian system seems to modulate stress responses, this study aimed to evaluate if the combination of circadian strain and stress amplifies changes expected from each factor alone. Control Balb/c mice (12:12-NS) kept in standard 12:12 light:dark cycles (LD) and submitted to no stress procedures (NS) were compared to groups submitted to shortened LD (10:10-NS), chronic mild stress (CMS) but no circadian strain (12:12-CMS), or shortened LD followed by CMS (10:10 CMS). Rest-activity/temperature rhythms and body weight were assessed throughout the experiments. In Experiment 1 mice were submitted to 3 weeks of CMS; in Experiment 2 sucrose preference and light-dark tests were performed. Also, blood samples were collected at the end of Experiment 2 to assess metabolic parameters. Relative amplitude of temperature after CMS was increased only in the 10:10-CMS group, while body weight change was reduced during CMS regardless of LD intervention. During the CMS, the relative amplitude of temperature was negatively correlated with body weight gain. No differences in behavior and metabolic parameters were seen among groups. Identifying suitable research designs to investigate our hypothesis that circadian disturbances may increase vulnerability to stress-induced depression and anxiety is warranted. PMID- 30445125 TI - Sub-acute restraint stress progressively increases oxidative/nitrosative stress and inflammatory markers while transiently upregulating antioxidant gene expression in the rat hippocampus. AB - We have previously demonstrated that acute stress decreases neuronal nitric oxide synthase (NOS) expression in the hippocampus despite increased concentrations of nitric oxide which may indicate feedback inhibition of neuronal NOS expression via inducible NOS-derived nitric oxide. Moreover, the hippocampus undergoes an initial oxidative/nitrosative insult that is rapidly followed by upregulation of protective antioxidants, including the zinc-binding metallothioneins, in order to counter this and restore redox balance following acute stress exposure. In the present study, we have utilized indicators of oxidative/nitrosative stress, members of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, antioxidant metallothioneins, and neuroinflammatory markers to observe the changes occurring in the hippocampus following short term repeated stress exposure. Male Wistar rats were subjected to control conditions or 6 h of restraint stress applied for 1, 2, or 3 days (n = 8 per group) after which the hippocampus was isolated for redox assays and relative gene expression. The hippocampus showed increased oxidative stress, transient dys-homeostasis of total zinc, and increased expression of the Nrf2 pathway members. Moreover, repeated stress increased nitrosative status, nitric oxide metabolites, and 3 nitrotyrosine, indicative of nitrosative stress in the hippocampus. However, levels of neuronal NOS decreased over all stress treatment groups, while increases were observed in inducible NOS and xanthine dehydrogenase. In addition to inducible NOS, mRNA expression of other inflammatory markers including interleukin-6 and interleukin-1beta also increased even in the presence of increased anti-inflammatory glucocorticoids. Together, these results demonstrate that despite increases in antioxidant expression, sub-acute stress causes an inflammatory phenotype in the hippocampus by inducing oxidative/nitrosative stress, zinc dys-homeostasis, and the accumulation of nitrotyrosinated proteins which is likely driven by increased inducible NOS signaling. PMID- 30445126 TI - Mitochondrial disfunction and ROS production are essential for anti-Trypanosoma cruzi activity of beta-lapachone-derived naphthoimidazoles. AB - Chagas disease is caused by the hemoflagellate protozoa Trypanosoma cruzi and is one of the most important neglected tropical diseases, especially in Latin American countries, where there is an association between low-income populations and mortality. The nitroderivatives used in current chemotherapy are far from ideal and present severe limitations, justifying the continuous search for alternative drugs. Since the1990s, our group has been investigating the trypanocidal activity of natural naphthoquinones and their derivatives, and three naphthoimidazoles (N1, N2 and N3) derived from beta-lapachone were found to be most effective in vitro. Analysis of their mechanism of action via cellular, molecular and proteomic approaches indicates that the parasite mitochondrion contains one of the primary targets of these compounds, trypanothione synthetase (involved in trypanothione production), which is overexpressed after treatment with these compounds. Here, we further evaluated the participation of the mitochondria and reactive oxygen species (ROS) in the anti-T. cruzi action of naphthoimidazoles. Preincubation of epimastigotes and trypomastigotes with antioxidants (alpha-tocopherol and urate) strongly protected the parasites from the trypanocidal effect of naphthoimidazoles, decreasing the ROS levels produced and reverting the mitochondrial swelling phenotype. The addition of pro-oxidants (menadione and H2O2) before the treatment induced an increase in parasite lysis. Despite the O2 uptake and mitochondrial complex activity being strongly reduced by N1, N2 and N3, urate partially restored the mitochondrial metabolism only in N1-treated parasites. In parallel, MitoTEMPO, a mitochondrial-targeted antioxidant, protected the functionality of the mitochondria in N2- and N3 treated parasites. In addition, the trypanothione reductase activity was remarkably increased after treatment with N1 and N3, and molecular docking demonstrated that these two compounds were positioned in pockets of this enzyme. Based on our findings, the direct impairment of the mitochondrial electron transport chain by N2 and N3 led to an oxidative misbalance, which exacerbated ROS generation and led to parasite death. Although other mechanisms cannot be discounted, mainly in N1-treated parasites, further investigations are required. PMID- 30445127 TI - Blood-based redox-signature and their association to the cognitive scores in MCI and Alzheimer's disease patients. AB - Oxidative stress plays a pivotal and early role in the pathophysiology of Alzheimer's disease (AD). There is convincing evidence that oxidative alterations in AD and in mild cognitive impairment (MCI) patients are not limited to the brain but are extended to the blood compartment. However, the oxidative pattern in plasma is still inconclusive. Moreover, their potential association with the clinical scores MMSE (Mini-Mental State Examination) and MoCA (Montreal Cognitive Assessment) is poorly investigated. The aim of our study was to establish a pattern of blood-based redox alterations in prodromal AD and their evolution during the progression of the disease. Our results showed a reduction in the total antioxidant capacity (TAC) and an increase of the stress-response proteins apolipoprotein J (ApoJ) and Klotho in MCI subjects. For the first time, we evidenced circulating-proteasome activity. We found that the alteration of the circulating-proteasome activity is associated with the accumulation of oxidized proteins in plasma form early AD. Interestingly, the TAC, the levels of vitamin D and the activity of proteasome were positively associated to the clinical scores MMSE and MoCA. The levels of protein carbonyls and of ApoJ were negatively associated to the MMSE and MoCA scores. The levels of apolipoprotein D (ApoD) were not different between groups. Interestingly, the receiver operating characteristic (ROC) curves analysis indicated that these redox markers provide a fair classification of different groups with high accuracy. Overall, our results strengthen the notion that some specific oxidative markers could be considered as non-invasive blood-based biomarkers for an early MCI diagnosis and AD progression. PMID- 30445128 TI - Urinary oxidative stress biomarkers and accelerated time to spontaneous delivery. AB - BACKGROUND: Oxidative stress has been implicated in numerous birth outcomes, including spontaneous preterm birth. However, the relationship with presentation at delivery has been less well studied. We assessed the relationship between oxidative stress biomarkers and gestational duration with a focus on spontaneous presentation for delivery. METHODS: Our sample included 740 women from a multi center prospective cohort study, recruited from 2010 to 2012. Resultant measures of oxidative stress in pregnancy prostaglandin F2alpha (PGF2alpha), 8-iso prostaglandin F2alpha (8-iso-PGF2alpha), and the primary 8-iso-PGF2alpha metabolite were measured in third trimester urine samples. Information on presentation for delivery was abstracted from medical records. We examined associations with preterm birth using adjusted logistic models. Time to event (overall delivery and spontaneous delivery) was examined using adjusted accelerated failure time models. RESULTS: The 8-iso-PGF2alpha metabolite was associated with increased odds of overall preterm birth (OR: 1.44 [95% CI: 1.00, 2.06]), and the association with spontaneous preterm birth was similar in magnitude but not statistically significant (OR: 1.45 [95% CI: 0.96, 2.20]). We did not detect associations between other biomarkers and preterm birth, or between biomarkers and timing of overall or spontaneous delivery in accelerated failure time models. CONCLUSIONS: Our data suggest that increased oxidative stress, as indicated by the 8-iso-PGF2alpha metabolite, may be associated with preterm birth. In contrast to previous studies, associations were similar among individuals with spontaneous versus non-spontaneous presentation for delivery. PMID- 30445129 TI - Dynamical analysis of a stage-structured predator-prey model with cannibalism. AB - This paper concerns with a stage-structured predator-prey model with cannibalism in the predator, where the predator population is divided into two stages, a juvenile stage and a mature stage. The effects of cannibalism on the model have been partially discussed by Magnusson [12] and Marik and Pribylona [13] by means of numerical simulation and simple mathematical analysis. Here we reinvestigate the dynamics of this model. We obtain the global stability of the model, illustrate the effects of the two factors (one describes the cannibalization and the other the benefit from cannibalism) on dynamics of the model, and find that the positive equilibrium can undergo stability switch (from stable to unstable to stable, or from unstable to stable to unstable) with the change of the cannibalization rate. The obtained results indicate that large cannibalization rate can make the positive equilibrium globally stable although its stability would change with the increase of the rate. We also analyze theoretically Hopf bifurcation. It turns out that supercritical/subcritical Hopf bifurcation can occur with the rates of the above mentioned two factors as bifurcation parameters. Finally, we introduce some quantities with clear biological meanings to better understand our results from the point of biology. PMID- 30445130 TI - A proteomics approach for the identification of species-specific immunogenic proteins in the Mycobacterium abscessus complex. AB - The Mycobacterium abscessus complex can cause fatal pulmonary disease, especially in cystic fibrosis patients. Diagnosing M. abscessus complex pulmonary disease is challenging. Immunologic assays specific for M. abscessus are not available. In this study seven clinical M. abscessus complex strains and the M. abscessus reference strain ATCC19977 were used to find species-specific proteins for their use in immune assays. Six strains showed rough and smooth colony morphotypes simultaneously, two strains only showed rough mophotypes, resulting in 14 separate isolates. Clinical isolates were submitted to whole genome sequencing. Proteomic analysis was performed on bacterial lysates and culture supernatant of all 14 isolates. Species-specificity for M. abscessus complex was determined by a BLAST search for proteins present in all supernatants. Species-specific proteins underwent in silico B- and T-cell epitope prediction. All clinical strains were found to be M. abscessus ssp. abscessus. Mutations in MAB_4099c as a likely genetic basis of the rough morphotype were found in six out of seven clinical isolates. 79 proteins were present in every supernatant, of which 12 are exclusively encoded by all members of M. abscessus complex plus Mycobacterium immunogenum. In silico analyses predicted B- and T-cell epitopes in all of these 12 species-specific proteins. PMID- 30445131 TI - Silver nanoparticles synthesized with Eucalyptus critriodora ethanol leaf extract stimulate antibacterial activity against clinically multidrug-resistant Acinetobacter baumannii isolated from pneumonia patients. AB - The increasing multidrug resistance of Acinetobacter baumannii has been highlighted as a worldwide therapeutic problem. Despite the wide range of studies on green synthesis of silver nanoparticles, there is currently no alternative treatment for MDR A. baumannii infection. This study investigated the potential of silver nanoparticles synthesized with Eucalyptus critriodora leaf extract as an inhibitor of MDR A. baumannii infection. The results demonstrated that silver nanoparticles synthesized with E. critriodora leaf extract triggered MDR A. baumannii DNA condensation, induced bacterial cell death and had a significant effect on biofilm formation, biofilm-grown cells, bacterial attachment and invasion of human lung cells in a concentration dependent manner. Silver nanoparticles synthesized with E. critriodora leaf extract had no obvious effects on the viability of human lung cells. The synthesized silver nanoparticles inhibited MDR A. baumannii infection by approximately 90% without cytotoxicity with a 50% effective concentration of 0.028 MUg/ml. Thus silver nanoparticles with E. critriodora leaf extract had the potential to be a promising anti-MDR A. baumannii agent for effective treatment and they point the way to further development of a wide range of effective biomedical applications. PMID- 30445132 TI - Antibacterial properties and modulation analysis of antibiotic activity of NaCe(MoO4)2 microcrystals. AB - This study reports the antibacterial properties and modulation analysis of antibiotic activity by NaCe(MoO4)2 microcrystals as well as their structural and morphological characterization. Evaluation of the antibacterial and antibiotic modulating activity was carried out using the broth microdilution method. The Minimum Inhibitory Concentrations (MICs) of the compounds were expressed as the geometric mean of the triplicate values obtained through the use of Resazurin. Compound concentrations in the plates ranged from 512 to 0.5 MUg/mL. Regarding its direct antibacterial activity, NaCe(MoO4)2 had a MIC >= 1024 MUg/mL against all studied strains. As for its modulatory effect, it presented synergism with the antibiotic Gentamicin against the S. aureus strain and with Norfloxacin against E. coli, causing a reduction of 75% and 60%, respectively, in the antibiotic quantity required to have the same effect on the strain in study. PMID- 30445133 TI - Computation-aided rational design of a halophilic choline kinase for cytidine diphosphate choline production in high-salt condition. AB - Biocatalysis has become the main approach to produce cytidine diphosphate choline (CDP-choline), which has been applied for treatment of acute craniocerebral injury and consciousness after brain surgery. However, salt accumulates with the production and inhibits enzyme activity, and eventually reduces yield and product accumulation rate. Our work provided a possible solution to this problem by applying a computational designed halophilic choline kinase. The halotolerant CKI (choline kinase) was designed following a unique strategy considering the most variable residue positions on the protein surface among target enzymes from different sources. The basic and neutral surface residues were replaced with acidic ones. This approach was enlightened by features of natural halophilic enzymes. Mutants in the work represented higher catalytic activities and IC50 (inhibit activity by 50 %) at high salt concentrations (over 1200 mM). Furthermore, when the mutant was used in fed-batch production, the CDP-choline accumulation rate doubled comparing with process using wild-type CKI at acetate concentration of over 700 mM. The maximum titer was 151 +/- 3.2 mM, the productivity was 5.8 +/- 0.1 mM.L-1 h-1, and molar yield to CMP and utilization efficiency of energy were 85.3 and 63.5 %. The idea of computational design in our work can also be applied to modify other enzymes in industry, and sheds light on alleviating effect of salt accumulation during industrial manufacturing process. PMID- 30445134 TI - The association between near-infrared spectroscopy-derived and flow-mediated dilation assessment of vascular responsiveness in the arm. AB - INTRODUCTION: Following a period of blood flow occlusion, the near-infrared spectroscopy (NIRS)-derived reperfusion slope of the oxygen saturation signal (StO2) is a measure of microvascular responsiveness that has been shown to be positively correlated with flow-mediated dilation (FMD) assessment of conduit artery function in the lower limb vasculature. Given that previously established differences in structure and function of the vessels in the upper compared to the lower limbs may change this relationship, investigating whether this correlation between the reperfusion slope of the StO2 and the FMD response is maintained in upper limbs is important. Accordingly, this study investigated the correlation between the reperfusion slope of the StO2 and FMD in the arm vasculature. METHODS: 18 physically active individuals were submitted to a vascular occlusion test (VOT). Microvascular responsiveness was calculated as the NIRS-derived reperfusion slope assessed in a forearm muscle. Macrovascular responsiveness was assessed at the brachial artery and calculated as a percent of change in FMD (%FMD). RESULTS: A statistically significant correlation (r = 0.66; P = 0.001) was found between the reperfusion slope and %FMD response. CONCLUSION: The significant correlation between the reperfusion slope in the forearm muscle and %FMD in the brachial artery, reinforces the relationship between downstream and upstream vascular reactivity in healthy human limbs. PMID- 30445135 TI - Chronic + binge alcohol exposure promotes inflammation and alters airway mechanics in the lung. AB - INTRODUCTION: Alcohol use disorders are major risk factors for the development of and susceptibility to acute respiratory distress syndrome. Although these risks of alcohol consumption on the lung are well described, mechanisms by which alcohol abuse promotes acute lung injury are poorly understood. These gaps in our understanding are due, at least in part, to limitations of animal models to recapitulate human alcohol consumption. Recently, a new model of chronic plus binge alcohol exposure was developed that is hypothesized to better model drinking patterns of individuals with alcohol use disorders. Specifically, this paradigm models chronic consumption coupled with periodic bouts of heavy drinking. The impacts of this alcohol exposure regimen on the lung are uncharacterized. Therefore, the goal of this study was to examine lung injury and inflammation in a well-characterized experimental model of chronic + binge alcohol exposure. METHODS: 10-week male C57Bl6/J mice were administered ethanol containing (or isocaloric control) liquid diet for ten days, followed by a single ethanol gavage (5 g/kg). Lung inflammation and pulmonary function were assessed. RESULTS: Ten days of ethanol-containing liquid diet alone (chronic) did not detectably affect any variables measured. However, ethanol diet plus gavage (chronic + binge) caused neutrophils to accumulate in the lung tissue and in the bronchoalveolar lavage fluid 24 hours post-binge. This inflammatory cell recruitment was associated with airway hyper-responsiveness to inhaled methacholine, as indicated by elevated resistance, Newtonian resistance, and respiratory resistance. CONCLUSIONS: Taken together, the novel findings reveal that ethanol alone, absent of any secondary inflammatory insult, is sufficient to produce inflammation in the lung. Although these changes were relatively mild, they were associated with functional changes in the central airways. This animal model may be useful in the future for identifying mechanisms by which alcohol abuse sensitizes at-risk individuals to lung injury. PMID- 30445136 TI - Influence of machine-based puffing parameters on aerosol and smoke emissions from next generation nicotine inhalation products. AB - There is increasing diversity of nicotine inhalation products worldwide. Next Generation Products (NGP) such as e-cigarettes, have gained mass popularity, and there is increasing use of electrical and carbon-based Tobacco-Heating Products (e-THP and c-THP respectively). Recently, emission levels from these products have been compared to conventional cigarettes (CC); however, few formal laboratory testing standards exist, and inconsistent puffing parameters have been used. We investigated the impact of how a number of NGPs, including two e cigarettes, a carbon-heated THP, and both pulse- and continuously-heated e-THPs, are puffed on the magnitude of their emissions, examining the influence of puff profile, volume, frequency and duration, in comparison to standard CCs. Our findings demonstrated that for each NGP choice of puffing parameters has a substantial impact on the magnitude of aerosol and smoke emissions, and that significant differences exist between different types of NGP. With e-cigarettes and pulse-heated e-THPs puff duration is the most important puffing parameter influencing yields. In contrast, for CCs, c-THPs and continuously-heated e-THPs, puff volume and puff frequency were the critical parameters. For e-cigarettes, there was no significant difference in emissions between rectangular and bell shaped profiles. Our study has also shown that these different behaviours are a result of how heat-management within different NGPs, from heat-source to the nicotine- and aerosol-releasing substrates, is a vital mechanistic factor impacting aerosol generation. These findings point the need for detailed real world e-cigarette and THP puffing topography data in order to identify the most appropriate puffing parameters for laboratory testing; our findings will help focus these studies on the most important parameters and can thereby support the future development of robust standardised NGP testing regimes. PMID- 30445137 TI - Dissipation behavior and dietary risk assessment of lambda-cyhalothrin, thiamethoxam and its metabolite clothianidin in apple after open field application. AB - The dissipation dynamics and residue amounts of lambda-cyhalothrin, thiamethoxam and clothianidin in apple were investigated by using rapid resolution liquid chromatography triple quadrupole mass spectrometer (RRLC-MS/MS) and gas chromatography mass spectrometry (GC-MS). The developed method performed satisfactory recoveries of 88%-105% and the limit of quantitation (LOQ) was 0.01 mg kg-1. The suspension concentrate (SC) formulation of lambda-cyhalothrin and thiamethoxam was applied on apple field in accordance with good agricultural practice (GAP). The half-lives of two pesticides ranged from 7.01 d to 17.3 d and the terminal residues were <0.01-0.21 mg kg-1. Based on the Chinese dietary pattern, the dietary risk of lambda-cyhalothrin and total thiamethoxam were predicted by comparing intake amounts with the toxicological data, namely acceptable daily intake (ADI) and acute reference dose (ARfD). The chronic and acute risk quotients were 0.1080-0.4463 and 0.0008-0.2005, respectively, which showed negligible risk for general consumers. The pre-harvest interval (PHI) of 21 d was suggested for the formulation in compliance with maximum residue limit (MRL) and dietary risk assessment, meanwhile, the MRL of 0.1 mg kg-1 was recommended for thiamethoxam in apple. These results were vital for guiding reasonable usage of two insecticides and for approval of formulation use. PMID- 30445138 TI - Investigation of menthol content and transfer rates in cigarettes and Tobacco Heating System 2.2. AB - Menthol cigarettes account for a significant market share in many countries. However, little recent data exists on menthol levels in cigarettes and in mainstream smoke, limited to some markets or specific cigarette designs, such as cigarettes containing capsules filled with flavoring liquids. Samples of mentholated cigarettes bought worldwide with a variety of cigarette designs were analyzed for menthol content in cigarettes and in cigarette mainstream smoke with two analytical machine smoking regimes. A wide range of menthol content in cigarettes, from 1 to 22 mg/cigarette, was observed. The transfer of menthol to the cigarette mainstream smoke was generally slightly higher than the transfer of nicotine, with a range of 17%-40% using an intense smoking regime and 1%-17% using the ISO smoking regime. For the Tobacco Heating System (THS) 2.2, the menthol content was 12.8 mg/stick, and the transfer of menthol into the aerosol was about 17% with the ISO intense smoking regime, similar to the transfer of nicotine. The menthol content of the novel product THS 2.2 corresponds to the midpoint of the menthol content range of cigarettes, and the transfer of menthol to its aerosol is in the low range of cigarette menthol transfer. PMID- 30445139 TI - Conditioned media from contracting skeletal muscle potentiates insulin secretion and enhances mitochondrial energy metabolism of pancreatic beta-cells. AB - AIMS/HYPOTHESIS: In this study, we aimed to examine real-time effects of molecules released by contracting skeletal muscle on the insulin secretory function of beta-cells using a novel perifusion platform. We hypothesised that media conditioned by contracting skeletal muscle will influence insulin secretion and mitochondrial energy metabolism in beta-cells under normal and type-2 diabetic conditions. METHODS: INS-1832/3 pseudoislets were perifused with media from C2C12 myotubes treated with or without electrical pulse stimulation (EPS; 40 V, 1.0 Hz, 2 ms). Insulin secretory function of pseudoislets was measured before, during, and after EPS to simulate pre-, during-, and post-exercise like effects. Additional experiments were completed in INS-1832/3 cells under "healthy" and "diabetic-like" conditions as well as human pancreatic islets isolated from nondiabetic and type 2 diabetic donors. RESULTS: Insulin secretion increased significantly (P < 0.05) by pseudoislets when perifused with media from myotubes treated with but not without EPS. Conditioned media from EPS-treated myotubes also potentiated insulin secretion from INS-1832/3 cell monolayers in the presence (P < 0.05) and absence of palmitate (P < 0.001) and in nondiabetic (P < 0.01) and type-2 diabetic (P = 0.06) isolated human islets. Pre-treatment of INS 1832/3 cells to 24-h high glucose +/- palmitate dampened this effect. Moreover, conditioned media from myotubes treated with EPS significantly increased mitochondrial respiratory activity of INS-1832/3 cells. CONCLUSION/INTERPRETATION: Conditioned media from myotubes treated with EPS potentiates acute insulin release from normal cultured beta-cells, nondiabetic islets and Type-2 diabetic islets and is associated with enhanced mitochondrial substrate oxidation. PMID- 30445140 TI - CHARACTERISTICS OF OBESITY IN POLYCYSTIC OVARY SYNDROME: ETIOLOGY, TREATMENT, AND GENETICS. AB - Polycystic ovary syndrome (PCOS) has multiple etiologies including ovarian and adrenal hyperandrogenism, neuro-endocrine and hypothalamic-pituitary dysfunction, and disorders of peripheral insulin resistance. Obesity is neither necessary nor sufficient for the PCOS phenotype, and the association of PCOS with obesity is not universal, with national, cultural, and ethnic differences. Obesity, particularly visceral adiposity which is common in obese and non-obese women with PCOS, amplifies and worsens all metabolic and reproductive outcomes in PCOS. Obesity increases insulin resistance and compensatory hyperinsulinemia, which in turn increases adipogenesis and decreases lipolysis. Obesity sensitizes thecal cells to LH stimulation and amplifies functional ovarian hyperandrogenism by upregulating ovarian androgen production. Obesity increases inflammatory adipokines which, in turn, increase insulin resistance and adipogenesis. Lifestyle interventions focused on diet-weight loss and concurrent exercise are central to therapy which also commonly subsequently needs to include pharmacologic therapy. PCOS symptoms commonly improve with 5% to 10% weight loss, but 25% to 50% weight loss, usually achievable only through bariatric surgery, may be required for morbid obesity unresponsive to lifestyle-medical treatment. Bariatric surgery is a valuable approach to weight loss in PCOS where BMI is >=40 kg/m2 when non-surgical treatment and/or induction of pregnancy have failed, and can be an initial treatment when BMI is >=50 kg/m2. Further research in PCOS is needed to better understand the fundamental basis of the disorder, to ameliorate obesity, to correct hyperandrogenism, ovulation, hyperinsulinemia, and to optimize metabolic homeostasis. PMID- 30445141 TI - Obesity and Cancer Risk: Emerging biological mechanisms and perspectives. AB - Continuously rising trends in obesity-related malignancies render this disease spectrum a public health priority. Worldwide, the burden of cancer attributable to obesity, expressed as population attributable fraction, is 11.9% in men and 13.1% in women. There is convincing evidence that excess body weight is associated with an increased risk for cancer of at least 13 anatomic sites, including endometrial, esophageal, renal and pancreatic adenocarcinomas; hepatocellular carcinoma; gastric cardia cancer; meningioma; multiple myeloma; colorectal, postmenopausal breast, ovarian, gallbladder and thyroid cancers. We first synopsize current epidemiologic evidence; the obesity paradox in cancer risk and mortality; the role of weight gain and weight loss in the modulation of cancer risk; reliable somatometric indicators for obesity and cancer research; and gender differences in obesity related cancers. We critically summarize emerging biological mechanisms linking obesity to cancer encompassing insulin resistance and abnormalities of the IGF-I system and signaling; sex hormones biosynthesis and pathway; subclinical chronic low-grade inflammation and oxidative stress; alterations in adipokine pathophysiology; factors deriving from ectopic fat deposition; microenvironment and cellular perturbations including vascular perturbations, epithelial-mesenchymal transition, endoplasmic reticulum stress and migrating adipose progenitor cells; disruption of circadian rhythms; dietary nutrients; factors with potential significance such as the altered intestinal microbiome; and mechanic factors in obesity and cancer. Future perspectives regarding prevention, diagnosis and therapeutics are discussed. The aim of this review is to investigate how the interplay of these main potential mechanisms and risk factors, exerts their effects on target tissues provoking them to acquire a cancerous phenotype. PMID- 30445142 TI - Intravenous dexmedetomidine augments the oculocardiac reflex. PMID- 30445143 TI - Oral doxycycline and azithromycin in the management of recurrent conjunctival dehiscence following glaucoma drainage implantation in a child. PMID- 30445144 TI - Fibrin glue-assisted excision of a large recurrent microphthalmic cyst. PMID- 30445145 TI - Infantile sialidosis: natural history in a preterm infant with two new pathogenic mutations and new ocular findings. PMID- 30445146 TI - Visualizing and quantifying flow stasis in abdominal aortic aneurysms in men using 4D flow MRI. AB - PURPOSE: To examine methods for visualizing and quantifying flow stasis in abdominal aortic aneurysms (AAA) using 4D Flow MRI. METHODS: Three methods were investigated: conventional volumetric residence time (VRT), mean velocity analysis (MVA), and particle travel distance analysis (TDA). First, ideal 4D Flow MRI data was generated using numerical simulations and used as a platform to explore the effects of noise and background phase-offset errors, both of which are common 4D Flow MRI artifacts. Error-free results were compared to noise or offset affected results using linear regression. Subsequently, 4D Flow MRI data for thirteen (13) subjects with AAA was acquired and used to compare the stasis quantification methods against conventional flow visualization. RESULTS: VRT (R2 = 0.69) was more sensitive to noise than MVA (R2 = 0.98) and TDA (R2 = 0.99) at typical non-contrast signal-to-noise ratio levels (SNR = 20). VRT (R2 = 0.14) was more sensitive to background phase-offsets than MVA (R2 = 0.99) and TDA (R2 = 0.96) when considering a 95% effective background phase-offset correction. Qualitatively, TDA outperformed MVA (Wilcoxon p < 0.005, mean score improvement 1.6/5), and had good agreement (median score 4/5) with flow visualizations. CONCLUSION: Flow stasis can be quantitatively assessed using 4D Flow MRI. While conventional residence time calculations fail due to error accumulation as a result of imperfect measured velocity fields, methods that do not require lengthy particle tracking perform better. MVA and TDA are less sensitive to measurement errors, and TDA generates results most similar to those obtained using conventional flow visualization. PMID- 30445147 TI - Trafficking of the amino acid transporter B0,+ (SLC6A14) to the plasma membrane involves an exclusive interaction with SEC24C for its exit from the endoplasmic reticulum. AB - A plasma membrane amino acid transporter B0,+ (ATB0,+), encoded by the SLC6A14 gene, is specific for neutral and basic amino acids. It is up-regulated in several types of malignant cancers. Neurotransmitter transporters of the SLC6 family interact with specific SEC24 proteins of the COPII complex along their pathway from the endoplasmic reticulum (ER) to Golgi. This study focused on the possible role of SEC24 proteins in ATB0,+ trafficking. Rat ATB0,+ was expressed in HEK293 cells, its localization and trafficking were examined by Western blot, deglycosylation, immunofluorescence (co-localization with ER and trans-Golgi markers) and biotinylation. The expression of ATB0,+ at the plasma membrane was decreased by dominant negative mutants of SAR1, a GTPase, whose activity triggers the formation of the COPII complex. ATB0,+ co-precipitated with SEC24C (but not with the remaining isoforms A, B and D). This interaction was confirmed by immunocytochemistry and the proximity ligation assay. Co-localization of SEC24C with endogenous ATB0,+ was also observed in MCF-7 breast cancer cells. Contrary to the endogenous transporter, part of the overexpressed ATB0,+ is directed to proteolysis, a process significantly reversed by a proteasome inhibitor bortezomib. Co-transfection with a SEC24C dominant negative mutant attenuated ATB0,+ expression at the plasma membrane, due to proteolytic degradation. These results support a hypothesis that lysine at position +2 downstream of the ER export "RI" motif on the cargo protein is crucial for SEC24C binding and for further trafficking to the Golgi. Moreover, there is an equilibrium between ER export and degradation mechanisms in case of overexpressed transporter. PMID- 30445148 TI - Assessment of mesoscopic properties of deep gray matter iron through a model based simultaneous analysis of magnetic susceptibility and R2* - A pilot study in patients with multiple sclerosis and normal controls. AB - Most studies of brain iron relied on the effect of the iron on magnetic resonance (MR) relaxation properties, such as R2*, and bulk tissue magnetic susceptibility, as measured by quantitative susceptibility mapping (QSM). The present study exploited the dependence of R2* and magnetic susceptibility on physical interactions at different length-scales to retrieve information about the tissue microenvironment, rather than the iron concentration. We introduce a method for the simultaneous analysis of brain tissue magnetic susceptibility and R2* that aims to isolate those biophysical mechanisms of R2* -contrast that are associated with the micro- and mesoscopic distribution of iron, referred to as the Iron Microstructure Coefficient (IMC). The present study hypothesized that changes in the deep gray matter (DGM) magnetic microenvironment associated with aging and pathological mechanisms of multiple sclerosis (MS), such as changes of the distribution and chemical form of the iron, manifest in quantifiable contributions to the IMC. To validate this hypothesis, we analyzed the voxel based association between R2* and magnetic susceptibility in different DGM regions of 26 patients with multiple sclerosis and 33 age- and sex-matched normal controls. Values of the IMC varied significantly between anatomical regions, were reduced in the dentate and increased in the caudate of patients compared to controls, and decreased with normal aging, most strongly in caudate, globus pallidus and putamen. PMID- 30445149 TI - TRP channels in cardiac and intestinal fibrosis. AB - It is now widely accepted that advanced fibrosis underlies many chronic inflammatory disorders and is the main cause of morbidity and mortality of the modern world. The pathogenic mechanism of advanced fibrosis involves diverse and intricate interplays between numerous extracellular and intracellular signaling molecules, among which the non-trivial roles of a stress-responsive Ca2+/Na+ permeable cation channel superfamily, the transient receptor potential (TRP) protein, are receiving growing attention. Available evidence suggests that several TRP channels such as TRPC3, TRPC6, TRPV1, TRPV3, TRPV4, TRPA1, TRPM6 and TRPM7 may play central roles in the progression and/or prevention of fibroproliferative disorders in vital visceral organs such as lung, heart, liver, kidney, and bowel as well as brain, blood vessels and skin, and may contribute to both acute and chronic inflammatory processes involved therein. This short paper overviews the current knowledge accumulated in this rapidly growing field, with particular focus on cardiac and intestinal fibrosis, which are tightly associated with the pathogenesis of atrial fibrillation and inflammatory bowel diseases such as Crohn's disease. PMID- 30445150 TI - A fetal case of microphthalmia and limb anomalies with abnormal neuronal migration associated with SMOC1 biallelic variants. AB - Microphthalmia with limb anomalies (MLA, OMIM, 206920) is a rare autosomal recessive disease caused by biallelic pathogenic variants in the SMOC1 gene. It is characterized by ocular disorders (microphtalmia or anophtalmia) and limb anomalies (oligodactyly, syndactyly, and synostosis of the 4th and 5th metacarpals), variably associated with long bone hypoplasia, horseshoe kidney, venous anomalies, vertebral anomalies, developmental delay, and intellectual disability. Here, we report the case of a woman who interrupted her pregnancy after ultrasound scans revealed a depression of the frontal bone, posterior fossa anomalies, cerebral ventricular enlargement, cleft spine involving the sacral and lower-lumbar vertebrae, and bilateral microphthalmia. Micrognathia, four fingers in both feet and a slight tibial bowing were added to the clinical picture after fetal autopsy. Exome sequencing identified two variants in the SMOC1 gene, each inherited from one of the parents: c.709G>T - p.(Glu237*) on exon 8 and c.1223G>A - p.(Cys408Tyr) on exon 11, both predicted to be pathogenic by different bioinformatics software. Brain histopathology showed an abnormal cortical neuronal migration, which could be related to the SMOC1 protein function, given its role in cellular signaling, proliferation and migration. Finally, we summarize phenotypic and genetic data of known MLA cases showing that our case has some unique features (Chiari II malformation; focal neuropathological alterations) that could be part of the variable phenotype of SMOC1-associated diseases. PMID- 30445151 TI - Gamma tACS over M1 and cerebellar hemisphere improves motor performance in a phase-specific manner. AB - Transcranial alternating current stimulation (tACS) modulates neural connectivity in the cortical area under the electrodes. Although gamma tACS over the M1 and the cerebellar hemisphere has been shown to improve motor performance, the details of this effect remain unclear. This study aimed to clarify whether the effect of gamma tACS over the M1 and the cerebellar hemisphere is a phase specific. We applied tACS at 70 Hz over the left M1 and the right cerebellar hemisphere to 20 healthy adults while they performed a visuomotor control task using their right index finger for 30 s. Three stimulation conditions were applied: (1) pseudo-stimulation (sham condition), (2) 180 degrees phase difference in the two cortical target areas (anti-phase condition) and (3) 0 degrees phase difference (in-phase condition). The anti-phase condition decreased task error compared to the sham condition (P = 0.021), but did not differ from the in-phase condition. Our study demonstrated that the effect of gamma tACS over the M1 and the cerebellar hemisphere has phase specificity. This result suggests that intercortical functional synchronization is involved in the improvement of motor performance during gamma tACS over the M1 and the cerebellar hemisphere. PMID- 30445152 TI - Mindful eating and change in depressive symptoms: Mediation by psychological eating styles. AB - Earlier cross-sectional research showed that a higher level of mindful eating is associated with less depression. This study investigated associations of attentive mindful eating with change in depressive symptoms, as well as mediation by psychological eating styles, in the Longitudinal Aging Study Amsterdam (n = 946). The mindful eating domains Focused Eating, Eating in response to Hunger and Satiety Cues, Eating with Awareness and Eating without Distraction were measured by the Mindful Eating Behavior Scale. Three-year change in depressive symptoms was measured with the Center for Epidemiologic Studies Depression Scale. Emotional, external and restrained eating were measured by the 20-item version of the Dutch Eating Behaviour Questionnaire. Higher baseline scores on Focused Eating, Eating with Awareness and Eating without Distraction were associated with a 3-year decrease in depressive symptoms. Eating in response to Hunger and Satiety Cues was not associated with a change in depressive symptoms. Multiple mediation models showed mediation by external eating for the domains Eating with Awareness, Eating without Distraction, and Eating in response to Hunger and Satiety Cues, but no mediation by emotional and restrained eating. No mediation by the eating styles was found for Focused Eating. In this study, higher scores on three mindful eating domains were associated with a decrease in depressive symptoms. Mediation analyses suggest that three domains are associated with depression through external eating. PMID- 30445153 TI - Preparation sequence of two snack components influences snack composition and calorie intake. AB - Many contextual factors appear to influence both food intake as well as quality perception. A recent study showed the influence of pouring sequence in food preparation on food amount, ingredient ratio and calorie content. Two studies were conducted to further investigate the influence of pouring and preparation order on food intake. Using a within-subject design in study 1, participants were randomized to either pour yogurt or muesli first into a bowl before consuming the prepared snack. While the total amount of the snack did not differ between the two pouring order groups, participants poured significantly more yogurt and muesli when either snack component was poured first compared to when poured second. The second study used a real world setting asking participants to follow a certain preparation order when pouring their muesli and yogurt at home for one week. Again, whichever component was poured or spooned first was significantly more than when poured second. This effect remained over time. Depending on the caloric content of each snack component, the preparation sequence influenced total calorie consumption. It can be concluded that preparation sequence impacts total calorie intake even over time and has the potential to be used as a tool in weight management. PMID- 30445154 TI - Portion size influences intake in Samburu Kenyan people not exposed to the Western obesogenic environment. AB - For people in the modernized food environment, external factors like food variety, palatability, and ubiquitous learned cues for food availability can overcome internal, homeostatic signals to promote excess intake. Portion size is one such external cue; people typically consume more when served more, often without awareness. Though susceptibility to external cues may be attributed to the modernized, cue-saturated environment, there is little research on people living outside that context, or with distinctly different food norms. We studied a sample of Samburu people in rural Kenya who maintain a traditional, semi nomadic pastoralist lifestyle, eat a very limited diet, and face chronic food insecurity. Participants (12 male, 12 female, aged 20-74, mean BMI = 18.4) attended the study on two days and were provided in counterbalanced order an individual serving bowl containing 1.4 or 2.3 kg of a familiar bean and maize stew. Amount consumed was recorded along with post-meal questions in their dialect about their awareness of intake amount. Data were omitted from two participants who consumed the entire portion in a session. Even though the 'smaller' serving was a very large meal, participants consumed 40% more when given the larger serving, despite being unable to reliably identify which day they consumed more food. This result in the Samburu demonstrates the portion size effect is not a by-product of the modern food environment and may represent a more fundamental feature of human dietary psychology. PMID- 30445155 TI - Crystal structure and substrate recognition mechanism of Aspergillus oryzae isoprimeverose-producing enzyme. AB - Isoprimeverose-producing enzymes (IPases) release isoprimeverose (alpha-d xylopyranosyl-(1 -> 6)-d-glucopyranose) from the non-reducing end of xyloglucan oligosaccharides. Aspergillus oryzae IPase (IpeA) is classified as a member of the glycoside hydrolase family 3 (GH3); however, it has unusual substrate specificity compared with other GH3 enzymes. Xylopyranosyl branching at the non reducing ends of xyloglucan oligosaccharides is vital for IpeA activity. We solved the crystal structure of IpeA with isoprimeverose at 2.4 A resolution, showing that the structure of IpeA formed a dimer and was composed of three domains: an N-terminal (beta/alpha)8 TIM-barrel domain, alpha/beta/alpha sandwich fold domain, and a C-terminal fibronectin-like domain. The catalytic TIM-barrel domain possessed a catalytic nucleophile (Asp300) and acid/base (Glu524) residues. Interestingly, we found that the cavity of the active site of IpeA was larger than that of other GH3 enzymes, and subsite -1' played an important role in its activity. The glucopyranosyl and xylopyranosyl residues of isoprimeverose were located at subsites -1 and -1', respectively. Gln58 and Tyr89 contributed to the interaction with the xylopyranosyl residue of isoprimeverose through hydrogen bonding and stacking effects, respectively. Our findings provide new insights into the substrate recognition of GH3 enzymes. PMID- 30445156 TI - Association of anti-nuclear matrix protein 2 antibody with complications in patients with idiopathic inflammatory myopathies: A meta-analysis of 20 cohorts. AB - BACKGROUND: Several complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications. OBJECTIVE: The aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients. METHODS: Two investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2 < 25%, otherwise a random-effects model (the Mantel-Haenszel method) was used. RESULTS: Twenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled OR = 4.00, 95% CI: 2.65-6.06 in adults; pooled OR = 1.62, 95% CI: 1.14-2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19-0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled OR = 1.42, 95% CI: 0.69 2.91). CONCLUSION: The present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients. PMID- 30445157 TI - Osseointegration and current interpretations of the bone-implant interface. AB - Complex physical and chemical interactions take place in the interface between the implant surface and bone. Various descriptions of the ultrastructural arrangement to various implant design features, ranging from solid and macroporous geometries to surface modifications on the micron-, submicron-, and nano- levels, have been forwarded. The current knowledge regarding the structural organisation of the bone-implant interface is reviewed with a focus on solid devices, mainly metal (or alloy) intended for permanent anchorage in bone. Certain biomaterials that undergo surface and bulk degradation are also considered. The bone-implant interface is a heterogeneous zone consisting of mineralised, partially mineralised, and unmineralised areas. Within the meso micro-nano-continuum, mineralised collagen fibrils form the structural basis of the bone-implant interface, in addition to accumulation of non-collagenous macromolecules such as osteopontin, bone sialoprotein, and osteocalcin. Based on the available literature, eight distinct interpretations of the ultrastructure of the bone-implant interface are revealed. The interpretation is influenced by the in vivo model and species-specific characteristics, healing time point(s), physico-chemical properties of the implant surface, implant geometry, sample preparation route(s) and associated artefacts, analytical technique(s) and their limitations, and non-compromised vs compromised local tissue conditions. The understanding of the ultrastructure of the interface during experimental conditions is rapidly evolving due to the introduction of novel techniques for the preparation and analysis of the interface. Nevertheless, the current understanding of the interface zone in humans in relation to clinical implant performance is still hampered by the shortcomings of clinical methods to determine the fine details of the bone-implant interface. STATEMENT OF SIGNIFICANCE: Being a hierarchical material by design, the overall strength of bone is governed by composition and structure. Understanding the structure of the bone-implant interface is essential in the development of novel bone repair materials and strategies, and their long-term success. Here, the current knowledge regarding the eventual structural organisation of the bone-implant interface is reviewed, with a focus on solid devices intended for permanent anchorage in bone, and certain biomaterials that undergo surface and bulk degradation. The bone-implant interface is a heterogeneous zone consisting of mineralised, partially mineralised, and unmineralised areas. Within the meso micro-nano-continuum, mineralised collagen fibrils form the structural basis of the bone-implant interface, in addition to accumulation of non-collagenous macromolecules such as osteopontin, bone sialoprotein, and osteocalcin. PMID- 30445159 TI - Effect of stress on corrosion of high-purity magnesium in vitro and in vivo. AB - Magnesium-based implants are subjected to complicated stresses during implantation in the human body. The stress effects on corrosion of magnesium (Mg) in vitro were investigated in previous studies, whereas in this study, the corrosion behaviors of high-purity (HP) Mg under stress were comparatively studied in vitro in Hank's solution and in vivo in the subcutaneous environment of rats. Loading devices were designed to apply compressive stress (15.1 +/- 0.5 MPa) and tensile stress (13.2 +/- 0.2 MPa) on HP Mg specimens both in vitro and in vivo. Corrosion rates of HP Mg were characterized by mass and volume losses. It was shown that the applied compressive stress had no effect on in vitro corrosion behaviors and the applied tensile stress accelerated the in vitro corrosion, thereby causing severe pitting corrosions and stress corrosion cracking (SCC). However, there was no significant change for corrosion behaviors in vivo under neither compressive stress nor tensile stress. Severe pitting corrosion and SCC did not occur in vivo. Histological evaluation revealed that a fibrotic capsule induced by foreign body reaction was formed on the corrosion surfaces of HP Mg in the subcutaneous environment. It was proposed that the fibrotic capsule suppressed the effects of stress in vivo by protecting the corrosion surfaces. These results provided new insights into understanding the stress effects on the corrosion of Mg both in vitro and in vivo. STATEMENT OF SIGNIFICANCE: Mg and its alloys have shown potential as biodegradable metallic materials. During implantation, Mg is subjected to various mechanical environments in the human body. It is necessary to have a clear understanding of different effects of stress on Mg corrosion. However, few studies were performed in vivo. It is important to analyze the effect of quantitative stress on Mg corrosion in vivo. Therefore, in this study, quantitative stresses were applied on Mg both in vitro and in vivo. The effects of stress on in vitro and in vivo corrosions of Mg were investigated and compared. PMID- 30445158 TI - Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on Ti6Al4V ELI scaffolds for bone regeneration in an osteoporotic bone environment. AB - The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone. STATEMENT OF SIGNIFICANCE: Reconstruction of bones after severe trauma or tumors extirpation is one of the most challenging tasks in the field of orthopedic surgery. This scenario is even more complicated in the case of osteoporotic patients, since their bone regeneration capability is decreased. In this work we present a porous implant that promotes bone regeneration even in osteoporotic bone. By coating the implant with osteogenic bioceramics such as silicon substituted hydroxyapatite and subsequent adsorption of vascular endothelial growth factor, these implants stimulate the bone ingrowth when they are implanted in osteoporotic sheep. PMID- 30445161 TI - Low-Gradient Aortic Stenosis: Solving the Conundrum Using Multi-Modality Imaging. AB - Up to 1/3 of patients with both reduced or preserved left ventricular ejection fraction (LVEF), harbor a mean pressure gradient (MPG) < 40 mm Hg (peak velocity (PV) < 4 m/s), suggesting moderate aortic stenosis (AS) and an aortic valve area (AVA) < 1 cm2 suggesting severe AS raising uncertainties regarding AS severity and appropriate management. In patients with reduced LVEF, increased transvalvular flow and stroke volume >= 20% (i.e. contractile reserve) during low dose dobutamine echocardiography enables distinguishing patients with "true severe AS" (severe AS with secondary LV dysfunction, PV >= 4 m/s or MPG > 30-40 mm Hg at peak while AVA remains <1 cm2) from patients with "pseudo-severe AS" (moderate AS with associated LV dysfunction due to ischemic or dilated cardiomyopathy, AVA at peak >=1 cm2 with a MPG < 30-40 mm Hg). However, interpretation of dobutamine stress echocardiography is often challenging, and absence of contractile reserve is observed in 20 to 30% of patients. Measurement of the degree of calcification (AVC) using computed tomography is an accurate and flow-independent method for the assessment of AS severity. A score > 1250 AU in women and >2000 UA in men strongly suggest severe AS. Combination of dobutamine echocardiography and AVC scoring enables assessment of AS severity with high confidence. The subset of patients with discordant grading and preserved LVEF is heterogenous and encompasses various conditions. A minority harbor a low flow state related to a reduced myocardial performance, an increased arterial afterload or combination of both. A low flow state is an important prognostic factor but does not provide any information regarding AS severity. Similarly to patients with reduced LVEF, assessment of the degree of AVC seems the best method to differentiate patients with pseudo-severe AS from patients with true severe AS. The latter should be referred for an intervention if symptomatic whereas the optimal management of the former subset remains uncertain. PMID- 30445160 TI - An Update on the Role of Cardiorespiratory Fitness, Structured Exercise and Lifestyle Physical Activity in Preventing Cardiovascular Disease and Health Risk. AB - The cardiovascular disease (CVD) pandemic has placed considerable strain on healthcare systems, quality of life, and physical function, while remaining the leading cause of death globally. Decades of scientific investigations have fortified the protective effects of cardiorespiratory fitness (CRF), exercise training, and physical activity (PA) against the development of CVD. This review will summarize recent efforts that have made significant strides in; 1) the application of novel analytic techniques to increase the predictive utility of CRF; 2) understanding the protective effects of long-term compliance to PA recommendations through large cohort studies with multiple points of assessment; 3) and understanding the potential harms associated with extreme volumes of PA. PMID- 30445162 TI - Echocardiography in Congenital Heart Disease. AB - As the prevalence of adult congenital heart disease continues to grow secondary to advances in surgical and diagnostic techniques, it is important for a physician to supplement their examinations with non-invasive imaging techniques to assess their patients. Although a number of these patients have regular cardiology followup, some may be new patients that do not even know their cardiac history. Echocardiography has proven to be a useful tool for this purpose and its utility has expanded drastically with the development of better technology and newer techniques. In this article, we highlight some of these advancements including 2D echocardiography, agitated saline, contrast echocardiography, stress, and 4D, in addition to how each modality can help assess key aspects of the structure and function of a congenital heart defect. PMID- 30445163 TI - Content and commentary: HPV vaccine and YouTube. AB - STUDY OBJECTIVE: Human Papilloma Virus (HPV) vaccination has demonstrated efficacy; however, many vaccine-eligible remain unvaccinated. YouTube is a popular video-sharing platform with several topics, including the HPV vaccine. Our purpose is to examine the tone of YouTube videos toward the HPV vaccine, accuracy of the information displayed, and content of commentary. DESIGN: This observational study investigated publicly available content regarding the HPV vaccine on the video-sharing website YouTube (www.youtube.com). Videos and comments were collected between June 22, 2014 and December 19th, 2014. A total of 35 videos, with the 100 most recent comments for each video were collected and coded by a single researcher. A 25% subsample were by a second researcher to ensure inter-rater agreement of greater than 80%. MAIN OUTCOME MEASURES: Videos were evaluated for four types of information: descriptive information, tone toward the vaccine (anti- or pro-vaccine), content and commentary content, sorted by 11 frequently identified themes. SETTING, PARTICIPANTS, INTERVENTIONS: Not applicable. RESULTS: The majority of videos were negative in tone toward the vaccine. Tone of the video was not a predictor of video popularity. Pro-vaccine videos were four times more likely to report information accurately than anti vaccine videos. Anti-vaccine videos were more likely to report information incorrectly and omit information. The most frequent commentary themes were concerning serious side effects, conspiracy theories and vaccines generally being unhealthy. CONCLUSIONS: The internet is an important resource for the general population; widely-viewed YouTube videos contain erroneous and incomplete information. Anti-vaccine ideology is prevalent in video content and commentary. PMID- 30445164 TI - Cubosomes for topical delivery of the antimicrobial peptide LL-37. AB - In this study, the use of cubosomes for topical delivery of the antimicrobial peptide (AMP) LL-37 was investigated. Topical delivery of AMPs is of great interest for treatment of skin infections caused by bacteria, such as Staphylococcus aureus. AMP containing cubosomes were produced by three different preparation protocols and compared: i) pre-loading, where LL-37 was incorporated into a liquid crystalline gel, which thereafter was dispersed into nanoparticles, ii) post-loading, where LL-37 was let to adsorb onto pre-formed cubosomes, and iii) hydrotrope-loading, where LL-37 was incorporated during the spontaneously formed cubosomes in an ethanol/glycerol monooleate mixture. Particle size and size distribution were analyzed using dynamic light scattering (DLS), liquid crystalline structure by small angle x-ray scattering (SAXS) and release of LL-37 by a fluorescamine assay. Proteolytic protection of LL-37 as well as bactericidal effect after enzyme exposure was investigated. The skin irritation potential of cubosomes was examined by an in vitro epidermis model. Finally, the bacterial killing property of the cubosomes was examined by an ex vivo pig skin wound infection model with Staphylococcus aureus. Data showed that a high loading of LL 37 induced formation of vesicles in case of cubosomes prepared by sonication (pre loading). No release of LL-37 was observed from the cubosomes, indicating strong association of the peptide to the particles. Proteolysis studies showed that LL 37 was fully protected against enzymatic attacks while associated with the cubosomes, also denoting strong association of the peptide to the particles. As a consequence, bactericidal effect after enzyme exposure remained, compared to pure LL-37 which was subjected to proteolysis. No skin irritation potential of the cubosomes was found, thus enabling for topical administration. The ex vivo wound infection model showed that LL-37 in pre-loaded cubosomes killed bacteria most efficient. PMID- 30445165 TI - Maternal eicosapentaenoic acid feeding promotes placental angiogenesis through a Sirtuin-1 independent inflammatory pathway. AB - Maternal overnutrition or obesity is associated with a wide range of metabolic disorders and may impair placental angiogenesis. Previous studies have shown that n-3 polyunsaturated fatty acids (PUFA) promote fetal growth in both rodents and humans. Whether n-3 PUFA impacts on placental angiogenesis in vivo remains unclear. Sirtuin-1 (SIRT1) is a protein deacetylase that plays an important role in regulating inflammation and endothelial function. Little information is available on a putative role of SIRT1 in placental angiogenesis. The goal of this study was to examine the capability of eicosapentaenoic acid (EPA) to regulate angiogenesis and inflammation in SIRT1-deficient placentas. In the present study, male and female SIRT1+/- mice were mated overnight, then primiparous SIRT1+/- mice were fed a 60% kcal HFD or equienergy EPA diet (4.4% EPA-ethyl ester). We found that the EPA diet significantly improved maternal insulin sensitivity and decreased plasma levels of inflammatory factors IL-6 and TNFalpha concentration. Moreover, EPA treatment promoted fetus growth and placental angiogenesis, and inhibited the hypoxia inducible factor-1alpha(HIF1alpha) pathway. SIRT1 deficiency exhibited an opposite effect, leading to decrease in placental angiogenesis and fetal weight. No significant effect was observed between diet and genotype. Here, we reported for the first time that EPA treatment increased the expression of placental inflammatory genes and promoted translocation of NFkappaB into the nucleus. On the contrary, SIRT1-deficient placentas showed a decreased inflammation state. Together, these data demonstrate a previously unknown role of EPA to promote placental angiogenesis through a SIRT1 independent inflammatory pathway. PMID- 30445166 TI - The methodological quality of dose-response meta-analyses needed substantial improvement: A cross-sectional survey and proposed recommendations. AB - OBJECTIVES: To investigate methodological quality of published dose-response meta analysis (DRMA) and explore study characteristics associated with the quality. STUDY DESIGN AND SETTING: We searched three databases for published DRMAs, and used a modified AMSTAR (15 items) checklist to assess the methodological quality. We summarized the compliance of those DRMAs to the AMSTAR items and used multivariable regression analysis to explore the association between pre specified study characteristics with the overall methodological quality. RESULTS: We identified 529 DRMAs. Of the methodological quality items, six were well complied (80% or more) and 6 poorly complied (30% or fewer) by these DRMAs. The median score was 9 points [first and third quartile: 7, 10] and only 64/529 had score over 10 points. Regression analysis suggested that studies with more authors (beta = 0.19; 95%CI: 0.05, 0.33), published more recently (beta = 0.29; 95%CI: 0.21, 0.36), with financial support (beta = 0.41; 95%CI: 0.13, 0.70), conducted by authors from European (other regions vs. European, beta = -0.68; 95%CI: -1.05, -0.31) were associated with better methodological quality. CONCLUSION: The methodological quality of published DRMAs was suboptimal. Substantial efforts are warranted to improve the quality, including developing methodology guideline, involving more methodological trained authors, and so forth. PMID- 30445167 TI - Bevacizumab induces inflammation in MDA-MB-231 breast cancer cell line and in a mouse model. AB - BACKGROUND: Bevacizumab or Avastin(r) (Av) is an anti-vascular endothelial growth factor agent. It does not improve survival of breast cancer patients due to development of refractoriness. Av treatment was shown to increase inflammation in a diabetic mouse model, and also to induce epithelial-to-mesenchymal transition of non-transformed breast epithelia. This study aimed to understand if the Av induced inflammatory microenvironment could be a mechanism of Av refractoriness. Expression profiles of inflammatory mediators, in vitro in MDA-MB-231 cells, in vivo in a mouse model xenografted with MDA-MB-231 cells and from archived cases of human breast carcinoma tissues were evaluated. Gap junctions are also crucial for angiogenesis and tumor cell extravasation. The effect of connexin 43 (Cx43) overexpression on the expression of inflammatory markers in MDA-MB-231 cells treated with Av was assessed. METHODS: MDA-MB-231 cells, control or overexpressing Cx43, were used in this study. Proliferation and invasion assays were performed. Quantitative PCR, ELISA and western blotting were performed to assess the regulation of inflammatory mediators and other factors upon Av treatment. Immunofluorescence was performed to document the translocation of Nuclear Factor-kappa B p65. RESULTS: Breast cancer tissues had elevated transcriptional levels of inflammatory mediators. Av treatment increased expression levels of inflammatory mediators and metastatic factors in vitro and in vivo. Interestingly, overexpressing Cx43 in MDA-MB-231 cells alleviated the inflammatory effects induced by Av treatment. CONCLUSION: This study attributes Av refractoriness to the Av therapy-induced inflammatory microenvironment. PMID- 30445168 TI - A New Paradigm of Resuscitation: Perfusion-Guided Cardiopulmonary Resuscitation. PMID- 30445169 TI - Preoperative Imaging in Search of Ventricular Tachycardia Circuit. PMID- 30445170 TI - The Small Conductance Calcium Activated Potassium Current Modulates the Ventricular Escape Rhythm in Normal Rabbit Hearts. AB - BACKGROUND: The apamin-sensitive small-conductance calcium-activated K (SK) current (IKAS) modulates automaticity of the sinus node; IKAS blockade by apamin causes sinus bradycardia. OBJECTIVE: To test the hypothesis that IKAS modulates ventricular automaticity. METHODS: We tested the effects of apamin (100 nM) on ventricular escape rhythms in Langendorff perfused rabbit ventricles with atrioventricular (AV) block (Protocol 1) and on recorded transmembrane action potential (TMP) of pseudotendons of superfused right ventricular (RV) endocardial preparations (Protocol 2). RESULTS: All preparations exhibited spontaneous ventricular escape rhythms. In Protocol 1, apamin decreased the atrial rate from 186.2+/-18.0 bpm to 163.8+/-18.7 bpm (N=6, p=0.006) but accelerated the ventricular escape rate from 51.5+/-10.7 to 98.2+/-25.4 bpm (p=0.031). Three preparations exhibited bursts of nonsustained ventricular tachycardia (NSVT) and pauses, resulting in repeated burst-termination pattern. In Protocol 2, apamin increased the ventricular escape rate from 70.2+/-13.1 to 110.1+/-2.2 bpm (p=0.035). Spontaneous phase 4 depolarization was recorded from the pseudotendons in 6 of 10 preparations at baseline and in 3 in the presence of apamin. There were no changes of phase 4 slope (18.37+/-3.55 vs. 18.93+/-3.26 mV/s, p=0.231, N=3), but the threshold of phase 0 activation (mV) reduced from -67.97+/-1.53 to 75.26+/-0.28 (p=0.034). Addition of JTV-519, a ryanodine receptor 2 (RyR2) stabilizer, in 5 preparations reduced escape rate back to baseline. CONCLUSIONS: Contrary to its bradycardic effect in the sinus node, IKAS blockade by apamin accelerates ventricular automaticity and causes repeated NSVT in normal ventricles. RyR2 blockade reversed the apamin effects on ventricular automaticity. PMID- 30445171 TI - IMRT and image-guided adapted brachytherapy for cervix cancer. AB - PURPOSE: To report long-term outcomes of cervical cancer patients treated with intensity-modulated radiation therapy and 3D image-guided adapted brachytherapy (IMRT/3D-IGABT) compared to 2D external irradiation and 2D brachytherapy (2D EBRT/BT). METHODS AND MATERIALS: This study included patients with newly diagnosed cervical cancer and pre-treatment FDG-PET treated with curative-intent irradiation from 1997-2013. Treatment policy changed from 2D EBRT/BT to IMRT/3D IGABT in 2005. Patterns of recurrence, cancer specific survival (CSS), and overall survival (OS) were evaluated. Late GI and GU toxicity was scored with Common Terminology Criteria for Adverse Events. RESULTS: Median follow-up for patients alive at the time of last follow-up in the 2D EBRT/BT group (n=300) was 15.3 years (10.8-20.5) and in the IMRT/3D-IGABT group (n=300) 7 years (5-12.4). Tumors were FIGO stage IB1-IB2 (33%), IIA-IIB (41%), and IIIA-IVA (26%). The 5 year freedom from recurrence (FFR), CSS, and OS for 2D EBRT/BT patients was 57% FFR, 62% CSS, and 57% OS. For IMRT/3D-IGABT, the 5-year results were 65% FFR (p=0.04), 69% CSS (p=0.01), and 61% OS (p=0.04). When stratified by PET lymph node status, disease control was most improved with IMRT/3D-IGABT vs. 2D EBRT/BT in patients with positive pelvic lymph nodes only (p=0.02). Cumulatively, there were 88 (15%) grade >=3 late bowel/bladder toxicity (2D EBRT/BT: 55 (18%) vs. IMRT/3D-IGABT: 33 (11%), p=0.02). CONCLUSIONS: IMRT/3D-IGABT was associated with improved survival and decreased GI and GU toxicity in cervical cancer patients compared to 2D EBRT/BT. PMID- 30445172 TI - SABR in high risk prostate cancer: outcomes from two prospective clinical trials with and without elective nodal irradiation. AB - PURPOSE: There is limited data on SABR in high-risk prostate cancer (PCa) especially regarding the role of elective nodal irradiation (ENI). This study compares two prospective phase II trials using SABR in high-risk prostate cancer, with and without ENI. METHODS: Patients had high-risk PCa. Trial1 received 40Gy/5 to the prostate and 30Gy/5 to the seminal vesicles. Trial2 received 40Gy/5 to the prostate and 25Gy/5 to the pelvis and seminal vesicles. CTCAE toxicities were collected. Biochemical failure (BF) was defined as nadir+2 and 4-year PSA response rate (4yPSARR) was < 0.4 ng/ml. RESULTS: 60 patients were included (trial1, n=30; trial2, n=30). Median follow-up was 5.6y and 4.0y. Median nPSA was 0.02ng/ml for both. Six patients had BF, all from trial1. The BF rate was 14.6% at 5y in trial1and 0% in trial2. 63% of patients in trial1 and 93% in trial2 had a 4yPSARR. Two patients died in trial1, one from metastatic disease. One patient in trial2 died from other causes. No other patients developed metastatic disease, and one patient in trial1 had CRPC. OS at 5y was 93.2% and 96.7% (p=0.86). There was significantly worse late GI and sexual toxicity in trial1, but no difference in late GU toxicity. CONCLUSIONS: SABR in high-risk prostate cancer yields biochemical control rates that may be comparable to other radiotherapy modalities. ENI using SABR is feasible and may lead to a significant improvement in biochemical control as well as in 4yPSARR, without an increase in late GI or GU toxicity. Longer follow-up would provide a better assessment of biochemical control. Well conducted phase III trials are needed to fully establish the role of SABR as well as ENI in high-risk prostate cancer. PMID- 30445173 TI - Early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy for breast cancer, lung cancer and lymphoma. AB - PURPOSE: We characterized the early changes in cardiovascular biomarkers with contemporary thoracic radiation therapy (RT) and evaluated their associations with radiation dose volume metrics including mean heart dose (MHD), V5 and V30. METHODS AND MATERIALS: In a prospective longitudinal study of 87 patients with breast cancer, lung cancer or mediastinal lymphoma treated with photon or proton thoracic RT, blood samples were obtained pre-RT and after completion of RT (median 20 days, interquartile range (IQR) 1,35). High sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), placental growth factor (PIGF) and growth differentiation factor 15 (GDF-15) were measured. Associations between MHD, V5 and V30, and biomarker levels, and associations between echocardiography-derived measures of cardiac function and biomarker levels, were assessed in multivariable linear regression models. Analyses were performed according to the following subgroups: 1) breast cancer alone and 2) lung cancer and lymphoma combined. RESULTS: The median (IQR) estimates of MHD ranged from 1.3 Gy (0.9,2.4) in breast cancer (n=60) to 6.8 Gy (5.4,10.2) in mediastinal lymphoma (n=14) and 8.4 Gy (6.7,16.1) in lung cancer (n=13) patients (p<0.001). There were no significant increases in biomarker levels from pre-RT to post-RT in breast cancer. In lung cancer/lymphoma, PIGF increased from a median (IQR) of 20 ng/L (16,26) to 22 ng/L (16,30) (p=0.005) and GDF-15 increased from 1171 ng/L (755,2493) to 1887 ng/L (903,3763) (p=0.006). MHD, V5, and V30 were significantly associated with post-RT PIGF and GDF-15 levels in multivariable models. Changes in biomarkers were not significantly associated with changes in echocardiography-derived measures of cardiac function. CONCLUSION: Contemporary thoracic RT induces acute abnormalities in vascular and inflammatory biomarkers that are associated with radiation dose volume metrics, particularly in lung cancer and mediastinal lymphoma. Long-term follow-up studies are needed to determine the impact of these changes on the development of overt cardiac disease. PMID- 30445174 TI - Jet nebulization of bacteriophages with different tail morphologies - Structural effects. AB - It was previously demonstrated that the loss of infectivity of a myovirus PEV44 after jet nebulization was closely related to a change in bacteriophage (phage) structure. In this follow-up study, we further examined the impact of jet nebulization on tailed phages, which constitute 96% of all known phages, from three different families, Podoviridae (PEV2), Myoviridae (PEV40) andSiphoviridae (D29). Transmission electron microscopy (TEM) identified major changes in phage structures after jet nebulization, correlating with their loss of infectivity. For the podovirus PEV2, jet nebulization had a negligible impact on its activity (0.04 log10 pfu/mL loss) and structural change. On the other hand, the proportion of intact phages in the nebulized samples dropped from 50% to ~27% for PEV40 and from 15% to ~2% for D29. Phage deactivation of PEV40 measured by the TEM structural damage (0.52 log10 pfu/mL) was lower than that obtained by plaque assay (1.02 log10 pfu/mL), but within the range of variation (+/-0.5 log10 pfu/mL). However, TEM quantification considerably underestimated the titer reduction of D29 phage, ~2 log pfu/mL lower than that obtained in plaque assay (3.25 log10 pfu/mL loss). In conclusion, nebulization-induced titre loss was correlated with morphological damage to phages and in particular, the tail length may be an important consideration for selection of phages in inhaled therapy using jet nebulization. PMID- 30445175 TI - A four-strain probiotic exerts positive immunomodulatory effects by enhancing colonic butyrate production in vitro. AB - Poorly formulated probiotic supplements intended for oral administration often fail to protect bacteria from the challenges of human digestion, meaning bacteria do not reach the small intestine in a viable state. As a result, the ability of probiotics to influence the human gut microbiota has not been proven. Here we show how (i) considered formulation of an aqueous probiotic suspension can facilitate delivery of viable probiotic bacteria to the gut and (ii) quantitate the effect of colonisation and proliferation of specific probiotic species on the human gut microbiota, using an in-vitro gut model. Our data revealed immediate colonisation and growth of three probiotic species in the luminal and mucosal compartments of the proximal and distal colon, and growth of a fourth species in the luminal proximal colon, leading to higher proximal and distal colonic lactate concentrations. The lactate stimulated growth of lactate-consuming bacteria, altering the bacterial diversity of the microbiota and resulting in increased short-chain fatty acid production, especially butyrate. Additionally, an immunomodulatory effect of the probiotics was seen; production of anti inflammatory cytokines (IL-6 and IL-10) was increased and production of inflammatory chemokines (MCP-1, CXCL 10 and IL-8.) was reduced. The results indicate that the probiotic species alone do not result in a clinical effect; rather, they facilitate modulation of the gut microbiota composition and metabolic activity thereby influencing the immune response. PMID- 30445176 TI - Fit & quit: An efficacy trial of two behavioral post-cessation weight gain interventions. AB - While smoking cessation leads to significant improvements in both mortality and morbidity, post-cessation weight gain partially attenuates this benefit. Even though post-cessation weight gain is small (4.7 kg on average), it is a stated reason to delay cessation attempts and is associated with smoking relapse. Fit & Quit is a randomized, controlled efficacy trial that aims to examine the ability of a weight stability intervention and a weight loss intervention to reduce post cessation weight gain. For this purpose, Fit & Quit will randomize participants to three conditions: (a) Small Changes, a weight gain prevention intervention; (b) Look AHEAD Intensive Lifestyle Intervention; and (c) a lower-intensity bibliotherapy intervention. All conditions will receive a highly efficacious behavioral (i.e., rate reduction skills, motivational interviewing) and pharmacological (i.e., varenicline) smoking cessation program. A total of 400 participants will be recruited and randomized to the three interventions. Participants will be recruited in waves, with 10 waves of approximately 40 participants per wave. The primary outcomes of this study include post-cessation weight gain and cessation status at 12-month follow-up. Fit & Quit will integrate and adapt the strongest evidence-based interventions available for weight management and smoking cessation. Fit & Quit is highly innovative in the areas of the target population, study design, and use of technology. For these reasons, we expect that Fit & Quit will make a significant public health contribution to curtailing the important cessation barrier of post-cessation weight gain. PMID- 30445177 TI - Therapeutic efficacy of intense pulsed light in patients with refractory meibomian gland dysfunction. AB - PURPOSE: To evaluate the efficacy and safety of intense pulsed light (IPL) combined with meibomian gland expression (MGX) for treatment of refractory meibomian gland dysfunction (MGD). METHODS: Ninety eyes of 45 patients were randomly assigned to receive either the combination of IPL and MGX or MGX alone (control). Each eye underwent eight treatment sessions at 3-week intervals. Parameters were evaluated before and during treatment as well as at 3-11 weeks after the last treatment session. Measured parameters included the Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire score, noninvasive breakup time (NIBUT), fluorescein breakup time (BUT), lipid layer grade, lipid layer thickness (LLT), lid margin abnormalities, corneal and conjunctival fluorescein staining (CFS) score, meibum grade, and meiboscore. RESULTS: A significant improvement in lipid layer grade was apparent in the IPL-MGX group from 6 to 32 weeks after treatment onset (adjusted P < 0.001) but was not observed in the control group. The IPL-MGX group also showed significant improvements in LLT, NIBUT, BUT, lid margin abnormalities, and meibum grade compared with the control group at 24 and 32 weeks (adjusted P < 0.001) as well as significant improvements in the SPEED score at 32 weeks (adjusted P = 0.044) and in CFS score at 24 (adjusted P = 0.015) and 32 (adjusted P = 0.006) weeks. CONCLUSIONS: The combination of IPL and MGX improved homeostasis of the tear film and ameliorated ocular symptoms in patients with refractory MGD and is thus a promising modality for treatment of this condition. PMID- 30445178 TI - Biogeography of the human ocular microbiota. AB - PURPOSE: The human eye is composed of numerous microhabitats. The aim of this study was to understand the communality and differences in the microbiomes of various regions of the eye. METHODS: Four ocular sites from different subject groups were assessed including the eyelid margin tissue from patients with lid abnormalities (n = 20), fornix and limbus conjunctival tissue from patients with pterygia (n = 23), ocular (conjunctival) surface swabs (n = 45) and facial skin swabs (n = 16). Microbial communities were analysed by extracting total DNA from samples and sequencing the 16S ribosomal(r)RNA gene using the Illumina MiSeq platform. Sequences were quality filtered, clustered into unique sequences (zOTUs) using the UNOISE pipeline in USEARCH and taxonomically classified using SILVA. RESULTS: A difference in bacterial richness and diversity was found between sites (P < 0.001) and for age (P < 0.035) but not for sex (P > 0.05). There was a difference in bacterial community structure and composition between sites (P < 0.001). Bacterial distribution could be broadly classified into three groups - zOTUs resident on the skin and lid margin but with low abundances at other sites (Corynebacterium, Staphylococcus), zOTUs found mainly on the ocular surface (Acinetobacter, Aeribacillus) and zOTUs mostly present in the conjunctiva and lid margin (Pseudomonas). CONCLUSION: The microhabitats of the human eye (ocular surface, conjunctiva, lid margin and skin) have a distinct bacterial biogeography with some bacteria shared between multiple regions while other bacteria occupy a more confined niche. PMID- 30445179 TI - Optimization of DamID for use in primary cultures of mouse hepatocytes. AB - DamID, a method to identify DNA associating with a particular protein, was originally developed for use in immortalized tissue culture lines. The power of this technique has led to its adaptation for a number of additional systems. Here we report adaptations for its use in primary cells isolated from rodents with emphasis on the challenges this presents. Specifically, we present several modifications that allow the method to be performed in mouse acutely isolated primary hepatocytes while seemingly maintaining tissue genome architecture. We also describe the downstream bioinformatic analysis necessary to identify LADs and discuss some of the parameters and their effects with regards to the sensitivity of the method. PMID- 30445180 TI - A reflection on the role of ICP-MS in proteomics: Update and future perspective. AB - Mass spectrometry is the technique of reference for the identification and quantification of proteins. Whereas ESI and MALDI ionization sources are inherently not quantitative being highly influenced by the chemical nature of the analyte and the matrix, ICP-MS uses a hard ionization source that destroys proteins into its atoms and measures the elemental signal, which is independent of its chemical environment. As a consequence, ICP-MS turns up as an excellent technique for the screening, mapping and quantification of peptides and proteins in a sample through elemental detection (any element but C, H, N, or O) once they have been previously separated by chromatography. In this time, great efforts have been put in developing instrumentation and new methodologies that enable a better, more efficient, and more useful analysis of proteins with ICP-MS. Moreover, quantitative capabilities but lack of molecular information of ICP has led to a synergic relationship both with identifying capabilities of ESI-MS, or the use of protein-specific antibodies carrying an elemental label. JOURNAL SIGNIFICANCE: We are delighted to participate in this special issue and have the chance to congratulate Journal of Proteomics for its 10th Anniversary, and wish for many further successful anniversaries. During this last decade, Journal of Proteomics has been a clear promotor of works integrating ICP-MS for proteomics analysis. In fact, already in 2009, a review was published by invitation of the editor in chief focused on the established and potential role of ICP-MS in different areas of the proteomics analysis at the time: "The emerging role of ICP MS in proteomics" [1]. Even though ICP-MS is not fully known or acknowledged in the proteomics world yet, its impact was significant as demonstrated by the really high interest in such publication (over 150 citations). Since then, several excellent papers relating to ICP-MS applications in proteomics have been published in this journal. Following the trend, we expect through this personal view of the current standing of ICP-MS in proteomics to enlighten the readers of Journal of Proteomics with a vision of the full present and future potential of ICP-MS in proteomics. PMID- 30445181 TI - Using proteins to study how microbes contribute to soil ecosystem services: The current state and future perspectives of soil metaproteomics. AB - Metaproteomics was established to analyse both the structure and the function of microbial communities and, particularly in soils, their contribution to ecosystem services. In this review, we provide an overview on how the study of the soil metaproteome can provide fundamental information on the role of microbial communities in soil ecosystem services. We further discuss the strengths and weaknesses of soil metaproteomics in comparison to other culture-independent OMIC techniques. We critically review its bottlenecks but also provide strategies to mitigate and possible directions for future research as the direct link of structure and function is advantageous and complementary to metagenomics, metatranscriptomics and metametabolomics. PMID- 30445182 TI - Association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and motor behavior in healthy adults: A study review. AB - The influence of individual differences in cognition and behavior may be partly explained by the different genetic polymorphisms. Among the genetic polymorphisms capable of altering cognitive and behavioral functions, the catechol-O methyltransferase (COMT) Val158Met polymorphism regulates the availability of dopamine (DA) in the prefrontal cortex and has a trimodal distribution in the population. The Met allele has higher DA availability in the synaptic clefts and can be associated with cognitive stability. Val homozygous individuals exhibit lower DA concentrations in the synaptic clefts, which can be associated with cognitive flexibility. Heterozygotes have intermediate DA concentrations in the synaptic clefts. In the perspective of motor behavior, greater cognitive stability would be advantageous when the practice requires maintenance and refinement of a movement pattern, while a greater cognitive flexibility would be fundamental for practices demanding motor adaptation caused by disturbances. Thus, this integrative review aimed to analyze, in healthy populations, possible associations between the COMT polymorphism and motor behavior, as well as to investigate whether the effects of the COMT genotypes from the perspective of the roles played by tonic and phasic DA are associated with the stability/flexibility required by the nature of the motor task. The search for the articles was carried out in the PubMed, ISI Web of Science and Scopus databases. Six studies that met all the requirements specified in the inclusion criteria were selected. Results suggest an association between COMT polymorphism and motor behavior. Conflicting results regarding the effects of the different COMT polymorphisms on adaptation and sequential motor tasks were found, as well as on the roles played by tonic and phasic DA. Despite the inconsistencies encountered, it was possible to identify that the different COMT genotypes lead to different effects in relation to the nature of the practiced motor task. Due to the reduced number of articles investigating the association between COMT polymorphism and motor behavior, relevant questions about this relation remain under-investigated. PMID- 30445183 TI - Neuroprotective effects of matrix metalloproteinases in cerebral ischemic rats by promoting activation and migration of astrocytes and microglia. AB - Matrix metalloproteinases (MMPs) cleave almost all components of the extracellular matrix (ECM) and cause acute neurovascular disruption and parenchymal destruction. Previously, MMPs inhibition was considered to be a therapeutic strategy in early stages of ischemia. This study was designed to investigate whether early MMPs inhibition could promote the recovery of cerebral ischemia. Male Sprague-Dawley rats underwent right middle cerebral artery occlusion (MCAO) for 1 h and reperfusion. The rats were divided into three groups: sham + vehicle (S + V) group, MCAO + vehicle (M + V) group, and MCAO + GM6001 (M + G) group. Infarct volume was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, and the expression of GFAP, IBA1, p-ERK, ERK, and MMP9 were evaluated by Western blot and immunofluorescence staining on 1, 4, 7, and 14 days after MCAO. Neuronal apoptosis was assessed by Fluoro-Jade C staining. The results showed that MMPs inhibition significantly increased the infarct volume and the expressions of GFAP and IBA1 in the M + V group were much higher than those in the M + G group; whereas the expression of p-ERK was upregulated in both the M + V and M + G groups. These findings suggest that MMPs promote the activation and migration of astrocytes and microglia to form protected zone in the penumbra and lessen the infarct volume after cerebral ischemic stroke. PMID- 30445184 TI - Sacral chordoma: a clinical review of 101 cases with 30-year experience in a single institution. AB - BACKGROUND: Local recurrence rates are high in sacral chordoma patients. Adjuvant radiotherapy may play a role in increasing local control. Patients with locally recurrent tumors continue to comprise a significant proportion of the sacral chordoma population and appear to have worse prognosis than those with primary tumors. High-quality studies comparing presentation and treatments for primary and first local recurrent sacral chordoma tumors are sparse. PURPOSE: To determine: whether there is a difference in how primary and tumors at first recurrence present; the overall survival, local relapse-free survival, and distant relapse-free survival rates and prognostic factors for patients presenting with a primary tumor; overall survival, local relapse-free survival, and distant relapse-free survival rates and prognostic factors for patients presenting with a first local relapse; if there any differences in overall survival, local relapse-free survival, and distant relapse-free survival rates between patients presenting with a primary tumor and those with a first local relapse. STUDY DESIGN: Retrospective case series. PATIENT SAMPLE: One hundred one sacral chordoma cases. OUTCOME MEASURE: Overall survival, local relapse-free survival, and distant relapse-free survival rates. METHODS: Between 1978 and 2013, 131 patients with sacral chordoma were seen. Of them, 17 patients (13%) presented with a history of more than one local recurrence. One patient (1%) presented with multiple distant metastases. Ten patients (8%) had less than 36 months of follow-up and had no event (eg, death, local recurrence, or distant metastasis). A total of 102 patients met our inclusion criteria: patients with primary or first recurrent tumors, without metastatic disease, who underwent surgery and with at least 36 months of follow-up. One patient (1%) died intraoperatively; therefore, 101 patients were included in the present analysis. Cox proportional hazards regression analysis was performed for primary and local recurrent tumor separately and to compare primary and local recurrent tumors. RESULTS: We analyzed 73 primary and 28 first time recurrent sacral chordomas. Tumor size at presentation was different for primary and recurrent tumors (primary median size: 158 cm3, interquartile range [IQR]: 46-634; recurrent median size: 39 cm3, IQR: 14-175; p=.001). Overall survival at 5 and 10 years for the primary tumors was 79% and 59%, respectively. Local relapse-free survival at 5 years was 86%. For primary tumors, not receiving radiation was an independent predictor for worse local relapse-free survival (hazard ratio [HR]: 0.20; 95% confidence interval [CI]: 0.0043-0.90; p=.004) and increased tumor size was an independent predictor for both worse overall survival (HR: 1.68; 95% CI: 1.38 2.42; p=.004) and worse distant relapse-free survival (HR: 2.25; 95% CI: 1.47 3.44; p<.001). For recurrent tumors, the 5- and 10-year overall survival was 65% and 40%, respectively. Local relapse-free survival at 5 years was 79% for recurrent tumors. On bivariate analysis, increased tumor size was a significant predictor for worse survival (LR median: 338 mL; IQR: 218-503 mL; no LR median: 26 mL; IQR: 9-71 mL). A trend was seen toward better distant relapse survival for tumors presenting as a primary tumor (HR: 0.51; 95% CI: 0.25-1.06; p=.072). CONCLUSION: Using a combination of surgical resection and adjuvant radiotherapy allowed us to obtain a good overall survival, local relapse-free survival, and distant relapse-free survival in patients presenting with either a primary tumor or with a first time local recurrent tumor. PMID- 30445185 TI - Glucocorticoid signaling and osteoarthritis. AB - Glucocorticoids are steroid hormones synthesized and released by the adrenal cortex. Their main function is to maintain cell homeostasis through a variety of signaling pathways, responding to changes in an organism's environment or developmental status. Mimicking the actions of natural glucocorticoids, synthetic glucocorticoids have been recruited to treat many diseases that implicate glucocorticoid receptor signaling such as osteoarthritis. In osteoarthritis, synthetic glucocorticoids aim to alleviate inflammation and pain. The variation of patients' response and the possibility of complications associated with their long-term use have led to a need for a better understanding of glucocorticoid receptor signaling in osteoarthritis. In this review, we performed a literature search in the molecular pathways that link the osteoarthritic joint to the glucocorticoid receptor signaling. We hope that this information will advance research in the field and propose new molecular targets for the development of more optimized therapies for osteoarthritis. PMID- 30445186 TI - The biopolymer produced by Rhizobium viscosum CECT 908 is a promising agent for application in Microbial Enhanced Oil Recovery. AB - Polymer flooding is one of the most promising techniques used to increase the productivity of mature oil reservoirs. Polymers reduce the mobility ratio of the injected water relative to the crude oil, improving the displacement of the entrapped oil and consequently, increasing oil recovery. Biopolymers such as xanthan gum have emerged as environmentally friendly alternatives to the chemical polymers commonly employed by the oil industry. However, in order to seek more efficient biomolecules, alternative biopolymers must be studied. Here, the applicability of a biopolymer produced by Rhizobium viscosum CECT 908 in Microbial Enhanced Oil Recovery (MEOR) was evaluated. This biopolymer exhibited better rheological properties (including higher viscosity) when compared with xanthan gum. Its stability at high shear rates (up to 300 s-1), temperatures (up to 80 degrees C) and salinities (up to 200 g/L of NaCl) was also demonstrated. The biopolymer exhibited better performance than xanthan gum in oil recovery assays performed with a heavy crude oil, achieving 25.7 +/- 0.5% of additional recovery. Thus the R. viscosum CECT 908 biopolymer is a promising candidate for application in MEOR. PMID- 30445187 TI - Tension and resolution: Dynamic, evolving populations of organelle genomes within plant cells. AB - Mitochondria and plastids form dynamic, evolving populations physically embedded in the fluctuating environment of the plant cell. Their evolutionary heritage has shaped how the cell controls the genetic structure and the physical behaviour of its organelle populations. While the specific genes involved in these processes are gradually being revealed, the governing principles underlying this controlled behaviour remain poorly understood. As the genetic and physical dynamics of these organelles are central to bioenergetic performance and plant physiology, this challenges both fundamental biology and strategies to engineer better-performing plants. This article will review current knowledge of the physical and genetic behaviour of mitochondria and chloroplasts in plant cells. An overarching hypothesis is proposed, whereby organelles face a tension between genetic robustness and individual control and responsiveness, and different species resolve this tension in different ways. As plants are immobile and therefore subject to fluctuating environments, their organelles are proposed to favour individual responsiveness, sacrificing genetic robustness. Several notable features of plant organelle dynamics including mtDNA recombination and plastid/mitochondrial differences may be explained by this hypothesis. Finally, the article highlights how tools from quantitative and systems biology can help shed light on the plethora of open questions in this field. PMID- 30445188 TI - Comparison Study of Laparoscopic Sentinel Lymph Node Mapping in Endometrial Carcinoma Using Carbon Nanoparticles and Lymphatic Pathway Verification. AB - STUDY OBJECTIVE: To evaluate the detection rate and accuracy of sentinel lymph node (SLN) mapping using cervical and fundal injection of carbon nanoparticles (CNPs) in laparoscopic surgery of endometrioid endometrial cancer (EC), and to identify uterine lymphatic drainage pathways validated by mapping. DESIGN: A prospective consecutive study (Canadian Task Force classification II-2) SETTING: A academic research center. PATIENTS: Consecutive patients with a pathological diagnosis of early-stage EC scheduled for primary laparoscopic-assisted staging surgery (laparoscopic hysterectomy, bilateral salpingo-oophorectomy, comprehensive lymphadenectomy). INTERVENTIONS: Enrolled patients underwent laparoscopic SLN mapping with a 50mg carbon nanoparticle tracer injection. Fifty patients received fundal sub-serosal injections at 4 sites (fundal group), while 65 patients received cervical sub-mucosal injections at 2 sites (cervical group). After SLN mapping, all patients underwent laparoscopic staging surgery. MEASUREMENTS AND MAIN RESULTS: No allergic reactions to CNPs was observed in either group. The overall SLN detection rates were 100% and 92% in cervical and fundal group, and the bilateral SLN detection rates were 97% and 68% (p<0.001) respectively. A total of 12 metastatic SLNs were accurately detected in 5 patients. The sensitivity of metastatic lymph nodes detection was 100% in cervical group which is higher than that in fundal group (80%). The false negative rates were 0% and 20% respectively in cervical and fundal group. We further certificated 3 uterine lymphatic pathways by the 2 injection methods. The upper paracervical pathway (UPP) was the most common drainage pathway in both groups (91.4% in cervical group vs. 80.24% in fundal group), whereas the infundibulo-pelvic pathway (IPP) was observed only in fundal group (15.11%). CONCLUSION: SLN mapping by CNPs in laparoscopic surgery for EC is a safe and effective alternative, with a higher detection rate and better accuracy in cervical injection than fundal injection. The UPP was the most common lymphatic pathway, while the IPP was only displayed in fundal injections. PMID- 30445189 TI - Role of low-dose computerized tomography in lung cancer screening among never smokers. AB - INTRODUCTION: The incidence of lung cancer among never-smokers has been increasing rapidly. The United States National Lung Screening Trial (NLST) study and NELSON trial showed that screening using low-dose computerized tomography effectively reduced lung cancer mortality among heavy smokers. However, its effectiveness in never-smokers has not been well investigated. This study investigated the role of low-dose computerized tomography (LDCT) in lung cancer screening among never-smokers. METHODS: The study was designed as a single center, retrospective cohort study. We analyzed data of patients who received low dose computerized tomography screening between May 2003 and June 2016. Nodules detected by computerized tomography were classified according to the Lung Imaging Reporting and Data System criteria. The detection rate and lung cancer outcomes (pathology, staging of lung cancer, and mortality) according to smoking history were determined. RESULTS: Among 28,807 enrolled patients, 12,176 patients were never-smokers; of these, 7,744 (63.6%) were women and lung nodules were found in 1,218 (10.0%) patients. Overall, lung cancer was diagnosed in 55 (0.45%) never smokers. In contrast, lung cancer was diagnosed in 143 (0.86%) patients among 16,631 ever-smokers. Among never-smokers with lung cancer, 51 (92.7%) presented with stage I, and all patients had adenocarcinomas. CONCLUSIONS: In the never smoker population, low-dose computerized tomography screening helped to detect a significant number of lung cancers. Most of these lung cancers were detected at a very early stage. The positive results of NLST in the US and the NELSON trial may have established the value of LDCT screening for heavy smokers, but future research should consider the value of using LDCT screening in the never-smoker population. PMID- 30445190 TI - Epinephrine Use in Austin Independent School District After Implementation of Unassigned Epinephrine. PMID- 30445192 TI - Prevalence of Arnold nerve reflex in subjects with and without chronic cough: Relevance to Cough Hypersensitivity Syndrome. AB - INTRODUCTION: Cough is induced by stimulation of structures innervated by the vagus nerve, including the upper and lower airways and distal esophagus. The Arnold nerve reflex describes cough resulting from stimulation of the external auditory canal, which is innervated by the auricular branch of the vagus. We have recently reported the increased prevalence of this reflex in adults, but not children, with chronic cough, relative to healthy adult and pediatric subjects. The prevalence of the Arnold nerve reflex in patients with pulmonary disease but without chronic cough has not been investigated previously. METHODS: Three hundred adults and 100 children with chronic cough, 50 adults with stable pulmonary disease but without chronic cough, as well as 100 adult and 100 pediatric volunteers, underwent evaluation consisting of stimulation of the external auditory canal of each ear with a cotton-tipped applicator. Cough occurring within 10 s of stimulation was considered induced by the intervention. RESULTS: Arnold's nerve reflex was present in 23.3% of adults and 3% of children with chronic cough. The prevalence of the reflex was 2% among healthy adults and children. In adults with chronic cough, Arnold's nerve reflex was observed more commonly in women (29.3%) than men (10.5%), and was unilateral in the majority of patients (88.6%). In patients with respiratory disease but without chronic cough, Arnold nerve reflex was present in 2%. CONCLUSIONS: The greater than 11-fold prevalence of the Arnold nerve reflex in adults with chronic cough compared with healthy volunteers and adults with respiratory disease but without chronic cough, supports the concept of the Cough Hypersensitivity Syndrome (CHS), in which vagal hypersensitivity is proposed to underlie chronic refractory cough. The absence of increased prevalence among children with chronic cough suggests that CHS is an acquired condition, perhaps triggered by viral respiratory infection or other environmental factor. PMID- 30445191 TI - Measles in Italy: viral strains and crossing borders. AB - In 2017, Italy experienced one of the largest outbreaks of recent years with 5 404 notified and 4 347 confirmed cases [1]. Further 2 029 cases were notified during the first six months of 2018, and 1516 of them were laboratory confirmed. B3 and D8 genotypes were identified as the ones responsible of the outbreak. Possible transmission routes can be established by monitoring the circulating MV strains in support of the national health authorities to warn people and travelers. PMID- 30445193 TI - Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. AB - The mammalian retina displays no intrinsic regenerative capacities, therefore retinal degenerative diseases such as age-related macular degeneration (AMD) or retinitis pigmentosa (RP) result in a permanent loss of the light-sensing photoreceptor cells. The degeneration of photoreceptors leads to vision impairment and, in later stages, complete blindness. Several therapeutic strategies have been developed to slow down or prevent further retinal degeneration, however a definitive cure i.e. replacement of the lost photoreceptors, has not yet been established. Cell-based treatment approaches, by means of photoreceptor transplantation, have been studied in pre-clinical animal models over the last three decades. The introduction of pluripotent stem cell derived retinal organoids represents, in principle, an unlimited source for the generation of transplantable human photoreceptors. However, safety, immunological and reproducibility-related issues regarding the use of such cells still need to be solved. Moreover, the recent finding of cytoplasmic material transfer between donor and host photoreceptors demands reinterpretation of several former transplantation studies. At the same time, material transfer between healthy donor and dysfunctional patient photoreceptors also offers a potential alternative strategy for therapeutic intervention. In this review we discuss the history and current state of photoreceptor transplantation, the techniques used to assess rescue of visual function, the prerequisites for effective transplantation as well as the main roadblocks, including safety and immune response to the graft, that need to be overcome for successful clinical translation of photoreceptor transplantation approaches. PMID- 30445194 TI - Ticks and tick-borne infections in Asia: Implications for travellers. PMID- 30445195 TI - Surveillance for Zika virus infection in travelers returning to the Republic of Korea. PMID- 30445196 TI - Comparison of effects of four treatment methods for unstable intertrochanteric fractures: A network meta-analysis. AB - PURPOSE: The optimal internal fixation device for unstable intertrochanteric fracture remains a matter of controversy. By performing network meta-analysis, we developed a ranking of the following four surgical methods: proximal femoral nail antirotation, InterTan nail, gamma nail (GN) and sliding hip screws. We compare the complication rates in patients with unstable intertrochanteric fractures. MATERIALS AND METHODS: After an exhaustive search of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials for relevant studies, randomized controlled trials meeting selection criteria were entered into our network meta analysis. Statistical analyses were conducted using Stata software, version 13.0 (Stata Corporation, College Station, Texas, USA). RESULTS: We included 12 randomized controlled trials. Compared to Sliding hip screw, there were no substantial differences in rates of complications in unstable intertrochanteric fractures patient undergoing various treatments (all p > 0.05). Nevertheless, the surface under the cumulative ranking curve (SUCRA) for GN (80.6%) was significantly higher than those of the other three methods. CONCLUSION: GN had the highest probability of reducing the total incidence of complications among the four interventions for treating unstable intertrochanteric fractures. PMID- 30445197 TI - Is opening-wedge high tibial osteotomy superior to closing-wedge high tibial osteotomy in treatment of unicompartmental osteoarthritis? A meta-analysis of randomized controlled trials. AB - BACKGROUND: High tibial osteotomy (HTO) is an effective surgical technique that can stop or inhibit progression of knee osteoarthritis (OA) and avoid or postpone the need for knee arthroplasty. This meta-analysis determined whether opening wedge high tibial osteotomy (OWHTO) was superior to closing-wedge high tibial osteotomy (CWHTO) in treatment of unicompartmental OA. METHODS: Databases (PubMed, Embase, Web of Science, Cochrane Library and Google) were searched from the time of their establishment to 1st August 2018 for randomized controlled trials (RCTs) comparing OWHTO and CWHTO in patients with unicompartmental OA. The Cochrane risk of bias tool was used to assess methodological quality. Statistical analysis was performed with Stata 12.0. RESULTS: Nine RCTs (599 participants) were included in this meta-analysis. The pooled results showed that there were no significant differences between OWHTO and CWHTO VAS knee pain scores, HSS knee scores, walking distances or hip-knee-ankle (HKA) angles (P > 0.05). Furthermore, there were no significant differences between the two groups in complication and survival rates (p > 0.05). Nevertheless, there was a significantly greater tibial slope angle in OWHTO patients (P < 0.00001). CONCLUSION: CWHTO reduced the inclination of the tibial plateau, whereas OWHTO increased the posterior tilt, and these factors should be considered in the specific need of an individual patient when choosing the type of osteotomy. Therefore, we are unable to conclude which method is superior. PMID- 30445198 TI - Fasciola hepatica infection in children actively detected in a survey in rural areas of Mardan district, Khyber Pakhtunkhawa province, northern Pakistan. AB - Human fascioliasis is a freshwater snail borne, zoonotic disease caused by Fasciola liver flukes which are widely spread throughout Pakistan and has recently proved to be endemic in humans of the Punjab province. To verify whether fasciolids are also affecting humans outside this province, studies were conducted in four communities comprising rural and urban areas of Mardan district, Khyber Pakhtunkha province, northern Pakistan. Activities comprised two surveys, a coprological one to look for Fasciola infection and another to get information on potential human infection sources and risk factors by means of a questionnaire. Out of 540 subjects of all ages surveyed, only 4 children (0.74%) were found positive for Fasciola eggs: two 9- and 13-year old boys and two 7- and 16-year old girls. Burden per child ranged 73-146 eggs per gram of faeces (epg), with an average of 106 +/- 15.4 epg. Based on the egg size, the infection was diagnosed to be caused by F. hepatica. Serum analyses showed eosinophilia and elevated enzyme values in liver function tests. The Mardan area fits well to all transmission and epidemiological requirements of F. hepatica, namely the presence of infected livestock reservoirs throughout, the appropriate climatic factors (mainly monthly temperature variation along the year), and the existence of adequate freshwater collections. The existence of the specific lymnaeid snail vector species for F. hepatica transmission was reported in the neighbouring Swat valley time ago. Results show that human fascioliasis may be widespread in Pakistan and that both F. hepatica and F. gigantica may be involved. PMID- 30445199 TI - Characterization of Echinostoma revolutum and Echinostoma robustum from ducks in Bangladesh based on morphology, nuclear ribosomal ITS2 and mitochondrial nad1 sequences. AB - Precise discrimination of Echinostoma species within the 'revolutum' group is quite difficult because of their morphological similarities. The objective of this study was to precisely characterize the echinostomes of ducks from Bangladesh based on both morphological and molecular characteristics. Two Echinostoma species were identified: E. revolutum and E. robustum. In the phylogenetic trees (ITS2 and nad1), E. revolutum and E. robustum belonged to their respective Eurasian clade, which is distinct from the American clade. These results suggest that both species have two distinct and geographically separated lineages, Eurasian and American. Our molecular and morphological data combined with previously published data supports the synonymy of E. robustum, E. miyagawai, and E. friedi previously based on either molecular or morphological evidence. This study thus improves our understanding of species diversity of the 'revolutum' group, particularly in Asia. PMID- 30445200 TI - Prediction of early metastatic disease in experimental breast cancer bone metastasis by combining PET/CT and MRI parameters to a Model-Averaged Neural Network. AB - Macrometastases in bone are preceded by bone marrow invasion of disseminated tumor cells. This study combined functional imaging parameters from FDG-PET/CT and MRI in a rat model of breast cancer bone metastases to a Model-averaged Neural Network (avNNet) for the detection of early metastatic disease and prediction of future macrometastases. Metastases were induced in 28 rats by injecting MDA-MB-231 breast cancer cells into the right superficial epigastric artery, resulting in the growth of osseous metastases in the right hind leg of the animals. All animals received FDG-PET/CT and MRI at days 0, 10, 20 and 30 after tumor cell injection. In total, 18/28 rats presented with metastases at days 20 or 30 (64.3%). None of the animals featured morphologic bone lesions during imaging at day 10, and the imaging parameters acquired at day 10 did not differ significantly between animals with metastases at or after day 20 and those without (all p > 0.3). The avNNet trained with the imaging parameters acquired at day 10, however, achieved an accuracy of 85.7% (95% CI 67.3-96.0%) in predicting future macrometastatic disease (ROCAUC 0.90; 95% CI 0.76-1.00), and significantly outperformed the predictive capacities of all single parameters (all p <= 0.02). The integration of functional FDG-PET/CT and MRI parameters into an avNNet can thus be used to predict macrometastatic disease with high accuracy, and their combination might serve as a surrogate marker for bone marrow invasion as an early metastatic process that is commonly missed during conventional staging examinations. PMID- 30445201 TI - Identification of insect genes involved in baculovirus AcMNPV entry into insect cells. AB - The baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a model enveloped DNA virus that infects and replicates in lepidopteran insect cells, and can efficiently enter a wide variety of non-host cells. Budded virions of AcMNPV enter cells by endocytosis and traffic to the nucleus where the virus initiates gene expression and genome replication. While trafficking of nucleocapsids by actin propulsion has been studied in detail, other important components of trafficking during entry remain poorly understood. We used a recombinant AcMNPV virus expressing an EGFP reporter in combination with an RNAi screen in Drosophila DL1 cells, to identify host proteins involved in AcMNPV entry. The RNAi screen targeted 86 genes involved in vesicular trafficking, including genes coding for VPS and ESCRT proteins, Rab GTPases, Exocyst proteins, and Clathrin adaptor proteins. We identified 24 genes required for efficient virus entry and reporter expression, and 4 genes that appear to restrict virus entry. PMID- 30445202 TI - Characterizing excitability of Lamb waves generated by electromagnetic acoustic transducers with coupled frequency domain models. AB - Electromagnetic acoustic transducers (EMATs) are versatile non-contact ultrasonic transducers with relatively low transduction efficiency. A fundamental problem not answered completely yet is how the structure of an EMAT influences the generation of various Lamb wave modes. We tackle this problem with fully coupled frequency domain EMAT models where the underlying integro-differential equations are solved directly and the magnitudes of the phasors of the displacement components at a point in the middle plane of a plate are used to represent the strength of the S0 and A0 mode waves. Idealized single-wire, two-wire and wire bundle EMATs with uniform bias magnetic field and practical meander line and tightly wound EMATs with distributed bias field are studied. Polar plots of the idealized EMATs with swept angle of the bias field show that the vertical component of the bias field decides the strength of the S0 mode waves. Sweeping of the width of the magnet for the practical EMATs generates S0 mode curves that could be explained from the distribution of the vertical component of the bias field. This work represents the first attempt to solve the proposed problem of characterizing excitability of Lamb waves with EMATs quantitatively, via the model-based approach. PMID- 30445203 TI - Comparison of female sexual function in women who underwent abdominal or vaginal hysterectomy with or without bilateral salpingo-oophorectomy. AB - OBJECTIVE: To compare the effect of abdominal and vaginal hysterectomy with or without bilateral salpingo-oophorectomy on female sexuality. METHODS: Perimenopausal, sexually active, aged 45-50 years women who underwent abdominal or vaginal hysterectomy with or without bilateral salpingo-oophorectomy due to benign indications were included in this retrospective study. For the assessment of preoperative and postoperative female sexual function, Turkish validated Female Sexual Function Index form was used. RESULTS: Of the study population, 82 women (Group A) underwent hysterectomy + bilateral salpingo-oophorectomy and 78 women (Group B) underwent hysterectomy-only operations. The groups were statistically similar in terms of mean age, number of gravida and parity, body mass index, duration of postoperative evaluation, type of hysterectomy and presence of preoperative female sexual dysfunction. Both in Group A and B, postoperative total Female Sexual Function Index scores increased significantly compared to preoperative total scores. And there were no differences between the groups regarding the total preoperative and postoperative Female Sexual Function Index scores. However, postoperative arousal and orgasm scores were higher while pain score was lower in Group B than in Group A. CONCLUSION: Abdominal and vaginal hysterectomy with or without bilateral salpingo-oophorectomy for benign causes positively affect female sexuality in general. But, premenopausal bilateral oophorectomy may cause more pain during intercourse, decreased libido and orgasm than ovary conservation. PMID- 30445204 TI - Effects of multimodal synchrony on infant attention and heart rate during events with social and nonsocial stimuli. AB - Attention is a state of readiness or alertness, associated with behavioral and psychophysiological responses, that facilitates learning and memory. Multisensory and dynamic events have been shown to elicit more attention and produce greater sustained attention in infants than auditory or visual events alone. Such redundant and often temporally synchronous information guides selectivity and facilitates perception, learning, and memory of properties of events specified by redundancy. In addition, events involving faces or other social stimuli provide an extraordinary amount of redundant information that attracts and sustains attention. In the current study, 4- and 8-month-old infants were shown 2-min multimodal videos featuring social or nonsocial stimuli to determine the relative roles of synchrony and stimulus category in inducing attention. Behavioral measures included average looking time and peak look duration, and convergent measurement of heart rate (HR) allowed for the calculation of HR-defined phases of attention: Orienting (OR), sustained attention (SA), and attention termination (AT). The synchronous condition produced an earlier onset of SA (less time in OR) and a deeper state of SA than the asynchronous condition. Social stimuli attracted and held attention (longer duration of peak looks and lower HR than nonsocial stimuli). Effects of synchrony and the social nature of stimuli were additive, suggesting independence of their influence on attention. These findings are the first to demonstrate different HR-defined phases of attention as a function of intersensory redundancy, suggesting greater salience and deeper processing of naturalistic synchronous audiovisual events compared with asynchronous ones. PMID- 30445205 TI - Mitosis perturbation by MASTL depletion impairs the viability of thyroid tumor cells. AB - Even if thyroid tumors are generally curable, a fraction will develop resistance to therapy and progress towards undifferentiated forms, whose treatment remains a demanding challenge. To identify potential novel targets for treatment of thyroid cancer, in a previous study using siRNA-mediated functional screening, we identified several genes that are essential for the growth of thyroid tumor, but not normal cells. Among the top-ranking hits, we found microtubule associated serine/threonine kinase-like (MASTL), which is known to play an essential role in mitosis regulation, and is also involved in the DNA damage response. Herein, we examine the effects of MASTL depletion on growth and viability of thyroid tumor cells. MASTL depletion impaired cell proliferation and increased the percentage of cells presenting nuclear anomalies, which are indicative of mitotic catastrophe. Furthermore, MASTL depletion was associated with enhanced DNA damage. All these effects eventually led to cell death, characterized by the presence of apoptotic markers. Moreover, MASTL depletion sensitized thyroid tumor cells to cisplatin. Our results demonstrate that MASTL represents vulnerability for thyroid tumor cells, which could be explored as a therapeutic target for thyroid cancer. PMID- 30445206 TI - DNp73-induced degradation of tyrosinase links depigmentation with EMT-driven melanoma progression. AB - Melanoma is an aggressive cancer with poor prognosis, requiring personalized management of advanced stages and establishment of molecular markers. Melanomas derive from melanocytes, which specifically express tyrosinase, the rate-limiting enzyme of melanin-synthesis. We demonstrate that melanomas with high levels of DNp73, a cancer-specific variant of the p53 family member p73 and driver of melanoma progression show, in contrast to their less-aggressive low-DNp73 counterparts, hypopigmentation in vivo. Mechanistically, reduced melanin synthesis is mediated by a DNp73-activated IGF1R/PI3K/AKT axis leading to tyrosinase ER-arrest and proteasomal degradation. Tyrosinase loss triggers reactivation of the EMT signaling cascade, a mesenchymal-like cell phenotype and increased invasiveness. DNp73-induced depigmentation, Slug increase and changes in cell motility are recapitulated in neural crest-derived melanophores of Xenopus embryos, underscoring a previously unnoticed physiological role of tyrosinase as EMT inhibitor. This data provides a mechanism of hypopigmentation accompanying cancer progression, which can be exploited in precision diagnosis of patients with melanoma-associated hypopigmentation (MAH), currently seen as a favorable prognostic factor. The DNp73/IGF1R/Slug signature in colorless lesions might aid to clinically discriminate between patients with MAH-associated metastatic disease and those, where MAH is indeed a sign of regression. PMID- 30445207 TI - Molecular Epidemiology and Genetic Characterization of Carbapenem-Resistant Acinetobacter baumannii Isolates from Guangdong Province, South China. AB - OBJECTIVE: Carbapenem-resistant Acinetobacter baumannii (CRAB) infection has become a worldwide issue. This study aimed to characterize the epidemiology and genetic relationships of A. baumannii in Guangdong Province, China. METHODS: CRAB isolates were collected from five municipal hospitals from June to December 2017. 16S-23S rRNA intergenic spacer(ITS) was used for further strain identification. Antimicrobial susceptibility test and CarbAcineto NP test were performed to analyse antibiotic spectrum and carbapenemase production of those isolates, while PCR-based assays were used to detect beta-lactamase genes and related mobile genetic elements. Genetic diversity among the isolates was analyzed using enterobacterial repetitive intergenic consensus (ERIC)-PCR, multilocus sequence typing (MLST), and multiplex PCR. RESULTS: A total of 122 isolates were confirmed as A. baumannii and all were resistant to the tested antibiotics, except tigecycline and colistin. CarbAcineto NP test showed 93.4% of isolates produced carbapenemase. PCR assays showed blaOXA-23-like and extended-spectrum beta lactamases-encoding genes were found in 95% and 91.8% of those isolates, respectively. Furthermore, the genetic environment of blaOXA-23-like gene was mainly associated with transposons Tn2008 (46.1%), Tn2006 (27%), and Tn2009 (20.9%). MLST identified six existing sequence types (STs) and three novel STs, of which ST195 (35.7%) and ST208 (32%) were the most common, belonging to clonal group 92 and European clone II. CONCLUSION: Our study suggested that co production of beta-lactamases was the major mechanism of CRAB isolates. And the dissemination of blaOXA-23-like gene may be facilitated by the transposable elements. ST195 and ST208 of the A. baumannii isolates were the predominant epidemic type in Guangdong Province, China. PMID- 30445208 TI - Characterization of chromosomally-located blaCTX-M and its surrounding sequence in CTX-M type extended-spectrum beta-lactamase-producing Escherichia coli isolates. AB - OBJECTIVES: Although it has been regarded that CTX-M type extended-spectrum beta lactamase (ESBL) gene, blaCTX-M, is mainly carried by antibiotic-resistance plasmids, Escherichia coli-possessing chromosomally-located blaCTX-M has been reported in previous studies. This study aimed to characterize the genetic structures of chromosomally-located blaCTX-M transposition unit and its surrounding sequence in E. coli isolates-producing ESBL which were obtained in a Japanese hospital. METHODS: In this study, total of 81 ESBL-producing E. coli isolates were examined. Existence of chromosomally-located blaCTX-M were confirmed by S1 nuclease-digested pulsed-field gel electrophoresis (PFGE) and the Southern blot hybridization, and by sequencing analysis of PCR-amplified DNA fragments. RESULTS: Chromosomally-located blaCTX-M was confirmed in 22 of the examined 81 E. coli isolates (27.2%), 5 and 4 location types of the chromosomally located blaCTX-M-14, and -15 were determined, respectively. Among the 22 E. coli isolates, 15 isolates (68.2%) possessed single chromosomally-located blaCTX-M, probably due to single transposition of plasmid blaCTX-M to chromosome. In case of isolate N0057, blaCTX-M-15 transposition unit was transferred from plasmid into two different chromosomal regions. In addition, "recurrent" transposition of already existed chromosomally-located blaCTX-M-14 to other chromosomal region was observed in isolates N0211, N0214, N01127, N1682, and N1753; consequently, these isolates possessed two copies of chromosomally-located blaCTX-M-14. CONCLUSION: Considering that the isolates (N0211, N0214, N01127, N1682, and N1753) in which the "recurrent "transposition occurred were genetically related on PFGE analysis, our data suggest possibility of accumulation of blaCTX-M on chromosome in CTX-M type ESBL-producing E. coli. PMID- 30445209 TI - Antimicrobial susceptibility of Gram-negative and Gram-positive bacteria collected from Eastern Europe: results from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) 2011-2016. AB - OBJECTIVES: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance program that monitors the in vitro activity of a panel of antimicrobials against clinically important isolates. Data for Gram-positive and Gram-negative isolates collected in Eastern Europe between 2011 and 2016 are presented. METHODS: MICs were determined by broth microdilution using CLSI guidelines. Antimicrobial susceptibility was determined using European Committee on Antimicrobial Susceptibility Testing breakpoints. RESULTS: Nine Eastern European countries submitted 4289 isolates. Among Acinetobacter baumannii, resistance to levofloxacin, amikacin and meropenem was 77.5%, 63.4% and 62.2%, respectively. Multidrug resistance (MDR) among A. baumannii was higher in 2015 than previous years (44.1% in 2011, 71.0% in 2015), and then decreased to 51.7% in 2016. The MDR percentage for Pseudomonas aeruginosa was 26.9% and was relatively stable over time. The percentage of extended-spectrum beta-lactamase (ESBL)-positive isolates among Escherichia coli and Klebsiella pneumoniae was 20.1% and 55.7%, respectively. Resistance to amikacin, meropenem and tigecycline was low among E. coli and K. pneumoniae and the ESBL-producing subset (<=5.9%). Among Staphylococcus aureus isolates, 36.7% were methicillin-resistant (MRSA); percentages varied year-on-year. No S. aureus isolates, including MRSA, were resistant to linezolid, vancomycin or tigecycline. Among Enterococcus faecium isolates, resistance was 22.6% to vancomycin and 2.3% to linezolid; no isolates were resistant to tigecycline. CONCLUSION: This study shows low resistance to meropenem and tigecycline among the Enterobacteriaceae, and continued activity of linezolid, vancomycin and tigecycline against Gram-positive organisms. However, antimicrobial resistance continues to be problematic in Eastern Europe and requires continued surveillance. PMID- 30445210 TI - Draft genome sequence of an OXA-23, OXA-66, ADC-25 and TEM-1D co-producing Acinetobacter baumannii ST195 isolated from a patient with neonatal pneumonia in China. AB - OBJECTIVES: The rapid spread of multidrug-resistant (MDR) Acinetobacter baumannii poses a substantial threat for morbidity and mortality worldwide. In particular, carbapenem-resistant A. baumannii has caused a severe challenge to human health. Here we reported the draft genome sequence of A. baumannii S131434, an OXA-23, OXA-66, ADC-25 and TEM-1D co-producing strain recovered from a patient with neonatal pneumonia in China and belonging to the globally disseminated sequence type 195 (ST195) of clonal complex 92 (CC92). METHODS: Genomic DNA was sequenced using an Illumina HiSeq platform and the reads were de novo assembled into contigs using CLC Genomics Workbench. The assembled contigs were annotated and bioinformatics analysis was performed. RESULTS: The genome comprised a circular chromosome of 3898344bp. The presence of the blaOXA-23, blaOXA-66, blaADC-25 and blaTEM-1D genes was detected. In addition, genes conferring resistance to aminoglycosides, macrolides and tetracycline were also identified. Antimicrobial susceptibility testing revealed that the isolate was resistant to all of the tested antibiotics except for polymyxin B, piperacillin/sulbactam and trimethoprim/sulfamethoxazole. CONCLUSION: To our knowledge, this is the first report of a clinical A. baumannii ST195 (CC92) isolate producing OXA-23, OXA-66, ADC-25 and TEM-1D in southern China. This draft genome will facilitate further our understanding of the antimicrobial resistance and pathogenic mechanisms in this strain and provides valuable information regarding the colonisation and adaptation of MDR pathogens. PMID- 30445211 TI - The frequency of DNA gyrase and topoisomerase IV mutations, and plasmid-mediated quinolone resistance genes among Escherichia coli and Klebsiella pneumoniae isolated from urinary tract infections in Azerbaijan, Iran. AB - OBJECTIVES: The aims of the study were to assess genetic alterations in gyrA, gyrB, parC and parE genes and the prevalence of plasmid-mediated quinolone resistance (PMQR) among Escherichia coli and Klebsiella pneumoniae isolated from urinary tract infections (UTIs) in Azerbaijan, Iran. METHODS: A total of 205 clinical isolates of E. coli (n=177) and K. pneumoniae (n=28) were obtained from UTIs. The antimicrobial susceptibility determined by the disk diffusion agar and the agar dilution assays. The presence of PMQR genes was studied by the PCR and sequencing of gyrA, gyrB, parC and parE genes were also done. RESULTS: The rates of resistance to (fluoroquinolones) FQ in isolates were 77.1%. Mutations of Ser83Leu were observed in tested FQ- resistant isolates. Second common mutation in gyrA was Asp87Val. Mutations in parC were often Ser80Ile and Gln84Val. Ser359Ala, Ser367Thr and Gly385Cys substitution in gyrB were identified in one isolate of E. coli and K. pneumoniae, respectively. ParE had mutations at Ile529Leu, Ser458Ala and Leu416Phe. Overall, PMQR determinants were identified in 90% of E. coli and 100% K. pneumoniae isolates. The prevalence of PMQR genes was as follows: aac (6')-Ib-cr (71.7%), oqxB (51.7%), oqxA (36.7%), qnrB (28.3%), qnrS (21.7%), qnrD (16.7%), qepA (5%), qnrA (1.7%) and qnrC (1.7%). CONCLUSIONS: The rates of resistance to FQ were high. The mutations of DNA gyrase, topoisomerase IV and the prevalence of PMQR genes in E. coli and K. pneumonia isolates were alarming. Moreover, the combination of these resistance mechanisms plays an important role in high-level resistance to FQ. PMID- 30445212 TI - Carbapenemase producing Acinetobacter spp. from environmental sources in a hospital from French Polynesia. PMID- 30445213 TI - Dimorphism of sex and gonad-development-related genes in male and female lined seahorse, Hippocampus erectus, based on transcriptome analyses. AB - Seahorse is characterized by its male pregnancy and sex-role reversal. To better understand the sexual dimorphism of male and female seahorses based on essential genes, we performed systematic transcriptome studies for both genders. A total of 157,834,590 cleaned reads were obtained and assembled into 129,268 transcripts and 31,764 could be annotated. Results showed that 176 up-regulated and 391 down regulated transcripts were identified in the male seahorses compared with those in females. Genes involved in sex differentiation, such as dmrt1, sox9, fem1 and vasa, were identified and characterized. Moreover, the essential genes involved in reproductive molecular pathway were identified and analyzed in seahorses. In conclusion, the present study provides an archive for the future systematic research on seahorse sex differentiation. PMID- 30445214 TI - Block alignment: New representation and comparison method to study evolution of genomes. AB - Genomes are not random sequences because natural selection has injected information in biological sequences for billions of years. Inspired by this idea, we developed a simple method to compare genomes considering nucleotide counts in subsequences (blocks) instead of their exact sequences. We introduce the Block Alignment method for comparing two genomes and based on this comparison method, define a similarity score and a distance. The presented model ignores nucleotide order in the sequence. On the other hand, in this block comparison method, due to exclusion of point mutations and small size variations, there is no need for high coverage sequencing which is responsible for the high costs of data production and storage; moreover, the sequence comparisons could be performed with higher speed. Phylogenetic trees of two sets of bacterial genomes were constructed and the results were in full agreement with their already constructed phylogenetic trees. Furthermore, a weighted and directed similarity network of each set of bacterial genomes was inferred ab initio by this model. Remarkably, the communities of these networks are in agreement with the clades of the corresponding phylogenetic trees which means these similarity networks also contain phylogenetic information about the genomes. Moreover, the block comparison method was used to distinguish rob(15;21)c-associated iAMP21 and sporadic iAMP21 rearrangements in subgroups of chromosome 21 in acute lymphoblastic leukemia. Our results show a meaningful difference between the number of contigs that mapped to chromosomes 15 and 21 in these cases. Furthermore, the presented block alignment model can select the candidate blocks to perform more accurate analysis and it is capable to find conserved blocks on a set of genomes. PMID- 30445215 TI - Comparative genome analysis of arsenic reducing, hydrocarbon metabolizing groundwater bacterium Achromobacter sp. KAs 3-5T explains its competitive edge for survival in aquifer environment. AB - Whole genome sequence of arsenic (As) reducing, hydrocarbon metabolizing groundwater bacterium Achromobacter sp. KAs 3-5T was explored to understand the genomic basis of its As-ecophysiology and niche adaptation in aquifer environment. The genome (5.6 Mbp, 65.5 G + C mol %) encodes 4840 proteins, 1138 enzymes, 53 tRNAs, 11 rRNAs, 608 signal peptides, and 1.13% horizontally transferred genes. Presence of genes encoding cytosolic As5+-reduction (arsRCBH, ACR3), aromatics utilization (bph, naph, catABC, boxABCD, genACB), Fe transformation (tonB, achromobactin, FUR, FeR), and denitrification (nar, nap) processes were observed and validated through proteomics. Phylogenomic analysis (< 90% ANI, < 50% DDH) confirmed strain KAs 3-5T to be a novel representative of the genus Achromobacter. An asymptotic open pan-genome (20,855 genes) and high correlation between genomic and ecological diversity suggested niche preference ability of this genus. Assemblage of species specific genes affiliated to transcription-regulation, membrane transport, and redox-transformation explained the strain's competitive survival strategies in As-rich oligotrophic groundwater. PMID- 30445216 TI - Transcriptional differences provide insight into environmental acclimatization in wild amur ide (Leuciscus waleckii) during spawning migration from alkalized lake to freshwater river. AB - Amur ide (Leuciscus waleckii) inhabits alkaline water in Lake Dali Nur and migrates to fresh water river for spawning every year. To investigate the potential genetic mechanisms underlying their alkaline acclimation, adaptation, and spawning migration, we performed differential gene expression analysis using high-throughput RNA-Seq data from liver of Amur ide samples collected before and after spawning migration. First, the short RNA-Seq reads were de novo assembled into 44,318 contigs, and provided the transcriptome reference sequences. Differential gene expression analysis identified 2575 genes with significant differential expression (p-value <=.01, log2-fold-change >=2). GO enrichment and KEGG pathway analyses were subsequently performed to determine gene functions and regulation. The results indicated that there were numerous differentially expressed genes involved in acid-base regulation, nitrogenous waste excretion, sexual maturation and reproduction, and stress response. These results provide fundamental information for further analyses of the physiological and molecular mechanisms underlying Amur ide alkaline acclimation, adaptation, and spawning migration. PMID- 30445217 TI - The putative H3K36 demethylase BcKDM1 affects virulence, stress responses and photomorphogenesis in Botrytis cinerea. AB - The Leotiomycete Botrytis cinerea is a high-impact plant pathogen causing gray mold disease in a wide range of dicotyledonous species. Besides its efficient strategies to cause disease - either by being highly aggressive leading to rapid destruction of plant tissues or by keeping hidden for certain periods before damaging the host - the fungus is well-adapted to the changing environmental conditions due to different modes of reproduction for dispersal (macroconidia), survival (sclerotia) or adaptation (ascospores formed in the apothecia). The screening of a collection of B. cinerea mutants generated by Agrobacterium tumefaciens-mediated transformation (ATMT) has revealed a number of virulence attenuated mutants. In the avirulent mutant PA2810 the inserted T-DNA disrupts the gene encoding a putative histone 3 lysine 36 (H3K36)-specific demethylase (BcKDM1). Targeted mutagenesis of bckdm1 confirmed the gene-phenotype linkage and indicated that BcKDM1, despite its role in virulence (critical for penetration), is required for coping with excessive light, oxidative stress and for proper expression of light-responsive genes and photomorphogenesis. Thus, bckdm1 loss-of function mutants produce sclerotia under unfavorable conditions such as in the light. Notably, mutants expressing a truncated BcKDM1 (bckdm1991aa) showed deviating phenotypes from deletion (Deltabckdm1) and demethylase-deficient (bckdm1H360A) mutants but also from the wild type, thereby indicating the importance of the C-terminal region for some developmental processes. This effect may be specific to B. cinerea as the orthologs from other Ascomycetes cannot replace BcKDM1. PMID- 30445218 TI - CIBS: A biomedical text summarizer using topic-based sentence clustering. AB - Automatic text summarizers can reduce the time required to read lengthy text documents by extracting the most important parts. Multi-document summarizers should produce a summary that covers the main topics of multiple related input texts to diminish the extent of redundant information. In this paper, we propose a novel summarization method named Clustering and Itemset mining based Biomedical Summarizer (CIBS). The summarizer extracts biomedical concepts from the input documents and employs an itemset mining algorithm to discover main topics. Then, it applies a clustering algorithm to put the sentences into clusters such that those in the same cluster share similar topics. Selecting sentences from all the clusters, the summarizer can produce a summary that covers a wide range of topics of the input text. Using the Recall-Oriented Understudy for Gisting Evaluation (ROUGE) toolkit, we evaluate the performance of the CIBS method against four summarizers including a state-of-the-art method. The results show that the CIBS method can improve the performance of single- and multi-document biomedical text summarization. It is shown that the topic-based sentence clustering approach can be effectively used to increase the informative content of summaries, as well as to decrease the redundant information. PMID- 30445219 TI - Manifold regularized matrix factorization for drug-drug interaction prediction. AB - Drug-drug interaction (DDI) prediction is one of the most important tasks in drug discovery. Prediction of potential DDIs helps to reduce unexpected side effects in the lifecycle of drugs, and is important for the drug safety surveillance. Here, we formulate the drug-drug interaction prediction as a matrix completion task, and project drugs in the interaction space into a low-dimensional space. We consider drug features, i.e., substructures, targets, enzymes, transporters, pathways, indications, side effects, and off side effects, to calculate drug-drug similarities, and assume them as manifolds in feature spaces. In this paper, we present a novel computational method named "Manifold Regularized Matrix Factorization" (MRMF) to predict potential drug-drug interactions, by introducing the drug feature-based manifold regularization into the matrix factorization. In the computational experiments, the MRMF models, which utilize known drug-drug interactions and the drug feature-based manifold, produce the area under precision-recall curves (AUPR) up to 0.7963. We test manifold regularizations based on different drug features, and the MRMF models can produce robust performances. Compared with other state-of-the-art methods, the MRMF models can produce better performances in the cross validation and case study. The manifold regularization is the critical factor for the high-accuracy performances of our method. MRMF is promising and effective for the prediction of drug-drug interactions. PMID- 30445220 TI - An unsupervised and customizable misspelling generator for mining noisy health related text sources. AB - BACKGROUND: Data collection and extraction from noisy text sources such as social media typically rely on keyword-based searching/listening. However, health related terms are often misspelled in such noisy text sources due to their complex morphology, resulting in the exclusion of relevant data for studies. In this paper, we present a customizable data-centric system that automatically generates common misspellings for complex health-related terms, which can improve the data collection process from noisy text sources. MATERIALS AND METHODS: The spelling variant generator relies on a dense vector model learned from large, unlabeled text, which is used to find semantically close terms to the original/seed keyword, followed by the filtering of terms that are lexically dissimilar beyond a given threshold. The process is executed recursively, converging when no new terms similar (lexically and semantically) to the seed keyword are found. The weighting of intra-word character sequence similarities allows further problem-specific customization of the system. RESULTS: On a dataset prepared for this study, our system outperforms the current state-of-the art medication name variant generator with best F1-score of 0.69 and F14-score of 0.78. Extrinsic evaluation of the system on a set of cancer-related terms showed an increase of over 67% in retrieval rate from Twitter posts when the generated variants are included. DISCUSSION: Our proposed spelling variant generator has several advantages over the existing spelling variant generators-(i) it is capable of filtering out lexically similar but semantically dissimilar terms, (ii) the number of variants generated is low, as many low-frequency and ambiguous misspellings are filtered out, and (iii) the system is fully automatic, customizable and easily executable. While the base system is fully unsupervised, we show how supervision may be employed to adjust weights for task-specific customizations. CONCLUSION: The performance and relative simplicity of our proposed approach make it a much-needed spelling variant generation resource for health-related text mining from noisy sources. The source code for the system has been made publicly available for research. PMID- 30445221 TI - Association of patella alta with worsening of patellofemoral osteoarthritis related structural damage: data from the Osteoarthritis Initiative. AB - OBJECTIVES: To determine the association between Insall-Salvati ratio (ISR), a measure of patella alta, and worsening of Magnetic Resonance Imaging (MRI)-based osteoarthritis (OA)-related patellofemoral joint structural damages over 24-month in participants of the Osteoarthritis Initiative (OAI). DESIGN: Using weighted random sampling method, we selected a sample of 500 knees (from 1,677 knees with available baseline and 24-months MRI OA Knee Score (MOAKS) measurements), which is OAI-representative regarding knee OA-related factors (i.e., baseline age, sex, body mass index (BMI), and radiographic Kellgren-Lawrence grading). The ISR was measured in all enrolled knees using baseline sagittal 3T-MRI plane by three radiologists. Baseline and 24-month MOAKS variables for patellofemoral bone marrow lesions (BMLs), cartilage damages, and osteophytes were extracted, and the associations between ISR and 24-month worsening of these 3T-MRI features were evaluated using multivariable regression models. After computing receiver operating characteristic curves, the optimal cutoff point of ISR for indicating worsening of patellofemoral OA was determined. P-values were adjusted for multiple comparisons and false discovery rate (FDR) adjusted P-values were reported. RESULTS: In this longitudinal analysis, 24-month worsening of BML (odds ratio [OR] (95% confidence interval [95% CI]):11.18 (3.35-39.6), adjusted-p value:<0.001) and cartilage scores (OR:7.39 (1.62-34.71), adjusted-p-value:0.042) in lateral patella was associated with higher baseline ISR. However, higher ISR was not statistically associated with medial patellar or medial and lateral trochlear BML or cartilage scores worsening. We determined the optimal cutoff point of ISR>=1.14 (95% CI: 1.083-1.284) for predicting lateral patellofemoral OA related structural damages worsening over 24-months (sensitivity:73.73%; specificity: 66.67%). CONCLUSIONS: Given the uncertainly surrounding the results, our overall findings suggest that ISR could be considered as a predictor of lateral patellofemoral OA-related structural damages worsening with the optimal cutoff point of >=1.14 using knee sagittal MRI measurements. PMID- 30445222 TI - Trunk movement asymmetry associated with pain, disability, and quadriceps strength asymmetry in individuals with knee osteoarthritis: a cross-sectional study. AB - OBJECTIVE: This study examined 1) the clinical relevance of trunk movement asymmetry, which was evaluated using a trunk-mounted inertial measurement unit (IMU), and 2) the relationship between trunk movement asymmetry and lower limb muscle strength asymmetry in individuals with knee osteoarthritis (OA). DESIGN: One-hundred-thirty-one participants (mean age, 74.2 years; 71.8% female; Kellgren and Lawrence [K&L] grade >=1) underwent gait analysis at their preferred pace for IMU-based measurement of trunk movement asymmetry (harmonic ratio [HR] and improved HR). The isometric strength of quadriceps and hip abductors was evaluated using a hand-held dynamometer. Pain and disability level were evaluated using a validated self-reported questionnaire. Multiple regression analyses with covariate adjustment were performed to examine the relationship between trunk movement asymmetry (independent variable) and pain, disability level, or muscle strength asymmetry (dependent variables). RESULTS: Individuals with severe knee OA (K&L grade >=3) had increased trunk movement asymmetry in the medio-lateral axis compared to those with a K&L grade of 1. Increased trunk movement asymmetry was associated with a greater knee pain and disability. The increased trunk movement asymmetry was significantly associated with an increase in the asymmetry of quadriceps strength, but not with asymmetry in the strength of hip abductor. CONCLUSION: Our findings indicate that increased medio-lateral trunk movement asymmetry may be an indicator of impairment, rather than adaptation, in individuals with knee OA. This preliminary finding warrants validation by future study. Paying close attention to medio-lateral trunk movement asymmetry may be key to our understanding of OA-related pain and disability. PMID- 30445223 TI - Ethical challenges of kidney sale: A review of three major assumptions based on the theories of Tabataba'i. AB - This paper seeks to provide an ethical assessment of kidney sale based on the theories of a contemporary Shiite theologian, Muhammad Hussain Tabataba'i. It aims to offer a mechanism to decide the justifiability or unjustifiability of kidney sale in ethical terms. Tabataba'i considers ''Divine Consent'' as the criterion for the morality of an action. An action meets the "Divine Consent" requirement if it is done with a sincere intention, confirmed by reason and Divine revelations, brings about an internal peace for the agent, and preserves the agent's dignity and autonomy. Given this criterion and through an analytic and qualitative method, this paper aims to evaluate kidney sale in three cases: during one's lifetime, during brain death when the agent has left no will, and during brain death when the agent has left a will. It seems that, based on the theories of Tabataba'i, the above requirements are only met in the first two cases. Thus, kidney sale is morally justifiable in the first two cases but not in the third. PMID- 30445225 TI - Phaseolin ingestion affects vesicular traffic causing oxidative stress in the midgut of Callosobruchus maculatus larvae. AB - It has been reported that phaseolin, the major storage globulin of the common bean (Phaseolus vulgaris), is toxic to Callosobruchus maculatus larvae, an Old World bruchid beetle that is not capable of infesting this New World edible bean. It has also been demonstrated that vicilin, the major storage globulin found in cowpea (Vigna unguiculata) seeds, is absorbed through receptor-mediated endocytosis in the insect midgut. A putative vicilin receptor has been purified and showed high homology to alpha-tocopherol transfer protein. However, the ingestion of a variant vicilin purified from C. maculatus resistant seeds inhibits transcytosis, resulting in the accumulation of vicilins in the midgut cells and ultimately antibiosis. In the present work, we studied the cellular up take of phaseolin in C. maculatus larvae with the aim of discovering if this protein is also capable of inhibiting endocytic traffic in the enterocytes. FITC labelled vicilin and FITC-labelled phaseolin were incorporated into the diet of the larvae at a physiological concentration of 0.5% w/w. The fate of labelled and non-labelled globulins was monitored by confocal microscopy. Here we demonstrated that phaseolin is also endocytosed by enterocytes causing an accumulation of endocytic vesicles in the midgut when compared to the ingestion of vicilin obtained from a susceptible V. unguiculata cultivar. From the results obtained for HNE, MDA and TBARS, a pro-oxidative scenario was established in the intestinal epithelial cells of the larvae, which may explain the deleterious effect observed in larvae developing inside P. vulgaris seeds. PMID- 30445224 TI - Inclusion complexes of beta-cyclodextrin and polymorphs of mebendazole: Physicochemical characterization. AB - Mebendazole (MBZ), designated as a WHO essential drug, can exist in diverse solid forms and presents low absorption at the gastrointestinal level. Considering the potential of cyclodextrins to enhance the solubility and permeability of drugs, inclusion complexes of polymorphs A and C of MBZ with beta-cyclodextrin were obtained. The characterization of the complexes in solid state was performed by using a combination of experimental techniques including Fourier transform infrared spectroscopy, powder X-ray diffractometry and solid state nuclear magnetic resonance. Moreover, the effect of the binary complexes on their physical stability was evaluated. In addition, for a complete characterization of polymorphs A and C, one dimensional spectra and correlation nuclear magnetic resonance experiments were employed. Our physical studies showed that the inclusion complexes were new crystalline forms that induced shifts and broadening in the infrared and nuclear spectra. A molecular modelling analysis performed on the inclusion modes, demonstrated that the most favourable structure for the complex was the head down orientation. Moreover, the intermolecular interactions calculated for the complex with the atoms in molecules theory are in good agreement with the spectroscopic results. The inclusion complexes exhibited an increment of solubility in simulated physiological media. Furthermore, it was demonstrated that the complex formation did not affect the physical stability of the polymorphs. PMID- 30445226 TI - Hydrogen peroxide-Activatable polymeric prodrug of curcumin for ultrasound imaging and therapy of acute liver failure. AB - Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2 associated diseases. PMID- 30445227 TI - Interactive effects of osmotic stress and burrowing activity on protein metabolism and muscle capacity in the soft shell clam Mya arenaria. AB - Bioturbators such as sediment-dwelling marine bivalves are ecosystem engineers that enhance sediment-water exchange and benthic-pelagic coupling. In shallow coastal areas, bivalves are exposed to frequent disturbance and salinity stress that might negatively affect their activity and physiological performance; however, the mechanisms underlying these effects are not fully understood. We investigated the effects of osmotic stress (low and fluctuating salinity) and repeated burrowing on aerobic and contractile capacity of the foot muscle (assessed by the activity of succinate dehydrogenase and myosin ATPase) as well as the levels of organic osmolytes (free amino acids) and biochemical markers of protein synthesis and proteolysis in key osmoregulatory and energy storing tissues (gills and hepatopancreas, respectively) in a common bioturbator, the soft shell clam Mya arenaria. Osmotic stress and exhaustive exercise altered the foot muscle capacity of soft shell clams and had a strong impact on protein and amino acid homeostasis in tissues not directly involved in locomotion. Acclimation to constant low salinity (5 practical salinity units) depleted the whole-body free amino acid pool and affected protein synthesis but not protein breakdown in the gill. In contrast, fluctuating (5-15) salinity increased protein breakdown rate, suppressed protein synthesis, caused oxidative damage to proteins in the gill and selectively depleted whole-body glycine pool. Clams acclimated to normal salinity (15) increased the aerobic capacity of the foot muscle upon repeated burrowing, whereas acclimation to low and fluctuating salinity reduced this adaptive muscle plasticity. Under the normal and low salinity conditions, exhaustive exercise induced protein conservation pathways (indicated by suppression of protein synthesis and catabolism), but this effect was disrupted by fluctuating salinity. These findings indicate that exhaustive exercise and osmotic stress interactively affect whole-body protein homeostasis and functional capacity of the foot muscle in soft shell clams which might contribute to reduced burrowing activity of bivalve bioturbators in osmotically challenging environments such as estuaries and shallow coastal zones. PMID- 30445229 TI - Reducing the Radiotherapy Dose Prescription for Elective Treatment Areas in Human Papillomavirus (HPV)-Associated Oropharyngeal Carcinoma (OPC) Being Treated with Primary Chemoradiotherapy at XXXXX. AB - Data on the biology and radiosensitivity of HPV-related cancers has led many expert radiation oncologists to decrease the radiation dose to target areas in selected situations. At XXXXX, we have altered our radiation guidelines to allow substantial dose reduction to elective treatment; regions and to omit radiation completely in other regions that have historically been included in; the elective treatment volume. Here we summarize our current dose prescriptions and briefly explain the rationale behind these choices, which we anticipate will change when additional data matures. These recommendations are based on the AJCC 7th Edition TNM Staging System and applicable only to patients who receive concurrent platinum-based chemotherapy and in whom both p16 immuno-histochemistry, and HPV RNA in-situ hybridization, are positive. PMID- 30445230 TI - Mice-to-men comparison of inhaled drug-aerosol deposition and clearance. AB - Part of the effective prediction of the pharmacokinetics of drugs (or toxic particles) requires extrapolation of experimental data sets from animal studies to humans. As the respiratory tracts of rodents and humans are anatomically very different, there is a need to study airflow and drug-aerosol deposition patterns in lung airways of these laboratory animals and compare them to those of human lungs. As a first step, interspecies computational comparison modeling of inhaled nano-to-micron size drugs (50 nm < d<15MUm) was performed using mouse and human upper airway models under realistic breathing conditions. Critical species specific differences in lung physiology of the upper airways and subsequently in local drug deposition were simulated and analyzed. In addition, a hybrid modeling methodology, combining Computational Fluid-Particle Dynamics (CF-PD) simulations with deterministic lung deposition models, was developed and predicted total and regional drug-aerosol depositions in lung airways of both mouse and man were compared, accounting for the geometric, kinematic and dynamic differences. Interestingly, our results indicate that the total particle deposition fractions, especially for submicron particles, are comparable in rodent and human respiratory models for corresponding breathing conditions. However, care must be taken when extrapolating a given dosage as considerable differences were noted in the regional particle deposition pattern. Combined with the deposition model, the particle retention and clearance kinetics of deposited nanoparticles indicates that the clearance rate from the mouse lung is higher than that in the human lung. In summary, the presented computer simulation models provide detailed fluid particle dynamics results for upper lung airways of representative human and mouse models with a comparative analysis of particle lung deposition data, including a novel mice-to-men correlation as well as a particle-clearance analysis both useful for pharmacokinetic and toxicokinetic studies. PMID- 30445228 TI - Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study. AB - BACKGROUND: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. METHODS: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. RESULTS: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for >=20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). CONCLUSIONS: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms. PMID- 30445231 TI - Plasma beta-amyloid1-42 reference values. PMID- 30445232 TI - Low levels of alpha-synuclein in peripheral tissues are related to clinical relapse in relapsing-remitting multiple sclerosis: a pilot cross-sectional study. AB - The protein alpha-synuclein (alpha-Syn) has been linked to neuroinflammatory conditions. We investigated whether the presence of alpha-Syn in peripheral tissues is a surrogate of brain inflammatory status in a small group of relapsing remitting multiple sclerosis (RRMS) patients in a pilot cross-sectional study. Skin biopsies and peripheral blood were sampled from 34 healthy controls and 23 MS patients for measurement of alpha-Syn levels. Within the RRMS group 15 patients were in remission, and 8 patients were in the relapsing phase. The protein alpha-Syn was evaluated by means of immunohistochemistry and flow cytometry in skin and nucleated blood cells, respectively. In the skin, alpha-Syn levels were lower in relapsing MS than in the other groups, both in positive area (p = .021) and staining intensity (p = .004). In blood, the percentage of alpha Syn-positive lymphocytes and monocytes were not statistically different between study groups. Moreover, the use of systemic steroids did not affect alpha-Syn positivity in MS-relapse patients. Finally, epidermic Langerhans cells did not stain positively for alpha-Syn. Overall, the levels of alpha-Syn positivity were lower in inflammatory relapse of RRMS patients when measured in peripheral tissues. We discuss the role of alpha-Syn levels in inflammation according to the obtained results. PMID- 30445233 TI - Language support improves oral communication skills of undergraduate nursing students: A 6-month follow-up survey. AB - BACKGROUND: With the widening of participation in higher education, it is essential in the discipline of nursing that students are able to communicate proficiently to deliver quality patient care. However, undergraduate students can experience significant difficulties with spoken communication critical to professional nursing, which places them 'at risk' of failure during the nursing course. OBJECTIVES: To examine the relationship between students' use of academic literacy support and oral communication skills. DESIGN: Prospective, correlational survey design. SETTING: A large multi-campus university in Western Sydney, Australia. PARTICIPANTS: A total of 1699 assessment ratings of first and second year nursing students were completed at both baseline and at the 6-month follow-up in 2015. METHODS: The CLIP index was embedded as an assessment requirement in four clinical skills-based units and assessed at the end of each semester in the first two years of the Bachelor of Nursing program. In this study, first and second year students were assessed in Semester 1 at baseline and also six months later in Semester 2. RESULTS: From Semester 1 to Semester 2, the mean CLIP scores improved from 15.8 (SD: 3.7) to 17.2 (SD: 3.3) and all four components of the mean CLIP index improved. The smallest improvement was in the area of pronunciation while the lexical component had the greatest improvement. In addition, students who attended an academic literacy consultation or workshop for oral language support were over 1.5 times more likely to achieve an improvement in CLIP score (AOR: 1.58, 95% CI: 1.26 to 1.98). CONCLUSION: The CLIP tool can be used to track and monitor students' oral language skills over the course of their study, and identify 'at risk' students requiring additional support through on-campus language support programs. PMID- 30445234 TI - Light variability and mixotrophy: Responses of testate amoeba communities and shell delta13C values to a peatland shading experiment. AB - Paleoecological records suggest that growing season length and/or cloudiness may affect peatland carbon accumulation and testate amoeba-based environmental reconstructions, highlighting a need to understand how light intensity affects microbial communities. We shaded plots on two peatlands for two years to examine effects on testate amoeba communities, the relative abundance of mixotrophic and heterotrophic testate amoebae, transfer-function performance, and delta13C values of two species of mixotrophic testate amoebae. Surprisingly, relative abundance of mixotrophic species increased in shade, although compositional changes did not affect transfer-function performance. Shading did not affect delta13C values of Hyalosphenia papilio and Heleopera sphagni, which ranged from -23.5 to -19.60/00 and -23.2 to -19.20/00, respectively. These delta13C values were higher than those of potential food sources and lower than literature-derived values for Chlorella, the zoochlorellae inhabiting mixotrophic testate amoebae. delta13C values thus suggest that these mixotrophic species obtain some carbon from Chlorella, although coupled dietary and isotope studies are needed to quantify this contribution. More research is needed to assess impacts of light variability on peatland microbial communities; however, carbon sources are recorded by delta13C values of testate amoebae, indicating potential for studies of carbon cycling and how mixotrophy varies temporally and spatially. PMID- 30445235 TI - A clinical perspective on immunoglobulin heavy chain clonal heterogeneity in B cell acute lymphoblastic leukemia. AB - B cell acute lymphoblastic leukemia (B ALL) is a genetically heterogeneous neoplasm often demonstrating extensive subclone diversity within each patient's disease. The immunoglobulin heavy chain (IGH) locus is a marker of clonal variation in B ALL due to its intrinsic role in B lymphocyte development and its diverse Vh(D)Jh rearrangement patterns. B ALL IGH evolution may contribute to limitations in minimal residual disease (MRD) monitoring methods. Evolving technologies for IGH high-throughput sequencing (HTS) have demonstrated MRD detection as sensitive as 1 cell in 1,000,000. These methods may enhance the surveillance of B ALL in the setting of extensive subclone evolution and provide opportunities for detection and intervention before the onset of relapse. However, HTS MRD methods will need to be evaluated in the context of clinical trials in order to gain further insights about the clinical relevance of such sensitive B ALL MRD detection. PMID- 30445236 TI - The predictive value of morphological findings in early diagnosis of acute myeloid leukemia with recurrent cytogenetic abnormalities. AB - This study explores cytomorphologic features and their predictive role for early identification of acute myeloid leukemia (AML) with morphological distinctive recurrent cytogenetic abnormalities (RCA): t(15;17), t(8;21) and inv(16)/t(16;16). We retrospectively evaluated 396 de novo AML cases, diagnosed and treated at single institution, between 2013-2017. Specific cytomorphologic features suggesting distinctive AML-RCA were revealed at diagnosis in 62 (15.65%) patients, including AML with t(15;17) in 41 (66.13%), t(8;21) in 13 (20.97%) and inv(16)/t(16;16) in 8 (12.90%). Final diagnoses of AML-RCA according to WHO integrated diagnostic criteria were established in 66 (16.66%) cases, including AML with t(15;17) 40 (60.60%), t(8;21) 17 (25.76%), and inv(16)/t(16;16) 9 (13.64%). Discordance between cytomorphological and other integrated criteria was detected as missed/wrong-call in 0/1 for t(15;17), 6/2 for t(8;21) and 2/1 for inv(16)/t(16;16). The cytomorphological accuracy was 97.56% (40/41) for t(15;17), 57.89% (11/19) for t(8;21) and 70% (7/10) for inv (16)/t(16;16). Positive/negative predictive values of cytomorphological evaluation were: 97.56%/100% for t(15;17); 84.62%/88.68% for t(8;21); 87.50%/96.65% for inv(16)/t(16;16). Sensitivity/specificity were: 100%/96.15% for t(15;17); 64.10%/95.92% for t(8;21); 77.78%/98.25% for inv(16)/t(16;16). We confirmed that morphology is still a highly relevant evaluation method in diagnosing several common AML-RCAs before completing cytogenetic and molecular studies, enabling early detection, particularly of AML with t(15;17). PMID- 30445237 TI - Intensive chemotherapy vs. hypomethylating agents in older adults with newly diagnosed high-risk acute myeloid leukemia: A single center experience. AB - Acute myeloid leukemia (AML) in older patients is often associated with biologic and clinical characteristics that predict poor outcomes to cytarabine and anthracycline based induction chemotherapy (IC). The impact of hypomethylating agents (HMA) in the treatment of these high-risk patients is unknown. Here we retrospectively examined the remission rates and survival outcomes of 201 newly diagnosed patients >=60 years old with therapy-related (t-AML), secondary (s AML), or AML with myelodysplasia-related changes (AML-MRC). Ninety-eight patients received IC, and 103 received HMA. Patients in the IC cohort were younger than those who received HMA (68 vs. 74 years; p < 0.01) with lower comorbidity burden. Composite complete remission rates (CR) were 39% in IC and 27% in the HMA cohorts (p = 0.10). Overall survival (OS) was not significantly different between the two cohorts (7.59 mos vs. 5.49 mos; HR 0.75 95% CI 0.55-1.02) despite the fact that more patients in the IC cohort (33% versus 5%, p < 0.01) underwent allogeneic stem cell transplant. Patients with t-AML (HR 0.56; 95% CI 0.33-0.97) and complex karyotype without monosomal karyotype (CK + MK-; HR 0.37; 95% CI 0.19-0.75) had better OS following IC. Patients with CK + MK+ (HR 2.00; 95% CI 1.08-3.70) had improved OS following HMA. Our results support the use of HMA as an alternative upfront regimen in older individuals with newly diagnosed high-risk AML based on similar clinical outcomes to IC. PMID- 30445238 TI - Hyperoxia reduces salivary secretion by inducing oxidative stress in mice. AB - OBJECTIVE: The aim of this study was to determine the effects of prolonged hyperoxia on salivary glands and salivary secretion in mice. DESIGN: Male C57BL/6 J mice were kept in a 75% oxygen chamber (hyperoxia group) or a 21% oxygen chamber for 5 days. We measured the secretion volume, protein concentration, and amylase activity of saliva after the injection of pilocarpine. In addition, we evaluated the histological changes induced in the submandibular glands using hematoxylin and eosin and Alcian blue staining and assessed apoptotic changes using the TdT-mediated dUTP nick end labeling (TUNEL) assay. We also compared the submandibular gland expression levels of heme oxygenase-1 (HO-1), superoxide dismutase (SOD)-1, and SOD-2 using the real-time polymerase chain reaction. RESULTS: In the hyperoxia group, salivary secretion was significantly inhibited at 5 and 10 min after the injection of pilocarpine, and the total salivary secretion volume was significantly decreased. The salivary protein concentration and amylase activity were also significantly higher in the hyperoxia group. In the histological examinations, enlargement of the mucous acini and the accumulation of mucins were observed in the submandibular region in the hyperoxia group, and the number of TUNEL-positive cells was also significantly increased in the hyperoxia group. Moreover, the expression levels of HO-1, SOD-1, and SOD-2 were significantly higher in the hyperoxia group. CONCLUSION: Our results suggest that hyperoxia reduces salivary secretion, and oxidative stress reactions might be involved in this. PMID- 30445239 TI - IL-1beta rs1143634 and rs16944 polymorphisms in patients with periodontal disease. AB - BACKGROUND: Periodontal disease (PD) is a chronic inflammatory condition caused by pathogenic microflora in a biofilm, often leading to tooth loss. The inflammatory response of periodontal tissues to infection is influenced by both environmental and genetic factors. The interleukin (IL)-1 family of proinflammatory cytokines plays a role in the tissue destruction associated with PD due to their proinflammatory and bone-resorptive properties. In addition, recent studies have indicated that polymorphisms in the genes encoding IL-1 might be associated with greater PD severity. In this study, we examined the association between IL-1beta rs1143634 and rs16944 polymorphisms and PD in non smoking and smoking patients. MATERIALS AND METHODS: This study included 200 patients with PD (130 non-smokers and 70 smokers) and 156 control subjects (124 non-smokers and 32 smokers). Periodontal evaluation included approximal plaque index, modified sulcus bleeding index, probing pocket depth and clinical attachment loss. Genotyping was utilized for all samples by using allelic discrimination assays with TaqMan(r) probes on a 7500Fast Real-Time PCR Detection System. RESULTS: There were no statistically significant differences in the distribution of rs1143634 and rs16944 genotypes and alleles between patients with PD and control subjects, between smoking patients with PD and smoking controls, or between non-smoking patients with PD and non-smoking controls. CONCLUSIONS: The results of this study suggest there is no association between IL-1beta rs1143634 and rs16944 polymorphisms and PD. PMID- 30445240 TI - White matter structural differences in OSA patients experiencing residual daytime sleepiness with high CPAP use: a non-Gaussian diffusion MRI study. AB - OBJECTIVES: To investigate factors associated with residual sleepiness in patients who were highly adherent to continuous positive airway pressure (CPAP). Nocturnal inactivity, comorbidities, concomitant medications, and, in particular, white matter (WM) differences using diffusion magnetic resonance imaging (MRI) were explored using a continuous-time random-walk (CTRW) model. METHODS: Twenty seven male patients (30-55 years of age) with obstructive sleep apnea (OSA) received CPAP as the only treatment (CPAP >= 6 h/night) for at least 30 days. Based on the Psychomotor Vigilance Task (PVT) results, participants were divided into a non-sleepy group (lapses <= 5; n = 18) and a sleepy group (lapses > 5; n = 9). Mean nocturnal inactivity (sleep proxy) was measured using actigraphy for one week. Diffusion-weighted imaging (DWI) with high b-values, as well as diffusion tensor imaging (DTI), was performed on a 3 T MRI scanner. The DWI dataset was analyzed using the CTRW model that yielded three parameters: temporal diffusion heterogeneity alpha, spatial diffusion heterogeneity beta, and an anomalous diffusion coefficient Dm. The differences in alpha, beta, and Dm between the two groups were investigated by a whole-brain analysis using tract-based spatial statistics (TBSS), followed by a regional analysis on individual fiber tracts using a standard parcellation template. Results from the CTRW model were compared with those obtained from DTI. The three CTRW parameters were also correlated with the clinical assessment scores, Epworth Sleepiness Scale (ESS), PVT lapses, and PVT mean reaction time (MRT) in specific fiber tracts. RESULTS: There were no differences between groups in mean sleep duration, comorbidities, and the number or type of medications, including alerting and sedating medications. In the whole brain DWI analysis, the sleepy group showed higher alpha (17.27% of the WM voxels) and Dm (17.14%) when compared to the non-sleepy group (P < 0.05), whereas no significant difference in beta was observed. In the regional fiber analysis, the sleepy and non-sleepy groups showed significant differences in alpha, beta, or their combinations in a total of 12 fiber tracts; whereas similar differences were not observed in DTI parameters, when age was used as a covariate. Additionally, moderate to strong correlations between the CTRW parameters (alpha, beta, or Dm) and the sleepiness assessment scores (ESS, PVT lapses, or PVT MRT) were observed in specific fiber tracts (|R| = 0.448-0.654, P = 0.0003-0.019). CONCLUSIONS: The observed differences in the CTRW parameters between the two groups indicate that WM alterations can be a possible mechanism to explain reversible versus residual sleepiness observed in OSA patients with identical high level of CPAP use. The moderate to strong correlations between the CTRW parameters and the clinical scores suggest the possibility of developing objective and quantitative imaging markers to complement clinical assessment of OSA patients. PMID- 30445241 TI - Changes in the gills of the European eel (Anguilla anguilla) after chronic exposure to environmental cocaine concentration. AB - The recent discovery of illicit drugs in the aquatic environment has raised concerns about the possible effects on the aquatic fauna, because of the pharmacological activity of these substances. Cocaine is an illicit drug widespread in surface waters since it is the third most widely used drug in North America, Western and Central Europe, and the second in Latin America and the Caribbean. The aim of this study was to evaluate the influence of environmental concentrations of cocaine on the gills of the European eel (Anguilla anguilla). The gills of male silver eels exposed to 20 ng L-1 of cocaine for fifty days were compared to control, vehicle control and post-exposure recovery ten days groups. The following parameters were evaluated: the thickness of the interlamellar epithelium (TIE), the length of the secondary lamellae (LSL) and the fraction of the interlamellar epithelium and the secondary lamellae occupied by the mucous cells (MC(IE-SL)FA) 3) the plasma cortisol and prolactin levels. After cocaine exposure, the gill epithelium appeared hyperplastic. The following changes were observed: proliferation in the interlamellar epithelium; partial and total fusion of the secondary lamellae, that appeared shortened and dilated; epithelial lifting and aneurism in the secondary lamellae. Moreover, in cocaine exposed eels, an increase in TIE and MC(IE-SL)FA and a decrease in LSL were observed. These changes were still present ten days after the interruption of cocaine exposure. Plasma levels of both cortisol and prolactin increased after cocaine exposure; ten days after the interruption of cocaine exposure, the plasma cortisol levels were still higher, whereas the plasma prolactin levels were lower, than control values. Our results show that even a chronic exposure to low environmental cocaine concentrations severely harms the eel gills, suggesting damages to their functions, and potentially affecting the survival of this species. PMID- 30445242 TI - Analysis of glycerophospholipid metabolism after exposure to PCB153 in PC12 cells through targeted lipidomics by UHPLC-MS/MS. AB - Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that have neurotoxicity, reproductive toxicity, hepatotoxicity and immunotoxicity in both animals and humans. Few studies have focused on the changes to endogenous glycerophospholipid metabolism caused by PCB153. To evaluate the relationships between exposure to PCB153 and specific endogenous glycerophospholipid metabolism, an ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method was implemented in this study. Twenty-two endogenous glycerophospholipids in PC12 cells were analyzed after exposure to PCB153 at dosages of 0.05 MUg mL-1, 0.5 MUg mL-1 or 20 MUg mL-1 for 120 h. PC(14:0/14:0), PE(16:0/18:1), PE(16:0/18:2), PS(18:0/18:1) and PI(16:0/18:1) were identified as potential biomarkers under the rules of t-test (P) value < 0.05 and variable importance at projection (VIP) value > 1. It was also found that the alterations at 0.05 MUg mL-1 and 20 MUg mL-1 PCB153 were similar at 120 h, while 0.5 MUg mL-1 PCB153 presented an opposite trend. Additionally, significant upregulation of PC, PE and PS with the same fatty acid chains of 18:0/18:2 was found after exposure to 0.05 MUg mL-1 and 20 MUg mL-1 PCB153 at 120 h. This study revealed that PCB153 exposure modulated 22 endogenous glycerophospholipids in PC12 cells and provided the basis for the further study of PCB153 on the effects of glycerophospholipids on PC12 cells. PMID- 30445243 TI - Nanoelemental selenium alleviated the mercury load and promoted the formation of high-molecular-weight mercury- and selenium-containing proteins in serum samples from methylmercury-poisoned rats. AB - Selenite (Se4+) has been found to counteract the neurotoxicity of methylmercury (MeHg) in MeHg-poisoned rats. However, Se4+ has narrow range between its toxic and beneficial effects. Nanoelemental selenium (SeNPs) was found to be less toxic than other forms of Se such as Se4+. In this study, the effects of SeNPs on the load of mercury (Hg) in rats were investigated. Hyphenated technique based on size-exclusion chromatography coupled with UV and inductively coupled plasma mass spectrometry (SEC-ICP-MS) detection and synchrotron radiation X-ray fluorescence spectroscopy (SR-XRF) were used to analyze the Hg-Se-containing proteins in the serum from MeHg-poisoned rats. The Hg-Se-containing fractions monitored by UV and ICP-MS were further characterized by MALDI-TOF-MS. Elevated serum Hg and Se levels were found in MeHg-poisoned rats after SeNPs treatment. Three main Hg containing bands with molecular weights (MWs) of 25, 62 and 140 kDa were detected in the control samples. Treatment with SeNPs increased the Hg content in proteins at 62 and 170 kDa and decreased the Hg content at 25 kDa. The fraction with 25 kDa was assigned to metallothioneins (MTs), and fractions with 40 and 75 kDa were assigned to albumin. This study showed that the low-toxicity SeNPs could reduce the Hg load in the tissues and promote the formation of high molecular weight Hg- and Se-containing proteins in MeHg-poisoned rats. PMID- 30445244 TI - Phenolic metabolism and related heavy metal tolerance mechanism in Kandelia Obovata under Cd and Zn stress. AB - In the present study, a set of pot culture experiments was conducted to reveal how the metabolism process of phenolic compounds was affected by cadmium (Cd) and zinc (Zn) and to further uncover heavy metal tolerance mechanisms in Kandelia obovata. After 60d of treatment, the biomass and chlorophyll a content in the leaves were suppressed, but total phenolic compounds in roots and leaves were improved by the increasing gradient of Cd or Zn concentrations; Total phenolic compounds significantly increased by 3.6-44.6% in the roots, and by 0.4-126.6% in the leaves. At the meantime, the activity of Shikimate dehydrogenase (SKDH), cinnamyl alcohol dehydrogenase (CAD), and polyphenol oxidase (PPO) in the roots increased by 11.2-307.6%, 12.4-175.4% and - 2.7-392.8%, and the results were 3.4 69.5%, 1.7-40.0%, 16.0-99.7% in the leaves. Higher toxicity of Cd than Zn, as well as slight alleviating effect of 100 mg kg-1 Zn on 2.5 mg kg-1 Cd were found. Additionally, a significantly positive correlation coefficients for relationship between phenolic metabolism related enzyme activity and Cd/Zn contamination levels was found, and leaf SKDH, leaf CAD, and leaf PPO activities were moderately correlated with leaf Cd (r = 0.39, r = 0.43, and r = 0.57, respectively) and leaf Zn (r = 0.44, r = 0.41, r = 0.19, respectively) content, which indicate that Cd and Zn play a previously unrecognized but major role in phenolic compounds synthesis, transport, and metabolism in K. obovata. The results also provided evidence that the application of high levels of Cd and Zn was accompanied by three phenolic metabolism pathways participating in heavy metal tolerance process. PMID- 30445245 TI - Phosphorus sorption behavior on sediments in Sanggou Bay related with their compositions by sequential fractionation. AB - The surficial sediment samples collected from the Sanggou Bay in China were treated by a sequential extraction procedure. After removal of calcite, organic matter and Fe/Mn oxides, P adsorption onto the sediment residues was then evaluated through kinetic and thermodynamic characteristics. The sorption kinetic curves could be described by a two-compartment first order equation. The sorption isotherms fit well with the Langmuir and Freundlich equations. The HCl-treated sediments with calcite removed showed a rising fraction of the rapid step and a higher P adsorption potential compared with the un-extracted samples. For the clay minerals and silicate residue after NH2OH.HCl treatment, the rapid step fraction was dominant, the sorption capability was prohibited, and the process was much more reversible than the original and previously-generated samples. An increase of temperature was favorable for the sorption. Estimation of thermodynamic parameters showed that the process was spontaneous and endothermic, with an increased randomness at the solid-liquid interface. Compared with the un extracted sediment, the thermodynamic parameters in our case changed slightly after HCl treatment and NH2OH.HCl treatment. PMID- 30445246 TI - Accumulation of heavy metals in metallophytes from three mining sites (Southern Centre Morocco) and evaluation of their phytoremediation potential. AB - The current study aims to perform a field survey of three abandoned mining sites in the southern centre of Morocco to assess the recent metal pollution in soils and accumulation potential of plant species. Native plants and soils were sampled at several sites in the studied mines and analysed for Cu, Zn, Pb and Cd concentrations. Soils in the investigated sites proved to be deficient in major macronutrients and to contain toxic levels of Cu, Zn, Pb and Cd. Botanical survey of the prospected sites showed the abundance of diverse plant communities (46 species and 19 families), with no obvious toxicity symptoms. Results showed that the concentrations of heavy metals were different in the same plant species and from plant species to another. Eight plants of 46 species namely Hirschfeldia incana (L.) Lagr.-Foss, Citrullus vulgaris (L.) Schradi, Portulaca oleracea L., Stipa capensis Thunb., Lactuca viminea (L.) J.Presl & C.Presl, Forsskaolea tenacissima L., Lycium intricatum Boiss. and Hammada scoparia (Pomel) Iljin were considered as the best-performing specimens due to their high ability to accumulate multiple metals in their shoots and roots without being affected by excessive metal contents. This was confirmed by the transfer factors generally higher than 1. Consequently, these tolerant and native plant species could be used as tools for an effective phytorestoration of metal-contaminated sites. PMID- 30445247 TI - Bioaerosols emission and exposure risk of a wastewater treatment plant with A2O treatment process. AB - The characteristics of bioaerosol emissions from wastewater treatment plants (WWTPs) have attracted extensive attention. The anaerobic-anoxic-oxic (A2O) process, which uses the activated sludge approach to wastewater treatment, is the most widely used process in WWTPs. Concentration, size distribution, population, and exposure risk from bacteria and fungi in bioaerosols of WWTPs using the A2O process were studied in this work. The results showed that the maximum concentration of airborne bacteria (1.00 * 104 Colony Forming Units per cubic meter (CFU m-3)) and fungi (1.44 *104 CFU m-3) occurred from the facility's aerobic tank, in summer. As one of the main factors affecting bioaerosol exposure risk, particle size distribution was related to season. The study found that particles larger than 3.3 um in diameter were detected mainly in spring and summer, while particles less than 3.3 um were detected mainly in autumn and winter, whether bacterial aerosol or fungal aerosol. In addition, pathogenic bacteria were observed in bioaerosols from WWTPs, with 18 of the 65 species of bacteria detected found to be potentially or opportunistically pathogenic, such as Chryseobacterium, Stenotrophomonas, Alcaligenes, Micrococcus, Pantoea, Enterobacter and Escherichia-Shigella. The presence of these pathogens further increased the exposure risk from bioaerosols. The results of an inhalation risk assessment for airborne bacteria and fungi indicated that potential adverse health risks for adults mainly occurred in spring, summer, and autumn. On this basis, it was concluded that WWTP operators should set up effective bioaerosol controls as soon as possible to protect the health of workers, and of residents near the plant. PMID- 30445248 TI - Anti-addictive properties of COR659 - Additional pharmacological evidence and comparison with a series of novel analogues. AB - A recent study found that COR659 (methyl 2-[(4-chlorophenyl)carboxamido]-4-ethyl 5-methylthiophene-3-carboxylate) reduced operant alcohol and chocolate self administration in rats; COR659 also suppressed cue-induced reinstatement of chocolate seeking in rats. COR659 apparently exerts its effects via a composite mechanism, including positive allosteric modulation of the GABAB receptor and an action at the cannabinoid CB1 receptor. The present study investigated whether the reducing effect of COR659 on alcohol and chocolate self-administration was maintained after repeated treatment and if COR659 affected cue-induced reinstatement of alcohol seeking; additionally, it evaluated the ability of 9 structural analogues of COR659 - designed modifying the substituents on the phenylcarboxamido moiety and replacing the thiophene with the pyridine ring - to affect alcohol and chocolate self-administration. Alcohol self-administration experiments employed Sardinian alcohol-preferring (sP) rats trained to lever respond for alcohol (15% v/v). Chocolate self-administration experiments employed Wistar rats trained to lever-respond for a chocolate solution (5% w/v Nesquik(r)). In the reinstatement experiment, previously extinguished lever responding for alcohol in sP rats was reinstated by the non-contingent presentation of an alcohol-associated complex of cues. All drugs were tested at the doses of 0, 2.5, 5, and 10 mg/kg (i.p.). 10-Day treatment with COR659 produced a dose-related reduction of both alcohol and chocolate self administration, with limited loss of efficacy on continuing treatment. Acute COR659 suppressed reinstatement of alcohol seeking. Among the 9 tested analogues, only COR657 (methyl 2-(benzoylamino)-4-ethyl-5-methylthiophene-3-carboxylate) decreased alcohol self-administration similarly to COR659; all other compounds produced modest, or even no, effect on alcohol self-administration. COR659 excluded, no compound altered chocolate self-administration. These results confirm and extend the ability of COR659 to reduce several behaviors motivated by alcohol and palatable food in rats. Comparison of COR659 to its analogues provided disparate results that do not currently allow any conclusive structure activity relationship to be hypothesized, as their diverse pharmacological profile apparently does not depend on physicochemical properties. PMID- 30445249 TI - Effects of noncontingent ethanol, DHEA, and pregnanolone administration on ethanol self-administration in outbred female rats. AB - Previous research from this laboratory demonstrated that male outbred rats (Long Evans) can be trained to prefer ethanol (10% v/v) over water during 30-min home cage sessions and that higher ethanol concentrations (18-32% v/v) can serve as a reinforcer under various operant schedules. Further, we have shown that two neurosteroids, dehydroepiandrosterone (DHEA) and pregnanolone, can readily decrease ethanol self-administration in males. The present study used the same procedures in an attempt to systematically replicate the previous findings in female outbred rats. Rats were first trained to self-administer ethanol in the home cage using a saccharin-fading procedure. Subsequently, a two-bottle preference test was initiated by substituting different ethanol concentrations after subjects reliably consumed 10% ethanol alone. Water was always available during this phase. Next, subjects were transitioned to a fixed-ratio 10 (FR-10) schedule of reinforcement with 0.1 mL of ethanol (18% v/v) serving as the reinforcer so that a concentration-effect curve could be established. Upon completion, subjects were transitioned to an FR-10 FR-20 multiple schedule of ethanol (32% v/v) and food reinforcement to determine whether noncontingent ethanol, DHEA, and pregnanolone could selectively decrease ethanol intake. Not surprisingly, female subjects preferentially consumed ethanol over water at concentrations of 3.2-18% (v/v) during the home-cage procedure, and significantly increased the mean dose of ethanol consumed and blood ethanol concentration (BEC). Similarly, increasing concentrations under an FR-10 schedule significantly increased the dose of ethanol presented and BEC compared to control (water). Finally, under the multiple schedule, noncontingent injections of ethanol (0.32 1.8 g/kg), DHEA (10-100 mg/kg), and pregnanolone (1.8-32 mg/kg) dose-dependently decreased food- and ethanol-maintained responding and the dose of ethanol presented. BEC was significantly decreased by the neurosteroids, but increased by ethanol due to its noncontingent administration. Together, these data replicate only a subset of the data previously obtained in males, suggesting there are sex differences particularly with respect to the effects of DHEA and pregnanolone. PMID- 30445250 TI - Chemometric approach for discriminating tobacco trademarks by near infrared spectroscopy. AB - Cigarettes are consumer products with a broad market-driven orientation. In order to satisfy the different needs of smokers, cigarette trademarks with different aroma, taste and appearance are available on the market. In this study near infrared (NIR) spectroscopy in combination with chemometrics was applied in order to distinguish cigarette trademarks by analysing the tobacco. Calibration models were developed to differentiate three tobacco trademarks and their respective producers. The developed models also allowed the discrimination of the tobacco according to their geographical origin and may serve as a tool for the detection of counterfeit tobacco. PMID- 30445251 TI - Forensic personal identification utilizing part-to-part comparison of CT-derived 3D lumbar models. AB - The objective of this project was to document the efficacy of part-to-part comparison of computed tomography (CT)-derived three-dimensional (3D) models of the lumbar spine in forensic personal identification. By testing the methodology, this study aimed to provide a new technique of quantifiable (through a percent match) positive identification that meets the explicit requirements of the Daubert ruling and the challenges set forth in the 2009 NAS report. Ante-mortem (AM) and simulated post-mortem (PM) models of the lumbar vertebrae (L1-L5) for 30 unique individuals were compared via part comparison analyses. The threshold of +/-0.5mm with at least a 90% match was considered a positive identification. Using this threshold, the part comparison results had a perfect identification rate with no false positives and no false negative matches. A ROC curve was generated with a score of 1, signifying a "perfect" sensitivity and specificity, at a cut-off value of 65.5%. On average positive IDs had a 94.7% percent match within the established threshold, while negative IDs had an average of 21.4%. In looking at the impact of different components of the biological profile, age and sex of the unknown individual played a minimal role in the percent match for both a positive and a negative ID. Lumbar level also played a minor role in in both the positive and negative percent match. The real-world application of 3D part-to part comparison on AM and simulated PM scans demonstrate the potential usefulness of this technology in forensic identification. PMID- 30445252 TI - Contractile behaviors of cardiac muscle cells on mushroom-shaped micropillar arrays. AB - In this work we propose mushroom-shaped PDMS (Polydimethylsiloxane) MUpillar arrays for enhancing the contractile force of cardiomyocytes during cell culturing. Conventional micropillar (MUpillar) arrays with flat surfaces were employed as a standard sample to quantitatively recognize experimental data and to conclusively demonstrate the improved performance of mushroom-shaped PDMS MUpillar arrays. Cardiomyocytes isolated from experimental animals were cultured on both of the fabricated MUpillar arrays and then monitored over a growing period. Deflections of MUpillars were precisely measured through a home-built analyzing system quantitatively representing the contractile force of cardiomyocytes. Mushroom-shaped PDMS MUpillar arrays exhibited a 20% improved contractile force compared to conventional PDMS MUpillar arrays due to their topographical dependency. Preliminary results also show that the proposed mushroom-shaped PDMS MUpillar surface positively affects the Z-band width, actin filament polymerization and focal adhesion (FA) of cardiomyocytes. Further, the enhanced performance of mushroom-shaped PDMS MUpillar arrays was confirmed by measuring the cardiac sarcomere alpha-actin length and myofilament width via ICC (immunocytochemistry) staining and western blot experiments. PMID- 30445253 TI - Enhanced anti-tumor efficacy and reduced cardiotoxicity of doxorubicin delivered in a novel plant virus nanoparticle. AB - Plant viruses are one of the newly applied nanoparticles as drug delivery vehicles. Here, we investigated drug delivery performance of Johnson grass chlorotic stripe mosaic virus (JgCSMV) conjugated to folic acid (FA) for targeted delivery of doxorubicin (Dox). The FA-JgCSMV-Dox complex was synthesized and characterized using spectrophotometry, native and denaturing gel electrophoresis and transmission electron microscopy, which disclosed that JgCSMV virions encapsulated Dox and showed comparable size and morphology to the native particles. The JgCSMV nanoparticles loaded with Dox showed a sustained drug release profile in tumor tissue and improved the uptake of Dox in breast cancer cells, leading to enhanced tumor homing. Lastly, we demonstrated that FA-JgCSMV Dox reduced the tumor growth and cardiotoxicity of athymic mice bearing human breast cancer xenografts in comparison to free Dox. This study is the first report on applicability of JgCSMV for Dox delivery with superior benefits over generally marketed formulations of doxorubicin. PMID- 30445254 TI - Isoelectric point of free and adsorbed cytochrome c determined by various methods. AB - The purpose is to determine the isoelectric point (IEP) pIMU of cytochrome c (cytC, a globular haemoproteid) adsorbed on montmorillonite (MM, plate-like colloid particles) by microelectrophoresis and to compare the pIMU value with pIf9.44 measured by isoelectric focusing in gel with covalently linked ampholytes, and with pInz10.0-10.6 of free cytC globule calculated by three programs for pH-dependent net charge nz using the crystallographic structure of cytC. The pH-dependence of the electrophoretic mobility MU(pH) in the range pH 6 11 shows out that IEP of cytC-MM particles appears at pH 9.35. The near courses of MU(pH) and nz(pH) reveal that the pH-independent negative charge of the MM substrate is hydrodynamically shielded by the adsorbed protein globules. The nearness of IEP and pIf allows attributing IEP value of cytC-MM particles to the isoelectric point pIMU of cytC. A short survey for pI of cytC reported in the literature since 1941 shows out that pI is dispersed in the range pH 9.0-10.65 although cytC is used now as pIf marker with well known IEP; the reason for that and the imperfections of the employed methods are discussed. PMID- 30445255 TI - SPIONs functionalized with small peptides for binding of lipopolysaccharide, a pathophysiologically relevant microbial product. AB - Systemic inflammation such as sepsis represents an acute life-threatening condition, to which often no timely remedy can be found. A promising strategy may be to functionalize magnetic nanoparticles with specific peptides, derived from the binding motives of agglutinating salivary proteins, that allow immobilization of pathogens. In this work, superparamagnetic iron oxide nanoparticles with stable polycondensed aminoalkylsilane layer were developed, to which the heterobifunctional linkers N-succinimidyl 3-(2-pyridyldithio)-propanoate (SDPD) and N-succinimidyl bromoacetate (SBA) were bound. These linkers were further chemoselectively reacted with the thiol group of singularly present cysteines of selected peptides. The resulting functional nanoparticles underwent a detailed physicochemical characterization. The biocompatibility of the primarily coated aminoalkylsilane particles was also investigated. To test the pathogen-binding efficacy of the particles, the lipopolysaccharide-immobilization capacity of the peptide-coated particles was compared with free peptides. Here, one particle bound peptide species succeeded in capturing 90% of the toxin, whereas the degree of immobilization of the toxin with a system that varied in the sequence of the peptide dropped to 35%. With these promising results, we hope to develop extracorporeal magnetic clearance systems for removing pathogens from the human body in order to accelerate diagnosis and alleviate acute disease conditions such as sepsis. PMID- 30445256 TI - Timing and selection of first antiseizure medication in patients with pediatric status epilepticus. AB - OBJECTIVE: Pediatric status epilepticus (SE) may be associated with significant morbidity. We sought to evaluate timing and selection of antiseizure medications (ASM) in patients presenting in SE to a pediatric emergency department (ED). We hypothesized that delays in initial treatment are associated with longer overall duration of SE. METHODS: We identified patients with SE presenting to a single urban, academic pediatric hospital ED from 2009-2015. Patients were included in the study population with physician-documented ICD-9 code of SE. Medical record reviews were used to verify timing of seizure onset, ASM dosing, route, and timing. RESULTS: 141 patients had complete documentation to determine medication dosing and timing related to seizure onset. There were 75 boys and 66 girls. Median age was 45 months (IQR 20-97.5 months). Median overall duration of SE was 61.5 min (IQR 36-120 min). Median time to first ASM dose (whether given by parent, EMT or in ED) was 25 min (IQR 7-56 min). First dose ASM was a benzodiazepine (BDZ) in 92% of patients (130/141) and second-dose ASM was a BDZ in 95% of patients (90/95). Median seizure duration was 59.5 min and 151.5 min in patients who received first dose ASM in under 5 min and 60 min or more after seizure onset, respectively (p < 0.01). SE was stopped by first dose ASM in 32% of patients. SIGNIFICANCE: Our data suggest that there are delays in first dose ASM in patients presenting to our ED with SE. These results support the view that delays in initial ASM administration are associated with prolonged SE in some patients. A group of patients with prolonged SE had complete resolution after single dose of benzodiazepine, indicating that not all prolonged seizures become refractory. PMID- 30445257 TI - Persistent IKKalpha phosphorylation induced apoptosis in UVB and Poly I:C co treated HaCaT cells plausibly through pro-apoptotic p73 and abrogation of IkappaBalpha. AB - Toll-like receptor 3 (TLR3), a member of pattern recognition receptors, is reported to initiate skin inflammation by recognizing double-strand RNA (dsRNA) released from UVB-irradiated cells. Recently, we have discovered the NF-kappaB pathway activated by TLR3 is involved in apoptosis of UVB-Poly I:C-treated HaCaT cells. The real culprit for apoptosis has not been precisely identified since the system of NF-kappaB pathway is complex. In this study, we silenced main transcriptional factors in NF-kappaB family, RelA, RelB and c-Rel, but to our surprise the results show that none of them participate in apoptosis induction in UVB-Poly I:C-treated HaCaT cells. Therefore, we moved to investigate the apoptosis-associated molecules in the upstream of NF-kappaB pathway. We firstly checked the expression of IkappaBalpha, an NF-kappaB inhibitor. UVB (4.8 mJ/cm2) and Poly I:C (0.3 MUg/mL) co-treatment decreased IkappaBalpha expression level in a time-dependent manner. Silencing IkappaBalpha with siRNA further enhanced UVB Poly I:C-induced cell death. We then investigated IkappaB kinase (IKK) complex that contributes to the degradation of IkappaBalpha. IKK is composed of IKKalpha, IKKbeta and NEMO. Treatment with IKK-16, an IKKalpha/beta inhibitor, significantly diminished UVB-Poly I:C-induced IkappaBalpha degradation and thus apoptosis. Silencing either IKKalpha or NEMO but not IKKbeta with corresponding siRNA inhibited apoptosis. Tumor repressor p73, a homologue of p53, is reported to mediate IKKalpha-induced apoptosis in DNA damage response. Silencing p73 reduced cell apoptosis in UVB-Poly I:C-treated HaCaT cells. In summary, UVB and Poly I:C co-treatment activates IKKalpha and NEMO, which diminishes anti apoptotic IkappaBalpha, resulting in enhancement of apoptosis through p73. The findings partially clarify the possible molecular mechanism of pro-apoptotic NF kappaB pathway activated by TLR3 in the fate of UVB-irradiated epidermis. PMID- 30445258 TI - Characterization of CD40+ leukocytes in flounder (Paralichthys olivaceus) and its response after Hirame novirhabdovirus infection and immunization. AB - CD40 is a crucial signal mediating factor in T-dependent B cell responses and involved in many aspects of cellular and humoral immunity. In this paper, recombinant protein of CD40 in flounder (Paralichthys olivaceus) and its antibodies (Abs) were produced, native CD40 molecules in flounder tissues were identified, then the CD40+ leukocytes in T/B lymphocytes were characterized, and the variations of CD40+ leukocytes in flounder after Hirame novirhabdovirus (HIRRV) infection and immunization were investigated, respectively. The results showed that the Abs could specifically recognize native flounder CD40 molecule at 32 kDa. The proportions of CD40+ leukocytes were varied by flounder tissues. CD40+/IgM+ B lymphocytes, CD40+/CD4-1+ T lymphocytes, CD40+/CD4-2+ T lymphocytes and CD40+/CD8+ T lymphocytes in peripheral blood leukocytes (PBLs) were 1.18 +/- 0.27%, 0.69 +/- 0.17%, 0.75 +/- 0.14% and 0.25 +/- 0.14%; were 2.80 +/- 0.32%, 0.71 +/- 0.19%, 0.88 +/- 0.23% and 0.33 +/- 0.17% in spleen; 4.11 +/- 0.47%, 0.92 +/- 0.18%, 1.09 +/- 0.17% and 0.9 +/- 0.17% in head kidney; 1.92 +/- 0.39%, 1.02 +/- 0.23%, 1.33 +/- 0.38% and 0.67 +/- 0.24% in intestine; 1.24 +/- 0.36%, 1.21 +/- 0.24%, 1.70 +/- 0.3% and 0.97 +/- 0.21% in gill, respectively. The percentages of CD40+ leukocytes in PBLs were significantly increased in both HIRRV infection and immunization groups, and reached their peak levels at 3rd day with 5.70 +/- 0.16% and 6.40 +/- 0.13%, respectively. Concluded with our previous study, these data first reported that CD40 molecules were expressed on both B and T lymphocytes in teleost, and had a coordination with T and B lymphocytes in immune responses. PMID- 30445259 TI - A nanomolar detection of mercury(II) ion by a chemodosimetric rhodamine-based sensor in an aqueous medium: Potential applications in real water samples and as paper strips. AB - A new promising rhodamine based colorimetric and fluorometric chemosensor, RDV has been designed and synthesized for specific detection of Hg2+ ion. It acts as highly selective "turn-on" fluorescent chemosensor for Hg2+ ion without interference from other competitive metal ions in aqueous acetonitrile medium. The drastic color change with addition of Hg2+, from colorless to pink, indicates RDV can acts as "naked-eye" indicator for Hg2+. The Hg2+ promoted selective hydrolysis of appended vinyl ether group in RDV followed by Hg2+ chelated complex formation with concomitant opening of spirolactam ring is the plausible sensing mechanism. The detailed absorption, fluorescence, 1H NMR, 13C NMR and mass spectrometry confirms the proposed sensing mechanism. The limit of detection (LOD) of Hg2+ by RDV is 136 nM indicating the high sensitivity towards Hg2+. The RDV shows consistent spectroscopic response in biological pH range 4-10. In addition to explore practical applicability of RDV, its paper strips have been made and used to detect Hg2+ in pure water solution up to 10 ppm level. Furthermore, the potential application of RDV for the sensing of Hg2+ in real water samples (tap water and drinking waters from different sources) were also monitored and demonstrated. PMID- 30445260 TI - Study of vibrational spectra of monohalogenated acetylenes and their deuterated analogues using the U(4) algebraic model. AB - A detailed study on the vibrational spectra of monohalogenated acetylenes and their deuterated analogues has been reported in this work using the U(4) algebraic model. With detailed spectral analysis, it has been shown in this study that all the stable isotopes of monohalogenated acetylenes and their deuterated analogues can be approximated well using the U(4) algebraic model. PMID- 30445261 TI - Inhibition of catalytic activity of fibrinogen-stabilized gold nanoparticles via thrombin-induced inclusion of nanoparticle into fibrin: Application for thrombin sensing with more than 104-fold selectivity. AB - Citrate-capped gold nanoparticles (AuNPs) modified with thrombin-binding aptamer are often implemented for colorimetric, fluorescent, and electrochemical detection of thrombin in an aqueous solution. However, researchers have rarely explored the application of fibrinogen-modified AuNPs (F-AuNPs) for thrombin sensing. We present a simple, inexpensive, sensitive, and selective probe for colorimetric assay of thrombin through combining thrombin-induced inclusion of F AuNPs into Fibrin and F-AuNPs-catalyzed reduction of 4-nitrophenol with an excess amount of NaBH4. Considering that fibrinogen stabilized citrate-capped AuNPs against a high-ionic-strength buffer, F-AuNPs efficiently catalyzed the NaBH4 mediated decrease of yellow 4-nitrophenol to colorless 4-aminophenol. The presence of thrombin converted fibrinogen into fibrin on the nanoparticle surface, leading to the inclusion of nanoparticles into fibrin. The formation of fibrin inhibited that the AuNPs catalyzed the NaBH4-mediated reduction of 4 nitrophenol. Consequently, the color of the solution gradually varied from colorless to yellow with increasing thrombin concentration. The proposed system was shown to be accurate in the quantification of small differences in the concentration of human thrombin over the range of 4-60 pM. The lowest detectable concentration of human thrombin by the naked eye was as low as 16 pM. We demonstrated the practical application of the proposed system in quantifying 1-15 nM human thrombin in human plasma. PMID- 30445262 TI - Discovery, synthesis of novel fusidic acid derivatives possessed amino-terminal groups at the 3-hydroxyl position with anticancer activity. AB - A series of novel fusidic acid (FA) derivatives were synthesized and screened for their in vitro cytotoxicity against the Hela, U87, KBV and MKN45 cancer cell lines. Selected FA derivatives with anti-tumor activity were firstly identified including compound 4, which exhibited good anti-proliferative activity with IC50 values in the range of 1.26-3.57 MUM. Further research revealed that compound 4 induced Hela cells to undergo apoptosis by increasing the ratio of the cells in the Sub-G0/G1 phase via decreasing the neo-synthesized proteins in a dose dependent manner from 1 to 10 MUM. Compound 4 also showed good in vivo anti-tumor activity against the xenograft tumor of Hela cells and had no apparent toxicity. This study highlights the advantage of introducing the medium-length amino terminal groups at the 3-OH position of FA to enhance its anti-tumor activity and suggests that compound 4 provides a starting point for designing more potent derivatives in the future. PMID- 30445263 TI - Recent advances in the development of neuroprotective agents and therapeutic targets in the treatment of cerebral ischemia. AB - Stroke is a central nervous system disease that seriously affects people's quality of life and has the second highest rate of morbidity and mortality in the world. At present, clinical treatment strategies for acute ischemic stroke are mainly thrombolytic and thrombectomy therapy. However, these strategies are not able to protect patients from ischemic injuries. Therefore, treatment should further focus on methods that improve the survival rate of neurons around the ischemic area and neurological function. This article reviews current research and developments regarding small molecular compounds, including natural products and newly synthesized compounds that have neuroprotective effects and potential molecular targets for the recovery of post-ischemic stroke neural function that have been identified through lab investigations conducted during the last five years. Although pre-clinical studies of these compounds may not be immediately successful, current findings suggest that these therapeutic targets and neuroprotective agents are promising. PMID- 30445264 TI - Enhancement of the tail hydrophobic interactions within the carbonic anhydrase IX active site via structural extension: Design and synthesis of novel N-substituted isatins-SLC-0111 hybrids as carbonic anhydrase inhibitors and antitumor agents. AB - Herein we report the design and synthesis of novel N-substituted isatins-SLC-0111 hybrids (6a-f and 9a-l). A structural extension approach was adopted via N alkylation and N-benzylation of isatin moiety to enhance the tail hydrophobic interactions within the carbonic anhydrase (CA) IX active site. Thereafter, a hybrid pharmacophore approach was utilized via merging the pharmacophoric elements of isatin and SLC-0111 in a single chemical framework. As planned, a substantial improvement of inhibitory profile of the target hybrids (KIs: 4.7 86.1 nM) towards hCA IX in comparison to N-unsubstituted leads IVa-c (KIs: 192 239 nM), was achieved. Molecular docking of the designed hybrids in CA IX active site unveiled, as planned, the ability of N-alkylated and N-benzylated isatin moieties to accommodate in a wide hydrophobic pocket formed by T73, P75, P76, L91, L123 and A128, establishing strong van der Waals interactions. Hybrid 6c displayed good anti-proliferative activity under hypoxic conditions towards breast cancer MDA-MB-231 and MCF-7 cell lines (IC50 = 7.43 +/- 0.28 and 12.90 +/- 0.34 MUM, respectively). Also, 6c disrupted the MDA-MB-231 cell cycle via alteration of the Sub-G1 phase and arrest of G2-M stage. Additionally, 6c displayed significant increase in the percent of annexinV-FITC positive apoptotic cells from 1.03 to 18.54%. Furthermore, 6c displayed potent VEGFR-2 inhibitory activity (IC50 = 260.64 nM). Collectively, these data suggest 6c as a promising lead molecule for the development of effective anticancer agents. PMID- 30445265 TI - First-in-class DAPK1/CSF1R dual inhibitors: Discovery of 3,5-dimethoxy-N-(4-(4 methoxyphenoxy)-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-5-yl)benzamide as a potential anti-tauopathies agent. AB - Kinase irregularity has been correlated with several complex neurodegenerative tauopathies. Development of selective inhibitors of these kinases might afford promising anti-tauopathy therapies. While DAPK1 inhibitors halt the formation of tau aggregates and counteract neuronal death, CSF1R inhibitors could alleviate the tauopathies-associated neuroinflammation. Herein, we report the design, synthesis, biological evaluation, mechanistic study, and molecular docking study of novel CSF1R/DAPK1 dual inhibitors as multifunctional molecules inhibiting the formation of tau aggregates and neuroinflammation. Compound 3l, the most potent DAPK1 inhibitor in the in vitro kinase assay (IC50 = 1.25 MUM) was the most effective tau aggregates formation inhibitor in the cellular assay (IC50 = 5.0 MUM). Also, compound 3l elicited potent inhibition of CSF1R in the in vitro kinase assay (IC50 = 0.15 MUM) and promising inhibition of nitric oxide production in LPS-induced BV-2 cells (55% inhibition at 10 MUM concentration). Kinase profiling and hERG binding assay anticipated the absence of off-target toxicities while the PAMPA-BBB assay predicted potentially high BBB permeability. The mechanistic study and selectivity profile suggest compound 3l as a non-ATP competitive DAPK1 inhibitor and an ATP-competitive CSF1R inhibitor while the in silico calculations illustrated binding of compound 3l to the substrate-binding site of DAPK1. Hence, compound 3l might act as a protein-protein interaction inhibitor by hindering DAPK1 kinase reaction through preventing the binding of DAPK1 substrates. PMID- 30445266 TI - Synthesis and photocytotoxic activity of [1,2,3]triazolo[4,5 h][1,6]naphthyridines and [1,3]oxazolo[5,4-h][1,6]naphthyridines. AB - [1,2,3]Triazolo[4,5-h][1,6]naphthyridines and [1,3]oxazolo[5,4 h][1,6]naphthyridines were synthesized with the aim to investigate their photocytotoxic activity. Upon irradiation, oxazolo-naphtapyridines induced light dependent cell death at nanomolar/low micromolar concentrations (EC50 0.01-6.59 MUM). The most photocytotoxic derivative showed very high selectivity and photocytotoxicity indexes (SI = 72-86, PTI>5000), along with a triplet excited state with exceptionally long lifetime (18.0 MUs) and high molar absorptivity (29781 +/- 180 M-1cm-1 at lambdamax 315 nm). The light-induced production of ROS promptly induced an unquenchable apoptotic process selectively in tumor cells, with mitochondrial and lysosomal involvement. Altogether, these results demonstrate that the most active compound acts as a promising singlet oxygen sensitizer for biological applications. PMID- 30445267 TI - Antibacterial activity evaluation of synthetic novel pleuromutilin derivatives in vitro and in experimental infection mice. AB - A series of novel pleuromutilin derivatives embracing 7H-pyrrolo[2,3-d]pyrimidine moiety were synthesized and evaluated for their in vitro antibacterial activity against Gram-positive and Gram-negative pathogens as well as in vivo efficacy in lethal systemic infected mice. Most compounds displayed good in vitro potency against MSSA, MRSA, MSSE, MRSE and E. faecium (MIC = 0.0625-4 MUg/mL), especially 15a, 15b and 15o showed excellent activity that even more active than the comparator valnemulin. The in vivo efficacy investigation exhibited compound 15a (ED50 = 16.0 mg/kg) had comparable activity to valnemulin (ED50 = 13.5 mg/kg). The results provided by the dose-response study demonstrated 15a can supply infected mice with 70% survival rate at dose of 40 mg/kg via intragastric (i.g.) administration. PMID- 30445269 TI - Organic removal and synthesis of biopolymer from synthetic oily bilge water using the novel mixed bacterial consortium. AB - Synthetic oily bilge water (OBW) treatment and subsequent production of biopolymer were studied by using a sequential batch reactor (SBR). The effect of various influencing parameters such as solids retention time (SRT), cycle time (CT), substrate concentration, pH level on the organic removal and synthesis of polyhydroxyalkanoates (PHA) was examined by novel soil bacteria isolated from hydrocarbon contaminated site near Karaikal port, India. The isolates were identified as Pseudomonas tuomuerensis and Pseudomonas nitroreducens using 16S rRNA. Sudan Black B staining was performed to visualize the presence of PHA. The experimental results showed that a decrease in substrate concentration to 5000 mg/L of soluble COD (CODs) showed maximum organic removal (81%) and maximum PHA yields of its cell dry mass (81%). The PHA yield was maximum at SRT of 5 d, pH = 7 and CT of 24 h. The produced PHA was characterized by using FTIR, XRD and SEM analysis. PMID- 30445268 TI - NR2F1 mediated down-regulation of osteoblast differentiation was rescued by bone morphogenetic protein-2 (BMP-2) in human MSC. AB - Endochondral ossification is the process by which long bones are formed; the process of long bone formation is regulated by numerous factors such as transcription factors, cytokines, and extracellular matrix molecules. Human hormone Nuclear receptors (hHNR) are a family of ligand-regulated transcription factors that are activated by steroid hormones, such as estrogen and progesterone, and various lipid-soluble signals, including retinoic acid, oxysterols, and thyroid hormone. Whole genome microarray data from our previous study revealed that most hHNR's are up-regulated during osteoblast differentiation in hMSCS. NR2F1 was among the highest expressed hHNR during osteogenesis, NR2F1 belongs to the steroid/thyroid hormone nuclear receptor superfamily. NR2F1 is designated as an orphan nuclear receptor because its ligands are unknown. NR2F1 plays a wide range of roles, including cell differentiation, cancer progression, and central and peripheral neurogenesis. Identifying signaling networks involved in osteoblast differentiation is important in orchestrating new therapeutic and clinical applications in bone biology. This study aimed to identify alterations in signaling networks mediated by NR2F1 in osteoblast differentiation. siRNA-mediated down-regulation of NR2F1 leads to impairment in the differentiation of hBMSC-TERT to osteoblast; gene expression results confirmed the down-regulation of osteoblast markers such as RUNX2, ALPL, OSC, and BSP. Global whole gene expression analysis revealed that most down-regulated genes were associated with osteoblast differentiation (DDIT3, BMP2). Pathway analysis revealed prominent signaling pathways that were down regulated, including the TGFbeta pathway and MAPK pathway. Functional studies on NR2F1 transfected cells, during osteoblast differentiation in combination with TGFbeta1 and BMP-2, showed that TGFbeta1 does not recover osteoblast differentiation, whereas BMP-2 rescues osteoblast differentiation in NR2F1 siRNA transfected cells. Thus, our results showed that BMP-2 could intervene in NR2F1 down-regulated signaling pathways to recover osteoblast differentiation. PMID- 30445270 TI - Comprehensive characterization of microalgal isolates and lipid-extracted biomass as zero-waste bioenergy feedstock: An integrated bioremediation and biorefinery approach. AB - The present study investigated the feasibility of domestic sewage wastewater (DSW) as an alternate to fresh-water microalgae growth media towards high-value bioenergy feedstock production. Eight native microalgal strains were screened from DSW and the effect of raw DSW (RDSW), and autoclaved DSW (ADSW) on growth and bioremediation potential were evaluated and compared with control BG11 medium. The study confirmed RDSW as a potential growth medium while Monoraphidium sp. KMC4 showed superior biomass (1.47 +/- 0.08 g L-1) and lipid yield (436.01 +/ 0.06 mg L-1). The corresponding values for bioremediation of ammonia, nitrate, phosphate, as well as COD remained within 88-100%. CHNS, biochemical, TGA, FTIR, FAME analysis of KMC4 confirmed it's potential as bioenergy feedstock. Additionally, a comprehensive characterization of lipid-extracted microalgae biomass (LEMB) was carried out which suggested that LEMB can be used as a growth promoter as well as feedstock for biogas, bioethanol, and bio-oil production. PMID- 30445271 TI - EGFR-directed monoclonal antibodies in combination with chemotherapy for treatment of non-small-cell lung cancer: an updated review of clinical trials and new perspectives in biomarkers analysis. AB - Lung cancer still represents one of the most common and fatal neoplasm, accounting for nearly 30% of all cancer-related deaths. Targeted therapies based on molecular tumor features and programmed death-1 (PD-1)/programmed death ligand 1 (PDL-1) blockade immunotherapy have offered new therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC). Activation of the epidermal growth factor receptor (EGFR)-pathway promotes tumor growth and progression, including angiogenesis, invasion, metastasis and inhibition of apoptosis, providing a strong rationale for targeting this pathway. EGFR expression is detected in up to 85% of NSCLC and has been demonstrated to be associated with poor prognosis. Two approaches for blocking EGFR signaling are available: prevention of ligand binding to the extracellular domain with monoclonal antibodies (mAbs) and inhibition of the intracellular tyrosine kinase activity with small molecules. There is a strong rationale to consider the tumor's level of EGFR expression as one of the most significant predictive biomarkers in this setting. In this paper we provide an update focusing on the current status of EGFR-directed mAbs use for the treatment of patients with advanced NSCLC, through a review of all clinical trials involving anti-EGFR mAbs in combination with chemotherapy (CT) for advanced disease and with chemo radiotherapy for stage III disease. Here we also discuss the current status of predictive biomarkers for anti-EGFR mAbs when added to first-line CT in patients with advanced NSCLC. Finally, we focused on the relevance of EGFR fluorescence in situ hybridization (FISH)+ and immunohistochemistry (IHC)-Score >= 200 as predictive biomarkers for the selection of patients who would be most likely to derive a clinical benefit from treatment with CT in combination with anti-EGFR mAbs, with particular reference also to histology. PMID- 30445272 TI - An intervention trial targeting methadone maintenance treatment providers to improve clients' treatment retention in China. AB - BACKGROUND: Service providers including doctors, nurses, and other healthcare professionals play an essential role in methadone maintenance treatment (MMT). This study evaluated the impact of an intervention targeting MMT providers on their clients' treatment retention. METHODS: This study was conducted in 68 MMT clinics in five provinces of China with 36 clients randomly selected from each clinic. The clinics were randomized to intervention or control condition. The MMT CARE intervention started with group sessions to enhance providers' communication skills. The trained providers were encouraged to conduct individual sessions with clients to promote treatment engagement. The outcomes, which include client retention (main outcome) and their reception of provider-delivered individual sessions (process outcome), were measured over a 24-month period. RESULTS: Significantly fewer intervention clients dropped out from MMT than control clients during the study period (31% vs. 41%; p < 0.0001). Dropout hazard was significantly lower in the intervention condition compared to the control condition (HR = 0.71, 95% CI: 0.57, 0.89). More intervention clients had individual sessions than control clients (93% vs. 70%; p < 0.0001). Having individual sessions was associated with a significantly lower dropout hazard (HR = 0.30, 95% CI: 0.23, 0.40). The intervention clients had a significantly lower dropout hazard than the control clients if they started the individual sessions during the first six months (HR = 0.68, 95% CI: 0.51, 0.90). CONCLUSIONS: The MMT CARE intervention focusing on provider capacity building has demonstrated efficacy in reducing clients' treatment dropout. This study sheds light on MMT service improvement in China and other global community-based harm reduction programs. PMID- 30445273 TI - Greater tolerance to losses in sensation seeking: Evidence from probability and delay discounting. AB - BACKGROUND: Sensation seeking is a behavioral endophenotype of substance use and is associated with abnormalities in financial reward processing. Previous research suggests that high sensation seekers (HSS) relative to low sensation seekers (LSS) show either an enhanced sensitivity to financial rewards or a reduced sensitivity to financial punishments. However, there are few studies investigating the valuation of financial rewards and punishments as a function of delivery probability and delay, two important aspects of reward processing that influence the valuation. METHODS: We administrated a probability discounting task and a delay discounting task to 56 HSS and 57 LSS selected from a large sample. Each task was crossed with two factors: valence (gain vs. loss) and amount (?1000 vs. ?50000). RESULTS: For the probability discounting task, HSS discounted probabilistic losses but not gains more steeply than LSS, irrespective of the amount of outcome. For the delay discounting task, HSS discounted delayed losses more steeply than LSS, for the large but not small amount condition. In contrast, both groups exhibited comparable discounting rates for gains across the two amount conditions. These results remained significant when impulsivity levels were controlled for. CONCLUSIONS: Together, our data strengthen the argument that the dysfunctional valuation in sensation seeking is valence specific, which may be driven by a weaker avoidance system, rather than by a stronger approach system. PMID- 30445274 TI - Laws limiting the prescribing or dispensing of opioids for acute pain in the United States: A national systematic legal review. AB - BACKGROUND: Opioid overdose is a continuing public health crisis. In response to an increasing recognition of the negative outcomes sometimes associated with the use of opioid analgesics, states have taken a number of steps attempting to reduce inappropriate prescribing of these medications. These include the imposition of strict legal limitations on the amount or duration that opioid analgesics may be prescribed or dispensed to patients with acute pain. METHODS: We conducted a systematic, multi-source legal review of state laws that impose mandatory limits on the ability of medical professionals to prescribe or dispense opioids for the treatment of acute pain. We also systematically searched for and examined publicly available documents on state legislative and regulatory bodies' websites. All relevant laws were downloaded and systematically coded. RESULTS: By the end of 2017, twenty-six states had passed laws that impose mandatory limits on the prescribing or dispensing of opioids for acute pain. The oldest of these laws became effective as early as 1989, but most are much newer: approximately 65% (17/26) were passed in 2017. There is wide variation in the characteristics of these laws. CONCLUSION: Just over half of all states have enacted laws that restrict the prescribing or dispensing of opioids for acute pain. To date, there is no data on whether and to what extent these laws mediate opioid-related morbidity and mortality, as well as whether they are associated with negative unintended outcomes. Research into these questions is urgently needed. PMID- 30445275 TI - Effects of time-varying changes in tobacco and alcohol use on depressive symptoms following pharmaco-behavioral treatment for smoking and heavy drinking. AB - BACKGROUND: Complete abstinence from alcohol as well as smoking cessation have been shown to predict reductions in depressive symptoms over time. However, whether reducing alcohol use or smoking positively affect depressive symptoms has yet to be examined. The current study examined depressive symptoms as a function of time-varying changes in alcohol use and smoking status following a pharmaco behavioral treatment addressing smoking cessation and alcohol reduction. METHODS: Participants were heavy-drinking smokers (n = 150) followed for 26 weeks after their quit smoking date, with assessments of smoking, alcohol use, and depressive symptoms at baseline and 2, 8, 16, and 26 weeks. RESULTS: Abstinence from smoking was associated with significantly lower depressive symptoms, as compared to little to no reduction in smoking (B = -6.1) as well as significant reductions in smoking (B = 4.01). Exploratory analyses, which excluded observations in which a participant was abstinent, revealed a significant effect of percent change in cigarettes smoked, modeled continuously, on depressive symptoms, (B = 4.39). By contrast, no differences were observed in depressive symptoms in relation to changes in alcohol use. CONCLUSION: It appears that smoking abstinence is associated with improvements in depression as compared to any level of sustained or reduced use and that the magnitude of smoking reduction may be associated with lower depressive symptoms among those who did not quit successfully. If replicated, these findings may inform treatment for individuals for whom depression is a major barrier to cessation and who have been unable or are unwilling to be completely abstinent from smoking. PMID- 30445276 TI - Shared credit for shared success: Successful joint performance strengthens the sense of joint agency. AB - When people perform joint actions together, they experience a sense of joint agency, or shared control over actions and their effects. The current study examined how internal and external cues related to the success of a joint action influence joint agency. In three experiments, partners coordinated their actions to produce eight-tone sequences that matched a metronome pace. Across experiments, more successful joint performance (closer match to required pace) elicited stronger feelings of joint agency. This relationship was evident whether participants rated their control over sequence timing or responsibility for task outcome. Furthermore, the relationship was stronger when participants received external cues to joint success compared to when participants could rely only on internal cues. These findings indicate that people derive their sense of joint agency from success at the level of the dyad and that cues to joint agency may be weighted according to their salience in a given context. PMID- 30445277 TI - Comparison of overhead harness configurations for measuring trunk kinematics during treadmill disturbances. AB - BACKGROUND: Research has shown that postural perturbation training reduces falls. Trunk kinematics, at recovery step, are key outcome measures. Fall prevention training programs are being developed for routine clinical care. In these programs, the subject is positioned on a treadmill and subjected to forward and backward disturbances which simulate trips and slips. The patient wears a safety vest attached to an overhead harness to create a secure environment. Motion capture is used to measure trunk kinematics. RESEARCH QUESTION: It is important to verify that trunk kinematics are independent of harness configuration. The purpose of this study was to compare the trunk flexion angle and angular velocity at recovery step after forward and backward disturbances on a treadmill measured by motion capture with the harness in both a fixed and free position. METHODS: Ten healthy young adults (5/10 female, age: 29.2 +/- 6.3 years, BMI: 24.2 +/- 2.4) participated in this study. The subjects had retro-reflective markers placed on key anatomical landmarks to measure trunk kinematics. The participants experienced forward and backward disturbances, which incrementally increased in intensity until the harness clearly supported the subjects for three disturbances in both directions. The order of harness configurations was randomized across subjects and each subject participated in two consecutive rounds of disturbances, one round for each harness configuration. Equivalence testing was performed to demonstrate that the harness configurations were equivalent (alpha = 0.05). RESULTS AND SIGNIFICANCE: The Equivalence Test demonstrated that the trunk angle (TA) and angular velocity (TAV) were equivalent for the different harness configurations. The 95% Confidence Intervals (TA: [-2, 1], TAV: [-18, 16]) were within the equivalence interval (TA: [-3, 3], TAV: [-20, 20]) and the p-Values (TA: 0.008, TAV: 0.034) were less than alpha. Trunk kinematics are independent of overheard harness configurations during treadmill induced disturbances for clinical postural perturbation training. PMID- 30445278 TI - Cognitive and visual demands, but not gross motor demand, of concurrent smartphone use affect laboratory and free-living gait among young and older adults. AB - BACKGROUND: As smartphones are an integral part of daily activities, understanding the underlying mechanism associated with concurrent cell phone use while walking may help reduce the risks of injury. RESEARCH QUESTION: This study examined the effect of cognitive, visual, and gross motor demands while using a phone during gait among young and older adults in the laboratory and free-living environments. METHODS: Twelve young and twelve older adults walked along a 10-m walkway under five conditions: single-task walking (Walk), walking and bi manually holding a phone (Walk-Hold), walking while looking at a phone held in front of the participants (Walk-Look), walking while answering questions (Walk Answer), and walking while texting (Walk-Text). All conditions were performed in laboratory and free-living environments. Gait velocity, step time, step length, and cadence were obtained using a smartphone with a built-in accelerometer attached to the body. The dual-task cost (DTC) was also assessed. A three-way ANOVA was utilized for all parameters. RESULTS: While no three-way interactions were found for any parameter, group * condition interactions were significant for gait velocity, step time, step length, cadence and their corresponding DTC. Decreased gait velocity, step length and cadence, with increased step time was demonstrated during Walk-Look, Walk-Answer, and Walk-Text, compared to Walk and Walk-Hold. While older adults markedly changed their gait during Walk-Answer and Walk-Text, these changes were less pronounced among young adults. SIGNIFICANCE: Visual and cognitive demand while concurrently using a phone influenced gait, especially among the elderly. Environment did not accentuate gait alterations during concurrent phone use. Therefore, smartphone technology should be developed to detect dual-task walking and temporarily modify functionality to reduce risk of injury from divided attention. PMID- 30445279 TI - Patellofemoral joint stress measured across three different running techniques. AB - BACKGROUND: Patellofemoral pain (PFP) is the most common running-related injury. It has been shown in previous studies that gait retraining may have a beneficial effect on patellofemoral joint stress (PFJS). RESEARCH QUESTION: Is there a reduction of PFJS across 4 running conditions: 1. runner's typical rearfoot strike pattern, 2. forefoot landing, 3. step rate increase by 10% and 4. forward trunk lean? METHODS: Nineteen healthy runners (28.05 +/- 5.03 years; 26.58 +/- 8.85 km/week, 6.00 +/- 4.51 years of running experience) completed one running trial for each condition, at the same subject-specific comfortable speed on a treadmill. Kinetic and kinematic data were collected and measures of hip, knee and ankle joint moments and PFJS were calculated. RESULTS: Compared to rearfoot strike condition, peak PFJS and PFJS-time integral per step were significantly (P < 0.01) lower during forefoot landing and step rate increase conditions. PFJS per kilometer was significantly reduced for forefoot landing (17.01%; P < 0.01) and increased step rate (12.90%; P = 0.003). Forward trunk lean technique showed no significant differences in peak PFJS (P = 0.187), PFJS-time integral per step (P = 0.815) and PFJS per kilometer (P = 0.077) compared to rearfoot strike pattern. INTERPRETATION: The comparison between techniques revealed greater reductions on PFJS by forefoot landing, followed by 10% step rate increase condition. These changes were the result of different lower limb movement strategies across the 2 running conditions. We conclude that compared to a rearfoot strike pattern, both a forefoot landing and step rate increase result in lower cumulative PFJS joint stress in healthy runners, with the forefoot landing being the most effective. These running technique modifications could be recommended to reduce PFJS loads and may have implications for PFP prevention. PMID- 30445280 TI - Comparative immuno-Cerenkov luminescence and -PET imaging enables detection of PSMA+ tumors in mice using 64Cu-radiolabeled monoclonal antibodies. AB - Here, we describe immuno-Cerenkov luminescence imaging (immuno-CLI) with a specific monoclonal antibody-based tracer for the detection of prostate tumors, which is used in preclinical positron emission tomography (PET) imaging. As PET isotopes generate a continuous spectrum of light in the ultraviolet/visible (UV/vis) wavelength range (Cerenkov luminescence, CL) in dielectric materials and consequently inside living tissues, these isotopes can also be detected by luminescence imaging performed with optical imaging (OI) systems. Imaging tumors with tracers that are specifically binding to a tumor-associated antigen can increase diagnostic accuracy, enables monitoring of treatment efficacy, and can be advantageous compared to radiolabeled small molecules used in PET-oncology such as 2-deoxy-2-[18F]-fluoro-D-glucose ([18F]FDG; glucose metabolism) or [11C]choline (membrane synthesis) which was used to image prostate cancer. In this study, we compared on three consecutive days immuno-CLI and -PET of the applied 64Cu-labeled and well described monoclonal antibody 3/F11 in prostate specific membrane antigen (PSMA)-positive (C4-2, PSMA+) and -negative (DU 145, PSMA-) prostate tumor xenografts, inoculated in SCID mice. In vivo immuno-CLI and -PET measurements demonstrated linear correlation of both modalities, in line with ex vivo analysis performed with CLI and gamma-counting. As CLI is also able to trace radioisotopes used for theranostic approaches, immuno-CLI could be an interesting, low-cost imaging alternative to immuno-PET. PMID- 30445281 TI - Component-resolved bleaching correlation between OSL and IRSL signals in various geological materials. AB - The primary aim of the present study includes establishing a qualitative as well as quantitative correlation between OSL and IRSL signals in various materials of geological origin, by investigating the influence of the IR stimulation to the OSL signal. The materials which are the subject of the present study include one K-feldspar belonging to the group of microcline, two different grain size fractions of Durango apatite at the edge of the nano-scale and gypsum. A two-step stimulation protocol was applied, including an exposure of the irradiated sample to infrared stimulation for various time and a subsequent continuous wave OSL using blue light. In the framework of a component-resolved analysis, the IRSL decay curves were fitted using analytical equations describing the localized tunneling recombination model; the subsequent OSL decay curves were also fitted using a linear superposition of analytical expressions describing both delocalized and localized recombination processes. The selection of number and type of components in the latter case is also elaborated, based on the physical meaningfulness of the de-convolution results. PMID- 30445282 TI - Effect of post-harvest interventions on surficial carrot bacterial community dynamics, pathogen survival, and antibiotic resistance. AB - Strategies to mitigate antibiotic-resistant bacteria (ARB), including human pathogens, on raw vegetables are needed to reduce incidence of resistant infections. The objective of this research was to determine the effectiveness of standard post-harvest interventions, sanitizer washing and cold storage, to reduce ARB, including antibiotic resistant strains of the human pathogen E. coli O15:H7 and a common spoilage bacterium Pseudomonas, on raw carrots. To provide a background inoculum representing potential pre-harvest carryover of ARB, carrots were dip-inoculated in dairy cow manure compost slurry and further inoculated with known ARB. Inoculated carrots were washed with one of three treatments: sodium hypochlorite (50 ppm free chlorine), peroxyacetic acid (40 ppm peroxyacetic acid; 11.2% hydrogen peroxide), tap water (no sanitizer), or no washing (control). Washed carrots were air dried, packaged and stored at 10 degrees C for 7d or 2 degrees C for up to 60 d. Enumeration was performed using total heterotrophic plate counts (HPC), HPCs on antibiotic-containing media ("ARBs"), E. coli O157:H7, and Pseudomonas sp. immediately after washing (0 d) and after 7 d of storage. In addition to the cultured bacteria, changes to the surficial carrot microbiota were profiled by sequencing bacterial 16S rRNA gene amplicons to determine the effect of sanitizer wash, storage temperature, and time of storage (0, 1, 7, 14 and 60 d). Storage temperature, addition of a sanitizer during wash, and duration of storage significantly affected the bacterial microbiota (Wilcoxon, p < 0.05). Inclusion of either sanitizer in the wash water significantly reduced the log CFU/g of E. coli O157:H7 and Pseudomonas sp., as well as HPCs enumerated on cefotaxime- (10 MUg/ml), sulfamethoxazole- (100 MUg/ml), or tetracycline (3 MUg/ml) supplemented media compared to the unwashed control (ANOVA, p < 0.05). However, no significant reductions to bacteria resistant to vancomycin or clindamycin occurred after washing and storage. Members of the Proteobactetria, Firmicutes, Actinobacteria, Planctomycetes, and Acidobacteria comprised the bacterial carrot microbiota. The diversity of the carrot microbiota was significantly affected by the temperature of storage and by extended storage (60 d), when spoilage began to occur. There were no significant differences to the relative abundance of bacterial groups associated with the type of sanitizer used for washing. Results of this study indicate that inclusion of a sanitizer in wash water, followed by storage at 2 degrees C, might be an effective strategy to prevent re-growth of pathogenic E. coli O157:H7 and reduce levels of bacteria resistant to certain antibiotics on carrots. PMID- 30445283 TI - Prevalence, antimicrobial susceptibility and characterization of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus isolated from dairy industries in north-central and north-eastern Greece. AB - Staphylococcus aureus is an important cause of food intoxication, whereas methicillin-resistant S. aureus (MRSA) constitutes a serious public-health concern due to its ability to colonize and infect humans and animals. S. aureus and MRSA have often been isolated from milk and dairy products. The objectives of this study were to estimate the prevalence and the antimicrobial resistance of S. aureus and MRSA in four Greek dairy industries, to identify virulence factors of MRSA isolates and to describe their genetic diversity, in order to identify possible epidemiological links and evaluate the risk of MRSA dissemination to the community. S. aureus was isolated from 67 out of 305 (22.0%) dairy industry samples (bulk-tank milk, dairy products, employee nasal swabs and equipment/surface swabs). Almost all (99%) of the 227 corresponding S. aureus isolates (approximately 4 isolates per positive sample) were resistant to at least one antimicrobial and 22% were multi-drug resistant (MDR). MRSA were isolated from 11 different samples (3.6%) originating from three of the dairy plants. All MRSA isolates were capable of forming biofilms, while staphylococcal enterotoxin (SE) genes were detected in 91% of the MRSA isolates, with sec being the most frequent. All of the MRSA isolates harbored the mecA gene but the mecC and Pandon-Valentine leucocidin (PVL) genes were not detected. Pulse-Field Gel Electrophoresis (PFGE) analysis showed genetic diversity among the MRSA isolates and indicated clonal circulation in one of the dairy plants. Seven spa types were identified among the MRSA isolates with the most prevalent (t065) isolated only in one dairy plant. Certain spa types (t065, t337 and t3536) were isolated for the first time in Greece. The presence of MDR, biofilm-forming and enterotoxigenic MRSA strains in dairy plant facilities may lead to their dissemination to the community, but also to staphylococcal food poisoning, when conditions are favorable. The study's findings highlight the need for continuous monitoring of the dairy production chain, the need for re-evaluating the implemented cleaning and sanitizing processes and the adoption of preventive strategies in order to minimize public-health risks. PMID- 30445284 TI - Combined effects of thymol, carvacrol and packaging on the shelf-life of marinated chicken. AB - The demand for marinated chicken worldwide, is continuously growing. To date, limited data on addition of active components of Essential Oils (EOs) to marinades for chicken preservation are available. The antimicrobial effect of carvacrol and thymol, added at 0.4 and 0.8% v/w to marinated fresh chicken, stored in air and under vacuum packaging (VP), for 21 days at 4 degrees C, was examined. The samples were monitored for microbiological (total viable count (TVC), lactic acid bacteria (LAB), Brochothrix thermosphacta, Pseudomonas spp., total coliforms, Escherichia coli, yeasts and molds) and sensory attributes (odor characteristics). Our data supports that among the tested microorganisms, Pseudomonas spp., LAB and B. thermosphacta were the most dominant microbiota in the marinated chicken samples. Additionally, the use of active EOs components, especially the higher concentration (0.8% v/w) in combination with VP, retarded the growth of spoilage microbiota and resulted in a significant reduction of about 2.9-3.1 log cfu/g and a microbiological shelf-life extension of marinated chicken by >6 days, as judged by TVC data. Interestingly, the combination of active components of EOs at the lower concentration (0.4% v/w) and packaging (air or vacuum) resulted in a significant sensorial shelf-life extension of 15 and >21 days, as compared to the controls' shelf-life of 9 days. The results of our study demonstrated the potential of the active components, carvacrol and thymol, as natural effective antimicrobial hurdles to control the growth of spoilage microorganisms in marinated chicken meat. PMID- 30445285 TI - Reduction and inhibition of Listeria monocytogenes in cold-smoked salmon by Verdad N6, a buffered vinegar fermentate, and UV-C treatments. AB - Contamination, survival and growth of Listeria monocytogenes in cold-smoked salmon represent serious health hazards to consumers and major challenges for salmon processors. Verdad N6, a commercially available buffered vinegar, was evaluated as an ingredient in cold-smoked salmon with regard to anti-listerial effects under processing and storage, sensory quality and consumer preference, effects on background microbiota and yield during production. Cold-smoked salmon with Verdad N6 added in the dry-salting process was produced. Salmon fillets were surface contaminated with a mix of L. monocytogenes. Levels of L. monocytogenes were determined during vacuum pack refrigerated storage for 29 days. The use of Verdad N6 resulted in increased lag times and reduced growth rates of L. monocytogenes. The inhibitory effects were dependent on Verdad N6 levels (0-2%), storage time and temperature (4 or 8 degrees C), type of contamination (between slices or on non-sliced salmon) and degree of smoking. The presence of dextrose (1%) in the recipe had no significant effects on L. monocytogenes levels after storage. On sliced salmon, complete growth inhibition at 4 degrees C storage could be obtained using 1% Verdad N6 compared to a 3 log increase in L. monocytogenes counts in control salmon. At abuse temperatures (8 degrees C), corresponding L. monocytogenes levels increased <2 log and 5-6 log during 29 days storage. On non-sliced salmon, 1% Verdad N6 provided complete growth reductions at 4 and 8 degrees C storage while L. monocytogenes in control salmon increased 2.3 and 4.6 log, respectively, in the same period. The use of Verdad N6 in combination with bactericidal UV-C treatments (fluence 50 mJ/cm2) provided an initial 0.8 log reduction and complete L. monocytogenes growth inhibition on subsequent storage at 4 and 8 degrees C. Salmon with Verdad N6 showed reduced levels of total counts during storage and a shift in the dominating bacteria with reduced and increased relative levels of Photobacterium and lactic acid bacteria, respectively. A consumer test showed no consistent differences in liking of salmon with and without Verdad N6. In summary, Verdad N6 is an option for the production of high quality cold-smoked salmon with enhanced food safety through its robust listeriostatic effects. The application of Verdad N6 in combination with listericidal UV-C light treatment can further reduce the listeria-risks of this ready-to-eat food product category. PMID- 30445286 TI - Wind erosion on arable lands, associated with extreme blizzard conditions within the hilly area of Eastern Romania. AB - The removal of wind-blown soils from cultivated fields is often expensive. It physically removes the most fertile portion of the soil that can lead to yield reduction in areas where wind erosion is a recurring problem. Soil nutrients and surface-applied chemicals can also be carried along with soil particles, contributing to off-site impacts. An extreme blizzard event has been investigated as case study within the Moldavian Plateau of eastern Romania. The results obtained, based on 45 snow core samples, show that the deposited sediment widely varied depending on land-use. The highest mean value of 5967 g m-2 occurred on fallow land and it sharply decreased under winter wheat (445 g m-2) and pasture (345 g m-2). Regarding the major subunits of the Moldavian Plateau, the Jijia Rolling Plain (JRP) was the most affected, with mean value of 7547 g m-2. The Barlad Plateau (BP) and the Falciu Rolling Plain (FRP) are depicted by smaller values, namely: 395 g m-2 and 386 g m-2. By using remote sensing it was estimated that 208,990 ha under fallow from JRP (34% of the total) were heavily subjected to wind erosion with a mean soil loss of 2.04 t ha-1, while the depositional area comprised 175,440 ha (29% of the total). The deposited soil is loamy compared with the general clayey-loamy texture of local soils. The main source of the wind blown material is represented by the close proximity fields under fallow of the depositional areas. PMID- 30445287 TI - Identification of volatile metabolites in human saliva from patients with oral squamous cell carcinoma via zeolite-based thin-film microextraction coupled with GC-MS. AB - In recent years, volatile organic compounds (VOCs) discharged from the human body, of which some compounds exhibit strong correlations with pathological conditions, have attracted attention as a new means of disease diagnosis technology. The aim of this study was to establish the salivary metabolomic profiles of oral squamous cell carcinoma (OSCC) patients and healthy volunteers (control group) and to investigate VOCs as potential biomarkers in the diagnosis of oral cancer. We have demonstrated a method combining thin-film microextraction based on a ZSM-5/polydimethylsiloxane hybrid film coupled with gas chromatography mass spectrometry and carried out a comparative analysis of salivary VOC profiles between OSCC patients and healthy controls. The results depicted that 42 and 73 VOCs were detected and identified in samples from the healthy control group (n = 50) and oral cancer group (n = 24), respectively. Among them, twenty-seven VOCs (ten were decreased, seven disappeared, and ten were newly produced in the oral cancer group) depict significant differences between both the sample groups, and they have relevance as candidate biomarkers for OSCC. Twelve salivary VOCs that were characteristic of oral cancer patients were finally extracted and used for pattern recognition analyses for oral cancer diagnosis. The proposed TFME approach for analyzing human saliva on the basis of a ZSM-5-loaded PDMS hybrid thin film has been performed for the very first time in the field of dentistry. PMID- 30445288 TI - Metabolism and mutual biotransformations of anthraquinones and anthrones in rhubarb by human intestinal flora using UPLC-Q-TOF/MS. AB - Anthraquinones and anthrones are the main active components of rhubarb. To investigate the metabolism and possible mutual biotransformations pathways of anthraquinones and anthrones by human intestinal flora, 9 representative constituents (aloe-emodin, rhein, emodin, chrysophanol, physcion, sennosides A, B, C and D) were studied. An ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) with mass spectrometryElevated Energy (MSE) technology was employed to separate and identify their metabolites. As a result, a total of 64 metabolites were identified or characterized from 9 components. Among them, 12 of them were identified by compared with the reference substances, 52 of them were tentatively identified. The results indicated that reduction, hydrolysis, acetylation, oxidation, demethylation, methylation, hydroxylation, dehydroxylation and the bond cleavage of CO and CC were likely to be the metabolic pathways involved in the generation of these metabolites. Moreover, mutual biotransformations existed among the nine representative constituents in rhubarb by human intestinal flora. This study will provide evidences that intestinal flora may play an important role in mediating the bioactivities in vivo of anthraquinones and anthrones in rhubarb. PMID- 30445289 TI - A standardized protocol for comparable analysis of GSH/GSSG by UHPLC-ESI-MSMS for human plasma. AB - Variability in the levels of GSH and GSSG in plasma is suggested to derive from inadequate pre-processing methods. The aim of this study was to develop a protocol for comparable and reliable measurements of GSH/GSSG. Venous blood from 8 healthy individuals were collected and divided into 7 different pre-processing procedures. For three of the samples an extraction mixture was added after 0 (baseline), 4 and 8 min and for three of the samples the extraction mixture was added at different times during defrost. A worst case scenario where a sample was left in a cool box during 6 h was also included. The samples were analyzed with UHPLC-ESI-MSMS. A large difference in the levels of GSH and GSSG were identified and it was clearly associated with the sample handling procedures. A sample left untreated for 4 min will have significantly reduced amount of GSH. Stability tests showed that the level of GSH was reduced after 3 months in -80 degrees C. PMID- 30445290 TI - Simultaneous determination of bioactive flavonoids of Hoveniae Semen in rat plasma by LC-MS/MS: Application to a comparative pharmacokinetic study. AB - A selective, sensitive and fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the determination of dihydromyricetin, dihydroquercetin, myricetin and quercetin in rat plasma after intragastric administration of Hoveniae Semen total flavonoids. Baicalin was selected as the internal standard. Analytes were extracted from the rat plasma by protein precipitation with acetonitrile and separated on a C18 chromatographic column (Agilent ZORBAX Eclipse Plus, 4.6 mm * 100 mm, 3.5 MUm) using the mobile phase containing acetonitrile (A) and 0.1% formic acid-water (B) by gradient elution at 0.5 mL/min flow rate. A tandem mass spectrometer equipped with an electrospray ionization (ESI) source was used to detect analytes. The analytes were measured by multiple reaction monitoring (MRM) in the negative ionization mode. The lower limit of quantification of dihydromyricetin, dihydroquercetin, myricetin and quercetin were 0.70, 8.16, 1.62 and 0.56 ng/mL, respectively. The accuracy, intra-day and inter-day precision and recovery were all satisfactory and the compounds were stable in rat plasma under all tested conditions. The approach was successfully applied to study pharmacokinetic characteristics of the four bioactive flavonoids in plasma after administering Hoveniae Semen total flavonoids intragastrically to rat. Further investigation was carried out to assess pharmacokinetic comparability of the four bioactive flavonoids after intragastric administration of Hoveniae Semen total flavonoids to mixture of flavonoids. PMID- 30445291 TI - Rapid determination of bioactive compounds in the different organs of Salvia Miltiorrhiza by UPLC-MS/MS. AB - Salvia miltiorrhiza has been widely used in Asia for medicinal purposes for >1000 years due to the high levels of bioactive constituents it contains. In this study, a simple and rapid ultrasound-assisted liquid extraction (5 min) was applied for the extraction of these bioactive constituents. The extracts were analyzed by using rapid ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) with simultaneous positive and negative electrospray ionization in a single analytical run. Eight analytes were separated within 2.2 min during 6 min of run time with UHPLC-MS/MS operated in multiple reaction monitoring (MRM) mode. The concentration of salvianolic acids and tanshinones in the different organs of different varieties of Salvia miltiorrhiza ranged from 6.4 to 382.1 mg/g and 0.03 to 31.7 mg/g, respectively. To the best of our knowledge, this is the first report to characterize the tanshinone compounds found in the flower and stem/leaf of Salvia miltiorrhiza by UHPLC-MS/MS. PMID- 30445292 TI - Preparation of a hydroxyethyl-based monolithic column and its application in the isolation of intact proteins from complex bio-samples. AB - In this work, a monolithic hydroxyethyl-based column was fabricated in a stainless-steel column (50 mm * 4.6 mm i.d.) via radical polymerization technique using hydroxyethyl methylacrylate as the monomer. The morphology and pore size distribution indicate that the optimized monolith has a relatively uniform structure with macro-pores. The homemade monolith was used as the stationary phase of high performance liquid chromatography for the separation of intact proteins from complex bio-samples, including human plasma, egg white and snailase. The resulting monolith shows excellent selectivity for intact proteins mainly depending on the different relative hydrophobicity of the objective proteins with reversed-phase liquid chromatographic mechanism. Besides, the hydrogen-bond interaction and electrostatic interaction were the additional interactions in the chromatographic separation owing to hydroxyl groups present in the surface of monolithic material. PMID- 30445293 TI - Nursing competency and educational needs for clinical practice of Korean nurses. AB - The purpose of this study was to investigate the nursing competency and educational needs of nurses on clinical nursing practice in order to provide basic evidences for a developing nursing education program. Participants of this study were 211 nurses working at a general hospital in Seoul, Korea. The data were collected using self-report questionnaires on nursing competencies and educational needs. Collected data were analysed using an SPSS program for frequency, mean, standard deviation, t-test, ANOVA, and Scheffe's post-hoc comparison. The participants' nursing competency was significantly different based on their age, marital condition, level of education, current working department, and clinical experience. Among the subcategories of nursing competency, the ethical nursing competency was found to be the highest, whereas scientific nursing competency was shown the lowest competency. The order of top three educational needs of the participants was emergency nursing, intensive nursing care, and cardiopulmonary resuscitation in that order. To ensure the provision of nursing performances to healthcare service recipients grounded in a higher level of nursing competency, it is important to support nurses via evidence based effective clinical nursing education that is developed for the nurses' educational needs in relation to their clinical experiences. PMID- 30445294 TI - Evaluation of a questionnaire to measure parent/carer and child/young person experience of NHS epilepsy services. AB - PURPOSE: To validate a patient-reported-experience-measure, PREM, of the NHS paediatric epilepsy service. METHODS: Section 1 of the PREM recorded demographic and clinical characteristics, and Section 2 collected information about the users' experience with the service. Section 2 included eighteen statements around three constructs: communication and provision of information to service users, interpersonal skills of staff, and clinic visits and accessibility to the services. Face validity, construct validity, internal reliability, and internal consistency were used to examine the robustness of these statements. The PREM was completed by parents/carers and also children/young people. RESULTS: PREMs were received from 145 of the 192 audit units; 2335 completed forms were returned; the attitude statements were completed by 750 children/young people and 1550 parents/carers. Face validity of the PREM was good. Construct validity was indecisive; confirmatory factor analysis of the hypothesised construct was weak. Exploratory factor analysis identified a four factor solution for the parent/carers dataset and a five factor solution for the children/young people's dataset. Internal reliability was good for the parent/carers dataset but less good for the children/young people. Internal consistency was moderately good for both datasets. CONCLUSIONS: These findings indicate that the PREM is likely to be a valid tool with the potential to elicit a wide variety of reliable views from parents/carers of children with epilepsy. The construct validity for the PREM should be reassessed with confirmatory factor analysis in a new dataset. More work needs to be undertaken with children/young people to design statements that capture their specific needs. PMID- 30445295 TI - Broadband NMR with random-window noise excitation. AB - Motivated by recent generations of compact portable and benchtop NMR instrumentation, we present a new method for the acquisition of broad bandwidth NMR spectra using stochastic excitation. The new method decouples the spectral width from the durations of the excitation pulses and ring-down delays, allowing the receiver bandwidth to be arbitrarily large. This allows low-power, low-flip angle pulses to be used to acquire broad-band NMR spectra such as wideline powder patterns from solids. The new method divides experimental time into distinct "pulse" and "acquire" blocks that are interleaved according to a pseudo-random noise sequence and combined with a second sequence for phase modulation. The method is described mathematically, and is demonstrated with both liquids and wide-line solids experiments. PMID- 30445296 TI - A mosaic structure multi-level vascular network design for skull tissue engineering. AB - In human skull tissue engineering scaffolds, cell growth and osteogenesis are limited due to the lack of vascular structure. Therefore, a mosaic structure vascular parameterized design method is proposed according to the scanning characteristics of the diploic vein. Using micro-CT scans of skull samples, the features of the diploic vein were extracted, and a multi-level vascular network model was established based on a power diagram. Considering the characteristics of blood flow in the veins, finite element analysis (FEA) of the fluid-solid coupling was established to analyze the effect of blood on vessels with four level mosaic structures. The results showed that the deformation and stress distribution of vessels were reasonable, and the blood pressure, velocity and shear stress in the designed vascular structure could meet the cell growth requirements. The mosaic structure was prepared by PDMS and cultured in vitro using HUVECs. It was found that most of the cells survived after 48 h, and some cells were attached to the surface mosaic structure. In this method, different levels of vessels nest together, with a curvature that matches the shape of the skull, forming a similar morphology to the native diploic vein, and the local structures can be adjusted flexibly. This mosaic structure vascular design method can be used for network vascular design and experimental studies in hard tissues. PMID- 30445297 TI - Rhodomicranosides A-I, analgesic diterpene glucosides with diverse carbon skeletons from Rhododendron micranthum. AB - Nine previously undescribed diterpene glucosides, rhodomicranosides A-I, comprising leucothane, 4,5-seco-ent-kaurane, and grayanane types, respectively, were isolated from the leaves of Rhododendron micranthum, along with seven known diterpenoids. Their structures were elucidated based on extensive spectroscopic analyses such as HRESIMS, 1D and 2D NMR, UV, and IR, and their absolute configurations were determined by various methods including X-ray diffraction analysis, electronic circular dichroism spectroscopy (ECD), calculated ECD, and Mo2(OAc)4-induced ECD, as well as chemical methods. This is the first time to report the crystal structures of leucothane diterpene glycosides. Rhodomicranosides A-C represent the first examples of 15alpha-hydroxy-leucothane diterpenoids, leucothane diterpene diglucosides, and 9beta-hydroxy-leucothane diterpenoids, respectively. Rhodomicranosides D and E are the second and third examples of 4,5-seco-ent-kaurane diterpenoids, and this is the first time to report 4,5-seco-ent-kaurane-type diterpenoids from the genus of Rhododendron. Rhodomicranosides F and G are the first examples of 5alpha-H-grayan-1(10),9(11) diene-6-one diterpenoids. Some isolated diterpenoids were evaluated for their analgesic activity in an acetic acid-induced writhing test, and rhodomicranosides A-E and H, pierisformoside F, iso-grayanotoxin II, and grayanotoxins I, III, and IV showed significant analgesic effects with the percentage inhibitions over 50% at the dose of 1.0 mg/kg. In particular, grayanotoxins I and III exhibited more potent analgesic activity than morphine at a dose of 0.2 mg/kg, and they showed significant analgesic activity even at a lower dose of 0.04 mg/kg with the inhibition rates of 71.5% and 69.3%, respectively. Their preliminary structure activity relationships were discussed. PMID- 30445298 TI - Multichannel digital heteronuclear magnetic resonance biosensor. AB - Low-field, mobile NMR systems are increasingly used across diverse fields, including medical diagnostics, food quality control, and forensics. The throughput and functionality of these systems, however, are limited due to their conventional single-channel detection: one NMR probe exclusively uses an NMR console at any given time. Under this design, multi-channel detection could only be accomplished by either serially accessing individual probes or stacking up multiple copies of NMR electronics; this approach still retains limitations such as long assay times and increased system complexity. Here we present a new scalable architecture, HERMES (hetero-nuclear resonance multichannel electronic system), for versatile, high-throughput NMR analyses. HERMES exploits the concept of software-defined radio by virtualizing NMR electronics in the digital domain. This strategy i) creates multiple NMR consoles without adding extra hardware; ii) acquires signals from multiple NMR channels in parallel; and iii) operates in wide frequency ranges. All of these functions could be realized on-demand in a single compact device. We interfaced HERMES with an array of NMR probes; the combined system simultaneously measured NMR relaxation from multiple samples and resolved spectra of hetero-nuclear spins (1H, 19F, 13C). For potential diagnostic uses, we applied the system to detect dengue fever and molecularly profile cancer cells through multi-channel protein assays. HERMES holds promise as a powerful analytical tool that enables rapid, reconfigurable, and parallel detection. PMID- 30445299 TI - In-Situ imaging detection of cell membrane and intracellular cholesterol via cascade reactions. AB - Herein, an effective membrane-to-intracellular cholesterol detection strategy was designed based on cascade reactions. A biochip array was firstly fabricated by consecutively immobilizing luminol modified gold nanoparticles (Au@luminol), soybean peroxidase (SBP) and cholesterol oxidase (ChoX) on the cellulose acetate (CA) membrane functionalized home-made micropore array. When cholesterol existed, it was oxidized by ChoX generating H2O2, which further triggered the CL reaction under the SBP catalysis, the CL signals were collected by a charge-coupled device (CCD). The proposed strategy exhibited a wide linear range from 0.12 MUM to 1000 MUM and relatively low detection limit (LOD) of 0.08 MUM. Furthermore,it could be used to in-situ detect membrane cholesterol and intracelluar esterified cholesterol in HepG2 cells. After activated HepG2 cells were added to the modified biochip, membrane cholesterol was detected directly. Intracelluar esterified cholesterol was detected through the introduction of triton X-100 and cholesteryl esterase (ChoE). Additionally, the cholesterol content in cells was changed after stimulated by drugs, such as apolipoprotein A-I (ApoA-I), pitavastatin or probucol. The correlation of the CL signal with the amount of cholesterol confirmed that our strategy was feasible to simultaneously detect membrane and intracellular cholesterol at different cellular states. The proposed strategy exhibited excellent sensitivity, selectivity, stability, and reproducibility in a simple, cheap way, which opened a new door for studying clinic treatment of the cholesterol-related diseases. PMID- 30445300 TI - Combining 3D graphene-like screen-printed carbon electrode with methylene blue loaded liposomal nanoprobes for phospholipase A2 detection. AB - Phospholipase A2 (PLA2) enzyme could be acted as a unique biomarker for forecasting and diagnosing certain diseases. Therefore, it is important to monitor PLA2 activity in biological and clinical samples. In this work, a simple electrochemical assay for PLA2 activity was developed based on a screen-printed carbon electrode (SPCE) with 3D graphene-like surface. When the PLA2-containing sample was mixed with the nanoprobes, i.e. the electroactive marker methylene blue (MB) encapsulated within nanometer-sized phospholipid liposomes, MB was released and adsorbed/enriched in site onto the surface of SPCE in a micro-cell. The encapsulation and enzymatic release of MB were evaluated using UV-Vis and fluorescence. The peak current due to oxidation of the adsorbed MB on the SPCE was measured by square-wave voltammetry (SWV). The current was directly linear to the PLA2 activity from 5 U/L to 200 U/L with a detection limit of 3 U/L. The same method can also be used for screening PLA2 inhibitors. Thus, the enrichment strategy developed in this work could be a promising signal amplification method for the sensitive and selective detection of PLA2 in biological or clinical samples. PMID- 30445301 TI - Aptamer-DNA concatamer-quantum dots based electrochemical biosensing strategy for green and ultrasensitive detection of tumor cells via mercury-free anodic stripping voltammetry. AB - A electrochemical biosensing strategy was developed for green and ultrasensitive detection of tumor cells by combining aptamer-DNA concatamer-CdTe quantum dots (QDs) signal amplification probe with mercury-free anodic stripping voltammetry (ASV). First, aptamer-DNA concatamer- CdTe QDs probes were designed by DNA hybridization and covalent assembling, which contained specific recognition of aptamer and signal amplification incorporating the DNA concatamer with QDs. Meanwhile, the capture electrode, glassy carbon electrode (GCE)/Graphene oxide (GO)/Polyaniline (PANI) / Glutaraldehyde (GA) / concanavalin A (Con A) was fabricated by a layer-by-layer assembling technique. K562 cells, as model cancer cells were detected to demonstrate the feasibility of this sensing strategy. Then, novel composite, graphene (GR)- Poly diallyldimethylammonium chloride (PDDA)/L-Cysteine (L- Cys), was explored in ASV which replaced mercury electrodes using for determination of tumor cells. The proposed electrochemical biosensor showed high sensitivity with the detection limit of 60 cells mL-1. More importantly, this novel design of signal amplification probes and the exploration of new composites in mercury-free ASV analysis would provide a promising method for ultrasensitive biosensor preparation and green electrochemical detection of tumor cells. PMID- 30445302 TI - Sensitive surface plasmon resonance detection of methyltransferase activity and screening of its inhibitors amplified by p53 protein bound to methylation specific ds-DNA consensus sites. AB - Abnormal DNA methylation is closely related to cancer initiation and progression, and strategies to assay methyltransferase activity and screen its inhibitors are essential for cancer diagnosis and therapy. In this work, surface plasmon resonance (SPR)-based assay for real-time and sensitive monitoring of DNA methyltransferase activity and screening of its inhibitors was conducted via methylation of double-stranded (ds)-DNA consensus sites and the follow-up p53 protein recognition. The consensus ds-DNA possesses a specific sequence of 5' CCGG-3' in which the second C base can be methylated by M.SssI methyltransferase (M.SssI MTase) and the methylation process impedes the recognition and cleavage of the ds-DNA by HpaII endonuclease, thus, the attachment of p53 protein leads to remarkable SPR signals. In contrast, inhibition of M.SssI MTase activity by a potent inhibitor leaves the consensus ds-DNA unmethylated, and the cleavage of the ds-DNA by HpaII prevents p53 protein from adsorbing onto the chip surface, leading to tiny SPR signals. The binding affinity (KD) between p53 protein and the methylated consensus ds-DNA was deduced to be 3.04 nM, evidencing the strong binding capability. Two nucleoside inhibitors of 5-Azacytidine (5-Aza) and 5 aza-2'-deoxycytidine (5-Aza-dC), and a non-nucleoside inhibitor of procaine were examined, and their half-maximal inhibiting concentration (IC50) values were highly comparable with those by other methods. The sensing protocol has been successfully utilized for the assay of M.SssI MTase activity in normal and cancer cell lysates. The proof-of-concept experiments demonstrate that SPR serves as a viable means for sensitive detection of methyltransferase activity and screening of its inhibitors using p53 protein bound to methylation-specific ds-DNA consensus sites. PMID- 30445303 TI - Hybrid dual-functioning electrodes for combined ambient energy harvesting and charge storage: Towards self-powered systems. AB - In the last few years, there have been an increasing number of reports where different energy harvesters are directly combined with charge storing devices, based on dual-function electrodes able to convert and store electrical energy in the same volume. This includes (bio)fuel cells harvesting chemical energy, (bio)solar cells harvesting solar energy, tribo- and piezoelectric devices harvesting mechanical energy, and thermoelectrics harvesting thermal energy, which now have been intimately combined with batteries and electrochemical capacitors. These new types of hybrid electric devices show great promise especially for the design of self-powered electronics where an integrated hybrid power system is preferable to separated ones, capable of scavenging ambient energy and simultaneously store it and in this way increasing the efficiency and enabling further miniaturization. This paper details the recent emergence of hybrid energy systems, reviewing the progress made using widely different energy harvesting techniques, which have so-far not been described in a single body of work. PMID- 30445304 TI - An impedance biosensor for simultaneous detection of low concentration of Salmonella serogroups in poultry and fresh produce samples. AB - This paper reports the design, fabrication and testing of a microfluidic based impedance biosensor for rapid and simultaneous detection of three Salmonella serogroups. The microfluidic device consists of three microchannels, each one includes a region for focusing the Salmonella cells into the centerline of the microchannel and direct them toward the sensing region to obtain highly concentrated samples using positive dielectrophoresis force. A region for bacteria sensing consists of interdigitated electrode (IDE) array with 10 pairs of fingers. Three types of Salmonella antibodies (type B, D and E) were mixed separately with the cross-linker (Sulfo-LC-SPDP) to enhance the immobalization of the antibodies to the detection electrodes. The electrode surfaces was then functionalized with the three mixtures, one for each channel. As target antigen binds to the antibody, it results in impedance change. The Salmonella samples were spiked with Salmonella type B, introduced into the biosensor via the sample inlet into the focusing region, and then toward the sensing region where they bind to the immobilized antibody, causing a change in the impedance. The performance of the devices was tested using single Salmonella serotype B and two Salmonella serotypes B, and D, with a limit of detection of 7 cells/ml. The biosensor was also able to differentiate live from dead bacteria eliminating the false positive results. Finally, the device was also able to detect Salmonella selectively when other type of pathogen was present. PMID- 30445305 TI - Development of a multiplexed giant magnetoresistive biosensor array prototype to quantify ovarian cancer biomarkers. AB - In this work, we developed benchtop and handheld Giant Magnetoresistive (GMR) biosensing systems that serve as platforms for detecting a wide variety of protein biomarkers for human diseases. System development included spintronic and nanomagnetic materials, biomolecular chemistry, electronic circuitry, analog and digital signal processing, firmware programming, user interface programming on both PC and Android smartphone, communications over both USB and Bluetooth, and mechanical integration. In this work, we demonstrated the benchtop GMR biosensing system in the context of ovarian cancer assay development. The prototype system delivered the required performance in terms of high-sensitivity multiplex assays in a portable format with enough flexibility to serve as a platform for ovarian cancer and many other diseases. We achieved multiplex detection of cancer antigen 125 (CA125 II), human epididymis protein 4 (HE4), and interleukin 6 (IL6), with limits of detection (LOD) as low as 3.7 U/mL, 7.4 pg/mL, and 7.4 pg/mL, respectively. PMID- 30445306 TI - Comparison of the paracetamol electrochemical determination using boron-doped diamond electrode and boron-doped carbon nanowalls. AB - Two different type of electrodes, boron-doped diamond electrode (BDD) and boron doped carbon nanowalls (B:CNW) electrode, were used for the electrochemical determination of paracetamol using the cyclic voltammetry and the differential pulse voltammetry in phosphate buffered saline, pH = 7.0. The main advantage of these electrodes is their utilization without any additional modification of the electrode surface. The peak current was linearly related to the concentration of paracetamol in the range from 0.065 uM to 32 uM for BDD electrode and from 0.032 uM to 32 uM for B:CNW electrode. The limit of detection was 0.430 uM and 0.281 uM for BDD and B:CNW electrode, respectively. Additionally, we studied the effect of pH on the redox reaction of paracetamol at the both electrodes in Britton Robinson buffer solution in the range of pH 3.0-12.0, indicating the pH 7.0 value as the most suitable for the current experiments. The studies also included the various scan rates in range of 50-500 mV/s. Finally, our team selected the B:CNW electrode for the determination of paracetamol in the artificial urine sample using differential pulse voltammetry method, obtaining the calculated limit of detection on the level of 0.08006 uM. PMID- 30445307 TI - Purinergic P2X7 receptor blockade mitigates alcohol-induced steatohepatitis and intestinal injury by regulating MEK1/2-ERK1/2 signaling and egr-1 activity. AB - The P2X7 receptor is an ATP-binding cation channel involved in a broad range of inflammatory diseases. However, little is known about the potential role of P2X7R in alcohol-induced steatohepatitis and intestinal injury. In our study, C57BL/6 mice were intraperitoneally injected with P2X7R antagonists Brilliant Blue G and A438079 from the 4th day to the 10th day during the induction of chronic plus binge alcohol feeding model. Our results showed that alcohol feeding induced significant steatohepatitis and liver injury, which were mitigated by P2X7R blockade as evidenced by decreased serum levels of ALT, AST, T-CHO and TG, reduced lipid accumulation, and less inflammation. The increased intestinal inflammatory cytokines production and the prominent intestinal barrier disruption caused by alcohol were also modulated by P2X7R antagonism. Interestingly, alcohol feeding increased the relative abundance of phylum Bacteroidetes while decreased the number of phylum Verrucomicrobia and genus Akkermansia in the cecal content, which were reversed by P2X7R antagonist. Importantly, the improvement of intestinal barrier function and the restoration of partial taxonomic alterations in the gut microbiota might contribute to protect the liver from gut microbiota dysbiosis-induced second hit. Furthermore, P2X7R blockade inhibited MEK1/2-ERK1/2 phosphorylation and egr-1 expression in both liver and intestine from alcohol-fed mice. Collectively, P2X7R blockade mitigates alcohol-induced steatohepatitis and intestinal injury by inhibiting MEK1/2-ERK1/2 signaling and egr-1 expression. These studies strongly suggest that P2X7R blockade may be a promising therapeutic approach for treating alcoholic liver disease. PMID- 30445308 TI - Design and evaluation of a hypoallergenic peptide-based vaccine for Salsola kali allergy. AB - BACKGROUND: The Salsola kali (S. kali) pollen is one of the most important causes of allergic rhinitis in the deserts and semi-desert areas. Immunotherapy with allergen extracts remains the only available treatment addressing the underlying mechanism of allergy. However, given the low efficacy of this method, it is necessary to find more effective and alternative therapeutic interventions using molecular biology and bioinformatics tools. In this study, a hypoallergenic vaccine was designed on the basis of B-cell epitope approach for S. kali immunotherapy. METHODS: Using the Immune Epitope Database (IEDB), a 35-mer peptide was selected and chemically conjugated to a keyhole limpet hemocyanin (KLH) molecule. Specific IgG and IgE from immunized BALB/c mice sera against the vaccine (Sal k 1-KLH), S. kali extract and the recombinant protein, rSal k 1, were measured using ELISA. Also, inhibition of IgE by mouse IgG was evaluated using an inhibitory ELISA. Finally, the IgE reactivity and T-cell reactivity of the designed vaccine were evaluated by dot blot assay and MTT assay. RESULTS: Vaccination with the vaccine produced high levels of protective IgG in mice, which inhibited the binding of patients IgE to recombinant proteins. The result showed that the designed vaccine, unlike the recombinant protein and extract, did not induce T-cell lymphocytes response and also exhibited decreased IgE reactivity. CONCLUSION: The designed vaccine can be considered as a promising candidate for therapeutic allergen-specific immunotherapy. PMID- 30445309 TI - Protective and therapeutic role of Bilobalide in cuprizone-induced demyelination. AB - Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system characterized by recurrent and progressive demyelination, neuroinflammation and oligodendrocyte loss. The cuprizone (CPZ) model is characterized by primary and reversible demyelination, accompanied by oligodendrocyte loss and neuroinflammation. In the current study, we explored the efficiency of Bilobalide in the demyelination and remyelination. The results demonstrate that Bilobalide improved behavioral abnormality and promoted remyelination in the corpus callosum by using Luxol Fast Blue, Black Gold II and myelin basic protein (MBP) staining. We for the first time found that CPZ caused the splenic atrophy and induced the formation of myelin oligodendrocyte glycoprotein (MOG) antibody, which was attenuated by Bilobalide. Thus, Bilobalide decreased the loss of O4+ oligodendrocytes possibly through MOG antibody dependent cell cytotoxicity. Bilobalide also prevented the infiltration of CD4+ T cells, CD68+ macrophages and B220+ B cells within the brain, and reduced the inflammatory microenvironment mediated with Iba1+iNOS+ and Iba1+NF-kB+ microglia after CPZ challenge, accompanied by the inhibition of IL-1beta and IL-6 in the brain. These results identify a potent therapeutic efficiency for Bilobalide and highlight clear pleiotropic effects of the compound beyond specific autoantibody and inflammatory microenvironment in CPZ-mediated demyelination. PMID- 30445310 TI - Berberine suppresses IL-33-induced inflammatory responses in mast cells by inactivating NF-kappaB and p38 signaling. AB - Berberine (BBR) possesses many pharmacological characteristics including anti inflammation, anti-allergy, anti-angiogenesis and anti-tumor. However, the effects and mechanisms of BBR on IL-33-induced mast cell inflammatory responses are kept unknown. To investigate these, rat peritoneal mast cells (RPMCs) were isolated from the peritoneal cavity and cultured with BBR treatment in combination IL-33 stimulation. Firstly, cytotoxic effect of BBR on RPMCs was detected by MTT assay. Then, IL-33-induced cytokine production and the expression of ST2 receptor, were evaluated by ELISA and real-time PCR, respectively. In addition, NF-kappaB and MAPK signaling involved in IL-33-mediated mast cell activation were assessed by Western blot, which also was confirmed using the signal transduction inhibitors. Simultaneously, the effect of BBR on IL-33 activated enhancement of IgE-mediated mast cell responses was analyzed. Lastly, SD rats were used to explore the effect of BBR on IL-33-induced inflammation in vivo. BBR treatment significantly reduced IL-33-stimulated cytokine production in RPMCs, such as IL-6, TNF-alpha, IL-13 and MCP-1, but had little effect in ST2 expression. BBR modulated IL-33 signaling via suppressing IL-33-induced NF-KappaB transcription and p38 phosphorylation, but not ERK and JNK. Additionally, BBR also hampered the combined effects of IL-33 and IgE-mediated mast cell activation. Decreased cytokine production followed BBR treatment in vitro was consistent with that in vivo, where BBR injection i.p. into rats obviously inhibited IL-33-induced plasma cytokine levels. These findings demonstrated that BBR suppressed IL-33-mediated inflammation in mast cells by inactivating NF kappaB and p38 signaling, suggesting its potential application for the treatment of allergic inflammation. PMID- 30445312 TI - Activated toll-like receptor 4 is involved in oridonin-induced phagocytosis via promotion of migration and autophagy-lysosome pathway in RAW264.7 macrophages. AB - In our previous study, we demonstrated that oridonin enhances phagocytosis of apoptotic bodies by macrophage-like cells by inducing autophagy. However, the direct sensor of autophagy and the key event controlling phagocytosis remains unknown. Herein, we showed that Toll-like receptor 4 (TLR4), known to mediate immune responses, was activated by oridonin. Activated TLR4 contributes to phagocytosis of apoptotic cells by RAW264.7 macrophages. Indeed, inhibition or small interfering RNA (siRNA) silencing of TLR4 significantly attenuated oridonin induced phagocytosis. Inhibition of TLR4 also decreased the level of autophagy and its associated proteins, Beclin-1 and light chain 3 (LC3), suggesting that activated TLR4 is involved in activation of autophagy. LPS-induced activation of TLR4 promoted phagocytosis and autophagy progression. Activation of TLR4 accompany increase in activities of lysosome acid phosphatase and cathepsin B as well as in up-regulation of lysosomal-associated membrane protein (LAMP 1 and 2) levels. Furthermore, TLR4 in association with translocation to cytoplasm leads to macrophage motility or migration through increased plasticity of skeleton and/or membrane structure. These results suggest that oridonin-induced phagocytosis of apoptotic bodies by macrophages is TLR4 signal pathway-mediated, via activation of the autophagy-lysosome pathway as well as increase of cell migration. PMID- 30445311 TI - Increased GPIbalpha shedding from platelets treated with immune thrombocytopenia plasma. AB - Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by accelerated platelet destruction/clearance or decreased platelet production. ADAM17-mediated platelet receptor GPIbalpha extracellular domain shedding has been shown to be involved in platelet clearance. Whether GPIbalpha shedding participates in the pathogenesis of ITP remains poorly understood. This study aims to investigate the role of GPIbalpha shedding in the development of ITP via incubating normal platelets with ITP plasma to mimic ITP in vivo environment. Plasma was isolated from ITP patients or healthy control and incubated with platelets in vitro followed by measuring GPIbalpha expression by flow cytometry and western blot, ADAM17 expression by western blot, ROS generation and platelet activation by flow cytometry. Compared with control plasma, ITP plasma-treated platelet displayed significantly reduced GPIbalpha surface expression, increased ADAM17 expression and ROS generation. However, metalloproteinase inhibitor GM6001 blocked the ITP-plasma-induced decrease in GPIbalpha surface expression, increase in ADAM17 expression and platelet activation. In addition, inhibitors of NADPH oxidase or mitochondria respiration significantly inhibited ROS generation from ITP plasma-treated platelets. Moreover, ROS inhibition or blocking FcgammaRIIa attenuated the decrease in GPIbalpha surface expression, platelet activation and ROS generation (for blocking FcgammaRIIa) in ITP plasma-treated platelets. In conclusion, ITP plasma induces platelet receptor GPIbalpha extracellular domain shedding, suggesting that it might participate in the pathogenesis of ITP and targeting it might be a novel approach for treating ITP. PMID- 30445313 TI - Facial expressions of authenticity: Emotion variability increases judgments of trustworthiness and leadership. AB - People automatically generate first impressions from others' faces, even with limited time and information. Most research on social face evaluation focuses on static morphological features that are embedded "in the face" (e.g., overall average of facial features, masculinity/femininity, cues related to positivity/negativity, etc.). Here, we offer the first investigation of how variability in facial emotion affects social evaluations. Participants evaluated targets that, over time, displayed either high-variability or low-variability distributions of positive (happy) and/or negative (angry/fearful/sad) facial expressions, despite the overall averages of those facial features always being the same across conditions. We found that high-variability led to consistently positive perceptions of authenticity, and thereby, judgments of perceived happiness, trustworthiness, leadership, and team-member desirability. We found these effects were based specifically in variability in emotional displays (not intensity of emotion), and specifically increased the positivity of social judgments (not their extremity). Overall, people do not merely average or summarize over facial expressions to arrive at a judgment, but instead also draw inferences from the variability of those expressions. PMID- 30445314 TI - Long-distance signaling in plant stress response. AB - Vascular plants respond to various environmental stresses by integrating and transmitting environmental information perceived by roots and leaves, respectively. Long-distance signaling plays a crucial role in plant adaptation to and subsequent survival to severe environmental conditions. Recent studies have elucidated that various mobile molecules, such as small proteins, peptides, RNAs, metabolites, and second messengers, transmit extracellular stimuli from sensing tissues to target organs. Plants have unique and complex mechanisms for accurately connecting various organs despite the lack of a nervous system. In this short review, we summarize the current knowledge of plant molecules involved in long-distance signaling for optimal growth and stress response, with special focus on mobile peptides. PMID- 30445315 TI - Computational prediction of gene regulatory networks in plant growth and development. AB - Plants integrate a wide range of cellular, developmental, and environmental signals to regulate complex patterns of gene expression. Recent advances in genomic technologies enable differential gene expression analysis at a systems level, allowing for improved inference of the network of regulatory interactions between genes. These gene regulatory networks, or GRNs, are used to visualize the causal regulatory relationships between regulators and their downstream target genes. Accordingly, these GRNs can represent spatial, temporal, and/or environmental regulations and can identify functional genes. This review summarizes recent computational approaches applied to different types of gene expression data to infer GRNs in the context of plant growth and development. Three stages of GRN inference are described: first, data collection and analysis based on the dataset type; second, network inference application based on data availability and proposed hypotheses; and third, validation based on in silico, in vivo, and in planta methods. In addition, this review relates data collection strategies to biological questions, organizes inference algorithms based on statistical methods and data types, discusses experimental design considerations, and provides guidelines for GRN inference with an emphasis on the benefits of integrative approaches, especially when a priori information is limited. Finally, this review concludes that computational frameworks integrating large-scale heterogeneous datasets are needed for a more accurate (e.g. fewer false interactions), detailed (e.g. discrimination between direct versus indirect interactions), and comprehensive (e.g. genetic regulation under various conditions and spatial locations) inference of GRNs. PMID- 30445316 TI - A rapid and economical method for the quantification of hydrogen peroxide (H2O2) using a modified HPLC apparatus. AB - H2O2 is one of the most commonly used oxidants for the degradation of recalcitrant organic contaminants in advanced oxidation processes (AOPs). However, most research aiming to optimize AOPs is missing the monitoring of the remaining H2O2, an important parameter to assess the efficiency of the process. In this work, a novel method for [H2O2] quantification was developed using simple modifications of an HPLC-DAD setup that is available in most analytical chemistry laboratories. The modifications include the use of acidified potassium iodide solution as mobile phase and replacing the reverse phase column with a series of capillary columns. This instrument configuration allowed also the quantification of organic contaminants using the same H2O2 containing sample. The method's LOD and LOQ were calculated to be as low as 8.29 * 10-4 mM and 2.76 * 10-3 mM, respectively with an LDR range of 0.01-150 mM. The cost per analysis ranged between 0.8 and 1.8 USD cents depending on the concentration tested. This analytical method was validated by a statistical comparison to a well-known titrimetric method that is commonly used for H2O2 quantification. It was also tested using standards prepared in natural matrices such as spring and seawater, and in media containing high concentration of several spectator species such as chlorides, bicarbonates, humic acids, fumaric acids and micro pollutants. The method showed excellent robustness by maintaining high regression coefficient and excellent sensitivity in all calibration curves regardless of the matrix content. PMID- 30445317 TI - Strategic Noise Maps and Action Plans for the reduction of population exposure in a Mediterranean port city. AB - One of the major environmental problems in contemporary societies is noise pollution, as it is well-known that noise adversely affects both the physiological and the psychological human health and well-being. This paper presents the development of Strategic Noise Maps and Action Plans for the "agglomeration of Piraeus", an area with >15% of the total population and almost 12% of the total area of the "Athenian - Piraeus conurbation". In Piraeus different noise sources, such as the railway, port activities, the road network, industrial and logistic activities etc., in combination with mixed land uses, dense urban canopy characteristics, residential areas adjacent to major road arterials etc. create a complicated noise environment that causes annoyance to the population. For this study, a campaign of 55 24-hour noise measurements was carried out and a series of 200 traffic counts were used for the estimation of traffic characteristics. Annual road traffic data were derived from a validated traffic model, while vessel, rail and industrial activity data were obtained from the service operators and in-situ surveys. The aforementioned noise/traffic measurements were used to calibrate a complex geographical model of the urban canopy and the noise sources layout. Strategic Noise Maps were then developed, along with estimations of the population exposure and DALYs lost from environmental noise per source. Action Plans including intervention measures aiming at the reduction of noise pollution in the area were then proposed. It was found that when implementing the interventions proposed both the noise levels and the exposure of population were significantly reduced, highlighting the importance of exposure reduction, especially for the vulnerable subpopulations, through prevention measures and strategies. PMID- 30445318 TI - Microplastics in freshwater sediments of Atoyac River basin, Puebla City, Mexico. AB - Microplastics (MPs) are contaminants of emerging concern in aquatic environments. The abundance, distribution and characteristics (color, morphology, texture) of MPs from Atoyac River basin, a highly urbanized river system located in Central Mexico were investigated in this study. The sediment samples were collected from 29 different sites along the Atoyac River basin in four different zones: Zahuapan River, Atoyac River, Confluence zone and Valsequillo dam and processed for MPs extraction using ZnCl2 density separation method. The total number of MPs in Zahuapan River, Atoyac River, Confluence zone and Valsequillo dam was 1633.34 +/- 202.56, 1133.33 +/- 72.76, 833.33 +/- 80.79 and 900 +/- 346.12 items kg-1 respectively. It was found that the concentration of MPs is higher in the downstream section of the river (confluence zone: 833.33 +/- 80.79 & Valsequillo dam: 900 +/- 346.12 items kg-1), revealing significant impacts of dense population and industrial complex of Puebla City. Colored MPs were predominant accounting for 51% and white MPs for 49% of the total MPs. Films (25.9%) and fragments (22.2%) were the most abundant type followed by fibers (14.8%). Scanning electron microscope images revealed varying disintegration features and energy-dispersive X-ray spectra demonstrated the presence of different metal elements on the surface of MPs. The results highlighted the widespread distribution of MPs in the sediments of Atoyac River basin, Mexico. PMID- 30445319 TI - Local applications but global implications: Can pesticides drive microorganisms to develop antimicrobial resistance? AB - Pesticides are an important agricultural input, and the introduction of new active ingredients with increased efficiencies drives their higher production and consumption worldwide. Inappropriate application and storage of these chemicals often contaminate plant tissues, air, water, or soil environments. The presence of pesticides can lead to developing tolerance, resistance or persistence and even the capabilities to degrade them by the microbiomes of theses environments. The pesticide-degrading microorganisms gain and employ several mechanisms for attraction (chemotaxis), membrane transport systems, efflux pumps, enzymes and genetical make-up with plasmid and chromosome encoded catabolic genes for degradation. Even the evolution and the mechanisms of inheritance for pesticide degradation as a functional trait in several microorganisms are beginning to be understood. Because of the commonalities in the microbial responses of sensing and uptake, and adaptation due to the selection pressures of pesticides and antimicrobial substances including antibiotics, the pesticide-degraders have higher chances of possessing antimicrobial resistance as a surplus functional trait. This review critically examines the probabilities of pesticide contamination of soil and foliage, the knowledge gaps in the regulation and storage of pesticide chemicals, and the human implications of pesticide-degrading microorganisms with antimicrobial resistance in the global strategy of 'One Health'. PMID- 30445320 TI - Do humans spread zoonotic enteric bacteria in Antarctica? AB - Reports of enteric bacteria in Antarctic wildlife have suggested its spread from people to seabirds and seals, but evidence is scarce and fragmentary. We investigated the occurrence of zoonotic enteric bacteria in seabirds across the Antarctic and subantarctic region; for comparison purposes, in addition to seabirds, poultry in a subantarctic island was also sampled. Three findings suggest reverse zoonosis from humans to seabirds: the detection of a zoonotic Salmonella serovar (ser. Enteritidis) and Campylobacter species (e.g. C. jejuni), typical of human infections; the resistance of C. lari isolates to ciprofloxacin and enrofloxacin, antibiotics commonly used in human and veterinary medicine; and most importantly, the presence of C. jejuni genotypes mostly found in humans and domestic animals but rarely or never found in wild birds so far. We also show further spread of zoonotic agents among Antarctic wildlife is facilitated by substantial connectivity among populations of opportunistic seabirds, notably skuas (Stercorarius). Our results highlight the need for even stricter biosecurity measures to limit human impacts in Antarctica. PMID- 30445321 TI - Fate of pharmaceuticals in a spray-irrigation system: From wastewater to groundwater. AB - Land application of wastewater effluent is beneficial for recharging groundwater aquifers and avoiding direct pollutant discharges to surface waters. However, the fate of non-regulated organic wastewater pollutants, such as pharmaceuticals and personal care products (PPCPs), in such wastewater reuse systems is understudied. Here, a 14-month study (October 2016 through December 2017) was conducted to evaluate the fate and potential risks of seven commonly used PPCPs in a local wastewater treatment plant (WWTP) and from 13 groundwater monitoring wells at a spray-irrigation site where effluent has been spray-irrigated since the early 1980s. Acetaminophen and trimethoprim were the most frequently detected (93%) PPCPs in WWTP influent, while in the effluent, caffeine and trimethoprim were detected most frequently (70%). Wastewater treatment generally reduced concentrations of acetaminophen and caffeine by >88%; however, some compounds had low removal or were present at higher concentrations in the effluent compared with influent (e.g. naproxen, sulfamethoxazole, trimethoprim and ofloxacin). Seasonal trends were observed, with higher PPCP concentrations in the WWTP influent and effluent in the winter. Risk calculations conducted on the wastewater effluent suggest that the risk posed by PPCPs that persisted in the effluent are medium to high to aquatic organisms. Detection frequencies of PPCPs were lower in groundwater samples compared to the effluent, with sulfamethoxazole (40%) and caffeine (32%) as the most frequently detected compounds. Similarly, average concentrations of PPCPs in groundwater were found to be nearly two orders of magnitude lower than concentrations in the effluent. Minimal seasonal influence was observed for groundwater samples. Human health risk assessments indicate that concentrations in groundwater, which is used as a drinking water source, appear to pose minimal risk. PMID- 30445322 TI - The influence of a submerged meadow on uptake and trophic transfer of legacy mercury from contaminated sediment in the food web in a brackish Norwegian fjord. AB - There are contradicting results on the importance of legacy mercury (Hg) contaminated sediments to Hg fish tissue concentrations. Still, sediment remediation actions often aim at minimizing ecosystem exposure and human risk caused by the consumption of fish and seafood. The aim of this study was to investigate the possible influence of a permanently submerged meadow on the availability and transfer of Hg from sediment to biota, three decades after the Hg discharges was halted and the previous biota survey was carried out, in the severely contaminated brackish fjord Gunneklevfjorden in southern Norway. We examined total Hg (Tot-Hg) and methyl-Hg (MeHg) concentrations and stable isotopes of nitrogen (N) and carbon (C) in zooplankton, benthic invertebrates, and fish to map the food web and to investigate the trophic transfer of Hg. Sediment and water data were available from a previous study. Overlap in delta13C in benthos and fish reveals that benthos is a preferred prey to fish, though despite elevated Tot-Hg concentrations in benthos, fish predator (perch, pike and eel) Hg concentrations are comparable to concentrations reported in nearby lakes without contaminated sediments (mean 1.6 +/- 1.3 mg Tot-Hg kg-1 dw). We propose that habitat reliance is an important factor controlling the uptake of Hg from sediments, as both benthos and fish prefer to forage within the meadow where sediment concentrations of Tot-Hg are lower than outside the macrophyte meadow, though %MeHg is higher than outside. Further, we propose that sediment remediation actions performed outside the meadow may have limited effect on the Hg concentrations in fish. PMID- 30445323 TI - Assessing the impact of waste water effluents on native fish species from a semi arid region, NE Spain. AB - Mediterranean rivers are strongly affected by pollution and water scarcity. Over the summer period, urban and industrial effluents arrive into the rivers with little dilution. In order to assess the water quality, two native fish species, Barbus meridionalis and Squalius laietanus, were collected from six sites along the Ripoll River (Spain). PAH metabolites, alkylphenols (nonylphenol and octylphenol) and the musk galaxolide levels were determined in bile. 7 Ethoxyresorufin-O-deethylase (EROD) and 7-benzyloxy-4-trifluoromethyl-coumarin O debenzyloxylase (BFCOD) were measured as metabolic biomarkers, and the activity of CYP19 aromatase was determined in the ovaries of B. meridionalis as a biomarker of endocrine disruption. The analysis of bile indicated that fish from the lower course of the river were highly exposed to different pollutants. Accordingly, a significant induction of EROD (9 to 10-fold) and BFCOD (3 to 5 fold) activities were detected in both fish species together with an increased aromatase activity in females of B. meridionalis from the most polluted sites. Considering that sewage treatment plant (STP) effluents are essential for maintaining environmental flows in small Mediterranean rivers, this study highlights the need to improve the efficiency of STPs to protect fish health. PMID- 30445324 TI - Contamination patterns in river water from rural Beijing: A hydrochemical and multiple stable isotope study. AB - The pollution of urban river has reached a critical level. In the present study, the hydrochemical composition of local surface water collected during two seasons from the rural area around urban Beijing, China, was examined. Concentrations of selected cations and anions reveal the temporal and spatial distribution of anthropogenic and natural pollution. Multiple stable isotopes (delta15Nnitrate, delta18Onitrate, delta34Ssulfate, delta18Osulfate, Delta33Ssulfate) analyses were applied for detecting of specific hydrochemical processes and identifying the major sources of contamination. Twenty-eight percent of the river water samples from the wet season and 34% from the dry season exhibit a minor water quality of class IV (poor) and below due to high pH values as well as high nitrate, sulfate and fluoride concentrations. This water is hazardous for human health and the aquatic ecology. The seemingly better river water quality in the wet season is caused by higher precipitation and, hence, dilution of the water constituents. Multiple isotopes identify urban wastewater as the prime pollution source. The higher fraction of deteriorated river water in the southern rural area (42%) compared to the north (24%) points to a higher contribution of urban effluents to the downstream rivers in the rural south. It can, thus, be concluded that less discharge of wastewater to the local surface and subsurface environments by better controls of public and private sewage disposal combined with the renewal of leaking sewer pipes would reduce the risk of anthropogenic contamination of river water. PMID- 30445325 TI - Community diversity and potential functions of rhizosphere-associated bacteria of nickel hyperaccumulators found in Albania. AB - Ultramafic (i.e. serpentine) soils are widespread in the Balkans and particularly in Albania. They account for a large part of plant endemism in that region and host several hyperaccumulator species, which are characterized by leaf nickel concentrations frequently above 1%. This rich nickel hyperaccumulating flora could serve as candidate to be used in phytoextraction and agromining. Despite recent interest in metal hyperaccumulating plants and agromining, very few studies have investigated the bacterial diversity and the influence of environmental factors on microbial gene profiles in the rhizosphere of hyperaccumulator plants growing on ultramafic soils. Because rhizospheric bacteria could be crucial to the success of phytoremediation, we studied a total of 48 nickel-hyperaccumulating plants which were sampled from four species that are widespread in Albania: Noccaea ochroleuca, Odontarrhena smolikana, O. rigida and O. chalcidica. All samples were taken from the ultramafic regions of Librazhd and Pogradec in eastern Albania in October 2015. Our study shows that Proteobacteria, Actinobacteria and Acidobacteria dominated the soil bacterial communities. Of these three phyla, only Proteobacteria was relatively abundant. This study underlines the influence of soil Cation Exchange Capacity on the bacterial community's diversity and structure. Based on the predicted metagenomes, the genes belonging to amino acid, lipid and carbohydrate metabolisms were identified as major gene families. Our study sheds some light on our understanding of how bacterial communities are structured within and affect the rhizosphere of hyperaccumulator plants from ultramafic soils in Albania. PMID- 30445326 TI - Soil microbial community composition closely associates with specific enzyme activities and soil carbon chemistry in a long-term nitrogen fertilized grassland. AB - Due to the profound impact of nitrogen (N) input on soil systems, linking the activity and composition of soil microbial communities to soil organic carbon (SOC) is crucial to reveal the microbial-driven mechanisms underlying SOC decomposition by nitrogen fertilization. A long-term nitrogen fertilization experiment with 6 urea fertilizer gradients (0, 2, 4, 8, 16, and 32 g N m-2 yr-1) was conducted on a temperate grassland. The soil basic characteristics, microbial community DNA sequences, five soil enzymes including C, N, and phosphorus cycling, and soil C fractions were measured after 14 years of N addition. N fertilization significantly modified both the bacterial and fungal community composition, with larger variations at higher N levels. N fertilization increased the proportion of copiotrophic bacteria and saprotrophic fungi. Specific enzyme activities standardized by microbial biomass carbon among N fertilizing gradients demonstrated that the potential of labile C acquisition was stable, but the potential of N and P acquisition and recalcitrant C degradation were increased. Recalcitrant soil C fractions including alkyl C and aromatic C significantly differed among N levels, despite the stable SOC concentration. The variations of bacterial phyla and fungal trophic guilds were both associated with specific enzyme activities; meanwhile, fungal phyla were more related to soil C fractions, as the Basidiomycota abundance echoed the proportion of aromatic C at 4-16 g N m 2 yr-1. In conclusion, this study indicates that the changes in microbial community composition by N fertilization can have far-reaching impacts on SOC turnover and nutrient acquisition. PMID- 30445327 TI - Sugar-stimulated CO2 sequestration by the green microalga Chlorella vulgaris. AB - To convert waste CO2 from flue gases of power plants into value-added products, bio-mitigation technologies show promise. In this study, we cultivated a fast growing species of green microalgae, Chlorella vulgaris, in different sizes of photobioreactors (PBRs) and developed a strategy using small doses of sugars for enhancing CO2 sequestration under light-emitting diode illumination. Glucose supplementation at low levels resulted in an increase of photoautotrophic growth driven biomass generation as well as CO2 capture by 10% and its enhancement corresponded to an increase of supplied photon flux. The utilization of urea instead of nitrate as the sole nitrogen source increased photoautotrophic growth by 14%, but change of nitrogen source didn't compromise glucose-induced enhancement of photoautotrophic growth. The optimized biomass productivity achieved was 30.4% higher than the initial productivity of purely photoautotrophic culture. The major pigments in the obtained algal biomass were found comparable to its photoautotrophic counterpart and a high neutral lipids productivity of 516.6 mg/(L.day) was achieved after optimization. A techno economic model was also developed, indicating that LED-based PBRs represent a feasible strategy for converting CO2 into value-added algal biomass. PMID- 30445328 TI - NMR-based lipidomics of fish from a metal(loid) contaminated wetland show differences consistent with effects on cellular membranes and energy storage. AB - Metals and metalloids are priority contaminants due to their non-degradable and bioaccumulative nature, and their ability to regulate and perturb diverse physiological processes in various species. Metal(loid)s are known to cause oxidative stress through production of reactive oxygen species (ROS), thus related endpoints like lipid peroxidation (LPO) have received considerable attention as biomarkers of exposure. However, the implications of metal(loid) toxicity including LPO on actual lipid profiles of species inhabiting contaminated systems are poorly understood. Here we applied Nuclear Magnetic Resonance (NMR) spectroscopy for untargeted lipidomics of mosquitofish (Gambusia holbrooki) collected from reference and metal(loid)-contaminated wetlands. We measured a range of trace elements in water and fish using inductively coupled plasma - mass spectrometry (ICP-MS), and interpreted site differences in the lipid profiles of mosquitofish in the context of known physiological responses to sub-lethal metal(loid) exposure. Results indicate deregulation of cellular membrane lipids (i.e., glycerophospholipids, cholesterol and sphingolipids) and increased energy storage molecules (i.e., triacylglycerols and fatty acids) in fish from the contaminated wetland. These responses are consistent with the recognised induction of oxidative stress pathways in organisms exposed to metal(loid)s and could also be symptomatic of mitochondrial dysfunction and endocrine disruption. It is difficult to attribute metal(loid)s as the sole factor causing differences between wetlands, and a more controlled experimental approach is therefore warranted to further explore mechanistic pathways. Nevertheless, our study highlights the benefits of untargeted 1H NMR-based lipidomics as a relatively fast and simple approach for field-scale assessment and monitoring of organisms inhabiting metal(loid) contaminated environments. PMID- 30445329 TI - Response of antibiotic resistance genes abundance by graphene oxide during the anaerobic digestion of swine manure with copper pollution. AB - The pollution of various environments with antibiotic resistance genes (ARGs) is an urgent problem that needs to be addressed, especially in heavy metal-polluted environments. This study investigated the responses of ARGs and mobile genetic elements (MGEs) to the addition of graphene oxide (GO) to swine manure containing a high concentration copper during anaerobic digestion. The total copy numbers of ARGs and MGEs were significantly enhanced by the pressure due to Cu. GO significantly decreased the ARG and MGE copy numbers, where the low GO concentration performed better than the high GO concentration. Network analysis showed that most of the ARGs and MGEs co-occurred and they shared the same major potential host bacteria. The contributions of different factors to ARG abundances were assessed by redundancy analysis and MGEs had the most important effect on the fate of ARGs. Thus, GO may reduce the abundance of ARGs mainly by removing MGEs. PMID- 30445330 TI - Seasonal size distribution and mixing state of black carbon aerosols in a polluted urban environment of the Yangtze River Delta region, China. AB - The optical properties of black carbon aerosols (BC) are determined by the particles size and the associated non-BC materials, which may be source-related or modified during secondary processing. The one-year long monitoring of BC was first conducted using a Single Particle Soot Photometer (SP2) from December 2013 to November 2014 in Nanjing, a megacity in the Yangtze River Delta region of China. The seasonal variation in the BC size distribution and mixing state were investigated. There was no apparent systematic variation in the mean BC core mass median diameter between seasons, as these values were 226 +/- 12 nm, 217 +/- 13 nm, 211 +/- 15 nm and 221 +/- 12 nm for winter, spring, summer and autumn respectively. The mixing state of BC was quantified as the bulk relative coating thickness (defined as particle size Dp over core size Dc, Dp/Dc), which ranged from 1.05 to 2.65. The BC was found to be significantly more coated in the winter (Dp/Dc = 1.50 +/- 0.30) than in other seasons (Dp/Dc = 1.27 +/- 0.09, 1.28 +/- 0.10, 1.27 +/- 0.11 in spring, summer and autumn respectively). Higher levels of coating during the winter may due to the contributions of the primary source (with the highest BC mass loadings between seasons) or secondary processes such as low temperature that facilitated the condensation. It was found that the photochemical process may enhance the coatings on BC in summer. At nighttime, the reduced and stabilized planetary boundary layer and the nighttime secondary formation may also lead to BC becoming well mixed with other components. Moreover, BC was shown to be less coated when the NOx concentration was high. However, during all seasons, the BC coating was strongly correlated with other non-BC particulate mass, which suggests that at higher pollution levels BC was more significantly coated with other existing materials through coagulation or condensation by other secondary species. PMID- 30445331 TI - The effect of the composting time on the gaseous emissions and the compost stability in a full-scale sewage sludge composting plant. AB - Volatile organic compounds (VOCs) and ammonia are some of the compounds present in gaseous emissions from waste treatment facilities that contribute to odour pollution. In the present work, the effect of the residence time on the biological stability of raw sludge (RS) composted in dynamic windrows and the gaseous emissions generated were studied at a full-scale composting plant, aiming to provide specific pollutant emission factors and to determine their variability depending on the composting time. Waste stability and emissions analysis considered both a first phase where mixed RS and vegetal fraction (RS - VF) is actively composted in dynamic windrows and a second standard curing phase in turned piles, which lasted 31 days. Two windrows were operated at 4 days of composting time while two other windrows were operated simultaneously at 14 days composting time. Increasing the residence time leads to a better waste stabilization in the first composting phase, providing a 50% reduction of the Dynamic Respiration Index. A decrease of the ammonia emission factor was achieved when increasing the composting time (from 168.5 g NH3.Mg-1RS - VF d-1 to 114.3 g NH3.Mg-1RS - VF d-1), whereas the VOCs emission factor was maintained for the same process conditions (between 26.0 and 28.0 g C-VOC.Mg-1RS - VF d-1). However, an increase of the emission masses of both pollutants was observed (from 0.16 to 0.39 kg tVOCs.Mg-1RS - VF and from 1.21 to 1.60 kg NH3.Mg-1RS - VF). Finally, ammonia and VOCs emissions generated at the curing piles were nearly avoided when increasing the composting time of the first phase. PMID- 30445332 TI - Rice straw biochar modified by aluminum chloride enhances the dewatering of the sludge from municipal sewage treatment plant. AB - Enhancement of the dewatering of the sludge by using rice straw biochar (RSB) modified by aluminum chloride (AlCl3) was investigated, and the possible enhancing mechanisms were discussed. Results showed that the settled volume after 30 min (SV30%), specific resistance to filtration (SRF), moisture content (MC) and capillary suction time (CST) of the sludge were decreased and the net sludge solids yield (YN) was increased by the increasing raw or modified RSB, which indicated a higher sludge dewaterability. When the dosage of the modified RSB was adjusted to 0.3 g(RSB)/g(dry sludge), SV30%, SRF, MC and CST were decreased to 79.8%, 1.2 * 1012 m/kg, 81.4% and 38 s, respectively, YN was increased to 19.4 kg/(m2.h). Furthermore, performance of the modified RSB in the dewatering of the sludge was significantly better than that of the raw RSB. For the enhancing mechanisms, charge neutralization occurred when the modified RSB (loaded with positively charged aluminum species on its surface) was dosed into the sludge system, thus destroying the stable sludge colloidal system, thus far easier to congregate the sludge particles, which enhanced the dewatering of the sludge. Another main enhancing mechanism was that after conditioned by the modified RSB, certain skeleton structures were formed in sludge cake to make water pass through easily by decreasing the extracellular polymeric substances (EPS) of the sludge. We found that the effectiveness of using the modified RSB to enhance the dewatering of the sludge is substantial and promising. PMID- 30445333 TI - Assessing the effectiveness of Sustainable Land Management for large-scale climate change adaptation. AB - Climate change will strongly affect essential ecosystem services, like the provision of freshwater, food production, soil erosion and flood control. Sustainable Land Management (SLM) practices are increasingly promoted to contribute to climate change mitigation and adaptation, but there is lack of evidence at scales most relevant for policymaking. We evaluated the effectiveness of SLM in a large Mediterranean catchment where climate change is projected to significantly reduce water security. We show that the on-site and off-site impacts of climate change are almost entirely reversed by the large-scale implementation of SLM under moderate climate change conditions, characterized by limited reductions in annual precipitation but significant increased precipitation intensity. Under more extreme reductions of annual precipitation, SLM implementation reduces the impacts on water security, but cannot prevent significant increased plant water stress and reduced water availability. Under these conditions, additional adaptation measures are required considering their interactions and trade-offs regarding water security. PMID- 30445334 TI - Child protection reports and removals of infants diagnosed with prenatal substance exposure. AB - BACKGROUND: A frequent response for prenatal substance exposure (PSE) is intervention by child protective services (CPS). Previous research has examined differences in reports to CPS regarding PSE by substance exposure and by maternal race. However, little is known regarding the frequency of immediate removals by CPS relating to PSE and maternal race. METHODS: We investigated hospital reports to CPS and CPS removals of PSE infants by using linked birth, hospital discharge, and CPS records for all children born in Washington State between 2006 and 2013 (N = 760,863). We identified PSE using diagnostic codes, calculated prevalence by substance type and maternal race, and tested for differences by interactions of race and substance using multinomial logistic regression. RESULTS: Prevalence of PSE births varied by race with 8.1% of Native American, 2.8% of black, 1.9% of white, and 0.8% of Hispanic births diagnosed with PSE. Opioids was the most common type of PSE diagnosis at 48.2%. The majority of PSE infants (86.7%) were not removed by CPS but variations by substance type were observed. Of the interactions in the multinomial logistic regression model, only black infants exposed to alcohol were more likely to result in reports to CPS without removal than the referent group of white infants exposed to opioids. CONCLUSIONS: Findings indicate that most infants diagnosed with PSE were not removed by CPS and minority PSE infants were not reported to CPS or removed by CPS more than white infants. Racial differences identified in the prevalence of PSE present opportunities for targeted prevention efforts. PMID- 30445335 TI - Early life adversities and polyvictimization in young persons with sexual behavior problems: A longitudinal study of child protective service referrals. AB - There is scarce research on children and youth with sexual behavior problems (SBP) and their developmental antecedents and the research that does exist is mostly retrospective and correlational. While prior research focused on the central role of sexual victimization, recent research suggests that young persons with SBP are exposed to a series of adversities not limited to child sexual victimization and require multifaceted assessment and intervention using a developmental life course perspective. The current study includes an examination of the complete longitudinal sequence of child protective service (CPS) investigations involving young persons with SBP. The study is based on a sample of 957 youth referred to the CPS in Quebec, Canada. The data include their longitudinal sequence of referrals from birth to age 18. Semi-parametric analyses identified four trajectories of referrals with significant differences in terms of onset, frequency, types of life adversity, and polyvictimization. The trajectories suggest that a range of developmental profiles characterize young persons with SBP, with SBP often occurring after CPS contacts for compromising issues other than sexual victimization, especially parental neglect and serious behavior problems. Of importance, polyvictimization was relatively common for this group throughout childhood and adolescence, which highlights the multiintervention needs of this population. PMID- 30445336 TI - Stewardship as a Fundamental Challenge in Strategic Purchasing of Health Services: A Case Study of Iran. AB - OBJECTIVE: To understand the stewardship challenges in strategic purchasing of health care in Iran's health system from the viewpoints of experts, policy makers, and decision makers. STUDY DESIGN: This was a qualitative study. METHODS: Researchers used interviews and FGDs for collecting and framework analysis for analyzing data. RESULTS: Stewardship challenges were classified into three themes and nine subthemes. A lack of management information systems, a lack of enforcement for rules and laws, a lack of stewardship units, and the conflict of interest between the Ministry of Health and insurers as care purchasers in the health system are among the main challenges identified in the implementation of the strategic purchasing of health care in Iran. CONCLUSION: A strong stewardship is needed for implementing strategic purchasing of health care, which requires participation of all stakeholders. PMID- 30445337 TI - The relationship between obsessive compulsive symptoms and quality of life in Nigerian patients with schizophrenia. AB - BACKGROUND: Obsessive compulsive symptoms (OCS) are relatively common in schizophrenia. Their presence and severity can affect the quality of life (QoL) of schizophrenia patients. OBJECTIVE: This study aimed to determine the effect of OCS on the subjective QoL of the Nigerian outpatients with schizophrenia. It also determines the sociodemographic and clinical factors associated with OCS. METHOD: A cross-sectional study involving 232 patients with schizophrenia completed socio demographic and clinical characteristics questionnaire. OCS was examined with Obsessive Compulsive Inventory (OCI) and QoL was assessed using the brief version of the World Health Organisation Quality of Life questionnaire. RESULT: Most of the schizophrenia patients with OCS were unmarried, unemployed, had an earlier onset, longer duration of illness, and were on higher doses of antipsychotics. They reported lower QoL and more severity of symptoms of schizophrenia when compared to those without OCS. The OCI total and it's subscales had negative weak to moderate relationship with all the domains of the WHOQoL Bref. Being unemployed, dosage of antipsychotic medication, negative symptoms and OCI total were the predictors of the total quality of life among Nigerian schizophrenia patients. CONCLUSION: OCS are very common and reduce QoL of schizophrenia patients. Hence, there is a need to routinely screen patients with schizophrenia for OCS and manage them appropriately. PMID- 30445338 TI - The potential of natural product vs neurodegenerative disorders: In silico study of artoflavanocoumarin as BACE-1 inhibitor. AB - Increasing evidence suggests the beneficial impact of flavonoid-rich nutrition on normal cognitive function. It has been revealed that flavonoids can slow neurodegenerative processes in situations such as Alzheimer's disease (AD). The beta-secretase (BACE-1) is one of the most studied targets in AD therapy owing to its role in producing Abeta plaques. In fact the unique role of BACE-1 in pathogenesis of neurodegenerative diseases has made it a druggable target to develop anti-AD agents. Taking into account the anti-amyloidogenic and anti oxidative properties, flavonoids have received considerable attention as lead candidates for anti-AD drug discovery projects. In continuation to our interest toward rational exploration of potential anti-AD agents, it was attempted to conduct a combined structure based in silico study and explore pharmacophore of a flavanocoumarin derivative as BACE-1 Inhibitor. Ab initio studies showed that both pseudo-axial and pseudo-equatorial conformers could convert to each other freely at room temperature. Within this study it was revealed that artoflavanocoumarin possess essential pharmacophoric groups to inhibit BACE-1. Considering four different protonation states of BACE-1 as di-deprotonated, diprotonated, protonated Asp32 and protonated Asp228, it was also found that affinity of artoflavanocoumarin toward different protonation states of BACE 1could be ranked as Asp32p-Asp228i > di-deprotonated ~ Asp32i-Asp228p >> diprotonated. PMF study on artoflavanocoumarin showed that it could pass 1.8 kcal/mol free energy barrier from water to DPPC lipid bilayer. Moreover the pros and cons of artoflavanocoumarin as a lead compound were elucidated. PMID- 30445339 TI - Structure-activity relationships for highly potent half-sandwich organoiridium(III) anticancer complexes with C^N-chelated ligands. AB - We herein report the synthesis, characterization, catalytic ability in converting coenzyme NADH to NAD+ and anticancer activity of half-sandwich iridium(III) complexes, [(eta5-Cpxbiph)Ir(C^N)Cl]PF6-, where Cpxbiph = tetramethyl(biphenyl)cyclopentadienyl, C^N = varying imine-N-heterocyclic carbene ligands. The molecular structure of [(eta5-Cpxbiph)Ir(L6)Cl]PF6 (complex Ir6), exhibiting the familiar "piano-stool" geometry, has been authenticated by X-ray crystallography. The anticancer activities of these complexes can be governed via substituent effects of three tunable domains and the ligand substituted variants offer an effective chelate ligand set that distinguishes anticancer activity and catalytic ability. Notably, complex Ir6 displays the greatest cytotoxic activities (IC50 = 0.85 MUM), whose anticancer activity is more approximately 25 fold higher than that of cisplatin. The initial cell death mechanistic insight displays that this group of iridium(III) complexes exerts anticancer effects via cell cycle arrest, apoptosis induction and loss of the mitochondrial membrane potential. In addition, the confocal microscopy imaging shows that the complex Ir6 can damage lysosome. Overall, preliminary structure-activity relationships study and understanding of the cell death mechanism perhaps provide a rational strategy for enhancing anticancer activity of this family of complexes. PMID- 30445340 TI - Cancer risk in socially marginalised women: An exploratory study. AB - BACKGROUND: Cancer is a leading cause of premature death in women worldwide, and is associated with socio-economic disadvantage. Yet many interventions designed to reduce risk and improve health fail to reach the most marginalised with the greatest needs. Our study focused on socially marginalised women at two women's centres that provide support and training to women in the judicial system or who have experienced domestic abuse. METHODS: This qualitative study was framed within a sociological rather than behavioural perspective involving thirty participants in individual interviews and focus groups. It sought to understand perceptions of, and vulnerability to, cancer; decision making (including screening); cancer symptom awareness and views on health promoting activities within the context of the women's social circumstances. FINDINGS: Women's experiences of social adversity profoundly shaped their practices, aspirations and attitudes towards risk, health and healthcare. We found that behaviours, such as unhealthy eating and smoking need to be understood in the context of inherently risky lives. They were a coping mechanism whilst living in extreme adverse circumstances, navigating complex everyday lives and structural failings. Long term experiences of neglect, harm and violence, often by people they should be able to trust, led to low self-esteem and influenced their perceptions of risk and self-care. This was reinforced by negative experiences of navigating state services and a lack of control and agency over their own lives. CONCLUSION: Women in this study were at high risk of cancer, but it would be better to understand these risk factors as markers of distress and duress. Without appreciating the wider determinants of health and systemic disadvantage of marginalised groups, and addressing these with a structural rather than an individual response, we risk increasing cancer inequities by failing those who are in the greatest need. PMID- 30445341 TI - Education system stratification and health complaints among school-aged children. AB - Research shows that the school environment is an important social determinant of health among children and adolescents. However, we know virtually nothing of the health consequences of national education systems and policies, for example the stratification of pupils by academic ability. This study aimed to investigate if education system stratification is related to self-reported psychological and somatic health complaints of pupils aged 11 to 15, and social inequalities in such health complaints. Survey data from the Health Behaviors of School-aged Children (HBSC) survey, covering 33 countries and more than 180 000 pupils in primary and lower secondary school, were used. Multilevel models showed that education system stratification was not associated with the average levels of health complaints of pupils, but cross-level interaction effects showed that stratification moderated the relationship between social background and health complaints, such that inequalities in health complaints were smaller in countries with more stratified systems. Moreover, this moderating effect was mediated by the school learning environment and social relations in school. Specifically, social inequalities in school pressure, academic self-concept, school climate, and school satisfaction were smaller in more stratified education systems, which in turn accounted for smaller inequalities in health complaints in these countries. PMID- 30445342 TI - Modified frailty index predicts postoperative outcomes of spontaneous intracerebral hemorrhage. AB - OBJECTIVES: Frailty is an indispensable concept among elderly. The purpose of this study was to determine the association between modified frailty index (mFI) and the postoperative outcome of surgery for spontaneous intracerebral hemorrhage (sICH). PATIENTS AND METHODS: Outcome measures included an unfavorable outcome (modified Rankin Scale score of 4-6) or mortality at 6-8 months after hemorrhage. The prognostic ability of mFI was assessed by comparing adjusted and nonadjusted effects with the Hemphill's ICH score. The performance of the ICH score combined with mFI was assessed for discriminative ability. RESULTS: In total, 156 patients satisfied the inclusion criteria. Multivariate analyses revealed that higher mFI was significantly associated with an unfavorable outcome (p-value = 0.004) and mortality (p-value < 0.001). Compared with the ICH score alone, the ICH score combined with mFI revealed significantly higher discriminative ability for predicting postoperative outcome. CONCLUSION: mFI was a useful and reliable predictor of postoperative unfavorable outcome for sICH. Frailty may be an important essence to be considered before operation for sICS in the aging society. PMID- 30445343 TI - Cement-augmented anterior odontoid screw fixation in elderly patients with odontoid fracture. AB - OBJECTIVES: Osteoporotic bone predisposes to hardware loosening in patients with odontoid fracture treated with anterior odontoid screw fixation. Cement augmentation is an established method to increase screw anchorage in such cases. The aim of this study was to determine the intra- and perioperative surgical complications of this technique and a comparison with a non-cement augmented group. PATIENTS AND METHODS: During the period January 2012 to November 2017, 24 elderly patients with odontoid fractures and reduced bone mineral density were treated with cement-augmented anterior odontoid screw fixation. Demographic and clinico-anatomical parameters were contemporaneously recorded. A comparison group of 28 elderly patients treated with odontoid screw fixation without cement augmentation was used to determine the difference of bone fusion rate and whether cement-augmentation extended surgery duration. RESULTS: 24 patients (18 female, 6 male) were treated with cement-augmented anterior odontoid screw fixation during the study period. The median patient age was 84 years (IQR 81-86 years). In 6/24 cases, asymptomatic cement leakage occurred. Five of these cases involved prevertebral cement leakage into the longus colli muscle. In the other case, cement leaked into the C2/3 joint. There was no significant difference in the time required to perform cement-augmented anterior screw fixation compared to fixation without cement-augmentation (median 65 min versus 56.5 min; p = .119). After a median follow-up of 11 months, the bony-fusion rate in the cement augmented group was 75% (15/24 patients) versus 50% in the non-cement-augmented group (11/28 patients; p = .096). Revision surgery was necessary in none of the cases in the cement-augmented group and in three cases in the non-cement augmented group (10.7%; p=.048). CONCLUSION: Additional cement augmentation for anterior odontoid fracture repair is a feasible and safe procedure in elderly patients with reduced bone mineral density. Moreover, given that cement augmentation was associated with a trend towards a higher rate of medium-term bony fusion and a lower revision surgery rate, it is a treatment strategy that should be considered in the management of elderly patients with type IIb odontoid fractures. PMID- 30445344 TI - How foresight might support the behavioral flexibility of arthropods. AB - The small brains of insects and other invertebrates are often thought to constrain these animals to live entirely 'in the moment'. In this view, each one of their many seemingly hard-wired behavioral routines is triggered by a precisely defined environmental stimulus configuration, but there is no mental appreciation of the possible outcomes of one's actions, and therefore little flexibility. However, many studies show problem-solving behavior in various arthropod species that falls outside the range of fixed behavior routines. We propose that a basic form of foresight, the ability to predict the outcomes of one's own actions, is at the heart of such behavioral flexibility, and that the evolutionary roots of such outcome expectation are found in the need to disentangle sensory input that is predictable from self-generated motion versus input generated by changes in the outside world. Based on this, locusts, grasshoppers, dragonflies and flies seem to use internal models of the surrounding world to tailor their actions adaptively to predict the imminent future. Honeybees and orb-weaving spiders appear to act towards a desired outcome of their respective constructions, and the genetically pre-programmed routines that govern these constructions are subordinate to achieving the desired goal. Jumping spiders seem to preplan their route to prey suggesting they recognize the spatial challenge and actions necessary to obtain prey. Bumblebees and ants utilize objects not encountered in the wild as types of tools to solve problems in a manner that suggests an awareness of the desired outcome. Here we speculate that it may be simpler, in terms of the required evolutionary changes, computation and neural architecture, for arthropods to recognize their goal and predict the outcomes of their actions towards that goal, rather than having a large number of pre-programmed behaviors necessary to account for their observed behavioral flexibility. PMID- 30445345 TI - Comparative transcriptology reveals effects of circadian rhythm in the nervous system on precocious puberty of the female Chinese mitten crab. AB - In juvenile Chinese mitten crabs, ovarian maturation occurring in the first year is known as precocity, and can cause huge economic losses to crab breeding. To discover the molecular mechanisms underlying the regulation of the nervous system of female precocious crabs, eyestalk, brain, and thoracic ganglion transcriptome data were obtained in normal and precocious crabs via high-throughput sequencing technology. A total of 81, 4276, and 22,684 differentially-expressed genes were obtained from the eyestalk, brain, and thoracic ganglion groups, respectively. Functional analysis showed that these genes were significantly enriched in the categories of nutrition metabolism, immunity, endocrine regulation, and circadian rhythm. In precocious eyestalk, the expression of vrille was up-regulated significantly and the ribosome endocrine function decreased, which may result in the decline of gonad-inhibiting hormone secretion. In precocious brains, the expression of period2 with the function of delaying clock phase was down regulated significantly. In precocious thoracic ganglion, expression changes in circadian rhythm-related genes were very complex, and the precocity of female crabs may be the concrete reflex of integrated actions of many endocrine hormones such as estradiol, ecdysteroid, and juvenile hormone, among others. In addition, we found that the mRNA of vitellogenin was highly expressed in the thoracic ganglion. This study discovered some clock genes and related molecular regulatory mechanisms by the RNA-sequence, which would provide foundational information to further study precocity in female Chinese mitten crabs. PMID- 30445346 TI - Passivity analysis of delayed reaction-diffusion memristor-based neural networks. AB - This paper discusses the passivity of delayed reaction-diffusion memristor-based neural networks (RDMNNs). By exploiting inequality techniques and by constructing appropriate Lyapunov functional, several sufficient conditions are obtained in the form of linear matrix inequalities (LMIs), which can be used to ascertain the passivity, output and input strict passivity of delayed RDMNNs. In addition, the passivity of RDMNNs without any delay is also considered. These conditions, represented by LMIs, can be easily verified by virtue of the Matlab toolbox. Finally, some illustrative examples are provided to substantiate the effectiveness and validity of the theoretical results, and to present an application of RDMNN in pseudo-random number generation. PMID- 30445347 TI - Maternal anemia and pediatric neurological morbidity in the offspring - Results from a population based cohort study. AB - OBJECTIVE: Maternal anemia (Hemoglobin, <11 mg/dl) has been shown to affect fetal growth and pregnancy outcome. We aimed to study a possible association between maternal anemia and the risk for neurological morbidity in the offspring, during a follow-up period of up to 18 years. STUDY DESIGN: A population-based cohort analysis was performed at the Soroka University Medical Center (SUMC), a single regional tertiary center comparing total and specific subtypes of neurological morbidities associated with hospitalizations among children stratified by three maternal post-partum hemoglobin categories: >=11 mg/dl (no anemia); 11.0 mg/dl > Hb >= 7 mg/dl (mild-to-moderate anemia) and <7 mg/dl (severe anemia). Data on pregnancy course and outcome, and later offspring hospitalizations, were compared between the three study groups. All singleton deliveries between the years 1991 2014 were included in the analysis, and congenital malformations were excluded. A Kaplan-Meier survival curve was used to compare cumulative hospitalization incidence based on maternal anemia status, and a Weibull survival multivariable hazard model was constructed to adjust for confounding variables. RESULTS: The study population included 217,358 deliveries of which 50.6% were in mothers who were not anemic, 49.0% in mothers with moderate anemia and 0.4% in mothers with severe anemia. During the follow up period (0-18 years, median 10.22 years), 2.1% of offspring were hospitalized with a neurological diagnoses. Neurological hospitalization incidence decreased from 2.95/1000 person years, in the severe anemia group, to 2.32/1000 person years and 2.01/1000 person years, among the mild-to-moderate and no anemia groups, respectively (p = 0.007). The association between maternal anemia and offspring long-term pediatric neurological morbidity remained significant in a Weibull hazards model controlled for gestational age, delivery mode, SGA and insufficient prenatal care (adjusted HR 1.55; 1.05-2.31 and adjusted HR 1.13; 1.06-1.20; among the severe and mild-to-moderate anemia, vs. no anemia, respectively). CONCLUSION: Children born to anemic mothers are at an increased risk for pediatric neurological-related hospitalizations. PMID- 30445349 TI - Novel Ag2O nanoparticles modified MoS2 nanoflowers for piezoelectric-assisted full solar spectrum photocatalysis. AB - The separation of photoinduced electrons and holes can enhance the photocatalytic properties of photocatalysts. A piezoelectric field is created inside piezoelectric materials, such as ZnO and MoS2, by applying strain. The electrons and holes become separated under the driving force of the piezoelectric field. Here, we propose combining piezoelectric MoS2 nanoflowers (NFs) and full solar response Ag2O nanoparticles (NPs) to form a MoS2@Ag2O heterostructure and achieve high efficiency full solar (UV, visible, and near-infrared) photocatalysis. Under both full solar light and ultrasonic excitation, the MoS2@Ag2O heterostructures can rapidly degrade methyl orange (MO) in aqueous solution. A built-in electric field is formed by the spontaneous polarization potential of the MoS2 NFs during this process, and an ultrasonic wave as a driving force can consecutively change the potential created by the piezoelectric effect. Under light irradiation, electrons and holes are generated in the Ag2O NPs, and the photogenerated electrons and holes with opposite signs in the two Ag2O NPs at the two surfaces of the MoS2 NFs, can be separated respectively, along the spontaneous polarized direction. Therefore, the piezoelectric effect-induced enhancement of carrier separation under ultrasonic excitation can improve the full solar photocatalytic performance of the MoS2@Ag2O heterostructures. PMID- 30445348 TI - Fe3O4@MoS2/RGO as an effective nano-electrocatalyst toward electrochemical hydrogen evolution reaction and methanol oxidation in two settings for fuel cell application. AB - A three-component nano-electrocatalyst, magnetite coated molybdenum disulfide hybridized with reduced graphene oxide (Fe3O4@MoS2/RGO), is synthesized by a two step hydrothermal method. This catalyst is applied as an effective substitution for the platinum catalyst in methanol oxidation and hydrogen evolution reactions. Cyclic voltammetry, chronoamperometry, and linear sweep voltammetry are used to evaluate the performance of the electrocatalyst in acidic and basic media. The results of methanol oxidation reaction on the hybridized nano-electrocatalyst showed good electrocatalytic properties with considerable diffusion currents. This fact is confirmed by the Tafel plots and the calculated kinetic parameters of electron transfer. Fe3O4@MoS2/RGO showed an anodic transfer coefficient and exchange current of 0.464 and 4.80 * 10-8, respectively that are higher than Fe3O4/RGO. The presence of the porous MoS2 in catalyst has a key effect on supplying electroactive sites for electron transfer. Also, the high actual surface area obtained for the hybridized nano-electrocatalyst (A = 0.0295 cm2). The maximum power density of 35.03 mW cm-2 obtained for a single cell containing the prepared hybridized catalyst as the anode which shows a competitive feature of the synthetic catalyst compared to other reports. Furthermore, the synthetic catalyst shows the low-value overpotential of 108 mV and Tafel slope of 48 mV dec 1 during the hydrogen evolution process in acidic media. This is attributed to the synergistic effect between Fe3O4 and MoS2 and also increase the electron transfer rate due to adding conductive RGO to the catalyst. The results show that the synthetic nanocatalyst can have promising applications for hydrogen evolution and methanol oxidation reactions. PMID- 30445350 TI - Development of high flux nanofiltration membranes through single bilayer polyethyleneimine/alginate deposition. AB - The aim of this study is to prepare high flux, stable, antifouling nanofiltration membranes through single bilayer polyelectrolyte deposition. To this end, a tight ultrafiltration support membrane was prepared from a polysulfone/sulfonated polyethersulfone blend. Deposition of a polyethyleneimine and alginate pair on this support has reduced the molecular weight cut off from 6 kDa to below 1 kDa. The pure water permeability and polyethylene glycol 1000 rejection of the coated membrane were found to be 15.5 +/- 0.3 L/m2.h.bar and 90 +/- 0.6%, respectively, by setting the deposition pH for each layer to 8 and the ionic strengths to 0.5 M and 0 M. This membrane has exhibited significantly higher permeability than commercial membranes with the same molecular weight cut off, retaining 98% of the initial flux during 15 h filtration of bovine serum albumine. In addition, the membrane has been able to completely remove anionic dyes from aqueous solution by showing 99.9% retentions to Reactive red 141, Brilliant blue G and Congo red with a 2 bar transmembrane pressure. High flux and membrane stability in acidic and salty environments have been achieved when deposition conditions favor high adsorption levels for the first layer and strong ionic cross-linking between the carboxyl group on the alginate and the amine groups on the polyethyleneimine. PMID- 30445351 TI - The enhanced NO2 sensing properties of SnO2 nanoparticles/reduced graphene oxide composite. AB - Multiple techniques were utilized to characterize the structure and morphology of the SnO2/reduced graphene oxide (rGO) composite, in which the composite was prepared by a facile one-pot microwave-assisted hydrothermal method. As a result, SnO2 nanoparticles with diameters of 3-5 nm were anchored uniformly on both sides of the rGO sheets. Meanwhile, a series of resistive-type gas sensors based on SnO2/rGO composite and pure SnO2 were fabricated and tested for analyzing the effects on introducing rGO. The results revealed that, the composite exhibited obviously enhanced gas sensing properties towards NO2 with high response, fast response and recovery speed, and good selectivity and reproducibility. At 75 degrees C, the response of the composite to 350 ppb NO2 was about 6.6 times of that to pure SnO2. In addition, the response and recovery time of the sensor was greatly reduced from 39.2/54.7 to 6.5/1 min, and the detecting limit of the sensor was even as low as 50 ppb. Provided with the enlarged surface area and local p-n heterojunctions, the synergistic effect of SnO2 nanoparticles and rGO contributed to the enhanced gas sensing properties of SnO2/rGO composite. PMID- 30445352 TI - The reduction of Cr(VI) to Cr(III) mediated by environmentally relevant carboxylic acids: State-of-the-art and perspectives. AB - The detoxification process mediated by carboxylic acids (CAs) has received considerable spotlights since CAs are clean reagent and ubiquitous in the natural environments and effluents. Here, we present an exhaustive review on surface bound/dissolved metals-catalyzed Cr(VI) reduction by CAs and CAs-mediated Cr(VI) reduction by many highly/poorly reductive reagents. The overall mechanisms of Cr(VI) reduction are mainly associated with the coordination of CAs with surface bound/dissolved metals or Cr(VI,V,IV) species and the electron donating abilities of CAs. Additionally, the general decays of intermediate Cr(V,IV) complexes are clearly emerged in the Cr(VI) reduction processes. The performance of various reaction systems for Cr(VI) reduction that is greatly dependent on the operation parameters, including solution pH, reagent concentration, temperature, coexisting ions and gas atmosphere, are also critically commented. From the study survey presented herein, CAs-mediated Cr(VI) reduction processes exhibit good potential for remediation of various Cr(VI)-contaminated waters/sites. However, there is still a need to address the remained bottle-necks and challenges for the remediation of Cr(VI) mediated by CAs in the related natural attenuation cases and the treatment of industrial effluents. Overall, the present review offers the comprehensive understanding of the Cr(VI) reduction mediated by CAs and provide the engineering community with the guidelines for Cr(VI) remediation in the real world applications. PMID- 30445353 TI - The role of data source selection in chemical hazard assessment: A case study on organic photovoltaics. AB - Chemical hazard assessment (CHA), designed to evaluate the inherent hazard of chemicals used in everyday consumer products, is gaining in popularity and rigor. Although CHA is being more commonly used by industry and government organizations, there is limited information in the academic literature on the merits and limitations of CHA methods. In the current study, the significance of the need to use multiple data sources to successfully complete a CHA is explored. Specifically, a case study approach is used in which more than one hundred organic substances used in the synthesis of organic solar cells are evaluated using the GreenScreen(r) for Safer Chemicals framework as the basis for the CHA. Seven data sources, including three chemical-oriented, two hazard-trait-oriented, and two predictive data sources, are utilized to minimize data gaps and allow for complete assessments for most of the chemicals of interest. Findings from sensitivity analysis using single data sources and combinations of data sources highlight that the CHA outcomes can vary considerably as a function of data sources used, which highlights the importance of identifying and/or creating more comprehensive and standardized data sources. PMID- 30445354 TI - Allobodo chlorophagus n. gen. n. sp., a Kinetoplastid that Infiltrates and Feeds on the Invasive Alga Codium fragile. AB - A novel biflagellate protist that consumed chloroplasts inside material of the invasive marine green alga Codium fragile was reported from the U.S. east coast in 2003. We observed a similar association in C. fragile from five sites in Nova Scotia, Canada during 2013 and 2014. After incubating Codium fragments for 2-3 days, some utricles and filaments contained numerous chloroplast-consuming cells. Transmission electron microscopy (TEM) confirmed that these were kinetoplastids with a pankinetoplast, large electron-dense droplets in the cytoplasm and a connective between the paraxonemal rod bases, but no conspicuous para cytopharyngeal rod, all consistent with U.S. material observed in 2003. The ITS1 5.8S rRNA-ITS2 sequences from 13 Nova Scotia isolates were identical. SSU rRNA gene phylogenies placed the Codium-associated kinetoplastid in neobodonid clade '1E'. Clade 1E likely contains no previously described species, and branches outside all other major neobodonid groups, either as their sister or as a separate lineage, depending on rooting. These results indicate that the kinetoplastid represents a single species that merits a new genus (and family), and we describe it as Allobodo chlorophagus n. gen., n. sp. The lack of evidence for food sources other than Codium is consistent with a parasitic association, but other possibilities exist (e.g. necrotrophy). PMID- 30445355 TI - Altered profiles and metabolism of l- and d-amino acids in cultured human breast cancer cells vs. non-tumorigenic human breast epithelial cells. AB - Herein we describe for the first time the endogenous levels of free l-and d-amino acids in cultured human breast cancer cells (MCF-7) and non-tumorigenic human breast epithelial cells (MCF-10A). d-Asp and d-Ser, which are co-agonists of the N-methyl-d-aspartate (NMDA) receptors, showed significantly elevated levels in MCF-7 cancer cells compared to MCF-10A cells. This may result from upregulated enzymatic racemases. Possible roles of these d-amino acids in promoting breast cancer proliferation by regulating NMDA receptors were indicated. d-Asn may also be able to serve as exchange currency, like specific l-amino acids, for the required uptake of essential amino acids and other low abundance nonessential amino acids which were elevated nearly 60 fold in cancer cells. The relative levels of specific l- and d-amino acids can be used as malignancy indicators (MIs) for the breast cancer cell line in this study. High MIs (>50) result from the increased demands of specific essential amino acids. Very low MIs (<1) result from the increased demands of specific d-amino acids (i.e., d-Ser, d-Asp) or the cellular release of amino acid exchange currency (i.e., l- and d-Asn) used in the upregulated amino acid antiporters to promote cancer cell proliferation. PMID- 30445356 TI - LC-MS/MS analysis of the plasma concentrations of a cocktail of 5 cytochrome P450 and P-glycoprotein probe substrates and their metabolites using subtherapeutic doses. AB - Drug transporters and CYP enzymes are important sources of pharmacokinetics (PK) variability in drug responses and can cause various pharmacological and toxicological consequences, leading to either toxicity or an insufficient pharmacological effect. In recent years, the cocktail approach was developed to determine in vivo CYP and transporters activities, but these approaches are somewhat limited. We described the development and validation of three sensitive and specific LC-MS/MS assays for the determination of P-gp and major human CYP isoenzyme activities following oral administration of a drug cocktail of subtherapeutic doses (lower than 10 times) of caffeine (CAF), omeprazole (OME), losartan (LOS), midazolam (MDZ), metoprolol (METO) and fexofenadine (FEX) in healthy volunteers. The three validated methods were selective for all tested analytes. No interference or matrix effect was observed for the mass transition and retention times for all compounds monitored. Additionally, assays were linear over a wide range, and limits of quantification varied between 0.01-5 ng/mL plasma. The coefficients of variation obtained in the precision studies and the inter- and intra-assay accuracies were less than 15%, guaranteeing the reproducibility and repeatability of the results. All substrates and metabolites were stable in plasma during freeze-thaw cycles. Three healthy volunteers were selected based on genotyping for CYP2C9, CYP2C19 and CYP2D6. One volunteer was genotyped as an extensive metabolizer (EM) for all tested CYP isoforms, one volunteer was genotyped as a poor metabolizer (PM) for the CYP2C9 isoform (CYP2C9*3/*3), and one volunteer was genotyped as a PM for the CYP2D6 isoform (CYP2D6*4/*4). The methods allowed the quantification of all analytes over the entire sampling period (12 h) in all studied genotypes. Thus, the analytical methods described here were sufficiently sensitive for use in low-dose pharmacokinetic studies. PMID- 30445357 TI - Undiagnosed impacted knife blade from a penetrative orbital injury: A case report. AB - INTRODUCTION: Impacted foreign bodies in the complex maxillofacial region is uncommon and their safe removal is a challenge. CASE PRESENTATION: The authors report an unusual case of a 41 year old male patient who suffered from violence related orbital trauma with a knife. The presence of this foreign body was not diagnosed for a period of 20 months. After proper clinical and radiologic examination it was localized and extracted in the theater in a safe controlled manner. Although the tip of the blade was left in situ, the patient had a rapid uneventful recovery and follow up. DISCUSSION: The path of penetration of the foreign body in presented case didn't follow the predicted patterns of orbital injury described in literature. A dilemma exists as to how aggressive such injuries should be managed. Thus the surgical approach implemented for retrieving the current foreign body was highlighted. CONCLUSION: Radiographs are a crucial element for early diagnosis and proper management of foreign body injuries. Rapid postoperative recovery can be achieved with simple safe surgical retrieval maneuvers. PMID- 30445359 TI - Cancers related to lifestyle and environmental factors in France in 2015. AB - BACKGROUND: Cancer is a major cause of premature illness and death in France. To quantify how cancer prevention could reduce the burden, we present estimates of the contribution of lifestyle and environmental risk factors to cancer incidence in France in 2015, comparing these with other high-income countries. METHOD: Prevalences of, and relative risks for tobacco smoking, alcohol consumption, inadequate diet, overweight and obesity, physical inactivity, exogenous hormones, suboptimal breastfeeding, infectious agents, ionising radiation, air pollution, ultraviolet exposure, occupational exposures, arsenic in drinking water and indoor benzene were obtained to estimate the population attributable fraction (PAF) and the number of attributable cancers by the cancer site and sex. RESULTS: In 2015, 41% (or 142,000 of 346,000) of all new cancers diagnosed in France could be attributed to the aforementioned risk factors. The numbers and PAF were slightly higher in men than in women (84,000 versus 58,000 cases and 44% versus 37%, respectively). Smoking (PAF: 20%), alcohol consumption (PAF: 8%), dietary factors (PAF: 5%) and excess weight (PAF: 5%) were the most important factors. Infections and occupational exposures each contributed to an additional 4% of the cancer cases in 2015. CONCLUSION: Today, two-fifths of cancers in France are attributable to preventable risk factors. The variations in the key amenable factors responsible in France relative to other economically similar countries highlight the need for tailored approaches to cancer education and prevention. Reducing smoking and alcohol consumption and the adoption of healthier diet and body weight remain important targets to reduce the increasing number of new cancer patients in France in the decades to follow. PMID- 30445358 TI - Self-expanding metal stent restenosis in obstructive colon diverticulitis mimicking colon cancer: A case report. AB - INTRODUCTION: The self-expanding metal stent (SEMS) has been used in malignant colorectal obstruction as a bridge to surgery or for palliative treatment. We report a case of obstructive descending colon diverticulitis in-stent restenosis, which is difficult to distinguish from colon cancer. PRESENTATION OF CASE: A 48 year-old man presented with abdominal pain. Computed tomography demonstrated a segment of thickened wall in the descending colon with near-complete obstruction. Colonoscopy revealed stenosis over the entire circumference of the descending colon. Biopsy revealed no malignant findings. SEMS was inserted to improve bowel obstruction. However, bowel obstruction did not improve, and stent-in-stent insertion was performed. Because colon cancer could not be completely excluded, left hemicolectomy with lymph node dissection was performed. The pathological examination revealed colon diverticulitis and no malignant finding. DISCUSSION: Benign colorectal diseases can present with symptoms similar to those of obstructive colorectal cancer. As a result, it was benign colorectal stenosis, but it was thought that resection should be considered when the malignant lesion is suspected. The use of SEMS in benign colorectal disease has been reported a few. Reinsertion of the stent for restenosis, in bridge to surgery, was also considered useful from the viewpoint of avoiding emergent operation and reducing complications. CONCLUSION: For colon stenosis suspected of malignant disease, it was thought that resection by inserting SEMS should be taken into consideration even for benign disease as a result. PMID- 30445360 TI - Characterization of fluorescence foulants on ultrafiltration membrane using front face excitation-emission matrix (FF-EEM) spectroscopy: Fouling evolution and mechanism analysis. AB - The understanding of fouling behavior and mechanism is critical for fouling control in membrane processes. This study adopted a novel fluorescence front-face excitation-emission matrix (FF-EEM) approach to characterize the fluorescence foulants deposited on membrane surface. Methods for quantifying protein and humic substances deposited on ultrafiltration (UF) membrane were established. Foulants deposited on the membrane surface during the UF of model foulants (bovine serum albumin (BSA) and humic acids (HA)) and wastewater effluent organic matter (EfOM) were quantified using the FF-EEM and liquid EEM coupled with mass balance calculation. The foulants mass data obtained by FF-EEM were further used to analyze fouling mechanism involved in UF. The FF-EEM based method was more accurate than the liquid EEM based method, as the problems associated with liquid EEM based method (such as the error propagation in the mass balance calculation and the ineffectiveness of inner filter correction) were avoided in FF-EEM based method. The fouling resistance did not correlate well with the amount of foulants, as the major fouling mechanism instead of the mass of foulants mainly determined the extent of fouling. This work demonstrated FF-EEM could be a powerful tool for investigating fouling evolution and fouling mechanism in UF process. PMID- 30445361 TI - Detection and monitoring of in vitro formation of salicylic acid from aspirin using fluorescence spectroscopic technique and DFT calculations. AB - Acetylsalicylic acid commonly termed as aspirin (AS) is a well known antipyretic and anti-inflammatory drug which can also be used to reduce death risks due to heart attack. In addition to this, it also exhibits some adverse effect such as gastrointestinal, tinnitus, Reye's syndrome. The side effects of AS such as gastrointestinal ulcer, tinnitus and Reye's syndrome are caused due to conversion of AS into its active metabolite salicylic acid (SAL). Conversion of AS into SAL has been investigated generally at basic pH. Since the pH of Gastrointestinal tract is on average neutral ranging from 6.5-7.4. Therefore in the present research work, in vitro conversion of AS to SAL was detected at neutral pH in both aqueous medium and human blood serum samples by time series fluorescence measurements and DFT study. The SAL obtained from AS at neutral pH was observed to be stable for ~ 6 and ~ 4 days in aqueous medium and blood serum, respectively. The mechanism of conversion of AS into SAL was investigated using the transition state theory employing density functional theory (DFT). On the basis of DFT calculation the in vitro formation of SAL from AS at neutral pH was found to involve two intermediate transition states. PMID- 30445362 TI - Accumulation of protoporphyrin IX in medulloblastoma cell lines and sensitivity to subsequent photodynamic treatment. AB - BACKGROUND: Medulloblastoma (MB) is the most common malignant primary brain tumor of childhood. High risk patients still have a poor outcome, and especially young patients suffer from standard therapy induced sequelae. Therefore, other therapeutic options need to be explored. In glioblastoma (GBM), application of 5 aminolaevulinic acid (5-ALA) results in selective accumulation of protoporphyrin IX (PPIX) in the tumor cells, which can be exploited during fluorescence-guided surgery to increase the extent of resection or for photodynamic therapy (PDT) induced phototoxicity. It is not entirely clear, whether MB cells accumulate PPIX and are sensitive to PDT. METHODS: Human MYC-amplified (Med8A and D283) and non amplified (UW228-2 and ONS76) MB cell lines were incubated for 2, 4 or 6 h with increasing doses (0-100 MUg/ml) of 5-ALA, and PPIX accumulation was determined by flow cytometry. To assess sensitivity to 5-ALA/PDT, cells were incubated with 5 ALA and subsequently exposed to laser light of 635 nm wavelength (18.75 J/cm2). After an additional 24 h culture period, viability of cells was quantified using the WST-1 assay. Expression of ferrochelatase was detected by reverse transcription and quantitative polymerase chain reaction. Ferrochelatase activity was quantified by measuring the enzymatic conversion of PPIX to zinc protoporphyrin. Expression of the ABCG2 transporter protein CD338 was detected by flow cytometry. RESULTS: All MB cell lines showed a time- and dose-dependent accumulation of PPIX after exposure to exogenous 5-ALA and became sensitive to 5 ALA/PDT-induced phototoxicity. PPIX accumulation was reduced compared to U373 GBM cells at shorter incubation periods and limiting 5-ALA doses. Moreover, not all MB cells became PPIX positive and overall phototoxicity was lower in the MB cell lines. Notably, the MYC-amplified MB cells demonstrated a more pronounced photosensitivity compared to their non-amplified counterparts. There was no difference in expression of ferrochelatase, but enzymatic activity appeared to be reduced in the MB cells compared to U373 GBM cells, whereas CD338 was expressed on the MB cells only. CONCLUSION: Medulloblastoma cell lines accumulate PPIX after application of 5-ALA and become sensitive to PDT, associated with low ferrochelatase expression and activity. Photosensitivity is more pronounced in MYC-amplified cell lines. In contrast to GBM cells, however, PPIX accumulation appears to be reduced, restricted to a subset of cells and associated with lower photosensitivity of the MB cell lines, possibly due to expression of the ABCG2 transporter protein CD338 on MB cells. PMID- 30445363 TI - The utility of anti-SOX2 antibodies for cancer prediction in patients with paraneoplastic neurological disorders. AB - Antibodies to SOXB1 proteins in patients with paraneoplastic disorders are associated with small-cell lung cancer (SCLC), particularly in Lambert-Eaton myasthenic syndrome (LEMS). We aimed to establish if SOX2 antibodies could be used to identify SCLC and other tumours found in a range of paraneoplastic disorders and controls. SOX2 antibodies were detectable in 61% of patients with LEMS-SCLC, and in other paraneoplastic disorders, such as opsoclonus-myoclonus and paraneoplastic cerebellar degeneration, only when there was an underlying SCLC. SOX2 antibodies are specific (>90%) markers for SCLC, but are rarely found in patients with other tumours, whether neurological symptoms are present or not. PMID- 30445364 TI - How is the formation of microthrombi after traumatic brain injury linked to inflammation? AB - Traumatic brain injury (TBI) is characterized by mechanical disruption of brain tissue due to an external force and by subsequent secondary injury. Secondary brain injury events include inflammatory responses and the activation of coagulation resulting in microthrombi formation in the brain vasculature. Recent research suggests that these mechanisms do not work independently. There is strong evidence that FXII and platelet activation connects both, inflammation and the formation of microthrombi. This review summarizes the current knowledge on posttraumatic microthrombus formation and its link to inflammation. PMID- 30445365 TI - Shock absorbing ability in healthy and damaged cartilage-bone under high-rate compression. AB - Articular cartilage is a soft tissue that distributes the loads in joints and transfers the compressive load to the underlying bone. At high rate and magnitudes of mechanical loading, cartilage and subchondral bone together are susceptible to damage. In addition, any disruption to the cartilage's structure, caused by injury, trauma or disorder such as osteoarthritis (OA), can alter the mechanism of load transfer from the cartilage to the underlying bone. Changes in the cartilage structure can also alter the ability of cartilage-bone to absorb and dissipate the impact energy. To investigate the effects of cartilage degradation on cartilage-bone shock absorption ability, the top 50% of the cartilage thickness was removed (modified cartilage) to mimic the cartilage thickness reduction in Grade III cartilage lesion and the remaining cartilage bone unit (modified cartilage-bone) was compressed at high-rate (4% strain at 5 Hz). High-speed camera and microscope were used to capture microscopic deformation, and digital image correlation technique (DIC) employed to quantify the deformation of cartilage and bone. The mechanical properties (i.e. stiffness, strain, absorbed and dissipated energies) of cartilage and bone were calculated before and after the removal of the top 50% of the cartilage thickness, consisting of both the superficial tangential zone (STZ) and part of the middle zone of the cartilage. The results showed a significant degradation in the mechanical properties of the cartilage-bone unit after the removal of the top 50% cartilage thickness. The stiffness of the modified cartilage reduced significantly (by ~39%) and energy absorption in underlying bone increased by 32%, which can make the bone more vulnerable to damage in the modified cartilage bone unit. In addition, the energy dissipation in the modified cartilage-bone unit was also increased by approximately 14%. These changes in mechanical properties suggest a crucial role of the STZ and middle zone (within the top 50% cartilage thickness) in protecting the underlying bone from the severe compressive impact loading. Results also indicated that under physiological contact stress of 7 MPa, strain in damaged cartilage was increased by 3.22% without affecting the mechanical behaviour of the underlying bone. PMID- 30445366 TI - Mechanical behaviour of extremely tough TZP bioceramics. AB - Tetragonal Zirconia Polycrystals (TZP) is attractive for structural biomedical applications because of their excellent mechanical properties at room temperature, which include high strength, fracture toughness and wear resistance. In this work, zirconia stabilized with Y or Yb or Yb+Nd, all containing 0.5 vol.% Al2O3, were prepared by hot-pressing (HP) at 50-60 MPa and sintered at 1300-1350 degrees C for 1 h. Microstructural features, phase composition and mechanical properties were investigated. The strength was measured by 4-point bending (4P B), piston-on-three-balls (P-3B) and three-balls-on-three-balls (3B-3B) biaxial methods. Toughness was determined by indentation strength in bending (ISB). Vickers hardness (Hv) and the Young modulus (E) were also estimated. Preliminary aging behaviour (LTD) was also here considered. Measured biaxial strength was significantly higher (until 1.83 times) than the uniaxial one because of the tetragonal to monoclinic (t-m) zirconia phase transformation which is strongly influenced by the loading configuration. The variation of the strength with the testing method is attributed to the compressive stresses generated by the phase transformation which is particularly favoured under P-3B tests and also to the calculation of the stresses from elastic theories. LTD preliminary tests showed excellent aging resistance of 3Yb-0.5A ceramics. PMID- 30445367 TI - The mechanical response of commercially available bone simulants for quasi-static and dynamic loading. AB - Bone is a complex hierarchal structured material with varying porosity and mechanical properties. In particular, human cranial bone is essentially a natural composite consisting of low porosity outer and inner tables and a cancellous interior, or diploe. Experimental studies of biomechanically accurate cranial bone analogues are of high importance for biomechanical, forensics, and clinical researchers, which could improve the understanding and prevention of traumatic injury. Many reported studies use commercially available bone surrogates to draw biomechanical and forensics conclusions; however, their mechanical properties are not tabulated over a range of strain rates. This study elucidates the mechanical viability of three leading commercially available bone surrogates, i.e. Synbone, Sawbone, and Bonesim, over a large range of strain rates (10-3 to 103 s-1). Quasi static compression testing was conducted using a universal testing machine and a Split-Hopkinson Pressure bar system equipped with high-speed video was used to determine the dynamic mechanical behavior of these materials. Micro-computed X ray tomography (XRT) were performed on each material to investigate their pore structures and distributions. All materials exhibited strain rate dependent strength behavior, particularly at high loading rates (>=103 s-1). The Young's modulus was found to increase with strain rate from 10-3 to 10-1 s-1 for transversely and longitudinally loaded surrogate materials except for Synbone and the higher density Bonesim. The higher density Bonesim was determined to be the most suitable cranial bone simulant tested based on a combination of transverse Young's Modulus (1500 MPa), yield strength (19 MPa), ultimate strength (49 MPa), and ultimate strain (17%). These materials show limited promise for applications where the measured elastic properties and strengths are of interest. PMID- 30445368 TI - Effect of tribochemical silica coating or multipurpose products on bonding performance of a CAD/CAM resin-based material. AB - OBJECTIVES: Nanocomposite ceramics have been widely used in clinical practice; however, a standard, recommended bonding protocol has not been determined yet. The present study aimed to evaluate application of tribochemical silica coating or multipurpose products on bonding performance of a CAD/CAM resin-based material (known as nanocomposite ceramic). MATERIALS AND METHODS: Nanocomposite ceramic specimens were fabricated and assigned into 11 groups to build bonded specimens (n = 15) according to surface treatments (none; air particle abrasion with 50-MUm alumina followed by application of a silane coupling agent or a universal adhesive; tribochemical silica coating followed by application of a silane coupling agent or a universal adhesive) and resin luting cements (conventional resin cement, RelyX Veneer; self-adhesive resin cement RelyX Unicem) used. Micro shear bond strength (MU-SBS) was measured after 24-h water storage or ageing with 10,000 thermocycles plus additional 90-d water storage. Surface roughness after alumina air abrasion and tribochemical silica coating were determined using a profilometer. Surface morphology and element variation were observed by using a scanning electron microscope (SEM)/energy dispersion spectrum (EDS). X-ray photoelectron spectroscopy (XPS) was used to characterize nanocomposite ceramic powders conditioned with silane coupling agent or the universal adhesive used in the MU-SBS test. The nanocomposite ceramic plates received alumina air abrasion, tribochemical silica coating, or without, were determined using X-ray diffraction (XRD). RESULTS: Nanocomposite ceramic treated with alumina air abrasion achieved the highest surface roughness, followed by those treated with tribochemical silica coating. Newly formed Si-O-Si bonds on the nanocomposite ceramic surface were detected by XPS after treatment with silane coupling agent or universal adhesive, and a Zr-O-P bond was detected after treating with universal adhesive. MU-SBS was significantly affected by bond strategies and ageing. Ageing by thermocycling and water storage significantly decreased MU-SBS. MU-SBS values derived by use of a universal adhesive or self-adhesive resin cement alone were no lower than the values derived by use of a silane coupling agent alone. Pre silanization further enhanced the bonding improvement of universal adhesive or self-adhesive resin cement. However, tribochemical silica coating failed to provide higher MU-SBS compared with alumina air abrasion. XRD detected no monoclinic zirconia phase after alumina air abrasion or tribochemical silica coating, suggesting that these two roughening methods did not lead to phase transformation of zirconia fillers. CONCLUSIONS: Combination of presilanization and universal adhesives improve resin bonding of nanocomposite ceramics. Tribochemical silica coating is not superior to alumina air abrasion for pretreated nanocomposite ceramics. PMID- 30445369 TI - Mechanical performance of conical implant-abutment connections under different cyclic loading conditions. AB - OBJECTIVES: Conical implant-abutment connections are popular for its anti-bending performance; on the other hand, the torsional and axial forces also play important roles in occlusion. However, so far there were scarce studies on their effects on connection stability. Therefore, this study seeks to investigate the mechanical performance of conical connections under different cyclic loading conditions. METHODS: 15 conical implant-abutment assembles (Cowell Medi, Busan, South Korea) were divided into 3 groups according to different cyclic loadings. In group BTA, the loading condition of the posterior occlusion was simulated (20 200 N, 30 degrees off-axis and 4 mm eccentric to implant axis), generating a bending moment, a torsional moment, and an axial loading. In group BT, a bending moment and a torsional moment of the posterior occlusion were applied (10-100 N, 90 degrees off-axis and 4 mm eccentric to implant axis). In group B, only a bending moment was applied (10-100 N, 90 degrees off-axis and through implant axis). The fatigue testing machine ran at 10 Hz until failure, or to the upper limit of 106 cycles. The fatigue cycles and failure modes were recorded. Besides, the value of the torque loss of the abutment screw, the difference between initial torque and post-load reverse torque, was calculated. The data were statistically analyzed. Morphologies of the abutment conical surface were examined by scanning electron microscopy. RESULTS: In group B and BTA, all samples passed the test (106 cycles). While, in group BT, all abutments generated rotation within 140 cycles, showing significant differences compared to the other two groups (p < 0.001). However, from SEM observations, both group B and BT showed marked fretting wear, indicating obvious micromotion in the connection. Whereas group BTA showed indentation of tight contact, attributed to the axial loading. In terms of the torque loss of the abutment screw, the torque loss in group BT was much more than the other two groups with statistically significant differences (p < 0.05). CONCLUSION: Owing to the effect of the bending moment, marked fretting wear was generated in the conical connections and further led to loss of the anti-torsional ability. However, adding an axial loading could improve their anti-torsional ability significantly. PMID- 30445370 TI - Waterborne and diet-related effects of inorganic and organic fungicides on the insect leaf shredder Chaetopteryx villosa (Trichoptera). AB - It is well-documented that fungicides can affect crustacean leaf shredders via two effect pathways, namely waterborne exposure and their diet (i.e., via dietary uptake of fungicides adsorbed to leaf material and an altered microorganism mediated food quality). As a consequence of different life history strategies, the relevance of these effect pathways for aquatic shredders belonging to other taxonomic classes, for instance insects, remains unclear. Therefore, we investigated waterborne and diet-related effects in larvae of the caddisfly leaf shredder Chaetopteryx villosa (Insecta: Trichoptera) and compared our observations to previous reports on effects in adults of the crustacean leaf shredder Gammarus fossarum (Malacostraca: Amphipoda). We assessed acute waterborne effects of an organic fungicide mixture (OFM) and the inorganic fungicide copper (Cu) on the leaf consumption (n = 30) of the fourth-/fifth instar larvae of C. villosa and their food choice (n = 49) when offered leaf material, which was either conditioned in presence or in absence of the respective fungicide(s). Moreover, the larval leaf consumption (n = 50) and physiological fitness (i.e., growth as well as lipid and protein content) were examined after subjecting C. villosa for 24 days towards the combination of both effect pathways at environmentally relevant concentrations. G. fossarum and C. villosa exhibited similar sensitivities and the same effect direction when exposed to the OFM (either waterborne or dietary pathways). Both shredders also showed the same effect direction when exposed to dietary Cu, while with regards to mortality and leaf consumption C. villosa was less sensitive to waterborne Cu than G. fossarum. Finally, as observed for G. fossarum, the combined exposure to OFM over 24 days negatively affected leaf consumption and the physiology (i.e., growth and lipid reserves) of C. villosa. While no combined Cu effects were observed for larval leaf consumption, contrasting to the observations for G. fossarum, the physiology of both shredders was negatively affected, despite partly differing effect sizes and directions. Our results suggest that C. villosa and G. fossarum are of comparable sensitivity towards waterborne and diet-related organic fungicide exposure, whereas the trichopteran is less sensitive to Cu based waterborne fungicide exposure. However, when both pathways act jointly, organic and inorganic fungicides can affect the physiology of shredder species with completely different life history strategies. As caddisflies represent a subsidy for terrestrial consumers, these observations indicate that fungicide exposure might not only affect aquatic ecosystem functioning but also the flux of energy across ecosystem boundaries. PMID- 30445371 TI - Maternal violence experiences and risk of postpartum depression: A meta-analysis of cohort studies. AB - BACKGROUND: Most of original studies indicated maternal violence experiences is associated with adverse obstetric outcomes, to date, but it is not clear that the association of maternal violence experiences and the risk of postpartum depression (PPD). We aimed to assess the association between maternal violence experiences and risk of developing PPD by performing a meta-analysis of cohort studies. METHODS: PubMed, Google Scholar, Cochrane Libraries and Chinese databases were searched through December 2017 to identify studies that assessed the association between violence and PPD. Meta-analysis was conducted by the RevMan software and Stata software. Potential heterogeneity source was explored by subgroup analysis and potential publication bias was assessed by Begg's funnel plots and Egger's linear regression test. RESULTS: Overall, women experiencing any violence events compared with the reference group were at a higher risk of developing PPD (odds ratio [OR] = 2.04; 95% confidence interval [CI]: 1.72-2.41). Additionally, different types of violence events such as sexual (OR = 1.56; 95%CI: 1.35-1.81), emotional (OR = 1.75; 95%CI: 1.61-1.89), and physical violence (OR = 1.90; 95%CI: 1.36-2.67), as well as domestic (OR = 2.05; 95%CI: 1.50-2.80) or childhood violence (OR = 1.59; 95%CI: 1.34-1.88) also increased the risk of developing PPD. Relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analysis yielded consistent results. CONCLUSIONS: Maternal violence experiences are significantly associated with risk of developing PPD. These finding highlight the necessary to protect women from any types of violence and formulate preventive strategies to promote the maternal mental health. PMID- 30445372 TI - Percutaneous extrahepatic splenomeso-caval shunt creation in a patient with portal vein thrombosis after Whipple procedure. AB - A 72-year-old male presented with refractory ascites secondary to portal vein occlusion with cavernomatous transformation following pancreaticoduodenectomy (Whipple procedure). Due to the unfavorable anatomy, transjugular intrahepatic portosystemic shunt was not an option. However, given patency of the spleno mesenteric confluence and absence of the pancreatic head after the Whipple procedure, a splenomeso-caval shunt was successfully created using a transjugular transsplenic rendezvous technique. PMID- 30445373 TI - Toxic effects and possible mechanisms following malathion exposure in porcine granulosa cells. AB - Malathion is a wide spectrum organophosphorothionate insecticide that is frequently found in drinking water, food and foodstuffs. Ovarian granulosa cells modulate oogenesis by providing metabolic nutrients to oocytes. They can decide the fate of folliculogenesis and oocyte maturation by supplying regulatory cues that help in reproduction. However, little is known about the underlying mechanisms of malathion as a reproductive toxicant in porcine granulosa cells. In the present study, we found that malathion has obvious toxic effects on cultured porcine granulosa cells in a dose-dependent manner. Malathion exposure resulted in significantly increased oxidative stress levels and DNA damage response, which was measured by the mRNA expression levels of homologous recombination (HR) pathway and non-homologous end-joining (NHEJ) pathway-related genes. Subsequently, it was found that malathion exposure could induce apoptosis and autophagy by qRT-PCR and fluorescence intensity analysis. In conclusion, malathion is a reproductive toxicant by inhibiting granulosa cell proliferation by multiple pathways connected to oxidative stress, DNA damage, apoptosis and autophagy. PMID- 30445374 TI - Could the environmental toxicity of diclofenac in vultures been predictable if preclinical testing methodology were applied? AB - Diclofenac, a non-steroidal anti-inflammatory pharmaceutical agent was responsible for the death of millions of Gyps vulture's in the Indian sub-region with the safety of the other non-steroidal anti-inflammatory drugs (NSAIDs) being questionable. With preclinical safety testing not well established for avian species unlike for mammalian and environmental toxicity, we ask the question if a preclinical model could have predicted the toxic effect of the drug. For this study, we test an Organisation for Economic Co-operation and Development (OECD) guideline 223 for assessing the acute toxic potential of pesticides in birds by exposing three avian species to the drug. Exposed Japanese quails (Coturnix japonica) and Muscovy ducks (Cairina moschata) demonstrated clinical signs and pathology similar to those previously reported in vultures viz. hyperuricemia, depression, death, visceral gout and nephrosis. However, exposed domestic pigeons (Columba livia domestica) were insensitive. Following a pharmacokinetic analysis, the drug was well absorbed and distributed in the pigeons with a half-life below 6 h. A toxicokinetic evaluation in quails showed poisoning was due to metabolic constraint, with a half-life and mean residence time above 6 h and 8 h respectively resulting in death. Toxicity seen in the ducks was however not related to metabolic constraint but hyperuricemia as metabolism was rapid [half life (1-2 h) and mean residence time (2-3 h)] irrespective of survival or death. Despite succumbing to diclofenac, the established oral median lethal dose (LD50) of 405.42 mg/kg and 189.92 mg/kg in Japanese quails and Muscovy ducks respectively from this study were substantially higher than those reported for Gyps vultures (0.098 mg/kg) which is as a result of the rapid elimination of the drug from the body in the former species. More importantly, it suggests that these species are not suitable as surrogates for non-steroidal anti-inflammatory drug toxicity testing and that the toxicity of diclofenac in vultures is idiosyncratic most likely as a result of species specific metabolism. PMID- 30445375 TI - A step up therapeutic regimen for chronic post-Pfannenstiel pain syndrome. AB - OBJECTIVE: Up to 8% of patients undergoing surgery via a Pfannenstiel incision may develop chronic inguinal pain. This type of pain is frequently caused by inguinal nerve entrapment and may strongly interfere with daily functioning. We report our long term experience of a step up approach using tender point infiltration and surgical neurectomy for intractable neuropathic post Pfannenstiel groin pain. STUDY DESIGN: A retrospective database analysis identified patients with neuropathic groin pain due to iliohypogastric and/or ilioinguinal nerve entrapment following a Pfannenstiel incision in a single center between 2000 and 2015. Patients who underwent a neurectomy completed a previously published questionnaire including preoperative pain characteristics, pain reduction (5-point Verbal Rating Scale (VRS) and percentages), functional impairment, complications, recurrence of pain and current need for pain medication. RESULTS: Data of 186 women treated for chronic post-Pfannenstiel neuralgia during this 15 year time period were available. Pain reduction following tender point infiltration was successful in 24 patients (13%). In total, 134 of 144 women who underwent a neurectomy were available for follow up via the questionnaire, and 101 responded (response rate 75%). Median age was 52 years (49-54). Before operation, 87% (n = 88) suffered from (very) severe pain (median VRS of 4, range 3-5). Almost 5 years after the operation (median 57 months, range 8-189), 54% (n = 55) had no or only mild pain (p < 0.001). Two of three women reported at least >50% pain reduction and improvement of daily functioning. Eight patients (8%) experienced recurrence of pain after an initial substantial pain reduction. CONCLUSIONS: A step-up approach of tender point infiltration and surgical neurectomy is an effective treatment option in the majority of women with chronic post-Pfannenstiel pain syndrome. Surgeons, gynecologists and pain specialists should consider adopting this treatment regimen for chronic post-Pfannenstiel pain due to nerve entrapment. PMID- 30445376 TI - Outcomes of singleton versus twin pregnancies in the fifth and sixth decades. AB - BACKGROUND: Pregnancies in the fifth and sixth decades of life have been increasing, but current data are limited regarding the outcomes of twin compared with singleton pregnancies in this age group and to twin pregnancies at younger age. OBJECTIVE: To compare obstetrical and neonatal outcomes of IVF conceived pregnancies, in twin gestations of women who were >=45 years old at delivery to singletons at similar age and twin gestations at the age of <35 years, and to assess if the complications are mainly influenced by the very advanced maternal age or by the multifetal pregnancy. STUDY DESIGN: A retrospective cohort study from a single tertiary medical center of women aged >=45 at delivery between March 2011 and January 2018 and women aged <35 at delivery with twin pregnancies that conceived by IVF. Exclusion criteria were spontaneous pregnancies or pregnancies after ovulation induction, monochorionic twin pregnancies, higher order multiple gestations, or women that underwent fetal reduction. Pregnancy, delivery, postpartum and neonatal outcomes were compared between singleton and twin pregnancies. Multivariate logistic regression was used to evaluate the association between twin pregnancies and adverse outcomes. RESULTS: Out of 67,355 deliveries, 612 were of women >=45 years old, of whom 492 women conceived via IVF (395 singleton and 97 twin pregnancies). Of those, 60 women were >=50 years old, 49 of them carried singleton and 11 carried twin pregnancies. Baseline characteristics were similar between groups. Women at the fifth and sixth decades with twins had significantly higher rates of preeclampsia (32.0% vs. 10.9%, p < 0.001), gestational diabetes mellitus (35.4% vs. 23.8%, p = 0.020), preterm deliveries <32 weeks of gestation (8.2% vs. 1.3%, p = 0.001), and fetal growth restriction (18.6% vs. 7.6%, p = 0.001) compared with singleton pregnancies at similar maternal age. After multivariate analysis adjusting for confounders, the odds ratio for the composite of preeclampsia, gestational hypertension, intrauterine fetal growth restriction, and placental abruption was 3.19 for twin compared with singleton pregnancies and 1.73 for gestational diabetes mellitus. Pregnancy complications among older women with twins were also significantly higher when compared with younger women with twins (<35 years old). Women in the fifth and sixth decades with twins had higher rates of cesarean deliveries (91.8% vs. 56.4%, p<0.001), gestational hypertension, preeclampsia, and gestational diabetes mellitus (10.3% vs. 4.2%., p=0.016; 32.0% vs. 6.2%, p<0.001; 35.1% vs. 8.1%, p<0.001, respectively) than the younger group carrying twins. CONCLUSIONS: Twin pregnancies in the fifth and sixth decades carry significantly higher complications rate compared with singleton pregnancies at the same age and twin pregnancies at younger age. PMID- 30445377 TI - Editorial overview: Attachment in adulthood: A dynamic field with a rich past and a bright future. PMID- 30445378 TI - Consumer and clinician perspectives on personalising breast cancer prevention information. AB - BACKGROUND: Personalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (<=moderate risk). OBJECTIVES: To determine; 1) interest of women at <= moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at <= moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. METHODS: Seven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. RESULTS: Consumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at <= moderate risk and reacted positively to the potential of iPrevent to assist. CONCLUSIONS: While highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women. PMID- 30445379 TI - Discrimination and suicidality among racial and ethnic minorities in the United States. AB - BACKGROUND: Over the past decade, suicide rates have increased among certain racial/ethnic minority groups in the United States. To better understand suicide vulnerability among people of color, studies have examined the relations between social risk factors-such as discrimination-and suicidal thoughts and behaviors. However, the literature has been inconsistent, calling for more population studies. METHODS: This study analyzed data from two surveys: (1) The National Survey of American Life; and (2) The National Latino and Asian American Survey, which taken together are representative of Black, Latino, and Asians in the United States. Multivariable logistic regression models were used to examine the association between levels of discrimination on the Everyday Discrimination Scale and suicidal thoughts and behaviors. Additional models tested for effect modification by race and by psychiatric diagnosis. RESULTS: We found that individuals who reported the highest levels of discrimination had greater odds of reporting lifetime suicidal thoughts, plans, and attempts, when compared with people who did not report discrimination, after adjusting for socio-demographic characteristics. Notably, discrimination increased odds of reporting an unplanned suicide attempt and a suicide attempt without the intent to die. Adjusting for psychiatric diagnoses attenuated these effects. We found no evidence of effect modification by race or by psychiatric diagnosis. LIMITATIONS: Data were cross sectional, which did not allow for causal inferences. CONCLUSIONS: Future translational research can explore how screening for discrimination may help identify individuals and groups of racial/ethnic minorities at risk for suicidal thoughts and behaviors. PMID- 30445380 TI - A reliability generalization meta-analysis of the child and adolescent perfectionism scale. AB - BACKGROUND: Perfectionism is a prevalent disposition of personality involved in the development and maintenance of a wide range of psychological disorders. The Child and Adolescent Perfectionism Scale (CAPS) is the most usually applied test to assess perfectionism in children and adolescents. This study aimed: (a) to conduct a reliability generalization meta-analysis to estimate the average reliability of the CAPS scores and to search for characteristics of the studies that may explain the variability among reliability estimates, and (b) to estimate the reliability induction rate of the CAPS. METHOD: An exhaustive search allowed to select 56 studies that reported alpha coefficients with the data at hand for the CAPS. RESULTS: The average alpha coefficients were 0.87, 0.84 and 0.83, respectively for the CAPS total score and its two subscales, Socially Prescribed Perfectionism (SPP) and Self-Oriented Perfectionism (SOP). Regarding O'Connor's version, the average reliability coefficients were 0.82, 0.74 and 0.73, respectively, for SPP, SOP-Critical and SOP-Strivings. Some study characteristics (ethnicity, language, mean age and standard deviation of the scores, psychometric vs applied) showed a statistical association with the reliability coefficients of SPP and SOP. The reliability induction rate was 29.8%. LIMITATIONS: Due to the scarcity of studies, we could not examine the reliability scores of other versions of the CAPS and test-retest reliability. CONCLUSIONS: In terms of reliability, the original version of the CAPS present better results than O'Connor's version. The original version of the CAPS is a reliable instrument to be employed with general research purposes, but not for clinical practice. PMID- 30445381 TI - Are children with social anxiety disorder more likely than children with other anxiety disorders to anticipate poor social performance and reflect negatively on their performance? AB - BACKGROUND: The cognitive theory of social anxiety disorder (SAD) suggests that adults with SAD have a tendency to anticipate poor social performance and reflect negatively on their performance following a social event. While a number of studies with socially anxious adults have supported the role of poor performance anticipation and post-event rumination in SAD, to date, only a few studies have addressed whether this also applies to children with SAD. METHODS: Children (7-12 years) diagnosed with SAD (n = 40), other anxious children (n = 40) and non anxious children (n = 34) were exposed to a social stressor speech task and their pre- and post-performance appraisals assessed, taking into account objective performance ratings. RESULTS: Although observers rated some aspects of performance as significantly worse among children with SAD than children with other anxiety disorders, children with SAD were not more likely than their anxious or non-anxious peers to show a general bias in pre- or post-performance appraisals. Furthermore, children with SAD were just as likely as their anxious and non-anxious peers to recognize good performance but were more critical of themselves when their performance was poor. LIMITATIONS: The speech task did not involve a same-age peer. Participants were relatively affluent group of predominantly non-minority status. Specificity for SAD in relation to other anxiety disorders remains unclear. CONCLUSIONS: Focusing on counteracting pre- and post-event social performance appraisals may potentially be inappropriate for childhood SAD. Children with SAD might benefit from interventions that focus on helping them to become less critical of themselves after social interactions have not gone well. PMID- 30445382 TI - The multidimensional nature of adult social inhibition: Inhibition, sensitivity and withdrawal facets of the SIQ15. AB - BACKGROUND: Social inhibition may promote emotional problems in children, but little is known about this disposition in adults. Our research builds on a theory based model to suggest that adult social inhibition involves distinct behavioral (inhibition), cognitive (sensitivity), and affective (withdrawal) characteristics. METHODS: A total of 1385 adults completed measures of social inhibition, emotional distress, and social stress. Factor analyses, reliability estimates and regression analyses were used to examine the robustness of our model, and the validity of the 15-item Social Inhibition Questionnaire (SIQ15). RESULTS: In Study 1 (N = 1180; Mage 46.9 years; 52% women), factor analysis confirmed that behavioral inhibition, interpersonal sensitivity, and social withdrawal reflected distinct facets of social inhibition. Next, we developed the SIQ15 that covers these facets with 5 items each; e.g. has difficulty making contact; expects negative reactions from others; keeps others at a distance. Study 2 (N = 209; Mage 20.3 years; 77% women) showed that the SIQ15 and its 5 item Inhibition, Sensitivity and Withdrawal facet scales were internally consistent (Cronbach's alpha between 0.86/0.94) and stable over time (test-retest between r = 0.73/0.78). The SIQ15 facets differentially predicted related inhibition (Behavioral Inhibition Scale), rumination (Penn State Worry Questionnaire) and withdrawal (Personality Inventory for DSM-5) scores at 6 months follow-up. Younger age and having no partner were associated with more social inhibition. LIMITATIONS: Findings are based on self-report; experimental and prospective studies are needed to further validate our inhibition model. CONCLUSIONS: Inhibition, sensitivity, and withdrawal are distinct manifestations of adult social inhibition that can be reliably assessed with the SIQ15. Research needs to examine how this multidimensional nature of social inhibition has an effect on stress, health, and wellbeing. PMID- 30445383 TI - Familial and social transmission of suicidal behavior in older adults. AB - BACKGROUND: Both biological and social mechanisms have been implicated in the transmission of suicidal behavior in younger and middle-aged adults. Yet, while suicide rates rise with age, it is not clear whether such mechanisms operate in late life. Thus, we looked for evidence of social and familial suicidal transmission in elderly with late- vs. early-onset suicidal behavior by examining exposure to suicidal behavior within biological relatives and broader social networks. METHOD: Participants were 356 adults, aged 50 or older (mean: 67), divided into five groups: early-onset suicide attempters (first lifetime attempt before age 60), late-onset attempters, suicide ideators (without attempt history), depressed non-suicidal controls, and non-psychiatric controls. History of suicidal behavior in one's biological relatives and friends/unrelated kin was assessed via clinical interview, and group differences were examined via generalized linear mixed-effects models. RESULTS: There was a main effect of group (chi24 = 18.38, p < 0.001) such that familial or social exposure to suicidal behavior was more prevalent in early- than late-onset attempters. Late onset attempters' exposure was similar to non-suicidal groups'. However, there was no significant group by relationship interaction, indicating that suicidal behavior was not significantly more prominent among the biological relatives of either attempter group. LIMITATIONS: Participants' report of exposure is subject to awareness and recall biases. CONCLUSION: Suicidal clustering in biological relatives and friends/unrelated kin is associated with early-, but not late-onset suicidal behavior in older adults. Suicidal transmission in older adults follows a pattern of familial and social clustering suggestive of social transmission. PMID- 30445384 TI - Sex-specific effects of gain-of-function P2RX7 variation on bipolar disorder. AB - BACKGROUND: Patients with bipolar disorder demonstrate sex differences in clinical presentation, particularly in the sub-phenotypes related to periodicity of mood episodes, such as rapid cycling. Additionally, recent studies have linked P2RX7 gene variants with the risk of rapid cycling in clinical cohorts of patients with bipolar disorder, as well as other mood disorders. However, little is known about potential sex differences in the relationship between variants in P2RX7 and bipolar disorder. METHODS: We investigated sex-specific genetic associations between variants of P2RX7 (rs1621388 and rs2230912) in 756 patients with bipolar disorder and 787 control patients matched on age, sex, and ancestry. We examined sex-specific genetic associations with bipolar disorder by comparing cases and controls, as well as rapid cycling of mood episodes in cases. Findings were replicated in an independent dataset. RESULTS: P2RX7 variants implying an increased pore activity were more common in bipolar disorder, in females but not in males. Neither P2RX7 variants associated with rapid cycling among bipolar patients. LIMITATIONS: Low sample size limited power for tests of SNP by sex interaction, and data about the onset of rapid cycling and the timing of medication use were not available. CONCLUSION: The effects of P2RX7 variants on bipolar disorder may be sex-specific, with increased P2X7 activity potentially elevating risk for bipolar disorder in females. Future research to examine the effect of P2RX7 on bipolar disorder should consider sex-specific effects. PMID- 30445385 TI - Decreased plasma glial cell line-derived neurotrophic factor level in major depressive disorder is associated with age and clinical severity. AB - BACKGROUND: Glial cell line-derived neurotrophic factor (GDNF) as a neurotrophic factor closely related to depression is able to promote the growth, proliferation, differentiation, and survival of multiple neurons. Clinical features, recurrence rates and suicide rates are significant different in major depressive disorder (MDD) according to age. GDNF level changes in the peripheral blood has been reported in patients with MDD. In this study, we aimed to investigate whether GDNF levels differentiated within various age groups and its relationship with age/clinical severity. METHOD: MDD subjects and healthy controls (HC) are divided into younger (age 13-24 years) group (yMDD n = 35, yHC n = 44) and older (age 25-45 years) group (oMDD n = 30, oHC n = 55) based on the age of brain maturity. Clinical symptom severity was evaluated by the Hamilton Depression Rating Scale (HAMD-17) and the Hamilton Anxiety Rating Scale (HAMA 17). The levels of plasma GDNF were compared within subgroups. RESULTS: Plasma GDNF levels in yMDD patients were significantly decreased compared to yHC (yMDD 1.55 +/- 0.46pg/ml, yHC 1.77 +/- 0.47pg/ml, p < 0.05). Moreover, such difference was not found between oMDD group and oHC group. Our results also showed negative correlations between plasma GDNF levels and HAMD/HAMA scores (r = -0.33, p < 0.05; r = -0.39, p < 0.05). LIMITATIONS: This study was underpowered to observe dynamic changes between age and GDNF in MDD due to the cross-sectional design of present study. We also failed to divided subjects into more age groups because of moderate sample size. CONCLUSION: The present result showed the level of protective neurotrophic factor GDNF associated with age in MDD, suggesting a relevance between GDNF and MDD subjects abnormal brain development in adolescent and young adult period. PMID- 30445386 TI - Early versus late wake therapy improves mood more in antepartum versus postpartum depression by differentially altering melatonin-sleep timing disturbances. AB - BACKGROUND: Peripartum major depression (MD) disables mothers and impairs emotional and neurocognitive development of offspring. We tested the hypothesis that critically-timed wake therapy (WT) relieves peripartum MD by altering melatonin and sleep timing, differentially, in antepartum vs. postpartum depressed patients (DP). METHODS: In a university clinical research center, we initially randomized 50 women - 26 antepartum (17 healthy comparison-HC, 9 DP) and 24 postpartum (8 HC, 16 DP) - to a cross-over trial of one night of early night wake therapy (EWT: sleep 3:00-7:00 am) vs. late-night wake therapy (LWT: sleep 9:00 pm-01:00 am). Ultimately, we obtained mood, overnight plasma melatonin and polysomnography for: 15 antepartum women receiving EWT, 18 receiving LWT; 15 postpartum women receiving EWT, 14 receiving LWT. RESULTS: EWT improved mood more in antepartum vs. postpartum DP in conjunction with reduced (normalized) melatonin-sleep phase-angle differences (PADs) due to delayed melatonin onsets and advanced sleep onsets, and increased (from baseline) total sleep times (TST). LWT improved mood more in postpartum vs. antepartum DP in conjunction with increased TST. LIMITATIONS: Small samples potentially rendered the study underpowered to detect group differences, making confirmation with larger samples essential. Sufficient follow-up data were not available in most women to document the duration of the mood response to wake therapy. CONCLUSIONS: EWT benefitted antepartum DP more by realigning melatonin and sleep timing, whereas LWT benefitted postpartum DP more by increasing TST. Thus, consistent with precision medicine aims, maximum mood benefits accrue from timing sleep/wake interventions to specific peripartum circadian pathophysiologies. PMID- 30445387 TI - A naturalistic study exploring mental health outcomes following trauma-focused treatment among diverse survivors of crime and violence. AB - BACKGROUND: Although considerable research has tested evidence-based practices in clinical trials, research is needed on the use of trauma-focused treatments by victims of crime and violence in naturalistic settings. This study investigated four trauma-focused treatments, prolonged exposure therapy (PE), cognitive behavioral therapy (CBT), eclectic therapy, and person-centered therapy (PCT), and assessed treatment dropout and symptom improvement over five assessment time points. METHODS: Descriptive comparisons and pattern mixture multigroup growth models were used to assess differences between treatments on time in treatment, rate of dropout, and improvement in posttraumatic stress (PTSD) and depression symptoms in an outpatient sample of 526 clients seeking routine clinical care. RESULTS: PCT was significantly associated with the highest number of therapy sessions completed and the lowest rate of dropout (41.75%) compared to CBT and eclectic treatments. All treatment groups reported PTSD symptom improvement with no significant differences based on therapy type. For depression, the rate of improvement for clients in PCT who dropped out of treatment after session 3 was significantly steeper than the rate of improvement for clients in eclectic treatment who dropped out of treatment after session 3. Clients who stayed in treatment longer generally had larger decreases in symptoms compared to those who dropped out earlier. LIMITATIONS: The small sample size in each of the treatment groups may have limited power to detect change. CONCLUSIONS: Several trauma focused treatments offered in a community-based setting may result in significant symptomatic improvement. PMID- 30445388 TI - Definition of treatment-resistant depression - Asia Pacific perspectives. AB - BACKGROUND: The lack of uniformity in the definition of treatment resistant depression (TRD) within the Asia-Pacific (APAC) region may have implications for patient management. We aimed to characterize the most commonly used TRD definition in selected APAC countries. METHODS: A systematic literature review of TRD definitions in APAC countries was conducted in Medline and Embase (2010-2016) and conference proceedings (2014 and 2016). TRD guidelines (APAC, Europe regional, US, or international) were also searched. An expert-panel explored APAC nuances in TRD definitions to achieve consensus for a regional-level definition. RESULTS: Ten guidelines and 89 studies qualified for study inclusion. Among the studies, variations were observed in definitions regarding: number of antidepressants failed (range: >=1 to >=3), classes of antidepressants (same or different; 59% did not specify class), duration of previous treatments (range: 4 12 weeks), dosage adequacy, and consideration of adherence (yes/no; 88% of studies did not consider adherence). No TRD-specific guidelines were identified. The emerging consensus from the literature review and panel discussion was that TRD is most commonly defined as failure to >=2 antidepressant therapies given at adequate doses, for 6-8 weeks during a major depressive episode. LIMITATIONS: Few studies provided definitions of TRD used in daily clinical practice, and a limited number of countries were represented in the included studies and expert panel. CONCLUSION: Attaining consensus on TRD definition may promote accurate, and possibly early detection of patients with TRD to enable appropriate intervention that may impact patient outcomes and quality of life. PMID- 30445389 TI - Application of a transdiagnostic treatment for emotional disorders to body dysmorphic disorder: A randomized controlled trial. AB - BACKGROUND: Body dysmorphic disorder (BDD) is a common disorder which is associated with a high rate of comorbidity and functional impairment. Although research shows that cognitive-behavioral therapy can be an efficacious treatment for BDD, there is growing evidence that dysregulated emotion is a core deficit. The Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders (UP) is a transdiagnostic, emotion focused cognitive-behavioral therapy protocol that has been developed to target emotion regulation processes that play an important role in the development and maintenance of many emotional disorders METHODS: : In the present study, 128 patients meeting criteria for BDD were randomized to either the UP (n = 64) or waitlist/treatment-as-usual (WL/TAU) condition. Diagnoses were determined using semi-structural interviews and patients also completed the Brown Assessment of Beliefs Scale (BABS), the Appearance Anxiety Inventory (AAI), the Difficulties in Emotion Regulation Scale (DERS), the Beck Depression Inventory (BDI) and the Clinical Global Impression (CGI). RESULTS: Repeated measure ANOVA indicated that the UP significantly decreased depression, BDD symptoms and body-related anxiety, as well as significantly improving emotional regulation all with large effect sizes compared to the TAU/WL condition. Treatment gains as well as remission of comorbid conditions were maintained at the three-month follow-up. LIMITATIONS: Our study limitations include restricted follow-up periods and excluding participants who were actively suicidal. CONCLUSIONS: To our knowledge, this is the first examination of the UP for BDD, and results suggest that this disorder shares common mechanisms with other disorders of emotion, and that the UP may be an additional efficacious treatment for this condition. PMID- 30445390 TI - Family functioning, trauma exposure and PTSD: A cross sectional study. AB - OBJECTIVE: Only a minority of trauma-exposed individuals go on to develop post traumatic stress disorder (PTSD). Previous studies in high income countries suggest that maladaptive family functioning adversities (MFFA) in childhood may partially explain individual variation in vulnerability to PTSD following trauma. We test in a lower middle-income setting (Sri Lanka) whether: (1) MFFA is associated with trauma exposure; (2) MFFA moderates the association between exposure to trauma and later (a) PTSD (b) other psychiatric diagnoses; and (3) any association between MFFA and PTSD is explained by experiences of interpersonal violence, cumulative trauma exposure or comorbid psychopathology. METHODS: We conducted a population study of 3995 twins and 2019 singletons residing in Colombo, Sri Lanka. Participants completed the Composite International Diagnostic Interview, including nine traumatic exposures and a questionnaire on MFFA. RESULTS: 23.4% of participants reported exposure to MFFA. We found that (1) MFFA was strongly associated with trauma exposure (2) MFFA moderates the association between trauma exposure and both (a) PTSD and (b) other DSM psychiatric diagnosis. (3) This was not explained by interpersonal violence, cumulative trauma exposure or other psychopathology. CONCLUSIONS: MFFA moderates the association between trauma and PTSD, and the association between trauma and non-PTSD psychopathology. PMID- 30445391 TI - Suicidal thoughts and behaviors and social isolation: A narrative review of the literature. AB - BACKGROUND: Social isolation is one of the main risk factors associated with suicidal outcomes. The aim of this narrative review was to provide an overview on the link between social isolation and suicidal thoughts and behaviors. METHODS: We used the PubMed database to identify relevant articles published until April 13, 2018. We focused on: (a) systematic reviews, meta-analyses, and narrative reviews; (b) original observational studies with large samples (N >= 500); and (c) qualitative studies. We included all relevant suicidal outcomes: suicidal ideation (SI), suicidal planning, non-suicidal self-injury, deliberate self-harm, suicide attempt (SA), and suicide. RESULTS: The main social constructs associated with suicidal outcomes were marital status (being single, separated, divorced, or widowed) and living alone, social isolation, loneliness, alienation, and belongingness. We included 40 original observational studies, the majority of them performed on adolescents and/or young adults (k = 23, 57.5%). Both the objective condition (e.g., living alone) and the subjective feeling of being alone (i.e., loneliness) were strongly associated with suicidal outcomes, in particular with SA and SI. However, loneliness, which was investigated in most studies (k = 24, 60%), had a major impact on both SI and SA. These associations were transculturally consistent. LIMITATIONS: Confounding factors can limit the weight of the results obtained in observational studies. CONCLUSIONS: Data from the observational studies suggest that both objective social isolation and the subjective feeling of loneliness should be incorporated in the risk assessment of suicide. Interventional studies targeting social isolation for suicide prevention are needed. PMID- 30445392 TI - Childhood adversities and mid-late depressive symptoms over the life course: Evidence from the China health and retirement longitudinal study. AB - BACKGROUND: The cumulative effect of childhood adversities on depressive symptoms in later life is well documented. However, there is a dearth of accurate information about this effect among Chinese population. The aim of this study is to examine the cumulative effect of childhood adversities on mid-late depressive symptoms in the Chinese population. METHODS: Data were drawn from the China Health and Retirement Longitudinal Study (CHARLS). We included 17,425 respondents aged 45 and over, and retrospectively collected information of childhood adversities. The depressive symptoms were assessed using a 10-item Center for Epidemiologic Studies Depression Scale (CES-D). A structural equation model was employed for analysis. RESULTS: Parental mental health problems had a direct effect on mid-late depressive symptoms (beta = 0.180, P < 0.001). Lack of friends showed direct effect on mid-late depressive symptoms (beta = 0.118, P < 0.001) and indirect effect through low SES and poor health status in mid-late life (beta = 0.054, P < 0.001). Poor health status, child neglect and abuse, and low SES in childhood had an indirect effect on mid-late depressive symptoms (beta = 0.128, beta = 0.040, beta = 0.098, P < 0.001). LIMITATIONS: Limitations of this study include recall bias on life course data collection, absence of adolescent data, limited construction of latent variables. CONCLUSIONS: These findings are crucial for preventing childhood adversities and subsequently reducing the prevalence of depression. Moreover, the indirect effects of childhood adversities suggest that early intervention and resource mobilization can circumvent some of the long-term mental health consequences. PMID- 30445393 TI - Legionella occurrence in municipal and industrial wastewater treatment plants and risks of reclaimed wastewater reuse: Review. AB - Wastewater treatment plants (WWTPs) have been identified as confirmed but until today underestimated sources of Legionella, playing an important role in local and community cases and outbreaks of Legionnaires' disease. In general, aerobic biological systems provide an optimum environment for the growth of Legionella due to high organic nitrogen and oxygen concentrations, ideal temperatures and the presence of protozoa. However, few studies have investigated the occurrence of Legionella in WWTPs, and many questions in regards to the interacting factors that promote the proliferation and persistence of Legionella in these treatment systems are still unanswered. This critical review summarizes the current knowledge about Legionella in municipal and industrial WWTPs, the conditions that might support their growth, as well as control strategies that have been applied. Furthermore, an overview of current quantification methods, guidelines and health risks associated with Legionella in reclaimed wastewater is also discussed in depth. A better understanding of the conditions promoting the occurrence of Legionella in WWTPs will contribute to the development of improved wastewater treatment technologies and/or innovative mitigation approaches to minimize future Legionella outbreaks. PMID- 30445394 TI - Plant growth promoting rhizobacteria induced Cd tolerance in Lycopersicon esculentum through altered antioxidative defense expression. AB - The present study was designed to determine the role of plant growth-promoting rhizobacteria (Pseudomonas aeruginosa &Burkholderia gladioli) in alleviating Cd stress in Lycopersicon esculentum. Cd concentration of 0.4 mM enhanced superoxide anions, MDA and H2O2 by 136%, 378% and 137% that also caused nuclear and cell viability damage. Cd enhanced the activities of enzymatic antioxidants such as CAT, GST, GPOX, DHAR, and GR by 64%, 126%, 265%, 25% and 93% respectively. However, SOD, POD and PPO was decreased by Cd and enhanced by 119%, 198% and 42% by inoculation of P. aeruginosa and 65%, 119% and 33% by B. gladioli. The contents of non-enzymatic antioxidants and total antioxidants (WSA, LSA) were also enhanced in response to metal stress and reduced by supplementation with PGPR. Confocal microscopy revealed improved cell viability and decreased nuclear damage in Cd-treated L. esculentum roots supplemented with PGPRs. Gene expression studies conducted through qRT-PCR revealed that expression levels of the SOD, POD, and PPO genes were enhanced by 478%, 830% and 253%, while the expression of CAT, GR, GST, GPOX, and APOX genes decreased by 97%, 87%, 75%, 82%, 88% in P. aeruginosa-inoculated Cd-treated seedlings. Also, B. gladioli elevated the expression of SOD, POD and PPO genes and reduced the expression of CAT, GR, GPOX, APOX and GST genes respectively. Therefore, the results suggest that Cd induced oxidative stress in L. esculentum seedlings was reduced by PGPRs through modulation of antioxidative defence expression as demonstrated in terms of antioxidants both quantitatively as well as qualitatively. PMID- 30445395 TI - Application of a novel gene encoding bromophenol dehalogenase from Ochrobactrum sp. T in TBBPA degradation. AB - Tetrabromobisphenol-A (TBBPA), a typical brominated flame retardant, leaked from commercial products into the environments has attracted people's attention around the world. Ochrobactrum sp. T capable of degradation and mineralization of TBBPA was isolated in our early work. In this study, the identification of TBBPA degrading gene from the strain was further carried out by combining whole-genome sequencing with gene cloning and expression procedures. In total, 3877 open reading frames were found within 3.9 Mb genome and seven of them were identified as dehalogenating-relating genes. One gene with a significant ability to degrade TBBPA was designated as tbbpaA. Sequence alignments analysis showed that it shared 100% identity with haloacid dehalogenases. Furthermore, tbbpaA gene was cloned and expressed into E. coli to achieve a constructed strain. Like the original strain, the constructed strain could degrade TBBPA (6 mg L-1) with 78% of debromination efficiency and 37.8% mineralization efficiency within 96 h. Gene expression study revealed that tbbpaA was up-regulated in the presence of TBBPA. Overall, we report the identification of a functional TBBPA-degrading gene in an aerobe, which can deepen the knowledge of enhancing TBBPA removal by Strain T at the genetic level and facilitate in situ TBBPA bioremediation. PMID- 30445396 TI - mRNA expression of antioxidant and biotransformation enzymes in zebrafish (Danio rerio) embryos after exposure to the tricyclic antidepressant amitriptyline. AB - Now-a-days, the occurrence of antidepressant residues in surface waters has become a major concern. Amitriptyline (AMI) has been described to treat depression and other disorders for decades. However, little is known about its effect on non-target organisms. The aim of this study was to assess the potential impact of AMI on the mRNA expression of antioxidant and detoxification enzymes during the early embryonic development of zebrafish (Danio rerio). Fertilized D. rerio embryos were exposed to AMI at concentrations of 300 ng/L and 30 MUg/L and sampled 24, 48, 96, and 144 h post fertilization (hpf) to assess the mRNA expressions of cytochrome P450 1A1, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase, and catalase. The time courses of the mRNA expressions of antioxidant and detoxification enzymes revealed characteristic changes during embryonic development causing generally transient changes post hatching; however, AMI did not cause any significant impact except in the case of CAT after 144 h, which was significantly upregulated by the AMI concentration of 30 MUg/L. The results suggest that the antidepressant AMI causes only moderate to minor impacts on antioxidant and detoxification enzymes during early embryonic development of the non-target organism D. rerio and that CAT is the only biomarker affected by AMI. PMID- 30445397 TI - Microalgal whole-cell biomarkers as sensitive tools for fast toxicity and pollution monitoring of urban wet weather discharges. AB - Urban wet weather discharge (UWWD) management is an important issue. UWWD often represents a significant source of pollution in all aquatic bodies. The occurrence of this pollution is difficult to predict due to the variability of storm events and the unknown contents of urban watershed leached out by rain. Previous studies have tried to demonstrate the ecotoxic impact of UWWD. However, most of them merely highlight the limitations of classic monospecific bioassays, given the high dilution of micropollutants or the presence of nutrients masking toxic effects. Overcoming this problem is therefore of great interest. In this study, we demonstrated the utility of a battery of biomarkers (e.g. membrane permeability, chlorophyll fluorescence, esterase and alkaline phosphatase activities) on the microalgae Chlorella vulgaris to detect the toxic effects of 7 UWWD samples after short exposures (2 and 24 h). These biomarkers are linked to microalgal life traits. Complementarily, monospecific bioassays were carried on Pseudokirchneriella subcapitata, Chlorella vulgaris, Daphnia magna and Heterocypris incongruens to compare their sensitivity to the UWWD samples. No toxic effect was detected in any of the bioassays. Yet, algal biomarkers indicated a disturbance in microalgae physiology, and particularly a perturbation of chlorophyll fluorescence, which was observed in all of the samples tested. While algal membrane permeability was affected by only one UWWD, these two enzymatic activities were stimulated or inhibited depending on the sample. Finally, this study demonstrates the sensitivity of algal biomarkers and the need to develop new, fruitful approaches to characterizing UWWD toxicity. PMID- 30445398 TI - Assessment of agonistic and antagonistic properties of widely used oral care antimicrobial substances toward steroid estrogenic and androgenic receptors. AB - Personal care product consumption has increased in the last decades. A typical representative ingredient, i.e., triclosan, was identified in the scientific literature as an endocrine disruptor, and its use is restricted in several applications. Oral hygiene formulations contain various compounds, including synthetic phenol derivatives, quaternary ammonium compounds (QACs), various amides and amines, or natural essential oils containing terpenes. The aim of this paper was to explore possible endocrine-disrupting effects of these most-used compounds. For this purpose, two different assays based on recombinant yeast (BMAEREluc/ERalpha; BMAEREluc/AR) and human cell lines (T47D; AIZ-AR) were employed to investigate the agonistic and antagonistic properties of these compounds on human estrogen and androgen receptors. The results showed that none of the compounds were indicated as agonists of the steroid receptors. However, octenidine (OCT, QAC-like) and hexadecylpyridinium (HDP, QAC) were able to completely inhibit both androgenic (IC50 OCT = 0.84 MUM; IC50 HDP = 1.66 MUM) and estrogenic (IC50 OCT = 0.50 MUM; IC50 HDP = 1.64 MUM) signaling pathways in a dose-dependent manner. Additionally, chlorhexidine was found to inhibit the 17beta-estradiol response, with a similar IC50 (2.9 MUM). In contrast, the natural terpenes thymol and menthol were found to be competitive antagonists of the receptors; however, their IC50 values were higher (by orders of magnitude). We tried to estimate the risk associated with the presence of these compounds in environmental matrices by calculating hazard quotients (HQs), and the calculated HQs were found to be close to or greater than 1 only when predicted environmental concentrations were used for surface waters. PMID- 30445399 TI - Effects of low concentrations of psychiatric drugs (carbamazepine and fluoxetine) on the freshwater planarian, Schmidtea mediterranea. AB - There is increasing knowledge about the presence of psychiatric pharmaceutical substances in the aquatic environment due to increasing number of ecotoxicological studies with sensitive species in addition to improved methods of analysis. Here, we assessed the effects of two psychiatric substances carbamazepine and fluoxetine in the planarian Schmidtea mediterranea using endpoints such as survival, behaviour (feeding, locomotion), DNA damage and regeneration. Also, planarian asexual reproduction by fissioning was used to assess the reproductive effects of these compounds. Whereas for survival, no effect was observed for carbamazepine exposure, fluoxetine exposure was toxic to planarians with an LC50 of 357.93 and 160.01 MUg L-1 at 48 and 96 h, respectively. Time for head regeneration in decapitated planarians was not affected by either fluoxetine or carbamazepine exposures. Fluoxetine was more toxic than carbamazepine and caused concentration dependent increase in locomotor activity and DNA damage (LOEC's of 0.1-1.0 MUg L-1), and decrease in feeding and fissioning. Despite some alteration on planarian locomotion observed under exposure to intermediate concentrations, no significant effects were observed in the other endpoints in response to carbamazepine. The observations in the present study showed that freshwater planarians such as Schmidtea mediterranea, animal models in neuropharmacology, are sensitive to low concentrations of psychiatric drugs, displaying an array of sensitive sub-lethal endpoints that can be used for the ecological risk assessment of psychiatric substances. Future studies to determine effects of these psychiatric drugs on the levels of neurotransmitters and other biochemical biomarkers in planarians are recommended. PMID- 30445400 TI - Natural levels and photo-production rates of hydrogen peroxide (H2O2) in Andean Patagonian aquatic systems: Influence of the dissolved organic matter pool. AB - In aquatic environments the reactive oxygen species hydrogen peroxide (H2O2) is produced through photochemical reactions involving chromophoric dissolved organic matter (CDOM). Andean Patagonian freshwaters experience challenging underwater UV levels, which promote high levels of photochemical weathering. In this investigation, we study natural H2O2 levels and experimentally address the photochemical formation of H2O2 in stream and lake water with a range of dissolved organic matter (DOM) concentrations and quality. The screening of different pristine aquatic systems of Patagonia revealed that H2O2 concentration fluctuates between 8 and 60 nM. Laboratory incubation of different water types in PAR + UV showed photo-production of H2O2. The H2O2 formation rate increased linearly with dissolved organic carbon (DOC) in streams (13.5-20.5 nM h-1) and shallow lakes (25.7-37.8 nM h-1). In contrast, the H2O2 formation rate in deep lakes was much lower (2.1-7.1 nM h-1), and decreased with DOC. The natural potential for H2O2 formation was related to the concentration and quality of the DOM pool. At higher DOC levels, such as those present in shallow lakes, H2O2 production was directly related to DOC, whereas at low DOC levels in deep lakes and streams, two patterns were distinguished in relation to their DOM pool quality. Stream DOM, composed of high molecular weight/size humic compounds, proved to be a reactive substrate, as reflected by their high H2O2 formation rates. On the other hand, deep lake DOM, with its higher relative contribution of small and more processed compounds, was found to be a less reactive substrate, affording lower H2O2 formation rates. PMID- 30445401 TI - Biomonitoring of mercury in hair of children living in the Valencian Region (Spain). Exposure and risk assessment. AB - In this study, we assessed total mercury levels in hair specimens of 661 children, aged 6 to 11, participating in the BIOVAL programme, a human biomonitoring study carried out by the Health Department of the Regional Government of Valencia (Spain). The reference value (95th percentile) determined for this population, within this programme, was 3.25 MUg g-1. Hg concentrations ranged between 0.03 MUg g-1 and 8.71 MUg g-1, with a geometric mean of 0.79 (CI 95%: 0.73-0.85) MUg g-1. This mean value was five times higher than the average levels found in children of 17 other European countries (0.145 MUg g-1). About 13% of children had hair mercury levels above the FAO/WHO JECFA guideline of 2.3 MUg g-1 and 18% of children had levels above the EFSA health-based guidance value of 1.9 MUg. Multiple regression analysis revealed that fish consumption, mother's country of birth (Spain or abroad) and the employment situation of parents were the main predictors of mercury in hair. PMID- 30445402 TI - Enhancement of oil field-produced wastewater remediation by bacterially-augmented floating treatment wetlands. AB - Plants and bacteria individually as well as in synergism with each other hold a great potential to degrade a wide range of environmental pollutants. Floating treatment wetlands (FTWs) is an efficient and low-cost technology that uses the synergistic interaction between plant roots and microbes for in situ remediation of wastewater. The present study aims to assess the feasibility of FTW-based remediation of oil field-produced wastewater using an interaction between two plant species, Typha domingensis and Leptochloa fusca, in partnership with a consortium of crude oil-degrading bacterial species, Bacillus subtilis LORI66, Klebsiella sp. LCRI87, Acinetobacter Junii TYRH47, and Acinetobacter sp. BRSI56. All the treatments reduced contaminant levels, but T. domingensis, in combination with bacterial inoculation, exhibited the highest reduction in hydrocarbon (95%), COD (90%), and BOD content (93%) as compared to L. fusca. This combination maximally promoted increases in fresh biomass (31%), dry biomass (52%), and length (25%) of plants as well. This effect was further signified by the persistence of bacteria (40%) and considerable abundance (27%) and expression (28.5%) of the alkB gene in the rhizoplane of T. domingensis in comparison to that of L. fusca. The study, therefore, suggests that T. domingensis, in combination with bacterial consortium, has significant potential for treatment of oil field-produced water and can be exploited on large scale in FTWs. PMID- 30445403 TI - Response of freshwater sediment archaeal community to metal spill. AB - Archaea play an important role in the biogeochemical cycling of elements in the environment. Heavy metals are ubiquitous pollutants in the environment. Previous studies have revealed a considerable influence of metal pollution on the archaeal community, but the short-term response of the archaeal community to metal pollution remains unclear. Hence, the present study investigated the short versus long-term responses of overall archaeal communities in freshwater sediments after exposure to accidental metal pollution caused by the discharge of heavy metal containing wastewater from an indium-producing factory. Quantitative PCR was used to determine the archaeal abundance, while Illumina MiSeq sequencing was applied to characterize the diversity and structure of the archaeal community. The abundance (2.47 * 105-1.55 * 108 archaeal 16S rRNA gene copies per gram dry sediment), diversity (Shannon diversity index = 2.49-4.45) and structure of overall archaeal community illustrated a drastic temporal change. The archaeal communities mainly comprised the phyla Euryarchaeota, Thaumarchaeota and Bathyarchaeota. The exposure to metal pollution induced an increase in the proportion of Euryarchaeota but lowered the proportion of Thaumarchaeota. The accidental metal pollution exerted a profound impact on the archaeal community in freshwater sediment. This study could contribute our understanding of the short versus long-term response of archaeal communities to metal pollution. PMID- 30445404 TI - Selection of organosilicone surfactants for tank-mixed pesticides considering the balance between synergistic effects on pests and environmental risks. AB - In this study, the bioactivities of binary mixtures of organosilicone surfactants and indoxacarb against two Lepidopteran pests were investigated along with their environmental risks. All of the tested organosilicone surfactants had obvious synergistic effects on the contact toxicity of indoxacarb against Spodoptera exigua and Agrotis ipsilon. However, all of the organosilicone surfactants exhibited certain antagonism for indoxacarb against S. exigua in terms of stomach & contact toxicity; both Silwet-408 and Silwet-806 exhibited additivity against A. ipsilon, whereas Silwet-618 and Silwet-DRS-60 exhibited synergism and slight antagonism, respectively. All of the tested chemicals were highly toxic to Daphnia magna, among which Silwet-DRS-60 had the lowest acute toxicity (EC50 of 94.91 MUg/L). However, these chemicals were less toxic to Brachydanio rerio. Silwet-DRS-60 had a low toxicity to B. rerio, while Silwet-408, Silwet-806 and Silwet-618 were moderately toxic to B. rerio. For the joint toxicity evaluation of organosilicone surfactants and indoxacarb to D. magna and B. rerio, the additive index method, concentration addition method and toxicity unit method were robust in judging synergism or antagonism, whereas other methods were more conservative; the V-value method and equilibrium curve method exhibited high robustness and viability in evaluating the combined effects of binary mixtures. Overall, we should carefully select organosilicone surfactants for premixed or tank-mixed pesticides in agriculture to obtain a balance between synergistic effects on pests and environmental risks. PMID- 30445405 TI - Enhanced degradation of bisphenol A and ibuprofen by an up-flow microbial fuel cell-coupled constructed wetland and analysis of bacterial community structure. AB - This study aims to demonstrate that an up-flow microbial fuel cell-coupled constructed wetland (UCW-MFC) can effectively treat synthetic wastewater that contains a high concentration of pharmaceutical and personal care products (PPCPs, 10 mg L-1 level), such as ibuprofen (IBP) and bisphenol A (BPA). A significant decline in chemical oxygen demand (COD) and ammonia nitrogen (NH4+-N) removal was observed when BPA was added, which indicated that BPA was more toxic to bacteria. The closed circuit operation of UCW-MFC performed better than the open circuit mode for COD and NH4+-N removal. Similarly, the removal rates of IBP and BPA were increased by 9.3% and 18%, respectively, compared with the open circuit mode. The majority of PPCPs were removed from the bottom and anode layer, which accounted for 63.2-78.7% of the total removal. The main degradation products were identified. The removal rates of IBP and BPA decreased by 14.6% and 23.7% due to a reduction in the hydraulic detention times (HRTs) from 16 h to 4 h, respectively. Electricity generation performance, including voltage and maximum power density, initially increased and then declined with a decrease in the HRT. Additionally, both the current circuit operation mode and the HRT have an impact on the bacterial community diversity of the anode according to the results of high-throughput sequencing. The possible bacterial groups involved in PPCP degradation were identified. In summary, UCW-MFC is suitable for enabling the simultaneous removal of IBP and BPA and successful electricity production. PMID- 30445406 TI - The temporal involvement of the left supramarginal gyrus in planning functional grasps: A neuronavigated TMS study. AB - The left supramarginal gyrus (SMG) is a critical structure in tool use actions, including such simple acts as selection of appropriate grasps and, if necessary, their on-line corrections. Yet, its temporal contribution to initial planning of functional grasps of tools is largely unknown. We used MRI-guided, event-related transcranial magnetic stimulation (TMS) to determine the time point when SMG involvement in processing of tools for functional grasp decision was affected most. In Exp. 1, with 15 participants, triple-pulse (10 Hz) TMS was applied to either the left anterior-to-mid SMG (amSMG; subdivisions PFt/PF) or vertex at three different time points: starting from 17 ms (i.e., delivered at 17/117/217 ms), 117 ms (117/217/317 ms) or 217 ms (217/317/417 ms) after stimulus onset. In Exp. 2, with 12 participants, we applied single-pulse TMS to either left amSMG or the left rostral middle frontal gurus (rMFG; area 46) at these same time points relative to stimulus onset. Subject- and item-based analyses of response times (RTs) were performed. Whereas the amSMG and vertex stimulation with triple pulse has revealed differential effects on RTs in general, as well as on tool orientation processing, it gave only vague pointers as to their temporal contributions to the task. Yet, amSMG and rMFG stimulation with single pulse demonstrated that, while the processing in both of these areas can be enhanced at 17 ms and no doubt at 117 ms (as compared to 217 ms), the earliest stimulation facilitated amSMG (vs. rMFG) contribution, and the latest stimulation had the opposite effect, facilitating rMFG (vs. amSMG) contribution to planning functional grasps. These outcomes demonstrate that the critical role of SMG in tool-related actions can be invoked substantially earlier than previously thought. PMID- 30445407 TI - Pappa2 deletion has sex- and age-specific effects on bone in mice. AB - OBJECTIVE: In humans, loss-of-function mutations in the gene encoding pregnancy associated pregnancy protein-A2 cause short stature and slightly reduced bone density. The goal of this study was to determine the effects of Pappa2 deletion on bone in mice. DESIGN: Pappa2 deletion mice and littermate controls were culled at 10, 19 or 30 weeks of age and femurs were analysed by micro-computed tomography. Serum markers of bone turnover and insulin-like growth factor binding protein 5 (IGFBP-5), a proteolytic target of PAPP-A2, were measured by ELISA. RESULTS: At 10 and 19 weeks of age, Pappa2 deletion mice had slightly reduced trabecular parameters, but by 19 weeks of age, female deletion mice had increased cortical tissue mineral density, and this trait was increased by a small amount in deletion mice of both sexes at 30 weeks. Cortical area fraction was increased in Pappa2 deletion mice at all ages. Deletion of Pappa2 increased circulating IGFBP-5 levels and reduced markers of bone turnover (PINP and TRACP 5b). CONCLUSIONS: PAPP-A2 contributes to the regulation of bone structure and mass in mice, likely through control of IGFBP-5 levels. The net effect of changes in bone formation and resorption depend on sex and age, and differ between trabecular and cortical bone. PMID- 30445408 TI - Torsional flexibility of undecorated catechol diether compound as potent NNRTI targeting HIV-1 reverse transcriptase. AB - Conformational adaptation of non-nucleoside reverse transcriptase inhibitor (NNRTI) via torsional flexibility is found to be very significant for targeting human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) mutants. Catechol diether derivative including flexible torsions is new potent NNRTI with picomolar activity. Moreover, this derivative also reveals the good solubility, low toxicity and potent inhibition for HIV-1 mutants. In this study, torsional flexibility of an undecorated catechol diether compound in the binding pocket of wild type and mutants (Y181C and K103N/Y181C) HIV-1 RT is investigated by using QM/MM calculations. From the results, the uracil ring is found to exhibit more flexibility in the NNIBP. On the contrary, potential energy surfaces show that high energy is encountered by changing of the corresponding torsion of the cyanovinyl aryl ring indicating the limitation for torsional flexibility. For pointing out the key interaction for the binding, the residual interaction energies are performed by means of QM calculations. Important attractive interactions through hydrogen bonds between the inhibitor and K102, K/N103, V106, and Y188 are observed. The catechol ring is proposed to be modified in order to strengthen interactions with surrounding amino acids. The results may help for the designing of new potent NNRTIs. PMID- 30445409 TI - Stress and immunosenescence: The role of telomerase. AB - Chronic stress is associated with the accelerated aging of the immune system and represents a potent risk factor for the development and progression of a wide range of physical and mental disorders. The elucidation of molecular pathways and mechanisms underlying the link between stress and cellular aging is an area of considerable interest and investigation. In this context, telomere biology has emerged as a particularly attractive candidate mechanism. Several studies have linked immune cell telomere length with stress-related conditions and states, and also with several physical and mental disorders. Because the cellular reverse transcriptase enzyme telomerase is the primary regulator of telomere length (by adding telomeric DNA to telomeres and thereby attenuating telomere shortening), the understanding of its regulation and regulatory functions constitutes a prime target for developing strategies to prevent, attenuate or reverse the adverse consequences of immune system aging (immunosenescence). In this review we provide an overview of the mechanistic pathways linking telomerase with stress and cellular aging, with an emphasis on the immune system. We summarize and synthesize the current state of the literature on immune cell telomerase in different stress- and aging-related disease states and provide recommendations for future research directions. PMID- 30445410 TI - Evaluability assessment of a community development leisure program in Spain. AB - This paper presents the results of an evaluability assessment (EA) conducted in Spain. EAs are assessments that minimize the uncertainty and risk inherent in a subsequent evaluation (e.g. an impact or results assessment) that may require excessive resources. We designed our own EA model by combining three theoretical approaches, with a holistic and pedagogic vision of the process and a flexible methodology to enable adaptation to different programs and contexts, thus fostering transferability. The EA was carried using a qualitative methodology: documentary analysis, seven semi-structured interviews with stakeholders, eight direct observation sessions and a check-list for politicians and experts. The outcome report helped promote organizational learning, provided the program with a logical and assessable theoretical model, detected its strengths and helped overcome the barriers to efficient assessment. Based on these achievements, an evaluation of the results was recommended, with repeated pretest-posttest measurements and an equivalent control group. PMID- 30445411 TI - A20 deficiency in multipotent progenitors perturbs quiescence of hematopoietic stem cells. AB - Inflammatory signals have been shown to play a critical role in controlling the maintenance and functions of hematopoietic stem cells (HSCs). While the significance of inflammation in hematopoiesis has begun to unfold, molecular mechanisms and players that govern this mode of HSC regulation remain largely unknown. The E3 ubiquitin ligase A20 has been considered as a central gatekeeper of inflammation. Here, we have specifically depleted A20 in multi-potent progenitors (MPPs) and studied its impact on hematopoiesis. Our data suggest that lack of A20 in Flt3+ progenitors causes modest alterations in hematopoietic differentiation. Analysis of hematopoietic stem and progenitor cell (HSPC) pool revealed alterations in HSPC subsets including, HSCs, MPP1, MPP2, MPP3 and MPP4. Interestingly, A20 deficiency in MPPs caused loss of HSC quiescence and compromised long-term hematopoietic reconstitution. Mechanistic studies identified that A20 deficiency caused elevated levels of Interferon-gamma signaling and downregulation of p57 in HSCs. In essence, these studies identified A20 as a key regulator of HSC quiescence and cell fate decisions. PMID- 30445412 TI - Dexmedetomidine for craniotomy under general anesthesia: A systematic review and meta-analysis of randomized clinical trials. AB - STUDY OBJECTIVE: To assess the efficacy and safety of dexmedetomidine as an adjunct to general anesthesia for craniotomy. DESIGN: A meta-analysis after systematically searching PubMed, Medline, EMBASE, and Cochrane library for randomized trials (RCTs). Relative risk (RR) and weighted mean difference (WMD) were calculated using random-effects meta-analysis. SETTING: Perioperative setting. PATIENTS: Twenty-two RCTs (1348 patients) with craniotomy under general anesthesia were included. INTERVENTIONS: Dexmedetomidine as an adjunct to general anesthesia versus placebo or other anesthetics. MEASUREMENTS: Primary outcomes included procedure success and postoperative pain; Secondary outcomes included cardiac adverse events, postoperative nausea and vomiting (PONV) and other clinically important outcomes. MAIN RESULTS: Dexmedetomidine vs. Placebo: High to moderate quality evidence suggested that dexmedetomidine reduced postoperative pain (WMD -0.25 cm, 95%CI -0.43 to -0.07 cm on a 10 cm visual analogue scale), postoperative nausea and vomiting (PONV, RR 0.57, 95%CI 0.39 to 0.84), hypertension (RR 0.37, 95%CI 0.22 to 0.61) and tachycardia (RR 0.32, 95%CI 0.12 to 0.85) with no significant increase of hypotension and bradycardia. Moderate quality evidence suggested no significant difference in procedural success. Dexmedetomidine vs. Active Comparators (including remifentanil, fentanyl, or propofol): Moderate quality evidence showed no difference in procedural success and postoperative pain. CONCLUSIONS: Dexmedetomidine as an adjunct to general anesthesia shows small benefits in reduction of pain, PONV, and maintains more stable hemodynamics with comparable effects on procedural success versus placebo. Very limited evidence explored comparative effects between dexmedetomidine and active controls. Further evidence is required to evaluate patient-important outcomes and optimal dosing strategies, particularly versus active comparators. PMID- 30445413 TI - Gangrene and finger amputation after radial artery cannulation. PMID- 30445414 TI - The role of drinking motives and perceived controllability of events in the association between college women's sexual assault victimization and binge drinking. AB - Women with a history of sexual assault are at elevated risk for engaging in binge drinking. The aims of the current study are to investigate two types of drinking motives (coping and social) that potentially underlie the sexual assault-binge drinking link in a sample of female college drinkers (N = 691; 37.6% sexual assault prevalence), and to determine the extent to which the relationships between sexual assault history and each type of drinking motive depend on women's assumptions about the controllability of events. Conditional process analysis results indicated that women who experienced sexual assault (vs. those who did not) were more likely to report both coping and social drinking motives, which in turn, were both positively associated with increased binge drinking. Consistent with our hypothesis, results showed the relationship between sexual assault history and coping drinking motives was moderated by perceived controllability of events. Specifically, sexual assault victims reported high coping motives regardless of controllability of events. Nonvictims only reported high coping motives when their perceived controllability of events was low - comparable to coping motives of victims. This integrative approach affords a more comprehensive understanding of the context in which college women's binge drinking occurs, and offers insight into processes that could be targeted in interventions. PMID- 30445415 TI - The potential impact of naturally produced antibiotics, environmental factors, and anthropogenic pressure on the occurrence of erm genes in urban soils. AB - The occurrence of environmental antibiotic resistance genes (ARGs) are often attributed to selective pressure from antibiotics from point source pollution. However, the potential effects of natural production of antibiotics, environmental factors, and anthropogenic pressure on the development and spread of ARGs have not been fully investigated. This study evaluated the occurrence and distribution of erythromycin resistance methylase (erm) genes in urban soils. The ermA, ermB, ermC, ermD, ermF, ermG, ermT, and ermY genes were detected with detection frequencies ranging from 20% to 80% and abundances ranging between 5.95 * 101 and 6.94 * 106 copies g-1 dw soil. Both polyketide synthase (PKS) type I and type II biosynthesis genes-which are responsible for biosynthesis of polyketides, such as erythromycin-were detected in all soil samples with a range between 5.77 * 102 and 9.39 * 106 copies g-1 dw soil. The abundances of PKS genes were significantly correlated with 16S rRNA genes (r = 0.487 to 0.741, p < 0.001) and absolute abundances of ermB, ermC, ermD, ermG, and ermY (r = 0.302-0.490, p < 0.05), suggesting that the wide occurrence of ARGs in soils could be potentially driven by naturally produced antibiotics. Erythromycin was strongly correlated with ermB, ermC, ermF and ermY genes (r = 0.462 to 0.667, p < 0.05), but no significant correlation was observed between macrolides and PKS genes, suggesting other environmental factors may have contributed to detected macrolides. The fact that erm gene presented higher extent of variability than PKS genes in different land use types suggests that anthropogenic activity might also influence the occurrence of erm genes in urban soils. PMID- 30445416 TI - Adaptive shifts of bacterioplankton communities in response to nitrogen enrichment in a highly polluted river. AB - Anthropogenic activity-mediated nutrient pollution, especially nitrogen enrichment, poses one of the major threats to river ecosystems. However, it remains unclear how and to which extent it affects aquatic microbial communities, especially in heavily polluted rivers. In this study, a significant environmental gradient, particularly nitrogen gradient, was observed along a wastewater receiving river, the North Canal River (NCR). The pollution level was highest, moderate, and lowest in the up-, middle, and down-streams, respectively. The community composition of bacterioplankton transitioned from being Betaproteobacteria-dominated upstream to Gammaproteobacteria-dominated downstream. Copiotrophic groups, such as Polynucleobacter (Betaproteobacteria) and Hydrogenophaga (Betaproteobacteria), were dominant in the upstream. Multiple statistical analyses indicated that total nitrogen (TN) was the most important factor driving the adaptive shifts of community structure. Analyses of co occurrence networks showed that the complexity of networks was disrupted in the up- and middle streams, while enhanced in the downstream. Our findings here suggested that microbial interactions were reduced in response to the aggravation of nutrient pollution. Similar to these changes, we observed significant dissimilarity of composition of functional groups, with highest abundance of nitrogen metabolism members under the highest level of nitrogen enrichment. Further analyses indicated that most of these functional groups belonged to Betaproteobacteria, suggesting the potential coupling of community composition and function diversity. In summary, adaptive shifts of bacterioplankton community composition, as well as species interactions, occurred in response to nutrient pollution in highly polluted water bodies. PMID- 30445417 TI - (+)-Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation. AB - Depression is a mood disorder that is related to neuroinflammation and cognition loss. This study is aimed to determine the potential antidepressant effects of (+)-sesamin, a lignan component of sesame, in a mild stress-induced depression mouse model. CD-1 mice were treated with chronic unpredictable mild stress (CUMS) process and orally administrated with sesamin (50 mg/kg/d) for 6 weeks. Behavioral tests including forced swimming test, tail suspension test, open field test, and elevated plus maze test demonstrated that sesamin treatment inhibited CUMS-induced mice depressant-like behaviors and anxiety, without changing immobility. It was found that sesamin prevented stress-induced decease levels of 5-HT and NE in striatum and serum. Cognitive deficits were assessed using Y-maze and Morris water maze test. Sesamin treatment also prevented stressed-induced memory impairments and neuronal damages. Consistently, sesamin also enhanced synapse ultrastructure and improved expressions of PSD-95 in stressed mice hippocampus with improving neurotrophic factors expression including BDNF and NT3. Moreover, sesamin treatment significantly prevented CUMS-induced neuroinflammation by inhibiting over-activation of microglia and expressions of inflammatory mediators including iNOS, COX-2, TNF-alpha and IL-1beta in stressed mice hippocampus and cortex. These results illustrated that sesamin markedly improved CUMS-induced depression and memory loss via inhibiting neuroinflammation, which indicate that as food component, sesamin might be also a novel potential therapeutic for depression. PMID- 30445418 TI - Fluid therapy in non-septic, refractory acute decompensated heart failure patients - The cautious role of central venous pressure. AB - PURPOSE: Fluid therapy in congestive acute decompensated heart failure (ADHF) patients might be inappropriate and worsening the prognosis. The aim of our study was to analyze the effect of fluid administration on mortality in non-septic, ADHF patients with reduced ejection fraction. MATERIAL AND METHODS: We analyzed 41 ADHF consecutive 'cold-wet' patients (mean age 69.3 +/- 14.9 years, 27 men, LVEF 22.8 +/- 11.1%, lactates 2.2 +/- 1.6 mmol/L) without sepsis. At admission central venous pressure (CVP) was measured (17.6 +/- 7.2 cm H2O), and ultrasound examination of inferior vena cava (IVC) was performed (IVC min. 18.6 +/- 7.3 mm and IVC max. 24.6 +/- 4.3 mm). Moreover, the groups were compared (survivors vs. non-survivors as well as 1st and 4th quartile of CVP). RESULTS: Altogether 17 (41%) patients died: 16 (39%) during a mean of 11.2 +/- 7.8 days of hospitalization and 1 during a 30-day follow up. Patients in the lowest CVP quartile (<13 cm H2O) had significantly worse in-hospital survival as compared to patients in the highest quartile (>24 cm H2O), P = 0.012. Higher intravenous fluid volumes within the first 24 h were infused in patients in the lowest CVP quartile as compared to the highest CVP quartile (1791.7 +/- 1357.8 mL vs. 754.5 +/- 631.4 mL, P = 0.046). Moreover, more fluids were infused in a group of patients who died during a hospital stay and at 30-day follow up (1362.8 +/- 752.7 mL vs. 722.7 +/- 1046.5 mL, P = 0.004; 1348.8 +/- 731.0 mL vs. 703.6 +/- 1068.4 mL, P = 0.002, respectively). CONCLUSIONS: CVP-guided intravenous fluid therapy is a common practice which in high risk ADHF 'cold-wet' patients might be harmful and should rather be avoided. Lower CVP seems to be related with worse prognosis. PMID- 30445420 TI - Bayesian estimation of a semiparametric recurrent event model with applications to the penetrance estimation of multiple primary cancers in Li-Fraumeni syndrome. AB - A common phenomenon in cancer syndromes is for an individual to have multiple primary cancers (MPC) at different sites during his/her lifetime. Patients with Li-Fraumeni syndrome (LFS), a rare pediatric cancer syndrome mainly caused by germline TP53 mutations, are known to have a higher probability of developing a second primary cancer than those with other cancer syndromes. In this context, it is desirable to model the development of MPC to enable better clinical management of LFS. Here, we propose a Bayesian recurrent event model based on a non homogeneous Poisson process in order to obtain penetrance estimates for MPC related to LFS. We employed a familywise likelihood that facilitates using genetic information inherited through the family pedigree and properly adjusted for the ascertainment bias that was inevitable in studies of rare diseases by using an inverse probability weighting scheme. We applied the proposed method to data on LFS, using a family cohort collected through pediatric sarcoma patients at MD Anderson Cancer Center from 1944 to 1982. Both internal and external validation studies showed that the proposed model provides reliable penetrance estimates for MPC in LFS, which, to the best of our knowledge, have not been reported in the LFS literature. PMID- 30445419 TI - Effect Modification by Age on the Benefit or Harm of Antihypertensive Treatment for Elderly Hypertensives: A Systematic Review and Meta-analysis. AB - BACKGROUND: The influence of age on balance of benefit versus potential harm of blood pressure (BP)-lowering therapy for elderly hypertensives is unclear. We evaluated the modifying effects of age on BP lowering for various adverse outcomes in hypertensive patients older than 60 years without specified comorbidities. METHODS: All relevant randomized controlled trials (RCTs) were systematically identified. Coronary heart disease, stroke, heart failure (HF), cardiovascular death, major adverse cardiovascular events (MACE), renal failure (RF), and all-cause death were assessed. Meta-regression analysis was used to explore the relationship between achieved systolic BP (SBP) and the risk of adverse events. Random-effects meta-analysis was used to pool the estimates. RESULTS: Our study included eighteen RCTs (n=53993). Meta-regression analysis showed a lower achieved SBP related with a lower risk of stroke and cardiovascular death, but an increased risk of RF. The regression slopes were comparable between populations stratifying by age 75 years. In subgroup analysis, the relative risks of a more aggressive BP lowering strategy were similar between patients aged older or less than 75 years for all outcomes except for RF (P for interaction=0.02). Compared to treatment with final achieved SBP 140-150 mmHg, a lower achieved SBP (<140 mmHg) was significantly associated with decreased risk of stroke (relative risk, 0.68; 95% confidence interval, 0.55-0.85), HF (0.77; 0.60-0.99), cardiovascular death (0.68; 0.52-0.89), and MACE (0.83; 0.69-0.99). CONCLUSIONS: To treat hypertension in the elderly, age had trivial effect modification on most outcomes, except for renal failure. Close monitoring of renal function may be warranted in the management of elderly hypertension. PMID- 30445421 TI - High Throughput Identification of Plasma Proteomic Signature of Inflammatory Bowel Disease. AB - Background: The molecular etiology of inflammatory bowel disease (IBD) and its two subtypes, ulcerative colitis (UC) and Crohn's disease (CD), have been carefully investigated at genome and transcriptome levels. Recent advances in high throughput proteome quantification has enabled comprehensive large scale plasma proteomics studies of IBD. Methods: The study used two cohorts: (1) CERTIFI-cohort: 42 sample from the CERTIFI trial of anti TNFalpha refractory CD patients; (2) PROgECT-UNITI-HC cohort: 46 UC samples PROgECT study, 84 CD samples of UNITI I and UNITI II, and 72 healthy controls recruited in Mount Sinai Hospital, New York, USA. Plasma proteome for these two cohorts was quantified using high throughput platforms. Results: On PROgECT-UNITI-HC cohort, we measured a total of 1,310 proteins. 493 proteins showed different plasma levels in IBD patients versus controls at 10% FDR, among which 11, proteins had a fold change greater than 2. Proteins up-regulated in IBD were enriched for immunity functionality while the proteins down-regulated in IBD were enriched for nutrition and metabolism. Proteomic profiles were very similar between UC and CD. On CERTIFI cohort, 1,014 proteins were measured, and found plasma protein level had little correlation with blood or intestine transcriptome. Conclusions: We report the largest proteomics study to date on IBD and controls. A large proportion of plasma proteins are altered in IBD, revealing insights on the disease etiology indicating a potential for biomarker discovery. PMID- 30445422 TI - Accuracy of urinary symptoms and urine microscopy in diagnosing urinary tract infection in women. AB - Background: Women with urinary tract infections (UTIs) often present with urinary complaints such as frequency of micturition, dysuria, foul-smelling urine and other non-specific symptoms like fever. Physicians may order urine microscopy to guide empirical antibiotic prescription. However, the performance of this approach has not been assessed. Objectives: This study aimed to determine the accuracy of UTI symptoms and urine microscopy associated with culture-positive UTI in Asian women. Methods: A cross-sectional study of adult women who presented with UTI-related symptoms was conducted at three public primary care clinics in Singapore. Demographic data and information on their symptoms were collected, followed by urine microscopy and culture to diagnose UTI. The sensitivity, specificity, positive (PPV), negative predictive values (NPV), accuracy (ACC) and area under curve (AUC) of combinations of symptom and urine investigations were analysed in association with culture-positive UTI, which was regarded as a benchmark. Results: Data on 564 women (73.9% Chinese, 11.5% Malay, 8.2% Indian) were analysed, of which 259 (45.9%) had culture-positive UTI. Frequency and foul smelling urine, pyuria (WBC >=10/hpf) and semi-quantitative bacterial count (>=2+) were significantly associated with positive urine culture. The ACC and AUC for single or multiple urinary and/or general symptoms were low. Urine pyuria (minimally >10/hpf) alone or in combination with symptoms and/or semi quantitative bacterial count achieved high sensitivity (>85%) and PPV, NPV, ACC and AUC of >70%. Conclusion: Urinary symptoms have limited accuracy in diagnosing culture-positive UTI. Concurrent urine microscopy showing presence of pyuria and/or bacterial count increased the diagnostic accuracy of culture-positive UTI. PMID- 30445423 TI - SPINT2 (HAI-2) missense variants identified in congenital sodium diarrhea/tufting enteropathy affect the ability of HAI-2 to inhibit prostasin but not matriptase. AB - The syndromic form of congenital sodium diarrhea (SCSD) is caused by bi-allelic mutations in SPINT2, which encodes a Kunitz type serine protease inhibitor (HAI 2). We report three novel SCSD patients, two novel SPINT2 mutations, and review published cases. The most common findings in SCSD patients were choanal atresia (20/34), and keratitis of infantile onset (26/34). Characteristic epithelial tufts on intestinal histology were reported in 13/34 patients. Of 13 different SPINT2 variants identified in SCSD, four are missense variants and localize to the second Kunitz domain (KD2) of HAI-2. HAI-2 has been implicated in the regulation of the activities of several serine proteases including prostasin and matriptase, which are both important for epithelial barrier formation. No patient with bi-allelic stop mutations was identified, suggesting that at least one SPINT2 allele encoding a protein with residual HAI-2 function is necessary for survival. We show that the SCSD-associated HAI-2 variants p.Phe161Val, p.Tyr163Cys, and p.Gly168Ser all display decreased ability to inhibit prostasin catalyzed cleavage. However, the SCSD-associated HAI-2 variants inhibited matriptase as efficiently as the wild-type HAI-2. Homology modeling indicated limited solvent exposure of the mutated amino acids, suggesting that they induce misfolding of KD2. This suggests that prostasin needs to engage with an exosite motif located on KD2 in addition to the binding loop (Cys47/Arg48) located on the first Kunitz domain in order to inhibit prostasin. In conclusion our data suggests that SCSD is caused by lack of inhibition of prostasin or a similar protease in the secretory pathway or on the plasma membrane. PMID- 30445425 TI - PEPCK1 antisense oligonucleotide prevents adiposity and impairs hepatic glycogen synthesis in high-fat male fed rats. AB - The increase in hepatic gluconeogenesis in type 2 diabetes mellitus (T2DM) is often ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1 (cytosolic form, PEPCK1) though increasing evidence questions this attribution. To assess the metabolic role of PEPCK1, we treated regular chow (RC) fed and high fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them to control ASO treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in liver and white adipose tissue (WAT). In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose or insulin. In contrast, PEPCK1 ASO decreased WAT mass in HFF rats, but without altering basal rates of lipolysis, de novo lipogenesis or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO treated rats. PEPCK1 ASO worsened hepatic steatosis though without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and decrease in hepatic glycogen synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased synthesis of glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3 (ATF3), a negative regulator of GCK transcription. These studies demonstrate that PEPCK1 is integral to coordinating cellular metabolism in liver and adipose tissue though it does not directly impact hepatic glucose production or adipose glyceroneogenesis. PMID- 30445426 TI - Clinical outcomes of hypofractionated image-guided multifocal irradiation using volumetric-modulated arc therapy for brain metastases. AB - Volumetric-modulated arc therapy (VMAT) can be used to design hypofractionated radiotherapy treatment plans for multiple brain metastases. The purpose of this study was to evaluate treatment outcomes of hypofractionated image-guided multifocal irradiation using VMAT (HFIGMI-VMAT) for brain metastases. From July 2012 to December 2016, 67 consecutive patients with 601 brain metastases were treated with HFIGMI-VMAT at our institution. The prescribed dose was 50 Gy to a 95% volume of the planning target volume in 10 fractions. Fifty-five of the 67 patients had non-small-cell lung cancer, and the remaining 12 had other types of cancer. The median number of brain metastases was five, and the median maximum diameter was 1.2 cm. The median duration of follow-up was 12.0 months (range, 1.9 44.8 months), and the median survival time 18.7 months. Four patients with six lesions had local recurrences. The local control rate in the 64 assessed patients was 98.4% and 95.3% at 6 and 12 months, respectively (three died before assessment). The local control rate for the 572 assessed lesions was 99.8% and 99.3% at 6 and 12 months, respectively. Thirty-nine patients developed distant brain metastases, the distant brain control rate being 59.7% and 40.5% at 6 and 12 months, respectively. Acute toxicities were generally mild (Grade 1-2). Three patients (4.5%) developed radiation necrosis requiring corticosteroid therapy. The HFIGMI-VMAT technique with flat dose delivery was well tolerated and achieved excellent local control. This technique is a promising treatment option for patients with multiple and large brain metastases. PMID- 30445424 TI - BOARD-INVITED REVIEW: Arginine nutrition and metabolism in growing, gestating, and lactating swine. AB - Arginine (Arg) has traditionally not been considered as a deficient nutrient in diets for gestating or lactating swine due to the assumption that these animals can synthesize sufficient amounts of Arg to meet their physiological needs. The lack of full knowledge about Arg nutrition has contributed to suboptimal efficiency of pork production. Over the past 25 yr, there has been growing interest in Arg metabolism in the pig, which is an agriculturally important species and a useful model for studying human biology. Arginine is a highly abundant amino acid in tissues of pigs, a major amino acid in allantoic fluid, and a key regulator of gene expression, cell signaling, and antioxidative reactions. Emerging evidence suggests that dietary supplementation with 0.5% to 1% Arg maintains gut health and prevents intestinal dysfunction in weanling piglets, while enhancing their growth performance and survival. Also, the inclusion of 1% Arg in diets is required to maximize skeletal muscle accretion and feed efficiency in growing pigs, whereas dietary supplementation with 1% Arg reduces muscle loss in endotoxin-challenged pigs. Furthermore, supplementing 0.83% Arg to corn- and soybean meal-based diets promotes embryonic/fetal survival in swine and milk production by lactating sows. Thus, an adequate amount of dietary Arg as a quantitatively major nutrient is necessary to support maximum growth, lactation, and reproduction performance of swine. These results also have important implications for improving the nutrition and health of humans and other animals. PMID- 30445427 TI - 15 years of PhosphoSitePlus(r): integrating post-translationally modified sites, disease variants and isoforms. AB - For 15 years the mission of PhosphoSitePlus(r) (PSP, https://www.phosphosite.org) has been to provide comprehensive information and tools for the study of mammalian post-translational modifications (PTMs). The number of unique PTMs in PSP is now more than 450 000 from over 22 000 articles and thousands of MS datasets. The most important areas of growth in PSP are in disease and isoform informatics. Germline mutations associated with inherited diseases and somatic cancer mutations have been added to the database and can now be viewed along with PTMs and associated quantitative information on novel 'lollipop' plots. These plots enable researchers to interactively visualize the overlap between disease variants and PTMs, and to identify mutations that may alter phenotypes by rewiring signaling networks. We are expanding the sequence space to include over 30 000 human and mouse isoforms to enable researchers to explore the important but understudied biology of isoforms. This represents a necessary expansion of sequence space to accommodate the growing precision and depth of coverage enabled by ongoing advances in mass spectrometry. Isoforms are aligned using a new algorithm. Exploring the worlds of PTMs and disease mutations in the entire isoform space will hopefully lead to new biomarkers, therapeutic targets, and insights into isoform biology. PMID- 30445428 TI - FactorialHMM: Fast and exact inference in factorial hidden Markov models. AB - Motivation: Hidden Markov models (HMMs) are powerful tools for modeling processes along the genome. In a standard genomic HMM, observations are drawn, at each genomic position, from a distribution whose parameters depend on a hidden state; the hidden states evolve along the genome as a Markov chain. Often, the hidden state is the Cartesian product of multiple processes, each evolving independently along the genome. Inference in these so-called Factorial HMMs has a naive running time that scales as the square of the number of possible states, which by itself increases exponentially with the number of sub-chains; such a running time scaling is impractical for many applications. While faster algorithms exist, there is no available implementation suitable for developing bioinformatics applications. Results: We developed FactorialHMM, a Python package for fast exact inference in Factorial HMMs. Our package allows simulating either directly from the model or from the posterior distribution of states given the observations. Additionally, we allow the inference of all key quantities related to HMMs: (1) the (Viterbi) sequence of states with the highest posterior probability; (2) the likelihood of the data; and (3) the posterior probability (given all observations) of the marginal and pairwise state probabilities. The running time and space requirement of all procedures is linearithmic in the number of possible states. Our package is highly modular, providing the user with maximal flexibility for developing downstream applications. Availability: https://github.com/regevs/factorial_hmm. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445429 TI - Octapeptin C4 and polymyxin resistance occur via distinct pathways in an epidemic XDR Klebsiella pneumoniae ST258 isolate. AB - Background: Polymyxin B and E (colistin) have been pivotal in the treatment of XDR Gram-negative bacterial infections; however, resistance has emerged. A structurally related lipopeptide, octapeptin C4, has shown significant potency against XDR bacteria, including polymyxin-resistant strains, but its mode of action remains undefined. Objectives: We sought to compare and contrast the acquisition of resistance in an XDR Klebsiella pneumoniae (ST258) clinical isolate in vitro with all three lipopeptides to potentially unveil variations in their mode of action. Methods: The isolate was exposed to increasing concentrations of polymyxins and octapeptin C4 over 20 days. Day 20 strains underwent WGS, complementation assays, antimicrobial susceptibility testing and lipid A analysis. Results: Twenty days of exposure to the polymyxins resulted in a 1000-fold increase in the MIC, whereas for octapeptin C4 a 4-fold increase was observed. There was no cross-resistance observed between the polymyxin- and octapeptin-resistant strains. Sequencing of polymyxin-resistant isolates revealed mutations in previously known resistance-associated genes, including crrB, mgrB, pmrB, phoPQ and yciM, along with novel mutations in qseC. Octapeptin C4-resistant isolates had mutations in mlaDF and pqiB, genes related to phospholipid transport. These genetic variations were reflected in distinct phenotypic changes to lipid A. Polymyxin-resistant isolates increased 4-amino-4-deoxyarabinose fortification of lipid A phosphate groups, whereas the lipid A of octapeptin C4 resistant strains harboured a higher abundance of hydroxymyristate and palmitoylate. Conclusions: Octapeptin C4 has a distinct mode of action compared with the polymyxins, highlighting its potential as a future therapeutic agent to combat the increasing threat of XDR bacteria. PMID- 30445430 TI - School performance and educational attainment as early-life predictors of age related memory decline: Protective influences in later-born cohorts. AB - Objectives: Evidence is accumulating that early-life characteristics and experiences contribute significantly to differences in cognitive aging. This study investigated whether school performance at age 12 predicted late-life level and rate of memory change over 15-25 years, and whether its potential protective influence on memory change was mediated by educational attainment or income. Methods: Latent growth curve models were fitted to 15-25 year longitudinal memory data from a population-based sample, stratified on age-cohorts (n=227 born 1909 1935; n=301 born 1938-1954). Results: A latent-level school grade variable significantly predicted both memory level and slope in later-born cohorts. Higher grades were associated with higher level and reduced decline, measured between ages 45-70, on average. In the earlier-born cohorts grades predicted memory level, but not slope, measured between ages 66-81 years. Follow-up analyses indicated that the protective influence of higher school grades in later-born cohorts was partially mediated by educational attainment, but independent of income. Discussion: The results suggest that higher childhood school performance is protective against age-related cognitive decline in younger or later-born cohorts, for which further education has been more accessible. Education may exert such influence through increased cognitive reserve or more well-informed health- and lifestyle decisions. PMID- 30445431 TI - High Constitutive IL-10 Interferes with the Immune Response to Varicella-Zoster Virus (VZV) in Elderly Recipients of Live Attenuated Zoster Vaccine. AB - Introduction: Live attenuated zoster vaccine (ZostavaxTM) was used to test the hypothesis that constitutive IL-10, which may be high in elderly subjects, impairs vaccine efficacy. If true, then effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination. Methods: ZostavaxTM was given to 26 patients (ages 60-80). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) and gpELISA were used to assess humoral immunity; anti varicella T cell responses were studied in a subset of subjects. In a prospective animal model, T cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10. Results: FAMA assays revealed significant boosting (4-fold) of humoral immunity, which occurred only in subjects (10/26) with low constitutive IL-10 (< 20 pg/ml); moreover, the ZostavaxTM-induced FAMA and gpELISA responses were inversely related to constitutive IL-10. Significant VZV-specific T cell responses followed vaccination only in subjects with low constitutive IL-10. Vaccine-induced LCMV specific T cell responses in mice lacking IL-10 were greater than in wild-type animals. Conclusions: High constitutive IL-10 adversely affects vaccine efficacy. PMID- 30445432 TI - gmRAD: an integrated SNP calling pipeline for genetic mapping with RADseq across a hybrid population. AB - Restriction site-associated DNA sequencing (RADseq) is a powerful technology that has been extensively applied in population genetics, phylogenetics and genetic mapping. Although many software packages are available for ecological and evolutionary studies, a few effective tools are available for extracting genotype data with RADseq for genetic mapping, a prerequisite for quantitative trait locus mapping, comparative genomics and genome scaffold assembly. Here, we present an integrated pipeline called gmRAD for generating single nucleotide polymorphism (SNP) genotypes from RADseq data, de novo, across a genetic mapping population derived by crossing two parents. As an analytical strategy, the software takes five steps to implement the whole algorithms, including clustering the first (forward) reads of each parent, building two parental references, generating parental SNP catalogs, calling SNP genotypes across all individuals and filtering the genotype data for genetic linkage mapping. All the steps can be completed with a simple command line, but they can be also performed optionally if prerequisite files are available. To validate its application, we also performed a real data analysis with RADseq data from an F1 hybrid population derived by crossing Populus deltoides and Prunus simonii. The software gmRAD is freely available at https://github.com/tongchf/gmRAD. PMID- 30445433 TI - Microclimatic Conditions for Dung Beetle (Coleoptera: Scarabaeidae) Occurrence: Land Use System as a Determining Factor. AB - Tropical forests account for 7% of the earth's surface harboring more than 50% of the biodiversity on Earth. Unfortunately, deforestation continues at high rates with negative consequences for biodiversity. With the decrease of natural habitats, biodiversity maintenance in areas degraded by human activity is a challenge. In order to maintain biodiversity, both in natural areas and in agro ecosystems, knowledge of the structure and function of organism communities is important. Dung beetles (Scarabaeidae) play an important role in tropical ecosystems by recycling organic matter. Dung beetle diversity was appraised during 1 yr in an Atlantic forest remnant and five anthropic adjacent vegetation systems. In total, 1,047 individuals were sampled representing 17 species. Scybalocanthon nigriceps was the most abundant (523 individuals: 50%) almost exclusively in forest areas. Ataenius aff. platensis (48 individuals: 4.6%), and Canthon aff. luctuosus (109 individuals: 10.4%) were observed in all areas, while Canthon virens chalybaeus (111 individuals: 10.6%) was limited to anthropic areas. Dung beetle diversity was affected by microclimatic conditions concerning precipitation and air temperature. The greatest abundance and richness was found in the rainy season with a striking reduction in the dry period. The pasture sustained the lowest species diversity and abundance. However, there are clear signs that tree structure and microclimatic conditions similar to forests, as found in agroforestry, can help preserve biodiversity by creating a propitious habitat for native species. This is especially important in the forest regions of the Neotropics where dung beetles exhibit their greatest diversity. As dung beetles greatly depend on mammal feces and carrion, it is suggested that future studies incorporate the occurrence of mammals in investigations of the effects of landscape structure on scarab diversity. PMID- 30445435 TI - Semi-supervised learning of Hidden Markov Models for biological sequence analysis. AB - Motivation: Hidden Markov Models (HMMs) are probabilistic models widely used in applications in computational sequence analysis. HMMs are basically unsupervised models. However, in the most important applications, they are trained in a supervised manner. Training examples accompanied by labels corresponding to different classes are given as input and the set of parameters that maximize the joint probability of sequences and labels is estimated. A main problem with this approach is that, in the majority of the cases, labels are hard to find and thus the amount of training data is limited. On the other hand, there are plenty of unclassified (unlabeled) sequences deposited in the public databases that could potentially contribute to the training procedure. This approach is called semi supervised learning and could be very helpful in many applications. Results: We propose here, a method for semi-supervised learning of HMMs that can incorporate labeled, unlabeled and partially-labeled data in a straightforward manner. The algorithm is based on a variant of the Expectation-Maximization (EM) algorithm, where the missing labels of the unlabeled or partially-labeled data are considered as the missing data. We apply the algorithm to several biological problems, namely, for the prediction of transmembrane protein topology for alpha helical and beta-barrel membrane proteins and for the prediction of archaeal signal peptides. The results are very promising, since the algorithms presented here can significantly improve the prediction performance of even the top-scoring classifiers. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445436 TI - In-stent restenosis in the left anterior descending coronary artery: what is the solution for diffuse disease? Patch reconstruction and coronary artery bypass grafting-surgery as the first option in complex coronary artery disease. PMID- 30445434 TI - The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. AB - The GWAS Catalog delivers a high-quality curated collection of all published genome-wide association studies enabling investigations to identify causal variants, understand disease mechanisms, and establish targets for novel therapies. The scope of the Catalog has also expanded to targeted and exome arrays with 1000 new associations added for these technologies. As of September 2018, the Catalog contains 5687 GWAS comprising 71673 variant-trait associations from 3567 publications. New content includes 284 full P-value summary statistics datasets for genome-wide and new targeted array studies, representing 6 * 109 individual variant-trait statistics. In the last 12 months, the Catalog's user interface was accessed by ~90000 unique users who viewed >1 million pages. We have improved data access with the release of a new RESTful API to support high throughput programmatic access, an improved web interface and a new summary statistics database. Summary statistics provision is supported by a new format proposed as a community standard for summary statistics data representation. This format was derived from our experience in standardizing heterogeneous submissions, mapping formats and in harmonizing content. Availability: https://www.ebi.ac.uk/gwas/. PMID- 30445437 TI - Microbial subnetworks related to short-term diel O2 fluxes within geochemically distinct freshwater wetlands. AB - Oxygen (O2) concentrations often fluctuate over diel timescales within wetlands, driven by temperature, sunlight, photosynthesis and respiration. These daily fluxes have been shown to impact biogeochemical transformations (e.g. denitrification), which are mediated by the residing microbial community. However, little is known about how resident microbial communities respond to diel physical and chemical fluxes in freshwater wetland ecosystems. In this study, total microbial (bacterial and archaeal) community structure was significantly related to diel time points in just one out of four distinct freshwater wetlands sampled. This suggests that daily environmental shifts may influence wetlands differentially based upon the resident microbial community and specific physical and chemical conditions of a freshwater wetland. When exploring the microbial communities within each wetland at finer resolutions, subcommunities of taxa within two wetlands were found to correspond to fluctuating O2 levels. Microbial taxa that were found to be susceptible to fluctuating O2 levels within these subnetworks may have intimate ties to metabolism and/or diel redox cycles. This study highlights that freshwater wetland microbial communities are often stable in community structure when confronted with short-term O2 fluxes; however, specialist taxa may be sensitive to these same fluxes. PMID- 30445438 TI - Characteristics of plant circular RNAs. AB - Circular RNA (circRNA) is a kind of covalently closed single-stranded RNA molecules that have been proved to play important roles in transcriptional regulation of genes in diverse species. With the rapid development of bioinformatics tools, a huge number (95143) of circRNAs have been identified from different plant species, providing an opportunity for uncovering the overall characteristics of plant circRNAs. Here, based on publicly available circRNAs, we comprehensively analyzed characteristics of plant circRNAs with the help of various bioinformatics tools as well as in-house scripts and workflows, including the percentage of coding genes generating circRNAs, the frequency of alternative splicing events of circRNAs, the non-canonical splicing signals of circRNAs and the networks involving circRNAs, miRNAs and mRNAs. All this information has been integrated into an upgraded online database, PlantcircBase 3.0 (http://ibi.zju.edu.cn/plantcircbase/). In this database, we provided browse, search and visualization tools as well as a web-based blast tool, BLASTcirc, for prediction of circRNAs from query sequences based on searching against plant genomes and transcriptomes. PMID- 30445439 TI - Listeriolysin O-dependent host surfaceome remodeling modulates Listeria monocytogenes invasion. AB - Listeria monocytogenes is a pathogenic bacterium that invades epithelial cells by activating host signaling cascades, which promote bacterial engulfment within a phagosome. The pore-forming toxin listeriolysin O (LLO), which is required for bacteria phagosomal escape, has also been associated with the activation of several signaling pathways when secreted by extracellular bacteria, including Ca2+ influx and promotion of L. monocytogenes entry. Quantitative host surfaceome analysis revealed significant quantitative remodeling of a defined set of cell surface glycoproteins upon LLO treatment, including a subset previously identified to play a role in the L. monocytogenes infection process. Our data further shows that the lysosomal-associated membrane proteins LAMP-1 and LAMP-2 are translocated to the cellular surface and those LLO-induced Ca2+ fluxes are required to trigger the surface relocalization of LAMP-1. Finally, we identify late endosomes/lysosomes as the major donor compartments of LAMP-1 upon LLO treatment and by perturbing their function, we suggest that these organelles participate in L. monocytogenes invasion. PMID- 30445440 TI - Anatomical variations of the aortic arch branches in a sample of Chinese cadavers: embryological basis and literature review. AB - OBJECTIVES: The aim of this study is to determine the incidence and explore the types of aortic arch branch variations found in our cadavers. METHODS: The types and incidence of aortic branch variations in 120 cadavers were analysed after careful dissection. RESULTS: One hundred and six of 120 cadavers had normal aortic arch branches and gave rise to usual branches, namely the brachiocephalic trunk, the left common carotid artery and the left subclavian artery. The remaining 14 cadavers had 2 basic types of branch variations, thus accounting for an incidence of 11.67%. A total of 9 aortic arches emitted 4 branches; the brachiocephalic trunk, the left common carotid artery, the left vertebral artery and the left subclavian artery (incidence 7.5%). The second subgroup of 5 cadavers also emitted 4 aortic branches: the right common carotid artery, the left common carotid artery, the left subclavian artery and the right subclavian artery (incidence 4.16%). In this group, the right subclavian artery sprung as a distal branch of the aortic arch (descending), thus making a vascular ring that takes a superoposterior course round the back of the trachea and the oesophagus to reach the right side. There was a single cadaver, different from the other 4 aortic branches of the second group which had a common origin for the common carotid arteries, while the left subclavian artery and distally placed right subclavian artery were present. We did not observe any Kommerell's aortic diverticula. CONCLUSIONS: The variations of aortic arch branching are complex and diverse due to varied possible alterations in the embryological processes. There is an imperative need for further research on these variations to elucidate the possible relationships with clinical diagnostic or surgical events. PMID- 30445441 TI - Thyroid Cancer and Benign Nodules After Exposure In Utero to Fallout From Chernobyl. AB - Background: Children and adolescents exposed to radioactive iodine-131 (I-131) in fallout from the 1986 Chernobyl nuclear accident appear to be at increased risk of thyroid cancer and benign thyroid nodules. The prenatal period is also considered radiosensitive, and the fetal thyroid can absorb I-131 from the maternal circulation. Objectives: We aimed to estimate the risk of malignant and benign thyroid nodules in individuals exposed prenatally. Methods: We studied a cohort of 2582 subjects in Ukraine with estimates of I-131 prenatal thyroid dose (mean = 72.6 mGy), who underwent two standardized thyroid screening examinations. To evaluate the dose-response relationship, we estimated the excess OR (EOR) using logistic regression. Results: Based on a combined total of eight cases diagnosed at screenings from 2003 to 2006 and 2012 to 2015, we found a markedly elevated, albeit not statistically significant, dose-related risk of thyroid cancer (EOR/Gy = 3.91, 95% CI: -1.49, 65.66). At cycle 2 (n = 1,786), there was a strong and significant association between I-131 thyroid dose and screen-detected large benign nodules (>=10 mm) (EOR/Gy = 4.19, 95% CI: 0.68, 11.62; P = 0.009), but no significant increase in risk for small nodules (<10 mm) (EOR/Gy = 0.34, 95% CI: -0.67, 2.24; P = 0.604). Conclusions: The dose effect by nodule size, with I-131 risk for large but not small nodules, is similar to that among exposed children and adolescents in Belarus. Based on a small number of cases, there is also a suggestive effect of I-131 dose on thyroid cancer risk. PMID- 30445442 TI - More accurate prognostic prediction in diffuse large B-cell lymphoma: beyond cell of-origin. PMID- 30445443 TI - Identification of hypocrealean reptile pathogenic isolates with MALDI-TOF MS. AB - Biotyper analysis of Nannizziopsis guarroi, a fatal fungal pathogen in lizards, was described recently. Hypocrealean fungal infections in captive reptiles appear with an increasing frequency during the last decade. Therefore, the aim of this study was to proof Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) as diagnostic tool for the identification of reptile pathogenic hypocrealean fungi. Ten fungal isolates obtained from nine reptiles with fungal glossitis, disseminated visceral mycosis, pneumomycosis, and fungal keratitis were analyzed. Phylogeny consisted of fragments of the large subunit of nuclear encoded ribosomal DNA (D1/D2, LSU) and the internal transcribed spacer region 1 of nuclear encoded ribosomal DNA (ITS1) as well as the protein coding gene translation elongation factor 1 alpha (TEF). Results revealed unanimously two Metarhizium granulomatis genotypes in a total of three isolates, various M. viride genotypes (n = 3), two different Purpureocillium lilacinum isolates as well as one isolate of each P. lavendulum and Beauveria bassiana. Purpureocillium lilacinum and B. bassiana are likewise frequently employed as a mycoinsecticide and mycoacaricide in agriculture on a worldwide scale and have occasionally been reported in man, causing fungal keratitis, sclerokeratitis, nosocomial infections in immunosuppressed patients, as well as cavitary pulmonary disease and cutaneous hyalohyphomycosis in immunocompetent patients. According to the results establishment of Biotyper analysis for faster differentiation of reptile-associated fungal pathogens is entirely justified. PMID- 30445444 TI - Commentary: Deficiencies in Socioeconomic Training During Neurosurgical Training. PMID- 30445445 TI - An orientation for new researchers to key domains, processes, and resources in implementation science. AB - The growth of dissemination and implementation (D&I) research over the last decade has produced a wealth of theories, frameworks, methods, strategies, and resources to inform the translation of evidence into wider practice. This article seeks to frame and orient researchers from the behavioral sciences to the rapidly growing interdisciplinary field of D&I science. We describe five domains across D&I research and practice: context assessment and intervention selection, dissemination, adaptation, implementation, and sustainability. We also discuss evaluation and communication as critical processes to drive ongoing learning and improvement across the five domains. In each section, we include widely cited literature and resources that readers may use to orient themselves to the field, and identify areas that they may want to explore further. This article organizes major areas of D&I science focusing on key definitions, approaches, and commonly used resources. It provides an introduction to researchers new to this area on how to conceptualize and navigate the field of D&I science, with the ultimate goal of increasing the reach and impact of evidence-based interventions. PMID- 30445446 TI - A Molecular Targeted Immunotherapeutic Strategy for Ulcerative Colitis via Dual Targeting Nanoparticles Delivering miR-146b to Intestinal Macrophages. AB - BACKGROUND AND AIMS: Macrophages are a promising therapeutic target for intestinal mucosal repair. MiR-146b appears to control macrophage activation and cell proliferation. METHODS: By loading miR-146b mimic on mannose-modified trimethyl chitosan (MTC)-conjugated nanoparticles (NPs) (MTC-miR146b), a molecular targeted immunotherapeutic approach was developed to selectively target intestinal macrophages for mucosal regeneration and tumourigenesis in mouse models. RESULTS: We first confirmed that miR-146b expression was significantly enhanced during mucosal regeneration in a murine colitis model. Moreover,after mucosal damage, MTC-miR146b mimic-treated wild-type mice had dramatically restored body weight and mucosal barrier function compared to MTC-NC treated mice. Strikingly, MTC-miR146b mimic oral administration protected miR-146b deficient mice from dextran sodium sulfate (DSS) injury and the colitis associated cancer process. Mechanistically, miR-146b strongly inhibited M1 macrophage activation by suppressing the Toll-like receptor 4 (TLR4) signalling pathway, resulting in the repression of the induction of proinflammatory cytokines including TNF-alpha, IL-6 and IL-1beta. More importantly, miR-146b overexpression in bone marrow-derived macrophages (BMDMs) in M1 differentiation conditions induced a phenotype similar to M2 macrophages and improved the proliferation of co-cultured colonic epithelial cells via STAT3-dependent IL-10 production. CONCLUSION: MTC-miR146b should be regarded as an effective candidate for oral delivery and could improve the efficacy of immunotherapies for ulcerative colitis and colitis-associated cancer. PMID- 30445447 TI - An Acetobacterium strain isolated with metallic iron as electron donor enhances iron corrosion by a similar mechanism as Sporomusa sphaeroides. AB - Sporomusa sphaeroides related strains are to date the only homoacetogens known to increase metallic iron corrosion. The goal of this work was to isolate additional homoacetogenic bacteria capable of using Fe(0) as electron donor and to explore their extracellular electron transfer mechanism. Enrichments were started from anoxic corrosion products and yielded Acetobacterium as main homoacetogenic genus. Isolations were performed with a new procedure using plates with a Fe(0) powder top layer. An Acetobacterium strain, closely related to A. malicum and A. wieringae, was isolated, in addition to a S. sphaeroides strain. The Acetobacterium isolate significantly increased Fe(0) corrosion ((1.44 +/- 0.16) fold) compared to abiotic controls. The increase of corrosion by type strains ranged from (1.28 +/- 0.13)-fold for A. woodii to (2.03 +/- 0.22)-fold for S. sphaeroides. Hydrogen mediated the electron uptake from Fe(0) by the acetogenic isolates and tested type strains. Exchange of the medium and SEM imaging suggested that cells were attached to Fe(0). The corrosion enhancement mechanism is for all tested strains likely related to free extracellular components catalyzing hydrogen formation on the Fe(0) surface, or to the maintenance of low hydrogen concentrations on the Fe(0) surface by attached cells thereby thermodynamically favoring hydrogen formation. PMID- 30445449 TI - Systematic review methods for the Pregnancy and Birth to 24 Months Project. PMID- 30445448 TI - The impact of the General Data Protection Regulation on health research. AB - Background: On the May 25, 2018 the General Data Protection Regulation (hereafter the GDPR or the Regulation) came into force, replacing the Data Protection Directive 95/46/EC (upon which the Data Protection Act 1998 is based), and imposing new responsibilities on organizations which process the data of European Union citizens. Sources of data: This piece examines the impact of the Regulation on health research. Areas of agreement: The Regulation seeks to harmonize data privacy laws across Europe, to protect and empower all EU citizen's data privacy and to reshape the way that organizations approach data privacy (See the GDPR portal at: https://www.eugdpr.org/ (accessed 8 May 2018). As a Regulation the GDPR is directly applicable in all member states as opposed to a directive which requires national implementing measures (In the UK the Data Protection Act 1998 was the implementing legislation for the Data Protection Directive 95/46/EC.). Areas of controversy: The Regulation is sector wide, but its impact on organizations us sector specific. In some sectors, the Regulation inhibits the processing of personal data, whilst in others it enables that processing. The Regulation takes the position that the 'processing of data should be designed to serve mankind' (Recital 4). Whilst it does not spell out what exactly is meant by this, it indicates that a proportionate approach will be taken to the protection of personal data, where that data can be processed for common goods such as healthcare. Thus, the protection of personal data is not absolute, but considered in relation to its function in society and balance with other fundamental rights in accordance with the principle of proportionality (Recital 4). Differing interpretations of proportionality can detract from the harmonization objective of the Regulation. Growing points: Reflecting the commitment to proportionality, scientific research holds a privileged position in the Regulation. Throughout the Regulation provision is made for organizations that process personal data for scientific research purposes to avoid restrictive measures which might impede the increase of knowledge. However, the application of the Regulation differs across health research sectors and across jurisdictions. Transparency and engagement across the health research sector is required to promote alignment. Areas timely for developing research: Research which focuses on the particular problems which arise in the context of the regulation's application to health research would be welcome. Particularly in the context of the operation of the Regulation alongside the duty of confidentiality and the variation in approaches across Member States. PMID- 30445450 TI - Modelling the Inflammatory Bowel Disease Specialist Nurse Workforce Standards by Determination of Optimum Caseloads in the UK. AB - Background and Aims: Crohn's disease and ulcerative colitis are the most common forms of inflammatory bowel disease [IBD], affecting 1 in 250 of the population in the UK. It is accepted that access to a specialist nurse service improves patient experience and outcome. National Standards for the Healthcare of People Who Have Inflammatory Bowel Disease [2013] defined the number of nurse specialists required at 1.5 full time equivalent per 250000 population. The aim of this study was to determine if these standards were being met and to publish a new, robust, validated standard optimising the UK nursing workforce model. Methods: Existing national data and specific workload and service data were collected from 164 IBD specialist nurses who completed a questionnaire designed to collect information on activity and complexity of work both done and undone. Results: Data were received from all of the UK; 36% of respondents were specialist nurses in the field for 3 years or less. A higher caseload than the recommended level was reported by 63% of respondents. Unpaid overtime was regularly carried out by 84% of respondents. The IBD specialist nurse was involved in all areas of the patient pathway. Areas of work left undone were psychological interventions, prescribing medicines and physical assessments. Conclusions: Compared with other specialties, IBD specialist nurses are less experienced. It is recommended that the current standard be increased to 2.5 full time equivalent specialist nurses per 250000 patients, to mitigate the increasing complexity of the role, care and the 'rookie' factor. PMID- 30445452 TI - Mexico and mitochondrial replacement techniques: what a mess. AB - Background: The first live birth following the use of a new reproductive technique, maternal spindle transfer (MST), which is a mitochondrial replacement technique (MRT), was accomplished by dividing the execution of the MST procedure between two countries, the USA and Mexico. This was done in order to avoid US legal restrictions on this technique. Sources of data: Academic articles, news articles, documents obtained through freedom of information requests, laws, regulations and national reports. Areas of agreement: MRTs are new reproductive techniques that present novel ethical and legal challenges, since genetic material from three people is employed to create a child. Areas of controversy: Could the first MST procedure that culminated in a live birth negatively impact reproductive medicine in Mexico? Growing points: The USA and Mexico need specific and clear legislation on MRTs, in order for such techniques not to be governed by prior existing legislation on assisted reproduction that is inadequate for dealing with the new challenges that these techniques present. Areas timely for developing research: There is a pressing need for work to be done on the international governance of new reproductive techniques. PMID- 30445451 TI - Loss of zebrafish Ataxin-7, a SAGA subunit responsible for SCA7 retinopathy, causes ocular coloboma and malformation of photoreceptors. AB - Polyglutamine expansion in Ataxin-7 results in Spinocerebellar ataxia type 7 (SCA7) and causes visual impairment. SCA7 photoreceptors progressively lose their outer segments, a structure essential for their visual function. Ataxin-7 is a subunit of the transcriptional coactivator Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex, implicated in the development of the visual system in flies. To determine the function of Ataxin-7 in the vertebrate eye, we have inactivated Ataxin-7 in zebrafish. While Ataxin-7 depletion in flies led to gross retinal degeneration, in zebrafish it primarily results in ocular coloboma, a structural malformation responsible for pediatric visual impairment in human. Ataxin-7 inactivation leads to elevated Hedgehog signaling in the forebrain, causing an alteration of proximo-distal patterning of the optic vesicle during early eye development and coloboma. At later developmental stages, malformations of photoreceptors due to incomplete formation of their outer segments are observed, and correlate with altered expression of crx, a key transcription factor involved in the formation of photoreceptor outer segment. Therefore, we propose that a primary toxic effect of polyglutamine expansion is the alteration of Ataxin-7 function in the daily renewal of outer segment in SCA7. Together, our data indicate that Ataxin-7 plays an essential role in vertebrate eye morphogenesis and photoreceptor differentiation, and its loss of function may contribute to the development of human coloboma. PMID- 30445453 TI - The Differences in Antibiotic Decision-making Between Acute Surgical and Acute Medical Teams: An Ethnographic Study of Culture and Team Dynamics. AB - Background: Cultural and social determinants influence antibiotic decision-making in hospitals. We investigated and compared cultural determinants of antibiotic decision-making in acute medical and surgical specialties. Methods: An ethnographic observational study of antibiotic decision-making in acute medical and surgical teams at a London teaching hospital was conducted (August 2015-May 2017). Data collection included 500 hours of direct observations, and face-to face interviews with 23 key informants. A grounded theory approach, aided by Nvivo 11 software, analyzed the emerging themes. An iterative and recursive process of analysis ensured saturation of the themes. The multiple modes of enquiry enabled cross-validation and triangulation of the findings. Results: In medicine, accepted norms of the decision-making process are characterized as collectivist (input from pharmacists, infectious disease, and medical microbiology teams), rationalized, and policy-informed, with emphasis on de escalation of therapy. The gaps in antibiotic decision-making in acute medicine occur chiefly in the transition between the emergency department and inpatient teams, where ownership of the antibiotic prescription is lost. In surgery, team priorities are split between 3 settings: operating room, outpatient clinic, and ward. Senior surgeons are often absent from the ward, leaving junior staff to make complex medical decisions. This results in defensive antibiotic decision making, leading to prolonged and inappropriate antibiotic use. Conclusions: In medicine, the legacy of infection diagnosis made in the emergency department determines antibiotic decision-making. In surgery, antibiotic decision-making is perceived as a nonsurgical intervention that can be delegated to junior staff or other specialties. Different, bespoke approaches to optimize antibiotic prescribing are therefore needed to address these specific challenges. PMID- 30445454 TI - A randomized triple blind controlled trial comparing the live birth rate of IVF following brief incubation versus standard incubation of gametes. AB - STUDY QUESTION: Does brief incubation of oocytes and spermatozoa improve the live birth rate (LBR) of IVF when compared with that of standard incubation? SUMMARY ANSWER: Brief incubation of gametes does not improve the LBR of IVF when compared with standard incubation. WHAT IS KNOWN ALREADY: Some small randomized studies showed that brief incubation was associated with a significantly higher ongoing pregnancy rate than standard incubation. STUDY DESIGN, SIZE, DURATION: This is a randomized triple blind study of 320 infertile women for their first or repeated cycles undergoing IVF between September 2015 and October 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were randomized into the brief incubation group (n = 160) or the standard incubation group (n = 160) according to a computer-generated randomization list. Oocytes were incubated with spermatozoa (0.3-1.2 million motile sperm/ml) for 3-4 h in the brief incubation group while oocytes were incubated with spermatozoa at similar concentration for 20 h in the standard incubation group. The primary outcome was the LBR (a baby born alive after 22 weeks gestation) in the fresh cycle. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in the LBR between the brief and standard incubation groups based on both intention-to-treat [33.0% (53/160) versus 36.8% (59/160), relative risk (RR) 0.898 (95% CI = 0.666-1.212), P = 0.482] and per protocol [41.4%(53/128) versus 41.0% (59/144), RR1.011 (95% CI = 0.760-1.343), P = 0.942] analyses. Clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy and implantation rates were comparable for the two groups. Similar results were found with subgroup analysis of advanced maternal age, abnormal semen analysis and repeated IVF cycles. No differences were observed in cumulative LBR between two groups. LIMITATIONS, REASONS FOR CAUTION: Various motile sperm concentrations of 0.3-1.2 million per ml were used for insemination and the reactive oxygen species level in the insemination medium was not measured. The highest level at 1.2 million per ml is still relatively low compared to prior studies, therefore we do not know whether brief incubation can improve the LBR using higher concentrations of spermatozoa. The present sample size may not be adequate to detect a smaller difference in the LBR. WIDER IMPLICATIONS OF THE FINDINGS: The present study demonstrated that a brief incubation of gametes had no significant beneficial effect on the LBR when compared with the standard incubation. The practice of brief incubation of gametes is not necessary and this can save the already tight manpower in many laboratories. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Merck-Serono China Research Fund for Fertility Experts (2015), which was not involved in study design, execution, data analysis and manuscript preparation. There are no conflicts of interest for all authors. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier NCT02534857. TRIAL REGISTRATION DATE: 28 August 2015. DATE OF FIRST PATIENT'S ENROLMENT: 8 September 2015. PMID- 30445455 TI - Core fucose is essential glycosylation for CD14-dependent Toll-like receptor 4 and Toll-like receptor 2 signaling in macrophages. AB - Core fucosylation, catalyzed by alpha-1,6 fucosyltransferase (FUT8), regulates growth factor receptors in immune function. Although core fucose regulates many immune cell types, few reports confront the association between core fucose activity and an innate immune reaction. Here, we have investigated the function of core fucose in macrophages in vivo and in vitro using Fut8-deficient mice and cells. Following lipopolysaccharide (LPS) stimulation, inflammatory cytokine production in Fut8-deficient (Fut8-/-) macrophages was suppressed in both in vivo and in vitro experiments. Because LPS is recognized by Toll-like receptor 4 (TLR4), which induces the signaling cascade, TLR4 signaling was assumed to be impaired in Fut8-/- cells. Flow cytometry analyses revealed, however, that a lack of core fucose reduced the expression of, not TLR4, but CD14, which is necessary for TLR4 endocytosis. Because CD14 is necessary for TLR2 signaling, the immune response of TLR2 was also impaired in Fut8-/- macrophages. Moreover, in the dextran sodium sulfate (DSS)-induced murine colitis model, the mice grafted with Fut8-/- bone marrow cells exhibited higher resistance to inflammation than those grafted with Fut8+/+ bone marrow cells. These findings indicate that core fucose is essential for CD14-dependent TLR4 and TLR2 signaling in murine macrophage activity, leading to DSS-induced experimental colitis. PMID- 30445456 TI - Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt, and Pthlh signaling pathway gene expression in suture mesenchymal cells. AB - Cleidocranial dysplasia (CCD, #119600), which is characterized by hypoplastic clavicles, open fontanelles, supernumerary teeth, and a short stature, is caused by heterozygous mutations in RUNX2. However, it currently remains unclear why suture closure is severely impaired in CCD patients. The closure of posterior frontal (PF) and sagittal (SAG) sutures was completely interrupted in Runx2+/- mice, and the proliferation of suture mesenchymal cells and their condensation were less than those in wild-type mice. To elucidate the underlying molecular mechanisms, differentially expressed genes between wild-type and Runx2+/- PF and SAG sutures were identified by microarray and real-time RT-PCR analyses. The expression of hedgehog, Fgf, Wnt, and Pthlh signaling pathway genes, including Gli1, Ptch1, Ihh, Fgfr2, Fgfr3, Tcf7, Wnt10b, and Pth1r, which were directly regulated by Runx2, was reduced in the sutures, but not the calvarial bone tissues of Runx2+/- mice. Bone formation and suture closure were enhanced in an organ culture of Runx2+/- calvariae with ligands or agonists of hedgehog, Fgf, Wnt, and Pthlh signaling, while they were suppressed and suture mesenchymal cell proliferation was decreased in an organ culture of wild-type calvariae with their antagonists. These results indicate that more than a half dosage of Runx2 is required for the proliferation of suture mesenchymal cells, their condensation and commitment to osteoblast-lineage cells, and the induction of hedgehog, Fgf, Wnt, and Pthlh signaling pathway gene expression in sutures, but not in calvarial bone tissues, and also that the activation of hedgehog, Fgf, Wnt, and Pthlh signaling pathways is necessary for suture closure. PMID- 30445457 TI - Transient ST-segment myocardial infarction: a new category of high risk acute coronary syndrome? PMID- 30445458 TI - The effect of early-life and adult socioeconomic position on development of lifestyle-related diseases. AB - Background: Early-life socioeconomic position (SEP) is associated with lifestyle related diseases in adulthood. However, evidence is lacking on the extent to which adult SEP mediates this association. Methods: Time to either chronic obstructive pulmonary disease (COPD), cardiovascular disease or diabetes were assessed in the Danish population born between 1961 and 1971 (n = 793 674) from age 30 until 2015. Early-life position was assessed in 1981 (by parental) and again at age 30 (own) by four markers; income, occupation, education-divided into high, middle, low-and a combined score for all markers. Using a counterfactual approach, we estimated the total effect of early-life position on disease onset and the degree to which adult position mediated this effect. Results: Results of the time-to-event analysis showed a gradient of all early-life markers on the risk of developing all lifestyle-related diseases. Notably, comparing those in the lowest to the highest educational position, the hazard of COPD was 130% higher for women [hazard ratio = 2.30(95% confidence interval = 2.20-2.41)] and 114% higher for men [2.14 (2.05-2.25)]. About 67%(63-70%) of the effect of educational position was mediated through adult position for COPD, 55% for cardiovascular disease and 50% for diabetes. For the combined score 44, 29 and 33%, respectively, was mediated. Conclusion: About one-tenth to two-thirds of the effect of early-life position is mediated by the position attained in adulthood. The degree mediated depend on the outcome investigated, gender and the social position marker used indicating that alternative pathways may play a key role in developing effective policies targeting early-life behaviours. PMID- 30445459 TI - Intestinal glucose absorption is a key determinant of 1-hour post-load plasma glucose levels in non-diabetic subjects. AB - Context: One-hour post-load hyperglycemia, defined as 1-hour plasma glucose (1hPG) >=155 mg/dl during an oral glucose tolerance test (OGTT), has been proposed as an independent predictor of type 2 diabetes. Recent evidence suggests that 1-hour hyperglycemia can be explained by enhanced duodenal glucose absorption, which in turn may increase the rate of appearance of oral glucose in the systemic circulation (RaO). However, the impact of RaO on 1hPG and 1-hour glucose excursions (glucose iAUC1h) is still unknown. Objective: We quantified the relative contribution of post-load RaO to 1hPG and glucose iAUC1h with respect to other major glucose homeostatic mechanisms in non-diabetic subjects. Participants and Methods: Model-derived beta-cell function, insulin clearance, glucose metabolic fluxes, and peripheral and hepatic insulin sensitivity were measured during a 75-g OGTT by a double tracer method in 23 non-diabetic volunteers. Results: Early insulin secretion, whole-body insulin sensitivity, and plasma glucose disposal were significantly impaired in subjects with 1hPG >=155 mg/dl (n=11), who also showed nominally greater RaO (+19%, p=0.10). In multivariable models, post-load RaO showed an independent effect on both 1hPG and glucose iAUC1h (partial r2 = 0.26 and 0.48, respectively; p<0.003). The relative contribution of RaO to 1hPG (23%) and glucose iAUC1h (30%) was comparable to that of early insulin secretion and peripheral insulin sensitivity, and greater than that of hepatic insulin sensitivity. Conclusions: Our data highlight the primary role of RaO as a major determinant of 1-hour post-prandial glucose excursions in non-diabetic subjects. PMID- 30445461 TI - Effects of Aerobic and Resistance Training on Circulating micro-RNA Expression Profile in Subjects with Type 2 Diabetes. AB - Context: Structured exercise programs are of great benefit for the treatment of type 2 diabetes (T2DM). However, whether aerobic (AER) or resistance (RES) exercise training exert specific epigenetic changes through the expression profile of circulating miRNAs (c-miRNAs) is still largely unknown. Objective: To assess whether the c-miRNAs profile changes after either AER or RES training in subjects with T2DM. Research Design and Methods: Twenty-four T2DM individuals randomized to AER or RES training protocols were randomly selected from the RAED2 Trial (NAER=12; NRES=12). The baseline and post-training levels of 179 c-miRNAs were initially measured by RT-PCR in 6 individuals (NAER=3; NRES=3). C-miRNAs exhibiting >=40% fold-change variation and/or nominal significance from baseline were measured in the whole group. Results: Nineteen c-miRNAs were eventually assessed in the whole group. Compared to baseline, the post-training levels of miR-423-3p, miR-451a and miR-766-3p were significantly up-regulated, irrespective of exercise type (P<0.0026; 0.05/19), and targeted upstream pathways relevant to fatty acids biosynthesis and metabolic regulation. MiR-451a and miR-423-3p were significantly correlated with fat loss (rho=0.45 and 0.43, respectively) and resulted, alone or in combination, as predictors of fat loss in GLMs including exercise type as covariate. Only the association with miR-451a eventually retained significance after further correction for age, sex, BMI and HbA1c. Conclusions: Exercise training in T2DM is associated with significant c-miRNAs profile changes, irrespective of exercise type and other relevant metabolic covariates. The mechanistic significance of the observed relationship between fat loss and the epigenetic modifications induced by exercise warrants further investigation in larger datasets. PMID- 30445462 TI - A swollen arm after backcountry snowboarding in Japan. PMID- 30445463 TI - A neuronal enhancer network upstream of MEF2C is compromised in patients with Rett-like characteristics. AB - Mutations in myocyte enhancer factor 2C (MEF2C), an important transcription factor in neurodevelopment, are associated with a Rett-like syndrome. Structural variants (SVs) upstream of MEF2C, that do not disrupt the gene itself, have also been found in patients with a similar phenotype, suggesting that disruption of MEF2C regulatory elements can also cause a Rett-like phenotype. To characterize those elements that regulate MEF2C during neural development and which are affected by these SVs, we used genomic tools coupled with both in vitro and in vivo functional assays. Through 4C-seq and ATAC-seq, we revealed a complex interaction network in which the MEF2C promoter physicallycontacts several distal enhancers that are deleted or translocated by disease-associated SVs. Sixteen selected candidate regulatory sequences were tested for enhancer activity in vitro, with fourteen found to be functional enhancers. Further analyses of their in vivo activity in zebrafish showed that each of these enhancers has a distinct activity pattern during development, with eight enhancers displaying neuronal activity. In summary, our results disentangle a complex regulatory network governing neuronalMEF2Cexpression that involves multiple distal enhancers. In addition, the characterized neuronal enhancers pose as novel candidates to screen for mutations in neuro developmental disorders, such as Rett-likesyndrome. PMID- 30445464 TI - VvWRKY8 represses stilbene synthase gene through direct interaction with VvMYB14 to control resveratrol biosynthesis in grapevine. AB - Resveratrol (Res) belongs to stilbene, a plant-derived phenolic metabolite with activities against pests, pathogens and abiotic stresses. Only a few plant species, including grapevine (Vitis L.), synthesize and accumulate Res. Although stilbene synthases (STSs) have been isolated and characterized in several plant species, the gene regulatory mechanisms underlying stilbene biosynthesis are still established scarcely. Here, we report the characterization of a grapevine WRKY transcription factor, VvWRKY8, that regulates the Res biosynthetic pathway. The transient and stable overexpression of VvWRKY8 in grapevine resulted in the decreased expression of VvSTS15/21 and VvMYB14, as well as in the reduction of Res accumulation. VvWRKY8 does not bind to nor activate the promoters of VvMYB14 and VvSTS15/21. However, VvWRKY8 physically interacts with VvMYB14, through their N-terminal domains, to prevent VvMYB14 from binding to the VvSTS15/21 promoter. Application of exogenous Res resulted in the stimulation of VvWRKY8 expression and in the decrease of VvMYB14 and VvSTS15/21 expression in grapevine suspension cells, and in the activation of VvWRKY8 promoter in tobacco leaves. These results demonstrate that VvWRKY8 represses VvSTS15/21 expression and Res biosynthesis through interaction with VvMYB14. In this context, the VvMYB14-VvSTS15/21-Res VvWRKY8 regulatory loop may be an important mechanism for the fine-tuning of Res biosynthesis in grapevine. PMID- 30445465 TI - Appropriateness of antibiotic prescribing in the Emergency Department. AB - Background: Antibiotics are some of the most commonly prescribed drugs in the Emergency Department (ED) and yet data describing the overall appropriateness of antibiotic prescribing in the ED is scarce. Objectives: To describe the appropriateness of antibiotic prescribing in the ED. Methods: A retrospective, observational study of current practice. All patients who presented to the ED during the study period and were prescribed at least one antibiotic were included. Specialists from Infectious Disease, Microbiology and Emergency Medicine and a Senior Pharmacist assessed antibiotic appropriateness against evidence-based guidelines. Results: A total of 1019 (13.6%) of patient presentations involved the prescription of at least one antibiotic. Of these, 640 (62.8%) antibiotic prescriptions were assessed as appropriate, 333 (32.7%) were assessed as inappropriate and 46 (4.5%) were deemed to be not assessable. Adults were more likely to receive an inappropriate antibiotic prescription than children (36.9% versus 22.9%; difference 14.1%, 95% CI 7.2%-21.0%). Patients who met quick Sepsis-related Organ Failure Assessment (qSOFA) criteria were more likely to be prescribed inappropriate antibiotics (56.7% versus 36.1%; difference 20.5%, 95% CI, 2.4%-38.7%). There was no difference in the incidence of appropriate antibiotic prescribing based on patient gender, disposition (admitted/discharged), reason for antibiotic administration (treatment/prophylaxis) or time of shift (day/night). Conclusions: Inappropriate administration of antibiotics can lead to unnecessary adverse events, treatment failure and antimicrobial resistance. With over one in three antibiotic prescriptions in the ED being assessed as inappropriate, there is a pressing need to develop initiatives to improve antibiotic prescribing to prevent antibiotic associated patient and community harms. PMID- 30445466 TI - RNF8 mediates NONO degradation following UV-induced DNA damage to properly terminate ATR-CHK1 checkpoint signaling. AB - RNF8 plays a critical role in DNA damage response (DDR) to initiate ubiquitination-dependent signaling. To better characterize the role of RNF8 in UV induced DDR, we searched for novel substrates of RNF8 and identified NONO as one intriguing substrate. We found that: (i) RNF8 ubiquitinates NONO and (ii) UV radiation triggers NONO ubiquitination and its subsequent degradation. Depletion of RNF8 inhibited UV-induced degradation of NONO, suggesting that RNF8 targets NONO for degradation in response to UV damage. In addition, we found that 3 NONO lysine residues (positions 279, 290 and 295) are important for conferring its instability in UV-DDR. Depletion of RNF8 or expression of NONO with lysine to arginine substitutions at positions 279, 290 and 295 prolonged CHK1 phosphorylation over an extended period of time. Furthermore, expression of the stable mutant, but not wild-type NONO, induced a prolonged S phase following UV exposure. Stable cell lines expressing the stable NONO mutant showed increased UV sensitivity in a clonogenic survival assay. Since RNF8 recruitment to the UV damaged sites is dependent on ATR, we propose that RNF8-mediated NONO degradation and subsequent inhibition of NONO-dependent chromatin loading of TOPBP1, a key activator of ATR, function as a negative feedback loop critical for turning off ATR-CHK1 checkpoint signaling in UV-DDR. PMID- 30445467 TI - Leveraging mobile health applications for biomedical research and citizen science: a scoping review. AB - Objective: This systematic review aims to analyze current capabilities, challenges, and impact of self-directed mobile health (mHealth) research applications such as those based on the ResearchKit platform. Materials and Methods: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. English publications were included if: 1) mobile applications were used in the context of large-scale collection of data for biomedical research, and not as medical or behavioral intervention of any kind, and 2) all activities related to participating in research and data collection methods were executed remotely without any face-to-face interaction between researchers and study participants. Results: Thirty-six unique ResearchKit apps were identified. The majority of the apps were used to conduct observational studies on general citizens and generate large datasets for secondary research. Nearly half of the apps were focused on chronic conditions in adults. Discussion: The ability to generate large biomedical datasets on diverse populations that can be broadly shared and re-used was identified as a promising feature of mHealth research apps. Common challenges were low participation retention, uncertainty regarding how use patterns influence data quality, need for data validation, and privacy concerns. Conclusion: ResearchKit and other mHealth-based studies are well positioned to enhance development and validation of novel digital biomarkers as well as generate new biomedical knowledge through retrospective studies. However, in order to capitalize on these benefits, mHealth research studies must strive to improve retention rates, implement rigorous data validation strategies, and address emerging privacy and security challenges. PMID- 30445468 TI - Building a future with root architecture. PMID- 30445460 TI - Genomes of trombidid mites reveal novel predicted allergens and laterally transferred genes associated with secondary metabolism. AB - Background: Trombidid mites have a unique life cycle in which only the larval stage is ectoparasitic. In the superfamily Trombiculoidea ("chiggers"), the larvae feed preferentially on vertebrates, including humans. Species in the genus Leptotrombidium are vectors of a potentially fatal bacterial infection, scrub typhus, that affects 1 million people annually. Moreover, chiggers can cause pruritic dermatitis (trombiculiasis) in humans and domesticated animals. In the Trombidioidea (velvet mites), the larvae feed on other arthropods and are potential biological control agents for agricultural pests. Here, we present the first trombidid mites genomes, obtained both for a chigger, Leptotrombidium deliense, and for a velvet mite, Dinothrombium tinctorium. Results: Sequencing was performed using Illumina technology. A 180 Mb draft assembly for D. tinctorium was generated from two paired-end and one mate-pair library using a single adult specimen. For L. deliense, a lower-coverage draft assembly (117 Mb) was obtained using pooled, engorged larvae with a single paired-end library. Remarkably, both genomes exhibited evidence of ancient lateral gene transfer from soil-derived bacteria or fungi. The transferred genes confer functions that are rare in animals, including terpene and carotenoid synthesis. Thirty-seven allergenic protein families were predicted in the L. deliense genome, of which nine were unique. Preliminary proteomic analyses identified several of these putative allergens in larvae. Conclusions: Trombidid mite genomes appear to be more dynamic than those of other acariform mites. A priority for future research is to determine the biological function of terpene synthesis in this taxon and its potential for exploitation in disease control. PMID- 30445470 TI - Reply to Finn. PMID- 30445471 TI - Association between physical activity and alcohol consumption: sociodemographic and behavioral patterns in Brazilian adults. AB - Background: Our aim was to investigate the association between physical activity and alcohol consumption, as well as the sociodemographic and behavioral patterns of this association in a representative sample of Brazilian adults. Methods: Data from the Brazilian Health Survey (PNS), a nationally representative survey conducted in 2013 (n = 60 202; age>=18 years), were used. Time spent in leisure physical activity, alcohol consumption as well as sociodemographic (chronological age, educational status and skin color) and associated behavioral factors (TV viewing and tobacco smoking) were collected via interview. Logistic regression models were used for the main analyses. Results: Prevalence of weekly and almost daily alcohol consumption were 29.5% and 6.7% for men and 12.0% and 1.0% for women respectively. Adults with weekly alcohol consumption were more likely to be classified as physically active [young: men=OR:1.20 (CI 95%:1.02-1.39), women= OR:2.33 (CI 95%:1.92-2.82); middle-aged: men= OR:1.46 (CI 95%: 1.17-1.82), women= OR:1.75 (CI 95%:1.38-2.22); older: men= OR:1.83 (CI 95%:1.27-2.66), women= OR:2.11 (CI 95%: s1.26-3.52)], when compared to adults with no alcohol consumption. Almost daily alcohol consumption was associated with lower physical activity among young and middle-aged adults but with higher physical activity among older adults of both sexes and young women. Conclusions: Weekly alcohol consumption was associated with a higher level of physical activity among young, middle aged and older adults. PMID- 30445469 TI - The dominant prognostic value of physical functioning among quality of life domains in end-stage kidney disease. AB - Background: The prognostic relevance of health-related quality of life (HRQoL) has been scarcely studied in the dialysis population and the prognostic power for mortality of the HRQoL domains is unknown. Methods: We tested the prognostic value for mortality of the HRQoL domains included in the 36-item Short Form Health Survey (SF-36) by Cox's regression analysis and by state-of-the-art prognostic techniques {explained variation in mortality [R2], calibration, discrimination [Harrell's C], risk reclassification [Net Reclassification Index (NRI)], Integrated Discrimination Index [IDI]} in a cohort of 951 patients on chronic haemodialysis. Results: In multivariable Cox models, all but two domains (role limitation due to physical health and due to emotional problems) were independently related with mortality. Physical functioning was the domain adding the highest explanatory power (R2+5.3%) to a basic model including established risk factors for mortality in the dialysis population. The same domain improved risk calibration and showed the highest Harrell's C (+1.7%) and the highest reclassification power (categorical NRI + 8.7%, continuous NRI +46%, P <= 0.006) and the highest IDI (+3.4%, P < 0.001). These results were fully confirmed in analyses testing the additional prognostic power of SF-36 domains when combined to a well-validated risk score in dialysis patients. Conclusions: Physical functioning holds the highest prognostic power for mortality among the domains of SF-36. The gain in prognostic ability by this domain is relevant for clinical practice. Physical functioning has the potential for refining the prognosis and for informing exercise programmes in the dialysis population. PMID- 30445472 TI - An update of the ERA-EDTA Registry primary renal disease coding system: what's new? PMID- 30445473 TI - Neural evidence for persistent attentional bias to threats in patients with social anxiety disorder. AB - Does the biased attention toward social threats dwells on or disappears in patients with social anxiety disorder (SAD)? We investigated the neural mechanism of attentional bias in terms of attentional capture and holding in SAD. A total of 31 SAD patients and 30 healthy controls performed a continuous performance task detecting the orientation of a red letter 'T' while angry or neutral face distractors appeared or disappeared at the center of the screen. Behaviorally, typical attentional capture effects were found in response to abruptly appearing distractors in both groups. The patient group showed significant attentional dwelling effects in response to the angry face distractor only. Patients showed increased neural activity in the amygdala, insula/inferior frontal gyrus (IFG) and temporo-parietal junction (TPJ) compared with those of controls for the abruptly appearing angry distractor. Patients also maintained increased activities in brain regions related to attentional reorienting to distractor, namely the TPJ and IFG in line with their behavioral results of attentional holding effects. Our results indicate that patients with SAD showed prolonged attentional bias to task-irrelevant social threats. The underlying mechanism of prolonged attentional bias in SAD was indicated with amygdala hyperactivity and continued activity of the bottom-up attention network including the TPJ and IFG. PMID- 30445474 TI - Clonal expansion and horizontal transmission of epidemic F2:A1:B1 plasmids involved in co-spread of rmtB with qepA and blaCTX-M-27 in extensively drug resistant Salmonella enterica serovar Indiana isolates. AB - Objectives: To investigate the prevalence and transmission of 16S rRNA methylase genes among Salmonella isolates from food animals in China. Methods: A total of 310 Salmonella isolates collected from food animals in seven provinces of China during 2016-17 were screened for 16S RMTase genes. The clonal relationship of the 16S RMTase-producing isolates and their plasmid contents were also characterized. Results: rmtB and armA were respectively identified in 12 and 1 Salmonella enterica serovar Indiana (Salmonella Indiana) isolates from farmed ducks. These 13 isolates concurrently expressed high-level resistance to amikacin, cefotaxime and ciprofloxacin. They were assigned to seven distinct PFGE patterns and the high similarity among 10 of the 12 rmtB-carrying isolates suggests clonal expansion. The rmtB gene was co-transferred with blaCTX-M-27-qepA and qepA in eight and two of the isolates, respectively, and was located on F2:A1:B1 plasmids with sizes of 135 and 100 kb, respectively. These 10 rmtB-bearing plasmids showed four restriction patterns with a high similarity. Four representative rmtB bearing plasmids were fully sequenced and they exhibited remarkable similarity and possessed typical FII backbones. The primary differences were located in the region between blaTEM-1 and ycgA. Furthermore, a novel MDR region (13.5 kb) was identified that contained qepA, rmtB and blaCTX-M-27. Conclusions: This is the first report, to our knowledge, of the prevalence and complete sequences of plasmids simultaneously containing rmtB, qepA and blaCTX-M-27. These findings underscore a major public health threat posed by epidemic F2:A1:B1 plasmids bearing qepA-rmtB-blaCTX-M-27 that are circulating in XDR Salmonella Indiana clonal isolates from waterfowl husbandry. PMID- 30445475 TI - Single and double box HMGB proteins differentially destabilize nucleosomes. AB - Nucleosome disruption plays a key role in many nuclear processes including transcription, DNA repair and recombination. Here we combine atomic force microscopy (AFM) and optical tweezers (OT) experiments to show that high mobility group B (HMGB) proteins strongly disrupt nucleosomes, revealing a new mechanism for regulation of chromatin accessibility. We find that both the double box yeast Hmo1 and the single box yeast Nhp6A display strong binding preferences for nucleosomes over linker DNA, and both HMGB proteins destabilize and unwind DNA from the H2A-H2B dimers. However, unlike Nhp6A, Hmo1 also releases half of the DNA held by the (H3-H4)2 tetramer. This difference in nucleosome destabilization may explain why Nhp6A and Hmo1 function at different genomic sites. Hmo1 is enriched at highly transcribed ribosomal genes, known to be depleted of histones. In contrast, Nhp6A is found across euchromatin, pointing to a significant difference in cellular function. PMID- 30445476 TI - DNA sequence elements required for partitioning competence of the Saccharomyces cerevisiae 2-micron plasmid STB locus. AB - Equal partitioning of the multi-copy yeast 2-micron plasmid requires association of plasmid proteins Rep1 and Rep2 with tandem repeats at the plasmid STB locus. To identify sequence elements required for these associations we generated synthetic versions of a 63-bp section of STB, encompassing one repeat. A single copy of this sequence was sufficient for Rep protein association in vivo, while two directly arrayed copies provided partitioning function to a plasmid lacking all other 2-micron sequences. Partitioning efficiency increased with increasing repeat number, reaching that conferred by the native STB repeat array. By altering sequences in synthetic repeats, we identified the TGCA component of a TGCATTTTT motif as critical for Rep protein recognition, with a second TGCA sequence in each repeat also contributing to association. Mutation of TGCATTTTT to TGTATTTT, as found in variant 2-micron STB repeats, also allowed Rep protein association, while mutation to TGCATTAAT impaired inheritance without abolishing Rep protein recognition, suggesting an alternate role for the T-tract. Our identification of sequence motifs required for Rep protein recognition provides the basis for understanding higher-order Rep protein arrangements at STB that enable the yeast 2-micron plasmid to be efficiently partitioned during host cell division. PMID- 30445477 TI - DISTRIBUTIONS OF INDOOR GAMMA DOSE RATES IN RELATION TO GAMMA-RAY EMISSIONS FROM BUILDING MATERIALS: CASE STUDY OF HIGH-RISE CONCRETE BUILDING IN FUKUSHIMA. AB - The spatial distribution of ambient gamma dose rates in a high-rise steel reinforced concrete building in Fukushima, Japan, was examined relative to the gamma-ray emissions from building materials and radionuclides derived from the 2011 nuclear accident. The results revealed the minor role of accident-derived radionuclides in ambient gamma dose rates ~7 y after the accident. The ambient gamma dose rates were higher in the upper floors because of gamma-ray emissions from natural radionuclides in the floor slabs. The fractional contribution of natural radionuclides to the ambient gamma dose rates indicated compositional differences in concrete between the upper- and lower-floor slabs. PMID- 30445478 TI - The Hope-Simpson Hypothesis and Its Implications Regarding an Effect of Routine Varicella Vaccination on Herpes Zoster Incidence. PMID- 30445479 TI - Facts and hypotheses about the programming of neuroplastic deficits by prenatal malnutrition. AB - Studies in rats have shown that a decrease in either protein content or total dietary calories results in molecular, structural, and functional changes in the cerebral cortex and hippocampus, among other brain regions, which lead to behavioral disturbances, including learning and memory deficits. The neurobiological bases underlying those effects depend at least in part on fetal programming of the developing brain, which in turn relies on epigenetic regulation of specific genes via stable and heritable modifications of chromatin. Prenatal malnutrition also leads to epigenetic programming of obesity, and obesity on its own can lead to poor cognitive performance in humans and experimental animals, complicating understanding of the factors involved in the fetal programming of neuroplasticity deficits. This review focuses on the role of epigenetic mechanisms involved in prenatal malnutrition-induced brain disturbances, which are apparent at a later postnatal age, through either a direct effect of fetal programming on brain plasticity or an indirect effect on the brain mediated by the postnatal development of obesity. PMID- 30445480 TI - Therapies in ankylosing spondylitis-from clinical trials to clinical practice. AB - Until recently, the therapeutic options for patients suffering from active AS comprised NSAIDs and TNF inhibitor therapy. Although these are effective in a significant proportion of patients, not all patients respond and some are intolerant to these therapies. Therefore, there is a clear unmet treatment need in AS patients. This article reviews the evidence for targets currently being studied in AS. This includes the IL-12/23 inhibitor ustekinumab, the pan-Janus kinase inhibitor tofacitinib and the anti-IL-17A antibody secukinumab. PMID- 30445482 TI - Axial spondyloarthritis including ankylosing spondylitis. PMID- 30445481 TI - Defining the target: clinical aims in axial spondyloarthritis. AB - Treat-to-target (T2T) is an emerging treatment paradigm in axial spondyloarthritis (axSpA), originally based on evidence from other inflammatory conditions, which aims to direct therapy to a clear target such as disease remission or low disease activity, with the ultimate goal of maximizing quality of life in affected individuals. The 2016 update of the Assessment of Spondyloarthritis International Society/EULAR guidelines for axSpA have recommended that treatment should be guided according to a predefined target but controversy remains as to what this target should be. An international task force has recommended remission or inactive disease as the desired outcome; however, there are many disease outcome measures developed for use in clinical practice in axSpA and the question remains of which is the most appropriate to use. Another important consideration when discussing the T2T paradigm is when to intervene. Although evidence is limited in this respect, the available data suggest that therapy should be commenced at an early stage of the disease, when the process of bone repair expected to occur after an inflammatory phase has not yet started. It has also been argued that the success of the T2T paradigm may depend more on the treatment strategy than the individual therapies utilized. This article will explore the feasibility of using a T2T approach in axSpA clinical practice, the utilization of new composite outcome measures of disease activity such as the ASDAS, and the validity of different treatment strategies to allow for a T2T intervention in these patients. PMID- 30445483 TI - Progress in our understanding of the pathogenesis of ankylosing spondylitis. AB - AS is a common rheumatic condition characterized by inflammation and new bone formation. The pathogenesis of AS is likely multifactorial and has not been fully elucidated to date. A major genetic role has been demonstrated. The strongest genetic association is with HLA B27. Numerous other associated genetic polymorphisms have been identified, including those affecting the type 17 immune pathway, although the precise link between genetics and pathogenesis remains unexplained. Several immunological alterations, together with recent therapeutic advances, support a central role for IL-23- and IL-17-producing immune cells in disease pathogenesis. Recently, perturbations of gut microbiota of AS patients have further catalysed research and offer potential for future therapeutic intervention. In this review we outline the genetic basis of AS and describe the current hypotheses for disease pathogenesis. We synthesize recent experimental research data and clinical studies to support a central role for the type 17/23 immune axis in AS. PMID- 30445486 TI - The RecB helicase-nuclease tether mediates Chi hotspot control of RecBCD enzyme. AB - In bacteria, repair of DNA double-strand breaks uses a highly conserved helicase nuclease complex to unwind DNA from a broken end and cut it at specific DNA sequences called Chi. In Escherichia coli the RecBCD enzyme also loads the DNA strand-exchange protein RecA onto the newly formed end, resulting in a recombination hotspot at Chi. Chi hotspots regulate multiple RecBCD activities by altering RecBCD's conformation, which is proposed to include the swinging of the RecB nuclease domain on the 19-amino-acid tether connecting the helicase and nuclease domains. Here, we altered the tether and tested multiple RecBCD activities, genetically in cells and enzymatically in cell-free extracts. Randomizing the amino-acid sequence or lengthening it had little effect. However, shortening it by as little as two residues or making substitutions of >=10 proline or >=9 glycine residues dramatically lowered Chi-dependent activities. These results indicate that proper control of RecBCD by Chi requires that the tether be long enough and appropriately flexible. We discuss a model in which the swing-time of the nuclease domain determines the position of Chi-dependent and Chi-independent cuts and Chi hotspot activity. PMID- 30445484 TI - Optimizing outcomes for ankylosing spondylitis and axial spondyloarthritis patients: a holistic approach to care. AB - Axial SpA (axSpA) can affect diverse elements of an individual's life. The areas affected can be much more wide-ranging than the historical medical model of SpA, causing increased disease activity (pain and stiffness) and disability (reduced range of movement and physical function). A more holistic view of the individual results in the realization that many other areas of life can be adversely affected by axSpA, from the ability to work effectively and function socially, to effects on quality of life and the onset of worsening fatigue or mood disturbance. A good understanding of these areas outside the medical model allows for an improved understanding of the overall life impact of axSpA. This highlights the importance of understanding how to measure these elements of life using patient-reported outcome measures that can truly reflect an individual's experience of axSpA. These measures can then provide a better insight into the risks and benefits of interventions and medications used to treat axSpA. PMID- 30445485 TI - The current standard of care and the unmet needs for axial spondyloarthritis. AB - The aim of this article is to explore the benefits and limitations of the established treatments for axial SpA (axSpA), including physiotherapy, NSAIDs, conventional synthetic DMARDs and biologic DMARDs such as TNF inhibitors (TNFis). It also briefly discusses the emerging role of anti-IL-17 therapy, which could be used as a valuable alternative to first-line biologic DMARD treatment or as a second-line treatment for patients who are inadequate responders to TNFi therapy, as evidenced by various studies. Exercise programmes improve health-related quality of life and hydrotherapy improves disease activity and functional parameters in AS. NSAIDs have been proven to substantially relieve symptoms in 70 80% of patients and enhance physiotherapy by reducing pain and stiffness. The role of NSAIDs in preventing radiographic progression remains unclear. The use of conventional synthetic DMARDs (csDMARDs) is limited to peripheral arthritis; there is insufficient evidence to support the use of csDMARDs for axial disease. TNFi therapy reduces the disease activity of axSpA, however, as not all patients respond to treatment in the same way, it is good to have other therapeutic options available. Finally, this article explores the potential for IL-17 inhibition in AS and introduces clinical data for secukinumab, a fully human monoclonal antibody targeting IL-17A. PMID- 30445487 TI - G4HunterApps. AB - Motivation: In order to help G4Hunter users and make it more accessible, I have developed a set of small applications within the Shiny/R framework. Results: Each application fulfills simple tasks ranging from computing the G4Hunter score for a sequence or a list of sequence to extracting sequences with a G4Hunter score above a threshold for a sequence up to 5Mb or a list of short sequences. The application can be installed either on the user computer within Rstudio or on a Rstudio server. Availability: The source code for the ShinyApps is available on GitHub (https://github.com/LacroixLaurent). PMID- 30445488 TI - Pair Matcher (PaM): fast model-based optimisation of treatment/case-control matches. AB - Motivation: In clinical trials, individuals are matched using demographic criteria, paired, and then randomly assigned to treatment and control groups to determine a drug's efficacy. A chief cause for the irreproducibility of results across pilot to Phase III trials is population stratification bias caused by the uneven distribution of ancestries in the treatment and control groups. Results: Pair Matcher (PaM) addresses stratification bias by optimising pairing assignments a priori and/or a posteriori to the trial using both genetic and demographic criteria. Using simulated and real datasets, we show that PaM identifies ideal and near-ideal pairs that are more genetically homogeneous than those identified based on competing methods, including the commonly used principal component analysis (PCA). Homogenising the treatment (or case) and control groups can be expected to improve the accuracy and reproducibility of the trial or genetic study. PaM's ancestral inferences also allow characterizing responders and developing a precision medicine approach to treatment. Availability: PaM is freely available via Rhttps://github.com/eelhaik/PAM and a web-interface at http://elhaik-matcher.sheffield.ac.uk/ElhaikLab/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445489 TI - Predictors of mid-term outcomes in patients undergoing implantation of a ventricular assist device directly after extracorporeal life support. AB - OBJECTIVES: Extracorporeal life support (ECLS) can be applied as a bridge to diagnosis and decision-making for further treatment with long-term left ventricular assist devices (LVADs). METHODS: From January 2012 to January 2018, 714 adult patients were treated with ECLS in our institution. During the same period, 618 patients received an LVAD for long-term support. Of them, 100 patients were further supported with a long-term LVAD. We retrospectively analysed the datasets of these 100 consecutive patients with the goal of developing an algorithm to predict outcomes for a rational use of long-term ventricular assist device therapy in this setting. RESULTS: The mean age of the 100 patients was 54.1 +/- 11.6 years, and 72 were men. Twenty-nine patients had a BMI of >30 kg/m2. In 33 patients, a temporary right ventricular assist device was necessary postoperatively. The 30-day, 1-year and 2-year survival after ventricular assist device implantation was 62.0% [95% confidence interval (CI) 53.2-72.3], 43.0% (95% CI 34.3-53.9) and 37.1% (95% CI 28.2-48.7%), respectively. Penalized multivariable logistic regression analysis showed following predictors for 1-year mortality: bilirubin increase per mg/dl [odds ratio (OR) 1.41, 95% CI 1.12-1.77], C-reactive protein increase per mg/dl (OR 1.11, 95% CI 1.05-1.19), ECLS duration >7 days (OR 4.90, 95% CI 1.66-14.41), BMI >30 kg/m2 (OR 1.41, 95% CI 1.05-8.52) and female gender (OR 3.06, 95% CI 1.02-9.23). On the basis of these data, a nomogram to estimate 1-year mortality after LVAD implantation was created. CONCLUSIONS: After stabilization of patients experiencing cardiogenic shock using ECLS, LVAD implantation can be performed with elevated mortality in an otherwise futile situation. Liver dysfunction, inflammatory status and obesity increase the risk for mid-term mortality. PMID- 30445490 TI - Diagnostic methods for uncovering outcome dependent visit processes. AB - With the advent of electronic health records, information collected in the course of regular health care is increasingly being used for clinical research. The hope is that the wealth of clinical data and the realistic setting (compared with information derived from highly controlled experiments like randomized trials) will aid in the investigation of determinants of disease and understanding of which treatments are effective in regular practice and for which patients. The availability of information in such databases is often driven by how a patient feels and may therefore be associated with the health outcomes being considered. We call this an outcome dependent visit process and recent work has shown that ignoring the outcome dependence can produce significant bias in the regression coefficients when fitting longitudinal data models. It is therefore important to have tools to recognize datasets exhibiting outcome dependence. We develop a score statistic to motivate the form of diagnostic test statistics, suggest a variety of approaches for diagnosing such situations, and evaluate their performance. Simple diagnostic tests achieve high power for diagnosing outcome dependent visit processes. This occurs when generalized estimating equations methods begin to be exhibit bias in estimating regression coefficients and before likelihood based methods are substantially biased. PMID- 30445491 TI - Anti-Ace monoclonal antibody reduces Enterococcus faecalis aortic valve infection in a rat infective endocarditis model. AB - Ace (Adhesin to collagen from Enterococcus faecalis) is a cell-wall anchored protein that is expressed conditionally and is important for virulence in a rat infective endocarditis (IE) model. Previously, we showed that rats immunized with the collagen binding domain of Ace (domain A), or administered anti-Ace domain A polyclonal antibody, were less susceptible to E. faecalis endocarditis than sham immunized controls. In this work, we demonstrated that a sub nanomolar monoclonal antibody (mAb), anti-Ace mAb70, significantly diminished E. faecalis binding to ECM collagen IV in in vitro adherence assays and that, in the endocarditis model, anti-Ace mAb70 pre-treatment significantly reduced E. faecalis infection of aortic valves. The effectiveness of anti-Ace mAb against IE in the rat model suggests it might serve as a beneficial agent for passive protection against E. faecalis infections. PMID- 30445492 TI - Early failure of a bioprosthetic aortic valve due to thrombus formation while on rivaroxaban. AB - There is increasing evidence that bioprosthetic valve thrombosis (BPVT) is more common than previously thought. However, there are very few cases describing the occurrence of BPVT on therapeutic anticoagulation, and no previous cases are available stating the occurrence of BPVT on direct oral anticoagulant therapy. We describe the case of surgically managed aortic BPVT that was diagnosed while the patient was on rivaroxaban. PMID- 30445493 TI - Cohort profile: The AZAR cohort, a health-oriented research model in areas of major environmental change in Central Asia. PMID- 30445494 TI - Self- reported fitness and objectively measured physical activity profile among older adults: a twin study. AB - BACKGROUND: Maintaining good fitness and good level of physical activity are important factors for maintaining physical independence later in life. The aim was to investigate the relationship between self-reported fitness and objectively measured physical activity (PA) and sedentary behavior (SB) in the elderly. METHODS: Same-sex twin pairs born 1940-1944 in Finland were invited to the study. Altogether 787 individuals (mean age 72.9 years), of whom 404 were female, used a hip-worn triaxial accelerometer for at least four days and answered a question on perceived fitness. First, individual differences were studied between four fitness categories. Secondly, pairwise differences were examined among twin pairs discordant for fitness. RESULTS: Self-reported fitness explained moderately the variation in objectively measured PA parameters: R2 for daily steps 26%, for daily mean MET 31%, for daily moderate-to-vigorous activity (MVPA) time 31%, and lower for SB time 14 % (all p<0.001). Better self-reported fitness was associated with more steps taken on average (8558 daily steps (very good fitness) vs. 2797 steps (poor fitness), p<0.001) and with a higher amount of MVPA (61 min vs. 12 min p<0.001, respectively) in the adjusted multivariable model. Among 156 twin pairs discordant for self-reported fitness, co-twins with better fitness took more steps, did more MVPA and had less SB (all, p<0.05) compared to their less fit co-twins, however difference was smaller among MZ than DZ pairs. CONCLUSION: One simple question on self-reported fitness is associated with daily activity profile among community-dwelling older people. However, genetic factors modulate this association to some extent. PMID- 30445495 TI - GRNBoost2 and Arboreto: efficient and scalable inference of gene regulatory networks. AB - Summary: Inferring a Gene Regulatory Network (GRN) from gene expression data is a computationally expensive task, exacerbated by increasing data sizes due to advances in high-throughput gene profiling technology, such as single-cell RNA seq. To equip researchers with a toolset to infer GRNs from large expression datasets, we propose GRNBoost2 and the Arboreto framework. GRNBoost2 is an efficient algorithm for regulatory network inference using gradient boosting, based on the GENIE3 architecture. Arboreto is a computational framework that scales up GRN inference algorithms complying with this architecture. Arboreto includes both GRNBoost2 and an improved implementation of GENIE3, as a user friendly open source Python package. Availability: Arboreto is available under the 3-Clause BSD license at http://arboreto.readthedocs.io. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445496 TI - Detoxification Genes Differ Between Cactus-, Fruit- and Flower-Feeding Drosophila. AB - We use annotated genomes of fourteen Drosophila species covering diverse host use phenotypes to test whether five gene families which often have detoxification functions are associated with host shifts among species. Bark, slime flux, flower and generalist necrotic fruit feeding species all have similar numbers of carboxyl/cholinesterase, glutathione S-transferase, cytochrome P450 and UDP glucuronosyltransferase genes. However, species feeding on toxic Morinda citrifolia fruit and the fresh fruit feeding D. suzukii have about 30 and 60 more respectively. ABC transporters show a different pattern, with the flower feeding D. elegans and the generalist necrotic fruit and cactus feeder D. hydei having about 20 and >100 more than the other species, respectively. Surprisingly, despite the complex secondary chemistry we find that three cactophilic specialists in the mojavensis species cluster have variably fewer genes than any of the other species across all five families. We also find 82 positive selection events across the five families, with the terminal D. suzukii and M. citrifolia feeding D. sechellia branches again having the highest number of such events in proportion to their respective branch lengths. Many of the genes involved in these host-use-specific gene number differences or positive selection events lie in specific clades of the gene families which have been recurrently associated with detoxification. Several genes are also found to be involved in multiple duplication and or positive selection events across the species studied regardless of their host use phenotypes; the most frequently involved are the ABC transporter CG1718, which is not in a specific clade associated with detoxification, and the alpha-esterase gene cluster, which is. PMID- 30445497 TI - The role of sartorius muscle flaps in the management of complex groin wounds. AB - A best evidence topic in vascular surgery was written according to a structured protocol. The question addressed was whether sartorius muscle flaps (SMF) can be effectively used in the setting of complex groin wounds with exposed prosthetic grafts for graft salvage and limb salvage. The literature review identified 33 articles reporting on the use of SMF for complex vascular wounds. Of these, 7 articles reporting on the use of 539 SMFs were considered the best evidence to answer the clinical question. Indications included surgical site infections with or without wound dehiscence, lymph leaks, graft infection and groin pseudoaneurysms, whereas in 98 of the included 539 cases, the flaps were performed prophylactically. Vacuum-assisted closure systems were used in 25 cases to promote healing. The use of an SMF is associated with low rates of muscle flap and graft complications, whereas outcomes seem to be independent of the presence of occlusive disease in the superficial femoral artery. They can be effectively combined with aggressive debridement strategies and vacuum-assisted closure devices to optimize outcomes. The published literature supports the use of SMF in the management of complex groin wounds following vascular reconstruction and is associated with encouraging flap, limb and graft salvage rates. PMID- 30445498 TI - Quantifying Temporal Variation in the Benefits of Aphid Honeydew for Biological Control of Alfalfa Weevil (Coleoptera: Curculionidae). AB - Sugar feeding by biological control agents, such as parasitoid wasps, may enhance their ability to control crop pests, although its importance is likely to vary greatly through space and time. Here we quantified temporal variation in the potential importance of sugar resources associated with honeydew secreted by the pea aphid (Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae)) in determining levels of parasitism of the alfalfa weevil (Hypera postica (Gyllenhal) (Coleoptera: Curculionidae)) by its dominant parasitoid, Bathyplectes curculionis (Thomson) (Hymenoptera: Ichneumonidae) across irrigated alfalfa fields in Montana, United States over 5 yr. A positive association between parasitism of H. postica and A. pisum densities at the across-site scale was observed in 2 of 5 yr, with parasitism increasing twofold to fourfold over gradients in A. pisum density. The relationship was strongest in the 2 yr of lowest parasitoid relative to host densities, when increases in per capita effects of individual parasitoids would be expected to be particularly important. Acyrthosiphon pisum densities were at their lowest in these same years, suggesting that they may generally be sufficiently abundant that parasitoids are not limited by sugars in most years. This conclusion is supported by results of anthrone tests which revealed a high level of sugar-fed parasitoids (>50%) in a year of high aphid abundance. More studies, such as this one, that explore the frequency with which increasing sugar resource availability actually enhances parasitism levels in the field will be critical to gauge the broader potential of sugar resource addition (e.g., through flowering strips, banker plants or sugar sprays) to bolster biological control. PMID- 30445499 TI - The aortic balloon occlusion technique in total arch replacement with frozen elephant trunk. AB - The total aortic arch replacement with frozen elephant trunk is increasingly being used. However, deep hypothermic circulatory arrest is inevitable. We performed a novel surgical technique, the 'aortic balloon occlusion', in the surgical treatment of Stanford type A aortic dissection to reduce the adverse effects caused by deep hypothermic circulatory arrest. PMID- 30445500 TI - Description of two new species of Aliinostoc and one new species of Desmonostoc from India based on the Polyphasic Approach and reclassification of Nostoc punensis to Desmonostoc punense comb. nov. AB - Three heterocytous cyanobacterial strains were isolated from different habitats of Central India, and initial morphological studies indicated them to be members of the genus Nostoc or other closely related genera. Subsequent studies using morphological, ecological, molecular and phylogenetic methods indicated the three strains to be new members of the genera Aliinostoc and Desmonostoc. Folding of the D1-D1' helix of the ITS region clearly differentiated the three strains from the other closely related strains, thus providing final indications of the strains being different and new additions to the genera Aliinostoc and Desmonostoc. In accordance with the International Code of Nomenclature for algae, fungi and plants, we establish three new species: Aliinostoc tiwarii sp. nov, Aliinostoc soli sp. nov. and Desmonostoc magnisporum sp. nov. along with reclassifying Nostoc punensis as Desmonostoc punense comb. nov. PMID- 30445501 TI - The molecular biology of fruity and floral aromas in beer and other alcoholic beverages. AB - Aroma compounds provide attractiveness and variety to alcoholic beverages. We discuss the molecular biology of a major subset of beer aroma volatiles, fruity and floral compounds, originating from raw materials (malt and hops), or formed by yeast during fermentation. We introduce aroma perception, describe the most aroma-active, fruity and floral compounds in fruits and their presence and origin in beer. They are classified into categories based on their functional groups and biosynthesis pathways: 1) Higher alcohols and esters, 2) Polyfunctional thiols, 3) Lactones and furanones, and 4) Terpenoids. Yeast and hops are the main sources of fruity and flowery aroma compounds in beer. For yeast, the focus is on higher alcohols and esters, and particularly the complex regulation of the alcohol acetyl transferase ATF1 gene. We discuss the release of polyfunctional thiols and monoterpenoids from cysteine- and glutathione-S-conjugated compounds and glucosides, respectively, the primary biological functions of the yeast enzymes involved, their mode of action and mechanisms of regulation that control aroma compound production. Furthermore, we discuss biochemistry and genetics of terpenoid production and formation of non-volatile precursors in Humulus lupulus (hops). Insight in these pathways provides a toolbox for creating innovative products with a diversity of pleasant aromas. PMID- 30445503 TI - MHR | driving reproductive science. PMID- 30445502 TI - Endogenous oxytocin levels in relation to food intake, menstrual phase, and age in females. AB - Context: Oxytocin regulates a range of physiological processes including eating behavior, and oxytocin administration reduces caloric intake in men. There are few data on oxytocin levels and eating behavior in healthy females, or on the response of endogenous oxytocin to food intake and its relationship to appetite in humans. Objectives: To determine the postprandial pattern of oxytocin levels; the relationship between oxytocin and appetite; and the impact of menstrual cycle phase and age on oxytocin levels in females. Design: Cross-sectional. Setting: Clinical research center. Participants: Fifty-five healthy females (age 10-45). Interventions: A standardized mixed meal was administered. Main outcome measurements: Blood sampling for oxytocin occurred at fasting and at 30, 60, and 120 minutes post-meal. Appetite was assessed using Visual Analogue Scales pre- and post-meal. Results: Mean fasting oxytocin levels were 1011.2+/-52.3(SEM) pg/mL and decreased at 30 and 60 minutes post-meal (p=0.001 and p=0.003, respectively). Mean oxytocin levels dropped 19.6+/-3.0% from baseline to nadir. Oxytocin area under the curve was lower in the early-mid follicular menstrual cycle phase (p=0.0003) and higher in younger females (p=0.002). The % change in oxytocin (baseline to nadir) was associated with postprandial hunger (rs=-0.291, p=0.03) and fullness (rs=0.345, p=0.009). These relationships remained significant after controlling for calories consumed, menstrual cycle status, and age (p=0.023 and p=0.0001, respectively). Conclusions: Peripheral oxytocin levels in females decrease after a mixed meal and are associated with appetite independent of menstrual phase, age, and caloric intake, suggesting that endogenous oxytocin levels may play a role in perceived hunger and satiety. PMID- 30445504 TI - A State-of-the-Art Review of New and Emerging Therapies for the Treatment of IBD. AB - Over the last 2 decades, novel therapies targeting several immune pathways have been developed for the treatment of patients with inflammatory bowel disease (IBD). Although anti-tumor necrosis factor (anti-TNF) agents remain the firstline treatment for moderate to severe Crohn's disease and ulcerative colitis, many patients will require alternative agents, due to nonresponse, loss of response, or intolerance of anti-TNFs. Furthermore, patients may request newer therapies due to improved safety profiles or improved administration (ie, less frequent injection, oral therapy). This review will focus on new and emerging therapies for the treatment of IBD, with a special focus on their adverse effects. Although many of the agents included in this paper have been approved for use in IBD, a few are still in development but have been shown to be effective in phase II clinical trials.10.1093/ibd/izy327_video1izy327.video15967364908001. PMID- 30445505 TI - Repeated evolution of asexuality involves convergent gene expression changes. AB - Asexual reproduction has evolved repeatedly from sexual ancestors across a wide range of taxa. While the costs and benefits associated with asexuality have received considerable attention, the molecular changes underpinning the evolution of asexual reproduction remain relatively unexplored. In particular, it is completely unknown whether the repeated evolution of asexual phenotypes involves similar molecular changes, as previous studies have focused on changes occurring in single lineages. Here we investigate the extent of convergent gene expression changes across five independent transitions to asexuality in stick insects. We compared gene expression of asexual females to females of close sexual relatives in whole-bodies, reproductive tracts, and legs. We identified a striking amount of convergent gene expression change (up to 8% of genes), greatly exceeding that expected by chance. Convergent changes were also tissue-specific, and most likely driven by selection for functional changes. Genes showing convergent changes in the reproductive tract were associated with meiotic spindle formation and centrosome organization. These genes are particularly interesting as they can influence the production of unreduced eggs, a key barrier to asexual reproduction. Changes in legs and whole-bodies were likely involved in female sexual trait decay, with enrichment in terms such as sperm-storage and pigmentation. By identifying changes occurring across multiple independent transitions to asexuality, our results provide a rare insight into the molecular basis of asexual phenotypes and suggest that the evolutionary path to asexuality is highly constrained, requiring repeated changes to the same key genes. PMID- 30445506 TI - Is Preoperative Duration of Symptoms a Significant Predictor of Functional Outcomes in Patients Undergoing Surgery for the Treatment of Degenerative Cervical Myelopathy? AB - BACKGROUND: Preoperative duration of symptoms may significantly impact outcomes in patients treated surgically for degenerative cervical myelopathy (DCM). OBJECTIVE: To (i) analyze whether duration of symptoms is associated with preoperative functional impairment, disability, and quality of life and (ii) determine the optimal timing for decompressive surgery. METHODS: Patients with DCM were prospectively enrolled in either the AOSpine North American or International study at 26 global sites (n = 757). Postoperative functional impairment was evaluated at 1-yr using the modified Japanese Orthopaedic Association (mJOA) score. Change scores between baseline and 1-yr were computed for the mJOA. Duration of symptoms was dichotomized into a "short" and "long" group at several cut-offs. Analysis of covariance was used to evaluate differences in change scores on the mJOA between duration of symptoms groups in 4 mo increments. RESULTS: Our cohort consisted of 424 men and 255 women, with a mean duration of symptoms of 26.1 +/- 36.4 mo (0.25-252 mo). Duration of symptoms was not correlated with preoperative mJOA, Nurick, Neck Disability Index, or Short-Form (SF)-36 Physical and Mental Component Scores. Patients with a duration of symptoms shorter than 4 mo had significantly better functional outcomes on the mJOA than patients with a longer duration of symptoms (>4 mo). Thirty-two months was also a significant cut-off. CONCLUSION: Patients who are operated on within 4 mo of symptom presentation have better mJOA outcomes than those treated after 4 mo. It is recommended that patients with DCM are diagnosed in a timely fashion and managed appropriately. PMID- 30445507 TI - Formative, multimethod case studies of learn to quit, an acceptance and commitment therapy smoking cessation app designed for people with serious mental illness. AB - Despite public health efforts, individuals with serious mental illness (SMI) still have very high rates of tobacco smoking. Innovative approaches to reach this population are needed. These series of case studies aimed to descriptively evaluate the usability, user experience (UX), and user engagement (UE) of Learn to Quit (LTQ), an acceptance and commitment therapy smoking cessation app designed for people with SMI, and to compare it with an app designed for the general population, NCI (National Cancer Institute) QuitGuide (QG). Both apps were combined with nicotine replacement therapy and technical coaching. Inspired by the ORBIT model, we implemented two case studies with crossover AB interventions, two B-phase training designs, and three bi-phasic AB single-case designs with Start-Point and Order randomization (A = QG, B = LTQ). Study outcomes were measured using the System Usability Scale, UX interviews, and background analytics. LTQ's usability levels were above the standard cutoff and on average higher than QG. UX outcomes suggested the relative benefits of LTQ's visual design, gamification and simple design structure. LTQ's overall UE was high; the app was opened for an average of 14 min per day (vs. QG: 7 min). However, users showed low levels of UE with each of the app's tracking feature. Measures of psychiatric functioning suggested the safety of LTQ in people with SMI. LTQ appears to be a usable and engaging smoking cessation app in people with SMI. An optimized version of LTQ should be tested in a Phase II study. PMID- 30445508 TI - Writing a Clinical Research Question. AB - The bar for clinical research in surgical subspecialties has been rising over the past 10 yr. It is now essential that neurosurgeons are familiar with the principles of evidence-based medicine to evaluate and conduct sound clinical research. In this review, we highlight the importance of formulating a good research question, which serves as the foundation for meaningful investigation. PMID- 30445509 TI - One hour post-OGTT glucose improves the early prediction of type 2 diabetes by clinical and metabolic markers. AB - Context: Early prediction of dysglycaemia is crucial to prevent progression to type 2 diabetes. The one-hour post-load plasma glucose (1-h PG) has been reported a better predictor of dysglycaemia than fasting plasma glucose (FPG), 2-h PG, or glycated haemoglobin (HbA1c). Objective: To evaluate the predictive performance of clinical markers, metabolites, HbA1c, and plasma glucose (PG) and serum insulin (INS) levels during a 75-gram oral glucose tolerance test (OGTT). Design and Setting: We measured PG and INS levels at 0, 30, 60, and 120 minutes during an OGTT in 543 individuals in the Botnia Prospective Study, 146 of whom progressed to type 2 diabetes within a 10-year follow-up period. Using combinations of variables, we evaluated 1527 predictive models for progression to type 2 diabetes. Results: The 1-h PG outperformed every individual marker except 30-min PG or mannose, whose predictive performances were lower but not significantly worse. HbA1c performed inferior to 1-h PG according to DeLong test p-value but not false discovery rate. Combining the metabolic markers with PG measurements and HbA1c significantly improved the predictive models, and mannose was found to be a robust metabolic marker. Conclusions: The 1-h PG, alone or in combination with metabolic markers, is a robust predictor for determining the future risk of type 2 diabetes outperforms the 2-h PG, and is cheaper to measure than metabolites. Metabolites add to the predictive value of PG and HbA1c measurements. Shortening the standard 75-gram OGTT to one hour improves its predictive value as well as clinical usability. PMID- 30445510 TI - Evolution of the mutational process under relaxed selection in Caenorhabditis elegans. AB - The mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.Deleterious mutations are a ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups of Caenorhabditis elegans mutation accumulation (MA) lines that differ in their starting mutation loads. "First-Order MA" (O1MA) lines maintained under minimal selection for ~250 generations were divided into high-fitness and low fitness groups and sets of "second-order MA" (O2MA) lines derived from each O1MA line were maintained for ~150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate (ubs), but no effect of initial fitness; the indel rate is greater in high-fitness O2MA lines. Overall, ubs is positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 Kb GC content. However, probability of mutation is sufficiently predicted by the three-nucleotide motif alone. ~90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the "drift barrier" model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic. PMID- 30445511 TI - Two Medicaid health plans' models and motivations for improving colorectal cancer screening rates. AB - Screening rates for colorectal cancer (CRC) remain low, especially among certain populations. Mailed fecal immunochemical testing (FIT) outreach initiated by U.S. health plans could reach underserved individuals, while solving CRC screening data and implementation challenges faced by health clinics. We report the models and motivations of two health insurance plans implementing a mailed FIT program for age-eligible U.S. Medicaid and Medicare populations. One health plan operates in a single state with ~220,000 enrollees; the other operates in multiple states with ~2 million enrollees. We conducted in-depth qualitative interviews with key stakeholders and observed leadership and clinic staff planning during program development and implementation. Interviews were transcribed and coded using a content analysis approach; coded interview reports and meeting minutes were iteratively reviewed and summarized for themes. Between June and September 2016, nine participants were identified, and all agreed to the interview. Interviews revealed that organizational context was important to both organizations and helped shape program design. Both organizations were hoping this program would address barriers to their prior CRC screening improvement efforts and saw CRC screening as a priority. Despite similar motivations to participate in a mailed FIT intervention, contextual features of the health plans led them to develop distinct implementation models: a collaborative model using some health clinic staffing versus a centralized model operationalizing outreach primarily at the health plan. Data are not yet available on the models' effectiveness. Our findings might help inform the design of programs to deliver mailed FIT outreach. PMID- 30445513 TI - Differences in molecular profiles of glioblastomas according to location. PMID- 30445512 TI - Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments. AB - The underlying neurobiological basis of major depressive disorder (MDD) remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of MDD, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both MDD and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast-acting, robust, and relatively sustained antidepressant, anti-suicidal, and anti-anhedonic effects in individuals with treatment-resistant depression (TRD) have prompted tremendous interest in understanding the mechanisms responsible for ketamine's clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine's effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine's targets include non competitive N-methyl-D-aspartate receptor (NMDAR) inhibition, alpha-amino-3 hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) throughput potentiation coupled with downstream signaling changes, and NMDAR targets localized on gamma aminobutyric acid (GABA)-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for TRD, including: NMDAR antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described. PMID- 30445514 TI - Corrigendum. PMID- 30445515 TI - Abnormal Activation of Motor Cortical Network during Phasic REM Sleep in Idiopathic REM Sleep Behavior Disorder. AB - Study Objectives: We investigated EEG power spectral density and functional connectivity during phasic and tonic rapid eye movement (REM) sleep, and examined any differences between patients with idiopathic REM sleep behavior disorder (iRBD) and controls. Methods: EEG data from 13 iRBD patients (mean age, 66.3 years; men, 84.6%) and 10 controls (mean age, 62.3 years; men, 70%) were analyzed. We selected thirty 3-s mini-epochs of both tonic and phasic REM sleep. We estimated relative power for six frequency bands. For functional connectivity analysis, we calculated weighted phase lag index (wPLI) and conducted pairwise comparisons between the two groups. Results: EEG power spectral analysis revealed significant interactions between the REM sleep state (phasic vs. tonic) and group at sigma (P = 0.009), and beta (P = 0.002) bands. Sigma and beta power decrease during phasic REM sleep was more pronounced and extensive in patients with iRBD than in controls. Regarding functional connectivity, there were significant interactions between the REM sleep state and group at alpha (P = 0.029), sigma (P = 0.047), beta (P = 0.015), and gamma (P = 0.046) bands. The average wPLI was significantly higher during phasic REM sleep than during tonic REM sleep, which was observed in patients with iRBD but not in controls. The altered functional connections mainly involved the frontal and parietal regions at beta and gamma bands. Conclusions: Our findings provide neurophysiological evidence for pathological motor cortex activation during phasic REM sleep which may be associated with generation of dream-enacting behaviors in iRBD. PMID- 30445517 TI - Flow-Diverter Stent With an Incorporated Flow Sensor-The Integration of a Treatment and Diagnostic Device for Intracranial Aneurysms. PMID- 30445516 TI - Validation of the performance of TIMES genotoxicity models with EFSA pesticide data. AB - This study validates the performance of the TIssue MEtabolism Simulator (TIMES) genotoxicity models with data on pesticide chemicals included in a recently released European Food Safety Authority (EFSA) genotoxicity database. The EFSA database is biased towards negative chemicals. A comparison of substances included in the EFSA database and TIMES genotoxicity databases showed that the majority of the EFSA pesticides is not included in the TIMES genotoxicity databases and, thus, out of the applicability domains of the current TIMES models. However, the EFSA genotoxicity database provides an opportunity to expand the TIMES models. Where there is overlap of substances, consistency between EFSA and TIMES databases for the chemicals with documented data is found to be high (>80%) with respect to the Ames data and lower than the Ames data with respect to chromosomal aberration (CA) and mouse lymphoma assay (MLA) data. No conclusion for consistency with respect to micronucleus test and comet genotoxicity data can be provided due to the limited number of overlapping substances. Specificity of the models is important, given the prevalence of negative genotoxicity data in the EFSA database. High specificity (>80%) is obtained for prediction of the EFSA pesticides with Ames data. Moreover, this high specificity of the TIMES Ames models is not dependant on pesticides being within the domains. Specificity of the TIMES CA and MLA models is lower (>40%) to pesticides for out of domain. Sensitivity of TIMES in vitro and in vivo models cannot be properly estimated due to the small number of positive chemicals in the EFSA database. PMID- 30445518 TI - Condition-specific series of metabolic sub-networks and its application for gene set enrichment analysis. AB - Motivation: Genome-scale metabolic networks and transcriptomic data represent complementary sources of knowledge about an organism's metabolism, yet their integration to achieve biological insight remains challenging. Results: We investigate here condition-specific series of metabolic sub-networks constructed by successively removing genes from a comprehensive network. The optimal order of gene removal is deduced from transcriptomic data. The sub-networks are evaluated via a fitness function, which estimates their degree of alteration. We then consider how a gene set, i.e. a group of genes contributing to a common biological function, is depleted in different series of sub-networks to detect the difference between experimental conditions. The method, named metaboGSE, is validated on public data for Yarrowia lipolytica and mouse. It is shown to produce GO terms of higher specificity compared to popular gene set enrichment methods like GSEA or topGO. Availability: The metaboGSE R package is available at https://cran.r-project.org/web/packages/metaboGSE. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445519 TI - The needle in the (organ) haystack. PMID- 30445520 TI - Editor's Choice: Human Reproduction's greatest hits. PMID- 30445521 TI - Beta defensin 3 enhances ovarian granulosa cell proliferation and migration via ERK1/2 pathway in vitro. AB - Antimicrobial peptides (AMPs) are regarded as host defense peptides which possess bactericidal activity as well as immunomodulatory function. However, the role of AMP in the mammalian ovary is unknown. In the present study, porcine granulosa cells were utilized in a cell model to study the role of porcine beta defensin 2 (pBD2; pDEFB4B) and 3 (pBD3; pDEFB103A) during ovarian follicular development. Granulosa cells were cultured in the absence and presence of 1, 10, and 50 MUg/ml of pDEFB4B or pDEFB103A. After 24 hours of treatment, pDEFB103A but not pDEFB4B stimulated granulosa cell proliferation in a concentration dependent manner (P < 0.05). This effect was dependent on the stage of follicular development. In addition, transwell cell migration assay showed that in the presence of pDEFB103A (10 MUg/ml), a 2.5-fold increase in cell migration was achieved. Further, further study revealed that pDEFB103A increased the mRNA levels of cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA), both associated with cell proliferation. To study the potential pathway involved in pDEFB103A-induced cell proliferation and migration, western blots were performed. It was found that pDEFB103A significantly increased the phosphorylated-ERK1/2 to non-phosphorylated ratio. Moreover, pretreatment with the U0126, a specific ERK1/2 phosphorylation inhibitor, suppressed PDEFB103A inducing GCs ERK1/2 phosphorylation, as well as proliferation and migration, suggesting that PDEFB103A may act via activating the ERK1/2 pathway. Furthermore, using a signal transduction pathway Elk-1 trans reporting system, the activation of ERK1/2 pathway by PDEFB103A was further confirmed. Our data suggest that AMP may play a physiological role in the mammalian ovary. PMID- 30445522 TI - The Enhancement of Pyridine Degradation by Rhodococcus KDPy1 in Coking Wastewater. AB - Pyridine is a typical nitrogen heterocyclic and recalcitrant organic compound in coking wastewater. The pyridine-degrading bacterial strain KDPy1 was isolated from aerobic sludge in a coking wastewater treatment plant. The homology analysis based on 16S rDNA sequences suggested that KDPy1 belonged to Rhodococcus sp. The optimum temperature and pH for pyridine degradation by KDPy1 were 37 degrees C and 7-8, respectively. The strain KDPy1 degraded 1442 mg/L of pyridine nearly 99.6% after 48 h, and high concentration of 1442 mg/L pyridine did not show inhibitory effect to its degradation. The degradation kinetic of pyridine fitted with the Monod model. Furthermore, KDPy1 was capable of degrading pyridine efficiently in the synthetic wastewater containing quinoline and phenol. KDPy1 could degrade pyridine and reduce the total organic carbon (TOC) in the real coking wastewater. These results showed KDPy1 had a potential for improving the removal of pyridine from coking wastewater. PMID- 30445523 TI - When the A1c and the blood glucose don't match: how much is determined by race, by genetics, by differences in mean red blood cell age? PMID- 30445524 TI - Corrigendum: Estimation of clinical trial success rates and related parameters. PMID- 30445525 TI - A large primary cardiac glomus tumour: a surgical dilemma. PMID- 30445526 TI - Genetic basis of plasticity in plants. AB - The ability of an organism to change its phenotype in response to different environments, termed plasticity, is a particularly important characteristic for sessile plants to adapt to rapid changes in their climate. Plasticity is a quantitative trait which can provide a fitness advantage and mitigate negative effects due to environmental perturbations. Yet, its genetic basis is not fully understood. Alongside technological limitations, the main challenge in studying plasticity has been the selection of suitable approaches for quantification of phenotypic plasticity. Here we propose a categorization of the existing quantitative measures of phenotypic plasticity into nominal and relative approaches. Moreover, we highlight the recent advances in the understanding of the genetic architecture underlying phenotypic plasticity in plants. We identify four pillars for future research to uncover the genetic basis of phenotypic plasticity, with emphasis on development of computational approaches and theories. These developments will allow us to perform specific experiments to validate the causal genes for plasticity and to discover their role in plant fitness and evolution. PMID- 30445527 TI - Sigmoidouterine Fistula in Crohn's Disease: A First Case Report. PMID- 30445528 TI - Minimal incision palatoplasty with or without muscle reconstruction in patients with isolated cleft palate-a cephalometric study at 5 and 10 years. AB - Objective: To compare differences in facial growth in patients with isolated clefts of the hard and/or soft palate treated with the minimal incision technique without (MI) or with muscle reconstruction (MMI). Subjects and method: A consecutive series of 170 Caucasian children born with isolated cleft palate were studied. Individuals with other craniofacial malformations, apart from Pierre Robin sequence (PRS), were excluded. The patients were treated surgically with MI (n = 85) or MMI (n = 85) palatoplasty (mean age: 13 months) and divided further into two subgroups: clefts within the soft palate only (small cleft, n = 51) and within the hard and soft palate (big cleft, n = 119). A retrospective evaluation at 5 (mean 5.4) and 10 (mean 10.3) years was performed using lateral cephalograms. Twelve skeletal and one soft tissue measurement was evaluated. Both 95% and 99% confidence intervals were calculated, two-way ANOVA and mixed model analysis was performed including/excluding PRS. Results: At 5 years, statistically significant increased inclination of the palatal plane in the big MMI cleft group (P < 0.01), increased posterior upper face height (P < 0.01), and longer mandibular length (P < 0.001) in the small MI cleft group was observed. At 10 years, statistically significant increased inclination of the palatal plane (P < 0.001), decreased posterior upper face height (P < 0.001), and longer palatal length (P < 0.01) was seen in the big MMI group. Limitations: Retrospective single centre study, limited sample size, three surgeons. Conclusion: Minor differences in craniofacial morphology were found between patients with isolated clefts treated with MI or MMI technique and between small and big cleft lengths. PMID- 30445529 TI - Potential roles of CD34+ fibrocytes masquerading as orbital fibroblasts in thyroid-associated ophthalmopathy. AB - Context: Orbital tissues in thyroid-associated ophthalmopathy 1 exhibit particular reactivity and undergo characteristic remodeling. Mechanisms underlying these changes have remained largely unexplained. Studies have characterized orbital connective tissues and derivative fibroblasts to gain insights into local manifestations of a systemic autoimmune syndrome. Evidence Acquisition: A systematic search of PubMed was undertaken for studies related to TAO, orbital fibroblasts, and fibrocytes involved in pathogenesis. Evidence Synthesis: Orbital tissues display marked cellular heterogeneity. Fibroblast subsets, putatively derived from multiple precursors, inhabit the orbit in TAO. Among them are cells displaying the CD34+ CXCR4+ Col I+ phenotype, identifying them as fibrocytes, derived from the bone marrow monocyte lineage. Their unique presence in the TAO orbit helps explain the tissue reactivity and characteristic remodeling that occurs in the disease. Their unanticipated expression of several proteins traditionally thought to be thyroid gland-specific, including the thyrotropin receptor and thyroglobulin, may underlie orbital involvement in Graves' disease. While no currently available information unambiguously established that CD34+ orbital fibroblasts originate from circulating fibrocytes, inferences from animal models of lung disease suggest that they derive from bone marrow. Further studies will be necessary to determine whether fibrocyte abundance and activity in the orbit determine the clinical behavior of TAO. Conclusion: Evidence supports a role for fibrocytes in the pathogenesis of TAO. Recognition of their presence in the orbit now allows development of therapies specifically targeting these cells that ultimately could allow the restoration of immune tolerance within the orbit and perhaps systemically. PMID- 30445530 TI - Repeat renal biopsy improves the Oxford classification-based prediction of immunoglobulin A nephropathy outcome. AB - Background: The prognosis of IgA nephropathy (IgAN) is very heterogeneous. Predicting the nature and the rate of the disease progression is crucial for refining patient treatment. The aim of this study was to evaluate the prognostic impact of an Oxford classification-based repeat kidney tissue evaluation to predict end-stage renal disease (ESRD). Methods: Patients with biopsy-proven primary IgAN who underwent two renal biopsies at our centre were analyzed retrospectively. Renal biopsies were scored by two pathologists blinded to the clinical data and according to the updated Oxford classification. Cox models were generated to evaluate the prognostic impact considering the Oxford classification elementary lesions from the first (Model 1) or the second (Model 2) biopsy, adjusted on clinical data at time of reevaluation. The prognostic impacts of the dynamic evolution of each elementary lesion between biopsies were also assessed through univariate and multivariate evaluation. Results: A total of 168 adult patients were included, with a median follow-up duration of 18 (range 11-24) years. The second biopsy was performed either systematically (n = 112) of for cause (n = 56), after a median time of 5.4 years. The prognostic performances of Model 2 (second biopsy) were significantly better than Model 1 (first biopsy, analysis of deviance P < 0.0001). The dynamic changes of C and T lesions were significantly associated with the progression toward ESRD after adjustment on variables from Model 2. Conclusion: Both static and dynamic Oxford-based histological evaluation offered by a repeat biopsy improves the prediction of ESRD in patients with IgAN. PMID- 30445532 TI - Proteins and RNA sequences required for the transition of the t-Utp complex into the SSU processome. AB - Ribosomes are synthesized by large ribonucleoprotein complexes cleaving and properly assembling highly structured rRNAs with ribosomal proteins. Transcription and processing of pre-rRNAs are linked by the transcription-Utp sub complex (t-Utps), a sub-complex of the small subunit (SSU) processome and prompted the investigations for the requirements of t-Utp formation and transition into the SSU processome. The rDNA promoter, the first 44 nucleotides of the 5?ETS, and active transcription by pol I were sufficient to recruit the t Utps to the rDNA. Pol5, accessory factor, dissociated as t-Utps matured into the UtpA complex which permitted later recruitment of the UtpB, U3 snoRNP and the Mpp10 complex into the SSU processome. The t-Utp complex associated with short RNAs 121 and 138 nucleotides long transcribed from the 5?ETS. These transcripts were not present when pol II transcribed the rDNA or in nondividing cells. Depletion of a t-Utp, but not of other SSU processome components led to decreased levels of the short transcripts. However, ectopic expression of the short transcripts slowed the growth of yeast with impaired rDNA transcription. These results provide insight into how transcription of the rRNA primes the assemble of t-Utp complex with the pre-rRNA into the UtpA complex and the later association of SSU processome components. PMID- 30445531 TI - Chlamydiae in human intestinal biopsy samples. AB - Chlamydia trachomatis is frequently detected in anorectal specimens from men and women. A recent hypothesis suggests that C. trachomatis is a natural commensal organism asymptomatically colonizing the gastrointestinal tract. In this study, we investigated the presence of chlamydial DNA and antigen in intestinal biopsy samples taken during colonoscopy. Cases (n = 32) were patients whose histopathology reports included the term 'chlamydia', suggesting a possible history of infection. Control patients (n = 234) did not have chlamydia mentioned in their histopathology report and all tested negative for Chlamydiaceae DNA by 23S ribosomal RNA-based real-time PCR. Amongst the cases, C. trachomatis DNA was detected in the appendix and colon of two female and one male patients. Chlamydia abortus DNA was present in the colon of a fourth female patient. Thus, chlamydial DNA could be demonstrated in intestinal biopsy samples proximal to the anorectal site and inclusions were identified in rectum or appendix of two of these patients by immunohistochemistry. However, the findings in two cases were compatible with sexually acquired C. trachomatis. The identification of C. trachomatis DNA/antigen does not prove the presence of active infection with replicating bacteria. Larger prospective studies on fresh tissue samples are required to confirm the data obtained in this study. PMID- 30445533 TI - The genome landscape of Tibetan sheep reveals adaptive introgression from argali and the history of early human settlements on the Qinghai-Tibetan Plateau. AB - Tibetan sheep are the most common and widespread domesticated animals on the Qinghai-Tibetan Plateau (QTP), and have played an essential role in the permanent human occupation of this high-altitude region. However, the precise timing, route and process of sheep pastoralism in the QTP region remain poorly established, and little is known about the underlying genomic changes that occurred during the process. Here, we investigate the genomic variation in Tibetan sheep using whole genome sequences, SNP arrays, mitochondrial DNA and Y-chromosomal variants in 986 samples throughout their distribution range. We detect strong signatures of selection in genes involved in the hypoxia and ultraviolet signaling pathways (e.g., HIF-1 pathway and HBB and MITF genes) and in genes associated with morphological traits such as horn size and shape (e.g., RXFP2). We identify clear signals of argali (Ovis ammon) introgression into sympatric Tibetan sheep, covering 5.23% - 5.79% of their genomes. The introgressed genomic regions are enriched in genes related to oxygen transportation system, sensory perception and morphological phenotypes, in particular the genes HBB and RXFP2 with strong signs of adaptive introgression. The spatial distribution of genomic diversity and demographic reconstruction of the history of Tibetan sheep shows a stepwise pattern of colonization with their initial spread onto the QTP from its northeastern part c. 3,100 years ago, followed by further southwest expansion to the central QTP c. 1,300 years ago. Together with archeological evidence, the date and route reveals the history of human expansions on the QTP by the Tang-Bo Ancient Road during the late-Holocene. Our findings contribute to a depth understanding of early pastoralism and the local adaptation of Tibetan sheep as well as the late-Holocene human occupation of the QTP. PMID- 30445534 TI - Daytime sleepiness predicts future suicidal behavior: A longitudinal study of adolescents. AB - Study objectives: Daytime sleepiness is associated with poor daytime functioning and adverse cognitive and emotional consequences, such as impaired decision making and increased impulsivity. Little is known about the association between daytime sleepiness and suicidal behaviors. This study examined the prospective relationship between daytime sleepiness and suicidal behaviors, including suicidal thought (ST), suicide plan (SP), and suicide attempt (SA), in a large sample of adolescents. Methods: A prospective longitudinal study of 7,072 adolescents (mean age = 14.6 years) was conducted in Shandong province, China. Participants completed a self-administered questionnaire to assess suicidal behaviors, daytime sleepiness, nighttime sleep duration, insomnia, snoring, hopelessness, impulsivity, anxiety/depression, and family demographics. Participants were first surveyed in November-December 2015 and resurveyed one year later. Of the 7,072 participants, 77.1% (n=5,451) who did not report suicidal behaviors at baseline were included for primary analysis. Results: The incidence rates of ST, SP, and SA at 1-year follow-up were 6.0%, 2.1%, and 1.6%, respectively. The incidence rates of ST and SP significantly increased with elevated daytime sleepiness score at baseline. After adjusting for adolescent and family covariates including sleep-related variables (i.e., insomnia, nighttime sleep duration, and snoring), a daytime sleepiness score >= median at baseline was significantly associated with increased risk of ST (OR=1.55, 95%CI = 1.02 - 2.35) and SP (OR=2.60, 95%CI = 1.22 - 5.53). Conclusions: Daytime sleepiness appears to be a significant predictor of subsequent suicidal behaviors in adolescents. These findings emphasize the importance of assessing and intervening daytime sleepiness for preventing suicide in adolescents. PMID- 30445535 TI - Serotonin signaling trough prelimbic 5-HT1A receptors modulates CSDS induces behavioural changes in adult female voles. AB - Background: Most previous studies have focused on the effects of social defeat in male juvenile individuals. Whether chronic social defeat stress (CSDS) in adulthood affects female emotion and the underlying mechanisms remains unclear. Methods: Using highly aggressive adult female mandarin voles (Microtus mandarinus), the present study aimed to determine the effects of CSDS on anxiety- and depression-like behaviours in adult female rodents and investigate the neurobiological mechanisms underlying these effects. Results: Exposure of adult female voles to social defeat stress for 14 days reduced the time spent in the central area of the open field test and in the open arms of the elevated plus maze and lengthened the immobility time in the tail suspension and forced swimming tests, indicating increased anxiety- and depression-like behaviours. Meanwhile, defeated voles exhibited increased neural activity in the prelimbic (PrL) cortex of the medial prefrontal cortex (mPFC). Furthermore, CSDS reduced serotonin (5-HT) projections and levels of serotonin 1A receptors (5-HT1AR) in the mPFC-PrL. Intra-PrL microinjections of the 5-HT1AR agonist 8-OH-DPAT reversed the alterations in emotional behaviours, whereas injections of the 5-HT1AR antagonist WAY-100635 into the PrL of control voles increased the levels of anxiety- and depression-like behaviours. Conclusions: Taken together, our results demonstrated that CSDS increased anxiety- and depression-like behaviours in adult female voles, and these effects were mediated by the action of 5-HT on the 5 HT1AR in the PrL. The serotonin system may be a promising target to treat emotional disorders induced by CSDS. PMID- 30445536 TI - Stability and low induction propensity of cefiderocol against chromosomal AmpC beta-lactamases of Pseudomonas aeruginosa and Enterobacter cloacae. PMID- 30445537 TI - Metabolomic profiling of infants with recurrent wheezing after bronchiolitis. AB - Background and Objective: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently-available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolome analysis can be used to identify bronchiolitis children at risk of developing recurrent wheezing. Methods: 52 infants less than one year old treated at our department's ER for acute bronchiolitis were enrolled (77% RSV positive). Follow up visits were conducted for two years after the episode of bronchiolitis. Untargeted metabolomic analyses based on MS-spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses. Results: We distinguished children with and without post-bronchiolitis recurrent wheeze defined as three or more episodes of physicianan diagnosed wheezing. Pathway over-representation analysis pointed to a major involvement of the citric acid cycle (p-value <0.001), and some amino acids (lysine, cysteine, and methionine; p-value <=0.015) in differentiating between these two groups of children. Conclusion: This is the first study showing that metabolomic profiling of urine from infants with bronchiolitis allows identifying children at increased risk of developing recurrent wheezing. PMID- 30445538 TI - The Norovirus Epidemiologic Triad: Predictors of Severe Outcomes in US Norovirus Outbreaks, 2009-2016. AB - Background: Noroviruses are the leading cause of acute gastroenteritis outbreaks worldwide. Clarifying the viral, host, and environmental factors (epidemiologic triad) associated with severe outcomes can help target public health interventions. Methods: Acute norovirus outbreaks reported to the National Outbreak Reporting System (NORS) in 2009-2016 were linked to laboratory-confirmed norovirus outbreaks reported to CaliciNet. Outbreaks were analyzed for differences in genotype (GII.4 vs non-GII.4), hospitalization, and mortality rates by timing, setting, transmission mode, demographics, clinical symptoms, and health outcomes. Results: A total of 3747 norovirus outbreaks were matched from NORS and CaliciNet. Multivariable models showed that GII.4 outbreaks (n = 2353) were associated with healthcare settings (odds ratio [OR], 3.94 [95% confidence interval {CI}, 2.99-5.23]), winter months (November-April; 1.55 [95% CI, 1.24 1.93]), and older age of cases (>=50% aged >=75 years; 1.37 [95% CI, 1.04-1.79]). Severe outcomes were more likely among GII.4 outbreaks (hospitalization rate ratio [RR], 1.54 [95% CI, 1.23-1.96]; mortality RR, 2.77 [95% CI, 1.04-5.78]). Outbreaks in healthcare settings were also associated with higher hospitalization (RR, 3.22 [95% CI, 2.34-4.44]) and mortality rates (RR, 5.65 [95% CI, 1.92 18.70]). Conclusions: Severe outcomes more frequently occurred in norovirus outbreaks caused by GII.4 and those in healthcare settings. These results should help guide preventive interventions for targeted populations, including vaccine development. PMID- 30445540 TI - Interspecific variation of olfactory preferences in flies, mice, and humans. AB - Aiming to unravel interspecific differences in olfactory preferences, we performed comparative studies of odor valence in flies, mice, and humans. Our analysis suggests a model where flies and mice share similar olfactory preferences, but neither species share odor preferences with humans. This model contrasts with a previous study by Mandairon and colleagues, which suggested that the olfactory preferences of mice and humans are similar. A probabilistic examination revealed that underpowered studies can result in spurious significant correlations, which can account for the differences between both studies. Future analyses aimed at dissecting the olfactory preferences across species need to test large numbers of odorants in order to stress-test the model proposed here and identify robust associations. PMID- 30445541 TI - SIFTS: updated Structure Integration with Function, Taxonomy and Sequences resource allows 40-fold increase in coverage of structure-based annotations for proteins. AB - The Structure Integration with Function, Taxonomy and Sequences resource (SIFTS; http://pdbe.org/sifts/) was established in 2002 and continues to operate as a collaboration between the Protein Data Bank in Europe (PDBe; http://pdbe.org) and the UniProt Knowledgebase (UniProtKB; http://uniprot.org). The resource is instrumental in the transfer of annotations between protein structure and protein sequence resources through provision of up-to-date residue-level mappings between entries from the PDB and from UniProtKB. SIFTS also incorporates residue-level annotations from other biological resources, currently comprising the NCBI taxonomy database, IntEnz, GO, Pfam, InterPro, SCOP, CATH, PubMed, Ensembl, Homologene and automatic Pfam domain assignments based on HMM profiles. The recently released implementation of SIFTS includes support for multiple cross references for proteins in the PDB, allowing mappings to UniProtKB isoforms and UniRef90 cluster members. This development makes structure data in the PDB readily available to over 1.8 million UniProtKB accessions. PMID- 30445539 TI - CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. PMID- 30445542 TI - Specific T-cell activation in peripheral blood and cerebrospinal fluid in central disorders of hypersomnolence. AB - An autoimmune-mediated process in the pathophysiology of narcolepsy type 1 (NT1) is highly suspicious, if this pathomechanism is transferable to other types of central disorders of hypersomnolence (CDH), is still controversial. The association of NT1 with HLA-class-II system implicates a T-cell-mediated autoimmunity, in which helper CD4+ T-cells and cytotoxic CD8+ T-cells may be pathogenic.This study aimed to identify specific immune profiles in peripheral blood (PB) and cerebrospinal fluid (CSF) in different types of CDH.Forty-three patients with polysomnographically confirmed CDH (24 idiopathic hypersomnia (IH), 12 NT1, 7 NT2) were compared to 24 healthy controls (HC). PB and CSF were analysed with multiparameter flow cytometry to distinguish between subclasses of peripheral and intrathecal immune cells and specific surface markers of T cells.The overall proportion of helper CD4+ T-cells and cytotoxic CD8+ T-cells in PB and CSF did not differ between the patients and HC. Activated HLA-DR+ CD4+T cells and HLA-DR+ CD8+T-cells in PB and CSF both in NT1, NT2 and IH were significant increased compared to HC. A significant correlation of HLA-DR+ CD4+ - and HLA-DR+ CD8+ T-cells with higher amounts of excessive daytime sleepiness was found in the NT1- and IH groups, indicating an association of activated T-cells in the CNS with increased of sleepiness.These findings provide further evidence of a T-cell-mediated autoimmunity not only in NT1, but in NT2 and IH as well. Moreover, the identification of activated cytotoxic CD8+ T-cells further supports the evidence of T cell-mediated neuronal damage, which has previously been suggested in NT1. PMID- 30445543 TI - Patients at low surgical risk as defined by the Society of Thoracic Surgeons Score undergoing isolated interventional or surgical aortic valve implantation: in-hospital data and 1-year results from the German Aortic Valve Registry (GARY). AB - Aims: Transcatheter aortic valve implantation (TAVI) has become the standard treatment for patients with severe aortic valve stenosis at high surgical risk and may be considered for patients with intermediate risk. During the last few years, an increasing number of patients with low surgical risk have been treated with TAVI. In this study, low-risk patients undergoing isolated TAVI or surgical aortic valve replacement (SAVR) were analysed using data from the German Aortic Valve Registry (GARY). Methods and results: All patients with a Society of Thoracic Surgeons Score of <4% undergoing TAVI or SAVR in 2014 and 2015 were evaluated. A total of 20 549 low surgical risk patients remained for further analysis, comprising 14 487 surgical patients and 6062 TAVI patients. Since TAVI patients were significantly older and had significantly more co-morbidities, a weighted propensity score model was used to compare SAVR and TAVI patients for in hospital, 30-day, and 1-year mortality. Transcatheter aortic valve implantation patients showed a significantly higher in-hospital and 30-day survival than SAVR patients (in hospital survival TAVI vs. SAVR: 98.5% vs. 97.3%; P = 0.003; 30-day survival TAVI vs. SAVR: 98.1% vs. 97.1%; P = 0.014). At 1 year, survival rates did not differ significantly (survival TAVI vs. SAVR: 90.0% vs. 91.2%; P = 0.158). Conclusion: In this first GARY analysis of low-risk patients, weighted comparison showed similar 1-year survival for TAVI and SAVR and higher in hospital survival for TAVI patients. PMID- 30445544 TI - Outcomes of Retreatment for Intracranial Aneurysms - A Meta-Analysis. AB - BACKGROUND: Long-term results from the International Subarachnoid Hemorrhage Trial (ISAT) and Barrow Ruptured Aneurysm Trial (BRAT) indicate considerably higher retreatment rates for aneurysms treated with coiling compared to clipping, but do not report the outcome of retreatment. OBJECTIVE: To evaluate retreatment related outcomes. METHODS: A meta-analysis in accordance with PRISMA guidelines was conducted using Medline search engines PubMed and EMBASE to identify articles describing outcomes after retreatment for intracranial aneurysms. Pooled prevalence rates for complete occlusion rate and mortality were calculated. Outcomes of different treatment and retreatment combinations were not compared because of indication bias. RESULTS: Twenty-five articles that met the inclusion criteria were included in the meta-analysis. Surgery after coiling had a pooled complete occlusion rate of 91.2% (95% confidence interval [CI]: 87.0-94.1) and a pooled mortality rate of 5.6% (95% CI: 3.7-8.3). Coiling after coiling had a pooled complete occlusion rate of 51.3% (95% CI: 22.1-78.0) and a pooled mortality rate of 0.8% (95% CI: 0.15-3.7). Surgery after surgery did not provide a pooled estimate for complete occlusion as only one study was identified but had a pooled mortality rate of 5.9% (95% CI: 3.1-11.2). Coiling after surgery had a pooled complete occlusion rate of 56.1% (95% CI: 11.4-92.7) and a pooled mortality rate of 9.3% (95% CI: 4.1-19.9). All pooled incidence rates were produced using random-effect models. CONCLUSION: Surgical retreatment was associated with a high complete occlusion rate but considerable mortality. Conversely, endovascular retreatment was associated with low mortality but also a low complete occlusion rate. PMID- 30445545 TI - Targeted deletion of an NRL- and CRX-regulated alternative promoter specifically silences FERM and PDZ domain containing 1 (Frmpd1) in rod photoreceptors. AB - Regulation of cell type-specific gene expression is critical for generating neuronal diversity. Transcriptome analyses have unraveled extensive heterogeneity of transcribed sequences in retinal photoreceptors because of alternate splicing and/or promoter usage. Here we show that Frmpd1 (FERM and PDZ domain containing 1) is transcribed from an alternative promoter specifically in the retina. Electroporation of Frmpd1 promoter region, -505 to +382 bp, activated reporter gene expression in mouse retina in vivo. A proximal promoter sequence (-8 to +33 bp) of Frmpd1 binds to NRL and CRX, two rod-specific differentiation factors, and is necessary for activating reporter gene expression in vitro and in vivo. CRISPR/Cas9-mediated deletion of the genomic region including NRL and CRX binding sites in vivo completely eliminated Frmpd1 expression in rods and dramatically reduced expression in rod bipolar cells, thereby overcoming embryonic lethality caused by germline Frmpd1 deletion. Our studies demonstrate that a cell-type specific regulatory control region is a credible target for creating loss-of function alleles of widely-expressed genes. PMID- 30445546 TI - Exposure to the lampricide TFM elicits an environmental stress response in yeast. AB - The pesticide 3-trifluoromethyl-4-nitrophenol (TFM) is used to control sea lamprey populations in the Great Lakes and Lake Champlain. Little is known about the effects of this pesticide on gene expression in eukaryotic species. This study used microarray analysis to determine the effects of short term, high dose TFM exposure on gene expression in Saccharomyces cerevisiae. Yeast grown in standard glucose-containing media showed significant variation in gene expression in pathways related to cytoplasmic translation with the majority of these genes being downregulated. These findings were supported by the analysis of a similar but glucose-free experiment revealing that these cytoplasmic translation genes, mostly ribosomal subunit expressing genes, were similarly downregulated. The repression of the ribosomal subunit genes suggests that TFM exposure, regardless of glucose availability, evokes features of the environmental stress response in yeast. PMID- 30445547 TI - Algorithm to detect pediatric provider attention to high BMI and associated medical risk. AB - We developed and validated an algorithm that uses combinations of extractable electronic-health-record (EHR) indicators (diagnosis codes, orders for laboratories, medications, and referrals) that denote widely-recommended clinician practice behaviors: attention to overweight/obesity/body mass index alone (BMI Alone), with attention to hypertension/other comorbidities (BMI/Medical Risk), or neither (No Attention). Data inputs used for each EHR indicator were refined through iterative chart review to identify and resolve modifiable coding errors. Validation was performed through manual review of randomly selected visit encounters (n = 308) coded by the refined algorithm. Of 104 encounters coded as No Attention, 89.4% lacked any evidence (specificity) of attention to BMI/Medical Risk. Corresponding evidence (sensitivity) of attention to BMI Alone was identified in 96.0% (of 101 encounters coded as BMI Alone) and BMI/Medical Risk in 96.1% (of 103 encounters coded as BMI/Medical Risk). Our EHR data algorithm can validly determine provider attention to BMI alone, with Medical Risk, or neither. PMID- 30445548 TI - Phenotypic variations in transferred progeny due to genotype of surrogate mother: Surrogate mother modulates transferred progeny. AB - STUDY QUESTION: Does the genotype of the surrogate mother modulate the body composition and immunity of her offspring? SUMMARY ANSWER: C57BL/6J (B6) progenies carried by immunodeficient NOD SCID (NS) mothers had increased adaptive, but decreased innate, immune responsiveness in comparison with the same genotype offspring carried by immunocompetent mothers, B6 and BALB/c (C); the B6 progenies carried by the same genotype mothers also showed higher body fat than the others. WHAT IS KNOWN ALREADY: Differences in the major histocompatibility complex (MHC) genes between mother and foetus is considered as an important factor in prenatal embryo development, whereas the impact of such dissimilarity on the phenotype of the mature progeny is unclear. STUDY DESIGN SIZE, DURATION: Transplantation of two-cell mouse embryos into recipient females of the different MHC (H2) genotypes was used as an approach to simulate three variants of the immunogenic mother-foetus interaction: 1) bidirectional immunogenic dialogue between B6 (H2b haplotype) embryos and C (H2d haplotype) surrogate mother; 2) one way immunogenic interaction between B6 embryos and immunodeficient NS (H2g7 haplotype) surrogate mother; and 3) reduced immunogenetic dialogue between embryos and surrogate mother of the same H2b haplotype resulting in only a maternal response to HY antigens of male foetuses. Delivered by Caesarean section, pups were fostered by lactating B6 females and weighed after weaning (n=171). Body mass and composition and innate and adaptive immunity were assessed in selected progeny groups at 9-11 weeks of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed on the specific pathogen-free mouse, inbred strains C57BL/6J, NOD SCID and BALB/c. Plasma progesterone in pregnant females was measured by enzyme-linked immunosorbent assay (ELISA). Body composition was determined by magnetic resonance spectroscopy using a low-field NMR spectrometer (EchoMRI, USA). To assess peritoneal macrophage responses (innate immunity) to Anthrax, lactate dehydrogenase (LDH) and interleukin-1 (IL-1beta) were measured in a culture medium 24 hours after the addition of both Anthrax Lethal Factor and Anthrax Protective Antigen. To assess adaptive immunity, 9-10 males in experimental groups were infected with Helicobacter hepaticus. Faeces collected two and four weeks after infection was used for quantitative assessment of the H. hepaticus DNA by real time PCR. IgA, interferon (IFN- gamma), tumour necrosis factor (TNFalpha), interleukin-17 (IL-17) and interleukin-10 (IL-10) in colon tissue and IgG in serum were determined in samples collected four weeks after gavage with H. hepaticus using ELISA. For statistical analyses, ANCOVA, post-hoc least significant difference (LSD) test, Student's t-test, Spearman rank correlations and chi2 test were performed. P value < 0.05 was considered as a statistically significant difference. MAIN RESULTS AND THE ROLE OF CHANCE: ANCOVA with litter size and age as covariates revealed significant effects of the surrogate mother genotype on body mass and percent of fat in their adult progeny (F2,149=15.60, p<0.001 and F2,149=5.02, p=0.007 respectively). Adult B6 mice carried by B6 surrogate mothers were characterized by a higher percentage of body fat in comparison with offspring that were carried by NS and C females. In comparison with the male offspring carried by the B6 and C mothers, male B6 progenies carried by immunodeficient NS mothers had a higher humoral immune response (serum IgG) against oral infection with Helicobacter hepaticus, but lower in-vitro macrophage IL-1beta reaction to the Anthrax. Four weeks after the infection of offspring, concentrations of serum IgG and colon IL-10 correlated positively with maternal progesterone on day 4 after embryo transfer and negatively with DNA of H. hepaticus. One-way ANOVA confirmed a statistically significant impact of surrogate mother genotype on adaptive (IgG) and innate (IL 1beta) immunity (F2.26=26.39, p<0.001 and F2.27=5.89, p=0.008, respectively). LARGE SCALE DATAx: N/A. LIMITATIONS REASONS FOR CAUTION: The main limitation of our study is the number of combinations of mother and foetus interactions, in particular, transfer of only one embryo genotype was used. Also, it is a descriptive study, which requires further analysis of the epigenetic mechanisms of the observed phenotypic effects of surrogate mother genotype. WIDER IMPLICATIONS OF THE FINDINGS: Our experimental data demonstrate that the transfer of inbred embryos to surrogate mothers of the different genotypes is a prospective experimental model for the study of epigenetic effects of the immunogenetic interactions between mother and foetus. The experimental approach tested in our study will be in demand for the development of criteria for choosing surrogate mothers. In particular, immunocompetence of the surrogate mother along with genetic distance of her MHC alleles to the transferred embryos have a significant impact on offspring development. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Russian FPI (6/099/2017), budget projects (0324-2016-0002 and 0324-2018-0016), and implemented using the equipment of the Centre for Genetic Resources of Laboratory Animals at ICG SB RAS, supported by the Ministry of Education and Science of Russia (Unique project identifier RFMEFI62117X0015). The authors report no conflicts of interest. PMID- 30445549 TI - Posaconazole Administration in Hospitalized Children in the United States. AB - In this study, we evaluated posaconazole use among hospitalized children between October 2006 and September 2015 using data from the Pediatric Health Information System. A total of 878 children (in 1949 admissions) received posaconazole, and administration increased 22% per year overall and 27% per year in children aged <13 years for whom the drug was not approved. PMID- 30445550 TI - National quality evaluation of peri-surgical hearing care for pediatric otitis media with effusion. AB - Objective: Otitis media with effusion (OME) is a common disease among children that can lead to grave sequelae with respect to hearing. Thus, when treating OME, appropriate hearing care should be provided; ventilation tube insertion (VTI), a standard approach for treating OME, is no exception. This study examined hearing care for VTI and its associated factors, especially at the national level. Design: Retrospective database analysis. Setting: Taiwan's National Health Insurance Research Database. Participants: One thousand one hundred and fifty nine patients who received VTI (age <=12 years; 2011-12). Intervention: No intervention. Main Outcome Measures: Compliance to guidelines: sufficient observation time (OBS), tympanogram before VTI (TYM-B) and hearing tests before and after VTI (HEAR-B and HEAR-A, respectively). Results: The national proportions of completion for each procedure were 30.1% for OBS, 84.4% for TYM-B, 74.3% for HEAR-B and 36.0% for HEAR-A; those of OBS and HEAR-A were extremely low. Age, nasal allergy and even geographic area were associated with differences across completion patterns. Regression revealed some notable patterns. Compared with non-teaching hospitals, teaching hospitals administered HEAR-B most successfully (odds ratio [OR: 3.20, 95% CI: 1.06-9.63) and the smallest hospital group performed HEAR-B most successfully (OR: 2.92, 95% CI: 1.14-7.46). Conclusion: Several findings surfaced concerning VTI-related hearing care and its association with many clinical and socioeconomic factors in this national study. These findings could serve as a map for improving hearing care quality among children with OME. PMID- 30445551 TI - In Reply: Guidelines for the Use of Electrophysiological Monitoring for Surgery of the Human Spinal Column and Spinal Cord. PMID- 30445552 TI - Towards a monoclonal antibody-based therapy for prevention and treatment of Staphylococcus aureus infections. PMID- 30445553 TI - Single-molecule imaging of DNA gyrase activity in living Escherichia coli. AB - Bacterial DNA gyrase introduces negative supercoils into chromosomal DNA and relaxes positive supercoils introduced by replication and transiently by transcription. Removal of these positive supercoils is essential for replication fork progression and for the overall unlinking of the two duplex DNA strands, as well as for ongoing transcription. To address how gyrase copes with these topological challenges, we used high-speed single-molecule fluorescence imaging in live Escherichia coli cells. We demonstrate that at least 300 gyrase molecules are stably bound to the chromosome at any time, with ~12 enzymes enriched near each replication fork. Trapping of reaction intermediates with ciprofloxacin revealed complexes undergoing catalysis. Dwell times of ~2 s were observed for the dispersed gyrase molecules, which we propose maintain steady-state levels of negative supercoiling of the chromosome. In contrast, the dwell time of replisome proximal molecules was ~8 s, consistent with these catalyzing processive positive supercoil relaxation in front of the progressing replisome. PMID- 30445554 TI - Molecular regulatory mechanism of isoprene emission under short-term drought stress in the tropical tree Ficus septica. AB - Isoprene is emitted by many plants and is thought to function as an antioxidant under stressful conditions. However, the detailed regulatory mechanism of isoprene emission in relation to the antioxidant system remains unclear. Therefore, in this study, we explored the molecular regulatory mechanism of isoprene emission under short-term drought stress in the tropical tree Ficus septica Burm.f. We found that the soil moisture content gradually decreased from 55% on Day 1 (D1) to 23% (wilting point) on D5 after withholding water for 4 days and then returning to the initial level following re-watering on D6. On D5, drought-stressed plants had more than twofold higher isoprene emission and 90.6% lower photosynthesis rates, 99.5% lower stomatal conductance and 82.3% lower transpiration rates than well-watered control plants. It was also estimated that the isoprene concentration inside the leaf greatly increased on D5 due to the increased isoprene emission rate and reduced stomatal conductance. Among the traits related to the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, which is responsible for isoprene biosynthesis, the isoprene synthase (IspS) protein level was positively correlated with the isoprene emission rate in stressed plants. The transcripts of the antioxidant genes peroxidase 2 (POD2), POD4, copper-zinc superoxide dismutase 2 (Cu-ZnSOD2) and manganese superoxide dismutase 1 (Mn-SOD1) also increased during the drying period, while those of ascorbate peroxidase 1 (APX1) decreased. However, there was only a weak correlation between isoprene emission and antioxidant enzyme gene expression, indicating that the regulation of isoprene biosynthesis is not directly linked to the antioxidant defense network in drought-stressed F. septica. These findings suggest that the post transcriptional regulation of IspS led to the observed change in isoprene emission rate, which enhanced the quenching of reactive oxygen species (ROS) and, in combination with the increased antioxidant enzyme activity, conferred tolerance to drought stress in this species. PMID- 30445555 TI - The SUPERFAMILY 2.0 database: a significant proteome update and a new webserver. AB - Here, we present a major update to the SUPERFAMILY database and the webserver. We describe the addition of new SUPERFAMILY 2.0 profile HMM library containing a total of 27 623 HMMs. The database now includes Superfamily domain annotations for millions of protein sequences taken from the Universal Protein Recourse Knowledgebase (UniProtKB) and the National Center for Biotechnology Information (NCBI). This addition constitutes about 51 and 45 million distinct protein sequences obtained from UniProtKB and NCBI respectively. Currently, the database contains annotations for 63 244 and 102 151 complete genomes taken from UniProtKB and NCBI respectively. The current sequence collection and genome update is the biggest so far in the history of SUPERFAMILY updates. In order to the deal with the massive wealth of information, here we introduce a new SUPERFAMILY 2.0 webserver (http://supfam.org). Currently, the webserver mainly focuses on the search, retrieval and display of Superfamily annotation for the entire sequence and genome collection in the database. PMID- 30445556 TI - Identification of Somatotopic Organization and Optimal Stimulation Site Within the Subthalamic Nucleus for Parkinson's Disease. AB - BACKGROUND: Details of the somatotopy within the subthalamic nucleus (STN) are still poorly understood; however, the STN is a common target of deep brain stimulation (DBS) for Parkinson disease. OBJECTIVE: To examine somatotopic organization within the STN and identify optimal stimulation sites from 77 surgical cases with microelectrode recording. METHODS: STN-DBS was performed for 77 patients with Parkinson disease between 2010 and 2014. We performed passive movements of each joint and captured single neuronal activities to identify movement-related cells (MRCs). The sites of MRCs and active contacts were determined by measuring their distances from the first contact of DBS electrode. Their positional correlations were directly and indirectly analyzed. RESULTS: The number of obtained MRCs was 264, of which 151 responded to multiple joints. The average x-, y-, and z-coordinates of the cells of the upper and lower limbs from the midcommisural point were 13.1 +/- 1.1 and 12.7 +/- 1.2, 0.22 +/- 1.3 and 0.45 +/- 1.5, and -2.5 +/- 1.1 and -3.0 +/- 1.4 mm, respectively. Most MRCs were distributed in the upper third of the STN, in its superior, lateral, and posterior regions, along the DBS electrode routes. Active contacts were observed to lie slightly inferior, medial, and posterior to the average MRC position. CONCLUSION: Somatotopic organization of the STN was easier to observe in the present study than in previous studies. Optimal stimulation sites were located inferior, medial, and posterior to the average MRC location. The sites may correspond to associative or motor parts through which fibers from the supplementary motor area pass. PMID- 30445557 TI - Long-Term Update of Stereotactic Radiosurgery for Benign Spinal Tumors. AB - BACKGROUND: Stereotactic radiosurgery (SRS) for benign intracranial tumors is an established standard of care. The widespread implementation of SRS for benign spinal tumors has been limited by lack of long-term data. OBJECTIVE: To update our institutional experience of safety and efficacy outcomes after SRS for benign spinal tumors. METHODS: We performed a retrospective cohort study of 120 patients with 149 benign spinal tumors (39 meningiomas, 26 neurofibromas, and 84 schwannomas) treated with SRS between 1999 and 2016, with follow-up magnetic resonance imaging available for review. The primary endpoint was the cumulative incidence of local failure (LF), with death as a competing risk. Secondary endpoints included tumor shrinkage, symptom response, toxicity, and secondary malignancy. RESULTS: Median follow-up was 49 mo (interquartile range: 25-103 mo, range: 3-216 mo), including 61 courses with >5 yr and 24 courses with >10 yr of follow-up. We observed 9 LF for a cumulative incidence of LF of 2%, 5%, and 12% at 3, 5, and 10 yr, respectively. Excluding 10 tumors that were previously irradiated or that arose within a previously irradiated field, the 3-, 5-, and 10 yr cumulative incidence rates of LF were 1%, 2%, and 8%, respectively. At last follow-up, 35% of all lesions had decreased in size. With a total of 776 patient years of follow-up, no SRS-related secondary malignancies were observed. CONCLUSION: Comparable to SRS for benign intracranial tumors, SRS provides longer term local control of benign spinal tumors and is a standard-of-care alternative to surgical resection. PMID- 30445558 TI - Cholesterol controversy: considerations for mouse models of atherosclerosis. PMID- 30445559 TI - Prevalence and prognosis of ischaemic and non-ischaemic myocardial fibrosis in older adults. AB - Aims: Non-ischaemic cardiomyopathies (NICM) can cause heart failure and death. Cardiac magnetic resonance (CMR) detects myocardial scar/fibrosis associated with myocardial infarction (MI) and NICM with late gadolinium enhancement (LGE). The aim of this study was to determine the prevalence and prognosis of ischaemic and non-ischaemic myocardial fibrosis in a community-based sample of older adults. Methods and results: The ICELAND-MI cohort, a substudy of the Age, Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) study, provided a well characterized population of 900 subjects after excluding subjects with pre existing heart failure. Late gadolinium enhancement CMR divided subjects into four groups: MI (n = 211), major (n = 54) non-ischaemic fibrosis (well established, classic patterns, associated with myocarditis, infiltrative cardiomyopathies, or pathological hypertrophy), minor (n = 238) non-ischaemic fibrosis (remaining localized patterns not meeting major criteria), and a no LGE (n = 397) reference group. The primary outcome was time to death or first heart failure hospitalization. During a median follow-up of 5.8 years, 192 composite events occurred (115 deaths and 77 hospitalizations for incident heart failure). After inverse probability weighting, major non-ischaemic fibrosis [hazard ratio (HR) 3.2, P < 0.001] remained independently associated with the primary endpoint, while MI (HR 1.4, P = 0.10) and minor non-ischaemic LGE (HR 1.2, P = 0.39) did not. Major non-ischaemic fibrosis was associated with a poorer outcome than MI (HR = 2.3, P = 0.001) in the adjusted analysis. Conclusion: Major non-ischaemic patterns of myocardial fibrosis portended worse prognosis than no fibrosis/scar in an older community-based cohort. Traditional risk factors largely accounted for the effect of MI and minor non-ischaemic LGE. PMID- 30445561 TI - Heart-to-Brachium Pulse Wave Velocity as a Measure of Proximal Aortic Stiffness: MRI and Londitudinal Studies. AB - BACKGROUND: Stiffening of the proximal aorta is associated with heightened cardiovascular disease risks but can be quantified by limited methodologies (e.g., MRI). As an initial step to evaluate the emerging technique to assess proximal aortic stiffness via pulse wave velocity from the heart to the brachium (hbPWV), we determined the influences of aging on PWV and aortic hemodynamics. METHOD: Using the cross-sectional and follow-up study designs, hbPWV was compared and evaluated in relation to other PWV in various arterial segments. Arterial path lengths were measured by the 3-dimention arterial tracing of MRI. RESULTS: In the cross-sectional study including 190 subjects (aged 19-79 years), hbPWV exhibited one of the largest age-related increases and a stronger correlation with age (r=0.790) compared with the other measures of PWV including carotid femoral PWV, brachial-ankle PWV, and PWV of muscular arteries (r=0.445~0.688). In addition, hbPWV was correlated with aortic systolic blood pressure (BP) and augmentation index (r=0.380 and r=0.433, respectively) after controlling for brachial systolic BP. These results were confirmed by the 10-year follow-up study involving 84 individuals (53 years at baseline). The decadal changes in hbPWV were significantly correlated with the corresponding changes in several aortic hemodynamic variables (e.g., aortic systolic BP, augmentation pressure, and augmentation index) (r=0.240~0.349). CONCLUSIONS: The present findings indicate that hbPWV is a potential marker of proximal aortic stiffening that reflects age related changes and aortic hemodynamics. PMID- 30445560 TI - Association of prolactin receptor (PRLR) variants with prolactinomas. AB - Prolactinomas are the most frequent type of pituitary tumors, which represent 10 20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocyte, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (p<0.0001) in prolactinoma patients than in 60,706 individuals of the Exome Aggregation Consortium cohort and 7,045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild type PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, p<0.02) and proliferation (1.4-fold, p<0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to wild-type levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas, and reveal a new aetiology and potential therapeutic approach for these neoplasms. PMID- 30445562 TI - Mapping of HIE CT terms to LOINC(r): analysis of content-dependent coverage and coverage improvement through new term creation. AB - Objective: We describe and evaluate the mapping of computerized tomography (CT) terms from 40 hospitals participating in a health information exchange (HIE) to a standard terminology. Methods: Proprietary CT exam terms and corresponding exam frequency data were obtained from 40 participant HIE sites that transmitted radiology data to the HIE from January 2013 through October 2015. These terms were mapped to the Logical Observations Identifiers Names and Codes (LOINC(r)) terminology using the Regenstrief LOINC mapping assistant (RELMA) beginning in January 2016. Terms without initial LOINC match were submitted to LOINC as new term requests on an ongoing basis. After new LOINC terms were created, proprietary terms without an initial match were reviewed and mapped to these new LOINC terms where appropriate. Content type and token coverage were calculated for the LOINC version at the time of initial mapping (v2.54) and for the most recently released version at the time of our analysis (v2.63). Descriptive analysis was performed to assess for significant differences in content-dependent coverage between the 2 versions. Results: LOINC's content type and token coverages of HIE CT exam terms for version 2.54 were 83% and 95%, respectively. Two-hundred-fifteen new LOINC CT terms were created in the interval between the releases of version 2.54 and 2.63, and content type and token coverages, respectively, increased to 93% and 99% (P < .001). Conclusion: LOINC's content type coverage of proprietary CT terms across 40 HIE sites was 83% but improved significantly to 93% following new term creation. PMID- 30445563 TI - The Effect of Influenza Virus on the Human Oropharyngeal Microbiome. AB - Background: Secondary bacterial infections are an important cause of morbidity and mortality associated with influenza infections. As bacterial disease can be caused by a disturbance of the host microbiome, we examined the impact of influenza on the upper respiratory tract microbiome in a human challenge study. Methods: The dynamics and ecology of the throat microbiome were examined following an experimental influenza challenge of 52 previously-healthy adult volunteers with influenza A/Wisconsin/67/2005 (H3N2) by intranasal inoculation; 35 healthy control subjects were not subjected to the viral challenge. Serial oropharyngeal samples were taken over a 30-day period, and the V1-V3 region of the bacterial 16S ribosomal RNA sequences were amplified and sequenced to determine the composition of the microbiome. The carriage of pathogens was also detected. Results: Of the 52 challenged individuals, 43 developed proven influenza infections, 33 of whom became symptomatic. None of the controls developed influenza, although 22% reported symptoms. The diversity of bacterial communities remained remarkably stable following the acquisition of influenza, with no significant differences over time between individuals with influenza and those in the control group. Influenza infection was not associated with perturbation of the microbiome at the level of phylum or genus. There was no change in colonization rates with Streptococcus pneumoniae or Neisseria meningitidis. Conclusions: The throat microbiota is resilient to influenza infection, indicating the robustness of the upper-airway microbiome. PMID- 30445565 TI - Altered GLI3 and FGF8 signaling underlies Acrocallosal syndrome phenotypes in Kif7 depleted mice. AB - Acrocallosal syndrome (ACLS) is a rare genetic disorder characterized by agenesis or hypoplasia of corpus callosum (CC), polydactyly, craniofacial dysmorphism and severe intellectual deficiency. We previously identified KIF7, a key ciliary component of the Sonic hedgehog pathway, as being a causative gene for this syndrome, thus including ACLS in the group of ciliopathies. In both humans and mice, KIF7 depletion leads to abnormal GLI3 processing and over-activation of SHH target genes. To understand the pathological mechanisms involved in CC defects in this syndrome, we took advantage of a previously described Kif7-/- mouse model todemonstrate that in addition to polydactyly and neural tube closure defects, these mice present CC agenesis with characteristic Probst bundles, thus recapitulating major ACLS features. We show that CC agenesis in these mice is associated with specific patterning defects of the cortical septum boundary leading to altered distribution of guidepost cells required to guide the callosal axons through the midline. Furthermore, by crossing Kif7-/- mice with Gli3Delta699 mice exclusively producing the repressive isoform of GLI3 (GLI3R), we demonstrate that decreased GLI3R signaling is fully responsible for the ACLS features in these mice, as all phenotypes are rescued by increasing GLI3R activity. Moreover, we show that increased FGF8 signaling is responsible in part for CC defects associated to KIF7 depletion, as modulating FGF8 signaling rescued CC formation anteriorly in Kif7-/- mice. Taken together our data demonstrate that ACLS features rely on defective GLI3R and FGF8 signaling. PMID- 30445564 TI - Re-admission patterns in England and the Netherlands: a comparison based on administrative data of all hospitals. AB - Background: Examining variation in patterns of re-admissions between countries can be valuable for mutual learning in order to reduce unnecessary re-admissions. The aim of this study was to compare re-admission rates and reasons for re admissions between England and the Netherlands. Methods: We used data from 85 Dutch hospitals (1 355 947 admissions) and 451 English hospitals (5 260 227 admissions) in 2014 (96% of all Dutch hospitals and 100% of all English NHS hospitals). Re-admission data from England and the Netherlands were compared for all hospital patients and for specific diagnosis groups: pneumonia, urinary tract infection, chronic obstructive pulmonary disease, coronary atherosclerosis, biliary tract disease, hip fracture and acute myocardial infarction. Re admissions were categorized using a classification system developed on administrative data. The classification distinguishes between potentially preventable re-admissions and other reasons for re-admission. Results: England had a higher 30-day re-admission rate (adjusted for age and gender) compared to the Netherlands: 11.17% (95% CI 11.14-11.20%) vs. 9.83% (95% CI 9.77-9.88%). The main differences appeared to be in re-admissions for the elderly (England 17.2% vs. the Netherlands 10.0%) and in emergency re-admissions (England 85.3% of all 30-day re-admissions vs. the Netherlands 66.8%). In the Netherlands, however, more emergency re-admissions were classified as potentially preventable compared to England (33.8% vs. 28.8%). Conclusions: The differences found between England and the Netherlands indicate opportunities to reduce unnecessary re-admissions. For England this concerns more expanded palliative care, integrated social care and reduction of waiting times. In the Netherlands, the use of treatment plans for daily life could be increased. PMID- 30445566 TI - BGSA: A Bit-Parallel Global Sequence Alignment Toolkit for Multi-core and Many core Architectures. AB - Motivation: Modern bioinformatics tools for analyzing large-scale NGS datasets often need to include fast implementations of core sequence alignment algorithms in order to achieve reasonable execution times. We address this need by presenting the BGSA toolkit for optimized implementations of popular bit-parallel global pairwise alignment algorithms on modern microprocessors. Results: BGSA outperforms Edlib, SeqAn, and BitPAl for pairwise edit distance computations and Parasail, SeqAn, and BitPAl when using more general scoring schemes for pairwise alignments of a batch of sequence reads on both standard multi-core CPUs and Xeon Phi many-core CPUs. Furthermore, banded edit distance performance of BGSA on a Xeon Phi-7210 outperforms the highly optimized NVBio implementation on a Titan X GPU for the seed verification stage of a read mapper by a factor of 4.4. Availability: BGSA is open-source and available at https://github.com/sdu hpcl/BGSA. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445567 TI - OncoBase: a platform for decoding regulatory somatic mutations in human cancers. AB - Whole-exome and whole-genome sequencing have revealed millions of somatic mutations associated with different human cancers, and the vast majority of them are located outside of coding sequences, making it challenging to directly interpret their functional effects. With the rapid advances in high-throughput sequencing technologies, genome-scale long-range chromatin interactions were detected, and distal target genes of regulatory elements were determined using three-dimensional (3D) chromatin looping. Herein, we present OncoBase (http://www.oncobase.biols.ac.cn/), an integrated database for annotating 81 385 242 somatic mutations in 68 cancer types from more than 120 cancer projects by exploring their roles in distal interactions between target genes and regulatory elements. OncoBase integrates local chromatin signatures, 3D chromatin interactions in different cell types and reconstruction of enhancer-target networks using state-of-the-art algorithms. It employs informative visualization tools to display the integrated local and 3D chromatin signatures and effects of somatic mutations on regulatory elements. Enhancer-promoter interactions estimated from chromatin interactions are integrated into a network diffusion system that quantitatively prioritizes somatic mutations and target genes from a large pool. Thus, OncoBase is a useful resource for the functional annotation of regulatory noncoding regions and systematically benchmarking the regulatory effects of embedded noncoding somatic mutations in human carcinogenesis. PMID- 30445568 TI - PAVOOC: Designing CRISPR sgRNAs using 3D protein structures and functional domain annotations. AB - Summary: sgRNAs targeting the same gene can significantly vary in terms of efficacy and specificity. PAVOOC (Prediction And Visualization of On- and Off targets for CRISPR) is a web-based CRISPR sgRNA design tool that employs state of the art machine learning models to prioritize most effective candidate sgRNAs. In contrast to other tools, it maps sgRNAs to functional domains and protein structures and visualizes cut sites on corresponding protein crystal structures. Furthermore, PAVOOC supports homology-directed repair template generation for genome editing experiments and the visualization of the mutated amino acids in 3D. Availability and Implementation: PAVOOC is available under https://pavooc.me and accessible using modern browsers (Chrome/Chromium recommended). The source code is hosted at github.com/moritzschaefer/pavooc under the MIT License. The backend, including data processing steps, and the frontend are implemented in Python 3 and ReactJS respectively. All components run in a simple Docker environment. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445569 TI - Expert-level sleep scoring with deep neural networks. AB - Objectives: Scoring laboratory polysomnography (PSG) data remains a manual task of visually annotating 3 primary categories: sleep stages, sleep disordered breathing, and limb movements. Attempts to automate this process have been hampered by the complexity of PSG signals and physiological heterogeneity between patients. Deep neural networks, which have recently achieved expert-level performance for other complex medical tasks, are ideally suited to PSG scoring, given sufficient training data. Methods: We used a combination of deep recurrent and convolutional neural networks (RCNN) for supervised learning of clinical labels designating sleep stages, sleep apnea events, and limb movements. The data for testing and training were derived from 10 000 clinical PSGs and 5804 research PSGs. Results: When trained on the clinical dataset, the RCNN reproduces PSG diagnostic scoring for sleep staging, sleep apnea, and limb movements with accuracies of 87.6%, 88.2% and 84.7% on held-out test data, a level of performance comparable to human experts. The RCNN model performs equally well when tested on the independent research PSG database. Only small reductions in accuracy were noted when training on limited channels to mimic at-home monitoring devices: frontal leads only for sleep staging, and thoracic belt signals only for the apnea-hypopnea index. Conclusions: By creating accurate deep learning models for sleep scoring, our work opens the path toward broader and more timely access to sleep diagnostics. Accurate scoring automation can improve the utility and efficiency of in-lab and at-home approaches to sleep diagnostics, potentially extending the reach of sleep expertise beyond specialty clinics. PMID- 30445571 TI - Corrigendum. PMID- 30445570 TI - Benefit of Intracystic Bleomycin for Symptomatic Recurrent Rathke Cleft Cyst. AB - BACKGROUND: Management of recurrent Rathke cleft cysts (RCC) is problematic. The mainstay of treatment has been reoperation with cyst drainage. Radical cyst resection, although effective, results in a high incidence of diabetes insipidus. Several case reports suggest a potential benefit to radiation therapy or the use of intracystic bleomycin. The intracystic application of bleomycin is known to be beneficial in the treatment of cystic craniopharyngioma; however, its usefulness in the treatment of recurrent RCC has yet to be proven. OBJECTIVE: To present our 6-yr experience using intracystic bleomycin for recurrent RCC. METHODS: We performed a retrospective chart review of patients with RCC who underwent surgical resection between January 2010 and May 2016 by a single surgeon. Specific attention was paid to patients with recurrent RCC. RESULTS: Of the 59 patients operated on for RCC during this 6-yr interval, 6 patients with symptomatic recurrent RCC were identified and received intracystic bleomycin at the time of reoperation. To date, no symptomatic cyst recurrence has been documented in the patients receiving bleomycin (mean = 38.8 mo, range 21.2-79.8 mo). CONCLUSION: The use of intracystic bleomycin appears to be a safe and potentially effective treatment option in patients with recurrent RCC. Additional studies with longer follow-up are needed to further define the role of bleomycin in recurrent RCC. PMID- 30445572 TI - The effects of low suction on digital drainage devices after lobectomy using video-assisted thoracoscopic surgery: a randomized controlled trial. AB - OBJECTIVES: The optimal level of suction on digital chest drainage devices after lobectomy using video-assisted thoracoscopic surgery (VATS) is unknown and varies between thoracic centres. In this randomized controlled trial, we assessed the potential benefits of low suction of -2 cmH2O compared to -10 cmH2O, using a digital drainage device. METHODS: Two hundred and twenty-eight patients were randomized into 2 groups after VATS lobectomy for suspected or confirmed lung cancer. Primary outcome was time to chest drain removal. Drain data were obtained from the digital drainage devices, and patient data were obtained from medical records during admission, with a follow-up until postoperative day 30. RESULTS: For the -2 cmH2O and -10 cmH2O groups, median (interquartile range) drainage duration was 27.4 h (23.3-71.2) and 47.5 h (24.5-117.8) (P = 0.047), and the incidence of prolonged air leak >5 days was 14.4% and 24.3% (P = 0.089), respectively. Median total fluid production was 566 h (329-1155) ml and 795 h (454-1605) ml (P = 0.007). Median time to consistent air leak cessation (<20 ml/min) was 5.2 h (0.3-34.2) and 23.7 h (0.8-90.8) (P < 0.001). There were no differences in the proportion or the size of the pneumothorax or subcutaneous emphysema after drain removal, and no differences were observed in postoperative morbidity. Median length of in-hospital stay was 2.0 days (2.0-5.8) and 3.0 days (2.0-9.0) (P = 0.18). CONCLUSIONS: A low suction level significantly shortened drainage duration, time to air leak cessation and total fluid production, without increasing morbidity. Clinical trial registration number: NCT02911259. PMID- 30445574 TI - Splicing of long non-coding RNAs primarily depends on polypyrimidine tract and 5' splice-site sequences due to weak interactions with SR proteins. AB - Many nascent long non-coding RNAs (lncRNAs) undergo the same maturation steps as pre-mRNAs of protein-coding genes (PCGs), but they are often poorly spliced. To identify the underlying mechanisms for this phenomenon, we searched for putative splicing inhibitory sequences using the ncRNA-a2 as a model. Genome-wide analyses of intergenic lncRNAs (lincRNAs) revealed that lincRNA splicing efficiency positively correlates with 5'ss strength while no such correlation was identified for PCGs. In addition, efficiently spliced lincRNAs have higher thymidine content in the polypyrimidine tract (PPT) compared to efficiently spliced PCGs. Using model lincRNAs, we provide experimental evidence that strengthening the 5'ss and increasing the T content in PPT significantly enhances lincRNA splicing. We further showed that lincRNA exons contain less putative binding sites for SR proteins. To map binding of SR proteins to lincRNAs, we performed iCLIP with SRSF2, SRSF5 and SRSF6 and analyzed eCLIP data for SRSF1, SRSF7 and SRSF9. All examined SR proteins bind lincRNA exons to a much lower extent than expression matched PCGs. We propose that lincRNAs lack the cooperative interaction network that enhances splicing, which renders their splicing outcome more dependent on the optimality of splice sites. PMID- 30445573 TI - Flow-cytometric analysis of human monocyte subsets targeted by Mycobacterium bovis BCG before granuloma formation. AB - Infection with Mycobacterium tuberculosis (Mtb) is characterized by an inflammatory response resulting in the formation of granulomas. These tight aggregates of immune cells play an important role in bacterial containment and in the eventual outcome of infection. Monocytes are a major component of the early immune response to Mtb and contribute to the cellular matrix of the newly forming granuloma. Therefore, defining which monocyte subset is the target of mycobacterial infection is critical. Here, we describe a flow-cytometry-based assay to analyze infectivity in vitro of monocyte subsets by Mycobacterium bovis BCG before granuloma formation. We identified CD14+CD16- monocytes as the main target of infection in peripheral blood mononuclear cells from six healthy donors. CD14+CD16+ monocytes displayed the lowest infection rates and remained uninfected in some donors. We found that a longer infection time resulted in an increase of the percentage of monocytes infected and of the number of granulomas produced. We did not observe changes in monocyte cell death or subset expansion upon infection. Future experiments with our in vitro method could help define Mtb infectivity of monocyte subsets. Our study provides a platform to investigate how early infection of different monocyte subsets may alter granuloma formation and outcomes of Mtb infection. PMID- 30445575 TI - Quality of life assessment using patient reported outcome (PRO) measures - still a Cinderella outcome? PMID- 30445576 TI - Left ventricular 2D speckle tracking echocardiography for detection of systolic dysfunction in genetic, dilated cardiomyopathies. AB - Aims: Genetic, dilated cardiomyopathy (DCM) can be caused by a large variety of mutations. Mutation carriers are often asymptomatic until DCM is well established, presenting with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies can only be applied if DCM can be detected early. Echocardiographic, left ventricular (LV) global longitudinal strain (GLS) is a promising tool for early diagnosis, i.e. before a decrease in LV ejection fraction (EF) has occurred. We, therefore, investigated the role of LV GLS as an early disease marker in genetic DCM. Methods and results: Genetic DCM patients and genotyped family members were evaluated. The study population was grouped as (i) genotype-positive, phenotype-positive (GPFP) patients with a pathogenic mutation and LVEF <55% (ii) genotype-positive, phenotype-negative (GPFN) individuals with a pathogenic mutation and LVEF >=55%, and (iii) genotype negative, phenotype-negative (GNFN) individuals without a pathogenic mutation and LVEF >=55%. One hundred and fifteen individuals (53 +/- 15 years, 51% male) were analysed: 28 (24%) were classified as GNFN, 50 (44%) as GPFN, and 37 (32%) as GPFP. Various mutations were represented: 39 (34%) titin, 14 (12%) lamin A/C, 13 (11%) sarcomeric, and 21 (18%) less frequent mutations (grouped together). The mean LVEF was 58 +/- 14% for all subjects. The mean LV GLS in the GNFN group was 21.7 +/- 1.5% vs. -19.7 +/- 3.5% for the GPFN group (P = 0.036). The mean LV GLS was -12.9 +/- 4.3% for the GPFP category (P < 0.001 vs. GPFN and GNFN). Conclusion: Decreased LV GLS discriminates GPFN individuals from normal controls, which may permit early institution of therapy for genetic DCM. PMID- 30445577 TI - How often can meta-analyses of individual-level data individualize treatment? A meta-epidemiologic study. AB - Background: One of the claimed main advantages of individual participant data meta-analysis (IPDMA) is that it allows assessment of subgroup effects based on individual-level participant characteristics, and eventually stratified medicine. In this study, we evaluated the conduct and results of subgroup analyses in IPDMA. Methods: We searched PubMed, EMBASE and the Cochrane Library from inception to 31 December 2014. We included papers if they described an IPDMA based on randomized clinical trials that investigated a therapeutic intervention on human subjects and in which the meta-analysis was preceded by a systematic literature search. We extracted data items related to subgroup analysis and subgroup differences (subgroup-treatment interaction p < 0.05). Results: Overall, 327 IPDMAs were eligible. A statistically significant subgroup-treatment interaction for the primary outcome was reported in 102 (36.6%) of 279 IPDMAs that reported at least one subgroup analysis. This corresponded to 187 different statistically significant subgroup-treatment interactions: 124 for an individual level subgrouping variable (in 76 IPDMAs) and 63 for a group-level subgrouping variable (in 36 IPDMAs). Of the 187, only 7 (3.7%; 6 individual and 1 group-level subgrouping variables) had a large difference between strata (standardized effect difference d >= 0.8). Among the 124 individual-level statistically significant subgroup differences, the IPDMA authors claimed that 42 (in 21 IPDMAs) should lead to treating the subgroups differently. None of these 42 had d >= 0.8. Conclusions: Availability of individual-level data provides statistically significant interactions for relative treatment effects in about a third of IPDMAs. A modest number of these interactions may offer opportunities for stratified medicine decisions. PMID- 30445578 TI - The Influence of Depression on Health Care Expenditures Among Adults with Spondylosis, Intervertebral Disc Disorders, and Other Back Problems in the United States. AB - Background: Back pain is a very prevalent complaint, affecting two-thirds of the US population, and it accounts for $100 billion annually in health care expenditures. The occurrence of depression has been reported in existing literature among patients with back pain, but there is limited information regarding health care expenditures among patients with back pain and concurrent depression. Objective: To assess excess total and subtypes of health care expenditures among adults with spondylosis, intervertebral disc disorders, and other back problems who reported having depression compared with those without depression in the United States. Methods: We utilized a cross-sectional design, pooling Medical Expenditure Panel Survey data from 2010-2012. The eligible study sample included adults (age >=18 years) who reported positive health care expenditure. Total and subtypes of health care expenditures constituted the dependent variable. Ordinary least squares (OLS) regressions on logged expenditures were performed. Four models were developed to assess influence of demographics, functional ability, and concurrent diagnoses on health care expenditures. Results: A total of 6,739 adults with spondylosis, intervertebral disc disorders, and other back problems were assessed, 20.2% (N = 1,316) of whom had concurrent depression. Adults with concurrent depression had significantly higher total health care expenditures ($13,153) compared with the nondepression group ($7,477, P < 0.001). Outpatient and prescription expenditures showed similar findings. After adjusting for demographics, functional disabilities, and comorbidities, excess cost remained higher in the group reporting concurrent depression (46%). Conclusions: This study demonstrates that the presence of depression in adults with spondylosis, intervertebral disc disorders, and other back problems is associated with greater economic burden. These findings remained consistent after adjusting for all independent sets of variables. The study's findings suggest that interventions resulting in better management of depression have the potential to significantly reduce the economic burden in this population. PMID- 30445579 TI - Treating ulcerative colitis during pregnancy: evidence of materno-fetal transfer of golimumab. PMID- 30445580 TI - Diversity of endophytic fungi of Paeonia lactiflora Pallas and screening for fungal paeoniflorin producers. AB - Endophytic fungi from Paeonia lactiflora Pallas, which is mainly distributed in China, were characterized and screened to identify those capable of producing paeoniflorin. A total of 101 isolates obtained from the roots, stems and leaves of P. lactiflora were grouped into 16 fungal taxa based on morphological traits and internal transcribed spacers sequences, indicating that endophytic fungi of P. lactiflora are abundant and diverse. The dominant endophytic fungi were Aspergillus, Alternaria and Penicillium. More fungi were recovered from leaves than from roots and stems. The similarity index was highest between the stems and leaves (0.733), followed by the roots and leaves (0.615) and the stems and roots (0.563). Analyses of the fermentation extracts of 22 endophytic fungi by high performance liquid chromatography and mass spectrometry revealed that three strains (R12, Alternaria tenuissima; S4, Aspergillus flavus; and R17 Penicillium commune) were able to produce paeoniflorin. Among the paeoniflorin-producing fungi, the yield of paeoniflorin from A. flavus S4 was 342.4 MUg/L, and this strain could be used as a candidate for the industrial production of paeoniflorin. PMID- 30445582 TI - Outbreak Epidemiology: One of Many New Frontiers of Norovirus Biology. PMID- 30445581 TI - Intratumoral IL17-producing cells infiltration correlate with anti-tumor immune contexture and improved response to adjuvant chemotherapy in gastric cancer. AB - Background: Tumor IL17-producing (IL17A+) cells infiltration has different prognostic value among various cancers. The objective of this study was to assess the effect of IL17A+ cells in gastric cancer. Patients and methods: The study included two patient cohorts, the Cancer Genome Atlas cohort (TCGA, n=351) and the Zhongshan Hospital cohort (ZSHC, n = 458). The TCGA and ZSHC were used for mRNA-related and cells infiltration-related analyses, respectively. The roles of IL17A mRNA and IL17A+ cells in overall survival (OS), response to adjuvant chemotherapy (ACT), and immune contexture were evaluated. Another independent cohort was included to identify the correlation between mRNA of IL17A and IL17A+ cells infiltration (the preliminary Zhongshan Hospital cohort, PZSHC, n=21). Results: The infiltration of IL17A+ cells was positively correlated with the expression of IL17A mRNA (Spearman's r = 0.811; p<0.001). High IL17A mRNA expression and intratumoral IL17A+ cells were correlated with improved OS and remained to be significant after adjusted for confounders. Patients with TNMII/III disease whose tumor present higher intratumoral IL17A+ cells or lower peritumoral IL17A+ cells can benefit more from ACT. Elevated IL17A mRNA expression and increased intratumoral IL17A+ cells infiltration was associated with more anti-tumor mast cells and nature killer cells infiltration and less pro tumor M2 macrophages infiltration. High IL17A mRNA expression represented a Th17 cells signature and immune response process, and was correlated with increased cytotoxic GZMA, GZMB, IFNG, PRF1, and TNFSF11 genes expression. Conclusions: IL17A mRNA expression and intratumoral IL17A+ cells infiltration was correlated with anti-tumor immune contexture. IL17A+ cells infiltration could be used as an independent prognostic biomarker for OS and predictive biomarker for superior response to ACT, and further prospective validation needs to be conducted. PMID- 30445583 TI - Wood decomposition in aquatic and terrestrial ecosystems in the tropics: contrasting biotic and abiotic processes. AB - Wood decomposition, a critical process in carbon and nutrient cycles, is influenced by environmental conditions, decomposer communities and substrate composition. While these factors differ between land and stream habitats, across habitat comparisons of wood decay processes are rare, limiting our ability to evaluate the context- dependency of the drivers of decay. Here we tracked wood decomposition of three tree species placed in stream and terrestrial habitats in a lowland tropical forest in Panama. At 3 and 11 months we measured mass loss, wood nitrogen and wood polymer concentrations, and sampled wood-associated fungal and bacterial communities. After 11 months of decay we found that mass loss occurred 9% faster in streams than on land, but loss of cellulose, hemicellulose and lignin did not differ between habitats. We also observed large differences in microbial decomposer communities between habitats. Overall, we found faster mass loss of wood in water, but no differences in biotic decay processes between habitats despite distinct microbial communities in streams and on land. Our research challenges the assumption that wood decays relatively slowly in water reflecting unfavorable environmental conditions and a limited capacity of aquatic microbial communities to effectively degrade wood polymers. PMID- 30445585 TI - Body flexibility enhances maneuverability in the world's largest predator. AB - Blue whales are often characterized as highly stable, open-ocean swimmers who sacrifice maneuverability for long-distance cruising performance. However, recent studies have revealed that blue whales actually exhibit surprisingly complex underwater behaviors, yet little is known about the performance and control of these maneuvers. Here, we use multi-sensor biologgers equipped with cameras to quantify the locomotor dynamics and the movement of the control surfaces used by foraging blue whales. Our results revealed that simple maneuvers (rolls, turns, and pitch changes) are performed using distinct combinations of control and power provided by the flippers, the flukes, and bending of the body, while complex trajectories are structured by combining sequences of simple maneuvers. Furthermore, blue whales improve their turning performance by using complex banked turns to take advantage of their substantial dorso-ventral flexibility. These results illustrate the important role body flexibility plays in enhancing control and performance of maneuvers, even in the largest of animals. The use of the body to supplement the performance of the hydrodynamically active surfaces may represent a new mechanism in the control of aquatic locomotion. PMID- 30445584 TI - The Pathogenesis of Extraintestinal Manifestations: Implications for IBD research, diagnosis and therapy. PMID- 30445586 TI - Exosome-mediated intracellular signalling impacts the development of endometriosis - new avenues for endometriosis research. PMID- 30445587 TI - Single-cell RNA-sequencing in facioscapulohumeral muscular dystrophy disease etiology and development. AB - Facioscapulohumeral muscular dystrophy (FSHD) is characterized by sporadic de repression of the transcription factor DUX4 in skeletal muscle. DUX4 activates a cascade of muscle disrupting events, eventually leading to muscle atrophy and apoptosis. Yet, how sporadic DUX4 expression leads to the generalized muscle wasting remains unclear. Transcriptome analyses have systematically been challenged by the majority of nuclei being DUX4neg, weakening the DUX4 transcriptome signature. Moreover, DUX4 has been shown to be expressed in a highly dynamic burst-like manner, likely resulting in the detection of the downstream cascade of events long after DUX4 expression itself has faded. Identifying the FSHD-transcriptome in individual cells and unraveling the cascade of events leading to FSHD development, may therefore provide important insights in the disease process.We employed single-cell RNA-sequencing, combined with pseudotime trajectory modeling, to study FSHD disease etiology and cellular progression in human primary myocytes. We identified a small FSHD-specific cell population in all tested patient-derived cultures and detected new genes associated with DUX4 de-repression. We furthermore generated an FSHD cellular progression model, reflecting both the early burst-like DUX4 expression as well as the downstream activation of various FSHD-associated pathways, which allowed us to correlate DUX4 expression signature dynamics with that of regulatory complexes, thereby facilitating the prioritization of epigenetic targets for DUX4 silencing.Single-cell transcriptomics combined with pseudotime modeling thus holds valuable information on FSHD disease etiology and progression which can potentially guide biomarker and target selection for therapy. PMID- 30445588 TI - Mental health and parenting stress in mothers of children with diabetes treated in a patient-centred medical home. AB - Background: Mothers of children with diabetes are at-risk for experiencing parenting stress and diminished mental/emotional health. To the best of our knowledge, no studies to date have examined whether there are differences in these outcomes between mothers whose diabetic child is managed in a patient centred medical home or not. Objective: The objective of the present study was to assess whether there were differences in mental health and parenting stress among mothers whose diabetic child was managed in a patient-centred medical home or not. Methods: Two hundred fifty-three mothers of children with diabetes (mean age = 12.50 years; SD = 3.90) from the 2011-2012 National Survey of Children's Health were included in this study. Hierarchical multiple regression was conducted to determine the amount of variance that having a patient-centred medical home contributed to maternal emotional/mental health and parenting stress. Results: After controlling for child sex, age, race/ethnicity and family poverty level, patient-centred medical home status was associated with better mental health for mothers and less parenting stress. Effective care coordination was the only subcomponent of the patient-centred medical home that significantly contributed to the variance in mother's mental/emotional health and parenting stress. Conclusions: Receiving care in a patient-centred medical home, particularly the care coordination component, may mitigate some of the negative maternal effects of managing a child's diabetes. PMID- 30445589 TI - Letter: Guidelines for the Use of Electrophysiological Monitoring for Surgery of the Human Spinal Column and Spinal Cord. PMID- 30445590 TI - Neurobiological substrates underlying the effect of genomic risk for depression on the conversion of amnestic mild cognitive impairment. AB - Depression increases the conversion risk from amnestic mild cognitive impairment to Alzheimer's disease with unknown mechanisms. We hypothesize that the cumulative genomic risk for major depressive disorder may be a candidate cause for the increased conversion risk. Here, we aimed to investigate the predictive effect of the polygenic risk scores of major depressive disorder-specific genetic variants (PRSsMDD) on the conversion from non-depressed amnestic mild cognitive impairment to Alzheimer's disease, and its underlying neurobiological mechanisms. The PRSsMDD could predict the conversion from amnestic mild cognitive impairment to Alzheimer's disease, and amnestic mild cognitive impairment patients with high risk scores showed 16.25% higher conversion rate than those with low risk. The PRSsMDD was correlated with the left hippocampal volume, which was found to mediate the predictive effect of the PRSsMDD on the conversion of amnestic mild cognitive impairment. The major depressive disorder-specific genetic variants were mapped into genes using different strategies, and then enrichment analyses and protein-protein interaction network analysis revealed that these genes were involved in developmental process and amyloid-beta binding. They showed temporal specific expression in the hippocampus in middle and late foetal developmental periods. Cell type-specific expression analysis of these genes demonstrated significant over-representation in the pyramidal neurons and interneurons in the hippocampus. These cross-scale neurobiological analyses and functional annotations indicate that major depressive disorder-specific genetic variants may increase the conversion from amnestic mild cognitive impairment to Alzheimer's disease by modulating the early hippocampal development and amyloid-beta binding. The PRSsMDD could be used as a complementary measure to select patients with amnestic mild cognitive impairment with high conversion risk to Alzheimer's disease. PMID- 30445591 TI - Mitochondrial energetics is impaired in very long-chain acyl-CoA dehydrogenase deficiency and can be rescued by treatment with mitochondria-targeted electron scavengers. AB - Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common defect of mitochondrial long-chain fatty acid beta-oxidation (FAO). Patients present with heterogeneous clinical phenotypes affecting heart, liver, and skeletal muscle predominantly. The full pathophysiology of the disease is unclear and patient response to current therapeutic regimens is incomplete. To identify additional cellular alterations and explore more effective therapies, mitochondrial bioenergetics and redox homeostasis were assessed in VLCAD deficient fibroblasts, and several protective compounds were evaluated. The results revealed cellular and tissue changes, including decreased respiratory chain function, increased reactive oxygen species (ROS) production, and altered mitochondrial function and signaling pathways in a variety of VLCAD deficient fibroblasts. The mitochondrially enriched electron and free radical scavengers JP4-039 and XJB-5-131 improved respiratory chain function and decreased ROS production significantly, suggesting that they are viable candidate compounds to further develop to treat VLCAD deficient patients. PMID- 30445592 TI - Effects of B. amyloliquefaciens and B. subtilis on ileal digestibility of amino acids and total tract digestibility of crude protein and gross energy in diets fed to growing pigs. AB - The objective of this experiment was to test the hypothesis that the apparent ileal digestibility (AID) of AA, CP, and GE, the apparent total tract digestibility (ATTD) of CP and GE, and the apparent hindgut digestibility of CP and GE by growing pigs may be improved by supplementing diets with 2 direct fed microbials (DFM) containing different Bacillus strains. Twenty-four growing barrows (initial BW: 22.69 +/- 1.48 kg) that had a T-cannula installed in the distal ileum were individually housed and randomly allotted to a 3 diet, 3 period design with 24 pigs and three 21-d periods. There were 8 pigs per diet in each period for a total of 24 observations per diet. Three diets that were based on corn, soybean meal, and distillers dried grains with solubles were formulated. The control diet contained no DFM, but 2 additional diets contained 2 different bacillus strains (B. amyloliquefaciens or B. subtilis). Feed was provided in mash form in 2 daily meals at 0800 and 1600 h. The initial 12 d of each period was the adaptation period to the diet. Fecal and urine samples were collected from d 13 to 18, and ileal digesta were collected for 8 h on d 20 and 21. Results indicated that there were no differences among diets in ATTD of CP, but the AID of CP was reduced (P < 0.05) for the B. subtilis diet compared with control and B. amyloliquefaciens diets. Therefore, the apparent hindgut digestibility of CP was greater (P < 0.005) in pigs fed the B. subtilis diet compared with the other diets. The AID of total indispensable, total dispensable, and total AA was greater (P < 0.05) in the B. amyloliquefaciens diet compared with the control diet. There were no differences among diets in ATTD of GE, but the AID of GE was greater for the B. amyloliquefaciens diet than for the control and the B. subtilis diets (P < 0.001). Therefore, the apparent hindgut digestibility of GE was less (P < 0.05) in the B. amyloliquefaciens diet compared with the other diets. The DE (DM-basis) for the B. subtilis diet was greater (P < 0.05) compared with the control and the B. amyloliquefaciens diets. In conclusion, supplementation of Bacillus spp. to diets fed to growing pigs may increase the AID of AA and GE, but there appears to be differences among strains of Bacillus spp. in their impact on AA and energy digestibility. PMID- 30445593 TI - Black athletes' hearts. PMID- 30445594 TI - Short lifetime structures appearing in RNA and DNA. AB - The structure and function of unstable single-stranded DNA (ssDNA) have not been widely examined. While numerous studies have investigated DNA as an information molecule, the different potentials of DNA, particularly those of ssDNA, remain unclear. For polypeptides, the significance of denatured structures has been established in the past two decades. Polynucleotides have chemically distinct properties from polypeptides, but their behaviours have not been thoroughly studied. In this review, three different phenomena related to unstable ssDNA are discussed: i) ssDNA cleavage of restriction enzymes; ii) single-stranded conformation polymorphism, which can be theoretically explained by single stranded conformation dynamics; and iii) random PCR (Polymerase Chain Reaction). These features can be utilized for scientific or technical applications. Previous studies showed that the phenomena exhibited by ssDNA were correctly understood only when unstable and transient structures were taken into account. Transient structures of ssDNA may have undiscovered functions governed by very rapid processes and/or multi-diversity states because of their intrinsic natures. PMID- 30445595 TI - Breast cancer survivors' preferences for social support features in technology supported physical activity interventions: findings from a mixed methods evaluation. AB - Incorporating peer and professional social support features into remotely delivered, technology-supported physical activity interventions may increase their effectiveness. However, very little is known about survivors' preferences for potential social features. This study explored breast cancer survivors' preferences for both traditional (e.g., coaching calls and peer support) and innovative (i.e., message boards and competitions) social support features within remotely delivered, technology-supported physical activity interventions. Survivors [N = 96; Mage = 55.8 (SD = 10.2)] self-reported demographic and disease characteristics and physical activity. A subset (n = 28) completed semistructured phone interviews. Transcribed interviews were evaluated using a thematic content analysis approach and consensus review. Following interviews, the full sample self-reported preferences for social features for remotely delivered physical activity interventions via online questionnaires. Questionnaire data were analyzed using descriptive statistics. Four themes emerged from interview data: (a) technology increases social connectedness; (b) interest in professional involvement/support; (c) connecting with similar survivors; and (d) apprehension regarding competitive social features. Quantitative data indicated that most survivors were interested in social features including a coach (77.1 per cent), team (66.7 per cent), and exercise buddy (57.3 per cent). Survivors endorsed sharing their activity data with their team (80.0 per cent) and buddy (76.6 per cent), but opinions were mixed regarding a progress board ranking their activity in relation to other participants' progress. Survivors were interested in using a message board to share strategies to increase activity (74.5 per cent) and motivational comments (73.4 per cent). Social features are of overall interest to breast cancer survivors, yet preferences for specific social support features varied. Engaging survivors in developing and implementing remotely delivered, technology-supported social features may enhance their effectiveness. PMID- 30445596 TI - High doses of phytase on growth performance and apparent ileal amino acid digestibility of broilers fed diets with graded concentrations of digestible lysine. AB - Two experiments of the same design were conducted to determine the influence of phytase on performance and apparent ileal digestibility (AID) of amino acids in broilers fed graded concentrations of digestible lysine (dgLys). Cobb 400, male broilers were allocated to one of 16 diets consisting of four basal diets formulated at 80, 88, 96 or 104% of the Cobb 400 dgLys requirements for each feeding phase. Phytase was included in each basal diet at 0, 750, 1,500 or 3,000 phytase units (FTU)/kg. In experiment 1, 33 birds/pen from hatch to d 42 were fed a two-phase feeding program with 12 replicate pens/diet. In experiment 2, there were 25 birds/pen from hatch to d 21 and 8 replicate pens/diet. Data were analyzed as a 4 x 4 factorial and means separated using orthogonal contrasts. In experiment 1, feed intake (FI) increased (quadratic, P<0.05) as dgLys increased in the diet. Body weight gain (BWG) increased (quadratic, P<0.05) as dgLys concentration or phytase dose increased in the diet. As phytase dose increased in the diet, feed conversion ratio (FCR) was improved in a linear or quadratic (P<0.05) manner depending on the dgLys concentration of the diet (dgLys * phytase, P<0.05). In experiment 2, FI linearly (P<0.05) increased as dgLys increased in the diet. Increasing the concentration of dgLys or phytase in the diet increased (quadratic, P<0.05) BWG and improved (quadratic, P<0.05) FCR. The AID of most amino acids was influenced by a dgLys * phytase interaction (P<0.05), except threonine, valine, tryptophan, serine, cysteine, or leucine (linear or quadratic effect of phytase, P < 0.05), where phytase improved the AID in birds fed diets containing 80, 88 or 96% of the dgLys requirement, but not birds fed 104%. The predicted dgLys requirement to maximize performance, carcass, and digestible lysine intake was 97.6 to >= 104%. The predicted dose of phytase to maximize BWG or FCR was between 1,990 to 2,308 FTU/kg, regardless of the dgLys concentration in the diet. The predicted dose of phytase to maximize carcass weight was between 1,527 to 2,658 FTU/kg of diet and to maximize breast weight was 0 to >= 3,000 FTU/kg diet, depending on the dgLys concentration in the diet. In conclusion, optimal performance in the absence of phytase could be achieved at much lower levels of lysine in the presence of phytase. PMID- 30445597 TI - A prospective Phase II study for the efficacy of radiotherapy in combination with zoledronic acid in treating painful bone metastases from gastrointestinal cancers. AB - We investigated the efficacy of combined radiotherapy (RT) and zoledronic acid in treating painful bone metastases from gastrointestinal cancers. Sixty patients were prospectively enrolled between November 2014 and July 2016. The most common primary cancer type was hepatocellular carcinoma (HCC, n = 25), followed by colorectal cancer (n = 6). Patients received external beam RT of 30-54 Gy in 10 17 fractions or 20 Gy in 5 fractions for symptomatic bone metastases. On the first day of RT, patients received 4 mg intravenous zoledronic acid, which was repeated monthly for a total of six cycles. The mean pain score before treatment was 6.7, and it decreased to 2.8 at 1 month and 2.1 at 3 months (P < 0.001).The overall pain response rates at 1 and 3 months were 95% and 96%, respectively. Among the 24 patients who underwent magnetic resonance imaging, 71% were responders, with a complete response in 1 patient and partial in 16 patients. Combined treatment significantly decreased levels of macrophage inflammatory protein-1alpha and matrix metalloproteinase (MMP)-2 and -3 compared with baseline (all P < 0.05). In HCC patients, IL-6 and MMP-9 levels were significantly lower 1 month after treatment (P < 0.05). The mean quality of life (QOL) score improved from 66 to 56 at 1 month (P < 0.001) and 55 at 3 months (P = 0.016). The median survival was 7 months. In conclusion, RT with zoledronic acid decreased bone pain and improved QOL in patients with painful bone metastases from gastrointestinal cancers. Radiographic findings and serum biomarker measurements were closely correlated with therapeutic responses. PMID- 30445598 TI - Erratum to: The genome sequence and transcriptome of Potentilla micrantha and their comparison to Fragaria vesca (the woodland strawberry). PMID- 30445599 TI - IL23R-protective coding variant promotes beneficial bacteria and diversity in the ileal microbiome in healthy individuals without inflammatory bowel disease. AB - Background and aims: This study aimed to characterise the mucosa-associated microbiota in ileal Crohn's disease (CD) patients and in healthy controls in terms of host genotype and inflammation status. Methods: The mucosa-associated microbiota of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed by 16S ribosomal sequencing to determine microbial profile differences between (1) IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, (2) ileal CD patients and control subjects, and (3) inflamed and non-inflamed mucosal tissue in CD patients. Results: The protective variant of the IL23R gene (rs11209026) significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the Christensenellaceae family as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability but no significant alterations in diversity, richness and taxa were identified. Calprotectin correlated positively with Proteobacteria abundance and negatively with diversity in the samples from healthy subjects. Conclusions: The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R (rs11209026) wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Fecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation. PMID- 30445600 TI - TIPE1 promotes cervical cancer progression by repression of p53 acetylation and is associated with poor cervical cancer outcome. AB - Previous studies have shown that TIPE1 inhibits tumor proliferation and metastasis in certain cancers; however, increased expression of TIPE1 is observed in cervical cancer cell lines and tissues, indicating it might exert a distinctive role in cervical cancer. Cell and xenograft tumorigenicity assays showed that TIPE1 facilitates cervical cancer progression in this study. Further investigation demonstrated that TIPE1 binds to p53 and impairs its activity via inhibition of its acetylation. In addition, TIPE1 promoted cell proliferation and suppressed cisplatin susceptibility in a p53-dependent manner, indicating that TIPE1 facilitates cervical cancer progression primarily through the p53 pathway. TIPE1 expression in clinical samples also demonstrated that its upregulation predicts poor prognosis in patients with cervical cancer. Taken together, the results of the present study showed that TIPE1 serves as an oncogene by restricting p53 activity in the development of cervical cancer, suggesting that TIPE1 will provide a new potential target for cervical cancer therapy and can be used as a biomarker to predict patient prognosis. PMID- 30445601 TI - RNAct: Protein-RNA interaction predictions for model organisms with supporting experimental data. AB - Protein-RNA interactions are implicated in a number of physiological roles as well as diseases, with molecular mechanisms ranging from defects in RNA splicing, localization and translation to the formation of aggregates. Currently, ~1400 human proteins have experimental evidence of RNA-binding activity. However, only ~250 of these proteins currently have experimental data on their target RNAs from various sequencing-based methods such as eCLIP. To bridge this gap, we used an established, computationally expensive protein-RNA interaction prediction method, catRAPID, to populate a large database, RNAct. RNAct allows easy lookup of known and predicted interactions and enables global views of the human, mouse and yeast protein-RNA interactomes, expanding them in a genome-wide manner far beyond experimental data (http://rnact.crg.eu). PMID- 30445602 TI - Intention to return to the town of Tomioka in residents 7 years after the accident at Fukushima Daiichi Nuclear Power Station: a cross-sectional study. AB - The aim of our study was to identify the factors associated with intention to return (ITR) in residents of Tomioka town, Fukushima Prefecture. We contacted approximated 8000 residents aged 20 years or older who lived in Tomioka. We invited them to take part in a written survey on ITR. In all, 1749 residents' replies were included in the analysis. We asked about ITR in former residents of Tomioka town. We also asked about relevant factors and about risk perception in relation to the health effects of radiation exposure. Of those contacted, 469 (26.8%) had an ITR. Logistic regression analysis revealed that being male (OR = 1.6, 95% Cl: 1.24-1.96, P < 0.001), the anticipation of improving shopping in the town (OR = 1.5, 95% Cl: 1.26-1.67, P < 0.001) and requests for individual consultation with experts on the health effects of radiation (OR = 2.7, 95% Cl: 2.10-3.48, P <0.001) were associated with the ITR (+), and living with children under 18 years of age (OR = 0.7, 95% Cl: 0.51-0.95, P = 0.023), reluctance to drink tap water (OR = 0.5, 95% Cl: 0.36-0.69, P < 0.001) and anxiety regarding genetic effects of radiation in the next generation (OR = 0.6, 95% Cl: 0.45-079, P <0.001) were associated with the ITR (-) to Tomioka town, independent of other covariates. To allay the anxieties of residents who have an ITR to their hometown, careful risk communication, including information on the potential effects of radiation on health, is important. PMID- 30445603 TI - Novel pseudo-staphylococcal cassette chromosome mec element (phiSCCmecT55) in MRSA ST9. PMID- 30445604 TI - Fermenters in the Earthworm Gut: Do Transients Matter? AB - Earthworms have profound impact on soil-based ecosystems. Although theoretical considerations suggest that most microbes in the earthworm gut are likely ingested and transient, the non-responsiveness of soil microbes to a specific high value gut nutrient and anoxia has made it difficult to demonstrate that responsive gut fermenters are derived from soil. Therefore, soil and gut content of the model earthworm Lumbricus terrestris were examined for their fermentative capabilities. In unsupplemented anoxic microcosms, fermentation was negligible with soil but rapid with gut content. However, both soil and gut content facilitated robust fermentations when challenged with complex nutrients indicative of those released from gizzard-disrupted cells. Based on the relative abundances of 16S rRNA and 16S rRNA gene sequences, the responsive fermentative taxa in unsupplemented gut content treatments were negligible in unsupplemented soil treatments. In contrast, the responsive fermentative taxa in soil and gut content treatments supplemented with complex nutrients displayed marked similarities, with numerous Proteobacteria- and Firmicutes-affiliated phylotypes being dominant. These findings indicated that detectable differences between the fermentative taxa in soil and gut contents are due in part to the nutrient dependent metabolic status of community members and reinforce the likelihood that ingested transient microbes contribute to fermentation in the alimentary canal. PMID- 30445605 TI - Addressing cardiovascular risk in type 2 diabetes mellitus: a report from the European Society of Cardiology Cardiovascular Roundtable. PMID- 30445607 TI - pyNVR: Investigating factors affecting feature selection from scRNA-seq data for lineage reconstruction. AB - Motivation: The emergence of single-cell RNA-sequencing (scRNA-seq) has enabled analyses that leverage transitioning cell states to reconstruct pseudotemporal trajectories. Multidimensional data sparsity, zero inflation, and technical variation necessitate the selection of high-quality features that feed downstream analyses. Despite the development of numerous algorithms for the unsupervised selection of biologically relevant features, their differential performance remains largely unaddressed. Results: We implemented the Neighborhood Variance Ratio (NVR) feature selection approach as a Python package with substantial improvements in performance. In comparing NVR with multiple unsupervised algorithms such as dpFeature, we observed striking differences in features selected. We present evidence that quantifiable dataset properties have observable and predictable effects on the performance of these algorithms. Availability: pyNVR is freely available at https://github.com/KenLauLab/NVR. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30445606 TI - Differences in First Trimester Maternal Metabolomic Profiles in Pregnancies Conceived from Fertility Treatments. AB - Context: Maternal metabolic status reflects underlying physiological changes in the maternal-placental-fetal unit, which can identify contributors to adverse pregnancy outcomes associated with infertility and treatments utilized. Objective: To determine if maternal metabolomic profiles are different between spontaneous pregnancies and pregnancies conceived with fertility treatments, including in vitro fertilization (IVF) and non-IVF fertility treatments (NIFT) that may explain differences in pregnancy outcomes. Design: Metabolon(r) metabolomic analysis and ELISA assays for 17-beta-estradiol and progesterone were performed during the late first trimester from spontaneous conceptions and those conceived through fertility treatments, including NIFT and IVF. Setting: Academic institution. Subjects: The SMAART (Spontaneous/Medically Assisted/ART) cohort which consisted of 409 women, 208 conceived spontaneously, 201 with infertility that used fertility treatments (90 NIFT, 111 IVF). Intervention(s): Mode of conception (Spontaneous, NIFT and IVF). Main Outcome Measure(s): 806 metabolites within 8 super pathways, 17-beta-estradiol and progesterone levels in maternal plasma in the late first trimester. Results: Metabolomic differences in the lipid super pathway (steroid metabolites, lipids with DHA acyl chains, acyl cholines), xanthine and benzoate metabolites (p<0.05) were significantly different among the Spontaneous and Infertility groups, with greatest differences between Spontaneous and IVF groups. 17-beta-estradiol and progesterone were significantly elevated in the Infertility group, with greatest differences among the Spontaneous and IVF groups. Conclusions: Metabolomic profiles differ between spontaneous and infertility pregnancies, likely driven by IVF. Elevated steroids and their metabolites are likely due to increased hormone production from placenta reprogrammed from fertility treatments which may contribute to adverse outcomes associated with infertility and treatments utilized. PMID- 30445608 TI - Management of atrial fibrillation for older people with frailty: a systematic review and meta-analysis. AB - Background: despite a large and growing population of older people with frailty and atrial fibrillation (AF), there is a lack of guidance on optimal AF management in this high-risk group. Objective: to synthesise the existing evidence base on the association between frailty, AF and clinical outcomes. Methods: a systematic review of studies examining the association between validated measures of frailty, AF and clinical outcomes, and meta-analysis of the association between frailty and oral anticoagulation (OAC) prescription. Results: twenty studies (30,883 patients) were included, all observational. Fifteen were in hospital, four in the community, one in nursing care. Risk of bias was low-to moderate. AF prevalence was 3%-38%. In people with AF, frailty was associated with increased stroke incidence, all-cause mortality, symptom severity and length of hospital stay. Meta-analysis of six studies showed frailty was associated with decreased OAC prescription at hospital admission (pooled adjusted OR 0.45 [95%CI 0.22-0.93], three studies), but not at discharge (pooled adjusted OR 0.40 [95%CI 0.13-1.23], three studies). A community-based study showed increased OAC prescription associated with frailty (OR 2.33 [95%CI 1.03-5.23]). Conclusion: frailty is common, and associated with adverse clinical outcomes in patients with AF. There is evidence of an association between frailty status and OAC prescription, with different direction of effect in community compared with hospital cohorts. Despite the majority of care for older people being provided in the community, there is a lack of evidence on the association between frailty, AF, anticoagulation and clinical outcomes to guide optimal care in this setting. PMID- 30445609 TI - Clinical outcome in anti-neutrophil cytoplasmic antibody-associated vasculitis and gene variants of 11beta-hydroxysteroid dehydrogenase type 1 and the glucocorticoid receptor. AB - Objectives: We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis. Methods: Patients diagnosed with ANCA associated vasculitis (n = 241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non carriers of GR haplotypes and the HSD11B1 genotype. Results: Carriers of haplotype 4 (ER22/23EK + 9beta+TthIII1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (BclI) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes. Conclusion: Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis. PMID- 30445610 TI - Post-mitotic BET-induced reshaping of integrase quaternary structure supports wild-type MLV integration. AB - The Moloney murine leukemia virus (MLV) is a prototype gammaretrovirus requiring nuclear disassembly before DNA integration. In the nucleus, integration site selection towards promoter/enhancer elements is mediated by the host factor bromo and extraterminal domain (BET) proteins (bromodomain (Brd) proteins 2, 3 and 4). MLV-based retroviral vectors are used in gene therapy trials. In some trials leukemia occurred through integration of the MLV vector in close proximity to cellular oncogenes. BET-mediated integration is poorly understood and the nature of integrase oligomers heavily debated. Here, we created wild-type infectious MLV vectors natively incorporating fluorescent labeled IN and performed single molecule intensity and Forster resonance energy transfer experiments. The nuclear localization of the MLV pre-integration complex neither altered the IN content, nor its quaternary structure. Instead, BET-mediated interaction of the MLV intasome with chromatin in the post-mitotic nucleus reshaped its quaternary structure. PMID- 30445611 TI - Causal Effects of Blood Lipids on Amyotrophic Lateral Sclerosis: A Mendelian Randomization Study. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disorder that is predicted to increase across the globe by ~70% in the following decades. Understanding the disease causal mechanism underlying ALS and identifying modifiable risks factors for ALS hold the key for the development of effective preventative and treatment strategies. Here, we investigate the causal effects of four blood lipid traits that include high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol (TC), and triglycerides (TG) on the risk of ALS. By leveraging instrument variables from multiple large-scale genome-wide association studies in both European and East Asian populations, we carry out one of the largest and most comprehensive Mendelian randomization analyses performed to date on the causal relationship between lipids and ALS. Among the four lipids, we found that only LDL is causally associated with ALS and that higher LDL level increases the risk of ALS in both the European and East Asian populations. Specifically, the odds ratio of ALS per one standard deviation (i.e. 39.0 mg/dL) increase of LDL is estimated to be 1.14 (95% CI 1.05 - 1.24, p = 1.38E-3) in the European and population and 1.06 (95% CI 1.00 - 1.12, p = 0.044) in the East Asian population. The identified causal relationship between LDL and ALS is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our study provides important evidence supporting the causal role of higher LDL on increasing the risk of ALS, paving ways for the development of preventative strategies for reducing the disease burden of ALS across multiple nations. PMID- 30445612 TI - Genetic evidence of focal Plasmodium falciparum transmission in a pre-elimination setting in Southern Province, Zambia. AB - Background: Southern Province, Zambia, has experienced a dramatic decline in Plasmodium falciparum malaria transmission in the past decade and is targeted for elimination. Zambia's National Malaria Elimination Program recommends reactive case detection (RCD) within 140m of index households to enhance surveillance and eliminate remaining transmission foci. Methods: To evaluate whether RCD captures local transmission, we genotyped 26 microsatellites from 106 samples collected from index (n=27) and secondary (n=79) cases detected through RCD in the Macha Hospital catchment area between January 2015 and April 2016. Results: Participants from the same RCD event harbored more genetically related parasites than those from different RCD events, suggesting that RCD captures, at least in part, infections related through local transmission. Related parasites clustered in space and time, up to at least 250m from index households. Spatial analysis identified a putative focal transmission hotspot. Conclusions: The current RCD strategy detects focal transmission events, although programmatic guidelines to screen within 140m of index households may fail to capture all secondary cases. This study highlights the utility of parasite genetic data in assessing programmatic interventions, and similar approaches may be useful to malaria elimination programs seeking to tailor intervention strategies to the underlying transmission epidemiology. PMID- 30445613 TI - UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase is indispensable for oogenesis, oocyte-to-embryo transition, and larval development of the nematode Caenorhabditis elegans. AB - N-linked glycosylation of proteins is the most common post-translational modification of proteins. The enzyme UDP-N-acetylglucosamine-dolichyl-phosphate N acetylglucosaminephosphotransferase (DPAGT1) catalyses the first step of N glycosylation, and DPAGT1 knockout is embryonic lethal in mice. In this study, we identified the sole orthologue (algn-7) of the human DPAGT1 in the nematode C. elegans. The gene activity was disrupted by RNAi and deletion mutagenesis, which resulted in larval lethality, defects in oogenesis and oocyte-to-embryo transition. Endomitotic oocytes, abnormal fusion of pronuclei, abnormal AB cell rotation, disruption of permeation barriers of eggs, and abnormal expression of chitin and chitin synthase in oocytes and eggs were the typical phenotypes observed. The results indicate that N-glycosylation is indispensable for these processes. We further screened an N-glycosylated protein database of C. elegans, and identified 456 germline-expressed genes coding N-glycosylated proteins. By examining RNAi phenotypes, we identified five germline-expressed genes showing similar phenotypes to the algn-7 (RNAi) animals. They were ribo-1, stt-3, ptc-1, ptc-2, and vha-19. We identified known congenital disorders of glycosylation (CDG) genes (ribo-1 and stt-3) and a recently found CDG gene (vha-19). The results show that phenotype analyses using the nematode could be a powerful tool to detect new CDG candidate genes and their associated gene networks. PMID- 30445614 TI - Withdrawn as Duplicate: The many nuanced evolutionary consequences of duplicated genes. PMID- 30445615 TI - Are Surgeons Different? The Case for Bespoke Antimicrobial Stewardship. PMID- 30445616 TI - Coexistent bicuspid aortic valve and mitral valve prolapse: epidemiology, phenotypic spectrum, and clinical implications. AB - Aims: Bicuspid aortic valve (BAV) and mitral valve prolapse (MVP) are common but the prevalence and significance of coexistent conditions are unknown. This study investigated the prevalence, phenotypic expression, and clinical significance of coexistent MVP-BAV. Methods and results: Retrospective comparison of MVP-BAV and MVP-tricuspid aortic valve (TAV) prevalence including de novo echocardiographic analysis of all MVP-BAV patients between 2005 and 2015 was performed. The community prevalence of MVP-BAV was 2.7% vs. 3.4% for MVP-TAV (P = 0.45). Posterior mitral leaflet (PML)-MVP was the most common phenotype in both BAV and TAV (P = 0.38), but anterior mitral leaflet (AML)-MVP was twice more prevalent in BAV (31% vs. 15%, P < 0.0001). Among 130 subjects with coexistent MVP-BAV (81% men, 51 +/- 16 years old), 31 (24%) exhibited AML:PML length ratio >=3:1, termed large-AML prolapse (LAP-BAV), who had predominant BAV regurgitation when compared with those with non-LAP-BAV (P <= 0.001). An extreme phenotype of LAP-BAV with giant-AML prolapse and diminutive PML (GAP-BAV) was identified in 18/130 (14%) subjects. Compared with posterior-MVP-BAV, GAP-BAV patients were younger (42 +/- 15 vs. 64 +/- 12 years, P < 0.0001), had larger aortic annulus (28 +/- 3 vs. 26 +/- 2 mm, P = 0.01), and 61% had >= moderate BAV regurgitation (vs. 16%, P = 0.0007). Mitral repair occurred in 37/130 (28%) subjects. After median follow-up 5.5 months (4-83), 4/5 (80%) GAP-BAV patients required redo surgery for recurrent mitral regurgitation vs. 2/31 (6%) for non-LAP-BAV (P = 0.001). Conclusion: The community prevalence of coexistent MVP-BAV is comparable to MVP-TAV and their most common phenotype is posterior-MVP. However, anterior-MVP is twice as prevalent in MVP-BAV. A large-AML phenotype (LAP-BAV) with predominant BAV regurgitation affects 24% of MVP-BAV patients. An extreme phenotype of anterior MVP (GAP-BAV) affects 14% of BAV patients; characterized by exceptionally large AML, diminutive PML, high mitral and aortic regurgitation prevalence, and high mitral repair failure rate. PMID- 30445617 TI - Comparison of Quantitative Exposure Models for Occupational Exposure to Organic Solvents in Korea. AB - This study aims to evaluate the accuracy, precision and conservatism of three models (ECETOC TRA 3.1, Stoffenmanager 7.0 and ART 1.5) by comparing model predictions and repeated exposure measurements in Korea. We collected the exposure measurements (n = 390) and detailed contextual information extracted from 10 survey reports published by Ministry of Employment and Labour in the mid 2000s. Using these three models, seven occupational health professionals predicted inhalation exposure to 10 solvents used for cleaning tasks in 51 situations at 33 companies in 15 industries. We applied four comparison approaches previously used by several European studies and calculated the lack of agreement (bias, relative bias, precision), Pearson correlation coefficients (r), level of conservatism, and residuals between the log-transformed predicted estimates and measured exposures on both individual and situation levels. The overall bias and precision were -0.53 +/- 2.11 with ART, -1.32 +/- 5.88 with Stoffenmanager, and -1.03 +/- 8.88 with ECETOC TRA. Pearson correlation coefficients were significantly high in ART (r = 0.95) and Stoffenmanager (r = 0.82), but moderate in ECETOC TRA (r = 0.58). We found ART to be the most accurate model, and Stoffenmanager was the most balanced model in terms of good accuracy, high correlation, and medium conservatism in the model predictions. However, ECETOC TRA showed less accurate outcomes and lower level of conservatism but still had moderate correlations. We observed a systematic tendency to overestimate low exposures and underestimate higher exposures in all models, similar to previous studies. Therefore, our findings suggest that these European models can be used to predict occupational exposure to solvents in Korea. PMID- 30445618 TI - Negative self-perception of aging and mortality in very old Chinese adults: The mediation role of healthy lifestyle. AB - Objectives: Previous literature has consistently shown a positive association between negative self-perception of aging and mortality in middle-aged and older adults. However, two questions remain unsolved: 1) whether such association holds among very old people (i.e., the fourth age); and 2) the potential mediators that could contribute to the positive association. The present study sought to fill in the research gap by examining the association between self-perception of aging and mortality in a group of very old Chinese participants (i.e. aged over 78). Methods: Four waves of data across a span of 8 years (2000-2008) were obtained from the Chinese Longitudinal Health Longevity Survey (CLHLS), which measured a total of 9683 participants' negative self-perception of aging, survival status, cognitive functioning, diet as well as other demographic information. Results: Latent growth models with survival analysis were conducted and the results replicated previous findings indicating an association between negative self perceptions of aging and reduced survival. Moreover and more importantly, a potential mediator - healthy lifestyle (e.g., eating fresh vegetables and fruits, exercising regularly and no smoking), was identified, such that older adults with more negative self-perception of aging tended to engage in less healthy lifestyle, which could lead to increased risk of mortality. Discussion: The findings provided support for a longitudinal behavioral pathway of health linking negative perceptions of aging to mortality, and also yielded important practical implications for older adults to reach longevity. PMID- 30445619 TI - GTRD: a database on gene transcription regulation-2019 update. AB - The current version of the Gene Transcription Regulation Database (GTRD; http://gtrd.biouml.org) contains information about: (i) transcription factor binding sites (TFBSs) and transcription coactivators identified by ChIP-seq experiments for Homo sapiens, Mus musculus, Rattus norvegicus, Danio rerio, Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, Schizosaccharomyces pombe and Arabidopsis thaliana; (ii) regions of open chromatin and TFBSs (DNase footprints) identified by DNase-seq; (iii) unmappable regions where TFBSs cannot be identified due to repeats; (iv) potential TFBSs for both human and mouse using position weight matrices from the HOCOMOCO database. Raw ChIP-seq and DNase-seq data were obtained from ENCODE and SRA, and uniformly processed. ChIP-seq peaks were called using four different methods: MACS, SISSRs, GEM and PICS. Moreover, peaks for the same factor and peak calling method, albeit using different experiment conditions (cell line, treatment, etc.), were merged into clusters. To reduce noise, such clusters for different peak calling methods were merged into meta-clusters; these were considered to be non-redundant TFBS sets. Moreover, extended quality control was applied to all ChIP-seq data. Web interface to access GTRD was developed using the BioUML platform. It provides browsing and displaying information, advanced search possibilities and an integrated genome browser. PMID- 30445620 TI - Early Surgical Management of Thermal Airway Injury: A case series. AB - Introduction: Inhalation injury is an independent risk factor in burn mortality, imparting a 20% increased risk of death. Yet there is little information on the natural history, functional outcome, or pathophysiology of thermal injury to the laryngotracheal complex, limiting treatment progress. Methods: Case series (n=3) of significant thermal airway injury. Results: In all cases, the initial injury was far exceeded by the subsequent immune response and aggressive fibro inflammatory healing. Serial examination demonstrated progressive epithelial injury, mucosal inflammation, airway remodeling, and luminal compromise. Histologic findings in the first case demonstrate an early IL-17A response in the human airway following thermal injury. This is the first report implicating IL 17A in the airway mucosal immune response to thermal injury. Our 2nd and 3rd patients received Azithromycin targeting IL-17A and showed clinical responses. The third patient also presented with exposed tracheal cartilage and underwent mucosal reconstitution via split-thickness skin graft over an endoluminal stent in conjunction with tracheostomy. This was associated with rapid abatement of mucosal inflammation, resolution of granulation tissue and return of laryngeal function. Conclusion: Patients who present with thermal inhalation injury should receive a thorough multidisciplinary airway evaluation, including early otolaryngologic evaluation. New early endoscopic approaches (scar lysis, and mucosal reconstitution with autologous grafting over an endoluminal stent), when combined with targeted medical therapy aimed at components of mucosal airway inflammation (local corticosteroids and systemic Azithromycin targeting IL-17A) may have potential to limit chronic cicatricial complications. PMID- 30445621 TI - Planning and implementing sexual orientation and gender identity data collection in electronic health records. AB - Lesbian, gay, bisexual, transgender, and queer (LGBTQ) people experience significant health disparities across the life course and require health care that addresses their unique needs. Collecting information on the sexual orientation and gender identity (SO/GI) of patients and entering SO/GI data in electronic health records has been recommended by the Institute of Medicine, the Joint Commission, and the Health Resources and Services Administration as fundamental to improving access to and quality of care for LGBTQ people. Most healthcare organizations, however, have yet to implement a system to collect SO/GI data due to multiple barriers. This report addresses those concerns by presenting recommendations for planning and implementing high-quality SO/GI data collection in primary care and other health care practices based on current evidence and best practices developed by a federally qualified health center and leader in LGBTQ health care. PMID- 30445622 TI - In Reply: Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: Magnetic Resonance Imaging-Based Anatomoclinical Correlations and Optimal Target. PMID- 30445623 TI - Work-disability in low back pain patients with or without surgery, and the role of social insurance regulation changes in Sweden. AB - Background: The aims were to study the differences in work-disability in patients with low back pain (LBP) in relation to (i) treatment provided (non-surgical or lumber spine surgery (decompression or fusion), and (ii) two time points, i.e. before and after the social insurance regulation changes in the in 2008. Methods: All non-pensioned individuals, aged 19-60 years, living in Sweden, diagnosed with LBP in 2004-06 or 2008-10 were included (n = 153739). Hazard ratios (HRs) with 95% confidence intervals for long-term sickness absence (>90 days, LTSA) and disability pension (DP) for LBP-patients (non-surgical, decompression, fusion, both surgeries) were estimated by Cox regression compared with the matched references from the general population without LBP (n = 566008). Results: LBP patients had a higher risk of subsequent work-disability compared with the references before and after insurance regulation changes. LBP-patients receiving decompression surgery had similar risk for later work-disability as those treated non-surgically. However, following regulation changes, LBP-patients undergoing fusion surgery had higher risk estimates of both LTSA (HR: 3.3) and DP (HR: 4.8) than patients treated non-surgically (HR: LTSA 2.1; DP 2.5) or with decompression (HR: LTSA 2.6; DP 2.1). In the adjusted models, risk estimates mainly attenuated after controlling for previous sickness absence. Conclusion: Risk for subsequent work-disability among LBP-patients was higher compared with people without LBP and lumbar spine surgery. Discrepancies in risk were explained by the treatment provided previous sickness absence and changes in the social insurance regulations, specifically LBP-patients treated with fusion surgery had an increased risk of subsequent work-disability after changes in regulations. PMID- 30445624 TI - Distinct bacterial and archaeal diversities and spatial distributions in surface sediments of the Arctic Ocean. AB - Environmental changes in the polar oceans are more pronounced than in other regions. The lack of knowledge regarding the microbial diversity, distribution and succession in the polar oceans has hampered our understanding about the effects of environmental changes on microbial ecosystems. This study investigated bacterial and archaeal diversities and spatial distributions in surface sediments of the Bering Sea and the Chukchi Sea. The results showed that bacterial alpha diversity was higher than archaea, and these differences were due to compositional changes. beta-diversities were not significantly different for bacterial and archaeal communities. Proteobacteria and Bacteroidetes were the dominant bacterial phyla, and the subdivisions of Proteobacteria changed obviously when compared with previous results. However, different assemblages dominated archaeal communities in different regions. Bacterial and archaeal communities were mainly determined by metallic ions, and geochemical properties were the major contributors to community dissimilarities. Interactions between geographical and geochemical properties had more pronounced impacts on archaeal communities. PMID- 30445626 TI - Leaveism in English and Welsh police forces: baseline reference values. AB - Background: Leaveism is a recently coined term for alternative attendance behaviours to sickness absence and sickness presence. Initial studies suggest that leaveism might mask the true extent of sickness in organizations and represent a response to perceived job insecurity, the belief that sickness absence could harm promotion prospects, and low job gratification. Aims: To generate baseline reference values for leaveism in English and Welsh police forces to facilitate benchmarking and risk-reduction activities. Methods: Officers represented by the Police Federation of England and Wales contributed survey data on the incidence of three leaveism dimensions in the year to February 2016. We applied descriptive statistics to characterize leaveism and Pearson's chi2 tests to examine differences in incidence rates by socio- and occupational demographic factors. Results: Annual leave or rest days were used to take time off from work due to physical health complaints by 8499/14 451 (59%) of respondents and psychological health complaints by 5983/14 326 (42%) (dimension 1). Work was taken home that could not be completed in normal working hours by 7515/14 959 (50%) of respondents (dimension 2), and 5974/14 963 (40%) reported having worked while on annual leave in order to catch up with work (dimension 3). Incidence rates on dimensions 2 and 3 differed markedly by rank, with higher ranks reporting higher rates. Conclusions: These sector-wide findings suggest that leaveism is a cause for concern. Further research is required to identify sector-specific causes of leaveism with a view to informing interventions to tackle the problem. PMID- 30445625 TI - Defining faecal calprotectin thresholds as a surrogate for endoscopic and histological disease activity in ulcerative colitis - a prospective analysis. AB - Background: Faecal calprotectin (FCal) levels are used as a surrogate marker for mucosal inflammation, but thresholds for defining endoscopic or histological disease activity in ulcerative colitis (UC) remain unclear. Methods: Using validated indices, prospective measurements of FCal, symptoms (Simple Colitis Clinical Activity Index, SCCAI), endoscopic (Ulcerative Colitis Endoscopic Index of Severity, UCEIS) and histological activity (Nancy index) were made over 6 months in patients enrolled into the TrueColours UC web-based monitoring programme. Repeated measurements correlation was performed between FCal and SCCAI, UCEIS and Nancy indices using definitions for remission and active disease (UCEIS: remission1, active4; Nancy: remission1, active2; Combined criteria: remission UCEIS1 and Nancy1, active UCEIS4 and Nancy2). Receiver operating characteristic curves investigated FCal thresholds after maximising sensitivity for active disease. Results: In 39 patients followed prospectively for 6 months, correlation coefficients between FCal and SCCAI, UCEIS and Nancy indices were 0.271 (95% CI 0.114-0.415), 0.741 (95% CI 0.289-0.922) and 0.876 (95% CI 0.605 0.965) respectively. Median FCal thresholds for remission using endoscopic, histologic, or combined criteria were 71g/g (range 8-624), 91g/g (range 8-858) and 67g/g (range 8-479), respectively. The FCal threshold above which active disease was confirmed was 187g/g for UCEIS (AUC 0.915), 72g/g for Nancy (AUC 0.824) and 187g/g for combined endoscopic and histologic criteria (AUC 0.936). Conclusions: Correlation between FCal and symptoms in UC is weak. In contrast, the correlation between FCal and endoscopic or histological activity is strong. An FCal 72g/g indicates histological inflammation (Nancy 2) and 187g/g indicates endoscopically active disease (UCEIS 4), whether combined with histopathology or not. PMID- 30445627 TI - Morphological Datasets Fit a Common Mechanism Much More Poorly than DNA Sequences and Call Into Question the Mkv Model. AB - The Mkv evolutionary model, based on minor modifications to models of molecular evolution, is being increasingly used to infer phylogenies from discrete morphological data, often producing different results from parsimony. The critical difference between Mkv and parsimony is the assumption of a "common mechanism" in the Mkv model, with branch lengths determining that probability of change for all characters increases or decreases at the same tree branches by the same exponential factor. We evaluate whether the assumption of a common mechanism applies to morphology, by testing the implicit prediction that branch lengths calculated from different subsets of characters will be significantly correlated. Our analysis shows that DNA (38 datasets tested) is often compatible with a common mechanism, but morphology (86 datasets tested) generally is not, showing very disparate branch lengths for different character partitions. The low levels of branch length correlation demonstrated for morphology (fitting models without a common mechanism) suggest that the Mkv model is too unrealistic and inadequate for the analysis of most morphological datasets. PMID- 30445629 TI - The Story of The Science & Entertainment Exchange, a Program of the National Academy of Sciences. AB - SYNOPSIS: Mainstream film and television play a critical role in inspiring public interest in science. It can provide an enticing platform to share scientific information through storytelling. This requires collaboration between storytellers and scientists. However, such opportunities often lie outside the awareness or perceived interest of both filmmakers and scientists. The National Academy of Sciences therefore created The Science & Entertainment Exchange (The Exchange) to serve as a credible conduit to facilitate scientific input on film and television projects. In this paper, we combine Hollywood storytelling with academic research to describe the history, mission, and activity of The Exchange as a model for science engagement with the public. By connecting entertainment professionals to great science communicators, The Exchange aims to improve the science that appears in narrative mainstream media and generate positive portrayals of STEM professionals. Since its launch in 2008, The Exchange has completed more than 2,300 consultations on films such as Avengers: Infinity War, A Wrinkle in Time, and Black Panther. Additionally, the program has produced more than 250 live events, primarily in New York and Los Angeles. Over the course of the program's eight years, it has built a guest list of 6,000 entertainment professionals and scientists and created a database of more than 2,700 science communicators. The Exchange's ongoing work, as well as those of scientists, engineers, and medical professionals who take additional time to work as film and media consultants, improves STEM depictions and brings more science to the public through engaging stories. We discuss the future potential impact of popular media on science literacy and perception, and encourage scientists to embrace opportunities to use popular media to engage the public with science. PMID- 30445628 TI - BRCA1 represses DNA replication initiation through antagonizing estrogen signaling and maintains genome stability in parallel with WEE1-MCM2 signaling during pregnancy. AB - The mammary gland undergoes fast cell proliferation during early pregnancy, yet the mechanism to ensure genome integrity during this highly proliferative stage is largely unknown. We show that pregnancy triggers replicative stresses leading to genetic instability in mice carrying a mammary specific disruption of BRCA1. The fast cell proliferation was correlated with enhanced expression of most genes encoding replisomes, which are positively regulated by estrogen/ERalpha signaling but negatively regulated by BRCA1. Our further analysis revealed two parallel signaling pathways, which are mediated by ATR-CHK1 and WEE1-MCM2, respectively, and are responsible for regulating DNA replication checkpoint. Upon DNA damage, BRCA1 deficiency markedly enhances DNA replication initiation, and preferably impairs DNA replication checkpoint mediated by ATR and CHK1. Meanwhile, DNA damage also activates WEE1-MCM2 signaling, which inhibits DNA replication initiation and enables BRCA1-deficient cells to avoid further genomic instability. Finally, we demonstrated that overriding this defense by WEE1 inhibition in combination with cisplatin, which causes DNA damage, serves as a promising therapeutic approach for killing BRCA1-deficient cancer cells. PMID- 30445630 TI - The soil microbial community of turf: linear and nonlinear changes of taxa and N cycle gene abundances over a century long turf development. AB - Turf, consisting of closely-spaced grasses and the subtending soil, is a unique ecosystem subject to intense management. Yet, soil organic matter accumulates quickly and reaches equilibrium after 20 to 50 years. Resource availability is an important driver of species richness and theoretically their relationship is expected to be unimodal. In this work, we examined the effects of turf development (i.e. 1, 15, 20, and 109 year-old chronosequence) on microbial taxon richness, community composition, and abundances of genes putatively involved in N cycling through 16S rRNA gene and ITS region amplicon sequencing. Microbial alpha diversity remained relatively stable although soil organic C and N increased up to 3 folds over a century long turf development. However, both bacterial and fungal community compositions changed substantially from those in the previous land use, pine stands and along turf development. Youngest turf was closer to the oldest turf than to middle-aged ones, specifically for bacterial community. Microbial changes to resource availability were also taxonomically specific. The relative abundance of Proteobacteria was independent of resource availability; Nitrospirae increased monotonically, and Bacteroidetes, Actinobacteria, and Glomeromycota varied curvilinearly. However, abundances of most taxa from the phylum to OTU level and N-cycle genes varied nonlinearly with turf development. PMID- 30445632 TI - Enhancer deletion and allelic effects define a regulatory molecular mechanism at the VLDLR cholesterol GWAS locus. AB - Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are heritable risk factors for cardiovascular disease, yet the molecular mechanisms underlying the majority of blood lipid-associated GWAS signals remain elusive. One association signal is located in intron 3 of VLDLR; rs3780181-A is a risk allele associated (P<=2x10-9) with increased TC and LDL-C. We investigated variants, genes, and mechanisms underlying this association signal. We used a functional genetic approach to show that the intronic region spanning rs3780181 exhibited 1.6 to 7.6-fold enhancer activity in human HepG2 hepatocyte, THP-1 monocyte, and SGBS preadipocyte cells and that the rs3780181-A risk allele showed significantly less enhancer activity compared to the G-allele, consistent with the direction of an eQTL in liver. In addition, rs3780181 alleles showed differential binding to multiple nuclear proteins, including stronger IRF2 binding to the rs3780181 G-allele. We used a CRISPR-cas9 approach to delete 475 and 663 bp of the putative enhancer element in HEK293T kidney cells; compared to expression of mock-edited cell lines, the homozygous enhancer deletion cell lines showed 1.2-fold significantly (P<0.04) decreased expression of VLDLR, as well as 1.5-fold decreased expression of SMARCA2, located 388 kb away. Together, these results identify an enhancer of VLDLR expression and suggest that altered binding of one or more factors bound to rs3780181 alleles decreases enhancer activity and reduce at least VLDLR expression, leading to increased TC and LDL-C. PMID- 30445631 TI - Recruiting for a pragmatic trial using the electronic health record and patient portal: successes and lessons learned. AB - Objective: Querying electronic health records (EHRs) to find patients meeting study criteria is an efficient method of identifying potential study participants. We aimed to measure the effectiveness of EHR-driven recruitment in the context of ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness)-a pragmatic trial aiming to recruit 15 000 patients. Materials and Methods: We compared the participant yield of 4 recruitment methods: in-clinic recruitment by a research coordinator, letters, direct email, and patient portal messages. Taken together, the latter 2 methods comprised our EHR-driven electronic recruitment workflow. Results: The electronic recruitment workflow sent electronic messages to 12 254 recipients; 13.5% of these recipients visited the study website, and 4.2% enrolled in the study. Letters were sent to 427 recipients; 5.6% visited the study website, and 3.3% enrolled in the study. Coordinators recruited 339 participants in clinic; 23.6% visited the study website, and 16.8% enrolled in the study. Five-hundred-nine of the 580 UNC enrollees (87.8%) were recruited using an electronic method. Discussion: Electronic recruitment reached a wide net of patients, recruited many participants to the study, and resulted in a workflow that can be reused for future studies. In-clinic recruitment saw the highest yield, suggesting that a combination of recruitment methods may be the best approach. Future work should account for demographic skew that may result by recruiting from a pool of patient portal users. Conclusion: The success of electronic recruitment for ADAPTABLE makes this workflow well worth incorporating into an overall recruitment strategy, particularly for a pragmatic trial. PMID- 30445633 TI - Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway. AB - Metformin is a widely used anti-diabetic drug for the management of type 2 diabetes mellitus. Recently, epidemiological studies demonstrate that metformin has anti-cancer effects on esophageal squamous cell carcinoma (ESCC) and other cancers. However, the effects and potential mechanisms of metformin on ESCC remain elusive. In this study, we employed N-nitroso-N-methylbenzylamine (NMBzA), a special carcinogen for esophagi, to develop a rat ESCC model, in which the carcinogenesis progression of ESCC in rat was induced and promoted. We investigated the effects of metformin on carcinogenesis of ESCC in this model. Our results revealed that metformin significantly decreased the incidence and precancerous lesions of ECSS and inhibited proliferation and promoted apoptosis of esophageal epithelial cells in rat treated with NMBzA. Moreover, metformin also increased apoptosis and inhibited migration, colony formation and tumor sphere formation of human ESCC cells in vitro. Immunohistochemistry and Western blotting showed that without interfering the metabolism of NMBzA, metformin inhibited the inflammation of esophagi via reducing the expressions of iNOS, COX 2 and IL-6. Treatment of metformin led to activation of AMP-activated protein kinase (AMPK) and attenuated signaling of the downstream molecules such as p mTOR, p-p70S6K and cyclin D1 expression both in vivo and in vitro. Taken together, our study demonstrated that metformin suppressed the carcinogenesis of ESCC through inhibiting AMPK/mTOR pathway, resulting in its chemo-preventive effects on the carcinogenesis of ESCC. PMID- 30445634 TI - Self-reported Polycystic Ovary Syndrome is Associated with Hypertension: A Northern Finland Birth Cohort 1966 Study. AB - Context: PCOS is associated with many traditional cardiovascular disease risk factors, but it is unclear whether PCOS is an independent risk factor for hypertension. Objective: To investigate in a population-based set-up whether PCOS associates with the risk of hypertension independently of body-mass-index (BMI), and with cardiovascular manifestations. Design: Cross-sectional assessments in the Northern Finland Birth Cohort 1966 at ages 31 and 46. Setting: General community. Participants: Women who reported both oligo/amenorrhea and hirsutism at age 31 and/or diagnosis of PCOS by age 46 (self-reported PCOS [srPCOS], n=279) and women without PCOS symptoms or diagnosis (n=1577). Intervention: None. Main Outcome Measures: Blood pressure (BP), BMI, cardiovascular manifestations. Results: Use of antihypertensive medication was significantly more common in women with srPCOS. At age 31, women with srPCOS had significantly higher systolic (SBP) and diastolic BP (DBP) than control women (SBP: normal-weight: 119.9+/-13.2 vs. 116.9+/-11.4mmHg, P=0.017; overweight/obese: 126.1+/-14.3 vs. 123.0+/ 11.9mmHg, P=0.031; and DBP: normal-weight: 75.5+/-10.0 vs. 72.4+/-9.6mmHg, P=0.003; overweight/obese: 80.7+/-11.8 vs. 78.0+/-10.6mmHg, P=0.031). At age 46, srPCOS was significantly associated with hypertension (AOR=1.56 [1.14-2.13]) independently of BMI, and with higher cardiovascular morbidity (6.8% vs. 3.4%, P=0.011). Hypertensive srPCOS displayed consistent, unfavorable changes in cardiac structure and function compared with controls. Conclusion: Women with srPCOS displayed higher BP compared with controls already at early age and srPCOS was associated with hypertension independently of overweight/obesity. srPCOS was associated with increased cardiovascular morbidity in premenopausal women, suggesting that cardiovascular disease risk factors should be screened and efficiently managed early enough in women with PCOS. PMID- 30445635 TI - Dairy Products Added to Rearing Media Negatively Effect Drosophila melanogaster (Diptera: Drosophilidae) Egg Production and Larval Development. AB - This study examined the effect of kefir, yogurt, and milk on egg production and development in Drosophila melanogaster Meigen. Kefir, yogurt, and milk were added to the Drosophila culture medium. First they were fed to mature individuals and then these females laid eggs on medium containing kefir, yogurt, and milk. Later the development of eggs and larvae was examined. The experiments were conducted on two generations, the F1 generation reared with additives in the media and F2 without the additives. The effects of these substances on the basic stages of development were also examined. In the experimental groups, the numbers of eggs and larvae decreased considerably in both the F1 and F2 generations. The comparison between the experimental groups themselves also showed a difference. In both generations, development of eggs into third instar larvae was reduced and metamorphosis was delayed. In addition, morphological abnormalities were observed in the larvae. Overall the results showed that kefir, yogurt, and milk affected egg and larva development negatively and this negative effect continued in the F2 generation. The continuation of this negative effect in the F2 generation, which was not exposed to various milk additives, is an interesting finding. These results indicate that the nutrients from the milk and the milk products used were neither utilized by nor beneficial for this insect. PMID- 30445636 TI - Survival and Fecundity Parameters of Two Drosophila suzukii (Diptera: Drosophilidae) Morphs on Variable Diet Under Suboptimal Temperatures. AB - Life history parameters are used to estimate population dynamics, mortality, and reproduction in insects relative to their surrounding environment. For Drosophila suzukii Matsumura (Diptera: Drosophilidae), an invasive agricultural pest, previous studies have estimated net reproductive rate (Ro), generation time (T), and intrinsic rate of population increase (rm). A main limitation is that these estimates were measured under relatively favorable settings, and do not reflect environmental conditions and physiological states encountered during dormancy periods. Therefore, this study investigated the impacts of 1) low temperatures and 2) dietary protein: carbohydrate ratios (P:C) on both survival and fecundity parameters of D. suzukii summer morphs (SM) and postoverwintering winter morphs (WM) over physiological age (degree-days, DD). In both morphs, reproductive rates were higher and lifespan was longer when flies were exposed to low protein (P:C 1:4) or carbohydrate-only diets (P:C 0:1) compared with high protein diets (P:C 1:1). WM had higher reproductive rates and longer generation times than SM on optimal 1:4 diet in all trialed temperatures, but at the lowest temperatures, SM had higher reproductive rates than WM in carbohydrate-only and high protein diets. This likely reflected delayed oogenesis and hindered reproduction after an overwintering period in WM receiving suboptimal diets. Oviposition for SM and WM receiving 1:4 diet commenced from 0 to 100 DD, and peaked between 400 and 500 DD, earlier than flies receiving 0:1 diet. These results suggest that dietary protein has a crucial role in early oogenesis, particularly for postoverwintering WM. The parameters developed here reflect the population dynamics of D. suzukii before and after the crop growing season, an essential time for population buildup, survival, and early and late host infestation. PMID- 30445638 TI - Intentional transcatheter laceration of the coronary cusp to prevent left main stem obstruction during transcatheter aortic valve implantation: first European experience with the BASILICA technique in a native aortic valve. PMID- 30445639 TI - Delivering information about medication assisted treatment to individuals who misuse opioids through a mobile app: a pilot study. AB - Background: Digital therapeutic tools (e.g. mobile applications) can be accessible, low-cost interventions that counter misconceptions about medication assisted treatment (MAT) and/or improve deficits in MAT knowledge that are common barriers to treatment entry among individuals with opioid dependence. The purpose of this pilot study was to examine the preliminary effectiveness of a mobile application, 'uMAT-R', that includes health information about OUD recovery supported by science and MAT benefits. Methods: Twenty-six adult participants with OUD recruited via social media completed all modules and pre/post assessments within uMAT-R. McNemar's test was used to compare interest in treatment before and after completing the app, and paired t tests were used to compare MAT attitude scores before and after completing the modules within uMAT R. Results: Before viewing uMAT-R, 32% agreed/strongly agreed that they were interested in starting treatment to recover from opioid misuse, compared to 48% after completing uMAT-R. The average scores on the MAT attitudes scale and its Aid to Behavior Change subscale improved from before to after viewing uMAT-R. Among the participants, 88% felt that uMAT-R would be useful to consult when making decisions about recovery. Conclusions: Our encouraging pilot findings support the use of uMAT-R to help address the current opioid epidemic. PMID- 30445641 TI - The ahpD gene of Corynebacterium glutamicum plays an important role in hydrogen peroxide-induced oxidative stress response. AB - In this study, we analyzed the ahpD gene from Corynebacterium glutamicum, which may function in a H2O2-mediated stress responses. Cells overexpressing C. glutamicum ahpD (P180-ahpD) showed increased sensitivity to H2O2 when exposed to the latter in concentrations of 8 mM or greater while showing reduced expression of katA, which encodes catalase. On the other hand, cells that lack ahpD (DeltaahpD) displayed increased sensitivity when exposed to low levels of H2O2 while showing katA transcription that was comparable to the level in the wild type strain. Accordingly, transcription of ahpD and katA was stimulated by low and high concentration of H2O2, respectively. Further, the NAD+/NADH ratio was severely reduced in the DeltaahpD (3.03) and P180-ahpD (0.47) strains as compared to that in the wild-type (4.55) strain. Transcriptional analysis indicated that ahpD and upstream genes such as cg2675, cg2676, cg2677, and cg2678, which were annotated as ABC-type transporter, were organized into an operon. Collectively, these findings indicate that C. glutamicum possesses bi-level defense pathways against hydrogen peroxide, involving katA and ahpD. Further, ahpD, along with cg2675-cg2678 genes, may play a novel role in cellular activities against oxidative stress. PMID- 30445637 TI - Endogenous single-strand DNA breaks at RNA polymerase II promoters in Saccharomyces cerevisiae. AB - Molecular combing and gel electrophoretic studies revealed endogenous nicks with free 3'OH ends at ~100 kb intervals in the genomic DNA (gDNA) of unperturbed and G1-synchronized Saccharomyces cerevisiae cells. Analysis of the distribution of endogenous nicks by Nick ChIP-chip indicated that these breaks accumulated at active RNA polymerase II (RNAP II) promoters, reminiscent of the promoter proximal transient DNA breaks of higher eukaryotes. Similar periodicity of endogenous nicks was found within the ribosomal rDNA cluster, involving every ~10th of the tandemly repeated 9.1 kb units of identical sequence. Nicks were mapped by Southern blotting to a few narrow regions within the affected units. Three of them were overlapping the RNAP II promoters, while the ARS-containing IGS2 region was spared of nicks. By using a highly sensitive reverse-Southwestern blot method to map free DNA ends with 3'OH, nicks were shown to be distinct from other known rDNA breaks and linked to the regulation of rDNA silencing. Nicks in rDNA and the rest of the genome were typically found at the ends of combed DNA molecules, occasionally together with R-loops, comprising a major pool of vulnerable sites that are connected with transcriptional regulation. PMID- 30445640 TI - Cytonuclear coevolution following homoploid hybrid speciation in Aegilops tauschii. AB - The diploid D-genome lineage of the Triticum/Aegilops complex has an evolutionary history involving genomic contributions from ancient A- and B/S-genome species. We explored here the possible cytonuclear evolutionary responses to this history of hybridization. Phylogenetic analysis of chloroplast DNAs indicate that the D genome lineage has a maternal origin of the A-genome or some other closely allied lineage. Analyses of the nuclear genome in the D-genome species Aegilops tauschii indicate that accompanying and/or following this ancient hybridization, there has been biased maintenance of maternal A-genome ancestry in nuclear genes encoding cytonuclear enzyme complexes (CECs). Our study provides insights into mechanisms of cytonuclear coevolution accompanying the evolution and eventual stabilization of homoploid hybrid species. We suggest that this coevolutionary process includes likely rapid fixation of A-genome CEC orthologs as well as biased retention of A genome nucleotides in CEC homologs following population level recombination during the initial generations. PMID- 30445642 TI - Unique mechanism of target recognition by PfoI restriction endonuclease of the CCGG-family. AB - Restriction endonucleases (REs) of the CCGG-family recognize a set of 4-8 bp target sequences that share a common CCGG or CCNGG core and possess PD...D/ExK nuclease fold. REs that interact with 5 bp sequence 5'-CCNGG flip the central N nucleotides and 'compress' the bound DNA to stack the inner base pairs to mimic the CCGG sequence. PfoI belongs to the CCGG-family and cleaves the 7 bp sequence 5'-T|CCNGGA ("|" designates cleavage position). We present here crystal structures of PfoI in free and DNA-bound forms that show unique active site arrangement and mechanism of sequence recognition. Structures and mutagenesis indicate that PfoI features a permuted E...ExD...K active site that differs from the consensus motif characteristic to other family members. Although PfoI also flips the central N nucleotides of the target sequence it does not 'compress' the bound DNA. Instead, PfoI induces a drastic change in DNA backbone conformation that shortens the distance between scissile phosphates to match that in the unperturbed CCGG sequence. Our data demonstrate the diversity and versatility of structural mechanisms employed by restriction enzymes for recognition of related DNA sequences. PMID- 30445643 TI - CHALLENGES IN CLINICAL PRACTICE OF CR MAMMOGRAPHY IN TANZANIA. AB - The aim of this study was to evaluate the clinical practice of CR mammography in Tanzania. The equipment performance and operational conditions were studied; and mean glandular dose (DG) estimated to 75 women undergoing diagnosis at three mammography facilities. All mammograms during this study were reported to be useful for the intended diagnosis. The median DG for craniocaudal and mediolateral oblique projections ranged from 1.27 +/- 0.18 mGy to 1.9 +/- 0.27 mGy and from 1.3 +/- 0.18 mGy to 1.9 +/- 0.27 mGy, respectively, and were below the national regulatory guidance of 2.5 mGy. Despite this positive result, unavoidable inappropriate use of beam quality and tube loading settings which could have been through appropriate staff training and performing routine quality control were not uncommon. This work provides an insight of current operational conditions of CR in Tanzania and what strategy should be employed to this service to improve patient care in the country. PMID- 30445644 TI - Efficacy of a free-play intervention to increase physical activity during childcare: a randomized controlled trial. AB - The primary aim of this study was to assess the efficacy of a childcare-based intervention in increasing child physical activity by allowing children unrestricted access to outdoor areas for free-play when structured activity is not taking place. A randomized controlled trial was conducted in six childcare services. Intervention services provided children unrestricted access outdoors for active free-play, while control services provided their usual scheduled periods of outdoor play. Consent was obtained from 231 children. Child moderate to vigorous activity (MVPA), the primary trial outcome, was assessed via accelerometer at baseline and 3 months post baseline. Intervention effects were examined using Generalised Linear Mixed Models. Controlling for child age, gender and baseline outcome measure, at follow-up there were no significant differences between groups in minutes of MVPA in-care (mean difference: 4.85; 95% CI: -3.96, 13.66; P = 0.28), proportion of wear time in-care spent in MVPA (mean difference: 1.52%; 95% CI: -0.50, 3.53; P = 0.14) or total physical activity in-care (mean difference in counts per minute: 23.18; 95% CI: -4.26, 50.61; P = 0.10), nor on measures of child cognition (P = 0.45-0.91). It was concluded that interventions addressing multiple aspects of the childcare and home environment might provide the greatest potential to improve child physical activity. PMID- 30445645 TI - OMIM.org: leveraging knowledge across phenotype-gene relationships. AB - For over 50 years Mendelian Inheritance in Man has chronicled the collective knowledge of the field of medical genetics. It initially cataloged the known X linked, autosomal recessive and autosomal dominant inherited disorders, but grew to be the primary repository of curated information on both genes and genetic phenotypes and the relationships between them. Each phenotype and gene is given a separate entry assigned a stable, unique identifier. The entries contain structured summaries of new and important information based on expert review of the biomedical literature. OMIM.org provides interactive access to the knowledge repository, including genomic coordinate searches of the gene map, views of genetic heterogeneity of phenotypes in Phenotypic Series, and side-by-side comparisons of clinical synopses. OMIM.org also supports computational queries via a robust API. All entries have extensive targeted links to other genomic resources and additional references. Updates to OMIM can be found on the update list or followed through the MIMmatch service. Updated user guides and tutorials are available on the website. As of September 2018, OMIM had over 24,600 entries, and the OMIM Morbid Map Scorecard had 6,259 molecularized phenotypes connected to 3,961 genes. PMID- 30445646 TI - Presence of Histopathological Treatment Effects at Resection of Recurrent Glioblastoma: Incidence and Effect on Outcome. AB - BACKGROUND: Resection may be appropriate for select patients with recurrent glioblastoma. The incidence of histopathological findings related to prior treatment and their prognostic implications are incompletely characterized. OBJECTIVE: To quantify the incidence and survival outcomes associated with treatment effect at resection of recurrent glioblastoma (GBM). METHODS: Patients who underwent resection for recurrent GBM were retrospectively reviewed, and pathology, treatment history, and survival data were collected. Treatment effect was defined as any component of treatment-related changes on pathology. RESULTS: In total, 110 patients underwent 146 reoperations. Median age at first reoperation was 57.2 yr and overall survival from reoperation was 10.8 mo. Treatment effect of any kind was noted in 81 of 146 reoperations (55%). Increased treatment effect was observed closer to radiotherapy; by quartile of time from radiotherapy, the rates of treatment effect were 77.8%, 55.6%, 40.7%, and 44.4% (P = .028). Treatment effect was associated with earlier reoperation (8.9 vs 13.8 mo after radiotherapy, P = .003), and the presence of treatment effect did not impact survival from primary surgery (25.4 vs 24.3 mo, P = .084). Patients treated with bevacizumab prior to reoperation were less likely to have treatment effect (20% vs 65%, P < .001). CONCLUSION: Histopathological treatment-related changes are evident in a majority of patients undergoing resection for recurrent glioblastoma. There was no association of treatment effect with overall survival from primary surgery. PMID- 30445647 TI - Preventing Rabies: The New WHO Recommendations and Their Impact on Travel Medicine Practice. PMID- 30445648 TI - Impacts of a web-based educational program for veterans who read their mental health notes online. AB - Objective: This study evaluates whether a web-based educational program for patients who read their mental health notes online improves patient-clinician communication and increases patient activation. Methods: The web-based educational program, developed with end-user input, was designed to educate patients on the content of mental health notes, provide guidance on communicating with clinicians about notes, and facilitate patients' safe and purposeful use of their health information. Eligible patients were engaged in mental health treatment (>=1 visit in the prior 6 months) and had logged into the Veterans Health Administration (VHA) patient portal at least twice. Participants completed measures of patient activation, perceived efficacy in healthcare interactions, patient trust in their clinicians, and patient assessment of the therapeutic relationship before and after participating in the program. A total of 247 participants had complete data and engaged with the program for 5 minutes or more, comprising the analytic sample. Multivariate analysis using mixed effects models were used to examine pre-post changes in outcomes. Results: In bivariate analyses, patient activation, perceived efficacy in healthcare interactions, and trust in clinicians increased significantly between pre- and post-training assessments. In fully adjusted models, changes in patient activation [b = 2.71 (1.41, 4.00), P < 0.01] and perceived efficacy in healthcare interactions [b = 1.27 (0.54, 2.01), P < 0.01)] remained significant. Conclusions: Findings suggest that this educational program may help empower mental health patients who read their notes online to be active participants in their care, while also providing information and tools that may facilitate better relationships with their clinicians. PMID- 30445649 TI - True Homoplasy of Retrotransposon Insertions in Primates. AB - How reliable are the presence/absence insertion patterns of the supposedly homoplasy-free retrotransposons, that were randomly inserted in the quasi infinite genomic space? To systematically examine this question in an up-to-date, multi-genome comparison, we screened millions of primate transposed Alu SINE elements for incidences of homoplasious precise insertions and deletions. In genome-wide analyses, we identified and manually verified nine cases of precise parallel Alu insertions of apparently identical elements at orthologous positions in two ape lineages and twelve incidences of precise deletions of previously established SINEs. Correspondingly, eight precise parallel insertions and no exact deletions were detected in a comparison of lemuriform primate and human insertions spanning the range of primate diversity. With an overall frequency of homoplasious Alu insertions of only 0.01% (for human-chimpanzee-rhesus macaque) and 0.02-0.04% (for human-bushbaby-lemurs) and precise Alu deletions of 0.001 0.002% (for human-chimpanzee-rhesus macaque), real homoplasy is not considered to be a quantitatively relevant source of evolutionary noise. Thus, presence/absence patterns of Alu retrotransposons and, presumably, all LINE1-mobilized elements represent indeed the virtually homoplasy-free markers they are considered to be. Therefore, ancestral incomplete lineage sorting and hybridization remain the only serious sources of conflicting presence/absence patterns of retrotransposon insertions, and as such are detectable and quantifiable. PMID- 30445650 TI - NMR solution structure of an asymmetric intermolecular leaped V-shape G quadruplex: selective recognition of the d(G2NG3NG4) sequence motif by a short linear G-rich DNA probe. AB - Aside from classical loops among G-quadruplexes, the unique leaped V-shape scaffold spans over three G-tetrads, without any intervening residues. This scaffold enables a sharp reversal of two adjacent strand directions and simultaneously participates in forming the G-tetrad core. These features make this scaffold itself distinctive and thus an essentially more accessible target. As an alternative to the conventional antisense method using a complementary chain, forming an intermolecular G-quadruplex from two different oligomers, in which the longer one as the target is captured by a short G-rich fragment, could be helpful for recognizing G-rich sequences and structural motifs. However, such an intermolecular leaped V-shape G-quadruplex consisting of DNA oligomers of quite different lengths has not been evaluated. Here, we present the first nuclear magnetic resonance (NMR) study of an asymmetric intermolecular leaped V shape G-quadruplex assembled between an Oxytricha nova telomeric sequence d(G2T4G4T4G4) and a single G-tract fragment d(TG4A). Furthermore, we explored the selectivity of this short fragment as a potential probe, examined the kinetic discrimination for probing a specific mutant, and proposed the key sequence motif d(G2NG3NG4) essential for building the leaped V-shape G-quadruplexes. PMID- 30445651 TI - Androgen Receptor Expression and Breast Cancer Survival: Results From the Nurses' Health Studies. AB - Background: Hormone receptor signaling is critical in the progression of breast cancers, although the role of the androgen receptor (AR) remains unclear, particularly for estrogen receptor (ER)-negative tumors. This study assessed AR protein expression as a prognostic marker for breast cancer mortality. Methods: This study included 4147 pre- and postmenopausal women with invasive breast cancer from the Nurses' Health Study (diagnosed 1976-2008) and Nurses' Health Study II (1989-2008) cohorts. AR protein expression was evaluated by immunohistochemistry and scored through pathologist review and as a digitally quantified continuous measure. Hazard ratios (HR) and 95% confidence intervals (CI) of breast cancer mortality were estimated from Cox proportional hazards models, adjusting for patient, tumor, and treatment covariates. Results: Over a median 16.5 years of follow-up, there were 806 deaths due to breast cancer. In the 7 years following diagnosis, AR expression was associated with a 27% reduction in breast cancer mortality overall (multivariable HR = 0.73, 95% CI = 0.58 to 0.91) a 47% reduction for ER+ cancers (HR = 0.53, 95% CI = 0.41 to 0.69), and a 62% increase for ER- cancers (HR = 1.62, 95% CI = 1.18 to 2.22) (P heterogeneity < .001). A log-linear association was observed between AR expression and breast cancer mortality among ER- cancers (HR = 1.14, 95% CI = 1.02 to 1.26 per each 10% increase in AR), although no log-linear association was observed among ER+ cancers. Conclusions: AR expression was associated with improved prognosis in ER+ tumors and worse prognosis in ER- tumors in the first 5 10 years postdiagnosis. These findings support the continued evaluation of AR targeted therapies for AR+/ER- breast cancers. PMID- 30445652 TI - Perceived barriers and facilitators in the assessment of occupational diseases. AB - Background: Information is collected worldwide on the diagnosis and assessment of occupational diseases (ODs) by occupational physicians (OPs). However, information on perceived facilitators and barriers to assessment is scarce. Aims: To evaluate the perceived barriers and facilitators in the assessment of ODs by OPs. Methods: We conducted a qualitative study, using interviews and focus groups. We held 12 interviews and two focus groups with Dutch OPs, to identify barriers and facilitators in the assessment of ODs. Results: Case definition, exposure assessment, attribution to work, guidelines and decision tools, external expertise, individual motivation and consequences were identified as themes. Barriers and facilitators were mainly reported regarding assessing work attribution, e.g. how to assess multifactorial causes or the need for training, and individual motivation such as the perceived lack of usefulness or the need for monitoring suspected OD cases. Within the theme of consequences, only barriers to the assessment of ODs were reported, including the liability of employers. Conclusions: Perceived facilitators in the assessment of ODs were practical assessment tools, multifaceted education, ability to assess work exposures and professional independence. Perceived barriers were lack of usefulness, lack of urgency, complexity of assessment and concerns about liability issues. PMID- 30445653 TI - Fatigue risk management systems needed in healthcare. PMID- 30445654 TI - The psychological and physiological health effects of fatigue. AB - Background: The issue of employee fatigue is becoming increasingly prominent, particularly in safety-critical industries. Aims: To produce an in-depth review collating the known psychological and physiological health and work effects of fatigue to guide mitigation strategies in safety-critical industries. Methods: Literature searches were conducted via scientific databases using appropriate filters and keywords. The available results were collated into a review and commentary. Results: Decreased sleep duration and chronodisruption have been shown to cause both significant morbidity and mortality. There is a large body of evidence showing strong associations between fatigue, reduced cognition and occupational accidents, as well as increased metabolic and reproductive health sequelae, some forms of cancer and mortality. Additional evidence links fatigue with mental, gastrointestinal, neurological and chronic pain sequelae. Conclusions: Fatigue risk mitigation strategies should be implemented, not only to reduce these short- and long-term health risks in employees of safety-critical industries, but also to create more efficient, productive and effective workplace personnel with longer and more fulfilling careers. This requires improved acute fatigue mitigation, as well as the prevention of cumulative fatigue build-up and the formation of acute-on-chronic fatigue. The health recommendations for fatigue mitigation outlined in this paper are pertinent to all professions where employees have high rates of both acute and chronic fatigue. PMID- 30445655 TI - Severe learning disabilities and consent. PMID- 30445656 TI - ANALYSIS OF THE RADIOLOGICAL SAFETY CONTROL LEVEL VERSUS THE EXPOSURE OF RADIATION WORKERS IN SOUTH KOREA FROM 2008-17. AB - In this study, the radiation exposure of workers at workplaces registered and licensed between 2008 and 2017 for the production/sale/use of radioactive isotopes (RI) and radioactive generators (RG) was analysed to evaluate the quality of radiation safety management controls in use. The number of facilities using RIs increased by ~26% from 2008 to 2017 whereas the number of facilities using RGs increased by ~166% over the same period. There were 33 029 radiation workers in all fields in 2008, and the number increased by ~32% to 43 467 by 2017. However, the collective effective dose of radiation received by workers decreased in all industries except for those working in nuclear power plants. In other words, the quality of radiation safety management improved over that same time period due to the systematic, continuous introduction of safety mechanisms by the regulatory authority. PMID- 30445657 TI - The European Bioinformatics Institute in 2018: tools, infrastructure and training. AB - The European Bioinformatics Institute (https://www.ebi.ac.uk/) archives, curates and analyses life sciences data produced by researchers throughout the world, and makes these data available for re-use globally (https://www.ebi.ac.uk/). Data volumes continue to grow exponentially: total raw storage capacity now exceeds 160 petabytes, and we manage these increasing data flows while maintaining the quality of our services. This year we have improved the efficiency of our computational infrastructure and doubled the bandwidth of our connection to the worldwide web. We report two new data resources, the Single Cell Expression Atlas (https://www.ebi.ac.uk/gxa/sc/), which is a component of the Expression Atlas; and the PDBe-Knowledgebase (https://www.ebi.ac.uk/pdbe/pdbe-kb), which collates functional annotations and predictions for structure data in the Protein Data Bank. Additionally, Europe PMC (http://europepmc.org/) has added preprint abstracts to its search results, supplementing results from peer-reviewed publications. EMBL-EBI maintains over 150 analytical bioinformatics tools that complement our data resources. We make these tools available for users through a web interface as well as programmatically using application programming interfaces, whilst ensuring the latest versions are available for our users. Our training team, with support from all of our staff, continued to provide on-site, off-site and web-based training opportunities for thousands of researchers worldwide this year. PMID- 30445658 TI - Postoperative Cervical Sagittal Realignment Improves Patient-Reported Outcomes in Chronic Atlantoaxial Anterior Dislocation. AB - BACKGROUND: Chronic atlantoaxial anterior dislocation (AAD) not only results in myelopathy, but dislocation-related kyphosis also results in cervical malalignment, which permanently affects neck function and patient-reported outcomes (PROs). OBJECTIVE: To investigate the effect of kyphotic correction on realigning cervical spine and independent cervical alignment parameters, which may be correlated with an improvement of PROs. METHODS: The study included 21 patients with chronic AAD-related kyphosis who underwent C1-2 reduction and correction surgery. Radiographic parameters were measured to assess cervical realignment preoperatively and postoperatively. Neck disability index (NDI), short form 12 physical component summary (SF-12 PCS), and Japanese Orthopaedic Association (JOA) scores were recorded to reveal changes in PROs. The independent parameters correlated with the improvements of PROs were analyzed. RESULTS: Of the radiographic parameters, the C1-2 Cobb angle, the C2-7 Cobb angle, thoracic inlet angle, cervical tilt, and T1 slope were significantly changed from -4.0 degrees +/- 16.2 degrees , -29.2 degrees +/- 11.2 degrees , 73.1 degrees +/- 13.3 degrees , 30.4 degrees +/- 8.5 degrees , and 29.1 degrees +/- 8.8 degrees preoperatively to -13.5 degrees +/- 8.1 degrees (P = .005), -18.0 degrees +/- 12.0 degrees (P < .001), 67.1 degrees +/- 11.6 degrees (P = .042), 23.1 degrees +/- 10.3 degrees (P = .007), and 24.0 degrees +/- 7.0 degrees (P = .011) at last follow-up, respectively. NDI, JOA, and SF-12 PCS scores were significantly improved postoperatively. The C1-2 Cobb angle was an independent parameter correlated with the improvements in SF-12 PCS, NDI, and JOA scores. CONCLUSION: Correction and reduction surgery can realign cervical spine in chronic AAD patients. The C1-2 Cobb angle was an independent parameter correlated with the improvements of PROs. PMID- 30445659 TI - Cerebrovascular Operative Anatomy: An Immersive 3D and Virtual Reality Description. AB - BACKGROUND: The innate detail of the cerebrovasculature is a demonstration of the structural complexity exhibited within the nervous system and highlights the challenges intrinsic to surgically influencing this system. Bridging the knowledge gap between the 2-dimentional learning environment and the 3 dimensional (3D) clinical setting is a challenge requiring experience. Computer graphic technology provides an opportunity for the learner to step into a new era of learning via the use of interactive 3D models and virtual reality. OBJECTIVE: To create virtually anatomically accurate cerebrovascular models with superior detail and visual appeal. METHODS: High-resolution angiographic radiological studies were utilized to create virtual 3D models which were edited for anatomical accuracy and artistry post-processing. RESULTS: We have created anatomically realistic and detailed 3D virtual models of the cerebrovascular structures including the arterial and venous systems. The relevant surgical anatomy of the bony and brain structures was also included. In addition, these models were used to illustrate the pathoanatomy of a deep vascular malformation to demonstrate the potential of this technology. These models allow user interactivity in the 3D environment for improved understanding of anatomical relationships. CONCLUSION: Advances in computer graphics have invited a new era of education and experiential learning. The authors have created an immersive virtual 3D model of the cerebrovasculature to augment education, research, and clinical applications. PMID- 30445660 TI - Letter: Microsurgical Anatomy of the Vertical Rami of the Superior Longitudinal Fasciculus: An Intraparietal Sulcus Dissection Study. PMID- 30445661 TI - The involvement of microglia in Alzheimer's disease: a new dog in the fight. AB - First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such central nervous system (CNS) cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in the disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. PMID- 30445662 TI - Macrophage functions in wound healing. AB - Macrophages play a crucial role in regeneration and consecutive phases of wound healing. In this review we summarize current knowledge on the ontogeny, origin, phenotypical heterogeneity and functional exchangeability of macrophages participating in these processes. We also describe the genetic, pharmacologic and bioengineering methods for manipulation of macrophage phenotype and functions and their potential for development of the novel, clinically applicable, therapies. PMID- 30445663 TI - Understanding the growing epidemic of type 2 diabetes in the Hispanic population living in the United States. AB - The prevalence and incidence of type 2 diabetes (T2D) among the Hispanic population in the United States are higher than the national average. This is partly due to sociocultural factors, such as lower income and decreased access to education and health care, as well as a genetic susceptibility to obesity and higher insulin resistance. This review focuses on understanding the Hispanic population living in the United States from a multidisciplinary approach and underlines the importance of cultural, social, and biological factors in determining the increased risk of T2D in this population. An overview of the acute and chronic complications of T2D upon this population is included, which is of paramount importance to understand the toll that diabetes has upon this population, the health system, and society as a whole. Specific interventions directed to the Hispanic populations are needed to prevent and alleviate some of the burdens of T2D. Different prevention strategies based on medications, lifestyle modifications, and educational programmes are discussed herein. Diabetes self-management education (DSME) is a critical element of care of all people with diabetes and is considered necessary to improve patient outcomes. To be more effective, programmes should take into consideration cultural factors that influence the development and progression of diabetes. These interventions aim to enhance long-term effects by reducing the incidence, morbidity, and mortality of T2D in the Hispanic population of the United States. PMID- 30445664 TI - Substitution Reactions of Gaseous Ions in a Three-Dimensional Quadrupole Ion Trap. AB - Substitution reactions between gaseous ions and neutral substrate molecules are of ongoing high interest. To investigate these processes in a qualitative and quantitative manner, we have constructed a device, with which a defined amount of a volatile substrate can be mixed with a defined amount of helium gas and added into a three-dimensional quadrupole ion trap. From the known inner volume of the device, the known ratio nsubstrate :nHe of the mixture, and the determined absolute partial pressure of helium in the ion trap, we can derive the partial pressure of the substrate in the ion trap and, thus, convert the directly observable pseudo-first order rate constants of the substitution reactions into absolute bimolecular rate constants. We have tested the device by investigating a series of SN 2 reactions of Br- and CF3 CH2 O- anions as well as ligand exchange reactions of ligated Na+ cations. As the obtained results suggest, the described device makes it possible to determine the bimolecular rate constants of substitution reactions as well as other ion-molecule reactions with satisfactory accuracy and reliability. PMID- 30445665 TI - Molecular mechanism of enzyme tolerance against organic solvents: Insights from molecular dynamics simulation. AB - Biocatalysis in presence of organic solvents has numerous industrially attractive advantages in comparison to traditional aqueous solvents. In some cases, the presence of organic molecules such as methanol in the processes such as enzymatic production of biodiesel is inevitable. However, enzyme inactivation and/or instability in organic solvents limits such biotechnological processes. Although it was found that some enzymes are more and others are less tolerant against organic solvents, the structural basis of such differences is relatively unknown. In this work, using molecular dynamics simulations, we have investigated the structural behavior of enzymes with completely different structural architecture including lipase, laccase and lysozyme in the presence of methanol as polar and hexane as non-polar organic solvents. In agreement with the previous experimental observations, simulations showed that lipase is more tolerant against both polar and non-polar organic solvents. It is found that lipase has high stability in pure hexane even higher than that obtained in the aqueous solvent. In contrast, laccase shows better stability in the aqueous conditions. To obtain general mechanism of enzyme inactivation in the presence of methanol and hexane, we have treated lysozyme as model enzyme in the different percentages of these solvents in long MD simulations. It is found that lysozyme is completely denatured at high concentration- of methanol, but it remains native at low concentration of this solvent. Interestingly, the concentration-dependence structural behavior of enzyme was completely different in the presence of hexane. It was obtained that low concentrations of hexane may impose more instability on the enzyme conformation than higher percentages. Results also showed that presence of water is determining factor in the enzyme stability at high concentrations of hexane. Pure hexane may also lead to the surface denaturation of the enzymes. Both methanol and hexane denaturation mechanisms were initiated by diffusion of organic solvent in hydrophobic core. However, enzyme denaturation in hexane was continued by a collapse of hydrophobic core and entering hexane molecules to the core, but in methanol it was completed by decomposition of the secondary structures. In both cases it was found that beta structures are more prone to destabilize than helix structures. This may be a reason for obtained results about lower stability of laccase with beta-barrel architecture than lipase with multiple helixes at it surface. In total, by our extensive structural data, it was found that the forces which stabilize tertiary structure have pivotal role in enzyme tolerance against both polar and non-polar organic solvents. PMID- 30445666 TI - Transcriptome analysis of immune response in fat greenling (Hexagrammos otakii) against Vibrio harveyi infection. AB - Fat greenling (Hexagrammos otakii) is an important aquaculture fish species in northern China. Unfortunately, Vibrio infections have caused considerable losses to the fat greenling aquaculture industry. However, the study on immune response of fat greenling against Vibrio species has not been reported yet. In this paper, the immune response of fat greenling against V. harveyi at gene expression level was studied by transcriptome analysis. A total of 189753 high-quality unigenes with a N50 length of 672bp were obtained by transcriptome profiling, which provided abundant data for the future study of fat greenling. Comparative analysis showed that 5425 differentially expressed genes (DEGs) were identified on day 3 post-infection (3dpi), containing 1837 up-regulated and 3588 down regulated genes. Further annotation and analysis revealed that the DEGs were enriched in complement and coagulation cascades, ribosome, oxidative phosphorylation, glycine, serine and threonine metabolism and peroxisome proliferator-activated receptor (PPAR) signaling pathway. These pathways were mainly associated with phagocytosis and pathogen clearance, rarely involved in bacteria adhesion and pathogen identification, which suggested that the host might begin to clear and kill the invading bacteria on 3dpi. The research might provide a valuable resource to further study immune response and suggest strategies against V. harveyi infection in fat greenling. PMID- 30445667 TI - Oral yeast-based DNA vaccine confers effective protection from Aeromonas hydrophila infection on Carassius auratus. AB - Our previous study has demonstrated that recombinant yeast can induce specific immune responses in Carassius auratus and may serve as a potential carrier for oral DNA vaccines in aquaculture. In this study, we further developed an effective yeast-based oral DNA vaccine against the bacteria Aeromonas hydrophila, which was expected to provide protection from the motile aeromonad septicemia (MAS). First, two candidate antigen genes, ompG and omp48, were cloned from the Aeromonas hydrophila genome DNA. Then, relative yeast-eukaryote shuttle vectors were constructed and their expression in eukaryotes was validated. Next, crucian carps were orally administered with ompG or omp48 recombinant yeast, and the expression of the genes in the intestinal mucosa was confirmed by immunohistochemistry (IHC). The specific immune responses were further detected by Western blot and enzyme-linked immunosorbent assay (ELISA). The ELISA results showed that the production of the OVA-specific antibody in the OVA-ompG group was significantly higher than that of the OVA-omp48 group, indicating that the OVA ompG group elicited obviously stronger immune response than OVA-omp48. Finally, the challenge experiment against Aeromonas hydrophila infection demonstrated decreased fish mortality rate after the oral administration of the OVA-ompG yeast vaccine. In conclusion, our work provided a framework for the further development of oral yeast-based fishery vaccines. PMID- 30445668 TI - Chitosan Oleate Salt as an Amphiphilic Polymer for the Surface Modification of Poly-Lactic-Glycolic Acid (PLGA) Nanoparticles. Preliminary Studies of Mucoadhesion and Cell Interaction Properties. AB - Most of the methods of poly-lactic-glycolic acid (PLGA) preparation involve the passage through the emulsification of a PLGA organic solution in water followed by solvent evaporation or extraction. The choice of the droplet stabilizer during the emulsion step is critical for the dimensions and the surface characteristics of the nanoparticles (NPs). In the present work, a recently described ionic amphiphilic chitosan derivative, chitosan oleate salt (CS-OA), was proposed for the first time to prepare PLGA NPs. A full factorial design was used to understand the effect of some formulation and preparation parameters on the NP dimensions and on encapsulation efficiency (EE%) of Nile red, used as a tracer. On the basis of the DoE study, curcumin loaded NPs were prepared, having 329 +/- 42 nm dimensions and 68.75% EE%. The presence of a chitosan coating at the surface was confirmed by positive zeta potential and resulted in mucoadhesion behavior. The expected improvement of the interaction of the chitosan surface modified nanoparticles with cell membrane surface was confirmed in Caco-2 cell culture by the internalization of the loaded curcumin. PMID- 30445669 TI - Chinese Sexual Minority Male Adolescents' Suicidality and Body Mass Index. AB - Excess weight status may increase the risk of suicidality among sexual minority females, but few studies have examined this suicidality disparity in sexual minority males. This study examined the association between sexual minority status and suicide attempts in Chinese male adolescents and tested whether body mass index (BMI) had a moderating effect on that association. Data were collected from 7th to 12th graders from seven randomly selected provinces of China in the 2015 School-Based Chinese Adolescents Health Survey. In total, 72,409 male students completed the questionnaires regarding sexual attraction, self-reported weight and height, and suicide attempts. After adjustment for covariates, sexual minority status was associated with suicide attempts among male students (AOR = 1.74, 95% CI = 1.57-1.93). Stratification analyses showed that BMI category moderated this association; compared with the results before stratification analyses, sexual minority males who were obese had increased risk of suicide attempts (AOR = 2.15, 95% CI = 1.09-4.24), sexual minority males who were overweight had reduced odds of suicide attempts (AOR = 1.40, 95% CI = 1.01-1.92), and no significant association change was found in sexual minority males who were underweight (AOR = 1.82, 95% CI = 1.43-2.33). Our study indicated that BMI moderated the risk of suicide attempts in sexual minority males. Suicide prevention targeting sexual minority males should be focused on weight status disparity and the creation of a positive climate to reduce minority stressors due to body image. PMID- 30445670 TI - Alkali-Silica Reactivity of High Density Aggregates for Radiation Shielding Concrete. AB - Long-term exposure of concrete to nuclear reactor environments may enhance the ageing phenomena. An investigation concerning a possible deleterious alkali silica reaction (ASR) in concrete containing high-density aggregates is presented in this paper. The scope of this investigation was limited to heavy aggregates that could be used for the construction of the first Polish nuclear power plant (NPP). Five different high-density aggregates were selected and tested: three barites, magnetite, and hematite. Mineralogical analysis was conducted using thin section microscopic observation in transmitted light. The accelerated mortar beam test and the long-time concrete prism test were applied to estimate the susceptibility of heavy aggregates to ASR. X-ray diffraction (XRD) and scanning electron microscopy (SEM) analyses were conducted on aggregates and mortars. The quartz size in aggregate grains was evaluated using image analysis. Application of the accelerated mortar beam method confirmed the observations of thin sections and XRD analysis of high-density aggregates. The microcrystalline quartz in hematite aggregate and cristobalite in one of barite aggregate triggered an ASR. The composition of ASR gel was confirmed by microscopic analysis. The long-term concrete test permitted the selection of innocuous high-density aggregates from among the other aggregates available, which showed practically no reactivity. PMID- 30445671 TI - Sugar-Sweetened Beverage Intake among Chilean Preschoolers and Adolescents in 2016: A Cross-Sectional Analysis. AB - BACKGROUND: Chile has the highest sugar-sweetened beverage (SSB) sales of any country and a growing burden of childhood obesity. This study examines SSB intake in Chilean children after a 5% SSB tax increase in 2014 but prior to marketing, labeling, and school policies implemented in 2016. METHODS: 24-h recalls were collected in 2016 from two cohorts comprised of preschoolers 3-5 years of age (n = 961) and adolescents 12-14 years of age (n = 770) from low-moderate income neighborhoods. Beverages were categorized as regulated or unregulated according to whether they exceeded nutrient thresholds established by the 2016 policies. RESULTS: Preschoolers consumed mainly beverage calories from regulated dairy beverages and substitutes (109 kcal, SD 30), unregulated dairy beverages (102 kcal, SD 24), and regulated fruit and vegetables drinks (44 kcal, SD 20). For adolescents, the greatest contributions came from regulated sodas (77 kcal, SD 47), regulated dairy beverages and substitutes (41 kcal, SD 16), and unregulated coffee and tea (41 kcal, SD 11). Overall, regulated beverages provided a greater proportion of calories than unregulated for preschoolers (15.0% vs. 11.8%) and for adolescents (9.1% vs. 5.0%). CONCLUSIONS: Before major policy implementation, regulated beverages accounted for a higher percentage of energy intake than unregulated beverages among both age groups. Future research will be needed to evaluate the impact of Chile's new policies on sugary beverage intake in children. PMID- 30445672 TI - Evolution of Secondary alpha Phase during Aging Treatment in Novel near beta Ti 6Mo-5V-3Al-2Fe Alloy. AB - Evolution of secondary alpha phase during aging treatment of a novel near beta titanium alloy Ti-6Mo-5V-3Al-2Fe(wt.%) was studied by OM, SEM, and TEM. Results indicated that size and distribution of secondary alpha phase were strongly affected by aging temperature and time. Athermal omega phase formed after super transus solution treatment followed by water quenching, and promoted nucleation of needle-like intragranular alpha in subsequent aging process. When aged at 480 degrees C, fine scaled intragranular alpha with small inter-particle spacing precipitated within beta grains and high ultimate tensile strength above 1500 MPa was achieved. When the aging temperature increased, the size and inter-particle spacing of intragranular alpha increased and made the strength reduce, but the ductility got improved. When aging temperature reached as high as 600 degrees C, omega phase disappeared and intragranular alpha coarsened obviously, resulting in serious decrease of strength. While mutually parallel Widmanstatten alpha laths formed at the vicinity of beta grain boundaries and grew into the internal area of beta grains, and significant improvement of ductility was achieved. As the aging time increased from 4 h to 16 h at 600 degrees C, the intragranular alpha grew slightly and brought about minor change of mechanical properties. PMID- 30445674 TI - Study of Deformation Behavior and Microstructural Evolution in Multiphase Steel. AB - In the present work, the tensile deformation characteristics of the high performance multiphase steel with complex microstructures are investigated. A mixture of ferrite, bainite, and 14.4 vol% retained austenite (RA) with an average grain size of less than 3 MUm of the matrix is obtained after specific heat treatment. Tensile tests are performed with increasing strain, i.e., 0%, 5%, 10%, 15%, and 20%. Then X-ray diffraction, transmission electron microscope and electron backscatter diffraction are utilized to analyze the deformation transformation behaviors of the complex microstructures. Phase transformation of the RA, which is controlled by its morphology and distribution, contributes to high strain hardening capacity of the steel. The blocky-type RA that locates in ferrite grain boundaries shows less stability and transforms easily at early deformation stage, while the film-like RA that distributes between bainitic ferrite shows higher stability and transforms continuously throughout plastic deformation. Moreover, the substructure formation by dislocation configuration in ferrite grains begins with randomly distributed dislocations and ends up with cellular structures, resulting in ferrite subdivision during deformation and also grain refinement strengthening. As a result, the experimental steel is reinforced not only by the martensite transformation of RA, but also ferrite refinement. PMID- 30445673 TI - Design of a 3D BMP-2-Delivering Tannylated PCL Scaffold and Its Anti-Oxidant, Anti-Inflammatory, and Osteogenic Effects In Vitro. AB - In this study, a novel three-dimensional (3D) bone morphogenic protein-2 (BMP-2) delivering tannylated polycaprolactone (PCL) (BMP-2/tannic acid (TA)/PCL) scaffold with anti-oxidant, anti-inflammatory, and osteogenic activities was fabricated via simple surface coating with TA, followed by the immobilization of BMP-2 on the TA-coated PCL scaffold. The BMP-2/TA/PCL scaffold showed controlled and sustained BMP-2 release. It effectively scavenged reactive oxygen species (ROS) in cells, and increased the proliferation of MC3T3-E1 cells pre-treated with hydrogen peroxide (H2O2). Additionally, the BMP-2/TA/PCL scaffold significantly suppressed the mRNA levels of pro-inflammatory cytokines, including matrix metalloproteinases-3 (MMP-3), cyclooxygenase-2 (COX-2), interleukin-6 (IL 6), and tumor necrosis factor-alpha (TNF-alpha), in lipopolysaccharide (LPS) induced MC3T3-E1 cells. Furthermore, it showed outstanding enhancement of the osteogenic activity of MC3T3-E1 cells through increased alkaline phosphatase (ALP) activity and calcium deposition. Our findings demonstrated that the BMP 2/TA/PCL scaffold plays an important role in scavenging ROS, suppressing inflammatory response, and enhancing the osteogenic differentiation of cells. PMID- 30445675 TI - Pharmacological Inhibition of Inward Rectifier Potassium Channels Induces Lethality in Larval Aedes aegypti. AB - The inward rectifier potassium (Kir) channels play key roles in the physiology of mosquitoes and other insects. Our group, among others, previously demonstrated that small molecule inhibitors of Kir channels are promising lead molecules for developing new insecticides to control adult female mosquitoes. However, the potential use of Kir channel inhibitors as larvicidal agents is unknown. Here we tested the hypothesis that pharmacological inhibition of Kir channels in the larvae of Aedes aegypti, the vector of several medically important arboviruses, induces lethality. We demonstrated that adding barium, a non-specific blocker of Kir channels, or VU041, a specific small-molecule inhibitor of mosquito Kir1 channels, to the rearing water (deionized H2O) of first instar larvae killed them within 48 h. We further showed that the toxic efficacy of VU041 within 24 h was significantly enhanced by increasing the osmolality of the rearing water to 100 mOsm/kg H2O with NaCl, KCl or mannitol; KCl provided the strongest enhancement compared to NaCl and mannitol. These data suggest: (1) the important role of Kir channels in the acclimation of larvae to elevated ambient osmolality and KCl concentrations; and (2) the disruption of osmoregulation as a potential mechanism of the toxic action of VU041. The present study provides the first evidence that inhibition of Kir channels is lethal to larval mosquitoes and broadens the potential applications of our existing arsenal of small molecule inhibitors of Kir channels, which have previously only been considered for developing adulticides. PMID- 30445676 TI - Development and Characterization of Double-Antibody Sandwich ELISA for Detection of Zika Virus Infection. AB - Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defect and Guillain-Barre syndrome during pregnancy. Although, several molecular diagnostic methods have been developed to detect the ZIKV, these methods pose challenges as they cannot detect early viral infection. Furthermore, these methods require the extraction of RNA, which is easy to contaminate. Nonstructural protein 1 (NS1) is an important biomarker for early diagnosis of the virus, and the detection methods associated with the NS1 protein have recently been reported. The aim of this study was to develop a rapid and sensitive detection method for the detection of the ZIKV based on the NS1 protein. The sensitivity of this method is 120 ng mL-1 and it detected the ZIKV in the supernatant and lysates of Vero and BHK cells, as well as the sera of tree shrews infected with the ZIKV. Without the isolation of the virus and the extraction of the RNA, our method can be used as a primary screening test as opposed to other diagnosis methods that detect the ZIKV. PMID- 30445677 TI - Is More Always Merrier? Intersectionality as an Antecedent of Job Insecurity. AB - As modern workplace environments are becoming increasingly diverse, the experiences of disenfranchised employees have become a topic of great interest to scholars and business professionals alike. While the experiences of individuals with singular stigmatized identities have been well-established, a dearth of research has assessed how intersectionality, i.e., holding multiple stigmatized identities, combine and intertwine to shape workplace experiences. We contribute to a growing literature on intersectionality by assessing the extent to which employees identifying with multiple stigmatized identities may constitute a risk factor for the experience of job insecurity, a prevalent and potent economic stressor. Additionally, we propose that job insecurity will partially mediate the relationship between intersectionality and a variety of adverse workplace outcomes associated with increased job insecurity perceptions. In order to test these hypotheses, we collected survey data from 449 employed individuals within the United States over two timepoints. Results of the tests of our direct and indirect hypotheses revealed that individuals with more stigmatized identities reported greater perceptions of job insecurity, and intersectionality indirectly affected workplace outcomes via this heightened job insecurity. Our results highlight a new antecedent of job insecurity for consideration and is meant to motivate others to approach diversity-related research questions with multiple identities in mind, in an effort to encapsulate the full spectrum of one's experience based on their identity makeup. PMID- 30445679 TI - A Cyclic Vernier Two-Step TDC for High Input Range Time-of-Flight Sensor Using Startup Time Correction Technique. AB - Herein, we present a low-power cyclic Vernier two-step time-to-digital converter (TDC) that achieves a wide input range with good linearity. Since traditional approaches require a large area or high power to achieve an input range >300 ns, we solve this problem by proposing a simple yet efficient TDC suitable for time of-flight (TOF) sensors. In previous studies using the cyclic structure, the effect of startup time on the linearity of the TDC is not described. Thus, the achievable linearity has been limited when the TDC is used for applications requiring a high input range. We solve this problem by using a simple yet effective technique to compensate. The proposed technique is realized using (1) digitally-controlled oscillators (DCOs) that have dual frequency control and matched startup time; (2) an alignment detector that performs startup time correction by proper timing control; and (3) a fully symmetric arbiter that precisely detects the instant of edge alignment. To achieve a fine resolution for the cyclic Vernier TDC, we design two closely-matched DCOs with dual frequency control. The alignment detector performs the critical task of cancelling startup time via timing control. The detector is delay-compensated by using a dummy to provide matched loading for the two DCOs. To enhance the detection speed under low power, a current-reuse approach is employed for the arbiter. The TDC is fabricated using a 0.18 MUm complementary metal-oxide-semiconductor (CMOS) process in a compact chip area of 0.028 mm2. Measured results show a dynamic range of 355 ns and a resolution of 377 ps. When the result is applied for TOF sensing, it corresponds to a distance range of 53.2 m and a resolution of 5.65 cm. Over a relatively large input range, good linearity is achieved, which is indicated by a DNL of 0.28 LSBrms and an INL of 0.96 LSBrms. The result corresponds to root mean square (RMS) error distance of 5.42 cm. The result is achieved by consuming a relatively low power of 0.65 mW. PMID- 30445678 TI - Cangrelor Induces More Potent Platelet Inhibition without Increasing Bleeding in Resuscitated Patients. AB - Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12 inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9-71.6) vs. 160.9 (47.1-193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding. PMID- 30445680 TI - Simultaneous Robot-World and Hand-Eye Calibration without a Calibration Object. AB - An extended robot-world and hand-eye calibration method is proposed in this paper to evaluate the transformation relationship between the camera and robot device. This approach could be performed for mobile or medical robotics applications, where precise, expensive, or unsterile calibration objects, or enough movement space, cannot be made available at the work site. Firstly, a mathematical model is established to formulate the robot-gripper-to-camera rigid transformation and robot-base-to-world rigid transformation using the Kronecker product. Subsequently, a sparse bundle adjustment is introduced for the optimization of robot-world and hand-eye calibration, as well as reconstruction results. Finally, a validation experiment including two kinds of real data sets is designed to demonstrate the effectiveness and accuracy of the proposed approach. The translation relative error of rigid transformation is less than 8/10,000 by a Denso robot in a movement range of 1.3 m * 1.3 m * 1.2 m. The distance measurement mean error after three-dimensional reconstruction is 0.13 mm. PMID- 30445681 TI - Spatial-Temporal Variations in NO2 and PM2.5 over the Chengdu-Chongqing Economic Zone in China during 2005-2015 Based on Satellite Remote Sensing. AB - The Chengdu-Chongqing Economic Zone (CCEZ), which is located in southwestern China, is the fourth largest economic zone in China. The rapid economic development of this area has resulted in many environmental problems, including extremely high concentrations of nitrogen dioxide (NO2) and fine particulate matter (PM2.5). However, current ground observations lack spatial and temporal coverage. In this study, satellite remote sensing techniques were used to analyze the variation in NO2 and PM2.5 from 2005 to 2015 in the CCEZ. The Ozone Monitoring Instrument (OMI) and the Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) product were used to retrieve tropospheric NO2 vertical columns and estimate ground-level PM2.5 concentrations, respectively. Geographically, high NO2 concentrations were mainly located in the northwest of Chengdu and southeast of Chongqing. However, high PM2.5 concentrations were mainly located in the center areas of the basin. The seasonal average NO2 and PM2.5 concentrations were both highest in winter and lowest in summer. The seasonal average NO2 and PM2.5 were as high as 749.33 * 1013 molecules.cm-2 and 132.39 ug.m-3 in winter 2010, respectively. Over 11 years, the annual average NO2 and PM2.5 values in the CCEZ increased initially and then decreased, with 2011 as the inflection point. In 2007, the concentration of NO2 reached its lowest value since 2005, which was 230.15 * 1013 molecules.cm-2, and in 2015, the concentration of PM2.5 reached its lowest value since 2005, which was 26.43 ug.m-3. Our study demonstrates the potential use of satellite remote sensing to compensate for the lack of ground-observed data when quantitatively analyzing the spatial-temporal variations in regional air quality. PMID- 30445683 TI - Enhancing Protective Efficacy of Poultry Vaccines through Targeted Delivery of Antigens to Antigen-Presenting Cells. AB - Avian viral diseases including avian influenza, Marek's disease and Newcastle disease are detrimental to economies around the world that depend on the poultry trade. A significant zoonotic threat is also posed by avian influenza viruses. Vaccination is an important and widely used method for controlling these poultry diseases. However, the current vaccines do not provide full protection or sterile immunity. Hence, there is a need to develop improved vaccines. The major aim of developing improved vaccines is to induce strong and specific humoral and cellular immunity in vaccinated animals. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to antigen-presenting cells (APCs) including dendritic cells, macrophages and B cells. APCs have a central role in the initiation and maintenance of immune responses through their ability to capture, process and present antigens to T and B cells. Vaccine technology that selectively targets APCs has been achieved by coupling antigens to monoclonal antibodies or ligands that are targeted by APCs. The aim of this review is to discuss existing strategies of selective delivery of antigens to APCs for effective vaccine development in poultry. PMID- 30445682 TI - Beneficial Effect of Oligofructose-Enriched Inulin on Vitamin D and E Status in Children with Celiac Disease on a Long-Term Gluten-Free Diet: A Preliminary Randomized, Placebo-Controlled Nutritional Intervention Study. AB - Prebiotics have been shown to improve absorption of some nutrients, including vitamins. This pilot study evaluated the effect of the prebiotic oligofructose enriched inulin (Synergy 1) on fat-soluble vitamins status, parathormone, and calcium-related elements in pediatric celiac disease (CD) patients (n = 34) on a strict gluten-free diet (GFD). Participants were randomized into a group receiving 10 g of Synergy 1 or placebo (maltodextrin) together with a GFD. At baseline and after 3 months of intervention, 25-hydroxyvitamin D [25(OH)D], parathormone, vitamin E and A, calcium, phosphate, magnesium, total protein, and albumin were determined. Concentration of 25(OH)D increased significantly (p < 0.05) by 42% in CD patients receiving Synergy 1 in GFD, whereas no change was observed in placebo. Vitamin D status reached an optimal level in 46% of patients receiving Synergy 1. No significant difference in parathormone, calcium, and phosphate levels was observed. Concentration of vitamin E increased significantly (p < 0.05) by 19% in patients receiving Synergy 1, but not in the placebo. Vitamin A levels were not changed. Supplementation of GFD with Synergy 1 improved vitamin D and vitamin E status in children and adolescents with CD and could be considered a novel complementary method of management of fat-soluble vitamins deficiency in pediatric CD patients. PMID- 30445684 TI - Dynamic Speed Control of Unmanned Aerial Vehicles for Data Collection under Internet of Things. AB - With the new advancements in flight control and integrated circuit (IC) technology, unmanned aerial vehicles (UAVs) have been widely used in various applications. One of the typical application scenarios is data collection for large-scale and remote sensor devices in the Internet of things (IoT). However, due to the characteristics of massive connections, access collisions in the MAC layer lead to high power consumption for both sensor devices and UAVs, and low efficiency for the data collection. In this paper, a dynamic speed control algorithm for UAVs (DSC-UAV) is proposed to maximize the data collection efficiency, while alleviating the access congestion for the UAV-based base stations. With a cellular network considered for support of the communication between sensor devices and drones, the connection establishment process was analyzed and modeled in detail. In addition, the data collection efficiency is also defined and derived. Based on the analytical models, optimal speed under different sensor device densities is obtained and verified. UAVs can dynamically adjust the speed according to the sensor device density under their coverages to keep high data collection efficiency. Finally, simulation results are also conducted to verify the accuracy of the proposed analytical models and show that the DSC-UAV outperforms others with the highest data collection efficiency, while maintaining a high successful access probability, low average access delay, low block probability, and low collision probability. PMID- 30445685 TI - Profiles of Environmental Mold: Indoor and Outdoor Air Sampling in a Hematology Hospital in Seoul, South Korea. AB - Inhalation of fungal spores can cause various spectrums of fungal diseases in immunocompromised hosts. The aim of this study was to evaluate the concentrations and profiles of fungal species in air collected at different locations in hematology wards and outside of the hospital in Seoul St. Mary's Hospital over the course of a year. Air sampling was performed at four locations-outside the hospital (O), in the general ward (GW), in the lounge in the cleanroom (CRL), and in the patients' room in the cleanroom (CRR)-by using Andersen single-stage air sampler at every two weeks between May 2017 and May 2018. The results showed higher mean fungal density in summer, and the concentrations of fungi decreased as follows: O (954.8 colony-forming units, CFU/m3) > GW (4.2 CFU/m3) > CRL (0.7 CFU/m3) > CRR (0 CFU/m3). Aspergillus was most prevalent both inside (47%) and outside (62%) of the hospital. However, the outdoor fungal profile was more diverse than the indoor profile. Within the hospital, Penicillium was the second most dominant species. In conclusion, the outdoor fungal profile is diverse even in Seoul, a highly urbanized area in Korea. The distribution of indoor air fungi is significantly different from outdoor due to air quality systems. Heating, ventilation, and air conditioning (HVAC), as well as high-efficiency particulate air (HEPA)-filtered systems should be established to effectively reduce levels of indoor fungi. PMID- 30445686 TI - Effect of Dietary Crude Protein Level and Supplemental Herbal Extract Blend on Selected Blood Variables in Broiler Chickens Vaccinated against Coccidiosis. AB - Immunoprophylaxis with a live anticoccidial vaccine is regarded as the most promising alternative in place of in-feed coccidiostats in the poultry industry. An experiment, designed as a 2 * 2 * 2 factorial arrangement with 6 replicate pens per treatment and 8 male Ross 308 chicks per pen, was conducted to evaluate the effect of dietary crude protein (CP) levels (21.6% or 23.6%, during the starter phase) and a herbal extract (HE) blend dietary supplementation (Echinacea purpurea, Salvia officinalis, Thymus vulgaris, Rosmarinus officinalis, Allium sativum, Origanum vulgare; 0 or 2 g/kg of feed) on selected hematological, biochemical, redox, and immunological parameters in broilers vaccinated against coccidiosis (anticoccidial vaccine (ACV); none or 1* dose, administered at 1 d of age). The blood samples were collected at 14 d of age. Anticoccidial vaccination (p < 0.05) had a negative effect on immune responses, as shown by a reduced total white blood cells (WBC) count, a reduced lymphocytes count (L), a higher proportion of heterophils (H) in leukogram assessments, as well as H/L-ratio increase. ACV resulted in a decrease in phagocytic activity assessed as decreased percentage of phagocytic cells, phagocytic index and NBT test, as well as in reductions in plasma glucose and LDL-cholesterol concentrations, and increases in HDL-cholesterol and aspartate aminotransferase (AST) activity. In terms of redox status, ACV significantly increased the catalase (CAT) activity and ferric reducing ability of plasma (FRAP), and decreased malondialdehyde concentrations. An increase in dietary CP in vaccinated chickens resulted in higher relative L and lower relative H counts, a lower H/L ratio, a decrease in AST and an increase in CAT activities, but also a decrease in FRAP and concentrations of lipid peroxides. Vaccinated chickens fed a diet supplemented with HE were characterized by higher relative L and lower relative H counts, a lower H/L ratio, and a decrease in AST activity. A change of diet composition, such as an increase in CP content and dietary HE supplementation, can be recommended in broilers vaccinated against coccidiosis, mainly due to its positive effect in alleviating stress levels. However, the simultaneous increase of CP and HE dietary supplementation offered no additional relevant benefits in most of the blood indices of vaccinated chickens. PMID- 30445687 TI - Evaluation of Chemical Mechanical Polishing-Based Surface Modification on 3D Dental Implants Compared to Alternative Methods. AB - Chemical mechanical polishing (CMP) has been introduced in previous studies as a synergistic technique to modify the surface chemistry and topography of titanium based implants to control their biocompatibility. In this study, the effectiveness of CMP implementation on titanium-based implant surface modification was compared to machined implants, such as baseline and etching and biphasic calcium phosphate (BCP) particle-based sand blasting treatments, in terms of the surface chemical and mechanical performance. Initially, a lab-scale 3D CMP technique was developed and optimized on commercial dental implant samples. The mechanical competitiveness of the dental implants treated with the selected methods was examined with the Vickers microhardness test as well as pull out force and removal torque force measurements. Furthermore, the surface structures were quantified through evaluation of the arithmetic mean roughness parameter (Ra). Subsequently, the surface chemistry changes on the treated implants were studied as wettability by contact angle measurement, and surface passivation was evaluated through electrochemical methods. In each evaluation, the CMP treated samples were observed to perform equal or better than the baseline machined implants as well as the current method of choice, the BCP treatment. The ability to control the surface topography and chemistry simultaneously by the use of CMP technique is believed to be the motivation for its adaptation for the modification of implant surfaces in the near future. PMID- 30445689 TI - Investigation on the Influence of Humidity on Stimulated Brillouin Backscattering in Perfluorinated Polymer Optical Fibers. AB - In this paper perfluorinated graded-index polymer optical fibers are characterized with respect to the influence of relative humidity changes on spectral transmission absorption and Rayleigh backscattering. The hygroscopic and thermal expansion coefficient of the fiber are determined to be C H E = (7.4 +/- 0.1) . 10 - 6 %r.h.-1 and C T E = (22.7 +/- 0.3) . 10 - 6 K-1, respectively. The influence of humidity on the Brillouin backscattering power and linewidth are presented for the first time to our knowledge. The Brillouin backscattering power at a pump wavelength of 1319 nm is affected by temperature and humidity. The Brillouin linewidth is observed to be a function of temperature but not of humidity. The strain coefficient of the BFS is determined to be C S = (-146.5 +/- 0.9) MHz/% for a wavelength of 1319 nm within a strain range from 0.1% to 1.5%. The obtained results demonstrate that the humidity-induced Brillouin frequency shift is predominantly caused by the swelling of the fiber over-cladding that leads to fiber straining. PMID- 30445690 TI - Single Cylinder-Type Piezoelectric Actuator with Two Active Kinematic Pairs. AB - There is an ever-increasing demand for small-size, low-cost, and high-precision positioning systems. Therefore, investigation in this field is performed to search for various solutions that can meet technical requirements of precise multi-degree-of-freedom (DOF) positioning systems. This paper presents a new design of a piezoelectric cylindrical actuator with two active kinematic pairs. This means that a single actuator is used to create vibrations that are transformed into the rotation of the sphere located on the top of the cylinder and at the same time ensure movement of the piezoelectric cylinder on the plane. Numerical and experimental investigations of the piezoelectric cylinder have been performed. A mathematical model of contacting force control was developed to solve the problem of positioning of the rotor when it needs to be rotated or moved according to a specific motion trajectory. The numerical simulation included harmonic response analysis of the actuator to analyze the trajectories of the contact points motion. A prototype actuator has been manufactured and tested. Obtained results confirmed that such a device is suitable for both positioning and movement of the actuator in the plane. PMID- 30445688 TI - A Retrospective Study on Dietary FODMAP Intake in Celiac Patients Following a Gluten-Free Diet. AB - Our aim was to evaluate the intake of foods containing fermentable oligo/di/mono saccharides and polyols (FODMAP) as a possible factor that induces gastrointestinal symptoms in treated celiac disease (CD) patients. We collected seven-day weighed food records for 104 CD patients and 91 healthy volunteers. All evaluated food items were from sources with high and low content of FODMAP, which were divided into cereals and sweets, sweeteners and soft drinks, fruits, dried fruits, and vegetables. Nutrient intake was calculated using the food database of the European Institute of Oncology. The symptoms reported were assessed by a Rome IV Irritable bowel syndrome (IBS) diagnostic questionnaire and by specific questions for the evaluation of functional gastrointestinal disorders (FGIDs). The 12% of CD patients met IBS symptoms criteria as opposed to 6% of controls (p = 0.09) and 27% of patients reported FGIDs symptoms vs. 22% of healthy controls (p = 0.42). The intake by CD patients was significantly higher than healthy volunteers for: sweeteners and sugars with low content of FODMAP (p = 0.0007), fruits, dried fruits, and vegetables high in FODMAP (p = 0.003) and low in FODMAP (p = 0.04) when compared to controls. CD patients had a lower intake of cereals and sweets with a high content of FODMAP (p = 0.00001). Healthy volunteers consumed significantly higher alcoholic beverages and fats high in FODMAP (both p < 0.044). The mean daily intake of other food categories did not differ between both groups. Even though CD patients had a low intake of gluten-free cereals high in FODMAP, they still consumed a significant amount of fruits and vegetables high in FODMAP. The clinical effect of a concomitant gluten-free diet and low-FODMAP diet should be prospectively evaluated as a supportive therapy in CD patients. PMID- 30445691 TI - Old Receptor, New Tricks-The Ever-Expanding Universe of Aryl Hydrocarbon Receptor Functions. Report from the 4th AHR Meeting, 29-31 August 2018 in Paris, France. AB - In a time where "translational" science has become a mantra in the biomedical field, it is reassuring when years of research into a biological phenomenon suddenly points towards novel prevention or therapeutic approaches to disease, thereby demonstrating once again that basic science and translational science are intimately linked. The studies on the aryl hydrocarbon receptor (AHR) discussed here provide a perfect example of how years of basic toxicological research on a molecule, whose normal physiological function remained a mystery for so long, has now yielded a treasure trove of actionable information on the development of targeted therapeutics. Examples are autoimmunity, metabolic imbalance, inflammatory skin and gastro-intestinal diseases, cancer, development and perhaps ageing. Indeed, the AHR field no longer asks, "What does this receptor do in the absence of xenobiotics?" It now asks, "What doesn't this receptor do?". PMID- 30445693 TI - Non-Linear Enthalpy-Entropy Correlation for Nitrogen Adsorption in Zeolites. AB - The thermodynamics of dinitrogen adsorption in faujasite-type zeolites, Na-Y, Ca Y and Sr-Y, were investigated by means of variable-temperature infrared spectroscopy, a technique that affords determination of the standard adsorption enthalpy (DeltaH0) and entropy (DeltaS0) from an analysis of the IR spectra recorded over a range of temperatures. The results obtained, taken together with previously reported values for N2 adsorption on protonic zeolites, revealed a non linear correlation between DeltaH0 and DeltaS0. Implications of such a correlation for gas separation and purification by adsorption in porous solids are highlighted. PMID- 30445692 TI - First Case of Human Primary Vertebral Cystic Echinococcosis Due to Echinococcus Ortleppi. AB - Cystic echinococcosis (CE) is a cosmopolitan parasitic zoonosis affecting more than one million people worldwide. In humans, primary bone CE is rare and involvement of E. ortleppi is very uncommon. We report here the first case of primary vertebral cystic echinococcosis due to E. ortleppi in Burgundy, France. PMID- 30445694 TI - An Overview of the Synthesis of Gold Nanoparticles Using Radiation Technologies. AB - At a nano-level, optical properties of gold are unique and gave birth to an emerging platform of nanogold-based systems for diverse applications, because gold nanoparticle properties are tunable as a function of size and shape. Within the available techniques for the synthesis of gold nanoparticles, the radiolytic synthesis allows proper control of the nucleation process without the need for reducing agents, in a single step, combined or not with simultaneous sterilization. This review details and summarizes the use of radiation technologies for the synthesis and preparation of gold nanoparticles concerning fundamental aspects, mechanism, current pathways for synthesis and radiation sources, as well as briefly outlines final applications and some toxicity aspects related to nanogold-based systems. PMID- 30445696 TI - A Non-Intrusive Approach for Indoor Occupancy Detection in Smart Environments. AB - Smart Environments try to adapt their conditions focusing on the detection, localisation, and identification of people to improve their comfort. It is common to use different sensors, actuators, and analytic techniques in this kind of environments to process data from the surroundings and actuate accordingly. In this research, a solution to improve the user's experience in Smart Environments based on information obtained from indoor areas, following a non-intrusive approach, is proposed. We used Machine Learning techniques to determine occupants and estimate the number of persons in a specific indoor space. The solution proposed was tested in a real scenario using a prototype system, integrated by nodes and sensors, specifically designed and developed to gather the environmental data of interest. The results obtained demonstrate that with the developed system it is possible to obtain, process, and store environmental information. Additionally, the analysis performed over the gathered data using Machine Learning and pattern recognition mechanisms shows that it is possible to determine the occupancy of indoor environments. PMID- 30445695 TI - Modelling a Silent Epidemic: A Review of the In Vitro Models of Latent Tuberculosis. AB - Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. Approximately 1.7 billion people are latently infected with TB and on reactivation many of these infections are drug resistant. As the current treatment is ineffective and diagnosis remains poor, millions of people have the potential to reactivate into active TB disease. The immune system seeks to control the TB infection by containing the bacteria in a granuloma, where it is exposed to stressful anaerobic and nutrient deprived conditions. It is thought to be these environmental conditions that trigger the NRP state. A number of in vitro models have been developed that mimic conditions within the granuloma to a lesser or greater extent. These different models have all been utilised for the research of different characteristics of NRP Mycobacterium tuberculosis, however their disparity in approach and physiological relevance often results in inconsistencies and a lack of consensus between studies. This review provides a summation of the different NRP models and a critical analysis of their respective advantages and disadvantages relating to their physiological relevance. PMID- 30445697 TI - Simulation of Temperature Distribution and Microstructure Evolution in the Molten Pool of GTAW Ti-6Al-4V Alloy. AB - In this paper, a three-dimensional (3D) finite element model was established by ABAQUS software to simulate the welding temperature field of a Ti-6Al-4V alloy under different welding currents based on a Gaussian heat source model. The model uses thermo-mechanical coupling analysis and takes into account the effects of convection and radiation on all weld surfaces. The microstructure evolution of the molten pool was calculated using the macro-micro coupling cellular automaton finite different (CA-FD) method. It was found that with the increase of the welding current, the temperature in the central region of the moving heat source was improved and the weld bead became wider. Then, the dendritic morphology and solute concentration of the columnar to equiaxed transition (CET) in the weld molten pool was investigated. It is shown that fine equiaxed crystals formed around the columnar crystals tips during solidification. The coarse columnar crystals are produced with priority in the molten pool and their growth direction is in line with the direction of the negative temperature gradient. The effectiveness of the model was verified by gas tungsten arc welding experiments. PMID- 30445698 TI - A POSHE-Based Optimum Clip-Limit Contrast Enhancement Method for Ultrasonic Logging Images. AB - Enabled by piezoceramic transducers, ultrasonic logging images often suffer from low contrast and indistinct local details, which makes it difficult to analyze and interpret geologic features in the images. In this work, we propose a novel partially overlapped sub-block histogram-equalization (POSHE)-based optimum clip limit contrast enhancement (POSHEOC) method to highlight the local details hidden in ultrasonic well logging images obtained through piezoceramic transducers. The proposed algorithm introduces the idea of contrast-limited enhancement to modify the cumulative distribution functions of the POSHE and build a new quality evaluation index considering the effects of the mean gradient and mean structural similarity. The new index is designed to obtain the optimal clip-limit value for histogram equalization of the sub-block. It makes the choice of the optimal clip limit automatically according to the input image. Experimental results based on visual perceptual evaluation and quantitative measures demonstrate that the proposed method yields better quality in terms of enhancing the contrast, emphasizing the local details while preserving the brightness and restricting the excessive enhancement compared with the other seven histogram equalization-based techniques from the literature. This study provides a feasible and effective method to enhance ultrasonic logging images obtained through piezoceramic transducers and is significant for the interpretation of actual ultrasonic logging data. PMID- 30445699 TI - Fabrication of (111)-Oriented Nanotwinned Au Films for Au-to-Au Direct Bonding. AB - We reported that highly (111)-oriented nanotwinned gold can be fabricated by periodical-reverse electroplating. The as-deposited films are shown to have a strong (111) preferred orientation, increasing with the reverse current time. The ratios of I(111)/I(220) and I(111)/I(200) in X-ray diffraction signals indicates a strong (111) preferred orientation. Using the advantage of the fast surface diffusion of (111) plane compared to the other planes of gold, we performed direct bonding with different thicknesses. Grain growth was observed over two films' interfaces to eliminate the bonding interface, when annealed at 250 degrees C for 1 h. Shear tests were performed to gain insight on the bonding quality. All the chips failed at either the silicon substrate or substrate adhesion layer, showing possible higher strength than the tested maximum, 40.8 MPa. PMID- 30445700 TI - A Graded Multifunctional Hybrid Scaffold with Superparamagnetic Ability for Periodontal Regeneration. AB - The regeneration of dental tissues is a still an unmet clinical need; in fact, no therapies have been completely successful in regenerating dental tissue complexes such as periodontium, which is also due to the lack of scaffolds that are able to guide and direct cell fate towards the reconstruction of different mineralized and non-mineralized dental tissues. In this respect, the present work develops a novel multifunctional hybrid scaffold recapitulating the different features of alveolar bone, periodontal ligament, and cementum by integrating the biomineralization process, and tape casting and electrospinning techniques. The scaffold is endowed with a superparamagnetic ability, thanks to the use of a biocompatible, bioactive superparamagnetic apatite phase, as a mineral component that is able to promote osteogenesis and to be activated by remote magnetic signals. The periodontal scaffold was obtained by engineering three different layers, recapitulating the relevant compositional and microstructural features of the target tissues, into a monolithic multifunctional graded device. Physico chemical, morphological, and ultrastructural analyses, in association with preliminary in vitro investigations carried out with mesenchymal stem cells, confirm that the final scaffold exhibits a good mimicry of the periodontal tissue complex, with excellent cytocompatibility and cell viability, making it very promising for regenerative applications in dentistry. PMID- 30445701 TI - A Batteryless, Wireless Strain Sensor Using Resonant Frequency Modulation. AB - In this study, we demonstrated the feasibility of a wireless strain sensor using resonant frequency modulation through tensile impedance test and wireless sensing test. To achieve a high stretchability, the sensor was fabricated by embedding a copper wire with high conductivity in a silicone rubber with high stretchability, in which the resonant frequency can be modulated according to changes in strain. The characteristics of the sensor and the behavior of wireless sensing were calculated based on equations and simulated using finite element method. As the strain of the sensor increased, the inductance increased, resulting in the modulation of resonant frequency. In experimental measurement, as the strain of the sensor increased from 0% to 110%, its inductance was increased from 192 nH to 220 nH, changed by 14.5%, and the resonant frequency was shifted from 13.56 MHz to 12.72 MHz, decreased by 6.2%. It was demonstrated that using the proposed sensor, strains up to 110% could be detected wirelessly up to a few centimeters. PMID- 30445702 TI - DNA Vaccines-How Far From Clinical Use? AB - Two decades ago successful transfection of antigen presenting cells (APC) in vivo was demonstrated which resulted in the induction of primary adaptive immune responses. Due to the good biocompatibility of plasmid DNA, their cost-efficient production and long shelf life, many researchers aimed to develop DNA vaccine based immunotherapeutic strategies for treatment of infections and cancer, but also autoimmune diseases and allergies. This review aims to summarize our current knowledge on the course of action of DNA vaccines, and which factors are responsible for the poor immunogenicity in human so far. Important optimization steps that improve DNA transfection efficiency comprise the introduction of DNA complexing nano-carriers aimed to prevent extracellular DNA degradation, enabling APC targeting, and enhanced endo/lysosomal escape of DNA. Attachment of virus derived nuclear localization sequences facilitates nuclear entry of DNA. Improvements in DNA vaccine design include the use of APC-specific promotors for transcriptional targeting, the arrangement of multiple antigen sequences, the co delivery of molecular adjuvants to prevent tolerance induction, and strategies to circumvent potential inhibitory effects of the vector backbone. Successful clinical use of DNA vaccines may require combined employment of all of these parameters, and combination treatment with additional drugs. PMID- 30445704 TI - Silver Nanoparticle Conjugation-Enhanced Antibacterial Efficacy of Clinically Approved Drugs Cephradine and Vildagliptin. AB - This paper sets out to determine whether silver nanoparticles conjugation enhance the antibacterial efficacy of clinically approved drugs. Silver conjugated Cephradine and Vildagliptin were synthesized and thoroughly characterized by ultraviolet visible spectrophotometry (UV-vis), Fourier transform infrared (FT IR) spectroscopic methods, atomic force microscopy (AFM), and dynamic light scattering (DLS) analysis. Using antibacterial assays, the effects of drugs alone and drugs-conjugated with silver nanoparticles were tested against a variety of Gram-negative and Gram-positive bacteria including neuropathogenic Escherichia coli K1, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus cereus and Streptococcus pyogenes. Cytopathogenicity assays were performed to determine whether pretreatment of bacteria with drugs inhibit bacterial-mediated host cell cytotoxicity. The UV-vis spectra of both silver-drug nanoconjugates showed a characteristic surface plasmon resonance band in the range of 400-450 nm. AFM further confirmed the morphology of nanoparticles and revealed the formation of spherical nanoparticles with size distribution of 30-80 nm. FT-IR analysis demonstrated the involvement of Hydroxyl groups in both drugs in the stabilization of silver nanoparticles. Antibacterial assays showed that silver nanoparticle conjugation enhanced antibacterial potential of both Cephradine and Vildagliptin compared to the drugs alone. Pretreatment of bacteria with drugs inhibited E. coli K1-mediated host cell cytotoxicity. In summary, conjugation with silver nanoparticle enhanced antibacterial effects of clinically approved Cephradine. These findings suggest that modifying and/or repurposing clinically approved drugs using nanotechnology is a feasible approach in our search for effective antibacterial molecules. PMID- 30445703 TI - Does the Mediterranean Diet Protect against Stress-Induced Inflammatory Activation in European Adolescents? The HELENA Study. AB - Stress increases inflammation but whether adherence to Mediterranean diet counteracts this association and how early can these effects be observed is not well known. We tested whether (1) cortisol is associated to inflammation, (2) cortisol is associated to the adolescent Mediterranean diet score (aMDS), (3) aMDS lessens inflammation, (4) aMDS associates with cortisol levels and inflammation. Two hundred and forty-two adolescents (137 females; 12.5-17.5 years old) provided salivary cortisol, blood and 2-day 24-h dietary recall from which aMDS was derived. Cortisol levels were associated with increased tumor necrosis factor (TNF-alpha B = 11.887, p = 0.001) when adjusted for age, gender, parental education and body mass index (BMI). Moreover, cortisol levels were inversely associated to adherence to the Mediterranean Diet (B = -1.023, p = 0.002). Adolescents with higher adherence to aMDS had lower levels of interleukins (IL) IL-1, IL-2, IL-6 and TNF-alpha, compared to those who did not adhere. The association between cortisol and TNF-alpha was no longer significant when aMDS was included in the model (B = 6.118, p = 0.139). In addition, comparing lower and higher aMDS groups, the association between cortisol and TNF-alpha was only observed in those with lower aMDS adherence. Our study suggests that adherence to the Mediterranean Diet may counteract the effect of stress on inflammatory biomarkers which may contribute to decreasing the risk of future mental health. PMID- 30445705 TI - Evaluation of beta-Sitosterol Loaded PLGA and PEG-PLA Nanoparticles for Effective Treatment of Breast Cancer: Preparation, Physicochemical Characterization, and Antitumor Activity. AB - beta-Sitosterol (beta-Sit) is a dietary phytosterol with demonstrated anticancer activity against a panel of cancers, but its poor solubility in water limits its bioavailability and therapeutic efficacy. In this study, poly(lactide-co-glycolic acid) (PLGA) and block copolymers of poly(ethylene glycol)-block-poly(lactic acid) (PEG-PLA) were used to encapsulate beta-Sit into nanoparticles with the aim of enhancing its in vitro anticancer activity. beta-Sitosterol-loaded PLGA and PEG-PLA nanoparticles (beta-Sit-PLGA and beta-Sit-PEG-PLA) were prepared by using a simple emulsion-solvent evaporation technique. The nanoparticles were characterized for size, particle size distribution, surface charge, and encapsulation efficiency. Their cellular uptake and antiproliferative activity was evaluated against MCF-7 and MDA-MB-231 human breast cancer cells using flow cytometry and MTT assays, respectively. beta-Sit-PLGA and beta-Sit-PEG-PLA nanoparticles were spherical in shape with average particle sizes of 215.0 +/- 29.7 and 240.6 +/- 23.3 nm, a zeta potential of -13.8 +/- 1.61 and -23.5 +/- 0.27 mV, respectively, and with narrow size distribution. The encapsulation efficiency of beta-Sit was 62.89 +/- 4.66 and 51.83 +/- 19.72 % in PLGA and PEG-PLA nanoparticles, respectively. In vitro release in phosphate-buffered saline (PBS) and PBS/with 0.2% Tween 20 showed an initial burst release, followed by a sustained release for 408 h. beta-Sit-PLGA nanoparticles were generally stable in a protein-rich medium, whereas beta-Sit-PEG-PLA nanoparticles showed a tendency to aggregate. Flow cytometry analysis (FACS) indicated that beta-Sit-PLGA nanoparticles were efficiently taken up by the cells in contrast to beta-Sit-PEG PLA nanoparticles. beta-Sit-PLGA nanoparticles were therefore selected to evaluate antiproliferative activity. Cell viability was inhibited by up to 80% in a concentration range of 6.64-53.08 MUg/mL compared to the untreated cells. Taken together, encapsulation of beta-Sitosterol in PLGA nanoparticles is a promising strategy to enhance its anticancer activity against breast cancer cells. PMID- 30445706 TI - Electrochemical Determination of beta-Lactoglobulin Employing a Polystyrene Bead Modified Carbon Nanotube Ink. AB - In this article, we introduce the use of a carboxy-functionalized waterborne carbon nanotube ink for the fabrication of an amperometric biosensor aimed at the quantification of beta-lactoglobulin. Detection of this protein from cow's milk was performed by a sandwich immunoassay onto printed carbon nanotube electrodes. The electrodes were printed using a carbon nanotube ink modified with polystyrene beads containing a high amount of carboxylic groups for protein immobilization. This strategy showed enhanced sensing performance compared to the use of oxidative treatments for the functionalization of electrodes. These electrodes showed an excellent electrochemical behavior, and proteins could be immobilized on their surface via the carbodiimide reaction. These antibody-immobilized carbon nanotube electrodes allowed for the detection of beta-lactoglobulin in sub-ppm concentrations. PMID- 30445708 TI - Contact Force Measurement in an Operational Thrust Bearing using PVDF Film at the Blade and Pad Passing Frequencies. AB - A major contributor to longitudinal vibration in marine propulsion systems is propeller induced excitation. This constitutes a key source of underwater acoustical radiation through excitation of the hull. Understanding this hydrodynamic force at the interface of the thrust bearing is important in order to develop an accurate vibrational model of the propulsion system and in determining potential control mechanisms. In order to investigate the thrust force during operation of a propulsion system, Polyvinylidene Fluoride (PVDF) was embedded into the stationery collar inside a custom thrust bearing in a scaled model of a typical propulsion system. The number of blades of the propeller and its rotational speed were altered to obtain an understanding of the characteristic vibrations of the shaft propulsion system. The rig comprised of the propeller, shaft, journal bearings and a thrust bearing. A two and three blade propeller and a four, five and six pad bearing were tested. A strain gauge and accelerometer were used to infer the propeller force and enable comparison with the PVDF signals. As a result of the asymmetrical flow around the propeller, the blade passing frequencies (BPF) are clearly observed. This frequency contribution was present at all speeds tested. The PVDF signal also showed significant pad passing frequency (PPF) and BPF and modulation of both. PMID- 30445707 TI - The In Ovo Delivery of CpG Oligonucleotides Protects against Infectious Bronchitis with the Recruitment of Immune Cells into the Respiratory Tract of Chickens. AB - The in ovo delivery of cytosine-guanosine (CpG) oligodeoxynucleotides (ODNs) protects chickens against many bacterial and viral infections, by activating the toll-like receptor (TLR)21 signaling pathway. Although the delivery of CpG ODNs in ovo at embryo day (ED) 18 has been shown to reduce infectious bronchitis virus (IBV) loads in embryonic chicken lungs pre-hatch, whether in ovo delivered CpG ODNs are capable of protecting chickens against a post-hatch challenge is unknown. Thus, our objectives were to determine the protective effect of the in ovo delivery of CpG ODNs at ED 18 against IBV infection encountered post-hatch and, then, to investigate the mechanisms of protection. We found significantly higher survival rates and reduced IBV infection in the chickens following the pre treatment of the ED 18 eggs with CpG ODNs. At 3 days post infection (dpi), we found an increased recruitment of macrophages, cluster of differentiation (CD)8alpha+ and CD4+ T lymphocytes, and an up-regulation of interferon (IFN) gamma mRNA in the respiratory tract of the chickens. Overall, it may be inferred that CpG ODNs, when delivered in ovo, provide protection against IBV infection induced morbidity and mortality with an enhanced immune response. PMID- 30445709 TI - Glycans Controlling Virus Infections: Meeting Report on the 1st International Symposium on Glycovirology Schontal, Germany, 02-04 May 2018. AB - Glycans are, with nucleic acids, proteins and lipids, one of the four founding structures of cellular life. Due to their non-template synthesis, they are inherently heterogeneous and difficult to study with regards to their structure and function. Since 2016, the research group ViroCarb, funded by the German Research Foundation, has investigated the role of glycans in non-enveloped virus infections with a highly interdisciplinary approach. The core idea was to bring together scientists and students from various disciplines such as structural biology, cell biology, virology and chemistry to advance research by an interdisciplinary means. In 2018, ViroCarb hosted the 1st International Symposium on Glycovirology in Schontal, Germany, with a similar aim. Scientists from various disciplines gathered to discuss their area of study, present recent findings, establish or strengthen collaborations, and mentor the next generation of glycovirologists through formal presentations and informal discussions. The secluded meeting at the monastery of Schontal gave ample time for in-depth discussions. On behalf of ViroCarb, this report summarizes the reports and highlights advances in the field. PMID- 30445710 TI - Application of Physical and Chemical Enhanced Backwashing to Reduce Membrane Fouling in the Water Treatment Process Using Ceramic Membranes. AB - This study investigated the improvement of operating efficiency through physical cleaning and chemical enhanced backwashing (CEB) using ceramic membranes with high permeability and chemical safety compared to organic membranes. The turbidity and DOC (Dissolved Organic Carbon) concentrations were selected to ensure that the degree of contamination was always constant. The operating pressures were fixed at 100, 200, and 300 kPa, and the filtration was terminated when the effluent flow rate decreased to 30% or less from the initial value. After filtration, backwashing was performed at a pressure of 500 kPa using 500 mL backwash water. The membrane was cleaned by dipping in NaOCl, and a new washing technique was proposed for steam washing. In this study, we investigated the recovery rate of membranes by selectively performing physical cleaning and CEB by changing the influent water quality and operating pressure conditions. PMID- 30445711 TI - Preparation of Hydrogen Peroxide Sensitive Nanofilms by a Layer-by-Layer Technique. AB - H2O2-sensitive nanofilms composed of DNA and hemin-appended poly(ethyleneimine) (H-PEI) were prepared by a layer-by-layer deposition of DNA and H-PEI through an electrostatic interaction. The (H-PEI/DNA)5 film was decomposed by addition of 10 mM H2O2. H2O2-induced decomposition was also confirmed in the hemin-containing (PEI/DNA)5 in which hemin molecules were adsorbed by a noncovalent bond to the nanofilm. On the other hand, the (PEI/DNA)5 film containing no hemin and the (H PEI/PSS)5 film using PSS instead of DNA did not decompose even with 100 mM H2O2. The mechanism of nanofilm decomposition was thought that more reactive oxygen species (ROS) was formed by reaction of hemin and H2O2 and then the ROS caused DNA cleavage. As a result (H-PEI/DNA)5 and hemin-containing (PEI/DNA)5 films were decomposed. The decomposition rate of these nanofilms were depended on concentration of H2O2, modification ratio of hemin, pH, and ionic strength. PMID- 30445712 TI - Cytotoxic and Membrane Cholesterol Effects of Ultraviolet Irradiation and Zinc Oxide Nanoparticles on Chinese Hamster Ovary Cells. AB - Zinc Oxide (ZnO) nanoparticles are suspected to produce toxic effects toward mammalian cells; however, discrepancies in the extent of this effect have been reported between different cell lines. Simultaneously, high levels of ultraviolet (UV-C) radiation can have carcinogenic effects. The mechanism of this effect is also not well understood. Due to similarities in phenotype morphology after cell exposure to ZnO nanoparticles and UV-C irradiation, we emit the hypothesis that the toxicity of both these factors is related to damage of cellular membranes and affect their sterol content. Wild-type Chinese Hamster Ovary (CHO-K1) cells were exposed to ZnO nanoparticles or UV-C radiation. The amount of absorbed ZnO was determined by UV-visible spectroscopy and the changes in sterol profiles were evaluated by gas chromatography. Cell viability after both treatments was determined by microscopy. Comparing morphology results suggested similarities in toxicology events induced by ZnO nanoparticles and UV exposure. UV-C exposure for 360 min disrupts the sterol metabolic pathway by increasing the concentration of cholesterol by 21.6-fold. This increase in cholesterol production supports the hypothesis that UV irradiation has direct consequences in initiating sterol modifications in the cell membrane. PMID- 30445713 TI - Patulin in Apples and Apple-Based Food Products: The Burdens and the Mitigation Strategies. AB - Apples and apple-based products are among the most popular foods around the world for their delightful flavors and health benefits. However, the commonly found mold, Penicillium expansum invades wounded apples, causing the blue mold decay and ensuing the production of patulin, a mycotoxin that negatively affects human health. Patulin contamination in apple products has been a worldwide problem without a satisfactory solution yet. A comprehensive understanding of the factors and challenges associated with patulin accumulation in apples is essential for finding such a solution. This review will discuss the effects of the pathogenicity of Penicillium species, quality traits of apple cultivars, and environmental conditions on the severity of apple blue mold and patulin contamination. Moreover, beyond the complicated interactions of the three aforementioned factors, patulin control is also challenged by the lack of reliable detection methods in food matrices, as well as unclear degradation mechanisms and limited knowledge about the toxicities of the metabolites resulting from the degradations. As apple-based products are mainly produced with stored apples, pre- and post-harvest strategies are equally important for patulin mitigation. Before storage, disease-resistance breeding, orchard-management, and elicitor(s) application help control the patulin level by improving the storage qualities of apples and lowering fruit rot severity. From storage to processing, patulin mitigation strategies could benefit from the optimization of apple storage conditions, the elimination of rotten apples, and the safe and effective detoxification or biodegradation of patulin. PMID- 30445714 TI - Micro-Magnetic and Microstructural Characterization of Wear Progress on Case Hardened 16MnCr5 Gear Wheels. AB - The evaluation of wear progress of gear tooth flanks made of 16MnCr5 was performed using non-destructive micro-magnetic testing, specifically Barkhausen noise (BN) and incremental permeability (IP). Based on the physical interaction of the microstructure with the magnetic field, the micro-magnetic characterization allowed the analysis of changes of microstructure caused by wear, including phase transformation and development of residual stresses. Due to wide parameter variation and application of bandpass filter frequencies of micro magnetic signals, it was possible to indicate and separate the main damage mechanisms considering the wear development. It could be shown that the maximum amplitude of BN correlates directly with the profile form deviation and increases with the progress of wear. Surface investigations via optical and scanning electron microscopy indicated strong surface fatigue wear with micro-pitting and micro-cracks, evident in cross-section after 3 * 105 cycles. The result of fatigue on the surface layer was the decrease of residual compression stresses, which was indicated by means of coercivity by BN-analysis. The different topographies of the surfaces, characterized via confocal white light microscopy, were also reflected in maximum BN-amplitude. Using complementary microscopic characterization in the cross-section, a strong correlation between micro magnetic parameters and microstructure was confirmed and wear progress was characterized in dependence of depth under the wear surface. The phase transformation of retained austenite into martensite according to wear development, measured by means of X-ray diffraction (XRD) and electron backscatter diffraction (EBSD) was also detected by micro-magnetic testing by IP analysis. PMID- 30445715 TI - Simultaneous Determination and Pharmacokinetics Study of Six Triterpenes in Rat Plasma by UHPLC-MS/MS after Oral Administration of Sanguisorba officinalis L. Extract. AB - A selective and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the determination of ziyuglycoside I (I), 3beta,19alpha-dihydroxyurs-12-en-28-oic acid 28-beta-d-glucopyranosyl ester (II), 3beta-[(alpha-l-arabinopyranosyl) oxy] urs-12,18(19)-dien-28-oic acid beta-d-glucopyranosyl ester (III), rosamultin (IV), 1beta-hydroxyeuscaphic acid (V) and alpinoside (VI) in rats after oral administration of Sanguisorba officinalis L. (S. officinalis) extract. The 3beta,19alpha-dihydroxyurs-12-en-28-oic-acid 28-beta-d-glucopyranosyl ester, 3beta-[(alpha-l-arabinopyranosyl) oxy]-urs-12,18(19)-dien-28-oic acid beta-d glucopyranosyl ester, rosamultin, 1beta-hydroxyeuscaphic acid and alpinoside in rat plasma were the first report in the pharmacokinetics study in the present study. The analytes were quantified using the multiple reaction monitoring (MRM) mode with the electrospray ion source in positive electrospray ionization. Plasma was extracted with ethyl acetate via liquid-liquid extraction. Bifendate was used as internal standard (IS). The current method was validated for linearity, intra day and inter-day precisions, accuracy, extraction recovery, matrix effect and stability. The lower limits of quantification of ziyuglycoside I, 3beta,19alpha dihydroxyurs-12-en-28-oic-acid 28-beta-d-glucopyranosyl ester, 3beta-[(alpha-l arabinopyranosyl) oxy]-urs-12,18(19)-dien-28-oic acid beta-d-glucopyranosyl ester, rosamultin, 1beta-hydroxyeuscaphic acid and alpinoside were 6.1, 4.9, 1.3, 3.8, 1.5 and 5.7 ng/mL, respectively. Intra-day and inter-day precision and the accuracy of the assay were in range from -9.48 to 12.74%. The extraction recoveries of analytes and bifendate (IS) from rat plasma ranged from 77.17% to 92.48%. Six compounds could be rapidly absorbed into blood (Tmax, 0.58-1.58 h), and then eliminated relatively slowly (t1/2, 6.86-11.63 h). The pharmacokinetic results might contribute to further guide the clinical application of S. officinalis. PMID- 30445716 TI - Stone/Coating Interaction and Durability of Si-Based Photocatalytic Nanocomposites Applied to Porous Lithotypes. AB - The use of hybrid nanocoatings for the protection of natural stones has received increasing attention over the last years. However, the interaction of these materials with stones and, in particular, its modification resulting from the blending of nanoparticles and matrices, are yet little explored. In this work, the interaction of two nanocomposite coatings (based on alkylalkoxysilane matrices and TiO2 nanoparticles in water and 2-propanol) with two different porous stones is examined in detail by comparing their absorption behaviour and protection performance with those of the respective TiO2-free matrices. It is shown that the protective effectiveness of both matrices is not negatively affected by the presence of TiO2, as the desired water barrier effect is retained, while a significant photocatalytic activity is achieved. The addition of titania leads to a partial aggregation of the water-based matrix and accordingly reduces the product penetration into stones. On the positive side, a chemical interaction between titania and this matrix is observed, probably resulting in a greater stability of nanoparticles inside the protective coating. Moreover, although an effect of TiO2 on the chemical stability of matrices is observed upon UV light exposure, the protective performance of coatings is substantially maintained after ageing, while the interaction between matrices and nanoparticles results in a good retention of the latter upon in-lab simulated rain wash-out. PMID- 30445717 TI - Base-By-Base Version 3: New Comparative Tools for Large Virus Genomes. AB - Base-By-Base is a comprehensive tool for the creation and editing of multiple sequence alignments that is coded in Java and runs on multiple platforms. It can be used with gene and protein sequences as well as with large viral genomes, which themselves can contain gene annotations. This report describes new features added to Base-By-Base over the last 7 years. The two most significant additions are: (1) The recoding and inclusion of "consensus-degenerate hybrid oligonucleotide primers" (CODEHOP), a popular tool for the design of degenerate primers from a multiple sequence alignment of proteins; and (2) the ability to perform fuzzy searches within the columns of sequence data in multiple sequence alignments to determine the distribution of sequence variants among the sequences. The intuitive interface focuses on the presentation of results in easily understood visualizations and providing the ability to annotate the sequences in a multiple alignment with analytic and user data. PMID- 30445719 TI - "Being in Control of My Asthma Myself" Patient Experience of Asthma Management: A Qualitative Interpretive Description. AB - Asthma control can be achieved with effective and safe medication use; however, many patients are not controlled. Patients' perceptions of asthma, asthma treatment, and pharmacist roles can impact patient outcomes. The purpose of this study was to explore patients' experiences and patient-pharmacist relationships in asthma care. Qualitative Interpretive Description method guided the study. Semi-structured individual interviews were conducted with 11 patients recruited from personal contacts, pharmacies, and asthma clinics. Categories and themes were identified using inductive constant comparison. Themes indicated patients had a personalized common sense approach to asthma management, "go-to" health care provider, and prioritized patient-pharmacist relationships. Patients described their illness experiences and asthma control based on personal markers similar to the common sense model of self-regulation. Patients chose a family physician, asthma specialist, respiratory therapist, or pharmacist as an expert resource for asthma management. Patient perceived pharmacists' roles as information provider, adviser, or care provider. Pharmacists who develop a collaborative relationship with their asthma patients are better positioned to provide tailored education and self-management support. Inviting patients to share their perspective could increase patient engagement and uptake of personalised asthma action plans to achieve asthma control. PMID- 30445718 TI - Associations of Brain Reactivity to Food Cues with Weight Loss, Protein Intake and Dietary Restraint during the PREVIEW Intervention. AB - The objective was to assess the effects of a weight loss and subsequent weight maintenance period comprising two diets differing in protein intake, on brain reward reactivity to visual food cues. Brain reward reactivity was assessed with functional magnetic resonance imaging in 27 overweight/obese individuals with impaired fasting glucose and/or impaired glucose tolerance (HOMA-IR: 3.7 +/- 1.7; BMI: 31.8 +/- 3.2 kg/m2; fasting glucose: 6.4 +/- 0.6 mmol/L) before and after an 8-week low energy diet followed by a 2-year weight maintenance period, with either high protein (HP) or medium protein (MP) dietary guidelines. Brain reactivity and possible relationships with protein intake, anthropometrics, insulin resistance and eating behaviour were assessed. Brain reactivity, BMI, HOMA-IR and protein intake did not change differently between the groups during the intervention. In the whole group, protein intake during weight maintenance was negatively related to changes in high calorie images>low calorie images (H > L) brain activation in the superior/middle frontal gyrus and the inferior temporal gyrus (p < 0.005, corrected for multiple comparisons). H > L brain activation was positively associated with changes in body weight and body-fat percentage and inversely associated with changes in dietary restraint in multiple reward, gustatory and processing regions (p < 0.005, corrected for multiple comparisons). In conclusion, changes in food reward-related brain activation were inversely associated with protein intake and dietary restraint during weight maintenance after weight loss and positively associated with changes in body weight and body-fat percentage. PMID- 30445720 TI - The Effect of Boron Nitride on the Thermal and Mechanical Properties of Poly(3 hydroxybutyrate-co-3-hydroxyvalerate). AB - The thermal and mechanical properties of poly(3-hydroxybutyrate-co-3 hydroxyvalerate, PHBV) composites filled with boron nitride (BN) particles with two different sizes and shapes were studied by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR), thermal gravimetric analysis (TGA) and mechanical testing. The biocomposites were produced by melt extrusion of PHBV with untreated BN and surface-treated BN particles. Thermogravimetric analysis (TGA) showed that the thermal stability of the composites was higher than that of neat PHBV while the effect of the different shapes and sizes of the particles on the thermal stability was insignificant. DSC analysis showed that the crystallinity of the PHBV was not affected significantly by the change in filler concentration and the type of the BN nanoparticle but decreasing of the crystallinity of PHBV/BN composites was observed at higher loadings. BN particles treated with silane coupling agent yielded nanocomposites characterized by good mechanical performance. The results demonstrate that mechanical properties of the composites were found to increase more for the silanized flake type BN (OSFBN) compared to silanized hexagonal disk type BN (OSBN). The highest Young's modulus was obtained for the nanocomposite sample containing 1 wt.% OSFBN, for which increase of Young's modulus up to 19% was observed in comparison to the neat PHBV. The Halpin-Tsai and Hui-Shia models were used to evaluate the effect of reinforcement by BN particles on the elastic modulus of the composites. Micromechanical models for initial composite stiffness showed good correlation with experimental values. PMID- 30445723 TI - Information-Centric Network-Based Vehicular Communications: Overview and Research Opportunities. AB - Information Centric Network (ICN) is expected to be the favorable deployable future Internet paradigm. ICN intends to replace the current IP-based model with the name-based content-centric model, as it aims at providing better security, scalability, and content distribution. However, it is a challenging task to conceive how ICN can be linked with the other most emerging paradigm, i.e., Vehicular Ad hoc Network (VANET). In this article, we present an overview of the ICN-based VANET approach in line with its contributions and research challenges.In addition, the connectivity issues of vehicular ICN model is presented with some other emerging paradigms, such as Software Defined Network (SDN), Cloud, and Edge computing. Moreover, some ICN-based VANET research opportunities, in terms of security, mobility, routing, naming, caching, and fifth generation (5G) communications, are also covered at the end of the paper. PMID- 30445721 TI - Caffeine in the Diet: Country-Level Consumption and Guidelines. AB - Coffee, tea, caffeinated soda, and energy drinks are important sources of caffeine in the diet but each present with other unique nutritional properties. We review how our increased knowledge and concern with regard to caffeine in the diet and its impact on human health has been translated into food-based dietary guidelines (FBDG). Using the Food and Agriculture Organization list of 90 countries with FBDG as a starting point, we found reference to caffeine or caffeine-containing beverages (CCB) in 81 FBDG and CCB consumption data (volume sales) for 56 of these countries. Tea and soda are the leading CCB sold in African and Asian/Pacific countries while coffee and soda are preferred in Europe, North America, Latin America, and the Caribbean. Key themes observed across FBDG include (i) caffeine-intake upper limits to avoid risks, (ii) CCB as replacements for plain water, (iii) CCB as added-sugar sources, and (iv) health benefits of CCB consumption. In summary, FBDG provide an unfavorable view of CCB by noting their potential adverse/unknown effects on special populations and their high sugar content, as well as their diuretic, psycho-stimulating, and nutrient inhibitory properties. Few FBDG balanced these messages with recent data supporting potential benefits of specific beverage types. PMID- 30445722 TI - Safety Studies of Pneumococcal Endolysins Cpl-1 and Pal. AB - Bacteriophage-derived endolysins have gained increasing attention as potent antimicrobial agents and numerous publications document the in vivo efficacy of these enzymes in various rodent models. However, little has been documented about their safety and toxicity profiles. Here, we present preclinical safety and toxicity data for two pneumococcal endolysins, Pal and Cpl-1. Microarray, and gene profiling was performed on human macrophages and pharyngeal cells exposed to 0.5 uM of each endolysin for six hours and no change in gene expression was noted. Likewise, in mice injected with 15 mg/kg of each endolysin, no physical or behavioral changes were noted, pro-inflammatory cytokine levels remained constant, and there were no significant changes in the fecal microbiome. Neither endolysin caused complement activation via the classic pathway, the alternative pathway, or the mannose-binding lectin pathway. In cellular response assays, IgG levels in mice exposed to Pal or Cpl-1 gradually increased for the first 30 days post exposure, but IgE levels never rose above baseline, suggesting that hypersensitivity or allergic reaction is unlikely. Collectively, the safety and toxicity profiles of Pal and Cpl-1 support further preclinical studies. PMID- 30445724 TI - Structural Health Monitoring (SHM) and Determination of Surface Defects in Large Metallic Structures using Ultrasonic Guided Waves. AB - Ultrasonic guided wave (UGW) is one of the most commonly used technologies for non-destructive evaluation (NDE) and structural health monitoring (SHM) of structural components. Because of its excellent long-range diagnostic capability, this method is effective in detecting cracks, material loss, and fatigue-based defects in isotropic and anisotropic structures. The shape and orientation of structural defects are critical parameters during the investigation of crack propagation, assessment of damage severity, and prediction of remaining useful life (RUL) of structures. These parameters become even more important in cases where the crack intensity is associated with the safety of men, environment, and material, such as ship's hull, aero-structures, rail tracks and subsea pipelines. This paper reviews the research literature on UGWs and their application in defect diagnosis and health monitoring of metallic structures. It has been observed that no significant research work has been convened to identify the shape and orientation of defects in plate-like structures. We also propose an experimental research work assisted by numerical simulations to investigate the response of UGWs upon interaction with cracks in different shapes and orientations. A framework for an empirical model may be considered to determine these structural flaws. PMID- 30445725 TI - Can Adsorption on Graphene be Used for Isotopic Enrichment? A DFT Perspective. AB - We have explored the theoretical applicability of adsorption on graphene for the isotopic enrichment of aromatic compounds. Our results indicate that for nonpolar molecules, like benzene, the model compound used in these studies shows a reasonable isotopic fractionation that is obtained only for the deuterated species. For heavier elements, isotopic enrichment might be possible with more polar compounds, e.g., nitro- or chloro-substituted aromatics. For benzene, it is also not possible to use isotopic fractionation to differentiate between different orientations of the adsorbed molecule over the graphene surface. Our results also allowed for the identification of theory levels and computational procedures that can be used for the reliable prediction of the isotope effects on adsorption on graphene. In particular, the use of partial Hessian is an attractive approach that yields acceptable values at an enormous increase of speed. PMID- 30445727 TI - Population-Level Analysis to Determine Parameters That Drive Variation in the Plasma Metabolite Profiles. AB - The plasma metabolome is associated with multiple phenotypes and diseases. However, a systematic study investigating clinical determinants that control the metabolome has not yet been conducted. In the present study, therefore, we aimed to identify the major determinants of the plasma metabolite profile. We used ultra-high performance liquid chromatography (UHPLC) coupled to quadrupole time of flight mass spectrometry (QTOF-MS) to determine 106 metabolites in plasma samples from 2503 subjects in a cross-sectional study. We investigated the correlation structure of the metabolite profiles and generated uncorrelated metabolite factors using principal component analysis (PCA) and varimax rotation. Finally, we investigated associations between these factors and 34 clinical covariates. Our results suggest that liver function, followed by kidney function and insulin resistance show the strongest associations with the plasma metabolite profile. The association of specific phenotypes with several components may suggest multiple independent metabolic mechanisms, which is further supported by the composition of the associated factors. PMID- 30445728 TI - Molecular Docking, Computational, and Antithrombotic Studies of Novel 1,3,4 Oxadiazole Derivatives. AB - A new series of 1,3,4-oxadiazoles derivatives was synthesized, characterized, and evaluated for their in vitro and in vivo anti-thrombotic activity. Compounds (3a 3i) exhibited significant clot lysis with respect to reference drug streptokinase (30,000 IU), and enhanced clotting time (CT) values (130-342 s) than heparin (110 s). High affinity towards 1NFY with greater docking score was observed for the compounds (3a, 3i, 3e, 3d, and 3h) than the control ligand RPR200095. In addition, impressive inhibitory potential against factor Xa (F-Xa) was observed with higher docking scores (5612-6270) with Atomic Contact Energy (ACE) values ( 189.68 to -352.28 kcal/mol) than the control ligand RPR200095 (Docking score 5192; ACE -197.81 kcal/mol). In vitro, in vivo, and in silico results proposed that these newly synthesized compounds might be used as anticoagulant agents. PMID- 30445726 TI - Molecular Mechanisms Regulating Organ-Specific Metastases in Epithelial Ovarian Carcinoma. AB - Epithelial ovarian carcinoma is the most predominant type of ovarian carcinoma, the deadliest gynecologic malignancy. It is typically diagnosed late when the cancer has already metastasized. Transcoelomic metastasis is the most predominant mechanism of dissemination from epithelial ovarian carcinoma, although both hematogenously and lymphogenously spread metastases also occur. In this review, we describe molecular mechanisms known to regulate organ-specific metastasis from epithelial ovarian carcinoma. We begin by discussing the sites colonized by metastatic ovarian carcinoma and rank them in the order of prevalence. Next, we review the mechanisms regulating the transcoelomic metastasis. Within this chapter, we specifically focus on the mechanisms that were demonstrated to regulate peritoneal adhesion-one of the first steps in the transcoelomic metastatic cascade. Furthermore, we describe mechanisms of the transcoelomic metastasis known to regulate colonization of specific sites within the peritoneal cavity, including the omentum. Mechanisms underlying hematogenous and lymphogenous metastatic spread are less comprehensively studied in ovarian cancer, and we summarize mechanisms that were identified to date. Lastly, we discuss the outcomes of the clinical trials that attempted to target some of the mechanisms described in this review. PMID- 30445729 TI - User Characteristic Aware Participant Selection for Mobile Crowdsensing. AB - Mobile crowdsensing (MCS) is a promising sensing paradigm that leverages diverse embedded sensors in massive mobile devices. One of its main challenges is to effectively select participants to perform multiple sensing tasks, so that sufficient and reliable data is collected to implement various MCS services. Participant selection should consider the limited budget, the different tasks locations, and deadlines. This selection becomes even more challenging when the MCS tries to efficiently accomplish tasks under different heat regions and collect high-credibility data. In this paper, we propose a user characteristics aware participant selection (UCPS) mechanism to improve the credibility of task data in the sparse user region acquired by the platform and to reduce the task failure rate. First, we estimate the regional heat according to the number of active users, average residence time of users and history of regional sensing tasks, and then we divide urban space into high-heat and low-heat regions. Second, the user state information and sensing task records are combined to calculate the willingness, reputation and activity of users. Finally, the above four factors are comprehensively considered to reasonably select the task participants for different heat regions. We also propose task queuing strategies and community assistance strategies to ensure task allocation rates and task completion rates. The evaluation results show that our mechanism can significantly improve the overall data quality and complete sensing tasks of low heat regions in a timely and reliable manner. PMID- 30445730 TI - An Intelligent Smart Plug with Shared Knowledge Capabilities. AB - The massive dissemination of smart devices in current markets provides innovative technologies that can be used in energy management systems. Particularly, smart plugs enable efficient remote monitoring and control capabilities of electrical resources at a low cost. However, smart plugs, besides their enabling capabilities, are not able to acquire and communicate information regarding the resource's context. This paper proposes the EnAPlug, a new environmental awareness smart plug with knowledge capabilities concerning the context of where and how users utilize a controllable resource. This paper will focus on the abilities to learn and to share knowledge between different EnAPlugs. The EnAPlug is tested in two different case studies where user habits and consumption profiles are learned. A case study for distributed resource optimization is also shown, where a central heater is optimized according to the shared knowledge of five EnAPlugs. PMID- 30445731 TI - Roof Shape Classification from LiDAR and Satellite Image Data Fusion Using Supervised Learning. AB - Geographic information systems (GIS) provide accurate maps of terrain, roads, waterways, and building footprints and heights. Aircraft, particularly small unmanned aircraft systems (UAS), can exploit this and additional information such as building roof structure to improve navigation accuracy and safely perform contingency landings particularly in urban regions. However, building roof structure is not fully provided in maps. This paper proposes a method to automatically label building roof shape from publicly available GIS data. Satellite imagery and airborne LiDAR data are processed and manually labeled to create a diverse annotated roof image dataset for small to large urban cities. Multiple convolutional neural network (CNN) architectures are trained and tested, with the best performing networks providing a condensed feature set for support vector machine and decision tree classifiers. Satellite image and LiDAR data fusion is shown to provide greater classification accuracy than using either data type alone. Model confidence thresholds are adjusted leading to significant increases in models precision. Networks trained from roof data in Witten, Germany and Manhattan (New York City) are evaluated on independent data from these cities and Ann Arbor, Michigan. PMID- 30445732 TI - Human Bocavirus Infection Markers in Peripheral Blood and Stool Samples of Children with Acute Gastroenteritis. AB - Human bocaviruses (HBoVs) 1-4 belong to the Parvoviridae family, and they infect the respiratory or gastrointestinal tracts in children. We investigated the prevalence of HBoV1-4 DNAs in the blood and stool samples, and of HBoV1-4 IgG and IgM in the plasma samples, of children presenting with acute gastroenteritis (AGE). In addition, we identified HBoV co-infections with the five most frequent gastrointestinal pathogens. A total of 83 paired blood and stool samples were collected from children aged five years or less. Infection markers of HBoV1, 2, or 3 (viral DNA in blood and/or stool and/or antibodies) were detected in 61 out of 83 (73.5%) patients. HBoV1, 2, or 3 DNA as a monoinfection was revealed in 18.1%, 2.4%, and 1.2%, respectively, and 21.7% in total. In 56.1% of the HBoV DNA positive patients, the presence in stool of another virus-most frequently norovirus or rotavirus-was observed. In conclusion, this study, for the first time, illustrates the prevalence and genetic diversity of HBoVs in Latvian children with gastroenteritis, and shows a widespread distribution of these viruses in the community. HBoV1 and 2 are commonly found as single infectious agents in children with AGE, suggesting that the viruses can be as pathogenic by themselves as other enteric agents are. PMID- 30445734 TI - A Rapid, Sensitive, and Portable Biosensor Assay for the Detection of Botulinum Neurotoxin Serotype A in Complex Food Matrices. AB - Botulinum neurotoxin (BoNT) intoxication can lead to the disease botulism, characterized by flaccid muscle paralysis that can cause respiratory failure and death. Due to the significant morbidity and mortality costs associated with BoNTs high toxicity, developing highly sensitive, rapid, and field-deployable assays are critically important to protect the nation's food supply against either accidental or intentional contamination. We report here that the B-cell based biosensor assay CANARY(r) (Cellular Analysis and Notification of Antigen Risks and Yields) Zephyr detects BoNT/A holotoxin at limits of detection (LOD) of 10.0 +/- 2.5 ng/mL in assay buffer. Milk matrices (whole milk, 2% milk and non-fat milk) with BoNT/A holotoxin were detected at similar levels (7.4-7.9 ng/mL). BoNT/A complex was positive in carrot, orange, and apple juices at LODs of 32.5 75.0 ng/mL. The detection of BoNT/A complex in solid complex foods (ground beef, smoked salmon, green bean baby puree) ranged from 14.8 ng/mL to 62.5 ng/mL. Detection of BoNT/A complex in the viscous liquid egg matrix required dilution in assay buffer and gave a LOD of 171.9 +/- 64.7 ng/mL. These results show that the CANARY(r) Zephyr assay can be a highly useful qualitative tool in environmental and food safety surveillance programs. PMID- 30445733 TI - Adsorption of Cu(II) and Zn(II) Ions from Aqueous Solution by Gel/PVA-Modified Super-Paramagnetic Iron Oxide Nanoparticles. AB - Super-paramagnetic iron oxide nanoparticles (SPIONs)/gelatin (gel)/polyvinyl alcohol (PVA) nanoparticles were designed and synthesized by the co-precipitation method and further modified with gel and PVA. These nanoparticles were used for the removal of Cu(II) and Zn(II) from aqueous solutions. The adsorbents were rich in different functional groups for chemisorption and showed effective adsorption properties. The adsorption of Cu(II) and Zn(II) on the SPIONs/gel and SPIONs/gel/PVA materials were investigated with respect to pH, adsorption kinetics, and adsorption isotherms. The adsorption data was fitted to the Langmuir, Freundlich, and Sips models at the optimum pH 5.2 (+/-0.2) over 60 min; SPIONs/gel showed maximum adsorption capacities of 47.594 mg/g and 40.559 mg/g for Cu(II) and Zn(II); SPIONs/gel/PVA showed those of 56.051 mg/g and 40.865 mg/g, respectively. The experimental data fitted the pseudo-second-order model, indicating that the process followed chemical monolayer adsorption. In addition, the SPIONs/gel/PVA showed better stability and Cu(II) adsorption efficiency than SPIONs/gel. PMID- 30445735 TI - TRPM8 Channels and Dry Eye. AB - Transient receptor potential (TRP) channels transduce signals of chemical irritation and temperature change from the ocular surface to the brain. Dry eye disease (DED) is a multifactorial disorder wherein the eyes react to trivial stimuli with abnormal sensations, such as dryness, blurring, presence of foreign body, discomfort, irritation, and pain. There is increasing evidence of TRP channel dysfunction (i.e., TRPV1 and TRPM8) in DED pathophysiology. Here, we review some of this literature and discuss one strategy on how to manage DED using a TRPM8 agonist. PMID- 30445736 TI - Structural Formation of UHMWPE Film Tracked by Real-Time Retardation Measurements during Uniaxial/Biaxial Stretching. AB - This work reports on an experimental study of the stretching of ultra-high molecular weight polyethylene (UHMWPE) film in various uniaxial/biaxial stretching modes at various temperatures and stretching speeds. We examined the stress-birefringence relationship as a stress-optical rule (SOR) under uniaxial stretching and evaluated the stress-optical coefficient (SOC). Wide-angle X-ray diffraction (WAXD) measurements were applied to evaluate the contribution to birefringence of the crystalline and amorphous phases and to characterize stretching modes. In simultaneous biaxial stretching, the melting temperature (Tm) proved critical to structural formation. We applied thermal analysis techniques and tensile testing to evaluate higher order structures after each stretching mode. PMID- 30445737 TI - Qualitative Behavioural Assessment as a Method to Identify Potential Stressors during Commercial Sheep Transport. AB - Land transport is an unavoidable experience for most livestock, yet there is limited research comparing animal welfare under different conditions. We video recorded sheep responses during short (2 h) commercial road transport journeys. Using Qualitative Behavioural Assessment, observers (blinded to the treatments) scored the behavioural expression of sheep and reached significant consensus in their scoring patterns (p < 0.001). There were also significant effects of vehicle crate design (sheep transported in a 'standard' crate were more calm/relaxed than those transported in a 'convertible' crate), deck position (sheep on upper decks were more curious/alert than those on lower decks), and sheep breed (fat-tail sheep were more agitated/distressed than merino sheep) on observer scores. We only found marginal differences for sheep originating from feedlot or saleyard. Significant effects of vehicle driver (included as a random factor in all but one of our analyses) suggest driving patterns contributed to demeanour of the sheep. Finally, the fourteen drivers who participated in the study were asked their opinions on livestock transport; none of the factors we tested were identified by drivers as important for sheep welfare during transport. This study supports the use of qualitative measures in transport and revealed differences that could inform truck design. PMID- 30445738 TI - Thermal Stress Relaxation and High-Temperature Corrosion of Cr-Mo Steel Processed Using Multifunction Cavitation. AB - This research investigated high-temperature corrosion (500 degrees C) of Cr-Mo steel processed using water jet peening or multifunction cavitation (MFC), and the suitability of such steel for high-temperature boilers and reaction vessels. High-temperature corrosion was induced using an embedment test and a coating test using sulfide-type K2SO4-Na2SO4 powder. To measure the relaxation of the residual stress due to the decrease in work hardening caused by an increase in specimen temperature and the difference in thermal shrinkage between the surface and interior of the specimen, a thermal cycling test was conducted. For the MFC processed specimen, the oxide film that formed on the surface suppressed mass loss, prevented crack formation, and reduced the compressive residual stress caused by high-temperature corrosion. MFC-processed Cr-Mo steel is thus suitable for a high-temperature corrosion environment. PMID- 30445739 TI - Unstable Tetramic Acid Derivatives from the Deep-Sea-Derived Fungus Cladosporium sphaerospermum EIODSF 008. AB - Seven new unstable tetramic acid derivatives, cladosporiumins I-O (1-7), together with the known analogue cladodionen (8) were isolated from the extract of the deep-sea-derived fungus Cladosporium sphaerospermum EIODSF 008. Their structures were elucidated by spectroscopic analysis, quantum chemical calculations and ECD spectra. Compound 4 was a Mg complex of tetramic acid derivative. In acidic solvent, 4 could change to 1 and 6, and 7 could change to 5. In addition, 1, 5 and 8 existed as two exchangeable isomers, respectively. The structures of cladosporiumins E-H were reassigned as their Na complexes. The antibacterial and cytotoxic activities of 1-8 were also evaluated. However, because of their instability, all of the isolated compounds did not show significant antibacterial activity as the preliminary EtOAc extracts of the fungal strain. PMID- 30445740 TI - A Randomness Detection Method of ZigBee Protocol in a Wireless Sensor Network. AB - This study investigates the randomness detection of cryptographic algorithms in network security. To effectively test and verify the security of ZigBee protocol in the Internet of Things, the study combines with the characteristics of ZigBee networks, and it rationally organizes and divides test modes based on the binary matrix rank theory test. Then this paper proposes a randomness detection method of ZigBee protocol in a wireless sensor network. The proposed method solves the one-sidedness that the binary matrix rank test simply assesses random sequences by linear correlation. The proposed assessment method can effectively appraise whether the ZigBee protocol has an encryption mechanism and encryption strength. Simulation results show that this method has the characteristics of fewer errors and high reliability. PMID- 30445741 TI - Selection and Characterization of Packaged FBG Sensors for Offshore Applications. AB - With the development in the exploitation of maritime resources, the structural health monitoring (SHM) of offshore structures becomes necessary. This study focuses on addressing the practical issues of application of fiber Bragg grating (FBG) sensors for the SHM of offshore structures, in particular an FPSO (floating, production, storage, and offloading unit) vessel. Due to the harsh marine environment and tough working conditions, the FBG sensors must have sufficient protection and good repeatability for long-term monitoring. Thorough research has been conducted to identify the most suitable, commercially available protection packaging for FBG sensors for offshore applications. Further, the performance of the selected FBG sensor packaging is tested under conditions of strong sunlight, heavy rain, and salty water in order to emulate the marine environment. Moreover, the installation method of the packaged FBG sensors is equally important, as it ensures the repeatability and durability of the sensors for their long-term performance. It is shown that the packaged FBG sensors can be installed using resin-based epoxy to maintain the repeatability of the sensor over the long-term. Further, the packaged FBG sensors are installed and tested on a simple FPSO model. The experimental results under full load and ballast draft conditions show that the proposed FBG sensors are competent for the SHM of offshore structures. PMID- 30445742 TI - IP6 Regulation of HIV Capsid Assembly, Stability, and Uncoating. AB - The mechanisms that drive formation of the HIV capsid, first as an immature particle and then as a mature protein shell, remain incompletely understood. Recent discoveries of positively-charged rings in the immature and mature protein hexamer subunits that comprise them and their binding to the cellular metabolite inositol hexakisphosphate (IP6) have stimulated exciting new hypotheses. In this paper, we discuss how data from multiple structural and biochemical approaches are revealing potential roles for IP6 in the HIV-1 replication cycle from assembly to uncoating. PMID- 30445743 TI - Premature Puberty and Thimerosal-Containing Hepatitis B Vaccination: A Case Control Study in the Vaccine Safety Datalink. AB - Studies suggest a relationship between exposure to endocrine disrupters, such as mercury (Hg), and premature puberty. Hg exposure from Thimerosal-containing hepatitis B vaccine, administered at specific intervals within the first six months of life, and the child's long-term risk of being diagnosed with premature puberty (ICD-9 code: 259.1), was retrospectively examined, using a hypothesis testing, longitudinal case-control design on prospectively collected data, in the Vaccine Safety Datalink (VSD). Cases diagnosed with premature puberty were significantly more likely to have received increased exposure to Hg from hepatitis B vaccines preserved with Thimerosal given in the first month after birth (odds ratio (OR) = 1.803), first two months after birth (OR = 1.768), and first six months after birth (OR = 2.0955), compared to control subjects. When the data were separated by gender, the effects remained among females but not males. Female cases, as compared to female controls, were significantly more likely in a dose-dependent manner to have received a greater exposure to Hg from hepatitis B vaccines preserved with Thimerosal, given in the first six months after birth (OR = 1.0281 per ug Hg). The results of this study show a dose dependent association between increasing organic Hg exposure from Thimerosal containing hepatitis B vaccines administered within the first six months of life and the long-term risk of the child being diagnosed with premature puberty. PMID- 30445744 TI - Methylation-Based Classification of Cervical Squamous Cell Carcinoma into Two New Subclasses Differing in Immune-Related Gene Expression. AB - Cervical cancer is traditionally classified into two major histological subtypes, cervical squamous cell carcinoma (CSCC) and cervical adenocarcinoma (CA). However, heterogeneity exists among patients, comprising possible subpopulations with distinct molecular profiles. We applied consensus clustering to 307 methylation samples with cervical cancer from The Cancer Genome Atlas (TCGA). Fisher's exact test was used to perform transcription factors (TFs) and genomic region enrichment. Gene expression profiles were downloaded from TCGA to assess expression differences. Immune cell fraction was calculated to quantify the immune cells infiltration. Putative neo-epitopes were predicted from somatic mutations. Three subclasses were identified: Class 1 correlating with the CA subtype and Classes 2 and 3 dividing the CSCC subtype into two subclasses. We found the hypomethylated probes in Class 3 exhibited strong enrichment in promoter region as compared with Class 2. Five TFs significantly enriched in the hypomethylated promoters and their highly expressed target genes in Class 3 functionally involved in the immune pathway. Gene function analysis revealed that immune-related genes were significantly increased in Class 3, and a higher level of immune cell infiltration was estimated. High expression of 24 immune genes exhibited a better overall survival and correlated with neo-epitope burden. Additionally, we found only two immune-related driver genes, CARD11 and JAK3, to be significantly increased in Class 3. Our analyses provide a classification of the largest CSCC subtype into two new subclasses, revealing they harbored differences in immune-related gene expression. PMID- 30445745 TI - Simultaneous All-Parameters Calibration and Assessment of a Stereo Camera Pair Using a Scale Bar. AB - Highly accurate and easy-to-operate calibration (to determine the interior and distortion parameters) and orientation (to determine the exterior parameters) methods for cameras in large volume is a very important topic for expanding the application scope of 3D vision and photogrammetry techniques. This paper proposes a method for simultaneously calibrating, orienting and assessing multi-camera 3D measurement systems in large measurement volume scenarios. The primary idea is building 3D point and length arrays by moving a scale bar in the measurement volume and then conducting a self-calibrating bundle adjustment that involves all the image points and lengths of both cameras. Relative exterior parameters between the camera pair are estimated by the five point relative orientation method. The interior, distortion parameters of each camera and the relative exterior parameters are optimized through bundle adjustment of the network geometry that is strengthened through applying the distance constraints. This method provides both internal precision and external accuracy assessment of the calibration performance. Simulations and real data experiments are designed and conducted to validate the effectivity of the method and analyze its performance under different network geometries. The RMSE of length measurement is less than 0.25 mm and the relative precision is higher than 1/25,000 for a two camera system calibrated by the proposed method in a volume of 12 m * 8 m * 4 m. Compared with the state-of-the-art point array self-calibrating bundle adjustment method, the proposed method is easier to operate and can significantly reduce systematic errors caused by wrong scaling. PMID- 30445746 TI - Anti-Carcinogenic Glucosinolates in Cruciferous Vegetables and Their Antagonistic Effects on Prevention of Cancers. AB - Glucosinolates (GSL) are naturally occurring beta-d-thioglucosides found across the cruciferous vegetables. Core structure formation and side-chain modifications lead to the synthesis of more than 200 types of GSLs in Brassicaceae. Isothiocyanates (ITCs) are chemoprotectives produced as the hydrolyzed product of GSLs by enzyme myrosinase. Benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane ([1-isothioyanato-4-(methyl-sulfinyl) butane], SFN) are potential ITCs with efficient therapeutic properties. Beneficial role of BITC, PEITC and SFN was widely studied against various cancers such as breast, brain, blood, bone, colon, gastric, liver, lung, oral, pancreatic, prostate and so forth. Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a key transcription factor limits the tumor progression. Induction of ARE (antioxidant responsive element) and ROS (reactive oxygen species) mediated pathway by Nrf2 controls the activity of nuclear factor-kappaB (NF-kappaB). NF-kappaB has a double edged role in the immune system. NF-kappaB induced during inflammatory is essential for an acute immune process. Meanwhile, hyper activation of NF-kappaB transcription factors was witnessed in the tumor cells. Antagonistic activity of BITC, PEITC and SFN against cancer was related with the direct/indirect interaction with Nrf2 and NF-kappaB protein. All three ITCs able to disrupts Nrf2-Keap1 complex and translocate Nrf2 into the nucleus. BITC have the affinity to inhibit the NF kappaB than SFN due to the presence of additional benzyl structure. This review will give the overview on chemo preventive of ITCs against several types of cancer cell lines. We have also discussed the molecular interaction(s) of the antagonistic effect of BITC, PEITC and SFN with Nrf2 and NF-kappaB to prevent cancer. PMID- 30445747 TI - QSAR and Molecular Docking Studies of the Inhibitory Activity of Novel Heterocyclic GABA Analogues over GABA-AT. AB - We have previously reported the synthesis, in vitro and in silico activities of new GABA analogues as inhibitors of the GABA-AT enzyme from Pseudomonas fluorescens, where the nitrogen atom at the gamma-position is embedded in heterocyclic scaffolds. With the goal of finding more potent inhibitors, we now report the synthesis of a new set of GABA analogues with a broader variation of heterocyclic scaffolds at the gamma-position such as thiazolidines, methyl substituted piperidines, morpholine and thiomorpholine and determined their inhibitory potential over the GABA-AT enzyme from Pseudomonas fluorescens. These structural modifications led to compound 9b which showed a 73% inhibition against this enzyme. In vivo studies with PTZ-induced seizures on male CD1 mice show that compound 9b has a neuroprotective effect at a 0.50 mmole/kg dose. A QSAR study was carried out to find the molecular descriptors associated with the structural changes in the GABA scaffold to explain their inhibitory activity against GABA AT. Employing 3D molecular descriptors allowed us to propose the GABA analogues enantiomeric active form. To evaluate the interaction with Pseudomonas fluorescens and human GABA-AT by molecular docking, the constructions of homology models was carried out. From these calculations, 9b showed a strong interaction with both GABA-AT enzymes in agreement with experimental results and the QSAR model, which indicates that bulky ligands tend to be the better inhibitors especially those with a sulfur atom on their structure. PMID- 30445748 TI - Potential Antiviral Xanthones from a Coastal Saline Soil Fungus Aspergillus iizukae. AB - Five new (1-5) and two known xanthones (6 and 7), one of the latter (6) obtained for the first time as a natural product, together with three known anthraquinones, questin, penipurdin A, and questinol, were isolated from the coastal saline soil-derived Aspergillus iizukae by application of an OSMAC (one strain many compounds) approach. Their structures were determined by interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectroscopy (HRESIMS) data, as well as comparison of these data with those of related known compounds. Antiviral activity of xanthones 1-7 was evaluated through the cytopathic effect (CPE) inhibition assay, and compound 2 exhibited distinctly strong activity towards influenza virus (H1N1), herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) with IC50 values of 44.6, 21.4, and 76.7 MUM, respectively, which indicated that it was worth to further investigate it as a potential lead compound. The preliminary structure activity relationship of the xanthones is discussed. PMID- 30445749 TI - Sensors Based on Metal Nanoclusters Stabilized on Designed Proteins. AB - Among all new nanomaterials, metal nanoclusters (NCs) have attracted special attention due to their interesting optical properties, among others. Metal NCs have been recently studied and used as sensors for different analytes. However, there is a need to explore the potential of these new sensors in a systematic manner and to develop new systems to broaden the possibilities that sensing offers to the industry. In this work, we show the potential use of repeat protein scaffolds as versatile templates for the synthesis and stabilization of various metal NCs, specifically Au, Ag, and CuNCs. The resulting protein-metal NCs hybrids are evaluated as sensors for different stimuli such as temperature, ions, or reactive oxygen species (ROS). Among the three protein-metal NCs, all performed nicely as temperature sensors, AuNCs responded to metal ions, and AgNCs were able to detect ROS. PMID- 30445750 TI - Cell Death Patterns Due to Warm Ischemia or Reperfusion in Renal Tubular Epithelial Cells Originating from Human, Mouse, or the Native Hibernator Hamster. AB - Ischemia-reperfusion injury contributes to the pathogenesis of many diseases, with acute kidney injury included. Hibernating mammals survive prolonged bouts of deep torpor with a dramatic drop in blood pressure, heart, and breathing rates, interspersed with short periods of arousal and, consequently, ischemia reperfusion injury. Clarifying the differences under warm anoxia or reoxygenation between human cells and cells from a native hibernator may reveal interventions for rendering human cells resistant to ischemia-reperfusion injury. Human and hamster renal proximal tubular epithelial cells (RPTECs) were cultured under warm anoxia or reoxygenation. Mouse RPTECs were used as a phylogenetic control for hamster cells. Cell death was assessed by both cell imaging and lactate dehydrogenase (LDH) release assay, apoptosis by cleaved caspase-3, autophagy by microtubule-associated protein 1-light chain 3 B II (LC3B-II) to LC3B-I ratio, necroptosis by phosphorylated mixed-lineage kinase domain-like pseudokinase, reactive oxygen species (ROS) fluorometrically, and lipid peroxidation, the end point of ferroptosis, by malondialdehyde. Human cells died after short periods of warm anoxia or reoxygenation, whereas hamster cells were extremely resistant. In human cells, apoptosis contributed to cell death under both anoxia and reoxygenation. Although under reoxygenation, ROS increased in both human and hamster RPTECs, lipid peroxidation-induced cell death was detected only in human cells. Autophagy was observed only in human cells under both conditions. Necroptosis was not detected in any of the evaluated cells. Clarifying the ways that are responsible for hamster RPTECs escaping from apoptosis and lipid peroxidation-induced cell death may reveal interventions for preventing ischemia reperfusion-induced acute kidney injury in humans. PMID- 30445751 TI - Multidisciplinary Investigations on Galphimia glauca: A Mexican Medicinal Plant with Pharmacological Potential. AB - Galphimia glauca (Cav.) Kuntze is an important endemic plant species, which possesses many medicinal properties and has been used in the Mexican traditional medicine for its sedative, anxiolytic, anticonvulsant, antiasthmatic and antiallergic properties. The therapeutic properties of this plant are mainly due to the presence of diverse bioactive compounds such as flavonoids, triterpenoids, and phenolics. Several triterpenoids and flavonoids compounds have been isolated and identified. Modern studies have demonstrated many biological activities such as anti-inflammatory, antidiarrheal, gastroenteritis, antimalarial and cytotoxic activities. Nevertheless, many studies are restricted to the crude extract, and many bioactive compounds are yet to be identified and validated according to its traditional use. However, its commercial exploitation and use are highly limited due to the non-availability of enough plant material and lack of knowledge about its agronomical practices. Moreover, the misinterpretation and mislabeling of closely related species of the genus Galphimia Cav. as G. glauca or G. gracilis is a common problem for its rigorous scientific study and commercial exploitation. The present review provides comprehensive knowledge based on the available scientific literature. To the best of our knowledge, this is the first review on G. glauca. This comprehensive information will certainly provide a guide for the better understanding and utilization of G. glauca for its scientific and industrial exploitation. PMID- 30445752 TI - Retrieving the Diurnal FPAR of a Maize Canopy from the Jointing Stage to the Tasseling Stage with Vegetation Indices under Different Water Stresses and Light Conditions. AB - The fraction of absorbed photosynthetically active radiation (FPAR) is a key variable in the model of vegetation productivity. Vegetation indices (VIs) that were derived from instantaneous remote-sensing data have been successfully used to estimate the FPAR of a day or a longer period. However, it has not yet been verified whether continuous VIs can be used to accurately estimate the diurnal dynamics of a vegetation canopy FPAR, which may fluctuate dramatically within a day. In this study, we measured the high temporal resolution spectral data (480 to 850 nm) and FPAR data of a maize canopy from the jointing stage to the tasseling stage under different irrigation and illumination conditions using two automatic observation systems. To estimate the FPAR, we developed regression models based on a quadratic function using 13 kinds of VIs. The results show the following: (1) Under nondrought conditions, although the illumination condition (sunny or cloudy) influenced the trend of the canopy diurnal FPAR, it had only a slight effect on the model accuracies of the FPAR-VIs. The maximum coefficients of determination (R2) of the FPAR-VIs models generated for the sunny nondrought data, the cloudy nondrought data, and all of the nondrought data were 0.895, 0.88, and 0.828, respectively. The VIs-including normalized difference vegetation index (NDVI), green NDVI (GNDVI), red-edge simple ratio (SR705), modified simple ratio 2 (mSR2), red-edge normalized difference vegetation index (NDVI705), and enhanced vegetation index (EVI)-that were related to the canopy structure had higher estimation accuracies (R2 > 0.8) than the other VIs that were related to the soil adjustment, chlorophyll, and physiology. The estimation accuracies of the GNDVI and some red-edge VIs (including NDVI705, SR705, and mSR2) were higher than the estimation accuracy of the NDVI. (2) Under drought stress, the FPAR decreased significantly because of leaf wilting and the effective leaf area index decrease around noon. When we included drought data in the model, accuracies were reduced dramatically and the R2 value of the best model was only 0.59. When we built the regression models based only on drought data, the EVI, which can weaken the influence of soil, had the best estimate accuracy (R2 = 0.68). PMID- 30445753 TI - Eating Frequency Is Not Associated with Obesity in Chinese Adults. AB - The prevalence of overweight and obesity has been increasing globally. Recent studies suggest that eating frequency (EF) might be a factor influencing the development of overweight and obesity. This study aims to explore the association between eating frequency and obesity in Chinese adults. A cross-sectional study was conducted in Wuhan, China, from March to June 2016. A self-administered questionnaire and 24-h dietary recall were used to collect data on sociodemographic variables, lifestyle factors, nutrition knowledge, and eating frequency. Participants were divided into four groups according to eating frequency and meal timing: traditional time pattern (TTP), traditional time plus late snack pattern (TTLSP), irregular time pattern (ITP), and all-day pattern (ADP). We performed the chi-squared test and multiple logistic regression to assess associations among variables using JMP statistical software version 14.0.0 (SAS Institute Inc., Cary, NC, USA). Respondents were Chinese adults (N = 2290; range 29-74 years; 1162 men). Lower education level, higher food budget, and lower nutrition knowledge were associated with higher likelihood of irregular EF patterns (TTLSP, ITP, or ADP). Men, non-smokers, and participants with less physical activity, lower education level, or lower nutrition knowledge were more likely to be obese. Body mass index (BMI) categorization was significantly different among EF pattern groups (chi2 = 25.40, p = 0.003); however, this association was no longer significant in the regression model after adjustment for age, sex, education, smoking, food budget, nutrition knowledge, and physical activity. Thus, EF is not associated with obesity in Chinese adults. PMID- 30445754 TI - Development of Zinc-Doped Hydroxyapatite by Sol-Gel Method for Medical Applications. AB - Zinc- (Zn) doped hydroxyapatite (HAp) were prepared by sol-gel method. Zinc-doped hydroxyapatite (ZnHAp) and HAp were analyzed by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The Rietveld analysis revealed that the HAp and 7ZnHAp powders obtained by sol-gel method have a monophasic hydroxyapatite structure belonging to the P63/m spatial group. The results obtained from the ultrasound characterization of HAp and ZnHAp are also presented in this study. The effect of zinc concentration on properties that were deduced from ultrasonic measurements are studied in the case of a significant zinc concentration (xZn = 0.07). From the values of the ultrasonic waves velocities were determined by the pairs of elastic coefficients of the suspensions (Young modulus E, Poisson coefficient nu), which have proven to be similar to those determined by other authors. PMID- 30445755 TI - Method for Handling Massive IoT Traffic in 5G Networks. AB - The ever-growing Internet of Things (IoT) data traffic is one of the primary research focuses of future mobile networks. 3rd Generation Partnership Project (3GPP) standards like Long Term Evolution-Advanced (LTE-A) have been designed for broadband services. However, IoT devices are mainly based on narrowband applications. Standards like LTE-A might not provide efficient spectrum utilization when serving IoT applications. The aggregation of IoT data at an intermediate node before transmission can answer the issues of spectral efficiency. The objective of this work is to utilize the low cost 3GPP fixed, inband, layer-3 Relay Node (RN) for integrating IoT traffic into 5G network by multiplexing data packets at the RN before transmission to the Base Station (BS) in the form of large multiplexed packets. Frequency resource blocks can be shared among several devices with this method. An analytical model for this scheme, developed as an r-stage Coxian process, determines the radio resource utilization and system gain achieved. The model is validated by comparing the obtained results with simulation results. PMID- 30445757 TI - Effects of Grinding Passes and Direction on Material Removal Behaviours in the Rail Grinding Process. AB - A three-dimensional finite element model of rail grinding was established to explore the effects of grinding passes and grinding direction on the material removal behaviour of grinding rails during the grinding process. The results indicate that as the number of grinding passes increases, a decrease in the grinding force reduces both the amount of removed rail material and the surface roughness. There is a decrease in the grinding ratio caused by the increase in the wear on the grinding wheel and the decreased removal of the rail material. When the grinding direction changes, the wear of the grinding wheel decreases, which is contrary to the increasing trend of the amount of removed rail material, the grinding ratio, the surface roughness and the grinding force. PMID- 30445756 TI - The Intermolecular Interaction of Ephexin4 Leads to Autoinhibition by Impeding Binding of RhoG. AB - Ephexin4 is a guanine nucleotide-exchange factor (GEF) for RhoG and is involved in various RhoG-related cellular processes such as phagocytosis of apoptotic cells and migration of cancer cells. Ephexin4 forms an oligomer via an intermolecular interaction, and its GEF activity is increased in the presence of Elmo, an Ephexin4-interacting protein. However, it is uncertain if and how Ephexin4 is autoinhibited. Here, using an Ephexin4 mutant that abrogated the intermolecular interaction, we report that this interaction impeded binding of RhoG to Ephexin4 and thus inhibited RhoG activation. Mutation of the glutamate residue at position 295, which is a highly conserved residue located in the region of Ephexin4 required for the intermolecular interaction, to alanine (Ephexin4E295A) disrupted the intermolecular interaction and increased binding of RhoG, resulting in augmented RhoG activation. In addition, phagocytosis of apoptotic cells and formation of membrane ruffles were increased more by expression of Ephexin4E295A than by expression of wild-type Ephexin4. Taken together, our data suggest that Ephexin4 is autoinhibited through its intermolecular interaction, which impedes binding of RhoG. PMID- 30445758 TI - Extracellular Vesicles: A Potential Novel Regulator of Obesity and Its Associated Complications. AB - Childhood obesity continues to be a major public health concern. Obesity causes various metabolic complications, including insulin resistance, type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and cardiovascular disease. However, currently, we have a limited understanding of the pathophysiology in the development of these processes. Extracellular vesicles (EVs) are nano-sized vesicles secreted by different cell types that travel to various organ systems carrying molecular and genetic information. These vesicles have been proposed as a novel intercellular communication mode in systemic metabolic regulation and in several pathophysiologic processes. In particular, recent studies indicate that EVs play a critical role in the pathogenesis of obesity and its metabolic complications. In this study, we reviewed the current literature that supports the role of EVs in the regulation of metabolic homeostasis and pathogenesis of obesity and its associated metabolic complications, with a short discussion about future directions in the EV research field. PMID- 30445759 TI - A Spherical Hybrid Triboelectric Nanogenerator for Enhanced Water Wave Energy Harvesting. AB - Water waves are a continuously generated renewable source of energy. However, their random motion and low frequency pose significant challenges for harvesting their energy. Herein, we propose a spherical hybrid triboelectric nanogenerator (SH-TENG) that efficiently harvests the energy of low frequency, random water waves. The SH-TENG converts the kinetic energy of the water wave into solid-solid and solid-liquid triboelectric energy simultaneously using a single electrode. The electrical output of the SH-TENG for six degrees of freedom of motion in water was investigated. Further, in order to demonstrate hybrid energy harvesting from multiple energy sources using a single electrode on the SH-TENG, the charging performance of a capacitor was evaluated. The experimental results indicate that SH-TENGs have great potential for use in self-powered environmental monitoring systems that monitor factors such as water temperature, water wave height, and pollution levels in oceans. PMID- 30445760 TI - Causal Transcription Regulatory Network Inference Using Enhancer Activity as a Causal Anchor. AB - Transcription control plays a crucial role in establishing a unique gene expression signature for each of the hundreds of mammalian cell types. Though gene expression data have been widely used to infer cellular regulatory networks, existing methods mainly infer correlations rather than causality. We developed statistical models and likelihood-ratio tests to infer causal gene regulatory networks using enhancer RNA (eRNA) expression information as a causal anchor and applied the framework to eRNA and transcript expression data from the FANTOM Consortium. Predicted causal targets of transcription factors (TFs) in mouse embryonic stem cells, macrophages and erythroblastic leukaemia overlapped significantly with experimentally-validated targets from ChIP-seq and perturbation data. We further improved the model by taking into account that some TFs might act in a quantitative, dosage-dependent manner, whereas others might act predominantly in a binary on/off fashion. We predicted TF targets from concerted variation of eRNA and TF and target promoter expression levels within a single cell type, as well as across multiple cell types. Importantly, TFs with high-confidence predictions were largely different between these two analyses, demonstrating that variability within a cell type is highly relevant for target prediction of cell type-specific factors. Finally, we generated a compendium of high-confidence TF targets across diverse human cell and tissue types. PMID- 30445761 TI - Student's-t Mixture Regression-Based Robust Soft Sensor Development for Multimode Industrial Processes. AB - Because of multiple manufacturing phases or operating conditions, a great many industrial processes work with multiple modes. In addition, it is inevitable that some measurements of industrial variables obtained through hardware sensors are incorrectly observed, recorded or imported into databases, resulting in the dataset available for statistic analysis being contaminated by outliers. Unfortunately, these outliers are difficult to recognize and remove completely. These process characteristics and dataset imperfections impose challenges on developing high-accuracy soft sensors. To resolve this problem, the Student's-t mixture regression (SMR) is proposed to develop a robust soft sensor for multimode industrial processes. In the SMR, for each mixing component, the Student's-t distribution is used instead of the Gaussian distribution to model secondary variables, and the functional relationship between secondary and primary variables is explicitly considered. Based on the model structure of the SMR, a computationally efficient parameter-learning algorithm is also developed for SMR. Results conducted on two cases including a numerical example and a real life industrial process demonstrate the effectiveness and feasibility of the proposed approach. PMID- 30445762 TI - Economical High-Low Temperature and Heading Rotation Test Method for the Evaluation and Optimization of the Temperature Control System for High-Precision Platform Inertial Navigation Systems. AB - Inertial navigation systems (INSs) use the temperature control system to ensure the stability of the temperature of the inertial sensors for improving the navigation accuracy of the INSs. That is, the temperature control accuracy affects the performance of the INSs. Thus, the performance of temperature control systems must be evaluated before their application. However, nearly all high precision INSs are large and heavy and require long-term testing under many different experimental conditions. As a result, conducting an outdoor navigation experiment, which involves high-low temperature and heading rotation tests, is time consuming, laborious, and costly for researchers. To address this issue, an economical high-low temperature and heading rotation test method for high precision platform INSs is proposed, and an evaluation system based on this method is developed to evaluate the performance of the temperature control systems for high-precision platform INSs indoors. The evaluation system uses an acrylic chamber, exhaust fans, temperature sensors, and an air conditioner to simulate the environment temperature change. The outer gimbals of the platform INSs are utilized to simulate the heading rotation. The temperature control system of a high-precision platform INS is evaluated using the proposed evaluation method. The temperature difference of the gyros is obtained in the high-low temperature test, and the temperature fluctuation of the temperature control system is observed in the rotation test. These tests verify the effectiveness of the proposed evaluation method. Then, the corresponding optimization method for the temperature control system of this high-precision platform INS is put forward on the basis of the test results of the evaluation system. Experimental results show that the maximum temperature differences of the two gyros between high- and low-temperature tests are decreased from 1.51 degrees C to 0.50 degrees C, and the maximum temperature fluctuation value of the temperature control system is decreased from 0.81 degrees C to 0.27 degrees C after the proposed evaluation and optimization processes. Therefore, the proposed methods are cost effective and useful for evaluating and optimization of the temperature control system for INSs. PMID- 30445763 TI - Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells. AB - Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability. PMID- 30445764 TI - Exercise Training-Induced Changes in MicroRNAs: Beneficial Regulatory Effects in Hypertension, Type 2 Diabetes, and Obesity. AB - MicroRNAs are small non-coding RNAs that regulate gene expression post transcriptionally. They are involved in the regulation of physiological processes, such as adaptation to physical exercise, and also in disease settings, such as systemic arterial hypertension (SAH), type 2 diabetes mellitus (T2D), and obesity. In SAH, microRNAs play a significant role in the regulation of key signaling pathways that lead to the hyperactivation of the renin-angiotensin aldosterone system, endothelial dysfunction, inflammation, proliferation, and phenotypic change in smooth muscle cells, and the hyperactivation of the sympathetic nervous system. MicroRNAs are also involved in the regulation of insulin signaling and blood glucose levels in T2D, and participate in lipid metabolism, adipogenesis, and adipocyte differentiation in obesity, with specific microRNA signatures involved in the pathogenesis of each disease. Many studies report the benefits promoted by exercise training in cardiovascular diseases by reducing blood pressure, glucose levels, and improving insulin signaling and lipid metabolism. The molecular mechanisms involved, however, remain poorly understood, especially regarding the participation of microRNAs in these processes. This review aimed to highlight microRNAs already known to be associated with SAH, T2D, and obesity, as well as their possible regulation by exercise training. PMID- 30445765 TI - In Vitro and In Silico Analyses of Nicotine Release from a Gelisphere-Loaded Compressed Polymeric Matrix for Potential Parkinson's Disease Interventions. AB - This study aimed to develop a prolonged-release device for the potential site specific delivery of a neuroprotective agent (nicotine). The device was formulated as a novel reinforced crosslinked composite polymeric system with the potential for intrastriatal implantation in Parkinson's disease interventions. Polymers with biocompatible and bioerodible characteristics were selected to incorporate nicotine within electrolyte-crosslinked alginate hydroxyethylcellulose gelispheres compressed within a release rate-modulating external polymeric matrix, comprising either hydroxypropylmethylcellulose (HPMC), polyethylene oxide (PEO), or poly(lactic-co-glycolic) acid (PLGA) to prolong nicotine release. The degradation and erosion studies showed that the produced device had desirable robustness with the essential attributes for entrapping drug molecules and retarding their release. Zero-order drug release was observed over 50 days from the device comprising PLGA as the external matrix. Furthermore, the alginate-nicotine interaction, the effects of crosslinking on the alginate hydroxyethycellulose (HEC) blend, and the effects of blending PLGA, HPMC, and PEO on device performance were mechanistically elucidated using molecular modelling simulations of the 3D structure of the respective molecular complexes to predict the molecular interactions and possible geometrical orientation of the polymer morphologies affecting the geometrical preferences. The compressed polymeric matrices successfully retarded the release of nicotine over several days. PLGA matrices offered minimal rates of matrix degradation and successfully retarded nicotine release, leading to the achieved zero-order release for 50 days following exposure to simulated cerebrospinal fluid (CSF). PMID- 30445766 TI - Transcriptome Analysis of Long Non-Coding RNA in the Bovine Mammary Gland Following Dietary Supplementation with Linseed Oil and Safflower Oil. AB - This study aimed to characterize the long non-coding RNA (lncRNA) expression in the bovine mammary gland and to infer their functions in dietary response to 5% linseed oil (LSO) or 5% safflower oil (SFO). Twelve cows (six per treatment) in mid lactation were fed a control diet for 28 days followed by a treatment period (control diet supplemented with 5% LSO or 5% SFO) of 28 days. Mammary gland biopsies were collected from each animal on day-14 (D-14, control period), D+7 (early treatment period) and D+28 (late treatment period) and were subjected to RNA-Sequencing and subsequent bioinformatics analyses. Functional enrichment of lncRNA was performed via potential cis regulated target genes located within 50 kb flanking regions of lncRNAs and having expression correlation of >0.7 with mRNAs. A total of 4955 lncRNAs (325 known and 4630 novel) were identified which potentially cis targeted 59 and 494 genes in LSO and SFO treatments, respectively. Enrichments of cis target genes of lncRNAs indicated potential roles of lncRNAs in immune function, nucleic acid metabolism and cell membrane organization processes as well as involvement in Notch, cAMP and TGF-beta signaling pathways. Thirty-two and 21 lncRNAs were differentially expressed (DE) in LSO and SFO treatments, respectively. Six genes (KCNF1, STARD13, BCL6, NXPE2, HHIPL2 and MMD) were identified as potential cis target genes of six DE lncRNAs. In conclusion, this study has identified lncRNAs with potential roles in mammary gland functions and potential candidate genes and pathways via which lncRNAs might function in response to LSO and SFA. PMID- 30445767 TI - Menstrual Hygiene Management and Waste Disposal in Low and Middle Income Countries-A Review of the Literature. AB - Menstrual hygiene management (MHM) has gained some attention and several literature reviews have been published. However, both original papers and reviews tend to focus on absorbent access and use and not on the disposal of menstrual waste. This review aims to fill a gap in the water, sanitation and hygiene (WASH) sector by bringing a focus specifically on menstrual hygiene safe disposal in low and middle-income countries (LMIC). We reviewed published literature since 2002 on menstrual hygiene with a focus on menstrual waste management and menstrual absorbent disposal in LMIC. Database searches were conducted of both peer reviewed literature and grey literature, in addition to hand searching of references of relevant earlier literature reviews. In total 152 articles and reports were identified and 75 met the inclusion criteria and was included in the final review. Existing polices on MHM was also reviewed with a focus on India and South Africa. The review showed that disposal of menstrual waste is often neglected MHM and sanitation value chains, leading to improper disposal and negative impacts on users, the sanitation systems and the environment. Findings call for further research to gain better understandings of MHM waste streams, disposal behaviors, absorbent materials and waste management technologies to deliver health, safety, mobility and dignity for women and girls. PMID- 30445768 TI - Densely PEGylated Polybenzofulvene Brushes for Potential Applications in Drug Encapsulation. AB - The technique of grafting side chains onto a linear polymeric backbone is commonly used to confer to the new polymeric material with desired properties, such as tunable solubility, ionic charge, biocompatibility, or specific interactions with biological systems. In this paper, two new polybenzofulvene backbones were assembled by spontaneous polymerization of the appropriate benzofulvene monomers (4,6-PO-BF3k and 4',6-PO-BF3k) bearing two clickable propargyloxy groups in different positions of the 3-phenylindene scaffold. Poly 4,6-PO-BF3k and poly-4',6-PO-BF3k were grafted with monomethyl oligo(ethylene glycol) (MOEG) to prepare two new polybenzofulvene brushes (i.e., poly-4,6-MOEG-9 TM-BF3k and poly-4',6-MOEG-9-TM-BF3k) by means of a "grafting onto" approach, that were characterized from the point of view of their macromolecular features, aggregation liability, and in a preliminary evaluation of biocompatibility. The obtained results make these PEGylated polybenzofulvene brushes (PPBFB) derivatives potentially useful as nanocarriers for nanoencapsulation and delivery of drug molecules. PMID- 30445770 TI - Dual-Family Peptidylprolyl Isomerases (Immunophilins) of Select Monocellular Organisms. AB - The dual-family peptidylprolyl cis-trans isomerases (immunophilins) represent a naturally occurring chimera of the classical FK506-binding protein (FKBP) and cyclophilin (CYN), connected by a flexible linker. They are found exclusively in monocellular organisms. The modular builds of these molecules represent two distinct types: CYN-(linker)-FKBP and FKBP-3TPR (tetratricopeptide repeat)-CYN. Abbreviated respectively as CFBP and FCBP, the two classes also exhibit distinct organism preference, the CFBP being found in prokaryotes, and the FCBP in eukaryotes. This review summarizes the mystery of these unique class of prolyl isomerases, focusing on their host organisms, potential physiological role, and likely routes of evolution. PMID- 30445771 TI - Performance Evaluation of a Quality of Service Control Scheme in Multi-Hop WBAN Based on IEEE 802.15.6. AB - The performance of a quality of service (QoS) control scheme in a multi-hop wireless body area network (WBAN) based on the IEEE Std. 802.15.6 is evaluated. In medical Internet of Things systems, WBANs are an important technology. In a previous study, an optimal quality of service control scheme that employs a multiplexing layer for priority scheduling and a decomposable error control coding scheme for WBANs were proposed. However, the two-hop extension supported by IEEE Std.802.15.6 has not been considered. Here, the two-hop extension is applied. Then, the packet error ratio, number of transmissions, and energy efficiency of our previously proposed system are compared to a standard scheme under several conditions. Also, novel evaluations based on communication distance are conducted. Numerical results demonstrate that our proposed scheme, in which coding rates change relative to channel conditions, outperforms standard schemes in many aspects. In addition, those systems show the best performance when the communication distance of the first hop equals that of the second hop. In addition, the above result is theoretically clarified. PMID- 30445769 TI - Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy. AB - Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib-a third-generation EGFR-TKI targets the T790M mutation and has demonstrated high efficacy against EGFR mutated lung cancer. However, the development of acquired resistance to third generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial-mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs. PMID- 30445772 TI - Pharmacokinetics of Sublingually Delivered Fentanyl in Head and Neck Cancer Patients Treated with Curatively Aimed Chemo or Bioradiotherapy. AB - Over 90% of patients treated for head and neck cancer with curatively aimed chemo or bioradiotherapy will develop painful mucositis and xerostomia. Sublingually delivered fentanyl (SDL) is a rapid acting opioid to treat breakthrough pain. It is unclear how SDL is absorbed by the mucosa of these patients. Therefore, the aim of this study was to investigate the effects of mucositis and xerostomia on the absorption of SDL. Thirteen patients who received chemo or bioradiotherapy (RT), were given a single dose of fentanyl: Before start of RT, 3 and 6 weeks after start of RT, and 6 weeks after finishing RT. Pharmacokinetic samples were taken. The primary endpoint was the relative difference (RD) between systemic exposure to fentanyl (area under the curve; AUC) at baseline (AUCbaseline) and fentanyl AUC in the presence of mucositis grade >=2. The secondary endpoint was the RD between AUCbaseline and fentanyl AUC in the presence of xerostomia, which were analyzed by means of a paired t-test on log-transformed data. Mucositis resulted in a 12.7% higher AUC (n = 13; 95% CI: -10.7% to +42.2%, p = 0.29) compared to baseline levels and xerostomia resulted in a 22.4% lower AUC (n = 8; 95% CI: -51.9% to +25.3%, p = 0.25) compared to baseline levels. Mucositis grade >=2 or xerostomia caused by chemo or bioradiotherapy does not significantly alter the systemic exposure to SDL. Patients with pain during and after chemo or bioradiotherapy may be safely treated with SDL. PMID- 30445774 TI - The Effect of Sulforaphane on Glyoxalase I Expression and Activity in Peripheral Blood Mononuclear Cells. AB - Studies demonstrate that the potential health-beneficial effect of sulforaphane (SR), a compound formed in broccoli, is the result of a number of mechanisms including upregulation of phase two detoxification enzymes. Recent studies suggest that SR increases expression/activity of glyoxalase 1 (Glo1), an enzyme involved in the degradation of methylglyoxal, is major precursor of advanced glycation end products. Those compounds are associated with diabetes complications and other age-related diseases. In this study, the effect of SR on the expression/activity of Glo1 in peripheral blood mononuclear cells (PBMCs) from 8 healthy volunteers was investigated. PBMCs were isolated and incubated with SR (2.5 MUM-concentration achievable by consuming a broccoli portion) for 24 h and 48 h. Glo1 activity/expression, reduced glutathione (GSH), and glutathione S-transferase gene expression were measured. Glo1 activity was not affected while after 48 h a slight but significant increase of its gene expression (1.03-fold) was observed. GSTP1 expression slightly increased after 24 h incubation (1.08 fold) while the expressions of isoform GSTT2 and GSTM2 were below the limit of detection. GSH sharply decreased, suggesting the formation of GSH-SR adducts that may have an impact SR availability. Those results suggest that a regular exposure to SR by broccoli consumption or SR supplements may enhance Glo1. PMID- 30445773 TI - Proteomic Signatures of Clostridium difficile Stressed with Metronidazole, Vancomycin, or Fidaxomicin. AB - The anaerobic pathogen Clostridium difficile is of growing significance for the health care system due to its increasing incidence and mortality. As C. difficile infection is both supported and treated by antibiotics, a deeper knowledge on how antimicrobial agents affect the physiology of this important pathogen may help to understand and prevent the development and spreading of antibiotic resistant strains. As the proteomic response of a cell to stress aims at counteracting the harmful effects of this stress, it can be expected that the pattern of a pathogen's responses to antibiotic treatment will be dependent on the antibiotic mechanism of action. Hence, every antibiotic treatment is expected to result in a specific proteomic signature characterizing its mode of action. In the study presented here, the proteomic response of C. difficile 630?erm to vancomycin, metronidazole, and fidaxomicin stress was investigated on the level of protein abundance and protein synthesis based on 2D PAGE. The quantification of 425 proteins of C. difficile allowed the deduction of proteomic signatures specific for each drug treatment. Indeed, these proteomic signatures indicate very specific cellular responses to each antibiotic with only little overlap of the responses. Whereas signature proteins for vancomycin stress fulfil various cellular functions, the proteomic signature of metronidazole stress is characterized by alterations of proteins involved in protein biosynthesis and protein degradation as well as in DNA replication, recombination, and repair. In contrast, proteins differentially expressed after fidaxomicin treatment can be assigned to amino acid biosynthesis, transcription, cell motility, and the cell envelope functions. Notably, the data provided by this study hint also at so far unknown antibiotic detoxification mechanisms. PMID- 30445775 TI - Pharmaceutical Standardization and Physicochemical Characterization of Traditional Ayurvedic Marine Drug: Incinerated Conch Shell (Shankha Bhasma). AB - Natural resources such as plants, animals and minerals have always been used by mankind to develop drugs and marine world is no exception. Marine by-products like conches, pearls, mother of pearl shells, corals and so forth have been used by traditional Ayurvedic practitioners for centuries. The unique methods of these preparations are scientifically designed to eliminate unwanted impurities and convert them into bioavailable form. In this study, Conch (Xanchus pyrum) was used as a marine resource of calcium carbonate and was converted pharmaceutically from its aragonite form to calcite. All the steps of preparations and changes in the properties therein were documented and validated. Further, traditional as well as modern analytical tools were used to study its physical and chemical characters to develop a monograph. The physical characterization included particle size, X-ray diffraction (XRD), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TGA) and Fourier Transform Infra-red (FTIR). Metal composition and heavy metal limits were determined using Inductively Coupled Plasma Optical Emission Spectrometry (ICPOES). This study revealed the rearrangement of aragonite crystals into calcite form by grinding, trituration with aloe vera juice and incineration under controlled conditions. Moreover, the finished product was found to be devoid of organic matrix that is nacre. This study creates a foundation for the development of a master formula for commonly used Shankha Bhasma in Ayurvedic medicines. PMID- 30445776 TI - Fundamentals of Force-Controlled Friction Riveting: Part I-Joint Formation and Heat Development. AB - This work presents a systematic study on the correlations between process parameters and rivet plastic deformation, produced by force-controlled friction riveting. The 5 mm diameter AA2024 rivets were joined to 13 mm, nominal thickness, polyetherimide plates. A wide range of joint formations was obtained, reflecting the variation in total energy input (24-208 J) and process temperature (319-501 degrees C). The influence of the process parameters on joint formation was determined, using a central composite design and response surface methodology. Friction time displayed the highest contribution on both rivet penetration (61.9%) and anchoring depth (34.7%), and friction force on the maximum width of the deformed rivet tip (46.5%). Quadratic effects and two-way interactions were significant on rivet anchoring depth (29.8 and 20.8%, respectively). Bell-shaped rivet plastic deformation-high mechanical interlocking results from moderate energy inputs (~100 J). These geometries are characterized by: rivet penetration depth of 7 to 9 mm; maximum width of the deformed rivet tip of 9 to 12 mm; and anchoring depth higher than 6 mm. This knowledge allows the production of optimized friction-riveted connections and a deeper understanding of the joining mechanisms, further discussed in Part II of this work. PMID- 30445777 TI - The Role of TGF-beta Signaling in Lung Cancer Associated with Idiopathic Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown etiology and dismal prognosis. IPF patients are known to have an increased risk of lung cancer and careful decision-making is required for the treatment of lung cancer associated with IPF. Transforming growth factor (TGF) beta signaling plays a central role in tissue fibrosis and tumorigenesis. TGF beta-mediated pathological changes that occur in IPF lung tissue may promote the process of field cancerization and provide the microenvironment favorable to cancer initiation and progression. This review summarizes the current knowledge related to IPF pathogenesis and explores the molecular mechanisms that underlie the occurrence of lung cancer in the background of IPF, with an emphasis on the multifaceted effects of TGF-beta signaling. PMID- 30445779 TI - Identification of Self-Incompatibility Alleles by Specific PCR Analysis and S RNase Sequencing in Apricot. AB - Self-incompatibility (SI) is one of the most efficient mechanisms to promote out crossing in plants. However, SI could be a problem for fruit production. An example is apricot (Prunus armeniaca), in which, as in other species of the Rosaceae, SI is determined by an S-RNase-based-Gametophytic Self-Incompatibility (GSI) system. Incompatibility relationships between cultivars can be established by an S-allele genotyping PCR strategy. Until recently, most of the traditional European apricot cultivars were self-compatible but several breeding programs have introduced an increasing number of new cultivars whose pollination requirements are unknown. To fill this gap, we have identified the S-allele of 44 apricot genotypes, of which 43 are reported here for the first time. The identification of Sc in 15 genotypes suggests that those cultivars are self compatible. In five genotypes, self-(in)compatibility was established by the observation of pollen tube growth in self-pollinated flowers, since PCR analysis could not allowed distinguishing between the Sc and S8 alleles. Self-incompatible genotypes were assigned to their corresponding self-incompatibility groups. The knowledge of incompatibility relationships between apricot cultivars can be a highly valuable tool for the development of future breeding programs by selecting the appropriate parents and for efficient orchard design by planting self compatible and inter-compatible cultivars. PMID- 30445778 TI - Liquid-Phase Exfoliation of Graphene: An Overview on Exfoliation Media, Techniques, and Challenges. AB - Graphene, a two-dimensional (2D) carbon nanomaterial, has attracted worldwide attention owing to its fascinating properties. One of critical bottlenecks on some important classes of applications, such as printed electronics, conductive coatings, and composite fillers, is the lack of industrial-scale methods to produce high-quality graphene in the form of liquid suspensions, inks, or dispersions. Since 2008, when liquid-phase exfoliation (LPE) of graphene via sonication was initiated, huge progress has been made in the past decade. This review highlights the latest progress on the successful preparation of graphene in various media, including organic solvents, ionic liquids, water/polymer or surfactant solutions, and some other green dispersants. The techniques of LPE, namely sonication, high-shear mixing, and microfluidization are reviewed subsequently. Moreover, several typical devices of high-shear mixing and exfoliation mechanisms are introduced in detail. Finally, we give perspectives on future research directions for the development of green exfoliation media and efficient techniques for producing high-quality graphene. This systematic exploratory study of LPE will potentially pave the way for the scalable production of graphene, which can be also applied to produce other 2D layered materials, such as BN, MoS2, WS2, etc. PMID- 30445780 TI - Cryptic Diversity Hidden within the Leafminer Genus Liriomyza (Diptera: Agromyzidae). AB - Leafminer insects of the genus Liriomyza are small flies whose larvae feed on the internal tissue of some of the most important crop plants for the human diet. Several of these pest species are highly uniform from the morphological point of view, meaning molecular data represents the only reliable taxonomic tool useful to define cryptic boundaries. In this study, both mitochondrial and nuclear molecular markers have been applied to investigate the population genetics of some Tunisian populations of the polyphagous species Liriomyza cicerina, one of the most important pest of chickpea cultivars in the whole Mediterranean region. Molecular data have been collected on larvae isolated from chickpea, faba bean, and lentil leaves, and used for population genetics, phylogenetics, and species delimitation analyses. Results point toward high differentiation levels between specimens collected on the three different legume crops, which, according to the species delimitation methods, are also sufficient to define incipient species differentiation and cryptic species occurrence, apparently tied up with host choice. Genetic data have also been applied for a phylogenetic comparison among Liriomyza species, further confirming their decisive role in the systematic studies of the genus. PMID- 30445781 TI - Lateral Flow Immunoassay for Rapid Detection of Grapevine Leafroll-Associated Virus. AB - Grapevine leafroll-associated virus 3 (GLRaV-3) is one of the main pathogens of grapes, causing a significant loss in yield and decrease in quality for this agricultural plant. For efficient widespread control of this infection, rapid and simple analytical techniques of on-site testing are requested as a complementary addition for the currently applied hybridization (PCR) and immunoenzyme (ELISA) approaches. The given paper presents development and approbation of the immunochromatographic assay (ICA) for rapid detection of GLRaV-3. The ICA realizes a sandwich immunoassay format with the obtaining complexes ((antibody immobilized on immunochromatographic membrane)-(virus in the sample)-(antibody immobilized on gold nanoparticles (GNP)) during sample flow along the membrane compounds of the test strip. Three preparations of GNPs were compared for detection of GLRaV-3 at different dilutions of virus-containing sample. The GNPs with maximal average diameters of 51.0 +/- 7.9 nm provide GLRaV-3 detection for its maximal dilutions, being 4 times more than when using GNPs with a diameter of 28.3 +/- 3.3 nm, and 8 times more than when using GNPs with a diameter of 18.5 +/ 3.3 nm. Test strips have been manufactured using the largest GNPs conjugated with anti-GLRaV-3 antibodies at a ratio of 1070:1. When testing samples containing other grape wine viruses, the test strips have not demonstrated staining in the test zone, which confirms the ICA specificity. The approbation of the manufactured test strips indicated that when using ELISA as a reference method, the developed ICA is characterized by a sensitivity of 100% and a specificity of 92%. If PCR is considered as a reference method, then the sensitivity of ICA is 93% and the specificity is 92%. The proposed ICA can be implemented in one stage without the use of any additional reactants or devices. The testing results can be obtained in 10 min and detected visually. It provides significant improvement in GLRaV-3 detection, and the presented approach can be transferred for the development of test systems for other grape wine pathogens. PMID- 30445782 TI - An Efficient Availability Guaranteed Deployment Scheme for IoT Service Chains over Fog-Core Cloud Networks. AB - High availability is one of the important requirements of many end-to-end services in the Internet of Things (IoT). This is a critical issue in network function virtualization (NFV) and NFV-enabled service function chaining (SFC) due to hard- and soft-ware failures. Thus, merely mapping primary VNFs is not enough to ensure high availability, especially for SFCs deployed over fog - core cloud networks due to resource limitations of fogs. As a result, additional protection schemes, like VNF redundancy deployments, are required to improve the availability of SFCs to meet predefined requirements. With limited resources of fog instances, a cost-efficient protection scheme is required. This paper proposes a cost-efficient availability guaranteed deployment scheme for IoT services over fog-core cloud networks based on measuring the improvement potential of VNFs for improving the availability of SFCs. In addition, various techniques for redundancy placement for VNFs at the fog layer are also presented. Obtained analysis and simulation results show that the proposed scheme achieves a significant improvement in terms of the cost efficiency and scalability compared to the state-of-the-art approaches. PMID- 30445783 TI - Quantitative Evaluation of Broadband Photoacoustic Spectroscopy in the Infrared with an Optical Parametric Oscillator. AB - We evaluate the spectral resolution and the detection thresholds achievable for a photoacoustic spectroscopy (PAS) system in the broadband infrared wavelength region 3270 n m ? lambda ? 3530 n m driven by a continuous wave optical parametric oscillator (OPO) with P - ~ 1.26 W . The absorption spectra, I PAS ( lambda i ) , for diluted propane, ethane and methane test gases at low concentrations ( c ~ 100 ppm ) were measured for ~1350 discrete wavelengths lambda i . The I PAS ( lambda i ) spectra were then compared to the high resolution cross section data, sigma FTIR , obtained by Fourier Transform Infrared Spectroscopy published in the HITRAN database. Deviations of 7.1(6)% for propane, 8.7(11)% for ethane and 15.0(14)% for methane with regard to the average uncertainty between I PAS ( lambda i ) and the expected reference values based on sigma FTIR were recorded. The characteristic absorption wavelengths lambda res can be resolved with an average resolution of delta lambda res ~ 0.08 nm . Detection limits range between 7.1 ppb (ethane) to 13.6 ppb (methane). In an additional step, EUREQA, an artificial intelligence (AI) program, was successfully applied to deconvolute simulated PAS spectra of mixed gas samples at low limits of detection. The results justify a further development of PAS technology to support e.g., biomedical research. PMID- 30445784 TI - Methylation and Acetylation Enhanced the Antidiabetic Activity of Some Selected Flavonoids: In Vitro, Molecular Modelling and Structure Activity Relationship Based Study. AB - Flavonoids have been reported to exert antihyperglycemic effects and have potential to enhance the current therapy options against type 2 diabetes mellitus. However, the structure activity relationships (SAR) studies of flavonoids against this disease have not been thoroughly comprehended. Hence, in the present study, 14 structurally related flavonoids viz. wogonin, techtochrysin, norwogonin, isoscutellarein, hypolaetin, kaempferol, quercetin, methyl ether of wogonin, acetate of wogonin, acetate of norwogonin, 8-hydroxy-7 methoxyflavone, chrysin, (+)-catechin and (-)-epicatechin were taken into account for in vitro antidiabetic evaluation. Cell viability of RIN-5F pancreatic cells and 3T3-L1 pre-adipocyte cells was initially tested, then an insulin secretion assay of RIN-5F as well as adipogenesis and glucose uptake measurements of adipocyte were investigated. Subsequently, protein expressions study through adipokines measurement (leptin, adiponectin, TNF-alpha, RBP-4) via enzyme-linked immunosorbent assay (ELISA) kit, Western blotting analysis against GLUT4 and C/EBP-alpha as well as molecular docking against GLUT1 were analyzed. The results from cell culture antidiabetic assays (insulin secretion, adipogenesis, and glucose uptake), protein expressions and molecular docking pointed that the methoxy group at position C-8 is responsible for antidiabetic property of selected flavonoids via glucose uptake mechanism indicated by up regulation of GLUT4 and C/EBP-alpha expressions. The mechanism could be enhanced by the addition of an acetate group at C-5 and C-7 of the flavone skeleton. PMID- 30445785 TI - An Integrated LC-MS-Based Strategy for the Quality Assessment and Discrimination of Three Panax Species. AB - : The quality assessment and discrimination of Panax herbs are very challenging to perform due to the complexity and variability of their chemical compositions. An integrated strategy was established using UHPLC-Q-Exactive/HRMS and HPLC-ESI MS/MS to achieve an accurate, rapid, and comprehensive qualitative and quantitative analysis of Panax japonicas (PJ), Panax japonicus var. major (PM), and Panax zingiberensis (PZ). Additionally, discrimination among the three species was explored with partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) score plots. A total of 101 compounds were plausibly or unambiguously identified, including 82 from PJ, 78 from PM, and 67 from PZ. Among them, 16 representative ginsenosides were further quantified in three herbs. A clear discrimination between the three species was observed through a multivariate statistical analysis on the quantitative data. Nine compounds that allowed for discrimination between PJ, PM, and PZ were discovered. Notably, ginsenoside Rf (G-Rf), ginsenoside F3 (G-F3), and chikusetsu saponin IV (CS-IV) were the three most important differential compounds. The research indicated that the integrated LC-MS-based strategy can be applied for the quality assessment and discrimination of the three Panax herbs. PMID- 30445786 TI - A NiFe Alloy Reduced on Graphene Oxide for Electrochemical Nonenzymatic Glucose Sensing. AB - A NiFe alloy nanoparticle/graphene oxide hybrid (NiFe/GO) was prepared for electrochemical glucose sensing. The as-prepared NiFe/GO hybrid was characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). The results indicated that NiFe alloy nanoparticles can be successfully deposited on GO. The electrochemical glucose sensing performance of the as-prepared NiFe/GO hybrid was studied by cyclic voltammetry and amperometric measurement. Results showed that the NiFe/GO-modified glassy carbon electrode had sensitivity of 173 MUA mM-1 cm-2 for glucose sensing with a linear range up to 5 mM, which is superior to that of commonly used Ni nanoparticles. Furthermore, high selectivity for glucose detection could be achieved by the NiFe/GO hybrid. All the results demonstrated that the NiFe/GO hybrid has promise for application in electrochemical glucose sensing. PMID- 30445787 TI - Monitoring Fatigue Damage of Modular Bridge Expansion Joints Using Piezoceramic Transducers. AB - Modular bridge expansion joints (MBEJs) are commonly used in bridges and are often subjected to fatigue damages, which necessitate fatigue monitoring of MBEJs to ensure the reliable operation of the bridges. In this paper, a stress wave based active sensing approach using piezoceramic transducers is developed to monitor the fatigue damage of MBEJ. A MBEJ involves mainly center beam, edge beam, support bar, support box, sliding bearing, sliding spring, elastomeric strip seal, full-penetration weld and reinforcing plate. In practice, for a MBEJ, the part that is most prone to fatigue damage is the full-penetration weld between the center beam and the support bar. In this paper, a specimen, which is the full-scale center-beam/support-bar (CB/SB) assembly, was designed and fabricated to facilitate the experimental study. The assembly mainly includes center beam, support bar, reinforcing plate, and full-penetration weld. The lead zirconate titanate (PZT) transducer bonded on the support bar was used as the actuator and the PZT transducer mounted on the center beam was as the sensor. Dial indicators were utilized to measure the vertical displacement of the center beam. Two series of tests, including static test, and fatigue test, were performed on the specimen in an alternating fashion. Based on the number of cyclic loading, the experiment was divided into six different stages: 0th cycle (the healthy state), 0.8 million cycles, 1.6 million cycles, 2.4 million cycles, 3.2 million cycles, and 4 million cycles. The signals received by the PZT sensor were analyzed with the help of wavelet packet analysis. In addition, the structure stiffness also was considered as a comparative approach in this paper. Experimental results show that during the fatigue test, the structure stiffness decreases with the number of cycle loading. However, the method can only obtain the fatigue damage impact on the entire structure, and cannot determine the fatigue damage degree of a certain weld. On the other hand, the proposed method can accurately monitor the fatigue damage degree of full-penetration welds. The research results show that the developed piezoceramic enabled active sensing approach can monitor and estimate the fatigue damage in MBEJ in real-time. PMID- 30445788 TI - Genetic Dissection of Azuki Bean Weevil (Callosobruchus chinensis L.) Resistance in Moth Bean (Vigna aconitifolia [Jaqc.] Marechal). AB - The azuki bean weevil (Callosobruchus chinensis L.) is an insect pest responsible for serious postharvest seed loss in leguminous crops. In this study, we performed quantitative trait locus (QTL) mapping of seed resistance to C. chinensis in moth bean (Vigna aconitifolia [Jaqc.] Marechal). An F2 population of 188 plants developed by crossing resistant accession 'TN67' (wild type from India; male parent) and susceptible accession 'IPCMO056' (cultivated type from India; female parent) was used for mapping. Seeds of the F2 population from 2014 and F2:3 populations from 2016 and 2017 were bioassayed with C. chinensis, and the percentage of damaged seeds and progress of infestation severity were measured. Segregation analysis suggested that C. chinensis resistance in TN176 is controlled by a single dominant gene, designated as Rcc. QTL analysis revealed one principal and one modifying QTL for the resistance, named qVacBrc2.1 and qVacBrc5.1, respectively. qVacBrc2.1 was located on linkage group 2 between simple sequence repeat markers CEDG261 and DMB-SSR160 and accounted for 50.41% to 64.23% of resistance-related traits, depending on the trait and population. Comparative genomic analysis suggested that qVacBrc2.1 is the same as QTL Brc2.1 conferring C. chinensis resistance in wild azuki bean (V. nepalensis Tateishi and Maxted). Markers CEDG261 and DMB-SSR160 should be useful for marker-assisted selection for C. chinensis resistance in moth bean. PMID- 30445789 TI - LSRR-LA: An Anisotropy-Tolerant Localization Algorithm Based on Least Square Regularized Regression for Multi-Hop Wireless Sensor Networks. AB - As is well known, multi-hop range-free localization algorithms demonstrate pretty good performance in isotropic networks in which sensor nodes distribute evenly and densely. However, these algorithms are easily affected by network topology, causing a significant decrease in positioning accuracy. To improve the localization performance in anisotropic networks, this paper presents a multi-hop range-free localization algorithm based on Least Square Regularized Regression (LSRR). By building a mapping relationship between hop counts and real distances, we can regard the process of localization as a regularized regression. Firstly, the proximity information of the given network is measured. Then, a mapping model between the geographical distances and the hop distances is constructed by LSRR. Finally, each sensor node finds its own position via this mapping. The Average Localization Error (ALE) metric is used to evaluate the proposed method in our experiments, and results show that, compared with similar methods, our approach can effectively decrease the effect of anisotropy, thus considerably improving the positioning accuracy. PMID- 30445790 TI - Application of Glycation in Regulating the Heat-Induced Nanoparticles of Egg White Protein. AB - Due to the poor thermal stability of egg white protein (EWP), important challenges remain regarding preparation of nanoparticles for EWP above the denaturation temperature at neutral conditions. In this study, nanoparticles were fabricated from conjugates of EWP and isomalto-oligosaccharide (IMO) after heating at 90 degrees C for 30 min. Meanwhile, the effects of protein concentration, temperature, pH, ionic strength and degree of glycation (DG) on the formation of nanoparticles from IMO-EWP were investigated. To further reveal the formation mechanism of the nanoparticles, structures, thermal denaturation properties and surface properties were compared between EWP and IMO-EWP conjugates. Furthermore, the emulsifying activity index (EAI) and the emulsifying stability index (ESI) of nanoparticles were determined. The results indicated that glycation enhanced thermal stability and net surface charge of EWP due to changes in the EWP structure. The thermal aggregation of EWP was inhibited significantly by glycation, and enhanced with a higher degree of glycation. Meanwhile, the nanoparticles (<200 nm in size) were obtained at pH 3.0, 7.0 and 9.0 in the presence of NaCl. The increased thermal stability and surface net negative charge after glycation contributed to the inhibition. The EAI and ESI of nanoparticles were increased nearly 3-fold and 2-fold respectively, as compared to unheated EWP. PMID- 30445791 TI - Hyperglycemia Affects miRNAs Expression Pattern during Adipogenesis of Human Visceral Adipocytes-Is Memorization Involved? AB - microRNAs are increasingly analyzed in adipogenesis, whose deregulation, especially visceral, contributes to the development of diabetes. Hyperglycemia is known to affect cells while occurring acutely and chronically. Therefore, we aimed to evaluate the effect of hyperglycemia on human visceral pre/adipocytes from the perspective of microRNAs. The relative expression of 78 microRNAs was determined by TaqMan Low Density Arrays at three stages of HPA-v adipogenesis conducted under normoglycemia, chronic, and intermittent hyperglycemia (30 mM). Hierarchical clustering/Pearson correlation revealed the relationship between various microRNAs' expression profiles, while functional analysis identified the genes and signaling pathways regulated by differentially expressed microRNAs. Hyperglycemia affected microRNAs' expression patterns during adipogenesis, and at the stage of pre-adipocytes, differentiated and matured adipocytes compared to normoglycemia. Interestingly, the changes that were evoked upon hyperglycemic exposure during one adipogenesis stage resembled those observed upon chronic hyperglycemia. At least 15 microRNAs were modulated during normoglycemic and/or hyperglycemic adipogenesis and/or upon intermittent/chronic hyperglycemia. Bioinformatics analysis revealed the involvement of these microRNAs in cell cycles, lipid metabolism, ECM-receptor interaction, oxidative stress, signaling of insulin, MAPK, TGF-beta, p53, and more. The obtained data suggests that visceral pre/adipocytes exposed to chronic/intermittent hyperglycemia develop a microRNAs' expression pattern, which may contribute to further visceral dysfunction, the progression of diabetic phenotype, and diabetic complications possibly involving "epi"-memory. PMID- 30445792 TI - How to Improve Sensitivity of Sandwich Lateral Flow Immunoassay for Corpuscular Antigens on the Example of Potato Virus Y? AB - A simple approach was proposed to decrease the detection limit of sandwich lateral flow immunoassay (LFIA) by changing the conditions for binding between a polyvalent antigen and a conjugate of gold nanoparticles (GNPs) with antibodies. In this study, the potato virus Y (PVY) was used as the polyvalent antigen, which affects economically important plants in the Solanaceae family. The obtained polyclonal antibodies that are specific to PVY were characterized using a sandwich enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). For LFIA, the antibodies were conjugated with GNPs with a diameter of 17.4 +/- 1.0 nm. We conducted LFIAs using GNP conjugates in a dried state on the test strip and after pre-incubation with a sample. Pre-incubating the GNP conjugates and sample for 30 s was found to decrease the detection limit by 60-fold from 330 ng?mL-1 to 5.4 ng?mL-1 in comparison with conventional LFIA. The developed method was successfully tested for its ability to detect PVY in infected and uninfected potato leaves. The quantitative results of the proposed LFIA with pre-incubation were confirmed by ELISA, and resulted in a correlation coefficient of 0.891. The proposed approach is rapid, simple, and preserves the main advantages of LFIA as a non-laboratory diagnostic method. PMID- 30445794 TI - Reusability of SPE and Sb-modified SPE Sensors for Trace Pb(II) Determination. AB - In this work, unmodified screen-printed electrode (bare SPE) and Sb-film modified SPE (SbFSPE) sensors were employed for the analysis of trace amounts of Pb(II) in non-deaerated water solutions. The modified electrode was performed in situ in 0.5 mg/L Sb(III) and 0.01 M HCl. The methodology was validated for an accumulation potential of -1.1 V vs. Ag/AgCl and an accumulation time of 60 s. A comparative analysis of bare SPE and SbFSPE showed that the detection and quantification limits decrease for the bare SPE. The method with the bare SPE showed a linear response in the 69.8-368.4 ug/L concentration range, whereas linearity for the SbFSPE was in the 24.0-319.1 ug/L concentration range. This work also reports the reason why the multiple standard addition method instead of a linear calibration curve for Pb(II) analysis should be employed. Furthermore, the analytical method employing SbFSPE was found to be more accurate and precise compared to the use of bare SPE when sensors were employed for the first time, however this performance changed significantly when these sensors were reused in the same manner. Furthermore, electrochemical impedance spectroscopy was used for the first time to analyse the electrochemical response of sensors after being used for multiple successive analyses. Surface characterisation before and after multiple successive uses of bare SPE and SbFSPE sensors, with atomic force microscopy and field emission scanning electron microscopy, showed sensor degradation. The interference effect of Cd(II), Zn(II), As(III), Fe(II), Na(I), K(I), Ca(II), Mg(II), NO3-, Bi(III), Cu(II), Sn(II), and Hg(II) on the Pb(II) stripping signal was also studied. Finally, the application of SbFSPE was tested on a real water sample (from a local river), which showed high precision (RSD = 8.1%, n = 5) and accurate results. PMID- 30445793 TI - Tumor-Targeted Immunotherapy by Using Primary Adipose-Derived Stem Cells and an Antigen-Specific Protein Vaccine. AB - Cancer is a leading cause of mortality and a major public health problem worldwide. For biological therapy against cancer, we previously developed a unique immunotherapeutic platform by combining mesenchymal stem cells with an antigen-specific protein vaccine. However, this system possesses a few limitations, such as improperly immortalized mesenchymal stem cells (MSCs) along with transfected oncogenic antigens in them. To overcome the limitations of this platform for future clinical application, we freshly prepared primary adipose derived stem cells (ADSCs) and modified the E7' antigen (E7') as a non-oncogenic protein. Either subcutaneously co-inoculated with cancer cells or systemically administered after tumor growth, ADSC labeled with enhanced green fluorescent protein (eGFP) and combined with modified E7' (ADSC-E7'-eGFP) cells showed significant antitumor activity when combined with the protein vaccine in both colon and lung cancer in mice. Specifically, this combined therapy inhibited tumor through inducing cell apoptosis. The significantly reduced endothelial cell markers, CD31 and vascular endothelial growth factor (VEGF), indicated strongly inhibited tumor angiogenesis. The activated immune system was demonstrated through the response of CD4+ T and natural killer (NK) cells, and a notable antitumor activity might be contributed by CD8+ T cells. Conclusively, these evidences imply that this promising immunotherapeutic platform might be a potential candidate for the future clinical application against cancer. PMID- 30445795 TI - Towards Simazine Monitoring in Agro-Zootechnical Productions: A Yeast Cell Bioprobe for Real Samples Screening. AB - Simazine is an herbicide that is able to contaminate surface waters, ground waters, and milk/dairy products, thus posing concerns in both environmental health and food safety. A yeast-based bioprobe was utilized to detect simazine in spiked real samples of livestock drinking water and raw cow's milk. Yeast aerobic respiration was taken as short-term toxicological endpoint. We carried out comparative measures of yeast oxygen consumption between simazine-spiked samples and blank samples. Percentage interference (%rho) on yeast aerobic respiration was calculated through the comparison of aerobic respiration of simazine-exposed and non-exposed yeast cells. The method was optimized for raw cow's milk samples by using boric acid as fungistatic agent in order to avoid cellular proliferation. Overall, the results have shown that simazine can be detected up to concentrations five times below the EU legal concentration limits for drinking water (0.02 ppb) and cow's milk (2 ppb) (%rho values of 18.53% and 20.43% respectively; %RSD <= 15%). Dose-effect relationships of simazine were assessed. The findings of the bioassays match reasonably well with known mechanisms of toxicity and intracellular detoxification in yeast. A correlation between fat content in milk samples and analytical performance of the bioprobe was established. Results suggest the involvement of a matrix effect, presumably due to lipid sequestration of simazine. The yeast-based bioprobe has proved to be sensitive and suitable for the detection of simazine in real samples in concentrations of interest. PMID- 30445796 TI - Erratum: Zalameda, J. et al. Detection and Characterization of Damage in Quasi Static Loaded Composite Structures using Passive Thermography. Sensors 2018, 18, 3562. AB - The authors wish to correct Table 3 in their paper published in Sensors [...]. PMID- 30445797 TI - Titania-Based Hybrid Materials with ZnO, ZrO2 and MoS2: A Review. AB - Titania has properties that enable it to be used in a variety of applications, including self-cleaning surfaces, air and water purification systems, hydrogen evolution, and photoelectrochemical conversion. In order to improve the properties of titanium dioxide, modifications are made to obtain oxide/hybrid systems that are intended to have the properties of both components. In particular, zinc oxide, zirconia and molybdenum disulfide have been proposed as the second component of binary systems due to their antibacterial, electrochemical and photocatalytic properties. This paper presents a review of the current state of knowledge on the synthesis and practical utility of TiO2-ZnO and TiO2-ZrO2 oxide systems and TiO2-MoS2 hybrid materials. The first part focuses on the hydrothermal method; then a review is made of the literature on the synthesis of the aforementioned materials using the sol-gel method. In the last section, the literature on the electrospinning method of synthesis is reviewed. The most significant physico-chemical, structural and dispersive morphological properties of binary hybrid systems based on TiO2 are described. A key aim of this review is to indicate the properties of TiO2-ZnO, TiO2-ZrO2 and TiO2-MoS2 hybrid systems that have the greatest importance for practical applications. The variety of utilities of titania-based hybrid materials is emphasized. PMID- 30445798 TI - EmoTour: Estimating Emotion and Satisfaction of Users Based on Behavioral Cues and Audiovisual Data. AB - With the spread of smart devices, people may obtain a variety of information on their surrounding environment thanks to sensing technologies. To design more context-aware systems, psychological user context (e.g., emotional status) is a substantial factor for providing useful information in an appropriate timing. As a typical use case that has a high demand for context awareness but is not tackled widely yet, we focus on the tourism domain. In this study, we aim to estimate the emotional status and satisfaction level of tourists during sightseeing by using unconscious and natural tourist actions. As tourist actions, behavioral cues (eye and head/body movement) and audiovisual data (facial/vocal expressions) were collected during sightseeing using an eye-gaze tracker, physical-activity sensors, and a smartphone. Then, we derived high-level features, e.g., head tilt and footsteps, from behavioral cues. We also used existing databases of emotionally rich interactions to train emotion-recognition models and apply them in a cross-corpus fashion to generate emotional-state prediction for the audiovisual data. Finally, the features from several modalities are fused to estimate the emotion of tourists during sightseeing. To evaluate our system, we conducted experiments with 22 tourists in two different touristic areas located in Germany and Japan. As a result, we confirmed the feasibility of estimating both the emotional status and satisfaction level of tourists. In addition, we found that effective features used for emotion and satisfaction estimation are different among tourists with different cultural backgrounds. PMID- 30445799 TI - A Review for Compact Model of Thin-Film Transistors (TFTs). AB - Thin-film transistors (TFTs) have grown into a huge industry due to their broad applications in display, radio-frequency identification tags (RFID), logical calculation, etc. In order to bridge the gap between the fabrication process and the circuit design, compact model plays an indispensable role in the development and application of TFTs. The purpose of this review is to provide a theoretical description of compact models of TFTs with different active layers, such as polysilicon, amorphous silicon, organic and In-Ga-Zn-O (IGZO) semiconductors. Special attention is paid to the surface-potential-based compact models of silicon-based TFTs. With the understanding of both the charge transport characteristics and the requirement of TFTs in organic and IGZO TFTs, we have proposed the surface-potential-based compact models and the parameter extraction techniques. The proposed models can provide accurate circuit-level performance prediction and RFID circuit design, and pass the Gummel symmetry test (GST). Finally; the outlook on the compact models of TFTs is briefly discussed. PMID- 30445801 TI - A Survey of the Techniques for The Identification and Classification of Human Actions from Visual Data. AB - Recognition of human actions form videos has been an active area of research because it has applications in various domains. The results of work in this field are used in video surveillance, automatic video labeling and human-computer interaction, among others. Any advancements in this field are tied to advances in the interrelated fields of object recognition, spatio- temporal video analysis and semantic segmentation. Activity recognition is a challenging task since it faces many problems such as occlusion, view point variation, background differences and clutter and illumination variations. Scientific achievements in the field have been numerous and rapid as the applications are far reaching. In this survey, we cover the growth of the field from the earliest solutions, where handcrafted features were used, to later deep learning approaches that use millions of images and videos to learn features automatically. By this discussion, we intend to highlight the major breakthroughs and the directions the future research might take while benefiting from the state-of-the-art methods. PMID- 30445802 TI - Immunotherapy: A Novel Era of Promising Treatments for Multiple Myeloma. AB - Multiple myeloma (MM) remains an incurable hematological malignancy characterized by clonal proliferation of malignant plasma cells in bone marrow. In the last 20 years, the introduction of autologous stem cell transplantation, followed by proteasome inhibitors and immunomodulatory agents, increased the survival of MM patients by 50%. However, still a high proportion of patients relapse and become refractory, especially, high-risk patients with adverse cytogenetics where these treatment combinations have shown limited benefit. Therefore, novel strategies, such as immunotherapy, have been developed in the last few years to help improve the survival of these patients. Immunotherapy treatments include a high number of different strategies used to attack the tumor cells by using the immune system. Here, we will review the most successful immunotherapy strategies published up to date in patients with relapsed or refractory (R/R) MM, including monoclonal antibodies targeting specific antigens on the tumor cells, antibodies combined with cytotoxic drugs or Antibodies Drug Conjugates, immune checkpoint inhibitors which eliminate the barriers that damper immune cells and prevent them from attacking tumor cells, bi-specific T-cell engagers antibodies (BiTEs), bi specific antibodies and the infusion of chimeric antigen receptor-modified T cells. We overview the results of clinical studies that have been presented up to date and also review pre-clinical studies describing potential novel treatments for MM. PMID- 30445800 TI - Lipid Metabolic Reprogramming in Hepatocellular Carcinoma. AB - Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This "lipid-rich condition" is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming. PMID- 30445803 TI - A Novel Framework and Enhanced QoS Big Data Protocol for Smart City Applications. AB - Various heterogeneous devices or objects will be integrated for transparent and seamless communication under the umbrella of Internet of things (IoT). This would facilitate the open access of data for the growth of various digital services. Building a general framework of IoT is a complex task because of the heterogeneity in devices, technologies, platforms and services operating in the same system. In this paper, we mainly focus on the framework for Big Data analytics in Smart City applications, which being a broad category specifies the different domains for each application. IoT is intended to support the vision of Smart City, where advance technologies will be used for communication to improve the quality of life of citizens. A novel approach is proposed in this paper to enhance energy conservation and reduce the delay in Big Data gathering at tiny sensor nodes used in IoT framework. To implement the Smart City scenario in terms of Big Data in IoT, an efficient (optimized in quality of service) wireless sensor network (WSN) is required where communication of nodes is energy efficient. Thus, a new protocol, QoS-IoT(quality of service enabled IoT), is proposed on the top layer of the proposed architecture (the five-layer architecture consists of technology, data source, data management, application and utility programs) which is validated over the traditional protocols. PMID- 30445804 TI - A Novel Device-Free Counting Method Based on Channel Status Information. AB - Crowd counting is of significant importance for numerous applications, e.g., urban security, intelligent surveillance and crowd management. Existing crowd counting methods typically require specialized hardware deployment and strict operating conditions, thereby hindering their widespread application. To acquire a more effective crowd counting approach, a device-free counting method based on Channel Status Information (CSI) is proposed. The wavelet domain denoising is introduced to mitigate environment noise. Furthermore, the amplitude or phase covariance matrix is extracted as the eigenmatrix. Moreover, both the spatial diversity and frequency diversity are leveraged to improve detection robustness. At the same experimental environment, the accuracy of the proposed CSI-based method is compared with a renowned crowd counting one, i.e., Electronic Frog Eye: Counting Crowd Using WiFi (FCC). The experimental results reveal an accuracy improvement of 30% over FCC. PMID- 30445805 TI - Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins. AB - Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of "unstructured" proteins used for IDPs in the early days, the notion that IDPs would be completely unstructured down to the level of secondary structures has prevailed for a long time. During the last two decades, ample evidence has been accumulated showing that IDPs in their target free state are pre-populated with transient secondary structures critical for target binding. Nevertheless, such a message did not seem to have reached with sufficient clarity to the IDP or protein science community largely because similar but different expressions were used to denote the fundamentally same phenomenon of presence of such transient secondary structures, which is not surprising for a quickly evolving field. Here, we summarize the critical roles that these transient secondary structures play for diverse functions of IDPs by describing how various expressions referring to transient secondary structures have been used in different contexts. PMID- 30445806 TI - Thermal Treatment of Aerosol Deposited NiMn2O4 NTC Thermistors for Improved Aging Stability. AB - This paper examines the influence of a short-term thermal treatment of aerosol deposited negative temperature coefficient (NTC) thermistor films on the NTCR characteristics and their long-term stability with different electrode materials. An aerosol deposition of a spinel-based NiMn2O4 powder on alumina substrates with screen-printed AgPd and Au interdigital electrode structures was performed. The manufactured components of the typical size of 1206 were tempered in a moderate temperature range of 200 degrees C to 800 degrees C and aged for 1000 h at 125 degrees C in air. Based on R-T measurements in a high-precision silicone oil thermostat bath and high temperature XRD analyses, the influence of the thermal treatment was analyzed and discussed. A 60-min tempering at 400 degrees C proved to be optimal, as both the NTCR parameters and their ageing stability could be significantly improved. The findings are explained. PMID- 30445807 TI - Surface Oxidation of TiNiSn (Half-Heusler) Alloy by Oxygen and Water Vapor. AB - TiNiSn-based half-Heusler semiconducting compounds have the highest potential as n-type thermoelectric materials for the use at elevated temperatures. In order to use these compounds in a thermoelectric module, it is crucial to examine their behaviour at a working temperature (approximately 1000 K) under oxygen and a humid atmosphere. Auger electron spectroscopy (AES) and X-ray photoelectron spectroscopy (XPS) were utilized to study the surface composition and oxidation of the TiNiSn alloy at elevated temperatures. It was found that during heating in vacuum, Sn segregates to the surface. Exposing the alloy to oxygen at room temperature will cause surface oxidation of Ti to TiO2 and Ti2O3 and some minor oxidation of Sn. Oxidation at 1000 K induces Ti segregation to the surface, creating a titanium oxide layer composed of mainly TiO2 as well as Ti2O3 and TiO. Water vapor was found to be a weaker oxidative gas medium compared to oxygen. PMID- 30445809 TI - 8-Bit Adder and Subtractor with Domain Label Based on DNA Strand Displacement. AB - DNA strand displacement, which plays a fundamental role in DNA computing, has been widely applied to many biological computing problems, including biological logic circuits. However, there are many biological cascade logic circuits with domain labels based on DNA strand displacement that have not yet been designed. Thus, in this paper, cascade 8-bit adder/subtractor with a domain label is designed based on DNA strand displacement; domain t and domain f represent signal 1 and signal 0, respectively, instead of domain t and domain f are applied to representing signal 1 and signal 0 respectively instead of high concentration and low concentration high concentration and low concentration. Basic logic gates, an amplification gate, a fan-out gate and a reporter gate are correspondingly reconstructed as domain label gates. The simulation results of Visual DSD show the feasibility and accuracy of the logic calculation model of the adder/subtractor designed in this paper. It is a useful exploration that may expand the application of the molecular logic circuit. PMID- 30445810 TI - Noncovalent PEGylation via Sulfonatocalix[4]arene-A Crystallographic Proof. AB - Noncovalent or supramolecular PEGylation, in combination with the site of administration, has great potential to increase the half-life of therapeutic proteins. To date, a variety of noncovalent PEGylation strategies have been devised. However, questions remain concerning the nature of the protein-PEG interaction. Here, we report structural analyses of a model system that comprised the lysine-rich cytochrome c and two PEGylated variants of sulfonatocalix[4]arene. Complex formation was characterized in solution by NMR spectroscopy. It was found that mono- or di-PEGylated sulfonatocalix[4]arene bound the protein similar to the parent calixarene. X-ray crystal structures at <2.7 A resolution of the PEGylated derivatives in complex with cytochrome c revealed that the PEG chains were mostly disordered or encapsulated within the calixarene cavity. These results suggest that there was minimal interaction between the PEG and the protein surface, providing further evidence in favor of PEG maintaining a random coil conformation. PMID- 30445808 TI - Household Air Pollution Is Associated with Chronic Cough but Not Hemoptysis after Completion of Pulmonary Tuberculosis Treatment in Adults, Rural Eastern Democratic Republic of Congo. AB - Little is known about the respiratory health damage related to household air pollution (HAP) in survivors of pulmonary tuberculosis (PTB). In a population based cross-sectional study, we determined the prevalence and associated predictors of chronic cough and hemoptysis in 441 randomly selected PTB survivors living in 13 remote health zones with high TB burden in the South Kivu province of the Democratic Republic of Congo (DRC). Trained community and health-care workers administered a validated questionnaire. In a multivariate logistic regression, chronic cough was independently associated with HAP (adjusted odds ratios (aOR) 2.10, 95% CI: 1.10-4.00) and PTB treatment >6 months (aOR 3.80, 95% CI: 1.62-8.96). Among women, chronic cough was associated with cooking >=3 h daily (aOR 2.74, 95% CI: 1.25-6.07) and with HAP (aOR 3.93, 95% CI: 1.15-13.43). Independent predictors of hemoptysis were PTB retreatment (aOR 3.04, 95% CI: 1.04 5.09) and ignorance of treatment outcome (aOR 2.24, 95% CI: 1.09-4.58) but not HAP (aOR 1.86, 95% CI: 0.61-5.62). Exposure to HAP proved a major risk factor for chronic cough in PTB survivors, especially in women. This factor is amenable to intervention. PMID- 30445811 TI - An Artificial Molecular Shuttle Operates in Lipid Bilayers for Ion Transport. AB - Inspired by natural biomolecular machines, synthetic molecular-level machines have been proven to perform well-defined mechanical tasks and measurable work. To mimic the function of channel proteins, we herein report the development of a synthetic molecular shuttle, [2]rotaxane 3, as a unimolecular vehicle that can be inserted into lipid bilayers to perform passive ion transport through its stochastic shuttling motion. The [2]rotaxane molecular shuttle is composed of an amphiphilic molecular thread with three binding stations, which is interlocked in a macrocycle wheel component that tethers a K+ carrier. The structural characteristics enable the rotaxane to transport ions across the lipid bilayers, similar to a cable car, transporting K+ with an EC50 value of 1.0 MUM (3.0 mol % relative to lipid). We expect that this simple molecular machine will provide new opportunities for developing more effective and selective ion transporters. PMID- 30445812 TI - Direct Cloning of Bacterial Surface Polysaccharide Gene Cluster for One-step Production of Glycoconjugate Vaccine. AB - Bacterial pathogen infections are fast-growing public health threats and worldwide problems. Glycoconjugate vaccines are among the most effective means in combating such infections. Recent advances in bacterial protein glycan coupling technology (PGCT) have revolutionized the production of glycoconjugate vaccines, and draw enormous attention from both researchers and pharmaceutical companies. Cloning of bacterial surface polysaccharide gene cluster is a prerequisite for the application of PGCT. In this study, we applied RecET direct cloning strategy for rapid and efficient cloning of O-antigen polysaccharide gene clusters from Escherichia coli serotypes O25b, O26 and O55 in a high-fidelity manner. Then, these gene clusters were applied in PGCT to produce corresponding glycoconjugates. Subsequent immunological studies verified the abilities of glycoconjugate vaccine candidates O25-MBP, O26-MBP and O55-MBP to generate serotype-specific antibodies and confer protection against E. coli infections. The combination of RecET direct cloning and PGCT makes it possible for the rapid production of glycoconjugate vaccines against fast-expanding bacterial pathogens. PMID- 30445813 TI - Icephobic Strategies and Materials with Superwettability: Design Principles and Mechanism. AB - Ice formation and accretion on surfaces is a serious economic issue in energy supply and transportation. Recent strategies for developing icephobic surfaces are intimately associated with superwettability. Commonly, the superwettability of icephobic materials depends on their surface roughness and chemical composition. This article critically categorizes the possible strategies to mitigate icing problems from daily life. The wettability and classical nucleation theories are used to characterize the icephobic surfaces. Thermodynamically, the advantages/disadvantages of superhydrophobic surfaces are discussed to explain icephobic behavior. The importance of elasticity, slippery liquid-infused porous surfaces (SLIPSs), amphiphilicity, antifreezing protein, organogels, and stimuli responsive materials has been highlighted to induce icephobic performance. In addition, the design principles and mechanism to fabricate icephobic surfaces with superwettability are explored and summarized. PMID- 30445814 TI - Redistribution of acute traumatic infratentorial subdural hematoma to the spinal subdural space. AB - Spinal subdural hematoma is a rare and potentionally life-threatening condition associated with trauma and other pathological conditions. In this paper we report the autopsy findings of a 64 year old male who was repeatedly hospitalized with traumatic head injuries in the past. In this case spinal subdural hematoma was diagnosed post-mortem and later comfirmed by ante-mortem CT scan revaluation. Keywords: intracranial subdural hematoma - recurrent spinal subdural hematoma - diffuse axonal injury - autopsy findings. PMID- 30445815 TI - Intraoperative consultation in gynecologic pathology. AB - Intraoperative consultation represents an integral part of diagnostic protocols in gynecologic oncology. It may be indicated 1) to evaluate the biologic nature of a pathologic process (distinction between nonneoplastic lesions and tumors), 2) to classify the histologic type of tumor and assess its biologic behavior (typing), 3) to confirm or rule out the metastatic origin of a tumor, 4) to determine the degree of differentiation and extent of local spread of a malignant tumor (grading and staging), 5) to detect tumor deposits in lymph nodes, 6) to examine surgical resection margins, 7) to detect products of conception in uterine curettings when ectopic pregnancy is suspected and 8) to collect native tumor tissue for ancillary studies (molecular methods, flow cytometry). A frozen section of adnexal masses is commonly requested and focused primarily on the recognition of malignant tumors, the distinction between borderline tumors and carcinomas, and the identification of a metastatic process in the ovary. An intraoperative consultation may also be beneficial in the risk stratification of patients with endometrial carcinoma for the indication of lymphadenectomy, in the assessment of an endocervical surgical resection margin during fertility sparing and less radical surgery for the carcinoma of uterine cervix and in the detection of tumor spread into the lymph nodes (including sentinel lymph nodes). For the appropriate evaluation of a frozen section, awareness of the relevant clinical data and history of the patient, interpretation of the histologic findings in the context of macroscopic appearance of a specimen and an active interaction with the surgeon are required as essential conditions. Keywords: intraoperative consultation - frozen section - gynecologic pathology - tumors of ovary - metastases - sentinel lymph node. PMID- 30445816 TI - Frozen section of lung, pleura and mediastinum specimen: Retrospective analysis of 5-years practical experiences and review of the literature. AB - Thoracic frozen section biopsies including lungs, pleura and mediastinum have crucial role in differential diagnosis of solitary lesions of the lungs and mediastinum. There is a significant difference in patient's therapeutical management, if the patients suffer from lung primary malignant tumour, metastasis or non-malignant lesion. In this review, we summarize the usefulness of frozen section biopsies in thoracic surgery and provide 5-years of experiences with thoracic frozen section biopsies performed at the Department of Pathology and Molecular Medicine of Thomayer Hospital in Prague. Keywords: frozen section - lung - mediastinum. PMID- 30445817 TI - Molecular methods for detection of prognostic and predictive markers in diagnosis of adenoid cystic carcinoma of the salivary gland origin. AB - Adenoid cystic carcinoma of salivary gland origin (AdCC) is second most common salivary carcinoma characterized by frequent recurrences, perineural invasion and high long-term mortality rate. The surgical resection of the tumor in combination with adjuvant radiotherapy is the only method of choice. AdCC has been studied, altogether with immunohistochemistry, by numerous molecular-genetic techniques. Some of them, e.g. reverse-transcription PCR or fluorescent in situ hybridization contributed to the identification of translocation t(6;9)(q22-23;p23-24), which results in fusion of two transcription factors MYB-NFIB. For AdCC is this fusion unique among salivary gland carcinomas and serves as a diagnostical tool in differential diagnosis of histopathologically difficult cases. More complex methods, such as next-generation sequencing helped to detect other molecular level changes; and hence improved understanding of a development, behavior and pathogenesis of this possibly fatal malignancy. This review summarizes basic knowledge of AdCC on the genome, transcriptome and epigenetic level, which were achieved using molecular-genetic and immunohistochemical methods. Keywords: adenoid cystic carcinoma - salivary carcinoma - MYB-NFIB - FISH - aCGH - NGS. PMID- 30445818 TI - Clinicopathological analysis of programmed death-ligand 1 testing in tumor cells of 325 patients with non-small cell lung cancer: Its predictive and potential prognostic value. AB - INTRODUCTION: Recent studies on check-point inhibitor therapy, which seems to improve the prognosis of patients with advanced non-small cell lung carcinoma increase the importance of immunohistochemical analyses of the programmed-death receptor and of its ligand, PD-L1 protein. MATERIAL AND METHODS: In our study we present results of PD-L1 immunohistochemical tumor cell expression in a series of 325 lung carcinoma patients biopsies, using the clone 22C3 (and DAKO Link 48 immunostainer). Evaluation of the expression using tissue proportion scoring system allowed to distinguish negative cases (either 0 % or < 1 % of positive tumor cells) versus positive cases in the categories 1-9 %, 10-49 % and >= 50 % of positive tumor cells. RESULTS: In association to histopathologic parameters we observed similar rates of positive expression in patients with adenocarcinoma types (47,8 % of all the cases) as well as with squamous cell carcinomas (44,4 %). Within these histological categories, the rates of positivity were similar also in patients with small versus large (resectional) biopsies. In the biopsies of patients with adenocarcinoma we identified differences in the PD-L1 protein expression associated with its histological subtype. In the cases with predominant lepidic pattern the PD-L1 positivity was present in 18,8 %, with predominant acinar or papillary pattern in 40,8 % and in cases with predominant solid or micropapillary component in 74,1 % of the cases resp. Keratinizing squamous cell carcinomas were positive in 38,5 % and non-keratinizing in 53,8 % of all the cases. The hiqhest incidence of an extensive posivity was observed in sarcomatoid carcinoma type. DISCUSSION AND CONCLUSION: Immunohistochemically verified PD-L1 protein expression represents a broadly accepted predictive biomarker for immunotherapy of NSCLC patients. The indicated differences of the expression among various NSCLC types and subtypes require to be verified in larger cohorts of patients in relation with clinical parameters to demonstrate whether it could be plausible to use the PD-L1 expression in a role of a negative prognostic parameter. PMID- 30445819 TI - Aberrant axillary breast tissue with pseudoangiomatous stromal hyperplasia in a man. AB - Diagnosing accessory breast tissue in a male patient is difficult when the condition is unilateral, and there is no areola or nipple. Pseudoangiomatous hyperplasia of the mammary stroma is an uncommon benign mesenchymal proliferation that may mimic low-grade angiosarcoma. We report herein an example of tumoriform pseudoangiomatous hyperplasia of the stroma arising in the accessory breast tissue of a 38-year-old man. The condition presented as a palpable tender axillary mass. Histopathologically, there were no changes of gynecomastia. Only two cases of pseudoangiomatous hyperplasia of the stroma have been previously reported in the accessory breast tissue of men showing unilateral or bilateral gynecomastia. Our case is the first report without associated gynecomastia. Radiologic imaging features are not sufficiently specific to enable a prospective diagnosis of pseudoangiomatous hyperplasia of the stroma. Microscopic examination of the lesion is indispensable in making a definitive diagnosis. Awareness of the condition can avoid difficulty in diagnosing it. Aberrant breast tissue with mass forming pseudoangiomatous hyperplasia of the stroma, whilst rare, should be included among the benign proliferative mesenchymal lesions of the axilla. Keywords: aberrant breast tissue-accessory breast tissue-pseudoangiomatous stromal hyperplasia-gynecomastia-angiosarcoma-axilla. PMID- 30445820 TI - JOSE VEROCAY - "Pragues pathologist". The history of a Latin-American doctor. AB - Jose Verocay (Paysandu 1876 - Eichwald/Dubi, Bohemia 1927) was a Uruguayan anatomopathologist, recognized worldwide as "Prague's pathologist" (Fig. 1). In 1910, he described, for the first time, the morphological structure later called Verocay's bodies, which are used for diagnosing schwannoma. He spent the end of the XIXth century and the beginning of XXth century in Charles-Ferdinand University in Prague. During the last years of his life, he tried unsuccessfully to reintegrate himself into the Uruguayan academic community. In 1927, he passed away in Eichwald, Teplitz district, Bohemia. Keywords: Prague's pathologist - Veroca y - Verocay's bodies. PMID- 30445821 TI - Aesthetic Dermatologic Surgery Training in Canadian Residency Programs. AB - BACKGROUND:: The public and other physicians expect dermatologists to be experts on aesthetic dermatology services. In Canada, current challenges may limit residents from achieving competency in aesthetic dermatology during their training. This may adversely affect patient safety, create medicolegal risks, and deter graduates from offering aesthetic procedures. OBJECTIVES:: The objective of this article is to characterize the curriculum, hands-on learning opportunities, and perceptions of aesthetic dermatologic training in Canadian dermatology residency training programs. METHODS:: An online survey of faculty and residents within Canadian dermatology residency programs was performed. The main outcome measures were the hours of formal aesthetic dermatology teaching, the frequency of hands-on dermatology resident training with injectables and devices, and comparing faculty and resident perspectives regarding resident aesthetic dermatology training. RESULTS:: Thirty-six faculty members (40%) and 47 residents (34%) responded to the survey. Lasers, fillers, neuromodulators, and mole removal were most commonly taught in the 10 hours or fewer of formal instruction. Residents commonly observed rather than performed procedures. High dissatisfaction among residents was reported with the quality and quantity of aesthetic dermatology training. Faculty and resident respondents supported increasing aesthetic dermatology education, and approximately 70% of residents plan to offer aesthetic services. Discounted pricing or resident-led clinics were felt to be ways to increase resident hands-on experience. CONCLUSIONS:: The standardization of core competencies in aesthetic dermatologic procedures is essential to ensure patient safety and practitioner competence. At present, formal aesthetic dermatology training in residency may be insufficient for hands on training. The majority of dermatology faculty and resident respondents support increasing aesthetic dermatology training. PMID- 30445822 TI - Allocation of trisoxazole macrolides in the sponge Penares cf. nux and the impact on epiphytic bacterial cohabitants. AB - The correlation between the allocation of trisoxazole macrolides in the capitums, appendages, and bases of the sponge Penares cf. nux and the surface-attached bacteria on the corresponding parts was examined. The kabiramide contents were highest in the capitums, followed by the appendages and bases. Conversely, direct counts of cultivable surface-attached bacteria showed that the bacteria aggregate more densely on the surfaces of the bases. This suggested the repelling effects of the kabiramides against the fouling bacteria, particularly on the capitums and appendages. Twenty-two bacterial strains were isolated and identified to 15 species; however, none has shown the potentials as a producer of any secondary metabolites in the sponge P. nux. PMID- 30445823 TI - Anti-inflammatory activity of 4',6,7-trihydroxy-5-methoxyflavone from Fridericia chica (Bonpl.) L.G.Lohmann. AB - Fridericia chica, Bignoniaceae, is a tropical tree-creeper used as a traditional remedy for a number of diseases, highlighting inflammation. Our objective was to corroborate the popular anti-inflammatory use of the hydroethanolic extract from the leaves (HEFc) and of its isolated 4',6,7-trihydroxy-5-methoxyflavone (5-O methylscutellarein) [1], described here for the first time. Quantitative analysis indicated 8.77 +/- 0.23 mg/g of this compound in the extract. Neither HEFc nor [1] was cytotoxic in vitro. In LPS-induced peritonitis in mice, oral pre treatment with HEFc or [1] led to decreased leukocyte migration to the peritoneal cavity and a reduction in the concentrations of pro-inflammatory cytokines (TNFalpha and IL-1beta). Also, the anti-inflammatory cytokine IL-10 was enhanced following treatment with [1]. Overall, these results validate the traditional use of Fridericia chica as anti-inflammatory, and indicate that the compound 5-O methylscutellarein may participate in this effect. PMID- 30445824 TI - Isolation, identification of secondary metabolites from Salvia absconditiflora and evaluation of their antioxidative properties. AB - Salvia absconditiflora Greuter & Burdet (Synonym Salvia cryptantha Montbret & Aucher ex Benth) has been used extensively for traditional medicine. The aerial of plant material was boiled in water then filtrated. The filtrate was partitioned with ethyl acetate and n-butanol sequentially to yield the ethyl acetate and n-butanol extract. A sample of water was lyophilized to yield the water extract. Ethyl acetate extract revealed the highest antioxidant activity and included the most phenolic compounds among the extracts. Hence, ethyl acetate extract was subjected to chromatographic techniques. Ursolic acid (1), crismaritin (2), luteolin (3), rosmarinic acid methyl ester (4), 3,4-dihydroxyl benzaldehyde (protocatechuic aldehyde) (5), caffeic acid (6), apigenin-7-O-beta glucoside (7), rosmarinic acid (8) and luteolin-7-O-beta-glucoside (9) were isolated and the structures were elucidated by spectroscopic methods including 1D, 2D NMR, and LC-TOF/MS. Cirsimaritin (2), luteolin (3), rosmarinic acid methyl ester (4), rosmarinic acid (8), luteolin-7-O-beta-glucoside (9) displayed the considerable antioxidant activity. PMID- 30445825 TI - Phytotoxic metabolites by nine species of Botryosphaeriaceae involved in grapevine dieback in Australia and identification of those produced by Diplodia mutila, Diplodia seriata, Neofusicoccum australe and Neofusicoccum luteum. AB - Botryosphaeria dieback is one of the main trunk diseases of grapevine caused by several species of Botryosphaeriaceae. Twenty-four fungal isolates representing the eight most widespread and most virulent Botryosphaeriaceae were tested for their ability to produce phytotoxic metabolites. The chromatographic profiles of their culture filtrates organic extracts showed the ability of all isolates to produce several and different metabolites. When tested on grapevine leaves and tomato cuttings the organic extracts phytotoxicity varied among isolates and species. To our knowledge, this is the first study on phytotoxic compounds produced by Botryosphaeriaceae species found in Australian vineyards. The phytotoxic metabolites produced by Diplodia seriata, Diplodia mutila, Neofusicoccum australe and, for the first time, by Neofusicoccum luteum were isolated and chemically identified essentially by spectroscopic methods. [Formula: see text]. PMID- 30445826 TI - Chemical profile and biological activities of Peltigera horizontalis (Hudson) Baumg. thallus and apothecia extracts. AB - The aim of this study was to determine, for the first time, the chemical composition of Peltigera horizontalis thallus and apothecia extracts (ether, ethyl acetate, dichloromethane and acetone) by HPLC-UV and GC-MS, and evaluate activity of genotoxic, anticholinesterase, antioxidant and antibacterial potential of acetone extracts. Major constituents of thallus extracts were gyrophoric acid, and methyl gyrophorate while dominant component of apothecia extracts was tenuiorin. The predominant volatile compounds in extracts were methyl orsellinate, dodecyl acrylate, orcinol and orcinol monomethyl ether. The thallus acetone extract at concentration of 2.0 ug mL-1 gave the greatest decrease in the micronuclei frequency (22.4%) of all tested extracts. Apothecia extract showed stronger antioxidant activity as compared to thallus extract. Tested extracts at concentration of 10 mg mL-1 exhibited inhibitory effect (16.5% for thallus and 12.8% for apothecia) on pooled human serum cholinesterase. P. horizontalis acetone extracts had no activity against the tested five bacteria strains. PMID- 30445827 TI - Two new monoterpenoid indole alkaloids from Tabernaemontana divaricata. AB - Two new monoterpenoid indole alkaloids, tabervarines A (1) and B (2), along with seven known monoterpenoid indole alkaloids, were isolated from the methanol extract of the twigs and leaves of Tabernaemontana divaricata. The structures including the absolute configurations of the new alkaloids were elucidated based on MS, NMR, and ECD calculation. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines were also evaluated. PMID- 30445829 TI - Routinely collected data for trialists: The need for continued conversations and solution sharing. PMID- 30445828 TI - Parents' future visions for their autistic transition-age youth: Hopes and expectations. AB - Researchers have documented that young adults with autism spectrum disorder have poor outcomes in employment, post-secondary education, social participation, independent living, and community participation. There is a need to further explore contributing factors to such outcomes to better support successful transitions to adulthood. Parents play a critical role in transition planning, and parental expectations appear to impact young adult outcomes for autistic individuals. The aim of this study was to explore how parents express their future visions (i.e. hopes and expectations) for their autistic transition-age youth. Data were collected through focus groups and individual interviews with 18 parents. Parents' hopes and expectations focused on eight primary domains. In addition, parents often qualified or tempered their stated hope with expressions of fears, uncertainty, realistic expectations, and the perceived lack of guidance. We discuss our conceptualization of the relations among these themes and implications for service providers and research. PMID- 30445830 TI - The absolute configuration of anti-Vibrio citrinin dimeric derivative by VCD, ECD and NMR methods. AB - Citrinin dimeric derivatives are bioactive polyketides previously reported from Penicillium, Aspergillus and Monascus fungi species. Due to the large distance between the stereogenic centers of the two monomer units, it was difficult to determine the absolute configuration of the whole molecule (1). In previous work, the absolute configuration of 1 was just proposed by biogenetic considerations. To address this problem, the experimental VCD of 1 was compared with the corresponding DFT calculations for two diastereomers (1a and 1b). Also, the experimental ECD and NMR spectra of 1 were combined for analysis with the corresponding theoretical predictions for different diastereomers. Additionally, compound 1 showed promising anti-Vibrio activity against pathogenic Vibrio spp. with MIC values ranging from 0.4 to 0.8 MUM. [Formula: see text]. PMID- 30445831 TI - Two new phenolic compounds and some biological activities of Scorzonera pygmaea Sibth. & Sm. subaerial parts. AB - Phytochemical composition of ethyl acetate fraction and total phenolic content, in vitro antioxidant, anti-inflammatory, antimicrobial activities of petroleum ether, chloroform, ethyl acetate and n-butanol fractions of the ethanol extract obtained from the subaerial parts of Scorzonera pygmaea Sibth. & Sm. (Asteraceae) were investigated. Nine compounds; scorzopygmaecoside (1), scorzonerol (2), cudrabibenzyl A (3), thunberginol C (4), scorzocreticoside I (5) and II (6), chlorogenic acid (7), chlorogenic acid methyl ester (8), 3,5-di-O-caffeoylquinic acid (9) were isolated and identified using spectroscopic methods. All substances were isolated for the first time from this species. Compounds 1 and 2 are new. The fractions showed high antioxidant capacity correlated with their phenolic content and no significant antimicrobial activity against tested bacteria and fungi. COX inhibition test was used to evaluate the anti-inflammatory activity and all the fractions showed low inhibition in comparison with indomethacin. [Formula: see text]. PMID- 30445832 TI - Analysis of chemical components in herbal formula Qi Bai Granule by UPLC-ESI-Q TOF-MS. AB - Qi Bai Granule (QBG), a traditional Chinese medicine formula for the treatment of idiopathic thrombocytopenic purpura, is composed of seven herbs. It is necessary to learn its chemical composition for quality control. In this study, a method for rapid separation and structural identification of the constituents in QBG was established by UPLC-ESI-Q-TOF-MS in negative and positive ion mode. As a result, 112 compounds, such as triterpenoids, flavonoids and monoterpenes were detected. Based on the retention times, accurate masses, fragment ions, related literatures, and/or authentic standards, 107 compounds were unambiguously identified or tentatively characterized. Additionally, 20% monarch, 50% minister, 5% assistant and 24% guide drugs of 112 compounds were detected, which on the whole was consistent with the compatibility of QBG. The results would provide a scientific basis for the quality control, quantitative analysis and further study in vivo or vitro of QBG. PMID- 30445833 TI - Beware of on-treatment safety analyses. AB - INTRODUCTION:: Assessing safety is important to evaluating new medications. In many randomized clinical trials, assessment of safety relies on so-called on treatment analysis, where data on adverse events are collected only while the participant is taking study medication and perhaps for a few (7, 14, or 30) days after stopping. This article discusses the consequence of such failure to use intent-to-treat analyses in assessing safety. METHODS:: This article discusses two approaches to analysis of safety data: intention-to-treat and on-treatment analysis with reference to principles of the design of randomized clinical trial. RESULTS:: On-treatment analysis violates randomization and is often not well defined. Moreover, because the typical on-treatment analysis ignores the reason participants in clinical trials stop treatment, on-treatment analyses can lead to biased estimates of risk. Examples show biases that can result from failure to count all adverse events. An example from a study of rofecoxib shows an on treatment analysis that led to likely underestimation of harm; an example from a study of saxagliptin shows an on-treatment analysis that led to a likely overestimate of harms. CONCLUSION:: For major safety outcomes in long-term clinical trials, intention-to-treat analysis should be performed in the framework of benefit-risk evaluation. More generally, analyses of safety should be tailored to the specific question being asked with the specific study design under consideration. On-treatment analyses are subject to bias; however, the direction of that bias is not necessarily clear. PMID- 30445834 TI - Anti-beta-amyloid aggregation activity of enantiomeric furolactone-type lignans from Archidendron clypearia (Jack) I.C.N. AB - The phytochemical investigation on the twigs and leaves of Archidendron clypearia (Jack) I.C.N. led to the isolation of three pairs of furolactone-type lignans enantiomers, including a pair of new compounds (1R,5S,6S)-Kachiranol (1a) and (1S,5R,6R)-Kachiranol (1b) and four known compounds (2a/2b and 3a/3b). Separation of the furolactone-type lignans enantiomeric mixtures was achieved using chiral HPLC for the first time. Their structures were determined by spectroscopic analysis and comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. All optical pure compounds were evaluated for their inhibitory effects on beta-amyloid aggregation by ThT assay. Among them, the inhibitory activity of the compound 1b (71.1%) was higher than the positive control (61.0%) and other compounds. In addition, molecular dynamics and molecular docking were employed to explore the binding relationship between the ligand and the receptor. PMID- 30445835 TI - FDA-Catalyst-Using FDA's Sentinel Initiative for large-scale pragmatic randomized trials: Approach and lessons learned during the planning phase of the first trial. AB - BACKGROUND:: The US Food and Drug Administration's Sentinel Initiative is well positioned to support pragmatic clinical trials. FDA-Catalyst combines direct contact with health plan members and/or providers with data in the Sentinel infrastructure. Here, we describe the rationale, feasibility analyses, and lessons learned from the planning phase of the first large pragmatic trial conducted using the Sentinel Initiative's delivery system capabilities IMplementation of a randomized controlled trial to imProve treatment with oral AntiCoagulanTs in patients with Atrial Fibrillation (the IMPACT-AFib trial). METHODS:: During the planning phase, we convened representatives from five commercial health plans, FDA, study coordinating centers, and a patient representative for protocol development, institutional review board preparation, and other activities. Administrative claims data from the plans were included in a retrospective cohort analysis to assess sample size for the trial. Members >=30 years old with >=365 days of medical/pharmacy coverage, >=2 diagnosis codes for atrial fibrillation, a guideline-based indication for oral anticoagulant use for stroke prevention, and no evidence of oral anticoagulant use in the 365 days prior to the index atrial fibrillation diagnosis in 2013 were included. Exclusions for the analysis included other conditions requiring anticoagulation, history of intracranial hemorrhage, and gastrointestinal bleed. We calculated rates of oral anticoagulant use, transient ischemic attack or stroke, and bleeding in the 365 days following the index atrial fibrillation diagnosis. RESULTS:: A total of 44,786 members with atrial fibrillation with no evidence of recent oral anticoagulant use were identified. In total, 87% (n = 38,759) were classified as having a guideline-based indication for oral anticoagulants. Of those, 33% (n = 12,867) had a new oral anticoagulant dispensed during the following year, 15% (n = 5917) were hospitalized for stroke or transient ischemic attack, and 9% (n = 3469) for bleeding events. This information was used to develop the trial protocol including sample size, power calculations, and level of randomization. CONCLUSION:: Sentinel infrastructure generated preliminary data that supported planning and implementation of a large pragmatic trial embedded in health plans. This planning identified unanticipated challenges that must be addressed in similar trials. PMID- 30445836 TI - Antimicrobial tunicamycin derivatives from the deep sea-derived Streptomyces xinghaiensis SCSIO S15077. AB - Tunicamycin E (1), featuring a methyl substitution at C-10', was isolated from marine-derived Streptomyces xinghaiensis SCSIO S15077 originated from the South China Sea sediment together with six known compounds, tunicamycin B (2), tunicamycin X (3), tunicamycin A (4), streptovirudin D2 (5), tunicamycin C (6), and tunicamycin C3 (7). The structure of compound 1 was elucidated by detailed spectroscopic data analyses. All the compounds exhibited strong to moderate antibacterial activity against Gram-positive bacteria Bacillus thuringiensis BT01 and B. thuringiensis W102 with MIC values ranging from 0.008 to 2 MUg/mL. Moreover, compounds 1-7 exhibited moderate antifungal activity against Candida albicans ATCC 96901 and C. albicans CMCC (F) 98001 with MIC values ranging from 2 to 32 MUg/mL. This is the first report that tunicamycins exhibit antimicrobial activities against B. thuringiensis, C. albicans CMCC (F) 98001 and a fluconazole resistant strain C. albicans ATCC 96901. PMID- 30445837 TI - Two new bioactive triterpenoids from the roots of Colubrina asiatica. AB - Two new ceanothane triterpenes, 3,7-O,O-dibenzoyl ceanothic acid methylester (1) and 3-O-acetyl-7-O-benzoyl ceanothic acid methylester (2), along with nine known compounds (3-11), were isolated from the roots of Colubrina asiatica. The isolated compounds were identified by spectroscopic evidence. Compounds 1 and 2 showed antimalarial activity against Plasmodium falciparum with IC50 values of 4.67 and 3.07 ug/mL, respectively. Compound 2 also showed antimycobacterial activity against Mycobacterium tuberculosis (MIC 6.25 ug/mL). In addition, compounds 1, 2, 10 and 11 showed cytotoxicity against three cancer cell lines (KB, NCI-H187 and MCF-7) with IC50 values ranging from 8.32 to 46.72 ug/mL. PMID- 30445838 TI - Cytotoxic constituents from Helicteres hirsuta collected in Vietnam. AB - Phytochemical study on the extract of Vietnamese medicinal plant Helicteres hirsuta Lour. has led to the isolation and structural elucidation of twelve secondary metabolites, 3-O-trans-caffeoylbetulinic acid (1), 3beta benzoylbetulinic acid (2), betulinic acid methyl ester (3), betulinic acid (4), lupeol (5), 4-hydroxybenzoic acid (6), 3,4-dihydroxybenzoic acid methyl ester (7), 4-hydroxy-3,5-dimethoxybenzoic acid (8), 5,8-dihydroxy-7,4'-dimethoxyflavone (9), isoscutellarein 4'-methyl ether 8-O-beta-D-glucopyranoside (10), methyl caffeate (11) and stigmasterol (12). Especially, compound 2 was reported as a new natural product. Their structures were elucidated by a combination of 2D NMR and ESI-FT-ICR-MS spectroscopies. Furthermore, eight compounds were tested for their cytotoxicity against five cancer cell lines (Hela, HepG2, SK-LU-1, AGS and SK-MEL 2). The results showed that compounds (1, 3-5, 9) have moderate activities. This is the first study on the chemical constituents and their cytotoxicity of the Vietnamese Helicteres hirsuta L. PMID- 30445839 TI - Flavonoids: biological activities and therapeutic potential. AB - Flavonoids have aroused much interest in research, since they present a great diversity of biological activities observed in vitro, such as: antioxidant effect, modulation of the enzymatic activity and inhibition of cellular proliferation, exerting beneficial effects on the organism, as well as the use of its therapeutic potential. With wide distribution in the plant kingdom represent a class of phenolic compounds that differ in their chemical structure and particular characteristics. The objective of this review was to describe the relevant aspects of flavonoids, reporting the different known groups, the probable mechanisms by which they act, their pharmacological properties and to gain a better understanding of the reported beneficial health effects of these substances. This systematic review consisted of research using scientific databases such as Scopus, Science Direct, PubMed, SciVerse and SciELO, without time limitation. Some pharmacological properties of some flavonoids and their health benefits have been confirmed by previous studies.[Formula: see text]. PMID- 30445840 TI - Chemical composition and antioxidant capacity of extracts from the whole berry, pulp and seed of Hippophae rhamnoides ssp. yunnanensis. AB - In the present study, profiles of fatty acid, sn-2 fatty acid, triglyceride, phytochemical (including tocopherol/tocotrienol, phytosterol, flavonoid, carotenoid and polyphenol) and antioxidant capacity of extracts from the whole berry, pulp and seed of Hippophae rhamnoides ssp. yunnanensis were investigated and compared. The distributions of fatty acid, sn-2 fatty acid and triglyceride that was identified using ultra-performance liquid chromatography tandem quadrupole time of flight mass spectrometry (UPLC-Q-TOF/MS) showed obvious differences among the different parts of the ssp. yunnanensis. The whole berry and pulp extracts exhibited high flavonoid, carotenoid and polyphenol contents, whereas, the seed portion expressed high tocopherol/tocotrienol and phytosterol concentrations. Results deduced from this study demonstrated that ssp. yunnanensis is a rich source of unsaturated fatty acid and bioactive minor component, which should be further developed and utilized by breeders and planters. PMID- 30445842 TI - Essential oil and fractions isolated of Laurel to control adults and larvae of cattle ticks. AB - This study, was to evaluate the acaricidal effect of the essential oil (EO) and fractions (FR) obtained from Laurus nobilis leaves on Rhipicephalus (Boophilus) microplus. Eight fractions were obtained, however FR1: sabinene (37.83%), beta pinene (13.50%), 1,8-cineole (12.66%), alpha-pinene (12.56%) and FR8: alpha terpineol (79.19%) were highlighted as to the larvicidal potential when submitted by Larval Packet Test. The EO was tested by the Adult Immersion Test, at concentrations of 200.00; 100.00 and 50.00 uL/mL caused mortality of engorged females, egg mass reduction and hatching inhibition. Two fractions are shown to be efficient in controlling larvae FR8 (LC50 = 0.13 uL/mL, LC99 = 0.51 uL/mL) and FR1 (LC50 = 0.20 uL/mL, LC99 = 0.56 uL/mL). The fractionation of EO was determinant to elucidate which compounds were responsible for the larvicidal potential. This study opens new perspectives to direct new bioassays with the compounds obtained in the fractionation, since they present high potential on cattle tick larvae. PMID- 30445841 TI - Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial. AB - BACKGROUND/AIMS:: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS:: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS:: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION:: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials. PMID- 30445843 TI - Four new compounds from Dendrobium devonianum. AB - Two new phenanthrenes dendrodevonin A and B, two new aliphatic acids dendrodevonic acid A and B, along with ten known compounds, were isolated from the stems of Dendrobium devonianum. The structures of new compounds were elucidated on the basis of MS and NMR spectroscopic data, and single-crystal X ray diffraction analysis. The cytotoxicities of isolates towards HT-29 cell were discussed, and 4-methoxy-2,7-phenanthrenediol exhibited inhibitory activity compared with other studied compounds. PMID- 30445844 TI - Chemical constituents, cytotoxic and antioxidant activities of extract from the rhizomes of Osmunda japonica Thunb. AB - Thirty-three compounds (1-33) were isolated from the rhizomes of Osmunda japonica. Their structures were elucidated on the basis of spectral analysis and identified as ent-kaurene terpenoids (1-3), anthraquinones (4-8), flavonoids (9 12), steroids (13-15), and other compounds (16-33). Compound 1-14, 19-27 were isolated from the genus osmunda for the first time. Compound 28-29 were isolated from the plant for the first time. Cytotoxicities of all compounds against Hela, HepG2 and A549 cell lines were measured by MTT assay, and their antioxidant activities were determined by DPPH and ABTS radical scavenging assays. Compound 2 exhibited potent cytotoxicity against Hela, HepG2 cell lines with IC50 values of 9.31 and 9.66 MUM, respectively. Compound 9 showed good antioxidant activity. The Trolox-equivalent antioxidant capacity (TEAC) value was 0.95 mM in ABTS assay, and the IC50 value was 18.63 MUM in DPPH assay. PMID- 30445845 TI - Antioxidant potential and phytochemical composition of extracts obtained from Phyllanthus phillyreifolius by different extraction methods. AB - Phyllanthus phillyreifolius (Euphorbiaceae), poorly studied plant species, was fractionated using conventional and high pressure extraction techniques such as supercritical fluid and pressurized liquid extractions. Lipophilic substances were extracted with n-hexane and supercritical CO2 with or without co-solvent ethanol, meanwhile higher polarity fractions were recovered with acetone and 70% ethanol. Antioxidant potential was assessed by various chemical assays, which revealed that 70% ethanol was the most effective solvent for recovery of antioxidants. UPLC-MS phytochemical analysis of hydrophilic extracts confirmed geraniin as the main constituent of P. phillyreifolius. Other quantitatively important compounds were phyllanthusiin D and elaeocarpusin. Three isomers of tocopherol (alpha, beta and gamma) were quantified by HPLC in lipofhilic extracts. Generally, the results from this study revealed high antioxidant potential of P. phillyreifolius; consequently the plant may be considered as a promising source of antioxidants for functional foods, nutraceuticals and pharmaceutical formulations. PMID- 30445846 TI - GC-MS and GC-FID analyses of the volatile constituents of Brachychiton rupestris and Brachychiton discolor, their biological activities and their differentiation using multivariate data analysis. AB - The volatile constituents of the leaves and flowers of Brachychiton rupestris and Brachychiton discolor (Malvaceae) were characterized by GC-FID and GC-MS. A total of 92 compounds were identified. The major component of B. rupestris leaves was alpha-farnesene (34.57%) while in the flowers it was n-heptacosane (29.5%). (8Z, 11Z, 14Z)-heptadecatrienal (21.2%) in the leaves and palmitic acid (83.49%) in the flowers represent the abundant ingredients of B. discolor. Unsupervised pattern recognition techniques of multivariate data analysis exemplified by hierarchical cluster analysis (HCA) and principle component analysis (PCA) relying upon chromatographic results effectively discriminate the two related species. Also, both investigated species were assessed for their cytotoxic and antimicrobial efficacy. Results revealed that B. discolor flowers showed the highest cytotoxicity against human lung carcinoma (A-549) cell lines with IC50 equals 7.98 MUg/mL, whereas B. discolor leaves exhibited the highest antimicrobial potency against all tested microorganisms namely Streptococcus pneumonia, Bacillus subtilis, Escherichia coli as well as Aspergillus fumigatus and Geotrichum candidum (MICs between 0.98 and 15.63 ug/mL) except for Salmonella typhi. PMID- 30445847 TI - One new Lignan derivative from the fruiting bodies of Ganoderma lipsiense. AB - One new lignan derivative 2,3-dimethyl-4-(4'-hydroxy-3',5'-dimethoxyphenyl)-6 hydroxy-7-methoxy-naphthalene (1), together with four known analogues (2-5), were isolated from acetone extract of the fruiting bodies of Ganoderma lipsiense collected in the Hainan Province, China. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. Compound 1 showed insecticidal activity against newly hatched karvae of Helicoverpa armigera Hubner. Compounds 1-5 showed moderate antibacterial activity against Staphylococcus aureus with the same MIC value of 1.25 MUg/mL. PMID- 30445848 TI - Influence of new effective allelochemicals on the distribution of Cleome arabica L. community in nature. AB - New allelochemicals were identified through bio-guided fractionation from the ethyl acetate of seeds extracts, which was the most autotoxic compared to the other plant parts. Phytochemical investigation of the seeds extracts of C. arabica by spectroscopy analyses has led to identify two new dammarane type triterpenes (4 and 9), with nine known analogues (1 - 3, 5 - 8, 10 and 11), a new cucurbitane triterpene (12), acylated dehydrodiconiferyl alcohol (13), and three highly oxygenated flavonols (14-16). The most autotoxic compounds on germination and seedling growth were elucidated as dammarane type triterpenes. However, less autotoxic effect was recorded by an inhibition under 50% for most of the identified flavonoids. These results suggest that those autotoxic substances may be used as a new bio-herbicide that may contribute to manage the distribution of C. arabica in agronomic field. PMID- 30445849 TI - Protein tyrosine phosphatase 1B inhibitors from a marine-derived fungal strain aspergillus sp. SF-5929. AB - In the course of our continuing investigation of bioactive secondary metabolites from marine-derived fungal strains, a racemate of a novel diphenolic derivative named (+/-)-tylopilusin D (1) along with ten previously known secondary metabolites (2-11) were isolated from a marine-derived fungal strain Aspergillus sp. SF-5929. Their structures were elucidated mainly by analysis of NMR and MS data. In addition, the inhibitory effects of the isolated compounds against protein tyrosine phosphatase 1B (PTP1B) activity were evaluated, and compounds 1, 2, and 5-7 inhibited PTP1B activity with IC50 values ranging from 3.3 to 8.1 uM. Kinetics studies suggested that compounds 1, 2, and 5 had noncompetitive inhibitory effects against PTP1B.[Formula: see text]. PMID- 30445850 TI - Chemical constituents from the leaves of Melia azedarach. AB - Six compounds, benzyl 3-O-beta-D-glucopyranosyl-7-hydroxybenzoate (1), spathulenol (2), 1,7,8-trihydroxy-2-naphtaldehyde (3), quercetin (4), astragalin (5) and 2-methoxy-4-(2-propenyl)phenyl beta-D-glucoside (6), were isolated from the leaves of Melia azedarach L. The structure elucidation of compound 1 was discussed in detail based on its 2D-NMR data. Compound 1 showed weak cytotoxicity against the cell lines of T-24, NCI-H460, HepG2, SMMC-7721, CNE, MDA-MB-231 and B16F10 with the inhibition rates from 10.01% to 34.05% at the concentration of 80 MUM.[Formula: see text]. PMID- 30445852 TI - Silychristin derivatives conjugated with coniferylalcohols from silymarin and their pancreatic alpha-amylase inhibitory activity. AB - Silymarin is a mixture of flavonolignans extracted from the fruit of Silybum marianum (milk thistle). The latter is used as a medicinal plant to treat liver and gallbladder disorders. Recently, silymarin has been investigated for its effects against diabetes mellitus, and shown to reduce serum levels of glucose in model animals and in clinical trials. This effect can be explained mainly by the protective effect of silymarin against pancreatic beta-cells, but the involvement of other mechanisms is possible. We demonstrated the alpha-amylase inhibitory activity of silymarin and investigated the components responsible for this effect. Two major flavonolignans, silibinin and silychristin, did not show inhibition against alpha-amylase, but two novel silychristin derivatives conjugated with dehydrodiconiferyl alcohol were isolated as the mildly inhibiting components of silymarin. Further analyses indicated the presence of various silychristin derivatives in silymarin that may act synergistically to show alpha amylase inhibitory activity. PMID- 30445851 TI - Synthesis of triterpenoid derivatives and their anti-tumor and anti-hepatic fibrosis activities. AB - Oleanolic acid (1), ursolic acid (2), hederagenin (3), betulinol (4), betulinic acid (5), and glycyrrhetinic acid (6) are obtained from acorn/licorice industrial wastes with common triterpenoid structure as a model set for esterification. Eight 3,4,5-methoxybenzoyl triterpenoid derivatives (1a-6a), including four new derivatives (1a, 3a-1, 3a-2, and 3a-3), are synthesized by classical procedures. Their antitumor and anti-hepatic fibrosis activities are evaluated on four human tumor cell lines and t-HSC/Cl-6 cells. Derivative 1a shows maximum antiproliferative effects against all cell lines, especially against tumor cells with IC50 values in the range of 5.32-15.23 MUM, but does not affect the viability of normal cells. The anti-tumor mechanisms of 1a are also investigated by western blot and docking studies. The 3,4,5-methoxybenzoyl triterpenoids offers an intriguing solution for naturally derived antitumor drugs and may be invaluable for further development of cancer therapy. PMID- 30445853 TI - Antibacterial and antifungal properties of crude extracts and isolated compounds from Lychnophora markgravii. AB - Antimicrobial activity of dichloromethane and ethanol extracts and five compounds: pinostrobin (I), pinocembrin (II), tectochrysin (III), galangin 3 methyl ether (IV) and tiliroside (V) isolated from Lychnophora markgravii aerial parts against fifteen microorganisms was determined. The structures of these compounds were elucidated based on ESI-MS and NMR spectroscopic data. Both extracts showed antimicrobial activity against several tested microorganisms. Pinostrobin, tectochrysin and galangin 3-methyl ether showed the strongest antibacterial and antifungal effects. PMID- 30445854 TI - Quantification of withaferin-A and withanolide-A in diploid (n = 12) and tetraploid cytotypes (n = 24) of "Rassbhary", Physalis angulata L. AB - During the present study an analytical method based on reverse-phase high performance liquid chromatography photodiode array detection method was developed for simultaneous determination of withaferin-A and withanolide-A in plant parts of two cytotypes (diploid n = 12 & tetraploid n = 24) of Physalis angulata. All the plant parts were extracted in different solvent solutions i.e., acidic [HCl] methanol (i.e., methanol containing 0.3% of HCl), methanol, n-hexane, chloroform. Both the compounds were comparatively analysed. The results revealed that tetraploid cytotype (n = 24) showed the higher composition of both the reference compounds. The method is simple, rapid and provides better resolution can be easily applied to the quantitative analyses of withanolides in plant matrices. PMID- 30445855 TI - Allurin and egg jelly coat impact on in-vitro fertilization success of endangered Albanian water frog, Pelophylax shqipericus. AB - Amphibian egg-jelly coat plays an important role in successful fertilization and development. Here, we ask whether proteins like allurin in the jelly coats of frog eggs might influence fertilization rate success. Using in vitro fertilization of Albanian water frog, Pelophylax shqipericus, we found that body cavity eggs or eggs deprived of jelly coat were not fertilized, compromising the success of in vitro fertilization procedure. When de-jellied eggs were inseminated with sperm suspension, the fertilization efficiency is dramatically decreased even inhibited, suggesting that the gel structure is one of the major factors in the achievement of fertilization in the frogs. Fertilization of de jellied eggs with sperm pre-treated with egg jelly coat, restored the fertilization competency. Such a result suggests that egg jelly coat probably guides the sperm to the egg surface while maintaining the fertilization ability, contributing to a successful in vitro fertilization of Pelophylax shqipericus. PMID- 30445856 TI - Characterization and bioactive potentials of secondary metabolites from Fusarium chlamydosporum. AB - A search for bioactive secondary metabolites from the endophytic fungus Fusarium chlamydosporum, isolated from the root of Suaeda glauca, led to the isolation of three indole derivatives (1-3), three cyclohexadepsipeptides (4-6), and four pyrones (7-10). The structures of new (1) and known compounds (2-10) were elucidated on the basis of extensive spectroscopic analysis. All these compounds were evaluated for phytotoxic, antimicrobial activities, and brine shrimp lethality. Compound 1 showed significant phytotoxic activity against the radicle growth of Echinochloa crusgalli, even better than the positive control of 2,4-D. Cyclohexadepsipeptides (4-6) and pyrones (7-10) exhibited brine shrimp lethality, especially 4 and 7 with the LD50 values of 2.78 and 7.40 MUg mL-1, respectively, better than the positive control. PMID- 30445857 TI - Membrane insertion and intercellular transfer of glycosylphosphatidylinositol anchored proteins: potential therapeutic applications. AB - Anchorage of a subset of cell surface proteins in eukaryotic cells is mediated by a glycosylphosphatidylinositol (GPI) moiety covalently attached to the carboxy terminus of the protein moiety. Experimental evidence for the potential of GPI anchored proteins (GPI-AP) of being released from cells into the extracellular environment has been accumulating, which involves either the loss or retention of the GPI anchor. Release of GPI-AP from donor cells may occur spontaneously or in response to endogenous or environmental signals. The experimental evidence for direct insertion of exogenous GPI-AP equipped with the complete anchor structure into the outer plasma membrane bilayer leaflets of acceptor cells is reviewed as well as the potential underlying molecular mechanisms. Furthermore, promiscuous transfer of certain GPI-AP between plasma membranes of different cells in vivo under certain (patho)physiological conditions has been reported. Engineering of target cell surfaces using chimeric GPI-AP with complete GPI anchor may be useful for therapeutic applications. PMID- 30445858 TI - A comparative study on the essential oil composition and antibacterial activities of different organs of wild growing Paeonia daurica subsp. tomentosa from Iran. AB - Paeonia daurica subsp. tomentosa (Lomakin) D.Y.Hong is an herbaceous perennial and flowering plant from the Paeoniaceae family. In this research, the roots, stems, leaves and fruits of P. daurica subsp. tomentosa were investigated for a comparative identification of essential oil composition. The essential oils constituents were identified by GC/MS and then compared. The study leads to the identification of 31, 57, 66, and 57 components in the essential oils obtained from the roots, stems, leaves and fruits, respectively. These chemicals make up more than 99% of the essential oil. Some of the identified compounds (alpha Pinene, 4-ethyloctane, 5-methylnonane, benzaldehyde, myrtanal, 4,7-dimethyl benzofuran, n-decane, cuminaldehyde, cis-p-mentha-6,8-diene-2-ol, salicylaldehyde, tetradecane, tetradecanal, and n-tricosane) occurred in all parts of the plant. The existence of compounds such as cembrene (1.1%), 13-epi manool (1.5%), 2-hydroxy methyl benzoate (10.1%), and tridecanal (0.7%), however, were confirmed exclusively in the fruit, stem, root, and leaf, respectively. The antibacterial activities (MIC) of the oils obtained from the four studied Paeonia parts against Escherichia coli and Staphylococcus aureus was studied. Staphylococcus aureus was the most sensitive microorganism to the oil obtained from the fruits of P. daurica subsp. tomentosa with the value of 0.04 +/- 0.005 mg mL-1. PMID- 30445859 TI - A new indole alkaloid, antioxidant and antibacterial activities of crude extracts from Saccocalyx satureioides. AB - The new acylated indole alkaloid glucoside indole-3-carboxylic acid-(6'-O caffeoyl)-beta-D-glucoside 1 has been isolated from the ethyl acetate (EtOAC) extract of Saccocalyx satureioides Coss. & Dur. (Lamiaceae) together with eight known secondary metabolites 2-9. Two indoles 2 and 3, five methylated flavone aglycones 4-8 and one monoterpene glucoside 9 were reported for the first time in the genus Saccocalyx. The structural elucidation of these compounds was accomplished by spectroscopic methods including 1 D (1H and 13C) and 2 D (COSY, HSQC and HMBC) NMR techniques, and mass spectrometry, and by comparison with literature data. Light petroleum, EtOAc, chloroform and n-butanol (n-BuOH) extracts of S. Satureioides were screened for their antioxidant activity using DPPH radical scavenging and beta-carotene bleaching methods. The antibacterial activity of these extracts indicates that n-BuOH and EtOAc extracts possess the strongest activity. PMID- 30445860 TI - Optimization of polysaccharides extraction from quince peels: partial characterization, antioxidant and antiproliferative properties. AB - In this study, Box-Behnken Design was used to optimize the ultrasonic extraction of polysaccharides from quince peels (QPPs) by ascorbic acid and the effect of extraction temperature, extraction time and pH was evaluated. Under optimized conditions of temperature 90 degrees C, 60 min sonication time and pH = 3.26, the extraction yield, the galacturonic acid yield and the concentration of sample required to scavenge 50% of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic) acid (ABTS) values of QPPs were respectively 10.25%, 3.86% and 1.35 mg/mL. The QPPs extracted under optimum conditions was characterized by Fourier transform infrared spectroscopy (FTIR), Nuclear magnetic resonance (1 H NMR) and Size exclusion chromatography (SEC/MALS/VD/DRI). The monosaccharide analysis revealed that arabinose was the most abundant, followed by galactose, glucose, mannose and xylose. Moreover, QPPs showed significant antioxidant activities (2,2-diphenyl-1 picrylhydrazyl (DPPH) and Ferric- reducing antioxidant power (FRAP)) and reduced viability of human Caco-2 and murine B-16 cell lines in a dose-dependent manner. Hence QPPs could be used as antitumor agent in functional foods andpharmaceutical industries. PMID- 30445861 TI - Anti-inflammatory activity of saponins from roots of Impatiens parviflora DC. AB - Two triterpene saponins (IPS-1, IPS-2) for the first time were isolated from the roots of Impatiens parviflora DC. (Balsaminaceae). Their anti-inflammatory activity was evaluated by means of two in vitro models: anti-hyaluronidase and anti-denaturation assays. Both saponins were shown to be potent hyaluronidase inhibitors that affect the enzyme in a dose-dependent manner. The anti hyaluronidase effect of IPS-2 (IC50 = 286.7 ug/mL) was higher than that of the reference drug: escin (IC50 = 303.93 ug/mL). Both saponins protected bovine serum albumin from heat-induced denaturation in a dose-dependent manner. IPS-1 demonstrated higher anti-denaturation effect (IC50 = 86.7 ug/ml) than IPS-2 (IC50 = 109.76 ug/mL) or the standard drug: acetylsalicylic acid (IC50 = 262.22 ug/mL). In conclusion, potent activity of IPS-1, IPS-2 in both in vitro assays shows that saponins from I. parviflora have anti-inflammatory activity. The obtained results allow to suggest that such compounds may be beneficial in inflammatory conditions, especially associated with excessive degradation of hyaluronic acid. PMID- 30445862 TI - Cytotoxic components from the Xisha sponge Fascaplysinopsis reticulata. AB - A new dolabellane diterpenoid, clavirolide H (1), together with eleven known compounds, including two dolabellane diterpenoid (2 and 3), a rare cavernosine type C17 gamma-lactone terpenoid (4), a diketopiperazine (5) and seven sterols (6 12), were isolated from the Xisha sponge Fascaplysinopsis reticulata. Their structures were elucidated by extensive spectroscopic analysis, and the four types of compounds of the above isolates were reported from the genus Fascaplysinopsis for the first time. Selected compounds 1, 4-6 and 9-12 were evaluated for cytotoxic activities against K562, HL-60, Hela, HCT-116, A549, L-02 and BEL-7402 cell lines. Compounds 4-6 and 10-12 showed potent cytotoxicitives against HL-60 with IC50 values ranging from 8.8 to 12.4 MUM. Compounds 4 and 5 exhibited weak cytotoxic activities against HeLa with IC50 of 20.7 and 27.4 MUM, and 5 also has moderate cytotoxicity against HCT-116 with IC50 of 16.3 MUM. [Formula: see text]. PMID- 30445863 TI - Antiproliferative effect of 2-Hydroxy-6-tridecylbenzoic acid from ginkgo biloba sarcotestas through the aryl hydrocarbon receptor pathway in triple-negative breast cancer cells. AB - This study aims to isolate the potential antiproliferative and cytotoxic compounds from ginkgo biloba sarcotestas (GBS) and investigates the underlying mechanism in human MDA-MB-231 and mouse 4T-1 triple-negative breast cancer cells. Our results showed that 2-Hydroxy-6-tridecylbenzoic acid was isolated by cytotoxicity-guided fractionation where different fractions were assessed using MTT assay against MDA-MB-231 and 4T-1 cells. Colony formation assay showed that 2 Hydroxy-6-tridecylbenzoic acid significantly inhibited cell proliferation. The inhibition was associated with the enhancement of cytochrome P450 (CYP) 1B1 expression in a dose- and time-dependent manner and no significant change of CYP1A1 expression by qPCR and Western blot assays in MDA-MB-231 and 4T-1 cells. The mechanism was further demonstrated by the activation of aryl hydrocarbon receptor (AhR) pathway with the upregulation of AhR, AhR nuclear translocator (ARNT) and AhR-dependent xenobiotic response elements (XRE) activity. These findings may have implications for development of anticancer agents containing 2 Hydroxy-6-tridecylbenzoic acid as functional additives. PMID- 30445864 TI - Isolation, purification and identification of two new alkaloids metabolites from marine-derived Verrucosispora sp. FIM06025. AB - Chemical investigation of a marine-derived actinomycete strain Verrucosispora sp. FIM06025 isolated from a marine sponge sample collected from the East China Sea, resulted in the discovery of two new alkaloids, (2-(hydroxymethyl)-3-(2 (hydroxymethyl)-3-methylaziridin-1-yl) (2-hydroxyphenyl) methanone (1) and 2-(1 hydroxyethyl)-3,4-dihydrobenzo [f] [1,4]oxazepin-5(2H)-one (2). The structures of compounds 1 and 2 were determined by the detailed analysis of 1D, 2D NMR and HR TOF-MS data, along with literature data analysis. The bioefficacy investigations revealed that compound 1 exhibited a broad spectrum of antimicrobial activity with MIC (minimum inhibitory concentration) values ranging from 3.4 to 200 MUg.mL 1 against H. pylori, P. aeroginosa, A. baumanniiin, E. coli and K. pneumonia, S. aureus, C. albicans and E. faecium, however, compound 2, up to 200 MUg/mL, displayed no antibacterial activity against these bacteria. PMID- 30445865 TI - Inhibitory effects of Dulcitol on rat C6 glioma by regulating autophagy pathway. AB - In the study, we treated C6 rat glioma cells with 25 mg/ml Dulcitol for 24 h. 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to detect cellular growth. The measurements of the superoxide dismutase (SOD), malondialdehyde (MDA) and catalase (CAT) were used to assess oxidative stress level. Western was performed to detect the autophagy and apoptosis expression. The data showed that Dulcitol significantly decreased the cell viability, upregulated the Bax level in mitochondria and the Cytochrome C level in cytoplasm, and downregulated anti-apoptotic protein Bcl-xl. Moreover, it enhanced MDA level, reduced CAT and SOD activities, decreased LC3-II/LC3-I ratio, and increased P62 expression. However, rapamycin increased autophagy level and cell viability, and decreased ROS in Dulcitol treated C6 cells. Moreover, Dulcitol inhibited the glioma growth and enhanced survival in vivo. These results suggest that Dulcitol evidently increase cellular ROS levels and apoptosis in glioma cells, which can be significantly regulated by autophagy. PMID- 30445866 TI - Antifungal, anti-inflamatory and neuritogenic activity of newly-isolated compounds from Disporopsis aspersa. AB - A new ester (1) and a terpenoid (2) were isolated from the dried whole plant of Disporopsis aspersa (HUA) ENGL. ex DIELS for the first time and their structures were elucidated, as well as their biological activities are described. The two compounds all showed good antifungal activities, especially furanone (2) exhibited better antifungal activity against Pseudoperonospora cubensis and Phytophthora infestans with EC50 value of 22.82, 18.90 MUg/mL, respectively. Compound 1 exhibited a significant promotion on the neurite outgrowth in NGF induced PC-12 cells, and moderate inhibition on the NO production induced by lipopolysaccharide (LPS) in BV-2 microglial cells. PMID- 30445867 TI - Synthesis, structural elucidation and biological evaluations of new guanidine containing terpenoids as anticancer agents. AB - Using sclareol and sclareolide as starting materials, the guanidine derivatives of 12-amino-11-dihomodrimane-8alpha-ol and 13-amino-14,15-bis-dinorlabd-8(9)-ene were synthesized by the reaction of the corresponding amines with sodium hydrogencyanamide in ethanol - water solution. Monoacyl- and diacylguanidines were prepared from activated with N,N-carbonyldiimidazole Delta8,9 bicyclohomofarnesenoic acid by the reaction with guanidine. Their structures were confirmed by the 1H and 13C NMR, IR spectral and elemental analysis data. The compounds 12, 13 and 15 were screened for their antiproliferative and cytotoxicity activities against Colo 205, Colo 320 and MRC 5 human lung fibroblasts with respect to standard drug, Cisplatin. The compounds 12 and 15 exhibits excellent results than positive control. Hence these two compounds may be act as drug lead molecules in cancer chemotherapy. PMID- 30445868 TI - A novel semi-synthesis of spinetoram-J based on the selective hydrolysis of 5,6 dihydro spinosyn A. PMID- 30445869 TI - Antiglycation, antioxidant, and cytotoxic activities of Uvaria chamae root and essential oil composition. AB - Uvaria chamae (Annonaceae), is an essential oil bearing plant; the root is acclaimed as an effective remedy for folkloric diabetic therapy. The root extracts were evaluated for composition, antiglycation, antioxidant, and cytotoxicity. Flavonoids, cardiac glycosides, and tannins were relatively high in the alcohol extract; benzyl benzoate (23.3%), dimethoxy-p-cymene (14.2%), tau cadinol (12.1%), and methyl thymol (8.7%) predominated the constituents identified by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The ethanol extract demonstrated significant antiglycation activity (IC50, 1.12 mg/mL), and cytotoxicity to brine shrimp (LC50, 25.01 ug/mL). The extract (IC50, 8.0 ug/mL; absorbance 0.531, 100 ug/mL) also exhibited better antioxidant effects compared with the essential oil (IC50, 50.0 ug/mL; absorbance 0.292, 100 ug/mL) using 2,2-diphenyl-1-picrylhydrazyl radical and ferric reducing power assays respectively. U. chamae root possess antiglycation effect, and may also reduce oxidative stress in patients with diabetes; its antiglycation effect, oil composition, and cytotoxicity are reported for the first time. PMID- 30445870 TI - Enhancement of phenolic and flavonoids compounds, antioxidant and cytotoxic effects in regenerated red cabbage by application of Zeatin. AB - This study evaluated the roles of zeatin (2 mg/L) on direct organogenesis, phytochemical compounds, antioxidant activity, and cytotoxic activity in regenerated shoots of red cabbage. The results revealed that the extract of explant treated by 2 mg/L zeatin gives the highest content of total phenolics (5.18 mg gallic acid equivalent/g dry weight) and flavonoids (1.52 mg rutin equivalent/g dry weight). Moreover, HPLC and GC-MS analyses indicated that various bioactive compounds in red cabbage are significantly enhanced with increasing zeatin concentration. Besides that, antioxidant activity test showed that in vitro shooting culture using 2 mg/L zeatin displayed higher antioxidant activity in all assays (DPPH, FRAP and ABTS) compared to control with respective values of 68.12%, 73.28%, and 54.1%, respectively. Finally, the cytotoxic properties illustrated that the extracts of red cabbage explant treated by 2 mg/L zeatin exhibited the strongest cytotoxic effect towards cancer cells compared to control. PMID- 30445871 TI - Multiple analytical approaches for the organic and inorganic characterization of Origanum vulgare L. samples. AB - Origanum vulgare L. samples, marketed in different geographic locations, were characterized by their organic and inorganic chemical composition. A total of 35 commercial samples were collected from various sites and analyzed to determine the qualitative and quantitative profile of essential oils, phenolic compounds and some inorganic elements. The variation in the content and composition of the essential oil was assessed by GC and GC-MS analyses, the phenolic fraction was investigated by UPLC(r)/PDA, and the inorganic elements were determined by ICP MS. The Principal Component Analysis (PCA) was applied with the aim to sort out the Origanum vulgare L. samples with different composition according to the different belonging origins. The results showed appreciable qualitative and quantitative differences among samples from different geographic origin. PMID- 30445872 TI - Centaurea microcarpa Coss. & Dur. (Asteraceae) extracts: New cyanogenic glucoside and other constituents. AB - The phytochemical investigation of both chloroform and ethyl acetate extracts of Centaurea microcarpa Coss. & Dur. led to the isolation of a new cyanogenic glucoside 6'-methacrylate prunasin (3) together with seven known compounds: hydroxy-11beta,13-dihydro onopordaldehyde (1), beta-sitosterol (2), daucosterol (4), nepetin (5), prunasin (6), astragalin (7) and 7-O-beta-D-glucopyranosyl centaureidin (8). Their structures were established by spectral analysis, mainly UV, IR, ESI-MS, 1D & 2D-NMR experiments (COSY, HSQC, HMBC and ROESY). PMID- 30445873 TI - A problem in the structure assignment of acremolin C, which is most probably identical with acremolin B. AB - With the help of chemical shifts computed with density functional theory (DFT), it is demonstrated that the reported experimental 13C NMR data of acremolin C are incompatible with the claimed structure of an N2,3-ethenoguanine with an isopropyl group at C-1'. An alternative structure, which is in agreement with both experimental and computed data, presents an isopropyl group at the C-2' position of an N2,3-ethenoguanine and leads to the conclusion that acremolin C is identical with acremolin B. PMID- 30445874 TI - Financial difficulties in bipolar disorder part 1: longitudinal relationships with mental health. AB - BACKGROUND: There has been little research on whether finances affect mental health in bipolar disorder. AIMS: This study aimed to examine the relationship between finances and mental health in bipolar disorder across two time points. METHODS: Fifty-four participants with bipolar disorder in a National Health Service community mental health service completed questionnaires examining financial difficulties, compulsive buying and perceived financial well-being. Questionnaires also measured alcohol dependence, stress, depression, anxiety, past and current manic symptoms. RESULTS: Partial correlations showed correlations over time: depression, anxiety and stress predicted later compulsive buying. Compulsive buying also predicted later anxiety. Lower perceived financial wellness increased anxiety and stress over time. Being on benefits was associated with higher depression and going without items such as clothes was linked to higher depression, stress, anxiety and past hypomanic symptoms. CONCLUSIONS: Financial difficulties are related to mental health in bipolar disorder. Poor mental health leads to compulsive buying, whereas worry about finances increases anxiety and stress, with a vicious cycle for anxiety. PMID- 30445875 TI - Schizophrenia literacy: the effects of an educational intervention on populations with and without prior health education. AB - BACKGROUND: Mental health literacy is an important predictor of appropriate help seeking behaviour. AIMS: This study investigated (a) the effects of an educational intervention on schizophrenia mental health literacy, beliefs about causes, discrimination, treatment, and attitudes that promote recognition, and (b) whether schizophrenia literacy would be higher in people with prior education in a health-related area than people without such education. METHOD: A randomised control design tested the effects of an educational intervention on schizophrenia literacy relative to a control group. Participants (N = 260; mean age = 31.18 years, SD = 11.43, female = 78.8%) answered a mental health literacy questionnaire, based on a vignette of a person with schizophrenia, before and after watching either an educational video on schizophrenia or a control video. RESULTS: The intervention significantly increased schizophrenia identification and literacy, reduced personal stigma, and increased perceived discrimination in society. The health background group reported significantly greater schizophrenia identification than the no health background group. Participants thought help should be sought from health care professionals and through psychotherapy, close friends and physical activity. CONCLUSIONS: Targeted education can significantly improve the ability to identify schizophrenia which may have positive implications for reducing the time individuals take to seek help. PMID- 30445876 TI - GC-MS and LC-MS Identification of the Phenolic Compounds Present in the ethyl Acetate Fraction Obtained from Senna tora, L. Roxb. seeds. AB - The aim of this work is to characterize the active constituents present in the ethyl acetate fraction of Senna tora, L. Roxb. seeds. Due to the fact that the main biological activity of S. tora, L seeds is attributed to its phenolic compounds which are mainly isolated from Ethyl acetate fraction, to avoid repetition of work and to save time, it was deemed necessary to confirm the identity of these phenolic compounds. This was done by GC-MS and LC-MS analysis of the ethyl acetate fraction where the structures of the isolated compounds were established on the basis of molecular ion peak and their fragmentation pattern. They were identified as Chrysophanol, Chrysarobin, 10-hydroxy-5-methoxy-2-methyl 1, 4-anthracenedione, Rubrofusarin, Parietin, Griseoxanthone-B, Isotorachrysone, and Cumbiasin B. [Formula: see text]. PMID- 30445877 TI - Three new labdane-type diterpenoids from Callicarpa macrophylla Vahl. AB - Three new labdane-type diterpenoids, callicapene M3-M5 (1-3) were isolated from the Callicarpa macrophylla Vahl. Their structures were identified by spectroscopic method. The isolated compounds were evaluated for inhibitory activity on NO production in LPS-activated RAW 264.7 macrophage cells by using MTT assays. Compounds 1-3 showed potent inhibitory activity, with IC50 value of 48.15, 46.31 and 38.72 MUM respectively. PMID- 30445878 TI - Triterpenoid saponins with hepatoprotective effects from the fresh leaves of Metapanax delavayi. AB - The fresh leaves of Metapanax delavayi (Araliaceae) have been used as a common wild vegetable for salad and soup, and also herbal tea by the local people living in its growing areas of Yunnan province, China. Detailed chemical investigation led to the identification of a new triterpenoid saponin, 3-O-alpha-L arabinopyranosyl-28-O-beta-D-glucopyranosyl-(1->6)-O-beta-D-glucopyranosyl-3beta hydroxyolean-12-ene-28,29-dioic acid (1) from the fresh leaves, together with 11 known compounds, including six triterpenoid saponins (2-7), two caffeoylquinic acid derivatives (8-9), and three flavonoid glycosides (10-12). Their structures were determined on the basis of spectroscopic analysis and acidic hydrolysis. Compounds 3-5 and 8-12 were isolated from M. delavayi for the first time. Moreover, the known saponins 3-O-beta-D-xylopyranosyl-3beta-hydroxyolean-12-ene 28,29-dioic acid (3) and yiyeliangwanoside IV (5) exhibited protective effects on HepG2 cells damaged by the alcohol intakes, at a concentration of 1.0 ug/mL. The results indicated M. delavayi is an ideal dietary vegetable and herbal tea with potential hepatoprotective activity. PMID- 30445879 TI - An insight into chemical composition and bioactivity of 'Prokupac' red wine. AB - Autochthonous variety 'Prokupac' (Vitis vinifera L.) red wines with the addition of selected aromatic herbs (Artemisia absinthium, Cinnamomum zeylanicum, Glycyrrhiza glabra and Pimpinella anisum L.) were evaluated for chemical composition and biological activity. Furthermore, their polyphenolic profiles were determined by HPLC-DAD. While total phenolic (TPC) and flavonoid (TFC) contents, along with antioxidant activity, were significantly higher in all examined wine samples, the content of total anthocyanins was decreased, compared to a pure 'Prokupac' wine, used as the control one. On the other hand, 'Prokupac' wines with the addition of cinnamon (S. zeylanicum) and wormwood (A. absinthium) displayed highest antioxidant (EC50, 0.021 +/- 0.001 mg/mL) and antibacterial (Enterococcus faecalis, MIC/MBC 15.63/62.50 MUL/mL) activities, respectively. The study showed that 'Prokupac' wine with the addition of cinnamon was significantly enriched both with TPC and TFC, compared to control wine (p < 0.05), which may contribute to its market potential. [Formula: see text]. PMID- 30445880 TI - The association between renal function and neurological diseases in type 2 diabetes: a multicenter nationwide cross-sectional study. AB - BACKGROUND: The evidence for an association between renal function and neurological diseases among type 2 diabetes mellitus (T2DM) patients, particularly in the Asian population, is limited. This study aimed to assess the association between glomerular filtration rate (GFR) and various neurological diseases among T2DM patients in Thailand using a nationwide patient sample. METHODS: We conducted a nationwide cross-sectional study based on the DM/HT study of the Medical Research Network of the Consortium of Thai Medical Schools. This study evaluated adult T2DM patients receiving care at public Thailand hospitals in the year 2014. GFR was categorized into >=60, 30-59, and < 30 mL/min/1.73 m2. Neurological diseases studied included ischemic stroke/transient ischemic attack (TIA), hemorrhagic stroke, dementia, all cerebrovascular disease, and peripheral neuropathy. Multivariate logistic regression was performed to assess the association between GFR and neurological diseases. RESULTS: A total of 30,423 T2DM patients with available GFR data were included in the analysis. The mean GFR was 68.18 +/- 26.45 mL/min/1.73 m2. The prevalence of ischemic stroke/TIA, hemorrhagic stroke, dementia, any cerebrovascular diseases and peripheral neuropathy were 2.9%, 0.3%, 0.1%, 3.2%, and 3.1%, respectively. Patients with GFR of 30-59 and <30 mL/min/1.73 m2 were significantly associated with increased rates of ischemic stroke/TIA, any cerebrovascular diseases, and peripheral neuropathy when compared with patients with GFR of >=60 mL/min/1.73 m2. This association remained significant after adjustment for potential confounders. CONCLUSION: Decreased GFR was associated with increased ischemic stroke/TIA, all cerebrovascular diseases, and peripheral neuropathy. GFR should be monitored in diabetic patients for neurological disease awareness and prevention. PMID- 30445881 TI - High-Detailed evaluation of the right atrial anatomy by three-dimensional rotational angiography during ablation procedures for atrioventricular nodal reentrant tachycardia and atrial flutter. AB - AIM: 3D Rotational angiography (3DRA) allows for detailed reconstruction of atrial anatomy and is often used in the left atrium to facilitate pulmonary vein isolation. This study aimed to reappraise the anatomy of the right atrium (RA) using 3DRA, specifically looking at Koch's triangle and the cavotricuspid isthmus (CTI) in procedures for atrio-ventricular reentrant tachycardia (AVNRT) and atrial flutter (AFl) ablation. METHODS AND RESULTS: 3DRA was performed in 97 patients undergoing ablation for AVNRT (n = 51) or AFl (n = 46). Detailed 3D reconstruction and evaluation of right atrial anatomy was possible in all patients. Dimensions of Koch's triangle and CTI were highly variable between individuals but were not significantly different in both ablation groups. Absolute RA volume was significantly larger in AFl patients (p = 0.004) while indexed RA volume to the body surface area (RAVI) was only lightly different (p = 0.024). In univariate Cox analysis, age (p = 0.003), RAVI (p < 0.001) and previous ablation of AFl (p = 0.003) were predictors of AF occurrence during a mean follow-up of 23 +/- 16 months. In multivariate Cox analysis, RAVI was the only independent predictor of AF occurrence. RAVI >80 ml/m2 was a strong predictor for AF during follow up (sensitivity 77.7%, specificity 86.4%). CONCLUSION: 3DRA allows for detailed per-procedural evaluation of right atrial anatomy and revealed a great variability in Koch's triangle and CTI dimensions and morphology. Right atrial enlargement as measured by RAVI was an independent predictor for AF occurrence during follow-up. PMID- 30445882 TI - Heart failure in immigrant groups: a cohort study of adults aged 45 years and over in Sweden. AB - OBJECTIVE: An increased risk of being diagnosed with coronary heart disease or atrial fibrillation has been shown among different immigrant groups. However, less is known on the risk of being diagnosed with congestive heart failure (CHF). DESIGN: We studied CHF in immigrants including all adults >=45 years in Sweden (n = 3,274,119) from 1998 to 2012. CHF was defined as at the first event registered in the National Patient Register. Risk of incident CHF in immigrant groups compared to the Swedish-born population was assessed by Cox regression, stratified by sex, adjusting for age, socio-demographic status, and co morbidities. RESULTS: During a mean follow-up of 14 years in total, a total of 302,340 (9.2%) events of CHF were registered. We found the following: higher incidence in men from Bosnia, Iraq, Lebanon, Russia and Africa; among women from Bosnia, Iraq, Lebanon, Turkey, Central Europe and Finland; lower incidence in men from Iceland, Latin America, Southern Europe, Norway and Western Europe; and among women from Iceland, Southern Europe, Norway, Denmark and Western Europe. CONCLUSION: It is important to be aware of the increased incidence of CHF in some immigrant groups, especially from countries and areas where the immigrants have been refugees, in order to enable for a timely diagnosis, treatment of and prevention of CHF and its debilitating complications. PMID- 30445883 TI - Oxidative/nitrosative stress, autophagy and apoptosis as therapeutic targets of melatonin in idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease associated with disruption of alveolar epithelial cell layer and expansion of fibroblasts/myofibroblasts. Excessive levels of oxidative/nitrosative stress, induction of apoptosis, and insufficient autophagy may be involved in IPF pathogenesis; hence, the targeting of these pathways may ameliorate IPF. Areas covered: We describe the ameliorative effect of melatonin on IPF. We summarize the research on IPF pathogenesis with a focus on oxidative/nitrosative stress, autophagy and apoptosis pathways and discuss the potential effects of melatonin on these pathways. Expert opinion: Oxidative/nitrosative stress, apoptosis and autophagy could be interesting targets for therapeutic intervention in IPF. Melatonin, as a potent antioxidant, induces the expression of antioxidant enzymes, scavenges free radicals and modulates apoptosis and autophagy pathways. The effect of melatonin in the induction of autophagy could be an important mechanism against fibrotic process in IPF lungs. Further clinical studies are necessary to determine if melatonin could be a candidate for treating IPF. PMID- 30445884 TI - Effects of heart rate reduction with ivabradine on the international index of erectile function (IIEF-5) in patients with heart failure. PMID- 30445885 TI - A mechanistic study of the effect of transferrin conjugation on cytotoxicity of targeted liposomes. AB - This study was performed to prepare 5-fluorouracil (5FU) containing targeted liposomes for the safety and efficacy enhancement. Liposomes were prepared using thin layer method and transferrin (Tf) was employed as the targeting ligand. Morphology of 5FU-loaded liposomes was assessed by transmission electron microscopy (TEM). The in vitro cytotoxicity was investigated via MTT assay on HT 29, CT26 and fibroblast cells. Mitochondrial membrane and cell death evaluations were also investigated. Resulted showed that the encapsulation efficiency (EE%) and particle size of the liposomes were 40.12% and 130 nm, respectively. TEM image implied that liposomes were spherical in shape. In cancer cells, targeted liposomes triggered the mitochondrial apoptotic pathway by lower production of reactive oxygen species (ROS) (63.58 vs 84.95 fluorescence intensity), reduced mitochondrial membrane potential and releasing of cytochrome c (68.66 vs 51.13 ng/mL). The results of this study indicated that Tf-targeted 5FU liposomes can be employed as promising nanocarrier for the delivery of drugs to cancer cells. PMID- 30445886 TI - A closed-form formulation for the conformal articulation of metal-on-polyethylene hip prostheses: Contact mechanics and sliding distance. AB - Using Hertz contact law results in inaccurate outcomes when applied to the soft conformal hip implants. The finite element method also involves huge computational time and power. In addition, the sliding distance computed using the Euler rotation method does not incorporate tribology of bearing surfaces, contact mechanics and inertia forces. This study, therefore, aimed to develop a nonlinear dynamic model based on the multibody dynamic methodology to predict contact pressure and sliding distance of metal-on-polyethylene hip prosthesis, simultaneously, under normal walking condition. A closed-form formulation of the contact stresses distributed over the articulating surfaces was derived based upon the elastic foundation model, which reduced computational time and cost significantly. Three-dimensional physiological loading and motions, inertia forces due to hip motion and energy loss during contact were incorporated to obtain contact properties and sliding distance. Comparing the outcomes with that available in the literature and a finite element analysis allowed for the validation of our approach. Contours of contact stresses and accumulated sliding distances at different instants of the walking gait cycle were investigated and discussed. It was shown that the contact point at each instant was located within the zone with the corresponding highest accumulated sliding distance. In addition, the maximum contact pressure and area took place at the stance phase with a single support. The stress distribution onto the cup surface also conformed to the contact point trajectory and the physiological loading. PMID- 30445888 TI - Bone mass preservation with high-dose cholecalciferol and dietary calcium in HIV patients following antiretroviral therapy. Is it possible? AB - OBJECTIVE: To evaluate whether treatment with 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation in HIV patients following different cART regimens yields normal levels of vitamin D3 and PTH as well as whether changes in bone mineral density are clinically significant. METHODS: Consecutive HIV patients following different cART regimens received 100,000 IU/month (equivalent to 3200 IU/day) of cholecalciferol and 1 g/day of dietary calcium supplementation. The participants underwent BMD assessment via dual energy X-ray absorptiometry of the spine and hip at baseline (T0) and after 24 months (T1). Levels of 25(OH) vitamin D3 and parathyroid hormone (PTH) were assessed at T0 and T1. Quantitative variables were assessed with a paired t-test, independent t-test or analysis of variance, as appropriate. A chi-squared analysis was used to assess the association between qualitative variables. A p-value <0.05 was considered significant. Patients were divided into three groups depending on the cART regimen. RESULTS: A total of 79 patients were included (40 males, 51% and 39 females, 49%), with a mean age of 46.6 (SD +/ 11.2) years, a baseline CD4 count of 649 cells/ul and a mean 25 hydroxycholecalciferol (25(OH) D3) value of 25 + 10 ng/ml. After 24 months, the 25(OH) D3 increased to 40 + 11 ng/ml. The initial BMDs at T0 were estimated as 0.919 (+/-0.27) and 0.867 (+/-0.14) g/cm2 at the spine and hip, respectively. After 24 months, the BMD was 0.933 (+/-0.15) g/cm2 at the spine and 0.857 (+/ 0.14) g/cm2 at the hip. Based on a BMD change exceeding 3%, a worsening was observed in 23% of patients at the spine and 27% at the hip, whereas stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip. Subgrouping patients based on antiretroviral therapy indicated that, at T1, there was a statistically significant increase in vitamin D3 concentration in all patients, while PTH concentration was not significantly reduced in patients taking tenofovir or efavirenz. BMD stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip after 24 months. The multivariate analysis confirms a decrease in vitamin D3 and an increase in PTH levels in smokers, as well higher vitamin D3 concentrations in males and lower spine BMDs in menopausal females. CONCLUSION: The proposed protocol of cholecalciferol and dietary calcium supplementation is safe and valid for correcting vitamin D abnormalities in almost all patients as well as reducing PTH levels in a high percentage of patients; however, it is not sufficient for normalization, particularly in patients exposed to tenofovir or efavirenz. At the spine, no significant BMD change was found in any of the therapy groups. At the hip, our data confirm a modest negative effect on bone mass caused by tenofovir and efavirenz. PMID- 30445887 TI - Preliminary Evidence of a Missing Self Bias in Face Perception FOR Individuals with Dissociative Identity Disorder. AB - Failing to recognize one's mirror image can signal an abnormality in one's sense of self. In dissociative identity disorder (DID), individuals often report that their mirror image can feel unfamiliar or distorted. They also experience some of their own thoughts, emotions, and bodily sensations as if they are nonautobiographical and sometimes as if instead, they belong to someone else. To assess these experiences, we designed a novel backwards masking paradigm in which participants were covertly shown their own face, masked by a stranger's face. Participants rated feelings of familiarity associated with the strangers' faces. 21 control participants without trauma-generated dissociation rated masks, which were covertly preceded by their own face, as more familiar compared to masks preceded by a stranger's face. In contrast, across two samples, 28 individuals with DID and similar clinical presentations (DSM-IV Dissociative Disorder Not Otherwise Specified type 1) did not show increased familiarity ratings to their own masked face. However, their familiarity ratings interacted with self-reported identity state integration. Individuals with higher levels of identity state integration had response patterns similar to control participants. These data provide empirical evidence of aberrant self-referential processing in DID/DDNOS and suggest this is restored with identity state integration. PMID- 30445889 TI - Structural basis of different substrate preferences of two old yellow enzymes from yeasts in the asymmetric reduction of enone compounds. AB - Old yellow enzymes (OYEs) are potential targets of protein engineering for useful biocatalysts because of their excellent asymmetric reductions of enone compounds. Two OYEs from different yeast strains, Candida macedoniensis AKU4588 OYE (CmOYE) and Pichia sp. AKU4542 OYE (PsOYE), have a sequence identity of 46%, but show different substrate preferences; PsOYE shows 3.4-fold and 39-fold higher catalytic activities than CmOYE toward ketoisophorone and (4S)-phorenol, respectively. To gain insights into structural basis of their different substrate preferences, we have solved a crystal structure of PsOYE, and compared its catalytic site structure with that of CmOYE, revealing the catalytic pocket of PsOYE is wider than that of CmOYE due to different positions of Phe246 (PsOYE)/Phe250 (CmOYE) in static Loop 5. This study shows a significance of 3D structural information to explain the different substrate preferences of yeast OYEs which cannot be understood from their amino acid sequences. Abbreviations: OYE: Old yellow enzymes, CmOYE: Candida macedoniensis AKU4588 OYE, PsOYE: Pichia sp. AKU4542 OYE. PMID- 30445890 TI - Subcellular localisation of an endoplasmic reticulum-plasma membrane tethering factor, SYNAPTOTAGMIN 1, is affected by fluorescent protein fusion. AB - Membrane contact sites (MCS) have increasingly received attention because of their general role in a number of important cellular processes. SYNAPTOTAGMIN 1 (SYT1) is a tethering factor connecting the endoplasmic reticulum (ER) and the plasma membrane (PM) in plant cells. Confocal microscopy using fluorescent protein fusion is an indispensable tool for studying protein localisation and functions. However, several studies have reported that fluorescent protein dimerisation affects the subcellular localisation of proteins tagged by the fluorescent protein. Here, we investigate the effects of fluorescent protein dimerisation by comparing the subcellular localisation of SYT1 fused with a synthetic GFP (SYT1-sGFP) and SYT1 fused with a monomeric GFP (SYT1-mGFP). SYT1 mGFP was confined to specific domains in the ER, whereas SYT1-sGFP spread along the ER when transiently overexpressed. SYT1-localised regions were suggested to correspond to ER-PM contact sites because of its immobility. Similar results were obtained in the transgenic Arabidopsis, even though SYT1-sGFP and SYT1-mGFP were expressed at comparable levels. It is suggested that SYT1-mGFP more accurately reproduced SYT1 localisation in intact cells because the proportion of persistent area in the ER was more similar between the wild type and the plant expressing SYT1-mGFP than between the wild type and the plant expressing SYT1-sGFP. Taken together, these results suggest that the fusion of sGFP makes SYT1-sGFP form excessive ER-PM contact sites in the ER. PMID- 30445891 TI - How do we know that plants listen: Advancements and limitations of transcriptomic profiling for the identification of sound-specific biomarkers in tomato. AB - Sound vibration has been recently identified as an important physical trigger to elicit plant responses. Naturally occurring sound waves modulate diverse aspects of plant physiology, such as root growth, stress responses, and seed germination. However, it has been debated whether plants perceive artificially generated sound vibration and exhibit similar phenotypic changes to those exhibited after perception of natural sound waves. Recently, analysis of RNA-Seq and microRNA-Seq using tomato fruits treated with optimized sound waves to attenuate fruit ripening revealed sound-specific microRNAs, which could be used as sound-specific biomarkers in tomato. These data provide solid molecular evidence of sound perception in plants. Despite these results, there are obvious limitations of biomarkers' specificity and selectivity that need be addressed to facilitate the application of sound treatment in agriculture. Here, the pros and cons of sequencing technologies used to identify sound-associated molecules suggest recommendations for the effective identification of biomarkers responsive to sound treatment in plants. PMID- 30445892 TI - Increased Connectivity Between the Nucleus Accumbens and the Default Mode Network in Patients With Schizophrenia During Cigarette Cravings. AB - OBJECTIVE: Compared to the general population, tobacco smoking cessation rates are lower in populations with schizophrenia. Unfortunately, the potential neurophysiologic mechanisms underlying these low cessation rates in schizophrenia have been seldom studied using functional neuroimaging. Recently, it has been shown that tobacco cravings are increased in smokers with schizophrenia compared to smokers with no comorbid psychiatric disorder. Given the critical role of the brain reward system in the neurobiology of addiction, we sought to examine the functional connectivity of core regions of this system in smokers with schizophrenia during the viewing of appetitive smoking cues. METHODS: Smokers with (n = 18) and without (n = 24) schizophrenia were scanned using functional magnetic resonance imaging while viewing appetitive cigarette images. Functional connectivity analyses were performed using the bilateral nucleus accumbens as the seed regions. RESULTS: Smokers with schizophrenia and smokers with no psychiatric comorbidity did not differ in subjective cravings in response to appetitive smoking cues. However, in smokers with schizophrenia relative to control smokers, we found an increased connectivity between the nucleus accumbens and regions involved in the default mode network (e.g., middle temporal gyrus and precuneus), which are involved in self-referential processes. Moreover, a positive correlation was observed between the left nucleus accumbens and left middle temporal gyrus connectivity and cigarette cravings across both groups of smokers. CONCLUSIONS: These results highlight a key role of the nucleus accumbens in cigarette craving in schizophrenia and suggest that the subjective valuation of cigarette cues is increased in this population. Similar neurofunctional studies on cravings for other psychoactive substances in schizophrenia are warranted. PMID- 30445893 TI - Effect of video-assisted patient education on compliance with therapy, quality of life, psychomorbidity, and cost of illness in irritable bowel syndrome. AB - OBJECTIVE: Patient education is important in irritable bowel syndrome (IBS), but its effects on outcomes have not been studied extensively. METHODS: Patients were enrolled and prospectively divided into an interventional and usual care group. Both received standard of care, but the former additionally received video assisted patient education. Self-administered questionnaires IBS-quality of life (QOL), Beck Anxiety-Depression Inventory II (BAI, BDI), and Hospital Anxiety and Depression Scale (HADS) were administered at baseline, 3 months, and 6 months. Compliance was defined as drug intake of >80% of the prescribed dose. COI included prospective, prevalence-based, societal perspective. RESULTS: Of the 107 patients included, 84 [78.5%; male = 66 (78.57%); median age = 44 (range 20-77 years)] completed the follow up. While the median (inter-quartile range; IQR) QOL scores decreased significantly in both the groups (p < 0.001 for either group), the final scores were significantly better in the interventional group [49 (44 52.5) versus 80 (76-103), respectively; p < 0.005]. There was a significant improvement in the BDI; p < 0.001]. However, the rest did not achieve statistical significance. At 6 months, total median (IQR) semi-annual cost per patient was INR 14,639 (8253-17,909) [US $240 (135-294]. CONCLUSION: Video-assisted patient education should be a part of the treatment of IBS since it improves the QOL and depression scores. PMID- 30445894 TI - Open chest epicardial and transapical endocardial substrate ablation for ventricular tachycardia with left ventricular aneurysm in a porcine model. AB - BACKGROUND:: Endo-epicardial radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) as a first-line strategy has been shown to improve outcomes. This study sought to evaluate the feasibility and validity of open chest epicardial and transapical endocardial substrate ablation for VT with left ventricular aneurysm (LVA) applying to routine cardiac surgery. METHODS:: Porcine models of LVA with VT were developed and were divided into a study group (RFCA from the epicardium via direct-view and endocardium via transapical access) and a control group (endocardial RFCA via retrograde transaortic access). Substrate based mapping and ablation targeting abnormal potentials were performed under thoracotomy. Outcomes, including procedural success and acute freedom from VT, were analysed. RESULTS:: Twenty-four of 35 (68.57%) acute myocardial infarction (AMI) pigs developed LVA with VT in a 6-week survival period and were randomly divided into a study group (n=12) and a control group (n=12). All animals in the study group successfully underwent endocardial mapping and ablation by transapical access. The scar size of the endocardium and the left ventricular chamber volume were similar in the two groups. Acute freedom from VT in the study group was remarkably superior to that in the control group (88.33% vs. 58.33%, p=0.04). CONCLUSIONS:: Combined, direct epicardial and transapical endocardial substrate mapping and ablation appeared to be feasible and effective for treating VT with LVA under thoracotomy. PMID- 30445895 TI - Outcome of neuropsychiatric symptoms and daily functioning of patients with dementia treated on an acute psychogeriatric ward. AB - BACKGROUND: Dementia is associated with progressive deterioration in multiple cognitive domains, functional impairment and neuropsychiatric symptoms (NPS). AIMS: The aim of this study was to explore the factors associated with the outcome of NPS and daily functioning in patients with dementia during acute psychogeriatric hospitalization. MATERIALS AND METHOD: The data (n = 175) were collected between 2009 and 2013 in naturalistic settings on one acute psychogeriatric ward at one university hospital in Finland. Behavioural symptoms were assessed using the Neuropsychiatric Inventory (NPI) and activities of daily living using the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). RESULTS: During the hospital stay (45 days +/-30.4) NPI total score decreased from 33.9 to 18.2 (p < .001). Daily functioning score decreased from 31.7 to 20.9 (p < .001). The number of patients taking antipsychotics (96-130, p = .004) and anxiolytics (54-102, p < .001) increased from admission to discharge. Overall mean dosage (mg/day) of antipsychotics (from 40.2 to 72.0 in chlorpromazine equivalents, p < .00) and anxiolytics (from 3.43 to 7.47 in diazepam equivalents, p < .001) also increased. Higher antipsychotic dosage at discharge was a significant predictor for large NPI score change (p = .002) indicating better symptom reduction. Neither higher antipsychotic dosage or anxiolytic dosage at discharge were significant predictors for ADL score change. CONCLUSIONS: Neuropsychiatric symptoms improved while deterioration was found in daily functioning from admission to discharge. Higher antipsychotic dosage at discharge was a predictor for larger NPI score change indicating better symptom reduction. Preventing threatening ADL decline during hospital stay is especially important. PMID- 30445896 TI - Satisfaction and acceptability of cabotegravir long-acting injectable suspension for prevention of HIV: Patient perspectives from the ECLAIR trial. AB - BACKGROUND: Cabotegravir (GSK1265744) is an integrase strand transfer inhibitor in development as a long-acting (LA) intramuscular injectable suspension for HIV 1 pre-exposure prophylaxis (PrEP). OBJECTIVE: We report participant outcomes from the phase IIa ECLAIR study related to tolerability, acceptability, and satisfaction of cabotegravir LA. METHODS: The ECLAIR study (ClinicalTrials.gov identifier, NCT02076178) was a randomized, placebo-controlled study in healthy men not at high risk of acquiring HIV-1. Participants were randomized (5:1) to once-daily oral cabotegravir 30 mg or placebo tablets for 4 weeks, followed by gluteal intramuscular injections of cabotegravir LA 800 mg or saline placebo every 12 weeks. The primary objective was to evaluate the safety of cabotegravir LA over three injection cycles (to Week 41). Secondary objectives assessed the tolerability, satisfaction, and acceptability of cabotegravir LA. RESULTS: Among 115 participants who received injections in the cabotegravir (n = 94) and placebo (n = 21) groups, 93% (n = 87) and 95% (n = 20) completed the injection phase, respectively. Injection intolerability led to withdrawal in 4 participants (4%) receiving cabotegravir LA. The most frequently reported Grade >=2 adverse event was injection-site pain. Most participants (74% [n = 67]) receiving consecutive injections favored cabotegravir LA vs oral cabotegravir. Most participants were satisfied with cabotegravir LA (75% [n = 64]), were willing to continue (79% [n = 68]), and would recommend (87% [n = 75]) the therapy. CONCLUSIONS: While Grade >=2 injection-site pain was common, most participants reported overall satisfaction with and preference for cabotegravir LA, with few discontinuations due to injection intolerance. These findings support investigation of cabotegravir LA as an alternative to daily oral PrEP regimens. PMID- 30445897 TI - Genetic association study of CSNK1E gene in bipolar disorder and circadian characteristics. AB - BACKGROUND: A circadian rhythm disturbance is one of the essential components of the phenotype of bipolar disorder. It has been reported that casein kinase 1 epsilon (CSNK1E), a member of the clock gene family, is associated with psychiatric phenotypes. OBJECTIVES: We performed a genetic association study to determine the genetic role of CSNK1E in bipolar disorder and circadian rhythm disturbances in the Korean population. METHODS: The present study included 215 patients with bipolar disorder and 773 controls. Circadian characteristics were measured by the Korean version of the Composite Scale of Morningness (CS). Single nucleotide polymorphisms (SNPs) of CSNK1E, rs1534891 and rs2075984, were genotyped. Chi-square analyses were performed to evaluate associations involving alleles and genotypes. Haplotype analysis was also performed, and the permutation p value was calculated. We also tested further associations involving these SNPs and scores on the CS. RESULTS: We found a positive association between SNP rs2075984 and bipolar disorder in both the allelic (p = .003) and genotypic (p = .006) distributions. No allelic or genotypic association between SNP rs1534891 and bipolar disorder was observed. A significant association of haplotype with bipolar disorder was found (p = .033). However, no association between the CS and the genotype of either SNP was found in the total sample. CONCLUSION: CSNK1E SNP rs2075984 seemed to play a significant role in the development of bipolar disorder in this Korean sample. This association does not seem to relate to the phase preference measured by the CS. Further studies on CSNK1E with larger samples and more SNPs are necessary. PMID- 30445898 TI - The independent reinforcement effect: The role diverse social ties play in the credibility assessment process. AB - In this study, we explore the effect of diversity among people who share a story about a scientific discovery, on the recipient's credibility assessment regarding that story. The data used in this study were gathered in two phases. Initial data were collected through the Twitter application program interface. The data were then used in an experimental setting: We manipulated the level of diversity of real-life Twitter followings, supposedly retweeting a story to our participants ( n = 274). Each of our participants was then asked to complete a paper-based survey. Our findings show that social diversity can enhance the perceived credibility of a shared item. This effect is amplified among individuals with high digital literacy, as well as individuals with high need for cognition. The study offers a deeper understanding of credibility assessment mechanisms within Twitter and other social networking sites. PMID- 30445899 TI - Identifying probable post-traumatic stress disorder: applying supervised machine learning to data from a UK military cohort. AB - BACKGROUND: Early identification of probable post-traumatic stress disorder (PTSD) can lead to early intervention and treatment. AIMS: This study aimed to evaluate supervised machine learning (ML) classifiers for the identification of probable PTSD in those who are serving, or have recently served in the United Kingdom (UK) Armed Forces. METHODS: Supervised ML classification techniques were applied to a military cohort of 13,690 serving and ex-serving UK Armed Forces personnel to identify probable PTSD based on self-reported service exposures and a range of validated self-report measures. Data were collected between 2004 and 2009. RESULTS: The predictive performance of supervised ML classifiers to detect cases of probable PTSD were encouraging when compared to a validated measure, demonstrating a capability of supervised ML to detect the cases of probable PTSD. It was possible to identify which variables contributed to the performance, including alcohol misuse, gender and deployment status. A satisfactory sensitivity was obtained across a range of supervised ML classifiers, but sensitivity was low, indicating a potential for false negative diagnoses. CONCLUSIONS: Detection of probable PTSD based on self-reported measurement data is feasible, may greatly reduce the burden on public health and improve operational efficiencies by enabling early intervention, before manifestation of symptoms. PMID- 30445900 TI - Cell migration is negatively modulated by ABCA1. AB - Temporal and spatial changes of membrane lipid distribution in the plasma membrane are thought to be important for various cellular functions. ATP-Binding Cassette A1 (ABCA1) is a key lipid transporter for the generation of high density lipoprotein. Recently, we reported that ABCA1 maintains an asymmetric distribution of cholesterol in the plasma membrane. Here we report that ABCA1 suppresses cell migration by modulating signal pathways. ABCA1 knockdown in mouse embryonic fibroblasts accelerated cell migration and increased activation of Rac1 and its localization to detergent-resistant membranes. Phosphorylation of MEK and ERK also increased. Inhibition of Rac1 or MEK-ERK signals suppressed cell migration in ABCA1 knockdown cells. Because our experimental conditions for cell migration did not contain cholesterol or lipid acceptors for ABCA1, cellular cholesterol content was not changed. These data suggest that ABCA1 modulates cell migration via Rac1 and MEK-ERK signaling by altering lipid distribution in the plasma membrane. PMID- 30445901 TI - The clinical role of well-being therapy. AB - PURPOSE: There are several clinical areas where psychological well-being may play an important role: the assessment of the dynamic balance between ill-being and well-being; reduction of incidence, prevention of recurrence and achievement of full recovery in psychiatric disorders such as depression; patient's satisfaction and perceived change after treatment. The aim of this article is to discuss the clinical role of Well-Being Therapy (WBT). MATERIALS AND METHODS: A critical review of the literature concerned with psychological well-being and its treatment was performed. WBT is a short-term psychotherapeutic strategy that emphasizes self-observation of psychological well-being, with the use of a structured diary, cognitive restructuring of interfering thoughts and/or behaviors through cognitive behavioral techniques, and homework assignments (i.e. pursuing optimal experiences). WBT is based on a multidimensional model of psychological well-being that was originally developed by Marie Jahoda and it is aimed at achieving a state of euthymia. RESULTS: WBT has been validated in a number of randomized controlled trials. The sequential combination of cognitive behavior therapy (CBT) and WBT has mainly characterized its use so far. Illustration of a clinical case exemplifies its application and the potential role of psychological well-being in the clinical process. CONCLUSIONS: Even though more randomized controlled trials concerned with WBT are needed, consideration of psychological well-being may unravel innovative approaches to the prevention, assessment and treatment of mood and anxiety disorders. PMID- 30445902 TI - Differential effect of surgical manipulation on gene expression in normal breast tissue and breast tumor tissue. AB - BACKGROUND: Gene expression profiles of normal and tumor tissue reflect both differences in biological processes taking place in vivo and differences in response to stress during surgery and sample handling. The effect of cold (room temperature) ischemia in the time interval between surgical removal of the specimen and freezing is described in a few studies. However, not much is known about the effect of warm (body temperature) ischemia during surgery. METHODS: Three women with primary operable breast cancer underwent in situ biopsies from normal breast and tumor tissue prior to radical mastectomy. Ex vivo biopsies from normal and tumor tissue were collected immediately after surgical excision. The putative effects on gene expression of malignancy (tumor versus normal), surgical manipulation (post- versus pre-surgical) and interaction between the two (differences in effect of surgical manipulation on tumor and normal samples) were investigated simultaneously by Generalized Estimating Equation (GEE) analysis in this self-matched study. RESULTS: Gene set enrichment analysis (GSEA) demonstrates a marked difference in effect of surgical manipulation on tumor compared to normal tissue. Interestingly, a large proportion of pathways affected by ischemia especially in tumor tissue are pathways considered to be specifically up regulated in tumor tissue compared to normal. CONCLUSION: The results of this study suggest that a large contribution to this differential expression originates from altered response to stress in tumor cells rather than merely representing in vivo differences. It is important to bear this in mind when using gene-expression analysis to deduce biological function, and when collecting material for gene expression profiling. PMID- 30445904 TI - Modified Pearson correlation coefficient for two-color imaging in spherocylindrical cells. AB - The revolution in fluorescence microscopy enables sub-diffraction-limit ("superresolution") localization of hundreds or thousands of copies of two differently labeled proteins in the same live cell. In typical experiments, fluorescence from the entire three-dimensional (3D) cell body is projected along the z-axis of the microscope to form a 2D image at the camera plane. For imaging of two different species, here denoted "red" and "green", a significant biological question is the extent to which the red and green spatial distributions are positively correlated, anti-correlated, or uncorrelated. A commonly used statistic for assessing the degree of linear correlation between two image matrices R and G is the Pearson Correlation Coefficient (PCC). PCC should vary from - 1 (perfect anti-correlation) to 0 (no linear correlation) to + 1 (perfect positive correlation). However, in the special case of spherocylindrical bacterial cells such as E. coli or B. subtilis, we show that the PCC fails both qualitatively and quantitatively. PCC returns the same + 1 value for 2D projections of distributions that are either perfectly correlated in 3D or completely uncorrelated in 3D. The PCC also systematically underestimates the degree of anti-correlation between the projections of two perfectly anti correlated 3D distributions. The problem is that the projection of a random spatial distribution within the 3D spherocylinder is non-random in 2D, whereas PCC compares every matrix element of R or G with the constant mean value [Formula: see text] or [Formula: see text]. We propose a modified Pearson Correlation Coefficient (MPCC) that corrects this problem for spherocylindrical cell geometry by using the proper reference matrix for comparison with R and G. Correct behavior of MPCC is confirmed for a variety of numerical simulations and on experimental distributions of HU and RNA polymerase in live E. coli cells. The MPCC concept should be generalizable to other cell shapes. PMID- 30445903 TI - Comparative evolutionary histories of fungal proteases reveal gene gains in the mycoparasitic and nematode-parasitic fungus Clonostachys rosea. AB - BACKGROUND: The ascomycete fungus Clonostachys rosea (order Hypocreales) can control several important plant diseases caused by plant pathogenic fungi and nematodes. Subtilisin-like serine proteases are considered to play an important role in pathogenesis in entomopathogenic, mycoparasitic, and nematophagous fungi used for biological control. In this study, we analysed the evolutionary histories of protease gene families, and investigated sequence divergence and regulation of serine protease genes in C. rosea. RESULTS: Proteases of selected hypocrealean fungal species were classified into families based on the MEROPS peptidase database. The highest number of protease genes (590) was found in Fusarium solani, followed by C. rosea with 576 genes. Analysis of gene family evolution identified non-random changes in gene copy numbers in the five serine protease gene families S1A, S8A, S9X, S12 and S33. Four families, S1A, S8A, S9X, and S33, displayed gene gains in C. rosea. A gene-tree / species-tree reconciliation analysis of the S8A family revealed that the gene copy number increase in C. rosea was primarily associated with the S08.054 (proteinase K) subgroup. In addition, regulatory and predicted structural differences, including twelve sites evolving under positive selection, among eighteen C. rosea S8A serine protease paralog genes were also observed. The C. rosea S8A serine protease gene prs6 was induced during interaction with the plant pathogenic species F. graminearum. CONCLUSIONS: Non-random increases in S8A, S9X and S33 serine protease gene numbers in the mycoparasitic species C. rosea, Trichoderma atroviride and T. virens suggests an involvement in fungal-fungal interactions. Regulatory and predicted structural differences between C. rosea S8A paralogs indicate that functional diversification is driving the observed increase in gene copy numbers. The induction of prs6 expression in C. rosea during confrontation with F. graminearum suggests an involvement of the corresponding protease in fungal-fungal interactions. The results pinpoint the importance of serine proteases for ecological niche adaptation in C. rosea, including a potential role in the mycoparasitic attack on fungal prey. PMID- 30445905 TI - A practical implementation of large transcriptomic data analysis to resolve cryptic species diversity problems in microbial eukaryotes. AB - BACKGROUND: Transcriptome sequencing has become a method of choice for evolutionary studies in microbial eukaryotes due to low cost and minimal sample requirements. Transcriptome data has been extensively used in phylogenomic studies to infer ancient evolutionary histories. However, its utility in studying cryptic species diversity is not well explored. An empirical investigation was conducted to test the applicability of transcriptome data in resolving two major types of discordances at lower taxonomic levels. These include cases where species have the same morphology but different genetics (cryptic species) and species of different morphologies but have the same genetics. We built a species comparison bioinformatic pipeline that takes into account the nature of transcriptome data in amoeboid microbes exemplifying such discordances. RESULT: Our analyses of known or suspected cryptic species yielded consistent results regardless of the methods of culturing, RNA collection or sequencing. Over 95% of the single copy genes analyzed in samples of the same species sequenced using different methods and cryptic species had intra- and interspecific divergences below 2%. Only a minority of groups (2.91-4.87%) had high distances exceeding 2% in these taxa, which was likely caused by low data quality. This pattern was also observed in suspected genetically similar species with different morphologies. Transcriptome data consistently delineated all taxa above species level, including cryptically diverse species. Using our approach we were able to resolve cryptic species problems, uncover misidentification and discover new species. We also identified several potential barcode markers with varying evolutionary rates that can be used in lineages with different evolutionary histories. CONCLUSION: Our findings demonstrate that transcriptome data is appropriate for understanding cryptic species diversity in microbial eukaryotes. PMID- 30445906 TI - RefCell: multi-dimensional analysis of image-based high-throughput screens based on 'typical cells'. AB - BACKGROUND: Image-based high-throughput screening (HTS) reveals a high level of heterogeneity in single cells and multiple cellular states may be observed within a single population. Currently available high-dimensional analysis methods are successful in characterizing cellular heterogeneity, but suffer from the "curse of dimensionality" and non-standardized outputs. RESULTS: Here we introduce RefCell, a multi-dimensional analysis pipeline for image-based HTS that reproducibly captures cells with typical combinations of features in reference states and uses these "typical cells" as a reference for classification and weighting of metrics. RefCell quantitatively assesses heterogeneous deviations from typical behavior for each analyzed perturbation or sample. CONCLUSIONS: We apply RefCell to the analysis of data from a high-throughput imaging screen of a library of 320 ubiquitin-targeted siRNAs selected to gain insights into the mechanisms of premature aging (progeria). RefCell yields results comparable to a more complex clustering-based single-cell analysis method; both methods reveal more potential hits than a conventional analysis based on averages. PMID- 30445907 TI - Adaptation and constraint in the evolution of the mammalian backbone. AB - BACKGROUND: The axial skeleton consists of repeating units (vertebrae) that are integrated through their development and evolution. Unlike most tetrapods, vertebrae in the mammalian trunk are subdivided into distinct thoracic and lumbar modules, resulting in a system that is constrained in terms of count but highly variable in morphology. This study asks how thoracolumbar regionalization has impacted adaptation and evolvability across mammals. Using geometric morphometrics, we examine evolutionary patterns in five vertebral positions from diverse mammal species encompassing a broad range of locomotor ecologies. We quantitatively compare the effects of phylogenetic and allometric constraints, and ecological adaptation between regions, and examine their impact on evolvability (disparity and evolutionary rate) of serially-homologous vertebrae. RESULTS: Although phylogenetic signal and allometry are evident throughout the trunk, the effect of locomotor ecology is partitioned between vertebral positions. Lumbar vertebral shape correlates most strongly with ecology, differentiating taxa based on their use of asymmetric gaits. Similarly, disparity and evolutionary rates are also elevated posteriorly, indicating a link between the lumbar region, locomotor adaptation, and evolvability. CONCLUSION: Vertebral regionalization in mammals has facilitated rapid evolution of the posterior trunk in response to selection for locomotion and static body support. PMID- 30445908 TI - Quantifying the genetic parameters of feed efficiency in juvenile Nile tilapia Oreochromis niloticus. AB - BACKGROUND: Improving feed efficiency in fish is crucial at the economic, social and environmental levels with respect to developing a more sustainable aquaculture. The important contribution of genetic improvement to achieve this goal has been hampered by the lack of accurate basic information on the genetic parameters of feed efficiency in fish. We used video assessment of feed intake on individual fish reared in groups to estimate the genetic parameters of six growth traits, feed intake, feed conversion ratio (FCR) and residual feed intake in 40 pedigreed families of the GIFT strain of Nile tilapia, Oreochromis niloticus. Feed intake and growth were measured on juvenile fish (22.4 g mean body weight) during 13 consecutive meals, representing 7 days of measurements. We used these data to estimate the FCR response to different selection criteria to assess the potential of genetics as a means of increasing FCR in tilapia. RESULTS: Our results demonstrate genetic control for FCR in tilapia, with a heritability estimate of 0.32 +/- 0.11. Response to selection estimates showed FCR could be efficiently improved by selective breeding. Due to low genetic correlations, selection for growth traits would not improve FCR. However, weight loss at fasting has a high genetic correlation with FCR (0.80 +/- 0.25) and a moderate heritability (0.23), and could be an easy to measure and efficient criterion to improve FCR by selective breeding in tilapia. CONCLUSION: At this age, FCR is genetically determined in Nile tilapia. A selective breeding program could be possible and could help enabling the development of a more sustainable aquaculture production. PMID- 30445909 TI - Quantitative trait loci for resistance to Flavobacterium psychrophilum in rainbow trout: effect of the mode of infection and evidence of epistatic interactions. AB - BACKGROUND: Bacterial cold-water disease, which is caused by Flavobacterium psychrophilum, is one of the major diseases that affect rainbow trout (Oncorhynchus mykiss) and a primary concern for trout farming. Better knowledge of the genetic basis of resistance to F. psychrophilum would help to implement this trait in selection schemes and to investigate the immune mechanisms associated with resistance. Various studies have revealed that skin and mucus may contribute to response to infection. However, previous quantitative trait loci (QTL) studies were conducted by using injection as the route of infection. Immersion challenge, which is assumed to mimic natural infection by F. psychrophilum more closely, may reveal different defence mechanisms. RESULTS: Two isogenic lines of rainbow trout with contrasting susceptibilities to F. psychrophilum were crossed to produce doubled haploid F2 progeny. Fish were infected with F. psychrophilum either by intramuscular injection (115 individuals) or by immersion (195 individuals), and genotyped for 9654 markers using RAD-sequencing. Fifteen QTL associated with resistance traits were detected and only three QTL were common between the injection and immersion. Using a model that accounted for epistatic interactions between QTL, two main types of interactions were revealed. A "compensation-like" effect was detected between several pairs of QTL for the two modes of infection. An "enhancing-like" interaction effect was detected between four pairs of QTL. Integration of the QTL results with results of a previous transcriptomic analysis of response to F. psychrophilum infection resulted in a list of potential candidate immune genes that belong to four relevant functional categories (bacterial sensors, effectors of antibacterial immunity, inflammatory factors and interferon-stimulated genes). CONCLUSIONS: These results provide new insights into the genetic determinism of rainbow trout resistance to F. psychrophilum and confirm that some QTL with large effects are involved in this trait. For the first time, the role of epistatic interactions between resistance-associated QTL was evidenced. We found that the infection protocol used had an effect on the modulation of defence mechanisms and also identified relevant immune functional candidate genes. PMID- 30445910 TI - CDSS-RM: a clinical decision support system reference model. AB - Clinical Decision Support Systems (CDSS) provide aid in clinical decision making and therefore need to take into consideration human, data interactions, and cognitive functions of clinical decision makers. The objective of this paper is to introduce a high level reference model that is intended to be used as a foundation to design successful and contextually relevant CDSS systems. The paper begins by introducing the information flow, use, and sharing characteristics in a hospital setting, and then it outlines the referential context for the model, which are clinical decisions in a hospital setting. Important characteristics of the Clinical decision making process include: (i) Temporally ordered steps, each leading to new data, which in turn becomes useful for a new decision, (ii) Feedback loops where acquisition of new data improves certainty and generates new questions to examine, (iii) Combining different kinds of clinical data for decision making, (iv) Reusing the same data in two or more different decisions, and (v) Clinical decisions requiring human cognitive skills and knowledge, to process the available information. These characteristics form the foundation to delineate important considerations of Clinical Decision Support Systems design. The model includes six interacting and interconnected elements, which formulate the high-level reference model (CDSS-RM). These elements are introduced in the form of questions, as considerations, and are examined with the use of illustrated scenario-based and data-driven examples. The six elements /considerations of the reference model are: (i) Do CDSS mimic the cognitive process of clinical decision makers? (ii) Do CDSS provide recommendations with longitudinal insight? (iii) Is the model performance contextually realistic? (iv) Is the 'Historical Decision' bias taken into consideration in CDSS design? (v) Do CDSS integrate established clinical standards and protocols? (vi) Do CDSS utilize unstructured data? The CDSS-RM reference model can contribute to optimized design of modeling methodologies, in order to improve response of health systems to clinical decision-making challenges. PMID- 30445911 TI - Comparative genomics of nuclear envelope proteins. AB - BACKGROUND: The nuclear envelope (NE) that encapsulates the nuclear genome is a double lipid bilayer with several integral and peripherally associated proteins. It is a characteristic feature of the eukaryotes and acts as a hub for a number of important nuclear events including transcription, repair, and regulated gene expression. The proteins associated with the nuclear envelope mediate the NE functions and maintain its structural integrity, which is crucial for survival. In spite of the importance of this structure, knowledge of the protein composition of the nuclear envelope and their function, are limited to very few organisms belonging to Opisthokonta and Archaeplastida supergroups. The NE composition is largely unknown in organisms outside these two supergroups. RESULTS: In this study, we have taken a comparative sequence analysis approach to identify the NE proteome that is present across all five eukaryotic supergroups. We identified 22 proteins involved in various nuclear functions to be part of the core NE proteome. The presence of these proteins across eukaryotes, suggests that they are traceable to the Last Eukaryotic Common Ancestor (LECA). Additionally, we also identified the NE proteins that have evolved in a lineage specific manner and those that have been preserved only in a subset of organisms. CONCLUSIONS: Our study identifies the conserved features of the nuclear envelope across eukaryotes and provides insights into the potential composition and the functionalities that were constituents of the LECA NE. PMID- 30445912 TI - The prone position in healthy pregnant women and in women with preeclampsia - a pilot study. AB - BACKGROUND: The prone position is rarely used in medical settings in pregnancy. There is no published information about the prone position in women with preeclampsia. This study examined the feasibility and acceptability of the prone position in pregnant women, and the short-term effect of the prone position on blood pressure (BP) in term healthy pregnant women and in women with preeclampsia. METHODS: After ethics approval, written consent and trial registration (ACTRN:12615000160538 registered 18/02/2015, date of first participant enrolled 03/03/2015), 50 healthy term pregnant women and 15 women with preeclampsia had BP, heart rate (HR), oxygen saturation (SpO2), respiratory rate (RR), fetal heart rate (FHR) and comfort levels measured in two positions: left lateral, and prone. Measurements were after five minutes rest in each position. RESULTS: Mean +/- SD age, gestation and body mass index for healthy pregnant women was 33 +/- 4.1 years, 38 +/- 1.0 weeks and 27 +/- 3.2 kg.m- 2 and for women with preeclampsia was 32 +/- 4.7 years, 36 +/- 3.4 weeks, 31 +/- 5.6 kg.m- 2 respectively. No clinically significant changes occurred in healthy pregnant women in the prone position. Systolic BP was reduced in the prone position in women with preeclampsia (P = 0.019, mean difference - 6.6 mmHg, 95% confidence interval - 11.9 to - 1.3 mmHg). 33% of women with preeclampsia experienced a 10 mmHg or greater reduction in systolic BP in the prone position. 42% of healthy pregnant women and 47% of women with preeclampsia preferred the prone position to lateral. CONCLUSIONS: This is the first study to examine the prone position in women with preeclampsia. For short periods of time the prone position is feasible and comfortable in pregnant women including those at term. The prone position may reduce systolic BP in women with preeclampsia without obvious adverse effects. Larger studies with women lying for longer periods in the prone position are required. Pregnancy should not be a contraindication to the prone position for short periods of time. TRIAL REGISTRATION: ACTRN:12615000160538. PMID- 30445913 TI - Case report: two confirmed cases of human Seoul virus infections in Indonesia. AB - BACKGROUND: Seoul virus (SEOV) is a member of hantavirus family, which is transmitted to humans by Rattus rattus and Rattus norvegicus. Diagnosing SEOV infection is difficult because the clinical presentations are often undifferentiated with other viral or bacterial infections and assays to test antibodies seroconversion and RNA detection are not available in resource-limited setting like Indonesia. CASE PRESENTATION: We report two confirmed cases of SEOV infection from Indonesia. Here, we illustrate the clinical presentations, hematology and biochemistry profiles, and outcomes of the two cases. Phylogenetic analysis revealed that SEOV sequences have highest homology to isolates obtained from rodents in Indonesia. CONCLUSIONS: This report highlights the importance of considering SEOV infection in febrile patients with lymphopenia, thrombocytopenia, and elevation of liver enzyme despite the absence of hemorrhagic manifestations and renal syndromes. The public health importance of rodent-borne diseases such as SEOV infection urges an integrated epidemiological surveillance both in humans and rodents in Indonesia. PMID- 30445914 TI - The impact of status and social context on health service co-design: an example from a collaborative improvement initiative in UK primary care. AB - BACKGROUND: Increasingly, collaborative participatory methods requiring open and honest interaction between a range of stakeholders are being used to improve health service delivery. To be successful these methodologies must incorporate perspectives from a range of patients and staff. Yet, if unaccounted for, the complex relationships amongst staff groups and between patients and providers can affect the veracity and applicability of co-designed solutions. METHODS: Two focus groups convened to discuss suggestions for the improvement of blood testing and result communication in primary care. The groups were mixed of patients and staff in various combinations drawn from the four participating study practices. Here we present a secondary mixed-method analysis of the interaction between participants in both groups using sociogrammatic and thematic analysis. RESULTS: Despite a similar mix of practice staff and patients the two groups produced contrasting discussions, seemingly influenced by status and social context. The sociograms provided a useful insight into the flow of conversation and highlighted the dominance of the senior staff member in the first focus group. Within the three key themes of social context, the alliances formed between participants and the fluidity of the roles assumed manifested differently between groups apparently dictated by the different profile of the participants of each. CONCLUSIONS: For primary care service improvement attention must be paid to the background of participants when convening collaborative service improvement groups as status and imported hierarchies can have significant connotations for the data produced. PMID- 30445915 TI - Joint modeling of multivariate longitudinal data and survival data in several observational studies of Huntington's disease. AB - BACKGROUND: Joint modeling is appropriate when one wants to predict the time to an event with covariates that are measured longitudinally and are related to the event. An underlying random effects structure links the survival and longitudinal submodels and allows for individual-specific predictions. Multiple time-varying and time-invariant covariates can be included to potentially increase prediction accuracy. The goal of this study was to estimate a multivariate joint model on several longitudinal observational studies of Huntington's disease, examine external validity performance, and compute individual-specific predictions for characterizing disease progression. Emphasis was on the survival submodel for predicting the hazard of motor diagnosis. METHODS: Data from four observational studies was analyzed: Enroll-HD, PREDICT-HD, REGISTRY, and Track-HD. A Bayesian approach to estimation was adopted, and external validation was performed using a time-varying AUC measure. Individual-specific cumulative hazard predictions were computed based on a simulation approach. The cumulative hazard was used for computing predicted age of motor onset and also for a deviance residual indicating the discrepancy between observed diagnosis status and model-based status. RESULTS: The joint model trained in a single study had very good performance in discriminating among diagnosed and pre-diagnosed participants in the remaining test studies, with the 5-year mean AUC = .83 (range .77-.90), and the 10-year mean AUC = .86 (range .82-.92). Graphical analysis of the predicted age of motor diagnosis showed an expected strong relationship with the trinucleotide expansion that causes Huntington's disease. Graphical analysis of the deviance-type residual revealed there were individuals who converted to a diagnosis despite having relatively low model-based risk, others who had not yet converted despite having relatively high risk, and the majority falling between the two extremes. CONCLUSIONS: Joint modeling is an improvement over traditional survival modeling because it considers all the longitudinal observations of covariates that are predictive of an event. Predictions from joint models can have greater accuracy because they are tailored to account for individual variability. These predictions can provide relatively accurate characterizations of individual disease progression, which might be important in the timing of interventions, determining the qualification for appropriate clinical trials, and general genotypic analysis. PMID- 30445916 TI - The efficacy of paritaprevir/ritonavir/ombitasvir+dasabuvir and ledipasvir/sofosbuvir is comparable in patients who failed interferon-based treatment with first generation protease inhibitors - a multicenter cohort study. AB - BACKGROUND: According to the EASL and AASLD guidelines, the recommended treatment for patients who failed to achieve a sustained virologic response (SVR) on prior interferon-based triple therapy with protease inhibitors (PI), is a combination of sofosbuvir and NS5A inhibitors. Polish national recommendations also allow the use of paritaprevir/ritonavir/ombitasvir+dasasbuvir+/-ribavirin (PrODR) in this group of patients. The aim of the study was to evaluate the efficacy and safety of PrODR vs. ledipasvir/sofosbuvir+/-RBV (LSR) in PI-experienced patients in real life setting. METHODS: Our analysis included patients registered in the nationwide, investigators initiated, multicentre EpiTer-2 database. Among 4530 patients registered, 335 with genotype 1 (93% 1b) were previously treated with IFN-based regimens with PIs: 127 with boceprevir (BOC), 208 with telaprevir (TVR). Patients with advanced fibrosis (F3/F4) were significantly predominant (BOC 28.4%/61.4%, TVR 18.8%/64.4%, respectively). Subjects were assigned to IFN free retreatment as follows: BOC - 64 (50.4%) PrODR and 63 (49.6%) LSR; TVR- 103 (49.5%) PrODR and 105 (50.5%) LSR. RESULTS: SVR rates were comparable for particular groups: BOC -> PrODR- 100%; BOC -> LSR - 98%; TVR -> PrODR - 97%; TVR > LSR - 96% (intent-to treat analysis-ITT) and BOC -> PrODR->100%; BOC -> LSR - 99%; TVR -> PrODR - 99%; TVR -> LSR - 98% (modified intent-to treat analysis mITT). Both treatment regimens had a favourable safety profile. Adverse events (AEs) were generally mild or moderate in severity. Three deaths were reported. The treatment was stopped due to AEs in five patients (three treated with PrODR and two with LSR). CONCLUSION: Efficacy and safety of treatment with PrODR and LSR is comparable in BOC or TVR-experienced patients. PMID- 30445917 TI - Assessing the effect of risk factors on rates of obstetric transfusion over time using two methodological approaches. AB - BACKGROUND: While red blood cell transfusion rates have declined in most Australian medical specialties, obstetric transfusion rates have instead been increasing. Obstetric transfusions are mostly linked to postpartum haemorrhage, the rates of which have also increased over time. This study used two methodological approaches to investigate recent trends in obstetric transfusion in New South Wales (NSW) and the extent to which this was influenced by changing maternal and pregnancy characteristics. METHODS: Linked birth and hospital records were used to examine rates of red blood cell transfusion in the postpartum period for mothers giving birth in NSW hospitals from 2005 to 2015. Logistic regression models were run to examine the contribution of maternal and pregnancy risk factors to changing rates of transfusion. Risk factors were divided into "pre-pregnancy" and "pregnancy related". Crude and adjusted estimates of the effect of year of birth on obstetric transfusion rates were compared to assess the effect of risk factors on rates over time using two approaches. The first compared actual and predicted odds ratios of transfusion for each year. The second compared the observed increase in transfusion rate with that predicted after controlling for the risk factors. RESULTS: Among 935,659 births, the rate of obstetric transfusion rose from 13 per 1000 births in 2005 to 17 in 2011, and remained stable until 2015. From 2005 to 2015, postpartum haemorrhage increased from 74 to 114 per 1000 births. Compared with the rate in 2005, the available maternal and pregnancy characteristics only partially explained the change in rate of transfusion by 2015 (Method 1, crude odds ratio 1.39 (95% CI 1.25, 1.56); adjusted odds ratio 1.29 (95% CI 1.15, 1.45)). After adjustment for maternal and pregnancy characteristics, obstetric transfusion incidence was predicted to increase by 10.3%, but a 38.7% increase was observed (Method 2). CONCLUSION: Rates of obstetric transfusion have stabilised after a period of increase. The trend could not be fully explained by measured maternal and pregnancy characteristics with either of the two approaches. Further investigation of rates and maternal and clinical risk factors will help to inform and improve obstetric blood product use. PMID- 30445918 TI - Taxonomic classification for microbiome analysis, which correlates well with the metabolite milieu of the gut. AB - BACKGROUND: 16S rRNA gene amplicon sequencing analysis (16S amplicon sequencing) has provided considerable information regarding the ecology of the intestinal microbiome. Recently, metabolomics has been used for investigating the crosstalk between the intestinal microbiome and the host via metabolites. In the present study, we determined the accuracy with which 16S rRNA gene data at different classification levels correspond to the metabolome data for an in-depth understanding of the intestinal environment. RESULTS: Over 200 metabolites were identified using capillary electrophoresis and time-of-flight mass spectrometry (CE-TOFMS)-based metabolomics in the feces of antibiotic-treated and untreated mice. 16S amplicon sequencing, followed by principal component analysis (PCA) of the intestinal microbiome at each taxonomic rank, revealed differences between the antibiotic-treated and untreated groups in the first principal component in the family-, genus, and species-level analyses. These differences were similar to those observed in the PCA of the metabolome. Furthermore, a strong correlation between principal component (PC) scores of the metabolome and microbiome was observed in family-, genus-, and species-level analyses. CONCLUSIONS: Lower taxonomic ranks such as family, genus, or species are preferable for 16S amplicon sequencing to investigate the correlation between the microbiome and metabolome. The correlation of PC scores between the microbiome and metabolome at lower taxonomic levels yield a simple method of integrating different "-omics" data, which provides insights regarding crosstalk between the intestinal microbiome and the host. PMID- 30445919 TI - The prevalence and characteristics of frailty by frailty phenotype in rural Tanzania. AB - BACKGROUND: The frailty phenotype is defined by the presence of three from the following five clinical features: weakness, slow walking speed, unintentional weight loss, exhaustion, and low physical activity. It has been widely applied in different research and clinical contexts, including across many low and middle income countries. However, there is evidence that the operationalisation of each component of the frailty phenotype significantly alters its characteristics and predictive validity, and care is needed when applying the phenotype across settings. The study's objective was to operationalise the frailty phenotype in a rural Tanzanian population of older community-dwelling adults. METHODS: Consenting adults aged >=60 years, and resident in five randomly selected villages of Hai district Demographic Surveillance Site, were eligible to participate in this cross-sectional study. From a screened sample of 1207 older adults, 235 were randomised and consented to an assessment of their frailty status by the frailty phenotype. Trained research fieldworkers (Tanzanian medical doctors and nurses) carried out measurements and questionnaires at local village centres or at participants' homes. RESULTS: The prevalence of the frailty phenotype, calculated from complete data for 196 participants, was 9.25% (95% CI 4.39-14.12) When missing data were counted as meeting frailty criterion (i.e. missing due to inability to perform an assessment), the prevalence increased to 11.22% (95% CI 7.11-15.32). Frailty by phenotype criteria was more common in older age groups, and was associated with self-assessed poor health and depression symptoms. CONCLUSIONS: Frailty can be successfully estimated using the frailty phenotype, however there are challenges in its operationalisation cross culturally. Further work is needed to explore the potential clinical application of the frailty phenotype in such settings. PMID- 30445920 TI - MicroRNA profiling analysis of developing berries for 'Kyoho' and its early ripening mutant during berry ripening. AB - BACKGROUND: 'Fengzao' is an early-ripening bud mutant of 'Kyoho', which matures nearly 30 days earlier than 'Kyoho'. To gain a better understanding of the regulatory role of miRNAs in early-ripening of grape berry, high-throughput sequencing approach and quantitative RT-PCR validation were employed to identify miRNAs at the genome-wide level and profile the expression patterns of the miRNAs during berry development in 'Kyho' and 'Fengzao', respectively. RESULTS: Nine independent small RNA libraries were constructed and sequenced in two varieties from key berry development stages. A total of 108 known miRNAs and 61 novel miRNAs were identified. Among that, 159 miRNAs identified in 'Fengzao' all completely expressed in 'Kyoho' and there were 10 miRNAs specifically expressed in 'Kyoho'. The expression profiles of known and novel miRNAs were quite similar between two varieties. As the major differentially expressed miRNAs, novel_144, vvi-miR3626-3p and vvi-miR3626-5p only expressed in 'Kyoho', vvi-miR399b and vvi miR399e were down-regulated in 'Fengzao', while vvi-miR477b-3p up-regulated in 'Fengzao'. According to the expression analysis and previous reports, miR169-NF-Y subunit, miR398-CSD, miR3626-RNA helicase, miR399- phosphate transporter and miR477-GRAS transcription factor were selected as the candidates for further investigations of miRNA regulation role in the early-ripening of grape. The qRT PCR analyses validated the contrasting expression patterns for these miRNAs and their target genes. CONCLUSIONS: The miRNAome of the grape berry development of 'Kyoho', and its early-ripening bud mutant, 'Fengzao' were compared by high throughput sequencing. The expression pattern of several key miRNAs and their target genes during grape berry development and ripening stages was examined. Our results provide valuable basis towards understanding the regulatory mechanisms of early-ripening of grape berry. PMID- 30445921 TI - Genome-wide transcriptome analysis reveals small RNA profiles involved in early stages of stolon-to-tuber transitions in potato under photoperiodic conditions. AB - BACKGROUND: Small RNAs (sRNAs), especially miRNAs, act as crucial regulators of plant growth and development. Two other sRNA groups, trans-acting short interfering RNAs (tasiRNAs) or phased siRNAs (phasiRNAs), are also emerging as potential regulators of plant development. Stolon-to-tuber transition in potato is an important developmental phase governed by many environmental, biochemical and hormonal cues. Among different environmental factors, photoperiod has a major influence on tuberization. Several mobile signals, mRNAs, proteins and transcription factors have been widely studied for their role in tuber formation in potato, however, no information is yet available that describes the molecular signals governing the early stages of stolon transitions or cell-fate changes at the stolon tip before it matures to potato. Stolon could be an interesting model for studying below ground organ development and we hypothesize that small RNAs might be involved in regulation of stolon-to-tuber transition process in potato. Also, there is no literature that describes the phased siRNAs in potato development. RESULTS: We performed sRNA profiling of early stolon stages (4, 7 and 10 d) under long-day (LD; 16 h light, 8 h dark) and short-day (SD; 8 h light, 16 h dark) photoperiodic conditions. Altogether, 7 (out of 324) conserved and 12 (out of 311) novel miRNAs showed differential expression in early stolon stages under SD vs LD photoperiodic conditions. Key target genes (StGRAS, StTCP2/4 and StPTB6) exhibited differential expression in early stolon stages under SD vs LD photoperiodic conditions, indicative of their potential role in tuberization. Out of 830 TAS-like loci identified, 24 were cleaved by miRNAs to generate 190 phased siRNAs. Some of them targeted crucial tuberization genes such as StPTB1, POTH1 and StCDPKs. Two conserved TAS loci, referred as StTAS3 and StTAS5, which share close conservation with members of the Solanaceae family, were identified in our analysis. One TAS-like locus (StTm2) was validated for phased siRNA generation and one of its siRNA was predicted to cleave an important tuber marker gene StGA2ox1. CONCLUSION: Our study suggests that sRNAs and their selective target genes could be associated with the regulation of early stages of stolon-to-tuber transitions in a photoperiod-dependent manner in potato. PMID- 30445922 TI - Telemonitoring to improve nutritional status in community-dwelling elderly: design and methods for process and effect evaluation of a non-randomized controlled trial. AB - BACKGROUND: A good nutritional status is key for maintaining health and quality of life in older adults. In the Netherlands, 11 to 35% of the community-dwelling elderly are undernourished. Undernutrition or the risk of it should be signalled as soon as possible to be able to intervene at an early stage. However, in the context of an ageing population health care resources are scarce, evoking interest in health enabling technologies such as telemonitoring. This article describes the design of an intervention study focussing at telemonitoring and improving nutritional status of community-dwelling elderly. METHODS: The PhysioDom Home Dietary Intake Monitoring intervention was evaluated using a parallel arm pre-test post-test design including 215 Dutch community-dwelling elderly aged > 65 years. The six-month intervention included nutritional telemonitoring, television messages, and dietary advice by a nurse or a dietician. The control group received usual care. Measurements were performed at baseline, after 4.5 months, and at the end of the study, and included the primary outcome nutritional status and secondary outcomes behavioural determinants, diet quality, appetite, body weight, physical activity, physical functioning, and quality of life. Furthermore, a process evaluation was conducted to provide insight into intervention delivery, feasibility, and acceptability. DISCUSSION: This study will improve insight into feasibility and effectiveness of telemonitoring of nutritional parameters in community-dwelling elderly. This will provide relevant insights for health care professionals, researchers, and policy makers. TRIAL REGISTRATION: The study was retrospectively registered at Clinical Trials.gov (identifier NCT03240094 ) since August 3, 2017. PMID- 30445923 TI - The effectiveness of an integrated care pathway in geriatric rehabilitation among older patients with complex health problems and their informal caregivers: a prospective cohort study. AB - BACKGROUND: To improve continuity and coordination of care in geriatric rehabilitation, an integrated care pathway was developed and implemented in The Netherlands. The purpose of this study was to assess the effects of this pathway on patients and informal caregivers. METHODS: Two cohorts of patients and their informal caregivers were prospectively recruited before implementation of the pathway (2011-2012) and after implementation of the pathway (2013-2014). Primary outcome measures were dependence in activities of daily living in patients (KATZ 15) and self-rated burden among informal caregivers (SRB-VAS). Secondary outcome measures were the frequency of performing extended daily activities, social participation, psychological well-being, quality of life and discharge location (patients) and quality of life and objective care burden (informal caregivers). Outcomes were measured at baseline, after three and after nine months. RESULTS: No effect was shown on the KATZ-15 after three and nine months. However, a larger percentage of patients were discharged home in the care pathway cohort (83% vs 58.1% after three months and 88.6% vs 67.4% after nine months; p = 0.004). Furthermore, after three months, patients from the care pathway cohort performed more extended daily activities (p = 0.014) and informal caregivers experienced a lower self-rated burden (p = 0.05). After nine months, these effects disappeared. No differences were found for the other outcome measures. CONCLUSIONS: Due to the positive effects of the integrated care pathway, we are inclined to recommend implementing the care pathway in regular care. To have longer lasting effects among patients and informal caregivers, we suggest actively disseminating information about the pathway to primary care providers who are currently still unaware of its content. TRIAL REGISTRATION: ISRCTN90000867 (date of registration: 07-04-2016). PMID- 30445924 TI - Evaluation of Influenza A H1N1 infection and antiviral utilization in a tertiary care hospital. AB - BACKGROUND: Influenza A H1N1 infections carry a significant mortality risk. This study describes inpatients with suspected and confirmed Influenza A H1N1 infection who were prescribed oseltamivir, the risk factors associated with infection, the association between infection and mortality, and the factors associated with in-hospital mortality in infected patients. METHODS: This study was a matched case-control study of hospitalized patients who underwent real-time polymerase chain reaction testing for Influenza A H1N1 and were treated with oseltamivir from 2009 to 2015 in a tertiary care hospital. Cases (patients with positive Influenza A H1N1 testing) were matched 1:1 to controls (patients with negative test results). RESULTS: A total of 1405 inpatients who underwent PCR testing and received treatment with oseltamivir were identified in our study and 157 patients confirmed Influenza A H1N1. Almost one third of patients with Influenza A H1N1 were diagnosed in the pandemic period. There was no difference in mortality between cases and controls. Immunocompromised status, requirement of vasoactive drugs, mechanical ventilation, acute hemodialysis, albumin administration, surgical procedures and thoracic procedures and length of stay were associated with increased risk of death in Influenza A H1N1 infected patients. CONCLUSIONS: We found no increased risk of mortality for patients with proven Influenza A H1N1 when compared to similar patients without confirmed Influenza. PMID- 30445925 TI - A systematic review of adherence to oral pre-exposure prophylaxis for HIV - how can we improve uptake and adherence? AB - INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is an effective strategy to reduce the risk of HIV transmission in high risk individuals. However, the effectiveness of oral pre-exposure prophylaxis is highly dependent on user adherence, which some previous trials have struggled to optimise particularly in low and middle income settings. This systematic review aims to ascertain the reasons for non-adherence to pre-exposure prophylaxis to guide future implementation. METHODS: We performed structured literature searches of online databases and conference archives between August 8, 2016 and September 16, 2017. In total, 18 prospective randomized control trials and implementation studies investigating oral pre-exposure prophylaxis were reviewed. A structured form was used for data extraction and findings summarized regarding efficacy, effectiveness, adherence and possible reasons for non-adherence. RESULTS: Adherence varied between differing populations both geographically and socioeconomically. Common reasons for non-adherence reported over multiple studies were; social factors such as stigma, low risk perception, low decision making power, an unacceptable dosing regimen, side effects, and the logistics of daily life. Oral pre-exposure prophylaxis with included antiviral regimens was not associated with a high risk of antiviral resistance development in the reviewed studies. CONCLUSION: Our findings indicate that oral pre-exposure prophylaxis should be delivered within a holistic intervention, acknowledging the other needs of the targeted demographic in order to maximise acceptability. Socioeconomic factors and poor governmental policy remain major barriers to widespread implementation of pre-exposure prophylaxis. PMID- 30445926 TI - A qualitative approach to guide choices for designing a diary study. AB - BACKGROUND: Electronic diaries are increasingly used in diverse disciplines to collect momentary data on experienced feelings, cognitions, behavior and social context in real life situations. Choices to be made for an effective and feasible design are however a challenge. Careful and detailed documentation of argumentation of choosing a particular design, as well as general guidelines on how to design such studies are largely lacking in scientific papers. This qualitative study provides a systematic overview of arguments for choosing a specific diary study design (e.g. time frame) in order to optimize future design decisions. METHODS: During the first data assessment round, 47 researchers experienced in diary research from twelve different countries participated. They gave a description of and arguments for choosing their diary design (i.e., study duration, measurement frequency, random or fixed assessment, momentary or retrospective assessment, allowed delay to respond to the beep). During the second round, 38 participants (81%) rated the importance of the different themes identified during the first assessment round for the different diary design topics. RESULTS: The rationales for diary design choices reported during the first round were mostly strongly related to the research question. The rationales were categorized into four overarching themes: nature of the variables, reliability, feasibility, and statistics. During the second round, all overarching themes were considered important for all diary design topics. CONCLUSIONS: We conclude that no golden standard for the optimal design of a diary study exists since the design depends heavily upon the research question of the study. The findings of the current study are helpful to explicate and guide the specific choices that have to be made when designing a diary study. PMID- 30445927 TI - Human cytomegalovirus and Epstein-Barr virus infections, risk factors, and their influence on the liver function of patients with acute-on-chronic liver failure. AB - BACKGROUND: Studies on human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) have focused primarily on the immunosuppressed population. Few studies have considered immunocompetent and not severely immunocompromised patients. We determined the infection rates of HCMV and EBV, their risk factors and their influence on liver function in patients with HBV-related acute-on-chronic liver failure (ACLF). METHODS: Patients infected with ACLF-based hepatitis B virus (HBV) from 1 December 2016 to 31 May 2018 were enrolled in our study and were divided into infected and uninfected groups. The risk factors for HCMV and EBV infection and their influence on liver function were analysed. RESULTS: A total of 100 hospitalized patients with ACLF due to HBV infection were enrolled in this study. Of these patients, 5% presented HCMV deoxyribonucleic acid (DNA) and 23.0% presented EBV DNA. An HBV DNA count of < 1000 IU/mL increased the occurrence of HCMV infection (P = 0.003). Age, especially older than 60 years, was a risk factor for EBV infection (P = 0.034, P = 0.033). HCMV-infected patients had lower alanine aminotransferase (ALT) levels; albumin levels and Child-Pugh scores in EBV-infected patients were higher than those in uninfected patients. CONCLUSIONS: HCMV and EBV were detected in patients with ACLF caused by HBV infection. Lower replication of HBV (HBV DNA < 1000 IU/mL) may increase the probability of HCMV infection; age, especially older than 60 years of age, was a risk factor for EBV infection. HCMV infection may inhibit HBV proliferation and did not increase liver injury, while co-infection with EBV may influence liver function and may result in a poor prognosis. PMID- 30445928 TI - Does fibrosis have an impact on survival of patients with hepatocellular carcinoma: evidence from the SEER database? AB - BACKGROUND: Liver fibrosis is involved in hepatocellular carcinoma (HCC), but its effect on the survival of patients with HCC remains controversial. This study aims to explore whether the severity of liver fibrosis has an impact on HCC overall survival (OS) and disease-specific survival (DSS) in Surveilance, Epidemiology, and End-Results (SEER) database. METHODS: A total of 11,783 HCC patients diagnosed between 2004 and 2014 from SEER database were enrolled. Cox proportional hazard regression models were used to estimate crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for fibrosis group associated with survival. Decision curve analysis (DCA) was also performed to compare the effect of fibrosis with other clinicopathological characteristics for survival outcome. RESULTS: Patients with high fibrosis score (5-6) had a greater proportion than those with low fibrosis score (0-4) (80.3% vs. 19.7%). Fibrosis score was an independent prognostic factor for OS (HR = 1.09, 95%CI: 1.02-1.16), but not for DSS (HR = 1.05, 95%CI: 0.98-1.13) by multivariate Cox proportional hazard models. Additionally, there was no significant effect of liver fibrosis on OS and DSS with stratification of TNM stage and therapy. Findings of DCA showed that fibrosis was less associated with survival outcome in comparison with other tumor characteristics. CONCLUSIONS: The effect of fibrosis on HCC survival was less important than that of other clinicopathological characteristics (like TNM stage or tumor size). PMID- 30445929 TI - Differences between evidence-based recommendations and actual clinical practice regarding tocolysis: a prospective multicenter registry study. AB - BACKGROUND: International guidelines recommend that tocolytic therapy be restricted to a single 48-h application. However, multiple cycles of tocolytic therapy and maintenance therapy that exceeds 48 h appear to play a role in daily clinical practice. We aimed to evaluate current trends in clinical practice with respect to treatment with tocolytic agents and to identify differences between evidence-based recommendations and daily clinical practice in Austria. METHODS: A prospective multicenter registry study was conducted from October 2013 through April 2015 in ten obstetrical departments in Austria. Women >=18 years of age who received tocolytic therapy following a diagnosis of threatened preterm birth were included, and details were obtained regarding clinical characteristics, tocolytic therapy, and pregnancy outcome. RESULTS: A total of 309 women were included. We observed a median of 2 cycles of tocolytic therapy per patient (IQR 1-3) with a median duration of 2 days per cycle (IQR 2-5). Repeat tocolysis was administered in 41.7% of women, resulting in up to six tocolysis cycles; moreover, 40.8% of the first tocolysis cycles were maintenance tocolysis (i.e., longer than 48 h). Only 25.6% of women received one single 48-h tocolysis cycle in which they received antenatal corticosteroids for fetal lung maturation in accordance evidence-based recommendations. CONCLUSIONS: Here, we report a clear disparity between evidence-based recommendations and daily practice with respect to tocolysis. We believe that the general practice of prescribing tocolytic therapy must be revisited. Furthermore, our findings highlight the need for contemporary studies designed to investigate the effectiveness of performing maintenance and/or repetitive tocolysis treatment. PMID- 30445930 TI - Risk of febrile neutropenia among patients with multiple myeloma or lymphoma who undergo inpatient versus outpatient autologous stem cell transplantation: a systematic review and meta-analysis. AB - BACKGROUND: Outpatient autologous stem cell transplantations (ASCTs) in multiple myeloma and lymphoma patients have been shown to reduce the overall costs and improve the quality of life relative to inpatient ASCTs. This systematic review and meta-analysis was performed with the aim of comprehensively comparing the risk of febrile neutropenia developing in ASCT outpatients and inpatients who have multiple myeloma or lymphoma. METHODS: To be eligible for the meta-analysis, studies needed to be either randomized, controlled studies or cohort studies. They also need to have two groups of patients with multiple myeloma or lymphoma who underwent ASCT, with the treatment being provided to one group in an outpatient setting and to the other on an inpatient basis. The studies had to report our primary outcome of interest, the rate of febrile neutropenia after stem cell infusion, for both groups. The Mantel-Haenszel method was used to pool the effect estimates and 95% confidence intervals of each study. RESULTS: From 9 eligible studies, a total of 1940 patients were included in the meta-analysis. Contrary to conventional concerns, the patients who underwent the outpatient ASCT had a significantly lower risk of developing febrile neutropenia than those admitted for ASCT, with a pooled odds ratio (OR) of 0.44 (95% confidence interval [CI]: 0.29-0.65; p < 0.0001; I2 = 52%). The risk of septicemia was also significantly lower for the outpatients than the inpatients, with a pooled OR of 0.40 (95% CI: 0.16-0.97; p = 0.04; I2 = 23%). Additional analyses found that the odds of having grade 2-3 mucositis and transplant-related mortality were numerically lower for the outpatient group, although the pooled result was not statistically significant. The odds of surviving at 2-3 years was also numerically higher for the ASCT outpatients, but the difference did not reach statistical significance. CONCLUSIONS: This study found a significantly lower odds of developing febrile neutropenia and septicemia among patients with multiple myeloma and lymphoma who received an outpatient ASCT than among those who had an inpatient ASCT. PMID- 30445931 TI - Factors predicting the need for hemorrhage control intervention in patients with blunt pelvic trauma: a retrospective study. AB - BACKGROUND: Blunt pelvic injuries are often associated with pelvic fractures and injuries to the rectum and genitourinary tract. Pelvic fractures can lead to life threatening hemorrhage, which is a common cause of morbidity and mortality in trauma. Thus, early identification of patients with pelvic fractures at risk severe bleeding requiring urgent hemorrhage control is crucial. This study aimed to investigate early factors predicting the need for hemorrhage control in blunt pelvic trauma. METHODS: The medical records of 1760 trauma patients were reviewed retrospectively between January 2013 and June 2018. We enrolled 187 patients with pelvic fracture due to blunt trauma who were older than 15 years. The pelvic fracture pattern was classified according to the Orthopedic Trauma Association/Arbeitsgemeinschaft fur Osteosynthesefragen (OTA/AO) classification. A multivariate logistic regression model was used to determine independent predictors of the need for pelvic hemorrhage control intervention. RESULTS: The most common pelvic fracture pattern was type A (54.5%), followed by types B (36.9%) and C (8.6%). Of 187 patients, 48 (25.7%) required pelvic hemorrhage control intervention. Hemorrhage control interventions were most frequently performed in patients with type B fractures (54.2%). Multivariate logistic regression analysis revealed that type B (odds ratio [OR] = 4.024, 95% confidence interval [CI] = 1.666-9.720, p = 0.002) and C (OR = 7.077, 95% CI = 1.781-28.129, p = 0.005) fracture patterns, decreased body temperature (OR = 2.275, 95% CI = 0.134-0.567, p < 0.001), and elevated serum lactate level (OR = 1.234, 95% CI = 1.061-1.435, p = 0.006) were factors predicting the need for hemorrhage control intervention in patients with blunt pelvic trauma. CONCLUSION: Patients with type B and C fracture patterns on the OTA/AO classification, hypothermia, or an elevated serum lactate level are at risk for bleeding and require pelvic hemorrhage control intervention. PMID- 30445933 TI - Homoharringtonine interacts synergistically with bortezomib in NHL cells through MCL-1 and NOXA-dependent mechanisms. AB - BACKGROUND: Interactions between the protein synthesis inhibitor homoharringtonine (HHT) and the proteasome inhibitor bortezomib were investigated in DLBCL and mantle cell lymphoma cells (MCL). METHODS: Various DLBCL and MCL cells were exposed to HHT and bortezomib alone or together after which apoptosis and signaling pathway perturbations were monitored by flow cytometry and Western blot analysis. Xenograft mouse models were used to assess tumor growth and animal survival. RESULTS: HHT and bortezomib co-administration synergistically induced apoptosis in GC-, ABC- and double-hit DLBCL cells. Similar interactions were observed in MCL cells and in primary lymphoma cells. HHT/bortezomib co administration diminished binding of MCL-1 to both BAK and NOXA. Knock-down of NOXA significantly diminished lethality whereas MCL-1 knock-down or ectopic NOXA expression increased cell death. Notably, HHT/bortezomib lethality was dramatically reduced in BAK knockout or knockdown cells. Finally, HHT/bortezomib co-administration significantly improved survival compared to single agents in GC and ABC- xenograft models while exhibiting little toxicity. CONCLUSIONS: These findings indicate that HHT and bortezomib cooperate to kill DLBCL and MCL cells through a process involving MCL-1 down-regulation, NOXA up-regulation, and BAK activation. They also suggest that a strategy combining HHT with bortezomib warrants attention in DLBCL and MCL. PMID- 30445932 TI - BKCa participates in E2 inducing endometrial adenocarcinoma by activating MEK/ERK pathway. AB - BACKGROUND: The large-conductance, voltage-gated, calcium (Ca (2+))-activated potassium channel (BKCa) plays an important role in regulating Ca (2+) signaling and cell physiological function, and is aberrantly expressed in some types of cancers. The present study focuses on identifying the oncogenic potential and clinical significance of BKCa in endometrial adenocarcinoma, as well as exploring the mechanistic relevance by 17beta -estradiol (E2) inducing aberrant activation of MEK1/2 and ERK1/2 via BKCa. METHODS: The expression of BKCa, ERK1/2 and p ERK1/2 were examined by immunohistochemical staining in 263 cases, including 185 primary types I endometrial cancer tissues, 38 atypical endometrial hyperplasia tissues and 40 normal endometrium tissues. Cell growth, cycle, apoptosis rate, migration and invasion was separately tested in Ishikawa cells using siRNA-BKCa and/or E2 treatment, as well as the expression of these interested proteins by western blot analysis. RESULTS: We showed that expression of BKCa is significantly elevated in 185 types I endometrial adenocarcinoma tissues compared to those of the normal endometrium and atypical endometrial hyperplasia tissues. Furthermore, in vitro observations revealed that down-regulation of BKCa expression inhibited cell growth by both enhancing apoptosis and blocking G1/S transition, suppressed cell migration and invasion in Ishakiwa cells, and decreased the expression of p-MEK1/2 and p-ERK1/2. Additionally, RNAi-mediated knockdown of BKCa attenuated the increased cellular growth and invasion, as well as the elevated expression of p-MEK1/2 and p-ERK1/2 proteins, induced by E2 stimulation. More importantly, the aberrant expression of BKCa and p-ERK1/2 were closely related with poor prognostic factors in type I endometrial cancer, and up regulated expression of p-ERK1/2 was significantly associated with shorter disease-free survival (DFS) and overall survival (OS) and was an independent prognostic factor in type I endometrial cancer patients. CONCLUSION: Our results demonstrated that BKCa and the key downstream effectors p-ERK1/2 could be involved in important signaling pathways in initiation and development of endometrial adenocarcinoma and may provide a new therapeutic approach for women with endometrial cancer. PMID- 30445935 TI - Biosimilar filgrastim treatment patterns and prevention of febrile neutropenia: a prospective multicentre study in France in patients with solid tumours (the ZOHe study). AB - BACKGROUND: The ZOHe study was a prospective, non-interventional, multicentre study in France to assess the use of biosimilar filgrastim Zarzio(r) (Sandoz filgrastim) in routine clinical practice in patients at risk of neutropenia inducing chemotherapy (CT). METHODS: Patients >= 18 years undergoing CT for a malignant disease and with a first prescription for Zarzio(r) were enrolled in two cohorts according to tumour type: solid tumour or haematological malignancy; results from the solid tumour cohort are reported here. Analyses primarily described the prescription and use of Zarzio(r) in current practice, and also included identification of factors linked to prescription for primary prophylaxis and comparison of Zarzio(r) use in relation to European Organisation for Research and Treatment of Cancer (EORTC) guidelines. RESULTS: Responses were obtained from 125 physicians and 1179 patients with solid tumours, allowing robust statistical analysis of the data. Use of Zarzio(r) in clinical practice was relatively standardised and followed label indication. The patient profile was in line with EORTC guidelines for granulocyte colony-stimulating factor (G-CSF) febrile neutropenia (FN) prophylaxis, and the majority of patients had >= 1 EORTC factor(s) for increased risk of febrile neutropenia. Some patients (10.8%) received Zarzio(r) despite receiving CT regimens categorised in guidelines as low (< 10%) FN risk ('over prophylaxis'). Nearly half of patients' CT regimens did not have a recommended FN risk category. Zarzio(r) was commonly initiated as primary prophylaxis; initiation in Cycle >= 2 of the current line of CT was associated more with a history of neutropenia. The safety profile of Zarzio(r) was confirmed. CONCLUSIONS: Use of Zarzio(r) in routine clinical practice is generally in line with EORTC guidelines for prophylaxis of CT-induced neutropenia. Patient-related risk factors appear to be a stronger driver of clinicians' decision to initiate Zarzio(r) than CT risk category for FN. The intrinsic risk of FN associated with a specific CT protocol is often miscategorised by physicians. In contrast to earlier reports of underuse of G-CSF prophylaxis, over prophylaxis is observed in a small subgroup of patients with FN risk of < 10%. PMID- 30445936 TI - Incidence and factors associated with outcomes of uterine rupture among women delivered at Felegehiwot referral hospital, Bahir Dar, Ethiopia: cross sectional study. AB - BACKGROUND: Maternal mortality is a major public health challenge in Ethiopia. Uterine rupture is an obstetrical emergency with serious undesired complications for laboring mothers resulting in fatal maternal and neonatal outcomes. Uterine rupture has been contributing to high maternal morbidity and mortality. However, there is limited research on the factors and management outcomes of women with uterine rupture. Understanding the factors and management outcomes might delineate strategies to support survivors. Therefore the aim of this study is to assess the incidence and factors associated with outcomes of uterine rupture among laboring mothers at Felegehiwot Referral Hospital in Bahir Dar City, Northwest Ethiopia. METHODS: This is a cross sectional study with retrospective facility based data collection technique. All pregnant women who were managed for ruptured uterus at Felegehiwot referral hospital from September 11 2012 to August 30 2017 were included. The chart numbers of the women collected from operation theatre registers. Their case folders retrieved from the medical records room for analysis. Using structured check list, information on their sociodemography, booking status, clinical features at presentation and the place of attempted vaginal delivery was extracted. Data on the intraoperative findings, treatment, and associated complications and outcomes also collected. The collected data cleaned, coded and entered into EPI- Info version (7.1.2.0) and then exported in to SPSS Version 20.0 for analysis. Statistical comparison was done using chi square (X2). Strength of association between the explanatory variables and outcome variables described using odds ratio at 95% CI and P value less than 0.05. The results presented in tables. RESULTS: We studied 239 cases of uterine rupture in the 5 years period. Mothers without previous cesarean delivery including eight primigravidas took 87% of the cases. From all study participants, 54 of mothers (22.6%) developed undesired outcomes whereas 185(77.4%) discharged without major sequel. More than half (56.9%) arrived in hypovolemic shock. Total abdominal hysterectomy was the commonest procedure accounting for 61.5%. Duration of surgery was less than 2 h in 67.8% of the procedures. Anemia is the commonest complication (80.3%) followed by wound infection and VVF (11.7% each). There were 5 maternal deaths (2.1%). Mothers who had prolonged operation time (> 2 h) (AOR: 2.2, 95% CI: 1.10, 4.63) were significantly associated with undesired maternal outcomes after management of uterine rupture. CONCLUSION: Incidence of ruptured uterus and its complications were high in the study area. It reflects the need for improvement in obstetric care and strong collaboration with referring health facilities to ensure prompt referral and management. PMID- 30445934 TI - Pattern of care of prostate cancer patients across the Martinique: results of a population-based study in the Caribbean. AB - BACKGROUND: The French West-Indies rank first for both prostate cancer incidence and mortality rates. Analyzing diagnostic and therapeutic procedures among patients with prostate cancer, using data from a population-based cancer registry, is essential for cancer surveillance and research strategies. METHODS: This retrospective observational cohort study was based on data from the Martinique Cancer Registry. Records of 452 patients diagnosed with prostate cancer in 2013 were retrieved from the registry. Data extracted were: socio demographic and clinical characteristics, circumstances of diagnosis, PSA level at diagnosis, Gleason score and risk of disease progression. Stage at diagnosis and patterns of care among prostate cancer patients were analyzed. RESULTS: Mean age at diagnosis was 67 +/- 8 years; 103 (28.5%) were symptomatic at diagnosis. Digital rectal exam was performed in 406 (93.8%). Clinical stage was available in 385 (85.2%); tumours were localized in 322/385 (83.6%). Overall, 17.9% were at low risk, 36.4% at intermediate and 31.9% at high risk; 13.8% were regional/metastatic cancers. Median PSA level at diagnosis was 8.16 ng/mL (range 1.4-5000 ng/mL). A total of 373 patients (82.5%) received at least one treatment, while 79 (17.5%) had active surveillance or watchful waiting. Among patients treated with more than one therapeutic strategy, the most frequent combination was external radiotherapy with androgen deprivation (n = 102, 22.6%). CONCLUSIONS: This study provides detailed data regarding the quality of diagnosis and management of patients with prostate cancer in Martinique. Providing data on prostate cancer is essential for the development of high-priority public health measures for the Caribbean. PMID- 30445937 TI - The impact of attending day care designed for home-dwelling people with dementia on nursing home admission: a 24-month controlled study. AB - BACKGROUND: Day care services offer meaningful activities, a safe environment for attendees and respite for family caregivers while being expected to delay the need for nursing home (NH) admission. However, previous research has shown inconsistent results regarding postponement of NH admission. The objective of the study was to explore the influence of a day care programme designed for home dwelling people with dementia on NH admission. METHOD: A quasi-experimental trial explored the proportion of patients permanently admitted to nursing homes after 24 months as the main outcome by comparing a group of day care attendees (DG) and a group of participants without day care (CG). In all, 257 participants were included (181 in DG and 76 in CG). A logistic regression model was developed with NH admission as the outcome. Participant group (DG or CG) was the main predictor, baseline patient and family caregiver characteristics and interactions were used as covariates. RESULTS: The mean age of participants was 81.5 (SD 6.4), 65% were women and 53% lived alone. The mean MMSE score was 20.4 (SD 3.5). In all, 128 (50%) of the participants were admitted to a nursing home by the 24-month follow up, 63 participants (25%) completed the follow-up assessment and 66 (26%) dropped out due to death (8%) and other reasons (18%). In the logistic unadjusted regression model for NH admission after 24 months, participant group (DG or CG) was not found to be a significant predictor of NH admission. The results from the adjusted model revealed that the participant group was associated with NH admission through the interactions with age, living conditions, affective symptoms, sleep symptoms and practical functioning, showing a higher probability for NH admission in DG compared to CG. CONCLUSION: The study reveals no evidence to confirm that day care services designed for people with dementia postpone the need for NH admission. Admission to nursing homes seems to be based on a complex mix of personal and functional characteristics both in the person with dementia and the family caregivers. The findings should be considered in accordance with the limitation of inadequate power and the high drop-out rate. TRIAL REGISTRATION: The study is registered in Clinical Trials ( NCT01943071 ). PMID- 30445938 TI - Solitary pancreatic metastasis of extremity myxoid liposarcoma: a case report and literature review. AB - BACKGROUND: Myxoid liposarcoma has a distinct migration aptitude; however, pancreatic metastasis is rare. CASE PRESENTATION: We report on the case of a 40 year-old female patient who suffered solitary pancreatic metastasis of myxoid liposarcoma and had a right thigh myxoid liposarcoma radical resection 5 years ago. The patient underwent a medial pancreatectomy and pancreaticojejunostomy for solitary pancreatic metastasis of myxoid liposarcoma. After 12 months of disease free survival, the patient underwent an extended radical resection for the recurrence of the right thigh primary myxoid liposarcoma and received postoperative radiotherapy. Currently, the disease-free survival time after the last operation has been 22 months. CONCLUSIONS: We reviewed the relevant literature and suggest that radical surgery might result in a good prognosis for patients with solitary pancreatic metastasis of myxoid liposarcoma. PMID- 30445940 TI - Associations of smoking behavior with lifestyle and mental health among Japanese dental students. AB - BACKGROUND: Smoking is a major risk factor for cancer and cardiovascular disease. However, mental stress leads to smoking in dental students. We believe that dentists, as health professionals, should set an example for the public. Therefore, this study determined the prevalence of and factors associated with regular smoking among Japanese dental students. We also surveyed their attitudes regarding smoking cessation and how to counsel smokers about quitting. METHODS: We collected demographic and behavioral data from 453 students at Kyushu Dental University, and evaluated their mental health with the 12-item General Health Questionnaire (GHQ 12). We also asked them nine questions related to their intentions to counsel smokers about quitting. A multivariate binary logistic regression analysis was used to identify factors associated with smoking. RESULTS: Fifty-two (11.5%) of the dental students smoked. Univariate analyses indicated that male gender, higher academic year, greater number of times eating out per day, alcohol consumption, prevalence of skipping breakfast, poor health, and poor sleep habits were significantly associated with regular smoking. Regular smokers were less likely to have GHQ 12 scores >=4. On multivariate analysis, male gender (OR = 5.449, 95% CI = 1.851-16.040), sixth year students (OR = 21.971, 95% CI = 1.686-286.290), eating out two or more times a day (OR = 2.492, 95% CI = 1.165-5.331), drinking alcohol three or more times per week (OR = 9.484, 95% CI = 3.335-26.970), and GHQ 12 score >= 4 (OR = 0.339, 95% CI = 0.136-0.845) were significantly associated with regular smoking. Overall, 50.1% of the non smokers and 71.2% of the regular smokers responded that patients' chances of quitting smoking are not increased when a dentist advises them to quit. CONCLUSIONS: Regular smoking was strongly associated with male gender, higher academic year, alcohol consumption, and higher frequency of eating out per day. Mental health status among regular smokers was better than that among non-current smokers. Furthermore, we found that more than half of dental students have inadequate attitudes to advise their patients to quit smoking. It is necessary to develop educational programs regarding smoking for dental students. PMID- 30445941 TI - Delays and routes to diagnosis of neuroendocrine tumours. AB - BACKGROUND: Neuroendocrine tumours are uncommon tumours; there is often a long period between the onset of symptoms and diagnosis. This study aims to address the symptoms prior to diagnosis of people with known neuroendocrine tumours and also the involvement of healthcare providers prior to the diagnosis. METHODS: A web based survey was designed to cover two broad areas of patient symptoms and healthcare interactions prior to diagnosis. This was tested and adapted by patient and clinician input prior to distribution via Survey Monkey. RESULTS: The results demonstrated a median time from first symptom to diagnosis of 53.8 months. The most frequent initial symptoms were of pain, change in bowel habit and fatigue. 31% of respondents noted weight loss prior to diagnosis. 80% of respondents visited their GP regarding the symptoms a median of 11 times. 58% of respondents were referred to secondary care where they were seen a median 3 times. 30% presented acutely to A&E and this led to their diagnosis. CONCLUSION: In conclusion, there is a long time from onset of symptoms to diagnosis in all types of NETs. This is despite many respondents having alarm symptoms at diagnosis. Further education and awareness regarding malignancy may help with earlier diagnosis. PMID- 30445939 TI - Development of a scalable weight loss intervention for low-income workers through adaptation of interactive obesity treatment approach (iOTA). AB - BACKGROUND: Describing how and why an evidence-based intervention is adapted for a new population and setting using a formal evaluation and an adaptation framework can inform others seeking to modify evidence-based weight management interventions for different populations or settings. The Working for You intervention was adapted, to fit a workplace environment, from Be Fit Be Well, an evidence-based intervention that targets weight-control and hypertension in patients at an outpatient clinic. Workplace-based efforts that promote diet and activity behavior change among low-income employees have potential to address the obesity epidemic. This paper aims to explicitly describe how Be Fit Be Well was adapted for this new setting and population. METHODS: To describe and understand the worksite culture, environment, and policies that support or constrain healthy eating and activity in the target population, we used qualitative and quantitative methods including key informant interviews, focus groups, and a worker survey; these data informed intervention adaptation. We organized the adaptations made to Be Fit Be Well using an adaptation framework from implementation science. RESULTS: The adapted intervention, Working for You, maintains the theoretical premise and evidence-base underpinning Be Fit Be Well. However, it was modified in terms of the means of delivery (i.e., rather than using interactive voice response, Working for You employs automated SMS text messaging), defined as a modification to context by the adaptation framework. The adaptation framework also includes modifications to content; in this case the behavioral goals were modified for the target population based on updated science related to weight loss and to target a workplace population (e.g., a goal to avoiding free food at work). CONCLUSIONS: If effective, this scalable and relatively inexpensive intervention can be translated to other work settings to reduce obesity and diabetes risk among low-SES workers, a group with a higher prevalence of these conditions. Using a formal evaluation and framework to guide and organize how and why an evidence-based intervention is adapted for a new population and setting can push the field of intervention research forward. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02934113 ; Received: October 12, 2016; Updated: November 7, 2017. PMID- 30445942 TI - Weekend admissions may be associated with poorer recording of long-term comorbidities: a prospective study of emergency admissions using administrative data. AB - BACKGROUND: Many studies have investigated the presence of a 'weekend effect' in mortality following hospital admission, and these frequently use diagnostic codes from administrative data for information on comorbidities for risk adjustment. However, it is possible that coding practice differs between week and weekend. We assess patients with a confirmed history of certain long-term health conditions and investigate how well these are recorded in subsequent week and weekend admissions. METHODS: We selected six long-term conditions that are commonly assessed when risk-adjusting mortality rates, via the Charlson and Elixhauser indices. Using Hospital Episode Statistics data from England for the period April 2009 to March 2011, we identified patients with the condition recorded at least twice, on separate emergency admissions. Then we assessed how often each condition was recorded on subsequent emergency admissions between April 2011 and March 2013. We then compared coding between week and weekend admissions using the Cochran-Mantel-Haenszel test, stratifying by hospital. RESULTS: We studied 111,457 patients with chronic pulmonary disease, 106,432 with diabetes, 36,447 with congestive heart failure, 30,996 with dementia, 7808 with hemiplegia or paraplegia and 5877 with metastatic cancer. Across the entire week, between April 2011 and March 2013, coding completeness ranged from 89% for diabetes to 43% for hemiplegia/paraplegia. Compared with weekday admissions, congestive heart failure was less likely to be recorded as a secondary diagnosis at the weekend (odds ratio 0.92, 95% CI, 0.88 to 0.97), with smaller but statistically significant differences also detected for chronic pulmonary disease (odds ratio 0.96, 95% CI, 0.93 to 0.99) and diabetes (odds ratio 0.95, 95% CI 0.91 to 0.99). There was no statistically significant difference in recording between week and weekend admissions for dementia (odds ratio 1.04, 95% CI 0.97 to 1.11), hemiplegia/paraplegia (odds ratio 0.99, 95% CI 0.89 to 1.10) or metastatic cancer (odds ratio 1.04, 95% CI 0.90 to 1.20). CONCLUSIONS: Long-term conditions are often not recorded on administrative data and the lack of recording may be worse for weekend admissions. Studies of the weekend effect that rely on administrative data might have underestimated the health burden of patients, particularly if admitted at the weekend. PMID- 30445943 TI - Laparoscopic versus open gastrectomy for elderly local advanced gastric cancer patients: study protocol of a phase II randomized controlled trial. AB - BACKGROUND: Gastric cancer is one of the most common malignant tumors worldwide. With the rapid aging of global population, the number of elderly patients with local advanced gastric cancer is increasing. Surgery is the essential treatment for local advanced gastric cancer. However, elderly patients are at high risk of postoperative complications due to reduced functional reserve and increased comorbidities. Laparoscopic gastrectomy may be a promising surgery approach for elderly patients but its benefits remain controversial. We therefore proposed this randomized trial to evaluate the safety and efficacy of laparoscopic versus open gastrectomy for local advanced gastric cancer in patients aged 70 and above. METHODS: The current study has a randomized, parallel controlled, single-center, open-label, superiority design with two arms. A sample of 180 local advanced gastric cancer patients aged 70 and above will be recruited in Peking University Cancer Hospital and Institute. Participants will be randomized to either receive open or laparoscopic gastrectomy. The primary outcome is surgical safety, including complication rate, reoperation rate, readmission rate, and mortality rate within 30 days after surgery. The secondary endpoints include postoperative rehabilitation status, one-year postoperative life quality, three-year overall and disease-free survival. Assessments will take place at baseline (before random assignment), at 30 days, one-year, and three-year after the surgery. The study has been approved by an ethical review board. DISCUSSION: We hypothesized that laparoscopic gastrectomy is superior to open gastrectomy in terms of perioperative safety for local advanced gastric cancer patients aged 70 and above. If this hypothesis is statistically proved, the rational introduction of minimally invasive surgery technique in traditional gastrectomy can help improve the surgical safety for elderly patients, reduce patient financial burden, shorten hospital stay, and improve hospital beds turnover rate. Our research data will also provide high quality clinical evidence and data support for the conduction of multicenter phase III clinical trials. TRIAL REGISTRATION: The study has been prospectively registered in ClinicalTrial.gov ( NCT03564834 ). PMID- 30445945 TI - Diversity of indigenous sheep of an isolated population. AB - BACKGROUND: Because of the influence of genetics on animal production and the risk of losing genetic diversity of naturally adapted breeds, this study evaluated the genetic diversity of sheep of the Morada Nova breed belonging to an animal science institute in Brazil. The herd in question is one of the country's most representative of the breed. Samples of DNA extracted from the plasma of 61 animals were used for later analysis of the genotypes using microsatellite molecular markers. RESULTS: The polymorphic information content was 0.66, the observed heterozygosity was 0.65 and the fixation index was 0.048. According to the results, there is moderate genetic diversity in the studied population, suggesting the implantation of breeding programs aimed at conservation of the observed genetic diversity. CONCLUSION: The results obtained in this study will be of great importance to decisions on herd structure, besides contributing to other work to be carried out at the research center. PMID- 30445944 TI - A tight balance of Karyopherin beta1 expression is required in cervical cancer cells. AB - BACKGROUND: Karyopherin beta1 (Kpnbeta1) is the main nuclear import protein involved in the transport of cargoes from the cytoplasm into the cell nucleus. Previous research has found Kpnbeta1 to be significantly overexpressed in cervical cancer and other cancer tissues, and further studies showed that inhibition of Kpnbeta1 expression by siRNA resulted in cancer cell death, while non-cancer cells were minimally affected. These results suggest that Kpnbeta1 has potential as an anticancer therapeutic target, thus warranting further research into the association between Kpnbeta1 expression and cancer progression. Here, the biological effects associated with Kpnbeta1 overexpression were investigated in order to further elucidate the relationship between Kpnbeta1 and the cancer phenotype. METHODS: To evaluate the effect of Kpnbeta1 overexpression on cell biology, cell proliferation, cell cycle, cell morphology and cell adhesion assays were performed. To determine whether Kpnbeta1 overexpression influences cell sensitivity to chemotherapeutic agents like Cisplatin, cell viability assays were performed. Expression levels of key proteins were analysed by Western blot analysis. RESULTS: Our data revealed that Kpnbeta1 overexpression, above that which was already detected in cancer cells, resulted in reduced proliferation of cervical cancer cells. Likewise, normal epithelial cells showed reduced proliferation after Kpnbeta1 overxpression. Reduced cancer cell proliferation was associated with a delay in cell cycle progression, as well as changes in the morphology and adhesion properties of cells. Additionally, Kpnbeta1 overexpressing HeLa cells exhibited increased sensitivity to cisplatin, as shown by decreased cell viability and increased apoptosis, where p53 and p21 inhibition reduced and enhanced cell sensitivity to Cisplatin, respectively. CONCLUSIONS: Overall, our results suggest that a tight balance of Kpnbeta1 expression is required for cellular function, and that perturbation of this balance results in negative effects associated with a variety of biological processes. PMID- 30445946 TI - Satellite telemetry tracks flyways of Asian Openbill storks in relation to H5N1 avian influenza spread and ecological change. AB - BACKGROUND: Asian Openbills, Anastomus oscitans, have long been known to migrate from South to Southeast Asia for breeding and nesting. In Thailand, the first outbreak of H5N1 highly pathogenic avian influenza (HPAI) infection in the Openbills coincided with the outbreak in the poultry. Therefore, the flyways of Asian Openbills was determined to study their role in the spread of H5N1 HPAI virus to poultry and wild birds, and also within their flocks. RESULTS: Flyways of 5 Openbills from 3 colonies were monitored using Argos satellite transmitters with positioning by Google Earth Programme between 2007 and 2013. None of the Openbills tagged with satellite telemeters moved outside of Thailand. Their home ranges or movement areas varied from 1.6 to 23,608 km2 per month (95% utility distribution). There was no positive result of the viral infection from oral and cloacal swabs of the Openbills and wild birds living in the vicinity by viral isolation and genome detection during 2007 to 2010 whereas the specific antibody was not detected on both Openbills and wild birds by using microneutralization assay after 2008. The movement of these Openbills did not correlate with H5N1 HPAI outbreaks in domestic poultry but correlated with rice crop rotation and populations of the apple snails which are their preferred food. Viral spread within the flocks of Openbills was not detected. CONCLUSIONS: This study showed that Openbills played no role in the spread of H5N1 HPAI virus, which was probably due to the very low prevalence of the virus during the monitoring period. This study revealed the ecological factors that control the life cycle of Asian Openbills. PMID- 30445947 TI - Secondary glioblastoma after treatment of intracranial germinoma - would radiation-only therapy still be safe? Case report. AB - BACK GROUND: Intracranial germinomas are one of the most radiosensitive tumors and are curable by radiotherapy (RT) alone. RT-only therapy without chemotherapy is effective. But, as patients with germinoma can expect long-term survival, the adverse effects of RT and late sequelae in survivors are of most concern. So, recently, standard treatment protocol of combination with chemotherapy and reduced dose of RT could be widely acceptable. CASE PRESENTATION: We report a patient with germinoma who developed RT-induced glioblastoma. He was diagnosed as biopsy-proven germinoma at the age of 12. Postoperatively, he underwent RT alone without chemotherapy and remained free of tumor without recurrence during long term follow up. However, after almost 20 year, he developed RT-induced glioblastoma. CONCLUSIONS: Although RT has the highest priority among treatments on intracranial germinomas, RT-only therapy with full dose for germinoma can have delayed severe complications. So, chemotherapy prior to reduced dose RT is more desirable. PMID- 30445948 TI - Unexpected renal hemorrhage after endovascular repair of complicated type B aortic dissection: two cases report. AB - BACKGROUND: Thoracic endovascular aortic repair (TEVAR) is the therapeutic choice for type B aortic dissection. One of the most unfavored complications of this procedure is hemorrhage, which has a low incidence but high mortality. Renal hemorrhage (RH) after endovascular aortic repair has been rarely reported. We presented two cases of unexpected RH after TEVAR for complicated type B aortic dissection, and the potential causes, diagnosis and therapeutic management were discussed. CASE PRESENTATION: A 67-year-old female developed hypotension and progressively decrease of hemoglobin within 5 h after TEVAR for acute complicated type B dissection. Bedside ultrasonography and abdominal computed tomography angiography revealed a massive right perinephric hematoma. The right renal angiography detected multiple tortuous vascular branches with diffuse perinephric bleeding. The main trunk of right renal artery was embolized. The patient recovered uneventfully and presented with normal renal function 6 months later. Another patient was a 69-year-old male who was admitted for endovascular repair of a chronic complicated type B aortic dissection. The patient presented with hemodynamic instability early after TEVAR. Bedside ultrasonography showed a giant left retroperitoneal hematoma. The abdominal angiography revealed two active bleeding sits located in the distal branches of left renal artery. A super selective embolization of the two arteries was performed, however the patient developed abdominal compartment syndrome and died of multiple organ failure. CONCLUSIONS: Unexpected RH after endovascular repair of aortic dissection might be associated with iatrogenic and idiopathic factors. Close surveillance and clinician's awareness of this rare complication is crucial for accurate and prompt diagnosis. Renal angiography and subsequent selective embolization of bleeding vessels are effective interventions for treating this fatal condition. PMID- 30445949 TI - Words matter: a call for humanizing and respectful language to describe people who experience incarceration. AB - BACKGROUND: Words matter when describing people involved in the criminal justice system because language can have a significant impact upon health, wellbeing, and access to health information and services. However, terminology used in policies, programs, and research publications is often derogatory, stigmatizing, and dehumanizing. DISCUSSION: In response, health experts from Europe, the United States, and Australia recommend that healthcare professionals, researchers, and policy makers working with people in detention follow key principles that foster constructive and humanizing language. These principles include: engage people and respect their preferences; use stigma-free and accurate language; prioritize individuals over their characteristics; and cultivate self-awareness. The article offers examples of problematic terms to be avoided because they do not convey respect for incarcerated people and propose preferred wording which requires contextualization to local language, culture, and environment. CONCLUSION: The use of respectful and appropriate language is a cornerstone of reducing harm and suffering when working with people involved in the criminal justice system; the use of stigmatizing and dehumanizing language must therefore come to an end. PMID- 30445951 TI - Safety profile of trifluridine/tipiracil monotherapy in clinical practice: results of the German compassionate-use program for patients with metastatic colorectal cancer. AB - BACKGROUND: Trifluridine/tipiracil (TAS-102, Lonsurf(r)), a novel oral anti-tumor agent combining an anti-neoplastic thymidine-based nucleoside analogue (trifluridine, FTD) with a thymidine phosphorylase inhibitor (tipiracil hydrochloride, TPI) presents a new treatment option for metastatic colorectal cancer (mCRC) patients refractory or intolerant to standard therapies. FTD/TPI was approved in the European Union (EU) in April 2016 and launched on the German market in August 15, 2016. METHODS: We investigated the characteristics of patients (pts) with mCRC treated with FTD/TPI at 118 centers in Germany from January 12 to August 14, 2016 and analyzed the safety in a clinical real-world setting. RESULTS: In Germany, a total of 226 mCRC patients were included into a compassionate-use-program (CUP) and received FTD/TPI. For 45.5% of patients (n = 101), 253 adverse events (AE) were documented, most of them drug-related (n = 135). From January 12 (2016) to March 2 (2017), 124 serious adverse events (SAE) were reported (74 drug related). The most common serious adverse drug reactions (SADR) were leukopenia (12 events), neutropenia (8 events), anemia (7 events), diarrhea and nausea (5 events each) (observation period January 12 2016 to October 7 2016). In total, 122 patients (54%) discontinued FTD/TPI treatment, mostly due to progression (n = 75) followed by AEs (n = 21), deaths (n = 16), and non-specified reasons (n = 16). Interestingly, 12 patients with ECOG PS >=2 achieved up to 3 cycles of FTD/TPI and in this patient population only 3 treatment discontinuations due to AEs were documented and the safety profile was comparable to the entire population. CONCLUSION: The patient characteristics as well as the safety profile of FTD/TPI documented in the German CUP were consistent with those reported in the pivotal trial RECOURSE without unexpected safety signals. PMID- 30445950 TI - Follicular flushing increases the number of oocytes retrieved in poor ovarian responders undergoing in vitro fertilization: a retrospective cohort study. AB - BACKGROUND: To investigate the impact of follicular flushing on the number of oocytes retrieved and embryo quality and to determine the optimal number of flushings for poor ovarian responders (PORs) undergoing in vitro fertilization (IVF). METHODS: This retrospective study included 291 IVF cycles in 224 patients who were PORs and had no more than three dominant follicles on retrieval day. During oocyte retrieval, follicular fluid was aspirated and examined for an oocyte. If no oocyte was identified, follicular flushing was repeated until an oocyte was retrieved or up to a maximum of nine times. RESULTS: The mean number of oocytes retrieved by aspiration and subsequent flushes was significantly higher than the number retrieved from the initial aspirate (1.73 +/- 0.96 VS. 1.23 +/- 1.00, P = 0.000). The total recovery rate was 83.7% (503/601), which was significantly higher than the 59.6% recovery rate for direct aspiration (P = 0.000). Before the 4th follicular flushing, the cumulative recovery rate increased significantly as flushing was repeated, but after the 4th flushing, the ascending trend was mitigated; and the risk ratio of recovering fewer oocytes after 4 flushes compared with after 9 flushes was 0.765 (95%CI, 0.570-1.026, P = 0.074). Significant differences were not observed in maturation rate, fertilization rate, cleavage rate or high-quality embryo rate (P > 0.05). CONCLUSIONS: Follicular flushing may increase the number of oocytes retrieved and does not have adverse effects on oocyte or embryo quality in PORs undergoing IVF. Four times may be an optimal number of follicular flushings. PMID- 30445952 TI - Severe ophthalmic manifestation in pituitary-involved granulomatosis with polyangiitis: a case report and literature review. AB - BACKGROUND: Granulomatosis with polyangiitis (GPA), a necrotizing granulomatous disease, very rarely involves the central nervous system (CNS), particularly the pituitary. Delayed treatment may cause permanent bilateral blindness. We report an isolated case of pituitary GPA that manifested as a progressive bilateral temporal visual field (VF) defect and was diagnosed via pituitary biopsy. Additionally, we review ocular, chiasmal and cranial nerve involvement in pituitary GPA. CASE PRESENTATION: A 20-year-old Chinese man was referred for repeated fever, sudden headache, diplopia with a bilateral best-corrected visual acuity (BCVA) of 10/20, ptosis in both eyes and restricted abduction on the right side. VF tests showed bitemporal hemianopsia. Laboratory tests revealed hypothyroidism and were negative for autoimmune markers. Enhanced magnetic resonance imaging (MRI) showed pituitary enlargement. The diagnosis was lymphocytic pituitaritis. After intravenous (IV) dexamethasone treatment, full recovery occurred within 2 months. Two years later, the patient was readmitted for headache recurrence. With oral prednisone, the visual acuity in his right eye rapidly decreased to hand motion (HM) within one month. Enhanced MRI showed pituitary enlargement and a new, invasive suprasellar CNS lesion. All infection- and autoimmune-related tests were negative. The visual acuity in his right and left eye decreased to no light perception (NLP) after 6 days and 2 weeks, respectively. The biopsy results suggested GPA. After IV methylprednisolone treatment, complete remission of the symptoms occurred and was confirmed by MRI. The 15-month follow-up showed no signs of recurrence. CONCLUSION: GPA typically affects the respiratory tract, lungs and kidneys. To date, 50 cases with pituitary involvement have been reported. Chiasmal and cranial nerve involvement leading to visual acuity impairment are common. We found 2 cases with severe visual loss resembling our case and discuss certain similarities. PMID- 30445953 TI - Development of luciferase-linked antibody capture assay based on luciferase immunoprecipitation systems for antibody detection of porcine reproductive and respiratory syndrome virus. AB - BACKGROUND: Early detection of porcine reproductive and respiratory syndrome virus (PRRSV) infection of swine is necessary to control this devastating disease. By monitoring host serum antibodies to viral antigens, early virus detection within herds is feasible. In this study, recombinant antigens were generated using recombinant DNA techniques to fuse PRRSV structural protein (N) or nonstructural protein 1alpha (nsp1alpha) with the Rellina luciferase gene. Next, fused genes were cloned into plasmids and transfected into HEK-293 T cells for transient expression. Upon co-incubation of lysates with pig sera, antigen antibody complexes formed that bound to Protein-G coated onto microplates. By further measurement of luminance value, a modified form of Luciferase Immunoprecipitation Systems, namely luciferase-linked antibody capture assay (LACA) was developed for detection of PRRSV-specific antibodies. RESULTS: Known anti-PRRSV antibody-positive or -negative serum samples (125 and 122 samples, respectively) were used to validate the LACA and compared it with IDEXX PRRS *3 ELISA. Based on the result, N-Rluc and nsp1alpha-Rluc LACA results were 95.3 and 94.4% in agreement with IDEXX ELISA, suggested a similar specificity of LACA to IDEXX ELISA. Moreover, when both LACA and IDEXX ELISA were used to evaluate sequential serum samples obtained from PRRSV experimentally infected pigs, the PRRSV-specific antibody response was detectable as early as 3 days post inoculation (dpi) using N-Rluc LACA, but undetectable until 7 dpi using IDEXX ELISA, suggesting an improved sensitivity of LACA. Meanwhile, antibodies specific for nsp1alpha were detected at higher levels overall, but were undetectable until 10 dpi. Furthermore,. Notably, one IDEXX ELISA positive result was not confirmed by LACA or IFA and was thus considered a false-positive result. CONCLUSION: The LACA exhibited similar specificity but improved sensitivity to that of the commercial IDEXX PRRS *3 ELISA kit for detection of PRRSV-specific antibodies in pig serum. Importantly, LACA could be adapted for detecting antibodies against other PRRSV targets, such as nsp1alpha, to achieve earlier detection of PRRSV infection. PMID- 30445954 TI - Fibroblast growth factor-1 as a mediator of paracrine effects of canine adipose tissue-derived mesenchymal stem cells on in vitro-induced insulin resistance models. AB - BACKGROUND: In the field of diabetes research, many studies on cell therapy have been conducted using mesenchymal stem cells. This research was intended to shed light on the influence of canine adipose-tissue-derived mesenchymal stem cell conditioned medium (cAT-MSC CM) on in vitro insulin resistance models that were induced in differentiated 3T3-L1 adipocytes and the possible mechanisms involved in the phenomenon. RESULTS: Gene expression levels of insulin receptor substrate 1 (IRS-1) and glucose transporter type 4 (GLUT4) were used as indicators of insulin resistance. Relative protein expression levels of IRS-1 and GLUT4 were augmented in the cAT-MSC CM treatment group compared to insulin resistance models, indicating beneficial effects of cAT-MSC to DM, probably by actions of secreting factors. With reference to previous studies on fibroblast growth factor 1 (FGF1), we proposed FGF1 as a key contributing factor to the mechanism of action. We added anti-FGF1 neutralizing antibody to the CM-treated insulin resistance models. As a result, significantly diminished protein levels of IRS-1 and GLUT4 were observed, supporting our assumption. Similar results were observed in glucose uptake assay. CONCLUSIONS: Accordingly, this study advocated the potential of FGF-1 from cAT-MSC CM as an alternative insulin sensitizer and discovered a signalling factor associated with the paracrine effects of cAT-MSC. PMID- 30445955 TI - Comparative study of dual energy CT iodine imaging and standardized concentrations before and after chemoradiotherapy for esophageal cancer. AB - BACKGROUND: To compare dual energy CT iodine imaging and standardized iodine concentration before and after chemoradiotherapy (CRT) for esophageal cancer and evaluate the efficacy of CRT for EC by examining DECT iodine maps and standard CT values. METHODS: The clinical data of 45 patients confirmed by pathology with newly diagnosed esophageal cancer who underwent concurrent CRT from February 2012 to January 2017 in our department of radiology were collected. All patients underwent dual-source dual-energy CT (DECT) before and after CRT. Normalized iodine concentration (NIC) and normalized CT (NCT) corresponding to the overall cancer lesion and its maximum cross-sectional area were observed and compared. Additionally, 30 healthy individuals were compared as control group. After treatment, the patients were divided into two groups according to RECIST1.1: treatment effective group and ineffective group. RESULTS: There were 33 patients (CR 9, PR 24) in the effective group and 12 patients (SD 12, PD 0) in the ineffective group. There was no significant difference in the NIC-A, NIC-V, NCT-A and NCT-A indexes between the effective group (B group) and the ineffective group (C group) before treatment (P > 0.05). After the treatment, the above-mentioned indexes in the effective group of patients were significantly lower than before treatment, and compared with the ineffective group, the NIC-A, NIC-V, NCT-A and NCT-V values of the effective group were significantly lower than those of ineffective group (P < 0.05). After treatment, the NIC-V and NCT-V in the ineffective group were lower than before treatment, and the difference was statistically significant (P < 0.05). However, their NIC-A and NCT-A were not statistically different from those before treatment (P > 0.05). CONCLUSION: Using DECT iodine map, the changes of NIC and NIC before and after CRT in patients with esophageal cancer can evaluate the effect of CRT, and does not increase the radiation dose, so it is suitable for clinical use. PMID- 30445956 TI - Outcomes of early relaparotomy in pediatric patients at Tikur Anbessa teaching hospital, Addis Ababa, Ethiopia: a five-year retrospective review. AB - BACKGROUND: Early relaparotomy is defined as relaparotomy within the first 30 days following surgery. The aim of this study is to explore the indications, outcomes and factors associated with relaparotomy in our pediatric population. METHODS: We performed a retrospective study of pediatric surgical patients (< 13 yrs.) who underwent relaparotomy at Tikur Anbessa Teaching Hospital between September 1, 2011 and August 31, 2016. All children who had relaparotomy within the first 30 days of the initial surgery were included. We collected patient data including demographics, operative indication, and postoperative outcomes. Data analysis was performed using SPSS Version 23. Chi-square and Fisher's exact tests were used to report outcomes stratified by patient characteristics. Multivariable logistic regression was used to identify patient variables associated with relaparotomy and other outcomes. RESULTS: In our patient population, relaparotomy rate was 17.2%. Patient age ranged from 2 days to 12 years with mean age of 37.5 months. Male to female ratio was 1.2:1. Thirty-one (58.5%) relaparotomies were performed between the 5th and 8th postoperative days. The two most common indications for relaparotomy were postoperative intra-abdominal collection and anastomotic leak, accounting for 18 (34.0%) and 17 (32.1%) respectively. Mortality rate following relaparotomy was 26.4%. The most common cause of mortality was sepsis with multi-system organ failure (90.6%). Neonatal age was found to be the independent risk factors for death following relaparotomy, (AOR = 27.59, 95% CI [2.0-379.9]). CONCLUSION: Prevalence of relaparotomy in pediatric patients is high (17.2%) in our patient population. Neonatal age was associated with increased mortality following relaparotomy. PMID- 30445957 TI - Evaluation of the humoral immune response induced by vaccination for canine distemper and parvovirus: a pilot study. AB - BACKGROUND: Canine Distemper Virus (CDV) and Canine Parvovirus (CPV) lead to infections with high mortality rates in dogs. These viruses affect unvaccinated dogs or dogs with incomplete vaccination protocols. Vaccination plays an important role in reducing death rates, preventing clinical cases and controlling the spread of virus However, the efficacy of vaccination might be affected by different factors including vaccine scheduling and the neutralization of the vaccine targets by maternal antibodies. In face of these factors, the main goals of this study are (i) to investigate the antibody responses of puppies undergoing different primary vaccination protocols against CPV and CDV and (ii) to estimate the time until seroreversion in adult dogs unvaccinated for at least 3 years. RESULTS: Antibody protection against CDV and CPV was evaluated in a total of 20 dogs: 5 puppies that initiated immunization at 6 weeks after birth (group A), 8 animals that started vaccination between 8 and 12 weeks of age (group B), and 7 adult dogs that have not been vaccinated for at least 3 years (group C). Blood samples were collected from each animal, with 3 to 4 weeks apart. Antibody responses were measured using indirect ELISA. In the second immunization point, no significant differences were found between the seroconversion of groups A and B for each viral infection (p = 0.81 and 0.20 for CDV and CPV, respectively). In the third immunization, there was evidence for a shorter time to achieve a protective titer against CPV in group B when compared to group A (p = 0.015). Similar evidence was not found for CDV (p-value = 0.41). In Group C, the average time until seroveversion was estimated at 2.86 years and 7.63 years for CDV and CPV, respectively. CONCLUSION: Vaccine response to CDV and CPV is specific in each individual. Effective immune protection in primary vaccination depends mainly on the initial titer of maternal antibodies acquired by the neonate. Other factors such as environmental exposure, immunization schedules and immune system activity influence the duration of immunity in adult dogs. The variability found reinforces the need to determine individual humoral immunity levels in order to assess vaccine efficacy. PMID- 30445958 TI - Assessing pharmacy student experience with, knowledge of and attitudes towards harm reduction: illuminating barriers to pharmacist-led harm reduction. AB - BACKGROUND: As the burden from the opioid epidemic continues to increase in the state of Minnesota and across the nation, the University of Minnesota College of Pharmacy seeks to design an innovative, comprehensive harm reduction curriculum in order to better train student pharmacists to serve the varied needs of the greater community. This study examines incoming individuals' baseline knowledge of and attitudes toward harm reduction in order to better inform curriculum planning and to ultimately produce pharmacists capable of impacting the devastating effects of the opioid crisis. METHODS: Incoming first-year pharmacy students took a survey focused on their knowledge of opioid overdose and the drug naloxone and also provided written reflections on their perceptions of harm reduction. Data was coded using consensual qualitative research (CQR) into appropriate domains. RESULTS: Pharmacy students beginning their professional education revealed a lack of knowledge of proper response to an overdose situation, with 18.56% unfamiliar with the opioid antagonist drug naloxone. Close to 10% (9.58%) of students expressed unwillingness to do anything other than call an ambulance during an overdose event, while 8.98% were either unsure or felt that they would not feel compelled to do something to help. Qualitative coding revealed many barriers to students' becoming capable harm reductionists, including lack of knowledge of substance use, addiction, and harm reduction, in addition to the presence of bias and stigma. CONCLUSION: In order to interrupt the cycle of misinformation and stigma within the larger community and the subgroup of medical providers, gaps in student knowledge must be addressed in meaningful, specific ways over the course of their pharmacy education. Evaluating baseline knowledge and beliefs informs the design of a flexible, action-oriented curriculum to produce well-trained pharmacists ready to engage in finding solutions to the opioid crisis. PMID- 30445959 TI - Inter-sectoral approaches for the prevention and control of malaria among the mobile and migrant populations: a scoping review. AB - BACKGROUND: Malaria cases among mobile and migrant populations (MMPs) represent a large and important reservoir for transmission, if undetected or untreated. The objectives of this review were to identify which intersectoral actions have been taken and how they are applied to interventions targeted at the MMPs and also to assess the effect of interventions targeted to these special groups of population. RESULTS: A total of 36 studies met the inclusion criteria for this review. Numerous stakeholders were identified as involved in the intersectoral actions to defeat malaria amongst MMPs. Almost all studies discussed the involvement of Ministry of Health/Public Health (MOH/MOPH). The most frequently assessed intervention among the studies that were included was the coverage and utilization of insecticide-treated nets as personal protective measures (40.5%), followed by the intervention of early diagnoses and treatment of malaria (33.3%), the surveillance and response activities (13.9%) and the behaviour change communication (8.3%). There is a dearth of information on how these stakeholders shared roles and responsibilities for implementation, and about the channels of communication between-and-within the partners and with the MOH/MOPH. Despite limited details in the studies, the intermediate outcomes showed some evidence that the intersectoral collaborations contributed to improvement in knowledge about malaria, initiation and promotion of bed nets utilization, increased access to diagnosis and treatment in a surveillance context and contributed towards a reduction in malaria transmission. Overall, a high proportion of the targeted MMPs was equipped with correct knowledge about malaria transmission (70%, 95% CI 57-83%). Interventions targeting the use of bed nets utilization were two times more likely to reduce malaria incidence amongst the targeted MMPs (summary OR 2.01, 95% CI 1.43-2.6) than the non-users. The various intersectoral actions were often more vertically organized and not fully integrated in a systemic way within a given country or sub-national administrative setting. CONCLUSION: Findings suggest that interventions supported by the multiple stakeholders had a significant impact on the reduction of malaria transmission amongst the targeted MMPs. Well-designed studies from different countries are recommended to robustly assess the role of intersectoral interventions targeted to MMPs and their impact on the reduction of transmission. PMID- 30445960 TI - Production of mannosylglycerate in Saccharomyces cerevisiae by metabolic engineering and bioprocess optimization. AB - BACKGROUND: Mannosylglycerate (MG) is one of the most widespread compatible solutes among marine microorganisms adapted to hot environments. This ionic solute holds excellent ability to protect proteins against thermal denaturation, hence a large number of biotechnological and clinical applications have been put forward. However, the current prohibitive production costs impose severe constraints towards large-scale applications. All known microbial producers synthesize MG from GDP-mannose and 3-phosphoglycerate via a two-step pathway in which mannosyl-3-phosphoglycerate is the intermediate metabolite. In an early work, this pathway was expressed in Saccharomyces cerevisiae with the goal to confirm gene function (Empadinhas et al. in J Bacteriol 186:4075-4084, 2004), but the level of MG accumulation was low. Therefore, in view of the potential biotechnological value of this compound, we decided to invest further effort to convert S. cerevisiae into an efficient cell factory for MG production. RESULTS: To drive MG production, the pathway for the synthesis of GDP-mannose, one of the MG biosynthetic precursors, was overexpressed in S. cerevisiae along with the MG biosynthetic pathway. MG production was evaluated under different cultivation modes, i.e., flask bottle, batch, and continuous mode with different dilution rates. The genes encoding mannose-6-phosphate isomerase (PMI40) and GDP-mannose pyrophosphorylase (PSA1) were introduced into strain MG01, hosting a plasmid encoding the MG biosynthetic machinery. The resulting engineered strain (MG02) showed around a twofold increase in the activity of PMI40 and PSA1 in comparison to the wild-type. In batch mode, strain MG02 accumulated 15.86 mgMG g DCW -1 , representing a 2.2-fold increase relative to the reference strain (MG01). In continuous culture, at a dilution rate of 0.15 h-1, there was a 1.5-fold improvement in productivity. CONCLUSION: In the present study, the yield and productivity of MG were increased by overexpression of the GDP-mannose pathway and optimization of the mode of cultivation. A maximum of 15.86 mgMG g DCW -1 was achieved in batch cultivation and maximal productivity of 1.79 mgMG g DCW -1 h-1 in continuous mode. Additionally, a positive correlation between MG productivity and growth rate/dilution rate was established, although this correlation is not observed for MG yield. PMID- 30445961 TI - Appropriate preoperative membranous urethral length predicts recovery of urinary continence after robot-assisted laparoscopic prostatectomy. AB - PURPOSE: We investigated that preoperative membranous urethral length (MUL) would be associated with the recovery of urinary continence after robot-assisted laparoscopic prostatectomy (RALP). PATIENTS AND METHODS: We studied 204 patients who underwent RALP between May 2013 and March 2016. All patients underwent pelvic magnetic resonance imaging (MRI) preoperatively to measure MUL. Urinary continence was defined as the use of one pad or less (safety pad). The 204 patients were divided into two groups: continence group, those who achieved recovery of continence at 3, 6, and 12 months after RALP, and incontinence group, those who did not. We retrospectively analyzed the patients in terms of preoperative clinical factors including age, body mass index (BMI), estimated prostate volume, neurovascular bundle salvage, history of preoperative hormonal therapy, and MUL. RESULTS: The safety pad use rate was 69.6%, 86.9%, and 91.1% at 3, 6, and 12 months, respectively. On univariate and multivariate analyses, MUL were significant factors in every term of recovery of urinary continence in both groups. According to the receiver operating characteristic (ROC) curve analysis, the preoperative MUL that could best predict early recovery of urinary continence at 3 months after RALP was 12 mm. CONCLUSIONS: We suggest that preoperative MUL > 12 mm would be a predictor of early recovery of urinary continence after RALP. PMID- 30445962 TI - Bayesian spatiotemporal analysis of malaria infection along an international border: Hlaingbwe Township in Myanmar and Tha-Song-Yang District in Thailand. AB - BACKGROUND: One challenge in moving towards malaria elimination is cross-border malaria infection. The implemented measures to prevent and control malaria re introduction across the demarcation line between two countries require intensive analyses and interpretation of data from both sides, particularly in border areas, to make correct and timely decisions. Reliable maps of projected malaria distribution can help to direct intervention strategies. In this study, a Bayesian spatiotemporal analytic model was proposed for analysing and generating aggregated malaria risk maps based on the exceedance probability of malaria infection in the township-district adjacent to the border between Myanmar and Thailand. Data of individual malaria cases in Hlaingbwe Township and Tha-Song Yang District during 2016 were extracted from routine malaria surveillance databases. Bayesian zero-inflated Poisson model was developed to identify spatial and temporal distributions and associations between malaria infections and risk factors. Maps of the descriptive statistics and posterior distribution of predicted malaria infections were also developed. RESULTS: A similar seasonal pattern of malaria was observed in both Hlaingbwe Township and Tha-Song-Yang District during the rainy season. The analytic model indicated more cases of malaria among males and individuals aged >= 15 years. Mapping of aggregated risk revealed consistently high or low probabilities of malaria infection in certain village tracts or villages in interior parts of each country, with higher probability in village tracts/villages adjacent to the border in places where it could easily be crossed; some border locations with high mountains or dense forests appeared to have fewer malaria cases. The probability of becoming a hotspot cluster varied among village tracts/villages over the year, and some had close to no cases all year. CONCLUSIONS: The analytic model developed in this study could be used for assessing the probability of hotspot cluster, which would be beneficial for setting priorities and timely preventive actions in such hotspot cluster areas. This approach might help to accelerate reaching the common goal of malaria elimination in the two countries. PMID- 30445963 TI - Knowledge mobilisation for chronic disease prevention: the case of the Australian Prevention Partnership Centre. AB - BACKGROUND: Cross-sectoral, multidisciplinary partnership research is considered one of the most effective means of facilitating research-informed policy and practice, particularly for addressing complex problems such as chronic disease. Successful research partnerships tend to be underpinned by a range of features that enable knowledge mobilisation (KMb), seeking to connect academic researchers with decision-makers and practitioners to improve the nature, quality and use of research. This paper contributes to the growing discourse on partnership approaches by illustrating how knowledge mobilisation strategies are operationalised within the Australian Prevention Partnership Centre (the Centre), a national collaboration of academics, policy-makers and practitioners established to develop systems approaches for the prevention of lifestyle-related chronic diseases. METHODS: We undertook interviews with key academics, policy, and practice partners and funding representatives at the mid-point of the Centre's initial 5-year funding cycle. We aimed to explore how the Centre is functioning in practice, to develop a conceptual model of KMb within the Centre for use in further evaluation, and to identify ways of strengthening our approach to partnership research. Inductive and deductive thematic analysis was used to identify the key mechanisms underpinning the Centre's KMb approach. RESULTS: Six key mechanisms appeared to facilitate KMb within our Centre, namely Engagement, Partnerships, Co-production, Capacity and Skills, Knowledge Integration, and Adaptive Learning and Improvement. We developed a conceptual model that articulated these mechanisms in relation to the structures and processes that support them, as well as the Centre's goals. Findings also informed adaptations designed to strengthen the Centre. CONCLUSIONS: Findings provide insights into the practical realities of operationalising KMb strategies within a research partnership. Overall, the centre is perceived to be progressing towards its KMb goals, but challenges include stakeholders from different settings understanding each other's contexts and working together effectively, and ensuring knowledge generated across different projects within the Centre is integrated into a more comprehensive understanding of chronic disease prevention policy and practice. Our conceptual model is now informing ongoing developmental evaluation activities within the Centre, where it is being tested and refined. PMID- 30445964 TI - Detection of patients at high risk for nonocclusive mesenteric ischemia after cardiovascular surgery. AB - OBJECTIVES: Nonocclusive mesenteric ischemia (NOMI) is a rare but life threatening complication after cardiovascular surgery. Early diagnosis and treatment is essential for a chance to cure. The aim of this study is to identify the independent risk factors for NOMI based on the evaluation of 12 cases of NOMI after cardiovascular surgery. METHODS: We retrospectively analyzed 12 patients with NOMI and 674 other patients without NOMI who underwent cardiovascular surgery in our hospital. We reviewed the clinical data on NOMI patients, including their characteristics and the clinical course. In addition, we performed a statistical comparison of each factor from both NOMI and non-NOMI groups to identify the independent risk factors for NOMI. RESULTS: The median duration between the cardiac surgery and the diagnosis of NOMI was 14.0 (10.3 20.3) days. The in-hospital mortality of NOMI patients was 75.0%. Age (p < 0.05), peripheral arterial disease (p < 0.001), postoperative hemodialysis (p < 0.001), intraaortic balloon pump (p < 0.05), norepinephrine (NOE) > 0.10gamma (p < 0.0001), percutaneous cardiopulmonary support (p < 0.001), sepsis (p < 0.05), loss of sinus rhythm (p < 0.05), prolonged ventilation (p < 0.0001), and resternotomy for bleeding (p < 0.05) showed significant differences between NOMI and non-NOMI groups. In the multivariate logistic regression model, prolonged ventilation [odds ratio (OR) = 18.1, p < 0.001] and NOE > 0.10 MUg/kg/min (OR = 130.0, p < 0.0001) were detected as independent risk factors for NOMI. CONCLUSIONS: We have identified the risk factors for NOMI based on the evaluation of the 12 cases of NOMI after cardiovascular surgery. This result may be useful in predicting NOMI, which is considered difficult in clinical practice. For the patient with suspected of NOMI who has these risk factors, early CT scan and surgical exploration should be performed without delay. PMID- 30445966 TI - Frailty in people living with HIV. AB - The life expectancy of people living with HIV (PLHIV) has dramatically improved with effective and well-tolerated antiretroviral therapy. This presents a new challenge in caring for this patient population, with up to 28% of older PLHIV being identified as frail. Studies suggest that the prevalence of frailty is higher in PLHIV compared to the general population, and that the onset of frailty occurs at an earlier age. Frail individuals often present with multiple and non specific health complaints, fluctuating disability, falls and delirium, and are at higher risk for multiple adverse outcomes, post-operative complications, poor responses to vaccination and functional decline. They tend to require longer hospital admissions, are more likely to require nursing home care, and are at greater risk of mortality. The degree of frailty can fluctuate over time. Limited evidence exists to support the reversal of frailty, but epidemiological evidence suggests that interventions to assess and manage co-morbidities, reducing risk factors such as smoking, increasing exercise and optimising BMI, and improving personal and community resources, are all likely to reduce the risk of frailty. Physicians who care for PLHIV need to recognise and manage frailty in this patient population. This includes an understanding of: when to intervene aggressively in the management of an older patient with a new HIV diagnosis to delay or prevent permanent debility and frailty; when to acknowledge that the patient has become frail; and the role of geriatric medicine in addressing the specific issues and needs of this patient, such as maximising functional ability, preventing falls, reducing social isolation and improving quality of life. PMID- 30445967 TI - Severe Plasmodium vivax malaria, HIV, tuberculosis co-infection in a Sri Lankan traveller: case management and challenges during the prevention of malaria reintroduction phase. AB - BACKGROUND: The country received malaria-free certification from WHO in September 2016, becoming only the second country in the WHO South East Asia region to be declared malaria-free. Imported malaria cases continue to be reported, with 278 cases reported between 2013 and 2017. The diagnosis of a severe Plasmodium vivax patient co-infected with HIV and tuberculosis is discussed with an overview of the rapid response mounted by the Anti Malaria Campaign (AMC), Sri Lanka. CASE PRESENTATION: A Sri Lankan gem miner who returned from Madagascar on the 6th of April 2018 presented to a private hospital for a malaria diagnostic test on the 21st April, 2 days after the onset of fever. He came on his own for this test due to the awareness he had regarding the risk of imported malaria. As the patient was positive for P. vivax malaria, he was admitted to a government hospital for further management. The patient had features of severe malaria upon admission with a systolic BP < 80 mmHg and thrombocytopaenia (38,000 cells/mm3). Treatment with IV artesunate was initiated immediately and management was carried out rapidly and efficiently by the clinicians with guidance from the staff of the AMC headquarters, which resulted in a rapid recovery of the patient. IV artesunate was followed by a course of artemether plus lumefantrine and the blood smear was negative for malaria by the 2nd day. A 14-day course of primaquine was commenced after excluding a G6PD deficiency. Due to an accidental needle stick injury of a health care worker attending on the patient was tested for HIV and subsequently tuberculosis and was found to be positive for both infections. The patient was discharged on the 1st of May with instructions for follow up visits for malaria. Management of the HIV and tuberculosis infections was attended to by the clinicians and staff of the appropriate disease control programmes (i.e. the national STD/AIDS Control Programme in Sri Lanka and the National Programme for tuberculosis control and chest diseases). CONCLUSIONS: It is important to consider comorbid conditions and immunosuppression when a patient with a benign form of malaria presents with severe manifestations. Measures should be strengthened to prevent importation of diseases, such as malaria and AIDS through migrant workers who return from high-risk countries. PMID- 30445965 TI - Characterization of a novel N-acylhomoserine lactonase, AidP, from Antarctic Planococcus sp. AB - BACKGROUND: N-acylhomoserine lactones (AHLs) are well-studied signalling molecules produced by some Gram-negative Proteobacteria for bacterial cell-to cell communication or quorum sensing. We have previously demonstrated the degradation of AHLs by an Antarctic bacterium, Planococcus versutus L10.15T, at low temperature through the production of an AHL lactonase. In this study, we cloned the AHL lactonase gene and characterized the purified novel enzyme. RESULTS: Rapid resolution liquid chromatography analysis indicated that purified AidP possesses high AHL-degrading activity on unsubstituted, and 3-oxo substituted homoserine lactones. Liquid chromatography-mass spectrometry analysis confirmed that AidP functions as an AHL lactonase that hydrolyzes the ester bond of the homoserine lactone ring of AHLs. Multiple sequence alignment analysis and phylogenetic analysis suggested that the aidP gene encodes a novel AHL lactonase enzyme. The amino acid composition analysis of aidP and the homologous genes suggested that it might be a cold-adapted enzyme, however, the optimum temperature is 28 degrees C, even though the thermal stability is low (reduced drastically above 32 degrees C). Branch-site analysis of several aidP genes of Planococcus sp. branch on the phylogenetic trees also showed evidence of episodic positive selection of the gene in cold environments. Furthermore, we demonstrated the effects of covalent and ionic bonding, showing that Zn2+ is important for activity of AidP in vivo. The pectinolytic inhibition assay confirmed that this enzyme attenuated the pathogenicity of the plant pathogen Pectobacterium carotovorum in Chinese cabbage. CONCLUSION: We demonstrated that AidP is effective in attenuating the pathogenicity of P. carotovorum, a plant pathogen that causes soft-rot disease. This anti-quorum sensing agent is an enzyme with low thermal stability that degrades the bacterial signalling molecules (AHLs) that are produced by many pathogens. Since the enzyme is most active below human body temperature (below 28 degrees C), and lose its activity drastically above 32 degrees C, the results of a pectinolytic inhibition assay using Chinese cabbage indicated the potential of this anti-quorum sensing agent to be safely applied in the field trials. PMID- 30445968 TI - Antibody-mediated prevention and treatment of HIV-1 infection. AB - Novel broadly neutralizing antibodies targeting HIV-1 hold promise for their use in the prevention and treatment of HIV-1 infection. Pre-clinical results have encouraged the evaluation of these antibodies in healthy and HIV-1-infected humans. In first clinical trials, highly potent broadly neutralizing antibodies have demonstrated their safety and significant antiviral activity by reducing viremia and delaying the time to viral rebound in individuals interrupting antiretroviral therapy. While emerging antibody-resistant viral variants have indicated limitations of antibody monotherapy, strategies to enhance the efficacy of broadly neutralizing antibodies in humans are under investigation. These include the use of antibody combinations to prevent viral escape, antibody modifications to increase the half-life and the co-administration of latency reversing agents to target the cellular reservoir of HIV-1. We provide an overview of the results of pre-clinical and clinical studies of broadly HIV-1 neutralizing antibodies, discuss their implications and highlight approaches for the ongoing advancement into humans. PMID- 30445969 TI - Association of serum angiopoietin-2 with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients: a prospective cohort study. AB - BACKGROUND: To examine serum angiopoietin-2 (Angpt-2) in relation to malnutrition, inflammation, atherosclerosis and cardiac valvular calcification, so-called MIAC syndrome and its predictive role in outcomes of peritoneal dialysis (PD) patients. METHODS: A prospective observational study was conducted in 324 chronic PD patients. Biochemical analysis was performed at baseline for serum angiopoietins, albumin and high sensitive C-reactive protein (hs-CRP) and echocardiography was done to detect cardiac valvular calcification. Primary study end points were fatal or nonfatal cardiovascular events and mortality. RESULTS: The median of serum Angpt-2 levels was 5.44 ng/mL (interquartile range, 3.41 7.85). Across the three tertiles of serum Angpt-2, a significant trend effect was observed for body mass index, normalized protein catabolic rate, calcium * phosphorus product, hs-CRP, brain natriuretic peptide, lower-density lipoprotein cholesterol, left ventricular ejection fraction, total weekly urea clearance and residual renal function (all p < 0.05). Serum Angpt-2 showed a significant increase across the four groups of patients with increasing components of MIAC syndrome (p < 0.001). There were 77 deaths and 57 cardiovascular events. High serum Angpt-2 was an independent predictor of fatal and nonfatal cardiovascular events in PD patients (p = 0.02), however serum Angpt-2 was not an independent predictor of all-cause mortality (p = 0.3). CONCLUSIONS: Serum Angpt-2 showed close association with valvular calcification, atherosclerosis, inflammation and malnutrition, having significant independent prognostic value and is useful for cardiovascular event stratification in chronic PD patients. Angpt-2 might be a potential mediator of increased cardiovascular risk in patients undergoing PD treatment. PMID- 30445971 TI - Derivation and validation of plasma endostatin for predicting renal recovery from acute kidney injury: a prospective validation study. AB - BACKGROUND: Acute kidney injury (AKI) is associated with high morbidity and mortality in surgical patients. Nonrecovery from AKI may increase mortality and early risk stratification seems key to improving clinical outcomes. The aim of the current study was to explore and validate the value of endostatin for predicting failure to recover from AKI. METHODS: We conducted a prospective cohort study of 198 patients without known chronic kidney disease who underwent noncardiac major surgery and developed new-onset AKI in the first 48 h after admission to the ICU. The biomarkers of plasma endostatin, neutrophil gelatinase associated lipocalin (NGAL) and cystatin C were detected immediately after AKI diagnosis. The primary endpoint was nonrecovery from AKI (within 7 days). Cutoff values of the biomarkers for predicting nonrecovery were determined in a derivation cohort (105 AKI patients). Predictive accuracy was then analyzed in a validation cohort (93 AKI patients). RESULTS: Seventy-six of 198 (38.4%) patients failed to recover from AKI onset, with 41 in the derivation cohort and 35 in the validation cohort. Compared with NGAL and cystatin C, endostatin showed a better prediction for nonrecovery, with an area under the receiver operating characteristic curve (AUC) of 0.776 (95% confidence interval (CI) 0.654-0.892, p < 0.001) and an optimal cutoff value of 63.7 ng/ml. The predictive ability for nonrecovery was greatly improved by the prediction model combining endostatin with clinical risk factors of Sequential Organ Failure Assessment (SOFA) score and AKI classification, with an AUC of 0.887 (95% CI 0.766-0.958, p < 0.001). The value of the endostatin-clinical risk prediction model was superior to the NGAL clinical risk and cystatin C-clinical risk prediction models in predicting failure to recover from AKI, which was supported by net reclassification improvement and integrated discrimination improvement. Further, the endostatin clinical risk prediction model achieved sensitivity and specificity of 94.6% (76.8-99.1) and 72.7% (57.2-85.0), respectively, when validated in the validation cohort. CONCLUSION: Plasma endostatin shows a useful value for predicting failure to recover from AKI. The predictive ability can be greatly improved when endostatin is combined with the SOFA score and AKI classification. PMID- 30445970 TI - Appropriateness of empiric antimicrobial therapy with imipenem/colistin in severe septic patients: observational cohort study. AB - BACKGROUND: Empiric antimicrobial therapy (EAMT) using imipenem/colistin is commonly prescribed as a first line therapy in critically ill patients with severe sepsis. We aimed to assess the appropriateness of prescribing imipenem/colistin as EAMT in ICU patients. METHODS: A 3-year observational prospective study included ICU patients that required imipenem/colistin as EAMT. The EAMT was assessed according to microbiological and clinical outcomes. The outcomes were: delay in apyrexia, delay in the decrease of the biological inflammatory parameters (BIP), the requirement for vasoactive agents, bacteriological eradication, length of stay, ventilator days and 30-day mortality. RESULTS: 79 administrations of EAMT in 70 patients were studied. EAMT was appropriate in 52% of the studied cases. An ICU stay > 6 days was related to inappropriateness, and chronic respiratory failure was associated with appropriateness. In the appropriate EAMT group, we showed: earlier apyrexia, shorter delay in the decrease of the BIP and a reduced significant vasopressors requirement. Furthermore, EAMT improved survival with a median gain of 4 days. Inappropriate EAMT increased the mortality risk by six. The acquisition of NI in ICU was also an independent factor of mortality. CONCLUSIONS: EAMT using imipenem colistin was appropriate in half of the cases and inappropriateness was associated with an increased ICU mortality risk. PMID- 30445972 TI - A new method of measuring the thumb pronation and palmar abduction angles during opposition movement using a three-axis gyroscope. AB - BACKGROUND: Thumb opposition is vital for hand function and involves pronation and palmar abduction. The improvement of pronation is often used as one of the evaluation items of the opponensplasty method for severe carpal tunnel syndrome. However, most of the studies used substitution evaluation methods for measurement of the pronation angle. Thus, there is still no appropriate method for measuring thumb pronation angle accurately in carpal tunnel syndrome patients. In recent reports, a wearable gyroscope was used to evaluate upper extremity motions and it can be possibly used for accurate measurement of the thumb pronation angle along the three-dimensionally moving bone axis. Thus, we investigated the reliability of measuring thumb pronation using a gyroscope and evaluated whether this method can be used to detect opposition impairment. METHODS: The participants were volunteers with unaffected upper limbs (32 hands) and patients with carpal tunnel syndrome (27 hands). The pronation and palmar abduction angles during opposition movements were measured using a three-axis gyroscope that included a three-axis accelerometer. The gyroscope was fixed onto the first metacarpal bone and the thumb phalanx. RESULTS: The pronation and palmar abduction angles of the metacarpal bone and the palmar abduction angles of the phalanx significantly decreased in the carpal tunnel syndrome group. The pronation angle of the metacarpal bone during opposition movement peaked later than the palmar abduction angle in all hands. CONCLUSIONS: We were able to measure the thumb pronation and palmar abduction angles using the three-axis gyroscope, and this tool was able to detect impairments of thumb opposition due to carpal tunnel syndrome. This could be a tool for measuring thumb and finger angles and for detecting impairments caused by various diseases. PMID- 30445973 TI - Impact of occupational environmental stressors on blood pressure changes and on incident cases of hypertension: a 5-year follow-up from the VISAT study. AB - BACKGROUND: The role of occupational stressors (OS) on blood pressure (BP) is often suspected, but asserting its impact remains uncertain. Our goal was to evaluate their impact on BP increase and on incident cases of hypertension over a 5-year period. METHODS: One thousand, one hundred and fifty-six men and women from the French prospective VISAT study were followed up over five-years (T1 to T2). Exposures to a large panel of OS (physical, organizational, psychosocial and employment categories) were collected. Linear and logistic regressions were used to assess associations between OS and T2-T1 SBP difference and incident cases of hypertension. They were performed to determine the role of OS first considered separately, then in combination, in crude and adjusted models for main cardiovascular risk factors (gender, age, education, BMI, lifestyle habits and medical history). RESULTS: For initial SBP level < 130 mmHg, carrying loads, intense noise exposure, working more than 48 h/week, active and high strain tended to be associated with an SBP difference increase, while job recognition was associated with a decrease. After adjustment, only significant associations with job strain and job recognition persisted. For initial SBP level >= 130 mmHg, being exposed to an active job strain was positively associated with T2-T1 SBP difference only in unadjusted model. Considering all the OS, the recognition of completed tasks had a major protective role. No impact of OS on incident cases of hypertension was observed. CONCLUSION: Associations between OS and SBP were observed mainly when initial SBP is within the normal range, and are mainly explained by cardiovascular factors, requiring physician's particular attention to people exposed to these OS. VISAT study is registered in "LE PORTAIL EPIDEMIOLOGIE - FRANCE- AVIESAN -ID 3666". PMID- 30445974 TI - Gynecologic assessment of 19 adult females with cartilage-hair hypoplasia - high rate of HPV positivity. AB - BACKGROUND: Patients with cartilage-hair hypoplasia (CHH), a rare metaphyseal chondrodysplasia, manifest severe growth failure, variable immunodeficiency and increased risk of malignancies. The impact of CHH on gynecologic and reproductive health is unknown. Vulnerability to genital infections may predispose CHH patients to prolonged human papillomavirus (HPV) infections potentially leading to cervical, vaginal and vulvar cancer. METHODS: We carried out gynecologic evaluation, pelvic ultrasound and laboratory assessment in 19 women with genetically confirmed CHH. All patients were clinically examined and retrospective data were collected from hospital records. RESULTS: The women ranged in age from 19.2 to 70.8 years (median 40.8 years) and in height from 103 to 150 cm (median 123 cm). All women had undergone normal pubertal development as assessed by breast development according to Tanner scale and by age of menarche (mean 12.5 yrs., range 11-14 yrs). Despite significant short stature and potentially small pelvic diameters, a well-developed uterus with fairly normal size and shape was found by pelvic ultrasound in most of the patients. Ovarian follicle reserve, assessed by ultrasound was normal in relation to age in all premenopausal women it could be assessed (12 cases). Anti-Mullerian hormone was normal in relation to age in 17 women (89%). HPV was detected in 44% (8/18) and three women carried more than one HPV serotype; findings did not associate with immunological parameters. Three patients had a concurrent cell atypia in Pap smear. CONCLUSIONS: Pubertal development, reproductive hormones and ovarian structure and function were usually normal in women with CHH suggesting fairly normal reproductive health. However, the immunodeficiency characteristic to CHH may predispose the patients to HPV infections. High prevalence of HPV infections detected in this series highlights the importance of careful gynecologic follow up of these patients. PMID- 30445975 TI - Clinicopathological characteristics and prognosis of primary appendiceal stromal tumors. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) account for less than 1% of all gastrointestinal tumors. The biological behaviors of GISTs vary from benign to malignant. GISTs are common in the stomach (55.6%) and small intestine (31.8%), but rarely in the rectum, colon (6%), and other sites (5.5%). Currently, the majority of published reports of primary appendiceal stromal tumors (PASTs) are case reports or case series. METHODS: The PASTs described in this study were identified from a literature review (23 cases) and our center (one case). The relationship between PAST gross types and clinicopathological factors was analyzed and summarized. At the same time, the study also analyzed the related risk factors and survival of PASTs and GISTs. RESULTS: Twenty-four cases of PASTs were compared with 254 cases of GISTs from our center. The results showed that there was a significant difference between the two groups in tumor size (P < 0.001), histological type (P = 0.013), CD34 expression (P < 0.001), and DOG-1 expression (P < 0.001). Disease-free survival (DFS) analysis of 11 cases of PASTs and 227 cases of GISTs found that a comparison of 3-year and 5-year DFS was not statistically significant (P = 0.894 and P = 0.846, respectively). In the DFS multivariate analysis, tumor mucosal ulceration, tumor size, and NIH risk classification were independent prognostic factors in 3-year and 5-year DFS. CONCLUSION: In this study, there was no significance in the survival of patients with appendix and gastric stromal tumors, which we hypothesized to be associated with the low sample size and incomplete follow-up records. Based on this, we conclude that the prognosis of primary appendiceal stromal tumors may be better than gastric tumors, but this needs to be confirmed in further prospective studies. PMID- 30445976 TI - Hemotrophic mycoplasma in Simmental cattle in Bavaria: prevalence, blood parameters, and transplacental transmission of 'Candidatus Mycoplasma haemobos' and Mycoplasma wenyonii. AB - BACKGROUND: The significance of hemotrophic mycoplasma in cattle remains unclear. Especially in Europe, their epidemiological parameters as well as pathophysiological influence on cows are lacking. The objectives of this study were: (1) to describe the prevalence of 'Candidatus Mycoplasma haemobos' ('C. M. haemobos') and Mycoplasma wenyonii (M. wenyonii) in Bavaria, Germany; (2) to evaluate their association with several blood parameters; (3) to explore the potential of vertical transmission in Simmental cattle; and (4) to evaluate the accuracy of acridine-orange-stained blood smears compared to real-time polymerase chain reaction (PCR) results to detect hemotrophic mycoplasma. A total of 410 ethylenediaminetetraacetic acid-blood samples from cows from 41 herds were evaluated by hematology, acridine-orange-stained blood smears, and real-time PCR. Additionally, blood samples were taken from dry cows of six dairy farms with positive test results for hemotrophic mycoplasma to investigate vertical transmission of infection. RESULTS: The period prevalence of both species was 60.24% (247/410), C. M. haemobos 56.59% (232/410), M. wenyonii 8.54% (35/410) and for coinfection 4.88% (20/410). Of the relevant blood parameters, only mean cell volume (MCV), mean cell hemoglobin (MCH), and white blood cell count (WBC) showed differences between the groups of infected and non-infected individuals. There were lower values of MCV (P < 0.01) and MCH (P < 0.01) and higher values of WBC (P < 0.05) in 'C. M. haemobos'-infected cows. In contrast, co-infected individuals had only higher WBC (P < 0.05). In M. wenyonii-positive blood samples, MCH was significantly lower (P < 0.05). Vertical transmission of 'C. M. haemobos' was confirmed in two calves. The acridine-orange-method had a low sensitivity (37.39%), specificity (65.97%), positive predictive value (63.70%) and negative predictive value (39.75%) compared to PCR. CONCLUSIONS: 'Candidatus Mycoplasma haemobos' was more prevalent than M. wenyonii in Bavarian Simmental cattle, but infection had little impact on evaluated blood parameters. Vertical transmission of the infection was rare. Real-time PCR is the preferred diagnostic method compared to the acridine-orange-method. PMID- 30445977 TI - Epicardial infrared ablation to create a linear conduction block on a beating right atrium. AB - BACKGROUND: It is still difficult to create a secure linear conduction block on a beating heart from the epicardial side. To overcome this drawback we developed an infrared coagulator equipped with a cuboid light-guiding quartz rod. This study was designed to electrophysiologically confirm the efficacy of a new ablation probe using infrared energy in a clinical case. METHODS: The infrared light from a lamp is focused into the newly developed cuboid quartz rod, which has a rectangular distal exit-plane that allows 30 mm * 10 mm linear photocoagulation. Two pairs of electrodes were attached to the right atrium of a patient who was undergoing surgery. Each pair of electrodes was placed 10 mm from an ablation line. The change in conduction time between the two pairs of electrodes was measured during ablation. The predicted conduction time delay ratio was 1.54. RESULTS: The actual conduction time after ablation was 1.38-1.43 times longer than the pre-ablation conduction time. CONCLUSIONS: The infrared ablation using a newly developed cuboid probe made it possible to create a linear conduction block on the beating right atrial free wall clinically. PMID- 30445978 TI - Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated beta catenin nuclear accumulation. AB - BACKGROUND: Knockdown of Akt1 promotes Epithelial-to-Mesenchymal Transition in breast cancer cells. However, the mechanisms are not completely understood. METHODS: Western blotting, immunofluorescence, luciferase assay, real time PCR, ELISA and Matrigel invasion assay were used to investigate how Akt1 inhibition promotes breast cancer cell invasion in vitro. Mouse model of lung metastasis was used to measure in vivo efficacy of Akt inhibitor MK2206 and its combination with Gefitinib. RESULTS: Knockdown of Akt1 stimulated beta-catenin nuclear accumulation, resulting in breast cancer cell invasion. beta-catenin nuclear accumulation induced by Akt1 inhibition depended on the prolonged activation of EGFR signaling pathway in breast cancer cells. Mechanistic experiments documented that knockdown of Akt1 inactivates PIKfyve via dephosphorylating of PIKfyve at Ser318 site, resulting in a decreased degradation of EGFR signaling pathway. Inhibition of Akt1 using MK2206 could induce an increase in the expression of EGFR and beta-catenin in breast cancer cells. In addition, MK2206 at a low dosage enhance breast cancer metastasis in a mouse model of lung metastasis, while an inhibitor of EGFR tyrosine kinase Gefitinib could potentially suppress breast cancer metastasis induced by Akt1 inhibition. CONCLUSION: EGFR-mediated beta catenin nuclear accumulation is critical for Akt1 inhibition-induced breast cancer metastasis. PMID- 30445979 TI - Organizational capacities of national pharmacovigilance centres in Africa: assessment of resource elements associated with successful and unsuccessful pharmacovigilance experiences. AB - BACKGROUND: National pharmacovigilance centres (national centres) are gradually gaining visibility as part of the healthcare delivery system in Africa. As does happen in high-income countries, it is assumed that national centres can play a central coordinating role in their national pharmacovigilance (PV) systems. However, there are no studies that have investigated whether national centres in Africa have sufficient organizational capacity to deliver on this mandate and previous studies have reported challenges such as lack of funding, political will and adequate human resources. We conducted interviews with strategic leaders in national centres in 18 African countries, to examine how they link the capacity of their organization to the outcomes of activities coordinated by their centres. Strategic leaders were asked to describe three situations in which activities conducted by their centre were deemed successful and unsuccessful. We analyzed these experiences for common themes and examined whether strategic leaders attributed particular types of resources and relationships with stakeholders to successful or unsuccessful activities. RESULTS: We found that strategic leaders most often attributed successful experiences to the acquisition of political (e.g. legal mandate) or technical (e.g. active surveillance database) resources, while unsuccessful experiences were often attributed to the lack of financial and human resources. Stakeholders that were most often mentioned in association with successful experiences were national government and development partners, whereas national government and public health programmes (PHPs) were often mentioned in unsuccessful experiences. All 18 centres, regardless of maturity of their PV systems had similar challenges. CONCLUSIONS: The study concludes that national centres in Africa are faced with 3 core challenges: (1) over-reliance on development partners, (2) seeming indifference of national governments to provide support after national centres have gained membership of the World Health Organization (WHO) Programme for International Drug Monitoring (PIDM) and (3) engaging public health programmes in a sustainable way. PMID- 30445980 TI - An integrative review of potential enablers and barriers to accessing mental health services in Ghana. AB - INTRODUCTION: The importance of accessible mental health treatment is a global concern, particularly when one in five people will experience a mental health problem in their lifespan. This is no less important in Ghana; however, no studies have yet attempted to appraise and synthesise the potential enablers and barriers to accessing services in Ghana. The aim of this integrative review is therefore to identify and synthesise existing evidence on the barriers and enablers to accessing mental health services in Ghana. METHODS: A search of the published literature was conducted using Medline, EMBASE, PsycINFO, CINAHL (EBSCO), Web of Science, and Scopus electronic databases. The search was limited to papers published in English and within 2000-2018. Using pre-defined inclusion and exclusion criteria, two reviewers independently screened the titles and abstracts of the retrieved papers. A data extraction form and a Critical Appraisal Checklist were used to extract and appraise data, respectively. The integrative review incorporates both qualitative and quantitative data into a single synthesis. RESULTS: Out of 42 papers that met the inclusion criteria, 50% used qualitative methods, 33.3% used mixed methods and 16.7% used quantitative methods alone. The potential barriers in accessing mental health services were attitudinal, knowledge about services, treatment cost, transportation and geographical proximity, as well as perceived efficacy of medication. Similarly, the health systems factors contributing to barriers were low priority, limited funding sources, irregular medicine supply, limited services for marginalised groups and poor state of psychiatric facilities, together with poor management of mental health cadres. The potential enablers for service users involved increased decentralisation and integration, task-shifting and existing support services. CONCLUSION: The existing evidence on mental health in Ghana is skewed towards weaknesses in the systems and stigma, with rationally little, or no, evidence or emphasis on the effectiveness, or quality of mental health services. These attributes largely neglect the provision of psychiatric services for marginalised mental health service user groups, including children, adolescents, people with disabilities and the elderly. PMID- 30445981 TI - Bone marrow-derived mononuclear cell therapy can attenuate systemic inflammation in rat heatstroke. AB - BACKGROUND: This study was performed to gain insights into novel therapeutic approaches for acute systemic inflammation in heatstroke. Bone marrow-derived mononuclear cells (BMMNCs) secrete anti-inflammatory proteins and have protective effects against acute inflammation. Recent evidence suggested that transplantation of BMMNCs can reduce the acute tissue injury caused by regional myocardial reperfusion and the lung dysfunction induced by lipopolysaccharides. We evaluated whether BMMNCs attenuate systemic inflammatory response induced by severe heatstroke. MATERIAL AND METHODS: Anesthetized 12-week-old male Wistar rats were subjected to heat stress (41.8 degrees C for 30 min) with/without transplantation of BMMNCs. Bone marrow cells were harvested from the femur and tibia of other Wistar rats. BMMNCs were separated by density centrifugation, dissolved in phosphate-buffered saline (PBS), and injected intravenously immediately after heat stress (HS-BMMNCs group). The control group was administered an equal volume of PBS, and the sham group underwent the same procedure without heat stress. RESULTS: Seven-day survival improved significantly in the HS-BMMNCs group versus control group (83.3% vs 41.7%). Transplantation of BMMNCs significantly suppressed serum levels of pro-inflammatory mediators, such as tumor necrosis factor-alpha, interleukin-6 and histone H3 at 3, 6, and 12 h after heat stress. Besides, the elevation of serum syndecan-1, a main component of the vascular endothelial glycocalyx layer, in the BMMNCs group was significantly suppressed compared to that in the control group at 6 and 12 h after heat stress. Histological analysis revealed that edema of the alveolar septum and vascular endothelial injury in the lung were evident in the control group 6 h after heat stress, whereas the morphological alteration was ameliorated in the HS-BMMNCs group. Also, histological analysis using BMMNCs derived from green fluorescent protein transgenic rats showed that the transplanted BMMNCs migrated into lung, kidney, and spleen at 24 h after heat stress but did not engraft to host tissues. CONCLUSION: Transplantation of BMMNCs attenuated acute systemic inflammation and vascular endothelial injury, reduced organ dysfunction, and improved survival in a rat heatstroke model. These findings provide a possible therapeutic strategy against critical heatstroke. PMID- 30445983 TI - Chile's role in global health diplomacy: a narrative literature review. AB - BACKGROUND: Global health diplomacy (GHD) has become an important field of investigation due to health concerns increasingly entering the foreign policy domain. Much of the existing academic writing focuses on North-South cooperation in global health, and emphasizes the role of security and economic interests by Northern countries as drivers of GHD. Chile presents a favourable environment for an expanded involvement in future GHD activities. However, there is little knowledge about what has been driving Chile's integration of health into foreign policy, and little effort to appropriate knowledge from international relations theories to better theoretically grasp the emergence of GHD. METHODS: To fill this knowledge gap, we conducted a narrative literature review of the driving forces behind Chile's integration of health into foreign policy. Drawing on a popular analytical framework used in international relations scholarship, we identified driving forces of the integration of health into Chile foreign policy at three levels of analysis. RESULTS: At the international/global level of analysis, the main driving forces were related to national security concerns and compliance with regulations of international organizations. At the regional level, GHD was driven by a commitment to regional solidarity through mutually beneficial cooperation in response to neoliberal reforms; health coordination in emergencies; and protection of indigenous peoples. Finally, at the domestic level, drivers identified include economic interests of various productive sectors and how health regulations might impact those; the high degree of social inequity which impacts on access to healthcare; and management of natural disasters. CONCLUSION: Health actions in the context of international relations in Chile are still mainly motivated by more traditional foreign policy interests rather than by a desire to satisfy health needs per se. This seems to conform with findings of existing GHD scholarship that emphasize the importance of security and economic interests as driving forces of GHD, and how health is often appropriated instrumentally within foreign policy settings to achieve other goals. But the review also reveals that in the context of South-South cooperation (and regional health diplomacy), solidarity and normative considerations can be important driving forces as well. Finally, the review demonstrates that there has been an evolution from chiefly domestically focused health policies (e.g. maternal and child nutrition treatment) towards internationally inspired integrated policies (e.g. maternal and child nutrition promotion aligned with international guidelines). PMID- 30445982 TI - Human papillomavirus type 16 E6 and E7 oncoproteins interact with the nuclear p53 binding protein 1 in an in vitro reconstructed 3D epithelium: new insights for the virus-induced DNA damage response. AB - BACKGROUND: Despite vaccination and screening measures, anogenital cancer, mainly promoted by HPV16 oncoproteins, still represents the fourth tumor and the second cause of death among women. Cell replication fidelity is the result of the host DNA damage response (DDR). Unlike many DNA viruses that promote their life cycle through the DDR inactivation, HR-HPVs encourage cells proliferation despite the DDR turned on. Why and how it occurs has been only partially elucidated. During HPV16 infection, E6 links and degrades p53 via the binding to the E6AP LXXLL sequence; unfortunately, E6 direct role in the DDR response has not clearly identified yet. Similarly, E7 increases DDR by competing with E2F1-pRb interaction, thus leading to the inactivation of pRb, and promotion, E2F1 mediated, of DDR genes translation, by binding to the pRb-like proteins CBP/p300 and p107, that also harbour LXXLL sequence, and via the interaction and activation of several DDR proteins. METHODS: To gain information regarding E6 and E7 contribution in DDR activation, we produced an in vitro 3D HPV16-E6E7 infected epithelium, already consolidated study model for HPVs, and validated it by assessing H&E staining and BrdU, HPV16 DNA, E6E7 proteins and gammaH2A.X/53BP1 double-strand break (DSBs) sensors expression; then we made an immuno colocalization of E6 and E7 with cyclin E2 and B1. Since 53BP1, like E6 and E7, also binds p53 and pRb, we supposed their possible direct binding. To explore this hypothesis, we performed a double immunofluorescence of E6 and E7 with 53BP1, a sequence analysis of 53BP1 within its BRCT2 domain and then an in situ PLA within CaSki, E6E7HPV16 NHEKs and the 3D model. RESULTS: The in vitro epithelium resembled the histology and the events typical of in vivo infected tissues. E6E7HPV16 were both expressed in basal and differentiated strata and induced H2A.X phosphorylation and 53BP1 increment into nuclear foci. After highlighting E6 and E7 co-expression with 53BP1 and a LKVLL sequence within the 53BP1 BRCT2 domain, we demonstrated the bindings via the PLA technique. CONCLUSIONS: Our results reinforce E6 and E7 role in cellular function control providing potentially new insights into the activity of this tumor virus. PMID- 30445984 TI - Factors associated with viral non-suppression among adolescents living with HIV in Cambodia: a cross-sectional study. AB - BACKGROUND: Adolescents living with HIV on antiretroviral therapy (ART) have worse treatment adherence, viral suppression, and mortality rates compared to adults. This study investigated factors associated with viral non-suppression among adolescents living with HIV in Cambodia. METHODS: A cross-sectional study was conducted in August 2016 among 328 adolescents living with HIV aged 15-17 years who were randomly selected from 11 ART clinics in the capital city of Phnom Penh and 10 other provinces. Clinical and immunological data, including CD4 count and viral load, were obtained from medical records at ART clinics. Adolescents were categorized as having achieved viral suppression if their latest viral load count was < 1000 ribonucleic acid (RNA) copies/mL. Multivariate logistic regression analysis was performed to identify factors independently associated with viral non-suppression. RESULTS: The mean age of the participants was 15.9 years (SD = 0.8), and 48.5% were female. Median duration on ART was 8.6 (interquartile range = 6.0-10.6) years. Of total, 76.8% of the participants had achieved viral suppression. After adjustment for other covariates, the likelihood of having viral non-suppression remained significantly lower among adolescents who were: older/aged 17 (AOR = 0.46, 95% CI 0.21-0.98), had been on ART for more than 9 years (AOR = 0.35, 95% CI 0.19-0.64), had most recent CD4 count of > 672 (AOR = 0.47, 95% CI 0.26-0.86), had a relative as the main daily caregiver (AOR = 0.37, 95% CI 0.17-0.80), and did not believe that there is a cure for AIDS (AOR = 0.40, 95% CI 0.21-0.75) compared to their reference group. The likelihood of having viral non-suppression also remained significantly higher among adolescents who had first viral load > 628 RNA copies/mL (AOR = 1.81, 95% CI 1.05-4.08) and among those who were receiving HIV care and treatment from an adult clinic (AOR = 2.95, 95% CI 1.56-5.59). CONCLUSIONS: The proportion of adolescents living with HIV with viral suppression in this study was relatively high at 76.8%, but falls short of the global target of 90%. Programs targeting younger adolescents and adolescents in transition from pediatric to adult care with a range of interventions including psychosocial support and treatment literacy could further improve viral suppression outcomes. PMID- 30445985 TI - Radiations and male fertility. AB - During recent years, an increasing percentage of male infertility has to be attributed to an array of environmental, health and lifestyle factors. Male infertility is likely to be affected by the intense exposure to heat and extreme exposure to pesticides, radiations, radioactivity and other hazardous substances. We are surrounded by several types of ionizing and non-ionizing radiations and both have recognized causative effects on spermatogenesis. Since it is impossible to cover all types of radiation sources and their biological effects under a single title, this review is focusing on radiation deriving from cell phones, laptops, Wi-Fi and microwave ovens, as these are the most common sources of non ionizing radiations, which may contribute to the cause of infertility by exploring the effect of exposure to radiofrequency radiations on the male fertility pattern. From currently available studies it is clear that radiofrequency electromagnetic fields (RF-EMF) have deleterious effects on sperm parameters (like sperm count, morphology, motility), affects the role of kinases in cellular metabolism and the endocrine system, and produces genotoxicity, genomic instability and oxidative stress. This is followed with protective measures for these radiations and future recommendations. The study concludes that the RF-EMF may induce oxidative stress with an increased level of reactive oxygen species, which may lead to infertility. This has been concluded based on available evidences from in vitro and in vivo studies suggesting that RF-EMF exposure negatively affects sperm quality. PMID- 30445986 TI - The role of a checklist for assessing the quality of basic life support performance: an observational cohort study. AB - BACKGROUND: Training lay rescuers in Basic Life Support (BLS) is essential to improve bystander cardiopulmonary resuscitation (CPR) rates; in addition, simple methods are needed to provide feedback on CPR performance. This study evaluated whether a simple observational checklist can be used by BLS instructors to adequately measure the quality of BLS performance as an alternative to other feedback devices. METHODS: The BLS performances of 152 first-year medical students (aged 21.4 +/- 3.9 years) were recorded on video, and objective data regarding the quality of the BLS were documented using Laerdal PC SkillReporting software. The performances were categorized according to quality. Ten BLS instructors observed the videos and completed a ten-point checklist based on the Cardiff Test of BLS (version 3.1) to assess the performances. The validity of the checklist was reviewed using interrater reliability as well as by comparing the checklist-based results with objective performance data. RESULTS: Matching the checklist-based evaluation with the objective performance data revealed high levels of agreement for very good (82%) and overall insufficient (75%) performances. Regarding the checklist-based evaluation, interrater reliability depended on the checklist item; thus, some items were more easily identified correctly than others. The highest and lowest levels of agreement were observed for the items "undressed torso" and "complete release between compressions" (mean joint-probability 95 and 67%, respectively). CONCLUSIONS: The observational checklist adequately distinguished sufficient from insufficient BLS performances and offered an assessment of items not incorporated by SkillReporting software such as the initial assessment or undressing the chest. Although its usefulness was reduced for scaling intermediate performance groups, the checklist may be overall a useful rating tool in BLS-training if objective feedback devices are not available, for example, due to large groups of participants or limited training time. PMID- 30445987 TI - Sirtuin 3 deficiency aggravates contrast-induced acute kidney injury. AB - BACKGROUND: Sirtuin 3 (Sirt3) is a key regulator of energy metabolism and oxidative stress. To investigate the role of Sirt3 in contrast-induced acute kidney injury (CIAKI), we established the model both in vivo and in vitro to explore the potential mechanisms. METHODS: In vivo, we established CIAKI models in wild-type (WT) and Sirt3-knockout (Sirt3-KO) mice. Blood urea nitrogen (BUN) and serum creatinine (Scr) were detected by enzyme-linked immunosorbent assay, Glomerular Filtration Rate (GFR) and creatinine clearance were also investigated. We detected the production of reactive oxygen species (ROS) via 2'7' dichlorodihydro-fluorescein diacetate. The expressions of Sirt3, oxidative stress and apoptosis related markers (MnSOD, Catalase, Acetyl-MnSOD K68, Nox4, Bax, Bcl 2 and Caspase3) were measured and analyzed. In addition, we observed the effect of nicotinamide riboside (NR) on CIAKI in WT and Sirt3-KO mice. In vitro, Sirt3 was knocked out by siRNA transfection method in HK-2 cells. Sirt3, ROS, oxidative stress and apoptosis markers in HK-2 cells were also measured. RESULTS: Our data demonstrated that the levels of Scr and BUN in Sirt3-KO mice were increased while the levels of the GFR and creatinine clearance were decreased in CIAKI mice. In Sirt3-KO or siRNA groups, the activities of MnSOD and Catalase were markedly down regulated. Also, the expression of Caspase3 were markedly increased and the ratio of Bcl-2/Bax was decreased, while the ROS level was increased in Sirt3 deficiency groups. NR ameliorated CIAKI in WT mice but not in Sirt3-KO mice. CONCLUSION: Our results suggest that Sirt3 deficiency aggravates contrast-induced acute kidney injury. Sirt3 is critical in NR-mediated renoprotection in CIAKI. PMID- 30445989 TI - Decreasing the use of edible oils in China using WeChat and theories of behavior change: study protocol for a randomized controlled trial. AB - BACKGROUND: The consumption of edible oils in China has increased rapidly in recent years, and the total amount of edible-oil intake in the country has ranked first in the world. The choice and intake of edible oils, as a source of fats, are important factors that affect people's health. Many chronic diseases are closely associated with high-calorie and saturated-fat intake. The influence of traditional concepts that promote the use of edible oils among women, particularly housewives, plays a key role in a household's diet and nutrition because the diet-related knowledge, attitude and behaviour of housewives are dominant factors in planning and preparing their family's meals. WeChat, which was developed by Tencent, is a multipurpose messaging, social media and mobile payment application (app) in China. Described by Forbes as one of the world's most powerful apps, WeChat provides considerable convenience in disseminating knowledge. Accordingly, this study aims to design a pilot intervention to decrease the use of edible oils in Chinese households. The intervention, which is based on theories of behaviour change, will be implemented through WeChat. DESIGN AND METHODS: The study design is a randomised controlled trial that adopts knowledge, attitude and practice, social cognitive and stages of change theories as theoretical models. A total of 800 housewives between the ages of 25 and 45 years will be recruited on WeChat and from the communities in four areas (including rural and urban) in Chongqing, China. A self-administered questionnaire will be used to collect information regarding age, educational level, occupation, family members, edible-oil intake habits, knowledge of edible oils and WeChat usage habits. A total of 200 participants will be selected and randomly assigned to two equal-sized groups: group A (the intervention group) and group B (the control group). Group A will receive health education regarding edible oils for four consecutive weeks, whereas group B will be treated as the blank control. Each participant will complete a battery of knowledge, attitude and behaviour tests immediately, 3 months and 6 months after the intervention. In addition, weight, moisture rate, fat rate, visceral fat level and body mass index will be calculated using a multifunctional weighing scale, namely, Tanita BC-601 (Japan). The study is currently in the design stage. DISCUSSION: This study aims to increase knowledge and awareness of the appropriate use of edible oils, thereby encouraging participants to change behaviour by decreasing the intake of unhealthy levels of edible oils. It will be the first intervention to investigate the use of edible oils in China through WeChat. We predict that receiving health education regarding edible oils through WeChat will substantially improve the knowledge and attitude of the respondents. The members of the intervention group will have increased awareness and will be willing to decrease their use of edible oils to remain healthy. Results of this study may provide scientific evidence for the effect of health education through WeChat on edible oil-intake behaviour, thereby offering a comprehensive intervention to decrease the use of edible oils and promote a healthy lifestyle. TRIAL REGISTRATION: Chinese Clinical Trial Registry (primary registry in the World Health Organisation registry network): ChiCTR-IOR-17013472 . Registered on 21 November 2017. PMID- 30445990 TI - Treatment of central line-associated bloodstream infections. PMID- 30445991 TI - Focused antenatal care utilization and associated factors in Debre Tabor Town, northwest Ethiopia, 2017. AB - OBJECTIVE: Attending antenatal care helps to reduce the occurrence of maternal morbidity and mortality by providing chances for health promotion and information about danger signs, birth preparedness and where to seek care for pregnancy complications. Therefore identifying factors affecting the utilization of focused ANC service is of supreme importance. RESULTS: A total of 317 mothers who had a history of antenatal care for their last birth during the previous 6 months were included in the study from which 112 (35.3%, 95% CI 30.6, 40.4) of mothers attended focused antenatal care services. Age of mother [AOR = 4.7, 95% CI 1.87, 11.88], Educational status [AOR = 2.5, 95% CI 1.00, 6.19], history of still birth [AOR = 13.1, 95% CI 2.14, 80.20] and planned pregnancy [AOR = 3.7, 95% CI 1.23, 11.12] were found to be major predictors for focused ANC service utilization. Proportion of focused antenatal care was low (35.3%). Age of mother, education, history of stillbirth and planned pregnancy were identified as predictors affecting focused antenatal care service utilization. Encouraging women's educational status, behavioral change communication at grass root level and improving the capacity and quality of ANC service are some of the recommendations forwarded. PMID- 30445988 TI - Effect of a high-protein diet with beta-cryptoxanthin supplementation on metabolic risk factors, oxidative and inflammatory biomarkers in non-alcoholic fatty liver disease (NAFLD): study protocol for a randomized controlled clinical trial. AB - BACKGROUND: Excessive hepatic fat is associated with increased metabolic risk factors, production of inflammatory factors, and oxidative stress. High protein intake might trigger an increased hepatic lipid oxidation through an increase in hepatic energy expenditure. Furthermore, the majority of randomized controlled trials (RCT) in humans have failed to show whether carotenoids can be used to prevent and treat non-alcoholic fatty liver disease (NAFLD). However, it is notable and contradictory that NAFLD is rapidly escalating in Iran and other countries with lower intakes of fruit and vegetables (as sources of beta cryptoxanthin [beta-CX] and carbohydrates) and higher intake of carbohydrates (as an agent of NAFLD); and the effects of beta-CX and a high protein diet (HPD) on NAFLD need to be investigated further. METHODS/DESIGN: This study will be conducted as a randomized, double-blind, placebo-controlled clinical trial for 12 weeks to receive daily beta-CX 6 mg supplementation combined with a HPD on levels of metabolic factors, beta-CX, glycemic and lipid profiles, inflammatory factors, adipocytokines, and body composition. Ninety-two eligible patients, aged 18-60 years, of both genders, who are obese and overweight (body mass index [BMI] 25-40 kg/m2) will be randomly assigned to four groups as follow: HPD + placebo; normal protein diet + beta-CX (NPD + beta-CX); HPD + beta-CX; and NPD + placebo (control group). Two populations will be analyzed in this work. The intention-to-treat (ITT) population includes all patients who will be randomized, while the per protocol (PP) population includes all individuals who complete the 12- week intervention (i.e. study completers). DISCUSSION: Our findings from this trial will contribute to the knowledge of the relationship between beta-CX supplementation and a HPD on NAFLD patients and determination of optimal macronutrient ratios without energy restriction. TRIAL REGISTRATION: Iran clinical trials registry, IRCT2017060210181N10 . Registered on 20 June 2017. PMID- 30445993 TI - KrakenUniq: confident and fast metagenomics classification using unique k-mer counts. AB - False-positive identifications are a significant problem in metagenomics classification. We present KrakenUniq, a novel metagenomics classifier that combines the fast k-mer-based classification of Kraken with an efficient algorithm for assessing the coverage of unique k-mers found in each species in a dataset. On various test datasets, KrakenUniq gives better recall and precision than other methods and effectively classifies and distinguishes pathogens with low abundance from false positives in infectious disease samples. By using the probabilistic cardinality estimator HyperLogLog, KrakenUniq runs as fast as Kraken and requires little additional memory. KrakenUniq is freely available at https://github.com/fbreitwieser/krakenuniq . PMID- 30445994 TI - Consumption habits of pregnant women in the Jazan region, Saudi Arabia: a descriptive study. AB - OBJECTIVE: Maternal nutritional habits are critical for the health of both mother and offspring. Postpartum outcomes for mother and infant are strongly influenced by the mother's nutritional status. Information about consumption habits among pregnant women in Saudi Arabia is scarce. Thus, this study aims to describe the consumption habits of pregnant women in the Jazan region, Saudi Arabia. RESULTS: Meat, fish, and fruits were consumed by 97%, 86%, and 90% of the sample. Sugary desserts, fast food, and canned food were consumed by 90%, 81%, and 71% of the sample. Caffeine, juices, and milk were consumed by 75%, 92%, and 81% of the sample. Previous percentages show general higher consumption habits of food and beverages. Over-the-counter medication was used by only 17%. Folic acid, iron, and calcium use by 77%, 64%, and 58% of the sample, respectively. These percentage shows conservative use of Over-the-counter medication and sub-optimal use of important dietary supplements. Moreover, there was a positive association between caffeine intake and trimesters. Furthermore, there was negative association between education level and fish intake. Finally, canned foods consumption was higher among low income pregnant women. PMID- 30445992 TI - High-resolution mapping of centromeric protein association using APEX-chromatin fibers. AB - BACKGROUND: The centromere is a specialized chromosomal locus that forms the basis for the assembly of a multi-protein complex, the kinetochore and ensures faithful chromosome segregation during every cell division. The repetitive nature of the underlying centromeric sequence represents a major obstacle for high resolution mapping of protein binding using methods that rely on annotated genomes. Here, we present a novel microscopy-based approach called "APEX chromatin fibers" for localizing protein binding over the repetitive centromeric sequences at kilobase resolution. RESULTS: By fusing centromere factors of interest to ascorbate peroxidase, we were able to label their binding profiles on extended chromatin fibers with biotin marks. We applied APEX-chromatin fibers to at least one member of each CCAN complex, most of which show a localization pattern different from CENP-A but within the CENP-A delineated centromeric domain. Interestingly, we describe here a novel characteristic of CENP-I and CENP B that display extended localization beyond the CENP-A boundaries. CONCLUSIONS: Our approach was successfully applied for mapping protein association over centromeric chromatin, revealing previously undescribed localization patterns. In this study, we focused on centromeric factors, but we believe that this approach could be useful for mapping protein binding patterns in other repetitive regions. PMID- 30445995 TI - Whole-genome sequencing and analysis of Plasmodium falciparum isolates from China Myanmar border area. AB - BACKGROUND: China has made progress in malaria control and aims to eliminate malaria nationwide, but implementing effective interventions along the border regions remain a huge task. The Plasmodium falciparum cases imported from Southeast Asia has frequently reported especially in the China-Myanmar border (CMB) area. Though, information is scant on P. falciparum genetic variability in this area. METHODS: This study reported P. falciparum isolates genome sequence of six clinical isolates in the CMB area. Furthermore, we estimated the nucleotide diversity, Watterson's estimator and Tajima's D value for the whole genome mutation rate in slide window. RESULTS: Our data were aligned onto 96.05-98.61% of the reference 3D7 genome in high fold coverages. Principal component analysis result showed that P. falciparum clustered generally according to their geographic origin. A total of 91 genes were identified as positive selection with Ka/Ks ratio significantly higher than 1, and most of them were multigene families encoding variant surface antigens (VSAs) such as var, rif and stevor. The enrichment of the positive selection on VSA genes implied that the environment complexity subjected CMB's P. falciparum to more pressure for survival. CONCLUSIONS: Our research suggests that greater genetic diversity in CMB area and the positive selection signals in VSA genes, which allow P. falciparum to fit the host immune system well and aggravate the difficulty of treatment. Meanwhile, results obtained from this study will provide the fundamental basis for P. falciparum population genomic research in CMB area. PMID- 30445996 TI - Mechanical ventilation enhances extrapulmonary sepsis-induced lung injury: role of WISP1-alphavbeta5 integrin pathway in TLR4-mediated inflammation and injury. AB - BACKGROUND: High tidal volume ventilation of healthy lungs or exacerbation of existing acute lung injury (ALI) by more moderate mechanical ventilation (MTV) produces ventilator-induced lung injury. It is less clear whether extrapulmonary sepsis sensitizes the lung to MTV. METHODS: We used a two-hit model of cecal ligation and puncture (CLP) followed 12 h later by MTV (10 ml/kg; 6 h) to determine whether otherwise noninjurious MTV enhances CLP-induced ALI by contrasting wildtype and TLR4-/- mice with respect to: alveolar-capillary permeability, histopathology and intrapulmonary levels of WNT-inducible secreted protein 1 (WISP1) and integrin beta5; plasma levels of cytokines and chemokines (TNF-alpha, IL-6, MIP-2, MCP-1) and intrapulmonary neutrophil infiltration; and other inflammatory signaling via intrapulmonary activation of JNK, p38 and ERK. A separate cohort of mice was pretreated with intratracheal neutralizing antibodies to WISP1, integrin beta5 or IgG as control and the presented phenotyping repeated in a two-hit model; there were 10 mice per group in these first three experiments. Also, isolated peritoneal macrophages (PM) from wildtype and TLR4-/ , MyD88-/- and TRIF-/- mice were used to identify a WISP1-TLR4-integrin beta5 pathway; and the requisite role of integrin beta5 in WISP1-induced cytokine and chemokine production in LPS-primed PM was examined by siRNA treatment. RESULTS: MTV, that in itself did not cause ALI, exacerbated increases in alveolar capillary permeability, histopathologic scoring and indices of pulmonary inflammation in mice that previously underwent CLP; the effects of this two-hit model were abrogated in TLR4-/- mice. Attendant with these findings was a significant increase in intrapulmonary WISP1 and integrin beta5 in the two-hit model. Anti-WISP1 or anti-integrin beta5 antibodies partially inhibited the two hit phenotype. In PM, activation of TLR4 led to an increase in integrin beta5 expression that was MyD88 and NF-kappaB dependent. Recombinant WISP1 increased LPS-induced cytokine release in PM that was inhibited by silencing either TLR4 or integrin beta5. CONCLUSIONS: These data show for the first time that otherwise noninjurious mechanical ventilation can exacerbate ALI due to extrapulmonary sepsis underscoring a potential interactive contribution of common events (sepsis and mechanical ventilation) in critical care, and that a WISP1-TLR4-integrin beta5 pathway contributes to this phenomenon. PMID- 30445997 TI - The burden of gastroenteritis in Switzerland (BUGS) study: a research proposal for a 1-year, prospective cohort study. AB - OBJECTIVES: Acute gastroenteritis (AG) is a usually self-limiting, but common disease worldwide. In Europe, incidence estimates range from 0.3-1.5 AG episodes/person-year. For Switzerland, available information on AG is restricted to notifiable foodborne diseases and findings from research studies starting at primary care level. The aims of this 1-year, population-based prospective cohort study are to assess the incidence, burden of disease, aetiology and socio economic impact of AG in the Swiss general population. Additionally, the prevalence of bacterial gastrointestinal pathogens and bacteria harbouring antimicrobial resistances in the asymptomatic population shall be assessed. RESULTS: Weekly follow-up of the cohort consisting of 3000 participants will provide incidence estimates of AG. Furthermore, information collected will be used to assess risk factors for experiencing an episode of AG, to explore determinants for help seeking, and to characterise the socio-economic impact of AG including absence from work and inability to perform daily activities. Aetiology of AG is determined by investigating stool samples from symptomatic participants. Finally, stool samples from participants collected during an asymptomatic period will be used to assess the prevalence of enterohaemorrhagic E. coli, Campylobacter spp., Salmonella spp. and Shigella spp. as well as of resistance to different antibiotics (extended-spectrum beta-lactamase-, fluoroquinolone- and carbapenemase-resistance). PMID- 30445999 TI - A randomized controlled trial comparing lifestyle intervention to letrozole for ovulation in women with polycystic ovary syndrome: a study protocol. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 8 and 18% of women and is the leading cause of female anovulatory infertility. Unfortunately, common treatments for women trying to conceive can be ineffective as well as disruptive or harmful to patients' quality of life. Despite evidence that women with PCOS have expressed the need for alternative fertility treatments, lifestyle interventions incorporating a nutritional plan with supplementation, increased physical activity, and techniques for stress management have not been combined as a program and studied in this population. Literature suggests that each of these individual components can positively influence reproductive hormones and metabolic health. METHODS/DESIGN: This is a randomized controlled trial which will include 240 women diagnosed with PCOS, according to the Rotterdam criteria, who are trying to conceive. Participants will be randomized to either a comprehensive lifestyle intervention program or prescribed an oral fertility medication, letrozole. These two groups will be further randomized to consume either myo-inositol or a placebo. Participants will be between the ages of 18 and 37 years. Exclusion criteria include women who have already begun fertility treatment, who are currently using myo-inositol or have taken it within the past 3 months, or who are being treated for, or have a history of, an eating disorder. The primary outcome will be the ovulation rate, the secondary outcome will be conception. Other outcomes include miscarriage rates, validated rating measures of overall quality of life (including social, relational, mind/body and emotional sub-categories) and mental health scores (depression, anxiety, and stress). DISCUSSION: This trial will determine the effectiveness of a structured lifestyle based comprehensive intervention program for women with PCOS experiencing infertility. In addition, it will determine whether supplementing with myo inositol provides any further benefit. The objective of this study is to assess a possible non-pharmacological solution to ovulatory dysfunction in these patients and perhaps improve other associated features of PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02630485 . Registered on 15 December 2015. PMID- 30445998 TI - ZEB2 stably represses RAB25 expression through epigenetic regulation by SIRT1 and DNMTs during epithelial-to-mesenchymal transition. AB - BACKGROUND: Epithelial mesenchymal transition (EMT) is tightly regulated by a network of transcription factors (EMT-TFs). Among them is the nuclear factor ZEB2, a member of the zinc-finger E-box binding homeobox family. ZEB2 nuclear localization has been identified in several cancer types, and its overexpression is correlated with the malignant progression. ZEB2 transcriptionally represses epithelial genes, such as E-cadherin (CDH1), by directly binding to the promoter of the genes it regulates and activating mesenchymal genes by a mechanism in which there is no full agreement. Recent studies showed that EMT-TFs interact with epigenetic regulatory enzymes that alter the epigenome, thereby providing another level of control. The role of epigenetic regulation on ZEB2 function is not well understood. In this study, we aimed to characterize the epigenetic effect of ZEB2 repressive function on the regulation of a small Rab GTPase RAB25. RESULTS: Using cellular models with conditional ZEB2 expression, we show a clear transcriptional repression of RAB25 and CDH1. RAB25 contributes to the partial suppression of ZEB2-mediated cell migration. Furthermore, a highly significant reverse correlation between RAB25 and ZEB2 expression in several human cancer types could be identified. Mechanistically, ZEB2 binds specifically to E-box sequences on the RAB25 promoter. ZEB2 binding is associated with the local increase in DNA methylation requiring DNA methyltransferases as well as histone deacetylation (H3K9Ac) depending on the activity of SIRT1. Surprisingly, SIRT1 and DNMTs did not interact directly with ZEB2, and while SIRT1 inhibition decreased the stability of long-term repression, it did not prevent down regulation of RAB25 and CDH1 by ZEB2. CONCLUSIONS: ZEB2 expression is resulting in drastic changes at the chromatin level with both clear DNA hypermethylation and histone modifications. Here, we revealed that SIRT1-mediated H3K9 deacetylation helps to maintain gene repression but is not required for the direct ZEB2 repressive function. Targeting epigenetic enzymes to prevent EMT is an appealing approach to limit cancer dissemination, but inhibiting SIRT1 activity alone might have limited effect and will require drug combination to efficiently prevent EMT. PMID- 30446000 TI - Using dried blood spot for the detection of HBsAg and anti-HCV antibodies in Cameroon. AB - OBJECTIVE: Dried blood spots (DBS) offer multiple benefits for collecting, storing and shipping whole blood samples. Our objective was to compare, for the first time in Africa, the performance of DBS with respect to plasma in the detection of Hepatitis B surface antigen (HBsAg) and antibodies to Hepatitis C Virus (anti-HCV) using Architect, Abbott Diagnostics. RESULTS: DBS had a sensitivity of 99%, a specificity of 100%, a positive predictive value of 99%, a negative predictive value of 100% and a kappa index of 0.99 for the detection of HBsAg. For anti-HCV detection, the sensitivity, specificity, positive predictive value, negative predictive value and kappa index were 99%, 98%, 98%, 99%, and 0.97, respectively. This study confirms that DBS may be a reliable alternative specimen type for HBV and HCV diagnosis. PMID- 30446002 TI - How much allopurinol does it take to get to target urate? Comparison of actual dose with creatinine clearance-based dose. AB - OBJECTIVE: Allopurinol dosing has frequently been limited based on creatinine clearance (CrCL), resulting in failure to achieve target serum urate (SU). The aim of this analysis was to determine how many milligrams of allopurinol above the recommended CrCL-based dose (R+) are required to achieve target SU and to investigate the factors that influence R+. METHODS: We analysed data from participants in a 24-month open, randomized, controlled, parallel-group, comparative clinical trial. Data obtained during the 12-month dose escalation (DE) phase of the study (year 1 for DE/DE and year 2 for control/DE) were combined. R+ dose was defined as the number of milligrams of allopurinol above the CrCL-based dose at the final visit. RESULTS: Of the 132 participants, R+ allopurinol dose at the final visit was <= 100 mg/day in 38 (28.8%), 101-200 mg/day in 46 (34.8%) and > 200 mg/day in 48 participants (37.1%). There was no significant difference between the R+ groups in the number of participants achieving target SU. There was an increase in plasma oxypurinol and a larger percentage and absolute change in SU as R+ increased. Multivariate analysis revealed CrCL, weight, baseline SU and allopurinol dose, were significantly positively associated with allopurinol dose at 12 months. There were no significant differences across R+ groups in renal or liver function adverse events, although there were numerically more serious adverse events in the higher R+ groups. CONCLUSION: A wide range of R+ doses are required to achieve target SU. Four easily obtained clinical variables (baseline SU, CrCL, weight, and allopurinol dose) may be helpful to predict allopurinol dose. TRIAL REGISTRATION: ANZCTR, ACTRN12611000845932 . Registered on 10 August 2011. PMID- 30446001 TI - Footprints of antigen processing boost MHC class II natural ligand predictions. AB - BACKGROUND: Major histocompatibility complex class II (MHC-II) molecules present peptide fragments to T cells for immune recognition. Current predictors for peptide to MHC-II binding are trained on binding affinity data, generated in vitro and therefore lacking information about antigen processing. METHODS: We generate prediction models of peptide to MHC-II binding trained with naturally eluted ligands derived from mass spectrometry in addition to peptide binding affinity data sets. RESULTS: We show that integrated prediction models incorporate identifiable rules of antigen processing. In fact, we observed detectable signals of protease cleavage at defined positions of the ligands. We also hypothesize a role of the length of the terminal ligand protrusions for trimming the peptide to the MHC presented ligand. CONCLUSIONS: The results of integrating binding affinity and eluted ligand data in a combined model demonstrate improved performance for the prediction of MHC-II ligands and T cell epitopes and foreshadow a new generation of improved peptide to MHC-II prediction tools accounting for the plurality of factors that determine natural presentation of antigens. PMID- 30446003 TI - Does a Screening Trial for Spinal Cord Stimulation in Patients with Chronic Pain of Neuropathic Origin have Clinical Utility and Cost-Effectiveness? (TRIAL-STIM Study): study protocol for a randomised controlled trial. AB - BACKGROUND: The TRIAL-STIM Study aims to assess the diagnostic performance, clinical outcomes and cost-effectiveness of a screening trial prior to full implantation of a spinal cord stimulation (SCS) device. METHODS/DESIGN: The TRIAL STIM Study is a superiority, parallel-group, three-centre, randomised controlled trial in patients with chronic neuropathic pain with a nested qualitative study and economic evaluation. The study will take place in three UK centres: South Tees Hospitals NHS Foundation Trust (The James Cook University Hospital); Basildon and Thurrock University Hospitals NHS Foundation Trust; and Leeds Teaching Hospitals NHS Trust. A total of 100 adults undergoing SCS implantation for the treatment of neuropathy will be included. Subjects will be recruited from the outpatient clinics of the three participating sites and randomised to undergo a screening trial prior to SCS implant or an implantation-only strategy in a 1:1 ratio. Allocation will be stratified by centre and minimised on patient age (>= 65 or < 65 years), gender, presence of failed back surgery syndrome (or not) and use of high frequency (HF10TM) (or not). The primary outcome measure is the numerical rating scale (NRS) at 6 months compared between the screening trial and implantation strategy and the implantation-only strategy. Secondary outcome measures will include diagnostic accuracy, the proportion of patients achieving at least 50% and 30% pain relief at 6 months as measured on the NRS, health related quality-of-life (EQ-5D), function (Oswestry Disability Index), patient satisfaction (Patients' Global Impression of Change) and complication rates. A nested qualitative study will be carried out in parallel for a total of 30 of the patients recruited in each centre (10 at each centre) to explore their views of the screening trial, implantation and overall use of the SCS device. The economic evaluation will take the form of a cost-utility analysis. DISCUSSION: The TRIAL STIM Study is a randomised controlled trial with a nested qualitative study and economic evaluation aiming to determine the clinical utility of screening trials of SCS as well as their cost-effectiveness. The nested qualitative study will seek to explore the patient's view of the screening trials, implantation and overall use of SCS. TRIAL REGISTRATION: ISRCTN, ISRCTN60778781 . Registered on 15 August 2017. PMID- 30446005 TI - Correction to: Histone isoform H2A1H promotes attainment of distinct physiological states by altering chromatin dynamics. AB - After publication of this article [1], it was noticed Duane Smoot and Hassan Ashktorab who made and provided the cell line HFE145 were not included in the author list. PMID- 30446004 TI - Lipid damage is the best marker of oxidative injury during the cardiac remodeling process induced by tobacco smoke. AB - BACKGROUND: Oxidative stress is one potential mechanism that explain the direct effects of smoking on cardiac remodeling process. However, no study has compared different myocardial products of macromolecule oxidation after tobacco smoke exposure. Thus, the aim of this study was to investigate the lipid hydroperoxide (LH) levels, protein carbonyl concentrations and DNA damage in cardiac tissue of rats exposed to tobacco smoke. METHODS: Male Wistar rats were divided into two groups: group C (control, n = 14) composed of animals not exposed to cigarette smoke; group ETS (exposed to tobacco smoke, n = 14) composed by animals exposed to cigarette smoke. The animals were exposed to 2 month of ETS and morphological, biochemical and functional analyses were performed. RESULTS: Cardiac cotinine levels were elevated in the ETS group. In addition, the myocyte cross-sectional area was higher in the ETS group. (C = 266.6 +/- 23.2 MUm2 and ETS = 347.5 +/- 15.1 MUm2, p < 0.001). Cardiac LH was higher in the ETS group than in group C (C = 196.4 +/- 51.5 nmol/g and ETS = 331.9 +/- 52.9 nmol/g, p < 0.001). However, there were no between-group differences in cardiac protein carbonyl concentration or DNA damage. CONCLUSIONS: Therefore, our results suggest that, in this model, lipid damage is a good marker of oxidative damage during the cardiac remodeling process induced by 2 months of exposure to tobacco smoke. PMID- 30446006 TI - Transcanalicular laser dacryocystorhinostomy for acquired nasolacrimal duct obstruction: an audit of 104 patients. AB - PURPOSE: External dacryocystorhinostomy (DCR) is considered as the gold standard in the treatment of acquired nasolacrimal duct obstruction. However, many advances have been made towards the development of modern minimally invasive therapies. These new techniques were proven less harmful to the patients' skin and medial palpebral structures with their palpebral-canalicular pump mechanism. Options include endonasal and transcanalicular procedures. Here, we report on our 2-year experience with the surgical technique, results and complications of transcanalicular laser-assisted DCR. METHODS: This is a retrospective study. A total of 104 patients with acquired nasolacrimal duct obstruction underwent transcanalicular laser-assisted DCR combined with bicanalicular silicon intubation. We then analyzed intra-/post-operative complications and subjective and objective success rates. The institutional ethics committee ruled that approval was not necessary. The trial was registered with the German Clinical Trials Register (DRKS00012879). RESULTS: Transcanalicular laser-assisted DCR in combination with bicanalicular silicon intubation could be performed surgically successfully in 101 patients (97%). In three cases (3%) using the superior canalicular approach, positioning of the laser instrument at the anteroinferior rim of the middle turbinate failed. Complications included thermal injury to the canaliculus (one), canalicular infection (two) and silicon tube prolapse (ten). Functional success (resolution of preoperative symptoms) was achieved in 80 cases (77%), functional failure occured in 24 cases with all patients reporting persisting epiphora, 15 reporting failure to irrigate the nasolacrimal duct and 15 requiring secondary external DCR. CONCLUSIONS: Laser-assisted DCR shows promising results with few complications. It seems well suited as a second-step procedure after failed recanalization and before external DCR. PMID- 30446007 TI - STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. AB - BACKGROUND: The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL. METHODS: Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells. RESULTS: Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance. CONCLUSIONS: AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012. PMID- 30446009 TI - Immune checkpoint inhibitor-related acral vasculitis. AB - Commentary on " Ipilimumab induced vasculitis " by Padda A. et al., J Immunother Cancer. 2018;6:12. The authors diagnosed a small vessel vasculitis following treatment with anti-CTLA-4 (ipilimumab) for a resected stage III B/C melanoma. We report a similar case of acral vasculitis occurring with a combination of anti CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) prescribed for the management of a metastatic urothelial bladder cancer. In contrast to Padda A. et al., we observed a significant improvement with oral corticosteroids. PMID- 30446008 TI - CMT3 and SUVH4/KYP silence the exonic Evelknievel retroelement to allow for reconstitution of CMT1 mRNA. AB - BACKGROUND: The Chromomethylase 1 (CMT1) has long been considered a nonessential gene because, in certain Arabidopsis ecotypes, the CMT1 gene is disrupted by the Evelknievel (EK) retroelement, inserted within exon 13, or contains frameshift mutations, resulting in a truncated, non-functional protein. In contrast to other transposable elements, no transcriptional activation of EK was observed under stress conditions (e.g., protoplasting). RESULTS: We wanted to explore the regulatory pathway responsible for EK silencing in the Ler ecotype and its effect on CMT1 transcription. Methylome databases confirmed that EK retroelement is heavily methylated and methylation is extended toward CMT1 downstream region. Strong transcriptional activation of EK accompanied by significant reduction in non-CG methylation was found in cmt3 and kyp2, but not in ddm1 or RdDM mutants. EK activation in cmt3 and kyp2 did not interfere with upstream CMT1 expression but abolish transcription through the EK. We identified, in wild-type Ler, three spliced variants in which the entire EK is spliced out; one variant (25% of splicing incidents) facilitates proper reconstitution of an intact CMT1 mRNA. We could recover very low amount of the full-length CMT1 mRNA from WT Ler and Col, but not from cmt3 mutant. CONCLUSIONS: Our findings highlight CMT3-SUVH4/KYP as the major pathway silencing the intragenic EK via inducing non-CG methylation. Furthermore, retroelement insertion within exons (e.g., CMT1) may not lead to a complete abolishment of the gene product when the element is kept silent. Rather the element can be spliced out to bring about reconstruction of an intact, functional mRNA and possibly retrieval of an active protein. PMID- 30446010 TI - Epigenomic profiling of archived FFPE tissues by enhanced PAT-ChIP (EPAT-ChIP) technology. AB - BACKGROUND: The introduction of pathology tissue-chromatin immunoprecipitation (PAT-ChIP), a technique allowing chromatin immunoprecipitation (ChIP) from formalin-fixed paraffin-embedded (FFPE) tissues, has extended the application of chromatin studies to clinical patient samples. However, extensive crosslinking introduced during routine tissue fixation of clinical specimens may hamper the application of PAT-ChIP to genome-wide studies (PAT-ChIP-Seq) from archived tissue samples. The reduced efficiency in chromatin extraction from over-fixed formalin archival samples is the main hurdle to overcome, especially when low abundant epigenetic marks (e.g., H3K4me3) are investigated. RESULTS: We evaluated different modifications of the original PAT-ChIP protocol to improve chromatin isolation from FFPE tissues. With this aim, we first made extensive usage of a normal human colon specimen fixed at controlled conditions (24 h, 48 h, and 72 h) to mimic the variability of tissue fixation that is most frequently found in archived samples. Different conditions of chromatin extraction were tested applying either diverse sonication protocols or heat-mediated limited reversal of crosslinking (LRC). We found that, if compared with canonical PAT-ChIP protocol, LRC strongly increases chromatin extraction efficiency, especially when 72-h fixed FFPE samples are used. The new procedure, that we named enhanced PAT-ChIP (EPAT-ChIP), was then applied at genome-wide level using an archival sample of invasive breast carcinoma to investigate H3K4me3, a lowly abundant histone modification, and H3K27me3 and H3K27ac, two additional well-known histone marks. CONCLUSIONS: EPAT-ChIP procedure improves the efficiency of chromatin isolation from FFPE samples allowing the study of long time-fixed specimens (72 h), as well as the investigation of low distributed epigenetic marks (e.g., H3K4me3) and the analysis of multiple histone marks from low amounts of starting material. We believe that EPAT-ChIP will facilitate the application of chromatin studies to archived pathology samples, thus contributing to extend the current understanding of cancer epigenomes and enabling the identification of clinically useful tumor biomarkers. PMID- 30446011 TI - A five-DNA methylation signature act as a novel prognostic biomarker in patients with ovarian serous cystadenocarcinoma. AB - BACKGROUND: Ovarian cancer is the most fatal tumor of the female reproductive system and the fifth leading cause of cancer death among women in the USA. The prognosis is poor due to the lack of biomarkers for treatment options. RESULTS: The methylation array data of 551 patients with ovarian serous cystadenocarcinoma (OSC) in The Cancer Genome Atlas (TCGA) database were assessed in this study to explore the methylation biomarkers associated with prognosis and improve the prognosis of patients. These patients were divided into training (first two thirds) and validation datasets (remaining one third). A five-DNA methylation signature was found to be significantly associated with the overall survival of patients with OSC using the Cox regression analysis in the training dataset. The Kaplan-Meier analysis showed that the five-DNA methylation signature could significantly distinguish the high- and low-risk patients in both training and validation sets. The receiver operating characteristic (ROC) analysis further confirmed that the five-DNA methylation signature exhibited high sensitivity and specificity to predict the prognostic survival of patients. Also, the five-DNA methylation signature was not only applicable in patients of different ages, stages, histologic grade, and size of residual tumor after surgery but also more accurate in predicting OSC prognosis compared with known biomarkers. CONCLUSIONS: This five-DNA methylation signature demonstrated the potential of being a novel independent prognostic indicator and served as an important tool for guiding the clinical treatment of OSC to improve outcome prediction and management for patients. Hence, the findings of this study might have potential clinical significance. PMID- 30446012 TI - Limited genetic diversity of N-terminal of merozoite surface protein-1 (MSP-1) in Plasmodium ovale curtisi and P. ovale wallikeri imported from Africa to China. AB - BACKGROUND: Plasmodium merozoite surface protein-1 (MSP-1) is released into the bloodstream during merozoite invasion, and thus represents a crucial malarial vaccine target. Although substantial research effort has been devoted to uncovering the genetic diversity of MSP-1 for P. falciparum and P. vivax, there is minimal information available regarding the genetic profiles and structure of P. ovale. Therefore, the aim of the present study was to determine the extent of genetic variation among two subspecies of P. ovale by characterizing the MSP-1 N terminal sequence at the nucleotide and protein levels. METHODS: N-terminal of MSP-1 gene were amplified from 126 clinical samples collected from imported cases of malaria in migrant workers returning to Jiangsu Province from Africa using a conventional polymerase chain reaction (PCR) assay. The PCR products were then sequenced and analyzed using the GeneDoc, MegAlign, MEGA7 and DnaSP v.6 programs. RESULTS: The average pairwise nucleotide diversities (pi) of P. ovale curtisi and P. ovale wallikeri MSP-1 genes (pomsp1) were 0.01043 and 0.01974, respectively, and the haplotype diversity (Hd) were 0.746 and 0.598, respectively. Most of the nucleotide substitutions detected were non-synonymous, indicating that the genetic variations of pomsp1 were maintained by positive diversifying selection, thereby suggesting their role as a potential target of a protective immune response. Amino acid substitutions of P. ovale curtisi and P. ovale wallikeri MSP 1 could be categorized into five and three unique amino acid variants, respectively. CONCLUSIONS: Low mutational diversity was observed in pomsp1 from the Jiangsu Province imported malaria cases; further studies will be developed such as immunogenicity and functional analysis. PMID- 30446014 TI - Prediction of acute kidney injury in intensive care unit patients. PMID- 30446013 TI - Secretion of tumoricidal human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by recombinant Lactococcus lactis: optimization of in vitro synthesis conditions. AB - BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively eliminates tumor cells. However, the short biological half-life of this molecule limits its potential use in the clinic. Our aim was to construct a recombinant strain of nonpathogenic Lactococcus lactis bacteria as a vector for effective and prolonged human TRAIL production. Herein, we examined the expression and secretion conditions leading to the production of biologically active protein in vitro. RESULTS: The human soluble TRAIL-cDNA (hsTRAIL-cDNA) with optimized codons was designed to fit the codon usage pattern (codon bias) of the L. lactis host. This cDNA construct was synthesized and cloned in lactococcal plasmid secretion vector pNZ8124 under the control of the nisin-induced PnisA promoter. The pNZ8124-hsTRAIL plasmid vector was transformed into the L. lactis NZ9000 host strain cells by electroporation. Secretion of the protein occurred at the neutral pH during induction, with optimized concentration of the inducer and presence of serine proteases inhibitor. Using Western blotting and amino acid sequencing method we found that TRAIL was secreted in two forms, as visualized by the presence of two distinct molecular size bands, both deprived of the usp45 protein, the bacterial signal peptide. By the use of MTS assay we were able to prove that hsTRAIL present in supernatant from L. lactis (hsTRAIL+) broth culture was cytotoxic to human HCT116 colon cancer cells but not to normal human fibroblasts. Flow cytometry analysis revealed TRAIL-induced apoptosis of cancer cells. CONCLUSIONS: We designed recombinant L. lactis bacteria, which efficiently produce biologically active, anti-tumorigenic human TRAIL in vitro. Further studies in tumor-bearing NOD-SCID mice will reveal whether the TRAIL-secreting L. lactis bacteria can be used as a safe carrier of this protein, capable of inducing effective elimination of human colon cancer cells in vivo. PMID- 30446015 TI - Cerebellar large B-cell lymphoma: a case report. AB - BACKGROUND: Primary central nervous system lymphoma is a rare, malignant non Hodgkin lymphoma that can arise in the brain, spinal cord, eye, leptomeninges, or cranial nerves. Primary central nervous system lymphoma is rare, accounting for 2 6% of all primary brain neoplasms and 1-2% of all non-Hodgkin lymphomas, and it usually presents as a solitary lesion. Cerebellar involvement is present in only 9% of cases. We present an unusual case of primary central nervous system lymphoma presenting as multiple lesions in the cerebellum in an immunocompetent host. CASE PRESENTATION: A 71-year-old Caucasian man presented to our hospital with acute onset of dizziness, nausea, vomiting, and gait imbalance. Contrast enhanced computed tomography revealed three intensely enhancing masses in the right cerebellar hemisphere. Whole-body positron emission tomography and computed tomography failed to demonstrate a primary tumor of origin outside the central nervous system. The patient underwent right suboccipital craniotomy with partial resection of the visible tumor from the right cerebellum. Histopathology revealed diffuse large B-cell lymphoma, non-germinal center type. CONCLUSIONS: Primary central nervous system lymphoma is rare, even more so in the cerebellum. However, the overall incidence of primary central nervous system lymphoma is rising in both immunocompromised and immunocompetent patients. The highly aggressive nature of primary central nervous system lymphoma necessitates timely diagnosis and intervention. In this report, we review the available literature for a better understanding of the pathophysiology and management of primary central nervous system lymphoma. To the best of our knowledge, this is the first reported case of a patient with primary central nervous system lymphoma presenting with multiple masses in the cerebellum. PMID- 30446016 TI - Secretory carcinoma: the eastern Canadian experience and literature review. AB - BACKGROUND: Secretory Carcinoma (SC) is a recently described malignancy affecting salivary glands of the head and neck, with a paucity of evidence regarding the natural history, morbidity, and mortality. This study aimed to investigate the current treatment options utilized for SC, as well as its presentation and outcomes. METHODS: This study is a retrospective case series and includes patients diagnosed with SC at four Maritime Canadian institutions. Literature review of patient outcomes following treatment of SC is also included. RESULTS: Thirteen patients were identified. Parotid was the most common subsite (69%), followed by minor salivary gland (23%) and submandibular gland (8%). All patients were S100 positive and had at least one additional positive confirmatory stain, including mammaglobin, CK7, or vimentin. Two patients had N2b disease. All patients were treated with primary surgery, and four were offered adjuvant radiotherapy. There was one instance of locoregional recurrence, and one of metastasis. Three patients displayed perineural invasion on pathology, and one patient displayed lymphovascular invasion. CONCLUSION: Secretory Carcinoma remains understudied regarding its natural history, presentation, and treatment options. This study is the largest single case series in Canada, and highlights the young age and possible aggressiveness of SC. As well, we provide the most comprehensive literature review to date, with a focus on treatment and outcomes for this disease entity. PMID- 30446018 TI - Analytical Eco-Scale for Assessing the Greenness of a Developed Potentiometric Method for Lomefloxacin Hydrochloride Determination in its Different Dosage Forms, Plasma, and Dissolution Medium. AB - Background: Traditional methods for Lomefloxacin hydrochloride (LOM) determination involve pretreatment steps, which extend analysis time and use hazardous chemicals. Objective: The ability to provide a rapid route without sample pretreatment for quantitative determination of compounds via a low-cost instrument is a challenging task. In this work, a simple potentiometric method was developed to determine the antibacterial LOM via in-house fabricated ion selective electrodes. Methods: Different sensors were fabricated using a poly vinyl chloride-based membrane, potassium tetrakis(4-chlorophenyl) borate as a cation exchanger, and 2-Nitrophenyl octyl ether as a plasticizer (sensor 1). To increase the selectivity of sensor 1, a selective molecular recognition component 2-hydroxypropyl-beta-cyclodextrin was used as ionophore (sensor 2). Results: The proposed method was validated according to International Union of Pure and Applied Chemistry recommendations, in which the proposed sensors show a linear dynamic range from 1 * 10-5 to 1 * 10-2 mol/L, with Nernstian slopes of 55.829 and 58.229 mV/decade for sensors 1 and 2, respectively. It was applied to determine LOM in bulk powder, in different dosage forms, and in plasma with no sample pretreatment. Also, the suggested method can be used as a green, in-line bench top real-time analyzer for in-process monitoring of LOM release from its tablets, under U.S. Food and Drug Administration dissolution regulations, with clear discrimination from common excipients. Results obtained by the proposed potentiometric method were compared with those obtained by a reported HPLC method. Conclusions: The proposed method is considered as a perfect alternative to traditional reported methods for LOM determination. PMID- 30446019 TI - An Alanine-Rich Peptide Attenuates Quorum Sensing-Regulated Virulence and Biofilm Formation in Staphylococcus aureus. AB - Background: Alanine-rich proteins/peptides (ARP), with bioactivity of up to 20 amino acid residues, can be observed by the body easily during gastrointestinal digestion. Objective: Populus trichocarpa extract's capability to attenuate quorum sensing-regulated virulence and biofilm formation in Staphylococcus aureus is described. Methods: PT13, an ARP obtained from P. trichocarpa, was tested for its activity against S. aureus using the broth microdilution test; a crystal violet biofilm assay was performed under a scanning electron microscope. The production of various virulence factors was estimated with PT13 treatment. Microarray gene expression profiling of PT13-treated S. aureus was conducted and compared with an untreated control. Exopolysaccharides (EPS) was estimated to observe the PT13 inhibition activity. Results: PT13 was antimicrobial toward S. aureus at different concentrations and showed a similar growth rate in the presence and absence of PT13 at concentrations <=8 MUg/mL. Biofilm production was interrupted even at low concentrations, and biofilm-related genes were down regulated when exposed to PT13. The genes encoding cell adhesion and bacterial attachment protein were the major genes suppressed by PT13. In addition, hemolysins, clumping activity, and EPS production of S. aureus decreased after treatment in a concentration-dependent manner. Conclusions: A long-chain PT13 with effective actions that, even at low concentration levels, not only regulated the gene expression in the producer organism but also blocked the virulence gene expression in this Gram-positive human pathogen is described. Highlights: We identified a PT13 as a potential antivirulence agent that regulated production of bacterial virulence determinants (e.g., toxins, enzymes and biofilm), downwards and it may be a promising anti-virulence agent to be further developed as an anti infective agent. PMID- 30446020 TI - Sample Processing and Preparation Considerations for Solid Cannabis Products. AB - Background: The nascent cannabis industry is often challenged by a lack of guidance, unproven methodologies and conflicting legal challenges. The actual sampling and sample preparation of cannabis can be a difficult endeavor due the economic value, material complexity and heterogeneous nature of a plant based material. Objective: Examine the challenges of cannabis material sampling and sample processing as it relates to other similar materials. Method: In this paper, the complexity of sampling and sample preparation are reviewed for use in the cannabis industry. The mechanisms for sample processing are examined and compared for the best preparation techniques for targeted analytes in cannabis analysis. Results: Cryogenic grinding is one of the best methods for sample processing for the preservation of volatile compounds. Conclusions: Proper sampling techniques and procedures, including the use of standards, ensure homogeneity and improve analysis accuracy. Highlights: Methods of sample processing and preparation for cannabis plant material were examined to ensure homogeneity, accuracy and reproducibility. PMID- 30446021 TI - A Novel Approach of Matching Mass-to-Charge Ratio for Compound Identification in Gas Chromatography-Mass Spectrometry. AB - Background: Gas chromatography-mass spectrometry (GC-MS) is one of the most widely used analytical techniques for analyzing chemical or biological samples in many fields. One of the most important approaches for the identification of compound in GC-MS is to compare an experimental mass spectrum with a compound recorded in a reference spectral library through a spectrum-matching algorithm. Objective: To develop a novel method to speed up compound identification. Method: In this study, a method based on m/z matching is proposed. We selected the highest m/z values and m/z values corresponding to the largest peak intensities of a mass spectrum and stepwise modified the matching threshold (MTh) based on the principle of local optimum in the pre-search process. The performance of the approach is evaluated using the mass spectral library maintained by the National Institute of Standards and Technology as a reference library and repetitive mass spectra as query spectra. Results: Compared with two-step spectral library pre search and "ten peaks," the method based on m/z matching has higher accuracy, smaller number of remaining (missing) spectra, and shorter computational time. Conclusions: Therefore, the method can effectively speed up compound identification. Highlights: A method based on m/z matching is proposed. The accuracy is higher, the number of remaining spectra is less, and the computational time is shorter. PMID- 30446022 TI - Determination of 27 Elements in Animal Feed by Inductively Coupled Plasma-Mass Spectrometry. AB - A method was developed to determine 27 elements (aluminum, arsenic, boron, cadmium, calcium, chromium, cobalt, copper, iron, lead, magnesium, manganese, mercury, molybdenum, nickel, phosphorus, potassium, selenium, sodium, sulfur, vanadium, zinc, antimony, uranium, beryllium, thallium, and thorium) in animal feeds and pet foods using closed vessel microwave digestion and inductively coupled plasma-mass spectrometry. These elements can adversely affect animal health when amounts become excessive or deficient in food. For potentially toxic elements, the target LOQ was determined to be 1/10 the lowest maximum tolerable level (MTL) for the most sensitive animal species. For nutritionally essential elements, the target LOQ was determined to be 1/10 the concentration that would be considered deficient in feed if that level is lower than 1/10 the lowest MTL. The targeted high end of the quantitation range was selected as twice the highest MTL. A single-laboratory validation (SLV) was performed to determine the accuracy and precision of the method, and the results were evaluated with respect to predetermined performance characteristics. The test materials used in the SLV included two National Institute of Standards and Technology certified reference materials, two Association of American Feed Control Officials (AAFCO) check samples, and one in-house previously analyzed feed sample. The concentrations of each element determined were the result of spiked analyte, incurred analyte, or a combination of spiked and incurred analyte. All samples were analyzed seven times on different days at 2 * LOQ and at the midrange concentration. For most data, the results of the SLV met or exceeded the criteria for accuracy and repeatability. For accuracy, K at the midrange level had a mean recovery of 95%, which is just below the low preferred accuracy threshold of 97%. For repeatability, all the 2 * LOQ CVr values were below the preferred values. Be, Cr, Ni, Na, Mn, and S all had midrange CVr values exceeding the preferred values. Be had the highest midrange CVr value of 9.93. Eight AAFCO check samples were also analyzed to determine the method's accuracy and repeatability for elements at the manufacturer's claimed levels. For accuracy, all results had z-scores <1.5. For repeatability, three CVr values from two AAFCO check samples were greater than the preferred limits. PMID- 30446024 TI - Single-Laboratory Validation of a Gas Chromatographic Method of Direct Determination of Volatile Compounds in Spirit Drinks: Need for an Improved Interlaboratory Study. AB - Background: The quality and safety control of an alcoholic drink is mainly the establishment of its chemical content, particularly the quantity of volatile compounds. Objective: A single-laboratory validation of a gas chromatographic method of direct determination of volatile compounds in spirit drinks was conducted. The discussed method applies ethanol, the major volatile component of an alcoholic beverage, as an internal standard. Possible algorithms of method validation based on interlaboratory study were proposed and described. Methods: Seven standard solutions of the following volatile compounds were prepared gravimetrically in 40% (v/v) water-ethanol solution: acetaldehyde, methyl acetate, ethyl acetate, methanol, 2-propanol, 1-propanol, isobutanol, 1-butanol, and isoamylol. Each sample was measured with the proposed method 30 times in repeatability conditions. Results: Flame ionization detector response was linearly correlated with assigned concentrations at a range of 2 to 5000 mg/L of absolute alcohol (AA) with coefficients of determination (R2) more than 0.995 for all analyzed components. Repeatability (RSDr <= 4.5%; RSDr <= 2.0%), reproducibility (RSDR <= 5.0%; RSDR <= 2.0%), and trueness (relative bias <= 2.6%; relative bias <= 1.4%) were obtained for low (10-25 mg/L AA for methanol and 2-10 for other volatiles) and high (25-5000 mg/L AA for methanol and 10-5000 for other volatiles) ranges of concentrations, correspondingly. Conclusions: The method increases the reliability of measurements and eliminates manual procedures of internal standard addition into both calibration standard solutions and spirit drinks. PMID- 30446023 TI - The Rapid Detection of Sage Adulteration Using Fourier Transform Infra-Red (FTIR) Spectroscopy and Chemometrics. AB - Background: Sage, a common term for the various species of the genus Salvia L., is an herb that is mainly used as a seasoning, or for medicinal purposes. Valuable herbs such as sage, are under constant threat from criminals dealing in economically motivated adulteration. Objective: In this study, the development of a rapid screening technique to detect adulteration in sage was developed using FTIR and chemometrics. Method: A range of sage samples were collected, along with possible known adulterants, olive leaves, myrtle leaves, sumac, hazelnut leaves, cistus and phlomis, strawberry tree leaves and sandalwood. The samples were analyzed on the Thermo Nicolet iS5 FTIR with iD7 attenuated total reflectance accessory and diamond crystal. Chemometric techniques were applied to convert this raw spectral data obtained from the instrument into qualitative models. The qualitative chemometric models for adulteration detection were obtained using principal component analysis and orthogonal partial least squares-discriminant analysis following preprocessing of the spectra. Results: The orthogonal partial least squares-discriminant analysis models had a measurement of fit of 0.978 and 0.952 and a measurement of prediction of 0.975 and 0.936 for binary and multiclass models, respectively. The receiver operating curves following external validation had an area under the curve of 1, indicating excellent method performance. Conclusions: The use of FTIR and chemometrics can potentially screen unknown sage samples for adulteration and can be used in the fight against fraud in the herb and spice industry. PMID- 30446025 TI - Authentication, Quality, Health, and Regulation of Spices and Herbs. PMID- 30446026 TI - Comparative Validation Study to Demonstrate the Equivalence of an Alternate Next Day Enrichment Protocol for VIP(r)Gold for Salmonella Method to Culture Methods for the Detection of Salmonella in Selected Foods and Environmental Surfaces. AB - Background: VIP(r)Gold for Salmonella is a lateral flow immunodetection device that was validated by AOAC in 1999 as Official Method of Analysis 999.09. It was improved upon in 2009 by introducing gold colloid as the detection method. Objective: A simple next-day enrichment protocol using modified enterohemorrhagic Escherichia coli media was developed for the VIP Gold for Salmonella to improve the time-to-results and laboratory work flow. Methods: We tested 128 Salmonella strains, representing all serotypes from A to Z and 51 to 66 as well as 50 non Salmonella strains for inclusivity/exclusivity. Performance of the VIP using the new enrichment protocol was compared with the U.S. Department of Agriculture (USDA) Microbiology Laboratory Guidebook reference culture procedure for the detection of Salmonella in ready-to-eat poultry, roast beef, and chicken carcass rinsate. VIP performance was also compared with the U.S. Food and Drug Administration (FDA) Bacteriological Analytical Manual (BAM) for the detection of Salmonella from raw spinach, raw almonds, raw pasta, and environmental surfaces (stainless steel, rubber, and plastic). Results: The VIP detected all 128 of Salmonella strains and none of the 50 non-Salmonella strains. There was no statistically significant difference in the numbers of positive results with VIP Gold for Salmonella protocol compared with appropriate USDA-Food Safety and Inspection Service or FDA-BAM reference methods for any of these matrixes. Conclusions: This new enrichment protocol has met all the requirements to be approved as a Performance Tested MethodSM. Highlights: The new enrichment protocol will improve the time-to-results and allow quicker decisions about the contamination of food products. PMID- 30446027 TI - Development and Validation of an Affordable, Nonperishable Suturing Simulator. PMID- 30446028 TI - Single-Center Experience with Subvesical Bile Ducts (Ducts of Luschka). PMID- 30446029 TI - Infrarenal Infected Aneurysm of Abdominal Aorta Caused by Clostridium Perfringens. PMID- 30446030 TI - Incidence of and Risk Factors for Incisional Hernia after Liver Surgery Performed with a J-Shaped Right Subcostal Incision. PMID- 30446031 TI - Missile Embolism to the Pulmonary Artery. PMID- 30446033 TI - Asymptomatic Metastatic Carcinoid Tumor Discovered by Routine Screening Mammography. PMID- 30446017 TI - Brain death and postmortem organ donation: report of a questionnaire from the CENTER-TBI study. AB - BACKGROUND: We aimed to investigate the extent of the agreement on practices around brain death and postmortem organ donation. METHODS: Investigators from 67 Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study centers completed several questionnaires (response rate: 99%). RESULTS: Regarding practices around brain death, we found agreement on the clinical evaluation (prerequisites and neurological assessment) for brain death determination (BDD) in 100% of the centers. However, ancillary tests were required for BDD in 64% of the centers. BDD for nondonor patients was deemed mandatory in 18% of the centers before withdrawing life-sustaining measures (LSM). Also, practices around postmortem organ donation varied. Organ donation after circulatory arrest was forbidden in 45% of the centers. When withdrawal of LSM was contemplated, in 67% of centers the patients with a ventricular drain in situ had this removed, either sometimes or all of the time. CONCLUSIONS: This study showed both agreement and some regional differences regarding practices around brain death and postmortem organ donation. We hope our results help quantify and understand potential differences, and provide impetus for current dialogs toward further harmonization of practices around brain death and postmortem organ donation. PMID- 30446034 TI - Is Neoadjuvant Radiotherapy Alone a Good Alternative to Neoadjuvant Chemoradiotherapy in Patients with Low Performance Status? PMID- 30446035 TI - Parental Mental Health in Childhood as a Risk Factor for Anxiety and Depression among People Seeking Help for Tinnitus and Hyperacusis. AB - BACKGROUND: Parental mental illness is a risk factor for mental health disorders in the offspring. However, the relationship between parental illness in childhood and mental health disorders in adulthood among patients with tinnitus and/or hyperacusis is not known. PURPOSE: The aim was to explore the relationship between parental mental health in childhood and anxiety and depression for patients experiencing tinnitus and/or hyperacusis. RESEARCH DESIGN: This was a retrospective cross-sectional study with a correlational design. STUDY SAMPLE: Two hundred eighty-seven consecutive patients who attended a Tinnitus and Hyperacusis Therapy Specialist Clinic in the United Kingdom were included. Their average age was 52.5 years. DATA COLLECTION AND ANALYSIS: The association was explored between anxiety and depression measured via the Generalized Anxiety Disorder questionnaire (GAD-7) and the Patient Health questionnaire (PHQ-9) and responses to the question "While you were growing up during the first 18 years of life did your parent(s) have depression or mental illness?" RESULTS: Thirty-nine percent of patients (111/287) responded "yes" to the question about their parents' mental health, which is about double the incidence in the general population. Regression analysis showed that parental mental illness significantly increased the risk of anxiety and depression, with unadjusted odds ratios (ORs) of 2.7 (95% confidence interval [CI]: 1.5-4.9, p = 0.001) for the PHQ-9 and 2.6 (95% CI: 1.4-4.8, p = 0.002) for the GAD-7. However, when the models were adjusted for the effects of age, gender, tinnitus handicap as measured via the Tinnitus Handicap Inventory, hyperacusis handicap as measured via the Hyperacusis questionnaire, uncomfortable loudness levels, GAD-7 scores (for the depression model only), and PHQ-9 scores (for the anxiety model only), parental mental health was only significantly associated with depression, with an OR of 2.7 (95% CI: 1.08-6.7, p = 0.033). CONCLUSIONS: Audiologists offering tinnitus and hyperacusis rehabilitation should screen patients for parental mental illness in childhood, especially for those with comorbid depression, and make onward referral to appropriate mental health services when needed. Future research should analyze the breadth and type of adverse childhood experiences among patients with tinnitus and hyperacusis and their relationship with mental problems and treatment efficacy. PMID- 30446036 TI - A Qualitative Study of the Effects of Hearing Loss and Hearing Aid Use on Music Perception in Performing Musicians. AB - BACKGROUND: Hearing aids (HAs) are important for the rehabilitation of individuals with hearing loss. Although the rehabilitation of speech communication is well understood, less attention has been devoted to understanding hearing-impaired instrumentalists' needs to actively participate in music. Despite efforts to adjust HA settings for music acoustics, there lacks an understanding of instrumentalists' needs and if those HA adjustments satisfy their needs. PURPOSE: The purpose of the current study was to explore the challenges that adult HA-wearing instrumentalists face, which prevent them from listening, responding to, and performing music. RESEARCH DESIGN: A qualitative methodology was employed with the use of semistructured interviews conducted with adult amateur instrumentalists. STUDY SAMPLE: Twelve HA users who were amateur ensemble instrumentalists (playing instruments from the percussion, wind, reed, brass, and string families) and between the ages of 55 and 83 years (seven men and five women) provided data for analysis in this study. Amateur in this context was defined as one who engaged mindfully in pursuit of an activity. DATA COLLECTION AND ANALYSIS: Semistructured interviews were conducted using an open ended interview guide. Interviews were recorded and transcribed verbatim. Transcripts were analyzed using conventional qualitative content analysis. RESULTS: Three categories emerged from the data: (1) participatory needs, (2) effects of HA use, and (3) effects of hearing loss. Participants primarily used HAs to hear the conductor's instructions to meaningfully participate in music rehearsals. Effects of HA use fell within two subcategories: HA music sound quality and use of an HA music program. The effects of hearing loss fell within three subcategories: inability to identify missing information, affected music components, and nonauditory music perception strategies. CONCLUSIONS: Not surprisingly, hearing-impaired instrumentalists face challenges participating in their music activities. However, although participants articulated ways in which HAs and hearing loss affect music perception, which in turn revealed perspectives toward listening using the auditory system and other sensory systems, the primary motivation for their HA use was the need to hear the conductor's directions. These findings suggest that providing hearing-impaired instrumentalists access to musical experience via participation should be prioritized above restoring the perception of musical descriptors. Future research is needed with instrumentalists who no longer listen to or perform music because of hearing loss, so that the relationship between musical auditory deficiencies and participation can be better explored. PMID- 30446037 TI - Preoperative Anesthetic Considerations in the Podiatric Surgical Candidate. AB - There are multiple challenges the podiatric surgeon faces while attempting to treat patients in the perioperative setting. Given the aging and increasingly complex surgical population, preoperative evaluation is of utmost importance to mitigate unnecessary risks and to optimize patient outcomes. This article reviews key preoperative considerations, patient evaluation, and factors affecting selection of anesthetic technique. PMID- 30446038 TI - Perioperative Cardiac Considerations in the Surgical Patient. AB - The ability to identify and guide evaluation of the patient with cardiac disease represents a necessary skill for success in surgery of the foot and ankle. Common risk factors, such as diabetes and peripheral arterial disease, are encountered in podiatric practice. Recognition of patients at risk for cardiac disease and a predilection for sustaining a major adverse cardiac event perioperatively advocates for preoperative cardiology consultation. Identification of risk factors, assessment of functional capacity, and appropriate work-up mitigate any untoward cardiac events surrounding surgery. This optimization results from appropriate medical and interventional treatment plans directed at minimizing or eliminating identified risks factors. PMID- 30446039 TI - Perioperative Management of the Rheumatoid Patient. AB - Rheumatoid arthritis is a complex disease state with multiple associated comorbidities. Perioperative evaluation of the rheumatoid patient from a multidisciplinary approach is necessary to achieve favorable outcomes. A complete history and physical, laboratory, cervical, cardiovascular, pulmonary, and medication assessment before surgery should be performed. Educating the patient on potential complications, such as wound dehiscence, infection, and venous thromboembolism, as well as general postoperative expectations, is essential when evaluating the rheumatoid patient for surgery. PMID- 30446040 TI - Perioperative Understanding of Geriatric Patients. AB - Surgical treatment of the elderly can be a very difficult and complex endeavor. Appropriate and thorough evaluation of this group of patients is essential to identify surgical candidates who may be at increased risk for developing age related problems, such as cognitive impairment or postoperative delirium. Involvement of family members and ancillary caregivers is ideal. In order to optimize surgical results, communication of goals of surgery and expectations of patients in order to achieve these goals is paramount. Physical therapy assessment of the elderly will give input on patients' capacity to perform needed changes in ambulatory status after surgery. PMID- 30446041 TI - Obesity-Related Foot Pain: Diagnosis and Surgical Planning. AB - Obese patients are at higher risk for surgical complications and consist of a large portion of podiatric patients. Obese patients are additionally at increased risk of developing specific podiatric conditions, and it is important to be able to identify and appropriately treat these conditions accordingly. Initially, conservative treatment is adequate for a variety of pathologic conditions related to obesity. Occasionally surgical intervention is warranted depending on the severity and lack of response to conservative measures. Arthrodesis-type procedures are often preferable and may be necessary, as opposed to periarticular osteotomy, in obese patients even if the deformity is flexible. PMID- 30446042 TI - Postoperative Convalescence. AB - Foot and ankle surgery can impose significant hardship on a patient when carrying out their essential activities of daily living including mobility, sourcing and preparing food, as well as maintaining personal hygiene. Pre-operative planning between the surgeon, patient and caregivers can circumvent most of the challenges imposed by the post-operative restrictions of foot and ankle surgery. Depending on the weight bearing status of the operated extremity, a wide array of durable medical equipment devices are available to provide mobility and safety for the patient. Various devices are also available to protect the patient and the operative site during bathing. Pre-operative gait training can be valuable in selecting the most appropriate mobility aid for the patient, assuring safe ambulation while keeping the operated extremity protected. PMID- 30446043 TI - Prevention of Deep Venous Thromboembolism in Foot and Ankle Surgery. AB - Although rare, deep vein thrombosis (DVT) and pulmonary embolism remain a concern for foot and ankle surgeons. Most prophylactic measures against DVT formation are synthesized from orthopedic hip and knee data, and therefore the routine use of these recommendations may place patients at risk for complications associated with unnecessary prophylaxis. In this article we review and present the most current literature specific to venous thromboembolism (VTE) in foot and ankle surgery. It is clear that, given our current literature, a case-by-case approach for VTE prophylaxis should be used following foot and ankle surgery. PMID- 30446044 TI - Prevention of Infection in Foot and Ankle Surgery. AB - The literature for prevention of surgical infection related primarily to foot and ankle surgery is sparse, with most attention on total joint replacement and abdominal surgery. Attention should be paid to preoperative, intraoperative, and postoperative elements, which can have an effect on the development of postoperative infection. Although antibiotic prophylaxis typically is discussed in isolation, inclusion of this step into the process enhances the overall evaluation of surgery with respect to infection. This evolution provides for better patient outcomes and decreases the likelihood of an infection incurred after foot and ankle surgery. PMID- 30446045 TI - Periprocedural Concerns in the Patient with Renal Disease. AB - Treating patients with kidney disease can be both a difficult and a complex process. Understanding how to care for patients who have kidney disease is essential for lowering perioperative as well as periprocedural morbidity and mortality. The primary aim in renal evaluation and care is to control and mitigate factors that may result in acute kidney injury (AKI) and/or cause further decline in renal function. It is essential for the foot and ankle specialist to recognize patients who are predisposed to developing or already have impairment of renal function. PMID- 30446046 TI - Evaluation and Perioperative Management of the Diabetic Patient. AB - Diabetes mellitus is a devastating disease that has reached epidemic proportions. The surgical patient with diabetes is at increased risk for developing complications when compared with patients without diabetes. A comprehensive preoperative work-up must be performed, including ancillary studies, with optimization of the patient's glucose levels during the perioperative period to decrease the chance of developing surgical complications. A multispecialty team approach for the care of patients with diabetes should be used to produce successful surgical outcomes. PMID- 30446047 TI - Perioperative Considerations in the Surgical Patient. PMID- 30446048 TI - Perioperative Considerations in the Surgical Patient. PMID- 30446049 TI - The Evolution of Steroid-liganded Nuclear Receptors. PMID- 30446050 TI - Diagnostic Decision-Making in the Emergency Department. AB - Emergency medicine requires diagnosing unfamiliar patients with undifferentiated acute presentations. This requires hypothesis generation and questioning, examination, and testing. Balancing patient load, care across the severity spectrum, and frequent interruptions create time pressures that predispose humans to fast thinking or cognitive shortcuts, including cognitive biases. Diagnostic error is the failure to establish an accurate and timely explanation of the problem or communicate that to the patient, often contributing to physical, emotional, or financial harm. Methods for monitoring diagnostic error in the emergency department are needed to establish frequency and serve as a foundation for future interventions. PMID- 30446051 TI - Recognition, Diagnostics, and Management of Pediatric Severe Sepsis and Septic Shock in the Emergency Department. AB - Several new studies have emerged in recent years that have attempted to aid emergency department providers in recognizing and treating pediatric patients with severe sepsis and septic shock. National guidelines and supporting literature are unanimous in recommendations that early recognition and timely therapeutics are necessary for improved survival and decreased morbidity. The literature is less concrete in defining how emerging advances in the field can aid in time-sensitive care of these patients. This article summarizes the recent literature as it pertains to the initial presentation of severe sepsis and septic shock in the pediatric patient within the emergency department. PMID- 30446052 TI - Critical Care in the Pediatric Emergency Department. AB - In caring for critically ill children, recognition and management often begins in the pediatric emergency department. A seamless transition in care is needed to ensure appropriate care to the sickest of children. This review covers the management of critically ill children in the pediatric emergency department beyond the initial stabilization for conditions such as acute respiratory failure and pediatric acute respiratory distress syndrome, traumatic brain injury, status epilepticus, congenital heart disease, and metabolic emergencies. PMID- 30446053 TI - Child Abuse and Conditions That Mimic It. AB - One percent to 2% of children in the United States are confirmed victims of child abuse, with many more likely affected. It can be difficult to diagnose, with often misleading medical histories, but acute care providers should be aware of its presenting warning signs and how to evaluate and document suspicious physical findings. Young children who cannot disclose are most vulnerable to forms of abuse with high morbidity and mortality, so it is important to keep it in the differential diagnosis and to be aware of and know how to rule out medical conditions that mimic abuse. PMID- 30446054 TI - Recent Advances in Pediatric Concussion and Mild Traumatic Brain Injury. AB - Concussions after a head injury among children continues to be a substantial public health concern. An increasing number of concussions are being managed initially by primary care physicians. The diagnosis of concussion remains a clinical diagnosis despite the availability of ancillary tests such as computerized neuropsychological testing, advanced imaging, and blood biomarkers. Clinically, overlooking other injuries and comorbidities may lead to prolonged recovery for the patient. Addressing concussions in a multidisciplinary approach may help in reducing recovery time for patients. Retirement from sport in the pediatric population remains a controversial issue lacking evidenced-based studies. PMID- 30446055 TI - Management of Adult Patients in the Pediatric Emergency Department. AB - Adult patients often present to the pediatric emergency department (ED) for treatment of a wide variety of diseases. However, pediatric emergency medicine physicians are primarily trained to provide specialized care for children. Studies have shown that the number of adult patients presenting to pediatric EDs has increased significantly since the introduction of the Emergency Medicine Transfer and Active Labor Act in 1986. This article discusses the management of common adult complaints presenting to the pediatric ED. The focus is on stabilization in the pediatric ED and safe transfer to a more appropriate facility. PMID- 30446056 TI - Indications and Interpretation of Common Laboratory Assays in the Emergency Department. AB - Laboratory assays are commonly used to help clinicians more accurately gauge the risk a child has for a certain condition. This article reviews commonly obtained laboratory tests (complete blood cell counts, metabolic panels, blood gases, and urine assays) and discusses the data supporting obtaining these tests and reasons for spuriously positive or negative results. PMID- 30446057 TI - Pediatric Disaster Preparedness. AB - Children can be victims of mass casualty or illness, but their needs, with respect to their care and recovery are substantially different from adults. Emergency or urgent care physicians must be prepared to evaluate and manage child victims presenting to their facility in numbers or acuity that could significantly overwhelm normal operations. This article presents the general approach to pediatric disaster preparation in the United States, the expectations of emergency department providers, and different methods of disaster triage, and introduces the most likely types of mass illness (some of which are bioweapons or chemical agents) and their management. PMID- 30446058 TI - Advances in Medical Education and Implications for the Pediatric Emergency Department. AB - The learning environment of the pediatric emergency department is composed of many layers that provide opportunity for intervention to improve the education of residents and medical students. Creating an intentional plan of targeted interventions at the levels of learner, teacher, and department can create a culture where education is highly regarded. This article briefly defines the learning environment and explores strategies for improving clinical teaching at these various levels through improved teacher-learner relationships, entrustment, and the implementation of teaching strategies that can be easily incorporated into the busy and time-stretched work of the pediatric emergency department. PMID- 30446059 TI - Recent Advances in Technology and Its Applications to Pediatric Emergency Care. AB - Advances in technology are continuously transforming medical care, including pediatric emergency medicine. The increasing adoption of point-of-care ultrasound examination can improve timely diagnoses without radiation and aids the performance of common procedures. The recent dramatic increase in electronic health record adoption offers an opportunity for enhanced clinical decision making support. Simulation training and advances in technologies can provide continued proficiency training despite decreasing opportunities for pediatric procedures and cardiorespiratory resuscitation performance. This article reviews these and other recent advances in technology that have had the greatest impact on the current practice of pediatric emergency medicine. PMID- 30446060 TI - The Impact of the Evolving Health Care System on Pediatric Emergency Care. AB - This article discusses the implications of health care reform on the pediatric emergency department (ED). The author briefly discusses the health care costs and outcomes in the United States in comparison to other developed nations. The article discusses the impact of the Affordable Care Act and insurance expansion on the pediatric ED. Then the article addresses the impacts of the growing patient financial responsibility on ED use. There will be a discussion of the development of pediatric accountable care organizations and how payment mechanisms are evolving, and the challenges the pediatric ED may face in these new payment strategies. PMID- 30446061 TI - Pediatric Urgent Care-New and Evolving Paradigms of Acute Care. AB - Parents of pediatric patients seek appropriate high-quality care in a timely, cost-effective, and convenient manner. Pediatric urgent care offers a new and evolving delivery model that serves a growing demand by complementing services provided by the medical home and by pediatric emergency departments. Pediatric urgent care services are used by both nonprofit and for-profit sectors and include hospital and satellite clinics, free-standing clinics, retail-based clinics, and telemedicine services. The clinical scope is variable and there are distinct and unique operational considerations. Training models are evolving and further research is warranted. PMID- 30446062 TI - Quality Improvement and Safety in Pediatric Emergency Medicine. AB - Pediatric emergency medicine quality work continues to focus on the National Academies of Sciences, Engineering, and Medicine's 6 domains of quality, with a need for specific emphasis on equity and patient centeredness. Adopting the principles of high-reliability organizations, pediatric emergency departments should become increasing transparent with benchmarking and collaboration across institutions in order to develop an infrastructure for quality and safety to improve the care of pediatric patients in the emergency department. PMID- 30446063 TI - Quality Improvement Methodologies: Principles and Applications in the Pediatric Emergency Department. AB - The origins of quality improvement in health care trace back to industry. Lessons learned from the "flow production" system of the Ford Model-T assembly line in Michigan and the Toyota Production System led to direct applications of Lean and Six Sigma to improve health care systems. Emergency medicine is well suited as a testing and proving ground for quality improvement methodologies because of high patient volume and rapid turnover. This article reviews the history of quality improvement in health care, describes Lean principles in detail, and provides illustrative examples of applications of Lean and quality improvement methodologies in the pediatric emergency department. PMID- 30446064 TI - The Changing Role of Emergency Medicine. PMID- 30446065 TI - Pediatric Emergency Medicine. PMID- 30446066 TI - Editorial-science and justice 58(6). PMID- 30446067 TI - The effect of mark enhancement techniques on the presumptive and confirmatory tests for blood. AB - An investigation into the effects of physical and chemical enhancement on subsequent presumptive and confirmatory tests for human blood is presented. Human blood was deposited onto porous (white 80 gsm paper and brown envelope) and non porous (tile and linoleum) substrates in a depletion series (30 depletions on non porous and 20 on porous) and subjected to three ageing periods; 1, 7 and 28 days. A number of enhancement techniques were tested [fluorescence, black magnetic powder (BMP), iron-oxide black powder suspension (PS), cyanoacrylate (CA) fuming, acid violet 17 (AV17), acid yellow 7 (AY7), ninhydrin, DFO and Bluestar Forensic Magnum (BFM) luminol] to evaluate their potential effects on subsequent presumptive and confirmatory tests. AV17 and Bluestar provided the best enhancement and fully enhanced all depletions in the series. The sensitivity of the Kastle-Meyer (KM) (presumptive), Takayama and RSID-Blood tests (confirmatory) was initially investigated to determine the range of detectable depletions. The KM test detected all depletions, whereas the Takayama test detected up to depletion 6 and RSID-Blood detected up to depletion 20 (paper), 10 (envelope), 15 (tile) and 9 (lino). The abilities of these tests to detect blood after enhancement were then observed. A number of techniques resulted in little to no effect on any of the blood tests, whereas adverse effects were observed for others. Ninhydrin and CA fuming caused weak but instantaneous positive KM results whereas methanol-based AV17 and AY7 delayed the reaction by as much as 1 min. The Takayama test was not very sensitive, therefore, its performance was easily affected by enhancement and negative results were often observed. RSID-Blood tests were largely unaffected by chemical enhancement although a drop in positive results was observed for some of the techniques when compared to positive controls. Using a standard procedure for DNA extraction, all the tested blood samples (before and after enhancement) gave a detectable quantity of DNA and were successfully profiled. Out of the 45 samples processed for DNA profiling, 41 gave full profiles, while the remaining showed allele drop out in one or two loci. PMID- 30446068 TI - Investigation of infinite focus microscopy for the determination of the association of blood with fingermarks. AB - The determination of the type of deposition mechanism of blood within fingermarks at the scene of violent crimes is of great importance for the reconstruction of the bloodshed dynamics. However, to date, evaluation still relies on the subjective visual examination of experts. Practitioners encounter three types of scenarios in which blood may be found in fingermarks and they refer to the following three deposition mechanisms: (i) blood marks, originating from a bloodied fingertip; (ii) marks in blood, originating from a clean fingertip contacting a blood contaminated surface; (iii) coincidental deposition mechanisms, originating from a clean fingertip contacting a clean surface, leaving a latent fingermark, and subsequent contamination with blood. The authors hypothesised that, due to differences in distribution of blood in the furrows and on the ridges, the height of blood depositions on the ridges and furrows (and their relative proportions), will differ significantly across the three depositions mechanisms. A second hypothesis was made that the differences would be significant and consistent enough to exploit their measurement as a quantitative and objective way to differentiate the deposition mechanisms. In recent years, infinite focus microscopy (IFM) has been developed, allowing for the computational generation of a 3D image of the topology of a sample via acquisition of images on multiple focal planes. On these bases, it was finally hypothesised that the application of this technique would allow the distinction of deposition mechanisms (i) to (iii). A set of preliminary experiments were designed to test whether IFM was "fit for purpose" and, subsequently, to test if any of the three deposition mechanisms scenarios could be differentiated. Though IFM enabled the analysis of tape lifted samples with some success, for samples produced and analysed directly on the surface of deposition, the results show that the measurements from any scenario will be highly dependent on the original surface of deposition (both in terms of its nature and of the variable exposure to environment); as crime scenes exhibit a wide range of possible relevant surfaces of deposition, the technique showed to not have the desired wide appeal for inclusion into a standardised set of protocols within a routine crime scene workflow. PMID- 30446069 TI - Exposing latent fingermarks on problematic metal surfaces using time of flight secondary ion mass spectroscopy. AB - Fingermarks are a key form of physical evidence for identifying persons of interest and linking them to the scene of a crime. Visualising latent (hidden) fingermarks can be difficult and the correct choice of techniques is essential to develop and preserve any fingermarks or other (e.g. DNA) evidence that might be present. Metal surfaces (stainless steel in particular) have proven to be challenging substrates from which to reliably obtain fingermarks. This is a great cause for concern among police forces around the globe as many of the firearms, knives and other metal weapons used in violent crime are potentially valuable sources of fingermark evidence. In this study, a highly sensitive and non destructive surface science technique called time of flight secondary ion mass spectroscopy (ToF-SIMS) was used to image fingermarks on metal surfaces. This technique was compared to a conventional superglue based fuming technique that was accompanied by a series of contrast enhancing dyes (basic yellow 40 (BY40), crystal violet (CV) and sudan black (SB)) on three different metal surfaces. The conventional techniques showed little to no evidence of fingermarks being present on the metal surfaces after a few days. However, ToF-SIMS revealed fingermarks on the same and similar substrates with an exceptional level of detail. The ToF-SIMS images demonstrated clear ridge definition as well as detail about sweat pore position and shape. All structures were found to persist for over 26 days after deposition when the samples were stored under ambient conditions. PMID- 30446070 TI - Study of the adhesion of explosive residues to the finger and transfer to clothing and luggage. AB - It is important to understand the extent of transfer of explosive particles to different surfaces in order to better evaluate potential cross-contamination by explosives in crowded security controls such as those at airports. This work investigated the transfer of nine explosive residues (ANFO, dynamite, black powder, TNT, HMTD, PETN, NH4NO3, KNO3, NaClO3) through fingerprints from one surface to another. First, the extent of adhesion of explosive residues from different surfaces to the bare finger, nitrile and latex gloves was studied. Then, the transfer of explosive residues from one surface to another through fingerprints was investigated. Cotton fabric (hereinafter referred to as cotton) as clothing material and polycarbonate plastic (hereinafter referred to as polycarbonate) as luggage material were chosen for the experiments. These surfaces containing explosive particles were imaged using a reflex camera before and after the particles were transferred. Afterwards the images were processed in MATLAB where pixels corresponding to explosive residues were quantified. Results demonstrated that transfer of explosive residues frequently occurred with certain differences among materials. Generally, the amount of explosive particles adhered to the finger decreased in the following order: skin>latex>nitrile, while the transfer of particles from the finger to another surface was the opposite. The adhesion of explosive residues from polycarbonate to the finger was found to be better compared to cotton, while the amount of particles transferred to cotton was higher. PMID- 30446071 TI - A forensic visual aid: Traces versus knowledge. AB - In this paper, I introduce the Forensic Field Map (FFM) that provides a two dimensional view on the forensic field. This field is by definition very broad, encompassing a wide range of scientific areas and activities. The forensic work that supports solving criminal cases ranges from recognizing and preserving traces at crime scenes to explaining forensic results as expert witness in court. This goes hand in hand with the development of scientifically based methods and tooling as well as legal, forensic and laboratory procedures. Although the FFM came into being while developing a (visual) framework for digital forensic investigations, the framework turned out to be generically applicable to other forensic disciplines. PMID- 30446072 TI - "I couldn't find it your honour, it mustn't be there!" - Tool errors, tool limitations and user error in digital forensics. AB - The field of digital forensics maintains significant reliance on the software it uses to acquire and investigate forms of digital evidence. Without these tools, analysis of digital devices would often not be possible. Despite such levels of reliance, techniques for validating digital forensic software are sparse and research is limited in both volume and depth. As practitioners pursue the goal of producing robust evidence, they face the onerous task of both ensuring the accuracy of their tools and, their effective use. Whilst tool errors provide one issue, establishing a tool's limitations also provides an investigatory challenge leading the potential for practitioner user-error and ultimately a grey area of accountability. This article debates the problems surrounding digital forensic tool usage, evidential reliability and validation. PMID- 30446073 TI - Stature estimation from tibia percutaneous length: New equations derived from a Mediterranean population. AB - Stature is a fundamental anthropometric character to trace the biological profile of a person. In some cases, when dismembered or mutilated bodies are discovered in a forensic context, it is essential to estimate stature from single districts of the body. Nevertheless, to date and worldwide, there are only few population specific studies on stature estimation from leg length and none of them concerns modern populations in southern Europe. We attempted to fill this gap, focusing on the estimation of stature from the length of the tibia in a Mediterranean population (Italians). We carried out the current study on a sample of 374 Italian university students of both sexes (age range: 19.9-34.4). Both, actual stature and percutaneous length of tibia were measured and new equations were developed for stature estimation. We tested separate regression equations for each sex, as well as an equation for remains, whose sex is unknown. To assess their reliability, the equations were tested on a holdout sample of 30 individuals from the same population. Moreover, results of new specific linear regression equations were compared to others from the literature. We demonstrated that the newly proposed formulae (for males and combined sexes) and the ones by Olivier (for females) provided the most reliable estimations of stature for southern Europeans. PMID- 30446074 TI - Isolation and characterisation of a novel sildenafil analogue adulterant, desmethylpiperazinyl propoxysildenafil, in a dietary supplement. AB - A new sildenafil analogue was detected during routine screening of dietary supplements suspected to be adulterated with an erectile dysfunction drug(s) using HPLC-DAD. The UV spectrum of this compound was highly similar to that of sildenafil and almost identical to that of desmethylpiperazinyl sildenafil. The analogue was purified by using semi-preparative HPLC and structurally elucidated by performing mass spectrometric and NMR spectroscopic experiments. The spectral data revealed that this sildenafil analogue bears an n-propoxy group instead of an ethoxy group and possesses no methylpiperazinyl moiety. The isolated compound, structure of which was further confirmed by spectral comparison with synthetic one, was thus named as desmethylpiperazinyl propoxysildenafil. PMID- 30446075 TI - Forensic DNA retention: Public perspective studies in the United Kingdom and around the world. AB - This review analysed public perspective studies on forensic DNA retention in the United Kingdom and around the world. The studies generally show strong public support for the long-term or indefinite retention of DNA from convicts and suspects. There is considerable support for the retention of DNA from all or some arrestees and potentially the entire population. This was predicated upon the belief that forensic DNA databases have crime-solving abilities, which the public rate highly. In the UK, it was found that the current Protection of Freedoms Act 2012 regime is broadly representative of the recommendations of the surveyed British public. Nevertheless, the studies highlighted a gap in forensic DNA education among the public, suggesting that public views may not be well informed. Overall, there was clear evidence of privacy concerns and the potential misuse of DNA records among the public, with a significant number opposing the retention of DNA from the innocent. It was found that most of the studies were qualitative or non-representative of the relevant population, limiting the generalisation of the results. There was also limited studies among a representative sample of primary stakeholders who are well-informed or directly exposed to the benefits, challenges and risks associated with DNA retention. A research into stakeholders rating of different forensic DNA retention regimes is therefore highly recommended. This is important because the studies suggest divergent views among criminal justice professionals and other members of the public, with the former expressing expansive views and the latter expressing restrictive views. The primary stakeholder's survey will help establish whether the relevant safeguards have been put in place to protect both public security and individual interests. PMID- 30446076 TI - Better science for better justice: A proposal for joint experts. PMID- 30446078 TI - The one hundredth and tenth anniversary. PMID- 30446077 TI - From unknown to known: Identification of the remains at the mausoleum of fosse Ardeatine. AB - During the Second World War, on 24th March 1944, 335 Italians were massacred near Rome by the occupying forces of Nazi Germany. Four months later forensic examination led to the identification of 323 out of 335 victims. After approximately 60 years, the identification of the remaining unidentified twelve victims began with anthropological and genetic analysis carried out by a team of Italian forensic experts. Anthropological analysis was performed in field in order to confirm the sex of each victim and verify the presence of only one individual in each grave for a correct sampling. Selected bone fragments for each individual were then collected and transferred to the laboratory for genetic analysis. Although the anthropological ante mortem information was limited, morphological and metrical data was collected for a possible future identification of the victims. Subsequently, the typing of autosomal loci, Y-STR and mtDNA D-loop region of all bone and available reference samples was conducted. LR and cumulative LRs obtained from autosomal STR and Y-STR results confirmed the alleged relationship between three victims and their relatives with values over 104 (one sample) and 106 (two samples). Therefore, the genetic analysis offered the families the possibility of replacing the number of the grave with the name of the victim. PMID- 30446079 TI - President Message. PMID- 30446080 TI - Drug transport-based therapeutic resistance in breast cancer liver metastases. PMID- 30446082 TI - Retraction to "A Fluorescent molecularly-imprinted polymer gate with temperature and pH as inputs for detection of alpha-fetoprotein", [Biosensors and Bioelectronics, 78 (2016) 454-463]. PMID- 30446083 TI - Retraction notice to "Size-specific imprinted polymer embedded carbon nanodots modified magnetic nanoparticle for specific recognition of titanium nanoparticle: The round versus round", [Biosensors and Bioelectronics, 86 (2016) 818-826]. PMID- 30446084 TI - Development of cellulose based aerogel utilizing waste denim-A Morphology study. AB - Cellulose aerogels with orientated micron-sized pore structure were obtained from denim waste utilizing ionic liquid solvents through dissolution, regeneration and drying. The pore structure of denim-derived aerogels was comprised of a mixture of micron-sized vertically aligned pores and a nanoporous fibrous network. The size and distribution of vertically aligned pores and the nanopores were influenced by the choice of ionic liquid solvent, amount of denim used and drying method employed. A detailed study on the morphology of the cellulose aerogels produced from waste denim is provided. PMID- 30446085 TI - Hydrogel as an alternative structure for food packaging systems. AB - Hydrogels are three-dimensional, hydrophilic networks, comprising polymeric chains linked through physical or chemical bonds. In the area of food, hydrogels have great potential to be used in food packaging systems or as carriers of bioactive components. This paper reviews the nature of hydrogels, their 3D network conformation, their functional properties, and their potential applications in food packaging systems. Regarding their potential food packaging applications, hydrogels can present a conformation which allows their use as part of a packaging system to control the humidity generated by food products with high water content. Moreover, the incorporation of nanoparticles into hydrogels may grant them antimicrobial activity. Finally, although the current research in this field is still limited, the results obtained so far are promising for innovative and potential applications in the food field, which also include their integration into intelligent food packaging systems and their direct incorporation into food matrices as a flavor carrier system. PMID- 30446086 TI - Low-energy nano-emulsification approach as a simple strategy to prepare positively charged ethylcellulose nanoparticles. AB - Positively charged ethylcelulose nanoparticles have been obtained from alkylamidoammonium/Span 80 based nano-emulsion templates. Oil-in-water polymeric nano-emulsions form in a broad range of oil-to-surfactant ratios and water contents above 75 wt% by a low-energy method at 25 degrees C. Nano-emulsions with a water content of 90 wt% showed droplet sizes typically below 300 nm and high positive zeta potential values (~55 mV). If oleylamine is added to the system, smaller droplet sizes and higher zeta potential values (~66 mV) are obtained, but the stability of the nano-emulsions decreases. Although these nano emulsions are destabilized by creaming, the period of stability is large enough to allow nanoparticle preparation by solvent evaporation. Polymeric nanoparticles obtained show a globular core-shell-like morphology, with mean diameters of around 250 nm. The surface charge of the nanoparticles is similar to that of the nano-emulsion template and remains positive after 24 h dialysis, suggesting slow desorption kinetics of the alkylamidoammonium from the nanoparticle surface. These results indicate that the proposed nano-emulsion approach is a good strategy for the preparation of positively charged nanoparticles from nonionic ethylcellulose polymers. PMID- 30446087 TI - Controlled synthesis of sodium alginate electrospun nanofiber membranes for multi occasion adsorption and separation of methylene blue. AB - Herein, the three kinds of water-insoluble alginate-based nanofiber membranes were prepared by electrospinning and followed with crosslinking by calcium chloride (CaCl2), glutaraldehyde vapor (GA), and trifluoroacetic acid (TFA) crosslinking, respectively. All the sodium alginate(SA) nanofiber membranes present excellent integrated adsorption performance toward methylene blue (MB). Among these, CaCl2 crosslinked SA membranes exhibit the maximum actual adsorption capacity of 2230 mg/g and shortest adsorption equilibrium time of 50 min to date. On the basis of the selective adsorption of SA, the nanofiber membranes can separate MB/ methyl orange (MO) mixture solution and maintain high separation efficiency even after five cycles. In addition, respective applicable condition for differentially crosslinked SA nanofiber membranes was evaluated. The TFA crosslinked membranes have the least reduction in the adsorption capacity in acidic environment and GA crosslinked membranes adsorb better in alkaline environment. For seawater environment, GA crosslinked membranes show obvious adsorption performance than other crosslinked membranes. PMID- 30446088 TI - Comparative study of hemicelluloses from Hybrid Pennisetum via a green and clean integrated process. AB - In this study, a green and clean integrated process based on microwave-assisted hydrothermal pretreatment (MHTP) and subsequent alkali post-treatment was performed to isolate and characterize water- and alkali-soluble hemicelluloses (SHs and AHs) from Hybrid Pennisetum (HP) as well as to improve the enzymatic digestibility of HP. Meanwhile, part of hemicelluloses was degraded into the value-added xylo-oligosaccharides (XOS) during the MHTP process, which would be applied to the food and pharmaceuticals industries. State-of-the-art analytical techniques (e.g., HPLC, HPAEC, GPC, and 2D-HSQC) were used to investigate the main component streams (SHs, AHs, XOS, and glucose). Results showed that the structural characteristic of SHs and AHs was mainly composed of beta-(1->4) linked xylans. Additionally, the enzymatic digestibility of the cellulose-rich substrate (A190(10)) was 92.8%, which was 3.4 times higher than that of raw material (27.4%). In short, the proposed integrated process was considered as a promising biorefinery strategy for both hemicellulose-based products and bioethanol. PMID- 30446089 TI - Macromolecular characteristics and fine structure of amylomaltase-treated cassava starch. AB - This work investigates the macromolecular structure of native and amylomaltase (AM) treated cassava starch at various reaction times. AM-treated starches showed lower amylose content compared to their parental starch. Long chain proportions (DP 25-80) increased with reaction time up to 4 h and then slightly decreased at 24 h. Macromolecular and fine structure of AM-treated starches for 5 min (AM5min) and 4 h (AM4 h) were characterized more deeply by using HPSEC-MALLS and H1 NMR combined with beta-amylolysis and MALDI-TOF-MS. Molar mass and dispersity of both AM-treated starches were lowered. Nevertheless, AM5min had longer external chains whereas AM4 h exhibited a larger and denser macromolecular core. A cyclo structure with DP 8 was found in both AM-treated starches; however, AM4 h contained cyclo-structures with various sizes (DP 8-32). Finally, by controlling reaction time and substrate constituents, which are important factors affecting the AM action modes, AM-treated starch with various structural features can be obtained. PMID- 30446090 TI - Recycling of Cr (VI) from weak alkaline aqueous media using a chitosan/ triethanolamine/Cu (II) composite adsorbent. AB - A Chitosan/triethanolamine/Cu (II) (CTS/TEA/Cu (II)) composite adsorbent was prepared and applied to recycle Cr (VI) from aqueous media in alkaline conditions. To investigate the adsorption behavior, the influence of pH was evaluated via batch experiments, and the prepared adsorbent was characterized by FT-IR, SEM, XRD, and Zeta potential. This adsorbent exhibited high adsorption capacity for Cr (VI) in a wide pH range (especially above 7), suggesting a possible way to separate Cr (VI) from other metal cations by adjusting the pH value prior to adsorption. Adsorption kinetic and thermodynamic experiments were conducted to explore the adsorption mechanism. Regeneration studies showed that the adsorbent can be reused for five adsorption-desorption cycles without substantial loss of adsorption capacity. Overall, the CTS/TEA/Cu (II) adsorbent exhibits high potential for recyclingCr (VI) from wastewater. PMID- 30446091 TI - Production of hydroxyapatite-bacterial nanocellulose scaffold with assist of cellulose nanocrystals. AB - Bacterial nanocellulose/hydroxyapatite/cellulose nanocrystal (BHC) composites were synthesized via in-situ synthesis using cellulose nanocrystals (CNCs) to improve colloidal stability and the dispersion of hydroxyapatite (HA) during the bacterial nanocellulose (BNC) cultivation period. Transmission electron microscopy images and energy dispersive spectroscopy (EDS) results confirmed the dispersion of HA on the CNC particles with a Ca/P ratio of 1.66 corresponding to that of the stoichiometric HA. The SEM images and EDS results showed that the integration of the HA and BNC network without CNC assistance (BHA (0.25 and 0.5 wt.%) composites) was less than that for BHC at both concentrations. Fourier transform infrared analysis, XRD and thermal degradation revealed the effect of HA on the BHC composites with a decreased CrI% and improved thermal property. Cytotoxicity proved the potential for using BHC composites for bone tissue engineering scaffold with cell viability up to 83.4 +/- 3.6% compared to the negative control (99.2 +/- 0.08%). PMID- 30446092 TI - Glycopolymers/PEI complexes as serum-tolerant vectors for enhanced gene delivery to hepatocytes. AB - Serum stability is a crucial factor for ideal polymeric gene vectors. In this work, a series of serum-tolerant and low-toxicity glycopolymers/poly(ethyleneimine) (PEI) complexes were designed for gene delivery. Atomic transfer radical polymerization (ATRP) was used to synthesize the comb-shaped random copolymers dextran-g-poly(2-dimethylaminoethyl methacrylate-co-2-lactobionamidoethyl methacrylate) (DDrL). Then DDrLs/PEI were investigated for their use as plasmid DNA (pDNA) vectors, which can completely condense the pDNA into nanoparticles. The DDrLs/PEI/pDNA complexes in serum containing media showed better stability than PEI/pDNA complexes. in vitro gene transfection studies showed that DDrLs/PEI exhibited a remarkable transfection efficiency enhancement in the presence of serum compared to that in serum-free conditions. Moreover, the transfection level of DDrLs/PEI were two orders of magnitude higher than that of PEI alone in the presence of 30% serum. DDrLs/PEI complexes with galactose enhanced pDNA delivery to hepatocytes, with higher protein expression in ASGPr-presenting HepG2 than in HeLa cells, which lack the receptor. All of the DDrLs/PEI/pDNA complexes had lower cytotoxicity than PEI/pDNA. PMID- 30446093 TI - Downscale fermentation for xylooligosaccharides production by recombinant Bacillus subtilis 3610. AB - The global demand of prebiotics such as xylooligosaccharides (XOS) has been growing over the years, motivating the search for different production processes with increased efficiency. In this study, a cloned Bacillus subtilis 3610, containing the xylanase gene xyn2 of Trichoderma reesei coupled with an endogenous secretion tag, was selected for XOS production through direct fermentation of beechwood xylan. A mixture of XOS with a degree of polymerization ranging from 4 to 6 was obtained, presenting high stability after a static in vitro digestion (98.5 +/- 0.2%). The maximum production yield expressed as total XOS per amount of xylan (306 +/- 4 mg/g) was achieved after 8 h of fermentation operating under one-time impulse fed-batch. The optimal conditions found were pH 6.0 and 42.5 degrees C, using 2.5 g/L of initial concentration of xylan increased up to 5.0 g/L at 3 h. Xylopentaose was the major oligosaccharide produced, representing 47% of the total production yield. PMID- 30446094 TI - The structural amphiphilicity of cellulose nanocrystals characterized from their cohesion parameters. AB - Cellulose nanocrystals (CNCs), usually considered as isotropically polar nanoparticles, are sheet-like crystalline assemblies of cellulose chains. Here, we link the anisotropy of the CNC structure to an amphiphilic behavior in suspension. The Hansen solubility parameters (HSP: deltaD;deltaP;deltaH) of wood based H2SO4-hydrolyzed CNCs were measured from sedimentation tests in a wide set of 59 solvents and binary mixtures. Two sets of cohesion parameters corresponding to a polar surface (18.1; 20.4; 15.3) +/- (0.5; 0.5; 0.4) MPa1/2 and to a mildly non-polar one (17.4; 4.8; 6.5) +/- (0.3; 0.5; 0.6) MPa1/2 were determined, with respective solubility radii of 7.8 and 2.1 MPa1/2. The polar sphere is thought to correspond to the (110) & (11-0) surfaces of cellulose Ibeta nanocrystals, while the smaller non-polar sphere is coherent with the exposure of (200) surfaces. The HSP graph provides new insights on the amphiphilic nature of CNCs and a mapping of their chemical affinity for solvents and polymer matrices. PMID- 30446097 TI - Effect of low loadings of cellulose nanocrystals on the significantly enhanced crystallization of biodegradable poly(butylene succinate-co-butylene adipate). AB - Biodegradable poly(butylene succinate-co-butylene adipate) (PBSA)/cellulose nanocrystals (CNC) nanocomposites were successfully prepared via a solution and casting method at low CNC loadings. The nonisothermal and isothermal melt crystallization behaviors of PBSA/CNC nanocomposites were significantly enhanced by low loading of CNC. The nonisothermal melt crystallization peak temperature obviously increased from 56 degrees C for neat PBSA to 63.6 degrees C for PBSA/CNC1 (the nanocomposite containing 1 wt% CNC) at 10 degrees C/min. Crystallization half-time at 80 degrees C significantly decreased from 31 min for neat PBSA to 8.4 min for PBSA/CNC1. CNC apparently increased the crystallization rate of PBSA; however, the crystallization mechanism remained unchanged. The crystalline morphology study verified the enhanced nucleation density of PBSA spherulites, indicating the role of CNC as an efficient nucleating agent. In addition, low loadings of CNC did not modify the crystal structure of PBSA. PMID- 30446096 TI - Poly(methacrylic acid)-modified medical cotton gauzes with antimicrobial and drug delivery properties for their use as wound dressings. AB - Medical cotton gauzes were modified by grafting poly(methacrylic acid) (PMAA) via free radical polymerization to obtain wound dressings with antimicrobial and drug delivery properties. The effect of several reaction parameters including monomer and initiator concentrations, reaction time, and temperature was studied. The grafting was confirmed by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), swelling studies, and scanning electron microscopy (SEM). The grafted cotton gauzes (gauze-g-PMAA) samples were loaded with ZnO nanoparticles to endow with antibacterial properties. Also, they were tested as drug eluting systems using nalidixic acid as antimicrobial agent. The antibacterial activity of the ZnO-loaded gauze-g-PMAA samples was evaluated against Escherichia coli (E. coli) and Staphylococcus epidermidis (S. epidermidis). The PMAA-grafted gauzes showed antibacterial activity and inhibited the growth of both microorganisms. These results suggest that the PMAA-grafted cotton gauzes could be used in the biomedical area particularly as antimicrobial and drug-eluting wound dressings. PMID- 30446095 TI - Effective cancer immunotherapy by Ganoderma lucidum polysaccharide-gold nanocomposites through dendritic cell activation and memory T cell response. AB - Polysaccharides purified from natural herbs possess immunoregulatory functions, while the efficacy of natural polysaccharides on cancer treatment remains unreliable, likely due to their low prescribed doses and fast clearances in clinical settings. In this study, gold nanocomposites containing Ganoderma lucidum polysaccharide (GLP-Au) efficiently induced dendritic cell (DC) activation, evident by the increase of CD80/CD86/CD40/MHCII, decrease of phagocytic ability and acid phosphatase activity, and increased cytokine transcription. GLP-Au significantly promoted the proliferation of CD4+ and CD8+ T cells in splenocytes. DC/T cell co-culture study proved that GLP-Au activation on DC directly resulted in T cell proliferation. GLP-Au exhibited strong inhibitory effects on 4T1 tumor growth and pulmonary metastasis when combined with doxorubicin. GLP-Au recovered body weight loss by doxorubicin and increased the percentage of CD4+/CD44+ memory T cells. This work suggests that polysaccharides from natural herbs can be incorporated into nanocomposites with immunoregulatory characteristics for enhanced efficacy on tumor therapy. PMID- 30446098 TI - Glucuronoxylan 3-O-acetylated on uronic acid-substituted xylopyranosyl residues and its hydrolysis by GH10, GH11 and GH30 endoxylanases. AB - Glucuronoxylan selectively 3-O-acetylated on uronic acid-substituted xylopyranosyl residues was prepared by deacetylation of steam explosion-extracted aspenwood acetylglucuronoxylan by the CE6 acetylxylan esterase from Orpinomyces sp. The 3-O-acetylation of MeGlcA-substituted xylopyranosyl residues did not influence the mode of action of GH10, 11 and 30 xylanases, resulting in similar aldouronic acids as are found in alkali-extracted glucuronoxylan hydrolysates. In all three hydrolysates of the selectively acetylated glucuronoxylan, however, 3-O acetylated aldouronic acids predominated over non-acetylated ones, suggesting that in native aspenwood xylan almost all MeGlcA-substituted Xylp residues are 3 O-acetylated. The results contribute to current knowledge of the mode of action of xylanases and also point to a possibility to produce novel types of xylooligosaccharides. The 3-O-acetylated aldouronic acids, along with the specifically 3-O-acetylated glucuronoxylan, may serve as model substrates for searching for a novel type of esterase able to liberate this MeGlcA-shielded acetyl group. Such esterases are important to improve significantly saccharification yields. PMID- 30446099 TI - Construction of ordered structure in polysaccharide hydrogel: A review. AB - Hydrogels are three-dimensional, hydrophilic, polymeric networks, held together by a variety of physical or chemical crosslinks. Among the numerous polymers that can be employed to fabricate hydrogel, polysaccharides have attracted enormous attention due to their peculiar properties that make them suitable for various applications. Compared with homogeneous hydrogels, hydrogels with ordered structures on various length scales are endowed with excellent properties and promising applications in materials science. In the present review, a wide range of techniques were introduced and discussed, which had been utilized to construct ordered hierarchical structures in polysaccharide hydrogels. These techniques focused on the construction of multi-layered and orientated structure, which are two typical and very important forms of hierarchical structure. PMID- 30446100 TI - Sustainable co-solvent induced one step extraction of low molecular weight chitin with high purity from raw lobster shell. AB - The co-solvent prepared from glycerol and hydrochloric acid (HCl) was used for producing low molecular weight chitin from lobster shell. Different reaction temperature, time and acid concentration were studied. The results suggested that the effect of reaction temperature and acid concentration on molecular weight of chitin is most remarkable. The physicochemical properties of chitins were intact during co-solvent treatment. At least 5% HCl was necessary for demineralization and deproteinization. Low molecular weight chitin could be obtained by increasing reaction temperature, acid concentration and prolonging time. The optimized condition for production low molecular weight chitin was at 120 degrees C for 2 h with acid concentration of 7% (55 kDa) or at 150 degrees C for 2 h with acid concentration of 5% (57 kDa). This method provides a fast strategy to obtain low molecular weight chitin with high purity from lobster shell. PMID- 30446101 TI - Microfibrillated cellulose enhancement to mechanical and conductive properties of biocompatible hydrogels. AB - A combination of conductive polymer with natural biomass is an ideal alternative to the classical conductive materials. In this study, PPy/SA/TOMFC composite hydrogels were fabricated by incorporation of TEMPO-oxidized microfibrillated cellulose (TOMFC) into the alginate-based matrix along with the in situ polymerization of pyrrole monomer. It was found that the mechanical and conductive properties of the composite hydrogels were associated with the concentration of TOMFC, which facilitated the formation of more compact 3D network structures and the growing of PPy conductive network. The mechanical properties of the synthesized hydrogels were significantly enhanced by incorporation of higher amount of TOMFC. In addition, with the introduction of 5.0 wt% TOMFC, the electrical conductivity of composite hydrogels could be ten times higher than that of PPy/SA hydrogels. Moreover, the obtained PPy/SA/TOMFC hydrogels exhibited tunable swelling properties and good biocompatibility, making them promising candidates for the use as biomaterial. PMID- 30446102 TI - Green synthesis of cellulose nanofibers using immobilized cellulase. AB - Isolation of cellulose nanofibers (CNF) using cellulase immobilized on cheap and easily formed polymeric gel disks is discussed. Such gel disks based on carrageenan gel coated with hyperbranched polyamidoamine that can covalently bind to cellulase through glutaraldehyde spacer. Thermal and mechanical stability of the coated gel disks were significantly improved. Free and immobilized cellulase exhibited maximum activities at 50 degrees C and pH 5. However, immobilized cellulase exhibited broader temperature stability than in the free form. Additionally, immobilized cellulase gel disks can be easily separated and reused with great reusability capacity of about 85% of the initial activity after six cycles. Immobilized cellulase was capable to disintegrate cellulose fibers providing nanofibers with diameter of 15-35 nm and several micrometers long. Overall, enhanced thermal stability and reusability of immobilized cellulase pave the way for its use in industrial production of CNF that can be applicable for biomedical and food packaging applications. PMID- 30446103 TI - Purification, structural analysis and mechanism of murine macrophage cell activation by sulfated polysaccharides from Cystoseira indica. AB - Sulfated polysaccharides were isolated and purified from the water extract of Cystoseira indica using DEAE Sepharose Fast Flow column to evaluate their structure and macrophage stimulating capacity. Crude and fractionated polysaccharides, CIF1 and CIF2, were mostly composed of neutral sugars (73.1% 78.6%) with relatively lower amounts of acidic sugars (1.3%-9.0%) and sulfate esters (6.9%-9.7%). The polymer chains of polysaccharides were mainly built of different levels of glucose (2.1%-30.8%), fucose (17.2%-24.4%), mannose (17.8% 20.6%) and galactose (16.7%-17.3%). The weight average molecular weight (Mw) of polysaccharides varied between 573.1 * 103 g/mol to 1146.6 * 103 g/mol. The CIF2 polysaccharide, as the most immunostimulating polysaccharide, remarkably induced the release of nitric oxide and inflammatory cytokines including TNF-alpha, IL 1beta, IL-6 and IL-10 from RAW264.7 murine macrophage cells through NF-kappaB and PAMKs transduction signaling pathways via cell surface TLR4. The interconnections of sugars in CIF2 polysaccharide were complex with (1->3)-fucopyranose, (1 >2,3,4)-glucopyranose, (->1)-galactopyranose, (->1)-xylopyranose, (1->2) rhamnopyranose and (1->2,3)-mannopyranose units being the most predominant residues. PMID- 30446104 TI - PHBV-graft-GMA via reactive extrusion and its use in PHBV/nanocellulose crystal composites. AB - Reactive extrusion was used for dicumyl peroxide (DCP)-initiated grafting of glycidyl methacrylate (GMA) to poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV). The effects of GMA and DCP content and their weight ratio on the GMA grafting percentage (GP%), the polymer melt viscosity, and the PHBV molecular weight were investigated. FTIR spectroscopy determined that the DCP did indeed initiate GMA grafting. However, the changes in both the zero-shear viscosity (eta0) and the molecular weight suggested the existence of crosslinking products in the extruded polymers. A negative correlation between the degree of crystallinity (chic) of the PHBV-g-GMA and the GP% suggested the influence of chain branching on crystallinity. In addition, the GMA content was found as a key factor determining the GP%. The PHBV-g-GMA was used as a matrix polymer in cellulose nanocomposites to evaluate its effects on CNC dispersion and CNC-matrix adhesion relative to the unmodified PHBV matrix. The SEM images and the change in crystallization temperature suggested enhanced dispersion of CNC in a PHBV-g-GMA matrix. However, little increase in strength properties were found with CNC addition suggesting inadequate stress transfer between the matrix and CNCs. PMID- 30446105 TI - Production, structure and morphology of exopolysaccharides yielded by submerged fermentation of Antrodia cinnamomea. AB - Carbon and nitrogen sources in culture medium of Antrodia cinnamomea were optimized to eliminate the interference of exterior macromolecules on exopolysaccharide (EPS) yield by submerged fermentation. The results suggested that culture medium containing 50 g/L of glucose and 20 g/L of yeast extract as the optimal carbon and nitrogen sources could produce 1.03 g/L of exopolysaccharides. After purification, two heteropolysaccharides (AC-EPS1 and AC EPS2) were obtained and characterized to provide the basic structure information. As the main component of the produced EPS, AC-EPS2 (accounting for 89.63%) was mainly composed of galactose (87.42%) with Mw (molecular weight) and R.M.S. (root mean-square) radius of 1.18 * 105 g/mol and 25.3 nm, respectively. Furthermore, the spherical and flexible chain morphologies of EPS were observed in different solvents by TEM. The structural and morphological information of purified EPS were significant for further study on their structure-activity relationship and related applications. PMID- 30446106 TI - Enzymatic fingerprinting of isomalto/malto-polysaccharides. AB - In this study, we present an enzymatic fingerprinting method for the characterization of isomalto/malto-polysaccharides (IMMPs). IMMPs are produced by the modification of starch with the 4,6-alpha-glucanotransferase (GTFB) enzyme and consist of alpha-(1->4), alpha-(1->6) and alpha-(1->4,6) linked glucoses. Enzymes were used separately, simultaneously or in successive order to specifically degrade and/or reveal IMMP substructures. The enzymatic digests were subsequently analysed with HPSEC and HPAEC to reveal the chain length distribution (CLD) of different IMMP substructures. The presence of amylose in the substrate resulted in the formation of linear alpha-(1->6) linked glycosidic chains (13.5 kDa) in the former amylopectin fraction. The length of these chains indicates that GTFB transferase activity on amylopectin is more likely to elongate single amylopectin chains than to provide an even distribution. Enzymatic fingerprinting also revealed that the GTFB enzyme is capable of introducing large (20 kDa) linear alpha-(1->6) linked glycosidic chains in the alpha-glucan substrate. PMID- 30446107 TI - In-situ determination of time-dependent alginate-hydrogel formation by mechanical texture analysis. AB - Although alginate-based hydrogels are widely used, determining their mechanical properties and explaining their ability to form a hydrogel in situ remains a challenge. A new method of external gelation using calcium chloride (CaCl2) is proposed to quantify the formation of alginate hydrogel and its mechanical properties as well as to observe its temporal behaviour. To this end, small inhomogeneous alginate beads were formed, which comprised a shell and a core. The bead's shell consisted of calcium alginate hydrogel, while its core was sodium alginate sol. The beads were mechanically tested with a texture analyser to provide a detailed description of the structure. Different alginate samples could be clearly identified, and the M(mannuron)/G(guluron) acid ratios could be extrapolated quickly and easily from the test results if calibrated by NMR. This enables a fast and cost-effective characterisation of different alginates with regard to their composition and gel formation properties. PMID- 30446108 TI - Porous structured cellulose microsphere acts as biosensor for glucose detection with "signal-and-color" output. AB - In order to develop a biosensor based on porous structured cellulose microspheres for glucose detection with "signal-and-color" output, in this work, active group carboxyl was introduced to cellulose matrix by using plasma technology, and then glucose oxidase (GOx) was chemically immobilized through EDC-NHS cross-linking reaction. The cellulose microgels containing 21.28 mg/g of enzymes exhibited a fast response to 0.003 M glucose within only 4 min. As for detecting subject with a lower concentration of glucose, the probe still worked. When the concentration of glucose solution was 0.005 M, it took only 2 min that the reaction mixture changed from colorless to yellow. By the introduction of starch, the reaction mixture presented as amaranth color. Besides, the porous-structured substrate and the facile plasma technology were also promising for constructing enzyme-driven catalytic systems with enhanced performance. PMID- 30446109 TI - Surface modification of Ti-6Al-4V alloy for osseointegration by alkaline treatment and chitosan-matrix glass-reinforced nanocomposite coating. AB - Individual and combined treatments of alkaline (NaOH) and chitosan/bioactive glass (SiO2-CaO-MgO) nanocomposite coating were applied on Ti-6Al-4V alloy surfaces with the objective of investigating and improving i) wettability, ii) apatite-formation ability, iii) corrosion resistance, and iv) biocompatibility. Individual applications of each surface treatment were found to enhance hydrophilicity, apatite-forming ability, corrosion resistance, and cytocompatibility (MG-63 cells). The most improved properties, except apatite formation ability, were obtained using the combined treatment yielding a reduction of 64 and 93% in sessile contact angle and corrosion rate, respectively, than the untreated substrate. These improvements originate from the desired roughness and apatite-formation ability of the alkaline treatment and the appropriate biocompatibility and corrosion protection of the nanocomposite coating. That is, the combined application of alkaline treatment and chitosan nanocomposite coating is demonstrated as a promising surface-engineering strategy for hard-tissue replacement applications. PMID- 30446110 TI - Influence of chitosan oligosaccharide on the gelling and wound healing properties of injectable hydrogels based on carboxymethyl chitosan/alginate polyelectrolyte complexes. AB - In situ injectable hydrogels for wound healing based on carboxymethyl chitosan (CMCS) and alginate were developed in this work. The liquid mixture of CMCS and alginate solutions formed a gel by polyelectrolyte complexation after addition of d-glucono-delta-lactone (GDL), which slowly hydrolyzed and donated protons. When chitosan oligosaccharide (COS) was added into the mixture, a two-stage gelling process occurred. The primary gelling process was similar to that of the hydrogel without COS, while the secondary gelling process appeared about 20 min later, and much stronger hydrogels with storage modulus G' about 1 MPa, 104 times higher, were obtained. COS also significantly influenced the microstructure of hydrogels as well as their biological activities. The hydrogels with 0.5% of COS significantly promoted proliferation of human umbilical cord mesenchymal stem cells (HUMSCs). These injectable hydrogels, especially when COS was added, remarkably accelerated the wound healing process in a mouse skin defect model. Microscopic wound analysis showed an increase of the thickness and integrity of epidermal tissue, increased formation of collagen fibers, and enhanced expression of vascular endothelial growth factor as compared to the control group. PMID- 30446111 TI - A comparative study on grafting polymers from cellulose nanocrystals via surface initiated atom transfer radical polymerization (ATRP) and activator re-generated by electron transfer ATRP. AB - Both Surface-Initiated Atom Transfer Radical Polymerization (SI-ATRP) and Surface Initiated Activator Re-Generated by Electron Transfer ATRP (SI-ARGET ATRP) were performed to graft polystyrene and poly(4-vinylpyridine) on the surface of cellulose nanocrystals (CNCs) to evaluate the potential benefits of each method. The polymer grafted CNCs and their corresponding free polymers initiated from sacrificial initiators were characterized by Fourier transform infrared spectroscopy, gel permeation chromatography, dynamic light scattering, differential scanning calorimetry, thermogravimetric analysis, and elemental analysis, respectively. It was found that SI-ARGET ATRP favored the grafting of longer polymer chains with lower grafting density compared with the classical SI ATRP. The surface initiation efficiency of brominated CNCs in SI-ARGET ATRP is much lower than that in SI-ATRP, which is mainly due to the much lower amount (ppm level) of catalysts and faster propagation rate in SI-ARGET ATRP system. PMID- 30446112 TI - Effect of polyethylene glycol (PEG) molecular weight and nanofillers on the properties of banana pseudostem nanocellulose films. AB - The aims of this study were to investigate the effects of polyethylene glycol (PEG) molecular weight (MW) and PEG interaction with nanofillers (nanoclay and graphene oxide) on the properties of banana pseudostem nanocellulose films. PEG MW significantly affected the properties of the films. Low MW PEGs (400 and 1000 g/mol) had better interaction with nanocellulose than the PEG with higher MW and improved the flexibility of the films by about 100%. Interaction between PEG1000 and nanofillers significantly modified the properties of the composite films. PEG1000 had a good interaction with nanoclay, which was reflected by the formation of intercalated nanoclay in the cellulose matrix. The presence of nanoclay and graphene oxide in the PEG plasticised films improved the tensile strength and contact angle of the films compared to the film that only contained PEG. These findings suggest that the properties of banana pseudostem nanocellulose film can be improved by combining PEG with nanofillers. PMID- 30446113 TI - Chitosan as a stabilizer and size-control agent for synthesis of porous flower shaped palladium nanoparticles and their applications on photo-based therapies. AB - This study reported a newly developed green synthesis method using chitosan and vitamin C to prepare porous flower-shaped palladium nanoparticles. We found that chitosan not only worked as a stabilizer but also as a size-control agent for the synthesis of these nanoparticles. The growth model of flower-shaped palladium nanoparticles was proposed to interpret mechanistic understanding. The obtained nanoparticles showed good biocompatibility and strong near-infrared absorption. The nanoparticles were successfully demonstrated to be highly efficient for both in vitro photothermal therapy and in vitro photoacoustic imaging. PMID- 30446114 TI - Fabrication of metal-organic frameworks@cellulose aerogels composite materials for removal of heavy metal ions in water. AB - In the present work, we develop novel method of loading metal-organic frameworks (UiO-66 and UiO-66-NH2) on the flexible cellulose aerogels as metal-organic frameworks@cellulose aerogels composite materials by using in situ growth procedure at room temperature. The as prepared metal-organic frameworks@cellulose aerogels composite materials were well characterized via SEM, XRD, atomic absorption spectrometer, and TG analysis, besides the adsorption of Pb2+ and Cu2+ in metal-organic frameworks@cellulose aerogels composite materials was investigated. The amount of metal ions adsorbed by metal-organic frameworks@cellulose aerogels composite materials is equal to the sum of metal organic frameworks and cellulose aerogels, indicating that the metal-organic frameworks are not blocked after cellulose aerogels growth and still have adsorption properties. It was found that metal-organic frameworks@cellulose aerogels composite materials can be recycled to adsorb Pb2+ and Cu2+ in water after simple cleaning. The equilibrium adsorption capacity of Pb2+ adsorbed by UiO-66-NH2@CA was 89.40 mg g-1, and can be easily reused for more than 5 cycles without significant decrease in performance. Moreover, the maximum decomposition temperature (Tmax) of UiO-66-NH2@CA was increased by 62.1C. This result suggested that such metal-organic frameworks@cellulose aerogels composite materials could adsorb heavy metal ions in water could by avoiding secondary pollution and show great potential in water treatment. PMID- 30446115 TI - Highly efficient polyurethane membrane based on nanocomposite of sulfonated thiacalix[4]arene-sodium alginate for desalination. AB - In this study, a series of polyurethane (PU) films based on three different type of chain extenders including glycerol, sodium alginate (SA) and nanocomposite of tetrasodium thiacalix[4]arene tetrasulfonate-sodium alginate (TS-SA) were synthesized. The effect of SA and TS-SA chain extenders on different properties of the PU films were studied using FTIR, XRD, DSC, TGA, SEM, AFM, and tensile analysis and the obtained results were compared with the polyurethane film extended with glycerol. The TGA and tensile studies confirmed that incorporation of TS-SA into the polyurethane backbone provide the superior thermal and mechanical properties compared to SA. Moreover, the influence of the SA and TS-SA chain extenders on hydrophilicity of the prepared films was also investigated by contact angle measurement. The results showed that the hydrophilicity of PU/TS-SA is higher than the PU/Gly and PU/SA samples. In comparison with PU/Gly and PU/SA samples, the PU/TS-SA sample showed significant performance in water desalination via reverse osmosis technique due to its favorable porosity and improved hydrophilicity. The AFM analysis confirmed that the PU/TS-SA sample has the highest surface rouphness which cause an increase in the flux and anti-fouling property of this sample. Therefore, PU/TS-SA sample can be introduced as an efficient membrane for water desalination with enhanced thermal stability, mechanical properties, high salt rejection and water permeability. PMID- 30446116 TI - Hydrophobically modified xanthan: Thickening and surface active agent for highly stable oil in water emulsions. AB - Oil-in-water (O/W) emulsions were prepared using exclusively a hydrophobically modified xanthan (HMX) under ordered conformation without any surfactant. A series of HMX differing in grafting density were utilized at different concentrations. It was demonstrated that HMX stabilizes O/W emulsions where pristine xanthan do not. Indeed, in some cases, emulsions with HMX proved to be homogeneous and stable over months. Emulsions microstructure and rheological properties were investigated over time as a function of HMX concentration and grafting density in order to determine the mechanisms governing this efficient stability. The higher the HMX concentration is, the better the emulsions stability. However, unexpectedly, increasing the HMX grafting density leads to faster destabilization. The whole set of results demonstrate that the stability of the emulsions against coalescence and creaming is explained by partitioning of HMX molecules between bulk and interface, thus split between viscosifying the aqueous phase and stabilizing the interface. PMID- 30446117 TI - Water-soluble carboxymethylchitosan used as corrosion inhibitor for carbon steel in saline medium. AB - Biodegradability and ecotoxicity of products used in oil industry are of great relevance and corrosion inhibitor could not be an exception. In earlier reports, chitosan and some derivatives were evaluated as corrosion inhibitors at acid pH, mainly due to polymer solubility. An eco-friendly corrosion inhibitor with water solubility in all pH range should be ideal, as well as that could act under the high salinity of oil field environment. Thus, herein is presented the performance of a water-soluble carboxymethylchitosan (CMC) as corrosion inhibitor in presence of chlorides (3.5% NaCl) in 1020 carbon steel, without any addition of acid or base. CMC showed good properties as corrosion inhibitor in media containing Cl-, and behaved as an anodic inhibitor. CMC exhibited inhibitory efficiency of about 80% and 67%, according to Tafel curve and electrochemical impedance, respectively, which was attributed to chemisorption mechanism (DeltaGads ~ -45 kJ/mol). PMID- 30446118 TI - Stimuli-responsive hybrid cluster bombs of PEGylated chitosan encapsulated DOX loaded superparamagnetic nanoparticles enabling tumor-specific disassembly for on demand drug delivery and enhanced MR imaging. AB - Facile approach was established to fabricate the hybrid cluster bombs of PEGylated chitosan encapsulated doxorubicin (DOX)-loaded superparamagnetic nanoparticles as tumor-specific theranostics for targeted DOX delivery and magnetic resonance (MR) imaging, by simply co-precipitation of poly(ethylene glycol) modified chitosan (CS-PEG), oleylamine modified Fe3O4 (OA-Fe3O4) nanoparticles and DOX. In presence of OA-Fe3O4, the particle size of the DOX/OA Fe3O4@CS-PEG cluster bombs decreased to around 80 nm from 300 nm of the DOX/CS PEG nanoparticles, with high drug-loading capacity (DLC) of 24.3% and saturation magnetization (Ms) of 4.11 emu/g, respectively. The in vitro evaluation results indicated that the blank OA-Fe3O4@CS-PEG clusters showed excellent cytocompatibility, while the DOX/OA-Fe3O4@CS-PEG clusters could be uptaken into HepG2 cells to deliver DOX into the cell nuclei with enhanced anti-cancer efficacy in comparison with free DOX. In the tumor intracellular micro environment, the stimuli-responsive hybrid cluster bombs disassembled and re-self assembled into the OA-Fe3O4 nanoparticle clusters with higher Ms for MR imaging guided diagnosis, owing to the tumor-specific DOX release and dissolution of CS PEG. PMID- 30446120 TI - Five different chitin nanomaterials from identical source with different advantageous functions and performances. AB - Chitin is a renewable and sustainable biomass material that can be converted into various one-dimensional crystalline nanomaterials different in 1) length, 2) diameter, 3) charge density, 4) type of charge, and 5) crystallinity via diverse top-down synthetic methods. These nanomaterials have great potential as sustainable reinforcing and biologically functional materials. The proper design of chitin nanomaterials maximizes their performances in specific applications. Extensive efforts are devoted to understanding each type of chitin nanomaterial produced from different chitin sources; however, few studies have compared different chitin nanomaterials. Herein, we synthesize five different types of chitin nanomaterials from identical sources and compare their physical and chemical properties, including suitability for assorted purposes. Factors 1)-5) are discussed regarding their dominance in determining functionality depending on the specific goals of a) gas barriers, b) mechanical reinforcements, c) dispersibility in various pH aqueous buffers, d) thermal dimensional stability, and e) antibacterial activity. This study gives insights to design new chitin nanomaterial-based materials. PMID- 30446119 TI - Polymeric fluorescent heparin as one-step FRET substrate of human heparanase. AB - Heparanase, an endo-beta-D-glucuronidase, cleaves cell surface and extracellular matrix heparan sulfate (HS) chains and plays important roles in cellular growth and metastasis. Heparanase assays reported to-date are labor intensive, complex and/or expensive. A simpler assay is critically needed to understand the myriad roles of heparanase. We reasoned that fluorescent heparin could serve as an effective probe of heparanase levels. Following synthesis and screening, a heparin preparation labeled with DABCYL and EDANS was identified, which exhibited a characteristic increase in signal following cleavage by human heparanase. This work describes the synthesis of this heparin substrate, its kinetic and spectrofluorometric properties, optimization of the heparanase assay, use of the assay in inhibitor screening, and elucidation of the state of heparanase in different cell lines. Our FRET-based assay is much simpler and more robust than all assays reported in the literature as well as a commercially available kit. PMID- 30446121 TI - Hydroxypropyltrimethyl ammonium chloride chitosan activates RAW 264.7 macrophages through the MAPK and JAK-STAT signaling pathways. AB - Hydroxypropyltrimethyl ammonium chloride chitosan (HACC) is a water-soluble derivative of chitosan. To investigate the immunostimulatory effects of HACC, quaternized chitosans with different molecular weights were prepared and their effects on RAW 264.7 macrophages were compared. The results showed that HACC promoted nitric oxide (NO) production in a molecular weight- and dose-dependent manner. Lower molecular weight HACC was more active in promoting NO production. Furthermore, flow cytometry analysis showed that HACC significantly promoted the production of interleukin-6 and tumor necrosis factor-alpha. These results were further demonstrated by quantitive real-time reverse transcription polymerase chain reaction and western blot analysis. Moreover, western blotting revealed that HACC induced the phosphorylation of extracellular signal-regulated kinase, c Jun N-terminal kinase, p38, and signal transducer and activator of transcription (STAT) proteins. In conclusion, HACC activated RAW 264.7 cells through the mitogen-activated protein kinases and Janus kinase/STAT pathways. PMID- 30446122 TI - Design of self-healable supramolecular hybrid network based on carboxylated styrene butadiene rubber and nano-chitosan. AB - In this paper, carboxylated styrene butadiene rubber (XSBR)/nano-chitosan (NCS) composites were prepared via a salt-forming reaction, in which NCS participated in constructing a supramolecular hybrid network. NCS served as multiple functional cross-linker as well as reinforcer for XSBR. This turned out that the mechanical properties of XSBR could be improved by NCS, and simultaneously, the self-healing property was retained to utmost extent. With 20 wt% NCS, the tensile strength of NCS/XSBR composite was increased to 1.3 MPa, more than 2-time that of the neat XSBR, meanwhile, the healing efficiency was as high as to 92% after healing at ambient temperature for 24 h. PMID- 30446123 TI - Host flexibility and space filling in supramolecular complexation of cyclodextrins: A free-energy-oriented approach. AB - Cyclodextrins (Cds) are versatile carbohydrate hosts for developing multifunctional nanostructures of pharmaceutical interest. Factors affecting the thermodynamic signatures and stability of beta- and gamma-Cd complexes are detailed at the atomic level. The MD/PMF-based method is combined with the description of the nature and strength of the inter-partner affinity. Naphthalene, adamantane and lycorine derivatives are used as models of drug leading structures. Guest size affects Cd-guest contact and the inclusion degree, inducing Cd deformation, which opposes inclusion. Complexation depends on the available Cd cavity volume, as guest fitting variations and the enthalpy penalty from Cd deformation impact on the binding constants (promoting a reduction of up to 104). The often neglected Cd deformation plays, thus, an important role in the interaction behavior of larger cavity Cd-based systems, being crucial in carbohydrate-mediated recognition phenomena. It corresponds to an increase in energy of ca. 90 kJ mol-1 in the simpler analyzed model system. PMID- 30446124 TI - Exploring the hydrogen-bond structures in sodium alginate through two-dimensional correlation infrared spectroscopy. AB - In this paper, the heat-induced hydrogen bonding evolution in the sodium alginate (SA) film is explored mainly by FTIR spectroscopy in combination with perturbation correlation moving window (PCMW) technique and 2D correlation spectroscopy (2Dcos). Due to the strong hydrophilicity, hydrogen bonds formed between water molecules and polar groups (including OH and COO-) along SA chains hold an predominant role at room temperature, which is believed to disrupt the inter/intra-molecular hydrogen bonding in SA chains. During heating from 30 to 60 degrees C, most water molecules evaporate abruptly, resulting in the formation of inter/intra-molecular hydrogen bonding within SA chains, such as O3H3...O5 and O2H2...O = C-O-. Upon further heating form 60 to 170 degrees C, both inter/intra molecular hydrogen bonding in SA chains and hydrogen bonds of SA with water molecules are gradually broken, leading to the appearance of relatively free COH and COO- groups. PMID- 30446125 TI - Pectin-bioactive glass self-gelling, injectable composites with high antibacterial activity. AB - The present work focuses on the development of novel injectable, self-gelling composite hydrogels based on two types of low esterified amidated pectins from citrus peels and apple pomace. Sol-gel-derived, calcium-rich bioactive glass (BG) fillers in a particle form are applied as delivery vehicles for the release of Ca2+ ions to induce internal gelation of pectins. Composites were prepared by a relatively simple mixing technique, using 20% w/v BG particles of two different sizes (2.5 and <45 MUm). Smaller particles accelerated pectin gelation slightly faster than bigger ones, which appears to result from the higher rate of Ca2+ ion release. MUCT showed inhomogeneous distribution of the BG particles within the hydrogels. All composite hydrogels exhibited strong antibacterial activity against methicilin-resistant Staphylococcus aureus. The mineralization process of pectin-BG composite hydrogels occurred upon incubation in simulated body fluid for 28 days. In vitro studies demonstrated cytocompatibility of composite hydrogels with MC3T3-E1 osteoblastic cells. PMID- 30446126 TI - Hydrophobization of chitosan films by surface grafting with fluorinated polymer brushes. AB - Chitosan with its surface-properties and biodegradability is a promising biomaterial for green packaging applications. Till now, this application is still limited due to chitosan high sensitivity to water. Some existing studies deal with the incorporation of hydrophobic additives to enhance water-proof performances of chitosan films. As these additives may impair the film properties, our study focuses on chitosan efficient hydrophobization by means of simple and successful surface grafting reactions. Chitosan films prepared by solvent casting were modified by means of surface-initiated activators regenerated by electron transfer atom radical polymerization (SI-ARGET-ATRP) of 2 hydroxyethyl methacrylate (HEMA) followed by esterification reaction with fluorinated acyl compound. X-ray photoelectron spectroscopy (XPS), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and Time-of Flight Secondary Ion Mass Spectroscopy (ToF-SIMS) highlighted the surface chemical changes after each step. Surface properties were investigated by contact angle measurements and surface energy calculations. Hydrophobic surfaces with low surface energy and good water-repellent properties were obtained using a simple handling polymerization procedure. This is the first study in applying ARGET ATRP to prepare hydrophobic biopolymer films offering potential applications in packaging. PMID- 30446127 TI - Multifunctional nano-cellulose composite films with grape seed extracts and immobilized silver nanoparticles. AB - Nowadays, traditional packaging films with weak activity or single function cannot satisfy the active packaging requirements. In this paper, novel multifunctional films (TNC/GSE/AgNPs) based on TEMPO-oxidized nano-cellulose (TNC), grape seed extract (GSE) and TNC immobilized silver nanoparticles (TNC@AgNPs) are reported. The results showed that transparent TNC/GSE/AgNPs films exhibited better mechanical properties, lower water vapor permeability and oxygen permeability compared to pure TNC films. Moreover, due to the effect of TNC immobilization on AgNPs, only 5.77%, 3.62% and 3.11% of AgNPs were released from TNC/GSE/AgNPs films under the pH 4.0, 6.9 and 9.2, respectively. Nevertheless, the films had good antimicrobial activity against E. coli and S. aureus. Moreover, TNC/GSE/AgNPs films showed strong antioxidant activity which has been evaluated by DPPH (6.87 MUg Vc/mg d.w.) and TRAP (82.67 MUg Trolox/mg d.w.) methods. The prepared films will exhibit multifunction as food packaging to extend storage period. PMID- 30446128 TI - Pectin gelling in acidic gastric condition increases rheological properties of gastric digesta and reduces glycaemic response in mice. AB - The rheological characteristics and transit time of gastric digesta and the postprandial glycaemic response in mice orally administered with water (control) or pectin solutions supplemented (AP-Ca) or not supplemented (AP) with CaCO3 were elucidated. AP and AP-Ca increased viscosity, storage and loss moduluses (G' and G'') of mice gastric digesta. The gelling capacity of AP-Ca in acidic gastric conditions appeared to provide a greater enhancement of gastric digesta viscosity compared with AP. The postprandial blood glucose concentration was lower in mice orally administered with AP or AP-Ca compared with control mice. The transit time of gastric digesta and the blood glucose concentration were affected in mice orally administered with AP during the early postprandial period. The effect of AP-Ca on the gastric digesta rheology and transit time was stronger than that of AP. Both of the pectin solutions failed to reduce food intake in mice. PMID- 30446129 TI - Radiosensitizing effect of the fucoidan from brown alga Fucus evanescens and its derivative in human cancer cells. AB - Fucoidan from brown alga Fucus evanescens and its product of enzymatic hydrolysis have precisely established structure and possess significant biological activities. The aim of present study was to determine radiosensitizing activity of fucoidan from brown alga F. evanescens and its derivative in human melanoma, breast adenocarcinoma, and colorectal carcinoma cell lines and elucidate mechanism of their action. The fucoidan from F. evanescens and its derivative had a comparable radiosensitizing activity and increased the inhibiting effect of X ray radiation on proliferation and colony formation of human cancer cells, with significant inhibition of melanoma cells. The molecular mechanism of this action was associated with the induction of apoptosis by activating the initiator and effector caspases, suppressing the expression of the anti-apoptotic protein, and enhancing the fragmentation of DNA. The obtained data confirm the prospects of using fucoidan's derivative in combination with radiation therapy for the improvement of the schemes of cancer therapy. PMID- 30446130 TI - Production of reducing sugar from cassava starch waste (CSW) using solution plasma process (SPP). AB - The cassava starch processing plays an important role in food industries. During starch processing stage, a large amount of cassava starch waste (CSW) which mainly contains lost starch product and solid residue such as cassava bagasse are produced. Starch and cassava bagasse can be hydrolyzed into fermentable sugar such as glucose. In the present study, the solution plasma process (SPP) is used to treat CSW to prepare reducing sugar. The investigated parameters are treatment time, solvent concentration, applied pulsed frequency, and CSW concentration. The %yield of total reducing sugar (TRS) and glucose were calculated by DNS method and glucose assay kit, respectively. The chemical structure, morphology, and crystal structure of plasma-treated CSW were investigated. The results showed that the %yield of TRS was greatly enhanced by SPP treatment compared to that of acid hydrolysis. The CSW powder completely broke down into pieces after SPP treatment was applied. The amorphous and crystalline regions of CSW were destroyed during SPP treatment. SPP treatment of CSW with light sulfuric acid concentration of 0.08 M, applied pulsed frequency of 30 kHz, and CSW concentration of 0.5%w/v provided 99.0% TRS and 47.9% glucose. PMID- 30446131 TI - Synthesis and characterization of supramolecular systems containing nifedipine, beta-cyclodextrin and aspartic acid. AB - The purpose of this work was to characterize complexes of nifedipine with beta cyclodextrin (beta-CD), with and without auxiliary agents, to improve aqueous solubility and the dissolution profile of nifedipine. Complexes were characterized using infrared spectroscopy, thermoanalytical methods, powder X-Ray diffraction, scanning electron microscopy, phase solubility analysis and dissolution studies. Spatial configurations were determined by NMR and further examined using computational techniques. This investigation showed that the amino acid Asp was the most efficient auxiliary agent for multicomponent complexes. The spatial configurations were consistent with those obtained by molecular modelling; evidencing that nifedipine inserted its aromatic ring into beta-CD, in all complexes, with Asp interacting with the wide hydrophilic rim of beta-CD. The dissolution rates of nifedipine:beta-CD:Asp complexes were significantly increased compared to those of the pure drug or nifedipine:beta-CD. These results indicate that the nifedipine:beta-CD:Asp system is a promising approach for the preparation of optimized formulations of nifedipine. PMID- 30446132 TI - Novel fabrication of high-modulus cellulose-based films by nanofibrillation under alkaline conditions. AB - We herein propose a novel continuous process for fabricating high-modulus films based on cellulose nanofibers. In place of a dissolution process, the pulps were mechanically disintegrated into nanofibers by ball-milling in an 8% NaOH solution. NaOH treatment loosened the hydrogen bonding between the cellulose microfibrils in the pulps, and a highly concentrated suspension (8%) of cellulose nanofibers with a uniform diameter of approximately 20-50 nm was prepared after ball-milling for 90 min. The resulting nanofiber suspensions prepared in the NaOH solution exhibited the crystal forms of both Cellulose I and Cellulose II, although the Cellulose II content gradually increased upon increasing the milling time. Finally, hydrogels were formed following neutralization of the suspensions, and the hydrogel sheets were hot-pressed into thin films at 120 degrees C. The Young's moduli of the films were significantly higher than those of typical regenerated cellulose films due to the presence of some remaining Cellulose I and a high crystallinity. PMID- 30446133 TI - Facile synthesis of degradable CA/CS imprinted membrane by hydrolysis polymerization for effective separation and recovery of Li. AB - Lithium resources are attractive for different applications because of their specific properties. Therefore, it is more significant to find a cost-effective and environment-friendly method to selective adsorption and recovery of Li+. In this work, a renewable and easy degradable CA/CS hybrid membrane was modified with polydopamine as adhesion layer to anchored TiO2. The simple imprinting process could be realized by hydrolysis polymerization. The adsorption process followed Langmuir isotherm model and pseudo-second-order kinetic equation were researched in detail. The results displayed the maximum adsorption capacity is 20.08 mg g-1 for Li+. The selectivity factors of Li+ to Na+, K+, Mg2+ and Ca2+ are 1.78, 2.43, 2.60 and 3.61, respectively, which mainly attributed to imprinting effect. The LIICMs also exhibited the superior reusability and durability. Thus, the LIICMs provide a powerful tool for selective separation and recovery of Li+ from mixed solutions. PMID- 30446134 TI - A polysaccharide extracted from Astragalus membranaceus residue improves cognitive dysfunction by altering gut microbiota in diabetic mice. AB - A novel polysaccharide named as AERP was extracted from industrial Astragalus membranaceus-extracted waste residue, which was composed of two components coded as AERP1 and AERP2. The structures of AERP1 and AERP2 were determined by HPLC-SEC RID, HPLC-C18-UV, FT-IR, and NMR. The results showed that AERP1 was an acidic component with a molecular weight of 2.01 * 106 Da and glycosidic bonds of ->3/5 alpha-araf-(1->, T-alpha-araf, ->4,6-beta-manp-(1->, ->3/3,6-beta-galp-(1->, >2/2,4-alpha-rha-(1->, ->-4/4,6-alpha-glcp-(1->, ->4-alpha-galpA-(1-> and ->4)-6 OMe-alpha-galpA-(1->. AERP2 was a glucan with 2.11 * 103 Da by ->4/6-alpha-glcp (1-> linkage. In vitro, AERP retarded glucose diffusion significantly than each single component. In vivo, AERP had a hypoglycemic effect on db/db diabetic mice by alleviating the hyperglycemia, tissue impairment, and inhibiting cognitive impairment. AERP could alter the gut microbiota and modulate the composition of SCFAs. This study gives an opportunity for exploring the industrial waste of Astragalus membranaceus in diabetic complication therapy. PMID- 30446135 TI - GC-MS characterisation of novel artichoke (Cynara scolymus) pectic oligosaccharides mixtures by the application of machine learning algorithms and competitive fragmentation modelling. AB - Novel artichoke pectic-oligosaccharides (POS) mixtures have been obtained by enzymatic hydrolysis using four commercial enzyme preparations: Glucanex(r)200G, Pentopan(r)Mono-BG, Pectinex(r)Ultra-Olio and Cellulase from Aspergillus niger. Analysis by HPAEC-PAD showed that Cellulase from A. niger produced the greatest amount of POS (310.6 mg g-1 pectin), while the lowest amount was produced by Pentopan(r)Mono-BG (45.7 mg g-1 pectin). To determine structural differences depending on the origin of the enzyme, GC-MS spectra of di- and trisaccharides have been studied employing three machine learning algorithms: multilayer perceptron, random forest and boosted logistic regression. Machine learning models allowed characteristic m/z ions patterns to be established for each enzyme based on their GC-MS spectra with high prediction rates (above 95% on the test set). Possible chemical structures were given for some m/z ions having a decisive influence on these classifications. Finally, it was observed that several ions could be formed from specific POS structures. PMID- 30446136 TI - Dependence of cellulose dissolution in quaternary ammonium-based ionic liquids/DMSO on the molecular structure of the electrolyte. AB - We synthesized a series of quaternary ammonium acetates (QAAcOs) and assessed their solutions in DMSO as cellulose solvents. NBz111AcO/DMSO did not dissolve cellulose; substitution of its methyl groups resulted in efficient cellulose solvents; NBz31AcO/DMSO dissolved cellulose with difficulty. We attribute the inefficiency of both QAAcOs to: strong anion-cation interactions, NBz111AcO; steric effects and cation-cation hydrophobic interactions, NBz31AcO. Using isothermal titration calorimetry, we determined the enthalpies (HE) of QAAcO (endothermic) dissolution, and QAAcO/cellobiose (exothermic) interactions; both in dimethyl sulfoxide/acetonitrile. The ratios of HE are 5.34:1:1.45, for NBz111AcO, NAl2Bz1AcO, and NBz31AcO, respectively, i.e., dissolution of the first and third QAAcO in the solvent requires more energy. The corresponding ratios for QAAcO interaction with cellobiose are: 0.74:1:0.79, i.e., the second QAAcO interacts more strongly with cellobiose. This order of solvent efficiency is corroborated by SEM images of regenerated cotton linters. Light scattering showed that dissolved cellulose can be regenerated as nanoparticles by dialysis. PMID- 30446137 TI - Light controllable chitosan micelles with ROS generation and essential oil release for the treatment of bacterial biofilm. AB - Bacterial biofilms are widely associated with persistent infections and food contamination. High resistance to conventional antimicrobial agents resulted in an urgent need for novel formulation to eliminate these bacterial communities. Herein we fabricated light controllable chitosan micelles loading with thymol (T TCP) for elimination of biofilm. Due to the exterior chitosan, T-TCP micelles easily bind to negative biofilm through electrostatic interaction and efficiently deliver the essential oil payloads. Under irradiation, T-TCP micelles generated ROS, which triggered simultaneous thymol release and also resulted in additional ROS-inducing bactericidal effects, both effectively eradicating biofilms of Listeria monocytogenes and Staphylococcus aureus. This formulation provided a platform for other water-insoluble antimicrobials and might be used as a potent and controllable solution to biofilm fighting. PMID- 30446138 TI - Mechanism of Lycium barbarum polysaccharides liposomes on activating murine dendritic cells. AB - Dendritic cells (DCs) are professional antigen-presenting cells (APC) that play a central role in the initiation and regulation of immune responses. We have previously demonstrated that Lycium barbarum polysaccharides liposomes (LBPL) as immune adjuvant elicits strong antigen-specific Th1 immune responses. The purpose of this study was to investigate underlying mechanism of liposomes promoting effect of Lycium barbarum polysaccharides (LBP) on activating DCs. LBP were loaded with high entrapment efficiency (86%) into liposomes using reverse phase evaporation. LBPL activation of phenotypic and functional maturation of DCs was explored through mechanistic studies of the TLR4-MyD88-NF-kappaB signaling pathway and amount of proinflammatory cytokines released. We found that LBPL indeed activated immature DCs and induced DCs maturation characterized by up regulation of co-stimulatory molecules (MHCII, CD80, CD86), production of cytokines (IL-12p40, TNF-alpha), and enhancement of antigen uptake. Additionally, we demonstrated that liposomes could promote LBP up-regulation of TLR4, MyD88, TRAF6, NF-kappaB gene and protein expression. PMID- 30446139 TI - Bio-based and photocrosslinked electrospun antibacterial nanofibrous membranes for air filtration. AB - Air pollution is becoming more and more severe especially in developing countries. It is urgent to seek an effective protection for the unacceptable levels of the air pollution. Up to date, the air filtration is a widely used method to protect us from the air pollution. However, most of the air filtration membranes in fabrication process is required to use harmful organic solvents. Here, we report a human friendly, multifunctional and bio-based chitosan/poly (vinyl alcohol) air filtration membrane via green electrospinning and UV-cured. This green approach avoid use hazardous organic solvents which caused the residual solvents could bring the human subprime damage. Specifically, the superhydrophobic silica nanoparticles is introduced on the nanofibers to formation of the rough surface to increase filtration efficiency. In addition, the Ag nanoparticles (NPs) are fabricated on the surface through UV reduction of AgNO3 to achieve the aim of antibacterial treatment. The CS/PVA@SiO2/Ag NPs membranes not only possess excellent filtration performance but efficiently antibacterial activities. As this green, multifunctional and bio-based CS/PVA@SiO2/Ag NPs air filtration membranes have several superior features like high air filtration performance, biological compatibility and antibacterial, it has great potential application in eco-friendly air filtration materials, especially in personal air filtration materials. PMID- 30446140 TI - Chitin and waste shrimp shells liquefaction and liquefied products/polyvinyl alcohol blend membranes. AB - Ball-milled chitin was liquefied with an optimal yield of 92% under sulfuric acid in diethylene glycol (DEG) at 160 degrees C for 120 min. The resulting liquid mixture was roughly separated into two portions: the real products of the reaction (liquefied ball-milled chitin, LBMC) and the remaining unreacted DEG. LBMC was further mingled with polyvinyl alcohol (PVA) to prepare LBMC/PVA blend membranes. To promote the direct utilization of shellfishery waste, raw shrimp shells were used to replace chitin for the liquefaction and membrane preparation operations. Liquefied ball-milled shrimp shells (LBMS) and the corresponding LBMS/PVA blend membranes were obtained. After adding LBMC or LBMS, the mechanical, thermal, water content and antibacterial performance of blend membranes were significantly improved compared to pure PVA membrane. Surprisingly, all the measured properties of LBMC/PVA and LBMS/PVA blend membranes were comparable, and even some properties of the latter were slightly superior than those of the former. PMID- 30446141 TI - Bio-based (chitosan/PVA/ZnO) nanocomposites film: Thermally stable and photoluminescence material for removal of organic dye. AB - Preparation of hitherto unreported chitosan/poly(vinyl alcohol)/ZnO nanocomposites film (designated as CS/PVA/ZnO) as an efficient bio-based nanocomposites is carried out by a greener approach involving mixing, solution casting and solvent evaporation. Synthesized chitosan-based nanocomposites films are characterized by various analytical techniques such as Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The photoluminescent properties of CS/PVA/ZnO films are thoroughly studied and compared with CS/PVA. The outcome suggested that the addition of ZnO nanoparticles increased the intensities and red shifting with respect to CS/PVA. The toxicity of chitosan based nanocomposites films was examined by MTT assay using the NIH3T3 cells. The viability of chitosan-based nanocomposites films was found to be better than native chitosan and PVA films. Furthermore, the adsorption property of prepared chitosan-based nanocomposites films was tested for the removal of AB 1 dye. PMID- 30446142 TI - The exopolysaccharide properties and structures database: EPS-DB. Application to bacterial exopolysaccharides. AB - The EPS Database (EPS-DB) is a web-based, platform-independent database of bacterial exopolysaccharides (EPSs) providing access to detailed structural, taxonomic, growth conditions, functional properties, genetic, and bibliographic information for EPSs. It is freely available on the Internet as a website at http://www.epsdatabase.com. Several structural data representation schemes are used following the most commonly accepted formats. This guarantees full interoperability with other structural, experimental, and functional databases in the area of glycoscience. The scientific usage of EPS-DB throughout a user friendly interface is presented with a subsection of the database exemplified by EPSs from lactic acid bacteria. PMID- 30446144 TI - Sucrose-based biosynthetic process for chain-length-defined alpha-glucan and functional sweetener by Bifidobacterium amylosucrase. AB - A unique thermostable amylosucrase from Bifidobacterium thermophilum was produced as a recombinant protein with the half-life of 577 h at 50 degrees C. By adding 1.0 M fructose, turanose yield was improved from 22.7% to 43.3% with 1.0 M sucrose, and from 23.7% to 39.4% with 1.5 M sucrose. Sucrose consumption rate was greatest at 55 degrees C, but the lowest amount of turanose was produced. Thus, turanose yield from sucrose biomass was inversely proportional to reaction temperature and was highly dependent on [fructose]. Meanwhile, insoluble alpha glucan yield was clearly reduced as [fructose] increased. With 1.0 M fructose + 1.0 M sucrose, glucan byproduct yield significantly decreased from 29.4% to 1.1%. Molecular weights of linear glucans were almost identical among various [sucrose]s and were homogenous with very low polydispersity. This unique dual reaction patterns of amylosucrase enzyme would be very useful for massive productions of two different biomaterials simply by changing sucrose biomass concentration. PMID- 30446143 TI - Linolenic acid-modified methoxy poly (ethylene glycol)-oligochitosan conjugate micelles for encapsulation of amphotericin B. AB - Introduction of linolenic acid (LNA) and methoxy poly (ethylene glycol) (MPEG) to the backbone of oligochitosan (CS) afforded LNA-modified MPEG-CS conjugate (MPEG CS-LNA). Amphotericin B-loaded MPEG-CS-LNA micelles (AmB-M) were prepared via dialysis method with 82.27 +/- 1.96% of drug encapsulation efficiency and 10.52 +/- 0.22% of drug loading capacity. The AmB-M enhanced AmB's water-solubility to 1.64 mg/mL, being 1640-folds higher than native AmB. The AmB-M obviously reduced hemolytic effect and renal toxicity of AmB when compared to marketed AmB injection (AmB-I). Its antifungal activity against Candida albicans was equivalent to AmB-I although AmB's release from AmB-M was significantly retarded. According to fluorescence microscopy test, the unchanged activity should be attributed to enhanced fungal cellular uptake of AmB-M caused by combined inducement of LNA and CS. The pharmacokinetic studies demonstrated that AmB-M also improved the pharmacokinetic parameters of AmB with AmB-I as control. Conclusively, developed LNA-modified MPEG-CS micellar system could be a viable alternative to the current toxic commercial AmB-I as a highly efficacious drug delivery system. PMID- 30446145 TI - A novel controlled release system based on Tragacanth nanofibers loaded Peppermint oil. AB - In this paper, a novel controlled release system based on Tragacanth nanofibers loaded with Peppermint oil is introduced by using a sonochemical/microemulsion method. The synthesized Tragacanth nanofibers showed a one-dimensional shape with 58 nm thickness and relatively smooth surface. Also, the loading of Peppermint oil into the synthesized nanofibers confirmed with FT-IR spectra. Further, a relatively good controlled release property (92.38%) reported for the loaded Peppermint oil nanofibers after 18 h. Finally, the synthesized nanofibers loaded with 18.3% Peppermint oil presented reasonably good antibacterial activities against E. coli and S. aureus and a low-cytotoxicity against human fibroblast cells as the most important properties. PMID- 30446146 TI - Jellylike flexible nanocellulose SERS substrate for rapid in-situ non-invasive pesticide detection in fruits/vegetables. AB - This study aimed to develop a jellylike flexible substrate based on nanocellulose decorated with Ag nanoparticles (Ag/NC substrate) and explore its applications for rapid in-situ pesticide detections in fruits and vegetables by surface enhanced Raman spectroscopy (SERS). The performances of Ag/NC substrate were characterized by rhodamine 6G (R6G). The limit of detection recorded by a portable Raman spectrometer is 10-8 M. The substrate still exhibited satisfactory sensitivity after 60-day preservation. Jellylike and slightly sticky Ag/NC substrate demonstrated good adaptabilities in attaching to sample surfaces and is suitable for in-situ SERS detection. Two types of pesticides on apple peels and cabbages were detected by rapid in-situ and non-invasive SERS method coupled with Ag/NC substrate. The lowest detectable level was 0.5 ng/cm2 for thiram and 5 ng/cm2 for thiabendazole, which were well below the maximum residue levels. These results demonstrate that Ag/NC substrate is sensitive for rapid in-situ multi pesticide detection in food. PMID- 30446147 TI - Polysaccharides for tissue engineering: Current landscape and future prospects. AB - Biological studies on the importance of carbohydrate moieties in tissue engineering have incited a growing interest in the application of polysaccharides as scaffolds over the past two decades. This review provides a perspective of the recent approaches in developing polysaccharide scaffolds, with a focus on their chemical modification, structural versatility, and biological applicability. The current major limitations are assessed, including structural reproducibility, the narrow scope of polysaccharide modifications being applied, and the effective replication of the extracellular environment. Areas with opportunities for further development are addressed with an emphasis on the application of rationally designed polysaccharides and their importance in elucidating the molecular interactions necessary to properly design tissue engineering materials. PMID- 30446148 TI - Sustainable biosynthesis of curdlan from orange waste by using Alcaligenes faecalis: A systematically modeled approach. AB - This study presents an engineered approach for sustainable biosynthesis of curdlan by Alcaligenes faecalis using orange peels. To confirm the substrate suitability a four step study was organized. Firstly, drying of substrate was carried within temperature range of 60-120 degrees C, along with the application of moisture diffusion control model. Secondly, fermentation medium was obtained via saccharification and detoxification, releasing highest sugar at 72.34 g/L with phenolics removal of 95-98%. Thirdly, curdlan fermentation was conducted in detoxified orange peel hydrolysate followed by optimization of batch culture fermentation via kinetic modeling using Logistic and Luedeking-Piret equations. In 5 L bioreactor, highest specific growth rate (MUm = 0.233/h), highest curdlan production (Pm = 23.24 g/L) and growth associated rate constant (alpha = 3.403) were achieved. Moreover, the total sugar consumption and conversion rates were 83.27% and 53.20%. Lastly, characterization techniques such as FTIR, NMR, XRD, TGA, HPGPC and EDS were applied to biosynthesized curdlan for qualitative validation. PMID- 30446149 TI - Structural characteristics and anticancer/antioxidant activities of a novel polysaccharide from Trichoderma kanganensis. AB - A novel water-soluble polysaccharide designated as TPS was isolated from the fermentation mycelia of Trichoderma kanganensis. TPS had a weight-average molecular mass of 3.074 * 105 Da, and the monosaccharide composition was consisted of Man (45.5%), GlcA (5.5%), Glc (10%), and Gal (39%). The major backbone of TPS was ->6-alpha-d-Galp-1->5-beta-d-Manf-1->5,6-beta-d-Manf-1->5,6 beta-d-Manf-1->, and the side chains are alpha-d-Glcp-1->4-alpha-d-Glcp-1->, beta d-Galf-1->, and alpha-d-Glcp-1->. In addition, we demonstrated that TPS was non toxic in normal cells (LO2 cells) and inhibited the proliferation of mouse colon cells (CT26 cells). TPS also showed free radical scavenging activity against hydrogen peroxide. Overall, these results suggested that TPS from Trichoderma kanganensis may have potential application in biomedical fields. PMID- 30446150 TI - Mussel-inspired codepositing interconnected polypyrrole nanohybrids onto cellulose nanofiber networks for fabricating flexible conductive biobased composites. AB - The exploitation of an efficient strategy for preparing flexible green conductive composites with an interconnected filler network is of great scientific and technical interest. Herein, a high-performance interconnected cellulose nanofiber (CNF) template functionalized tannic acid (TA)/polypyrrole (PPy) nanohybrid network (TPy@CNF) is fabricated by a green mussel-inspired co-modification approach. The network offers high electrical conductivity to prepare flexible, plant-derived soy protein isolate (SPI) composites. The mussel-inspired interface design demonstrates versatile functions of a reactive adhesion layer to construct a multiple-bond-regulated interconnected TPy@CNF conductive polymer network architecture without the need for harsh conditions and toxic reagents. This well defined conducting TA/PPy-encapsulated CNF network is of great benefit in achieving strong synergistic interactions by enhancing electrical conductivity, reducing junction contact resistance, and ensuring efficient load transfer during bending. When integrating 7.5 wt% TPy@CNF, the prepared SPI composites deliver significantly enhanced conductivity of 0.078 S m-1 along with superior mechanical robustness (improved tensile strength and toughness) and excellent structural stability. This interconnected network design strategy can provide a green yet feasible approach for elaborate construction of CNF/conducting polymers in advanced energy-storage technologies. PMID- 30446151 TI - Extremophilic exopolysaccharides: A review and new perspectives on engineering strategies and applications. AB - Numerous microorganisms inhabiting harsh niches produce exopolysaccharides as a significant strategy to survive in extreme conditions. The exopolysaccharides synthesized by extremophiles possess distinctive characteristics due to the varied harsh environments which stimulate the microorganisms to produce these biopolymers. Despite many bioprocesses have been designed to yield exopolysaccharides, the production of exopolysaccharides by extremophiles is inefficient compared with mesophilic and neutrophilic exopolysaccharide producers. Meanwhile, the industrial development of novel extremophilic exopolysaccharides remains constrained due to the lack of exploration. In this review, we summarize the structure and properties of various exopolysaccharides produced by extremophiles, and also discuss potential metabolic and genetic engineering strategies for enhanced yield and modified structure of extremophilic exopolysaccharides. Special focus is given to the applications of extremophilic exopolysaccharides in the areas of biomedicine, food industry, and biomaterials via nano-techniques, casting and electrospinning. PMID- 30446152 TI - Preparation of polyacrylic acid-grafted-acryloyl/hemicellulose (PAA-g-AH) hybrid films with high oxygen barrier performance. AB - Developing high-performance oxygen barrier films using biomass-based materials is crucial for the development of green and sustainable society. Herein, we develop a strategy to synthesize polyacrylic acid-grafted-acryloyl/hemicellulose composites (PAA-g-AH) as film materials with excellent oxygen barrier property. The as-synthesized films were extensively characterized by Fourier transform infrared (FT-IR), scanning electron microscopy (SEM), gel permeation chromatography (GPC), 1H nuclear magnetic resonance (1H NMR), mechanical test, light transmittance and oxygen transmission rate (OTR) measurement. All these testing results showed that the optimum film exhibit great oxygen barrier property with a low OTR value of 0.25 +/- 0.01 cm3* MUm/(m2*d*kPa), which was much lower than that of pure PAA film. Moreover, the hybrid films possess well mechanical strength, light transmittance and recycle usage properties. Experimental results indicated that the as-synthesized films have great potential applications in several fields as packaging materials, such as drug, food and electronic products. PMID- 30446154 TI - Engineering rheological properties of edible oleogels with ethylcellulose and lecithin. AB - Addition of 1% (w/w) soy lecithin increased the shear moduli 10-fold and gel hardness 20-fold for 10% ethylcellulose (EC) oleogels. Higher lecithin addition levels or addition to gels with a higher EC concentration caused smaller increases. Similar trends were observed in the penetration force of the gels. Gels displayed thermal reversibility and a high temperature plateau at T~120-130 degrees C. Large amplitude oscillatory shear rheology demonstrated similar solid to-fluid transitions indicating that the polymer drives elastic softening and failure of the network. However, EC oleogels differed in their resistance to flow: the addition of unsaturated lecithin promoted a more gradual thickening response compared to gels containing saturated lecithin or only EC (the last two types of gels display strong intra-cycle thickening and thinning, more indicative of brittle failure). The thickening response of EC oleogels containing unsaturated lecithin, resembles more closely that of a model edible fat (lard). PMID- 30446153 TI - Heparin as a molecular spacer immobilized on microspheres to improve blood compatibility in hemoperfusion. AB - Heparin, a highly sulfated linear polysaccharide, with anticoagulation function and blood compatibility is widely used as a biomaterials in medical application, but the most importance of heparin is its structure function as the macromolecular space arm. In this study, heparin as a spacer was covalently immobilized on the chloromethylated polystyrene microspheres (Ps) and then connected with l-phenylalanine forming the Ps-Hep-Phe structure, which was developed for endotoxin adsorption in hemoperfusion. The grafting density of heparin reach the maximum when the initial concentration of heparin solution was 5 mg/mL. The adsorbents with the heparin as a spacer showed the prolonged clotting times, low protein adsorption, and reduced the hemolysis rate, indicating that heparin-modified adsorbents have great blood compatibility. The adsorption capacity of Ps-Hep-Phe for endotoxin was 25.15 EU/g in dynamic adsorption, higher than that of Ps. Therefore, this study imply that heparin would be promising for modification of adsorbents in hemoperfusion. PMID- 30446155 TI - Very low certainty in evidence suggesting no differences in caries development when comparing glass ionomer cement sealants and resin-based sealants. PMID- 30446156 TI - Corticosteroids may reduce pain after endodontic treatment. PMID- 30446157 TI - [Development of a standardized guide for optimizing drug adherence information to be dispensed during a pharmaceutical counseling with a multiple myeloma patient: Final validation]. AB - An initial validation of a standardized pharmaceutical counselling guide was carried out in a previous study to improve medication adherence in patients treated for multiple myeloma with oral anticancer therapies. The main objective of this work was the final validation of this guide with 10 naive patients. The main secondary objectives were to assess for the patient the evolution of knowledge about the treatment, understanding of the purpose of the pharmaceutical counselling, adherence to the tools. Each patient completed a self-administered questionnaire: before and after the first pharmaceutical counselling. The primary endpoint was the average success rate per question after the pharmaceutical counselling (a value of >= 90% validated knowledge acquisition). Secondary judgement criteria were: change in average success rates per patient and question, rate of reformulation of the objective of the pharmaceutical counselling, response rate to presentation questions, readability and understanding. No average success rate per question after the pharmaceutical counselling was statistically less than 90%. The average success rates per patient before and after the pharmaceutical counselling were 78.9+/-13.7% vs 96.1+/-3.9% (P=0.01). The average success rates per question were different for 4 questions. All patients were able to reformulate the objective of the pharmaceutical counselling and validated the presentation, readability and understanding of the documents. This study led to the final validation of the pharmaceutical counselling guide. PMID- 30446158 TI - Dynamics of PAR Proteins Explain the Oscillation and Ratcheting Mechanisms in Dorsal Closure. AB - We present a vertex-based model for Drosophila dorsal closure that predicts the mechanics of cell oscillation and contraction from the dynamics of the PAR proteins. Based on experimental observations of how aPKC, Par-6, and Bazooka translocate from the circumference of the apical surface to the medial domain, and how they interact with each other and ultimately regulate the apicomedial actomyosin, we formulate a system of differential equations that captures the key features of dorsal closure, including distinctive behaviors in its early, slow, and fast phases. The oscillation in cell area in the early phase of dorsal closure results from an intracellular negative feedback loop that involves myosin, an actomyosin regulator, aPKC, and Bazooka. In the slow phase, gradual sequestration of apicomedial aPKC by Bazooka clusters causes incomplete disassembly of the actomyosin network over each cycle of oscillation, thus producing a so-called ratchet. The fast phase of rapid cell and tissue contraction arises when medial myosin, no longer antagonized by aPKC, builds up in time and produces sustained contraction. Thus, a minimal set of rules governing the dynamics of the PAR proteins, extracted from experimental observations, can account for all major mechanical outcomes of dorsal closure, including the transitions between its three distinct phases. PMID- 30446159 TI - A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy. AB - Accumulation of fibrillar amyloid beta protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesis of this condition. Herein, we describe the generation and characterization of a novel transgenic rat (rTg-DI) that produces low levels of human familial CAA Dutch/Iowa E22Q/D23N mutant amyloid beta protein in brain and faithfully recapitulates many of the pathologic aspects of human small-vessel CAA. rTg-DI rats exhibit early-onset and progressive accumulation of cerebral microvascular fibrillar amyloid accompanied by early-onset and sustained behavioral deficits. Comparable to CAA in humans, the cerebral microvascular amyloid in rTg-DI rats causes capillary structural alterations, promotes prominent perivascular neuroinflammation, and produces consistent, robust microhemorrhages and small-vessel occlusions that are readily detected by magnetic resonance imaging. The rTg-DI rats provide a new model to investigate the pathogenesis of small-vessel CAA and microhemorrhages, to develop effective biomarkers for this condition and to test therapeutic interventions. PMID- 30446160 TI - Pneumomediastinum in blunt trauma: If aerodigestive injury is not seen on CT, invasive workup is not indicated. AB - BACKGROUND: Pneumomediastinum following blunt trauma is often observed on CT imaging, and concern for associated aerodigestive injury often prompts endoscopy and/or fluoroscopy. In recent years, adoption of multi-detector CT technology has resulted in high resolution images that may clearly identify aerodigestive injuries. The purpose of this study was to evaluate the utility of multi-detector CT in the identification of blunt aerodigestive injuries. METHODS: Over five years, patients with pneumomediastinum following blunt trauma were identified from the registry of a level 1 trauma center. All CT imaging of trauma patients during this time period was accomplished with 64-slice scanners. RESULTS: 127 patients with blunt traumatic pneumomediastinum were identified. Five airway injuries were identified, and all injuries were evident on CT imaging. No patient was found to have airway injury by endoscopy that was not evident on CT. No patient had an esophageal injury. CONCLUSION: Multi-detector CT imaging identifies aerodigestive injuries associated with pneumomediastinum following blunt trauma. The absence of a recognizable aerodigestive injury by CT effectively rules out the presence of such injury. PMID- 30446161 TI - A randomized double blinded study to determine the effectiveness of utilizing intraperitoneal bupivacaine: Does it reduce postoperative opioid use following laparoscopic appendectomy? AB - BACKGROUND: Improving postoperative pain control may lead to improved outcomes including decreased opioid use, shorter hospital stays, and improved patient satisfaction. This study examined the effects of instilling intraperitoneal bupivacaine following laparoscopic appendectomy. METHODS: In this prospective, randomized, double-blinded, placebo-controlled study, patients with appendicitis were randomized to receive either the bupivacaine or normal saline instilled at the appendectomy site prior to close. Postoperative pain scores, opioid doses and length of stay were recorded. RESULTS: Pain scores were lower (mean 2.48 versus 3.8; p = 0.014), and postoperative opioid use was lower (mean 7.394 mg versus 16.921 mg; p = 0.007) in the bupivacaine group. CONCLUSIONS: Instilling bupivacaine at the base of the cecum at the conclusion of laparoscopic appendectomy was associated with reducing postoperative pain scores and in hospital opioid use. STATEMENT: This prospective, randomized, double-blinded, placebo-controlled study enrolled subjects with acute appendicitis undergoing laparoscopic appendectomy. Subjects were randomized to receive either bupivacaine or normal saline intraperitoneally at the close of surgery. In the bupivacaine group, pain scores at 1 h were improved and inpatient postoperative opioid use was less. PMID- 30446162 TI - Ruining the surprise: The effect of safety information before extinction on return of fear. AB - BACKGROUND AND OBJECTIVES: In psychoeducation before exposure treatment patients are sometimes provided with information about the (low) probability that the feared outcome would occur. Since it has been proposed in the literature that this might have adverse effects, the current study investigated the effect of providing participants with this type of safety information on return of fear. METHOD: In an ABA-renewal paradigm, participants in the experimental group were instructed between acquisition and extinction that the probability of US occurrence would be extremely small in the remainder of the experiment. Participants in the control group did not receive this information. RESULTS: Less return of fear in US-expectancy ratings was observed in participants who received the safety information. LIMITATIONS: We failed to find successful acquisition in the skin-conductance data, which prevented us from interpreting the results of this outcome measure. CONCLUSIONS: These results suggest that providing safety information is not deleterious for the effects of exposure and can even be beneficial for its effects. However, further clinical research is needed. PMID- 30446163 TI - Social anxiety and sensitivity to social-rank features in male faces. AB - BACKGROUND AND OBJECTIVES: Evolutionary theories propose that socially anxious individuals are especially sensitive to social-rank signals, presumably at the expense of the attunement to signals of affiliation. Despite this theoretical claim, few empirical attempts examined the association between social anxiety (SA) and sensitivity to specific features of social-rank and affiliation. This study aims to fill this gap. METHOD: Participants (N = 67) completed two tasks in which two emotionally neutral computer-generated male faces of the same character were presented side-by-side. In the Social-Rank-Sensitivity Task, the faces within each pair differed in their level of dominance and, in the Affiliation Sensitivity Task, the faces differed in their level of trustworthiness. The participants' task was to decide which of the two faces looked more dominant or friendly. RESULTS: There were no differences in accuracy between high- and low-SA participants in the Affiliation-Sensitivity Task. In contrast, high-SA participants were more accurate than low-SA participants in the Social-Rank Sensitivity Task. No group differences were found in decision latencies in either task. LIMITATIONS: Limitations of the study are that a non-clinical sample was used and that only computer-generated male faces were considered. CONCLUSIONS: Our findings suggest that SA is related to an enhanced ability to discriminate faces based on social-rank features. Examining sensitivity to facial cues signaling social-rank and affiliation may help to specify the nature of social threat sensitivity in SA. PMID- 30446164 TI - Acute Lung Injury: Endothelial Progenitor Cells to the Rescue? PMID- 30446165 TI - An analysis of characterized plant sesquiterpene synthases. AB - Plants exhibit a vast array of sesquiterpenes, C15 hydrocarbons which often function as herbivore-repellents or pollinator-attractants. These in turn are produced by a diverse range of sesquiterpene synthases. A comprehensive analysis of these enzymes in terms of product specificity has been hampered by the lack of a centralized resource of sufficient functionally annotated sequence data. To address this, we have gathered 262 plant sesquiterpene synthase sequences with experimentally characterized products. The annotated enzyme sequences allowed for an analysis of terpene synthase motifs, leading to the extension of one motif and recognition of a variant of another. In addition, putative terpene synthase sequences were obtained from various resources and compared with the annotated sesquiterpene synthases. This analysis indicated regions of terpene synthase sequence space which so far are unexplored experimentally. Finally, we present a case describing mutational studies on residues altering product specificity, for which we analyzed conservation in our database. This demonstrates an application of our database in choosing likely-functional residues for mutagenesis studies aimed at understanding or changing sesquiterpene synthase product specificity. PMID- 30446166 TI - Current therapeutic options in metastatic castration-resistant prostate cancer. AB - BACKGROUND: The tumors of many patients with prostate cancer eventually become refractory to androgen deprivation therapy with progression to metastatic castration-resistant disease. Significant advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) have been made in recent years, and new treatment strategies have recently been made available. The aim of this report was to schematically review all the approved pharmacologic treatment options for patients with mCRPC through 2018, analyzing the efficacy and possible side effects of each therapy to assist clinicians in reaching an appropriate treatment decision. New biomarkers potentially of aid in the choice of treatment in this setting are also briefly reviewed. METHODS: We performed a literature search of clinical trials of new drugs and treatments for patients diagnosed with mCRPC published through 2018. RESULTS: Two new hormonal drugs, abiraterone acetate and enzalutamide have been approved by FDA in 2011 and 2012, respectively for the treatment of patients with mCRPC and have undergone extensive testing. While these treatments have shown a benefit in progression-free and overall survival, the appropriate sequencing must still be determined so that treatment decisions can be made based on their specific clinical profile. Cabazitaxel has been shown to be an efficient therapeutic option in a postdocetaxel setting, while its role in chemotherapy-naive patients must still be determined. Sipuleucel-T and radium-223 have been studied in patients without visceral metastases and have achieved overall survival benefits with good safety profiles. The feasibility and efficacy of combinations of new treatments with other known therapies such as chemotherapy are currently under investigation. CONCLUSIONS: Drug development efforts continue to attempt to prolong survival and improve quality of life in the mCRPC setting, with several therapeutic options available. Ongoing and future trials are needed to further assess the efficacy and safety of these new drugs and their interactions, along with the most appropriate sequencing. PMID- 30446167 TI - Management of immunotherapy toxicities in older adults. AB - Advanced age is a risk factor for cancer and is attributed to dysregulation of the immune system. Historically, treatment of advanced cancer has primarily involved systemic chemotherapy that is associated with high treatment related toxicity especially in older adults. Immune checkpoint inhibitors (ICIs) provide an exciting treatment option for older adults in terms of efficacy and safety as compared to systemic chemotherapy. Given the pace of approval of ICIs for multiple cancers, there is an increase in both the use of ICIs and the associated immune-related adverse events. In this article, we address how to approach immunotherapy related toxicities in older adults given the availability of limited data. PMID- 30446168 TI - Self-acceptance, resilience, coping and satisfaction of life in people who stutter. AB - PURPOSE: The purpose of the present study was to evaluate self-acceptance and satisfaction with life with people who stutter and the influence of coping and resilience on the two factors. METHOD: Forty-seven people who stutter (PWS) and 47 people who do not stutter (PWNS) participated in an online survey. Participants completed a survey assessing 6 main areas: (a) background information, (b) satisfaction with life, (c) coping, (d) avoidance, (e) self acceptance, and resilience. RESULTS: Avoidant coping and maladaptive coping moderated the association between stuttering and self- acceptance but not satisfaction with life. Resilience was found to moderate the association between stuttering and self-acceptance as well as satisfaction with life. CONCLUSION: Stuttering was associated with lower self-acceptance at higher levels of avoidant coping and maladaptive coping. PWS who have lower levels of resilience were more likely to have a lower satisfaction with life indicating that higher levels of resilience could serve as a protective factor for having a greater satisfaction with life. Further, stuttering was associated with lower self-acceptance at lower levels of resilient attitude. Resilience and coping appear to protect against having diminished self-acceptance and satisfaction with life for PWS. PMID- 30446169 TI - Environmental characteristics of a tundra river system in Svalbard. Part 2: Chemical stress factors. AB - Bacterial communities in the Arctic environment are subject to multiple stress factors, including contaminants, although typically their concentrations are small. The Arctic contamination research has focused on persistent organic pollutants (POPs) because they are bioaccumulative, resistant to degradation and toxic for all organisms. Pollutants have entered the Arctic predominantly by atmospheric and oceanic long-range transport, and this was facilitated by their volatile or semi-volatile properties, while their chemical stability extended their lifetimes following emission. Chemicals present in the Arctic at detectable and quantifiable concentrations testify to their global impact. Chemical contamination may induce serious disorders in the integrity of polar ecosystems influencing the growth of bacterial communities. In this study, the abundance and the types of bacteria in the Arctic freshwater were examined and the microbial characteristics were compared to the amount of potentially harmful chemical compounds in particular elements of the Arctic catchment. The highest concentrations of all determined PAHs were observed in two samples in the vicinity of the estuary both in June and September 2016 and were 1964 ng L-1 (R12) and 3901 ng L-1 (R13) in June, and 2179 ng L-1 (R12) and 1349 ng L-1 (R13) in September. Remarkable concentrations of the sum of phenols and formaldehyde were detected also at the outflow of the Revelva river into the sea (R12) and were 0.24 mg L-1 in June and 0.35 mg L-1 in September 2016. The elevated concentrations of chemical compounds near the estuary suggest a potential impact of the water from the lower tributaries (including the glacier-fed stream measured at R13) or the sea currents and the sea aerosol as pollutant sources. The POPs' degradation at low temperature is not well understood but bacteria capable to degrading such compounds were noted in each sampling point. PMID- 30446170 TI - Caveolin-1 is related to lipid droplet formation in hepatic stellate cells in human liver. AB - Caveolins (CAVs) regulate intracellular cholesterol transport by a complex process involving caveolae, endoplasmic reticulum (ER), and the Golgi network. Hepatic stellate cells (HSCs) are the central site for retinoid storage in the liver and indeed the entire body. Herein, we attempted to elucidate the ultrastructural localization and expression of caveolin-1 (CAV-1) in human HSCs during the progression of liver cirrhosis (LC). Normal and hepatitis C-related cirrhotic liver samples were prepared using a modified perfusion-fixation method to fix organelle structures and molecules in their in vivo positions, and examined using immunoelectron microscopy. In control liver specimens, CAV-1 was minimally associated with low electron density lipid droplets (LDs) segregated around zones 1-2, and specifically associated with membranes surrounding LDs. CAV 1 was segregated in high-density LDs, consistent with the formation of membrane enclosed lipid-rich vesicular structures, as well as caveolae on plasma membranes around zones 2-3. In cirrhotic liver specimens, CAV-1 molecules were inserted into the cytoplasmic leaflets of ER membranes for transportation to LDs. Thus, CAV-1 transport to LDs might represent an intracellular pathway from the ER in cirrhotic liver tissue. PMID- 30446172 TI - New report on assessing mobility has us moving toward consensus on the care we need as we age. PMID- 30446171 TI - Validation of index-based IWATE criteria as an improved difficulty scoring system for laparoscopic liver resection. AB - BACKGROUND: The original difficulty scoring system was revised after discussion at the 2nd International Consensus Conference on Laparoscopic Liver Resection held in Morioka (Iwate Prefecture) in Japan and renamed the IWATE criteria (a 4 level classification system involving 6 preoperative factors). We used Japanese and French cohorts to validate the IWATE criteria by evaluating their association with the procedure-based difficulty classification proposed by the Institut Mutualiste Montsouris. METHOD: Patients who had undergone laparoscopic liver resection at multiple Japanese multi-institutions or the Institut Mutualiste Montsouris were assigned to the multiple Japanese multi-institution (n = 1,867) or Institut Mutualiste Montsouris cohort (n = 433). We analyzed clinical characteristics and outcomes according to the 4-level IWATE criteria difficulties (low, intermediate, advanced, and expert) and evaluated their association with 11 laparoscopic liver resection procedures in the Institut Mutualiste Montsouris classification (low, intermediate, and high levels). RESULTS: We found significant differences in age, surgical indications, and the 4-level IWATE criteria difficulties between the cohorts (all, P < .001). Operation time and blood loss were significantly different among the 4-level difficulties in both cohorts (all, P < .001). The rates of conversion, postoperative complications, liver failure, and in-hospital deaths also increased significantly with increasing difficulty (all, P < .001). The IWATE criteria classified the three low-level Institut Mutualiste Montsouris procedures in the low-to-intermediate levels, the two intermediate-level procedures in the intermediate-to-advanced levels, and the six high-level procedures in the advanced-to-expert levels. CONCLUSION: We observed associations between the IWATE criteria and intraoperative and postoperative outcomes in the Japanese multi-institution and Institut Mutualiste Montsouris cohorts and thus validated the IWATE system. PMID- 30446173 TI - Anti-tumor necrosis factor agents in sarcoidosis: A systematic review of efficacy and safety. AB - BACKGROUND: Though anti-tumor necrosis factor agents (anti-TNFs) have been recommended as third-line therapy for sarcoidosis, an up-to-date systematic synthesis of their efficacy and safety is lacking. OBJECTIVES: To systematically review the literature to characterize the efficacy and safety of anti-TNFs in sarcoidosis. SETTINGS: All countries and treatment settings were included. METHODS: We searched MEDLINE, EMBASE, CINAHL, Web of Science, ClinicalTrials.gov, Cochrane Library, and Google Scholar from inception to November 27, 2017. Studies of five or more cases of sarcoidosis treated with anti-TNFs were included. Descriptive statistics were performed. RESULTS: Sixty-five studies (including five randomized controlled trials [RCTs]) were identified, comprising 1525 patients. For pulmonary sarcoidosis, one RCT found infliximab (IFX) significantly improved vital capacity vs. placebo; a second detected no difference. In non randomized studies, IFX improved pulmonary function in 79% of patients. For cutaneous sarcoidosis, compared to placebo, adalimumab (ADA) showed greater Physician Global Assessment response and significantly reduced target lesion area, and IFX significantly decreased Sarcoidosis Area and Severity Index induration and erythema scores. In non-randomized studies of cutaneous, ocular, neurologic, and multisystem sarcoidosis, IFX improved 89%, 69%, 77%, and 71% of cases, respectively. ADA improved 77% of ocular sarcoidosis cases. IFX displayed a steroid-sparing effect. Half of patients relapsed after discontinuation of IFX, ADA, etanercept, or certolizumab pegol. In RCTs, compared to placebo, anti-TNFs had comparable overall and serious adverse events and slightly more serious infections. CONCLUSIONS: Available evidence suggests the efficacy and safety of IFX in pulmonary, cutaneous, ocular, neurologic, and multisystem sarcoidosis, and ADA in cutaneous and ocular sarcoidosis. PMID- 30446174 TI - Mild encephalopathy/encephalitis with a reversible splenial lesion associated with acute pyelonephritis: A case report. PMID- 30446175 TI - Autoantibodies to cytoplasmic rods and rings in patients with hepatitis C virus infection treated with direct-acting antivirals: The role of prior treatment with interferon plus ribavirin. AB - INTRODUCTION: The cytoplasmic rods-rings (RR) pattern is found in hepatitis C (HCV) patients treated with interferon-ribavirin when studied with ANA-IIF. Ribavirin aggregates/induces antigenic changes in IMPDH-2, an enzyme necessary for ribavirin action. PATIENTS AND METHOD: Prospective search for anti-RR autoantibodies (HEp-2, INOVA) in patients treated with direct-acting antivirals (DAAs) from October 2015 to June 2017. HCV-negative patients from up to June 2016 acted as controls. Anti-RR was analyzed at baseline and, mainly, during treatment and follow-up. The Chi-square test, Student's t-test and a logistic regression analysis were performed. RESULTS: Between October 2015 and June 2016, 1258 men and 2389 women who were HCV-negative and 137 men and 112 women who were HCV positive patients were studied. Approximately 22.9% of HCV-negative and 13.2% of HCV-positive were ANA-IIF-positive (p<0.05). Three HCV-negative (0.08%) and 23 (9.2%) HCV-positive patients had anti-RR (p<0.001). A total of 122 patients received DAAs; 30 received DAA+RBV; 46 pre-treated with IFN-RBV received DAA; 31 pre-treated with IFN-RBV received DAA+RBV; 16 received IFNpeg-RBV; and 24 received IFN-RBV-DAA. None of the 122 DAA-treated patients showed anti-RR; anti RR were identified in 14.8% of those treated with DAA-RBV; in 25.9% of those pre treated with IFN-RBV receiving DAA; in 22.2% of IFN-RBV-pre-treated patients who received DAA+RBV; in 7.4% of those treated with IFNpeg-RBV and in 29.6% of those treated with IFNpeg-RBV-DAA. The multivariate analysis showed significant associations between anti-RR and "Exposure to IFN" and "Time of exposure to RBV". CONCLUSIONS: Anti-RR autoantibodies were detected only in patients with current or past treatments with RBV, even in cases in which only DAAs were later administered. PMID- 30446176 TI - Evaluation of the protective efficacy of four newly identified surface proteins of Erysipelothrix rhusiopathiae. AB - Erysipelothrix rhusiopathiae is the causative agent of animal erysipelas and human erysipeloid. Bacterial surface proteins are promising vaccine candidates. We recently identified 3 E. rhusiopathiae surface proteins (GAPDH, HP0728, and HP1472) and characterized their roles as virulence factors. However, their efficacy as protective antigens is still unknown. The N-terminal region of a previously identified surface protein, CbpB (CbpB-N), is speculated to be a protective antigen, but this needs to be verified. The aim of this study was to evaluate the protective efficacy of GAPDH, HP0728, HP1472, and CbpB-N. Immunization with recombinant GAPDH provided complete protection in a mouse model, recombinant CbpB-N provided partial protection, while recombinant HP0728 and HP1472 provided no protection. Recombinant GAPDH also provided good protection in a pig model. GAPDH antiserum exhibited significant blood bactericidal activity against E. rhusiopathiae. In conclusion, GAPDH and CbpB-N were found to be protective antigens of E. rhusiopathiae, and GAPDH is a promising vaccine candidate. PMID- 30446177 TI - The effects of vaccination forecasts and value-based payment on adult immunizations by community pharmacists. AB - BACKGROUND: The prevalence of vaccine-preventable diseases in adults remains a significant public health issue in the United States. The objectives of this demonstration project were to increase the number of influenza, pneumococcal, pertussis, and herpes zoster immunizations administered to adults by community pharmacists, evaluate the percentage of immunizations documented in the state immunization information system (IIS), and design and pilot a value-based payment model. METHODS: A one-year prospective, observational demonstration project was conducted in 70 community pharmacies in western Washington State from September 1, 2016 to August 31, 2017. An immunization interface was integrated into workflow at each pharmacy to enable "forecasting" of and proactive recommendation to patients about their vaccine needs and documentation of vaccines administered in the state IIS. Categorical value-based payment models were developed and implemented in a subgroup of 12 community pharmacies from March 1 to November 30, 2017. The change in the number of immunizations administered in comparison to the baseline period and the percentage of immunizations documented in the state IIS during the demonstration period were analyzed using descriptive statistics. RESULTS: There was a 15% total increase in the collective number of influenza, pneumococcal, pertussis, and herpes zoster vaccines administered in the demonstration year in the 70 pharmacies, due to increases in influenza and pertussis vaccinations. Eighty-three percent of the vaccines administered were documented in the state IIS. Pneumococcal, pertussis, and herpes zoster performance appeared to be unaffected by the value-based payment models while influenza performance improved across the 12 pilot pharmacies. CONCLUSIONS: This work demonstrated that community pharmacists contribute to improving adult immunizations through vaccine "forecasting" and proactive recommendation. Meaningful quality measures with both positive and negative incentives could further drive adoption of best immunization practices. Further implementation and outcomes research is needed to fully examine the impact and scalability of these strategies. PMID- 30446178 TI - Reply - Letter to the Editor - Impact of route and adequacy of nutritional intake on outcomes of allogeneic hematopoietic cell transplantation for hematologic malignancies. PMID- 30446179 TI - Salts and energy balance: A special role for dietary salts in metabolic syndrome. AB - BACKGROUND: Dietary salts sodium (Na+), potassium (K+), magnesium (Mg2+), and calcium (Ca2+) are important in metabolic diseases. Yet, we do not have sufficient understanding on the salts global molecular network in these diseases. In this systematic review we have pooled information to identify the general effect of salts on obesity, insulin resistance and hypertension. AIMS: To assess the roles of salts in metabolic disorders by focusing on their individual effect and the network effect among these salts. METHODS: We searched articles in PubMed, EMBASE and Google Scholar. We selected original laboratory research, systematic reviews, clinical trials, observational studies and epidemiological data that focused on dietary salts and followed the preferred reporting items for systematic review in designing the present systematic review. RESULTS: From the initial search of 2898 studies we selected a total of 199 articles that met our inclusion criteria and data extraction. Alterations in metabolic pathways associated with the sensitivity of sodium, potassium, magnesium and calcium may lead to obesity, hypertension, and insulin resistance. We found that the results of most laboratory research, animal studies and clinical trials are coherent but some research outcome are either inconsistent or inconclusive. CONCLUSION: Important of salts in metabolic disorder is evident. In order to assess the effects of dietary salts in metablic diseases, environmental factors, dietary habits, physical activity, and the microbiome, should be considered in any study. Although interest in this area of research continues to grow, the challenge is to integrate the action of these salts in metabolic syndrom. PMID- 30446180 TI - Corrigendum to 'A novel regulatory function of CDKN1A/p21 in TNFalpha-induced matrix metalloproteinase 9-dependent migration and invasion of triple-negative breast cancer cells' cellular signalling, volume 47, July 2018, Pages 27-36. PMID- 30446181 TI - Association of elevated circulating fibroblast growth factor 21 levels with prevalent and incident metabolic syndrome: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND AND AIMS: Fibroblast growth factor 21 (FGF21) plays an important role in glucose and lipid metabolism. We have investigated the relationship of plasma FGF21 levels with both prevalent and incident metabolic syndrome (MetS) in participants from the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: 5783 participants from four major ethnic groups (non-Hispanic white, African American, Hispanic American, and Chinese American) were included in the cross-sectional analysis. Longitudinal analysis involved 3479 participants without MetS at baseline, of whom 1100 participants developed incident MetS over 9.2 years. RESULTS: Elevated FGF21 levels were found in participants with prevalent MetS (median [interquartile range] = 189.4 [114.4-302.1] vs. 123.7 [65.9-210.3] pg/mL, p < 0.001) or incident MetS (145.6 [84.9-240.8] vs 112.0 [57.0-194.5] pg/mL, p < 0.001), compared to those without. After adjusting for baseline demographic, socioeconomic and lifestyle factors, as well as cardiovascular risk factors and biomarkers, and compared to the lowest quartile, the highest FGF21 quartile was associated with prevalent MetS (odds ratio 2.80; 95% confidence interval, 2.30 3.40, p < 0.001). Among participants without MetS at baseline, the highest FGF21 quartile was associated with higher risk of incident MetS (hazards ratio 1.76; 95% confidence interval, 1.46-2.12, p < 0.001). Similar results were obtained when assessing ln-transformed FGF21 levels. Overall, no significant interaction was found with age, sex, and race/ethnicity for both prevalent and incident MetS. CONCLUSIONS: Higher FGF21 levels significantly predict the development of MetS in an ethnically diverse population followed long term. Further studies are needed to confirm the potential role of FGF21 as a biomarker for MetS. PMID- 30446182 TI - [Twenty years later... A story of intra-thoracic textiloma]. AB - INTRODUCTION: Intrathoracic textiloma is a rare complication possibly leading to misdiagnosis. It could present as haemoptysis, lung abscess, pseudo-tumour or a chronic cough. CASE REPORT: A 65-year-old patient with a history of multiple cardiac problems and needing long-term anticoagulation, complained since 2007 of recurrent haemoptysis of increasing abundance, the etiological investigation of which was negative. A thoracic CT-scan revealed a lesion in the lingula in contact with the pericardial plates of an implanted automatic defibrillator dating from 1989. In 2016, after two failures of arterial embolization, a diagnostic and therapeutic surgical exploration was undertaken on this patient who was a high operative risk. A segmental resection revealed an intra-pulmonary textiloma on pathological examination. CONCLUSION: The diagnosis of intrathoracic textiloma remains rare and its late presentation is non specific. Radiological imaging with a CT-scan and/or MRI could lead to the diagnosis. Surgery remains the reference treatment for the diagnosis and cure of intrathoracic textiloma with pathological examination, essential for confirmation. A means of prevention has to be developed because swab count is not totally reliable. PMID- 30446184 TI - The UK gender identity clinic for young people. PMID- 30446183 TI - Increased Survivorship of Cementless versus Cemented TKA in the Morbidly Obese. A Minimum 5-Year Follow-Up. AB - BACKGROUND: Total knee arthroplasty (TKA) in the morbidly obese patients can be challenging with an increased risk of complications. Studies have shown increased aseptic failures with well-aligned cemented TKAs in the obese patient. The purpose of this study is to determine if TKA in the morbidly obese (body mass index [BMI] >= 40) using cementless implants would demonstrate improved results and survivorship compared to cemented TKA at a minimum 5-year follow-up. METHODS: This is a retrospective study comparing clinical results of cemented vs cementless primary TKA with a posterior stabilized design TKA in morbidly obese (BMI >= 40) patients with minimal 5-year follow-up. There were 108 patients in the cementless group with a mean BMI of 45.6. In the cemented cohort, there were 85 cemented TKAs with a mean BMI of 45.0. Demographic, clinical, surgical, and radiographic data along with complications were extracted for all study patients. RESULTS: There were 5 failures requiring revision in the cementless group, including 1 for aseptic tibial loosening (0.9%). In the cemented group, there were 22 failures requiring revision, including 16 implants for aseptic loosening (18.8%; P = .0001). Survivorship with aseptic loosening as the endpoint was 99.1% in the cementless group vs 88.2% in the cemented cohort at 8 years (P = .02). CONCLUSION: Morbidly obese patients (BMI >= 40) have a higher failure due to aseptic loosening with cemented TKA with decreasing survivorship over time. The use of cementless TKA in morbidly obese patients with the potential of durable long-term biologic fixation and increased survivorship appears to be a promising alternative to mechanical cement fixation. PMID- 30446185 TI - Wonder-full: Curiosity Cabinets and imagination in education. PMID- 30446186 TI - The meaning of home. PMID- 30446187 TI - Inherent antimicrobial activity by bacteria-derived vesicles. PMID- 30446188 TI - Psychiatric dermatology: Management. PMID- 30446189 TI - Correlating the Dermatology Life Quality Index with psychiatric measures: A systematic review. AB - Skin conditions may have a major impact on the psychologic well-being of patients, ranging from depression to anxiety. The Dermatology Life Quality Index (DLQI) is the most commonly used quality of life tool in dermatology, though it has yet to be correlated with psychiatric measures used in clinical therapeutic trials. We conducted a systematic review to determine whether there is any correlation between the DLQI and psychiatric measure scores, potentially allowing the DLQI to be used as a surrogate measure for depression or psychiatric screening. Six databases were searched using the following keywords: "DLQI," "Dermatology Life Quality Index," "Psych*," "depression," "anxiety," "stress," and "trial*." All randomized trials where full DLQI and psychiatric scores were provided were included. PRISMA guidelines were followed. In all, 462 records were screened, but only seven met inclusion criteria. Hospital Anxiety and Depression Scale (HADS) was the most commonly used psychiatric measure; the "depression" component score changes correlated strongly with the DLQI (r = 0.715). There needs to be guidance on psychiatric measurement and reporting in clinical trials. Although the DLQI correlated well with the "depression" domain of the HADS scale, interviews and screening for depression are still vital for full assessment of patient psychologic well-being. PMID- 30446190 TI - Psoriasis: Psychosomatic, somatopsychic, or both? AB - Psoriasis is a chronic inflammatory disorder characterized by substantial psychiatric comorbidity. Historically, anecdotal observations have suggested that psychosocial distress can trigger flares of psoriasis, but over the past several decades, high-quality data from experimental studies support the assertion that stress plays a critical role in the pathogenesis of psoriasis. There may be a subset of patients unable to elicit an appropriate immunosuppressive response to stress through upregulation of cortisol, with resultant exacerbation of their psoriasis. Other notable studies revealed that key neuromodulators, including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, and nerve growth factor may be potent regulators of neurogenic inflammation that induce psoriasis flares through a stress-mediated mechanism. Preliminary trials in humans that examine psychosocial interventions to reduce stress, as well as animal studies targeting specific neuropeptides, provide support for the concept that alteration of pathways mediated by the stress response represents novel forms of therapy in the management of psoriasis. PMID- 30446191 TI - Psychosomatic and psychiatric disorders and psychologic factors in pruritus. AB - Chronic pruritus (CP) is a bothersome symptom of many different diseases and is often associated with psychosomatic and psychiatric comorbidity. This review gives an overview of psychologic factors that influence the perception and modulation of pruritus based on the well-known biopsychosocial model. Not only psychic comorbidities, such as anxiety and depression, play an important role in the etiology and perception of pruritus, but also internal factors, including personality, mentalization, suggestibility, and external factors, as well as stress. Expectations concerning the intensity of pruritus can also play a role in itch perception that can be modulated by cognitions and behavior of the patient. Obsessive rituals of scratching and skin manipulation with instruments present challenges in the treatment of CP. Initial studies on the efficacy of psychotherapeutic approaches to different problems, such as scratching, comorbidity, or stress-associated itch, show that these might be very useful additions to the multidisciplinary treatment of pruritus. PMID- 30446192 TI - Psychosomatic aspects of alopecia areata. AB - Psychologic and social effects of scalp hair are more important than its biologic significance. Etiology of alopecia areata (AA) suggests a predominantly autoimmune reaction. Correlation between AA and psychologic disorders is reciprocal. Psychiatric disorders can trigger the onset of AA and its negative consequences may develop or exacerbate psychologic problems. The high incidence of a neurotic personality, depression, anxiety, and deficiency in coping with stress strengthen the role of psychic factors in the pathogenesis of AA. Strategies to assess these patients are often not apparent for the clinician and identifying patients in need of extra psychologic support should be a mainstay for successful treatment. Women, young patients, and those with significant AA or previous psychiatric disorders are at greater risk, requiring careful monitoring. Proper awareness and consciousness about the close relationship between AA and psychologic factors are essential. PMID- 30446193 TI - Delusional infestation versus Morgellons disease. AB - Delusional infestation is the conviction that one is infested with pathogens either animate or inanimate-despite medical or microbiologic evidence to the contrary. Infestation with inanimate pathogens, specifically fibers or filaments, has been controversially termed Morgellons disease by the patients themselves, who believe that this is not a psychiatric disease but rather a new organic condition or a skin manifestation of an infection, such as Lyme disease. A large scale study by the Centers of Disease Control and Prevention on patients presenting with Morgellons clinical manifestations did not find evidence of fibers in the skin nor an association with any infection, including Lyme disease. Once the diagnosis of delusional infestation is made, the cornerstone of treatment is antipsychotics, although this is often quite challenging, as patients are reluctant to take these medications. PMID- 30446194 TI - Dermatitis artefacta. AB - Dermatitis artefacta, also known as factitial dermatitis, is a condition whereby self-induced skin damage is the means used to satisfy a conscious or unconscious desire to assume the sick role. It is particularly common in women and in those with an underlying psychiatric diagnosis or external stress. The diagnosis is one of exclusion, and it is often difficult to confirm, with patients rarely admitting their role in the creation of their lesions. Treatment can be challenging, and management should adopt a multidisciplinary team approach composed of dermatologists and mental health professionals. We present a literature review of dermatitis artefacta, highlighted by a case report of a patient with bilateral ulcerations to the legs, which after thorough investigation represented dermatitis artefacta. PMID- 30446195 TI - Body-focused repetitive behaviors and the dermatology patient. AB - Body-focused repetitive behaviors (BFRBs) are psychiatric disorders that involve recurrent pulling and picking one's own body resulting in skin lesions with varying degrees of severity. For that reason, the interface with dermatology is important. Currently, the classified BFRBs are trichotillomania and excoriation disorder. Both trichotillomania and excoriation disorder appear to be more common than previously thought. Besides that, most patients are unlikely to seek mental health treatment for their condition. Thus, many patients will instead seek dermatologic help due to the cosmetic damage incurred. In trichotillomania, the main characteristic is the pulling out of one's hair, most commonly from the scalp. It is associated with many negative consequences. Patients may present with different patterns of alopecia. Often, more than one body part will be affected. In excoriation disorder, the pathologic behavior frequently starts with picking at an underlying dermatologic condition such as acne but can continue after dermatologic treatment. The body area most frequently picked is the face, but other sites may also be involved. The dermatologic findings and distribution are atypical and will help the clinician differentiate from other dermatologic conditions. A complete therapeutic plan for BFRBs should include a dermatologic assessment of the affected areas, psychotherapy, and possibly pharmacotherapy. PMID- 30446196 TI - Assessment and treatment of trichotillomania (hair pulling disorder) and excoriation (skin picking) disorder. AB - Recommendations are provided for the assessment and treatment of trichotillomania (hair pulling disorder, or HPD) and excoriation disorder (skin picking disorder, or SPD), two body-focused repetitive behavior (BFRB) disorders, based on their severity, comorbidities, and behavioral style. Habit reversal training (HRT) and stimulus control are first-line behavioral treatments that can be used in cases of all severity levels and may be particularly helpful when pulling or picking is performed with lowered awareness/intention. Acceptance and commitment therapy (ACT) and dialectical behavior therapy (DBT) are behavioral treatments that can be employed to augment HRT/stimulus control, especially when negative emotions trigger the pulling or picking. There are currently no FDA-approved pharmacologic treatments for HPD or SPD, though certain medications/supplements have shown varying degrees of efficacy in trials. N-acetylcysteine (NAC) should be considered for all severity levels and styles given its moderate gain/low side effect profile. Other pharmacologic interventions, including selective serotonin reuptake inhibitors (SSRIs), should be considered in cases with significant comorbidities or previous behavioral/NAC treatment failure. PMID- 30446197 TI - Psychodermatology: An Indian perspective. AB - Psychodermatology, a relatively neglected branch of dermatology in India, refers to a holistic approach to skin diseases involving not only the mind and skin, but also the cutaneous effects of psychologic stress. Among many Indian people, culture, religion, the belief in karma, and the tendency to prefer indigenous medical systems can all have a major impact on lifestyle, as well as the approach to managing various diseases, including dermatologic conditions. The origin of psychodermatology in India can be traced to Buddha's period. Indigenous medical systems, such as Ayurveda, Yoga, and Unani, advocate control of skin disease through meditation, exercises, and related practices. Scientific practice of psychodermatology is still lacking in India, although there is an increasing understanding of the mind-skin connection among both health care providers and patients who have access to information over the Internet. The first dedicated psychodermatology liaison clinic was established in 2010 in Manipal, India. The common problems encountered have been anxiety, dysthymia, and depression, especially in patients with psoriasis, vitiligo, and urticaria. PMID- 30446199 TI - Use of psychotropic drugs in the dermatology patient: When to start and stop? AB - Dermatologists often find themselves treating patients with psychiatric disorders, most commonly anxiety and depression, in the context of skin disease. The psychiatric condition may either be present before the skin condition developed and exacerbate it or, in some cases, even create it (eg, delusions of parasitosis). Alternatively, the psychiatric condition may occur subsequent to the development of the dermatologic condition. The treatment of psychodermatogic disorders requires collaboration between psychiatrists and dermatologists. Dermatologists should be able to recognize primary psychiatric disorders and refer patients to psychiatrists for appropriate treatment; however, the patient may encounter delays in accessing psychiatric care, and dermatologists should be familiar with the basic use of psychotropic drugs. This review describes common psychiatric disorders encountered in a dermatology practice and their treatment with psychotropic drugs. For each commonly used drug, dose range, side effects, and how to initiate and terminate treatment are described. Although psychotherapy is an important part of the treatment of most psychiatric disorders, we have limited our focus to psychotropic drugs in this review. PMID- 30446198 TI - The potential role of mindfulness in psychosocial support for dermatology patients. AB - While it is widely acknowledged that people living with skin conditions can experience higher levels of psychosocial distress than the general population, access to psychologic support in dermatology is limited. Given the physical and psychosocial consequences of living with skin conditions, interventions used within physical and mental health may be beneficial. Mindfulness, defined as "paying attention in a particular way: on purpose in the present moment and non judgmentally," has shown promise in improving outcomes in both mental and physical health populations, and studies have implicated a role for mindfulness in improving distress associated with skin conditions. The current review explores the theoretical underpinnings of mindfulness, in particular, the role it may play in reducing physiologic arousal and managing maladaptive thought processes. Although mindfulness interventions offer promise in reducing distress associated with skin conditions, further research is required to fully understand the underlying mechanisms of mindfulness and the active ingredient responsible for improving outcomes in dermatology patients. Mindfulness is one potential psychologic intervention and practitioners should be aware of the range of psychologic support options available. The current review also draws attention to the urgent need for further research into the effectiveness of psychologic interventions for dermatology patients. PMID- 30446200 TI - Use of antiepileptic mood stabilizers in dermatology. AB - Several antiepileptic drugs (AEDs) are approved by the US Food and Drug Administration for the treatment of bipolar disorder (valproic acid, divalproex, lamotrigine, carbamazepine) and some cutaneous neuropathic pain syndromes (carbamazepine, gabapentin, pregabalin). The AEDs may be effective in the management of (1) chronic pruritus, including pruritus due systemic disease, including uremia, neuropathic pain, neuropathic pruritus, and complex cutaneous sensory syndromes, especially where central nervous system (CNS) sensitization plays a role; (2) management of emotional dysregulation and the resultant repetitive self-excoriation or other cutaneous self-injury in patients who repetitively stimulate or manipulate their integument to regulate emotions (prurigo nodularis, lichen simplex chronicus, skin picking disorder, trichotillomania); (3) management of dermatologic clinical manifestations associated with autonomic nervous system activation (hyperhidrosis, urticaria, flushing; these often occur in conjunction with psychiatric disorders with prominent autonomic activation and dysregulation, eg, social anxiety disorder, posttraumatic stress disorder); and (4) when certain anticonvulsants have a direct therapeutic effect (eg, in psoriasis); currently the use of AEDs for such cases is largely experimental. Gabapentin (dosage range 300-3600 mg daily) is the most widely studied AED mood stabilizer in dermatology and is especially effective in situations where CNS sensitization is a mediating factor. Further larger-scale controlled studies of AEDs in dermatology are necessary. PMID- 30446201 TI - Use of antipsychotic drugs in dermatology. AB - Antipsychotic drugs can be beneficial in dermatology because of their both central nervous system and peripheral effects. All antipsychotic drugs have a central postsynaptic dopamine D2 receptor blocking effect, which underlies their antipsychotic action. The antipsychotic drugs have varying degrees of histamine H1-receptor, cholinergic muscarinic receptor, and alpha1-adrenergic receptor blocking effects, which can affect cutaneous perception and the autonomic reactivity of the skin and can be potentially beneficial in the management of certain histamine or sympathetically mediated dermatologic manifestations (eg, urticaria, pruritus, hyperhidrosis). In addition to their antipsychotic effect, antipsychotic drugs also have a general anxiolytic effect related in part to their alpha1-adrenergic receptor blocking action, which can be of benefit in many dermatologic conditions, including pruritus. The antipsychotic drugs are most commonly used in dermatology for the management of a delusional disorder, somatic type, manifesting as delusional infestation, and as monotherapy or as augmentation therapy of selective serotonin reuptake inhibitor (SSRI) antidepressants, and for management of trichotillomania and skin-picking or excoriation disorder. There is earlier literature (1) on the possible beneficial effect of the phenothiazine antipsychotics in a wide range of pruritic dermatoses, and (2) the efficacy of pimozide as adjunctive therapy for metastatic melanoma, which both warrant further investigation. PMID- 30446202 TI - How I learned to stop worrying and love machine learning. AB - Artificial intelligence and its machine learning (ML) capabilities are very promising technologies for dermatology and other visually oriented fields due to their power in pattern recognition. Understandably, many physicians distrust replacing clinical finesse with unsupervised computer programs. We describe convolutional neural networks and discuss how this method of ML will impact the field of dermatology. ML is a form of artificial intelligence well suited for pattern recognition in visual applications. Many dermatologists are wary of such unsupervised algorithms and their future implications. PMID- 30446203 TI - Father Adam Wisniewski, MD, and his work for lepromatous patients in India. AB - Father Adam Wisniewski (1913-1987), who was a Pallottine and a medical doctor with specialization in tropical diseases, devoted his life to helping and curing leprosy patients in India. His life proved difficult and varied. He began his medical studies during World War II in occupied Warsaw. What is more, he participated in the Warsaw Uprising in 1944, for which he later received the Cross of Valour, one of the highest Polish commendations. He learned about leprosy in France and then moved to India to use his medical knowledge to treat lepers and stop the spread of the disease. He created a center for the impoverished at Jeevodaya, India, which is still serves as a refuge for patients with leprosy. PMID- 30446204 TI - Parental Infections Before, During, and After Pregnancy as Risk Factors for Mental Disorders in Childhood and Adolescence: A Nationwide Danish Study. AB - BACKGROUND: Previous studies have shown associations between maternal infections during pregnancy and increased risks of schizophrenia and autism spectrum disorder in the offspring. However, large-scale studies investigating an association between parental infections both during and outside the pregnancy period and the risk of any mental disorder in the child are lacking. METHODS: A nationwide Danish cohort study identified 1,206,600 children born between 1996 and 2015 and followed them to a maximum of 20 years of age. Exposure included all maternal and paternal infections treated with anti-infective agents or hospital contacts before, during, or after pregnancy. The main outcome was a diagnosis of any mental disorder in the child. Hazard ratios (HRs) were calculated using Cox regression analysis. RESULTS: Maternal infections during pregnancy treated with anti-infective agents (n = 567,016) increased the risk of mental disorders (n = 70,037) in the offspring (HR, 1.09; 95% confidence interval [CI], 1.06-1.12), which was more elevated (p < .001) than after paternal infections (n = 350,835; HR, 1.01; 95% CI, 0.98-1.03). Maternal hospital contacts for infections (n = 39,753) conferred an increased HR of 1.21 (95% CI, 1.14-1.28), which was not significantly (p = .08) different from the risk after paternal infections (n = 8559; HR, 1.07; 95% CI, 0.95-1.20). The increased risks observed during pregnancy were not different from the similarly increased risks for maternal and paternal infections before and after pregnancy. The risk of mental disorders increased in a dose-response relationship with the number of maternal infections treated with anti-infective agents, particularly during and after pregnancy (both p < .001). CONCLUSIONS: Maternal infections were associated with an increased risk of mental disorder in the offspring; however, there were similar estimates during and outside the pregnancy period. PMID- 30446205 TI - The Relative Contributions of Cell-Dependent Cortical Microcircuit Aging to Cognition and Anxiety. AB - BACKGROUND: Aging is accompanied by altered thinking (cognition) and feeling (mood), functions that depend on information processing by brain cortical cell microcircuits. We hypothesized that age-associated long-term functional and biological changes are mediated by gene transcriptomic changes within neuronal cell types forming cortical microcircuits, namely excitatory pyramidal cells (PYCs) and inhibitory gamma-aminobutyric acidergic neurons expressing vasoactive intestinal peptide (Vip), somatostatin (Sst), and parvalbumin (Pvalb). METHODS: To test this hypothesis, we assessed locomotor, anxiety-like, and cognitive behavioral changes between young (2 months of age, n = 9) and old (22 months of age, n = 12) male C57BL/6 mice, and performed frontal cortex cell type-specific molecular profiling, using laser capture microscopy and RNA sequencing. Results were analyzed by neuroinformatics and validated by fluorescent in situ hybridization. RESULTS: Old mice displayed increased anxiety and reduced working memory. The four cell types displayed distinct age-related transcriptomes and biological pathway profiles, affecting metabolic and cell signaling pathways, and selective markers of neuronal vulnerability (Ryr3), resilience (Oxr1), and mitochondrial dynamics (Opa1), suggesting high age-related vulnerability of PYCs, and variable degree of adaptation in gamma-aminobutyric acidergic neurons. Correlations between gene expression and behaviors suggest that changes in cognition and anxiety associated with age are partly mediated by normal age related cell changes, and that additional age-independent decreases in synaptic and signaling pathways, notably in PYCs and somatostatin neurons, further contribute to behavioral changes. CONCLUSIONS: Our study demonstrates cell dependent differential vulnerability and coordinated cell-specific cortical microcircuit molecular changes with age. Collectively, the results suggest intrinsic molecular links among aging, cognition, and mood-related behaviors, with somatostatin neurons contributing evenly to both behavioral conditions. PMID- 30446206 TI - Amino Acid Dysregulation Metabotypes: Potential Biomarkers for Diagnosis and Individualized Treatment for Subtypes of Autism Spectrum Disorder. AB - BACKGROUND: Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children. METHODS: Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation. RESULTS: We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort. CONCLUSIONS: Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions. PMID- 30446207 TI - Acute Corticonuclear Tract Ischemic Stroke with Isolated Central Facial Palsy. AB - OBJECTIVE: The clinical distinction between habitual facial asymmetry, early stage peripheral facial palsy, and isolated central facial palsy is sometimes difficult. The diagnosis of acute central facial palsy is of importance to identify patients for stroke work-up and appropriate treatment. We aimed to evaluate the prevalence and localization of acute ischemic lesions associated with isolated central facial palsy. METHODS: We screened our stroke database for patients presenting with isolated central facial palsy related to ischemic stroke between 2012 and 2017. All identified patients were comprehensively characterized including magnetic resonance (MR) diffusion-weighted imaging (DWI). RESULTS: We identified four out of 5169 patients (one male; 62-83 years) with isolated facial palsy as a result of acute ischemic stroke (NIHSS 1-2). All four had circumscribed DWI lesions in different regions of the corticonuclear tract in different areas with different etiologies. CONCLUSION: Isolated central facial palsy is a rare manifestation of acute ischemic stroke and may be missed if clinical suspicion is not raised. MR-DWI identifies small ischemic lesions in the corticonuclear tract, which results in appropriate diagnostic work-up and secondary prophylaxis. PMID- 30446208 TI - [Cerebellar infarct following orchidopexy under spinal anesthesia]. AB - The report describes a case of peri-operative stroke that presented as diplopia and gait difficulty on 2nd post-operative day after routine orchidopexy under spinal anesthesia in an otherwise healthy young boy. Magnetic resonance imaging of the brain revealed acute infarct in bilateral cerebellar hemispheres, left half of medulla and left thalamus. A diagnosis of acute stroke (infarct) was made and patient was started on oral aspirin 75mg.day-1, following which his vision started improving after 2 weeks. Possible mechanisms of development of stroke in the peri-operative period are discussed, but, even after extensive investigations, the etiology of infarct may be difficult to determine. Acute infarct after elective non-cardiac, non-neurological surgery is rare; it may not be possible to identify the etiology in all cases. Clinicians must have a high index of suspicion to diagnose such unexpected complications even after routine surgical procedures in order to decrease the morbidity and long term sequelae. PMID- 30446209 TI - [Effects of repeated exposure to different concentrations of sevoflurane on the neonatal mouse hippocampus]. AB - BACKGROUND AND OBJECTIVES: Developing brain is more vulnerable to environmental risk than is the developed brain. We evaluated the effects of repeated exposure to different concentrations of sevoflurane on the neonatal mouse hippocampus using stereological methods. METHODS: Eighteen neonatal male mice were randomly divided into three groups. Group A, inhaled sevoflurane at a concentration of 1.5%; Group B, inhaled sevoflurane at a concentration of 3%; and Group C (control group), inhaled only 100% oxygen. Treatments were applied for 30min a day for 7 consecutive days. The hippocampal volume, dendrite length, number of neurons, and number of glial cells were evaluated in each group using stereological estimations. RESULTS: We identified a ~2% reduction in the volume of the hippocampus in Group A compared to Group C. Mean hippocampal volume was ~11% smaller in Group B than it was in Group C. However, these differences in hippocampal volume between the groups were not statistically significant (p>0.05 for all). As for the number of neurons, we found significantly fewer neurons in Group A (~29% less) and Group B (~43% less) than we did in Group C (p<0.05 for both). The dendrite length was ~8% shorter in Group A and ~11% shorter in Group B than it was in Group C. CONCLUSIONS: Repeated exposure to sevoflurane, regardless of the concentration, reduced the volume of the neonatal mouse hippocampus, as well as the number of neurons and dendrite length. PMID- 30446210 TI - [Anesthetic management for patient with severe cyanosis following bioprosthetic valve stenosis]. AB - We presented a 39-year-old female patient with life-threatening hypoxemia after tricuspid valve replacement because of Ebstein's anomaly. And the severe cyanosis is due to bioprosthetic valve stenosis and atrial septal defect. Anesthetic management of a patient with severe obstructive prosthetic valve dysfunction can be challenging. Similar considerations should be given to patients with Ebstein's anomaly to maintain the pressure equalized between the right and left atrial. Transesophageal echocardiography and cerebral oxygen saturation provided real time information in perioperative care. PMID- 30446211 TI - Geroneuroprotectors: Effective Geroprotectors for the Brain. AB - Geroprotectors are compounds that slow the rate of biological aging and therefore may reduce the incidence of age-associated diseases such as Alzheimer's disease (AD). However, few have therapeutic efficacy in mammalian AD models. Here we describe the identification of geroneuroprotectors (GNPs), novel AD drug candidates that meet the criteria for geroprotectors. PMID- 30446212 TI - Acquired factor XIII deficiency: A review. AB - Acquired factor XIII (FXIII) deficiency is a rare bleeding disorder that can manifest with spontaneous or delayed life-threatening hemorrhage. Causes of acquired deficiency include immune-mediated inhibition, as well as non-immune FXIII hyperconsumption or hyposynthesis. The occurrence of acquired FXIII deficiency can be idiopathic or may be associated with comorbidities, such as malignancies or autoimmune disorders. Recognition of acquired FXIII deficiency and its underlying cause is imperative, as treatment options vary depending on the etiology. Diagnosis requires quantitative FXIII testing in addition to supplemental inhibitor studies if the clinical situation suggests an immune mediated pathophysiology. Treatment may involve FXIII replacement, antifibrinolytic administration, and/or inhibitor eradication. However, treatment targets and thresholds are undefined in acquired FXIII deficiency. This review will focus on the clinical characteristics, diagnostic issues and therapeutic options for both immune and non-immune acquired FXIII deficiency. Cases are described to illustrate the clinical features of acquired FXIII deficiency. PMID- 30446214 TI - Cell phone use and risk of thyroid cancer: a population-based case-control study in Connecticut. AB - PURPOSE: This study aims to investigate the association between cell phone use and thyroid cancer. METHODS: A population-based case-control study was conducted in Connecticut between 2010 and 2011 including 462 histologically confirmed thyroid cancer cases and 498 population-based controls. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between cell phone use and thyroid cancer. RESULTS: Cell phone use was not associated with thyroid cancer (OR: 1.05, 95% CI: 0.74-1.48). A suggestive increase in risk of thyroid microcarcinoma (tumor size <=10 mm) was observed for long-term and more frequent users. Compared with cell phone nonusers, several groups had nonstatistically significantly increased risk of thyroid microcarcinoma: individuals who had used a cell phone >15 years (OR: 1.29, 95% CI: 0.83-2.00), who had used a cell phone >2 hours per day (OR: 1.40, 95% CI: 0.83-2.35), who had the most cumulative use hours (OR: 1.58, 95% CI: 0.98-2.54), and who had the most cumulative calls (OR: 1.20, 95% CI: 0.78-1.84). CONCLUSIONS: This study found no significant association between cell phone use and thyroid cancer. A suggestive elevated risk of thyroid microcarcinoma associated with long-term and more frequent uses warrants further investigation. PMID- 30446215 TI - Crosstalk between inflammatory mediators and endoplasmic reticulum stress in liver diseases. AB - An excessive inflammatory response is frequently associated with cellular dysfunction and cell death. The latter may cause single and multiple organ failure. The most susceptible organs are liver, lung, kidney, heart and intestine. This review will focus on the liver as a target organ for an excessive inflammatory response. It is commonly accepted that organ failure is caused by the action of inflammatory cytokines released in excess during the inflammatory response. It has been suggested that inflammation mediated liver failure is not due to an increased death rate of parenchymal cells, but due to an intracellular metabolic disorder. This metabolic disorder is associated with mitochondrial and endoplasmic reticulum (ER) dysfunction during the acute phase response elicited by systemic inflammation. An overproduction of acute phase proteins in the liver as well as elevated reactive oxygen species (ROS) generation induce ER stress, triggering the unfolded protein response (UPR), which may initiate or aggravate inflammation. It is known that certain inflammatory mediators, such as the pro inflammatory cytokines IL-1beta, IL-6 and TNF-alpha induce ER stress. These findings suggest that ER stress and the subsequent UPR on the one hand, and the inflammatory response on the other create a kind of feed forward loop, which can be either beneficial (e.g., elimination of the pathogen and restoration of tissue homeostasis) or deleterious (e.g., excessive cell dysfunction and cell death). This review aims to unfurl the different pathways contributing to this loop and to highlight the relevance of UPR signaling (IRE1alpha, ATF6, and PERK) and mediators of the inflammatory response (NF-kappaB, STAT3, IL-1beta, IL-6, TLR) which have a particular role as pathophysiological triggers in the liver. PMID- 30446216 TI - The effects of knee support on the sagittal lower-body joint kinematics and kinetics of deep squats. AB - : Little work has been done to examine the deep squat position (>130 degrees sagittal knee flexion). In baseball and softball, catchers perform this squat an average of 146 times per nine-inning game. To alleviate some of the stress on their knees caused by this repetitive loading, some catchers wear foam knee supports. OBJECTIVES: This work quantifies the effects of knee support on lower body joint kinematics and kinetics in the deep squat position. METHODS: Subjects in this study performed the deep squat with no support, foam support, and instrumented support. In order to measure the force through the knee support, instrumented knee supports were designed and fabricated. We then developed an inverse dynamic model to incorporate the support loads. From the model, joint angles and moments were calculated for the three conditions. RESULTS: With support there is a significant reduction in the sagittal moment at the knee of 43% on the dominant side and 63% on the non-dominant side compared to without support. These reductions are a result of the foam supports carrying approximately 20% of body weight on each side. CONCLUSION: Knee support reduces the moment necessary to generate the deep squat position common to baseball catchers. Given the short moment arm of the patella femoral tendon, even small changes in moment can have a large effect in the tibial-femoral contact forces, particularly at deep squat angles. Reducing knee forces may be effective in decreasing incidence of osteochondritis dissecans. PMID- 30446217 TI - Exploiting Bayesian networks for fault isolation: A diagnostic case study of diesel fuel injection system. AB - Fault isolation is known to be a challenging problem in machinery troubleshooting. It is not only because the isolation of multiple faults contains considerable number of uncertainties due to the strong correlation and coupling between different faults, but often massive prior knowledge is needed as well. This paper presents a Bayesian network-based approach for fault isolation in the presence of the uncertainties. Various faults and symptoms are parameterized using state variables, or the so-called nodes in Bayesian networks (BNs). Probabilistically causality between a fault and a symptom and its quantization are described respectively by a directed edge and conditional probability. To reduce the qualitative and quantitative knowledge needed, particular considerations are given to the simplification of Bayesian networks structures and conditional probability expressions using rough sets and noisy-OR/MAX model, respectively. By adopting the simplified approach, symptoms under multiple-fault are decoupled into the ones under every single fault, while the quantity of the conditional probabilities is simplified into the linear form of the faults quantity. Prior knowledge needed in Bayesian network-based diagnostic model is reduced significantly, which decreases the complexity in establishing and applying this diagnosis model. The computational efficiency is improved accordingly in the simplified BN model, after eliminating the redundant symptoms. The fault isolation methodology is illustrated through an example of diesel engine fuel injection system to verify the developed model. PMID- 30446218 TI - Crystal structure of hydroxyquinol 1,2-dioxygenase PnpC from Pseudomonas putida DLL-E4 and its role of N-terminal domain for catalysis. AB - Hydroxyquinol 1,2-dioxygenase is a key enzyme in the hydroxyquinol pathway of p nitrophenol (PNP) degradation, and catalyzes the ring cleavage of benzenetriol to maleylacetate. Here, we report the first structure of a hydroxyquinol 1,2 dioxygenase from the Gram-negative bacterium Pseudomonas putida DLL-E4 (PnpC) at the resolution of 2.1 A. The tertiary structure of PnpC resembles that of the homologous intradiol dioxygenases. The catalytic Fe(III) is pentacoordinated by the conserved Tyr160, Tyr194, His218 and His220, the citrate anion and one water molecule. Among the residues expected to interact with the substrate, structural comparison with the (chloro)catechol dioxygenases suggested that Asp80, Thr81 and Val248 are responsible for the substrate specificity. Moreover, truncation of the N-terminal alpha-helix of PnpC suggested the N-terminal domain is required for its soluble expression and enzyme catalysis. Our results might provide insights in the substrate recognition and rational design of this enzyme class to be used in bioremediation. PMID- 30446219 TI - Cardioprotective effect of levosimendan against homocysteine-induced mitochondrial stress and apoptotic cell death in H9C2. AB - Levosimendan is a cardiac inotropic and vasodilator agent that has been reported to have anti-oxidative, anti-inflammatory, and smooth muscle vasodilatory properties. The purpose of this study was to examine the effect of levosimendan on homocysteine-induced cardiomyocyte injury and to explore its underlying mechanisms. H9C2 myocardial cells were incubated with levosimendan 30 min before exposure to homocysteine (Hcy) for 24 h. The effect of levosimendan on cell viability was assessed using the MTT assay. Biological markers of oxidative stress were examined by assessment of lipid peroxidation (LPO), total antioxidant power (TAP), and total thiol groups. Moreover, the expression of caspase-3, Bcl 2, and Bax proteins was determined by western blot analysis. These results showed that levosimendan increased survival of cardiomyocytes in Hcy condition. Treatment with levosimendan decreased lipid peroxidation level. It also enhanced the TAP and total thiol groups. Further, levosimendan pretreatment upregulated the expression of Bcl-2 and downregulated the expression of Bax. The experiments also demonstrated that levosimendan could decrease the expression and activity of caspase-3, which is a key factor in regulating apoptosis. Taken together, these results indicated that levosimendan protects H9C2 myocardial cells against Hcy induced oxidative stress and apoptosis by scavenging free radicals and modulating the mitochondrial-mediated apoptotic signaling pathway. PMID- 30446220 TI - Structural and biochemical insights into inhibition of human primase by citrate. AB - The eukaryotic primase/polymerase complex synthesizes approximately 107 primers, one per Okazaki fragment, during the replication of mammalian chromosomes, which contain 109 base pairs. Primase catalyzes the synthesis of a short RNA segment to a single-stranded DNA template. Primase is important in DNA replication because no known replicative DNA polymerases can initiate the synthesis of a DNA strand without an initial RNA primer. The primase subcomplex is composed of a small catalytic subunit (p49), and a large accessory subunit (p58). Priming mechanisms remain poorly understood, although large numbers of structures of archaeal and eukaryotic p49 and/or p58 as well as structures of bacterial enzymes have been determined. In this study, we determined the structure of human p49 at 2.2 A resolution with citrate in its inactive forms. Dibasic citrate was bound at the nucleotide triphosphate (NTP) beta, gamma-phosphate binding site through nine hydrogen bonds. We also measured the dissociation constant of citrate and NTPs. We further demonstrated that the p49 activity is regulated by pH and citrate, which was not previously recognized as a key regulator of DNA replication. We propose that the citrate inhibits the primase and regulates DNA replication at the replication fork. PMID- 30446221 TI - Alleviation of fatty liver in a rat model by enhancing N1-methylnicotinamide bioavailability through aldehyde oxidase inhibition. AB - Nonalcoholic fatty liver disease (NAFLD) has increased worldwide in recent years. NAFLD is classified into two types, nonalcoholic fatty liver (NAFL), with few complications, and nonalcoholic steatohepatitis (NASH), which leads to liver cirrhosis or cancer. This study was based on previous reports that N1 methylnicotinamide (MNA) can stabilise sirtuin 1 protein, leading to decreased lipid levels in the liver. We hypothesised that fatty liver improvement by MNA would be further enhanced by suppressing its rapid metabolism by aldehyde oxidase in the liver. To test this, hydralazine (HYD), a potent aldehyde oxidase inhibitor, was administered orally to NAFL model rats. Liver triglyceride (TG) levels in the model were nearly unchanged by administration of MNA alone. In contrast, TG levels were marked decreased in NAFL rats treated with a combination of MNA and HYD. In addition, TG levels were decreased even in NAFL rats treated with only HYD. These findings supported our hypothesis that maintaining MNA concentrations in the liver, by suppressing MNA metabolism, would at least partially ameliorate fatty liver. PMID- 30446222 TI - The LINC01138 interacts with PRMT5 to promote SREBP1-mediated lipid desaturation and cell growth in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC), the most common type of kidney malignancy, is an incurable disease characterized by multiple metabolic abnormalities, especially lipid accumulation and desaturation. Though great progresses have been made in understanding the mechanisms of ccRCC, metabolic abnormalities remain largely unclear. Here, we found lncRNA LINC01138 is highly expressed in ccRCC and is associated with poor patient survival. LINC01138 regulates ccRCC growth through sterol regulatory element-binding protein 1 (SREBP1)-mediated lipid desaturation. Mechanistically, we demonstrated that LINC01138 interacts with PRMT5 to increase arginine methylation and protein stability of SREBP1, promoting lipid desaturation and cell proliferation in ccRCC. Our study identified LINC01138 as a novel regulator of metabolic abnormalities in ccRCC, providing a potential therapeutic target for metabolic therapy. PMID- 30446223 TI - A putative cyclin, SiPHO80 from root endophytic fungus Serendipita indica regulates phosphate homeostasis, salinity and heavy metal toxicity tolerance. AB - Serendipita indica previously known as Piriformospora indica is an arbuscular mycorrhizal fungi (AMF) like endophytic fungus which can be cultivated axenically and colonizes an array of plants, thereby promoting their growth and confers biotic and abiotic stress tolerance to the colonized host plant. It efficiently sequestrates heavy metals and defends host plant against heavy metal-induced toxicity. In the present study, SiPHO80, a homologue of S. cerevisiae PHO80 was isolated from S. indica and functionally characterized in S. cerevisiae. SiPHO80 has conserved 'cyclin box' domain and closely related to negative regulator cyclin of the wood decaying fungi. In S. indica, its expression gets upregulated in phosphate-rich media. The regulation of Pi homeostasis which was disrupted in S. cerevisiae Deltapho80 grown under high Pi condition was restored upon complementation with SiPHO80. Also, the expression of SiPHO80 in Deltapho80 mutant restored osmotolerance and heavy metal tolerance. This is the first report of a cyclin which is involved in Pi homeostasis, salt tolerance, heavy metal toxicity tolerance in any plant growth promoting endophytic fungi. PMID- 30446224 TI - Retinoic acid modulates iron metabolism imbalance in anemia of inflammation induced by LPS via reversely regulating hepcidin and ferroportin expression. AB - The present study was designed to investigate the effect of retinoic acid (RA) on anemia of inflammation (AI) induced by lipopolysaccharide (LPS) and explore the potential mechanisms. BALB/c mice were randomly assigned into four groups: control group; LPS (10 mg/kg) group, LPS + RA (3 mg/kg) and LPS + RA (15 mg/kg) groups. Red blood cell count (RBC), hemoglobulin (Hb), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin contentration (MCHC), erythropoietin (EPO) and iron content in both serum and liver tissue were measured. The AI model induced by LPS was successfully established represented by the decreases in RBC, Hb, HCT, MCV, MCHC and EPO for anemia indicators and by the increases in TNF-alpha, IL-18 and IL-1beta contents for inflammation indicators. However, supplementation of RA increased the levels of anemia indicators and decreased the content of inflammation indicators. In addition, RA increased the content of iron in serum, while decreased its content in liver tissue. Furthermore, RA down-regulated the protein expression of hepcidin, toll-like receptor 4 (TLR4) and p-p65 in liver tissue, while up-regulated that of ferroportin. RA modulates iron metabolism imbalance in AI induced by LPS via reversely regulating hepcidin and ferroportin expression, which might be mediated by TLT-4/NFkappaB signaling pathway. PMID- 30446225 TI - Syk and JNK signaling pathways are involved in inflammasome activation in macrophages infected with Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a pathogen of significant clinical importance worldwide that can cause severe invasive diseases, such as pneumonia, otitis media and meningitis. Inflammsomes has been reported to participate in host defense against S. pneumoniae infection. S. pneumoniae could induce the assembly of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/absent in melanoma 2 (AIM2) inflammasome, which mediates the activation of caspase-1 and the subsequent maturation of Interleukin 1beta (IL-1beta). However, the precise signals that activate inflammasomes during pneumococcal infection remain to be fully elucidated. In the present study, primary mouse macrophages were selected as a cell model, and the effects of kinases on inflammasome activity induced by S. pneumoniae infection were examined by ELISA and western blotting after pretreatment with a kinase inhibitor. Here, we show that Syk and JNK signaling are required for S. pneumoniae-induced activation of the inflammasome. Inhibitors of Syk and JNK almost abolished the oligomerization of apoptosis-associated speck-like protein containing a caspase activating and recruitment domain (ASC) and subsequent caspase-1 activation and IL-1beta secretion. Moreover, pneumolysin (PLY) participated in this process and was critical for Syk/JNK activation. These results suggested that the Syk/JNK signaling pathway may play a vital role in the inflammasome activation and modulate host immune responses against S. pneumoniae. PMID- 30446226 TI - Interferon-beta signal may up-regulate PD-L1 expression through IRF9-dependent and independent pathways in lung cancer cells. AB - The programmed death ligand-1 (PD-L1) (also called B7-H1 and CD274) belonging to the CD28 family of co-stimulatory molecules is ectopically expressed on the surface of various cancer cells. PD-L1 interacts with programmed death-1 (PD-1) on T cells to trigger an inhibitory signal that suppresses anti-tumor T cell responses as an important mechanism of tumor escape from anti-tumor immune response. Recent development of PD-1/PD-L1 blockades has provided novel immunotherapy strategies for cancers including non-small cell lung cancer (NSCLC). Although the therapy is quite effective for some patients with NSCLC, others are resistant to the treatment, so that regulatory mechanisms of PD-L1 in lung cancer cells need to be understood in detail. Here we analyzed effect of interferon-beta (IFN-beta) that can be produced in cancer microenvironment on PD L1 expression in lung tumor cells. An addition of IFN-beta elevated PD-L1 expression in mouse and human lung cancer cell lines in culture. This phenomenon was totally dependent on JAK signaling molecules, while IRF9 deficiency in murine lung cancer cells partially attenuated the IFN-beta-induced increase in PD-L1. mTOR may not be significantly involved in the regulation of PD-L1, whereas PI3-K pathway played differential roles on PD-L1 mRNA and cell-surface PD-L1 expression, in the cells treated with IFN-beta. These results strongly suggest that the type I IFN receptor signal elicits an increase in PD-L1 expression in lung cancer cells through IRF9-dependent and independent pathways. PMID- 30446227 TI - Leukemia inhibitory factor promotes extracellular matrix synthesis in degenerative nucleus pulposus cells via MAPK-ERK1/2 signaling pathway. AB - Extracellular matrix (ECM) anabolism and catabolism imbalance is key feature of chondrocyte and intervertebral disc nucleus pulposus (NP) cell degeneration. The role of LIF as a multifunctional cytokine in the ECM metabolism of chondrocytes is controversial, but no relevant research in the ECM metabolism of NP cells. This study aimed to explore the biofunction and related mechanisms of LIF in the degenerative NP cells. We obtained an increase in the expression of LIF in the human degenerated NP specimens. The addition of recombinant human leukemia inhibitory factor (rhLIF) to the degenerated NP cells cultured in vitro was found to stimulate the synthesis of ECM, and rhLIF could activate the ERK1/2 signaling pathway. However, coculture with PD98059, a signal inhibitor of ERK1/2, blocked the effect of rhLIF on the synthesis of ECM. To furtherly clarify the role of LIF, we carried out animal experiments and found that rhLIF treatment could successfully delay the degree of degeneration of the intervertebral disc in a rabbit model; but with the addition of PD98059, the function of rhLIF for degeneration protection disappeared. In summary, this study demonstrates that LIF plays a role in promoting ECM synthesis in the degenerated NP cells as a protective role in intervertebral disc degeneration (IDD), which is related to the activation of ERK1/2 signaling pathway. PMID- 30446229 TI - Demography of neurosurgery in France in 2018. Current state and a call to educate more young neurosurgeons. PMID- 30446228 TI - MYPT1 is targeted by miR-145 inhibiting viability, migration and invasion in 2D and 3D HeLa cultures. AB - The miR-143/145 cluster is down-regulated in cervical tumor cells suggesting a role in tumorigenesis including cytoskeleton remodeling, a key event for tumor progression. The aim of the present work was to determine the role of miR-143/145 in the modulation of the myosin regulator phospho-myosin light chain (pMLC). HeLa monolayer and tridimensional cultures were transfected with miR-143 or miR-145 mimics inhibiting cell viability, proliferation, migration and invasion, mainly through miR-145. MiR-145 transfection increased pMLC levels by targeting the MYPT1 subunit of the regulatory myosin phosphatase. MYPT1 knockdown by siRNAs reproduced miR-145 effects suggesting miR-145 as a tumor suppressor through MYPT1 targeting, leading to a subsequent increase of pMLC levels with implications for cervical cell viability, migration and invasion. PMID- 30446230 TI - Clinical implications of the rheological theory in the prevention of ventilator induced lung injury. Is mechanical power the solution? PMID- 30446232 TI - Outcomes of surgical treatment for osteochondritis dissecans of the elbow: evaluation by lesion location. AB - BACKGROUND: For treatment of advanced elbow osteochondritis dissecans (OCD), we have used surgical treatment. Although favorable treatment outcomes have been reported for centrally located OCD, treatment outcomes are generally questionable and the choice of surgical method is controversial for laterally located OCD. Our purpose was to evaluate the treatment outcomes based on lesion location. METHODS: The patients were 30 young (mean age, 14 years) male athletes who underwent surgical treatment of elbow OCD and were monitored for more than 1 year. Osteochondral autografts harvested from the knee were transplanted to centralized (13 patients) or lateral localized (9 patients) OCD lesions. For lateral widespread (8 patients) OCD lesions, a detached osteochondral fragment was fixed using small osteochondral plugs. When the remaining cartilage defect was large after fragment fixation, a large-sized osteochondral plug was transplanted to the defect. Treatment outcomes were evaluated by the Japanese Orthopaedic Association score, elbow range of motion (ROM), and radiographic findings. RESULTS: The Japanese Orthopaedic Association score significantly improved in patients with centralized, lateral localized, and lateral widespread types of OCD. ROM significantly improved in patients with centralized and lateral localized, and they returned to playing sports within 6 months. However, patients with lateral widespread OCD exhibited no significant ROM improvement, and returning to sports was difficult for 3 patients because of poor osseous integration of the fixed osteochondral fragment. CONCLUSIONS: Osteochondral autograft transplantation provided favorable outcomes for centralized and lateral localized elbow OCD lesions. However, for lateral widespread OCD lesions, reconstruction of the entire capitellar lesion area may be necessary. PMID- 30446231 TI - The position of sling immobilization influences the outcomes of anatomic total shoulder arthroplasty: a randomized, single-blind, prospective study. AB - BACKGROUND: To date, no studies have been published that have assessed the optimal position of sling immobilization after anatomic total shoulder arthroplasty for glenohumeral osteoarthritis. METHODS: Thirty-six patients undergoing anatomic total shoulder arthroplasty for osteoarthritis were randomized to a neutral rotation sling versus an internal rotation sling. The primary outcomes assessed included the Disabilities of the Arm, Shoulder and Hand score; Western Ontario Osteoarthritis of the Shoulder score; Single Assessment Numeric Evaluation score; visual analog scale (VAS) scores for pain and satisfaction; compliance ratings; and radiographic and range-of-motion measurements. Primary outcomes were assessed at baseline and postoperatively at 2 weeks, 6 weeks, 3 months, 6 months, and 1 year. RESULTS: All patient-determined outcome scores for both groups revealed statistically significant improvements (P < .0001) from enrollment to final follow-up. There were statistically significant advantages to the neutral rotation sling group compared with the internal rotation sling group when we evaluated the improvements in (1) active external rotation (42 degrees vs 25 degrees , P = .03), (2) passive external rotation (44 degrees vs 26 degrees , P = .02), (3) passive horizontal adduction (7.7 cm vs 3.7 cm, P = .05), and (4) pain relief with passive adduction (VAS score, 6.2 cm vs 3.5 cm; P = .002). There was a trend toward greater improvements in the neutral rotation sling group when we measured (1) active horizontal adduction (8.3 cm vs 2.9 cm, P = .06) and (2) active internal rotation behind the back (18 cm vs 11.1 cm, P = .09). At 2 weeks, the neutral rotation sling group had significantly less night pain than the internal rotation sling group (mean VAS score, 18 mm vs 34 mm; P = .047). CONCLUSIONS: Neutral rotation sling use after anatomic total shoulder arthroplasty resulted in statistically significant improvements in external rotation and adduction, as well as decreased night pain, compared with an internal rotation sling. PMID- 30446233 TI - Heterotopic ossification after superior capsular reconstruction. PMID- 30446234 TI - Biological allograft healing after superior capsule reconstruction. PMID- 30446235 TI - [Shift-workers and night-workers' medical watching and prevention: State of art and recommendations]. AB - Night work is not only a work performed at night. It has also to be considered as a specifically organized work with its own duties and moving tasks in a different relational context. Primary preventive assessments regarding work schedules and occupational associated constraints have to be considered beside family potential consequences. Taking account of the consensually accepted impact of night-shift work on health, particularly on sleep, we recommend an annual medical visit for night-shift workers. We also recommend to declare the night shift diseases to the Regional committee of occupational diseases via the "alinea 4". PMID- 30446236 TI - [Shift-workers and night-workers' health consequences: State of art and recommendations]. AB - There are in France several millions of shift-workers and night-workers (20 to 25% of employees). These workers are therefore subject to variations in their working and rest schedules. These regular schedule changes are associated with repeated desynchronization of circadian biological clock. The negative impacts on sleep are insomnia, drowsiness, and reduced sleep time in 24hours. There is also a proven effect on the occurrence of a metabolic syndrome, with a likely effect on obesity, type 2 diabetes, blood pressure and coronary artery disease. There is a likely effect on the occurrence of cancer (including breast cancer). Night working is not recommended for pregnant women because of the risk of miscarriage, prematurity and intrauterine growth retardation. PMID- 30446237 TI - Seven cervical sensorimotor control tests measure different skills in individuals with chronic idiopathic neck pain. AB - BACKGROUND: Sensorimotor control is commonly reported in neck pain research and rapidly gaining interest in clinical practice. Joint position error (conventional and torsion), postural balance, subjective visual vertical, head tilt response, The Fly(r), smooth pursuit neck torsion and head steadiness are tests that have been reported to assess cervical sensorimotor control. However, it is unknown whether clinicians could use one test, or a test battery, to appropriately assess cervical sensorimotor control and improve efficiency. Our main research question is: Do seven cervical sensorimotor control tests measure unique or similar characteristics of sensorimotor control in individuals with chronic idiopathic neck pain? METHODS: Principle components factor analysis. Data from seven cervical sensorimotor control tests of 50 participants with chronic idiopathic neck pain were included. Individual factors, potentially related to sensorimotor control, were determined by Eigen values >1.00 and inspection of a loading plot. Items with loadings >=0.40 were considered satisfactory for inclusion in a factor. RESULTS: All cervical sensorimotor control tests were found to measure unique skills. Four factors were isolated with two, postural balance and head steadiness, accounting for most of the variance across tests. The remaining two factors, continuous movement accuracy and perceived verticality, contributed less to the observed variance. CONCLUSION: Postural balance and head steadiness were the major underlying factors explaining cervical sensorimotor control in the current sample. However, our results imply that all seven tests are independent and measure different skills. It is not possible to recommend a test battery for clinical practice, as all tests measure unique skills which appear to be independent of each other. PMID- 30446238 TI - Functional balance assessment in recreational college-aged individuals with a concussion history. AB - OBJECTIVES: Despite evidence for increased musculoskeletal injury after concussion recovery, there is a lack of dynamic balance assessments that could inform management and research into this increased injury risk post-concussion. Our purpose was to identify tandem gait dynamic balance deficits in recreational athletes with a concussion history within the past 18-months compared to matched controls. DESIGN: Cross-sectional, laboratory study. METHODS: Fifteen participants with a concussion history (age: 19.7+/-0.9years; 9 females; median time since concussion 126 days, range 28-432 days), and 15 matched controls (19.7+/-1.6years; 9 females) with no recent concussion history participated. We measured center-of-pressure (COP) outcomes (velocity, path length, speed, dual task cost) under 4 tandem gait conditions: (1) tandem gait, (2) tandem gait, eyes closed, (3) tandem gait, eyes open, cognitive distraction, and (4) tandem gait, eyes closed, cognitive distraction. RESULTS: The concussion history group demonstrated slower tandem gait velocity compared to the control group (4.0cm/s difference), thus velocity was used as a covariate when analyzing COP path length and speed. The concussion history group (23.5%) demonstrated greater COP speed dual-task cost than the control group (16.3%) during the eyes closed dual-task condition. No other comparisons were statistically significant. CONCLUSIONS: There may be subtle dynamic balance differences during tandem gait that are detectable after return-to-activity following concussion, but the clinical significance of these findings is unclear. Longitudinal investigations should identify acute movement deficits in varying visual and cognitive scenarios after concussion in comparison with recovery on traditional concussion assessment tools while also recording musculoskeletal injury outcomes. PMID- 30446239 TI - Sclerochoroidal calcification as casual finding. AB - Sclerochoroidal calcification (SCC) is uncommon and benign. It is usually detected in a routine examination, finding multiple yellow-white lesions in the upper temporal region of the retina in middle-aged and elderly men. A case report is presented of a 79 year-old male patient, who during a routine examination with a pseudoexfoliative glaucoma in the right eye, as well as raised white-yellow subretinal lesions in the upper temporal region in both eyes. After establishing hypotensive treatment and performing autofluorescence, optical coherence tomography (OCT), ultrasound, ocular computed tomography (CT) and complete laboratory analysis, idiopathic SCC was diagnosed. SCC requires a complete ophthalmological and systemic study as it can be associated with endocrine disease. Periodic follow-up is also recommended, as well as to rule out possible complications, such as atrophy of the overlying pigment epithelium, serous detachment, or the appearance of neovascularization. The differential diagnosis should be made of benign and malignant lesions, in order to avoid unnecessary treatment. PMID- 30446240 TI - Quality of life and visual function in children with glaucoma in Spain. AB - OBJECTIVE: To evaluate the effect of glaucoma on visual function, as well as quality of life in children and quality of life perceived by caregivers in children up to 16 years of age. MATERIAL AND METHODS: An observational and prospective study was designed using the questionnaire GQL-15 (Glaucoma Quality of Life) and conducted on children and caregivers. The questionnaire VFQ-25 (Visual Functioning Questionnaire) was conducted on children. Different variables of the clinical history that could influence the quality of life and visual function were recorded. RESULTS: The study included 24 patients with a mean age of 9.13+/-3.08 years, and included 3 with unilateral involvement, and 20 diagnosed with primary congenital glaucoma. Parents reported a worse quality of life than children. The result of the GQL-15 survey was 32.3+/-11.56 points in children and 37.52+/-14.59 points in caregivers (P=.001). The parameter most related to quality of life and visual function was the mean deviation (MD) of the visual field in the best eye. A statistically significant correlation was found between the result of GQL-15 and the mean deviation of the visual field (children: R=0.63, P<.01, caregivers: R=0.81, P<.001). CONCLUSIONS: Functional loss has an impact on the quality of life and visual function in children with glaucoma, although the quality of life perceived by the caregivers is worse than that perceived by the child. PMID- 30446242 TI - An Update on the Diagnosis and Management of Catecholaminergic Polymorphic Ventricular Tachycardia. PMID- 30446241 TI - A review of international medical device regulations: Contact lenses and lens care solutions. AB - Medical devices are under strict regulatory oversight worldwide and such regulations prioritise patient safety and efficacy over anything else. Contact lenses fall under the medical device category - a result of direct contact with the eye. Equally regulated are the contact lens care product solutions, which include cleaning and maintenance solutions and lubricating and rewetting drops. In the USA, it is the FDA Centre for Devices and Radiological Health (CDRH) overseeing the regulations of medical devices, since 1976. In the European Union, it is the EU Commission responsible for regulating devices in Member States. The categorisation of contact lenses into medical devices is based on their inherent risk to the wearer. Contact lenses are subject to crucial regulatory oversight from concept to clinical evaluation, clinical investigations through to the finished lens product, and finally, strict conditions associated with their marketing approval including post-marketing surveillance. The physiochemical and manufacturing testing, such as biocompatibility testing alongside pre-clinical stability, sterility and microbiological testing are just some of the essential testing lenses must endure. Only through understanding the inherent risks and potential complications that can arise from contact lens wear, can one truly appreciate the need to adhere to strict regulations. The challenge however, lies in the need for more standardised regulations and flexible approaches, ensuring innovative device technologies reach patients in a timely manner without compromising public health and safety. This review highlights some key requirement, differences and similarities between the FDA and EU administrations in the approval of contact lenses. PMID- 30446243 TI - Arrhythmogenic Cardiomyopathy in 2018: ARVC/ALVC or Both? AB - Arrhythmogenic cardiomyopathy (ACM) is now commonly used to describe any form of non-hypertrophic, progressive cardiomyopathy characterised by fibrofatty infiltration of the ventricular myocardium. Right ventricular (RV) involvement refers to the classical arrhythmogenic right ventricular cardiomyopathy, but left ventricular, or bi-ventricular involvement are now recognised. ACM is mostly hereditary and associated with mutations in genes encoding proteins of the intercalated disc. ACM classically manifests as ventricular arrhythmias, and sudden death may be the first presentation of the disease. Heart failure is seen with advanced stages of the disease. Diagnosis can be challenging due to variable expressivity and incomplete penetrance, and is guided by established Taskforce criteria that incorporate electrical features (12-lead electrocardiography (ECG), features of ventricular arrhythmias), structural features (on imaging via echo and cardiac magnetic resonance imaging [MRI]), tissue characteristics (via biopsy), and familial/genetic evaluation. Electrical abnormalities may precede structural alterations, which also make diagnosis challenging, especially in differentiating ACM from other conditions such as benign right ventricular arrhythmias, channelopathies such as Brugada, or the Athlete's Heart. Genetic testing is critical in identifying familial mutations and initiating cascade testing, but finds a pathogenic mutation in only ~50% of patients. Some critical genotype-phenotype correlations do exist and may help guide risk stratification and give clues to disease progression. Therapeutic strategies include restriction from high endurance and competitive sports, beta-blockers, antiarrhythmic drugs, heart failure medications, implantable cardioverter-defibrillators and combined endocardial/epicardial catheter ablation. Ablation has emerged as the treatment of choice for recurrent ventricular arrhythmias in ACM. This state-of-the-art review outlines the pathogenesis, diagnosis and treatment of ACM in the contemporary era. PMID- 30446244 TI - Association of long-term PM2.5 exposure with traditional and novel lipid measures related to cardiovascular disease risk. AB - BACKGROUND: Fine particulate matter (PM2.5) exposure is associated with increased morbidity and mortality, particularly for cardiovascular disease. The association between long-term exposure to PM2.5 and measures of lipoprotein subfractions remains unclear. Therefore, we examined associations between long-term PM2.5 exposure and traditional and novel lipoprotein measures in a cardiac catheterization cohort in North Carolina. METHODS: This cross-sectional study included 6587 patients who had visited Duke University for a cardiac catheterization between 2001 and 2010 and resided in North Carolina. We used estimates of daily PM2.5 concentrations on a 1 km-grid based on satellite measurements. PM2.5 predictions were matched to the address of each patient and averaged for the year prior to catheterization date. Serum lipids included HDL, LDL, and triglyceride-rich particle, and apolipoprotein B concentrations (HDL-P, LDL-P, TRL-P, and apoB, respectively). Linear and quantile regression models were used to estimate change in lipoprotein levels with each MUg/m3 increase in annual average PM2.5. Models were adjusted for age, sex, race/ethnicity, history of smoking, area-level education, urban/rural status, body mass index, and diabetes. RESULTS: For a 1-MUg/m3 increment in PM2.5 exposure, we observed increases in total and small LDL-P, LDL-C, TRL-P, apoB, total cholesterol, and triglycerides. The percent change from the mean outcome level was 2.00% (95% CI: 1.38%, 2.64%) for total LDL-P and 2.25% (95% CI: 1.43%, 3.06%) for small LDL-P. CONCLUSION: Among this sample of cardiac catheterization patients residing in North Carolina, long-term PM2.5 exposure was associated with increases in several lipoprotein concentrations. This abstract does not necessarily reflect U.S. EPA policy. PMID- 30446245 TI - School start time changes in the COMPASS study: associations with youth sleep duration, physical activity, and screen time. AB - BACKGROUND: To date, no longitudinal population-based studies of school start times have been conducted within Canada. School schedule changes provided an opportunity to examine start times in association with youth sleep, physical activity, and screen use over time. METHODS: This longitudinal study included grade 9-12 students attending 49 Ontario secondary schools that participated in at least two consecutive years of the COMPASS study (2012-2017). Fixed effects models tested whether differences in within-student change in self-reported sleep duration, moderate-to-vigorous physical activity, and screen time were associated with school start time changes, adjusting for student- (grade, sex, ethnicity, spending money) and school-level covariates (median income, urbanicity, geographical area). RESULTS: Thirteen start time changes of 5-10 min were reported. Ten-minute advances at earlier clock times (8:30 AM-8:20 AM; 8:40 AM 8:30 AM) were associated with steeper sleep duration declines than schools with consistent start times but had no effect at later times (9:00 AM-8:50 AM). While sleep change did not differ with 5-min delays, 10-min delays (8:50 AM-9:00 AM) were associated with additional sleep (23.7 min). Apart from one school that shifted from 8:30 AM to 8:35 AM, in which screen time and physical activity decreased more steeply, no effect was found for screen time, and 5-min delays were associated with more physical activity (10.9 min) and advances with less activity (-8.0 min). CONCLUSIONS: Results support start time delays as a valuable strategy to help ameliorate sleep debt among youth. Interference with physical activity or increased screen time appear unlikely with modest schedule changes. Potential adverse impacts on sleep require consideration with 10-min advances. PMID- 30446246 TI - Reduction of No Reflow with a Loading Dose of Atorvastatin before Primary Angioplasty in Patients with Acute ST Myocardial Infarction. AB - BACKGROUND: No reflow defined as an altered myocardial reperfusion and failure at microvascular level is a frequent complication in acute myocardial infarction that attenuates beneficial effect of reperfusion therapy leading to poor outcomes. There is not enough evidence to support that previous use of statins improves coronary flow in patients undergoing primary percutaneous coronary intervention (PCI). AIM OF STUDY: To determine if a loading dose of 80 mg of atorvastatin before primary angioplasty reduces the frequency of no reflow, hs CRP, IL6 intracoronary levels, and major combined cardiovascular events at 30 d. METHODS: In this controlled clinical trial, we randomly assigned 103 adult patients within the 12 h of acute ST-elevation myocardial infarction (STEMI) to receive 80 mg of atorvastatin additional to standard treatment (AST) before performing primary PCI versus standard treatment (ST) alone. The primary outcomes were the occurrence of no reflow and high sensitivity C-reactive protein (hs-CRP) and interleukin 6 levels and secondary outcomes were major adverse cardiovascular events at 30 d. RESULTS: 103 patients were analyzed, 49 (48%) received AST, 54 (52%) ST. Frequency of no reflow among groups was 27 vs. 63% respectively, p <=0.0001. hs-CRP level was 2.69 mg/dL for AST vs. 2.2 mg/dL in ST, meanwhile IL-6 levels were 5.2 pg/mL vs. 6.35 pg/mL respectively, p = ns. Cox regression model demonstrated that the treatment assigned is an independent predictor for no reflow occurrence (HR 0.34 95%, CI 0.18-0.61, p <=0.001). CONCLUSION: The administration of a loading dose of 80 mg atorvastatin before primary PCI is an effective strategy for prevention of no reflow improving also clinical outcomes and free survival rate for the presentation of major adverse cardiovascular events at 30 d. PMID- 30446248 TI - [Extrapulmonary tuberculosis versus pulmonary tuberculosis: epidemiological, diagnosis and evolutive aspects]. AB - INTRODUCTION: Tuberculosis remains a public health problem around the world. Several factors can influence its location. The objective of this research is to analyze the factors influencing the diagnostic and evolutive aspects of extra pulmonary tuberculosis (PET) compared to pulmonary tuberculosis (PT) at the anti tuberculosis center of Adjame (Ivory Coast). PATIENTS AND METHODS: This is a retrospective comparative study between PET and PT's patients based on the diagnostic and evolutive aspects of tuberculosis cases reported from January 1st, 2010 to December 31st, 2012 at the Adjame anti-tuberculosis center. RESULTS: During the study period, 9442 patients were enrolled. Patients at advanced ages, were more affected by PET while younger adults were more affected by PT (P=0.001). Women and Adjame's residents were respectively more affected by PT compared to men and non-Adjame's residents. The majority of patients suffering from PET were HIV-positive while those suffering from PT were predominantly HIV negative (P=0.001). The proportion of new cases was higher among populations with PET than in subjects with PT (P=0.001). Both groups of patients (PT and PET) were positively responsive to treatments. PMID- 30446247 TI - Metabolic imaging with the use of fluorescence lifetime imaging microscopy (FLIM) accurately detects mitochondrial dysfunction in mouse oocytes. AB - OBJECTIVE: To determine whether metabolic imaging with the use of fluorescence lifetime imaging microscopy (FLIM) identifies metabolic differences between normal oocytes and those with metabolic dysfunction. DESIGN: Experimental study. SETTING: Academic research laboratories. PATIENT(S): None. INTERVENTION(S): Oocytes from mice with global knockout of Clpp (caseinolytic peptidase P; n = 52) were compared with wild-type (WT) oocytes (n = 55) as a model of severe oocyte dysfunction. Oocytes from old mice (1 year old; n = 29) were compared with oocytes from young mice (12 weeks old; n = 35) as a model of mild oocyte dysfunction. MAIN OUTCOME MEASURE(S): FLIM was used to measure the naturally occurring nicotinamide adenine dinucleotide dehydrogenase (NADH) and flavin adenine dinucleotide (FAD) autofluorescence in individual oocytes. Eight metabolic parameters were obtained from each measurement (4 per fluorophore): short (tau1) and long (tau2) fluorescence lifetime, fluorescence intensity (I), and fraction of the molecule engaged with enzyme (F). Reactive oxygen species (ROS) levels and blastocyst development rates were measured to assess illumination safety. RESULT(S): In Clpp-knockout oocytes compared with WT, FAD tau1 and tau2 were longer and I was higher, NADH tau2 was longer, and F was lower. In old oocytes compared with young ones, FAD tau1 was longer and I was lower, NADH tau1 and tau2 were shorter, and I and F were lower. FLIM did not affect ROS levels or blastocyst development rates. CONCLUSION(S): FLIM parameters exhibit strong differentiation between Clpp-knockout versus WT, and old versus young oocytes. FLIM could potentially be used as a noninvasive tool to assess mitochondrial function in oocytes. PMID- 30446249 TI - Pulmonary Ultrasound and Diaphragmatic Shortening Fraction Combined Analysis for Extubation-Failure-Prediction in Critical Care Patients. AB - INTRODUCTION: Invasive respiratory support is a cornerstone of Critical Care Medicine, however, protocols for withdrawal of mechanical ventilation are still far from perfect. Failure to extubation occurs in up to 20% of patients, despite a successful spontaneous breathing trial (SBT). METHODS: We prospectively included ventilated patients admitted to medical and surgical intensive care unit in a university hospital in northern Mexico. At the end of a successful SBT, we measured diaphragmatic shortening fraction (DSF) by the formula: diaphragmatic thickness at the end of inspiration - diaphragmatic thickness at the end of expiration/diaphragmatic thickness at the end of expiration*100, and the presence of B-lines in five regions of the right and left lung. The primary objective was to determine whether analysis of DSF combined with pulmonary ultrasound improves prediction of extubation failure. RESULTS: Eighty-two patients were included, 24 (29.2%) failed to extubation. At univariate analysis, DSF (Youden's J: >30% [sensibility and specificity 62 and 50%, respectively]) and number of B-lines regions (Youden's J: >1 zone [sensibility and specificity 66 and 92%, respectively]) were significant related to extubation failure (area under the curve 0.66 [0.52-0.80] and 0.81 [0.70-0.93], respectively). At the binomial logistic regression, only the number of B-lines regions remains significantly related to extubation failure (OR 5.91 [2.33-14.98], P<.001). CONCLUSION: In patients with a successfully SBT, the absence of B-lines significantly decreases the probability of extubation failure. Diaphragmatic shortening fraction analysis does not add predictive power over the use of pulmonary ultrasound. PMID- 30446251 TI - A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease. AB - Susceptibility to multiple autoimmune diseases is associated with common gene polymorphisms influencing IL-2 signaling and Treg function, making Treg-specific expansion by IL-2 a compelling therapeutic approach to treatment. As an in vivo IL-2 half-life enhancer we used a non-targeted, effector-function-silent human IgG1 as a fusion protein. An IL-2 mutein (N88D) with reduced binding to the intermediate affinity IL-2Rbetagamma receptor was engineered with a stoichiometry of two IL-2N88D molecules per IgG, i.e. IgG-(IL-2N88D)2. The reduced affinity of IgG-(IL-2N88D)2 for the IL-2Rbetagamma receptor resulted in a Treg-selective molecule in human whole blood pSTAT5 assays. Treatment of cynomolgus monkeys with single low doses of IgG-(IL-2N88D)2 induced sustained preferential activation of Tregs accompanied by a corresponding 10-14-fold increase in CD4+ and CD8+ CD25+FOXP3+ Tregs; conditions that had no effect on CD4+ or CD8+ memory effector T cells. The expanded cynomolgus Tregs had demethylated FOXP3 and CTLA4 epigenetic signatures characteristic of functionally suppressive cells. Humanized mice had similar selective in vivo responses; IgG-(IL-2N88D)2 increased Tregs while wild-type IgG-IL-2 increased NK cells in addition to Tregs. The expanded human Tregs had demethylated FOXP3 and CTLA4 signatures and were immunosuppressive. These results describe a next-generation immunotherapy using a long-lived and Treg-selective IL-2 that activates and expands functional Tregsin vivo. Patients should benefit from restored immune homeostasis in a personalized fashion to the extent that their autoimmune disease condition dictates opening up the possibility for remissions and cures. PMID- 30446252 TI - Successful percutaneous treatment of osteoid osteoma in a 13 month-old boy with radiofrequency ablation under CT guidance. AB - We present a 13-month-old boy who had a successful Computed Tomography (CT) guided percutaneous radiofrequency ablation (RFA) treatment for the osteoid osteoma (OO) on proximal part of the tibial diaphysis. The complaints of the patient were being restless due to pain and refusing to bear any weight on his left leg for 6 months. An asymmetrical cortical thickening and a focal sclerosis was detected on medial proximal diaphysis of the left tibia on radiographs and axial T2-weighted STIR-MR image showed bone marrow and soft-tissue edema with low signal-intensity nidus due to central calcification with a high-signal intensified unmineralized periphery. CT findings (the nidus on the cortex of tibia with well circumscribed lucent region around a central sclerotic dot and cortical thickening around the nidus) confirmed the diagnosis of OO. After CT guided percutaneous RFA treatment, the patient had an immediate pain relief in 24 h after and could bear weight on the leg. 12 and 16 months after RFA respectively, CT images and radiographs revealed sclerotic healing of the nidus and a slow regression of the adjacent cortical thickness without any recurrence. PMID- 30446250 TI - Continuous Positive Airway Pressure Treatment Does not Reduce Uric Acid Levels in OSA Women. AB - OBJECTIVES: Although an association between uric acid (UA) levels and obstructive sleep apnea (OSA) has been reported, the effect of continuous positive airway pressure (CPAP) on this measure is yet unclear. We aimed to investigate the effect of CPAP therapy on serum UA levels in patients with OSA. METHODS: We conducted a multicenter, open-label, randomized controlled trial in 307 women diagnosed with moderate-to-severe OSA (apnea-hypopnea index [AHI]>=15) in 19 Spanish Sleep Units. Women were randomized to CPAP (n=151) or conservative treatment (n=156) for 12 weeks. Changes in serum UA measures were assessed on an intention-to-treat basis. Additional analyses were conducted in the subgroup of women with CPAP adherence >=4h/night and those with UA levels >=6mg/dl. RESULTS: Women had a mean (SD) age of 57.1 (10.1) years, median (first-third quartile) body mass index of 33.7 (29.0-38.5) mg/kg2 and AHI of 32.0 (22.6-48.5). The average serum UA measure was 5.11 (1.26) mg/dl, and 80 (26.1%) participants had UA>=6mg/dl. Compared with the control group, the CPAP group did not achieve any reduction in UA levels (non-adjusted intergroup difference -0.03mg/dl, 95%CI 0.20 to 0.13; p=0.702) after 12 weeks of follow-up. These results did not change when the analysis was restricted to women with CPAP adherence >=4h/night, or the subgroup of women with hyperuricemia. CONCLUSIONS: Twelve weeks of CPAP therapy does not reduce UA levels compared to conservative treatment in women with moderate-to-severe OSA. PMID- 30446253 TI - Additive effect of walnut and chokeberry on regulation of antioxidant enzyme gene expression and attenuation of lipid peroxidation in d-galactose-induced aging mouse model. AB - Studies have highlighted the association between the cellular damage caused by reactive oxygen species and aging. The reducing sugar d-galactose causes aging related changes and oxidative stress. Lipids are the first target of free radicals, and lipid peroxidation is related to aging. Walnut (Juglans regia Chandler) kernel contains antioxidant phenolic compounds, and chokeberry (Aronia melanocarpa) is one of the richest sources of polyphenols, including anthocyanins, among other fruits. Polyphenols from chokeberry exhibit antioxidant and anti-inflammatory activities. In this study, the additive antioxidative effect of walnut and chokeberry mixture was evaluated by oxidative stress index in d-galactose-induced aging model. Thirty-five Balb/c mice (8 weeks old) were divided into following five groups (n = 7 in each group): normal control (C), d galactose control (D), d-galactose with chokeberry diet (CH), d-galactose with walnut diet (W), and d-galactose with walnut and chokeberry mixture diet (WCH). In all treatment diets groups, the levels of serum, hepatic, and kidney malonaldehyde were significantly lower than D group and the levels were approaching to control level. Moreover, the kidney malondialdehyde levels were significantly lower in WCH group compared with the control group. This study also confirmed the activities of antioxidant enzymes in liver, as the levels of superoxide dismutase, and glutathione peroxidase were significantly increased in CH group compared to in W or CH groups. The results of this study supported the additive effect of walnut and chokeberry on increment of antioxidant enzyme gene expression in liver and consequently the attenuation of lipid peroxidation in serum, liver, and kidney in d-galactose-induced aging-mouse model. Further studies are needed to investigate the detailed mechanism underlying the additive antioxidative effects in various tissues. PMID- 30446254 TI - Current status of food waste generation and management in China. AB - The current status of FW generation, including its characteristics, management, and current challenges in China, were analyzed, and further suggestions were made with regards to improvement. About 19.50% of the FW generated could be treated under the current designs for treatment capacity in China. FW characteristics show great variability in different economic regions in China, where both treatment efficiency and FW management are poor. Combined pretreatment and three phase separation is the most used pretreatment method, and of the current FW pilot projects, anaerobic digestion is the most prevalent, accounting for 76.1% of all projects. Significant regional characteristics have been identified regarding FW generation and the treatment capacity for FW processing. Possible factors influencing FW management in China were also discussed. Finally, detailed suggestions are given for further development of FW treatment capacity, particularly regarding potential technical routes and management measures. PMID- 30446255 TI - Review of seasonal influenza vaccination in the Eastern Mediterranean Region: Policies, use and barriers. AB - Vaccination is the main control measure for influenza and its severe complications. To better understand the influenza vaccination situation in the Eastern Mediterranean Region, we conducted an extensive review of literature published between 2006 and 2016 in the region on influenza vaccine policies, use, recommendations and coverage. Forty-eight articles met the inclusion criteria. These originated from 11 of the 22 countries of the region, with most being from Saudi Arabia and Iran. The review revealed knowledge gaps and misconceptions about influenza and its vaccines even among healthcare workers. Most of the papers reviewed reported low coverage in the target populations. Limited literature on the number of countries with concrete national influenza vaccination policies was available, which may not accurately represent the situation in the Region. In conclusion, lack of awareness and knowledge are the main barriers to influenza vaccination, which remains very low in the Eastern Mediterranean Region. Countries of the region need to promote and invest in research on influenza vaccination, which is critical to inform evidence-based programmes and policies to improve vaccination rates and control influenza. PMID- 30446256 TI - Comparison of individual and composite radiographic markers of frailty in trauma. AB - BACKGROUND: Clinical frailty scores usually involve questionnaires or physical testing. Many trauma patients are not able to participate in these. Radiographic measurement of frailty may be a viable alternative. Individual radiographic markers of frailty have been investigated, such as sarcopenia or osteopenia. The ideal radiographic variable (or variables) to measure frailty in trauma is unknown. STUDY DESIGN: A retrospective review was performed of restrained drivers ages 40 and greater at a single institution from 2010-2015. Multiple markers of radiographic frailty were measured including: sarcopenia, osteopenia, vascular calcifications, sarcopenic obesity, emphysema, renal volume, cervical spine degeneration, and cerebral atrophy. Frailty was defined as the worst quartile for each radiographic variable, and these values were summed to create a composite marker of frailty. The primary outcome was discharge disposition. We hypothesized that a composite frailty score would be associated with discharge disposition while individual markers would not be associated with discharge disposition. RESULTS: Overall 489 patients were included in this study. Cerebral atrophy (p = 0.05), renal volume (p = 0.004), sarcopenia (p = 0.05), vascular calcifications (p = 0.02) and sarcopenic obesity (p = 0.01) were associated with discharge disposition. Pearson's correlation coefficients between radiographic frailty markers were all less than 0.4. Youden's Index was 0.26 (p < 0.001) at a composite score of 3. In multivariable analysis, the composite score of 3 or greater was associated with poor discharge disposition (OR 2.39, 95% CI 1.10 5.18, p = 0.03). CONCLUSIONS: Individual radiographic frailty markers are inadequate markers of frailty, as they may miss patients who are frail. This study also suggests that a composite radiographic frailty score may better predict patient outcome than individual radiographic markers of frailty. PMID- 30446257 TI - Effectiveness of interventions aiming at reducing sedentary behaviour in a non surgical population with overweight or obesity: A systematic review and meta analysis. AB - AIM: This systematic review and meta-analyses of randomised controlled trials (RCTs) investigated the effectiveness of interventions to reduce sedentary behaviour amongst people with overweight or obesity. Secondarily, it aimed to investigate the effectiveness of these interventions on body mass index (BMI), time spent in moderate-to-vigorous physical activity (MVPA) and health-related quality of life (HRQoL). METHODS: A search of six databases (CENTRAL, PubMed, Embase, PEDro, CINAHL and PsycINFO) was conducted from inception to July 2018. RCTs in which sedentary behaviour was measured by accelerometry or inclinometry, with participants of any age with overweight or obesity were included. Subgroup analyses were undertaken comparing studies that included adults versus children and studies with an active component (e.g., treadmill desk, physically active breaks) versus no active component to their intervention. RESULTS: Nine studies (n=1859) were included. Compared to the control group, the interventions significantly reduced time spent in sedentary behaviour (standardised mean difference [95% confidence interval] -0.33 [-0.59 to -0.08] overall; -0.53 [-0.95 to -0.11] in adults). Subgroup analyses demonstrated that only interventions that included active components reduced time spent in sedentary behaviour (-0.54 [ 0.88 to -0.20]) and increased time spent in MVPA (1.29 [0.02 to 2.56]). Subgroup analyses demonstrated that interventions only reduced BMI in studies of children (-0.09 [-0.18 to -0.00]) and in those with no active component (-0.09 [-0.18 to 0.01]). There were insufficient data to investigate the effectiveness of these interventions on HRQoL. CONCLUSIONS: This novel systematic review and meta analyses suggests interventions aiming to effectively reduce objectively-measured sedentary behaviour need to specifically include an active component. PMID- 30446258 TI - Corrigendum to "Neuroprotective effects of quercetin 4'-O-beta-d-diglucoside on human striatal precursor cells in nutrient deprivation condition." [Acta Histochemica, 2018 Feb;120(2):122-128]. PMID- 30446259 TI - Corrigendum to 'The presence of abalone egg-laying hormone-like peptide in the central nervous system and ovary of the Spotted Babylon, Babylonia areolata' [Acta histochemica 119 (2017) 701-707]. PMID- 30446260 TI - Alteration of BRCA-1 tumor suppressor gene expression in serous and mucinous ovarian neoplasms in the benign-borderline-malignant pathway. AB - Alteration of expression of the tumor suppressor gene BRCA-1 has been widely studied in breast and ovarian carcinoma. However, pattern of this alteration in the benign-borderline-carcinoma sequence in serous and mucinous ovarian neoplasms have not yet fully described. Tissue sections from 214 formalin-fixed paraffin embedded ovarian specimens were stained immunohistochemically with BRCA-1 antibody. Specimens were 10 normal ovarian surface epithelium, 10 fallopian tube epithelium, 70 benign adenoma (50 serous and 20 mucinous), 28 borderline (13 serous and 15 mucinous), 78 carcinoma (58 serous and 20 mucinous), and 18 metastatic deposit (13 serous and 5 mucinous). Expression was evaluated into 0, +1, +2, and +3. Score +3 staining similar to normal tissues was considered normal and other scores were considered altered expression. Strong expression was seen in all normal epithelium specimens. Altered expression was seen in 34 serous neoplasms; 17 of 50 (34%) of benign cystadenomas, 6 of 13 (46%) of borderline tumors, 43 of 58 (74%) of primary carcinoma, and in 8 of 13 (62%) of metastatic carcinoma. This alteration was significantly associated with higher histopathologic grade (P = 0.049), presence of necrosis (P = 0.0001), and higher proliferation rate (P = 0.001). In mucinous neoplasms; altered BRCA-1 was detected in 25 specimens; 7 of 20 (41%) of benign cystadenomas, 5 of 15 (33%) of borderline neoplasms, 9 of 20 (45%) of primary carcinoma, and 4 of 5 (80%) of the metastatic deposits. This alteration was not associated with any of the clinicopathologic tumor characteristics. In conclusion, alteration of BRCA-1 expression is more frequent in serous than in mucinous carcinomas and is associated with tumors of higher grades and high proliferation rate. PMID- 30446261 TI - Awareness and management of low anterior resection syndrome: A Dutch national survey among colorectal surgeons and specialized nurses. AB - INTRODUCTION: Substantial progress has been made in the treatment of rectal cancer in the past two decades. Low anterior resection is a cornerstone in current treatment, combined with neo-adjuvant (chemo-) radiation in selected cases. However, side effects such as increased frequency, urgency and incontinence are seen in a majority of patients postoperatively. These symptoms, referred to as low anterior resection syndrome (LARS), have a severe impact on quality of life. Management of LARS is complex, and surgeons seem to underestimate and misinterpret the impact of symptoms associated with LARS. AIM AND METHODS: We investigated the awareness and management of LARS in The Netherlands, conducting a national survey in which colorectal surgeons and colorectal care nurses were asked for their views on this complex syndrome. RESULTS: 242 health-care professionals participated in the survey. Most participants estimate the prevalence of major LARS is 20-40% after low anterior resection (LAR); a severe underestimation of actual prevalence - around 70%. Only 10% of surgeons use LARS screening tools in the preoperative period, and fewer than half of surgeons use LARS scores before or after a LAR. Although most surgeons inform their patients preoperatively about the changes in bowel function that they may experience after rectal cancer treatment, a majority of these surgeons indicate more information and patient counselling would improve the quality of life of their patients. DISCUSSION: Impact and prevalence of LARS is underestimated by their physicians. Uniform clinical guidelines should be developed to guide physicians in adequate management of patients with LARS. PMID- 30446262 TI - Flavored electronic cigarette use, preferences, and perceptions in pregnant mothers: A correspondence analysis approach. AB - Use, preferences, and perceptions of flavored electronic cigarettes (e cigarettes) were investigated in an ethnically diverse sample of pregnant mothers (N = 100; 50% smokers, Mage = 26; 66% low income; 65% minorities) via detailed interviews. Fruit and mint were the most commonly used flavors. Pregnant women endorsed increased use of fruit flavored e-cigarettes in preconception and pregnancy, greater preferences and intentions to use sweet flavors (fruit and candy), and lowest preferences for tobacco flavors. No differences in perceptions of general, pregnancy, or fetal-related health risks emerged across flavors. Latent factor mapping (biplots) based on correspondence analyses of contingency tables revealed clustering of more-preferred fruit and candy flavors versus least preferred tobacco flavored e-cigarettes, with other sweet flavors-mint and alcohol-clustering more closely with fruit and candy flavors, and more pungent flavors-spice, coffee, chocolate-clustering near tobacco. Correspondence analysis also revealed uncorrelated clustering of preferences and harm perceptions, with intentions showing associations with both preferences and harm perceptions. Preference for fruit and mint flavored e-cigarettes and decreased harm perceptions significantly differentiated lifetime e-cigarette users from non users. Results highlight preferences for fruit and mint flavored e-cigarettes during preconception and pregnancy, and links between preferences for fruit and mint flavors and lifetime use of e-cigarettes. These findings also highlight the utility of correspondence analysis for elucidating clustering of flavor perceptions and preferences for novel tobacco products. PMID- 30446263 TI - Synthetic Biology Toolbox and Chassis Development in Bacillus subtilis. AB - Based on technical advances in the sequencing and synthesis of genetic components as well as the genome, significant progress has recently been made in developing synthetic biology toolboxes and chassis for the model Gram-positive bacterium Bacillus subtilis. In this review, we discuss recently developed synthetic biology toolboxes, including gene expression toolsets and genome editing tools. Next, advances in the B. subtilis chassis and its applications are discussed in comparison to those of other model microorganisms. Finally, future directions for the integrative use of B. subtilis synthetic biology tools and the development of an advanced chassis for efficient biomanufacturing are discussed. These factors are expected to become a major driving force for facilitating biotechnological applications of B. subtilis. PMID- 30446264 TI - Outbreak reports. PMID- 30446265 TI - Detailed efficiency analysis of columns with a different packing quality and confirmation via total pore blocking. AB - We report on a systematic study involving columns with a clearly different efficiency (4 distinct quality groups) obtained by packing the columns that were C18 bonded and endcapped with a different carbon loading. Using B-term analysis (via peak parking) and theoretical models to estimate the magnitude of the Cm- and Cs-term contributions, it could be concluded that the difference in efficiency among the groups was entirely due to a difference in eddy dispersion. As such, the columns provided an ideal testing ground to verify how well the total pore blocking (TPB)-method can be used to probe differences in packing heterogeneity. In agreement with earlier literature observations, it turns out the TPB-method is much more sensitive to packing heterogeneities than the eddy dispersion (Heddy)-contribution measured under open-pore conditions via B- and C- term subtraction. Typically, differences in Heddy on the order of 0.1-0.5MUm translate into a difference on the order of 0.5-2MUm in the TPB mode. This confirms the TPB as a powerful technique to make very sensitive measurements of the homogeneity of packed beds. PMID- 30446266 TI - Systematic characterization and quantification of Rubiaceae-type cyclopeptides in 20 Rubia species by ultra performance liquid chromatography tandem mass spectrometry combined with chemometrics. AB - Rubiaceae-type cyclopeptides (RAs) are one of characteristic constituents isolated from Rubia species, which are candidates of innovative anti-tumor drugs due to their significant bioactivity. However, approaches on the systematic characterization and quantification of RAs are still not available because of low contents and complicated purification. In this study, an ultra performance liquid chromatography coupled triple quadrupole tandem mass spectrometry (UPLC-QqQ MS/MS) method was established and validated for qualitative and quantitative analysis of 14 RAs (1-14) in 20 Rubia plants from China. The separation was achieved on a Waters ACQUITY UPLC(r) BEH C18 column (50 * 2.1 mm, 1.7 MUm) using gradient elution with a mobile phase consisting of 0.1% formic acid in acetonitrile and water. Multiple reaction monitoring (MRM) in positive mode was used to enable the selective detection of RAs from the Rubia root and rhizome extracts within 10 min. This method was proved to be specific, sensitive, precise, and accurate with the limits of detection and quantification at 0.6-11.4 ng/mL and 1.9-34.2 ng/mL, respectively, and the relative standard deviation (RSD) of the overall intra-day and inter-day precision less than 5.24%. Satisfactory recovery was obtained from 83.80% to 111.77%, with the RSD less than 5.32%. Totally, 67 samples were then qualitatively and quantitatively analyzed by this method and 51 of them were proved to contain RAs. Thereinto, R. podantha and R. yunnanensis from Yunnan were the two most abundant species. Additionally, RAs were detected in 8 Rubia species for the first time. Then chemometric approaches were revealed to explain the relationship between samples based on their contents of RAs. This study demonstrated that the method was not only useful for RAs source discovery and chemotaxonomy of Rubia species, but also could be extended to standardization of RAs medical materials and their new drug research and development. PMID- 30446267 TI - Formation of by-products during chemical interesterification of lipids. Detection and characterization of dialkyl ketones by non-aqueous reversed-phase liquid chromatography-high resolution mass spectrometry and gas chromatography-mass spectrometry. AB - A new class of foreign substances present in the unsaponifiable fraction of vegetable oils undergone to chemical interesterification was systematically investigated. Their chemical structure, corresponding to dialkyl ketones (DAK) molecules, was elucidated both by gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-high resolution mass spectrometry (LC-HRMS). An analytical protocol aimed to qualitative and quantitative detection of DAK molecules in vegetable oils of confectionery industry interest was developed. Being the range of concentration levels to be evaluated dependent on the technological task of interesterification process, the quantitation step was thoroughly examined. All the validation parameters were satisfactory and particularly the concentration determinations were made more reliable by the contemporary use of several quantitation standards. GC-MS and LC-HRMS analytical techniques exhibited comparable performances even if the second one shown better detection sensitivity. PMID- 30446268 TI - A comparison of the opinions of intensive care unit staff and family members of the treatment intensity received by patients admitted to an intensive care unit: A multicentre survey. AB - BACKGROUND: Achieving shared decision-making in the intensive care unit (ICU) is challenging because of limited patient capacity, leading to a reliance on surrogate decision-makers. Prior research shows that ICU staff members often perceive that patients receive inappropriate or futile treatments while some surrogate decision-makers of patients admitted to the ICU report inadequate communication with physicians. Therefore, understanding the perceptions of both ICU staff and surrogate decision-makers around wishes for ICU treatments is an essential component to improve these situations. OBJECTIVES: The objectives of this study were to compare perceptions of ICU staff with surrogate decision makers about the intensity and appropriateness of treatments received by patients and analyse the causes of any incongruence. METHODS: A multicentred, single-day survey of staff and surrogate decision-makers of ICU inpatients was conducted across four Australian ICUs in 2014. Patients were linked to a larger prospective observational study, allowing comparison of patient outcomes. RESULTS: Twelve of 32 patients were identified as having a mismatch between staff and surrogate decision-maker perceptions. For these 12 patients, all 12 surrogate decision makers believed that the treatment intensity the patient was receiving was of the appropriate intensity and duration. Mismatched patients were more likely to be emergency admissions to ICU compared with nonmismatched patients (0.0% vs 42.1%, p = 0.012) and have longer ICU admissions (7.5 vs 3, p = 0.022). There were no significant differences in perceived communication (p = 0.61). CONCLUSIONS: Family members did not share the same perceptions of treatment with ICU staff. This may result from difficulty in prognostication; challenges in conveying poor prognoses to surrogate decision-makers; and the accuracy of surrogate decision makers. PMID- 30446269 TI - Bioelectrical Impedance Analysis-Derived Phase Angle Predicts Protein-Energy Wasting in Maintenance Hemodialysis Patients. AB - OBJECTIVE(S): To explore the validity of using bioelectrical impedance analysis (BIA)-derived 50 kHz phase angle (PhA) in predicting protein-energy wasting (PEW) in Chinese maintenance hemodialysis (MHD) patients. DESIGN AND METHODS: The design was a cross-sectional study. A total of 173 of MHD patients and 173 healthy adults were enrolled in the study. The prevalence of PEW in patients was performed by the International Society of Renal Nutrition and Metabolism criteria. The PhA, body cell mass, fat mass, body fat percentage, fat-free mass, and extracellular water/total body water were measured by InBody S10 body composition analyzer. The biochemical indices and anthropometric measurements were assessed using the way published elsewhere. The PhA, other values of BIA and its relationship with age, visceral protein, anthropometric measurements of the MHD patients were compared with the healthy group. The independent variables for predicting PEW and its cutoff values were explored using logistic regression model and receiver operating characteristic curve analysis, respectively. RESULTS: The MHD patients' PhA value was significantly lower than the healthy group (4.89 degrees +/- 1.19 vs. 6.32 degrees +/- 2.23, P < .01). A total of 34.1% MHD patients with PEW had significantly lower PhA values compared with well nourished patients (P < .05). The PhA decreased more significantly with age in MHD (r = -0.35, P < .001), compared with controls (r = -0.26, P < .001). The PhA values were positively associated with nutritional indices related to serum albumin, prealbumin, fat-free mass, and mid-arm muscle circumference. PhA values were not associated significantly with fat mass and body fat percentage (P > .05). Multivariate logistic regression analysis showed that PhA and body mass index were independent predictors of PEW, but the PhA was the stronger predictor (odds ratio = 4.48, P < .05). Receiver operating characteristic curve analysis suggested that the optimal PhA cutoff value to predict PEW was 4.6 degrees . CONCLUSIONS: BIA-derived PhA appears to be a useful bioelectrical marker for predicting PEW in Chinese hemodialysis patients with a cutoff value of 4.6 degrees . PMID- 30446270 TI - Cause-specific life years lost among persons diagnosed with schizophrenia: Is it getting better or worse? AB - BACKGROUND: People with schizophrenia have an increased risk of premature mortality compared to the general population. We aimed to quantify which types of causes of death contributed to the excess mortality, and to examine whether there has been an increase in the excess mortality among persons with schizophrenia in the period 1995 to 2015. METHOD: We used a cohort design including the entire Danish population. We calculated life years lost of the cohort members compared to a set reference-age at 95 years old. Using a decomposition model we examined differences of cause-specific death among those with schizophrenia and the general population, including calendar trends during the last two decades. RESULTS: In the general population, as well as in persons with schizophrenia, we found improvements in life years lost during the last two decades. Men with schizophrenia lost 13.5 years more than the general population (women; 11.4 years). Compared to the general population, a large improvement in life years lost with respect to suicide and accidents was found in those with schizophrenia, but, this improvement was offset by an increasing number of life years lost in deaths from diseases and medical conditions. CONCLUSION: Our findings highlight the urgent need for focused treatment of general medical conditions in those with schizophrenia. Without such an investment, it is probable that the life years lost among persons with schizophrenia (compared to the general population) will continue to worsen in future decades. PMID- 30446271 TI - Predictors of social functioning in patients with higher and lower levels of reduced emotional experience: Social cognition, social competence, and symptom severity. AB - BACKGROUND: Deficits in social functioning in schizophrenia are primarily predicted by negative symptoms, social cognition deficits, and social skills deficits. Here we examine those predictive variables across variations in the severity of reduced emotional experience. We hypothesized that in patients with high symptom severity, factors such as social cognition would have reduced importance for predicting social outcomes. METHODS: Participants with schizophrenia (n = 312) were tested using five different measures of social cognition. Performance-based assessments and clinical ratings of reduced emotion experience were used to assess social competence. High contact informants rated interpersonal functioning and social acceptability of behavior, while unaware of other patient data. Patients were divided into higher and lower reduced emotional experience using previously validated criteria. RESULTS: 33% of the patients had at least moderate symptoms of reduced emotional experience. Patients with greater severity had more social functioning impairment, but not poorer social competence and social cognition. In the patients with lower severity, social cognition accounted for 9% of the variance in interpersonal functioning, while in patients with higher severity, social cognition did not predict any variance. In the patients with lower severity, social cognition accounted for 4% of the variance in social acceptability of behavior, while in patients with higher severity, social cognition also did not predict any variance. IMPLICATIONS: The influence of social cognition on social outcomes appears greater in patients with less severe symptoms of reduced emotional experience. As there are treatments for both these symptoms and social cognition with demonstrated efficacy, these data suggest differential application of these interventions based on symptom severity. PMID- 30446272 TI - Characterization of the Continuous Elastic Parameters of Porcine Vocal Folds. AB - This paper presents an evaluation of the elastic properties of porcine vocal folds through uniaxial tensile tests. Inferior vocal fold tissue samples were subjected to tension in the longitudinal direction while digital image correlation techniques were employed to determine strain values throughout the tests. The stress-strain results showed a low-strain linear region, followed by both a nonlinear exponential and then a higher strain linear region. Data from 16 porcine vocal fold samples were analyzed following a similar optimization method as proposed in prior studies [1] to yield continuous model parameters which describe the elastic properties of the tissue. The average low and high strain linear modulus values were found to be 17.86 kPa and 609.27 kPa, respectively. The model also identified the location of two transition points: p1, describing the transition from the low-strain linear region to an exponential region at 0.122 +/- 0.058 mm/mm and p2, describing the transition from the exponential to the high strain linear region at 0.308 +/- 0.069 mm/mm. The exponential region of the averaged data set was found to be described by the relationship [Formula: see text] kPa. In addition to locating transition points, the optimization method maintained modulus continuity across all strain values. Averaged elastic modulus values across strain from 0 to 0.40 mm/mm were compared to representative low and high strain linear modulus which were measured at 0.05 and 0.35 mm/mm, respectively. Statistically significant differences were found among all strain intervals between the two transition points and the linear modulus values. These results indicate the need to consider the location of transition points and further highlight the nonlinearity and changes in elastic modulus which are especially important when using excised porcine vocal folds as a model for phonation. The results quantify continuous linear and nonlinear parameters describing the elastic properties which can be used as a framework for future excised larynx tests and while evaluating the dynamics of sound production, which rely heavily on the elastic properties of the tissue. PMID- 30446273 TI - A systematic review of comorbidity between cerebral palsy, autism spectrum disorders and Attention Deficit Hyperactivity Disorder. AB - OBJECTIVES: The aim of this systematic review was to examine the incidence and prevalence of comorbidity between Cerebral Palsy (CP), Autism spectrum disorders (ASDs) and Attention-Deficit/Hyperactivity Disorder (ADHD). METHODS: We searched for articles indexed in PubMed, EBSCOhost, Scopus, Web of Science and other potentially relevant internet sources using a combination of expressions including "cerebral palsy" AND "autism" OR "ASD" OR "pervasive development disorder" AND "Attention Deficit Hyperactivity Disorder" OR "ADHD". RESULTS: We identified 2542 studies on CP and ASD and 998 studies on CP and ADHD. After screening titles and abstracts and removing duplicated studies, 47 full papers (CP and ASD n = 28; CP and ADHD n = 19) were downloaded and screened for eligibility. Twenty-eight (CP and ASD n = 16; CP and ADHD n = 12) studies were identified in the peer-review literature. Based on this systematic review, ASD and ADHD seem to be more common in people with CP than in the general population, yet the gold standard methods for diagnosing ASD or ADHD are not suitable for children with motor problems. CONCLUSIONS: Assessing the occurrence of ASD and ADHD would improve the significant cost of healthcare, therapies, and overall daily living for families with children affected by CP. However, psychometric studies are needed in the future to promote development of measures suitable for individuals with CP. In addition, this review highlights the paucity of peer reviewed studies investigating the occurrence of ASD and ADHD in children with different CP subtypes or functional abilities, and there are still some open questions about pathogenic mechanisms common to CP, ASD and ADHD. PMID- 30446276 TI - A perspective on the one-year results of the Aspirin and Tranexemic Acid in Coronary Artery Surgery trial. PMID- 30446274 TI - Pathogenic BRCA1 mutations may be necessary but not sufficient for tissue genomic heterogeneity: Deep sequencing data from ovarian cancer patients. AB - BACKGROUND: Tissue genomic heterogeneity (t-HET) in patients with epithelial ovarian cancer (OVCA) is related to tissue plasticity, i.e., flexibility to adapt to adverse molecular environments. Here, we interrogated the presence and clinical relevance of OVCA t-HET. METHODS: We applied high-depth (>2000*) sequencing on 297 paraffin tissue samples (fallopian tubes, ovaries, intra abdominal metastases) from 71 treatment-naive patients who subsequently received first-line platinum-based chemotherapy. Based on tissue mutation patterns, we distinguished tissue genotypes into: no mutation (33/297 samples; 11.1%), stable (173; 58.2%) and unstable (91; 30.7%). We profiled genotypes per patient and assessed t-HET in 69 patients. Predicted pathogenic mutations refer to germline and/or tissues. RESULTS: Among all 71 patients, 46 (64.8%) had pathogenic BRCA1 mutations and 15 (21.7%) had BRCA1/2 disruption (i.e., pathogenic mutations with position-LOH). We classified 29 patients with t-HET (42%), all with pathogenic BRCA1; t-HET was observed in 64% with such mutations (p < 0.001). As opposed to non-t-HET, matched tissues in t-HET shared pathogenic BRCA1 (p < 0.001) but not BRCA2 and TP53. Germline BRCA1 mutations in tissues exhibited position-LOH; heterozygous status; or, partial loss of the inherited allele accompanied by additional clonal mutations. Patients with t-HET had worse outcome (log-rank p = 0.048 [progression-free]; p = 0.037 [overall survival]), including 12/15 patients with disrupted BRCA1/2 and 3 BRCA1 carriers with partial germline loss in tissues. CONCLUSIONS: Pathogenic BRCA1 mutations appear necessary but may not be sufficient for the establishment of t-HET. t-HET may be associated with worse outcome, including in patients with disrupted BRCA1/2, which is usually considered as a favourable marker. OVCA t-HET may need to be addressed for treatment decisions. PMID- 30446275 TI - Non-pegylated liposomal doxorubicin (NPLD, Myocet(r)) + carboplatin in patients with platinum sensitive ovarian cancers: A ARCAGY-GINECO phase IB-II trial. AB - BACKGROUND: Carboplatin and pegylated liposomal doxorubicin combination is a standard regimen in platinum-sensitive recurrent ovarian cancer patients. The pegylated liposomal doxorubicin shortage from 2011 to 2013 urged assessment of the efficacy and tolerance of non-pegylated liposomal doxorubicin in combination with carboplatin. METHODS: MYCA was a multicenter 2-step phase Ib-II single arm trial meant to assess the safety and efficacy of carboplatin AUC 5 mg/min.mL combined with non-pegylated liposomal (dose escalation from 40 to 50 mg/m2 during phase Ib step; and 50 mg/m2 during phase II step), every 4 weeks in patients with platinum-sensitive relapse. The primary objective was disease control rate (DCR) at 12 months. RESULTS: From 2012 to 2014, 87 patients were enrolled. They were treated as second (78%) or third line (22%) treatment. Total of 67 patients (78%) completed 6 cycles. G-CSF support was prescribed to 58% patients. The DCR at 12 months was 30.0% (95% CI, 20.3-39.7); the median PFS was 10.0 months (95% CI, 8.6 11.0). The median overall survival was 28.1 months (95% CI, 22.3-32.5); and the objective response rate was 58% (95% CI, 47-68). Grade 3-4 neutropenia, anemia and thrombocytopenia were observed in 17%, 13% and 1%, respectively; febrile neutropenia in 6%. One patient who did not receive GCSF support died from febrile neutropenia. CONCLUSION: Non-pegylated liposomal doxorubicin-carboplatin combination exhibits an acceptable safety profile, with GCSF prophylaxis. Acknowledging the lack of direct comparison, efficacy in terms of 12 month DCR was comparable with standard treatments. PMID- 30446277 TI - Vascular conduits modified by gene therapy. PMID- 30446278 TI - Location, location, location. PMID- 30446279 TI - Linear mixed-effect models in longitudinal data analysis: Shaken not stirred. PMID- 30446280 TI - Thoracic endovascular aortic repair for ruptured pseudocoarctation: "There is no need to like the coming world to see it coming." F.-R. Chateaubriand. PMID- 30446281 TI - Tucked in or tuckered out? Pectus excavatum and sleep. PMID- 30446282 TI - Late false-lumen expansion predicted by preoperative blood flow simulation in a patient with chronic type B aortic dissection. PMID- 30446283 TI - Pursuit of the green jacket: Mastery of the long and short games. PMID- 30446284 TI - Corrigendum to "The role of technical protocols and partnership engagement in developing a decision support framework for fisheries management" [J. Environ. Manag. 223 (2018) 503-516]. PMID- 30446285 TI - Effect of a novel Ca-Si composite mineral on Cd bioavailability, transport and accumulation in paddy soil-rice system. AB - Ubiquitous cadmium (Cd) contamination in mine impacted paddy soil has been jeopardizing regional rice quality, which represents a dominant pathway of Cd exposure in populations depending on a rice diet. Two major aspects of mitigation, soil liming and Si fertilization, were integrated and investigated with a Ca-Si-rich composite mineral (CS) derived from feldspar and carbonate. With the CS amendment, bioavailable Cd in rice rhizosphere was reduced by 92-100% from tillering to maturation stage, paralleled by a marked increase in Cd bound to Fe/Mn oxides and carbonate. As indicated by XRD analysis, the much reduced labile pool of Cd in the CS-amended soil could be mainly attributed to Cd (co)precipitation (Cd(OH)2, Cd2(OH)3Cl, CH6Br3CdN) and surface complexation on more negatively charged oxides at elevated soil pH with CS addition. EDX line scan illustrated much more intensified Si deposition along root cross-section in the CS treatment, which resulted in 1.5-2.1-fold higher Cd sequestration in the CS-amended root than control. As a direct result, the root-to-shoots Cd translocation was reduced significantly by 42-51%, while a slightly less significant decrease in brown rice Cd was obtained with the CS treatment relative to control. The CS amendment showed differing effects on brown rice mineral accumulation, with 1.2-1.5-fold increase in brown rice Zn and simultaneously reduced Fe, Mn, Mg and Cu in brown rice. Our results call the readers' attention to the potential impact of soil ameliorator on grain mineral uptake, and we suggest that proper fortification with mineral fertilizers should be supplemented to assist sustainable rice production with improved mineral nutrition. PMID- 30446286 TI - ["VigilanSeu.r.se": A new profession?] AB - In January 2015, in accordance with decades of scientific work based on maintaining contact, was born an innovative device for suicide prevention: VigilanS. To ensure this link, the choice was made to build a team with an equal number of nurses and psychologists, all located within the medical regulation. Nowadays, they are named "VigilanSeur": an original entity that highlights the emergence of this new profession, at the crossroads of several disciplines. PMID- 30446287 TI - [Three clinical risk profiles of violent behavior in a cohort of early psychosis patients]. AB - OBJECTIVE: This study aims to determine whether it is possible to identify clinical profiles at risk of violent behaviors (VB) in the early phase of psychotic disorders, on the basis of the main dynamic psychopathological risk factors and describe characteristics of the groups with highest levels of violent behaviors. METHOD: A total of 265 patients, aged 18 to 35, treated at the Treatment and early Intervention in Psychosis Program (TIPP-Lausanne), a specialized early psychosis program, were included in this study. We conducted a latent-class analysis and a discriminative analysis on the basis of the main dynamic VB risk factors: substance use disorder, impulsivity, positive symptoms, insight, aggression, hostility, anger, emotional instability and adherence to treatment. These factors were evaluated by specialized scales and on the basis of the Positive and Negative Syndrome Scale (PANSS). VB were restricted to physical aggression against people, defined as "serious violence". They were assessed on the basis of a questionnaire listing violent offenses (Swiss Criminal Code) and VB such as assault and battery, information through the forensic psychiatric services and on the basis of the Staff Observation Aggression Scale (SOAS-R scale) during inpatient treatment phase. RESULTS: Four heterogeneous subgroups were identified with respect to the studied clinical characteristics, including two groups with high rates of VB. The first group, comprising 46% of patients with VB, is distinguished by the prevalence of a range of dimensions related to hostility, impulsivity and emotional instability, associated with high levels of substance abuse and positive symptoms. These clinical dimensions are very significant at the statistical level, since they explain 70% of the construction of subgroups (discriminant analysis). The second group with 37% of patients with VB, is characterized by a lack of insight, lack of adherence to treatment and substance use. These two clinical profiles could increase the impairment of cognitive, functional and relational abilities and contribute to the development of VB in this early phase of psychosis. The third subgroup, with a violent behaviors rate of 28.6%, is distinguished by its high proportion of diagnoses of substance abuse (100%) and women (54%). A last subgroup of patients, the largest quantitatively, has a low proportion of VB (15%) and the lowest levels on the studied factors, suggesting that the majority of patients with this profile commit few VB. CONCLUSION: Our results show that it is possible to identify groups at risk of violent behaviors during the early phase of psychosis on the basis of clinical characteristics that may evolve and therefore be the focus of preventive care. These results highlight the need to target substance use, impulsivity and lack of insight at follow-up in order to prevent VB. PMID- 30446288 TI - [Plain Packaging: The study that makes tabacologists coff]. PMID- 30446289 TI - Why is chronic obstructive pulmonary disease linked to atrial fibrillation? A systematic overview of the underlying mechanisms. PMID- 30446290 TI - Patient blood management for liver resection: consensus statements using Delphi methodology. AB - BACKGROUND: Blood loss and transfusion remain a significant concern in liver resection (LR). Patient blood management (PBM) programs reduce use of transfusions and improve outcomes and costs, but are not standardized for LR. This study sought to create an expert consensus statement on PBM for LR using modified Delphi methodology. METHODS: An expert panel representing hepato-biliary surgery, anesthesiology, and transfusion medicine was invited to participate. 28 statements addressing the 3 pillars of PBM were created. Panelists were asked to rate statements on a 7-point Likert scale. Three-rounds of iterative rating and feedback were completed anonymously, followed by an in-person meeting. Consensus was reached with at least 70% agreement. RESULTS: The 35 experts panel recommended routine pre-operative transfusion risk assessment, and investigation and management of anemia with iron supplementation. Intra-operatively, restrictive fluid administration without routine central line insertion was recommended, along with intermittent hepatic pedicle occlusion and surgical techniques considerations. Specific criteria for restrictive intra-operative and post-operative transfusion strategy were recommended. CONCLUSIONS: PBM for LR included medical and technical interventions throughout the perioperative continuum, addressing specificities of LR. Diffusion and adoption of these recommendations can standardize PBM for LR to improve patient outcomes and resource utilization. PMID- 30446292 TI - Traumatic Airway Injuries: Role of Imaging. AB - Airway Injuries are rare but often immediately life threatening. Incidence ranges from 0.5-2 % in blunt and 1-6 % in penetrating trauma. Upper airway injuries (UAI) are often clinically apparent and get shunted during the primary survey in the emergency department. Few UAI and majority of lower airway injuries (LAI) are occult on primary survey and need a high suspicion index. Clinically, the diagnosis of tracheobronchial injury is delayed in many patients because the airway column is maintained by the peribronchial tissue. Imaging in the form of MDCT, in conjunction with endoscopy, plays a role in delineating the exact site and extent of injury and ruling out associated vascular and esophageal injuries for definitive management of UAI. Chest radiographs and ultrasonography help raise suspicion of LAI by detection of pneumomediastinum, persistent pneumothorax and/or subcutaneous emphysema and should be followed up with multidetector computed tomography (MDCT) which is the mainstay of diagnosis. However, it requires careful evaluation of the airway tract and a thorough knowledge about the mechanism of trauma for detection of subtle injuries. Reconstructions in multiple planes and use of various post-processing techniques including minimum intensity projection (MinIP) images enhance the detection rate. The specific signs of LAI on CT include discontinuity in the tracheobronchial tree, focal intimal flap projecting in the lumen, focal soft tissue attached to the tracheal/bronchial wall, complete cut off of the bronchus/trachea and the fallen lung sign. We, hereby, illustrate the imaging spectrum of traumatic airway injuries in detail and discuss their management implications. PMID- 30446291 TI - Role of pharmacists in the Opioid Use Disorder (OUD) crisis. PMID- 30446293 TI - [Doctor patient relationship: With a dermatologic tact]. PMID- 30446294 TI - Pollicization of the Index Finger in the United States: Early Readmission and Complications. AB - PURPOSE: Pollicization is a well-accepted treatment for thumb hypoplasia, yet little is known about the reasons why patients return early in the postoperative period and complications that occur after surgery. The purpose of this investigation was to describe 30-day returns, readmission, and complication rates after pollicization in the United States. METHODS: A total of 459 pollicization procedures performed in 408 patients at 38 U.S. pediatric hospitals from 2003 to 2014 were identified using the Pediatric Health Information System database. A stepwise search strategy identified returns and readmissions within 30 days after pollicization to quantify complications and/or additional procedures. Risk factors for readmission and complications were compared across groups using uni- and multivariable general linear modeling. RESULTS: There were 61 patients who returned to the hospital (emergency department, ambulatory surgery, or inpatient hospitalization) within 30 days of their pollicization. Of those, 39 patients returned for suture removal, cast changes, or other expected aspects of postoperative care. The remaining 22 patients had a total of 26 complications, accounting for a 4.8% complication rate. The majority had vascular complications and wound problems. Single complications ranging from wound infection to hemorrhage were found in 20 cases. Overall, 35 of the 61 returns were readmitted to the hospital for treatment of complications or additional procedures. There was no effect of age group, diagnosis, geographical region, or physician subspecialty on the likelihood of complication or readmission. CONCLUSIONS: Sixty one patients returned within 30 days of their pollicization, and 22 presented with a complication (4.8%), most commonly vascular in nature. These baseline data are informative because they identify opportunities for future preventative measures and quality improvement. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 30446295 TI - A Prospective Evaluation of Early Postoperative Complications After Distal Biceps Tendon Repairs. AB - PURPOSE: The reported incidence of postoperative complications after distal biceps tendon repairs (DBTRs) has been determined largely by retrospective studies. We hypothesized that a large prospective cohort study of DBTRs would demonstrate increased complication rates relative to existing literature values. Secondarily, we hypothesized that most complications would be transient and self limiting, regardless of the surgical technique employed for the repair. METHODS: Consecutive patients undergoing acute, primary DBTR from July 2016 to December 2017 were enrolled. The repair technique, postoperative protocol, and follow-up intervals were determined by the individual surgeons' protocols. Demographic information, surgical data, and complications were tabulated prospectively. Exclusion criteria included chronic DBTRs, secondary DBTRs requiring allograft, DBTRs of partial tears, and postoperative follow-up of less than 12 weeks. We included 212 repairs performed by 37 orthopedic surgeons in 3 different subspecialties. RESULTS: Sixty-five patients (30.7%) had 73 complications. Fifty patients (44.6%) in the 1-incision group experienced complications compared with 15 (15.0%) in the 2-incision group. Sixty patients (28.3%) developed a minor complication. Fifty-seven patients (26.9%) had sensory neurapraxias, 47 after a 1 incision procedure and 10 after a 2-incision procedure, a statistically significant difference. Of the patients with neurapraxias, 94.7% were resolved or improving at the time of the latest follow-up. Five patients (2.4%) developed a major complication, defined as a return to the operating room in the postoperative period due to deep infection or rerupture. CONCLUSIONS: The complication rate after DBTR appears to be higher than 2 other retrospective studies and is predominantly in the form of transient neurapraxias. This study confirms that there is a higher complication rate in 1-incision techniques as compared with 2-incision techniques. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II. PMID- 30446296 TI - Corrigendum to "SPECT perfusion changes during ictal automatisms with preserved responsiveness in patients with right temporal lobe epilepsy" [Epilepsy Behav 80C (2018) 11-14]. PMID- 30446297 TI - Transcranial direct current stimulation (tDCS) modulates biometric and inflammatory parameters and anxiety-like behavior in obese rats. AB - Obesity is a multifactorial disease associated with metabolic dysfunction and the prevention and treatment of obesity are often unsatisfactory. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that has proven promising in the treatment of eating disorders such as obesity. We investigate the effects of tDCS on locomotor and exploratory activities, anxiety like and feeding behavior, and levels of brain-derived neurotrophic factor (BDNF), IL (interleukin)-10, IL-1beta, and tumor necrosis factor-alpha (TNF alpha) in the cerebral cortex of obese rats. A total of 40 adult male Wistar rats were used in our study. Animals were divided into groups of three or four animals per cage and allocated to four treatment groups: standard diet plus sham tDCS treatment (SDS), standard diet plus tDCS treatment (SDT), hypercaloric diet plus sham tDCS treatment (HDS), hypercaloric diet plus tDCS treatment (HDT). After 40 days on a hypercaloric diet and/or standard diet were to assessed the locomotor and exploratory activity and anxiety-like behavior to by the open field (OF) and elevated plus maze (EPM) tests respectively before and after exposure to tDCS treatment. The experimental groups were submitted to active or sham treatment tDCS during eight days. Palatable food consumption test (PFT) was performed 24 h after the last tDCS session under fasting and feeding conditions. Obese animals submitted to tDCS treatment showed a reduction in the Lee index, visceral adipose tissue weight, and food craving. In addition, bicephalic tDCS decreased the cerebral cortex levels of IL-1beta and TNF-alpha in these animals. Exposure to a hypercaloric diet produced an anxiolytic effect, which was reversed by bicephalic tDCS treatment. These results suggest that, in accordance with studies in humans, bicephalic tDCS could modulate biometric and inflammatory parameters, as well as anxiety-like and feeding behavior, of rats subjected to the consumption of a hypercaloric diet. PMID- 30446298 TI - Recurrent aphthous stomatitis - Etiology, serum autoantibodies, anemia, hematinic deficiencies, and management. AB - Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases characterized by recurrent and painful ulcerations on the movable or nonkeratinized oral mucosae. Clinically, three types of RAS, namely minor, major, and herpetiform types, can be identified. RAS more commonly affects labial mucosa, buccal mucosa, and tongue. Previous studies indicate that RAS is a multifactorial T cell-mediated immune-dysregulated disease. Factors that modify the immunologic responses in RAS include genetic predisposition, viral and bacterial infections, food allergies, vitamin and microelement deficiencies, systemic diseases, hormonal imbalance, mechanical injuries, and stress. Our previous study found the presence of serum gastric parietal cell antibody, thyroglobulin antibody, and thyroid microsomal antibody in 13.0%, 19.4%, and 19.7% of 355 RAS patients, respectively. We also found anemia, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia in 20.9%, 20.1%, 4.8%, 2.6%, and 7.7% of 273 RAS patients, respectively. Therefore, it is very important to examine the complete blood count, serum autoantibody, hematinic, and homocysteine levels in RAS patients before we start to offer treatments for RAS. Because RAS is an immunologically-mediated disease, topical and systemic corticosteroid therapies are the main treatments of choice for RAS. PMID- 30446299 TI - Tubulocystic anomalies of the mesonephric duct associated with ipsilateral renal dysgenesis. AB - INTRODUCTION: Renal agenesis and multicystic dysplastic kidney (MCDK) are usually associated with either an absent or atretic ureter. Occasionally, these renal anomalies may be associated with a dilated tortuous ureter, ureterocele or other cystic malformation of mesonephric duct (MND) remnants. OBJECTIVES: The objective of this study was to identify and classify anatomical variants of tubulocystic remnants of the MND, with a secondary focus on natural history and management outcomes. PATIENTS AND METHODS: A retrospective cohort study of patients seen in the study institution between 2007 and 2014 with a tubulocystic abnormality of MND structures associated with either MCDK or renal agenesis was conducted. Medical imaging and progress notes were reviewed for all patients. Data collected included anatomical information, surgical intervention, histology and outcomes of both conservatively managed and surgically resected MND remnant structures. RESULTS: Nineteen patients were identified, 5 girls and 14 boys. Median age at presentation was 4.6 years. Anomalies of the MND occurred on the left in 9 patients and on the right in 10 patients. Mean follow-up was 3.4 years. Patients fell into 3 distinct anatomical groups: Type I, including orthotopic remnants corresponding to ureteric bud structures (ureter and trigone); Type II, including ectopic MND remnants of ureteric bud structures, and Type III, including complex remnants corresponding to MND structures other than those from ureteric bud (vas, epididymis and seminal vesicles). Anomalies of structures arising from urogenital sinus and paramesonephric ducts were also identified. Most patients were asymptomatic and successfully managed conservatively. Transvesical puncture of trigonal cysts provided effective decompression in 5 patients. Partial or complete MCDK regression was seen in 7 patients, whereas MND cystic anomalies did not regress spontaneously. DISCUSSION: When MND tubulocystic structures persist along with renal agenesis or MCDK, most arise from ureteric bud structures in an orthotopic position as a ureterocele with or without a blind-ending ureter-like structure. Less commonly, ureteric bud structures insert ectopically into the urogenital tract, or tubulocystic structures arising from the remainder of the MND occur. Embryogenesis of other urogenital structures may also be abnormal, and conditions such as Zinner syndrome and obstructed hemivagina and ipsilateral renal agenesis syndrome should be considered. CONCLUSIONS: Complications are uncommon, and surgical intervention should be limited to symptomatic patients. Remnants of metanephric blastema may involute, but MND remnants persist. PMID- 30446300 TI - Modulators of inflammation in Bronchopulmonary Dysplasia. AB - Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30-50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory response and ends in aberrant lung development with dysregulated angiogenesis and alveolarization. Significant morbidity and mortality are associated with this most common chronic lung disease of childhood. Thus, any therapies that decrease the incidence or severity of this condition would have significant impact on morbidity, mortality, human costs, and healthcare expenditure. It is clear that an inflammatory response and the elaboration of growth factors and cytokines are associated with the development of BPD. Numerous approaches to control the inflammatory process leading to the development of BPD have been attempted. This review will examine the anti inflammatory approaches that are established or hold promise for the prevention or treatment of BPD. PMID- 30446301 TI - Is there a causal relationship between obesity and puberty? AB - The onset of puberty in adolescents and whether it is related to obesity is an ongoing topic for debate. Epidemiological cross-sectional and longitudinal studies show a shift towards earlier onset of puberty in girls who are obese; however, the situation is less clear in boys. Boys who are overweight seem to mature earlier, and boys who are obese mature later, than boys at a healthy weight. The underlying mechanisms are not yet fully understood, and whether earlier onset of puberty in obese girls is based on the activation of the hypothalamic-pituitary-gonadal axis is unclear. The most promising link between obesity and puberty is the adipokine leptin and its interaction with the kisspeptin system, which is an important regulator of puberty. However, peripheral action of adipose tissue (eg, via other adipokines, aromatase activity) could also be involved in changes to the onset of puberty. In addition, nutritional factors, epigenetics, or endocrine disrupting chemicals are potential mediators linking the onset of puberty to obesity. This Review summarises our knowledge concerning the relationship between obesity and onset and tempo of puberty, and the consequences of early puberty on obesity. PMID- 30446302 TI - Call for more translational research in burn injury prevention. PMID- 30446303 TI - Anesthetics, Anesthesia, and Plants. AB - General anesthesia, its nature, and how exactly it works are still poorly understood. Plants can also be anesthetized and lose their responses to external stimuli. Interestingly, plants are known to produce endogenous anesthetic compounds to deal with stress. Plants offer an excellent model object for studies on anesthetics and anesthesia. PMID- 30446304 TI - Revisiting the Origin of Plant NBS-LRR Genes. AB - The NBS-LRR genes are functionally responsible for plant resistance to alien pathogens. Here, we show that NBS-LRR genes originated in the common ancestor of the whole green lineage, and have rapidly diverged into three subclasses with different domain combinations (TNL, CNL, and RNL) before the split of green algae. PMID- 30446306 TI - Protists: Puppet Masters of the Rhizosphere Microbiome. AB - The rhizosphere microbiome is a central determinant of plant performance. Microbiome assembly has traditionally been investigated from a bottom-up perspective, assessing how resources such as root exudates drive microbiome assembly. However, the importance of predation as a driver of microbiome structure has to date largely remained overlooked. Here we review the importance of protists, a paraphyletic group of unicellular eukaryotes, as a key regulator of microbiome assembly. Protists can promote plant-beneficial functions within the microbiome, accelerate nutrient cycling, and remove pathogens. We conclude that protists form an essential component of the rhizosphere microbiome and that accounting for predator-prey interactions would greatly improve our ability to predict and manage microbiome function at the service of plant growth and health. PMID- 30446305 TI - Melatonin: A New Plant Hormone and/or a Plant Master Regulator? AB - Melatonin is a pleiotropic molecule with many diverse actions in plants. It is considered primarily an antioxidant with important actions in the control of reactive oxygen and nitrogen species (ROS and RNS), among other free radicals, and harmful oxidative molecules present in plant cells. In addition, plant melatonin is involved in multiple physiological actions, such as growth, rooting, seed germination, photosynthesis, and protection against abiotic and/or biotic stressors. The recent identification of the first plant melatonin receptor opened the door to this regulatory molecule being considered a new plant hormone. However, due to the diversity of its actions, melatonin has also been proposed as a plant master regulator. Here, we discuss the most recent data in respect to both perspectives. PMID- 30446307 TI - Cytokinin - A Developing Story. AB - In the past decade tremendous advances have been made in understanding the biosynthesis, perception, and signaling pathways of the plant hormone cytokinin. It also became clear that interfering with any of these steps greatly impacts all on stages of growth and development. This has recently spurted renewed effort to understand how cytokinin signaling affects developmental processes. As a result, new insights on the role of cytokinin signaling and the downstream targets during, for example, shoot apical meristem, flower, female gametophyte, stomata and vascular development are being unraveled. In this review we aim to give a comprehensive overview of recent findings on how cytokinin influences growth and development in plants, and highlight areas for future research. PMID- 30446308 TI - Does presence of adenomyosis affect reproductive outcome in IVF cycles? A retrospective analysis of 973 patients. AB - RESEARCH QUESTION: Reports on the effect of adenomyosis on assisted reproductive technology (ART) outcomes are conflicting. Does presence of adenomyosis affect reproductive outcome in IVF cycles in women pretreated with gonadotrophin releasing hormone (GnRH) agonist? DESIGN: In this retrospective cohort study, 973 women were divided into four groups: only endometriosis (n = 355); endometriosis and adenomyosis (n = 88); adenomyosis alone (n = 64); and tubal factor infertility as controls (n = 466). The pregnancy outcome parameters (clinical pregnancy, miscarriage rate, live birth rate) were compared between these groups. RESULTS: The clinical pregnancy rate was 36.62% in women with endometriosis alone, 22.72% in women with endometriosis and adenomyosis, 23.44% in women who only had adenomyosis and 34.55% in controls. Miscarriage rates were as follows: 14.62%, 35%, 40% and 13.04%, respectively. Live birth rates were 27.47% in controls; 26.48% in women with only endometriosis; 11.36% in women with endometriosis and adenomyosis; and 12.5% in women with only adenomyosis. Live birth was observed to be less in adenomyosis groups compared with controls and women with only endometriosis. No significant difference was observed in clinical pregnancy, miscarriage or live birth rate between controls and women with only endometriosis. Live birth rate was significantly different between controls and women with adenomyosis only (P = 0.01) and women with endometriosis and adenomyosis (P = 0.002). CONCLUSION: Presence of adenomyosis seems to have adverse effects on IVF outcomes in clinical pregnancy rate, live birth rate and miscarriage rate. Screening for adenomyosis might be considered before ART so that the couple has better awareness of the prognosis. PMID- 30446309 TI - Active compounds present in Rosmarinus officinalis leaves and Scutellaria baicalensis root evaluated as new therapeutic agents for endometriosis. AB - RESEARCH QUESTION: Can carnosic acid, (CA) rosmarinic acid (RA) and wogonin (WG) inhibit the growth of cultured human endometrial stromal cells and endometriotic like lesions induced in a BALB/c model of endometriosis? DESIGN: Primary stromal cell cultures were established from endometrial biopsies from women with endometriosis and controls. The human endometrial stromal cell line T-HESC was also used for in-vitro experiments. Endometriosis was surgically induced in BALB/c mice, which were randomly assigned to CA 2 mg/kg/day (n = 11); CA 20 mg/kg/day (n = 10); RA 1 mg/kg/day (n = 11); RA 3 mg/kg/day (n = 10); WG 20 mg/kg/day (n = 12); intraperitoneal vehicle control (n = 8) or oral vehicle control (n = 11). After surgery, CA and RA were administered intraperitoneally on days 14-28. WG was administered orally by intragastric gavage on days 14-26. RESULTS: CA, RA and WG significantly inhibited in-vitro cell proliferation in primary and T-HESC cell cultures (P < 0.05). CA and WG induced cell cycle arrest of T-HESC at the G2/M phase (P < 0.01). RA reduced intracellular ROS accumulation (P < 0.001), whereas WG increased it (P < 0.05). WG significantly inhibited oestrogen receptor alpha expression in T-HESC (P < 0.01). In-vivo, CA, RA and WG significantly reduced lesions size (P < 0.05). All compounds significantly decreased the percentage of cells in proliferation (P < 0.05) whereas RA and WG further increased the percentage of apoptotic cells (P < 0.05) in endometriotic like lesions. CONCLUSIONS: The results are promising; further investigation of these compounds as new therapeutics is needed. PMID- 30446310 TI - Targeting tyrosine kinase: Development of acridone - pyrrole - oxindole hybrids against human breast cancer. AB - Based on the molecular modelling studies, a rational modification of the lead molecule was made to develop highly potent compounds showing anti-cancer activity against human breast cancer cell lines MCF 7, MDA-MB-468 and T-47D. The most potent compounds have Log P and total polar surface area 4.4-5.4 and 59.8 A, respectively and they also exhibited promising ADME profile. PMID- 30446311 TI - Discovery of 4-alkoxy-6-methylpicolinamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. AB - This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28 day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand. PMID- 30446313 TI - Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects. AB - Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for MU- and delta-opioid receptors. We discovered peripherally restricted dual antagonists for MU/delta-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood-brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate. PMID- 30446312 TI - Rotenoisin A is a novel anti-adipogenic compound. AB - The purpose of this study was to investigate the mechanisms underlying the inhibitory effects of rotenoisin A on adipogenesis in 3T3-L1 preadipocytes. 3T3 L1 cells were treated with rotenoisin A for 8 days after the induction of differentiation. Oil-red O staining showed that rotenoisin A significantly inhibited DMI-induced lipid accumulation and adipocyte differentiation. We found that rotenoisin A treatment of 3T3-L1 preadipocytes significantly reduced the mRNA and protein levels of the key adipocyte-specific transcription factors C/EBPbeta, C/EBPalpha, and PPARgamma and markedly inhibited the expression of fatty acid-binding protein (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Furthermore, we observed that rotenoisin A substantially increased the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target phosphorylated acetyl CoA carboxylase (ACC). However, co-treatment with Compound C, an AMPK inhibitor, reversed the rotenoisin A-induced inhibition of the expression of the adipogenic transcription factors C/EBPalpha and PPARgamma and decreased the levels of phosphorylated AMPK in differentiated 3T3-L1 cells. These results demonstrated that the anti-adipogenesis mechanism involves the down regulation of critical adipogenic transcription factors, including C/EBPbeta, C/EBPalpha, and PPARgamma, through activation of the AMPK signaling pathway by rotenoisin A. PMID- 30446314 TI - Synthesis and tyrosinase inhibitory activities of 4-oxobutanoate derivatives of carvacrol and thymol. AB - Carvacrol (1) and thymol (2) were converted to their alkyl 4-oxobutanoate derivatives (7-20) in three steps, and evaluated for tyrosinase inhibitory activity. The compounds showed structure-dependent activity, with all alkyl 4 oxobutanoates, except 7 and 20, showing better inhibitory activity than the precursor 4-oxobutanoic acids (5 and 6). In general, thymol derivatives exhibited a higher percent inhibitory activity than carvacrol derivatives at 500 MUM. Derivatives containing three-carbon and four-carbon alkyl groups gave the strongest activity (carvacrol derivatives 9-12, IC50 = 128.8-244.1 MUM; thymol derivatives 16-19, IC50 = 102.3-191.4 MUM). PMID- 30446315 TI - Patterns of re-irradiation for recurrent gliomas and validation of a prognostic score. AB - PURPOSE OR OBJECTIVE: Re-irradiation is a generally accepted method for salvage treatment in patients with recurrent glioma. However, no standard radiation regimen has been defined. This study aims to compare the efficacy and safety of different treatment regimens and to independently externally validate a recently published reirradiation risk score. MATERIAL AND METHODS: We retrospectively analyzed a cohort of patients with recurrent malignant glioma treated with salvage conventionally fractionated (CFRT), hypofractionated (HFRT) or stereotactic radiotherapy (SRT) between 2007 and 2017 at the University Medical Centers in Utrecht and Groningen. RESULTS: Of the 121 patients included, 60 patients (50%) underwent CFRT, 22 (18%) HFRT and 39 (32%) SRT. The primary tumor was grade II-III in 52 patients and grade IV in 69 patients with median Overall Survival (mOS) since first surgery of 113 [Interquartile range: 53.2-137] and 39.7 [24.6-64.9] months respectively (p < 0.01). Overall, mOS from the first day of re-irradiation was 9.7 months [6.5-14.6]. No significant difference in mOS was found between the treatment groups. In multivariate analysis, the Karnofsky performance scale >=70% (p < 0.01), re-irradiation for first recurrence (p = 0.02), longer time interval between RT start dates (p < 0.01) and smaller planning target volume (p < 0.05) were significant favorable prognostic factors. The reirradiation risk score was validated. CONCLUSION: In our series, mOS after reirradiation was sufficient to justify use of this modality. Until a reliable treatment decision tool is developed based on larger retrospective research, the decision for re-irradiation schedule should remain personalized and based on a multidisciplinary evaluation of each patient. PMID- 30446316 TI - Influence of volumetric modulated arc therapy and FET-PET scanning on treatment outcomes for glioblastoma patients. AB - BACKGROUND: We sought to assess the influence of the clinical introduction of new radiotherapy technologies on glioblastoma patients' outcomes. METHODS: Newly diagnosed glioblastoma patients treated with 60 Gy and temozolomide (2005-2014) were analyzed. The patients' GTV and CTV were defined based on MR (n = 521) or FET-PET/MR (n = 190), and were treated using conformal radiotherapy (CRT, n = 159) or image-guided volumetric modulated arc therapy with hippocampal sparing (IG-VMAT, n = 362). Progression-free survival (PFS) was assessed using the McDonald criteria. Associations between clinical data, dosimetry data, treatment technology, for PFS and overall survival (OS) were explored. RESULTS: The PFS (7 months) and OS (15 months) were unaffected by CRT, IG-VMAT and FET-PET technology. Mean brain dose was correlated with tumor volume, and was lower for IG-VMAT vs. CRT (p < 0.001). Larger mean brain dose was associated with inferior PFS (univariate/multivariate Cox models, p < 0.001) and OS (univariate, p < 0.001). Multivariate Cox models revealed association of larger mean brainstem dose (p < 0.001), BTV (p = 0.045), steroid use at baseline (p = 0.003), age (p = 0.019) and MGMT status (p = 0.022) with lower OS. CONCLUSIONS: Introduction of hippocampal-sparing IG-VMAT technology appeared to be safe, and may have reduced toxicity and cognitive impairment. Larger mean brain dose was strongly associated with inferior PFS and OS. PMID- 30446317 TI - Comment on Long-term risks of secondary cancer for various whole and partial breast irradiation techniques. PMID- 30446318 TI - Quantification of cardiac subvolume dosimetry using a 17 segment model of the left ventricle in breast cancer patients receiving tangential beam radiotherapy. AB - PURPOSE: Subacute changes following breast radiotherapy have been demonstrated in discrete areas of the left ventricle (LV), with recent guidelines being developed to help determine dose to subvolumes of the LV. This study aims to determine doses to the 17 segments of the LV as per the American Heart Association (AHA) and other cardiac subvolumes, and to correlate mean heart (MHD) dose with various subvolume dosimetric indices. These results may direct focus to specific left ventricular segments in studies of radiation-related heart disease incorporating surveillance imaging, help to determine more precise dose response relationships, and potentially aid prediction of late radiation effects. METHODS AND MATERIALS: The heart and cardiac subvolumes of 29 patients treated with tangential radiotherapy for left breast cancer were contoured. Delineation of cardiac subvolumes (cardiac chambers, cardiac valves and the 17 segments of the LV) was undertaken using a novel contouring method on planning CT data reformatted into the cardiac axis. Individual segments were then combined to determine doses to the basal, mid and apical left ventricular regions, and the anterior, septal, inferior and lateral ventricular walls. Radiotherapy doses (including maximum, mean, D1cc, V25) were determined. Correlation analyses were performed between MHD and various substructure dosimetric indices. RESULTS: Twenty five patients received tangential breast free breathing radiotherapy alone, and four patients received regional nodal irradiation including the internal mammary chain with deep inspiration breath hold (DIBH). For patients receiving breast only radiation, the median mean heart radiation dose was 2.62 Gy (range 1.52-3.90 Gy), and a heterogeneous dose distribution to the LV was noted, with the apical region receiving the highest median mean dose (14.99 Gy) compared with the mid and basal regions (3.10 Gy and 1.51 Gy respectively). The anterior LV wall received the highest median mean dose (9.21 Gy) with the remaining walls receiving similar mean doses (range 1.79-3.05 Gy). The anterior LV apical segment (segment 13) and apex (segment 17) received the highest individual median mean segment doses (26.73 Gy and 30.02 Gy respectively). Apical segments received the highest median mean doses (segments 13, 14, 15, 16), followed by the mid anterior (segment 7) and anteroseptal (segment 8) segments. Segments receiving the highest doses remained unchanged between the DIBH cohort and free breathing cohort. MHD showed a high correlation with the anterior wall r = 0.71, p < 0.05 and entire left ventricle r = 0.82, p < 0.05, but correlations varied from weak to high when MHD was correlated with segments receiving highest doses (range r = 0.43-0.76), p < 0.05. CONCLUSIONS: In the setting of breast cancer radiotherapy, there are substantial RT dose variations within specific LV segments, with mid and apical anterior ventricular segments (segments 7, 13) and the apical region of the LV (segments 13, 14, 15, 16, 17) being consistently exposed to the highest radiation doses. Determining segmental and regional RT doses to the left ventricle may help guide focus in diagnostic cardiology in the post radiotherapy setting. PMID- 30446319 TI - Reply to Laprie A. et al. PMID- 30446320 TI - Location of arm draining lymph node in relation to breast cancer radiotherapy field and target volume. AB - BACKGROUND: Lymphoedema of the arm following axillary surgery or radiotherapy remains a significant side effect affecting some women after breast cancer treatment. Axillary reverse mapping (ARM) is a technique used to identify the lymph node draining the arm (ARM node). Our study aim was to examine the location of the ARM nodes in relation to target volumes and treatment fields for breast cancer radiotherapy. MATERIALS AND METHODS: Eighteen breast cancer patients underwent lymphoscintigraphy of contralateral arm (left 10, right 8) and SPECT CT scan on a research study. Patient position for the SPECT CT scan approximated the position used for radiotherapy. Using MIM softwareTM, the ARM node for each subject was contoured on the SPECT CT and verified by a nuclear medicine physician. The CT component of the SPECT CT was then transferred to ECLIPSETM radiotherapy planning software, and the contralateral breast and axilla were contoured on this CT scan according to the ESTRO contouring guideline. Two radiotherapy plans were generated for each subject using standard tangential IMRT technique at a dose of 50 Gy in 25 fractions, one treating contralateral breast alone, the other treating contralateral breast and contralateral axilla level 1 4. The ARM node was considered "within the radiotherapy field" if the mean dose received by the ARM node was more than 50% of the prescribed dose: i.e., 25 Gy. RESULTS: One right-sided subject had 2 ARM nodes, all others had 1 ARM node. All ARM nodes (left 10, right 9) were located within level 1 of the axilla. For the subject with 2 ARM nodes, the node that received a higher dose was used for the analysis. The mean dose received by the ARM node in the whole breast radiotherapy plans ranged from 0.8 to 45.5 Gy, with a median of 10.9 Gy. The mean dose received by the ARM node in the whole breast and axilla plans ranged from 43.4 to 52.5 Gy, with a median of 49.3 Gy. In the whole breast radiotherapy plans, only 5 out of 18 ARM nodes were found to be "within radiotherapy field", and only 2 ARM nodes received more than 40 Gy. In the breast and axilla plans, all 18 ARM nodes were "within radiotherapy field" and all received more than 40 Gy. To better visualise the locations of ARM nodes, all left sided ARM nodes were then mapped onto a CT set from one of the left-sided subjects, and all the right sided ARM nodes mapped onto one of the right-sided subjects, and digitally reconstructed radiograph (DRR) for radiotherapy fields were produced. CONCLUSIONS: Our study demonstrates that the vast majority of ARM nodes (72%) are outside the tangential whole breast radiotherapy fields. In our study, all the ARM nodes were within the axillary radiotherapy fields covering level 1-4 axillary volumes according to the ESTRO contouring guideline, and complete shielding of the humeral head according to the EORTC consensus did not lead to sparing of the ARM nodes. A prospective study is needed to examine the oncological safety of ARM node-sparing axillary radiotherapy and its potential to reduce the risk of arm lymphoedema. PMID- 30446322 TI - Wildlife crime: The application of forensic geoscience to assist with criminal investigations. AB - Wildlife crime is a growing problem in many rural areas. However, it can often be difficult to determine exactly what had happened and provide evidential Court material, especially where evidence is ephemeral. This paper presents a case study where a badger sett had been illegally filled and evidence was rapidly required to support a prosecution before it was either destroyed by the suspect/further badger activities or eroded by weather/time. A topographic surface survey was undertaken, quantifying the number and spatial position of sett entrances, as well as which had been filled by a slurry material. A ground penetrating radar survey was also undertaken to quantify how much tunnels were filled. Study results evidenced five sett tunnels were filled out of twelve observed. The slurry fill material was not being observed elsewhere on the surface. GPR survey data evidenced ~1m-5m of slurry fill in tunnels. A subsequent report was forwarded to the CPS as evidential material. Study implications suggest the importance of rapid geoscience surveys to assist Police Forces to both gain scientific evidence for prosecutions and to deter future wildlife crime. PMID- 30446321 TI - Predictors of statin use among older adults: A nationwide cross-sectional study. AB - BACKGROUND: Statins comprise a key strategy for the prevention and treatment of arteriosclerotic cardiovascular disease, but prescribing remains suboptimal. OBJECTIVES: The objective of this study was to characterize the predictors of statin use among adults aged >=65 years. METHODS: A cross-sectional study using Pharmaceutical Benefits Scheme (PBS) data on reimbursed prescriptions for a 10% random sample of the Australian population in 2016 was performed. Predictors of statin use were identified via multivariable logistic regression. Analyses were performed separately for people who were concessional beneficiaries (with a low, capped copayment) and other ("general") people. RESULTS: Among 351,471 (concessional = 295,875 and general = 55,596) older adults, 44.2% were dispensed statins (concessional = 46.4% and general = 32.2%). Among the concessional beneficiaries, people aged 75 to 84 years were more likely to use statins (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.06-1.10), whereas those aged >=85 years were less likely to use statins (OR 0.71, 95% CI 0.69-0.72), compared with people aged 65 to 74 years. Men were more likely to use statins than women (OR 1.14, 95% CI 1.12-1.16). Diabetes was associated with over 2-fold (OR 2.48, 95% CI 2.43-2.53) increased likelihood of statin use. People with cardiovascular related conditions including hypertension, angina, and congestive heart failure experienced increased likelihood of statin use as was being dispensed anticoagulant or antiplatelet medication. Having malignancy, psychotic illness, or pain were associated with lower likelihood of statin use. Similar predictors of statin use were noted for the general population. CONCLUSION: More than 40% of older adults in Australia used statins in 2016 with uptake dependent on individual-level factors such as demographics and comorbidities. Future research should examine the extent to which provider and/or health system-level factors contribute to the variable uptake of statin therapy. PMID- 30446323 TI - Documented composition of cadaveric skeletal remains in the University of Cape Town Human Skeletal Collection, South Africa. AB - The University of Cape Town Human Skeletal Collection is one of the oldest documented skeletal collections in South Africa. The skeletal remains housed in this collection have been used for a variety of studies, but no complete description of the composition of the collection currently exists in the published literature. The aim of this study is to provide a detailed description of the composition of the cadaveric collection to encourage use thereof by national and international researchers. As of 2016, the collection contained the skeletal remains of 343 cadaveric individuals, 163 of which have mostly complete crania and postcrania. The male to female ratio of the collection is approximately 3:2. White individuals constitute 70% of the collection, with smaller contributions by individuals of the Black and Coloured population groups. Most of the individuals in the collection were 60-90 years old at death, though the mean age of the Black and Coloured groups was much lower, likely due to differences in origin of the cadavers received by the Faculty of Health Sciences. The most common reported cause of death in the collection was circulatory disease, followed by neoplasms and respiratory disease. Despite differences in the composition of this collection and the provincial and national demographic profiles, the collection remains an invaluable resource for training and research in a wide variety of scientific fields. PMID- 30446324 TI - Third molar maturity index for indicating the legal adult age in southeastern France. AB - The estimation of age in living subjects is today a significant issue because of the increase in the situations in which it arises and its legal consequences. In line with the Study Group on Forensic Age Diagnostics of the German Association of Legal Medicine's recommendations, it is based on the concomitant use of physical examination and methods for estimating bone age and dental age. Given the variations between the populations, the use of the latter requires their validation on all the ethnic groups on which they can be used. This aim of this study was to access the interest of the Cameriere's third molar maturity index (I3M) to indicate if an individual had reached the age of 18 in a sample of individuals from southeastern France. The studied sample consisted of OPTs 339 (184 females and 155 males) subjects aged between 14 and 22 years old. A logistic regression analysis with the adult age and minor age as dichotomous dependent variable and gender and I3M as predictor variables showed that gender was not statistically significant in discriminating adults and minors. The receiver operating curve (ROC) analysis showed the best discrimination performance of the specific cut-off value of I3M<0.08 in discriminating adults from minors. The proportion of accurate classification was 0.897 and 0.916 for females and males, respectively. The specificity (Sp) and sensitivity (Se) results for females were 0.962 and 0.813, respectively. Sp and Se for males were 0.953 and 0.871, respectively. The Bayes post-test probability was 0.961 and 0.955 in females and males respectively. Obtained results showed that a cut-off value of I3M<0.08 may be an additional tool for indicating adult age in the tested population. PMID- 30446325 TI - Double puncture versus single puncture arthrocentesis for the management of unilateral temporomandibular joint disc displacement without reduction: A randomized controlled trial. AB - PURPOSE: To compare the clinical efficacy of the conventional double puncture versus single puncture type 2 arthrocentesis for management of temporomandibular joint disc displacement without reduction (DDWOR). MATERIALS AND METHODS: Twenty six patients with DDWOR were randomly and blindly allocated into two treatment groups (N = 13): Group 1, conventional double puncture arthrocentesis; Group 2, single puncture type 2 arthrocentesis. Data on gender, side of painful joint complaint, age (years), duration of joint pain (months), maximum interincisal distance (MID - mm), and pain intensity self-reported with a visual analog scale (VAS; 0-10) were collected. VAS scores and MID were measured before (baseline) and 6 months after arthrocentesis (final). RESULTS: Both techniques resulted in significantly reduced VAS scores and increased MID (p = 0.001) after 180 days. However, there were no statistically significant differences between techniques (p > 0.05). CONCLUSIONS: The two arthrocentesis methods tested were effective in reducing VAS scores and increasing MID in patients with DDWOR. PMID- 30446326 TI - New molecular aspects in the mechanism of oromaxillofacial cleft prevention by B vitamins. AB - Clinical and experimental studies show a clear positive effect of B-vitamins in the prevention of oromaxillofacial clefts, especially cleft lip and palate (CL/P). Hereby the local effect of thiamin (B1) in the amniotic fluid is very important for the embryonic facial development as seen in palatal organ models stimulated by topical B-vitamin application (Scheller et al., 2013a). Moreover a low B1 concentration in the serum and amniotic fluid was found in pregnant mice with clefts in their offspring (Scheller et al., 2013b). Immunochemical analyses of midface sections (ThTr-1 transporter) and the placenta (ThTr-2 transporter) of cleft fetuses with orofacial clefts showed an atypical cytoplasmatic localization (Scheller et al., 2017). mRNA nalyses of different B-vitamin transporters (B1, B2, B5, B7, B9) were performed and showed ThTr2 transporter in a short splice variant in all cleft fetuses. This splice variant may cause a functional loss of the transport capacity through the placenta barrier and result in a low amniotic fluid concentration of vitamin B1. All other analyzed transport proteins showed no functional change. These findings confirm the hypothesis that cleft prevention by high vitamin B1 substitution fails in genetically determined cleft mice, caused by an insufficient B1 uptake and missing local effect. PMID- 30446327 TI - Biomechanical evaluation of hybrid fixation method of sagittal split ramus osteotomy in mandibular advancement. AB - PURPOSE: In this study, eight different fixation methods applied after sagittal split ramus osteotomy (SSRO) were compared experimentally. MATERIALS AND METHODS: SSRO was performed to 48 sheep hemimandibles in eight groups of 6 each. Group A- a four hole standard miniplate; Group B- a four hole standard miniplate and one bicortical screw; Group C-a four hole locking plate; Group D-a four hole locking plate and one bicortical screw; Group E-a six hole straight miniplate; Group F-a six hole straight miniplate and one bicortical screw; Group G- a sliding plate, which was specifically designed for SSRO; Group H- sliding plate and one bicortical screw. RESULTS: In terms of measured values of displacement, the highest degrees of displacement were observed in decreasing order in Groups G, C, A, and E. The least displacement values were detected in Groups H, F, D and B with values being very close to each other. For linear force applied up to 70N, 3 mm or higher displacement values were not seen in any fixation system. CONCLUSION: According to the results of study, all systems are suitable for clinic usage. However, intermaxillary fixation or functional elastics may be needed for sliding plate systems during the healing period of hard tissue. PMID- 30446329 TI - The Role of Time Use Behaviors in the Risk of Obesity among Low-Income Mothers. AB - OBJECTIVES: Childrearing responsibilities create additional demands on women's time and effort, especially in low-income families. We explore whether childrearing demands and differences in time use increase the risk of overweight and obesity for women in different income brackets. METHODS: We use data for women ages 18-55 years from the 2006-2008 and 2014-2015 American Time Use Surveys (N = 17,914). We predict whether women engage in particular activities using logistic regression and, among those who do particular activities, we predict the minutes spent in various activities using ordinary least squares models. We also predict women's risk of overweight or obesity using logistic regression. All models examine conditional relationships between income level and motherhood status. RESULTS: Replicating prior research, we find a greater risk of overweight and obesity for mothers with low (odds ratio, 1.66; p < .001) and subpoverty (odds ratio, 1.93; p < .001) incomes compared with mothers with moderate/upper incomes and all child-free women. Motherhood and income status jointly predict women's time use, but including these time use behaviors in models of overweight and obesity does not attenuate the significantly higher risks for mothers with low and subpoverty incomes. CONCLUSIONS: Mothers experiencing economic hardship are at greater risk of overweight and obesity relative to other women. Additional research is warranted, however, because differences in time use do not explain this important health disparity. PMID- 30446328 TI - Obesity and Disparities in Human Papillomavirus Vaccination for U.S. Adolescent Girls and Young Women. AB - BACKGROUND: Obesity is recognized as a barrier to receiving women's preventive health services, including cervical and breast cancer screening. Little is known about whether obesity is associated with a lower incidence of human papillomavirus (HPV) vaccination, another important preventive care service for adolescent girls and young women. The objective of this study was to determine if adolescent girls and young women with obesity are less likely to receive HPV vaccination compared with individuals with normal weight. METHODS: We examined whether HPV vaccination was associated with obesity status in women aged 9-30 years surveyed from 2009 to 2016 by the U.S. National Health and Nutrition Examination Study. Results from logistic and linear regression models were adjusted for age, race, income, insurance status, self-reported health, and health care use, accounting for the weighted survey design. RESULTS: The final cohort included 5,517 women. Overall, 32.9% of participants reported vaccination, with a mean age at vaccination of 15.8 years. Adolescent girls and young women with obesity were less likely to report vaccination; the adjusted odds ratio of vaccination was 0.79 (p = .01) compared with normal weight women. Among those vaccinated, the age at vaccination was significantly older for women with obesity, 16.3 years compared with 15.2 years (p = .002), but there was no difference in the completion of the vaccination series rate by obesity. CONCLUSIONS: Adolescent girls and young women with obesity were less likely to report HPV vaccination and, if they were vaccinated, received the vaccination at a later age. PMID- 30446330 TI - Factors Impacting Perceived Access to Early Prenatal Care among Pregnant Veterans Enrolled in the Department of Veterans Affairs. AB - BACKGROUND: Despite the relatively recent Department of Veterans Affairs (VA) policy advances in providing care for veterans and their infants during the perinatal period, little information exists regarding access to prenatal care for women veterans. Currently, VA medical centers do not provide onsite pregnancy care for veterans, but pay for care from community obstetricians through the Veterans Choice Program (VCP) and related non-VA care programs. The VCP is subcontracted to two large contractors, Health Net and TriWest, to assist the VA in administering the VCP. To date, no studies have evaluated women's perceived access to prenatal care under the VCP. OBJECTIVE: The purpose of this study was to understand pregnant veterans' perceived access to community prenatal care through the VCP. DESIGN: The Center for Maternal and Infant Outcomes Research in Translation (COMFORT) study is a longitudinal, prospective multisite observational cohort study of pregnant and postpartum veterans at 15 VA facilities nationwide. Telephone surveys were conducted with women veterans at 20 weeks of pregnancy. We used multivariable logistic regression to examine the odds of receiving care early enough adjusted for these key factors. Measures included perceived access to early prenatal care by race, age, marital status, history of mental health conditions, urban/rural residence, and the VCP contractor (Health Net vs. TriWest). RESULTS: Overall, 519 women veterans completed the baseline pregnancy survey. A sizeable proportion of participants reported a history of mental health conditions, including depression (56.7%), anxiety disorder (45.5%), and posttraumatic stress disorder (40.5%). White veterans were more likely to report perceived timely access to prenatal care than minority veterans (66% vs. 52%; p = .0038). Veterans receiving care at Health Net facilities were more likely to report receiving prenatal care as early as desired in comparison to veterans at TriWest facilities (adjusted odds ratio, 0.48; 95% CI, 0.32-0.73), whereas veterans with a history of depression were 1.7 times more likely to report perceived delays in desired prenatal care compared with veterans without a history of depression (adjusted odds ratio, 1.65; 95% CI, 1.08-2.53). CONCLUSIONS: We found that nearly one-third of women reported problems receiving early prenatal care as soon as they would have liked. Women with histories of depression and racial minorities may require additional maternity care coordination services to ensure they receive timely prenatal care. Community based provider networks under the VCP should continue to be expanded so that pregnant veterans are able to access high-quality prenatal care in a timely manner. PMID- 30446331 TI - Perceptions of Pregnancy and Contraceptive Use: An In-Depth Study of Women in Los Angeles Methadone Clinics. AB - INTRODUCTION: In 2016, 2.1 million people in the United States were estimated to have an opioid use disorder. Although the disorder can be safely and effectively treated with prescription methadone, and treatment is potentially long term and may span women's peak childbearing ages. Little is known about women's reproductive health needs while on methadone. METHODS: We interviewed 22 sexually active, nonpregnant women ages 21-39 years at two Los Angeles methadone clinics in 2016. The interviews were transcribed and coded by four researchers using thematic and open coding techniques. RESULTS: One-half of the women were nulliparous and 17 were in stable, monogamous relationships with men. Women reported a range of feelings and perceptions about pregnancy, but nearly all wanted to delay pregnancy until discontinuing methadone. However, many women indicated limited interest in preventing pregnancy because of the relative stability of their relationships, fear of infertility, and low perceived risk of pregnancy. These factors influenced contraceptive use. Women described mixed feelings about pregnancy and many ultimately felt that an unplanned pregnancy would be acceptable in the context of their relationships and uncertain fertility. These findings provide context for previous quantitative findings that women in methadone treatment have higher rates of unintended pregnancy and lower rates of contraceptive use than the general population. CONCLUSIONS: Accurate information about pregnancy in the context of methadone treatment may help women to make proactive family planning decisions. Health care providers should discuss the guidelines for pregnancy on methadone and offer a range of options to help women achieve their reproductive goals. PMID- 30446332 TI - Development of a patient-oriented disease specific outcome measure of health related quality of life (HRQOL) for musculoskeletal oncology patients. AB - BACKGROUND: According to improved functional outcome and life expectancy in orthopaedic oncology patients, there has been a growing interest in not only oncologic and functional outcomes but also health-related quality of life (HRQOL), including body image, mental status, or social activities, after surgery. However, there has been a lack of disease-specific measures focusing on the ability of orthopaedic oncology patients to evaluate their HRQOL comprehensively. Therefore, our aims in the present study were 1) to develop a patient-oriented disease-specific outcome measure of HRQOL for musculoskeletal oncology patients (COMMON-LE), and 2) to examine the practical applicability, reliability and validity of the COMMON-LE for patients with musculoskeletal tumors in the lower extremity. METHODS: The COMMON-LE was developed by expert committee of orthopaedic oncology and rehabilitation. A total of 101 patients were surveyed using the COMMON-LE, as well as the TESS, the MSTS score, and the SF-36, to assess their psychometric characteristics, including reliability, validity, and responsiveness. RESULTS: The COMMON-LE showed no marked floor and ceiling effects. Test-retest reliability and internal consistency determined using the intraclass correlation coefficient (0.928) and Cronbach's alpha (0.948 0.968), respectively, were excellent. Each domain of the COMMON-LE (pain, ADL, socioemotional condition and general health) was well correlated with the scores of the standard measures (SF-36, TESS, MSTS score). Factor analysis and the AIC network showed the questionnaire items of the COMMON-LE were clearly separable into three clusters according to their content, corresponding to each domain of the questionnaire. CONCLUSIONS: We have successfully developed and validated a disease-specific measure, the COMMON-LE, to evaluate not only physical function, but also various aspects of HRQOL in patients with musculoskeletal tumors. The COMMON-LE has sufficient reliability and internal consistency, and good validity, and appears to be practically applicable to this group of patients. PMID- 30446333 TI - Anatomical relationship between insertion sites, tunnel placement, and lateral meniscus anterior horn injury during single and double bundle anterior cruciate ligament reconstructions: A comparative macroscopic and histopathological evaluation in cadavers. AB - PURPOSE: The influence of tunnel extension outside the anatomical anterior cruciate ligament (ACL) insertion in single-bundle (SB) or double-bundle (DB) ACL reconstruction is unclear. This study aimed to investigate the anatomical relationship between ACL insertion and tunnel extension in SB and DB ACL reconstruction, and the impact of tibial tunnel extension to the insertion of anterior horn of lateral meniscus in terms of injury. METHODS: Forty-six paired cadaver knees (mean age, 82.7 +/- 10.7 years) were used. Right and left knees were used for SB (10 mm) and DB tunnel reaming (6 mm for the anteromedial and posterolateral bundles). Tibial and femoral tunnels were created to aim at the center of the ACL insertion by arthroscopic visualization. The relationship between tunnel extension and ACL insertion was evaluated macroscopically, and there ratio in two groups were compared by chi-square test. Further, the relative risk for meniscus injury based on tunnel placement was estimated. Coronal section of tibia and parallel section to Blumensaat line in femur were prepared to evaluate the relationship among tunnel position, ACL insertion, and anterior horn of the meniscus histologically. RESULTS: Tibial tunnel extension out of the ACL insertion was observed macroscopically in 9 (39.1%) knees of the SB group, and 3 (13.0%) of the DB group (p = 0.045). In femoral tunnels, extension out of the ACL insertion was seen in 8 (34.8%) knees of the SB group and 1 (4.3%) of the DB group (p = 0.011). Partial injuries of the lateral meniscus anterior horn (LMAH) were observed in 5 (21.7%) knees of the SB group and 1 (4.3%) knee of the DB group (p = 0.091). The relative risk for LMAH injury was calculated as 5.0 (odds ratio, 6.1). Microscopically, SB tunnels appeared to expand out of ACL insertion, both in the femur and tibia. CONCLUSIONS: The incidence of tunnel extension out of the ACL insertion in femur and tibia were higher with SB than with DB reconstruction. Furthermore, injury rate of the LMAH in the DB group was lower. PMID- 30446334 TI - Evaluation of humeral head cartilage using magnetic resonance imaging T1 rho mapping for patients with small-to-medium rotator cuff tears: A pilot study. AB - BACKGROUND: It is unclear whether smaller rotator cuff tears cause cartilage degeneration. This study was designed to detect early humeral head cartilage degeneration in patients with small-to-medium cuff tears using magnetic-resonance imaging T1 rho mapping. METHODS: Five male and 5 female volunteers without shoulder symptoms (control group) and 5 male and 5 female patients with small-to medium (<3 cm) rotator cuff tears underwent 3.0-T magnetic resonance imaging of a single shoulder. T1 rho values of the humeral head cartilage were measured and analyzed. RESULTS: The total mean T1 rho value was 40.4 +/- 3.4 ms for the control group and 45.0 +/- 5.3 ms for the patient group. In the control group, the T1 rho values in the inferior articular cartilage were significantly higher than those in the superior and middle articular cartilage. In the patient group, there was no significant difference between all regions. A comparison between the patient and control groups showed that the mean T1 rho values in the superior-to middle articular cartilage were significantly higher for the patient group than for the control group. However, in the inferior articular cartilage, there was no significant difference between both groups. CONCLUSIONS: This study showed the possibility of early cartilage degenerative changes in the superior-to-middle humeral head articular cartilage of patients with small-to-medium rotator cuff tears. PMID- 30446335 TI - Increased central adiposity is associated with pro-inflammatory immunoglobulin G N-glycans. AB - BACKGROUND: Increased body fat may be associated with an increased risk of developing an underlying pro-inflammatory state, thus leading to greater risk of developing certain chronic conditions. Immunoglobulin G has the ability to exert both anti- and pro-inflammatory effects, and the N-glycosylation of the fragment crystallisable portion is involved in mediating this process. Body mass index, a rudimentary yet gold standard indication for body fat, has been shown to be associated with agalactosylated immunoglobulin G N-glycans. AIM: We aimed to determine the association between increased body fat and the immunoglobulin G glycosylation features, comparing body mass index to other measures of body fat distribution. METHODS: We investigated a sample of 637 community-based 45-69 year olds, with mixed phenotypes, residing in Busselton, Western Australia. Body mass index and the waist-to-hip and waist-to-height ratios were calculated using anthropometry, while dual-energy x-ray absorptiometry was performed to gain an accurate measure of total and area specific body fat. Serum immunoglobulin GN glycans were analysed by ultra-performance liquid chromatography. RESULTS: Twenty two N-glycan peaks were found to be associated with at least one of the fat measures. While the previous association of body mass index to agalactosylated immunoglobulin G was replicated, measures of central adiposity explained the most variation in the immunoglobulin G glycome. CONCLUSION: Central adiposity is associated with an increased pro-inflammatory fraction of immunoglobulin G, suggesting that the android/gynoid ratio or waist-to-height ratio instead be considered when controlling for adiposity in immunoglobulin G glycome biomarker studies. PMID- 30446336 TI - Celiac disease-specific and inflammatory bowel disease-related antibodies in patients with recurrent aphthous stomatitis. AB - The etiology of recurrent aphthous stomatitis (RAS) remains unknown. RAS can be presented as primary, idiopathic condition and as a secondary RAS, which is associated with a systemic disease. The aim of our study was to evaluate the presence and concentrations of antibodies specific for celiac disease (CeD) and antibodies related to inflammatory bowel diseases (IBD) in patients with RAS without gastrointestinal symptoms. Antibodies against tissue transglutaminase (anti-tTG), deaminated gliadin peptides (DGP), deaminated gliadin-analogous fragments (anti-GAF-3X) and Saccharomyces cerevisiae (ASCA) were determined by ELISA and antineutrophil cytoplasmic antibodies (ANCA) by indirect immunoflurescence (IIF) in 57 patients with RAS and 60 control subjects. The prevalence of CeD specific antibodies did not differ between RAS patients and controls. However, the concentrations of IgA anti-tTG, IgA anti-GAF-3X antibodies in patients with RAS were significantly higher compared to controls (p = 0.002 and p = 0.04 respectively). Histological changes consistent with CeD were confirmed by duodenal biopsy in one RAS patient with highly positive IgA anti tTG, anti-GAF-3X and anti-DGP antibodies. Higher prevalence along with higher concentrations of IgG ASCA were found in RAS patients compared to controls (p < 0.01). Patients with positive IgG ASCA in the absence of clinical symptoms decided not to pursue any further testing. Dysfunction of oral mucosa and the exposure to various antigens might be a reason for the loss of tolerance resulting in increased production of autoantibodies. It seems likely that antibodies are markers of aberrant immune response, rather than key effectors involved in the pathogenesis of the disease. PMID- 30446337 TI - PHA eludes macrophage suppression to activate CD8+ T cells. AB - Tumors may include a high proportion of immune modulatory cells and molecules that restrain the anti-cancer response. Activation of T cells to eliminate cancer cells within the immune-suppressive tumor microenvironment remains a challenge. We have shown that C57BL/6 J peritoneal cell culture models features of macrophage-dense tumors as TCR ligation fails to activate T cells unless IFNgamma is neutralized or iNOS is inhibited. We tested other forms of T cell activation and found phytohemagglutinin (PHA) distinctive in the ability to markedly expand CD8 T cells in this model. IFNgamma or iNOS inhibition was not necessary for this response. PHA triggered less IFNgamma production and inhibitory PD-L1 expression than TCR ligation. Macrophages and CD44hi T cells bound PHA. Spleen T cell responses to PHA were markedly enhanced by the addition of peritoneal cells revealing that macrophages enhance T cell expansion. That PHA increases CD8 T cell responses within macrophage-dense culture suggests this mitogen might enhance anti-tumor immunity. PMID- 30446338 TI - Corrigendum to "The impact of a remote monitoring program on the prenatal follow up of women with gestational hypertensive disorders" [Eur. J. Obstet. Gynecol. Reprod. Biol. 223 (2018) 72-78]. PMID- 30446339 TI - [Imaging of Reis-Buckler corneal dystrophy]. PMID- 30446340 TI - [Pyogenic granuloma of the palpebral conjunctiva associated with scleral prothesis]. PMID- 30446341 TI - [Conjunctival hemangioma: From atypical presentation to topical beta-blocker treatment]. PMID- 30446342 TI - [External ophthalmomyiasis]. PMID- 30446343 TI - [Posttraumatic macular dystrophy]. PMID- 30446344 TI - Clinical and para-clinical description of a novel mutation for Schnyder dystrophy in a French family. AB - INTRODUCTION: The objective of this article is to describe the evolution of Schnyder dystrophy in 3 related patients of different ages and to highlight the discovery of a new mutation unidentified until now. CASE REPORT: We present a series of 3 cases, all first-degree relatives with no suggestion of consanguinity, of different ages (30, 40 and 59 years) and two distinct generations (mother and children). Slit lamp examination revealed the same lesions in our three patients: an early-onset corneal arcus senilis, central corneal deposits, and a gray stromal haze in the two oldest subjects. The older the patient, the more numerous and dense were these lesions. The various anterior segment OCTs showed an increase in the number of hyperreflective opacities in the anterior stroma and, in the older subject, the appearance of many posterior shadows. Monitoring of pachymetry by Pentacam(r) showed progressive age-related thickening. All three patients had dyslipidemia treated with statins or diet alone. In our case we proposed treatment only to subject A because of the significant impact on her visual acuity. DISCUSSION: Numerous clinical, para clinical and genetic descriptions of this disease are found in the literature. Schnyder dystrophy is rare but not unheard of and may be discovered fortuitously or in the setting of decreased visual acuity. Genetic analysis of our family revealed a mutation of the UBIAD1 gene not described in the literature. UBIAD1 encodes the protein domain-containing UbiA prenyltransferase 1 which converts vitamin K1 into K2 and is involved in the cholesterol synthesis pathway. In the case of a mutation, it is no longer functional, leading to the accumulation of cholesterol crystals. Given the clinical context and the presence of this variant of the reference sequence in all relatives, its pathogenesis is strongly suspected in our family. The originality of our article is to present the progression of the same pathology in 3 patients with the same mutation at different ages and degrees of severity. This notion of progressive worsening and the need to treat late in the majority of cases are found in literature. CONCLUSION: The discovery of a new variant within the UBAID1 gene suggests its pathogenesis in view of the clinical features available to us. The dystrophy is initially asymptomatic before the high number of deposits becomes disabling. PMID- 30446345 TI - Intra- and subretinal neovascularization following radiation therapy: Contribution of OCT-angiography. PMID- 30446346 TI - [Fraser syndrome: Case report]. PMID- 30446347 TI - Physical and spatial assessment of school neighbourhood built environments for active transport to school in adolescents from Dunedin (New Zealand). AB - Adolescent active transport to school (ATS) is influenced by demographic, social, environmental and policy factors. Yet, the relationship between school neighbourhood built environment (SN-BE) and adolescents' ATS remains largely unexplored. This observational study examined associations between observed, objectively-measured and perceived SN-BE features and adolescents' ATS in Dunedin (New Zealand). Adolescents' perception of safety of walking to school was the strongest correlate of ATS among adolescents living <= 2.25 km of school, whereas assessed micro- and macro-scale SN-BE features were not significantly correlated with ATS. Adolescents' perceptions of walking safety should be considered as a part of comprehensive efforts to encourage ATS. PMID- 30446348 TI - Biomechanical evaluation of opening-wedge high tibial osteotomy with composite materials using finite-element analysis. AB - BACKGROUND: Medial opening-wedge high tibial osteotomy (HTO) has been used to treat osteoarthritis of the medial compartment of the knee. However, this makes the proximal tibia a highly unstable structure and causes the plate to be a potential source of mechanical failure. Consequently, proper design and material use of the fixation device are essential in HTO, especially for overweight or full-weight-bearing patients. METHODS: This study investigated the biomechanical effects of the TomoFix plate composed of conventional titanium (Ti) in comparison to plates composed of carbon short-fiber-reinforced (CSFR) polyetheretherketone (PEEK) and carbon long-fiber-reinforced (CLFR) PEEK, in medial opening-wedge HTO. A medial opening was simulated with various HTO plate models subjected to a 2500 N vertical load simulating the peak walking force using a validated knee-joint finite-element (FE) model. The stress on the plate and the bone, the contact stress on the menisci and articular cartilage, as well as wedge micromotion were measured. RESULTS: The results of the FE analysis indicated that the Ti plate showed the best functional outcome in terms of micromotion. However, the CSFR PEEK plate showed a positive effect on relieving stress shielding. In addition, there was less contact stress on the meniscus and articular cartilage with the CSFR PEEK plate in comparison to CLFR PEEK and Ti plates. CONCLUSION: These results can provide insights into the design of high-performing composite HTO plates to produce more desirable biomechanical effects. PMID- 30446349 TI - Analysis of delays in the prescription of oseltamivir in hospitals and potential for improvement. AB - OBJECTIVES: Patients hospitalized for influenza should receive early treatment with a neuraminidase inhibitor. PATIENTS AND METHODS: We conducted a retrospective study of the prescription of oseltamivir during the 2016-2017 influenza epidemic among patients hospitalized for influenza confirmed by RT-PCR in the infectious disease department. RESULTS: Treatment with oseltamivir was initiated as recommended in 96% of hospitalized patients presenting with influenza. However, a delay in prescription was observed with only 18% of prescriptions made on the first day. The prescriptions were exclusively initiated in the infectious disease department. CONCLUSION: To improve the early prescription of oseltamivir during the influenza season, two recommendations are essential: oseltamivir availability in the emergency department pharmacy, awareness of physicians of the need to prescribe to any patient hospitalized for a lower respiratory tract infection treatment with a neuraminidase inhibitor upon admission to the emergency department. PMID- 30446350 TI - Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease. AB - Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid beta oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1alpha, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose up-regulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1-knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the alpha subunit of the stimulatory G protein (Gsalpha), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC 1alpha and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial beta-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial. PMID- 30446351 TI - Editorial overview: Endocrine and metabolic diseases Druggable diabetes: identification of therapeutic opportunities. PMID- 30446352 TI - Does the Addition of Vasopressin to Catecholamine Vasopressors Affect Outcomes in Patients With Distributive Shock? PMID- 30446353 TI - Are Antibiotics Effective in the Treatment of Children With Prolonged Wet Cough? PMID- 30446355 TI - Acutely decompensated heart failure with chronic obstructive pulmonary disease: Clinical characteristics and long-term survival. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is among the most common comorbidities in patients hospitalized with heart failure and is generally associated with poor outcomes. However, the results of previous studies with regard to increased mortality and risk trajectories were not univocal. We sought to assess the prognostic impact of COPD in patients admitted for acutely decompensated heart failure (ADHF) and investigate the association between use of beta-blockers at discharge and mortality in patients with COPD. METHODS: We studied 1530 patients. The association of COPD with mortality was examined in adjusted Fine-Gray proportional hazard models where heart transplantation and ventricular assist device implantation were treated as competing risks. The primary outcome was 5-year all-cause mortality. RESULTS: After adjusting for establisked risk markers, the subdistribution hazard ratios (SHR) of 5-year mortality for COPD patients compared with non-COPD patients was 1.25 (95% confidence intervals [CIs] 1.06-1.47; p = .007). The relative risk of death for COPD patients increased steeply from 30 to 180 days, and remained noticeably high throughout the entire follow-up. Among patients with comorbid COPD, the use of beta-blockers at discharge was associated with a significantly reduced risk of 1 year post-discharge mortality (SHR 0.66, 95%CIs 0.53-0.83; p <=.001). CONCLUSIONS: Our data indicate that ADHF patients with comorbid COPD have a worse long-term survival than those without comorbid COPD. Most of the excess mortality occurred in the first few months following hospitalization. Our data also suggest that the use of beta-blockers at discharge is independently associated with improved survival in ADHF patients with COPD. PMID- 30446356 TI - Midbrain dysfunction in anorexia nervosa. PMID- 30446354 TI - Patients with HFpEF and HFmrEF have different clinical characteristics in Turkey: A multicenter observational study. AB - BACKGROUND: To determine and compare the demographic characteristics, clinical profile and management of patients with heart failure with mid-range ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) in a Turkish cohort. METHODS: The APOLLON trial (A comPrehensive, ObservationaL registry of heart faiLure with mid-range and preserved ejection fractiON) is an observational and multicenter study conducted in Turkey. Consecutive patients admitted to the cardiology clinics who were at least 18 years of age and had HFmrEF or HFpEF were included (NCT03026114). RESULTS: The study population included 1065 (mean age of 67.1 +/- 10.6 years, 54% women) patients from 12 sites in Turkey. Among participants, 246 (23.1%) had HFmrEF and 819 (76.9%) had HFpEF. Compared to patients with HFpEF, those with HFmrEF were more likely to be male (57.7 vs 42.2%; p < 0.001), had higher N-terminal pro-B-type natriuretic peptide levels (853 vs 528 pg/ml, p < 0.001), were more likely to have ECG abnormalities (72.4 vs 53.5%, p < 0.001) and hospitalization history for heart failure (28 vs 18.6%; p = 0.002). HFmrEF patients were more likely to use beta-blockers (69.9 vs 55.2%, p < 0.001), aldosterone receptor antagonists (24 vs 14.7%, p = 0.001), statins (37 vs 23%, p < .001), and loop diuretics (39.8 vs 30.5%, p = 0.006) compared to patients with HFpEF. CONCLUSIONS: The results of APOLLON study support that the basic characteristics and etiology of HFmrEF are significantly different from HFpEF. This registry also showed that the patients with HFmrEF and HFpEF were younger but undertreated in Turkey compared to patients in western countries. PMID- 30446357 TI - Clinical factors associated with augmentation treatment with second-generation antipsychotics and lithium in major depression - Results from a European multicenter study. AB - This cross-sectional European multicenter study with retrospective assessment of treatment response sought to determine variables associated with the administration of augmentation strategies with second-generation antipsychotics (SGAs) and lithium in the pharmacotherapy of major depressive disorder (MDD). In 349 DSM-IV-TR MDD patients, differences in socio-demographic, clinical, treatment, and pharmacological features between participants receiving add-on treatment of their antidepressants with either SGAs (n = 318) or lithium (n = 31) were investigated using analyses of covariance, chi-squared tests, and binary logistic regression analyses. As only significant between-group difference, we found SGA augmentation (compared with lithium augmentation) to be associated with high depressive symptom severity expressed by a higher mean Montgomery and Asberg Depression Rating (MADRS) total score (27.19 +/- 11.35 vs 18.87 +/- 12.88, F = 14.82, p = < .0001) and a higher mean 21-item Hamilton Rating Scale for Depression (HAM-D) total score (21.27 +/- 9.30 vs 13.74 +/- 9.11, F = 18.60, p = < .0001). No significant differences for socio-demographic features, psychotic symptoms, suicidality, psychiatric and somatic comorbidities, antidepressant pharmacotherapy, and other add-on medications could be seen. Even if there was no significant superiority of one augmentation strategy with regard to treatment response pattern, a trend whereupon adjunctive SGAs were more likely dispensed in treatment-resistant and difficult-to-treat MDD conditions could be observed. In terms of the prescription pattern, we could demonstrate that lithium is less frequently used than SGAs in the clinical routine care which may reflect the need of continuous plasma level determinations and the anticipation of adverse effects. PMID- 30446358 TI - "Am I OK?" using human centered design to empower rheumatoid arthritis patients through patient reported outcomes. AB - OBJECTIVE: Use of patient reported outcomes (PROs) in the routine care of rheumatoid arthritis (RA) has been shown to improve health outcomes, However, integration of PROs into the clinical visit is inconsistent. We aimed to develop a "dashboard" for RA patients to display relevant PRO measures for discussion during a routine RA clinical visit. METHODS: Patients (N = 45) and providers (N = 12) were recruited from rheumatology clinics at a university center and a safety net hospital. Using a human-centered design process involving patients, clinicians, designers, and health-IT experts, we performed interviews, clinic observations, and focus groups, which subsequently guided an iterative phase of prototype testing. RESULTS: RA patients and their providers shared the goals of assessing wellbeing and developing a personalized treatment plan. We found conflicting views of which data were most important for guiding decision-making and for answering the patient's overarching question of "Am I OK?" CONCLUSION: The final dashboard simplified the display of PRO data and correlated it longitudinally to the patient's medication regimen. It also included laboratory values relevant for RA care. PRACTICE IMPLICATIONS: By presenting data graphically, the dashboard may provide a platform for patients and providers to communicate around PROs and shared goals. PMID- 30446359 TI - Improving quality in cardiometabolic medicine real-world evidence. PMID- 30446360 TI - Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient. AB - Biallelic pathogenic variants in FA2H gene have been repeatedly described as a cause of hereditary spastic paraplegia (HSP) type35 (SPG35). Targeted massive parallel sequencing (MPS) of the HSP genes panel revealed a novel homozygous variant c.130C > T (p.P44S) in the FA2H gene in the 30-year-old patient presenting with spastic paraplegia. The patient originated form the Czech minority in Romania. The patient manifests typical clinical signs for SPG35 (youth onset gait impairment, progressive spastic paraparesis on lower limbs, dysarthria, white matter changes in MRI). PMID- 30446361 TI - Tumour volume reduction following PET guided intensity modulated radiation therapy and temozolomide in IDH mutated anaplastic glioma. AB - The role of maximal surgical debulking in isocitrate dehydrogenase (IDH) mutated anaplastic glioma prior to adjuvant radiation therapy remains uncertain. This study assessed the reduction in tumour volume following intensity modulated radiation therapy (IMRT) and temozolomide in this favourable and more responsive tumour pathology. 56 patients were managed from 2011 to 2014 and 53 had residual disease. To assess radiological response, tumour volumes were created on representative T1/T2Flair MRI sequences using identical slice-levels in three planes for pre-IMRT, month + 3 and month + 12 post-IMRT scans. Change in volumes was assessed between time periods. Progression-free survival (PFS) was calculated from start of radiotherapy. Median follow-up for survivors is 48.2 months. Pathology was anaplastic oligodendroglioma (AOD) and anaplastic astrocytoma IDH mutated (AAmut) in 32 and 21 patients respectively. 93% received sequential chemotherapy. The median residual disease on T1 and T2Flair imaging was 9.7 cm3 and 20.6 cm3. 17 patients relapsed for projected 5 year PFS of 74.9%; with 8 isolated relapses within initial surgical site. On MRI at month + 3, the median volume for T1 and T2Flair reduced by 69.4% and 67.3% respectively; which further decreased to 82.4% and 81.3% at month + 12. By month + 12, 69.2% and 62.2% of patients had >75% volume reduction. Patients with AOD had superior reduction at month + 3 compared with AAmut (p = 0.02); but equivalent reduction at month + 12 (p = 0.14). Thus, in patients with anaplastic glioma harbouring an IDH mutation, where an attempt at near-total resection may be associated with unacceptable morbidity, this data suggests that the radiation therapy may provide effective cytoreduction of residual disease. PMID- 30446362 TI - Association between vertebral artery hypoplasia and vertebral artery aneurysms: A case-control study. AB - BACKGROUND: The aim of this retrospective case-control study is to determine the association of vertebral artery hypoplasia (VAH) and other anatomical variants with saccular vertebral artery posterior inferior cerebellar artery (VA-PICA) aneurysms. METHODS: The prevalence of VAH, vertebral artery (VA) atresia, VA aplasia, and PICA aplasia was analyzed using CT angiography in 64 patients with VA-PICA aneurysms (43 ruptured and 21 unruptured) and compared to 128 age- and sex-matched controls. Logistic regression was performed to identify independent risk factors for aneurysm formation. RESULTS: Univariate analysis showed patients with VA-PICA aneurysms had significantly higher incidence of VAH (53% vs. 17%; odds ratio [OR] 4.8; 95% confidence interval [CI] 2.4-9.4; p < 0.0001) and VA aplasia (14% vs. 1%; OR 20.8; 95% CI 2.5-168.0; p = 0.004) compared with controls. Multivariate analysis identified VAH (odds ratio, 3.6; 95% CI 1.8-7.3; p < 0.0001) as an independent strong risk factor for VA-PICA aneurysm formation. VA-PICA aneurysms are detected significantly more often in the dominant VA, which is contralateral to VAH. Other anatomical variants are not related to aneurysm formation. CONCLUSIONS: VAH and VA aplasia are potential risk factors for VA-PICA aneurysms. Altered hemodynamics caused VAH may result in intracranial aneurysm formation. Additional research should clarify the pathophysiological association of VAH, VA aplasia, or vascular occlusion with arteriosclerosis and intracranial aneurysm formation. PMID- 30446363 TI - Sylvian fissure splitting revisited: Applied arachnoidal anatomy and proposition of a live practice model. AB - Opening the Sylvian fissure is an important technique in neurosurgery. Despite providing excellent anatomic fidelity, cadaveric and synthetic models lack real time hemodynamics and coagulation physiology. We introduce a live rat aortoiliac model to practice the basic skills of Sylvian fissure splitting based on its arachnoidal microanatomy. Cadaveric dissections were carried out to assess the microanatomical relationships between the Sylvian fissure arachnoid and its contents, namely arteries (A), veins (V), and brain (B). Rat surgeries were performed to assess the similarities between separating aortoiliac arteries from adjacent veins and the various technical aspects of dissecting the Sylvian fissure. The Sylvian fissure could be divided into 3 compartments regarding the progressive steps of its dissection: (1) superficial opercular, (2) deep opercular, and (3) cisternal. The major arachnoidal connections that required division during dissection of each Sylvian compartment were as follows: B-V and V V types in the superficial opercular; B-B and A-B types in the deep opercular; and A-B and A-A types in the cisternal compartments. Dissection techniques in the rat aortoiliac model correlated with key techniques in Sylvian fissure dissection. Despite lacking brain tissue, the rat aortoiliac arteries offer a model in which the arteries and veins with their investing connective tissues mimic the arachnoid-vessel interconnections in the Sylvian fissure. Therefore, using this model simulates the essential sub-techniques of splitting the Sylvian fissure. The rat model may be used to provide trainees with an opportunity to practice under the duress of the real-time hemodynamics and coagulation physiology. PMID- 30446364 TI - Seizures occurring while driving in patients with and without diagnosis of epilepsy: Frequency and association with automobile accidents. AB - Seizure may occur during any human activity, including driving. The objectives of this study were to report the frequency of seizure occurring while driving, clarify patient characteristics and analyze the behavioral patterns of drivers afflicted by seizure. A single-center, retrospective study was conducted using prospectively acquired data. Data of 658 adult seizure patients who visited our emergency department between January 2011 and December 2016 were used for analysis, focusing on daily activities immediately before seizure. Nineteen of the 658 patients (2.9%) sustained seizure while driving. The 658 patients were dichotomized on the basis of whether he or she had been diagnosed with epileptic seizure (ES). Seven of the 307 patients with ES vs. 12 of the 351 patients without ES sustained seizure while driving. The frequencies did not differ significantly between the two groups (2.3% vs. 3.4%, p = 0.49). Structural lesions on brain imaging studies were found in 6 of the 12 patients without ES (50%). Sixteen of the 19 patients (84%) caused automobile accidents after seizure. Among the 7 patients with ES, antiepileptic drugs had not been prescribed in 3 (43%). Although seizures occurring while driving have been studied extensively, most researchers focused on patients with ES. This study was unique because it focused on patients without ES, and the current findings that seizures in patients without ES outnumbered seizures in those with ES may be informative to clinical neuroscientists and emergency physicians. Prospective studies are expected to identify individuals at risk for first seizure occurring while driving. PMID- 30446365 TI - Association between sensory nerve action potential and lumbar dorsal root ganglion area. AB - OBJECTIVE: To quantify the cross-sectional area (CSA) of lumbar dorsal root ganglion (DRG) by magnetic resonance imaging (MRI) and investigate the relationship between the cross-sectional area (CSA) of DRGs and sensory nerve action potentials (SNAP) amplitude in the lower extremities. METHODS: Thirty eight DRGs (20 L5 roots and 18 S1 roots) in 10 adult subjects were reviewed retrospectively. The CSA of the DRG was calculated from MR images of the coronal plane. SNAP amplitudes of the superficial peroneal nerve and sural nerve were corresponded to L5 and S1-DRGs. RESULTS: The mean CSA of DRGs was 66.6 +/- 13.7 mm2 in L5-DRG and 79.5 +/- 14.3 mm2 in S1-DRG. The means of SNAP amplitudes were 19.6 +/- 6.2 MUV in superficial peroneal nerves and 24.6 +/- 9.0 MUV in sural nerves. In multivariate regression analysis, the CSA of DRGs had a significant correlation with SNAP amplitude. CONCLUSION: The area of L5 and S1-DRGs may be positively correlated with SNAP amplitude. PMID- 30446366 TI - Efficacy, tolerability, and blood concentration of zonisamide in daily clinical practice. AB - We aimed to evaluate the efficacy, tolerability, and blood concentration of zonisamide (ZNS) used in daily clinical practice. This was a retrospective study performed at a single epilepsy center and included 149 patients with epilepsy. The efficacy and retention of ZNS for 52 weeks, percentage of patients who were seizure free for 26 weeks, and the 5-year retention rate were analyzed. The tolerability was assessed based on treatment-emergent adverse effects (AEs) and the adverse effect profile (AEP). More than 70% (105/149) of patients were on ZNS polytherapy. The mean dose of ZNS was 300 +/- 170.6 mg/day, and the antiepileptic drug (AED) load was 2.0 +/- 1.1 (median 1.8, range 0.2-5.3). The retention rate for 52 weeks and the percentage of patients who were seizure-free for 26 weeks were 73% and 42%, respectively. The retention rate decreased with time and reached 43% in 5 years. Younger age of onset was a significant variable affecting retention rate for 52 weeks (p = 0.044), whereas fewer concomitant AEDs were significantly associated with being seizure free for 26 weeks (p = 0.0006). AEs were reported in 24% (36/147) of patients. The number, mechanism of action, or drug load of the AEDs did not predict the development of AEs; however, blood concentration of ZNS was significantly higher in patients with AEs (p = 0.0011) than in those without AEs. ZNS is a well-tolerated and effective AED in daily clinical practice, and several clinical factors may predict the efficacy and tolerability of ZNS. PMID- 30446367 TI - Comparison of Dolenc and pterional approach in the microsurgery for blood blister like aneurysms (BBAs) of internal carotid artery. AB - OBJECTIVES: Blood blister-like aneurysms (BBAs) were considered a great therapeutic challenge with high morbidity and mortality. A variety of microsurgical techniques to treat BBAs had been proposed, but few had investigated the optimal surgical approach toward the exposure of BBAs. In this study, we aimed to compare the advantages and disadvantages of Dolenc and pterional approach in the microsurgery of BBAs. PATIENTS AND METHODS: We retrospectively reviewed medical and surgical records of ICA (internal carotid artery) blister-like aneurysms that had been treated by microsurgery at our hospital during 2012 to 2017 and compared postoperative complications and outcomes between Dolenc and pterional approach. RESULTS: Seventeen BBAs of 16 patients with complete information were identified from our database based on intraoperative findings. All 17 BBAs were treated with direct clipping successfully with no death or re-bleeding occurred. Six patients were performed with Dolenc approach and 10 with pterional approach. No significant difference was found regarding the incidence of intraoperative rupture (42.9% vs 0.0%, P = 0.051) or postoperative complications (ocular complications:33.3% vs 0.0%, P = 0.125; ischemic events: 33.3% vs 10.0%, P = 0.518) between the two groups. CONCLUSION: Dolenc approach and pterional approach were both applicable craniotomies for supraclinoid BBAs of ICA. Dolenc approach provided more exposure of ICA trunk, which ensured reliable proximal control but might also bring higher risk of oculomotor paralysis. Choice of approach should be based on the location of BBA and the available form of proximal control. PMID- 30446368 TI - Impact of major earthquakes on Parkinson's disease. AB - In April of 2016, major earthquakes occurred in Kumamoto, Japan. There is limited information on how major earthquakes affect patients with Parkinson's disease (PD). This study investigates the effect of major earthquakes on patients with PD. The participants were outpatients with PD from hospitals located in areas heavily damaged by the earthquakes. We performed an anonymous survey at nine medical institutions to investigate the condition of these patients during the month following the earthquakes. We collected questionnaires from 335 patients with PD. The mean age was 72.6, and the mean disease duration was 7.4 years. Regarding physical conditions, 29.3% of the patients worsened, 1.5% improved, and 68.1% had no change. The mental health of 35.2% of the patients worsened, 2.4% improved, and 57.9% had no change. The most frequently exacerbated neurologic symptoms included bradykinesia (56.1%), gait disturbance (51.0%), freezing of gait (40.8%), extension of "off" time (38.8%), and constipation (38.8%). The worsening mental conditions included fear of an aftershock (77.1%), anxiety (49.2%), insomnia (47.5%), melancholy feelings (45.8%), and fatigability (38.1%). Patients forced to evacuate reported significantly more physical and mental health symptoms (p < 0.01). The influences of major earthquakes on patients with PD were identified. After major earthquakes, we should consider the care required for patients' physical and mental health especially for those who experienced evacuation. PMID- 30446369 TI - The effect of flow diverting stents on in vivo intrasaccular aneurysm pressure. PMID- 30446370 TI - C/EBP homologous protein investigation in the serum and cerebro-spinal fluid of relapsing-remitting multiple sclerosis patients. AB - The exact determination of endoplasmic reticulum (ER) stress-associated proteins is not completely elucidated in the multiple sclerosis (MS) patients. We measured CHOP concentrations in the serum and cerebro-spinal fluid (CSF) of relapsing remitting MS (RRMS) patients (n = 20) in comparison with the non-MS control group (n = 20) to determine whether this marker could be detected in the body fluids of RRMS patients. CHOP marker was not detectable in all harvested CSF samples. However, its levels were detectable in all serums harvested from both non-MS and RRMS patients and its levels in the latter group were not significantly higher than those of the non-MS control group (P value = 0.265). CHOP was not detectable in the CSF of RRMS patients in spite of the recent reports on the RRMS autopsies. Additionally, there were not any significant correlations (Spearman's correlation) between both of EDSS score and age with CHOP serum concentrations in all subjects. PMID- 30446371 TI - Charcot spinal arthropathy presenting as adjacent segment disease after lumbar spinal fusion surgery in Parkinson's disease: A case report. AB - Charcot spinal arthropathy (CSA) is a rare spinal disorder presenting neuropathic osteoarthropathy of facet joints leading to progressive destruction. After L4-5 PLIF, a 63-year-old woman with Parkinson's disease (PD) underwent L3-4 and L5-S1 PLIF for primary adjacent segment disease caused by degenerative change, which was found as facet joint osteophytes and a vacuum disc phenomenon with endplate sclerosis. However, her postural disorder from PD deteriorated, and strong opioid analgesics were administered for severe recurring low back pain. Anterior subluxation at L2-3 occurred because of destructive secondary adjacent segment disease, which was found as destruction of the endplate and the facet without degenerative change, and formation of paravertebral osteophytes and fluid collection in the intervertebral space. The appearance on imaging met that for neuroarthropathic change, which was previously reported as CSA. L2-3 PLIF following extension of posterior fusion to T10 was additionally performed, and the postoperative course was uneventful with symptomatic improvement. In this case, the important finding was in the different appearance of the disease between adjacent segments on imaging. It is possible that deterioration of PD and administration of the analgesics inhibited deep pain sensation, and concentration of mechanical stress in the proximal adjacent segment by the long lever arm because of extension of the fusion level resulted in neuroarthropathic change of the facets in the secondary adjacent segments. The pathophysiology of association of CSA and PD remains unknown. However, we recommend vigilance for destructive neuroarthropathic facet change as CSA after spinal surgery in patients with severe PD. PMID- 30446372 TI - Seizure frequency and risk of cognitive impairment in people living with epilepsy in a sub-urban community in South Eastern Nigeria. AB - This study is aimed at assessing the impact of seizure frequency on the cognitive performance of epileptic adult patients in a rural community in South Eastern Nigeria. A total of 51 patients with epilepsy (33 males and 18 females) with a mean age of 30.7 +/- 12.1 years and 51 age and sex matched controls participated in this study. The cognitive performances of the people with epilepsy and controls were assessed using the Community Screening Interview for Dementia (CSID) and the computerized cognitive assessment test battery, the FePsy. The control group performed better in almost all the neurocognitive tests compared with the low seizure frequency (LSF) and high seizure frequency (HSF) groups. Analysis of covariance revealed that patients with LSF performed better (p = 0.04) in visual reaction time - dominant hand (VRT-D) compared with the HSF group. There was lack of significant differences in mean total CSID scores and mean sub-total scores for language, memory, orientation, attention, constructional praxis, auditory reaction time-dominant hand and non-dominant hand, VRT - non-dominant hand and figure recognition. HSF patients indicated significantly greater prevalence (80% vs. 20%; p = 0.020) and risk (OR, 8.0; 95% CI, 1.8-33.8)) of memory impairment, but not in the other neurocognitive domains compared with the LSF group. In conclusion, the present study indicated that adults with epilepsy performed poorly in a wide range of neurocognitive variables compared with the controls. However, no significant adverse effects of high seizure frequency were observed on almost all the neurocognitive variables. PMID- 30446373 TI - Effects of various lengths of hypoglossal nerve resection on motoneuron survival. AB - We employed stereological analyses for whole quantification of hypoglossal (XII) motoneurons in adult rats that received varying degrees of resection of the XII nerve. Various lengths of nerve gaps (0.0-13.3 mm) were made at the main trunk of the unilateral XII nerve, and the total number of XII neurons on the injured and uninjured sides was counted 12 weeks after nerve resection. The stereologically estimated total number of XII neurons decreased after various lengths of nerve resection, and survival rates ranged from 34.4% to 87.1%. Statistically significant negative correlations were observed between increasing length of the resected nerve and decreasing XII neuron survival. It was concluded that the total number of XII neurons decreased after nerve resection and that survival rates of XII neurons were related to distances between resected nerve stamps. PMID- 30446374 TI - Designing an Elusive C*G->G*C CRISPR Base Editor. AB - Protein engineering advances, including DNA repair manipulation of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) machinery, have paved the way for the first set of DNA precision base editors (C*G->T*A and A*T->G*C), with wide-ranging implications for treating many human genetic diseases. By utilizing the latest protein evolution advances, a hypothetical model for the first transversion (C*G->G*C) base editor can now be proposed. PMID- 30446375 TI - PXE, a Mysterious Inborn Error Clarified. AB - Ever since Garrod deduced the existence of inborn errors in 1901, a vast array of metabolic diseases has been identified and characterized in molecular terms. In 2018 it is difficult to imagine that there is any uncharted backyard left in the metabolic disease landscape. Nevertheless, it took until 2013 to identify the cause of a relatively frequent inborn error, pseudoxanthoma elasticum (PXE), a disorder resulting in aberrant calcification. The mechanism found was not only biochemically interesting but also points to possible new treatments for PXE, a disease that has remained untreatable. In this review we sketch the tortuous road that led to the biochemical understanding of PXE and to new ideas for treatment. We also discuss some of the controversies still haunting the field. PMID- 30446376 TI - Signaling Size: Ankyrin and SOCS Box-Containing ASB E3 Ligases in Action. AB - Ankyrin repeat and suppressor of cytokine signaling (SOCS) box (Asb) proteins are ubiquitin E3 ligases. The subfamily of six-ankyrin repeat domain-containing Asb proteins (Asb5, Asb9, Asb11, and Asb13) is of specific interest because they display unusual strong evolutionary conservation (e.g., urochordate and human ASB11 are >49% similar at the amino acid level) and mediate compartment size expansion, regulating, for instance, the size of the brain and muscle compartment. Thus, they may be involved in the explanation of the differences in brain size between humans and apes. Mechanistically, many questions remain, but it has become clear that regulation of canonical Notch signaling and also mitochondrial function are important effectors. Here, we review the action and function of six ankyrin repeat domain-containing Asb proteins in physiology and pathophysiology. PMID- 30446377 TI - High burdens of Ixodes scapularis larval ticks on white-tailed deer may limit Lyme disease risk in a low biodiversity setting. AB - An inverse relationship between biodiversity and human health has been termed the 'dilution effect' paradigm. In the case of tick-borne infections such as Lyme disease, the key assumption is that Borrelia burgdorferi sensu lato abundance is increased by the loss of less competent (dilution) hosts as biodiversity declines. White-tailed deer play a dual role in the pathogen cycle, as key reproductive hosts for adult ticks and incompetent hosts for the pathogen. While the role of deer as hosts of adult ticks is well established, the extent to which deer also feed immature ticks and reduce the proportion infected is unknown because of logistic constraints in measuring this empirically. We estimated the proportion of larvae that fed on deer in an extremely species-poor community on Block Island, RI, where tick nymphal infection prevalence was found to be lower than expected. In 2014, we measured the density, larval tick burdens, and realized reservoir competence of small mammal and bird hosts on Block Island, RI. In 2015, we measured the infection prevalence of host-seeking Ixodes scapularis nymphs resulting from larvae fed on available hosts in 2014. We back-estimated the proportion of larvae expected to have fed on deer in 2014 (the only unknown parameter) to result in the nymphal infection prevalence observed in 2015. Back estimation predicted that 29% of larval ticks must have fed on deer to yield the observed 30% nymphal infection prevalence. In comparison, the proportion of larvae feeding on mice was 44% and 27% on birds. Our study identified an influential role of deer in reducing nymphal tick infection prevalence and a potential role as dilution hosts if the reduction in nymphal infection prevalence outweighs the role of deer as tick population amplifiers. Because both deer and competent hosts may increase in anthropogenic, fragmented habitats, the links between fragmentation, biodiversity, and Lyme disease risk may be complex and difficult to predict. Furthermore, a nonlinear relationship between deer abundance and Lyme disease risk would reduce the efficacy of deer population reduction efforts to control Lyme disease. PMID- 30446378 TI - Hepatocellular carcinoma in Gaucher disease: Reinforcing the proposed guidelines. PMID- 30446379 TI - Phytochemical analysis of Pathyashadangam kwath and its standardization by HPLC and HPTLC. AB - BACKGROUND: Pathyashadangam kwath, a classical ayurvedic polyherbal formulation is used for the treatment of cluster head ache, migraine, upper respiratory diseases, ear ache and night blindness. Review of literature suggested that characterization parameters of Pathyashadangam kwath are not reported. OBJECTIVE: To report characteristic parameters of Pathyashadangam kwath to confirm quality and purity. MATERIALS AND METHODS: The fruit pericarps of Haritaki, Bibhitaki and Amalaki, aerial parts of Bhunimba, rhizome of Haridra, stem bark of Nimba and stem of Guduchi were the ingredients of Pathyashadangam kwath. Three batches of the kwath were prepared as per standard procedures. The kwath was evaluated for organoleptic, physical, phytochemical and chromatographic parameters as per standard methods. RESULTS: HPTLC analysis revealed that Toluene: Ethyl Acetate: Formic acid (2.5: 2.0: 0.5) was a suitable mobile phase for characterization of the kwath. HPLC analysis revealed that andrographolide was a suitable marker for standardization of the kwath. CONCLUSION: The characterization parameters presented in this paper may serve as standard reference for quality control analysis of Pathyashadangam kwath. PMID- 30446380 TI - How do aging and comorbidities impact risk of ischemic stroke in patients with atrial fibrillation. AB - Stroke is a notorious complication in patients with atrial fibrillation (AF) and risk stratification is pivotal for stroke prevention strategy. The risk of AF related stroke is a mixture of complex interaction between increasing age and important comorbidities. Therefore, this article aims to provide a comprehensive review on these important risk factors of stroke in AF patients, mainly focusing on the component of CHA2DS2-VASc score, as well as some other potential risk factors. PMID- 30446381 TI - Introduction. PMID- 30446382 TI - The Role of Survivorship Care for Patients with Glioma. AB - OBJECTIVES: To discuss the role of survivorship care and survivorship care plans, including a recently developed neuro-oncology-specific plan care (https://www.soc neuro-onc.org/SNO/Resources/Survivorship_Care_Plan.aspx) for adult patients diagnosed with primary glial neoplasms and the necessary educational needs of oncology nurses. DATA SOURCES: Published peer-reviewed literature and resources from cancer and neuro-oncology professional organizations and patient advocacy organizations. CONCLUSION: The current Commission on Cancer mandates adult cancer patients treated with curative intent each receive an individualized survivorship care plan. Patients with glioma are likely to benefit from receiving survivorship care, including survivorship care plans aimed at addressing the complex and evolving needs of this unique patient population throughout their illness trajectory. IMPLICATIONS FOR NURSING PRACTICE: Nurse professionals are critical to the development and implementation of cancer survivorship care. This growing leadership role presents oncology nurses with specific and new educational needs regarding survivorship care. PMID- 30446383 TI - RAS P21 Protein Activator 3 (RASA3) Specifically Promotes Pathogenic T Helper 17 Cell Generation by Repressing T-Helper-2-Cell-Biased Programs. AB - Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases. PMID- 30446385 TI - Microbiota-Derived Lactate Activates Production of Reactive Oxygen Species by the Intestinal NADPH Oxidase Nox and Shortens Drosophila Lifespan. AB - Commensal microbes colonize the gut epithelia of virtually all animals and provide several benefits to their hosts. Changes in commensal populations can lead to dysbiosis, which is associated with numerous pathologies and decreased lifespan. Peptidoglycan recognition proteins (PGRPs) are important regulators of the commensal microbiota and intestinal homeostasis. Here, we found that a null mutation in Drosophila PGRP-SD was associated with overgrowth of Lactobacillus plantarum in the fly gut and a shortened lifespan. L. plantarum-derived lactic acid triggered the activation of the intestinal NADPH oxidase Nox and the generation of reactive oxygen species (ROS). In turn, ROS production promoted intestinal damage, increased proliferation of intestinal stem cells, and dysplasia. Nox-mediated ROS production required lactate oxidation by the host intestinal lactate dehydrogenase, revealing a host-commensal metabolic crosstalk that is probably broadly conserved. Our findings outline a mechanism whereby host immune dysfunction leads to commensal dysbiosis that in turn promotes age-related pathologies. PMID- 30446384 TI - Aryl Hydrocarbon Receptor Signaling Cell Intrinsically Inhibits Intestinal Group 2 Innate Lymphoid Cell Function. AB - Innate lymphoid cells (ILCs) are important for mucosal immunity. The intestine harbors all ILC subsets, but how these cells are balanced to achieve immune homeostasis and mount appropriate responses during infection remains elusive. Here, we show that aryl hydrocarbon receptor (Ahr) expression in the gut regulates ILC balance. Among ILCs, Ahr is most highly expressed by gut ILC2s and controls chromatin accessibility at the Ahr locus via positive feedback. Ahr signaling suppresses Gfi1 transcription-factor-mediated expression of the interleukin-33 (IL-33) receptor ST2 in ILC2s and expression of ILC2 effector molecules IL-5, IL-13, and amphiregulin in a cell-intrinsic manner. Ablation of Ahr enhances anti-helminth immunity in the gut, whereas genetic or pharmacological activation of Ahr suppresses ILC2 function but enhances ILC3 maintenance to protect the host from Citrobacter rodentium infection. Thus, the host regulates the gut ILC2-ILC3 balance by engaging the Ahr pathway to mount appropriate immunity against various pathogens. PMID- 30446386 TI - Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function. AB - The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4 1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcgammaR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcgammaR-dependent Treg cell depleting capacity and FcgammaR-independent agonism delivered enhanced anti tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic. PMID- 30446387 TI - The Microbial Metabolite Butyrate Stimulates Bone Formation via T Regulatory Cell Mediated Regulation of WNT10B Expression. AB - Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRbeta-/- mice with CD8+ T cells from Wnt10b-/- mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell mediated regulation of CD8+ T cell Wnt10b production. PMID- 30446389 TI - Subcutaneous phaeohyphomycosis caused by Amesia atrobrunnea in Kuwait. AB - The recently described genus Amesia encompasses four species but only Amesia atrobrunnea (=Chaetomium atrobrunneum) is known to be pathogenic to humans. Here, we describe a case of subcutaneous phaeohyphomycosis in Kuwait in an apparently immunocompetent patient diagnosed by direct microscopy of the infected tissue and culture. The identity of A. atrobrunnea was established by typical morphological characteristics and by sequencing of internally transcribed spacer (ITS) region and D1/D2 domains of rDNA. To the best of our knowledge, this is the first report documenting etiologic role of this species in causing a locally invasive subcutaneous infection. PMID- 30446388 TI - Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis. AB - Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine "depot" in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources. PMID- 30446390 TI - Murine model of invasive pulmonary Aspergillosis: Follow-up of tissue injury, fungal burden and mortality with distinct elastase production strains. AB - To study invasive pulmonary Aspergillosis (IPA), we depleted neutrophils in mice using the monoclonal antibody anti-Gr-1/Ly-6G. Immunocompetent and neutropenic mice were infected via intratracheal with conidia of Aspergillus fumigatus clinical isolates, characterized as either higher or lower elastase producers. Neutropenic animals exhibited 100% mortality in 5 days, for both strains, and were observed survival curves overlapped, lungs with angioinvasion, rupture of bronchial and vascular walls, associated with exuberance of conidia filamentation. The immunocompetent animals infected with the lower elastase producer strain presented with upregulated inflammatory processes, and a lack of conidia filamentation in the tissue. The fungal burden in the lungs was not different in the immunocompetent and neutropenic groups. These findings confirm the protective role of neutrophils against A. fumigatus and suggest that the fungal elastinolytic activity is not a critical virulence factor but may be involved in tissue injury. PMID- 30446391 TI - A Stem Cell-Based Screening Platform Identifies Compounds that Desensitize Motor Neurons to Endoplasmic Reticulum Stress. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease selectively targeting motor neurons in the brain and spinal cord. The reasons for differential motor neuron susceptibility remain elusive. We developed a stem cell based motor neuron assay to study cell-autonomous mechanisms causing motor neuron degeneration, with implications for ALS. A small-molecule screen identified cyclopiazonic acid (CPA) as a stressor to which stem cell-derived motor neurons were more sensitive than interneurons. CPA induced endoplasmic reticulum stress and the unfolded protein response. Furthermore, CPA resulted in an accelerated degeneration of motor neurons expressing human superoxide dismutase 1 (hSOD1) carrying the ALS-causing G93A mutation, compared to motor neurons expressing wild type hSOD1. A secondary screen identified compounds that alleviated CPA-mediated motor neuron degeneration: three kinase inhibitors and tauroursodeoxycholic acid (TUDCA), a bile acid derivative. The neuroprotective effects of these compounds were validated in human stem cell-derived motor neurons carrying a mutated SOD1 allele (hSOD1A4V). Moreover, we found that the administration of TUDCA in an hSOD1G93A mouse model of ALS reduced muscle denervation. Jointly, these results provide insights into the mechanisms contributing to the preferential susceptibility of ALS motor neurons, and they demonstrate the utility of stem cell-derived motor neurons for the discovery of new neuroprotective compounds. PMID- 30446392 TI - Early first episode of pouchitis after ileal pouch-anal anastomosis for pediatric ulcerative colitis is a risk factor for development of chronic pouchitis. AB - BACKGROUND: The predictive factors for chronic pouchitis after ileal pouch-anal anastomosis (IPAA) in pediatric-onset ulcerative colitis (UC) remain unclear. This study evaluated the predictive factors for chronic pouchitis after IPAA in patients with pediatric UC. METHODS: The data from 52 patients with pediatric onset UC who underwent IPAA in Mie University Hospital were retrospectively reviewed. The endoscopy surveillance was performed yearly or at the timing of the symptom. Chronic pouchitis was defined as antibiotic-dependent/-refractory and relapsing cases. Potential predictors of chronic pouchitis were analyzed. RESULTS: During the first 5 years after IPAA, pouchitis was identified in 32.7%. Of these patients, 12 (70.6%) developed chronic pouchitis. The predictor of chronic pouchitis was a preoperative history of immunomodulator use before IPAA (p = 0.04). Life table analysis revealed that patients with chronic pouchitis tended to develop pouchitis earlier after IPAA than did patients without chronic pouchitis (p = 0.012). Receiver operating characteristic curve analysis showed that the occurrence of pouchitis within 15 months after IPAA surgery predicted the development of chronic pouchitis (sensitivity, 92%; specificity, 80%). CONCLUSION: In pediatric patients with UC, the predictive factors for chronic pouchitis are immunomodulator use and early occurrence of the first episode of pouchitis within 15 months after IPAA. LEVEL OF EVIDENCE: III. PMID- 30446393 TI - Children after motor vehicle crashes: Restraint utilization and injury severity. AB - BACKGROUND: Although injury patterns after motor vehicle crashes (MVCs) are well documented, association between adequate restraint and injury severity is unclear. We aimed to determine if improper restraint affects injury rates and severity. METHODS: A retrospective chart review of 477 children hospitalized in Pediatric Trauma Center after MVC was performed. Injuries in various age groups (0-7, 8-12, 13-16, 17-18 years) with different restraint quality measures (proper [PR] and improper/unrestrained [IUR]) as well as injury severity score (ISS: mild [1-9], moderate [10-15], severe [16-25], and profound [>25]) were evaluated and compared. Chi-square and Wilcoxon rank-sum tests were used for statistics. RESULTS: In all age groups head/neck injuries were most common (55-63%), while abdominal and pelvic injuries were least likely except group 8-12 years where abdominal injuries ranked third (17.1%). Overall, 64.5% had PR and 35.5% IUR. Interestingly, that greatest proportion of IUR was in the youngest age group (0 7). It decreased with aging and children aged 17-18 years were significantly less likely to be IUR compared to those 0-7 years (OR[odds ratio] = 0.58; 95%CI[confidence interval] 0.35-0.94). We did not find significant differences in rates of various injuries between PR and IUR. However, ISS severity in IUR was significantly greater than in PR (median with interquartile range 6(2-14) and 5(1 9), respectively; P = 0.001). As a result, IUR compared to PR were less likely to have mild ISS (OR = 0.6, 95%CI 0.39-0.90) but more likely to have profound ISS (OR = 3.3, 95%CI 1.48-7.43). CONCLUSION: Restraint quality has significant impact on injury severity in children after MVC. LEVEL OF EVIDENCE: Level III. PMID- 30446394 TI - Integrated Mosquito Management: Is Precision Control a Luxury or Necessity? AB - The versatility of mosquito species that spread emerging arthropod-borne viruses such as Zika has highlighted the urgent need to re-evaluate mosquito-control standards. The prospect of using precise knowledge of the geographic distribution and vector status of local populations to guide targeted interventions has gained renewed attention, but the feasibility and utility of such an approach remain to be investigated. Using the example of mosquito management in the USA, we present ideas for designing, monitoring, and assessing precision vector control tailored to different environmental and epidemiological settings. We emphasize the technical adjustments that could be implemented in mosquito-control districts to enable targeted control while strengthening traditional management. PMID- 30446395 TI - Regional disparity in outcomes among patients hospitalized for Takotsubo cardiomyopathy in the United States?. AB - INTRODUCTION: Takotsubo cardiomyopathy (TTCM), an entity first described in Japan over two decades ago following myocardial stunning cases without evidence of coronary stenosis, has emerged as a unique entity with global recognition. We sought to investigate the extent and magnitude of regional variations in its outcomes. METHOD: We used the National Inpatient Sample (NIS) of the Agency for Healthcare Research and Quality (2010-2014). Risk-adjusted rates of outcomes across the US geographical regions were calculated by fitting a Poisson regression model with a robust error variance under generalized estimating equations. Discrete numeric variables with over-dispersed count distributions length of stay and continuous variables with a right skewed spread- cost of hospitalization were modeled using a generalized linear regression with a negative binomial function and gamma function respectively. RESULT: We found significant regional variations in-patient mortality. While there was significantly higher risk of in-hospital death in the West (5.28 [4.34-6.44]) vs 4.40 [3.57-5.43] vs 4.10 [3.38-498] vs 4.78 [3.96-5.77]), there was a different pattern of variation in the length of days with longer hospital stay in the Northeast. Likewise, the risk-adjusted rate of non-routine home discharges was highest for Northeast. The West had the highest cost of hospitalization (West: $40,217 vs. South: $28,465) CONCLUSION: Significant geographic variation exists in the cost of hospitalization and in-hospital mortality of TTCM across the US. Understanding this variation requires a detailed understanding of the processes of care and identification of effective strategies to eliminate these disparities. PMID- 30446397 TI - Role of the Medical Physicist in the Health Care Artificial Intelligence Revolution. PMID- 30446396 TI - The Resident Preliminary Report. PMID- 30446398 TI - Drug-eluting versus bare-metal stents in older patients: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Despite the high prevalence of ischemic heart disease in older patients, there is a substantial lack of evidence to guide clinical decision making in this population. Hence, we performed a meta-analysis to determine the safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stents (DES) versus bare-metal stents (BMS). METHODS: Electronic databases were searched for randomized trials comparing DES with BMS in patients >=70 years-old. The primary outcome was major adverse cardiovascular events (MACE). Secondary outcomes included different ischemic and bleeding events. Subgroup analyses for dual-antiplatelet therapy (DAPT) duration were conducted. RESULTS: We included 7 trials with a total of 5449 patients. The use of DES compared with BMS was associated with a significant reduction in MACE (odds ratio [OR]:0.76; 95% confidence interval [CI]:0.62-0.93; P = 0.007) with no increased risk of bleeding events (OR: 1.07; 95% CI: 0.89-1.27; P = 0.48). However, longer duration of DAPT (>6 months) for the DES group increased bleeding events (OR: 1.52; 95% CI: 1.05 2.20; P = 0.03). In contrast, shorter DAPT showed persistent efficacy in reducing MACE in DES-treated patients with no increased bleeding events (OR: 0.72; 95% CI: 0.60-0.87; P < 0.01 and OR: 1.01; 95% CI: 0.84-1.22; P = 0.89, respectively). CONCLUSIONS: In older patients who had undergone PCI, DES showed superior efficacy in reducing MACE with no increased risk of bleeding compared with BMS. Persistent MACE reduction was evident with shorter DAPT durations in DES-treated patients. SUMMARY: This meta-analysis of randomized clinical trials demonstrated that drug-eluting stents were associated with a significant reduction in major adverse cardiovascular events with no increased risk of bleeding compared with bare-metal stents. The risk of bleeding was high with longer dual antiplatelet therapy duration for patients who underwent DES placement. However, short duration of dual antiplatelet therapy substantially reduced major adverse cardiovascular events with no increased bleeding risk. PMID- 30446399 TI - Plasma epinephrine levels and its causal link to takotsubo syndrome revisited: Critical review with a diverse conclusion. AB - Takotsubo syndrome (TS) is a recognized acute cardiac syndrome with a clinical presentation resembling that of an acute coronary syndrome (ACS). The defining feature of TS is the reversible left ventricular wall motion abnormality (LVWMA), which has a unique circumferential pattern resulting in a conspicuous ballooning of the left ventricle during systole, and extending beyond the coronary artery supply territory. The pathogenesis of TS is still elusive and several pathophysiological mechanisms have been proposed. A common portrayal of the syndrome in the literature is that the disease is characterized by massive surge of plasma catecholamines including epinephrine. Based on the assumption of massive plasma epinephrine elevation, some investigators hypothesized that the circulatory plasma epinephrine plays a pivotal role in the pathogenesis of TS. One typical such hypothesis is epinephrine induced switch in signal trafficking causing apical or mid-apical ballooning in TS. In-depth analysis of the literature reveals that no study with certainty has shown "massive" plasma epinephrine elevations in TS. Furthermore, the literature evidences challenging the epinephrine-induced switch in signal trafficking are substantial. In this review, sufficient data, indicating that the plasma epinephrine in TS is either normal or moderately elevated in all studies, are provided. Noteworthy, epinephrine may act as a trigger factor for TS-induction but there is no evidence for a direct causal link between epinephrine and TS. PMID- 30446400 TI - Outcomes in Organ Transplant Recipients With Prostate Cancer Treated With Radiotherapy. AB - BACKGROUND: Few data exist in the literature regarding outcomes of men with prostate cancer (CaP) who are receiving immunosuppression from prior organ transplantation. The aim of this study was to evaluate biochemical disease-free survival, distant metastasis-free survival, overall survival, and toxicity in patients with organ transplants who were later treated with definitive radiotherapy for CaP. PATIENTS AND METHODS: Our institutional CaP registry was reviewed to identify patients who had undergone an organ transplantation before CaP diagnosis. Between 1999 and 2013, a total of 28 organ transplant recipients treated with definitive radiotherapy for CaP were identified. Treatment consisted of either I-125 low-dose-rate brachytherapy or external-beam radiotherapy. All patients were receiving immunosuppressive medications. RESULTS: The median age was 66 years. Median follow-up time was 30 months. Twenty-four patients (86%) were treated with brachytherapy, and 4 patients (14%) were treated with external beam radiotherapy. Nine patients (32%) had low-risk CaP, 14 (50%) had intermediate-risk CaP, and 5 (18%) had high-risk CaP. At the time of last follow up, 2 patients had died, 1 from metastatic CaP and 1 from other causes. The 3 year biochemical disease-free survival was 95.8%. The 3-year distant metastasis free survival was 93.1%. The 3-year overall survival was 93.8%. One patient developed grade 3 late gastrointestinal toxicity. CONCLUSION: This represents one of the largest reported series of outcomes in patients with organ transplantation and CaP. Organ transplant recipients treated with prostate radiotherapy have excellent 3-year outcomes. PMID- 30446401 TI - Prevalence and pathophysiology of early dumping in patients after primary Roux-en Y gastric bypass during a mixed-meal tolerance test. AB - BACKGROUND: Early dumping is a poorly defined and incompletely understood complication after Roux-en-Y gastric (RYGB). OBJECTIVE: We performed a mixed-meal tolerance test in patients after RYGB to address the prevalence of early dumping and to gain further insight into its pathophysiology. SETTING: The study was conducted in a regional hospital in the northern part of the Netherlands. METHODS: From a random sample of patients who underwent primary RYGB between 2008 and 2011, 46 patients completed the mixed-meal tolerance test. The dumping severity score for early dumping was assessed every 30 minutes. A sum score at 30 or 60 minutes of >=5 and an incremental score of >=3 points were defined as indicating a high suspicion of early dumping. Blood samples were collected at baseline, every 10 minutes during the first half hour, and at 60 minutes after the start. RESULTS: The prevalence of a high suspicion of early dumping was 26%. No differences were seen for absolute hematocrit value, inactive glucagon-like peptide-1, and vasoactive intestinal peptide between patients with or without early dumping. Patients at high suspicion of early dumping had higher levels of active glucagon-like peptide-1 and peptide YY. CONCLUSION: The prevalence of complaints at high suspicion of early dumping in a random population of patients after RYGB is 26% in response to a mixed-meal tolerance test. Postprandial increases in both glucagon-like peptide-1 and peptide YY are associated with symptoms of early dumping, suggesting gut L-cell overactivity in this syndrome. PMID- 30446402 TI - The Effect of Heating to Intracanal Temperature on the Stability of Sodium Hypochlorite Admixed with Etidronate or EDTA for Continuous Chelation. AB - INTRODUCTION: Tetrasodium etidronate (Na4 etidronate) and tetrasodium EDTA (Na4 EDTA) are chelators that can combine with sodium hypochlorite (NaOCl) as a 1-mix endodontic irrigant in a process called continuous chelation. The therapeutic window of these mixtures is determined by the chemical reaction between NaOCl and the chelator. At room temperature, this window is 60 minutes for Na4 etidronate and 30 minutes for Na4 EDTA. Because reaction kinetics are influenced by heat, this study assesses the influence of heating to an intracanal temperature of 35 degrees C on the therapeutic window in continuous chelation. METHODS: The loss of free available chlorine (FAC) in NaOCl mixtures with Na4 etidronate or Na4EDTA was determined by iodometric titration at 23 degrees C +/- 0.7 degrees C (23 degrees C) and 34.6 degrees C +/- 0.3 degrees C (35 degrees C) at 1, 20, 40, and 60 minutes after mixing. The pH and temperature of the mixtures were measured. RESULTS: At 23 degrees C, 18% Na4 etidronate/5% NaOCl solutions at 20, 40, and 60 minutes lost 4%, 9% and 18% FAC, and at 35 degrees C, they lost 20%, 68% and 92% FAC; 5% Na4 EDTA/2.5% NaOCl solutions at 20, 40, and 60 minutes at 23 degrees C lost 88%, 94%, and 97% FAC, and at 35 degrees C, they lost 96%, 99%, and 100%. Decreases in FAC were accompanied by pH declines. CONCLUSIONS: The effect of heating to 35 degrees C from a room temperature of 23 degrees C on 18% Na4 etidronate/5% NaOCl solutions reduces its therapeutic window to 20 minutes. Solutions of 5% Na4 EDTA/2.5% NaOCl are not useful in the continuous chelation technique. Tracking pH changes could be used to estimate NaOCl degradation. PMID- 30446403 TI - Efficacy of Autologous Platelet Concentrates in Regenerative Endodontic Treatment: A Systematic Review of Human Studies. AB - INTRODUCTION: The latest research concerns the use of platelet concentrates, which are introduced into the root canal. The aim of this study was to examine the effectiveness of platelet-rich fibrin and platelet-rich plasma in regenerative endodontics. METHODS: This literature review was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The literature search included all publications without a year limit. The last search was performed on January 31, 2018. An electronic search was performed using MEDLINE (PubMed), Cochrane, and Scopus. Articles were selected that addressed the following research question: Is the use of platelet concentrates effective in regenerative endodontics? The necessary information was extracted by 2 authors independently using a standardized form. RESULTS: The search resulted in 426 titles from all databases, and 26 studies met the inclusion criteria. Five were randomized trials, and the others were case reports. All described cases were asymptomatic. Only 3 cases from randomized trials were unsuccessful. Ten of the case reports found positive results for pulp vitality. In randomized trials, the teeth treated with platelet concentrates showed better results for pulp vitality. In almost all cases, they also described thickening and lengthening of the root wall and closure of the apical foramen, which are important for successful treatment of permanent teeth. CONCLUSIONS: This review showed that procedures using autologous platelet concentrates were successful in treating permanent teeth with root development. However, more long term clinical studies are needed. PMID- 30446404 TI - Ludwig Angina after First Aid Treatment: Possible Etiologies and Prevention-Case Report. AB - Ludwig angina is a life-threatening type of soft tissue cellulitis involving 3 compartments on the floor of the mouth including the submental, sublingual, and submandibular spaces bilaterally. Prevention, early recognition, and treatment of Ludwig angina are critical because this is a clinical diagnosis with unpredictable progression. This article describes a rare case of Ludwig angina that evolved from an odontogenic infection and the specific microbiology and clinical course and discusses possible etiologies and prevention. PMID- 30446405 TI - Root Canal Shaping Using Nickel Titanium, M-Wire, and Gold Wire: A Micro-computed Tomographic Comparative Study of One Shape, ProTaper Next, and WaveOne Gold Instruments in Maxillary First Molars. AB - INTRODUCTION: The aim of this study was to evaluate the root canal shaping effect of instruments manufactured from nickel titanium, M-Wire, and Gold wire with different glide path preparation techniques. METHODS: One hundred thirty-five mesiobuccal canals of extracted human maxillary molars were randomly divided into 3 equal groups (N = 45) for glide path preparation with K-files (KF) (Dentsply Sirona, Ballaigues, Switzerland), One G (OG) files (Micro-Mega, Besancon, France), and ProGlider (PG) files (Dentsply Sirona). Specimens of each glide path group were further divided equally into 3 groups for instrumentation with ProTaper Next (PTN, Dentsply Sirona), One Shape (OS, Micro-Mega), and WaveOne Gold (WOG, Dentsply Sirona) systems (n = 15). Micro-computed tomographic imaging was used to scan teeth before instrumentation and after shaping to compare centering ratio and canal transportation values at the apical, midroot, and coronal levels and the overall changes in canal volume. Data sets were statistically analyzed (analysis of variance and Kruskal-Wallis H tests). RESULTS: The centering ratios for all groups were statistically similar at all levels. Apical canal transportation was significantly high for K/OS and K/PTN (P = .003). Midroot canal transportation was significantly high for K/PTN, K/OS, and OG/OS (P = .0003). Coronal canal transportation was significantly high for K/PTN and K/OS (P = .011). The highest change in canal volume was observed with all PTN groups and the lowest with PG/WOG (P = .06). CONCLUSIONS: WOG manufactured from Gold wire combined with PG showed better root canal shaping ability and removed less dentin from the canal walls. The nickel-titanium (OS) and M-Wire (PTN) instruments used in combination with KF significantly transported more canals. PTN removed the most dentin from the canal walls regardless of the GPP technique. PMID- 30446406 TI - Pneumonectomy in Stage IIIA-N2 NSCLC: Should It Be Considered After Neoadjuvant Chemotherapy? AB - BACKGROUND: Owing to the expected poor long-term outcomes and high postoperative morbidity and mortality, patients with stage IIIA-N2 tumors candidate to pneumonectomy (PN) are usually excluded from surgery. This study aims to analyze the outcome of patients who underwent PN to prove its safety and feasibility. PATIENTS AND METHODS: We retrospectively analyzed data from 233 patients who underwent PN for N2 non-small-cell lung cancer (NSCLC) between 1998 and 2015. Eighty-five patients were occult N2 disease (group 1), whereas 148 patients underwent induction therapy (IT) for stage IIIA-N2 (group 2). RESULTS: Overall morbidity, postoperative mortality, and 90-day mortality rates were 46.8%, 2.6%, and 8.6%, respectively. The 2 groups (group 1 vs. 2) had similar postoperative and 90-day mortality rates: 2.4% versus 2.7% (P = 1.00), and 9.4% versus 8.1% (P = .81), respectively. The incidence of major morbidity was higher and statistically significant in group 2 compared with group 1: 23% versus 12.9% (P = .1). Postoperative bronchopleural fistula occurred in 4.7% (4/85) of patients with occult N2 (group 1) and in 10.1% (15/148) of patients undergoing IT (group 2) (P = .10). Median overall survival (OS) was 2.2 years, with a 3 and 5-year OS of 43.4% and 31.6%, respectively. Disease-free survival (DFS) was 1.5 years, with 3 and 5-year DFS of 41.6% and 32%, respectively; no difference in OS and DFS between the 2 groups was found. CONCLUSIONS: Considering the acceptable morbidity and mortality rate and the long-term survival, PN should not be excluded for selected patients with stage IIIA-N2 NSCLC as a matter of principle. PMID- 30446407 TI - Clinical pharmacokinetics of pramipexole, ropinirole and rotigotine in patients with Parkinson's disease. AB - INTRODUCTION: Pramipexole (PRA), ropinirole (ROP) and rotigotine (ROT) are non ergoline dopaminergic agonists (DAs) used to treat Parkinson's disease (PD). Clinical pharmacokinetics of DAs is poorly characterized in PD. The main purpose of our study was to investigate the effect of dose, age and sex on steady-state plasma concentrations of DAs in real life PD patients on chronic DAs therapy. METHODS: The study was single center, open and prospective. Blood samples for measurement of DAs plasma concentrations were drawn in the morning, at a median 18-h distance from the last DA dose. RESULTS: Ninety-one patients treated with PRA, 50 with ROP and 37 with ROT were enrolled in the study. Plasma concentration of DAs significantly correlated with weight-adjusted daily dose in all subgroups, although at a given dose, matched plasma concentrations highly varied among patients. Median PRA plasma concentration-to-daily dose ratio (C/D) [(ng/mL)/(mg/kg/d)] was 68% higher in patients >65 years than <=65 years (158 vs 94, p < 0.001), while was not affected by age in ROP and ROT subgroups. No sex mediated differences in C/D ratios were observed in any group. CONCLUSION: These are the first observations on DAs pharmacokinetics in PD patients' everyday clinical practice. Of relevance, patients over 65yrs may require about one third of PRA dose compared to under 65yrs to achieve the same plasma concentration. Due to the high intersubject variability in plasma concentrations at the same dosage, we speculate that monitoring of plasma DAs might be helpful in the individualization of treatment in selected patients. PMID- 30446408 TI - Grow Smart and Die Young: Why Did Cephalopods Evolve Intelligence? AB - Intelligence in large-brained vertebrates might have evolved through independent, yet similar processes based on comparable socioecological pressures and slow life histories. This convergent evolutionary route, however, cannot explain why cephalopods developed large brains and flexible behavioural repertoires: cephalopods have fast life histories and live in simple social environments. Here, we suggest that the loss of the external shell in cephalopods (i) caused a dramatic increase in predatory pressure, which in turn prevented the emergence of slow life histories, and (ii) allowed the exploitation of novel challenging niches, thus favouring the emergence of intelligence. By highlighting convergent and divergent aspects between cephalopods and large-brained vertebrates we illustrate how the evolution of intelligence might not be constrained to a single evolutionary route. PMID- 30446409 TI - Uniting Discoveries of Abundance-Size Distributions from Soils and Seas. AB - Science is a search for patterns but there are few cross-habitat patterns in ecology. We propose key questions following the findings of consistent scaling of abundance versus body mass from bacteria to earthworms and whales, based on an almost forgotten study of soils and a well-known one from the open ocean. PMID- 30446410 TI - Complete assessment of occlusal dynamics and establishment of a digital workflow by using target tracking with a three-dimensional facial scanner. AB - PURPOSE: To introduce a new and simple digital workflow to record dynamic occlusion, and apply it to occlusal analysis and prosthetic treatment in a virtual environment. METHODS: A table-top scanner (Identica hybrid) was used to transfer fabricated casts into a virtual environment. A facial scanner (Rexcan CS2) was used for facial scanning and target tracking. Four targets were attached to each of the four incisors in the maxilla and mandible to track jaw movement. Target position data were recorded in real time during eccentric movement. The targets were replaced with maxilla and mandible cast scan data, and mandibular movement relative to the maxilla was reconstructed. Four types of antagonist meshes were reconstructed in computer-aided design (CAD) software (EzScan8). The CAD software (Exocad) enabled checking of occlusal contacts in the maximal intercuspation position during eccentric movement. CONCLUSIONS: Target tracking data were transformed into video clips of dental cast scan data, which showed jaw movements in real time. Occlusal contact information was produced by the CAD software. Both dynamic and static occlusion analyses were performed with reconstructed eccentric movement antagonist meshes. Our new method for reconstructing eccentric movements of the mandible can reveal the occlusal dynamics of a patient within a virtual environment. PMID- 30446411 TI - Effect of veneering materials on fracture loads of implant-supported zirconia molar fixed dental prostheses. AB - PURPOSE: To determine the effect of veneering material and framework design on fracture loads of implant-supported zirconia molar fixed dental prostheses (FDPs). METHODS: Sixty-six zirconia FDPs were manufactured onto two implants and classified as uniform thickness (UT) or anatomic design (AD). These framework design groups were then further divided into three subgroups (n=11): feldspathic porcelain-veneered zirconia FDPs (PVZ), indirect composite-veneered zirconia FDPs (IVZ), and metal-ceramic FDPs (MC). The FDPs were luted on the implant abutments and underwent fracture load testing. Significant differences were assessed by the Kruskal-Wallis test and Mann-Whitney U-test (alpha=0.05). RESULTS: For UT group, median fracture load was significantly higher for the IVZ (1.87kN) and MC (1.90kN) specimens than for the PVZ specimens (1.38kN) (p<0.05). In the AD group, the IVZ specimens had the highest median fracture load (4.10kN) of the three groups tested. The AD group exhibited higher median fracture loads than the UT group in all subgroups. CONCLUSIONS: Indirect composite appears to be a useful alternative to feldspathic porcelain as the layering material for implant supported zirconia FDPs. The AD group had higher fracture loads than UT group. In addition, implant-supported indirect composite-veneered zirconia-based FDPs appear to be clinically feasible. PMID- 30446412 TI - Comparing the precision of reproducibility of computer-aided occlusal design to conventional methods. AB - PURPOSE: Reconstruction of patients' dental occlusion should be performed to fulfill esthetic and functional demands. These applied restorations should be in harmony with the existing occlusion and should not have any negative effects on intraoral dynamics. The aim of this clinical study is to compare the accuracy of the occlusal design shaped by conventional Wax Up methods and computer-aided design (CAD) regarding their similarity to the natural tooth morphology. METHODS: Impressions of 10 caries-free jaws were taken, and the resulting gypsum casts were scanned with a laboratory scanner. Preparations for all-ceramic full crowns were performed on second premolars and second molars. Occlusal design of 40, 3 member fixed partial dentures (FPD) were obtained with two different methods 10 FPD was designed with conventional wax up technique (Wax Up), 30 design was performed with CAD Dental wings open system (DWOS) software using three different anatomy libraries (Dental Wings (DW), Merz, Vita). The data of the bridges in the STereo-Lithography Interface Format (STL) was compared with the pre-cut data, which was regarded as a reference in terms of accuracy in the Atos so high end 3D digitizer. RESULTS: According to the results of Kruskal-Wallis test, there was no statistical difference between the Wax Up, Vita, Merz and Dental Wings groups (p>0.05) when compared to the natural teeth. The main difference between all four groups and natural surface was 550+/-130MUm. CONCLUSIONS: Occlusal design produced by conventional techniques and CAM DWOS system compared to natural tooth morphology showed no statistically significant difference. PMID- 30446413 TI - Arthroscopic reconstruction of the lateral ankle ligaments: Radiological evaluation and short-term clinical outcome. AB - PURPOSE: The purpose of this study was to describe the positioning of bone tunnels of arthroscopic anatomical reconstruction of lateral ankle ligaments (AAR LAL) and identify radiological measurements associated with short-term clinical outcome one year after surgery. MATERIALS AND METHODS: A total of 61 patients were included in this IRB-approved retrospective study. There were 52 men and 9 women, with a mean age of 36.3 +/- 10.8 (SD) years. AAR-LAL was performed to treat chronic instability secondary to strain sequelae after failure of conservative treatment. Good short-term clinical outcome was defined by Karlsson score>=80 (n=40) one year after surgery. Sixteen radiological measurements were studied to characterize the positionings of fibular, talar and calcaneal tunnels (FT, TT and CT, respectively). Feasibility and inter-observer agreement were calculated for each measurement. Receiver operating characteristic curves were used to identify optimal thresholds for measurements associated with outcome at univariate analysis. A binary logistic regression was used to identify independent predictors. RESULTS: Two measurements were associated with good outcome: distance from the proximal FT entrance to the distal end of the fibula on anteroposterior (AP) view (called 'AP distal FT', P=0.005), and the ratio between the distance from TT entrance to the talo-navicular joint and the talus length on lateral view (P=0.009). Optimal thresholds were of >35mm and<0.445, respectively. At multivariate anlysis, only 'AP distal FT'>35mm remained independent predictor of good outcome (P=0.002). CONCLUSION: Radiological evaluation of bone tunnels following AAR-LAL is feasible, reproducible, and helps predict short-term outcome after reconstruction of lateral ankle ligaments. PMID- 30446414 TI - Should we thrombolyse prior to endovascular treatment in acute stroke? AB - The superiority of endovascular treatment (EVT) in acute stroke due to large vessel occlusion has been proven in recent randomized trials. Yet, there are no randomized trials which have tested the additive effect of standard treatment with intravenous thrombolysis (IVT) as pretreatment to EVT over EVT treatment alone. So far, the EVT treatment groups of RCTs most often had pretreatment with IVT. The current guidelines on acute stroke treatment rely on meta-analyses and systematic analyses from RCTs and observational studies on pretreatment with IVT + EVT. Clinicians also apply their clinical experience and local "in-house" protocols. We performed literature search on randomized controlled trials, systematic and meta-analyses and observational studies on recanalization therapies including intravenous thrombolysis and endovascular treatment or thrombectomy in acute stroke. Here we present a review and an opinion on the current choice of treatment modalities. PMID- 30446415 TI - Letter to the editor regarding "Utility of CT angiography in screening for traumatic cerebrovascular injury". PMID- 30446416 TI - Disease burden and government spending on mental, neurological, and substance use disorders, and self-harm: cross-sectional, ecological study of health system response in the Americas. AB - BACKGROUND: Disorders affecting mental health are highly prevalent, can be disabling, and are associated with substantial premature mortality. Yet national health system responses are frequently under-resourced, inefficient, and ineffective, leading to an imbalance between disease burden and health expenditures. We estimated the disease burden in the Americas caused by disorders affecting mental health. This measure was adjusted to include mental, neurological, and behavioural disorders that are frequently not included in estimates of mental health burden. We propose a framework for assessing the imbalance between disease burden and health expenditures. METHODS: In this cross sectional, ecological study, we extracted disaggregated disease burden data from the Global Health Data Exchange to produce country-level estimates for the proportion of total disease burden attributable to mental disorders, neurological disorders, substance use disorders, and self-harm (MNSS) in the Americas. We collated data from the WHO Assessment Instrument for Mental Health Systems and the WHO Mental Health Atlas on country-level mental health spending as a proportion of total government health expenditures, and of psychiatric hospital spending as a proportion of mental health expenditures. We used a metric capturing the imbalance between disease burden and mental health expenditures, and modelled the association between this imbalance and real (ie, adjusted for purchasing power parity) gross domestic product (GDP). FINDINGS: Data were collected from July 1, 2017, to March 1, 2017. MNSS comprised 19% of total disability-adjusted life-years in the Americas in 2015. Median spending on mental health was 2.4% (IQR 1.3-4.1) of government health spending, and median allocation to psychiatric hospitals was 80% (52-92). This spending represented an imbalance in the ratio between disease burden and efficiently allocated spending, ranging from 3:1 in Canada and the USA to 435:1 in Haiti, with a median of 32:1 (12-170). Mental health expenditure as a proportion of government health spending was positively associated with real GDP (beta=0.68 [95% CI 0.24-1.13], p=0.0036), while the proportion allocated to psychiatric hospitals (beta=-0.5 [-0.79 to 0.22], p=0.0012) and the imbalance in efficiently allocated spending (beta=-1.38 [-1.97 to -0.78], p=0.0001) were both inversely associated with real GDP. All estimated coefficients were significantly different from zero at the 0.005 level. INTERPRETATION: A striking imbalance exists between government spending on mental health and the related disease burden in the Americas, which disproportionately affects low-income countries and is likely to result in undertreatment, increased avoidable disability and mortality, decreased national economic output, and increased household-level health spending. FUNDING: Weatherhead Center for International Affairs, Harvard University. PMID- 30446417 TI - Disparity between burden and budget for mental health. PMID- 30446418 TI - A retrospective study on surgical outcomes and patient satisfaction of EGIS(r) ADM in one-stage implant-based breast reconstruction. PMID- 30446419 TI - Neural network modelling of soft tissue deformation for surgical simulation. AB - This paper presents a new neural network methodology for modelling of soft tissue deformation for surgical simulation. The proposed methodology formulates soft tissue deformation and its dynamics as the neural propagation and dynamics of cellular neural networks for real-time, realistic, and stable simulation of soft tissue deformation. It develops two cellular neural network models; based on the bioelectric propagation of biological tissues and principles of continuum mechanics, one cellular neural network model is developed for propagation and distribution of mechanical load in soft tissues; based on non-rigid mechanics of motion in continuum mechanics, the other cellular neural network model is developed for governing model dynamics of soft tissue deformation. The proposed methodology not only has computational advantage due to the collective and simultaneous activities of neural cells to satisfy the real-time computational requirement of surgical simulation, but also it achieves physical realism of soft tissue deformation according to the bioelectric propagation manner of mechanical load via dynamic neural activities. Furthermore, the proposed methodology also provides stable model dynamics for soft tissue deformation via the nonlinear property of the cellular neural network. Interactive soft tissue deformation with haptic feedback is achieved via a haptic device. Simulations and experimental results show the proposed methodology exhibits the nonlinear force-displacement relationship and associated nonlinear deformation of soft tissues. Furthermore, not only isotropic and homogeneous but also anisotropic and heterogeneous materials can be modelled via a simple modification of electrical conductivity values of mass points. PMID- 30446420 TI - Do confidentiality concerns impact pre-exposure prophylaxis willingness in emergency department adolescents and young adults? PMID- 30446422 TI - Pharmacist documentation of gaps in care identified during diabetes coaching. AB - OBJECTIVES: 1) To identify the number of gaps, type of gaps, and contributing factors to gaps in diabetes care reported by pharmacists in the Diabetes Gaps in Care Portal (Gaps Portal). 2) To understand how pharmacists used the Gaps Portal and the implications for quality diabetes care. DESIGN: The Alliance for Patient Medication Safety developed an online Gaps Portal as a tool for pharmacists to identify and document gaps in care when managing patients with diabetes. SETTING: Pharmacists from across the United States in community pharmacy and ambulatory care settings who were engaged in diabetes coaching activities participated. MAIN OUTCOME MEASURES: Pharmacists entered gaps in diabetes care into the Gaps Portal from April 2016 to June 2017. Descriptive statistics were used to determine the type and number of gaps and contributing factors. A qualitative analysis of pharmacist interviews was conducted to identify themes related to pharmacist perceptions of the portal. RESULTS: Ten pharmacists entered 528 gaps in diabetes care (n = 469; 565 encounters). The most common category of gaps in diabetes care was drug therapy (n = 420/528; 79.6%). Of the drug therapy gaps reported, the most common gap occurred in patients with or at risk for atherosclerotic cardiovascular disease and not on a high-intensity statin (122/420), followed by those not on a moderate statin (106/420). Themes focused on during interviews included integration of diabetes coaching and documentation, impact of Gaps Portal on workflow, and prioritization of gaps. CONCLUSION: Pharmacists most commonly identified drug therapy gaps, predominantly pertaining to statin use, which coincides with a change in the guidelines for statin use in diabetics. Telephone interviews indicated that the Gaps Portal template served as a useful checklist to identify gaps in care during diabetes coaching activities and that the Gaps Portal was useful for reporting and monitoring purposes. PMID- 30446421 TI - The clinical practice of risk reduction for Alzheimer's disease: A precision medicine approach. AB - Like virtually all age-related chronic diseases, late-onset Alzheimer's disease (AD) develops over an extended preclinical period and is associated with modifiable lifestyle and environmental factors. We hypothesize that multimodal interventions that address many risk factors simultaneously and are individually tailored to patients may help reduce AD risk. We describe a novel clinical methodology used to evaluate and treat patients at two Alzheimer's Prevention Clinics. The framework applies evidence-based principles of clinical precision medicine to tailor individualized recommendations, follow patients longitudinally to continually refine the interventions, and evaluate N-of-1 effectiveness (trial registered at ClinicalTrials.gov NCT03687710). Prior preliminary results suggest that the clinical practice of AD risk reduction is feasible, with measurable improvements in cognition and biomarkers of AD risk. We propose using these early findings as a foundation to evaluate the comparative effectiveness of personalized risk management within an international network of clinician researchers in a cohort study possibly leading to a randomized controlled trial. PMID- 30446423 TI - Enhanced communication between inpatient and community pharmacists to optimize medication management during transitions of care. AB - OBJECTIVES: To describe the Pharmacy Communication Partnership (PROMPT) program's approach to improving medication management for patients during transitions from hospital to the community. SETTING: Two general internal medicine units within a multisite academic hospital in Canada. PRACTICE INNOVATION: Designed by an interprofessional working group, PROMPT uses evidence-informed approaches to facilitate communication between pharmacists in different settings: faxing of the discharge prescription and medical discharge summary to a patient's community pharmacy, followed by a telephone call to the community pharmacist. EVALUATION: A multimethod cross-sectional study used telephone surveys and retrospective chart reviews to describe: 1) the characteristics of patients that hospital pharmacists thought would benefit from PROMPT and the community pharmacies that served them; 2) the number and nature of communication attempts made by community and hospital pharmacists; and 3) community pharmacists' views about PROMPT's potential impact on continuity of care and potential program enhancements. RESULTS: A convenience sample of 100 patients (median age 77 years, interquartile range 66 to 83) who received care from 86 pharmacies were used to evaluate the program. The majority of community pharmacists participating in the surveys considered the intervention to be helpful. Of the 53.7% (n = 44/82) community pharmacists who received discharge summaries, 93.2% (n = 41/44) found the summaries to be useful. Themes arising from community pharmacists' comments were categorized into 3 topics: 1) the benefits of PROMPT; 2) topics of discussion and clarification during telephone calls with hospital pharmacists; and 3) future program improvements. CONCLUSION: Community pharmacists described PROMPT as a time-efficient and helpful bridge linking community pharmacy to hospital inpatient care. Opportunities for future research include determining the characteristics of patients who may benefit most from PROMPT, determining the optimal components of discharge information needed by community pharmacists to enhance medication management, and evaluating whether follow-up telephone calls from the hospital to community pharmacists are necessary for all patients. PMID- 30446424 TI - A comparison of aesthetic outcome between tissue adhesive and subcuticular suture in thyroidectomy wound closure in a multiracial country: A randomized controlled trial. AB - OBJECTIVES: Monofilament sutures, both absorbable and non-absorbable, have been used for wound closure. Tissue adhesive has been used in closure of clean, low tension wounds. However, there have been very few published studies on the aesthetic outcomes in neck surgeries. The aim of this study is to compare the patients' and doctors' satisfaction scores in the aesthetic outcome between both methods of closure of thyroidectomy wounds using validated scoring systems. METHODS: A double-blinded randomised controlled trial comparing the aesthetic outcome between tissue adhesive and conventional suture was conducted among patients undergoing thyroid and parathyroid surgeries. Ninety-six patients were randomised into two treatment groups. Patients' wounds were scored by an independent observer using the SBSES score at 6 weeks postoperatively and observer component of the POSAS score at 3 months. RESULTS: Forty-nine patients were randomised to the tissue adhesive group while forty-seven patients received the conventional method. There was no statistical difference in the aesthetic outcome using the patient's scoring system between both arms, with a median score of 9 (p = 0.25, SD +/- 6.5). The observer's satisfaction score using POSAS was also not statistically significant (median score of 14 (p = 0.77, SD +/- 6.2)). No significance was found in the observer's median score using the SBSES scoring system either (score 3, p = 0.12, SD +/- 1.3). However, there was significant reduction in the duration of closure using glue (4.42 mins vs 6.36 mins, p < 0.05). CONCLUSION: Tissue adhesive offers a comparable cosmetic result to the absorbable suture in thyroidectomy wound closure. PMID- 30446425 TI - Operative treatment of hepatic hydatid cysts: A single center experience. AB - BACKGROUND: Hydatid cyst is a zoonotic disease caused by Echinococcus genera. Surgery is needed in most cases. We aimed to describe our center's experience in the surgical management of hepatic hydated cysts (HHC). METHODS: Data was retrospectively collected for patients who underwent operative management for HHC between the years 1994-2014. RESULTS: Sixty-nine underwent surgical treatment for HHC. Group A included 34 treated with an unroofing procedure, group B included 24 patients who underwent hepatectomy and group C included 11 patients who underwent peri-cystectomy. The median +/- (range) age for groups A, B and C were 39.5 (6.5 69), 40 (17-74) and 32 (20-62), respectively (P > 0.1). Post-operative complications occurred in 16, 11 and 5 patients in group A, B and C, respectively, as assessed by clavien-dindo classification (CDC). The average CDC was significantly higher in the hepatectomy group as compared to the unroofing group (2.3 vs.1.5, P = 0.04). Recurrence was significantly higher after the unroofing procedure as compared to the hepatectomy group (P = 0.05). CONCLUSION: Surgery remains the mainstay of treatment for HHC, once surgery is pursued, the results are satisfactory. PMID- 30446426 TI - Longitudinal analysis of laparoendoscopic single-site adrenalectomy and conventional laparoscopic adrenalectomy regarding patient-reported satisfaction and cosmesis outcomes. AB - BACKGROUND/OBJECTIVE: To compare longitudinal patient-reported cosmesis of laparoendoscopic single-site adrenalectomy (LESS-A) to that of conventional laparoscopic adrenalectomy (CLA). METHODS: A total of 23, 15, and 9 patients underwent transumbilical LESS-A (TU-LESS), subcostal LESS-A (SC-LESS), and CLA, respectively. A questionnaire was administered asking the patient to assess wound pain (0: not painful to 10: very painful), satisfaction (0: not satisfied to 10: very satisfied), and cosmesis (0: very ugly to 10: very beautiful) on the basis of a visual analogue scale. We mailed questionnaires to all patients who received LESS-A and CLA at postoperative 1, 3, 6, 9, and 12 months. RESULTS: No significant differences were observed in the pain scores between TU-LESS, SC LESS, and CLA at every time point. In the CLA group, the cosmesis and satisfaction scores were significantly lower at postoperative 3 months (p = 0.0033, 0.0130). There were no significant inter-group differences in the cosmesis score between the three groups after postoperative 6 months. However, the satisfaction score of SC-LESS decreased after postoperative 3 months and was significantly lower at postoperative 9 and 12 months (p = 0.0333, 0.0160). The difference between the satisfaction scores of each procedure gradually increased after postoperative 6 months. CONCLUSION: This study is the first comprehensive longitudinal analysis of patient-reported satisfaction and cosmesis outcomes between LESS-A and CLA. The resulting data provide important insights into the improvement in satisfaction in patients who underwent TU-LESS. These findings can facilitate the treatment decision-making process for patients who are considering laparoscopic adrenalectomy. PMID- 30446427 TI - Family matters in diabetes care. PMID- 30446428 TI - Daily Patterns of Caffeine Intake and the Association of Intake with Multiple Sociodemographic and Lifestyle Factors in US Adults Based on the NHANES 2007-2012 Surveys. AB - BACKGROUND: Caffeine increases alertness when consumed in single servings of various products including coffee, tea, soft drinks, and energy drinks. Although not a nutrient, caffeine is consumed by 90% of the adult population in the United States. OBJECTIVE: This study examined the daily pattern of caffeine intake and its relationship to multiple demographic variables. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2007-2012 (adults aged 19+ years; n=16,173) were used to determine the time of day at which caffeine is consumed and demographic factors associated with intake. Regression analyses characterized factors associated with caffeine intake including sex, age, ethnicity, education, smoking status, physical activity, employment status, total work hours, alcohol, and energy intake. RESULTS: Mean adult per capita caffeine intake was 169+/-4 mg/d (mean+/-standard error). Most caffeine (70%) was consumed before noon, often at breakfast, and intake decreased progressively over the day, with little consumed after 9:00 pm. Intake was associated with age, ethnicity, smoking status, total calorie intake, and work hours (P<0.01) but not physical activity, economic status, education level, or employment status. Variables with the largest associations with intake were, respectively, ethnicity and age. Non Hispanic black individuals consumed the smallest amounts (80+/-2 mg/d), non Hispanic white individuals consumed the greatest amounts (194+/-3 mg/d), and Asian individuals (126+/-7 mg/d) and Hispanic individuals consumed intermediate amounts (127+/-3 mg/d). Middle-aged individuals (aged 50 to 54 years) consumed more caffeine (211+/-6 mg/d) than younger (107+/-4 mg/d, aged 20 to 24 years) and older individuals (153+/-4 mg/d, aged 75 to 79 years). CONCLUSION: Most caffeine is consumed in the morning, when alertness is lowest, and very little in the evening before sleep. Ethnicity and age were the variables most strongly associated with intake; work hours, occupation, energy and alcohol intake, and smoking were also associated with intake. Because caffeine increases alertness, it is not surprising that its pattern of consumption and factors associated with its intake vary from those of most other food constituents. PMID- 30446429 TI - Comparison of Label and Laboratory Sodium Values in Popular Sodium-Contributing Foods in the United States. AB - BACKGROUND: Nutrition labels are important tools for consumers and for supporting public health strategies. Recent, published comparison of label and laboratory sodium values for US foods, and differences by brand type (national or private label) or source (store or restaurant [fast-food and sit-down]) is unavailable. OBJECTIVE: The objective was to compare label and laboratory values for sodium and related nutrients (ie, total sugars, total fat, and saturated fat) in popular, sodium-contributing foods, and examine whether there are differences by brand type, and source. DESIGN: During 2010 to 2014, the Nutrient Data Laboratory of the US Department of Agriculture collected 3,432 samples nationwide of 125 foods, combined one or more samples of the same food (henceforth referred to as composites), and chemically analyzed them. For this comparative post hoc analysis, the Nutrient Data Laboratory linked laboratory values for 1,390 composites (consisting of one or more samples of the same food) of 114 foods to corresponding label or website (restaurant) nutrient values. MAIN OUTCOME MEASURES: Label and laboratory values and their ratio for each composite, for each of the four nutrients (sodium, total fat, total sugars, and saturated fat). STATISTICAL ANALYSES PERFORMED: Nutrient Data Laboratory analysis determined the ratio of laboratory to label value for each composite, and categorized them into six groups: >=141%, 121% to 140%, 101% to 120%, 81% to 100%, 61% to 80%, and <=60%. For sodium, the Nutrient Data Laboratory analysis determined the distribution of the ratios by food, food category, brand type, and source. RESULTS: For sodium, 5% of the composites had ratios of laboratory to label values >120% and 14% had ratios <=80%. Twenty-two percent of private-label brand composites had ratios <=80%, compared with 12% of national brands. Only 3% of store composites had ratios >120% compared with 11% of restaurant composites. Ratios <=80% were more prevalent among sit-down restaurants (37%) compared with fast-food restaurants (9%). CONCLUSIONS: This study shows that a majority of label and laboratory values sampled agree and underdeclaration of label values is limited. However, there is some disagreement. Periodic monitoring of the nutrient content of foods through laboratory analyses establishes validity of the food labels and helps identify foods and food categories where the label and laboratory values do not compare well, and hence may need laboratory analyses to support accuracy of food composition data. PMID- 30446430 TI - Patterns in Adult Malnutrition Assessment and Diagnosis by Registered Dietitian Nutritionists: 2014-2017. PMID- 30446431 TI - Fogarty International Center collaborative networks in infectious disease modeling: Lessons learnt in research and capacity building. AB - Due to a combination of ecological, political, and demographic factors, the emergence of novel pathogens has been increasingly observed in animals and humans in recent decades. Enhancing global capacity to study and interpret infectious disease surveillance data, and to develop data-driven computational models to guide policy, represents one of the most cost-effective, and yet overlooked, ways to prepare for the next pandemic. Epidemiological and behavioral data from recent pandemics and historic scourges have provided rich opportunities for validation of computational models, while new sequencing technologies and the 'big data' revolution present new tools for studying the epidemiology of outbreaks in real time. For the past two decades, the Division of International Epidemiology and Population Studies (DIEPS) of the NIH Fogarty International Center has spearheaded two synergistic programs to better understand and devise control strategies for global infectious disease threats. The Multinational Influenza Seasonal Mortality Study (MISMS) has strengthened global capacity to study the epidemiology and evolutionary dynamics of influenza viruses in 80 countries by organizing international research activities and training workshops. The Research and Policy in Infectious Disease Dynamics (RAPIDD) program and its precursor activities has established a network of global experts in infectious disease modeling operating at the research-policy interface, with collaborators in 78 countries. These activities have provided evidence-based recommendations for disease control, including during large-scale outbreaks of pandemic influenza, Ebola and Zika virus. Together, these programs have coordinated international collaborative networks to advance the study of emerging disease threats and the field of computational epidemic modeling. A global community of researchers and policy-makers have used the tools and trainings developed by these programs to interpret infectious disease patterns in their countries, understand modeling concepts, and inform control policies. Here we reflect on the scientific achievements and lessons learnt from these programs (h-index = 106 for RAPIDD and 79 for MISMS), including the identification of outstanding researchers and fellows; funding flexibility for timely research workshops and working groups (particularly relative to more traditional investigator-based grant programs); emphasis on group activities such as large-scale modeling reviews, model comparisons, forecasting challenges and special journal issues; strong quality control with a light touch on outputs; and prominence of training, data-sharing, and joint publications. PMID- 30446433 TI - Novel gene fusions found in cervical cancer. PMID- 30446432 TI - Changes in Splicing Machinery Components Influence, Precede, and Early Predict the Development of Type 2 Diabetes: From the CORDIOPREV Study. AB - BACKGROUND: Type-2 diabetes mellitus (T2DM) is a major health problem with increasing incidence, which severely impacts cardiovascular disease. Because T2DM is associated with altered gene expression and aberrant splicing, we hypothesized that dysregulations in splicing machinery could precede, contribute to, and predict T2DM development. METHODS: A cohort of patients with cardiovascular disease (CORDIOPREV study) and without T2DM at baseline (at the inclusion of the study) was used (n = 215). We determined the expression of selected splicing machinery components in fasting and 4 h-postprandial peripheral blood mononuclear cells (PBMCs, obtained at baseline) from all the patients who developed T2DM during 5-years of follow-up (n = 107 incident-T2DM cases) and 108 randomly selected non-T2DM patients (controls). Serum from incident-T2DM and control patients was used to analyze in vitro the modulation of splicing machinery expression in control PBMCs from an independent cohort of healthy subjects. FINDINGS: Expression of key splicing machinery components (e.g. RNU2, RNU4 or RNU12) from fasting and 4 h-postprandial PBMCs of incident-T2DM patients was markedly altered compared to non-T2DM controls. Moreover, in vitro treatment of healthy individuals PBMCs with serum from incident-T2DM patients (compared to non T2DM controls) reduced the expression of splicing machinery elements found down regulated in incident-T2DM patients PBMCs. Finally, fasting/postprandial levels of several splicing machinery components in the PBMCs of CORDIOPREV patients were associated to higher risk of T2DM (Odds Ratio > 4) and could accurately predict (AUC > 0.85) T2DM development. INTERPRETATION: Our results reveal the existence of splicing machinery alterations that precede and predict T2DM development in patients with cardiovascular disease. FUND: ISCIII, MINECO, CIBERObn. PMID- 30446434 TI - Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs. AB - BACKGROUND: Carotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity. METHODS: Adult male guinea pigs were exposed to CIH (6.5% O2 at nadir, 6 cycles.hour-1) for 8 h.day-1 for 12 consecutive days. FINDINGS: CIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but beta-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls. INTERPRETATION: Increased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota gut-brainstem axis. The findings have relevance to human sleep-disordered breathing. FUNDING: The Department of Physiology, and APC Microbiome Ireland, UCC. PMID- 30446436 TI - Chronic Early Stress Impairs Default Mode Network Connectivity in Preadolescents and Their Mothers. AB - BACKGROUND: Early life stress (ELS) bears long-term negative consequences throughout life. Yet ELS effect is mostly unknown, and no study has followed children to test its impact on the default mode network (DMN) in relation to maternal behavior across childhood. Focusing on brain oscillations, we utilized a unique cohort of war-exposed preadolescent children (11-13 years of age) and their mothers followed from early childhood to examine the effects of ELS combined with observed parenting on DMN connectivity and power in mother and child. METHODS: Participants included 161 mothers and children (children: 39 exposed/36 control subjects; mothers: 44 exposed/42 control subjects) who underwent magnetoencephalography scanning during rest. RESULTS: Stress exposure reduced DMN connectivity in mother and child; however, in mothers, the impaired connectivity occurred in the alpha band, whereas among children it occurred in the theta band, a biomarker of the developing brain. Maternal anxiety, depression, and posttraumatic symptoms in early childhood predicted lower maternal DMN connectivity. Among children, the experience of intrusive, anxious, and uncontained parenting across the first decade and greater cortisol production in late childhood predicted reduced DMN connectivity in preadolescence. Impairments to theta DMN connectivity increased in children with posttraumatic stress disorder. CONCLUSIONS: Findings indicate that ELS disrupts the synchronous coordination of distinct brain areas into coherent functioning of the DMN network, a core network implicated in self-relevant processes. Results suggest that one pathway for the lifelong effects of ELS on psychopathology and physical illness relate to impaired coherence of the DMN and its role in maintaining quiescence, alternating internal and external attention, and supporting the sense of self. PMID- 30446437 TI - Structural development of non-secosteroidal vitamin D receptor (VDR) ligands without any asymmetric carbon. AB - Non-secosteroidal VDR ligands without any assymmetric carbon were designed and synthesized based on the structure of the previously reported non-secosteroidal VDR agonist LG190178. The VDR-agonistic activity of all synthesized compounds was evaluated, and 7b emerged as a potent agonist activity with an EC50 value of 9.26 nM. Moreover, a docking simulation analysis was also performed to determine the binding mode of 7b with VDR-LBD. PMID- 30446438 TI - Design, synthesis and biological evaluation of anthranilamide derivatives as potential factor Xa (fXa) inhibitors. AB - Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models. The bleeding risk evaluation showed that 16g had a safer profile than that of betrixaban at 1 mg/kg and 5 mg/kg dose. Additionally, 16g also exhibited satisfactory PK profiles. Eventually, 16g was selected to investigate its effect on hypoxia-reoxygenation- induced H9C2 cell viability. MTT results showed that H9C2 cell viability can be remarkably alleviated by 16g. PMID- 30446435 TI - Restricted and Repetitive Behavior and Brain Functional Connectivity in Infants at Risk for Developing Autism Spectrum Disorder. AB - BACKGROUND: Restricted and repetitive behaviors (RRBs), detectable by 12 months in many infants in whom autism spectrum disorder (ASD) is later diagnosed, may represent some of the earliest behavioral markers of ASD. However, brain function underlying the emergence of these key behaviors remains unknown. METHODS: Behavioral and resting-state functional connectivity (fc) magnetic resonance imaging data were collected from 167 children at high and low familial risk for ASD at 12 and 24 months (n = 38 at both time points). Twenty infants met criteria for ASD at 24 months. We divided RRBs into four subcategories (restricted, stereotyped, ritualistic/sameness, self-injurious) and used a data-driven approach to identify functional brain networks associated with the development of each RRB subcategory. RESULTS: Higher scores for ritualistic/sameness behavior were associated with less positive fc between visual and control networks at 12 and 24 months. Ritualistic/sameness and stereotyped behaviors were associated with less positive fc between visual and default mode networks at 12 months. At 24 months, stereotyped and restricted behaviors were associated with more positive fc between default mode and control networks. Additionally, at 24 months, stereotyped behavior was associated with more positive fc between dorsal attention and subcortical networks, whereas restricted behavior was associated with more positive fc between default mode and dorsal attention networks. No significant network-level associations were observed for self-injurious behavior. CONCLUSIONS: These observations mark the earliest known description of functional brain systems underlying RRBs, reinforce the construct validity of RRB subcategories in infants, and implicate specific neural substrates for future interventions targeting RRBs. PMID- 30446439 TI - Synthesis and evaluation of potent and selective MGL inhibitors as a glaucoma treatment. AB - Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based 1H NMR experiments indicated that inhibitor 2 rapidly formed a covalent adduct with MGL with a residence time of about 6 h. This interconversion process "intrinsic reversibility" was exploited by modifications of the ligand's size (length and bulkiness) to generate analogs with "tunable' adduct residence time (tau). Inhibitor 2 was evaluated in a normotensive murine model for assessing intraocular pressure (IOP), which could lead to glaucoma, a major cause of blindness. Inhibitor 2 was found to decrease ocular pressure by ~4.5 mmHg in a sustained manner for at least 12 h after a single ocular application, underscoring the potential for topically-administered MGL inhibitors as a novel therapeutic target for the treatment of glaucoma. PMID- 30446440 TI - Dimeric cinnamoylamide analogues for regulation of tyrosinase activity in melanoma cells: A role of diamide-link chain length. AB - Dimeric cynnamoyl analogues (DCAs) with depigmenting activity have been developed. In this study, a role of diamide linkage chain length of DCAs as a tyrosinase inhibitor was investigated on tyrosinase inhibitory activity, antioxidative activity, hydrophobicity and anti-melanogenesis as well as structural characteristics and dipole moments based on density functional theory. DCAs with different diamide-link chain lengths (n = 2, 3, and 4) and various functional groups (m-coumaroyl, p-coumaroyl, isoferuloyl and feruloyl groups) were synthesized. DCAs with a diamide-link chain length of three indicated high inhibitory effect of melanin production on alpha-melanocyte stimulating hormone (alpha-MSH) stimulated B16F1 cells. Approach of p-hydroxyl group of DCAs to active site of tyrosinase, an important melanogenic enzyme, is interfered by addition of m-methoxy group. In structural modeling based on density functional theory, DCAs with a diamide-link chain length of three showed folded shapes, and they had lower dipole moment than with a diamide-link chain length of two or four. Thus, for the enhancement of the depigmenting activities of dimeric compounds, the diamide-link chain length is important. Our results provide an important index for the design of dimeric compounds with physiological activities. PMID- 30446441 TI - Predictive value of lymphangiogenesis and proliferation markers on mRNA level in urothelial carcinoma of the bladder after radical cystectomy. AB - OBJECTIVE: To evaluate the mRNA expression of lymphangiogenesis and proliferation markers and to examine its association with histopathological characteristics and clinical outcome in patients with urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC). PATIENTS AND METHODS: Gene expression analysis of the vascular endothelial growth -C and -D (VEGF-C/-D), its receptor VEGF receptor-3 (VEGFR-3), MKI67, and RACGAP1 was performed in 108 patients after radical cystectomy and their correlation with clinical-pathological parameters was investigated. Uni- and multivariate regression analyses were used to identify predictors for cancer-specific survival (CSS), recurrence-free survival (RFS) and overall survival (OS) after RC. RESULTS: The expression of RACGAP1 and VEGFR-3 showed an association with a higher pT stage (P = 0.049; P = 0.009). MKI67 showed an association with a high-grade urothelial carcinoma of the bladder (P = 0.021). VEGFR-3 expression was significantly associated with the presence of lymphovascular invasion (LVI) (P = 0.016) and lymph node metastases (pN+) (P = 0.028). With the univariate analysis, overexpression of VEGFR-3 (P = 0.029) and the clinical-pathological parameters pT stage (P < 0.0001), pN+ (P = 0.0004), LVI (P < 0.0001) and female gender (P = 0.021) were significantly associated with a reduced CSS. Multivariate analysis identified a higher pT stage (P = 0.017) and LVI (P = 0.008) as independent predictors for reduced CSS. Independent predictors for reduced OS were a higher pT stage (P = 0.0007) and LVI (P = 0.0021), while overexpression of VEGF-D was associated with better OS (P < 0.0001). CONCLUSIONS: The mRNA expression of the investigated markers showed associations with common histopathological parameters. Increased expression of VEGF-D is independently associated with better overall survival. PMID- 30446443 TI - Tumor expression of miR-34a-3p is an independent predictor of recurrence in non muscle-invasive bladder cancer and promising additional factor to improve predictive value of EORTC nomogram. AB - OBJECTIVES: Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease characterized by a high primary tumor recurrence rate. Current prognostic systems used for predicting recurrence in individual patients have limitations and do not consider the biological background of this tumor type. Our study aimed to find microRNAs (miRNAs) associated with NMIBC recurrence. METHODS: Seventy-eight NMIBC patients were prospectively enrolled and divided into exploratory and validation cohorts. Out of these patients, 32 developed recurrence within 18 months after surgery, while 46 did not show any sign of recurrence after 30 months. Expression profiles of 2,578 miRNAs were obtained using Affymetrix miRNA microarrays and candidate miRNAs validated using the individual quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The expression profiling revealed a set of 137 miRNAs differentially expressed between NMIBC patients with and without recurrence (P < 0.05). In the validation phase, miR-34a 3p had a significantly higher expression in tumors of NMIBC patients without recurrence (P = 0.0155). Decreased expression of miR-34a-3p was associated with significantly shorter recurrence-free survival (P = 0.009). Cox regression analysis confirmed that miR-34a-3p is an independent biomarker associated with a lower risk of recurrence (hazard ratio (HR) = 0.3184, 95% confidence interval = 0.003-0.681, P = 0.0258). Combination of miR-34a-3p and European Organization for Research and Treatment of Cancer risk score into one predictive model enabled to predict individual risk of recurrence with high statistical significance and analytical performance (P < 0.0001; area under curve = 0.8368; sensitivity 83%, and specificity 75%). CONCLUSIONS: Our data suggest that miR-34a-3p is an independent biomarker of NMIBC recurrence and a promising candidate for further independent validations as an additional factor to improve predictive value of European Organization for Research and Treatment of Cancer nomogram. PMID- 30446444 TI - Mutational landscape of non-muscle-invasive bladder cancer. AB - Non-muscle-invasive bladder cancer (NMIBC) includes stage Ta and stage T1 tumors and carcinoma in situ (CIS). Grading of Ta tumors subdivides these lesions into papillary urothelial neoplasms of low malignant potential and low- and high-grade noninvasive papillary urothelial carcinoma. CIS is by definition high-grade and the majority of stage T1 tumors are of high-grade. This pathologic heterogeneity is associated with divergent clinical outcome, with significantly worse prognosis for patients with T1 tumors or CIS. A wealth of molecular information has accumulated on NMIBC including mutational data that ranges from the whole chromosome level to next generation sequence data at nucleotide level. This has not only identified key genes that are mutated in NMIBC, but also provides insight into the processes that shape their mutational landscape. Although molecular analyses cannot yet provide definitive personal prognostic information, many differences between these entities promise improved disease management in the future. Most information is available for Ta and T1 samples and this is the focus of this review. PMID- 30446442 TI - Propensity-score-matched comparison of soft tissue surgical margins status between open and robotic-assisted radical cystectomy. AB - INTRODUCTION: The use of robotic-assisted radical cystectomy (RARC) is becoming more widespread. While its safety is accepted, its oncological efficacy as compared to the current standard, open radical cystectomy (ORC), remains debatable. MATERIALS AND METHODS: The aim of this study is to compare the rates of positive soft tissue surgical margins (STSM), between patients treated with RARC or ORC, using a large contemporaneous collaborative database. We included 2,536 patients with urothelial carcinoma of the bladder treated at 26 institutions. A propensity-score matching 1:1 was performed with 3 ORC patients matched to 1 RARC patient. The final cohort included 1,614 patients. Uni- and multivariable logistic regression analyses tested the impact of surgical technique on STSM status, before and after propensity-score matching. RESULTS: Overall, 870 (34%) patients underwent RARC and 1,666 (66%) ORC. The overall STSM rate was 11%; 10% in the ORC group and 13% in the RARC group. Within the propensity-score-matched cohort, the positive STSM rate were 14% and 13% in the ORC and RARC group, respectively (P = 0.1). In multivariable analysis, after propensity match RARC approach was not associated with the risk of a positive STSM (P = 0.1). These results were confirmed in the subgroup of patients with pathologic non-organ-confined or organ-confined diseases. CONCLUSIONS: While treatment with RARC is associated with a higher absolute rate of STSM, the difference did not remain after adjustment for the effects of other established prognostic factors. Results from ongoing trials are awaited to assess the validity of these findings. PMID- 30446445 TI - The role of inguinal lymph node dissection in men with urethral squamous cell carcinoma. AB - INTRODUCTION: Urethral squamous cell cancer is a rare disease with limited clinical recommendations regarding management of the inguinal lymph nodes. Despite the similarities to penile cancer in terms of squamous cell carcinoma (SCC) histology and lymphatic drainage, there is not enough evidence to recommend for or against a prophylactic inguinal lymph node dissection (ILND) in patients with clinically negative groins and a primary tumor stage of T1b or higher. The objective of the study was to identify the rate of prophylactic inguinal lymph node dissection, node positive rate, and overall survival in patients with clinical T1 to T4 stage. The patients were separated into clinical N stage and the rates of node positivity were compared. We hypothesize that the node positivity rate would be similar to that observed in penile cancer of similar clinical T and N stage and provide evidence for prophylactic inguinal lymph node dissection in urethral squamous cancer. We also sought to determine the value of ILND in clinically node positive (cN+) and clinically node negative (cN-) patients. METHODS: The National Cancer Database was queried for all cases of primary urethral cancer in men from 2004 to 2014. Patients with other cancer diagnoses, metastasis, nonsquamous histology, female patients, and patients with a history of radiation therapy were excluded. Male patients with urethral squamous cell cancer of the anterior urethra with T1 or higher T stage were included in this study. All-cause mortality was compared using multivariable Cox regression controlling for covariates. RESULTS: The study included 725 men with urethral SCC with T1 or higher clinical T stage. The median age was 63 years (33 83 interquartile range). Of the 725 men, 536 men did not receive an ILND and 189 (26%) underwent ILND. Patients who received LND had significantly higher clinical T and clinical N stage. There was no difference in age, sex, or histology between those with ILND versus no ILND. In patients with T1 to T4 and clinical N0, the ILND rate was 21.8% (89/396). The lymph node positive rate in patients with N0 and T1 to T4 primary tumor was 9%. In patients with clinically node positive disease (N1/N2), the overall ILND rate was 76%. The lymph node positive rate for patients with clinical nodal disease was 84%. On multivariable analysis cox regression, lymph node positivity was associated with worse overall survival when controlling for T stage, clinical N stage, and age (HR 1.56, 95% 1.3-1.9, P = 0.000). On multivariable analysis after controlling for T stage, sex, and age, having an ILND was associated with improved OS in patients with clinical N1 or N2 disease (HR 0.46, 95% 0.28-0.78 P = 0.002). CONCLUSION: The node positivity rate in patients with T1 to T4 and N0 is 9%, much lower than reported in penile cancer with a high-risk primary tumor but clinically negative groins. This argues against routine prophylactic inguinal ILND in patients with urethral SCC who are clinically N0, perhaps suggesting different biological behavior of urethral SCC compared to penile SCC. Performing a lymph node dissection in patients with clinically N1 or N2 disease is associated with improved OS. PMID- 30446446 TI - Molecular footprints of muscle-invasive bladder cancer in smoking and nonsmoking patients. AB - BACKGROUND: Bladder cancer is the fifth most common cancer in the United States and smoking is the largest known risk factor. Tobacco-derived carcinogens may induce the accumulation of somatic mutations in urothelial cells, and likely promote tumorigenesis. However, it is still unknown whether smoking-induced bladder carcinogenesis results in tumors with distinctive molecular features that can be therapeutically exploited. METHODS: We investigated the genomic alterations of human bladder cancer and examined their association with patient smoking history. We performed bioinformatic analyses and looked at differences in gene expression, somatic mutations, and DNA mutational signatures comparing nonsmokers, reformed smokers, and current smokers. RESULTS: We detected a limited set of gene expression and gene mutation differences between smokers and nonsmokers. We also identified a specific mutational signature that is enriched in tumors from smokers. This mutational signature was described before and has been linked to specific DNA repair defects in human bladder tumors, as well as to the direct effect of nitrosamine carcinogens in the BBN murine model of bladder cancer. CONCLUSION: We showed associations between smoking status and selected mutational signatures, which could provide insights in the biology of bladder carcinogenesis and tumor progression. PMID- 30446447 TI - Free-hand transperineal prostate biopsy provides acceptable cancer detection and minimizes risk of infection: evolving experience with a 10-sector template. AB - INTRODUCTION AND OBJECTIVES: Free-hand transperineal prostate (fTP-Bx) biopsy offers an alternative to transrectal prostate biopsy (TRUS-Bx) in the diagnosis of prostate cancer. Our objectives were to determine whether fTP-Bx achieves cancer detection rates comparable to historic TRUS-Bx cohorts; to determine infectious and other complications associated with fTP-B; and to propose a standardized fTP-Bx template. PATIENTS AND METHODS: We present a single institution, retrospective review of fTP-Bx in 1,000 men with elevated prostate specific antigen, abnormal digital rectal examination, or on an active surveillance protocol. A fan-like biopsy scheme was used in 883 patients. A 10 sector prostate biopsy template was developed for use in the final 117 patients. The primary outcome was detection of any cancer and detection of clinically significant cancer (Grade Group >= 2). Secondary outcomes included procedural specifics and complications. Chi Square and Mann-Whitney U were used for analysis of categorical and continuous variables, respectively. RESULTS: The median age of the cohort was 68 (interquartile range 61-74) years, and the median prostate specific antigen was 7.9 (interquartile range 5.5-11.9) ng/ml. Total cancer (60.7%) and clinically significant cancer (40.3%) detection for fTP-Bx were comparable to those reported for TRUS-Bx. Detection of any cancer (70.9% vs. 59.3%, P < 0.01) and clinically significant cancer (51.3% vs. 38.9%, P = 0.01) was higher using the 10-sector biopsy template relative to the fan-like pattern. No patients were hospitalized for sepsis and no culture-proven urinary tract infections were diagnosed. CONCLUSION: Cancer detection rates using fTP-Bx are comparable to TRUS-Bx, and fTP-Bx nearly eliminates the risk of infection. We propose a 10-sector biopsy template for fTP-Bx that easily translates to established MRI prostate sector maps for use in clinical care and future research studies exploring the efficacy of MRI-guided fTP-Bx. PMID- 30446448 TI - Exercise medicine for the management of androgen deprivation therapy-related side effects in prostate cancer. AB - Androgen deprivation therapy (ADT) is associated with considerable adverse side effects which compromise the health and wellbeing of many men with prostate cancer. Exercise has been identified as a therapy to help manage ADT-related treatment toxicities. This paper systematically reviews the scientific literature investigating the impact of exercise on men receiving ADT and discusses strategies to effectively implement exercise in clinical practice. The findings of this review demonstrate that exercise has therapeutic benefit for the management of ADT-related side effects. Significant positive effects following exercise were observed for aerobic fitness, muscular strength, physical function, body composition, fatigue, sexual wellbeing, mental wellbeing, social function, comorbid disease risk factors, and quality of life. Emerging evidence suggests exercise may also play a role in managing bone loss, cognitive decline, and urinary problems, and may be delivered without exacerbating bone pain. Exercise did not negatively influence ADT treatment efficacy and led to few adverse events of minor severity, rendering it a safe intervention for men receiving ADT. To maximize the therapeutic effect of exercise, men with prostate cancer should participate in moderate-to-high intensity aerobic, resistance and impact exercise which is prescribed and supervised by a qualified exercise physiologist and delivered at a convenient location in a prostate cancer specific group-based environment. The level of evidence now available supports the view that the prescription of exercise medicine should be part of routine prostate cancer care. PMID- 30446449 TI - The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer. AB - Immunotherapy-particularly immune checkpoint blockade-has seen great success in many tumor types. However, checkpoint-based therapies have not demonstrated high levels of success in prostate cancer, and there is much to be learned from both the successes and failures of these treatments. Here we review the evidence that composition of infiltrating immune cells in the tumor microenvironment is fundamental to the response to immunotherapy. Additionally, we discuss the emerging idea that the organization of these immune cells may also be crucial to this response. In prostate cancer, the composition and organization of the tumor immune microenvironment are preeminent topics of discussion and areas of important future investigation. PMID- 30446450 TI - Implications of micropapillary urothelial carcinoma variant on prognosis following radical cystectomy: A multi-institutional investigation. AB - PURPOSE: To determine the association of micropapillary urothelial carcinoma (MUC) variant histology with bladder cancer outcomes after radical cystectomy. MATERIALS AND METHODS: Information on MUC patients treated with radical cystectomy was obtained from five academic centers. Data on 1,497 patients were assembled in a relational database. Tumor histology was categorized as urothelial carcinoma without any histological variants (UC; n = 1,346) or MUC (n = 151). Univariable and multivariable models were used to analyze associations with recurrence-free (RFS) and overall (OS) survival. RESULTS: Median follow-up was 10.0 and 7.8 years for the UC and MUC groups, respectively. No significant differences were noted between UC and MUC groups with regard to age, gender, clinical disease stage, and administration of neoadjuvant and adjuvant chemotherapy (all, P >= 0.10). When compared with UC, presence of MUC was associated with higher pathologic stage (organ-confined, 60% vs. 27%; extravesical, 18% vs. 23%; node-positive, 22% vs. 50%; P < 0.01) and lymphovascular invasion (29% vs. 58%; P < 0.01) at cystectomy. In comparison with UC, MUC patients had poorer 5-year RFS (70% vs. 44%; P < 0.01) and OS (61% vs. 38%; P < 0.01). However, on multivariable analysis, tumor histology was not independently associated with the risks of recurrence (P = 0.27) or mortality (P = 0.12). CONCLUSIONS: This multi-institutional analysis demonstrated that the presence of MUC was associated with locally advanced disease at radical cystectomy. However, clinical outcomes were comparable to those with pure UC after controlling for standard clinicopathologic predictors. PMID- 30446451 TI - Local failure is a dominant mode of recurrence in locally advanced and clinical node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy. AB - BACKGROUND: The recurrence patterns of high-risk, N1 prostate cancer after radiation therapy (RT) including the pelvic lymph nodes have not been fully investigated. MATERIAL AND METHODS: We have a prospective clinical study since 2004 that has followed 138 men with locally advanced prostate cancer (T1-T4N0 N1M0) treated with definitive RT encompassing the prostate and pelvic lymph nodes and long-term androgen deprivation therapy (ADT). Forty nine of the 52 patients that developed recurrence were imaged at biochemical failure to detect the site of recurrence. RESULTS: Imaging identified the site of recurrence in 46 patients. Twenty five patients had prostatic recurrence only, none had local lymph node recurrence only, 11 had distant metastases only, 7 had prostatic recurrence and distant metastases, 2 had prostatic recurrence, local nodal recurrence and distant metastases, and 1 had local nodal recurrence with distant metastases. The mean time to recurrence was 62 months for prostate only, 40 months for distant only and 50 months for prostate and distant recurrence. There was a 69% recurrence rate for patients with magnetic resonance imaging -detected N1 disease. There was significantly longer survival for patients with prostate recurrence only compared to patients with distant recurrence (P < 0.018). Five year prostate cancer-specific survival were 85% for prostate only, 44% for distant only and 48% for prostate and distant recurrence (prostate only vs. distant only; P = 0.008, prostate only vs. prostate and distant; P = 0.018, distant vs. prostate and distant; P = 0.836). CONCLUSIONS: The predominant recurrence pattern for high-risk, N1 prostate cancer was prostatic recurrence and distant spread after pelvic RT and androgen deprivation therapy. Our data argue for further local dose escalation and pelvic nodal radiation to prevent recurrence in these sites. Lymph node metastasis at initial staging with an magnetic resonance imaging was a strong predictor of recurrence and poor survival and may identify patients in need of more aggressive treatment. PMID- 30446452 TI - Variation in surgical treatment patterns for patients with prostate cancer in the United States: Do patients in academic hospitals fare better? AB - INTRODUCTION: With prostate cancer (CaP) screening, overtreatment of low-risk CaP remains a concern. We investigated the patterns of radical prostatectomy (RP) for pathologic insignificant (iCaP) and significant CaP (sCaP) as well as variations between academic and nonacademic hospitals. PATIENTS AND METHODS: Patients undergoing RP for clinical T1c CaP were identified in the National Cancer Database between 2006 and 2013. The primary outcome was the trend of RP for insignificant prostate cancer (iCaP) and significant prostate cancer (sCaP) over the study period. The secondary outcome was to compare the RP rate in academic vs. nonacademic institutions. Univariable and multivariable analysis were utilized to evaluate the association between overtreatment and practice type. iCaP was defined as organ confined CaP with Gleason Score <=6. RESULTS: The total number of RP increased from 17,970 cases in 2006 to 25,324 in 2013. The RP rate decreased for iCaP from 39.9% to 19.8%, while increasing for sCaP from 18% to 27% over the study period. Patients undergoing RP in academic settings were less likely to have iCaP (odds ratio 0.88, 95% confidence interval 0.80-0.97). Caucasian race, private insurance, younger age, and treatment in the Eastern United States were associated with higher rates of iCaP at RP. CONCLUSION: The rate of iCaP has declined over time in the United States for patients undergoing RP. Although RP in nonacademic setting was more likely to have iCaP on surgical pathology, this trend has been downward among practice types. Treatment appropriateness is an underrecognized, undermeasured, but increasingly important component of the high-value care discussion that warrants greater attention. PMID- 30446453 TI - Immunohistochemical expression of Ki-67, Cyclin D1, p16INK4a, and Survivin as a predictive tool for recurrence and progression-free survival in papillary urothelial bladder cancer pTa / pT1 G2 (WHO 1973). AB - OBJECTIVES: To investigate the expression of several immunohistochemical (IHC) markers and their predictive ability for the recurrence-free and progression-free survival of papillary urothelial bladder cancer (UBC) pTa/pT1 G2 (WHO 1973) compared to classical anatomo-clinical variables using a multidimensional analysis. MATERIALS AND METHODS: A population-based cohort of 213 primary stage UBC (pTa/pT1) G2 (WHO 1973) was evaluated by classic anatomopathological variables and characterized by immunohistochemistry (23 IHC markers, representative of different oncogenic pathways). The most important variables as a predictor of recurrence-free and progression-free survival were selected using multidimensional statistical models, such as random survival forests and least absolute shrinkage and selection operator (. Recurrence and progression-free survival of the previously selected variables were also calculated. RESULTS: Mean follow-up was 58 +/- 33.5 months. Recurrence and progression rates were 54.5% (n = 116) and 17,4% (n = 37), respectively. The most influential variables in the low recurrence-free survival were in order: number of resected tumors, high expression of Ki67 (>10%), Cyclin D1 (>10%), and low cytoplasmic staining of p16INK4a. Regarding low progression-free survival, the most important variables were Ki67 (>15%), multicentric tumor arrangement and Survivin nuclear expression (>20%). Kaplan-Meier and cox-regression model analyses showed that the variables selected by multidimensional models were able to discriminate the clinical outcome. CONCLUSIONS: Ki67 index is the most useful IHC marker, since it can improve the prediction of both recurrence and progression-free survival in papillary UBC pTa/pT1 G2 (WHO 1973). There are other markers, whose utility is specific to recurrence-free survival, such as Cyclin D1 and p16INK4a or in progression-free survival, such as Survivin. PMID- 30446454 TI - Diagnostic value of combined IQGAP3/BMP4 and IQGAP3/FAM107A expression ratios in urinary cell-free DNA for discriminating bladder cancer from hematuria. AB - BACKGROUND: Urinary cell-free DNA (ucfDNA) has great potential as a "liquid biopsy" for use in diagnosis of urological cancers. In this study, we compared ucfDNA gene expression levels between patients with bladder cancer (BC) and those with hematuria, and determined whether they could be used as a noninvasive urine based marker. METHODS: The study cohort of 355 patients included a screening group (40 BC and 41 hematuria controls) and a validation cohort (149 BC and 125 hematuria controls). Expression levels ratios of 1 up-regulated gene (IQGAP3) to those of 7 down-regulated genes were examined in ucfDNA in the screening group to identify ratios that differed significantly between BC and hematuria patients. IQGAP3/BMP4 and IQGAP3/FAM107A ratios were selected and combined to develop a discriminant score (DS) index, which was tested in the validation cohort. Receiver operating characteristic curves and areas under the curve were calculated to evaluate the performance of the DS index. RESULTS: IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were both significantly higher in BC patients than in hematuria patients (both P < 0.001). The DS index had an area under the curve of 0.862, a sensitivity of 71.0%, a specificity of 88.6%, a positive predictive value of 90.3%, and a negative predictive value of 67.2%. CONCLUSIONS: Both IQGAP3/BMP4 and IQGAP3/FAM107A ratios in ucfDNA were significantly higher in patients with BC than in those with hematuria. The DS index exhibits good diagnostic performance as a noninvasive biomarker. PMID- 30446455 TI - Current controversies on the role of retroperitoneal lymphadenectomy for testicular cancer. AB - Retroperitoneal lymph node dissection (RPLND) is an important component of the multimodal treatment which cures most patients diagnosed with testicular germ cell tumors. Considering the high cure rates achieved, research focus in recent years has been directed toward improving quality of life and decreasing long-term treatment related sequelae. Consequently, the role of RPLND has evolved over the past 3 decades in both low-stage and advanced testicular cancer. The use of RPLND in clinically stage I and low volume stage II disease may offer the advantages of treating retroperitoneal teratoma which is present in 15% to 20% of patients, avoiding chemotherapy and reducing the need for frequent imaging during follow up. Similarly, ongoing studies are evaluating the safety and effectiveness of RPLND for the treatment of early stage seminoma to avoid the long-term effects of chemotherapy and radiotherapy. RPLND is traditionally used for the treatment of residual masses >1 cm after completion of chemotherapy. Its role in subcentimeter residual masses remains somewhat controversial given the fact that 25% to 30% of these patients are found to harbor either teratoma or viable nonteratomatous germ cell tumors. The presence of teratoma increases the probability of teratoma in metastatic sites. Modified unilateral templates were developed based on early mapping studies with the aim of preserving antegrade ejaculation. Recent data suggests initial mapping studies underestimated the risk of contralateral retroperitoneal metastases which may reach 32%. Furthermore, antegrade ejaculation may be preserved in >95% of patients undergoing bilateral nerve sparing primary RPLND and >80% undergoing nerve-sparing PC-RPLND, which, in our view is the more prudent oncologic approach. Recently, multiple series have demonstrated the safety and short-term efficacy of minimally invasive RPLND; however, larger studies with prolonged follow-up are required to validate the long-term oncologic efficacy of newer techniques. PMID- 30446456 TI - Diagnosis and management of the growing teratoma syndrome: A single-center experience and review of the literature. AB - OBJECTIVES: To evaluate the diagnostic, surgical as well as oncological outcome of patients with a growing teratoma syndrome. MATERIAL AND METHODS: We performed a retrospective analysis including 680 patients with advanced nonseminomatous germ cell tumors who underwent a postchemotherapy retroperitoneal lymph node dissection. The peri- and postoperative outcome of 22 patients (3%) that fulfilled the criteria of a growing teratoma syndrome were analyzed: nonseminomatous germ cell tumors with increasing tumor size during or after chemotherapy despite normalized or decreasing tumor markers. RESULTS: The median tumor diameter at time of surgery was 6 cm (4-12.2). For a complete resection of the residual masses, adjunctive surgery had to be performed in 4 (18%) patients: resection of the abdominal aorta, inferior vena cava or renal vein with graft replacement, nephrectomy and resection of parts of the intestine. Eight postoperative complications occurred in 5 (23%) patients, with 4/8 of these complications affecting only one patient. Fifty percent of all complications were classified as Clavien-Dindo grade III or IV. After a median follow-up of 25 months, relapse occurred in 2 patients (9%); all but one patient is alive resulting in an overall survival of 95.5%. CONCLUSIONS: The growing teratoma syndrome is a rare phenomenon among patients with advanced nonseminomatous germ cell tumors and necessitates complete surgical resection of the masses with curative intention. Due to its complexity and potential adjunctive surgery, the treatment should be performed in tertiary referral centers only. PMID- 30446457 TI - Loss of BAP1 expression in metastatic tumor tissue is an event of poor prognosis in patients with metastatic clear cell renal cell carcinoma. AB - PURPOSE: To evaluate the prognostic impact of the protein expression of both PBRM1 and BAP1 in metastatic tissue of patients with metastatic clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In all 124 consecutive cases of metastatic ccRCC, who underwent metastasectomy or biopsy of metastatic tumor tissue between 2007 and 2016 were selected from the medical records of our institution. Additionally, 38 paired cases with tissue from the primary tumor involving radical or partial nephrectomy for ccRCC were also selected. All cases were reviewed for uniform reclassification and the most representative tumor areas were selected for the construction of a tissue microarray. RESULTS: PBRM1 nuclear staining of the 124-immunostained metastases of ccRCC specimens showed that 98 (79.0%) had negative expression and 26 (21.0%) positive expression of PBRM1. Regarding BAP1 expression, we observed that 77 (62.1%) specimens were negative and 47 (37.9%) showed positive nuclear staining. When we compared the expression of both markers on primary tumor and tumor metastasis, we found disagreement in half of the cases. Five-year overall survival rates in patients with positive expression and negative expression of BAP1 were 53.2% and 35.1%, respectively (P = 0.004). Five-year progression-free survival rates in patients with positive expression and negative expression of BAP1 were 14.9% and 3.9%, respectively (P = 0.003). Conversely, PBRM1 expression did not significantly influence either overall survival or progression-free survival rates. In multivariate analysis, negative expression of BAP1 tumors also presented higher risks of death (hazard ratio (HR) = 1.913, P = 0.041) and disease progression (HR = 1.656, P = 0.021). CONCLUSION: The use of prognostic biomarkers identified in the primary tumor tissue might be not reliable in the metastatic disease scenario. Patients with metastatic ccRCC that present loss of BAP1 expression in metastatic tissue demonstrated poor survival rates and represent a relevant risk group for tumor recurrence and death. PMID- 30446458 TI - Trends and outcomes of lymphadenectomy for nonmetastatic renal cell carcinoma: A propensity score-weighted analysis of the National Cancer Database. AB - PURPOSE: Lymph node (LN) involvement in renal cell carcinoma (RCC) is associated with a poor prognosis. While lymph node dissection (LND) may provide diagnostic information, its therapeutic benefit remains controversial. Thus, the aim of our study is to analyze survival outcomes after LND for nonmetastatic RCC and to characterize contemporary practice patterns. MATERIALS AND METHODS: The National Cancer Database was queried for patients with nonmetastatic RCC who underwent either partial or radical nephrectomy from 2010 to 2014. A total of 11,867 underwent surgery and LND. Chi-square tests were used to examine differences in patient demographics. To minimize selection bias, propensity score matching (PSM) was used to select one control for each LND case (n = 19,500). Cox regression analyses were conducted to examine overall survival (OS) in patients who received LND compared to those who did not. RESULTS: Of all patients undergoing LND for RCC (n = 11,867), 5%, 23%, 31%, 47% were performed for tumors of clinical T stage 1, 2, 3, and 4, respectively. Proportions of LND have not significantly changed from 2010 to 2014. No significant improvement in median OS for patients undergoing LND compared to no LND was shown (34.7 vs. 34.9 months, respectively; P = 0.98). Similarly, no significant improvement in median OS was found for clinically LN positive patients undergoing LND compared to no LND (P = 0.90). On Cox regression analysis, LND dissection was not associated with an OS benefit (hazard ratio: 1.00; 95% confidence interval 0.97 to 1.04). CONCLUSIONS: Among all RCC patients, LNDs are often performed for low stage disease, suggesting a potential overutilization of LND. No OS benefit was seen in any subgroup of patients undergoing LND. Further investigation is needed to determine which patient populations may benefit most from LND. PMID- 30446459 TI - Use of delayed intervention for small renal masses initially managed with active surveillance. AB - INTRODUCTION: A number of patients who elect active surveillance of their small renal masses (<=4 cm) subsequently pursue delayed intervention (DI). The indications, timing, and rates of DI have not been well determined prospectively. MATERIALS AND METHODS: Data from Delayed Intervention and Surveillance for Small Renal Masses, a prospective, multi-institutional registry was utilized to evaluate factors associated with DI between 2009 and 2018. RESULTS: Of 371 patients enrolled in AS, 46 (12.4%) pursued DI. Patients who pursued DI spent a median 12 months on surveillance (interquartile range 5.5-23.6), had better functional status (P < 0.01), and had greater median growth rate vs. those who remained on surveillance (0.38 vs. 0.05, P < 0.001). Indications for intervention included growth rate >0.5 cm/y for 23 (50%) patients, patient preference for 22 (47.8%) patients, and qualification for renal transplant in 1 (2.2%) patient. Thirty-two patients (69.6%) underwent nephron-sparing surgery, 5 (10.9%) underwent radical nephrectomy, and 9 (19.6%) underwent percutaneous cryoablation. Renal mass biopsy was utilized in 37 (11.4%) and 15 (32.7%) patients in the AS and DI arms, respectively (P = 0.04). No patients experienced metastatic progression or died of kidney cancer. CONCLUSIONS: As nearly 50% of patients pursue DI secondary to anxiety in the absence of clinical progression, comprehensive counseling is essential to determine if patients are suitable for a surveillance protocol. AS remains a safe initial management option for many patients but may not be a durable strategy for patients who are acceptable surgical candidates with an extended life expectancy. DI does not compromise oncologic outcomes or limit treatment options. PMID- 30446460 TI - Optimal sampling scheme in men with abnormal multiparametric MRI undergoing MRI TRUS fusion prostate biopsy. AB - OBJECTIVES: To determine the implications of different prostate sampling schemes on the diagnosis of clinically significant prostate cancer (csPCA, ISUP group 2 5) and clinically insignificant prostate cancer (ciPCA, ISUP group 1) in men with abnormal multiparametric magnetic resonance imaging (mpMRI) undergoing MRI transrectal ulrasound fusion targeted biopsies. MATERIALS AND METHODS: This is a retrospective analysis of a cohort including all men who had a single lesion on mpMRI of the prostate performed between January 2016 and June 2017. All men underwent an MRI-transrectal ulrasound fusion biopsy and systematic (SBx) sampling of the prostate, which combined and were considered the standard of reference. The hypothetical 3 biopsy sampling schemes were defined as follows: Targeted biopsy only (TBx), TBx + ipsilateral SBx (ipsi-SBx) and TBx + contralateral SBx (contra-SBx) and were evaluated for the detection of csPCA and ciPCA. Sensitivity and 95% intervals were calculated, McNemar test was used to compare sensitivities between the various sampling schemes. RESULTS: TBx + SBx detected csPCa in 47% (55 of 116) of the 116 men who met eligibility criteria. Sensitivity and 95% confidence intervals for csPCa detection was 85.5% (73.3% 93.5%), 96.4% (87.5%-99.6%), and 92.7 (82.4%-98%) for TBx alone, TBx + ipsi-SBx and TBx + contra-SBx, respectively. csPCa detection rates were higher for both TBx + ipsi-SBx and TBx + contra-SBx compared to TBx alone. Clinically insignificant cancers alone were detected in 7.7% (9 of 116), 10.3% (12 of 116), and 14.6% (17 of 116) of the cohort by TBx only and TBx + ipsi-SBx, and TBx + contra-SBx, respectively. CONCLUSIONS: TBx + ipsi-SBx may increase the detection of csPCa while limiting overdiagnosis of indolent cancers. PMID- 30446462 TI - Hospital length of stay following radical cystectomy for muscle-invasive bladder cancer: Development and validation of a population-based prediction model. AB - OBJECTIVE: Length of hospital stay for patients following radical cystectomy is an important determinant for improved quality of care. We sought to develop and validate a predictive model for length of hospital stay following radical cystectomy. METHODS: Patients aged 66 to 90 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer who underwent radical cystectomy were included from January 1, 2002 through December 31, 2011 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Linear regression analyses were used to develop and validate a predictive model for length of hospital stay. RESULTS: A total of 2,448 patients met inclusion criteria. After random assignment, 1,224 patients were included in the discovery cohort and 1,224 patients included in the validation cohort. The cohorts were well balanced with no significant difference in any of the preoperative variables. A best model was developed using marital status, Surveillance, Epidemiology, and End Results (SEER) region, clinical stage, Charlson comorbidity index, logarithm of hospital cystectomy volume, and use of neoadjuvant chemotherapy in a backward selection to predict the length of stay. There was robust internal validation (sum square error (SSE): 258.1 vs. predicted sum of squares (PRESS): 264.0 at SLS = 0.10), consistent with the external validation (average square error (ASE): discovery (0.248) vs. validation (0.258)) cohort. The strength of the model in predicting length of stay for the entire cohort was (R2 = 0.048). CONCLUSION: In this large population-based study, we developed and validated a model to predict length of hospital stay following radical cystectomy. Identification of at-risk patients for prolonged hospital stay may aid in targeted interventions to reduce length of stay, improve quality of care, and decrease healthcare costs. PMID- 30446461 TI - Clinical value of cholinesterase in the prediction of biochemical recurrence after radical prostatectomy. AB - PURPOSE: To evaluate the predictive and prognostic role as well as the clinical impact on decision-making of serum cholinesterase (ChoE) levels in patients treated with radical prostatectomy for clinically nonmetastatic prostate cancer. MATERIALS AND METHODS: We conducted a retrospective analysis of our multi institutional database. Preoperative ChoE was evaluated as continuous and dichotomized variable using a visual assessment of the functional form of the association of ChoE with biochemical recurrence (BCR)-free survival. We assessed its association with perioperative clinicopathologic characteristics and outcomes. Multivariable models established its independent prognostic value for BCR. Cox proportional hazard coefficients were used to build nomograms for the prediction of early and late BCR. Decision curve analysis was used to assess the clinical impact on decision making of preoperative ChoE. RESULTS: In all, 6,041 patients were available for the analysis. Decreased ChoE was associated with higher biopsy Gleason score, preoperative PSA levels, pathologic Gleason score, pathological stage, lymph node metastasis, positive surgical margin, and lymphovascular invasion at radical prostatectomy (all P < 0.01). Preoperative ChoE <= 6.52 U/ml was associated with higher probability of BCR (HR 1.72, 95% CI 1.48-1.99, P < 0.001). Preoperative and postoperative multivariable models that adjusted for the effects of established clinicopathologic features confirmed its independent association with BCR. In decision curve analysis inclusion of preoperative ChoE did not improve the net benefit of preoperative and postoperative models for the prediction of BCR. CONCLUSIONS: Despite independent association with clinicopathologic features and BCR, preoperative serum ChoE has no impact on clinical decision making. Future studies should investigate the possible relationship between ChoE activity and neoplastic cell transformation with a rational for targeting. PMID- 30446463 TI - Management of bone and metabolic effects of androgen deprivation therapy. AB - Androgen deprivation therapy (ADT) is commonly given to men with prostate cancer. Both its benefits as well as its adverse effects are a direct consequence of sex steroid withdrawal. While ADT improves oncologic outcomes in appropriately selected men, it is associated with adverse effects, including accelerated bone loss leading to increased fracture risk, and with metabolically unfavorable body composition changes that predispose to diabetes and may increase cardiovascular risk. In this review, we will describe the pathophysiology behind these ADT associated adverse effects, and discuss the clinical evidence guiding clinical assessment and management. A proactive approach is important to minimize ADT associated adverse sequelae, so that the benefit-risk ratio of this treatment is optimized. PMID- 30446464 TI - Serum testosterone level as possible predictive marker in androgen receptor axis targeting agents and taxane chemotherapies for castration-resistant prostate cancer. AB - PURPOSE: Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC. PATIENTS AND METHODS: The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined. RESULTS: Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively. CONCLUSIONS: The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC. PMID- 30446465 TI - EGFR mono-antibody salvage therapy for locally advanced and distant metastatic penile cancer: Clinical outcomes and genetic analysis. AB - PURPOSE: There are limited therapeutic options for patients with advanced penile squamous cell carcinoma (PSCC) after chemotherapy failure. Thus, we evaluated the feasibility of salvage treatment using the epidermal growth factor receptor (EGFR) mono-antibody nimotuzumab in chemotherapy-failed PSCC patients and explored potential response or resistance biomarkers. MATERIALS AND METHODS: Six chemotherapy-failed PSCC patients with locally advanced disease or distant metastasis were enrolled consecutively to nimotuzumab treatment. Clinical responses and side effects were evaluated, and genetic characteristics of cancer specimens were analyzed through the next-generation sequencing of hotspot regions in cancer-related genes. RESULTS: Two of 6 patients showed partial responses, one was identified as having stable disease, while the other 3 had disease progression after nimotuzumab therapy. Side effects were all welltolerated. Genetic analysis revealed that TP53, CDKN2A, RB1, SMAD4, FLT3, and PIK3CA were the most frequently mutated genes in PSCC specimens, while altered KRAS, HRAS, EGFR, ERBB2, and FLT3 may be correlated with nimotuzumab resistance. Furthermore, 3 patients that were human papillomavirus-positive each showed clinical response or stable disease. CONCLUSIONS: EGFR mono-antibody may be a potential modality for locally advanced PSCC patients after chemotherapy failure. Further large scale clinical studies are needed to elucidate the role of human papillomavirus status and critical gene mutations in the clinical response to EGFR-targeted therapy. PMID- 30446467 TI - Corrections. PMID- 30446466 TI - Impact of metabolic syndrome on oncologic outcomes at radical prostatectomy. AB - PURPOSE: The associations between metabolic syndrome (MetS) and prostate cancer (CaP) outcomes following radical prostatectomy (RP) are not clear. This study aims to understand the role of MetS in influencing oncological outcomes at RP. MATERIALS AND METHODS: Patients who underwent RP for CaP at our institution from 2000 to 2010 were identified; MetS prior to RP was ascertained with a modified version of the IDF-AHA/NHLBI using ICD-9 codes. Histopathological outcomes included surgical margins, pathological stage, and Gleason score (GS) upgrading. Long-term outcomes included biochemical recurrence (BCR), local recurrence, systemic progression, and CaP-specific mortality. Multivariable adjusted logistic regression and Cox proportional hazards regression assessed the association between MetS status and histopathological and long-term outcomes, respectively. RESULTS: Of 8,504 RP patients, 1,054 (12.4%) had MetS at the time of RP. MetS patients were older, had higher biopsy GS, but lower pre-op prostatic specific antigen (PSA), higher pathological GS, and larger prostate volume. Adjusted logistic regression suggested an association between MetS and positive margins (odds ratio [OR] = 1.22, P = 0.025) and GS upgrading (OR = 1.28, P = 0.002). There was evidence of an increased risk of local recurrence (hazard ratio [HR] = 1.33, P = 0.037) and CaP-specific mortality (HR = 1.58, P < 0.001) for MetS patients. There was no evidence to suggest an association with BCR or systemic progression. CONCLUSION: Men with MetS are at higher risk of GS upgrade and positive surgical margins at surgery, local recurrence, and CaP-specific mortality. Pathological stage, BCR, and systemic progression were not associated with MetS. Our data may be useful in patients' counseling, especially when active surveillance is an option. PMID- 30446468 TI - Purulent Inflatable Penile Prostheses Can Be Safely Immediately Salvaged in Insulin-Dependent Diabetics. AB - INTRODUCTION: Historically, contra-indications for immediate salvage of an infected penile prosthesis have included purulence on the device, purulent infections in diabetic patients, and severe diabetes. These clinical principles are from the 1990s to early 2000s and based on limited retrospective series or expert opinion. Since the publication of these contra-indications there have been improvements in device design, surgical technique, corporal washout protocols, and perioperative antibiotic prophylaxis that allow us to re-evaluate whether we can broaden the criteria for immediate salvage of an infected penile prosthesis. AIM: To report whether patients with severe diabetes can safely have a purulent inflatable penile prosthesis (IPP) immediately salvaged. METHODS: We considered a "severe diabetic" as a patient whose disease has progressed past diet control and oral medications and, therefore, has insulin-dependent type 2 diabetes mellitus (IDDM II). We retrospectively reviewed 6 consecutive patients with IDDM II and a purulent IPP who had been immediately salvaged from July 2011 to November 2017. In addition to immediate exchange, each received catheter-directed anti-microbial intracorporal irrigation and device culture. All patients were discharged home the next day with oral antibiotics. MAIN OUTCOME MEASURE: Outcomes included repeat penile prosthesis infection or any other complication following immediate salvage. RESULTS: All 6 patients have healed well and remained infection free at their 6- to 8-week post-operative follow-up appointment. 15-39 months after salvage, no patients have had a repeat infection or any other complication. 5 patients received a malleable replacement device and 1 patient was electively converted to an IPP 7 months after his salvage procedure. 1 patient received an IPP during salvage per patient preference. All patients are currently pleased with either their malleable penile prosthesis or IPP. CLINICAL IMPLICATIONS: Immediate salvage attenuates the morbidity associated with an infected penile prosthesis such as irreversible penile shortening and corporal fibrosis. Our findings suggest that more patients than originally thought may be a candidate for immediate salvage. STRENGTH & LIMITATIONS: To our knowledge, this is the first study evaluating outcomes after immediate salvage of a purulent IPP in patients with advanced diabetes. Limitations of the study include the small sample size and retrospective nature. CONCLUSION: Our results suggest that those with IDDM II who have a purulent penile prosthesis may be candidates for safe and effective immediate salvage. Peters CE, Carlos EC, Lentz AC. Purulent Inflatable Penile Prostheses Can Be Safely Immediately Salvaged in Insulin-Dependent Diabetics. J Sex Med 2018;XX:XXX-XXX. PMID- 30446469 TI - Outcome of Medical and Psychosexual Interventions for Vaginismus: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: Although vaginismus is a condition with a great impact on psychosexual well-being, the evidence on the efficacy of interventions is lacking. AIM: To review all information on vaginismus treatment, including data from randomized clinical trials (RCTs) and observational studies. METHODS: A systematic search was conducted of MEDLINE, EMBASE, PsycINFO, and ClinicalTrials.gov. 2 Independent meta-analyses of RCTs and observational studies were performed. For RCTs, only those having no treatment as the comparator were considered eligible. MAIN OUTCOME MEASURE: The primary outcome was the success rate (number of successes/total sample) in the completion of sexual intercourse. RESULTS: 43 Observational studies (n = 1,660) and 3 RCTs (n = 264) were included in the final analyses, respectively. In the meta-analysis of RCTs, the use of psychological interventions showed a trend toward a significantly better result vs waiting list control (OR 10.27 [95% CI 0.79-133.5], P = .075). The combination of the results obtained from the observational studies showed that treating vaginismus is associated with the completion of sexual penetrative intercourse in 79% of cases, independently of the therapy used (success rate 0.79 [0.74-0.83]). When only moderate- or strong-quality studies were considered, the success rate was 0.82 (0.73-0.89). As for the different definitions of vaginismus, studies with unconsummated marriage as the inclusion criterion showed the worst success rate (0.68). The origin of vaginismus (primary, secondary, or both), its duration, the mean age of the participants, the involvement of the partner in the intervention, or the geographic setting did not exert a significant effect on the outcome. Studies enrolling women with unconsummated marriage showed a significantly worse success rate. CLINICAL IMPLICATIONS: No approach is superior to the others in allowing the achievement of penetrative intercourse in women with vaginismus. STRENGTH & LIMITATIONS: Only studies specifically enrolling patients with vaginismus were selected, and analyses were performed on an intention-to-treat approach. The main limitations are the small number of trials in the meta-analysis of RCTs and the lack of a comparison group in the meta analysis of observational studies, which cannot rule out a placebo effect. Due to the limited evidence available, great caution is required in the interpretation of results. Further well-designed trials, with more appropriate outcomes than penetrative sex, are required. CONCLUSION: The meta-analysis of RCTs documented a trend toward higher efficacy of active treatment vs controls, whereas the meta analysis of observational studies indicated that women with vaginismus benefit from a range of treatments in almost 80% of cases. Maseroli E, Scavello I, Rastrelli G, et al. Outcome of Medical and Psychosexual Interventions for Vaginismus: A Systematic Review and Meta-Analysis. J Sex Med 2018;XX:XXX-XXX. PMID- 30446470 TI - Psychosexual Correlates of Unwanted Sexual Experiences in Women Consulting for Female Sexual Dysfunction According to Their Timing Across the Life Span. AB - BACKGROUND: Comparative data on the psychopathologic and sexual correlates of unwanted sexual experiences (USEs) occurring during childhood, adolescence, or adult life are lacking. AIM: To investigate the prevalence of USEs in a setting of female sexual dysfunction (FSD) and to examine whether they are associated with different psychosexual parameters depending on the timing of occurrence. METHODS: A consecutive series of 200 heterosexual women attending our clinic for FSD was consecutively recruited. MAIN OUTCOME MEASURE: Patients underwent a structured interview and completed the Female Sexual Function Index, the Middlesex Hospital Questionnaire, the Female Sexual Distress Scale-Revised, the Body Uneasiness Test, and the Childhood Experience of Care and Abuse questionnaire. USEs were classified as occurring in adult life (>=17), adolescence (<17 and >=14), or childhood (<14 years). RESULTS: 47 women (23.5%) reported USEs, occurring in childhood, adolescence, and adult life in 38.3% (n = 18), 31.9% (n = 15), and 29.8% (n = 14) of cases, respectively. We observed an association between history of lifetime USEs and indexes of psychopathology, specifically diagnosis of psychiatric diseases, use of psychiatric medications, and anxiety symptoms (Middlesex Hospital Questionnaire free-floating anxiety score). USEs were associated with lower orgasm ability (Female Sexual Function Index orgasm domain), higher sexually related distress levels (Female Sexual Distress Scale-Revised total score), and higher body image concerns (Body Uneasiness Test) including depersonalization symptoms. Notably, women exposed to USEs in adolescence reported a stronger impairment of arousal, orgasm, and satisfaction domains and higher sexual distress when compared to women without a history of USEs or reporting USEs in childhood. Women exposed to USEs in childhood exhibited higher body image concerns and depersonalization symptoms when compared to those not reporting USEs. CLINICAL IMPLICATIONS: USEs should be investigated in women consulting for FSD because patients who had USEs may require unique strategies to optimize the diagnostic and therapeutic work-up of their sexual symptoms. STRENGTH & LIMITATIONS: Our main contribution is that we addressed the different impacts of USEs depending on their timing across the life span. However, the cross-sectional nature of the study does not allow determination of the cause-and-effect nature of the associations, and the selectivity of the sample (women consulting for FSD) limits the generalizability of the results. CONCLUSION: The negative outcomes of USEs vary according to their timing of occurrence: adolescence appears as the most sensitive temporal window for USEs to exert their deleterious effects on female sexuality, whereas childhood USEs are more tightly related to a severe body uneasiness in adult life. Maseroli M, Scavello I, Campone B, et al. Psychosexual Correlates of Unwanted Sexual Experiences in Women Consulting for Female Sexual Dysfunction According to Their Timing Across the Life Span. J Sex Med 2018;XX:XXX-XXX. PMID- 30446471 TI - Is Sexual Function Better Preserved After Water Vapor Thermal Therapy or Medical Therapy for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia? AB - BACKGROUND: Men often experience deterioration of sexual function after the use of alpha-blockers and 5-alpha reductase inhibitors for the treatment of lower urinary tract symptoms (LUTS) attributed to benign prostatic hyperplasia. Thus, an alternative treatment with water vapor thermal therapy (Rezum System, Boston Scientific, Marlborough, MA, USA) which is an efficacious minimally invasive surgical treatment that preserves sexual function was examined. AIM: To compare sexual function over 3 years after continuous daily treatment with pharmaceutical agents in the Medical Therapy of Prostatic Symptoms (MTOPS) study vs a single thermal therapy procedure (Rezum study) in subjects with matched criteria for LUTS severity and prostate size. METHODS: We used sexual function data from sexually active cohorts in the MTOPS study (1,209) randomized to doxazosin, finasteride, combination drugs and placebo, and sexually active men who received thermal therapy (86). MTOPS study participants completed the Brief Male Sexual Function Inventory; men in the Rezum trial completed the International Index of Erectile Function and Male Sexual Health Questionnaire. MAIN OUTCOME MEASURE: Estimated mean changes from baseline for sexual function variables were compared using a linear mixed repeated measures model with fixed effects for treatment and follow-up visits. RESULTS: With continued daily drug use, men experienced significant worsening of sexual desire, erectile and ejaculatory function with finasteride and combination drug therapy, and reduced desire and erectile function with doxazosin. Thermal therapy was not associated with significant negative changes in sexual function throughout 3 years after treatment. CLINICAL IMPLICATIONS: Water vapor thermal therapy can result in greater LUTS improvements than either doxazosin or finasteride alone, whereas combination drug therapy may equal that of this Rezum procedure, but all drug therapies did have a significant negative impact on sexual function in contrast to the preservation of libido, erectile, and ejaculatory function after thermal therapy. STRENGTH & LIMITATIONS: The report includes high-quality data from 2 large randomized controlled trials in subjects with similar baseline inclusion criteria for LUTS severity and prostate size. It is the first longitudinal assessment of sexual function domains restricted to sexually active men treated with drugs or a single minimally invasive surgical treatment with the Rezum procedure. A limitation of the study is the use of 2 different, although validated sexual function inventories (Brief Male Sexual Function Inventory and International Index of Erectile Function). CONCLUSION: A single water vapor thermal therapy procedure for targeted prostate tissue ablation for LUTS/ benign prostatic hyperplasia had no deleterious effect on 4 sexual function domains compared with appreciable worsening of sexual function after long-term single or combination drug use. McVary KT, Rogers T, Mahon J, et al. Is Sexual Function Better Preserved After Water Vapor Thermal Therapy or Medical Therapy for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia? J Sex Med 2018;XX:XXX-XXX. PMID- 30446472 TI - Structure of Epithelial and Stromal Compartments of Vulvar and Vaginal Tissue From Women With Vulvo-Vaginal Atrophy Taking Ospemifene. AB - INTRODUCTION: Vulvo-vaginal atrophy affects the daily lives of most post menopausal women. We know that ospemifene intake can induce vaginal epithelial improvements within a few weeks; however, direct evidence of the effects of ospemifene on the human vulva and on connective tissue of both the vagina and vulva are lacking. AIM: To evaluate the changes induced by ospemifene on epithelium thickness, glycogen content proliferation index, collagen content, and type I/III collagen ratio in vulvar and vaginal tissue of post-menopausal women. METHODS: 20 women who attended our gynecologic clinic for planned surgery were recruited for the study. 11 subjects were taking ospemifene at the time of inclusion, and 9 subjects who were not taking ospemifene were selected as control group. Vaginal and vulvar biopsies were taken during surgery. Histological features and glycogen content were evaluated by standard hematoxylin-eosin and periodic acid-Schiff staining, total collagen and collagen type I/III ratio were evaluated by hydroxyproline assay and Sirius red staining, while the expression of Ki67 was evaluated by immunohistochemistry. MAIN OUTCOME MEASURE: We analyzed histological features of the epithelial and stromal layer of the vaginal and vulvar vestibule mucosa. RESULTS: Vaginal and vulvar biopsies from women taking ospemifene showed an increased epithelium thickness, glycogen content, and proliferation index compared with the control group. Collagen content was also higher in women taking ospemifene, while an increased ratio between type I and III collagen fibers was found only at vaginal level. CLINICAL IMPLICATIONS: Our study shows that the effectiveness of ospemifene on vaginal tissue also extends to the vulvar vestibule. STRENGTH & LIMITATIONS: This study provides direct evidence of the impact of ospemifene on vaginal and vulvar tissue. A specifically designed longitudinal study may further support our findings. CONCLUSION: Ospemifene intake is associated with a marked improvement of various morphological and physiological features of both vaginal and vulvar vestibule epithelium, including the collagen content of the tissues. Alvisi S, Baldassarre M, Gava G, et al. Structure of Epithelial and Stromal Compartments of Vulvar and Vaginal Tissue From Women With Vulvo-Vaginal Atrophy Taking Ospemifene. J Sex Med 2018;XX:XXX-XXX. PMID- 30446473 TI - Complications of Genital Enlargement Surgery. AB - INTRODUCTION: The objective of genital enlargement surgery is to increase length and/or girth for cosmetic reasons; however, newer techniques have been recently reported to be associated with only minor complications in a small percentage of patients. AIM: We aim to report the severe complications of penile augmentation surgery seen at a referral center and describe their subsequent management. METHODS: Institutional review board approval was obtained. We reviewed our prospectively collected database for all patients who presented with complications of genital enlargement surgery from 2002-2016. MAIN OUTCOME MEASURE: Interventions following complications of genital enlargement surgery. RESULTS: 11 Patients were identified. Mean age was 47 (21-77) years. Prior procedures included subcutaneous injection of silicone outside a medical setting, girth enhancement procedures involving the subcutaneous placement or injection of substances including fat, other substances, or subcutaneous silicone implants. All patients who underwent subcutaneous penile implant underwent removal prior to presentation. Adverse changes included sexually disabling penile deformity and severe shortening, curvature, edema, subcutaneous masses, infection, non-healing wounds, and sexual dysfunction. 10 patients underwent corrective surgery, with 2 requiring multiple procedures and 3 requiring split-thickness skin grafting. All 10 patients had an improved cosmetic appearance and those who had disabling shortening had significantly improved functional length. CLINICAL IMPLICATIONS: Report of such adverse events should assist in appropriate perioperative counseling prior to genital enhancement surgery. STRENGTH & LIMITATIONS: Few reports of debilitating complications of penile enlargement exist in literature. However, without knowing the overall number of procedures performed, the true complication incidence is not known. CONCLUSION: Penile and scrotal enhancement surgery can be associated with major disabling complications, leading to deformity and functional compromise in men with prior normal anatomy and function. Patients should be aware of these risks. Furr J, Hebert K, Wisenbaugh E, et al. Complications of Genital Enlargement Surgery. J Sex Med 2018;XX:XXX XXX. PMID- 30446474 TI - Prospective Cohort of Deep Dyspareunia in an Interdisciplinary Setting. AB - INTRODUCTION: Deep dyspareunia is a common symptom in women, including in half of women with endometriosis, but little is known about its response to treatment and predictors of persistent deep dyspareunia over time. AIM: To follow up deep dyspareunia severity over a 1-year prospective cohort at an interdisciplinary center, and to identify baseline predictors of more persistent deep dyspareunia at 1 year. METHODS: Prospective 1-year cohort study at a tertiary referral center for pelvic pain and endometriosis, where a range of interdisciplinary treatments are provided at a single center (surgical, hormonal, physical, and psychological therapies). Exclusion criteria were menopause, age >50 years, and never previously sexually active. Primary outcome (deep dyspareunia severity) and secondary outcome (sexual quality of life) were followed up over 1 year. Ordinal logistic regression was performed, controlling for baseline severity of deep dyspareunia, to identify baseline predictors of deep dyspareunia severity at 1 year. MAIN OUTCOME MEASURE: Primary outcome was severity of deep dyspareunia on an 11-point numeric rating scale (0-10), categorized into absent-mild (0-3), moderate (4-6), and severe (7-10); secondary outcome was sexual quality of life measured by the Endometriosis Health Profile-30. RESULTS: 1-year follow-up was obtained for 278 subjects (56% response rate at 1 year; 278/497). Severity of deep dyspareunia improved over the 1 year (McNemar test, P < .0001): the proportion of patients in the severe category decreased from 55.0% to 30.4%, the moderate category remained similar from 17.7% to 25.0%, and the absent-mild category increased from 27.3% to 44.6%. Sexual quality of life also improved (56% to 43% on the sex subscale of the Endometriosis Health Profile-30) (Welch t test, P < .001). On ordinal regression, severity of deep dyspareunia at 1 year was independently associated with younger age (OR = 0.94, 95% CI = 0.91-0.97, P = .008), and with a higher baseline depression score on the Patient Health Questionnaire-9 (OR = 1.07, 95% CI = 1.03-1.11, P = .01). CLINICAL IMPLICATIONS: Clinicians should consider employing an interdisciplinary approach for deep dyspareunia, and screening for and treating depression symptoms in these women. STRENGTH & LIMITATIONS: Strengths of the study include its prospective nature, and assessment of deep dyspareunia specifically (as opposed to superficial dyspareunia). Limitations include non-randomized design, and the patients lost to follow-up over the 1 year. CONCLUSION: Over 1 year in an interdisciplinary setting, improvements were observed in deep dyspareunia and sexual quality of life, but younger women and those with more severe depression at baseline had more persistent deep dyspareunia at 1 year. Yong PJ, Williams C, Bodmer-Roy S, et al. Prospective Cohort of Deep Dyspareunia in an Interdisciplinary Setting. J Sex Med 2018;XX:XXX-XXX. PMID- 30446476 TI - Erratum to "Responsive antimicrobial dental adhesive based on drug-silica co assembled particles" [Acta Biomater. 76 (2018) 283-294]. PMID- 30446475 TI - Feasibility and Acceptability of a Peer Mentoring Program for Older Adults Following Hospitalization for Hip Fracture. PMID- 30446477 TI - Freestyle Libre trend arrows for the management of adults with insulin-treated diabetes: A practical approach. AB - Freestyle Libre (FSL) system is a new method to detect glucose enabling a new paradigm in glucose monitoring and self-management. The sensor, reading the interstitial fluid glucose concentration, provides a numerical data of glucose level and a trend arrow that add context to static measurement of glucose level. Therefore, patients could easily follow the progression of their glucose levels over the time, allowing early detection and timely treatment of deviations from targeted glucose level range, thus preventing extreme fluctuations. In order to take full advantage of the system both the caregiver and the person with diabetes must appreciate the need of careful interpretation of the data generated by the FSL. To this purpose we have generated recommendations that are based on methods suggested for CGM, our clinical experience and discussion with experienced patients using FSL, to provide a pragmatic approach to use FSL trend arrow data for managing diabetes in adults. PMID- 30446478 TI - Prognostic tools for cardiovascular disease in patients with type 2 diabetes: A systematic review and meta-analysis of C-statistics. AB - BACKGROUND: Diabetes is associated with an increased risk for cardiovascular diseases (CVD). Risk prediction models are tools widely used to identify individuals at particularly high-risk of adverse events. Many CVD risk prediction models have been developed but their accuracy and consistency vary. OBJECTIVE: This study reviews the literature on available CVD risk prediction models specifically developed or validated in patients with diabetes and performs a meta analysis of C-statistics to assess and compare their predictive performance. METHODS: The online databases and manual reference checks of all identified relevant publications were searched. RESULTS: Fifteen CVD prediction models developed for patients with diabetes and 11 models developed in a general population but later validated in diabetes patients were identified. Meta analysis of C-statistics showed an overall pooled C-statistic of 0.67 and 0.64 for validated models developed in diabetes patients and in general populations respectively. This small difference in the C-statistic suggests that CVD risk prediction for diabetes patients depends little on the population the model was developed in (p = 0.068). CONCLUSIONS: The discriminative ability of diabetes specific CVD prediction models were modest. Improvements in the predictive ability of these models are required to understand both short and long-term risk before implementation into clinical practice. PMID- 30446479 TI - The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus. AB - AIMS: To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO2) in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 163 participants were recruited; 100 with T2DM and 63 healthy individuals. Peripheral arterial disease (PAD) was defined as ankle-brachial index (ABI) values <=0.90. Diagnosis of DPN was based on neuropathy symptom score and neuropathy disability score (NDS), while diagnosis of CAN on the battery of the cardiovascular autonomic function tests. TcPO2 was measured using a TCM30 system. RESULTS: Patients with T2DM had lower TcPO2 levels when compared with healthy individuals. Among the diabetic cohort, those who had either PAD, DPN or CAN had significantly lower TcPO2 values than participants without these complications. Multivariate linear regression analysis, after controlling for diabetes duration, diastolic blood pressure, HbA1c, albumin to creatinine ratio and CAN score, demonstrated that TcPO2 levels were significantly and independently associated with current smoking (p = 0.013), ABI (p = 0.003), and NDS (p = 0.013). CONCLUSION: Presence of DPN is independently associated with impaired cutaneous perfusion. Low TcPO2 in subjects with DPN may contribute to delay in healing of diabetic foot ulcers, irrespectively of PAD. PMID- 30446480 TI - What Is the Role of Increasing Inhaled Corticosteroid Therapy in Worsening Asthma in Children? AB - The treatment of "yellow zone," or worsening, asthma in children remains controversial. The 2018 Global Initiative for Asthma strategy recommends increasing the dose of inhaled corticosteroid (ICS) for the short (1-2 weeks) or longer (3 months) term in children older than 5 years with worsening asthma. In contrast, the National Heart, Lung, and Blood Institute's Expert Panel Report 3 guideline for the diagnosis and management of asthma notes that doubling the dose of ICS therapy is "not sufficient" in worsening asthma, as does the Canadian Thoracic Society guideline on asthma management in children. Both guidelines do comment that higher than double dosing may be effective. In particular, the Expert Panel Report 3 guideline specifies that more than doubling the dose of ICS therapy may be useful in the emergency department management of worsening asthma, because it may prevent oral corticosteroid requirement. The Canadian Thoracic Society suggests that adolescents (older than 12 years) quadruple ICS maintenance dosing by 4- or 5-fold for 7 to 14 days with worsening asthma if there is a history of a severe exacerbation in the past year. All these recommendations were published before a recent, large randomized double-blind controlled trial by Jackson et al that further calls into question the efficacy of increased ICS dosing in worsening asthma in children. The goal of this Rostrum was to review available data and consider the role of increasing doses of ICS and potential alternative approaches to this common practice. PMID- 30446481 TI - Barriers to physical activity in university students with disabilities: Differences by sociodemographic variables. AB - BACKGROUND: Despite the positive effects of regular physical activity (PA), university students with disabilities are less active than their able-bodied peers, which could be due to the wide range of barriers to PA that these individuals face across all social ecological levels. OBJECTIVE: To identify the barriers to PA experienced by university students with disabilities at the different social ecological levels and to examine the differences in these barriers by sociodemographic variables. METHODS: The reduced Spanish version of the Barriers to Physical Activity Questionnaire for People with Mobility Impairments was administered to a sample of 1219 Spanish university students with disabilities. Non-parametric tests were performed to examine the differences in the barriers experienced by sociodemographic variables. RESULTS: The most important barriers were intrapersonal (e.g. fatigue, pain, lack of motivation), followed by organizational ones (e.g. lack of adapted programs, economic cost). At the interpersonal level, the inactivity of friends and family were the main barriers. Potholes in the streets or other public spaces were found to be the most important barriers at the community level. Significant differences were found in barriers by sex, age, disability grade, congenital-acquired disability and disability type. The groups most affected by the barriers were, in general, those with multiple disabilities and higher disability grade. CONCLUSIONS: The results indicate the need for PA promotion programs to be implemented for university students with disabilities addressing the most important barriers found at each social ecological level, as well as the differences identified by sociodemographic variables. PMID- 30446482 TI - Measuring Engagement in eHealth and mHealth Behavior Change Interventions: Viewpoint of Methodologies. AB - Engagement in electronic health (eHealth) and mobile health (mHealth) behavior change interventions is thought to be important for intervention effectiveness, though what constitutes engagement and how it enhances efficacy has been somewhat unclear in the literature. Recently published detailed definitions and conceptual models of engagement have helped to build consensus around a definition of engagement and improve our understanding of how engagement may influence effectiveness. This work has helped to establish a clearer research agenda. However, to test the hypotheses generated by the conceptual modules, we need to know how to measure engagement in a valid and reliable way. The aim of this viewpoint is to provide an overview of engagement measurement options that can be employed in eHealth and mHealth behavior change intervention evaluations, discuss methodological considerations, and provide direction for future research. To identify measures, we used snowball sampling, starting from systematic reviews of engagement research as well as those utilized in studies known to the authors. A wide range of methods to measure engagement were identified, including qualitative measures, self-report questionnaires, ecological momentary assessments, system usage data, sensor data, social media data, and psychophysiological measures. Each measurement method is appraised and examples are provided to illustrate possible use in eHealth and mHealth behavior change research. Recommendations for future research are provided, based on the limitations of current methods and the heavy reliance on system usage data as the sole assessment of engagement. The validation and adoption of a wider range of engagement measurements and their thoughtful application to the study of engagement are encouraged. PMID- 30446483 TI - The Rise of Pregnancy Apps and the Implications for Culturally and Linguistically Diverse Women: Narrative Review. AB - BACKGROUND: Pregnancy apps are a booming global industry, with most pregnant women in high-income countries now using them. From the perspective of health care and health information provision, this is both encouraging and unsettling; the demand indicates a clear direction for the development of future resources, but it also underscores the importance of processes ensuring access, reliability, and quality control. OBJECTIVE: This review provides an overview of current literature on pregnancy apps and aims at describing (1) the ways in which apps are used by women, in general, and by those of a culturally and linguistically diverse (CALD) background; (2) the utility and quality of information provided; and (3) areas where more research, development, and oversight are needed. METHODS: We chose a narrative review methodology for the study and performed a structured literature search including studies published between 2012 and 2017. Searches were performed using MEDLINE, EMBASE, and CINAHL databases. Studies were identified for inclusion using two separate search criteria and strategies: (1) studies on pregnancy apps and pregnant women's use of these apps and (2) studies on CALD pregnant women and their use of technology for accessing information on and services for pregnancy. Overall, we selected 38 studies. RESULTS: We found that pregnancy apps were principally used to access pregnancy health and fetal development information. Data storage capability, Web-based features or personalized tools, and social media features were also popular app features sought by women. Lower rates of the pregnancy app uptake were indicated among lower-income and non-English-speaking women. Preliminary evidence indicates that a combination of technological, health literacy, and language issues may result in lower uptake of pregnancy apps by these groups; however, further investigation is required. A marked limitation of the health app industry is lack of regulation in a commercially dominated field, making it difficult for users to assess the reliability of the information being presented. Health professionals and users alike indicate that given the choice, they would prefer using pregnancy apps that are relevant to their local health care context and come from a trusted source. Evidence indicates a need for greater health professional and institutional engagement in the app development, as well as awareness of and guidance for women's use of these resources. CONCLUSIONS: This is the first review of pregnancy app use, types of information provided, and features preferred by pregnant women in general and by those of a CALD background in particular. It indicates the demand for access to accurate information that is relevant to users, their community, and their associated health services. Given the popularity of pregnancy apps, such apps have enormous potential to be used for the provision of accurate, evidence-based health information. PMID- 30446484 TI - Mental Health Mobile Phone App Usage, Concerns, and Benefits Among Psychiatric Outpatients: Comparative Survey Study. AB - BACKGROUND: Despite the popularity of mental health apps, it is unknown if they are actually used by those with mental illness. This study assessed whether differences in clinic setting may influence the use of mental health apps and which factors influence patient perception of apps. OBJECTIVE: The objective of this study was to gain an understanding of how individuals with mental illness use their mobile phones by exploring their access to mobile phones and their use of mental health apps. METHODS: A single time point survey study was conducted over a 2-week period in February 2018 at two nearby outpatient psychiatry clinics: one serving largely mood and anxiety disorder patients with private insurance staffed by both faculty and residents and the other serving largely psychotic disorder patients in a state Department of Mental Health (DMH) setting. A total of 25 patients at the state DMH clinic also consented for a single time point observation of apps currently installed on their personal mobile phone. RESULTS: A total of 113 patients at the private insurance clinic and 73 at the state DMH clinic completed the survey. Those in the private insurance clinic were more likely to download a mental health app compared to the state DMH clinic, but actual rates of reported current app usage were comparable at each clinic, approximately 10%. Verifying current apps on patients' mobile phones at the state DMH clinic confirmed that approximately 10% had mental health apps installed. Patients at both clinics were most concerned about privacy of mental health apps, although those at the state DMH clinic viewed cost savings as the greatest benefit while those at the private clinic reported time as the greatest benefit. CONCLUSIONS: High interest in mental health apps does not automatically translate into high use. Our results of low but similar rates of mental health app use at diverse clinics suggests DMH patients with largely psychotic disorders are as interested and engaged with apps as those in a private insurance clinic treating largely mood and anxiety disorders. Results from our study also highlight the importance of understanding how actual patients are using apps instead of relying on internet-based samples, which often yield higher results due to their likelihood of being selected. PMID- 30446485 TI - Medical cannabis in the UK. PMID- 30446487 TI - Abortion: US global gag rule is having "chilling effect" on sexual health service providers. PMID- 30446486 TI - Fecal microbiota transplantation with frozen capsules for a patient with refractory acute gut graft-versus-host disease. PMID- 30446488 TI - Factors associated with place of death for children in South Yorkshire: a retrospective cohort study. AB - OBJECTIVES: Place of death (POD) is considered a key quality indicator for adult end of-life care, but paediatric evidence is limited. Data from Child Death Overview Panel (CDOP) databases provides an opportunity to describe trends in POD as regional paediatric palliative medicine (PPM) options have increased. Aims were to identify and describe trends in POD for children in South Yorkshire. METHODS: Retrospective cohort study. Anonymised data extracted from five CDOP databases 2008-2015. Data included age, gender, ethnicity, postcode (outward code only), POD, classification and category of death. Descriptive statistical analysis using chi2 test was used to assess intergroup differences. RESULTS: 748 deaths were notified from 2008 to 2015. Neonatal deaths were excluded, 46% (n=345). Of non-neonatal deaths (n=403), 58% (n=232) were 'expected'. Of expected deaths (n=232), 19% (n=45) died in home, 19% (n=45) died in hospice and 61% (n=141) died in hospital. This was significantly different from comparable national data which showed considerably more hospital deaths. There was no significant change in POD over time. CONCLUSION: Hospital remains the POD for most children, whether deaths are 'expected' or not, suggesting specialised PPM should be expanded into the hospital setting. More research is needed regarding preference for POD. This study may help inform future service planning for PPM and hospice development. PMID- 30446489 TI - Better drug use in advanced disease: an international Delphi study. AB - Patients with a limited life expectancy use many medications, some of which may be questionable. OBJECTIVES : To identify possible solutions for difficulties concerning medication management and formulate recommendations to improve medication management at the end of life. METHODS : A two-round Delphi study with experts in the field of medication management and end-of-life care (based on ranking in the citation index in Web of Science and relevant publications). We developed a questionnaire with 58 possible solutions for problems regarding medication management at the end of life that were identified in previously performed studies. RESULTS : A total of 42 experts from 13 countries participated. Response rate in the first round was 93%, mean agreement between experts for all solutions was 87 % (range 62%-100%); additional suggestions were given by 51%. The response rate in the second round was 74%. Awareness, education and timely communication about medication management came forward as top priorities for guidelines. In addition, solutions considered crucial by many of the experts were development of a list of inappropriate medications at the end of life and incorporation of recommendations for end-of-life medication management in disease-specific guidelines. CONCLUSIONS : In this international Delphi study, experts reached a high level of consensus on recommendations to improve medication management in end-of-life care. These findings may contribute to the development of clinical practice guidelines for medication management in end-of life care. PMID- 30446490 TI - Conscientious objection and physician-assisted suicide: a viable option in the UK? AB - Conscience objection is a proposed way of ensuring that medical practitioners who object to physician-assisted suicide may avoid having to be involved in such a procedure if this is legalised. This right on the part of healthcare professionals already exists in certain circumstances. This paper examines the ethical and legal grounds for conscientious objection for medical professionals and shows how it is heavily criticised in circumstances where it is already used. The paper comes to the conclusion that as the grounds and application of conscience objection are no longer as widely accepted, its future application in any legislation can be called into question. PMID- 30446491 TI - State of the science: heart rate variability in health and disease. PMID- 30446492 TI - Speech-language pathologists in paediatric palliative care: a Delphi study protocol. AB - BACKGROUND: Given the dearth of literature and no clinical practice guidelines written for speech-language pathologists (SLPs) working in paediatric palliative care (PPC), a need has been identified to explore the scope of clinical practice and strategies used by SLPs. OBJECTIVE: This study aims to undertake an international investigation into the role and scope of practice of SLPs working in PPC to develop consensus-driven 'Recommendations for Speech-Language Pathologists in Paediatric Palliative Care Teams' (ReSP3CT). METHODS: A modified Delphi process will be used to synthesise consensus-based statements from SLPs in six different countries about their role and practice working in PPC. Initially, preliminary survey data will be collected from SLPs to obtain demographic and caseload information. Respondents will then be invited to participate in an in depth interview to explore common and unique themes that emerge from the online survey. Participants from the interview will then 'opt-in' to become Delphi panel members and receive questionnaires comprising statements for agreement over multiple rounds. Statements will be based on common themes that arise from the literature review, survey and interview data. The Delphi process for each statement will stop if statements achieve >= 70 % agreement and an IQR of <= 1 (maximum of five rounds). CONCLUSION: This is the first study to investigate the role and practice of SLPs in PPC across internationally accepted scope of practice areas. The study will use existing frameworks for statistical analysis and a mixed-methods approach to aid in the synthesis of statements/recommendations for international consensus. PMID- 30446493 TI - Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET CT: a collaborative study by ILROG. AB - Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40-50%. As 18F-FDG PET-CT upstages 10-60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study. Inclusion criteria were: RT alone for untreated stage I-II FL (grade 1-3A) with dose equivalent >=24 Gy, staged by PET-CT, age >=18 years, and follow up >=3 months. Endpoints were freedom from progression (FFP), local control, and overall survival (OS). FFP and OS were estimated with Kaplan-Meier, and uni- and multivariable analyses of prognostic factors performed with Cox Regression. 512 patients treated from 2000-2017 at 16 centres were eligible for analysis. Median age was 58 years (range 20-90). 410 patients (80.1%) had stage I disease. Median RT dose was 30 Gy (24-52). Median follow up was 52 months (3.2 174.6). 5y-FFP and OS were 68.9% and 95.7%. For stage I, 5y-FFP was 74.1%, vs 49.1% for stage II (p<0.0001). 8 patients relapsed infield (1.6%).4 had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (HR=2.11, 95%CI=1.44-3.10) and BCL2 expression (HR =1.62, 95%CI 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated. PMID- 30446494 TI - Genomic alterations important for the prognosis in patients with follicular lymphoma treated on SWOG study S0016. AB - Although recent advances in molecular genetics have enabled improved risk classification of follicular lymphoma (FL) using, for example, the m7-FLIPI score, the impact on treatment has been limited. We aimed to assess the prognostic significance of copy number aberrations (CNAs) and copy neutral loss of heterozygosity (cnLOH) identified by chromosome genomic array testing (CGAT) at FL diagnosis using prospectively collected clinical trial specimens from 255 patients enrolled in SWOG S0016. The impact of genomic aberrations was assessed for early progression (progressed or died within 2 years after registration), progression free survival (PFS), and overall survival (OS). We showed that increased genomic complexity (i.e., the total number of aberration calls) was associated with poor outcome in FL. Certain chromosome arms were critical for clinical outcome. Prognostic CNAs/cnLOH were identified: while early progression was correlated with 2p gain [P=0.007, OR=2.55 (1.29, 5.03)] and 2p cnLOH [P=0.005, OR=10.9 (2.08, 57.2)], 2p gain specifically encompassing VRK2 and FANCL predicted PFS [P=0.01, HR=1.80 (1.14, 2.68)] as well as OS [P=0.005, 2.40 (1.30, 4.40)]; CDKN2A/B (9p) deletion correlated with worse PFS [P=0.004, 3.50 (1.51, 8.28)]; whereas CREBBP (16p) [P<0.001, 6.70 (2.52, 17.58)] and TP53 (17p) [P<0.001, 3.90 (1.85, 8.31)] deletion predicted worse OS. An independent cohort from the m7-FLIPI study was explored, and the prognostic significance of aberration count, and TP53 and CDKN2A/B deletion were further validated. In conclusion, assessing genomic aberrations at FL diagnosis with CGAT improves risk stratification independent of known clinical parameters, and provides a framework for development of future rational targeted therapies. PMID- 30446496 TI - Government must guarantee EU doctors' rights after Brexit, says BMA. PMID- 30446497 TI - Omega 3 fatty acids can reduce risk of premature birth, finds Cochrane review. PMID- 30446495 TI - The genomic landscape of plasma cells in systemic light chain amyloidosis. PMID- 30446498 TI - Rescuing ocular development in an anophthalmic pig by blastocyst complementation. AB - Porcine-derived xenogeneic sources for transplantation are a promising alternative strategy for providing organs for treatment of end-stage organ failure in human patients because of the shortage of human donor organs. The recently developed blastocyst or pluripotent stem cell (PSC) complementation strategy opens a new route for regenerating allogenic organs in miniature pigs. Since the eye is a complicated organ with highly specialized constituent tissues derived from different primordial cell lineages, the development of an intact eye from allogenic cells is a challenging task. Here, combining somatic cell nuclear transfer technology (SCNT) and an anophthalmic pig model (MITF L 247S/L247S), allogenic retinal pigmented epithelium cells (RPEs) were retrieved from an E60 chimeric fetus using blastocyst complementation. Furthermore, all structures were successfully regenerated in the intact eye from the injected donor blastomeres. These results clearly demonstrate that not only differentiated functional somatic cells but also a disabled organ with highly specialized constituent tissues can be generated from exogenous blastomeres when delivered to pig embryos with an empty organ niche. This system may also provide novel insights into ocular organogenesis. PMID- 30446500 TI - HIP1R Is a Negative Regulator of PD-L1. AB - HIP1R targets PD-L1 for lysosomal degradation, thereby enhancing the antitumor activity of T cells. PMID- 30446499 TI - TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology. AB - The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the beta-tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non-functional alpha/beta-tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock-out disrupted microtubule integrity by preventing beta1-tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for beta1-tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin-coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis. PMID- 30446501 TI - Pembrolizumab Produces Durable Responses in Melanoma Brain Metastases. AB - Pembrolizumab is well tolerated and achieves durable intracranial responses lasting more than 24 months. PMID- 30446502 TI - Two MYC Homology Boxes Drive Tumorigenesis. AB - A protein interaction screen reveals 336 MYC-binding proteins that bind to distinct MYC homology boxes (MB). PMID- 30446503 TI - A Developed STING Agonist Has Systemic Antitumor Activity. AB - A dimeric amidobenzimidazole (diABZI) STING agonist enhances adaptive immunity and antitumor activity. PMID- 30446504 TI - Near-infrared spectroscopy monitoring during out-of-hospital cardiac arrest: can the initial cerebral tissue oxygenation index predict ROSC? AB - STUDY OBJECTIVES: Near-infrared spectroscopy is a modality that can monitor tissue oxygenation index (TOI) and has potential to evaluate return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). This study's objectives were to evaluate whether TOI could be associated with ROSC and used to help guide the decision to either terminate CPR or proceed to extracorporeal CPR (ECPR). METHODS: In this observational study, we assessed the patients with out-of-hospital cardiac arrest with non-traumatic cause receiving CPR on arrival at our ED between 2013 and 2016. TOI monitoring was discontinued either on CPR termination after ROSC was reached or on patient death. Patients were classified into two groups: ROSC and non-ROSC group. RESULTS: Out of 141 patients, 24 were excluded and the remaining 117 were classified as follows: ROSC group (n=44) and non-ROSC group (n=73). ROSC group was significantly younger and more likely to have their event witnessed and bystander CPR. ROSC group showed a higher initial TOI than non-ROSC group (60.5%+/-17.0% vs 37.9%+/-13.7%: p<0.01). Area under the curve analysis was more accurate with the initial TOI than without it for predicting ROSC (0.88, 95% CI 0.82 to 0.95 vs 0.79, 95% CI 0.70 to 0.87: p<0.01). TOI cut-off value >=59% appeared to favour survival to hospital discharge whereas TOI <=24% was associated with non-ROSC. CONCLUSIONS: This study demonstrated an association between higher initial TOI and ROSC. Initial TOI could increase the accuracy of ROSC prognosis and may be a clinical factor in the decision to terminate CPR and select patients who are to proceed to ECPR. PMID- 30446506 TI - Occupational psychology in the UK Ministry of Defence. AB - Psychologists first became prominent within the Armed Forces largely as a result of their contributions to military systems, operations and personnel during the First and Second World Wars. In the early years of the 20th century, as psychology was becoming a profession in its own right, its association with the military arose within the emerging concept of 'shell shock' during World War I and supporting selection activities in World War II. There are approximately 25 occupational psychologists currently employed within the Ministry of Defence (MoD), operating across all branches of the MoD, within the department of the Chief of Defence Personnel, the UK Defence Academy and a small number at the Defence Science and Technology Laboratory. The aim of this paper is to discuss the history and current application of occupational psychology within the UK MoD. PMID- 30446505 TI - Single-cell transcriptional analysis reveals ILC-like cells in zebrafish. AB - Innate lymphoid cells (ILCs) are important mediators of the immune response and homeostasis in barrier tissues of mammals. However, the existence and function of ILCs in other vertebrates are poorly understood. Here, we use single-cell RNA sequencing to generate a comprehensive atlas of zebrafish lymphocytes during tissue homeostasis and after immune challenge. We profiled 14,080 individual cells from the gut of wild-type zebrafish, as well as of rag1-deficient zebrafish that lack T and B cells, and discovered populations of ILC-like cells. We uncovered a rorc-positive subset of ILCs that could express cytokines associated with type 1, 2, and 3 responses upon immune challenge. Specifically, these ILC like cells expressed il22 and tnfa after exposure to inactivated bacteria or il13 after exposure to helminth extract. Cytokine-producing ILC-like cells express a specific repertoire of novel immune-type receptors, likely involved in recognition of environmental cues. We identified additional novel markers of zebrafish ILCs and generated a cloud repository for their in-depth exploration. PMID- 30446508 TI - Oddballs in the Shaker family: Kv2-related regulatory subunits. PMID- 30446510 TI - FLCN is a novel Rab11A-interacting protein and is involved in the Rab11A-mediated recycling transport. AB - The Birt-Hogg-Dube (BHD) syndrome related protein FLCN has recently been implicated in the vesicular trafficking processes by interacting with several Rab family GTPases. In the previous studies, we have shown that FLCN could inhibit the binding of overexpressed PAT1, which is a membrane-bound amino acid transporter, to the lysosome in human embryonic kidney 293 cells. This tends to stabilize the lysosomal amino acid pool that is a critical signal to activate the mTORC1 signalling pathway. However, the mechanisms of FLCN during this process remain unexplored. Here we report that FLCN can bind via its C-terminal DENN-like domain to the recycling transport regulator, Rab11A. Suppression of either Rab11A or FLCN facilitated the localization of the overexpressed PAT1 on the lysosome and inhibited its targeting on the plasma membrane. As a consequence, the mTORC1 was down-regulated. The in vitro GEF activity assay does not support FLCN modifies the Rab11A activity directly. Instead, we found FLCN promoted the loading of PAT1 on Rab11A. Our data uncover a function of FLCN in the Rab11A mediated recycling pathway and may provide new clues to understand the BHD conditions. PMID- 30446511 TI - Direct binding of Talin to Rap1 is required for cell-ECM adhesion in Drosophila. AB - Attachment of cells to the Extracellular Matrix (ECM) via integrins is essential for animal development and tissue maintenance. The cytoplasmic protein Talin is necessary for linking integrins to the cytoskeleton and its recruitment is a key step in the assembly of the adhesion complex. However, the mechanisms that regulate Talin recruitment to sites of adhesion in vivo are still not well understood. Here we show that Talin recruitment to, and maintenance at, sites of integrin-mediated adhesion requires a direct interaction between Talin and the GTPase Rap1. A mutation that blocks the direct binding of Talin to Rap1 abolished Talin recruitment to sites of adhesion and the resulting phenotype phenocopies null alleles of Talin. Moreover, we show that Rap1 activity modulates Talin recruitment to sites of adhesion via its direct binding to Talin. These results identify the direct Talin-Rap1 interaction as a key in vivo mechanism for controlling integrin-mediated cell-ECM adhesion. PMID- 30446509 TI - TREK-1 channels regulate pressure sensitivity and calcium signaling in trabecular meshwork cells. AB - Mechanotransduction by the trabecular meshwork (TM) is an essential component of intraocular pressure regulation in the vertebrate eye. This process is compromised in glaucoma but is poorly understood. In this study, we identify transient receptor potential vanilloid isoform 4 (TRPV4) and TWIK-related potassium channel-1 (TREK-1) as key molecular determinants of TM membrane potential, pressure sensitivity, calcium homeostasis, and transcellular permeability. We show that resting membrane potential in human TM cells is unaffected by "classical" inhibitors of voltage-activated, calcium-activated, and inwardly rectifying potassium channels but is depolarized by blockers of tandem pore K+ channels. Using gene profiling, we reveal the presence of TREK-1, TASK-1, TWIK-2, and THIK transcripts in TM cells. Pressure stimuli, arachidonic acid, and TREK-1 activators hyperpolarize these cells, effects that are antagonized by quinine, amlodipine, spadin, and short-hairpin RNA-mediated knockdown of TREK-1 but not TASK-1. Activation and inhibition of TREK-1 modulates [Ca2+]TM and lowers the impedance of cell monolayers. Together, these results suggest that tensile homeostasis in the TM may be regulated by balanced, pressure-dependent activation of TRPV4 and TREK-1 mechanotransducers. PMID- 30446507 TI - Nepsilon-lysine acetylation in the endoplasmic reticulum - a novel cellular mechanism that regulates proteostasis and autophagy. AB - Protein post-translational modifications (PTMs) take many shapes, have many effects and are necessary for cellular homeostasis. One of these PTMs, Nepsilon lysine acetylation, was thought to occur only in the mitochondria, cytosol and nucleus, but this paradigm was challenged in the past decade with the discovery of lysine acetylation in the lumen of the endoplasmic reticulum (ER). This process is governed by the ER acetylation machinery: the cytosol:ER-lumen acetyl CoA transporter AT-1 (also known as SLC33A1), and the ER-resident lysine acetyltransferases ATase1 and ATase2 (also known as NAT8B and NAT8, respectively). This Review summarizes the more recent biochemical, cellular and mouse model studies that underscore the importance of the ER acetylation process in maintaining protein homeostasis and autophagy within the secretory pathway, and its impact on developmental and age-associated diseases. PMID- 30446512 TI - Evaluation of in vitro susceptibility of Gram-positive pathogens from a tertiary care hospital in Singapore to a novel oxazolidinone, tedizolid, by a gradient diffusion method and broth microdilution. AB - We compared the in vitro antimicrobial activities of tedizolid and linezolid on the Sensititre broth microdilution system for Gram-positive cocci isolates (n=146) from skin and skin structure infections and bloodstream infections, bronchoalveolar lavage and sputum. These pathogens included 40 methicillin resistant Staphylococcus aureus, 38 coagulase-negative staphylococci, 20 Enterococcus faecalis and 48 beta-haemolytic Streptococcus spp. Susceptibility was simultaneously determined for 48 vanA vancomycin-resistant enterococci isolates 2013-2016 from rectal swabs (23 E. faecalis and 25 E. faecium, of which 4 were linezolid-non-susceptible). MIC90s for tedizolid were fourfold to eightfold lower than linezolid on the Sensititre and ranged from 0.12 to 0.5 ug/mL for the different pathogen groups. All isolates were susceptible to tedizolid except two vanA E. faecium strains (MICs of 1 and 2 ug/mL, respectively). Categorical and essential agreement for tedizolid were 99.48% and 92%, respectively, between Liofilchem gradient diffusion and Sensititre methods. Overall, the drug exhibited excellent activity against the surveyed Gram-positive pathogens. PMID- 30446514 TI - Whitish-yellow tapeworm. PMID- 30446513 TI - Juvenile murine models of prediabetes and type 2 diabetes develop neuropathy. AB - Peripheral neuropathy (neuropathy) is a common complication of obesity and type 2 diabetes in children and adolescents. To model this complication in mice, 5-week old male C57BL/6J mice were fed a high-fat diet to induce diet-induced obesity (DIO), a model of prediabetes, and a cohort of these animals was injected with low-dose streptozotocin (STZ) at 12 weeks of age to induce hyperglycemia and type 2 diabetes. Neuropathy assessments at 16, 24, and 36 weeks demonstrated that DIO and DIO-STZ mice displayed decreased motor and sensory nerve conduction velocities as early as 16 weeks, hypoalgesia by 24 weeks, and cutaneous nerve fiber loss by 36 weeks, relative to control mice fed a standard diet. Interestingly, neuropathy severity was similar in DIO and DIO-STZ mice at all time-points despite significantly higher fasting glucose levels in the DIO-STZ mice. These mouse models provide critical tools to better understand the underlying pathogenesis of prediabetic and diabetic neuropathy from youth to adulthood, and support the idea that hyperglycemia alone does not drive early neuropathy. PMID- 30446515 TI - Blisters on the sun-exposed area: as a clue for underlying hepatitis C virus infection. PMID- 30446516 TI - Brexit: Doctors must speak up about risks to patients, says BMA chair. PMID- 30446517 TI - Reply to Qi and Dong: Policy clarification and robustness of effects. PMID- 30446518 TI - Dietary Tomato Powder Inhibits High-Fat Diet-Promoted Hepatocellular Carcinoma with Alteration of Gut Microbiota in Mice Lacking Carotenoid Cleavage Enzymes. AB - Both incidence and death rate due to liver cancer have increased in the United States. Higher consumption of lycopene-rich tomato and tomato products is associated with a decreased risk of cancers. beta-Carotene-15, 15'-oxygenase (BCO1), and beta-carotene-9', 10'-oxygenase (BCO2) cleave lycopene to produce bioactive apo-lycopenoids. Although BCO1/BCO2 polymorphisms affect human and animal lycopene levels, whether dietary tomato consumption can inhibit high-fat diet (HFD)-promoted hepatocellular carcinoma (HCC) development and affect gut microbiota in the absence of BCO1/BCO2 is unclear. BCO1/BCO2 double knockout mice were initiated with a hepatic carcinogen (diethylnitrosamine) at 2 weeks of age. At 6 weeks of age, the mice were randomly assigned to an HFD (60% of energy as fat) with or without tomato powder (TP) feeding for 24 weeks. Results showed that TP feeding significantly decreased HCC development (67%, 83%, and 95% reduction in incidence, multiplicity, and tumor volume, respectively, P < 0.05). Protective effects of TP feeding were associated with (1) decreased hepatic inflammatory foci development and mRNA expression of proinflammatory biomarkers (IL1beta, IL6, IL12alpha, monocyte chemoattractant protein-1, and inducible NO synthase); (2) increased mRNA expression of deacetylase sirtuin 1 and nicotinamide phosphoribosyltransferase involving NAD+ production; and (3) increased hepatic circadian clock genes (circadian locomotor output cycles kaput, period 2, and cryptochrome-2, Wee1). Furthermore, TP feeding increased gut microbial richness and diversity, and significantly decreased the relative abundance of the genus Clostridium and Mucispirillum, respectively. The present study demonstrates that dietary tomato feeding independent of carotenoid cleavage enzymes prevents HFD induced inflammation with potential modulating gut microbiota and inhibits HFD promoted HCC development. Cancer Prev Res; 11(12); 1-14. (c)2018 AACR. PMID- 30446520 TI - Conidial Morphogenesis and Septin-Mediated Plant Infection Require Smo1, a Ras GTPase-Activating Protein in Magnaporthe oryzae. AB - The pathogenic life cycle of the rice blast fungus Magnaporthe oryzae involves a series of morphogenetic changes, essential for its ability to cause disease. The smo mutation was identified more than twenty-five years ago and affects the shape and development of diverse cell types in M. oryzae, including conidia, appressoria and asci. All attempts to clone the SMO1 gene by map-based cloning or complementation, have failed over many years. Here, we report the identification of SMO1 by a combination of bulk segregant analysis and comparative genome analysis. SMO1 encodes a GTPase-activating protein (GAP), which regulates Ras signalling during infection-related development. Targeted deletion of SMO1 results in abnormal, non-adherent conidia, impaired in their production of spore tip mucilage. Smo1 mutants also develop smaller appressoria, with a severely reduced capacity to infect rice plants. SMO1 is necessary for organisation of microtubules and for septin-dependent remodelling of the F-actin cytoskeleton at the appressorium pore. Smo1 physically interacts with components of the Ras2 signaling complex, and a range of other signalling and cytoskeletal components, including the four core septins. SMO1 is therefore necessary for regulation of RAS activation required for conidial morphogenesis and septin-mediated plant infection. PMID- 30446519 TI - Comparison of Performance Between a Short Categorized Lifestyle Exposure-based Colon Cancer Risk Prediction Tool and a Model Using Continuous Measures. AB - Risk prediction models that estimate an individual's risk of developing colon cancer could be used for a variety of clinical and public health interventions, including offering high-risk individuals enhanced screening or lifestyle interventions. However, if risk prediction models are to be translated into actual clinical and public health practice, they must not only be valid and reliable, but also be easy to use. One way of accomplishing this might be to simplify the information that users of risk prediction tools have to enter, but it is critical to ensure no resulting detrimental effects on model performance. We compared the performance of a simplified, largely categorized exposure-based colon cancer risk model against a more complex, largely continuous exposure-based risk model using two prospective cohorts. Using data from the Nurses' Health Study and the Health Professionals Follow-up Study we included 816 incident colon cancer cases in women and 412 in men. The discrimination of models was not significantly different comparing a categorized risk prediction model with a continuous prediction model in women (c-statistic 0.600 vs. 0.609, P diff = 0.07) and men (c-statistic 0.622 vs. 0.618, P diff = 0.60). Both models had good calibration in men [observed case count/expected case count (O/E) = 1.05, P > 0.05] but not in women (O/E = 1.19, P < 0.01). Risk reclassification was slightly improved using categorized predictors in men [net reclassification index (NRI) = 0.041] and slightly worsened in women (NRI = -0.065). Categorical assessment of predictor variables may facilitate use of risk assessment tools in the general population without significant loss of performance. Cancer Prev Res; 11(12); 1-8. (c)2018 AACR. PMID- 30446521 TI - Female Sex Development and Reproductive Duct Formation Depend on Wnt4a in Zebrafish. AB - In laboratory strains of zebrafish, sex determination occurs in the absence of a typical sex chromosome and it is not known what regulates the proportion of animals that develop as males or females. Many sex determination and gonad differentiation genes that act downstream of a sex chromosome are well conserved among vertebrates, but studies that test their contribution to this process have mostly been limited to mammalian models. In mammals, WNT4 is a signaling ligand that is essential for ovary and Mullerian duct development, where it antagonizes the male-promoting FGF9 signal. Wnt4 is well conserved across all vertebrates, but it is not known if Wnt4 plays a role in sex determination and/or the differentiation of sex organs in non-mammalian vertebrates. This question is especially interesting in teleosts, such as zebrafish, because they lack an Fgf9 ortholog. Here we show that wnt4a is the ortholog of mammalian Wnt4, and that wnt4b in teleosts was present in the last common ancestor of humans and zebrafish, but was lost in mammals. We show that wnt4a loss-of-function mutants develop predominantly as males and conclude that wnt4a activity promotes female sex determination and/or differentiation in zebrafish. Additionally, both male and female wnt4a mutants are sterile due to defects in reproductive duct development. Together these results strongly argue that Wnt4a is a conserved regulator of female sex determination and reproductive duct development in mammalian and non-mammalian vertebrates. PMID- 30446522 TI - Global Diversity of the Brachypodium Species Complex as a Resource for Genome Wide Association Studies Demonstrated for Agronomic Traits in Response to Climate. AB - The development of model systems requires a detailed assessment of standing genetic variation across natural populations. The Brachypodium species complex has been promoted as a plant model for grass genomics with translation to small grain and biomass crops. To capture the genetic diversity within this species complex, thousands of Brachypodium accessions from around the globe were collected and genotyped by sequencing. Overall 1,897 samples were classified into two diploid or allopolyploid species and then further grouped into distinct inbred genotypes. A core set of diverse B. distachyon diploid lines were selected for whole genome sequencing and high resolution phenotyping. Genome Wide Association Studies (GWAS) across simulated seasonal environments were used to identify candidate genes and pathways tied to key life history and agronomic traits under current and future climatic conditions. A total of 8, 22 and 47 QTLs were identified for flowering time, early vigour and energy traits, respectively. The results highlight the genomic structure of the Brachypodium species complex, and the diploid lines provided a resource that allowed complex trait dissection within this grass model species. PMID- 30446523 TI - A20 rescues hepatocytes from apoptosis through the NF-kappaB signaling pathway in rats with acute liver failure. AB - Background: Acute liver failure (ALF) is a disease of acute derangements in the hepatic synthetic function with defects involving innate immune responses, which was reported to be negatively regulated by tumor necrosis factor alpha-induced protein 3 (A20). Herein, this study was conducted to investigate the effects the A20 protein on the proliferation and apoptosis of hepatocytes through the nuclear factor (NF)-kappaB signaling pathway in the rat models simulating ALF. Methods: Male Wistar rats were used to simulate ALF in the model rats. Next, the positive expression of A20 and Caspase-3 proteins was measured in liver tissues. Rat hepatocytes were separated and subjected to PDTC (inhibitor of NF-kappaB pathway) or A20 siRNA. Additionally, both mRNA and protein levels of A20, NF-kappaB, TNF receptor-associated factor 6 (TRAF6), and receptor-interacting protein 1 (RIP1) were determined. Finally, we detected the hepatocyte proliferation, cell cycle entry, and apoptosis. Results: ALF rats displayed a lower positive expression of A20 protein and a higher expression of Caspase-3 protein. Furthermore, A20 was downregulated, while NF-kappaB, TRAF6, and RIP1 were all upregulated in ALF rats. Notably, A20 inhibited activation of NF-kappaB signaling pathway. The blockade of NF-kappaB signaling pathway enhanced proliferation and cell cycle progression of hepatocytes, whereas inhibited apoptosis of hepatocytes. On the contrary, A20 siRNA reversed the above situation. Conclusion: A20 inhibits apoptosis of hepatocytes and promotes the proliferation through the NF-kappaB signaling pathway in ALF rats, potentially providing new insight into the treatment of ALF. PMID- 30446524 TI - Over-expression of microRNA-758 inhibited proliferation, migration, invasion and promoted apoptosis of non-small cell lung cancer cells by negatively regulating HMGB. AB - Non-small cell lung cancer (NSCLC) is one of the most fatal types of cancer and with significant mortality and morbidity worldwide. microRNAs (miRs) have been confirmed to have positive functions in NSCLC. In the present study, we try to explore the role of miR-758 in proliferation, migration, invasion and apoptosis of NSCLC cells by regulating HMGB3. NSCLC and adjacent tissues were collected. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was employed to detect expression of miR-758 and HMGB3 in NSCLC and adjacent tissues, in BEAS-2B cells and NSCLC cell lines. The targeted relationship between miR-758 and HMGB3 was identified by dual luciferase reporter gene assay. A549 cell line was chosen for further experimentation. MTT, wound healing, Transwell and flow cytometry assays were applied to detect effects of miR-758 on proliferation, migration, invasion, cell cycle and apoptosis of A549 cells. RT-qPCR and Western blot analysis were performed to detect expression of related genes. MiR-758 expression was lower in NSCLC tissues, which was opposite to HMGB3 expression. The results also demonstrated that miR-758 can target HMGB3. The cells transfected with miR-758 mimic had decreased HMGB3 expression, proliferation, migration, and invasion, with more arrested cells in G1 phase and increased apoptosis. Our results support that over-expression of miR-758 inhibits proliferation, migration and invasion, and promotes apoptosis of NSCLC cells by negative regulating HMGB2. This study may provide a novel target for NSCLC treatment. PMID- 30446525 TI - Quantitative assessment of the association between GRIA1 polymorphisms and migraine risk. AB - PURPOSE: The association between GRIA1 rs548294 G>A and rs2195450 C>T polymorphisms and migraine risk has been reported in several case-control studies. However, the results of studies are inconsistent. Thus, we conducted a meta-analysis to more precisely estimate the association of the two polymorphisms with migraine risk. Methods: Eligible studies were retrieved and screened from the online databases (EMBASE, PubMed, Web of Science, Wanfang, and Chinese National Knowledge Infrastructure). The pooled odds ratio (OR) with corresponding 95.0% confidence intervals (CI) was assessed using random- or fixed-effects model. Results: A total of 1233 cases and 1374 controls from four eligible studies were included. The pooled analysis showed that GRIA1 rs548294 G>A polymorphism was not significantly associated with migraine risk. GRIA1 rs2195450 C>T polymorphism was significantly associated with migraine risk under heterozygous model (CT vs. CC, OR=1.23, 95%CI=1.02-1.48, P Z=0.03). Further subgroup analysis based on ethnicity showed a significant association of GRIA1 rs2195450 C>T polymorphism with migraine risk in Asian population, but not in Caucasian population. CONCLUSIONS: Our results indicates that GRIA1 rs2195450 C>T polymorphism is significantly associated with migraine risk. However, the number of studies included in the meta-analysis was small. Thus more high-quality case-control studies with a large sample size are still required to confirm these findings. PMID- 30446527 TI - Making a point: shared mechanics underlying the diversity of biological puncture. AB - A viper injecting venom into a target, a mantis shrimp harpooning a fish, a cactus dispersing itself via spines attaching to passing mammals; all these are examples of biological puncture. Although disparate in terms of materials, kinematics and phylogeny, all three examples must adhere to the same set of fundamental physical laws that govern puncture mechanics. The diversity of biological puncture systems is a good case study for how physical laws can be used as a baseline for comparing disparate biological systems. In this Review, I explore the diversity of biological puncture and identify key variables that influence these systems. First, I explore recent work on biological puncture in a diversity of organisms, based on their hypothesized objectives: gripping, injection, damage and defence. Variation within each category is discussed, such as the differences between gripping for prey capture, gripping for dispersal of materials or gripping during reproduction. The second half of the Review is focused on specific physical parameters that influence puncture mechanics, such as material properties, stress, energy, speed and the medium within which puncture occurs. I focus on how these parameters have been examined in biology, and how they influence the evolution of biological systems. The ultimate objective of this Review is to outline an initial framework for examining the mechanics and evolution of puncture systems across biology. This framework will not only allow for broad biological comparisons, but also create a baseline for bioinspired design of both tools that puncture efficiently and materials that can resist puncture. PMID- 30446526 TI - Prognostic and clinicopathological significance of neutrophil-to-lymphocyte ratio in patients with oral cancer: a meta-analysis. AB - OBJECTIVES: Many studies have examined the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) in oral cancer; however, the results are contradictory. We therefore conducted a meta-analysis aiming to clarify the prognostic value of the NLR in oral cancer patients. METHODS: A literature search was conducted in the PubMed, Web of Science, and Embase databases. Stata version 12.0 was used for statistical analysis. RESULTS: A total of 14 studies with 3216 patients were finally included. The results indicated that a high NLR was significantly associated with worse DFS (n = 10, HR = 1.73, 95% CI = 1.44-2.07, p < 0.001). Similar results were observed for OS (n = 9, HR = 1.61, 95% CI = 1.39 1.86, p < 0.001). Moreover, a high NLR was also correlated with lymph node metastasis (n = 7, odds ratio [OR] = 1.62, 95% CI = 1.32-1.98, p < 0.001), advanced tumor stage (n = 7, OR = 2.63, 95% CI = 2.12-3.25, p < 0.001), T stage (n = 6, OR = 3.22, 95% CI = 2.59-4.01, p < 0.001), tumor differentiation (n = 5, OR = 1.48, 95% CI = 1.03-2.11, p =0.033) and perineural invasion (n = 4, OR = 1.83, 95% CI = 1.4-2.39, p <0.001). However, an elevated NLR was not correlated with gender. CONCLUSION: This meta-analysis showed that the NLR might be a potential independent prognostic factor in patients with oral cancer. PMID- 30446528 TI - Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection. AB - While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus. PMID- 30446529 TI - Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity. AB - Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knockout, CST-/- ) or complex gangliosides (beta-1,4-N acetylegalactosaminyltransferase1 knockout, GalNAc-T-/- ) display prominent disorganization of proteins at the node of Ranvier (NoR) in early life, and age dependent neurodegeneration. Loss of neuronal rather than glial complex gangliosides underpins the GalNAc-T-/- phenotype, as shown by neuron or glial specific rescue, whereas sulfatide is principally expressed and functional in glial membranes. The similarities in NoR phenotype of CST-/- , GalNAc-T-/- and axo-glial protein deficient mice suggests these glycolipids stabilise membrane proteins including neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) at axo-glial junctions. To assess the functional interactions between sulfatide and gangliosides, CST-/- and GalNAc-T-/- genotypes were interbred. CST /- x GalNAc-T-/- mice develop normally to P10, but all die between P20-P25, coinciding with peak myelination. Ultrastructural, immunohistological and biochemical analysis of either sex reveals widespread axonal degeneration and disruption to the axo-glial junction at the NoR. In addition to sulfatide dependent loss of NF155, CST-/-x GalNAc-T-/- mice exhibited a major reduction in MAG protein levels in CNS myelin, compared to wild type and single lipid deficient mice. The CST-/- x GalNAc-T-/- phenotype was fully restored to that of CST-/- mice by neuron-specific expression of complex gangliosides, but not by their glial-specific expression nor by the global expression of a-series gangliosides. These data indicate that sulfatide and complex b-series gangliosides on the glial and neuronal membranes respectively act in concert to promote NF155 and MAG in maintaining the stable axo-glial interactions essential for normal nerve function.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin associated glycoprotein that interact to maintain the nodal complex. PMID- 30446530 TI - Individual differences in dopamine are associated with reward discounting in clinical groups but not in healthy adults. AB - Some people are more willing to make immediate, risky, or costly reward-focused choices than others, which has been hypothesized to be associated with individual differences in dopamine (DA) function. In two studies using PET imaging, one empirical (Study 1: N=144 males and females across 3 samples) and one meta analytic (Study 2: N=307 across 12 samples), we sought to characterize associations between individual differences in DA and time, probability, and physical effort discounting in human adults. Study 1 demonstrated that individual differences in DA D2-like receptors were not associated with time or probability discounting of monetary rewards in healthy humans, and associations with physical effort discounting were inconsistent across adults of different ages. Meta analytic results for temporal discounting corroborated our empirical finding for minimal effect of DA measures on discounting in healthy individuals, but suggested that associations between individual differences in DA and reward discounting depend on clinical features. Addictions were characterized by negative correlations between DA and discounting but other clinical conditions like Parkinson's Disease, obesity, and ADHD were characterized by positive correlations between DA and discounting. Together the results suggest that trait differences in discounting in healthy adults do not appear to be strongly associated with individual differences in D2-like receptors. The difference in meta-analytic correlation effects between healthy controls and individuals with psychopathology suggests that individual difference findings related to DA and reward discounting in clinical samples may not be reliably generalized to healthy controls, and vice-versa.SIGNIFICANCE STATEMENTDecisions to forgo large rewards for smaller ones due to increasing time delays, uncertainty, or physical effort have been linked to differences in dopamine (DA) function, which is disrupted in some forms of psychopathology. It remains unclear whether alterations in DA function associated with psychopathology also extend to explaining associations between DA function and decision making in healthy individuals. We show that individual differences in dopamine D2 receptor availability are not consistently related to monetary discounting of time, probability, or physical effort in healthy individuals across a broad age range. By contrast, we suggest that psychopathology accounts for observed inconsistencies in the relationship between measures of dopamine function and reward discounting behavior. PMID- 30446531 TI - Dopamine restores limbic memory loss, dendritic spine structure and NMDAR dependent LTD in the nucleus accumbens of alcohol-withdrawn rats. AB - Alcohol abuse leads to aberrant forms of emotionally salient memory - i.e. limbic memory - that promote escalated alcohol consumption and relapse. Accordingly, activity-dependent structural abnormalities, are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing chronic alcohol consumption. Here we show that alcohol dependent male rats fail to perform an emotional-learning task during abstinence but recover their functioning by L-DOPA administration during early withdrawal. L-DOPA also reverses the selective loss of dendritic "long thin" spines observed in medium spiny neurons of the nucleus accumbens (NAc) shell of alcohol-dependent rats during abstinence, as well as the reduction in tyrosine hydroxylase (TH) immunostaining and postsynaptic density-95 (PSD-95) positive elements. Patch-clamp experiments in NAc slices reveal that both in-vivo systemic L-DOPA administration and in-vitro exposure to dopamine can restore the loss of long-term depression (LTD) formation, counteract the reduction in NMDAR mediated synaptic currents and rectify the altered NMDAR/AMPAR ratio observed in alcohol-withdrawn rats. Further, in-vivo microdialysis experiments show that blunted dopaminergic signaling is revived after L-DOPA treatment during early withdrawal. These results suggest a key role of an efficient dopamine signaling for maintaining - and restore - neural trophism, NMDA-dependent LTD and ultimately optimal learning.SIGNIFICANCE STATEMENTBlunted dopamine signaling and altered glutamate connectivity in the nucleus accumbens represent the neuroanatomical basis for the impairment in aversive limbic memory observed during withdrawal in alcohol dependence. Supplying L-DOPA during withdrawal re establishes synaptic morphology and functional neuroadaptations, suggesting a complete recovery of nucleus accumbens glutamatergic synaptic plasticity when dopamine is revived. Importantly, restoring dopamine transmission allows those synapses to encode emotionally relevant information and rescue flexibility in the neuronal circuits that process limbic memory formation. Under these conditions, drugs capable of selectively boosting the dopaminergic function during the "fluid" and still responsive state of the early withdrawn maladaptive synapses may help in the treatment of alcohol addiction. PMID- 30446532 TI - Chemogenetic Manipulations of Ventral Tegmental Area Dopamine Neurons Reveal Multifaceted Roles in Cocaine Abuse. AB - Ventral tegmental area (VTA) dopamine (DA) neurons perform diverse functions in motivation and cognition, but their precise roles in addiction-related behaviors are still debated. Here, we targeted VTA DA neurons for bidirectional chemogenetic modulation during specific tests of cocaine reinforcement, demand, and relapse-related behaviors in male rats, querying the roles of DA neuron inhibitory and excitatory G-protein signaling in these processes. Designer receptor stimulation of Gq-, but not Gs-signaling in DA neurons enhanced cocaine seeking via functionally distinct projections to forebrain limbic regions. In contrast, engaging inhibitory Gi/o signaling in DA neurons blunted cocaine's reinforcing and priming effects, reduced stress-potentiated reinstatement, and altered behavioral strategies for cocaine seeking and taking. Results demonstrate that DA neurons play several distinct roles in cocaine seeking, depending on behavioral context, G-protein signaling cascades, and DA neuron efferent targets highlighting their multifaceted roles in addiction.SIGNIFICANCE STATEMENTG protein coupled receptors are crucial modulators of VTA dopamine neuron activity, but how this metabotropic signaling impacts dopamine's complex roles in reward and addiction is poorly understood. Here, we bidirectionally modulate dopamine neuron G-protein signaling with DREADDs during a variety of cocaine seeking behaviors, revealing nuanced, pathway-specific roles in cocaine reward, effortful seeking, and relapse-like behaviors. Gq- and Gs-stimulation activated dopamine neurons, but only Gq stimulation robustly enhanced cocaine seeking. Gi/o inhibitory signaling reduced some, but not all types of cocaine seeking. Results show that VTA dopamine neurons modulate numerous distinct aspects of cocaine addiction- and relapse-related behaviors, and point to potential new approaches for intervening in these processes to treat addiction. PMID- 30446533 TI - A proposed mechanism for spontaneous transitions between interictal and ictal activity. AB - Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled in silico and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. In silico small world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity. In silico, neurons were connected by abundant local synapses and rare long-distance synapses. Activity-dependent synaptic depression and gradual recovery delimited synchronous activity. Full synaptic recovery engendered interictal population spikes that spread via long-distance synapses. When synaptic recovery was incomplete, postsynaptic neurons required coincident activation of multiple presynaptic terminals to reach firing threshold. Only local connections were sufficiently dense to spread activity under these conditions. This coalesced network activity into traveling waves whose velocity varied with synaptic recovery. Seizures were comprised of sustained traveling waves that were similar to those recorded during experimental and human neocortical seizures. Sustained traveling waves occurred only when wave velocity, network dimensions, and the rate of synaptic recovery enabled wave re entry into previously depressed areas at precisely ictogenic levels of synaptic recovery. Wide-field, cellular-resolution GCamP7b calcium imaging demonstrated similar initial patterns of activation in the hippocampus, although the anatomical distribution of traveling waves of synaptic activation were altered by the pattern of synaptic connectivity in the organotypic hippocampal cultures.Significance Statement: When computerized distributed neural network models are required to generate both features of epileptic networks, i.e. spontaneous interictal population spikes and seizures, the network structure is substantially constrained. These constraints provide important new hypotheses regarding the nature of epileptic networks and mechanisms of seizure onset. PMID- 30446534 TI - Identification of novel circadian transcripts in the zebrafish retina. AB - High fecundity, transparent embryos for monitoring the rapid development of organs and the availability of a well-annotated genome has made zebrafish a model organism of choice for developmental biology and neurobiology. This vertebrate model, a favourite in chronobiology studies, shows striking circadian rhythmicity in behaviour. Here, we identify novel genes in the zebrafish genome, which are expressed in the zebrafish retina. We further resolve the expression pattern over time and tentatively assign specific novel transcripts to retinal bipolar cells of the inner nuclear layer. Using chemical ablation and free run experiments we segregate the transcripts that are rhythmic when entrained by light from those that show sustained oscillations in the absence of external cues. The transcripts reported here with rigorous annotation and specific functions in circadian biology provide the groundwork for functional characterisation of novel players in the zebrafish retinal clock. PMID- 30446535 TI - Lateral line sensitivity in free swimming toadfish, Opsanus tau. AB - A longstanding question in aquatic animal sensory physiology is the impact of self-generated movement on lateral line sensitivity. One hypothesis is that efferent modulation of the sensory hair cells cancels self-generated noise and allows fish to sample their surroundings while swimming. In the current experiments, microwire electrodes were chronically implanted into the anterior lateral line nerve of oyster toadfish and neural activity was monitored during forward movement. Fish were allowed to freely swim or were moved by a tethered sled. In all cases, neural activity increased during movement with no evidence of efferent modulation. The anterior lateral line of moving fish responded to a vibrating sphere or the tail oscillations of a robotic fish, indicating that the lateral line also remains sensitive to outside stimulus during self-generated movement. The results suggest that during normal swim speeds, lateral line neuromasts are not saturated and retain the ability to detect external stimuli without efferent modulation. PMID- 30446536 TI - Encoding lateralization of jump kinematics and eye use in a locust via bio robotic artifacts. AB - The effect of earlier exposure to lateral sensory stimuli in shaping the response to subsequent symmetric stimuli represents an important overlooked issue in neuroethology, with special reference to arthropods. In this research, we investigated the hypothesis to "program" jumping escape direction as well as surveillance orientation, in young and adult individuals of Locusta migratoria, as an adaptive consequence of prior exposure to directional-biased predator approaches generated by a robotic leopard gecko, Eublepharis macularius The manipulation of the jumping escape direction was successfully achieved in young locusts, although young L. migratoria did not exhibit innately lateralized jumping escapes. Jumping escape direction was successfully manipulated also in adult locusts exhibiting innate lateralized jumping escape at individual level. The innate lateralization of each instar of L. migratoria in using a preferential eye during surveillance was not affected by prior lateralized exposure to the robotic gecko. Our results indicate a high plasticity of those escape motor outputs, that are occurring almost in real time with the perceived stimuli, making them greatly adaptable and compliant to environmental changes, to be effective and reliable. In addition, surveillance lateralization innately occurs at population-level in each instar of L. migratoria Therefore, its low forgeability by environmental factors would avoid disorganization at swarm level and improving swarm coordination during group tasks. These findings are consistent with the fact that, as in vertebrates, in insects the right hemisphere is specialized in controlling fear and escape functions. PMID- 30446537 TI - Wing morphology, flight type and migration distance predict accumulated fuel load in birds. AB - Birds often accumulate large fat and protein reserves to fuel long-distance flights. While it is well known that species that fly the longest accumulate the largest amounts of fuel, considerable cross-species variation in fuel load is seen after controlling for overall migration distance. It remains unclear whether this variation can be explained by aerodynamic attributes of different species, despite obvious ecological and conservation implications. Here we collected data on wing morphology, flight type, migration distance and fuel load from 213 European bird species and explored three questions: (1) Does maximum fuel load relate to migration distance across species?; (2) Does wing morphology, as described by wing aspect ratio and wing loading, influence maximum fuel load, and; (3) Does flight type influence maximum fuel load? Our results indicate that maximum fuel load increases with migration across species, but residual variance is high. Our results indicate that maximum fuel load is also correlated with migration distance, but again residual variance is high. The latter variance is explained by aspect ratio and flight type, while wing loading and body mass explain little variance. Birds with slender wings accumulate less fuel than species with low wing aspect ratio when covering a similar migration distance. Continuously flapping species accumulate the largest amounts of fuel, followed by flapping and soaring, flapping and gliding species, while the smallest fuel loads were observed in birds with passerine-type flight. These results highlight complex eco-evolutionary adaptations to migratory behaviour, pointing toward the importance of energy-minimisation. PMID- 30446538 TI - Cyclic nature of the REM sleep-like state in the cuttlefish Sepia officinalis. AB - Sleep is a state of immobility characterized by three key criteria: an increased threshold of arousal, rapid reversal to an alert state, and evidence of homeostatic "rebound sleep" in which there is an increase of time spent in this quiescent state following sleep deprivation. Common European cuttlefish, Sepia officinalis, show states of quiescence during which they meet the last two of these three criteria, yet also show spontaneous bursts of arm and eye movements that accompany rapid changes in chromatophore patterns in the skin. Here we report that this rapid-eye movement sleep-like (REMS-like) state is cyclic in nature. Iterations of the REMS-like state last 2.42+/-0.22 min (+/-SE) and alternate with 34.01+/-1.49 min of the quiescent sleep-like state. These states alternate for durations lasting 176.89+/-36.71 min. We found clear evidence that this REMS-like state (i) occurs in animals younger than previously reported; (ii) follows an ultradian pattern; (iii) includes intermittent dynamic chromatophore patterning, representing fragments of normal patterning seen in the waking state for a wide range of signaling and camouflage; and (iv) shows variability in the intensity of expression of these skin patterns between and within individuals. These data suggest that cephalopods, which are molluscs with an elaborate brain and complex behavior, possess a sleep-like state that resembles behaviorally the vertebrate REM sleep state, although the exact nature and mechanism of this form of sleep may differ from that of vertebrates. PMID- 30446539 TI - Object features and T4/T5 motion detectors modulate the dynamics of bar tracking by Drosophila. AB - Visual objects can be discriminated by static spatial features such as luminance or dynamic features such as relative movement. Flies track a solid dark vertical bar moving on a bright background, a behavioral reaction so strong that for a rigidly tethered fly, the steering trajectory is phase advanced relative to the moving bar, apparently in anticipation of its future position. By contrast, flickering bars that generate no coherent motion, or whose surface texture moves in the direction opposite to the bar generate steering responses that lag behind the stimulus. It remains unclear how the spatial properties of a bar influence behavioral response dynamics. We show that a dark bar defined by its luminance contrast to the uniform background drives a co-directional steering response that is phase-advanced relative to the response to a textured bar defined only by its motion relative to a stationary textured background. The textured bar drives an initial contra-directional turn and phase-locked tracking. The qualitatively distinct response dynamics could indicate parallel visual processing of a luminance versus motion-defined object. Calcium imaging shows that T4/T5 motion detecting neurons are more responsive to a solid dark bar than a motion defined bar. Genetically blocking T4/T5 neurons eliminates the phase-advanced co directional response to the luminance-defined bar, leaving the orientation response largely intact. We conclude that T4/T5 neurons mediate a co-directional optomotor response to a luminance defined bar, thereby driving phase-advanced wing kinematics, whereas separate unknown visual pathways elicit the contra directional orientation response. PMID- 30446540 TI - Developmental carry over effects of ocean warming and acidification in corals from a potential climate refugium, Gulf of Aqaba. AB - Coral reefs are degrading from the effects of anthropogenic activities including climate change. Under this stress, their ability to survive depends upon existing phenotypic plasticity, but also transgenerational adaptation. Parental effects are ubiquitous in nature, yet empirical studies of these effects in corals are scarce, particularly in the context of climate change. This study exposed mature colonies of the common reef building coral Stylophora pistillata from the Gulf of Aqaba to seawater conditions likely to occur just beyond the end of this century during the peak planulae brooding season (Representative Concentration Pathway 8.5: pH -0.4 and +5 degrees C beyond present day). Parent and planulae physiology were assessed at multiple time-points during the experimental incubation. After five weeks incubation, parent colony's physiology exhibited limited treatment induced changes. All significant time-dependent changes in physiology occurred in both ambient and treatment conditions. Planulae were also resistant to future ocean conditions with protein content, symbiont density, photochemistry, survival, and settlement success not significantly different compared to ambient conditions. High variability in offspring physiology was independent of parental or offspring treatments and indicate the use of bet-hedging strategy in this population. This study thus demonstrates weak climate change associated carry over effects. Furthermore, planulae display temperature and pH resistance similar to adult colonies and therefore do not represent a larger future population size bottleneck. The findings add support to the emerging hypothesis that the Gulf of Aqaba may serve as a climate change coral refugium aided by these corals' inherent broad physiological resistance. PMID- 30446541 TI - A gyroscopic advantage: phylogenetic patterns of compensatory movements in frogs. AB - Head and eye compensatory movements known as vestibulo-ocular and vestibulo cervical reflexes are essential to stay orientated in space while moving. We have used a previously developed methodology focused on the detailed mathematical description of head compensatory movements in frogs without the need for any surgical procedures on the examined specimens. Our comparative study comprising 35 species of frogs from different phylogenetic background revealed species specific head compensatory abilities ensuring gaze stabilization. Moreover, we found a strong phylogenetical signal highlighting the great ability of compensatory head movements in families of Pyxicephalidae and Rhacophoridae from Natatanura group. On the other hand, families of Dendrobatidae and Microhylidae exhibited only poor or no head compensatory movements. Contrary to our expectation, the results did not corroborate an ecomorphological hypothesis anticipating a close relationship between ecological parameters and the head compensatory movements. We did not find any positive association between a more complex (3D structured, arboreal or aquatic) habitats as well as more saltatory behaviour and elevated abilities of head compensatory movements. Moreover, we found compensatory movements in most basal Archeobatrachia giving an indication of common ancestry of these abilities in frogs but variously pronounced in particular families. We hypothesize that the uncovered proper gaze stabilization during locomotion provided by the higher head compensatory abilities can improve or even enable visual perception of the prey. We interpret this completely novel finding as a possible gyroscopic advantage in a foraging context. We discuss putative consequences of such advanced neuromotor skills for diversification and ecological success of Natatanura group. PMID- 30446542 TI - Determinants of optimal leg use strategy: horizontal to vertical transition in the parkour wall climb. AB - This study examined the mechanics of the horizontal to vertical transition used by parkour athletes in wall climbing. The study serves as an alternative assessment of leg control strategy for a task related to normal running, but where the functional options differ substantially, so can expose the movement control priorities required to successfully complete the task. Ground reaction forces were measured in several expert parkour athletes and centre of mass trajectory was calculated from force plates embedded in the ground and the wall. Empirical measures were compared with movements predicted by a work-based control optimization model. The model captured the fundamental dynamics of the transition, so allowed an exploration of parameter sensitivity for success at the maneuver (run-up speed, foot placement, etc.). The optimal transition of both the model and the parkour athletes used a common intermediate run-up speed and appears determined largely by a trade-off of positive and negative leg work that accomplishes the task with minimum overall work. PMID- 30446543 TI - Phenotypic flexibility in respiratory traits is associated with improved aerial respiration in an amphibious fish out of water. AB - Amphibious fishes have evolved multiple adaptive strategies for respiring out of water, but there has been less focus on reversible plasticity. We tested the hypothesis that when amphibious fishes leave water, enhanced respiratory performance on land is the result of rapid functional phenotypic flexibility of respiratory traits. We acclimated four isogenic strains of Kryptolebias marmoratus to air for 0, 1, 3 or 7 days. We compared respiratory performance out of water with traits linked to the O2 cascade. Aerial O2 consumption rate was measured over a step-wise decrease in O2 levels. There were significant differences between strains, but time out of water had the largest impact on measured parameters. K. marmoratus had improved respiratory performance (lower aerial critical oxygen tension (Pcrit), higher regulation index (RI)) after only 1 day of air exposure and these changes were strongly associated with the change in hematocrit and dorsal cutaneous angiogenesis. Additionally, we found that 1 hour of air exposure induced the expression of four angiogenesis-associated genes, vegfa, angpt2, pecam-1 and efna1 in the skin. After 7 days in air, respiratory traits were not significantly linked to the variation in either aerial Pcrit or RI. Overall, our data indicate that there are two phases involved in the enhancement of aerial respiration; an initial rapid response (1 day) and a delayed response (7 days). We found evidence for the hypothesis that respiratory performance on land in amphibious fishes is the result of rapid flexibility in both O2 uptake and O2 carrying capacity. PMID- 30446544 TI - Effectiveness and efficiency of two distinct mechanisms for take-off in a derbid planthopper insect. AB - Analysis of the kinematics of take-off in the planthopper Proutista moesta (Hemiptera, Fulgoroidea, family Derbidae) from high speed videos showed that individual insects used two distinct mechanisms involving different appendages. The first was a fast take-off (55.7% of 106 take-offs by 11 insects) propelled by a synchronised movement of the two hind legs and without participation of the wings. The body was accelerated in 1 ms or less to a mean take-off velocity of 1.7 m s-1 while experiencing average forces of more than 150 times gravity. The power required from the leg muscles implicated a power-amplification mechanism. Such take-offs propelled the insect along its trajectory a mean distance of 7.9 mm in the first 5 ms after take-off. The second and slower take-off mechanism (44.3% of take-offs) was powered by beating movements of the wings alone with no discernible contribution from the hind legs. The resulting mean acceleration time was 16 times slower at 17.3 ms, the mean final velocity was six times lower at 0.27 m s-1, the g forces experienced were 80 times lower and the distance moved in 5 ms after take-off was 7 times shorter. The power requirements could be readily met by direct muscle contraction. The results suggest a testable hypothesis that the two mechanisms serve distinct behavioural actions; the fast take-offs could enable escape from predators; the slow take-offs that exert much lower ground reaction forces could enable take-off from more flexible substrates while also displacing the insect in a slower and more controllable trajectory. PMID- 30446545 TI - Caught red-handed: behaviour of brood thieves in an Indian ant. AB - Theft of resources is ubiquitous in the animal kingdom. An evolutionary arms race between thieves and their victims is expected. Though several studies have documented inter- and intraspecific theft of resources in different taxa, studies that delve into the behaviour of thieves and the factors that influence their behaviour have not been undertaken. In the current study on primitively eusocial ant Diacamma indicum we caught brood thieves red-handed, i.e. we observed them in the act of stealing brood and examined their behaviour. Thieves were persistent in their attempts though they faced aggression in the victim colony. Receiving aggression or failure to steal in the previous attempt negatively impacted thieves' drive to reattempt. Successful thieves exited from victim nests about three times faster than others who were procuring brood from unguarded nests to avoid the risks associated with theft. On examining the factors that caused thieves to increase their exit speed using a series of experiments, we found that indirect cues of foreign colonies presence like odour or mere presence of foreign ants did not induce these changes in thieves. Thus we conclude that these ant thieves only respond to the direct threat posed by aggressive foreign ants. In this comprehensive study using behavioural experiments we reveal the simple rules of engagement between victims and brood thieves. Keywords: Diacamma indicum, Primitively eusocial, Ponerinae, Intraspecific stealing. PMID- 30446546 TI - Changes of gene expression but not cytosine methylation are associated with male parental care reflecting behavioural state, social context, and individual flexibility. AB - Behaviour is often on the front line response to changing environments. Recent studies show behavioural changes are associated with changes of gene expression; however, these studies have primarily focused on discrete behavioural states. We build on these studies by addressing additional contexts that produce qualitatively similar behavioural changes. We measured levels of gene expression and cytosine methylation, which is hypothesized to regulate the transcriptional architecture of behavioural transitions, within the brain during male parental care of the burying beetle Nicrophorus vespilloides in a factorial design. Male parenting is a suitably plastic behaviour because while male N. vespilloides typically do not provide direct care (i.e., feed offspring) when females are present, levels of feeding by a male equivalent to the female can be induced by removing the female. We examined three different factors: behavioural state (caring vs non-caring), different social contexts (with or without a female mate), and individual flexibility (if a male switched to direct care after his mate was removed). The greatest number of differentially expressed genes were associated with behavioural state, followed by social contexts, and lastly by individual flexibility. Cytosine methylation was not associated with changes of gene expression in any of the conditions. Our results suggest a hierarchical association between gene expression and the different factors, but that this process is not controlled by cytosine methylation. Our results further suggest that the extent a behaviour is transient plays an underappreciated role in determining its underpinning molecular mechanisms. PMID- 30446547 TI - Age related responses to injury and repair in insect cuticle. AB - The ability of female adult desert locusts (Schistocerca Gregaria) to repair injuries to their exoskeletons and restore mechanical strength over the course of their natural life was evaluated. It was discovered that younger insects are more capable of repairing injuries, displaying no significant decreases in failure strength, stiffness or bending moment to failure after 3 weeks of repair. Older insects in contrast were only capable of repairing to ~ 70% of their original strength. Both older and younger insects carry out targeted deposition to repair injuries. Different mechanisms of failure were also examined and it was discovered that the cuticle of older insects is more susceptible to crack growth due to a large decrease in fracture toughness with age, making them more sensitive to scalpel cuts and punctures. The biological mechanisms that drive these changes are still under investigation. PMID- 30446549 TI - ABN news for the December 2018 issue. PMID- 30446550 TI - Identification and characterization of a GlcNAc de-N-acetylase from the hyperthermophilic archaeon Sulfolobus solfataricus. AB - Sulfolobus solfataricus is an aerobic crenarchael hyperthermophile with optimum growth at T>80 degrees C and pH 2-4. Within the crenarchaeal group of Sulfolobales, N-acetyl-glucosamine (GlcNAc) has been shown to be a component of exopolysaccharides (EPS), forming their biofilms, and of the N-glycan decorating some proteins. The metabolism of GlcNAc is still poorly understood in Archaea and one approach to gaining information on that is through the identification and functional characterization of carbohydrate active enzymes (CAZymes) involved in the modification of GlcNAc. The screening of S. solfataricus extracts allowed the detection of a novel alpha-N-acetyl-glucosamidase activity, which has never been identified in Archaea. The mass spectrometry analysis of the purified activity showed a protein encoded by the sso2901 gene. Interestingly, the purified recombinant enzyme, which was characterized in detail, revealed a novel de-N acetylase activity specific for GlcNAc and derivatives. Thus, assays to identify an alpha-GlcNAcase found a GlcNAc de-N-acetylase instead. The alpha-GlcNAcase activity observed in S. solfataricus extracts did occur when SSO2901 was used in combination with an alpha-glucosidase. Furthermore, the inspection of the genomic context and the preliminary characterization of a putative glycosyltransferase immediately upstream of sso2901 (sso2900) suggest the involvement of these enzymes in the GlcNAc metabolism in S. solfataricus IMPORTANCE In this work, a preliminary screening of cellular extracts of S. solfataricus allowed the identification of an alpha-N-acetyl-glucosamidase activity. However, the characterization of the corresponding recombinant enzyme revealed a novel GlcNAc de-N-acetylase, which, in cooperation with the alpha-glucosidase, catalyzed the hydrolysis of O-alpha-GlcNAc glycosides. Additionally, we showed that the product of a gene flanking the one encoding for the de-N-acetylase is a putative glycosyltransferase, thus suggesting the involvement of the two enzymes in the metabolism of GlcNAc. The discovery and functional analysis of novel enzymatic activities involved in the modification of this essential sugar is a powerful strategy to shed light on the physiology and metabolism of Archaea. PMID- 30446551 TI - Iron homeostasis in Bacillus subtilis requires siderophore production and biofilm formation. AB - Iron (Fe) is the most important metal in biology. Despite its abundance, Fe is mostly present under ferric form in soils, strongly limiting its bioavailability. To overcome the challenge of Fe acquisition, many microorganisms produce siderophores to retrieve Fe from natural sources. Another ubiquitous feature of bacteria in natural environments is biofilm formation. Previous studies showed that external Fe strongly influenced biofilm formation in several bacteria, suggesting that this microenvironment could play a mechanistic role in micronutrient acquisition for bacteria.Here, we apply a complementary set of analytical methods and deletion mutants to evaluate the role of biofilm formation, siderophore production, and their interaction, on Fe homeostasis in Bacillus subtilis We observed that Fe homeostasis, i.e. active growth at constant intracellular Fe concentration, requires both siderophore production and biofilm formation. Also, we report that in B. subtilis both biofilm formation and siderophore production are required to achieve active Fe acquisition from the medium, and to sustain normal growth. Furthermore, we provide evidences that the formation of biofilm slightly enhances the kinetics of Fe complexation by catechol siderophores and markedly improves siderophore use efficiency. These results provide new perspectives on the mechanism underlying siderophore-based acquisition of Fe in biofilm-forming bacteria.IMPORTANCE Iron acquisition is of fundamental importance for microorganisms, since this metal is generally poorly bioavailable in natural conditions. In the environment, most bacteria are found tightly packed within multicellular communities also named biofilms. Here, using the soil Gram-positive bacterium Bacillus subtilis, we show that biofilm formation and siderophores production, i.e. small molecules specifically binding metals, are both essential to ensure Fe uptake from the medium and maintain cellular iron homeostasis. The biofilm matrix appears to play an important role favoring the efficient usage of siderophores. Put together, our results demonstrate a close link between biofilm formation and iron acquisition in B. subtilis, allowing a better comprehension of how bacteria can cope with metal limitation in environmental conditions. PMID- 30446553 TI - Periodic and spatial spreading of alkanes and Alcanivorax bacteria in deep waters of the Mariana Trench. AB - In subduction zones, serpentinization and biological processes may release alkanes to the deep waters, which will probably result in rapid spread of Alcanivorax However, the time and space of the alkane distribution and associated enrichment of alkane-degrading microbes had not been explored in the dark world. In this study, we report richness (up to 17.8%) of the alkane-degrading bacteria represented by Alcanivorax jadensis in deep waters obtained between 3000-6000 meters of the Mariana Trench in two cruises. The relative abundance of A. jadensis correlated with copy numbers of functional genes almA and alkB involved in alkane degradation. In these water samples, we detected high flux of alkanes, which probably resulted in the prevalence of A. jadensis in the deep waters. Contigs of A. jadensis were binned from the metagenomes for examination of alkane degradation pathways and deep-sea specific pathways, which revealed lack of nitrate and nitrite dissimilatory reduction in our A. jadensis strains. Comparing the results for the two cruises conducted nearby, we speculate periodic release of alkanes that may spread widely but periodically in the trench. Distribution of alkane-degrading bacteria in the world oceans suggests the periodic and remarkable contribution of Alcanivorax to the deep-sea organic carbon and nitrogen sources.IMPORTANCE In the oligotrophic environment of the Mariana Trench, alkanes as carbohydrate are important for the ecosystem but their spatial and periodic spreading was never reported in deep waters. The alkanes-degrading bacteria such as Alcanivorax sp. are biological signals of the alkane distribution. In the present study, Alcanivorax was abundant in some waters at depths up to 6000 m in the Mariana Trench. Genomics, transcriptomics and chemical analysis provide evidence for the presence and activities of Alcanivorax jadensis in the deep-sea zones. The periodic spreading of the alkanes probably from the subductive plates might have fundamentally modified the local microbial communities perhaps as well as deep-sea microenvironment. PMID- 30446552 TI - Diversity in CO2 concentrating mechanisms among chemolithoautotrophs from genera Hydrogenovibrio, Thiomicrorhabdus, and Thiomicrospira, ubiquitous in sulfidic habitats worldwide. AB - Members of Hydrogenovibrio, Thiomicrospira and Thiomicrorhabdus fix carbon at hydrothermal vents, coastal sediments, hypersaline lakes, and other sulfidic habitats. The genome sequences of these ubiquitous and prolific chemolithoautotrophs suggest a surprising diversity of mechanisms for dissolved inorganic carbon (DIC) uptake and fixation; these mechanisms are verified here. Carboxysomes are apparent in transmission electron micrographs of most of these organisms; lack of carboxysomes in Thiomicrorhabdus sp. Milos T2 and Tmr. arctica, and an inability to grow under low DIC conditions by Thiomicrorhabdus sp. Milos T2 are consistent with an absence of carboxysome loci in their genomes. For the remaining organisms, genes encoding potential DIC transporters from four evolutionarily distinct families (Tcr0853/0854, Chr, SbtA, SulP) are located downstream of carboxysome loci. Transporter genes collocated with carboxysome loci, as well as some homologs located elsewhere on the chromosomes, had elevated transcript levels under low DIC conditions, as assayed by qRT-PCR. DIC uptake was measureable via silicone oil centrifugation when a representative of each of the four types of transporter was expressed in Escherichia coli Expression of these genes in carbonic anhydrase-deficient E. coli EDCM636 enabled it to grow under low DIC conditions, consistent with DIC transport by these proteins. The results from this study expand the range of DIC transporters within the SbtA and SulP transporter families, verify DIC uptake by transporters encoded by Tcr_0853 and Tcr_0854 and their homologs, and introduce DIC as a potential substrate for transporters from the Chr family.IMPORTANCE Autotrophic organisms take up and fix DIC, introducing carbon into the biological component of the global carbon cycle. The mechanisms for DIC uptake and fixation by autotrophic Bacteria and Archaea are likely to be diverse, but have only been well-characterized among "Cyanobacteria". Based on genome sequences, members of Hydrogenovibrio, Thiomicrospira and Thiomicrorhabdus have a variety of mechanisms for DIC uptake and fixation. We verified that most of these organisms are capable of growing under low DIC conditions, when they upregulate carboxysome loci and transporter genes collocated with these loci on their chromosomes. When these genes, which fall into four evolutionarily independent families of transporters, are expressed in E. coli, DIC transport is detected. This expansion in known DIC transporters across four families, from organisms from a variety of environments, provides insight into the ecophysiology of autotrophs, as well as a toolkit for engineering microorganisms for carbon-neutral biochemistries of industrial importance. PMID- 30446554 TI - Metabolites of an oil field sulfide-oxidizing nitrate-reducing Sulfurimonas sp. cause severe corrosion. AB - Oil reservoir souring and associated materials integrity challenges are of great concern to the petroleum industry. The bioengineering strategy of nitrate injection has proven successful for controlling souring in some cases, but recent reports indicate increased corrosion in nitrate-treated produced water re injection facilities. Sulfide-oxidizing nitrate-reducing bacteria (soNRB) have been suggested to be the cause of such corrosion. Using the model oil field soNRB Sulfurimonas sp. strain CVO we conducted a detailed analysis of soNRB-induced corrosion at initial nitrate to sulfide (N/S) ratios relevant to oil field operations. The activity of strain CVO caused severe corrosion rates of up to 0.27 mm y-1 and up to 60 um deep pitting within only nine days. The highest corrosion during growth of strain CVO was associated with production of zero valent sulfur during sulfide oxidation, and accumulation of nitrite, when initial N/S ratios were high. Abiotic corrosion tests with individual metabolites confirmed biogenic zero-valent sulfur and nitrite as the main causes of corrosion under the experimental conditions. Mackinawite (FeS) deposited on carbon steel surfaces accelerated abiotic reduction of both sulfur and nitrite, exacerbating corrosion. Based on these results a conceptual model for nitrate-mediated corrosion by soNRB is proposed.IMPORTANCE Ambiguous reports of corrosion problems associated with the injection of nitrate for souring control necessitate a deeper understanding of this frequently applied bioengineering strategy. Sulfide oxidizing nitrate-reducing bacteria have been proposed as key culprits, despite the underlying microbial corrosion mechanisms remaining insufficiently understood. This study provides a comprehensive characterization of how individual metabolic intermediates of the microbial nitrogen and sulfur cycles can impact the integrity of carbon steel infrastructure. The results help explain the, at times, dramatic increases in corrosion rates observed during nitrate injection in field and laboratory trials and point to strategies for reducing adverse integrity-related side effects of nitrate-based souring mitigation. PMID- 30446555 TI - Salmonella enterica filamentation induced by pelargonic acid is a transient morphotype. AB - Under stressful conditions, Salmonella enterica forms multi-nucleated, elongated filaments. The triggers and outcomes of filamentation are not well characterized. S. Newport, Javiana and Typhimurium were evaluated for their ability to form filaments on exposure to 20 mM pelargonic acid. S Newport was used as a model to investigate progression and fate of filamentation via culturable population size, cell length and viability assays. All serotypes displayed filament formation after 16 h of incubation. Pelargonic acid amendment of tryptic soy broth (TSBpel) produced a five-log CFU reduction compared to TSB after 24 h (p<0.05) and growth rate was slowed (p<0.02). Cell elongation started within 12 h, peaked at 16 h and was followed by filament disintegration at 20-24 h. The ratio of filaments to regular-sized cells (F:R) in TSBpel was 3.86+/-0.68 at 16 h, decreasing to 0.23+/ 0.04 and 0.03+/-0.01 (p<0.05) at 20 and 24 h, respectively. Mg2+ supplementation repressed filamentation (F:R=0.27+/-0.11) and enhanced culturable cell counts (p<0.05). Continued exposure to pelargonic acid inhibited growth in TSB and M9 compared to unamended media (p<0.05). However, in M9pel, filament fragmentation progressed independently of pelargonic acid or Mg2+ When cells were pre-treated with pelargonic acid to induce filamentation, then transferred to fresh media, a positive effect of Mg2+ was noted in nutrient-deficient conditions, with higher Live:Dead ratios in M9Mg than M9 (p<0.05). No change was observed when pelargonic acid was also added. Filamentation was ubiquitous in all serotypes tested, transient and sensitive to Mg2+ Fragmentation, but not recovery, progressed irrespective of antimicrobial or Mg2+ presence.Importance Some bacteria form elongated, multi-nucleated structures, or filaments, when exposed to stress. The filamentous form of foodborne bacterial pathogens can interfere with food protection practices and diagnostic testing. Filamentation in Salmonella enterica Newport was investigated in response to pelargonic acid, a compound naturally found in several fruit and vegetables, and also used commercially as a herbicide. Salmonella readily formed filaments when exposed to pelargonic acid. Filaments were not stable however, and fragmented to individual cells even when the fatty acid was still present, recovering fully when the stress was alleviated. A deeper exploration of the molecular mechanisms regulating filamentation, and the conditions that induce it in agriculture and the food supply chain, are needed to devise strategies that curb this response. PMID- 30446556 TI - Identification of metabolites involved in the aerobic degradation of estrogen A/B rings. AB - Various bacteria, mainly actinobacteria and proteobacteria, are capable of aerobic estrogen degradation. In a previous study, we used the obligate aerobic alphaproteobacterium, Sphingomonas sp. strain KC8 as a model microorganism to identify initial metabolites involved in the oxygenolytic cleavage of the estrogen A-ring: 4-hydroxyestrone, a meta-cleavage product, and a dead-end product pyridinestrone acid. In this study, we managed to identify the downstream metabolites of this aerobic degradation pathway using UPLC-HRMS. 4-Norestrogen 5(10)-en-3-oyl-CoA and its closely related deconjugated (non-CoA) structure, 4 norestrogenic acid, were detected in the estrone-grown strain KC8 cultures. The structure of 4-norestrogenic acid was elucidated using NMR spectroscopy. The extracellular distribution and the accumulation of 4-norestrogenic acid in the bacterial cultures indicate that the estrogen-degrading bacteria cannot degrade this deconjugated product. We also observed temporal accumulation and subsequent consumption of a common steroid metabolite, 3aalpha-H-4alpha(3'-propanoate) 7abeta-methylhexahydro-1,5-indanedione (HIP), in the bacterial cultures. The metabolite profile and genomic analyses shed light on the biochemical mechanisms involved in the degradation of the A/B-rings of natural estrogens. In this proposed aerobic pathway, C-4 of the meta-cleavage product is removed by a 2 oxoacid oxidoreductase through an oxidative decarboxylation to produce the 4 norestrogen-5(10)-en-3-oyl-CoA. Subsequently, the B-ring is cleaved through hydrolysis. The resulting A/B-rings cleaved product is transformed into a common steroid metabolite HIP through beta-oxidation reactions. Accordingly, the A/B rings of different steroids are degraded through at least three peripheral pathways, which converge at HIP, and HIP is then degraded through a common central pathway.ImportanceEstrogens, often detected in surface waters worldwide, have been classified as endocrine disrupting chemicals and carcinogens. Bacterial degradation is crucial for removing natural estrogens from natural and engineered ecosystems; however, current knowledge regarding biochemical mechanisms and catabolic enzymes involved in estrogen biodegradation is very limited. Our estrogen metabolite profile and genomic analyses on estrone-degrading bacteria enabled us to characterize the aerobic estrogen degradation pathway. The results greatly expand our understanding of microbial steroid degradation. In addition, the characteristic metabolites, dead-end products, and degradation genes can be used as biomarkers to investigate fate and biodegradation potential of estrogens in the environment. PMID- 30446557 TI - RNA Sequencing Based Transcriptional Overview of Xerotolerance in Cronobacter sakazakii SP291. AB - Cronobacter sakazakii is a xerotolerant neonatal pathogen epidemiologically linked to powdered infant food formula, often resulting in high mortality rates. Here, we used RNA-seq to provide transcriptional insights into the survival of C. sakazakii in desiccated conditions. Our RNA-seq data shows that about 22% of the total C. sakazakii genes were significantly up-regulated and 9% were down regulated during desiccation survival. When qRT-PCR was used to validate the RNA seq data, we found that the primary desiccation response was gradually down regulated during the tested four hours of desiccation while the secondary response remained constitutively up-regulated. The 4-hour desiccation tolerance of C. sakazakii was dependent on the immediate microenvironment surrounding the bacterial cell. Removal of TSB salts and the introduction of sterile infant formula residues in the microenvironment enhanced the desiccation survival of C. sakazakii SP291. The trehalose biosynthetic pathway encoded by otsA and otsB, a prominent secondary bacterial desiccation response, was highly up-regulated in desiccated C. sakazakii C. sakazakii SP291 DeltaotsAB was significantly inhibited compared to the isogenic wild type in an eight hour desiccation survival assay confirming the physiological importance of trehalose in desiccation survival. Overall, we provide a comprehensive RNA-seq based transcriptional overview along with confirmation of the phenotypic importance of trehalose metabolism in Cronobacter sakazakii during desiccation.IMPORTANCE Cronobacter sakazakii is a pathogen of importance to neonatal health that is known to persist in dry food matrices such as powdered infant formula (PIF) and its associated production environment. When infections are reported in neonates, mortality rates can be high. The success of this bacterium in surviving these low-moisture environments suggests that Cronobacter species can respond to a variety of environmental signals. Therefore, understanding those signals that aid persistence of this pathogen in these ecological niches, is an important step towards the development of strategies to reduce the risk of contamination of PIF. This research led to the identification of candidate genes that play a role in the persistence of this pathogen in desiccated conditions and, thereby, serve as a model target to design future strategies to mitigate PIF associated survival of C. sakazakii. PMID- 30446558 TI - Analysis of the thermal stability of a mercuric reductase from the Red Sea Atlantis II hot brine environment by site-directed mutagenesis. AB - The lower convective layer (LCL) of the Atlantis II brine pool of the Red sea is a unique environment in terms of high salinity, temperature, and high concentrations of heavy metals. Mercuric reductase enzymes functional in such extreme conditions could be considered as a potential tool in the environmental detoxification of mercurial poisoning and might alleviate ecological hazards in the mining industry. Here, we constructed a mercuric reductase library from Atlantis II, from which we identified genes encoding two thermostable mercuric reductase (MerA) isoforms: one is halophilic (designated ATII-LCL) while the other is not (designated ATII-LCL-NH). The ATII-LCL MerA has a short motif composed of four aspartic acids (4D414-417) and two characteristic signature boxes that played a crucial role in its thermal stability. To further understand the mechanism behind the thermostability of the two studied enzymes, we mutated the isoform ATII-LCL-NH and found that the substitution of 2D at positions 415/416 enhanced the thermal stability, while other mutations had the opposite effect. The 2D mutant showed superior thermal tolerance as it retained 81% of its activity after 10 minutes incubation at 70 degrees C. Three-dimensional structure prediction revealed newly formed salt-bridges and H-bonds in the 2D mutant, compared to the parent molecule. To the best of our knowledge, this study is the first to rationally design a mercuric reductase with enhanced thermal stability, which we propose to have a strong potential in bioremediation of mercurial poisoning.Importance The Red Sea is an attractive environment for bioprospecting. There are 25 brine-filled deeps in the Red Sea. The Atlantis II brine pool is the biggest and hottest of such hydrothermal ecosystems. We generated an environmental mercuric reductase library from the lowermost layer of the Atlantis II brine pool, in which we identified two variants of the mercuric reductase enzyme (MerA). One is the previously described halophilic and thermostable ATII LCL MerA and the other is a non-halophilic, relatively less thermostable, designated ATII-LCL-NH MerA enzyme. We used the ATII-LCL-NH enzyme as a parent molecule to locate the amino acid residues involved in the noticeable higher thermo-tolerance of the homolog ATII-LCL MerA. Moreover, we designed a novel enzyme with superior thermal stability. This enzyme could have strong potential in bioremediation of mercuric toxicity. PMID- 30446559 TI - Feeding rapidly alters microbiome composition and gene transcription in the clownfish gut. AB - BackgroundDiet is a major determinant of intestinal microbiome composition. While studies have evaluated microbiome responses to diet variation, less is understood of how the act of feeding influences the microbiome, independent of diet type. Here, we use the clownfish Premnas biaculeatus, a species reared commonly in ornamental marine aquaculture, to test how the diversity, predicted gene content, and gene transcription of the microbiome vary over a two-day diurnal period with a single daily feeding event. This study used fish fed four times daily, once daily, or every three days prior to the diurnal period, allowing us also to test how feeding frequency affected microbiome diversity. The amount of time between feedings had no affect on baseline diversity of the microbiome. In contrast, the act of feeding itself caused a significant short term change in the microbiome, with microbiome diversity, predicted gene content, and gene transcription varying significantly between time points immediately before and 1.5 hours post feeding. Variation was driven by abundance shifts involving exact sequence variants (ESVs), with one ESV identified as Photobacterium sp. increasing from <0.5% of sequences immediately pre-feeding to 34% at 1.5 hours post-feeding. Other ESVs from a range of microbial groups also increased dramatically after feeding, with the majority also detected in the food. One ESV identified as Clostridium perfringens represented up to 55% of sequences but did not vary significantly over the diurnal period and was not detected in the food. Post-feeding samples were enriched in transcripts and predicted genes for social interactions, cell motility, and coping with foreign DNA, whereas time points farther from feeding were enriched in genes of diverse catabolic and biosynthetic functions. These results confirm feeding as a significant destabilizing force in clownfish intestinal microbiomes, likely due to both input of cells attached to food and stimulation of resident microbes. Microbes such as Photobacterium may episodically transition from environmental reservoirs to growth in the gut, likely in association with food particles. This transition may be facilitated by functions for navigating a new environment and interacting with neighboring microbes and host cells. Other taxa, such as Clostridium, are comparatively stable intestinal members and less likely to be affected by passing food. Conclusions about microbiome ecology may therefore differ based on when samples were collected relative to the last feeding.ImportanceDespite extensive study of intestinal microbiome diversity and the role of diet type in structuring gut microbial communities, we know very little about short-term changes in the intestinal microbiome as a result of feeding alone. Sampling microbiomes over a feeding cycle will allow us to differentiate opportunistic, feeding-responsive microbes from resident, potentially commensal members of the gut community. Also, since feeding has the potential to alter microbiome structure, sampling at different points relative to the last feeding event will likely yield different conclusions about microbiome composition and function. This variation should be addressed in comparative microbiome studies. Our study contributes to knowledge of short-term changes in the gut microbiome associated with feeding events. PMID- 30446560 TI - Novel cholera toxin variant and ToxT regulon in environmental Vibrio mimicus strains: potential resources for the evolution of Vibrio cholerae hybrid strains. AB - Atypical El Tor strains of Vibrio cholerae O1 harboring variant ctxB genes of cholera toxin (CT) are gradually becoming a major cause of recent cholera epidemics. Vibrio mimicus occasionally produces CT, encoded by ctxAB on CTXF genome; and toxin-coregulated pilus (TCP), a major intestinal colonization factor and also the CTXF-specific receptor. This study carried out extensive molecular characterization of CTXF and ToxT regulon in ctx+ve strains of V. mimicus isolated from the Bengal coast. Southern hybridization, PCR, and DNA sequencing of virulence related-genes revealed the presence of an El Tor type CTX prophage (CTXET) carrying a novel ctxAB, tandem copies of environmental type pre-CTX prophage (pre-CTXEnv), and RS1 elements, which were organized in an array of RS1 CTXET-RS1-pre-CTXEnv-pre-CTXEnv Additionally, a novel variant of tcpA and toxT respectively, showing phylogenetic lineage to a clade of V. cholerae non-O1/O139, was identified. The V. mimicus strains lacked the RTX and TLC elements, and Vibrio seventh pandemic islands of the El Tor strains, but contained five heptamer (TTTTGAT) repeats in ctxAB promoter region like some classical strains of V. cholerae O1. PFGE analysis showed all the ctx +ve V. mimicus strains were clonally related. However, their in vitro CT production and in vivo toxigenecity were variable, which could be explained by differential transcription of virulence genes along with ToxR regulon. Taken together, our findings strongly suggest that environmental V. mimicus strains act as potential reservoir of atypical virulence factors, including variant CT and ToxT regulon, and may contribute to the evolution of V. cholerae hybrid strains.IMPORTANCE Natural diversification of CTXF and ctxAB genes certainly influences disease severity and shifting patterns in major etiological agents of cholera, e.g., the overwhelming emergence of hybrid El Tor variants, replacing the prototype El Tor strains of V. cholerae This study showing the occurrence of CTXET comprising a novel variant of ctxAB in V. mimicus points out a previously unnoticed evolutionary event, independent to that of the El Tor strainsof V. cholerae Identification and cluster analysis of the newly-discovered alleles of tcpA and toxT suggests their horizontal transfer from an uncommon clone of V. cholerae The genomic contents of ToxT regulon, and tandemly arranged multiple pre-CTXFEnv and a CTXFET in V. mimicus probably act as salient raw materials inducing natural recombination among the hallmark virulence genes of hybrid V. cholerae strains. This study provides valuable information to enrich our knowledge on the evolution of new variant CT and ToxT regulon. PMID- 30446561 TI - Anti-Parasitic Effect of Copper Alloy Surface on Cryptocaryon irritans in Aquaculture of Larimichthys crocea. AB - Copper and its alloys containing greater than 60% copper by weight are antimicrobial. In aquaculture, copper alloys are used as part of corrosion resistant cages or as part of copper coating. To test whether an alloy of copper surface prevents the outbreak of parasitosis in the aquaculture of Larimichthys crocea, we covered the bottom of the aquaculture tank with sheets of copper alloy containing 74% to 78% copper and cultured L. crocea juveniles that were artificially infected with the protozoan parasite Cryptocaryon irritans Our results show that these copper alloy sheets effectively block the infectious cycle of C. irritans within a one week period, and significantly reduce the number of C. irritans trophonts and tomonts, thereby decreasing the mortality rate of L. crocea In in vitro assays, the cytoplasmic membrane of protomonts disintegrated and the cytoplasm overflowed following just five minutes of contact with copper alloy surfaces. Even though the same cytoplasmic membrane disintegration was not observed in tomonts, they completely lost their capacity for proliferation and eventually died following direct contact with copper alloy sheets for one hour. This is likely because C. irritans tomonts took in over 100 times more copper ions following contact with the copper alloy sheets than within the control aquaculture environment. Exposure to copper alloy sheets also did not lead to excessive heavy metal levels in the aquacultured fish or in the culture seawater.Importance: Cryptocaryon irritans, a parasitic ciliate that penetrates the epithelium of the gills, skin, and fins of marine fish, causes acute suffocation and mortality in cultured fish within days of infection. Much of the existing research centers around the prevention of C. irritans infection, but no cure has been found. Studies demonstrate that copper has strong anti-microbial properties, and fish grown in copper-containing cages have a lower rate of infection by C. irritans compared to other currently used aquaculture cages. In this study, we found that an alloy containing 74% to 78% copper by weight effectively kills C. irritans cells and prevents cryptocaryoniasis outbreaks within a one-week period. These findings offer a new perspective on the prevention and control of cryptocaryoniasis. PMID- 30446563 TI - Non-invasive detection of equid herpesviruses in fecal samples. AB - Equid Herpesviruses (EHV) are pathogens of equid and non-equid hosts that can cause disease and fatalities in captivity and in the wild. EHVs establish latent infections but can reactivate, and most EHVs are shed via the nasal passage. Therefore, nasal swabs are generally used for EHV monitoring. However, invasive sampling of wild equids is difficult. While feces is a commonly used substrate for detecting other pathogens, to our knowledge EHVs have never been detected in feces of naturally infected equids. We systematically tested zebra feces for EHV presence by A) establishing nested PCR conditions for fecal DNA extracts, B) controlling for environmental EHV contamination, and C) large-scale testing on a free-ranging zebra population. A dilution minimizing inhibition while maximizing viral DNA concentration was determined in captive Grevys zebra (Equus grevyi) fecal samples from individuals shedding EHV nasally. Sixteen of 42 fecal samples (38%) were EHV-positive. To demonstrate that the EHV positivity was not a result of environmental contamination, rectal swabs of wild zebras were screened (N = 18; E. quagga and E. zebra), and 50% were EHV-positive, indicating that the source of EHV in feces is likely the intestinal mucosa, and not post-defecation contamination. Out of 270 fecal samples of wild zebras 26% were EHV-positive. Quantitative PCRs showed that the amount of virus DNA in feces was not significantly lower than in other samples. In summary, fecal sampling facilitates large scale screening and may be useful to non-invasively investigate phylogenetic EHV diversity in wild and domestic equids.ImportanceEquid Herpesviruses (EHV) establish latent infections and most EHVs are shed and transmitted via nasal discharge and transmitted primarily through droplet and aerosol infection with nasal discharge. Obtaining nasal swabs and other invasive samples from wildlife is often not possible without capture and physical restraint of individuals, which is resource-intensive and is a health risk for the captured animals. Fecal EHV shedding has never been demonstrated for naturally infected equids. We established the conditions for fecal EHV screening, and our results suggest that fecal samples are an effective non-invasive approach for monitoring acute EHV shedding in equids. PMID- 30446562 TI - Metal Reduction and Protein Secretion Genes Required for Iodate Reduction by Shewanella oneidensis. AB - The metal-reducing gamma-proteobacterium Shewanella oneidensis reduces iodate (IO3 -) as anaerobic terminal electron acceptor. Microbial IO3 - electron transport pathways are postulated to terminate with nitrate (NO3 -) reductase, which reduces IO3 - as alternative electron acceptor. Recent studies with S. oneidensis, however, have demonstrated that NO3 - reductase is not involved in IO3 - reduction. The main objective of the present study was to determine the metal reduction and protein secretion genes required for IO3 - reduction by Shewanella oneidensis with lactate, formate, or H2 as electron donors. With all electron donors, the type I and type V protein secretion mutants retained wild type IO3 - reduction activity, while the type II protein secretion mutant lacking the outer membrane secretin GspD was impaired in IO3 - reduction. Deletion mutants lacking the cyclic AMP receptor protein CRP, cytochrome maturation permease CcmB, and inner membrane-tethered c-type cytochrome CymA were impaired in IO3 - reduction with all electron donors, while deletion mutants lacking c type cytochrome MtrA and outer membrane beta-barrel protein MtrB of the outer membrane MtrAB module were were impaired in IO3 - reduction with only lactate as electron donor. With all electron donors, mutants lacking the c-type cytochromes OmcA and MtrC of the metal-reducing extracellular electron conduit MtrCAB retained wild-type IO3 - reduction activity. These findings indicate that IO3 - reduction by S. oneidensis involves electron donor-dependent metal reduction and protein secretion pathway components, including the outer membrane MtrAB module and type II protein secretion of an unidentified IO3 - reductase to the S. oneidensis outer membrane.IMPORTANCE Microbial iodate (IO3 -) reduction is a major component in the biogeochemical cycling of iodine and the bioremediation of iodine-contaminated environments, however, the molecular mechanism of microbial IO3 - reduction is poorly understood. Results of the present study indicate that outer membrane (type II) protein secretion and metal reduction genes encoding the outer membrane MtrAB module of the extracellular electron conduit MtrCAB are required for IO3 - reduction by S. oneidensis On the other hand, the metal reducing c-type cytochrome MtrC of the extracellular electron conduit is not required for IO3 - reduction by S. oneidensis These findings indicate that the IO3 - electron transport pathway terminates with an as yet unidentified IO3 - reductase that associates with the outer membrane MtrAB module to deliver electrons extracellularly to IO3. PMID- 30446564 TI - Induction of a Long Noncoding RNA Transcript, NR_045064, Promotes Defense Gene Transcription and Facilitates Intestinal Epithelial Cell Responses against Cryptosporidium Infection. AB - Cryptosporidium is an important opportunistic intestinal pathogen for immunocompromised individuals and a common cause of diarrhea in young children in developing countries. Gastrointestinal epithelial cells play a central role in activating and orchestrating host immune responses against Cryptosporidium infection, but underlying molecular mechanisms are not fully understood. We report in this paper that C. parvum infection causes significant alterations in long noncoding RNA (lncRNA) expression profiles in murine intestinal epithelial cells. Transcription of a panel of lncRNA genes, including NR_045064, in infected cells is controlled by the NF-kappaB signaling. Functionally, inhibition of NR_045064 induction increases parasite burden in intestinal epithelial cells. Induction of NR_045064 enhances the transcription of selected defense genes in host cells following C. parvum infection. Epigenetic histone modifications are involved in NR_045064-mediated transcription of associated defense genes in infected host cells. Moreover, the p300/MLL-associated chromatin remodeling is involved in NR_045064-mediated transcription of associated defense genes in intestinal epithelial cells following C. parvum infection. Expression of NR_045064 and associated genes is also identified in intestinal epithelium in C57BL/6J mice following phosphorothioate oligodeoxynucleotide or LPS stimulation. Our data demonstrate that lncRNAs, such as NR_045064, play a role in regulating epithelial defense against microbial infection. PMID- 30446565 TI - Sialic Acid-Dependent Inhibition of T Cells by Exosomal Ganglioside GD3 in Ovarian Tumor Microenvironments. AB - The tumor microenvironment is rendered immunosuppressive by a variety of cellular and acellular factors that represent potential cancer therapeutic targets. Although exosomes isolated from ovarian tumor ascites fluids have been previously reported to induce a rapid and reversible T cell arrest, the factors present on or within exosomes that contribute to immunosuppression have not been fully defined. In this study, we establish that GD3, a ganglioside expressed on the surface of exosomes isolated from human ovarian tumor ascites fluids, is causally linked to the functional arrest of T cells activated through their TCR. This arrest is inhibited by Ab blockade of exosomal GD3 or by the removal of GD3+ exosomes. Empty liposomes expressing GD3 on the surface also inhibit the activation of T cells, establishing that GD3 contributes to the functional arrest of T cells independent of factors present in exosomes. Finally, we demonstrate that the GD3-mediated arrest of the TCR activation is dependent upon sialic acid groups, because their enzymatic removal from exosomes or liposomes results in a loss of inhibitory capacity. Collectively, these data define GD3 as a potential immunotherapeutic target. PMID- 30446566 TI - Colitis Promotes a Pathological Condition of the Liver in the Absence of Foxp3+ Regulatory T Cells. AB - Inflammatory bowel disease is associated with extraintestinal diseases such as primary sclerosing cholangitis in the liver. Interestingly, it is known that an imbalance between Foxp3+ regulatory T cells (Treg) and Th17 cells is involved in inflammatory bowel disease and also in primary sclerosing cholangitis. To explain these associations, one hypothesis is that intestinal inflammation and barrier defects promote liver disease because of the influx of bacteria and inflammatory cells to the liver. However, whether and how this is linked to the Treg and Th17 cell imbalance is unclear. To address this, we used dextran sodium sulfate (DSS) and T cell transfer colitis mouse models. We analyzed the pathological conditions of the intestine and liver on histological, cellular, and molecular levels. We observed bacterial translocation and an influx of inflammatory cells, in particular Th17 cells, to the liver during colitis. In the DSS colitis model, in which Treg were concomitantly increased in the liver, we did not observe an overt pathological condition of the liver. In contrast, the T cell-mediated colitis model, in which Treg are not abundant, was associated with marked liver inflammation and a pathological condition. Of note, upon depletion of Treg in DEREG mice, DSS colitis promotes accumulation of Th17 cells and a pathological condition of the liver. Finally, we studied immune cell migration using KAEDE mice and found that some of these cells had migrated directly from the inflamed intestine into the liver. Overall, these data indicate that colitis can promote a pathological condition of the liver and highlight an important role of Treg in controlling colitis-associated liver inflammation. PMID- 30446567 TI - Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool. AB - Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine-, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases. PMID- 30446568 TI - Nonredundant Roles of IL-21 and IL-4 in the Phased Initiation of Germinal Center B Cells and Subsequent Self-Renewal Transitions. AB - We examined the unique contributions of the cytokines IL-21 and IL-4 on germinal center (GC) B cell initiation and subsequent maturation in a murine model system. Similar to other reports, we found T follicular helper cell expression of IL-21 begins prior to T follicular helper cell migration into the B cell follicle and precedes that of IL-4. Consistent with this timing, IL-21 signaling has a greater influence on the perifollicular pre-GC B cell transition to the intrafollicular stage. Notably, Bcl6hi B cells can form in the combined absence of IL-21R- and STAT6-derived signals; however, these nascent GC B cells cease to proliferate and are more prone to apoptosis. When B cells lack either IL-21R or STAT6, aberrant GCs form atypical centroblasts and centrocytes that differ in their phenotypic maturation and costimulatory molecule expression. Thus, IL-4 and IL-21 play nonredundant roles in the phased progression of GC B cell development that can initiate in the combined absence of these cytokine signals. PMID- 30446570 TI - Rapid and Efficient Production of Human Functional Mast Cells Through a Three Dimensional Culture of Adipose Tissue-Derived Stromal Vascular Cells. AB - Mast cells (MC) are innate immune cells involved in many physiological and pathological processes. However, studies of MC function and biology are hampered by the difficulties to obtain human primary MC. To solve this problem, we established a new method to produce easily and rapidly high numbers of MC for in vitro studies using human adipose tissue, which is an abundant and easy access tissue. Stromal vascular fraction of adipose tissue, obtained from human abdominal dermolipectomy, was cultured as spheroids in serum free medium supplemented in stem cell factor. Using this method, we generated, within 3 wk, a highly pure population of connective tissue-type MC expressing MC typical peptidases (tryptase, chymase, and carboxypeptidase-A3) with a yield increasing over time. Stem cell factor was required for this culture, but unlike MC derived from CD34+ cells, this culture did not depend on IL-3 and -6. MC obtained with this method degranulated following FcepsilonRI cross-linking or stimulation by C5a, compound 48/80, and substance P. Interestingly, activation by anti-IgE of both white adipose tissue-MC and MC obtained from peripheral blood-derived CD34+ pluripotent progenitor cells induced the production of PGs as well as proinflammatory cytokines (TNF-alpha, Il-6, and GM-CSF). In conclusion, we developed a new time saving and reproducible method to produce highly pure and functional human MC in 3 wk from human adipose tissue. PMID- 30446569 TI - IL-33 Released in the Liver Inhibits Tumor Growth via Promotion of CD4+ and CD8+ T Cell Responses in Hepatocellular Carcinoma. AB - IL-33 released by epithelial cells and immune cells functions as an alarmin and can induce both type 1 and type 2 immune responses. However, the role of IL-33 release in tumor development is still not clear. In this study, we examined the function of released IL-33 in murine hepatocellular carcinoma (HCC) models by hydrodynamically injecting either IL-33-expressing tumor cells or IL-33 expressing plasmids into the liver of tumor-bearing mice. Tumor growth was greatly inhibited by IL-33 release. This antitumor effect of IL-33 was dependent on suppression of tumorigenicity 2 (ST2) because it was diminished in ST2-/- mice. Moreover, HCC patients with high IL-33 expression have prolonged overall survival compared with the patients with low IL-33 expression. Further study showed that there were increased percentages and numbers of activated and effector CD4+ and CD8+ T cells in both spleen and liver in IL-33-expressing tumor bearing mice. Moreover, IFN-gamma production of the CD4+ and CD8+ T cells was upregulated in both spleen and liver by IL-33. The cytotoxicity of CTLs from IL 33-expressing mice was also enhanced. In vitro rIL-33 treatment could preferentially expand CD8+ T cells and promote CD4+ and CD8+ T cell activation and IFN-gamma production. Depletion of CD4+ and CD8+ T cells diminished the antitumor activity of IL-33, suggesting that the antitumor function of released IL-33 was mediated by both CD4+ and CD8+ T cells. Taken together, we demonstrated in murine HCC models that IL-33 release could inhibit tumor development through its interaction with ST2 to promote antitumor CD4+ and CD8+ T cell responses. PMID- 30446571 TI - International experiments with different models of allocating funds to facilitate integrated care: a scoping review protocol. AB - INTRODUCTION: Integrated care is viewed widely as a potential solution to some of the major challenges faced by health and social care systems, such as those posed by service duplication, fragmentation and poor care coordination, and associated impacts on the quality and cost of services. Fragmented models of allocating funds to and across sectors, programmes and providers are frequently cited as a major barrier to integration and countries have experimented with different models of allocating funds to enhance care coordination among service providers and to reduce ineffective care and avoid costly adverse events. This scoping review aims to assess published international experiences of different models of allocating funds to facilitate integration and the evidence on their impacts. METHODS AND ANALYSIS: We will adopt a scoping review methodology due to the potentially vast and multidisciplinary nature of the literature on different models of allocating funds in health and social care systems, as well as the scarcity of existing knowledge syntheses. The framework developed by Arksey and O'Malley will be followed that entails six steps: (1) identifying the research question(s), (2) searching for relevant studies, (3) selecting studies, (4) charting the data, (5) collating, summarising and reporting the results and (6) and conducting consultation exercises. These steps will be conducted iteratively and reflexively, making adjustments and repetitions when appropriate to make sure the literature has been covered as comprehensively as possible. To ensure comprehensiveness of our literature review, we also search a wide range of sources. ETHICS AND DISSEMINATION: An integrated knowledge translation strategy will be pursued by engaging our knowledge users through all stages of the review. We will organise two workshops or policy roundtables/policy dialogues in Alberta and British Columbia with participation of diverse knowledge users to discuss and interpret the findings of our review and to draw out policy opportunities and lessons that can be applied to the context of these two provinces. PMID- 30446572 TI - Delivery, setting and outcomes of paediatric Outpatient Parenteral Antimicrobial Therapy (OPAT): a scoping review. AB - BACKGROUND: There has been little detailed systematic consideration of the delivery, setting and outcomes of paediatric Outpatient Parenteral Antimicrobial Therapy (OPAT), although individual studies report that it is a safe and effective treatment. OBJECTIVE: This scoping review aimed to examine what is known about the delivery, settings and outcomes of paediatric OPAT and to identify key knowledge deficits. DESIGN: A scoping review using Arksey and O'Malley's framework was undertaken. DATA SOURCES: Keywords were identified and used to search MEDLINE and CINAHL. STUDY APPRAISAL METHODS: Primary research studies were included if samples comprised children and young people 21 or under, who had received OPAT at home or in a day treatment centre. The Mixed Methods Appraisal Tool was used to review the methodological quality of the studies MAIN FINDINGS: From a preliminary pool of 157 articles, 51 papers were selected for full review. 19 studies fitted the inclusion criteria. Factors influencing delivery of OPAT were diverse and included child's condition, home environment, child-related factors, parental compliance, training and monitoring. There is little consensus as to what constitutes success of and adverse events in OPAT. CONCLUSIONS: Future studies need to clearly define and use success indicators and adverse events in order to provide evidence that paediatric OPAT is safe and effective. IMPLICATIONS: Consensus outcomes that include child and parent perspectives need to be developed to allow a clearer appreciation of a successful paediatric OPAT service. PMID- 30446573 TI - Catastrophic health expenditure among industrial workers in a large-scale industry in Nepal, 2017: a cross-sectional study. AB - OBJECTIVES: The study aimed at estimating out-of-pocket (OOP) expenditure, catastrophic health expenditure (CHE) and distress financing due to hospitalisation and outpatient care among industrial workers in Eastern Nepal. METHODS: We conducted a cross-sectional study involving industrial workers employed in a large-scale industry in Eastern Nepal. Those who were hospitalised in the last 1 year or availed outpatient care within the last 30 days were administered a structured questionnaire to estimate the cost of illness. CHE was defined as expenditure more than 20% of annual household income. Distress financing was defined as borrowing money/loan or selling assets to cope with OOP expenditure on health. RESULTS: Of 1824 workers eligible for the study, 1405 (77%) were screened, of which 85 (6%) were hospitalised last year; 223 (16%) attended outpatient department last month. The median (IQR) OOP expenditure from hospitalisation and outpatient care was US$124 (71-282) and US$36 (19-61), respectively. Among those hospitalised, the prevalence of CHE and distress financing was found to be 13% and 42%, respectively, and due to outpatient care was 0.4% and 42%, respectively. Drugs and diagnostics account for a large share of direct costs in both public and private sectors. More than 80% sought hospitalisation and outpatient care in a private sector. CONCLUSION: Industrial workers face significant financial risks due to ill health compared with the general population. Poor utilisation and higher cost of care in public health facilities warrant strengthening of public sector through increased government spending. The labour act 2014 of Nepal should be strictly adhered. PMID- 30446574 TI - Epidemiology of injuries, treatment (costs) and outcome in burn patients admitted to a hospital with or without dedicated burn centre (Burn-Pro): protocol for a multicentre prospective observational study. AB - INTRODUCTION: The Emergency Management of Severe Burns (EMSB) referral criteria have been implemented for optimal triaging of burn patients. Admission to a burn centre is indicated for patients with severe burns or with specific characteristics like older age or comorbidities. Patients not meeting these criteria can also be treated in a hospital without burn centre. Limited information is available about the organisation of care and referral of these patients. The aims of this study are to determine the burn injury characteristics, treatment (costs), quality of life and scar quality of burn patients admitted to a hospital without dedicated burn centre. These data will subsequently be compared with data from patients with<10% total bodysurface area (TBSA) burned who are admitted (or secondarily referred) to a burn centre. If admissions were in agreement with the EMSB, referral criteria will also be determined. METHODS AND ANALYSIS: In this multicentre, prospective, observational study (cohort study), the following two groups of patients will be followed: 1) all patients (no age limit) admitted with burn-related injuries to a hospital without a dedicated burn centre in the Southwest Netherlands or Brabant Trauma Region and 2) all patients (no age limit) with<10% TBSA burned who are primarily admitted (or secondarily referred) to the burn centre of Maasstad Hospital. Data on the burn injury characteristics (primary outcome), EMSB compliance, treatment, treatment costs and outcome will be collected from the patients' medical files. At 3 weeks and at 3, 6 and 12 months after trauma, patients will be asked to complete the quality of life questionnaire (EuroQoL-5D), and the patient-reported part of the Patient and Observer Scar Assessment Scale (POSAS). At those time visits, the coordinating investigator or research assistant will complete the observer-reported part of the POSAS. ETHICS AND DISSEMINATION: This study has been exempted by the medical research ethics committee Erasmus MC (Rotterdam, The Netherlands). Each participant will provide written consent to participate and remain encoded during the study. The results of the study are planned to be published in an international, peer-reviewed journal. TRIAL REGISTRATION NUMBER: NTR6565. PMID- 30446575 TI - Long-term prognosis and quality of life in patients with early rheumatoid arthritis treated according to the 2015 ACR guideline (LELAND): protocol for a multicentre prospective observational study in Southern China. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic disease and one of the most disabling diseases for patients. The American College of Rheumatology (ACR) issued a new guideline in 2015 for the treatment of RA based on the treat to-target strategy to achieve better outcomes. This study will focus on the real world rates of remission and low disease activity of patients with early RA in China, who will be treated according to the 2015 ACR guideline. Additionally, factors influencing treat-to-target outcomes will be analysed, and long-term prognosis and quality of life will be assessed. METHOD AND ANALYSIS: Two-hundred patients with early RA will be enrolled, treated and followed up once every 3 months for 48 months. These patients should fulfil the 2010 RA classification criteria of the ACR/European League Against Rheumatism with a disease course of no more than 6 months and should also fulfil other eligibility criteria. The patients will be treated following the 2015 ACR guideline. Their disease activity will be assessed, and they will be instructed to complete several questionnaires once every 3 months. The primary outcomes are the Disease Activity Score on 28 joints and Health Assessment Questionnaire Disability Index. The secondary outcome variables are the Simplified Disease Activity Index, Clinical Disease Activity Index and Routine Assessment of Patient Index Data 3 results, imaging data and personal medical costs. The data will be analysed using appropriate statistical analyses. ETHICS AND DISSEMINATION: This research was approved by the Nanfang Hospital Ethics Committee (NFEC-2017-192). The results of the study will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03508713; Pre-results. PMID- 30446576 TI - Diagnostic accuracy of imaging brain vesicular monoamine transporter type 2 (VMAT2) in clinically uncertain parkinsonian syndrome (CUPS): a 3-year follow-up study in community patients. AB - OBJECTIVES: To further validate the diagnostic utility of 18F-AV-133 vesicular monoamine transporter type 2 (VMAT2) positron emission tomography (PET) in patients with clinically uncertain parkinsonian syndromes (CUPS) by comparison to clinical diagnosis at 3 years follow-up. DESIGN, SETTING AND PARTICIPANTS: In a previous study, we reported that 18F-AV-133 PET in community patients with CUPS changed diagnosis and management and increased diagnostic confidence. The current diagnosis of this cohort was obtained from the patient and treating specialist and compared with the diagnosis suggested 3 years earlier by the 18F-AV-133 PET. A second 18F-AV-133 PET was available in those with a discordant or inconclusive final diagnosis. STUDY OUTCOME MEASURES: The primary end point was the proportion of patients who had a follow-up clinical diagnosis, which was concordant with their initial 18F-AV-133 PET scan. Secondary end points were the proportion of patients who had the same diagnosis at follow-up as that reached after the initial scan and the stability of diagnostic changes made after the first scan. RESULTS: 81 of the 85 patients previously recruited to the CUPS study had follow up of which 79 had a clinical diagnosis and 2 remained CUPS. The diagnosis was in agreement with the initial 18F-AV-133 PET scan result in 74 cases. Five patients had a discordant diagnosis; one patient with rubral tremor had a severely abnormal scan that had worsened when rescanned; four cases with normal initial and repeat scans had a clinical diagnosis of Parkinson's disease. Two patients with suspected genetic disorders remained classified as CUPS and both had normal scans. In the 24 CUPS cohort patients where 18F-AV-133 PET initially changed diagnosis, this change was supported by follow-up diagnosis in all but the one rubral tremor case. CONCLUSION: 18F-AV-133 PET is a useful tool in improving diagnostic accuracy in CUPS providing results and diagnostic changes that remain robust after 3 years follow-up. PMID- 30446577 TI - SSHeW study protocol: does slip resistant footwear reduce slips among healthcare workers? A randomised controlled trial. AB - INTRODUCTION: Slips, trips and falls are common causes of injuries in the workplace. It is estimated that in Great Britain, nearly 1 million days are taken off work due to these injuries. There is some evidence to suggest this accident burden could be reduced by the use of slip resistant footwear. This protocol describes a multicentre trial investigating the effectiveness and cost effectiveness of slip resistant footwear to prevent slips in National Health Service (NHS) staff working in clinical, general or catering environments. METHODS AND ANALYSIS: A two-arm, randomised controlled trial conducted within England, with 4400 NHS staff, aged 18 years and above, who adhere to a dress code policy and work in a clinical, catering or general hospital environment. Participants will be randomised 1:1 to the intervention or waiting list control group. The intervention group will be offered a pair of 5-star GRIP rated slip resistant footwear. The control group will be offered the footwear at the end of the trial. The primary outcome is the incidence rate of self-reported slips in the workplace over a 14-week period, as reported via weekly text messages. Secondary outcomes include: time to first slip/fall, proportion of participants who slip and fall over 14 weeks and incidence rate of falls resulting from and not resulting from a slip in the workplace over 14 weeks. An economic evaluation will assess cost-effectiveness, in terms of cost per quality-adjusted life year gained. A nested qualitative study will explore the acceptability of the footwear and compliance. ETHICS AND DISSEMINATION: This protocol received a favourable ethical opinion from the University of York, Department of Health Sciences Research Governance Committee. The trial results will be published in peer reviewed journals and at conferences. A summary of the findings will be made available to participants. TRIAL REGISTRATION NUMBER: ISRCTN33051393; Pre results. PMID- 30446578 TI - Nicotine modulates growth factors and microRNA to promote inflammatory and fibrotic processes. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal disease that destroys the structure and function of the lungs. Risk factors include advanced age and genetic predisposition. However, tobacco use is the chief modifiable risk factor. The prevalence of tobacco use in IPF reaches up to 80%. Although tobacco smoke contains over 5,000 chemicals, nicotine is a major component. Nicotine is a bioactive molecule that acts upon nicotinic acetylcholine receptors expressed on neuronal and non-neuronal cells including endothelial cells. Accordingly, it has pleiotropic effect including on cell proliferation and angiogenesis. The angiogenic effect is partly mediated by stimulation of growth factors including FGF, PDGF, and VEGF. Nintedanib, FDA-approved drug for IPF, works by inhibiting receptors for these growth factors suggesting pathobiologic role of the growth factors in IPF, and a potential mechanism by which tobacco use may exacerbate the disease process. Additionally, nicotine downregulates anti-inflammatory microRNAs (miRs) in lung cells. Here, we profiled the expression of miRs in lung tissues explanted from lung injury model and examined the effect of nicotine on one of the identified miRs (miR-24) and its downstream targets. Our data shows that miR 24 is downregulated during lung injury and is suppressed by nicotine. We also found that nicotine upregulates the expression of inflammatory cytokines targeted by miR-24. Finally, nicotine stimulated growth factors, fibroblast proliferation, collagen release and expression of myofibroblast markers. Taken together, nicotine, alone or as component of tobacco smoke, may accelerate the disease process in IPF through stimulation of growth factors and downregulation of anti inflammatory miRs. PMID- 30446579 TI - A newly identified mutation in the PEX26 gene is associated with a milder type of Zellweger spectrum disorder. AB - Using clinical exome sequencing (ES), we identified an autosomal recessive missense variant, c.153C>A (p.F51L), in the peroxisome biogenesis factor 26 gene (PEX26) in a 19-year old female who was referred for moderate to severe hearing loss. The proband and three affected siblings are all homozygous for the c.153C>A variant. Skin fibroblasts from this patient show normal morphology in immunostaining of matrix proteins, although the level of catalase was elevated. Import rate of matrix proteins was significantly decreased in the patient-derived fibroblasts. Binding of Pex26-F51L to the AAA ATPase peroxins, Pex1 and Pex6, is severely impaired and affects peroxisome assembly. Moreover, Pex26 in the patient's fibroblasts is reduced to ~30% of the control, suggesting that Pex26 F51L is unstable in cells. In the patient's fibroblasts, peroxisome-targeting signal 1 (PTS1) proteins, PTS2 protein 3-ketoacyl-CoA thiolase, and catalase are present in a punctate staining pattern at 37 degrees C and in a diffuse pattern at 42 degrees C, suggesting that these matrix proteins are not imported to peroxisomes in a temperature-sensitive manner. Analysis of peroxisomal metabolism in the patient's fibroblasts showed that the level of docosahexaenoic acid (C22:6n-3; DHA) in ether phospholipids is decreased, whereas other lipid metabolism, including peroxisomal fatty-acid beta-oxidation, is normal. Collectively, the functional data support the mild phenotype of nonsyndromic hearing loss in patients harboring the F51L variant in PEX26. PMID- 30446580 TI - Whole genome and transcriptome profiling of a metastatic thyroid-like follicular renal cell carcinoma. AB - INTRODUCTION: Thyroid-like follicular renal cell carcinoma (TLFRCC) is a rare cancer with few reports of metastatic disease. Little is known regarding genomic characteristics and therapeutic targets. We present the clinical, pathologic, genomic and transcriptomic analyses of a case of a 27-year-old male with TLFRCC who presented initially with bone metastases of unknown primary. METHODS: Genomic DNA from peripheral blood and metastatic tumor samples were sequenced. A transcriptome of 280 million sequence reads was generated from the same tumor sample. Tumor somatic expression profiles were analyzed to detect aberrant expression. Genomic and transcriptomic data sets were integrated to reveal dysregulation in pathways and identify potential therapeutic targets. RESULTS: Integrative genomic analysis with The Cancer Genome Atlas (TCGA) dataset revealed the following outliers in gene expression profiles: CDK6 (81st percentile), MYC (99th percentile), AR (100th percentile), PDGFRA and PDGFRB (99th and 100th percentiles, respectively), and MAP2K2 (86th percentile). The patient received first-line sunitinib to target PDGFRA and PDGFRB and had stable disease for over 6 months, followed by nivolumab upon progression. CONCLUSIONS: To the authors' knowledge, this is the first reported case of comprehensive somatic genomic analyses in a patient with metastatic TLFRCC. Somatic analyses provided molecular confirmation of the primary site of cancer and potential therapeutic strategies in a rare disease with little evidence of efficacy on systemic therapy. PMID- 30446582 TI - Tobacco Use Assessment and Treatment in Cancer Patients: A Scoping Review of Oncology Care Clinician Adherence to Clinical Practice Guidelines in the U.S. AB - BACKGROUND: Smoking after a cancer diagnosis negatively impacts health outcomes; smoking cessation improves symptoms, side effects, and overall prognosis. The Public Health Service and major oncology organizations have established guidelines for tobacco use treatment among cancer patients, including clinician assessment of tobacco use at each visit. Oncology care clinicians (OCCs) play important roles in this process (noted as the 5As: Asking about tobacco use, Advising users to quit, Assessing willingness to quit, Assisting in quit attempts, and Arranging follow-up contact). However, OCCs may not be using the "teachable moments" related to cancer diagnosis, treatment, and survivorship to provide cessation interventions. MATERIALS AND METHODS: In this scoping literature review of articles from 2006 to 2017, we discuss (1) frequency and quality of OCCs' tobacco use assessments with cancer patients and survivors; (2) barriers to providing tobacco treatment for cancer patients; and (3) the efficacy and future of provider-level interventions to facilitate adherence to tobacco treatment guidelines. RESULTS: OCCs are not adequately addressing smoking cessation with their patients. The reviewed studies indicate that although >75% assess tobacco use during an intake visit and >60% typically advise patients to quit, a substantially lower percentage recommend or arrange smoking cessation treatment or follow-up after a quit attempt. Less than 30% of OCCs report adequate training in cessation interventions. CONCLUSION: Intervention trials focused on provider- and system-level change are needed to promote integration of evidence-based tobacco treatment into the oncology setting. Attention should be given to the barriers faced by OCCs when targeting interventions for the oncologic context. IMPLICATIONS FOR PRACTICE: This article reviews the existing literature on the gap between best and current practices for tobacco use assessment and treatment in the oncologic context. It also identifies clinician- and system-level barriers that should be addressed in order to lessen this gap and provides suggestions that could be applied across different oncology practice settings to connect patients with tobacco use treatments that may improve overall survival and quality of life. PMID- 30446581 TI - Applying Artificial Intelligence to Address the Knowledge Gaps in Cancer Care. AB - BACKGROUND: Rapid advances in science challenge the timely adoption of evidence based care in community settings. To bridge the gap between what is possible and what is practiced, we researched approaches to developing an artificial intelligence (AI) application that can provide real-time patient-specific decision support. MATERIALS AND METHODS: The Oncology Expert Advisor (OEA) was designed to simulate peer-to-peer consultation with three core functions: patient history summarization, treatment options recommendation, and management advisory. Machine-learning algorithms were trained to construct a dynamic summary of patients cancer history and to suggest approved therapy or investigative trial options. All patient data used were retrospectively accrued. Ground truth was established for approximately 1,000 unique patients. The full Medline database of more than 23 million published abstracts was used as the literature corpus. RESULTS: OEA's accuracies of searching disparate sources within electronic medical records to extract complex clinical concepts from unstructured text documents varied, with F1 scores of 90%-96% for non-time-dependent concepts (e.g., diagnosis) and F1 scores of 63%-65% for time-dependent concepts (e.g., therapy history timeline). Based on constructed patient profiles, OEA suggests approved therapy options linked to supporting evidence (99.9% recall; 88% precision), and screens for eligible clinical trials on ClinicalTrials.gov (97.9% recall; 96.9% precision). CONCLUSION: Our results demonstrated technical feasibility of an AI-powered application to construct longitudinal patient profiles in context and to suggest evidence-based treatment and trial options. Our experience highlighted the necessity of collaboration across clinical and AI domains, and the requirement of clinical expertise throughout the process, from design to training to testing. IMPLICATIONS FOR PRACTICE: Artificial intelligence (AI)-powered digital advisors such as the Oncology Expert Advisor have the potential to augment the capacity and update the knowledge base of practicing oncologists. By constructing dynamic patient profiles from disparate data sources and organizing and vetting vast literature for relevance to a specific patient, such AI applications could empower oncologists to consider all therapy options based on the latest scientific evidence for their patients, and help them spend less time on information "hunting and gathering" and more time with the patients. However, realization of this will require not only AI technology maturation but also active participation and leadership by clincial experts. PMID- 30446583 TI - EGFR Mutation Testing: Changing Patterns of Molecular Testing in Brazil. AB - BACKGROUND: In Brazil, cancer is the second most common cause of death. Most patients in resource-limited countries are diagnosed in advanced stages. Current guidelines advocate for EGFR mutation testing in all patients with metastatic adenocarcinoma. Tyrosine kinase inhibitors are recommended in patients with advanced or metastatic disease harboring sensitizing mutations. In Brazil, there are limited data regarding the frequency of EGFR testing and the changes in patterns of testing overtime. MATERIALS AND METHODS: This was an observational, retrospective study. We obtained deidentified data from a commercial database, which included 11,684 patients with non-small cell lung cancer treated between 2011 and 2016 in both public and private settings. We analyzed the frequency of EGFR mutation testing over time. We also directly studied 3,664 tumor samples, which were analyzed between 2011 and 2013. These samples were tested for EGFR mutations through an access program to tyrosine kinase inhibitors in Brazil. RESULTS: Overall, 38% of patients were tested for EGFR mutations; 76% of them were seen in the private sector, and 24% were seen in the public center. The frequency of testing for EGFR mutations increased significantly over time: 13% (287/2,228 patients) in 2011, 34% (738/2,142) in 2012, 39% (822/2,092) in 2013, 44% (866/1,972) in 2014, 53% (1,165/2,184) in 2015, and 42% (1,359/3,226) in 2016. EGFR mutations were detected in 25.5% of analyzed samples (857/3,364). Deletions in Exon 19 were the most frequent mutations, detected in 54% of patients (463/857). CONCLUSION: Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia but higher than in North American and Western European populations. The most commonly found mutations were in Exon 19 and Exon 21. Our study shows that fewer than half of patients are being tested and that the disparity is greater in the public sector. IMPLICATIONS FOR PRACTICE: These data not only indicate the shortage of testing but also show that the rates of positivity in those tested seem to be higher than in other cohorts for which data have been published. This study further supports the idea that awareness and access to testing should be improved in order to improve survival rates in lung cancer in Brazil. PMID- 30446584 TI - Role of the cGAS-STING pathway in cancer development and oncotherapeutic approaches. AB - The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway mediates anti-microbial innate immunity by inducing the production of type I interferons (IFNs) and inflammatory cytokines upon recognition of microbial DNA. Recent studies reveal that self-DNA from tumors and by-products of genomic instability also activates the cGAS-STING pathway and either promotes or inhibits tumor development. This has led to the development of cancer therapeutics using STING agonists alone and in combination with conventional cancer treatment or immune checkpoint targeting. On the other hand, for cancers lacking the cGAS STING pathway and thus a regular innate immunity response, oncolytic virus therapy has been shown to have therapeutic potential. We here review and discuss the dichotomous roles of the cGAS-STING pathway in cancer development and therapeutic approaches. PMID- 30446585 TI - AKT inhibition modulates H3K4 demethylase levels in PTEN null prostate cancer. AB - Hyperactivated AKT kinase due to loss of its negative regulator PTEN influences many aspects of cancer biology including chromatin. AKT primarily regulates acetyl-CoA production and phosphorylates many histone modulating enzymes resulting in their activation or inhibition. Therefore, understanding the therapeutic impact of AKT inhibition on chromatin related events is essential. Here, we report that AKT inhibition in prostate specific PTEN knockout mice significantly induces di- and tri-methylation of H3K4 with concomitant reduction in H3K9 acetylation. Mechanistically, we observed that AKT inhibition reduces expression of the H3K4 methylation specific histone demethylases KDM5 family, especially KDM5B expression at transcriptional levels. Further, we observed that AKT negatively regulates miR-137 levels, which transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 methylation levels but failed to change AKT phosphorylation. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR 137. Our data identify a mechanism by which AKT kinase modulates the prostate cancer epigenome through regulating H3K4 methylation. Additional studies on AKT inhibition mediated induction of H3K4 methylation will help in designing strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors. PMID- 30446586 TI - Induction of MNK kinases-dependent eIF4E phosphorylation by inhibitors targeting BET proteins limits efficacy of BET inhibitors. AB - BET inhibitors (BETis), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, since BETis show limited single agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinases-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a pro-survival feedback mechanism in response to BETis. BET PROTACs, which promote degradation of BET proteins, also induced eIF4E phosphorylation in cancer cells. Mechanistically, we show that the effect of BETis on MNK-eIF4E phosphorylation was mediated by p38 MAPKs. We also show that BETis suppressed RacGAP1 to induce Rac signaling-mediated eIF4E phosphorylation. Significantly, MNK inhibitors and MNK1/2 knockdown enhanced the efficacy of BETis in suppressing proliferation of cancer cells in vitro and in a syngeneic mouse model. Together, these results demonstrate a novel pro-survival feedback signaling induced by BETis, providing a mechanistic rationale for combination therapy with BET and MNK inhibitors for synergistic inhibition of cancer cells. PMID- 30446587 TI - Inhibition of LEF1-mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness. AB - PURPOSE: Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem-like cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. The current study aimed to examine how Wnt inhibition by niclosamide preferentially targets CSCs. EXPERIMENTAL DESIGN: The mechanistic role of niclosamide in CSC inhibition was examined in public databases, human colorectal cancer (CRC) cells, CRC xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC model. RESULTS: Niclosamide suppresses CSC populations and their self-renewal activities in CRC cells, and this CSC targeting effect leads to irreversible disruption of tumor-initiating potential in vivo. Mechanistically, niclosamide downregulates multiple signaling components of the Wnt pathway, specifically lymphoid enhancer-binding factor 1 (LEF1) expression, which is critical for regulating stemness. Subsequently, we identified that the doublecortin-like kinase1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in CRC cells. We first documented that niclosamide blocks the transcription of DCLK1-B by interrupting the binding of LEF1 to DCLK1 B promoter. DCLK1-B depletion impairs cancer stemness resulting in reduced survival potential and increased apoptosis, thus sensitizing CRC to chemoradiation. CONCLUSIONS: Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on CRC initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of CRC. PMID- 30446588 TI - Predicting Treatment Response Based on RNA Expression in Large Datasets. AB - PD-L1 expression levels derived from >16,000 samples guided the selection of tumor types likely to benefit from pembrolizuamb monotherapy in clinical trials. While not fail-proof, FDA approvals for most of the prioritized indications speak to the power of RNA expression profiling and the value of large genomic datasets. PMID- 30446589 TI - ----Immunotherapy for Glioblastoma: Adoptive T-cell Strategies. AB - Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immune therapy via adoptive cell transfer (ACT), especially with T cells engineered to express chimeric antigen receptors (CARs), represents a particularly promising approach. Despite the recent success of CAR T cells for blood cancers, the question remains whether this powerful anti-cancer therapy will ultimately work for brain tumors, and if the primary immunologic challenges in this disease-which include antigenic heterogeneity, immune suppression and T cell exhaustion-can be adequately addressed. Here, we contextualize these concepts by reviewing recent developments in ACT for GBM, with a special focus on pioneering clinical trials of CAR T-cell therapy. PMID- 30446590 TI - Neutrophil extracellular traps induced by IL-8 promote diffuse large B cell lymphoma progression via the TLR9 signaling. AB - PURPOSE: Over 30% of patients with diffuse large B cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism. EXPERIMENTAL DESIGN: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored. And the mechanism of NET formation was also studied by a series of in vitro and in vivo assays. RESULTS: Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in DLBCL patients. Further, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph nodal dissemination in vivo. Mechanistically, DLBCL-derived IL-8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38 and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NF-kappaB, STAT3 and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL-8-CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models. CONCLUSIONS: Our data reveal a tumor-NETs aggressive interaction in DLBCL, and indicate that NETs is a useful prognostic biomarker and targeting this novel crosstalk represents a new therapeutic opportunity in this challenging disease. PMID- 30446591 TI - Corrigendum: Inhibition of SF3B1 by molecules targeting the spliceosome results in massive aberrant exon skipping. PMID- 30446592 TI - RNA: Reviewers for Volume 24, 2018. PMID- 30446593 TI - RNA: Author Index for Volume 24, 2018. PMID- 30446594 TI - Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial. AB - OBJECTIVE: In this secondary analysis of the Glyburide Advantage in Malignant Edema and Stroke (GAMES-RP) Trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints. METHODS: Blinded adjudicators assigned designations for hemorrhagic transformation, neurologic deterioration, malignant edema, and edema-related death to patients from the GAMES-RP phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment on additional markers of edema and clinical deterioration were examined. RESULTS: In the per protocol sample, 41 patients received glyburide and 36 received placebo. There was no difference in the frequency of hemorrhagic transformation (n = 24 [58.5%] in IV glyburide vs n = 23 [63.9%] in placebo, p = 0.91) or the incidence of malignant edema (n = 19 [46%] in IV glyburide vs n = 17 [47%] in placebo, p = 0.94). However, treatment with IV glyburide was associated with a reduced proportion of deaths attributed to cerebral edema (n = 1 [2.4%] with IV glyburide vs n = 8 [22.2%] with placebo, p = 0.01). In the subset of patients with malignant edema, those treated with IV glyburide had less midline shift (p < 0.01) and reduced MMP-9 (matrix metalloproteinase 9) levels (p < 0.01). The glyburide treatment group had lower rate of NIH Stroke Scale (NIHSS) increase of >=4 during the infusion period (n = 7 [37%] in IV glyburide vs n = 12 [71%] in placebo, p = 0.043), and of change in level of alertness (NIHSS subscore 1a; n = 11 [58%] vs n = 15 [94%], p = 0.016). CONCLUSION: IV glyburide was associated with improvements in midline shift, level of alertness, and NIHSS, and there were fewer deaths attributed to edema. Additional studies of IV glyburide in large hemispheric infarction are warranted to corroborate these findings. CLINICALTRIALSGOV IDENTIFIER: NCT01794182. LEVEL OF EVIDENCE: This study provides Class II evidence that for patients with large hemispheric infarction, IV glyburide improves some edema-related endpoints. PMID- 30446596 TI - Galcanezumab in chronic migraine: The randomized, double-blind, placebo controlled REGAIN study. AB - OBJECTIVE: To evaluate the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in the preventive treatment of chronic migraine. METHODS: A phase 3, randomized, double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month double-blind, placebo-controlled treatment phase and a 9-month open-label extension. Eligible patients 18 to 65 years of age with chronic migraine were randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558), galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240 mg (n = 277). The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days (MHDs) during the 3-month double-blind treatment phase. RESULTS: Mean number of monthly MHDs at baseline was 19.4 for the total sample. Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs compared to placebo (placebo -2.7, galcanezumab 120 mg -4.8, galcanezumab 240 mg 4.6) (p < 0.001 for each dose compared to placebo). There were no clinically meaningful differences between galcanezumab doses and placebo on any safety or tolerability outcome except for a higher incidence of treatment-emergent injection-site reaction (p < 0.01), injection-site erythema (p < 0.001), injection-site pruritus (p < 0.01), and sinusitis (p < 0.05) in the galcanezumab 240-mg group relative to placebo. CONCLUSIONS: Both doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs. Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine. CLINICALTRIALSGOV IDENTIFIER: NCT02614261. CLASSIFICATION OF EVIDENCE: This interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs. PMID- 30446595 TI - Lasmiditan is an effective acute treatment for migraine: A phase 3 randomized study. AB - OBJECTIVE: To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. METHODS: Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). RESULTS: Of the 1,856 patients who treated an attack, 77.9% had >=1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0-3.6, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6-3.0, p< 0.001). Furthermore, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3-2.1, p< 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3-2.2, p< 0.001) were free of their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity. CONCLUSIONS: Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors. CLINICALTRIALSGOV IDENTIFIER: NCT02439320. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack. PMID- 30446598 TI - Attenuation of PKCdelta enhances metabolic activity and promotes expansion of blood progenitors. AB - A finely tuned balance of self-renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood-forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCdelta) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCdelta-deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long-term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress. PKCdelta-deficient HSPCs also showed accelerated proliferation and reduced apoptosis, but did not exhaust in serial transplant assays or induce leukemia. Using inducible knockout and transplantation models, we further found that PKCdelta acts in a hematopoietic cell-intrinsic manner to restrict HSPC number and bone marrow regenerative function. Mechanistically, PKCdelta regulates HSPC energy metabolism and coordinately governs multiple regulators within signaling pathways implicated in HSPC homeostasis. Together, these data identify PKCdelta as a critical regulator of HSPC signaling and metabolism that acts to limit HSPC expansion in response to physiological and regenerative demands. PMID- 30446597 TI - Synergistic recruitment of UbcH7~Ub and phosphorylated Ubl domain triggers parkin activation. AB - The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early-onset Parkinson's disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin's N terminal ubiquitin-like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phospho-ubiquitin-loaded C-terminus of parkin, derived from NMR chemical shift perturbation experiments. We show the UbcH7~Ub conjugate binds in the open state whereby conjugated ubiquitin binds to the RING1/IBR interface. Further, NMR and mass spectrometry experiments indicate the RING0/RING2 interface is re-modelled, remote from the E2 binding site, and this alters the reactivity of the RING2(Rcat) catalytic cysteine, needed for ubiquitin transfer. Our experiments provide evidence that parkin phosphorylation and E2~Ub recruitment act synergistically to enhance a weak interaction of the pUbl domain with the RING0 domain and rearrange the location of the RING2(Rcat) domain to drive parkin activity. PMID- 30446600 TI - Shuffle methodological deck chairs or abandon theoretical ship? The complexity turn in injury prevention. PMID- 30446601 TI - gamma-Crystallin redox-detox in the lens. AB - In the vertebrate eye, limiting oxidation of proteins and lipids is key to maintaining lens function and avoiding cataract formation. A study by Serebryany et al. identifies a surprising contributor to the eye's oxidative defense in their demonstration that gammaD-crystallin (HgammaD) functions as an oxidoreductase and uses disulfide exchange to initiate aggregation of mutant crystallins that mimic oxidative damage. These insights suggest a mechanism by which a dynamic pool of closely packed proteins might avoid oxidation-driven protein-folding traps, providing new avenues to understand the basis of a human disease with global impact. PMID- 30446599 TI - A conserved mechanism drives partition complex assembly on bacterial chromosomes and plasmids. AB - Chromosome and plasmid segregation in bacteria are mostly driven by ParABS systems. These DNA partitioning machineries rely on large nucleoprotein complexes assembled on centromere sites (parS). However, the mechanism of how a few parS bound ParB proteins nucleate the formation of highly concentrated ParB clusters remains unclear despite several proposed physico-mathematical models. We discriminated between these different models by varying some key parameters in vivo using the F plasmid partition system. We found that "Nucleation & caging" is the only coherent model recapitulating in vivo data. We also showed that the stochastic self-assembly of partition complexes (i) is a robust mechanism, (ii) does not directly involve ParA ATPase, (iii) results in a dynamic structure of discrete size independent of ParB concentration, and (iv) is not perturbed by active transcription but is by protein complexes. We refined the "Nucleation & caging" model and successfully applied it to the chromosomally encoded Par system of Vibrio cholerae, indicating that this stochastic self-assembly mechanism is widely conserved from plasmids to chromosomes. PMID- 30446602 TI - Correction: AMP-activated protein kinase antagonizes pro-apoptotic extracellular signal-regulated kinase activation by inducing dual-specificity protein phosphatases in response to glucose deprivation in HCT116 carcinoma. PMID- 30446603 TI - Withdrawal: AMP-activated protein kinase activity is critical for hypoxia inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. PMID- 30446604 TI - Withdrawal: Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. PMID- 30446605 TI - Withdrawal: Inhibition of AMP-activated protein kinase sensitizes cancer cells to cisplatin-induced apoptosis via hyper-induction of p53. PMID- 30446606 TI - Hypertrophic cardiomyopathy-linked variants of cardiac myosin binding protein C3 display altered molecular properties and actin interaction. AB - The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 ( c-MYBPC3 ) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3+V4), all located within the C1 & C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos were observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared to control zebrafish. Molecular analysis of recombinant C0-C2 protein fragments revealed that c-MYBPC3 variants alter the C0-C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0-C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c-MYBPC3 mutations. PMID- 30446607 TI - Protein phosphatases in the regulation of mitosis. AB - The accurate segregation of genetic material to daughter cells during mitosis depends on the precise coordination and regulation of hundreds of proteins by dynamic phosphorylation. Mitotic kinases are major regulators of protein function, but equally important are protein phosphatases that balance their actions, their coordinated activity being essential for accurate chromosome segregation. Phosphoprotein phosphatases (PPPs) that dephosphorylate phosphoserine and phosphothreonine residues are increasingly understood as essential regulators of mitosis. In contrast to kinases, the lack of a pronounced peptide-binding cleft on the catalytic subunit of PPPs suggests that these enzymes are unlikely to be specific. However, recent exciting insights into how mitotic PPPs recognize specific substrates have revealed that they are as specific as kinases. Furthermore, the activities of PPPs are tightly controlled at many levels to ensure that they are active only at the proper time and place. Here, I will discuss substrate selection and regulation of mitotic PPPs focusing mainly on animal cells and explore how these actions control mitosis, as well as important unanswered questions. PMID- 30446608 TI - Model metabolic strategy for heterotrophic bacteria in the cold ocean based on Colwellia psychrerythraea 34H. AB - Colwellia psychrerythraea 34H is a model psychrophilic bacterium found in the cold ocean-polar sediments, sea ice, and the deep sea. Although the genomes of such psychrophiles have been sequenced, their metabolic strategies at low temperature have not been quantified. We measured the metabolic fluxes and gene expression of 34H at 4 degrees C (the mean global-ocean temperature and a normal growth temperature for 34H), making comparative analyses at room temperature (above its upper-growth temperature of 18 degrees C) and with mesophilic Escherichia coli When grown at 4 degrees C, 34H utilized multiple carbon substrates without catabolite repression or overflow byproducts; its anaplerotic pathways increased flux network flexibility and enabled CO2 fixation. In glucose only medium, the Entner-Doudoroff (ED) pathway was the primary glycolytic route; in lactate-only medium, gluconeogenesis and the glyoxylate shunt became active. In comparison, E. coli, cold stressed at 4 degrees C, had rapid glycolytic fluxes but no biomass synthesis. At their respective normal-growth temperatures, intracellular concentrations of TCA cycle metabolites (alpha-ketoglutarate, succinate, malate) were 4-17 times higher in 34H than in E. coli, while levels of energy molecules (ATP, NADH, NADPH) were 10- to 100-fold lower. Experiments with E. coli mutants supported the thermodynamic advantage of the ED pathway at cold temperature. Heat-stressed 34H at room temperature (2 hours) revealed significant down-regulation of genes associated with glycolytic enzymes and flagella, while 24 hours at room temperature caused irreversible cellular damage. We suggest that marine heterotrophic bacteria in general may rely upon simplified metabolic strategies to overcome thermodynamic constraints and thrive in the cold ocean. PMID- 30446610 TI - ACSL6 is critical for maintaining brain DHA levels. PMID- 30446609 TI - Partitioning mortality into growth-dependent and growth-independent hazards across 203 tropical tree species. AB - Tree death drives population dynamics, nutrient cycling, and evolution within plant communities. Mortality variation across species is thought to be influenced by different factors relative to variation within species. The unified model provided here separates mortality rates into growth-dependent and growth independent hazards. This model creates the opportunity to simultaneously estimate these hazards both across and within species. Moreover, it provides the ability to examine how species traits affect growth-dependent and growth independent hazards. We derive this unified mortality model using cross-validated Bayesian methods coupled with mortality data collected over three census intervals for 203 tropical rainforest tree species at Barro Colorado Island (BCI), Panama. We found that growth-independent mortality tended to be higher in species with lower wood density, higher light requirements, and smaller maximum diameter at breast height (dbh). Mortality due to marginal carbon budget as measured by near-zero growth rate tended to be higher in species with lower wood density and higher light demand. The total mortality variation attributable to differences among species was large relative to variation explained by these traits, emphasizing that much remains to be understood. This additive hazards model strengthens our capacity to parse and understand individual-level mortality in highly diverse tropical forests and hence to predict its consequences. PMID- 30446611 TI - Generalizability of heterogeneous treatment effect estimates across samples. AB - The extent to which survey experiments conducted with nonrepresentative convenience samples are generalizable to target populations depends critically on the degree of treatment effect heterogeneity. Recent inquiries have found a strong correspondence between sample average treatment effects estimated in nationally representative experiments and in replication studies conducted with convenience samples. We consider here two possible explanations: low levels of effect heterogeneity or high levels of effect heterogeneity that are unrelated to selection into the convenience sample. We analyze subgroup conditional average treatment effects using 27 original-replication study pairs (encompassing 101,745 individual survey responses) to assess the extent to which subgroup effect estimates generalize. While there are exceptions, the overwhelming pattern that emerges is one of treatment effect homogeneity, providing a partial explanation for strong correspondence across both unconditional and conditional average treatment effect estimates. PMID- 30446612 TI - Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model. AB - Genetic treatments of renal ciliopathies leading to cystic kidney disease would provide a real advance in current therapies. Mutations in CEP290 underlie a ciliopathy called Joubert syndrome (JBTS). Human disease phenotypes include cerebral, retinal, and renal disease, which typically progresses to end stage renal failure (ESRF) within the first two decades of life. While currently incurable, there is often a period of years between diagnosis and ESRF that provides a potential window for therapeutic intervention. By studying patient biopsies, patient-derived kidney cells, and a mouse model, we identify abnormal elongation of primary cilia as a key pathophysiological feature of CEP290 associated JBTS and show that antisense oligonucleotide (ASO)-induced splicing of the mutated exon (41, G1890*) restores protein expression in patient cells. We demonstrate that ASO-induced splicing leading to exon skipping is tolerated, resulting in correct localization of CEP290 protein to the ciliary transition zone, and restoration of normal cilia length in patient kidney cells. Using a gene trap Cep290 mouse model of JBTS, we show that systemic ASO treatment can reduce the cystic burden of diseased kidneys in vivo. These findings indicate that ASO treatment may represent a promising therapeutic approach for kidney disease in CEP290-associated ciliopathy syndromes. PMID- 30446613 TI - Phosphatidylserine hide-and-seek. PMID- 30446614 TI - Resistance protein Pit interacts with the GEF OsSPK1 to activate OsRac1 and trigger rice immunity. AB - Resistance (R) genes encode intracellular nucleotide-binding/leucine-rich repeat containing (NLR) family proteins that serve as critical plant immune receptors to induce effector-triggered immunity (ETI). NLR proteins possess a tripartite domain architecture consisting of an N-terminal variable region, a central nucleotide-binding domain, and a C-terminal leucine-rich repeat. N-terminal coiled-coil (CC) or Toll-interleukin 1 receptor (TIR) domains of R proteins appear to serve as platforms to trigger immune responses, because overexpression of the CC or TIR domain of some R proteins is sufficient to induce an immune response. Because direct downstream signaling molecules of R proteins remain obscure, the molecular mechanisms by which R proteins regulate downstream signaling are largely unknown. We reported previously that a rice R protein named Pit triggers ETI through a small GTPase, OsRac1, although how Pit activates OsRac1 is unclear. Here, we identified OsSPK1, a DOCK family guanine nucleotide exchange factor, as an interactor of Pit and activator for OsRac1. OsSPK1 contributes to signaling by two disease-resistance genes, Pit and Pia, against the rice blast fungus Magnaporthe oryzae and facilitates OsRac1 activation in vitro and in vivo. The CC domain of Pit is required for its binding to OsSPK1, OsRac1 activation, and the induction of cell death. Overall, we conclude that OsSPK1 is a direct and key signaling target of Pit-mediated immunity. Our results shed light on how R proteins trigger ETI through direct downstream molecules. PMID- 30446615 TI - Temperature-dependent vitamin D signaling regulates developmental trajectory associated with diapause in an annual killifish. AB - The mechanisms that integrate environmental signals into developmental programs remain largely uncharacterized. Nuclear receptors (NRs) are ligand-regulated transcription factors that orchestrate the expression of complex phenotypes. The vitamin D receptor (VDR) is an NR activated by 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3], a hormone derived from 7-dehydrocholesterol (7-DHC). VDR signaling is best known for regulating calcium homeostasis in mammals, but recent evidence suggests a diversity of uncharacterized roles. In response to incubation temperature, embryos of the annual killifish Austrofundulus limnaeus can develop along two alternative trajectories: active development and diapause. These trajectories diverge early in development, from a biochemical, morphological, and physiological perspective. We manipulated incubation temperature to induce the two trajectories and profiled changes in gene expression using RNA sequencing and weighted gene coexpression network analysis. We report that transcripts involved in 1,25(OH)2D3 synthesis and signaling are expressed in a trajectory-specific manner. Furthermore, exposure of embryos to vitamin D3 analogs and Delta4 dafachronic acid directs continuous development under diapause-inducing conditions. Conversely, blocking synthesis of 1,25(OH)2D3 induces diapause in A. limnaeus and a diapause-like state in zebrafish, suggesting vitamin D signaling is critical for normal vertebrate development. These data support vitamin D signaling as a molecular pathway that can regulate developmental trajectory and metabolic dormancy in a vertebrate. Interestingly, the VDR is homologous to the daf-12 and ecdysone NRs that regulate dormancy in Caenorhabditis elegans and Drosophila We suggest that 7-DHC-derived hormones and their associated NRs represent a conserved pathway for the integration of environmental information into developmental programs associated with life history transitions in animals. PMID- 30446617 TI - Reply to Yan and Akiyama: Nitrous oxide emissions from rice and their mitigation potential depend on the nature of intermittent flooding. PMID- 30446616 TI - Nanomagnetic properties of the meteorite cloudy zone. AB - Meteorites contain a record of their thermal and magnetic history, written in the intergrowths of iron-rich and nickel-rich phases that formed during slow cooling. Of intense interest from a magnetic perspective is the "cloudy zone," a nanoscale intergrowth containing tetrataenite-a naturally occurring hard ferromagnetic mineral that has potential applications as a sustainable alternative to rare earth permanent magnets. Here we use a combination of high-resolution electron diffraction, electron tomography, atom probe tomography (APT), and micromagnetic simulations to reveal the 3D architecture of the cloudy zone with subnanometer spatial resolution and model the mechanism of remanence acquisition during slow cooling on the meteorite parent body. Isolated islands of tetrataenite are embedded in a matrix of an ordered superstructure. The islands are arranged in clusters of three crystallographic variants, which control how magnetic information is encoded into the nanostructure. The cloudy zone acquires paleomagnetic remanence via a sequence of magnetic domain state transformations (vortex to two domain to single domain), driven by Fe-Ni ordering at 320 degrees C. Rather than remanence being recorded at different times at different positions throughout the cloudy zone, each subregion of the cloudy zone records a coherent snapshot of the magnetic field that was present at 320 degrees C. Only the coarse and intermediate regions of the cloudy zone are found to be suitable for paleomagnetic applications. The fine regions, on the other hand, have properties similar to those of rare-earth permanent magnets, providing potential routes to synthetic tetrataenite-based magnetic materials. PMID- 30446619 TI - Balancing fairness and efficacy in lung allocation for transplantation: unfinished business. PMID- 30446618 TI - Overestimation of N2O mitigation potential by water management in rice paddy fields. PMID- 30446620 TI - Gbetagamma signaling to the chemotactic effector P-REX1 and mammalian cell migration is directly regulated by Galphaq and Galpha13 proteins. AB - G protein-coupled receptors stimulate Rho guanine nucleotide exchange factors that promote mammalian cell migration. Rac and Rho GTPases exert opposing effects on cell morphology, and are stimulated downstream of Gbetagamma and Galpha12/13 or Galphaq, respectively. These Galpha subunits might in turn favor Rho pathways by preventing Gbetagamma signaling to Rac. Here, we investigated whether Gbetagamma signaling to phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 1 (P-REX1), a key Gbetagamma chemotactic effector, is directly controlled by Rho-activating Galpha subunits. We show that pharmacological inhibition of Galphaq makes P-REX1 activation by Gq/Gi-coupled lysophosphatidic acid receptors more effective. Moreover, chemogenetic control of Gi and Gq by designer receptors exclusively activated by designer drugs (DREADDs) confirmed that Gi differentially activates P-REX1. GTPase-deficient GalphaqQL and Galpha13QL variants formed stable complexes with Gbetagamma, impairing its interaction with P-REX1. The N-terminal regions of these variants were essential for stable interaction with Gbetagamma. Pulldown assays revealed that chimeric Galpha13-i2QL interacts with Gbetagamma unlike to Galphai2-13QL, the reciprocal chimera, which similarly to Galphai2QL could not interact with Gbetagamma. Moreover, Gbetagamma was part of tetrameric Gbetagamma/GalphaqQL/RGS2 and Gbetagamma/Galpha13-i2QL/RGS4 complexes, whereas Galpha13QL dissociated from Gbetagamma to interact with the PDZ-RhoGEF-RGS domain. Consistent with an integrated response, Gbetagamma and AKT kinase were associated with active SDF 1/CXCL12-stimulated P-REX1. This pathway was inhibited by GalphaqQL and Galpha13QL, which also prevented CXCR4-dependent cell migration. We conclude that a coordinated mechanism prioritizes Galphaq- and Galpha13-mediated signaling to Rho over a Gbetagamma-dependent Rac pathway, attributed to heterotrimeric Gi proteins. PMID- 30446621 TI - Membrane-anchored carbonic anhydrase IV interacts with monocarboxylate transporters via their chaperones CD147 and GP70. AB - Monocarboxylate transporters (MCTs) mediate the proton-coupled exchange of high energy metabolites, including lactate and pyruvate, between cells and tissues. The transport activity of MCT1, MCT2, and MCT4 can be facilitated by the extracellular carbonic anhydrase IV (CAIV) via a non-catalytic mechanism. Combining physiological measurements in HEK-293 cells and Xenopus oocytes with pulldown experiments, we analyzed the direct interaction between CAIV and the two MCT chaperones basigin (CD147) and embigin (GP70). Our results show that facilitation of MCT transport activity requires direct binding of CAIV to the transporters chaperones. We found that this binding is mediated by the highly conserved His-88 residue in CAIV, which is also the central residue of the enzyme's intramolecular proton shuttle, and a charged amino acid residue in the Ig1 domain of the chaperone. Although the position of the CAIV-binding site in the chaperone was conserved, the amino acid residue itself varied among different species: In human CD147, binding of CAIV was mediated by the negatively charged Glu-73 and in rat CD147 by the positively charged Lys-73. In rat GP70, we identified the positively charged Arg-130 as the binding site. Further analysis of the CAIV-binding site revealed that the His-88 in CAIV can either act as H donor or H acceptor for the hydrogen bond, depending on the charge of the binding residue in the chaperone. Our results suggest that the CAIV-mediated increase in MCT transport activity requires direct binding between CAIV-His-88 and a charged amino acid in the extracellular domain of the transporter's chaperone. PMID- 30446622 TI - Domain analysis of PNKP/XRCC1 interactions: influence of genetic variants of XRCC1. AB - Polynucleotide kinase/phosphatase (PNKP) and X-ray repair cross-complementing 1 (XRCC1) are key proteins in the ssDNA break repair pathway. Phosphorylated XRCC1 stimulates PNKP by binding to its FHA domain, while nonphosphorylated XRCC1 stimulates PNKP by interacting with the PNKP catalytic domain. Here, we have further studied the interactions between these two proteins, including two variants of XRCC1 (R194W and R280H) arising from SNPs that have been associated with elevated cancer risk in some reports. We observed that interaction of the PNKP FHA domain with phosphorylated XRCC1 extends beyond the immediate, well characterized phosphorylated region of XRCC1 (residues 515-526). We also found that an XRCC1 fragment, comprising residues 166-436, binds tightly to PNKP and DNA and efficiently activates PNKP's kinase activity. However, interaction of either of the SNP-derived variants of this fragment with PNKP was considerably weaker, and their stimulation of PNKP was severely reduced, although they still could bind DNA effectively. Laser microirradiation revealed reduced recruitment of PNKP to damaged DNA in cells expressing either XRCC1 variant compared with PNKP recruitment in cells expressing wild-type XRCC1 even though wild-type and variant XRCC1s were equally efficient at localizing to the damaged DNA. These findings suggest that the elevated risk of cancer associated with these XRCC1 SNPs reported in some studies may be due in part to the reduced ability of these XRCC1 variants to recruit PNKP to damaged DNA. PMID- 30446623 TI - Over-expression of the CORVET complex alleviates the fungicidal effects of fludioxonil on the yeast Saccharomyces cerevisiae expressing Hybrid histidine kinase 3. AB - The hybrid histidine kinase 3 (HHK3) is a highly conserved sensor kinase in fungi that regulates the downstream HOG/p38 mitogenactivated protein kinase (MAPK). In addition to its role in osmoadaptation, HHK3 is involved in hyphal morphogenesis, conidiation, virulence and cellular adaptation to oxidative stress. However, the molecular mechanisms by which it controls these processes remain obscure. Moreover, HHK3 is a molecular target for antifungal agents such as fludioxonil which thereby interferes with the HOG/p38 pathway, leading to the abnormal accumulation of glycerol and subsequent cell lysis. Here, we used a chemical genomics approach with the yeast Saccharomyces cerevisiae to better understand the fungicidal action of fludioxonil and also the role of HHK3 in fungal growth and physiology. Our results indicated that the abnormal accumulation of glycerol is not the primary cause of fludioxonil toxicity. Fludioxonil appears to impair endosomal trafficking in the fungal cells. We found that the components of class C core vacuole-endosome tethering (CORVET) complex are essential for yeast viability in the presence of a sub-threshold dose of fludioxonil and that their over expression alleviates fludioxonil toxicity. We also noted that by impeding secretory vesicles trafficking, fludioxonil inhibits hyphal growth in the opportunistic fungal pathogen Candida albicans Our results suggest that HHK3 regulates fungal hyphal growth by affecting vesicle trafficking. Together, our results reveal an important role of CORVET complex in the fungicidal action of fludioxonil downstream of HHK3. PMID- 30446624 TI - Mitochondrial DNA mutations are associated with ulcerative colitis preneoplasia but tend to be negatively selected in cancer. AB - The role of mitochondrial DNA (mtDNA) mutations in cancer remains controversial. Ulcerative Colitis (UC) is an inflammatory bowel disease that increases the risk of colorectal cancer and involves mitochondrial dysfunction, making it an ideal model to study the role of mtDNA in tumorigenesis. Our goal was to comprehensively characterize mtDNA mutations in UC tumorigenesis using Duplex Sequencing, an ultra-accurate next generation sequencing method. We analyzed 46 colon biopsies from non-UC and UC patients with and without cancer, including biopsies at all stages of dysplastic progression. mtDNA was sequenced at a mean depth of 1,417x. Mutations were classified by mutant allele frequency: clonal >0.95, subclonal 0.01-0.95, and very low frequency (VLF)<0.01. We identified 208 clonal and subclonal mutations and 56,764 VLF mutations. Mutations were randomly distributed across the mitochondrial genome. Clonal and subclonal mutations increased in number and pathogenicity in early dysplasia, but decreased in number and pathogenicity in cancer. Most clonal, subclonal, and VLF mutations were C>T transitions in the heavy strand of mtDNA, which likely arise from DNA replication errors. A subset of VLF mutations were C>A transversions, which are probably due to oxidative damage. VLF transitions and indels were less abundant in the non D loop region and decreased with progression. Our results indicate that mtDNA mutations are frequent in UC preneoplasia but negatively selected in cancers. Implications: While mitochondrial DNA mutations might contribute to early UC tumorigenesis, they appear to be selected against in cancer, suggesting that functional mitochondria might be required for malignant transformation in UC. PMID- 30446625 TI - CCR2 chemokine receptors enhance growth and cell cycle progression of breast cancer cells through SRC and PKC activation. AB - Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor and Her2 expression, and are resistant to anti-hormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal like breast cancer, primary tumor growth was significantly increased with co transplantation of patient derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell cycle inhibitor protein p27KIP1, and are necessary for CCL2 induced breast cancer cell proliferation. Implications: This report sheds novel light on CCL2/CCR2 chemokine signaling as a mitogenic pathway and cell cycle regulator in breast cancer cells. PMID- 30446626 TI - SETDB1 is essential for mouse primordial germ cell fate determination by ensuring BMP signaling. AB - In mouse embryos, primordial germ cells (PGCs) are fate-determined from epiblast cells. Signaling pathways involved in PGC formation have been identified, but their epigenetic mechanisms remain poorly understood. Here, we show that the histone methyltransferase SETDB1 is an epigenetic regulator of PGC fate determination. Setdb1-deficient embryos exhibit drastic reduction of nascent PGCs. Dppa2, Otx2 and Utf1 are de-repressed whereas mesoderm development-related genes, including BMP4 signaling-related genes, are downregulated by Setdb1 knockdown during PGC-like cell (PGCLC) induction. In addition, binding of SETDB1 is observed at the flanking regions of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs, and trimethylation of lysine 9 of histone H3 is reduced by Setdb1 knockdown at those regions. Furthermore, DPPA2, OTX2 and UTF1 binding is increased in genes encoding BMP4 signaling-related proteins, including SMAD1. Finally, overexpression of Dppa2, Otx2 and Utf1 in cell aggregates containing PGCLCs results in the repression of BMP4 signaling-related genes and PGC determinant genes. We propose that the localization of SETDB1 to Dppa2, Otx2 and Utf1, and subsequent repression of their expression, are crucial for PGC determination by ensuring BMP4 signaling. PMID- 30446627 TI - The RhoGEF protein Plekhg5 regulates apical constriction of bottle cells during gastrulation. AB - Apical constriction regulates epithelial morphogenesis during embryonic development, but how this process is controlled is not understood completely. Here, we identify a Rho guanine nucleotide exchange factor (GEF) plekhg5 as an essential regulator of apical constriction of bottle cells during Xenopus gastrulation. plekhg5 is expressed in the blastopore lip and its expression is sufficient to induce ectopic bottle cells in epithelia of different germ layers in a Rho-dependent manner. This activity is not shared by arhgef3, another organizer-specific RhoGEF. Plekhg5 protein is localized in the apical cell cortex via its PH domain, and the GEF activity enhances its apical recruitment. Plekhg5 induces apical actomyosin accumulation and cell elongation. Knockdown of plekhg5 inhibits activin-induced bottle cell formation and endogenous blastopore lip formation in gastrulating frog embryos. Apical accumulation of actomyosin, apical constriction, and bottle cell formation fail to occur in these embryos. Taken together, our data indicate that transcriptional regulation of plekhg5 expression at the blastopore lip determines bottle cell morphology via local polarized activation of Rho by Plekhg5 which stimulates apical actomyosin activity to induce apical constriction. PMID- 30446628 TI - Conserved regulation of Nodal-mediated left-right patterning in zebrafish and mouse. AB - The TGF-beta signal Nodal is the major effector of left-right axis development. In mice, Nodal forms heterodimers with Gdf1 and is restricted to the left side by Cerl2/Dand5. Nodal expression then propagates up the lateral plate mesoderm (LPM) by autoinduction, while Lefty1 inhibition maintains it on the left. Studies in zebrafish have suggested some parallels, but also differences, between the modes of left-right patterning in mouse and zebrafish. To address these discrepancies, we generated single and double zebrafish mutants for spaw (the Nodal ortholog), dand5 (the Cerl2 ortholog) and lefty1, and performed biochemical and activity assays with Spaw and Vg1/Gdf3 (the Gdf1 ortholog). Contrary to previous findings, spaw mutants failed to initiate spaw expression in the LPM, and asymmetric heart looping was absent, similar to mouse Nodal mutants. In blastoderm assays, Vg1 and Spaw were interdependent for inducing target gene expression, and contrary to previous results, formed heterodimers. Loss of Dand5 or Lefty1 caused bilateral spaw expression, similar to mouse mutants, and premature expression and propagation of spaw in the LPM. Finally, Lefty1 inhibition of Nodal activity could be replaced by uniform exposure to a Nodal signaling inhibitor. Collectively, these results indicate that Dand5 activity biases Spaw-Vg1 heterodimer activity to the left, Spaw around Kupffer's vesicle induces the expression of spaw in the LPM, and global Nodal inhibition maintains the left bias of Spaw activity, demonstrating conservation between zebrafish and mouse mechanisms of left-right patterning. PMID- 30446629 TI - Spatiotemporal control of axillary meristem formation by interacting transcriptional regulators. AB - Branching is a common feature of plant development. In seed plants, axillary meristems (AMs) initiate in leaf axils to enable lateral shoot branching. AM initiation requires a high level of expression of the meristem marker SHOOT MERISTEMLESS (STM) in the leaf axil. Here, we show that modules of interacting transcriptional regulators control STM expression and AM initiation. Two redundant AP2-type transcription factors, DORNROSCHEN (DRN) and DORNROSCHEN-LIKE (DRNL), control AM initiation by regulating STM expression. DRN and DRNL directly up-regulate STM expression in leaf axil meristematic cells, as does another transcription factor REVOLUTA (REV). The activation of STM expression by DRN/DRNL depends on REV, and vice versa. DRN/DRNL and REV have overlapping expression patterns and protein interactions in the leaf axil, which are required for the up regulation of STM expression. Furthermore, LITTLE ZIPPER3, another REV interacting protein, is expressed in the leaf axil and interferes with the DRN/DRNL-REV interaction to negatively modulate STM expression. Our results support a model in which interacting transcriptional regulators fine-tune the expression of STM to precisely regulate AM initiation. Thus, shoot branching recruits the same conserved protein complexes used in embryogenesis and leaf polarity patterning. PMID- 30446631 TI - Improving Timeliness of Medical Evaluations for Children Entering Foster Care. AB - BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics (AAP) recommends children in foster care (FC) have an initial medical evaluation within 3 days of custody initiation; however, this vulnerable population often suffers from disjointed care. Our aim was to improve the mean time to initial foster care evaluation (TIE) from 32 to <7 days within 12 months for children in FC in Durham County, North Carolina. METHODS: This study was a time series, quality improvement project used to target interventions within an academic clinic and a community agency. Interventions were tested through multiple plan-do-study-act cycles. Control charts of the primary outcome, the TIE, were constructed. Charts were annotated with the dates of interventions, including workshops, performance feedback, integration of state forms, identification of appointments, development of an urgent appointment pathway, and empowerment of the scheduler. RESULTS: The mean TIE improved from 32 to 9 days within 12 months. Significant improvement in the following 2 process measures contributed to this: the time from custody initiation to the referral date improved from an average of 10 to 3 days, and the time from referral date to the initial evaluation improved from an average of 22 to 6 days. CONCLUSIONS: Improvement interventions and increased collaboration between medical and child welfare agencies can result in significant improvement of the TIE. However, despite improvement efforts, challenges remain in meeting the AAP 3-day TIE recommendation. We recommend further assessment of the AAP guideline as it relates to implementation feasibility and health outcomes of children in FC. PMID- 30446630 TI - Neurodevelopmental Outcomes in Infants With Birth Weight <=500 g at 3 Years of Age. AB - OBJECTIVES: To determine neurodevelopmental outcomes at 3 years of age in children born with a birth weight (BW) of <=500 g. METHODS: Infants who were born with a BW of <=500 g from 2003 to 2012 in the Neonatal Research Network of Japan and survived to discharge from the NICU were eligible in this study. The study population consisted of 460 children (56.7% of 811 surviving infants) who were evaluated at 36 to 42 months of age. Neurodevelopmental impairment (NDI) was defined as having cerebral palsy, visual impairment, hearing impairment, or a developmental quotient score of <70. RESULTS: The overall proportion of NDI was 59.1% (95% confidence interval [CI]: 54.6%-63.5%). The trend revealed no significant change during the study period. In a multivariate modified Poisson regression analysis, NDI was associated with severe intraventricular hemorrhage (adjusted risk ratio [RR]: 1.42; 95% CI: 1.19-1.68; P < .01), cystic periventricular leukomalacia (adjusted RR: 1.40; 95% CI: 1.13-1.73; P < .01), severe necrotizing enterocolitis (adjusted RR: 1.31; 95% CI: 1.07-1.60; P < .01), surgical ligation for patent ductus arteriosus (adjusted RR: 1.29; 95% CI: 1.09 1.54; P < .01), and male sex (adjusted RR: 1.19; 95% CI: 1.01-2.40; P = .04). CONCLUSIONS: This cohort showed that neurodevelopmental outcomes of infants with a BW of <=500 g have not improved from 2003 to 2012. Multivariate analysis revealed that severe intracranial hemorrhage and cystic periventricular leukomalacia were the strongest risk factors for NDIs. Our data suggested that measures aimed at reducing neurologic morbidities will be important for improving outcomes of infants with a BW of <=500 g. PMID- 30446632 TI - ZNF185 is a p53 target gene following DNA damage. AB - The transcription factor p53 is a key player in the tumour suppressive DNA damage response and a growing number of target genes involved in these pathways has been identified. p53 has been shown to be implicated in controlling cell motility and its mutant form enhances metastasis by loss of cell directionality, but the p53 role in this context has not yet being investigated. Here, we report that ZNF185, an actin cytoskeleton-associated protein from LIM-family of Zn-finger proteins, is induced following DNA-damage. ChIP-seq analysis, chromatin crosslinking immune precipitation experiments and luciferase assays demonstrate that ZNF185 is a bona fide p53 target gene. Upon genotoxic stress, caused by DNA-damaging drug etoposide and UVB irradiation, ZNF185 expression is up-regulated and in etoposide treated cells, ZNF185 depletion does not affect cell proliferation and apoptosis, but interferes with actin cytoskeleton remodelling and cell polarization. Bioinformatic analysis of different types of epithelial cancers from both TCGA and GTEx databases showed a significant decrease in ZNF185 mRNA level compared to normal tissues. These findings are confirmed by tissue micro-array IHC staining. Our data highlight the involvement of ZNF185 and cytoskeleton changes in p53 mediated cellular response to genotoxic stress and indicate ZNF185 as potential biomarker for epithelial cancer diagnosis. PMID- 30446633 TI - A Clinical Prognostic Score to Predict Survival of Advanced or Metastatic Non Small Cell Lung Cancer (NSCLC) Patients Receiving First-Line Chemotherapy: A Retrospective Analysis. AB - BACKGROUND Although several complicated models have been built to evaluate the prognosis of NSCLC patients receiving chemotherapy, simple economic models are still needed to give a preliminary survival assessment of these patients. MATERIAL AND METHODS This study retrospectively assessed the clinical and biological parameters of 223 patients with advanced NSCLC. Univariate and multivariate analyses of overall survival (OS) and progression-free survival (PFS) for the parameters and the prognostic score were assessed. RESULTS Performance status (PS) score=1, smoking history, fibrinogenemia, thrombocytosis, increased lactate dehydrogenase (LDH) level, and anemia were independent predictors of poor prognosis in the univariate analysis of OS and were assessed in multivariate analysis. There was a significant difference in PS=1 (HR=2.134, p<0.0001), increased LDH level (HR=1.508, p=0.014), thrombocytosis (HR=1.547, p=0.012), and smoking history (HR=1.491, p=0.008), based on which the patients were classified into 3 risk groups: low risk (0-1 points), moderate risk (2 points), and high risk (3-5 points). At p values of <0.0001, the median OS was 565, 340, and 273 days and the median progression-free survival was 250, 209, and 135 days, respectively in these 3 risk groups. CONCLUSIONS We established a new prognostic score model using PS, LDH level, PLT count, and smoking history to predict the survival of patients receiving first-line chemotherapy for advanced NSCLC, which might be useful in clinical practice. PMID- 30446634 TI - Cholecystocolic Fistula Misdiagnosed as Colon Cancer: A Case Report. AB - BACKGROUND Due to the absence of specific symptoms and signs, cholecystocolic fistula is easy to miss as a diagnosis or misdiagnose. CASE REPORT We report a case of an older male patient who had cholecystocolic fistula which was misdiagnosed as colon cancer. The cholecystocolic fistula was incidentally discovered during surgery and was appropriately treated. CONCLUSIONS Cholecystocolic fistula is a rare complication of gallstone disease. Symptoms can be nonspecific. This case report demonstrates that despite modern diagnostic tools available, a high degree of suspicion is required to diagnose cholecystocolic fistula preoperatively. Open cholecystectomy and closure of fistula is the treatment of choice. PMID- 30446635 TI - NMT1 inhibition modulates breast cancer progression through stress-triggered JNK pathway. AB - Myristoylation is one of key post-translational modifications that involved in signal transduction, cellular transformation and tumorigenesis. Increasing evidence demonstrates that targeting myristoylation might provide a new strategy for eliminating cancers. However, the underlying mechanisms are still yielded unclear. In this study, we demonstrated that genetic inhibition of N myristoyltransferase NMT1 suppressed initiation, proliferation and invasion of breast cancer cells either in vitro or in vivo. We identified ROS could negatively regulate NMT1 expression and NMT1 knockdown conversely promoted oxidative stress, which formed a feedback loop. Furthermore, inhibition of NMT1 caused degraded proteins increase and ER stress, which cross-talked with mitochondria to produce more ROS. And both of oxidative stress and ER stress could activate JNK pathway, leading to autophagy which abrogated breast cancer progression especially triple-negative breast cancer (TNBC). These studies provide a preclinical proof of concept for targeting NMT1 as a strategy to treat breast cancer. PMID- 30446637 TI - Developmental changes of cortical white-gray contrast as predictors of autism diagnosis and severity. AB - Recent studies suggest that both cortical gray and white-matter microstructural characteristics are distinct for subjects with autism. There is a lack of evidence regarding how these characteristics change in a developmental context. We analysed a longitudinal/cross-sectional dataset of 402 magnetic resonance imaging (MRI) scans (171 subjects with autism and 231 with typical development) from the Autism Brain Imaging Data Exchange, cohorts I-II (ABIDE-I-II). In the longitudinal sample, we computed the rate of change in the white-gray contrast, a measure which has been related to age and cognitive performance, at the boundary of the cerebral cortex. Then, we devised an analogous metric for the cross sectional sample of the ABIDE dataset to measure age-related differences in cortical contrast. Further, we developed a probabilistic model to predict the diagnostic group in the longitudinal sample of the cortical contrast change data, using results obtained from the cross-sectional sample. In both subsets, we observed a similar overall pattern of greater decrease within the autistic population in intensity contrast for most cortical regions (81%), with occasional increases, mostly in primary sensory regions. This pattern correlated well with raw and calibrated behavioural scores. The prediction results show 76% accuracy for the whole-cortex diagnostic prediction and 86% accuracy in prediction using the motor system alone. Our results support a contrast change analysis strategy that appears sensitive in predicting diagnostic outcome and symptom severity in autism spectrum disorder, and is readily extensible to other MRI-based studies of neurodevelopmental cohorts. PMID- 30446636 TI - Cerebral organoids reveal early cortical maldevelopment in schizophrenia computational anatomy and genomics, role of FGFR1. AB - Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia. PMID- 30446638 TI - The impact of combined gene mutations in inhA and ahpC genes on high levels of isoniazid resistance amongst katG non-315 in multidrug-resistant tuberculosis isolates from China. AB - Whole-genome sequencing was used to analyze the profiles of isoniazid (INH) resistance-related mutations among 188 multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and mono-INH-resistant isolates collected in a recent Chinese national survey. Mutations were detected in 18 structural genes and two promoter regions in 96.8% of 188 resistant isolates. There were high mutation frequencies in katG, the inhA promoter, and ahpC-oxyR regulator regions in INH-resistant isolates with frequencies of 86.2%, 19.6%, and 18.6%, respectively. Moreover, a high diversity of mutations was identified as 102 mutants contained various types of single or combined gene mutations in the INH resistant group of isolates. The cumulative frequencies of katG 315 or inhA P/inhA mutations was 68.1% (128/188) for the INH-resistant isolates. Of these isolates, 46 isolates (24.5% of 188) exhibited a high level of resistance. A high level of resistance was also observed in 21 isolates (11.2% of 188) with single ahpC-oxyR mutations or a combination of ahpC-oxyR and katG non-315 mutations. The remaining 17 mutations occurred sporadically and emerged in isolates with combined katG mutations. Such development of INH resistance is likely due to an accumulation of mutations under the pressure of drug selection. Thus, these findings provided insights on the levels of INH resistance and its correlation with the combinatorial mutation effect resulting from less frequent genes (inhA and/or ahpC). Such knowledge of other genes (apart from katG) in high-level resistance will aid in developing better strategies for the diagnosis and management of TB. PMID- 30446639 TI - CYP6AE gene cluster knockout in Helicoverpa armigera reveals role in detoxification of phytochemicals and insecticides. AB - The cotton bollworm Helicoverpa armigera, is one of the world's major pest of agriculture, feeding on over 300 hosts in 68 plant families. Resistance cases to most insecticide classes have been reported for this insect. Management of this pest in agroecosystems relies on a better understanding of how it copes with phytochemical or synthetic toxins. We have used genome editing to knock out a cluster of nine P450 genes and show that this significantly reduces the survival rate of the insect when exposed to two classes of host plant chemicals and two classes of insecticides. Functional expression of all members of this gene cluster identified the P450 enzymes capable of metabolism of these xenobiotics. The CRISPR-Cas9-based reverse genetics approach in conjunction with in vitro metabolism can rapidly identify the contributions of insect P450s in xenobiotic detoxification and serve to identify candidate genes for insecticide resistance. PMID- 30446642 TI - Shockwave generates < 100 > dislocation loops in bcc iron. AB - The formation mechanism of < 100 > interstitial dislocation loops in ferritic steels stemming from irradiation remains elusive, as their formations are either too short for experiments, or too long for molecular dynamics simulations. Here, we report on the formation of both interstitial and vacancy dislocation loops in high energy displacement cascades using large-scale molecular dynamics simulations with up to 220 million atoms. Riding the supersonic shockwave generated in the cascade, self-interstitial atoms are punched out to form < 100 > dislocation loops in only a few picoseconds during one single cascade event, which is several orders of magnitude faster than any existing mechanisms. The energy analysis suggests that the formation of the interstitial loops depends on kinetic energy redistribution, where higher incidence energy or larger atom mass could improve the probability of the direct nucleation of interstitial dislocation loops. PMID- 30446640 TI - Endothelial cell rearrangements during vascular patterning require PI3-kinase mediated inhibition of actomyosin contractility. AB - Angiogenesis is a dynamic process relying on endothelial cell rearrangements within vascular tubes, yet the underlying mechanisms and functional relevance are poorly understood. Here we show that PI3Kalpha regulates endothelial cell rearrangements using a combination of a PI3Kalpha-selective inhibitor and endothelial-specific genetic deletion to abrogate PI3Kalpha activity during vessel development. Quantitative phosphoproteomics together with detailed cell biology analyses in vivo and in vitro reveal that PI3K signalling prevents NUAK1 dependent phosphorylation of the myosin phosphatase targeting-1 (MYPT1) protein, thereby allowing myosin light chain phosphatase (MLCP) activity and ultimately downregulating actomyosin contractility. Decreased PI3K activity enhances actomyosin contractility and impairs junctional remodelling and stabilization. This leads to overstretched endothelial cells that fail to anastomose properly and form aberrant superimposed layers within the vasculature. Our findings define the PI3K/NUAK1/MYPT1/MLCP axis as a critical pathway to regulate actomyosin contractility in endothelial cells, supporting vascular patterning and expansion through the control of cell rearrangement. PMID- 30446644 TI - Over 1000-fold enhancement of upconversion luminescence using water-dispersible metal-insulator-metal nanostructures. AB - Rare-earth activated upconversion nanoparticles (UCNPs) are receiving renewed attention for use in bioimaging due to their exceptional photostability and low cytotoxicity. Often, these nanoparticles are attached to plasmonic nanostructures to enhance their photoluminescence (PL) emission. However, current wet-chemistry techniques suffer from large inhomogeneity and thus low enhancement is achieved. In this paper, we report lithographically fabricated metal-insulator-metal (MIM) nanostructures that show over 1000-fold enhancement of their PL. We demonstrate the potential for bioimaging applications by dispersing the MIMs into water and imaging bladder cancer cells with them. To our knowledge, our results represent one and two orders of magnitude improvement, respectively, over the best lithographically fabricated structures and colloidal systems in the literature. The large enhancement will allow for bioimaging and therapeutics using lower particle densities or lower excitation power densities, thus increasing the sensitivity and efficacy of such procedures while decreasing potential side effects. PMID- 30446641 TI - Cellular metabolism constrains innate immune responses in early human ontogeny. AB - Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-gamma-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny. PMID- 30446645 TI - Graphene mechanical pixels for Interferometric Modulator Displays. AB - Electro-optic modulators based on micro-electromechanical systems have found success as elements for optical projectors, for simplified optical spectrometers, and as reflective-type screens that make use of light interference (Interferometric Modulator Display technology). The latter concept offers an exciting avenue for graphene nanomechanical structures to replace classical micro electromechanical devices and bring about enhancement in performance, especially switching speed and voltage. In this work we study the optical response of electrically actuated graphene drumheads by means of spectrometric and stroboscopic experiments. The color reproducibility and speed of these membranes in producing the desired electro-optic modulation makes them suitable as pixels for high refresh rate displays. As a proof of concept, we demonstrate a Graphene Interferometric Modulator Display prototype with 5 MUm-in-diameter pixels that compose a high resolution image (2500 pixels per inch)-equivalent to a 5" display of 12K-whose color can be changed at frame rates of at least 400 Hz. PMID- 30446643 TI - A hPSC-based platform to discover gene-environment interactions that impact human beta-cell and dopamine neuron survival. AB - Common disorders, including diabetes and Parkinson's disease, are caused by a combination of environmental factors and genetic susceptibility. However, defining the mechanisms underlying gene-environment interactions has been challenging due to the lack of a suitable experimental platform. Using pancreatic beta-like cells derived from human pluripotent stem cells (hPSCs), we discovered that a commonly used pesticide, propargite, induces pancreatic beta-cell death, a pathological hallmark of diabetes. Screening a panel of diverse hPSC-derived cell types we extended this observation to a similar susceptibility in midbrain dopamine neurons, a cell type affected in Parkinson's disease. We assessed gene environment interactions using isogenic hPSC lines for genetic variants associated with diabetes and Parkinson's disease. We found GSTT1-/- pancreatic beta-like cells and dopamine neurons were both hypersensitive to propargite induced cell death. Our study identifies an environmental chemical that contributes to human beta-cell and dopamine neuron loss and validates a novel hPSC-based platform for determining gene-environment interactions. PMID- 30446647 TI - Author Correction: Comprehensive integrative analyses identify GLT8D1 and CSNK2B as schizophrenia risk genes. AB - In the original version of this Article, the affiliation details for Qiushuo Shen incorrectly omitted 'Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China'. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30446646 TI - Glucose metabolism induced by Bmp signaling is essential for murine skeletal development. AB - Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Despite much knowledge about growth factors and nuclear proteins in skeletal development, little is understood about the role of metabolic regulation. Here we report that genetic deletion of the glucose transporter Glut1 (Slc2a1), either before or after the onset of chondrogenesis in the limb, severely impairs chondrocyte proliferation and hypertrophy, resulting in dramatic shortening of the limbs. The cartilage defects are reminiscent to those caused by deficiency in Bmp signaling. Importantly, deletion of Bmpr1a in chondrocytes markedly reduces Glut1 levels in vivo, whereas recombinant BMP2 increases Glut1 mRNA and protein levels, boosting glucose metabolism in primary chondrocytes. Biochemical studies identify a Bmp-mTORC1 Hif1a signaling cascade resulting in upregulation of Glut1 in chondrocytes. The results therefore uncover a hitherto unknown connection between Bmp signaling and glucose metabolism in the regulation of cartilage development. PMID- 30446649 TI - Coherent multidimensional spectroscopy of dilute gas-phase nanosystems. AB - Two-dimensional electronic spectroscopy (2DES) is one of the most powerful spectroscopic techniques with unique sensitivity to couplings, coherence properties and real-time dynamics of a quantum system. While successfully applied to a variety of condensed phase samples, high precision experiments on isolated systems in the gas phase have been so far precluded by insufficient sensitivity. However, such experiments are essential for a precise understanding of fundamental mechanisms and to avoid misinterpretations. Here, we solve this issue by extending 2DES to isolated nanosystems in the gas phase prepared by helium nanodroplet isolation in a molecular beam-type experiment. This approach uniquely provides high flexibility in synthesizing tailored, quantum state-selected model systems of single and many-body character. In a model study of weakly-bound Rb2 and Rb3 molecules we demonstrate the method's unique capacity to elucidate interactions and dynamics in tailored quantum systems, thereby also bridging the gap to experiments in ultracold quantum science. PMID- 30446648 TI - Pleiotropic effects of schizophrenia-associated genetic variants in neuron firing and cardiac pacemaking revealed by computational modeling. AB - Schizophrenia patients have an increased risk of cardiac dysfunction. A possible factor underlying this comorbidity are the common variants in the large set of genes that have recently been discovered in genome-wide association studies (GWASs) as risk genes of schizophrenia. Many of these genes control the cell electrogenesis and calcium homeostasis. We applied biophysically detailed models of layer V pyramidal cells and sinoatrial node cells to study the contribution of schizophrenia-associated genes on cellular excitability. By including data from functional genomics literature to simulate the effects of common variants of these genes, we showed that variants of voltage-gated Na+ channel or hyperpolarization-activated cation channel-encoding genes cause qualitatively similar effects on layer V pyramidal cell and sinoatrial node cell excitability. By contrast, variants of Ca2+ channel or transporter-encoding genes mostly have opposite effects on cellular excitability in the two cell types. We also show that the variants may crucially affect the propagation of the cardiac action potential in the sinus node. These results may help explain some of the cardiac comorbidity in schizophrenia, and may facilitate generation of effective antipsychotic medications without cardiac side-effects such as arrhythmia. PMID- 30446650 TI - A majority of HIV persistence during antiretroviral therapy is due to infected cell proliferation. AB - Antiretroviral therapy (ART) suppresses viral replication in people living with HIV. Yet, infected cells persist for decades on ART and viremia returns if ART is stopped. Persistence has been attributed to viral replication in an ART sanctuary and long-lived and/or proliferating latently infected cells. Using ecological methods and existing data, we infer that >99% of infected cells are members of clonal populations after one year of ART. We reconcile our results with observations from the first months of ART, demonstrating mathematically how a fossil record of historic HIV replication permits observed viral evolution even while most new infected cells arise from proliferation. Together, our results imply cellular proliferation generates a majority of infected cells during ART. Therefore, reducing proliferation could decrease the size of the HIV reservoir and help achieve a functional cure. PMID- 30446651 TI - Reward regulation in plant-frugivore networks requires only weak cues. AB - Theory assumes that fair trade among mutualists requires highly reliable communication. In plant-animal mutualisms the reliability of cues that indicate reward quality is often low. Therefore, it is controversial whether communication allows animal mutualists to regulate their reward intake. Here we show that even loose relationships between fruit brightness and nutritional rewards (r2 = 0.11 0.35) allow birds to regulate their nutrient intake across distinct European plant-frugivore networks. Resident, over-wintering generalist frugivores that interact with diverse plant species select bright, lipid-rich fruits, whereas migratory birds select dark, sugar- and antioxidant-rich fruits. Both nutritional strategies are consistent with previous physiological experiments suggesting that over-wintering generalists aim to maximize their energy intake, whereas migrants aim to enhance the build-up of body fat, their immune response and oxidative status during migration. Our results suggest that animal mutualists require only weak cues to regulate their reward intake according to specific nutritional strategies. PMID- 30446653 TI - Warming assessment of the bottom-up Paris Agreement emissions pledges. AB - Under the bottom-up architecture of the Paris Agreement, countries pledge Nationally Determined Contributions (NDCs). Current NDCs individually align, at best, with divergent concepts of equity and are collectively inconsistent with the Paris Agreement. We show that the global 2030-emissions of NDCs match the sum of each country adopting the least-stringent of five effort-sharing allocations of a well-below 2 degrees C-scenario. Extending such a self-interested bottom-up aggregation of equity might lead to a median 2100-warming of 2.3 degrees C. Tightening the warming goal of each country's effort-sharing approach to aspirational levels of 1.1 degrees C and 1.3 degrees C could achieve the 1.5 degrees C and well-below 2 degrees C-thresholds, respectively. This new hybrid allocation reconciles the bottom-up nature of the Paris Agreement with its top down warming thresholds and provides a temperature metric to assess NDCs. When taken as benchmark by other countries, the NDCs of India, the EU, the USA and China lead to 2.6 degrees C, 3.2 degrees C, 4 degrees C and over 5.1 degrees C warmings, respectively. PMID- 30446654 TI - Mechanism of copper-free Sonogashira reaction operates through palladium palladium transmetallation. AB - The seminal contributions by Sonogashira, Cassar and Heck in mid 1970s on Pd/Cu- and Pd-catalysed (copper-free) coupling of acetylenes with aryl or vinyl halides have evolved in myriad applications. Despite the enormous success both in academia and in industry, however, critical mechanistic questions of this cross coupling process remain unresolved. In this study, experimental evidence and computational support is provided for the mechanism of copper-free Sonogashira cross-coupling reaction. In contrast to the consensus monometallic mechanism, the revealed pathway proceeds through a tandem Pd/Pd cycle linked via a multistep transmetallation process. This cycle is virtually identical to the Pd/Cu tandem mechanism of copper co-catalysed Sonogashira cross-couplings, but the role of CuI is played by a set of PdII species. Phosphine dissociation from the square-planar reactants to form transient three-coordinate Pd species initiates transmetallation and represents the rate-determining step of the process. PMID- 30446652 TI - RET rearrangements are actionable alterations in breast cancer. AB - Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers. PMID- 30446655 TI - Systematic review of association between critical errors in inhalation and health outcomes in asthma and COPD. AB - Inhaled medications are the cornerstone of treatment and management of asthma and COPD. However, inhaler device errors are common among patients and have been linked with reduced symptom control, an increased risk of exacerbations, and increased healthcare utilisation. These observations have prompted GINA (Global INitiative for Asthma) and GOLD (Global initiative for chronic Obstructive Lung Disease) to recommend regular assessment of inhaler technique in a bid to improve therapeutic outcomes. To better define the relationship between device errors and health outcomes (clinical outcomes, quality of life, and healthcare utilisation) in asthma and COPD, we conducted a systematic review of the literature, with a particular focus on the methods used to assess the relationship between device errors and outcomes. Sixteen studies were identified (12 in patients with asthma, one in patients with COPD, and three in both asthma and COPD) with varying study designs, endpoints, and patient populations. Most of the studies reported that inhalation errors were associated with worse disease outcomes in patients with asthma or COPD. Patients who had a reduction in errors over time had improved outcomes. These findings suggest that time invested by healthcare professionals is vital to improving inhalation technique in asthma and COPD patients to improve health outcomes. PMID- 30446656 TI - Dna2 processes behind the fork long ssDNA flaps generated by Pif1 and replication dependent strand displacement. AB - Dna2 is a DNA helicase-endonuclease mediating DSB resection and Okazaki fragment processing. Dna2 ablation is lethal and rescued by inactivation of Pif1, a helicase assisting Okazaki fragment maturation, Pol32, a DNA polymerase delta subunit, and Rad9, a DNA damage response (DDR) factor. Dna2 counteracts fork reversal and promotes fork restart. Here we show that Dna2 depletion generates lethal DNA structures activating the DDR. While PIF1 deletion rescues the lethality of Dna2 depletion, RAD9 ablation relieves the first cell cycle arrest causing genotoxicity after few cell divisions. Slow fork speed attenuates DDR in Dna2 deprived cells. Electron microscopy shows that Dna2-ablated cells accumulate long ssDNA flaps behind the forks through Pif1 and fork speed. We suggest that Dna2 offsets the strand displacement activity mediated by the lagging strand polymerase and Pif1, processing long ssDNA flaps to prevent DDR activation. We propose that this Dna2 function has been hijacked by Break Induced Replication in DSB processing. PMID- 30446658 TI - Author Correction: Dynamic intercellular transport modulates the spatial patterning of differentiation during early neural commitment. AB - In the original version of this Article, an incorrect DOI number was provided in the Code Availability statement regarding the deposition of the computational model. The correct DOI is 10.5281/zenodo.1413539. This error has been corrected in both the PDF and HTML versions of the Article. PMID- 30446659 TI - In situ synthesis of supported metal nanocatalysts through heterogeneous doping. AB - Supported metal nanoparticles hold great promise for many fields, including catalysis and renewable energy. Here we report a novel methodology for the in situ growth of architecturally tailored, regenerative metal nanocatalysts that is applicable to a wide range of materials. The main idea underlying this strategy is to selectively diffuse catalytically active metals along the grain boundaries of host oxides and then to reduce the diffused metallic species to form nanoclusters. As a case study, we choose ceria and zirconia, the most recognized oxide supports, and spontaneously form various metal particles on their surface with controlled size and distribution. Metal atoms move back and forth between the interior (as cations) and the exterior (as clusters) of the host oxide lattice as the reductive and oxidative atmospheres repeat, even at temperatures below 700 degrees C. Furthermore, they exhibit excellent sintering/coking resistance and reactivity toward chemical/electrochemical reactions, demonstrating potential to be used in various applications. PMID- 30446657 TI - NUAK2 is a critical YAP target in liver cancer. AB - The Hippo-YAP signaling pathway is a critical regulator of proliferation, apoptosis, and cell fate. The main downstream effector of this pathway, YAP, has been shown to be misregulated in human cancer and has emerged as an attractive target for therapeutics. A significant insufficiency in our understanding of the pathway is the identity of transcriptional targets of YAP that drive its potent growth phenotypes. Here, using liver cancer as a model, we identify NUAK2 as an essential mediator of YAP-driven hepatomegaly and tumorigenesis in vivo. By evaluating several human cancer cell lines we determine that NUAK2 is selectively required for YAP-driven growth. Mechanistically, we found that NUAK2 participates in a feedback loop to maximize YAP activity via promotion of actin polymerization and myosin activity. Additionally, pharmacological inactivation of NUAK2 suppresses YAP-dependent cancer cell proliferation and liver overgrowth. Importantly, our work here identifies a specific, potent, and actionable target for YAP-driven malignancies. PMID- 30446661 TI - Water assisted biomimetic synergistic process and its application in water-jet rewritable paper. AB - The colour of water-jet rewritable paper (WJRP) is difficult to be expanded via single hydrochromic molecule, especially black. Here, inspired by the amazing phenomenon of bound-water in cells enabling various biological transformations via facilitating synergistic inter-/intra-molecular proton transfer, we present a simple strategy toward WJRP based on binary systems containing less-sensitive acidochromic dyes and mild proton donors (or developers). With such a binary system containing commercial black dye as the colouring agent, benzyl 4 hydroxybenzoate as the developer, and biomimetic bound-water as proton transferring medium, we successfully achieve the long-awaited black WJRP. Printed images on such WJRP have excellent performances and long retaining time (>1 month). In addition, the robustness, durability and reversibility of WJRP could be increased distinctly by using polyethylene terephthalate as substrate. This strategy significantly expands hydrochromic colours to entire visible range in an eco-friendly way, which opens an avenue of smart materials for practical needs and industrialization. PMID- 30446662 TI - Barren plateaus in quantum neural network training landscapes. AB - Many experimental proposals for noisy intermediate scale quantum devices involve training a parameterized quantum circuit with a classical optimization loop. Such hybrid quantum-classical algorithms are popular for applications in quantum simulation, optimization, and machine learning. Due to its simplicity and hardware efficiency, random circuits are often proposed as initial guesses for exploring the space of quantum states. We show that the exponential dimension of Hilbert space and the gradient estimation complexity make this choice unsuitable for hybrid quantum-classical algorithms run on more than a few qubits. Specifically, we show that for a wide class of reasonable parameterized quantum circuits, the probability that the gradient along any reasonable direction is non zero to some fixed precision is exponentially small as a function of the number of qubits. We argue that this is related to the 2-design characteristic of random circuits, and that solutions to this problem must be studied. PMID- 30446660 TI - Proteostasis by STUB1/HSP70 complex controls sensitivity to androgen receptor targeted therapy in advanced prostate cancer. AB - Protein homeostasis (proteostasis) is a potential mechanism that contributes to cancer cell survival and drug resistance. Constitutively active androgen receptor (AR) variants confer anti-androgen resistance in advanced prostate cancer. However, the role of proteostasis involved in next generation anti-androgen resistance and the mechanisms of AR variant regulation are poorly defined. Here we show that the ubiquitin-proteasome-system (UPS) is suppressed in enzalutamide/abiraterone resistant prostate cancer. AR/AR-V7 proteostasis requires the interaction of E3 ubiquitin ligase STUB1 and HSP70 complex. STUB1 disassociates AR/AR-V7 from HSP70, leading to AR/AR-V7 ubiquitination and degradation. Inhibition of HSP70 significantly inhibits prostate tumor growth and improves enzalutamide/abiraterone treatments through AR/AR-V7 suppression. Clinically, HSP70 expression is upregulated and correlated with AR/AR-V7 levels in high Gleason score prostate tumors. Our results reveal a novel mechanism of anti-androgen resistance via UPS alteration which could be targeted through inhibition of HSP70 to reduce AR-V7 expression and overcome resistance to AR targeted therapies. PMID- 30446663 TI - Cross-ecosystem carbon flows connecting ecosystems worldwide. AB - Ecosystems are widely interconnected by spatial flows of material, but the overall importance of these flows relative to local ecosystem functioning remains unclear. Here we provide a quantitative synthesis on spatial flows of carbon connecting ecosystems worldwide. Cross-ecosystem flows range over eight orders of magnitude, bringing between 10-3 and 105 gC m-2 year-1 to recipient ecosystems. Magnitudes are similar to local fluxes in freshwater and benthic ecosystems, but two to three orders of magnitude lower in terrestrial systems, demonstrating different dependencies on spatial flows among ecosystem types. The strong spatial couplings also indicate that ecosystems are vulnerable to alterations of cross ecosystem flows. Thus, a reconsideration of ecosystem functioning, including a spatial perspective, is urgently needed. PMID- 30446664 TI - Optogenetic dissection of Rac1 and Cdc42 gradient shaping. AB - During cell migration, Rho GTPases spontaneously form spatial gradients that define the front and back of cells. At the front, active Cdc42 forms a steep gradient whereas active Rac1 forms a more extended pattern peaking a few microns away. What are the mechanisms shaping these gradients, and what is the functional role of the shape of these gradients? Here we report, using a combination of optogenetics and micropatterning, that Cdc42 and Rac1 gradients are set by spatial patterns of activators and deactivators and not directly by transport mechanisms. Cdc42 simply follows the distribution of Guanine nucleotide Exchange Factors, whereas Rac1 shaping requires the activity of a GTPase-Activating Protein, beta2-chimaerin, which is sharply localized at the tip of the cell through feedbacks from Cdc42 and Rac1. Functionally, the spatial extent of Rho GTPases gradients governs cell migration, a sharp Cdc42 gradient maximizes directionality while an extended Rac1 gradient controls the speed. PMID- 30446665 TI - Non-obstructive intracellular nanolasers. AB - Molecular dyes, plasmonic nanoparticles and colloidal quantum dots are widely used in biomedical optics. Their operation is usually governed by spontaneous processes, which results in broad spectral features and limited signal-to-noise ratio, thus restricting opportunities for spectral multiplexing and sensing. Lasers provide the ultimate spectral definition and background suppression, and their integration with cells has recently been demonstrated. However, laser size and threshold remain problematic. Here, we report on the design, high-throughput fabrication and intracellular integration of semiconductor nanodisk lasers. By exploiting the large optical gain and high refractive index of GaInP/AlGaInP quantum wells, we obtain lasers with volumes 1000-fold smaller than the eukaryotic nucleus (Vlaser < 0.1 um3), lasing thresholds 500-fold below the pulse energies typically used in two-photon microscopy (Eth ~ 0.13 pJ), and excellent spectral stability (<50 pm wavelength shift). Multiplexed labeling with these lasers allows cell-tracking through micro-pores, thus providing a powerful tool to study cell migration and cancer invasion. PMID- 30446666 TI - Sequential state discrimination of coherent states. AB - Sequential state discrimination is a strategy for quantum state discrimination of a sender's quantum states when N receivers are separately located. In this report, we propose optical designs that can perform sequential state discrimination of two coherent states. For this purpose, we consider not only binary phase-shifting-key (BPSK) signals but also general coherent states, with arbitrary prior probabilities. Since our optical designs do not include electric feedback, they can be implemented without difficulty. Furthermore, we analyze our proposal for the case of photon loss. We also demonstrate that sequential state discrimination of two coherent states performs better than the probabilistic quantum cloning strategy. This proposal can facilitate multiparty QKD based on coherent states. PMID- 30446667 TI - Construction and characterization of a Saccharomyces cerevisiae strain able to grow on glucosamine as sole carbon and nitrogen source. AB - Saccharomyces cerevisiae can transport and phosphorylate glucosamine, but cannot grow on this amino sugar. While an enzyme catalyzing the reaction from glucosamine-6-phosphate to fructose-6-phosphate, necessary for glucosamine catabolism, is present in yeasts using N-acetylglucosamine as carbon source, a sequence homology search suggested that such an enzyme is absent from Saccharomyces cerevisiae. The gene YlNAG1 encoding glucosamine-6-phosphate deaminase from Yarrowia lipolytica was introduced into S. cerevisiae and growth in glucosamine tested. The constructed strain grew in glucosamine as only carbon and nitrogen source. Growth on the amino sugar required respiration and caused an important ammonium excretion. Strains overexpressing YlNAG1 and one of the S. cerevisiae glucose transporters HXT1, 2, 3, 4, 6 or 7 grew in glucosamine. The amino sugar caused catabolite repression of different enzymes to a lower extent than that produced by glucose. The availability of a strain of S. cerevisiae able to grow on glucosamine opens new possibilities to investigate or manipulate pathways related with glucosamine metabolism in a well-studied organism. PMID- 30446668 TI - Computational Imaging Prediction of Starburst-Effect Diffraction Spikes. AB - When imaging bright light sources, rays of light emanating from their centres are commonly observed; this ubiquitous phenomenon is known as the starburst effect. The prediction and characterization of starburst patterns formed by extended sources have been neglected to date. In the present study, we propose a novel trichromatic computational framework to calculate the image of a scene viewed through an imaging system with arbitrary focus and aperture geometry. Diffractive light transport, imaging sensor behaviour, and implicit image adjustments typical in modern imaging equipment are modelled. Characterization methods for key optical parameters of imaging systems are also examined. Extensive comparisons between theoretical and experimental results reveal excellent prediction quality for both focused and defocused systems. PMID- 30446670 TI - Skyrmionium - high velocity without the skyrmion Hall effect. AB - The lateral motion of a magnetic skyrmion, arising because of the skyrmion Hall effect, imposes a number of restrictions on the use of this spin state in the racetrack memory. A skyrmionium is a more promising spin texture for memory applications, since it has zero total topological charge and propagates strictly along a nanotrack. Here, the stability of the skyrmionium, as well as the dependence of its size on the magnetic parameters, such as the Dzyaloshinskii Moriya interaction and perpendicular magnetic anisotropy, are studied by means of micromagnetic simulations. We propose an advanced method for the skyrmionium nucleation due to a local enhancement of the spin Hall effect. The stability of the skyrmionium being in motion under the action of the spin polarized current is analyzed. PMID- 30446671 TI - Combinational Biomarkers for Atrial Fibrillation Derived from Atrial Appendage and Plasma Metabolomics Analysis. AB - Atrial fibrillation (AF) is one of the most common types of arrhythmias and often leads to clinical complications. The objectives of this study were to offer insights into the metabolites of AF and to determine biomarkers for AF diagnosis or prediction. Sixty atrial appendage samples (AF group: 30; non-AF group: 30) and 163 plasma samples (AF group: 48; non-AF group: 115) from 49 AF patients and 116 non-AF patients were subjected to liquid chromatography positive ion electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) metabolomics analysis. Consequently, 24 metabolites in atrial appendage samples and 24 metabolites in plasma samples were found to reflect metabolic differences between AF and non-AF patients (variable importance in projection (VIP) >= 1, P <= 0.05). Five identical metabolites including creatinine, D-glutamic acid, choline, hypoxanthine, and niacinamide (VIP >= 1.5, P < 0.01, FDR < 0.05) in atrial appendage and plasma samples were considered prominent features of AF patients, and the D-glutamine and D-glutamate metabolic pathway was also identified as a feature of AF patients. Finally, in plasma samples, the combination of D-glutamic acid, creatinine, and choline had an AUC value of 0.927 (95% CI: 0.875-0.979, P < 0.001) and displayed 90.5% sensitivity and 83.3% specificity; this group of metabolites was thus defined as a combinational biomarker for the recognition of AF and non-AF patients. PMID- 30446669 TI - Serotonin signals through a gut-liver axis to regulate hepatic steatosis. AB - Nonalcoholic fatty liver disease (NAFLD) is increasing in worldwide prevalence, closely tracking the obesity epidemic, but specific pharmaceutical treatments for NAFLD are lacking. Defining the key molecular pathways underlying the pathogenesis of NAFLD is essential for developing new drugs. Here we demonstrate that inhibition of gut-derived serotonin synthesis ameliorates hepatic steatosis through a reduction in liver serotonin receptor 2A (HTR2A) signaling. Local serotonin concentrations in the portal blood, which can directly travel to and affect the liver, are selectively increased by high-fat diet (HFD) feeding in mice. Both gut-specific Tph1 knockout mice and liver-specific Htr2a knockout mice are resistant to HFD-induced hepatic steatosis, without affecting systemic energy homeostasis. Moreover, selective HTR2A antagonist treatment prevents HFD-induced hepatic steatosis. Thus, the gut TPH1-liver HTR2A axis shows promise as a drug target to ameliorate NAFLD with minimal systemic metabolic effects. PMID- 30446672 TI - Direct mineralogical imaging of economic ore and rock samples with multi-modal nonlinear optical microscopy. AB - Multi-modal nonlinear optical (NLO) microscopy, including stimulated Raman scattering (SRS) and second harmonic generation (SHG), was used to directly image mineralogical features of economic ore and rock samples. In SRS/SHG imaging, ore samples generally require minimal preparation and may be rapidly imaged, even in their wet state. 3D structural details, at submicron resolution, are revealed tens of microns deep within samples. Standard mineral imaging based on scanning electron microscopy (SEM), with elemental analysis via energy dispersive X-Ray spectroscopy, was used to independently validate the mineral composition of the samples. Spatially-resolved SRS from dominant Raman-resonant bands precisely maps the locations of specific minerals contained within the samples. SHG imaging reveals locally non-centrosymmetric structures, such as quartz grains. Competing absorption and nonlinear scattering processes, however, can reduce contrast in SRS imaging. Importantly, the correlation between standard electron microscopy and multi-modal NLO optical microscopy shows that the latter offers rapid image contrast based on the mineral content of the sample. PMID- 30446673 TI - Multi-color live-cell super-resolution volume imaging with multi-angle interference microscopy. AB - Imaging and tracking of near-surface three-dimensional volumetric nanoscale dynamic processes of live cells remains a challenging problem. In this paper, we propose a multi-color live-cell near-surface-volume super-resolution microscopy method that combines total internal reflection fluorescence structured illumination microscopy with multi-angle evanescent light illumination. We demonstrate that our approach of multi-angle interference microscopy is perfectly adapted to studying subcellular dynamics of mitochondria and microtubule architectures during cell migration. PMID- 30446674 TI - Health behaviour changes after type 2 diabetes diagnosis: Findings from the English Longitudinal Study of Ageing. AB - Healthy lifestyle is key for type 2 diabetes (T2D) management. It is unclear whether individuals change health behaviours in response to T2D diagnosis. We compared smoking, physical activity, fruit and vegetable intake and alcohol consumption at three times (pre-diagnosis, at diagnosis, 2-4 years post diagnosis) in individuals who developed T2D and controls. Behaviours were assessed in 6877 individuals at waves 3-7 of the English Longitudinal Study of Ageing. Generalized estimating equations were used to examine differences by group and time and group-by-time interactions. The T2D group were less active (p < 0.001) and consumed less alcohol (p < 0.001). Smoking (p < 0.001), alcohol consumption (p = 0.037) and physical activity (p = 0.042) decreased over time in the overall sample, fruit and vegetable intake (p = 0.012) and sedentary activity (p < 0.001) increased. A group-by-time interaction was found for smoking, with the T2D group having greater reductions in smoking over time (p < 0.001). No significant interactions were detected for other behaviours. We found limited evidence that T2D diagnosis encourages behaviour change, other than a reduction in smoking. Given the importance of lifestyle for T2D outcomes, strategies for motivating behaviour change need to be identified. PMID- 30446675 TI - Expression profiling and in situ screening of circular RNAs in human tissues. AB - Circular RNAs (circRNAs) were recently discovered as a class of widely expressed noncoding RNA and have been implicated in regulation of gene expression. However, the function of the majority of circRNAs remains unknown. Studies of circRNAs have been hampered by a lack of essential approaches for detection, quantification and visualization. We therefore developed a target-enrichment sequencing method suitable for screening of circRNAs and their linear counterparts in large number of samples. We also applied padlock probes and in situ sequencing to visualize and determine circRNA localization in human brain tissue at subcellular levels. We measured circRNA abundance across different human samples and tissues. Our results highlight the potential of this RNA class to act as a specific diagnostic marker in blood and serum, by detection of circRNAs from genes exclusively expressed in the brain. The powerful and scalable tools we present will enable studies of circRNA function and facilitate screening of circRNA as diagnostic biomarkers. PMID- 30446676 TI - Safranal induces DNA double-strand breakage and ER-stress-mediated cell death in hepatocellular carcinoma cells. AB - Poor prognoses remain the most challenging aspect of hepatocellular carcinoma (HCC) therapy. Consequently, alternative therapeutics are essential to control HCC. This study investigated the anticancer effects of safranal against HCC using in vitro, in silico, and network analyses. Cell cycle and immunoblot analyses of key regulators of cell cycle, DNA damage repair and apoptosis demonstrated unique safranal-mediated cell cycle arrest at G2/M phase at 6 and 12 h, and at S-phase at 24 h, and a pronounced effect on DNA damage machinery. Safranal also showed pro-apoptotic effect through activation of both intrinsic and extrinsic initiator caspases; indicating ER stress-mediated apoptosis. Gene set enrichment analysis provided consistent findings where UPR is among the top terms of up-regulated genes in response to safranal treatment. Thus, proteins involved in ER stress were regulated through safranal treatment to induce UPR in HepG2 cells. PMID- 30446677 TI - Induction of N-Ras degradation by flunarizine-mediated autophagy. AB - Ras GTPases are powerful drivers for tumorigenesis, but directly targeting Ras for treating cancer remains challenging. The growth and transforming activity of the aggressive basal-like breast cancer (BLBC) are driven by N-Ras. To target N Ras in BLBC, this study screened existing pharmacologically active compounds for the new ability to induce N-Ras degradation, which led to the identification of flunarizine (FLN), previously approved for treating migraine and epilepsy. The FLN-induced N-Ras degradation was not affected by a 26S-proteasome inhibitor. Rather, it was blocked by autophagy inhibitors. Furthermore, N-Ras can be seen co localized with active autophagosomes upon FLN treatment, suggesting that FLN alters the autophagy pathway to degrade N-Ras. Importantly, FLN treatment recapitulated the effect of N-RAS silencing in vitro by selectively inhibiting the growth of BLBC cells, but not that of breast cancer cells of other subtypes. In addition, in vivo FLN inhibited tumor growth of a BLBC xenograft model. In conclusion, this proof-of-principle study presents evidence that the autophagy pathway can be coerced by small molecule inhibitors, such as FLN, to degrade Ras as a strategy to treat cancer. FLN has low toxicity and should be further investigated to enrich the toolbox of cancer therapeutics. PMID- 30446678 TI - Verbascoside: Identification, Quantification, and Potential Sensitization of Colorectal Cancer Cells to 5-FU by Targeting PI3K/AKT Pathway. AB - Colorectal cancer (CRC) is the third most common cancer mortality worldwide. Although, 5-Fluorouracil (5-FU)-based chemotherapeutic regimens remain the mainstay for treatment of CRC, intrinsic and acquired resistance to 5-FU is the main reason for treatment failure and relapse. Adjunct or add-on therapy, therefore, should be thought of to enhance responsiveness to 5-FU. Verbascoside (VER) is a phenylethanoid glycoside ingredient present in many Plantago species and was widely used in traditional medicine. VER showed antiproliferative effects in many cancer types including CRC. In the present study, VER in Plantago seeds was identified using UPLC-MS/MS and quantified using newly developed and validated UPLC-DAD followed by investigating its potential sensitization of CRC cells to 5-FU in vitro. The potential impact on PI3K/AKT pathway was also investigated. A synergistic cytotoxic interaction between 5-FU and VER besides G1 cell cycle arrest were detected. Enhanced apoptosis mainly by affecting Bax and Bcl-2 and to a lesser extent Bcl-xL and p53 was also observed. Additionally, 5-FU combined to VER was capable of significantly reducing PI3K and p-AKT/total AKT ratio. Overall, these results suggest a potential role of VER as an adjuvant treatment to decrease the resistance of CRC cells to 5-FU possibly by targeting the PI3K/AKT pathway. PMID- 30446680 TI - Employing a spatio-temporal contingency table for the analysis of cork oak cover change in the Sa Serra region of Sardinia. AB - Land cover change analyses are common and, especially in the absence of explanatory variables, they are mainly carried out by employing qualitative methods such as transition matrices or raster operations. These methods do not provide any estimation of the statistical significance of the changes, or the uncertainty of the model and data, and are usually limited in supporting explicit biological/ecological interpretation of the processes determining the changes. Here we show how the original nearest-neighbour contingency table, proposed by Dixon to evaluate spatial segregation, has been extended to the temporal domain to map the intensity, statistical significance and uncertainty of land cover changes. This index was then employed to quantify the changes in cork oak forest cover between 1998 and 2016 in the Sa Serra region of Sardinia (Italy). The method showed that most statistically significant cork oak losses were concentrated in the centre of Sa Serra and characterised by high intensity. A spatial binomial-logit generalised linear model estimated the probability of changes occurring in the area but not the type of change. We show how the spatio temporal Dixon's index can be an attractive alternative to other land cover change analysis methods, since it provides a robust statistical framework and facilitates direct biological/ecological interpretation. PMID- 30446679 TI - OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans. AB - Organic cation transporter 3 (OCT3) is expressed in various organs in humans and plays an important role in the transport of organic cations and drugs including metformin. In this study, we identified genetic variations of the OCT3 promoter and functionally characterized each variant by in vitro assays. Next, the association between the functional haplotype of the OCT3 promoter and pharmacokinetics of metformin was evaluated. In our study population, 7 variations and 2 major haplotypes were identified, of which H2 haplotype yielded a significantly higher luciferase activity than did the wild type. Two variants of H2, c.-1603G > A and c.-1547T > G, yielded significantly lower luciferase activities, whereas the luciferase activity of another variant, c.-29G > A, was significantly higher. Two transcription factors, Sp1 and USF1, were involved in the regulation of OCT3 transcription. Analysis of clinical data revealed that 25 subjects, either homozygous or heterozygous for H2, showed increased AUCinf and Cmax by 17.2% and 15.9%, respectively [P = 0.016 and 0.031, GMR (90% CI) = 1.17 (1.06-1.29) and 1.17 (1.04-1.31), respectively], compared to the 20 subjects in the control group. Our study suggests that an OCT3 promoter haplotype affects the pharmacokinetics of metformin in Koreans as well as the OCT3 transcription rate. PMID- 30446681 TI - Characteristics of the retinal microvasculature in association with cardiovascular risk markers in children with overweight, obesity and morbid obesity. AB - To aim of this study was to evaluate characteristics of the retinal microvasculature, but particularly potential associations with classic and novel (endothelial function and low-grade inflammation)markers for cardiovascular risk, in a cohort of children with overweight and (morbid) obesity. Central retinal arteriolar equivalent(CRAE) and central retinal venular equivalent(CRVE) were assessed. CRAE was significantly lower and AVR significantly higher in children with morbid obesity than in children with overweight and normal weight(p < 0.01). CRVE did not differ significantly between the four weight categories. A multiple linear regression model with CRAE as dependent variable showed that only DBP z score(beta = -2.848,p = 0.029) and plasma glucose concentrations(beta = 6.029,p = 0.019) contributed significantly to the variation in CRAE. Remarkably, despite a correlation between CRAE and circulating concentrations of the adhesion molecules VCAM-1 or ICAM-1, markers for inflammation and endothelial function did not contribute to the variation in CRAE. This is the first study showing in population of children with overweight and obesity that the retinal arteriolar microvasculature, but not venular diameter is aberrant, with increasing BMI z score. CRAE was significantly associated with several cardiovascular risk markers, and multiple linear regression showed that a higher diastolic blood pressure z-score and lower fasting plasma glucose concentrations significantly contributed to the variance in CRAE. PMID- 30446682 TI - DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate. AB - The role of NOTCH signaling in adipogenesis is highly controversial, with data indicating null, positive or negative effects on this differentiation process. We hypothesize that these contradictory results could be due to the different global NOTCH signaling levels obtained in different experimental settings, because of a specific modulation of NOTCH receptors' activity by their ligands. We have previously demonstrated that DLK1 and DLK2, two non-canonical NOTCH1 ligands that inhibit NOTCH1 signaling in a dose-dependent manner, modulate the adipogenesis process of 3T3-L1 preadipocytes. In this work, we show that over-expression of any of the four NOTCH receptors enhanced adipogenesis of 3T3-L1 preadipocytes. We also determine that DLK proteins inhibit not only the activity of NOTCH1, but also the activity of NOTCH2, 3 and 4 receptors to different degrees. Interestingly, we have observed, by different approaches, that NOTCH1 over expression seems to stimulate the differentiation of 3T3-L1 cells towards a brown like adipocyte phenotype, whereas cells over-expressing NOTCH2, 3 or 4 receptors or DLK proteins would rather differentiate towards a white-like adipocyte phenotype. Finally, our data also demonstrate a complex feed-back mechanism involving Notch and Dlk genes in the regulation of their expression, which suggest that a precise level of global NOTCH expression and NOTCH-dependent transcriptional activity of specific targets could be necessary to determine the final phenotype of 3T3-L1 adipocytes. PMID- 30446684 TI - Influences of vertical differences in population emigration on mountainous vegetation greenness: A case study in the Taihang Mountains. AB - With the rapid advance of urbanization, rural population emigration has become a key factor that affects the man-land relationship in China's mountainous areas and may have a huge impact on ecological restoration. This study used the NDVI in the growing seasons to analyze the variation trend of vegetation greenness at different elevations in the Taihang Mountains during 2000-2010, employing trend analysis method. Then, we selected 990 samples, each of which was a circular area with a radius of 3 km. On this basis, we quantitatively analyzed the contribution degree of population emigration to this variation trend after eliminating the influences of precipitation, temperature, and other factors. The results showed that rural population emigration was significant in the Taihang Mountains in the past 10 years, with a rural population emigration rate of up to 16.3%; The vegetation in the Taihang Mountains presented a trend of overall improvement, but local deterioration; The results of the regression analysis showed that population emigration had significantly impacts on vegetation greenness at 1% significance level and 1% of population emigration can increase the NDVI variation trend by 0.06%. Furthermore, the impact gradually weakened with increasing elevation. PMID- 30446683 TI - Persistent metabolic changes in HIV-infected patients during the first year of combination antiretroviral therapy. AB - The HIV-human metabolic relationship is a complex interaction convoluted even more by antiretroviral therapy (cART) and comorbidities. The ability of cART to undo the HIV induced metabolic dysregulation is unclear and under-investigated. Using targeted metabolomics and multiplex immune biomarker analysis, we characterized plasma samples obtained from 18 untreated HIV-1-infected adult patients and compared these to a non-HIV infected (n = 23) control population. The biogenic amine perturbations during an untreated HIV infection implicated altered tryptophan- nitrogen- and muscle metabolism. Furthermore, the lipid profiles of untreated patients were also significantly altered compared to controls. In untreated HIV infection, the sphingomyelins and phospholipids correlated negatively to markers of infection IP-10 and sIL-2R whereas a strong association was found between triglycerides and MCP-1. In a second cohort, we characterized plasma samples obtained from 28 HIV-1-infected adult patients before and 12 months after the start of cART, to investigate the immune-metabolic changes associated with cART. The identified altered immune-metabolic pathways of an untreated HIV infection showed minimal change after 12 months of cART. In conclusion, 12 months of cART impacts only mildly on the metabolic dysregulation underlying an untreated HIV infection and provide insights into the comorbidities present in virally suppressed HIV patients. PMID- 30446685 TI - Simultaneous Blood Flow Measurement and Dermoscopy of Skin Lesions Using Dual Mode Dermascope. AB - Dermascopes are commonly utilized for the qualitative visual inspection of skin lesions. While automated image processing techniques and varied illumination strategies have been used to aid in structural analysis of lesions, robust quantification of functional information is largely unknown. To address this knowledge gap, we have developed a compact, handheld dermascope that enables real time blood flow measurements of skin during conventional visual inspection. In vitro characterization demonstrated that the dermascope is capable of quantifying changes in flow across a physiologically relevant range even when used in a handheld manner with clinic lighting and dermascope LEDs on. In a small pilot clinical study, we demonstrated the dermascope's ability to detect flow differences between two distinct lesion types. PMID- 30446686 TI - Identification of Two Mannosyltransferases Contributing to Biosynthesis of the Fungal-type Galactomannan alpha-Core-Mannan Structure in Aspergillus fumigatus. AB - Fungal-type galactomannan (FTGM) is a polysaccharide composed of alpha-(1 -> 2) /alpha-(1 -> 6)-mannosyl and beta-(1 -> 5)-/beta-(1 -> 6)-galactofuranosyl residues located at the outer cell wall of the human pathogenic fungus Aspergillus fumigatus. FTGM contains a linear alpha-mannan structure called core mannan composed of 9 or 10 alpha-(1 -> 2)-mannotetraose units jointed by alpha-(1 -> 6)-linkages. However, the enzymes involved in core-mannan biosynthesis remain unknown. We speculated that two putative alpha-1,2-mannosyltransferase genes in A. fumigatus, Afu5g02740/AFUB_051270 (here termed core-mannan synthase A [CmsA]) and Afu5g12160/AFUB_059750 (CmsB) are involved in FTGM core-mannan biosynthesis. We constructed recombinant proteins for CmsA and detected robust mannosyltransferase activity using the chemically synthesized substrate p nitrophenyl alpha-D-mannopyranoside as an acceptor. Analyses of CmsA enzymatic product revealed that CmsA possesses the capacity to transfer a mannopyranoside to the C-2 position of alpha-mannose. CmsA could also transfer a mannose residue to alpha-(1 -> 2)-mannobiose and alpha-(1 -> 6)-mannobiose and showed a 31-fold higher specific activity toward alpha-(1 -> 6)-mannobiose than toward alpha-(1 -> 2)-mannobiose. Proton nuclear magnetic resonance (1H-NMR) spectroscopy and gel filtration chromatography of isolated FTGM revealed that core-mannan structures were drastically altered and shortened in disruptant A. fumigatus strains ?cmsA, ?cmsB, and ?cmsA?cmsB. Disruption of cmsA or cmsB resulted in severely repressed hyphal extension, abnormal branching hyphae, formation of a balloon structure in hyphae, and decreased conidia formation. The normal wild type core-mannan structure and developmental phenotype were restored by the complementation of cmsA and cmsB in the corresponding disruptant strains. These findings indicate that both CmsA, an alpha-1,2-mannosyltransferase, and CmsB, a putative mannosyltransferase, are involved in FTGM biosynthesis. PMID- 30446688 TI - Low level DUX4 expression disrupts myogenesis through deregulation of myogenic gene expression. AB - Loss of silencing of the DUX4 gene on chromosome 4 causes facioscapulohumeral muscular dystrophy. While high level DUX4 expression induces apoptosis, the effects of low level DUX4 expression on human myogenic cells are not well understood. Low levels and sporadic expression of DUX4 have been reported in FSHD biopsy samples and myoblast cultures. Here, we show that a large set of human myogenic genes is rapidly deregulated by DUX4, including MYOD1 and MYF5, which are efficiently repressed even by low, non-toxic levels of DUX4. Human myoblasts modified to express low nontoxic levels of DUX4 were significantly impaired from differentiating into myotubes in vitro. Surprisingly, inhibition of differentiation does not require the transcriptional activation domain, thus is likely a feature of all mammalian DUX genes. DUX4 does not bind near the MYF5 gene, but has a prominent ChIP-seq peak within the MYF5 -118 kb enhancer. We find that when DUX4 binds at this site, it directs enhancer activity towards a nearby transcriptional start site for a noncoding nonfunctional RNA we name DIME (DUX4 induced MYF5 enhancer) transcript. These data highlight the anti-myogenic properties of DUX4 in human myogenic progenitor cells, and provide an example of enhancer disruption in the downregulation of MYF5. PMID- 30446689 TI - Author Correction: NIN interacts with NLPs to mediate nitrate inhibition of nodulation in Medicago truncatula. AB - In the version of this Article originally published, the name of author Zhenpeng Luo was incorrectly listed as Zhenpeng Luo Luo. Additionally, nitrate in Fig. 6b was incorrectly shown as 'NO3+' rather than 'NO3-'. This has now been amended. PMID- 30446687 TI - Combining fish and benthic communities into multiple regimes reveals complex reef dynamics. AB - Coral reefs worldwide face an uncertain future with many reefs reported to transition from being dominated by corals to macroalgae. However, given the complexity and diversity of the ecosystem, research on how regimes vary spatially and temporally is needed. Reef regimes are most often characterised by their benthic components; however, complex dynamics are associated with losses and gains in both fish and benthic assemblages. To capture this complexity, we synthesised 3,345 surveys from Hawai'i to define reef regimes in terms of both fish and benthic assemblages. Model-based clustering revealed five distinct regimes that varied ecologically, and were spatially heterogeneous by island, depth and exposure. We identified a regime characteristic of a degraded state with low coral cover and fish biomass, one that had low coral but high fish biomass, as well as three other regimes that varied significantly in their ecology but were previously considered a single coral dominated regime. Analyses of time series data reflected complex system dynamics, with multiple transitions among regimes that were a function of both local and global stressors. Coupling fish and benthic communities into reef regimes to capture complex dynamics holds promise for monitoring reef change and guiding ecosystem-based management of coral reefs. PMID- 30446690 TI - Genetic structure and differentiation in Dendrocalamus sinicus (Poaceae: Bambusoideae) populations provide insight into evolutionary history and speciation of woody bamboos. AB - Evolutionary processes, speciation in woody bamboos are presently little understood. Here we used Dendrocalamus sinicus Chia & J.L. Sun as a model species to investigate dispersal or vicariance speciation in woody bamboos. Variation in three chloroplast DNA (cpDNA) fragments and eight simple sequence repeat markers (SSR) among 232 individuals sampled from 18 populations across the known geographic range of D. sinicus was surveyed. D. sinicus populations exhibited a high level of genetic differentiation which divided them into two groups that are consistent with different culm types. Eleven haplotypes and two lineages (Straight-culm and Sinuous-culm lineages) were identified from phylogenetic analyses, and a strong phylogeographic structure across the distribution range was found. The demographic and spatial expansion times of the Straight-culm lineage were calculated as 11.3 Kya and 20.8 Kya, respectively. The populations of D. sinicus had experienced dispersal and long-term isolation, although this trace was diluted by contemporary gene flow revealed by SSR data. Our results provide an phylogeographic insight to better understand the speciation processes of woody bamboos. PMID- 30446691 TI - Genetic engineering a large animal model of human hypophosphatasia in sheep. AB - The availability of tools to accurately replicate the clinical phenotype of rare human diseases is a key step toward improved understanding of disease progression and the development of more effective therapeutics. We successfully generated the first large animal model of a rare human bone disease, hypophosphatasia (HPP) using CRISPR/Cas9 to introduce a single point mutation in the tissue nonspecific alkaline phosphatase (TNSALP) gene (ALPL) (1077 C > G) in sheep. HPP is a rare inherited disorder of mineral metabolism that affects bone and tooth development, and is associated with muscle weakness. Compared to wild-type (WT) controls, HPP sheep have reduced serum alkaline phosphatase activity, decreased tail vertebral bone size, and metaphyseal flaring, consistent with the mineralization deficits observed in human HPP patients. Computed tomography revealed short roots and thin dentin in incisors, and reduced mandibular bone in HPP vs. WT sheep, accurately replicating odonto-HPP. Skeletal muscle biopsies revealed aberrant fiber size and disorganized mitochondrial cristae structure in HPP vs. WT sheep. These genetically engineered sheep accurately phenocopy human HPP and provide a novel large animal platform for the longitudinal study of HPP progression, as well as other rare human bone diseases. PMID- 30446692 TI - Genome-wide analysis of Streptococcus pneumoniae serogroup 19 in the decade after the introduction of pneumococcal conjugate vaccines in Australia. AB - The decline in invasive pneumococcal disease (IPD), following the introduction of the 7-valent pneumococcal conjugate vaccination (PCV-7), was tempered by emergence of non-vaccine serotypes, particularly 19A. In Australia, three years after PCV-7 was replaced by PCV-13, containing 19A and 19F antigens, serogroup 19 was still a prominent cause of IPD in children under five. In this study we examined the evolution of serogroup 19 before and after introduction of paediatric vaccines in New South Wales (NSW), Australia. Genomes of 124 serogroup 19 IPD isolates collected before (2004) and after introduction of PCV-7 (2008) and PCV-13 (2014), from children under five in NSW, were analysed. Eleven core genome sequence clusters (cgSC) and 35 multilocus sequence types (ST) were identified. The majority (78/124) of the isolates belonged to four cgSCs: cgSC7 (ST199), cgSC11 (ST320), cgSC8 (ST63) and cgSC9 (ST2345). ST63 and ST2345 were exclusively serotype 19A and accounted for its predominantly intermediate penicillin resistance; these two clusters first appeared in 2008 and largely disappeared after introduction of PCV-13. Serogroup 19 was responsible for the highest proportion of vaccine failures in NSW. Relatively low immunogenicity of serogroup 19 antigens and Australia's three-dose vaccine schedule could affect the population dynamics of this serogroup. PMID- 30446693 TI - Tear Proteins Calcium binding protein A4 (S100A4) and Prolactin Induced Protein (PIP) are Potential Biomarkers for Thyroid Eye Disease. AB - There are no reliable biomarkers to predict thyroid eye disease (TED) in patients with autoimmune thyroid disease (AITD) currently. Several evidences support the involvement of the lacrimal gland in TED. The aim of our study was to quantitatively correlate the changes in tear protein profile with increasing severity of TED. Tear samples were collected from four groups of patients; AITD without TED (AITD), AITD with mild TED (mild TED), AITD with severe TED (severe TED) and normal controls. A total of 72 patients were recruited for the study. In discovery phase, isobaric tags for relative and absolute quantification (iTRAQ) 4 plex was used for quantitative proteomics analysis. For verification of results from discovery phase, sequential window acquisition of all theoretical fragment ion spectra (SWATH) was used to analyze an independent cohort from normal controls, AITD, mild TED and severe TED. Two proteins, S100A4 and PIP showed consistent dysregulation trends in the discovery and validation phase experiments. Our study demonstrated the differences in tear proteome across the spectrum of different severity and activity of TED in patients with AITD. Two tear proteins, S100A4 and PIP may serve as potential biomarkers to predict progression to severe TED in patients with AITD. PMID- 30446694 TI - Single-molecule long-read sequencing facilitates shrimp transcriptome research. AB - Although shrimp are of great economic importance, few full-length shrimp transcriptomes are available. Here, we used Pacific Biosciences single-molecule real-time (SMRT) long-read sequencing technology to generate transcripts from the Pacific white shrimp (Litopenaeus vannamei). We obtained 322,600 full-length non chimeric reads, from which we generated 51,367 high-quality unique full-length transcripts. We corrected errors in the SMRT sequences by comparison with Illumina-produced short reads. We successfully annotated 81.72% of all unique SMRT transcripts against the NCBI non-redundant database, 58.63% against Swiss Prot, 45.38% against Gene Ontology, 32.57% against Clusters of Orthologous Groups of proteins (COG), and 47.83% against Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Across all transcripts, we identified 3,958 long non-coding RNAs (lncRNAs) and 80,650 simple sequence repeats (SSRs). Our study provides a rich set of full-length cDNA sequences for L. vannamei, which will greatly facilitate shrimp transcriptome research. PMID- 30446695 TI - Immunogenicity of anthrax recombinant peptides and killed spores in goats and protective efficacy of immune sera in A/J mouse model. AB - Anthrax is primarily recognized as an affliction of herbivores with incubation period ranging from three to five days post-infection. Currently, the Sterne live spore vaccine is the only vaccine approved for control of the disease in susceptible animals. While largely effective, the Sterne vaccine has several problems including adverse reactions in sensitive species, ineffectiveness in active outbreaks and incompatibility with antibiotics. These can be surmounted with the advent of recombinant peptides (non-living) next generation vaccines. The candidate vaccine antigens comprised of recombinant protective antigen (PA), spore-specific antigen (bacillus collagen-like protein of anthracis, BclA) and formaldehyde inactivated spores (FIS). Presently, little information exists on the protectivity of these novel vaccine candidates in susceptible ruminants. Thus, this study sought to assess the immunogenicity of these vaccine candidates in goats and evaluate their protectivity using an in vivo mouse model. Goats receiving a combination of PA, BclA and FIS yielded the highest antibody and toxin neutralizing titres compared to recombinant peptides alone. This was also reflected in the passive immunization experiment whereby mice receiving immune sera from goats vaccinated with the antigen combination had higher survival post challenge. In conclusion, the current data indicate promising potential for further development of non-living anthrax vaccines in ruminants. PMID- 30446697 TI - Dilemmas of penile prosthesis implantation in healthy homosexual males in heterosexual relationships. PMID- 30446696 TI - Molecular basis of Mitomycin C enhanced corneal sensory nerve repair after debridement wounding. AB - The ocular surface is covered by stratified squamous corneal epithelial cells that are in cell:cell contact with the axonal membranes of a dense collection of sensory nerve fibers that act as sentinels to detect chemical and mechanical injuries which could lead to blindness. The sheerness of the cornea makes it susceptible to superficial abrasions and recurrent erosions which demand continuous regrowth of the axons throughout life. We showed previously that topical application of the antibiotic and anticancer drug Mitomycin C (MMC) enhances reinnervation of the corneal nerves and reduces recurrent erosions in mice via an unknown mechanism. Here we show using RNA-seq and confocal imaging that wounding the corneal epithelium by debridement upregulates proteases and protease inhibitors within the epithelium and leads to stromal nerve disruption. MMC attenuates these effects after debridement injury by increasing serpine1 gene and protein expression preserving L1CAM on axon surfaces of reinnervating sensory nerves. These data demonstrate at the molecular level that gene expression changes in the corneal epithelium and stroma modulate sensory axon integrity. By preserving the ability of axons to adhere to corneal epithelial cells, MMC enhances sensory nerve recovery after mechanical debridement injury. PMID- 30446698 TI - Relationship between orgasm experience and sexual excitation: validation of the model of the subjective orgasm experience. AB - The aim of this study was to provide validity evidence of the Model of the Subjective Orgasm Experience (MSOE) associating its components with different types of sexual excitation. A total of 96 participants (48 men and 48 women) performed an experimental laboratory task, in which neutral and erotic content films were presented while the genital response was registered. After exposure to sexual stimulus presentation, participants reported their subjective sexual arousal. In addition, four dimensions (affective, sensory, intimacy, and rewards) of the subjective orgasm experience and the individual propensity for sexual excitation were assessed. Results showed that, in men, the affective, sensory, and rewards dimensions of the orgasm experience significantly correlated with the propensity for becoming sexually excited, and the intimacy dimension correlated with the genital response. In women, the sensory dimension of the orgasm experience positively correlated with the subjective sexual arousal. Types of sexual excitation which previously correlated with the orgasm experience were able to predict its four dimensions. The validation of the MSOE provides a more delimited explanation of the psychological experience of orgasm applicable to both sexes. It is an adequate model for both clinical and research purposes. PMID- 30446699 TI - Light modulates oscillatory alpha activity in the occipital cortex of totally visually blind individuals with intact non-image-forming photoreception. AB - The discovery of intrinsically photosensitive retinal ganglion cells (ipRGCs) marked a major shift in our understanding of how light information is processed by the mammalian brain. These ipRGCs influence multiple functions not directly related to image formation such as circadian resetting and entrainment, pupil constriction, enhancement of alertness, as well as the modulation of cognition. More recently, it was demonstrated that ipRGCs may also contribute to basic visual functions. The impact of ipRGCs on visual function, independently of image forming photoreceptors, remains difficult to isolate, however, particularly in humans. We previously showed that exposure to intense monochromatic blue light (465 nm) induced non-conscious light perception in a forced choice task in three rare totally visually blind individuals without detectable rod and cone function, but who retained non-image-forming responses to light, very likely via ipRGCs. The neural foundation of such light perception in the absence of conscious vision is unknown, however. In this study, we characterized the brain activity of these three participants using electroencephalography (EEG), and demonstrate that unconsciously perceived light triggers an early and reliable transient desynchronization (i.e. decreased power) of the alpha EEG rhythm (8-14 Hz) over the occipital cortex. These results provide compelling insight into how ipRGC may contribute to transient changes in ongoing brain activity. They suggest that occipital alpha rhythm synchrony, which is typically linked to the visual system, is modulated by ipRGCs photoreception; a process that may contribute to the non conscious light perception in those blind individuals. PMID- 30446700 TI - Controlled electron injection facilitated by nanoparticles for laser wakefield acceleration. AB - We propose a novel injection scheme for laser-driven wakefield acceleration in which controllable localized electron injection is obtained by inserting nanoparticles into a plasma medium. The nanoparticles provide a very confined electric field that triggers localized electron injection where nonlinear plasma waves are excited but not sufficient for background electrons self-injection. We present a theoretical model to describe the conditions and properties of the electron injection in the presence of nanoparticles. Multi-dimensional particle in-cell (PIC) simulations demonstrate that the total charge of the injected electron beam can be controlled by the position, number, size, and density of the nanoparticles. The PIC simulation also indicates that a 5-GeV electron beam with an energy spread below 1% can be obtained with a 0.5-PW laser pulse by using the nanoparticle-assisted laser wakefield acceleration. PMID- 30446701 TI - Unique, Intersecting, and Overlapping Roles of C/EBP beta and CREB in Cells of the Innate Immune System. AB - CREB and C/EBP beta signaling pathways are modulated during inflammation and also targeted by Bacillus anthracis edema toxin (ET), but how these factors individually and jointly contribute to changes in immune cell function is poorly understood. Using CRISPR/Cas9 gene editing, macrophage cell lines lacking CREB and isoforms of C/EBP beta were generated and analyzed for changes in responses to LPS, ET, and IL-4. Macrophages lacking C/EBP beta suppressed induction of IL 10 and Arg1, while IL-6 was increased in these cells following exposure to LPS. Examination of C/EBP beta isoforms indicated the 38 kDa isoform was necessary for the expression of IL-10 and Arg1. ChIP-Seq analysis of CREB and C/EBP beta binding to targets on the chromosome of human PBMC identified several regions where both factors overlapped in their binding, suggesting similar gene targeting or cooperative effects. Based on the ChIP-Seq data, a panel of previously unknown targets of CREB and C/EBP beta was identified and includes genes such as VNN2, GINS4, CTNNBL1, and SULF2. Isoforms of a transcriptional corepressor, transducin like enhancer of Split (TLE), were also found to have CREB and C/EBP beta binding their promoter and were up regulated by ET. Finally, we explore a possible layer of C/EBP beta regulation by a protein complex consisting of adenomatous polyposis coli (APC) and PKA. Collectively, these data provide new insights into the role of CREB and C/EBP beta as immunosignaling regulators and targets of an important bacterial virulence factor. PMID- 30446702 TI - Publisher Correction: Calcium and vitamin-D deficiency marginally impairs fracture healing but aggravates posttraumatic bone loss in osteoporotic mice. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30446703 TI - Negativity volume of the generalized Wigner function as an entanglement witness for hybrid bipartite states. AB - In a recent paper, Tilma, Everitt et al. derived a generalized Wigner function that can characterize both the discrete and continuous variable states, i.e., hybrid states. As such, one can expect that the negativity of the generalized Wigner function applied to the hybrid states can reveal their nonclassicality, in analogy with the well-known Wigner function defined for the continuous variable states. In this work, we demonstrate that, indeed, the negativity volume of the generalized Wigner function of the hybrid bipartite states can be used as an entanglement witness for such states, provided that it exceeds a certain critical value. In particular, we study hybrid bipartite qubit-bosonic states and provide a qubit-Schrodinger cat state as an example. Since the detection of the generalized Wigner function of hybrid bipartite states in phase space can be experimentally simpler than the tomographic reconstruction of the corresponding density matrix, our results, therefore, present a convenient tool in the entanglement identification of such states. PMID- 30446704 TI - Carbenoxolone-mediated cytotoxicity inhibits Vaccinia virus replication in a human keratinocyte cell line. AB - The re-emergence of poxviral zoonotic infections and the threat of bioterrorism emphasise the demand for effective antipoxvirus therapies. Here, we show that carbenoxolone, a pharmacological inhibitor of gap junction function and a compound widely used in cell culture, is capable of hindering the replication of Vaccinia virus, the prototypical poxvirus, in a gap junction-independent manner in a human keratinocyte cell line. Viral protein synthesis occurs in the presence of carbenoxolone but infectious virion formation is minimal, indicating that carbenoxolone blocks viral morphogenesis. Initial viability tests suggested that carbenoxolone was not toxic to cells. However, electron microscopic analysis of carbenoxolone treated cells revealed that it alters the cellular endomembrane system. This widespread ultrastructural damage prevents Vaccinia virus virion assembly. These results strengthen the need for thorough characterisation of the effects of antiviral compounds on the cellular ultrastructure. PMID- 30446705 TI - A sixfold rise in concurrent day and night-time heatwaves in India under 2 degrees C warming. AB - Heatwaves with severe impacts have increased and projected to become more frequent under warming climate in India. Concurrent day and nighttime heatwaves can exacerbate human discomfort causing high morbidity and mortality; however, their changes in the observed and projected climate remain unrecognized. Here using observations and model simulations from climate of 20th century plus (C20C+) detection and attribution (D&A) and coupled model intercomparison project 5 (CMIP5) projects, we show that 1 and 3-day concurrent hot day and hot night (CHDHN) events have significantly increased during the observed climate in India. Our results show that the anthropogenic emissions contribute considerably to the increase of 1 and 3-day CHDHN events in India. The frequency of 3-day CHDHN events is projected to increase 12-fold of the current level by the end of 21st century and 4-fold by the mid 21st century under the high emission pathway of RCP 8.5. The increase in 3-day CHDHN events can be limited to only 2-fold by the end of 21st century under low emission scenario of RCP 2.6. One and 3-day CHDHN events are projected to increase by 4, 6, and 8 folds of the current level in India under the 1.5, 2, and 3 degrees C warming worlds, respectively. Restricting global mean temperature below 1.5 degrees from the pre-industrial level can substantially reduce the risk of 1 and 3-day CHDHN events and associated implications in India. PMID- 30446706 TI - Correction: Homozygosity mapping provides supporting evidence of pathogenicity in recessive Mendelian disease. AB - The original version of this Article contained an error in the top left of Figure 2: the number 1 on the y-axis had been changed to 0 during the typesetting process. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30446707 TI - ADP-Ribosylation Factor-Like 2 (ARL2) regulates cilia stability and development of outer segments in rod photoreceptor neurons. AB - Photoreceptor cells are specialized neurons with a sensory cilium carrying an elaborate membrane structure, the outer segment (OS). Inherited mutations in genes involved in ciliogenesis frequently result in OS malformation and blindness. ADP-ribosylation factor-like 2 (ARL2) has recently been implicated in OS formation through its association with Binder of ARL2 (BART or ARL2BP), a protein linked to inherited blinding disease. To test the role of ARL2 in vision we created a transgenic mouse model expressing a tagged-dominant active form of human ARL2 (ARL2-Q70L) under a rod-specific promoter. Transgenic ARL2-Q70L animals exhibit reduced photoreceptor cell function as early as post-natal day 16 and progressive rod degeneration. We attribute loss of photoreceptor function to the defective OS morphogenesis in the ARL2-Q70L transgenic model. ARL2-Q70L expression results in shortened inner and outer segments, shortened and mislocalized axonemes and cytoplasmic accumulation of rhodopsin. In conclusion, we show that ARL2-Q70L is crucial for photoreceptor neuron sensory cilium development. Future research will expand upon our hypothesis that ARL2-Q70L mutant interferes with microtubule maintenance and tubulin regulation resulting in impaired growth of the axoneme and elaboration of the photoreceptor outer segment. PMID- 30446708 TI - Decreased serum potassium may disturb sleep homeostasis in essential hypertensives. AB - The aim is to investigate the association between alterations in the serum potassium (K+) concentration and sleep architecture parameters in essential hypertensives. Two hundred ninety-two hypertensives undergoing polysomnography and providing blood samples were recruited. The sleep architecture was composed of sleep stages 1 (N1), 2 (N2), 3 (N3), 4 (N4) and REM. The light sleep stage (LST) was composed of N1 + N2, and the deep sleep stage (DST) was composed of N3 + N4. The potentialrelationships between electrolytes and sleep parameters were determined via univariate and multivariate analyses. The subjects were divided into two groups via the serum K+ median (3.86 mmol/L). The K+ < 3.86 mmol/L group showed significantly decreased N1 (7.10 +/- 4.55% vs 8.61 +/- 5.23%, p = 0.002), LST (71.48 +/- 11.33% vs 75.92 +/- 17.08%, p = 0.013), and periodic leg movement during sleep related to microarousals (MA) /arousal (PLMS-A) [4 (1~10) vs 8 (3~15)/night, p < 0.001] and increased REM (17.38 +/- 6.43% vs 15.37 +/- 6.18%, p = 0.007) compared to the K+ >= 3.86 mmol/L group. A subdivided analysis by gender showed that these changes were more statistically significant in men than in women. Significant positive correlations were identified between K+ and N1 (r = 0.169, p = 0.004), as well as PLMS-A (r = 0.222, p < 0.001) in subjects. Compared to women, a significantly strong correlation was identified between K+ and REM sleep in men (r = 0.158, p = 0.028 vs. r = 0.078, p = 0.442). Multiple linear regression analysis indicated that K+ is significantly associated with N1 in all subjects (p = 0.03) and with REM in men (p = 0.008), even after adjusting for confounders. Decreased K+ may disturb the homeostasis of the sleep architecture, and gender may interfere with their links in the hypertensive population. PMID- 30446710 TI - Author Correction: Comparing Sanger sequencing and high-throughput metabarcoding for inferring photobiont diversity in lichens. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30446711 TI - Enhancing all-in-one bioreactors by combining interstitial perfusion, electrical stimulation, on-line monitoring and testing within a single chamber for cardiac constructs. AB - Tissue engineering strategies have been extensively exploited to generate functional cardiac patches. To maintain cardiac functionality in vitro, bioreactors have been designed to provide perfusion and electrical stimulation, alone or combined. However, due to several design limitations the integration of optical systems to assess cardiac maturation level is still missing within these platforms. Here we present a bioreactor culture chamber that provides 3D cardiac constructs with a bidirectional interstitial perfusion and biomimetic electrical stimulation, allowing direct cellular optical monitoring and contractility test. The chamber design was optimized through finite element models to house an innovative scaffold anchoring system to hold and to release it for the evaluation of tissue maturation and functionality by contractility tests. Neonatal rat cardiac fibroblasts subjected to a combined perfusion and electrical stimulation showed positive cell viability over time. Neonatal rat cardiomyocytes were successfully monitored for the entire culture period to assess their functionality. The combination of perfusion and electrical stimulation enhanced patch maturation, as evidenced by the higher contractility, the enhanced beating properties and the increased level of cardiac protein expression. This new multifunctional bioreactor provides a relevant biomimetic environment allowing for independently culturing, real-time monitoring and testing up to 18 separated patches. PMID- 30446709 TI - Genome sequence analysis of an extensively drug-resistant Acinetobacter baumannii indigo-pigmented strain depicts evidence of increase genome plasticity. AB - Acinetobacter baumannii is a multidrug resistant nosocomial pathogen that shows an outstanding ability to undergo genetic exchange, thereby acquiring different traits that contribute to its success. In this work, we identified genetic features of an indigo-pigmented A. baumannii strain (Ab33405) that belongs to the clonal complex CC113B/CC79P. Ab33405 possesses a high number of genes coding for antibiotic resistance and virulence factors that may contribute to its survival, not only in the human host, but also in the hospital environment. Thirteen genes conferring resistance to different antibiotic families (trimethoprim, florfenicol, beta-lactams, aminoglycosides and sulfonamide) as well as the adeIJK genes and the capsule locus (KL) and outer core locus (OCL) were identified. Ab33405 includes 250 unique genes and a significant number of elements associated with Horizontal Gene Transfer, such as insertion sequences and transposons, genomic islands and prophage sequences. Also, the indigo-pigmented uncommon phenotype that could be associated with the monooxygenase or dioxygenase enzyme coded for by the iacA gene within the iac cluster was probably conferred by insertion of a 18-kb DNA fragment into the iacG gene belonging to this cluster. The Ab33405 genome includes all type VI secretion system genes and killing assays showed the ability of Ab33045 to kill Escherichia coli. In addition, Ab33405 can modulate susceptibility antibiotics when exposed to blue light. PMID- 30446713 TI - Mechanistic Interaction Study of Bromo-Noscapine with Bovine Serum Albumin employing Spectroscopic and Chemoinformatics Approaches. AB - Bromo-Noscapine (BrNs) is a tubulin-binding cytotoxic agent with significant activity against breast and lung cancer. The mechanistic interaction insight into the binding of bovine serum albumin (BSA) with BrNs can provide critical information about the pharmacodynamics and pharmacokinetics properties. Here, various spectroscopic techniques and computational methods were employed to understand the dynamics of BrNs and BSA interaction. The intrinsic fluorescence of BSA was quenched by BrNs through a static quenching procedure. The stoichiometry of BrNs-BSA complex was 1:1 and binding constant of the complex was in the order of 103 M-1 at 298 K. Based on thermodynamic analysis, it was deduced that binding process of the BrNs with BSA was spontaneous and exothermic, and the major forces between BrNs and BSA were van der waals forces and hydrogen bonding. Moreover, results of FT-IR, CD, UV spectra concluded significant conformational change in BSA on binding with BrNs. The in vitro findings were further confirmed by in silico assays. Molecular docking showed strong interactions with score of 8.08 kcal/mol. Molecular dynamics simulation analysis also suggested the stable binding with lower deviation in RMSD and RMSF values through persistent long simulation run. This study suggests optimal efficiency of diffusion of the BrNs into the bloodstream for the treatment of cancer. PMID- 30446714 TI - Effects of an Online Mind-Body Training Program on the Default Mode Network: An EEG Functional Connectivity Study. AB - Online mind-body training (MBT) programs can improve the psychological capabilities of practitioners. Although there has been a lot of effort to understand the neural mechanisms underlying the therapeutic effects of meditation, little is known about changes in electroencephalographic (EEG) functional connectivity that accompany mind-body training. The present study aimed to investigate how an online MBT program alters EEG functional connectivity in the default mode network (DMN). We assessed a group of healthcare providers, including 14 females who participated in the 4-week MBT program and 15 females who underwent a 4-week of waiting period. EEG data and information about psychological states were obtained at baseline and 4 weeks. The result was that the intervention group showed significant reductions in anxiety and trait anger that were accompanied by increased global DMN network strengths in the theta and alpha (but not beta and delta) frequency bands; these changes were not observed in the control group. Other variables including state anger, positive and negative affect, and self-esteem have not been changed over time in both groups. These findings suggest that practicing the mind-body training could have a relevance to the functional differences in network related to stress and anxiety reaction. PMID- 30446712 TI - Surface mechanomyography and electromyography provide non-invasive indices of inspiratory muscle force and activation in healthy subjects. AB - The current gold standard assessment of human inspiratory muscle function involves using invasive measures of transdiaphragmatic pressure (Pdi) or crural diaphragm electromyography (oesEMGdi). Mechanomyography is a non-invasive measure of muscle vibration associated with muscle contraction. Surface electromyogram and mechanomyogram, recorded transcutaneously using sensors placed over the lower intercostal spaces (sEMGlic and sMMGlic respectively), have been proposed to provide non-invasive indices of inspiratory muscle activation, but have not been directly compared to gold standard Pdi and oesEMGdi measures during voluntary respiratory manoeuvres. To validate the non-invasive techniques, the relationships between Pdi and sMMGlic, and between oesEMGdi and sEMGlic were measured simultaneously in 12 healthy subjects during an incremental inspiratory threshold loading protocol. Myographic signals were analysed using fixed sample entropy (fSampEn), which is less influenced by cardiac artefacts than conventional root mean square. Strong correlations were observed between: mean Pdi and mean fSampEn |sMMGlic| (left, 0.76; right, 0.81), the time-integrals of the Pdi and fSampEn |sMMGlic| (left, 0.78; right, 0.83), and mean fSampEn oesEMGdi and mean fSampEn sEMGlic (left, 0.84; right, 0.83). These findings suggest that sMMGlic and sEMGlic could provide useful non-invasive alternatives to Pdi and oesEMGdi for the assessment of inspiratory muscle function in health and disease. PMID- 30446715 TI - Gene-ecology of durum wheat HMW glutenin reflects their diffusion from the center of origin. AB - The production of many food items processed from wheat grain relies on the use of high gluten strength flours. As a result, about 80% of the allelic variability in the genes encoding the glutenin proteins has been lost in the shift from landraces to modern cultivars. Here, the allelic variability in the genes encoding the high molecular weight glutenin subunits (HMW-GSs) has been characterized in 152 durum wheat lines developed from a set of landraces. The allelic composition at the two Glu-1 loci (Glu-A1 and -B1) was obtained at both the protein and the DNA level. The former locus was represented by three alleles, of which the null allele Glu-A1c was the most common. The Glu-B1 locus was more variable, with fifteen alleles represented, of which Glu-B1b (HMW-GSs 7 + 8), B1d (6 + 8) and -B1e (20 + 20) were the most frequently occurring. The composition of HMW-GSs has been used to make inferences regarding the diffusion and diversification of durum wheat. The relationships of these allelic frequencies with their geographical distribution within the Mediterranean basin is discussed in terms of gene-ecology. PMID- 30446716 TI - Inherited genetic predispositions in F13A1 and F13B genes predict abdominal adhesion formation: identification of gender prognostic indicators. AB - Abdominal adhesions (AA) account for the most common complication of peritoneal surgery with bowel obstruction being the severest problem in the absence of effective predicting biomarkers. Anti-AA-barriers or adhesiolysis did not completely prevent bowel obstruction, although there is evidence they might reduce related complications requiring reoperation. In addition, gender-related predispositions have not been adequately investigated. We explored the role of coagulation Factor XIII (F13A1 and F13B subunit-genes) in patients following laparotomy, mostly median/lower median incision line. Globally, 426 patients (54%,?), were PCR-SNP-genotyped for FXIIIA V34L (rs5985), FXIIIA P564L (rs5982), FXIIIA Y204F (rs3024477) and FXIIIB H95R (rs6003). Patients' clinical phenotypes were: Group-A (n = 212), those who developed AA, and 55.2% of them developed bowel obstruction (subgroup-A1), the remaining were subgroup-A2; Group B (n = 214) were those who did not develop AA (subgroup-B1; 53.3%) or symptoms/complications (subgroup-B2). Among different laparotomy, colon surgery associated with AA at a major extent (OR = 5.1; 3.24-7.8; P < 0.0001) with different gender scores (?OR = 5.33; 2.32-12.23; P < 0.0001 and ?OR = 3.44; 1.58 7.49; P < 0.0001). Among SNPs, P564L (OR = 4.42; 1.45-13.4; P = 0.008) and Y204F (OR = 7.78; 1.62-37.3; P = 0.01) significantly predicted bowel obstruction and survival-analyses yielded interesting gender distinctions (?HR = 5.28; 2.36-11.8; P = 0.00005; ?HR = 2.22; 1.31-3.85; P = 0.0034). Active compounds preventing AA belong to the anticoagulant/fibrinolysis areas, suggesting them candidate investigation targets. We identified novel prognostic markers to predict AA/bowel obstruction giving insights to design novel therapeutic and gender prevention programs. PMID- 30446717 TI - MEF2B is a member of the BCL6 gene transcriptional complex and induces its expression in diffuse large B-cell lymphoma of the germinal center B-cell-like type. AB - Myocyte enhancer-binding factor 2B (MEF2B) has been implicated as a transcriptional regulator for BCL6. However, details about the interaction between MEF2B and BCL6 during expression, as well as the relationship of MEF2B to the expression of other germinal center (GC) markers, have not yet been fully explained. Using germinal center B-cell-like diffuse large B-cell lymphoma (GC DLBCL) and activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) cell lines, we analyzed the expression of MEF2B and its associations with BCL6, CD10, and ERK. Furthermore, small interfering RNA (siRNA) was used to study the possible effects of MEF2B knockdown on these proteins and cell growth. Analysis of the BCL6 transcriptional complex was performed using electrophoretic mobility shift assay. The correlation between MEF2B expression and the genetic type of DLBCL was assessed using immunohistochemistry on 111 patient samples, and via in silico analysis of publicly available microarray (Gene Expression Omnibus (GEO)) datasets. Our results indicate that the expression of MEF2B protein is important for the growth of GC-DLBCL cells, as evidenced by MEF2B knockdown inhibition of cell growth and the subsequent suppression of BCL6, CD10, and ERK phosphorylation. Analysis of BCL6 transcription factors in nuclear extracts of MEF2-expressing DLBCL cells showed involvement of MEF2B with AP-2alpha and BCL6 proteins in the formation of the BCL6 gene transcriptional complex. Indeed, differential expression of MEF2B in the GC-DLBCL is statistically significant compared to the ABC-DLBCL in the GEO datasets, as well as in tissue microarray, as indicated via immunohistochemistry (Visco-Young algorithm). Our findings indicate that MEF2B is an essential component of the BCL6 gene transcriptional complex for the regulation of DLBCL growth via the promotion of BCL6 expression. Beyond its regulatory role in DLBCL growth, MEF2B expression correlated positively with BCL6 and CD10 expression, and was preferentially expressed in the GBC-DLBCL group. PMID- 30446718 TI - Cued reactivation during slow-wave sleep induces brain connectivity changes related to memory stabilization. AB - Memory reprocessing following acquisition enhances memory consolidation. Specifically, neural activity during encoding is thought to be 'replayed' during subsequent slow-wave sleep. Such memory replay is thought to contribute to the functional reorganization of neural memory traces. In particular, memory replay may facilitate the exchange of information across brain regions by inducing a reconfiguration of connectivity across the brain. Memory reactivation can be induced by external cues through a procedure known as "targeted memory reactivation". Here, we analysed data from a published study with auditory cues used to reactivate visual object-location memories during slow-wave sleep. We characterized effects of memory reactivation on brain network connectivity using graph-theory. We found that cue presentation during slow-wave sleep increased global network integration of occipital cortex, a visual region that was also active during retrieval of object locations. Although cueing did not have an overall beneficial effect on the retention of cued versus uncued associations, individual differences in overnight memory stabilization were related to enhanced network integration of occipital cortex. Furthermore, occipital cortex displayed enhanced connectivity with mnemonic regions, namely the hippocampus, parahippocampal gyrus, thalamus and medial prefrontal cortex during cue sound presentation. Together, these results suggest a neural mechanism where cue induced replay during sleep increases integration of task-relevant perceptual regions with mnemonic regions. This cross-regional integration may be instrumental for the consolidation and long-term storage of enduring memories. PMID- 30446719 TI - Drivers for Livestock-Associated Methicillin-Resistant Staphylococcus Aureus Spread Among Danish Pig Herds - A Simulation Study. AB - To gain insight into the rapid increase in the number of livestock-associated Methicillin-resistant Staphylococcus aureus (LA-MRSA)-positive herds in Denmark, we developed an individual-based Monte Carlo simulation model. We aimed to assess whether transmission of LA-MRSA via pig movements could explain the observed increase in the number of positive herds in Denmark, and to evaluate the effect of other between-herd transmission mechanisms. Pig movements alone were not sufficient to mimic the observed increase in LA-MRSA-positive herds in Denmark in any of the modelled scenarios. The model identified three factors that played important roles in the between-herd spread of LA-MRSA: (1) the within-herd dynamics, (2) the frequency and effectiveness of indirect transmissions, and (3) unexplainable introduction of LA-MRSA to swine herds. These factors can act as starting points for the development of LA-MRSA control programs in pig herds in order to limit the risk of its transmission to humans. PMID- 30446720 TI - Femtosecond diffraction studies of solid and liquid phase changes in shock compressed bismuth. AB - Bismuth has long been a prototypical system for investigating phase transformations and melting at high pressure. Despite decades of experimental study, however, the lattice-level response of Bi to rapid (shock) compression and the relationship between structures occurring dynamically and those observed during slow (static) compression, are still not clearly understood. We have determined the structural response of shock-compressed Bi to 68 GPa using femtosecond X-ray diffraction, thereby revealing the phase transition sequence and equation-of-state in unprecedented detail for the first time. We show that shocked-Bi exhibits a marked departure from equilibrium behavior - the incommensurate Bi-III phase is not observed, but rather a new metastable phase, and the Bi-V phase is formed at significantly lower pressures compared to static compression studies. We also directly measure structural changes in a shocked liquid for the first time. These observations reveal new behaviour in the solid and liquid phases of a shocked material and give important insights into the validity of comparing static and dynamic datasets. PMID- 30446721 TI - Low-level light therapy reduces platelet destruction during extracorporeal circulation. AB - Extracorporeal circulation causes many deleterious effects on blood cells. Low level light therapy (LLLT) in the red/near-infrared spectral range is known for its cytoprotective properties but its use during cardiopulmonary bypass (CPB) has not yet been studied. We aimed to assess whether LLLT protects platelets during CPB. 24 pigs were connected to 1-hour-CPB and observed for the next 23 hours. In 12 animals, blood circulating through the oxygenator was treated with LLLT. Platelet count and function were monitored throughout the experiment. The decrease in platelet count was greater in the control group, especially during CPB and after 24 hours. In LLLT group CD62P expression remained quite stable up to the 12th hour of the experiment, whereas in the control group it continuously decreased till the end of observation. Platelets in the control group were more prone to aggregation in the postoperative period than at the beginning of the experiment, whereas platelets in the LLLT group aggregated similarly or less intense. Limitation of platelet loss, pattern of aggregation and CD62P expression suggest that LLLT may stabilize platelet function during CPB and diminish the negative effects associated with the interaction of cells with an artificial surface. PMID- 30446722 TI - Large-scale conformational changes and redistribution of surface negative charge upon sugar binding dictate the fidelity of phosphorylation in Vibrio cholerae fructokinase. AB - Fructokinase (FRK) catalyzes the first step of fructose metabolism i.e., D fructose to D-fructose-6-phosphate (F6P), however, the mechanistic insights of this reaction are elusive yet. Here we demonstrate that the putative Vibrio cholerae fructokinase (VcFRK) exhibit strong fructose-6-kinase activity allosterically modulated by K+/Cs+. We have determined the crystal structures of apo-VcFRK and its complex with fructose, fructose-ADP-Ca2+, fructose-ADP-Ca2+ BeF3-. Collectively, we propose the catalytic mechanism and allosteric activation of VcFRK in atomistic details explaining why K+/Cs+ are better activator than Na+. Structural results suggest that apo VcFRK allows entry of fructose in the active site, sequester it through several conserved H-bonds and attains a closed form through large scale conformational changes. A double mutant (H108C/T261C VcFRK), that arrests the closed form but unable to reopen for F6P release, is catalytically impotent highlighting the essentiality of this conformational change. Negative charge accumulation around ATP upon fructose binding, is presumed to redirect the gamma-phosphate towards fructose for efficient phosphotransfer. Reduced phosphotransfer rate of the mutants E205Q and E110Q supports this view. Atomic resolution structure of VcFRK-fructose-ADP-Ca2+-BeF3-, reported first time for any sugar kinase, suggests that BeF3- moiety alongwith R176, Ca2+ and 'anion hole' limit the conformational space for gamma-phosphate favoring in-line phospho-transfer. PMID- 30446724 TI - Paul G. Allen (1953-2018). PMID- 30446723 TI - Coordinated Turning Behaviour of Loitering Honeybees. AB - Turning during flight is a complex behaviour that requires coordination to ensure that the resulting centrifugal force is never large enough to disrupt the intended turning trajectory. The centrifugal force during a turn increases with the curvature (sharpness) of the turn, as well as the speed of flight. Consequently, sharp turns would require lower flight speeds, in order to limit the centrifugal force to a manageable level and prevent unwanted sideslips. We have video-filmed honeybees flying near a hive entrance when the entrance is temporarily blocked. A 3D reconstruction and analysis of the flight trajectories executed during this loitering behaviour reveals that sharper turns are indeed executed at lower speeds. During a turn, the flight speed is matched to the curvature, moment to moment, in such a way as to maintain the centrifugal force at an approximately constant, low level of about 30% of the body weight, irrespective of the instantaneous speed or curvature of the turn. This ensures that turns are well coordinated, with few or no sideslips - as it is evident from analysis of other properties of the flight trajectories. PMID- 30446725 TI - The Doctor Who theme and beyond: female pioneers of electronic music. PMID- 30446726 TI - Enhanced protection conferred by mucosal BCG vaccination associates with presence of antigen-specific lung tissue-resident PD-1+ KLRG1- CD4+ T cells. AB - BCG, the only vaccine licensed against tuberculosis, demonstrates variable efficacy in humans. Recent preclinical studies highlight the potential for mucosal BCG vaccination to improve protection. Lung tissue-resident memory T cells reside within the parenchyma, potentially playing an important role in protective immunity to tuberculosis. We hypothesised that mucosal BCG vaccination may enhance generation of lung tissue-resident T cells, affording improved protection against Mycobacterium tuberculosis. In a mouse model, mucosal intranasal (IN) BCG vaccination conferred superior protection in the lungs compared to the systemic intradermal (ID) route. Intravascular staining allowed discrimination of lung tissue-resident CD4+ T cells from those in the lung vasculature, revealing that mucosal vaccination resulted in an increased frequency of antigen-specific tissue-resident CD4+ T cells compared to systemic vaccination. Tissue-resident CD4+ T cells induced by mucosal BCG displayed enhanced proliferative capacity compared to lung vascular and splenic CD4+ T cells. Only mucosal BCG induced antigen-specific tissue-resident T cells expressing a PD-1+ KLRG1- cell-surface phenotype. These cells constitute a BCG induced population which may be responsible for the enhanced protection observed with IN vaccination. We demonstrate that mucosal BCG vaccination significantly improves protection over systemic BCG and this correlates with a novel population of BCG-induced lung tissue-resident CD4+ T cells. PMID- 30446727 TI - Selective expression of constitutively activated STAT6 in intestinal epithelial cells promotes differentiation of secretory cells and protection against helminths. AB - Intestinal epithelial cells (IECs) constitute an important barrier between host and pathogen. Immune mechanisms that provide protection against gastrointestinal helminths often require IL-4Ralpha-induced activation of STAT6-regulated genes in IECs. However, it is not known whether STAT6 activation in IECs enhances protective immunity against helminths. Furthermore, the regulation of proliferation and differentiation processes of the intestinal epithelium by IEC intrinsic STAT6 signaling remains unclear. To address these questions, we generated mice with specific expression of a constitutively active version of STAT6 in IECs. These VillinCre_STAT6vt mice show accumulation of secretory IECs, increased proliferation of IECs and lengthening of the small intestine. They rapidly expelled Nippostrongylus brasiliensis worms even in the absence of T cells. Furthermore, primary infection with Heligmosomoides polygyrus resulted in larval trapping in the submucosa and the fecundity of adult worms was severely impaired. Our results reveal an important IEC-intrinsic role of STAT6-regulated genes for intestinal homeostasis and protective immunity against helminths. PMID- 30446728 TI - PIWI-interacting RNAs: small RNAs with big functions. AB - In animals, PIWI-interacting RNAs (piRNAs) of 21-35 nucleotides in length silence transposable elements, regulate gene expression and fight viral infection. piRNAs guide PIWI proteins to cleave target RNA, promote heterochromatin assembly and methylate DNA. The architecture of the piRNA pathway allows it both to provide adaptive, sequence-based immunity to rapidly evolving viruses and transposons and to regulate conserved host genes. piRNAs silence transposons in the germ line of most animals, whereas somatic piRNA functions have been lost, gained and lost again across evolution. Moreover, most piRNA pathway proteins are deeply conserved, but different animals employ remarkably divergent strategies to produce piRNA precursor transcripts. Here, we discuss how a common piRNA pathway allows animals to recognize diverse targets, ranging from selfish genetic elements to genes essential for gametogenesis. PMID- 30446729 TI - The oracle of inDelphi predicts Cas9 repair outcomes. PMID- 30446731 TI - Increased susceptibility to cortical spreading depression and epileptiform activity in a mouse model for FHM2. AB - Migraine is a highly prevalent, debilitating, episodic headache disorder affecting roughly 15% of the population. Familial hemiplegic migraine type 2 (FHM2) is a rare subtype of migraine caused by mutations in the ATP1A2 gene, encoding the alpha2 isoform of the Na+/K+-ATPase, predominantly expressed in astrocytes. Differential comorbidities such as epilepsy and psychiatric disorders manifest in patients. Using a mouse model harboring the G301R disease-mutation in the alpha2 isoform, we set to unravel whether alpha2+/G301R mice show an increased susceptibility for epilepsy and cortical spreading depression (CSD). We performed in vivo experiments involving cortical application of KCl in awake head restrained male and female mice of different age groups (adult and aged). Interestingly, alpha2+/G301R mice indeed showed an increased susceptibility to both CSD and epileptiform activity, closely replicating symptoms in FHM2 patients harboring the G301R and other FHM2-causing mutations. Additionally, this epileptiform activity was superimposed on CSDs. The age-related alteration towards CSD indicates the influence of female sex hormones on migraine pathophysiology. Therefore, the FHM2, alpha2+/G301R mouse model can be utilized to broaden our understanding of generalized epilepsy and comorbidity hereof in migraine, and may be utilized toward future selection of possible treatment options for migraine. PMID- 30446730 TI - Demographic histories and genetic diversity across pinnipeds are shaped by human exploitation, ecology and life-history. AB - A central paradigm in conservation biology is that population bottlenecks reduce genetic diversity and population viability. In an era of biodiversity loss and climate change, understanding the determinants and consequences of bottlenecks is therefore an important challenge. However, as most studies focus on single species, the multitude of potential drivers and the consequences of bottlenecks remain elusive. Here, we combined genetic data from over 11,000 individuals of 30 pinniped species with demographic, ecological and life history data to evaluate the consequences of commercial exploitation by 18th and 19th century sealers. We show that around one third of these species exhibit strong signatures of recent population declines. Bottleneck strength is associated with breeding habitat and mating system variation, and together with global abundance explains much of the variation in genetic diversity across species. Overall, bottleneck intensity is unrelated to IUCN status, although the three most heavily bottlenecked species are endangered. Our study reveals an unforeseen interplay between human exploitation, animal biology, demographic declines and genetic diversity. PMID- 30446732 TI - THZ1 suppresses human non-small-cell lung cancer cells in vitro through interference with cancer metabolism. AB - Cancer cells always require more nutrients, energy, and biosynthetic activity to sustain their rapid proliferation than normal cells. Previous studies have shown the impact of THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), on transcription regulation and cell-cycle arrest in numerous cancers, but its effects on cellular metabolism in cancer cells remain unknown. In this study we elucidated the anticancer mechanism of THZ1 in human non-small-cell lung cancer (NSCLC) cells. We showed that treatment with THZ1 (10-1000 nM) dose-dependently suppressed the proliferation of human NSCLC cell lines H1299, A549, H292, and H23, and markedly inhibited the migration of these NSCLC cells. Furthermore, treatment with THZ1 (50 nM) arrested cell cycle at G2/M phase and induced apoptosis in these NSCLC cell lines. More importantly, we revealed that treatment with THZ1 (50 nM) blocked the glycolysis pathway but had no effect on glutamine metabolism. We further demonstrated that THZ1 treatment altered the expression pattern of glutaminase 1 (GLS1) isoforms through promoting the ubiquitination and degradation of NUDT21. Combined treatment of THZ1 with a glutaminase inhibitor CB 839 (500 nM) exerted a more potent anti-proliferative effect in these NSCLC cell lines than treatment with THZ1 or CB-839 alone. Our results demonstrate that the inhibitory effect of THZ1 on the growth of human NSCLC cells is partially attributed to interfering with cancer metabolism. Thus, we provide a new potential therapeutic strategy for NSCLC treatment by combining THZ1 with the inhibitors of glutamine metabolism. PMID- 30446733 TI - Endothelial cell-specific anticoagulation reduces inflammation in a mouse model of acute lung injury. AB - Tissue factor (TF)-dependent coagulation contributes to lung inflammation and the pathogenesis of acute lung injury (ALI). In this study, we explored the roles of targeted endothelial anticoagulation in ALI using two strains of transgenic mice expressing either a membrane-tethered human tissue factor pathway inhibitor (hTFPI) or hirudin fusion protein on CD31+ cells, including vascular endothelial cells (ECs). ALI was induced by intratracheal injection of LPS, and after 24 h the expression of TF and protease-activated receptors (PARs) on EC in lungs were assessed, alongside the extent of inflammation and injury. The expression of TF and PARs on the EC in lungs was upregulated after ALI. In the two strains of transgenic mice, expression of either of hTFPI or hirudin by EC was associated with significant reduction of inflammation, as assessed by the extent of leukocyte infiltration or the levels of proinflammatory cytokines, and promoted survival after LPS-induced ALI. The beneficial outcomes were associated with inhibition of the expression of chemokine CCL2 in lung tissues. The protection observed in the CD31-TFPI-transgenic strain was abolished by injection of an anti hTFPI antibody, but not by prior engraftment of the transgenic strains with WT bone marrow, confirming that the changes observed were a specific transgenic expression of anticoagulants by EC. These results demonstrate that the inflammation in ALI is TF and thrombin dependent, and that expression of anticoagulants by EC significantly inhibits the development of ALI via repression of leukocyte infiltration, most likely via inhibition of chemokine gradients. These data enhance our understanding of the pathology of ALI and suggest a novel therapeutic strategy for treatment. PMID- 30446734 TI - Paeoniflorin-6'-O-benzene sulfonate alleviates collagen-induced arthritis in mice by downregulating BAFF-TRAF2-NF-kappaB signaling: comparison with biological agents. AB - Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a new ester derivative of paeoniflorin with improved lipid solubility and oral bioavailability, as well as better anti-inflammatory activity than its parent compound. In this study we explored whether CP-25 exerted therapeutic effects in collagen-induced arthritis (CIA) mice through regulating B-cell activating factor (BAFF)-BAFF receptors mediated signaling pathways. CIA mice were given CP-25 or injected with biological agents rituximab or etanercept for 40 days. In CIA mice, we found that T cells and B cells exhibited abnormal proliferation; the percentages of CD19+ total B cells, CD19+CD27+-activated B cells, CD19+BAFFR+ and CD19+TACI+ cells were significantly increased in PBMCs and spleen lymphocytes. CP-25 suppressed the indicators of arthritis, alleviated histopathology, accompanied by reduced BAFF and BAFF receptors expressions, inhibited serum immunoglobulin levels, decreased the B-cell subsets percentages, and prevented the expressions of key molecules in NF-kappaB signaling. Furthermore, we showed that treatment with CP 25 reduced CD19+TRAF2+ cell expressions stimulated by BAFF and decreased TRAF2 overexpression in HEK293 cells in vitro. Thus, CP-25 restored the abnormal T cells proliferation and B-cell percentages to the normal levels, and normalized the elevated levels of IgA, IgG2a and key proteins in NF-kappaB signaling. In comparison, rituximab and etanercept displayed stronger anti-inflammatory activities than CP-25; they suppressed the elevated inflammatory indexes to below the normal levels in CIA mice. In summary, our results provide evidence that CP 25 alleviates CIA and regulates the functions of B cells through BAFF-TRAF2-NF kappaB signaling. CP-25 would be a soft immunomodulatory drug with anti inflammatory effect. PMID- 30446735 TI - Platelet microparticles contribute to aortic vascular endothelial injury in diabetes via the mTORC1 pathway. AB - Platelet microparticles (PMPs) are closely associated with diabetic macrovascular complications. The present study aimed to investigate the effects of PMPs in diabetes on aortic vascular endothelial injury and to explore the underlying mechanisms. Peritoneal injection of streptozotocin was used to generate a diabetic rat model in vivo, and human umbilical vein endothelial cells (HUVECs) treated with PMPs were used in vitro. PMP levels in the circulation and aorta tissues were time-dependently increased in streptozotocin-induced diabetic rats at weeks 4, 8, and 12 (P < 0.05). Aspirin significantly inhibited the PMP levels at each time point (P < 0.05). In diabetic rats, the endothelial nitric oxide levels were decreased significantly combined with increased endothelial permeability. PMPs were internalized by HUVECs and primarily accumulated around the nuclei. PMPs inhibited endothelial nitric oxide levels to about 50% and caused approximately twofold increase in reactive oxygen species production. Furthermore, PMPs significantly decreased the endothelial glycocalyx area and expression levels of glypican-1 and occludin (P < 0.05). Interestingly, the PMP induced endothelial injuries were prevented by raptor siRNA and rapamycin. In conclusion, increased PMPs levels contribute to aortic vascular endothelial injuries in diabetes through activating the mTORC1 pathway. PMID- 30446736 TI - Amyotrophic lateral sclerosis - a multisystem neurodegenerative disorder. PMID- 30446737 TI - Linking bacterial community composition to soil salinity along environmental gradients. AB - Salinization is recognized as a threat to soil fertility worldwide. A challenge in understanding the effects of salinity on soil microbial communities is the fact that it can be difficult to disentangle the effects of salinity from those of other variables that may co-vary with salinity. Here we use a trait-based approach to identify direct effects of salinity on soil bacterial communities across two salinity gradients. Through dose-response relationships between salinity and bacterial growth, we quantified distributions of the trait salt tolerance within the communities. Community salt tolerance was closely correlated with soil salinity, indicating a strong filtering effect of salinity on the bacterial communities. Accompanying the increases in salt tolerance were consistent shifts in bacterial community composition. We identified specific bacterial taxa that increased in relative abundances with community salt tolerance, which could be used as bioindicators for high community salt tolerance. A strong filtering effect was also observed for pH across the gradients, with pH tolerance of bacterial communities correlated to soil pH. We propose phenotypic trait distributions aggregated at the community level as a useful approach to study the role of environmental factors as filters of microbial community composition. PMID- 30446738 TI - A Foraging Mandala for Aquatic Microorganisms. AB - Aquatic environments harbor a great diversity of microorganisms, which interact with the same patchy, particulate, or diffuse resources by means of a broad array of physiological and behavioral adaptations, resulting in substantially different life histories and ecological success. To date, efforts to uncover and understand this diversity have not been matched by equivalent efforts to identify unifying frameworks that can provide a degree of generality and thus serve as a stepping stone to scale up microscale dynamics to predict their ecosystem-level consequences. In particular, evaluating the ecological consequences of different resource landscapes and of different microbial adaptations has remained a major challenge in aquatic microbial ecology. Here, inspired by Ramon Margalef's mandala for phytoplankton, we propose a foraging mandala for microorganisms in aquatic environments, which accounts for both the local environment and individual adaptations. This biophysical framework distills resource acquisition into two fundamental parameters: the search time for a new resource and the growth return obtained from encounter with a resource. We illustrate the foraging mandala by considering a broad range of microbial adaptations and environmental characteristics. The broad applicability of the foraging mandala suggests that it could be a useful framework to compare disparate microbial strategies in aquatic environments and to reduce the vast complexity of microbe-environment interactions into a minimal number of fundamental parameters. PMID- 30446739 TI - Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. AB - Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit of ATG on post-transplant survival. We performed a systematic review of randomized controlled trials (RCTs) to assess benefits and harms of thymoglobulin and Fresenius (re-branded as Grafalon) ATG formulations in patients undergoing allo-HCT for a variety of hematologic malignancies and bone marrow failure syndromes. A comprehensive search of MEDLINE, EMBASE, and Cochrane Library was performed. Data on methodological quality, benefits, and harms were extracted for each trial and pooled under a random-effects model. Eight RCTs (1134 patients) met the inclusion criteria. Methodological quality ranged from moderate to very low. Pooled results showed no difference in overall survival (OS) with the use of ATG (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.74-1.28; P = 0.83). ATG reduced grade II/III acute GVHD (risk ratio (RR) = 0.61; 95% CI = 0.48-0.77; P < 0.0001), grade III/IV acute GVHD (RR = 0.52; 95% CI = 0.34-0.81; P = 0.004), and chronic GVHD (RR = 0.52; 95% CI = 0.40-0.69; P < 0.00001) without an increase in non-relapse mortality (NRM) (RR = 0.91; 95% CI = 0.74-1.13; P = 0.40). Future studies with better methodological quality are needed to provide conclusive answers related to optimal dosing and timing of ATG for prevention of GVHD. PMID- 30446740 TI - Primary plasma cell leukemia: autologous stem cell transplant in an era of novel induction drugs. AB - Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM) with poor long-term survival after cytotoxic chemotherapy. Many novel drugs have revolutionized the treatment algorithms for MM. The impact of targeted therapy, both pre- and post-autologous stem cell transplant (auto-HCT) remains an area of ongoing interest. In this study, we report outcomes post auto HCT for pPCL and the impact of maintenance therapy posttransplant with novel agents. PMID- 30446741 TI - Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide as graft-versus-host disease prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood for patients with hematologic malignancies: a prospective, phase II study. AB - Nowadays, the most wildly used regimens for graft-versus-host disease (GvHD) prophylaxis in haplo-hematopoietic stem cell transplantation (Haplo-HSCT) are based on in vivo T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy). To improve the efficiency of GvHD prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood (Haplo-PBSCT-Cord), a novel regimen, which is composed of low dose of ATG (5 mg/kg) and low-dose PTCy (50 mg/kg) for GvHD prophylaxis, was evaluated in a prospective phase II clinical trial (Clinicaltrials.org NCT03395860). Thirty-two patients diagnosed with hematological malignancies were enrolled in this trial. All patients received myeloablative conditioning regimens except for three patients. The cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD were 19.4% (95% CI, 5.5-33.3%) and 6.9% (95% CI, 0-16.3%) by day 100, respectively. The 1-year probability of relapse, disease free survival (DFS) and overall survival (OS) was 25.1% (95% CI, 7.3-42.9%), 59% (95% CI, 33.3 84.7%) and 78.4% (95% CI, 63-93.8%), respectively. The CIs of CMV and EBV reactivation by day 180 were 37.5% (95% CI, 19.8-55.2%) and 40.6% (95% CI, 22.6 58.6%), respectively. The results suggested that low-dose ATG with low-dose PTCy as GvHD prophylaxis in Haplo-PBSCT-Cord had promising activity. PMID- 30446742 TI - Indications for allogeneic hematopoietic cell transplantation for adults with Philadelphia-chromosome negative acute lymphoblastic leukemia in first complete remission: all about MRD? PMID- 30446743 TI - Early childhood - a critical period for obesity prevention. PMID- 30446744 TI - Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases. AB - Obesity and its comorbidities, such as type 2 diabetes mellitus and cardiovascular disease, constitute growing challenges for public health and economies globally. The available treatment options for these metabolic disorders cannot reverse the disease in most individuals and have not substantially reduced disease prevalence, which underscores the unmet need for more efficacious interventions. Neurobiological resilience to energy homeostatic perturbations, combined with the heterogeneous pathophysiology of human metabolic disorders, has limited the sustainability and efficacy of current pharmacological options. Emerging insights into the molecular origins of eating behaviour, energy expenditure, dyslipidaemia and insulin resistance suggest that coordinated targeting of multiple signalling pathways is probably necessary for sizeable improvements to reverse the progression of these diseases. Accordingly, a broad set of combinatorial approaches targeting feeding circuits, energy expenditure and glucose metabolism in concert are currently being explored and developed. Notably, several classes of peptide-based multi-agonists and peptide-small molecule conjugates with superior preclinical efficacy have emerged and are currently undergoing clinical evaluation. Here, we summarize advances over the past decade in combination pharmacotherapy for the management of obesity and type 2 diabetes mellitus, exclusively focusing on large-molecule formats (notably enteroendocrine peptides and proteins) and discuss the associated therapeutic opportunities and challenges. PMID- 30446745 TI - Quenched Stochastic Optical Reconstruction Microscopy (qSTORM) with Graphene Oxide. AB - Quenched Stochastic Optical Reconstruction Microscopy (qSTORM) was demonstrated with graphene oxide sheets, peptides and bacteria; a method of contrast enhancement with super-resolution fluorescence microscopy. Individual sheets of graphene oxide (GO) were imaged with a resolution of 16 nm using the quenching of fluorescence emission by GO via its large Resonant Energy Transfer (RET) efficiency. The method was then extended to image self-assembled peptide aggregates (resolution 19 nm) and live bacterial cells (resolution 55 nm, the capsular structure of E. coli from urinary tract infections) with extremely low backgrounds and high contrasts (between one and two orders of magnitude contrast factor improvements that depended on the thickness of the graphene oxide layer used). Graphene oxide films combined with STORM imaging thus provide an extremely convenient method to image samples with large backgrounds due to non-specifically bound fluorophores (either due to excess labelling or autofluorescent molecules), which is a common occurrence in studies of both biological cells and soft condensed matter. The GO quenches the fluorescence across a thin layer at distances of less than 15 nm. Graphene oxide films coated with thin layers (<=15 nm) of polystyrene, polymethylmethacrylate and polylysine are shown to be effective in producing high contrast qSTORM images, providing a convenient modulation of sample/substrate interactions. The GO coatings can also provide an increased image resolution and a factor of 2.3 improvement was observed with the peptide fibres using a feature of interest metric,when there was a large non specifically bound background. PMID- 30446747 TI - Efficient and robust proteome-wide approaches for cross-linking mass spectrometry. AB - Cross-linking mass spectrometry (XL-MS) has received considerable interest, owing to its potential to investigate protein-protein interactions (PPIs) in an unbiased fashion in complex protein mixtures. Recent developments have enabled the detection of thousands of PPIs from a single experiment. A unique strength of XL-MS, in comparison with other methods for determining PPIs, is that it provides direct spatial information for the detected interactions. This is accomplished by the use of bifunctional cross-linking molecules that link two amino acids in close proximity with a covalent bond. Upon proteolytic digestion, this results in two newly linked peptides, which are identifiable by MS. XL-MS has received the required boost to tackle more-complex samples with recent advances in cross linking chemistry with MS-cleavable or reporter-based cross-linkers and faster, more sensitive and more versatile MS platforms. This protocol provides a detailed description of our optimized conditions for a full-proteome native protein preparation followed by cross-linking using the gas-phase cleavable cross-linking reagent disuccinimidyl sulfoxide (DSSO). Following cross-linking, we demonstrate extensive sample fractionation and substantially simplified data analysis with XlinkX in Proteome Discoverer, as well as subsequent protein structure investigations with DisVis and HADDOCK. This protocol produces data of high confidence and can be performed within ~10 d, including structural investigations. PMID- 30446748 TI - Mitigating head motion artifact in functional connectivity MRI. AB - Participant motion during functional magnetic resonance image (fMRI) acquisition produces spurious signal fluctuations that can confound measures of functional connectivity. Without mitigation, motion artifact can bias statistical inferences about relationships between connectivity and individual differences. To counteract motion artifact, this protocol describes the implementation of a validated, high-performance denoising strategy that combines a set of model features, including physiological signals, motion estimates, and mathematical expansions, to target both widespread and focal effects of subject movement. This protocol can be used to reduce motion-related variance to near zero in studies of functional connectivity, providing up to a 100-fold improvement over minimal processing approaches in large datasets. Image denoising requires 40 min to 4 h of computing per image, depending on model specifications and data dimensionality. The protocol additionally includes instructions for assessing the performance of a denoising strategy. Associated software implements all denoising and diagnostic procedures, using a combination of established image-processing libraries and the eXtensible Connectivity Pipeline (XCP) software. PMID- 30446749 TI - Tutorial: guidelines for the experimental design of single-cell RNA sequencing studies. AB - Single-cell RNA sequencing is at the forefront of high-resolution phenotyping experiments for complex samples. Although this methodology requires specialized equipment and expertise, it is now widely applied in research. However, it is challenging to create broadly applicable experimental designs because each experiment requires the user to make informed decisions about sample preparation, RNA sequencing and data analysis. To facilitate this decision-making process, in this tutorial we summarize current methodological and analytical options, and discuss their suitability for a range of research scenarios. Specifically, we provide information about best practices for the separation of individual cells and provide an overview of current single-cell capture methods at different cellular resolutions and scales. Methods for the preparation of RNA sequencing libraries vary profoundly across applications, and we discuss features important for an informed selection process. An erroneous or biased analysis can lead to misinterpretations or obscure biologically important information. We provide a guide to the major data processing steps and options for meaningful data interpretation. These guidelines will serve as a reference to support users in building a single-cell experimental framework-from sample preparation to data interpretation-that is tailored to the underlying research context. PMID- 30446746 TI - Speed breeding in growth chambers and glasshouses for crop breeding and model plant research. AB - 'Speed breeding' (SB) shortens the breeding cycle and accelerates crop research through rapid generation advancement. SB can be carried out in numerous ways, one of which involves extending the duration of plants' daily exposure to light, combined with early seed harvest, to cycle quickly from seed to seed, thereby reducing the generation times for some long-day (LD) or day-neutral crops. In this protocol, we present glasshouse and growth chamber-based SB approaches with supporting data from experimentation with several crops. We describe the conditions that promote the rapid growth of bread wheat, durum wheat, barley, oat, various Brassica species, chickpea, pea, grass pea, quinoa and Brachypodium distachyon. Points of flexibility within the protocols are highlighted, including how plant density can be increased to efficiently scale up plant numbers for single-seed descent (SSD). In addition, instructions are provided on how to perform SB on a small scale in a benchtop growth cabinet, enabling optimization of parameters at a low cost. PMID- 30446751 TI - Introducing our Tutorials. PMID- 30446750 TI - Fast and high-resolution mapping of elastic properties of biomolecules and polymers with bimodal AFM. AB - Fast, high-resolution mapping of heterogeneous interfaces with a wide elastic modulus range is a major goal of atomic force microscopy (AFM). This goal becomes more challenging when the nanomechanical mapping involves biomolecules in their native environment. Over the years, several AFM-based methods have been developed to address this goal. However, none of these methods combine sub-nanometer spatial resolution, quantitative accuracy, fast data acquisition speed, wide elastic modulus range and operation in physiological solutions. Here, we present detailed procedures for generating high-resolution maps of the elastic properties of biomolecules and polymers using bimodal AFM. This requires the simultaneous excitation of the first two eigenmodes of the cantilever. An amplitude modulation (AM) feedback acting on the first mode controls the tip-sample distance, and a frequency modulation (FM) feedback acts on the second mode. The method is fast because the elastic modulus, deformation and topography images are obtained simultaneously. The method is efficient because only a single data point per pixel is needed to generate the aforementioned images. The main stages of the bimodal imaging are sample preparation, calibration of the instrument, tuning of the microscope and generation of the nanomechanical maps. In addition, with knowledge of the deformation, bimodal AFM enables reconstruction of the true topography of the surface. It takes ~9 h to complete the whole procedure. PMID- 30446753 TI - LAG-3: a very singular immune checkpoint. PMID- 30446755 TI - Villus regional heterogeneity. PMID- 30446754 TI - The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis. AB - The skin provides both a physical barrier and an immunologic barrier to external threats. The protective machinery of the skin has evolved to provide situation specific responses to eliminate pathogens and to provide protection against physical dangers. Dysregulation of this machinery can give rise to the initiation and propagation of inflammatory loops in the epithelial microenvironment that result in inflammatory skin diseases in susceptible people. A defective barrier and microbial dysbiosis drive an interleukin 4 (IL-4) loop that underlies atopic dermatitis, while in psoriasis, disordered keratinocyte signaling and predisposition to type 17 responses drive a pathogenic IL-17 loop. Here we discuss the pathogenesis of atopic dermatitis and psoriasis in terms of the epithelial immune microenvironment-the microbiota, keratinocytes and sensory nerves-and the resulting inflammatory loops. PMID- 30446756 TI - Rules of engagement. PMID- 30446757 TI - Metabolic crosstalk. PMID- 30446752 TI - Multiple forest attributes underpin the supply of multiple ecosystem services. AB - Trade-offs and synergies in the supply of forest ecosystem services are common but the drivers of these relationships are poorly understood. To guide management that seeks to promote multiple services, we investigated the relationships between 12 stand-level forest attributes, including structure, composition, heterogeneity and plant diversity, plus 4 environmental factors, and proxies for 14 ecosystem services in 150 temperate forest plots. Our results show that forest attributes are the best predictors of most ecosystem services and are also good predictors of several synergies and trade-offs between services. Environmental factors also play an important role, mostly in combination with forest attributes. Our study suggests that managing forests to increase structural heterogeneity, maintain large trees, and canopy gaps would promote the supply of multiple ecosystem services. These results highlight the potential for forest management to encourage multifunctional forests and suggest that a coordinated landscape-scale strategy could help to mitigate trade-offs in human-dominated landscapes. PMID- 30446758 TI - Treg cell tune-up. PMID- 30446759 TI - Microglial activity in brain injury. PMID- 30446760 TI - Identification of key influence factors and an empirical formula for spring snowmelt-runoff: A case study in mid-temperate zone of northeast China. AB - Because of the unique climate characteristics, the runoff law in mid-temperate zone is very different from other regions in spring. Accurate runoff simulation and forecasting is of great importance to spring flood control and efficient use of water resources. Baishan reservoir is located in the upper Second Songhua River Basin in Northeast China, where snowmelt is an important source of runoff that contributes to the water supply. This study utilized long-term hydrometeorological data, in the contributing area of Bashan reservoir, to investigate factors and time-lag effects on spring snowmelt and to establish a snowmelt-runoff model. Daily precipitation, temperature, and wind data were collected from three meteorological stations in this region from 1987-2016. Daily runoff into the Baishan reservoir was selected for the same period. The snowmelt period was identified from March 23 to May 4 through baseflow segmentation with the Eckhardt recursive digital filtering method combined with statistical analyses. A global sensitivity analysis, based on the back propagation neural network method, was used to identify daily radiation, wind speed, mean temperature, and precipitation as the main factors affecting snowmelt runoff. Daily radiation, precipitation, and mean temperature factors had a two-day lag effect. Based on these factors, an empirical snowmelt runoff model was established by genetic algorithm (GAS) to estimate the snowmelt runoff in this area. The model showed an acceptable performance with coefficient of determination (R2) of 73.6%, relative error (Re) of 25.10%, and Nash-Sutcliffe efficiency coefficient (NSE) of 66.2% in the calibration period of 1987-2010, while reasonable performance with R2 of 62.3%, Re of 27.2%, and NSE of 46.0% was also achieved during the 2011-2016 validation period. PMID- 30446761 TI - Predictors of weight status in school-aged children: a prospective cohort study. AB - BACKGROUND/OBJECTIVES: To prospectively investigate the predictors of overweight/obesity and of body mass index (BMI) change in schoolchildren. SUBJECTS/METHODS: A cohort of 2755 Irish children (53.7% girls), aged 6-10 years at baseline, participating in the Childhood Obesity Surveillance Initiative were included. Height and weight were objectively measured and BMI was calculated. Overweight/obesity were defined according to the International Obesity Task Force cut-offs. Prevalence of overweight/obesity at baseline and follow-up, incidence of overweight/obesity and changes in BMI over time were computed. Lifestyle indicators were parentally reported with a questionnaire. Predictors of overweight/obesity were investigated by multivariate mixed logistic regression models. RESULTS: Baseline BMI (OR = 6.46, 95% CI = 4.56-9.17) and school socioeconomic level (OR = 2.12, 95% CI = 1.16-3.86) were associated with higher risk of becoming overweight/obese. Children with no savoury snacks consumption (OR = 0.22, 95% CI = 0.07-0.69), or with frequent sports/dancing clubs attendance (OR = 0.41, 95% CI = 0.19-0.88) had lower odds of overweight/obesity at follow up. Poor fruit intake was associated with higher risk of overweight/obesity (OR = 2.16, 95% CI = 1.23-3.78). CONCLUSIONS: Initial BMI was the main predictor of subsequent overweight/obesity in schoolchildren, followed, to a lesser extent, by school socioeconomic status. Although lifestyle behaviours appeared to have lower effect as compared with prior BMI, children with healthier lifestyle behaviours were at reduced risk of overweight/obesity at follow-up. Programmes that aim at preventing the onset of overweight and obesity need to be a priority given the existing difficulties to reverse this condition later in life. PMID- 30446762 TI - Prenatal iron containing supplements provided to Chinese women with no or mild anemia had no effect on hemoglobin concentration in post-partum women or their infants at 6 and 12 months of age. AB - BACKGROUND: Although prenatal iron-containing supplements have been associated with lower anemia prevalence in later pregnancy, few trials have examined the effect of supplements on the anemia status of post-partum women and their infants. OBJECTIVE: We compared the effects of folic acid alone (FA), iron-folic acid (IFA) and multiple micronutrients (MMN) when provided to pregnant women with no or mild anemia on the hemoglobin levels of post-partum women and their infants at 6 and 12 months of age. We also examined the potential modifying effect of maternal hemoglobin concentration at enrollment. METHODS: A double-blind randomized controlled trial was conducted in China; 18,775 nulliparous women with a hemoglobin concentration > 100 g/L were randomly assigned to receive daily FA (400 MUg); IFA (FA, Fe 30 mg), or MMN (FA, Fe and 13 micronutrients) from before 20 gestational weeks until delivery. RESULTS: Compared with daily prenatal FA, supplementation with IFA or MMN did not affect the prevalence of anemia at 4-6 weeks post-partum (27.2%, 26.8%, and 26.3%, respectively). At 6 months of age, the anemia prevalence in infants was 6.9%, 6.7%, and 6.7%, respectively. Findings were similar at 12 months of age. Among both post-partum women and infants, findings were similar across all levels of hemoglobin at enrollment. CONCLUSIONS: Compared to FA alone, prenatal IFA and MMN provided to women with no or mild anemia did not affect anemia in women post-partum or their infants regardless of baseline maternal hemoglobin concentration at enrollment. PMID- 30446763 TI - Time trends in adherence to UK dietary recommendations and associated sociodemographic inequalities, 1986-2012: a repeated cross-sectional analysis. AB - BACKGROUND/OBJECTIVES: Little is known about time trends in diet quality and associated inequalities in the UK. This study aimed to examine trends in adherence to four UK dietary recommendations, overall and among sociodemographic subgroups, from 1986 to 2012. SUBJECTS/METHODS: We conducted a repeated cross sectional analysis using data from three UK diet surveys: Dietary and Nutritional Survey of British Adults 1986-87 (n = 2018), National Diet and Nutrition Survey (NDNS) 2000-01 (n = 1683) and NDNS Rolling Programme 2008-12 (n = 1632). We measured adherence to dietary recommendations for fruit and vegetables, salt, oily fish, and red and processed meat, estimated using food diary record data. We compared adherence across surveys and by four sociodemographic characteristics: sex, age, socioeconomic position and ethnicity. RESULTS: Overall, population adherence to dietary recommendations was low to moderate, but improved over time. There were inequalities in adherence to all recommendations at all timepoints according to one or more sociodemographic characteristic. When inequalities were present, women, older adults, those with non-manual occupations and non-Whites were more likely to adhere to dietary recommendations. Although some dietary inequalities declined, most persisted across the three surveys. CONCLUSIONS: The persistence of most inequalities highlights the need for further interventions to reduce dietary inequalities as well as improve overall population diet. The greatest simultaneous improvement in population adherence and reduction of inequalities was observed for salt, which may reflect the success of the UK Salt Reduction Programme. Similarly comprehensive programmes should be encouraged for other dietary components. PMID- 30446765 TI - Publisher Correction: A short isoform of ATG7 fails to lipidate LC3/GABARAP. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30446764 TI - Asymmetry in Mechanosensitive Gene Expression during Aortic Arch Morphogenesis. AB - Embryonic aortic arches (AA) are initially bilaterally paired, transitional vessels and failures in remodeling based on hemodynamic and growth-related adaptations cause a spectrum of congenital heart disease (CHD) anatomies. Identifying regulatory mechanisms and cross-talk between the genetic elements of these vessels are critical to understand the ethiology of CHD and refine predictive computational models. This study aims to screen expression profiles of fundamental biological pathways in AA at early stages of chick embryo morphogenesis and correlate them with our current understanding of growth and mechanical loading. Reverse transcription-quantitative PCR (RT-qPCR) was followed by correlation and novel peak expression analyses to compare the behaviour and activation period of the genes. Available protein networks were also integrated to investigate the interactions between molecules and highlight major hierarchies. Only wall shear stress (WSS) and growth-correlated expression patterns were investigated. Effect of WSS was seen directly on angiogenesis as well on structural and apoptosis-related genes. Our time-resolved network suggested that WSS-correlated genes coordinate the activity of critical growth factors. Moreover, differential gene expression of left and right AA might be an indicator of subsequent asymmetric morphogenesis. These findings may further our understanding of the complex processes of cardiac morphogenesis and errors resulting in CHD. PMID- 30446766 TI - In vitro neural networks minimise variational free energy. AB - In this work, we address the neuronal encoding problem from a Bayesian perspective. Specifically, we ask whether neuronal responses in an in vitro neuronal network are consistent with ideal Bayesian observer responses under the free energy principle. In brief, we stimulated an in vitro cortical cell culture with stimulus trains that had a known statistical structure. We then asked whether recorded neuronal responses were consistent with variational message passing based upon free energy minimisation (i.e., evidence maximisation). Effectively, this required us to solve two problems: first, we had to formulate the Bayes-optimal encoding of the causes or sources of sensory stimulation, and then show that these idealised responses could account for observed electrophysiological responses. We describe a simulation of an optimal neural network (i.e., the ideal Bayesian neural code) and then consider the mapping from idealised in silico responses to recorded in vitro responses. Our objective was to find evidence for functional specialisation and segregation in the in vitro neural network that reproduced in silico learning via free energy minimisation. Finally, we combined the in vitro and in silico results to characterise learning in terms of trajectories in a variational information plane of accuracy and complexity. PMID- 30446767 TI - October ECI Biocommentary. PMID- 30446768 TI - Neuroinflammation in preterm babies and autism spectrum disorders. AB - Genetic anomalies have a role in autism spectrum disorders (ASD). Each genetic factor is responsible for a small fraction of cases. Environment factors, like preterm delivery, have an important role in ASD. Preterm infants have a 10-fold higher risk of developing ASD. Preterm birth is often associated with maternal/fetal inflammation, leading to a fetal/neonatal inflammatory syndrome. There are demonstrated experimental links between fetal inflammation and the later development of behavioral symptoms consistent with ASD. Preterm infants have deficits in connectivity. Most ASD genes encode synaptic proteins, suggesting that ASD are connectivity pathologies. Microglia are essential for normal synaptogenesis. Microglia are diverted from homeostatic functions towards inflammatory phenotypes during perinatal inflammation, impairing synaptogenesis. Preterm infants with ASD have a different phenotype from term born peers. Our original hypothesis is that exposure to inflammation in preterm infants, combined with at risk genetic background, deregulates brain development leading to ASD. PMID- 30446770 TI - Etiologies and outcomes of emergency surgery for acute abdominal pain: an audit of 1456 cases in a single center. AB - PURPOSE: There are few studies that have reported the details of emergency surgery for acute abdominal pain. This study aimed to clarify the etiologies and outcomes of emergency abdominal surgery among patients in different age categories. METHODS: Between January 2014 and December 2016, 1456 patients aged 7 years or older who underwent emergency surgery for acute abdominal pain at our institution were enrolled in this study. The patients were divided into three age groups: 7-17 years (n = 146), 18-64 years (n = 628), and 65 years or older (n = 682). The clinical characteristics, etiology of abdominal emergency surgery, and surgical outcomes were compared among the three groups. RESULTS: The proportion of patients with comorbid conditions significantly increased with increasing ages. In patients in between 7 and 17 and in those between 18 and 64 years, acute appendicitis was the most frequent etiology, followed by bowel obstruction. Conversely, the most frequent etiology was bowel obstruction, followed by biliary disease in patients 65 years or older. The morbidity and mortality rate were 12% and 0.2% in patients 18-64 years, and 25% and 1.8% in patients 65 years or older (P < 0.001 and P = 0.004, respectively). In the group of patients 65 years or older, more patients were transferred to different hospitals for rehabilitation or recovery. CONCLUSIONS: This study demonstrated significant differences among patients in different age categories in terms of the etiologies and outcomes of emergency abdominal surgery. PMID- 30446769 TI - Effect of N-acetyl cysteine (NAC) supplementation on positive and negative syndrome scale in schizophrenia: a systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To conduct a systematic review and meta-analysis of published randomised controlled trials on the efficacy of NAC supplementation on positive and negative syndrome scale in schizophrenia. METHODS: A meta-analysis was conducted, and studies were identified by a search of electronic databases from inception to May 2018. Combined and stratified analyses were used. RESULTS: Seven trials were identified, and data from n = 447 participants were included. Pooled analysis showed improvement of positive and negative syndrome scale following NAC treatment compared with placebo, for total (SMB = - 0.96) [95% CI - 1.69, - 0.24; P = 0.009], general (SMB = - 1.04) [95% CI - 1.80, - 0.27; P = 0.008] and negative (SMB = - 0.73) [95% CI - 1.29, - 0.17; P = 0.01] scores, respectively. Significant heterogeneity was found, and subgroup analysis showed significant reductions in studies with a treatment duration of <= 24 weeks, with a considerable effect size on total, general, and negative scores (Total SMD = - 0.83; General SMD = - 0.67; Negative SMD = - 1.09) following NAC. CONCLUSIONS: NAC improved all aspects of positive and negative syndrome scale in schizophrenic populations and may be more efficacious with treatment durations up to 24 weeks. PMID- 30446771 TI - Bisphosphonates Use and Risk of Subtrochanteric and Diaphyseal Femur Fractures in Korea: Results from the National Claim Registry. AB - Although Asian with bisphosphonate has been considered to have higher risk of subtrochanteric and diaphyseal femur (ST/DF) fractures, the occurrence of those fractures has been still unclear in Asia. The purpose of this study was to investigate the incidence rate of ST/DF fractures among bisphosphonate users from nationwide database in South Korea. Using national health insurance claim database, we only included the bisphosphonate users who took bisphosphonate for the first time in 2008 and evaluated the incidence rate of ST/DF fracture from 2008 to 2013. Non-user controls were matched to bisphosphonate users by propensity score matching with age and gender. Cox regression models were used to calculate hazard ratios of ST/DF fracture with and without adjustment for comorbidity. A total of 682 ST/DF fractures were observed among 348,311 bisphosphonate users. The incidence rate of ST/DF fracture among bisphosphonate users (37.75/100,000 person years, 95% CI 35.02-40.70) was higher compared with non-users (24.41/100,000 person years, 95% CI 22.31-26.71). The risk of ST/DF fracture was greater in bisphosphonate users compared with non-users (hazard ratio 1.541, 1.370-1.734; p < 0.001). The incidence rate of ST/DF fracture after bisphosphonate use could be determined in Korean patients, which can provide basal information for further studies on risk and benefit of continuing bisphosphonate. PMID- 30446774 TI - Highlight report: spheroids from stem cell-derived hepatocyte-like cells. PMID- 30446773 TI - Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo. AB - N-nitroso compounds are alkylating agents, which are widespread in our diet and the environment. They induce DNA alkylation adducts such as O6-methylguanine (O6 MeG), which is repaired by O6-methylguanine-DNA methyltransferase (MGMT). Persistent O6-MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O6-MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to monitor O6-MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adduct-specific antibody, allowed for the semi quantitative, dose-dependent assessment of O6-MeG in CRC cells. Using the highly sensitive and specific UPLC-MS/MS, TMZ-induced O6-MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O6-MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC-MS/MS measurements and dose-response modeling revealed a non linear formation of hepatic and colonic O6-MeG adducts in WT, whereas linear O6 MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC-MS/MS analysis is highly sensitive and specific for O6 MeG, thereby allowing for the first time for the determination of a genotoxic threshold upon exposure to O6-methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures. PMID- 30446772 TI - Associations between perceived social and physical environmental variables and physical activity and screen time among adolescents in four European countries. AB - OBJECTIVES: Associations between the perceived social and physical environment and self-reported moderate-to-vigorous physical activity (MVPA) and screen time (ST) were examined among adolescents in four European countries. METHODS: Representative samples were surveyed with standardised methodologies. Associations between environmental variables and meeting MVPA recommendations and tertiles of ST were tested in gender-specific logistic regression models. Moderation by country and country-specific relationships were also examined. RESULTS: The most consistent findings across countries were found for the significant associations between neighbourhood social environment and MVPA in both boys and girls. Significant associations with the physical environment varied more between countries and by gender. The most consistent negative associations with ST were found for the social environmental variable of having parental rules for spending time outside the home. CONCLUSIONS: The present findings provided evidence for the generalisability of the associations between environmental correlates and MVPA across four European countries. The findings show clear differences in correlates for MVPA and ST. Further research is needed to better understand the unique aspects of the social and physical environment which explain each of the two behaviours. PMID- 30446775 TI - Bardet-Biedl Syndrome proteins regulate cilia disassembly during tissue maturation. AB - Primary cilia are conserved organelles that mediate cellular communication crucial for organogenesis and homeostasis in numerous tissues. The retinal pigment epithelium (RPE) is a ciliated monolayer in the eye that borders the retina and is vital for visual function. Maturation of the RPE is absolutely critical for visual function and the role of the primary cilium in this process has been largely ignored to date. We show that primary cilia are transiently present during RPE development and that as the RPE matures, primary cilia retract, and gene expression of ciliary disassembly components decline. We observe that ciliary-associated BBS proteins protect against HDAC6-mediated ciliary disassembly via their recruitment of Inversin to the base of the primary cilium. Inhibition of ciliary disassembly components was able to rescue ciliary length defects in BBS deficient cells. This consequently affects ciliary regulation of Wnt signaling. Our results shed light onto the mechanisms by which cilia-mediated signaling facilitates tissue maturation. PMID- 30446776 TI - Emerging role of circadian rhythm in bone remodeling. AB - The 24-h rhythm of behavioral and physiological processes is a typical biological phenomenon regulated by a group of circadian rhythm genes. Dysfunction of the circadian rhythm can cause a wide range of problems, such as cancer and metabolic diseases. In recent decades, increased understanding of the roles of circadian rhythm genes in the bone remodeling process have been documented, including osteoblastic bone formation, osteoclastic bone resorption, and osteoblast/osteoclast communication. A timely review of the current findings may help to facilitate the new field of circadian rhythmic bone remodeling research. Targeted pharmacological modulation of circadian rhythm genes is a possible therapeutic approach through which to overcome bone remodeling problems in the future. PMID- 30446777 TI - [Glaucoma treatment in high myopia]. AB - Both high myopia and glaucoma can have devastating effects on the visual function. Diagnostic tests and treatment can be challenging when both diseases are coexistent. This article discusses some of the typical problems in the management of glaucoma in highly myopic patients. PMID- 30446778 TI - Clostridial whole cell and enzyme systems for hydrogen production: current state and perspectives. AB - Strictly anaerobic bacteria of the Clostridium genus have attracted great interest as potential cell factories for molecular hydrogen production purposes. In addition to being a useful approach to this process, dark fermentation has the advantage of using the degradation of cheap agricultural residues and industrial wastes for molecular hydrogen production. However, many improvements are still required before large-scale hydrogen production from clostridial metabolism is possible. Here we review the literature on the basic biological processes involved in clostridial hydrogen production, and present the main advances obtained so far in order to enhance the hydrogen productivity, as well as suggesting some possible future prospects. PMID- 30446779 TI - Ectopias of the kidney, urinary tract organs, and male genitalia. AB - The most frequent anomaly of the urogenital tract is a simple renal ectopia with one organ lying in the pelvis. Crossed renal ectopia is a less common condition in which the ectopic kidney is located on the opposite side of the midline from the ureteral insertion in the urinary bladder. The cause of both types of renal ectopia is the arrest or failure of the kidney ascent from the pelvic to the lumbar position. Whereas an accelerated ascent leads to a subdiaphragmal or intrathoracic ectopic position, an ectopic ureter can be defined as one that does not drain into the trigonum vesicae. The ectopic orificium can be located situated in the bladder neck and urethra as well as somewhere in the genital area.Exstrophy of the urinary bladder is not a complete ectopia. Because the abdominal wall and the anterior part of the bladder wall are lacking, the bladder mucosa grows directly into the skin. The complex exstrophy of the bladder and intestine corresponds to a cloacal exstrophy, in which the bladder is split in two halves on either side of the gut portion. Testicular ectopia refers to the location of the testis in a position outside of its normal course of descent.Prostatic ectopia does not refer to the wrong location of the entire organ, but to a scattered group of prostate glands, which are mostly found in the submucosal part of the urinary bladder or proximal urethra. Other described locations are the intestinal wall, anus, pericolic fat tissue, spleen, seminal vesicle, testis, and cervix uteri.The associated ectopic penis, scrotum, and penoscrotal transposition are the least common and probably the absolutely most unknown malformations of the male genitalia. The ectopic penis and scrotum are located in the perineum, whereas in the transposition the penis lies above the scrotum. PMID- 30446780 TI - [The German Mesothelioma Register : Current pathological diagnostics and services]. AB - BACKGROUND: In Germany, asbestos-related diseases (asbestosis, lung cancer, mesothelioma) are recognised and compensated occupational diseases. The histologic diagnosis of mesothelioma is sometimes a challenge; additional immunohistochemical and molecular methods are needed. With lung dust analysis, the current asbestos fibre burden of the lung is measured (biomonitoring). Identification of grade I asbestosis (minimal asbestosis) requires directed histological examinations with up to 400-fold magnification, additional iron staining and possibly in connection with a lung dust analysis. OBJECTIVES: Demonstration of current pathologic diagnostics in association with mesothelioma and lung dust analysis. MATERIALS AND METHODS: Analysis of routine data from the German Mesothelioma Register. RESULTS: Contrary to reactive mesothelial hyperplasia, malignant mesotheliomas have a nuclear BAP1 loss-of-expression in up to 66% of cases. For differential diagnosis between reactive versus malignant, a p16-FISH test may be helpful. BAP1 loss-of-expression and p16-deletion are independent markers. Evaluation of the dataset of the German Mesothelioma Register of patients with repeated tissue sampling proves the detection of asbestos fibres at the same level even after 40 years. The asbestos fibre burden in the human lung remains stable over this long period of time. In the electron microscopic analysis, white asbestos was predominantly found. CONCLUSIONS: The well-known and industrially appreciated characteristics of asbestos fibres (in ancient ?sigmabetaepsilonsigmatauomicronsigma asbestos "imperishable") as biopersistent have also been experimentally confirmed in human lungs. PMID- 30446781 TI - [Partial gland ablation with vascular-targeted phototherapy versus active surveillance for low-risk prostate cancer : Results of a randomized trial]. PMID- 30446782 TI - Comparison Between Two Submerged Macrophytes as Biomonitors of Trace Elements Related to Anthropogenic Activities in the Ctalamochita River, Argentina. AB - The temporal variation of As, Co, Cr, Cu, Fe, Mn, Ni, Pb, V and Zn in surface waters and sediments, and trace element accumulation and physiological changes in the macrophytes Stuckenia filiformis and Potamogeton pusillus, were estimated in the Ctalamochita River, Argentina, both upstream and downstream of Rio Tercero. Chromium, Fe, Pb and Zn in surface water were higher at the downstream site, while Cu and Mn were higher upstream. Chromium, Mn and Zn in S. filiformis correlated with concentrations observed in sediments, whereas only Zn did in water. In P. pusillus, As, Co, Cr, Ni, Pb and Zn correlated with concentrations in sediments. P. pusillus revealed greater variations in the photosynthetic pigments and malondialdehyde content in the site downstream of the city than those observed in S. filiformis. Therefore, P. pusillus has a greater potential use in monitoring studies in aquatic environments with ecological risk than S. filiformis. PMID- 30446783 TI - The 6-m timed hop test is a prognostic factor for outcomes in patients with meniscal tears treated with exercise therapy or arthroscopic partial meniscectomy: a secondary, exploratory analysis of the Odense-Oslo meniscectomy versus exercise (OMEX) trial. AB - PURPOSE: To identify the prognostic factors for 2-year patient-reported outcomes in middle-aged patients with degenerative meniscal tears treated with exercise therapy (ET) or arthroscopic partial meniscectomy (APM). METHODS: One hundred and seven patients, with mean age 49.6 (SD 6.2) years and BMI 25.7 (SD 3.7), were included in this analysis of data from the OMEX trial ( http://www.clinicaltrials.gov NCT01002794). Linear and Poisson regression models were built to explore the associations between potential prognostic factors (patient characteristics, knee function-related and disease-related factors) and 2-year patient-reported outcomes: the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales Pain, Symptoms, ADL, Sport/Rec, QoL and 5-point Global Rating of Change scales for knee pain (GRC Pain) and function (GRC Function). Analyses were performed for the whole cohort and for the two treatment groups (n = 55 and 52) with adjustments for age, sex, BMI and baseline KOOS. RESULTS: For the whole cohort, a 1-s better baseline 6-m timed hop test result was associated with 3.1-7.1 points better 2-year scores for all KOOS subscales (95% CIs 1.1-5.2 to 4.1-10.1 points). A 1.61-2.80 s better test was associated with scores equivalent to previously calculated clinical relevant differences for each KOOS subscale. For the groups of patients treated with ET and APM, respectively, 2.09 3.60 s and 0.63-1.99 s better tests were associated with clinical relevant differences. For the whole cohort, a 1-s better test was associated with 26% (95% CI 15-38%) and 22% (95% CI 11-34%) higher possibility for better or much better GRC Pain and Function scores. Patients treated with ET had 17% (95% CI 2-33%) increased possibility for better or much better GRC Pain score, and patients treated with APM had 65% (95% CI 32-108%) and 70% (95% CI 38-109%) increased possibility for better or much better GRC Pain and Function scores. CONCLUSIONS: The 6-m timed hop test result was a significant prognostic factor for 2-year patient-reported outcomes in middle-aged patients with degenerative meniscal tears, especially in those treated with APM. LEVEL OF EVIDENCE: II. PMID- 30446784 TI - Lower patient-reported function at 2 years is associated with elevated knee cartilage T1rho and T2 relaxation times at 5 years in young athletes after ACL reconstruction. AB - PURPOSE: The purpose was to test the following hypotheses: (1) magnetic resonance imaging (MRI) markers of early knee cartilage degeneration would be present in the involved limb of young athletes after anterior cruciate ligament reconstruction (ACLR) and (2) poor knee function would be associated with MRI markers of cartilage degeneration. METHODS: Twenty-five young athletes after primary, unilateral ACLR (mean age, 16.7 years) were followed to 5-year post return-to-sport (RTS) clearance, as a part of a larger, prospective cohort study in young athletes post-ACLR. At 2-year post-RTS, patient-reported knee function was evaluated using the Knee injury and Osteoarthritis Outcome Score (KOOS). At 5 year post-RTS, qualitative MRI sequences (3 T) and quantitative T1rho and T2 maps segmented into six regions at the femur and tibia were performed for the involved and uninvolved knee cartilages. Relaxation times were compared between knees using Holm-corrected paired t tests. Linear regression was used to examine the association between KOOS scores at 2 years and relaxation times at 5 years. RESULTS: Elevated T1rho and T2 relaxation times were observed in the involved knee at the anterior medial femoral condyle compared to the uninvolved knee (p = 0.006, p = 0.024, respectively). Lower KOOS-Pain, KOOS-Symptoms, KOOS-ADL, and KOOS-Sport scores at 2-year post-RTS were associated with higher T1rho or T2 relaxation times in various regions of the involved knee at 5-year post-RTS (all p < 0.05). CONCLUSIONS: MRI markers of early cartilage degeneration were identified in the medial compartment of the involved knee in young athletes 5 year post-RTS after ACLR. Lower KOOS scores at 2-year post-RTS were associated with elevated knee cartilage T1rho and T2 relaxation times at 5-year post-RTS. Evaluating patient-reported function over time after ACLR appears to provide insight into future degenerative changes in the knee cartilage matrix. PMID- 30446785 TI - A phase I study of single-agent BEZ235 special delivery system sachet in Japanese patients with advanced solid tumors. AB - PURPOSE: BEZ235 is a dual kinase inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin, which are key components of the PI3K pathway. This was an open-label, multicenter, dose-escalation, phase I study of single-agent BEZ235 in Japanese oncology patients to determine the maximum tolerated dose (MTD) of BEZ235 based on dose-limiting toxicities (DLTs). METHODS: Dose escalation was guided by a standard 3 + 3 method and was based on DLTs observed in Cycle 1 and other safety, pharmacokinetic, and pharmacodynamic information. A total of 35 adult Japanese patients with advanced solid tumors received BEZ235 according to once daily (qd; n = 27) or twice daily (bid; n = 8) dosing schedules. RESULTS: Two DLTs, namely, allergic reaction and thrombocytopenia, were observed at 1200 and 1400 mg qd, respectively, while liver dysfunction was reported as a DLT at 400 mg bid. The most common adverse events suspected to be related to BEZ235 in both dosing schedules were diarrhea, nausea, decreased appetite, stomatitis, and thrombocytopenia. CONCLUSIONS: Although the MTD was not established, the maximum clinically tolerable dose was determined to be 1200 mg because two out of six patients required dose reduction in Cycle 2. The recommended dose was determined to be 1000 mg qd, which was comparable with the results of the first-in-human BEZ235 study in Western patients with advanced solid tumors (NCT00620594). Additionally, the tolerability of BEZ235 400 mg bid in Japanese oncology patients was confirmed in this study. CLINICALTRIALS. GOV IDENTIFIER: NCT01195376. PMID- 30446786 TI - Population pharmacokinetics of FOLFIRINOX: a review of studies and parameters. AB - PURPOSE: FOLFIRINOX regimen is commonly used in colorectal and more recently pancreatic cancer. However, FOLFIRINOX induces significant and dose-limiting toxic effects leading to empirical dose reduction and sometimes treatment discontinuation. Model-based FOLFIRINOX regimen optimization might help improving patients' outcome. As a first step, the current review aims at bringing together all published population pharmacokinetics models for FOLFIRINOX anticancer drugs. METHODS: A literature search was conducted in the PubMed database from inception to February 2018, using the following terms: population pharmacokinetic(s), irinotecan, oxaliplatin, fluorouracil, FOLFIRI, FOLFOX, FOLFIRINOX. Only articles displaying nonlinear mixed effect models were included. Study description, pharmacokinetic parameter values and influential covariates are reported. For each model, the typical pharmacokinetic profile was simulated for the standard FOLFIRINOX protocol. RESULTS: The FOLFIRINOX compounds have been studied only separately so far. A total of six articles were retained for 5-fluorouracil, 6 for oxaliplatin and 5 for irinotecan (also including metabolites). Either one- or two-compartment models have been described for 5-fluorouracil, while two- or three-compartment models were reported for oxaliplatin and irinotecan pharmacokinetics. Non-linear elimination was sometimes reported for 5 fluorouracil. Sex and body size were found as influential covariates for all molecules in some publications. Despite some differences in model structures and parameter values, the simulated profiles and subsequent exposure were consistent between studies. CONCLUSIONS: The current review allows for a global understanding of FOLFIRINOX pharmacokinetics, and will provide a basis for further development of pharmacokinetics-pharmacodynamics-toxicity models for model-driven FOLFIRINOX protocol optimization to reach the best benefit-to-risk ratio. PMID- 30446787 TI - Hymenobacter pomorum sp. nov., Isolated from Apple Orchard Soil. AB - A Gram-stain-negative, non-motile, rod-shaped bacterial strain, designated 9-2-1 1T, was isolated from apple orchard soil in Daegu, Republic of Korea. Comparative 16S rRNA gene sequence analysis showed that the isolate belongs to the family Cytophagaceae, Bacteroidetes and it is most closely related to Hymenobacter metalli A2-91T (97.8% similarity) and Hymenobacter marinus KJ035T (96.6%). Growth of strain 9-2-1-1T was observed at 4-30 degrees C, pH 6-8, and in the presence of 0-1.0% NaCl. The G+C content of the genomic DNA was 62.0 mol%. The predominant respiratory quinone of the isolate was MK-7; the major fatty acids were C15:0 iso (29.3%), C16:1 omega5c (15.4%), C15:0 anteiso (12.5%), summed feature 3 (C16:1 omega7c/C16:1 omega6c; 12.3%), and C16:0 (10.6%); and the major polar lipid was phosphatidylethanolamine. The phenotypic and chemotaxonomic data supported the affiliation of strain 9-2-1-1T with the genus Hymenobacter. However, the DNA-DNA relatedness between the isolate and H. metalli and H. marinus were 31.3% and 24.7%, respectively. The DNA-DNA hybridization result and the differentiating phenotypic properties clearly indicate that strain 9-2-1-1T is the representative of a novel species in the genus Hymenobacter, for which the name Hymenobacter pomorum sp. nov. is proposed. The type strain is 9-2-1-1T (=KCTC 52740T = JCM 32193T). PMID- 30446788 TI - Shoulder manipulation under targeted ultrasound-guided rotator interval block for adhesive capsulitis. AB - OBJECTIVE: To describe and evaluate the outcome following shoulder manipulation under rotator interval block for the treatment of adhesive capsulitis. MATERIALS AND METHODS: Patients with adhesive capsulitis referred by our local orthopaedic shoulder surgeons consented to targeted ultrasound-guided injection of the glenohumeral joint via the rotator interval. Inclusion criteria included a failure to respond to conservative treatment and the absence of a full-thickness rotator cuff tear. Twelve millilitres of a mixture of local anaesthetic and steroid was injected into the rotator interval using a 21-gauge needle, with a small volume of the same solution instilled into the subacromial bursa. Following injection, under local anaesthetic block, patients were gently manipulated into abduction, external rotation and internal rotation as far as they could comfortably tolerate. Patients were assessed pre-injection with documented pain scores from 0 to 10 on a visual analogue scale (VAS) and the Oxford Shoulder Score (OSS) questionnaire. Initial follow-up comprised a VAS pain score at 1 h, 24 h and 2 weeks. Clinical review by the referring orthopaedic surgeon was performed at 2 months post-injection. Long-term follow-up involved a VAS pain score and the OSS questionnaire at 5 months. RESULTS: Forty patients were suitable for inclusion in the study. Twenty-three were female (57.5%) and 17 were male. The mean age was 52 years (range, 31-73 years). Twelve patients were post operative. The duration of symptoms ranged from 3 months to 18 months. Mean pre procedure OSS was recorded as 23.3 (range, 4-36). The mean VAS pain score was 7.7 before the procedure (range, 4 - 10), 3.4 at 1 h (range, 0-8), 2.9 at 24 h (range, 0-8), and 1.8 at 2 weeks (range 1-4). Orthopaedic follow-up at an average of 66 days post-injection was recorded in 18 patients. All patients reported initial improvement of their shoulder pain and return to near full range of movement; however, recurrence of adhesive capsulitis symptoms was recorded in 5 patients. One case of rupture of the long head of the biceps tendon was reported, but the patient remained asymptomatic. Long-term follow-up at 5 months was obtained in 31 patients, with a mean OSS of 42 (range, 21-60) and VAS of 2.3 (range, 0-7). CONCLUSION: Manipulation under general anaesthesia is a well recognised treatment for adhesive capsulitis. We report that targeted ultrasound guided injection of the rotator interval and manipulation of the shoulder under local anaesthetic blockade result in good outcomes in reducing shoulder pain and symptoms of adhesive capsulitis with low recurrence and complication rates. PMID- 30446789 TI - [Self-help groups and patient participation: current results and projects in the Belgian region of Flanders]. AB - In 2018, around 1500 self-help groups existed in the Belgian region of Flanders, dealing with almost 200 different diseases or problems. Most have existed for 25 to 35 years, with new initiatives added annually. The first part of this article describes the development of self-help groups and patient participation in Flanders. The second part discusses the legal framework for the participation of patient associations at the micro-, meso-, and macrolevel. The third section describes two current practical examples of patient participation in the health system: the "self-help-friendly hospital" and "the integration of experts by experience in hospitals" with initial interim results. Finally, we discuss development and growth opportunities, as well as needs of self-help groups and patient associations and their support agencies and umbrella associations. More support for self-help groups and increased recognition of their achievements can promote structural forms of cooperation with the professional health system and boost patient participation. PMID- 30446790 TI - Expression of seven carbonic anhydrases in red alga Gracilariopsis chorda and their subcellular localization in a heterologous system, Arabidopsis thaliana. AB - KEY MESSAGE: Red alga, Gracilariopsis chorda, contains seven carbonic anhydrases that can be grouped into alpha-, beta- and gamma-classes. Carbonic anhydrases (CAHs) are metalloenzymes that catalyze the reversible hydration of CO2. These enzymes are present in all living organisms and play roles in various cellular processes, including photosynthesis. In this study, we identified seven CAH genes (GcCAHs) from the genome sequence of the red alga Gracilariopsis chorda and characterized them at the molecular, cellular and biochemical levels. Based on sequence analysis, these seven isoforms were categorized into four alpha-class, one beta-class, and two gamma-class isoforms. RNA sequencing revealed that of the seven CAHs isoforms, six genes were expressed in G. chorda in light at room temperature. In silico analysis revealed that these seven isoforms localized to multiple subcellular locations such as the ER, mitochondria and cytosol. When expressed as green fluorescent protein fusions in protoplasts of Arabidopsis thaliana leaf cells, these seven isoforms showed multiple localization patterns. The four alpha-class GcCAHs with an N-terminal hydrophobic leader sequence localized to the ER and two of them were further targeted to the vacuole. GcCAHbeta1 with no noticeable signal sequence localized to the cytosol. The two gamma-class GcCAHs also localized to the cytosol, despite the presence of a predicted presequence. Based on these results, we propose that the red alga G. chorda also employs multiple CAH isoforms for various cellular processes such as photosynthesis. PMID- 30446792 TI - Val M. Runge, Wolfgang R. Nitz, Johannes T. Heverhagen: the physics of clinical MR taught through images : Thieme, New York Stuttgart Delhi Rio de Janeiro, 2018, 318 p., format 15 * 23 * 1.5 cm, ISBN 978-1-62623-427-7, eISBN 978-1-62623-428-4. PMID- 30446793 TI - Prospects of pan-genomics in barley. AB - The concept of a pan-genome refers to intraspecific diversity in genome content and structure, encompassing both genes and intergenic space. Pan-genomic studies employ a combination of de novo sequence assembly and reference-based alignment to discover and genotype structural variants. The large size and complex structure of Triticeae genomes were for a long time an obstacle for genomic research in barley and its relatives. Now that a reference genome is available, computational pipelines for high-quality sequence assembly are in place, and sequence costs continue to drop, investigations into the structural diversity of the barley genome seem within reach. Here, we review the recent progress on pan genomics in the model grass Brachypodium distachyon, and the cereal crops rice and maize, and devise a multi-tiered strategy for a pan-genome project in barley. Our design involves: (1) the construction of high-quality de novo sequence assemblies for a small core set of representative genotypes, (2) short-read sequencing of a large diversity panel of genebank accessions to medium coverage and (3) the use of complementary methods such as chromosome-conformation capture sequencing and k-mer-based association genetics. The in silico representation of the barley pan-genome may inform about the mechanisms of structural genome evolution in the Triticeae and supplement quantitative genetics models of crop performance for better accuracy and predictive ability. PMID- 30446791 TI - Perspective: cancer vaccines in the era of immune checkpoint blockade. AB - Current excitement about cancer immunotherapy is the result of unprecedented clinical impact from immune checkpoint inhibitors, particularly those that target programmed death (PD)-1 and PD-ligand (L)-1. Numerous other immunotherapeutics are also finding their way into the clinic either alone or in combination, and these have potential applications in many cancer types. Therapeutic cancer vaccines have been a major focus for many pioneers in the field yet have largely failed to live up to expectations as game-changing immunotherapeutics. This, despite decades of focussed efforts that have identified antigens, optimised adjuvants and refined approaches to pre-clinical modelling and clinical monitoring. If antigen-directed immunotherapeutics are to take a place in the anti-cancer therapeutic armamentarium, it will be crucial to understand the potential niche that could be occupied by cancer vaccines that can specifically induce or modify immune response against cancer antigens. PMID- 30446794 TI - An evolutionarily conserved non-synonymous SNP in a leucine-rich repeat domain determines anthracnose resistance in watermelon. AB - KEY MESSAGE: A non-synonymous SNP of CC-NBS-LRR was firstly mapped to confer resistance to anthracnose in watermelon. Newly proposed LRR domain harboring the SNP is evolutionary conserved in the Cucurbitaceae and Fabaceae. Anthracnose disease caused by Colletotrichum devastates many plants. Despite the importance of the disease, the mechanisms of resistance against it are poorly understood. Here, we identified a non-synonymous single-nucleotide polymorphism (SNP) located in a leucine-rich repeat domain as a marker for resistance to anthracnose race 1 in watermelon, using a combination of genetic analyses. We validated this SNP in segregating populations and 59 watermelon accessions using high-resolution melting assays and Sanger sequencing. We demonstrated that the resulting arginine to-lysine substitution is particularly conserved among the Cucurbitaceae and Fabaceae. We identified a conserved motif, IxxLPxSxxxLYNLQTLxL, found in 1007 orthologues/paralogues from 89 plant species, and discovered that residue 18 of this motif could determine resistance to disease caused by external invaders. This study provides a step forward in understanding anthracnose resistance in watermelon, as well as functional and evolutionary insight into leucine-rich repeat proteins. PMID- 30446795 TI - Genetic architecture of wheat stripe rust resistance revealed by combining QTL mapping using SNP-based genetic maps and bulked segregant analysis. AB - KEY MESSAGE: A major stripe rust resistance QTL was mapped to a 0.4 centimorgan (cM) genetic region on the long arm of chromosome 7B, using combined genome-wide linkage mapping and bulk segregant analysis. The German winter wheat cv. Centrum has displayed high levels of adult plant stripe rust resistance (APR) in field environments for many years. Here, we used the combined genome-wide linkage mapping and pool-extreme genotyping to characterize the APR resistance. One hundred and fifty-one F2:7 recombinant inbred lines derived from a cross between susceptible landrace Mingxian 169 and Centrum were evaluated for stripe rust resistance in multiple environments and genotyped by the wheat 35K single nucleotide polymorphism (SNP) array. Three stable quantitative trait loci (QTL) were identified using QTL analysis across five field environments. To saturate the major QTL, the wheat 660K SNP array was also used to genotype bulked extremes. A major QTL named QYrcen.nwafu-7BL from Centrum was mapped in a 0.4 cM genetic interval flanking by AX-94556751 and AX-110366788 across a 2 Mb physical genomic region, explaining 19.39-42.81% of the total phenotypic variation. It is likely a previously uncharacterized QTL based on pedigree analysis, reaction response, genotyping data and map comparison. The SNP markers closely linked with QYrcen.nwafu-7BL were converted to KASP markers and validated in a subset of 120 wheat lines. A 211 F2 breeding population from a cross of an elite cultivar Xinong 979 with Centrum were developed for marker-based selection. Three selected lines with desirable agronomic traits and the positive alleles of both KASP markers showed acceptable resistance which should be used as resistance donors in wheat breeding programs. The other QTL QYrcen.nwafu-1AL and QYrcen.nwafu-4AL with additive effects could enhance the level of resistance conferred by QYrcen.nwafu 7BL. PMID- 30446796 TI - Different loci associated with root and foliar resistance to sudden death syndrome (Fusarium virguliforme) in soybean. AB - KEY MESSAGE: Different loci associated with root resistance to F. virguliforme colonization and foliar resistance to phytotoxin damage in soybean. Use of resistant cultivars is the most efficacious approach to manage soybean sudden death syndrome (SDS), caused by Fusarium virguliforme. The objectives of this study were to (1) map the loci associated with root and foliar resistance to F. virguliforme infection and (2) decipher the relationships between root infection, foliar damage, and plot yield. A mapping population consisting of 153 F4-derived recombinant inbred lines from the cross U01-390489 * E07080 was genotyped by SoySNP6 K BeadChip assay. Both foliar damage and F. virguliforme colonization in roots were investigated in the field, and a weak positive correlation was identified between them. Foliar damage had a stronger negative correlation with plot yield than F. virguliforme colonization. Twelve loci associated with foliar damage were identified, and four of them were associated with multiple traits across environments. In contrast, only one locus associated with root resistance to F. virguliforme colonization was identified and mapped on Chromosome 18. It colocalized with the locus associated with foliar damage in the same environment. The locus on Chromosome 6, qSDS6-2, and the locus on Chromosome 18, qSDS18-1, were associated with resistance to SDS phytotoxins and resistance to F. virguliforme colonization of roots, respectively. Both loci affected plot yield. Foliar damage-related traits, especially disease index, are valuable indicators for SDS resistance breeding because of consistency of the identified loci and their stronger correlation with plot yield. The information provided by this study will facilitate marker-assisted selection to improve SDS resistance in soybean. PMID- 30446798 TI - Hemoadsorption with CytoSorb(r). PMID- 30446797 TI - Professional burnout among physicians and nurses in Asian intensive care units: a multinational survey. AB - PURPOSE: Professional burnout is a multidimensional syndrome comprising emotional exhaustion, depersonalization, and diminished sense of personal accomplishment, and is associated with poor staff health and decreased quality of medical care. We investigated burnout prevalence and its associated risk factors among Asian intensive care unit (ICU) physicians and nurses. METHODS: We conducted a cross sectional survey of 159 ICUs in 16 Asian countries and regions. The main outcome measure was burnout as assessed by the Maslach Burnout Inventory-Human Services Survey. Multivariate random effects logistic regression analyses of predictors for physician and nurse burnout were performed. RESULTS: A total of 992 ICU physicians (response rate 76.5%) and 3100 ICU nurses (response rate 63.3%) were studied. Both physicians and nurses had high levels of burnout (50.3% versus 52.0%, P = 0.362). Among countries or regions, burnout rates ranged from 34.6 to 61.5%. Among physicians, religiosity (i.e. having a religious background or belief), years of working in the current department, shift work (versus no shift work) and number of stay-home night calls had a protective effect (negative association) against burnout, while work days per month had a harmful effect (positive association). Among nurses, religiosity and better work-life balance had a protective effect against burnout, while having a bachelor's degree (compared to having a non-degree qualification) had a harmful effect. CONCLUSIONS: A large proportion of Asian ICU physicians and nurses experience professional burnout. Our study results suggest that individual-level interventions could include religious/spiritual practice, and organizational level interventions could include employing shift-based coverage, stay-home night calls, and regulating the number of work days per month. PMID- 30446800 TI - Active reviewers (from October 1, 2017 through September 30, 2018). PMID- 30446799 TI - Evaluating the cost of surveillance for non-muscle-invasive bladder cancer: an analysis based on risk categories. AB - INTRODUCTION: Non-muscle-invasive bladder cancer (NMIBC) is a biologically heterogeneous disease and is one of the most expensive malignancies to treat on a per patient basis. In part, this high cost is attributed to the need for long term surveillance. We sought to perform an economic analysis of surveillance strategies to elucidate cumulative costs for the management of NMIBC. METHODS: A Markov model was constructed to determine the average 5-year costs for the surveillance of patients with NMIBC. Patients were stratified into low, intermediate, and high-risk groups based on the EORTC risk calculator to determine recurrence and progression rates according to each category. The index patient was a compliant 65-year-old male. A total of four health states were utilized in the Markov model: no evidence of disease, recurrence, progression and cystectomy, and death. RESULTS: Cumulative costs of care over a 5-year period were $52,125 for low-risk, $146,250 for intermediate-risk, and $366,143 for high risk NMIBC. The primary driver of cost was progression to muscle-invasive disease requiring definitive therapy, contributing to 81% and 92% of overall cost for intermediate- and high-risk disease. Although low-risk tumors have a high likelihood of 5-year recurrence, the overall cost contribution of recurrence was 8%, whereas disease progression accounted for 71%. CONCLUSION: Although protracted surveillance cystoscopy contributes to the expenditures associated with NMIBC, progression increases the overall cost of care across all three patient risk groups and most notably for intermediate- and high-risk disease patients. PMID- 30446803 TI - The impact of chronic myeloid leukemia on employment: the French prospective study. AB - Patients with chronic myeloid leukemia treated with breakpoint cluster region Abelson tyrosine kinase inhibitors are likely to survive in excess of 20 years after diagnosis. New challenges appear as we consider life after the disease, including professional challenges and the social reintegration of patients. The purpose of this study was to determine the impact of chronic myeloid leukemia on employment within 2 years after diagnosis. This prospective, observational study included patients diagnosed with chronic myeloid leukemia and treated with a tyrosine kinase inhibitor. Two populations were defined as patients who reported modifications in their professional activity during the study (Acti-Pro+) and patients who did not report a modification (Acti-Pro-). Cancer survivors received a self-assessment questionnaire. The primary endpoint was to determine the professional status of patients. One hundred patients completed the questionnaire. Sixty-six patients out of 100 reported professional activity within 2 years after their diagnosis. During the 2 years after the diagnosis, 65.2% (95% confidence interval (CI), 53.7-76.7) of patients faced modifications in their professional activity due to chronic myeloid leukemia or adverse effects of drug treatments (group Acti-Pro+); in contrast, 34.8% of patients did not report any impact on their occupational activity (group Acti-Pro-). Among modifications to work organization, a change in the number of working hours was the most represented. Other modifications comprised changes in status or work pace. A majority of chronic myeloid leukemia patients face professional consequences of their disease and treatments. Our findings suggest that adverse drug reactions are a major factor affecting the occurrence of work modifications in this context. PMID- 30446802 TI - Safety and efficacy of bosutinib in fourth-line therapy of chronic myeloid leukemia patients. AB - Bosutinib is a second-generation tyrosine kinase inhibitor (2GTKI) approved at 400 mg once daily (QD) as first-line therapy in patients with chronic myeloid leukemia (CML) patients and at 500 mg QD in patients who are resistant to or intolerant of prior therapy. In clinical practice, bosutinib is often given to patients who have failed imatinib, nilotinib, and dasatinib (i.e., as fourth-line treatment), despite the limited data on its clinical benefit in this setting. We have retrospectively evaluated the results of bosutinib in a series of 62 CML patients who have failed to prior treatment with all three, imatinib, nilotinib, and dasatinib. Median time on TKI treatment before bosutinib start was 105 (9 163) months, and median duration on bosutinib was 9 months (1-30). Overall, probabilities to achieve complete cytogenetic response (CCyR) and major molecular response (MMR) were 25% and 24% respectively. After a median follow-up period of 14 months, the event-free survival and progression-free survival were 68 and 85%, respectively. Sixty-four percent of patients in CCyR at the time of bosutinib start were able to achieve MMR. In contrast, patients without CCyR, probabilities to obtain CCyR and MMR were 25% and 14%. Bosutinib was well tolerated in this heavily pretreated patients' cohort. Pleural effusions and diarrhea were the most frequent grade II-IV side effects, leading to treatment discontinuation in 16% of patients. Bosutinib is an effective treatment option for patients who have failed previous 2GTKIs due to intolerance. However, efficacy seems to be related to the molecular response that the patient achieved prior to bosutinib. PMID- 30446804 TI - Platelet aggregation response in immune thrombocytopenia patients treated with romiplostim. AB - The thrombopoietin receptor agonist romiplostim is used for the long-term treatment of chronic immune thrombocytopenia (ITP). ITP patients have an increased thrombotic risk, which could be exacerbated if romiplostim increased platelet hyperreactivity or caused spontaneous platelet aggregation. To investigate this possibility, this study examined platelet function in romiplostim-treated ITP patients and healthy subjects. Light transmission platelet aggregometry utilizing arachidonic acid, collagen, epinephrine, ristocetin, ADP, and saline (to assess spontaneous aggregation) was performed for each subject. In addition, the ADP AC50 (ADP concentration that induced half maximal aggregation) was determined for each patient as a sensitive measurement of altered platelet reactivity. Fifteen ITP patients and 7 healthy subjects entered the study. All ITP patients had active disease and were receiving weekly romiplostim as the sole ITP-directed therapy. Platelet aggregation in response to the strong agonists arachidonic acid, collagen, and ristocetin was not significantly different between ITP patients and healthy subjects (P = 0.2442, P = 0.0548, and P = 0.0879, respectively). Platelet aggregation in response to weak agonists was significantly reduced in ITP patients compared with that in healthy subjects: median (range) aggregation to ADP, 45% (15-84%) versus 89% (70-95%) (P = 0.0010), and epinephrine, 21% (1.6-90%) versus 88% (79-94%) (P = 0.0085). The median AC50 of ADP was threefold higher in ITP patients versus that in healthy subjects (6.3 MUM vs 2.1 MUM) (P = 0.0049). Significant spontaneous aggregation was not observed in any patient. Platelets from romiplostim-treated ITP patients do not show evidence for spontaneous aggregation or hyperreactivity, but instead have a modestly reduced aggregation response to ADP and epinephrine. PMID- 30446805 TI - Panel-based next-generation sequencing identifies prognostic and actionable genes in childhood acute lymphoblastic leukemia and is suitable for clinical sequencing. AB - Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although the cure rate of ALL has greatly improved, a considerable number of patients suffer from relapse of leukemia. Therefore, ALL remains the leading cause of death from cancer during childhood. To improve the cure rate of these patients, precisely detecting patients with high risk of relapse and incorporating new targeted therapies are urgently needed. This study investigated inexpensive, rapid, next-generation sequencing of more than 150 cancer-related genes for matched diagnostic, remission, and relapse samples of 17 patients (3 months to 15 years old) with relapsed ALL. In this analysis, we identified 16 single-nucleotide variants (SNVs) and insertion/deletion variants and 19 copy number variants (CNVs) at diagnosis and 28 SNVs and insertion/deletion variants and 22 CNVs at relapse. With these genetic alterations, we could detect several B cell precursor ALL patients with high-risk gene alterations who were not stratified into the highest-risk group (5/8, 62.5%). We also detected potentially actionable genetic variants in about half of the patients (8/17, 47.1%). Among them, we found that one patient harbored germline TP53 mutation as a secondary finding. This inexpensive, rapid method can be immediately applied as clinical sequencing and could lead to better management of these patients and potential improvement in the survival rate in childhood ALL. PMID- 30446806 TI - Calcium-sensing receptor: evidence and hypothesis for its role in nephrolithiasis. AB - Calcium-sensing receptor (CaSR) is a plasma-membrane G protein-coupled receptor activated by extracellular calcium and expressed in kidney tubular cells. It inhibits calcium reabsorption in the ascending limb and distal convoluted tubule when stimulated by the increase of serum calcium levels; therefore, these tubular segments are enabled by CaSR to play a substantial role in the regulation of serum calcium levels. In addition, CaSR increases water and proton excretion in the collecting duct and promotes phosphate reabsorption and citrate excretion in the proximal tubule. These CaSR activities form a network in which they are integrated to protect the kidney against the negative effects of high calcium concentrations and calcium precipitates in urine. Therefore, the CaSR gene has been considered as a candidate to explain calcium nephrolithiasis. Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5' untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion. These findings suggest that CaSR may play a complex role in lithogenesis through different pathways having different relevance under different clinical conditions. PMID- 30446807 TI - [Transfer of a cockpit strategy to anesthesiology : Clinical example: introduction of canned decisions to solve cannot intubate cannot oxygenate situations]. AB - BACKGROUND: Safety strategies in civil aviation are well-established. The authors present a possible structure for induction of anesthesia, which includes elements of the so-called cockpit strategy. The objective is to reduce anesthesia-related mortality caused by the unexpected difficult airway through early detection and solution of cannot intubate cannot oxygenate (CICO) situations. METHODS: After approval by the responsible ethics committee, a prospective pilot study was conducted to analyze the process quality of uncomplicated induction of anesthesia on a simulator using audiovisual recording. An evaluation list with 44 items was created, which met the following requirements: items were dichotomous, accessible to an audiovisual evaluation and according to current scientific consensus should be considered during induction of anesthesia. Standard induction of anesthesia was supplemented by several crew resource management elements (cockpit strategy). Two canned decisions (CD, CD 1: end tidal CO2, etCO2 < 10 mm Hg, CD 2: SpO2 < 80%) signaled the emergency of an unexpected difficult airway and CICO with emergency coniotomy. This concept was repetitively trained and transferred to the daily routine. After 6 months the process quality was re-evaluated in simulated scenarios. In order to review whether the effect of the cockpit strategy with the CD can contribute to solving the CICO situation, all emergency coniotomies carried out in this clinic between 2010 and 2016 were retrospectively analyzed. RESULTS: The cockpit strategy significantly improved the process quality during the simulated induction of anesthesia (78% vs. 36% items fulfilled), while the duration of induction was reduced by 36%. In the subsequent 6-year study period, 7 CICO situations with emergency coniotomy occurred. All teams performed in accordance with the algorithm and with respect to the CDs. No patient suffered from hypoxia or any other damage. CONCLUSION: The transfer and implementation of a cockpit strategy in anesthesiology for improvement of patient safety is possible. The acceptance of the aviation safety strategy in medicine is a necessary prerequisite. A profound training in technical and non-technical skills and regular team training to solve CICO situations must be an integral part of advanced training in anesthesiology. PMID- 30446808 TI - [How many potential organ donors are there really? : Retrospective analysis of why determination of irreversible loss of brain function was not performed in deceased patients with relevant brain damage]. AB - BACKGROUND: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out. OBJECTIVE: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors. METHOD: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage. RESULTS: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed. CONCLUSION: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment. PMID- 30446809 TI - In focus in HCB. PMID- 30446810 TI - Comparison of the characteristics of mesenchymal stem-like cells derived by integration-free induced pluripotent stem cells in different single-cell culture media under feeder-free conditions. AB - Generating mesenchymal stem-like cells (MSLCs) from induced pluripotent stem cells (iPSCs) can be a practical method for obtaining the sufficient cells for autologous tissue engineering. Single-cell culturing in specific medium and non feeder cells is an alternative and promising strategy to overcome problems of embryo culture; however, little is known about how different culture media affect the proliferation and differentiation of MSLCs. We first derived MSLCs from iPSCs with non-integrating episomal plasmid vectors (hereafter 409B2 cells) using three different cell culture media, including single-cell culture medium in feeder-free condition: mTeSR1, DEF-CS500, or StemFit AK02N. The morphology of all MSLCs was completely altered to a fibroblastic morphology after four passages. Surface antigens CD29, CD44, CD73, CD90, but not CD34 and CD45, were expressed in all passages. RUNX2 was expressed in MSLCs cultured in all three feeder-free media, while SOX9 and PPARgamma were expressed in MSLCs cultured in only DEF-CS500. MSLCs derived from DEF-CS500, which is a single-cell culture medium, grew at a slightly faster rate than those cultured in other media and expressed early-stage genes for tri-lineage differentiation. Taken together, these findings provide valuable information for generating MSLCs using single-cell culture methods. PMID- 30446811 TI - The State Scientific Automated Medical Registry, Kazakhstan: an important resource for low-dose radiation health research. AB - Direct quantitative assessment of health risks following exposure to ionizing radiation is based on findings from epidemiological studies. Populations affected by nuclear bomb testing are among those that allow such assessment. The population living around the former Soviet Union's Semipalatinsk nuclear test site is one of the largest human cohorts exposed to radiation from nuclear weapons tests. Following research that started in the 1960s, a registry that contains information on more than 300,000 individuals residing in the areas neighboring to the test site was established. Four nuclear weapons tests, conducted from 1949 to 1956, resulted in non-negligible radiation exposures to the public, corresponding up to approximately 300 mGy external dose. The registry contains relevant information about those who lived at the time of the testing as well as about their offspring, including biological material. An international group of scientists worked together within the research project SEMI-NUC funded by the European Union, and concluded that the registry provides a novel, mostly unexplored, and valuable resource for the assessment of the population risks associated with environmental radiation exposure. Suggestions for future studies and pathways on how to use the best dose assessment strategies have also been described in the project. Moreover, the registry could be used for research on other relevant public health topics. PMID- 30446812 TI - How the activity of natural enemies changes the structure and metabolism of the nutritive tissue in galls? Evidence from the Palaeomystella oligophaga (Lepidoptera) -Macairea radula (Metastomataceae) system. AB - Insect-induced galls usually develop nutritional cells, which they induce and consume directly, and any metabolic modification of those cells may reflect changes of the insect's own metabolism. The system Palaeomystella oligophaga (Lepidoptera)-Macairea radula (Melastomataceae) presents a series of natural enemies, including parasitoids and cecidophages that can function as a natural experiment, respectively removing the specific galling feeding stimulus and providing a nonspecific one. Considering that the process of induction and maintenance of gall tissues strictly depends on the constant specific stimulus of galling, question I:What kind of metabolic changes these different groups of natural enemies can promote in chemical and structural composition of these galls? II: How the specialized tissues are metabolically dependent on the constant specific stimulus of galling in latter stages of gall development? Galls without natural enemies, with parasitoids or cecidophages in larvae or pupae stages were analyzed through histochemistry and cytological profiles and all compared to galls in natural senescence state. The analysis revealed the accumulation of proteins and lipids in typical nutritive tissue and starch in the storage tissue, as well a high integrity of cellular organelles and membrane systems on galls with gallings in the larval stage. Both parasitoids and cecidophages stop galling feeding activities, which resulted in the paralysis of the stimulus that maintain the metabolism of gall tissues, leading to generalized collapse. We demonstrate that the development and metabolic maintenance of a typical nutritive tissue in these galls are completely dependent on constant larval stimulus. PMID- 30446813 TI - Treatment-refractory Escherichia coli subdural empyema caused by infection of a chronic subdural hematoma in an infant. AB - INTRODUCTION: Subdural empyema (SDE) is a neurosurgical emergency that is typically treated with surgical drainage, either by burr hole or by craniotomy. Escherichia coli is an uncommon cause of SDE and is associated with infection of a pre-existing subdural hematoma. CASE REPORT: We report the case of an otherwise healthy, immunocompetent 4-month-old infant girl with an E. coli-infected subdural hematoma. The infection persisted despite aggressive neurosurgical treatment that included drainage of the subdural space through burr holes and, subsequently, a wide craniotomy was performed. Ultimately, after 30 days, the SDE resolved with good neurological outcome. A review of prior literature indicates that infected subdural hematomas (including those caused by E. coli) are typically less aggressive and respond to burr hole drainage. CONCLUSION: We illustrate the fulminant progression of the SDE in the face of neurosurgical treatment. Our experience suggests lowering the threshold for wide craniotomy in these incompletely understood cases. PMID- 30446814 TI - Quantitative characteristics of pubescence in wheat (Triticum aestivum L.) are associated with photosynthetic parameters under conditions of normal and limited water supply. AB - MAIN CONCLUSION: Density and length of leaf pubescence are important factors of diversity in the response to water deficiency among wheat genotypes. Many studies evidence an important protective value of leaf hairiness in plants, especially under the conditions of drought, thermal loads and increased solar radiation. However, the physiological and adaptive roles of such traits in cereals, including cultivated plants, have not been sufficiently studied to date. The aim of this work was to study the association of morphological characteristics of leaves with parameters of gas exchange and chlorophyll fluorescence in wheat lines carrying a genetically different leaf hairiness. Isogenic and inter varietal substitution wheat lines were used, carrying various combinations of dominant and recessive alleles of the known genes. A quantitative assessment of the pubescence was carried out in contrasting watering conditions to establish the physiological role of this trait in adaptation to drought. With the help of a portable system for studying the gas exchange and chlorophyll fluorescence, ten parameters of photosynthesis were studied, as well as morphological features of leaves and shoot biomass. It was found that gas exchange parameters are inversely proportional to the density and length of trichomes. In drought conditions, the trichome density increased and the length of trichomes decreased under the observed decrease in the level of gas exchange. A similar dependence was observed for the level of non-photochemical quenching of chlorophyll fluorescence. Under optimal conditions, the poorly haired cultivars exhibited a higher biomass than the densely haired. However, under water deficiency they significantly reduced the biomass and showed a low value of the tolerance index. PMID- 30446815 TI - Correction to: Casein kinase 2 alpha and beta subunits inversely modulate ABA signal output in Arabidopsis protoplasts. AB - The article Casein kinase 2 alpha and beta subunits inversely modulate ABA signal output in Arabidopsis protoplasts, written by Yukari Nagatoshi, Miki Fujita, and Yasunari Fujita, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 May 2018 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 19 November 2018 to (c) The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. PMID- 30446816 TI - Efficacy of Lactobacillus-supplemented triple therapy for Helicobacter pylori infection in children: a meta-analysis of randomized controlled trials. AB - Therapy-related side effects and severe antimicrobial resistance still remain an obstacle to Helicobacter pylori eradication. This meta-analysis aimed to investigate the efficacy of Lactobacillus-supplemented triple therapy on H. pylori eradication rates and therapy-related side effects in children. Five studies involving 484 pediatric patients were included in our analysis. The pooled relative risk (RR) for eradication rates in the Lactobacillus group versus the control group was 1.19 [95% confidence interval (CI) 1.07-1.33]. In subgroup analyses based on dose and duration of Lactobacillus supplementation, the pooled RRs for eradication rates were 1.36 (95% CI 1.15-1.60) in the high-dose group, 1.08 (95% CI 0.86-1.35) in the low-dose group, 1.24 (95% CI 1.06-1.46) in the long-term group, and 1.17 (95% CI 0.96-1.44) in the short-term group. With respect to side effects, Lactobacillus supplementation significantly reduced the incidence of diarrhea (RR = 0.30, 95% CI 0.10-0.85).Conclusions: Lactobacillus, as an adjunct to triple therapy, can increase H. pylori eradication rates as well as reduce the incidence of therapy-related diarrhea in children. And a higher dose and a longer duration of supplementation may conduce to the positive impact of Lactobacillus on H. pylori eradication. What is Known: * Probiotics supplemented triple therapy may be beneficial in improving H. pylori eradication rates and reducing therapy-related side effects in children. However, not all probiotics are beneficial to H. pylori eradication and the pooled outcomes based on different probiotics may be erroneously extrapolated to other ineffective strains. What is New: * Lactobacillus, as an adjunct to triple therapy, can increase H. pylori eradication rates as well as reduce the incidence of therapy related diarrhea in children. PMID- 30446817 TI - Analysis of 21 X-chromosome polymorphisms in urban and rural populations in Salta province (north-western Argentina). AB - Population genetic data for 21 X-chromosome markers (Alu insertions and STRs) are reported for two populations (rural and urban) in Salta province (north-western Argentina). New variants are described, confirming the complexity and variability of some markers in this set. Results reveal Salta populations harbor a high Native American component, despite their self-recognized European ancestry. Notwithstanding the high genetic similarity of both populations, the rural sample seems to have maintained a larger Amerindian legacy. Data further show these X linked markers, especially STRs, are highly informative in Salta populations and, therefore, can contribute to the development of a local database for forensic purposes in north-western Argentina. PMID- 30446818 TI - Outdoor microalgae cultivation in airlift photobioreactor at high irradiance and temperature conditions: effect of batch and fed-batch strategies, photoinhibition, and temperature stress. AB - The microalgae Scenedesmus abundans cultivated in five identical airlift photobioreactors (PBRs) in batch and fed-batch modes at the outdoor tropical condition. The microalgae strain S. abundans was found to tolerate high temperature (35-45 degrees C) and high light intensity (770-1690 umol m- 2 s- 1). The highest biomass productivities were 152.5-162.5 mg L- 1 day- 1 for fed batch strategy. The biomass productivity was drastically reduced due to photoinhibition effect at a culture temperature of > 45 degrees C. The lipid compositions showed fatty acids mainly in the form of saturated and monounsaturated fatty acids (> 80%) in all PBRs with Cetane number more than 51. The fed-batch strategies efficiently produced higher biomass and lipid productivities at harsh outdoor conditions. Furthermore, the microalgae also accumulated omega-3 fatty acid (C18:3) up to 14% (w/w) of total fatty acid at given outdoor condition. PMID- 30446819 TI - Genome-wide analysis reveals the evolution and structural features of WRINKLED1 in plants. AB - WRINKLED1 (WRI1), an AP2/ERE transcription factor, is one of the most important regulators of oil accumulation. It has been extensively studied in angiosperms, but its evolution and overview features in plants remain unknown. In this study, WRI1s, as well as WRI1-likes in non-WRI1 species, were investigated in 64 genome sequenced plants. Their origin, distribution, duplication, evolution, functional domains, motifs, properties, and cis-elements were analyzed. Results suggest that WRI1 and WRI1-like may originate from Chlorophyta, and WRI1-likes in angiosperms resemble phylogenetically and structurally WRI1s from Chlorophyta and non vascular plants. WRI1 or WRI1-like may be essential to vascular plants but not to non-vascular plants. Two YRG elements and two RAYD elements, as well as their phosphorylation sites and the 14-3-3 binding motif, are relatively conserved from Chlorophyta to angiosperm. The predicted DNA-binding domains are slightly shorter than the combination of one YRG element and one RAYD element. WRI1 gradually evolves from alkalinity to acidity. More motifs were developed in N-terminuses and C-terminuses in vascular plants. A short acidic amino-acid-enriched domain in the C-terminal region is predicted to be the putative transactivation domain. The VYL exon appears randomly in different WRI1 transcripts and it is not important for the function of WRI1. In addition, more cis-elements developed during WRI1 evolution may suggest its more complicated regulation and physiological functions. These results will assist future function studies of WRI1 and evolution studies of fatty acid biosynthesis regulation in plants. PMID- 30446820 TI - Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination. PMID- 30446821 TI - ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1-related tumors. PMID- 30446822 TI - Mindfulness-based cognitive therapy (MBCT) in patients with obsessive-compulsive disorder (OCD) and residual symptoms after cognitive behavioral therapy (CBT): a randomized controlled trial. AB - Up to one-third of individuals with obsessive-compulsive disorder (OCD) do not benefit from evidence-based psychotherapy. We examined the efficacy of mindfulness-based cognitive therapy (MBCT) as a complementary treatment option. In a prospective, bicentric, assessor-blinded, randomized, and actively controlled clinical trial, 125 patients with OCD and residual symptoms after cognitive behavioral therapy (CBT) were randomized to either an MBCT group (n = 61) or to a psychoeducational group (OCD-EP; n = 64) as an active control condition. At post-treatment, there was no significant benefit of MBCT over OCD EP with the Yale-Brown-Obsessive-Compulsive Scale (Y-BOCS) as the primary outcome measure, but with the Obsessive-Compulsive Inventory [OCI-R; F(1, 101) = 5.679, p = .036, effect size eta2partial = 0.053]. Moreover, the response rate and the improvement on secondary outcomes such as obsessive beliefs and quality of life was significantly larger in the MBCT group. Non-completion rates were below 10%. At the 6-month follow-up, OC symptoms were further improved in both groups; group differences were no longer significant. Our findings suggest that MBCT, compared to a psychoeducational program, leads to accelerated improvement of self-reported OC symptoms and secondary outcomes, but not of clinician-rated OC symptoms. In the midterm, both interventions yield similar and stable, but small improvements, suggesting that additional treatment options may be necessary. PMID- 30446823 TI - Maternal postnatal mental health and offspring symptoms of ADHD at 8-9 years: pathways via parenting behavior. AB - Exposure to maternal mental health problems during pregnancy and the first year of life has been associated with the development of ADHD. One pathway through which maternal mental health may influence children's outcomes is via its effects on parenting. This study aimed to investigate the mediating role of parenting behavior in the pathway between maternal postnatal distress and later symptoms of ADHD in the child. Biological mothers living with their children participating in the Longitudinal Study of Australian Children with data available from waves 1 (child age 3-12 months) and 5 (child age 8-9 years) were included in the current study (n = 3456). Postnatal distress was assessed by parent report at wave 1. Parenting warmth, hostility and consistency were assessed by parent report at wave 5. ADHD status at wave 5 was ascertained by parent report of the child having a diagnosis of ADHD/ADD or by elevated ADHD symptoms by both parent and teacher report. There was evidence of an indirect pathway from maternal postnatal distress to child ADHD at age 8-9 years via parenting hostility, but not through parenting warmth or consistency, even after accounting for concurrent maternal mental health. Our findings highlight the importance of early identification and intervention for maternal postnatal distress, as treatment may prevent mothers from developing hostile parenting practices and also disrupt the pathway to ADHD in their offspring. PMID- 30446824 TI - Early development of the feeding larva of the sea urchin Heliocidaris tuberculata: role of the small micromeres. AB - The two modes of development in sea urchins are direct development, in which the adult develops directly from the gastrula to the adult and does not feed, and indirect development, in which the adult develops indirectly through a feeding larva. In this account of the indirect, feeding larva of Heliocidaris tuberculata, the question raised is whether an evolutionary difference of unequal cell divisions contributes to the development of feeding structures in the indirect larva. In indirect development, the cell divisions at the fourth and fifth cell cycles of the zygote are unequal, with four small micromeres formed at the vegetal pole at the fifth cell division. In direct development, these cell divisions are not unequal. From their position at the head of the archenteron, the small micromeres are strategically located to contribute to the feeding tissues of the larva and the adult of H. tuberculata. PMID- 30446825 TI - Evaluating the psychometric properties of two-item and four-item short forms of the Japanese Pain Self-Efficacy Questionnaire: a cross-sectional study. AB - PURPOSE: The Pain Self-Efficacy Questionnaire is a valid measure assessing self efficacy in individuals with chronic pain. Short-form versions of the measure have been developed to decrease the assessment burden. However, few studies have evaluated the psychometric properties of the short forms in languages other than English. The aim of this study was to evaluate two 2-item short forms and one 4 item short form of the Japanese Pain Self-Efficacy Questionnaire in terms of internal consistency, criterion validity, structural validity, and construct validity. METHODS: This was a cross-sectional study. Data from 150 individuals with mixed chronic pain at a pain management center in a university hospital were extracted from clinical records and analyzed. The data included the information of the original version and short forms of the Japanese Pain Self-Efficacy Questionnaire, and other pain-related measures assessing pain intensity, pain interference, anxiety, depression and pain catastrophizing. RESULTS: Item statistics supported the item selection for each of the three short forms. All the short forms demonstrated adequate internal consistency and criterion validity. With respect to construct validity, one of the 2-item short forms failed to meet the criterion regarding the change in the magnitude of correlation with a depression scale. The 4-item short form met all the criteria including structural validity. CONCLUSION: The study findings provide evidence for the reliability and validity of 2- and 4-item versions of the Japanese Pain Self Efficacy Questionnaire for use in clinical and research settings. PMID- 30446826 TI - Three versus five lumbar paravertebral injections for inguinal hernia repair in the elderly: a randomized double-blind clinical trial. AB - PURPOSE: The objective of the study was to compare three nerve stimulator-guided paravertebral injections versus five injections for elderly patients undergoing inguinal hernia repair in terms of the amount of intraoperative fentanyl and propofol consumption and conversion to general anesthesia. The secondary objective was postoperative pain. METHODS: A prospective, randomized, double blind clinical trial was performed. 200 elderly patients undergoing unilateral herniorrhaphy were randomized into two groups. Group III received three PVB injections from T12 to L2 and placebo at T11 and L3. Group V received five PVB injections from T11 to L3. RESULTS: The mean intraoperative fentanyl and propofol consumption were significantly lower in group V (4.9 +/- 7.2 ug versus 20.0 +/- 12.9 ug and 5.7 +/- 11.6 mg versus 34.6 +/- 22.9 mg, respectively, p value < 0.0001). Five patients (5.0%) in group III had failed block and were converted to general anesthesia (p value = 0.024). Group V had significantly lower pain scores compared to group III during the first three postoperative days (p value < 0.0001). CONCLUSION: The five PVB injection technique is more suitable as a sole anesthetic technique for elderly patients undergoing herniorrhaphy, since it required less intraoperative supplemental analgesia and provided lower postoperative pain scores compared to the three PVB injection technique. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02537860. PMID- 30446827 TI - Emergence of a complex movement pattern in an unfamiliar food place by foraging ants. AB - Although visual cues are essential for navigation in ants, few studies address movement dynamics in ants when they search and forage after finding food in an unfamiliar environment. Here I introduced Japanese wood ants to an unfamiliar food location by capturing individuals leaving their nest. The food was located at the centre of a straight, narrow, open-top channel. Next, I determined the segment lengths of the foraging paths of the ants between consecutive U-turns. I found that individuals travelled along characteristic and complex paths if they detected a visual landmark. This movement property was not detectable when individuals foraged in the channel without any visual landmarks. These results reveal the movement dynamics of ants when they encounter food in a novel place. PMID- 30446828 TI - Different effects of allergic rhinitis on nasal mucosa remodeling in chronic rhinosinusitis with and without nasal polyps. AB - BACKGROUND: Allergic rhinitis (AR) has been reported to be associated with chronic rhinosinusitis (CRS). The objective of this study was to investigate the effect of AR on nasal mucosa remodeling in CRS. METHODS: Patients were enrolled and divided into the following groups: CRS with nasal polyps (NP) with allergic rhinitis (AR)(CRSwNPwAR; n = 20), CRS with NP without AR (CRSwNPsAR; n = 20), CRS without NP with AR (CRSsNPwAR; n = 20), CRS without NP without AR (CRSsNPsAR; n = 20), AR without CRS (AR; n = 20) and controls (n = 14). Eosinophil infiltration, mucus production, and collagen deposition were examined by hematoxylin and eosin, periodic acid schiff and masson's trichrome staining, respectively. VEGF-A and microvessel density were detected by immunohistochemistry. The expression of remodeling markers, including TGF-beta1, MMP-7, MMP-9 and TIMP-1 were measured by Western blot. RESULTS: The expression of remodeling factors, including VEGF-A, CD31, CD34 and TIMP-1 were significantly increased in CRSwAR compared to CRSsAR. Goblet cell hyperplasia, as well as VEGF-A, CD31, CD34, and MMP-9 expression were significantly higher in CRSwNPwAR compared to CRSwNPsAR. However, the expression of collagen fibers, MMP-7 and TGF-beta1 were significantly higher in CRSsNPwAR compared to CRSsNPsAR. CONCLUSIONS: AR could enhance the remodeling process in CRS. Moreover, AR had different effects on CRSwNP and CRSsNP. PMID- 30446829 TI - The ratio of 11beta-hydroxysteroid dehydrogenase 1/11beta-hydroxysteroid dehydrogenase 2 predicts glucocorticoid response in nasal polyps. AB - BACKGROUND: Glucocorticoids are the first-line medical treatment for chronic rhinosinusitis with nasal polyps (CRSwNP), whose local metabolism is catalyzed by 11beta-HSD1 and 11beta-HSD2. This study investigates the role of 11beta-HSD1 and 11beta-HSD2 on the glucocorticoid response of CRSwNP patients and the pathogenic mechanism of these polyps. METHODS: Forty-three adult CRSwNP patients were enrolled in this study. We evaluated the endoscopic scores by a nasal polyp grading system before and after treatment. We estimated the response to glucocorticoids by the total endoscopic scores. The logistic regression models and inflammatory characteristic curves were conducted to explore the prediction of the response to glucocorticoid in CRSwNP. The expression of 11beta-HSD1 and 11beta-HSD2 on human sinonasal epithelial cells (HSECS) was measured under the stimulation of toll-like receptor agonists and dexamethasone. RESULTS: The endoscopic scores in the CRSwNP group declined, the expression of 11beta HSD1/11beta-HSD2 increased (r = 0.5276, P = 0.0011), and the cutoff value of the ratio of 11beta-HSD1/11beta-HSD2 was 0.4654 (sensitivity 79.17%, specificity 88.89%). Dexamethasone induced a decrease in the ratio of 11beta-HSD1/11beta-HSD2 (P = 0.049) by the stimulation of PGN-BS. CONCLUSION: We found a strong correlation between the response to glucocorticoids and the ratio of 11beta HSD1/11beta-HSD2, which could be used as a marker in predicting the level of tissue response to glucocorticoid therapy in CRSwNP. In addition, PGN-BS could also be a therapeutic target, as it is the negative factor that will decrease the sensitivity of glucocorticoids by reducing the ratio of 11beta-HSD1/11beta-HSD2. PMID- 30446830 TI - Negative metacognitive beliefs predict sexual distress over and above pain in women with endometriosis. AB - The aim of the study was to assess the predictive value of dyspareunia, general chronic pain, and metacognitive beliefs to sexual distress in a sample of women with endometriosis. Ninety-six women (mean age = 34.60 +/- 6.44 years) with a diagnosis of endometriosis took part to this cross-sectional study. Sociodemographic and clinical data were collected by means of a structured ad hoc questionnaire. Metacognitive beliefs and sexual distress were assessed by means of the Metacognitions Questionnaire (MCQ30) and the Female Sexual Distress Scale R (FSDS-r). General chronic pain intensity was collected by means of a Numeric Rating Scale. Data were subjected to Hierarchical logistic regression. We found high percentages of dyspareunia and sexual distress (i.e., 66% and 76%). Findings suggested that dyspareunia and chronic pain did not predict sexual distress, while negative beliefs about worries predicted sexual distress over and above them (p = .040, odd ratio 1.159). In the target population, metacognitive beliefs may have more influence on sexual distress than pain symptomatology. PMID- 30446831 TI - Wet work exposure: comparison of observed and self-reported data. AB - PURPOSE: Wet work is the most important exposure leading to occupational hand eczema; however, the prevalence and character of wet work in various wet work professions remain not fully covered. Self-reported data are widely used in studies of wet work although the validity of these remains uncertain. The objective of the present study is to provide information on validity of self reported wet work exposure in different professions by comparing work place observations with self-reported data. METHODS: 114 workers from 15 various wet work professions were observed. The observations covered duration and frequency of wet work activities. The observed population as well as a non-observed population from each work place were given a questionnaire covering the same wet work activities. RESULTS: Correspondence analysis between self-reported and observed wet work showed that misclassification was larger regarding duration than frequency. 29.2% overestimated and 23.9% underestimated total wet work with more than 2 h/day. Professions with high wet work prevalence overestimated duration of wet work activities, but underestimated frequency. Females overestimated frequency, but not duration. The observed group (45%) significantly more often, than the non-observed group (32%), reported having more than 2 h of wet work/day (OR 2.8, 95% CI 1.6-4.9). Sensitivity and specificity of the questionnaire regarding total wet work in the observed population showed 51% sensitivity and 59% specificity. CONCLUSION: Over- and underestimation of wet work were found to be equally distributed. The correspondence analyses illustrate a noticeable misclassification between the estimations and the observations on all wet work variables, but largest for total wet work. PMID- 30446832 TI - Production of nanocalcite crystal by a urease producing halophilic strain of Staphylococcus saprophyticus and analysis of its properties by XRD and SEM. AB - Cementation of salt-containing soils can be achieved by salt-tolerant or halophilic calcite precipitation bacteria. Therefore, the isolation of calcite producing bacteria in the presence of salt is the first step in the microbial cementation of saline soils. Urease producing bacteria can cause calcite nano crystals to precipitate by producing urease in the presence of urea and calcium. The purpose of this study was to isolate urease producing halophilic bacteria in order to make calcite precipitate in saline soil. The calcite and the properties of the strains were further analyzed by X-ray diffraction (XRD) and scanning electron microscope equipped with an energy dispersive X-ray detector. In this study, a total of 110 halophilic strains were isolated, from which 58 isolates proved to have the ability of urease production. Four strains were identified to produce nano-calcite using urease activity in the precipitation medium. The XRD studies showed that the size of these particles was in the range of 40-60 nm. Strain H3 revealed that calcite is mostly produced in the precipitation medium containing 5% salt in comparison with other strains. This strain also produced calcite precipitates in the precipitation medium containing 15% salt. Phylogenetic analysis indicated that these isolates are about 99-100% similar to Staphylococcus saprophyticus. PMID- 30446833 TI - Fermentative hydrogen production from low-value substrates. AB - Hydrogen is a promising energy source that is believed to replace the conventional energy sources e.g. fossil fuels over years. Hydrogen production methods can be divided into conventional production methods which depend mainly on fossil fuels and alternative production methods including electrolysis of water, biophotolysis and fermentation hydrogen production from organic waste materials. Compared to the conventional methods, the alternative hydrogen production methods are less energy intensive and negative-value substrates i.e. waste materials can be used to produce hydrogen. Among the alternative methods, fermentation process including dark and photo-fermentation has gained more attention because these processes are simple, waste materials can be utilized, and high hydrogen yields can be achieved. The fermentation process is affected by several parameters such as type of inoculum, pH, temperature, substrate type and concentration, hydraulic retention time, etc. In order to achieve optimum hydrogen yields and maximum substrate degradation, the operating conditions of the fermentation process must be optimized. In this review, two routes for biohydrogen production as dark and photo-fermentation are discussed. Dark/photo fermentation technology is a new approach that can be used to increase the hydrogen yield and improve the energy recovery from organic wastes. PMID- 30446834 TI - Quick and accurate detection of Fusarium oxysporum f. sp. carthami in host tissue and soil using conventional and real-time PCR assay. AB - Safflower wilt, caused by Fusarium oxysporum f. sp. carthami (Foc) is a major limiting factor for safflower (Carthamus tinctorius) production worldwide. In India alone, about 40-80% disease incidence has been reported. A rapid, efficient, specific, and sensitive diagnostic technique for Foc is therefore crucial to manage Fusarium wilt of safflower. Twenty-five isolates of F. oxysporum formae speciales infecting other crops, 17 isolates of Fusarium spp. and seven isolates of other fungal pathogens of safflower along with 75 Foc isolates were used for identification of band specific to Foc using inter-simple sequence repeat (ISSR) analysis. Out of 70 ISSR primers, the one that specifically amplified a 490 bp fragment from all the Foc isolates was selected. Sequence of the amplified fragment was utilized to design sequence characterized amplified region (SCAR) primers (FocScF/FocScR). The primer pair unambiguously and exclusively amplified a DNA fragment of approximately 213 bp in all the 75 Foc isolates. The primer set was able to detect as low as 10 pg of Foc genomic DNA using conventional PCR, while the SCAR primers when coupled with real-time qPCR demonstrated detection limits of 1 pg for Foc genomic DNA and 1000 conidia/g for soil. The assay enabled reliable diagnosis of Foc DNA in contaminated safflower fields and expedited Foc detection at 72 h post inoculation in asymptomatic seedlings. This method facilitates quick and precise detection of Foc in plant and soil samples and can be exploited for timely surveillance and sustainable management of the disease. PMID- 30446835 TI - Is trabecular bone score less affected by degenerative-changes at the spine than lumbar spine BMD? AB - : It has been established that degenerative-changes at the spine elevate bone mineral density at the lumbar spine. This study in men reports that trabecular bone score may be less affected by spinal degenerative-changes. PURPOSE: A recent tool for assessing trabecular microarchitecture at the lumbar spine, trabecular bone score (TBS), provides information about bone health complementary to lumbar spine areal BMD (here referred to as BMD). In men, mean BMD increases with increasing age due to degenerative-changes at the spine including osteophytes and aortic calcification. The aim of this study was to investigate whether TBS is similarly affected by the presence of degenerative-changes in men. METHODS: This study included 728 men aged 40-90 years enrolled in the Geelong Osteoporosis Study. Lumbar spine DXA scans (Lunar Prodigy) were used to determine TBS retrospectively (TBS iNsight software, Version 2.2), and for identification of degenerative-changes. Using multivariable regression techniques, the relationships between TBS or BMD and degenerative-changes were assessed, further adjusting for age and weight. The difference between each of the two methods was examined through testing interactions between method, degenerative-changes and age. RESULTS: Of 728 men, 439 (60.3%) were identified as having one or more degenerative-changes at the lumbar spine. Adjusted mean TBS was 1.219 (1.203 1.232) and 1.196 (1.179-1.212) for those with and without degenerative-changes, respectively. Adjusted mean BMD was 1.317 g/cm2 (1.297-1.336) and 1.198 g/cm2 (1.173-1.223) for those with and without degenerative-changes, respectively. Partial r2 for degenerative-changes in the model for TBS was 0.076 and for BMD, 0.257 (both p < 0.05). The three-way interaction between method, degenerative changes and age was significant (p = 0.05) indicating significant effect of artefacts on the standardised values, affected by age and method. CONCLUSION: This study suggests that TBS is less affected by degenerative-changes at the spine than is BMD. Thus, TBS may prove useful in the assessment of fracture risk in men with degenerative-changes at the spine. PMID- 30446837 TI - Epigenetically modified cardiac mesenchymal stromal cells limit myocardial fibrosis and promote functional recovery in a model of chronic ischemic cardiomyopathy. AB - Preclinical investigations support the concept that donor cells more oriented towards a cardiovascular phenotype favor repair. In light of this philosophy, we previously identified HDAC1 as a mediator of cardiac mesenchymal cell (CMC) cardiomyogenic lineage commitment and paracrine signaling potency in vitro suggesting HDAC1 as a potential therapeutically exploitable target to enhance CMC cardiac reparative capacity. In the current study, we examined the effects of pharmacologic HDAC1 inhibition, using the benzamide class 1 isoform-selective HDAC inhibitor entinostat (MS-275), on CMC cardiomyogenic lineage commitment and CMC-mediated myocardial repair in vivo. Human CMCs pre-treated with entinostat or DMSO diluent control were delivered intramyocardially in an athymic nude rat model of chronic ischemic cardiomyopathy 30 days after a reperfused myocardial infarction. Indices of cardiac function were assessed by echocardiography and left ventricular (LV) Millar conductance catheterization 35 days after treatment. Compared with naive CMCs, entinostat-treated CMCs exhibited heightened capacity for myocyte-like differentiation in vitro and superior ability to attenuate LV remodeling and systolic dysfunction in vivo. The improvement in CMC therapeutic efficacy observed with entinostat pre-treatment was not associated with enhanced donor cell engraftment, cardiomyogenesis, or vasculogenesis, but instead with more efficient inhibition of myocardial fibrosis and greater increase in myocyte size. These results suggest that HDAC inhibition enhances the reparative capacity of CMCs, likely via a paracrine mechanism that improves ventricular compliance and contraction and augments myocyte growth and function. PMID- 30446836 TI - Chronic kidney disease predicts a lower probability of improvement in patient reported experience measures among patients with fractures: a prospective multicenter cohort study. AB - : Patient-reported experience measures (PREMs) are integral component of care for fracture patients. Using a multicenter cohort, we showed that the presence of chronic kidney disease (CKD) attenuated the probability of PREM improvement in fracture patients. INTRODUCTION: Assessing PREM can assist physicians in improving patients' experiences. Patients with CKD are at an increased risk of exhibiting poor PREM and developing fractures. We aimed to assess whether CKD influences the probability of PREM improvement during follow-up among patients with fractures. METHODS: We prospectively enrolled patients with hip or vertebral fractures from different institutes into a fracture liaison service program. After registering clinical histories, they received a baseline PREM assessment based on EuroQol group-5 dimension content, including self-care, daily activity, and pain severity using a 5-point Likert scale. A follow-up PREM assessment was arranged 4 months later, and we evaluated whether baseline CKD was predictive of PREM improvement. RESULTS: Among 593 fracture patients (18% with CKD), 37.3% and 62.7% presented with hip and vertebral fractures, respectively. Self-care, daily activity, and pain severity improved after follow-up in 32%, 27%, and 43% participants; those with CKD exhibited worse self-care ability and daily activity than those without. Multivariate logistic regression analyses showed that baseline CKD was significantly associated with lower possibility of improvement in daily activity (odds ratio [OR] 0.58, p = 0.049) and pain severity (OR 0.52, p = 0.01), and an insignificant change in the possibility of improvement in self care ability (OR 0.61, p = 0.09). CONCLUSIONS: The presence of CKD predicts a significantly lower probability of PREM improvement among fracture patients. An early emphasis on renal function during fracture care should be considered. PMID- 30446838 TI - Climate change vulnerability in a tropical region based on environmental and socio-economic factors. AB - The understanding of the regional and local dimensions of vulnerability due to climate change is essential to develop appropriate and targeted adaptation efforts. We assessed the local dimensions of vulnerability in the tropical state of Kerala, India, using a purposely developed vulnerability index, which accounts for both environmental and socio-economic factors. The large extents of coastal wetlands and lagoons and high concentration of mangrove forests make the state environmentally vulnerable. Low human development index, large population of socially deprived groups, which are dependent on the primary sector, and high population density make the state vulnerable from a socio-economic point of view. The present study investigates climate change vulnerability at the district level in the State of Kerala relying on a purposely developed composite vulnerability index that encompasses both socio-economic and environmental factors. The Kerala coast contains the socio-economically and ecologically most vulnerable regions, as demonstrated by a composite vulnerability index. PMID- 30446839 TI - Simultaneous elimination of Malachite Green, Rhodamine B and Cresol Red from aqueous sample with Sistan sand, optimized by Taguchi L16 and Plackett-Burman experiment design methods. AB - The purpose of this study was to investigate the feasibility of simultaneous optimization and removal of dyes, Malachite green (MG), Rhodamine B (RhB) and Cresol Red (CR) from aqueous solutions by using Sistan sand as an extremely low cost adsorbent. Factors affecting adsorption of the analytes on the sorbent were investigated experimentally and by using Taguchi and Plackett-Burman experimental design methods. In most cases, the results of these two models were in agreement with each other and with experimental data obtained. Taguchi method was capable to predict results with accuracies better than 97.89%, 95.43%, and 97.79% for MG, RhB, and CR, respectively. Under the optimum conditions, the sorbent could remove simultaneously more than 83% of the dyes with the amount of adsorbed dyes of 0.132, 0.109, and 0.120 mg g-1 for MG, RhB and CR on sand, respectively. Kinetic studies showed that pseudo second order is the best model of adsorption for all analytes. Thermodynamic parameters revealed that this process is spontaneous and endothermic. PMID- 30446840 TI - Resected thymic large cell neuroendocrine carcinoma: report of a case. AB - BACKGROUND: Thymic large cell neuroendocrine carcinoma (LCNEC) is extremely rare. The detailed clinical features of thymic LNCECs remain unknown. CASE PRESENTATION: A 90-year-old man with a history of diabetes mellitus, chronic renal failure, and an abdominal aortic aneurysm underwent computed tomography for follow-up, which showed an anterior mediastinal tumor, measuring 31 mm * 28 mm in diameter. Magnetic resonance imaging showed an iso-intensity mass on T1-weighted images and high intensity on T2-weighted images. 18F-Fluorodeoxyglucose-positron emission tomography showed marked uptake in the mass, which was diagnosed as invasive thymoma or thymic carcinoma. Video-assisted thoracic surgery through the left thoracic cavity was converted to median sternotomy due to severe adhesions between the left lung and the chest wall. Partial thymectomy and combined partial resection of left upper lobectomy and the first and the second costal cartilages were performed. The pathologic diagnosis was thymic LCNEC, Masaoka stage III. The patient developed pleural dissemination and left lung metastases in 5 months and died 12 months after surgery. CONCLUSIONS: Thymic LCNEC has high malignant potential. More cases need to be studied. PMID- 30446841 TI - Inflammatory and coagulatory parameters linked to survival in critically ill children with sepsis. AB - BACKGROUND: Sepsis is associated with a deflection of inflammatory and coagulative parameters, since some clotting factors are known to be involved in the host's defense against infection and inflammation. These parameters could play a crucial role in the course of sepsis and be used as prognostic markers in critically ill children. METHODS: A total of 250 critically ill pediatric patients diagnosed with sepsis were retrospectively analyzed to identify routinely measured predictors for in-hospital mortality at the peak level of C reactive protein. Those parameters entered multivariate logistic regression analysis as well as a decision tree for survival. RESULTS: Multivariate logistic regression analysis revealed fibrinogen, platelets and activated partial thromboplastin time (aPTT) at the peak level of C-reactive protein to be predictors for survival (p = 0.03, p = 0.01 and p = 0.02, respectively). An increase in fibrinogen and platelets is linked to survival, whereas an aPTT prolongation is associated with higher mortality; adjusted odds ratios (95% CI) for an increase of 100 mg/dl in fibrinogen are 1.35 (1.04-1.82) per 50 G/l platelets 1.94 (1.3-3.29) and 0.83 (0.69-0.96) for an aPTT prolongation of 10 s. Decision tree analysis shows that a fibrinogen level below 192 mg/dl (90.9% vs. 13% mortality) is most distinctive in non-survivors. CONCLUSIONS: High levels of fibrinogen and platelets as well as a non-overshooting aPTT are associated with a higher survival rate in pediatric patients with diagnosed sepsis. In particular, hypofibrinogenemia is distinctive for a high mortality rate in septic critically ill children. PMID- 30446842 TI - Performance of computerized cardiotocography-based short-term variation in late onset small-for-gestational-age fetuses and reference ranges for the late third trimester. AB - PURPOSE: Fetal Doppler changes are well characterized in early-onset small-for gestational-age (SGA) and fetal growth restriction (FGR) but less well characterized where the condition is late-onset. The aim of the study was to evaluate the role of computerized CTG (cCTG)-based short-term variation (STV) in late-onset SGA and FGR as an additional monitoring modality and to establish STV reference ranges in late third trimester healthy pregnancies. METHODS: Of 86 late onset SGA fetuses diagnosed after 32 weeks, 66 were diagnosed with FGR. 138 healthy pregnancies acted as controls. All underwent umbilical artery pulsatility index (PI), middle cerebral artery PI, cerebroplacental ratio and mean uterine artery PI. cCTG recordings were analyzed by Sonicaid FetalCare software for STV calculation as described by Dawes/Redman. RESULTS: Median interval between inclusion and delivery was 13 (interquantile range = 4-30) days in the FGR group, 22 (12-37) days in the SGA group and 25 (10-40) days in the control group. STV was not different between controls (11.2 ms, 9.7-13.1), late-onset SGA (11.2 ms, 8.1-12.6) and FGR (10.5 ms, 8.5-12.4) fetuses. A greater proportion of late-onset SGA fetuses had STV < 5th percentile (7/86) compared to controls (4/138) (8.1% vs. 2.9%, p = 0.077). In the control group a significant positive correlation was seen between STV, and 1-min (rho = 0.195, p = 0.026), 5-min (rho = 0.247, p = 0.004) and 10-min (rho = 0.211, p = 0.014) Apgar values. CONCLUSIONS: We report no significant difference in STV median values between controls, SGA and FGR pregnancies. However, more SGA fetuses had a low STV compared to controls. Prospective longitudinal studies are needed to investigate if low STV is a useful surveillance method for late-onset FGR. PMID- 30446843 TI - Abnormal expressions of ADAMTS-1, ADAMTS-9 and progesterone receptors are associated with lower oocyte maturation in women with polycystic ovary syndrome. AB - PURPOSE: ADAMTS-1 and 9 play a crucial role in the ovulation and their altered levels may play a role in the pathogenesis of polycystic ovary syndrome (PCOS). The aim of this study was to assess ADAMTS-1 and 9 expression and their correlation with the oocyte quality and maturity in the cumulus cells (CCs) of PCOS patients and normovulatory women during an IVF procedure. METHODS: Expression of ADAMTS-1 and 9 and progesterone receptors (PRs) in the CCs containing MII and germinal vesicle (GV) oocytes of 37 PCOS patients and 37 women with normal ovulatory function who underwent IVF treatment was evaluated using qRT-PCR. Moreover, correlation between ADAMTS-1 and 9 expression and oocyte quality were also investigated. RESULTS: mRNA expression levels of ADAMTS-1 and ADAMTS-9 were significantly reduced in the women with PCOS compared to the normovulatory women. ADAMTS-1 and ADAMTS-9 mRNA expression levels in the CCs showed a considerable correlation. Lower expression levels of ADAMTS-1 and ADAMTS 9 in PCOS patients were strongly correlated with diminished oocyte maturation. There was a remarkable association between ADAMTS-1 and ADAMTS-9 mRNA expression levels and oocyte quality. PRs (PRA and PRB) were dramatically decreased in PCOS patients when compared with the control group. CONCLUSIONS: The results of the present study indicated that ADAMTS-1 and ADAMTS-9 as well as PRs are downregulated in the human CCs in PCOS patients, which could be associated with impaired oocyte maturation and may result in a lower oocyte recovery and oocyte maturity rates, as well as lower fertilization rate. PMID- 30446844 TI - Illuminating the physiological implications of artificial light on an insectivorous bat community. AB - Global light pollution threatens to disturb numerous wildlife species, but impacts of artificial light will likely vary among species within a community. Thus, artificial lights may change the environment in such a way as to create winners and losers as some species benefit while others do not. Insectivorous bats are nocturnal and a good model to test for differential effects of light pollution on a single community. We used a physiological technique to address this community-level question by measuring plasma beta-hydroxybutyrate (a blood metabolite) concentrations from six species of insectivorous bats in lit and unlit conditions. We also recorded bat calls acoustically to measure activity levels between experimental conditions. Blood metabolite level and acoustic activity data suggest species-specific changes in foraging around lights. In red bats (Lasiurus borealis), beta-hydroxybutyrate levels at lit sites were highest early in the night before decreasing. Acoustic data indicate pronounced peaks in activity at lit sites early in the night. In red bats on dark nights and in the other species in this community, which seem to avoid lights, beta-hydroxybutyrate remained relatively constant. Our results suggest red bats are more willing to expend energy to actively forage around lights despite potential negative impacts, while other, generally rarer species avoid lit areas. Artificial light appears to have a bifurcating effect on bat communities, whereby some species take advantage of concentrated prey resources, yet most do not. Further, this may concentrate light-intolerant species into limited dark refugia, thereby increasing competition for depauperate, phototactic insect communities. PMID- 30446845 TI - Transient electrohydrodynamics of a liquid drop in AC electric fields. AB - The transient behavior of a leaky dielectric liquid drop under a uniform AC electric field of small strength is investigated, using a closed form analytical solution. The drop settles to a quasi-steady state in a relaxation time that is set by the viscosities of the drop and the ambient fluid and the surface tension, and oscillates around a mean deformation with a frequency that is twice the electric field frequency. The mode of instantaneous deformation remains the same (oblate or prolate) or switches between oblate and prolate, depending on the relative importance of the time-periodic component of the deformation compared to that of the time-exponential. The structure of the flow field and its evolution is studied for representative fluid systems at a high and a low electric field frequency. The individual contribution of the net tangential and normal electric stresses, which are the driving forces of the problem, on the flow structure and drop deformation is characterized. On the basis of the mean (time-independent) and time-periodic components of the driving forces, the flow field is represented as the superposition of three different flow patterns. It is shown that the interplay of these flow patterns leads to formation and destruction of toroidal vortices, and that the residence time of these vortices correlates inversely with the field frequency. PMID- 30446846 TI - CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK 3-targeting inhibitor. AB - PURPOSE: Glycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers. METHODS: Here, SKBr3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [14C (U)] glucose and [3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to 31P NMR spectroscopy. RESULTS: SB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components. CONCLUSION: SB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDP choline detectable by 31P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3. PMID- 30446847 TI - Sensitivity analysis of muscle mechanics-based voice simulator to determine gender-specific speech characteristics. AB - The purpose of this study was to investigate the gender differences in voice simulation using a sensitivity analysis approach. A global, Monte Carlo-based approach was employed, and the relationships between biomechanical inputs (lung pressure and muscle activation levels) and acoustic outputs (fundamental frequency, f0, and sound pressure level, SPL) were investigated for male and female versions of a voice simulator model. The gender distinction in the model was based on an anatomical scaling of the laryngeal structures. Results showed strong relationships for f0 and SPL as functions of lung pressure, as well as for f0 as a function of cricothyroid and thyroarytenoid muscle activity, in agreement with previous literature. Also expected was a systematic shift in f0 range between the genders. It was found that the female model exhibited greater pitch strength (saliency) than the male model, which might equate to a perceptually more periodic or higher-quality voice for females. In addition, the female model required slightly higher lung pressures than the male model to achieve the same SPL, suggesting a possibly greater phonatory effort and predisposition for fatigue in the female voice. The methods and results of this study lay the groundwork for a complete mapping of simulator sound signal characteristics as a function of simulator input parameters and a better understanding of gender specific voice production and vocal health. PMID- 30446848 TI - Starch Paper-Based Triboelectric Nanogenerator for Human Perspiration Sensing. AB - A disposable and ecofriendly starch paper was used to fabricate a triboelectric nanogenerator (TENG) for the sensing of human perspiration. Using cost-effective and commercially accessible materials, the starch paper-based TENG (S-TENG) can be achieved through a rapid and simple fabrication method. The output performance varies with the absorbed water content, which can be utilized for human perspiration sensing. The starch structure can be broken down in water within 4 min. The proposed S-TENGs have a considerable potential in the field of green wearable electronics. PMID- 30446849 TI - MELD-Na score associated with postoperative complications in hernia repair in non cirrhotic patients. AB - PURPOSE: In patients with cirrhosis, the Model for End-Stage Liver Disease Sodium (MELD-Na) score is a validated predictor of outcomes after transplant and non transplant surgical procedures. This study investigates the association of MELD Na score with complications following elective ventral hernia repair in non cirrhotic patients. METHODS: The ACS NSQIP database was queried (2005-2016) for all elective laparoscopic and open ventral hernia procedures in patients without ascites or esophageal varices. Postoperative outcomes were compared by MELD-Na score using Chi-square tests. Multivariate logistic regression was used to control for potentially confounding variables. RESULTS: A total of 48,955 elective hernia repairs were identified; 68.7% were open repairs. The overall complication rate (Clavien-Dindo >= 1) was 14.3%, with a wound complication rate of 5.5%, and major complication rate (Clavien-Dindo >= 3) of 4.3%. A preoperative MELD-Na score >= 10 was present in 29.4%. Incremental increases in MELD-Na score (10-14, 15-19, and >= 20) were associated with increased overall complications (OR 1.25, CI 1.31-1.37; OR 1.53, CI 1.30-1.80; OR 1.70, CI 1.24-2.31, respectively), major complications (OR 1.42, CI 1.20-1.69; OR 1.85, CI 1.43-2.39; OR 2.13, CI 1.35-3.38, respectively), 30-day mortality (OR 1.58, CI 1.05-2.37; OR 2.34, CI 1.39-3.96; OR 3.16, CI 1.37-7.28, respectively), and return to the operating room (OR 1.19, CI 1.01-1.41; OR 1.38, CI 1.05-1.81; OR 1.78, CI 1.10 2.90, respectively). CONCLUSION: MELD-Na score is independently associated with postoperative complications in ventral hernia repair. As an objective and simple predictive model, it may be useful in preoperative risk calculations for complex patients. PMID- 30446850 TI - Space-time clustering of childhood cancers: a systematic review and pooled analysis. AB - The aetiology of childhood cancers remains largely unknown. Space-time clustering of cases might imply an aetiological role of infections. We aimed to review the evidence of space-time clustering of specific childhood cancers. We searched Medline and Embase for population-based studies that covered a pre-defined study area, included cases under 20 years of age and were published before July 2016. We extracted all space-time clustering tests and calculated the proportion of positive tests per diagnostic group. In a pooled analysis, we performed a Knox test of the number of pairs of cases close to each other in time and space pooled across studies. 70 studies met our eligibility criteria, 32 of which reported Knox tests. For leukaemia, the proportion of positive tests was higher than expected by chance at both time of diagnosis (26%) and birth (11%). The pooled analysis showed strong evidence of clustering at diagnosis for children aged 0-5 years for a spatial and temporal lag of 5 km and 6 months, respectively (p < 0.001). The evidence was mixed for lymphoma and tumours of the central nervous system. The current study suggests that leukaemia cases cluster in space-time due to an aetiological factor affecting children under 5 years of age. The observed pattern of clustering of young children close to time of diagnosis is compatible with Greaves' delayed-infections-hypothesis. PMID- 30446851 TI - Associations between motivational factors for studying medicine, learning approaches and empathy among medical school candidates. AB - Previous research highlighted associations between students' motivation for medical studies and their learning approaches on the one hand and empathy on the other. Internal motivational factors for studying medicine (e.g., care for patients, save lives) coupled with a deep approach to learning have been positively related to empathy in contrast to external motivational factors (e.g., future earning potential, prestige) and surface learning. However, assessments of these assumptions among medical school candidates are scarce. This study examined the relationship between different motivational factors and empathy among students enrolled in a selection year in medicine by testing the mediating role of learning approaches. A sample of 572 candidates for medical studies answered a self-reported questionnaire half way through their selection year. Measures included internal and external motivational factors for studying medicine, deep and surface learning approaches and empathy. Path-analysis tested the mediation effects of deep and surface approaches to learning on the relationship of internal and external motivational factors with empathy. The deep learning approach partially mediated the significant positive association between internal motivational factors and empathy, while the surface learning approach fully mediated the significant negative association between external motivational factors and empathy. These results suggest that learning approaches could be a pathway by which internal and external motives for studying medicine are related to empathy among medical school candidates. Pedagogical strategies and educational environments accounting for individual differences in motivation and learning may contribute to training students to become professional and caring doctors in the future. PMID- 30446852 TI - Sonography in acute ocular pathology: a kaleidoscopic view. AB - Ocular emergencies contribute to a large proportion of ocular pathologies. These may even be organ-threatening diseases such as central retinal artery and vein occlusion or globe rupture. Conventional physical examination may not always be feasible in emergency situations but decision-making in time is critical in the interest of patient in few of these conditions. Sonography in this setting plays an important role, allowing real-time, quick and dynamic evaluation. Common acute ocular pathologies such as retinal detachment, lens dislocation and globe rupture can be easily diagnosed by ultrasound. Vascular lesions can be identified using Doppler. This article illustrates the sonographic appearance in traumatic and non traumatic acute ocular pathologies. PMID- 30446853 TI - Association between pre-operative magnetic resonance imaging (MRI) and surgical outcomes in breast cancer: not yet determined. PMID- 30446854 TI - Depression Among Alcohol Consuming, HIV Positive Men on ART Treatment in India. AB - Depression, as well as other psychosocial factors, remains largely unaddressed among people living with HIV (PLHIV) in low and middle-income countries. Depression is a common occurrence among PLHIV and is elevated in those who consume alcohol. This paper will document the presence of depressive symptoms in alcohol-consuming male PLHIV receiving antiretroviral treatment (ART) in India. It examines the correlates of depressive symptoms and uses the data from in-depth interviews to explain the nature of the statistical relationships obtained from an NIH-funded a multilevel, multi-centric intervention study. A cross-sectional, baseline survey was administered to 940 alcohol consuming, male PLHIV in five hospital-based ART Centers in urban Maharashtra, India via face to face interviews from October 2015 to April 2016. An additional 55 men were recruited independently to engage in in-depth interviews on alcohol use and other factors related to adherence. The results of the survey showed that approximately 38% of PLHIV reported having moderate to severe depressive symptoms. Depressive symptoms were positively associated with higher levels of family-related concerns (OR 1.18; 95% CI 1.12-1.23), work difficulties (OR 2.04; 95% CI 1.69-2.69) and HIV related self-stigma (OR 1.05; 95% CI 1.03-1.07) and a lower level of ART service satisfaction (OR 0.58 95% CI 0.44-0.77). The results of in-depth interviews showed that PLHIV's tenshun (a Hindi term most closely corresponding to depressive symptoms) resulted from feelings of guilt and concerns about how family, friends, and neighbors might react to their HIV status and the potential for loss of a job as a result of disclosure of their HIV status at work. The level of depressive symptoms among male PLHIV involved in ART treatment points to the need to strengthen the psychological component of PLHIV treatment in India. PMID- 30446855 TI - ADAM10 controls the differentiation of the coronary arterial endothelium. AB - The coronary vasculature is crucial for normal heart function, yet much remains to be learned about its development, especially the maturation of coronary arterial endothelium. Here, we show that endothelial inactivation of ADAM10, a key regulator of Notch signaling, leads to defects in coronary arterial differentiation, as evidenced by dysregulated genes related to Notch signaling and arterial identity. Moreover, transcriptome analysis indicated reduced EGFR signaling in A10DeltaEC coronary endothelium. Further analysis revealed that A10DeltaEC mice have enlarged dysfunctional hearts with abnormal myocardial compaction, and increased expression of venous and immature endothelium markers. These findings provide the first evidence for a potential role for endothelial ADAM10 in cardioprotective homeostatic EGFR signaling and implicate ADAM10/Notch signaling in coronary arterial cell specification, which is vital for normal heart development and function. The ADAM10/Notch signaling pathway thus emerges as a potential therapeutic target for improving the regenerative capacity and maturation of the coronary vasculature. PMID- 30446856 TI - Achievement of a good death among young adult patients with cancer: analyses of combined data from three nationwide surveys among bereaved family members. AB - PURPOSE: Although little improvement has been made in the survival rate among young cancer patients over recent decades, whether they have achieved a good death has never been systematically explored. We aimed to clarify whether young cancer patients (aged 20-39 years) have achieved a good death, and compare their achievement with that of middle-aged patients (aged 40-64 years). METHODS: We analyzed combined data of three nationwide, cross-sectional surveys of families of cancer patients who died at inpatient hospices in Japan (2007-2014). We measured 10 core items of the Good Death Inventory (GDI) short-version on a 7 point scale, and calculated rates of "agree/absolutely agree" and the mean scores. RESULTS: We analyzed 245 and 5140 responses of families of young and middle-aged patients, respectively. Less than 60% of families of young patients reported "agree/absolutely agree" regarding 9 items, which included "feeling that one's life was completed" in 44 (18%; 95% confidence interval (CI) = 14-23%), "being independent in daily life" in 48 (20%; 95% CI = 15-25%), and "being free from physical distress" in 103 (42%; 95% CI = 36-48%) young patients. Young patients were significantly less likely to feel "one's life was completed" (mean = 3.3 (standard deviation = 2.0) vs. 3.8 (1.9), respectively; effect size (ES) = 0.29; adjusted p value = 0.000) and "not being a burden to others" (3.1 (1.5) vs. 3.5 (1.6), respectively; ES = 0.24; adjusted p value = 0.010) than the middle aged. CONCLUSIONS: Overall, young cancer patients did not achieve a good death. Future efforts are needed to improve the quality of palliative care for young patients, focusing on psychosocial/spiritual suffering. PMID- 30446857 TI - Toward the development of a comprehensive cancer experience measurement framework. AB - A diagnosis of cancer and its treatment often have a profound impact on an individual's health-related quality of life-affecting physical, psychological, social, occupational, and financial domains. Person-centered care (PCC)-defined as a respectful, responsive, and tailored approach that meets patients' needs, values, and preferences-is becoming an integral part of comprehensive cancer care. The implementation of PCC into clinical practice provides benefits such as improvement in the quality of patient care, enhanced health-related outcomes, and significantly higher satisfaction with care. However, to guide and document more precisely the effects of PCC, various authors have argued that a more comprehensive measurement framework is needed. The primary goal of this paper is to present such an evolving framework based on extant evidence and developed in the context of a series of expert stakeholder meetings spearheaded by the Canadian Partnership Against Cancer (CPAC) that began in 2012. Developed collaboratively, the Cancer Experience Measurement Framework goes beyond existing patient experience frameworks by focusing on four key elements and related measures: the patient perspective, the family perspective, the combined patient family perspective, and interactions with the healthcare system. In light of current healthcare trends promoting cancer self-management, patients as partners, and patient and family engagement in care, it is imperative that we conduct ongoing assessments using shared and psychometrically sound measures to ensure sound comparisons across settings, as well as better cancer-related processes and outcomes for indivduals affected by cancer. PMID- 30446858 TI - Gigantic mammary Paget's disease of a very elderly woman. AB - BACKGROUND: Recently, surgical stress due to breast cancer has been reduced, more so for elderly patients. However, an expanded resection is still required in some situations. CASE PRESENTATION: We present a case of a 90-year-old woman with a 15 * 15 cm2 erythema and localized skin ulceration with hemorrhage in her right breast. A punch biopsy indicated mammary Paget's disease. Computed tomography showed that the tumor was only located on the surface of the breast with no metastasis, including of the axillar lymph nodes. We decided to perform surgery with sufficient informed consent. We performed muscle-sparing mastectomy with sampling of an axillar lymph node, adding two stress-relaxation sutures to avoid diastasis. The patient's postoperative course was good. A histological examination revealed mammary Paget's disease without invasion and no evidence of a residual tumor of the entire stumps. Her quality of life was improved after surgery. CONCLUSION: Mammary Paget's disease has a relatively good prognosis. However, advanced mammary Paget's disease leads to a decrease of quality of life with symptoms such as skin ulcer and bleeding. Surgery should be performed in such cases, considering the risks and benefits, even in older patients with comorbidities. PMID- 30446859 TI - Gene cloning, expression in E. coli, and in vitro refolding of a lipase from Proteus sp. NH 2-2 and its application for biodiesel production. AB - OBJECTIVE: To obtain active lipases for biodiesel production by refolding Proteus sp. lipase inclusion bodies expressed in E. coli. RESULTS: A lipase gene lipPN1 was cloned from Proteus sp. NH 2-2 and expressed in E. coli BL21(DE3). Non reducing SDS-PAGE revealed that recombinant LipPN1(rLipPN1) were prone to form inclusion bodies as disulfide-linked dimers in E. coli. Site-directed mutagenesis confirmed that Cys85 in LipPN1 was involved in the dimer formation. After optimizing the inclusion body refolding conditions, the maximum lipase activity reached 1662 U/L. The refolded rLipPN1 exhibited highest activity toward p nitrophenyl butyrate at pH 9.0 and 40 degrees C. It could be activated by Ca2+ with moderate tolerance to organic solvents. It could also convert soybean oil into biodiesel at a conversion ratio of 91.5%. CONCLUSION: Preventing the formation of disulfide bond could enhance the refolding efficiency of rLipPN1 inclusion bodies. PMID- 30446860 TI - The effect of Er,Cr:YSGG laser, fluoride, and CPP-ACP on caries resistance of primary enamel. AB - The aim of this in vitro study was to determine the effect of different remineralization agents and laser on caries resistance of primary enamel. In the study, 150 sound primary molars were used. The initial microhardness values were measured and the teeth were randomly assigned to ten treatment groups (n = 15): no treatment/negative control (C), NaF, APF, fluoride varnish (FV), CPP-ACP, laser (L), L + NaF, L + APF, L + FV, L + CPP-ACP. The microhardness values were measured after the treatments and the pH cycle. The obtained data were analyzed statistically. One sample from each group was examined before treatment, after treatment, and after the pH cycle with a scanning electron microscope. While microhardness values after treatment compared to baseline increased, microhardness after the pH cycle decreased compared to after treatment values in all experimental groups (p < 0.05). In regard to the difference in microhardness after the pH cycle and baseline, there were no statistically significant differences between groups C and NaF and between C and CPP-ACP (p > 0.05). There was a significant difference between groups L and L + FV (p < 0.05), while no significant difference was noted between groups L and L + NaF, L + APF, L + CPP ACP (p > 0.05). As a conclusion, FV is more effective when used in combination with laser than laser alone. NaF, CPP-ACP, and laser may be insufficient in protecting the primary teeth against acid attacks compared to FV used with laser. PMID- 30446861 TI - Meta-Perceptions of Others' Attitudes Toward Bisexual Men and Women Among a Nationally Representative Probability Sample. AB - Researchers posit that negative attitudes, prejudice, and discrimination (i.e., binegativity) from heterosexual and gay/lesbian individuals may contribute to health disparities among bisexual individuals relative to heterosexual and gay/lesbian individuals. Recent studies have focused on gay, lesbian, and heterosexual people's (e.g., "others") attitudes toward bisexual people. No studies have investigated how bisexual individuals perceive others' attitudes toward bisexual people, which are generally known as "meta-perceptions." As part of the 2015 National Survey of Sexual Health and Behavior, we collected data from a nationally representative probability sample of 2999 adults, including from a subsample of 33 men and 61 women self-identified as bisexual. The Bisexualities: Indiana Attitudes Scale-bisexual (BIAS-b), a modified 5-item scale assessing bisexual people's perceptions of others' attitudes toward bisexual individuals, was included and was followed by an open-ended text box question. Quantitative scale data were analyzed using descriptive and gamma regression methods. Two coders thematically analyzed the open-ended text box data. The internal consistency of the BIAS-b was high (Cronbach's alpha = 0.85). An exploratory factor analysis supported a one-factor solution. Participants responded to statements regarding others' attitudes toward them as bisexual people, including the domains of confusion, HIV/STD risk, incapability of monogamy, promiscuity, and instability ("just a phase"). Participants' text box descriptions largely aligned with these five domains, with the exception of HIV/STD risk. Additionally, some participants reported others' positive perceptions of them as bisexual individuals. In sum, we observed a range of meta-perceptions, primarily neutral to negative, but also including some relatively positive. These results show the need for interventions to promote acceptance of bisexual individuals among heterosexual and gay/lesbian individuals. PMID- 30446862 TI - First records of metal concentrations in the Pacific oyster (Crassostrea gigas) from a Southwest Atlantic estuary. AB - The Pacific oyster (Crassostrea gigas) is one of the world's most widespread bivalves and a suitable species for biomonitoring metals in coastal environments. In the present research, wild individuals were collected from an Argentinian estuary and the coastal beaches nearby. The concentrations of eight metals (Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn) were quantified in the soft tissues of the Pacific oyster. Among the metals, Cu, Fe and Zn reached the highest concentrations in the soft tissues over the rest of the elements. The results showed the highest values to be estuary related, with the beach site achieving the lowest values. These results possibly lie on the impact of human activities surrounding the estuary, as well as streams and rivers that outflow within it. Higher Cu and Zn levels, both port related, were mainly found toward the outer estuary. On the other hand, high levels of Cr, Fe and Mn were found toward the inner zone of the estuary, an area with sewage sludge from the cities located on the margins of the BBE. Regarding the potential risk to public health, Cu and Zn levels found in C. gigas were above national and international safety guidelines in 100% and 11% of the samples, respectively. PMID- 30446863 TI - Cardiovascular and autonomic responses to passive arm or leg movement in men and women. AB - PURPOSE: Women display an attenuated mechanoreflex during leg movement; however, sex differences in the response to arm movement are unknown. METHODS: Men (n = 12) and women (n = 10) performed passive arm or leg movement where either the right elbow or right knee was passively flexed/extended for 3 min at 30 times/min. Mean arterial pressure (MAP), cardiac output index (Qi), and heart rate (HR) were continuously measured and 1-min averages along with peak values were obtained. Heart rate variability was measured at baseline and throughout 3 min of passive movement. RESULTS: Men had a greater average HR (P = 0.006) and Qi (P = 0.05) responses to passive limb movement compared to women. Men also had a greater (P = 0.02) and faster (P = 0.04) peak Qi response compared to women. During arm movement, men exhibited a greater change of average MAP compared to both women (P = 0.002) and leg movement (P = 0.05). Movement of either limb in both sexes decreased low-frequency power (LF; P = 0.04), decreased low-frequency to high-frequency ratio (LF/HF; P = 0.03), and increased high-frequency power (HF; P = 0.01) of heart rate variability. Women had lower pulse wave velocity (P = 0.02), higher root mean square of the successive differences (RMSSD; P = 0.04), lower LF power (P = 0.04), higher HF power (P = 0.03), and higher cardiovagal baroreceptor sensitivity (P = 0.003) compared to men at all time points. CONCLUSIONS: We have found sex- and limb-dependent responses where men exhibit higher blood pressure in response to passive arm movement compared to women and compared to leg movement. PMID- 30446864 TI - Predictive model for major complications 2 years after corrective spine surgery for adult spinal deformity. AB - PURPOSE: ASD surgery improves a patient's health-related quality of life, but it has a high complication rate. The aim of this study was to create a predictive model for complications after surgical treatment for adult spinal deformity (ASD), using spinal alignment, demographic data, and surgical invasiveness. METHODS: This study included 195 surgically treated ASD patients who were > 50 years old and had 2-year follow-up from multicenter database. Variables which included age, gender, BMI, BMD, frailty, fusion level, UIV and LIV, primary or revision surgery, pedicle subtraction osteotomy, spinal alignment, Schwab-SRS type, surgical time, and blood loss were recorded and analyzed at least 2 years after surgery. Decision-making trees for 2-year postoperative complications were constructed and validated by a 7:3 data split for training and testing. External validation was performed for 25 ASD patients who had surgery at a different hospital. RESULTS: Complications developed in 48% of the training samples. Almost half of the complications developed in late post-op period, and implant-related complications were the most common complication at 2 years after surgery. Univariate analyses showed that BMD, frailty, PSO, LIV, PI-LL, and EBL were risk factors for complications. Multivariate analysis showed that low BMD, PI-LL > 30 degrees , and frailty were independent risk factors for complications. In the testing samples, our predictive model was 92% accurate with an area under the receiver operating characteristic curve of 0.963 and 84% accurate in the external validation. CONCLUSION: A successful model was developed for predicting surgical complications. Our model could inform physicians about the risk of complications in ASD patients in the 2-year postoperative period. These slides can be retrieved under Electronic Supplementary Material. PMID- 30446865 TI - The "Risser+" grade: a new grading system to classify skeletal maturity in idiopathic scoliosis. AB - PURPOSE: This study aims to propose and validate a new unified "Risser+" grade that combines the North American (NA) and European (EU) variants of the classic Risser score. The "Risser+ " grade can effectively combine the North American and European Risser Classifications for skeletal maturity with adequate intra rater/inter-rater reliability and agreement. METHODS: Agreement and reliability were evaluated for 6 raters (3-NA, 3-EU) who assessed 120 pelvic radiographs from the BrAIST trial, all female, average age 13.4 (range 10.1-16.5 years). Blinded raters reviewed x-rays at two time-points. Intra- and inter-rater agreement (RA) were established with Krippendorff's alpha (k-alpha), while intra- and inter rater reliability (RR) were established with intraclass correlation coefficients (ICC). Acceptable agreement and reliability were set a priori at 0.80. RESULTS: Inter-RA for the second reading met study requirements (k-alpha = 0.86 [0.81 0.90]) compared to the first reading (0.72 [0.63-0.79]) while combined readings was close to target agreement (0.79 [0.74-0.84]). Removal of 20 readings demonstrating outlier tendencies increased agreement for the first, second, and combined reads (k-alpha = 0.85, 0.89, 0.87, respectively). Intra-RA was sufficient for 4 out of 6 raters (k-alpha > 0.80) and one rater from EU and NA presented subpar intra-RA (k-alpha = 0.64 and 0.74, respectively). Inter-RR met study requirements overall reads (ICC = 0.96 [0.95-0.97]) including the first (0.94 [0.92-0.95]) and second (0.97 [0.97-0.98]) reads, independently. CONCLUSIONS: The Risser+ system showed excellent reliability across multiple reads and raters and demonstrated 79% agreement overall reads and ratings. Agreement increased to over 85% when raters could distinguish Risser 0 + from Risser 5. These slides can be retrieved from electronic supplementary material. PMID- 30446866 TI - Development and validation of an android-based application for anaesthesia neuromuscular monitoring. AB - Quantitative neuromuscular block (NMB) assessment is an internationally recognised necessity in anesthesia care whenever neuromuscular blocking agents are administered. Despite this, the incidence of residual neuromuscular block and its associated major respiratory morbidity and mortality remain unacceptably high considering its preventable nature. Recent surveys show that quantitative NMB assessment is not consistently employed by anesthesiologists. Availability, price and practical concerns are some of the factors determining this phenomenon. Clinically assess and validate an Android cell phone application conceived specifically for NMB Monitoring in the anesthesia setting. Twenty-two adult ASA I to III patients scheduled to undergo elective surgical procedures under general anaesthesia requiring administration of a neuromuscular blocking agent were included. After anaesthesia induction, the grade of neuromuscular block was assessed at multiple independent time-points by paired comparison of the train of four (TOF) Ratios obtained by a StimpodTM accelerometer and the currently developed application. Accelerometric measurements were made at the patient's hand after retrograde supramaximal stimulation of the ipsilateral ulnar nerve. TOF-ratios were subjected to bias analysis with 0.001 as the a priori established clinical significance cut-off. The difference between the two methods averaged 0.0004 (95% limits of agreement: +/- 0.12), with 83.3% of the differences being under 0.05. This average inter-method difference was not significantly different than the a priori hypothesized difference cut-off of 0.001 (p = 0.78). Lin's concordance correlation coefficient and Pearson's correlation were both of 0.98. The custom developed Android application proved accurate for diagnosis of residual neuromuscular block. PMID- 30446868 TI - Cross-Cultural Differences in the Influences of Spiritual and Religious Tendencies on Beliefs in Genetic Determinism and Family Health History Communication: A Teleological Approach. AB - Adopting a teleological approach, this study investigates how beliefs in genetic determinism, intentional spirituality, and religious tendencies are associated with family health history (FHH) communication among European American, Chinese, and Korean college students. The results indicate that intentional spirituality was negatively associated with beliefs in genetic determinism and FHH communication, while beliefs in genetic determinism were positively associated with FHH communication. Intrinsic and extrinsic religiosity and paranormal beliefs showed interesting dynamics with beliefs in genetic determinism and FHH communication. An interaction effect regarding cultural identity, beliefs in genetic determinism, and FHH communication was likewise found. The findings have meaningful implications for future studies about religious influences on health behaviors. PMID- 30446867 TI - Clinical and molecular characterization of non-syndromic retinal dystrophy due to c.175G>A mutation in ceroid lipofuscinosis neuronal 3 (CLN3). AB - PURPOSE: Mutation of the CLN3 gene, associated with juvenile neuronal ceroid lipofuscinosis, has recently been associated with late-onset, non-syndromic retinal dystrophy. Herein we describe the multimodal imaging, immunological and systemic features of an adult with compound heterozygous CLN3 mutations. METHODS: A 50-year-old female with non-syndromic retinal dystrophy from the age of 36 years underwent multimodal retinal imaging, electroretinography, neuroimaging, immunological studies and genetic testing. CLN3 transcripts were amplified from patient leukocytes by reverse transcriptase polymerase chain reaction and characterized by Sanger sequencing. RESULTS: Visual acuity declined to 6/12 and 6/76 due to asymmetrical central scotoma. ERG responses became electronegative and patient's serum contained anti-retinal antibodies. Final visual acuity stabilized at 6/60 bilaterally 3 years after peri-ocular steroid and rituximab infusion. Genetic testing revealed compound heterozygous CLN3 mutations: the 1.02 kb deletion and a novel missense mutation (c.175G>A). In silico, analyses predicted the c.175G>A mutation disrupted an exonic splice enhancer site in exon 3. In patient leukocytes, CLN3 expression was reduced and novel CLN3 transcripts lacking exon 3 were detected. CONCLUSIONS: Our case study shows that (1) non syndromic CLN3 disease leads to rod and delayed primary cone degeneration resulting in constricting peripheral field and enlarging central scotoma and, (2) the c.175G>A CLN3 mutation, altered splicing of the CLN3 gene. Overall, we provide comprehensive clinical characterization of a patient with non-syndromic CLN3 disease. PMID- 30446870 TI - Hi-TOM: a platform for high-throughput tracking of mutations induced by CRISPR/Cas systems. AB - The CRISPR/Cas system has been extensively applied to make precise genetic modifications in various organisms. Despite its importance and widespread use, large-scale mutation screening remains time-consuming, labour-intensive and costly. Here, we developed Hi-TOM (available at https://doi.org/www.hi-tom.net/hi tom/ ), an online tool to track the mutations with precise percentage for multiple samples and multiple target sites. We also described a corresponding next-generation sequencing (NGS) library construction strategy by fixing the bridge sequences and barcoding primers. Analysis of the samples from rice, hexaploid wheat and human cells reveals that the Hi-TOM tool has high reliability and sensitivity in tracking various mutations, especially complex chimeric mutations frequently induced by genome editing. Hi-TOM does not require special design of barcode primers, cumbersome parameter configuration or additional data analysis. Thus, the streamlined NGS library construction and comprehensive result output make Hi-TOM particularly suitable for high-throughput identification of all types of mutations induced by CRISPR/Cas systems. PMID- 30446869 TI - Sexual Risk Behaviors in Adolescent Sexual Minority Males: A Systematic Review and Meta-Analysis. AB - Although adolescent sexual minority males (ASMM) are at increased risk for human immunodeficiency virus (HIV) in the United States (US), studies that estimate sexual risk behaviors that contribute to HIV risk in ASMM are limited. We completed a systematic review and meta-analysis to compile available data and estimate the prevalence of risk behaviors in this population. We searched four databases for key terms related to ASMM, defined as males aged 14 through 19 who identified as gay or bisexual, reported sex with a male in their lifetime, and/or were considered sexual minority by the study. Articles eligible for inclusion were in English, from US studies, and reported quantitative data on sexual risk behaviors among ASMM. We extracted data from eligible articles and meta-analyzed outcomes reported in three or more articles using random effects. Of 3864 articles identified, 21 were eligible for data extraction. We meta-analyzed nine outcomes. Sixty-two percent of adolescent males self-identifying as gay or bisexual ever had sex with a male, and 67% of participants from ASMM studies recently had sex. Among ASMM who had sex in the last 6 months or were described as sexually active, 44% had condomless anal intercourse in the past 6 months, 50% did not use a condom at last sex, and 32% used alcohol or drugs at their last sexual experience. Available data indicate that sexual risk behaviors are prevalent among ASMM. We need more data to obtain estimates with better precision and generalizability. Understanding HIV risk in ASMM will assist in intervention development and evaluation, and inform behavioral mathematical models. PMID- 30446871 TI - Targeting the Proteasome in Refractory Pediatric Leukemia Cells: Characterization of Effective Cytotoxicity of Carfilzomib. AB - BACKGROUND: Leukemia accounts for 30% of all childhood cancers and although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Therefore, the development and introduction of novel therapeutics to treat relapsed pediatric leukemia is urgently needed. The proteasome inhibitor bortezomib has been shown to be effective against adult hematological malignancies such as multiple myeloma and lymphoma, but is frequently associated with the development of resistance. Carfilzomib is a next generation proteasome inhibitor that has shown promising results against refractory adult hematological malignancies. OBJECTIVE: Carfilzomib has been extensively studied in adult hematological malignancies, providing the rationale for evaluating proof-of-concept activity of carfilzomib in pediatric leukemia. METHODS: The effects of carfilzomib on pediatric leukemia cell lines and primary pediatric leukemia patient samples were investigated in vitro using the alamar blue cytotoxicity assay, western blotting, and a proteasome activity assay. Synergy with commonly used anticancer drugs was determined by calculation of combination indices. RESULTS: In vitro preclinical data show pharmacologically relevant concentrations of carfilzomib are cytotoxic to pediatric leukemia cell lines and primary pediatric leukemia cells. Target modulation studies validate the effective inhibition of the proteasome and induction of apoptosis. We also identify agents that have effective synergy with carfilzomib in these cells. CONCLUSIONS: Our data provide pre-clinical information that can be incorporated into future early-phase clinical trials for the assessment of carfilzomib as a treatment for children with refractory hematological malignancies. PMID- 30446872 TI - Real-World Use and Outcomes of Olaparib: a Population-Based Cohort Study. AB - BACKGROUND: Although olaparib, the first poly (adenosine diphosphate [ADP] ribose) polymerase (PARP) inhibitor approved, has been used in routine clinical practice for over three years, little has been published on its uptake, utilization patterns, and clinical outcomes. OBJECTIVE: To examine real-world use and outcomes of olaparib treatment in Swedish patients during the first three years following regulatory approval. PATIENTS AND METHODS: This is a population based cohort study using data from the Swedish national registers. All individuals initiating olaparib treatment from regulatory approval to 31 December 2017 were included. The extent of off-label use was assessed based on recorded diagnoses. Ovarian cancer patients were followed until death or the end of the study period. Starting dose and dose adjustments were assessed. Time to olaparib discontinuation and overall survival were plotted using Kaplan-Meier survival curves. RESULTS: We identified 109 patients to whom olaparib was dispensed in Sweden during the study period. Nine of these were prescribed olaparib off-label for either breast or prostate cancer and were excluded from further analyses. Median age among the remaining 100 patients with ovarian cancer was 59 years (range: 42-83). Almost all patients (96%) started on the recommended dose (400 mg [eight capsules] taken twice daily). Dose reductions were explicitly recorded for 14% of patients. Median time to discontinuation was 289 days (95% confidence interval [CI]: 226; 338). Median overall survival from olaparib initiation was 1002 days (95% CI: 676; not calculable). CONCLUSIONS: To our knowledge, this is the first population-based study of olaparib real-world use and outcomes. During the first three years following regulatory approval, olaparib was mainly prescribed to ovarian cancer patients. Ovarian cancer patients stayed on olaparib for a median of 9.5 months and the treatment appeared to be well tolerated. PMID- 30446873 TI - Environmental Factors Associated with Physical Activity and Screen Time Among Children With and Without Autism Spectrum Disorder. AB - This study aimed to examine how environmental factors are associated with physical activity (PA) and screen-time (ST) among children with and without ASD (n = 1380 and 1411, respectively). For TD children, the absence of a bedroom television and neighborhood support were associated with PA. For children with ASD, no environmental factors were associated with PA. Regarding ST, the presence of a bedroom television, absence of limits on ST, lack of neighborhood amenities and support, and adverse neighborhood factors were all associated with ST among TD children. For children with ASD, the presence of a bedroom television and the absence of limits on ST were associated with ST. Potential explanations for this dichotomy and suggestions for future research are discussed. PMID- 30446874 TI - Autoinflammatory Disease-Associated Vasculitis/Vasculopathy. AB - PURPOSE OF REVIEW: Autoinflammatory diseases (AIDs) constitute several disorders that share similar characteristics, clinical features, disease course, and prognosis. They are characterized by the presence of recurrent episodes of unprovoked inflammation due to dysregulated innate immune system in the absence of autoantibodies or infections. AIDs include periodic fever syndromes and other less commonly growing list of syndromes. In this review, vasculitis associated with different AIDs will be highlighted. RECENT FINDINGS: Vasculitis is inflammation and necrosis of the blood vessels causing impaired blood flow, ischemia, and infarction of the dependent tissues. It is a very rare manifestation of AIDs and when it occurs, the skin is the most affected tissue than any other organs such as kidneys, lungs, or CNS. Although vasculitis and AIDs share similar manifestations such as fever, skin rashes, and neuropathy, vasculitis is not a characteristic feature of AIDs and still not clear if it represents a main clinical feature or a manifestation of other disease process. PMID- 30446875 TI - The effect of a high-impact jumping intervention on bone mass, bone stiffness and fitness parameters in adolescent athletes. AB - : This study demonstrates that a 9-month jumping intervention can improve bone mass gains and physical fitness performance in adolescent males participating in non-osteogenic sports, such as swimming and cycling. PURPOSE: To examine the effect of a jumping intervention on bone mass, bone stiffness and fitness parameters in adolescents involved in different sports. METHODS: Ninety-three adolescent male swimmers (SWI), footballers (FOO) and cyclists (CYC) were randomised to intervention (INT) and sport (INT-SWI = 19, INT-FOO = 15, INT-CYC = 14) or sport only (CON-SWI = 18, CON-FOO = 15, CON-CYC = 12) groups. The 9-month jumping intervention consisted of 3 levels (12 weeks each) of 20 repetitions per set of counter movement jumps (CMJ) using adjustable weight vests (level 1 = 20 CMJ jumps/set, 0 kg, 3 sets/day, 3 times/week; level 2 = 20 CMJ jumps/set, 2 kg, 4 sets/day, 3 times/week; level 3 = 20 CMJ jumps/set, 5 kg, 4 sets/day, 4 times/week). Total body bone mineral content (BMC) at total body less head (TBLH) was measured using dual-energy X-ray absorptiometry and bone stiffness using quantitative ultrasound. Fitness was assessed using the 20-m shuttle run (20mSRT), CMJ and standing long jump (SLJ) tests. RESULTS: INT-SWI had significantly higher increase in BMC legs and bone stiffness compared to CON-SWI (4.2-12.7%). INT-CYC had significantly higher increase in BMC at TBLH and legs and bone stiffness compared to CON-CYC (5.0-12.3%). There were no significant differences between INT-FOO and CON-FOO in any bone outcomes (0.9-3.9%). The increase in CMJ performance was significantly higher in INT-SWI (3.1 cm) and INT CYC (3.2 cm) compared to CON-SWI and CON-CYC groups, respectively. CONCLUSIONS: A 9-month jumping intervention can improve bone mass, bone stiffness and muscular fitness in adolescent males participating in non-osteogenic sports, such as swimming and cycling. CLINICAL TRIAL REGISTRATION: ISRCTN17982776. PMID- 30446877 TI - Comprehensive analysis of microarray expression profiles of circRNAs and lncRNAs with associated co-expression networks in human colorectal cancer. AB - Increasing data demonstrate that circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. However, the mechanisms in colorectal cancer (CRC) remain unclear. Here, hundreds of significantly expressed circRNAs, and thousands of lncRNAs as well as mRNAs were identified. By qRT-PCR, one abnormal circRNA, lncRNA, and three mRNAs were verified in 24 pairs of tissues and blood samples, respectively. Then, by GO analysis, we found that the gene expression profile of linear counterparts of upregulated circRNAs in human CRC tissues preferred positive regulation of GTPase activity, cellular protein metabolic process, and protein binding, while that of downregulated circRNAs of CRC preferred positive regulation of cellular metabolic process, acetyl-CoA metabolic process, and protein kinase C activity. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that p53 signaling pathway was an important pathway in upregulated protein-coding genes, whereas cyclic guanosine monophosphate-protein kinase G (cGMP-PKG) signaling pathway was the top enriched KEGG pathway for downregulated transcripts. Furthermore, lncRNA-mRNA co expression analysis demonstrated that downregulated lncRNA uc001tma.3 was negatively with CDC45 and positively with ELOVL4, BVES, FLNA, and HSPB8, while upregulated lncRNA NR_110882 was positively with FZD2. In addition, lncRNA transcription factor (TF) co-expression analysis showed that the most relevant TFs were forkhead box protein A1 (FOXA1), transcription initiation factor TFIID submint 7 (TAF7), and adenovirus early region 1A(E1A)-associated protein p300 (EP300). Our findings offer a fresh view on circRNAs and lncRNAs and provide the foundation for further study on the potential roles of circRNAs and lncRNAs in colorectal cancer. PMID- 30446876 TI - Hotspots in the genomic architecture of field drought responses in wheat as breeding targets. AB - Wheat can adapt to most agricultural conditions across temperate regions. This success is the result of phenotypic plasticity conferred by a large and complex genome composed of three homoeologous genomes (A, B, and D). Although drought is a major cause of yield and quality loss in wheat, the adaptive mechanisms and gene networks underlying drought responses in the field remain largely unknown. Here, we addressed this by utilizing an interdisciplinary approach involving field water status phenotyping, sampling, and gene expression analyses. Overall, changes at the transcriptional level were reflected in plant spectral traits amenable to field-level physiological measurements, although changes in photosynthesis-related pathways were found likely to be under more complex post transcriptional control. Examining homoeologous genes with a 1:1:1 relationship across the A, B, and D genomes (triads), we revealed a complex genomic architecture for drought responses under field conditions, involving gene homoeolog specialization, multiple gene clusters, gene families, miRNAs, and transcription factors coordinating these responses. Our results provide a new focus for genomics-assisted breeding of drought-tolerant wheat cultivars. PMID- 30446879 TI - Calorie restriction and its impact on gut microbial composition and global metabolism. AB - Calorie restriction (CR) is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. It has long been recognized as a natural strategy for promoting health, extending longevity, and prevents the development of metabolic and age-related diseases. In the present review, we focus on the general effect of CR on gut microbiota composition and global metabolism. We also propose mechanisms for its beneficial effect. Results showed that probiotic and butyrate-producing microbes increased their relative abundance, whereas proinflammatory strains exhibited suppressed relative abundance following CR. Analyses of the gut microbial and host metabolisms revealed that most host microbial co-metabolites were changed due to CR. Examples of dramatic CR-induced changes in host metabolism included a decrease in the rate of lipid biosynthesis and an increase in the rates of fatty acid catabolism, beta oxidation, glycogenolysis, and gluconeogenesis. The observed phenotypes and the further verification of the direct link between gut microbiota and metabolome may benefit patients that are at risk for developing metabolic disease. Thus, improved gut microbiota composition and metabolome are potential biomarkers for determining the effectiveness of dietary interventions for age-related and metabolic diseases. PMID- 30446878 TI - Type 2 diabetes is causally associated with depression: a Mendelian randomization analysis. AB - Type 2 diabetes (T2D) has been associated with a high prevalence of depression.We aimed to determine the causal relation by performing a Mendelian randomization (MR) study using 34 T2D risk genetic variants validated in East Asians as the instrumental variable (IV). An MR analysis was performed involving 11 506 participants from a large longitudinal study. The T2D genetic risk score (GRS) was built using the 34 typical T2D common variants. We used T2D_GRS as the IV estimator and performed inverse-variance weighted (IVW) and Egger MR analysis. The T2D_GRS was found to be associated with depression with an OR of 1.21 (95% CI: 1.07-1.37) after adjustments for age, sex, body mass index, current smoking and drinking, physical activity, education, and marital status. Using T2D_GRS as the IV, we similarly found a causal relationship between genetically determined T2D and depression (OR: 1.84, 95% CI: 1.25-2.70). Though we found no association between the combined effect of the genetic IVs for T2D and depression with EggerMR(OR: 0.95, 95%CI: 0.42-2.14), we found an association for T2D and depression with IVW (OR: 1.75, 95% CI: 1.31-2.46) after excluding pleiotropic SNPs. Overall, the MR analyses provide evidence inferring a potential causal relationship between T2D and depression. PMID- 30446880 TI - Multiple sclerosis and oncocytic thyroid carcinoma: fortuitous or drug-related association? PMID- 30446881 TI - Suicide with an unusual home-manufactured firearm. AB - A 22-year-old male with a medical history of depression was found lying on his right side with a pool of blood around his head. A pistol-shaped metal device was found next to the right hand of the deceased. Examination of the body revealed the presence of a gunshot wound to the head. The entrance wound was located in the right temporal area and was partially surrounded by a semicircular muzzle imprint. Analysis of the firearm revealed a home-manufactured device constructed from the posterior part of a captive bolt gun chamber containing a firing pin. The front part of an original captive bolt's cylinder was replaced with a conical iron tube, which could be detached from the chamber by an unscrewing action. The tube was unrifled and drilled in order to accept standard 9 mm ammunition. A hollow rectangular piece of metal was welded to the posterior part of the chamber perpendicularly and used as a grip. Cases of injuries caused by different types of captive bolt guns are well documented in the forensic literature. However, conversions of captive bolts in projectile-discharging devices or their use in the construction of zip guns, as well as the injuries produced by such types of firearms, are extremely rare in forensic and medico-legal practice. PMID- 30446882 TI - Neurochemical alterations following the exposure to di-n-butyl phthalate in rats. AB - Due to its ability to cross blood brain barrier and placenta, dibutyl phthalate (di-n-butyl phthalate, DBP) is expected to cause severe side effects to the central nervous system of animals and humans. A little data is available about the potential DBP neurotoxicity; therefore, this work was designed to investigate the brain tissue injury induced by DBP exposure. Forty Wister albino rats were allocated randomly into 4 groups (10 rats each). Group 1 served as control and the rats administered with physiological saline (0.9% NaCl) orally for 12 weeks. Groups 2, 3 and 4 were orally treated with DPB (100, 250 and 500 mg/kg) respectively for 12 weeks. DBP-intoxicated rats showed a disturbance in the oxidative status in cerebral cortex, striatum and brainstem, as represented by the elevated oxidants [malondialdehyde (MDA), nitric oxide (NO), 8-hydroxy-2 deoxyguanosine (8-OHdG)] and the decreased antioxidant molecules [reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)]. DBP also enhanced a pro inflammatory state through increasing the release of tumor necrosis factor- alpha (TNF-alpha) and interleukin-1beta (IL-1beta). The increase of these cytokines was associated with the increase of pro-apoptotic proteins [Bcl-2 associated X protein (Bax) and caspase-3] and the decrease of the anti-apoptotic protein, B cell lymphoma 2 (Bcl-2). In addition, the levels of norepinephrine (NE), dopamine (DA) and acetylcholine esterase (AChE) activity were decreased. This was accompanied by the alterations in the major excitatory and inhibitory amino acids neurotransmitters levels. The present findings indicated that DBP could exert its neuronal damage through oxidative stress, DNA oxidation, neuroinflammation, activation of apoptotic proteins and altering the monoaminergic, cholinergic and amino acids transmission. PMID- 30446883 TI - Medical Expenditures Among Medicare Beneficiaries with Statin-Associated Adverse Effects Following Myocardial Infarction. AB - PURPOSE: Compare medical expenditures among adults with statin-associated adverse effects (SAAE) and high statin adherence (HSA) following myocardial infarction (MI). METHODS: We analyzed expenditures in 2016 US dollars among Medicare beneficiaries with SAAE (n = 1741) and HSA (n = 55,567) who were >= 66 years of age and initiated moderate/high-intensity statins following an MI in 2007-2013. SAAE were identified through a claims-based algorithm, which included down titrating statins and initiating ezetimibe, switching to ezetimibe monotherapy, having a rhabdomyolysis or antihyperlipidemic adverse event followed by statin down-titration or discontinuation, or switching between >= 3 statin types within 365 days following MI. HSA was defined by having a statin available to take for >= 80% of the days in the 365 days following MI. RESULTS: Expenditures among beneficiaries with SAAE and HSA were $40,776 (95% CI $38,329-$43,223) and $26,728 ($26,482-$26,974), respectively, in the 365 days following MI, and $34,238 ($31,396-$37,080) and $29,053 ($28,605-$29,500), respectively, for every year after the first 365 days. Multivariable-adjusted ratios comparing expenditures among beneficiaries with SAAE versus HSA in the first 365 days and after the first 365 days following MI were 1.51 (95% CI 1.43-1.59) and 1.23 (1.12-1.34), respectively. Inpatient and outpatient expenditures were higher among beneficiaries with SAAE versus HSA during and after the first 365 days following MI. Compared to beneficiaries with HSA, medication expenditures among those with SAAE were similar in the 365 days following MI, but higher afterwards. Other medical expenditures were higher among beneficiaries with SAAE versus HSA. CONCLUSION: SAAE are associated with increased expenditures following MI compared with HSA. PMID- 30446885 TI - A note from the Editor. PMID- 30446884 TI - Representations of microgeometric tactile information during object recognition. AB - Object recognition through tactile perception involves two elements: the shape of the object (macrogeometric properties) and the material of the object (microgeometric properties). Here we sought to determine the characteristics of microgeometric tactile representations regarding object recognition through tactile perception. Participants were directed to recognize objects with different surface materials using either tactile information or visual information. With a quantitative analysis of the cognitive process regarding object recognition, Experiment 1 confirmed the same eight concepts (composed of rules defining distinct cognitive processes) commonly generated in both tactile and visual perceptions to accomplish the task, although an additional concept was generated during the visual task. Experiment 2 focused only on tactile perception. Three tactile objects with different surface materials (plastic, cloth and sandpaper) were used for the object recognition task. The participants answered a questionnaire regarding the process leading to their answers (which was designed based on the results obtained in Experiment 1) and to provide ratings on the vividness, familiarity and affective valence. We used these experimental data to investigate whether changes in material attributes (tactile information) change the characteristics of tactile representation. The observation showed that differences in tactile information resulted in differences in cognitive processes, vividness, familiarity and emotionality. These two experiments collectively indicated that microgeometric tactile information contributes to object recognition by recruiting various cognitive processes including episodic memory and emotion, similar to the case of object recognition by visual information. PMID- 30446886 TI - Utility of neutrophil CD64 and serum TREM-1 in distinguishing bacterial infection from disease flare in SLE and ANCA-associated vasculitis. AB - Bacterial and opportunistic infections are a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis owing to treatment with immunosuppressants. Commonly used laboratory tests are unreliable in differentiating infection from active disease patients. Fc receptor (FcgammaR1 or CD64) expression on neutrophils and soluble TREM-1 (triggering receptor expressed on monocytes) are potential biomarkers of bacterial infections. Our aim was to measure the clinical usefulness of quantitative CD64 measurement on neutrophils and soluble TREM-1 measurements in differentiating bacterial infection from active disease in patients with SLE and ANCA vasculitis. Patients with bacterial infection (n = 25), active disease (n = 51), and healthy controls (n = 20) were included. Neutrophil CD64 expression using flow cytometry and sTREM-1 and procalcitonin levels by ELISA were studied. The percentage of neutrophils with CD64 expression and their mean fluorescence intensity in patients with infection (68.8 (56.9-86.5)%, 1037 (229-1828)) were significantly (p < 0.05) higher as compared to those without infection (7.7 (2.6-13.1)%, 456 (20-968)) and controls (7.05 (1.4-9.5)%, 99.5 (54.7-140.7)). The sensitivity and specificity of CD64 expression on neutrophils to diagnose bacterial infection (using a cutoff value of 30%) was 85% and 84%, respectively, whereas the sensitivity and specificity of procalcitonin was 75% and 85%, respectively. There was no significant difference in soluble TREM-1 levels between the two groups. Quantitative measurement of CD64 on neutrophils can distinguish between systemic infection and the flare of autoimmune diseases. PMID- 30446887 TI - Effect of the Plasticizer DEHP in Blood Collection Bags on Human Plasma Fraction Unbound Determination for Alpha-1-Acid Glycoprotein (AAG) Binding Drugs. AB - Fraction unbound (fu) is a critical drug distribution parameter commonly utilized for modeling efficacious dosage and safety margin predictions. An over-estimation of fu for 13 chemically diverse small molecule drugs primarily bound to alpha-1 acid glycoprotein (AAG) in human plasma was discovered when in vitro results from our screening lab were compared to literature values. Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to be used in the manufacture of blood collection bags, was extracted from plasma obtained through three common techniques that allowed contact with DEHP, and drug fu values in plasma from each collection method were estimated using the HTDialysis protein binding methodology. Additionally, fu of test compounds in plasma spiked with varying concentrations of DEHP (0-800 MUM) was determined, and DEHP extractions were performed from plasma stored in Terumo bags over 7 days. Blood stored in Terumo bags, blood collected in Terumo bags, but immediately transferred to conical vials, and vacutainer-collected blood yielded DEHP concentrations of 300-1000 MUM, 1-10 MUM, and 0.1-2 MUM, respectively. This finding corresponded with the fu of tested drugs in DEHP-spiked plasma increasing between 2- and 5-fold. Additionally, DEHP was discovered to leach from the Terumo bag, with concentrations increasing 10 fold over a 7-day test period. In summary, the presence of DEHP in commercially available blood collection bags confounds in vitro fu estimation for drugs that bind primarily to AAG. It is recommended that vacutainer-collected human plasma, which contains negligible DEHP, be used for the most accurate estimation of fu in human plasma. PMID- 30446888 TI - Association Between the Interleukin-17 Gene Polymorphism -197G>A and the Risk of Prostate Cancer in a Galician Population. AB - A case-control study was carried out in which the role of the Single Nucleotide Polymorphism rs2275913 in the pathogenesis of prostate cancer was analysed for the first time. This polymorphism is located in -197 position of IL-17A gene and implies a A>G change. The sample consists of 433 Galician men, 241 of whom are prostate cancer patients and 192 are healthy men with no tumours. Besides the influence of this marker, directly involved in the inflammatory process, other variables that were described as prostate cancer risk factors were also studied: age, smoking and Body Mass Index (BMI). By the analysis of Odds Ratio (OR) (CI 95%) a protective effect of heterozygous genotype AG was observed in comparison with homozygous genotypes AA and GG. As regards other risk factors, a significant increased risk was observed in smokers homozygous between 10 and 32 pack-years (p = 0.032). Age and BMI show interesting patterns, but not significant ones. This study shows a possible link between the rs2275913 and the onset of PCa which could be influenced by age, BMI and above all, smoking. PMID- 30446889 TI - The Coherence Problem: Finding Meaning in GWAS Complexity. AB - Genome wide association studies (GWAS) for behavioral traits and psychiatric disorders have inspired both confident optimism and withering criticism. Although many recent findings from well powered GWAS have been replicated in independent data sets, the genes identified have pinned down few if any underlying causal mechanisms. Therefore, a key issue is whether or not the genes implicated by GWAS form a coherent story on their own and thus could in principle lead to insight into the biological mechanisms underlying the trait or disorder. We sketch here four scenarios for how genes may contribute to traits and disorders; genetic studies may help elucidate mechanisms under only two of our scenarios. We also describe here an approach to characterize, in an unbiased fashion, the molecular coherence of the gene sets implicated by GWAS of various behavioral and psychiatric phenotypes and we sketch how the four scenarios may be reflected in our molecular coherence measure. PMID- 30446890 TI - Metabolic engineering of Corynebacterium glutamicum for improved L-arginine synthesis by enhancing NADPH supply. AB - Corynebacterium glutamicum SNK 118 was metabolically engineered with improved L arginine titer. Considering the crucial role of NADPH level in L-arginine production, pntAB (membrane-bound transhydrogenase) and ppnK (NAD+ kinase) were co-expressed to increase the intracellular NADPH pool. Expression of pntAB exhibited significant effects on NADPH supply and L-arginine synthesis. Furthermore, argR and farR, encoding arginine repressor ArgR and transcriptional regulator FarR, respectively, were removed from the genome of C. glutamicum. The competitive branch pathway gene ldh was also deleted. Eventually, an engineered C. glutamicum JML07 was obtained for L-arginine production. Fed-batch fermentation in 5-L bioreactor employing strain JML07 allowed production of 67.01 g L-1 L-arginine with productivity of 0.89 g L-1 h-1 and yield of 0.35 g g-1 glucose. This study provides a productive L-arginine fermentation strain and an effective cofactor manipulating strategy for promoting the biosynthesis of NADPH dependent metabolites. PMID- 30446891 TI - Heterologous expression-facilitated natural products' discovery in actinomycetes. AB - Actinomycetes produce many of the drugs essential for human and animal health as well as crop protection. Genome sequencing projects launched over the past two decades reveal dozens of cryptic natural product biosynthetic gene clusters in each actinomycete genome that are not expressed under regular laboratory conditions. This so-called 'chemical dark matter' represents a potentially rich untapped resource for drug discovery in the genomic era. Through improved understanding of natural product biosynthetic logic coupled with the development of bioinformatic and genetic tools, we are increasingly able to access this 'dark matter' using a wide variety of strategies with downstream potential application in drug development. In this review, we discuss recent research progress in the field of cloning of natural product biosynthetic gene clusters and their heterologous expression in validating the potential of this methodology to drive next-generation drug discovery. PMID- 30446892 TI - [Integrated neurorehabilitation improves efficacy of treatment]. AB - Neurorehabilitation comprises medical and functional treatment. If patients in the post-hospital phase need acute medical interventions but these cannot be provided by the rehabilitation center, patients must be referred to suitable acute care hospitals; however, such referrals incur additional costs, are fraught with medical risks and delay further rehabilitation. We evaluated how integrating non-neurological medical specialties and a hospital unit into a neurorehabilitation center affects the rate of acute hospital referrals. The special situation in North-Rhine Westfalia, which was the last state in Germany to grant restricted hospital certification to neurorehabilitation centers, enabled a longitudinal assessment over 10 years. We analyzed the referral rate at one of the first hospitals in the state, which in addition to rehabilitation treatment (according to S 40 of the Social Security Code V, SGB V) now also provide hospital treatment (according to S 39 SGB V) and have reorganized in preparation for integrated treatment structures. In the center investigated (St. Mauritius Therapy Hospital Meerbusch) the average patient age increased between 2007 and 2017 from 69 years to 72 years and the proportion of severely ill patients on admission by 70%. Starting in 2012 integrated structures were established in a stepwise fashion with the inclusion of specialists in intensive care, cardiology and neurosurgery, extension of the diagnostic and interventional spectrum and establishment of a 24/7 emergency team with back-up from a new intensive care and mechanical ventilation unit. As a result referrals to hospitals dropped by more than 50% in all categories of disease severity despite the increase in age and morbidity. In view of the savings in costs of hospital treatment, reduced risks due to transfer and less interruption of rehabilitation, it is concluded that the efficacy of patient treatment is improved by discipline and sector integrated neurorehabilitation compared to isolated structures. PMID- 30446894 TI - Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation. AB - Background Dosage quantities of tacrolimus (TAC) vary according to cytochrome P450 3A5 (CYP3A5) genotype. Genotyping is expected to optimize the response to TAC response and to minimize adverse effects. In Thailand, kidney transplantation is reimbursable with the same diagnosis-related group payment regardless of patient's CYP3A5 genotype. Objective This study aimed to determine the costs of TAC administration, therapeutic drug monitoring (TDM), and hospitalization for kidney transplantation across CYP3A5*1/*1, *1/*3, and *3/*3 genotypes. Setting A single transplant center in a university hospital. Method This is an observational study that collected data from patients pooled from both arms of a randomized controlled trial that tested initial doses of TAC. Main outcome measure TAC and TDM cost and hospitalization cost for transplantation were compared between genotypes. Results The CYP3A5*1/*1 patients had the highest median combined TAC-TDM cost and hospitalization cost ($1062 and $9097), followed by CYP3A5*1/*3 ($859 and $6467) and CYP3A5*3/*3 patients ($761 and $5604). The CYP3A5*1/*1 patients had a higher hospitalization cost by $2787 over the CYP3A5*1/*3 patients, despite marginal significance. The CYP3A5*1/*1 patients had a significantly higher cost of TAC plus TDM (by $309) and hospitalization cost (by $3275) than the CYP3A5*3/*3 patients. Both study costs were significantly higher in patients with delayed graft functioning than in patients with instant or slow graft functioning. Conclusion The benefits of genotype detection in patients with CYP3A5*1/*1 should be considered for a higher reimbursement rate because of the substantial differences in total hospitalization cost for kidney transplantation among patients with different CYP3A5 genotypes. PMID- 30446893 TI - [Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. AB - Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology. PMID- 30446896 TI - Medication prescribing errors: a pre- and post-computerized physician order entry retrospective study. AB - Background The computerization of prescriptions with a computerized physician order entry contributes to securing the error-free drug supply, but is not risk free. Objective: To determine the impact of a computerized physician order entry system on prescribing errors immediately after its implementation and 1 year later. Setting The Cardiology and Diabetology Departments at Toulouse University Hospital, France. Method The prescriptions were analysed by pharmacists over three 30-day periods for 3 consecutive years (N: computerization period, N - 1, N + 1). For each identified error, the prescriber was informed by a pharmaceutical intervention. The pharmaceutical interventions were counted and arranged according to the classification by the French Society of Clinical Pharmacy. Their average numbers and clinical impacts were compared for each period using t-tests and Kruskal-Wallis tests. Main outcome measure The average numbers of pharmaceutical interventions. Results In total, 12.1 pharmaceutical interventions per 100 patient days were done during the N - 1 period, 14.1 during N and 9.6 during N + 1. Among those, 3.6 (N) and 2.1 (N + 1) were related to the computerization itself, and 10.5 (N) and 7.5 (N + 1) were not. The average number of computerization-related pharmaceutical interventions significantly decreased from N to N + 1 (p = 0.04). The average number of classic interventions decreased from N - 1 to N + 1 (p = 0.02). The clinical impacts of the computerization related errors were similar to those of other errors. Conclusion The implementation of the computerized physician order entry induced the appearance of specific computerized-related errors, but the number of classic errors decreased. The entry-system related errors were not more severe than other errors, and the number decreased after 1 year. PMID- 30446895 TI - Effectiveness of antibiotic therapy in pediatric patients with cat scratch disease. AB - Background Appropriate antibiotic treatment of cat scratch disease (CSD) in pediatrics is not well established. Objective The purpose of this study was to evaluate the response rates of antibiotic therapy in pediatrics with CSD. Methods The electronic medical records of a cohort of pediatric patients with confirmed diagnosis of CSD (2006-2016) were reviewed, retrospectively. Data collection included patient demographics, clinical and laboratory results, antibiotic treatment and follow-up evaluations. Results One hundred and seventy-five patients (aged 7.4 +/- 4.4 years) had confirmed CSD. Azithromycin and trimethoprim/sulfamethoxazole (TMP/SMX) were the largest groups with documented effectiveness at follow-up visits. Resolution and improvement of CSD was observed in 51.4% and 61.5% of patients with azithromycin and TMP/SMX, respectively among those with follow-up assessment. The effectiveness of azithromycin and TMP/SMX was comparable (p = 0.56). Conclusion Azithromycin and TMP/SMX were most frequently prescribed antibiotics. Azithromycin appeared to be an appropriate option for the treatment of CSD. TMP/SMX may be considered as an alternative antibiotic when azithromycin cannot be used. PMID- 30446897 TI - Survey of outpatients' use and needs of patient medicine information leaflets in Thailand. AB - Background Patient information leaflets are important sources of medicine information. Regulations of patient information leaflet provision varies among country. Little is known regarding patients' behavior and expectation on use of patient information leaflets. Objectives To explore patients' use of either package inserts or patient information leaflets and to survey patients' expectations and needs on use of patient information leaflets and their associated factors. Setting Two university hospitals in Thailand. Methods Cross sectional study using self-administered questionnaires distributed to outpatients over a 3-month period. Participants were selected through systematic random sampling. Logistic regression was used for data analysis. Main outcome measure Patient use of medicine information. Visual Analogue Scale scores for patient needs and their expectation of knowledge gains from using patient information leaflets. Results The response rate was 77.0%. Most respondents had received package inserts (91.3%) with 59.4% reporting that they sometimes read them. While most respondents had not previously known about patient information leaflets (75.9%), 97.3% reported that patient information leaflets would be useful. Respondents scored their needs and expected knowledge gains after reading patient information leaflets as 9.68 +/- 0.97 and 9.64 +/- 0.99, respectively. Previous experience with package inserts was associated with increased patient need scores (p = 0.002) and higher expected knowledge gains from use of patient information leaflets (p = 0.037). In addition, patients who had not previously known about patient information leaflets had higher expectations of knowledge gains (p = 0.016). Conclusion Overall, patients showed good behavior on reading package inserts. Although many patients were not previously aware of patient information leaflets, they realized the importance. Hence, patient information leaflets should be developed and provided to Thai patients. PMID- 30446899 TI - Functional relevance of genes predicted to be affected by epigenetic alterations in atypical teratoid/rhabdoid tumors. AB - PURPOSE: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly arising in infants. Mutations of SWI/SNF chromatin remodeling complex members SMARCB1/INI1 or (rarely) SMARCA4/Brg1 are the sole recurrent genetic lesions. Epigenetic studies revealed a large number of genes predicted to be affected by differential histone modifications in ATRT, but the role of these genes in the biology of ATRT remains uncertain. We therefore aimed at exploring the role of these genes in the detrimental effects of SMARCB1-deficiency. METHODS: The functional relevance of 1083 genes predicted to be affected by epigenetic alterations in ATRT was examined in vivo using a Drosophila melanogaster model of SMARCB1-deficiency. Human orthologues of genes whose knockdown modified the phenotype in the Gal4-UAS fly model were further examined in ATRT samples and SMARCB1-deficient rhabdoid tumor cells. RESULTS: Knockdown of Snr1, the fly orthologue of SMARCB1, resulted in a lethal phenotype and epigenetic alterations in the fly model. The lethal phenotype was shifted to later stages of development upon additional siRNA knockdown of 89 of 1083 genes screened in vivo. These included TGF-beta receptor signaling pathway related genes, e.g. CG10348, the fly orthologue of transcriptional regulator PRDM16. Subsequently, PRDM16 was found to be over-expressed in ATRT samples and knockdown of PRDM16 in SMARCB1-deficient rhabdoid tumor cells reduced proliferation. CONCLUSIONS: These results suggest that a subset of genes affected by differential histone modification in ATRT is involved in the detrimental effects of SMARCB1-deficiency and also relevant in the biology of ATRT. PMID- 30446898 TI - International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma. AB - PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor. PMID- 30446900 TI - Tubular brain tumor biopsy improves diagnostic yield for subcortical lesions. AB - PURPOSE: Molecular data has become an essential part of the updated World Health Organization (WHO) grading of central nervous system tumors. However, stereotactic needle biopsies provide only small volume specimens and limit the extent of histologic and molecular testing that can be performed. We assessed the use of a tubular retractor-based minimally invasive biopsy technique to provide improved tissue yield and diagnostic data compared to needle biopsy. METHODS: Eighteen patients underwent an open transtubular biopsy compared to 146 stereotactic biopsies during the years of 2010-2018. RESULTS: Tubular biopsies resulted in a higher volume of tissue provided to the pathologist than needle biopsies (1.26 cm3 vs. 0.3 cm3; p < 0.0001). There was a higher rate of non diagnostic sample with stereotactic compared to transtubular biopsy (13% vs. 0%; p = 0.13). Six patients who underwent stereotactic biopsy required reoperation for diagnosis, while no transtubular biopsy patient required reoperation in order to obtain a diagnostic specimen. Postoperative hematoma was the most common post operative complication in both groups. CONCLUSIONS: Stereotactic transtubular biopsies are a viable alternative to stereotactic needle biopsies with excellent rates of diagnostic success and acceptable morbidity relative to the needle biopsy technique. As molecular data begins to increasingly drive treatment decisions, additional biopsy techniques that afford large tissue volumes may be necessary to adapt to the new needs of pathologists and treating oncologists. PMID- 30446901 TI - Lower expression of Bax predicts poor clinical outcome in patients with glioma after curative resection and radiotherapy/chemotherapy. AB - BACKGROUND: The prognosis in patients with gliomas after surgical resection followed by radiotherapy and/or chemotherapy is still very poor. The pro apoptotic protein Bax, a short-lived protein in cancers, plays important roles in the sensitivity of glioma cells to spontaneous and therapy-induced apoptosis but and its prognostic value in gliomas is unknown. METHODS: By an immunohistochemical method, we determined Bax protein expression from 96 patients with gliomas after curative resection. Two statistical analyses were performed to evaluate the prognostic significance of Bax protein: an independent continuous and a multivariate categorical analysis, with test/validation set-defined cut points, and Kaplan-Meier estimated outcome measures of overall survival (OS) and relapse-free survival (RFS). RESULTS: Bax protein levels in glioblastoma were significantly decreased compared with grade II gliomas. Lower levels of Bax expression confer worse OS (continuous P = 0.025; categorical P = 0.003) and RFS (continuous P = 0.014; categorical P < 0.0001) and negatively correlate with the grades of gliomas. Patients underwent radiotherapy followed by surgical resection showed significantly increased OS (median = 45 vs. 17 months) and RFS (median = 39 vs. 16 months). Patients with higher levels of Bax and radiotherapy showed greatly increased survival rates (median OS = 66 months and median RFS = 105 months). Lower expression of Bax also confers inferior clinical outcome for gliomas patients after chemotherapy with temozolomide (OS and RFS P < 0.0001). CONCLUSION: Decreased expression of Bax correlates with poor clinical outcome in patients with gliomas. We propose that Bax protein levels can be used as a reliable prognostic marker for risk-stratify patients with gliomas after curative resection and radiotherapy and/or chemotherapy. PMID- 30446902 TI - Effects of surgery on neurocognitive function in patients with glioma: a meta analysis of immediate post-operative and long-term follow-up neurocognitive outcomes. AB - PURPOSE: This study aims to identify the neuropsychological tests commonly used for assessment in each neurocognitive domain, and quantify the post-operative changes in neurocognitive function in the immediate post-operation and follow-up. METHODS: With the use of the PubMed, a comprehensive search of the English literature was performed following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. There were 1021 publications identified for screening. Standardized mean differences (SMD) in neuropsychological task performance were calculated both for immediate post operation (up to 1 week) and follow-up (up to 6 months). RESULTS: Out of 12 studies which met the inclusion criteria, 11 studies were analyzed in this meta analysis, with a total of 313 patients (age range 18-82, 50% males) with intracranial gliomas (45% high-grade, 55% low-grade). Complex attention, language and executive function were the most frequently tested neurocognitive domains. Surgery had a positive impact in the domains of complex attention, language, learning and memory tasks in the immediate post-operative period and sustained improvement at follow-up. In contrast, surgery was found to negatively impact performance for executive function in the immediate post-operative period with sustained decline in performance in the long term. CONCLUSIONS: This meta analysis suggests that surgery for glioma confers a benefit for the domains of complex attention, language, learning and memory, while negatively affecting executive function, in the periods immediately after surgery and at 6 months follow-up. In addition, awake surgery seemed to confer a beneficial effect on neurocognitive functions. Future research should attempt to standardize a battery of neuropsychological tests for patients undergoing surgical resection for glioma, perhaps with a particular focus on executive function. PMID- 30446904 TI - Motivational Interviewing Training Outcomes Among Providers in a Children's Hospital. AB - Motivational interviewing (MI) has proven a well-established psychotherapeutic intervention designed to enhance motivation for behavior change. While the benefits of MI have been established, little research has systematically evaluated dissemination of MI efforts to healthcare providers, especially among pediatric providers. The present pilot study evaluated whether healthcare providers gained valuable knowledge, confidence and desire to utilize MI, and skills in MI techniques and if these outcomes varied based on provider characteristics or duration and intensity of MI training. Twenty pediatric healthcare professionals in a large academic pediatric hospital completed an advanced 20-h MI training and 103 pediatric healthcare professionals completed a basic 4-h MI workshop. The study demonstrated no significant differences in post workshop MI knowledge, confidence, or desire based on trainee demographics. We also found no significant change from post-basic workshop to post-advanced workshop for advanced MI trainees. However, the advanced training workshop participants evidenced significant growth in utilizing MI skills (via MITI coding) and self-reported confidence in using MI skills. We therefore conclude that while the basic workshop allows participants to gain valuable MI knowledge and confidence and desire to utilize MI, it is through the advanced training that providers have the opportunity to practice these skills, receive feedback, and ultimately gain the expertise necessary to be effective MI providers. Overall, results from this pilot study suggest MI training in pediatric hospitals represents an important area of opportunity for multidisciplinary training, dissemination, and practice. PMID- 30446903 TI - Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma. AB - PURPOSE: The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic characteristics in glioblastoma tumors resected after chemoradiotherapy are associated with overall survival (OS). METHODS: The following characteristics were quantified in recurrent glioblastoma specimens at our institution: extent of viable tumor (accounting for % of specimen comprised of tumor and tumor cellularity), mitoses per 10 high-power fields (0, 1-10, > 10), Ki-67 proliferative index (0-100%), hyalinization (0-6; none to extensive), rarefaction (0-6), hemosiderin (0-6), and % of specimen comprised of geographic necrosis (0-100%; converted to 0-6 scale). Variables associated with OS in univariate analysis, as well as age, eastern cooperative oncology group performance status (ECOG PS), extent of repeat resection, time from initial diagnosis to repeat surgery, and O6-methylguanine-DNA methyltransferase promoter methylation, were included in a multivariable Cox proportional hazards model. RESULTS: 37 specimens were assessed. In a multivariate model, high Ki-67 proliferative index was the only histopathologic characteristic associated with worse OS following repeat surgery for glioblastoma (hazard ratio (HR) 1.3, 95% CI 1.1-1.5, p = 0.003). Shorter time interval from initial diagnosis to repeat surgery (HR 1.11, 95% CI 1.02-1.21, p = 0.016) and ECOG PS >= 2 (HR 4.19, 95% CI 1.72-10.21, p = 0.002) were also independently associated with inferior OS. CONCLUSION: In patients with glioblastoma undergoing repeat resection following chemoradiotherapy, high Ki-67 index in the recurrent specimen, short time to recurrence, and poor PS are independently associated with worse OS. Histopathologic quantification of viable tumor versus therapy-related changes has limited prognostic influence. PMID- 30446905 TI - Active Commuting and Multiple Health Outcomes: A Systematic Review and Meta Analysis. AB - BACKGROUND: Active commuting is associated with greater physical activity, but there is no consensus on the actual beneficial effects of this type of physical activity on health outcomes. OBJECTIVE: To examine the association between active commuting and risk of all-cause mortality, incidence and mortality from cardiovascular diseases, cancer and diabetes through meta-analysis. METHODS: A comprehensive search of MEDLINE, Embase, Google Scholar, Web of Science, The Cochrane Library, Transport Research International Documentation database, and reference lists of included articles was conducted. Only prospective cohort studies were included. RESULTS: Twenty-three prospective studies including 531,333 participants were included. Participants who engaged in active commuting had a significantly lower risk of all-cause mortality [relative risk (RR) 0.92, 95% CI 0.85-0.98] and cardiovascular disease incidence (RR 0.91; 95% CI 0.83 0.99). There was no association between active commuting and cardiovascular disease mortality and cancer. Participants who engaged in active commuting had a 30% reduced risk of diabetes (RR 0.70; 95% CI 0.61-0.80) in three studies after removal of an outlying study that affected the heterogeneity of the results. Subgroup analyses suggested a significant risk reduction (- 24%) of all-cause mortality (RR 0.76; 95% CI 0.63-0.94) and cancer mortality (- 25%; RR 0.75; 95% CI 0.59-0.895) among cycling commuters. CONCLUSION: People who engaged in active commuting had a significantly reduced risk of all-cause mortality, cardiovascular disease incidence and diabetes. PMID- 30446906 TI - Neuroprotective influence of sitagliptin against cisplatin-induced neurotoxicity, biochemical and behavioral alterations in Wistar rats. AB - Cisplatin has been extensively used as a chemotherapeutic agent since around 40 years, though its usage is limited due to severe adverse effects like neurotoxicity that might be because of oxidative stress. Hence, the present study was planned to investigate the possible protective role of sitagliptin against cisplatin-associated neurotoxic, biochemical, and behavioral alterations in male Wistar rats. Sitagliptin is a dipeptidyl peptidase-4 inhibitor that shows dual effects by improving the control on metabolism as well as decreasing the debility in cognitive function that is associated with increased insulin sensitivity and antioxidant property. For the in vitro assay, cultured rat pheochromocytoma (PC12) cells were exposed to different concentrations (10, 20, and 50 mM) of sitagliptin for 24 h. Cisplatin at 5 mM concentrations was added and cell viability was assessed using MTT assay. For in vivo study, animals were divided into four groups. Group I (Vehicle control): animals were administered 0.9% (w/v) of normal saline (1 mL/100 g; p.o.). Group II (Cisplatin): animals were treated with cisplatin (2 mg/kg; i.p.). Group III (Cisplatin + sitagliptin): animals were administered cisplatin along with sitagliptin. Group IV (Sitagliptin): animals were given sitagliptin (10 mg/kg; p.o.). All the treatments were administered for 8 weeks. On last day of treatment, behavioral evaluations including locomotor and rotarod studies were performed. In addition, several antioxidant enzymes were also estimated from cerebellum tissues; such as levels of thiobarbituric acid reactive substance (TBARS) were determined as a marker of lipid peroxidation, reduced glutathione (GSH) and catalase (CAT) were also estimated. Histological study of cerebellum tissue was also performed after performing the behavioral study. Exposure to cisplatin decreased cell viability in PC12 cells which were significantly increased by co-treatment with sitagliptin. In in vivo study, cisplatin significantly elevated the level of TBARS and reduced the level of antioxidant enzymes such as GSH and CAT which were significantly restored in sitagliptin + cisplatin group of rats. In addition, cisplatin impaired performance on the locomotor and rotarod activities, whereas sitagliptin significantly improved the performance of both activities. These results suggested the neuroprotective influence of sitagliptin by protecting cerebellum part of brain against cisplatin-induced toxicity. PMID- 30446907 TI - Concomitance of downregulated active caspase-3 and upregulated X-chromosome linked inhibitor of apoptosis protein as a sensitive diagnostic approach for breast cancer. AB - We aimed to explore the efficacy of active caspase-3 and X-chromosome linked inhibitor of apoptosis protein (XIAP) as diagnostic markers for breast cancer. Furthermore, we examined the relationship between the examined parameters and clinicopathological factors. The current study involved 96 patients diagnosed with breast cancer and 40 patients had benign breast diseases. The expression of active caspase-3 was analyzed by both ELISA and Western blot, whereas the expression of XIAP was determined by ELISA in cell lysates. Active caspase-3 was significantly downregulated, while XIAP was markedly upregulated in patients with breast cancer in comparison to benign group. A significant negative correlation was observed between active caspase-3 and XIAP in breast cancer patients. Low active caspase-3 expression was associated with high grade, whereas, the high XIAP level was correlated with poorly differentiated tumors and late tumor stages. The sensitivity and specificity were 73.96% and 80.0% for active caspase 3, and, 70.83% and 82.5% for XIAP. A combination of active caspase-3 and XIAP provided a promising sensitivity of 88.54% and specificity of 90.0%. Our data indicate that active caspase-3 and XIAP could be substantial diagnostic markers for breast cancer patients. PMID- 30446908 TI - Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonin and omega-3 fatty acids in female rats. AB - We aimed to explore whether specific high-sucrose intake in older female rats affects myocardial electrical coupling protein, connexin-43 (Cx43), protein kinase C (PKC) signaling, miR-1 and miR-30a expression, and susceptibility of the heart to malignant arrhythmias. Possible benefit of the supplementation with melatonin (40 ug/ml/day) and omega-3 polyunsaturated fatty acids (Omacor, 25 g/kg of rat chow) was examined as well. Results have shown that 8 weeks lasting intake of 30% sucrose solution increased serum cholesterol, triglycerides, body weight, heart weight, and retroperitoneal adipose tissues. It was accompanied by downregulation of cardiac Cx43 and PKCepsilon signaling along with an upregulation of myocardial PKCdelta and miR-30a rendering the heart prone to ventricular arrhythmias. There was a clear benefit of melatonin or omega-3 PUFA supplementation due to their antiarrhythmic effects associated with the attenuation of myocardial Cx43, PKC, and miR-30a abnormalities as well as adiposity. The potential impact of these findings may be considerable, and suggests that high-sucrose intake impairs myocardial signaling mediated by Cx43 and PKC contributing to increased susceptibility of the older obese female rat hearts to malignant arrhythmias. PMID- 30446909 TI - Improving Patients' Choice of Clinician by Including Roll-up Measures in Public Healthcare Quality Reports: an Online Experiment. AB - BACKGROUND: Public reports on healthcare quality typically include complex data. To lower the cognitive burden of interpreting these data, some report designers create summary, or roll-up, measures combining multiple indicators of quality into one score. Little is known about how the availability of roll-ups affects clinician choice. OBJECTIVE: To determine how presenting quality scores at different levels of aggregation affects patients' clinician choices. DESIGN: We conducted a simulated clinician-choice experiment, randomizing participants to three versions of a public reporting website and comparing their clinician choices. One version aggregated all clinician-level quality measures into roll ups, the second provided disaggregated (drill-down) scores only, and the third offered both roll-ups and drill-downs. PARTICIPANTS: Five hundred fifty panelists drawn from a probability-based Internet panel. MAIN MEASURES: We assessed the amount of effort participants exerted by tracking the length of time spent on the website and the number of concrete actions taken on the website (e.g., clicking items). We evaluated decision quality by measuring whether participants selected a clinician who performed more poorly than others and incongruence between participants' stated preferences for dimensions of quality and their chosen clinician's performance on those dimensions. KEY RESULTS: Participants seeing drill-downs alone (mean = 14.9) or with roll-ups (mean = 19.2) took more actions than those who saw roll-ups alone (mean = 10.5) (ps < 0.05). However, participants seeing only drill-downs made poorer choices than those who saw roll ups alone or with drill-downs. More participants seeing drill-downs chose a clinician who was outperformed (36.3% versus 23.4% [roll-up] and 25.6% [drill down + roll-up], ps < 0.05) and made choices incongruent with stated preferences (51.2% versus 45.6% [roll-up] and 47.5% [drill-down + roll-up], ps < 0.05). The distinction between roll-up and drill-down was somewhat stronger for sicker participants. CONCLUSIONS: Our results suggest that roll-ups in healthcare quality reports, alone or as a complement to drill-downs, can help patients make better decisions for themselves. PMID- 30446910 TI - Preparation of carbonaceous materials from pyrolysis of chicken bones and its application for fuchsine adsorption. AB - Activated carbon and biochar were obtained from chicken bone (CB), characterized, and applied to remove basic fuchsine from aqueous media. The adsorbent dosage and pH effects were studied, as well as kinetic, equilibrium, and thermodynamic curves were constructed. The values of BET surface area and total pore volume were 108.94 m2 g-1 and 0.219 cm3 g-1 for the activated carbon and, 18.72 m2 g-1 and 0.075 cm3 g-1 for the biochar. The dye removal percentages were 93.63 and 55.38% when 2.5 g L-1 of activated carbon and biochar were used, respectively. The adsorption was favored using 0.5 g L-1 of adsorbent and pH of 7.0. Adsorption kinetics was well represented by the pseudo-second-order model. Langmuir model was the best to represent the equilibrium. Maximum adsorption capacity was 260.8 mg g-1, obtained using activated carbon. The process was endothermic, favorable, and spontaneous. Results showed that alternative carbonaceous materials can be obtained from chicken bones and used as adsorbents to treat colored effluents containing fuchsine. PMID- 30446911 TI - Adsorption characteristics of Cu(II) and Zn(II) by nano-alumina material synthesized by the sol-gel method in batch mode. AB - This study mainly focuses on the preparation, characterization, and sorption performance for Cu(II) and Zn(II) by using nano-alumina material (NA) synthesized through the sol-gel method. The SEM, EDS, FT-IR, and XRD analysis methods were implemented to identify the micromorphology and crystal structure of the synthesized NA absorbent and its structure after the adsorbing procedure. The effect of effective variables including various absorbent dose, contact time, initial ion concentration, and temperature on the removal of Cu(II) and Zn(II) from aqueous solution by using NA was investigated through a single factor experiment. Kinetic studies indicated that adsorption of copper and zinc ions by NA was chemical adsorption. The adsorption isotherm data were fitted by Langmuir (R2: 0.919, 0.914), Freundlich (R2: 0.983, 0.993), and Temkin (R2: 0.876, 0.863) isotherms, indicating that copper and zinc ions were easily adsorbed by NA with maximum adsorption capacities of 87.7 and 77.5 mg/g for Cu2+ and Zn2+, respectively. Thermodynamic parameters indicated that the adsorption of Cu2+ was spontaneous(G<0) and the adsorption of Zn2+ might not be spontaneous (G > 0) by NA. Graphical abstract ?. PMID- 30446912 TI - Removal of low-concentration thiophene by DC corona discharge plasma. AB - This study focuses on the removal of C4H4S using DC corona discharge plasma. The influences of various factors such as C4H4S concentration (ppm), temperature ( degrees C), O2 concentration (%), and dust concentration (mg/m3) on the conversion of C4H4S were studied. Furthermore, gaseous compositions were determined using Fourier transform infrared (FTIR) spectroscopy. Solid products, which were collected from earth and discharge electrodes, were analyzed using X ray diffraction (XRD). The results showed that, under the condition of DC corona discharge plasma, C4H4S converted to CO, CO2, S, SO2, and SO42-, and that the conversion rate increased with the increase in specific input energy (SIE). The increase of O2 concentration led to further energy consumption that generated O3, which in turn decreased the conversion rate of C4H4S. The increase in temperature exhibited a positive influence on the conversion of C4H4S when the SIE was less than 268 J/L. However, above this value of SIE, the temperature affected the conversion of C4H4S negatively with the increase in SIE. When dust was introduced, the conversion of C4H4S was significantly improved and the yield of SO2 reduced due to the reaction which took place among C4H4S, SO2 and dust in the electric field. The results showed that the DC corona discharge plasma exhibited considerable potential to remove C4H4S, while dust contributed positively towards the disposal of C4H4S. Graphical abstract In this work, DC corona plasma was used to remove thiophene (C4H4S) from a dust-containing gas stream. The results showed that electron collision, oxidizability of radicals, and existence of O3 were the main causes of C4H4S decomposition. The electron collision effects, contents of radicals, O3, and the conversion rate of C4H4S were enhanced with the increase in SIE (specific input energy). The main products consisted of CO, CO2, SO2, and solid products. The solid products and dust moved to the earth electrode in the electric field. PMID- 30446913 TI - Spatial distribution of heavy metal concentrations in peri-urban soils in eastern China. AB - Complex land use patterns and intense human activities significantly affect the spatial distribution of heavy metals in soils. This is especially true in peri urban areas. The land use in peri-urban areas is complex and the risk of heavy metal pollution is relatively high. Identifying the correlations between land use patterns and spatial distribution of heavy metals in peri-urban soils is important for enhancing soil security and sustaining soil ecosystem services in areas undergoing rapid urbanisation. In this study, soil samples were collected from 82 experimental sites in a typical peri-urban watershed in eastern China. Copper (Cu), zinc (Zn), cadmium (Cd), nickel (Ni), arsenic (As), chromium (Cr), lead (Pb) and mercury (Hg) concentrations at different soil depths were analysed. Results showed that heavy metal concentrations in peri-urban soils were significantly affected by land use type and varied with soil depth. Farmland had the highest heavy metal concentrations, whereas forestland had the lowest concentrations; the concentrations in soils decreased with increasing soil depth. Spatial analysis of heavy metals in soils showed that their concentrations rapidly increased with the increasing percentage of town areas in buffer zones. This indicated that land use structure influenced the heavy metal concentrations in peri-urban soils and the influences were correlated to the locations of towns and villages. Correlation analysis showed that Cu, Zn, Cd, Pb and Hg concentrations in soils were significantly affected by altitude, distance from roads, distance from towns and villages and soil clay content. Interestingly, historic land use was also found to affect heavy metal concentrations in forestland. These results can provide scientific guidance for designing effective soil management practices for peri-urban areas. PMID- 30446914 TI - A novel approach to preparation of nano-adsorbent from agricultural wastes (Saccharum officinarum leaves) and its environmental application. AB - Saccharum officinarum leaves (SL) assisted nano-silica (NS) were synthesized and used as adsorbent to remove Pb2+ and Zn2+ from aqueous solutions. The crystalline nature, functional group, and morphology structure of synthesized NS were characterized by X-ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), field emission-scanning electron microscopy (FESEM) with EDS mapping, and transmission electron microscopy (TEM). The surface area and charge of the NS were also analyzed by Brunauer-Emmett-Teller (BET) and zeta potential analysis. Removal efficiency of Pb2+ and Zn2+ from aqueous solutions was carried out under batch mode studies (pH, dose, equilibrium time with initial heavy weight metal ion concentration). The adsorption parameters were determined using pseudo-first-order, pseudo-second-order, Langmuir, and Freundlich models. The kinetics and isotherms data were well fitted with pseudo-second-order and both Langmuir and Freundlich isotherm models. The maximum adsorption capacities for Pb2+ and Zn2+ onto NS at room temperature (37 degrees C) were found to be 148 mg/g and 137 mg/g, respectively. Finally, we conclude that the NS synthesized from SL leaves (agricultural waste material) were found to be economically viable, promising adsorbent for metal ions from aqueous solutions and also efficient technology for waste management. PMID- 30446915 TI - Bioconcentration studies with the freshwater amphipod Hyalella azteca: are the results predictive of bioconcentration in fish? AB - Bioconcentration factors (BCF) for regulatory purposes are usually determined by fish flow-through tests according to technical guidance document OECD 305. Fish bioconcentration studies are time consuming, expensive, and use many laboratory animals. The aim of this study was to investigate whether the freshwater amphipod Hyalella azteca can be used as an alternative test organism for bioconcentration studies. Fourteen substances of different hydrophobicity (log Kow 2.4-7.6) were tested under flow-through conditions to determine steady state and kinetic bioconcentration factors (BCFss and BCFk). The results were compared with fish BCF estimates for the same substances described in the literature to show the relationship between both values. Bioconcentration studies with the freshwater amphipod H. azteca resulted in BCF estimates which show a strong correlation with fish BCF values (r2 = 0.69). Hyalella BCF values can be assessed in accordance with the regulatory B criterion (BCF > 2000, i.e., REACH) and thereby enable the prediction of B or non-B classification in the standard fish test. Therefore, H. azteca has a high potential to be used as alternative test organism to fish for bioconcentration studies. PMID- 30446916 TI - Correction to: Tree-Based Unrooted Phylogenetic Networks. AB - The level-5 example of a network presented in Fig. 4 of Francis et al. (2018) is tree-based even though it states in the caption and in the text that this is not the case. PMID- 30446917 TI - Author's reply. PMID- 30446918 TI - The role of extracellular vesicles as biomarkers in colorectal cancer. PMID- 30446919 TI - Culotte versus the novel nano-crush technique for unprotected complex bifurcation left main stenting: difference in procedural time, contrast volume and X-ray exposure and 3-years outcomes. AB - To assess the procedural performance and 3-years outcomes of unprotected complex bifurcation Left Main (LM) stenting using either Culotte or the novel nano-crush techniques, consisting in the use of two ultra-thin strut stents with a 1-ring stent crushed into the LM. We analysed the records of patients with complex distal/bifurcation LM disease and contraindications and/or refusal of bypass surgery, who from 1 January 2014 to 1 November 2017, received at operators' discretion LM double stenting by means of nano-crush technique using Orsiro (Biotronik Inc, Bulack, Switzerland) or Onyx (Medtronic Inc, Galway, Ireland) stents or Culotte stenting using same stent platforms. Among 65 patients (28 females, mean age 77.2 +/- 6.2 years), 32 received nano-crush while 33 patients received Culotte technique. Mean angles between left anterior descending coronary artery and left circumflex was 63.6 +/- 21.3 degrees . Post-operative success was achieved in 100% of cases. Nano-crush patients showed lower contrast medium volume and X-ray exposure, shorter fluoroscopy and procedural times compared to Culotte patients group. At a mean follow-up of 27.4 +/- 10.8 months, clinical driven target lesion revascularization, myocardial infarction and cardiovascular death were 0 versus 4/33 (12.1%, p = 0.04), 1/32 (3.1%) versus 6/33 (18.1%, p = 0.03) and 2/32 (6.2%) versus 8/33 (24.2%, p = 0.04) in nano-crush versus Culotte patients, respectively. In this single center study, the nano-crush technique was associated with less use of contrast, less procedural time and less X-ray exposure compared to the culotte technique for the treatment of unprotected left main bifurcation lesions. PMID- 30446920 TI - Physical activity, sitting, and risk factors of cardiovascular disease: a cross sectional analysis of the CARRS study. AB - We aimed to estimate the associations between substituting 30-min/day of walking or moderate-to-vigorous physical activity (MVPA) for 30 min/day of sitting and cardiovascular risk factors in a South Asian population free of cardiovascular disease. We collected information regarding sitting and physical activity from a representative sample of 6991 participants aged 20 years and above from New Delhi, India and Karachi, Pakistan enrolled in 2010-2011 in the Center for cArdio metabolic Risk Reduction in South Asia study using the International Physical Activity Questionnaire (short form). We conducted isotemporal substitution analyses using multivariable linear regression models to examine the cross sectional associations between substituting MVPA and walking for sitting with cardiovascular risk factors. Substituting 30 min/day of MVPA for 30 min/day of sitting was associated with 0.08 mmHg lower diastolic blood pressure (beta = 0.08 [- 0.15, - 0.0003]) and 0.13 mg/dl higher high-density lipoprotein cholesterol (beta = 0.13 [0.04, 0.22]). Substituting 30 min/day of walking for 30 min/day of sitting was associated with 0.08 kg/m2 lower body mass index (beta = 0.08 [- 0.15, - 0.02]), and 0.25 cm lower waist circumference (beta = -0.25 [- 0.39, - 0.11]). In conclusion, substituting time engaged in more-active pursuits for time engaged in less-active pursuits was associated with modest but favorable cardiovascular risk factor improvements among South Asians. PMID- 30446921 TI - The relationship between indoor tanning and body mass index, physical activity, or dietary practices: a systematic review. AB - A systemic review was conducted to better understand the relationship between indoor tanning and body mass index (BMI), physical activity, or dietary practices. Articles included in this review were obtained via a systematic search of PubMed following PRISMA guidelines. Available articles were published between September, 2003 and May, 2017 and contained data regarding indoor tanning and BMI, physical activity, or dietary practices. Sixteen publications met final inclusion criteria. Results of this review indicate significant positive associations between indoor tanning and high physical activity levels, playing sports, and both unhealthy and healthy diet and weight control practices. Frequent or dependent indoor tanning was associated with unhealthy dietary practices in most studies or risk for exercise addiction in one study. Results were mixed for BMI. This review demonstrates associations between indoor tanning and physical activity or dietary practices. Despite the use of some unhealthy strategies (e.g., indoor tanning, fasting, vomiting, laxative, or steroid use), common motives for these behaviors include a desire to appear attractive and/or healthy. Findings from this study can help inform future research and possible interventions for individuals engaging in relevant risky health behaviors. PMID- 30446922 TI - Pancreatic Cancer and Immunotherapy: Resistance Mechanisms and Proposed Solutions. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most aggressive and lethal diseases in the world. The success of immunotherapy in other types of malignancy has led to further trials to understand better the role of immunotherapy in PDAC. However, initial studies with immunotherapy, namely, the checkpoint inhibitors, in PDAC have not been met with the same outcomes. The purpose of this review is to identify and discuss the various resistance mechanisms of PDAC to immunotherapy (pancreatic stroma, genetic predisposition/epigenetics, and the immune inhibitory cells, cytokines, soluble factors, and enzymes that comprise the tumor microenvironment) and the solutions currently being studied to overcome them. CONCLUSIONS: Various preclinical and early clinical studies have shown that immunotherapy, especially checkpoint inhibitors, in PDAC may be efficacious as part of a multi-modal treatment, in combination with other therapies that target these resistance mechanisms. Several clinical trials are ongoing to explore this concept further. PMID- 30446923 TI - Evaluation of linoleic acid on lipid peroxidative/antioxidative parameters, motility and viability of rooster spermatozoa during cold storage. AB - Sustainable reduction in semen quality due to detrimental effects of primary and secondary peroxidative products was occurred during liquid storage. The objective of the current experiment was to explore the influence of bovine serum albumin conjugated linoleic acid (LA) on the rooster spermatozoa routine tests and lipid peroxidative/antioxidative levels stored at 4 degrees C over 48 h. For this purpose, collected ejaculates (>= 80% progressive motile spermatozoa) pooled and extended with the phosphate buffer medium without (control) or enriched with different amounts of LA (0.125, 0.25 or 0.50 mM). Contents of total antioxidant status (TAS) and thiobarbituric reactive substances (TBARS) were measured separately in the medium and spermatozoa, as well as percent of viability and motility at 0, 24 and 48 h intervals. Viability was not affected by treatment during the study intervals (P > 0.05). While, higher motility was recorded in LA 0.50 mM group (77.98 +/- 1.89 and 57.02 +/- 2.45) compared to the control group (68.78 +/- 1.29 and 45.09 +/- 1.86) at 24 and 48 h, respectively (P < 0.03). Amounts of TBARS in medium and spermatozoa were lower in LA 0.25 and 0.50 groups compared to the control at 48 h (P < 0.01). Moreover, TAS levels of medium and spermatozoa were lower in control samples compared to LA treated groups at 48 h (P < 0.03). Because of the ability of the LA to lowering the quantities of lipid peroxidation index and improving motility especially at 0.5 mM levels, it can be proposed as an additive during liquid storage of rooster semen. PMID- 30446924 TI - Improving recognition of potential tissue donors: a quality improvement project by a hospitalist in training in The Hague, The Netherlands. AB - The number of tissue donations decreased in The Netherlands over recent years. The aim of this project was to determine the number of missed tissue donors in the Haaglanden Medical Centre and to develop a strategy to improve the number of tissue donors. We retrospectively analyzed patient files of all deceased patients in 2014 for their potential as tissue donors. Our objectives were to determine the number of missed tissue donors and the percentage of correctly identified tissue donors among all physicians and hospitalists in training. In addition, a clinical audit and three focus group interviews were used to determine the level of knowledge about and adherence to local and national protocols. The findings enabled us to suggest national and local improvements to reduce the percentage of missed tissue donors. The number of missed tissue donors was 94 (17.2%) of 548 deceased patients in 2014. The percentage of correctly identified tissue donors was 65.7% among all physicians (Cohen's Kappa coefficient 0.557, p <= 0.001) and 57.1% among hospitalists in training (Cohen's Kappa coefficient 0.492, p <= 0.001). In 31 patients (32.4%), the reported contra-indication by physicians was not a contra-indication for tissue donation in The Netherlands. There was no statistical difference in correct identification between physicians and hospitalists in training (p = 0.321, Mann-Whitney). The most effective actions to increase the number of tissue donations include to better inform physicians about contra-indications and help them in the recognition of a tissue donor. PMID- 30446925 TI - VARV B22R homologue as phylogenetic marker gene for Capripoxvirus classification and divergence time dating. AB - Sheeppox disease is associated with significant losses in sheep production world over. The sheep pox virus, the goatpox virus, and the lumpy skin disease virus cannot be distinguished by conventional serological tests. Identification of these pathogens needs molecular methods. In this study, seven genes viz. EEV maturation protein-F12L, Virion protein-D3R, RNA polymerase subunit-A5R, Virion core protein-A10L, EEV glycoprotein-A33R, VARV B22R homologue, and Kelch like protein-A55R that cover the start, middle, and end of the genome were selected. These genes were amplified from Roumanian-Fanar vaccine strain and Jaipur virulent strain, cloned, and sequenced. On analysis with the available database sequences, VARV B22R homologue was identified as a marker for phylogenetic reconstruction for classifying the sheeppox viruses of the ungulates. Further, divergence time dating with VARV B22R gene accurately predicted the sheeppox disease outbreak involving Jaipur virulent strain. PMID- 30446926 TI - Plantago squarrosa Murray extracts inhibit the growth of some bacterial triggers of autoimmune diseases: GC-MS analysis of an inhibitory extract. AB - Ankylosing spondylitis, multiple sclerosis, rheumatoid arthritis and rheumatic fever are autoimmune inflammatory diseases that may be triggered in genetically susceptible individuals by specific bacterial pathogens. Inhibiting the growth of these bacteria with high antioxidant plant extracts may inhibit the aetiology of these diseases, as well as inhibiting the later phase symptoms. P. squarrosa extracts were analysed for antioxidant activity using a DPPH free radical scavenging assay. Bacterial growth inhibitory activity was evaluated using disc diffusion assays and the activity was quantified by MIC determination. The extracts were screened for toxicity by A. franciscana nauplii assays. The most potent antibacterial extract (ethyl acetate) was analysed by GC-MS headspace profile analysis and compounds were identified with reference to a phytochemical database. All extracts displayed strong DPPH radical scavenging activity. The ethyl acetate extract was particularly potent (IC50 1.4 ug/mL), whilst the other extracts also had significant radical scavenging activity (IC50 values between 11 and 22 ug/mL). Notably, the bacterial growth inhibitory activity of the extracts correlated with their DPPH radical scavenging activity. The ethyl acetate extract, which had the greatest DPPH scavenging activity, generally displayed the most potent bacterial growth inhibitory activity. This extract was particularly potent against P. mirabilis, P. vulgaris and A. baylyi (MIC values of 484, 575 and 880 ug/mL, respectively). It also inhibited P. aeruginosa and S. pyogenes growth, albeit with higher MICs (1600-3700 ug/mL). All other extract-bacteria combinations were either inactive or resulted in mid-low potency inhibition. All extracts were non-toxic in the A. franciscana bioassay (LC50 substantially > 1000 ug/mL). In total, 89 unique mass signals were identified in the P. squarrosa ethyl acetate extract by non-biased GC-MS headspace analysis. A number of compounds which may contribute to the antibacterial activity of this extract have been highlighted. PMID- 30446927 TI - Inhibitory effects of Clematis orientalis aqueous ethanol extract and fractions on inflammatory markers in complete Freund's adjuvant-induced arthritis in Sprague-Dawley rats. AB - Clematis orientalis Linn has long been used as ethnopharmacy for the treatment of arthritis. This study is intended to evaluate the curative efficacy of Clematis orientalis in treating polyarthritis in rats. Aqueous ethanolic extract and fractions (hexane, butanol and aqueous) were administered orally at 200 mg/kg for 28 days after CFA immunization. Paw swelling, paw diameter, arthritic score, body weight, hematological parameters, radiographic and histological analysis of ankle joints were evaluated. Moreover, levels of various inflammatory markers through RT-PCR and ELISA were measured. DPPH and reducing power assays were used to appraise antioxidant capacity. Qualitative phytochemical analysis, determination of total phenolic and flavonoid contents were also carried out. Aqueous ethanolic extract and fractions significantly (p < 0.001) reduced paw volume, paw thickness and arthritic score and considerably prevented decrease in body weight along with anomalous alterations in hematological parameters in comparison with arthritic control. X-ray and histological examination revealed no significant structural changes in ankle joints of treated rats. Expression levels of IL-1beta, TNF alpha, IL-6, COX-2 and NF-Kbeta were significantly (p < 0.05-0.001) suppressed as well as noteworthy increase in the levels of IL-4 and IL-10 among treated animals has been detected. Overproduction of TNF-alpha and PGE2 was substantially prevented in animals given different treatments. Aqueous ethanol extract and its fractions demonstrated significant and concentration-dependent antioxidant potential. In general, among fractions aqueous fraction exhibited a greater anti arthritic effect. Phytochemical analysis of aqueous fraction confirmed the presence of flavonoids and glycosides, 215.29 mgGAE/ml phenolic content and 633.03 MUgQE/ml flavonoid content. Thus, we suggest Clematis orientalis as a potent strategy for the treatment of rheumatoid arthritis. PMID- 30446929 TI - Protease Activated Receptor-2 Induces Immune Activation and Visceral Hypersensitivity in Post-infectious Irritable Bowel Syndrome Mice. AB - BACKGROUND: The role of protease activated receptor-2 (PAR-2) in the pathogenesis of abdominal pain in irritable bowel syndrome (IBS) is not well defined. AIMS: To investigate the role of PAR-2-mediated visceral hypersensitivity in a post infectious IBS (PI-IBS) mouse model. METHODS: T. spiralis-infected PI-IBS mouse model was used. Fecal serine protease activity and intestinal mast cells were evaluated. Intestinal permeability was assessed by urine lactulose/mannitol ratio, and colonic expressions of PAR-2 and tight junction (TJ) proteins were examined by Western blot. Intestinal immune profile was assessed by measuring Th (T helper) 1/Th2 cytokine expression. Visceral sensitivity was evaluated by abdominal withdrawal reflex in response to colorectal distention. RESULTS: Colonic PAR-2 expression as well as fecal serine protease activity and intestinal mast cell counts were elevated in PI-IBS compared to the control mice. Decreased colonic TJ proteins expression, increased lactulose/mannitol ratio, elevated colonic Th1/Th2 cytokine ratio, and visceral hypersensitivity were observed in PI IBS compared to the control mice. Administration of PAR-2 agonist in control mice demonstrated similar changes observed in PI-IBS mice, while PAR-2 antagonist normalized the increased intestinal permeability and reduced visceral hypersensitivity observed in PI-IBS mice. CONCLUSIONS: PAR-2 activation increases intestinal permeability leading to immune activation and visceral hypersensitivity in PI-IBS mouse model. PMID- 30446928 TI - High-Dose Infliximab Rescue Therapy for Hospitalized Acute Severe Ulcerative Colitis Does Not Improve Colectomy-Free Survival. AB - BACKGROUND AND OBJECTIVE: Optimization strategies with infliximab (IFX) are increasingly used as rescue therapy for steroid refractory acute severe ulcerative colitis (ASUC). We aim to determine if intensified IFX induction improves colectomy rate and identifies outcome predictors. METHODS: Hospitalized adult patients who received IFX for ASUC between 2010 and 2016 were identified. We compared standard inductions (5 mg/kg) vs high-dose induction (10 mg/kg) with 3-month colectomy rate as primary outcome. RESULTS: Seventy-two patients (62.5% male, median age 38.5) were identified. Thirty-seven patients (51.3%) received 5 mg/kg IFX and 35 received 10 mg/kg. Baseline clinical, biochemical and endoscopic parameters were well matched between these two groups. 10 mg/kg was more likely to be used by clinicians from 2014 onwards (p < 0.001). Three-month colectomy rate was 9.7%; which was not significantly different between the standard (5.4%) and high-dose (14.3%) IFX induction (p = 0.205). CRP >= 60 (OR 10.9 [95% CI 1.23 96.50], p = 0.032), hemoglobin <= 90 g/L (OR 15.6 [95% CI 2.61-92.66], p = 0.036) and albumin < 30 g/L (OR 9.4 [95% CI 1.06-83.13], p = 0.044) were associated with increased risk of colectomy at 3 months in univariate regression analysis. CONCLUSION: Use of high-dose infliximab rescue therapy did not improve 3-month colectomy-free survival in this cohort. Tailored use in high-risk patients may be beneficial although further validation is required. PMID- 30446930 TI - Risk of Rebleeding After Hemostasis for Peptic Ulcer. PMID- 30446931 TI - Adaptations in the IMCI Algorithm in Diagnosis of Acute Respiratory Tract Infections. PMID- 30446932 TI - The effects of curcumin on the metabolic parameters of non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials. AB - AIMS: Evidence indicates that curcumin seems to improve outcomes in non-alcoholic fatty liver disease (NAFLD). A meta-analysis was performed to evaluate the effects of curcumin inNAFLD. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from inception through March 2018 to identify randomized controlled trials (RCTs) evaluating the role of curcumin inNAFLD. The mean difference (MD) and 95% confidence interval (CI) were calculated. RESULTS: Four RCTs with a total of 229 NAFLD patients were included. Curcumin was more likely to lower LDL-C, triglycerides, FBS, HOMA-IR, weight and AST levels compared with placebo, and the difference was statistically significant [MD = - 27.02, 95% CI ( 52.30, - 1.74); MD = - 33.20, 95% CI (- 42.30, - 24.09); MD = - 5.63, 95% CI (- 10.36, - 0.90); MD = - 0.53, 95% CI (- 1.00, - 0.05); MD = - 2.27, 95% CI (- 3.11, - 1.44); MD = - 7.43, 95% CI (- 11.31, - 3.54), respectively]. However, the beneficial effect of curcumin did not achieve statistical significance in lowering total cholesterol, HDL-C, HbA1c, ALT or insulin levels [MD = - 30.47,95% CI (- 60.89. - 0.06); MD = - 0.98, 95% CI (- 2.88, 0.92); MD = - 0.41, 95% CI (- 1.41, 0.59); MD = - 6.02, 95% CI (- 15.61, 3.57); MD = - 0.92, 95% CI (- 2.33, 0.49)]. CONCLUSIONS: Curcumin is effective in lowering LDL-C, triglycerides, FBS, HOMA-IR, weight, and AST levels in NAFLD patients, and it is well tolerated. Further RCTs are required to confirm our findings. PMID- 30446933 TI - Thrombus "Squeezing" Through Patent Foramen Ovale After Traumatic Brain Injury. PMID- 30446934 TI - Current Practices of Intraventricular Antibiotic Therapy in the Treatment of Meningitis and Ventriculitis: Results from a Multicenter Retrospective Cohort Study. AB - BACKGROUND: Central nervous system (CNS) infections are particularly prevalent in the adult neurocritical care patient population and are associated with significant morbidity and mortality. Factors relevant to the nature of CNS infections pose significant challenges to clinicians treating afflicted patients. Intraventricular (IVT) administration of antibiotics may offer several benefits over systemic therapy; however, the outcomes and current practices of such treatments are poorly described in the literature. OBJECTIVE: To describe current practices and outcomes of patients receiving intraventricular antibiotic treatment for CNS infections in neurological intensive care units of academic medical centers nationwide. METHODS: A retrospective cohort study was conducted on patients admitted to intensive care units who received IVT antibiotic treatment at participating centers in the USA between January 01, 2003, and December 31, 2013. Clinical and laboratory parameters, microbiology, surgical and antimicrobial management, and treatment outcomes were collected and described. RESULTS: Of the 105 patients included, all received systemic antimicrobial therapy along with at least one dose of IVT antimicrobial agents. Intraventricular vancomycin was used in 52.4% of patients. The average dose was 12.2 mg/day for a median duration of 5 days. Intraventricular aminoglycosides were used in 47.5% of the patients, either alone or in combination with IVT vancomycin. The average dose of gentamicin/tobramycin was 6.7 mg/day with a median duration of 6 days. Overall mortality was 18.1%. Cerebrospinal fluid (CSF) culture sterilization occurred in 88.4% of the patients with a rate of recurrence or persistence of positive cultures of 9.5%. CONCLUSION: Intraventricular antimicrobial agents resulted in a high CSF sterilization rate. Contemporary use of this route typically results in a treatment duration of less than a week. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration. PMID- 30446935 TI - Malignant spindle cell cardiac tumour: one of the rarest of rare cardiac tumour. PMID- 30446936 TI - Enchanted nature, dissected nature: the case of Galen's anatomical theology. AB - Through the historical portrait of Galen, I argue that even an enchanted nature does not prevent the performance of violence against nature. Galen (129-c. 216 CE), the great physician-philosopher of antiquity, is best known for his systematization and innovation of the Hippocratic medical tradition, whose thought was the reigning medical orthodoxy from the medieval period into the Renaissance. His works on anatomy were the standard that Vesalius' works on anatomy overturned. What is less known about Galen's study of anatomy, however, is its philosophical and theological edge. In this paper, I show that it is precisely because nature is enchanted that Galen undertakes the grisly practices of anatomical dissection and vivisection, which entail violence against nature. First, I illustrate the violent character of Galen's anatomical experiments. Second, I elucidate Galen's anatomical methodology as a form of philosophizing and theologizing with a scalpel. Third, I explicate the importance of the demonstration of divine teleology that anatomical dissection reveals. Fourth, I sketch how anatomical dissection as a way of knowing nature and God becomes a kind of anatomical, liturgical theology. I conclude that, at least for Galen, an enchanted nature is not in itself exempt from violence. PMID- 30446937 TI - Is obesity associated with impaired reaction time in youth? AB - BACKGROUND AND PURPOSE: Recent research demonstrates a significant relationship between weight status and impaired reaction time in young, adult, and elderly individuals. However, most such studies were performed on small samples, used only body mass index as the body obesity index, used simple reaction time, and oftentimes did not consider some potential confounders such as age, socioeconomic status, or physical activity in their studies. The present study explored the relationship between various reaction time tasks and various obesity indices in a sample of youth. METHODS: Two hundred and thirty-four young males (19-24 years) underwent standard anthropometry, various information processing tasks (e.g., clinical reaction time, simple audio and visual reaction time, and choice reaction time), as well as an inhibitory control task (congruent and incongruent Simon reaction time). RESULTS: Results revealed no significant relationship between any of the information processing tests and body mass index, nor for fat percentage, waist circumference, and waist-to-height ratio after adjustment for potential confounders. A weak positive association was observed only between congruent Simon reaction time (but not incongruent Simon reaction time) and waist circumference in participants (t value = 0.199; Std error = 0.0014; p = 0.047; Cohen's f2 = 0.09). CONCLUSION: Inhibitory control, but not information processing speed, was associated only with waist circumference in apparently healthy young men. LEVEL OF EVIDENCE: Level I, experimental study. PMID- 30446939 TI - New insights from shale gas production at the microscopic scale. AB - Until recently, natural gas encountered in tight shales, which provided the source and seal of the gas, was considered uneconomical to produce. Although unconventional formations may be as porous as other reservoir rocks, their exceedingly small pore sizes and low permeability render them resistant to gas movement. Considering their importance to gas transport, we outline the characteristics of shale rocks, the mechanisms of Fickian and Knudsen diffusion as well as Klinkenberg's permeability. Given the challenges in unlocking natural gas from tight formations, various techniques such as the generation of artificial fractures and the introduction of pressurised fluids are detailed. To identify the parameters which govern natural gas production, we propose a computational porous rock model inspired from an actual image of a shale formation. The solution of the conservation of mass, momentum and energy equations appear to adequately capture the physics of gas transport at the microscopic level. Permitting the comparison between numerical and analytical gas velocity results, the validation framework we developed, demonstrates good agreement of numerical with theoretical findings. Gas pressure and velocity results point to the importance of pore throats, shale permeability and pressure maintenance in dislodging gas from the shale formations. PMID- 30446938 TI - A Novel Score Predicts HBV-Related Hepatocellular Carcinoma Recurrence After Hepatectomy: a Retrospective Multicenter Study. AB - BACKGROUND: In China, hepatitis B virus (HBV) is an important causative factor of hepatocellular carcinoma (HCC). The contribution and interaction of fibrosis-4 (FIB-4) score and total tumor volume (TTV) in association with HCC recurrence is unknown. A reliable point score based on the FIB-4 score, TTV, and differentiation grade was established to predict the postoperative recurrence of HBV-related HCC patients who underwent hepatic resection (HR). METHODS: Three hundred thirty-eight HBV-related HCC patients from three institutions treated by HR were enrolled in this retrospective study. Prognostic factors were also evaluated by univariate and multivariate analysis using Cox's proportional hazards model in the training cohort. The DFT score was established by a Cox regression model and validated in the internal cohort and the external cohorts from the other two institutions. RESULTS: The DFT score differentiated four groups of HBV-related HCC patients (0, 1-2, 3, 4-5 points) with distinct prognosis (median recurrence-free survival (RFS), 72.7 vs. 53.0 vs. 23.2 vs. 5.7 months; P < 0.05). Its predictive accuracy as determined by the area under the receiver operating characteristic curve (AUC) at 1, 3, and 5 years (AUCs 0.7319, 0.7031, and 0.6972) was greater than the other three staging systems for HCC. These findings were supported by the validation cohorts. CONCLUSIONS: The DFT model is a reliable and objective model to predict the RFS of HBV-related HCC patients after HR. PMID- 30446940 TI - New hardware, new software, different results: The estimation of left ventricular volumes and ejection fractions with gated myocardial perfusion SPECT. PMID- 30446941 TI - Minimal/Measurable Residual Disease Detection in Acute Leukemias by Multiparameter Flow Cytometry. AB - PURPOSE OF REVIEW: Minimal or measurable residual disease (MRD) detected by multiparameter flow cytometry (MFC) is an independent prognostic indicator in acute leukemia. However, the predictive value of MFC MRD is affected by technical challenges, interpretive complexities, and inadequate standardization, particularly in acute myeloid leukemia (AML). Here, we critically review the methodological principles of the MFC MRD assay and discuss clinical implications of MRD. RECENT FINDINGS: Key components of MFC MRD assays to be discussed include the principles of MFC, panel selection, analysis approaches, level of quantifiable MRD and calculation, reporting, and areas of improvements. Key components of clinical implications include context-dependent detection threshold and the integral role of MRD assessment by MFC in the era of ever-expanding molecular testing. With advancements in technology and standardization, MFC along with molecular assays will continue to play an important role in MRD assessment to evaluate treatment response and risk stratification. PMID- 30446942 TI - A high titer of acquired factor V inhibitor in a hemodialysis patient who developed arterial thrombosis. AB - An 87-year-old man with diabetes mellitus was admitted to control recurrent bleeding from hemodialysis puncture sites. He was a smoker and had been diagnosed with arteriosclerosis obliterans. His PT and APTT were markedly prolonged, and all coagulation factors were markedly decreased (factor V [FV] activity < 1%) or below the measurement threshold, with the exception of fibrinogen and factor XIII. Neither PT nor APTT were corrected upon mixing with normal plasma. A high titer of FV inhibitor was found at 415 BU/mL, and anti-FV autoantibody was detected by both immunoblot assay and ELISA. Prednisolone administration and plasma exchange partially improved prolonged PT and APTT and decreased the FV inhibitor level. Five months later, he manifested symptoms of severe ischemia in both legs. Angiography revealed diffuse stenosis downstream of both common iliac arteries. Endovascular therapy was repeated four times, the prednisolone dose was reduced, and low-dose antiplatelet therapy was initiated. After the final successful endovascular therapy, arterial thrombosis was detected using ultrasound and angiography. Aspiration thrombectomy and thrombolytic therapy failed to achieve recanalization, and necrosis of the legs worsened. Despite the severe coagulation abnormalities, vascular interventions should have been performed with regular-dose antiplatelet therapy, as the patient exhibited multiple risk factors for atherothrombosis. PMID- 30446943 TI - Methods for quantification of growth and productivity in anaerobic microbiology and biotechnology. AB - Anaerobic microorganisms (anaerobes) possess a fascinating metabolic versatility. This characteristic makes anaerobes interesting candidates for physiological studies and utilizable as microbial cell factories. To investigate the physiological characteristics of an anaerobic microbial population, yield, productivity, specific growth rate, biomass production, substrate uptake, and product formation are regarded as essential variables. The determination of those variables in distinct cultivation systems may be achieved by using different techniques for sampling, measuring of growth, substrate uptake, and product formation kinetics. In this review, a comprehensive overview of methods is presented, and the applicability is discussed in the frame of anaerobic microbiology and biotechnology. PMID- 30446944 TI - Therapeutic targeting potential of chromatin-associated proteins in MLL rearranged acute leukemia. AB - BACKGROUND: Acute leukemias (AL) with a Mixed Lineage Leukemia (MLL) gene rearrangement (MLLr) represent a group of leukemic entities conferring intermediate to adverse prognoses. Multiple chromatin-associated proteins have been shown to play essential roles during the genesis of MLLr AL. Some chromatin associated proteins function as negative regulators of MLLr AL whereas others are required for leukemic initiation or maintenance - the latter group constituting potential therapeutic targets. Most of the identified proteins have been functionally analyzed using experimental models with human/murine normal cells transformed by MLL-AF9 or other MLL fusion products, which may recapitulate most but not all aspects of human AML, such as immune system interactions - features of which the importance is rapidly emerging. CONCLUSIONS: Here, we review chromatin-associated proteins fundamental to MLLr AL development, highlighting those with targeting potential by small molecule inhibitors. In particular, we focus on synthetic targeting of multiple chromatin-associated proteins, a strategy that shows superior therapeutic efficacy and offers hope for overcoming drug resistance. PMID- 30446945 TI - Discovery of myosin I and Pollard-san. AB - In this short review, I describe a brief history of the discovery of myosin I isolated from Acanthamoeba in 1973 by Tom Pollard and Ed Korn. Today, myosins form a large "family tree" that includes more than 30 types of myosins. I discuss the importance of the relationship among actin, myosin, and other actin-binding proteins, many of which were pioneered by Pollard-san ("-san" is a Japanese honorific suffix showing respect, politeness and friendship). At the first conference devoted to actin, Pollard-san, Korn-san, and I discussed the importance of the nucleotide bound at the two ends of the actin filament. I conclude that life is a dynamic accumulation of molecule-molecule bindings, and although we do not yet know how they coordinate with each other to operate a living cell, many enthusiastic and excellent researchers like Pollard-san will unveil mechanisms that will show us what life really looks like. PMID- 30446946 TI - Analysis of RNA Expression Profiles Identifies Dysregulated Vesicle Trafficking Pathways in Creutzfeldt-Jakob Disease. AB - Functional genomics applied to the study of RNA expression profiles identified several abnormal molecular processes in experimental prion disease. However, only a few similar studies have been carried out to date in a naturally occurring human prion disease. To better characterize the transcriptional cascades associated with sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, we investigated the global gene expression profile in samples from the frontal cortex of 10 patients with sCJD and 10 non-neurological controls by microarray analysis. The comparison identified 333 highly differentially expressed genes (hDEGs) in sCJD. Functional enrichment Gene Ontology analysis revealed that hDEGs were mainly associated with synaptic transmission, including GABA (q value = 0.049) and glutamate (q value = 0.005) signaling, and the immune/inflammatory response. Furthermore, the analysis of cellular components performed on hDEGs showed a compromised regulation of vesicle-mediated transport with mainly up-regulated genes related to the endosome (q value = 0.01), lysosome (q value = 0.04), and extracellular exosome (q value < 0.01). A targeted analysis of the retromer core component VPS35 (vacuolar protein sorting-associated protein 35) showed a down-regulation of gene expression (p value= 0.006) and reduced brain protein levels (p value= 0.002). Taken together, these results confirm and expand previous microarray expression profile data in sCJD. Most significantly, they also demonstrate the involvement of the endosomal-lysosomal system. Since the latter is a common pathogenic pathway linking together diseases, such as Alzheimer's and Parkinson's, it might be the focus of future studies aimed to identify new therapeutic targets in neurodegenerative diseases. PMID- 30446947 TI - Ultrasonography of the pediatric spleen: a pictorial essay. AB - In infants and children, the spleen is involved in many pathological processes, whether those processes are isolated or related to systemic diseases. Pathology of the pediatric spleen includes congenital anomalies, splenomegaly, trauma, focal lesions, infarction, and tumors. Ultrasonography (US) is a widely available, fast, noninvasive imaging technique to assess the size, shape, and position of the spleen, as well as to define splenic echotexture. US is capable of screening for splenic disorders without the risk of ionizing radiation; it is the initial imaging examination performed to evaluate suspected splenic pathology, providing clinicians with helpful decisional support. US plays an important role in the detection of even very small amounts of hemoperitoneum, a herald of significant abdominal organ injury, in pediatric blunt abdominal trauma. Moreover, contrast-enhanced US may allow early detection of splenic injuries, ideally minimizing children's risk from radiation exposure. This pictorial essay illustrates the normal ultrasound appearance of the pediatric spleen and the sonographic findings which may guide clinicians to a correct diagnosis of pathologic conditions. PMID- 30446949 TI - Easily detected signs of perineural tumour spread in head and neck cancer. AB - Perineural tumour spread (PNTS) in head and neck oncology is most often caused by squamous cell carcinoma. The most frequently affected nerves are the trigeminal and facial nerves. Up to 40% of patients with PNTS may be asymptomatic. Therefore, the index of suspicion should be high when evaluating imaging studies of patients with head and neck cancer. This review describes a "quick search checklist" of easily detected imaging signs of PNTS. TEACHING POINTS: * A distinctive feature of head and neck tumours is growth along nerves. * Perineural tumour spread is most often caused by squamous cell carcinoma. * There are several key findings for the detection of perineural tumour spread. PMID- 30446950 TI - Dopamine: Functions, Signaling, and Association with Neurological Diseases. AB - The dopaminergic system plays important roles in neuromodulation, such as motor control, motivation, reward, cognitive function, maternal, and reproductive behaviors. Dopamine is a neurotransmitter, synthesized in both central nervous system and the periphery, that exerts its actions upon binding to G protein coupled receptors. Dopamine receptors are widely expressed in the body and function in both the peripheral and the central nervous systems. Dopaminergic signaling pathways are crucial to the maintenance of physiological processes and an unbalanced activity may lead to dysfunctions that are related to neurodegenerative diseases. Unveiling the neurobiology and the molecular mechanisms that underlie these illnesses may contribute to the development of new therapies that could promote a better quality of life for patients worldwide. In this review, we summarize the aspects of dopamine as a catecholaminergic neurotransmitter and discuss dopamine signaling pathways elicited through dopamine receptor activation in normal brain function. Furthermore, we describe the potential involvement of these signaling pathways in evoking the onset and progression of some diseases in the nervous system, such as Parkinson's, Schizophrenia, Huntington's, Attention Deficit and Hyperactivity Disorder, and Addiction. A brief description of new dopaminergic drugs recently approved and under development treatments for these ailments is also provided. PMID- 30446951 TI - Eliciting tacit knowledge: The potential of a reflective approach to video stimulated interviewing. PMID- 30446952 TI - Acute gastritis caused by concurrent infection with Epstein-Barr virus and cytomegalovirus in an immunocompetent adult. AB - Herein, we describe an extremely rare case of gastritis due to concurrent infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) occurring in an immunocompetent adult. The patient was a 35-year-old man who presented with slight fever, nausea, anorexia, weight loss for 3 weeks, mild transaminitis, and leukocytosis with atypical lymphocytes in peripheral blood. The clinical presentation and elevated IgM titers to both EBV-VCA and CMV strongly suggested infectious mononucleosis syndrome caused by co-infection with EBV and CMV. A computed tomographic scan of the abdomen showed diffuse thickening of the gastric wall mimicking linitis plastica, and upper endoscopy revealed thickened and eroded mucosa throughout the stomach. Histologic examination of gastric biopsies showed a dense lymphoid and neutrophilic infiltrate in the lamina propria with erosion. In situ hybridization assay revealed many lymphocytes positive for EBV encoded RNA. Moreover, immunohistochemistry using an anti-CMV monoclonal antibody identified some CMV-positive cells (i.e. foveolar epithelium and endothelium). We finally diagnosed this case as gastric involvement in infectious mononucleosis, and the patient recovered without the administration of antiviral drugs. To our knowledge, this is the first reported case of gastritis co-infected with EBV and CMV, as a manifestation of infectious mononucleosis in an immunocompetent adult. PMID- 30446953 TI - Usefulness of diffusion-weighted magnetic resonance imaging for evaluating the effect of hemostatic radiotherapy for unresectable gastric cancer. AB - There are several reports that vouch for the usefulness of diffusion-weighted image (DWI) in making a diagnosis before treatment. However, no study has evaluated the effect of radiotherapy (RT) for unresectable gastric cancer. In the present case report, we evaluated the effectiveness of RT using DWI. An 81-year old man was hospitalized with a broken bone and then diagnosed with advanced gastric cancer with breeding. He had chorionic renal failure and surgery was impossible. Further, contrast-enhanced computed tomography and magnetic resonance imaging (MRI) were not performed due to renal failure, whereas palliative RT was performed. We followed up the patient using blood test and MRI (DWI) to estimate whether bleeding had stopped or not after radiotherapy. Hemostasis effect was found after 2 weeks of RT. In DWI examination, there was a decrease in the tumor signal intensity 30 days after RT. Similarly, at day 60, the tumor signal intensity further decreased on DWI and the blood test results indicated no progression of anemia. At 4 months after the RT, the patient died because of respiratory failure without any bleeding. DWI is useful not only for the initial diagnosis but also for evaluating the effectiveness of RT. Trial registration: National clinical study registered number: UMIN000026362. PMID- 30446954 TI - Successful direct-acting antiviral treatment of three patients with genotype 2/1 recombinant hepatitis C virus. AB - There have been a few reports on the treatment of patients infected with recombinant hepatitis C virus (HCV) genotype 2/1 strains with direct-acting antivirals (DAAs). We experienced three patients, with genotype 2/1 recombinant HCV, treated with DAAs successfully. The first, a 39-year-old man, was infected with recombinant HCV genotype 2a/1b, a rare variant. The sequence of the relapsed virus showed chimeric HCV 2a/1b with the recombinant breakpoint found at nucleotide +49 from the start of the NS3 region. Sofosbuvir plus ribavirin, a regimen recommended for HCV genotype 2, did not lead to a sustained viral response (SVR). Retreatment with grazoprevir plus elbasvir resulted in an SVR. The second case, a 70-year-old woman, was infected with recombinant HCV genotype 2b/1b. DAA therapy with sofosbuvir plus ledipasvir resulted in an SVR. The third case, a 48-year-old woman, was also infected with recombinant HCV genotype 2b/1b. DAA therapy with daclatasvir plus asunaprevir resulted in an SVR. The baseline sequences of the viruses from both the second and third cases showed chimeric HCV 2b/1b with the recombinant breakpoint found at nucleotide +10 from the NS3 start. We report three cases with 2/1 chimeras and discuss the prevalence and response to therapy. PMID- 30446955 TI - Intraperitoneal abscess formation spreading to the liver after endoscopic ultrasound-guided fine-needle aspiration for abdominal lymphadenopathy. AB - A 75-year-old woman was admitted to our hospital because of anemia and appetite loss. She had rheumatoid arthritis and was taking 1 mg of prednisolone and 150 mg of peficitinib orally. She was detected with lymphadenopathy, 18 mm in diameter, around the common hepatic artery with abdominal ultrasonography and abdominal computed tomography. Upper gastrointestinal endoscopy, colonoscopy, and chest computed tomography did not show any evidence of malignant disease. Using endoscopic ultrasound-guided fine-needle aspiration, the lymphadenopathy was punctured through the stomach. She was discharged 4 days after endoscopic ultrasound-guided fine needle aspiration. However, 3 days following discharge, she developed fever and was admitted again 14 days after the endoscopic ultrasound-guided fine-needle aspiration. Abdominal ultrasonography revealed that, at the site of the lymphadenopathy where the endoscopic ultrasound-guided fine-needle aspiration was performed, an intraperitoneal abscess was formed and spreading to the lateral segment of the liver, penetrating the hepatic capsule. Antibiotics failed to improve her condition. Percutaneous transhepatic abscess aspiration was performed 4 days following admission. Thereafter, her condition improved, and she was discharged 10 days after the transhepatic abscess aspiration. It should be noted that intraperitoneal abscess formation in the puncture can occur after ultrasound-guided fine-needle aspiration. Particularly in immunosuppressed patients such as our case, attention may be needed more than those with normal immune function. PMID- 30446956 TI - The Use of Technology by Youth: Implications for Psychiatric Educators. PMID- 30446957 TI - To Dodge or Disclose: a Faculty Development Workshop to Promote Discussion of Racial/Ethnic Minority Trainee Cultural Identity. PMID- 30446958 TI - Issues in the Design of Discrete Choice Experiments. PMID- 30446959 TI - Comparative analysis of three methods from dried blood spots for expeditious DNA extraction from mosquitoes; suitable for PCR based techniques. AB - The objective of this work was to compare the quality, purity and quantity of DNA isolated from dried blood spots (DBS) by three methods (Chelex-100, QIAamp DNA mini kit, and TE (Tris EDTA)-Buffer). Sample collection was performed in six districts in Odisha, India and screened for cases of clinical malaria and dengue and vector density. Mosquito abdomens were spotted on Whatman 3MM (MERCK) Filter paper and dried for 10 min at room temperature. DNA was isolated from DBS using three methods (Chelex-100, QIAamp DNA mini kit, and TE-Buffer), and PCR was used to determine the feeding behaviours of vector mosquitoes. DNA was quantified using a UV-spectrophotometer, and q-PCR was used to determine the target gene copy number to compare the methods. The QIAamp DNA mini kit method was used as the reference method. The yield and purity of DNA extracted with Chelex-100 and TE were 14-72 ng/ul and 1.51-1.85 and 9-50 ng/ul and 1.68-2.1, respectively. DNA extracted using the Chelex-100 method was stored for over 1 month at - 20 degrees C and was suitable for later use. The Chelex-100 method had a sensitivity of 99.5% and specificity of 78%. A Bland-Altman plot suggested that the Chelex 100 method was similar to the QIAamp DNA mini kit method for determining the feeding behaviours of vector mosquitoes. The Chelex-100 method is simple, cost effective, and safe and requires minimal time for DNA extraction from dried blood spots. In malaria and dengue research, detecting the feeding behaviours from mosquito DNA from dried blood spots on filter paper by PCR is an easy, minimally invasive and inexpensive molecular technique that can be performed in remote areas. PMID- 30446960 TI - Genome-wide analysis of the MATE gene family in potato. AB - The multidrug and toxic compound extrusion (MATE) protein family is a newly discovered family of secondary transporters that extrude metabolic waste and a variety of antibiotics out of the cell using an electrochemical gradient of H+ or Na+ across the membrane. The main function of MATE gene family is to participate in the process of plant detoxification and morphogenesis. The genome-wide analysis of the MATE genes in potato genome was conducted. At least 48 genes were initially identified and classified into six subfamilies. The chromosomal localization of MATE gene family showed that they could be distributed on 11 chromosomes except chromosome 9. The number of amino acids is 145-616, the molecular weight of proteins is 15.96-66.13 KD, the isoelectric point is 4.97 9.17, and they were located on the endoplasmic reticulum with having 4-13 transmembrane segments. They contain only two parts of the exons and UTR without introns. Some members of the first subfamily of potato MATE gene family are clustered with At2g04070 and they may be related to the transport of toxic compounds such as alkaloids and heavy metal. The function of the members of the second subfamily may be similar to that of At3g23560, which is related to tetramethylammonium transport. Some members of the third subfamily are clustered with At3g59030 and they may be involved in the transport of flavonoids. The fifth subfamily may be related to the transport of iron ions. The function of the sixth subfamily may be similar to that of At4g39030, which is related to salicylic acid transport. There are three kinds of conserved motifs in potato MATE genes, including the motif 1, motif 2, and motif 3. Each motif has 50 amino acids. The number of each motif is different in the gene sequence, of which 45 MATE genes contain at least a motif, but there is no motif in ST0015301, ST0045283, and ST0082336. These results provide a reference for further research on the function of potato MATE genes. PMID- 30446961 TI - L-Asparaginase from Erwinia carotovora: insights about its stability and activity. AB - Enzymatic prospection indicated that L-asparaginase from Erwinia carotovora (ECAR LANS) posses low glutaminase activity and much effort has been made to produce therapeutic ECAR-LANS. However, its low stability precludes its use in therapy. Herein, biochemical and biophysical assays provided data highlighting the influence of solubilization and storage into ECAR-LANS structure, stability, and activity. Moreover, innovations in recombinant expression and purification guaranteed the purification of functional tetramers. According to solubilization condition, the L-asparaginase activity and temperature of melting ranged up to 25 32%, respectively. CD spectra indicate the tendency of ECAR-LANS to instability and the influence of beta-structures in activity. These results provide relevant information to guide formulations with prolonged action in the bloodstream. PMID- 30446962 TI - Genetic polymorphism analysis of mitochondrial DNA from Chinese Xinjiang Kazak ethnic group by a novel mitochondrial DNA genotyping panel. AB - Genetic polymorphism analysis of 60 mitochondrial DNA (mtDNA) loci in Chinese Xinjiang Kazak group was conducted in this study. Blood samples from 141 unrelated healthy volunteers were randomly collected from Chinese Kazak ethnic group in Ili, Xinjiang Uygur Autonomous region. Among these mtDNA loci, single nucleotide transition was the most commonly observed variant (87.93%). A total of 25 haplogroups and 79 haplotypes were found in Kazak group, and Haplogroup D4 was the most common haplogroup (21.28%). Among the entire 79 haplotypes, 53 of them were observed for only once, 14 for twice. The haplotype diversity was 0.978 +/- 0.005, and the nucleotide diversity was 0.17449. The detection of (CA)n and 9-bp deletion polymorphisms could improve the discrimination power of the mtDNA genetic marker. Moreover, Xinjiang Kazak group was compared with other previously reported groups to infer its genetic background. The present results revealed that Xinjiang Kazak ethnic group was genetically closer related to Xinjiang Uygur, Xinjiang Uzbek and Xinjiang Han populations. Meanwhile, our results also indicated the potential closer genetic relationships among Xinjiang Kazak group with Altaian Kazak as well as Xinjiang Xibe group. In conclusion, this novel mtDNA panel could be effectively utilized for forensic applications. Additionally, to further reveal the genetic background of Chinese Kazak group, more relevant populations and genetic markers should be incorporated in our future study. PMID- 30446963 TI - Detecting optic nerve lesions in clinically isolated syndrome and multiple sclerosis: double-inversion recovery magnetic resonance imaging in comparison with visually evoked potentials. AB - BACKGROUND AND AIM: Optic neuritis (ON) is a frequent manifestation of multiple sclerosis (MS), traditionally diagnosed clinically and by visually evoked potentials (VEP). However, ON can also be assessed by MRI. Here we compare the diagnostic performance of 3D-double inversion recovery-MRI (3D-DIR) and VEPs in patients with definite MS or clinically isolated syndrome (CIS). METHODS: 39 patients and 17 healthy controls were studied. Whole-brain-3D-DIR images (3T) were independently assessed for DIR-hyperintense optic nerve lesions (DHLs) by two neuroradiologists, and results related to quantitative VEP-parameters. RESULTS: Interrater concordance for DHLs was high (kappa = 0.82). No DHLs were observed in controls. In patients, abnormal VEPs, i.e. prolonged latencies, diminished amplitudes or abnormal latency or amplitude differences (re contralateral nerve) of the P100-component, were observed in 22, and DHLs in 32 of 78 optic nerves, the latter including 11 nerves with normal VEPs, 10 without clinical signs or history of ON, and 6 with both normal VEPs and no clinical evidence for ON. Using either abnormal VEPs and/or presence of DHLs and/or clinical evidence for ON as a compound reference criterion of optic nerve affection, sensitivity was significantly higher for 3D-DIR than for VEPs (91%, 95%-CI 77-98% vs. 63%, 95%-CI 45-79%, respectively, p = 0.006). CONCLUSION: DHLs are highly specific for optic nerve pathology. In the context of MS, 3D-DIR-MRI is a suitable tool to reveal acute or chronic optic nerve lesions and more sensitive than VEPs. The significance of optic nerve involvement in the diagnostic classification of CIS vs. definite MS requires further study. PMID- 30446964 TI - Non-invasive evaluation of cerebral perfusion in patients with transient ischemic attack: an fMRI study. AB - Detection of hypoperfused tissue due to the ischemia is considered to be important in understanding the cerebral perfusion status and may be helpful in guiding therapeutic decisions for patients with transient ischemic attack (TIA). We hypothesized that the combination of two non-invasive fMRI techniques: resting state BOLD-fMRI time-shift analysis (TSA) approach and 3D ASL, could detect the cerebral hemodynamic status in TIA patients noninvasively. From April 2015 to June 2016, 51 TIA patients were recruited in this study. We calculated the time delay between the resting-state BOLD signal at each voxel and the whole-brain signal using TSA approach and compared the results to CBF map derived from ASL. Out of the 51 patients, 24 patients with normal arrival time and CBF were in Stage 0; 14 patients who showed delayed arrival time and normal CBF which indicated elevated CBV were in Stage I; the other 13 patients who had both delayed arrival time and decreased CBF were in Stage II, the group average spatial overlap, i.e., Dice coefficient, of the two measurements was 0.55. Four patients in Stage 0 (17.4%), three patients in Stage I (23.1%) and five patients in Stage II (45.5%) suffered ischemic stroke or TIA symptoms in 1 year after MRI scan. The patients in Stage II was at highest risk of subsequent events when compared to other two stages. The combination of resting-state BOLD-fMRI and ASL hold the potential to noninvasively identify the hemodynamic status in TIA patients and help predict the risk of subsequent events. PMID- 30446965 TI - Sporadic CJD in association with HIV. AB - BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive fatal neurodegenerative disorder. We report an unusual case of pathologically confirmed sporadic CJD developing in a HIV-positive patient but presenting with clinical and radiological features suggestive of variant CJD. CASE PRESENTATION: A 63-year old man with chronic stable HIV developed progressive difficulties with decision making, obsessive compulsive disorder and visual hallucinations over 3 months. CSF examination detected a weakly positive 14-3-3 protein, elevated S-100 protein, and siginificantly elevated total-Tau protein. Brain MRI revealed bilateral abnormal signal within the posterolateral thalami compatible with pulvinar sign. Further investigations revealed a negative tonsillar biospy and positive blood test consistent with variant CJD. However, prion protein genotyping detected MV heterozygosity at codon 129 and post-mortem histopathological examination was consistent with sporadic CJD. CONCLUSION: Although MRI findings were suggestive of variant CJD, the short residence in the UK and MV heterozygosity are aytpical, and the histopathological examination was consistent with sporadic CJD. With only two cases of HIV and sporadic CJD reported so far, the association of CJD with HIV remains unclear. PMID- 30446966 TI - Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. AB - BACKGROUND: Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce. OBJECTIVE: To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ. METHODS: We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation. RESULTS: 195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26 4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time). CONCLUSION: Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ. PMID- 30446967 TI - Spinal motor neurons and motor function in older adults. AB - This study examined the relation between lumbar spinal motor neuron (SMN) indices and motor function proximate to death in community-dwelling older adults. Older adults (N = 145) participating in the Rush Memory and Aging Project underwent structured clinical testing proximate to death and brain and spinal cord autopsy at time of death. Ten motor performances were summarized by a composite global motor score. Choline acetyltransferase immunostaining was used to identify spinal motor neurons of the L4/5 segment. SMN counts and area and ventral horn area were collected. Linear regression modeling showed that the association of SMN counts and density with global motor scores proximate to death varied with sex. Separate models in men and women showed that this significant interaction was due to the association of higher SMN counts and density with higher global motor scores proximate to death in men but not women. These associations were unchanged when we controlled for indices of brain pathologies or chronic health conditions. In 38 cases with counts of activated microglia available, higher counts of activated microglia were associated with lower SMN counts. Activated spinal microglia and loss of spinal motor neurons may contribute to motor impairments in older men. PMID- 30446969 TI - Prior experience informs ensemble encoding. AB - People quickly form summary representations that capture the statistical structure in a set of simultaneously-presented objects. We present evidence that such ensemble encoding is informed not only by the presented set of objects, but also by a meta-ensemble, or prototype, that captures the structure of previously viewed stimuli. Participants viewed four objects (shaded squares in Experiment 1; emotional expressions in Experiment 2) and estimated their average by adjusting a response object. Estimates were biased toward the central value of previous stimuli, consistent with Bayesian models of how people combine hierarchical sources of information. The results suggest that an inductively learned prototype may serve as a source of prior information to adjust ensemble estimates. To the extent that real environments present statistical structure in a given moment as well as consistently over time, ensemble encoding in real-world situations ought to take advantage of both kinds of regularity. PMID- 30446968 TI - Isoliquiritigenin Provides Protection and Attenuates Oxidative Stress-Induced Injuries via the Nrf2-ARE Signaling Pathway After Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a serious public health and medical problem worldwide. Oxidative stress plays a vital role in the pathogenesis of TBI. Nuclear factor erythroid 2-related factor 2 (Nrf2), an important factor in the cellular defense against oxidative stress, is activated following TBI. In this study, the protective effects of Isoliquiritigenin (ILG), a promising antioxidant stress drug, was evaluated as a protective agent against TBI. In a mouse model of controlled cortical impact Injury, we found that the ILG administration reduced the Garcia neuroscore, injury histopathology, brain water content, cerebral vascular permeability, the expression of cleaved caspase3, aquaporin-4, glial fibrillary acidic protein and the increased the expression of neurofilament light chain protein, indicating the protective effects against TBI in vivo. ILG treatment after TBI also restored the oxidative stress and promoted the Nrf2 protein transfer from the cytoplasm to the nucleus. We then used Nrf2-/- mice to test the protective effect of Nrf2 during ILG treatment of TBI. Our findings indicated that Nrf2-/- mice had greater brain injury and oxidative stress than wild-type (WT) mice and ILG was less effective at inhibiting oxidative stress and repairing the brain injury than in the WT mice. In vitro studies in SY5Y cells under oxygen glucose deprivation/re-oxygenation stimulation yielded results that were consistent with those obtained in vivo showing that ILG promotes Nrf2 protein transfer from the cytoplasm to the nucleus. Taken together, our findings demonstrate that Nrf2 is an important protective factor against TBI-induced injuries, which indicates that the protective effects of ILG are mediated by inhibiting oxidative stress after TBI via a mechanism that involves the promotion of Nrf2 protein transfer from the cytoplasm to the nucleus. PMID- 30446970 TI - Critical appraisal and systematic review of guidelines for perioperative diabetes management: 2011-2017. AB - PURPOSE: To systematically evaluate the quality, consistency and the evidence support of guidelines for perioperative diabetes management. METHODS: We retrieved guidelines through systematic search, critically evaluated their quality and compared the recommendations of included guidelines. Five aspects were compared: target level, management of hyper- and hypoglycaemia, frequency of monitoring, management of insulin, and management of oral anti-diabetic drugs (OADs). RESULTS: Fourteen guidelines met our criteria, and 342 recommendations were extracted, the results of Appraisal of Guidelines for Research and Evaluation II (AGREE II) evaluation showed that none of the mean score in each domain was higher than 50%. On average, most guidelines had only one domain scored above 50%. Most recommendations (78.9%) did not specify their supporting evidence, 71 (20.8%) were formed using grading criteria, none cited systematic review or meta-analysis. Recommendations were inconsistent across different guidelines. CONCLUSIONS: The existing guidelines about perioperative management of diabetes needs improvement in methodology, as well as the production of evidence with high quality. Evidence-based guidelines are required for the perioperative management of diabetes. PMID- 30446971 TI - Identification of differentially expressed genes and typical fusion genes associated with three subtypes of breast cancer. AB - BACKGROUND: This study aimed to identify the differentially expressed genes (DEGs) and the typical fusion genes in different types of breast cancers using RNA-seq. METHODS: GSE52643 was downloaded from Gene Expression Omnibus, which included 1 normal sample (MCF10A) and 7 breast cancer samples (BT-474, BT-20, MCF7, MDA-MB-231, MDA-MB-468, T47D, and ZR-75-1). The transcript abundance and the DEGs screening were performed by Cufflinks. The functional and pathway enrichment was analyzed by Gostats. SnowShoes-FTD was applied to identify the fusion genes. RESULTS: We screened 430, 445, 397, 417, 369, 557, and 375 DEGs in BT-474, BT-20, MCF7, DA-MB-231, MDA-MB-468, T47D, and ZR-75-1, respectively, compared with MCF10A. DEGs in each comparison group (such as CD40 and CDH1) were significantly enriched in the functions of cell adhesion and extracellular matrix organization and pathways of CAMs and ECM receptor interaction. UCP2 was a common DEG in the 7 comparison groups. SFRP1 and MMP7 were significantly enriched in wnt/-catenin signaling pathway in MDA-MB-231. FAS was significantly enriched in autoimmune thyroid disease pathway in BT-474. Besides, we screened 96 fusion genes, such as ESR1-C6orf97 in ZR-75-1, COBRA1-C9orf167 in BT-20, and VAPB-IKZF3 and ACACA-STAC2 in BT-474. CONCLUSIONS: The DEGs such as SFRP1, MMP7, CDH1, FAS, and UCP2 might be the potential biomarkers in breast cancer. Furthermore, some pivotal fusion genes like ESR1-C6orf97 with COBRA1-C9orf167 and VAPB-IKZF3 with ACACA-STAC2 were found in Luminal A and Luminal B breast cancer, respectively. PMID- 30446972 TI - Clinicopathological features of breast cancer in Japanese female patients with Lynch syndrome. AB - BACKGROUND: Lynch syndrome (LS) is a predominantly inherited syndrome caused by a pathological germline mutation in one of the mismatch repair (MMR) genes. Whether breast cancer (BC) is one of the LS-associated tumors is controversial. The aim of this retrospective cohort study was to evaluate the clinical features of BC in Japanese patients with LS. METHODS: Of 38 mutation carriers, 4 females with BC were examined in this study. RESULTS: Two of the four patients had multiple BC. Their median age at the diagnosis of BC was 63 (range, 47-84) years. The TNM (6th revision) stages of the six BCs were as follows: stage I, 33% (2/6); stage IIA, 50% (3/6); and stage IIB, 17% (1/6). Histological examination revealed four scirrhous, one papillotubular, and one medullary carcinoma. The positive ratios for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth receptor 2 (HER2) were 83.3% (5/6), 83.3% (5/6), and 16.7% (1/6), respectively. Two of the three specimens showed MSI-H and one showed MSS. These MSI-H BCs had tumor-infiltrating lymphocytes. Two of the three specimens showed an absence of MLH1 and PMS2 proteins on immunohistochemistry. The cumulative risks for a person with LS to develop BC were 4.35% at the age of 50 years, 8.70% at 60 years, and 21.5% at 70 years. CONCLUSIONS: Our study results showed BC in Japanese females with LS to be an MSI-H tumor, which was ER and PgR positive and HER2 negative. PMID- 30446974 TI - Long-term prognosis of low-risk neuroblastoma treated by surgery alone: an experience from a single institution of China. AB - BACKGROUND: Low-risk neuroblastomas have favorable biologic characteristics. Children Oncology Group (COG) proposed that surgical resection of the primary tumor was sufficient. We evaluated the long-term prognosis of surgery alone for patients with low-risk neuroblastoma in China. METHODS: A total of 34 patients with low-risk neuroblastoma were treated in our center between Jan 2009 and Dec 2013. The medical records of these patients were reviewed. RESULTS: The primary lesion was located in the adrenal gland in 19 patients, the retroperitoneum in 5, the posterior mediastinum in 9 and the neck in 1. The tumor diameters and volumes were 1.80-10.0 cm (average 5.5 +/- 2.3 cm) and 1.28-424.10 cm3 (average 58.81 +/- 92.00 cm3), respectively. The stages of the patients were as follows: stage I in 25, stage II in 7, and stage IVs in 2. All patients were in the low-risk group according to COG risk stratification criteria. No patients showed MYCN amplification. The primary tumors of all patients were completely resected. Nine adrenal tumors were completely resected by laparoscopy. All patients were successfully followed for 66-115 (average 89.71 +/- 16.17) months. Recurrence was observed in 4 patients. In addition to one local recurrence, another three recurrences were metastases. The lesions were effectively controlled in all patients with recurrences. All patients survived, including 28 cases of tumor free survival; the 4-year overall and event-free survival rates were both 100%. CONCLUSIONS: Surgery alone is a safe and effective treatment strategy for low risk neuroblastoma. Recurrent lesions may be controlled and treated by rescue chemotherapy and surgery. PMID- 30446973 TI - Isolation and characterization of aerobic, culturable, arsenic-tolerant bacteria from lead-zinc mine tailing in southern China. AB - Bioremediation of arsenic (As) pollution is an important environmental issue. The present investigation was carried out to isolate As-resistant novel bacteria and characterize their As transformation and tolerance ability. A total of 170 As resistant bacteria were isolated from As-contaminated soils at the Kangjiawan lead-zinc tailing mine, located in Hunan Province, southern China. Thirteen As resistant isolates were screened by exposure to 260 mM Na2HAsO4.7H2O, most of which showed a very high level of resistance to As5+ (MIC >= 600 mM) and As3+ (MIC >= 10 mM). Sequence analysis of 16S rRNA genes indicated that the 13 isolates tested belong to the phyla Firmicutes, Proteobacteria and Actinobacteria, and these isolates were assigned to eight genera, Bacillus, Williamsia, Citricoccus, Rhodococcus, Arthrobacter, Ochrobactrum, Pseudomonas and Sphingomonas. Genes involved in As resistance were present in 11 of the isolates. All 13 strains transformed As (1 mM); the oxidation and reduction rates were 5 30% and 10-51.2% within 72 h, respectively. The rates of oxidation by Bacillus sp. Tw1 and Pseudomonas spp. Tw224 peaked at 42.48 and 34.94% at 120 h, respectively. For Pseudomonas spp. Tw224 and Bacillus sp. Tw133, the highest reduction rates were 52.01% at 48 h and 48.66% at 144 h, respectively. Our findings will facilitate further research into As metabolism and bioremediation of As pollution by genome sequencing and genes modification. PMID- 30446975 TI - Current perspectives on the correlation of nocturnal enuresis with obstructive sleep apnea in children. AB - BACKGROUND: Obstructive sleep apnea (OSA) and nocturnal enuresis (NE) are common clinical problems in children. OSA and NE are thought to be interrelated, but the exact pathophysiological mechanisms are not yet clear. This review aims to explain the possible pathogenesis of NE in children with OSA. DATE SOURCES: We have retrieved all relevant original articles from Database that have been published so far, including the prevalence studies of NE and OSA in children, sleep characteristic studies that use polysomnography (PSG) to focus on children with NE, and studies on the relationship between OSA and NE. RESULTS: Clinical studies have revealed that the risk of NE in children with OSA was increased compared with that of their healthy peers. This increased risk may be associated with sleep disorders, bladder instability, detrusor overactivity, nocturnal polyuria, endocrine and metabolic disorders, and inflammation. CONCLUSIONS: Cardiopulmonary and renal reflex-induced neuroendocrine disorder may play an important role in the mechanism of NE in children with OSA, but this remains to be confirmed by animal studies. Other causes such as oxidative stress and inflammatory responses need to be further researched. PMID- 30446976 TI - Reliability and validity of the translated Chinese version of Autism Spectrum Rating Scale (2-5 years). AB - BACKGROUND: Early autism screening is of great value, but there is lack of a screening tool of early age (2-5 years) in China. The Autism Spectrum Rating Scale (ASRS, 2-5 years) is a newly developed autism screening tool in the USA. This study aimed to evaluate the reliability and validity of the translated Chinese version of ASRS (C_ASRS) in Chinese children population before its application in China for early autism screening. METHODS: Caregivers of general children aged 2-5 years from 17 kindergartens and autism spectrum disorder (ASD) cases from five special education schools in five cities were recruited to complete the C_ASRS. 1910 valid questionnaires from kindergarteners and 192 from ASD cases were included for analyses. RESULTS: The item reliability (Cronbach's alpha) was more than 0.80 in the screening scale and DSM-5 scale, and 0.51-0.81 in the treatment scale. ASD cases scored higher on total score and most subscales compared to the kindergarteners (Cohen's d ranging from 1.34 to 3.37). C_ASRS showed good discriminatory validity with an area under the receiver operating characteristic curve of 0.850 (95% confidence interval: 0.819-0.881). The cutoff >= 60 achieved sensitivity of 65.63% and specificity of 85.63% in discriminating autism children from the general population. CONCLUSION: The results indicate that C_ASRS (2-5 years) could be used as an early level-2 screening tool for autism screening in China and should be further revised for level-1 screening. PMID- 30446977 TI - A modular, extensible approach to massive ecologically valid behavioral data. AB - We explore here the application of modern computer hardware and software to the collection and analysis of behavioral data. We discuss the issues of ecological validity, storage and processing, data permanence, automation, validity, and algorithmic determinism. Taking the modern landscape into account, we demonstrate several varying projects we have recently undertaken as proofs of concept of the viability and utility of this approach. In particular, we describe four research projects, which involve work on child-directed speech; the application of automatic methods to clinical populations, including children with hearing loss; quality control and the assessment of validity; and the sharing of data in a public database. We conclude by pointing out how the methodology described here can be extended to a wide variety of interdisciplinary and detailed projects that are likely to lead to better science and improved outcomes for populations served by the behavioral, social, and health sciences. PMID- 30446978 TI - Steady Flow in a Patient-Averaged Inferior Vena Cava-Part II: Computational Fluid Dynamics Verification and Validation. AB - PURPOSE: The embolus trapping performance of inferior vena cava (IVC) filters critically depends on how emboli flow through the IVC and, thereby, on the underlying hemodynamics. Most previous studies of IVC hemodynamics have used computational fluid dynamics (CFD), but few have validated their results by comparing with quantitative experimental measurements of the flow field and none have validated in an anatomical model of the IVC that includes the primary morphological features that influence the hemodynamics (iliac veins, infrarenal curvature, and non-circular vessel cross-section). In this study, we perform verification and validation of CFD simulations in a patient-averaged anatomical model of the IVC. METHODS: Because we are most interested in the fluid dynamics that influence embolus transport and IVC filter embolus trapping, we focus our analyses on the velocity distribution and the amount of swirl and mixing in the infrarenal IVC. A rigorous mesh refinement study is first conducted at the highest flow rate condition to verify the computed solutions. To validate the CFD predictions of the flow patterns, we then compare with particle image velocimetry (PIV) data acquired in the same model in two planes (coronal and sagittal) within the infrarenal IVC at two flow rates corresponding to rest and exercise conditions. RESULTS: Using unstructured hexahedral meshes ranging in size from 800,000 to 102.5 million computational cells, we demonstrate that a coarse mesh may be used to resolve the gross flow patterns and velocity distribution in the IVC. A finer mesh is, however, required to obtain asymptotic mesh convergence of swirl and mixing in the IVC, as quantified by the local normalized helicity, LNH, and the volume-averaged helicity intensity, [Formula: see text]. Based on the results of the mesh refinement study, we use a moderately fine mesh containing approximately 26 million cells for comparison with experimental data. The validation study demonstrates excellent qualitative agreement between CFD predictions and PIV measurements of the velocity field at both conditions. Quantitatively, we show that the global relative comparison error, E, between CFD and PIV ranges from 3 to 11%. By performing sensitivity studies, we demonstrate that the quantitative discrepancy is attributable to a combination of uncertainty in the inlet flow rates and uncertainty associated with precisely aligning the PIV data with the CFD geometry. CONCLUSIONS: Overall, the study demonstrates mesh convergent CFD simulations that predict IVC flow patterns that agree reasonably well with PIV data, even at exercise conditions where the flow in the IVC is extremely complex. PMID- 30446979 TI - Meditation experience predicts negative reinforcement learning and is associated with attenuated FRN amplitude. AB - Focused attention meditation (FAM) practices are cognitive control exercises where meditators learn to maintain focus and attention in the face of distracting stimuli. Previous studies have shown that FAM is both activating and causing plastic changes to the mesolimbic dopamine system and some of its target structures, particularly the anterior cingulate cortex (ACC) and striatum. Feedback-based learning also depends on these systems and is known to be modulated by tonic dopamine levels. Capitalizing on previous findings that FAM practices seem to cause dopamine release, the present study shows that FAM experience predicts learning from negative feedback on a probabilistic selection task. Furthermore, meditators exhibited attenuated feedback-related negativity (FRN) as compared with nonmeditators and this effect scales with meditation experience. Given that reinforcement learning and FRN are modulated by dopamine levels, a possible explanation for our findings is that FAM practice causes persistent increases in tonic dopamine levels which scale with amount of practice, thus altering feedback processing. PMID- 30446980 TI - Why Biologics and Biosimilars Remain So Expensive: Despite Two Wins for Biosimilars, the Supreme Court's Recent Rulings do not Solve Fundamental Barriers to Competition. AB - Biologics and biosimilars are medicines made from living cells that treat common and serious diseases such as cancer, diabetes, rheumatoid arthritis, and other inflammatory diseases. They are highly targeted, efficacious, and represent an increasingly important part of physicians' armamentaria in the combat against these medical conditions. Yet they are extremely expensive, costing on average $10,000-$30,000 per year and exceed $500,000 for the most expensive biologics. The advent of biosimilar drugs, or high similar copies of biologics, was supposed to help reduce costs, but thus far the cost of treatment with biologics or biosimilars has not fallen sharply in the USA. We argue that a primary hurdle is the extent of patent protection for the reference biologics that impedes greater numbers of biosimilars entering into the market. To date, of the 12 biosimilars approved for marketing by the US Food and Drug Administration (FDA), only five are commercially available. All but one of the remaining biosimilars are withheld from commercialization due to patent disputes. We argue that the market for biologics and biosimilars will become price competitive only if more biosimilars are available to patients. To this end, the process to eliminate marginally inventive patents held by the reference drug makers must be streamlined and improved. In this perspective article, we suggest actions to improve the pre-FDA approval patent resolution process known as the patent dance, the streamlined patent invalidation process known as Inter Partes Reviews, and the process of granting patents. PMID- 30446981 TI - Perspective of Turkish Medicine Students on Cancer, Cancer Treatments, Palliative Care, and Oncologists (ARES Study): a Study of the Palliative Care Working Committee of the Turkish Oncology Group (TOG). AB - Cancer is one of the most common causes of death all over the World (Rahib et al. in Cancer Res 74(11):2913-2921, 2014; Silbermann et al. in Ann Oncol 23(Suppl 3):iii15-iii28, 2012). It is crucial to diagnose this disease early by effective screening methods and also it is very important to acknowledge the community on various aspects of this disease such as the treatment methods and palliative care. Not only the oncologists but every medical doctor should be educated well in dealing with cancer patients. Previous studies suggested various opinions on the level of oncology education in medical schools (Pavlidis et al. in Ann Oncol 16(5):840-841, 2005). In this study, the perspectives of medical students on cancer, its treatment, palliative care, and the oncologists were analyzed in relation to their educational status. A multicenter survey analysis was performed on a total of 4224 medical school students that accepted to enter this study in Turkey. After the questions about the demographical characteristics of the students, their perspectives on the definition, diagnosis, screening, and treatment methods of cancer and their way of understanding metastatic disease as well as palliative care were analyzed. The questionnaire includes questions with answers and a scoring system of Likert type 5 (absolutely disagree = 1, completely agree = 5). In the last part of the questionnaire, there were some words to detect what the words "cancer" and "oncologist" meant for the students. The participant students were analyzed in two study groups; "group 1" (n = 1.255) were phases I and II students that had never attended an oncology lesson, and "group 2" (n = 2.969) were phases III to VI students that had attended oncology lessons in the medical school. SPSS v17 was used for the database and statistical analyses. A value of p < 0.05 was noted as statistically significant. Group 1 defined cancer as a contagious disease (p = 0.00025), they believed that early diagnosis was never possible (p = 0.042), all people with a diagnosis of cancer would certainly die (p = 0.044), and chemotherapy was not successful in a metastatic disease (p = 0.003) as compared to group 2. The rate of the students that believed gastric cancer screening was a part of the national screening policy was significantly more in group 1 than in group 2 (p = 0.00014). Group 2 had a higher anxiety level for themselves or their family members to become a cancer patient. Most of the students in both groups defined medical oncologists as warriors (57% in group 1 and 40% in group 2; p = 0.097), and cancer was reminding them of "death" (54% in group 1 and 48% in group 2; p = 0.102). This study suggested that oncology education was useful for the students' understanding of cancer and related issues; however, the level of oncology education should be improved in medical schools in Turkey. This would be helpful for medical doctors to cope with many aspects of cancer as a major health care problem in this country. PMID- 30446982 TI - Breast Implant Texturization Does Not Affect the Crosstalk Between MSC and ALCL Cells. AB - In the last decade, there has been a growing interest about the possible association between anaplastic large cell lymphoma (ALCL) and breast implants (BIA-ALCL). Many variables, such as breast implants texturization, have been investigated. Breast implants often lead to the formation of a periprosthetic capsule, characterized by inflammation. The presence of the inflamed capsule has been found in the majority of patients with BIA-ALCL. Inflammation may be sustained or counteracted by mesenchymal stem cells (MSCs) by the secretion of pro- or anti-inflammatory cytokines. MSCs were isolated from three capsules surrounding micro-textured (micro-MSCs) and from three capsules surrounding macro textured (macro-MSCs) implants; after characterization, MSCs were co-cultured with KI-JK cells (a cell line derived from the cutaneous form of ALCL). The secretion of cytokines related to inflammation, the proliferation rate, and the expression of genes referred to pro-tumoral mechanisms were evaluated. Co cultures of KI-JK cells with micro- or macro-MSCs gave the same results about the secretion of cytokines (increase of IL10, G-CSF, and TGF-beta1 and decrease of IL4, IL5, IL12, IL13, IL17A, IFN-gamma (p < 0.05) with respect to mock sample), expression of selected genes (increase for ACVR1, VEGF, TGF-betaR2, CXCL12, and MKi67 (p < 0.05) with respect to control sample), and the proliferation rate (no variation between mock and co-cultured samples). Our results suggest that MSCs derived from capsules surrounding micro- and macro-textured implants display the same effects on the ALCL cells. PMID- 30446983 TI - Improvement of appropriate pharmacological prophylaxis in hospitalised cancer patients with a multiscreen e-alert system: a single-centre experience. AB - PURPOSE: Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. METHODS: Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. RESULTS: E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043-0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. CONCLUSIONS: E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence. PMID- 30446984 TI - Cancer immunotherapy of patients with HIV infection. AB - Cancer immunotherapy with antibodies against immune checkpoints has made impressive advances in the last several years. The most relevant drugs target programmed cell death 1 (PD-1) expressed on T cells or its ligand, the programmed cell death ligand 1 (PD-L1), expressed on cancer cells, and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Unfortunately, cancer patients with HIV infection are usually excluded from cancer clinical trials, because there are concerns about the safety and the anti-tumoral activity of these novel therapies in patients with HIV infection. Several retrospective studies and some case reports now support the notion that antibodies against immune checkpoints are safe and active in cancer patients with HIV infection, but prospective data in these patients are lacking. In addition, signs of antiviral activity with increase in CD4 T cell counts, plasma viremia reduction or decrease in the viral reservoir have been reported in some of the patients treated, although no patient achieved a complete clearance of the viral reservoir. Here we briefly summarize all clinical cases reported in the literature, as well as ongoing clinical trials testing novel immunotherapy drugs in cancer patients with HIV infection. PMID- 30446985 TI - SEOM clinical guidelines for the treatment of non-small cell lung cancer (2018). AB - Non-small cell lung cancer (NSCLC) accounts for up to 85% of all lung cancers. The last few years have seen the development of a new staging system, diagnostic procedures such as liquid biopsy, treatments like immunotherapy, as well as deeper molecular knowledge; so, more options can be offered to patients with driver mutations. Groups with specific treatments account for around 25% and demonstrate significant increases in overall survival, and in some subgroups, it is important to evaluate each treatment alternative in accordance with scientific evidence, and even more so with immunotherapy. New treatments similarly mean that we must reconsider what should be done in oligometastatic disease where local treatment attains greater value. PMID- 30446986 TI - Jiao Shao: A forerunner of physiological psychology and comparative psychology in China. PMID- 30446987 TI - Does Tobacco Outlet Inequality Extend to High-White Mid-Atlantic Jurisdictions? A Study of Socioeconomic Status and Density. AB - Tobacco outlet density research has evolved to require a more refined examination of socioeconomic status' influence beyond median household income. This study investigates the effects of SES on census-tract-level tobacco outlet density in five predominantly White Maryland jurisdictions. Tobacco license addresses and demographic data were analyzed via t tests and spatial lag modeling. Results showed that higher SES jurisdictions had lower tobacco outlet density than lower SES jurisdictions despite similar White populations and that median household income had consistent associations with tobacco outlet density. This study corroborates findings that differences in SES correlate with differences in tobacco outlet density between racially similar areas. PMID- 30446988 TI - Racial-Ethnic Variations in Potentially Inappropriate Psychotropic Medication Use Among the Elderly. AB - OBJECTIVE: Psychotropic drugs are among the most frequently prescribed medications to the elderly in the USA. Yet, many of those drugs have been used inappropriately. Increased risks of potentially inappropriate psychotropic medication (PIPM) utilization are associated with several patient and provider characteristics. However, little is known whether and to what extent patient race and ethnicity is related to PIPM use patterns among the elderly. METHODS: We used multiyear (2012-2015) Medical Expenditure Panel Survey (MEPS) data. Among elderly psychotropic drug users (N = 7616), we identified PIPM prescription fills based on a Beers criterion, a list of drugs (by generic names) that should be avoided at any circumstances among the elderly. Logistic regression was used for the likelihood analysis. RESULTS: The likelihood of filling PIPMs was higher among Hispanics than among Whites (adjusted odds ratio [AOR] = 1.22; 95% confidence interval [CI] = 1.02-1.46). No differences were found between Whites and Blacks. The prevalence of PIPM use is high in all racial groups (43-52%). CONCLUSION: We found differences in the use of PIPMs by patient race and ethnicity between 2012 and 2015: among elderly psychotropic medication users, Hispanics were more likely than Whites to receive PIPMs. More clinical and policy efforts should aim to reduce PIPM use in all groups, particularly among Hispanic, given potentially negative health consequences related with the use of inappropriate medications. PMID- 30446989 TI - Test-retest reliability of and age-related changes in the subjective postural vertical on the diagonal plane in healthy subjects. AB - The subjective postural vertical (SPV) reflects gravity perception when the eyes are closed. Changes in the SPV on both the frontal and sagittal planes occur in response to neurological disorders and aging; however, these changes on the diagonal plane are unclear. Here we examined test-retest reliability (n=16) of and age-related changes (n=38) in the SPV on the diagonal plane. Subjects sat on an electrical vertical board (EVB), which was used to measure the SPV on the diagonal plane. An experimenter controlled and moved the EVB seat at a constant speed on the diagonal plane and measured the seat's tilt using a digital inclinometer when subjects verbally reported that they had reached a true vertical position. Measurement was performed for eight trials, and the mean (tilt direction) and standard deviation (variability) were calculated. To determine test-retest reliability, the same experimenter repeatedly measured the SPV 1 week later. To assess age-related changes, tilt direction and variability were compared between the young (n=20) and elderly (n=18) groups. Test-retest reliability on the right and left diagonal planes was 0.61 or more. Moreover, tilt direction on the right diagonal plane - but not on the left diagonal plane - indicated a significant diagonally backward deviation in the elderly group compared with that in the young group. Variability was significantly higher in the elderly group on both planes. SPV measurement on the diagonal plane was indicated, and age-related changes were identified. Thus, future studies should assess the potential clinical applications of SPV in neurological disorders. PMID- 30446990 TI - Evaluation of different methods of securing cellophane bands for portosystemic shunt attenuation. AB - OBJECTIVE: To compare mechanisms of and pressures at failure of 4 methods of securing 2 types of cellophane bands around a vein. STUDY DESIGN: Ex vivo mechanical evaluation. METHODS: Cellophane bands composed of 3 or 4 layers were applied around a cadaveric external jugular vein (EJV) to create 25% or 50% attenuation. These bands were secured with a medium or medium-large polymer locking ligation clip (PLLC), or a medium or medium-large titanium ligation clip (TLC). Sterile saline 0.9% was instilled into the lumen of the EJV until a pressure of 100 mm Hg was reached. Failure mechanism and luminal pressure at failure were compared between groups. RESULTS: Medium clips failed less often than medium-large clips (P < .001) and consistently sustained 100 mm Hg without failing. Three-layer cellophane bands were 4.1 times more likely to fail than 4 layer bands (P = .003, CI 1.6-10.2) and failed at lower pressures (28.32 +/- 3.59 mm Hg and 44.81 +/- 6.51 mm Hg, respectively, P = .027). Failure rates of the cellophane band constructs did not differ whether secured with PLLC or with TLC (P = .635) or with 25% vs 50% attenuation (P = .780). CONCLUSION: A single medium clip withstood physiological forces and secured a cellophane band at up to 50% attenuation. A 3-layer cellophane band was more likely to fail compared with a 4 layer cellophane band. CLINICAL SIGNIFICANCE: These ex vivo results provide evidence to support the application of a 4-layer cellophane band secured with a single medium PLLC or TLC for portosystemic shunt attenuation. A single medium PLLC should be used to eliminate computed tomography artifacts during postoperative evaluation of shunt closure. PMID- 30446992 TI - SUNCT Headache Attacks Associated With Reactivation of Varicella Zoster Virus in a Trigeminal Distribution. PMID- 30446991 TI - Serotonin and Aggressive Behaviour in Children and Adolescents: A Systematic Review. AB - OBJECTIVE: The role of serotonin (5-HT) in human aggression has been the subject a large number of studies, mostly with adults. Meta-analyses indicate a small but significant inverse relationship between central nervous 5-HT availability and aggression, but genetically-informed studies suggest two pathways: one to reactive aggression, the other to proactive aggression. METHOD: We conducted a systemic review on central nervous 5-HT function in children and adolescents, with attention to the function of aggression. RESULTS: In total, 675 articles were screened for relevance, with 45 reviewed. These included blood assays (e.g., plasma, 5-HIAA; platelet 5-HTR2A ), epigenetic studies, retrospective PET studies, and 5-HT challenge paradigms (e.g., tryptophan depletion). Overall, findings were mixed, with support both for negative and positive associations of central nervous 5-HT function with aggression in children and adolescents. CONCLUSION: We propose factors that may be blurring the picture, including problems in the conceptualization and measurement of aggression in young people, the lack of prospective designs, and the bias towards clinical samples of boys. Research needs to account for variance both in the motivation for and implementation of aggression, and look to the behavioural economics literature to consider the roles of reward, vengeance and self-control more clearly. This article is protected by copyright. All rights reserved. PMID- 30446993 TI - Cortisol secretion moderates the association between mother-infant attachment at 17 months and child behavior at age 5 years. AB - This study examined infant cortisol secretion as a moderator of the association between mother-infant attachment security at age 17 months and child behavior at age 5 years. A longitudinal community sample of 96 mother-child dyads participated in the strange situation procedure (SSP) at age 17 months. Cortisol was collected at baseline, and at 20 and 40 min post-SSP. Maternal reports of child behavior were collected at age 5 years. Results revealed that the associations between nonsecure mother-infant attachment and higher total, internalizing, and externalizing behavior were stronger for infants with high cortisol secretion, relative to infants with low cortisol secretion. The model of interaction differed depending on the outcome, with diathesis-stress explaining variance in total as well as internalizing behavior, and with differential susceptibility explaining variance in externalizing behavior. These findings augment our understanding of risk and resilience to the impact of the early rearing environment on later psychopathology. PMID- 30446994 TI - Neuromuscular organization of the Ctenophore Pleurobrachia bachei. AB - Ctenophores are descendants of one of the earliest branching metazoan lineage with enigmatic nervous systems. The lack of convenient neurogenic molecules and neurotransmitters suggests an extensive parallel evolution and independent origins of neurons and synapses. However, the field lags due to the lack of microanatomical data about the neuro-muscular systems in this group of animals. Here, using immunohistochemistry and scanning electron microscopy, we describe the organization of both muscular and nervous systems in the sea gooseberry, Pleurobrachia bachei, from North Pacific. The diffuse neural system of Pleurobrachia consists of two subsystems: the subepithelial neural network and the mesogleal net with about 5,000-7,000 neurons combined. Our data revealed the unexpected complexity of neuromuscular organization in this basal metazoan lineage. The anatomical diversity of cell types includes at least nine broad categories of neurons, five families of surface receptors and more than two dozen types of muscle cells as well as regional concentrations of neuronal elements to support ctenophore feeding, complex swimming, escape, and prey capture behaviors. In summary, we recognize more than 80 total morphological cell types. Thus, in terms of cell-type specification and diversity, ctenophores significantly exceed what we currently know about other prebilaterian groups (placozoan, sponges, and cnidarians), and some basal bilaterians. PMID- 30446995 TI - Accuracy of patient-specific three-dimensional-printed osteotomy and reduction guides for distal femoral osteotomy in dogs with medial patella luxation. AB - OBJECTIVE: To compare precorrectional and postcorrectional femoral alignment following distal femoral osteotomy using patient-specific 3-dimensional (3D) printed osteotomy and reduction guides in vivo and ex vivo. STUDY DESIGN: Prospective study. SAMPLE POPULATION: Ten client-owned dogs and matching 3D printed plastic bone models. METHODS: Distal femoral osteotomy was performed via a standard approach using osteotomy and reduction guides developed with computer aided design software prior to 3D-printing. Femoral osteotomy and reduction was also performed on 3D-printed models of each femur with identical reprinted guides. Femoral varus angle (FVA) and femoral torsion angle (FTA) were measured on postoperative computed tomographic images by 3 observers. RESULTS: In vivo, the mean difference between target and achieved postoperative was 2.29 degrees (+/-2.29 degrees , P = .0076) for the FVA, and 1.67 degrees (+/-2.08 degrees , P = .300) for the FTA. Ex vivo, the mean difference between target and achieved postoperative was 0.29 degrees (+/-1.50 degrees , P = .813) for the FVA, and 2.33 degrees (+/-3.21 degrees , P = .336) for the FTA. Intraobserver intraclass correlation coefficients (ICC; 0.736-0.998) and interobserver ICC (0.829 to 0.996) were consistent with an excellent agreement. CONCLUSION: Use of 3D-printed osteotomy and reduction guides allowed accurate correction of FTA in vivo and both FVA and FTA ex vivo. CLINICAL SIGNIFICANCE: Use of 3D-printed osteotomy and reduction guides may improve the accuracy of correction of femoral alignment but warrant further evaluation of surgical time, perioperative complications, and patient outcomes compared with conventional techniques. PMID- 30446997 TI - Prostaglandin E2 decrease in induced sputum of hypersensitive asthmatics during oral challenge with aspirin. AB - BACKGROUND: A special regulatory role for prostaglandin E2 (PGE2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD). OBJECTIVE: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC). METHODS: Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE2 , 8-iso-PGE2 , tetranor-PGE-M, 8-iso-PGF2 alpha, and leukotriene C4 , D4 , and E4 , were determined using mass spectrometry. Urinary excretion of LTE4 was measured by ELISA. RESULTS: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE2 as in HC resulted from 2.8 times lower dose of aspirin. CONCLUSION: Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE2 biosynthesis. These results support the mechanism of PGE2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD. PMID- 30446996 TI - Measurement of Tumor Mutational Burden (TMB) in routine molecular diagnostics: in silico and real-life analysis of three larger gene panels. AB - Assessment of Tumor Mutational Burden (TMB) for response stratification of cancer patients treated with immune checkpoint inhibitors is emerging as a new biomarker. Commonly defined as the total number of exonic somatic mutations, TMB approximates the amount of neoantigens that potentially are recognized by the immune system. While whole exome sequencing (WES) is an unbiased approach to quantify TMB, implementation in diagnostics is hampered by tissue availability as well as time and cost constrains. Conversely, panel-based targeted sequencing is nowadays widely used in routine molecular diagnostics, but only very limited data are available on its performance for TMB estimation. Here, we evaluated three commercially available larger gene panels with covered genomic regions of 0.39 Megabase pairs (Mbp), 0.53 Mbp and 1.7 Mbp using I) in silico analysis of TCGA data and II) wet-lab sequencing of a total of 92 formalin-fixed and paraffin embedded (FFPE) cancer samples grouped in three independent cohorts (NSCLC, CRC and mixed cancer types) for which matching WES data were available. We observed a strong correlation of the panel data with WES mutation counts especially for the gene panel > 1Mbp. Sensitivity and specificity related to TMB cutpoints for checkpoint inhibitor response in non-small cell lung cancer (NSCLC) determined by wet-lab experiments well reflected the in silico data. Additionally, we highlight potential pitfalls in bioinformatics pipelines and provide recommendations for variant filtering. In summary, this study is a valuable data source for researchers working in the field of immuno-oncology as well as for diagnostic laboratories planning TMB testing. This article is protected by copyright. All rights reserved. PMID- 30446998 TI - Activation of Toll-like receptor 7 signaling in labial salivary glands of primary Sjogren's syndrome patients. AB - The aim of this study was to determine the expressions of Toll-like receptors (TLRs) 7-9 and type I interferon (IFN) signal in labial salivary glands (LSGs) and cultured salivary gland epithelial cells (SGECs) from primary Sjogren's syndrome (pSS) patients. We performed an immunohistochemistry analysis of LSGs from 11 patients with pSS as defined by American-European Consensus Group classification criteria and five healthy subjects. The pSS patients' SGECs were analyzed by immunofluorescence and western blotting. IFN-alpha expression was examined by immunosorbent assay and flow cytometry. Mononuclear cells (MNCs) from pSS patients' LSGs showed TLR-7-dominant expression. B cells, plasma cells and plasmacytoid dendritic cells (pDCs) co-expressed with TLR-7. Myeloid differentiation primary response gene 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6) and interferon regulatory factor 7 (IRF7) co expressed with the pDC marker CD303 in LSGs. Ducts from pSS patients dominantly expressed TLR-7, and TLR-7 in the ducts co-expressed with MyD88, TRAF6 and IRF7. Type I IFNs including IFN-alpha and IFN-beta were detected in MNCs and ducts in pSS patients' LSGs. Increased TRAF6 expression and the nuclear translocation of IRF7 in SGECs were detected by immunofluorescence following loxoribine (a TLR-7 ligand) stimulation despite IFN-beta pretreatment. Western blotting showed increased TRAF6 expression in SGECs following IFN-beta and loxoribine stimulation. Although no increase in IFN-alpha was detected in supernatant from stimulated SGECs, the IFN-alpha in supernatant from stimulated peripheral blood pDCs from pSS patients was significantly increased. Our findings suggest that TLR 7 is dominantly expressed in both MNCs and ducts with downstream signals for type I IFNs, indicating that TLR7-dominant innate immunity is related to the development of sialadenitis in pSS. PMID- 30446999 TI - Social psychological research on prejudice as collective action supporting emergent ingroup members. AB - Why does social psychological research on prejudice change across time? We argue that scientific change is not simply a result of empirical evidence, technological developments, or social controversies, but rather emerges out of social change-driven shifts in how researchers categorize themselves and others within their larger societies. As mainstream researchers increasingly recategorize former outgroup members as part of a novel ingroup, prejudice research shifts in support of emergent ingroup members against their emergent outgroup opponents. Although social change-driven science results in valuable opportunities for researchers, it also results in significant risks for research collective, scientific biases in the inclusion and exclusion of social groups in prejudice research that are not readily detected or managed by traditional controls. We present the Emergent Ingroup Model (EIM) to encourage reflection on shared biases, as well as to spark a broader conversation on how to strengthen our field for a rapidly changing and increasingly global world. PMID- 30447000 TI - The shear complexity of insulin-stimulated vasodilation. PMID- 30447001 TI - Regulation of heterologously expressed 5-HT1B receptors coupling to K channels in AtT-20 cells. AB - BACKGROUND AND PURPOSE: Serotonin 5-HT1B receptors are widely expressed G protein coupled receptors and a target of triptans, the most commonly prescribed anti migraine drugs. There is very limited information about the acute, agonist induced regulation of 5-HT1B receptor signalling and so we sought to characterize this in a neuron-like system. EXPERIMENTAL APPROACH: Epitope-tagged human 5-HT1B receptors were expressed in mouse AtT20 cells. 5-HT1B receptor signalling was assessed using whole-cell patch-clamp recordings of endogenous G protein-gated inwardly rectified K channels (GIRK), and receptor localization measured using immunofluorescence. KEY RESULTS: 5-HT (EC50 65 nM) and sumatriptan (EC50 165 nM) activated GIRK in AtT20 cells expressing 5-HT1B receptors. Continuous application of both 5-HT (EC50 120 nM) and sumatriptan (EC50 280 nM) produced profound desensitization of 5-HT1B receptor signalling within a few minutes. Complete recovery from desensitization was observed after 10 min. Both 5-HT and sumatriptan induced significant heterologous desensitization of somatostatin activated GIRK currents, with the 5-HT-induced heterologous desensitization being blocked by the protein kinase inhibitor staurosporine. Both agonists induced modest 5-HT1B receptor internalization, with a time course much slower than receptor desensitization. CONCLUSIONS AND IMPLICATIONS: In AtT-20 cells, 5-HT1B receptors undergo rapid and reversible desensitization at concentrations of agonist similar to those required to activate the receptor. Desensitization is incomplete, and the continued signalling of the receptor in the presence of the agonist may lead to cellular adaptations. Finally, 5-HT1B receptor activation causes significant heterologous desensitization, which may lead to a reduced effectiveness of unrelated drugs in vivo. PMID- 30447003 TI - The sleep environment and its association with externalizing behaviors in a sample of low-income adolescents. AB - This study examined the sleep environment and its association with externalizing problems in adolescents attending an alternative high school. Participants included 114 students (56% female, 91% Black, mean age = 18.03, standard deviation [SD] = 1.49) from an alternative high school in a southeastern city. Most participants reported sleeping in a bed (83%) and at their house (72%) for 7 nights in the past week. Participants reported an average of 2.34 (SD = 1.86) past-week ambient sleep disruptions. Sleeping fewer nights in their own home and experiencing higher levels of ambient sleep disruptions were associated with delinquency engagement. Fewer nights sleeping in a bed and higher levels of ambient sleep disruptions were associated with a significant arrest history. The sleep environment is important to consider when assessing sleep problems, particularly among low-income adolescents living in urban environments. This information may inform comprehensive interventions to address behavioral health concerns. PMID- 30447002 TI - Use it or lose it? Effects of age, experience, and disuse on crawling. AB - What happens to early acquired but later abandoned motor skills? To investigate effects of disuse on early-developing motor skills, we examined crawling in two groups of habitual crawlers (34 6-12-month-old infants and five adults with Uner Tan Syndrome) and two groups of rusty crawlers (27 11-12-year-old children and 13 college-aged adults). Habitual crawlers showed striking similarities in gait patterns, limbs supporting the body, and crawling speed, despite dramatic differences in crawling practice, posture, and body size. Habitual crawlers trotted predominantly, whereas rusty crawlers showed a variety of gait patterns. Within sequences, habitual crawlers and children showed more switches in gait patterns than young adults. Children crawled faster and kept fewer limbs on the grounds than the other groups. Old crawling patterns were retained despite disuse, but new ones were also added. Surprisingly, results indicate that nothing was lost with disuse, but some features of crawling were gained or altered. PMID- 30447004 TI - Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D) 39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional non-subset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness. This article is protected by copyright. All rights reserved. PMID- 30447006 TI - Challenges in Assessing the Sunscreen-Melanoma Association. AB - Whether sunscreen use affects melanoma risk has been widely studied with contradictory results. To answer this question we performed a systematic review of all published studies, accounting for sources of heterogeneity and bias. We searched for original articles investigating the sunscreen-melanoma association in humans to 28.02.2018. We then used random-effects meta-analysis to combine estimates of the association, stratified by study design. Stratified meta analysis and meta-regression were used to identify sources of heterogeneity. We included 21'069 melanoma cases from 28 studies published 1979-2018: 23 case control (11 hospital-based, 12 population-based), 1 ecological, 3 cohort and 1 randomized controlled trial (RCT). There was marked heterogeneity across study designs and among case-control studies but adjustment for confounding by sun exposure, sunburns and phenotype systematically moved estimates towards decreased melanoma risk amongst sunscreen users. Ever- vs. never-use of sunscreen was inversely associated with melanoma in hospital-based case-control studies (adjusted odds ratio (OR)=0.57, 95%confidence interval (CI) 0.37-0.87, pheterogeneity <0.001), the ecological study (rate ratio=0.48, 95%CI 0.35-0.66), and the RCT (hazard ratio (HR)=0.49, 95%CI 0.24-1.01). It was not associated in population-based case-control studies (OR=1.17, 95%CI 0.90-1.51, pheterogeneity <0.001) and was positively associated in the cohort studies (HR=1.27, 95%CI 1.07 1.51, pheterogeneity =0.236). The association differed by latitude (pinteraction =0.042), region (pinteraction =0.008), adjustment for naevi/freckling (pinteraction =0.035), and proportion of never-sunscreen-users (pinteraction =0.012). Evidence from observational studies on sunscreen use and melanoma risk was weak and heterogeneous, consistent with the challenges of controlling for innate confounding by indication. The only RCT showed a protective effect of sunscreen. This article is protected by copyright. All rights reserved. PMID- 30447005 TI - Smoking confounds the periodontal diagnostics using saliva biomarkers. AB - AIM: Smoking is a risk factor for periodontal disease due to its complex impact on the inflammatory response in the periodontium. We investigated the effect of smoking on salivary periodontal biomarkers, matrix metalloproteinase (MMP)-8, MMP 9, tissue inhibitor of metalloproteinase (TIMP)-1 and myeloperoxidase (MPO). MATERIALS AND METHODS: Saliva biomarkers were analyzed in the Parogene population (n = 480) comprising a random cohort of patients undergone coronary angiography and oral examination. The effect of time since cessation and pack years of smoking on biomarkers were investigated. RESULTS: Saliva MMP-8, MMP-9, TIMP-1, and MPO concentrations distinguished periodontitis patients significantly from patients without periodontitis. When the time since cessation was considered, the area-under-the-curve values (p-value) for periodontitis were 0.76 (<0.001), 0.74 (<0.001), 0.70 (<0.001), and 0.76 (<0.001), respectively. Adding information about smoking habits in the models improved slightly the sensitivities of all biomarkers. In logistic regression model saliva MMP-8 was mainly affected by pack years of smoking, while saliva MMP-9, TIMP-1, and MPO were mostly affected by time since cessation, especially if smoking currently or quit recently (<1 year ago). CONCLUSIONS: Smoking confounds the salivary diagnostics of periodontitis and should be considered when interpreting the results obtained by potential diagnostic tests. This article is protected by copyright. All rights reserved. PMID- 30447007 TI - Valuing height: diagnosis, valuation and the case of idiopathic short stature. AB - This paper proposes a 'valuographic' approach to diagnosis, exploring how values and valuation practices are implicated in the contested diagnostic category of idiopathic short stature (ISS). ISS describes children who are 'abnormally' short but do not have any other detectable pathology. In the USA growth-promoting hormone therapy has been approved for ISS children, since 2003. However, no other jurisdiction has approved this treatment and the value of ISS as a diagnostic category remains disputed among healthcare professionals. Drawing on qualitative interviews with paediatric endocrinologists in the UK and the US, this study presents a historical snapshot illustrating how the problematisation of ISS as a diagnosis involved multiple registers of value including epistemic, economic and moral calculations of worth. Contestation of the diagnosis was not just about what counts but about what ought to be counted, as respondents' accounts of ISS gave differential weight to a range of types of evidence and methods of assessment. Ultimately what was at stake was not just the value of increased height for short patients, but what it meant to properly practice paediatric endocrinology. Consideration is then given to how a valuographic approach can be applied to sociological studies of diagnosis more broadly. PMID- 30447008 TI - Severity, course trajectory and within-person variability of individual symptoms in patients with major depressive disorder. AB - BACKGROUND: Depression shows a large heterogeneity of symptoms between and within persons over time. However, most outcome studies have assessed depression as a single underlying latent construct, using the sum score on psychometric scales as an indicator for severity. This study assesses longitudinal symptom-specific trajectories and within-person variability of major depressive disorder over a 9 year period. METHODS: Data were derived from the Netherlands Study of Depression and Anxiety (NESDA). This study included 783 participants with a current major depressive disorder at baseline. The Inventory Depressive Symptomatology-Self Report (IDS-SR) was used to analyze 28 depressive symptoms at up to six time points during the 9-year follow up. RESULTS: The highest baseline severity scores were found for the items regarding energy and mood states. The core symptoms depressed mood and anhedonia had the most favorable course, whereas sleeping problems and (psycho-)somatic symptoms were more persistent over 9-years follow up. Within-person variability was highest for symptoms related to energy and lowest for suicidal ideation. CONCLUSIONS: The severity, course, and within person variability differed markedly between depressive symptoms. Our findings strengthen the idea that employing a symptom-focused approach in both clinical care and research is of value. This article is protected by copyright. All rights reserved. PMID- 30447009 TI - Long non-coding RNA MIR31HG is a bona fide prognostic marker with colorectal cancer cell-intrinsic properties. AB - Elevated miR-31 expression is associated with poor outcome in colorectal cancer (CRC). Whether the prognostic information is independent of known molecular subgroups and gene expression-based consensus molecular subtypes (CMS) is currently unknown. To investigate this, we analyzed nearly two thousand CRC biopsies and pre-clinical models. The expression of miR-31-5p and its host transcript, long non-coding RNA MIR31HG, was strongly correlated (Spearman's rho>0.80). MIR31HG outlier expression was observed in 158/1265 (12%) of pCRCs and was associated with depletion of CMS2-canonical subgroup (odds ratio=0.21 [0.11 0.35]) and shorter relapse-free survival (RFS) in multivariable analysis (adjusted hazard ratio=2.2 [1.6-3.0]). For stage II disease, 5-year RFS for patients with MIR31HG outlier status was 49% compared to 77% for those with normal-like expression. MIR31HG outlier status was associated with inferior outcome also within clinical high risk groups and within the poor prognostic CMS4 mesenchymal gene expression subtype specifically. Pre-clinical models with MIR31HG outlier expression were characterized by reduced expression of MYC targets as well as elevated epithelial-mesenchymal transition, TNF alpha/NFkappaB, TGF-beta, and IFN-alpha/gamma gene expression signatures, indicating cancer cell-intrinsic properties resembling the CMS4 subgroup associations which were recapitulated in patient biopsies. Moreover, the prognostic value of MIR31HG outlier status was independent of cytotoxic T lymphocyte and fibroblast infiltration. We here present evidence that MIR31HG expression provides clinical stratification beyond major gene expression phenotypes and tumor immune and stromal cell infiltration and propose a model where increased expression is an indicator of a cellular state conferring intrinsic invasive and/or immuno-evasive capabilities. This article is protected by copyright. All rights reserved. PMID- 30447010 TI - Non-Canonical Activation of CREB Mediates Neuroprotection in a C. elegans Model of Excitotoxic Necrosis. AB - Excitotoxicity, caused by exaggerated neuronal stimulation by Glutamate (Glu), is a major cause of neurodegeneration in brain ischemia. While we know that neurodegeneration is triggered by overstimulation of Glu-Receptors (GluRs), the subsequent mechanisms that lead to cellular demise remain controversial. Surprisingly, signaling downstream of GluRs can also activate neuroprotective pathways. The strongest evidence involves activation of the transcription factor cAMP Response Element Binding-protein (CREB), widely recognized for its importance in synaptic plasticity. Canonical views describe CREB as a phosphorylation-triggered transcription factor, where transcriptional activation involves CREB phosphorylation and association with CREB Binding Protein (CBP). However, given CREB's ubiquitous cross-tissue expression, the multitude of cascades leading to CREB phosphorylation, and its ability to regulate thousands of genes, it remains unclear how CREB exerts closely-tailored, differential neuroprotective responses in excitotoxicity. A non-canonical, alternative cascade for activation of CREB-mediated transcription involves the CREB co-factor cAMP regulated transcriptional co-activator (CRTC), and may be independent of CREB phosphorylation. To identify cascades that activate CREB in excitotoxicity we used a C. elegans model of neurodegeneration by excitotoxic necrosis. We demonstrated that CREB's neuroprotective effect was conserved, and seemed most effective in neurons with moderate Glu exposure. We found that factors mediating canonical CREB activation were not involved. Instead, phosphorylation-independent CREB activation in nematode excitotoxic necrosis hinged on CRTC. CREB-mediated transcription that depends on CRTC, but not on CREB phosphorylation, might lead to expression of a specific subset of neuroprotective genes. Elucidating conserved mechanisms of excitotoxicity-specific CREB activation can help us focus on core neuroprotective programs in excitotoxicity. This article is protected by copyright. All rights reserved. PMID- 30447011 TI - In Reply to Dr. Lambein et al "HER2 protein overexpression in non-amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry?" AB - We were pleased to read Dr. Lambein and colleagues' insightful and thought provoking correspondence. We acknowledge that there are alternatives to the three mechanisms we proposed to explain the discordant HER2 findings. The transcriptional mechanisms broached by Lambein et al. constitute a plausible explanation for our collective findings and are soundly supported by the literature [1-2]. This article is protected by copyright. All rights reserved. PMID- 30447012 TI - How families prepare their children for tooth extraction under general anaesthesia: Family and clinical predictors of non-compliance with a 'serious game'. AB - OBJECTIVE: To explore family and clinical factors for usage of an online serious game designed to prepare children with ECC for dental treatment under general anaesthesia. DESIGN: Observational study. Secondary data of 60 children, aged 5 to-7, randomised to the intervention group in a phase-III randomised controlled trial [NIHR Portfolio 10006, ISRCTN: 18265148] testing the efficacy of the serious game http://www.scottga.org (available online). Usage was captured automatically, with each click, in real time. The total number of replays and total number of missing slides per game-run performed by the child, were recorded and used to monitor usage. Compliance outcomes were: total time running the game and number of completely missed slides. RESULTS: 57/60 played the game. Median age of parent/carer was 32. For 74% of the families, fathers resided at home and for 65% the parent/carer had A-levels-to-university education. At recruitment, 70% of the children were reported as anxious/highly-fearful and 37% as "significantly psychologically disturbed". CONCLUSIONS: Factors for non compliance were absence of a father (P=0.01) and higher child-anxiety (P=0.01) and, to a lesser extent, a low parent/carer education level (P=0.09). Interactive cartoons featuring dental assessment, oral health messages and modelling featured in the more popular slides. This article is protected by copyright. All rights reserved. PMID- 30447013 TI - Integrating anatomo-physiological changes and pharmacogenomics in anti-infective therapy management: is it a major concern? AB - Success of anti-infective therapy is a major challenge in some patients given anatomo-physiological changes and genetic variations. In this case anecdote, we report the management strategy of a patient suffering from chronic pulmonary aspergillosis in a context of anorexia nervosa and genetic polymorphism. PMID- 30447014 TI - Case of generalized anhidrosis associated with diffuse reticular hyperpigmentation and syndactyly. PMID- 30447015 TI - Progressive annular verrucous erosive plaques on the face. PMID- 30447016 TI - In vivo voltammetric evidence that locus coeruleus activation predominantly releases norepinephrine in the infralimbic cortex: Effect of acute ethanol. AB - The prefrontal cortex (PFC) plays a critical role in the control of many physiological processes including attention, learning and decision making (Dalley, Cardinal, & Robbins, 2004; Arnsten & Li, 2005; Funahashi & Andreau, 2013). This brain region receives dopamine (DA) and norepinephrine (NE) axons from the ventral tegmental area (VTA) and locus coeruleus (LC), respectively (Waterhouse, Lin, Burne, & Woodward, 1983; Chandler, Lamperski, & Waterhouse, 2013). Therefore, revealing alterations in catecholamine (CA) dynamics in these circuitries is necessary to understand the pathogenesis of different psychiatric diseases, including addiction to drugs and alcohol. Since the PFC is widely involved in complex mental functions, ethanol-induced neuroadaptations can be implicated in impaired cognitive ability and aversive outcomes that facilitate dependence on alcohol. However, changes in cortical CA release under ethanol effects remain unclear. This article is protected by copyright. All rights reserved. PMID- 30447017 TI - Study on immortal conditions of chicken embryonic stem cells. AB - In recent years, considerable attention has been paid to chicken embryonic stem cells (ESCs) studies in relation to extensive applications in gene therapy and regenerative medicine. However, the approaches used are still immature. In this study, we showed that the chicken ESCs clones with a clear border can express alkaline phosphatase and marker proteins such as SSEA-1, SOX2, and OCT4 stably. In addition, culture medium containing 10 MUmol/L of vitamin C (VC) could significantly promote the proliferation of ESCs cells. Moreover, ESCs transfected with p:enhanced green fluorescent protein (pEGFP)-hTERT could be subcultured more than tenth generations in culture medium containing exogenous factors (mLIF + bFGF + hSCF) and VC, and these ESCs clone could still be regenerated following cryopreservation. Quantitative real-time polymerase chain reaction results showed that there was no significant difference between SSEA-1, SOX2, and OCT4 expression during ESCs immortalization and that the tenth generation of ESCs was still able to express marker proteins SSEA-1, SOX2, and OCT4. Our results showed that an immobilized system for ESCs was established, and the ESCs were cultured in vitro maintaining their pluripotency. PMID- 30447018 TI - Understanding Moment-to-Moment Processing of Visual Narratives. AB - What role do moment-to-moment comprehension processes play in visual attentional selection in picture stories? The current work uniquely tested the role of bridging inference generation processes on eye movements while participants viewed picture stories. Specific components of the Scene Perception and Event Comprehension Theory (SPECT) were tested. Bridging inference generation was induced by manipulating the presence of highly inferable actions embedded in picture stories. When inferable actions are missing, participants have increased viewing times for the immediately following critical image (Magliano, Larson, Higgs, & Loschky, ). This study used eye-tracking to test competing hypotheses about the increased viewing time: (a) Computational Load: inference generation processes increase overall computational load, producing longer fixation durations; (b) Visual Search: inference generation processes guide eye-movements to pick up inference-relevant information, producing more fixations. Participants had similar fixation durations, but they made more fixations while generating inferences, with that process starting from the fifth fixation. A follow-up hypothesis predicted that when generating inferences, participants fixate scene regions important for generating the inference. A separate group of participants rated the inferential-relevance of regions in the critical images, and results showed that these inferentially relevant regions predicted differences in other viewers' eye movements. Thus, viewers' event models in working memory affect visual attentional selection while viewing visual narratives. PMID- 30447019 TI - The prodromes of Parkinson's disease. AB - Whilst the diagnosis of Parkinson's disease (PD) relies on the motor triad of bradykinesia, rigidity and tremor, the underlying pathological process starts many years before these signs are overt. In this prodromal phase of PD, a diverse range of non-motor and motor features can occur. Individually they do not allow a diagnosis of PD, but when considered together, they reflect the gradual development of the clinical syndrome. Different subgroups within the prodromal phase may exist and reflect different underlying pathology. Here, we summarise the evidence on the prodromal phase of PD in patient groups at increased risk of PD with well described prodromal features: patients with idiopathic rapid eye movement sleep behaviour disorder, patients with idiopathic anosmia and families with monogenic mutations that are closely linked to PD pathology. In addition, we discuss the information on prodromal features from ongoing studies aimed at detecting prodromal PD in the general population. It is likely that better delineation of the clinical prodromes of PD and their progression in these high risk groups will improve understanding of the underlying pathophysiology. PMID- 30447020 TI - Circadian pacemaker neurons of the Madeira cockroach are inhibited and activated by GABAA and GABAB receptors. AB - GABA is the most abundant neurotransmitter in the circadian pacemaker circuits of mammals and insects. In the Madeira cockroach the accessory medulla (AME) in the brain's optic lobes is the circadian clock that orchestrates rest-activity rhythms in synchrony with light dark cycles. Three prominent GABAergic tracts connect the AME to termination sites of compound eye photoreceptors in the lamina and medulla. Parallel GABAergic light entrainment pathways were suggested to either advance or delay the clock for adjustment to changing photoperiods. In agreement with this hypothesis GABA activated or inhibited AME clock neurons, allowing for distinction of three different GABA response types. Here, we examined which GABA receptors are responsible for these response types. We found that both ionotropic GABAA receptors and metabotropic GABAB receptors were expressed in AME clock cells. Via different signaling pathways, either one of them could account for all three GABA response types. The muscimol-dependently activated GABAA receptor formed a chloride channel, while the SKF 97541 dependently activated GABAB receptor signaled via G-proteins, apparently targeting potassium channels. Expression of chloride exporters or -importers determined whether GABAA receptor activation hyper- or depolarized AME neurons. For GABAB receptor responses second messenger gated channels present in the clock cells appeared to decide about the polarity of the GABA response. In summary, circadian clock neurons co-expressed inhibitory and/or excitatory GABAA and GABAB receptors in various combinations, while cotransporter expression and the set of second messenger gated ion channels present allowed for distinct signaling in different clock neurons. This article is protected by copyright. All rights reserved. PMID- 30447021 TI - Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction. AB - The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum-specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum controlled fine motor coordination. PMID- 30447022 TI - Effects of cone combinations on accurate and precise Mg isotopic determination using MC-ICP-MS. AB - RATIONALE: High-precision determination of magnesium (Mg) isotopes can now be routinely achieved by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). The analytical sensitivity and instrumental mass discrimination behavior of this method are, however, sensitive to the types of sample and skimmer cones used in these measurements, so it is important that these parameters should be investigated. METHODS: Using the sample-standard bracketing method in the wet-plasma mode, four available combinations of sample and skimmer cones [Jet sample cone + H skimmer cone (Jet + H), standard sample cone + H skimmer cone (Standard + H), standard sample cone + X skimmer cone (Standard + X), and Jet sample cone + X skimmer cone (Jet + X)] were systematically investigated for peak shape, sensitivity, mass discrimination, accuracy, and precision in Mg isotope ratio determination using a Neptune plus MC ICP mass spectrometer. RESULTS: The results showed that different cone combinations do not affect peak shapes but would significantly change the sensitivities for Mg isotope determinations. Compared with using the Standard + H, the sensitivities of Mg isotope determinations were enhanced by approximately a factor of 1.3, 1.4, and 1.9 by using the Standard + X, the Jet + H, and the Jet + X combinations, with the most stable mass discrimination behaviors obtained by the Jet + H. The instrumental mass fractionation slope for any combination of a modified cone geometry (i.e. Standard + X, Jet + X, and Jet + H) is 0.500, while it is 0.510 for the Standard + H. In addition, the mass discrimination behavior is related to Mg concentrations once the combination is set, indicating the necessity of concentration match during Mg isotopic determination. CONCLUSION: The precision and accuracy of the Jet + H combination are better than those of the other combinations, and this is further supported by the validation of the Mg isotope data for four international reference materials: Cambridge-1, NASS-6, AGV 2, and BHVO-2. As the Jet + H combination also provides a high signal, this combination gives the most robust strategy for the highly precise and accurate determination of Mg isotopes. PMID- 30447023 TI - Demographic and clinical characteristics of spinal calcinosis in systemic sclerosis: Possible association with peripheral angiopathy. AB - The objective was to evaluate the demographic and clinical characteristics of systemic sclerosis (SSc) patients with spinal calcinosis. Paraspinal and intraspinal calcinosis was assessed blindly by orthopedic surgeons specializing in spinal diseases using chest high-resolution computed tomography (CT) that was performed for the screening and prospecting of interstitial lung disease in 159 Japanese SSc patients. Among these patients, we identified 27 (17%) with spinal calcinosis, and the most common site was cervical level at 77.8% (21/27). The frequency of spinal calcinosis in the late stage was higher than in the early stage (44.4% vs 29.6%). Multiple calcinosis was identified in 18.5% (5/27). The frequency of paraspinal calcinosis only was 59.3%, intraspinal calcinosis only 18.5%, and both intraspinal and paraspinal calcinosis 22.2%. Among SSc patients, 4.4% (7/159) had CT-based evidence of spinal cord compression. Among cases with spinal cord compression, only one had neurological symptoms, and surgical removal improved the symptoms. The other six SSc patients with spinal calcinosis (3.8% of 159) had no symptoms. Male sex (29.6%) and severe peripheral vasculopathy such as digital ulcers (55.6%) and acro-osteolysis (33.3%) were significantly more frequent in the SSc patients with spinal calcinosis than in the SSc patients without spinal calcinosis (10.6%, 32.6% and 14.4%, respectively). Our results suggest that severe peripheral vasculopathy may be associated with the development of spinal calcinosis. Because SSc patients are prone to spinal calcinosis, when SSc patients claim symptoms such as pain, numbness and movement disorder of the extremities, spinal calcinosis is a complication that should be taken into consideration. PMID- 30447024 TI - Reply to "Early ambulation versus bedrest after skin grafting in extramammary Paget's disease". PMID- 30447025 TI - Emerging trends of inflammatory bowel disease in South Korea: a nationwide population-based study. AB - : Background and Aims Little is known regarding the exact burden of inflammatory bowel disease (IBD) in Asian countries because previous epidemiologic studies were hospital-based. We aimed to develop and validate an operational definition of IBD cases from health insurance claims data and to examine the epidemiological features of IBD in Korea. METHODS: We analyzed stratified sample data from the Korean Health Insurance Review and Assessment (2010-2016) database using 12 different definitions and applied the best definition to the entire (2007-2016) dataset. RESULTS: The definition that combined the ICD-10 code with IBD-specific medications had the best performance characteristics among the 12 tested definitions. During the 8-year study period, IBD prevalence increased from 25,345 in 2009 to 47,444 in 2016. Over that period, the prevalence of Crohn's disease (CD) increased 1.9-fold (from 16.0/100,000 in 2009 to 29.6/100,000 in 2016) and that of ulcerative colitis (UC) increased 1.6-fold (from 41.4/100,000 in 2009 to 66.0/100,000 in 2016). Similarly, the estimated incidence of CD also increased 1.2-fold (from 2.4 to 2.9 per 100,000) and that of UC rose 1.3-fold (from 4.0 to 5.3 per 100,000). During the study period, the predominant increase in IBD incidence was among younger individuals, especially those aged <30 years. CONCLUSION: Patients with IBD can be accurately identified using Korean insurance claims data by combining information regarding the ICD-10 codes and the IBD medications used. The prevalence of IBD continues to increase, with an apparent shift toward younger (<30 years) age groups. PMID- 30447026 TI - Individual Risk Assessment Tool for School Age Asthma Prediction in UK Birth Cohort. AB - BACKGROUND: Current published asthma predictive tools have moderate positive likelihood ratios (LR+) but high negative likelihood ratios (-LR) based on their recommended cut-offs, which limit their clinical usefulness. OBJECTIVE: To develop a simple clinically applicable asthma prediction tool within a population based birth cohort. METHOD: Children from the Manchester Asthma and Allergy Study (MAAS) attended follow-up at ages 3, 8 and 11 years. Data on pre-school wheeze was extracted from primary-care records. Parents completed validated respiratory questionnaires. Children were skin prick tested (SPT). Asthma at 8/11 years (school -age) was defined as parentally-reported (1) physician-diagnosed asthma and wheeze in the previous 12 months or (2) >=3 wheeze attacks in the previous 12 months. An asthma prediction tool (MAAS APT) was developed using logistic regression of characteristics at age 3 years to predict school-age asthma. RESULTS: Of 336 children with physician-confirmed wheeze by age 3 years, 117(35%) had school-age asthma. Logistic regression selected 5 significant risk factors which formed the basis of the MAAS APT: wheeze after exercise; wheeze causing breathlessness; cough on exertion; current eczema and SPT sensitisation(maximum score 5). A total of 281(84%) children had complete data at age 3 years and were used to test the MAAS APT. Children scoring >=3 were at high risk of having asthma at school-age(PPV>75%; +LR 6.3,-LR 0.6), whereas children who had a score of 0 had very low risk(PPV 9.3%; LR 0.2). CONCLUSION: MAAS APT is a simple asthma prediction tool which could easily be applied in clinical and research settings. This article is protected by copyright. All rights reserved. PMID- 30447027 TI - Cu@Cu3P core-shell nanowires attached on Ni foam as high-performance electrocatalyst for hydrogen evolution reaction. AB - The development of highly efficient and inexpensive electrocatalysts is of great importance for generating renewable energy. In this work, Cu@Cu3P core-shell nanowires grown on nickel foam (Cu@Cu3P/NF) are prepared by a novel in-situ reduction of CuSO4.5H2O which forms Cu, then followed by surface oxidation and low-temperature phosphorization treatments. The unique hierarchical architecture of Cu@Cu3P/NF integrated the advantages of enlarged surface area, fast electron transport, numerous channels for gas rapid diffusion, non-polymer binder and enhanced catalytic performance. Remarkably, Cu@Cu3P/NF-50 with a molar ratio of Cu/Cu3P around 2.63 reveals high-efficient catalytic performance for HER in alkaline solution with a Tafel slope of 59 mV dec-1 and a long-time durability of 48 h. Overpotentials as low as 218 and 302 mV are required to reach current densities of 10 and 100 mA cm-2, respectively. Furthermore, the scientific understanding and design principle of Cu@Cu3P/NF with controlled performance will encourage more research into other high-performance and low cost electrocatalysts for renewable energy. PMID- 30447028 TI - The plasma membrane H+ -ATPase, a simple polypeptide with a long history. AB - The plasma membrane H+ -ATPase of fungi and plants is a single polypeptide of fewer than 1,000 residues that extrudes protons from the cell against a large electric and concentration gradient. The minimalist structure of this nanomachine is in stark contrast to that of the large multi-subunit FO F1 ATPase of mitochondria, which is also a proton pump, but under physiological conditions runs in the reverse direction to act as an ATP synthase. The plasma membrane H+ ATPase is a P-type ATPase, defined by having an obligatory phosphorylated reaction cycle intermediate, like cation pumps of animal membranes, and thus this pump has a completely different mechanism to that of FO F1 ATPases, which operates by rotary catalysis. The work that led to these insights in plasma membrane H+ -ATPases of fungi and plants has a long history, which is briefly summarized in this review. PMID- 30447029 TI - Harm reduction in opioid treatment: an established idea under threat. PMID- 30447030 TI - The SOS System: A complex and tightly regulated response to DNA damage. AB - Genomes of all living organisms are constantly threatened by endogenous and exogenous agents that challenge the chemical integrity of DNA. Most bacteria have evolved a coordinated response to DNA damage. In Escherichia coli, this inducible system is termed the SOS response. The SOS global regulatory network consists of multiple factors promoting the integrity of DNA as well as error-prone factors allowing for survival and continuous replication upon extensive DNA damage at the cost of elevated mutagenesis. Due to its mutagenic potential, the SOS response is subject to elaborate regulatory control involving not only transcriptional derepression, but also post-translational activation and inhibition. This review summarizes current knowledge about the molecular mechanism of the SOS response induction and progression and its consequences for genome stability. This article is protected by copyright. All rights reserved. PMID- 30447031 TI - R-omega-Transaminase Covalently Linking to D-Amino Acid Oxidase Through Protein Splicing to Enhance Enzymatic Catalysis of Transamination of Amines. AB - R-omega-Transaminases (RTA) catalyze the conversion of (R)-amines (e.g. (R)-1 phenylethylamine) to corresponding ketones (e.g. acetylbenzene), by transferring an amino group from an amino donor (e.g. (R)-1-phenylethylamine) onto an amino acceptor (e.g. pyruvate), resulting in a co-product (e.g. D-alanine). D-alanine can be deaminated back to pyruvate by D-amino acid oxidase (DAAO). Herein, through the vivo subunit splicing, the N-terminus of the RTA subunit (RTAS) was specifically ligated to the C-terminus of the DAAO subunit (DAAOS) with native peptide bonds (RTA&DAAO). RTAS is in close proximity to DAAOS at a molecular distance. Thus the transferring of pyruvate and D-alanine between RTA and DAAO can be directional and efficient. The pyruvate->D-alanine->pyruvate cycles are efficiently formed, promoting the transamination reaction forward. In an in vitro non-covalent approach, through the coiled-coil association, the N-terminus of RTAS was specifically associated with the C-terminus of DAAOS (RTA#DAAO). In addition, the mixed two enzymes RTA+DAAO was also studied. RTA&DAAO has a shorter distance between the paired subunits RTAS-DAAOS than RTA#DAAO, and the number of the paired subunits is higher than that of RTA#DAAO. While RTA+DAAO cannot form the paired subunits. For transamination of the amines, RTA&DAAO exhibited a higher catalysis efficiency than RTA#DAAO, and a much higher catalysis efficiency than RTA+DAAO. PMID- 30447032 TI - Evaluation of non-monoexponential diffusion models for hepatocellular carcinoma using b values up to 2000 s/mm2 : A short-term repeatability study. AB - BACKGROUND: Non-monoexponential diffusion models are being used increasingly for the characterization and curative effect evaluation of hepatocellular carcinoma (HCC). But the fitting quality of the models and the repeatability of their parameters have not been assessed for HCC. PURPOSE: To evaluate kurtosis, stretched exponential, and statistical models for diffusion-weighted imaging (DWI) of HCC, using b-values up to 2000 s/mm2 , in terms of fitting quality and repeatability. STUDY TYPE: Prospective. POPULATION: Eighteen patients with HCC. FIELD STRENGTH/SEQUENCE: Conventional and DW images (b = 0, 200, 500, 1000, 1500, 2000 s/mm2 ) were acquired at 3.0T. ASSESSMENT: The parameters of the kurtosis, stretched exponential, and statistical models were calculated on regions of interest (ROIs) of each lesion. STATISTICAL TESTS: The fitting quality was evaluated through comparing the fitting residuals produced on the average data of ROI between different models using a paired t-test or Wilcoxon rank-sum test. Repeatability of the fitted parameters at the median values on the voxelwise data of ROI was assessed using the within coefficient of variation (WCV), the intraclass correlation coefficient (ICC), and the 95% Bland-Altman limits of agreements (BA-LA). The repeatability was divided into four levels: excellent, good, acceptable, and poor, referring to the values of ICC and WCV. RESULTS: Among three models, the stretched exponential model provided the best fit to HCC (P < 0.05), whereas the statistical model produced the largest fitting residuals (P < 0.05). The repeatability of K from the kurtosis model was excellent (ICC 0.915; WCV 8.79%), while the distributed diffusion coefficient (DDC) from the stretched model was just acceptable (ICC 0.477; WCV 27.83%). The repeatability was good for other diffusion-related parameters. DATA CONCLUSION: Considering the model fit and repeatability, the kurtosis and stretched exponential models are the preferred models for the description of the DW signals of HCC with respect to the statistical model. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30447034 TI - Should more donation after cardiac death livers be used in pediatric transplantation? AB - INTRODUCTION: There is a mismatch that exists in donor liver organ supply and demand. DCD livers represents a potential source to increase the number of liver grafts available for use in pediatric recipients; however, there has been hesitancy to use such organs. We evaluated patient and allograft outcomes in pediatric liver transplant recipients of DCD livers. METHODS: The UNOS database was queried to examine outcomes in all liver transplant recipients from 1993 to 2017. Patients were then divided according to adult and pediatric status, DBD or DCD allograft status, and era of transplant. Donor and recipient demographic data were examined, and patient and allograft survival were calculated. A P-value of <0.05 was considered to be significant. RESULTS: A total of 57 pediatric recipients received a DCD liver allograft. DCD recipients were older than DBD recipients. There was no difference in the final PELD score between the groups. There were no differences in causes of allograft failure between the DCD and DBD groups. Importantly, the overall allograft survival in the DCD and DBD groups was similar, as was allograft survival based on era. CONCLUSION: Pediatric liver transplant recipients of DCD allografts have comparable patient and allograft survival when compared to DBD allograft recipients. Use of DCD allografts in the pediatric liver transplant population should be strongly considered to increase the donor organ pool. PMID- 30447033 TI - Prevalence of heart failure and the diagnostic value of MR-proANP in outpatients with type 2 diabetes. AB - The prevalence of heart failure (HF) in patients with type 2 diabetes (T2DM) is debatable and no data exist concerning the diagnostic value of mid-regional pro atrial natriuretic peptide (MR-proANP). We aimed to identify HF prevalence and evaluate the diagnostic value of MR-proANP in outpatients followed in two specialized diabetes clinics. HF was pre-defined as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The prevalence of HFrEF and HFpEF was 2.4% and 17.5%, respectively. An MR-proANP <60 pmol/L ruled out HFrEF in the total population (n = 806) and in patients reporting dyspnea (n = 311) with a sensitivity of 94.7% and 87.5%, a negative predictive value of 99.7% and 99.0%, a specificity of 39.5% and 33.0%, and a positive predictive value of 3.6% and 3.3%, respectively. In a multivariable model including age, sex, T2DM duration, albuminuria, uncontrolled systolic blood pressure, abnormal electrocardiogram and ischaemic heart disease for diagnosis of HF in patients reporting dyspnea, adding MR-proANP increased the area under the curve from 0.69 to 0.78 (P < 0.001). In conclusion, HFrEF was rare among outpatients with T2DM. MR-proANP rules out HFrEF and contributes independent information relevant to diagnosis of HF in patients reporting dyspnea. PMID- 30447035 TI - Examining determinants of health service utilisation among Filipino older people: A cross-sectional study. AB - OBJECTIVE: This study was done to study, using Andersen's Behavioral Model, factors affecting health service utilisation among older Filipinos. METHODS: A total of 237 older people from Marikina City, Philippines, were randomly selected and surveyed face-to-face on factors affecting health service utilisation, specifically age, civil status, educational level, employment status, sex, health insurance coverage, household income, chronic disease status and perceived health status. RESULTS: Seventy-nine per cent had used health services in the past year (mean: 5.7 visits per year). Female sex and having a chronic disease were significantly associated with health service utilisation. The odds of using health services was 3.1 times higher for those who had a chronic disease and 2.2 times higher for female sex, assuming all other variables are held constant. CONCLUSION: Findings of this study support targeting men in health promotion campaigns and implementing population-based, chronic disease screening programs to improve the reach of health services among Filipino older people. PMID- 30447036 TI - Cooperative Chirality and Sequential Energy Transfer in Supramolecular Light harvesting Nanotube. AB - By constructing a supramolecular light-harvesting chiral nanotube in aqueous phase, we demonstrated the cooperative energy and chirality transfer that revealed some new aspects. It was found that a cyanostilbene-appended glutamate compound (CG) self-assembled into helical nanotubes exhibiting both supramolecular chirality and circularly polarized luminescence (CPL). When two achiral acceptors ThT and AO with different energy bands were co-assembled with the nanotube, the CG nanotube could transfer its chirality to both of the acceptors. The excitation energy could be transferred to ThT but only be sequentially transferred to AO. During such process, the CPL ascribed to the acceptor could be sequentially amplified. This work provides a new insight into the understanding the cooperative chirality and energy transfer in a chiral supramolecular system, which is more similar to the natural light-harvesting antennas. PMID- 30447037 TI - Effect of Canagliflozin Treatment on Hepatic Triglyceride Content and Glucose Metabolism in Patients with Type 2 Diabetes. AB - AIMS: Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves glycemic control by increasing urinary glucose excretion, but its impact on intrahepatic triglyceride (IHTG) accumulation and relationship to changes in body weight and glucose metabolism remain unknown. MATERIALS AND METHODS: In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c=7.7+/-0.7%) from two centers were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome); hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycemic insulin clamp; and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS: Between 09/08/2014-06/13/2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [ 1.08;-0.33]) and body weight (-3.4% [-5.4;-1.4]; both p<=0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (-4.6% [-6.4;-2.7]) versus placebo (-2.4% [-4.2;-0.6]; p=0.09). In patients with NAFLD (n=37), the decrease in IHTG was -6.9% (-9.5;-4.2) versus -3.8% (-6.3;-1.3; p=0.05), and strongly correlated with the magnitude of weight loss (r=0.69, p<0.001). Weight loss >=5% with a >=30% relative reduction in IHTG occurred more often with canagliflozin (38% versus 7%, p=0.009). Hepatic insulin sensitivity improved with canagliflozin (p<0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance and disposition index improved more with canagliflozin (p<0.05). CONCLUSIONS: Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of weight loss, which tended to be greater and occur more often with canagliflozin. This article is protected by copyright. All rights reserved. PMID- 30447038 TI - Sleep and type 1 diabetes in children and adolescents: Proposed theoretical model and clinical implications. AB - Youth with type 1 diabetes mellitus (T1D) experience more sleep disturbances and shorter sleep durations compared to their healthy peers. Researchers have now uncovered the negative mental health and physical health outcomes associated with poor sleep in youth with T1D. The field of T1D sleep research currently operates under the broad notion that sleep behaviors impact treatment adherence, which ultimately lead to worse long-term health outcomes. This model however does not explain how behavior influences T1D management and sleep outcomes on a day-to-day basis, leading to difficulties in providing tailored treatment recommendations. In this review, we present a theoretical framework that describes the recursive cycle between sleep behaviors, T1D outcomes, and symptoms of negative affect/stress over a 24-hour period. This model is guided by the sleep literature, showing a clear relationship between poor sleep and negative affect, and the T1D literature demonstrating a link between poor sleep and disease management for youth with T1D. Further, emerging literature indicates a need for additional parent sleep assessment considering that T1D management and fear of hypoglycemia negatively impact parent sleep behaviors. Recommendations are provided to move the field toward effective intervention studies and new areas of research to evaluate and modify the proposed model. PMID- 30447039 TI - The use of quantitative imaging to investigate regulators of membrane trafficking in Arabidopsis stomatal closure. AB - Expansion of gene families facilitates robustness and evolvability of biological processes but impedes functional genetic dissection of signalling pathways. To address this, quantitative analysis of single cell responses can help characterise the redundancy within gene families. We developed high-throughput quantitative imaging of stomatal closure, a response of plant guard cells, and performed a reverse genetic screen in a group of Arabidopsis mutants to five stimuli. Focussing on the intersection between guard cell signalling and the endomembrane system, we identified eight clusters based on the mutant stomatal responses. Mutants generally affected in stomatal closure were mostly in genes encoding SNARE and SCAMP membrane regulators. By contrast, mutants in RAB5 GTPase genes played specific roles in stomatal closure to microbial but not drought stress. Together with timed quantitative imaging of endosomes revealing sequential patterns in FLS2 trafficking, our imaging pipeline can resolve non redundant functions of the RAB5 GTPase gene family. Finally, we provide a valuable image-based tool to dissect guard cell responses and outline a genetic framework of stomatal closure. This article is protected by copyright. All rights reserved. PMID- 30447040 TI - Intravenous contrast-free standardized exercise perfusion imaging in diabetic feet with ulcers. AB - BACKGROUND: Impaired foot perfusion is a primary contributor to foot ulcer formation. There is no existing device nor method that can be used to measure local foot perfusion during standardized foot muscle exercise in an MRI environment. PURPOSE: To develop a new MRI-compatible foot dynamometer and MRI methods to characterize local perfusion in diabetic feet with ulcers. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Seven participants without diabetes and 10 participants with diabetic foot ulcers. FIELD STRENGTH/SEQUENCE: 3.0T, arterial spin labeling (ASL). ASSESSMENTS: Using a new MRI-compatible foot dynamometer, all participants underwent MRI ASL perfusion assessment at rest and during a standardized toe-flexion exercise. The participants without diabetes were scanned twice to assess the reproducibility of perfusion measurements. The absolute perfusion and perfusion reserve values were compared between two groups and between regions near ulcers (peri-ulcer) and away from ulcers (away-ulcer). STATISTICAL TESTS: Bland-Altman methods for the calculation of coefficient of repeatability (CR) and two-sided and unpaired Student's t-test to compare multiple differences. RESULTS: The perfusion reserves measured had the best reproducibility (CR in medial region: 1.6, lateral region: 0.9). The foot perfusion reserve was significantly lower in the participants with diabetes compared with the participants without diabetes (1.34 +/- 0.32, 95% confidence interval [CI]: 1.1, 1.58 vs. 1.76 +/- 0.31, 95% CI: 1.53, 1.98, P = 0.02). Both peri-ulcer exercise perfusion (8.7 +/- 3.9 ml/min/100g) and perfusion reserve (1.07 +/- 0.39, 95% CI: 0.78, 1.35) were significantly lower than away-ulcer exercise perfusion (12.7 +/- 3.8 ml/min/100g, P = 0.02) and perfusion reserve (1.39 +/- 0.37, 95% CI: 1.11, 1.66, P = 0.03), respectively. DATA CONCLUSION: This study demonstrates intravenous contrast-free methods for local perfusion in feet with ulcers by standardized exercise-based MRI. Ischemia regions around foot ulcers can be quantitatively distinguished from normal perfused muscle regions. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30447041 TI - Chronological change in oropharyngeal leak pressure of pediatric i-gelTM. AB - Sir-The i-gelTM (Intersurgical, Wokingham, UK) is a single-use supraglottic airway device with a noninflatable cuff made of a soft, gel-like thermoplastic elastomer. It was previously reported that oropharyngeal leak pressure (OLP) of i gelTM improved over time after insertion in adults.1 However, there is limited evidence regarding the change in sealing ability of pediatric i-gelTM . This article is protected by copyright. All rights reserved. PMID- 30447043 TI - Borane-Catalyzed Cross-Metathesis Strategy for Facile Transformation of Cyclic (Alkyl)(Amino)Germylenes. AB - A borane B(C6 F5 )3 -catalyzed metathesis reaction between the Si-C bond in the cyclic (alkyl)(amino)germylene (CAAGe) 1 and the Si-H bond in a silane (R3 SiH; 2) is reported. Mechanistic studies propose that the initial step of the reaction involves Si-H bond activation to furnish an ionic species [1-SiR3 ]+ [HB(C6 F5 )3 ]- , from which [Me3 Si]+ [HB(C6 F5 )3 ]- and an azagermole intermediate are generated. The former yields Me3 SiH concomitant with the regeneration of B(C6 F5 )3 whereas the latter undergoes isomerization to afford CAAGes bearing various silyl groups on the carbon atom next to the germylene center. This strategy allows the straightforward synthesis of eight new CAAGes starting from 1. PMID- 30447042 TI - Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. AB - Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1 3, fibroblast growth factor receptor 1-4, platelet-derived growth factor receptor alpha, KIT and RET) and the combined antitumor activity of lenvatinib plus anti programmed cell death 1 (PD-1) antibody in the Hepa1-6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti-PD-1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single-cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti-PD-1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti PD-1 antibody. Combination treatment of lenvatinib plus anti-PD-1 antibody therefore warrants further investigation against advanced HCC. PMID- 30447044 TI - Acquired mania associated with a left temporal meningioma. PMID- 30447045 TI - Impact of ureteral stent removal by string on patient's quality of life and complications at post-ureteroscopy for urolithiasis: a controlled trial. AB - OBJECTIVES: To evaluate the impact of ureteral stent removal by string in comparison with stent removal by cystoscope regarding with the pain at ureteral stent removal, complications, and quality of life as well as self-rated symptoms of patients after ureteroscopy for urolithiasis. PATIENTS AND METHODS: Of 328 patients who underwent ureteroscopy for upper urinary tract stones at our institution, 149 were randomly divided into a ureteral stent removal by string (string group) and by flexible cystoscope (cystoscope group) using gender as a stratification factor. We focused on four sites, namely upper abdomen, bladder, flank, and urethra, to evaluate the most painful site at stent removal. Primary endpoint was total pain scores of four sites at stent removal in the string group versus cystoscope group. Secondary endpoints included comparison of the psychological well-being of patients using the WHO-5 well-being index at pre operation, pre-stent removal, and 2 weeks after stent removal between string group and cystoscope group. RESULTS: Of 149 patients analyzed, 74 were in the string group and 75 in the cystoscope group. In most patients, the ureteral stent was removed around 10 days after ureteroscopy. The string group was significantly less pain compared with the cystoscope group (mean VAS scores 2.73 vs 5.67, p<0.001). Although VAS scores for females were not significantly different between the groups (p=0.300), those for males were significantly less in the string group (p<0.001). Especially, male removed ureteral stent by string experienced significantly less urethral pain than those by cystoscope. WHO-5 well being index scores between the groups were not significantly different at pre operation, pre-stent removal, and 2 weeks after stent removal. Stent string related complications and self-rated symptoms were also not significantly different. CONCLUSION: Ureteral stent removal by string after ureteroscopy significantly provides less pain than those by cystoscope for male patients. There were no increased complications in terms of UTI or accidental dislodgement in the string group. This article is protected by copyright. All rights reserved. PMID- 30447046 TI - BK polyomavirus viremia and antibody responses of pediatric kidney transplant recipients in Finland. AB - BACKGROUND: BKPyV is an important cause of premature graft failure after KT. Most clinical studies describe BKPyV infection in adult KT patients. We studied the prevalence of post-transplant BKPyV viremia, serology, and graft function in pediatric KT recipients. METHODS: Forty-six pediatric patients transplanted between 2009 and 2014 were followed up for BKPyV DNAemia by plasma PCR for median 2.3 (range: 1-6) years. BKPyV-specific antibodies were retrospectively analyzed using virus-like particle ELISA. GFR was measured annually by 51 Cr-EDTA clearance, and serum samples were screened for DSAs by Luminex assay. RESULTS: BKPyV viremia was demonstrated in nine patients at a median of 6 months post-KT. Early BKPyV viremia at 3 months post-KT associated with decreased concomitant GFR and tendency for decreased subsequent graft function. Three of nine patients with BKPyV viremia developed DSA, all against class II antigens. PyVAN developed to four patients and responded to judicious reduction in IS. One graft was lost later due to ABMR. BKPyV-IgG was found in 18 of 31 patients (58%) tested at transplantation, and seven recipients seroconverted after transplantation with a significant increase in IgG levels with IgM. Finally, BKPyV-IgG was detectable in 31 of 40 patients (78%) at the end of the study. CONCLUSIONS: Post-transplant BKPyV viremia in pediatric KT patients may alter graft function and contribute to progression of chronic allograft injury. BKPyV-IgG predicts past exposure. Low or absent BKPyV-specific antibody levels were seen pretransplant in 42% of tested patients, but were not predictive of prolonged replication or poor outcome. PMID- 30447047 TI - Cutaneous malignancies in Indigenous Peoples of urban Sydney. AB - INTRODUCTION: Despite 3% of Australians identifying as Indigenous, cutaneous malignancies in these patients, including incidence, risk factors and outcomes have not been investigated. This is despite recognition that cancer outcomes in this population are significantly poorer. METHODS: We undertook a retrospective case series of Indigenous Peoples who presented to two urban cancer therapy centres for the management of cutaneous malignancies from 2003 to 2017. Risk factors, tumour-specific characteristics, treatments and outcomes were reviewed. RESULTS: Twenty-two patients identified as Aboriginal and/or Torres Strait Islander. The median age at presentation was 61 years and the majority were male (63.6%) and had skin phototype III (86.4%). Patients presented with basal cell carcinoma (50%), squamous cell carcinoma (31.8%), melanoma (9.1%) and cutaneous sarcomas (9.1%). The majority (68.2%) presented with stage II or higher disease, and there were high rates of immunosuppression (45.5%). At the time of reporting, 68.2% patients were alive, 18.2% had died from their skin cancers and 13.6% had died from unrelated causes. CONCLUSION: This cohort has demonstrated late-stage presentation of skin cancers, with substantial morbidity and mortality from potentially treatable cutaneous malignancies. This parallels other health conditions in Indigenous Australians and has highlighted the need for improved data collection of Indigenous status to better quantify the epidemiology of skin cancer in this population. There is an imperative to improve skin cancer awareness in this population to allow earlier detection and management to ensure better outcomes. PMID- 30447048 TI - Which Type of Temporary Hemodialysis Catheter to Be Used for the Right Internal Jugular Vein? Prospective Observational Study of Straight vs Precurved Caths. AB - INTRODUCTION: Weak evidence is present for choosing amongst different temporary hemodialysis catheter (THC) designs with regards to the risk of venous thrombosis, therefore two THC designs for the right internal jugular vein (RIJV) were compared. METHODS: Patients aged >= 18 years who needed THC insertion into the RIJV for acute hemodialysis due to either acute or chronic renal failure were included. The type of THC (precurved/straight) was dependent on the date of hospital admission. Clinical and ultrasonographic surveillance was conducted prospectively. Thrombosis of the RIJV was the primary objective. RESULTS: Precurved and straight catheters were inserted into 32 and 23 patients (mean age 63+/-15 years, females 28), respectively. The baseline characteristics and catheter dwell-times were similar in both groups. Partial and total thrombosis of the RIJV during catheter dwell-time developed at a higher rate in the straight group (52% vs 9.3%, p=0.000; 47.8% vs 9.3%, p=0.001, respectively). At least two weeks after catheter removal, total thrombosis was found in 43.4% vs 9.6% (p=0.004) of patients with straight and precurved THCs, respectively. The hazard ratios for total thrombosis was 0.161 (p=0.006) during catheter dwell-time and 0.190 (p=0.012) after catheter removal. Catheter dysfunction did not occur and only one catheter-related bloodstream infection (CRBI) was seen. CONCLUSIONS: Thrombosis rates of the RIJV was higher with straight versus precurved THCs, both during catheter dwell-time and after catheter removal. Catheter dysfunction was not noted in any group and the rate of CRBI was extremely low. PMID- 30447049 TI - Development and evaluation of realistic optical cell models for rapid and label free cell assay by diffraction imaging. AB - Methods for rapid and label-free cell assay are highly desired in life science. Single-shot diffraction imaging presents strong potentials to achieve this goal as evidenced by past experimental results using methods such as polarization diffraction imaging flow cytometry. We present here a platform of methods toward solving these problems and results of optical cell model (OCM) evaluations by calculations and analysis of cross-polarized diffraction image (p-DI) pairs. Four types of realistic OCMs have been developed with two prostate cell structures and adjustable refractive index parameters to investigate the effects of cell morphology and index distribution on calculated p-DI pairs. Image patterns have been characterized by a gray-level co-occurrence matrix (GLCM) algorithm and 4 GLCM parameters and linear depolarization ratio deltaL have been selected to compare calculated against measured data of prostate cells. Our results show that the irregular shapes of and heterogeneity in refractive index (RI) distributions for organelles play significant roles in the spatial distribution of scattered light by cells in comparison to the average RI values and their differences among the organelles. Discrepancies in GLCM and deltaL parameters between calculated and measured p-DI data provide useful insight for understanding light scattering by single cells and improving OCM. This article is protected by copyright. All rights reserved. PMID- 30447050 TI - A novel urine analysis technique combining affinity chromatography with Au nanoparticle based SERS spectroscopy for potential applications in noninvasive cancer screening. AB - Modified nucleoside in urine samples is one of the most common biomarkers for cancer screening. Therefore, we developed a novel detection method for modified nucleoside detection in human urine. In this work, the modified nucleoside from real cancer patient's urine samples was firstly separated and purified using the affinity chromatography (AC) technology relying on its specific adsorption capacity. Then, a surface enhanced Raman spectroscopy (SERS) technology with the capable of single molecular detection was employed for sensitively characterizing the biomolecular features of modified nucleoside. A total of 141 high quality SERS spectra of urinary modified nucleoside can be obtained from 50 gastric cancer patients, 43 breast cancer patients as well as 48 healthy volunteers. Using principal component analysis combined with linear discriminant analysis (PCA-LDA), the diagnostic sensitivities for identifying gastric cancer vs. normal, breast cancer vs. normal, gastric cancer vs. breast cancer were 84.0%, 76.7% and 82.0%, respectively. And the corresponding diagnostic specificities for each combination were 95.8%, 87.5% and 90.7%, respectively. These results show that this novel method based on urinary modified nucleoside detection combining AC and SERS technologies holds promising potential for developing a specific, non invasive and label-free tool for cancer screening. This article is protected by copyright. All rights reserved. PMID- 30447051 TI - When to switch from bilateral to unilateral electroconvulsive therapy: A simple way to elicit seizures in high seizure threshold cases. AB - AIMS: Although electroconvulsive therapy (ECT) is effective for various psychiatric disorders, its therapeutic effect depends on the occurrence of adequate seizures. Thus, the management of inadequate seizures remains a clinical problem. Here, we aimed to develop a simple method to elicit adequate seizures in high seizure threshold patients during ECT sessions. METHODS: Right unilateral ECT was performed in 87 sessions (22 inpatients) in which 504 millicoulombs bilateral (bitemporal or bifrontal) electrical stimulation had failed to induce adequate seizures. A Thymatron(r) System IV (Somatics LLC, Lake Bluff, IL, USA) and the LOW 0.5 program were used in accordance with the manufacturer's instructions. The electrode placement was bitemporal, bifrontal, or right unilateral (d'Elia placement). The minimum duration for an adequate seizure was 15 seconds in the electroencephalogram record of the Thymatron(r) stimulator. The efficacy of treatment was estimated by the Global Assessment of Functioning at the time of admission and discharge. Cognitive assessment was not performed. RESULTS: By switching to right unilateral stimulation immediately after failure of bilateral stimulation, adequate seizures were achieved in 71 of 87 (81.6%) sessions. Improvement in the Global Assessment of Functioning was observed in 23 of 28 (82.1%) treatment courses. CONCLUSION: Switching from bilateral to unilateral electrode placement may be a simple clinical option for eliciting adequate seizures in high seizure threshold cases. PMID- 30447052 TI - Resistin is a prognostic factor in type 2 diabetes. AB - PURPOSE: To investigate the association of leptin, resistin and tumor necrosis factor alpha (TNF-alpha) with prognosis in type 2 diabetes (T2D). METHODS: Analysis included 284 T2D patients. Apart from routine laboratory parameters, baseline leptin, resistin and TNF-alpha concentrations were measured. Patients were followed for a median of 5.4 years. The primary endpoint was all-cause death at follow-up. The secondary endpoint was a composite of death, acute coronary syndrome and stroke or transient ischemic attack. RESULTS: At baseline, median age was 68 years and 48% of patients were female. Data on the primary endpoint were obtained for all patients: 32 (11%) died during follow-up. Data on the secondary endpoint were available for 230 patients, of whom 45 (20%) reached the secondary endpoint. In univariate analyses, older age, heart failure, lower glomerular filtration rate, and higher resistin, TNF-alpha and NT-proBNP concentrations were predictors of the study endpoints. Of these variables, only resistin remained an independent predictor of both study endpoints in multivariate models. In receiver operating characteristic analysis, area under the curve for resistin was 0.7. Resistin concentration of >=11.4 ng/mL had sensitivity of 41% and specificity of 91% for prediction of death at follow-up (Youden's index). CONCLUSIONS: Higher resistin is associated with reduced survival in T2D, irrespectively of TNF-alpha. Resistin concentration of above 11 ng/mL indicates T2D patients at an increased risk of unfavorable outcomes. Leptin was not a prognostic factor. These results suggest that in T2D, association of resistin with unfavorable outcomes might, at least in part, result from its pro inflammatory properties. PMID- 30447053 TI - The influence of the nylon balloon stiffness on the efficiency of the intra aortic balloon occlusion. AB - In interventional procedures the balloon inflation is used to occlude the artery and thus reduce bleeding. There is no practically accepted measure of the procedure efficiency. A finite element method model with state of the art modelling techniques was built in order to predict the occlusions levels under the influence of different balloon inflation and its material stiffness. The geometries of a healthy human thoracic aorta and an occlusion balloon were idealized. The non-linear constitutive material of Gasser-Ogden-Holzapfel model was employed for the thoracic aorta, the balloon was model as the hyperelastic model. The realistic physiological blood pressure and the balloon inflation pressures were applied to simulate the different occlusions levels. The final outcome shows an important influence of the material stiffness on the balloon deformation and thus the occlusion efficiency. PMID- 30447054 TI - Mutations in STAG2 cause an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphia: Expanding the phenotype in males. AB - BACKGROUND: The cohesin complex is a multi-subunit protein complex which regulates sister chromatid cohesion and separation during cellular division. In addition, this evolutionarily conserved protein complex plays an integral role in DNA replication, DNA repair, and the regulation of transcription. The core complex is composed of four subunits: RAD21, SMC1A, SMC3, and STAG1/2. Mutations in these proteins have been implicated in human developmental disorders collectively termed "cohesinopathies." METHODS: Using clinical exome sequencing, we have previously identified three female cases with heterozygous STAG2 mutations and overlapping syndromic phenotypes. Subsequently, a familial missense variant was identified in five male family members. RESULTS: We now present the case of a 4-year-old male with developmental delay, failure to thrive, short stature, and polydactyly with a likely pathogenic STAG2 de novo missense hemizygous variant, c.3027A>T, p.Lys1009Asn. Furthermore, we compare the phenotypes of the four previously reported STAG2 variants with our case. CONCLUSION: We conclude that mutations in STAG2 cause a novel constellation of sex-specific cohesinopathy-related phenotypes and are furthermore, essential for neurodevelopment, human growth, and behavioral development. PMID- 30447055 TI - Distribution of ABO and RHD blood group antigens in blood donors in Burkina Faso. AB - Geographical distribution of ABO and RHD antigens is important for blood transfusion services and population genetics studies. There are few data on this topic in Burkina Faso, a multi-ethnic country. Our study aims at reporting phenotypic and allelic frequencies of ABO and RHD blood groups among voluntary blood donors from various ethnical regions of Burkina Faso. We conducted a cross sectional study including 81,486 blood donors. ABO allelic frequencies were determined using the Bernstein method. Differences in phenotypic distribution of blood groups were assessed using the chi-square test; a p value <0.05 being considered as statistically significant. We noticed that O+>B+>A+>AB+>O->B->A->AB in our population. Phenotypic frequencies of blood groups A, B, O and AB were respectively 22.54%, 28.56%, 43.30% and 5.60%. RHD+was 92.24%. The allelic frequencies of A, B, O and D were respectively 0.1524; 0.1887; 0.6590 and 0.7214. We noticed statistical differences (p < 0.05) between these administrative regions which corresponded roughly to some natural ethnic areas. Indeed, the phenotype O was more frequent in the Central-west, Central and East regions corresponding to "Mossi," "Gourounsi," "Gourmantche" areas while the phenotype A and AB were more reported in "Boucle du mouhoun" and "Hauts-Bassins" regions where we have "Bwaba" and "Bobo." The phenotype O negative was less frequent in "Bwaba." Our study provides interesting information to blood services that will allow them to better refine their donor recruitment strategies. PMID- 30447057 TI - Cytometry in the air. PMID- 30447056 TI - Can Google Trends data improve forecasting of Lyme disease incidence? AB - BACKGROUND: Online activity-based epidemiological surveillance and forecasting is getting more and more attention. To date, Google search volumes have not been assessed for forecasting of tick-borne diseases. Thus, we performed an analysis of forecasting of the Lyme disease incidence based on the traditional data extended with Google Trends. METHODS: Data on the weekly incidence of Lyme disease in Germany from 16 June 2013 to 27 May 2018 were obtained from the database of the Robert Koch Institute. Data of Internet searches were obtained from Google Trends searching "Borreliose" in Germany for the "last 5 years" as a timespan category. Data were split into the training (from 16 June 2013 to 11 June 2017) and validation (from 12 June 2017, to 27 May 2018) data sets. A seasonal autoregressive moving average model, SARIMA (0,1,1) (0,1,1) [52] model was selected to describe the time series of the weekly Lyme incidence. After this, we added the Google Trends data as an external regressor and identified the SARIMA (0,1,1) (0,1,1) [52] model as optimal. We made predictions for the validation interval using these two models and compared predictions with the values of the validation data set. RESULTS: Forecasting for the validation timespan resulted in similar values for the models. Comparing the forecasted values with the reported ones resulted in an residual mean squared error (RMSE) of 0.3763; the mean absolute percentage error (MAPE) was 8.233 for the model without Google searches with an RMSE of 0.3732; and the MAPE was 8.17495 for the Google Trends values-expanded model. The difference between the predictive performances was insignificant (Diebold-Mariano Test, p-value = 0.4152). CONCLUSION: Google Trends data are a good correlate of the reported incidence of Lyme disease in Germany, but it failed to significantly improve the forecasting accuracy in models based on traditional data. PMID- 30447058 TI - Frequent human-poultry interactions and low prevalence of Salmonella in backyard chicken flocks in Massachusetts. AB - The backyard chicken (BYC) movement in the USA has increased human contact with poultry and subsequently, human contact with the pathogen Salmonella. However, to date, there have been few studies assessing prevalence of Salmonella in backyard flocks, despite the known public health risk this zoonotic bacterium poses. The objective of this study was to characterize human-BYC interactions and assess the prevalence of Salmonella among BYC flocks. We interviewed 50 BYC owners using a structured questionnaire to determine flock and household characteristics that facilitate contact with BYC and that may be associated with Salmonella in the BYC environment. Composite faecal material, cloacal swabs and dust samples from 53 flocks housed on 50 residential properties in the Greater Boston, Massachusetts area were tested for Salmonella using standard culture techniques and confirmed using Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometer. Microbroth dilution and whole genome sequencing were used to determine phenotypic and genotypic resistance profiles, respectively, and sequence results were used to determine multilocus sequencing type. No owners self-reported a diagnosis of salmonellosis in the household. Over 75% of a subset of owners reported that they and their children consider BYC pets. This perception is evident in how owners reported interacting with their birds. Salmonella enterica subspecies enterica serotype Kentucky ST152 (serogroup C)-a strain not commonly associated with human infection-was confirmed in one flock, or 2% of tested flocks, and demonstrated resistance to tetracycline and streptomycin. We detected Salmonella at low prevalence in BYC. Further study of the health effects of exposure to zoonotic gastrointestinal pathogens such as Salmonella among families with BYC is warranted. PMID- 30447059 TI - Synthesis of Azobenzene Dyes Mediated by CotA Laccase. AB - An eco-friendly protocol for the synthesis of azobenzene dyes by oxidative coupling of primary aromatic amines is reported. As efficient biocatalytic systems, CotA laccase and CotA laccase/ABTS (2,2'-azinobis(3-ethylbenzothiazoline 6-sulfonic acid)) enable the oxidation of various substituted anilines, in aqueous medium, ambient atmosphere and under mild reaction conditions of pH and temperature. A series of azobenzene dyes were prepared in good to excellent yields in an one-pot reaction. A mechanistic proposal for the formation of the azo derivatives is presented. Our strategy offers an alternative approach for the direct synthesis of azobenzene dyes, avoiding the harsh conditions generally required for most of the traditional synthetic methods. PMID- 30447060 TI - Real-time oncological guidance using diffuse reflectance spectroscopy in electrosurgery: the effect of coagulation on tissue discrimination. AB - In breast surgery, a lack of knowledge about what is below the tissue surface may lead to positive tumor margins and iatrogenic damage. Diffuse reflectance spectroscopy (DRS) is a spectroscopic technique that can distinguish between healthy and tumor tissue making it a suitable technology for intraoperative guidance. However, because tumor surgeries are often performed with an electrosurgical knife, the effect of a coagulated tissue layer on DRS measurements must be taken into account. It is evaluated whether real-time DRS measurements obtained with a photonic electrosurgical knife could provide useful information of tissue properties also when tissue is coagulated and cut. The size of the coagulated area is determined and the effect of its presence on DR spectra is studied using ex vivo porcine adipose and muscle tissue. A coagulated tissue layer with a depth of 0.1 to 0.4 mm is observed after coagulating muscle with an electrosurgical knife. The results show that the effect of coagulating adipose tissue is negligible. Using the fat/water ratio's calculated from the measured spectra of the photonic electrosurgical knife, it was possible to determine the distance from the instrument tip to a tissue transition during cutting. In conclusion, the photonic electrosurgical knife can determine tissue properties of coagulated and cut tissue and has, therefore, the potential to provide real-time feedback about the presence of breast tumor margins during cutting, helping surgeons to establish negative margins and improve patient outcome. PMID- 30447061 TI - Study Break: Recent Advances in Hemophilia Gene Therapy PMID- 30447062 TI - Aminoglycoside Revival: Review of a Historically Important Class of Antimicrobials Undergoing Rejuvenation. AB - Aminoglycosides are cidal inhibitors of bacterial protein synthesis that have been utilized for the treatment of serious bacterial infections for almost 80 years. There have been approximately 15 members of this class approved worldwide for the treatment of a variety of infections, many serious and life threatening. While aminoglycoside use declined due to the introduction of other antibiotic classes such as cephalosporins, fluoroquinolones, and carbapenems, there has been a resurgence of interest in the class as multidrug-resistant pathogens have spread globally. Furthermore, aminoglycosides are recommended as part of combination therapy for empiric treatment of certain difficult-to-treat infections. The development of semisynthetic aminoglycosides designed to overcome common aminoglycoside resistance mechanisms, and the shift to once-daily dosing, has spurred renewed interest in the class. Plazomicin is the first new aminoglycoside to be approved by the FDA in nearly 40 years, marking the successful start of a new campaign to rejuvenate the class. PMID- 30447063 TI - Alteration of Circadian Rhythms in 2D2 Transgenic Mice. AB - BACKGROUND Several immunological functions are dependent on circadian rhythms. However, there are still relatively few studies about circadian rhythms in neuromyelitis optica spectrum disorders (NMOSD) and 2D2 transgenic mice. We explore whether 2D2 mice have abnormalities in circadian rhythms and the potential underlying molecular mechanism. MATERIAL AND METHODS We first observed the wheel-running motion of the control and 2D2 mice using wheel-running measurements. The cytokine levels were also analyzed using enzyme-linked immunosorbent assay (ELISA), and the results of clock gene expressions in the suprachiasmatic nucleus (SCN) were investigated using real-time polymerase chain reaction (real-time PCR). RESULTS The wheel-running rhythm in 2D2 mice differed from that of the controls. The TNF-alpha and IL-10 rhythms were disrupted in 2D2 mice. Additionally, the rhythm of the clock genes, Per1 and Per2, and expression in the SCN of 2D2 mice were also changed. CONCLUSIONS The results presented here indicate that alteration of circadian rhythms in 2D2 mice affects behavior and immune function, and the potential molecular mechanism might be the Per1 and Per2 expression disorders in the SCN. 2D2 mice might be a suitable model for studying circadian disruption in NMOSD. PMID- 30447064 TI - Ecology of fish hearing. AB - Underwater sound is directional and can convey important information about the surrounding environment or the animal emitting the sound. Therefore, sound is a major sensory channel for fishes and plays a key role in many life-history strategies. The effect of anthropogenic noise on aquatic life, which may be causing homogenisation or fragmentation of biologically important signals underwater is of growing concern. In this review we discuss the role sound plays in the ecology of fishes, basic anatomical and physiological adaptations for sound reception and production, the effects of anthropogenic noise and how fishes may be coping to changes in their environment, to put the ecology of fish hearing into the context of the modern underwater soundscape. PMID- 30447065 TI - Polyamines interfere with protein ubiquitylation and cause depletion of intracellular amino acids: a possible mechanism for cell growth inhibition. AB - Spermidine is a polyamine present in eukaryotes with essential functions in protein synthesis. At high concentrations spermidine and norspermidine inhibit growth by unknown mechanisms. Transcriptomic analysis of the effect of norspermidine on the plant Arabidopsis thaliana indicates upregulation of the response to heat stress and denatured proteins. Accordingly, these polyamines inhibit protein ubiquitylation, both in vivo (in yeast, Arabidopsis, and human Hela cells) and in vitro (with recombinant ubiquitin ligase). This interferes with protein degradation by the proteasome, a situation known to deplete cells of amino acids. Norspermidine treatment of yeast cells induces amino acid depletion, and supplementation of media with amino acids counteracts growth inhibition and cellular amino acid depletion but not inhibition of protein polyubiquitylation. This article is protected by copyright. All rights reserved. PMID- 30447067 TI - Protein abundance of clinically relevant drug transporters in the human liver and intestine: a comparative analysis in paired tissue specimens. AB - Bioavailability of orally administered drugs is partly determined by function of drug transporters in the liver and intestine. We therefore explored ABC and SLC family transporters expression (qPCR) and protein abundance (LC-MS/MS) in human liver and duodenum, jejunum, ileum and colon in paired tissue specimens from 9 organ donors. The transporter proteins were detected in the liver (P-gp, MRP2, MRP3, BCRP, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT3, OAT2, NTCP, MCT1, MATE1) and the intestine (P-gp, MRP2, MRP3, MRP4, BCRP, OATP2B1, OCT1, ASBT (only ileum), MCT1, PEPT1). Significantly higher hepatic gene expression and protein abundance of ABCC2/MRP2, SLC22A1/OCT1 and SLCO2B1/OATP2B1 were found, as compared to all intestinal segments. No correlations between hepatic and small intestinal protein levels were observed. These observations provide a description of drug transporters distribution without the impact of inter-individual variability bias, and may help in construction of superior PBPK and humanized animal models. This article is protected by copyright. All rights reserved. PMID- 30447066 TI - Utilization of Palliative Care in Patients Hospitalized with Heart Failure: A Contemporary National Perspective. AB - BACKGROUND: Despite advances in therapy, heart failure (HF) patients have significant symptom burden, and poor quality of life. However, data on palliative care (PC) utilization in this population are scarce. We sought to assess national trends in PC utilization in patients admitted with acute HF. METHODS: Adults hospitalized with HF without acute coronary syndrome were identified in the National inpatient sample. Palliative care was identified using ICD-9-CM-Code V66.7. Trends in PC utilization, its predictors and its association with length of-stay and cost were assessed. RESULTS: A total of 939,680 HF patients were hospitalized with HF between 2003 and 2014. Of those,1.2% received PC during the hospitalization, with an upward trend in the use of PC over time (0.12% in 2003 to 3.6% in 2014, p<0.001). Compared with patients who did not receive PC, those who had PC were older (79+/-12 vs. 69+/-16 years), and had higher prevalence of Caucasian race (73.4% vs. 51.8%), coronary disease (45.6% vs. 39.3%), chronic renal disease (79.3% vs. 42.8%), and pulmonary hypertension (28.3% vs. 15.1%) (p<0.001). In-hospital mortality (35.2% vs. 2.2%), length-of-stay (9+/-13 days vs. 6+/-6, p<0.001), cost ($19,984+/-42,922 vs.. $11,921+/-18175), and non-home discharges (46% vs. 19.2%) (p<0.001) were higher in the PC group. In-hospital mortality in PC group trended downward over time (69% in 2003 vs. 29% in 2014, p<0.001). CONCLUSION: Palliative care is being utilized in an increasing but overall small number of patients hospitalized with HF. Further research is needed to identify the optimal role and timing of PC in HF patients. PMID- 30447068 TI - Variation in thermal tolerances of native freshwater fishes in South Africa's Cape Fold ecoregion: examining the east-west gradient in species' sensitivity to climate warming. AB - The Cape Fold Ecoregion (CFE) is a biodiversity hotspot with high levels of endemism in its freshwater fish fauna. This study examined inter and intra specific variation in critical thermal maxima (TCmax ) for eight native species of freshwater fish from the CFE. Cape galaxias Galaxias zebratus, Breede River redfin Pseudobarbus burchelli, Berg River redfin Pseudobarbus burgi, Clanwilliam redfin Pseudobarbus calidus and fiery redfin Pseudobarbus phlegethon were the most thermally sensitive (TCmax = 29.8-32.8 degrees C). Clanwilliam rock-catfish Austroglanis gilli, Eastern Cape redfin Pseudobarbus afer and Cape kurper Sandelia capensis were moderately sensitive (TCmax = 33.0-36.8 degrees C). An increase in intra-specific thermal sensitivity of S. capensis was observed from east to west. The results were related to in situ water temperature, which influenced TCmax for all species, suggesting that thermal history is a major driver of variation in thermal tolerance amongst populations. These thermal tolerance data for freshwater fishes in the CFE demonstrate that resilience to climate warming follows a geographical cline and that the more sensitive western species and regions are conservation priorities. PMID- 30447069 TI - Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. AB - TPMT activity exhibits a monogenic co-dominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced pharmalogic effecs of thiopurines. Loss-of-function alleles in the NUDT15 gene are common in Asians and Hispanics and reduces the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting dosesof azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes. This article is protected by copyright. All rights reserved. PMID- 30447070 TI - Change in the dominance structure of two marine-fish assemblages over three decades. AB - Marine fish are an irreplaceable resource, but are currently under threat through overfishing and climate change. To date, most of the emphasis has been on single stocks or populations of economic importance. However, commercially valuable species are embedded in assemblages of many species and there is only limited understanding of the extent to which the structure of whole communities has altered in recent years. Most assemblages are dominated by one or a few species, with these highly abundant species underpinning ecosystem services and harvesting decisions. This paper shows that there have been marked temporal changes in the dominance structure of Scottish marine-fish assemblages over the past three decades, where dominance is measured as the proportional numerical abundance of the most dominant species. We report contrasting patterns in both the identity of the dominant species and shifts in the relative abundance of the dominant in assemblages to the east and west of Scotland, UK. This result highlights the importance of multi-species analyses of harvested stocks and has implications not only for fisheries management but also for consumer choices. PMID- 30447071 TI - GcvB small RNA uses two distinct seed regions to regulate an extensive targetome. AB - GcvB small RNA is described as post-transcriptional regulator of 1-2% of all mRNAs in Escherichia coli and Salmonella Typhimurium. At least 24 GcvB:mRNA interactions have been validated in vivo, establishing the largest characterized sRNA targetome. By performing MS2-affinity purification coupled with RNA sequencing (MAPS) technology, we identified 7 additional mRNAs negatively regulated by GcvB in E. coli. Contrary to the vast majority of previously known targets, which pair to the well-conserved GcvB R1 region, we validated 4 mRNAs targeted by GcvB R3 region. This indicates that base-pairing through R3 seed sequence seems relatively common. We also noticed unusual GcvB pairing sites in the coding sequence of two target mRNAs. One of these target mRNAs has a pairing site displaying a unique ACA motif, suggesting that GcvB could hijack a translational enhancer element. The second target mRNA is likely regulated via an active RNase E-mediated mRNA degradation mechanism. Remarkably, we confirmed the importance of the sRNA sponge SroC in the fine-tuning control of GcvB activity in function of growth conditions such as growth phase and nutrient availability. This article is protected by copyright. All rights reserved. PMID- 30447072 TI - Spanish survey on follow-up programmes for children born very preterm. AB - AIM: To describe variations in practice between follow-up programmes for very preterm children born at less than 32 weeks' gestation or with very low birth weight of less than 1,500g. METHODS: A survey on follow-up practices was electronically distributed to level II and III units among hospitals of the Spanish National Health Service in 2016. The survey included 70 questions covering issues such as follow-up organisation and resources, routine assessments, relationships with other services and families, information management, and training. RESULTS: The response rate was 91.5% (141/154). Among respondents, 70.9% (100/141) reported that they do provide follow up and 42% do so up to 6 years of age. Routine neurological and ophthalmological follow up is not performed in 60% and 37% of hospitals, respectively, and a second hearing assessment is not given in 62%. Just 38% of units have psychologist. In 41% of hospitals, training in follow-up skills is not included in Paediatric Residency training program. CONCLUSION: Although Spain has a nationwide health system that provides universal health coverage, we found that follow-up care for children born very preterm/very low birth weight is not equitable. Nearly half of paediatric residents receive no training in follow up for this high-risk population. This article is protected by copyright. All rights reserved. PMID- 30447073 TI - Use of the shock index to predict maternal outcomes in women referred for postpartum hemorrhage. AB - OBJECTIVE: To evaluate the clinical significance of various vital signs in women referred for postpartum hemorrhage (PPH). METHODS: This retrospective study included patients with primary PPH who were referred to Korea University Medical Center, Ansan, between January 1, 2004, and December 31, 2016. We analyzed data for systolic and diastolic blood pressure, heart rate, and shock index (heart rate divided by systolic blood pressure) at time of arrival. Significant morbidity, such as massive transfusion, invasive procedures, and admission to the intensive care unit were reviewed. We used the area under the receiver operating characteristic curve (AUROC) for each vital sign to predict adverse maternal outcomes. Sensitivity, specificity, and negative and positive predictive values were assessed. RESULTS: 118 women with PPH were identified. The shock index had the highest AUROC to predict massive transfusion (0.815, 95% confidence interval [CI] 0.727-0.883). A shock index greater than 0.9 had 93.8% (95% CI 69.8-99.8) sensitivity and 51.2% (35.1-67.1) specificity for prediction of massive transfusion, and 93.6% (78.6-99.2) sensitivity and 31.0% (15.3-50.8) specificity for prediction of invasive procedures. CONCLUSION: The shock index has significant ability to predict adverse outcomes of PPH compared with other initial vital signs when patients are referred. This article is protected by copyright. All rights reserved. PMID- 30447074 TI - Cryosurgery combined with topical interventions for actinic keratosis: A systematic review and meta-analysis. AB - BACKGROUND: Actinic keratoses (AK) are early in situ carcinomas of the skin due to cumulative sun exposure. Cryosurgery is an easy and practicable lesion directed approach for isolated lesions. OBJECTIVES: To investigate if an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for AK. METHODS: We performed a systematic literature research in Medline, Embase, and CENTRAL and hand-searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random-effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach. RESULTS: Out of 1,758 records initially identified, 9 studies with a sample size of 1,644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates compared to monotherapy (RR 1.74, 95% CI 1.25-2.43, I2=73%, 8 studies. The participant partial clearance rate was not statistically different (RR 1.64, 95% CI 0.88-3.03, I2=77%, 3 studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0.98, 95% CI 0.95-1.01, I2=75%, 7 studies). The studies were estimated at high risk for selective reporting bias. CONCLUSIONS: Our results suggest superiority of a combination regimen regarding AK clearance with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AK or field-cancerization. This article is protected by copyright. All rights reserved. PMID- 30447075 TI - Bioelectrical impedance analysis of body composition and survival in patients with heart failure. AB - BACKGROUND: Studies have shown that higher body mass index (BMI) is associated with improved prognosis in heart failure (HF), and this is often termed the obesity paradox. HYPOTHESIS: Analysis of body composition may reveal that muscle mass rather than adipose tissue accounts for the obesity paradox. METHODS: Bioelectrical impedance analysis of body composition in 359 outpatients with HF was performed using an In Body 520 body composition scale (Biospace Inc., California). Body fat and lean mass were indexed by height (m2 ). The cohort was stratified by median fat and lean mass indexed by height. RESULTS: The mean age of patients studied was 56 +/- 14; mean left ventricular ejection fraction was 38 +/- 16%. Patients with higher indexed body fat mass had improved 5-year survival over patients with lower indexed body fat mass (90.2% vs 80.1%, P = 0.008). There was also improved survival in patients with high vs low indexed lean body mass (89.3% vs 80.9%, P = 0.036). On multivariable analysis, higher indexed body fat mass, but not lean body mass, was independently associated with improved survival (HR 0.89, per kg/m2 increase in indexed body fat mass, P = 0.044); however, this was attenuated after adjustment for diabetes. The combination of low lean with low-fat mass was independently associated with poor prognosis. CONCLUSIONS: Our data suggest that higher fat mass-and to a lesser extent higher lean mass-is associated with improved outcomes in HF. Further investigations of specific components of body composition and outcomes in HF are warranted. PMID- 30447076 TI - Frequency-specific noninvasive modulation of memory retrieval and its relationship with hippocampal network connectivity. AB - Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal-cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network-targeted transcranial magnetic stimulation. Healthy humans participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta-burst stimulation, intermittent theta burst stimulation, and beta-frequency (20-Hz) repetitive stimulation, and one sham condition. Resting-state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta-burst stimulation conditions would most strongly influence hippocampal-HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta-band activity for HCN memory function. Continuous theta-burst stimulation improved item retrieval success relative to sham and relative to beta-frequency stimulation, whereas intermittent theta-burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta-burst stimulation affected memory-related hippocampal-HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory-related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta-burst noninvasive stimulation. This article is protected by copyright. All rights reserved. PMID- 30447077 TI - Three-dimensional Doppler ultrasonography for the assessment of fetal liver vascularization in fetuses with intrauterine growth restriction. AB - OBJECTIVE: To demonstrate changes in hepatic volume and vascular indices in fetuses with intrauterine growth restriction (IUGR) compared with normal-growth fetuses, using a noninvasive method (three-dimensional power Doppler ultrasound). METHODS: The present cross-sectional study was conducted between September 1 and November 30, 2014, at a maternal-fetal medicine unit in Bogota, Colombia; it included consecutive women at 24-34 weeks of pregnancy. The fetal liver volume and indices of hepatic vascularization were determined with three-dimensional power Doppler ultrasonography and compared between fetuses with and without a diagnosis of IUGR. Results A total of 119 women met study inclusion criteria; 97 fetuses had no growth restriction, whereas 22 fetuses had IUGR. The latter group had decreased liver volume (57.85 +/- 29.71 mL vs 86.99 +/- 31.24 mL; P=0.010) and increased vascular indices (vascularization index, 47.92 +/- 34.44 versus 22.46 +/- 18.95; flow index, 71.39 +/- 42.01 versus 41.11 +/- 23.24; vascularization flow index, 47.94 +/- 47.96 versus 13.67 +/- 22.38; P=0.003 for all comparisons). CONCLUSION: Liver volume was decreased and liver vascular indices values were increased in fetuses with IUGR. These findings imply that evaluation of hepatic vascularization with three-dimensional hepatic Doppler could be useful in the diagnosis of IUGR. PMID- 30447078 TI - Efficacy of nivolumab monotherapy against acral lentiginous melanoma and mucosal melanoma in Asian patients. AB - Early clinical trials showed that treatment with anti-programmed death-1 (anti-PD 1) agents, such as nivolumab and pembrolizumab, led to marked improvements in the prognosis of advanced melanoma patients. However, most of the large-scale studies of such treatment mainly analyzed the efficacy of anti-PD-1 agents in Caucasian populations. Since the clinical subtypes of melanoma differ widely among populations, and the response to anti-PD-1 agents is known to vary among the clinical subtypes of the disease, the efficacy of anti-PD-1 agents in Asian populations remains unclear. This article is protected by copyright. All rights reserved. PMID- 30447079 TI - Molecular-based Design of Microporous Carbon Nanosheets. AB - Microporous carbons afford high surface areas, large pore volumes, and good conductivity, which are fascinating in a wide range of applications. Traditional synthesized microporous carbon materials usually suffer some limitations, such as poor accessibility and slow mass transport of molecules due to the micrometer scale diffusion pathway and space confinement imposed by small pore sizes. Two dimensional (2D) microporous carbon materials, denoted as microporous carbon nanosheets (MCNs), possess nanoscale thickness, allowing fast mass and heat transport on the z axis, thus overcoming the drawbacks of their bulk counterparts. In this minireview, recent breakthroughs are summarized in the synthesis strategies of MCNs. Three typical methods are discussed in detail with several examples: pyrolysis of organic precursors with 2D units, templating method using wet chemistry, and molten salt method. Among them, the molecular based assembling of MCNs in liquid phase shows more controllable morphology, thickness, and pore-size distribution. Finally, the challenges in this research area are discussed to inspire future explorations. PMID- 30447080 TI - Increased risk of melanoma in C9ORF72 repeat expansion carriers: A case-control study. AB - INTRODUCTION: Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are considered part of the same pathological spectrum. There is an increased risk of ALS in patients who have had melanoma. The risk of FTLD in melanoma (or cancer) patients is unknown. We aimed to study if C9ORF72 expansion is linked to a higher prevalence of melanoma. METHODS: We selected patients with a diagnosis in the ALS-FTLD spectrum who were tested for pathogenic mutations. Medical history was reviewed, to identify those with pathologically documented melanomas. RESULTS: We included 189 patients. 62 had identified pathogenic mutations (39 C9ORF72). C9ORF72 carriers had a significantly higher risk of melanoma (OR=24.709, p<0.007). There was no association with phenotype. DISCUSSION: These findings suggest that patients with a history of melanoma may have an increased probability of carrying a C9ORF72 repeat expansion. ALS or FTLD carriers of C9ORF72 should undergo surveillance for skin changes. This article is protected by copyright. All rights reserved. PMID- 30447081 TI - Orthogonal Array Design for Optimization of Phenyllactic acid-Sodium alginate Blend Coating and Its Effect on the Browning and Quality of Minimally Processed Lily Bulbs. AB - BACKGROUND: In order to develop active packaging of lily products, we for the first time investigated the effects of phenyllatic acid (PLA) incorporated into a sodium alginate (SA)-based coating on the quality of minimally processed lily bulbs stored at 4 degrees C for 15d. RESULTS: L9 (34 ) orthogonal array design was showed that the optimal concentrations of PLA, SA and glycerinum were 0.03 mol L-1 , 0.03mol L-1 and 0.05 mol L-1 to prepare blend coating. It was noticed that PLA/SA blend coating treatment could inhibit browning and maintain the firmness and ascorbic acid of minimally processed lily bulbs. Compared with the control, polyphenol oxidase (PPO), peroxidase (POD) and phenylalnine ammonialyase (PAL) activities of PLA/SA blend coating treated minimally processed lily bulbs reduced by about 31 %, 21 % and 29 % on the 15th day, respectively. Total phenolic and quinone contents decreased respectively by 16 % and 55 % at the same time. Moreover, PLA/SA blend coating treatment eliminated the accumulation of malonaldehyde (MDA) while inhibited microbial growth of minimally processed lily bulbs. CONCLUSIONS: These results showed PLA/SA blend coating could effectively maintain quality of minimally processed lily bulbs stored at 4 degrees C, and it might be a prospective technology. This article is protected by copyright. All rights reserved. PMID- 30447082 TI - Imaging functional motor connectivity in hemiparetic children with perinatal stroke. AB - Perinatal stroke causes lifelong disability, particularly hemiparetic cerebral palsy. Arterial ischemic strokes (AIS) are large, cortical, and subcortical injuries acquired near birth due to acute occlusion of the middle cerebral artery. Periventricular venous infarctions (PVI) are smaller, subcortical strokes acquired prior to 34 weeks gestation involving injury to the periventricular white matter. Both stroke types can damage motor pathways, thus, we investigated resulting alterations in functional motor networks and probed function. We measured blood oxygen level dependent (BOLD) fluctuations at rest in 38 participants [10 arterial patients (age = 14.7 +/- 4.1 years), 10 venous patients (age = 13.5 +/- 3.7 years), and 18 typically developing controls (TDCs) (age = 15.3 +/- 5.1 years)] and explored strength and laterality of functional connectivity in the motor network. Inclusion criteria included MRI-confirmed, unilateral perinatal stroke, symptomatic hemiparetic cerebral palsy, and 6-19 years old at time of imaging. Seed-based functional connectivity analyses measured temporal correlations in BOLD response over the whole brain using primary motor cortices as seeds. Laterality indices based on mean z-scores in lesioned and nonlesioned hemispheres explored laterality. In AIS patients, significant differences in both strength and laterality of motor network connections were observed compared with TDCs. In PVI patients, motor networks largely resembled those of healthy controls, albeit slightly weaker and asymmetric, despite subcortical damage and hemiparesis. Functional connectivity strengths were not related to motor outcome scores for either stroke group. This study serves as a foundation to better understand how resting-state fMRI can assess motor functional connectivity and potentially be applied to explore mechanisms of interventional therapies after perinatal stroke. PMID- 30447083 TI - Dosage Considerations for Canakinumab in Children with Periodic Fever Syndromes. AB - Periodic fever syndromes are a group of rare diseases with a highly variable onset, yet limited treatment options are available for children at an early age. Canakinumab has been approved to treat patients with cryopyrin-associated periodic syndrome (CAPS), a periodic fever syndrome, and systemic juvenile systemic arthritis (SJIA), with age cutoffs of 4 years and 2 years, respectively. In 2016, FDA approved canakinumab, without an age restriction, for the treatment of three conditions of periodic fever syndromes including familial Mediterranean fever (FMF), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), and tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS). This review discusses the PK, efficacy, safety, and exposure-response relationship of canakinumab, and provides the rationale for dosage recommendation in children younger than 2 years of age with the three conditions of periodic fever syndromes. The approval of canakinumab for these pediatric patients addresses a critical unmet medical need. This article is protected by copyright. All rights reserved. PMID- 30447084 TI - Unrolr: Structural analysis of protein conformations using stochastic proximity embedding. AB - Molecular dynamics (MD) simulations are widely used to explore the conformational space of biological macromolecules. Advances in hardware, as well as in methods, make the generation of large and complex MD datasets much more common. Although different clustering and dimensionality reduction methods have been applied to MD simulations, there remains a need for improved strategies that handle nonlinear data and/or can be applied to very large datasets. We present an original implementation of the pivot-based version of the stochastic proximity embedding method aimed at large MD datasets using the dihedral distance as a metric. The advantages of the algorithm in terms of data storage and computational efficiency are presented, as well as the implementation realized. Application and testing through the analysis of a 200 ns accelerated MD simulation of a 35-residue villin headpiece is discussed. Analysis of the simulation shows the promise of this method to organize large conformational ensembles. (c) 2018 Wiley Periodicals, Inc. PMID- 30447085 TI - Metabolic syndrome and periodontitis: A structural equation modeling approach. AB - BACKGROUND: This study aimed to investigate the association between metabolic syndrome (MetS) and periodontitis among young adults, and also to compare results using observed and latent variables for MetS and periodontitis. METHODS: Data from the 1982 Pelotas Birth Cohort, Brazil, were used. Metabolic syndrome at the age of 23 years was measured using clinical and biochemical analysis and set as the main exposure. Periodontitis at the age of 31 years was clinically measured and set as the outcome. Confounding variables included sex and maternal education, assessed at birth, family income at 23 years, and smoking status at the age of 23 and 30 years. Factor analyses (exploratory and confirmatory) were performed to define latent variables for MetS and periodontitis. In addition, both conditions were also defined as categorical observed variables. The association between MetS and periodontitis was tested in structural equation models. RESULTS: Two latent periodontal variables were identified: "initial" and "advanced" periodontitis, while one latent variable was identified for MetS. Metabolic syndrome is positively associated with "advanced" (coefficient 0.11; P value < 0.01), but not with "initial" (coefficient -0.01; P value = 0.79) periodontitis. When MetS and periodontitis were set as observed variables in the structural equation models, no association was found irrespective of the criteria used for periodontitis classification. CONCLUSIONS: There was a positive association between metabolic syndrome and "advanced" periodontitis, when the multiple dimensions of both diseases were accounted in latent variables. Nevertheless, when MetS and periodontitis were treated as observed variables, no association was detected irrespective of the criteria used for periodontitis classification. PMID- 30447086 TI - Rootstock effects on grape anthocyanins, skin and seed proanthocyanidins and wine color and phenolic compounds from Vitis vinifera L. Merlot grapevines. AB - BACKGROUND: Rootstocks affect vegetative and reproductive parameters of the scion. However, limited knowledge exists on the effects of the adoption of a specific rootstock on grape and wine phenolic composition, which contribute to certain sensory attributes such as color, body and astringency of wine. These compounds are mainly affected by the variety, viticultural management and rootstock. The aim of this work was to study the influence of eight rootstocks on grape anthocyanin content, skin and seed proanthocyanidins and wine chromatic characteristics obtained from Merlot vines. RESULTS: Grapevines grafted onto SO4 rootstock, in general, presented a higher concentration of total proanthocyanidins in skins and seeds compared to the rest of the rootstocks, whereas grapevines grafted onto Gravesac presented a lower concentration of proanthocyanidins in skins and seeds. These differences were found in the wines elaborated from grapevines grafted onto SO4. Wines from grapevines grafted onto SO4, 140 Ruggeri, Gravesac and 4453 M rootstocks presented, in general, better chromatic characteristics and a higher anthocyanin and tannin content than the rest of the samples. CONCLUSION: This work gives additional information concerning the influence of rootstock on grape and wine phenolic composition. This article is protected by copyright. All rights reserved. PMID- 30447087 TI - Course of disinhibited social engagement behavior in clinically referred home reared preschool children. AB - BACKGROUND: Evidence supporting clinical relevance and persistence of disinhibited social engagement behavior (DSEB) pertains mostly to children reared in institutions and foster care. This study examined the course of DSEB in clinically referred home-reared children from early into middle childhood, and associations with neglect/emotional maltreatment, effortful control, Attention Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, and Autism Spectrum Disorder. METHODS: Disinhibited social engagement behavior was examined in 124 children (82% boys, M = 4.06 years, SD = 0.89), referred for treatment of emotional and behavioral problems, by use of the Disturbances of Attachment Interview (DAI) with biological parents. Neglect and emotional maltreatment were assessed from case records and effortful control by use of the Child Behavior Questionnaire. At follow-up, on average 4 years later, DSEB was examined by use of DAI as well as two observational ratings: the Stranger at the Door procedure (SatD) and a structured home observation of stranger approach. Psychiatric disorders were assessed by means of the Kiddie-Schedule for Affective Disorders and Schizophrenia. RESULTS: Persistence of parent-reported DSEB was found in 57% (n = 27) of the children with DSEB at baseline (n = 47). Parent-reported DSEB at follow-up was significantly related to DSEB observed in the SatD (rpb = .31, p = .001) and to observed stranger approach (rs = .41, p < .001), but only stranger approach was associated with baseline DSEB. The course of DSEB was not related to neglect/emotional maltreatment, nor to the level of effortful control. There was no association between DSEB and Autism Spectrum Disorder, but course of DSEB was associated with Attention Deficit/Hyperactivity Disorder/Oppositional Defiant Disorder at follow-up (chi2 = 13.08, p = .004). CONCLUSIONS: Although explanations for the onset and course of DSEB in home-reared children remain elusive, findings suggest that DSEB is part of a complex of clinically significant problem behaviors in referred home-reared preschool children. PMID- 30447088 TI - Thyroid-stimulating hormone within the normal range and risk of major adverse cardiovascular events in non-ischemic dilated cardiomyopathy patients with severe left ventricular dysfunction. AB - BACKGROUND: The association between thyroid-stimulating-hormone(TSH) and prognosis of nonischemic dilated cardiomyopathy(NIDCM) in patients with normal thyroid function remains unclear. OBJECTIVE: The present study investigated whether TSH is associated with major adverse cardiovascular events in euthyroid NIDCM patients. METHODS: The original cohort consisted of 216 consecutive euthyroid NIDCM patients, with left ventricular ejection fraction(LVEF) <= 35%, who were observed from 2010 to 2013. Patients with persistent ventricular arrhythmia (VA) histories, amiodarone taken for VA prevention, or on heart transplant list within one year were excluded. A follow-up evaluation was performed, and VA events, heart failure(HF) exacerbation/heart transplant, cardiac death or death from any cause were separately evaluated. RESULTS: A total of 184 patients were enrolled, and 97.8% (180/184) ultimately received follow-up evaluations. During the median 4.6-year follow-up, 24 VA events, 28 cardiac deaths, 30 all-cause deaths, 40 HF exacerbations and 11 heart transplant events occurred. Serum TSH levels showed good predictive efficacies for VA events(AUC=0.702, 95% CI: 0.629-0.767), and the risk of VA events increased, according to serum TSH quarters, as determined by Kaplan-Meier analysis (2.2% vs 13.4% vs 21.0% vs 30.0%, Q1-Q4, P=0.011). Multivariable Cox analysis showed that patients at the Q4 level of serum TSH(>2.67 mIU/L) suffered an increased risk of VA events, compared with those at the Q1 level of TSH(HR=15.88, 95%CI:2.01-65.15) or those at the other three quarters(HR=3.17, 95%CI:1.38-7.26). However, the Q4 TSH level was not associated with other adverse cardiac events. CONCLUSION: An association between TSH levels and the risk of VA events may exist in euthyroid NIDCM patients. PMID- 30447089 TI - Lipoprotein(a) and Low-density lipoprotein apolipoprotein-B metabolism following apheresis in patients with elevated lipoprotein(a) and coronary artery disease. AB - BACKGROUND: Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. PATIENTS AND METHODS: A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500 mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. RESULTS: The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 (0.31, 0.49) vs 0.57 (0.46, 0.71) pools/day, P=0.03) with no significant differences in the corresponding PR (14.80 (11.34, 19.32) vs 15.73 (11.93, 20.75) mg/kg/day, P=0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. CONCLUSIONS: In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease. This article is protected by copyright. All rights reserved. PMID- 30447090 TI - Freshwater chronic ammonia toxicity: a tropical-to-temperate comparison. AB - The chronic toxicity of ammonia to tropical freshwater species is under represented, leading to the use of temperate species to derive water quality guideline values (GV) for tropical regions. Such practices may lead to under protective GVs due to differences in toxicities observed between tropical and temperate species. Additionally, there are limited studies assessing the toxicity of ammonia in low ionic strength waters, which may also result in higher toxicity. This study assessed the toxicity of ammonia to six tropical freshwater species in low ionic-strength waters. As ammonia toxicity varies depending on the pH and temperature, test water pH concentrations were maintained at approximately pH 6.0 +/- 0.3 at temperatures between 27.5 and 30 degrees C. Low effect, chronic inhibition concentrations (IC10) for these species were derived: Chlorella sp. 66 mg L-1 ; Lemna aequinoctialis 22 mg L-1 ; Hydra viridissima 1.8 mg L-1 ; Moinodaphnia macleayi 27 mg L-1 ; Amerianna cumingi 17 mg L-1 ; and Mogurnda mogurnda 5.4 mg L-1 total ammonia nitrogen. Two of the species tested (a cnidarian and a fish species) were among the most sensitive reported anywhere within their taxonomic group. Chronic ammonia datasets representing toxicity estimates for temperate and tropical species were plotted and compared using Species Sensitivity Distributions. The results indicate the differences in chronic toxicity observed between tropical and temperate species were likely due to the low ionic strength of the waters to which tropical species were exposed, rather than any inherent physiological differences between species from tropical and temperate regions. This suggests that tropical waters of low ionic strength may be at a higher risk from ammonia compared to other freshwater ecosystems. This article is protected by copyright. All rights reserved. PMID- 30447091 TI - Optimal needle placement for extensor hallucis longus muscle using ultrasound verification. AB - INTRODUCTION: The extensor hallucis longus (EHL) muscle is important for diagnosis of neurologic lesions. It is also a target muscle for treatment. We investigated EHL with ultrasonography to determine optimal needle placement for safety and accuracy. METHODS: A total of 96 legs of 48 healthy volunteers were examined through ultrasonography. Four published electromyographic (EMG) methods for finding the EHL were assessed. We identified the midpoint of EHL (MD) using landmarks to determine optimal needle placement. RESULTS: Mean values of bimalleolar line-MD on skin (MD-S) and tibial crest-MD-S were 10.5 +/- 1.2 cm and 3.6 +/- 0.4 cm, respectively. The depth of MD was 1.6 +/- 0.2 cm. According to four EMG methods, the probability of needle penetrating EHL was 13% to 79% and that of needle penetrating the neurovascular bundle was 50% to 89%. DISCUSSION: Using ultrasonography, we could determine optimal needle placement in the EHL. This article is protected by copyright. All rights reserved. PMID- 30447092 TI - Reply to the comment on: "Reporting matters: Brain mapping with transcranial magnetic stimulation". PMID- 30447093 TI - Cover Image, Volume 526, Issue 16. AB - The cover image is based on the Research Article Alignment of EphA4 and ephrin-B2 expression patterns with developing modularity in the lateral cortex of the inferior colliculus by Gideon Sean M. Gay et al., DOI: 10.1002/cne.24525. PMID- 30447094 TI - Guiding Uniform Li Plating/Stripping via Lithium Aluminum Alloying Medium for Long-Life Li Metal Batteries. AB - The uncontrolled growth of Li dendrites upon cycling might engender low Coulombic efficiency and severe safety hazards. Here, a lithiophilic binary alloy phase lithium aluminum layer, which generated via a in situ electrochemical process, was utilized to guide the uniform metallic Li nucleation and growth, free from the dendrites. Moreover, the formed LiAl alloy layer can function as a Li reservoir to compensate the irreversible Li loss, enabling a long-term stability. The protected Li electrode renders superior cycling over 1700 h in a Li|Li symmetric cell. PMID- 30447095 TI - Acceptable-by-design QSARs to predict the dietary biomagnification of organic chemicals in fish. AB - This work presents the first-time QSAR approach to predict the laboratory-based fish Biomagnification Factor (BMF) of organic chemicals, to be used as a supporting tool for assessing the bioaccumulation at the regulatory level. The developed strategy is based on two levels of prediction with a varying trade-off between interpretability and performance according to the user's needs. We designed our models to be intrinsically acceptable at the regulatory level (in what we defined as "acceptable-by-design" strategy), by (i) complying with OECD principles directly in the approach development phase, (ii) choosing easy-to apply modelling techniques, (iii) preferring simple descriptors, when possible, and (iv) striving to provide data-driven mechanistic insights. Our novel tool has an error comparable to the observed experimental inter- and intra-species variability and is stable on borderline compounds (root mean square error [RMSE] ranging from RMSE = 0.45 to RMSE = 0.45 log units on test data). Additionally, the models' molecular descriptors are carefully described and interpreted, allowing us to gather additional mechanistic insights into the structural features controlling the dietary bioaccumulation of chemicals in fish. To improve the transparency and promote the application of the model, the dataset and the freely-available and standalone prediction tool are provided free of any charge at https://github.com/grisoniFr/bmf_qsar. This article is protected by copyright. All rights reserved. PMID- 30447096 TI - Long-Lasting Insecticide-treated Nets: a new Integrated Pest Management approach for Popillia japonica (Coleoptera: Scarabaeidae). AB - The Japanese beetle Popillia japonica Newman is a US and EU quarantine insect pest that recently has invaded Northern Italy. Its ability to rapidly spread in new areas make this insect a threat to agriculture. In the last decades, several trials on biological control of the Japanese beetle by entomopathogenic nematodes and fungi have been carried out with variable efficacy. However, the necessity of an integrated pest management to improve the control has arisen. Long-Lasting Insecticide-treated Nets (LLINs) have been used to control other agricultural pests using an attract-and-kill strategy. Here we present results from laboratory evaluation of two LLINs, Storanet(r) (BASFTM) and ZeroFly(r) (VestergaardTM), against P. japonica adults. Both of them were effective in killing the beetles; however, some differences emerged if compared with different exposure times: ZeroFly(r) always gave 100% mortality in tests from 5 s to 30 min exposure; Storanet(r) showed 100% mortality only with 30 min exposure, down to 89-99% mortality for 5 s to 15 min exposure. A description of the paralysis process occurring at 5 s exposure is given. Possible field application of LLINs within programs of integrated pest management is discussed. This article is protected by copyright. All rights reserved. PMID- 30447097 TI - Identification of genes involved in the regulation of Telomerase Reverse Transcriptase in hepatocellular carcinoma. AB - Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We conducted a genome-wide short-hairpin RNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55- and C7orf43-responsive sites exist between base pairs -58 and +36 and -169 and -59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression via YAP1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non-tumor tissues, compared to normal liver tissues from non-HCC patients. Analysis of 377 HCC patients in the Cancer Genome Atlas (TCGA) dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment. This article is protected by copyright. All rights reserved. PMID- 30447098 TI - How in silico and QSAR approaches can increase confidence in environmental hazard and risk assessment. AB - In silico methods are typically underrated in the current risk assessment paradigm, as evidenced by the recent document from European CHemicals Agency (ECHA) on animal alternatives, where QSARs were practically used only as a last resort. Their primary use is still to provide supporting evidence for read-across strategies or to add credence to experimental results of unknown or limited validity (non-GLP or old studies, limited information reported etc.) in hazard assessment, but under the pressure of increasing burdens of testing, industry and regulators alike are at last warming to them. Nevertheless, their true potential for data-gap filling, and to resolve sticking points in risk assessment methodology and beyond has yet to be recognised. We postulate that it is possible to go beyond the level of simply increasing confidence to the point of using in silico approaches to accurately predict results that cannot be resolved analytically. For example, under certain conditions it is possible to obtain meaningful results by in silico extrapolation for tests that would be technically impossible to conduct in the laboratory or at least extremely challenging to obtain reliable results. These and other concepts are explored in this article: 1) the Mechanism of Action (MechoA) of the substance should be determined, as an aid verifying that the QSAR model is applicable to the substance under review. 2) accurate QSARs should be built using high quality data that were not only curated, but also validated using expert judgement. 3) while a rule of thumb for Acute to Chronic ratios appears applicable for non-polar narcotics, it seems unlikely that a 'one-value-fits-all' answer exists for other MechoAs. 4) a holistic approach to QSARs can be employed (via reverse engineering) to help validate or invalidate an experimental endpoint value based on multiple experimental studies. This article is protected by copyright. All rights reserved. PMID- 30447099 TI - The impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX. AB - Studies have demonstrated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We conducted this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients administered with FOLFIRINOX in the JASPAC06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (Oxaliplatin85mg/m2 , Irinotecan180mg/m2 , Leucovorin200mg/m2 , bolus5 FU400mg/m2 , and continuous5-FU2,400mg/m2 ) or a modified FOLFIRINOX (Oxaliplatin85mg/m2 , Irinotecan150mg/m2 , Leucovorin200mg/m2 , and continuous5 FU2,400mg/m2 ) as first-line chemotherapy were included. Of 199patients eligible for this analysis, 79patients were administered the original FOLFIRINOX regimen and 120patients were administered the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 wild type, and 25 were UGT1A1 heterozygous type (-/*6, 12patients; -/*28, 13patients). In the modified FOLFIRINOX group, 64 were UGT1A1 wild type, and 56 were UGT1A1 heterozygous type (-/*6, 33patients; -/*28, 23patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 wild type, and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 -/*6 than among those with UGT1A1 -/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 -/*6 tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. On the other hand, for patients administered the modified FOLFIRINOX, there was no difference in frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with wild type UGT1A1. This article is protected by copyright. All rights reserved. PMID- 30447100 TI - Light-triggered Covalent Assembly of Gold Nanoparticles for Cancer Cell Photothermal Therapy. AB - Manipulating the assembly of gold nanoparticles (AuNPs) for maximizing the photothermal effect is a promising strategy for cancer therapy. Herein, taking advantage of the well-known tetrazole/alkene photo-click chemistry, we for the first time demonstrated that small AuNPs (23 nm) decorated with both 2, 5 diphenyltetrazole and methacrylic acid on the surface could form covalently cross linked aggregates upon laser irradiation (lambda = 405 nm). The in vitro studies indicated that the light-triggered assembling remarkably shifted the surface plasmon resonance of AuNPs to near-infrared (NIR) regions, which in consequence effectively enhanced the efficacy of photothermal therapy for 4T1 breast cancer cells. We thus believe that this new light-triggered assembly approach may offer a valuable tool for cancer treatment. PMID- 30447102 TI - Corrigendum to "Tunable Poly((methacrylic acid)-co-acrylamide) Nanoparticles through Inverse Emulsion Polymerization." PMID- 30447101 TI - Endoscopic Bariatric and Metabolic Therapies: Another Tool for the Management of Diabetes and Obesity. AB - Endoscopic bariatric and metabolic therapies (EBMTs) have sparked significant interest as minimally invasive therapeutic options for weight loss. Although bariatric surgery remains an effective option for sustained weight loss and improvement in the metabolic syndrome, access and utilization are limited. Various EBMTs have been designed to emulate the physiologic effects of established surgical interventions, including space-occupying and non-space occupying gastric therapies, gastric remodeling procedures, and small bowel therapies. This review will discuss the safety and efficacy of available FDA approved minimally invasive endoscopic bariatric interventions, as well as those currently under investigation. In addition, the role of endoscopic revision after failed surgical intervention will also be discussed. PMID- 30447103 TI - Enhanced selective cellular proliferation by multi-biofunctionalization of medical implant surfaces with heterodimeric BMP-2/6, fibronectin, and FGF-2. AB - Increasing cell adhesion on implant surfaces is an issue of high biomedical importance. Early colonization with endogenous cells reduces the risk of bacterial contamination and enhances the integration of an implant into the diverse cellular tissues surrounding it. In vivo integration of implants is controlled by a complex spatial and temporal interplay of cytokines and adhesive molecules. The concept of a multi-biofunctionalized TiO2 surface for stimulating bone and soft tissue growth is presented here. All supramolecular architectures were built with a biotin-streptavidin coupling system. Biofunctionalization of TiO2 with immobilized FGF-2 and heparin could be shown to selectively increase the proliferation of fibroblasts while immobilized BMP-2 only stimulated the growth of osteoblasts. Furthermore, TiO2 surfaces biofunctionalized with either the BMP-2 or BMP-2/6 growth factor and the cell adhesion-enhancing protein fibronectin showed higher osteoblast adhesion than a TiO2 surface functionalized with only one of these proteins. In conclusion, the presented immobilization strategy is applicable in vivo for a selective surface coating of implants in both hard and connective tissue. The combined immobilization of different extracellular proteins on implants has the potential to further influence cell specific reactions. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2910-2922, 2018. PMID- 30447105 TI - Occupational Groups and Environmental Justice: A Case Study in the Bronx, New York. AB - We used spatial analyses to examine exposure of people in vulnerable occupational groups to neighborhood-level environmental pollutants in the Bronx borough of New York City. Five-year estimates of environmental ambient exposures (derived from land use regression models for PM2.5 [particulate matter with an aerodynamic diameter <=2.5 um] and black carbon) and demographic and occupational variables were harmonized at the census tract level. Correlations revealed that areas with high environmental exposures also had high proportions of people in service industries and manufacturing and high proportions of socioeconomically vulnerable populations. This combination of vulnerabilities may be cumulative, suggesting residents could have high occupational and residential exposures in addition to sociodemographic-related inequity. PMID- 30447104 TI - Mobile Mammography Participation Among Medically Underserved Women: A Systematic Review. AB - INTRODUCTION: Although breast cancer deaths have declined, the mortality rate among women from medically underserved communities is disproportionally high. Screening mammography is the most effective tool for detecting breast cancer in its early stages, yet many women from medically underserved communities do not have adequate access to screening mammograms. Mobile mammography may be able to bridge this gap by providing screening mammograms at no cost or low cost and delivering services to women in their own neighborhoods, thus eliminating cost and transportation barriers. The objective of this systematic review was to describe the scope and impact of mobile mammography programs in promoting mammographic screening participation among medically underserved women. METHODS: We searched electronic databases for English-language articles published in the United States from January 2010 through March 2018 by using the terms "mobile health unit," "mammogram," "mammography," and "breast cancer screening." Of the 93 articles initially identified, we screened 55; 16 were eligible to be assessed and 10 qualified for full text review and data extraction. Each study was coded for study purpose, research design, data collection, population targeted, location, sample size, outcomes, predictors, analytical methods, and findings. RESULTS: Of the 10 studies that qualified for review, 4 compared mobile mammography users with users of fixed units, and the other 6 characterized mobile mammography users only. All the mobile mammography units included reached underserved women. Most of the women screened in mobile units were African American or Latina, low income, and/or uninsured. Mobile mammography users reported low adherence to 1-year (12%-34%) and 2-year (40%-48%) screening guidelines. Some difficulties faced by mobile clinics were patient retention, patient follow-up of abnormal or inconclusive findings, and women inaccurately perceiving their breast cancer risk. CONCLUSION: Mobile mammography clinics may be effective at reaching medically underserved women. Adding patient navigation to mobile mammography programs may promote attendance at mobile sites and increase follow-up adherence. Efforts to promote mammographic screening should target women from racial/ethnic minority groups, women from low-income households, and uninsured women. Future research is needed to understand how to best improve visits to mobile mammography clinics. PMID- 30447106 TI - Dietary Impact of Produce Prescriptions for Patients With Hypertension. AB - INTRODUCTION: Little is known regarding the impact of produce prescriptions within the context of hypertension visits at safety net clinics. We evaluated intervention effectiveness on patient usage of farmers markets and dietary change related to fruit and vegetable consumption. METHODS: Health Improvement Partnership - Cuyahoga worked with 3 clinics to integrate, implement, and evaluated a produce prescription for hypertension (PRxHTN) program. PRxHTN involves 3 monthly, nonphysician provider visits, comprising blood pressure measurement, nutrition counseling, and four $10 farmers market produce vouchers, for hypertensive adult patients screening positive for food insecurity. Dietary measures were collected at visits 1 and 3. Voucher use was tracked via farmers market redemption logs. RESULTS: Of the 224 participants from 3 clinics, most were middle-aged (mean age, 62 y), female (72%), and African American (97%) and had a high school education or less (62%). Eighty-six percent visited a farmers market to use their produce vouchers, with one-third reporting it was their first farmers market visit ever. Median number of farmers market visits was 2 (range: 0 6), and median number of vouchers redeemed was 8 (range: 0-12). Among the subsample with follow-up survey data (n = 137), significant improvement in fruit and vegetable consumption was observed as well as a decline in fast food consumption. CONCLUSION: PRxHTN participants visited at least 1 farmers market, reported increases in provider communication related to diet, and exhibited significant changes in dietary behavior. PRxHTN can serve as a strong model for linking safety net clinics with farmers markets to promote community resource use and improve fruit and vegetable consumption among food-insecure patients with hypertension. PMID- 30447107 TI - Circulating exosomes regulate T-cell-mediated inflammatory response in oral lichen planus. AB - BACKGROUND: Exosomes are newly recognized natural nanocarrier and intercellular messenger that emerge as important mediators of signal transmission. Exosomes have been reported to modulate the inflammatory response of a number of diseases. This study investigated the effects of circulating exosomes from oral lichen planus (OLP) on T cells. METHODS: Plasma-derived exosomes were purified from both OLP patients and control groups. T cells were observed under a confocal laser scanning microscope after co-cultivation with PKH67 labeled exosomes for 12, 24, and 48 hours. The effects of exosomes exposure on T cells were analyzed with several functional assays, investigating proliferation, apoptosis, and migration. Production of interleukin (IL)-2, -4, -10, and interferon (IFN)-gamma was measured via enzyme-linked immunosorbent assay. RESULTS: PKH67-labeled exosomes were taken up by T cells in a time- and dose-dependent manner. Several biological functions of T cells were promoted. In particular, the circulating erosive OLP exosomes significantly enhanced T-cell proliferation and attenuated the apoptosis. The migration capacity of T cells increased remarkably in response to erosive OLP exosome treatment. In addition, the ratio of IFN-gamma/IL-4 was significantly elevated in OLP patients. CONCLUSIONS: Our findings indicate that the circulating OLP exosomes are involved in the biological functions of T cells, potentially promoting the OLP progression by regulating the T-cell-mediated inflammatory response. PMID- 30447108 TI - Sex-related differences in response to zinc pyrithione shampoo versus non-anti dandruff shampoo. AB - OBJECTIVE: Sex-related differences in skin properties may be expected to impact on dandruff formation and treatment. A meta-analysis approach was undertaken to investigate potential differences between males and females in response to zinc pyrithione (ZnPT) treatment versus non-anti-dandruff (AD) shampoo. A separate pooled statistical analysis of ceramide and total protein loss endpoints was also undertaken to assess potential sex-related differences in stratum corneum properties that might influence response to ZnPT versus non-AD shampoo in subjects with dandruff. METHODS: The meta-analysis approach included data from 17 half-head, double-blind, randomized studies (N=2088) undertaken in Asia to assess the effectiveness of 1% ZnPT shampoo and/or non-AD shampoo in reducing dandruff severity, as assessed by Total Weighted Head Score Adherent Flake (TWHS-AF) methodology. Treatment duration was 4 weeks, with TWHS-AF measured at weekly intervals. Data from an additional three studies (N=143) conducted in Asia were included in the pooled analysis of ceramide levels and protein loss from scalp skin of subjects with dandruff. RESULTS: Response to 1% ZnPT versus non-AD shampoo was greater in males than in females at all time points; after 4 weeks, the between-treatment difference in TWHS-AF was -17.5 (95% confidence interval [CI] -19.5, -15.5) in males and -11.1 (-13.2, -8.9) in females. Sex-related differences were observed between males and females in response to both 1% ZnPT and non-AD shampoos. Males had a stronger response than females to treatment with 1% ZnPT shampoo, while dandruff decreased to a greater extent in females than in males when using non-AD shampoo. Statistically significant sex-related differences in ceramide levels and total protein loss were observed (both P<0.01). Ceramide levels were 0.76 times lower (95% CI 0.60, 0.97) in males than in females, while total protein loss was 1.4 times greater (95% CI 1.1, 1.9) in males than in females. CONCLUSION: Males show a greater response than females to 1% ZnPT shampoo, while females show a greater response than males to non-AD shampoo. These findings may in part be explained by the sex-related differences observed in stratum corneum properties, which may make males more prone to dandruff than females. This article is protected by copyright. All rights reserved. PMID- 30447109 TI - Effects of rheological properties of rice dough during manufacture of rice cracker on the quality of the end product. AB - Influence of the viscoelastic properties of rice dough on the mechanical properties and the microstructure of rice crackers had been experimentally investigated to predict and control the quality of the rice cracker in the early stage of the lengthy manufacturing process. Various rice doughs steamed for 5, 30, or 60 minutes and kneaded for 5, 10, or 15 minutes were examined. Longer steaming and kneading resulted in lower G' and G" and higher tan delta, specific volume of the rice crackers, decreased non-uniform and deficient network, and thinner cell wall in rice cracker sections. There was a high correlation between tan delta of rice dough and specific volume of the rice cracker samples (R2 >0.79). The hardness of the rice crackers increased with extending the kneading time for 5 minutes and 30 minutes as the tan delta increased, while those of the rice crackers made from the rice doughs steamed for 60 minutes decreased inversely. These results indicated that qualities of rice crackers can be predicted and quantified by measuring viscoelasticity of actual rice doughs during the process. This article is protected by copyright. All rights reserved. PMID- 30447110 TI - Short Total Syntheses of C3a-C7' Linked Diketopiperazine Alkaloids (+)-Asperazine and (+)-Pestalazine A Enabled by a Ni-Catalyzed Reductive Coupling of Tertiary Alkyl Chloride. AB - Short gram-scale asymmetric syntheses of asperazine, pestalazine A, and their unnatural congeners thereof, have been achieved in ~10 steps by using readily accessible starting materials. The nickel-catalyzed reductive coupling protocol was utilized as a key step for the direct construction of C3asp3-C7'sp2 bond furnishing the diaryl-substituted quaternary carbon centers with remarkable steric hindrance. The streamlined access to this core structure of heterodimeric tryptophans under the mild reaction conditions, make this strategy hold a great promise in the concise synthesis of other relevant oligomeric pyrroloindoline alkaloids with unique C3a-C7' linkages. PMID- 30447111 TI - Versatility of cervicofacial flaps: Cervical-medial cheek flap for reconstruction in cutaneous substance loss of the inner cheek. AB - BACKGROUND: Preservation of facial harmony is a major challenge in reconstruction after resection of head and neck skin tumors. For large medial cheek-skin defects, we used a derived posterior-based cervicofacial flap, or cervical-medial cheek flap (CMCF). METHODS: We present a retrospective review of cases treated at a university-based cancer center. Patient characteristics, surgical technique, and complication rates are described. RESULTS: Eighteen patients were treated between 2014 and 2017 with reconstruction for integumentary cheek defect after skin tumor surgery using CMCF. Mean defect size was 5.7 cm in length and 3.9 cm in width. The main histological subtype was lentigo maligna (33.3%). We report no flap necrosis but 4 minor complications occurred over a mean follow-up of 14.4 months. At last follow-up, satisfaction rate was very high (88.9%) with no evidence of recurrence. CONCLUSION: The CMCF is a promising yet infrequently used option in medial cheek reconstruction, with excellent cosmetic and functional outcomes. PMID- 30447112 TI - Reporter-based forward genetic screen to identify bundle sheath anatomy mutants in A. thaliana. AB - The evolution of C4 photosynthesis proceeded stepwise with each small step increasing the fitness of the plant. An important precondition for the introduction of a functional C4 cycle is the photosynthetic activation of the C3 bundle sheath by increasing its volume and organelle number. Therefore, to engineer C4 photosynthesis into existing C3 crops, information about genes controlling bundle sheath cell size and organelle content is needed. However, very little is known about the genes that could be manipulated in order to create a more C4 -like bundle sheath. To this end, we established an EMS-based forward genetic screen in the Brassicaceae C3 species Arabidopsis thaliana. To ensure a high-throughput primary screen, the bundle sheath cells of A. thaliana were labeled by a luciferase (LUC68) or by a chloroplast-targeted green fluorescent reporter protein (sGFP) using bundle sheath specific promoter. The signal strength of the reporter genes was used as a proxy to search for mutants with altered bundle sheath anatomy. Here we show that our genetic screen identified predominantly mutants that were primarily affected in the architecture of the vascular bundle, which secondarily led to an increase in bundle sheath volume. By using mapping-by-sequencing approach we could identify the genomic segments containing mutated candidate genes. This article is protected by copyright. All rights reserved. PMID- 30447113 TI - LncRNA LINC00974 activates TGF-beta/Smad signaling to promote oral fibrogenesis. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a progressive scarring disease and has been considered as a premalignant condition of the oral cavity. However, the detailed molecular mechanisms underlying the pathogenesis of OSF are still unclear. METHOD: Here, we examined the expression of a novel long non-coding RNA LINC00974 in OSF and investigated its function role in myofibroblast transdifferentiation. Phenotypic analyses, including collagen gel contraction, migration, invasion and wound healing assays, were used to assess the myofibroblast activities following overexpression or inhibition of LINC00974. RESULTS: We found that the expression of LINC00974 in OSF tissues or myofibroblasts was aberrantly upregulated, and there was a positive correlation between LINC00974 and myofibroblast markers. Our results showed that inhibition of LINC00974 suppressed the myofibroblast activities, while overexpression of LINC00974 increased the activation. We demonstrated that the expression levels of alpha-SMA, alpha-1 type I collagen, fibronectin were downregulated in the LINC00974-inhibited myofibroblasts. Additionally, the TGF-beta secretion and phosphorylated Smad2 expression were also repressed in the LINC00974-inhibited myofibroblasts. We further demonstrated that silence of LINC00974 prevented the arecoline-induced myofibroblast activation, and LINC00974-increased myofibroblast activities were via TGF-beta pathway. CONCLUSION: Altogether, these findings suggested that arecoline-increased myofibroblast transdifferentiation was via LINC00974-mediated activation of TGF-beta signaling. This article is protected by copyright. All rights reserved. PMID- 30447114 TI - Prognostic value of serum liver enzymes in oral and oropharynx squamous cell carcinomas. AB - BACKGROUND: Serum liver enzymes, which catalyze relevant catabolic pathways, have been indicated to be diagnostic and prognostic tools for several malignant tumors. The correlation between serum liver enzymes levels and survival in patients with oral and oropharynx squamous cell carcinomas (OSCC) is still absent. Here, we conducted a study focusing on predictive value of serum liver enzymes in terms of prognosis in the patients. METHODS: A retrospective study including 134 OSCC patients from years 2009 to 2014 was performed to investigate the association between levels of pre-treatment serum liver enzymes, various clinical parameters and prognostic outcomes, which are overall survival (OS) and disease-free survival (DFS). Log-rank tests with Kaplan-Meier method were used to detect potential prognostic biomarkers. Multivariate analyses by Cox proportional hazards model were used to identify significant predictors of prognosis. RESULTS: Serum adenosine deaminase (ADA) level was associated with patients' OS and DFS by univariate analyses (P = 0.006 and P = 0.024, respectively). Multivariate analyses showed that higher serum ADA (>17.2 U/L) (P = 0.019) as well as positive lymph node status (P = 0.035) independently predicted worse OS of patients with OSCC. In addition, older age (>=60 years) (P = 0.043) and positive lymph node status (P = 0.027) were independently prognostic parameters for poorer DFS. CONCLUSIONS: Pre-operative serum ADA levels may serve as a reliable independent prognostic predictor for OS in OSCC patients. PMID- 30447116 TI - 1st European Mass Spectrometry Conference (EMSC). PMID- 30447115 TI - The potentiality of NMR based metabolomics in food science and food authentication assessment. AB - In the last years there was an increasing interest on NMR spectroscopy, whose applications experienced an exponential growth in several research fields, particularly in food science. NMR was initially developed as the elective technique for structure elucidation of single molecules and nowadays is playing a dominant role in complex mixtures investigations. In the era of the "omics" techniques, NMR was rapidly enrolled as one of the most powerful methods to approach metabolomics studies. Its use in analytical routines, characterized by rapid and reproducible measurements, would provide the identification of a wide range of chemical compounds simultaneously, disclosing sophisticated frauds or addressing the geographical origin, as well as revealing potential markers for other authentication purposes. The great economic value of high quality or guaranteed foods demands highly detailed characterization to protect both consumers and producers from frauds. The present scenario suggests metabolomics as the privileged approach of modern analytical studies for the next decades. The large potentiality of high resolution NMR techniques is here presented through specific applications and using different approaches focused on the authentication process of some foods, like tomato paste, saffron, honey, roasted coffee, and Balsamic and Traditional Balsamic vinegar of Modena, with a particular focus on geographical origin characterization, ageing determination and fraud detection. PMID- 30447117 TI - The fate of genes that cross species boundaries after a major hybridization event in a natural mosquito population. AB - Animal species are able to acquire new genetic material via hybridization and subsequent introgression. However, little is known about how foreign genomic material is incorporated into a population over time and what genes are susceptible to introgression. Here, we follow the closely related mosquito sister species Anopheles coluzzii and Anopheles gambiae in a sympatric natural population in Mali at multiple time points spanning a period of 25 years. During this period, we observed the temporary breakdown of mating barriers, which allowed us to explore the fate of alleles that crossed the species boundary in a natural population. Whole genome sequencing of 74 individuals revealed introgression within only 34 genes (0.26% of total genes) from A. gambiae to A. coluzzii, the majority contained within a 4 Mb region on the 2L chromosome which includes the insecticide resistance gene (AGAP004707). We designed a genotyping assay to follow 25 of the 34 introgressed alleles over time and found that all A. gambiae alleles, except four, reached a frequency of 50% in the A. coluzzii population within 4 years (~50 generations) and increased to ~80% within 6 years (~75 generations). However, the frequency of all introgressed alleles, except three, decreased to ~60% in 2016. This suggests an ongoing process of purifying selection in the population against DNA of foreign ancestry, except for alleles that are under positive selection, resulting in a complex genomic landscape. This study shows that stable introgression is limited to only specific genes even within closely related species. This article is protected by copyright. All rights reserved. PMID- 30447118 TI - Life Course Trajectories of Negative and Positive Marital Experiences and Loneliness in Later Years: Exploring Differential Associations. AB - Loneliness is relatively common among older adults in the United States, and there can be significant physical, psychological, and cognitive impairments associated with feelings of loneliness. Consequently, this study seeks to uncover determinants of loneliness, particularly the impact of couples' negative and positive marital experiences (i.e., marital strain and strength) over the life course on loneliness in later adulthood. To accomplish this goal, an integrated analytical framework is utilized, incorporating growth curves within an actor partner interdependence model, to capture the initial level and the rate of change in marital strain and strength over a period of 25 years (from 1991 to 2015) with a sample of 257 couples in enduring, long-term marriages. Couples first participated in the Iowa Youth and Family Project in 1989 and most recently participated in the Later Adulthood Study in 2015. The confirmatory factor analyses showed that latent constructs of marital strain and marital strength are distinct constructs. The univariate growth curve analyses showed that there were significant interindividual variations in the initial level (1991) and rate of change (1991-2015) in marital strain and marital strength for both husbands and wives. While the initial level and rate of change in perceived marital strain from 1991 to 2015 was generally of consequence for both spouses' loneliness in 2015 (actor and partner effects), only actor effects were noted for marital strength. Findings are discussed as they relate to health policies and interventions focusing on the well-being of married couples in later life. PMID- 30447119 TI - Profiles of women in science: Carmen Sandi, President of the Federation of European Neuroscience Societies. PMID- 30447120 TI - Self-Criticism, Interpersonal Conditions, and Bio-systemic Inflammation in Suicidal Thoughts and Behaviors within Mood Disorders: A Bio-Cognitive Interpersonal Hypothesis. AB - We review the theoretical and empirical literature on the role of the self concept in suicidal behavior in the context of mood disorders (i.e., unipolar depression and bipolar spectrum disorders). The main themes emanating from this review are then juxtaposed against (1) the Interpersonal-Psychological Theory of Suicide (IPTS; Joiner, 2005), and (2) biological research on the role of inflammatory processes in suicidality. Such a juxtaposition paves the way for a bio-cognitive-interpersonal hypothesis: Pathologies of the self-concept-primarily self-criticism-propel mood disorder sufferers to generate interpersonal stress that culminates in two proximal causes of suicidality: thwarted belongingness and perceived burdensomeness. In turn, these two interpersonal conditions set in motion systemic biosystemic inflammation, serving as a proximal cause for suicidality in mood disorders. We conclude by describing a research project aimed at testing this hypothesis, and by outlining pertinent implications for assessment, treatment, and prevention. This article is protected by copyright. All rights reserved. PMID- 30447121 TI - A coupled role for CsMYB75 and CsGSTF1 in anthocyanin hyper-accumulation in purple tea. AB - Cultivars of purple tea (Camellia sinensis) that accumulate anthocyanins in place of catechins, are currently attracting global interest in their use as functional health beverages. RNA-seq of normal (LJ43) and purple Zijuan (ZJ) cultivars identified the transcription factor CsMYB75 and phi (F) class glutathione transferase CsGSTF1 as being associated with anthocyanin hyper-accumulation. Both genes mapped as a QTL to the purple bud leaf color (BLC) trait in F1 populations, with CsMYB75 promoting the expression of CsGSTF1 in transgenic tobacco. While CsMYB75 elevates the biosynthesis of both catechins and anthocyanins, only the latter accumulate in purple tea, indicating selective downstream regulation. As GSTs in other plants are known to act as transporters (ligandins) of flavonoids, directing them for vacuolar deposition, the role of CsGSTF1 in selective anthocyanin accumulation was investigated. In tea, anthocyanins accumulate in multiple vesicles, with the expression of CsGSTF1 correlated to BLC, but not catechin content in diverse germplasm. Complementation of the Arabidopsis tt19-8 mutant, that is unable to express the orthologous ligandin AtGSTF12, restored anthocyanin accumulation, but did not rescue the transparent testa phenotype, confirming CsGSTF1 did not function in catechin accumulation. Consistent with a ligandin function, transient expression of CsGSTF1 in Nicotiana occurred in the nucleus, cytoplasm and membrane. Further, RNA-Seq of the complemented mutants exposed to 2% sucrose as a stress treatment, showed unexpected roles for anthocyanin accumulation in affecting the expression of genes involved in redox responses, phosphate homeostasis and the biogenesis of photosynthetic components, as compared with non-complemented plants. This article is protected by copyright. All rights reserved. PMID- 30447122 TI - Applying core theory and spatial analysis to identify Hepatitis C Virus infection 'core areas' in British Columbia, Canada. AB - 'Core areas' of transmission for bacterial sexually transmitted infections (STIs) have been identified. However, it is unclear whether core areas apply to viral infections, such as hepatitis C virus (HCV). We used geographic mapping and spatial analysis to identify distinct core areas of HCV infection in British Columbia (BC) using the BC Hepatitis Testers Cohort (BC-HTC), 1990-2013. The BC HTC includes all BC residents tested for HCV (~1.5 million; 1990-2013). Core HCV infection areas were identified spatially and temporally for five time periods (1990-93, 1994-98, 1999-2003, 2004-08 and 2009-13) through thematic mapping, Kernel Density Estimation, Hotspot analysis and cluster analysis at the Census dissemination area level in ArcGIS and SatScan. HCV infection core areas were consistently identified. HCV core areas expanded from the downtown of major cities in different regions of BC (Metro Vancouver, Vancouver Island, and Northern BC; 1990-1998), to smaller cities in Metro Vancouver and Interior BC (2000 onward). Statistically significant clusters, or hotspots, were also observed for downtown Vancouver, Northern BC (Prince George) and Vancouver Island from 1990- 2008 with expansion to other urban areas in Metro Vancouver from 1990 2013. Statistically significant clusters persisted after adjustment for injection drug use, number of HCV tests, age, sex, material and social deprivation. Persistence of areas with high HCV diagnoses rates in Vancouver and Prince George supports the theory of core areas of HCV transmission. Identification of core areas can inform prevention, care and treatment program interventions and evaluate their impact over time. This article is protected by copyright. All rights reserved. PMID- 30447123 TI - Testing a Clinical Staging Model for Bipolar Disorder using Longitudinal Life Chart Data. AB - OBJECTIVE: Bipolar disorder has a wide range of clinical manifestations which may progress over time. The aim of this study was to test the applicability of a clinical staging model for bipolar disorder and to gain insight into the nature of the variables influencing progression through consecutive stages. METHODS: Using retrospectively reported longitudinal life chart data of 99 subjects from the Stanley Foundation Bipolar Network Naturalistic Follow-up Study, the occurrence, duration and timely sequence of stages 2 - 4 were determined per month. A multi-state model was used to calculate progression rates and identify determinants of illness progression. Stages 0, 1 and several other variables were added to the multi-state model to determine their influence on the progression rates. RESULTS: Five years after onset of BD (stage 2), 72% reached stage 3 (recurrent episodes) and 21% had reached stage 4 (continuous episodes), of whom 8% recovered back to stage 3. The progression from stage 2 to 3 was increased by a biphasic onset for both the depression-mania and the mania-depression course and by male sex. CONCLUSIONS: Staging is a useful model to determine illness progression in longitudinal life chart data. Variables influencing transition rates were successfully identified. This article is protected by copyright. All rights reserved. PMID- 30447124 TI - Laparoscopic repair of bevacizumab-induced vesicovaginal fistula in metastatic colon cancer - a video vignette. PMID- 30447125 TI - Severe outcomes of pediatric perioperative adverse events occurring in operating rooms compared to off-site anesthetizing locations in the Wake-Up Safe Database. AB - BACKGROUND: Anesthesia services are frequently provided outside of the traditional operating room environment for children. It is unclear if adverse events which occur in off-site anesthetizing locations result in more severe outcomes compared to events in traditional operating rooms. AIM: We used a multi institutional registry of pediatric patients to compare outcomes of perioperative adverse events between location types. METHODS: De-identified data from 24 pediatric tertiary care hospitals participating in the Wake Up Safe registry during 2010-2015 were analyzed. Peri-procedural adverse events occurring in operating rooms or off-site locations were included. The primary outcome was whether the adverse event was severe, defined as requiring escalation of care or resulting in temporary or significant harm. Multivariable logistic regression was used to compare location type (operating room vs. off-site) and the likelihood of a severe outcome among reported events. RESULTS: There were 1,594 adverse events, of which 362 were associated with off-site anesthetizing locations. In multivariable logistic regression, off-site location was associated with greater odds of severe adverse event outcome (adjusted odds ratio, 1.31; 95% confidence interval: 1.01, 1.69; p=0.044). Comparing adverse events in cardiac catheterization suites to events in operating rooms confirmed higher odds of severe outcome in the former group (adjusted odds ratio = 1.48; 95% confidence interval: 1.05, 2.08; p=0.025) while this difference was not found for other off site locations. CONCLUSION: Multivariable analysis of a large registry revealed a greater likelihood of severe outcome for adverse events occurring in cardiac catheterization suites (but not other out of the OR sites), compared to adverse events occurring in the operating room. Additional prospective studies are needed which better control for patient and environmental characteristics and their effect on severe outcomes after anesthesia. This article is protected by copyright. All rights reserved. PMID- 30447126 TI - Prognostic factors and survival in adenoid cystic carcinoma of the sinonasal cavity. AB - BACKGROUND: Optimal treatment and prognostic factors affecting long-term survival in patients with sinonasal adenoid cystic carcinoma (ACC) have yet to be clearly defined. METHODS: We conducted a retrospective review of patients treated with curative intent from 1980-2015 at MD Anderson Cancer Center. RESULTS: One hundred sixty patients met inclusion criteria, including 8 who were treated with radiotherapy alone. Median follow-up time was 55 months. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 67.0% and 49.0%, respectively. The 10-year OS and DFS rates were 44.8% and 25.4%, respectively. Factors that portended for poor survival on multivariate analysis were recurrent disease, any solid type histology, epicenter in the sinus cavity, the presence of facial symptoms, or the original disease not treated with surgery. There was no association between surgical margin status or nodal status and survival. CONCLUSION: In this large cohort of patients with sinonasal ACC with extended follow-up, long-term survival is better than reported in prior literature. Future research should target patients with adverse risk factors. PMID- 30447127 TI - Impact of treatment expertise on the outcome of patients with head and neck cancer treated within 6 randomized trials. AB - BACKGROUND: We evaluated the impact of center expertise, in terms of number of patients treated, on the overall survival (OS) and progression-free survival (PFS) of patients with head and neck squamous cell carcinoma (SCC). METHODS: We performed a pooled analysis including data from 6 randomized trials in head and neck SCC conducted in Italy. We evaluated the association between OS or PFS and the number of patients recruited by the center. RESULTS: The outcome of 903 patients who had received radiotherapy (RT) was analyzed (median follow-up 76 months). The hazard ratio (HR) comparing the third and the first quartiles of the distribution of number of patients per center showed an advantage in PFS (HR 0.59, range 0.53-0.65, P < .0001) and in OS (HR 0.70, 0.60-0.81, P < .0001) for centers with a higher number of patients recruited. A similar benefit was observed in PFS (HR 0.63, 0.60-0.66) and OS (HR 0.74, 0.69-0.79) considering the mean number of patients per year. CONCLUSIONS: The PFS and OS were longer for patients treated in high-case-volume centers. PMID- 30447128 TI - A hand-eye calibration method for augmented reality applied to computer-assisted orthopedic surgery. AB - BACKGROUND: Augmented reality (AR) allows the surgeon to represent holographic patient-specific anatomical information and surgical instruments in the physical world. To correctly superimpose virtual and physical objects, a hand-eye (HE) calibration method for mapping the virtual and physical spaces was proposed. METHODS: Mathematical relationships between the virtual camera and the physical space were derived. Finally, the accuracy and robustness of the proposed HE calibration method were qualitatively and quantitatively evaluated. RESULTS: The proposed calibration method allows us to determine an optimal invariant spatiotemporal mapping between the virtual camera and the physical space. CONCLUSION: Qualitatively and quantitatively reliable and accurate estimates for the physical-virtual mapping transformation were verified. Consequently, imaging data and surgical instruments holograms can be precisely represented in the physical space. PMID- 30447129 TI - A novel ceramic coating for reduced metal ion release in metal-on-metal hip surgery. AB - An ovine total hip arthroplasty model was developed to evaluate metal ion release, wear, the biological response and adverse tissue reaction to metal-on metal (MoM) bearing materials. The performance of an advanced superlattice ceramic coating (SLC) was evaluated as a bearing surface and experimental groups divided into; (1) MoM articulating surfaces coated with a SLC coating (SLC-MoM), (2) uncoated MoM surfaces (MoM), and (3) metal on polyethylene (MoP) surfaces. Implants remained in vivo for 13 months and blood chromium (Cr) and cobalt (Co) metal ion levels were measured pre and postoperatively. Synovial tissue was graded using an ALVAL scoring system. When compared with the MoM group, sheep with SLC-MoM implants showed significantly lower levels of chromium and cobalt metal ions within blood over the 13-month period. Evidence of gray tissue staining was observed in the synovium of implants in the MOM group. A significantly lower ALVAL score was measured in the SLC-MoM group (3.88) when compared with MoM components (6.67) (p = 0.010). ALVAL results showed no significant difference when SLC-MOM components were compared to MoP (5.25). This model was able to distinguish wear and the effect of released debris between different bearing combinations and demonstrated the effect of a SLC coating when applied onto the bearing surface. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res B Part B: Appl Biomater, 2018. PMID- 30447130 TI - Diabetic retinopathy detection and classification using hybrid feature set. AB - Complicated stages of diabetes are the major cause of Diabetic Retinopathy (DR) and no symptoms appear at the initial stage of DR. At the early stage diagnosis of DR, screening and treatment may reduce vision harm. In this work, an automated technique is applied for detection and classification of DR. A local contrast enhancement method is used on grayscale images to enhance the region of interest. An adaptive threshold method with mathematical morphology is used for the accurate lesions region segmentation. After that, the geometrical and statistical features are fused for better classification. The proposed method is validated on DIARETDB1, E-ophtha, Messidor, and local data sets with different metrics such as area under the curve (AUC) and accuracy (ACC). PMID- 30447131 TI - Introduction to the special section on light sheet fluorescence illumination microscopy. PMID- 30447132 TI - Influence of Omega-3 Fatty Acid on Orthodontic Tooth Movement in Rats: A Biochemical, Histological, Immunohistochemical and Gene Expression Study. AB - OBJECTIVE: The aim of this study was to investigate the effects of omega-3 fatty acids on orthodontic tooth movement. SETTING AND SAMPLE POPULATION: For this study, 56 12-week-old adult male Wistar albino rats from the Animal Laboratory at Adnan Menderes University, Faculty of Medicine, were used. MATERIAL AND METHODS: Rats were randomly divided into 7 groups (n=8 each): control group (without any treatment), tooth movement groups (three groups of animals with only tooth movement) and omega groups (three groups of animals with tooth movement and omega 3 administration). Omega-3 fatty acids were administered to the rats systemically during the tooth movement period. On the 3rd, 7th and 14th days after the orthodontic tooth movement, the rats were sacrificedand biochemical, histological, immunohistochemical andgene expression examinations were performed. RESULTS: On the 14th experimental day, the amount of tooth movement in the omega groups was significantly lower than the tooth movement groups (p = 0.012). Biochemical experimentsshowed that the omega groups had significantly lower total oxidant levels and higher total antioxidant levels compared to the tooth movement group on the 14th experimental day (p=0,001). The levels of RANKL, IL-6 and IL 1beta in the omega groups were significantly lower than the tooth movement groups on all experimental days (p<0,05). CONCLUSION: Systemic administration of omega-3 fatty acids showed antioxidant and antiinflammatory effects and decelerate the orthodontic tooth movement. This article is protected by copyright. All rights reserved. PMID- 30447133 TI - Slick, stretchy fascia underlies the sliding tongue of rorquals. AB - The tongue of rorqual (balaenopterid) whales slides far down the throat into the expanded oral pouch as an enormous mouthful of water is engulfed during gulp feeding. As the tongue and adjacent oral floor expands and slides caudoventrally, it glides along a more superficial (outer) layer of ventral body wall musculature, just deep to the accordion-like ventral throat pleats. We hypothesize that this sliding movement of adjacent musculature is facilitated by a slick, stretchy layer of loose areolar connective tissue that binds the muscle fibers and reduces friction: fascia. Gross anatomical examination of the gular region of adult minke, fin, and humpback whales confirms the presence of a discrete, three-layered sublingual fascia interposed between adhering fasciae of the tongue and body wall. Histological analysis of this sublingual fascia reveals collagen and elastin fibers loosely organized in a random feltwork along with numerous fibroblasts in a watery extracellular matrix. Biomechanical testing of tissue samples in the field and laboratory, via machine-controlled or manual stretching, demonstrates expansion of the sublingual fascia and its three layers up to 250% beyond resting dimensions, with slightly more extension observed in anteroposterior (rather than mediolateral or oblique) stretching, and with the most superficial of the fascia's three layers. This article is protected by copyright. All rights reserved. PMID- 30447134 TI - Diagnostic pitfalls and treatment challenges in interstitial pneumonia with autoimmune features. AB - In the recently published article, Wilfong et al reviewed the diagnostic challenges and treatment options in patients with interstitial pneumonia with autoimmune features (IPAF). This term, which was created by the European Respiratory Society/American Thoracic Society, describes patients with idiopathic interstitial pneumonia who do not meet classification criteria for a connective tissue disease (CTD) but have features of autoimmunity. From a rheumatologist perspective, IPAF, particularly with extra-thoracic clinical manifestations or specific autoantibodies, represents an early manifestation of a probable autoimmune disease and may precede the involvement of the other organs. The latter may be masked or prevented by immunosuppressive therapy. This article is protected by copyright. All rights reserved. PMID- 30447135 TI - Anatomy and Functional Morphology of the Mysticete Rorqual Whale Larynx: Phonation Positions of the U-fold. AB - Many Mysticetes (baleen whales) are acoustically active marine mammals. This is epitomized by rorquals, and specifically male humpback whales (Megaptera novaeangliae) whose complex songs comprise a wide range of vocalizations. The sound production mechanism of odontocetes (toothed whales, including dolphins and porpoises) is well described, in contrast to that of mysticetes whose vocalization mechanism remains a subject of active scientific investigation. Anatomical observations and acoustic signal processing have led to divergent hypotheses under the framework of a production-based approach. We attempt to unify these hypotheses by broadening existing data with our new anatomical investigation, interpreted in light of known acoustical properties of mysticete vocalizations. We examined 15 specimens of four rorqual species: sei whale (Baleanoptera borealis), fin whale (Baleanoptera physalus), minke whale (Baleanoptera acutorostrata), and humpback whale (Megaptera novaeangliae). Based on these data and on previous literature, we propose a description of three functional positions (rest, breathing and recirculation), unidirectional egressive airflow for sound production (from lungs to laryngeal sac), and new nomenclature for different parts of the U-fold (distal section, midsection, corniculate flaps). Each of these sections has specific morphological and acoustical properties that support the concept of "mode variation" in baleen whale vocalizations. This article is protected by copyright. All rights reserved. PMID- 30447136 TI - S100A12-induced sterile inflammatory activation of human coronary artery endothelial cells is driven by monocyte-derived interleukin 1beta: implications for Kawasaki disease pathology. AB - OBJECTIVE: Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting coronary arteries. S100A12 is a granulocyte-derived agonist of both the receptor for advanced glycation end products (RAGE) and toll like receptor (TLR) 4. S100A12 is strongly upregulated in KD but it is unknown if or how it contributes to KD pathogenesis. METHODS: Serum samples from patients with KD at different stages pre- and post-intravenous immunoglobulin (IVIG) treatment were analyzed for S100A12, cytokines, chemokines and soluble markers of endothelial activation. Primary human coronary artery endothelial cells (HCAECs) were analyzed for responsiveness (assessed by qPCR analysis of cytokine and endothelial adhesion molecule mRNA) following direct stimulation with S100A12 or lipopolysaccharide (LPS). Alternatively, HCAEC were cultured in conditioned medium obtained from primary human monocytes stimulated with LPS or S100A12 in the absence or presence of IVIG or cytokine antagonists. RESULTS: In KD patients' sera, pre-treatment S100A12 levels are associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) titers in course of IVIG-therapy. Yet, HCAECs were not responsive to direct S100A12 stimulation, despite the presence of appropriate receptors (RAGE, TLR4). HCAECs did however respond to supernatants obtained from S100A12-stimulated primary human monocytes, as evidenced by expression of inflammatory cytokines and adhesion molecules. This response was strictly dependent on IL-1beta-signaling. CONCLUSION: S100A12 as a highly expressed mediator of sterile inflammation in KD can activate coronary artery endothelial cells in an IL-1beta-dependent manner. Our data provide new mechanistic insights on the contribution of S100A12 and IL-1beta in disease pathogenesis and support current IL-1 targeting studies in KD. This article is protected by copyright. All rights reserved. PMID- 30447138 TI - Malprogramming of Hepatic Lipid Metabolism due to Excessive Early Cholesterol Exposure in Adult Progeny. AB - SCOPE: The programming of hepatic lipid dysfunction in response to early cholesterol exposure and the influencing effects of postnatal diet is evaluated in apoE-/- mice. METHODS AND RESULTS: In two separate studies, female mice are assigned to a standard chow (S) or a cholesterol-enriched chow (C) diet during gestation and lactation. Male offspring from each dam are weaned on a postnatal S or a hypercaloric western (W) diet resulting in four experimental groups: S-S and C-S (Experiment 1) and S-W and C-W (Experiment 2). At weaning, litters from hypercholesterolemic mothers weighed less (p < 0.05) and pups had higher blood lipids, glucose, and hepatic cholesterol compared with pups from S-fed mothers. Adult C-S offspring demonstrate an atherogenic lipid profile and increased (p < 0.05) hepatic cholesterol and triglyceride content with altered lipid regulatory mRNA expression and protein content compared with S-S offspring. Alternatively, no difference (p > 0.05) is observed between S-W and C-W in serum and hepatic lipid profiles; however, serum AST and ALT are higher (p < 0.05) in C-W versus S W offspring. CONCLUSION: The degree of hepatic lipid deposition observed in adult offspring exposed to excessive early cholesterol is influenced by the postnatal diet. PMID- 30447137 TI - The Prevention of a High Dose of Vitamin D or Its Combination with Sulforaphane on Intestinal Inflammation and Tumorigenesis in Apc1638N Mice Fed a High-Fat Diet. AB - SCOPE: The previous study shows that obesity-promoted inflammation is responsible for the activation of the intestinal tumorigenic Wnt-signaling. The present study aims to test a dietary strategy, dietary supplementation with a high dose of vitamin D (VD) or its combination with sulforaphane (SFN) to inhibit intestinal inflammation and obesity-associated tumorigenesis. METHODS AND RESULTS: Apc1638N mice are randomly divided into four groups: LF, a low-fat diet (10 kcal% fat) with 200 IU VD; HF, a high-fat diet (60 kcal% fat) with 200 IU VD; HFD, a high fat diet with 5000 IU VD; and HFDS, a high-fat diet plus 5000 IU VD and 0.23 g SFN per ~4000 kcal. VD administration decreased tumor incidence and size, and the co-administration with SFN (HFDS) magnified the effects. Inflammation and Wnt signaling are suppressed by VD. The addition of SFN decreased the activity of histone deacetylase (HDAC) and increased autophagy. CONCLUSION: The administration of VD, at 5000 IU level, exerts an anti-inflammatory property and leads to suppressed intestinal Wnt-signaling and tumorigenesis in obese mice. The molecular function of SFN on a high dose of VD supplementation, although displayed on the inhibition of HDAC and the activation of autophagy, needs further investigation. PMID- 30447139 TI - Design, microwave-assisted synthesis and in vitro antibacterial and antifungal activity of 2,5-disubstituted benzimidazole. AB - Seventeen novel 2,5-disubstituted benzimidazole derivatives were designed, synthesized and evaluated for their antibacterial activities. The tested compounds B1-B4 and C2-C6 exhibited not only good antifungal activity but also favorable broad-spectrum antibacterial activity. Also, the lowest MIC of antibacterial and antifungal activity was 2 MUg/mL and 4 MUg/mL, respectively. It suggested that the structure of compound including the different substituent and its sites directly affected on efficacy of the synthesized compound. PMID- 30447140 TI - Impact of progestogens on hemostasis. AB - Combined hormonal contraception containing estrogen and progestogen and postmenopausal hormone therapy with estrogen +/- progestogen are reported risk factors for venous thrombosis. The thrombotic risk varies by estrogen dose and type of progestogen. Estrogen combined with "newer generation" progestogens in combined oral contraceptives may have higher thrombotic risk than estrogen combined with older generation progestogens. Among postmenopausal women thrombotic risk also varies by type of hormone and mode of delivery. Although the risk of thrombosis with the different hormonal compounds is uncertain, it has definitely been attributed to the pharmacological effect of the hormones on hemostasis. Animal and cell culture studies have demonstrated the pharmacodynamics of progestogens with respect to hemostasis. Extrapolation from these studies to clinical conditions and further to clinical end points such as cardiovascular disease is, however, controversial. Few clinical studies have focused on the effect of progestogen only therapy on the hemostatic system in vivo. Most of the current knowledge regarding the in vivo effect of progestogens on hemostasis is obtained from studies with combined contraceptives. These results obviously reflect the combined influence of both estrogen and progestogen on hemostasis, and extrapolation to progestogen-only conditions is challenging. This paper discusses the pharmacodynamics of progestogens in relation to the hemostatic system, addressing results obtained in animal and cell culture studies and in clinical studies employing progestogen-only and combined oral contraceptives. The compiled results suggest that the major effect of progestogens on hemostasis is related to alterations in platelet function and the tissue factor pathway of coagulation. More studies focusing on these topics are warranted. PMID- 30447141 TI - Adolescents' smartphone use at night, sleep disturbance and depressive symptoms. AB - Nowadays smartphones are used anywhere and at any time, day or night, by adolescents. Smartphone use, especially at night, is a risk factor for sleep disturbance and depression in adolescents. The purpose of this study was to analyse the correlation between smartphone use at night, sleep disturbance and depression symptoms in adolescents. This cross-sectional study analysed the data from 714 students in Surabaya, who were selected by using a simple random sampling technique. The independent variable was smartphone usage at night while the dependent variable was sleep disturbance and depressive symptoms. The data was collected using three questionnaires: the smartphone usage at night questionnaire, the Insomnia Severity Index questionnaire and the Kutcher Adolescent Depression Scale questionnaire. The data was then analysed using Spearman's rho analysis (alpha < 0.05). The results indicated that there was a relationship between the use of smartphones at night and sleep disturbance in adolescents with a positive correlation (r = 0.374), and that there was a relationship between the use of smartphones at night and depression symptoms in adolescents with a positive correlation (r = 0.360). This study highlights that the excessive use of smartphones during the night may play a significant role in sleep problems and depressive symptoms among teenagers. Adolescents with sleep disturbance and depressive symptoms should be carefully monitored for signs of smartphone addiction. Nurses should improve health education for adolescents to inform them about the positive use of smartphones to prevent sleep disturbance and to minimise depressive symptoms. PMID- 30447142 TI - Tramadol-induced parkinsonism: a case report of a 75-year-old woman. AB - Adverse drug reaction (ADR) is a form of unwanted reaction and is the crucial reason for illness and death. Tramadol-induced parkinsonism is a kind of ADR that occurs after the repeated intake of tramadol. Long-term exposure to tramadol has been known to induce tremor and alter the functioning of dopamine. This case report introduces a 75-year-old woman diagnosed with tramadol-induced parkinsonism due to the administration of tramadol for the treatment of post operated (breast cancer) acute onset of severe pain on the left side of the chest. The assessment of the offending drug was carried out via Naranjo probability scale. A score of 6 was reported for this patient, defining tramadol as a probable cause of this reaction. For the management of the drug-induced parkinsonism, levodopa/carbidopa was prescribed and the symptoms related to parkinsonism resolved within a week. The age of the patient and the female gender is considered to be the main risk factor for the occurrence of such reaction. This case report is an attempt to spread awareness about the negative consequences of long-term use of tramadol in old patients. Thus, the medical practitioners must be very careful while administering tramadol to the old aged population. PMID- 30447143 TI - Dysregulated glucose homeostasis in congenital central hypoventilation syndrome. AB - Background Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic control. A hypoglycaemic seizure in a 4-year-old girl with CCHS led to a more detailed examination of glycaemic control in a cohort of children with CCHS. Methods We conducted an observational cohort study of glucose homeostasis in seven children (3 months to 12 years) with genetically confirmed CCHS using a combination of continuous glucose monitoring (CGM), fasting studies and oral glucose tolerance test (OGTT). CGM was used to compare the effect of diazoxide and dietary intervention in the index patient. Results Hypoglycaemia was not elicited by fasting in any of the patients. Increased postprandial glycaemic variability was evident in all patients using CGM, with seven of seven patients demonstrating initial postprandial hyperglycaemia (plasma-glucose concentration >7.8 mmol/L), followed by asymptomatic hypoglycaemia (plasma-glucose concentration <=2.8 mmol/L) in two of seven patients that was also demonstrated on OGTT. Both diazoxide and low Glycaemic Index (GI) dietary intervention reduced the proportion of CGM readings <4 mmol/L; however, diazoxide also increased the proportion of readings in the hyperglycaemic range. Conclusions Glucose variability associated with autonomic dysfunction may be unrecognised in CCHS, particularly in children with more severe phenotypes. This report highlights the occurrence of hyperglycaemia as well as hypoglycaemia in CCHS. Given the challenges of recognising hypoglycaemia based on clinical symptomatology, the use of CGM may facilitate its identification allowing appropriate management. The observed normoglycaemia during fasting combined with increased postprandial plasma blood glucose level (BGL) variability is more consistent with dumping syndrome than persistent hyperinsulinism. Dietary modifications therefore may be more effective than diazoxide in managing hypoglycaemia. PMID- 30447144 TI - Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY). AB - Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel. PMID- 30447145 TI - Possible hints and pitfalls in diagnosing Peutz-Jeghers syndrome. AB - Background Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal polyposis, mucocutaneous pigmentation and cancer predisposition. Patients with PJS can develop large calcifying Sertoli cell tumors (LCSTs). Case presentation A patient presented at 3 years of age with delayed development, hypermobility and later also with tall stature and advanced bone age. Extensive endocrine evaluation, mutation analysis of genes associated with connective tissue disorders and a single nucleotide polymorphism (SNP) array showed no abnormalities. At 8 years of age, gynecomastia developed as well as pigmentations on the lips, both of which are associated with PJS. Mutation analysis showed a heterozygous deletion of the whole STK11 gene confirming PJS. Testicular ultrasound confirmed the presence of LCSTs. Interestingly, the previously performed SNP array did not report deletion of the STK11 gene. Conclusions We advise excluding LCSTs in children with tall stature and advanced bone age where more common causes have been eliminated. Although STK11 deletions are documented in control databases, reporting the deletion of this gene even in the absence of a phenotype is advised for patient management. PMID- 30447146 TI - Serum vitamin D level was not associated with severity of ventilator associated pneumonia. AB - BACKGROUND AND OBJECTIVE: Vitamin D deficiency is considered one of the most common nutritional deficiencies associated with weakened immune system and increased likelihood of sepsis. The current study was conducted to investigate the association between serum vitamin D level and the severity and prognosis of ventilator associated pneumonia (VAP) in inpatients in intensive care unit (ICU). METHODS: Eighty-four consecutive patients with VAP were enrolled in this observational, prospective study conducted in the ICU of Besat Hospital, Hamadan. The patients were examined for serum 25-hydroxyvitamin D (vitD3) level and VAP severity and prognosis. Clinical pulmonary infection score was used for the diagnosis, and Sequential Organ Failure Assessment (SOFA) Score was used to determine the severity of VAP. RESULTS: Low level serum vitD3 (under 30 ng/ml) was found in 66 (78.6%) patients. In this series of VAP patients, there were no significant differences in blood culture results, 14 and 28-day sepsis-associated mortality, mechanical ventilation duration, or SOFA Score on days 3, 7, and 14 between the low level and normal level vitD3 patients (p>0.05). CONCLUSION: Serum vitD3 level was not associated with mortality from VAP or complications due to sepsis in the inpatients in the ICU. PMID- 30447147 TI - Liver stiffness in chronic hepatitis C virus infection. AB - INTRODUCTION: The severity of liver fibrosis can be assessed noninvasively today by liver stiffness measurements. Vibration-controlled transient elastography, shear wave elastography or magnetic resonance elastography are techniques increasingly used for this purpose. METHODS: This article presents the recent advances in the use of new techniques for liver fibrosis assessment in chronic hepatitis C: the correlation between liver stiffness values and liver fibrosis estimated by liver biopsies, the prognosis role of liver stiffness values, their usefulness in monitoring the treatment response, in assessing the severity of portal hypertension and in estimating the presence of esophageal varices. Scientific articles from January 2017 to January 2018 were searched in PubMed and PubMed Central databases, using the terms "liver stiffness" and "hepatitis C". RESULTS: The median liver stiffness values measured with different techniques are not identical, so that FibroScan thresholds can not be used on any other elastographic machine. The higher the liver's stiffness measurement, the higher the liver-related events in patients with chronic hepatitis C. A liver stiffness measurement over 17 kPa could be an independent predictor for the presence of esophageal varices as well as a spleen with a longitudinal span >=15 cm for patients with a value of liver stiffness <17 kPa. A progressive and persistent decrease in liver stiffness is dependent on sustained virological response achievement. The lack of liver stiffness decrease has been associated with relapsers and a low value of liver stiffness at baseline. CONCLUSION: Liver stiffness provides clues about the severity and evolution of liver disease. PMID- 30447148 TI - Effect of Statins on Hearing Function and Subjective Tinnitus in Hyperlipidemic Patients. AB - INTRODUCTION: It is known that hyperlipidemia reduces hearing functions. In this study, we aimed to study the effect of antihyperlipidemic drugs on hearing functions and tinnitus. METHODS: Eighty-four patients aged 18 to 84, who were diagnosed with hyperlipidemia and started treatment with the statin group (atorvastatin 20 mg and 40 mg, rosuvastatin 10 mg and 20 mg, and simvastatin 20 mg) of antihyperlipidemic drugs, were included in this study. All patients underwent pure-tone audiometry before starting treatment with antihyperlipidemic drugs. Patients with tinnitus were evaluated by Tinnitus Severity Index and Visual Analogue Scale. In the 6th month of the therapy, otologic examination, pure-tone audiometry and tinnitus evaluation of the patients were repeated. RESULTS: No significant difference was found in the pure-tone averages of the patients before and after statin use (p>0.05). However, it was found in the audiometry that, after statin use, all drugs caused to statistically significant decrease in the hearing thresholds at 6000 Hertz (p<0.05). Also, strongly increase was found in the Speech Discrimination percentages after treatment in patients using rosuvastatin 10 mg (p= 0.022). A significant decrease was found in the tinnitus frequency, duration, severity and degree of annoyance in patients using rosuvastatin 10 mg and 20 mg (p<0.05). CONCLUSION: Statin group of drugs can have a positive effect on the hearing functions and subjective tinnitus. In particular, it is seen that rosuvastatin group of statins has a more notable effect on tinnitus. It was considered that further studies with larger patient groups are needed. PMID- 30447150 TI - Chest pain with increased troponin level; not always a cardiology issue. AB - Thrombotic Thrombocytopenic Purpura (TTP) is a thrombotic microangiopathy syndrome resulting from decrease or absence of "a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13" (ADAMTS13). TTP has been characterized by the classical pentad of thrombocytopenia, hemolysis, fever, renal injury and neurological deficits, yet the patient may present with any atypical symptom related to microthrombi formation in the microcirculation. Here we present a rare case of a young patient with retrosternal chest pain and myocardial injury as the first manifestation of TTP. PMID- 30447149 TI - Metabolic and bone profile in postmenopausal women with and without type 2 diabetes: a cross-sectional study. AB - INTRODUCTION: Current studies support the implication of metabolic changes associated with type 2 diabetes in altering bone metabolism, structure and resistance. OBJECTIVE: We conducted a cross-sectional study on postmenopausal women aimed to analyze the differences in metabolic and bone profile in patients with and without type 2 diabetes Methods: We analyzed the metabolic and bone profile in postmenopausal women with and without type 2 diabetes(T2DM). Clinical, metabolic, hormonal parameters, along with lumbar, hip and femoral bone mineral density (BMD) and trabecular bone score (TBS) were evaluated. RESULTS: 56 women with T2DM(63.57+/-8.97 years) and 83 non-T2DM (60.21+/-8.77 years) were included. T2DM patients presented a higher value of body mass index (BMI) and BMD vs. control group (p 0.001; p=0.03-lumbar level, p=0.07-femoral neck and p=0.001 total hip). Also, BMI correlated positively with lumbar-BMD and glycated hemoglobin (HbA1c) (r=0.348, p=0.01; r=0.269, p=0.04), correlation maintained even after age and estimated glomerular filtration rate (eGFR) adjustment (r = 0.383, p = 0.005; r=0.237, p=0.08). Diabetic patients recorded lower levels of 25(OH)D(p=0.05), bone markers (p <=0.05) and TBS(p=0.07). For the entire patient group we found a negative correlation between HbA1clevel and bone markers: r = 0.358, p = 0.0005-osteocalcin, r =-0.40, p = 0.0005-P1NP, r =-0.258, p = 0.005 crosslaps. CONCLUSIONS: Our results indicate the presence of altered bone microarchitecture in T2DZ patients according to the TBS score, combined with lower levels of bone markers, with a statistically significant negative correlation between HbA1c level and bone markers. PMID- 30447151 TI - A novel method to accurately calculate statistical significance of local similarity analysis for high-throughput time series. AB - In recent years, a large number of time series microbial community data has been produced in molecular biological studies, especially in metagenomics. Among the statistical methods for time series, local similarity analysis is used in a wide range of environments to capture potential local and time-shifted associations that cannot be distinguished by traditional correlation analysis. Initially, the permutation test is popularly applied to obtain the statistical significance of local similarity analysis. More recently, a theoretical method has also been developed to achieve this aim. However, all these methods require the assumption that the time series are independent and identically distributed. In this paper, we propose a new approach based on moving block bootstrap to approximate the statistical significance of local similarity scores for dependent time series. Simulations show that our method can control the type I error rate reasonably, while theoretical approximation and the permutation test perform less well. Finally, our method is applied to human and marine microbial community datasets, indicating that it can identify potential relationship among operational taxonomic units (OTUs) and significantly decrease the rate of false positives. PMID- 30447152 TI - Investigation of Brain Impairment Using Diffusion-Weighted and Diffusion Tensor Magnetic Resonance Imaging in Experienced Healthy Divers. AB - BACKGROUND The aim of this study was to understand the changes of decompression illness in healthy divers by comparing diffusion-weighted (DWI) and diffusion tensor MRI findings among healthy professional divers and healthy non-divers with no history of diving. MATERIAL AND METHODS A total of 26 people were recruited in this prospective study: 11 experienced divers with no history of neurological decompression disease (cohort) and 15 healthy non-divers (control). In all study subjects, we evaluated apparent diffusion coefficient (ADC) and type of diffusion tensor metric fractional anisotropy (FA) values of different brain locations (e.g., frontal and parieto-occipital white matter, hippocampus, globus pallidus, putamen, internal capsule, thalamus, cerebral peduncle, pons, cerebellum, and corpus callosum). RESULTS ADC values of hippocampus were high in divers but low in the control group; FA values of globus pallidus and putamen were lower in divers compared to the control group. DWI depicted possible changes due to hypoxia in different regions of the brain. Statistically significant differences in ADC values were found in hypoxia, particularly in the hippocampus (p=0.0002), while FA values in the globus pallidus and putamen were statistically significant (p=0.015 and p=0.031, respectively). We detected forgetfulness in 6 divers and deterioration in fine-motor skills in 2 divers (p=0.002 and p=0.17, respectively). All of them were examined using neuro-psychometric tests. CONCLUSIONS Repeated hyperbaric exposure increases the risk of white matter damage in experienced healthy divers without neurological decompression illness. The hippocampus, globus pallidus, and putamen are the brain areas responsible for memory, learning, navigation, and fine-motor skills and are sensitive to repeated hyperbaric exposure. PMID- 30447154 TI - Alkaline extracellular conditions promote the proliferation and mineralization of a human cementoblast cell line. AB - AIM: To investigate the proliferation and mineralization of a human cementoblast cell line under alkaline conditions. METHODOLOGY: A human cementoblast cell line was cultured in alkaline media with several pHs (pH 7.6, 8.0 and 8.4) without CO2 . Cell numbers, phospho-p44/42 expression, alkaline phosphatase (ALP) activity, and mineralization were evaluated. The significance of differences between groups was assessed using a two-way analysis of variance 15 (ANOVA) followed by Bonferroni's multiple comparison test (alpha=0.01). RESULTS: Cell numbers increased in a time-dependent manner in the high pH medium groups. Western blot analysis revealed the up-regulated expression of phospho-p44/42 under alkaline conditions. ALP activity was also increased at pH 8.0 and 8.4. Alizarin red staining showed increased mineralization in the high pH medium groups. The incorporation of the transient receptor potential ankyrin subfamily member 1 (TRPA1) antagonist HC030031 markedly negated the effect on proliferation and mineralization. CONCLUSIONS: Extracellular alkaline conditions promoted the proliferation and mineralization of human cementoblasts in vitro via TRPA1. This article is protected by copyright. All rights reserved. PMID- 30447153 TI - Protamine-like proteins have bactericidal activity. The first evidence in Mytilus galloprovincialis. AB - The major acid-soluble protein components of the mussel Mytilus galloprovincialis sperm chromatin consist of the protamine-like proteins PL-II, PL-III and PL-IV, an intermediate group of sperm nuclear basic proteins between histones and protamines. The aim of this study was to investigate the bactericidal activity of these proteins since, to date, there are reports on bactericidal activity of protamines and histones, but not on protamine-like proteins. We tested the bactericidal activity of these proteins against Gram-positive bacteria: Enterococcus faecalis and two different strains of Staphylococcus aureus, as well as Gram-negative bacteria: Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhmurium, Enterobacter aerogenes, Enterobacter cloacae, and Escherichia coli. Clinical isolates of the same bacterial species were also used to compare their sensitivity to these proteins. The results show that Mytilus galloprovincialis protamine-like proteins exhibited bactericidal activity against all bacterial strains tested with different minimum bactericidal concentration values, ranging from 15.7 to 250 ug/mL. Furthermore, these proteins were active against some bacterial strains tested that are resistant to conventional antibiotics. These proteins showed very low toxicity as judged by red blood cell lysis and viability MTT assays and seem to act both at the membrane level and within the bacterial cell. We also tested the bactericidal activity of the product obtained from an in vitro model of gastrointestinal digestion of protamine-like proteins on a Gram-positive and a Gram-negative strain, and obtained the same results with respect to undigested protamine-like proteins on the Gram-positive bacterium. These results provide the first evidence of bactericidal activity of protamine-like-proteins. PMID- 30447155 TI - Evaluation of Tumour Coverage after MR-Guided Prostate Focal Laser Ablation Therapy. AB - PURPOSE: Prostate cancer is the most common non-cutaneous cancer among men in the USA.[1] Focal laser thermal ablation (FLA) has the potential to control small tumours while preserving urinary and erectile function by leaving the neurovascular bundles and urethral sphincters intact. Accurate needle guidance is critical to the success of FLA. Multi-parametric magnetic resonance images (mpMRI) can be used to identify targets, guide needles, and assess treatment outcomes. In this study, we evaluated the location of ablation zones relative to targeted lesions in 23 patients who underwent FLA therapy in a phase II trial. The ablation zone margins and unablated tumour volume were measured to determine whether complete coverage of each tumour was achieved, which would be considered a clinically successful ablation. METHODS: Pre-operative mpMRI were acquired for each patient two to three months preceding the procedure and the prostate and lesion(s) were manually contoured on 3T T2-weighted axial images. The prostate and ablation zone(s) were also manually contoured on post-ablation 1.5T T1 weighted contrast-enhanced axial images acquired immediately after the procedure intra-operatively. The lesion surface was non-rigidly regis-tered to the post ablation image using an initial affine registration followed by non-rigid thin plate spline registration of the prostate surfaces. The margins between the registered lesion and ablation zone were calculated using a uniform spherical distribution of rays, and the volume of inter-section was also calculated. Each prostate was contoured five times to determine the segmentation variability and its effect on intersection of the lesion and ablation zone. RESULTS: Our study showed that the boundaries of the segmented tu-mour and ablation zone were close. Of the 23 lesions that were analyzed, eleven were completely covered by the ablation zone and twelve were par-tially covered. A shift of 1.0, 2.0, and 2.6 mm would result in 19, 21, and all tumours completely covered by the ablation zone, respectively. The median unablated tumour volume across all tumours was 0.1 mm3 with an IQR of 3.7 mm3 , which was 0.2% of the median tumour volume (46.5 mm3 with an IQR of 46.3 mm3 ). The median extension of the tumours beyond the ablation zone, in cases which were partially ablated, was 0.9 mm (IQR of 1.3 mm), with the furthest tumour extending 2.6 mm. CONCLUSION: In all cases the boundary of the tumour was close to the boundary of the ablation zone and in some cases the boundary of the ablation zone did not completely enclose the tumour. Our results suggest that some of the ablations were not clinically successful and that there is a need for more accurate needle tracking and guidance methods. Limitations of the study include errors in the registration and segmenta-tion methods used, as well as different voxel sizes and contrast between the registered T2 and T1 MRI sequences and asymmetric swelling of the prostate post procedurally. This article is protected by copyright. All rights reserved. PMID- 30447156 TI - Assessment of Multi-Ion Channel Block in a Phase-1 Randomized Study Design:Results of the CiPA Phase 1 ECG Biomarker Validation Study. AB - Balanced multi-ion channel-blocking drugs have low torsade risk because they block inward currents. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative proposes to use an in-silico cardiomyocyte model to determine the presence of balanced block, and absence of J-Tpeakc prolongation would be expected for balanced blockers. This study included 3 balanced blockers in a 10 subject per drug parallel-design; lopinavir/ritonavir and verapamil met the primary endpoint of DeltaDeltaJ-Tpeakc upper bound <10 ms, while ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). A predominant hERG blocker (chloroquine) prolonged DeltaDeltaQTc and DeltaDeltaJ-Tpeakc by >=10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide-induced DeltaQTc prolongation, but shortened DeltaJ-Tpeakc and prolonged DeltaTpeak-Tend. Absence of J-Tpeakc prolongation appears consistent with balanced block, however, small sample size (10 subjects) may be insufficient to characterize concentration-response in some cases. This article is protected by copyright. All rights reserved. PMID- 30447157 TI - Water Filtered Infrared Radiation Decreases the Generation of Photodermatoses Dependent on Ultraviolet and Visible Radiation. AB - The potential role of infrared radiation in photodermatoses has received very little attention, even though the main sources of radiation used for photobiological studies (UVA, UVB, and visible light) include infrared radiation. The objective of the work was assess whether infrared radiation is involved in the development of skin lesions in patients with different types of photodermatoses. Twenty patients with different photodermatoses were exposed to UVA, UVB, and visible radiation using a high pressure mercury UVA lamp, a fluorescent broadband UVB lamp, a tungsten bulb and a slide projector for visible radiation. Part of the radiation emitted by these lamps was water filtered to block infrared radiation above 1300 nm. All 20 patients developed lesions when exposed to different light sources used for phototest. When exposed to same sources without infrared radiation, 17 patients (85%) did not develop any lesions and the other three (15%) developed less severe lesions than in the area exposed to unfiltered light. Our results show that infrared radiation was necessary for the development of skin lesions in 85% of the patients with photodermatoses in our study. We believe that infrared radiation studies should be included in standard photobiology protocols. This article is protected by copyright. All rights reserved. PMID- 30447158 TI - INH14, a small-molecule urea derivative, inhibits the IKKalpha/beta-dependent TLR inflammatory response. AB - INH14 (N-(4-ethylphenyl)-N'-phenylurea) is a fragment-like compound that inhibits the Toll-like receptor 2 (TLR2)-mediated inflammatory activity and also other inflammatory pathways (i.e. TLR4, TNF-R and IL-1R). In this study, we determined the molecular target of INH14. Over-expression of proteins which are part of the TLR2 pathway in cells treated with INH14 indicated that the compound's target lies downstream of the complex TAK1/TAB1. Immunoblot assays showed that INH14 decreased IkBalpha degradation in cells activated by lipopeptide (TLR2 ligand). These data pointed to the kinases IKKalpha and/or IKKbeta as the targets of INH14, which was confirmed with kinase assays (IC50 IKKalpha= 8.97 uM; IC50 IKKbeta= 3.59 uM). Further, in vivo experiments showed that INH14 decreased the TNFalpha formed after lipopeptide-induced inflammation and treatment of ovarian cancer cells with INH14 led to a reduction of NF-kB constitutive activity and a reduction in the wound-closing ability of these cells. Our results demonstrate that INH14 decreases NF-kB activation via IKKs inhibition. Optimization of INH14 may lead to potent inhibitors of IKKs that may be used as anti-inflammatory drugs. PMID- 30447159 TI - Do elevated autoantibodies in patients with multiple sclerosis matter? AB - OBJECTIVES: The incidence and clinical impact of serum autoantibodies in patients with multiple sclerosis (MS) are controversially discussed. The aim of the study was to reassess the value of elevated serum autoantibodies in our MS study cohort. MATERIAL & METHODS: In total, 176 MS patients were retrospectively analyzed for coexistence and clinical impact of increased serum autoantibody levels. RESULTS: The 18.8% of the MS cohort showed elevated serum autoantibody levels, but only 10.2% of all MS patients were diagnosed with a further autoimmune disease (AI). Patients with elevated serum autoantibodies (AABS) were not significantly more often diagnosed with a clinical manifest AI as compared to patients with negative autoantibodies (P = 0.338). MS patients with disease duration of more than 10 years showed no significant increase of positive autoantibodies as compared to patients with a more recent disease onset (P = 1). MS patients with elevated serum autoantibodies did not exhibit a significantly worse disease course (P = 0.428). CONCLUSIONS: According to our data, elevated serum autoantibodies do not have the potential to serve as a prognostic tool for disease severity in patients with MS Since MS patients with positive serum AABS did not significantly more often suffer from clinical manifest AIs than MS patients with negative serum AABS, the role of routine testing of serum AABS in MS patients should be critically called into question. PMID- 30447160 TI - Using readability software to enhance the health literacy of equine veterinary clients: An analysis of 17 Association of American Equine Practitioners' Newsletter and Website Articles. AB - BACKGROUND: Veterinarians often provide supplemental healthcare information to horse owners via newsletters and website articles. However, articles written above the reading level of the intended audience contributes to misunderstanding. To ensure that the text in equine healthcare articles and brochures is consistent with the literacy of clients, veterinarians can adopt guidelines set forth by the National Institutes of Health (NIH) and the American Medical Association (AMA) for a target 6th grade readability level. OBJECTIVES: The goal of this study was to evaluate the readability levels of a sample of American Association of Equine Practitioners' (AAEP) Newsletter and Website Articles prepared expressly for veterinarians to download and share with their clients. Examples from these handouts are used to illustrate principles and techniques veterinary professionals can use to align their writing with the literacy of their intended audience. STUDY DESIGN: Software-based readability analysis of 17 AAEP Newsletter and Website Articles. METHODS: A free online readability calculator was used to generate a consensus grade level readability score for 17 downloadable AAEP Veterinary Newsletter and Website Articles. RESULTS: Sixteen of 17 articles were written above the recommended 6th grade reading level. MAIN LIMITATIONS: We propose that a 6th grade readability level, as set forth by the AMA, is a reasonable target for the diverse population that makes up veterinary clients; however, there is currently no research that establishes this target for veterinary clients and the American Veterinary Medical Association (AVMA) has yet to issue a consensus statement on the subject. CONCLUSIONS: Awareness of the issue of client literacy and use of tools such as readability analysis software can help veterinarians provide clients with "easy to read" written materials that deliver a message that clients can comprehend, thus improving their health literacy and empowering them as partners in the veterinary-client relationship. This article is protected by copyright. All rights reserved. PMID- 30447162 TI - Early sensitivity of evoked potentials to surface and volumetric structure during the visual perception of three-dimensional object shape. AB - This study used event-related potentials (ERPs) to elucidate how the human visual system processes three-dimensional (3D) object shape structure. In particular, we examined whether the perceptual mechanisms that support the analysis of 3D shape are differentially sensitive to higher-order surface and volumetric part structure. Observers performed a whole-part novel object matching task in which part stimuli comprised sub-regions of closed edge contour, surfaces or volumetric parts. Behavioural response latency data showed an advantage in matching surfaces and volumetric parts to whole objects over contours, but no difference between surfaces and volumes. ERPs were analysed using a convergence of approaches based on stimulus dependent amplitude modulations of evoked potentials, topographic segmentation and spatial frequency oscillations. The results showed early differential perceptual processing of contours, surfaces and volumetric part stimuli. This was first reliably observed over occipitoparietal electrodes during the N1 (140-200ms) with a mean peak latency of 170ms, and continued on subsequent P2 (220-260ms) and N2 (260-320ms) components. This differential sensitivity in perceptual processing during the N1 was accompanied by distinct microstate patterns that distinguished among contours, surfaces and volumes, and predominant theta band activity around 4-7Hz over right occipitoparietal and orbitofrontal sites. These results provide the first evidence of early differential perceptual processing of higher-order surface and volumetric shape structure within the first 200ms of stimulus processing. The findings challenge theoretical models of object recognition that do not attribute functional significance to surface and volumetric object structure during visual perception. This article is protected by copyright. All rights reserved. PMID- 30447161 TI - Characterization of kinetics of human cytochrome P450s involved in bioactivation of flucloxacillin: inhibition of CYP3A-catalyzed hydroxylation by sulfaphenazole. AB - BACKGROUND AND PURPOSE: The aim of this study was to characterize the human cytochrome P450s (CYPs) involved in oxidative bioactivation of flucloxacillin to 5-hydroxymethylflucloxacillin, a metabolite with high cytotoxicity toward biliary epithelial cells. EXPERIMENTAL APPROACH: The CYPs involved in hydroxylation of flucloxacillin were characterized using recombinant human CYPs, pooled liver microsomes in presences of CYP-specific inhibitors, and by correlation analysis using a panel of liver microsomes from 16 donors. KEY RESULTS: Recombinant CYPs showing the highest specific activity were CYP3A4, CYP3A7 and to lower extent CYP2C9 and CYP2C8. Michaelis Menten enzyme kinetics were determined for pooled HLM, recombinant CYP3A4, CYP3A7 and CYP2C9. Remarkably, sulfaphenazole appeared a potent inhibitor of 5'-hydroxylation of FLX by both recombinant CYP3A4 and CYP3A7. CONCLUSIONS AND IMPLICATIONS: The combined results show that the 5' hydroxylation of FLX is primarily catalysed by CYP3A4, CYP3A7 and CYP2C9. The large variability of the hepatic expression of these enzymes could affect the formation of 5'-hydroxymethylfucloxacillin, which may determine the differences in susceptibility to flucloxacillin-induced liver injury. Additionally, the strong inhibition in CYP3A-catalyzed flucloxacillin metabolism by sulfaphenazole suggest that unanticipated drug-drug interactions could occur with coadministered drugs. PMID- 30447163 TI - The biotroph Agrobacterium tumefaciens thrives in tumors by exploiting a wide spectrum of plant host metabolites. AB - Agrobacterium tumefaciens is a niche-constructing biotroph that exploits host plant metabolites. We combined metabolomics, transposon-sequencing (Tn-seq), transcriptomics and reverse genetics to characterize A. tumefaciens pathways involved in the exploitation of resources from the Solanum lycopersicum host plant. Metabolomics of healthy stems and plant tumors revealed the common (e.g., sucrose, glutamate) and enriched (e.g., opines, GABA, GHB, pyruvate) metabolites that A. tumefaciens could use as nutrients. Transposon-sequencing and transcriptomics pinpointed the genes that are crucial and/or up-regulated when the pathogen grew on either sucrose (pgi, kdgA, pycA, cisY) or GHB (blcAB, pckA, eno, gpsA) as a carbon source. While sucrose assimilation involved the Entner Doudoroff and tricarboxylic acid (TCA) pathways, GHB degradation required the blc genes, tricarboxylic acid cycle and gluconeogenesis. The tumor-enriched metabolite pyruvate is at the node connecting these pathways. Using reverse genetics, we showed that the blc, pckA and pycA loci were important for aggressiveness (tumor weight), proliferation (bacterial charge) and/or fitness (competition between the constructed mutants and wild-type) of A. tumefaciens in plant tumors. This work highlighted how a biotroph mobilizes its central metabolism for exploiting a wide diversity of resources in plant host. It further shows the complementarity of functional genome-wide scans by transcriptomics and transposon-sequencing to decipher the lifestyle of a plant pathogen. This article is protected by copyright. All rights reserved. PMID- 30447165 TI - Effect of oral hygiene programmes on oral opportunistic pathogens during stroke rehabilitation. AB - OBJECTIVES: This study was to assess the effectiveness of a conventional oral hygiene care programme (COHCP) and an advanced oral hygiene care programme (AOHCP) on prevalence and viable counts of oral opportunistic pathogens among patients undergoing stroke rehabilitation. METHODS: A total of 94 patients were randomized to two groups. Subjects were block randomized to: either (1) COHCP: manual toothbrushing with oral hygiene instruction (OHI); or (2) AOHCP: powered toothbrushing, mouthrinsing with chlorhexidine and OHI. Prevalence and viable counts of oral opportunistic pathogens including yeasts, aerobic and facultative anaerobic gram-negative bacilli, Staphylococcus aureus, were assessed at baseline, the end of three months, and six months. RESULTS: No significant difference was observed in the prevalence of oral opportunistic pathogens within each group over the clinical trial period. A significant decrease in the viable counts of S. aureus was found over the clinical trial period within AOHCP group (p<0.05), while the viable counts of yeasts and AGNB remained stable within each group. Regression analysis failed to detect an association between intervention and the prevalence/viable counts of oral opportunistic pathogens. CONCLUSIONS: Neither oral health care programme significantly affect AGNB, yeast or S. aureus over the study period in terms of prevalence and viable counts. This article is protected by copyright. All rights reserved. PMID- 30447164 TI - Disentangling the heterogeneity of allergic respiratory diseases by latent class analysis reveals novel phenotypes. AB - BACKGROUND: Refined phenotyping of allergic diseases may unravel novel phenotypes. Conjunctivitis as an independent disorder has never been approached. AIM: To identify distinct classes of allergic respiratory diseases using latent class analysis (LCA) and distinguish each class using classification and regression tree (CART) analysis. METHODS: Seven hundred and twenty-eight adults from the Portuguese general population study ICAR had a structured medical interview combined with blood collection, skin prick tests, spirometry with bronchodilation, and exhaled nitric oxide. LCA was applied to 19 variables. The CART algorithm selected the most likely variables distinguishing LCA-classes. RESULTS: A six-class model was obtained. Class 1 (25%): nonallergic participants without bronchial or ocular symptoms. Classes 2 (22%) and 3 (11%): nasal and ocular (low levels) symptoms without nasal impairment, monosensitized (Class 2) or polysensitized (Class 3). Class 4 (13%): polysensitized participants with high levels of nasal and ocular symptoms, and nasal impairment. Classes 5 (16%) and 6 (14%): high level of nasal, bronchial and ocular symptoms with nasal impairment (non-allergic or polysensitized, respectively). Participants in classes 5 and 6 had more bronchial exacerbations and unscheduled medical visits (P < 0.001). Ocular symptoms were significantly higher in classes with nasal impairment, compared to those without impairment (P < 0.001) or no nasal symptom (P < 0.001). CART highlighted ocular symptoms as the most relevant variable in distinguishing LCA-classes. CONCLUSION: Novel severe phenotypes of participants with co occurrence of ocular, nasal and bronchial symptoms, and exacerbation-prone were identified. The tree algorithm showed the importance of the ocular symptoms in the expression of allergic diseases phenotypes. PMID- 30447166 TI - Menopause is associated with decreased postprandial ghrelin, while a history of anorexia nervosa is associated with increased total ghrelin. AB - INTRODUCTION: Middle age has been linked with various dysfunctional eating patterns in women. The hormone ghrelin is related to food intake, with plasma levels rising before eating and decreasing immediately afterwards. Animal research has shown that estradiol is an antagonist of ghrelin. Given that both menopause and anorexia nervosa (AN) are states characterised by reduced estradiol, the goal of the present study was to investigate for the first time whether menopausal status and a history of AN are linked with altered ghrelin levels in middle-aged women. Based on previous research, we hypothesised that a) post-menopausal women would demonstrate comparably increased ghrelin after food intake and b) women with a history of AN would exhibit increased total ghrelin levels. METHODS: Healthy, middle-aged women (N=57) were recruited. N=31 were post menopausal and n=27 had a history of AN. Plasma was repeatedly collected before and after a meal standardised in terms of caloric content. Areas under the curves were calculated to indicate total (AUCg) and postprandial ghrelin (AUCi). RESULTS: Menopausal status was linked with postprandial ghrelin (AUCi -1.6+/-2.2 vs. -2.9+/-2.6; p=.058), while a history of AN was linked with total ghrelin (AUCg 36.2+/-5.6 vs. 39.0+/-3.7; p=.050). There were no interaction effects (both p>.466). A closer examination of the effects revealed that post-menopausal women showed marginally greater decreases in ghrelin immediately after food intake (p=.064) and marginally greater re-increases after 60 min (p=.084) when compared to pre-menopausal women. Women with a history of AN had significantly higher total ghrelin when compared to women without a history of AN (p=.042). DISCUSSION: Post-menopause was linked with higher sensitivity of ghrelin to food intake (trend), while a history of AN was related to greater total ghrelin. Future research should investigate to what extent the observed alterations in ghrelin may affect dysfunctional eating behaviour during middle age. This article is protected by copyright. All rights reserved. PMID- 30447167 TI - A Study of the dosage and duration for levobupivacaine infusion by the caudal epidural route in infants aged 3-6 months. AB - AIM: To investigate total serum levobupivacaine concentrations after a caudal epidural loading dose followed by a maintenance infusion in infants aged 3-6 months over 48 hours. BACKGROUND: The local anaesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokinetic modelling with racemic bupivacaine. This study will inform clinical practice in this age group and validate the pharmacokinetic model for levobupivacaine infusions in infants, aged 3-6months. METHODS: The clinical trial was conducted in 8 infants aged 3-6 months, undergoing bladder exstrophy repair. Pharmacokinetic modelling allowed optimisation of clinical sampling to measure total levobupivacaine and alpha1 acid glycoprotein and prediction of the effect of alpha1 -acid glycoprotein on levobupivacaine plasma protein binding. RESULTS: The observed median total levobupivacaine serum concentration was 0.30 mg.L-1 (range: 0.20-0.70 mg.L-1 ) at 1 hour after the loading dose of 2 mg.kg-1 . The median total levobupivacaine concentration after 47 hours of infusion, at 0.2 mg.h-1 .kg-1 , was 1.21 mg.L-1 (0.07-1.85 mg.L-1 ). Concentrations of alpha1 -acid glycoprotein were found to rise throughout the study period. Pharmacokinetic modelling suggested that unbound levobupivacaine quickly reached steady state at a concentration of approximately 0.03 mg.L-1 . CONCLUSION: This study examines the pharmacokinetics of levobupivacaine after a loading dose (given over 5 minutes) followed by a maintenance infusion in infants 3-6 months. The study allows the development of a pharmacokinetic model, combining levobupivacaine and alpha1 -acid glycoprotein data. Modelling indicates that unbound levobupivacaine quickly reaches steady state once the infusion is started. Simulations suggest that it may be possible to continue the infusion beyond 48 hours. This article is protected by copyright. All rights reserved. PMID- 30447168 TI - Ethanol upregulates the P2X7 purinergic receptor in human macrophages. AB - Alcohol consumption is considered to be the third leading cause of death in the United States. In addition to its direct toxicity, ethanol has two contrasting effects on the immune system: the nucleotide oligomerization domain-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is inhibited by acute ethanol exposure but activated by chronic ethanol exposure. Purinergic receptors (especially the P2X7 receptor) are able to activate the NLRP3 inflammasome and are involved in many ethanol-related diseases (such as gout, pulmonary fibrosis, alcoholic steatohepatitis, and certain cancers). We hypothesized that ethanol regulates purinergic receptors and thus modulates the NLRP3 inflammasome's activity. In experiments with monocyte-derived macrophages, we found that interleukin (IL)-1beta secretion was inhibited after 7 h of exposure (but not 48 h of exposure) to ethanol. The disappearance of ethanol's inhibitory effect on IL 1beta secretion after 48 h was not mediated by the upregulated production of IL 1beta, IL-1alpha, IL-6 or the inflammasome components NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, and caspase 1. P2X7R expression was upregulated by ethanol, whereas expression of the P2X4 and P2X1 receptors was not. Taken as a whole, our results suggest that ethanol induces NLRP3 inflammasome activation by upregulating the P2X7 receptor. This observation might have revealed a new mechanism for inflammation in ethanol-related diseases. PMID- 30447169 TI - Predictive Factors for Adverse Outcomes in Pediatric Patients Undergoing Low Risk Skin and Soft Tissue Surgery: A Database Analysis of 6,730 Patients. AB - BACKGROUND: There is a paucity of data regarding risk stratification of pediatric patients presenting for low-risk skin and soft tissue surgery. AIM: We sought to determine the incidence and independent predictors of postoperative complications and unplanned 30-day readmission in a cohort of children undergoing low-risk skin and soft tissue surgery. METHODS: The study included pediatric patients who underwent minor procedures of the skin and soft tissue at continuously enrolled American College of Surgeons National Surgical Quality Improvement Program Pediatric hospitals over a two-year period. The primary outcome was a 30-day postoperative complication composite. The secondary outcome was unplanned 30-day readmission. RESULTS: The final analysis included 6,730 patients. There were a total of 170 postoperative complications among 152 patients (2.23%) with the majority of complications being either wound-related or postoperative mechanical ventilation. The independent predictors for an increased risk of postoperative complication were American Society of Anesthesiologists classification >= 3 and nutritional deficiency. There were 41 unplanned readmissions (0.61%). The presence of a postoperative wound complication or a postoperative pulmonary complication during the index hospital stay was an independent risk factor for unplanned 30-day readmission. CONCLUSIONS: Pediatric patients with American Society of Anesthesiologists classification >= 3 and nutritional deficiency undergoing low-risk surgery are at risk for the development of postoperative complications. Patients who develop wound and postoperative pulmonary complications are at higher risk for unplanned 30-day readmission. Identification of these higher risk patients may allow the anesthesiologist to implement targeted therapies to minimize the likelihood of occurrence of these complications. This article is protected by copyright. All rights reserved. PMID- 30447170 TI - Experiences of patients with colorectal cancer from diagnosis until completion of treatment: a meta-ethnography approach. AB - OBJECTIVE: The purpose of this meta-synthesis was to explore the experience of living with symptoms caused by colorectal cancer (CRC) and its treatment from the perspectives of those affected. METHODS: In a systematic search of qualitative studies published up to September 2017, seventeen relevant papers were identified. The meta-ethnography followed the approach developed by Noblit and Hare. To relate key themes from one paper to similar themes of different papers, a 'reciprocal translation' was carried out. RESULTS: Through synthesis, a new model was developed during treatment ('lines-of-argument synthesis'). Two constructs of experiences took place before the illness. Six third-order constructs were developed to capture patients' experiences during treatment, including 'Disruption in life through CRC' as well as the complex and circular experiences summarized as 'Experiences of symptoms and challenges by CRC'. In contrast, experiences in dealing with changes that CRC and the treatment imply, were: 'Making sense of the experience', 'Sharing the experience', 'Experiences with controlling ones' body' and 'Experiences with reforming life'. CONCLUSIONS: This meta-ethnography clarifies fundamental aspects of patients' experience in very different settings or starting points by specifying a more complete and holistic spectrum of experiences with CRC and its treatment. PMID- 30447171 TI - Nonrandom RNAseq gene expression associated with RNAlater and flash freezing storage methods. AB - RNA-sequencing is a popular next-generation sequencing technique for assaying genome-wide gene expression profiles. Nonetheless, it is susceptible to biases that are introduced by sample handling prior gene expression measurements. Two of the most common methods for preserving samples in both field-based and laboratory conditions are submersion in RNAlater and flash freezing in liquid nitrogen. Flash freezing in liquid nitrogen can be impractical, particularly for field collections. RNAlater is a solution for stabilizing tissue for longer-term storage as it rapidly permeates tissue to protect cellular RNA. In this study, we assessed genome-wide expression patterns in 30 day old fry collected from the same brood at the same time point that were flash-frozen in liquid nitrogen and stored at -80 degrees C or submerged and stored in RNAlater at room temperature, simulating conditions of fieldwork. We show that sample storage is a significant factor influencing observed differential gene expression. In particular, genes with elevated GC content exhibit higher observed expression levels in liquid nitrogen flash-freezing relative to RNAlater-storage. Further, genes with higher expression in RNAlater relative to liquid nitrogen experience disproportionate enrichment for functional categories, many of which are involved in RNA processing. This suggests that RNAlater may elicit a physiological response that has the potential to bias biological interpretations of expression studies. The biases introduced to observed gene expression arising from mimicking many field based studies are substantial and should not be ignored. This article is protected by copyright. All rights reserved. PMID- 30447172 TI - Prevalence and normative values for Jaw Functional Limitations in the general population in Sweden. AB - OBJECTIVES: For Jaw Functional Limitations measured by the Jaw Functional Limitation Scale (JFLS), (i) determining prevalence in the Swedish general adult population, (ii) investigating the influence of demographic factors and self reported dental status, and (iii) deriving normative values. METHODS: A random sample of the general adult population in Sweden was approached (response rate: 46%, N=1,372). Prevalence was determined for the JFLS summary score and individual items. The influence of age, gender, and dental status was investigated with regression analyses and normative values presented. RESULTS: The JFLS median score was 0 and all items had prevalences <30%. Age and gender did not influence Jaw Functional Limitations but dental status did. Normative JFLS scores were 1, 9 and 28 for the 7th , 8th , and 9th decile, respectively. In dental status-stratified norms, 9th deciles were 20, 43, and 100, for subjects with natural teeth only, removable and complete dentures, respectively. CONCLUSIONS: The Swedish general adult population had excellent jaw function, but dental status was major determinant. In the absence of information linking JFLS scores to important patient concerns, the score distribution can serve as a reference with the 9th decile as threshold for functional limitation. This article is protected by copyright. All rights reserved. PMID- 30447173 TI - Albumin: The Cons. AB - Intravenous albumin infusions have long been considered an important option in the treatment of patients with cirrhosis and ascites1 . Many studies have shown that 20% Human Albumin Solution (HAS) improves circulatory function2 and it is therefore recommended in international guidelines worldwide for use in hepatorenal syndrome (HRS), spontaneous bacterial peritonitis (SBP), as well as in preventing post paracentesis circulatory dysfunction following large volume paracentesis (LVP)3, 4 . Albumin has also been reported to have beneficial immunomodulatory and endothelial effects and therefore may have a particular beneficial role in sepsis5, 6 . This article is protected by copyright. All rights reserved. PMID- 30447174 TI - The role of sleep quality and fatigue on the benefits of an interdisciplinary treatment for adults with chronic pain. AB - BACKGROUND: Interdisciplinary chronic pain treatment is effective for reducing pain intensity and pain-related disability, and improving psychological function. However, the mechanisms that underlie these treatment-related benefits are not yet well-understood. Sleep problems and fatigue are modifiable factors often comorbid with chronic pain. The goal of this study was to evaluate the role that changes in sleep quality and fatigue might have on the benefits of an interdisciplinary chronic pain treatment. METHODS: A total of 125 adults with chronic pain participated in a four-week interdisciplinary pain management program. Measures of depression, sleep disturbance, fatigue, pain intensity, and physical function were administered at pre- and post-treatment. Three regression analyses were conducted to evaluate the contribution of pre- to post-treatment improvements in fatigue and sleep disturbance to the pre- to post-treatment improvements in pain intensity, disability, and depression, while controlling for demographic characteristics (age and sex) and pain intensity. RESULTS: Changes in fatigue and sleep disturbance, made independent and significant contributions to the prediction of treatment-related benefits in pain intensity; improvements in depressive symptoms were predicted by improvements in fatigue, and improvements in disability were only predicted by pre-treatment and pre- to post-treatment decreases in pain intensity (one of the control variables). CONCLUSIONS: In addition to sleep, fatigue emerged as a key potential mechanism of multidisciplinary chronic pain treatment-related improvements, suggesting that interventions including elements which effectively target sleep and fatigue may enhance the efficacy of interdisciplinary chronic pain programs. This possibility should be evaluated in future research. This article is protected by copyright. All rights reserved. PMID- 30447175 TI - Effect of Toxic Metal Ions on Photosensitized Singlet Oxygen Generation for Photodegradation of Polyaromatic Hydrocarbon Derivatives and Inactivation of Escherichia coli. AB - Here, we report an experimental study of the effect of toxic metal ions on photosensitized singlet oxygen generation for photodegradation of PAH derivatives, Anthracene-9,10-dipropionic acid disodium salt (ADPA) and 1,5 dihydroxynapthalene (DHN) and photoinactivation of Escherichia coli bacteria by using cationic meso-tetra(N-methyl-4-pyridyl)porphine tetrachloride (TMPyP) as a singlet oxygen photosensitizer. Three s-block metals ions, such as Na+ , K+ and Ca2+ and five toxic metals such as Cd2+ , Cu2+ , Hg2+ , Zn2+ and Pb2+ were studied. The s-block metal ions showed no change in the rate of photodegradation of ADPA or DHN by TMPyP, whereas a dramatic change in the photodegradation of ADPA and DHN was observed in the presence of toxic metals. The maximum photodegradation rate constants of ADPA and DHN were observed for Cd2+ ions [(3.91 +/- 0.20) * 10-3 s-1 and (7.18 +/- 0.35) * 10-4 s-1 , respectively]. Strikingly, the photodegradation of ADPA and DHN was almost completely inhibited in the presence of Hg2+ ions and Cu2+ ions. A complete inhibition of growth of E. coli was observed upon visible light irradiation of E. coli solutions with TMPyP and toxic metal ions particularly, Cd2+ , Hg2+ , Zn2+ and Pb2+ ions, except for Cu2+ ions where a significantly slow inhibition of E. coli's growth was observed. PMID- 30447176 TI - Detection of Francisella tularensis in three vole species in Central Europe. AB - Francisella tularensis is a zoonotic, gram-negative bacterium that causes tularemia in humans. Depending on its subspecies and the route of transmission, mild to lethal courses have been reported. F. tularensis subsp. holarctica is the only subspecies found in Europe and affects a plenitude of vertebrates including lagomorphs and rodents. Population outbreaks of certain rodent species are likely to be involved in the transmission of this pathogen. This molecular survey aims to evaluate the presence of F. tularensis in small mammals from three Central European countries. Using a real-time polymerase chain reaction, F. tularensis DNA was detected in common voles (Microtus arvalis) from Switzerland and in field voles (Microtus agrestis) and a bank vole (Myodes glareolus) from Germany, but not in any other small mammal species. All common voles from the Czech Republic were negative for F. tularensis DNA. The prevalence in the three vole species varied between 1.3% and 3.0%. In conclusion, Francisella tularensis DNA was detected in three vole species in two of three countries investigated. The observed low prevalence raises questions on the role of voles for the transmission of Francisella tularensis in Central Europe. This article is protected by copyright. All rights reserved. PMID- 30447177 TI - Increased temperatures may safeguard the nutritional quality of crops under future elevated CO2 concentrations. AB - Iron (Fe) and zinc (Zn) deficiencies are a global human health problem that may worsen by growth of crops at elevated atmospheric CO2 concentration (eCO2 ). However, climate change will also involve higher temperature, but it is unclear how the combined effect of eCO2 and higher temperature will affect the nutritional quality of food crops. To begin to address this question, we grew soybean (Glycine max) in a Temperature by Free-Air CO2 Enrichment (T-FACE) experiment in 2014 and 2015 under ambient (400 MUmol mol-1 ) and elevated (600 MUmol mol-1 ) CO2 concentrations and under ambient and elevated temperatures (+2.7 degrees C day and +3.4 degrees C at night). In our study, eCO2 significantly decreased Fe concentration in soybean seeds in both seasons (-8.7% and -7.7%) and Zn concentration in one season (-8.9%) while higher temperature (at ambient CO2 concentration) had the opposite effect. The combination of eCO2 with elevated temperature generally restored seed Fe and Zn concentrations to levels obtained under ambient CO2 and temperature conditions, suggesting that the potential threat to human nutrition by increasing CO2 concentration may not be realized. In general, seed Fe concentration was negatively correlated with yield suggesting inherent limitations to increasing seed Fe. In addition, we confirm our previous report that the concentration of seed storage products and several minerals varies with node position at which the seeds developed. Overall, these results demonstrate the complexity of predicting climate change effects on food and nutritional security when various environmental parameters change in an interactive manner. This article is protected by copyright. All rights reserved. PMID- 30447178 TI - Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature. PMID- 30447179 TI - Transmission electron microscopy revealing the mechanism of action of photodynamic therapy on Trichomonas vaginalis. AB - Trichomonas vaginalis is an amitochondrial parasite that causes human trichomoniasis. Despite metronidazole effectiveness, resistant cases are becoming more frequent. This scenario reveals the need to develop new therapeutic options. Photodynamic Therapy (PDT) is an experimental treatment that involves the activation of photosensitive substances and the generation of cytotoxic oxygen species and free radicals to promote the selective destruction of target tissues. In previous work, we identified an excellent in vitro PDT activity using methylene blue and light emitting diode against metronidazole sensitive and resistant strains of T. vaginalis. Here, we evaluated the efficacy of PDT in vivo and its high trichomonicidal activity was assessed through transmission electron microscopy. Female Balb/c mice were infected intravaginally with T. vaginalis trophozoites. On the third day of infection, methylene blue was introduced into the vaginal canal, which then received 68.1 J/cm2 of radiation for 35.6 s. Twenty four hours after treatment the vaginal canal of the animals was scraped and the samples processed by the immunocytochemistry technique. Besides that, in vitro photodynamic treatment was performed and T. vaginalis trophozoites were processed by transmission electron microscopy. PDT significantly reduced infection in animals treated, compared to control groups, being as efficient as metronidazole. Morphological changes observed have suggested that PDT activity on T. vaginalis was due to necrosis. These results, added to the high trichomonicidal activity of PDT confirm its feasibility for trichomoniasis treatment. PMID- 30447180 TI - Characterization of ADP-ribosyl cyclase 1-like (ARC1-like) activity and NAADP signaling during slow muscle cell development in zebrafish embryos. AB - We recently demonstrated the requirement of two-pore channel type 2 (TPC2) mediated Ca2+ release during slow muscle cell differentiation and motor circuit maturation in intact zebrafish embryos. However, the upstream trigger(s) of TPC2/Ca2+ signaling during these developmental processes remains unclear. Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+ mobilizing messenger, which is suggested to target TPC2 in mediating the release of Ca2+ from acidic vesicles. Here, we report the molecular cloning of the zebrafish ADP ribosyl cyclase (ARC) homolog (i.e., ARC1-like), which is a putative enzyme for generating NAADP. We characterized the expression of the arc1-like transcript and the NAADP levels between ~ 16 h post-fertilization (hpf) and ~ 48 hpf in whole zebrafish embryos. We showed that if ARC1-like (when fused with either EGFP or tdTomato) was overexpressed it localized in the plasma membrane, and associated with intracellular organelles, such as the acidic vesicles, Golgi complex and sarcoplasmic reticulum, in primary muscle cell cultures. Morpholino (MO)-mediated knockdown of arc1-like or pharmacological inhibition of ARC1-like (via treatment with nicotinamide), led to an attenuation of Ca2+ signaling and disruption of slow muscle cell development. In addition, the injection of arc1-like mRNA into ARC1-like morphants partially rescued the Ca2+ signals and slow muscle cell development. Together, our data might suggest a link between ARC1-like, NAADP, TPC2 and Ca2+ signaling during zebrafish myogenesis. PMID- 30447181 TI - Tocolytic activity of the Lippia alba essential oil and its major constituents, citral and limonene, on the isolated uterus of rats. AB - The species Lippia alba (Mill.) N. E. Brown belongs to the Verbenaceae family. It is abundant and grows spontaneously throughout the Brazilian territory. Popularly known as "erva-cidreira", it is widely used because of its sedative, carminative and analgesic properties. The objective of this study was to investigate the mechanism of action of the L. alba essential oil (EOLa) and its major constituents citral and limonene, on isolated rat uterus muscle. To evaluate the EOLa, citral and limonene effect, cumulative concentrations curves for EOLa and citral (1-600 MUg/mL) and for limonene (1-1200 MUg/mL) were constructed from contractions of rat uterine strips under a 1 g tension. EOLa, citral and limonene dose-dependently relaxed myometrial preparations pre-contracted with 60 mM KCl, 10-2 IU/mL oxytocin, serotonin (10 MUM), or ACh (10 MUM). The results demonstrate that the EOLa, citral and limonene cause relaxation of the uterine smooth muscle. These results suggest that the relaxation induced by EOLa, citral and limonene is caused by inhibition of L-type VOCC, inhibiting the Ca2+ current through these channels, although other mechanisms of action are likely to contributing to relaxant activity. There was no involvement of K+ channels (BKca, KATP, KV) or cyclooxygenase on the relaxation promoted by EOLa. Then studies of the tocolytic effects of EOLa, citral and limonene may yield new insights into their therapeutic use. PMID- 30447183 TI - Straightforward and rapid method for detection of cyclin-dependent kinase-like 5 activity. AB - Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase, with its gene mutation leading to a neurodevelopmental disorder. Pathogenic point mutations are mostly observed within the catalytic domain of CDKL5, therefore loss of catalytic activity may be related to disease onset. However, this hypothesis has rarely been demonstrated. Here, we report an efficient method for detecting CDKL5 activity. Appropriately, CDKL5 underwent autophosphorylation following expression in Escherichia coli, with autophosphorylated CDKL5 detected as a band shift by phos-tag SDS-PAGE, without enzyme purification. Thus, this protocol is useful for examining the relationship between disease-causing mutations and their activity. PMID- 30447182 TI - Time from venipuncture to cell isolation: Impact on granulocyte-reactive antibody testing. AB - BACKGROUND AND OBJECTIVES: Classical neutrophil-reactive antibody testing depends on the quick isolation of neutrophils from freshly taken whole blood. To allow a better logistic preparation before testing, the influence of time interval between venipuncture and cell isolation has been evaluated in this study. MATERIALS AND METHODS: Neutrophils and whole leukocytes were isolated from EDTA whole blood immediately (T0) as well as 4, 8 and 24 h after blood donation (T4, T8 and T24). These cells were tested against reference sera containing antibodies against HNA-1b, -2, -3a and HLA class I using granulocyte aggregation test (GAT), microscopic granulocyte immunofluorescence test (GIFT) and flow-cytometric white blood cell immunofluorescence test (Flow-GIFT/WIFT). RESULTS: GAT was the most error-prone test displaying overall weaker aggregation strengths already at T4 (overall accuracy OA = 0.72, kappa = 0.58). GIFT results showed good agreement at T4 (OA = 0.86, kappa = 0.79) and remained stable until T8, while test results were slightly impaired at T24 (OA = 0.71, kappa = 0.55). Flow-GIFT/WIFT was identified as the most robust screening method, remaining stable even at T24. Calculated ratios (sample/negative control) decreased non-significantly and remained highly above the cut-off in all samples. CONCLUSION: Acceptable time limits for cell isolation are different for each screening method investigated. For GAT, cell isolation should be performed within 4 h, while GIFT tolerates a neutrophil isolation delay of 8 h. Flow-GIFT/WIFT isolation can be performed even after 24 h without impairment of the results. Using the latter test as a stand alone pre-screening test, whole blood can be used from donors who are not directly accessible. PMID- 30447184 TI - Cation-dependent changes in the thylakoid membrane appression of the diatom Thalassiosira pseudonana. AB - Diatoms show a special organisation of their plastid membranes, such that their thylakoids span the entire plastid in bands of three. While in higher plants the interaction of the light harvesting complex II and photosystem II with divalent cations (especially Mg2+) was found to take part in the interplay of electrostatic attraction and repulsion in grana membrane appression, for diatoms the key players in maintaining proper membrane distances were not identified so far. In this work, we investigated the changes in the thylakoid architecture of Thalassiosira pseudonana in reaction to different salts by using circular dichroism and fluorescence spectroscopy in combination with other techniques. We show that divalent cations have an important influence on optimal pigment organisation and thus also on maintaining membrane appression. Thereby, monovalent cations are far less effective. The concentration needed is in a physiological range and fits well with the values obtained for higher plant grana stacking, despite the fact that strict protein segregation as seen in higher plant grana is missing. PMID- 30447185 TI - Hyperglycemia abolished Drp-1-mediated mitophagy at the early stage of cerebral ischemia. AB - Exposure to hyperglycemia after cerebral ischemia exacerbates cerebral damage; however, little is known regarding the mechanism. In this study, we focused on the relationship between post-ischemic hyperglycemia and mitochondrial homeostasis at the early stage of ischemia (within the 6 h clinical therapeutic window for thrombolysis). Permanent cerebral ischemia was induced by middle cerebral artery occlusion (pMCAO) for 1, 3, and 6 h. We first elucidated the role of post-ischemic hyperglycemia on mitochondria-mediated injury by testing reactive oxygen species generation, cyt-c release, and caspase-3 activation. Next, we analyzed mitochondrial homeostasis by testing the protein levels related to fission, fusion, biogenesis and elimination. The results showed that hyperglycemia further augmented the mitochondria-mediated injury induced by pMCAO. No significant differences of Fis1, Opa1 and Mfn2 were observed at each time point. There is no significant influence on these three proteins after hyperglycemia in rats of the experimental group compared to their counterparts in the control group. The translocation of the fission protein Drp1 to the mitochondrial outer-membrane increased at 1 h after pMCAO and later steadily decreased over time in normal animals. However, hyperglycemia inhibited both the levels of Drp1 in the cytoplasm and mitochondria. Moreover, hyperglycemia inhibited mitophagy induced by pMCAO at 1 h, although the overall autophagy was increased. In conclusion, pMCAO transiently induced the mitochondrial fission and their elimination by mitophagy. However, hyperglycemia abolished this adaptation reaction of the mitochondria and thus resulted in the accumulation of damaged mitochondria and subsequent damage. Our findings help to refine our understanding of the role of post-ischemic hyperglycemia in brain ischemic injury. PMID- 30447186 TI - Effect of Corticotropin-Releasing Hormone Receptor1 Gene Variation on Psychosocial Stress Reaction via the Dorsal Anterior Cingulate Cortex in Healthy Adults. AB - OBJECTIVE: It has been proposed that the common intronic CRHR1 SNP rs110402 is associated with anxiety and cortisol response patterns and plays a key role in vulnerability to certain mental disorders. The current study explored the effect of rs110402 genotype on psychological stress processing in healthy adults. METHODS: The Montreal Imaging Stress Task (MIST) was administered to 140 healthy adults (34 C carriers and 106 TT homozygotes) during functional magnetic resonance imaging. Between-group differences in self-reported stress level, whole brain activation, and cortisol levels were assessed. RESULTS: The rs110402 genotype groups differed in stress-induced cortisol response and bilateral dorsal anterior cingulate cortex (dACC) activity. The TT homozygotes showed greater stress-induced activation in the bilateral dACC compared to C carriers. Interestingly, dACC activity during MIST was negatively correlated with cortisol response in healthy adults. State anxiety, trait anxiety, and mental resilience did not differ between genotypes. CONCLUSIONS: CRHR1 SNP rs110402 genotype plays a role in psychosocial neural processing and cortisol response in healthy adults. The activity in dACC may mediate effect of rs110402 on psychosocial stress processing in the healthy population. Moreover, level of dACC activation may be associated with stress vulnerability. PMID- 30447187 TI - Uncommon cause of fever and embolism: Staphylococcus epidermidis infected myxoma. PMID- 30447188 TI - Pulmonary Arterial Bypass Surgery for Fibrosing Mediastinitis Causing Severe Pulmonary Hypertension. AB - In this case report, we present a patient with mediastinal fibrosis. The mass lesion was expanding from the mediastinum to the cervical region and surrounding the major vascular structures. The patient has symptomatic dyspnea at rest and pulmonary hypertension due to stenosis of the bilateral main pulmonary arteries (PA). To decrease pulmonary artery pressure (PAP) and improve blood flow to the lungs, grafting from the pulmonary trunk to the bilateral interlobar pulmonary arteries under cardiopulmonary bypass was performed. PMID- 30447189 TI - Recurrent Intracardiac Juvenile Xanthogranuloma in an Adult. PMID- 30447190 TI - Cannulation of the Femoral Arterial Bypass Cannula Allows Completion of TAVR in Unstable Patients. AB - When hemodynamic instability occurs during transcatheter aortic valve replacement peripheral cardiopulmonary bypass is required. The pigtail catheter, initially placed through the femoral artery to direct placement of the valve, is exchanged over a wire for an arterial bypass cannula. Other than time consuming arterial cut-down procedures in hypotensive patients, there are few techniques described to allow the operator to continue bypass and complete TAVR. We describe a method to re-introduce the pigtail catheter via puncturing the arterial bypass cannula. This allows us to support the patient, continue bypass, and successfully place the valve without aborting the procedure. PMID- 30447191 TI - Successful Cervical Esophageal Reconstruction Using Gastric Conduit without Gastroepiploic Artery. AB - The use of the stomach as an esophageal substitute after esophagectomy is the most commonly accepted as the standard. The colon and supercharged pedicled jejunum are acceptable options for esophageal reconstruction when the stomach is unavailable. We described a case of esophageal cancer with a history of right hemicolectomy scheduled Mckeown esophagogastrectomy. During celiac detection, gastroepiploic artery had been resected, and the jejunum had a relatively short mesentery. In such a dilemma, we used an unconventional gastric conduit with the right gastric artery as the sole blood supply to complete cervical reconstruction. PMID- 30447193 TI - Heparin Binding Protein in Adult Heart Surgery. AB - BACKGROUND: Heparin binding protein (HBP) is released from neutrophilic secretory vesicles upon neutrophil adhesion on the endothelium. HBP mediates capillary hyperpermeability experimentally. In sepsis, HBP predicts organ dysfunction. Cardiopulmonary bypass induces both neutrophil activation and hyperpermeability. We hypothesized that in cardiopulmonary bypass, HBP is released in the reperfused coronary circulation concomitantly with neutrophil adhesion. METHODS: In 30 patients undergoing aortic valve replacement, concomitant blood samples were drawn from the coronary sinus and arterial line before aortic crossclamping and 5 min after reperfusion to calculate transcoronary differences. Plasma HBP concentrations, neutrophil markers lactoferrin and myeloperoxidase, myocardial injury marker heart-type fatty acid binding protein (hFABP) and leukocyte differential counts were measured. RESULTS: Arterial HBP was 4.1 (3.6-5.3) ng/ml preoperatively and 150.0 (108.2-188.6) ng/ml after aortic declamping. HBP increased 39-fold, lactoferrin 16-fold and myeloperoxidase 4-fold during cardiopulmonary bypass. Before cardiopulmonary bypass, there were marginal transcoronary differences in HBP [1.4 (-0.4-3.6) ng/ml, p=0.001] and hFABP [0.4 ( 0.04-3.5) ng/ml, p=0.001] but not in the other parameters. During reperfusion, transcoronary HBP release [6.4 (1.8-13.7) ng/ml, p<0.001] was observed, concomitantly with transcoronary neutrophil sequestration [-0.14 (-0.28-0.01) x10^9/l, p=0.001] and transcoronary hFABP release [6.9 (3.0-25.8) ng/ml, p<0.001]. There were no transcoronary differences in lactoferrin or myeloperoxidase during reperfusion. CONCLUSIONS: CPB results in substantial increase in circulating HBP. HBP is also released from the reperfused coronary circulation, concomitantly with coronary neutrophil adhesion and myocardial injury. HBP may be one candidate for a humoral factor mediating capillary leak in cardiopulmonary bypass. PMID- 30447192 TI - Sarcopenia of the Psoas Muscles is Associated with Poor Outcomes Following Lung Transplantation. AB - BACKGROUND: Sarcopenia, a known component of frailty, defined by diminished cross sectional area of the psoas muscles, is associated with poor outcomes after a range of surgical procedures. However, little is known of the relationship between sarcopenia of the psoas muscles (SPM) and long-term mortality, decline in pulmonary function, and graft failure after lung transplantation. METHODS: We reviewed patients who underwent primary lung transplantation at our institution from 2011 to 2014. Cross-sectional areas of the psoas muscles at the L4 vertebral level were measured using preoperative computed tomography (CT). Gender-based cutoff values for sarcopenia were generated and validated. The primary outcomes were one-, two-, and three-year all-cause mortality, FEV1 values, and graft function. Adjusted logistic regression and survival analysis was used to analyze outcomes. RESULTS: 95 patients were included in this study. 39 (41.1%) patients were considered sarcopenic. SPM was significantly associated with short- and mid term mortality on multivariate analysis (1-year [OR: 8.7, p=0.017], 2-year [OR: 12.7, p<0.01], 3-year [OR: 13.4, p<0.01]). Survival analysis showed significantly decreased survival in sarcopenic patients at three-years (35.9% vs 76.8%, p<0.01). SPM is also associated with decreased FEV1 (Coeff: -17.3, p=0.03). Adjusted Cox analysis showed an increased hazard for all-cause mortality (HR: 5.8, p<0.01) and graft failure (HR: 14.7, p<0.01) in sarcopenic patients. CONCLUSIONS: This study demonstrates a significant association between SPM and mortality, pulmonary function, and graft failure in patients receiving a lung transplant. Determining SPM preoperatively may be a useful component of frailty assessment and a predictor of survival in this patient population. PMID- 30447194 TI - PORT in properly selected patients with completely resected NSCLC should not be quickly dismissed. PMID- 30447195 TI - Gait Impairments in Patients without Lower Limb Hypertonia Early after Stroke are Related to Weakness of Paretic Knee Flexors. AB - OBJECTIVE: To describe gait characteristics of patients without clinical evidence of lower limb hypertonia within 2 months of stroke and explore the relationship between gait and residual motor function. DESIGN: Cohort study. SETTING: Motion analysis laboratory in a tertiary-care free-standing rehabilitation hospital. PARTICIPANTS: Consecutive sample of 73 eligible inpatients (first-known stroke <2 months post-onset, walking independently, modified Ashworth score of 0 in the paretic lower limb) and 27 healthy controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Gait speed, stride/step length and cadence, stance time, single/double support time, and associated symmetry measures in patients at self selected normal speed and controls at very-slow speed (51.1+/-32.6 and 61.9+/ 21.8 cm/s, respectively, P=.115); Fugl-Meyer lower extremity motor score (FM-LE) and isometric knee flexion/extension strength in patients. RESULTS: Except the stride/step cadence, all temporospatial parameters significantly differed between the stroke and control participants. Furthermore, significantly greater asymmetries were found in the patients for the overall stance time, initial double-support and single-support times, and step cadence, reflecting smaller values in the paretic than non-paretic limb. Most temporospatial parameters moderately-to-strongly correlated with the gait speed (|r|: .72-.94, P<.0001), FM LE (|r|: .42-.62, P<=.0005), and paretic knee flexor strength (|r|: .47-.57, P<=.0004). CONCLUSIONS: Gait of patients without clinical evidence of lower limb hypertonia within 2 months of stroke is characterized by many temporospatial deviations and asymmetries. The self-selected normal gait speed, FM-LE, and paretic knee flexor strength can discriminate gait impairments in these patients shortly before inpatient discharge. It remains to be determined whether the observed relationships between paretic knee flexor strength and gait measures warrant the development of interventions for strengthening of the paretic knee flexors in order to improve gait early after stroke. PMID- 30447196 TI - Immediate effects of immersive biofeedback on gait in children with cerebral palsy. AB - OBJECTIVE: To investigate the immediate response to avatar-based biofeedback on three clinically important gait parameters; step length, knee extension and ankle power, in children with cerebral palsy (CP). DESIGN: Repeated measures design. SETTING: Rehabilitation clinic. PARTICIPANTS: Twenty-two children with spastic paresis (10y4m+/-3y1m), able to walk without assistive devices. INTERVENTION: Children walked on a treadmill with virtual reality environment. Following baseline gait analysis, they were challenged to improve aspects of gait. Children visualized themselves as an avatar, representing movement in real-time. They underwent a series of two-minute trials receiving avatar based biofeedback on step length, knee extension and ankle power. To investigate optimization of biofeedback visualization, additional trials in which knee extension was visualized as a simple bar with no avatar; and a further trial with avatar alone, and no specific biofeedback were carried out. MAIN OUTCOME MEASURES: Gait pattern, as measured by joint angles, powers and spatiotemporal parameters, were compared between baseline and biofeedback trials. RESULTS: Participants were able to adapt gait pattern with biofeedback, in an immediate response, reaching large increases in ankle power generation at push-off (37.7%) and clinically important improvements in knee extension (7.4o) and step length (12.7%). Biofeedback on one parameter had indirect influence on other aspects of gait. CONCLUSION: Children with CP show capacity in motor function to achieve improvements in clinically important aspects of gait. Visualizing biofeedback with an avatar was subjectively preferential compared to a simplified bar presentation of knee angle. Future studies are required to investigate if observed transient effects of biofeedback can be retained with prolonged training to test whether biofeedback-based gait training may be implemented as a therapy tool. PMID- 30447197 TI - Non-invasive dynamic assessment of conjunctival melanomas by photoacoustic imaging. AB - This study describes non-invasive photoacoustic imaging to detect and monitor the growth of conjunctival melanomas in vivo. Conjunctival melanomas were induced by injection of melanotic B16F10 cells into the subconjunctival space in syngeneic albino C57BL/6 mice. Non-invasive in vivo photoacoustic tomography was performed before, and after tumor induction up to 2 weeks. Spectral unmixing was performed to determine the location and to assess the distribution of melanin. The melanin photoacoustic signal intensity was quantified from the tumor-bearing and control eyes at all timepoints. For postmortem validation, total tumor and melanotic tumor volumes were measured using H&E stained tumor sections and were compared to in vivo photoacoustic imaging measurements. Photoacoustic imaging non-invasively detected eyes bearing conjunctival tumors of varying sizes. The melanin signal was detected as early as immediately following injection of melanotic tumor cells. Changes in tumor size over time were assessed with changes in the volume and intensity of the melanin signal. Four growing tumors and one regressing tumor were observed. Three tumors without significant change in signal intensity over time were observed, showing variable growth. Photoacoustic melanin signal on the last day of in vivo imaging correlated with postmortem total tumor volume (R2 = 0.81) and melanotic tumor volume (R2 = 0.80). The results of our study show that actively growing conjunctival melanomas can be quantified in a non-invasive manner using in vivo photoacoustic tomography. The photoacoustic melanin signal intensity correlated with total and melanotic tumor volume. This novel in vivo imaging platform may help to assess new treatment modalities to manage ocular tumors. PMID- 30447198 TI - All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome. AB - Glaucoma describes a distinct optic neuropathy with complex etiology and a variety of associated risk factors, but with similar pathological endpoints. Risk factors such as age, increased intraocular pressure (IOP), low mean arterial pressure, and autoimmune disease, can all be associated with death of retinal ganglion cells (RGCs) and optic nerve head remodeling. Today, IOP management remains the standard of care, even though IOP elevation is not pathognomonic of glaucoma, and patients can continue to lose vision despite effective IOP control. A contemporary view of glaucoma as a complex, neurodegenerative disease has developed, along with the recognition of a need for new disease modifying retinal treatment strategies and improved outcomes. However, the distinction between risk factors triggering the disease process and retinal injury responses is not always clear. In this review, we attempt to distinguish between the various triggers, and their association with subsequent key RGC injury mechanisms. We propose that distinct glaucomatous risk factors result in similar retinal and optic nerve injury cascades, including oxidative and metabolic stress, glial reactivity, and altered inflammatory responses, which induce common molecular signals to induce RGC apoptosis. This organization forms a coherent disease framework and presents conserved targets for therapeutic intervention that are not limited to specific risk factors. PMID- 30447199 TI - An optimized protocol for generating labeled and transplantable photoreceptor precursors from human embryonic stem cells. AB - Cell replacement therapy is a promising approach for treatment of retinal degenerative diseases. Several protocols for the generation of photoreceptor precursors (PRP) from human embryonic stem cells (hESC) have been reported with variable efficiency. Herein, we show the advantages of use of size-controlled embryoid bodies in the ESC differentiation process using two differentiation protocols. We further explored cell-labeling methods for following the survival of PRP transplanted subretinally in rat eyes. Size-controlled embryoid bodies (EBs) generated using microwell dishes and non-size-controlled EBs generated using V-shaped 96-well plates were differentiated into PRP using two differentiation protocols. The differentiation protocols utilized two different combinations of growth factors. The first, Dkk1, Noggin, and IGF1, and the second protocol used IWRIWR1e, SAG, and CHIR99021. Differentiation efficiency to PRP was analyzed by qPCR, immunocytochemistry, and fluorescence-assisted cell sorting (FACS). Size-controlled IWR1e yielded a significantly higher percent (86.4%) of PRP cells expressing CRX, compared with non-size-controlled IWR1e (51.4%, P = 0.026) or the size-controlled DKK1 protocol (70.5%, p = 0.007). In addition, the IWR1e differentiated cells exhibited a significantly higher fluorescence intensity of CRX immunostaining, compared with the DKK1 protocol, consistent with higher protein expression levels. The IWR1e cells exhibited higher maturation levels, as manifested by lower early neuronal marker PAX6 and pluripotency marker OCT4 levels compared with the DKK1 protocol. The expression of other late photoreceptor markers (NRL, recoverin) were similar among the differentiation groups. PRP cells were labeled by using hESC constitutively expressing eGFP or by AAV-GFP transduction. Finally, we transplanted the cells in the subretinal space of wild-type rats and monitored their survival over several weeks. The AAV2 serotype efficiently transduced the PRP cells, whereas other serotypes yielded low or no transduction. Following subretinal transplantation of GFP-labeled PRP, 63% of the cells were detected at 4 weeks post-transplantation. In conclusion, we show here that the IWR1e protocol using size-controlled EBs efficiently generated of PRP that could be labeled and followed in-vivo for weeks. The data from this study is an advance toward the goal of PRP transplantation therapy for retinal degenerative diseases. PMID- 30447200 TI - Temperature and pCO2 jointly affect the emergence and survival of cercariae from a snail host: implications for future parasitic infections in the Humboldt Current system. AB - Ocean warming and acidification are general consequences of rising atmospheric CO2 concentrations. In addition to future predictions, highly productive systems such as the Humboldt Current System are characterized by important variations in both temperature and pCO2 level, but how these physical-chemical ocean changes might influence the transmission and survival of parasites has not been assessed. This study experimentally evaluated the effects of temperature (14, 18 and 25 degrees C) and the combined effects of temperature (~15 and 20 degrees C) and pCO2 level (~500 and 1400 microatmospheres (uatm) on the emergence and survival of two species of marine trematodes-Echinostomatidae gen. sp. and Philophthalmidae gen. sp.-both of which infect the intertidal snail Echinolittorina peruviana. Snails were collected from intertidal rocky pools in a year-round upwelling area of the northern Humboldt Current System (23 degrees S). Two experiments assessed parasite emergence and survival by simulating emersion immersion tidal cycles. To assess parasite survival, 2 h old cercariae (on average) were taken from a pool of infected snails incubated at 20-25 degrees C, and their mortality was recorded every 6 h until all the cercariae were dead. For both species, a trade-off between high emergence and low survival of cercariae was observed in the high temperature treatment. Species-specific responses to the combination of temperature and pCO2 levels were also observed: the emergence of Echinostomatidae cercariae was highest at 20 degrees C regardless of the pCO2 levels. By contrast, the emergence of Philophthalmidae cercariae was highest at elevated pCO2 (15 and 20 degrees C), suggesting that CO2 may react synergistically with temperature, increasing transmission success of this parasite in coastal ecosystems of the Humboldt Current System where water temperature and pH are expected to decrease. In conclusion, our results suggest that integrating temperature-pCO2 interactions in parasite studies is essential for understanding the consequence of climate change in future marine ecosystem health. PMID- 30447201 TI - Ecological correlates and phylogenetic signal of host use in North American unionid mussels. AB - Mussels in the order Unionoida comprise ~75% of the world's freshwater bivalve species and are free-living apart from a brief larval stage that parasitizes fish. We investigated the relationships among species of North American unionid mussels and their known host fishes from a macroevolutionary perspective to test whether and how ecological and evolutionary factors correlate with patterns of host use. A subset of 69 mussel species was chosen based on data availability regarding their fish host repertoires, phylogenetic relationships, and ecology. Despite the brevity of their parasitic life stages, the mussels conformed to the right-skewed distribution of host specificity typical of parasitic taxa, in which most species are specialists and a few are generalists. Phylogenetic least squares regression models identified affinity for low-gradient and riffle habitats, and colonization of post-glacial watersheds as the best predictors for the number of fish host species per mussel. However, the second-best model identified citation number as a predictor of the number of hosts, implying that many mussel-host interactions still remain to be identified. A Multiple Regression Mantel test was performed to identify factors associated with the proportion of hosts shared between pairs of mussel species. Range overlap, citations, genetic distance, and similarity in host infection strategy were significantly correlated with the proportion of hosts shared, yet total variation as explained by the best model was low (R2 = 0.14). There was evidence of a topological association between mussels and their hosts (P = 0.001) and a significant phylogenetic signal of host specificity (lambda = 0.81, P = 0.003), indicating closely related mussels that overlap in range are more likely to be competing for hosts. Our results provide an initial macroevolutionary framework for studying the evolution of host infection strategies in these mussels but also highlights gaps still remaining in our fundamental ecological knowledge of this endangered clade. PMID- 30447202 TI - Climate impacts on blacklegged tick host-seeking behavior. AB - The nymph of the blacklegged tick (Ixodes scapularis), the primary North American vector of the causative agent of Lyme disease, must attach to a host by the end of its questing season in order to feed and subsequently molt into an adult. The proper timing of this behavior is critical both for the tick's survival and for perpetuating the transmission of tick-borne pathogens. Questing also depletes limited nymphal lipid reserves and increases desiccation risk. Given this tradeoff, questing behavior and its environmental influences can be expressed in a dynamic state variable model. We develop what we believe to be the first such model for a tick, and investigate the influence of climate on nymph fitness predictions. We apply these results to the hypothesized inland migration of I. scapularis from island refugia, evaluating fitness under suboptimal questing strategies and uncertain environmental conditions. PMID- 30447203 TI - DAYS SPENT AT HOME IN THE LAST SIX MONTHS OF LIFE AMONG COMMUNITY-LIVING OLDER PERSONS. AB - BACKGROUND: Days spent at home has recently been identified as an important patient-centered outcome; yet, relatively little is known about time spent at home at the end of life among community-living older persons. METHODS: The analytic sample included 457 decedents from an ongoing cohort study of 754 community-living persons, aged >= 70 years. Days spent at home were calculated as 180 days minus the number of days in a hospital, nursing home or hospice facility. The condition leading to death was determined from death certificates and comprehensive assessments. RESULTS: The median number of days at home was 159 (interquartile range, 125-174). 138 (30.2%) decedents were at home during the entire 6-month period, while 163 (35.7%) were at home for fewer than 150 days. Days at home did not differ significantly by age (P=.922), sex (P=.238), or race/ethnicity (P=.199), but did differ according to the condition leading to death (P=.001), with the lowest value observed for organ failure (150 [106.5 168.5]), highest values for sudden death (177 [172-179]) and cancer (167 [140 174]), and intermedicate values for advanced dementia (164 [118-174]), frailty (160.5 [130-174]), and other conditions (153 [118-175]). CONCLUSIONS: Among community-living older persons, days spent at home in the last six months of life do not differ by age, sex, or race/ethnicity, but are significantly lower for persons dying from organ failure. Additional efforts may be warranted to optimize time spent at home at the end of life, especially among older persons dying from organ failure. PMID- 30447204 TI - Typically Atypical: Merkel Cell Carcinoma. PMID- 30447206 TI - Nodular thyroid dermopathy: Not a hallmark of Graves' disease. PMID- 30447205 TI - CLINICAL CHARACTERISTICS AND ONE-YEAR OUTCOMES OF ELDERLY PATIENTS WITH ST ELEVATION OR NON-ST-ELEVATION ACUTE CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION. AB - INTRODUCTION: Acute coronary syndromes have been classified according to the finding of ST-segment elevation on the presenting ECG, with different treatment strategies and practice guidelines. However, a comparative description of the clinical characteristics and outcomes of acute coronary syndrome elderly patients undergoing percutaneous coronary intervention during index admission has not been published so far. METHODS: Retrospective cohort study of patients enrolled in the Elderly-ACS 2 multicenter randomized trial. Main outcome measures were crude cumulative incidence and cause-specific hazard ratio (cHR) of cardiovascular death, non-cardiovascular death, reinfarction and stroke. RESULTS: Of 1443 ACS patients aged >75 years (median age 80, IQR 77-84), 41% were classified as ST Elevation Myocardial Infarction (STEMI), and 59% had Non-ST Elevation ACS (NSTEACS) (48% NSTEMI and 11% unstable angina). As compared to those with NSTEACS, STEMI patients had more favorable baseline risk factors, less prior cardiovascular events and less severe coronary disease, but lower ejection fraction (45% vs 50%, p<0.001). At a median follow up of 12 months, 51 (8.6%) STEMI patients had died, versus 39 (4.6%) NSTEACS patients. After adjusting for sex, age and previous myocardial infarction, the hazard among the STEMI group was significantly higher for cardiovascular death (cHR- 1.85; 95% CI 1.02-3.36), non cardiovascular death (cHR 2.10; 95% CI 1.01-4.38), and stroke (cHR 4.8; 95% CI 1.7-13.7). CONCLUSIONS: Despite more favorable baseline characteristics, elderly STEMI patients have worse survival and a higher risk of stroke compared to NSTEACS patients after percutaneous coronary intervention. PMID- 30447207 TI - 1988-2018: Thirty years of drug smuggling at the nano scale. Challenges and opportunities of cell-penetrating peptides in biomedical research. AB - In 1988, two unrelated papers reported the discovery of peptide vectors with innate cell translocation properties, setting the ground for a new area of research that over the years has grown into considerable therapeutic potential. The vectors, named cell-penetrating peptides (CPPs), constitute a now large and diversified family, sharing the extraordinary ability to diffuse unaltered across cell membranes while ferrying diverse associated cargos. Such properties have made CPPs ideal tools for delivery of nucleic acids, proteins and other therapeutic/diagnostic molecules to cells and tissues via covalent conjugation or complexation. This year 2018 marks the 30th anniversary of a peptide research landmark opening new perspectives in drug delivery. Given its vastness, exhaustive coverage of the main features and accomplishments in the CPP field is virtually impossible. Hence this manuscript, after saluting the above 30th jubilee, focuses by necessity on the most recent contributions, providing a comprehensive list of recognized CPPs and their latest-reported applications over the last two years. In addition, it thoroughly reviews three areas of peptide vector research of particular interest to us, namely (i) efficient transport of low-bioavailability drugs into the brain; (ii) CPP-delivered disruptors of G protein-coupled receptor (GPCRs) heteromers related to several disorders, and (iii) CPP-mediated delivery of useful but poorly internalized drugs into parasites. PMID- 30447208 TI - Structural studies of Old Yellow Enzyme of Leishmania braziliensis in solution. AB - First described in yeast in 1932 by Christian & Warburg, the Old Yellow Enzyme (OYE) (EC 1.6.99.1) has aroused the interest of the scientific community regarding its high ability to catalyze stereoselective reactions of alpha/beta unsaturated carbonyl compounds with important industrial applications. In addition, the OYE family of proteins has been found in different organisms, such as plants, bacteria and protozoa, but not in mammals, which makes it an excellent candidate for a functional and molecular study aimed at more effective therapies with fewer undesirable side effects. Several OYE orthologues have been characterized; however, the real physiological role for most members of this family of proteins remains a mystery. In this paper, we present the structural studies of the OYE of Leishmania braziliensis. The findings are discussed in comparison with OYE of Trypanosoma cruzi, revealing some biophysical differences. The main differences are related to their chemical and thermal stabilities and behavior in solution. In addition, the L. braziliensis OYE shape is more elongated than that of the T. cruzi orthologue. Despite this, the active sites of these enzymes do not appear to have major differences, since their interactions with the substrate menadione occur with an affinity of the same order of magnitude, revealing that the binding sites in both proteins are essentially similar. PMID- 30447209 TI - Myocardial relaxation in human heart failure: Why sarcomere kinetics should be center-stage. AB - Myocardial relaxation is critical for the heart to allow for adequate filling of the ventricles prior to the next contraction. In human heart failure, impairment of myocardial relaxation is a major problem, and impacts most patients suffering from end-stage failure. Furthering our understanding of myocardial relaxation is critical in developing future treatment strategies. This review highlights processes involved in myocardial relaxation, as well as governing processes that modulate myocardial relaxation, with a focus on impairment of myocardium-level relaxation in human end-stage heart failure. PMID- 30447211 TI - "How to obtain diagnostic planes of the fetal central nervous system using three dimensional ultrasound and a context-preserving rendering technology." AB - The antenatal evaluation of the fetal central nervous system (CNS) is among the most difficult tasks of prenatal ultrasound (US) requiring technical skills in relation to ultrasound and image acquisition and knowledge of CNS anatomy and how this changes with gestation. According to the International Guidelines, the basic assessment of fetal CNS is most frequently performed on the axial planes, while the coronal and sagittal planes are required for the multiplanar evaluation of the CNS within the context of fetal neurosonology. It can be even more technically challenging to obtain "non-axial" views with two-dimensional (2D) US. The modality of three-dimensional (3D) US has been suggested as a panacea to overcome the technical difficulties of achieving non-axial views. The lack of familiarity of most sonologists in the use of 3D US and its related processing techniques may preclude its use even where it could play an important role in complementing antenatal 2D US assessment. Furthermore, once a 3D volume has been acquired, proprietary software allows it to be processed in different ways, leading to multiple ways of displaying and analyzing the same anatomical imaging or plane. These are difficult to learn and time consuming in the absence of specific training. In this manuscript we describe the key steps in volume acquisition of a 3D US volume, manipulation and processing with reference to images of the fetal CNS using a newly developed context-preserving rendering technique. PMID- 30447210 TI - Predictive performance of the competing risk model in screening for preeclampsia. AB - BACKGROUND: The established method of screening for preeclampsia (PE) is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high-risk and in their absence as low-risk. However, the performance of such approach is poor. We developed a competing risks model which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of PE, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of PE requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. OBJECTIVE: To examine the predictive performance of the competing risks model in screening for PE by a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (PI), and serum placental growth factor (PLGF), referred to as the triple test, in a training dataset for development of the model and two validation studies. STUDY DESIGN: The data for this study were derived from three previously reported prospective non-intervention multicenter screening studies for PE in singleton pregnancies at 11+0 - 13+6 weeks' gestation. In all three studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of PE and is therefore considered to be the training set. The two validation studies comprised of 8,775 and 16,451 women, respectively and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with PE at <34, <37 and <41+3 weeks' gestation were calculated using the competing risks model and the performance of screening for PE by maternal factors alone and the triple test in each of the three datasets was assessed. We examined the predictive performance of the model by first, the ability of the model to discriminate between the PE and no PE groups using the area under the receiver operating characteristic (AUROC) curve and the detection rate (DR) at fixed screen positive rate (SPR) of 10%, and second, calibration by measurements of calibration slope and calibration-in-the-large. RESULTS: The DR at SPR of 10% of early-PE, preterm-PE and all-PE was about 90%, 75% and 50%, respectively and the results were consistent between the training and two validation datasets. The AUROC curve was >0.95, >0.90 and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0 demonstrating a good agreement between the predicted risks and observed incidence of PE. In the prediction of early-PE and preterm-PE the observed incidence in the training set and one of the validation datasets was consistent with the predicted one. In the other validation dataset, which was specifically designed for evaluation of the model, the incidence was higher than predicted presumably because of better ascertainment of outcome. The incidence of all-PE was lower than predicted in all three datasets because at term many pregnancies deliver for reasons other than PE and therefore pregnancies considered to be at high-risk for PE that deliver for other reasons before they develop PE can be wrongly considered to be false positives. CONCLUSIONS: The competing risks model provides an effective and reproducible method for first-trimester prediction of early-PE and preterm-PE, as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm-PE is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease. PMID- 30447212 TI - Incidence of Sarcoma in Patients Undergoing Hysterectomy for Benign Indications: A Population-Based Study. AB - BACKGROUND: Minimally invasive hysterectomy may require the use of morcellation to remove the uterus. In the presence of unexpected sarcoma, morcellation risks disseminating malignant cells and worsening survival outcomes. As a consequence, in 2014 the US Food and Drug Administration (FDA) issued a black box warning against the use of power morcellator for the treatment of uterine fibroids. However, the proportion of unexpected sarcoma at the time of hysterectomy for presumed benign indication remains unclear. OBJECTIVE: To estimate the incidence of sarcoma among women undergoing hysterectomy for benign indication in Olmsted County, Minnesota, between 1999 and 2013. METHODS: We conducted a population based study including all hysterectomies performed for benign indication in Olmsted County women between 1/1/1999 and 12/31/2013. Cases were identified using the medical records-linkage system of the Rochester Epidemiology Project, and data were abstracted by a gynecologist who reviewed the complete medical records of each woman who underwent hysterectomy. An expert pathologist reviewed the pathologic slides of each sarcoma to ensure the accuracy of the diagnosis. Incidences of sarcoma (overall and by type of sarcoma) were estimated both overall and stratified by menopausal status, indication for surgery, and uterine weight as a rate per 100 persons. RESULTS: A total of 4,232 hysterectomies were performed during the study period. Among them, we identified 16 sarcomas, of which 11 (69%) were suspected pre-operatively and 5 (31%) were unexpected. Of the total number of hysterectomy, 3,759 (88.8%) were performed for benign indication. Among those, the incidence of unexpected sarcoma was 0.13% (5/3,759 [95% CI, 0.04 to 0.31%]). Uterine fibroids comprised 27.3% (n=1,025) of all hysterectomies for benign indication and was the indication most commonly associated with diagnosis of unexpected sarcoma. The incidence of unexpected sarcoma among surgeries for uterine fibroids was 0.35% (3/851) for premenopausal women and 0.57% (1/174) for peri/postmenopausal, and all 4 unexpected sarcomas were leiomyosarcoma. The incidence of unexpected sarcoma progressively increased with higher uterine weight with an incidence of 0.03% (1/2,993) among women with a uterine weight <250 grams versus 15.4% (2/13) with a uterine weight >=2,000 grams. CONCLUSIONS: Unexpected uterine sarcoma was low in all women undergoing hysterectomy for benign indication (0.13% or 1 in 752 surgeries), while increased in women with uterine fibroids (0.39% or 1 in 256 surgeries). Peri-post-menopausal women, women with large uteri, and age >45 were risk factors for sarcoma. PMID- 30447213 TI - Ecological dynamics of the vaginal microbiome in relation to health and disease. AB - The bacterial composition of the vaginal microbiome is thought to be related to health and disease states of women. This microbiome is particularly dynamic, with compositional changes related to pregnancy, menstruation, and disease states such as bacterial vaginosis. In order to understand these dynamics and their impact on health and disease, ecological theories have been introduced to study the complex interactions between the many taxa in the vaginal bacterial ecosystem. The goal of this review is to introduce the ecological principles that are used in the study of the vaginal microbiome and its dynamics, and to review the application of ecology to vaginal microbial communities with respect to health and disease. While applications of vaginal microbiome analysis and modulation have not yet been introduced into the routine clinical setting, a deeper understanding of its dynamics has the potential to facilitate development of future practices, for example in the context of postmenopausal vaginal symptoms, stratifying risk for obstetric complications, and control of sexually transmitted infections. PMID- 30447214 TI - The incremental value of DNA analysis in pancreatic cysts stratified by clinical risk factors. AB - BACKGROUND AND AIMS: We determined the incremental predictive value of pancreatic cyst fluid molecular analysis to assessing malignancy risk over long term follow up of a well-characterized cohort, given the underlying predictive value of imaging parameters routinely used to triage such patients. METHODS: Patients who lacked initial cytologic malignancy in cyst fluid and had final pathology or a follow-up period of >2 years were included. Patient outcomes determined the malignancy-free survival of patients with high-risk stigmata (HRS), worrisome features (WFs) and DNA abnormalities. DNA analysis included 3 abnormalities: (1) loss of heterozygosity mutations among a panel of tumor suppressor genes, (2) Kras mutation, (3) and elevated DNA quantity. RESULTS: 478 patients were included; 209 had surgical pathology derived outcomes and 269 had clinical follow up of >2 years. 11% had malignant outcome. 42 patients had HRS, 272 lacked both HRS and WFs, and 164 lacked HRS but had WFs. DNA abnormalities did not statistically change long-term malignancy risk in patients with HRS or in patients lacking both HRS and WFs. Among patients with WFs, the presence of >=2 DNA abnormalities significantly increased malignancy risk (RR 5.2, P=0.002) and the absence of all DNA abnormalities significantly decreased risk (RR 0.4, P=0.040). Sensitivity analysis confirmed results of survival analysis over differing baseline malignancy probabilities. CONCLUSION: Our study defines the clinical characteristic of patients in which DNA abnormality testing has the greatest impact on patient outcomes. Use of DNA abnormality testing is supported in a carefully selected patient population limited to cysts with worrisome features. PMID- 30447215 TI - Intestinal metaplasia of the gastric cardia: findings in patients with versus without Barrett's esophagus. AB - BACKGROUND AND AIMS: There is controversy about finding intestinal metaplasia (IM) of the gastric cardia on biopsy. The most recent American GI society guideline comments that IM cardia is not more common in patients with Barrett's. It provides limited guidance on whether the cardia should be treated when patients with Barrett's undergo endoscopic eradication therapy (EET) and whether the cardia should be biopsied after ablation. The aims of our study were to determine the frequency in the proximal stomach of (1) histologic gastric cardia mucosa and (2) IM cardia. A third aim was to explore the frequency of advanced pathology (dysplasia and adenocarcinoma) in the cardia after Barrett's patients have undergone EET. METHODS: Consecutive patients undergoing esophagogastroduodenoscopy between January 2008 and December 2014, who had proximal stomach biopsies were included. Patients who had histologically confirmed Barrett's were compared with those without Barrett's. RESULTS: Four hundred sixty-two patients, 289 with Barrett's and 173 without Barrett's, were included. Histologically confirmed cardiac mucosa was found in 81.6% of all patients. This was more frequent in those with versus without Barrett's (86% vs 75%; OR, 2.06; 95% CI, 1.28-3.32; p=0.003). IM cardia was more common in the Barrett's group (17% vs 7%; OR, 2.67; 95% CI, 1.38-5.19; p=0.004). Advanced pathology was more likely in the Barrett's patients who had undergone EET. CONCLUSIONS: Cardiac mucosa is present in most patients who undergo endoscopy for upper GI symptoms. IM cardia is more common in patients with Barrett's than those without. Advanced histologic changes of the cardia were seen only in the subgroup of Barrett's patients who had undergone EET. PMID- 30447217 TI - Why did the sham-treated EPISOD study subjects do so well? Important lessons for research and practice. PMID- 30447216 TI - Prevalence of Metastasis and Survival of 788 patients with T1 Rectal Carcinoid Tumors. AB - BACKGROUND & AIMS: Prevalence of rectal carcinoids is increasing, partly due to increased colorectal cancer screening. Local excision (endoscopic or trans-anal excision) is usually performed for small (<1-2 cm) rectal carcinoids but data on clinical outcomes from large population-based U.S. studies are lacking. The aims of this study were to determine the prevalence of metastasis of resected small rectal carcinoid tumors using a large national cancer database and to evaluate the long-term survival of patients after local resection as compared with radical surgery. METHODS: The SEER database was used to identify 788 patients with rectal T1 carcinoids <2 cm in size. Prevalence of metastases at initial diagnosis and risk factors for metastases were analyzed. Cancer-specific survival (CSS) was calculated. RESULTS: A total of 727 (92.3%) patients had tumors <10 mm in diameter and 61 (7.7%) had tumors 11 to 19 mm. Overall, 12 patients (1.5%) had metastasis at the time of diagnosis with prevalence of 1.1% in lesions <=10 mm and 6.6% in lesions 11 to 19 mm (p=0.01). Survival of patients with T1 rectal carcinoids without metastasis was significantly better than those with metastasis (5-year CSS of 100% vs 78%, p<0.001). Of 559 patients with T1N0M0 rectal carcinoids <10 mm, 5-year CSS was 100% in both groups who underwent local excision and those who underwent radical surgery. CONCLUSIONS: Larger T1 rectal carcinoid tumors (11 - 19 mm) have significantly higher risk of LN metastases compared with those <=10 mm. Survival is worse with metastatic disease. Local therapy is adequate for T1N0M0 rectal carcinoids <=10 mm in size with excellent long-term outcomes. PMID- 30447218 TI - Scutellarin alleviates blood-retina-barrier oxidative stress injury initiated by activated microglia cells during the development of diabetic retinopathy. AB - The breakdown of blood-retinal barrier (BRB) is an early and typical event during the development of diabetic retinopathy (DR). Scutellarin (SC) is a natural flavonoid. This study aims to investigate the protection of SC from BRB damage via focusing on inhibiting microglia-initiated inflammation and subsequent oxidative stress injury. SC attenuated BRB breakdown and the reduced expression of claudin-1 and claudin-19 in STZ-induced diabetic mice. SC reduced microglia cells activation both in vivo and in vitro. The results of transendothelial/transepithelial electrical resistance (TEER/TER) and fluorescein isothiocyanate (FITC)-conjugated dextran cell permeability assay showed that SC attenuated BRB damage induced by d-glucose (25 mM)-stimulated microglia BV2 cells. SC suppressed nuclear factor kappaB (NFkappaB) activation and tumor necrosis factor (TNF)-alpha expression induced by d-glucose (25 mM) in BV2 cells. SC decreased the phosphorylation of extracellular regulated protein kinase (ERK)1/2 both in vivo and in vitro. MEK1/2 inhibitor U0126 reduced the d-glucose induced NFkappaB nuclear accumulation and TNFalpha expression in BV2 cells. Next, SC improved the decreased expression of claudin-1 and claudin-19, the increased BRB damage and cellular reactive oxygen species (ROS) formation, and enhanced nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in TNFalpha-treated human retinal endothelial cells (HRECs) and APRE19 cells. Moreover, the SC-provided alleviation on BRB breakdown in STZ-induced diabetic mice was diminished in Nrf2 knock-out mice. In conclusion, SC alleviates BRB breakdown via abrogating retinal inflammatory responses and subsequent oxidative stress injury initiated by microglia cells that is activated by hyperglycemia during DR development. PMID- 30447219 TI - Assessing the influence of fasted and postprandial states on day-to-day variability of appetite and food preferences. AB - INTRODUCTION: Ratings of subjective appetite and food hedonics provide valuable information about energy and macronutrient intake. Ensuring reproducibility of measures of subjective appetite, and food liking and wanting is essential for accurate understanding about their implementation in intervention studies. METHODS: Nineteen participants participated in two separate 10-h test days consisting of 6 test meals. Subjective appetite was measured in the fasted state and periodically across the test day in a postprandial state. Liking and wanting were measured using the Leeds Food Preferences Questionnaire (LFPQ) immediately before and after breakfast, immediately before the second meal, and at the end of the test day. RESULTS: Reproducibility of appetite scores was similar to those previously reported in males, however females tended to have consistently higher CVs, wider CRs and wider 95% CIs. Variability in food hedonics was of a similar magnitude to subjective appetite with CVs for fasting explicit liking and wanting between 15.3 and 33.4%, correlations for both implicit and explicit liking and wanting between 0.18 and 0.87 and CRs indicating 95% of between-day changes for any given individual should fall within +/-43.4 mm of the mean change. Averages of food hedonics during the test day reduced CVs, improved correlations and reduced CRs. Despite no mean change in preceding energy and nutrient intake, individual changes in prior energy and macronutrient intake appeared to influence individual between-day changes in appetite and food hedonics, and appetite and food hedonics were intricately linked. CONCLUSIONS: Larger subject numbers may be required for appetite studies with female participants due to greater appetite variability. The LFPQ as a tool for measuring implicit and explicit liking and wanting is sufficiently reproducible and improved by averaging multiple measures across a day. PMID- 30447220 TI - Dried bonito dashi: Contributions of mineral salts and organic acids to the taste of dashi. AB - Dried bonito dashi is often used in Japanese cuisine with a number of documented positive health effects. Its major taste is thought to be umami, elicited by inosine 5'-monophosphate (IMP) and L-amino acids. Previously we found that lactic acid, a major component of dried bonito dashi, enhanced the contribution of many of these amino acids to the taste of dried bonito dashi, and reduced the contribution of other amino acids. In addition to amino acids, dried bonito dashi also has a significant mineral salt component. The present study used conditioned taste aversion methods with mice (all had compromised olfactory systems) to compare the taste qualities of dried bonito dashi with four salts (NaCl, KCl, CaCl2 and MgCl2), with and without lactic acid or citric acid. A conditioned taste aversion to 25% dried bonitio dashi generalized significantly to NaCl and KCl, with or without 0.9% lactic acid added but not when citric acid was added. Generalization of the CTA to dried bonito dashi was much stronger to the divalent salts, but when either lactic acid or citric acid was added, this aversion was eliminated. These results suggest that these salts contribute to the complex taste of dried bonito dashi and that both organic acids appear able to modify the tastes of divalent salts. PMID- 30447221 TI - The Biology and Application Areas of CRISPR Technologies. PMID- 30447222 TI - Doppler-Echocardiographic Assessment of Tricuspid Regurgitation. AB - Compared with the vast literature concerning the echocardiographic assessment of mitral, or aortic disease, the data concerning the evaluation of tricuspid regurgitation (TR) is very limited. In this review we summarized the present data concerning the assessment of TR. We review the present knowledge concerning the pathogenesis of TR showing that it is extremely multi-factorial, thus, when assessing patients with TR by echocardiography it is imperative to focus on four major aspects: evaluation of severity of TR, assessment of the etiology of TR, evaluation of the mechanism of TR and suitability for surgical or per-cutaneous repair. PMID- 30447223 TI - Obesity and dyslipidemia. AB - Obesity, a pandemic of the modern world, is intimately associated with dyslipidemia, which is mainly driven by the effects of insulin resistance and pro inflammatory adipokines. However, recent evidence suggests that obesity-induced dyslipidemia is not a unique pathophysiological entity, but rather has distinct characteristics depending on many individual factors. In line with that, in a subgroup of metabolically healthy obese (MHO) individuals, dyslipidemia is less prominent or even absent. In this review, we will address the main characteristics of dyslipidemia and mechanisms that induce its development in obesity. The fields, which should be further investigated to expand our knowledge on obesity-related dyslipidemia and potentially yield new strategies for prevention and management of cardiometabolic risk, will be highlighted. Also, we will discuss recent findings on novel lipid biomarkers in obesity, in particular proprotein convertase subtilisin/kexin type 9 (PCSK9), as the key molecule that regulates metabolism of low-density lipoproteins (LDL), and sphingosine-1 phosphate (S1P), as one of the most important mediators of high-density lipoprotein (HDL) particles function. Special attention will be given to microRNAs and their potential use as biomarkers of obesity-associated dyslipidemia. PMID- 30447224 TI - Mathematical models of DNA methylation dynamics: Implications for health and ageing. AB - DNA methylation is a key epigenetic process which has been intimately associated with gene regulation. In recent years growing evidence has associated DNA methylation status with a variety of diseases including cancer, Alzheimer's disease and cardiovascular disease. Moreover, changes to DNA methylation have also recently been implicated in the ageing process. The factors which underpin DNA methylation are complex, and remain to be fully elucidated. Over the years mathematical modelling has helped to shed light on the dynamics of this important molecular system. Although the existing models have contributed significantly to our overall understanding of DNA methylation, they fall short of fully capturing the dynamics of this process. In this paper we develop a linear and nonlinear model which captures more fully the dynamics of the key intracellular events which characterise DNA methylation. In particular the outcomes of our linear model result in gene promoter specific methylation levels which are more biologically plausible than those revealed by previous mathematical models. In addition, our nonlinear model predicts DNA methylation promoter bistability which is commonly observed experimentally. The findings from our models have implications for our current understanding of how changes to the dynamics which underpin DNA methylation affect ageing and health. We also propose how our ideas can be tested in the lab. PMID- 30447225 TI - Insights into ABA-mediated regulation of guard cell primary metabolism revealed by systems biology approaches. AB - Despite the fact that guard cell abscisic acid (ABA) signalling pathway is well documented, our understanding concerning how and to which extent ABA regulates guard cell metabolism remains fragmentary. Here we have adopted different systems approaches to investigate how ABA modulates guard cell central metabolism by providing genes that are possibly ABA-regulated. By using previous published Arabidopsis guard cell transcript profiling data, we carried out an extensive co expression network analysis using ABA-related genes and those related to the metabolism and transport of sugars, starch and organic acids. Next, we investigated the presence of ABA responsive elements (ABRE) in the promoter of genes that are highly expressed in guard cells, responsive to ABA and co expressed with ABA-related genes. Together, these analyses indicated that 44 genes are likely regulated by ABA and 8 of them are highly expressed in guard cells in both the presence and absence of ABA, including genes of the tricarboxylic acid cycle and those related to sucrose and hexose transport and metabolism. It seems likely that ABA may modulate both sucrose transport through guard cell plasma membrane and sucrose metabolism within guard cells. In this context, genes associated with sucrose synthase, sucrose phosphate synthase, trehalose-6-phosphate, invertase, UDP-glucose epimerase/pyrophosphorylase and different sugar transporters contain ABRE in their promoter and are thus possibly ABA regulated. Although validation experiments are required, our study highlights the importance of systems biology approaches to drive new hypothesis and to unravel genes and pathways that are regulated by ABA in guard cells. PMID- 30447227 TI - Pediatric Oral Formulations: An Updated Review of Commercially Available Pediatric Oral Formulations Since 2007. AB - Oral pediatric formulations are either ready-to-use or require manipulation, and multi-use or single-use. Strong encouragement for preservative-free pediatric formulations has resulted in fewer multi-use solutions or suspensions in favor of single-use solid oral dosage forms. This updated review covering new pediatric formulations marketed in the United States of America, Europe, and Japan spanning the years 2007 to mid-2018 identified 16 types of pediatric oral formulations of which 7 are ready-to-use and 9 require manipulation, and 51 total new pediatric oral formulations of which 21 are ready-to-use, and 30 require manipulation. Ready-to-use formulations include oral solution, oral suspension, oral soluble film, tablet, scored tablets, orally disintegrating tablet, chewable tablet, and mini-tablets. Formulations requiring manipulation include sprinkle capsule, powder for oral solution, powder for oral suspension, granules for oral suspension, oral powder, oral granules, tablet, dispersible tablet, dispersible scored tablet, tablet for oral suspension, and mini-tablets (oral granules). Significant advances in packaging technology include filling mini-tablets, granules, or powders into sachets, stick packets, blisters and two-piece capsules. The future of pediatric oral formulations will increasingly be with user-friendly, preservative-free, taste-masked formulations including multiparticulate single-use solid dosage forms including mini-tablets, orally disintegrating tablets and sprinkle capsules with or without a specialized package configuration. PMID- 30447226 TI - Healthcare Stakeholder Perceptions of Vision Loss. AB - Perceptions of the quality-of-life (QOL) associated with vision loss vary widely. Herein, we consider the perceptions of patients with vision loss as the criterion for QOL quantification associated with vision loss. With the QOL instrument, time tradeoff utility analysis, the upper anchor of 1.00 is associated with permanent normal vision, while the lower anchor of 0.00 is associated with death. A time tradeoff utility of 0.26 is associated with no light perception bilaterally. Patients with legal blindness in the U.S. (< 20/200 vision bilaterally) have a mean time tradeoff utility of 0.47. The general public, however, associates legal blindness with a time tradeoff utility of 0.86. Thus, legally blind patients consider their QOL loss from blindness to be 279% [(1.00-0.47/(1.00-0.86)] worse than does the American public. Public estimates of the QOL loss from blindness (utility=0.86) suggest it is less debilitating than patient QOL estimates for migraine headaches (utility=0.83). The mean medical student blindness utility estimate is 0.86, while that for non-ophthalmic physicians is 0.82. Ophthalmologists underestimated the QOL associated with vision loss in macular degeneration patients by 96%-750%. Underestimating the QOL loss from blindness likely diminishes the perceived benefit of blindness interventions. Minimization of interventional benefit by underestimating patient impairment from vision loss could lead to adverse consequences for patients with vision loss, vision research and those who treat vision loss. PMID- 30447228 TI - Inhibition of Kir2.1 channel-induced depolarization promotes cell biological activity and differentiation by modulating autophagy in late endothelial progenitor cells. AB - AIMS: Endothelial progenitor cells (EPCs) play a crucial role in postnatal angiogenesis and neovascularization. Inward rectifier potassium channel 2.1 (Kir2.1) have been identified in EPCs. However, the effect of Kir2.1 on EPC function is not known. Here, we try to establish the role of Kir2.1 channels in EPC function and to provide first insights into the mechanisms. METHODS AND RESULTS: We first observed that the expression of Kir2.1 gradually decreased with the differentiation of EPCs into ECs in gene and protein levels. Treatment with the Kir2.1-selective inhibitor ML133 or knockdown of Kir2.1 by shRNA triggered EPC depolarization and promoted EPC biological functions, such as migration, adhesion, angiogenesis and differentiation into ECs in vitro. Transplantation of ML133-treated or Kir2.1 knockdown EPCs facilitated re-endothelialization in the rat injured arterial segment and inhibited neointima formation in vivo. In parallel, ML133 significantly enhanced autophagy and autophagic flux. After suppression of autophagy by 3-methyladenine (3-MA), the effects of ML133 on in vitro function and in vivo endothelialization capacity of EPCs were significantly inhibited. Mechanistically, ML133-induced autophagy was mediated at least partly by increased the activity of reactive oxygen species (ROS) that likely through intracellular calcium. CONCLUSION: Our study indicates that blocking or knockdown Kir2.1 results in a moderate depolarization of EPCs, which directly participated in enhancing EPC functions both in vitro and in vivo. In the mean time, autophagy signaling pathway is, at least in part, involved in this process. It may provide a potential target for the treatment or prevention of vascular injury and disease. PMID- 30447229 TI - Inhibition of peptide BF-30 on influenza A virus infection in vitro/vivo by causing virion membrane fusion. AB - Influenza A virus is a leading cause of mortality in humans and poses a global health emergency due to its newly adapted and resistant strains. Thus, there is an urgency to develop novel anti-influenza drugs. Peptides are a type of biological molecule having a wide range of inhibitory effects against bacteria, fungi, viruses and cancer cells. The prospects of several peptides and their mechanisms of action have received significant attention. BF-30, a 30 amino acid residue peptide isolated from the venom of the snake, Bungarus fasciatus, is reported to have antibacterial and antitumor activities. Here, we demonstrated that the 50% cytotoxic concentration (CC50) of the peptide to MDCK cells is 67.7 MUM. While BF-30 could inhibit the influenza virus strains H1N1, H3N2 and the oseltamivir-resistant strain H1N1, in vitro, with 50% effective concentration (EC50) of 5.2, 7.4 and 18.9 MUM, respectively. In animal experiments, mice treated with BF-30 showed 50% survival at a dosage of 4 MUM, with an approximately 2 log viral titer decrease in the lung. However, further studies showed that BF-30 worked on only the virus invasion stage, and inhibited the influenza virus infection by causing virion membrane fusion rather than interacting with hemagglutinin or neuraminidase. These results demonstrated that the peptide BF-30 exhibited an effective inhibitory activity against the influenza A virus and could be a promising candidate for influenza virus therapy. PMID- 30447230 TI - The inverse relationship between life expectancy-induced changes in the old-age dependency ratio and the prospective old-age dependency ratio. AB - Unlike other biological populations, the human population is experiencing long run increases in life expectancy. Those lead to changes in age compositions not typical for other biological populations. Sanderson and Scherbov (2015a) demonstrated that, in many countries in Europe, faster increases in life expectancy lead to faster population aging when measured using the old-age dependency ratio and to slower population aging when measured using the prospective old-age dependency ratio that employs a dynamic old-age threshold. We examine this finding analytically and with simulations. We use an analytic decomposition of changes in mortality schedules into shift and compression processes. We show that shifts and compressions of mortality schedules push the two old-age dependency ratios in opposite directions. Our formal results are supported by simulations that show a positive effect of a mortality shift on the old-age dependency ratio and a negative effect of it on the prospective old-age dependency ratio. The effects are of opposite sign for a mortality compression. Our formal and simulation results generalize observed European trends and suggest that the inverse relationship between life expectancy and prospective old-age dependency would be observed more generally. PMID- 30447231 TI - Anterior insula activity regulates the associated behaviors of high fat food binge intake and cue reactivity in male rats. AB - Binge eating episodes are characterized by uncontrollable, excessive intake of food and are associated with binge eating disorder and some subtypes of obesity. One factor thought to contribute to binge episodes is a high level of reactivity to food-associated cues (i.e., cue reactivity). The insula is a neural node poised to regulate both binge eating and cue reactivity because of its prominent role in interpretation of internal and external cues. This work established a positive association between high fat food (HFF) binge intake and cue reactivity in male rats. Furthermore, we demonstrated that activation of the anterior insula suppressed both HFF binge intake and cue reactivity, without altering homeostatic intake of food. We further show that attenuation of HFF binge intake and cue reactivity is not due to decreased food-reward efficacy or deficits in motivation. Together, these data establish a key role for the anterior insula in the control of binge eating related-behaviors and support novel avenues for the treatment of binge eating. PMID- 30447232 TI - Sensory Eating Problems Scale (SEPS) for children: Psychometrics and associations with mealtime problems behaviors. AB - The present study developed the 22-item Sensory Eating Problems Scale (SEPS) to measure sensory aspects for children surrounding eating, documented psychometrics of SEPS subscales, and examined their association with mealtime behavior problems. Study participants were 449 caretakers of children referred to feeding clinics, including children in three special needs status groups: autism spectrum disorder (ASD), other special needs, and no special needs. Caretakers completed surveys to report children's demographics, four measures of children's mealtime behavior problems, and five-point ratings for how often children showed various sensory feeding reactions. Exploratory factor analysis of the sensory feeding items identified six SEPS subscales with acceptable goodness-of-fit, internal reliability, and test-retest reliability: Food Touch Aversion, Single Food Focus, Gagging, Temperature Sensitivity, Expulsion, and Overstuffing. ANCOVAs revealed that child demographics most associated with higher SEPS subscale scores were younger age and special needs. Multiple regression analyses found that children's mealtime behavior problems were most often associated with SEPS subscales of Food Touch Aversion, Single Food Focus, Expulsion, and Overstuffing, with the set of six subscales explaining 18-44% of variance in mealtime behavior problems. Suggestions for how clinicians and researchers may find the SEPS useful for assessment and intervention are provided. PMID- 30447233 TI - Insights into the dynamics of memory, effector and apoptotic cytotoxic T lymphocytes in channel catfish, Ictalurus punctatus. AB - In this study, we used the channel catfish model clonal TS32.15 alloantigen specific cytotoxic T cell (CTL) line to examine the dynamics of memory CTL expansion and senescence in teleosts. Although TS32.15 has been routinely cultured to study catfish CTL responses and killing mechanisms, little is known about the dynamics of the CTLs in these cultures. Here we show that this cell line consists of small non-cytotoxic T cells and larger granular effector T cells and that their ratios vary with time after stimulation. Small CTLs, when exposed to their irradiated targets, replicate and differentiate to morphologically distinct cytotoxic effectors, which do not replicate. After lysing target cells, or with prolonged absence of stimulation, the effector cells transition to a non cytolytic senescent stage or become apoptotic. In addition, we demonstrate that natural IgM in catfish serum binds lipids, including PIP2, on early apoptotic CTLs, and that these IgM+ CTL can be cleared by catfish head kidney-derived macrophages. PMID- 30447234 TI - Observation study of water outlet design from a cross infection / user perspective; time for a radical re-think? AB - BACKGROUND: Hand washing is a key barrier to cross infection performed at a Hand Wash Station (HWS). Elbow-operated outlets if used incorrectly (with hands) become highly touched objects potentially providing a route for cross infection. AIM: To look at how elbow operated outlets were used by staff in the hospital, whether the correct type of HWS had been installed in the various ward areas according to the Health Building Note (HBN) 00-10 Part C: sanitary assemblies (hands free outlets in clinical, food preparation and laboratory areas), and factors impinging on design/setup which may affect compliance with correct use. METHODS: Observation of outlet use was performed by mounting a video camera above four HWSs. Review of suitability of outlet was conducted by two of the authors visiting ward areas and assessing compliance against HBN recommendations. Angle of elbow operated lever set up was measured using a protractor and water temperature in relation to angle of movement of elbow lever was measured using a calibrated thermocouple. FINDINGS: 92% of staff used hands to turn on the outlet and 68% used hands to turn the outlet off potentially re-contaminating their hands. >70% of users moved the lever <= 450. Almost half of elbow levers were set up incorrectly being flush or within 3.5 cm of rear panel making elbow operation extremely difficult. Selection of outlet type according to HBN was most incorrect in the ITU but also occurred in the new build hospital. CONCLUSION: Although hand washing is a key barrier to cross infection poor selection and incorrect use of outlet undermines its effectiveness. Design and incorrect instalment further compromise the intended means of operation of elbow levers. Of equal concern is this risk mostly goes unrecognised. There is an opportunity to improve hand washing safety but it requires engagement across a broad stratum from Government Departments of Health and manufacturers down to the user. PMID- 30447235 TI - Influence of typicality in category-based fear generalization: Diverging evidence from the P2 and N400 effect. AB - The conceptual properties of a conditional stimulus could contribute to human fear generalization, but how typicality influences fear generalization involving different conceptual hierarchies remains unclear. This study used event-related potential technology to investigate this in four categories of generalized stimulus (GS). We divided the GS into four categories: inferior typical members of conditioned stimulus (CS+) (TCS+), inferior atypical members of CS+ (ATCS+), inferior typical members of CS- (TCS-), and inferior atypical members of CS- (ATCS-). The CS+ groups elicited a larger P2 versus the CS- groups suggesting that aversive stimuli can automatically capture attention with timely avoidance of danger. Stimulus type (CS+; CS-) and typicality (typical; atypical) showed an interaction with N400. The elicited N400 was larger for atypical than typical members in CS- groups, but not in CS+ groups. Fear emotion elicited by CS+ may feature restrained semantic networks, dissipating typicality effects. Separate processing stages may modulate category-based fear generalization, with P2 representing first-stage low-level perceptual processing, and N400 second-stage high-level cognitive processing. PMID- 30447236 TI - Perspective: HLA functional elements outside of the antigen recognition domain. PMID- 30447237 TI - The Molecular Basis of Chemical Chaperone Therapy for Oculocutaneous Albinism Type 1A. AB - Oculocutaneous albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair and eyes. No effective treatment for OCA is available at present. OCA type 1 (OCA1) is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some OCA1 mutants is retained within the endoplasmic reticulum (ER) and its catalytic activity is lost, a phenomenon known as ER-retention. However, the intracellular localization of tyrosinase in Japanese OCA1 missense mutants has not been reported. In this study, we firstly investigated the intracellular localization of Japanese OCA1A missense mutant tyrosinases using western blotting and immunohistochemical staining. R77Q, R239W, D383N and P431L mutant tyrosinases were retained within the ER, while H211Y mutant tyrosinase was partially transported to the Golgi apparatus. Secondly, we explored the possibility of chemical chaperone therapy for Japanese OCA1A missense mutants and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity following treatment with a low dose tyrosinase inhibitor, as a chemical chaperone, in a dose-dependent manner. These results provide the basis for a possible chemical chaperone therapy recovering tyrosinase activities of OCA1A. PMID- 30447238 TI - LPA induces keratinocyte differentiation and promotes skin barrier function through the LPAR1/LPAR5-RHO-ROCK-SRF axis. AB - The skin barrier protects our body from water loss, allergens and pathogens. Profilaggrin (proFLG) is produced by differentiated keratinocytes and is processed into FLG monomers. These monomers crosslink keratin filaments and are also decomposed to natural moisturizing factors in the stratum corneum for skin hydration and barrier function. Deficits in FLG expression impair skin barrier function and underlie skin diseases such as dry skin and atopic dermatitis (AD). However, intrinsic factors that regulate FLG expression and their mechanism of action remain unknown. Here, we show that lysophosphatidic acid (LPA) induces FLG expression in human keratinocytes via the LPAR1 and LPAR5 receptors and the downstream RHO-ROCK-SRF pathway. Comprehensive gene profiling analysis further revealed that LPA not only induces FLG expression but also facilitates keratinocyte differentiation. Moreover, LPA treatment significantly upregulated FLG production in a three-dimensional culture model of human skin, and promoted barrier function in mouse skin in vivo. Thus, our work demonstrates a previously unsuspected role for LPA and its downstream signaling in the maintenance of skin homeostasis, which may serve as a novel therapeutic target for skin barrier dysfunction. PMID- 30447239 TI - On association of the lethal yellow (AY) mutation in the agouti gene with the alterations in mouse brain and behavior. AB - Lethal yellow (AY) mutation causes obesity and type-2 diabetes in mice. Here we studied the effect of the AY mutation on the brain and behavior. The experiments were carried out on adult (11-12 weeks old) males of AY/a mice and their wild type littermates (a/a). Mice of AY/a and a/a genotypes did not differ in their home cage activity, sleep, food and water consumption, learning ability in the Morris water maze, anxiety in the open field and elevated plus-maze, as well as in the level of monoamines, metabolites and some genes expression in the brain. At the same time, the fat mass, depressive-like immobility in the forced swim and tail suspension tests were significantly increased in AY/a mice compared with a/a ones. Magnetic resonance imaging revealed a significant reduction of cortex volume in AY/a mice. The level of mRNA of Ptpn5 gene encoding striatal enriched tyrosine phosphatase in the frontal cortex of AY/a mice was significantly elevated compared with their wild-type littermates. This is the first report on the alterations in the brain and behavior in the AY/a mouse line. It is tempting to speculate that this mouse line can serve as a new and useful preclinical model to study neurobehavioral complications associated with obesity and type-2 diabetes. PMID- 30447240 TI - Changes in brain metabolites related to stress resilience: Metabolomic analysis of the hippocampus in a rat model of depression. AB - The ability to cope successfully with stress is known as 'resilience', and those with resilience are not prone to developing depression. One preclinical animal model for depression is the chronic mild stress (CMS) model. There are CMS resilient (do not manifest anhedonia) and CMS-susceptible (manifest anhedonia) rats. This study aimed to investigate the differences in the profiles of hippocampal metabolites between susceptible and resilient rats, and to identify a biomarker that can distinguish the two. We divided stress-loaded rats into susceptible and resilient types based on their sucrose preference values. We then conducted brain-derived neurotrophic factor (BDNF) quantification and metabolomic analysis in the hippocampus. Compared to the controls, no significant differences were observed in the hippocampal BDNF levels of susceptible and resilient rats. However, the control rats were clearly distinguishable from the susceptible rats in terms of their brain metabolite profiles; the control rats were difficult to distinguish from the resilient rats. CMS model rats showed an increase in the levels of N-acetylaspartate and glutamate, and a decrease in the levels of aspartate and gamma-aminobutyric acid in the hippocampus. Of the 12 metabolites measured in the present study, N-acetylaspartate was the only one that could differentiate the three types (control, susceptible, and resilient) of rats. Thus, brain metabolomic analyses can not only distinguish CMS model rats from control rats, but also indicate stress susceptibility. The variation in the levels of N-acetylaspartate in the hippocampus of control, resilient, and susceptible rats demonstrated that it could be a biomarker for stress susceptibility. PMID- 30447241 TI - Neonatal ethanol exposure impairs long-term context memory formation and prefrontal immediate early gene expression in adolescent rats. AB - Fetal alcohol exposure leads to severe disruptions in learning and memory involving the hippocampus and prefrontal cortex in humans. Animal model research on FASD has documented impairment of hippocampal neuroanatomy and function but animal studies of cognition involving the prefrontal cortex are sparse. We have found that a variant of contextual fear conditioning in which both the hippocampus and prefrontal cortex is required, the Context Preexposure Facilitation Effect (CPFE), is particularly sensitive to neurobehavioral disruption caused by neonatal ethanol exposure during the third trimester equivalent of human pregnancy in the rat (i.e., PD4-9). In the CPFE, learning about the context, acquiring a context-shock association, and retrieving contextual fear are temporally separated across three days. The current study asked whether neonatal alcohol exposure impairs context learning, consolidation, or retrieval and examined prefrontal and hippocampal molecular signaling as correlates of this impairment. Long-Evans rats that received oral intubation of ethanol (AE; 5.25 g/kg/day, split into two doses) or underwent sham-intubation (SI) from PND4-9 were tested on the CPFE on PD31-33. Extending our previous reports, ethanol abolished both post-shock and retention test freezing in the CPFE. Assays (qPCR) of immediate early gene expression revealed that ethanol disrupted prefrontal but not hippocampal expression of c-Fos, Arc, Egr-1, and Npas4 during context learning. Finally, ethanol-exposed animals were unimpaired in a standard contextual fear conditioning procedure in which learning about the context and acquiring a context-shock association occurs concurrently. These findings implicate impaired prefrontal function in cognitive deficits arising from 3rd-trimester equivalent alcohol exposure in the rat. PMID- 30447242 TI - The effects of sulfite on cPLA2, caspase-3, oxidative stress and locomotor activity in rats. AB - Sulfite is a commonly used preservative in food products, alcoholic beverages and pharmaceutical products. We investigated the effect of sulfite, on locomotor activity as well as the relationship of these effects with oxidant and antioxidant capacities, cPLA2 enzyme activity. Thirty male Wistar albino rats were randomly divided into two groups as control(C) and sulfite(S). Animals in the S group were given freshly prepared sulfite for 35 days via gastric gavage (100 mg/kg/day) while the C group received equal volumes of distilled water via gavage for the same period. Open-field tests were performed to all groups and animals were sacrificed. Total antioxidant capacity(TAC), TBARS levels, cPLA2 activity as well as amount of caspase-3 positive cells were analyzed on the hippocampi. In the open field test, distance and velocity values of the S group increased with respect to controls. TBARS and cPLA2 activity were also increased in the S group, while levels of TAC decreased compared to controls. Immunohistochemical analysis showed that sulfite ingestion caused an increase in the amount of hippocampal caspase-3 positive cells. In conclusion, sulfite seemed to increase locomotor activity. cPLA2 might play a role in ingested sulfite induced oxidative stress and apoptotic cell death in the hippocampus. PMID- 30447243 TI - Lab-on-a-Chip Technologies for Diagnosis and Monitoring of Airway Inflammation. PMID- 30447244 TI - Effect of peripheral blood mononuclear cell cryopreservation on innate and adaptive immune responses. AB - Cryopreservation of blood-derived immune cells is commonly used in clinical trials to examine immunological responses. However, studies elucidating the effects of cryopreservation on peripheral blood mononuclear cell (PBMC) responses have shown inconsistent results making it difficult to draw meaningful conclusions. Therefore we sought to address this issue by comparing key innate and adaptive immune parameters between freshly-isolated and cryopreserved PBMCs from healthy adults. We examined the effect of cryopreservation on the expression of key markers on innate and adaptive immune cell populations (i.e. CD4+ and CD8+ [T cells], CD14+ [monocytes], CD19+ [B cells], CD56+ [NK cells] or CD19 + CD27+ [memory B cells]), on cytokine secretion (TNF-alpha, INF-gamma, IL-1beta, IL-10, IL-6, MCP-1 and RANTES) in cultured PBMC supernatants following stimulation with a range of Toll-like receptor (TLR) agonists, as well as on antigen-specific memory B cell enumeration by ELISpot. We found that cryopreservation had no effect on the expression of immune markers on innate and adaptive immune cells as well on the number of antigen-specific memory B cells. However, the response to TLR ligands such as FLA-ST, CpG and LPS was variable with increased cytokine production by cryopreserved PBMCs observed compared to freshly-isolated PBMCs. Our results suggest that the effect of cryopreservation on the biological response of immune cell populations needs to be carefully considered, particularly in the context of clinical studies that rely on these immune outcomes. PMID- 30447245 TI - Deep sequencing prompts the modification of a real-time RT-PCR for the serotype specific detection of polioviruses. AB - Polioviruses are members of the Enterovirus C species and asymptomatic fecal shedding allows for their transmission and persistence in a community, as well as the emergence of vaccine-derived polioviruses. Using three serotype-specific real time RT-PCR (rRT-PCR) assays, the shedding and circulation of oral poliovirus vaccine (OPV) strains was previously investigated in a prospective cohort of Mexican children, their contacts, and nearby sewage. Subsequently, a deep sequencing approach targeting the P1 genomic region was applied to characterize OPV strains previously detected by rRT-PCR. Amplifiable RNA was obtained for sequencing from 40.3% (58/144) of stool samples and 71.4% (15/21) of sewage using nucleic acids extracted directly from primary rRT-PCR-positive specimens. Sequencing detected one or more OPV serotypes in 62.1% (36/58) of stool and 53.3% (8/15) of sewage samples. All stool and sewage samples in which poliovirus was not detected by deep sequencing contained at least one non-polio enterovirus C (NPEV-C) strain. To improve screening specificity, a modified, two-step, OPV serotype-specific multiplex rRT-PCR was evaluated. In stool specimens, the overall agreement between the original assays and the multiplex was 70.3%. By serotype, the overall agreement was 95.7% for OPV serotype-1 (S1), 65.6% for S2, and 96.1% for S3. Furthermore, most original rRT-PCR positive/multiplex rRT-PCR negative results were collected in the summer and fall months, consistent with NPEV-C circulation patterns. In conclusion, this deep sequencing approach allowed for the characterization of OPV sequences directly from clinical samples and facilitated the implementation of a more specific multiplex rRT-PCR for OPV detection and serotyping. PMID- 30447246 TI - Full genome characterization of two novel Alpha-coronavirus species from Italian bats. AB - Coronaviruses (CoVs) have been detected worldwide in several bat species, which are considered the main reservoir. The attention to the high diversity of CoVs hosted by bats has increased during the last decade due to the high number of human infections caused by two zoonotic Beta-CoVs, SARS-CoV and MERS-CoV, that cause several respiratory diseases. Among coronaviruses, two Alpha-CoV strains (HuCoV-229E and HuCoV-NL63) cause mild respiratory disease that can change to severe disease in children, elderly and individuals affected by illnesses. Phylogenetic analysis conducted on bat Alpha-CoV strains revealed their evolutive correlation to human strains, suggesting their origin in bats. The genome of CoVs is characterized by a high frequency of mutations and recombination events, increasing their ability to switch hosts and their zoonotic potential. In this study, three strains of Alpha-CoV genera detected in Italian bats (Pipistrellus kuhlii) were fully sequenced by Next Generation Sequencing (NGS) and characterized. The complete genome analysis showed the correlation of the Italians strains with a Chinese strain detected in 2013 and, based on CoV molecular species demarcation, two new Alpha-CoV species were established. The analysis of a fragment of the RNA-dependent RNA polymerase (RdRp) showed the correlation of the Italian strains with CoVs that was only detected in the bat Pipistrellus genera (Pipistrellus kuhlii and Pipistrellus Pipistrellus) in European countries. PMID- 30447247 TI - Male mammary gland development and methylation status of estrogen receptor alpha in Wistar rats are modified by the developmental exposure to a glyphosate-based herbicide. AB - Postnatal treatment with glyphosate-based herbicides (GBHs) induces endocrine disrupting effects on the male rat mammary gland. In this study, the effects of developmental exposure to GBH on mammary gland growth and development, and the possible molecular mechanisms involved, were evaluated in pre- and post-pubertal male rats. To this end, pregnant rats were orally exposed through the food to 0, 3.5 or 350 mg GBH/kg bw/day from gestational day 9 until weaning. Mammary gland development and estradiol (E2) and testosterone (T) serum levels of male offspring were evaluated on postnatal day (PND)21 and PND60. Besides, prolactin (PRL) serum levels, proliferation index, androgen (AR) and estrogen receptor alpha (ESR1) expression, ESR1 alternative transcript mRNA levels, and DNA methylation status of ESR1 promoters were assessed on PND60. No differences between groups were observed in mammary gland development at PND21 or in E2 and T levels on both PNDs studied. On PND60, GBH3.5-exposed animals presented similar mammary gland histology but higher AR protein expression than controls, whereas GBH350-exposed males presented a less developed mammary gland, accompanied by a lower proliferation index, similar AR levels, and slightly increased PRL serum levels than controls. In both exposed groups, ESR1 expression was lower than in control rats, being lower in GBH350-exposed rats. GBH also altered the abundance of ESR1 transcript variants by hypermethylation of ESR1 promoters. GHB3.5 decreased only ESR1-OS expression, whereas GBH350 affected ESR1-O, OT and E1 expression. Our results show that developmental exposure to GBH induces epigenetic changes in ESR1, which could be responsible for the altered male mammary gland development observed in GBH350-exposed animals. PMID- 30447248 TI - Trophoblastic microRNAs are downregulated in a diabetic pregnancy through an inhibition of Drosha. AB - MicroRNAs are promising biological markers for prenatal diagnosis. They regulate placental development and are present in maternal plasma. Maternal metabolic diseases are major risk factors for placental deterioration. We analysed the influence of a maternal insulin-dependent diabetes mellitus on microRNA expression in maternal plasma and in blastocysts employing an in vivo rabbit diabetic pregnancy model and an in vitro embryo culture in hyperglycaemic and hypoinsulinaemic medium. Maternal diabetes led to a marked downregulation of Dicer protein in embryoblast cells and Drosha protein in trophoblast cells. MiR 27b, miR-141 and miR-191 were decreased in trophoblast cells and in maternal plasma of diabetic rabbits. In vitro studies indicate, that maternal hyperglycaemia and hypoinsulinaemia partially contribute to the downregulation of trophoblastic microRNAs. As the altered microRNA expression was detectable in maternal plasma, too, the plasma microRNA signature could serve as an early biological marker for the prediction of trophoblast function during a diabetic pregnancy. PMID- 30447249 TI - Peripheral sensory organs vary among ant workers but variation does not predict division of labor. AB - The neural mechanisms underlying behavioral variation among individuals are not well understood. Differences among individuals in sensory sensitivity could limit the environmental stimuli to which an individual is capable of responding and have, indeed, been shown to relate to behavioral differences in different species. Here, we show that ant workers in Temnothorax rugatulus differ considerably in the number of antennal sensory structures, or sensilla (by 45% in density and over 100% in estimated total number). A larger quantity of sensilla may reflect a larger quantity of underlying sensory neurons. This would increase the probability that a given set of neurons in the antenna detects an environmental stimulus and becomes excited, thereby eliciting the expression of a behavior downstream at lower stimulus levels than an individual with comparatively fewer sensilla. Individual differences in antennal sensilla density, however, did not predict worker activity level or performance of any task, suggesting either that variation in sensilla density does not, in fact, reflect variation in sensory sensitivity or that individual sensory response thresholds to task-associated stimuli do not determine task allocation as is commonly assumed, at least in this social insect. More broadly, our finding that even closely related individuals can differ strongly in peripheral sensory organ elaboration suggests that such variation in sensory organs could underlie other cases of intraspecific behavioral variation. PMID- 30447250 TI - The evolution of the behavior systems framework and its connection to interbehavioral psychology. AB - The present article traces the development of Timberlake's behavior systems framework while noting connections between it and Kantor's interbehavioral psychology. Congruent with Timberlake's behavior systems approach, interbehaviorists assert that (a) behavior is best understood as part of a complex causal system instead of a simple linear model, (b) the study of learning and behavior analysis should consist of the study of multiple responses and the systematic observation of response forms, (c) learning involves the reorganization of a behavior system, (d) behavioral analyses should be more ecological in orientation, and (e) psychology would benefit from a set of methodologies and apparatuses broader than those normally used to study operant and Pavlovian conditioning. These connections may derive from two broad themes shared by the behavior systems framework and interbehavioral psychology: an appreciation for a systems view of behavior and the importance of ethological considerations. PMID- 30447251 TI - Elucidating effects of reaction rates on dynamics of the lac circuit in Escherichia coli. AB - Gene expression is regulated by a complex transcriptional network. It is of interest to quantify uncertainty of not knowing accurately reaction rates of underlying biochemical reactions, and to understand how they affect gene expression. Assuming a kinetic model of the lac circuit in Escherichia coli, regardless of how many reactions are involved in transcription regulation, transcription rate is shown to be the most important parameter affecting steady state production of mRNA and protein in the cell. In particular, doubling the transcription rate approximately doubles the number of mRNA synthesized at steady state for any rates of transcription inhibition and activation. On the other hand, increasing the rate of transcription inhibition by 10% reduces the average steady state count of mRNA by about 7%, whereas changes in the rate of transcription activation appear to have no such effect. Furthermore, for wide range of reaction rates in the kinetic model of the lac genetic switch considered, protein production was observed to always reach a maximum before the degradation reduces its count to zero, and this maximum was found to be always at least 27 protein molecules. Such value appears to be a fundamental structural property of genetic circuits making it very robust against changes in the internal and external conditions. PMID- 30447252 TI - Intermolecular crosslinking of abnormal prion protein is efficiently induced by a primuline-sensitized photoreaction. AB - In prion diseases, infectious pathogenic particles that are composed of abnormal prion proteins (PrPSc) accumulate in the brain. PrPSc is biochemically characterized by its protease-resistance core (PrPres), but its structural features have not been fully elucidated. Here, we report that primuline, a fluorescent dye with photosensitization activity, dramatically enhances UV irradiation-induced SDS-resistant PrPSc/res oligomer formation that can be detected by immunoblot analysis of prion-infected materials. This oligomer formation occurs specifically with PrPSc/res but not with normal prion protein, and it was demonstrated using purified PrPSc/res as well as unpurified materials. The oligomer formation proceeded in both primuline-dose- and UV irradiation time dependent manners. Treatment with urea or formic acid did not break oligomers into monomers. Neither did the presence of aromatic amino acids modify oligomer formation. Analysis with a panel of anti-prion protein antibodies showed that the antibodies against the N-terminal region of PrPres were less reactive in the dimer than the monomer. These findings suggest that the primuline-sensitized photoreaction enhances intermolecular crosslinking of PrPSc/res molecules at a hydrophobic area of the N-terminal region of PrPres. In the screening of other compounds, photoreactive compounds such as luciferin exhibited a similar but lower activity with respect to oligomer formation than primuline. The enhanced photoreaction with these compounds will be useful for evaluating the structural features of PrPSc/res, especially the interactions between PrPSc/res molecules. PMID- 30447253 TI - The thioredoxin system as a target for mercury compounds. AB - BACKGROUND: Mercury interaction with selenium in vivo has been recognized for >50 years. Several researchers attempted to use selenium to mitigate the detrimental effects of mercurial compounds but the results were controversial. Selenium pools in living organisms are quite low and the high affinity of mercury to bind selenols pointed out selenoproteins as possible targets of toxicity. Such was the case of the selenoenzyme thioredoxin reductase (TrxR) which is an integrant part of the thioredoxin system. Given the important role of this redox system for cellular functioning and the high affinity of mercury for TrxR's active site, this interaction can be key to understand the mechanism by which Hg causes cell death. SCOPE OF THE REVIEW: This review discusses the current state of knowledge concerning the interaction between mercury compounds and the thioredoxin system, its implications for the development of toxicity and the effects of selenium co exposure. MAJOR CONCLUSIONS: The mechanism of toxicity of mercurials is a complex chain of events starting with inhibition of the selenoenzyme, TrxR. Selenium supplementation protects TrxR from the toxicity of inorganic forms of mercury (i.e., Hg(II)) to a certain extent, but not from methylmercury. When TrxR is inhibited, thioredoxin is reduced by alternative mechanisms involving glutathione and glutaredoxin and only when this pathway is hampered does cell death occur. GENERAL SIGNIFICANCE: Understanding the molecular mechanism of mercury toxicity and the mechanisms of enzymatic compensation allows the design of mitigation strategies and, since TxrR and Trx exist in the plasma, puts forward the possibility for future use of changes in activity/expression of these enzymes as biomarkers of mercury toxicity, thus refining the risk assessment process. PMID- 30447254 TI - RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma via JNK dependent but p53-independent mechanism. AB - Overactivation of the Hedgehog (HH) signaling pathway is implicated in many cancers. In this study, we demonstrate that the small molecule RITA, a p53 activator, effectively downregulates HH signaling in human medulloblastoma and rhabdomyosarcoma cells irrespective of p53. This is mediated by a ROS-independent activation of the MAP kinase JNK. We also show that in vitro RITA sensitized cells to the GLI antagonist GANT61, as co-administration of the two drugs had more pronounced effects on cell proliferation and apoptosis. In vivo administration of RITA or GANT61 suppressed rhabdomyosarcoma xenograft growth in nude mice; however, co-administration did not further enhance tumor suppression, even though cell proliferation was decreased. RITA was more potent than GANT61 in downregulating HH target gene expression; surprisingly, this suppressive effect was almost completely eliminated when the two drugs were administered together. Notably, RNA-seq demonstrated a broader response of pathways involved in cancer cell growth in the combination treatment, providing a plausible interpretation for tumor reduction in the absence of HH signaling downregulation. PMID- 30447255 TI - HHLA2 is a novel immune checkpoint protein in pancreatic ductal adenocarcinoma and predicts post-surgical survival. AB - HHLA2 is a newly identified member of the B7 immune checkpoint family, but its function and crosstalk with immune cells is not fully understood. To gain insights into the HHLA2 expression profile and to determine the clinical significance and function of HHLA2 in pancreatic cancer, we performed immunohistochemistry (IHC) analyses on tissue microarrays (TMAs) of pancreatic ductal adenocarcinoma (PDAC, n = 92) with matched peritumoral tissues as well as in cohorts of precancerous lesions: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). We found that HHLA2 was rarely detected in normal acinar, islet, and ductal cells but widely expressed from early pancreatic precancerous lesions to invasive PDAC. The overall HHLA2 positivity was 95% (19/20) in low grade PanIN and 70.73% (29/41) in IPMN. HHLA2 expression was detected in 77.17% (71/92) of the PDAC cases and was significantly associated with better prognosis in this cohort. Our findings suggest that HHLA2 may behave as a costimulatory ligand in pancreatic cancer, which differs from other B7 family members that are largely characterized as checkpoint inhibitors. Further investigation of the HHLA2 signaling pathway and its receptors is warranted by our data and may lead to novel therapeutic interventions. PMID- 30447256 TI - Humble beginnings with big goals: Small molecule soluble epoxide hydrolase inhibitors for treating CNS disorders. AB - Soluble epoxide hydrolase (sEH) degrades epoxides of fatty acids including epoxyeicosatrienoic acid isomers (EETs), which are produced as metabolites of the cytochrome P450 branch of the arachidonic acid pathway. EETs exert a variety of largely beneficial effects in the context of inflammation and vascular regulation. sEH inhibition is shown to be therapeutic in several cardiovascular and renal disorders, as well as in peripheral analgesia, via the increased availability of anti-inflammatory EETs. The success of sEH inhibitors in peripheral systems suggests their potential in targeting inflammation in the central nervous system (CNS) disorders. Here, we describe the current roles of sEH in the pathology and treatment of CNS disorders such as stroke, traumatic brain injury, Parkinson's disease, epilepsy, cognitive impairment, dementia and depression. In view of the robust anti-inflammatory effects of stem cells, we also outlined the potency of stem cell treatment and sEH inhibitors as a combination therapy for these CNS disorders. This review highlights the gaps in current knowledge about the pathologic and therapeutic roles of sEH in CNS disorders, which should guide future basic science research towards translational and clinical applications of sEH inhibitors for treatment of neurological diseases. PMID- 30447258 TI - VCAM-1-mediated neutrophil infiltration exacerbates ambient fine particle-induced lung injury. AB - BACKGROUND: Fine ambient particle matter (PM2.5) induces inflammatory lung injury; however, whether intratracheal administration of PM2.5 increases pulmonary polymorphonuclear leukocyte (PMN) infiltration, the mechanism of infiltration, and if these cells exacerbate PM2.5-induced lung injury are unknown. METHODS: Using 32,704 subjects, the association between blood PMNs and ambient PM2.5 levels on the previous day was retrospectively analyzed. Neutropenia was achieved by injecting mice with PMN-specific antibodies. Inhibition of PMN infiltration was achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of PMNs on PM2.5-indcued lung injury and endothelial dysfunction were observed. RESULT: Short-term PM2.5 (> 75 MUg/m3 air) exposure increased the PMN/white blood cell ratio and the PMN count in human peripheral blood observed during routine examination. A significant number of PM2.5-treated PMNs was able to bind sVCAM-1. In mice, intratracheally-instilled PM2.5 deposited in the alveolar space and endothelial cells, which caused significant lung edema, morphological disorder, increased permeability of the endothelial-alveolar epithelial barrier, and PMN infiltration with increased VCAM-1 expression. Depletion of circulatory PMNs inhibited these adverse effects. Replenishment of untreated PMNs, but not those pretreated with soluble VCAM-1, restored lung injury. In vitro, PM2.5 increased VCAM-1 expression and endothelial and epithelial monolayer permeability, and promoted PMN adhesion to, chemotaxis toward, and migration across these monolayers. PMNs, but not those pretreated with soluble VCAM-1, exacerbated these effects. CONCLUSION: VCAM-1 mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury. Results suggest that drugs that inhibit PMN function might prevent acute deterioration of chronic pulmonary and cardiovascular diseases triggered by PM2.5. PMID- 30447257 TI - Expressing cytotoxic compounds in Escherichia coli Nissle 1917 for tumor targeting therapy. AB - Abnormal blood vessels and hypoxic and necrotic regions are common features of solid tumors and related to the malignant phenotype and therapy resistance. Certain obligate or facultative anaerobic bacteria exhibit inherent ability to colonize and proliferate within solid tumors in vivo. Escherichia coli Nissle 1917 (EcN), a non-pathogenic probiotic in European markets, has been known to proliferate selectively in the interface between the viable and necrotic regions of solid tumors. The objective of this study was to establish a tumor-targeting therapy system using the genetically engineered EcN for targeted delivery of cytotoxic compounds, including colibactin, glidobactin and luminmide. Biosynthetic gene clusters of these cytotoxic compounds were introduced into EcN and the corresponding compounds were detected in the resultant recombinant EcN strains. The recombinant EcN showed significant cytotoxic activity in vitro and in vivo as well, and significantly suppressed the tumor growth. Together, this study confirmed efficient tumor-targeting colonization of EcN and demonstrated its potentiality in the tumor-specific delivery of cytotoxic compounds as a new tumor-targeting therapy system. PMID- 30447260 TI - Issues in interpreting and estimating the excess risk in case of count data. PMID- 30447259 TI - Role of extracellular vesicles in release of protein adducts after acetaminophen induced liver injury in mice and humans. AB - Formation of acetaminophen (APAP) protein adducts are a critical feature of APAP hepatotoxicity, and circulating protein adducts have recently been utilized in bioassays for identification of APAP overdose in humans. Despite their clinical significance, mechanisms of adduct release into the circulation are not well understood. Extracellular vesicles (EVs) are discrete membrane bound vesicles, which package cellular cargo and function in extracellular transport. Clarification of their role in transport of APAP adducts is relevant since adduct packaging within these vesicles could shield them from detection by antibody based methods, resulting in under-estimating adduct levels. Hence, this study evaluated EV release after APAP overdose in primary mouse hepatocytes and human HepaRG cells in vitro, in mice and APAP overdose patients in vivo and examined their role in transport of APAP-protein adducts. EVs were characterized by size and protein composition and the levels of APAP-protein adducts were measured. Significant elevations in circulating EV numbers were observed 6 h after APAP overdose in vivo and by 4 h in primary mouse hepatocytes in culture. EVs were also elevated in media from HepaRG cells by 24 h after APAP exposure, an effect recapitulated in APAP overdose patients, where EV numbers were elevated compared to healthy controls. Although APAP-protein adducts were elevated in circulation and media parallel to the increased exosome release, no detectable adducts were observed within EVs. This suggests that although APAP overdose enhances EV release from hepatocytes in mice and humans, it is not a significant mechanism of release of APAP protein adducts into circulation. PMID- 30447261 TI - Association of hippocampal volume with gait variability in pre-dementia and dementia stages of Alzheimer disease: Results from a cross-sectional study. AB - BACKGROUND: Decreased hippocampal volume is a biomarker of Alzheimer disease (AD). The association of hippocampal volume with gait variability across the spectrum of AD, especially in early stages, has been few studied. The study aims to examine the association of hippocampal volume with the coefficient of variation (CoV) of stride time in individuals with mild and moderate to severe subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (na MCI), amnestic mild cognitive impairment (a-MCI), and mild to moderate AD dementia. METHODS: 271 individuals (79 mild SCI, 68 moderate to severe SCI, 47 na MCI, 42 a-MCI and 35 mild to moderate AD dementia) were included in this cross sectional study. Hippocampal volume was quantified from a three-dimensional T1 weighted MRI. CoV of stride time was recorded at self-selected pace with an electronic walkway. Age, sex, body mass index, number of drugs daily taken, history of falls, walking speed, type of MRI scanner, total intracranial volume, and white matter volume abnormality were used as covariates. RESULTS: Participants with moderate to severe SCI had a higher CoV of stride time compared to those with mild SCI and na-MCI (P < 0.010), and a higher hippocampal volume compared to other groups (P <= 0.001). Participants with moderate to severe SCI had increased hippocampal volume associated with increased CoV of stride time (coefficient of regression beta = 0.750 with P = 0.041), while the other groups did not show any significant association. CONCLUSIONS: A positive association between greater hippocampal volume (i.e., better brain morphological structure) and an increased stride time variability (i.e., worse gait performance) in individuals with moderate to severe SCI is reported. This association confirms the key role of the hippocampus in gait control and suggests an inefficient compensatory mechanism in early stages of pathological aging like AD. PMID- 30447262 TI - Validation of the return of spontaneous circulation after cardiac arrest (RACA) score in two different national territories. AB - BACKGROUND: The likelihood of return of spontaneous circulation (ROSC) after out of-hospital cardiac arrest (OHCA) is influenced by unmodifiable (gender, aetiology, location, the presence of witnesses and initial rhythm) and modifiable factors (bystander CPR and the time to EMS arrival). All of these have been included in the ROSC After Cardiac Arrest (RACA) score. PURPOSE: To test the ability of the RACA score to predict the probability of ROSC in two different regions with different local resuscitation networks: the Swiss Canton Ticino and the Italian Province of Pavia. METHODS AND RESULTS: All OHCAs occurred between January 1st 2015 and December 31st 2017 were included. The original regression coefficients for all RACA score variables were applied. The probability to obtain the ROSC as measured with the RACA score was divided in tertiles. Overall, 2041 OHCAs were included in the analysis. The RACA score showed good discrimination for ROSC (AUC 0.76) and calibration, without interaction (p 0.28) between the region and the probability of ROSC. The probability of ROSC was 15% for RACA scores <0.28, 20% for RACA scores between 0.28 and 0.42, increasing to 55% for RACA scores > 0.42. CONCLUSIONS: The application of the RACA score reliably assess the probability to obtain the ROSC, with equal effectiveness in the two regions, despite different organization of the resuscitation network. Patients with a RACA score >0.42 had more than 50% probability to obtain ROSC. PMID- 30447263 TI - Twenty-Year Trends in the Characteristic, Management and Outcome of Patients with ST-Elevation Myocardial Infarction and Out-of-hospital Reanimation. Insight from the National AMIS PLUS Registry 1997-2017. AB - BACKGROUND: Few studies describe recent changes in the incidence, treatment and outcome of successfully resuscitated STEMI patients after out-of-hospital cardiac arrest (OHCA) compared with non-OHCA STEMI patients. OBJECTIVE: To examine temporal trends in the incidence, therapeutic management, most serious complications, mortality rate and outcome of OHCA patients fulfilling criteria of STEMI compared with a reference group of STEMI patients without OHCA. METHODS: Analysis of registry data (AMIS Plus Registry) among STEMI patients both with and without OHCA between 1997 and 2017. RESULTS: Among 31,650 patients with STEMI, 6.8 % were successfully resuscitated prior to hospital admission. Increasing incidences of hospital-admitted patients following successful out-of-hospital CPR were observed (4.5 % in 1999 vs. 8.6 % in 2017). OHCA STEMI patients were at higher clinical risk at presentation (36.1 % vs. 2.7 %; p<0.001 with cardiogenic shock) despite a shorter time span from the onset of symptoms to hospitalization (195 min vs. 107 min; p<0.001) and a lower prevalence of cardiovascular risk factors except smoking. More PCIs were performed in STEMI patients with OHCA (78.9 % vs. 74.5 % for non-OHCA patients; p<0.001). However, over time PCI became the preferred primary intervention irrespective of the OHCA status of STEMI patients. For STEMI patients without OHCA, there was a significant correlation between PCI and time periods on in-hospital mortality (p<0.001), which was p=0.002 when adjusted for age and gender. For STEMI patients with OHCA, the interaction between PCI and time was unadjusted p=0.395 and p=0.438 when adjusted for age and gender. PMID- 30447264 TI - The effects and possible mechanisms of triclosan on steroidogenesis in primary rat granulosa cells. AB - BACKGROUND: Triclosan (TCS) has been detected in human tissues. It can disrupt steroidogenesis in vivo. The study on the effects of TCS on ovarian granulosa cells was lacking. METHODS: Primary rat granulosa cells (rGCs) were treated with TCS. Concentrations of estradiol (E2), progesterone (P4) in the cell culture supernatants were measured. Microarray was used to measure gene expression profiles. Pathway analysis was performed to identify signaling networks that linked differentially expressed genes (DEGs). Genes related with steroidogenesis were analyzed. RESULTS: TCS increased E2 and P4 production. A total of 2006 DEGs were identified. Pathway analysis revealed that ovarian steroidogenesis pathway was upregulated. Both PCR and Western-blot demonstrated that the expressions of key genes involved in this pathway were significantly increased. CONCLUSIONS: TCS co-administered with follicle-stimulating hormone (FSH) could increase E2 and P4 production in rGCs and up-regulate ovarian steroidogenesis pathway. StAR and aromatase protein were increased by TCS, while P450scc protein wasn't changed significantly. PMID- 30447265 TI - Isoflavone Intake in Early Pregnancy and Hypospadias in the Japan Environment and Children's Study. AB - OBJECTIVE: To explore the association between isoflavone intake in early pregnancy (the critical window of masculinisation) and hypospadias. Since oestrogen is likely to contribute to the differentiation of male external genitalia, dietary intake of isoflavone, which has a similar structure to human oestrogen, may be associated with the occurrence of hypospadias. However, there has been little evidence of this association. MATERIALS AND METHODS: We used data of a nationwide birth cohort study, which recruited women as early in pregnancy as possible throughout Japan between 2011 and 2014. From the response to a self administered food-frequency questionnaire, the daily intake of genistein (as a representative for isoflavone) was estimated. Information on hypospadias cases that were diagnosed until after the firth month after birth was obtained from medical records. Odds ratios (ORs) of hypospadias were estimated using a logistic regression model. RESULTS: Among 41,578 mothers, who delivered singleton live male births, the median genistein intake was 15.3 mg/day, and a total of 51 cases of hypospadias were identified. Compared with mothers in the reference group (genistein intake 11th-89th percentiles), those in the low intake group (<= 10th percentile) had an elevated risk of their sons having hypospadias (multivariable adjusted OR = 2.8, 95% confidence interval (CI) = 1.4-5.8). Adverse or beneficial effects of genistein on hypospadias were not observed in the high intake group (>= 90th percentile) (OR = 0.9, 95% CI = 0.4-2.4). CONCLUSION: Low maternal intake of isoflavone in early pregnancy was associated with an elevated risk of hypospadias. PMID- 30447266 TI - The DACRON Ureter: A Case of Ureter to Aorto-Femoral Dacron Graft Fistulization. AB - We present a case of chronic, severe, intermittent hematuria found to be associated with a ureteral to aorto-femoral bypass fistulization. The graft was directly visualized on ureteroscopy and identified as the source of hematuria during exploratory laparotomy. Ureteral fistulization is a rare etiology of hematuria. Ureteral fistulization to an arterial graft has been reported several times in past decades. However, no cases have reported direct visualization of the dacron graft on ureteroscopy. PMID- 30447267 TI - Clinical epidemiology: Detrusor voiding contraction maximum power, related to ageing. AB - OBJECTIVE: To report clinical epidemiology of detrusor (bladder) muscle contraction maximum related to ageing in patients referred with signs and symptoms of lower urinary tract dysfunction. STUDY DESIGN AND SETTING: 1308 urodynamic pressure-flow measurements were analysed in retrospective. Standard measures of detrusor muscle voiding contraction strength were compared for gender and ranked by age (range 20-90years). RESULTS: A decline in maximum detrusor contraction strength was observed when the results were ranked according to age. Detrusor muscle maximum voiding contraction was on average 30% less powerful in older women and 12% less powerful in the aged men, when compared to the younger. This is transversal data -interpreted in a longitudinal manner- and from persons referred to specialist care with (the full spectrum of) signs and symptoms of lower urinary tract dysfunction. Therefore these results are relevant for clinical epidemiology but not definitely generalizable to (symptom-free) population level. CONCLUSIONS: Clinical epidemiological evaluation of patients referred with lower urinary tract symptoms, found lower detrusor maximum contraction strength in higher-age cohorts, both for women as for men. The maximum detrusor strength difference in association with age, was lager in women than in men. PMID- 30447268 TI - Urethral Trauma Following Pelvic Fracture From Horseback Saddle Horn Injury Versus Other Mechanisms of Pelvic Trauma. AB - OBJECTIVE: To examine the rate of urethral trauma and pubic symphysis diastasis in saddle horn injury, which occurs when horseback riders are bucked into the air and land with their perineum striking the rigid saddle horn, compared to pelvic fracture from other mechanisms. METHODS: A retrospective review was performed of male patients presenting to our level-1 trauma center with pelvic ring fractures between January 1, 2001 and December 30, 2016. Demographics, injury severity score, mechanism of injury (saddle horn vs other), pubic symphysis diastasis, and lower genitourinary (GU) injuries (bladder and urethra) were identified in the trauma registry. Chart review confirmed accuracy of lower GU trauma. RESULTS: A total of 1195 males presented with pelvic ring fractures, average age 43 years (SD 19 years). Of these, 87 of 1195 (7%) presented with lower GU injuries. Saddle horn injuries had a higher rate of lower GU injuries, 12/60 (20%) versus 75 of 1135 (7%) [P = .001]. In those with lower GU injuries, 47 of 87 (54%) had urethral injury. The rate of urethral injury was significantly higher in the saddle horn cohort, 10 of 12 (83%) versus 37 of 75 (49%) [P = .03]. Furthermore, rate of pubic symphysis diastasis was higher amongst saddle horn injuries, 12 of 12 (100%) versus other mechanisms 39 of 75 (52%) [P = .001]. CONCLUSION: We found that urethral injury and pubic symphysis diastasis were higher in patients with saddle horn injury compared to other mechanisms of pelvic ring disruption. Clinicians should be aware of these associations when treating pelvic fracture following equestrian injuries. PMID- 30447269 TI - Medical treatments for hypogonadism do not significantly increase the risk of deep vein thrombosis over general population risk. AB - OBJECTIVE: To evaluate the risk of deep vein thrombosis (DVT) in men treated with testosterone replacement therapy (TRT) or Clomiphene Citrate (CC) and assess other etiologies for DVT as contributing factors. METHODS: Retrospective chart review of 1,180 consecutive hypogonadal men who were treated with either TRT or CC. Sixty-four percent had mixed, 16% had primary, and 20% had secondary hypogonadism. RESULTS: Of the 1,180 men with hypogonadism, 694 were treated with TRT, while 486 were treated with CC. Overall, 10/1180 (0.8%) men were diagnosed with a DVT during the treatment, nine of whom were on TRT and one on CC. Of the 10 men diagnosed with DVT while on treatment, seven (70%) had potential identifiable etiologies for DVT other than treatment for hypogonadism. None of the men were found to be polycythemic at the time of DVT diagnosis. There was a higher incidence of DVT in men treated with TRT than CC, however; the overall percentages of DVT in both treatment groups were relatively low. There was no difference in the percentages of men found to have other identifiable etiologies for DVT besides being on treatment between the TRT and CC groups. There was not a difference in testosterone levels between the TRT and CC groups. CONCLUSIONS: The overall of rates of DVT for TRT and CC treated patients are relatively low, and the majority of patients with DVT had other identifiable etiologies for DVT. Polycythemia was not found to be a risk factor in the patients diagnosed with DVTs. PMID- 30447270 TI - Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury. AB - BACKGROUND AND AIMS: ACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre injured liver (Abcb4/Mdr2-/-) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model. METHOD: Ten (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4-/- knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2-DeltaDeltaCt method. IL6 and HGF plasma levels were quantified by ELISA. RESULTS: Older mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels. CONCLUSION: We propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4-/- mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model. PMID- 30447271 TI - Conversion of PLGA nanoparticle suspensions into solid dosage forms via fluid bed granulation and tableting. AB - Incorporating poorly soluble drugs into polymeric nanoparticles is a widely investigated approach to improve their biopharmaceutical performance. Poly(DL lactide-co-glycolide) (PLGA) nanoparticle formulations have previously been tested and recommended as drug carriers for peroral administration of poorly soluble porphyrin derivatives intended for photodynamical therapy. Based on those PLGA formulations the present study investigates conventional techniques like fluid bed granulation and tableting for conversion of such polymeric nanoparticle suspensions into solid dosage forms. Analytical methods like asymmetrical flow field-flow fractionation (AF4) and photon correlation spectroscopy (PCS) were used to assess changes of the nanoparticle properties during processing and the recovery after redispersion of the solid dosage forms. Preliminary experiments were conducted to demonstrate the feasibility of the granulation and tableting strategy. Afterwards, design of experiments (DoE) was used to determine formulation and process parameters with critical influence on several properties of the solid forms, in particular the recovery of nanoparticles during dissolution testing. Fluid bed granulation with aqueous PLGA nanoparticle suspensions and soluble carriers was shown to be a simple and high yield process for drying of the nanoparticles. The nanoparticle concentration of the granulation suspension and the ratio of the spraying rate and the atomization air pressure were critical for the physicochemical characteristics of the granules like density and particle size distribution (PSD) as well as for the redispersibility to nanoparticle suspensions of original properties. The granules were compressed to tablets without impairing the nanoparticle diameter and the recovery when an adequate level of filler and low compression forces were used. PMID- 30447272 TI - Maternal folic acid deficiency stimulates neural cell apoptosis via miR-34a associated with Bcl-2 in the rat foetal brain. AB - Embryonic development is a critical period wherein brain neurons are generated and organized. Maternal dietary folate, a cofactor in one-carbon metabolism, modulates neurogenesis and apoptosis in foetal brain neurons. We hypothesized that aberrant neuronal apoptosis may affect the development of the central nervous system during maternal folic acid deficiency, with evident effects because maternal folic acid deficiency modulates the microRNA-34a associated with Bcl-2 pathway during embryonic development. Four-week-old female Sprague-Dawley rats were divided randomly into two groups (10 rats per group): a folate deficient diet group and a folate-normal diet group. The diets were administered to the rats 60 d before mating, which was continued for the pregnant dams until parturition. Maternal folic acid deficiency increased neuronal apoptosis in the hippocampus and the cortex in the offspring. Furthermore, maternal folic acid deficiency increased the ratio of cleaved caspase-3/caspase-3, followed by an increase in caspase-3 activity. Moreover, maternal folic acid deficiency downregulated Bcl-2 and upregulated Bax, and this effect associate with maternal folic acid deficient increases expression of microRNA-34a. Together, the present results indicate that maternal folic acid deficiency stimulates neuronal apoptosis via microRNA-34a associated with Bcl-2 signalling in rat offspring. PMID- 30447273 TI - Neurological syndrome in goats associated with Ipomoea trifida and Ipomoea carnea containing calystegines. AB - A disease characterized by ataxia, tremors and nystagmus had been observed in goats in Nicaragua. The main histologic lesions were loss and neuronal vacuolation of Purkinje cells and Wallerian-like degeneration mainly in the cerebellum, suggesting a glycoprotein storage disease. Ipomoea carnea and Ipomoea trifida found in the paddocks were negative for swainsonine, but contained calystegines at 0.02% and 0.06% suggesting that the disease was caused by these substances, which are competitive inhibitors of beta-glucosidase and alpha galactosidase activities. PMID- 30447274 TI - Protective effect of Myrsine parvifolia plant extract against the inflammatory process induced by Bothrops jararaca snake venom. AB - Accidents involving snakes from the genus Bothrops sp. constitute the most important cause of snake envenomation in Brazil. The Myrsine genus has been reported to be used in folk medicine against snakebites. In this work, the phytochemical profiles and ability of extracts from Myrsine parvifolia leaves to reduce the inflammatory process (edema, vascular permeability increase and leukocyte migration) induced by Bothrops jararaca venom were investigated in vivo. Chemical compounds were identified by chromatographic and spectroscopy techniques. Total polyphenol, tannin, and flavonoid contents were determined by spectrophotometric methods. Swiss male mice received an oral administration of extracts (100 mg/kg) in different protocols. Paw edema, intraperitoneal vascular permeability and pleurisy models in mice were used to evaluate the antiophidic potential of the extracts. Paw edema was induced by subplantar injection of B. jararaca venom and quantified as the increase in paw volume. Changes in vascular permeability were assessed by measuring the amount of Evans blue dye extravasation. Leukocyte migration was assessed by total and differential counts in the pleural cavity washes. Myricetin, myricetin-3-O-beta-arabinopyranoside, quercetin and kaempferol were isolated from the ethyl acetate extract and identified as the primary compounds of the dichloromethane extract. Terpenes and fatty acids were identified in the hexane and dichloromethane extracts. The pretreated group with hydroethanolic and dichloromethane extract reduced total edema (40 and 52%, respectively), vascular permeability increase (32.4 and 32.2%, respectively) and leukocyte influx into the pleural cavity (42 and 39%, respectively), while the group treated with hexane extract showed only reduced edema (37%) induced by B. jararaca venom. The hydroethanolic extract showed better results in all of the tests performed and was also administered by the protocol of post-poisoning, showing maintenance of paw edema reduction and cell migration. These data indicate a potential anti-inflammatory activity of M. parvifolia in poisoning by B. jararaca, especially to reduce local poison effects. PMID- 30447275 TI - Neutralizing properties of LY315920 toward snake venom group I and II myotoxic phospholipases A2. AB - A need exists to develop specific and clinically useful inhibitors of toxic enzymes present in snake venoms, responsible for severe tissue damage and life threatening effects occurring in thousands of people suffering envenomations globally. LY315920 (Varespladib, S-5920, A-001), a low molecular weight drug developed to inhibit several human secreted phospholipases A2 (PLA2s), was recently shown to also inhibit PLA2s in whole snake venoms with high potency, yet no studies have examined its direct effect on purified snake venom PLA2s. This work evaluated the ability of LY315920 to neutralize the enzymatic and toxic activities of three isolated PLA2 toxins of structural groups I (pseudexin) and II (crotoxin B and myotoxin I), and their corresponding whole venoms. In vitro, LY315920 inhibited the catalytic activity of these three enzymes upon a synthetic substrate. The drug also blocked their cytotoxic effect on cultured murine myotubes. In mice, preincubation of the toxins or venoms with LY315920, followed by their intramuscular injection, resulted in significant inhibition of muscle damage. Finally, immediate, independent injection of LY315920 at the site of toxin or venom inoculation also resulted in a large reduction of myonecrosis in the case of pseudexin and myotoxin-I, and of Pseudechis colletti and Bothrops asper whole venoms, suggesting a possible method of drug delivery in emergency situations. Present findings add evidence to suggest the possibility of using LY315920 as a field antidote in snakebites, aiming to limit the myonecrosis induced by many venom PLA2s in the clinical setting. PMID- 30447276 TI - Purification and identification of an aflatoxin B1 degradation enzyme from Pantoea sp. T6. AB - Aflatoxin B1 (AFB1) is a secondary metabolite produced by Aspergillus flavus and other fungi. Soil, crops, food, feed, etc. were susceptible to aflatoxin B1 contamination, which caused adverse economic and health consequences. It is necessary to search for microorganisms or microbial enzymes that can degrade AFB1. The degradation activity of AFB1 by cell-free supernatant (68.30%) of isolate Pantoea sp. T6 was significantly higher (P < 0.05) than viable bacterial cells (4.87%) and intracellular cell extracts (3.68%). The supernatant's AFB1 degradation activity was reduced from 68.30% to 5.33% in treatment with protease K and sodium dodecyl sulphate (SDS). An extracellular enzyme from the supernatant was secreted by Pantoea sp. T6 and was named as Pantoea aflatoxin degradation enzyme (PADE), which was obtained using Diethylaminoethanol (DEAE)-Sepharose chromatography. PADE was further purified by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The PADE, outer membrane protein A, was identified by mass spectrometry and molecular mass was 38180.1Da. The optimum temperature and pH for the reaction of PADE with AFB1 were 40 degrees C and 7.0, respectively. These finding showing that the PADE, which was isolated from the supernatant of Pantoea sp. T6, has the ability to degrade AFB1, and may have potential application for aflatoxin B1 reduction in the food and feed industry. PMID- 30447277 TI - Computational analysis of the Plasmodiophora brassicae genome: mitochondrial sequence description and metabolic pathway database design. AB - Plasmodiophora brassicae is an obligate biotrophic pathogenic protist responsible for clubroot, a root gall disease of Brassicaceae species. In addition to the reference genome of the P. brassicae European e3 isolate and the draft genomes of Canadian or Chinese isolates, we present the genome of eH, a second European isolate. Refinement of the annotation of the eH genome led to the identification of the mitochondrial genome sequence, which was found to be bigger than that of Spongospora subterranea, another plant parasitic Plasmodiophorid phylogenetically related to P. brassicae. New pathways were also predicted, such as those for the synthesis of spermidine, a polyamine up-regulated in clubbed regions of roots. A P. brassicae pathway genome database was created to facilitate the functional study of metabolic pathways in transcriptomics approaches. These available tools can help in our understanding of the regulation of P. brassicae metabolism during infection and in response to diverse constraints. PMID- 30447278 TI - Genes and transcription factors related to the adverse effects of maternal type I diabetes mellitus on fetal development. AB - PURPOSE: Maternal type I diabetes mellitus (T1DM) increases the risk of adverse pregnancy outcomes, but the corresponding mechanism is unclear. This study aims to investigate the mechanism underlying the adverse pregnancy outcomes of maternal T1DM. METHODS: Gene expression microarray (GSE51546) was down-loaded from the Gene Expression Omnibus. This dataset included 12 umbilical cord samples from the newborns of T1DM mothers (T1DM group, N = six) and non-diabetic mothers (control group, N = six). RESULTS: Consequently, 1051 differentially expressed genes (DEGs) were found between the two groups. The up-regulated DEGs enriched in 30 KEGG pathways. HLA-DPA1, HLA-DMA, HLA-DMB, HLA-DQA1, HLA-DQA2 and HLA-DRA enriched in "Type I diabetes mellitus". This pathway was strongly related to 14 pathways, most of which were associated with diseases. Then, a protein-protein interaction network was constructed, and 45 potential key DEGs were identified. The 45 DEGs enriched in pathways such as "Rheumatoid arthritis", "Chemokine signaling pathway" and "Cytokine-cytokine receptor interaction" (e.g. CXCL12 and CCL5). Transcription factors (TFs) of key DEGs were predicted, and a TF-DEG regulatory network was constructed. CONCLUSIONS: Some genes (e.g. CXCL12 and CCL5) and their TFs were significantly and abnormally regulated in the umbilical cord tissue from the pregnancies of T1DM mothers compared to that from non-T1DM mothers. PMID- 30447279 TI - Development of real-time PCR assays for single and simultaneous detection of infectious bursal disease virus and chicken anemia virus. AB - Infectious bursal disease virus (IBDV) and chicken anemia virus (CAV) cause relevant immunosuppressive diseases in poultry. Clinical diagnosis of these viruses is challenging given the different disease presentations and the frequent occurrence of co-infections with other pathogens. Here, we standardized and validated simplex and duplex RT-qPCR assays for the straightforward detection of IBDV and CAV. The qPCR assays are based on primers and hydrolysis probes that target highly conserved regions of IBDV and CAV genomes. Analytical sensitivity tests on 10-fold serial dilutions containing 100-108 viral genomes indicated that the simplex assays have good determination coefficients and efficiency and detect a wide range of virus doses (102 to 108 molecules copies/reactions). The relatively small values of intra- and inter-assay variability ensure the repeatability and support its reproducibility in different diagnostic and research facilities. The assays are also efficient tools for absolute quantification as indicated by the analytical performance analysis. The assays have an excellent specificity and absence of cross-reactivity with negative samples, or with other common avian viruses. The simplex IBDV and CAV assays use probes labelled with different dyes (FAM and HEX) and can be multiplexed for the simultaneous detection of both viruses. The determination coefficients, PCR efficiencies, and relatively small intra- and inter-assay variability were comparable to the simplex assays. This duplex assay is the first to simultaneously detect IBDV and CAV using the same RNA extraction from the bursa of Fabricius in a single and straightforward step. Therefore, this method is time saving, provides quantitative results for both targets without any cross reaction, and reduces the risk of carrying-over contaminations. The qPCR assays here developed can be used in simplex and duplex formats for detection and quantification of large number of samples with reliable sensitivity and specificity. These tools are expected to improve surveillance and control of these ubiquitous viruses. PMID- 30447280 TI - Elevated pro-inflammatory gene expression in the third trimester of pregnancy in mothers who experienced stressful life events. AB - BACKGROUND: Stress exposure is associated with risk for adverse pregnancy outcomes, potentially in part through dysregulated immune and inflammatory activity. Evidence suggests that stress during pregnancy is associated with inflammation during pregnancy, consistent with risk for preterm birth. However, research has not tested whether complementary changes are reflected in immune cell gene expression, or upstream regulation of inflammation. The purpose of this study was to test associations between preconception and prenatal stress exposure and third trimester immune cell gene expression, focusing specifically on sets of genes previously linked to stress in non-pregnant samples: Pro-inflammatory genes, and antiviral and antibody genes. METHODS: A sample of 116 low-income, diverse women was recruited from 5 U.S. sites by the Community Child and Health Network at the birth of a child. This study is of the subgroup of women who became pregnant again over the two-year follow-up period, and provided information on stressful life events that occurred both preconception and during the third trimester of the subsequent pregnancy. Dried blood spots (DBS) were collected in the third trimester of pregnancy, and used for gene expression analysis. RESULTS: Women with more prenatal stressful life events had higher expression of pro-inflammatory genes when compared to those with fewer life events, and the effect was driven by increased activation of pro-inflammatory transcription factors, NF-kappaB and AP-1. Preconception stressful life event exposure was not associated with gene expression profiles. When entered into models simultaneously, only prenatal stressful life events were associated with up-regulation of pro-inflammatory genes. No differences between high or low stress groups emerged for antiviral or antibody genes. CONCLUSIONS: Prenatal stress exposure was associated with up-regulated pro-inflammatory gene expression during pregnancy, and increased activity of NF-kappaB and AP-1. In contrast, stress occurring preconception was not associated with gene expression. These results are consistent with the hypothesis that stress-induced activation of pro inflammatory transcriptional pathways in pregnancy, but not earlier, may increase risk for inflammation-driven adverse pregnancy outcomes. PMID- 30447282 TI - Could glucagon-like peptide-1 be a potential biomarker of early-stage intestinal ischemia? AB - Intestinal ischemia, also called mesenteric ischemia, is a severe gastrointestinal and vascular medical emergency caused by a sudden decrease of blood flow through the mesenteric vessels. It generates hypoperfusion of intestinal tissues and can rapidly progress to intestinal wall infarction, systemic inflammation or even death if not treated in time. The mortality of this condition is still considerably high despite all the medical advances of the past few years. This is partially due to the difficulty of diagnosing early stage mesenteric ischemia. Indeed, a speedy and correct diagnosis is decisive for suitable medical care. However, early symptoms are unspecific and conventional clinical markers are neither specific nor sensitive enough. In the last few years, significant clinical and preclinical efforts have been made to find biomarkers which could predict gastrointestinal damage before it becomes irreversible. Here, the gut-derived hormone glucagon-like peptide-1 (GLP-1) is described as a potential early biomarker of this severe condition. Indeed, GLP-1 plasma levels rise rapidly in both mice and humans with intestinal ischemia. This discovery could counter the cruel lack of clinical biomarkers available to diagnose and therefore manage intestinal ischemia efficiently in the early stages. GLP-1 could thus become part of a panel of biomarkers for intestinal ischemia and could help to reduce the associated high mortality rates. PMID- 30447281 TI - Removal of microglial-specific MyD88 signaling alters dentate gyrus doublecortin and enhances opioid addiction-like behaviors. AB - Drugs of abuse promote a potent immune response in central nervous system (CNS) via the activation of microglia and astrocytes. However, the molecular mechanisms underlying microglial activation during addiction are not well known. We developed and functionally characterized a novel transgenic mouse (Cx3cr1 CreBTtg/0:MyD88f/f [Cretg/0]) wherein the immune signaling adaptor gene, MyD88, was specifically deleted in microglia. To test the downstream effects of loss of microglia-specific MyD88 signaling in morphine addiction, Cretg/0 and Cre0/0 mice were tested for reward learning, extinction, and reinstatement using a conditioned place preference (CPP) paradigm. There were no differences in drug acquisition, but Cretg/0 mice had prolonged extinction and enhanced reinstatement compared to Cre0/0 controls. Furthermore, morphine-treated Cretg/0 mice showed increased doublecortin (DCX) signal relative to Cre0/0 control mice in the hippocampus, indicative of increased number of immature neurons. Additionally, there was an increase in colocalization of microglial lysosomal marker CD68 with DCX+cells in morphine-treated Cretg/0 mice but not in Cre0/0 or drug-naive mice, suggesting a specific role for microglial MyD88 signaling in neuronal phagocytosis in the hippocampus. Our results show that MyD88 deletion in microglia may negatively impact maturing neurons within the adult hippocampus and thus reward memories, suggesting a novel protective role for microglia in opioid addiction. PMID- 30447283 TI - On-line rheological characterization of semi-solid formulations. AB - The rheological profile of a semi-solid product is a critical quality attribute. To monitor changes of this attribute during manufacturing, it would be beneficial to measure the rheological parameters in an on-line or in-line mode and implement this as a part of a control strategy for manufacturing of semi-solids. None of the process analytical technology (PAT) tools for measuring the rheological parameters have yet been widely accepted in the pharmaceutical area, as most of the equipment can only measure viscosity. Therefore, an automated system based on the measurement of pressure difference across both a topology optimized channel and a tube geometry (capillary viscometer) was investigated. The Pressure Difference Apparatus (PDA) can sample from the bulk intermediate/product stream and press the sample through the apparatus at different flow rates to yield a frequency sweep (G' and G") and a flow curve (viscosity). A calibration model was successfully prepared and verified with hydroxyethyl cellulose gels with polymer content varying from 1.0 to 1.5% (w/w) resulting in gels of different viscosities. The calibration model was used on-line during manufacturing of a gel and manufacturing changes related to dilution of the product were clearly reflected in the batch evolution profiles. The measurements with the PDA reflected the shear rate and frequency ranges relevant for manufacturing and thereby complemented the rheology measurements obtained with a standard rheometer with real time data. PMID- 30447284 TI - Pharmaceutical preformulation studies and paediatric oral formulations of sodium dichloroacetate. AB - The purpose of this study was to develop liquid and solid paediatric formulations of sodium dichloroacetate (DCA) for the treatment of congenital lactic acidosis (CLA). In this work preformulation studies on the active molecule were performed to identify those physico-chemical properties of the drug relevant to the design of the dosage forms and their process of manufacture. TGA and DSC analysis suggested that sodium DCA was very hygroscopic. HPLC and NMR analysis showed that the compound was widely stable in aqueous solutions at 25 and 40 degrees C at all the pH values studied. Based on these results, sodium DCA was formulated as palatable solutions containing sweetener, viscosity enhancer and flavoring excipients tolerated by paediatric patients affected by CLA. The developed liquid formulations resulted chemically stable at 25 and 4 degrees C over three months. In use-stability tests showed no chemical degradation and microbiological contamination over one month. Oral tablets of sodium DCA were prepared by molding technique as an alternative and more practical formulation, easier to administer for caregivers than the liquid one. Technological assays (reported in the European Pharmacopeia) showed that oral tablets disaggregated quickly within 3 min at 25 degrees C in water, thus they were classified as orally disintegrating tablets. Preformulation studies provided a set of parameters against which detailed formulation design could be carried out. Formulation studies showed that the developed dosage forms achieved adequate stability, producibility and patient acceptability. PMID- 30447285 TI - Analysis of a new flavodiiron core structural arrangement in Flv1-DeltaFlR protein from Synechocystis sp. PCC6803. AB - Flavodiiron proteins (FDPs) play key roles in biological response mechanisms against oxygen and/or nitric oxide; in particular they are present in oxygenic phototrophs (including cyanobacteria and gymnosperms). Two conserved domains define the core of this family of proteins: a N-terminal metallo-beta-lactamase like domain followed by a C-terminal flavodoxin-like one, containing the catalytic diiron centre and a FMN cofactor, respectively. Members of the FDP family may present extra modules in the C-terminus, and were classified into several classes according to their distribution and composition. The cyanobacterium Synechocystis sp. PCC6803 contains four Class C FDPs (Flv1-4) that include at the C-terminus an additional NAD(P)H:flavin oxidoreductase (FlR) domain. Two of them (Flv3 and Flv4) have the canonical diiron ligands (Class C, Type 1), while the other two (Flv1 and Flv2) present different residues in that region (Class C, Type 2). Most phototrophs, either Bacterial or Eukaryal, contain at least two FDP genes, each encoding for one of those two types. Crystals of the Flv1 two core domains (Flv1-DeltaFlR), without the C-terminal NAD(P)H:flavin oxidoreductase extension, were obtained and the structure was determined. Its pseudo diiron site contains non-canonical basic and neutral residues, and showed anion moieties, instead. The presented structure revealed for the first time the structure of the two-domain core of a Class C-Type 2 FDP. PMID- 30447286 TI - Vibrio cholerae LMWPTP-2 display unique surface charge and grooves around the active site: Indicative of distinctive substrate specificity and scope to design specific inhibitor. AB - Low molecular weight protein tyrosine phosphatases (LMWPTPs) are ubiquitously found as small cytoplasmic enzymes which act on phospho-tyrosine containing proteins that are engaged in various cellular functions. Vibrio cholerae O395 contains two LMWPTPs having widely different sequence. Phylogenetic analysis based on a non redundant set of 124 LMWPTP sequences, designate that LMWPTP-2 from Vibrio choleraeO395 (VcLMWPTP-2) is a single taxon. We have determined the crystal structure of VcLMWPTP-2 at 2.6 A with MOPS bound in the active site. Tertiary structure analysis indicates that VcLMWPTP-2 forms dimer. Studies in solution state also confirm exclusive presence of a dimeric form. Kinetic studies demonstrate that VcLMWPTP-2 dimer is catalytically active while inactivation through oligomerisation was reported as one of the regulatory mechanism in case of mammalian LMWPTP viz., Bos taurus LMWPTP, BPTP. Kinetic studies using p nitrophenyl phosphate (p-NPP) as a substrate demonstrate active participation of both the P-loop cysteine in catalysis. Vicinal Cys17, in addition plays a role of protecting the catalytic Cys12 under oxidative stress. Structural analysis and MD simulations allowed us to propose the role of several conserved residues around the active site. Distribution of surface charges and grooves around the active site delineates unique features of VcLMWPTP-2 which could be utilized to design specific inhibitor. PMID- 30447287 TI - Predictors of recurrence of paroxysmal atrial fibrillation following cryoablation based pulmonary vein isolation. PMID- 30447288 TI - Leveraging the genetic basis of Rett syndrome to ascertain pathophysiology. AB - Mutations in the methyl-CpG binding protein 2 (MECP2) gene cause Rett syndrome (RTT), a progressive X-linked neurological disorder characterized by loss of developmental milestones, intellectual disability and breathing abnormality. Despite being a monogenic disorder, the pathogenic mechanisms by which mutations in MeCP2 impair neuronal function and underlie the RTT symptoms have been challenging to elucidate. The seemingly simple genetic root and the availability of genetic data from RTT patients have led to the generation and characterization of a series of mouse models recapitulating RTT-associated genetic mutations. This review focuses on the studies of RTT mouse models and describe newly obtained pathogenic insights from these studies. We also highlight the potential of studying pathophysiology using genetics-based modeling approaches in rodents and suggest a future direction to tackle the pathophysiology of intellectual disability with known or complex genetic causes. PMID- 30447289 TI - Echocardiographic Assessment of Complete Atrioventricular Canal Defects: A Balancing Act. PMID- 30447290 TI - Multiple Ventricular Septal Defects - Strategy, Sandwich, and Vanishing Bands. PMID- 30447291 TI - Modes of operation: A topographic neural gradient supporting stimulus dependent and independent cognition. AB - Human cognition is flexible - drawing on both sensory input, and representations from memory, to successfully navigate complex environments. Contemporary accounts suggest this flexibility is possible because neural function is organized into a hierarchy. Neural regions are organized along a macroscale gradient, anchored at one end by unimodal systems involved with perception and action, and at the other by transmodal systems, including the default mode network, supporting cognition less directly tied to immediate stimulus input. The current study tested whether this cortical hierarchy captures modes of behaviour that depend on immediate input, as well as those that depend on representations from memory. Participants made decisions regarding the location or identity of shapes using information in the environment (0-back) or from a prior trial (1-back). Using task based imaging we established that, regardless of the nature of the decision, medial and lateral visual cortex were recruited when decisions rely on immediate input, while transmodal regions were recruited when judgments depend on information from the prior trial. Using principal components analysis, we demonstrated that shifting decision-making from perception to memory altered the focus of neural activity from unimodal to transmodal regions (and vice versa). Notably, the more pronounced these shifts in neural activity from unimodal to transmodal regions when decisions relied on memory, the more efficiently individuals performed this task. These data illustrate how the macroscale organization of neural function into a hierarchy allows cognition to rely on input, or information from memory, in a flexible and efficient manner. PMID- 30447292 TI - Prevalence and Location of Obstetric Lacerations in Adolescent Mothers. AB - STUDY OBJECTIVE: The objective of this study is to describe prevalence and location of obstetric lacerations in adolescents. DESIGN: Retrospective cohort study. SETTING: We performed an analysis of the Consortium on Safe Labor database including tertiary care university affiliated urban hospitals. PARTICIPANTS: All primiparous women who delivered vaginally were included. INTERVENTIONS: Vaginal and perineal lacerations were compared between age groups 15 or less, 16-21, 22 34, 35-39 and >40 years. MAIN OUTCOME MEASURES: Outcome measures included vaginal, perineal, labial and periurethral lacerations. Chi square and Fisher's exact tests were utilized as appropriate, with p<0.05 considered significant. RESULTS: A total of 9777 patients were included in the analysis. Young adolescents and adolescents, had significantly higher rates of labial and periurethral lacerations as compared to age 22-34. The prevalence of 3rd and 4th degree perineal tears increased with age. CONCLUSION: Adolescent primiparous women are less likely to have severe perineal obstetric tears, but have higher rates of labial and periurethral tears. PMID- 30447293 TI - The effect of vitamin D supplementation on oxidative stress parameters: A systematic review and meta-analysis of clinical trials. AB - Recent studies have shown that vitamin D supplementation beneficially decreases oxidative stress (OS) parameters; however, there is no consensus on this subject. In this systematic review and meta-analysis we aimed to investigate the effect of vitamin D supplementation on OS parameters. We searched electronic databases including Medline, Embase, Scopus, Web of Science and Cochrane Library up to July 2018 without any language restriction. Trials were reviewed using preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Cochrane handbook. To compare the effects of vitamin D with placebo, standardized mean difference (SMD) with 95% confidence intervals (CI) were pooled using random effects model. Across thirteen clinical trials, we found that vitamin D supplementation increased serum levels of total antioxidant capacity (TAC) (SMD: 0.54 mmol/L, 95% CI: 0.29 to 0.79; I2 = 65.4%, P = 0.001) and glutathione (GSH) (SMD: 0.33; 95% CI: 0.11 to 0.54, P = 0.003; I2 = 61.2%, P = 0.001). Besides, malondialdehyde (MDA) concentration decreased significantly (SMD: -0.40 mmol/L, 95% CI: -0.60 to -0.21, P < 0.001) following vitamin D supplementation compared to placebo. However, its effects on nitric oxide (NO) was not significant (0.17, 95% CI: -0.10 to 0.45, I2 = 71.1%, P = 0.21). Finally, we showed that vitamin D supplementation can improve OS parameters; however, this finding may not be clinically significant. Further large prospective clinical trials are needed to confirm the effect of vitamin D supplement on other OS parameters. PMID- 30447294 TI - How CaV1.2-bound verapamil blocks Ca2+ influx into cardiomyocyte: Atomic level views. AB - The first clinically used antiarrhythmic, antianginal and anti-hypertensive phenylalkylamine, verapamil's cardiovascular activity is inextricably linked to its ability to antagonize Ca2+ overload via blocking CaV1.2, a cardiac L-type Ca2+ channel of undisputed physiological and pharmacological importance in cardiovascular disorders such as myocardial ischemia-reperfusion injury. From a structural point of view, however, the action mechanism of verapamil is still elusive. Therefore, incorporating previous findings for verapamil and CaV1.2, this review article puts forward two experimental data-derived and -supported 3D structure models for CaV1.2's alpha1 subunit and its verapamil-bound form. Furthermore, this article suggests three biophysical mechanisms, namely competitive binding, steric hindrance and electrostatic repulsion, towards an atomic level understanding of how verapamil blocks the L-type Ca2+ current mediated by CaV1.2 in reality, which can be useful for the design and development of next-generation Ca2+ antagonists to provide safer and more effective treatment of cardiovascular diseases. PMID- 30447295 TI - Insight into pulmonary drug delivery: Mechanism of drug deposition to device characterization and regulatory requirements. PMID- 30447296 TI - pncA gene mutations in reporting pyrazinamide resistance among the MDR-TB suspects. AB - Mutations in pncA gene contributing to PZA resistance was not clearly elucidated in China. To reveal the correlated mutations of pncA gene on pyrazinamide (PZA) resistance. 148 Mycobacterium tuberculosis clinical isolates were included from multi-drug resistant tuberculosis suspects. The MGIT 960 test and microscopic observation drug susceptibility (MODS) assay were adopted for PZA phenotype drug susceptibility test. 120 isolates with consistent MGIT 960 and MODS results were selected for pncA gene sequencing. 68 samples (56.7%) were resistant to PZA while leaving 52 PZA susceptible samples. Out of the 68 PZA resistant isolates, 49 (72.1%) harbored mutations of pncA, and 4 (7.7%) of the 52 PZA susceptible samples harbored mutations of pncA as well. Compared to the phenotype drug resistant pattern of PZA, the mutations of pncA gene reached a sensitivity of 0.72 to report PZA resistance and a specificity of 0.92 to predict PZA susceptibility. Those mutations, Gln10Pro, Asp12Ala, Tyr41Stop, Gly97Asp, Val128Gly and FSC131(ins) exceeding 5% of the total PZA resistant isolates of each, might be helpful but not adequate in PZA molecular susceptibility test design and development. PMID- 30447297 TI - Osteoclast-like giant cell rich carcinomas of the lung: a Clinicopathological, Immunohistochemical, and molecular study of three cases. AB - Three cases of primary carcinomas of the lung each with an extensive osteoclast like giant cell component are presented. The patients are three men between the ages of 58 and 67years (average: 62.5years) who presented with non-specific symptomatology. A prior history of malignancy, infectious, or granulomatous disease was negative in all the patients. Diagnostic imaging disclosed the presence of a large intrapulmonary mass; in one case in the right upper lobe and in two cases in the right lower lobe. Surgical resection via lobectomy was performed in the three patients. Grossly, the tumors were described as soft, friable intrapulmonary masses, reddish in color, and measuring from 6 to 13cm in largest diameter. Histologically, the tumors were each characterized by the extensive presence of a multinucleated osteoclast-like giant cell component, which represented approximately 80% of the tumor mass. The osteoclast-like giant cell component was admixed with a sarcomatoid carcinoma in two cases and an adenocarcinoma in one case. Immunohistochemistry showed that the osteoclast-like giant cells were positive for CD-68, cathepsin K, and Histone H3, while the carcinoma component was positive for keratin, EMA, TTF-1, and Histone H3 (patchy). Molecular studies were performed in two patients with negative results. Clinical follow-up was obtained in two patients; one died 14months after initial diagnosis while one remains alive 6months after initial diagnosis. One patient was lost to follow-up. The current neoplasms represent an unusual type of lung carcinoma that needs highlighting as a separate type from conventional giant cell carcinoma. PMID- 30447298 TI - Immunohistochemistry expression of targeted therapies biomarkers in ovarian clear cell and endometrioid carcinomas (type I) and endometriosis. AB - Ovarian clear cell and endometrioid carcinomas (Type I) are thought to develop from endometriosis. ARID1A loss of expression is known to be related to the promotion of the endometriosis carcinogenesis. Despite the diverse origins and prognosis of Type I and Type II carcinomas, surgery followed by platinum-based chemotherapy is the mainstay of treatment for both. Limited knowledge about the expression of targeted therapies' biomarkers prevents the use of such markers as potential guides for tailored treatment. This study aimed to evaluate the expression of ARID1A gene and target therapies biomarkers (VEGF, PD-L1, and PARP 1) in ovarian clear cell and endometrioid carcinomas and endometriosis, and its relationship with prognosis. Forty-six ovarian clear-cell and endometrioid carcinomas, and 24 endometriosis foci samples retrieved from the same surgical specimens were studied. ARID1A, VEGF, PD-L1, and PARP-1 immunohistochemistry (IHC) expression was compared in carcinomas and endometriosis with regard to the clinicopathological features and prognosis. We found that endometriosis was associated with increased rates of diagnosis of cancer in the initial stages (P=.008). Different levels of expression of all biomarkers were detected in clear cell and endometrioid carcinomas and endometriosis. However, only the VEGF expression level showed a significant increase in the carcinoma group when compared with endometriosis (P=.0002). PARP-1 overexpression correlated with worse progression-free survival (P=.03) and overall survival (P=.01). In conclusion, endometriosis and ovarian clear-cell and endometrioid carcinomas exhibited ARID1A loss of expression, and VEGF, PD-L1, and PARP-1 expression. PARP 1 overexpression in clear-cell and endometrioid carcinomas was associated with early recurrence and worse overall survival. PMID- 30447299 TI - High Minichromosome maintenance protein 7 proliferation indices: a powerful predictor of progression in pancreatic neuroendocrine neoplasms without distant metastasis at the time of surgery. AB - Pancreatic neuroendocrine neoplasms (PanNENs) have an unpredictable clinical course that varies from indolent to highly malignant. No immunohistochemical markers are available for reliable prediction of the biological behavior of early stage PanNENs. Minichromosome maintenance protein 7 (MCM7) is a putative powerful marker of cell proliferation. Whether the expression of MCM7 is related to the risk of PanNENs progression remains unclear. We assessed the clinical behavior of 156 PanNENs with respect to stage, grade, Ki-67 index, MCM7 index, and other pathologic features. A high MCM7 index was significantly associated with larger tumor size (P<.001), nonfunctioning tumor (P<.001), increased grade (P<.0001), and later TNM stage (P<.001). In multivariate analysis, G2/G3 (hazard ratio (HR), 2.21; 95% confidence interval (CI), 1.35-3.62; P<.001), stage III/IV (HR, 2.11; 95% CI, 1.31-3.41; P<.001), and MCM7 labeling index (LI)>5% (HR, 3.81; 95% CI, 1.30-11.17; P=.02) were independent negative prognostic factors related to the risk of tumor progression in stage I-IV disease. MCM7 LI>5% was associated with an increased risk of progression in stages I-V, I-III, and I-II. Our study confirms that MCM7 is a valuable marker for assessing the progression of PanNENs, especially in patients with early-stage disease and without distant metastasis. PMID- 30447300 TI - Utility of JAK2 V617F allelic burden in distinguishing chronic Myelomonocytic leukemia from primary myelofibrosis with Monocytosis. AB - The concurrent presence of JAK2 V617F, monocytosis and bone marrow fibrosis can be observed in both chronic myelomonocytic leukemia (CMML) and primary myelofibrosis (PMF). It can be challenging to distinguish CMML with JAK2 mutation and fibrosis from other myeloid neoplasms, particularly PMF. To identify key features that may help distinguish these two entities, we retrospectively studied 21 cases diagnosed as "CMML" with JAK2 V617F and bone marrow fibrosis that were identified from a cohort of 610 cases of CMML diagnosed during 2006-2016. Upon further review, we confirmed the diagnosis of CMML in 7 cases, 11 cases were reclassified as PMF, and 3 cases had features intermediate between CMML and PMF (gray zone). These 11 cases of PMF with monocytosis featured a higher JAK2 V617F allelic burden (median 43%, range 20-62%) and atypical pleomorphic megakaryocytes with hyperchromatic nuclei. CBC showed more pronounced myeloid left shift. In contrast, 7 CMML cases had significantly lower JAK2 V617F allelic burden (median 17%, range, 5-36%, P<.0001) and dysplastic megakaryocytes along with variable degree of dysplasia in other lineages. The median survival of PMF and CMML patients was 32 and 40months, respectively. We conclude that besides morphology of megakaryocytes and other features, JAK2 V617F allelic burden can help differentiate CMML from PMF with monocytosis. SRSF2 and RAS mutations are observed in both disease categories. Rare gray zone cases exist with hybrid features. PMID- 30447301 TI - Targeted sequencing of Plasmacytoid urothelial carcinoma reveals frequent TERT promoter mutations. AB - Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. While the cadherin 1 (CDH1) gene is commonly mutated in the clinically aggressive plasmacytoid variant of urothelial carcinoma (PUC), little is known about their TERT promoter mutation status. A retrospective search of our archives for PUC and UC with plasmacytoid and/or signet ring cell features (2007-2014) was performed. Ten specimens from 10 patients had archived material available for DNA analysis and were included in the study. Intratumoral areas of non-plasmacytoid histology were also evaluated when present. Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform. TERT promoter mutations were detected in specimens with pure and focal plasmacytoid features (6 of 10). Similar to conventional UC, the predominant mutation identified was g.1295228C>T. In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas. Co-occurring mutations in tumor protein p53 (TP53, 2 cases) and kirsten rat sarcoma (KRAS) viral proto-oncogene (1 case) were also detected. TERT promoter mutations are frequently present in PUC, which provides further evidence that TERT promoter mutations are common events in bladder cancer, regardless of histologic subtype, and supports their inclusion in any liquid biopsy assay for bladder cancer. PMID- 30447302 TI - Gallic acid disruption of Abeta1-42 aggregation rescues cognitive decline of APP/PS1 double transgenic mouse. AB - Alzheimer's disease (AD) treatment represents one of the largest unmet medical needs. Developing small molecules targeting Abeta aggregation is an effective approach to prevent and treat AD. Here, we show that gallic acid (GA), a naturally occurring polyphenolic small molecule rich in grape seeds and fruits, has the capacity to alleviate cognitive decline of APP/PS1 transgenic mouse through reduction of Abeta1-42 aggregation and neurotoxicity. Oral administration of GA not only improved the spatial reference memory and spatial working memory of 4-month-old APP/PS1 mice, but also significantly reduced the more severe deficits developed in the 9-month-old APP/PS1 mice in terms of spatial learning, reference memory, short-term recognition and spatial working memory. The hippocampal long-term-potentiation (LTP) was also significantly elevated in the GA-treated 9-month-old APP/PS1 mice with increased expression of synaptic marker proteins. Evidence from atomic force microscopy (AFM), dynamic light scattering (DLS) and thioflavin T (ThT) fluorescence densitometry analyses showed that GA significantly reduces Abeta1-42 aggregation both in vitro and in vivo. Further, pre-incubating GA with oligomeric Abeta1-42 reduced Abeta1-42-mediated intracellular calcium influx and neurotoxicity. Molecular docking studies identified that the 3,4,5-hydroxyle groups of GA were essential in noncovalently stabilizing GA binding to the Lys28-Ala42 salt bridge and the -COOH group is critical for disrupting the salt bridge of Abeta1-42. The predicated covalent interaction through Schiff-base formation between the carbonyl group of the oxidized product and epsilon-amino group of Lys16 is also critical for the disruption of Abeta1-42 S-shaped triple-beta-motif and toxicity. Together, these studies demonstrated that GA can be further developed as a drug to treat AD through disrupting the formation of Abeta1-42 aggregation. PMID- 30447303 TI - Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice. AB - Diosmetin is an O-methylated flavone found naturally in citrus fruit, and it was identified in Amphilophium crucigerum (L.), a plant popularly used as an analgesic. This compound had different pharmacological effects and presented a chemical structure like the flavonoid eriodyctiol that exhibited antinociceptive effects by TRPV1 antagonism. However, the possible antinociceptive effect of this compound was not well documented. Thus, the goal of the present study was to evaluate the antinociceptive effect of diosmetin and its mechanism of action. The diosmetin effect on different pain models and its possible adverse effects were assessed on adult Swiss male mice (25-30 g). Mice spinal cord samples were used on calcium influx and binding assays using TRPV1 agonists. First, it was observed that the diosmetin reduced calcium influx mediated by capsaicin in synaptosomes and displace the specific binding to [3H]-resiniferatoxin in membrane fractions from the spinal cord of mice. Diosmetin (0.15 to 1.5 mg/kg, intragastric, i.g.) presented antinociceptive and antiedematogenic effect in the capsaicin intraplantar test and induced antinociception in a noxious heat test (48 degrees C). Also, treatment with diosmetin reduced mechanical and heat hypersensitivity observed in a model of inflammatory or neuropathic pain. Acute diosmetin administration in mice did not induce locomotor or body temperature changes, or cause liver enzyme abnormalities or alter renal function. Moreover, there were no observed changes in gastrointestinal transit or induction of ulcerogenic activity after diosmetin administration. In conclusion, our results support the antinociceptive properties of diosmetin which seems to occur via TRPV1 antagonist in mice. PMID- 30447304 TI - Involvement of inducible nitric oxide synthase and estrogen receptor ESR2 (ERbeta) in the vascular dysfunction in female type 1 diabetic rats. AB - AIMS: Inflammation is involved in diabetes-related vascular dysfunction. Estrogen receptor ESR2/ERbeta induces the expression of inducible nitric oxide (NO) synthase (iNOS) and inflammation. The present study investigated the effect of alloxan-induced type 1 diabetes on the iNOS and ESR2 expression and the effect of the chronic iNOS inhibition on the vascular smooth muscle dysfunction in diabetic female rats. In addition, we evaluated the involvement of ESR2 in iNOS expression. MAIN METHODS: Alloxan-induced diabetic female rats were treated or not with iNOS inhibitor (L-NIL). iNOS and ESR2 immunostaining, S-nitrosylated proteins and IL-1beta protein expression in aorta and plasmatic NO levels were analyzed. Contractile response to noradrenaline was analyzed in endothelium denuded aorta. iNOS mRNA expression was analyzed in isolated aortic smooth muscle cells (ASMCs) of female rats, incubated with 22 mM glucose and an ESR2 antagonist. KEY FINDINGS: Aortic iNOS and ESR2 immunostaining, S-nitrosylated proteins, IL-1beta protein expression and plasmatic NO levels were all increased, whereas noradrenaline-induced contraction was reduced in aorta of diabetic female rats. With the exception of iNOS and ESR2 immunostaining, all these parameters were corrected by L-NIL treatment. High glucose increased iNOS mRNA expression in ASMCs, which was reduced by an ESR2 antagonist. SIGNIFICANCE: We demonstrated that increased iNOS-NO contributed to the impairment of the contractile response of aortic smooth muscle cells in female type 1 diabetic rats and that increased expression of iNOS may involve the participation of ESR2/ERbeta. PMID- 30447305 TI - Prophylactic effect and mechanism of p-coumaric acid against hypoxic cerebral edema in mice. AB - Our previous study found that the anti-hypoxia effect of Tibetan turnip (Brassica rapa ssp. rapa) is directly related to its p-Coumaric acid (CA) and glucoside (pCoumaric acid-beta-d-glucopyranoside, CAG) contents. The present study aimed to investigate the role and mechanism of CA against hypoxic cerebral edema. Male mice were randomly divided into one normoxia group and three hypoxia groups, which were gavaged with sterilized water, CA, or dexamethasone, respectively, once daily for 4 days. The mice were then exposed to normoxia or hypoxia (9.5% O2) for 24 h. The results showed that the brain water content (BWC) and blood brain-barrier permeability were significantly lower in the CA treatment group than in the hypoxia vehicle group. Mice in the CA treatment group showed good blood-brain-barrier integrity; increased Na+-K+-ATPase activity and mitochondrial membrane potential; decreased oxidative stress and inflammation; and increased occludin protein levels. Prophylactic administration of CA and dexamethasone exerted similar effects against hypoxic cerebral edema. The mechanism involved improving the integrity of the blood-brain-barrier, and inhibiting oxidative stress and inflammation. PMID- 30447306 TI - Increased tongue use enhances 5-HT2C receptor immunostaining in hypoglossal motor nucleus. AB - Hypoglossal (XII) motoneurons are activated by type 2 receptors for serotonin (5 HT). This activation is especially strong during wakefulness which facilitates diverse motor functions of the tongue, including the maintenance of upper airway patency in obstructive sleep apnea (OSA) patients. We tested whether 5-HT2 receptor levels in the XII nucleus vary with intensity of tongue use. Three groups of rats were housed overnight under conditions of increasing oromotor activity: W-water available ad lib; S-sweetened water to stimulate drinking; S + O-sweetened water + oil applied on fur to increase grooming. After the exposures, immunostaining for 5-HT2C, but not 5-HT2A, receptors was higher in the XII nucleus in S + O than in W rats (65 +/- 1.8 (SE) vs. 60 +/- 2.0 arbitrary units; p = 0.008). In the medullary raphe obscurus region, the percentage of c-Fos positive 5-HT cells was 13% higher (p = 0.03) in S + O than in W rats. The positive feedback between tongue use and 5-HT2C receptor immunostaining reveals a novel mechanism potentially relevant for OSA and neuromuscular disorders. PMID- 30447307 TI - Autophagy activation alleviates nonylphenol-induced apoptosis in cultured cortical neurons. AB - Emerging evidence indicates that nonylphenol (NP), a widely diffused and stable environmental contaminant, causes damage to the central nervous system (CNS). Although NP could cross the blood-brain barrier (BBB) and accumulate in key brain regions, little is known about the direct effects of NP on neurons. In this study, we aimed to investigate the direct effects of NP exposure on induction of apoptosis and autophagy in primary cortical neurons. Results showed that exposure to NP decreased the cell viability in a concentration-dependent manner. The exposure led to both the increase of TUNEL-positive neurons and the activation of caspase-3. Increased levels of endoplasmic reticulum (ER) stress-related proteins, GRP78, CHOP, ATF4, and casepase-12, were observed in neurons exposed to NP. At the same time, the exposure decreased Bcl-2/Bax ratio and mitochondrial transmembrane potential, and increased the release of Cytochrome-C. In addition, NP exposure enhanced LC3-II conversion, decreased levels of SQSTM1/p62, and increased levels of Beclin-1 and LAMP2. NP exposure also reduced the protein levels of p-mTOR, and did not change the levels of total mTOR. Furthermore, to investigate the role of autophagy in NP-induced apoptosis, both the autophagy inhibitor chloroquine (CQ) and the autophagy inducer rapamycin (RAP) were applied to modulate autophagy activation in primary cortical neurons. The inhibition of autophagy caused by CQ enhanced NP-induced apoptosis; conversely, RAP-induced autophagy remarkably suppressed it. In conclusion, our findings demonstrate that NP exposure induced apoptosis with a concomitant increase of autophagic flux in primary cortical neurons, which supports the idea that this potential neurotoxin has direct effects of on neurons. Both ER stress and mitochondrial pathways may be involved in NP-induced apoptosis in neurons. Furthermore, our results also suggest that autophagy activation might be a protective strategy to ameliorate NP induced apoptosis in neurons. PMID- 30447308 TI - Designing a diagnostic kit for Oxalyl CoA Decarboxylase enzyme by ELISA method. AB - Urinary stones are the third most commonly reported urinary tract disease. Kidney stones are one of the most common types of urinary stones that most of them (70 80%) are calcium oxalate. Oxalic acid is highly oxidized organic compounds, which found in dietary and produced by the intestinal microflora. Oxalyl CoA decarboxylase is a key enzyme and plays an important role in oxalate degradation. In this study, the Oxalyl CoA decarboxylase gene which contains an -histidine tag was cloned in pET 28a (+) and expressed in Escherichia coli BL21 (DE3). The purified Oxalyl CoA decarboxylase protein was injected into rabbit for immunization. The antibody against Oxalyl CoA decarboxylase protein was used in ELISA assy. eventually, this ELISA system was used for patients with calcium oxalate kidney stones. ELISA analysis of serum samples of patient white calcium oxalate kidney stones showed that 88.8 % of patient was lacking in antibody against Oxalyl CoA decarboxylase. This study suggests that antibodies against oxalyl-co-decoxylase proteins are useful in the detection of urinary tract stones and It can be used to measure oxalyl CoAdecoxylase enzymes in a simple method. PMID- 30447309 TI - Functional insights into nucleotide-metabolizing ectoenzymes expressed by bone marrow-resident cells in patients with multiple myeloma. AB - Human myeloma cells grow in a hypoxic acidic niche in the bone marrow. Cross talk among cellular components of this closed niche generates extracellular adenosine, which promotes tumor cell survival. This is achieved through the binding of adenosine to purinergic receptors into complexes that function as an autocrine/paracrine signal factor with immune regulatory activities that i) down regulate the functions of most immune effector cells and ii) enhance the activity of cells that suppress anti-tumor immune responses, thus facilitating the escape of malignant myeloma cells from immune surveillance. Here we review recent findings confirming that the dominant phenotype for survival of tumor cells is that where the malignant cells have been metabolically reprogrammed for the generation of lactic acidosis in the bone marrow niche. Adenosine triphosphate and nicotinamide-adenine dinucleotide extruded from tumor cells, along with cyclic adenosine monophosphate, are the main intracellular energetic/messenger molecules that serve as leading substrates in the extracellular space for membrane-bound ectonucleotidases metabolizing purine nucleotides to signaling adenosine. Within this mechanistic framework, the adenosinergic substrate conversion can vary significantly according to the metabolic environment. Indeed, the neoplastic expansion of plasma cells exploits both enzymatic networks and hypoxic acidic conditions for migrating and homing to a protected niche and for evading the immune response. The expression of multiple specific adenosine receptors in the niche completes the profile of a complex regulatory framework whose signals modify multiple myeloma and host immune responses. PMID- 30447310 TI - Interleukin-33 Gene expression and rs1342326 Polymorphism in Behcet's Disease. AB - OBJECTIVE: Behcet's disease (BD) is a chronic multi-factorial inflammatory disease with the important role of genetic in activation of its inflammatory response. Interleukin (IL)-33 is a member of the IL-1 family of cytokines that affects innate and adaptive immune systems to promote inflammatory responses. In the current study, we investigated the association of IL-33 gene rs1342326 polymorphism and expression levels of this gene in peripheral blood mononuclear cells (PBMCs) with the susceptibility to BD in Azari population of Iran. METHODS: We recruited 44 patients with BD and 61 age and sex-matched healthy controls in this cross-sectional study. The existence of rs1342326 T/G IL-33 gene single nucleotide polymorphism was investigated using Tetra-Amplification Refractory Mutation System (Tetra-ARMS)-PCR. Allele and genotype distributions were evaluated among groups using chi-square or Fisher's test. Moreover, the mRNA levels of IL-33 in PBMCs were assessed through the Real-time PCR. RESULTS: Patients with BD exhibited a significantly higher prevalence of the T/G genotype of rs1342326 polymorphism compared with the control group. Moreover, the expression level of IL-33 in PBMCs was significantly higher in the BD group compared to the healthy controls. Interestingly, the rs1342326 T/G polymorphism was associated with higher IL-33 expression in patients with BD. There was no association between the clinical manifestation of BD and disease activity with rs1342326 polymorphism and IL-33 expression. CONCLUSIONS: Our study implies that rs1342326 T/G polymorphism of the IL-33 gene may contribute to the genetic susceptibility to BD in part through regulation of the IL-33 expression. PMID- 30447311 TI - Impact of the GK-1 adjuvant on peritoneal macrophages gene expression and phagocytosis. AB - PURPOSE: The synthetic peptide GK-1 potentiates protective immunity elicited by the influenza vaccine in mice. In order to understand its adjuvant properties, this study was designed to determine the impact of GK-1 on gene expression and phagocytosis of peritoneal macrophages (PMa). METHODS: Increased gene expression of chemokines involved in leukocyte recruitment and of pro-inflammatory mediators was detected by microarray analysis of control and GK-1 treated PMa macrophages. The expression profile was subsequently confirmed by Multiplex Immunoassays analysis to measure cytokines levels, flow cytometer to describe M1/M2 surface markers and an assay to evaluate their phagocytic activity. RESULTS: Treatment of PMa with GK-1 results in development to the classically activated M1 functional macrophage subpopulation with increased expression of the CCL3 and CXCLO2 chemokines, IL-6 and TNF-alpha proinflammatory cytokines with a concomitant increase in the levels of NO, accompanied by the expression of modulatory factors that downregulate the inflammatory phenotype. GK-1 treated PMa significantly increased their phagocytic activity. CONCLUSION: GK-1 classical activated with enhanced phagocitic capacity may underlie in the increased specific immunity induced when concomitant administered with other antigens. PMID- 30447312 TI - Benign Oral Mucosal Lesions: Clinical and Pathological Findings Part I- Benign Oral Mucosal lesions. AB - A diverse spectrum of benign oral mucosal lesions exists, presenting as either isolated oral findings or in association with dermatological conditions. Oral lesions can closely resemble one another; therefore, it is important for clinicians to be able to recognize their distinctive features and recognize benign versus malignant disease and when a biopsy is warranted. 1 In this continuing medical education series, we review oral anatomy and the clinical attributes of several benign lesions of the oral cavity along with the appropriate management and therapeutic modalities. PMID- 30447313 TI - Screening of thyroid function and autoantibodies in patients with alopecia areata: A systematic review and meta-analysis. PMID- 30447314 TI - Are alkyl glucosides really allergens? PMID- 30447315 TI - Anesthetization of the tragus and antitragus to utilize skin hooks for full visualization of the auricular concha. PMID- 30447316 TI - The "Rule of 10s" versus the "Rule of 2s": High complication rates after conventional excision with postoperative margin assessment of specialty site versus trunk and proximal extremity melanomas. AB - Specialty site melanomas on the head and neck, hands and feet, genitalia, and pretibial leg have higher rates of surgical complications after conventional excision with postoperative margin assessment (CE-POMA) compared to trunk and proximal extremity (T&PE) melanomas. The "rule of 10s" describes complication rates after CE-POMA of specialty site melanomas: ~10% risk of upstaging, ~10% risk of positive excision margins, ~10% risk of local recurrence, and ~10-fold increased likelihood of reconstruction with a flap or graft. T&PE melanomas encounter these complications at a lower rate, according to the "rule of 2s." Mohs micrographic surgery (MMS) with frozen section melanocytic immunostains (MMS I) and slow Mohs decrease complications for surgery of specialty site melanomas by detecting upstaging and confirming tumor removal with comprehensive microscopic margin assessment prior to reconstruction. This review article summarizes information that is important to counsel melanoma patients about surgical treatment options and to encourage development of consensus guidelines with clear indications for MMS-I or slow Mohs. PMID- 30447317 TI - Letter to the Editor: Surgical Smoke: Current Recommendations for Clinical Practice. PMID- 30447318 TI - Examining the epidemiology of coincident psoriasis and sarcoidosis: An observational cross-sectional study. PMID- 30447319 TI - Mobile Phone Reminders for Onychomycosis Medication Adherence. PMID- 30447320 TI - Multivariate analysis of potential risk factors for lymph node metastasis in patients with cutaneous squamous cell carcinoma of the head and neck. AB - Risk factors for metastasis from cutaneous squamous cell carcinoma are incorporated in tumor staging by the seventh edition of the American Joint Committee on Cancer Cancer Staging Manual.We confirmed most risk factors, and also identified moderate differentiation as a predictor for lymph node metastasis. Moderate differentiation can be considered in tumor staging. PMID- 30447321 TI - About "Surgical smoke: Risk assessment and mitigation strategies" and chemical adsorption by activated carbon N95 masks. PMID- 30447322 TI - Acquired cold urticaria: Clinical features, particular phenotypes, and disease course in a tertiary care center cohort. AB - Acquired cold urticaria (ACU) is characterized by the development of wheals, angioedema, or both after cold exposure. Age at diagnosis, disease severity, and response to the ice cube challenge test predicted both prognosis and response to therapy. Proper characterization of the type of acquired cold urticaria allows for appropriate counseling and choice of therapy. PMID- 30447323 TI - Clinical outcomes and response of patients applying topical therapy for pyoderma gangrenosum: A prospective cohort study. AB - Pyoderma gangrenosum is a painful ulcerating disease. The current evidence base for treatment is limited. In a large prospective study of topical treatments, 44% of patients were healed by 6 months. Ulcer size was a predictor of healing, and 15% of patients with pyoderma gangrenosum had a recurrence. Clobetasol propionate 0.05% is a potentially useful first-line therapy for patients with pyoderma gangrenosum, particularly for patients with small lesions. PMID- 30447324 TI - Intralesional Vitamin D3 in Periungual Warts. PMID- 30447325 TI - Premalignant and Malignant Mucosal lesions: Clinical and Pathological Findings Part II. Premalignant and malignant mucosal lesions. AB - Part 2 of this 2-part continuing medical education series discusses the clinical and histopathologic features of common premalignant and malignant lesions of the oral cavity. It is imperative for dermatologists to be able to recognize suspicious lesions, determine biopsy need, counsel, and refer patients presenting with premalignant or malignant conditions appropriately. Given the higher rates of mortality and morbidity of oral mucosal malignancies due to late diagnosis, appropriate treatment with multidisciplinary care in a timely manner is essential to these neoplasms. PMID- 30447326 TI - Evaluation of a Combined Approach to the Correction of Congenital Cervical or Cervicothoracic Scoliosis. AB - BACKGROUND CONTEXT: An anteroposterior combined approach has been used for the treatment of congenital cervical or cervicothoracic scoliosis. However, its outcomes and surgical risks have not been clarified. PURPOSE: We analyzed the characteristics of congenital cervical and cervicothoracic scoliosis and evaluated the outcomes of an anteroposterior combined approach for its treatment. STUDY DESIGN: We carried out a retrospective clinical study of prospectively collected data. PATIENT SAMPLE: Sixteen patients were treated between 2009 and 2013. Their average age was 9.2 years. OUTCOME MEASURES: Radiographic and surgical outcomes were measured and recorded. We compared morphological parameters and preoperative and postoperative results. METHODS: All patients underwent surgery with a combined approach. The following radiographic parameters were measured: head tilt (HT), mandible incline (MI), shoulder balance (SB), structural and compensatory curves, cervical lordosis, C7 central sacral vertical line (C7-CSVL) ratio, C7 sagittal vertical axis (C7-SVA) ratio, C2-C7 SVA ratio, the angle between the upper endplate of the T2 vertebra and a horizontal line (T2 tilt), gravity line (GL) ratio. Demographic and surgical data were also collected. RESULTS: On average, the duration of follow-up was 68.0 months, surgical blood loss was 675 mL, and the duration of surgery was 400.5 minutes. The average correction rate was 64.9% in the structural curve and 29.5% in the compensatory curve. Statistical analysis showed that MI significantly correlated with HT and SB (p < .05). The C7-CSVL ratio correlated with the HT, MI, and SB (p <.05). The C7-SVA ratio correlated with the structural curve and cervical lordosis (p <.05), and the GL ratio correlated with the structural and compensatory curve, cervical lordosis, and C7-SVA ratio (p <.05). Moreover, there were correlations between the structural and compensatory curves as well as between the structural curve and cervical lordosis (p <.05). There were significant differences before and after surgery in HT, MI, and structural and compensatory curves. Four patients developed nerve root palsy after surgical correction and totally recovered by 6months of follow-up. CONCLUSION: The combined approach is an effective surgical option for congenital cervical or cervicothoracic scoliosis. The resection of the hemivertebra cannot only improve head-neck aesthetic appearance but can also maintain the growth potential of the neck. PMID- 30447327 TI - Advances in thermochemical conversion of woody biomass to energy, fuels and chemicals. AB - Biomass has been recognised as a promising resource for future energy and fuels. The biomass, originated from plants, is renewable and application of its derived energy and fuels is close to carbon-neutral by considering that the growing plants absorb CO2 for photosynthesis. However, the complex physical structure and chemical composition of the biomass significantly hinder its conversion to gaseous and liquid fuels. This paper reviews recent advances in biomass thermochemical conversion technologies for energy, liquid fuels and chemicals. Combustion process produces heat or heat and power from the biomass through oxidation reactions; however, this is a mature technology and has been successfully applied in industry. Therefore, this review will focus on the remaining three thermochemical processes, namely biomass pyrolysis, biomass thermal liquefaction and biomass gasification. For biomass pyrolysis, biomass pretreatment and application of catalysts can simplify the bio-oil composition and retain high yield. In biomass liquefaction, application of appropriate solvents and catalysts improves the liquid product quality and yield. Gaseous product from biomass gasification is relatively simple and can be further processed for useful products. Dual fluidised bed (DFB) gasification technology using steam as gasification agent provides an opportunity for achieving high hydrogen content and CO2 capture with application of appropriate catalytic bed materials. In addition, multi-staged gasification technology, and integrated biomass pyrolysis and gasification as well as gasification for poly-generation have attracted increasing attention. PMID- 30447328 TI - A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. AB - Mood disorders represent the largest cause of disability worldwide. The monoaminergic deficiency hypothesis, which has dominated the conceptual framework for researching the pathophysiology of mood disorders and the development of novel treatment strategies, cannot fully explain the underlying neurobiology of mood disorders. Mounting evidence collected over the past two decades suggests the amino acid neurotransmitter systems (glutamate and GABA) serve central roles in the pathophysiology of mood disorders. Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217. PMID- 30447329 TI - Combining retinal-based and chlorophyll-based (oxygenic) photosynthesis: Proteorhodopsin expression increases growth rate and fitness of a ?PSI strain of Synechocystis sp. PCC6803. AB - To fill the "green absorption gap", a green absorbing proteorhodopsin was expressed in a PSI-deletion strain (DeltaPSI) of Synechocystis sp. PCC6803. Growth-rate measurements, competition experiments and physiological characterization of the proteorhodopsin-expressing strains, relative to the DeltaPSI control strain, allow us to conclude that proteorhodopsin can enhance the rate of photoheterotrophic growth of DeltaPSI Synechocystis strain. The physiological characterization included measurement of the amount of residual glucose in the spent medium and analysis of oxygen uptake- and production rates. To explore the use of solar radiation beyond the PAR region, a red-shifted variant Proteorhodopsin-D212N/F234S was expressed in a retinal-deficient PSI deletion strain (DeltaPSI/DeltaSynACO). Via exogenous addition of retinal analogue an infrared absorbing pigment (maximally at 740 nm) was reconstituted in vivo. However, upon illumination with 746 nm light, it did not significantly stimulate the growth (rate) of this mutant. The inability of the proteorhodopsin expressing DeltaPSI strain to grow photoautotrophically is most likely due to a kinetic rather than a thermodynamic limitation of its NADPH-dehydrogenase in NADP+-reduction. PMID- 30447330 TI - Improving recombinant bone morphogenetic protein-4 (BMP-4) production by autoregulatory feedback loop removal using BMP receptor-knockout CHO cell lines. AB - A Chinese hamster ovary (CHO) cell line producing recombinant human bone morphogenetic protein-4 (rhBMP-4) (CHO-BMP-4), which expresses essential components of BMP signal transduction, underwent autocrine BMP-4 signaling. RNA seq analysis on CHO host cells (DG44) treated with rhBMP-4 (20 ug/mL) suggested that rhBMP-4 induced signaling in CHO cells could be a critical factor in limiting rhBMP-4 production and should be removed to improve rhBMP-4 production in recombinant CHO (rCHO) cells. The inhibition of autocrine BMP signaling in CHO BMP-4 cells by the addition of LDN-193189, a chemical inhibitor of BMP receptor type I, significantly increased the mRNA expression levels of rhBMP-4. To establish BMP signaling-free host cells, a BMP receptor, the BMPRIA or BMPRII gene in DG44 cells, was knocked out using CRISPR/Cas9 gene-editing technology. Using three different knockout (KO) host cell lines as well as a DG44 wild-type (wt) cell line, rCHO cell clones producing rhBMP-4 were generated by a stepwise selection with increasing methotrexate concentrations. KO-derived clones showed a significantly higher maximum rhBMP-4 concentration than wt-derived clones in both batch and fed-batch cultures. Unlike wt-derived clones, KO-derived cell clones were able to produce higher amounts of hBMP-4 transcripts and proteins in the stationary phase of growth and did not experience growth inhibition induced by rhBMP-4. The mean maximum rhBMP-4 concentration of KO host-derived clones was approximately 2.4-fold higher than that of wt-derived clones (P < 0.05). Taken together, the disruption of BMP signaling in CHO cells by knocking out the BMP receptor significantly improved rhBMP-4 production. PMID- 30447331 TI - Alogliptin improves endothelial function by promoting autophagy in perivascular adipose tissue of obese mice through a GLP-1-dependent mechanism. AB - OBJECTIVE: Perivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice. METHODS: C57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes. RESULTS: The presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP 1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy. CONCLUSIONS: These results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent. PMID- 30447332 TI - Building transcription factor binding site models to understand gene regulation in plants. AB - Transcription factors (TF) are key cellular components that control gene expression. They recognize specific DNA sequences, the TF binding sites (TFBS), and thus are targeted to specific regions of the genome where they can recruit transcriptional cofactors and/or chromatin regulators for fine-tuning spatiotemporal gene regulation. Therefore, the identification of TFBS in genomic sequences and their subsequent quantitative modeling is of crucial importance for understanding and predicting gene expression. Here, we review how TFBS can be determined experimentally, how the TFBS models can be constructed in silico, and how they can be optimized by taking into account features such as position interdependence within TFBSs, DNA shape and/or by introducing state-of-the-art computational algorithms such as deep learning methods. In addition, we discuss the integration of context variables into the TFBS modeling, including nucleosome positioning, chromatin states, methylation patterns, 3D genome architectures and TF cooperative binding, in order to better predict TF binding under cellular contexts. Finally, we explore the possibilities of combining the optimized TFBS model with technological advances such as targeted TFBS perturbation by CRISPR to better understand gene regulation, evolution and plant diversity. PMID- 30447333 TI - Transcriptional Regulation of Nutrient Exchange in Arbuscular Mycorrhizal Symbiosis. PMID- 30447334 TI - Temporal proteomics of Arabidopsis plasma membrane during cold- and de acclimation. AB - Freezing stress is one of the most important limiting factors of plant survival. Plants have developed a freezing adaptation mechanism upon sensing low temperatures (cold acclimation). Compositional changes in the plasma membrane, one of the initial sites of freezing injury, is prerequisite of achieving cold acclimation and have been investigated in several plant species. Conversely, the cold dehardening process at elevated temperatures (de-acclimation) has not yet been fully characterized and few studies have addressed the importance of the plasma membrane in the de-acclimation process. In the present study, we conducted shotgun proteomics with label-free semiquantification on plasma membrane fractions of Arabidopsis leaves during cold acclimation and de-acclimation. We consequently obtained a list of 873 proteins with significantly changed proteins in response to the two processes. Although the cold-acclimation-responsive proteins were globally returned to non-acclimated levels by de-acclimation, several representative cold-acclimation-responsive proteins tended to remain at higher abundance during de-acclimation process. Taken together, our results suggest plants deharden right after cold acclimation to restart growth and development but some cold-acclimation-induced changes of the plasma membrane may be maintained under de-acclimation to cope with the threat of sudden freezing during de-acclimation process. SIGNIFICANCE: Plant freezing tolerance can be enhanced by low temperature treatment (cold acclimation), while elevated temperatures right after cold acclimation can result in the dehardening of freezing tolerance (de-acclimation). However, the de-acclimation process, particularly its relevance to the plasma membrane as the primary site of freezing injury, has not been elucidated. In the present study, a comprehensive proteomic analysis of the plasma membrane during cold acclimation and de-acclimation was carried out as a first step to elucidating how plants respond to rising temperatures. Cold acclimation induced a number of proteomic changes as reported in previous studies, but most proteins, in general, immediately returned to NA levels during de-acclimation treatment for two days. However, the abundances of stress-related proteins (e.g. LTI29, COR78 and TIL) decreased slower than other functional proteins during de-acclimation. Therefore, plants harden during cold acclimation by aborting growth and development and accumulating stress-responsive proteins but seem to deharden quickly under subsequent elevated temperature to resume these processes while guarding against the threat of sudden temperature drops. PMID- 30447335 TI - Study on the drug permeation mechanism from flurbiprofen-loaded glyceryl monooleyl ether-based lyotropic liquid crystalline nanoparticles across the skin: Synchrotron X-ray diffraction and confocal laser scanning microscopy study. AB - The mechanism underlying the skin permeation of flurbiprofen (FLU)-loaded, glyceryl monooleyl ether-based liquid crystalline nanoparticles (LCNs) with a hexagonal structure was examined by synchrotron X-ray diffraction and confocal laser scanning microscopy (CLSM). Fluorescent-labeled, FLU-loaded LCNs were prepared using coumarin 6 and rhodamine B 1,2-dihexadecanoyl-sn-glycero-3 phosphoethanolamine, triethylammonium salt (Rh-PE), which produce green and red fluorescence, respectively. Application of FLU-loaded LCNs to the hairless mouse stratum corneum (SC) induced expansion of the lattice spacing of the hexagonal structure with FLU release, as confirmed by the changes in the small-angle X-ray diffraction profiles. In addition, the FLU-loaded LCNs completely released FLU near the surface of the SC, which then penetrated the SC. Consequently, the repeat distance of the long periodicity phase was slightly modified. CLSM revealed green fluorescence in the epidermis and hair follicles and red fluorescence in the SC. In conclusion, LCNs adopt several permeation pathways: one is partly via the intercellular matrix and the other is the epidermis via hair follicles. PMID- 30447336 TI - The Multiscale Stiffness of Electrospun Substrates and Aspects of their Mechanical Biocompatibility. AB - In contrast to homogeneous materials, the mechanical properties of fibrous substrates depend on the probing lengthscale. This suggests that cells feel very different mechanical cues than expected from the macroscale characterisation of the substrate materials. By means of multiscale computational analyses we study here the mechanical environment of cells adhering to typical electrospun networks used in biomedical applications, with comparable macroscopic stiffness but different fibre diameters. The stiffness evaluated at the level of focal adhesions varies significantly, and the overall magnitude is strongly affected by the fibre diameter. The microscopic stiffness evaluated at cell scale depends substantially on the network topology and is about one order of magnitude lower than the macroscopic stiffness of the substrate, and two to three orders of magnitude below the fibres' elastic modulus. Moreover, the translation of stiffness over the scales is modulated by global deformations of the scaffold. In particular, uniaxial or biaxial stretching of the substrate induces nonlinear microscopic stiffening. Finally, although electrospun networks allow long-range transmission of cell-induced deformations, the comparison between the range of forces measured in cell traction force microscopy and those required to markedly deform typical electrospun networks reveals an order of magnitude difference, suggesting that these scaffolds provide a rather rigid environment for cells. All these results underline that the achievement of mechanical biocompatibility at all relevant lengthscales, and over the whole range of physiological loading states is extremely challenging. At the same time, the study shows that the diameter, length and curvature of fibre segments might be tunable towards achieving this goal. STATEMENT OF SIGNIFICANCE: Electrospun fabrics have growing use as substrates and scaffolds in tissue engineering and other biomedical applications. Based on multiscale computational analyses, this study shows that substrates of comparable macroscopic stiffness can provide tremendously different mechanical micro-environments, and that cells adhering to fibrous substrates may thus experience by orders of magnitude different mechanical cues than it would be expected from macroscale material characterisation. The simulations further reveal that the transfer of stiffness over the length scales changes with macroscopic deformation, and identify some key parameters that govern the transfer ratio. We believe that such refined understanding of the multiscale aspects of mechanical biocompatibility is key to the development of successful scaffold materials. PMID- 30447337 TI - Antibiotic resistance of Escherichia coli from outpatient urinary tract infection in women in six European countries including Russia. AB - OBJECTIVES: In the Northern Dimension Antibiotic Resistance Study Finland, Germany, Latvia, Poland, Russia and Sweden investigated the resistance levels of Escherichia coli (E. coli) isolated from urine of outpatient women (18-65 years) that had symptoms of uncomplicated UTI by collecting samples in each respective nation. METHODS: In total 775 E. coli isolates from 1278 clinical urinary samples were collected from October 2015-January 2017. Susceptibility testing was performed and results were interpreted according to the EUCAST criteria. RESULTS: Overall antibiotic resistance (ABR) rates to certain commonly used antibiotics, such as nitrofurantoin, fosfomycin and mecillinam were 1.2%, 1.3% and 4.1% (except for Germany that was missing result for mecillinam). Highest overall resistance rates were determined for ampicillin - 39.6%, trimethoprim -23.8%, trimethoprim/sulfamethoxazole -22.4%, amoxillin/clavulanic acid - 16.7% and ciprofloxacin - 15.1%, varying significantly among the countries. ESBL-production level was 8.7%. None of the isolates showed resistance to meropenem. CONCLUSIONS: In most cases, low ABR rates were detected against the first line antibiotics recommended in national UTI treatment guidelines which give support to their future use. Our results also support the European Association of Urology guidelines stating that nitrofurantoin, fosfomycin and mecillinam are viable treatment options for uncomplicated UTI. PMID- 30447338 TI - Miniaturization of tardigrades (water bears): Morphological and genomic perspectives. AB - Tardigrades form a monophyletic group of microscopic ecdysozoans best known for surviving extreme environmental conditions. Due to their key phylogenetic position as a subgroup of the Panarthropoda, understanding tardigrade biology is important for comparative studies with related groups like Arthropoda. Panarthropods - and Ecdysozoa as a whole - likely evolved from macroscopic ancestors, with several taxa becoming secondarily miniaturized. Morphological and genomic evidence likewise points to a miniaturized tardigrade ancestor. The five segmented tardigrade body typically measures less than 1 mm in length and consists of only about 1000 cells. Most organs comprise a relatively small number of cells, with the highest proportion belonging to the central nervous system, while muscles are reduced to a single cell each. Similarly, fully sequenced genomes of three tardigrade species - together with Hox gene expression data - point to extensive modifications, rearrangements, and major losses of genes and even a large body region. Parallels are evident with related ecdysozoans that may have also undergone genomic reductions, such as the nematode Caenorhabditis elegans. We interpret these data together as evidence of miniaturization in the tardigrade lineage, while cautioning that the effects of miniaturization may manifest in different ways depending on the organ or organ system under examination. PMID- 30447339 TI - Occurrence and predictive utility of isochronal, equiproportional, and other types of development among arthropods. AB - In isochronal (ICD) and equiproportional development (EPD), the proportion of total immature (egg, larval, and/or juvenile) development spent in each stage (developmental proportion) does not vary among stages or temperatures, respectively. ICD and EPD have mainly been reported in copepods, and whether they occur in other arthropods is not known. If they did, then rearing studies could be simplified because the durations of later developmental stages could be predicted based on those of earlier ones. The goal of this study was to test whether different taxa have ICD, EPD, or an alternative development type in which stage-specific proportions depend on temperature, termed 'variable proportional' development (VPD), and also how well each development type allowed later-stage durations to be predicted from earlier ones. Data for 71 arthropods (arachnids, copepod and decapod crustaceans, and insects) were tested, and most (85.9%) species were concluded to have VPD, meaning that ICD and EPD do not occur generally. However, EPD predicted later-stage durations comparably well to VPD (within 19-23%), and thus may still be useful. Interestingly, some species showed a 'mixed' form of development, where some stages' developmental proportions varied with temperature while those of others did not, which should be further investigated. PMID- 30447340 TI - Patients' experiences attributed to the use of Passiflora incarnata: A qualitative, phenomenological study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Passiflora incarnata Linnaeus (Passiflora incarnata) was established as a medicinal plant in Europe in the middle of the 19th century. Since then, it has been used for the treatment of anxiety, sleep disorders and restlessness in Western European phytotherapy. This study provides insights into how Passiflora incarnata is currently used and experienced as a medicinal plant by German-speaking patients in Switzerland. AIM: This qualitative study aimed to explore patients' experiences and the values, views and interpretive processes that formed their perceptions of the use of an ethanolic extract of Passiflora incarnata. METHODS: A total of 8 patients participated in this exploratory, qualitative observational study. The patients filled in pre- and posttreatment questionnaires, kept diaries and were interviewed in a face-to face setting. For the data analysis, descriptive statistics, qualitative content analysis, narrative inquiry and documentary methods were applied. RESULTS: This is the first qualitative study of patients' real-life experiences with an ethanolic extract of Passiflora incarnata. We identified three distinct types of patient biographical narratives attributed to different experiences when using Passiflora incarnata. Patients with type 1 narratives described moving from a performance orientation to resetting priorities and attaining calmness. Patients with type 2 narratives maintained a performance orientation while adopting calmness. Patients with type 3 narratives maintained a performance orientation and suffered from persistent illness. CONCLUSION: The distinct biographical narratives of the patients associated with their specific experiences of taking Passiflora incarnata provide an additional perspective on the use of Passiflora incarnata as a medicinal plant. PMID- 30447341 TI - Klf4 could be activated by Pou5f3/Stat3 to induce the expression of Nanog in Japanese flounder. AB - Kruppel-like factor 4 (Klf4) is a zinc finger protein transcription factor of the KLF family and plays an important role in various important biological process, including cell proliferation, differentiation, embryonic development, and cancer formation. In this study, the full length Klf4 cDNA sequence of Japanese flounder (Paralichthys olivaceus) was analyzed. Phylogenetic, gene structure, and synteny analysis revealed that PoKlf4 was conserved to that of teleost. Transcript of PoKlf4 showed that its expression was high during early embryonic development but reduced when gastrulation began, thus indicating its possible role in embryonic development. Tissue expression pattern showed that PoKlf4 was expressed higher in ovaries than in testes. ISH revealed that PoKlf4 was also expressed in spermatogonium, oocytes, and oogonia and in high levels in epithelial and lamellar epithelial cells of gills. Functional characterization of PoKlf4 gene promoter provided valuable information in understanding the molecular regulatory mechanisms of PoKlf4 gene. PoKlf4 could up-regulate Nanog, a gene that prevents ES cells from differentiating and being up-regulated by Pou5f3 and Stat3 genes that could maintain ES cell self-renewal. These results suggested that PoKlf4 maintains the pluripotency of ES cells. This study provides valuable information in exploring the regulatory network of PoKlf4 and lays the foundation for further research on the function of this gene. PMID- 30447342 TI - Co-expression profiling of plasma miRNAs and long noncoding RNAs in gastric cancer patients. AB - PURPOSE: The recent researches indicate that differential non-coding RNAs expression signatures could be associated with the pathogenesis of gastric cancer (GC). However, there are few studies focused on lncRNA-miRNAs co-expression profiling in GC patients. Therefore, in the present study the expression of H19 and MEG3 and their related miRNAs including miR-148a-3p, miR-181a-5p, miR-675-5p and miR-141-3p were determined in the plasma samples of GC patients and controls. MATERIALS AND METHODS: This case-control study included 62 GC patients and 40 age sex matched controls. The non-coding RNA levels were assessed by real-time PCR. Further, using in silico analysis, we identified shared targets of studied miRNAs and performed GC-associated pathway enrichment analysis. RESULTS: Our results showed that the H19 level was significantly (P = 0.008) elevated and MEG3 expression was significantly (P = 0.002) down-regulated in GC patients compared to healthy participants. Furthermore, it was revealed that the miR-675-5p level was increased, while miR-141-3p plasma levels were significantly reduced in GC patients (P < 0.05). We did not observe a significant difference for miR-148a-3p (P = 0.682) and miR-181a-5p (P = 0.098) expression between groups. In addition, the expression levels of H19, MEG3 and miR-148a-3p were associated with some clinicopathological features of patients (P < 0.05). ROC analysis revealed that a combination of H19, MEG3 and miR-675-5p levels able to discriminate controls and GC subjects with 88.87% sensitivity and 85% specificity (AUC, 0.927; 0.85-0.96 CI, P < 0.0001). CONCLUSION: The results of current study demonstrated that combination of H19, MEG3 and miR-675-5p expression levels could provide a potential diagnostic panel for GC. PMID- 30447343 TI - The hemodynamic and molecular mechanism study on the choke vessels in the multi territory perforator flap transforming into true anastomosis. AB - BACKGROUND: The aim of this study was to explore the hemodynamic and morphological changes of the choke vessels, and to investigate the role of HIF 1alpha in the flap adaptation to hypoxic and choke vessel transformation after multi-territory perforator flap transplantation. METHODS: Animal model of single pedicle multi-territory perforator flap was established in the back of SD rats and the blood supply characteristics were studied by gelatin-oxide perfusion technique. HE staining and stereomicroscope were used to observe vascular changes. Afterward, the influence of hypoxia on cell proliferation and apoptosis were detected by MTT assay and flow cytometry, respectively. Besides, the expression of HIF-1alpha, iNOS and VEGF expression of HUVECs under hypoxia were detected by qRT-PCR and Western blot. RESULTS: The results revealed that all the choke vessels immediately began to expand after operation. The day after operation, some of the choke vessels continued to grow and expand, turning into the true anastomosis, while the others gradually dwindled and finally disappeared. Compared with the control group, the day after transplantation, the expression levels of both HIF-1alpha and iNOS were significantly increased. The only different was that HIF-1alpha was then maintained a high level, iNOS was significantly decreased aftertimes. What's more, the expression of VEGF was increased to the maximum at 3 days after operation and then decreased. In HUVECs, hypoxia increased the expression of HIF-1alpha, iNOS and VEGF protein. Besides, it also promoted the proliferation and inhibited the apoptosis. In addition, we also found that hypoxia-induced VEGF and iNOS upregulation is mediated by HIF 1alpha overexpression and HIF-1alpha knockout can reverse the effects induced by hypoxia. CONCLUSIONS: We found that HIF-1alpha may participate in the early vascular dilatation of transregional skin flap by inducing iNOS expression and promoting the reconstruction of choke vessels through increase VEGF expression. PMID- 30447344 TI - Dickkopf-1 reduces hypertrophic changes in human chondrocytes derived from bone marrow stem cells. AB - The in vitro process of chondrogenic differentiation of mesenchymal stem cells (MSCs) induces a pre-apoptotic hypertrophic phenotype, guided by the active status of the WNT/beta-catenin pathway. To achieve a stable chondrocyte phenotype for cartilage tissue engineering, it is necessary to gain a better understanding of specific genes that regulate the cartilage tissue phenotype. RNA sequencing (RNA-seq) analysis of tissue samples from bone, cartilage, growth plate and muscle show that Dickkopf-1 (DKK1), a natural WNT canonical signaling inhibitor, is expressed in cartilage tissue. This observation reinforces the concept that inhibition of the WNT/beta-catenin pathway is critical for preventing avoid chondrocyte hypertrophy in vitro. We used two doses of DKK1 in a pellet cell culture system to inhibit the terminal differentiation of chondrocytes derived from bone marrow mesenchymal stem cells (MSCs). Bone marrow MSCs were cultured in chondrogenic induction medium with 50 and 200 ng/ml of DKK1 for 21 days. The highest doses of DKK1 reduce beta-catenin expression and nuclear localization at day 21, concomitant with reduced expression and activity of hypertrophy markers collagen type X (COL10A1) and alkaline phosphatase (ALPL), thus decreasing the pre-hypertrophic chondrocyte population. Furthermore, DKK1 stimulated expression of collagen type II (COL2A1) and glycosaminoglycans (GAGs), which represent healthy articular cartilage markers. We conclude that exogenous DKK1 impedes chondrocyte progression into a prehypertrophic stage and stimulates expression of healthy articular cartilage markers by blocking the WNT/beta-catenin pathway. Hence, DKK1 may promote a mature healthy articular cartilage phenotype and facilitate cartilage tissue engineering for joint repair. PMID- 30447345 TI - TGF-beta1 promotes cell migration in hepatocellular carcinoma by suppressing reelin expression. AB - Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is a leading cause of worldwide cancer mortality. Intrahepatic dissemination and extrahepatic metastasis are key factors in malignant growth of HCC. Reducing HCC-associated metastasis is critically dependent on uncovering molecular signaling pathways that promote HCC metastasis. In this study, we explored the effect of TGF-beta1 and RELN on cell migration, and the relationship between TGF-beta1 and RELN in HCC cells. The data presented that TGF-beta1 and RELN showed an opposite expression pattern, and either increased expression of TGF-beta1 or decreased expression of RELN increased HCC cell migration ability. We also found TGF-beta1 enhanced cell migration ability was through repressing RELN expression, as overexpression of RELN impaired TGF-beta1 enhanced cell migration. Our work revealed the relationship between TGF-beta1 and RELN and uncovered the important role of RELN in suppressing cell migration in HCC cells. PMID- 30447346 TI - Inactivation of SMARCA2 by promoter hypermethylation drives lung cancer development. AB - The SWI/SNF complex is a multimeric chromatin remodeling complex that has vital roles in regulating gene expression and cancer development. However, to date few studies have deeply explored the mechanism of SMARCA2 inactivation. We applied multi-omics analysis to explore the mechanism of SMARCA2 inactivation in The Cancer Genome Atlas (TCGA) database and performed the dCas9-DNMT3a system to evaluate the role of promoter methylation in SMARCA2 transcriptional regulation. We also assessed the tumor suppressing roles of SMARCA2 in lung cancer development by in vitro experiments. SMARCA2 promoter hypermethylation was significantly associated with decreased expression of SMARCA2. This result was further confirmed in the results of our own tissues. In addition, we observed that the mRNA level decreased by about 3 folds while the CpG island of promoter is nearly 30% hypermethylated by dCas9-DNMT3a system in H1299 cells. We identified SMARCA2 as a tumor suppressor gene whose expression was downregulated in lung cancers. Its inactivation was significantly associated with the poor survival of lung cancer patients [hazard ratio, HR = 0.35 (0.27-0.45)]. Besides, we found that SMARCA2 was a tumor suppressor and can significantly inhibit lung cancer cell vitality. We found that promoter hypermethylation contribute to the inactivation of SMARCA2. We also verified its oncogenetic roles of BRM inactivation in lung adenocarcinoma, which may provide a potential target for the clinical treatment. PMID- 30447347 TI - hnRNPDL extensively regulates transcription and alternative splicing. AB - RNA binding proteins (RBPs) are key players of genome regulation. Here we report the transcriptome study of HnRNP D-Like protein, which belongs to the hnRNP family. We used RNA-seq to analyze the global transcript level and alternative splicing on hnRNPDL shRNA-treated cells and control. Sh-hnRNPDL extensively increased in the expression of genes involved in female pregnancy, cell apoptosis, cell proliferation and cell migration. HnRNPDL regulated alternative splicing of hundreds of genes enriched in transcription regulation and signaling pathways including NOD-like receptor signaling, Notch signaling, and TNF signaling. This study provides the first transcriptome-wide analysis of hnRNPDL regulation of gene expression, which adds to the understanding of critical hnRNPDL functions. PMID- 30447348 TI - Vaginal cleansing prior to caesarian section: To do or not to do?: A randomized trial. AB - PURPOSE: To evaluate the efficacy of preoperative vaginal cleansing using povidone-iodine solution 10% on rates of post cesarean section (CS) infectious morbidities (endometritis, febrile morbidity and wound infection). METHODS: This prospective randomized trial was conducted among 226 pregnant women scheduled for term elective CS. Patients were equally divided into two groups by simple randomization method. The study group had preoperative vaginal cleansing using povidone-iodine solution 10% for about 1 min, while the control group did not. All cases received the prophylactic antibiotics and the usual abdominal scrub. Adverse post CS infectious morbidities such as endometritis, febrile morbidity and wound infection were observed at the time of hospital discharge and weekly for 6 weeks postpartum. RESULTS: Both groups were matched regarding the baseline patients' characteristics. Overall, post-CS infectious morbidity was significantly reduced from 20.7% in the control group to 7.5% in the intervention group. Marked significant reduction was seen in the incidence of endometritis (11.8% in the control group versus 2.8% in the intervention group). However, maternal fever and wound infection showed no significant difference between both groups. CONCLUSION: Vaginal cleansing with povidone-iodine solution 10% prior to elective CS appears to be effective in reducing rates of post-CS infectious morbidity mainly endometritis. PMID- 30447349 TI - State of knowledge on smartphone applications concerning contraception: A systematic review. AB - AIM: Women's knowledge of contraception is incomplete and a wide variety of information sources are used. Since the advent of smartphones, 325,000 healthcare apps have become available. Our aim is to conduct a literature review on smartphone applications for contraception. METHODS: 15 databases in English, Spanish and French were examined, which included studies published between 2007 and 2018 that describe or compare mobile applications for reversible contraceptive methods and interventional studies. The quality of the studies was assessed using the Cochrane scale or a scale created by the authors. RESULTS: 1786 articles were listed and 22 were included in the main text. In two randomised controlled trials, apps did not influence the choice of a contraceptive method. Two studies showed a significant improvement in knowledge after using an app. Comparative studies reported a large number of apps, the majority of which contained only incomplete information and few interactive features. CONCLUSION: Many applications deal with contraception, but few have reliable and exhaustive information. Further studies are needed to measure the impact of apps on observing compliance. PMID- 30447350 TI - (-)-Epicatechin in the control of glucose homeostasis: Involvement of redox regulated mechanisms. AB - Emerging evidence supports a beneficial action of the flavan-3-ol (-)-epicatechin (EC) on insulin sensitivity and potential impact on the development/progression of type 2 diabetes (T2D). In humans, supplementation with EC-rich foods, extracts, and pure EC improves insulin sensitivity and glucose tolerance in normal weight, overweight, obese and T2D individuals. These effects of EC are also observed in rodent models of diet-induced obesity and T2D. The events involved in the development of insulin resistance and T2D are multiple and interrelated. EC has been shown to inhibit inflammation, oxidative and endoplasmic reticulum stress, to modulate mitochondrial biogenesis and function, and to regulate events in the gastrointestinal tract and the pancreas that impact glucose homeostasis. A downregulation of oxidant production, particularly through direct inhibition or suppression of NADPH oxidase expression, and of redox sensitive signals (NF-kappaB, JNK1/2) that inhibit the insulin pathway, appear to be central to the beneficial actions of EC on insulin sensitivity. Overall, EC seems to have a positive role in the regulation of glucose homeostasis, however definitive answers on its importance for the management of T2D will depend on further clinical and mechanistic studies. PMID- 30447351 TI - N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation. AB - The mechanism underlying the development of chronic kidney disease (CKD) after acute kidney injury (AKI) remains unclear. Maladaptive repair has been considered an important mechanism of CKD post AKI. Renal tubular cells under maladaptive repair have characteristics of premature senescence. These premature senescent cells can generate profibrotic factors that promote organ fibrosis. The purpose of this study was to investigate whether cisplatin induces premature renal senescence and the role of premature renal senescence in the progression of CKD post AKI. As oxidative stress is a major cause of senescence, we further evaluated whether antioxidant therapy could protect renal tubular cells from cisplatin-induced premature senescence and retard the progression of CKD post AKI. The molecular mechanism of this protection was also investigated. We found that cisplatin induced premature renal senescence in vitro and in vivo. In a multiple-cisplatin-treatment murine model, renal interstitial fibrosis was accompanied by premature renal senescence. N-acetylcysteine (NAC), an antioxidant, attenuated premature senescence and decreased renal fibrosis, and its effects were dependent on sirtuin1 (SIRT1) activation and p53 deacetylation. These results indicate that cisplatin can induce premature renal senescence, which is associated with the development of CKD post cisplatin-induced AKI. SIRT1 activation and p53 deacetylation might be identified as potential targets for attenuating premature renal senescence and retarding the progression of CKD post AKI. PMID- 30447352 TI - Construction of an immunized rabbit phage display antibody library for screening microcystin-LR high sensitive single-chain antibody. AB - Microcystin-LR (MC-LR) is one of the most common biotoxin that pollutes water and agricultural products. The study aims to obtain the high sensitive anti-MC-LR single-chain antibody (scFv) for detecting MC-LR. Here, a MC-LR-immunized rabbit phage display scFv library with its capacity of 3.26 * 109 CFU/mL was constructed and used for anti-MC-LR phage scFv particles screening. After four rounds of biopanning, 18 positives were isolated and identified successfully. The most positive scFv (RscFv3) was expressed in Escherichia coli HB2151 and purified with a concentration of 796.7 MUg/mL, and the purified anti-MC-LR polyclonal antibodies (PAbs) were 3.6 mg/mL. The PAbs and scFv based indirect competitive enzyme linked immunosorbent assay (IC-ELISAs) were established for MC-LR and its analogues, and the results showed they all had high sensitive for MC-LR with detection limits of 0.03 and 0.05 MUg/L, and had strong cross-reactivity for MC RR, MC-WR and MC-YR, respectively. The average recovery rate was 91.9% with coefficient of variation <6.8% for scFv-based IC-ELISA to detect MC-LR spiked in water samples, which met the requirement of indoor testing. The present results indicate that we have obtained a high sensitive anti-MC-LR scFv by the MC-LR immunized phage library construction and screening, and the scFv-based IC-ELISA can be used for monitoring MC-LR in water samples. PMID- 30447353 TI - Sugar palm nanofibrillated cellulose (Arenga pinnata (Wurmb.) Merr): Effect of cycles on their yield, physic-chemical, morphological and thermal behavior. AB - Nanofibrillated cellulose (NFCs) were extracted from sugar palm fibres (SPS) in two separate stages; delignification and mercerization to remove lignin and hemicellulose, respectively. Subsequently, the obtained cellulose fibres were then mechanically extracted into nanofibres using high pressurized homogenization (HPH). The diameter distribution sizes of the isolated nanofibres were dependent on the cycle number of HPH treatment. TEM micro-images displayed the decreasing trend of NFCs diameter, from 21.37 to 5.5 nm when the number of cycle HPH was increased from 5 to 15 cycles, meanwhile TGA and XRD analysis showed that the degradation temperature and crystallinity of the NFCs were slightly increased from 347 to 347.3 degrees C and 75.38 to 81.19% respectively, when the number of cycles increased. Others analysis also were carried on such as FT-IR, FESEM, AFM, physical properties, zeta potential and yield analysis. The isolated NFCs may be potentially applied in various application, such as tissue engineering scaffolds, bio-nanocomposites, filtration media, bio-packaging and etc. PMID- 30447354 TI - A novel thiosemicarbazide modified chitosan (TSFCS) for efficiency removal of Pb (II) and methyl red from aqueous solution. AB - Thiosemicarbazide modified chitosan, TSFCS, was prepared and characterized by FTIR, SEM and TGA techniques and its application as a novel adsorbent for the removal of Pb(II) and methyl red (MR) was investigated. The effect of some adsorption parameters such as pH, TSFCS dosage and initial concentration of solutions were evaluated. The maximum removal percentage for MR and Pb(II) was found to be about 91% and 85.6% at pH 8 and 5 and TSFCS dosage of 3.33 g/l and 1.33 g/l, respectively. Langmuir, Freundlich and Temkin isotherms were evaluated and the maximum adsorption capacities for Pb(II) and MR were found to be 56.89 mg/g and 17.31 mg/g at 55 degrees C and 25 degrees C, respectively. Isotherm studies indicate that Pb (II) and MR adsorptions follow Freundlich and Langmuir models, respectively. The adsorption kinetic was more accurately fitted by the pseudo-second order model. Thermodynamic parameters including DeltaG degrees , DeltaH degrees and DeltaS degrees were determined over the temperature range of 25-55 degrees C. The findings show that the sorption process was spontaneous (DeltaG degrees < 0) and endothermic (DeltaH degrees > 0). PMID- 30447355 TI - The contribution of NOS3 variants to coronary artery disease: A combined genetic epidemiology and computational biochemistry perspective. AB - Cardiovascular diseases, particularly coronary artery disease (CAD) and myocardial infarction, are the leading cause of death among people worldwide. CAD is exceedingly complex in its interplay of environment and genetics, with numerous genetic loci contributing to its heritability. Here, we aim at looking into the effects of the NOS3 c.894G>T and 27-bp VNTR polymorphisms on susceptibility to CAD in a population of Turkish Cypriots, at seeing whether these effects correlate with plasma lipid levels and at predicting the functional consequences of each polymorphism tested. A total of 50 subjects with CAD and 100 otherwise healthy subjects were included in the present case-control study. Genomic DNA was extracted from peripheral blood samples, and the two NOS3 polymorphisms were determined by restriction endonuclease analysis of PCR amplicons. Complementary methods of statistical analysis and computational modeling were employed accordingly to achieve the aims above. Our findings show that the 27-bp VNTR polymorphic locus, but not the c.894G>T polymorphic locus, is associated with CAD and that it may regulate NOS3 pre-mRNA splicing in a length dependent manner. Overall, along with additional, yet-to-be ascertained susceptibility markers the 27-bp VNTR 4a/4b marker may be employed in risk stratification in community-level screening for CAD among Turkish Cypriots. PMID- 30447356 TI - Kinetics, thermodynamics, equilibrium isotherms, and reusability studies of cationic dye adsorption by magnetic alginate/oxidized multiwalled carbon nanotubes composites. AB - Magnetic beads (AO-gamma-Fe2O3) of alginate (A) impregnated with citrate coated maghemite nanoparticles (gamma-Fe2O3) and oxidized multiwalled carbon nanotubes (OMWCNTs) were synthesized and used as adsorbent for the removal of methylene blue from water. The XRD analysis revealed that the diameter of gamma-Fe2O3 is 10.24 nm. The mass saturation magnetization of AO-gamma-Fe2O3 and gamma-Fe2O3 were found to be 27.16 and 42.63 emu.g-1, respectively. The adsorption studies revealed that the data of MB isotherm were well fitted to the Freundlich model. The Langmuir isotherm model exhibited a maximum adsorption capacity of 905.5 mg.g 1. The adsorption was very dependent on initial concentration, adsorbent dose, and temperature. The beads exhibited high adsorption stability in large domain of pH (4-10). The thermodynamic parameters determined at 283, 293, 303, and 313 K revealed that the adsorption occurring was spontaneous and endothermic in nature. Adsorption kinetic data followed the intraparticle diffusion model. The AO-gamma Fe2O3 beads were used for six cycles without significant adsorptive performance loss. Therefore, the eco-friendly prepared AO-gamma-Fe2O3 beads were considered as highly recyclable and efficient adsorbent for methylene blue as they can be easily separated from water after treatment. PMID- 30447357 TI - Development of photocrosslinked salecan composite hydrogel embedding titanium carbide nanoparticles as cell scaffold. AB - Salecan is a water-soluble extracellular beta-glucan and appropriate for preparing hydrogels applicable in biomedical field. Herein, an innovative photocrosslinked composite hydrogel composed of salecan/poly(hydroxypropyl methacrylate (PHPMA) network and titanium carbide (TiC) nanoparticles was successfully prepared. XRD patterns clearly showed the crystal planes of Ti. More importantly, the introduction of TiC nanoparticles into the hydrogel network provided structural reinforcement, and thereby synergistically enhanced the mechanical strength and thermal stability of the hydrogels. The change of salecan content markedly affected the swelling behavior and morphology of the composite hydrogels. Cytotoxicity results revealed that the composite hydrogels were non toxic to L929 and 3T3L1 cells. Cell proliferation and Live/Dead assay further demonstrated excellent cytocompatibility of the cells within the composite hydrogels, which highlights the value of this system for potential application as soft tissue engineering scaffold. PMID- 30447358 TI - Chitosan-based magnetic adsorbent for removal of water-soluble anionic dye: Artificial neural network modeling and molecular docking insights. AB - Herein, we report a new composite magnetic-adsorbent made of doped spinel ferrite (15%) dispersed throughout a matrix of chitosan (CS) cross-linked with glutaraldehyde (GA). The composite material was well characterized by using instrumental methods of physical-chemical analysis (SEM, EDX, FTIR and VSM). The produced adsorbent was applied for the removal of Acid Orange 7 (AO7) dye from aqueous solutions. Aspects of adsorption kinetics, isotherms and thermodynamics were detailed. According to the Dubinin-Radushkevich (D-R) isotherm, the mean free energy of adsorption ranged from 14.37 to 16.59 (kJ/mol), suggesting ion exchange dominating phenomena. In addition, we developed an artificial neural network (ANN) model to explore extensively the effects of factors on the adsorption performance. The coupling of ANN model with a genetic algorithm provided optimal conditions of adsorption. A maximal color removal efficiency of 98.01% was observed experimentally under optimal conditions (pH 2.51, sorbent dosage 3.88 g/L, initial dye concentration 25.3 mg/L, contact time 204 min). To unveil interaction mechanism, we employed molecular docking simulations. Computational outcomes suggested the formation of hydrophobic contacts and hydrogen bonds between AO7 dye molecule and CS-GA receptor. Molecular docking results agreed with the D-R isotherm findings, highlighting that electrostatic forces were greater than Van-der-Waals interactions. PMID- 30447359 TI - Effect of the addition of potassium and magnesium ions on the thermal, pasting, and functional properties of plantain starch (Musa paradisiaca). AB - Starch is a biopolymer widely used in the industry; however, rarely used in its native form, making necessary its modification. This work studied the effect of the inclusion of potassium and magnesium ions on the physicochemical properties of plantain starch. Ionic solutions were prepared at five concentrations between 0.0 and 0.3 M. The gelatinization, thermal degradation, viscosity, swelling power, morphological and structural changes were studied. Results showed that ion addition increased the swelling and solubility index. Both ions affected the gelatinization temperature; shift in characteristic temperatures was observed. The more significant change in the viscosity profile was showed in the final region; both ions permitted the re-ordering of the polymeric chains, but magnesium showed a greater trend towards viscosity recovery. In the thermogravimetric analysis, a lower degradation temperature was observed for starch added with ions. Structural analysis showed that for higher concentrations of potassium the addition was not carried out and crystallographic phase potassium chloride appears in the diffractogram. All the results showed that the ions inclusion produced changes in the physicochemical properties on starch, but magnesium had a greater effect on its polymeric matrix according to infrared spectroscopy, which could be due to its high electronegativity and low molecular weight. PMID- 30447360 TI - Facile green synthesis of silver nanoparticles using Berberis vulgaris leaf and root aqueous extract and its antibacterial activity. AB - Most recently, silver nanoparticles due to antibacterial properties have been considered in medical science. So the aim of the study was green synthesis of silver nanoparticles using Berberis vulgaris leaf and root aqueous extract and its antibacterial activity. After collection, identification and extraction of Berberis vulgaris was performed production of silver nanoparticles. In the study effect of parameters such as AgNO3 concentration (0.5, 1, 3, 10 mM), aqueous extract (3, 5, 10, 15, 30 mL) and contact time (1, 2, 6, 12, 24 h) were investigated in the synthesis of nanoparticles and also the antibacterial effect of these nanoparticles was studied on Escherichia coli and Staphylococcus aureus bacteria by Disk diffusion test and Minimum Inhibitory Concentration test (MIC). According to XRD results and analysis of TEM, nanoparticles have spherical shapes and size of 30 to 70 nm. On the other hand antibacterial tests showed these nanoparticles have more antibacterial activity more than other extracts. Result showed the biosynthesis of silver nanoparticles using aqueous extract of Berberis vulgaris is a clean, inexpensive and safe method that has not been used any toxic substance and consequently does not side effects and this nanoparticles has a high antibacterial activity. PMID- 30447361 TI - A review on versatile applications of blends and composites of CNC with natural and synthetic polymers with mathematical modeling. AB - Cellulose is world's most abundant, renewable and recyclable polysaccharide on earth. Cellulose is composed of both amorphous and crystalline regions. Cellulose nanocrystals (CNCs) are extracted from crystalline region of cellulose. The most attractive feature of CNC is that it can be used as nanofiller to reinforce several synthetic and natural polymers. In this article, a comprehensive overview of modification of several natural and synthetic polymers using CNCs as reinforcer in respective polymer matrix is given. The immense activities of CNCs are successfully utilized to enhance the mechanical properties and to broaden the field of application of respective polymer. All the technical scientific issues have been discussed highlighting the recent advancement in biomedical and packaging field. PMID- 30447362 TI - Preparation and characterization of thermoplastic starch composite reinforced by plasma-treated poly (hydroxybutyrate) PHB. AB - The present work aims to study the effect of the addition of poly (hydroxybutyrate) PHB as reinforcement in thermoplastic cornstarch (TPS) produced by the thermal compression molding method. Initially, the physical and chemical properties of TPS with different amounts of glycerol as the plasticizer (25, 30 and 35 wt%), are evaluated. Then, the composites, including 35% glycerol and different PHB contents (10, 20 and 30 wt%), are prepared. Additionally, the surface of the PHB granules is modified by plasma treatment using atmospheric air and sulfur hexafluoride (SF6) gas. In order to evaluate the influence of the PHB contents before and after the plasma treatment, the composites are characterized by FTIR, TGA, DSC, XRD, SEM, and mechanical tests. SEM showed a homogeneous distribution of PHB granules in the TPS matrix. On the other hand, the micrographs of the composites, using the high concentration of plasma-treated PHB, showed the agglomerated particles in the starch matrix, which represented stress concentrators, and showed weak interfacial adhesion leading to the poor mechanical properties. The thermogravimetric analysis of the composites with PHB treated by plasma showed a higher thermal stability compared to the composites of TPS and untreated PHB. PMID- 30447363 TI - Structural characterization, hypoglycemic effects and mechanism of a novel polysaccharide from Tetrastigma hemsleyanum Diels et Gilg. AB - In the present study, a novel polysaccharide (THDP-3) purified from cane leaves of Tetrastigma hemsleyanum Diels et Gilg was obtained via anion exchange chromatography and the structural analyses of the compound indicated that THDP-3 is a homogenous polysaccharide with molecular weight of 77.98 kDa. Our results show that it consists of rhamnose, arabinose, mannose, glucose and galactose at molar ratio of 1.0: 1.3: 2.5: 2.3:3.1 with main backbones of ->4)-alpha-D-GalAp (1->, ->4)-beta-D-Galp-(1-> and ->4)-alpha-D-Glcp-(1->, and main branches of beta D-Manp-(1->, ->3,6-beta-D-Manp-1-> and alpha-D-Araf-(1->. In the anti-diabetic assays, THDP-3 showed significant hypoglycemic activity in alloxan-induced diabetic mice. In addition, THDP-3 was found regulating the expression of glucokinase, amp-activated protein kinase, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These new findings indicate the high potential in therapeutic mechanisms investigation using THDP-3. Moreover, our results of hypoglycemic activity using THDP-3 demonstrated that the compound could serve as a potential anti-diabetic agent. PMID- 30447364 TI - Sequential releasing of VEGF and BMP-2 in hydroxyapatite collagen scaffolds for bone tissue engineering: Design and characterization. AB - The property of biomaterials to control the sequential release of growth factors has been widely concerned in the field of bone repair and regeneration. Double factor sustained-release scaffolds have good biocompatibility and bioactivity. O Carboxymethyl chitosan microspheres (O-CMCS) has antimicrobial activity, biodegradability, biocompatibility and film formation. This study developed scaffolds materials with microspheres with a purpose of forming a controlled slow release secondary structure. O-CMCS were used as drug carrier to construct the compound sustained-release system with rhBMP-2 and VEGF double factors release. The O-CMCS were loaded with rhBMP-2 and the hydroxyapatite collagen (HC) scaffolds were loaded with VEGF to prepare the scaffolds. These were double factors composite sustained-release system scaffolds. The biocompatibility of the sustained-release system was evaluated by in vitro and in vivo experiments. HC composite scaffolds were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction detection (XRD), in vitro sustained release test, in vitro cell culture and in vivo animal experiments. The results showed that rhBMP-2/VEGF in HC composite scaffolds (HCBV) successfully achieved the sequential release of the double factors, which could benefit bone regeneration. PMID- 30447365 TI - A review on recent advances in chitosan based composite for hemostatic dressings. AB - High mortality rate in potentially survivable casualties due to severe hemorrhage is a major challenge in today's battlefield because technological advancements have revolutionized the combat tactics and complicated the type and severity associated with wound grades. Quality of pre-hospital care prior to patient evacuation is crucial in determining the survival rate in injured patients. To deal with this challenge, considerable improvements in the hemostatic dressings have been introduced and pre-hospital care has been upgraded in many tactical combat casually care guidelines. Combat Gauze has been widely used bandage which is now been replaced by different chitosan based hemostatic dressings. It not only exhibits anti-bacterial activity but also induces hemostasis via direct interaction with erythrocytes and platelets. Its hemostasis mechanism is not dependent on host coagulation pathway which makes it an ideal dressing to stop bleeding in coagulopathic patients. Different generations of chitosan bandages have been developed to overcome the limitations of previous ones. This review provides performance analysis of chitosan bandage generations and discusses the progress made in its fabrication methods during the recent years. PMID- 30447366 TI - Fluorine-ion-releasing injectable alginate nanocomposite hydrogel for enhanced bioactivity and antibacterial property. AB - The creation of a moist environment and promotion of cell proliferation and migration together with antibacterial property are critical to the wound-healing process. Alginate (Alg) is an excellent candidate for injectable wound dressing materials because it can form a gel in a mild environment. Taking advantage of its gelation property, an injectable nano composite hydrogel containing nano sized (about 90 nm) calcium fluoride (CaF2) particles was developed using in-situ precipitation process. The amount of released fluorine (F-) ion from the nanocomposite hydrogel increased with increasing CaF2 content inside the composite hydrogel and the ions stimulated both the proliferation and migration of fibroblast cells in vitro. The antibacterial property of the composite hydrogel against E. coli and S. aureus was confirmed through colony formation test where the number of bacterial colonies significantly decreased compared to Alg hydrogel. The in vivo results based on a full-thickness wound model showed that the nanocomposite hydrogel effectively enhanced the deposition of the extracellular matrix compared to that of the Alg hydrogel. This study demonstrates the potential of this nanocomposite hydrogel as a bioactive injectable wound-dressing material with the ability to inhibit bacterial growth and stimulate cell proliferation and migration for accelerated wound healing. PMID- 30447367 TI - Characterization of cross-linked amyloglucosidase aggregates from Aspergillus fumigatus KIBGE-IB33 for continuous production of glucose. AB - Current research deals with immobilization of amyloglucosidase through carrier free approach using cross-linking strategy. Cross-linked amyloglucosidase aggregates (CLAAs) with aggregation yield of 94% were prepared in 04 h by incorporating 40% ammonium sulfate and 1.5% glutaraldehyde in enzyme solution. CLAAs were characterized by optimizing various conditions including reaction time, pH, temperature and substrate concentration. It was noticed that after cross-linking no change in optimum reaction time and substrate concentration was observed however, a 5-degree shift in optimum temperature from 60 degrees C to 65 degrees C was obtained as compared to soluble amyloglucosidase. Activation energy (Ea) of amyloglucosidase as calculated from Arrhenius plot was 5.5 kcal mol-1 and 5.2 kcal mol-1 for soluble and cross-linked aggregates, respectively. Stability studies revealed that CLAAs can be used at higher temperatures for longer time period than soluble amyloglucosidase. Furthermore, data of recycling studies showed that CLAAs can be efficiently reused for 20 cycles with the retention of 63% of its initial activity. Due to the continuous reusability of CLAAs, the product formation is also increased 8 times from 5.71 mg ml-1 (soluble enzyme) to 46.548 mg ml-1 (CLAAs). Findings of this research show that carrier free strategy is more effective for continuous hydrolysis of starch and production of glucose. PMID- 30447368 TI - Synthesis of applicable hydrogel corn silk/ZnO nanocomposites on polyester fabric with antimicrobial properties and low cytotoxicity. AB - Corn silk as a clean and cheap agricultural waste with protein and cellulosic structure and traditionally usages was applied on polyester for the first time to increase the cell viability of zinc oxide on polyester fabric creating good hydrogel properties. The corn silk was first dried under sunlight, powdered and dispersed into the homogeneous solution using sodium hydroxide/urea at boil. Zinc acetate and a cationic surfactant along with the polyester fabric were placed in the alkali solution with or without corn silk at boil for 1 h. The samples were characterized by SEM images, EDX, FTIR spectroscopy and XRD. The vertical wicking, water absorption and self-cleaning activities of the treated fabrics were also investigated. The synthesized ZnO without corn silk was presented nanoplate and spherical shape nanoparticles however in presence of corn silk only the spherical shape nanoparticles were formed. Excellent antimicrobial properties against Escherichia coli, Staphylococcus aureus and Candida albicans and cell viability on the human cells were obtained on the fabric conataining corn silk/zinc oxide nanocomposites close to 100 and 87%, respectively. Finally, application of corn silk along with synthesis of ZnO nanoparticles introduced a novel polyester fabric with antimicrobial, highly hydrophilic, self-cleaning properties having low cytotoxicity. PMID- 30447369 TI - Enhanced heavy metal ions adsorption by 4-aminobenzoic acid grafted on chitosan/epichlorohydrin composite: Kinetics, isotherms, thermodynamics and desorption studies. AB - The multi-functional chitosan is important for the development of novel adsorbents which is needed for the effective removal of scavenging metal ions from water and wastewater. In this study the functionalized materials were characterize by FTIR, SEM/EDX, TGA/DTA, BET and XRD. Physicochemical parameters including pH, contact time, ionic strength and temperature were investigated in batch mode to optimize the conditions to be applied on a commercial scale for the maximum removal of metal ions using batch applications. The results showed that adsorption performance of grafted cross-linked chitosan beads can be modeled efficiently by Langmuir isotherm and pseudo-second order kinetic model. Thermodynamic parameters such as Gibb's free energy change (?G degrees ), enthalpy change (?H degrees ) and entropy change (?S degrees ) were calculated and the results showed the adsorption of Pb(II), Cu(II), Ni(II), Zn(II) and Cd(II) ions onto grafted crosslinked chitosan beads (G/ECH-CS) are spontaneous and endothermic in nature. Batch regeneration of the spent adsorbent from the single component mixture was effective. Multiple adsorption/desorption experiments were also carried out, and it was found that 0.0% mass loss of the G/ECH-CS was observed after the third cycle of adsorption/desorption studies. PMID- 30447370 TI - Exopolysaccharides production by Lactobacillus acidophilus LA5 and Bifidobacterium animalis subsp. lactis BB12: Optimization of fermentation variables and characterization of structure and bioactivities. AB - In this study, the most important variables (incubation temperature, fermentation time and yeast extract concentration) responsible for the exopolysaccharides (EPSs) production by Lactobacillus acidophilus LA5 and Bifidobacterium animalis subsp. lactis BB12 were screened. The EPSs synthesize by LA5, BB12, and their co culture were successfully optimized and were 349.82 +/- 5.39, 146.83 +/- 3.99 and 187.02 +/- 1.54 mg/L, respectively. GC-MS analysis indicated that the purified EPSs are heteropolysaccharide and consisted of glucose, galactose, glucuronic acid, and xylose. The FT-IR analysis was used to investigate functional groups of purified EPSs and NMR analysis was used to study the structure of them. The DSC, TGA and DTG analysis of the extracted EPSs showed that they had high thermal stability and degradation temperature. The results of bioactivity analysis indicated that maximum DPPH and hydroxyl radicals scavenging activity were 59.30 +/- 1.95, 56.76 +/- 0.79, 62.33 +/- 1.02% and 59.94 +/- 1.68, 46.40 +/- 0.73, 53.54 +/- 0.76%, respectively for the EPSs of LA5, BB12, and their co-culture. Additionally, reducing power of the produced EPSs by LA5, BB12, and their co culture were 1.047 +/- 0.001, 1.270 +/- 0.045 and 1.139 +/- 0.018, respectively. Consequently, all these results showed that the EPSs produced by LA5, BB12, and their co-culture had a high potential as natural antioxidants or bioactive additive in the food industry. PMID- 30447371 TI - NADH oxidase from Lactobacillus reuteri: A versatile enzyme for oxidized cofactor regeneration. AB - Pyridine nucleotide cofactors play important roles in biocatalytic processes that generate value-added chemicals for the pharmaceutical and food industries. Because of the high price of these pyridine cofactors, cofactor regeneration is highly desirable. However, recycling the oxidized form of cofactors, especially NADP+, remains a challenge. Here, we cloned and characterized an NADH oxidase from Lactobacillus reuteri (LreNox) which can oxidize both NADH and NADPH. Unlike many other Noxs, LreNox showed equal catalytic efficiency towards NADH and NADPH. To the best our knowledge, LreNox has the highest activity towards NADPH as a substrate compared to other wild type Noxs. Homology modeling and substrate docking studies provided insights into the dual substrate specificity of LreNox. Gly155, Ser179, and His184 in the LreNox substrate binding pocket, which are absent in other Noxs structures, are crucial for NADPH recognition, providing more space for interactions with the additional phosphate group present in NADPH. We also explored the utility of LreNox for NADP+ regeneration in l-sorbose production by coupling it with a sorbitol dehydrogenase. The turn over number (TTN) improved ~53-fold after using LreNox as the NADP+ recycling enzyme. This study demonstrates that LreNox could potentially be used for the regeneration of NAD(P)+ in commercial applications. PMID- 30447372 TI - Preparation and characterization of marine mineralized ASC nanocomposites through biomineralization. AB - Mineralized collagen provides new solutions in the manufacture of porous scaffolds for tissue engineering. In this research, the use of biomimetic mineralization, the process of mineralization of acid soluble collagen (ASC) type I extracted from white fish (Rutilus frisii kutum) scales, in a body simulated fluid (SBF) in the presence and absence of an anionic surfactant, sodium dodecyl benzene sulphonate (SDBS) was thoroughly investigated. The formation of beta tricalcium phosphate (beta-TCP) nanocrystals in mineralized nanocomposites was detected by XRD, TGA, and FT-IR techniques. The denaturation temperature (Td) of mineralized ASC was determined at 42.87 degrees C without surfactant, and at 70.2 degrees C with surfactant using DSC technique, which indicated a higher thermal stability of ASC without the SDBS surfactant. TEM images illustrated that the formation of beta-TCP crystals on collagen nano-fibrils was in an irregular form in the absence of surfactant while it was more regular and in the form of rectangular sheets in the presence of surfactant. The results of UV/Vis spectrophotometer for turbidity measurements during the initial step of biomineralization revealed that SDBS while accelerating the self-assembly process of collagen nano-fibrills, delayed the process of nucleation and the growth of calcium phosphate nanocrystals by increasing the kinetic energy barrier. PMID- 30447373 TI - Valorization of Opuntia monacantha (Willd.) Haw. cladodes to obtain a mucilage with hydrocolloid features: Physicochemical and functional performance. AB - Opuntia monacantha mucilage was investigated for its physicochemical characteristics and functional properties. The mucilage extraction yield was 12% (DW) and it consisted of 80.12% carbohydrates, 15.14% ashes, 3.55% proteins, and 1.19% lipids. Monosaccharide profiling demonstrated a predominantly presence of galactose, glucuronic acid, and arabinose. Viscosimetric measurements gave an intrinsic viscosity of 9.02 dL/g and a molar mass of 1.12 * 106 g/mol. Reconstituted mucilage solution (1% w/v) had a mean particle diameter (D4,3) of 648 nm and solubility above 85%. Its emulsifying capacity improved with the increment of mucilage solution in the emulsion; likewise, it provided high emulsion stability through different ratios of oil to polysaccharide solution. It displayed good foaming capacity, although its foam stability progressively reduced over time. In addition, its blending with ovalbumin resulted in a foaming capacity enhancement and in a markedly greater foam stability compared to ovalbumin alone. The rheological studies indicated the mucilage solutions exhibited shear-thinning behavior at concentrations between 1 and 10% and fairly stable viscous properties in the temperature range of 5-80 degrees C. These outcomes support that O. monacantha mucilage may find potentially useful applications in food systems, particularly as an emulsifying, foaming and thickening agent, or as a stabilizer. PMID- 30447374 TI - Preparation and characterization of porous starch reinforced with halloysite nanotube by solvent exchange method. AB - The aim of this study was to improvement of adsorption capacity of porous starch (PS) by incorporation of halloysite nanotube (HNT). PS/HNT carrier was synthesized through the solvent exchange method. Various fabrication approaches for PS were introduced and different ethanol ratio (40, 60, 80, 100%), HNT concentration (0, 0.1, 0.2, 0.3, 0.4 and 0.5 mg/mL) and drying method (oven, freeze dryer and microwave) were applied. The results indicated that high ratio of ethanol created larger pores and also the best results were obtained from freeze-dried samples (p < 0.05). Incorporation of HNT could further improve the adsorption capacity. However, the best oil and water adsorption capacity were related to PS alone. The nitrogen adsorption-desorption measurement and scanning electron microscopy elucidated the porous structure of samples. The experimental data were fitted successfully by the Langmuir model rather than Freundlich isotherm. Also PS/HNT had higher apparent density and more negative zeta potential rather than PS. However, the DSC results showed the similar thermal patterns for PS and PS/HNT. PMID- 30447375 TI - Analyses of active antioxidant polysaccharides from four edible mushrooms. AB - Four water-soluble polysaccharides were extracted from Pleurotus eryngii, Flammulina velutipes, Pleurotus ostreatus and white Hypsizygus marmoreus. Using anion exchange and gel permeation chromatography, a neutral and an acidic fraction were purified from each water-soluble polysaccharide. Their molecular weights were all around 20 kDa except that the acidic polysaccharide from Pleurotus ostreatus (named WPOPA) had a lower molecular weight of 5 kDa. Four neutral polysaccharides were mainly composed of galactose (42.7%-69.1%), followed by Man (19.4%-39.3%) and Glc (1.1%-15.9%). Four acidic polysaccharides contained glucose (59.0%-81.8%) as major sugar and minor glucuronic acid (4.5%-9.5%). Acidic polysaccharides exhibited stronger antioxidant activities than neutral fractions, and WPOPA showed the best antioxidant effects. Structural analysis indicated WPOPA had beta-(1 -> 6)-glucan backbone branched at O-3 by beta-1,3-d Glcp, t-beta-d-Glcp and t-beta-d-GlcpA. This investigation would be useful for screening natural antioxidants and significant in developing mushroom polysaccharides as functional foods. PMID- 30447376 TI - Insights into product release dynamics through structural analyses of thymidylate kinase. AB - Several studies on enzyme catalysis have pointed out that the product release event could be a rate limiting step. In this study, we have compared the release event of two products, Adenosine di-phosphate (ADP) and Thymidine di-phosphate (TDP) from the active-site of human and Thermus thermophilus thymidine mono phosphate kinase (TMPK), referred to as hTMPK and ttTMPK, respectively. TMPK catalyses the conversion of Thymidine mono-phosphate (TMP) to TDP using ATP as phosphoryl donor in the presence of Mg2+ ion. Most of the earlier studies on this enzyme have focused on understanding substrate binding and catalysis, but the critical product release event remains elusive. Competitive binding experiments of the substrates and the products using ttTMPK apo crystals have indicated that the substrate (TMP) can replace the bound product (TDP), even in the presence of an ADP molecule. Further, the existing random accelerated molecular dynamics (RAMD) simulation program was modified to study the release of both the products simultaneously from the active site. The RAMD simulations on product-bound structures of both ttTMPK and hTMPK, revealed that while several exit patterns of the products are permissible, the sequential exit mode is the most preferred pattern for both ttTMPK and hTMPK enzymes. Additionally, the product release from the hTMPK was found to be faster and more directional as compared to ttTMPK. Structural investigation revealed that the critical changes in the residue composition in the LID-region of ttTMPK and hTMPK have an effect on the product release and can be attributed to the observed differences during product release event. Understanding of these dissimilarities is of considerable utility in designing potent inhibitors or prodrugs that can distinguish between eukaryotic and prokaryotic homologues of thymidylate kinase. PMID- 30447377 TI - Association of CSF CD40 levels and synaptic degeneration across the Alzheimer's disease spectrum. AB - The CD40 pathway has been implicated in microglial activation, which is considered as a key factor in the pathogenesis of Alzheimer's disease (AD). However, the association of CSF CD40 and synaptic degeneration in living human is not clear. A total of 294 subjects with different severities of cognitive impairments were included in this study: 84 participants with normal cognition, 143 patients with mild cognitive impairment (MCI) and 67 patients with mild AD. Levels of CD40 in CSF were compared among the three groups. Further, several linear regression models were conducted to explore the associations of CSF CD40 and neurogranin levels (reflecting synaptic degeneration) when controlling for age, gender, educational attainment, APOE4 genotype, clinical diagnosis, CSF Abeta42 and tau proteins. We found that CSF CD40 levels were significantly decreased in patients with mild AD compared with healthy controls and MCI patients (control vs. AD, p = 0.0026; MCI vs. AD, p = 0.0268). However, there were no significant differences in CSF CD40 levels between controls and patients with MCI (p = 0.37). In addition, CSF CD40 levels were associated with neurogranin in the pooled sample when controlling for age, gender, educational attainment, APOE4 genotype and diagnosis. In summary, our findings support the notion that the CD40 pathway may contribute to an important mechanism underlying synaptic degeneration in AD. PMID- 30447378 TI - Dose-dependent effects of isoflurane on TrkB and GSK3beta signaling: Importance of burst suppression pattern. AB - OBJECTIVES: Deep burst-suppressing isoflurane anesthesia regulates signaling pathways connected with antidepressant responses in the rodent brain: activation of TrkB neurotrophin receptor and inhibition of GSK3beta kinase (glycogen synthase kinase 3beta). The main objective of this study was to investigate whether EEG (electroencephalogram) burst suppression correlates with these intriguing molecular alterations induced by isoflurane. METHODS: Adult male mice pre-implanted with EEG recording electrodes were subjected to varying concentrations of isoflurane (1.0-2.0% ad 20 min) after which medial prefrontal cortex samples were collected for molecular analyses, and the data retrospectively correlated to EEG (+/- burst suppression). RESULTS: Isoflurane dose-dependently increased phosphorylation of TrkBY816, CREBS133 (cAMP response element binding protein), GSK3betaS9 and p70S6kT412/S424. The time spent in burst suppression mode varied considerably between individual animals. Notably, a subset of animals subjected to 1.0-1.5% isoflurane showed no burst suppression. While p-GSK3betaS9, p-CREBS133 and p-p70S6kT412/S424 levels were increased in the samples obtained also from these animals, p-TrkBY816 levels remained unaltered. CONCLUSIONS: Isoflurane dose-dependently regulates TrkB and GSK3beta signaling and dosing associated with therapeutic outcomes in depressed patients produces most prominent effects. PMID- 30447379 TI - Safety and efficacy of colistin alone or in combination in adults with Acinetobacter baumannii infection: a systematic review and meta-analysis. AB - OBJECTIVES: To comprehensively assess the safety and efficacy of colistin alone or in combination in adults with Acinetobacter baumannii infection. METHODS: PubMed, Embase, and the Cochrane library were searched up to March, 2018. Studies were included if they evaluated colistin monotherapy compared with other antibiotic therapy or colistin-based combination therapy for the treatment of A. baumannii infection in adults. Clinical response and microbiological cure were efficacy outcome. Mortality and nephrotoxic adverse events were safety outcome. PROSPERO registration number is CRD42018093531. RESULTS: Four RCTs and fourteen observational studies were identified, including seven reporting colistin versus other antibiotics, twelve reporting colistin alone versus colistin based combination therapy. The overall clinical response, microbiological response and mortality did not differ significantly between colistin monotherapy with other antibiotics. However, incidences of nephrotoxicity was significantly higher in colistin monotherapy (OR= 2.50, 95% CI = 1.05-5.98, P = 0.04). No significant difference was detected in clinical response and >28 d mortality between colistin monotherapy and combination therapy. However, the colistin-based combination therapy was shown increasing the microbiological response (OR= 0.49, 95% CI = 0.32-0.74, P = 0.0009) and decreasing the incidences of nephrotoxicity (OR= 1.66, 95% CI = 0.99-2.78, P =0.05). CONCLUSIONS: For the treatment of AB infection, colistin alone is as effective as other antibiotics, but it has a higher risk of nephrotoxicity. Colistin based combination demonstrates microbiological benefit and no higher risk of nephrotoxicity compared with monotherapy. High-quality RCTs are still needed to confirm the beneficial role of colistin combination therapy. PMID- 30447380 TI - Repurposing azithromycin and rifampicin against Gram-negative pathogens by combination with peptide potentiators. AB - Gram-negative pathogens are intrinsically resistant to several antibiotics that are not able to penetrate the envelope barrier. The objective of this study was to identify peptides that at low concentrations induce susceptibility to these antibiotics in multidrug-resistant (MDR) Gram-negative strains of clinical relevance. A pairwise screening of 34 diverse peptides and four antibiotics (erythromycin, linezolid, rifampicin and vancomycin) with primary activity against Gram-positive bacteria identified four peptides that at sub-micromolar concentrations conferred susceptibility to rifampicin or erythromycin in Escherichia coli ATCC 25922. The identified peptides exhibited synergy with azithromycin and potentiated clindamycin in MDR E. coli ST131 and Klebsiella pneumoniae ST258. The low cytotoxicity toward eukaryotic cells (IC50 >50 uM) observed for two peptides (KLWKKWKKWLK-NH2 and GKWKKILGKLIR-NH2) prompted synthesis and evaluation of the corresponding all-D analogs (D1 and D2), which retained similar synergistic antibacterial profiles. Low concentrations of D1 and D2 in combination with azithromycin and rifampicin inhibited growth of most clinical E. coli, K. pneumoniae and Acinetobacter baumannii strains tested. Our data demonstrate that combinatorial screening at low concentrations constitutes an efficient approach to identify clinically relevant peptide-antibiotic combinations. In vivo PK/PD and toxicity studies are needed to further validate the use of the peptides identified by this study for repurposing azithromycin and rifampicin against Gram-negative pathogens. PMID- 30447381 TI - A brief measure for the assessment of competence in coping with death: The Coping with Death Scale short version. AB - CONTEXT: The coping with death competence is of great importance for palliative care professionals, who face daily exposure to death. It can keep them from suffering compassion fatigue and burnout, thus enhancing the quality of the care provided. Despite its relevance, there are only two measures of professionals' ability to cope with death. Specifically, the Coping with Death Scale (CDS) has repeatedly shown psychometric problems with some of its items. OBJECTIVE: The aim of this study was to develop and validate a short version of the CDS. METHODS: Nine items from the original CDS were chosen for the short version. Two cross sectional surveys were conducted in Spanish (N=385) and Argentinian (N=273) palliative care professionals. The CDS and the Professional Quality of Life Scale were used in this study. Statistical analyses included two Confirmatory Factor Analyses (CFA), followed by a standard measurement invariance routine. Reliability estimates and evidence of validity based on relations with other measures were also gathered. RESULTS: CFA models had excellent fit in both the Spanish (chi2(27)=107.043, p<.001; CFI=.978; TLI=.970; RMSEA=.093 [.075,.112]; SRMR=.030) and Argentinian (chi2(27)=102.982, p<.001; CFI=.963; TLI=.950; RMSEA=.106[.085,.128]) samples. A standard measurement invariance routine was carried out. The most parsimonious model (chi2(117)=191.738, p<.001; CFI=.987; TLI=.992; RMSEA=.046[.034,.058]; SRMR=.043) offered evidence of invariance across countries, with no latent mean differences. Evidence of reliability and evidence of validity based on relations with other measures were also appropriate. CONCLUSION: Results indicated the psychometric boundaries of the short version of the CDS. PMID- 30447382 TI - Prevalence and characteristics of patients being at risk of deteriorating and dying in primary care. AB - CONTEXT: Understanding the prevalence and characteristics of primary care outpatients being at risk of deteriorating and dying may allow general practitioners (GPs) to identify them, and initiate end-of-life discussions. OBJECTIVES: This study aimed to investigate the prevalence and characteristics of primary care outpatients being at risk of deteriorating and dying, as determined by the Supportive and Palliative Care Indicators Tool (SPICTTM). METHODS: A multicenter cross-sectional observational study was conducted at 17 clinics with 22 GPs. We enrolled all patients aged >=65 years who visited the GPs in March 2017. We used the Japanese version of the SPICTTM to identify patients being at risk of deteriorating and dying. We assessed the demographic and clinical characteristics of enrolled patients. RESULTS: In total, 382 patients with a mean age of 77.4 +/- 7.9 years were investigated. Sixty-six patients (17.3%) had >=2 positive general indicators or >=1 positive disease-specific indicator in the SPICT-JP. Patients with dementia/frailty, neurological disease, cancer, and kidney disease showed a significantly elevated risk of deteriorating and dying, while patients with other specific disease did not. The patients at risk were significantly older and less likely to be living with family at home. They also had a higher Charlson Comorbidity Index score and a lower Palliative Performance Scale score. CONCLUSION: Among primary care outpatients aged over 65 years, 17.3% were at risk of deteriorating and dying regardless of their estimated survival time, and many outpatients at risk were not receiving optimal multidisciplinary care. PMID- 30447383 TI - Attitudes, Beliefs, and Practices of Pediatric Palliative Care Physicians Regarding the Use of Methadone in Children with Advanced Cancer. AB - CONTEXT: Methadone is a long-acting opioid known for its unique pharmacokinetic and pharmacodynamic properties. Most research on methadone in children is limited to its effect on the prolongation of the corrected QT (QTc) interval. OBJECTIVES: To better understand the attitudes, beliefs, and practices of pediatric palliative care physicians regarding the use of methadone in children with advanced cancer. METHODS: A survey was sent to The American Academy of Pediatrics Section of Hospice and Palliative Medicine LISTSERV(r). Information on demographics, dosing of methadone, and the use of electrocardiograms (ECGs) was collected. RESULTS: One-hundred and five respondents (91%) provide palliative care to children >= 50% of the time, and a majority (81, 77%) prescribe methadone. Most (62, 77%) physicians were board-certified in Hospice and Palliative Medicine and most (39, 63%) certified via the direct pathway ("grandfathering"). Most physicians (57, 70%) do not use loading doses of methadone. Board-certified physicians trended towards decreasing methadone dose more (40% +/- 19%) than non-board-certified physicians (28%, +/-20%) when changing from the oral to intravenous route (p = 0.07). Respondents defined a QTc interval as "prolonged" (mean +/- SD) at 444 milliseconds (+/-68 milliseconds). The percentage of patients receiving a baseline ECG was 65% (+/-33%). The most common reason for not performing a baseline ECG was that the patient was on hospice (13, 36%). CONCLUSIONS: There are consistent practices, attitudes, and beliefs of pediatric palliative care providers with regards to methadone. More education is needed on the accurate value of a prolonged QTc interval. PMID- 30447384 TI - PC-FACS. AB - PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PCFACS, please encourage them to join the AAHPM at aahpm.org. Comments from readers are welcomed at pc facs@aahpm.org. PMID- 30447385 TI - Destination Therapy: Standardizing The Role of Palliative Medicine & Delineating The Dt-Lvad Journey. AB - CONTEXT: Destination therapy (DT) patients face significant challenges as they transition from chronic LVAD support to comfort-oriented care . Integration of Palliative Medicine (PM) into the multidisciplinary team is important to facilitate advanced care planning and improve quality of life (QoL). OBJECTIVE: We evaluated the impact of a structured programmatic approach to the end-of-life (EOL) process in DT patients as measured by QoL surveys and the utilization of advance care planning (ACP). METHODS: We instituted a four prong intervention approach: (1) delineated the path from implant to EOL by defining specific stages, including a transitional phase where care limits were agreed upon, (2) standardized the role of PM, (3) held transitional care meetings to support shared-decision making, and (4) held multidisciplinary team debriefings to facilitate communication. Pre- and post-intervention outcomes were measured for patients/caregivers by using the QUAL-E/QUAL-E (family) QoL instrument. Wilcoxon signed-ranks test compared non-parametric variables. RESULTS: All patients (n = 41)/caregivers (n = 28) reported improved QoL measures (patient p = .035/caregiver p = .046). Preparedness plans increased from 52% to 73% after implementation and advance directives increased from 71% to 83%. Fifty-nine percent of the patients completed an outpatient PM clinic visit; 51% completed/scheduled a second visit. Clinician outcomes improved including satisfaction with multidisciplinary team communication/expectations, ACP processes, and EOL management. CONCLUSION: A programmatic approach that standardizes the role of PM and delineates the patient's path from implant to EOL improved quality outcomes and increased implementation of ACP. A defined communication process allowed the multidisciplinary team to have a clear patient management approach. PMID- 30447386 TI - Factors Predisposing Terminally Ill Cancer Patients' Preferences for Distinct Patterns/States of Life-Sustaining Treatments over Their Last Six Months. AB - BACKGROUND: High-quality EOL care depends on thoroughly assessing terminally ill patients' preferences for end-of-life (EOL) care and tailoring care to individual needs. Studies on predictors of EOL-care preferences were primarily cross sectional and assessed preferences for multiple life-sustaining treatments (LSTs), making clinical applications difficult. OBJECTIVE: /Methods: We examined factors predisposing cancer patients (N=303) to specific LST-preference states (life-sustaining preferring, comfort preferring, uncertain, and nutrition preferring) derived from six LSTs (cardio-pulmonary resuscitation, intensive care unit care, chest compression, intubation with mechanical ventilation, intravenous nutrition, and tube feeding) in patients' last 6 months by multilevel multinomial logistic regression. RESULTS: Participants with accurate prognostic awareness and physician-patient EOL-care discussions were less likely to be in life-sustaining preferring, uncertain, and nutrition-preferring states than in the comfort preferring state. Better QOL and more depressive symptoms predisposed participants to be less likely to be in the uncertain than in the comfort preferring state. Membership in the nutrition-preferring rather than the comfort preferring state was significantly higher for participants in the state of moderate symptom distress with severe functional impairment than in the state of mild symptom distress with high functioning. CONCLUSION: Accurate prognostic awareness, physician-patient EOL-care discussions, QOL, depressive symptoms, and symptom-functional states predisposed terminally ill cancer patients to distinct LST-preference states. Clinicians should cultivate patients' accurate prognostic awareness and facilitate EOL-care discussions to foster realistic expectations of LST efficacy at EOL. Clinicians should enhance patients' QOL to reduce uncertainty in EOL-care decision making and provide adequate psychological support to those with more depressive symptoms who prefer comfort care only. PMID- 30447387 TI - 'Just as I expected': A longitudinal cohort study of the impact of response expectancies on side effect experiences during radiotherapy for prostate cancer. AB - CONTEXT: Previous research has indicated pre-treatment response expectancies of side effects often predict subsequent toxicity severity. However, this has been largely based on female patients undergoing chemotherapy. OBJECTIVES: We tested whether this association also occurred in a novel cohort; men with prostate cancer undergoing radiotherapy. We investigated these associations throughout treatment (before and after side effects were medically predicted to occur), controlling known and novel variables. METHODS: Homogenous male patients scheduled for radiotherapy (N = 35, mean age 71 years) completed baseline (pre treatment) measures; response expectancies of 18 treatment-related side effects, questions about baseline health and hormonal treatment, emotional state, and coping style. Response expectancies of the side effects were again measured 2 weeks into treatment. The severity of the same 18 toxicities were assessed 2- and 7-weeks into treatment. RESULTS: Hierarchical multiple linear regressions revealed baseline response expectancies significantly and independently predicted 6 of 18 toxicities 2-weeks into radiotherapy, contributing 12-30% of explained variance (beta=0.39-0.59). Response expectancies assessed 2-weeks into treatment significantly and uniquely predicted 7 of 17 experienced toxicities at 7-weeks, explaining 17-50% of variance (beta=0.49-0.91). Sexual toxicity response expectancies revealed the strongest associations with experience throughout treatment (beta=0.46-0.91), with 'inability to reach orgasm' showing the largest effect. CONCLUSION: In this older male sample, response expectancies of side effects predicted experiences throughout treatment, including the period before toxicities were medically expected. Response expectancies of sexual side effects were robust, independent predictors of subsequent toxicities across treatment, especially issues with orgasm; warranting focus in practice and future research. PMID- 30447388 TI - Methylglyoxal disturbs the expression of antioxidant, apoptotic and glycation responsive genes and triggers programmed cell death in human leukocytes. AB - Methylglyoxal (MG) is a alpha-dycarbonyl compound derived mainly from glycolysis, whose accumulation is harmful for cells and tissues. Here, we evaluated the cytotoxic effects induced by MG in leukocytes after an acute exposure, measuring as endpoints of toxicity some markers of oxidative stress and programmed cell death. Human leukocytes were isolated and incubated with MG at concentrations ranging from 0.1 to 10 mM for 2.5 h, and subsequently prepared for assays based in flow cytometry, gene expression and immunoreactivity profile. The cells exposed to higher concentrations of MG had significant loss of viability, increased reactive species (RS) production and apoptosis/necrosis rate. These phenomena were accompanied by morphological changes (increased size and granularity) and disruption in mRNA expression of antioxidant, apoptotic and glycation-responsive genes, particularly: Nrf2 (Nuclear factor (erythroid-derived 2)-like 2), SOD1 (CuZn-superoxide dismutase), SOD2 (Mn-superoxide dismutase), GSR (glutathione-S-reductase), BAX (BAX-associated X protein), BCL-2 (BCL-2 associated X protein), AIF (apoptosis inducing factor), GLO-1 (glyoxalase-1) and RAGE (receptor for advanced glycation end products). The mRNA expression of CASP 9 and CASP 3 (caspase-9 and 3) as well as the immunoreactivity of proteins were not changed by MG. Collectively, our data provide evidence that MG activates programmed cell death pathways in leukocytes and that this effect seems to be associated with disturbances in cell redox signaling. PMID- 30447389 TI - Triploidy in white sturgeon (Acipenser transmontanus): Effects of acute stress and warm acclimation on physiological performance. AB - Previous studies have demonstrated reduced performance in triploid fish when reared under suboptimal conditions, which may be the result of a higher susceptibility to stressors when compared to diploids. The goal of this project was to investigate differences in the capacity of diploid (8 N) and triploid (12 N) white sturgeon, Acipenser transmontanus, to respond to both warm acclimation (6-weeks of acclimation to either 18 or 22 degrees C) and a subsequent acute stress (10-min low water stress). Following the 6-week acclimation, fish were sampled either before or following an acute low water stress. Bioindices of the primary and secondary stress response, hematology and cellular metabolic status were measured. We also sought to determine if time to peak cortisol levels were similar between diploid and triploid sturgeon after exposure to a severe acute stressor (netting stress). While both ploidies had similar primary and secondary responses to acute stress, both with and without warm acclimation, warm acclimation impacted the ability of diploid and triploid white sturgeon to mount a typical stress response to an acute stressor. In response to warm acclimation, triploids exhibited little change in branchial lactate dehydrogenase activity, while diploids increased activity. After exposure to an acute water reduction stress, diploids increased citrate synthase activity, yet triploids showed a decrease in activity. Differences in metabolic enzyme activity in response to warm acclimation and acute stress suggest triploid white sturgeon may have a reduced cellular metabolic capacity under chronic and acute stress, which may impact performance of triploid sturgeon in suboptimal conditions. PMID- 30447390 TI - Does Seipin Play a Role in Oxidative Stress Protection and Peroxisome Biogenesis? New Insights from Human Brain Autopsies. AB - Seipin is a widely expressed protein but with highest levels found in the brain and testes. Seipin function is not yet completely understood, therefore the aim of this study was to evaluate the expression of BSCL2 transcripts in the central nervous system (CNS) of humans and investigate the effect of their overexpression on a neuron model and their relationship with oxidative stress protection, as well as shed light on the pathogenic mechanisms of Celia's Encephalopathy. We analyzed the expression of BSCL2 transcripts using real-time RT-PCR in samples across the brain regions of subjects who underwent necropsy and from a case with Celia's Encephalopathy. The transcript encoding the long seipin isoform (BSCL2 203, 462 aa) is expressed primarily in the brain and its expression is inversely correlated with age in the temporal lobe, amygdala, and hypothalamus. Strong positive correlations were found between BSCL2 expression and some genes encoding protective enzymes against oxidative stress including SOD1 and SOD2, as well as peroxisome proliferator-activated receptor gamma (PPARG) in the amygdala. These results were experimentally corroborated by overexpressing BSCL2 transcripts in SH-SY5Y cells with lentiviral transduction and assessing their effects on neuron differentiated cells. Confocal microscopy studies showed that both seipin and PEX16 are closely expressed in the hypothalami of healthy human brains, and PEX16 was absent in the same region of the PELD case. We hypothesize that seipin has specific CNS functions and may play a role in peroxisome biogenesis. PMID- 30447391 TI - Enhanced GABAergic Tonic Inhibition Reduces Intrinsic Excitability of Hippocampal CA1 Pyramidal Cells in Experimental Autoimmune Encephalomyelitis. AB - Cognitive impairment (CI), a debilitating and pervasive feature of multiple sclerosis (MS), is correlated with hippocampal atrophy. Findings from postmortem MS hippocampi indicate that expression of genes involved in both excitatory and inhibitory neurotransmission are altered in MS, and although deficits in excitatory neurotransmission have been reported in the MS model experimental autoimmune encephalomyelitis (EAE), the functional consequence of altered inhibitory neurotransmission remains poorly understood. In this study, we used electrophysiological and biochemical techniques to examine inhibitory neurotransmission in the CA1 region of the hippocampus in EAE. We find that tonic, GABAergic inhibition is enhanced in CA1 pyramidal cells from EAE mice. Although plasma membrane expression of the GABA transporter GAT-3 was decreased in the EAE hippocampus, an increased surface expression of alpha5 subunit containing GABAA receptors appears to be primarily responsible for the increase in tonic inhibition during EAE. Enhanced tonic inhibition during EAE was associated with decreased CA1 pyramidal cell excitability and inhibition of alpha5 subunit-containing GABAA receptors with the negative allosteric modulator L-655,708 enhanced pyramidal cell excitability in EAE mice. Together, our results suggest that altered GABAergic neurotransmission may underlie deficits in hippocampus-dependent cognitive function in EAE and MS. PMID- 30447392 TI - Electrophysiological Characterization of Novel Effects of the Uptake-2 Blocker Decynium-22 (D-22) on Dopaminergic Neurons in the Substantia Nigra Pars Compacta. AB - Extracellular levels of dopamine (DA) and other monoamines in the brain depend not only on the classic transporters encoded by SLC6A gene family such as DAT, NET and SERT, but also a more recently identified group of low-affinity/high capacity 'Uptake-2' transporters, mainly OCT3 and PMAT. The most frequently used pharmacological tool in functional studies of Uptake-2 is decynium-22 (D-22) known to block these transporters. However, the effectiveness of this drug in enhancing extracellular DA remains uncertain. Our aim was to test the hypothesis that D-22 increases extracellular levels of DA released from the somatodendritic region of dopaminergic neurons in the substantia nigra pars compacta (SNc) by reducing the OCT3/PMAT-dependent component of DA uptake. Extracellular DA was assessed indirectly, by evoking D2-IPSCs in SNc neurons following stimulated release of this neurotransmitter in midbrain slices obtained from mice. Recordings were conducted after partial inhibition of DAT with nomifensine, and after application of L-DOPA which increased the releasable DA pool. Contrary to our expectations, D-22 reduced, rather than increased, the amplitude of D2-IPSCs. Other effects included inhibition of GABAB-IPSCs and Ih current, and a reduction in firing frequency of nigral neurons. These results show that in addition to the previously known non-specific inhibitory action on alpha1 adrenoceptors, D-22 exerts additional off-target effects by inhibiting dopaminergic and GABAergic synaptic transmission in the SNc and the spontaneous (pacemaker) activity of nigral neurons. It remains to be established if these novel effects contribute to a reduction in spontaneous locomotor activity reported in previous studies after systemic drug administration. PMID- 30447393 TI - Comprehensive B Cell Phenotyping Profile for Chronic Graft-Versus-Host Disease Diagnosis. AB - Previous studies have reported single B cell related chronic graft-versus-host disease diagnostic (cGvHD) biomarkers such as B cell activating factor (BAFF), CD21low and immature B cells, but research on the performance of biomarker combinations and the covariate effect of steroids is lacking. The primary objective of this study was to determine the most accurate combination of B cell populations using cell surface staining flow cytometry in an independent cGvHD cohort. Secondary objectives included assessing the effect of corticosteroid use at sample collection on the make-up and accuracy of the diagnostic panel and identifying the mechanism underlying low surface expression of BAFF receptor (BAFF-R) on B cells in cGvHD. Flow cytometric analysis was performed in an adult cohort of post-HCT patients with cGvHD onset (n = 44) and time-matched recipients without cGvHD (n = 63). We confirmed that the onset of cGvHD was associated with higher soluble BAFF (sBAFF) levels, elevated numbers of CD27-CD10-CD21low CD19+ B cells and classical switched memory B cells, and reduced numbers of transitional and naive B cells. The highest single B cell population area under the Receiver Operator Characteristic (ROC) curve (AUC) was 0.72 for transitional type 1 CD21low B cells. We also showed a significant inverse relationship between sBAFF and surface BAFF-R expression caused by sBAFF modulation of BAFF-R. Steroid use at sample collection influenced the significance of the sBAFF: B cell ratio, naive and marginal zone-like B cells. The optimal combination of B cell subsets most significantly associated with cGvHD onset with or without concurrent corticosteroid use resulted in ROC AUC of 0.87 and 0.84 respectively. Transitional and CD21low B cells were the only populations present in both panels; however only analyzing them resulted in ROC AUC of 0.79 and 0.78 respectively. This suggests that the inclusion of other populations and use of different panels depending on steroid use is necessary to achieve better accuracy. Soluble BAFF was not part of either panel. These novel B cell profiles could be prospectively tested in patients post-HSCT and lead to focused mechanistic studies. PMID- 30447394 TI - Environmental pollutant-mediated disruption of gut microbial metabolism of the prebiotic inulin. AB - Exposure to environmental pollutants is associated with a greater risk for metabolic diseases including cardiovascular disease. Pollutant exposure can also alter gut microbial populations that may contribute to metabolic effects and progression of inflammatory diseases. Short-chain fatty acids (SCFAs), produced from gut fermentation of dietary carbohydrates, such as inulin, exert numerous effects on host energy metabolism and are linked to a reduced risk of diseases. The hypothesis was that exposure to dioxin-like pollutants modulate gut microbial viability and/or fermentation processes. An inulin-utilizing isolate was collected from murine feces, characterized and used in subsequent experiments. Exposure to polychlorinated biphenyl, PCB 126 impeded bacterial viability of the isolate at concentrations of 20 and 200 MUM. PCB 126 exposure also resulted in a significant loss of intracellular potassium following exposure, indicating cell membrane disruption of the isolate. Furthermore, total fecal microbe samples from mice were harvested, resuspended and incubated for 24 h in anaerobic media containing inulin with or without PCB 126. HPLC analysis of supernatants revealed that PCB 126 exposure reduced succinic acid production, but increased propionate production, both of which can influence host glucose and lipid metabolism. Overall, the presented evidence supports the idea that pollutant exposure may contribute to alterations in host metabolism through gut microbiota-dependent mechanisms, specifically through bacterial fermentation processes or membrane disruption. PMID- 30447395 TI - Targeting the R domain of coagulase by active vaccination protects mice against lethal Staphylococcus aureus infection. AB - Coagulase (Coa) secreted by Staphylococcus aureus is associated with the establishment of staphylococcal disease, which activates host prothrombin and generates fibrin shields. The R domain of Coa, consisting of several conserved repeats, is important in immune evasion during S. aureus infection. However, previous research showed that the Coa R domain induced very weak specific antibody responses. In this study, we constructed a new R domain, CoaR6, consisting of 6 repeats that occur most frequently in clinical isolates. By fusing CoaR6 with Hc, the C-terminal fragment of the heavy chain of tetanus neurotoxin, we successfully increased anti-CoaR6 IgG levels in immunized mice which were hardly detected in mice immunized with CoaR6 plus alum. To further improve anti-CoaR6 responses, the combination adjuvants alum plus CpG were formulated with the antigen and exhibited a significantly higher specific antibody response. Moreover, active Th1/Th17 immune responses were observed in Hc CoaR6 immunized group rather than CoaR6. Active immunization of Hc-CoaR6 with alum plus CpG showed protective effects in a peritonitis model induced by two S. aureus strains with different coagulase types. Our results provided strategies to improve the immunogenicity of R domain and supporting evidences for R domain to be an S. aureus vaccine candidate. PMID- 30447396 TI - Recommendations from the American College of Surgeons Committee on Trauma's Firearm Strategy Team (FAST) Workgroup: Chicago Consensus I. PMID- 30447397 TI - Cardiac sarcoidosis classification with deep convolutional neural network-based features using polar maps. AB - AIMS: The aim of this study was to determine whether deep convolutional neural network (DCNN)-based features can represent the difference between cardiac sarcoidosis (CS) and non-CS using polar maps. METHODS: A total of 85 patients (33 CS patients and 52 non-CS patients) were analyzed as our study subjects. One radiologist reviewed PET/CT images and defined the left ventricle region for the construction of polar maps. We extracted high-level features from the polar maps through the Inception-v3 network and evaluated their effectiveness by applying them to a CS classification task. Then we introduced the ReliefF algorithm in our method. The standardized uptake value (SUV)-based classification method and the coefficient of variance (CoV)-based classification method were used as comparative methods. RESULTS: Sensitivity, specificity and the harmonic mean of sensitivity and specificity of our method with the ReliefF algorithm were 0.839, 0.870 and 0.854, respectively. Those of the SUVmax-based classification method were 0.468, 0.710 and 0.564, respectively, and those of the CoV-based classification method were 0.655, 0.750 and 0.699, respectively. CONCLUSION: The DCNN-based high-level features may be more effective than low-level features used in conventional quantitative analysis methods for CS classification. PMID- 30447398 TI - Highly potent monomethyl auristatin E prodrug activated by caspase-3 for the chemoradiotherapy of triple-negative breast cancer. AB - Despite the emergence of advanced therapeutics such as targeted therapy and immunotherapy in the modern oncology, cytotoxic chemotherapy still remains as the first-line treatment option in a wide range of cancers attributing to its potency. Many endeavors have been made to overcome the toxicity issues of cytotoxic chemotherapy by improving the specific delivery to the tumor, with active tumor targeting being one of the most popular approaches. However, such an approach has been challenged by the intratumor heterogeneity and the lack of valid molecular target in many types of cancer. Here, we introduce a novel albumin-binding prodrug MPD02 that could specifically deliver highly potent cytotoxin monomethyl auristatin E (MMAE) to the tumor as an important component of chemoradiotherapy for the treatment of triple-negative breast cancer (TNBC). MPD02 was synthesized by conjugating MMAE to the C-terminus of the KGDEVD peptide via self-eliminating linker and introducing a maleimide group to the Lys side chain of the peptide. MPD02 was able to bind albumin after administration via maleimide group for an extended circulation time and metabolized into MMAE in tumor-specific manner by reacting with the caspase-3 upregulated in tumor by radiotherapy, exerting a highly potent anticancer effect with good safety profile in two different TNBC xenograft models. PMID- 30447399 TI - Dual responsive micelles capable of modulating miRNA-34a to combat taxane resistance in prostate cancer. AB - There is a direct correlation between increase in the number of cancer stem cells CSCs and chemoresistance that impedes successful chemotherapy. Synergistic therapy by targeting both bulk tumor cells and CSCs has shown promise in reversing chemoresistance and treating resistant prostate cancer. Herein, we demonstrated the fabrication of a pH and glutathione (GSH) sensitive nanocarrier for co-delivery of docetaxel (DTX) and rubone (RUB), a miR-34 activator for targeting CSCs, for the treatment of taxane resistant (TXR) prostate cancer. DTX loaded P-RUB (DTX/P-RUB) micelles were prepared by encapsulating DTX into pH responsive diisopropylaminoethanol (DIPAE) and GSH responsive RUB prodrug conjugated polycarbonate based micelles. The self-assembled DTX/P-RUB micelles displayed good stability in vitro and could efficiently target to tumors by enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the micelles underwent expansion and disassembly due to the protonation of DIPAE and GSH induced cleavage of disulfide bond in acidic endocytic vesicles, resulting in fast release of DTX and RUB. The released RUB then upregulated the intracellular miR-34a, which then affected the expression of proteins involved in chemoresistance, thus sensitizing the tumor cells towards DTX and further leading to significant inhibition of TXR tumor progression. Thus, DTX/P-RUB micelles have the potential to treat TXR prostate cancer. By taking advantage of this dual responsive strategy, the successful delivery of many other hydrophobic drugs can be achieved for cancer treatment. PMID- 30447400 TI - Evaluation of the efficacy of a dedicated table to improve CPAP adherence in children: a pilot study. AB - OBJECTIVE: Only a few studies have addressed strategies to improve continuous positive airway pressure (CPAP) adherence in children with obstructive sleep apnea. The aim of our study was to assess the efficacy of a table based on token economy to improve CPAP adherence. METHODS: A table was proposed to children nonadherent to CPAP (<3 h per night of CPAP use), eight days after CPAP initiation (D8). The child has to fill the table on a daily basis with green (I used my CPAP this night) or red (I did not use my CPAP) tokens. Objectives of CPAP use and rewards were decided between the child and their parents. An assessment of CPAP adherence was performed one month after initiation of table filling (M1) and compared to CPAP adherence at D8, and to data of adherent children. RESULTS: Data of six nonadherent and nine adherent children were gathered (age 5 +/- 5 vs. 5 +/- 3 years, p = 0.953; apnea-hypopnea index 20 +/- 15 vs. 25 +/- 16 events/h, p = 0.550, respectively). Mean CPAP adherence at D8 was 4.7 +/- 1.6 nights/wk and 1h00 +/- 0h33 in the nonadherent children, vs. 6.9 +/- 0.4 nights/wk and 7h16 +/- 1h51 in the adherent group (p < 0.01). The mean number of nights per week at M1 was 6.4 +/- 0.6 nights in nonadherent children (p = 0.086), and was equivalent to that in adherent children (6.8 +/- 0.6 nights, p = 0.126). Mean adherence at M1 increased to 4h31 +/- 1h12 in non-adherent children (p < 0.001), but was still lower when compared to that in adherent children (7h27 +/- 2h00, p = 0.007). CONCLUSION: The study findings imply that use of a simple table by a child appears to be effective in improving CPAP adherence at one month. PMID- 30447401 TI - Insufficient sleep and suicidal ideation: a survey of 12,046 female adolescents. AB - OBJECTIVES: Adolescence is a period of adaptation to social, hormonal, and physical changes. Because of these changes, adolescents are at risk for depression and suicidal thoughts. Female adolescents tend to be more sensitive to hormonal and emotional changes. Although the reciprocal relationship among depression, poor sleep quality, and suicide has been studied, whether decreased sleep time leads to depression-mediated suicide or induces suicide itself remains to be determined. Therefore, this study aimed to analyze (using a path analysis) the indirect (i.e., due to depression) and direct effects of sleep on suicidal ideation for female adolescents. METHODS: We use nationally representative data from the Korean juvenile health behavior online survey to analyze the sleep effects on suicidal ideation. A total of 12,046 Korean female adolescents were included in this study. We analyzed data from the juvenile health behavior online survey (2017) conducted by the Korea Centers for Disease Control and Prevention and identified variables that could affect the mental health of female adolescents. A path analysis was performed to determine the direct role of sleep in suicidal ideation. RESULTS: Decreased sleep was one of the several risk factors for suicidal ideation. Unexpectedly, after controlling for other risk factors including depression and socioeconomic factors, insufficient sleep was found to have direct effects on suicidal ideation. The indirect effect of insufficient sleep on suicidal ideation was mediated by depression. CONCLUSION: Sleep is a modifiable factor that could reduce the suicide rate among female adolescents and could be targeted through public health prevention efforts. PMID- 30447402 TI - Cord-blood vitamin D level and night sleep duration in preschoolers in the EDEN mother-child birth cohort. AB - OBJECTIVE: Deficiency in 25-hydroxyvitamin D (25OHD) has been associated with sleep disorders in adults. Only three cross-sectional studies were performed in children; which showed an association between 25OHD deficiency and both obstructive sleep apnea syndrome and primary snoring. No longitudinal study has been performed in children from the general population. We analyzed the association between cord-blood vitamin D levels at birth and night-sleep duration trajectories for children between 2 and 5-6 years old in a non-clinical cohort. METHOD: We included 264 children from the French EDEN mother-child birth-cohort with cord-blood 25OHD level determined by radio-immunoassay at birth, and night sleep trajectories for children between 2 and 5-6 years old obtained by the group based trajectory modeling method. Associations between 25OHD and sleep trajectories were assessed by multinomial logistic regression adjusted for maternal and child characteristics. RESULTS: The trajectories short sleep (<10h30/night), medium-low sleep (10h30-11h00/night), medium-high sleep (~11h30/night), long sleep (>=11h30/night) and changing sleep (decreased from >=11h30 to 10h30-11h00/night) represented 5%, 46%, 37%, 4% and 8% of the children, respectively. The mean 25OHD level was 19 ng/ml (SD = 11, range 3-63). It was 12 (SD = 7), 20 (SD = 11), 19 (SD = 10), 14 (SD = 7) and 16 (SD = 8) ng/ml for children with short, medium-low, medium-high, long and changing sleep trajectories, respectively. On adjusted analysis, for each 1-ng/ml decrease in 25OHD level, the odds of belonging to the short sleep versus medium-high sleep trajectory was increased (odds ratio = 1.12, 95% confidence interval [1.01 1.25]). We found no other significant association between 25OHD level and other trajectories. CONCLUSION: A low 25OHD level at birth may be associated with an increased probability of being a persistent short sleeper in preschool years. These results need confirmation. PMID- 30447403 TI - Association between sleep quality and bone mineral density in Chinese women vary by age and menopausal status. AB - OBJECTIVE: Sleep quality is closely related to bone health. Aging and estrogen deficiency are known determinants of poor sleep quality and osteoporosis. However, the impact of aging and menopause on the associations between sleep quality and bone mineral density (BMD) remains unclear. This study aimed to examine the association between sleep quality and BMD in Chinese women vary by age groups and menopausal status. METHODS: A total of 2067 women aged 18-80 years were included. Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI) and the score >7 was indicative of poor sleep quality. BMD was determined using the dual-energy X-ray absorptiometry. Participants were categorized into three age groups. Multiple linear regression models were conducted to evaluate the associations between sleep quality and BMD. Covariates included in the models were age, menopausal status, weight, height, percent body fat, physical activity, alcohol drinking, calcium supplement use, marital status, education and metabolic diseases. RESULTS: We observed that poor sleep quality was correlated to low total BMD and legs BMD in middle-aged women after adjusting for potential confounders. Furthermore, when we reran the regression models based on menopausal status in middle-aged women, significant associations between BMD and sleep quality were observed in premenopausal and early postmenopausal groups. CONCLUSION: Our findings showed a more robust association between sleep quality and BMD in premenopausal and early menopausal groups. Further studies should be conducted to explore whether sleep quality intervention would improve bone health of women in these periods and prevent osteoporosis in their late life. PMID- 30447404 TI - Improving Quality of Radiotherapy Care across Ontario Using a Community of Practice Approach. AB - INTRODUCTION: In 2003/2004 XXX (XXX) divested its assets and staff to regional hospitals, leading to decreased contact between radiotherapy departments across Ontario's Regional Cancer Centres (RCC). The XX (XX) at XXX developed a communities of practice (CoPs) program to re-build the provincial radiotherapy community to facilitate collaboration amongst centres with goals of decreasing variation in practice and improving the quality of patient care. XX's CoPs are led and driven by volunteer front-line healthcare practitioners, who identify and prioritize key quality issues and select corresponding projects to pursue. METHODS AND MATERIALS: An evaluation of XX's CoPs was conducted to assess whether they were successful in knowledge creation, knowledge transfer and exchange (KTE) and community building. The framework was developed based on the Centre for Disease Control and Prevention CoP evaluation framework and tools. Data was collected using prospectively administered member surveys (257 surveys), publications, and semi-structured interviews (18 participants). RESULTS: 95% of participants reported that CoP projects were very relevant to their practice and 50% reported changes in their practice stemming from CoP involvement. 90% of participants reported growth of their professional network as a result of CoPs. Overall 93% of participants and 100% of interviewees reported CoPs are a worthwhile initiative. The largest challenge of CoPs was the time commitment required to participate. CONCLUSIONS: This approach of member-driven CoPs should be explored and modeled in other healthcare settings as a means to develop and share knowledge to reduce variation in care, and improve the quality of radiotherapy care. PMID- 30447405 TI - Substantial volume changes and plan adaptations during preoperative radiotherapy in extremity soft tissue sarcoma patients. AB - INTRODUCTION: Many authors suggest that extremity soft tissue sarcomas (ESTS) do not change significantly in size during preoperative radiotherapy (RT). This conebeam CT study investigates the justification to deliver the entire course with one initial RT plan by observing anatomical changes during RT. METHODS: In 2015-2017, 99 ESTS patients were treated with either curative (n=80) or palliative intent (n=19) with a regimen of at least 6 fractions. CTV-to-PTV margin was 1cm. Action levels were assigned by radiation technicians. An extremity contour change >1cm and/or tumor size change >0.5cm required a physician's action prior to the next fraction. RESULTS: 982 CBCT logfiles were studied. In 41 of 99 patients the dose coverage of the initial treatment plan was fully satisfactory throughout the RT course. However, in 58 patients (59%) action levels were observed. In 41 of these 58 patients, a contour increase of 5-23mm was noted (29x a tumor size increase only, 3x an extremity contour increase and 9x both). In 21 of 58 patients, a decrease of 5-33mm was observed (20x a tumor size decrease only, 1x both a tumor size decrease and an extremity contour decrease). In 4 cases, contours initially increased and subsequently decreased. In 33 of the 41 patients with increasing contours, the dose distribution adequately covered GTV because of the 1cm PTV-margin applied. For the remaining 8 (8%), the plan needed to be adapted. CONCLUSION: ESTS volumes may change substantially during RT in 59% of all patients, leading to plan adaptations due to increased volumes in 8%. Daily critical observation of these patients is mandatory to avoid geographical misses (due to increase in size) as well as overdosing of normal tissues (when masses shrink). PMID- 30447406 TI - A 6-year longitudinal study: Are maternal depressive symptoms and Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant treatment during pregnancy associated with everyday measures of executive function in young children? AB - BACKGROUND: Building on research reports that early and chronic exposure to maternal depressive symptoms (MDS) adversely affects children's developing executive function (EF), this longitudinal study examined whether exposure to MDS and Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant treatment during pregnancy predicted individual differences in EF at school age. METHODS: In a longitudinal prospective cohort, maternal report of EF using the Behavior Rating Inventory of EF (BRIEF) was obtained from 139 children (77 females; non-exposed n = 88, SSRI exposed n = 51) at age 6 years. Clinician rated and self reports of MDS were also obtained spanning from the 2nd trimester to 6 years postpartum. RESULTS: Higher levels of MDS, especially at 3 years, were associated with poorer maternal reports of EF skills at 6 years. Associations between prenatal SSRI exposure and EF outcomes were not significant, even when controlling for maternal education and MDS at 3 years. CONCLUSIONS: Postnatal exposure to MDS adversely effects developing child EF, even when maternal symptoms were treated with an SSRI antidepressant. PMID- 30447407 TI - Bridging the gap between vaccination with Bacille Calmette-Guerin (BCG) and immunological tolerance: the cases of type 1 diabetes and multiple sclerosis. AB - At the end of past century, when the prevailing view was that treatment of autoimmunity required immune suppression, experimental evidence suggested an approach of immune-stimulation such as with the BCG vaccine in type 1 diabetes (T1D) and multiple sclerosis (MS). Translating these basic studies into clinical trials, we showed the following: BCG harnessed the immune system to 'permanently' lower blood sugar, even in advanced T1D; BCG appeared to delay the disease progression in early MS; the effects were long-lasting (years after vaccination) in both diseases. The recently demonstrated capacity of BCG to boost glycolysis may explain both the improvement of metabolic indexes in T1D, and the more efficient generation of inducible regulatory T cells, which counteract the autoimmune attack and foster repair mechanisms. PMID- 30447408 TI - Health and economic development since 1900. AB - The 20th century has brought unprecedented gains in health. While these have improved citizens' lives worldwide, progress has been uneven and have in turn led to substantial cross-country health inequalities. This article looks at the effects of these inequalities on between-country economic inequality since 1900 using a level accounting framework that includes life expectancy as an important part of human capital besides education. The main results show that health has been a historically important source of cross-country income variation. In 1900 and 1955, differences in life expectancy accounted for almost 20 percent and a quarter of between-country income inequality. In addition, I find that the reduction of cross-country health differentials between mid-20th century and 1990 was an important source of income convergence. In a counterfactual exercise, I show that between-country income inequality would have been almost 20 percent higher nowadays, had the process of health convergence after 1955 not taken place. Finally, I find that the relative importance of health for income levels has stayed constant in the last three decades due to a deceleration in the rate of health convergence. PMID- 30447409 TI - The effects of competition outcomes on health: Evidence from the lifespans of U.S. Olympic medalists. AB - This paper investigates the effects of competition outcomes on health by using U.S. Olympic medalists' lifespans and medal colors as a natural experiment. Whereas the life expectancies of gold and bronze medalists do not differ significantly, life expectancy of silver medalists is about 2.4 and 3.9 years less than these former, respectively. These findings are readily explainable by insights from behavioral economics, psychology, and human biology, which suggest that (perceived) dissatisfactory competition outcomes may adversely affect health. Competition outcomes that affect socioeconomic status (SES) could, therefore, play an important causal role in the positive SES-health gradient among the general population. PMID- 30447410 TI - Bombyx mori nucleopolyhedrovirus protein Bm11 is involved in occlusion body production and occlusion-derived virus embedding. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) orf11 (bm11) is a highly conserved gene with unknown function. It is homologous to AcMNPV orf19. In this study, a bm11 knockout virus was constructed and its role was investigated. Expression analysis indicated that bm11 is a late gene and confocal microscopy analysis demonstrated that Bm11 localizes predominantly in the nuclear ring zone at the late phase of infection. The bm11 deletion did not affect budded virus (BV) production or viral genome replication, but markedly reduced the production of occlusion bodies (OBs) and the embedding of occlusion-derived viruses (ODVs). Bio-assays showed that Bm11 was involved in BmNPV infectivity in vivo by direct injection. In conclusion, our results demonstrated that although Bm11 is not essential for BV production or mature ODV formation, it affects OB production and ODV occlusion. PMID- 30447411 TI - Update on prevalence and mechanisms of resistance to linezolid, tigecycline and daptomycin in enterococci in Europe: Towards a common nomenclature. AB - Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens. Invasive VRE infections are difficult to treat since common therapeutic options including ampicillin and glycopeptides often fail. In vitro, most VRE remain susceptible to last-resort antibiotics such as linezolid, tigecycline and daptomycin. However, neither tigecycline nor linezolid act in a bactericidal manner, and daptomycin has proven activity only at high dosages licensed for treating enterococcal endocarditis. Despite these pharmacological and therapeutic limitations, reports on resistance to these last-resort drugs in VRE, and enterococci in general, have increased in recent years. In this review, we briefly recapitulate the current knowledge on the mode of action as well as the known and novel mechanisms of resistance and describe surveillance data on resistance to linezolid, tigecycline and daptomycin in enterococci. In addition, we also suggest a common nomenclature for designating enterococci and VRE with resistances to these important last-resort antibiotics. PMID- 30447412 TI - Effect of photodynamic therapy by 810 and 940 nm diode laser on Herpes Simplex Virus 1: An in vitro study. AB - INTRODUCTION: Herpes simplex virus (HSV) is among the most common viruses in humans. HSV1 is often responsible for oral and perioral herpetic lesions. Photodynamic therapy (PDT) is a novel antimicrobial modality that involves the use of laser and a photosensitizer with a specific wavelength. This study aimed to assess and compare the effect of PDT with 810 and 940 nm diode laser and indocyanine green (ICG) photosensitizer on HSV1. METHODS: In this in vitro study, HSV1 isolated from herpes labialis and there were 6 experimental groups.The irradiation parameters were the same for all groups. Number of remaining viruses per milliliter in each group was determined using real-time polymerase chain reaction (PCR) and statistically analyzed by ANOVA. RESULTS: The virus count in all groups significantly decreased compared to the control group (P < 0.05) except in group ICG- without irradiation (P > 0.05). Comparison of groups 810- and 940- (use of each laser alone) with groups 810+ and 940+ (use of each laser plus ICG) revealed that reduction in virus count in groups 810+ and 940+ was significantly greater than that in groups 810- and 940-. CONCLUSION: 810 nm diode laser irradiation and ICG causes the greatest reduction in number of HSV1 compared to all the other groups. ICG without laser irradiation has not significant efficacy on reduction of virus count. PMID- 30447413 TI - Real-Time Mapping of Heat Generation and Distribution in a Laser Irradiated Agar Phantom Loaded with Gold Nanoparticles Using MR Temperature Imaging. AB - Gold nanoparticles (AuNPs) have shown potential strength in photothermal therapy of cancer. Several techniques have been developed to investigate local heat generation by AuNPs. However, a sensitive thermal imaging technology with high temporal resolution, minimum invasiveness and high spatial resolution is still lacking. In this research study, by using magnetic resonance thermal imaging (MRTI), we reported a technique for monitoring of heat generation and distribution in an AuNPs loaded agar phantom irradiated by laser. Three different agar phantoms with various AuNPs concentrations (0, 8 and 16 ug/ml) were produced and studied. The phantoms were exposed to an external laser [532 nm; 4 min] under MRTI. For real-time temperature monitoring, we employed the theory of proton resonance frequency (PRF) shift. Infrared (IR) camera was employed to measure the actual temperature of each point on the surface of irradiated agar gel. Finally, the correlation between the temperatures obtained by IR camera and MRTI was evaluated. We observed that temperature of the gels loaded by AuNPs at concentration of 0, 8 and 16 ug/ml reached 27.2, 37.8, 45 degrees C with a total area of heat distribution of 94.98, 452.16, and 907.34 mm2 (from the point of irradiation). During the process of laser irradiation, we observed: (i) a significant rise in temperature, (ii) a dependency between the rate of temperature rise and concentration of AuNPs, and (iii) a direct correlation between temperature change and MR image phase. In addition, statistical analysis showed that the variation of temperatures measured by IR camera and temperatures computed by MRTI had acceptable correlation (R > 0.9). In conclusion, MRTI has a good sensitivity and precision that can be employed for nano-photothermal therapy planning and may be considered for real-time mapping of heat generation and distribution in a laser irradiated tissue loaded by AuNPs. PMID- 30447414 TI - Perspective Clinical Study on Effect of 5-Aminolevulinic Acid Photodynamic Therapy (ALA-PDT) in Treating Condylomata Acuminata in Pregnancy. AB - OBJECTIVE: To observe the clinical efficacy of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) in treating vulval condylomata acuminata (CA) in pregnancy. METHODS: The clinical efficacies of ALA-PDT on 16 cases of CA in pregnancy as well as cryotherapy on 22 cases of CA in pregnancy were analyzed in this prospective study. RESULTS: The treatment group showed a wart clearance rate of 93.8% after 3 PDT treatments, while the control group showed a wart clearance rate of 72.7% after 3 cryotherapy treatments. After the 3-month follow-up period, the treatment group registered a recurrence rate of 6.3%, whereas the control group recorded a recurrence rate of 36.4%, indicating a statistically significant difference (chi2 = 4.674, p = 0.031<0.05). After the 1-month postpartum follow-up period, the newborns grew and developed well, without any abnormality in physical examinations. CONCLUSION: ALA-PDT is safe and effective in treating CA in pregnancy. PMID- 30447415 TI - A clinical evaluation of efficacy of photodynamic therapy in treatment of reticular oral lichen planus: A case series. AB - BACKGROUND: The aim of the study was to clinically evaluate the efficacy of photodynamic therapy in treatment of reticular oral lichen planus (OLP). METHODS: Fifty patients aged 26-84, with 124 OLP lesions in total, underwent photodynamic therapy (PDT) mediated with topically applied 5% 5-aminolevulinic acid. ALA was activated by a custom-made diode lamp with a high-power LED emitting light at 630 nm and 300 mW delivered through an optical fiber probe. A light exposure dose was 150 J/cm2. The therapy comprised of 10 weekly illumination sessions. The lesions' response was macroscopically measured in millimeters with a periodontal probe and clinically evaluated at each session, then on completion of the series and throughout the 12-month follow-up. RESULTS: The baseline mean size of lesions was 3.99 cm2+/-3.73. The lesions on the buccal mucosa and lips (lining mucosa) were larger than those on the gingiva and tongue (masticatory mucosa) - 4.58 cm2+/ 4.01 and 2.93 cm2+/-2.91 respectively. On completion of the therapy 109 sites improved, including 46 in complete remission. The mean reduction in size was 62.91% (p = 0.000000). 12-month after therapy mean reduction of the lesions was 78.7% (p = 0.000000), specifically 79.48% (p = 0.000000) within the lining mucosa and 76.11% on the masticatory mucosa. CONCLUSIONS: The results proved that ALA mediated photodynamic therapy with a 630 nm light was effective and as such it can be used as an optional treatment for symptomatic OLP. PMID- 30447416 TI - Adolescent psychosis risk symptoms predicting persistent psychiatric service use: A 7-year follow-up study. AB - BACKGROUND: We investigated whether psychosis risk symptoms predicted psychiatric service use using seven-year register follow-up data. METHODS: Our sample included 715 adolescents aged 15-18, referred to psychiatric care for the first time. Psychosis risk symptoms were assessed with the Prodromal Questionnaire (PQ) at the beginning of the treatment. We assessed the power of the overall PQ as well as its positive, negative, general, and disorganized psychosis risk symptom factors in predicting prolonged service use. Baseline psychiatric diagnoses (grouped into 7 categories) were controlled for. Based on both inpatient and outpatient psychiatric treatment after baseline, adolescents were divided into three groups of brief, intermittent, and persistent service use. RESULTS: Stronger symptoms on any PQ factor as well as the presence of a mood disorder predicted prolonged service use. All of the PQ factors remained significant predictors when adjusted for baseline mood disorder and multimorbidity. CONCLUSIONS: In a prospective follow-up of a large sample using comprehensive mental health records, our findings indicate that assessing psychosis risk symptoms in clinical adolescent settings at the beginning of treatment could predict long-term need for care beyond diagnostic information. Our findings replicate the previous findings that positive psychosis risk symptoms are unspecific markers of severity of psychopathology. Also psychosis risk symptoms of the negative, disorganization, and general clusters are approximately as strongly associated with prolonged psychiatric service use in the upcoming years. PMID- 30447417 TI - Understanding cosmetic surgery consideration in Chinese adolescent girls: Contributions of materialism and sexual objectification. AB - Based on objectification theory and the consumer culture impact model, this study examined psychological predictors of cosmetic surgery consideration in 314 Chinese adolescent girls. Path analyses revealed several findings. First, both interpersonal sexual objectification and materialism contributed to internalized appearance ideals, which in turn related to body surveillance, body shame, and facial appearance concerns. Second, the association between materialism and internalized appearance ideals was independent of the association between materialism and interpersonal sexual objectification. Third, internalized appearance ideals were linked to cosmetic surgery consideration via body surveillance and facial appearance concerns. Fourth, while internalized appearance ideals were associated with body shame, body shame did not mediate its association with cosmetic surgery consideration. Fifth, instead of body shame, facial appearance concerns mediated that link between body surveillance and cosmetic surgery consideration as well as the link between internalized appearance ideals and cosmetic surgery consideration. This study provides support to the basic tenets of objectification theory and the consumer culture impact model as applied to Chinese adolescent girls' willingness to consider cosmetic surgery. It suggests that using a measure that is more sensitive to salient cultural concerns is important when attempting to understand body image issues in different cultural contexts. PMID- 30447418 TI - In vivo visualization of age-related differences in the locus coeruleus. AB - The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinson's disease and Alzheimer's disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer-weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18-88 years). Study participants were part of the Cambridge Centre for Ageing and Neuroscience-an open-access, population-based data set. We found a quadratic relationship between LC CR and age, the peak occurring around 60 years, with no differences between males and females. Subregional analyses revealed that age-related decline in LC CR was confined to the rostral portion of the LC. Older adults showed greater variance in overall LC CR than younger adults, and the functional and clinical implications of these observed age-related differences require further investigation. Visualization of the LC in this study may inform how future scanning parameters can be optimized, and provides insight into how LC integrity changes across the life span. PMID- 30447420 TI - Determination of immunodominant scaffolds of Com1 and OmpH antigens of Coxiella burnetii. AB - Today, there is an increasing emphasis on recombinant vaccines to eliminate the side effects of conventional vaccines such as whole-cell bacteria. Query fever is an emerging disease that causes irreparable complications for both humans and domestic animals. The cause of this disease is Coxiella burnetii, a gram-negative intracellular bacteria. In order to determine the most immunodominant epitopes of Com1 and OmpH antigens of C. burnetii, the most reliable bioinformatics tools with high rates of citation in predicting B cell and T cell epitopes were used. Finally, by comparing the results of all servers, the best overlapped epitopes with the highest antigenicity among different servers were selected. In this regard, epitopes in 18-27and 67-82 amino acids residues were introduced for MHCI and MHCII of T cell, respectively, whereas epitope in 16-25 amino acids residues was introduced for B cell of OmpH antigen. The epitopes in the range of 193-202, 100-108 and 215-223 amino acid residues were preferred for MHCI class of T cell, MHCII class of T cell and B cell of Com1 antigen, respectively. For each antigen, some empirical common epitopic regions were introduced, which included both T and B cells epitopes, 53-65 and 102-111 amino acid residues of OmpH antigen as well as 38-54 range of the amino acid of Com1 antigen. All the predicted epitopes were selected based on their high antigenicity scores and number of non-digestive enzymes. To optimize the application of reported epitopes, various orders of epitopes were arranged in three categories of B cell, T cell and common T and B cells epitopes for each antigen. Then, the best immunodominant scaffolds for each antigen were proposed in these categories. The results demonstrated that the scaffold arranged based on B cell epitopes had the highest antigenicity in both antigens. PMID- 30447419 TI - Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study. AB - Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN beta) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-beta-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-beta ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA. PMID- 30447421 TI - Behavioral evaluation of BALB/c (Mus musculus) mice infected with genetically distinct strains of Toxoplasma gondii. AB - In relation to behavioral changes in rodents infected with Toxoplasma gondii (T. gondii), it is believed that the genotype of the infecting strain can have some influence. In this sense, the present work has sought to evaluate the effect of chronic infection by genetically distinct cystogenic strains of T. gondii on the behavior of mice. For this, experimental models of infection with ME-49 (type II) and VEG (type III) strains were developed in isogenic BALB/c mice. ELISA test was performed to evaluate the humoral immune response and real-time PCR test to quantify parasites in the CNS. Behavioral tests such as passive avoidance, open field and Y-maze tests were also used for, respectively, evaluation of learning and memory, locomotor activity and aversion to feline odor. The results showed that mice infected with VEG strain had higher total IgG level of anti-toxoplasma, higher tissue burden of T. gondii in the CNS, reduction in the long-term memory, lower activity (mobility) and lower aversion to cat urine and l-felinine than mice infected with ME-49 strain. The results suggest that different T. gondii genotypes have a differential impact on behavioral changes in infected mice. PMID- 30447422 TI - Hydrogen peroxide stimulates uropathogenic Escherichia coli strains to cellulose production. AB - Reactive oxygen intermediates, such as hydrogen peroxide, are toxic molecules produced by immune cells in response to bacterial invasion into the host. Bacteria try to protect themselves against the immune system through specific properties such as biofilm formation. This phenomenon occurs also during urinary tract infections. Cellulose is an important factor of Escherichia coli biofilm and contributes to building a protective shield around bacterial cells upon the host immune response. In this study, we aimed to analyze the effect of hydrogen peroxide on the production of this biofilm component. To achieve this goal, 25 clinical E. coli strains isolated from patients with urinary tract infections were used. These bacterial strains were characterized based on their growth characteristics, their ability to form biofilm and their capacity to produce cellulose upon exposure to sub-lethal concentrations of hydrogen peroxide growth, and the biofilm formation of these strains was analyzed. Our results revealed that the analyzed uropathogenic E. coli strains slightly, but significantly, reduced growth and biofilm production upon hydrogen peroxide treatment. However, when separating these strains regarding their ability to produce cellulose, we found that general biofilm production was reduced but cellulose expression was induced upon peroxide treatment. This finding contributes to a better understanding of how bacterial biofilm formation is triggered and provides interesting insights into how uropathogenic E. coli protect themselves in an inhospitable environment. PMID- 30447423 TI - Securing extraocular muscles in strabismus surgery: biomechanical analysis of muscle imbrication and knot tying technique. PMID- 30447424 TI - Unilateral cone-rod dysfunction and retinal thinning in a child carrying the 14484 mutation of Leber hereditary optic neuropathy. PMID- 30447425 TI - Microcornea and bilateral ectopia lentis in an infant: unusual severe ocular presentation of neonatal Marfan syndrome. PMID- 30447426 TI - Retinal astrocytoma in a young male with PTEN hamartoma tumor syndrome. AB - We present the novel finding of retinal astrocytoma in a 15-year-old boy with phosphatase and tensin homologue hamartoma tumor syndrome, confirmed by genetic testing. PMID- 30447427 TI - Impact of p38gamma Mitogen-Activated Protein Kinase (MAPK) on MDA-MB-231 Breast Cancer Cells Using Metabolomic Approach. AB - BACKGROUND: The expression of p38 MAPK is high in breast cancer while its subunit p38gamma had been rarely reported. We aimed to explain the effect of p38gamma in breast cancer from the perspective of metabolomics. METHODS: In this study, we detected the expression of p38gamma in 28 breast carcinoma and para-tumor samples. Following MDA-MB-231 cell transfection with p38gamma siRNAs and pc-DNA 3.1, cell viability, apoptosis, metastasis were determined through CCK-8, the cytometry analysis, transwell assay and wound healing assay. Finally, gas chromatograph-mass spectrometer (GC-MS) was used for analysis the differential metabolites. RESULTS: The expression of p38gamma was significantly up-regulated in breast cancer tissues. The transfection of si-p38gammas could inhibit MDA-MB 231 cell propagation, metastasis, and induced cell apoptosis while overexpressed p38gamma could promote the cell propagation, metastasis, and inhibit cell apoptosis. A total of 238 metabolites were identified and 72 of them differentially expressed in three groups (all P < 0.05, FDR<0.05). Then the metabolites were enriched in the metabolism pathway, 85 pathways were included and 27 were significant (all P < 0.05, FDR<0.05). CONCLUSIONS: p38gamma was up regulated in breast cancer, which exerts a great influence on the cell growth, cell mobility, invasiveness, and apoptosis of MDA-MB-231 cells and also affected the metabolism. PMID- 30447428 TI - The regulatory role of semaphorin 3E in allergic asthma. AB - Semaphorins were originally discovered as essential mediators involved in regulation of axonal growth during development of the nervous system. Ubiquitously expressed on various organs, they control several cellular functions by regulating essential signaling pathways. Among them, semaphorin3E binds plexinD1 as the primary receptor and mediates regulatory effects on cell migration, proliferation, and angiogenesis considered major physiological and pathological features in health and disease. Recent in vitro and in vivo experimental evidence demonstrate a key regulator role of semaphorin3E on airway inflammation, hyperresponsivenss and remodeling in allergic asthma. Herein, we aim to provide a broad overview of the biology of semaphorin family and review the recently discovered regulatory role of semaphorin3E in modulating immune cells and structural cells function in the airways. These findings support the concept of semaphorin3E/plexinD1 axis as a therapeutic target in allergic asthma. PMID- 30447429 TI - Transcriptomic profiles of striped snakehead cells (SSN-1) infected with snakehead vesiculovirus (SHVV) identifying IFI35 as a positive factor for SHVV replication. AB - Snakehead vesiculovirus (SHVV) has caused great economic loss in snakehead fish culture in China. However, there is no effective strategy to prevent the epidemic of the virus. Understanding the host factors in response to virus infection is the basis for the prevention of viral disease. In this study, the transcriptomic profiles of SHVV-infected and mock-infected SSN-1 cells (derived from striped snakehead, Channa striatus) at 3 and 24 h (h) post of infection (poi) were obtained using high-throughput sequencing technique. A total of 93,372 unigenes were obtained. The differently expressed genes (DEGs) of SSN-1 cells upon SHVV infection were thereby identified, including 3668 and 3536 DEGs at 3 and 24 h poi, respectively. These DEGs were involved in many pathways of viral pathogenesis, including retinoic acid-inducible gene I (RIG-I) like receptors pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway, PI3K Akt signaling pathway and MAPK signaling pathway. Therefore, several immune related DEGs were randomly selected and confirmed by quantitative real-time PCR (qRT-PCR). In addition, the effects of the interferon inducible protein 35 (IFI35) on SHVV replication were further investigated. Over-expression or inhibition of IFI35 significantly promoted or reduced SHVV replication at the level of viral gene expression, which indicated that IFI35 might be a positive factor for SHVV replication in SSN-1 cells. Our findings presented some valuable information, which will benefit for future study on SHVV-host interactions. PMID- 30447430 TI - The systematic identification and mRNA expression profiles post viral or bacterial challenge of complement system in grass carp Ctenopharyngodon idella. AB - Complement system is an immemorial and pivotal element in innate immunity, protecting individuals from invading pathogens. Due to the emergence of whole genomes and functional researches, systematic identifications of complement system are feasible in many non-model species. In the present study, BLAST analysis was employed to systematically identify and characterize complement system in grass carp (Ctenopharyngodon idella). The results showed that C. idella complement system consists of 64 members, including the complement system pattern recognition, proteases, complement components, receptors and regulators. In which, most genes were well conserved with those in higher vertebrates over the course of evolution. Phylogenetic and syntenic analyses revealed their homologous relationships with other species. mRNA expression analyses of complement system related genes indicated that many members are sustainably expressed in multiple tissues before and after grass carp reovirus (GCRV) or Aeromonas hydrophila infection, which provide in vivo evidence for the response patterns of complement system after viral or bacterial infection. Meanwhile, this study also explored the evolution of complement system from ancestral protists to mammals and then investigated the changes in gene diversification during the evolution. These results will serve the comparative studies on the complement system in evolution and further functional investigations in C. idella. PMID- 30447431 TI - The Penaeus stylirostris densovirus capsid interacts with Litopenaeus vannamei troponin I. AB - The Penaeus stylirostris densovirus (PstDNV) (also known as infectious hypodermal and hematopoietic necrosis virus, IHHNV), a very small DNA virus, is a major shrimp pathogen. The PstDNV genome encodes only two nonstructural proteins and one capsid protein. This virus is thus an ideal, simple model for the investigation of virus-host interactions. To explore the role of the PstDNV capsid in viral infections, a yeast two-hybrid (Y2H) cDNA library was constructed based on Pacific white shrimp, Litopenaeus vannamei mRNA. The Y2H library was then screened, using the PstDNV capsid protein as bait. We identified a host protein that interacted strongly with the PstDNV capsid as L. vannamei troponin I (LvTnI). An in vitro co-immunoprecipitation experiment further supported this interaction. In addition, an in vivo neutralization experiment showed that the vaccination with anti-LvTnI significantly reduced PstDNV copies in PstDNV challenged shrimp, indicating that the interaction between the PstDNV capsid and cellular LvTnI is essential for PstDNV infection. This result has important implications for our understanding of the mechanisms by which PstDNV infects shrimp. PMID- 30447432 TI - MicroRNA-155 promotes pro-inflammatory functions and augments apoptosis of monocytes/macrophages during Vibrio anguillarum infection in ayu, Plecoglossus altivelis. AB - Upon recognition of pathogen-associated molecular patterns by pattern-recognition receptors, immune cells are recruited, and multiple antibacterial/viral signaling pathways are activated, leading to the production of immune-related cytokines, chemokines, and interferons along with further activation of the adaptive immune response. MicroRNAs (miRs) play essential roles in regulating such immune signaling pathways, as well as the biological activities of immune cells; however, knowledge regarding the roles of miRs in the immune-related function of monocytes/macrophages (MO/MPhi) remains limited in teleosts. In the present study, we addressed the effects of miR-155 on Vibrio anguillarum-infected MO/MPhi. Our results showed that miR-155 augmented MO/MPhi expression of proinflammatory cytokines and attenuated the expression of anti-inflammatory cytokines. Additionally, the phagocytosis and bacteria-killing abilities of these cells were boosted by miR-155 administration, which also promoted M1-type polarization but inhibited M2-type polarization. Furthermore, the V. anguillarum infection-induced apoptosis was also enhanced by miR-155 mimic transfection, which might have been due to excessive inflammation or the accumulation of reactive oxygen species. These results represent the first report providing a detailed account of the regulatory roles of miR-155 on MO/MPhi functions in teleosts and offer insight into the evolutionary history of miR-155-mediated regulation of host immune responses. PMID- 30447433 TI - Design, synthesis and evaluation of hybrid of tetrahydrocarbazole with 2,4 diaminopyrimidine scaffold as antibacterial agents. AB - Several 6-substituted tetrahydrocarbazole derivatives were designed, synthesized and evaluated for the antibacterial activities against Staphylococcus aureus Newman strain. Subsequently, 2,4-diaminopyrimidine scaffold was merged with the tetrahydrocarbazole unit to generate a series of novel hybrid derivatives and the antibacterial activities were also investigated. Among these novel hybrids, compound 12c showed the most potent activity with a MIC of 0.39-0.78 MUg/mL against S. aureus Newman and Escherichia coli AB1157 strain. In addition, compound 12c exhibited low MIC values against a panel of multidrug-resistant strains of S. aureus. PMID- 30447434 TI - Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1 receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase. AB - Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the sigma1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition. PMID- 30447435 TI - A methodological dilemma for investigating consciousness empirically. AB - This paper exposes a methodological dilemma arising for the research program of finding the neural correlate of consciousness (NCC), the minimal set of brain processes sufficient for a particular percept. The main claim is that it is doubtful that the right kind of correlations will ever be obtained because the foregoing conceptual decisions regarding the relations between consciousness, attention, cognitive access, report, and other cognitive functions determine the interpretation of the correlation data that can be obtained. Relying on subjective reports likely leads to confounding the NCC with neural mechanisms for cognitive functions because reports presuppose cognitive access. No-report paradigms are in danger of confounding the NCC with neural mechanisms underlying unconscious processes. So there does not seem to be a way of making sure to have isolated the neural correlate of conscious experience. PMID- 30447436 TI - Cannabis use and suicide attempts among 86,254 adolescents aged 12-15 years from 21 low- and middle-income countries. AB - BACKGROUND: Evidence suggests that cannabis use may be associated with suicidality in adolescence. Nevertheless, very few studies have assessed this association in low- and middle-income countries (LMICs). In this cross-sectional survey, we investigated the association of cannabis use and suicidal attempts in adolescents from 21 LMICs, adjusting for potential confounders. METHOD: Data from the Global school-based Student Health Survey was analyzed in 86,254 adolescents from 21 countries [mean (SD) age = 13.7 (0.9) years; 49.0% girls]. Suicide attempts during past year and cannabis during past month and lifetime were assessed. Multivariable logistic regression analyses were conducted. RESULTS: The overall prevalence of past 30-day cannabis use was 2.8% and the age-sex adjusted prevalence varied from 0.5% (Laos) to 37.6% (Samoa), while the overall prevalence of lifetime cannabis use was 3.9% (range 0.5%-44.9%). The overall prevalence of suicide attempts during the past year was 10.5%. Following multivariable adjustment to potential confounding variables, past 30-day cannabis use was significantly associated with suicide attempts (OR = 2.03; 95% CI: 1.42-2.91). Lifetime cannabis use was also independently associated with suicide attempts (OR = 2.30; 95% CI: 1.74-3.04). CONCLUSION: Our data indicate that cannabis use is associated with a greater likelihood for suicide attempts in adolescents living in LMICs. The causality of this association should be confirmed/refuted in prospective studies to further inform public health policies for suicide prevention in LMICs. PMID- 30447437 TI - Predictive Factors of Spine Surgery Complications at a Major Government Hospital in Cambodia. AB - BACKGROUND: Spine pathology is a common reason for admission to neurosurgical units in low- and middle- income countries (LMICs) and can have high morbidity rates from lack of specialized institutes. However, good surgical outcomes and quality of life scores have been reported in LMICs. OBJECTIVES: This study details the complication rates and predictive factors from spine surgery at a large hospital in Cambodia, aiming to identify high-risk patients to improve surgeon understanding of these complications for improved pre-operative planning and patient counseling. METHODS: This is a retrospective review of patients admitted for spine conditions to Preah Kossamak Hospital, in Phnom Penh (2013 2017). Univariate analysis was conducted on potential predictive factors; variables with p<0.1 were entered into multivariate logistic regression models. RESULTS: 773 patients were included. 46 patients had complications including wrong level surgery, hardware failure, and infection. On multivariate analysis, patients from the provinces of Kratie (p=0.009) or Sihanoukville (p=0.036), and delay to evaluation of over one year (p=0.027) were significant predictive factors of postoperative complications and ASIA A injury (p=0.020) was a predictive factor of poor outcome. CONCLUSION: Many factors play a role in spine surgery complications in LMICs, including limited access to intra-operative technology, low follow-up rates, and minimal physiotherapy and rehabilitation capabilities. Patients with long delays in presentation, ASIA A injuries, and lumbar-level surgery may be especially susceptible to complications and post operative morbidity. Despite this, institutions have reported encouraging spine trauma outcomes, and spine surgeries are becoming more accepted and safe operations in many LMICs. PMID- 30447438 TI - Natural Cerebral Aneurysm and Spontaneous Subarachnoid Hemorrhage in Mammals Other Than Man: Is there a Scope for Comparative Medicine? AB - BACKGROUND: Concepts which showed substantial efficacy in animal models of subarachnoid hemorrhage (SAH), often failed improve outcome in humans with aneurysmal SAH. The concept of "comparative medicine", an open-minded comparison across species, might offer an alternative to the "constructed" animal models' approach. Naturally occurring diseases in animals might bear more similarity to human diseases than models. In this context, the question arises whether spontaneous intracranial aneurysms exist in animals or not, and whether they cause SAH or not. METHODS: A systematic literature search was performed. Only articles dealing with natural aneurysms and/or SAH of mammals other than man were included. All articles dealing with induced aneurysms and/or SAH were removed. RESULTS: Out of 2,812 screened articles, 9 articles describing natural intracranial aneurysms and/or SAH were found. In total 1,979 individual animals of 29 species were examined. Natural intracranial aneurysms were described in 7 individual animals of 6 species. Spontaneous SAH was described in 3 species. In one chimpanzee, a ruptured intracranial aneurysm caused a SAH. Histological descriptions of the aneurysms were strikingly similar to those of humans. CONCLUSION: Although interesting and innovative, the concept of "comparative medicine" seems to be impracticable due to the seemingly ultra-low incidence of natural aneurysmal SAH in mammals other than man. The answer to the question, why intracranial aneurysms are less common in animals despite the strong histological similarity of cerebral arteries, might be a key issue. Last but not least, primates likely matter in SAH-related research, as aneurysmal SAH occurs in primates.; Abbreviations: SAH: subarachnoid hemorrhage, CVS: cerebral vasospasm, AcomA: anterior communicating artery, CT: computed tomography, MCA: middle cerebral artery. PMID- 30447439 TI - Treatment protocol, long-term follow-up, and predictors of mortality in 302 cases of atypical meningioma. AB - OBJECTIVE: Despite the paucity of relevant data, treatment and outcomes in intracranial atypical meningioma (AM) remain unclear. The aim of this study was to find useful factors predicting survival and to evaluate the role of postoperative radiation (PRT ) following surgery. METHODS: Data were obtained from 302 patients with AM who received surgery between January 2008 and December 2015. RESULTS: A series of 302 patients, including 166 females and 136 males,underwent surgery at our institution. Gross total resection (GTR) was achieved in 201 (66.6%) patients. Seventy-five patients (24.8%) underwent PRT after surgery. For the entire cohort, there were 131 (43.4%) recurrences, 1 (0.33%) metastasis, and 56 (18.5%) mortalities during a median follow-up duration of 41.6months. The median recurrence-free survival (RFS) was 55.2 months after the date of the first AM surgery, with 1-year, 3-year, and 5-year RFS rates of 87.6%, 63.3% and 47.7%, respectively. The median overall survival (OS) for patients was 99.8 months, and the actuarial OS rates from the time of the first AM surgery at 1, 3, and 5 years were 97.0%, 90.6% and 78.8%, respectively. In multivariate analysis, preoperative Karnofsky performance scale (KPS) (>=80), primary tumor, tumor invasiveness, and GTR were associated with increased RFS, while preoperative KPS (>=80), primary tumor, supratentorial location, lack of peritumoral edema, radiotherapy and GTR were associated with increased OS. CONCLUSION: GTR is the first choice for patients with AM. We recommend that patients with secondary tumors receive radiotherapy following surgery. PMID- 30447440 TI - The Use of a Sub-Temporal Approach for a Salvage Placement of a Trigeminal Ganglion Stimulating Electrode for the Treatment of Trigeminal Neuropathic Pain. AB - BACKGROUND AND IMPORTANCE: Trigeminal ganglion stimulation can be effective for trigeminal neuralgia. For patients who respond well to neurostimulation delivered percutaneously through the foramen ovale but require extensive revision and removal of instrumentation, a sub-temporal approach for stimulation of the trigeminal ganglion is an alternative option as a salvage procedure. CLINICAL PRESENTATION: Here we report a 47-year old woman who responded well to neurostimulation for trigeminal neuropathic pain over a one-year period from 2008 2009. Her pre-operative pain on the numerical rating scale (NRS) was between 7 8/10, which decreased to 2/10 post-operatively. However, she developed lead migration due to a motor vehicle accident. Following revision surgeries to correct this, she continued to experience pain relief until 2011. At follow-up, signs of infection promped removal of instrumentation and subsequent return of her pain. She continued to experience persistent and severe pain, NRS 7/10, which was intractable to pharmacologic treatment over 5-years. She returned in 2016 to discuss neurosurgical options, and the original approach was ruled out due to the history of lead migration, erosion, and scarring. A sub-temporal approach was pursued as a salvage option, which provided several advantages for this patient. CONCLUSION: The sub-temporal approach for salvage placement of the trigeminal ganglion stimulating electrode was effective in this patient, and minimizes risks given her history of erosion and multiple operations. This suggests that the sub temporal is a viable salvage operation for trigeminal ganglion stimulation for trigeminal neuropathic pain. PMID- 30447441 TI - Relationship Between T1 slope minus C2-7lordosis and Cervical Alignment Parameters Following Adjacent Two-level Anterior Cervical Discectomy and Fusion of Lower Cervical Spine. AB - OBJECTIVE: To investigate the relationships between the sagittal alignment parameters and neck disability index (NDI) scores following adjacent two-level anterior cervical discectomy and fusion (ACDF) and to study the impact of the T1 slope (T1s) minus C2-7 lordosis (T1s-CL). METHODS: In total, 76 patients following adjacent two-level ACDF were retrospectively analyzed. Radiographic measurements included T1s, C2-7 lordosis, T1s-CL, segment angle (SA) and C2-7 sagittal vertical axis (SVA). NDI scores were used to evaluate the clinical prognosis. Pearson's correlation coefficient was calculated between radiographic measures. Linear regression analysis was used to analyze the relationships between follow-up cervical sagittal parameters and NDI. RESULTS: DeltaT1s was positively correlated with DeltaC2-7 lordosis (r=0.466, p<0.001), DeltaT1s-CL (r=0.337, p=0.003), DeltaC2-7 SVA (r=0.238, p<0.05) and DeltaSA (r=0.654, p=0.000). DeltaC2-7 lordosis was positively correlated with DeltaSA (r=0.692, p=0.000) and negatively correlated with DeltaT1s-CL (r=-0.676, p=0.000) and DeltaC2-7 SVA (r=-0.418, p=0.000). DeltaT1s-CL was positively correlated with DeltaC2-7 SVA (r=0.644, p=0.000). The preoperative and postoperative SA were significantly different (P<0.05), increasing from (3.71 +/- 8.92)o to (9.63 +/- 4.20)o. The preoperative NDI was positively correlated with the preoperative C2-7 SVA (r=0.325, p=0.004) and T1s-CL (r=0.498, p=0.000); the follow-up NDI was positively correlated with the follow-up T1s (r=0.359, p=0.001), C2-7 SVA (r=0.613, p=0.000) and T1s-CL (r=0.696, p=0.000) and negatively correlated with C2-7 lordosis (r=-0.491, p=0.000). The linear regression model showed that when preoperative T1s-CL was >21.43 degrees , NDI was >25 (R2=0.248, P=0.000), and when follow-up T1s-CL was >28.07 degrees , NDI was >25 (R2=0.484, P=0.000). CONCLUSIONS: Changes in cervical sagittal parameters after two-level ACDF were associated with quality of life. A greater T1S-CL mismatch was related to a greater degree of cervical malalignment. T1s-CL may be a more important predictor of cervical malalignment than C2-7 SVA. Specifically, a mismatch greater than 28.07 corresponded to positive cervical sagittal malalignment, defined as an NDI score greater than 25. PMID- 30447442 TI - Surgical management and outcomes of cavernous sinus hemangiomas: a single institution series of 47 patients. AB - OBJECTIVE: The purpose of this study was to analyze the outcomes of cavernous sinus hemangiomas (CSHs) treated surgically and to investigate factors that affect the gross total resection (GTR), newly developed or deteriorated cranial nerve injury (NDDCNI), and follow-up neurological performance, and further discuss the optimal treatment for CSHs. METHODS: Clinical data of 47 patients with CSHs treated surgically at our institution between 2012 and 2018 were retrospectively reviewed. RESULTS: GTR was achieved in 26 (55.3%) patients. Significant relations were identified between the invasion of the sella turcica (odds ratio [OR] = 0.012; 95% confidence interval [CI], 0.001-0.213; P = 0.002), skull base ward (OR = 27.838; 95% CI, 2.995-258.748; P = 0.003) and GTR. The preoperative KPS (OR =2.966, per 10 score increase; 95% CI, 1.136-7.743; P =0.026) and the invasion of the sella turcica (OR = 7.137; 95%CI, 1.282-39.726; P =0.025) were factors that significantly affect the incidence of NDDCNI. The average follow-up KPS, which increased significantly compared with the pre- (P < 0.001) and post-operative KPS (P < 0.001), was 89.1. Increased tumor size (OR = 0.044, per 1cm increase; 95% CI, 0.004-0.477; P = 0.010) was a risk factor for unfavorable follow-up KPS. CONCLUSIONS: Being treated by an experienced skull base surgeon favors the total removal of CSHs while the invasion of the sella turcica does just the opposite. Increased tumor size is a risk factor for unfavorable follow-up KPS. The invasion of the sella turcica was related to NDDCNI and unfavorable follow-up KPS. PMID- 30447443 TI - Local tumor control and clinical symptoms after Gamma Knife Radiosurgery for residual and recurrent vestibular schwannomas. AB - INTRODUCTION: The use of Gamma Knife radiosurgery (GKRS) for recurrent or residual Vestibular schwannoma (VS) after microsurgery (MS) has been investigated in several retrospective studies. The purpose of this study was to identify potential risk factors for both neurological deterioration and tumor progression after GKRS for previously operated VS in a prospective setting. METHODS: Patients who underwent GKRS (Elekta, AB, Stockholm,Sweden) for previously operated and histopathologically confirmed VS between 1998 and 2015 were prospectively followed-up. Risk factors for therapy side-effects and predictors for tumor control were investigated in uni- and multivariate analyses. RESULTS: 160 individuals with a median age of 55 years were included. Median tumor volume prior to GKRS was 1.40cm3(range: .06-35.80cm3). After a median follow-up of 36 months, hearing and facial nerve function were serviceable (modified Gardner Robertson and House&Brackmann grades I-II) in 7 (5%) and 82(55%) patients, respectively. Deterioration to a non-serviceable facial nerve function after GKRS was found in 3% (N=3/89) and tended to increase with rising tumor volume (OR:1.65/cm3, 95%CI;1.00-2.71; p=.051). Median tumor volume prior GKRS was higher in patients with radiological (p=.020) or clinical tumor progression (p<.001). Critical tumor volume prior to GKRS to predict clinical and radiological tumor progression was 1.30cm3 (p<0.001) and 3.30cm3 (p=.019), respectively. However, in multivariate analyses, none of the analyzed variables was found to independently predict tumor progression. CONCLUSION: Intended submaximal resection followed by GKRS is a viable treatment for VS. As tumor remnant size after MS was an important predictor for recurrence after adjuvant GKRS, both brain stem and cerebellar decompression as well as maximal safely achievable resection should remain major goals of microsurgery. PMID- 30447444 TI - Supracerebellar infratentorial variant approaches to the intercollicular safe entry zone. AB - OBJECTIVE: To describe and compare surgical exposure through microsurgical cadaveric dissection of the intercollicular region afforded by the median, paramedian and extreme-lateral supracerebellar infratentorial (SCIT) approaches. METHODS: Ten cadaveric heads were dissected using the SCIT variants approaches. Neuronavigation system was used to determine tridimensional coordinates for the intercollicular zone in each route. The area of surgical and angular exposures were evaluated and determined by software analysis for each specimen. RESULTS: The median surgical exposure was similar for the different craniotomies, 282.9 +/ 72.4 mm2 for the median, 341.2 +/- 71.2 mm2 for the paramedian and 312.0 +/- 79.3 mm2 for the extreme-lateral (p = 0.33). The vertical angular exposure to the center of the intercollicular safe entry zone was also similar between the approaches (p=0.92). On the other hand, the horizontal angular exposure was significantly wider for the median approach (p<0.001). CONCLUSION: All the SCIT approaches warrant a safe route to the quadrigeminal plate. Among the different variants the median approach had the smaller median surgical area exposure but presented superior results to access the intercollicular safe entry zone. PMID- 30447445 TI - Management of a steel bar injury penetrating the head and neck: a case report and review of the literature. AB - Non-missile penetrating injuries (NMPIs) to the head and neck caused by steel bar are rare and without standard management strategy. We report a case of a 42-years old female who experienced a steel bar injury penetrating to the head and neck. Computed tomography and three-dimensional reconstruction were applied for preoperative evaluation. Digital subtraction angiography was used to confirm potential vascular injury. The steel bar was successfully removed through open surgical procedure by a multi-disciplinary team. Relevant literature regarding NMPIs by steel bar was reviewed to propose appropriate management strategies. PMID- 30447446 TI - Distal Radial Artery Access in the Anatomical Snuffbox for Neurointerventions: Case Report. AB - BACKGROUND: The distal transradial approach (dTRA) is being widely adopted by interventional cardiologists, primarily due to reduced morbidity and mortality from access site complications. The distal radial artery has advantages over standard radial access in relation to procedural positioning as well as radial artery preservation, particularly in patients who may require multiple angiograms. One disadvantage is the smaller diameter of the artery as well as more challenging puncture of a smaller, weaker artery. In this case report we demonstrate the feasibility of dTRA in two patients who underwent successful diagnostic angiography and mechanical thrombectomy. RESULTS: Two patients underwent dTRA for neurointerventions. In one patient a 5 Fr Glidesheath Slender and a Sim2 catheter was used for a 6-vessel cerebral angiogram. In the second patient, a 0.88" sheathless guide catheter was used to perform a mechanical thrombectomy. Successful hemostasis in both cases was achieved with a Safeguard Radial Compression Device (Merit Medical, Utah, USA) and no complications were observed. CONCLUSION: Neurovascular access via dTRA is feasible and further exploration is warranted. PMID- 30447447 TI - The properties of an in vivo fractured PMMA cranioplasty after 15 years. PMID- 30447448 TI - Operative complications with and without image-guidance: A systematic review and meta-analysis of the Ommaya reservoir literature. AB - BACKGROUND: The use of image guidance (IG) in neurosurgery is ubiquitous, even though evidence from patient outcome data has remained limited to smaller, mostly observational, studies. Ommaya reservoir insertion (ORI) has been available as a treatment option for targeted intraventricular pharmacotherapy since the 1960's, far preceding the modern neuronavigation era. We conducted a systematic review and meta-analysis investigating the impact of IG on surgical outcome from ORI. METHODS: A systematic database search of MEDLINE and EMBASE was performed to identify studies on operative outcomes from ORI. Only studies reporting patient demographics and peri-operative outcomes (hemorrhage, infection, malposition, malfunction, and mortality) were included. Study quality was assessed via MINORS criteria. RESULTS: Of the 3560 records screened, 43 studies met study inclusion criteria, for a total of 1995 ORI procedures. Pooled rates of outcome for IG compared to non IG were 6.4% versus 14.1% for overall complications; 2.0% compared to 2.8% for catheter malfunction; 2.3% compared to 3.3% for catheter malposition; 0.7% compared to 4.5% for early infection; 0.6% compared to 1.4% for mortality. Post operative hemorrhage was increased at 3.4% compared to 2.4%. Subgroup analysis revealed a difference in early infection rate between frameless and frame-based IG at 0.0% versus 1.9%. Meta-regression revealed a relationship between publication date and all operative outcomes except for catheter malposition and hemorrhage. CONCLUSIONS: This study offers a historical context on the evolution of the practice of ORI and comprises the largest observational analysis of operative outcomes providing objective support for the use of IG in neurosurgery. CONCLUSION: PMID- 30447449 TI - Nanotechnology in Spine Surgery: a current update and critical review of literature. AB - OBJECTIVES: Nanotechnology is a promising field with numerous applications across various branches of medicine. The unique innate physical, chemical and biological properties of nano-particles enable them to serve as appropriate agents performing diverse functions at cellular and sub-cellular levels. Spinal pathologies constitute one major field where its applications are being explored. METHODS: A critical review of literature was performed to identify the current role of nanotechnology in spine surgery. A pubmed search was done using keywords "nanotechnology in neurosurgery", "nanotechnology in surgery", "nanotechnology in spine", "nanotechnology in spine surgery", "nanotechnology in disc regeneration", "nanotechnology in spinal injury", "nanotechnology in spinal cord regeneration", "nanotechnology in spine fusion", "nanotechnology in osteoporosis", nanotechnology in spinal drug delivery and "nanotechnology in spinal infection". Initial search revealed 347 articles. Articles were further screened. Duplicate articles, articles on non-nanotechnological topics, non-spine articles or articles with details not pertaining to the current field of interest and non English language studies were excluded. RESULTS: A total of 76 articles were finally included. Nanotechnological advancements in spine surgery include applications in spinal fusion, CNS drug delivery, neuronal regeneration, disc regeneration, spinal infection prophylaxis, management of osteoporosis, sutureless vascular anastomosis, molecular imaging and theranostic medicine. CONCLUSIONS: Nanotechnology in spine surgery is still in its early stages. Eventually, we may see the implementation of nanotechnology as an alternative to existing treatment options. Concerns regarding safety of this technology need to be addressed through future research projects. Although promising, exact role of nanotechnology in spine surgery remains to be seen. PMID- 30447450 TI - Surgical Management of Brainstem Cavernous Malformation: Report of 67 Patients. AB - BACKGROUND: Brainstem CMs are benign lesions, often show an acute onset, and result in a high rate of morbidity. Surgical resection could inhibit the progressive deterioration of the neurological function caused by repetitive hemorrhage. This study aimed to summarize the timing, approaches, and techniques of surgery, and to evaluate the outcomes of treatment. METHODS: Sixty seven patients (32 males and 35 females), with an average age of 40 years (14-68 years) with brainstem CM received surgical treatment between March 2011 and May 2013. The clinical presentation, surgical approaches taken and results of the follow-up were retrospectively analyzed. RESULTS: A total of 7 surgical approaches were used, including the orbitozygomatic approach (1 case), suboccipital - transtentorial approach (Poppen's approach) (3 cases), subtemporal - transtentorial approach (32 cases), subtemporal - transtentorial/anterior petrosectomy approach (9 cases), suboccipital - retrosigmoid approach (3 cases), midline suboccipital approach (16 cases), and the far lateral approach (3 cases). Total resection of the brainstem CM was achieved in all cases (100%). No operative death was encountered. Nine patients had new symptoms after surgery; 3 had diplopia, 3 had facial numbness, 1 had numbness of contralateral limbs, 1 had transient aphasia, and 1 had reduced muscle strength of contralateral limbs. 23 patients (34.3%) showed significantly improved symptoms, 36 (53.7%) showed no change in symptoms, and 9 (13.4%) had new postoperative symptoms. CONCLUSION: Choosing a proper surgical approach and using appropriate techniques are fundamental for favorable outcomes of patients with brainstem CM. PMID- 30447451 TI - Posterior nerve-sparing multilevel cervical corpectomy and reconstruction for metastatic cervical spine tumors: case report and literature review. AB - BACKGROUND: Cervical spine metastases with circumferential spinal cord compression are often treated with combined anterior-posterior decompression and stabilization. In patients with large anterior neck masses, prior radiotherapy to the neck, or prior anterior neck surgery, however, anterior approaches may pose additional risk. In such cases, posterior-only approaches that allow for circumferential decompression and anterior column reconstruction may be beneficial. CASE DESCRIPTION: We present the case of a seventy-year-old male with follicular thyroid carcinoma metastatic to the cervical spine causing spinal cord compression. We utilized a posterior-only approach for a C6/7 partial corpectomy and posterior decompression and fusion from C2-T2. Our technique involved pre operative embolization of the right vertebral artery to safely gain access to the ventral surface of the spinal cord and vertebral bodies. Anterior column support was provided by a chest tube/polymethylmethacrylate construct, allowing the implant to be placed within the anterior column from a posterior approach without nerve root sacrifice. The patient tolerated the procedure well. He had no post operative neurologic deficits. Two months later he underwent a total thyroidectomy followed by stereotactic radiotherapy to the tumor bed (2700 cGy total, 3 fractions). At one-year follow-up he was active and without significant pain or focal neurologic deficits. CONCLUSIONS: We propose a novel approach to ventral/circumferential cervical spine tumors that combines epidural decompression and cervical stabilization via a posterior-only approach. By using a chest tube/polymethylmethacrylate construct, anterior column support can be achieved through a posterior approach without nerve root sacrifice. PMID- 30447452 TI - Long-term survival following transformation of an adrenocorticotropic hormone secreting pituitary macroadenoma to a silent corticotroph pituitary carcinoma: Case report. AB - Pituitary carcinomas are rare and aggressive neoplasms that despite current treatment regimens continue to have a poor prognosis. Adrenocorticotrophic hormone (ACTH) pituitary tumors have been shown to alter their clinical manifestations with conversion to Cushing's disease and silent types. The purpose of this paper is to present the first documented case of an ACTH secreting pituitary adenoma with Cushing's disease that differentiated into a silent corticotroph pituitary carcinoma with metastases to distant sites in the central nervous system (CNS). This patient was later treated with radiotherapy, temozolomide (TMZ) and bevacizumab with 8 years of progression free survival. PMID- 30447453 TI - Minimally invasive thoracolumbar corpectomy and stabilization for unstable burst fractures using intraoperative computed tomography and computer assisted spinal navigation. AB - BACKGROUND: Minimally invasive (MIS) 'mini-open' lateral retropleural or retroperitoneal approach corpectomy is a well described procedure for treating unstable thoracolumbar burst fractures. Most surgeons incorporate fluoroscopy for localization and determination of hardware placement accuracy, but the utility of computer assisted image guided spinal navigation has not been well described. In this study, we report a series of mini-open lateral approach thoracolumbar corpectomy cases using either fluoroscopy or intraoperative computed tomography (iCT) with computer assisted navigation and discuss the technical nuances and advantages of using iCT with navigation versus fluoroscopy. METHODS: A retrospective review and analysis was performed of twenty patients with thoracolumbar burst fractures surgically managed via mini-open lateral corpectomy with fluoroscopy (2013-2015) or iCT navigation (2015-2017). Surgical outcomes were evaluated with estimated blood loss, operative time, hospital stays, and need for revisions. Clinical outcomes were evaluated with the Numeric Rating Scale pain score, and radiographic outcomes were assessed with CT scans at follow up appointments. The results were statistically analyzed via Wilcoxon-Mann Whitney. RESULTS: Mean follow-up period was 13.4 months in the fluoroscopy group and 14.7 months in the iCT group. There were no surgical complications or revisions. There were no statistical differences between the groups in surgical or clinical outcomes. However, radiation exposure to surgeons was significantly less in the iCT group (p < 0.003). CONCLUSIONS: The use of iCT with spinal navigation in mini-open lateral corpectomy for thoracolumbar burst fractures yields comparable perioperative and clinical outcomes compared to using traditional fluoroscopy and decreases radiation exposure to surgeons. PMID- 30447454 TI - A Case Report of Meningeal Hemangiopericytoma: A nine-year journey from the brain to the spine. AB - BACKGROUND AND IMPORTANCE: Hemangiopericytomas (HPC) are rare and aggressive vascular mesenchymal tumors. Unlike meningiomas which have a similar radiological appearance, these tumors have a higher risk of local recurrence after resection, and distant metastasis can reach up to 23%. Metastases to the vertebral bones from an intracranial HPC are very rare, with so far only 9 cases reported in the literature. CLINICAL PRESENTATION: We present the case of a 46-year-old male who was surgically treated for a presumed left parieto-occipital falx meningioma in 2008. He presented nine years later with a thoracic vertebral mass that was causing relentless pain. Reexamination of the cranial pathology allowed correction of the diagnosis performed in 2008 to a Meningeal Hemangiopericytoma (M-HPC) and the spinal lesion was confirmed after surgery to be a metastatic tumor. CONCLUSION: The literature lacks randomized clinical trials and large studies defining the natural history of HPC to draw clear recommendations for a precise management of the disease. However, en bloc resection followed by radiation therapy seems to provide the optimal treatment for a long patient disease-free survival. PMID- 30447455 TI - Real-world thrombectomy using the Sofia catheter. AB - BACKGROUND: We aimed to study the safety and performance of real-world thrombectomy using the Sofia catheter in our comprehensive stroke center. METHODS: We conducted a cohort study from a prospective clinical registry of consecutive stroke patients treated by mechanical thrombectomy (MT) between March 2016 and September 2017. Baselines clinical and imaging characteristics, recanalization rates, complications and clinical outcomes were analyzed. RESULTS: Among the 140 patients included, 54 were treated using aspiration first, 64 were treated using aspiration and stent-retriever straightaway and 22 were treated with Sofia as a rescue device. Successful recanalization (mTICI2b/3) was achieved in 82.1% patients and good outcome in 34.3%. Symptomatic intracranial hemorrhage occurred in 7.1% and mortality in 25%. CONCLUSION: In our single center experience, thrombectomy using the Sofia as an intermediate or aspiration catheter provided high recanalization rates under the everyday conditions. PMID- 30447456 TI - Surgical Management of Spinal Arachnoid Cysts in Adults. AB - BACKGROUND: Spinal arachnoid cysts (SACs) are uncommon lesions in the spinal canal. They are usually asymptomatic, but can occasionally cause mass effect leading to neurologic symptoms. They can be congenital or secondary to a variety of causes. They can produce a variety of neurologic symptoms including pain, weakness, sensory changes, incontinence, and more. Surgical intervention may be necessary when SACs cause symptomatic mass effect. METHODS: Thirteen consecutive patients who underwent surgical intervention for an SAC were retrospectively reviewed. The data included presenting symptoms, imaging findings, neurologic status, and follow-up. RESULTS: Of the 13 patients, the majority of cases were located in the thoracic spine (54%) and all but one case were located dorsally or dorsolaterally. Furthermore, 38% were located extradurally and 54% were located intradurally. Pain (80%) was the most common presenting symptom. Most patients had improvement or complete resolution of their symptoms after intervention. Extradural SACs and their capsules were completely resected, whereas intradural SACs underwent fenestration. No complications occurred in this series. CONCLUSIONS: SACs are usually asymptomatic, but rarely cause mass effect and neurologic deficits requiring surgical intervention. Surgical intervention is tailored to the position of the cysts' dorsal or ventral locations. Pain and weakness are the most likely symptoms to improve, whereas sensory symptoms are least likely to improve. PMID- 30447457 TI - Physiological cervical alignment change between whole-spine radiographs and normal standing cervical radiographs. AB - BACKGROUND: The objective of this study was to evaluate the physiological change of cervical spine alignment between two radiographs [Whole spine radiograph (WS) and cervical spine radiograph (CS)]. METHODS: Multilevel cervical segmental angles (horizontal gaze, C2-slope, C7-slope, and T-1 slope) were measured, and O C2 angle, O-C7 angle, and C2-7 angle were also calculated. The relative translation statuses of (C27- SVA, C07- SVA) were measured. RESULTS: Generally, statistically significant differences were found for occipital-slope (Delta 7.1) and C7-slope (Delta 2.1), and these results induced a significant O-C2 angle (Delta 4.6) and not significant C2-7 angle (Delta 1.2) change between the two types of radiographs. In the FHG (fixed horizontal gaze) group analysis, C7-s and C2-7A were significantly different between WS and CS radiographs. In the NFHG (non-fixed horizontal gaze) group analysis, C2-s exhibited significant upward movement (Delta 3.7) and C7-s did not showed significant change (Delta 0.1), which cause the constant value of cervical lordosis (C2-7A) between the two radiographs (P=0.084). CONCLUSIONS: Horizontal gaze fixation may induce untruthful results of cervical lordosis (C2-7A) and a non-physiological distribution ratio of cervical lordosis (O-C2 angle; 92 % vs. C2-7 angle; 8 %). However, if the horizontal gaze was not controlled, WS exhibited a constant value of C7-s compared with CS, which may induce the unchanged state of cervical lordosis and physiological distribution ratio of cervical lordosis (O-C2 angle; 74 % vs. C2-7 angle; 26 %). PMID- 30447458 TI - Quality of life changes before and after transsphenoidal surgery for sellar and parasellar lesions. PMID- 30447459 TI - Improving ventriculostomy management: risk and cost reduction through a multi disciplinary approach. AB - OBJECT: Infection is a life-threatening complication of ventriculostomies. The purpose of this quality improvement project was to develop a cost-effective, evidence-based intervention to reduce ventriculostomy-associated infection (VAI) rates. METHODS: In this retrospective study, patients undergoing ventriculostomy insertion between June 2008 and December 2016 were identified and charts reviewed. The study period between June 2008 and August 2010 constituted the baseline (phase 1) in which non-antibiotic coated ventriculostomies were utilized and cerebrospinal fluid (CSF) sampling was done daily. Then, two sequential interventions were implemented. Between September 2010 and January 2013, antibiotic-coated ventriculostomies (AC-V) were utilized (phase 2). Then, between February 2013 and December 2016, the frequency of CSF sampling was minimized to twice a week (phase 3). The rates of VAI and operational costs, or cost incurred for the EVD catheter, antibiotics, laboratory analysis, and CSF sampling supplies, were compared for each phase. RESULTS: The average infection rate for phase 1 was 3.3 infections per 1,000 device days. The VAI rates for phases 2 and 3 were 1.6 and 0.8, respectively. The use of AC-Vs and reduced CSF sampling resulted in a VAI rate decrease of 75.8% (p=0.01). During 2014, there were no VAIs. The intervention produced an estimated $1.02 million in savings for the institution during phase 3. The average projected savings of this intervention was $175 per patient per day and reduced cost by 72%. CONCLUSION: The use of AC Vs in combination with decreased frequency of CSF sampling was cost-saving and resulted in a significant reduction in device-related infections. PMID- 30447460 TI - Orbital arteriovenous fistula coexistent with an arteriovenous hemangioma: a rare occurrence and review of literature. AB - BACKGROUND: Orbital arteriovenous fistula (AVF) is a rare entity with only 17 cases reported so far. Arteriovenous hemangioma is a distinct entity of angioma that most frequently affects the skin. However, to our knowledge, there has not been a case arising in the orbit. CASE PRESENTATION: A previously healthy, 73 year-old man had progressive proptosis for one month. At presentation, the patient showed considerable proptosis, hyperemia in the lower eyelid, chemosis, and total ophthalmoplegia on the right side. Computed tomography and magnetic resonance imaging revealed a round retro-orbital mass, 23 mm in maximal dimension, and lying in the inferomedial aspect of the orbit with an irregular shaped lesion in the orbital apex. Cerebral angiography detected an orbital AVF fed by the ipsilateral maxillary and ophthalmic arteries and draining into the inferior ophthalmic vein. Stain of the retro-orbital mass was not identified. A transvenous coil embolization via the facial and superior ophthalmic veins achieved complete isolation of the AVF with satisfactory outcome. Two months later, the orbital mass, well-circumscribed and lacking perilesional hemosiderin deposition, was microsurgically resected via a lateral orbitotomy. Histological diagnosis was consistent with arteriovenous hemangioma. CONCLUSIONS: An AVF and arteriovenous hemangioma may simultaneously develop in the same orbit. In patients with symptomatic orbital AVF and coexisting other orbital pathology, strategies should be carefully planned before setting about the treatment. PMID- 30447461 TI - Cerebral Perfusion Territory Changes after Direct Revascularization Surgery in Moyamoya Disease: A Territory Arterial Spin Labeling Study. AB - OBJECTIVES: To use the territory arterial spin labeling (T-ASL) technique in the early postoperative period to evaluate the revascularization area (RA) obtained by a bypass from the superficial temporal artery (STA) to the middle cerebral artery (MCA), and to evaluate the subsequent perfusion territory changes of the major cerebral arteries. METHODS: Thirty patients with Moyamoya disease treated via unilateral STA-to-MCA bypass were included. T-ASL was performed preoperatively and within 1 week postoperatively. The RA was examined by labeling the STA-to-MCA bypass postoperatively. The pre- and postoperative perfusion territories of the bilateral internal carotid arteries, bilateral external carotid arteries, and the basilar artery were also examined and compared. Postoperative CT angiography was performed and compared with the T-ASL results. RESULTS: In 14 of 30 patients (46.7%), T-ASL demonstrated the presence of a RA (RA-positive), while 16 patients (53.3%) had no RA (RA-negative). In the RA positive group, the mean volume of the RA was 80.32+/-8.13 ml (range 34.95-142.50 ml). The postoperative perfusion territory changes of the major cerebral arteries differed between the RA-positive group and the RA-negative group. The incidence of preoperative external carotid artery compensation was significantly higher in the RA-negative group than the RA-positive group (F=0.011, P<0.05). There was good intermodality agreement between T-ASL and CT angiography (kappa=0.780). CONCLUSIONS: T-ASL can demonstrate the RA obtained by direct revascularization, and the postoperative perfusion territory changes of the major cerebral arteries. T-ASL is a promising technique in the postoperative evaluation of patients with Moyamoya disease. PMID- 30447462 TI - Safety and Outcome of Transsphenoidal Pituitary Adenoma Resection in the Elderly. AB - OBJECTIVE: Pituitary adenomas account for 10-20% of intracranial brain tumors, but have higher incidence in the elderly. We assessed microsurgical treatment for pituitary adenomas in this population. METHODS: A retrospective cohort of patients >=60 years of age was identified. Patients were divided into deciles by age for evaluation of variables affecting outcome: 60-70 (group 1), 71-80 (group 2), and >80 years (group 3). RESULTS: Two hundred five patients were identified among group 1 (n=131), group 2 (n=65), and group 3 (n=9). Preoperative variables other than age did not differ. Most patients presented with visual disturbance, in 56.5%, 73.8%, and 50% in groups 1, 2, and 3, respectively. The next most common indication was headache, followed by endocrinopathy. Tumors were overwhelmingly nonfunctional (p=0.97) and macroadenomas (p=0.5) in all 3 groups. Gross total resection in 56.9-80% of patients and this rate did not differ among groups. Complication rates of 6.9% in group 1, 9.2% in group 2, and 0.0% in group 3 were observed (p=0.8). No perioperative mortality was identified. Mean length of follow-up ranged from 8.9 to 28.3 months. CONCLUSIONS: In this series of microsurgical resection of pituitary adenomas in the elderly, good efficacy and safety of treatment was observed. Preclusion of surgical treatment, including open resection, simply because of age is not warranted and instead a comprehensive evaluation of a patient's risk profile and surgical goals should be undertaken. PMID- 30447463 TI - Delayed Remission of Growth Hormone-Secreting Pituitary Adenoma After Transsphenoidal Adenectomy. AB - OBJECTIVE: To investigate the clinical characteristics of delayed remission (DR) of growth hormone (GH)-secreting pituitary adenoma after transsphenoidal adenectomy and inform follow-up treatments. METHODS: We retrospectively reviewed 87 patients who had undergone transsphenoidal surgery for acromegaly. Demographic, radiological and endocrinological data were reviewed before, immediately after, 3 months after and in the long term (2.4+/-1.1 years) after surgery. The definition of DR was that patients did not achieve GH remission immediately, 3 months or later after surgery, but did so in the long term without any additional postoperative treatment. RESULTS: Fifty-one patients (58.6%) achieved long-term GH remission. There were 24 (27.6%) DR patients immediately postoperatively, and 9 (10.3%) DR patients 3-month postoperatively. On average, the 24 DR patients achieved remission at 10.2 (range, 3-32) months. Immediate postoperative random and nadir GH after an oral glucose load were significantly lower in the DR group than in the nonremission group (2.73+/-3.17 and 2.03+/-2.59 vs. 8.05+/-10.35 and 5.55+/-5.91 MUg/L, respectively). Three-month postoperative nadir GH was significantly lower in the DR group than in the nonremission group (1.63+/-2.82 vs. 3.48+/-4.25 MUg/L, p=0.007). Immediate postoperative random GH effectively predicted long-term remission (Spearman's rho=0.513, AUC=0.905>0.90). However, the best predictor of long-term remission was 3-month postoperative nadir GH (Spearman's rho=0.728, AUC=0.944>0.90), with 76.5% sensitivity and 97.2% specificity. CONCLUSIONS: For certain groups of patients likely to achieve DR, additional treatments should not be performed early after surgery. Prolonged follow-up and close observation could help determine the therapeutic effect of surgery and guide postoperative treatments. PMID- 30447464 TI - Long-Term Outcomes of Newly-Diagnosed Resected Atypical Meningiomas and the Role of Adjuvant Radiotherapy (ART). AB - OBJECTIVE: The role of adjuvant radiotherapy (ART) in patients with WHO Grade II atypical meningiomas (AM) remains controversial. METHODS: We retrospectively reviewed 149 patients with newly-diagnosed, resected AMs from 2000-2012. Gross total resection (GTR) was defined as Simpson Grade I-III and subtotal resection (STR) as Grade IV-V. Kaplan-Meier analyses of local control (LC), progression free survival (PFS), and overall survival (OS) were performed with the log-rank test and risk factors for progression/recurrence (P/R) were analyzed with multivariate Cox regression. RESULTS: Median follow-up was 74.2 months. GTR was achieved in 98 patients and STR in 51 patients. Fifty-three (35%) patients received ART. Overall, 46 patients (31%) experienced P/R with a median time to P/R of 32.4 months. ART was associated with a trend towards improved PFS (p=0.0669) in the GTR subset but significantly improved LC (p=0.0183) and PFS (p=0.0034) in the STR subset. Age, tumor size, and STR were significant risk factors for worse PFS while receiving ART was associated with improved PFS on multivariate analyses. Thirty-nine of the 46 progressive/recurrent patients underwent salvage therapy with only 22 patients experiencing long-term control. Five patients experience transformation to WHO Grade III malignant meningioma. CONCLUSIONS: Patients who undergo STR for newly diagnosed AM should receive ART based on improvements in LC and PFS. GTR patients should be considered for ART, but active surveillance is a reasonable management approach with the recognition that progressive/recurrent disease can act aggressively. Prospective, randomized trials are currently underway to evaluate the role of ART. PMID- 30447465 TI - Long-Term Tumor Control Rates Following Gamma Knife Radiosurgery for Acoustic Neuroma. PMID- 30447466 TI - Subarachnoid hemorrhage from a distal middle cerebral artery aneurysm possibly related to segmental arterial mediolysis. AB - BACKGROUND: Distal middle cerebral artery aneurysm (DMCAAn) is rare, and the clinical features and the etiology are not well understood. Segmental artery mediolysis (SAM) is a pathological entity that affects the media of the muscular artery and can cause arterial dissection and a hemorrhagic event. Subarachnoid hemorrhage (SAH) due to SAM in the vertebral artery has been documented. However, SAH from a ruptured DMCAAn due to SAM has not yet been described. CASE DESCRIPTION: A 49-year-old woman presented with a headache and vomiting. Computed tomography (CT) revealed SAH, and CT angiography (CTA) showed a DMCAAn, which was treated by trapping and resection. Histopathological studies showed loss of the media and reparative changes in the arterial wall including intimal hyperplasia and increased vasa vasorum in the adventitia. These findings were indicative of SAM in the reparative phase. She did not show any other possible etiologies of DMCAAn including infectious endocarditis and vasculitis, and CTA of the trunk did not show any other vascular lesions. She was discharged from the hospital approximately 3 weeks after the surgery without any apparent neurological deficits. CONCLUSION: Our case suggests that SAM can also occur in the middle cerebral artery and result in DMCAAn. PMID- 30447467 TI - Minimally Invasive, Far Lateral Lumbar Microdiscectomy with Intra-Operative CT Navigational Assistance and Electrophysiological Monitoring. AB - BACKGROUND: Patients with far lateral disc herniations (FLDH) experience more severe pain and sensory symptoms than paracentral disc herniations, and by comparison, surgical intervention is both more challenging and results in poorer outcomes. METHODS: We report our experience with intraoperative CT (iCT) navigation assisted minimally invasive tubular microdiscectomy via a paramedian approach with electrophysiological monitoring for precise three-dimensional anatomical localization and early electrophysiological identification of the exiting nerve. RESULTS: Five patients presenting with weakness and pain refractory to conservative management underwent iCT navigation surgery for lumbar FLDH with electrophysiological monitoring. The mean decrease in VAS pain score was -7.1 while Modified MacNab criteria outcomes were good/excellent/excellent/excellent/excellent. CONCLUSIONS: These results in a small group of patients suggest this is a safe approach with potential for improved outcomes in surgical treatment of FLDH. PMID- 30447468 TI - Management of chyloretroperitoneum after lumbar surgery by anterior approach. PMID- 30447469 TI - A Novel Mutation of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene Associated With Familial Isolated Pituitary Adenoma (FIPA) Mediates Tumor Invasion and Growth Hormone Hypersecretion. AB - BACKGROUND: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene were identified in nearly 20% of families with familial isolated pituitary adenoma (FIPA). Some variants of AIP have been confirmed to induce tumor cell proliferation and invasiveness, however the mechanism is still unclear. METHODS: A novel missense mutation (c. 512C>T, p. T171I) was discovered in three patients from a Chinese FIPA family. In silico and multiplex ligation dependent probe amplification (MLPA) analysis predicted the mutation to be pathogenic. GH3 and 293FT cell lines were used to verify the variant's effect on cell proliferation (CCK8), invasiveness (Transwell) and GH secretion (ELISA) by transfection with different vectors: control, blank vector, wild type AIP, p. T171I variant (experimental group), p. Q315* variant, and AIP siRNA. Furthermore, Zac1, Sstr2, IL-6 and Stat3/phosphorylation-Stat3 expression (RT-PCR, western blot) in each group was also evaluated. RESULTS: The experimental group, as p. Q315* variant group and AIP siRNA-overexpressing group, promoted cell proliferation at 24 and 48 h, respectively (compared with control group, both p < 0.01); Similarly, cells in the experimental group manifested more invasion and GH secretion, compared with the control group (p < 0.01, and p < 0.05, respectively). Furthermore, the experimental group cells expressed less Sstr2 (a prerequisite for the responsiveness to somatostatin analogues) and Zac1 (tumor suppressor gene), but more IL-6 and phosphorylated-State3 (GH-secretion related). CONCLUSIONS: The novel AIP mutation c. 512C>T (p. T171I), is a pathogenic variant that promoted cell proliferation, invasiveness and GH secretion through regulation of Sstr2, Zac1 and IL-6/phosphorylated-State3 expression. PMID- 30447470 TI - Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. AB - Hepatocellular carcinoma (HCC) is the most common primary liver cancer, representing the sixth leading cause of cancer and the third leading cause of cancer-related mortality. Patient stratification and treatment allocation are based on tumor stage, liver function, and performance status. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line treatment for patients with intermediate stage HCC, including those with large or multinodular HCC, well preserved liver function, and no cancer-related symptoms or evidence of vascular invasion or extrahepatic spread. Two TACE techniques have been used since 2004, conventional TACE (cTACE) and TACE with drug-eluting beads (DEB-TACE). cTACE was evidenced first to treat intermediate stage HCC patients. It combines the transcatheter delivery of chemotherapy using Lipiodol-based emulsion plus an embolizing agent to achieve strong cytotoxic and ischemic effects. Drug-eluting beads (DEBs) were developed in order to slowly release chemotherapeutic agents, and to increase ischemia intensity and duration. Recent advances allow TACE treatment of both early stage patients (i.e. those with a solitary nodule or up to 3 nodules under 3 cm) and some advanced stage patients. Here we review recent clinical evidence related to TACE treatment of patients with early, intermediate, and advanced stage HCC. Based on the 2014 TACE algorithm of Raoul et al., this international expert panel proposes an updated TACE algorithm and provides insights into TACE use for patients at any HCC stage. PMID- 30447471 TI - Transport of organic substances through the cytoplasmic membrane of cyanobacteria. AB - Cyanobacteria are mainly known to incorporate inorganic molecules like carbon dioxide and ammonia from the environment into organic material within the cell. Nevertheless cyanobacteria do import and export organic substances through the cytoplasmic membrane and these processes are essential for all cyanobacteria. In addition understanding the mechanisms of transport of organic molecules through the cytoplasmic membrane might become very important. Genetically modified strains of cyanobacteria could serve as producers and exporters of commercially important substances. In this review we attempt to present all data of transport of organic molecules through the cytoplasmic membrane of cyanobacteria that are currently available with the transported molecules ordered according to their chemical classes. PMID- 30447472 TI - A review of indirect N2O emission factors from agricultural nitrogen leaching and runoff to update of the default IPCC values. AB - Indirect N2O emissions from agricultural nitrogen (N) leaching and runoff in water bodies contribute significantly to the global atmospheric N2O budget. However, considerable uncertainty regarding this source remains in the bottom-up N2O inventory. Indirect N2O emission factor associated with N leaching and runoff (EF5; kg N2ON per kg of NO3--N) incorporate three components for groundwater and surface drainage (EF5g), rivers (EF5r), and estuaries (EF5e). The 2006 IPCC default EF5 value was based on a small number of studies available at the time. Here we present the synthesis of 254 measurements of EF5, dissolved N2O, and nitrate from 106 studies. Our results do not support the further downward revision of EF5g by the IPCC and suggest an upward revision of EF5g of 0.0060. The emission factors for groundwater and springs (0.0079) was higher than that for surface drainage (0.0040). The emission factor for lakes, ponds, and reservoirs was 0.0012, whereas that for rivers was 0.0030, and a combined EF5r was 0.0026. Estimated EF5r and EF5e (0.0026) values from the study were close to the current IPCC default values (0.0025 each). We estimated an updated default EF5 value of 0.01 for the refinement of IPCC guidelines. PMID- 30447473 TI - An adaptive transgenerational effect of warming but not of pesticide exposure determines how a pesticide and warming interact for antipredator behaviour. AB - The impact of pesticides on organisms may strongly depend on temperature. While many species will be exposed to pesticides and warming both in the parental and offspring generations, transgenerational effects of pesticides under warming are still poorly studied, particularly for behaviour. We therefore studied the single and combined effects of exposure to the pesticide chlorpyrifos (CPF) and warming both within and across generations on antipredator behaviour of larvae of the vector mosquito Culex pipiens. Within each generation pesticide exposure and warming reduced the escape diving time, making the larvae more susceptible to predation. Pesticide exposure of the parents did not affect offspring antipredator behaviour. Yet, parental exposure to warming determined how warming and the pesticide interacted in the offspring generation. When parents were reared at 24 degrees C, warming no longer reduced offspring diving times in the solvent control, suggesting an adaptive transgenerational effect to prepare the offspring to better deal with a higher predation risk under warming. Related to this, the CPF-induced reduction in diving time was stronger at 20 degrees C than at 24 degrees C, except in the offspring whose parents had been exposed to 24 degrees C. This dependency of the widespread interaction between warming and pesticide exposure on an adaptive transgenerational effect of warming is an important finding at the interface of global change ecology and ecotoxicology. PMID- 30447474 TI - DINP aggravates autoimmune thyroid disease through activation of the Akt/mTOR pathway and suppression of autophagy in Wistar rats. AB - Di-isononyl phthalate (DINP) is used as a substitute for traditional phthalates, in a wide range of applications. However, there is growing concern regarding its toxicity. Studies have indicated that DINP is related to thyroid hormone disorder and that phthalates can affect thyroid normal function. In this study, we aim to determine any effects of DINP exposure on autoimmune thyroid disease (AITD), the most common autoimmune disease, and to understand the underlying causal mechanism. AITD model Wistar rats were exposed to 0.15 mg/kg, 1.5 mg/kg or 15 mg/kg DINP. We assessed the thyroid globulin antibody levels, Th1/Th2 balance, histopathological changes and caspase-3 levels in the thyroid. The data show that exposure to DINP does indeed aggravate AITD. To explore the underlying mechanisms, we examined the levels of microtubule-associated protein 1 light chain 3 B (LC3B), Sequestosome 1 (SQSTM1) and the appearance of autophagosomes or autolysosomes to assess autophagy in the thyroid. The results show that DINP can suppress normal autophagy. We found that DINP induced an exacerbation of oxidative stress and the activation of the Akt/mTOR pathway, indicating that oxidative stress and activation of mTOR may play a key role in these processes. Moreover, the activation of mTOR also promoted the expression of IL-17. Importantly, blocking oxidative stress with VE or blocking Akt/mTOR with rapamycin mitigated the exacerbation of AITD and the suppression of normal autophagy. All these results indicate that exposure to DINP, especially high doses of DINP, can aggravate oxidative stress and activate the Akt/mTOR pathway. This exposure then leads to a suppression of normal autophagy and expression of IL-17 in the thyroid, resulting in an eventual exacerbation of AITD. PMID- 30447475 TI - Seasonal variations and inhalation risk assessment of short-chain chlorinated paraffins in PM2.5 of Jinan, China. AB - Short-chain chlorinated paraffins (SCCPs) were added to the Stockholm Convention on Persistent Organic Pollutants (POPs) at the eighth meeting of the conference of the parties in 2017. As a consequence, increasing environmental attention and international regulation on SCCPs is expected in the future. Inhalation uptake of particulate matter (PM) was an important exposure pathway for POPs into the human body. In the present study, a total of eighty PM2.5 samples were collected in the four seasons of the year at an urban site (Shandong University, Jinan) in Shandong province to investigate the seasonal changes of SCCPs and their inhalation exposure risks to human health. The concentrations of SCCPs ranged from 9.80 to 105 ng m-3, with the mean value of 38.7 ng m-3. The highest concentrations of SCCPs were detected in winter, while the lowest concentrations were in summer. SCCPs concentrations were positively correlated with the mass concentrations of PM2.5 (r = 0.629, p < 0.01), and negatively correlated with the ambient temperature (r = -0.447, p < 0.01). The SCCPs congeners with 10 carbon atoms (C10 congeners) and 7 chlorine numbers (Cl7 congeners) were the predominant congeners, which contributed 35% and 37% of the total SCCPs contamination, respectively. The average inhalation exposure was estimated to be 1.75 * 10-4 mg kg-1 day-1 for adults, which is much lower than the "no observed adverse effect level" (NOAEL) of 100 mg kg-1 day-1 given by European risk assessment for SCCPs. PMID- 30447476 TI - The state of POPs in Ghana- A review on persistent organic pollutants: Environmental and human exposure. AB - Ghana is one of the top pesticide users and highest persistent organic pollutant (POP) emitters in sub-saharan Africa. Despite recent increases in published data, there is limited information on how POP concentrations have changed, post ratification of the Stockholm Convention. As a result, this review aims to address these knowledge gaps by collating available data that reported POPs in Ghanaian environmental matrices, identify spatial and temporal trends, and establish potential health risks. It is worth noting that Ghana has not developed its own regulatory standards for POPs, but adapts United States Environmental Protection Agency (USEPA) standards. Results obtained showed concentrations in excess of USEPA regulatory standards for per- and poly-fluoroalkyl sulphonates (PFASs) and dichlorodiphenyldichloroethane (DDD) in water, polychlorinated and polybrominated dibenzo-p-dioxins and furans (PCDD/Fs and PBDD/Fs) in e-waste soils, and polybrominated diphenyl ethers in aquatic organisms and dairy products. The published studies do not cover major regions nationwide. The inconsistency in methods and analytes measured, along with data scarcity in some regions, makes it challenging to identify temporal trends. However, the data did indicate decreasing concentrations of some legacy POPs in soil/sediment and aquatic organisms, with increasing concentrations of some POPs in water, fish, fruits and vegetables. Studies that performed health risks assessments were limited although the data indicated risks to e-waste workers, some farmers and vulnerable sub-populations. This review identified potential human health risks from POPs in the Ghanaian environment and the need for more consistent and widespread monitoring program. PMID- 30447477 TI - Acceptability of potential interventions to increase firearm safety among patients in VA mental health treatment. AB - OBJECTIVE: Veterans in mental health care have high rates of firearm-related suicide; reducing firearm access during high-risk periods could save lives. We assessed veteran patients' attitudes towards voluntary interventions to reduce access. METHODS: Descriptive data came from surveys mailed to random samples of veterans receiving mental health care in five geographically diverse VA facilities. Survey items inquired about the acceptability of seven voluntary health system interventions to address firearm access, ranging from lower intensity interventions that addressed safety but might not reduce access (i.e., clinician screening; distribution of gunlocks) to interventions substantially limiting access (i.e., storage of firearms offsite; gun disposal). Mailings occurred between 5/11/15 and 10/19/15; 677 of 1354 veterans (50%) returned the surveys. RESULTS: 93.2% of respondents endorsed one or more health system interventions addressing firearm access; 75.0% endorsed interventions substantially limiting access. Although veterans with household firearms were less likely to endorse interventions, fully 50.4% would personally participate in at least one intervention that substantially limited access. DISCUSSION: A majority of veterans in VA mental health care endorse voluntary health system interventions addressing firearm access during high-risk periods for suicide. Approximately half of veterans with firearms would personally participate in an intervention that substantially limited firearm access. PMID- 30447478 TI - Presence of thrombophilia and levels of coagulation factors, coagulation inhibitors and TAFI do not affect global haemostasis or bleeding phenotype in patients with haemophilia A. PMID- 30447479 TI - Bimetallic Mn and Co encased within bamboo-like N-doped carbon nanotubes as efficient oxygen reduction reaction electrocatalysts. AB - The development of oxygen reaction reduction (ORR) electrocatalysts that are low cost, highly-active and have long-term stability for use in energy conversion and storage applications such as fuel cells and metal-air batteries is very important. In this paper, a facile one-step pyrolysis method was used to prepare bamboo-like N-doped carbon nanotubes (BNCNTs) as effective ORR electrocatalysts. Manganese and cobalt salts were used as the metal precursors, and urea was the C and N source. The resulting catalysts were characterized by the scanning electron microscopy, high resolution-transmission electron microscopy, X-ray photoelectron spectroscopy, Raman microscopy and X-ray power diffraction. The BNCNTs contained Mn and Co nanoparticles that were coated with graphitic carbon. The electrochemical performances of the catalysts in alkaline media were evaluated using cyclic voltammetry, linear sweep voltammetry and chronoamperometry. The BNCNTs prepared with a Mn to Co molar ratio of 1:1 at 800 degrees C had the best catalytic activity. The reaction followed a quasi-4 electron reaction pathway with a smaller Tafel slope (57.5 mV dec-1) than that of the commercial Pt/C (72.8 mV dec-1). In addition, the limiting current density, durability and methanol crossover resistance were all superior to those of Pt/C. The above results indicate that Mn/Co-BNCNTs-800 is an active electrocatalyst with earth-abundant non-precious elements for ORR. PMID- 30447480 TI - A diversity of amoebae colonise the gills of farmed Atlantic salmon (Salmo salar) with amoebic gill disease (AGD). AB - Neoparamoeba perurans is the aetiological agent of amoebic gill disease (AGD) in salmonids, however multiple other amoeba species colonise the gills and their role in AGD is unknown. Taxonomic assessments of these accompanying amoebae on AGD-affected salmon have previously been based on gross morphology alone. The aim of the present study was to document the diversity of amoebae colonising the gills of AGD-affected farmed Atlantic salmon using a combination of morphological and sequence-based taxonomic methods. Amoebae were characterised morphologically via light microscopy and transmission electron microscopy, and by phylogenetic analyses based on the 18S rRNA gene and cytochrome oxidase subunit I (COI) gene. In addition to N. perurans, 11 other amoebozoans were isolated from the gills, and were classified within the genera Neoparamoeba, Paramoeba, Vexillifera, Pseudoparamoeba, Vannella and Nolandella. In some cases, such as Paramoeba eilhardi, this is the first time this species has been isolated from the gills of teleost fish. Furthermore, sequencing of both the 18S rRNA and COI gene revealed significant genetic variation within genera. We highlight that there is a far greater diversity of amoebae colonising AGD-affected gills than previously established. PMID- 30447481 TI - The effect of group involvement on post-disaster mental health: A longitudinal multilevel analysis. AB - Involvement in voluntary associations is a key form of social capital and plays an especially important role following disaster as a venue for coordination and decision-making for the wider community. Yet, relatively little attention has been paid to how group involvement affects mental health, at either the individual or community level. The aim of this study was to assess the impact of involvement in voluntary associations on mental health among residents of bushfire-affected communities. A longitudinal sample of 642 individuals affected by the 2009 Victorian bushfires in south-eastern Australia were surveyed in 2012 and 2014 (3- and 5-years post-disaster). A further subsample (n = 552) of residents residing continuously within 22 bushfire-affected communities were examined for community-level effects using multilevel regression methods. After adjusting for demographics, disaster exposure, and network variables, group involvement at time 1 bore a curvilinear relationship with PTSD at both time points: moderate involvement was most beneficial, with no participation, or high amounts, yielding poorer outcomes. High amounts of group involvement was likewise linked to a greater risk of major depression. Furthermore, communities with higher median levels of group involvement reported lower levels of PTSD symptoms and major depression two years later. With respect to group involvement, more is not always better. For individuals, moderation - if possible - is key. Meanwhile, community-level health benefits come when most people participate to some extent, suggesting that the distribution of involvement across the community is important. PMID- 30447482 TI - Risk of cardiac disease after adjuvant radiation therapy among breast cancer survivors. AB - PURPOSE: Adjuvant radiation therapy (RT) for breast cancer is associated with heart disease, although the impact of patient-specific factors on the interaction between cardiac risk and RT is not well-studied in cancer patients. The objective of this study is to compare acute coronary events (ACE) among the general population and women with breast cancer after adjuvant RT. Secondary analysis evaluated whether a healthy lifestyle could protect against RT-related cardiac toxicity. METHODS: The National Health Insurance Service-Health Screening Cohort (2002-2013) was used to compare ACE risks among 1015 women with breast cancer and among 8120 women without cancer who were matched according to age, comorbidities, and smoking history. The risk of developing ACE over time while accounting for competing risks from other causes of death was analyzed. RESULTS: During 6.1 +/- 3.0 years of follow-up, the 5- and 10-year cumulative incidences of ACE were 5.5% and 11.3%, respectively. The breast cancer survivors who underwent breast radiotherapy and population-based matched sample had similar risks of ACE (hazard ratio: 0.94, 95% confidence interval: 0.69-1.28). However, in the sensitivity analysis, breast cancer survivors had increased risks of ACE if they did not exercise (hazard ratio 2.74, confidence interval: 1.27-5.91) or had a disability (hazard ratio 21.9, confidence interval: 2.50-191.6). CONCLUSIONS: In this matched cohort study, the cardiac risk after adjuvant RT increased with decreasing physical activity. The long-term effect of physical activity on ACE is uncertain, but these results can increase physicians' awareness of the approaches to increase exercise participation level among women undergoing RT for breast cancer. Confirmatory studies with individual doses of cardiac radiation and quantification of physical activity and sedentary time are required for validating our results. PMID- 30447483 TI - How the visual brain detects emotional changes in facial expressions: Evidence from driven and intrinsic brain oscillations. AB - The processing of facial expressions is often studied using static pictorial cues. Recent work, however, suggests that viewing changing expressions more robustly evokes physiological responses. Here, we examined the sensitivity of steady-state visual evoked potentials and intrinsic oscillatory brain activity to transient emotional changes in facial expressions. Twenty-two participants viewed sequences of grayscale faces periodically turned on and off at a rate of 17.5 Hz, to evoke flicker steady-state visual evoked potentials (ssVEPs) in visual cortex. Each sequence began with a neutral face (flickering for 2290 msec), immediately followed by a face from the same actor (also flickering for 2290 msec) with one of four expressions (happy, angry, fearful, or another neutral expression), followed by the initially presented neutral face (flickering for 1140 msec). The amplitude of the ssVEP and the power of intrinsic brain oscillations were analyzed, comparing the four expression-change conditions. We found a transient perturbation (reduction) of the ssVEP that was more pronounced after the neutral to-angry change compared to the other conditions, at right posterior sensors. Induced alpha-band (8-13 Hz) power was reduced compared to baseline after each change. This reduction showed a central-occipital topography and was strongest in the subtlest and rarest neutral-to-neutral condition. Thus, the ssVEP indexed involvement of face-sensitive cortical areas in decoding affective expressions, whereas mid-occipital alpha power reduction reflected condition frequency rather than expression-specific processing, consistent with the role of alpha power changes in selective attention. PMID- 30447484 TI - Optimization of cloned enzyme donor immunoassay cut-offs for drugs of abuse in whole blood of drivers involved in road accidents. AB - INTRODUCTION: Immunoassay (IA) tests should be able to detect low concentrations of illegal drugs when used for the screening of drugs in drivers. False negatives should be avoided, and false positives should be reduced as far as possible. In this study, semi-quantitative results for blood samples containing illicit drugs (cannabinoids, cocaine, amphetamines/methamphetamines, opiates and methadone) obtained with cloned enzyme donor immunoassay (CEDIA), were compared with results of confirmatory analysis performed through gas chromatography-mass spectrometry (GC-MS). Screening cut-off points for each class of drugs were retrospectively optimized. METHODS: Whole blood samples from drivers involved in road accidents in the period from January 2013-December 2017 were analyzed with CEDIA (4200 samples). Confirmatory analyses were performed through (GC-MS) on: (i) all samples with screening concentrations above 1ng/ml for at least one drug (positive screening results); (ii) 800 samples with screening concentration lower than 1ng/ml (negative screening results). Recommended per se limits in relation to driving under the influence of drugs were set as fixed values. Sensitivity, specificity, positive and negative predictive values were evaluated by contingency tables and compared to ROC-analysis in order to obtain ideal screening cut-offs. RESULTS: CEDIA results were available for 4200 blood samples and 1172 positive screening results were found. Among these, 1008 confirmation analysis were obtained through GC-MS. Optimized screening cut-offs obtained through ROC analysis were as follows: 8.0ng/ml for THC; 5.5ng/ml for THC-COOH; 21.1ng/ml for cocaine; 6.9ng/ml for benzoylecgonine; 33.1ng/ml for opiates; 61.6ng/ml for amphetamines; 5.0ng/ml for methadone. Using these cut-offs, sensitivity was above 97% for THC-COOH, cocaine, benzoylecgonine, amphetamines, opiates and methadone, and 92% for THC; specificity was above 90% for cocaine, benzoylecgonine, amphetamines, opiates and methadone, 80% for THC and 89% for THC COOH; negative predictive value was above 99% for all drugs and metabolites. CONCLUSION: Previous studies have shown that CEDIA tests are useful for preliminary screening of serum and urine. Its implementation in whole blood is of primary importance for the assessment of impaired driving, since the per se limits of many European countries refer to whole blood, and preparation of the serum and/or the collection of urine is not always possible in the hospital emergency department, where blood samples are withdrawn. Our study shows that CEDIA tests on whole blood permit the definition of cut-off values with optimal sensitivity and negative predictive values for all analytes (near to 100%), including very good specificity. PMID- 30447485 TI - Is the visibility of standardized inflicted bruises improved by using an alternate ('forensic') light source? AB - AIM: To study the visibility of standardized inflicted bruises by using an alternate ('forensic') light source compared to a white light source. METHODS: Bruises were inflicted on the flexor site of the forearm (halfway in the middle) in 76 adults, by suddenly allowing a cylindrical metal object (400g) with rounded edges to drop for 1m in a vertically positioned tube. At 0.25, 1, 2, 7 and 14days after this blunt force impact, the impact site on the forearm was photographed with a white light source and subsequently with an alternate light source at 415nm. Visibility of bruises on 170 randomized photographs was assessed on a calibrated monitor by 10 forensic medical specialists (physicians and pathologists) independently in two sessions: (1) with white light source photographs, and (2) after a mean of 11days with greyscale converted alternate light source photographs. Bruise visibility was expressed as a report mark between 1 (very bad) and 10 (excellent), or as 'no visible bruise'. To determine intra-rater agreement, 10 of 170 photographs were assessed twice (untold to the assessors). In total 3600 (180*10*2) photographs were assessed. RESULTS: 39 of 73 (53%) participants who completed the study, developed a visible bruise (women more often than men, p<0.001). Inter-rater agreement between assessors was high (mean inter-class coefficient, ICC, for white light source 0.66 (SD 0.14) and for alternate light source ICC 0.73 (0.09)). Intra-rater agreement was excellent (mean ICC 0.88 (SD 0.09)). Mean report marks for bruise visibility, recorded independently by 10 assessors on 170 unique photographs per light source, were significantly higher with an alternate light source than with a white light source, at 1 and 2days after impact: 4.4 (SD 2.0) vs 3.8 (1.8) (p<0.01) and 4.9 (2.1) vs 4.5 (2.0) (p<0.05), respectively. However, these differences were small, as the mean difference (effect size) in report marks were 0.6 (0.5) and 0.4 (0.3), at 1 and 2days after impact, respectively. The other time points showed no statistical significant differences in report marks. CONCLUSIONS: Bruises after standardized blunt force impact were slightly better visible with an alternate light source than with a white light source after 1 and 2 days, but not after 0.25, 7 and 14 days. The value of using an alternate light source at 415nm to improve bruise visibility was limited in this study. PMID- 30447486 TI - Alcohol consumption assessment in a student population through combined hair analysis for ethyl glucuronide and fatty acid ethyl esters. AB - This study aimed to assess alcohol consumption in a university student population though the combined analysis of the alcohol biomarkers ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEEs) in hair samples. A total of 975 hair samples were analysed for EtG and FAEEs using liquid chromatography coupled to mass spectrometry (LC-MS/MS) and gas chromatography coupled to mass spectrometry (GC MS/MS), respectively. The results were analysed using the cut-offs proposed by the Society of Hair Testing and receiver operating characteristic (ROC) curve analysis was performed to verify the adequacy of the proposed values for the study population. Good sensitivity and specificity were obtained for both biomarkers, especially for EtG, and a correlation was found with the self reported alcohol consumption habit. In 56.3% of the abstinent, 65.8% of the moderate and 80.0% of the excessive drinking cases, self-reported alcohol consumption could be confirmed by combined alcohol biomarker analysis. Combined analysis of EtG and FAEEs in hair samples proved to be a valuable tool for the monitoring of alcohol consumption in a student population. For a feasible result interpretation, it is very important to document the use of hair products, cosmetic treatments and washing frequency, and for these to be considered during interpretation. Overall the participants were aware of their consumption pattern, however for doubtful cases and to account for academic calendars, repeated analysis of samples collected at different time frames would be advisable. PMID- 30447487 TI - Efficacy of three-dimensional cinematic rendering computed tomography images in visualizing features related to age estimation in pelvic bones. AB - Morphological changes on the surface of the pelvic bone can be used to estimate the age at death of a person. These features can be visualized using three dimensional computed tomography (3D CT) images. A newly introduced 3D CT technique, cinematic volume rendering, improves visualization of the surface of bones by integrating the effect of light on the images. The aim of this study is to evaluate the efficacy of this 3D CT technique in visualizing features related to age estimation in pelvic bones. Dry pelvic bones of 35 subjects were scanned and then 3D reconstruction of the images was performed using the cinematic rendering technique. The 3D CT images of the pubic symphyses and the auricular surfaces were interpreted by two radiologists and a forensic osteologist using age estimation features derived from the Suchey-Brooks and the Buckberry Chamberlain methods The interpretation of the dry pelvic bones was done by an expert anatomist and used as a gold standard. The percentages of correct interpretations and level of agreement in grading using 3D CT and using dry bones were high for features in the pubic symphyses including surface patterns (100%, k=1), presence of lower extremities (100%, k=1), and patterns of pubic rims (91.4%, range 87.5-100%, k=0.88). In the auricular surface of the ilium, all specimens with an apical activity were correctly interpreted (100%, k=1), but detection was moderate to poor for transverse organization (71.4%, k=0.43), macroporosity (70%, k=0.38.), and microporosity (52.9%, k=0.25). Cinematic volume rendering has a high level of efficacy in identifying age-related features on pubic symphyses, but it inadequately displays features on the auricular surface. PMID- 30447488 TI - Novel enzymology in futalosine-dependent menaquinone biosynthesis. AB - The recently discovered futalosine-dependent menaquinone biosynthesis pathway employs radical chemistry for the naphthoquinol core assembly. Mechanistic studies on this pathway have resulted in the discovery of novel reaction motifs. MqnA is the first example of a chorismate dehydratase. MqnE is the first example of a radical SAM enzyme that catalyzes the addition of the 5'-deoxyadenosyl radical to the substrate double bond rather than hydrogen atom abstraction. Both MqnE and MqnC reaction sequences involve radical additions to a benzene ring followed by formation of an aryl radical anion intermediate. The enzymology of the tailoring reactions after dihydroxynaphthoic acid formation remains to be elucidated. Since the futalosine-dependent menaquinone biosynthesis pathway is absent in humans, mechanistic studies on this pathway may promote the development of new antibiotics. PMID- 30447489 TI - Intra-individual variability in neurocognitive function in schizophrenia: relationships with the corpus callosum. AB - Patients with schizophrenia not only have impairments in neurological function, but also have instability and variability in neurocognitive function. However, previous researchers have not fully studied the relationships between dispersion across multiple neurocognitive domains and white matter (WM) structures of the brain. This study focuses on intra-individual variability (IIV) in patients with schizophrenia and its relationship with WM integrity of the corpus callosum (CC). Thirty-eight patients with schizophrenia were enrolled in the study. All subjects underwent assessments of neurocognitive function using the Korean-Wechsler Adult Intelligence Scale-Revised (K-WAIS-R) and the severity of clinical symptoms using the Positive and Negative Syndrome Scale (PANSS). IIV across subtests of the K WAIS-R was calculated using the Holtzer's equation. Tract-based spatial statistics were used to analyze diffusion tensor images. In subjects with schizophrenia, a negative correlation was found between IIV in performance intelligence quotient (PIQ) and fractional anisotropy (FA) values in the genu of the CC. In addition, FA values of the same region were negatively correlated with the total and subscale scores of positive symptoms and general psychopathology from the PANSS. Our findings suggest that the genu of the CC may play an important role in IIV in PIQ and symptomatology in patients with schizophrenia. PMID- 30447490 TI - Vehicle registration year, age, and weight - Untangling the effects on crash risk. AB - The aim of the present study was to investigate the effects of passenger cars' first year of registration, weight, and age on the number of killed or seriously injured (KSI) car drivers, pedestrians, and cyclists. Poisson regression models were developed of injury crashes involving passenger cars in Norway in 2000-2016, with the following predictor variables: The cars' first year of registration and weight, either crash year or car age, the drivers age and gender, and in models for car-car collisions the crash partner cars' weight and either registration year or age. The results show that there are fewer KSI car drivers in more recent, newer, and heavier cars. It is estimated that the number of KSI car drivers in all types of crashes on average decreases by 6.7% for each consecutive registration year (-7.2% in car-car collisions and -6.0% in single vehicle crashes), increases by 3.7% for each consecutive year of age (+2.1% in car-car collisions and +5.3% in single vehicle crashes), and decreases by 4.9% on average for each 100 kg weight increase (-11.1% in car-car collisions and -2.3% in single vehicle crashes). In car-car collisions there are fewer KSI car drivers when the crash partner car is more recent (-4.4% for each consecutive registration year), and more KSI car drivers when the crash partner car is older (+4.1% for each consecutive year of age), or heavier (+6.8% per 100 kg weight increase). In collisions with pedestrians or cyclists, there are fewer KSI pedestrians/cyclists when the car is more recent (-3.3% per consecutive registration year) and more KSI pedestrians/cyclists when the car is heavier (+4.6% per 100 kg weight increase). Due to the large effects of safety improvements in more recent cars, an increased renewal rate in the passenger car fleet can be expected to contribute to large safety improvements. The increasing weight of more recent cars may contribute to improved safety for those who drive heavier cars, but overall the effect of increasing weight is probably small or even negative because heavier vehicles impose greater risk on other car drivers, pedestrians, and cyclists. PMID- 30447491 TI - Tomographic analysis of siliceous particulates in Australian turpentine wood (Syncarpia glomulifera) through X-ray micro-computed tomography. AB - X-ray micro-computed tomography (XMUCT) allows a non-destructive and three dimensional (3D) study of otherwise complex and opaque wood tissues. In wood research, XMUCT datasets are highly useful for the qualitative and quantitative examination of wood structures. In this study, XMUCT was introduced and tested for examining X-ray dense silica particles in the Australian turpentine wood (Syncarpia glomulifera). It was possible to three-dimensionally visualize and numerically quantify silica particles. Numerical analysis was performed to scrutinize the size and content of silica particles. In comparative studies of silica size through scanning electron microscopy and silica content through thermo-gravimetric analysis after acid digestion of ash, our findings pointed out that XMUCT is indeed a powerful tool for examining silica particles in wood; because XMUCT enables a simultaneous visualization and quantification of the silica particles in 3D without being destructive. Despite these benefits, comparative examination through scanning electron microscopy and energy dispersive X-ray spectroscopy is necessary to verify silica particles in tomographic images. XMUCT technology might further aid in probing the biological and ecological function of silica in silica-bearing wood species. PMID- 30447492 TI - An international survey of the comprehensiveness of the McKenzie classification system and the proportions of classifications and directional preferences in patients with spinal pain. AB - BACKGROUND: Classification of spinal pain has been a key goal identified in the research. However it is not clear if existing classification systems are comprehensive. OBJECTIVE: To examine the comprehensiveness and distribution of classifications within the McKenzie classification system (MDT), and the directional preference in consecutive patients with spine pain. STUDY DESIGN: Prospective, observational study. METHODS: Clinicians with a Diploma in MDT provided data on patients that they had assessed, classified, managed, and then confirmed their classification at discharge. They provided data on the spinal area, the MDT classification, and the loading strategy used in management. RESULTS: Fifty-four clinicians from at least 15 different countries provided data on 750 patients: lumbar 64.8%, cervical 29.6%, thoracic 5.6%. The distribution of classifications was as follows: Derangement 75.4%, OTHER 22.8%, Dysfunction 1.7%, Postural syndrome 0.1%. In Derangements 82.5% had a directional preference for extension, 12.9% for lateral forces, and 4.6% for flexion. Those patients classified as one of the OTHER subgroups were given specific classifications. CONCLUSION: Derangement was the most common classification and extension was by far the most common directional preference. A substantial proportion were classified as OTHER subgroups, for whom management is less straightforward. PMID- 30447493 TI - Cognitive-behavior therapy for children and adolescents with anxiety disorders: A meta-analysis of secondary outcomes. AB - Anxiety-focused cognitive-behavioral therapy (CBT) effectively reduces anxiety in children and adolescents. An important remaining question is to what extent anxiety-focused CBT also affects broader outcome domains. Additionally, it remains unclear whether parental involvement in treatment may have impact on domains other than anxiety. A meta-analysis (nstudies = 42, nparticipants = 3239) of the effects of CBT and the moderating role of parental involvement was conducted on the following major secondary outcomes: depressive symptoms, externalizing behaviors, general functioning, and social competence. Randomized controlled trials were included when having a waitlist or active control condition, a youth sample (aged<19) with a primary anxiety disorder diagnosis receiving anxiety-focused CBT and reported secondary outcomes. Controlled effect sizes (Cohen's d) were calculated employing random effect models. CBT had a large effect on general functioning (-1.25[-1.59;0.90], nstudies = 17), a small to moderate effect on depressive symptoms (-0.31[-0.41;-0.22], nstudies = 31) and a small effect on externalizing behaviors (-0.23[-0.38;-0.09], nstudies = 12) from pre-to post-treatment. Effects remained or even further improved at follow-up. Social competence only improved at follow-up (nstudies = 6). Concluding, anxiety focused CBT has a positive effect on broader outcome domains than just anxiety. Higher parental involvement seemed to have beneficial effects at follow-up, with improvements in general functioning and comorbid symptoms. PMID- 30447494 TI - Promoter methylation and expression analysis of Bvh gene in bulls with varying semen motility parameters. AB - Crossbreds of low-producing indigenous cattle and high-producing exotic dairy bulls (Holstein Friesian and Jersey) have contributed in ensuring that India continues to be the world's top milk-producing country. However, subfertility observed in crossbred male progenies has been a major obstacle in exploitation of heterosis due to crossbreeding. There is sufficient scientific evidence in support of genetic and epigenetic regulation of key physiological processes including spermatogenesis. Bovine Vasa Homology (Bvh) is considered a molecular marker for the study of gametogenesis. Significant negative correlation between DNA methylation and gene expression has been reported in cattle-yaks hybrids and their parents. The present study analyzed promoter methylation status and expression profile of Bvh gene in spermatozoa from exotic Holstein Friesian cattle, indigenous Sahiwal cattle and their crossbreds with varying semen motility parameters. The degree of methylation of the Bvh promoter region was significantly higher in poor motility crossbred bulls (13.3%) as compared to good motility crossbreds (5.3%), Sahiwal (3%) and Holstein Friesian bulls (1%) (P < 0.05). Gene expression analysis revealed significantly higher mRNA abundance of Bvh in purebreds (Holstein Friesian and Sahiwal) as compared to crossbred counterparts (P < 0.001). Inverse correlation observed in this study between promoter methylation and gene expression of Bvh gene in spermatozoa from crossbred bulls with poor motility phenotype as compared to purebred parents provides an important insight into understanding the graded fertility of crossbred bulls. PMID- 30447495 TI - Effects of icariin on ovarian function in d-galactose-induced aging mice. AB - In this study, effects of icariin (Ica) on were examined in a mouse model of d galactose (D-gal)-induced ovarian aging. Kunming white mice were divided into three groups: aging group induced with D-gal, experiment group treated with Ica at low (50 mg/kg), middle (100 mg/kg) and high (200 mg/kg) concentrations, and control group with no treatment. Ovarian histomorphology, serum FSH, LH and E2 levels, and reproductive function were compared among the groups. Ovarian expression of Amh, Bax and Bcl-2 was examined by qPCR and western blotting. Our results showed that diameters of secondary and tertiary follicles were significantly reduced in the aging group when compared with control group (P < 0.01), and were restored to normal in Ica 100 and Ica 200 treatment groups. The diameter of atretic follicles was significantly smaller in the aging group compared with control group and Ica 200 treatment group (P < 0.05). The proportion of secondary and atretic follicles was higher in the aging group compared with control group, Ica 100 and 200 treatment groups, whereas the proportion of tertiary and mature follicles was reduced in the aging group versus control, Ica 100 and 200 groups. The aging group lacked mature follicles, whereas Ica treatment induced mature follicle development. Primary and secondary follicles exhibited similar theca cell numbers and theca interna and externa cell layers in all groups examined, whereas theca interna and externa cell layers were decreased and increased, respectively, in tertiary follicles of aging group compared with control and I 200 groups. In the aging group, FSH and LH levels were significantly higher than those in control and Ica 200 groups (P < 0.05), and the E2 level was significantly reduced compared with control (P < 0.01), Ica 200 (P < 0.01), and Ica 100 (P < 0.05) groups. Serum hormone levels were equivalent in the control, Ica 100 and Ica 200 groups. The pregnancy rate was reduced in the aging group compared with other groups. The average litter size per birth, birth litter weight, and weaning weight of litters were all significantly lower in the aging group compared with control, Ica 100 and 200 groups (P < 0.05). The ovarian expression of AMH and Bcl-2 mRNA was significantly reduced in the aging group compared with those in control and Ica-treated groups (P < 0.01). In contrast, Bax expression was significantly higher in the aging group compared with all other groups (P < 0.01), and the Bcl-2/Bax ratio was markedly reduced in aging group compared with control, Ica 100 and 200 groups (P < 0.01), and Ica 50 group (P < 0.05). Ovarian expression of AMH protein was elevated in the Ica 100 group compared with the aging, control and Ica 50 groups (P < 0.01) and Ica 200 group (P < 0.05). Ovarian Bcl-2 protein levels and the Bcl 2/Bax ratio were significantly higher in the Ica 100 group than those in the Ica 50, 200 and aging groups (P < 0.05), and were similar or reduced (P < 0.05), respectively, compared to those in control group. Ovarian Bax expression was similar in each group. These findings suggest that Ica can improve ovarian follicular development, inhibit follicular atresia, decrease FSH and LH levels and increase E2, upregulate ovarian AMH expression and increase the Bcl-2/Bax ratio in aging mice. Therefore, Ica can partially restore ovarian function of aging mice and enhance their fertility. Optimal reproductive effects were obtained with the Ica 100 group. PMID- 30447496 TI - Impact of supplementation with long-acting progesterone on gestational loss in Nelore females submitted to TAI. AB - The goal of this study was to evaluate the effect of long-acting progesterone supplementation on pregnancy rates and gestational losses in Nelore females (Bos taurus indicus) submitted to Timed Artificial Insemination (TAI). Ovulations of multiparous (n = 534), primiparous (n = 117) and nulliparous (n = 81) Nelore females were synchronized for TAI and the day of insemination was considered D0. After TAI, the animals were allocated into three groups. Two groups received 150 mg of long acting injectable progesterone (P4) in a single dose, 5 (D = 5) or 11 (D = 11) days after TAI, resulting in the following treatments: 1) Group P4 - D5 (n = 235); 2) Group P4 - D11 (n = 245); and 3) Control Group (n = 252). The animals in the control group did not receive any supplementation. Pregnancy was checked by ultrasonography, 30 days after the TAI. The gestational losses were evaluated at two different periods: 1) from 30 to 60 days, and 2) from 60 to 90 days. The pregnancy rate and the gestational losses as a function of the treatments were tested by the non-parametric binomial test with 5% significance level. The pregnancy rates were different between the groups P4 - D5 and Control (47 and 39%, respectively) (P < 0.05), but no difference was observed in relation to the P4 - D11 group. There was a difference in gestational losses from 30 to 60 days and total losses between the groups treated with P4 on the fifth day and eleventh day after TAI in relation to the control group (P = 0.0173; P = 0.0454), but no difference was observed between the treatments in relation to the losses between 60 and 90 days (P >= 0.0578). Among the animals that were cycling at the beginning of the protocol, the groups supplemented with progesterone at day 5 or 11 after insemination had gestational losses significantly lower (P = 0.04) than the control group (P4 - D5 = 2%; P4 - D11 = 2%, control = 14%). The animals in anestrous that received supplementation 5 days after TAI had lower gestational losses (P = 0.049) compared with the other groups (P4 - D5 = 3%, P4 - D11 = 7% Control = 10%). Under the conditions of this study, the use of long-acting injectable progesterone 5 days after TAI in Nelore females increased the pregnancy rates, but when supplemented 11 days after TAI, it did not have the same effect. Also, when used 5 days after TAI, it significantly decreased gestational losses on both anestrous and cycling animals. Therefore, it may be an interesting alternative to increase reproductive and productive efficiencies. PMID- 30447497 TI - Temporal changes in temperature-related mortality in Spain and effect of the implementation of a Heat Health Prevention Plan. AB - Exposure to extreme ambient temperatures has been widely described to increase mortality. Exploring changes in susceptibility to temperatures over time can provide useful information for policy planning and can provide insights on the effectiveness of health preventive plans. The aims of this study were i) to compare changes in temperature-related mortality in Spain during a 20-year period and ii) to assess whether the number of actions implemented in each region as part of a Heat Health Prevention Plan (HHPP) was associated with the temporal changes in heat-related mortality. Daily counts of deaths and daily maximum temperature were obtained for each Spanish province (1993-2013). We used time varying distributed lag non-linear models to estimate the relationship between temperature and mortality. We compared the risk of death due to extreme temperatures (cold and heat) in the two periods (1993-2002 and 2004-2013), assuming a constant temperature distribution and different temperature-mortality function. Results were reported as mortality attributable fraction (%) (AF). Overall, there was a decrease in mortality attributable to temperature in period 2, more remarkable for extreme cold (from 1.01% to 0.52%), while for moderate heat there was an increase (from 0.38% to 1.21%). Provinces with more actions implemented in their HHPP showed stronger decreases in mortality attributable to extreme heat. Other variables (e.g. average temperature) could explain this association. The highest mortality-AF reductions were detected among the elderly, in mortality for cardiovascular causes and in towns with high socioeconomic vulnerability. Our results suggest that the implementation of the Spanish HHPP could help reduce heat-related mortality. PMID- 30447498 TI - Serum perfluoroalkyl substances (PFAS) and risk of asthma and various allergies in adolescents. The Tromso study Fit Futures in Northern Norway. AB - BACKGROUND: Exposure to environmental pollutants may contribute to the development of asthma and other allergies. The aim of this study was to investigate possible associations between asthma and other allergies with exposure to perfluoroalkyl substances (PFASs) in adolescents from the Arctic region of Norway. METHODS: The Tromso study Fit Futures 1 (TFF1) and 3-year follow-up Fit Futures 2 study (TFF2) included 675 adolescents that completed a questionnaire about health conditions and underwent a clinical examination with blood tests and fractional nitric oxide (FeNO) measurement. Serum concentrations of 18 PFASs were measured by UHPLC-MS/MS method. RESULTS: Total PFASs (SigmaPFAS) serum concentration over 4th quartile was positively associated with asthma in the TFF1 (OR 3.35 (95% CI 1.54-7.29), p = 0.002). Total perfluorooctane sulfonate (SigmaPFOS), linear PFOS (linPFOS), linear perfluorohexane sulfonate (linPFHxS) concentrations over 4th quartiles were associated with 2 times higher odds of asthma in the TFF1. The positive associations between SigmaPFAS, SigmaPFOS, linPFOS and asthma remained statistically significant in the TFF2. SigmaPFAS and linPFHxS concentrations over 3rd tertiles were associated with positive marker of eosinophilic airways inflammation FeNO> 25 ppb. Concentrations of SigmaPFOS and linPFOS over 3rd quartiles were positively associated with self-reported nickel allergy (OR 2.25 (95% CI 1.17-4.35) p = 0.016 and OR 2.53 (95% CI 1.30-4.90) p = 0.006, respectively). Allergic rhinitis, self-reported pollen allergy, food allergy and atopic eczema were not associated with PFASs concentrations. CONCLUSIONS: This study of Norwegian adolescents showed a positive association between several PFASs and asthma, as well as between PFOS and nickel allergy. PMID- 30447499 TI - Predictors of urinary phthalate biomarker concentrations in postmenopausal women. AB - BACKGROUND: Phthalates are ubiquitous endocrine disrupting chemicals present in a wide variety of consumer products. However, the personal characteristics associated with phthalate exposure are unclear. OBJECTIVES: We sought to describe personal, behavioral, and reproductive characteristics associated with phthalate metabolite concentrations in an ongoing study nested within the Women's Health Initiative (WHI). MATERIALS AND METHODS: We measured thirteen phthalate metabolites in two or three archived urine samples collected in 1993-2001 from each of 1257 WHI participants (2991 observations). We fit multivariable generalized estimating equation models to predict urinary biomarker concentrations from personal, behavioral, and reproductive characteristics. RESULTS: Older age was predictive of lower concentrations of monobenzyl phthalate (MBzP), mono-carboxyoctyl phthalate (MCOP), mono-3-carboxypropyl phthalate (MCPP), and the sum of di-n-butyl phthalate metabolites (SigmaDBP). Phthalate metabolite concentrations varied by race/region, with generally higher concentrations observed among non-Whites and women from the West region. Higher neighborhood socioeconomic status predicted lower MBzP concentrations, and higher education predicted lower monoethyl phthalate (MEP) and higher concentrations of the sum of metabolites of di-isobutyl phthalate (SigmaDiBP). Overweight/obesity predicted higher MBzP, MCOP, monocarboxynonyl phthalate (MCNP), MCPP, and the sum of metabolites of di(2-ethylhexyl) phthalate (SigmaDEHP) and lower MEP concentrations. Alcohol consumption predicted higher concentrations of MEP and SigmaDBP, while current smokers had higher SigmaDBP concentrations. Better diet quality as assessed by Healthy Eating Index 2005 scores predicted lower concentrations of MBzP, SigmaDiBP, and SigmaDEHP. CONCLUSION: Factors predictive of lower biomarker concentrations included increased age and healthy behaviors (e.g. lower alcohol intake, lower body mass index, not smoking, higher quality diet, and moderate physical activity). Racial group (generally higher among non Whites) and geographic regions (generally higher in Northeast and West compared to South regions) also were predictive of phthalate biomarker concentrations. PMID- 30447500 TI - The effect of dietary supplementation of low crude protein on intestinal morphology in pigs. AB - To explore the effects of reducing the Cp levels on intestinal barrier function, low Cp (LP) and NRC standard Cp (NP) diets were fed to pigs from 45 to 160 days, and in vitro experiments were performed using monolayers of IPEC-J2 cells. The number of goblet cells, expression of proteins related to cell junction, amino acid transport, glucose transport, transepithelial electrical resistance (TEER), dextran permeability, and IL-6 secretion level were detected in pigs. The results demonstrated that a moderate reduction of Cp levels did not affect intestinal morphology, as demonstrated by a normal villi height, crypt depth and normal numbers of goblet cells. The maintenance of the intestinal structure obtained with LP was also confirmed by stable mRNA expression levels of muc2 and E cadherin in the jejunum. We also found that LP did not affect the protein expression of cationic amino acid transporter 1 (CAT-1) and alanine serine cysteine transporter 1 (ASCT1) from 45 to 160 days. Moreover, the excitatory amino acid transporter 3 (EAAT3), sodium-glucose cotransporter 1 (SGLT1) and glucose transporter (GLUT2) protein expression levels in the jejunum were significantly increased at a certain age during the rearing period. Furthermore, we also demonstrated that a reduction in protein concentration up to 15% in the cultural medium of IPEC-J2 cells did not impact the mucosal barrier function. This study demonstrated that a moderate reduction of the protein level did not affect intestinal mucosal barrier function and morphology in the jejunum. PMID- 30447501 TI - Identification of bovine tuberculosis biomarkers to detect tuberculin skin test and IFNgamma release assay false negative cattle. AB - Bovine tuberculosis (bTB) is an important animal and zoonotic disease, which causes severe economic losses. The main focus of this study was to assess the predictive power of previously identified biomarkers of bTB in infected animals that were negative to the tuberculin skin test (TST). We studied 16 animals with bTB, in which the disease was confirmed by necropsy, and 16 healthy animals. The level of expression of ten biomarkers (CXCL9, THBS1, MMP9, IL-22, CXCL10, IFNgamma, IL-17, FYVE, CD14, IL-1R) was evaluated by RT-qPCR upon stimulation or not of peripheral blood mononuclear cells with PPDb (purified protein derivative of bovine tuberculin). In this assay, CXCL9, THBS1, MMP9, IL-22 and IFNgamma changed their expression level depending on the bTB status. In addition, we evaluated different biomarker candidates simultaneously to infer the animal condition. By performing an analysis with classification trees, we found that the sturdiest combination was IL-22, IFNgamma and IL-1R. On the other hand, CXCL10, IFNgamma and IL-22's expression distinguished between bTB positive animals that were negative to TST (TST false negative animals) and the bTB negative groups. Thus, these biomarkers are promising candidates to be tested as an ancillary diagnostic assay. In addition, the expression of CXCL10 and IL-22 exhibited also significant differences between the bTB positive animals that were undetectable by IFNgamma release assay (IGRA) and TST tests (TST and IGRA false negative animals) and the bTB negative groups. Therefore, CXCL10 and IL-22 constitute candidate biomarkers that could complement the two most widely used diagnostic tests. PMID- 30447502 TI - Child abuse in Pakistan: A qualitative study of knowledge, attitudes and practice amongst health professionals. AB - Child abuse is a global problem and pervades all cultures and socio-economic strata. The effects can be profound and life altering for victims. There is substantial literature from high income countries about signs of abuse, but a dearth of data from low and middle income countries like Pakistan. Healthcare professionals (HCP) are ideally placed to detect abuse, but, to inform interventions, an understanding of their experiences, training needs and cultural beliefs is needed. This study aimed to: (1) Explore the challenges that HCP face when managing cases of abuse; (2) Explore cultural beliefs and understand how these shape practice and (3) Identify training needs. A qualitative study using a phenomenological design was conducted. In-depth interviews were conducted with doctors, nurses and security staff in the emergency department of a large private hospital in Pakistan (n = 15). Interviews were undertaken in Urdu, translated into English and analysed using an inductive thematic approach. Multiple challenges were identified. The process of referral to legal services was poorly understood and further training and guidelines was suggested by participants. As the legal system in Pakistan does not allow HCP to keep potentially abused patients in their custody, they felt restricted in their ability to advocate and concerned about the safety of both the identified children and themselves. HCP have potential to detect abuse early; however, in Pakistan there are numerous challenges. HCP require support through training, as well as clear institutional frameworks and legal support to undertake this role. PMID- 30447503 TI - Professionals' preferences and experiences with inter-organizational consultation to assess suspicions of child abuse and neglect. AB - This study addresses the following questions in cases of suspected child abuse and neglect (CAN) in children up to four years of age: 1) How many professionals intend to seek inter-organizational consultation? 2) What types of organizations do professionals prefer to consult? and 3) What factors can be identified as facilitator(s) or barrier(s) regarding inter-organizational consultation, based on professionals' experiences? Professionals working with children in 101 organizations in a medium-sized Dutch city were invited to fill in an online questionnaire. The questionnaire included a vignette about a suspected case. Quantitative, qualitative, and social network analysis approaches were used to analyze the data. Seventy-eight questionnaires were available for analysis. Fifty five respondents (71%) intended to seek inter-organizational consultation. Ten different organization types were mentioned. The most frequently mentioned organization was preventive child healthcare. In total, 82 text fragments from 39 participants were available to analyze barriers and facilitators to inter organizational consultation, 60 fragments that entailed a facilitator and 22 fragments that entailed a barrier. The text fragments were subdivided into twelve factors. The three factors that were most often identified as a facilitator were 'support', 'undertaking action', and 'regard'. Barriers were found in relation to all twelve factors. No specific barrier(s) stood out. This study demonstrated that most professionals are inclined to seek inter-organizational consultation when they suspect CAN. They are especially likely to seek consultation from preventive child health care organizations. Their experiences mainly revealed facilitators and few barriers. The implications for research and practice are also discussed. PMID- 30447504 TI - Factor analysis and predictive validity of the Early Risks of Physical Abuse and Neglect Scale (ERPANS): A prospective study in Dutch public youth healthcare. AB - Early detection of child abuse risk factors in families of new-born babies is an important task of the public youth health care system in the Netherlands. The Early Risks of Physical Abuse and Neglect Scale (ERPANS) was originally developed in Belgium as an observation scale for public child healthcare nurses. The present longitudinal study is an independent prospective validation of the ERPANS in a Dutch community sample (N = 1257) of families with a new-born. Results showed a commonality of underlying subsets of items belonging to the 'Disturbed parent-child relationship' and 'Psychological problems' factors, but the factor 'Communication problems' of the original ERPANS could not be replicated. We found that parental psychological problems were a significant predictor of family problems, including involvement of child protection authorities, at an average follow-up of 22 months. Parents who reported feeling unloved by their own parents were at higher risk of reports of serious concern to child protection authorities at 22 months after birth. These findings support the utility of at least a subset of the ERPANS items as a screening tool for child abuse risk in preventive public youth health care for new-born babies. Our research adds to a growing body of evidence which points to the importance of parental mental health problems and adverse childhood experiences as precursors to child abuse risk. PMID- 30447505 TI - Monolinguals and bilinguals disengage attention differently following conflict and errors: Evidence from ERPs. AB - Monolingual and bilingual young adults performed a task-switching experiment while EEG was recorded to investigate how bilingualism affects cognitive control following conflict. Participants were given pure blocks composed of three intermixed tasks, each consisting of univalent trials in which they responded to one feature of the stimulus - color, shape, or size. In the crucial conflict block, an irrelevant feature was added to one of the tasks, creating bivalent trials that included conflict. Behaviorally, all participants slowed responses to univalent trials that followed conflict, reflecting the post-conflict slowing effect. Electrophysiologically, monolinguals displayed longer-lasting post conflict ERP effects and showed larger ERN amplitudes following responses than bilinguals, amplitudes that were associated with adjustments in response times. The interpretation is that bilinguals disengage attention following conflict from misleading stimuli or error responses more rapidly than do monolinguals. PMID- 30447506 TI - Effects of intermittent theta burst stimulation applied to the left dorsolateral prefrontal cortex on empathy and impulsivity in healthy adult males. AB - Impulsivity and empathy are clinically relevant multi-dimensional concepts. Existing evidence suggests the left dorsolateral prefrontal cortex (LDLPFC) plays a crucial role in impulsivity and empathy. However, the neuromodulation effect of excitatory repetitive transcranial magnetic stimulation at the LDLPFC is insufficiently explored in the current literature. To address this important gap in the literature, we aimed to examine the effects of intermittent theta burst stimulation (iTBS) at the LDLPFC on impulsivity and empathy. A single-blind sham controlled randomised crossover trial involving twenty-three healthy male adults was conducted. The iTBS protocol delivered 1800 pulses to the LDLPFC at 80% of the motor threshold in each condition. Trait impulsivity and empathy were measured at baseline using the Barrett Impulsiveness Scale and UPPS-P Impulsiveness Scale. The Reading the Mind in the Eyes Test, Information Sampling Task, and Adjusting Amount Task serving as behavioural measures of empathy, cognitive and temporal impulsivity respectively were administered before and after iTBS sessions. No significant changes were found on any of the measures after iTBS at the LDLPFC compared to the sham stimulation. Neuromodulation at the LDLPFC using iTBS may not alter cognitive empathy and temporal and cognitive impulsivity. Further research is required using amended protocols in a large scaled sample. PMID- 30447507 TI - Function first: classifying cell types and circuits of the retina. AB - Cell type classification has been a major part of retina research for over one hundred years. In recent years, the ability to sample large populations of retinal cells has accelerated cell type classification based on different criteria like genetics, morphology, function, and circuitry. For example, recent work includes bipolar and retinal ganglion cell classifications based on single cell transcriptomes, large-scale electron microscopy reconstruction, and population-level functional imaging. With comprehensive descriptions of several retinal cell classes now within reach, it is important to reflect on the priority of these different criteria to create an accurate and useful classification. Here, we argue that functional information about retinal cells should be prioritized over other criteria when addressing questions of visual function because this criterion provides the most meaningful information about how the retina works. PMID- 30447508 TI - Adjunctive second-generation antipsychotics for specific symptom domains of schizophrenia resistant to clozapine: A meta-analysis. AB - A fair amount of subjects with schizophrenia do not respond to clozapine and are defined 'ultra-resistant'. In this systematic review and meta-analysis, we tested the efficacy of adjunctive second-generation antipsychotics (SGAs) for main symptom domains (positive, negative, and depressive symptoms) in individuals with clozapine-resistant schizophrenia. We searched main electronic databases till December 2017. We included twelve double-blind, randomized, placebo-controlled trials (RCTs), evaluating the efficacy of SGAs for clozapine non/partial responders. We did not find any difference between SGAs and placebo (standardized mean difference, SMD = -0.21; p = 0.170; I2 = 68.0%) in improving positive symptoms. The effect size varied according to RCT duration (p = 0.025) and assessment methods (p = 0.016). Low-moderate effects of SGAs on both negative (SMD = -0.38; p = 0.005; I2 = 62.7%) and depressive symptoms (SMD = -0.35; p = 0.003; I2 = 4.9%), were estimated. In sum, our meta-analysis highlights the lack of efficacy of SGAs as add-on treatment for positive symptoms in clozapine resistant schizophrenia. A small benefit of SGAs was estimated for both negative and depressive symptoms. Further RCTs are needed to establish efficacy and tolerability of SGAs or other augmentation strategies for different symptoms of clozapine-resistant schizophrenia. PMID- 30447509 TI - Greater risk for frequent marijuana use and problems among young adult marijuana users with a medical marijuana card. AB - BACKGROUND: This study compared young adults with and without a medical marijuana (MM) recommendation from a provider ("MM card") on their developmental trajectories of frequent marijuana use and marijuana-related problems in young adulthood. METHODS: The analytic sample consists of young adult past month marijuana users (N = 671) who were part of a larger, diverse, and predominantly California cohort. Analyses are based on data from seven surveys completed from ages 13-19. RESULTS: At age 19, 28% of participants reported having an MM card to legally purchase marijuana from an MM dispensary. A multiple group latent growth model indicated that young adults who had an MM card showed steeper increases in frequent marijuana use (i.e., 20-30 days of use in the past month) from ages 13 19 compared to young adults who did not have an MM card. Logistic regression models that matched MM cardholders and non-MM cardholders on individual sociodemographic characteristics found that MM cardholders were more likely to report marijuana negative consequences, selling marijuana/hashish, and driving under the influence of marijuana in the past year. In addition, MM cardholders were more likely to have tried cutting down or quitting in the past 3-months. CONCLUSIONS: Among young adult marijuana users, those with an MM card had a higher risk profile for marijuana use and related problems compared to those without an MM card. Given expanding state legalization of MM, this issue warrants further attention. PMID- 30447510 TI - A randomized controlled trial and economic evaluation of the Parents Under Pressure program for parents in substance abuse treatment. AB - BACKGROUND: There is growing interest in the provision of parenting support to substance misusing parents. METHODS: This pragmatic, multi-center randomized controlled trial compared an intensive one-to-one parenting program (Parents under Pressure, PuP) with Treatment as Usual (TAU) in the UK. Parents were engaged in community-based substance misuse services and were primary caregivers of children less than 2.5 years of age. The primary outcome was child abuse potential, and secondary outcomes included measures of parental emotional regulation assessed at baseline, 6 and 12-months. A prospective economic evaluation was also conducted. RESULTS: Of 127 eligible parents, 115 met the inclusion criteria, and subsequently parents were randomly assigned to receive PuP (n = 48) or TAU (n = 52). Child abuse potential was significantly improved in those receiving the PuP program while those in TAU showed a deterioration across time in both intent-to-treat (p < 0.03) and per-protocol analyses (p < 0.01). There was also significant reliable change (recovery/improvement) in 30.6% of the PuP group compared with 10.3% of the TAU group (p < 0.02), and deterioration in 3% compared with 18% (p < 0.02). The probability that the program is cost effective was approximately 51.8% if decision-makers are willing to pay L1000 for a unit improvement in the primary outcome, increasing to 98.0% at a L20,000 cost effectiveness threshold for this measure. CONCLUSIONS: Up to one-third of substance dependent parents of children under 3-years of age can be supported to improve their parenting, using a modular, one-to-one parenting program. Further research is needed. PMID- 30447511 TI - Significance of reduced number of cigarettes smoked after release from smoke-free prisons. PMID- 30447512 TI - Use of the Fagerstrom test to assess differences in the degree of nicotine dependence in smokers from five ethnic groups: The HELIUS study. AB - BACKGROUND: The prevalence of smoking varies across ethnic groups in developed countries, but little is known about ethnic variations in specific aspects of nicotine dependence (ND). We conducted item-response analyses in current smokers to compare ND factors across five ethnic groups. METHODS: Data were obtained from a population-based, multi-ethnic cohort study conducted in the Netherlands. The Fagerstrom Test for Nicotine Dependence (FTND) was assessed in 1147 Dutch, 991 South-Asian Surinamese, 1408 African Surinamese, 1396 Turkish, and 584 Moroccan smokers (N = 5526). We tested whether the factorial structure of the FTND was invariant across ethnic groups using a multi-group confirmatory factor analysis. FTND item and total scores and factor means were compared across groups. RESULTS: The two-factor model representing "morning smoking" and "smoking patterns" provided an adequate fit. The items "Cigarettes smoked daily" and "Time until first cigarette" showed differential item functioning (DIF) as a function of ethnicity. Three out of four ethnic minority groups scored significantly higher on both factors compared to the Dutch origin group (all p < 0.001) before and after taking DIF into account, while the African Surinamese scored higher only on "morning smoking" when DIF was accounted for. DISCUSSION: The factor structure of the FTND is not measurement invariant across ethnic groups in this population based sample. Accounting for DIF affecting the nicotine dependence factor scores, although South-Asian Surinamese, Turkish, and Moroccan groups showed higher levels of dependence than the Dutch origin group, genetic as well as environmental factors may account for the observed differences. PMID- 30447513 TI - Perceptions of the harm, addictiveness, and smoking cessation effectiveness of e cigarettes among Australian young adults. AB - An extensive body of evidence indicates that e-cigarette use is highest among young adults, prompting concerns about the potential renormalization of smoking behaviors in a population segment that is particularly vulnerable to tobacco smoking initiation. Increasing levels of e-cigarette use among young adults are likely a reflection of favorable beliefs about the benefits and risks associated with use, but research assessing perceptions of e-cigarettes in this population segment is limited. The aim of the present study was to assess young adults' perceptions of (i) the absolute and relative harm associated with e-cigarette use and (ii) the efficacy of these devices for smoking cessation. In a sample of 1116 Australian 18 to 25 year olds, three-quarters believed e-cigarettes have some level of harm (72%), just over half believed them to be addictive (57%), and substantial minorities reported that they did not know whether these products are harmful (20%) or addictive (34%). Two-fifths believed e-cigarettes are effective at helping people quit smoking (42%). Differences were observed by smoking status and e-cigarette user status on several variables, with a general trend of more positive perceptions towards e-cigarettes among smokers and users, particularly in relation to cessation efficacy. Results suggest that a substantial minority of young adults are unaware of the harms that may be associated with e-cigarettes, underscoring the importance of public health efforts that aim to provide accurate information about these devices. PMID- 30447514 TI - Relapse after inpatient substance use treatment: A prospective cohort study among users of illicit substances. AB - AIMS: The main aim was to investigate the relative roles of mental distress and intrinsic motivation for relapse after inpatient substance use disorder (SUD) treatment, while adjusting for demographics and treatment variables. METHODS: The study is based on a prospective multicenter study with a baseline gross sample of 607 patients with SUD (response rate = 84%) admitted to an inpatient stay at one of five specialized SUD treatment centers in Norway. The analytical sample consisted of patients with illicit drug use (n = 374) who took part in a follow up interview three months after discharge from inpatient treatment (n = 249) (retention rate = 67%). Data were collected using information from electronic medical records, a self-report questionnaire at treatment entry, and a follow-up interview. RESULTS: Relapse occurred among 37% of the sample by three-month follow-up. Results of multivariable analysis showed that younger age and having a psychiatric diagnosis were associated with an elevated relapse risk. Patients who received treatment at a short-term clinic (2-4 months), as opposed to a long-term clinic (>6 months) were also at increased risk of relapse, regardless of their length of stay. Reduced risk of relapse was predicted by having completed the inpatient treatment stay. CONCLUSION: Identifying the treatment needs of young patients and patients with co-occurring psychiatric diagnoses during and following inpatient SUD treatment may contribute to reduced post-treatment relapse rates. Further research is needed to illuminate the treatment-related factors that contribute to reduced risk of relapse after inpatient SUD treatment. PMID- 30447515 TI - Differential effect of sex on pain severity and smoking behavior and processes. AB - Scientific evidence suggests that pain contributes to the maintenance of tobacco cigarette smoking among individuals with varying levels of pain. Yet, little is understood about factors that may moderate relations between pain severity and smoking processes. Considering that women are more likely to experience deleterious pain- and smoking-related outcomes, female smokers may be a particularly vulnerable group when considering pain in the maintenance of maladaptive smoking behavior. Thus, it is important to investigate the role of sex in pain-smoking relations. The current cross-sectional study examined sex differences in the relation between reported levels of pain and cessation relevant smoking processes (i.e. cigarette dependence, barriers for cessation, and past cessation-related problems). Participants included 100 adult daily cigarette smokers (Mage = 32.57 years, SD = 13.58; 33% female). Results indicated that greater pain was significantly associated with greater cigarette dependence, greater perceived barriers to cessation, and greater cessation-related problems among female, but not male, smokers. The current findings identify sex as a potentially important moderator of complex associations between pain and tobacco smoking and suggests that women may constitute a group that is especially vulnerable to the effects of pain in the maintenance of tobacco dependence. Based on the present data, integrated pain-smoking treatments may be especially useful for female, versus male, smokers. PMID- 30447516 TI - Vascular malformation in a bicuspid aortic valve. AB - We report here a case of capillary vascular malformation developed in a bicuspid aortic valve incidentally detected during valve replacement in a 67-year-old male patient. The International Society for the Study of Vascular Anomalies (ISSVA) classification was used to classify this vascular lesion instead of using the term hemangioma. The differential diagnosis and the literature are reviewed. PMID- 30447517 TI - Simultaneous atrazine degradation and E. coli inactivation by UV/S2O82-/Fe2+ process under KrCl excilamp (222 nm) irradiation. AB - This study is the first to reveal that the iron-catalyzed photo-activation of persulfate (UV/PS/Fe2+system) under mercury-free KrCl excilamp irradiation (222 nm) is capable of simultaneous degradation of an organic pollutant and inactivation of a microorganism in aqueous media using the herbicide atrazine (ATZ) and E. coli as model contaminants, respectively. Deionized water, natural water and wastewater effluents, contaminated with 4 mg/L ATZ and/or 105 CFU/mL E. coli, were sequentially treated by direct UV, UV/PS and UV/PS/Fe2+ processes. Lowering the pH to 3.5 accelerated both the degradation and inactivation during the UV/PS/Fe2+ treatment of natural water. Comparison of the apparent UV dose based pseudo first-order rate constants showed the negative effect of E. coli on ATZ degradation by decreasing rates in all of the examined water matrices. This can be due to the competitive effect between ATZ and bacterial cells for reactive oxygen species (ROS). By contrast, E. coli in the presence of ATZ was inactivated faster in natural water and wastewater (but not in deionized water), as compared to the case without ATZ. A scheme of possible synergistic inactivation under ROS exposure in water, containing ATZ, natural organic matter and chloride ions as primary constituents, was proposed. Radical scavenging experiments showed a major contribution of SO4*- to ATZ degradation by UV/PS/Fe2+ treatment of deionized water and natural water. The UV doses, required for 90% removal of ATZ from natural water and wastewater, achieve 160 mJ/cm2 (pH 5.5) and concurrently provide 99.99% E. coli inactivation. These results make the UV/PS/Fe2+ system with narrow band UV light sources promising for simultaneous water treatment and disinfection. PMID- 30447518 TI - The affective twitches of task switches: Task switch cues are evaluated as negative. AB - Task switching refers to the demanding cognitive control process that allows us to flexibly switch between different task contexts. It is a seminal observation that task switching comes with a performance cost (i.e., switch cost), but recent theories suggest that task switching could also carry an affective cost. In two experiments, we investigated the affective evaluation of task switching by having participants perform a task-switching paradigm followed by an affective priming procedure. Crucially, the transition cues of the task-switching paradigm, indicating task alternations or task repetitions, were used as primes in the affective priming procedure to assess their affective connotation. We found that task alternation primes were evaluated as more negative than task repetition primes. These findings show that task switching is affectively tagged, and suggest a potential role for emotion regulation processes in cognitive control. PMID- 30447519 TI - Nonlinear decision weights or moment-based preferences? A model competition involving described and experienced skewness. AB - The predictive power of cumulative prospect theory and expected utility theory is typically compared using decisions from description, where lotteries' outcome values and probabilities are explicitly stated. In decisions from experience, individuals sample (in the sampling paradigm without cost) from the return distributions to learn outcome values and their relative frequencies; here cumulative prospect theory and expected utility theory require the calculation of probabilities from experience. Individuals, however, may be more attuned to the experienced moments of outcome distributions, rather than the probabilities. We therefore test the mean-variance-skewness model, and retrieve the proportion of expected utility theory (over income), cumulative prospect theory, and mean variance-skewness populations using a latent-class hierarchical Bayesian model across six large datasets. For simple lotteries (with 1-2 outcomes), we find a mixture of cumulative prospect theory and mean-variance-skewness populations in decisions from both description and experience. For more complex lotteries (with 2-3 outcomes), all participants are classified as cumulative prospect theory types in decisions from description, but as mean-variance-skewness types in decisions from experience. This suggests that in decisions from experience with more complex return distributions, preferences for skewness are more predictive than nonlinear probability weighting. PMID- 30447520 TI - Biofilms and vulvovaginal candidiasis. AB - Candida species, including C. albicans, are part of the mucosal flora of most healthy women, and inhabit the gastrointestinal and genitourinary tracts. Under favourable conditions, they can colonize the vulvovaginal mucosa, giving rise to symptomatic vulvovaginal candidiasis (VVC). The mechanism by which Candida spp. produces inflammation is unknown. Both, the blastoconidia and the pseudohyphae are capable of destroying the vaginal epithelium by direct invasion. Although the symptoms are not always related to the fungal burden, in general, VVC is associated with a greater number of yeasts and pseudohyphae. Some years ago, C. albicans was the species most frequently involved in the different forms of VVC. However, infections by different species have emerged during the last two decades producing an increase in causative species of VVC such as C. glabrata, C. parapsilosis, C. krusei and C. tropicalis. Candida species are pathogenic organisms that have two forms of development: planktonic and biofilm. A biofilm is defined as a community of microorganisms attached to a surface and encompassed by an extracellular matrix. This form of presentation gives microorganisms greater resistance to antifungal agents. This review, about Candia spp. with a special emphasis on Candida albicans discusses specific areas such as biofilm structure and development, cell morphology and biofilm formation, biofilm associated gene expression, the cell surface and adherence, the extracellular matrix, biofilm metabolism, and biofilm drug resistance in vulvovaginitis biofilms as an important virulence factor in fungi. PMID- 30447521 TI - PEG-b-poly (carbonate)-derived nanocarrier platform with pH-responsive properties for pancreatic cancer combination therapy. AB - A pH-responsive nanoparticle platform, based on PEG-b-poly (carbonate) block copolymers have been proposed that can respond to low pH as found in many cancer micro- and intracellular environment, including that in pancreatic cancer. The hydrophobic domain, i.e., the poly (carbonate) segment has been substituted with tertiary amine side chains, such as N, N'-dibutylethylenediamine (pKa = 4.0, DB) and 2-pyrrolidin-1-yl-ethyl-amine (pka = 5.4, Py) to generate two different sets of block copolymers namely PEG-DB and PEG-PY systems. These side-chain appended amines promote disassembly of nanoparticles and activation of drug release in response to pH conditions mimicking extra- (pH 6.9-6.5) and intracellular compartments (5.5-4.5, from early endosome to lysosome) of cancer tissues respectively. A frontline chemotherapy used for pancreatic cancer, i.e., gemcitabine (GEM) and a Hedgehog inhibitor (GDC 0449) has been used as the model combination to evaluate the encapsulation and pH-dependent release efficiency of these block copolymers. We found that, depending on the tertiary amine side chains appended to the polycarbonate segment, these block copolymers self assemble to form nanoparticles with the size range of 100-150 nm (with a critical association concentration value in the order of 10-6 M). We also demonstrated an approach where GEM and GDC 0449-encapsulated PEG-DB and PEG-PY nanoparticles, responsive to two different pH conditions, when mixed at a 1:1 vol ratio, yielded a pH-dependent co-release of the encapsulated contents. We envision that such release behaviour can be exploited to gain spatiotemporal control over drug accumulation in pathological compartments with different pH status. The mixture of pH-responsive nanoparticles was found to suppress pancreatic cancer cell proliferation when loaded with anticancer agents in vitro. Cell-proliferation assay showed that both variants of PEG-b-polycarbonate block copolymers were inherently non-toxic. We have also immobilized iRGD peptide on intracellularly activable PEG-DB systems to augment cellular uptake. These targeted nanoparticles were found to promote selective internalization of particles in pancreatic cancer cells and tumor tissue. PMID- 30447522 TI - Human dermal fibroblast proliferation controlled by surface roughness of two component nanostructured latex polymer coatings. AB - In this study hierarchically-structured latex polymer coatings and self supporting films were characterised and their suitability for cell growth studies was tested with Human Dermal Fibroblasts (HDF). Latex can be coated or printed on rigid or flexible substrates thus enabling high-throughput fabrication. Here, coverslip glass substrates were coated with blends of two different aqueous latex dispersions: hydrophobic polystyrene (PS) and hydrophilic carboxylated acrylonitrile butadiene styrene (ABS). The nanostructured morphology and topography of the latex films was controlled by varying the mixing ratio of the components in the latex blend. Thin latex-coatings retain high transparency on glass allowing optical and high resolution imaging of cell growth and morphology. Compared to coverslip glass surfaces and commercial well-plates HDF cell growth was enhanced up to 150-250 % on latex surfaces with specific nanostructure. Growth rates were correlated with selected roughness parameters such as effective surface area (Sq), RMS-roughness (Sdr) and correlation length (Scl37). High resolution confocal microscopy clearly indicated less actin stress-fibre development in cells on the latex surface compared to coverslip glass. The results show that surface nanotopography can, by itself, passively modulate HDF cell proliferation and cytoskeletal architecture. PMID- 30447523 TI - High-throughput profiling of antibiotic resistance gene dynamic in a drinking water river-reservoir system. AB - The rapid construction of reservoir in river basin generates a river-reservoir system containing an environmental gradient from river system to reservoir system in modern aquatic environment worldwide. Profiles of antibiotic resistance genes (ARGs) in river-reservoir system is essential to better understand their dynamic mechanisms in aquatic eco-environment. In this study, we investigated the diversity, abundance, distribution of ARGs and mobile genetic elements (MGEs) in a representative river-reservoir system using high-throughput quantitative PCR, as well as ranked the factors (e.g. antibiotics, bacterial biomass, bacteria communities, and MGEs) influencing the patterns of ARGs based on structural equation models (SEMs). Seasonal variations in absolute abundance of ARGs and MGEs exhibited similar trends with local rainfall, suggesting that seasonal runoff induced by the rainfall potentially promote the absolute abundance of ARGs and MGEs. In contrast, environmental gradient played more important roles in the detected number, relative abundance, distribution pattern of ARGs and MGEs in the river-reservoir system. Moreover, environmental gradient also made the co occurrence patterns associated with ARGs subtypes, MGEs and bacteria genera in river system different from those in reservoir system. The SEMs revealed that MGEs contributed the most to shape the ARG profiles. Overall, our findings provide novel insights into the mechanisms of environmental gradient on ARGs dynamics in river-reservoir system, probably via influencing the MGEs, antibiotics, pathogenic bacteria community and nonpathogenic bacteria community. PMID- 30447524 TI - Formation and stability of NOM-Mn(III) colloids in aquatic environments. AB - Soluble Mn(III) species stabilized by natural organic matter (NOM) plays a crucial role in a number of biogeochemical processes. To date, current understanding of these phenomena has been primarily concerned on the occurrence and chemistry of soluble NOM-Mn(III) complexes; much less is known regarding the formation and stability of NOM-Mn(III) colloids in the environment. This presents a critical knowledge gap with regard to biogeochemical cycling of manganese and associated carbon, and for predicting the fate and transport of colloid associated contaminants, nutrients, and trace metals. In this work, we have characterized the chemical and physical properties of humic acid based (HA) Mn(III) colloids formed over a range of environmentally relevant conditions and quantified their subsequent aggregation and stability behaviors. Results show that molar C/Mn ratios and HA types (Aldrich HA (AHA) and Pahokee peat soil HA (PPSHA)) are critical factors influencing HA-Mn(III) colloidal properties. Both the amount and the stability of HA-Mn(III) colloids increased with increasing initial molar C/Mn ratios, regardless of HA type. The correlation between the critical coagulation concentration (CCC) and zeta potential (R2 > 0.97) suggests that both Derjaguin-Landau-Verwey-Overbeek (DLVO) type and non-DLVO interactions are responsible for enhanced stability of HA-Mn(III) colloids. For a given C/Mn ratio, PPSHA-Mn(III) colloids are significantly more stable against aggregation than AHA-Mn(III) colloids, which is likely due to stronger electrostatic interactions, hydration interactions, and steric hindrance. Further examination in real-world waters indicates that the HA-Mn(III) colloids are highly stable in surface river water, but become unstable (i.e. extensive aggregation) in solutions representing a groundwater-seawater interaction zone. Overall, this study provides new insights into the formation and stability of NOM-Mn(III) colloids which are critical for understanding Mn-based colloidal behavior(s), and thus Mn cycling processes, in aquatic systems. PMID- 30447525 TI - Cryptosporidium concentrations in rivers worldwide. AB - Cryptosporidium is a leading cause of diarrhoea and infant mortality worldwide. A better understanding of the sources, fate and transport of Cryptosporidium via rivers is important for effective management of waterborne transmission, especially in the developing world. We present GloWPa-Crypto C1, the first global, spatially explicit model that computes Cryptosporidium concentrations in rivers, implemented on a 0.5 * 0.5 degrees grid and monthly time step. To this end, we first modelled Cryptosporidium inputs to rivers from human faeces and animal manure. Next, we use modelled hydrology from a grid-based macroscale hydrological model (the Variable Infiltration Capacity model). Oocyst transport through the river network is modelled using a routing model, accounting for temperature- and solar radiation-dependent decay and sedimentation along the way. Monthly average oocyst concentrations are predicted to range from 10-6 to 102 oocysts L-1 in most places. Critical regions ('hotspots') with high concentrations include densely populated areas in India, China, Pakistan and Bangladesh, Nigeria, Algeria and South Africa, Mexico, Venezuela and some coastal areas of Brazil, several countries in Western and Eastern Europe (incl. The UK, Belgium and Macedonia), and the Middle East. Point sources (human faeces) appears to be a more dominant source of pollution than diffuse sources (mainly animal manure) in most world regions. Validation shows that GloWPa-Crypto medians are mostly within the range of observed concentrations. The model generally produces concentrations that are 1.5-2 log10 higher than the observations. This is likely predominantly due to the absence of recovery efficiency of the observations, which are therefore likely too low. Goodness of fit statistics are reasonable. Sensitivity analysis showed that the model is most sensitive to changes in input oocyst loads. GloWPa-Crypto C1 paves the way for many new opportunities at the global scale, including scenario analysis to investigate the impact of global change and management options on oocysts concentrations in rivers, and risk analysis to investigate human health risk. PMID- 30447526 TI - Applying bio-electric field of microbial fuel cell-upflow anaerobic sludge blanket reactor catalyzed blast furnace dusting ash for promoting anaerobic digestion. AB - In this study, a novel manner of bio-electric field (BEF) which generated by upflow anaerobic sludge blanket (UASB)-microbial fuel cell (MFC) integrated system facilitated iron-carbon micro-electrolysis in blast furnace dusting ash (BFDA) was proposed for the reinforcement of anaerobic digestion in UASB. The responses of COD removal efficiency and biogas production with (0.1-0.4 V) BEF catalyzed 5 g BFDA(RMFC-5gBFDA-UASB) were much higher than the other tests, and maximum reached 86% and 240 ml/d respectively. Ultra-fast acidogenesis was achieved with 0.3 V BEF supplied to BFDA and the time shortened 94 h compared controlled (RUASB) with RMFC-5gBFDA-UASB. With the electrochemical and microbial community analysis, the redox ability and direct interspecies electron transfer accumulated with BEF catalyzed. The abundance of Firmicutes which could generate bio-hydrogen was highest in RMFC-5gBFDA-UASB (44.58%) compared to RUASB (31.36%) and R5gBFDA-UASB (40.04%). In addition, the structure and morphology variation of BFDA revealed that the synergistic effects of BEF stimulated iron-carbon micro electrolysis for electron transferring and enhanced the activities of methanogens and acetogens with high relative abundance to biotransform organic compounds, as well as adsorption and precipitation of iron oxides (hematite and magnetite) promoting anaerobic digestion. The MFC-BFDA-UASB integrated system provides a promising and cost-effective way to enhance anaerobic digestion and recycled functionalized waste effectively. PMID- 30447527 TI - Synthesis and bactericide activity of nanofiltration composite membranes - Cellulose acetate/silver nanoparticles and cellulose acetate/silver ion exchanged zeolites. AB - The present work addresses the synthesis of nanofiltration composite membranes with bactericide properties. The cellulose acetate based membranes with polyvinylpyrrolidone coated silver nanoparticles, silver ion-exchanged beta zeolite and beta-zeolite are casted by the phase inversion technique and subjected to an annealing post-treatment. They are characterized in terms of the nanofiltration permeation performance and antibacterial properties. The incorporation of silver nanoparticles produces a threefold increase in the membrane hydraulic permeability when compared to the silver-free membranes and the incorporation of silver ion loaded zeolite resulted in a 56.3% increase in hydraulic permeability. In contrast to the influence of silver presence, either in nanometric or in the ionic form, the presence of zeolite does not significantly influence the hydraulic permeability. The rejection coefficients to salts range from 83% to 93% for the silver ion-exchanged zeolite membrane and from 84% to 97% for the polyvinylpyrrolidone coated silver nanoparticles membrane. They are higher for sulfate salts than for chloride salts. The antibacterial properties of the membranes were evaluated against Escherichia coli. The results have shown that the silver ion-exchanged beta-zeolite membrane was effective in inactivating Escherichia coli after just 210 min of contact time. No bacterial activity was detected following 24 h of contact time with the membrane containing polyvinylpyrrolidone coated silver nanoparticles. A reduction of more than 6-log, in the number of Escherichia coli, was achieved for both membranes. The different patterns of bactericide activity are associated to the silver speciation in metallic or ionic form. The high flux nanofiltration composite membranes with bactericidal properties represent a strong asset in water treatment biofouling control. PMID- 30447528 TI - Predation creates unique void layer in membrane-aerated biofilms. AB - The membrane-aerated biofilm reactor (MABR) is a novel wastewater treatment technology based on oxygen-supplying membranes. The counter diffusion of oxygen and electron donors in MABRs leads to unique behavior, and we hypothesized it also could impact predation. We used optical coherence tomography (OCT), microsensor analyses, and mathematical modeling to investigate predation in membrane-aerated biofilms (MABs). When protozoa were excluded from the inoculum, the MAB's OCT-observable void fraction was around 5%. When protozoa were included, the void fraction grew to nearly 50%, with large, continuous voids at the base of the biofilm. Real-time OCT imaging showed highly motile protozoa in the voids. MABs with protozoa and a high bulk COD (270 mg/L) only had 4% void fraction. DNA sequencing revealed a high relative abundance of amoeba in both high and low-COD MABs. Flagellates were only abundant in the low-COD MAB. Modeling also suggested a relationship between substrate concentrations, diffusion mode (co- or counter-diffusion), and biofilm void fraction. Results suggest that amoeba proliferate in the biofilm interior, especially in the aerobic zones. Voids form once COD limitation at the base of MABs allows predation rates to exceed microbial growth rates. Once formed, the voids provide a niche for motile protozoa, which expand the voids into a large, continuous gap. This increases the potential for biofilm sloughing, and may have detrimental effects on slow-growing, aerobic microorganisms such as nitrifying bacteria. PMID- 30447529 TI - The novel N-methyl-d-aspartate receptor antagonist MN-08 ameliorates lipopolysaccharide-induced acute lung injury in mice. AB - Acute lung injury (ALI) is a clinically severe respiratory disorder, and effective therapy is urgently needed. MN-08, a novel synthetic N-methyl-d aspartate receptor (NMDAR) antagonist, was investigated for its effect on lipopolysaccharide (LPS)-induced ALI. In vitro, the protective effect of MN-08 on inflammatory response, oxidative stress, and tight junctions (TJs) structure was explored in LPS-induced RAW 264.7 cells and A549 cells. MN-08 markedly decreased (p < 0.001) the levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS), whereas it moderately upregulated (p < 0.05) heme oxygenase (HO)-1 protein expression in LPS-induced RAW 264.7 cells. Moreover, MN-08 significantly inhibited (p < 0.001) cell apoptosis and improved (p < 0.001) protein expression of TJs in LPS-induced A549 cells. In vivo, the therapeutic effect of MN-08 was evaluated in the LPS-induced ALI model through intratracheal instillation in BALB/c mice. MN-08 administration dramatically attenuated (p < 0.001) pulmonary pathological changes and reduced (p < 0.001) the levels of glutamate, myeloperoxidase (MPO), malondialdehyde (MDA), and number of cells in BALF, whereas it increased (p < 0.05) superoxide dismutase (SOD) and glutathione (GSH) activities in ALI mice. Furthermore, MN-08 markedly blocked the mitogen-activated protein kinases (MAPKs)/nuclear translocation of nuclear factor-kappaB (NF kappaB) signaling pathways in RAW 264.7 cells and lung tissues. These results indicate that MN-08 exhibits lung protection in an LPS-induced ALI model via anti inflammatory and anti-oxidative activities. PMID- 30447530 TI - Privigen(r) has similar pharmacokinetic properties in primary and secondary immune deficiency. AB - PURPOSE: Primary (PID) and secondary immune deficiencies (SID) represent diverse groups of diagnoses, yet both can be effectively treated with intravenous immunoglobulin (IVIG) replacement therapy. Guidelines for the use of IVIG in SID vary due to the paucity of data. The objective was to analyze available IVIG Privigen(r) (IgPro10, CSL Behring, Bern, Switzerland) data on Efficiency Index (EI) and pharmacokinetic (PK) parameters in patients with PID and SID. METHODS: Three Privigen(r) studies (NCT00168025, NCT00322556, and the observational study IgPro10_5001) were used to identify patients with PID and SID meeting the qualifying criteria for the PK analysis. PK properties of IVIG were estimated using a population PK model based on a standard two-compartment PK model. Immunoglobulin G (IgG) EI was calculated as the gain in serum IgG level per unit external IgG dose. RESULTS: A similar IVIG dose-serum IgG concentration relationship was observed in patients with PID (N = 90) and SID (N = 91). IgG EI was inversely proportional to the endogenous IgG concentration and comparable in PID (slope = -1.079) and SID (slope = -2.12). CONCLUSIONS: These findings indicate that the disposition of Privigen(r) is similar during IgG replacement therapy in PID and SID. The results contribute to the understanding of IVIG treatment of SID and may support an evidence-based approach for the use of IVIG in SID in the future. PMID- 30447531 TI - Differences in violin fixation force and muscle activity among violinists with and without complaints of the neck shoulder region. AB - PURPOSE: The aim of this study is to determine the relationship between complaints of the neck and shoulder region, the jaw-shoulder violin fixation force, and the activity of the neck and shoulder muscles in violinists. METHODS: In this case-control study twenty professional violinists were included, of which ten with current complaints of the neck shoulder region and ten without these complaints. A questionnaire including the DASH and NDI was used; violin fixation force and activity of the superficial neck muscles were evaluated in five playing conditions. RESULTS: Each group consisted of eight female and two male violists with a mean age of 29 years. Violinists with complaints had more muscle activity of all evaluated muscles compared to violinists without complaints; complaints were significantly associated with the muscle activity of all evaluated muscles. Complaints were not significantly associated with the violin fixation force. The playing condition significantly predicted the violin fixation force and the activity of all muscles except the left mTP. CONCLUSIONS: Violinists with complaints have more muscle activity of some superficial neck and shoulder muscles. Co-contraction is thought to play a relevant role in violinists with these complaints. PMID- 30447532 TI - Ultra-high performance hydrophilic interaction liquid chromatography - Triple quadrupole tandem mass spectrometry method for determination of cysteine, homocysteine, cysteinyl-glycine and glutathione in rat plasma. AB - An ultra-high performance hydrophilic interaction liquid chromatography - triple quadrupole tandem mass spectrometry method was developed for the determination of biologically important thiols, namely cysteine, homocysteine, cysteinyl-glycine, glutathione, in rat plasma. The sample preparation procedure as well as the analytical method were comprehensively optimized and subsequently validated. An optimum sample preparation protocol was based on the simple and fast derivatization of the thiols with new derivatization reagent, N-phenylmaleimide, enabling highly selective and sensitive quantification in plasma matrices. The method, characterized by favourable performance parameters and meeting the FDA criteria for biomedical analysis, was successfully applied for monitoring the concentration levels of the selected thiols in the samples from transgenic rat model for tauopathy. The study revealed significant changes in homocysteine and glutathione levels related to tauopathy while other thiols did not indicate such relationship. Indeed, these findings could play an important role in further understanding of tauopathy process in the brain. Moreover, the proposed highly effective, reliable and robust analytical protocol can be easily adapted for other thiol compounds, spreading its application range in this biomedical field. PMID- 30447533 TI - Multi-arm PEG-maleimide conjugation intermediate characterization and hydrolysis study by a selective HPLC method. AB - Maleimide functionalized polyethylene glycol (PEG) with varying degrees of branched chains is gaining increasing interest in drug conjugation. Characterization of these molecules in solution is highly challenging due to the multiplicity of the hydrolysis products and the subtle differences between them, especially for high molecular weight PEG-maleimide. A highly selective, sensitive and stability indicating HPLC method employing charged surface hybrid (CSH) stationary phase was developed for 8-arm PEG-maleimide characterization. The method has been validated per ICH Q2 guideline for specificity, sensitivity, linearity, accuracy and precision for quality and process control. Hydrolysis of 8-arm PEG-maleimide in different buffer media, pH and temperature was studied. The kinetics revealed the hydrolysis is a first-order reaction. Hydrolysis rate constant and half-life were obtained to guide protein conjugation process development. PMID- 30447534 TI - Antioxidant properties of citric acid interfere with the uricase-based measurement of circulating uric acid. AB - BACKGROUND: Circulating uric acid (UA) is an important biomarker, not only in the detection and management of gout, but also in assessing the risk of related comorbidity. The impact of collection methods on clinical UA measurements has been the subject of limited study. After observing significant differences between UA concentrations of blood samples obtained by different collection tubes, we began examining the effects of exogenous tube components on measured UA concentrations. We aimed to: (1) demonstrate the variability in uricase-based UA measurements attributable to different collection methods and (2) identify factors influencing this variability. METHODS: Blood samples from human subjects were collected using Serum Separator Tubes (SST tubes), Acid Citrate Dextrose (ACD) tubes, and Sodium Citrate (SC) tubes. Circulating UA concentrations were measured by chemistry analyzers utilizing the uricase method. Absorbance assays were run in order to determine the effects of citric acid, sodium citrate, and dextrose on measured absorbance in the presence of leuco crystal violet dye, hydrogen peroxide, and peroxidase. Statistical analyses-including Student's T tests and ANOVA-were used to compare results. RESULTS: UA concentrations of blood samples collected in ACD tubes were significantly lower than those collected in SST tubes (P < 0.01). Samples collected in SC tubes trended towards lower UA measurements than samples collected in SST tubes, although this difference did not reach statistical significance (P = 0.06). Blood samples spiked with separate concentrations of sodium citrate (3.2 and 22.0 g/L), citric acid (8.0 g/L), and dextrose (24.5 g/L) demonstrated significantly lower UA measurements compared to controls (P < 0.01). Absorbance assays demonstrated that increasing concentrations of citric acid and sodium citrate-in the presence of leuco crystal violet, hydrogen peroxide, and peroxidase-decreased the amount of oxidized dye in the uricase method of UA measurement in a dose-dependent manner (P < 0.01). In contrast, dextrose did not significantly alter the amount of oxidized dye available. DISCUSSION: Our results indicate that citric acid obstructs accurate uricase-based UA measurement, providing falsely low values. Citric acid, a known antioxidant, scavenges hydrogen peroxide, a key intermediate using the uricase method. By scavenging hydrogen peroxide, citric acid decreases the amount of oxidized leuco dye leading to falsely low UA measurements. Therefore, collection tubes, like ACD and SC tubes, which contain concentrations of citric acid or its conjugate base sodium citrate should not be used to measure circulating UA levels when utilizing uricase-based measurement methods. PMID- 30447535 TI - Acceleration of nano-surface and molecular-orientation limited (nSMOL) proteolysis with acidified reduction pretreatment for quantification of Tocilizumab. AB - Antibody drugs are effective therapeutic agents and provide treatment for many types of diseases such as cancer and rheumatoid arthritis. Because many antibody drugs are developed and approved, quantification technologies of antibodies are required for drug development and individualized therapy. We recently reported a high reproducible and robust therapeutic drug monitoring method for antibody drugs. This method was developed to be applicable to all type of antibody drugs and to provide accurate quantification values. The method is named nano-surface and molecular-orientation limited (nSMOL) proteolysis. nSMOL limits the access of protease to immunoglobulin G molecules and aims to selectively proteolyze on Fab region of substrate. However, the bioanalysis of Tocilizumab using nSMOL has not been validated. We newly discovered that acidified reduction pretreatment of Tocilizumab promotes digestive efficiency by nSMOL proteolysis. Exposure of Tocilizumab to Tris(2-carboxyethyl)phosphine hydrochloride before nSMOL proteolysis significantly improved the recovery of peptides. Under this condition, the quantification range of Tocilizumab in human serum was from 0.781 to 200 MUg/mL. The quantification values of quality control samples fulfilled all guideline criteria for bioanalytical validation. The signature peptide with the highest quantitative sensitivity was on H-chain VTMLR. From these results, it is expected that the pretreatment with TCEP will broaden the application of antibody drugs quantification by nSMOL proteolysis. PMID- 30447536 TI - Are there any clinical and electrocardiographic predictors of heart rate reduction in relapsing- remitting multiple sclerosis patients treated with fingolimod? AB - BACKGROUND: Fingolimod, a sphingosine-1-phosphate receptor agonist, is used for treatment of relapsing-remitting multiple sclerosis (RRMS). S1P receptors that fingolimod acts upon have also been shown to be expressed on atrial myocytes. This expression pattern has been linked with the drug's cardiovascular effects, such as bradycardia. We aimed to evaluate the clinical and electrocardiographic predictors of heart rate (HR) reduction in patients receiving first-dose fingolimod. METHODS: We retrospectively analyzed subjects diagnosed with RRMS who were allocated to fingolimod treatment. HR, systolic and diastolic blood pressure values and electrocardiography during the first dose of fingolimod were accessed. RESULTS: A total of 114 RRMS patients (65.8% female, 33.58 +/- 8.63 years) were included. After the initial dose of fingolimod, the heart rate decreased significantly at each hour (each p < 0.001). Nadir heart rate was reached at 4 h. The multivariate binary logistic regression analysis revealed that BMI (OR: 0.878, p = 0.045), optic nerve involvement (OR: 3.205, p = 0.018), baseline HR (OR: 1.079, p = 0.002) and T-peak-T-end interval (OR: 1.046, p = 0.030) were independent predictors of greater HR reduction. During 6-h monitorization, none of the patients had relevant adverse reactions. CONCLUSION: Our findings provide an insight on clinical and electrocardiographic predictors of HR reduction that occurs in RRMS patients receiving first dose of fingolimod. PMID- 30447537 TI - Immune regulation and anti-cancer activity by lipid inflammatory mediators. AB - Rodent and clinical studies have documented that myeloid cell infiltration of tumors is associated with poor outcomes, neutrophilia and lymphocytopenia. This contrasts with increased lymphocyte infiltration of tumors, which is correlated with improved outcomes. Lifestyle parameters, such as obesity and diets with high levels of saturated fat and/or omega (omega)-6 polyunsaturated fatty acids (PUFAs), can influence these inflammatory parameters, including an increase in extramedullary myelopoiesis (EMM). While tumor secretion of growth factors (GFs) and chemokines regulate tumor-immune-cell crosstalk, lifestyle choices also contribute to inflammation, abnormal pathology and leukocyte infiltration of tumors. A relationship between obesity and high-fat diets (notably saturated fats in Western diets) and inflammation, tumor incidence, metastasis and poor outcomes is generally accepted. However, the mechanisms of dietary promotion of an inflammatory microenvironment and targeted drugs to inhibit the clinical sequelae are poorly understood. Thus, modifications of obesity and dietary fat may provide preventative or therapeutic approaches to control tumor-associated inflammation and disease progression. Currently, the majority of basic and clinical research does not differentiate between obesity and fatty acid consumption as mediators of inflammatory and neoplastic processes. In this review, we discuss the relationships between dietary PUFAs, inflammation and neoplasia and experimental strategies to improve our understanding of these relationships. We conclude that dietary composition, notably the ratio of omega-3 vs omega-6 PUFA regulates tumor growth and the frequency and sites of metastasis that together, impact overall survival (OS) in mice. PMID- 30447538 TI - Phosphatidylserine expressing microvesicles in relation to microvascular complications in type 1 diabetes. AB - INTRODUCTION: Type 1 diabetes is a prothrombotic state strongly linked to vascular complications. The role of microvesicles (MVs) as mediators and potential biomarkers in microangiopathy in type 1 diabetes remains unclear. MATERIALS AND METHODS: MV levels in plasma samples from 106 patients with type 1 diabetes with microangiopathy, 130 patients without microangiopathy and 100 healthy controls were analysed using flow cytometry. Phosphatidylserine (PS) expression in MVs was assessed by lactadherin, and the ability of MVs to induce thrombin generation was investigated in vitro. Endogenous plasma lactadherin levels were measured using ELISA. RESULTS: Patients with type 1 diabetes had higher MV levels compared to healthy controls, with no significant differences between patients with and without microangiopathy. MV-induced thrombin generation in normal-pooled plasma was blocked by addition of lactadherin. Endogenous lactadherin levels were higher in patients compared to controls, and the highest levels were found in patients with microangiopathy. Plasma lactadherin levels did not correlate with levels of PS positive/negative MVs. CONCLUSION: Patients with type 1 diabetes with and without microangiopathy have higher levels of circulating MVs than healthy controls, probably reflecting higher cellular activation and turnover. However, we found no associations between clinical microangiopathy and levels of MVs in total or PS-expressing MVs. Plasma levels of lactadherin, which is a glycoprotein important in the clearance of cells and MVs, are increased in patients with type 1 diabetes and correlate with microangiopathy. PMID- 30447539 TI - Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study. AB - AIM: The aim of the study was to evaluate the efficacy and safety of nivolumab combined with ipilimumab in treatment-naive Japanese patients with advanced melanoma. METHODS: In this multicentre, single-arm study, treatment-naive Japanese patients with unresectable stage III/IV or recurrent melanoma received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for four doses, followed by biweekly doses of nivolumab (3 mg/kg). The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included overall survival (OS), progression-free survival (PFS), disease control rate and safety. RESULTS: The subtypes of the thirty patients enrolled were: 12, mucosal; eight, non-acral cutaneous; seven, acral; two, uveal and one, unknown primary melanoma. The ORR was 43.3% (95% confidence interval [CI]: 25.5, 62.6) with central and local assessment. The centrally and locally assessed disease control rate (95% CI) were 73.3% (54.1, 87.7) and 86.7% (69.3, 96.2), respectively. At the median follow-up period of 14.1 months (range 5.2-27.7), median OS and centrally assessed PFS were not reached. OS (95% CI) at 6, 12, 18 and 24 months was 93.3% (75.9, 98.3), 83.3% (64.5, 92.7), 72.9% (50.0, 86.5) and 65.6% (40.4, 82.2), respectively. Treatment-related adverse events (AEs) occurred in all patients. Grade III-IV and serious AEs occurred, mostly during the combination phase, in 23 (76.7%) and 20 (66.7%) patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: This study confirmed the efficacy and safety of nivolumab plus ipilimumab in treatment-naive Japanese patients with advanced melanoma including rare subtypes. Incidence rates for grade III-IV AEs were high but manageable with appropriate medical attention and treatment. TRIAL REGISTRATION: JapicCTI-152869. PMID- 30447540 TI - Cost-Utility Study of PCV13 Versus PPSV23 in Adults in ChileESTUDIO DE COSTO UTILIDAD DE PCV13 Versus PPSV23 EN ADULTOS EN CHILE. AB - INTRODUCTION: Pneumococcal infections are a public health problem in older adults. In Chile there are two vaccines at this time, PPSV23 and PCV13. The first has lower immunogenicity and effectiveness in preventing pneumococcal pneumonia and a lower cost than PCV13. OBJECTIVE: To determine the cost-effectiveness of PCV13 versus PPSV23 in adults 18 years old and over in the Chilean Health System. MATERIAL AND METHOD: A cost-utility study was performed using the Markov model (population data for a time horizon of 10 years). Utilities and epidemiological data were obtained from the literature and costs from the Chilean Public sector. Vaccine's costs and quality-adjusted life years (QALYs) were determined and compared. RESULTS: PCV13 vaccination program in adults (>=18 years), generated savings of $42,195 USD and an increase of 6,820 QALYs, avoiding 107 cases of bacteremia, 13 meningitis, 6,706 inpatient pneumonia, 4,509 outpatient pneumonia and 1,189 deaths compared to PPSV23 without variation on sensitivity analysis on high impact variables. For the subgroup of patients over 65 years old PCV13 generates savings of $ 32,105.94USD and produces 5,430 QALYs more compared to PPSV23. CONCLUSION: PCV13 is dominant. A PCV13 vaccination program saves costs to the public system, reduces mortality and morbidity; these results are robust. PMID- 30447541 TI - Gasto de Bolsillo en Salud y Medicamentos en Chile: Analisis Comparativo de los Periodos 1997, 2007, y 2012. AB - OBJECTIVES: Out-of-pocket spent (OPS) of health services are considered inefficient and are a consequence of inequalities in financing and access. The main objective of this study was to compare OPS on health and medicine, including catastrophic expenditure, overall and by quintiles and deciles, for the great Santiago city in the periods 1997, 2007 and 2012. METHODS: Cross-sectional study based on household budget surveys 1997, 2007 and 2012. OPS on health and medicine for households of the great Santiago was estimated overall and for different quintiles and deciles. In addition, the probability of incurring in catastrophic due to health and drug expenditure were also estimated. RESULTS: OPS showed a progressive increase in the three periods. Drug spending showed a decrease concentrated in the lower deciles and an increase in top deciles of expenditure. Catastrophic drug expenditure decreased progressively. By observing the catastrophic drug spending by deciles were the three richest deciles which showed a large increase between 2007 and 2012. CONCLUSIONS: OPS on health remained high between 2007 and 2012, despite presenting slight decreases in some quintiles and deciles. However, drug coverage improved over time. This study demonstrates that improvements are needed in the financial protection mechanisms on health in Chile, especially for poorer quintiles and deciles. PMID- 30447542 TI - The relationship between pharmacy benefit managers (PBMs) and the cost of therapies in the US pharmaceutical market: A policy primer for clinicians. AB - Pharmaceutical benefit managers (PBMs) are playing an increasingly important role in establishing access to pharmaceutical products for patients. PBMs set retail prices for pharmaceutical products, negotiate "rebates" from manufacturers based on total sales volume of products, and achieve several types of postsale price concessions and payments from pharmacies. All of these activities describe a complex flow of funds that has not been transparent to clinicians or to patients. In this article, we describe these terms and processes to better understand how pharmaceutical products are financed in the United States. In 2016, US pharmaceutical manufacturers reported gross pharmaceutical sales of $462 billion and net pharmaceutical sales of $318 billion. The difference between gross and net sales is largely due to the different "payments" from manufacturers to PBMs and other intermediaries in the marketplace. We examine the flow of funds through the US pharmaceutical distribution system over time using data from the annual reports of 13 major pharmaceutical manufacturers for the period 2011-2016. Overall, we find that net revenues for our sample of firms grew by an average of 2.7% annually between 2011 and 2016, whereas rebates and other payments increased by 15% annually over the same period. Our examination of the pharmaceutical market reveals the enormous scale of payments from pharmaceutical manufacturers to intermediaries. We observed that these payments have been growing disproportionally to manufacturer net income over the past 5 years. We also found a lack of transparency regarding the flow of funds through intermediaries. This entire marketplace is now the subject of intense public debate. PMID- 30447543 TI - Sorensen test performance is driven by different physiological and psychological variables in participants with and without recurrent low back pain. AB - Time to task failure (TTF) on the Sorensen test predicts low back pain (LBP), but mechanisms driving TTF may vary in those with and without recurrent LBP. To determine the physiological and psychological predictors of TTF, 48 sex, age, and BMI matched participants (24 Healthy, 24 LBP) completed psychological surveys, maximal strength assessments, and the Sorensen test. A two-way ANOVA revealed no significant effects of group (p = 0.75) or sex (p = 0.21) on TTF. In the full sample, linear regression analyses revealed that normalized Median Power Frequency (MPF) slope of the Erector Spinae (beta = 0.350, p < 0.01), the Biceps Femoris (beta = 0.375, p < 0.01), and self-efficacy (beta = 0.437, p < 0.01) predicted TTF. In the Healthy group, normalized MPF slope of the Erector Spinae (beta = 0.470, p < 0.01), the Biceps Femoris (beta = 0.437, p < 0.01), and self efficacy (beta = 0.330, p = 0.02) predicted TTF. In the LBP group, trunk mass (beta = -0.369, p = 0.04) and self-efficacy (beta = 0.450, p = 0.02) predicted TTF. In sum, self-efficacy consistently predicts performance, while trunk mass appears to negatively influence TTF only for those with recurrent LBP. PMID- 30447544 TI - Automatic brain labeling via multi-atlas guided fully convolutional networks. AB - Multi-atlas-based methods are commonly used for MR brain image labeling, which alleviates the burdening and time-consuming task of manual labeling in neuroimaging analysis studies. Traditionally, multi-atlas-based methods first register multiple atlases to the target image, and then propagate the labels from the labeled atlases to the unlabeled target image. However, the registration step involves non-rigid alignment, which is often time-consuming and might lack high accuracy. Alternatively, patch-based methods have shown promise in relaxing the demand for accurate registration, but they often require the use of hand-crafted features. Recently, deep learning techniques have demonstrated their effectiveness in image labeling, by automatically learning comprehensive appearance features from training images. In this paper, we propose a multi-atlas guided fully convolutional network (MA-FCN) for automatic image labeling, which aims at further improving the labeling performance with the aid of prior knowledge from the training atlases. Specifically, we train our MA-FCN model in a patch-based manner, where the input data consists of not only a training image patch but also a set of its neighboring (i.e., most similar) affine-aligned atlas patches. The guidance information from neighboring atlas patches can help boost the discriminative ability of the learned FCN. Experimental results on different datasets demonstrate the effectiveness of our proposed method, by significantly outperforming the conventional FCN and several state-of-the-art MR brain labeling methods. PMID- 30447545 TI - Fusaricates H-K and fusolanones A-B from a mangrove endophytic fungus Fusarium solani HDN15-410. AB - Seven compounds including four undescribed fusaric acid derivatives, namely fusaricates H-K, and two undescribed gamma-pyrone derivatives, named fusolanones A-B, as well as a known compound fusaric acid, were isolated from a mangrove endophytic fungus Fusarium solani. Fusaricates H-K represent the first cases of fusaric acid butanediol esters and are diastereoisomers. Their structures including absolute configurations were elucidated based on NMR, MS, chemical synthesis, chiral HPLC analysis and ECD calculations. The antibacterial activity of all undescribed compounds were tested and fusolanone B showed the best activity with MIC value 6.25 MUg/mL on Vibrio parahaemolyticus. PMID- 30447546 TI - Bromocatechol conjugates from a Chinese marine red alga, Symphyocladia latiuscula. AB - This study describes an investigation into polybromocatechol conjugates isolated from a marine red alga, Symphyocladia latiuscula (Harvey) Yamada, collected from coastal waters off Qingdao, China. We report on the isolation and characterisation of eight undescribed aconitic acid conjugates, symphyocladins R X, including a likely solvolysis artifact of symphyocladin S, and an undescribed furanoyl conjugate, symphyocladin Y. Structure elucidation was achieved by detailed spectroscopic analysis. A plausible biosynthetic pathway linking all these co-metabolites through a cascade of quinone methide additions is proposed. PMID- 30447547 TI - Multiple spontaneous small bowel perforations due to clozapine-Case report. AB - INTRODUCTION: Spontaneous free perforation of the small bowel is unusual. There are many causes of spontaneous small bowel free perforation such as: immune mediated or inflammatory, infections, drugs and biological agents, congenital, metabolic, vascular and neoplasm. A severe adverse effect of antipsychotic drugs is intestinal ischemia, which could lead to perforation. CASE PRESENTATION: The authors report the clinical case of a 42-year-old schizophrenic patient, smoker, medicated with clozapine 600 mg per day, admitted to the emergency room with diffuse abdominal pain. On physical examination the patient presented abdominal rebound tenderness and peritoneal sign with raised inflammation markers and the abdominal tomography revealed pneumoperitoneum. An emergency laparotomy revealed multiple jejunal and ileal perforations. The patient was subject to small bowel resection complicated with anastomosis dehiscence, respiratory tract infection and intra-abdominal abscess. Histologic specimens showed nonspecific inflammatory findings with ischemia. The main infectious, inflammatory, congenital, auto immune and vascular causes of spontaneous perforations were excluded. DISCUSSION: Spontaneous free perforation of the small bowel is uncommon. An intestinal ischemia might be a rare adverse effect of antipsychotics. However, only colon perforations due to ischemic colitis are described in the literature. While diagnosis of the precise cause might be challenging, and after excluding other causes, these perforations may be attributed to an adverse effect of clozapine. CONCLUSION: The cause was attributed to clozapine as the other etiologies were excluded. The clozapine's reintroduction is controversial. In this case the clozapine dose was reduced successfully. PMID- 30447548 TI - Case report: Osteitis/osteomyelitis pubis simulating acute appendicitis. AB - There is a continuum between Athletic (Sports) Hernia, Osteitis Pubis, and Osteomyelitis Pubis. The pubis is the site of attachment of many "core" muscles. A lay term used to describe a hernia is "rupture". Athletic hernia denotes a tear. Chronic musculotendinous strain may cause inflammation (osteitis pubis). An inflammatory focus may become a nidus for infection (osteomyelitis pubis). The symptoms caused by these three entities blur one with the other and with those characterizing acute appendicitis. This is an important association for clinicians to know. PMID- 30447549 TI - Parastomal stomach herniation complicated by gastric outlet obstruction: A case report and literature review. AB - Introduction Parastomal herniation commonly occurs following formation of an end colostomy or ileostomy. Those patients presenting with acute complications of parastomal hernias typically undergo surgical repair. Stomach-containing parastomal hernias are rare. Presentation of case A 92-year-old lady presented to the emergency department with vomiting and abdominal pain. She had undergone a total colectomy with end-ileostomy many years earlier. A computed tomography scan of her abdomen diagnosed gastric outlet obstruction secondary to parastomal stomach herniation. The obstruction resolved with simple nasogastric decompression and the patient did not receive surgery. She was discharged from hospital after two days. Discussion Gastric outlet obstruction secondary to a parastomal hernia is rare. A systematic literature search found 12 previously reported cases. This is the first case managed without invasive procedures. Conclusion For gastric outlet obstruction caused by parastomal herniation, surgeons should consider non-operative management with nasogastric decompression when the patient in question is frail and a poor surgical candidate. PMID- 30447550 TI - Primary pelvic hydatid cyst: A rare case presenting with obstructive uropathy. AB - INTRODUCTION: Hydatid disease is caused by infection with larva of the cestode echinococcus. Humans are accidental intermediate hosts. Primary pelvic hydatid cyst is a rare entity. PRESENTATION OF CASE: This is a case report of a 50 year old gentleman who presented to us as a case of suprapubic swelling and difficulty in micturition. General physical examination and radiological evaluation confirmed a multiloculated pelvic swelling. Patient was subjected to laparotomy which confirmed the diagnosis of a primary pelvic hydatid disease. DISCUSSION: Surgery is the optimal treatment of the pelvic hydatid disease. Radical resectional procedure or en bloc resection that removes the entire pericyst is the surgical technique of choice. CONCLUSION: Familiarity with atypical manifestations of hydatid disease may be helpful in making a prompt and accurate diagnosis. Surgery is the treatment of choice. PMID- 30447551 TI - Hair as an alternative matrix to monitor human exposure to plasticizers - Development of a liquid chromatography - tandem mass spectrometry method. AB - The application and production of alternative plasticizers (APs) has been increasing in the last decade in replacement of conventional phthalates due to their toxicity. This calls for the development of non-invasive monitoring approaches to assess human exposure to APs. A method for the simultaneous measurement of exposure biomarkers of di(2-propylheptyl) phthalate (DPHP), di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) terephthalate (DEHTP) and di-2-ethylhexyl adipate (DEHA) in hair samples was developed and validated in this study. Prior to the analysis, the hair samples were washed in acetone and ultrapure water and pulverized to powder. Further, a solid-liquid and solid-phase extraction, followed by quantification using liquid chromatography - tandem mass spectrometry (LC-MS/MS) was performed. The method was validated in terms of recovery, matrix effects, carry-over, linearity, limits of quantification, within- and between-run precision and trueness. Satisfying results were obtained for all targeted compounds, except for mono(2-ethylhexyl) adipate (MEHA), which was monitored only qualitatively. The optimized method was implemented in a pilot biomonitoring study with hair samples from 9 healthy volunteers. Detection frequencies of seven metabolites ranged from 11% to 100%. Mono(2-ethylhexyl) terephthalate (MEHTP) and mono(2-ethyl-5-oxohexyl) adipate (oxo-MEHA) were found in all hair samples. More hydrophobic monoester metabolites were found to be incorporated in hair to a greater extent compared to their oxidized counterparts. Obtained results show that the developed method can detect AP metabolites in hair, supporting the use of this alternative matrix in human biomonitoring. PMID- 30447552 TI - Evidence-based guidelines for vaginal hysterectomy of the International Society for Gynecologic Endoscopy (ISGE). AB - OBJECTIVE: This project was established by the International Society for Gynecologic Endoscopy (ISGE) to provide evidence-based recommendations on the selection of women in whom vaginal hysterectomy can be safely performed. STUDY DESIGN: The ISGE Task Force for vaginal hysterectomy for non-prolapsed uterus defined key clinical questions that led the literature search and formulation of recommendations. The search included Medline/PubMed and Cochrane Database. English language articles were reviewed from January 2003 to January 2018, in conjunction with reviews published by the American College of Obstetricians and Gynecologists (ACOG) and the American Association of Gynecologic Laparoscopists (AAGL). The bibliographies of selected works were also checked to acquire additional data where relevant. The available information was graded by the level of evidence using the approach developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group. For each clinical question, the ISGE recommendations were defined in accordance with the evidence quality. RESULTS: Six recommendations on patient selection for vaginal hysterectomy, including two grade 1B and four grade 2B recommendations were established. CONCLUSION: Vaginal hysterectomy for non-prolapsed uterus is the treatment of choice for many gynaecological patients in whom hysterectomy is indicated. It may be safely executed, and thus, should be offered to a large group of appropriately selected women, who today are operated in the main by the abdominal or laparoscopic approach. All efforts should be directed towards teaching the technique of vaginal hysterectomy during residency. PMID- 30447553 TI - Estimation of radon diffusivity tensor for fractured rocks in cave mines using a discrete fracture network model. AB - This study develops a numerical model for predicting radon effective diffusivity tensor for fractured rocks using a two dimensional discrete fracture network (DFN) model. This is motivated by the limitations of existing techniques in predicting the radon diffusion coefficient for the fractured zones of cave mines. These limitations include access to the fractured zones for the purpose of conducting field studies as well as replication of the degree of fracturing in these zones for laboratory studies. The caving of a rock mass involves the fracturing and breaking of intact and naturally fractured rock, which creates migration pathways for radon gas trapped within uranium-rich rock. Therefore, this study develops a stochastic DFN model with equations derived from radon transport to predict diffusivity. Our simulation results reveal the establishment of a representative elementary volume (REV) for diffusivity tensor; approximately equal principal and cross diffusivity magnitudes for each of the DFN domain; a range of diffusivity with porosity (calculated based on the fractures in the domain); and a significant effect of fracture density on diffusivity tensor. These results are essential in developing proactive measures for mitigation of radon gas in cave mines. PMID- 30447554 TI - An improved method for radium-isotopes quartet determination by alpha-particle spectrometry by using 225Ra (229Th) as isotopic tracer. AB - A new method for the determination of radium quartet (223,224,226,228Ra) in environmental samples by alpha-particle spectrometry with PIPS detectors is described. This uses 225Ra as yield tracer, in equilibrium at the beginning with 229Th. Thorium is removed from the sample by using AG1X8 anion-resin, and then radium isotopes are isolated and purified with a cation-exchange column Biorad AG50X8, verifying that Ac has been fully removed from the sample to ensure the good evaluation of the Ra yield (average decontamination factor > 92%). Finally, the counting source of radium is obtained by micro-precipitation with BaSO4. This method produces high spectral resolution (<35 keV), and quantitative Ra recoveries (>70%). In this new method, NH4Ac in 0.1 M HNO3 is used to remove the 225Ac contained in the sample in order to avoid its future spectral interference in the yield calculation. The method has been validated by using certified reference samples with known concentrations of radium isotopes. PMID- 30447555 TI - The 1b gene of raspberry bushy dwarf virus is a virulence component that facilitates systemic virus infection in plants. AB - A product translated from the 1b gene of raspberry bushy dwarf virus (RBDV) was specifically detected in RBDV-infected Nicotiana benthamiana plants by immunoblot analysis. To analyze the effects of the 1b gene on virus infection in host plants, an RBDV deletion mutant virus (RB?1bstop), which is unable to express the 1b gene, was constructed and inoculated to N. benthamiana plants. The results showed that accumulation of the virus genomic (g) RNAs 1 and 2 decreased in inoculated leaves, and that systemic virus spread was delayed compared with wild type RBDV. In contrast, accumulation of the viral gRNAs 1 and 2 was elevated in RB?1bstop-infected leaf tissues during ectopic expression of the 1b gene. Furthermore, we found that the 1b has weak RNA silencing suppressor activity. PMID- 30447556 TI - Carbon Nanospikes: Synthesis, characterization and application for high resolution AFM. AB - We present a detailed study of synthesis, structural characterization of sharp, spike-like carbon structures and its application for high-resolution atomic-force microscopy (AFM) measurements of biological molecules. The probes are obtained by chemical vapor deposition of spike-like carbon structures on the apexes of common AFM silicon probes. The deposition process is carried out in carbonaceous gas mixture activated by a direct-current discharge. It was revealed by electron microscopy and Raman spectroscopy that the having dimensions at their ends of few nanometers the structures consist of amorphous carbon. The carbon spikes demonstrate high efficiency and resolutions in AFM studies of biological objects. Sub-molecular resolution is demonstrated on the samples of DNA and streptavidin molecules in AFM measurements with the ultra-sharp carbon tips. PMID- 30447557 TI - Ultra-thin occlusal veneers bonded to enamel and made of ceramic or hybrid materials exhibit load-bearing capacities not different from conventional restorations. AB - OBJECTIVES: The objective of this study was to test whether or not the load bearing capacity of occlusal veneers bonded to enamel and made of ceramic or hybrid materials does differ from those of porcelain-fused-to-metal or lithium disilicate glass ceramic crowns. MATERIAL AND METHODS: In 80 human molars occlusal enamel was removed without extending into the dentin in order to mimic substance defects caused by attrition. The restorations were digitally designed at a standardized thickness of either 0.5 mm or 1.0 mm. For each thickness, 4 test groups were formed each including a different restorative material: "0.5 ZIR": 0.5 mm thick zirconia (Vita YZ HT); "1.0-ZIR": 1.0 mm thick zirconia (Vita YZ HT); "0.5-LDC": 0.5 mm thick lithium disilicate ceramic (IPS e.max Press); "1.0-LDC": 1.0 mm thick lithium disilicate ceramic (IPS e.max Press); "0.5-HYC": 0.5 mm thick PICN (Vita Enamic); "1.0-HYC": 1.0 mm thick PICN (Vita Enamic); "0.5 COC": 0.5 mm thick tooth shaded resin composite (Lava Ultimate) and "1.0-COC": 1.0 mm thick tooth shaded resin composite (Lava ultimate). Each group consists of 10 specimens. Two additional groups of 10 specimens each were used as controls and exhibited conventional crown preparations. In one group the crowns were made of lithium-disilicate ceramic ("CLD": IPS e.max CAD) and the other group consisted of porcelain-fused to metal crowns ("PFM"). All restorations were cemented onto the prepared teeth following the manufacturer's instruction of the corresponding luting cement. Subsequently, they were thermo-mechanically aged and then loaded until fracture. Load-bearing capacities (Fmax) between the groups were compared applying the Kruskal-Wallis test (p < 0.05) and pairwise group comparisons using the Dunn's method. RESULTS: Median values (and quartiles) for the load-bearing capacity amounted to (Fmax) 2'407 (1'670; 2'490) N for the CLD group and to 2'033 (1'869; 2'445) N for the PFM group. For the 0.5 mm thick restorations Fmax reached the highest median value in group 0.5-HYC 2'390 (1'355; 2'490) N, followed by 0.5-COC 2'200 (1'217; 2'492) N and 0.5-LDC 1'692 (1'324; 2'355) N. No results were obtained for group 0.5-ZIR due to the impracticability to fabricate ultra-thin specimens. The distribution of the values for the 1.0 mm thick restorations was 2'489 (2'426; 2'491) N for 1.0-COC, 2'299 (2'156; 2'490) N for 1.0-ZIR, 2'124 (1'245; 2'491) N for 1.0-HYC, and 1'537 (1'245; 1'783) N for 1.0-LDC. The differences of the medians between the test and the control groups did not reach statistical significance for the 0.5 mm thick specimens (KW: p = 0.6952 and p = 0.6986). Within the groups exhibiting 1.0 mm thickness, however, significant different medians were found: 1.0-LDC < 1.0-ZIR and 1.0-LDC < 1.0-COC (KW: p < 0.0209). CONCLUSIONS: Regarding their maximum load-bearing capacity, minimally invasive occlusal veneers made of ceramic and hybrid materials can be applied to correct occlusal tooth wear and thus replace conventional crown restorations. PMID- 30447558 TI - Attachment style and history of childhood abuse in suicide attempters. AB - Insecure attachment style has been observed in some people with a history of suicide attempt. Furthermore, some types of abuse in childhood may predict suicide attempt in adulthood. The purpose of this study was to assess the attachment style, history of abuse, demographic information and number of suicide attempts in suicide attempters. This cross-sectional study was performed on 80 suicide attempters in Tehran in 2017. Demographic information, suicide behavior, attachment style and history of childhood abuse were assessed in a psychological interview using the Revised Adult Attachment Scale. Of all, 38.8% had attempted suicide once and 45% had experienced heavy maltreatment in childhood. There was no significant correlation between the number of suicide attempts and the attachment style. History of abuse could predict the number of suicide attempts in 17.3%, which was not significant; 78.8% had avoidant attachment style. The frequency of avoidant and ambivalent attachment styles was higher in suicide attempters who had experienced maltreatment in childhood. Considering the important role of attachment style and history of abuse in attempting suicide, knowledge in this regard is important especially in those at risk of suicide attempt to plan early psychological intervention and prevent suicide. PMID- 30447559 TI - Mechanism of the photo-induced activation of CoC bond in methylcobalamin dependent methionine synthase. AB - Methylcobalamin (MeCbl)-dependent enzyme methionine synthase (MetH), plays a critical role in the catalysis of methyl group transfer from methyltetrahydrofolate (CH3-H4folate) to homocysteine. It often performs a side reaction to generate cob(II)alamin through photolysis of the organometallic CoC sigma bond. A hybrid QM/MM method has been applied to explore the photochemistry of MeCbl-bound MetH. The photolytic properties of MeCbl inside MetH are mediated by its manifold of low-lying excited states. The corresponding potential energy surfaces (PESs) of the electronically excited S1 state has been constructed as a function of axial bond lengths to elucidate the mechanism of photo-induced activation of CoC bond inside the enzyme. The analysis of the S1 PES has revealed that the two different electronic states of the S1 PES, namely metal-to-ligand charge transfer (MLCT) and the ligand field (LF), are relevant to the photodissociation of the CoC bond. There are two possible pathways identified, Path A and Path B, that connect the MLCT to LF state that represent possible photodissociation mechanisms. In the case of MetH, one possible photodissociation pathway (Path B) was identified based on the energetics of the MLCT and LF states. The energetically accessible Path B involves the initial detachment of the Co-NIm bond followed by a subsequent displacement of the CoC bond prior to the formation of cob(II)alamin / CH3 radical pair (RP). The photochemical data of base-on MeCbl in solution was compared with the computed result of MeCbl-bound MetH to understand the effect of the enzymatic environment on the photolytic properties of MeCbl. PMID- 30447560 TI - Intensive care admission criteria for traumatic brain injury patients across Europe. AB - Within a prospective, observational, multi-center cohort study 68 hospitals (of which 66 responded), mostly academic (n = 60, 91%) level I trauma centers (n = 44, 67%) in 20 countries were asked to complete questionnaires regarding the "standard of care" for severe neurotrauma patients in their hospitals. From the questionnaire pertaining to ICU management, 12 questions related to admission criteria were selected for this analysis. The questionnaires were completed by 66 centers. The median number of TBI patients admitted to the ICU was 92 [interquartile range (IQR): 52-160] annually. Admission policy varied; in 45 (68%) centers, patients with a Glasgow Come Score (GCS) between 13 and 15 without CT abnormalities but with other risk factors would be admitted to the ICU while the rest indicated that they would not admit these patients routinely to the ICU. We found no association between ICU admission policy and the presence of a dedicated neuro ICU, the discipline in charge of rounds, the presence of step down beds or geographic location (North- Western Europe vs. South - Eastern Europe and Israel). Variation in admission policy, primarily of mild TBI patients to ICU exists, even among high-volume academic centers and seems to be largely independent of other center characteristics. The observed variation suggests a role for comparative effectiveness research to investigate the potential benefit and cost-effectiveness of a liberal versus more restrictive admission policies. PMID- 30447561 TI - Synergetic degradation of VOCs by vacuum ultraviolet photolysis and catalytic ozonation over Mn-xCe/ZSM-5. AB - Volatile organic compounds (VOCs) are one of the most important precursors to form the fine particulate matter and photochemical smog, and should be strictly controlled. Vacuum ultraviolet (VUV) photolysis has provided a facile and an effective way to remove VOCs due to its powerful oxidation capability under mild reaction conditions. However, VUV irradiation would generate ozone which brings about secondary pollution. In this study, ZSM-5 supported Mn-Ce mixed oxides (Mn xCe/ZSM-5) were fabricated as efficient catalysts for ozone catalytic oxidation (OZCO) process, which were applied in combination with VUV photolysis to remove O3 byproduct and simultaneously facilitate toluene oxidation. The results indicated that the Mn-3Ce/ZSM-5 catalyst considerably enhanced the catalytic degradation efficiency up to 93% for the gas-phase toluene, one of the hazardous VOCs. Meanwhile, almost all the O3 by-product could be eliminated in the process. It was found that the strong interaction of the MnOCe bond and the variable chemical valence of Mn and Ce based species in the mixed oxides would tune the redox capacity of Mn-xCe /ZSM-5. An increase in surface Ce3+ species and surface density of oxygen vacancies would benefit the adsorption and catalytic transformation of O3 which eventually form the reactive oxygen species over Mn xCe/ZSM-5. PMID- 30447562 TI - Plant tannin immobilized Fe3O4@SiO2 microspheres: A novel and green magnetic bio sorbent with superior adsorption capacities for gold and palladium. AB - In this paper, a new core-shell nanostructured magnetic bio-based composite was prepared by immobilizing persimmon tannin (PT) onto Fe3O4@SiO2 microspheres, and the as designed Fe3O4@SiO2@PT was utilized for adsorptive recovery of Au(III) and Pd(II). The preparation, morphology, composition and magnetic property of Fe3O4@SiO2@PT were characterized. Adsorption parameters of Fe3O4@SiO2@PT towards Au(III) and Pd(II) including initial pH, reaction time, initial concentration of metal ions, effect of acidity and interference of coexisting metal ions were investigated. It is sufficiently confirmed that silica was coated on Fe3O4 and persimmon tannin was immobilized on aminated Fe3O4@SiO2. The thickness of silica and loaded persimmon tannin are around 18 nm and 14 nm, respectively. With only 1.00 wt% of persimmon tannin, however, the maximum adsorption capacities of Fe3O4@SiO2@PT for Au(III) and Pd(II) were as high as 917.43 and 196.46 mg.g-1, respectively. In addition, after adsorption of Au(III) and Pd(II), the magnetization saturation values (Ms) of Fe3O4@SiO2@PT were high enough to guarantee efficient magnetic seperation. Metallic gold could be facilely recovered from wastewaters containing Au(III). PMID- 30447563 TI - Degradation behavior of palm oil mill effluent in Fenton oxidation. AB - An in-depth study on degradation behavior of palm oil mill effluent (POME) in Fenton oxidation was accomplished with complete carbon and nitrogen balances. Experiments were conducted for real POME with a pH range of 2-5. POME contained high COD (50,000 mg/L), nitrogen (520 mg/L) and phosphorous (510 mg/L). Carboxylic acids and phenol covered 88% of organic carbons while ammonia, NO2- and NO3- contributed for 73% of nitrogen. Most of carboxylic acids and phenol were decomposed forming easily-biodegradable formic, phthalic and acetic acids, and further decomposed to carbonate and gaseous carbon dioxide. Part of carbon in liquid phase in POME transferred to solid phase by oligomerization of aromatic compounds. Ammonia was oxidized to NO2-, NO3- and gaseous N2 while, acetamide degradation led to ammonia formation. 99.9% of phosphorus was removed. Increasing H2O2 concentration elevated organic reduction and the highest TOC reduction of 91% was obtained at TOC:H2O2:Fe2+ molar ratio of 1:3.7:0.6 within 90-180 min which is extremely faster over the available biological treatments. Under the reaction conditions used in this study, Fenton oxidation at pH 3 showed the best result in terms of TOC reduction. Outcomes of this study will provide a platform for advanced oxidation processes and POME treatment. PMID- 30447564 TI - Applying microbial biogeography in soil forensics. AB - The ubiquity, heterogeneity and transferability of soil makes it useful as evidence in criminal investigations, especially using new methods that survey the microbial DNA it contains. However, to be used effectively and reliably, more needs to be learned about the natural distribution patterns of microbial communities in soil. In this study we examine these patterns in detail, at local to regional scales (2 m-260 km), across an environmental gradient in three different soil types. Geographic location was found to be more important than soil type in determining the microbial community composition: communities from the same site but different soil types, although significantly different from each other, were still much more similar to each other than were communities from the same soil type but from different sites. At a local scale (25-1000 m), distance-decay relationships were observed in all soil types: the farther apart two soil communities were located, even in the same soil type, the more they differed. At regional-scale distances (1-260 km), differences between communities did not increase with increased geographic distance between them, and the dominant factor determining the community profile was the physico-chemical environment, most notably annual precipitation (R2 = 0.69), soil sodium (R2 = 0.49) and soil ammonium (R2 = 0.47) levels. We introduce a likelihood-ratio framework for quantitative evaluation of soil microbial DNA profile evidence in casework. In conclusion, these profiles, along with detailed knowledge of natural soil microbial biogeography, provide valuable forensic information on soil sample comparison and allow the determination of approximate source location on large (hundreds of km) spatial scales. Moreover, at small spatial scales it may enable pinpointing the source location of a sample to within at least 25 m, regardless of soil type and environmental conditions. PMID- 30447565 TI - A placebo controlled treatment trial of sertraline and interpersonal psychotherapy for postpartum depression. AB - BACKGROUND: The purpose of the present study was to test the efficacy of sertraline and Interpersonal Psychotherapy (IPT) relative to pill placebo in a two site randomized controlled trial over a period of 12 weeks. It was hypothesized that sertraline and IPT would be more efficacious than pill placebo with respect to depression and social adjustment. METHODS: 162 breastfeeding and non-breastfeeding women experiencing a major depressive episode in the first year postpartum from two sites in Iowa and Rhode Island were randomly assigned to IPT, sertraline-clinical management (CM), or pill placebo-CM. CM included infant focused psychoeducation. Interview-based and self-report measures of depression and social adjustment were obtained at baseline, 4-weeks, 8-weeks, and 12-weeks of treatment. Linear mixed effects regression (LMER) was used for the longitudinal data analysis. RESULTS: There was no significant effect for treatment condition associated with the primary outcome measure, the HamD-17, but there was a significant effect for sertraline-CM relative to the IPT and placebo conditions over the duration of the trial based on the General Depression scale of the Inventory of Depression and Anxiety Symptoms. There was a main effect for time in that study subjects across all three conditions showed significant improvement for the duration of the trial. LIMITATIONS: Limitations of the present study included significant non-engagement with assigned condition and differential effects of IPT across the two study sites. CONCLUSIONS: There was improvement for all postpartum women in all conditions. The results do suggest that active interventions with or without medication delivered over a period of twelve weeks can lead to significant improvement in depression and social adjustment among postpartum women. ClinicalTrials.gov identifier: NCT00602355. PMID- 30447566 TI - Inflammatory cytokines and cognitive functioning in early-stage bipolar I disorder. AB - BACKGROUND: Increased circulating inflammatory cytokines is a replicated finding in bipolar I disorder (BDI). Pro-inflammatory cytokines such as TNFalpha, IL-6 and IL-1 have also been associated with poorer cognitive functioning in patients with longer illness duration. However, the effect of inflammatory cytokines on cognition in early stage patients is not yet known. Here, we investigate the relationship between cytokines and cognition in BDI patients within three years of diagnosis. METHODS: Serum pro-inflammatory (TNFalpha, IL-6 and IL-1alpha) and anti-inflammatory (IL-4 and IL-10) cytokine levels were compared between 51 early stage BDI patients and 20 healthy controls. 46 patients completed neuropsychological testing, and multiple regression analysis was used to assess the association between cytokine levels and cognition after accounting for relevant clinical and demographic variables. RESULTS: TNFalpha was elevated at trend level significance in BDI patients compared to healthy controls, and was negatively associated with global cognition, processing speed, and working memory in patients. IL-6, IL-1alpha, IL-4 and IL-10 levels were comparable between groups and were not significantly associated with cognition. LIMITATIONS: Direct causation cannot be established in this cross-sectional study; in addition, cytokine levels were not taken on the same day as neuropsychological testing for all patients. CONCLUSIONS: TNFalpha may negatively impact cognition in early BDI. While replication is required in larger samples, these results suggest that inhibition of TNFalpha activity might be a strategy to preserve cognition in newly diagnosed BDI patients. PMID- 30447567 TI - A longitudinal view of rumination, poor sleep and psychological distress in adolescents. AB - BACKGROUND: Given the high prevalence and negative impact of psychological problems during adolescence, examining transdiagnostic factors that may have scope to positively influence a variety of psychological problems is imperative. The main purpose of this study was to investigate the longitudinal relationship between rumination and psychological distress and whether sleep mediated this relationship over a 2 year period. METHODS: Participants were 1620 high school students in the 7th and 8th grade at baseline from 17 public schools in three middle Sweden communities. Students completed questionnaires at school during the spring of 2014, 2015 and 2016. Rumination and psychological distress were self reported, and sleep duration was calculated from reported bed-times, wake-times and sleep onset latencies. RESULTS: Sleep duration declined with age, whereas rumination and psychological distress increased. Rumination was predictive of future psychological distress and distress at a given time was predictive of concurrent rumination. Sleep duration did not consistently mediate the reciprocal relationships between rumination and psychological distress over time. LIMITATIONS: Stronger longitudinal associations may have been obtained by using smaller measurement intervals or further delineation of outcome constructs. CONCLUSIONS: Reducing rumination, rather than targeting sleep patterns, may work towards preventing the development of a number of psychological problems and is a strategy anticipated to function across disorders to improve young people's mental wellbeing. PMID- 30447568 TI - Association between chronic somatic conditions and depression in children and adolescents: A retrospective study of 13,326 patients. AB - AIMS: The goal of this study was to analyze the association between chronic somatic conditions and depression diagnosis in children and adolescents. METHODS: The present case-control study included 13,326 children and adolescents with depression as well as controls without depression followed in 243 pediatric practices between 2010 and 2015. Cases and controls were matched by age, gender, index year, and physician. The effect of several chronic disorders in terms of the risk of developing depression was estimated using logistic regression models. RESULTS: Depression was diagnosed in 0.7% of the population. The prevalence of depression increased with age from 0.2% in individuals aged 7 years to 2.0% in those aged 15 years. Depression was significantly associated with anorexia nervosa (OR = 6.69), ADHD (OR = 2.32), chronic sinusitis (OR = 1.82), short stature due to endocrine disorder (OR = 1.70), obesity (OR = 1.57), disorders of the thyroid gland (OR = 1.53) and certain disorders involving the immune mechanism (OR = 1.42). The risk of a depression diagnosis also increased with the number of chronic conditions (one condition: OR = 1.69; two conditions: OR = 1.81; more than two conditions: OR = 2.03). CONCLUSIONS: Depression was associated with several chronic disorders and the number of such conditions in pediatric practices in Germany. Therefore, depression should be regularly assessed in young patients affected by chronic disorders. PMID- 30447569 TI - Spanish adaptation of the Dimensional Anhedonia Rating Scale (DARS). AB - BACKGROUND: Anhedonia is defined as the lack of enjoyment, engagement in, or energy for life's experiences. Only two scales to measure anhedonia have been adapted for use in Spanish-speaking populations. The aim of this study was to determine the reliability and validity of the Dimensional Anhedonia Rating Scale (DARS) following translation and adaptation for Spanish population. METHOD: The study sample included 134 patients over 18 years of age with a range of psychiatric diagnoses. Those with substance use, decompensated medical conditions, illiteracy, or lack of fluency in Spanish were excluded. The structure of the Spanish adaptation was evaluated through factor analysis. Internal reliability was assessed through Cronbach's alpha and validity was measured using Pearson's correlation between total scores for DARS and its subscales and SHAPS score. RESULTS: A strong internal consistency was observed (Cronbach alpha = 0.92 for total scale score and 0.91-0.92 for subscale scores). Similarly, a significant and strong correlation between total scores for DARS and SHAPS was found (r = 0.51, p < 0.01). LIMITATIONS: The heterogeneous distribution of diagnoses included in the study may limit our results. CONCLUSIONS: The Spanish DARS maintains the psychometric properties of the original questionnaire, with strong internal consistency and adequate validity. DARS is a specific questionnaire for evaluating anhedonia, incorporating elements that reflect motivation, interest, and effort, and one which offers possible advantages over other anhedonia scales. PMID- 30447570 TI - 'The Button Question': A mixed-methods study of whether patients want to keep or remove bipolar disorder and the reasons for their decision. AB - BACKGROUND: Many people with a diagnosis of bipolar disorder associate positive qualities with their condition, which may place a ceiling on the effectiveness of treatment and the likelihood of recovery. However, the extent to which patients would, or would not, want to be free of their bipolar disorder has not been directly assessed. METHOD: An international online survey of 103 people (80 female, 23 male) with bipolar disorder assessed whether they would want to permanently remove their bipolar disorder with a 'button press', as well as whether they would do the same if the effect was reversible. We also coded and analysed free-text reasons for their decisions. RESULTS: A total of 75 individuals (73%) would permanently remove their bipolar disorder and most of these did not report that bipolar disorder was part of their identity. A smaller number, 49 (48%) of the sample, would 'switch off' their bipolar disorder if the effect was reversible and most of these individuals reported enhanced qualities and the 'fun' of mania. Distinct positive and negative qualities of bipolar disorder were identified. CONCLUSIONS: This mixed-method analysis has revealed wide variation and contrasts in attitudes. There is a sizeable minority of individuals who would not wish to remove their bipolar disorder for specific reasons, and knowledge of these reasons can inform approaches to interventions that are tailored to the individual. PMID- 30447571 TI - Epigenetic variation at the SLC6A4 gene promoter in mother-child pairs with major depressive disorder. AB - BACKGROUND: Genetic and epigenetic variations of the serotonin transporter gene (SLC6A4) have been related to the etiology of depression. The 5-HTTLPR polymorphism at the SLC6A4 promoter region has two variants, a short allele (S) and a long allele (L), in which the S allele results in lower gene transcription and has been associated with depression. The short S-allele of 5-HTTLPR polymorphism of this gene has been associated with depression. In addition to molecular mechanisms, exposure to early life risk factors such as maternal depression seems to affect the development of depression in postnatal life. The present study investigated the association of 5-HTTLPR polymorphism and CpG DNA methylation (5mC) levels of an AluJb repeat element at the SLC6A4 promoter region in mother-child pairs exposed to maternal depression. METHODS: We analyzed DNA samples from 60 subjects (30 mother-child pairs) split into three groups, with and without major depression disorder (DSM-IV) among children and mothers. The genotyping of 5-HTTLPR polymorphism and quantification of 5mC levels was performed by qualitative PCR and methylation-sensitive restriction enzyme digestion, and real-time quantitative PCR (MSRED-qPCR), respectively. RESULTS: The sample analyzed presented a higher frequency of S allele of 5-HTTLPR (67.5%). Despite the high frequency of this allele, we did not find statistically significant differences between individuals carrying at least one S allele between the depression and healthy control subjects, or among the mother-child pair groups with different patterns of occurrence of depression. In the group where the mother and child were both diagnosed with depression, we found a statistically significant decrease of the 5mC level at the SLC6A4 promoter region. LIMITATIONS: The limitations are the relatively small sample size and lack of gene expression data available for comparison with methylation data. CONCLUSION: In this study, we demonstrated a repeat element specific 5mC level reduction in mother-child pairs, concordant for the diagnosis of depression. PMID- 30447572 TI - The effectiveness and cost-effectiveness of e-health interventions for depression and anxiety in primary care: A systematic review and meta-analysis. AB - PURPOSE: Psychological interventions are labor-intensive and expensive, but e health interventions may support them in primary care. In this study, we systematically reviewed the effectiveness and cost-effectiveness of e-health interventions for depressive and anxiety symptoms and disorders in primary care. METHODS: We searched MEDLINE, Cochrane library, Embase, and PsychINFO until January 2018, for randomized controlled trials of e-health interventions for depression or anxiety in primary care. Two reviewers independently screened the identified publications, extracted data, and assessed risk of bias using the Cochrane Collaboration's tool. RESULTS: Out of 3617 publications, we included 14 that compared 33 treatments in 4183 participants. Overall, the methodological quality was poor to fair. The pooled effect size of e-health interventions was small (standardized mean difference = -0.19, 95%CI -0.31 to -0.06) for depression compared to control groups in the short-term, but this was maintained in the long term (standardized mean difference = -0.22, 95%CI -0.35 to -0.09). Further analysis showed that e-health for depression had a small effect compared to care as usual and a moderate effect compared to waiting lists. One trial on anxiety showed no significant results. Four trials reported on cost-effectiveness. LIMITATIONS: The trials studied different types of e-health interventions and had several risks of bias. Moreover, only one study was included for anxiety. CONCLUSIONS: E-health interventions for depression have a small effect in primary care, with a moderate effect compared to waiting lists. The approach also appeared to be cost-effective for depression. However, we found no evidence for its effectiveness for anxiety. PMID- 30447573 TI - Molecular assessment of wild populations in the marine realm: Importance of taxonomic, seasonal and habitat patterns in environmental monitoring. AB - Scientists are currently faced with the challenge of assessing the effects of anthropogenic stressors on aquatic ecosystems. Cellular stress response (CSR) biomarkers are ubiquitous and phylogenetically conserved among metazoans and have been successfully applied in environmental monitoring but they can also vary according to natural biotic and abiotic factors. The reported variability may thus limit the wide application of biomarkers in monitoring, imposing the need to identify variability levels in the field. Our aim was to carry out a comprehensive in situ assessment of the CSR (heat shock protein 70 kDa, ubiquitin, antioxidant enzymes) and oxidative damage (lipid peroxidation) in wild populations across marine taxa by collecting fish, crustaceans, mollusks and cnidarians during two different seasons (spring and summer) and two habitat types (coast and estuary). CSR end-point patterns were different between taxa with mollusks having higher biomarker levels, followed by the cnidarians, while fish and crustaceans showed lower biomarker levels. The PCA showed clear clusters related to mobility/sessile traits with sessile organisms showing greater levels (>2-fold) of CSR proteins and oxidative damage. Mean intraspecific variability in the CSR measured by the coefficient of variation (% CV) (including data from all seasons and sites) was elevated (35-94%). Overall, there was a seasonal differentiation in biomarker patterns across taxonomic groups, especially evident in fish and cnidarians. A differentiation in biomarker patterns between habitat types was also observed and associated with phenotypic plasticity or local adaptation. Overall, specimens collected in the estuary had lower biomarker levels when compared to specimens collected in the coast. This work highlights the importance of assessing baseline biomarker levels across taxa, seasons and habitats prior to applying biomarker analyses in environmental monitoring. Selecting bioindicator species, defining sampling strategies, and identifying confounding factors are crucial preliminary steps that ensure the success of biomarkers as powerful tools in biomonitoring. PMID- 30447574 TI - Improvement of MODIS cloud mask over severe polluted eastern China. AB - Previous studies have proved that in the regions with severe air pollution, MODIS cloud mask product (MYD35) tends to overestimate the cloud cover largely. An important reason is that the dense aerosols could be misclassified as clouds. Identification of the misdetected "clouds" of passive remote sensing satellites remains challenging. In this study, we built an algorithm combining screening method and adjusted Fisher Discriminant Analysis (AFDA) to rectify the cloud free pixels misclassified as cloudy in the MYD35 product over the eastern China (EC), where heavy haze pollution occurs frequently in fall and winter. The CALIPSO vertical feature mask (VFM) product was used as an accurate reference. The results showed that our algorithm performs well in the discrimination of the true clouds and misdetected clouds, including the ones caused by the misjudgment of near surface aerosols in heavy haze. The average accuracy reached 96.72%. In EC, fogs ought to be classified as clouds often mixed with haze, resulting difficulty to distinguish fogs and haze. Compared with surface observed fogs, our algorithm also has a good effect on identification of the surface fog in EC with an accuracy of 81.53%. Mean values of a series of cloud properties showed great changes after filtering the misclassified MYD35 cloudy pixels. Thereinto, cloud cover decreased by 0.13, other parameters, including cloud top height, cloud optical thickness, cloud effective radius and cloud water path, also changed significantly. PMID- 30447575 TI - Vertical distribution of heavy metals in seawater column during IBA construction in land reclamation - Re-exploration of a large-scale field trial experiment. AB - Data from large-scale field trial experiments simulating the application of incineration bottom ash (IBA) for land reclamation were re-explored, to understand the spot-specific leaching characteristics and re-adsorption of heavy metals associated with various reclamation scenarios. Data showed that IBA leaching changed significantly as a function of seawater depth rather than time. The application of a chute had a minor effect on the total metal leached amounts; however, it would magnify the gradient of leaching concentrations across depths. Metal re-adsorption occurred within half an hour after IBA dumping, which however was significantly alleviated when a chute was applied. It may be ascribed to various degrees of contact with seawater of IBA, seawater movements and particle resuspension. Batch leaching tests from the laboratory under different L/S ratios were conducted as the references to "effective" leaching behaviors in the large scale experiments, suggesting that the batch leaching test with the liquid to solid ratio = 10 provide a closer estimation of IBA leaching concentrations during land reclamation. As the current study took account of major field factors during land reclamation, including seawater depth (m), IBA loading (ton), IBA dropping method, particle dispersive area (m2), and settling time (min), these findings are valuable for the risk assessment of IBA utilization in land reclamation. PMID- 30447576 TI - Hydroperiod, soil moisture and bioturbation are critical drivers of greenhouse gas fluxes and vary as a function of landuse change in mangroves of Sulawesi, Indonesia. AB - The loss and degradation of mangroves can result in potentially significant sources of atmospheric greenhouse gas (GHG) emissions. For mangrove rehabilitation carbon projects, quantifying GHG emissions as forests regenerate is a key accounting requirement. The current study is one of the first attempts to systematically quantify emissions of carbon dioxide (CO2), nitrous oxide (N2O) and methane (CH4) from: 1) aquaculture ponds, 2) rehabilitating mangroves, and 3) intact mangrove sites and frame GHG flux within the context of landuse change. In situ static chamber measurements were made at three contrasting locations in Sulawesi, Indonesia. The influence of key biophysical variables known to affect GHG flux was also assessed. Peak GHG flux was observed at rehabilitating (32.8 +/ 2.1 Mg CO2e ha-1 y-1) and intact, mature reference sites (43.8 +/- 4.5 Mg CO2e ha-1 y-1) and a dry, exposed disused aquaculture pond (30.6 +/- 1.9 Mg CO2e ha-1 y-1). Emissions were negligible at low productivity rehabilitating sites with high hydroperiod (mean 1.0 +/- 0.1 Mg CO2e ha-1 y-1) and an impounded, operational aquaculture pond (1.1 +/- 0.2 Mg CO2e ha-1 y-1). Heterogeneity in biophysical conditions and geomorphic position exerted a strong influence on GHG flux, with the longer hydroperiod and higher soil moisture content of seaward fringing mangroves correlated with decreased fluxes. A greater abundance of Mud lobster mounds and root structures in landward mangroves correlated to higher flux. When viewed across a landuse change continuum, our results suggest that the initial conversion of mangroves to aquaculture ponds releases extremely high rates of GHGs. Furthermore, the re-institution of hydrological regimes in dry, disused aquaculture ponds to facilitate tidal flushing is instrumental in rapidly mediating GHG flux, leading to a significant reduction in baseline emissions. This is an important consideration for forest carbon project proponents seeking to maximise creditable GHG emissions reductions and removals. PMID- 30447577 TI - Disentangling the role of climate and soil on tree growth and its interaction with seed origin. AB - When considering options for adapting forests under climate change, climate is treated as the dominant driver of forest growth, while soil properties are often ignored mainly due to shortage of accurate data. The effects of climate and soil on forest growth may vary due to local adaptation to both climate and soil, and these local adaptations might need to be considered when transferring seed provenances under climate change. Data from 29 provenance trials of Norway spruce (Picea abies (L.) Karst.) across a wide gradient of planting conditions in Austria was used to develop Structural Equation Models (SEMs) to quantified the role of climatic and soil drivers and their interactions on juvenile growth performance and to test if provenance origin affects the relative importance of these drivers. Climate and soil of the planting site location were found to have similar direct effects on juvenile tree growth, however, climate was found to be more important because of additional indirect effects via interactions with soil parameters. Notably, the relative effects of climate and soil vary among different provenance groups. Climate constraints are dominant for seed sources originating from colder and/or high altitude locations, while test site climate and soil are equally important contributors of growth for provenances originating from warmer origin and lower elevation sites. Together with the better growth performance of the latter provenance group their plasticity allows them to utilize a wide range of soil conditions. PMID- 30447578 TI - Zinc-biofortified wheat accumulates more cadmium in grains than standard wheat when grown on cadmium-contaminated soil regardless of soil and foliar zinc application. AB - Zinc (Zn)-biofortified wheat may contribute to decreasing widespread human Zn deficiency. Such genotypes may also accumulate cadmium (Cd) in grains that would expect to be decreased by Zn application. However, the influence of soil and foliar Zn application on grain Cd accumulation in Zn-biofortified versus standard wheat is unknown. In our experiment, we grew standard (Faisalabad-2008) and Zn biofortified (Zincol-2016) wheats in pots having uncontaminated (T0) or Cd-spiked (8 mg kg-1) soil. Plants in Cd-amended pots were treated with no Zn (T1), 8 mg Zn kg-1 to soil at sowing (T2), 0.5% w/v ZnSO4.7H2O to foliage at booting and heading (T3), or soil (as in T2) + foliar (as in T3) Zn application (T4). Only in the uncontaminated control, grain yield of Faisalabad-2008 was greater than Zincol-2016. Any Zn application to Zincol-2016 grown in Cd-spiked pots increased grain yield compared with the uncontaminated control. In both cultivars, grain Zn concentration was influenced more by foliar than soil Zn application. However, Zincol-2016 had 6 to 14 mg more Zn kg-1 in grains than Faisalabad-2008 in the comparable treatments. Cadmium exposure (T1 vs. T0) decreased grain yield of only Faisalabad-2008, and decreased grain Zn concentration only in Zincol-2016. Without any Zn application, grain Cd concentration in both cultivars exposed to Cd was above the permissible level (0.20 mg kg-1). Zinc application decreased grain Cd concentration, although it remained above the permissible level in both cultivars except in Faisalabad-2008 when treated with soil + foliar Zn. Foliar Zn application decreased grain Cd concentration more than soil Zn application, and more in Zincol-2016 than Faisalabad-2008. In the comparable Cd-spiked treatments, Zincol-2016 had 73 to 134% higher grain Cd concentration than Faisalabad-2008. The Zn-biofortified genotypes accumulating toxic metals may pose serious health issues. Therefore, future breeding for biofortification should focus on the selective accumulation of Zn. PMID- 30447579 TI - What do we know about lead contamination in wild vultures and condors? A review of decades of research. AB - Vultures and condors (hereafter vultures) make up one the most threatened avian guilds in the world due to a variety of human-mediated impacts and disturbances. In fact, 70% of vulture species are currently suffering impacted by significant conservation threats, with lead contamination being particularly important. Unfortunately, lead contamination in vulture species remains poorly studied in many regions of the world. We reviewed the existing scientific knowledge about this threat to vultures. We found 62 scientific articles studying lead contamination in vultures. Seventy-two percent of these articles were from North America and Europe, with the rest corresponding to Asia (13%), South America (8%), and Africa (7%). Most (92%) were published recently (2001-2018). Published articles included information on 13 vulture species out of a total of 23 from both the Old (9) and New World (4). Eighty-eight percent of the articles showed individuals with lead concentrations above threshold levels in some tissues sampled, with New World (Cathartidae) vultures more affected than Old World vultures (Accipitridae). The most suspected but rarely probed source of lead was lead ammunition, but other sources such as pollution or industry were also reported. It is concerning that lead contamination is considered a major threat for just 8% (2/23) of the vulture species categorized by the IUCN Red list. Our review shows that lead contamination is an important threat for several vulture species worldwide, but remains undiagnosed and not well-recognized in some species and geographical areas. The effect of this contaminant on vulture demography is not well known but merits particular attention since it may be leading to population declines in several species. PMID- 30447580 TI - The impact of political, socio-economic and cultural factors on implementing environment friendly techniques for sustainable land management and climate change mitigation in Romania. AB - Throughout the history of Romania, political decisions, socio-economic measures, and cultural (traditional) characters have affected the implementation of environment friendly techniques (EFTs) policies. In the context of this paper, EFTs can be defined as solutions for the use of land resources aiming the increasing of goods for meeting the changing human needs and with neutral or positive environmental impact. Changes in the political regime have always had a visible impact on the EFTs issue in Romania. EFTs has gone through several major phases. The political impact on EFTs implementation mainly affected sustainable land management (SLM) and to a small extent, at the end of the communist era and partly during the capitalist period, climate change mitigation. Throughout history, the political factor has dominated and influenced the capacity of the EFTs implementation process in responding to socio-economic stimuli. In addition, quality of life, rural-urban and urban-rural migrations, poverty, education level, and climate change adaptation have had impacts on the status of EFTs according to governance and political reflections. The agrarian reforms from the last two centuries, based on socio-economic demands, have strongly influenced the capacity to implement EFTs both positively and negatively. However, the cultural factor was least affected by political and socio-economic changes as a stability factor in ensuring continued implementation of the EFTs. Currently, there is a strong need to reconsider EFTs as sustainability tools for Romanian agriculture that can cope with climate change and sustainable land management (SLM) demands. This paper presents a brief history of EFTs in Romania and their benefits in achieving SLM equilibrium, describing the impacts of political decisions, socio economic measures, and cultural features on implementing ETFs policies. PMID- 30447581 TI - Quantifying and simulating landscape composition and pattern impacts on land surface temperature: A decadal study of the rapidly urbanizing city of Beijing, China. AB - The increase in impervious surfaces due to the urbanization has caused many adverse effects on urban ecological systems, including the urban heat environmental risk. Revealing the relationship between landscape composition and pattern and land surface temperature (LST) gives insight into how to effectively mitigate the urban heat island (UHI) effect. It is also essential to simulate and optimize the distribution of impervious surfaces in urban planning. In this study, the multi-scale relationship between impervious surface and LST in Beijing was analyzed. Different distributions of land cover types and the corresponding LSTs were simulated under two development scenarios. Various geospatial approaches, including geographic information system (GIS), remote sensing, and the Conversion of Land Use and its Effects at Small regional extent (CLUE-S), were used to facilitate the analysis. The results showed that (1) impervious surfaces increased from 36.76% to 44.95% of the total area between 2005 and 2015 and the mean LST of impervious surfaces was approximately 2 degrees C higher than that of the areas with vegetation cover; (2) impervious surfaces had a positive logarithmic correlation with LST, while the vegetation coverage had a negative linear correlation with LST; (3) as the grid size increased, the correlation coefficients between the impervious surface density and mean LST increased at different magnitudes, and the correlation coefficients stabilized after the scale of 900 * 900 m; (4) large and contiguous patches of impervious surfaces aggravated the UHI effect when the total percentage of impervious surface remained the same; and (5) to achieve an improved and healthier urban living environment, populations controls should be considered to decrease future impervious surface demands by 7.69%-which corresponds to an average LST decrease of 1.1 degrees C. Landscape distribution and configuration should also be better integrated into landscape and urban planning. PMID- 30447582 TI - The impact of straw mulching and salvage logging on post-fire runoff and soil erosion generation under Mediterranean climate conditions. AB - Forest fires-affected landscapes enhance sudden runoff discharges, high sediment loads and extreme soil erosion rates. Different soil stabilisation treatments, such as mulching, can be applied to avoid runoff and soil erosion after wildfires. To characterise the post-fire soil erosion rates and runoff generation, we selected a Mediterranean forest affected by a wildfire in Lietor (Spain) to determine the sediment yield (dry sediment (DS), total suspended sediment (TSS), total dissolved sediment (TDS)) and runoff discharge in twelve 200 m2 (10 * 20 m) plots. Immediately after the wildfire, six plots were covered by straw and six other plots were set up as controls. Three months after the wildfire, logging activities were performed and the experimental designs were as follows: mulching + logging (three replicates), non-mulching + logging (three replicates), non-mulching + non-logging (three replicates) and mulching + non logging (three replicates). During the period after wildfire and before salvage logging, the straw mulch controlled the soil erosion rates (DS, TSS and TDS) versus the non-mulched plots, but straw had no real impact on runoff discharge. For the period after salvage logging, once again runoff did not differ when comparing all the treatments. DS was higher in the non-mulched and non-logging plots, whereas the highest TSS was found in the non-mulched plots (in logged or non-logged plots). TDS was higher in the mulched and non-logged plots. We conclude that straw mulch is efficient management in recent fire-affected mountainous terrains to control soil loss immediately after wildfire. Moreover, logging operations done 3 months after wildfire did not necessary generate higher DS, TSS, TDS rates, mainly because of the type of machinery used for forest operations. PMID- 30447583 TI - Antibiotic resistance genes in bacteriophages from diverse marine habitats. AB - Although antibiotic resistance represents a significant and growing threat to human and environmental health worldwide, the contribution of bacteriophages (phages) to the acquisition and spread of antibiotic resistance genes (ARGs) in the environment has not been extensively explored. In this study, a comprehensive analysis of several viromes from diverse marine habitats was performed to investigate whether or not phages carry ARGs. The analysis provides strong evidence that phages from marine habitats are potential reservoirs of ARGs. In fact, genes conferring resistance to aminocoumarin, bacitracin and multidrug resistance (particularly the mexB gene) were found in all analyzed marine viromes. Given this, the role of phages as reservoirs of ARGs should not be underestimated considering their global distribution. PMID- 30447584 TI - Associations between the built environment and body mass index in the Mexican American Mano A Mano Cohort. AB - BACKGROUND: Obesity is highly prevalent in Mexican American adults. Studies on the role of the built environment in relation to obesity among this population are scarce. OBJECTIVES: To investigate cross-sectional associations between multiple components of the built environment, and Body Mass Index (BMI) as well as obesity status among Mexican American adults enrolled in the Mano a Mano Cohort (MAC) study in Houston, Texas. METHODS: We calculated BMI from measured height and weight among 9534 Mexican American adults (aged 20-60) who participated in the baseline survey during 2008-2013. Several metrics of exposure to the built environment (physical activity environment, land use, and food environment) were generated using Geographic Information System and Google Maps based on participants' residential address. Generalized linear regression and logistic regression models were used to estimate associations between exposure to the built environment, a continuous BMI variable and categorical BMI variables (<30, >=30 and >=35), respectively. RESULTS: Among all built environment exposure variables investigated, road density (total road length per km2) [0.21 (0.06, 0.36) as coefficient (95% CI)], intersection density (intersection links per km2) [0.74 (0.21, 1.28)], networked distance (km) [-0.29 (-0.47, -0.10)], and walking time (mins) [-0.02 (-0.04, -0.01)] to the nearest parks had statistically significantly linear associations with BMI. Those variables were found to have statistically significant associations with BMI >= 35 in logistic regression models, the odds ratio was 1.08 (1.02, 1.14) for road density, 1.31 (1.07, 1.60) for intersection density, 0.91 (0.85, 0.98) for networked distance, and 0.99 (0.99, 1.00) for walking time. None of the built environment exposure variables were found to be associated with BMI >= 30. CONCLUSIONS: Living in areas with high density of roads exhibited significant associations with increased BMI, in particular BMI >= 35, among enrolled Mexican American adults in the MAC study. PMID- 30447585 TI - Biochar additions alter phosphorus and nitrogen availability in agricultural ecosystems: A meta-analysis. AB - Biochar is a carbon (C) rich product of thermochemical conversion of organic material that is used as a soil amendment due to its resistance to decomposition and its influence on nutrient dynamics; however, individual studies on biochar effects on phosphorus (P) and nitrogen (N) have proven inconsistent. Herein, we performed a meta-analysis of 124 published studies to evaluate the influence of biochar on available P, microbial biomass P (MBP), and inorganic N (NO3--N and NH4+-N) in global agricultural ecosystems. Overall, the results showed that biochar applications significantly increased surface soil available P by 45% and MBP by 48% across the full range of biochar characteristics, soil type, or experimental conditions. By contrast, biochar addition to soil reduced NO3--N concentrations by 12% and NH4+-N by 11%, but in most cases biochar added in combination with organic fertilizer significantly increased soil NH4+-N compared to controls. Biochar C:N ratio and biochar source (feedstock) strongly influenced soil P availability response to biochar where inorganic N was most influenced by biochar C:N ratio and soil pH. Biochar made from manure or other low C:N ratio materials, generated at low temperatures, or applied at high rates were generally more effective at enhancing soil available P. It is important, however, to note that most negative results were observed in short-term (<6 months) where long term studies (>12 months) tended to result in neutral to modest positive effects on both P and N. This meta-analysis indicates that biochar generally enhances soil P availability when added to soils alone or in combination with fertilizer. These findings provide a scientific basis for developing more rational strategies toward widespread adoption of biochar as a soil amendment for agricultural P and N management. PMID- 30447586 TI - Bioavailable electron donors leached from leaves accelerate biodegradation of pyridine and quinoline. AB - Fallen leaves of Platanus orientalis and Ginkgo biloba linn were separately immersed in water to obtain leachates that were used as exogenous electron donors for accelerating pyridine and quinoline biodegradations. Leachate addition accelerated the pyridine removal rate by up to 4.4% and 3.6% and the quinoline removal rate by 9.5% and 11%. The rates increased further after the leachates were illuminated by UV light: up to 8.5% for pyridine and 12% for quinoline. Succinate and oxalate were separately added into solutions of pyridine and quinoline (respectively) to gauge the acceleration impact of the leaf leachates. Equations describing the relationships between addition of leachate and pyridine or quinoline removal rates were established based on electron-equivalent balances and comparison to the acceleration effects from succinate and oxalate. From 22% to 98% of the COD leached from leaves was available as an electron donor, with the fraction being greater for pyridine and after UV illumination. PMID- 30447587 TI - Optimizing genotype-environment-management interactions to enhance productivity and eco-efficiency for wheat-maize rotation in the North China Plain. AB - Agricultural production is facing unprecedented challenges to ensure food security by increasing productivity and in the meantime lowering environmental risk, especially in China. To enhance productivity and eco-efficiency of the typical winter wheat-summer maize rotation simultaneously in the North China Plain (NCP), we optimized the Genotype (G) * Environment (E) * Management (M) interactions to propose the optimal agronomic management practices and cultivars for four representative sites, with the Agricultural Production Systems sIMulator (APSIM) model and detailed field trial data. The results showed that an appropriate delay in sowing date could mitigate climatic negative effects and a proper increase in sowing density could increase yield. The optimal nitrogen application rate could be 180 kg N ha-1 year-1 for maize. For the cropping system, 240 mm of irrigation for wheat and 330-390 kg N ha-1 year-1 of nitrogen application rate (150-210 kg N ha-1 year-1 for wheat and 180 kg N ha-1 year-1 for maize) were suitable to sustain high yield, resource use efficiency, and lower N2O emissions. These recommended levels were, respectively, 40% less than the current irrigation and N application rate commonly used by local farmers. The recommended management practices could increase groundwater recharge while reducing nitrogen leaching and N2O emissions without reducing yield. The maize cultivars with a long growth duration, large grain number and grain-filling rate are desirable. The desirable wheat cultivars are characterized with a medium vernalization sensitivity and high grain filling rate. The present study demonstrated an effective approach to develop sustainable intensification options for producing more with less environmental costs through optimizing G * E * M interactions. PMID- 30447588 TI - Household solid fuel burning emission characterization and activity levels in India. AB - Emission factors (EFs) of PM2.5, carbon fractions, major ionic (K+, Ca2+, NH4+, SO42-, NO3- and Cl-) and elemental (Al, Cr, Cu and Fe) species from combustion of commonly used household solid fuel were determined in 10 different states in India during cooking practices. The study involved sampling during actual household cooking involving use of a variety of fuels including coal balls (CB), fuel wood (FW), dung cakes (DC), crop residues (CR), mixed fuels (MF: dung cakes + fuel woods). Species-wise highest EFs (g.kg-1) were: 34.16 +/- 10.1 for PM2.5 (CB), 14.18 +/- 5.8 for OC (CB), 2.33 +/- 1.4 for EC (DC), 1.03 +/- 0.2 for K+ (CR), 2.21 +/- 0.6 NH4+ (DC), 0.61 +/- 0.2 for NO3- (CB), 0.59 +/- 0.1 for SO42- (CB), 0.69 +/- 0.1 for Cl- (CR) among the fuels. Higher OC EFs for CB could be attributed to higher moisture content (>13%) in coal-powder that is used to handmade coal balls. It is observed that, in general, OC3 and EC1 were the dominant thermally evolved carbon mass fractions. The study averaged MCE values were in the range 0.93-0.98, which could be attributed to higher variability in flaming and smoldering episodes during the combustion of selected fuels. Sum of ionic EFs for emissions from DC, CR and MF were found to be higher than those observed for FW and CB. The K+/EC and Cl-/EC (~1) ratios could be better indicators of CR fuels to differentiate it from FW, whereas NH4+/EC (~1) is suitable to indicate DC. Average annual emission estimates of PM2.5 (2.00 +/- 0.53 Tg.yr-1), OC (0.86 +/- 0.23 Tg.yr-1) and EC (0.11 +/- 0.02 Tg.yr-1) for tested fuels are evaluated to be contributing 27, 15 and 4% of total PM2.5, OC and EC, respectively, toward annual emission budget from different anthropogenic activities in India. PMID- 30447589 TI - Effects of elevated ground-level ozone on paddy soil bacterial community and assembly mechanisms across four years. AB - It is well known that elevated ground-level ozone (eO3) poses a threat to the ecosystem. Little knowledge about the underground variables, especially on soil microorganisms, however, has been revealed. Such knowledge will tremendously help to advance our understanding of the correlation between ecosystems and climate change, as well as our ability to predict future trajectory. For this purpose, we have collected soil DNA samples (eO3 vs. Ambient, each having 36 samples) over four years. Our results have verified the temporal responses and the underlying assembly mechanisms of the paddy bacterial community to eO3. Contrary to the widespread consensus, it was found that eO3 stimulated bacterial alpha diversities. The higher complexity and the centralization of the co-occurrence network of the bacterial community suggested that this stimulation was due to a microbial survival strategy in response to the limited resources, which led to the instability of the community. Furthermore, the observed slower temporal turnover of the bacterial community composition in response to eO3 was due to the decreased deterministic processes derived from plants, which implied that eO3 disrupted the coordination between soil microorganisms and rice crop. All above phenomena provided novel insights into the adverse influences of eO3 on the soil microbial community. If O3 concentration increases continuously, the adverse effects will be aggravated and harm the related ecological functions. PMID- 30447590 TI - Estimation of personal exposure to fine particles (PM2.5) of ambient origin for healthy adults in Hong Kong. AB - Personal exposure and ambient fine particles (PM2.5) measurements for 13 adult subjects (ages 19-57) were conducted in Hong Kong between April 2014 and June 2015. Six to 21 personal samples (mean = 19) per subject were obtained throughout the study period. Samples were analyzed for mass by gravimetric analysis, and 19 elements (from Na to Pb) were analyzed using X-Ray Fluorescence. Higher subject specific correlations between personal and ambient sulfur (rs = 0.92; p < 0.001) were found as compared to PM2.5 mass (rs = 0.79; p < 0.001) and other elements (0.06 < rs < 0.86). Personal vs. ambient sulfur regression yielded an average exposure factor (Fpex) of 0.73 +/- 0.02, supporting the use of sulfur as a surrogate to estimate personal exposure to PM2.5 of ambient origin (Ea). Ea accounted for 41-82% and 57-73% of total personal PM2.5 exposures (P) by season and by subject, respectively. The importance of both Ea and non-ambient exposures (Ena, 11.2 +/- 5.6 MUg/m3; 32.5 +/- 10.9%) are noted. Mixed-effects models were applied to estimate the relationships between ambient PM2.5 concentrations and their corresponding exposure variables (Ea, P). Higher correlations for Ea (0.90; p < 0.001) than for P (0.58; p < 0.01) were found. A calibration coefficient < 1 suggests an attenuation of 22% (ranging 16-28%) of the true effect estimates when using average ambient concentrations at central monitoring stations as surrogates for Ea. Stationary ambient data can be used to assess population exposure only if PM exposure is dominated by Ea. PMID- 30447591 TI - What are the main factors affecting carbon price in Emission Trading Scheme? A case study in China. AB - Emission Trading Scheme (ETS) has the potential to influence energy consumption, environmental quality and economy directly and ETS price is the key of ETS market. On December 27, 2017, China's carbon trading market was officially launched, which may be the largest platform of ETS in the world. Therefore, this paper seeks to assess the influencing factors of emission trading price (industry coverage, the annual decline factor, and free allowance rate) and analyzes the impact mechanism in detail by applying computable general equilibrium model. The results show that ETS price and emission reduction have a significant positive correlation; key factors can impact the price significantly. Fewer industries, higher annual decline factor, and higher free allowance rate will push ETS price up. The paper also found that ETS prices are unpredictable when the mechanism is not yet fully determined. It further, argues that ETS prices are unpredictable when the mechanism is not yet fully determined because of the high relationship between ETS price and the mechanism of ETS. These findings will assist policymakers to build a healthy ETS market. The important implication is that we can adjust the market price by adjusting these mechanisms. PMID- 30447592 TI - Analysis of the relationship between electromagnetic radiation characteristics and urban functions in highly populated urban areas. AB - The electromagnetic environment (EME) in cities is becoming increasingly complex, and the resulting potential health hazards have attracted widespread attention. Large-scale field observations and monitoring of electromagnetic fields were performed in Xiamen Island over the past six years. The results show that the integrated electric field intensity in Xiamen Island ranged from 0.32 V/m to 1.70 V/m, while the integrated magnetic flux density ranged from 0.11 MUT to 0.50 MUT; where more electric power facilities and electronic equipment are present in the island, the electric and magnetic field strengths are higher; the radiation power of 2nd Generation mobile communication (2G) is higher than that of 3rd Generation mobile communication (3G) and 4th Generation mobile communication (4G), the coverage of the 3G signal was more uniform than the others and the 4G communication signal's coverage is still developing. The relationship between the EME characteristics and urban functions has been analyzed in this study. Results showed that electric field intensity had no correlation with urban functional areas, magnetic flux density had a positive correlation with residential area (q = 0.29); 2G and 4G radiation power are positively related to the educational (Edu) function area (960 MHz q = 0.22, 1.8 GHz q = 0.47, 2.61 GHz q = 0.28); there was a positive relationship between 2G (1.8 GHz) radiation power and residential area (q = 0.2). We concluded that there is a strong link between the Xiamen Island's EME and the distribution of electromagnetic radiation (EMR) sources, the denser and wider distributed EMR sources lead to a more complicated urban EME. PMID- 30447593 TI - Sewage sludge amendment improved soil properties and sweet sorghum yield and quality in a newly reclaimed mudflat land. AB - Growing bioenergy crop on marginal lands has the potential to minimize land use conflicts and meet global energy demand. The newly reclaimed mudflats through sewage sludge amendment can be used as a potential marginal land for bioenergy production. This paper was one of first studies to investigate the persistent impact of sewage sludge application at the rates of 0, 25, 50, 125, and 250 t ha 1 on selected soil physicochemical properties, yields and quality of sweet sorghum (Sorghum bicolor L.) cultivated in newly reclaimed mudflat saline alkaline soil. The results showed that sewage sludge amendment (SSA) improved physicochemical properties by decreasing bulk density, electric conductivity, pH, and increasing soil organic carbon, >0.25 mm water-stable aggregate fraction, cation exchange capacity, nitrogen, and phosphorus contents in mudflat soil. Consequently, the sweet sorghum biomass and gross energy content were significantly elevated by SSA. The sweet sorghum achieved the maximum biomasses of 4.73 and 6.62 t ha-1 at 250 t ha-1 SSA rate in 2016 and 2017, respectively. The gross energy content of sweet sorghum significantly increased with the SSA rates, although SSA slightly reduced the calorific values in stem and leaf of sweet sorghum. The maximum gross energy contents of sweet sorghum were 79.62 and 104.47 GJ ha-1 at SSA rate of 250 t ha-1 in 2016 and 2017, respectively. Although SSA led to accumulation of heavy metals in sweet sorghum, the growth of sorghum was not inhibited even at the highest SSA. In summary, cultivation of bioenergy crop in mudflat amended by sewage sludge is feasible and can be an innovative solution for mudflat reclamation, safe disposal of solid waste, resource reuse and recycle, and bioenergy production. PMID- 30447594 TI - Mitigation of downstream propagation of contaminated water in a carbonate aquifer - The northeastern Negev desert, Israel. AB - Groundwater pollution in Israel mainly occurs in the populated urban areas. Yet, in the 90's a major salinization was identified in a deep well in the northeastern part of the Negev desert, and a trend of increasing salinity was recognized in an adjacent spring. Since then the salinity of the spring is on the rise reaching a rate of 21 mgCl/L per month. New geochemical data allows the identification of the source, composition and volume of the contaminant, as well as its dispersion in the aquifer. The source of the contamination is attributed to highly saline (~40,000 mgCl/L), acidic and trace elements-rich industrial wastewater that leaked from evaporation ponds and also drained through karstic sinkhole to the subsurface over a period of decades. The contamination is reflected by a sharp increase in the concentrations of most major elements and by a moderate increase in a few trace elements. The total waste water volume that leaked is assessed to be 75 MCM. The study reveals that most of the contaminated water is still far upstream of the natural outlet. Due to the specific geological configuration the highly contaminated groundwater is channeled into a narrow corridor of an elongated syncline. Unlike other similar contamination cases around the world, pumping along this syncline can reduce the flow of the contaminated water further downstream towards a region where it disperses. The study provides the decision makers with tools that can reduce the environmental hazard and enable development of water production in this arid region. The current research emphasizes the importance of a combined geological, hydrological and geochemical study of a contaminated aquifer to fully understand the flow regime and contamination process. Such studies are a crucial step before an optimal mitigation action can be undertaken to rehabilitate a contaminated aquifer. PMID- 30447595 TI - Controls governing the spatial distribution of sediment arsenic concentrations and solid-phase speciation in a lake impacted by legacy mining pollution. AB - Forty-seven sediment cores were collected as part of a spatial survey of Long Lake, Yellowknife, NWT, Canada to elucidate the physical and geochemical controls on the distribution of arsenic (As) in sediments impacted by the aerial deposition of arsenic trioxide (As2O3) from ore roasting at legacy gold mines. High-resolution profiles of dissolved As in bottom water and porewater were also collected to determine As remobilization and diffusion rates across the sediment water interface. Arsenic concentrations in Long Lake sediments ranged from 2.2 to 3420 mg kg-1 (dry weight). Two distinct types of sediment As concentration profiles were identified and are interpreted to represent erosional and depositional areas. Water depth is the best predictor of As concentration in the top 5 cm of sediments due to the inferred focusing of fine-grained As2O3 into deeper water. At greater sediment depths, iron (Fe) concentration, as a likely indicator of As, Fe, and sulphur (S) co-diagenesis, was the best predictor of As concentration. The sediments are a source of dissolved As to surface waters through diffusion-controlled release to bottom water. Arsenic concentrations, solid-phase speciation, and diffusive efflux varied laterally across the lake bottom and with sediment depth due to the interplay between sediment-focusing processes and redox reactions, which has implications for human health and ecological risk assessments. PMID- 30447596 TI - Effects of plastic contamination on water evaporation and desiccation cracking in soil. AB - Environmental contamination of plastics is becoming an issue of concern globally. Detection of plastics, particularly microplastics, has been increasingly reported in both marine environments and inland waters. Recent work has indicated that soil in terrestrial environments has also been contaminated by plastics. Research has also shown that plastics can have adverse effects on soil biota. However, the impact of plastics on soil physical properties is still unclear. In this work, effects of plastic film of different sizes at environmental relevant concentrations on water evaporation and desiccation cracking in two clay soils were studied. The results showed that the presence of plastics in soil significantly increased the rate of soil water evaporation by creating channels for water movement. The effect was more pronounced in soils treated with 2 mm plastics than in soils treated with 5 and 10 mm plastics, and increased with increasing plastic content. Desiccation cracking was observed on the surface of soil treated with 5 and 10 mm plastics likely due to the destruction of soil structural integrity. While 2 mm plastics increased the rate of desiccation shrinkage, the shrinkage ratio was reduced at the residual stage. Results from this work suggest that plastic contamination can alter the water cycle in soils, which may exacerbate soil water shortages and affect the vertical transport of pollutants. Further work is required to study the effects of plastics of other shapes, and laboratory observations should be tested at field scale. PMID- 30447597 TI - Catchment soils supply ammonium to the coastal zone - Flood impacts on nutrient flux in estuaries. AB - Erosion of soil from catchments during floods can deliver large quantities of sediment to the coastal zone. The transformations and processes of nutrient release from catchment soils during flooding are not well understood. To test the hypothesis that catchment soils supply nutrients to the coastal zone, we examined nutrient release and transformation following wetting of soils formed from three distinct rock types (basalt, granite and sandstone) with fresh and marine water. The soil samples were collected from eroding areas of a subtropical river catchment. We simulated runoff, transport and deposition by tumbling the fine fraction of the soils in freshwater for three days and settling in seawater for four weeks. We also collected and incubated cores from an adjacent coastal bay and added a layer of catchment soil to simulate deposition of new sediment following flood plume settling. Dissolved nutrients were measured in both simulations. Basalt soils were relatively nutrient rich and released substantial quantities of organic and inorganic dissolved nutrients, particularly phosphate. However when soils were added to estuarine sediment cores and incubated, there was a net influx of phosphate from the overlying water. All soils continually released ammonium in both experiments, indicating that catchment soils may be an important source of ammonium to fuel productivity within the coastal zone. This study provides new insights into increased nitrogen availability in a nitrogen depauperate coastal zone and identifies catchment geology as an important influence in coastal productivity through delivery of soil nitrogen to downstream estuaries. PMID- 30447598 TI - Sub-lethal exposure to lead is associated with heightened aggression in an urban songbird. AB - Many urban areas have elevated soil lead concentrations due to prior large-scale use of lead in products such as paint and automobile gasoline. This presents a potential problem for the growing numbers of wildlife living in urbanized areas as lead exposure is known to affect multiple physiological systems, including the nervous system, in vertebrate species. In humans and laboratory animals, low level lead exposure is associated with neurological impairment, but less is known about how lead may affect the behavior of urban wildlife. We focused on the Northern Mockingbird Mimus polyglottos, a common, omnivorous North American songbird, to gain insights into how lead may affect the physiology and behavior of urban wildlife. We predicted that birds living in neighborhoods with high soil lead concentrations would (a) exhibit elevated lead concentrations in their blood and feathers, (b) exhibit lower body condition, (c) exhibit less diverse and consistent vocal repertoires, and (d) behave more aggressively during simulated conspecific territorial intrusions compared to birds living in neighborhoods with lower soil lead concentrations. Controlling for other habitat differences, we found that birds from areas of high soil lead had elevated lead concentrations in blood and feathers, but found no differences in body condition or vocal repertoires. However, birds from high lead areas responded more aggressively during simulated intrusions. These findings indicate that sub-lethal lead exposure may be common among wildlife living in urban areas, and that this exposure is associated with increased aggression. Better understanding of the extent of the relationship between lead exposure and aggression and the consequences this could have for survival and reproduction of wild animals are clear priorities for future work in this and other urban ecosystems. PMID- 30447599 TI - Nitrogenous air pollutants and ozone exposure in the central Sierra Nevada and White Mountains of California - Distribution and evaluation of ecological risks. AB - Ammonia (NH3), nitric oxide (NO), nitrogen dioxide (NO2), nitric acid (HNO3), and ozone (O3) were measured in summers of 2012 and 2013 with passive samplers. Nine monitoring sites were on W-E transect (511 to 3490 m) across central Sierra Nevada Mountains (SNM), and five sites on elevational gradient (1237 to 4346 m) in White Mountains (WM) of California. Levels of pollutants were similar in 2012 and 2013 in all sites. NH3, NO2, and HNO3 were highest near highly polluted Central Valley of California (CVC): maximum summer season means 7.8 MUg m-3, 3.0 ppb, and 3.0 MUg m-3, respectively. Regional background for NH3, NO2, and HNO3 in SNM occurred >20 km from CVC and >1500 m with seasonal averages: 2.1-4.8 MUg m-3; 0.8-1.7 ppb; 1.0-1.8 MUg m-3, respectively, during two seasons. Levels of NH3, NO2, and HNO3 in WM remote locations were similar: 1.2-3.3 MUg m-3, 0.6-1.1 ppb, and 1.0-1.3 MUg m-3, respectively. Seasonal mean O3 (38-60 ppb) in SNM did not change with distance from CVC nor elevation. In WM, O3 and NO mixing ratios were 41-61 ppb and 2.3-4.1 ppb, respectively, increasing with elevation. Even the lowest NH3 concentrations determined in this study were higher than NH3 continental background. This fact, as well as high values of Nreduced/Noxidized near CVC of 1.9 in 2012 and 2.0 in 2013, decreasing with distance to 0.7 in 2012 and 0.8 in 2013, show importance of NH3 emissions from CVC as a contributor to N deposition and ecological impacts in SNM. The phytotoxic O3 indices, AOT40 and W126, for selected sites on SNM and WM transects, showed high potential for negative O3 impacts on vegetation, including forest trees. CAPSULE: Elevated NH3, NO2, and HNO3 on the western slopes of the Sierra Nevada Mountains (SNM) near the Central Valley of California (CVC) decreased with distance from CVC and elevation to regional background levels also recorded at high elevation sites of the White Mountains (WM). PMID- 30447600 TI - Optimal irrigation planning for addressing current or future water scarcity in Mediterranean tree crops. AB - Water scarcity in the Mediterranean region is becoming a growing concern, threatening the viability of agriculture, which is one of the main economic sectors in many areas. The design of an optimal irrigation management plan, based on state-of-the-art measuring and modeling tools, can effectively contribute towards water saving efforts and potentially address the water scarcity issue in the region. This paper describes the development and application of an integrated decision-making system for the management of water resources of olive and citrus crops in the North of Chania, Crete, Greece. The system integrates different field measurements, for example 2088 soil moisture measurements taken within the study area, and modeling approaches to simulate flow in the unsaturated zone. After the successful calibration and validation of the model, the spatio-temporal representation of soil moisture and pore water pressure were used as guidance for developing optimal irrigation plans, taking into account the water needs of olive and citrus crops, aiming to maximize crop yield, agricultural income, and promote water saving efforts. According to the results, water use can be reduced by up to 36% during the dry season, compared to conventional irrigation practices for citrus trees. Similarly, for olive trees, the reduction in water use can reach up to 41%. The proposed methodology can also be cost-effective in terms of water value, saving about 40% from the typical water cost for irrigation in the study area. The impact of climate change on water resources availability in the area and water conservation efforts were also investigated for the period of (2019 2030). Results show that, comparing the Baseline, RCP 8.5 and RCP 4.5 climatic scenarios, the highest savings on average are observed for emission scenario RCP 4.5 with 53.3% water savings for olive trees and 46.7% for citrus trees. PMID- 30447601 TI - Applying stable isotopes to determine seasonal variability in evapotranspiration partitioning of winter wheat for optimizing agricultural management practices. AB - The partitioning of evapotranspiration (ET) into soil evaporation (E) and crop transpiration (T) is fundamental for accurately monitoring agro-hydrological processes, assessing crop productivity, and optimizing water management practices. In this study, the isotope tracing technique was used to partition ET of winter wheat under different irrigation (100, 160 and 240 mm) and fertilization (105, 210 and 315 kg N ha-1) treatments during the 2014 and 2015 growing seasons in Beijing, China. The correlations between seasonal ET partitioning and the leaf area index (LAI), grain yield, and water use efficiency (WUE, ratio of crop yield and ET) were investigated and agricultural management practices were optimized. The fraction of T in ET (FT) between the greening and harvest seasons was 0.82 on average and did not vary significantly among the treatments (p > 0.05). However, the values of FT during the individual growth periods ranged from 0.51 to 0.98, and they were remarkably distinct for all treatments. The seasonal variability in FT could be effectively explained via a power-law function of the LAI (FT = 0.61 LAI0.21, R2 = 0.66, p < 0.01). There was no significant relationship between FT and the grain yield or WUE (p > 0.05). The total T during the jointing-heading and heading-filling periods (Tjf) had significantly quadratic relationships with the crop yield and WUE (p < 0.01). Both the crop yield and the WUE had high values under the Tjf range of 117.5 155.8 mm. Furthermore, the WUE was higher under larger ratio of E in ET (FE) during the greening-jointing period and lower FE during the filling-harvest period. Two irrigations during the greening-jointing (20 mm) and heading-filling (80 mm) stages and one fertilization (105 kg ha-1 N) during the greening-jointing stage were determined as appropriate irrigation and fertilization schedules. PMID- 30447602 TI - Exposure to tetracycline perturbs the microbiome of soil oligochaete Enchytraeus crypticus. AB - Microbial symbiosis is essential for the normal development and growth of hosts. Past attention has mostly been paid to its effects on plants and vertebrates. The effects of environmental pressures such as antibiotics on the microbiome of soil fauna remain largely elusive. We used bacterial 16S rRNA gene high-throughput sequencing to examine the response of microbiome of soil invertebrate Enchytraeus crypticus to oral tetracycline exposure. After two-week exposure, tetracycline free oat was used as food to monitor the restoration of E. crypticus microbiome. The results showed that Proteobacteria, Actinobacteria and Planctomycetes were the three dominant phyla in all samples, Rhizobiaceae and Kaistia were the most abundant family and genus in all samples, respectively. After 14 days tetracycline exposure, Planctomycetes declined dramatically from 33.05% to 3.28% (P = 0.016), but Actinobacteria elevated substantially from 2.47% to 23.65% (P = 0.004). The alpha-diversity of microbial community increased significantly after tetracycline exposure compared to the control (P = 0.014). Terminating tetracycline exposure led to the recovery of E. crypticus microbiome back to the background level within 14 days. Our results suggest that while tetracycline can disturb the microbiome in E. crypticus significantly, the effects of the antibiotic on E. crypticus microbiome may not be permanent but reversibly diminish after stopping exposure for a period of time. The results may contribute to extending our understanding of the effect of antibiotics on microbiome of soil invertebrates. CAPSULE: The microbiome of E. crypticus exposed to tetracycline is perturbed and reversibly restored after terminating the exposure. PMID- 30447603 TI - Carbon sequestration and methane emissions along a microtopographic gradient in a tropical Andean peatland. AB - Tropical alpine peatlands are among the least studied wetlands types on earth. Their important ecosystem services at local and regional scope are currently threatened by climate and land use changes. Recent studies in these ecosystems suggest their importance to the provision of climate regulation services, prompting a better understanding of the underlying functions and their variability at ecosystem scales. The objective of this study is to determine the variability of methane (CH4) fluxes and carbon (C) sequestration within a tropical alpine peatland in three locations along a microtopographic gradient and its associated plant diversity. These locations accounted for: 1) hummocks, found mostly near the edge of the peat with a water table below the soil surface, 2) lawns, in the transition zone, with a water-table near the soil surface, and 3) hollows, permanently flooded with a water table above the soil surface, composed of small patches of open water intermingled with unconsolidated hummocks that surface the water level. Results indicate that CH4 flux is lowest in the lawns, while C sequestration is highest. Conversely, the hummock and hollow have higher CH4 flux and lower C sequestration. In addition, plant diversity in the lawns is higher than in the hummock and hollow location. Dryer conditions brought by current climate change in the northern Andes are expected to lower the water tables in the peatland. This change is expected to drive a change in CH4 flux and C sequestration at the lawns, currently dominating the peatland, towards values more similar to those measured in the hummocks. This decrease may also represent a change towards the lower plant diversity that characterized the hummock. Such changes will reduce the ratio of C sequestration:CH4 flux signifying the reduction of resilience and increment of vulnerability of the climate-regulating service to further perturbations. PMID- 30447604 TI - Factors underlying the development of chronic temporal lobe epilepsy in autoimmune encephalitis. AB - PURPOSE: Limbic encephalitis (LE) is an autoimmune condition characterized by amnestic syndrome, psychiatric features and seizures. Early diagnosis and prompt treatment are crucial to avoid long-term sequelae, including psycho-cognitive deficits and persisting seizures. The aim of our study was to analyze the characteristics of 33 LE patients in order to identify possible prognostic factors associated with the development of chronic epilepsy. METHODS: This is a retrospective cohort study including adult patients diagnosed with LE in the period 2010-2017 and followed up for >=12 months. Demographics, seizure semiology, EEG pattern, MRI features, CSF/serum findings were reviewed. RESULTS: All 33 LE patients (19 M/14F, mean age 61.2 years) presented seizures. Thirty subjects had memory deficits; 22 presented behavioural/mood disorders. Serum and/or CSF auto-antibodies were detected in 12 patients. In 31 subjects brain MRI at onset showed typical alterations involving temporal lobes. All patients received immunotherapy. At follow-up, 13/33 had developed chronic epilepsy; predisposing factors included delay in diagnosis (p = .009), low seizure frequency at onset (p = .02), absence of amnestic syndrome (p = .02) and absence/rarity of inter-ictal epileptic discharges on EEG (p = .06). CONCLUSIONS: LE with paucisymptomatic electro-clinical presentation seemed to be associated to chronic epilepsy more than LE presenting with definite and severe "limbic syndrome". PMID- 30447605 TI - A new Italian family with HTRA1 mutation associated with autosomal-dominant variant of CARASIL: Are we pointing towards a disease spectrum? PMID- 30447606 TI - Retinal microvasculature changes in amyloid-negative subcortical vascular cognitive impairment compared to amyloid-positive Alzheimer's disease. AB - BACKGROUND AND PURPOSE: To investigate small vessel abnormalities in patients with cognitive impairment, we compared retinal microvascular alterations between patients with cognitive impairment related to Alzheimer's disease (ADCI) and those with subcortical vascular cognitive impairment (SVCI). METHODS: We prospectively recruited 29 amyloid-positive ADCI patients, 28 amyloid-negative SVCI patients that were confirmed by 11C-PiB-PET scan and 34 individuals with normal cognition (NC). The three groups were compared in terms of retinal vascular variables (retinal fractal dimension, vascular caliber, tortuosity and branching angle) by using a semi-automated, computer-assisted analysis of digital fundus photographs. We also investigated the relationship between retinal variables and white matter hyperintensities (WMH) on MRI. RESULTS: Compared to NC individuals, the SVCI patients had smaller total and arteriolar fractal dimensions, whereas there was no significant difference of fractal dimension between ADCI and NC. Other retinal variables did not differ among the three groups. A significant correlation existed between fractal dimension and WMH volume. CONCLUSIONS: Retinal microvascular alterations, especially retinal fractal dimension, may be useful markers that reflect cerebral microvascular changes in patients with SVCI as opposed to ADCI, who had no definite difference in retinal variables compared to the NC group. PMID- 30447607 TI - Effect of osteoprotegerin gene polymorphisms on the risk of cervical spondylotic myelopathy in a Chinese population. AB - OBJECTIVE: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction. Our study aims to explore the correlation of osteoprotegerin (OPG) gene polymorphisms and the risk factors and severity of CSM. PATIENTS AND METHODS: The peripheral blood samples from 494 CSM patients and 515 healthy individuals were collected for detecting the 950T/C, 1181G/C and 163A/G genotypes and genetic equilibrium of OPG in the CSM and control groups and analyzing the genotype distribution and allele frequency. The severity of CSM and the impaired segments were evaluated by the Japanese Orthopedic Association (JOA) scoring combined with cervical magnetic resonance imaging (MRI), in order to investigate the relations between the three genotypes of OPG promoter gene loci (950T/C, 163A/G and 1181G/C) and occurrence as well as severity of CSM. RESULTS: The risk rate of TC genotype carrier suffered from CSM was 0.46, of TT genotype carrier was 0.27. The risk rate of T allele carrier suffered from CSM was 0.37. In 950T/C single nucleotide polymorphism (SNP), patients with TC, TT and T genotypes had lower risk to suffer from CSM. CONCLUSION: Taken together, OPG 950T/C SNP protects against CSM, and it is correlated with the severity of CSM, providing a new idea for the prevention and treatment of CSM. PMID- 30447608 TI - Biological impact of octyl d-glucopyranoside based surfactants. AB - Development of many branches of industry has stimulated the search for new, effective surfactants with interesting properties. Potential use of alkyl glucose derivatives on a large scale, raises questions about the possible risks associated with their entry into the natural environment. To be able to evaluate this risk, the aim of the study was to determine the physicochemical properties of octyl d-glucopyranoside and its three derivatives: N-(octyl d glucopyranosiduronyl)aspartic acid, N-(octyl d-glucopyranosiduronyl)glicyne and octyl d-glucopyranosiduronic acid. Moreover, their biodegradability by pure bacterial strains and biocenosis present in river water was examined. While descriptions of sugar-based surfactants on microbial cells are limited, the essential element of the study was to determine the effect of surfactants on cell surface properties of microorganisms isolated from activated sludge and compare it to the effects of the petroleum based surfactants and the surfactants produced from renewable materials. The results obtained indicate that physicochemical properties of surface active agents differ depending on the presence of functional groups in the surfactants molecules. What is more, the presence of amino acid substituent in the derivatives of octyl d-glucopyranoside resulted in a slight decrease in the surfactants biodegradation efficiency, in comparison to the compounds that did not contain such a substituent, prolonging this process from 5 to 10 days. Interestingly, even relatively slightly different derivatives modified the cell surface properties in a different way. Importantly, the surfactants based on octyl d-glucopyranoside have less negative impact on environmental microorganism and better biodegradability than the surfactant synthesized from petroleum products. PMID- 30447609 TI - Changes of nitrogen-removal performance and that of the bacterial community in a mixed culture comprising freshwater and marine anammox bacteria under averaged environmental condition. AB - Nitrogen-removal processes using anammox bacteria are expected to achieve high rate removal while remaining economical, and their practical applications have been investigated. However, anammox bacteria still have unfavorable characteristics for practical use, including susceptibility to a change in environmental conditions. In this study, with an aim of exploring the adaptability of mixed anammox bacteria to environmental conditions, the shift of nitrogen-removal performance and bacterial community in a mixed culture comprising freshwater anammox bacteria (FAB) and marine anammox bacteria (MAB) were investigated by a continuously stirred tank reactor (CSTR). The CSTR inoculated with the mixed anammox bacteria was operated for 180 days under an averaged condition between freshwater and marine conditions with a temperature of 27.5 degrees C and a synthetic medium with 15 g/L NaCl was used. Nitrogen removal performance became stable after 114 days and more than 90% of nitrogen that was loaded into the reactor was removed in the range of nitrogen loading rate 0.07-0.42 kg N/m3/d. After operating at 0.42 kg N/m3/d for one month, a biomass sample was taken and its bacterial community was analyzed by clone library analysis using a partial sequence of 16S rRNA. Among the clones of anammox bacteria that were made by an anammox-bacteria-specific primer, 97% of them were MAB and only 3% were FAB. These results indicate that the bacterial community including anammox bacteria was evidently changed due to environmental conditions and that the averaged condition in this study was suitable for marine bacteria rather than freshwater bacteria. PMID- 30447610 TI - Assessment of the adverse impacts of aflatoxin B1 on gut-microbiota dependent metabolism in F344 rats. AB - The adverse impacts of AFB1 on gut-microbiota dependent metabolism in F344 rats were assessed via ultra-high performance liquid chromatography (UHPLC)-profiling and UHPLC-mass spectrometry (MS) metabolomic analyses. UHPLC-profiling analysis found 1100 raw peaks from the fecal samples collected at week 4, of which 335 peaks showed peak shape qualified for quantitation. A total of 24, 40 and 71 peaks were significantly decreased (>2-fold, p < 0.05) among the exposure groups treated with 5, 25, and 75 MUg AFB1 kg-1 body weight (B. W.), respectively. Supervised orthogonal partial least squares projection to latent structures discriminant analysis revealed 11 differential peaks that may be used to predict AFB1-induced adverse changes of the metabolites. UHPLC-MS based metabolomic analysis discovered 494 features that were significantly altered by AFB1, and 234 of them were imputatively identified using Human Metabolome Data Base (HMDB). Metabolite set enrichment analysis showed that the highly disrupted metabolic pathways were: protein biosynthesis, pantothenate and CoA biosynthesis, betaine metabolism, cysteine metabolism, and methionine metabolism. Eight features were rated as indicative metabolites for AFB1 exposure: 3-decanol, xanthylic acid, norspermidine, nervonyl carnitine, pantothenol, threitol, 2-hexanoyl carnitine, and 1-nitrohexane. These data suggest that AFB1 could significantly reduce the variety of nutrients in gut and disrupt a number of gut-microbiota dependent metabolic pathways, which may contribute to the AFB1-associated stunted growth, liver diseases and the immune toxic effects that have been observed in animal models and human populations. PMID- 30447611 TI - Neurobehavioral effects of bisphenol S exposure in early life stages of zebrafish larvae (Danio rerio). AB - As an alternate of bisphenol A (BPA), bisphenol S (BPS) is now widely used to produce our daily consumer goods. Some studies have shown that BPS has the potential to disrupt the reproduction and glucose homeostasis. However, the impact of BPS on the nervous system remains unclear. The purpose of this study is to investigate the impact of BPS on the nervous systems of zebrafish in their early growing stages. The 96 h-LC50 value of BPS to zebrafish larvae was 323 mg/L (95%CI: 308-339 mg/L). Zebrafish embryos were exposed to BPS at concentrations of 0, 0.03, 0.3 and 3.0 mg/L until 6 days postfertilization. Our results showed that 0.3 and 3.0 mg/L BPS exposure markedly decreased locomotor behavior, accompany by the increased oxidative stress, promoted apoptosis and altered retinal structure in zebrafish. In addition, the expression levels of six neurodevelopment genes (alpha1-tubulin, elavl3, gap43, mbp, syn2a and gfap) were downregulated after 3.0 mg/L BPS treatment. In conclusion, BPS may affect locomotor behavior and alter retinal structure in zebrafish larvae partially by increasing oxidative stress, and by suppressing the expression levels of neurodevelopment genes. PMID- 30447612 TI - Characterization of leachates from waste landfill sites in a religious camp along Lagos-Ibadan expressway, Nigeria and its hepatotoxicity in rats. AB - Landfill sites near human settlements are known to have adverse health effects. Here, we investigated the effect of different concentrations of leachates from the Redemption Camp landfill (RCLL, 10%, 30%, 50%) on the liver of adult female rats after 21 days of exposure in their drinking water. The physicochemical and metal analyses showed that biochemical oxygen and chemical oxygen demand, zinc and magnesium levels were significantly high, whereas copper level was low in RCLL when compared to water samples from residential areas close to the landfill site, and were higher than the acceptable limits (p < 0.05). The predominant bacteria isolates recovered from the leachate and drinking water samples were Escherichia coli, Salmonella spp and Shigella spp. At the end of the 21-day exposure, RCLL increased the weight of the liver. Malondialdehyde concentrations were increased and glutathione levels were decreased significantly in the liver of treated animals at all concentrations of leachates tested. Furthermore, the activities of serum alanine amino transferase, aspartate amino transferase, gamma glutamyl transferase and cholesterol concentrations were increased whereas bilirubin and albumin levels were decreased dose-dependently. Histological examination of the liver was characterized by accumulation of inflammatory cells around hepatocytes, and extended sinusoids. The histo-pathological alterations and oxidative damage observed in the liver of treated rats and occurrence of pathogenic species and metals in the RCLL may suggest possible impaired hepatic health in subjects with occupational or environmental exposure. PMID- 30447613 TI - Comparative assessment of endocrine disrupting compounds removal in heterotrophic and enriched nitrifying biomass. AB - Despite the number of studies that have investigated the fate of endocrine disrupting compounds (EDCs), to date results are still contradictory and more research is required to evaluate the contribution of the microbial communities present in different engineered treatment systems. Thus, autotrophic and heterotrophic types of biomass were here compared in terms of efficiency in the removal of estrone (E1), 17beta-estradiol (E2), estriol (E3), 17alpha ethynilestradiol (EE2) and bisphenol A (BPA). Experiments were performed with enriched nitrifying activated sludge (NAS) and enriched ammonia oxidizing bacteria (AOB) sludge cultivated at lab-scale, as well as with conventional activated sludge (CAS) from a full-scale wastewater treatment plant. Both enriched NAS and AOB demonstrated a negligible degrading capacity. In both cases, the studied EDCs exhibited low removals (<14%) and showed no correlation with the increasing nitrification rates contradicting some of the hypothesis present in literature. Contrariwise, the biodegradation capabilities of the heterotrophic fraction of CAS were highlighted. E2 and E3 were removed by up to 100% and 78%, respectively. E1 was found to be the main transformation product of E2 (almost quantitative oxidation) and it was also highly eliminated. Finally, EE2 and BPA were more persistent biologically with removals ranging from 10% to 39%. For these two compounds similar removals were obtained during experiments with heat inactivated biomass suggesting that sorption could be a relevant route of elimination. PMID- 30447614 TI - Using an interpolation-based method (IDVequ) to predict the combined toxicities of hormetic ionic liquids. AB - In the field of computational toxicology, predicting toxicological interaction or hormesis effect of a mixture from individuals is still a challenge. The two most frequently used model concentration addition (CA) and independent action (IA) also cannot solve these challenges perfectly. In this paper, we used IDVequ (an interpolation method based on the Delaunay triangulation and Voronoi tessellation as well as the training set of direct equipartition ray design (EquRay) mixtures) to predict the toxicities of binary mixtures composed of hormetic ionic liquids (ILs). One of the purposes is to verify the predictive ability of IDVequ. The other one is to improve the risk assessment of ILs mixtures especial hormetic ILs, because the toxicity reports of ILs mixtures are rarely reported in particular the toxicity of the hormetic ILs mixtures. Hence, we determined time dependent toxicities of four ILs and their binary mixtures (designed by EquRay) to Vibrio qinghaiensis sp.-Q67 at first. Then, mixture toxicities were predicted and compared using the IDVequ and CA. The results show that, the accuracy of IDVequ is higher than the accuracy of CA. And, more important, to some mixtures out of the CA application, IDVequ also can predict the mixture effects accurately. It showed that IDVequ can be applied to predict the toxicity of any binary mixture regardless of the type of concentration-response curve of the components. These toxicity data provided useful information for researching the prediction of hormesis or toxicological interaction of the mixture and toxicities of ILs mixtures. PMID- 30447615 TI - Environmental and behavioral determinants affecting the association of airway macrophages carbon load with distance to major roads and traffic density. AB - Biomarkers are promising indicators to evaluate human exposure to air pollutants and to predict the health outcomes. Area of Airway macrophages that is occupied by Black Carbon could be used as a biomarker of personal long term exposure to traffic related air pollution. Association of airway macrophages carbon load with weighted average distance and environmental and subject-specific behavior are considered in this study. Sputum samples were taken from 160 healthy adult women and airway macrophages carbon load (AMCL) were determined in 93 subjects, which represent a success rate of 62% in sputum induction. Nearest distance of the subjects to major roads and average weighted distance were calculated for each subject. A questionnaire was field according to general and behavioral characteristics of the participants. There was not any significant difference (P value >0.05) between induced and non-induced subjects. Subjects with indoor kitchen without separation wall, passive smokers and those with longer presence time in high traffic streets showed higher carbon area. Weighted average distance had a better association (beta = -0.186, 95%CI: -0.139, -0.230, P-value = 0.00) with AMCL than nearest distance to major roads (beta = -0.155, 95%CI: -0.109, 0.201, P-value = 0.19). Association of Weighted average distance with AMCL was interrupted in subjects with a garage connected to house environment, those with IK kitchen, those with a hood above the stove and passive smokers. The findings indicated that more generation and distribution of indoor air pollutants can completely enhance the internal exposure and indoor pollution has the same importance as outdoor pollution. PMID- 30447616 TI - Is multilevel erector spinae block really necessary? PMID- 30447617 TI - Molecular Investigation of the Ciliate Spirostomum semivirescens, with First Transcriptome and New Geographical Records. AB - The ciliate Spirostomum semivirescens is a large freshwater protist densely packed with endosymbiotic algae and capable of building a protective coating from surrounding particles. The species has been rarely recorded and it lacks any molecular investigations. We obtained such data from S. semivirescens isolated in the UK and Sweden. Using single-cell RNA sequencing of isolates from both countries, the transcriptome of S. semivirescens was generated. A phylogenetic analysis identified S. semivirescens as a close relative to S. minus. Additionally, rRNA sequence analysis of the green algal endosymbiont revealed that it is closely related to Chlorella vulgaris. Along with the molecular species identification, an analysis of the ciliates' stop codons was carried out, which revealed a relationship where TGA stop codon frequency decreased with increasing gene expression levels. The observed codon bias suggests that S. semivirescens could be in an early stage of reassigning the TGA stop codon. Analysis of the transcriptome indicates that S. semivirescens potentially uses rhodoquinol-dependent fumarate reduction to respire in the oxygen-depleted habitats where it lives. The data also shows that despite large geographical distances (over 1,600km) between the sampling sites investigated, a morphologically-identical species can share an exact molecular signature, suggesting that some ciliate species, even those over 1mm in size, could have a global biogeographical distribution. PMID- 30447618 TI - Tridimensional Electron Microscopy Analysis of the Early Endosomes and Endocytic Traffic in Trypanosoma cruzi Epimastigotes. AB - Trypanosoma cruzi epimastigotes internalize macromolecules avidly by endocytosis. Previously, we identified a tubule-vesicular network likely to correspond to the early-endosomes. However, a detailed ultrastructural characterization of these endosomes was missing. Here, we combined endocytosis assays with ultrastructural data from high-resolution electron microscopy to produce a 3D analysis of epimastigote endosomes and their interactions with endocytic organelles. We showed that endocytic cargo was found in carrier vesicles budding from the cytopharynx. These vesicles appeared to fuse with a tubule-vesicular network of early endosomes identified by ultrastructural features including the presence of intermembrane invaginations and coated membrane sections. Within the posterior region of the cell, endosomes localized preferentially on the side nearest to the cytopharynx microtubules. At 4 degrees C, cargo accumulated at a shortened cytopharynx, and subsequent temperature shift to 12 degrees C led to slow cargo delivery to endosomes and, later, to reservosomes. Bridges between reservosomes and endosomes resemble heterotypic fusion. Reservosomes are excluded from the posterior end of the cell, with no preferential cargo delivery to reservosomes closer to the nucleus. Our 3D analysis indicates that epimastigotes accomplish high-speed endocytic traffic by cargo transfer to a bona fide early-endosome and then directly from endosomes to reservosomes, via multiple and simultaneous heterotypic fusion events. PMID- 30447619 TI - Specific quorum sensing signal molecules inducing the social behaviors of microbial populations in anaerobic digestion. AB - A series of dominant functional floras involved in anaerobic digestion was obtained by subculturing anaerobic sludge with specific substrates, respectively, and their specific quorum sensing signals (AHLs) were identified. It was found that most of the AHLs were secreted in starvation of the functional floras. One or two AHLs were found to have a significant positive correlation with the behavior of hydrolytic-fermentative bacteria, homoacetogens, syntrophic propionate-oxidizing bacteria, syntrophic butyrate-oxidizing bacteria and aceticlastic methanogens, respectively. Hydrogenotrophic methanogens had a various self-organization means and broader relations with the other populations, which was induced by six AHLs at least. Performance of an upflow anaerobic sludge blanket in the startup process revealed that the dominant populations involved in anaerobic digestion would secret specific AHLs to induce K-strategy in resource limited situation for reproduction and regulating their cooperation. This work presents a novel perspective on the social behaviors of microbial populations in anaerobic digestion. PMID- 30447620 TI - Improving the production of a novel antifungal alteramide B in Lysobacter enzymogenes OH11 by strengthening metabolic flux and precursor supply. AB - Lysobacter enzymogenes OH11 is currently considered to be a novel biocontrol agent for various plant fungi diseases. At present, only heat-stable antifungal factor (HSAF) has been isolated and identified in culture, although other active compounds also showed antifungal activity. In the present study, a novel active compound, alteramide B (ATB), which exhibits broad-spectrum antagonistic activity against phytopathogenic fungi and oomycetes, was isolated. The genes responsible for ATB biosynthesis were also determined. In addition, a strain producing ATB with minimal HSAF production was successfully generated by redirecting metabolic flux, namely L. enzymogenes OH57. Furthermore, ATB production increased to 893.32 +/- 15.57 mg/L through medium optimization and precursor supply strategy, which was 24.36-fold higher than that of 10% tryptic soy broth (36.67 +/- 1.63 mg/L). Taken together, this study indicates ATB has great development value as a biopesticide because of its bioactivity and high production. PMID- 30447621 TI - Cultivation of Chlorella vulgaris in manure-free piggery wastewater with high strength ammonium for nutrients removal and biomass production: Effect of ammonium concentration, carbon/nitrogen ratio and pH. AB - Ammonia toxicity is a major disadvantage of microalgal growth when high-strength ammonium wastewaters like manure-free piggery wastewater (MFPW) were used as microalgal growth medium. In the present study, the effect of ammonium concentration, carbon/nitrogen ratio, and pH on ammonia toxicity of Chlorella vulgaris cultivated in the MFPW and nutrients removal was investigated. The three important parameters affected ammonia toxicity of C. vulgaris and nutrients removal of the MFPW significantly. The ammonium concentration of the MFPW could be decreased by air stripping. Microalga grew best at a carbon/nitrogen ratio of 25:1 with the maximum biomass concentration of 3.83 g L-1, the highest cell viability of 97%, and the removal of 100% ammonia, 95% of total phosphorus, and 99% of chemical oxygen demand. Ammonia toxicity was alleviated by pH control. The application of the established strategies can enhance nutrients removal of the MFPW while mitigating ammonia toxicity of C. vulgaris. PMID- 30447622 TI - Dynamics of a microbial community during ensiling and upon aerobic exposure in lactic acid bacteria inoculation-treated and untreated barley silages. AB - This study investigated the effects of lactic acid bacteria on bacterial and fungal community during the fermentation process and aerobic exposure phase of barley ensiled with preparation of lactic acid bacteria (LAB). The inoculated silages displayed higher contents of lactic acid, acetic acid, and propionic acid as well as a greater number of lactic acid bacteria during ensiling. LAB-treated silage decreased the bacterial diversity during both ensiling and aerobic exposure but increased the fungal diversity during ensiling of barley. LAB treated silage during ensiling increased the abundance of Lactobacillus but decreased that of Weissella. After aerobic exposure, LAB-treated silage increased the abundance of Lactobacillus but decreased that of Acinetobacter. Acinetobacter, Enterococcus, Providencia, and Empedobacter were the dominant bacteria after aerobic exposure. In conclusion, LAB-treated silage enhanced the number of desirable Lactobacillus and inhibited the growth of undesirable microorganisms, such as Acinetobacter. PMID- 30447623 TI - Efficient l-lactic acid production from corncob residue using metabolically engineered thermo-tolerant yeast. AB - Lactic acid is an important industrial product and the production from inexpensive and renewable lignocellulose can reduce the cost and environmental pollution. In this study, a Kluyveromyces marxianus strain which produced lactic acid efficiently from corncob was constructed. Firstly, two of six different lactate dehydrogenases, which from Plasmodium falciparum and Bacillus subtilis, respectively, were proved to be effective for l-lactic acid production. Then, five single genetic modifications were conducted. The overexpression of Saccharomyces cerevisiae proton-coupled monocarboxylate transporter, K. marxianus 6-phosphofructokinase, or disruption of K. marxianus putative d-lactate dehydrogenase enhanced the l-lactic acid accumulation. Finally, the strain YKX071, obtained via combination of above effective genetic engineering, produced 103.00 g/L l-lactic acid at 42 degrees C with optical purity of 99.5% from corncob residue via simultaneous saccharification and co-fermentation. This study first developed an effective platform for high optical purity l-lactic acid production from lignocellulose using yeast with inexpensive nitrogen sources. PMID- 30447624 TI - Synergy of hemicelluloses removal and bovine serum albumin blocking of lignin for enhanced enzymatic hydrolysis. AB - A cost efficient synergistic strategy combining mild alkaline pretreatment (0.5 5% NaOH at 70 degrees C for 60 min) and bovine serum albumin (BSA) blocking of lignin was evaluated for effective conversion of poplar. The highest glucose yield of 69.2% was obtained for 5% alkaline pretreated sample, which was 4.4 times that of untreated sample. The enhanced enzymatic hydrolysis was attributed to significant hemicelluloses removal with limited delignification. Delignification mainly occurred in secondary wall, leading to more open cell wall structure, thus facilitating better transport of enzyme. Hemicelluloses removal helped split adjacent microfibrils, thus increased the specific sites for cellulase binding. After BSA addition in enzymatic hydrolysis, cellulose conversion further improved to 78.4% with 33% reduction of cellulase dosage due to decreased non-specific adsorption of cellulase on residual lignin. The utilization of synergistic alkaline pretreatment - BSA strategy may improve the overall economics of biomass conversion and successful commercial implementation of biorefineries. PMID- 30447625 TI - Chlorella vulgaris as a green biofuel factory: Comparison between biodiesel, biogas and combustible biomass production. AB - Biofuels are viewed as the answer to safeguard the currently challenged energy security. To this end, the present study provides a comparison between approaches regarding microalgal biomass conversion to bioenergy, with a view on sustainable implementation. The energetic valorization of Chlorella vulgaris biomass cultivated under heterotrophic, sulfur-limited conditions was investigated through the biofuels biodiesel, biogas (biomethane) and combustible dry biomass. The lipid productivity can reach the value of 442.9 +/- 6.5 mg L-1 d-1 containing suitable fatty acids for biodiesel production. Next, biochemical methane potential (BMP) assays yielded 360.9 +/- 20.2 mL CH4 g VS-1added under mesophilic conditions, while the calorific value of dry C. vulgaris biomass was measured as 24,538 +/- 182 kJ kgDW-1 (5,865 +/- 43 kcal kgDW-1). Considering the downstream processing required in each approach, the most promising energy valorization method is anaerobic digestion able to reach values up to 20,862 kJ Lreactor-1 day 1 in continuous systems. PMID- 30447626 TI - Theoretical modelling of the chemical reactivity of fresh biomass chars under non catalytic conditions. AB - This study developed a model for the chemical reactivity of fresh biomass chars, and built a calculation equation for the char gasification rate using simple gas solid collision theory (SCT). The effects of pore breaks, pore collapse and thermal annealing on the char reactivity were considered in the modelling. Experimental tests for six acid-washed biomass chars were performed under a CO2 atmosphere and used a thermo-gravimetric analyzer (TGA) over the temperature range of 1073-1273 K. The results showed that the reactivity of fresh char could be predicted quantitatively by some characteristic properties of certain kind of biomass and their combined parameters. For the instability of the biomass char structure, the internal pore length and gasification temperature showed a good exponential relationship. Good agreement was achieved, and the applicability of the model was demonstrated by comparing the predicted results with experimental data. PMID- 30447627 TI - Fractionation of copper activation products in debris samples from the National Ignition Facility. AB - Nuclear fusion experiments performed at the National Ignition Facility produce radioactive debris, arising in reactions of fast neutrons with the target assembly. We have found that postshot debris collections are fractionated, such that isotope ratios in an individual debris sample may not be representative of the radionuclide inventory produced by the experiment. We discuss the potential sources of this fractionation and apply isotope-correlation techniques to calculate unfractionated isotope ratios that are used in measurements of nuclear reaction cross sections. PMID- 30447628 TI - Mesoporosity based classification of ZSM-5 nano catalysts using DRIFT spectroscopy and chemometrics. AB - DRIFT spectra were used for classification of ZSM-5 catalysts according to their mesopore volumes. The spectra were pretreated by Savitzky-Golay smoothing and standard normal variate (SNV) algorithms prior to outlier detection by Hotelling T2 statistic technique. Supervised classification was applied to the spectra using partial least squares-discriminant analysis (PLS-DA) and soft independent modelling of class analogies (SIMCA) algorithms. The samples were classified into three classes related to their mesopore volumes by the proposed method and the results were in accordance with N2 physisorption textural analysis using Brunauer Emmett-Teller (BET) model. The confusion matrix and classification efficiency parameters including sensitivity, specificity, accuracy and precision were calculated. Classification accuracy of 96% and error rate of 2% was obtained using PLS-DA algorithm while SIMCA algorithm by providing 100% classification accuracy and zero error rate proved better performance in classification of ZSM-5 catalysts. PMID- 30447629 TI - Spectroscopic and theoretical studies of some 2-(methoxy)-2-[(4-substituted) phenylsulfanyl]-(4'-substituted) acetophenones. AB - The conformational analysis of some 2-(methoxy)-2-[(4-substituted) phenylsulfanyl]-(4'-substituted) acetophenones was performed through infrared (IR) spectroscopic analysis of the carbonyl stretching band (nuCO), supported by B3LYP/6-31+G(d,p) calculations and X-ray diffraction. Five (1-5) of the seven studied compounds (1-7) presented Fermi resonance (FR) on the nuCO fundamental transition band. Deuteration of these compounds (1a-5a) precluded the occurrence of FR, revealing a nuCO doublet for all compounds in all solvents used. The computational results indicated the existence of three conformers (c1, c2 and c3) for the whole series whose relative abundances varied with solvent permittivity. The higher nuCO frequency c1 conformer was assigned to the higher frequency component of the carbonyl doublet, while both c2 and c3 were assigned to the lower frequency one. Anharmonic vibrational frequencies and Potential Energy Distribution (PED) calculations of compound 3 indicated that the combination band (cb) between the methyne deltaCH and one skeletal mode couples with the nuCO mode giving rise to the FR on the c2 conformer in vacuum and on the c1 one in non polar solvents. The experimental data indicated a progressive increase in c1 conformer stability with the increase of the solvent dielectric constant, which is in good agreement with the polarizable continuum model (PCM) calculations. The higher nuCO frequency and the stronger solvation of the c1 conformer is a consequence of the repulsive field effect (RFE) originated by the alignment and closeness of the Cdelta+Odelta- and Cdelta+Odelta- dipoles. Finally, the balance between orbital and electrostatic interactions dictates the conformational preferences. X-ray single crystal analysis for compound 6 revealed the c1 geometry in the solid state and its stabilization by CH...O hydrogen bonds. PMID- 30447630 TI - Equilibrium and kinetic studies for silver removal from aqueous solution by hybrid hydrogels. AB - Hybrid hydrogels were prepared by blending Carboxymethyl chitosan (CMCts), Carboxymethyl cellulose (CMC) with Sodium sulfonate styrene (SSS) by 60-kGy gamma rays. The prepared hydrogels were utilized as silver-ion (Ag) sorbent under non- and competitive cases. Batch adsorption experiments were conducted in functional conditions including contact time, ratios of (CMC:CMCts) and SSS, pH value, temperature and adsorbent weight. Equilibrium contact time of 10 h. was obtained by the adsorption material. The optimal 4:2 ratio of (CMC:CMCts):SSS showed the Ag highest adsorption efficiency. The maximum percentage of Ag+ removal was achieved at the pH 5. The temperature effect on the adsorption ability of hybrid hydrogel indicated the Ag adsorption process was endothermic and spontaneous. The Langmuir isotherm model fitted Ag adsorption data well, assuming a monolayer adsorption with predicted maximum adsorption capacity of 451.74 * 10-3 mg. g-1. From the kinetic data, the process of Ag adsorption had higher agreement with the pseudo-2nd order model, predicting the amount of Ag+ uptake at different contact time intervals and at equilibrium. PMID- 30447631 TI - Role of interfacial reactions in biodegradation: A case study in a montmorillonite, Pseudomonas sp. Z1 and methyl parathion ternary system. AB - Organophosphate pesticides are currently the most commonly used pesticides, but the mechanisms of biodegradation of these compounds are often unknown. In this study, we constructed a ternary biodegradation system containing methyl parathion (MP), a bacterial strain of Pseudomonas sp. Z1 with capability of degrading MP and montmorillonite, which is a common clay mineral in soils. The role of interfacial reactions between montmorillonite and the MP degrader on the biodegradation of MP was investigated by batch adsorption as well as through semi permeable membrane experiments. The contact between degrader and montmorillonite in biodegradation was also dynamically examined using in situ attenuated total reflectance Fourier transform infrared spectroscopy. The metabolic activity of the degrading bacteria was also assessed using an isothermal microcalorimetric technique. The results indicate that sorption of bacterial cells onto montmorillonite enhances the metabolic activity of the bacteria and hence the biodegradation of MP by the bacteria, and that an amide group on a bacterial surface protein is responsible for the bacterial adhesion onto the montmorillonite. This stimulated effect ceased when the bacteria were physically separated from the surface of the clay by a membrane, demonstrating the importance of sorption of both the bacteria and the MP in the biodegradation process. PMID- 30447632 TI - Zn adsorption onto Irish Fucus vesiculosus: Biosorbent uptake capacity and atomistic mechanism insights. AB - This study presents a multifaceted approach of Zn adsorption onto dry Fucus vesiculosus originating from the Irish Sea. Metal chemistry as well as algae surface charge properties were characterized before adsorption. Zn adsorption tests were run as function of: pH, algae concentration and metal source. A comparison with Co, Cd, and Cu adsorption - in mono-ion solutions was also performed. Adsorption kinetics, fitted with pseudo-first order (PFO) and pseudo second order (PSO) kinetic model, allowed the uptake parameters to be found and a comparison of kinetic rates. Synchrotron X-Ray-Florescence and X-Ray Absorption Spectroscopy measurements of Zn on algae after exposure permitted the extraction of direct information about Zn spatial distribution and bonding environment. The results showed that the carboxylic groups are the ones involved in the heterogeneously distributed Zn adsorption at low pH, Zn being coordinated with 5 6 O at bond distances varying from 1.98 to 2.03 A - as in Zn alginate. Synchrotron results provide confirmation that, relative to Zn, alginate is one of the main algae components responsible for metal binding. PMID- 30447633 TI - Organophosphorus hydrolase-poly-beta-cyclodextrin as a stable self decontaminating bio-catalytic material for sorption and degradation of organophosphate pesticide. AB - A region suffering from an attack of a nerve agent requires not only a highly sorptive material but also a fast-acting catalyst to decontaminate the lethal chemical present. The product should be capable of high sorptive capacity, selectivity and quick response time to neutralize the long lasting harmful effects of nerve agents. Herein, we have utilized organophosphorus hydrolase (OPH) as a non-toxic bio-catalytic material held in with the supporting matrix of poly-beta-cyclodextrin (PCD) as a novel sorptive reinforced self-decontaminating material against organophosphate intoxication. OPH coated PCD (OPH-PCD) will not only be providing support for holding enzyme but also would be adsorbing methyl paraoxon (MPO) used as a simulant, in a host-guest inclusion complex formation. Sorption trend for PCD revealed preference towards the more hydrophobic MPO against para-nitrophenol (pNP). The results show sorption capacity of 1.26 mg/g of 100 MUM MPO with PCD which was 1.7 times higher compared to pNP. The reaction rate with immobilized OPH-PCD was found to be 23% less compared to free enzyme. With the help of OPH-PCD, continuous hydrolysis (100%) of MPO into pNP was observed for a period of 24 h through packed bed reactor with good reproducibility and stability of enzyme. The long-term stability also confirmed its stable nature for the investigation period of 4 days where it maintained activity. Combined with its fast and reactive nature, the resulting self decontaminating regenerating material provides a promising strategy for the neutralization of nerve agents and preserving the environment. PMID- 30447634 TI - Resistance and resilience of representative low nucleic acid-content bacteria to free chlorine exposure. AB - Two representative low nucleic acid-content (LNA) bacterial strains, Polynucleobacter sp. CB and Sphingopyxis sp. 15Y-HN, and two commonly used microbial indicators of drinking water disinfection efficiency, Escherichia coli and Pseudomonas aeruginosa, were used to investigate the effects of chlorine disinfection. LNA bacteria were found to be more tolerant than microbial indicator strains at the same free chlorine concentrations in batch experiments. Three-stage chlorination experiments were carried out for two strains (15Y-HN and E. coli K12) to compare their responses to long-term chlorine exposure. Results from the first stage (increasing chlorine exposure from 0.0 to 0.6 mg/L and 1.2 mg/L for strain K12 and strain 15Y-HN, respectively) showed the rate constants of 99% cell damage were 10-fold lower for strain 15Y-HN than for strain K12. A second regrowth stage at low free chlorine concentrations (<0.3 mg/L for 140 h) facilitated the regrowth of chlorine-resistant populations of strains 15Y-HN and K12 in the presence of assimilable organic carbon (AOC). In the third stage, during which bacteria were exposed to increasing chlorine from 0.0 to 0.5-0.6 mg/L, strain 15Y-HN was maintained at 80% and 105 cells/mL of intact cells whereas strain K12 was completely damaged. The overall results demonstrated that representative LNA bacteria exhibit strong resistance and resilience to chlorine under low AOC conditions, which should be taken into consideration in disinfection processes. PMID- 30447635 TI - Grain size distribution and exposure evaluation of organophosphorus and brominated flame retardants in indoor and outdoor dust and PM10 from Chengdu, China. AB - To investigate overall pollution and potential risk of 32 targets (11 PBDEs, 8 NBFRs, and 13 OPFRs) in indoor and outdoor environments, dust and PM10 samples were sampled from non-occupational and occupational zones in Chengdu, China. ?Cl OPFRs, BDE-209, and DBDPE were the dominant constitutes in both the non occupational and occupational dust. Regarding the PM10, no significant differences were found between the kitchen and the living room for studied OPFRs except TDCIPP, and TCEP, TCPP, TEHP, and TCP displayed significant correlation among the kitchen, the living room and personal samples. Profiles of the OPFRs in the PM10 from occupational areas presented great variation and ranked as: ?Aryl OPFRs < ?Alkyl-OPFRs < ?Cl-OPFRs. The estimated daily intakes (EDIs) of the investigated FRs via dust suggested dust ingestion and inhalation were the main exposure route to FRs, and the total of EDIs were at least one order of magnitude lower than reference data, indicating a low risk for the general public in Chengdu. However, with increasing usage of FRs in daily goods, a long-term monitoring should be conducted. PMID- 30447636 TI - Removal of imidazolium-based ionic liquid by coupling Fenton and biological oxidation. AB - In this work, we assessed the potential of combining Fenton's reagent and biological oxidation for removing the imidazolium-based ionic liquid 1-Ethyl-3 methylimidazolium chloride (EmimCl). Fenton-like oxidation was conducted at variable H2O2 doses from 20 to 100% the stoichiometric value as calculated from the theoretical chemical oxygen demand (COD). The stoichiometric H2O2 dose afforded Total Organic Carbon (TOC) conversion and COD removal of 50 and 62%, respectively. Identifying the reaction by-products formed at low hydrogen peroxide doses allowed a plausible pathway for EmimCl oxidation to be proposed. The effluents from Fenton-like oxidation at substoichiometric H2O2 doses were less ecotoxic and more biodegradable than was the parent ionic liquid. The effluent from Fenton-like oxidation with the 60% H2O2 dose (TOC conversion ? 41%, COD removal ? 31%) was subsequently subjected to an effective biological treatment that allowed complete removal of the starting compound, increased its ecotoxicity to a low-moderate level and rendered it acceptably biodegradable. Biological oxidation was performed in 8-h and 12-h cycles in a sequencing batch reactor. Combining Fenton and biological oxidation of EmimCl afforded TOC conversion and COD removal of around 90%. PMID- 30447637 TI - Low - cost multilayered green fiber for the treatment of textile industry waste water. AB - Layer by layer (LbL) assembly can be regarded as an emerging technology for the separation of organic micro-pollutants from water. Direct assembly of polyelectrolytes (PEs) under LbL mode on natural support material is rare. Here we report the integration of LbL to one of the most resourceful support materials that might have an enduring impact on water treatment in color industry. A low cost adsorbent is developed from chitosan (CHI) and polyacrylic acid (PAA) through LbL deposition on coir fiber (CF) by alternate exposure to their aqueous solutions. Their layer dependent formation is characterized by spectroscopic and microscopic techniques. CHI/PAA multilayer coated coir fiber or simply, layered coir fiber (LCF) showed high loading of cationic and anionic dyes both at acidic and alkaline loading pH. The loading was between 70% and 99% at the acidic pH 3 which is attributed to the binding between LCF and dye molecules by electrostatic and hydrophobic forces. The performance of LCF in presence of NaCl, Na2SO4 and sodium dodecyl sulfate (SDS) in dye solution is discussed. Textile industrial waste water showed significant reduction in dye (81%) content along with COD (84%) and TDS. PMID- 30447638 TI - Peroxide-treated metal-organic framework templated adsorbents for remediation of high level nuclear waste. AB - Remediation of legacy nuclear waste is one of the greatest challenges faced by the US Department of Energy, with projected cleanup efforts requiring over five decades and hundreds of billions of dollars. New materials are necessary to accelerate waste processing, achieving time and financial savings. Herein we report a peroxide treatment to a Ti metal-organic framework (MOF) and related MOF templated adsorbents. The resulting materials displayed exceptional affinity for Am(III), achieving distribution coefficients in excess of 105 mL/g, and out performing state-of-the-art benchmarks monosodium titanate (MST) and peroxo treated modified MST (mMST) for removal of 85Sr(II) and 239, 240Pu(IV) from legacy nuclear waste simulant. PMID- 30447639 TI - MIL-PVDF blend ultrafiltration membranes with ultrahigh MOF loading for simultaneous adsorption and catalytic oxidation of methylene blue. AB - Multifunctional ultrafiltration membranes need to be further developed with ultrafiltration performance and high multifunctional decontamination efficiency. Here, the MIL-PVDF multifunctional ultrafiltration membrane with ultrahigh MIL loading was demonstrated by a new blending method of predispersion in acetone and thermally induced phase separation. Due to the improved dispersity and restriction of pore size, the MIL-53(Fe) mass loading was as high as approximately 61%. The new membrane showed high performance for methylene blue (MB) removal and maintained high permeability and ultrafiltration efficiency. The characteristics of the membranes were analyzed to explain the above advantages. Meanwhile, compared to the traditional blend ultrafiltration membrane, the 67-MIL PVDF membrane showed an 9-fold increase in effective treatment volume for more than 75% MB removal. The contribution and efficiency of adsorption and catalytic oxidation were analyzed and explained. The relationship between them was confirmed as being independent, and the reasons for this independence were proposed. Additionally, the mechanism of multifunctional decontamination and permeability by MIL-PVDF membranes was proposed. Moreover, the 67-MIL-PVDF membrane was also suitable for long-term run and real wastewaters treatment. In conclusion, this study sheds new light on the preparation strategy for multifunctional blend ultrafiltration membranes with ultrahigh particles loading displaying high decontamination and permeability performance. PMID- 30447640 TI - Integrated approach to enhance the anaerobic biodegradation of benz[alpha]anthracene: A high-molecule-weight polycyclic aromatic hydrocarbon in sludge by simultaneously improving the bioavailability and microbial activity. AB - The biodegradation of benz[alpha]anthracene (BaA), which was a high-molecule weight PAH, was enhanced via a combination of alkaline and alkyl polyglucosides (APG) treatment during waste activated sludge (WAS) anaerobic fermentation. The biodegradation efficiency of BaA was increased from 14.1% in the control to 30.2 and 47.8% in pH 10 and pH 10 & APG reactors, respectively. Mechanism investigations found that the alkaline and APG treatments stimulated the processes of BaA desorption from sludge and transfer/entry into microorganisms, and ultimately improved the BaA bioavailability. Meanwhile, the huge released substrates from WAS not only served as carbon sources but also involved in the electron transfer among microorganisms which contributed to the BaA biodegradation process. Moreover, the microbial activities involved in BaA biodegradation, including the abundances of functional bacteria, activities of enzymes and quantities of genes, were also incremented due to the alkaline and APG treatments. Overall, the simultaneous improvement of BaA bioavailability and microbial activities enhanced its biodegradation efficiency. PMID- 30447642 TI - Review of a forensic pseudoscience: Identification of criminals from bitemark patterns. AB - The forensic sciences are a combination of laboratory procedures and physical comparisons of objects associated with victims, perpetrators, and crime scenes. The former is largely university-based protocols adopted by crime labs. The latter is predominantly pattern-matching tools originally developed by police examiners or experts deemed by courts to be relevant to forensic matters. These Court accepted experts bring their reasoning and conclusions into the legal arena. This subgroup of forensics has undergone significant scrutiny in regards to its history of exaggerated claims and weak scientific foundations. This paper addresses the rise and fall of bitemark pattern analysis (i.e. "matching" bitemarks in human flesh to human teeth) in the environment of opposing interests and agendas. PMID- 30447641 TI - Establishment of a Novel PDX Mouse Model and Evaluation of the Tumor Suppression Efficacy of Bortezomib Against Liposarcoma. AB - The patient-derived xenograft (PDX) model has been adopted as a major tool for studying tumorigenesis and differentiation in various carcinomas. In addition, it has been used in the development of anticancer agents. PDX models have been among the most meaningful tools used to understand the role of stromal cells and vascular cells in the body, which are major factors in cancer development and the application of therapeutic agents. Also, the establishment of PDX models from liposarcoma patients is considered to be important for understanding lipomagenesis and following drugs development. For these reasons, we developed patient-derived cell (PDC) and PDX models derived from 20 liposarcoma patients. The tissues of these patients were obtained in accordance with the principles of the Samsung Medical Center's ethics policy, and cell culture and xenografting onto the mice were performed under these principles. High-throughput drug screening (HTS) was carried out using established PDCs to select candidate drugs. Among the different candidate anticancer drugs, we tested the effect of bortezomib, which was expected to inhibit MDM2 amplification. First, we confirmed that the PDCs maintained the characteristics of liposarcoma cells by assessing MDM2 amplification and CDK4 overexpression using fluorescence in situ hybridization. Analysis of short tandem repeats and an array using comparative genomic hybridization confirmed that the PDX model exhibited the same genomic profile as that of the patient. Immunohistochemistry for MDM2 and CDK4 showed that the overexpression patterns of both proteins were similar in the PDX models and the PDCs. Specifically, MDM2 amplification was observed to be significantly correlated with the successful establishment of PDX mouse models. However, CDK4 expression did not show such a correlation. Of the anticancer drugs selected through HTS, bortezomib showed a strong anticancer effect against PDC. In addition, we observed that bortezomib suppressed MDM2 expression in a dose dependent manner. In contrast, p21 tended to elicit an increase in PDC expression. Treatment of the PDX model with bortezomib resulted in an anticancer effect similar to that seen in the PDCs. These results support that PDCs and PDX models are among the most powerful tools for the development and clinical application of anticancer drugs for the treatment of liposarcoma patients. PMID- 30447643 TI - Can pulmonary foam arise after postmortem submersion in water? An animal experimental pilot study. AB - It is difficult to differentiate drowning from postmortem submersion. Pulmonary foam can be found in bodies retrieved from water. It is unknown whether foam is a result of drowning or if it also forms after postmortem submersion. We divided deceased piglets into three groups: postmortem saltwater submersion (N = 20), postmortem freshwater submersion (N = 20) and dry-land controls (N = 20). All carcasses underwent endoscopic examination within 24 h of death and the presence of external and internal pulmonary foam was scored. No external foam was detected in the postmortem freshwater or the postmortem saltwater group. Internal foam was seen in 35% of the postmortem freshwater and 40% of the postmortem saltwater group. No external or internal foam was detected in the dry land control group. The literature shows external as well as internal foam in drowned humans. Internal foam is seen in postmortem submersion in the current piglet study and antemortem submersion in the literature in humans, and can therefore not be used to support/refute the diagnosis of drowning. No external foam was present in the postmortem submersed piglets, yet has been described in drowned humans. Hence the presence of external foam in bodies recovered from water may be indicative for drowning. The presence of external foam is a potentially valuable clinical sign in distinguishing drowning from postmortem submersion. PMID- 30447644 TI - Photosensitizing materials and platforms for light-triggered modulation of Alzheimer's beta-amyloid self-assembly. AB - The abnormal aggregation of beta-amyloid (Abeta) peptides is a hallmark of Alzheimer's disease (AD) that affects more than 10% of the people over the age 60 world-wide. While the exact mechanism of neuronal loss and cognitive decline has not been elucidated yet, the amyloid hypothesis about the causative role of Abeta aggregation in AD pathology has been widely supported by the numerous in vivo and in vitro data. In this respect, many efforts have been made to explore therapeutic agents that can modulate the aggregation of Abeta, but none of the efforts succeeded in producing effective anti-Abeta drugs for treating AD. This article provides an overview of recent attempts that have employed light energy to intervene with the self-assembly process of Abeta peptides via the generation of oxidative stress by photosensitizers, such as natural or synthetic dyes, light responsive nanomaterials, and photoelectrochemical platforms. The underlying mechanism of photodynamic reactions suppressing Abeta aggregation and the dilemma in generating long-been-blamed oxidative stress are discussed by addressing the positive role of oxidative stress produced by the photosensitizers in the light induced suppression of Abeta-mediated neurotoxicity. We have summarized current challenges and strategies to advance photo-induced inhibition and modulation of Abeta aggregation as a therapeutic option for treating AD in the future. PMID- 30447645 TI - Different trends in colorectal cancer mortality between age groups in China: an age-period-cohort and joinpoint analysis. AB - OBJECTIVES: China is undergoing a rapid aging transition. The trends in age specific mortality rates from colorectal cancer remain unknown, and a number of studies have not distinguished the age, period, and cohort effects simultaneously. STUDY DESIGN: A descriptive study was implemented with a joinpoint regression analysis and age-period-cohort (APC) model based on the intrinsic estimator (IE). METHODS: Age-specific mortality rates of colorectal cancer (1987-2016) were collected by gender (men/women) and region (urban/rural). The average annual percentage change (AAPC) and relative risks in the trend were identified using joinpoint Poisson regression and APC model (IE), respectively. RESULTS: Joinpoint regression analysis revealed that the rates decreased in the younger (men aged <45 years and women aged <75 years) but increased in the older (men aged >75 years and women aged >80 years) age groups. The APC model (IE) showed that the rates increased with age and time period but decreased with birth cohorts. But from 2000 to 2005, the period effects showed a substantial decline among urban residents. From the 1910-1914 to the 1915-1919 birth cohort, mortality increased among men, and from the 1925-1929 to the 1930-1934 birth cohort, mortality increased among rural residents. CONCLUSIONS: The trends in colorectal cancer mortality are different between age groups. The younger age groups show a decreasing trend, whereas the older age groups an increasing trend. Cost-effective prevention and control should be implemented more in the elderly and for older cohorts at high risk. PMID- 30447646 TI - Efficient CO2 Utilization via a Hybrid Na-CO2 System Based on CO2 Dissolution. AB - Carbon capture, utilization, and sequestration technologies have been extensively studied to utilize carbon dioxide (CO2), a greenhouse gas, as a resource. So far, however, effective technologies have not been proposed owing to the low efficiency conversion rate and high energy requirements. Here, we present a hybrid Na-CO2 cell that can continuously produce electrical energy and hydrogen through efficient CO2 conversion with stable operation for over 1,000 hr from spontaneous CO2 dissolution in aqueous solution. In addition, this system has the advantage of not regenerating CO2 during charging process, unlike aprotic metal CO2 cells. This system could serve as a novel CO2 utilization technology and high value-added electrical energy and hydrogen production device. PMID- 30447647 TI - Intra-embryo Gene Cassette Knockin by CRISPR/Cas9-Mediated Genome Editing with Adeno-Associated Viral Vector. AB - Intra-embryo genome editing by CRISPR/Cas9 enables easy generation of gene modified animals by non-homologous end joining (NHEJ)-mediated frameshift mutations or homology-directed repair (HDR)-mediated point mutations. However, large modifications, such as gene replacement or gene fusions, are still difficult to introduce in embryos without costly micromanipulators. Moreover, micromanipulation techniques for intra-embryo genome editing have been established in only a small set of animals. To overcome these issues, we developed a method of large-fragment DNA knockin without micromanipulation. In this study, we successfully delivered the knockin donor DNA into zygotes by adeno associated virus (AAV) without removing the zona pellucida, and we succeeded in both large-DNA fragment knockin and whole exon exchange with electroporation of CRISPR/Cas9 ribonucleoprotein. By this method, we can exchange large DNA fragments conveniently in various animal species without micromanipulation. PMID- 30447648 TI - CXCL12 G801A polymorphism is associated with significant liver fibrosis in HIV infected Thais: a cross-sectional study. AB - BACKGROUND: Previous studies indicate high prevalence of liver diseases in HIV infected patients, and their genetic risk factors are still unclear. The chemokine CXCL12 plays important roles in development of chronic liver injury and a single nucleotide polymorphism (SNP) G to A change at position 801 in CXCL12 gene has been demonstrated to affect CXCL12 production levels. OBJECTIVE: This study aimed to analyze the association of CXCL12 G801A SNP with liver complication in HIV-infected Thais. METHODS: A cross-sectional study was conducted in 164 patients who were evaluated for transaminitis and significant liver fibrosis, defined by fibrosis-4 (FIB-4) score and AST to platelet ratio index (APRI), and genotyped for the SNP using tetra-primer PCR-SSP. RESULTS: There were high rates of patients with transaminits (28.0%), and significant liver fibrosis by FIB-4 score (18.9%) and by APRI (14.0%). The CXCL12 G801A AA/GA genotypes were significantly associated with transaminitis (p = 0.014) and significant fibrosis by APRI (p = 0.020). Univariate and multivariate analyses identified the AA/GA genotypes as predictive factors for significant fibrosis (OR 6.8, 95%CI 1.7-28.2, p = 0.008), together with age older than 40 years, CD4+ cell count < 350 cells/MUl and hepatitis B and/or C virus coinfection. The significantly higher medians of APRI and FIB-4 score, in patients with AA/GA than those with GG genotypes (p < 0.05) were observed in the ART-naive, but not ART experienced groups. CONCLUSION: The CXCL12 G801A AA/GA genotypes are significant predictive factors for hepatic fibrosis potentially in the ART-naive HIV-infected Thais. PMID- 30447649 TI - Preventive and therapeutic effects of vitamin D in a mouse model of allergic asthma. AB - BACKGROUND: Vitamin D produces an anti-allergic effect that prevents inflammation due to asthma. OBJECTIVE: We investigated whether vitamin D has an anti inflammatory effect on the sensitization and challenge stages of asthma development in a murine model. METHODS: Mice were divided into the following five groups according to ovalbumin (OVA) and vitamin D (VD) administration: control group, OVA group, preventive VD group (VD injection before OVA sensitization), inhibitory VD group (VD injection after OVA challenge), and dual VD groups (VD injection before OVA sensitization and after OVA challenge). Each group was evaluated for airway hyperresponsiveness (AHR), cell counts, cytokines, total IgE, and OVA-specific IgE using bronchoalveolar lavage fluid (BALF). Cytokines in the lysate and eosinophils in the lung tissue were also evaluated. RESULTS: AHR occurred less in the groups to which VD was administered than in the OVA group. The eosinophils, neutrophils, IL-5 in BALF, IL-4, TGF-beta, and eosinophils in lysate decreased with the administration of VD in the preventive, inhibitory, and dual VD groups compared with the OVA group. Although the lymphocytes, macrophages, IL-4 in BALF, and IL-5 in lysate decreased with administration of VD in the inhibitory and dual VD groups, they were not affected by preventive VD administration. These anti-allergic effects of VD were most noticeable with VD administration for dual (preventive and inhibitory) purposes. CONCLUSIONS: VD may produce preventive and inhibitory effects on the development and exacerbation of asthma in a murine model. These effects are most noticeable when VD is used for dual purposes. PMID- 30447650 TI - Proteomic Identification of Allergenic Proteins of Morus alba L. Pollenexacerbation. AB - BACKGROUND: Tree pollens are well-known aeroallergens all over the world. Little is known about the allergenicity of Morus alba (white mulberry) pollen. OBJECIVE: We aimed to explore the potential allergens of this pollen and its clinical relevance in tree pollen allergic patients living in Istanbul, Turkey. METHODS: Twenty three seasonal allergic rhinitis patients with a confirmed tree pollen allergy and 5 healthy control subjects underwent skin prick and nasal provocation tests with M.alba pollen extract. The pollen extract was then resolved by gel electrophoresis, and immunoblotted with sera from patients/control individuals to detect the potential allergenic proteins. The prevalent IgE binding proteins from 1D-gel were analyzed by MALDI-TOF/TOF. RESULTS: Eleven out of 23 patients were reactive to the extract with skin prick tests. Seven of those patients also reacted positively to the nasal provocation tests. The most common IgE-binding pollen proteins were detected between 55-100 kDa, and also at molecular weights lower than 30 kDa for some patients. Mass spectrometry analyses revealed that the principal IgE-binding protein was methionine synthase (5 methyltetrahydropteroyltriglutamate homocysteine methyltransferase), which is then proposed as a novel allergen in M.alba pollen. CONCLUSION: This study provides the first detailed information for the potential allergens of Morus alba pollen of Istanbul. Methionine synthase with an apparent molecular weight of 80 to 85 kDa has been recognized as one of the allergens in Morus alba pollen for the first time. PMID- 30447651 TI - Prevalence and severity of asthma, rhinoconjunctivitis and eczema in children from the Bangkok area: The Global Asthma Network (GAN) Phase I. AB - BACKGROUND: As noted in the reports of ISAAC phase I and III, allergic diseases are very common in Thailand, especially among younger children. OBJECTIVE: The objectives of this project are to study the prevalence and severity of the most common allergic diseases. i.e. asthma, rhinoconjunctivitis and eczema among children living in Bangkok. METHODS: A cross-sectional multi-centers survey using GAN Core questionnaires on asthma, rhinoconjunctivitis and eczema symptoms were completed by parents of children aged 6-7 years and children aged 13-14 years. RESULTS: The total of 6,291 questionnaires were eligible for the analysis. The cumulative vs. 12-month period prevalence of the three conditions for all children were: 24.4% vs. 13.5% for wheezing, 51.1% vs. 43.6% for rhinitis and 15.8% vs. 14.2% for eczema, respectively. The period prevalence of wheezing for younger children (14.6%) was higher than for older children (12.5%). Prevalences of severe wheeze and exercise wheeze were more common among older children (2.9% and 14.8%). The 12-month prevalences of rhinitis (43.6%) and rhinoconjunctivitis (16.3%) were higher in both age groups. Eczema, as the same to the other conditions, occurred more frequently in both groups (period prevalence of 14.3% and 14.0%) comparing to ISAAC phase III. CONCLUSION: Allergic conditions are very common diseases among children residing in Bangkok. There is an urgent need for an in-depth study to define epidemiological factors responsible for this increase. PMID- 30447652 TI - Prevalence and cluster effect of self-reported allergic reactions among insect consumers: An internet survey from Thailand. AB - BACKGROUND: Entomophagy is a common practice in many parts of the world. Allergic symptoms after insect consumption have been reported in healthcare literature and in the news. OBJECTIVE: We evaluated prevalence and association of allergic history and self-reported allergic reactions after entomophagy. METHODS: We conducted a cross sectional internet-based survey. Participants were people who have consumed insects. Collected information included demographic data, the practice of entomophagy, allergic history and self-reported allergic symptoms. RESULTS: During May to October 2017, 140 people completed the survey. Median and range of age are 27 and 18-64 years. Ninety-two (65.7%) were female. Thirty-seven (26.4%) and 13 (9.3%) participants had history of allergy and seafood allergy, respectively. Eighteen (12.9%; 95% confidence intervals (CI) 7.3-18.4) participants reported allergic reactions after insect consumption. Nine symptomatic participants reported other people who partook insects to have allergic symptoms. Reported factors with significant association with allergic reactions were history of allergy and seafood allergy with prevalence ratios of 4.83 (CI 1.83-10.44) and 3.76 (CI 1.59-8.87), respectively. CONCLUSION: The prevalence of self-reported allergic reactions after entomophagy is 12.9%. Clusters of people with post-entomophagy allergic symptoms are found. History of allergy and seafood allergy are associated with post-entomophagy allergic reactions. PMID- 30447653 TI - WITHDRAWN:Comparison of immediate hypersensitivity reaction rate according to the type of radiocontrast media. AB - The paper entitled "Comparison of immediate hypersensitivity reaction rate according to the type of radiocontrast media" by Hye Jung Park et al, which was published online on 15 October 2018, has been withdrawn at the authors' request. PMID- 30447654 TI - Anaphylaxis: Ten-year retrospective study from a tertiary-care hospital in Northern Thailand. AB - BACKGROUND: The study of anaphylaxis in different geographic areas raises the awareness to improve prevention and medical care. OBJECTIVE: To investigate the incidence, causes, characteristics, and management of anaphylaxis in Chiang Mai, Thailand METHODS: We performed a retrospective review, based on ICD-10 electronic medical records of patients who attended the Out-Patient and Emergency Departments at Chiang Mai University Hospital from January 2007 to December 2016. RESULTS: A total of 441 episodes of anaphylaxis in 433 patients were analyzed. Three-hundred and sixty-two (84%) were adults and 71 (16%) were children. Anaphylaxis was common in the second and third decades of life. The incidence rate for all causes of anaphylaxis was 3.9 episodes per 100,000 out-patient and emergency visits per year. The rate in children was more frequent than in adults. Foods were the most common culprit (47%), followed by insect stings (23%) and drugs (18%). Severe anaphylaxis, defined as the loss of consciousness, hypotension, respiratory failure, or cyanosis were found in 163 events (37%). The time lapses between exposure with an allergen and the onset of symptom less than 30 minutes and triggered by insect stings were significantly associated with severe anaphylaxis. Biphasic reactions occurred in 6 patients (1.4%). Adrenaline injections were prescribed in most of patients (90%). There were no fatality cases in the past 10 years. CONCLUSION: The incidence of anaphylaxis in our hospital appears more often in children than in adults. The frequency in adults trends to be increasing. Food and insect stings are the common causative agents. PMID- 30447655 TI - Purpuric drug eruption without leukocytoclastic vasculitis associated with vancomycin. AB - Vancomycin (VCM) has been reported to elicit adverse cutaneous drug reactions. However, VCM-associated purpuric drug eruption has not been reported yet, except leukocytoclastic vasculitis. A 16-year-old Japanese girl was admitted with a respiratory infection. We initiated intravenous administration of VCM. After the start of treatment, impalpable purpuric eruption appeared on her trunk. The eruption gradually extended to her neck, legs, and arms. Skin biopsy showed vasculitis with lymphocyte infiltration in the superficial dermis. A drug lymphocyte stimulation test yielded positive results for VCM. Her cutaneous symptoms rapidly reversed after the withdrawal of VCM. To the best of our knowledge, this is the first reported case of VCM-associated purpuric drug eruption, which differs from leukocytoclastic vasculitis. We recommend that VCM associated purpuric drug eruption should be considered in the differential diagnosis during the administration of VCM, and a drug lymphocyte stimulation test may be useful for assessment of pathogenesis. PMID- 30447656 TI - Accuracy of in-house alcohol-dissolved wheat extract for diagnosing IgE-mediated wheat allergy. AB - BACKGROUND: The standard method for diagnosing immediate wheat allergy is oral food challenge test (OFC). However, OFC can provoke anaphylaxis during the challenge process. Skin prick test (SPT) using commercial wheat extract yielded unsatisfactory result for diagnosis of wheat allergy. As a result, an in-house, alcohol-dissolved (Coca-10% EtOH) wheat extract was developed to improve accuracy of the SPT. OBJECTIVE: To determine the accuracy of in-house, alcohol-dissolved wheat extract in children with immediate wheat allergy METHODS: This prospective cross-sectional study included children with history of immediate reaction after wheat ingestion. SPTs with commercial and in-house Coca-10% EtOH wheat extract were performed and wheat and omega-5 (omega-5) gliadin specific IgE (sIgE) were measured. Patients with no history of recent anaphylaxis after wheat ingestion underwent OFC with 31 grams of wheat flour. RESULTS: Thirty children were recruited. Thirteen of those had history of anaphylaxis after wheat ingestion. Eleven of the remaining 17 children (64.7%) had a positive result for wheat challenge test. Wheal size of 3 mm for both in-house and commercial wheat extract yielded the best accuracy for the test. Using these cutoff parameters, in-house Coca-10% EtOH wheat extract yielded 91.7% sensitivity, 66.7% specificity, and 86.7% accuracy. Comparatively, the commercial extract yielded 70.8% sensitivity, 100% specificity, and 76.6% accuracy. CONCLUSION: SPT using in-house Coca-10% EtOH wheat extract yielded better accuracy than commercial extract for diagnosing immediate type wheat allergy in children. PMID- 30447657 TI - Disseminated cryptococcosis in two boys with novel mutation of CD40 Ligand Associated X-linked hyper-IgM syndrome. AB - X-linked hyper-IgM syndrome (XHIM) caused by CD40L mutations is a primary immunodeficiency condition that increases susceptibility to opportunistic infections. Disseminated cryptococcosis in XHIM is rarely reported in children. Here, we report two related boys who have a novel hemizygous frameshift c.208delC mutation of CD40L. They live in the western region of Thailand and developed disseminated cryptococcosis while receiving regular intravenous immunoglobulin supplementation. PMID- 30447658 TI - What leads to the subjective perception of a 'rural area'? A qualitative study with undergraduate students and postgraduate trainees in Germany to tailor strategies against physician's shortage. AB - INTRODUCTION: The increasing shortage of physicians, especially general practitioners (GPs), in rural areas is an issue in most western countries. Many redistribution strategies have been utilized in the past to counter this shortage. The physician's perception of rural areas might be an underestimated aspect of a subsequent choice of living and working environment. The aim of this study was to explore determinants influencing this subjective perception of rurality and to develop further strategies to resolve the physician shortage in rural areas. METHODS: A qualitative study with semi-structured interviews and focus groups consisting of medical students and postgraduate trainees in Germany was conducted. The interviews and focus groups were recorded, transcribed and evaluated both deductively and inductively by two independent researchers using qualitative content analysis. RESULTS: Participants had an average age of 28 years. Of 16 medical students and 17 postgraduate trainees, there were 24 women and 9 men. The perception of rurality was strongly influenced by a personal connection (eg family background or personal experiences), which resulted in positive and/or negative associations with rural life and was also a decisive factor for the decision to live in rural areas. Without any kind of personal connection, the choice to work in a rural area was unlikely. Depending on life stage (eg having partners and/or children), different factors were relevant, such as cultural offerings, diversity, accessibility and quality of educational structures (kindergarten/school). Prejudices and a negative image of family medicine deterred students from choosing a career as a GP, whereas postgraduate trainees didn't feel adequately prepared to be fully competent to practice as a GP outside a metropolitan area. CONCLUSIONS: Strategies must be developed to raise awareness and create a personal connection to rural areas during under- and postgraduate medical training. Attention should be given to highlighting family friendliness (child care, schools), the attractiveness of working conditions and to improving deficiencies in local infrastructure (internet and or traffic connections). Additionally, there is a need to strengthen the national standardized and structured postgraduate training as well as collegial exchange and the possibility to work in a group practice or as an employee in rural areas. PMID- 30447659 TI - Current practices, barriers and enablers for advance care planning among healthcare workers of aged care facilities in western New South Wales, Australia. AB - INTRODUCTION: Advance care planning (ACP) and advance care directives (ACDs) play a vital role in preparing for end-of-life care. However, current literature suggests that uptake of ACP and ACDs in rural Australia is low, which may contribute to lower quality care for the older rural population, as patients' end of-life wishes may not be recognised and acknowledged. This study aims to provide a current perspective on the attitudes and practices of healthcare workers from residential aged care facilities towards ACP and ACDs in the central west, far west and Orana regions of New South Wales, Australia. METHODS: This was a mixed methods study incorporating anonymous survey and individual interviews. Healthcare workers from 12 residential aged care facilities within the studied region completed surveys (n=109). The 40-item survey assessed participant demographics, training and experience with ACP and ACD, attitudes towards ACP and ACDs, and barriers and facilitators towards the use of ACP and ACDs in their organisation. Five participants were interviewed to explore these issues in more depth. RESULTS: Almost three-quarters (71%) of respondents thought that ACP is necessary while almost half (48%) were involved with >5 ACDs in the past 12 months. Formal training was seen as beneficial by most (81%) but the importance of practical experience was also acknowledged. No statistically significant differences were found in attitudes between those with 5 years of experience. Avoidance of unnecessary resuscitation was a consistent theme in all interviews and the potential of a nurse-led model of delivery was identified. Patient factors such as decreased capacity to make informed decisions were identified as barriers that could be circumvented by pre-emptive implementation of ACP discussion. The rural setting was identified as a facilitator due to a supportive community, which helped to mitigate barriers such as limited staffing. CONCLUSIONS: Attitudes towards ACP in rural New South Wales are highly positive. The rural setting is a facilitator to ACP, and ACDs are approached in a multidisciplinary fashion. Further training is an identified need although on-the ground experience may be more beneficial. PMID- 30447660 TI - The early history of extracorporeal membrane oxygenation. PMID- 30447661 TI - A data sharing policy for Anaesthesia and Intensive Care. PMID- 30447663 TI - Mostly harmless? PMID- 30447662 TI - The Anaesthesia and Intensive Care Jeanette Thirlwell Best Paper Award turns 21, and our first Junior Investigator Award. PMID- 30447664 TI - Epinephrine (adrenaline) preventing recovery from intraoperative anaphylactic shock complicated by systolic anterior motion of the mitral valve with left ventricular outflow tract obstruction on transoesophageal echocardiography. AB - We describe a case of severe left ventricular outflow tract obstruction (LVOTO) with severe mitral incompetence due to systolic anterior motion of the anterior mitral leaflet (SAM) that was recognised thanks to the immediate availability of transoesophageal echocardiography during the resuscitation of anaphylactic shock. The patient rapidly responded to cessation of the epinephrine (adrenaline) infusion and intravascular volume expansion with intravenous crystalloid. The absence of risk factors for developing SAM/LVOTO serve as a warning to clinicians to consider this diagnosis in all cases of epinephrine non-responsive anaphylactic shock. PMID- 30447665 TI - Adhesive arachnoiditis following inadvertent epidural injection of 2% chlorhexidine in 70% alcohol-partial recovery over the ensuing eight years. AB - We report a case of serious neurologic injury due to inadvertent epidural injection of 8 ml of the antiseptic 2% chlorhexidine in 70% alcohol during a procedure aimed to relieve the pain of labour. This resulted in immediate severe back pain, progressive tetraparesis and sphincter dysfunction caused by damage to the spinal cord and nerve roots. Subacute hydrocephalus necessitated drainage, but cranial nerve and cognitive function were spared. Magnetic resonance imaging documented marked abnormality of the spinal cord and surrounding leptomeninges. In the ensuing eight years, there has been clinical and electrophysiological evidence of partial recovery, but neurologic deficit remains severe. PMID- 30447666 TI - Hyperinsulinaemic euglycaemic therapy use in neurogenic stunned myocardium following subarachnoid haemorrhage. AB - We present a 62-year-old female who collapsed with a subarachnoid haemorrhage. This was complicated by profound shock secondary to neurogenic stunned myocardium. As the patient demonstrated life-threatening catecholamine-resistant shock that was unresponsive to conventional treatment measures, hyperinsulinaemic euglycaemic therapy was utilised as a rescue therapy. To our knowledge this has not previously been described in the literature. The patient proceeded to stabilise and made a good recovery. PMID- 30447667 TI - Retrieval of critically ill adults using extracorporeal membrane oxygenation: the nine-year experience in New South Wales. AB - In New South Wales, a coordinated extracorporeal membrane oxygenation (ECMO) retrieval program has been in operation since 2007. This study describes the characteristics and outcomes of patients transported by this service. We performed a retrospective observational study and included patients who were transported on ECMO to either of two adult tertiary referral hospitals in Sydney, New South Wales, between February 28, 2007 and February 29, 2016. One hundred and sixty-four ECMO-facilitated transports occurred, involving 160 patients. Of these, 118 patients (74%) were treated with veno-venous (VV) ECMO and 42 patients (26%) were treated with veno-arterial ECMO. The mean (standard deviation, SD) age was 40.4 (15.0) years. Seventy-seven transports (47%) occurred within metropolitan Sydney, 52 (32%) were from rural or regional areas within NSW, 17 (10%) were interstate transfers and 18 (11%) were international transfers. Transfers were by road (58%), fixed wing aircraft (27%) or helicopter (15%). No deaths occurred during transport. The median (interquartile range) duration of ECMO treatment was 8.9 (5.2-15.3) days. One hundred and nineteen patients (74%) were successfully weaned from ECMO and 109 (68%) survived to hospital discharge or transfer. In patients treated with VV ECMO, age, sequential organ failure assessment score, pre-existing immunosuppressive disease, pre-existing diabetes, renal failure requiring dialysis and failed prone positioning prior to ECMO were independently associated with increased mortality. ECMO-facilitated patient transport is feasible, safe, and results in acceptable short-term outcomes. The NSW ECMO Retrieval Service provides specialised support to patients with severe respiratory and cardiovascular illness, who may otherwise be too unstable to undergo inter-hospital transfer to access advanced cardiovascular and critical care services. PMID- 30447668 TI - Vitamin D status and supplementation in adult patients receiving extracorporeal membrane oxygenation. AB - The prevalence of vitamin D deficiency in critical illness is known to be high and associated with adverse clinical outcomes. Patients receiving extracorporeal membrane oxygenation (ECMO) may be at increased risk of vitamin D deficiency due to high severity of acute illness. Challenges with drug dosing in ECMO patients are recognised due to increased volume of distribution and drug absorption to circuit components. To describe the prevalence of vitamin D deficiency in ECMO patients and the effect of intramuscular dosing of cholecalciferol on levels of vitamin D metabolites, and to compare these data with intensive care unit (ICU) patients not receiving ECMO, two prospective studies were performed sequentially: an observational study of 100 consecutive ICU patients and an interventional study assessing effects of intramuscular cholecalciferol in 50 ICU patients. The subgroup of patients who required ECMO support in each of these studies was analysed and compared to patients who did not receive ECMO. Twenty-four ECMO patients, 12 from the observational study and 12 from the interventional study (who received intramuscular cholecalciferol) were studied-21/24 (88%) ECMO patients were vitamin D deficient at baseline compared to 65/126 (52%) of non ECMO patients (P=0.006). Of the 12 ECMO patients who received cholecalciferol, six patients (50%) achieved correction of deficiency compared to 36/38 (95%) non-ECMO patients (P=0.001). The prevalence of vitamin D deficiency is higher in ECMO patients compared to other critically ill adults. Correction of deficiency with single dose cholecalciferol is not reliable; higher or repeated doses should be considered to correct deficiency. PMID- 30447669 TI - Postoperative cognitive dysfunction after sevoflurane or propofol general anaesthesia in combination with spinal anaesthesia for hip arthroplasty. AB - It is unknown if the type of general anaesthetic used for maintenance of anaesthesia affects the incidence of postoperative cognitive dysfunction (POCD). The aim of this study was to compare the incidence of POCD in patients administered either sevoflurane or propofol for maintenance of anaesthesia during total hip replacement surgery. Following administration of a spinal anaesthetic, patients received either sevoflurane (n=121) or propofol (n=171) at the discretion of the anaesthetist for maintenance of general anaesthesia to maintain the processed electroencephalogram (bispectral index, BIS) under 60. POCD was assessed postoperatively at day 7, three months, and 12 months using a neurocognitive test battery. There was no statistically significant difference between the incidence of POCD at any timepoint with sevoflurane compared to propofol. The mean BIS was significantly lower in the sevoflurane group than in the propofol group (mean BIS 44.3 [standard deviation, SD 7.5] in the sevoflurane group versus 53.7 [SD 8.1] in the propofol group, P=0.0001). However, there was no statistically significant association between intraoperative BIS level and the incidence of POCD at any timepoint. Our results suggest that the incidence of POCD is not strongly influenced by the type of anaesthesia used in elderly patients. PMID- 30447670 TI - Peripheral tissue oxygenation and the number of organs transplanted per donor. AB - Current donor management practices target macrohaemodynamic parameters, but it is unclear if this leads to improvements in microvascular perfusion and tissue oxygenation; the latter may have more impact on organ status. In a recent preclinical study we determined that brain death impaired tissue perfusion and oxygen utilisation in swine while pharmacologic correction of these deficits improved organ function and reduced markers of tissue injury. As a first step in translating the preclinical findings, we conducted a prospective observational study to determine if there was an association between peripheral tissue oxygenation (measured by near-infrared spectroscopy) in deceased by neurological criteria human donors and the number of organs transplanted. In 60 donors, the mean time-weighted average of tissue oxygenation was 87.5% (standard deviation, SD, 5.2%) and the average number of organs transplanted was 3.5 (SD 2); there was a positive linear relationship between these two parameters. A 5% rise in tissue oxygenation was associated with an increase of 0.47 organs transplanted (95% confidence intervals 0.16 to 0.78) after adjusting for age (P=0.004). No such correlations were observed for the macrohaemodynamic or macro-oxygenation parameters (including arterial blood oxygenation). The results of this clinical trial are consistent with our preclinical work and support the postulate that targeting the microvasculature to improve tissue perfusion and tissue oxygen delivery in human donors has the potential to increase the quantity of organs suitable for transplant. PMID- 30447671 TI - Preoperative gastric residual volumes in fasted patients measured by bedside ultrasound: a prospective observational study. AB - The purpose of this prospective observational study was to measure gastric volumes in fasted patients using bedside gastric ultrasound. Patients presenting for non-emergency surgery underwent a gastric antrum assessment, using the two diameter and free-trace methods to determine antral cross-sectional area (CSA). Gastric residual volume (GRV) was calculated using a validated formula. Univariate and multivariable analyses were performed to examine any potential relationships between 'at risk' GRVs (>100 ml) and patient factors. Two hundred and twenty-two successful scans were performed; of these 110 patients (49.5%) had an empty stomach, nine patients (4.1%) had a GRV >100 ml, and a further six patients (2.7%) had a GRV >1.5 ml/kg. There was no significant relationship between at risk GRV and obesity, diabetes mellitus, gastro-oesophageal reflux disease or opioid use, although our study had insufficient power to exclude an influence of one or more of these factors. Our results indicate that despite compliance with fasting guidelines, a small percentage of patients still have GRVs that pose a pulmonary aspiration risk. Anaesthetists should consider this background incidence when choosing anaesthesia techniques for their patients. While future observational studies are required to determine the role of preoperative bedside gastric ultrasound, it is possible that this technique may assist anaesthetists in identifying patients with 'at risk' GRVs. PMID- 30447672 TI - The effect of preload on electromyographic train-of-four ratio at the first dorsal interosseous muscle during spontaneous recovery from neuromuscular blockade. AB - Accurate and reliable quantitative neuromuscular function monitoring is desirable for the optimal management of neuromuscular blockade, selection of the most appropriate reversal agent and dosage, and assessing the completeness of reversal to exclude residual neuromuscular blockade. Applying preload to the thumb may affect the precision of electromyography. This study compared the precision and agreement of electromyography with and without preload during recovery from non depolarising neuromuscular blockade. After induction of anaesthesia and before neuromuscular blockade, the supramaximal current required at the first dorsal interosseous muscle with and without preload was determined. During recovery, train-of-four ratios were recorded using electromyography every 20 seconds. Alternating pairs of measurements (with and without preload) were obtained until spontaneous recovery was achieved. The preload device applied a resting tension of 75-150 g to the thumb. Bland-Altman analysis for repeated measurements was used to assess precision and agreement of electromyography responses with and without muscle preload. Two hundred and seventy-five sets of repeated measurements were collected from 35 participants. The repeatability coefficient for train-of-four ratios recorded by electromyography with a preload was 0.030 (95% confidence intervals, CI, 0.028 to 0.031) versus 0.068 (95% CI 0.064 to 0.072) without. Train-of-four ratios with preload demonstrated a bias of +0.038 (95% CI 0.037 to 0.042) compared to electromyography without, with 95% limits of agreement of 0.035-0.111. Preload significantly improved the precision of electromyographic train-of-four ratios, with 95% of consecutive measurements differing by less than 3%. Furthermore, electromyography with preload demonstrated a positive bias of 0.04 compared with electromyography alone, the clinical significance of which requires further research. PMID- 30447673 TI - An audit of the diagnostic accuracy of rotational thromboelastometry for the identification of hypofibrinogenaemia and thrombocytopenia during cardiopulmonary bypass. AB - We audited the diagnostic accuracy of ROTEM(r) (TEM Innovations, GmbH, Munich, Germany) measurements of hypofibrinogenaemia (fibrinogen <1.5 g/l) and thrombocytopenia (platelet count <100 x 109/l) in 200 adult non transplant patients during cardiopulmonary bypass (CPB). Blood samples were obtained for FIBTEM (assay for the fibrin part of the clot), PLTEM (calculated platelet-specific component), and laboratory measurements simultaneously. Our thresholds for FIBTEM and PLTEM were A10 (clot firmness 10 minutes after clotting time) <=8 mm, and <35 mm respectively. We also calculated the accuracy of smaller thresholds and earlier indices. We found that FIBTEM A10 <=8 mm had low sensitivity (0.62) for hypofibrinogenaemia. With the 13% hypofibrinogenaemia prevalence in our sample, the positive predictive value (PPV) was 0.47. In contrast, FIBTEM A10 <=8 mm had higher specificity (0.90) (negative predictive value [NPV] 0.94). Of the other FIBTEM values analysed, only A5 <=6 mm had similar or superior accuracy. The PLTEM results were less encouraging (sensitivity 0.81, specificity 0.62). With our prevalence of thrombocytopenia (also 13%), the PPV was only 0.24. However, the NPV was high (0.96). Of the other PLTEM values analysed, only A5 <25 mm had similar or superior accuracy. These findings indicate that during CPB FIBTEM A10 <=8 mm and PLTEM A10 <35 mm have greater accuracy in identifying the absence of hypofibrinogenaemia and thrombocytopenia respectively than their presence. On the basis of these results we would be reassured by FIBTEM A10 values >8 mm and PLTEM A10 values >=35 mm, but would continue to use laboratory measurements for confirmation. We would not use FIBTEM A10 <=8 mm or PLTEM A10 <35 mm values alone to guide replacement therapy unless clinical conditions warranted an immediate decision before laboratory measurements were available. PMID- 30447674 TI - Functional assessment tools in the intensive care unit: are we comparing apples and oranges? PMID- 30447675 TI - It's hard to kill off an old paradigm-starvation in the midst of plenty. PMID- 30447676 TI - In reply. PMID- 30447677 TI - Persistent opioid use after arthroplasty. PMID- 30447678 TI - Primum non nocere: greening anaesthesia. PMID- 30447679 TI - Use of the LMA(r) GastroTM Airway, a novel dual channel laryngeal mask airway, for endoscopic retrograde cholangiopancreatography: a report of two cases. PMID- 30447680 TI - A cost comparison between total intravenous and volatile-based anaesthesia. PMID- 30447681 TI - In reply. PMID- 30447682 TI - Postoperative residual curarisation is still an issue when weaning patients in intensive care following cardiac surgery. PMID- 30447683 TI - Higher PEEP improves outcomes in ARDS patients with clinically objective positive oxygenation response to PEEP: a systematic review and meta-analysis. AB - BACKGROUND: Mortality in patients with acute respiratory distress syndrome (ARDS) remains high. These patients require mechanical ventilation strategies that include high positive end-expiratory pressure (PEEP). It remains controversial whether high PEEP can improve outcomes for ARDS patients, especially patients who show improvement in oxygenation in response to PEEP. In this meta-analysis, we aimed to evaluate the effects of high PEEP on ARDS patients. METHODS: We electronically searched randomized controlled trials (RCTs) reported in the MEDLINE, CENTRAL, EMBASE, CINAHL and Web of Science databases from January 1990 to December 2017. Meta-analyses of the effects of PEEP on survival in adults with ARDS were conducted using the methods recommended by the Cochrane Collaboration. RESULTS: A total of 3612 patients from nine randomized controlled trials (RCTs) were included. There were 1794 and 1818 patients in the high and low PEEP groups, respectively. Hospital mortality showed no significant difference between the high and low PEEP groups (RR = 0.92; 95% CI, 0.79 to 1.07; P = 0.26). Similar results were found for 28-d mortality (RR = 0.88; 95% CI, 0.72 to 1.07; P = 0.19) and ICU mortality (RR = 0.83; 95% CI, 0.65 to 1.07; P = 0.15). The risk of clinically objectified barotrauma was not significantly different between the high and low PEEP groups (RR = 1.24; 95% CI, 0.74 to 2.09, P = 0.41). In the subgroup of ARDS patients who responded to increased PEEP by improved oxygenation (from 6 RCTs), high PEEP significantly reduced hospital mortality (RR = 0.83; 95% CI 0.69 to 0.98; P = 0.03), ICU mortality (RR = 0.74; 95% CI, 0.56 to 0.98; P = 0.04),but the 28-d mortality was not decreased(RR = 0.83; 95% CI, 0.67 to 1.01; P = 0.07). For ARDS patients in the low PEEP group who received a PEEP level lower than 10 cmH2O (from 6 RCTs), ICU mortality was lower in the high PEEP group than the low PEEP group (RR = 0.65; 95% CI, 0.45 to 0.94; P = 0.02). CONCLUSIONS: For ARDS patients who responded to increased PEEP by improved oxygenation, high PEEP could reduce hospital mortality, ICU mortality and 28-d mortality. High PEEP does not increase the risk of clinically objectified barotrauma. PMID- 30447684 TI - Sevoflurane preconditioning induces tolerance to brain ischemia partially via inhibiting thioredoxin-1 nitration. AB - BACKGROUND: Sevoflurane preconditioning induces brain ischemic tolerance, but the mechanism remains poorly elucidated. Nitration is an important form of post translational modification in pathological signaling. This study was to investigate the role of thioredoxin-1 (Trx-1) nitration in neuroprotection effect induced by sevoflurane preconditioning in a transient stroke model in rats. METHODS: Adult male Sprague-Dawley rats were preconditioned with 2% sevoflurane or vehicle oxygen exposure, 1 h per day, for 5 consecutive days. At 24 h after the last exposure, rats were subjected to focal brain ischemia induced by middle cerebral artery occlusion (MCAO) for 90 min, followed by 72-h reperfusion. Trx-1 expression and activity, as well as the content of nitrotyrosine at penumbra were detected at 24 h after preconditioning and 2, 8, 24, 72 h after MCAO. Nitrated Trx-1 was examined by immunoprecipitation at 8 h after MCAO. The role of Trx-1 nitration in ischemic tolerance was assessed by administration of nitrated human Trx-1 prior to MCAO. Neurological scores, brain infarct volumes and TUNEL staining were evaluated at 24 h after reperfusion. RESULTS: Ischemic stroke decreased Trx-1 activity but not the expression in penumbra tissue. The content of nitrotyrosine was elevated after MCAO. Preconditioning with sevoflurane increased Trx-1 activity and reduced its nitration at 8 h after MCAO in comparison with vehicle preconditioning. The decrement of Trx-1 activity was correlated with its nitration level. Exogenous administration of nitrated human Trx-1 reversed the brain ischemic tolerance of sevoflurane preconditioning, exacerbating brain infarct volume, neurobehavioral defects and apoptosis, while administration of human-Trx-1 had no effect on the sevoflurane preconditioning induced neuroprotection. CONCLUSION: Ischemic stroke reduces Trx-1 activity via post-translational nitrative modulation in rats. Sevoflurane preconditioning induces brain ischemic tolerance and anti-apoptosis by partially preserving Trx-1 activity via inhibiting nitration. PMID- 30447685 TI - The influence of gender concordance between general practitioner and patient on antibiotic prescribing for sore throat symptoms: a retrospective study. AB - BACKGROUND: Patient gender as well as doctor gender are known to affect doctor patient interaction during a medical consultation. It is however not known whether an interaction of gender influences antibiotic prescribing. This study examined GP's prescribing behavior of antibiotics at the first presentation of patients with sore throat symptoms in primary care. We investigated whether GP gender, patient gender and gender concordance have an effect on the GP's prescribing behavior of antibiotics in protocolled and non-protocolled diagnoses. METHODS: We analyzed electronic health record data of 11,285 GP practice consultations in the Netherlands in 2013 extracted from the Nivel Primary Care Database. Our primary outcome was the prescription of antibiotics for throat symptoms. Sore throat symptoms were split up in 'protocolled diagnoses' and 'non protocolled diagnoses'. The association between gender concordance and antibiotic prescription was estimated with multilevel regression models that controlled for patient age and comorbidity. RESULTS: Antibiotic prescription was found to be lower among female GPs (OR 0.88, CI 95% 0.67-1.09; p = .265) and female patients (OR 0.93, 95% 0.84-1.02; p = .142), but observed differences were not statistically significant. The difference in prescription rates by gender concordance were small and not statistically significant in non-protocolled consultations (OR 0.92, OR 95% CI: 0.83-1.01; p = .099), protocolled consultations (OR 1.00, OR 95% CI: 0.68-1.32; p = .996) and all GP practice consultations together (OR 0.92, OR 95% CI: 0.82-1.02; p = .118). Within the female GP group, however, gender concordance was associated with reduced prescribing of antibiotics (OR 0.85, OR 95% CI: 0.72-0.99; p = 0.034). CONCLUSIONS: In this study, female GPs prescribed antibiotics less often than male GPs, especially in consultation with female patients. This study shows that, in spite of clinical guidelines, gender interaction may influence the prescription of antibiotics with sore throat symptoms. PMID- 30447686 TI - High expression of Tob1 indicates poor survival outcome and promotes tumour progression via a Wnt positive feedback loop in colon cancer. AB - Tob1, a Tob/BTG anti-proliferative protein family member, functions as a tumour suppressor in many cancers. Here, we reveal a unique oncogenic role of Tob1 in colon cancer. Tob1 expression was upregulated during colon cancer progression, was significantly correlated with tumour size and tumour differentiation, and was a prognostic indicator of colon cancer. Unlike in other cancers, where nuclear Tob1 performs anticancer activity, Tob1 is predominantly localized in the cytosol of colon cancer cells, where this protein binds and stabilizes beta-catenin to activate Wnt/beta-catenin signalling, which in turn enhances Tob1 expression, thus forming a positive feedback loop to promote cell proliferation. Moreover, Tob1 deficiency led to reduced tumourigenesis in AOM/DSS-treated and ApcMin/+ mice. Our findings provide important insights into a previously unrecognized oncogenic role of Tob1 in colon cancer and suggest that Tob1 is an adverse prognostic factor and therapeutic target for colon cancer. PMID- 30447687 TI - A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. AB - BACKGROUND: Metabolic syndrome (MetS) is a prevalent risk factor for cardiac dysfunction. Although SGLT2-inhibitors have important cardioprotective effects in hyperglycemia, their underlying mechanisms are complex and not completely understood. Therefore, we examined mechanisms of a SGLT2-inhibitor dapagliflozin (DAPA)-related cardioprotection in overweight insulin-resistant MetS-rats comparison with insulin (INSU), behind its glucose-lowering effect. METHODS: A 28 week high-carbohydrate diet-induced MetS-rats received DAPA (5 mg/kg), INSU (0.15 mg/kg) or vehicle for 2 weeks. To validate MetS-induction, we monitored all animals weekly by measuring body weight, blood glucose and HOMO-IR index, electrocardiograms, heart rate, systolic and diastolic pressures. RESULTS: DAPA treatment of MetS-rats significantly augmented the increased blood pressure, prolonged Q-R interval, and low heart rate with depressed left ventricular function and relaxation of the aorta. Prolonged-action potentials were preserved with DAPA-treatment, more prominently than INSU-treatment, at most, through the augmentation in depressed voltage-gated K+-channel currents. DAPA, more prominently than INSU-treatment, preserved the depolarized mitochondrial membrane potential, and altered mitochondrial protein levels such as Mfn-1, Mfn-2, and Fis 1 as well as provided significant augmentation in cytosolic Ca2+-homeostasis. Furthermore, DAPA also induced significant augmentation in voltage-gated Na+ currents and intracellular pH, and the cellular levels of increased oxidative stress, protein-thiol oxidation and ADP/ATP ratio in cardiomyocytes from MetS rats. Moreover, DAPA-treatment normalized the increases in the mRNA level of SGLT2 in MetS-rat heart. CONCLUSIONS: Overall, our data provided a new insight into DAPA-associated cardioprotection in MetS rats, including suppression of prolonged ventricular-repolarization through augmentation of mitochondrial function and oxidative stress followed by improvement of fusion-fission proteins, out of its glucose-lowering effect. PMID- 30447688 TI - Initiation and cessation of mental healthcare after mental health screening in primary care: a prospective cohort study. AB - BACKGROUND: Mental health (MH) problems have considerable personal and societal implications. Systematic MH screening may raise general practitioners' (GP) awareness of the current need of treatment in their listed patients. The focus of MH screening has so far been on increasing diagnostic rates and treatment of mental disorders, whereas cessation of MH treatment after normal test results has rarely been studied. This study aims to examine the mental healthcare trajectories after MH screening combined with feedback on both positive and negative screening results to the GP. METHODS: This prospective cohort study is based on data from 11,714 randomly selected individuals aged 30-49 years, who were invited to a preventive health check in Denmark during 2012-2015. A total of 5970 (51%) were included. MH status was assessed using the SF-12 Health Survey Mental Component Summary score, and scores were categorised into poor, moderate, and good MH. 'Mental healthcare' within 1 year of follow-up covered the following MH support: psychometric testing by GP, talk therapy by GP, contact to psychologist, contact to psychiatrist, and psychotropic medication. RESULTS: MH was found to be poor in 9%, moderate in 25%, and good in 66% of participants. After 1 year, mental healthcare was initiated in 29% of the participants with poor MH who did not receive mental healthcare at baseline, and mental healthcare was ceased in 44% of the participants with good MH who received mental healthcare at baseline. Odds ratio (OR) for initiation of mental healthcare was associated with worse MH screening status: poor MH: OR 7.1 (5.4-9.4), moderate MH: OR 2.4 (1.9-3.1), compared to those with good MH. OR for cessation of mental healthcare was associated with better MH screening status: good MH: OR 1.6 (1.1-2.6), moderate MH: OR 1.6 (1.0-2.4), compared to those with poor MH. Initiation and cessation of mental healthcare appeared to be time-related to the MH screening. CONCLUSIONS: MH screening combined with feedback on both positive and negative screening results to the GP may contribute to relevant initiation and cessation of mental healthcare. TRIAL REGISTRATION: Registration of the Check Your Health trial: ClinicalTrials.gov ( NCT02028195 ), 7 March 2014. PMID- 30447689 TI - Hypothalamic hypopituitarism secondary to suprasellar metastases from small cell lung cancer: a case report and review of the literature. AB - BACKGROUND: Metastasis to the pituitary gland is an infrequent clinical problem, and the symptoms caused by metastases have been reported in only 2.5-18.2% of the cases. However, metastasis to the suprasellar lesion has rarely been reported in the literature. To the best of our knowledge, only nine cases of hypothalamic hypopituitarism due to metastases of solid tumors have been reported in English language journals. CASE PRESENTATION: A 67-year-old Japanese man presented to our hospital with generalized weakness, lethargy, and weight loss. Laboratory data showed hypoglycemia together with low thyroid-stimulating hormone and free thyroxine. We suspected hypopituitarism and performed imaging of the head, which revealed multiple tumors, one of which was in the suprasellar region. Computed tomography of the chest showed a tumor shadow, and a bronchoscopic biopsy pathologically showed small cell lung cancer. Hormone profiling demonstrated hypothalamic pan-hypopituitarism. We diagnosed hypothalamic hypopituitarism secondary to metastases from the primary lung cancer and initiated radiation, chemotherapy, and hormone replacement, but the patient died 10 months later. CONCLUSIONS: We report a case of a 67-year-old man with hypothalamic hypopituitarism secondary to a suprasellar metastasis from a primary small cell lung cancer, and we review ten cases of hypothalamic hypopituitarism due to metastases, including our patient. Recognizing hypopituitarism can be challenging, especially in the elderly, whose symptoms such as lethargy and visual decline may be mistaken for the natural aging process. In patients with established metastatic conditions, the symptoms may be wrongly attributed to malignancy or to the side effects of therapy. When a patient is suspected of having hypopituitarism, a hormone load test can help to diagnose the type of hypopituitarism. It is important to evaluate the brain and the whole body to confirm whether metastasis and primary cancer exist. Because the mortality rate is very high, aggressive intervention for both diagnosis and therapy is required in cases of hypothalamic hypopituitarism secondary to tumor metastasis. PMID- 30447691 TI - Recording of weight in electronic health records: an observational study in general practice. AB - BACKGROUND: Routine weight recording in electronic health records (EHRs) could assist general practitioners (GPs) in the identification, prevention, and management of overweight patients. However, the extent to which weight management is embedded in general practice in the Netherlands has not been investigated. The purpose of this study was to evaluate the frequency of weight recording in general practice in the Netherlands for patients who self-reported as being overweight. The specific objectives of this study were to assess whether weight recording varied according to patient characteristics, and to determine the frequency of weight recording over time for patients with and without a chronic condition related to being overweight. METHODS: Baseline data from the Occupational and Environmental Health Cohort Study (2012) were combined with data from EHRs of general practices (2012-2015). Data concerned 3446 self-reported overweight patients who visited their GP in 2012, and 1516 patients who visited their GP every year between 2012 and 2015. Logistic multilevel regression analyses were performed to identify associations between patient characteristics and weight recording. RESULTS: In 2012, weight was recorded in the EHRs of a quarter of patients who self-reported as being overweight. Greater age, lower education level, higher self-reported body mass index, and the presence of diabetes mellitus, chronic obstructive pulmonary disease, and/or cardiovascular disorders were associated with higher rates of weight recording. The strongest association was found for diabetes mellitus (adjusted OR = 10.3; 95% CI [7.3, 14.5]). Between 2012 and 2015, 90% of patients with diabetes mellitus had at least one weight measurement recorded in their EHR. In the group of patients without a chronic condition related to being overweight, this percentage was 33%. CONCLUSIONS: Weight was frequently recorded for overweight patients with a chronic condition, for whom regular weight measurement is recommended in clinical guidelines, and for which weight recording is a performance indicator as part of the payment system. For younger patients and those without a chronic condition related to being overweight, weight was less frequently recorded. For these patients, routine recording of weight in EHRs deserves more attention, with the aim to support early recognition and treatment of overweight. PMID- 30447692 TI - Novel mutation G324C in WNT1 mapped in a large Pakistani family with severe recessively inherited Osteogenesis Imperfecta. AB - INTRODUCTION: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disease with skeletal fragility and variable extra-skeletal manifestations. To date several point mutations in 18 different genes causing different types of OI have been identified. Mutations in WNT1 compromise activity of the osteoblasts leading to disturbed bone mass accrual, fragility fractures and progressive skeletal abnormalities. The present study was conducted to determine the underlying genetic cause of an autosomal recessive skeletal dysplasia in a large consanguineous family from Chinute, Pakistan. MATERIALS AND METHODS: Blood was collected from 24 individuals of affected family along with clinical data. Homozygosity mapping was performed to confirm consanguinity. SNPs were identified, followed by whole exome and Sanger sequencing. In silico characterization of WNT1 mutation was performed using multiple platforms. RESULTS: Nine affected family members exhibited severe bone deformities, recurrent fractures, short stature and low bone mineral density. SNP array data revealed homozygous segments > 1 Mb in length accounting for 2.1-12.7% of the genome in affected individuals and their siblings and a single 6,344,821 bp homozygous region in all affected individuals on chromosome 12q12-q13. This region includes two potential OI candidate genes WNT1 and VDR. We did whole-exome sequencing for both genes in two patients and identified a novel damaging missense mutation in exon 4 of WNT1: c.1168G > T (NM_005430) resulting in p.G324C. Sanger sequencing confirmed segregation of mutation with the disease in family. CONCLUSION: We report a novel mutation responsible for OI and our investigation expands the spectrum of disease-causing WNT1 mutations and the resulting OI phenotypes. PMID- 30447690 TI - Role of the NLRP3 inflammasome in cancer. AB - Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1beta and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy. PMID- 30447693 TI - Risk prediction model of dyslipidaemia over a 5-year period based on the Taiwan MJ health check-up longitudinal database. AB - OBJECTIVE: This study aimed to provide an epidemiological model to evaluate the risk of developing dyslipidaemia within 5 years in the Taiwanese population. METHODS: A cohort of 11,345 subjects aged 35-74 years and was non-dyslipidaemia in the initial year 1996 and followed in 1997-2006 to derive a risk score that could predict the occurrence of dyslipidaemia. Multivariate logistic regression was used to derive the risk functions using the check-up centre of the overall cohort. Rules based on these risk functions were evaluated in the remaining three centres as the testing cohort. We evaluated the predictability of the model using the area under the receiver operating characteristic (ROC) curve (AUC) to confirm its diagnostic property on the testing sample. We also established the degrees of risk based on the cut-off points of these probabilities after transforming them into a normal distribution by log transformation. RESULTS: The incidence of dyslipidaemia over the 5-year period was 19.1%. The final multivariable logistic regression model includes the following six risk factors: gender, history of diabetes, triglyceride level, HDL-C (high-density lipoprotein cholesterol), LDL-C (low-density lipoprotein cholesterol) and BMI (body mass index). The ROC AUC was 0.709 (95% CI: 0.693-0.725), which could predict the development of dyslipidaemia within 5 years. CONCLUSION: This model can help individuals assess the risk of dyslipidaemia and guide group surveillance in the community. PMID- 30447694 TI - Time-to-update of systematic reviews relative to the availability of new evidence. AB - BACKGROUND: A number of methods for deciding when a systematic review should be updated have been proposed, yet little is known about whether systematic reviews are updated more quickly when new evidence becomes available. Our aim was to examine the timing of systematic review updates relative to the availability of new evidence. METHODS: We performed a retrospective analysis of the update timing of systematic reviews published in the Cochrane Database of Systematic Reviews in 2010 relative to the availability of new trial evidence. We compared the update timing of systematic reviews with and without signals defined by the completion or publication of studies that were included in the updates. RESULTS: We found 43% (293/682) systematic reviews were updated before June 2017, of which 204 included an updated primary outcome meta-analysis (median update time 35.4 months; IQR 25.5-54.0), 38% (77/204) added new trials, and 4% (8/204) reported a change in conclusion. In the 171 systematic reviews with reconcilable trial reporting information, we did not find a clear difference in update timing (p = 0.05) between the 15 systematic reviews with a publication signal (median 25.3 months; IQR 15.3-43.5) and the 156 systematic reviews without a publication signal (median 34.4 months; IQR 25.1-52.2). In the 145 systematic reviews with reconcilable trial completion information, we did not find a difference in update timing (p = 0.33) between the 15 systematic reviews with a trial completion signal (median 26.0 months; IQR 19.3-49.5) and the 130 systematic reviews without a trial completion signal (median 32.4 months; IQR 24.1 to 46.0). CONCLUSION: A minority of 2010 Cochrane reviews were updated before June 2017 to incorporate evidence from new primary studies, and very few updates led to a change in conclusion. We did not find clear evidence that updates were undertaken faster when new evidence was made available. New approaches for finding early signals that a systematic review conclusion is at risk of change may be useful in allocated resources to the updating of systematic reviews. PMID- 30447695 TI - Prevention of cervical cancer in HIV-seropositive women from developing countries through cervical cancer screening: a systematic review. AB - BACKGROUND: There is scanty or inconclusive evidence on which cervical cancer screening tool is effective and suitable for human immunodeficiency virus (HIV) seropositive women. The aim of this review was to assess, synthesise and document published evidence relating to the available cervical cancer screening modalities for HIV-seropositive women in developing countries. This paper did not review the issue of human papillomavirus (HPV) prophylactic vaccine on HIV-seropositive women. METHODS: Five electronic databases were systematically searched from inception to January 2018 for relevant published original research examining cervical cancer prevention modalities for HPV infection, abnormal cytology and direct visualisation of the cervix amongst HIV-seropositive women in developing countries. Extra studies were identified through reference list and citation tracking. RESULTS: Due to methodological and clinical heterogeneity, a narrative synthesis was presented. Of the 2559 articles, 149 underwent full-text screening and 25 were included in the review. Included studies were of moderate quality, and no exclusions were made based on quality or bias. There is no standard cervical cancer screening test or programme for HIV-seropositive women and countries screening according to available resources and expertise. The screening methods used for HIV-seropositive women are the same for HIV-negative women, with varying clinical performance and accuracy. The main cervical cancer screening methods described for HIV-seropositive women are HPV deoxyribonucleic acid/messenger RNA (DNA/mRNA) testing (n = 16, 64.0%), visual inspection with acetic acid (VIA) (n = 13, 52.0%) and Pap smear (n = 11, 44.0%). HPV testing has a better accuracy/efficiency than other methods with a sensitivity of 80.0-97.0% and specificity of 51.0-78.0%. Sequential screening using VIA or visual inspection with Lugol's iodine (VILI) and HPV testing has shown better clinical performance in screening HIV-seropositive women. CONCLUSION: Although cervical cancer screening exists in almost all developing countries, what is missing is both opportunistic and systematic organised population-based screenings. Cervical cancer screening programmes need to be integrated into already existing HIV services to enable early detection and treatment. There is a need to offer opportunistic and coordinated screening programmes that are provider-initiated to promote early identification of cervical precancerous lesions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018095702. PMID- 30447696 TI - Use of indices to measure socio-economic status (SES) in South-Asian urban health studies: a scoping review. AB - BACKGROUND: Universal health coverage (UHC) is a key area in post-2015 global agenda which has been incorporated as target for achieving health-related Sustainable Development Goals (SDGs). A global framework has been developed to monitor SDG indicators disaggregated by socioeconomic and demographic markers. This review identifies the indices used to measure socio-economic status (SES) in South Asian urban health studies. METHODS: Two reviewers searched six databases including Cochran Library, Medline, LILACS, Web of Science, Science Direct, and Lancet journals independently. All South Asian health studies covering urban population, with any research-designs, written in English language, and published between January 2000 and June 2016 were included. Two reviewers independently screened and assessed for selection of eligible articles for inclusion. Any conflict between the reviewers was resolved by a third reviewer. RESULTS: We retrieved 3529 studies through initial search. Through screening and applying inclusion and exclusion criteria, this review finally included 256 articles for full-text review. A total of 25 different SES indices were identified. SES indices were further categorized into 5 major groups, e.g., (1) asset-based wealth index, (2) wealth index combining education, (3) indices based on income and expenditure, (4) indices based on education and occupation, and (5) "indices without description." The largest proportion of studies, irrespective of country of origin, thematic area, and study design, used asset-based wealth index (n = 142, 54%) as inequality markers followed by the index based on income and expenditure (n = 80, 30%). Sri Lankan studies used income- and expenditure-based indices more than asset-based wealth index. Majority of the reviewed studies were on "maternal, neonatal, and child health" (n = 98, 38%) or on "non-communicable diseases" (n = 84, 33%). Reviewed studies were mostly from India (n = 145, 57%), Bangladesh (n = 42, 16%), and Pakistan (n = 27, 11%). Among the reviewed articles, 55% (n = 140) used primary data while the rest 45% studies used secondary data. CONCLUSION: This scoping review identifies asset-based wealth index as the most frequently used indices for measuring socioeconomic status in South Asian urban health studies. This review also provides a clear idea about the use of other indices for the measurement SES in the region. PMID- 30447697 TI - Intake of medium-chain fatty acids induces myocardial oxidative stress and atrophy. AB - BACKGROUND: Oral intake of medium-chain fatty acids (MCFAs) reportedly suppresses the accumulation of visceral fat and has antitumor effects in tumor-bearing animals. MCFAs penetrate the mitochondrial membrane in a carnitine shuttle independent manner and are metabolized more quickly than long-chain fatty acids. Based on these characteristics, MCFAs may have pronounced effects in mitochondria rich tissues, such as the myocardium. We examined the effect of oral intake of MCFAs on the heart. METHODS: We fed BALB/c mice with a control diet supplemented with 0%, 2%, 5%, or 10% lauric acid (LAA; a 12-carbon saturated MCFA). After euthanasia, the hearts, both sides of quadriceps femoris muscle (QFM) and epididymal fat pad (EFP) were excised and weighed. Then myocardial tissue morphology, oxidative stress accumulation, and mitochondrial volume were observed by histological analysis. The expression levels of myosin light chain 1 were measured by ELISA. RESULTS: There were no differences among the groups in food and calorie intake, but the intake of LAA increased with the dietary proportion. The 10%-LAA-fed mice experienced significant weight loss and became moribund on day 6. The body, cardiac and EFP weights of the mice fed 5% and 10% LAA were lower than those of the control group. And 10% LAA fed group showed significant decrease of the QFM weights. Protein analysis of the excised hearts revealed higher expression of myosin light chain 1 in the 5% group than in the control group. Histological examination of the hearts revealed myocardial atrophy and accumulation of oxidative stress in the 10% group. Fewer mitochondria were observed with increased LAA intake. CONCLUSIONS: Excessive LAA consumption may damage the myocardium and the damage might result from oxidative stress accumulation and cellular atrophy. PMID- 30447698 TI - The effect of rehabilitation interventions on physical function and immobility related complications in severe stroke-protocol for a systematic review. AB - BACKGROUND: Stroke rehabilitation aims to optimise function and reduce complications post-stroke. Rehabilitation to optimise physical function post stroke has beneficial effects for survivors of mild to moderate stroke. However, little is known about the effectiveness of interventions to rehabilitate physical function or manage immobility-related complications for survivors of severe stroke. The systematic review aims to evaluate the effectiveness of rehabilitation interventions on physical function and immobility-related complications in severe stroke and identify topics for future research in this area. METHODS: A systematic review of relevant electronic databases (MEDLINE, Embase, CINAHL, AMED, PEDro, DORIS and CENTRAL) between January 1987 and July 2017 will be undertaken to identify eligible published randomised controlled trials (RCTs) in any language. Ongoing RCTs will be identified by searching health-care trial registers (Stroke Trials Registry, ClinicalTrials.gov). Hand searches of identified study reference lists will also be performed. The PRISMA statement will be used to guide the systematic review. Two reviewers will screen search results, select studies using pre-defined selection criteria, extract data from and assess risk of bias for selected studies. Studies comparing the effect of one type of rehabilitation intervention to another or usual care on physical function and immobility-related complications for patients with severe stroke will be included. Studies may include participants with all levels of stroke severity but must provide sub-group analysis based on stroke severity. Studies will focus on any phase of the stroke rehabilitation pathway and will be grouped and analysed according to their timeframe post-stroke into acute and early sub acute (up to 3 months post-stroke), early sub-acute to late sub-acute (from 3 to 6 months post-stroke) and chronic (greater than 6 months post-stroke). If sufficient studies demonstrate homogeneity, a meta-analysis will pool results of individual outcomes. The GRADE approach will be used to assess the evidence strength. DISCUSSION: The results of this systematic review will summarise the strength of evidence for rehabilitation interventions used in the rehabilitation of physical function and immobility-related complications in severe stroke and identify gaps in evidence. SYSTEMATIC REVIEW REGISTRATION: The systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO)-registration number CRD77737 . PMID- 30447699 TI - Different Fgfs have distinct roles in regulating neurogenesis after spinal cord injury in zebrafish. AB - BACKGROUND: Despite conserved developmental processes and organization of the vertebrate central nervous system, only some vertebrates including zebrafish can efficiently regenerate neural damage including after spinal cord injury. The mammalian spinal cord shows very limited regeneration and neurogenesis, resulting in permanent life-long functional impairment. Therefore, there is an urgent need to identify the cellular and molecular mechanisms that can drive efficient vertebrate neurogenesis following injury. A key pathway implicated in zebrafish neurogenesis is fibroblast growth factor signaling. METHODS: In the present study we investigated the roles of distinct fibroblast growth factor members and their receptors in facilitating different aspects of neural development and regeneration at different timepoints following spinal cord injury. After spinal cord injury in adults and during larval development, loss and/or gain of Fgf signaling was combined with immunohistochemistry, in situ hybridization and transgenes marking motor neuron populations in in vivo zebrafish and in vitro mammalian PC12 cell culture models. RESULTS: Fgf3 drives neurogenesis of Islet1 expressing motor neuron subtypes and mediate axonogenesis in cMet expressing motor neuron subtypes. We also demonstrate that the role of Fgf members are not necessarily simple recapitulating development. During development Fgf2, Fgf3 and Fgf8 mediate neurogenesis of Islet1 expressing neurons and neuronal sprouting of both, Islet1 and cMet expressing motor neurons. Strikingly in mammalian PC12 cells, all three Fgfs increased cell proliferation, however, only Fgf2 and to some extent Fgf8, but not Fgf3 facilitated neurite outgrowth. CONCLUSIONS: This study demonstrates differential Fgf member roles during neural development and adult regeneration, including in driving neural proliferation and neurite outgrowth of distinct spinal cord neuron populations, suggesting that factors including Fgf type, age of the organism, timing of expression, requirements for different neuronal populations could be tailored to best drive all of the required regenerative processes. PMID- 30447700 TI - Anti-inflammatory effects induced by pharmaceutical substances on inflammatory active brain astrocytes-promising treatment of neuroinflammation. AB - BACKGROUND: Pharmaceutical treatment with probable anti-inflammatory substances that attack cells in various ways including receptors, ion channels, or transporter systems may slow down the progression of inflammatory conditions. Astrocytes and microglia are the most prominent target cells for inflammation in the central nervous system. Their responses upon inflammatory stimuli work through the NO/cyclic GMP/protein kinase G systems that can downregulate the ATP induced Ca2+ signaling, as well as G protein activities which alter Na+ transporters including Na+/K+-ATPase pump activity, Toll-like receptor 4 (TLR4), glutamate-induced Ca2+ signaling, and release of pro-inflammatory cytokines. The rationale for this project was to investigate a combination of pharmaceutical substances influencing the NO and the Gi/Gs activations of inflammatory reactive cells in order to make the cells return into a more physiological state. The ATP evoked Ca2+ signaling is important maybe due to increased ATP release and subsequent activation of purinergic receptors. A balance between intercellular Ca2+ signaling through gap junctions and extracellular signaling mediated by extracellular ATP may be important for physiological function. METHODS: Astrocytes in primary cultures were incubated with lipopolysaccharide in a physiological glucose concentration for 24 h to induce inflammatory reactivity. The probable anti-inflammatory substances sildenafil and 1alpha,25 Dihydroxyvitamin D3 together with endomorphin-1, naloxone, and levetiracetam, were used in the presence of high glucose concentration in the medium to restore the cells. Glutamate-, 5-HT-, and ATP-evoked intracellular Ca2+ release, Na+/K+ ATPase expression, expression of inflammatory receptors, and release of tumor necrosis factor alpha were measured. RESULTS: Sildenafil in ultralow concentration together with 1alpha,25-Dihydroxyvitamin D3 showed most prominent effects on the ATP-evoked intracellular Ca2+ release. The MU-opioid agonist endomorphin-1, the MU-opioid antagonist naloxone in ultralow concentration, and the antiepileptic agent levetiracetam downregulated the glutamate-evoked intracellular Ca2+ release and TLR4. The combination of the pharmaceutical substances in high glucose concentration downregulated the glutamate- and ATP evoked Ca2+ signaling and the TLR4 expression and upregulated the Na+/K+-ATPase pump. CONCLUSION: Pharmaceutical treatment with the combination of substances that have potential anti-inflammatory effects, which attack different biochemical mechanisms in the cells may exert decisive effects to downregulate neuroinflammation in the nervous system. PMID- 30447702 TI - Effect of heifer age on the granulosa cell transcriptome after ovarian stimulation. AB - Genomic selection is accelerating genetic gain in dairy cattle. Decreasing generation time by using younger gamete donors would further accelerate breed improvement programs. Although ovarian stimulation of peripubertal animals is possible and embryos produced in vitro from the resulting oocytes are viable, developmental competence is lower than when sexually mature cows are used. The aim of the present study was to shed light on how oocyte developmental competence is acquired as a heifer ages. Ten peripubertal Bos taurus Holstein heifers underwent ovarian stimulation cycles at the ages of 8, 11 (mean 10.8) and 14 (mean 13.7) months. Collected oocytes were fertilised in vitro with spermatozoa from the same adult male. Each heifer served as its own control. The transcriptomes of granulosa cells recovered with the oocytes were analysed using microarrays. Differential expression of certain genes was measured using polymerase chain reaction. Principal component analysis of microarray data revealed that the younger the animal, the more distinctive the gene expression pattern. Using ingenuity pathway analysis (IPA) and NetworkAnalyst (www.networkanalyst.ca), the main biological functions affected in younger donors were identified. The results suggest that cell differentiation, inflammation and apoptosis signalling are less apparent in peripubertal donors. Such physiological traits have been associated with a lower basal concentration of LH. PMID- 30447701 TI - K13-propeller gene polymorphisms in Plasmodium falciparum parasite population: a systematic review protocol of burden and associated factors. AB - BACKGROUND: Malaria control and prevention efforts continue to rely heavily on the use of medicines especially artemisinin agents. However, currently, the emergence of artemisinin resistance threatens this effort globally. The K13-gene polymorphisms associated with artemisinin resistance have been detected in Southeast Asia. In countries outside Southeast Asia, artemisinin resistance has not yet been confirmed. METHODS/DESIGN: The articles will be obtained from the search of MEDLINE via PubMed, Scopus, EMBASE, and LILACS/VHL databases. Mesh terms will be used in the article search. Boolean operators ("AND", "OR") will be used in the article search. Article search will be done independently by two librarians (RS and AK). The articles will be screened for inclusion using set criteria and following the PRISMA guidelines. Data extraction will be done by two independent reviewers (NL and BB), Kappa statistic will be calculated, and any discrepancies resolved by discussion. Heterogeneity in the articles will be established using I2 statistic. DISCUSSION: This review will focus on establishing the K13-gene polymorphisms among Plasmodium falciparum parasites reported from previous studies in malaria-affected countries. Artemisinin resistance has not been widely reported among parasites in Africa and other malaria-endemic countries outside Southeast Asia. However, several studies on artemisinin resistance have reported different K13-gene polymorphisms from the validated mutations found in Southeast Asia. This study will collate evidence from previous studies on the commonly reported K13 -gene polymorphisms among P. falciparum parasites in malaria-affected countries. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD 42018084624. PMID- 30447703 TI - Global and national guidance for the use of pre-exposure prophylaxis during peri conception, pregnancy and breastfeeding. AB - Pre-exposure prophylaxis (PrEP) is a well-established biomedical HIV prevention strategy and recommended to reduce HIV risk during peri-conception, pregnancy and breastfeeding. Efforts are needed to translate global recommendations into national guidelines and implementation strategies. This article presents the current status of policy guidance for the use of PrEP during peri-conception, pregnancy and breastfeeding, with a particular focus on high prevalence countries, including those in sub-Saharan Africa. PrEP clinical guidelines released by ministries of health or other national-level health bodies, with a particular focus on recommendations for PrEP use during peri-conception, pregnancy and breastfeeding, were reviewed and summarised. Among countries with PrEP guidelines and/or policy, pregnancy is recognised as a period with increased HIV vulnerability, and some recommend PrEP use specifically during pregnancy. Only one country notes that PrEP is contraindicated during pregnancy, recognising a gap in complete safety data from women using PrEP throughout pregnancy. PrEP is not contraindicated as a peri-conception HIV prevention strategy in any country, but only three countries have specific guidance for peri-conception HIV prevention. Multiple barriers to the implementation of PrEP during pregnancy and breastfeeding are discussed, including barriers at the policy, health systems, social and personal levels. Although pregnancy is a period of heightened risk and fertility rates are high in many settings with high HIV burden, few PrEP policies have included guidance for PrEP use specific to peri-conception, pregnancy and breastfeeding periods. This gap can be overcome by the development or adoption of national clinical guidelines and implementation strategies from exemplary countries. PMID- 30447704 TI - Staphylococcus Aureus and Polymicrobial Skin and Soft Tissue Infections. PMID- 30447705 TI - Glycemic Variability: How to Measure and Its Clinical Implication for Type 2 Diabetes. AB - Glycated hemoglobin A1c (A1C) levels have traditionally been the gold standard for assessing glycemic control and treatment efficacy in patients with type 2 diabetes. However, A1C does not take into account fluctuations in blood glucose levels known as glycemic variability (GV). In recent years, GV has become increasingly clinically relevant, because of a better understanding of the need to reach target A1C while avoiding hypoglycemia. GV relates to both hyperglycemia and hypoglycemia, and has been associated with poorer quality of life. Diabetes treatments targeting multiple pathophysiological mechanisms are most beneficial in controlling A1C and reducing GV. In clinical trials, a number of metrics are used to measure GV, many of which are not well understood in the clinical practice. Until a gold standard metric for GV is established, the variety of measurements available may confound the choice of an optimal treatment for an individual patient. PMID- 30447706 TI - Correlations of MicroRNA-21 Gene Polymorphisms With Chemosensitivity and Prognosis of Cervical Cancer. AB - BACKGROUND: We investigated correlations of miR-21 gene polymorphisms including rs1292037 (A > G) and rs13137 (A > T) with the chemosensitivity to cisplatin plus paclitaxel, and prognosis before cervical cancer (CC) surgery, which may provide a novel target for prevention and treatment of CC. MATERIALS AND METHODS: A total of 165 patients with CC were divided into 2 groups, a sensitive group and resistance group. Gene polymorphisms of rs1292037 (A > G) and rs13137 (A > T) were detected respectively. Logistic and Cox multivariate regression analyses were used to explore factors that influence resistance to cisplatin plus paclitaxel. RESULTS: rs1292037 (A > G) locus AG, GG, AG + GG and G allele in miR 21 gene may increase chemoresistance to cisplatin plus paclitaxel in CC. The risk factors of prognosis included rs1292037 (A > G) locus, tumor stage, maximum lesion diameter and lymph node metastasis (hazard ratio [HR] = 1.819, 95% CI = 1.127-2.935; HR = 1.504, 95% CI = 1.070-2.114; HR = 1.671, 95% CI = 1.038-2.689; HR = 3.043, 95% CI = 1.783-5.193). The influencing factors of resistance to cisplatin plus paclitaxel included maximum lesion diameter, tumor stage, lymph node metastasis and rs1292037 (odds ratio [OR] = 14.047, 95% CI = 5.694-34.653; OR = 5.873, 95% CI = 3.104-11.110; OR = 3.574, 95% CI = 1.554-8.216; OR = 2.449, 95% CI = 1.052-5.705). CONCLUSIONS: rs1292037 (A > G) locus are associated with the chemoresistance to cisplatin plus paclitaxel and prognosis of patients with CC. In addition to that, the G allele at rs1292037 (A > G) locus increases the risk of preoperative chemoresistance to cisplatin plus paclitaxel and is a poor prognostic factor for patients with CC. PMID- 30447707 TI - The Properties of Cytokines in Multiple Sclerosis: Pros and Cons. AB - Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is characterized by demyelination, axonal loss, gliosis and inflammation. The last plays a major role in the onset and propagation of the disease. MS presents with heterogeneous lesions containing a broad range of cells and soluble mediators of the immune system such as T cells, B cells, macrophages, microglia, cytokines, chemokines, antibodies, complement and other toxic substances. This review outlines, analyzes and discusses the different immune mechanisms of MS that are responsible for the initiation and propagation of active lesions, demyelination, axonal injury, remyelination and cell loss as well as the role of cytokines in the disease process. Proinflammatory cytokines such as interleukin-17 (IL-17), IL-22, tumor necrosis factor-alpha, IL-1, IL-12 and interferon-gamma may cause MS through several signaling pathways. Conversely, anti-inflammatory circulating cytokines such as IL-4 and IL-10 are reduced and theoretically can exert a direct protective effect in this condition. Future studies are necessary to develop effective, safe and long-lasting strategies to reduce the abnormal cytokine cascades and to treat MS. PMID- 30447708 TI - Primary Bone Marrow Diffuse Large B-cell Lymphoma Presenting as Transverse Myelitis. AB - Primary bone marrow diffuse large B-cell lymphoma (BM-DLBCL) is uncommon, with prior reports largely limited to small case series. Here we report the case of a patient who presented with neurologic deficits consistent with acute transverse myelitis and was found to have DLBCL isolated to the bone marrow. We follow this case with a review of the literature summarizing 107 reported cases of BM-DLBCL. Consistent with our case, literature review indicates that BM-DLBCL is characterized by (1) frequent presentation with cytopenias and B symptoms (2) predominant non-germinal center phenotype and (3) aggressive disease with high International Prognostic Index score and low overall survival, with a median survival of 10.0 months in our cohort. PMID- 30447709 TI - Historical Perspectives in the Evolution of Hypertrophic Cardiomyopathy. AB - Since the first anatomic description of hypertrophic cardiomyopathy (HCM) in 1958, significant advancements have expanded the understanding of this condition. At the same time, new imaging tools and treatment modalities have contributed to an ever-changing armamentarium for the assessment and treatment of patients with HCM. The historical perspective of HCM discovery and the progress made in the last several decades shed light on the road still ahead, which is expected to lead to better forms of treatment and perhaps even prevention of this, at times, devastating disease. PMID- 30447710 TI - Advanced Heart Failure Management and Transplantation. AB - Hypertrophic cardiomyopathy is a genetic heart disease with heterogeneous clinical features, including progression to advanced heart failure. The development of these symptoms can be related to outflow obstruction but in some patients reflects an underlying process of fibrosis and progressive ventricular dysfunction. For patients with end-stage disease, traditional heart failure therapies have not proved beneficial. As such, more advanced therapies, such as left ventricular assist device or cardiac transplantation, should be considered for these patients. Although left ventricular assist device support is used infrequently due to the restrictive physiology underlying hypertrophic cardiomyopathy, transplant represents an effective treatment, with encouraging long-term outcome data. PMID- 30447711 TI - Echocardiography in the Diagnosis and Management of Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is an inherited condition present in about 1/500 individuals with more than 1500 causative mutations identified in primarily 10 sarcomeric proteins. Although HCM is inherited in an autosomal dominant way, there is often incomplete penetrance and variable phenotype even with the same genotype. It is characterized by a degree of hypertrophy (usually asymmetric), that is, not due to another identifiable cause, as well as variable degrees of myocardial fibrosis and microvascular abnormalities. PMID- 30447712 TI - Novel Pharmacotherapy for Hypertrophic Cardiomyopathy. AB - Medical therapy for hypertrophic cardiomyopathy (HCM) has focused on minimizing the impact of symptoms due to left ventricular outflow tract obstruction and diastolic dysfunction. This article briefly discusses currently available therapy and focuses on both clinically available medications with novel applications for HCM as well as novel medications under development with specific indication for HCM. Finally, a brief summary of the current gaps and potential targets for pharmacotherapy is discussed. PMID- 30447713 TI - Cardiac Magnetic Resonance for Diagnosis and Risk Stratification. AB - Cardiac MRI (CMR) is an essential tool for the evaluation of the patient with hypertrophic cardiomyopathy (HCM). First, the accurate morphologic imaging and measures that are possible with CMR help to ascertain the diagnosis. Second, the tissue characterization that can be done with MRI helps to define the abnormalities in the myocardium and to identify areas of fibrosis that have been linked to increase risk of sudden cardiac death and heart failure. In addition, CMR can help distinguish HCM from similar disease processes. PMID- 30447714 TI - Genetic Testing and Counseling for Hypertrophic Cardiomyopathy. AB - Genetic testing has become more accessible and is increasingly being incorporated into the care of patients with hypertrophic cardiomyopathy. Genetic test results can help to refine diagnosis and distinguish at-risk relatives from those who are not at risk. PMID- 30447716 TI - Arrhythmia Evaluation and Management. AB - Patients with hypertrophic cardiomyopathy may present with a number of arrhythmias. Although not unique, arrhythmias in hypertrophic cardiomyopathy require management approaches that may differ from other populations. Standard permanent pacemaker indications can be seen, but unique applications and implantation considerations pertain to this population. Ventricular and supraventricular tachyarrhythmias may be experienced by patients with hypertrophic cardiomyopathy, treatment for which must be tailored to the hypertrophic cardiomyopathy substrate. In this article, permanent pacemaker indications, techniques and special considerations, and specific management issues of ventricular and supraventricular tachyarrhythmias in hypertrophic cardiomyopathy, are discussed. PMID- 30447715 TI - Lifestyle Modification and Medical Management of Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy is a heterogenous condition associated with a myriad of symptoms. Just as in other disease states, the aim of medical therapy is the alleviation of suffering, improvement of longevity, and the prevention of complications. This article focuses on the associated comorbidities seen in patients with hypertrophic cardiomyopathy, potential lifestyle interventions, and conventional medical treatments for symptomatic hypertrophic cardiomyopathy. PMID- 30447717 TI - Sudden Cardiac Death Risk Stratification and the Role of the Implantable Cardiac Defibrillator. AB - Hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden cardiac death (SCD), although perhaps not as significantly as previously believed. Given the heterogeneous nature of this disease entity, risk stratification of individuals with HCM remains challenging. The recent HCM risk SCD prediction model seems to perform well in assessing individual SCD risk. Even though implantable cardiac defibrillators (ICDs) are effective in preventing SCD in patients at increased risk, the importance of shared decision making in deciding whether or not to undergo ICD implantation cannot be understated. PMID- 30447718 TI - Role of Advanced Testing: Invasive Hemodynamics, Endomyocardial Biopsy, and Cardiopulmonary Exercise Testing. AB - Hypertrophic cardiomyopathy affects 0.5% of the population. Advanced testing is considered, including cardiac catheterization, endomyocardial biopsy, and cardiopulmonary exercise testing. Right and left heart catheterization provides essential hemodynamic data, identifies patients who might benefit from septal reduction therapy, and assesses for comorbidities. Pathologic analysis reveals ventricular hypertrophy, myocardial disarray, and endocardial and interstitial fibrosis. Routine endomyocardial biopsy is not recommended unless other conditions that cause hypertrophy need to be ruled out. Cardiopulmonary exercise testing provides useful physiologic data, allows monitoring of the response to medication and surgical interventions, estimates prognosis, and guides referral for orthotopic heart transplantation. PMID- 30447719 TI - Choice of Septal Reduction Therapies and Alcohol Septal Ablation. AB - In patients with resting or provoked gradients and symptoms refractory to optimal medical therapy, alcohol septal ablation or surgical septal myectomy may be considered. Given the overall comparable outcomes after ablation and myectomy, there is, for many patients, equipoise between the two procedures. Septal ablation is performed with standard angioplasty guiding catheters, guidewires, and balloon catheters. In the Euro-ASA registry, NYHA functional class fell from 2.9 +/- 0.5 to 1.6 +/- 0.7 and gradient from 67 +/- 36 to 16 +/- 21 mm Hg at mean 3.9-year follow-up after septal ablation. PMID- 30447721 TI - Hypertrophic Cardiomyopathy: Mastering the Multiple Facets of a Complex Disease. PMID- 30447720 TI - Surgical Myectomy: Subaortic, Midventricular, and Apical. AB - Surgical septal myectomy is the preferred method of septal reduction for most patients with obstructive hypertrophic cardiomyopathy whose symptoms do not respond to medical management. Transaortic extended septal myectomy has low operative mortality and provides durable relief of symptoms. Surgical treatment is possible for patients with less common phenotypes, such as complex long segment septal hypertrophy, midventricular obstruction, or apical hypertrophic cardiomyopathy. For these anatomic subtypes, transapical myectomy can be used alone or combined with transaortic myectomy. This article describes both of these surgical techniques and discusses preoperative considerations and postoperative management for patients with hypertrophic cardiomyopathy. PMID- 30447722 TI - Conceptual Models of Borderline Personality Disorder, Part 1: Overview of Prevailing and Emergent Models. AB - Borderline personality disorder (BPD) is a debilitating condition with significant personal and societal costs. Throughout the history of the conceptualization of borderline pathology as a form of psychopathology, there has been debate concerning the essential attributes of this disorder, which has significant implications for its assessment and treatment. The first of this 2 part review evaluates the major approaches to conceptualizing BPD, from the traditional DSM diagnosis through the more recent Alternative Model in DSM-5, Section III, and the research domain criteria initiative of the National Institute of Mental Health that was articulated largely in response to limitations of the DSM. PMID- 30447723 TI - Conceptual Models of Borderline Personality Disorder, Part 2: A Process Approach and Its Implications. AB - In part 2, the authors argue for a greater focus on a process approach to conceptualizing borderline personality disorder (BPD). The studies reviewed highlight contextual aspects of the pathology, specifically the affective and relational conditions under which BPD features become evident. The authors identify at what level in a complex social cognitive process the pathology may emerge. The implications of these findings for future model conceptualization are discussed, including the centrality of understanding BPD as an emergent phenomenon that cannot be reduced to single explanatory dimensions. The implications of these models for assessment, research, and treatment of BPD are discussed. PMID- 30447724 TI - Community and Clinical Epidemiology of Borderline Personality Disorder. AB - Several studies of the prevalence of borderline personality disorder in community and clinical settings have been carried out to date. Although results vary according to sampling method and assessment method, median point prevalence is roughly 1%, with higher or lower rates in certain community subpopulations. In clinical settings, the prevalence is around 10% to 12% in outpatient psychiatric clinics and 20% to 22% among inpatient clinics. Further research is needed to identify the prevalence and correlates of borderline personality disorder in other clinical settings (eg, primary care) and to investigate the impact of demographic variables on borderline personality disorder prevalence. PMID- 30447725 TI - Differential Diagnosis of Borderline Personality Disorder. AB - Borderline personality disorder (BPD) has a wide range of symptoms and clinical features that overlap with other diagnostic categories. Diagnosis is important because different disorders respond to different forms of treatment. Differential diagnosis is particularly relevant for distinguishing BPD from bipolar spectrum disorders, requiring a careful evaluation of affective instability and hypomania. BPD may also be confused with major depression, schizophrenia, attention deficit/hyperactivity disorder, and posttraumatic stress disorder. PMID- 30447726 TI - Comorbidity of Borderline Personality Disorder: Current Status and Future Directions. AB - Patients with borderline personality disorder have high rates of comorbid mood, anxiety, substance use, and eating disorders. The longitudinal studies conducted on borderline patients over 10 years of prospective follow-up suggest that patients with borderline personality disorder experienced declining rates of Axis I disorders over time, but the rates of these disorders remained high compared with those with other personality disorders. In addition, patients whose borderline personality disorder remitted over time experienced a substantial decline in all comorbid Axis I disorders, but those whose borderline personality disorder did not remit over time, reported stable rates of comorbid disorders. PMID- 30447727 TI - An Object-Relations Based Model for the Assessment of Borderline Psychopathology. AB - The authors describe an object-relations based model drawing on the work of Kernberg and colleagues for the assessment of borderline pathology. The substrate of internal object relations that constitutes borderline pathology internally or structurally is described and a model for assessing such pathology in a clinical interview format focusing on identity, defensive style, and quality of object relations is presented. Two clinical examples illustrate how these data can be compiled for purposes of psychodynamic case formulation and decisions about psychodynamic treatment. PMID- 30447728 TI - Social Cognition and Borderline Personality Disorder: Splitting and Trust Impairment Findings. AB - The Borderline personality disorder (BPD) diagnosis has its origins in the concept of borderline personality organization (BPO). BPO is rooted in psychoanalytic object relations theory (ORT) which conceptualizes BPD and BPO to exhibit a propensity to view significant others as either idealized or persecutory (splitting) and a trait-like paranoid view of interpersonal relations. From the ORT model, those with BPD think that they will ultimately be betrayed, abandoned, or neglected by significant others, despite periodic idealizations. This article synthesizes the extant literature splitting and trust impairments in BPD, identifies avenues for further investigation, and discusses the relative promise of different methods to evaluate these clinical processes. PMID- 30447729 TI - The Neurobiology of Borderline Personality Disorder. AB - This article reviews the most salient neurobiological information available about borderline personality disorder (BPD) and presents a theoretic model for what lies at the heart of BPD that is grounded in those findings. It reviews the heritability, genetics, and the biological models of BPD, including the neurobiology of affective instability, impaired interoception, oxytocin and opiate models of poor attachment or interpersonal dysfunction, and structural brain imaging over the course of development in BPD; and posits that the core characteristic of BPD may be an impairment in emotional interoception or alexithymia. PMID- 30447730 TI - Attachment and Borderline Personality Disorder. AB - Borderline personality disorder is associated with predominant insecure and unresolved attachment representations, linked history of trauma, impaired cognitive functioning and oxytocin levels, and higher limbic activations. Two randomized clinical trials on transference-focused psychotherapy assessed change of attachment representation and reflective functioning. The first showed that transference-focused psychotherapy was superior, demonstrating significant improvements toward attachment security and higher reflective functioning. The second randomized clinical trial study on transference-focused psychotherapy compared with therapy as usual replicated these results and additionally showed a significant shift from unresolved to organized attachment in the transference focused psychotherapy group only, suggesting its effectiveness in traumatized patients. PMID- 30447731 TI - Adolescence as a Sensitive Period for the Development of Personality Disorder. AB - Over the last 15 years, controversy over the construct of adolescent personality disorder has largely been laid to rest because of accumulating empirical evidence in support of its construct validity. In this article, four conclusions that can be drawn from recent literature on borderline disorder in adolescents are discussed, with the ultimate goal of building an argument to support the idea that adolescence is a sensitive period for the development of personality disorder. PMID- 30447732 TI - The Longitudinal Course of Borderline Personality Disorder. AB - Findings from decades of longitudinal research have challenged the long-held notion that borderline personality disorder (BPD) is a chronically disabling condition. Instead, several prospective, long-term follow-up studies have found that most patients with BPD experience a remission from the disorder, and many experience a full recovery over the course of their lives. These studies also indicate that symptoms of BPD wax and wane over time, although more acute, behavioral symptoms of the disorder tend to remit rapidly and recur rarely. Further, findings regarding predictors of good and poor outcomes in BPD could influence further developments in treatments for the disorder. PMID- 30447733 TI - Borderline Personality Disorder: Barriers to Borderline Personality Disorder Treatment and Opportunities for Advocacy. AB - Patients experience difficulty in accessing the evidence-based treatments that exist for borderline personality disorder. This article identifies barriers to treatment within the US structural, economic, and political landscape and how families have created an advocacy movement to address this problem. It explores how the United States has addressed such barriers, in comparison to other countries. Finally, it offers recommendations for future advocacy to increase access to treatment for borderline personality disorder. PMID- 30447734 TI - Treatment of Borderline Personality Disorder. AB - Findings from randomized controlled trials and meta-analyses suggest that there are several efficacious treatments for borderline personality disorder, including those based on cognitive behavior theories and psychodynamic theories. In addition, there are generalist and adjunctive approaches. These treatments and the corresponding evidence associated with each are described. It is concluded randomized controlled trials and meta-analyses suggest little to no difference between any active specialty treatments for borderline personality disorder; there are no differences between dialectical behavior therapy and non-dialectical behavior therapy treatments or between cognitive behavior-based and psychodynamic theory-based treatments. Thus, clinicians are justified in using any of these efficacious treatments. PMID- 30447735 TI - Psychotherapy for Borderline Personality Disorder in Adolescents. AB - Research on borderline personality disorder (BPD) in adolescence has helped to clarify the characteristics of BPD in young people. The considerable emotional and economic cost associated with adolescent BPD supports calls for early intervention and requires that the assessment of personality functioning be an essential component in the psychological evaluation of adolescents. Adult treatment models with demonstrated efficacy have been adapted for adolescents. This article describes the implementation of these treatment approaches, factors that frequently complicate the recognition and diagnosis of BPD in young people, and an overview of research on BPD in adolescents that delineates its clinically relevant features. PMID- 30447736 TI - Borderline Personality Disorder. PMID- 30447737 TI - What's Next? A Clinical Overview. AB - This rich and comprehensive set of studies on the borderline personality disorder presents the reader with an up-to-date review of new findings and developments in our understanding of this serious and highly prevalent condition. It also outlines areas of controversies and open questions regarding conceptual models, psychopathology, genetic and environmental etiologic features, neurobiology, and treatment. PMID- 30447738 TI - The Economics of Rheumatology Practice in the United States. AB - The current environment shaping rheumatology practice economics, with a focus on revenues, is described. The policies and practices of private and public insurance companies, pharmaceutical manufacturers, and pharmacy benefit managers (PBMs) are summarized, identifying economic implications for rheumatologists. The role of rebates in shaping practice economics is discussed, along with the central role of payers in defining PBM policies. PMID- 30447739 TI - Challenges in Implementing Treat-to-Target Strategies in Rheumatology. AB - Despite evidence that treat-to-target (TTT) approaches lead to better disease outcomes in RA, TTT is not widely implemented in rheumatology clinics in North America. This article discusses the barriers (including access to care, patient and physician factors, and systems issues) to implementing TTT in the clinic, and proposes possible solutions and future research directions. PMID- 30447740 TI - Digital Medicine in Rheumatology: Challenges and Opportunities. AB - The exponential growth in technology has had a significant effect on the practice of medicine and will likely transform the practice of medicine. In this article, the authors review select technologies that are already influencing the practice of rheumatology. Social media Websites such as Twitter are now important sources of information and discussion for health care professionals interested in rheumatology. Virtual reality is an innovative technology with great potential for acute and chronic pain management. The authors also review several low-cost technology alternatives to commonly used tools used in rheumatology. PMID- 30447741 TI - Challenges in Optimizing Medical Education for Rheumatologists. AB - The field of rheumatology has expanded rapidly in recent years, and innovations in immunology, epigenetics, and bone metabolism continue at an astonishing pace. In this fast changing field, optimizing medical education for rheumatologists is vital for maintaining a competent workforce to meet the needs of patients with rheumatic diseases. Several key challenges lie ahead and efforts to optimize medical education for rheumatologists are discussed in this article. PMID- 30447742 TI - Workforce Trends in Rheumatology. AB - The United States is facing a rheumatology provider shortage over the next decade, which will negatively affect care for patients with rheumatic disease across the nation if this deficit is not thoughtfully addressed. The increasing numbers of retiring rheumatology specialists, women entering the workforce, and rheumatology graduates seeking part-time employment were identified as the most significant factors driving the projected decline in supply of providers. The major factors driving the projected increase in demand include an aging and growing population and improved treatment options, both of which increase disease prevalence and the challenge of managing chronic rheumatologic diseases. PMID- 30447743 TI - The Challenges of Approaching and Managing Gout. AB - Despite many effective treatments for gout, its management remains a challenge internationally. Options for optimizing gout management may differ in different practice sizes and settings. Gout incidence is rising and it continues to be associated with increased mortality. Education of patients and medical providers is essential, and newer gout medications need to be used in the most appropriate ways for cost-effective therapy. Special consideration needs to be given to such populations as the elderly and those with renal and cardiovascular disease in gout management. New agents are in development, which may add to the armamentarium for gout management. PMID- 30447744 TI - Challenges to Practicing Rheumatology in an Academic Center. AB - Rheumatologists working in academics participate in patient care, teaching, and research. There are several challenges associated with the pursuit of these academic missions, and these are the focus of this article. Additionally, how financial pressures faced by academic institutions have led to greater emphasis on the generation of revenue from clinical activities to the detriment of other academic pursuits is discussed. In an era of greater physical burnout and with the looming shortages of the rheumatology workforce, the importance of addressing these issues is stressed and potential solutions discussed. PMID- 30447745 TI - Challenges of Practicing Rheumatology in a Government Setting: A County Hospital and Veterans Affairs Hospital Perspective. AB - In this article, we review the challenges and opportunities afforded by working in a government setting by providing the perspective of the Veterans Affairs experience as well as the county/public hospital experience from Los Angeles County Department of Health Services. This article highlights processes and services that are unique to practicing rheumatology in a government setting, specifically, resource allocation with clinic space and staffing; protocols for access to conventional and biologic disease modifying antirheumatic drugs; and research opportunities for rheumatologists working in a government setting. Our aim is to expand the reader's understanding of this practice setting. PMID- 30447746 TI - The Focused Musculoskeletal Factory. AB - Rheumatology has evolved rapidly over the past 20 years. The availability of numerous treatment interventions has dramatically altered patient outcomes and revitalized the specialty. At the same time, the economics of medical practice is challenging the practicing rheumatologist to seek more efficient and more attractive models of care delivery. These models of care must be attractive not only to rheumatologists and their patients but also to other interested parties as well, such as payers, government agencies, and accreditation bodies. PMID- 30447747 TI - Challenges to Practicing Pediatric Rheumatology. AB - Pediatric rheumatology is an exciting and rewarding career area. However, challenges when attracting trainees to this field include practice often occurring in smaller groups compared with general pediatrics, available positions requiring relocation, and fluctuation in funding resulting in uncertainty regarding training positions. Having critical mass in pediatric divisions is important to ensure adequate mentoring and people power to produce scholarly work, reduce on-call frequency and mitigate faculty absences that result in unplanned addition of clinical work. Compensation has historically lagged behind that of general pediatrics. Increased research opportunities through organized networks, patient and parent engagement, and the increasing recognition of pediatric rheumatologists as contributing to scholarship has heightened the profile of pediatric rheumatology nationally and internationally. PMID- 30447748 TI - Clinical Trials in Rheumatology. AB - Clinical trials evaluate the benefits and harms of medical interventions with the ultimate goal of establishing an evidence-based regimen that contributes to clinical decision making. Physicians benefit greatly from clinical research because it provides a greater understanding of epidemiology and health outcomes, and patients are given opportunities to participate in such trials. In this review, we discuss the challenges of conducting clinical trials investigating rheumatic diseases, including that of recruitment, finding the right trial, designing a budget, and performing a study in a timely manner. If done right, clinical investigation can be particularly rewarding both intellectually and financially. PMID- 30447749 TI - Challenges in Having an Infusion Center. AB - This article presents a comprehensive overview of the model, care, costs, and considerations necessary in having an outpatient infusion suite in a practice. It provides a real-life assessment of the challenges infusion centers face, including financial and clinical impacts. It is also patient centric, showing how a comfortable patient experience can improve care and increase patient compliance in an outpatient setting. Also included is a list of specialty infusions and indications, medication procurement options, an internal process for outside referrals, using nurse practitioners and physician assistants, and the complexities of working with insurance companies and the regulations and requirements necessary. PMID- 30447750 TI - Best Practices and Challenges to the Practice of Rheumatologists. PMID- 30447751 TI - Best Practices and Challenges to the Practice of Rheumatologists. PMID- 30447752 TI - Overview of genetic models of autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are a group of neurodevelopment disorders that are characterized by heterogenous cognitive deficits and genetic factors. As more ASD risk genes are identified, genetic animal models have been developed to parse out the underlying neurobiological mechanisms of ASD. In this review, we discuss a subset of genetic models of ASD, focusing on those that have been widely studied and strongly linked to ASD. We focus our discussion of these models in the context of the theories and potential mechanisms of ASD, including disruptions in cell growth and proliferation, spine dynamics, synaptic transmission, excitation/inhibition balance, intracellular signaling, neuroinflammation, and behavior. In addition to ASD pathophysiology, we examine the limitations and challenges that genetic models pose for the study of ASD biology. We end with a review of innovative techniques and concepts of ASD pathology that can be further applied to and studied using genetic ASD models. PMID- 30447753 TI - From bedside to bench and back: Translating ASD models. AB - Autism spectrum disorders (ASD) represent a heterogeneous group of disorders defined by deficits in social interaction/communication and restricted interests, behaviors, or activities. Models of ASD, developed based on clinical data and observations, are used in basic science, the "bench," to better understand the pathophysiology of ASD and provide therapeutic options for patients in the clinic, the "bedside." Translational medicine creates a bridge between the bench and bedside that allows for clinical and basic science discoveries to challenge one another to improve the opportunities to bring novel therapies to patients. From the clinical side, biomarker work is expanding our understanding of possible mechanisms of ASD through measures of behavior, genetics, imaging modalities, and serum markers. These biomarkers could help to subclassify patients with ASD in order to better target treatments to a more homogeneous groups of patients most likely to respond to a candidate therapy. In turn, basic science has been responding to developments in clinical evaluation by improving bench models to mechanistically and phenotypically recapitulate the ASD phenotypes observed in clinic. While genetic models are identifying novel therapeutics targets at the bench, the clinical efforts are making progress by defining better outcome measures that are most representative of meaningful patient responses. In this review, we discuss some of these challenges in translational research in ASD and strategies for the bench and bedside to bridge the gap to achieve better benefits to patients. PMID- 30447754 TI - Studying child development in genetic models of ASD. AB - This chapter approaches the early development in autism spectrum disorder (ASD) through comparative study of some key monogenic syndromic models of ASD in humans. Using this method, as well as referring to relevant work in idiopathic ASD, we address three complimentary areas: (i) patterns of ASD behavioral phenotype expression across genetic syndromes, as a way of addressing gene phenotype correlations; (ii) longitudinal developmental trajectories toward autism in early childhood, as a way of addressing developmental specificity; and (iii) experimental intervention trials, for treatment and mechanism discovery. The comparative approach does not highlight striking phenotypic specificity, but early studies were often limited and more methodologically sophisticated recent studies may suggest subtle distinctions. Longitudinal studies are at an early stage but can build on the substantive work on early prodromal development of idiopathic ASD. Translational intervention trials to date have not found candidate treatments and we argue that a new generation of more ambitious experimental mechanism trials is needed. This field now has the opportunity to combine comparative prospective longitudinal developmental studies with in-depth cross-syndrome phenotyping and linked ambitious targeted mechanistic interventions in a way that could be mutually informing and maximize the potential of syndromic models to illuminate the pathophysiology of ASD. PMID- 30447755 TI - Measurement considerations in pediatric research on autism spectrum disorders. AB - Studying Autism Spectrum Disorders (ASD) in genetic syndromes has gained interest in the scientific community as a way to elucidate mechanisms and symptom profiles to understand ASD more broadly. Appropriate and adequate measurement of constructs, symptomatology, and outcomes in clinical research is of vital importance in establishing the prevalence of such symptoms and measuring change in symptoms in the context of clinical trials. As such, we provide an overview of the prevalence of ASD, present current diagnostic guidelines, discuss important comorbidities to consider, describe current assessment strategies in assessing ASD, and discuss these within the context of a specific genetic condition to highlight how ASD can be best evaluated. PMID- 30447756 TI - Neurofibromatosis type 1 as a model system to study molecular mechanisms of autism spectrum disorder symptoms. AB - Neurofibromatosis type 1 (NF1) is monogenic neurodevelopmental disorder caused by mutation of NF1 gene, which leads to increased susceptibility to various tumors formations. Additionally, majority of patients with NF1 are experience high incidence of cognitive deficits. Particularly, we review the growing number of reports demonstrated a higher incidence of autism spectrum disorder (ASD) in individuals with NF1. In this review we also discuss face validity of preclinical Nf1 mouse models. Then we describe discoveries from these animal models that have uncovered the deficiencies in the regulation of Ras and other intracellular pathways as critical mechanisms underlying the Nf1 cognitive problems. We also summarize and interpret recent preclinical and clinical studies that point toward potential pharmacological therapies for NF1 patients. PMID- 30447757 TI - ERK/MAPK signaling and autism spectrum disorders. AB - The MAPK pathway is a prominent intracellular signaling pathway regulating various intracellular functions. Components of this pathway are mutated in a related collection of congenital syndromes collectively referred to as neuro cardio-facio-cutaneous syndromes (NCFC) or Rasopathies. Recently, it has been appreciated that these disorders are associated with autism spectrum disorders (ASD). In addition, idiopathic ASD has also implicated the MAPK signaling cascade as a common pathway that is affected by many of the genetic variants that have been found to be linked to ASDs. This chapter describes the components of the MAPK pathway and how it is regulated. Furthermore, this chapter will highlight the various functions of the MAPK pathway during both embryonic development of the central nervous system (CNS) and its roles in neuronal physiology and ultimately, behavior. Finally, we will summarize the perturbations to MAPK signaling in various models of autism spectrum disorders and Rasopathies to highlight how dysregulation of this pivotal pathway may contribute to the pathogenesis of autism. PMID- 30447758 TI - Preface. PMID- 30447759 TI - Implementation of Choosing Wisely: Promise and Pitfalls. PMID- 30447760 TI - Choosing Wisely in Georgia: A Quality Improvement Initiative in 25 Adult Ambulatory Medicine Offices. AB - BACKGROUND: Scant evidence exists of effective Choosing Wisely(r) initiatives, which are intended to reduce the use of unnecessary care. In 2013 substantial variations existed at Kaiser Permanente Georgia in the frequency of nonbeneficial services in ambulatory care. A Choosing Wisely campaign was implemented across 25 medical offices serving approximately 300,000 members. METHODS: The initiative was designed to reduce the use of complete blood counts (CBCs) and electrocardiograms (EKGs) as routine screening tests in physical examination visits, age-inappropriate dual-energy x-ray absorptiometry (DEXA) scans, and imaging for uncomplicated headache. The change management package consisted of (1) guideline selection by clinical leaders, (2) continuing medical education for clinicians and training and education for clinic staff and advice nurses, (3) an internal and external communication plan, and (4) monthly reports. RESULTS: Between January 2013 and December 2016, CBC use as a routine screening test decreased by 39.5 percentage points (95% confidence interval [CI] = 39.0-40.0) from an average of 42.7% to 3.2%; EKG use as a routine screening test decreased by 15.5 percentage points (95% CI = 15.1-15.8)-from an average of 15.9% to 0.3%; inappropriate DEXA scan use decreased by 23.4 percentage points (95% CI = 22.5 24.5)-from an average of 25.4% to 2.0%; and imaging for uncomplicated headache decreased by 3.9 percentage points (95% CI = 3.3-4.6)-from an average of 10.8% to 6.9%. All decreases were statistically significant (p < 0.05) and were largely sustained after monthly reports ended. CONCLUSION: Sustained reductions in nonbeneficial services in ambulatory care followed implementation of a comprehensive change management package. PMID- 30447761 TI - Inclusion of Plaintiff Attorneys in Research into the Effects of Harmful Events. PMID- 30447762 TI - Plaintiff Attorneys in Communication and Resolution Programs. PMID- 30447764 TI - Acquired Donor Peanut Allergy From Lung Transplantation Resulting in Respiratory Failure: A Case Report. AB - This case report describes a patient who acquired a donor peanut allergy after lung transplantation. A 53-year-old woman with alpha-1 antitrypsin deficiency underwent left-sided lung transplant from a donor with a history of anaphylaxis to peanut. Two weeks after the transplant, the patient developed acute respiratory failure immediately after consuming a peanut butter and jelly sandwich. The donor's serum confirmed high titers of peanut-specific immunoglobulin E (IgE). The recipient patient had never had allergies to peanuts or other nuts before her transplant. After the transplant, she had negative serology but positive skin testing to peanuts. This case illustrates the importance of considering donor food allergies when caring for solid organ transplant recipients. PMID- 30447765 TI - Diagnostic Approaches to Understanding Equine Limb Wounds. AB - An accurate and timely diagnosis of the systemic and local tissue influences of a wound are essential to target successful treatment measures and reach the best result for an affected horse. A complete physical examination should be completed for any wounded horse and appropriate systemic therapies instituted. Visual and manipulative examinations aid in the complete understanding of wounded tissues. Imaging and invasive diagnostic techniques also have value in determining the extent of a wound. Considering what tissues are involved from an inside-out perspective can assist in developing a complete diagnosis. PMID- 30447766 TI - Equine Practice on Wound Management: Wound Cleansing and Hygiene. AB - The goal of wound cleansing and care is the control or removal of tissue infection to allow healing in the most functional, cosmetic, fastest, and least expensive manner possible. This is accomplished through the removal of debris and necrotic tissue while reducing the bacterial load via careful use of mechanical techniques and cleaning agents, accepting that some level of tissue trauma will result. Keep in mind that the benefit of a clean wound must be weighed against the trauma inflicted in the process of cleansing. Veterinary health care professionals should take steps to reduce hospital-acquired infections and zoonotic disease transmission. PMID- 30447767 TI - Topical Wound Medications. AB - Topical therapies are used in equine wound healing to clean and decontaminate the wound environment after acute injury and to promote healing and decrease the risk of infection once the wound has initially been treated. Evolving antibiotic resistance has prompted judicious use of systemic antimicrobials, particularly in the treatment of local infections, such as wounds. The use of topical antiseptics to disinfect acute wounds and topical antimicrobials to manage chronic wounds is necessary to achieve successful healing. In addition, many topical medications can alter the wound environment to promote rapid and effective wound healing. PMID- 30447768 TI - Wound Management: Wounds with Special Challenges. AB - Distal limb wounds in horses heal substantially different than trunk wounds, commonly resulting in exuberant granulation tissue and exposed and sequestered bone. Surgical intervention of severe rectovaginal lacerations in the mare should be delayed until the tissues have heeled and scar tissue has remodeled. Wounds resulting in severe hemorrhage require appropriate emergent fluid therapy and potentially transfusion therapy. PMID- 30447769 TI - Nonhealing Wounds of the Equine Limb. AB - Nonhealing wounds present a common challenge to the equine practitioner. An underlying source of inflammation and infection is almost always present and needs to be resolved for healing to proceed. Wound debridement is the mainstay for this resolution. In addition, wound closure, wound dressings, and skin grafts can be used to achieve successful wound healing. PMID- 30447770 TI - Equine Wounds over Synovial Structures. AB - Equine septic synovitis commonly occurs secondary to traumatic wounds. The distal limbs of horses have minimal soft tissue protection, thus wounds in these areas are more likely to involve adjacent synovial structures. Synovial sepsis can be debilitating due to difficulties clearing established infections and the degenerative changes that result from ongoing inflammation. Prompt diagnosis allows for immediate treatment, improving the prognosis. Goals for successful treatment of infected synovial structures due to wounds include early and accurate recognition of the condition, rapid resolution of pain and inflammation, complete elimination of microorganisms, appropriate wound healing, and a timely return to function. PMID- 30447771 TI - Regenerative Medicine Therapies for Equine Wound Management. AB - Wound management in horses can strike fear in some and passion in others. Wounds are common injuries in horses of all descriptions and requires exceptional knowledge and care to achieve a successful outcome. New treatments to overcome the critical challenges with equine wounds are always desired: managing dehisced and/or nonhealing wounds, managing exuberant granulation tissue, and ultimately achieving a functional tissue coverage. Regenerative medicine represents a broad set of tools with great promise to manipulate the deficiencies recognized in equine wound healing and improve the outcome. PMID- 30447772 TI - Brief Overview of Lung, Heart, and Heart-Lung Transplantation. AB - Lung transplantation, heart transplantation, and heart-lung transplantation are life-saving treatment options for patients with lung and/or cardiac failure. Evolution in these therapies over the past several decades has led to better outcomes with application to more patients. The complexity and severity of illness of patients in the pretransplant phase has steadily increased, making posttransplant intensive care unit management more difficult. Despite these factors and the pervasive complications of immunosuppressive therapy, outcomes continue to improve. PMID- 30447773 TI - Critical Care Management of Living Donor Liver Transplants. AB - This article represents a review of the postoperative management of donors and recipients after living donor liver transplant, including monitoring, liberation from mechanical ventilation, nutritional support, and pain control. Vascular complications, such as biliary and sepsis, and bleeding are also discussed. Finally, commonly used immunosuppression and antimicrobial prophylaxes are reviewed. PMID- 30447774 TI - Bridging to Lung Transplantation. AB - Lung transplantation is the gold standard for treating patients with end-stage lung disease. Such patients can present with severe illness on the waitlist and may deteriorate before a lung donor is available. Bridging strategies with extracorporeal membrane oxygenation (ECMO) are valuable for getting patients to transplant and provide a chance at survival. The current article describes the indications, contraindications, and techniques involved in bridging to lung transplantation with ECMO. PMID- 30447775 TI - Graft Dysfunction and Management in Liver Transplantation. AB - Graft dysfunction of the liver allograft manifests across a spectrum in both timing posttransplantation and clinical presentation. This can range from mild transient abnormalities of liver tests to acute liver failure potentially leading to graft failure. The causes of graft dysfunction can be divided into those resulting in early and late graft dysfunction. Although nonspecific, liver biochemistry abnormalities are still the mainstay investigation used in monitoring for dysfunction. This article provides a summary of the main causes and management strategies for liver graft dysfunction in the early through late posttransplant stages. PMID- 30447776 TI - Extracorporeal Devices. AB - Extracorporeal liver support (ECLS) emerged from the need stabilize high-acuity liver failure patients with the highest risk of death. The goal is to optimize the hemodynamic, neurologic, and biochemical parameters in preparation for transplantation or to facilitate spontaneous recovery. Patients with acute liver failure and acute-on-chronic liver failure stand to benefit from these devices, especially because they have lost many of the primary functions of the liver, including detoxifying the blood of various endogenous and exogenous substances, manufacturing circulating proteins, secreting bile, and storing energy. Existing ECLS devices are designed to mimic some of these functions. PMID- 30447777 TI - Infectious Complications Following Solid Organ Transplantation. AB - Infections in solid organ transplant recipients are complex and heterogeneous. This article reviews the clinical syndromes that will likely be encountered in the intensive care unit and helps to guide in the therapy and management of these patients. PMID- 30447778 TI - Complications of Solid Organ Transplantation: Cardiovascular, Neurologic, Renal, and Gastrointestinal. AB - Despite improvements in overall graft function and patient survival rates after solid organ transplantation, complications can lead to significant morbidity and mortality. Cardiovascular complications include heart failure, arrhythmias leading to sudden death, hypertension, left ventricular hypertrophy, and allograft vasculopathy in heart transplantation. Neurologic complications include stroke, posterior reversible encephalopathy syndrome, infections, neuromuscular disease, seizure disorders, and neoplastic disease. Acute kidney injury occurs from immunosuppression with calcineurin inhibitors or as a result of graft failure after kidney transplantation. Gastrointestinal complications include infections, malignancy, mucosal ulceration, perforation, biliary tract disease, pancreatitis, and diverticular disease. Immunosuppression can predispose to infections and malignancy. PMID- 30447779 TI - Perioperative Management of the Lung Graft Following Lung Transplantation. AB - Perioperative management of patients undergoing lung transplantation is one of the most complex in cardiothoracic surgery. Certain perioperative interventions, such as mechanical ventilation, fluid management and blood transfusions, use of extracorporeal mechanical support, and pain management, may have significant impact on the lung graft function and clinical outcome. This article provides a review of perioperative interventions that have been shown to impact the perioperative course after lung transplantation. PMID- 30447780 TI - Perioperative Management of the Cardiac Transplant Recipient. AB - Management of the cardiac transplant recipient includes careful titration of inotropes and vasopressors. Recipient pulmonary hypertension and ventilatory status must be optimized to prevent allograft right ventricular failure. Vasoplegia, coagulopathy, arrhythmias, and renal dysfunction also require careful management to achieve an optimal outcome. Primary graft dysfunction (PGD) can be an ominous problem after cardiac transplantation. Although mild degrees of PGD may be managed medically, mechanical circulatory support with extracorporeal membrane oxygenation or temporary ventricular assist devices may be required. Retransplantation may be necessary in some cases. PMID- 30447781 TI - Renal Complications Following Lung Transplantation and Heart Transplantation. AB - Renal complications are common following heart and/or lung transplantation and lead to increased morbidity and mortality. Renal dysfunction is also associated with increased mortality for patients on the transplant wait list. Dialysis dependence is a relative contraindication for heart or lung transplantation at most centers, and such patients are often listed for a simultaneous kidney transplant. Several factors contribute to the impaired renal function in patients undergoing heart and/or lung transplantation, including the interplay between cardiopulmonary and renal hemodynamics, complex perioperative issues, and exposure to nephrotoxic medications, mainly calcineurin inhibitors. PMID- 30447782 TI - Infections in Heart and Lung Transplant Recipients. AB - Infections in heart and lung transplant recipients are complex and heterogeneous. This article reviews the epidemiology, risk factors, specific clinical syndromes, and most frequent opportunistic infections in heart and/or lung transplant recipients that will be encountered in the intensive care unit and will provide a practical approach of empirical management. PMID- 30447783 TI - Perioperative Management of the Liver Transplant Recipient. AB - Perioperative management of the liver transplant recipient is a team effort that requires close collaboration between intensivist, surgeon, anesthesiologist, hepatologist, nephrologist, other specialists, and hospital staff before and after surgery. Transplant viability must be reassessed regularly and particularly with each donor organ. Regular discussions with patient and family facilitate realistic determinations of goals based on patient aspirations and clinical realities. Early attention to hemodynamics with optimal resuscitation and judicious vasopressor support, respiratory care designed to minimize iatrogenic injury, and early renal support is key. Preoperative and postoperative nutritional support and physical rehabilitation should remain a focus. PMID- 30447784 TI - Thoracic Transplantation. PMID- 30447785 TI - Caring for the Critically Ill Liver Transplant Patients: A Fifty-Year Journey! PMID- 30447786 TI - Simple Approaches for Establishing an Evidence-Based Dental Practice. AB - Constructing an evidence-based dental practice requires leadership, commitment, technology support, and time, as well as skill practice in searching, appraising, and organizing evidence. In mastering the skills of evidence-based dentistry, clinicians can implement high-quality science into practice through a variety of opportunities including the development of clinical care guidelines, procedural technique protocols, and electronic dental record auto-note templates, as well as treatment planning, care prioritization, and case presentation. The benefits of building an evidence-based dental practice are many, including improvements in patient care and satisfaction, increased treatment predictability and confidence in care approaches, as well as potential cost savings. PMID- 30447787 TI - Evidence-Based Dentistry Caries Risk Assessment and Disease Management. AB - The objective of this article was to provide a summary of evidence-based recommendations for the assessment of caries risk and management of dental caries. The goal is to help clinicians manage the caries disease process using personalized interventions supported by the best available evidence, taking into account the clinician's expertise and the patient's needs and preferences, to maintain health and preserve tooth structure. PMID- 30447788 TI - Translational Research: Bringing Science to the Provider Through Guideline Implementation. AB - Significant variation exists in health care practice patterns that creates concerns regarding the quality of care delivered. Clinical practice based on high quality evidence provides a rationale for clinical decision making. Resources, such as evidence-based guidelines, provide that evidence to clinicians and improve patient outcomes by decreasing unwanted variation in clinical practice. Because knowledge dissemination alone is ineffective to translate scientific evidence into clinical practice, the field of implementation science has emerged to facilitate this translation of research into routine clinical practice. This article provides an introduction to implementation science, and its application in dentistry to promote adoption of evidence-based guidelines. PMID- 30447789 TI - How Should We Evaluate and Use Evidence to Improve Population Oral Health? AB - Generating and implementing evidence-based policy is an important aim for many publicly funded health systems. In dentistry, this is based on the assumption that evidence-based health care increases the efficiency and effectiveness of interventions to improve oral health at a population level. This article argues that a linear logic model that links the generation of research evidence with its use is overly simplistic. It also challenges an uncritical interpretation of the evidence-based paradigm and explores approaches to the evaluation of complex interventions and how they can be embedded into policy and practice to improve oral health at a population level. PMID- 30447791 TI - Analgesic Therapy in Dentistry: From a Letter to the Editor to an Evidence-Base Review. AB - It has been known for centuries that opioids are highly addictive when consumed for prolonged periods of time. Pharmacologic tolerance to the efficacy of opioid analgesic results in a need for increased dosing and drug dependence. One must question the empirical sources of evidence that justified the belief that prescription opioids were safe and effective for treating acute and chronic pain. Progress in developing and applying evidence-based analgesic therapies for acute inflammatory pain is presented. PMID- 30447792 TI - Evidence-Based Dentistry Update on Silver Diamine Fluoride. AB - This article reviews current evidence on the effectiveness of silver diamine fluoride (SDF) as a caries arresting and preventive agent. It provides clinical recommendations around SDF's appropriate use as part of a comprehensive caries management program. Systematic reviews confirm that SDF is effective for caries arrest on cavitated lesions in primary teeth and root caries in the elderly. It may also prevent new lesions. Application is easy, noninvasive, affordable, and safe. Although it stains the lesions dark as it arrests them, it provides clinicians with an additional tool for caries management when esthetics are not a primary concern. PMID- 30447790 TI - Added Sugar and Dental Caries in Children: A Scientific Update and Future Steps. AB - Excess added sugars, particularly in the form of sugar-sweetened beverages, is a leading cause of tooth decay in US children. Although added sugar intake is rooted in behavioral and social factors, few evidence-based, theory-driven socio behavioral strategies are currently available to address added sugar intake. Dental health professionals are in a position to help identify and address problematic sugar-related behaviors in pediatric patients and advocate for broader upstream approaches, including taxes, warning labels, and policy changes, that can help reduce added sugar intake, prevent tooth decay, and improve health outcomes in vulnerable child populations. PMID- 30447793 TI - Evidence-Based Update on Diagnosis and Management of Gingivitis and Periodontitis. AB - This article is an overview to update the practicing general dental practitioner about clinically relevant evidence-based topics published in the recent past in the diagnosis, etiopathogenesis, and management of gingivitis and periodontitis. PMID- 30447794 TI - How Evidence-Based Dentistry Has Shaped the Practice of Oral Medicine. AB - Oral medicine is "the discipline of dentistry concerned with the oral health care of medically complex patients, including the diagnosis and primarily nonsurgical treatment and/or management of medically related conditions affecting the oral and maxillofacial region." In each of these areas, evidence-based medicine has shaped theoretic understanding and clinical practice. The available evidence allows for improved patient management. Further evidence, as it becomes available, should be reviewed on a regular basis to guide our clinical practice. PMID- 30447795 TI - Teaching Evidence-Based Practice: Considerations for Dental Education. AB - The motivation for teaching evidence-based practice is that, through the use of high-quality clinically relevant evidence, clinicians will make rationale decision that optimally improve patient health outcomes. Achieving that goal requires clinicians who are able to answer patient care-relevant clinical questions efficiently, which means that they must be able rapidly to retrieve, assess, and apply evidence of direct relevance to their patients. Educational programs designed to accomplish this vary in their effectiveness. This article reviews the evidence on educational approaches that may be beneficial when developing educational programs for both dental students and practicing dentists. PMID- 30447796 TI - Evidence-Based Dentistry: The Foundation for Modern Dental Practice. PMID- 30447797 TI - The Role of the Pelvic Floor in Respiration: A Multidisciplinary Literature Review. AB - OBJECTIVE: To conduct an interdisciplinary literature review on the function of the pelvic floor musculature during respiration and its role in phonation, particularly singing. STUDY DESIGN: This is a literature review. METHODS: A literature review was conducted using three electronic databases: PubMed, Scopus, and Google Scholar. An index search was also performed for the NATS Journal/Journal of Singing utilizing the keywords from the original search, as these articles did not appear in the original search. Peer-reviewed articles from 1985 to 2017 were gathered on the respiratory musculature and/or support mechanisms for phonation (anatomy and physiology). Articles that pertained to the muscular function of the respiratory system in breathing and/or phonation were utilized in the review. Eighty-five articles were included in this review. RESULTS: Breathing and support strategies were variable and nonspecific in much of the singing voice literature. The voice science literature was a rich source of articles written about breathing and support for singing. Multiple studies looked at musculature utilized in respiration and breath support and subglottal pressure generation for muscular support. However, little or no mention was made specifically of the pelvic floor. The physical medicine literature includes the pelvic floor musculature as having an important role in respiration, as a key player in the generation of intra-abdominal pressure, and as a primary expiratory muscle. CONCLUSIONS: The information gleaned from this literature review suggests that a cross-pollination between areas of science is needed, because quite obviously, the pelvic floor is a topic in physical medicine, but it is not (so much) in the voice literature. Reaching a consensus on how we describe the function of the respiratory musculature and specifically including the role of the pelvic floor in respiration and phonation deserves future attention. Further research looking specifically at the role of the pelvic floor in phonation is also warranted. PMID- 30447798 TI - Cochlear Implant Users' Vocal Control CorrelatesAcross Tasks. AB - Cochlear implants (CIs) provide access to auditory information that can affect vocal control. For example, previous research shows that, when producing a sustained vowel, CI users will alter the pitch of their voice when the feedback of their own voice is perceived to shift. Although these results can be informative as to how perception and production are linked for CI users, the artificial nature of the task raises questions as to the applicability of the results to real-world vocal productions. To examine how vocal control, when producing sustained vowels, relates to vocal control for more ecologically valid tasks, 10 CI users' vocal control was measured across two tasks: (1) sustained vowel production, and (2) singing. The results found that vocal control, as measured by the variability of the participants' fundamental frequency, was significantly correlated when producing sustained vowels and when singing, although variability was significantly greater when singing. This suggests that, despite the artificial nature of sustained vowel production, vocal control on such tasks is related to vocal control for more ecologically valid tasks. However, the results also suggest that vocal control may be overestimated with sustained vowel production tasks. PMID- 30447799 TI - My name is *** and I am a general surgeon. PMID- 30447800 TI - Calculation of impingement-free combined cup and stem alignments based on the patient-specific pelvic tilt. AB - Proper cup alignment is crucial in total hip arthroplasty for reducing impingement risks, dislocations and wear. The Lewinnek "safe zone" is often used in clinical routine. This safe zone does not consider functional aspects and dislocation can occur even when the cup is oriented within the safe zone. Functional safe zones based on the hip range of motion (ROM) were introduced but are not commonly used in clinical routine. The reason might be that these methods are time-consuming due to complex simulations. A relatively fast method based on analytical mathematical formulas was proposed, but it is difficult to consider arbitrary motion. This work introduces an efficient algorithm for calculating a patient-specific target zone based on the target ROM which can consider any set of motions. The method is based on matrix transformations and trigonometric formulas. The resulting target zone which contains all impingement-free cup orientations is dependent on the patient-specific pelvic tilt, the 3D angular neck and stem orientation within the femur, and the technical prosthesis ROM. This method could be integrated into computer-assisted preoperative planning and intra-operative navigation tools. As pelvic tilt and stem orientation influence the optimal cup orientation they need to be acquired from the patient to derive a patient-specific ROM-based target zone. PMID- 30447801 TI - Evidence of functional deficits at the single muscle fiber level in experimentally-induced renal insufficiency. AB - Chronic kidney disease patients present with metabolic and functional muscle abnormalities, called uremic myopathy, whose mechanisms have not yet been fully elucidated. We investigated whether chronic renal insufficiency (CRI) affects skeletal muscle contractile properties at the cellular level. CRI was induced surgically in New Zealand rabbits (UREM), with sham-operation for controls (CON), and samples were collected at 3 months post-surgery, following euthanasia. All protocols had University Ethics approval following national and European guidelines. Sample treatments and evaluations were blinded. Maximal isometric force was assessed in 382 permeabilized psoas fibers (CON, n = 142, UREM, n = 240) initially at pH7, 10 degrees C ('standard' conditions), in subsets of fibers in acidic conditions (pH6.2, 10 degrees C) but also at near physiological temperature (pH7, 30 degrees C and pH6.2, 30 degrees C). CRI resulted in significant smaller average cross sectional areas (CSAs) by ~11% for UREM muscle fibers (vs CON, P < 0.01). At standard conditions, UREM fibers produced lower absolute and specific forces (i.e. normalized force per fiber CSA) (vs CON, P < 0.01); force increased in 30 degrees C for both groups (P < 0.01), but the disparity between UREM and CON remained significant. Acidosis significantly reduced force (vs pH7, 10 degrees C P < 0.01), similarly in both groups (in UREM by -48% and in CON by -43%, P > 0.05). For the first time, we give evidence that CRI can induce significant impairments in single psoas muscle fibers force generation, only partly explained by fiber atrophy, thus affecting muscle mechanics at the cellular level. PMID- 30447802 TI - Optimizing exchange transfusion for patients with severe Babesia divergens babesiosis: Therapeutically-Rational Exchange (T-REX) of M antigen-negative and/or S antigen-negative red blood cells should be evaluated now. AB - Babesia divergens is an intraerythrocytic parasite, which is the major cause of babesiosis in Europe. For years, clinicians have been publishing stunning case reports that describe how some - but not all - conventional red blood cell (RBC) exchange transfusions have saved the lives of severely ill babesiosis patients. Due to markedly different patient outcomes, clinicians agree that new treatments and additional studies are needed. Here we argue that we should evaluate "therapeutically-rational exchange" (T-REX) in which the RBCs used to replace Babesia-parasitized RBCs are special disease-resistant RBC genetic variants (instead of the nondescript, "standard issue" RBCs used in conventional exchanges). T-REX seems prudent because with conventional exchange only some units of "standard issue" RBCs may be disease-resistant, while other units may not protect or may even promote disease. The random selection of RBCs for conventional RBC exchange may explain why clinical outcomes can vary dramatically. Fortunately, researchers have found that M antigen-negative (M-) and S antigen-negative (S-) RBCs resist invasion by B. divergens. Thus, we recommend evaluating T-REX of RBC variants that are B. divergens invasion resistant: RBCs that are (1) M-, (2) S-, or (3) both M- and S-. By using only Babesia-resistant RBCs, T-REX eliminates the risk of unintentionally infusing Babesia-susceptible RBCs that might increase the severity of babesiosis. Because the T-REX variation of the conventional RBC exchange procedure is feasible, safe, and biologically plausible, we feel T-REX of Babesia-resistant RBCs should now be evaluated. PMID- 30447803 TI - Prognostic significance of Chromogranin A in small pancreatic neuroendocrine tumors. AB - BACKGROUND: The incidence of nonfunctional pancreatic neuroendocrine tumors <=2cm is rising. The biologic behavior of these tumors is variable; thus, their management remains controversial. Chromogranin A upregulation is a useful diagnostic biomarker of neuroendocrine tumors; however, the prognostic significance of Chromogranin A is unclear. The objective of this study was to determine whether Chromogranin A levels have prognostic value in pancreatic neuroendocrine tumor patients and may help guide management. METHODS: We evaluated the National Cancer Database over a 10-year period (2004-2013). Patients with pancreatic neuroendocrine tumors measuring <=2cm, without distant metastases, were identified and categorized as Chromogranin A high (>420ng/mL) or Chromogranin A low (<=420ng/mL), and those lacking data on Chromogranin A levels were excluded from the study. Univariate and multivariate analyses were performed using Cox proportional hazards model. Cut-point determination was performed using the Contal and O'Quigley method. RESULTS: Of the 445 eligible patients, 352 (79%) were Chromogranin A low and 93 (21%) were Chromogranin A high. Median Chromogranin A level was 71ng/mL (interquartile range, 24-294ng/mL). Chromogranin levels were associated with clinical nodal status and grade. Furthermore, on multivariate analysis, Chromogranin A levels (Chromogranin A high versus Chromogranin A low) independently predicted overall survival after controlling for tumor size, grade, clinical nodal status, and academic status of the facility (hazard ratio: 7.90, 95%CI: 2.34-26.69, P = .001). The greatest benefit of surgical resection was noted in patients in the Chromogranin A high subgroup (log rank P <.001). CONCLUSION: Serum Chromogranin A levels can be incorporated in surgical decision-making for patients with small pancreatic neuroendocrine tumors. Patients in the Chromogranin A low group can be considered for observation, whereas patients in the Chromogranin A high group should be strongly considered for resection. PMID- 30447805 TI - Increased Nursing Participation in Multidisciplinary Rounds to Enhance Communication, Patient Safety, and Parent Satisfaction. AB - Effective communication among health care team members is a mainstay of patient safety, especially in a neonatal ICU (NICU), given small errors can have serious and life-threating consequences. Ineffective communication with families of hospitalized children can lead to decreased satisfaction and trust in the health care team. To enhance communication, the NICU nursing staff at the Johns Hopkins Children's Center spearheaded an initiative to create an enhanced nursing role in multidisciplinary patient rounds. Education of the nursing staff and other team members and the development of a rounding script for nurses was instrumental for successful implementation. PMID- 30447804 TI - The Late Preterm: A Population at Risk. AB - Late preterm infants (LPIs) are born between 34 0/7 and 36 6/7 weeks' gestation and account for 72% of all preterm births in the United States. Born as much as 6 weeks early, the LPI misses the critical growth and development specific to the third trimester. The loss of this critical period leaves the LPI physiologically and metabolically immature and prone to various morbidities. Common morbidities include respiratory complications, feeding difficulty, hypoglycemia, temperature instability, hyperbilirubinemia, and neurodevelopmental delays. PMID- 30447806 TI - Standardized Feeding Protocols to Reduce Risk of Necrotizing Enterocolitis in Fragile Infants Born Premature or with Congenital Heart Disease: Implementation Science Needed. AB - Although a unit-adopted standardized feeding protocol (SFP) for neonates is standard of care, implementation strategies for SFPs vary across neonatal and pediatric intensive care. Besides improving growth and reducing feeding interruptions, SFPs reduce risk for necrotizing enterocolitis in infants with heart disease or born premature. The purpose of this article is to bridge the gap between recommended and actual care using SFPs. PMID- 30447807 TI - Neonatal Hypoglycemia: Is There a Sweet Spot? AB - Hypoglycemia is one of the most common neonatal problems. Despite increasing evidence that hypoglycemia is linked to neurologic impairment, knowledge regarding the specific value or duration of hypoglycemia that results in injury to the brain remains unclear. Current published statements/guidelines focused on preventing clinically significant hypoglycemia are conflicting and continue to be based on low evidence. This article reviews transitional events leading to extrauterine euglycemia, risk factors contributing to transient or persistent hypoglycemia, and common treatment approaches. Current information related to neurodevelopmental outcomes and screening strategies to prevent significant hypoglycemia with early treatment is described. PMID- 30447808 TI - Big Data in Neonatal Health Care: Big Reach, Big Reward? AB - Analog-to-digital data conversion has created massive amounts of historical and real-time health care data. Costs associated with neonatal health issues are high. Big data use in the neonatal intensive care unit has the potential to facilitate earlier detection of clinical deterioration, expedite application of efficient clinical decision-making algorithms based on real-time and historical data mining, and yield significant cost-savings. PMID- 30447809 TI - Fetal Surgery and Delayed Cord Clamping: Neonatal Implications. AB - Advances made in the last several decades in the care of the fetus and newborn have had a significant impact on morbidity and mortality. Delayed umbilical cord clamping in the preterm newborn results in fewer transfusions for anemia, decreased intraventricular hemorrhage, and decreased necrotizing enterocolitis. Because of advances made in fetal ultrasound diagnosis and technological advances, fetal surgeries to treat congenital diaphragmatic hernia, myelomeningocele, twin-to-twin transfusion syndrome, fetal lower urinary tract obstructions, amniotic band syndrome, and congenital cystic adenoid malformation or congenital pulmonary airway malformations have improved the quality of life and survival for these patients. PMID- 30447810 TI - Neonatal Encephalopathy: Current Management and Future Trends. AB - It is well-documented in the literature that infants who suffer from hypoxic ischemic encephalopathy are at high risk for neurologic sequelae or even death. With the addition of therapeutic hypothermia into the treatment regimen for neonatal hypoxic ischemic encephalopathy, newborns afflicted with hypoxic ischemic encephalopathy were given the opportunity for a better outcome. Questions linger as to the most optimal treatment strategy of therapeutic hypothermia for these newborns. The goal of this article is to discuss current management strategies, as well as future trends, for infants with hypoxic ischemic encephalopathy. PMID- 30447811 TI - Modes of Neonatal Ventilation: Breathe Deeply! AB - The art and science of neonatal ventilation continue to evolve with advances in technology and as a result of evidenced based research. Although some historically administered therapies remain such as nasal continuous positive airway pressure, newer therapies have emerged in the neonatal intensive care unit such as pressure regulated volume control and neurally adjusted ventilatory assist. The challenge for clinicians continues to be which mode will support the patient's medical diagnosis with minimal barotrauma or lung injury. Vigilance and collaborative discussions among the treatment team remain the cornerstones of respiratory care practice parameters in the neonatal intensive care environment. PMID- 30447812 TI - Neonatal Resuscitation: Neonatal Resuscitation Program 7th Edition Practice Integration. AB - The Neonatal Resuscitation Program meets the education and training needs of health care professionals in the United States who manage newborns in hospitals. The Neonatal Resuscitation Program 7th edition materials were required for use on January 1, 2017. The Neonatal Resuscitation Program focuses on optimal resuscitation readiness and effective communication. This article briefly describes the preparation and principles of newborn resuscitation and selected components of the Neonatal Resuscitation Program Flow Diagram. Five resuscitation scenarios of increasing complexity are used to illustrate how the guidelines are integrated into clinical practice. PMID- 30447813 TI - Neonatal Pain: Perceptions and Current Practice. AB - Neonates may experience more than 300 painful procedures throughout their hospitalizations. Prior to 1980, there was a longstanding misconception that neonates do not experience pain. Current studies demonstrate that not only do neonates experience pain but also, due to their immature nervous systems, they are hypersensitive to painful stimuli. Poorly treated pain may lead to negative long-term consequences. Proper assessment of neonate pain is vital. The use of nonpharmacologic treatments may be beneficial in alleviating neonate pain. Pharmacologic treatments in the neonate have been well established. Pharmacologic and nonpharmacologic interventions can be used in conjunction to increase the efficacy of analgesia. PMID- 30447814 TI - Neuroprotective Care of Extremely Preterm Infants in the First 72 Hours After Birth. AB - Birth at extremely low gestational ages presents a significant threat to infants' survival, health, development, and future well-being. After birth, a critical period of brain development must continue outside the womb. Neuro-supportive and neuroprotective family centered developmental care for and standardized care practices for extremely preterm infants have been shown to improve outcomes. Neuroprotective interventions must include a focus on the emotional connections of infants and their families. Being in skin-to-skin contact with the mother is the developmentally expected environment for all mammals and is especially important for supporting physiologic stability and neurodevelopment of preterm infants. PMID- 30447815 TI - Neonatal Abstinence Syndrome: An Uncontrollable Epidemic. AB - There is an uncontrollable epidemic of drug abuse, with the misuse of opioids the most alarming. Along with the increase in opioid abuse, there exists a concomitant upsurge in the number of neonates experiencing neonatal abstinence syndrome (NAS) due to the effects of the mother's withdrawal from the drug. Neonates experiencing NAS exhibit various nervous system, gastrointestinal, and respiratory untoward symptoms. Diagnosis is determined by taking an accurate maternal history and assessment of clinical signs and symptoms. Clinical management strategies include pharmacologic and nonpharmacologic therapies. Nursing care is evidence based, includes nonpharmacologic therapies, and focuses on prevention and support. PMID- 30447816 TI - Neonatal Transport: Current Trends and Practices. AB - Since the inception of organized neonatal transport in the 1940s, advances in clinical care and technology have made the neonatal intensive care unit even more mobile in terms of care delivery. There currently exists an emphasis on quality metrics and simulation-based training for transport team members to achieve high levels of individual and team competence. Emerging therapies such as active cooling for neuroprotective hypothermia and high-frequency ventilation provide evidence-based care in the transport environment to enhance clinical outcomes. Accreditation of neonatal transport programs is now embraced as an indicator of competency and compliance with transport standards. PMID- 30447817 TI - Erratum. PMID- 30447818 TI - Neonatal Nursing: Clinical Concepts and Practice Implications. PMID- 30447819 TI - A reply to "Hormonal contraception, depression, and academic performance among females attending college in the United States". PMID- 30447820 TI - Corrigendum to "Diverse toxicological risks of PAHs in surface water with an impounding level of 175 m in the Three Gorges Reservoir Area, China" [Sci. Total Environ. 580(2017) 1085-1096]. PMID- 30447821 TI - The Obesity Epidemic and Bariatric Trends. AB - The United States has experienced a significant increase in obesity over the past several decades, including a substantial increase in obesity-related comorbidities, such as type 2 diabetes, hypertension, heart disease, and obstructive sleep apnea. With obesity reaching epidemic proportions, there has been an increasing need for surgical intervention as a treatment option. Bariatric procedures have not only contributed to the significant weight loss a patient may experience but they have also had a profound effect on the decrease of weight-related comorbidities. PMID- 30447822 TI - Face and Neck Lifting After Weight Loss. AB - After massive weight loss, deflation of the tissues and loss of skin elasticity in the face and neck can result in the appearance of accelerated facial aging. Surgical facial rejuvenation can be successfully performed with several modifications. Proper preoperative counseling and expectation management regarding staged or ancillary procedures is recommended. Wide undermining of the face and neck, and extended postauricular incisions are required to allow for mobilization of excess skin and access to the mobile superficial musculoaponeurotic system (SMAS). Fat transfer into the deep malar compartment for midface volumizing is helpful. Treatment of the SMAS and platysma are universally necessary. PMID- 30447823 TI - Common Complications and Management After Massive Weight Loss Patient Safety in Plastic Surgery. AB - This article discusses strategies to prevent and manage the most common complications seen in body contouring surgery. General approaches to avoidance and treatment of these complications are addressed, including wound dehiscence, delayed wound healing, seroma, hematoma, infections of the surgical or remote sites, lymphedema, suture extrusion, and fat necrosis. Procedure-specific complications and pearls to avoiding complications in these cases are presented. Difficult problems, such as management of the disappointed patient, also are discussed. PMID- 30447825 TI - Safety in Body Contouring to Avoid Complications. AB - Body contouring after weight loss is becoming more prevalent. An appropriate systematic approach that starts from the first consultation needs to focus on residual comorbidities and weight of the patient. A thorough discussion about potential outcomes manages expectations. Preoperative optimization with smoking, herbal cessation, and nutritional assessment is mandatory. Planned staged approach minimizes lengthy procedures associated with increased postoperative morbidity. In the operating room, appropriate ambient temperature, positioning of the patient, and continuous discussion between surgeon and anesthesiologist prevent further complications. Careful transition to postoperative care with early ambulation and use of compressive garments add to an approach to minimize postoperative complications. PMID- 30447824 TI - Patient-Reported Outcome Measures: BODY-Q. AB - Patient-reported outcome measures (PROMs) are questionnaires designed to measure outcomes of importance to patients from their perspective. The BODY-Q is a PROM designed to measure outcomes in weight loss and/or body contouring surgery. To develop the BODY-Q, a literature review, 63 patient interviews, 22 cognitive interviews, and input from 9 clinical experts were used to develop a conceptual framework that covers 3 broad domains: appearance concerns, health-related quality of life, and experience of care. For each aspect of the framework, multiple independently functioning scales were developed. PMID- 30447826 TI - Pain Management and Body Contouring. AB - Body contouring procedure is a catchall that includes mastopexy, abdominoplasty, liposuction, and lower body lift. It is well known that optimal postoperative pain control decreases hospitalization length of stay and promotes early ambulation, which in turn decreases the incidence of complications. There have been many innovations in pain control beyond opiate medications, including prolonged administration of local anesthesia, regional blocks, and the use of a multimodal regimen which utilizes nonopiates. All approaches aim to decrease oral or intravenous opiate use and, therefore, encourage faster return to normal bowel function and decreased risk of addiction. In this article, the authors focus on opiate alternatives. PMID- 30447827 TI - Abdominal Contouring and Combining Procedures. AB - The abdomen is the most common area of concern among patients with massive weight loss (MWL). Abdominal contouring techniques in the MWL population include panniculectomy, standard abdominoplasty, fleur-de-lis abdominoplasty, reverse abdominoplasty and various combinations of these techniques as part of circumferential procedures such as, circumferential abdominoplasty, and lower body lift. The authors believe that the optimal surgical approach to the abdomen is an integration of the patient aesthetic preferences and the surgeon assessment and experience. The authors recommend to limit total body reconstruction of MWL patients to 2 stages, and include the abdominal area in the first stage. PMID- 30447828 TI - Fleur-de-lis Abdominoplasty and Neo-umbilicus. AB - Body contouring for patients with massive weight loss may demand not only lifting but also some extent of central body tightening to achieve complete tissue readjustment. Although the fleur-de-lis procedure usually achieves nice contouring results, poor visible scars, including umbilical complications, have restricted the indications for the anterior vertical approach. The purpose of this article is to present the authors' experience with the inner scar umbilical reconstruction, enhancing overall results for vertical abdominoplasties. The inner scar umbilicus is a simple, safe, and reproducible technique, presenting low complication rates with sustainable and natural results. PMID- 30447829 TI - Buttock Lifting: The Golden Rules. AB - There are some precise rules to succeed with a buttock lift. The article begins with a reminder about the ideal buttock shape. It explains the different quality of skin that is essential to be aware of at the back part of the body. Afterward it gives the tightening rule and the author's application in buttock lift. The markings and the cutting principles are described in detail. At the end, the article describes the problems of volume at the buttocks and about the author's new flap that is useful to avoid violin deformation. The article finishes with some examples of surgeries. PMID- 30447830 TI - Breast Reshaping After Massive Weight Loss. AB - The technique of dermal suspension, parenchymal reshaping mastopexy is a useful procedure for patients with massive weight loss with a typical presentation. The operation is tailored to the individual deformity, powerfully reshapes the breast, and can be safely combined with other commonly performed procedures. It is long-lasting and associated with minor complications that are easily treated in an office setting. PMID- 30447831 TI - Bra-Line Back Lift. AB - Upper back deformity caused by aging or fluctuations in weight are cosmetically and functionally unappealing to patients. Natural upper torso adherence zones create tether points that lead to horizontal and vertical laxity. Bra-line back lift is a versatile technique that can be used in any individual showing signs of redundant skin and adiposity. A 3-layered space-obliterating suture closure method prevents seroma and eliminates need for drain. Predictable outcomes correcting laxity from neck to lower back can be achieved. Gentle learning curve yields consistent and predictable results. Patient acceptance of the procedure, its results, and satisfactory morbidity rates have been universal. PMID- 30447832 TI - Arm Contouring in the Massive-Weight-Loss Patient. AB - Brachioplasty is an increasingly popular procedure performed for improved arm contour in the massive-weight-loss population. There are challenging deformities presented in this population, such as redundant skin, posterior arm lipodystrophy, and loosening of fascial layers of the upper arm and chest wall that must be addressed to achieve successful contour of the arms. Common complications can be minimized with meticulous technique and knowledge of surgical anatomy. Additionally, brachioplasty can be combined with liposuction of the posterior arm as a safe and effective method for arm contouring without a higher risk of complications. PMID- 30447833 TI - Patient Evaluation and Surgical Staging. AB - Comprehensive evaluation of the massive-weight-loss patient is a key factor to minimize complications while optimizing surgical outcomes. Special attention is given to medical and weight loss history, nutritional status, and physical examination. Massive-weight-loss patients often present with multiple areas of concern and therefore benefit from staged procedures. Staging requires knowledge on how the tissues are affected by each procedure and an understanding of the patient's priorities and goals. PMID- 30447835 TI - Body Contouring After Massive Weight Loss. PMID- 30447834 TI - Vertical Medial Thigh Contouring. AB - Excess thigh laxity is a problem for many patients following significant weight loss. Thigh laxity has both vertical and horizontal components that require correction to optimize the aesthetic appearance of the thigh. The vertical vector is best corrected first with a lower body lift or extended abdominoplasty. The remaining loose skin in the medial thigh can then be removed using a horizontal vector resulting in a vertical incision. Residual vertical skin excess is also removed parallel to the groin crease. This article describes the author's surgical approach and management of medial thigh deformity in the significant weight loss patient. PMID- 30447836 TI - Large-Gland Proliferations of the Prostate. AB - Large-gland proliferations of the prostate have gained considerable attention in the past decade. The differential diagnosis is quite broad but can be refined using histologic criteria and, sometimes, immunostains. Pathologists have come to realize that cribriform and intraductal as well as ductal carcinomas are particularly aggressive patterns, and should name them in diagnostic reporting when present. PMID- 30447837 TI - Updates on the Genetics and Molecular Subtypes of Urothelial Carcinoma and Select Variants. AB - Urothelial carcinoma is a morphologically and genomically heterogeneous disease that exhibits a wide spectrum of morphologic features and molecular alterations and subtypes. Classic urothelial carcinoma (not otherwise specified) is the most common tumor type that develops in the urinary bladder but many, well-documented, variant histologies are commonly encountered in approximately one-third of invasive urothelial carcinoma, including squamous, glandular, micropapillary, sarcomatoid, small cell/neuroendocrine, clear cell, lymphoepithelioma-like, and plasmacytoid types, among others. In this review, we provide an update on the molecular advances in urothelial carcinoma and some of its variant histologies. PMID- 30447838 TI - Recognizing Hereditary Renal Cancers Through the Microscope: A Pathology Update. AB - A heightened understanding of hereditary renal cancer syndromes and their molecular basis has led to an increased awareness and recognition of these renal neoplasms by pathologists. Because a diagnosis of hereditary renal cell carcinoma has a profound impact on the patient and family members, when and how to raise such a suspicion via pathologic assessment has become an important yet very challenging task. This review discusses key clinicopathologic, immunohistochemical, and genetic characteristics of hereditary renal cancer syndromes, and important differential diagnostic challenges, emphasizing recent pathologic and molecular advances. PMID- 30447839 TI - A Contemporary Review of Common Adult Non-germ Cell Tumors of the Testis and Paratestis. AB - This article provides a comprehensive review of non-germ cell tumors of the testis and paratestis in adults, incorporating the latest 2016 World Health Organization updates. Clinical features, gross pathologic findings, key morphologic details, immunohistochemical profiles, and differential diagnoses are covered, with an emphasis on how to resolve commonly encountered, and sometimes difficult, differential diagnoses. PMID- 30447840 TI - Updates on Grading and Staging of Prostate Cancer. AB - Since its development between 1966 and 1977, the Gleason grading system has remained one of the most important prognostic indicators in prostatic acinar adenocarcinoma. The grading system was first majorly revised in 2005 and again in 2014. With the publication of the 8th edition of the American Joint Committee on Cancer TNM staging manual in 2018, the classification of prostate cancer and its reporting have further evolved and are now included as part of staging criteria. This article reflects the aspects that are most influential on daily practice. A brief summary of 3 ancillary commercially available genomic tests is also provided. PMID- 30447841 TI - Contemporary Grading and Staging of Urothelial Neoplasms of the Urinary Bladder: New Concepts and Approaches to Challenging Scenarios. AB - Grading and staging of urothelial neoplasm are the most crucial factors in risk stratification and management; both necessitate optimal accuracy and consistency. Several updates and recommendations have been provided though recent publications of the 4th edition of the World Health Organization classification, the 8th edition of the American Joint Committee on Cancer staging system, and the International Consultation on Urological Diseases-European Association of Urology updates on bladder cancer. Updates and recent studies have provided better insights into and approaches to the challenging scenarios in grading and staging of urothelial neoplasm; however, there remain aspects that need further investigation and refinement. PMID- 30447842 TI - Updates in Pathologic Staging and Histologic Grading of Renal Cell Carcinoma. AB - The most important prognostic parameter in renal cell carcinoma is tumor stage. Although pathologic primary tumor (pT) categories are influenced by tumor size (pT1-pT2), critical elements (>=pT3) are dictated by invasion of structures, including renal sinus, perinephric fat, and the renal vein or segmental branches. Because this invasion can be subtle, awareness of the unique characteristics of renal cell carcinoma is critical for the pathologist to aid in clinical decision making. This review addresses challenges in pathologic stage and grade reporting and updates to the World Health Organization and American Joint Commission on Cancer classification schemes. PMID- 30447843 TI - Updates in Staging and Reporting of Testicular Cancer. AB - The American Joint Committee for Cancer eighth edition staging manual incorporated several critical changes regarding staging of testis germ cell tumors, and these changes are summarized and discussed in this article. Further challenges, however, remain, and these are also highlighted. PMID- 30447844 TI - "Man in Istanbul" Lesions of the Urinary Tract (Known Entities in an Unusual Context): Melanoma, Carcinoid Tumors, Epithelioid Angiosarcoma. AB - Certain tumors are more difficult to recognize when they present in an unusual location. Within the urinary tract, primary melanomas, carcinoid tumors, or epithelioid angiosarcoma could present diagnostic challenges due to their infrequent occurrence. This article emphasizes the clinical and histopathologic features of these entities and their differential diagnoses including the immunophenotype and their prognoses. PMID- 30447845 TI - Mesenchymal Neoplasms of the Genitourinary System: A Selected Review with Recent Advances in Clinical, Diagnostic, and Molecular Findings. AB - Mesenchymal neoplasms of the genitourinary (GU) tract often pose considerable diagnostic challenges due to their wide morphologic spectrum, relative rarity, and unexpected incidence at GU sites. Soft tissue tumors arise throughout the GU tract, whether from adventitia surrounding or connective tissues within the kidneys, urinary bladder, and male and female genital organs. This selected article focuses on a subset of these lesions, ranging from benign to malignant and encompassing a range of patterns of mesenchymal differentiation, where recent scholarship has lent greater insight into their clinical, molecular, or diagnostic features. PMID- 30447846 TI - Genitourinary Pathology Reporting Parameters Most Relevant to the Medical Oncologist. AB - Pathologic variables play an important role in prognostication in urologic malignancies. Histologic subtype, histologic grade, and anatomic extent of disease (pathologic tumor and nodal staging) influence treatment decisions in both the adjuvant and metastatic settings. This article discusses treatment paradigms for the most common urologic malignancies, followed by the evidence base to support the relationship between pathologic assessment and decision making by the medical oncologist. PMID- 30447847 TI - Urologic Pathology: Key Parameters from a Urologist's Perspective. AB - Prostate cancer, bladder cancer, and kidney cancer represent the 3 most common urologic malignancies, and form a heterogenous group of disease processes, with a wide range of pathologic features. As a urologist, a strong understanding of the pathologic features of urologic malignancies is essential to prognosticate and counsel patients and to determine the most effective course of treatment. This review discusses the pathologic features of prostate, bladder, and kidney cancer, and examines how detailed pathologic reporting is critical to today's practicing urologist. PMID- 30447848 TI - Updates in Urologic Pathology: Emerging Areas, Staging, Grading, Unexpected Entities, and Clinical Significance. PMID- 30447850 TI - To Invest or Divest - Tough Choices in the Wake of VEST. PMID- 30447849 TI - Analysis of hospitalizations by cardiovascular disease in the population with diabetes in Spain. AB - OBJECTIVES: Diabetes mellitus is associated with a marked increase in cardiovascular disease. In this study, we analysed the prevalence of diabetes mellitus in hospitalised patients in Spain in 2015 and the burden of associated cardiovascular disease. METHODS: By analysing the 2015 minimum basic data set (MBDS) of the Spanish Ministry of Health, we included all patients discharged with a diagnosis of diabetes mellitus. We describe the epidemiological characteristics, distribution by the various hospital departments and the presence of cardiovascular disease. RESULTS: In 2015, there was 3,727,583 hospital discharges in Spain, 619,188 of which involved patients with diabetes (16.7%), 56.8% of whom were men and with a mean age of 73.2years. The prevalence of cardiovascular disease was 40.8%, distributed among congestive heart failure (20.1%), cerebrovascular disease (10.3%), coronary artery disease (9.4%) and peripheral arterial disease (9.1%). Most of the patients were admitted to internal medicine (34.2%), cardiology (9.5%) and general surgery (8.9%) departments. The mean overall stay was 8.2days, the readmission rate at 30days was 14%, and the mortality rate was 6.8%. The patients hospitalized in internal medicine had higher severity levels (3-4) than those hospitalized in other medical departments (41.9% vs. 31.6%, respectively; P<.01) and those hospitalized in surgical departments (11.2%; P<.01). CONCLUSIONS: Diabetes mellitus is a significant comorbidity for patients hospitalized in internal medicine. A significant proportion of these patients present cardiovascular disease, mostly heart failure. PMID- 30447851 TI - The trials and tribulations of urgent lung allocation. PMID- 30447852 TI - Increase in short-term of rejection in heart transplant patients receiving granulocyte colony-stimulating factor. PMID- 30447853 TI - Pirfenidone causes false-positive urine benzodiazepine results: Implications for patients with pulmonary fibrosis. PMID- 30447854 TI - Effectiveness of mirror therapy in phantom limb pain: A literature review. AB - INTRODUCTION: Phantom limb pain (PLP) is a type of neuropathic pain that affects the territory of an amputated limb or other surgically removed body parts. Between 60% and 90% of amputees suffer from PLP during follow-up. There are a range of therapeutic options for PLP, both pharmacological (gabapentin, amitriptyline, tricyclic antidepressants, etc) and non-pharmacological (transcutaneous electrical nerve stimulation, hypnosis, acupuncture, etc). A widely accepted hypothesis considers PLP to be the consequence of postamputation cortical reorganisation. New treatment approaches, such as mirror therapy (MT), have been developed as a result of Ramachandran's groundbreaking research in the 1990s. This review analyses the current evidence on the efficacy of MT for treating PLP. DEVELOPMENT: We performed a literature review of publications registered from 2012 to 2017 on the CINAHL, Cochrane, Scopus, and PubMed (including Medline) databases Using the descriptors "phantom limb" and "mirror therapy." We identified 115 publications addressing MT in PLP. Of these, 17 (15%) contributed useful information for pooled analysis. CONCLUSIONS: MT seems to be effective in relieving PLP, reducing the intensity and duration of daily pain episodes. It is a valid, simple, and inexpensive treatment for PLP. The methodological quality of most publications in this field is very limited, highlighting the need for additional, high-quality studies to develop clinical protocols that could maximise the benefits of MT for patients with PLP. PMID- 30447855 TI - Effect of exposure to low doses of ozone on interleukin 17A expression during progressive neurodegeneration in the rat hippocampus. AB - INTRODUCTION: Chronic exposure to low doses of ozone causes oxidative stress and loss of regulation of the inflammatory response, leading to progressive neurodegeneration. OBJECTIVE: We studied the effect of chronic exposure to low doses of ozone on IL-17A concentration and expression in neurons, microglia, astrocytes, and T cells in the rat hippocampus. METHODS: We used 72 Wistar rats, divided into 6 groups (n=12): a control group (no ozone exposure) and 5 groups exposed to ozone (0.25ppm, 4h daily) for 7, 15, 30, 60, and 90 days. We processed 6 rats from each group to quantify IL-17A by ELISA; the remaining 6 were processed for immunohistochemistry (against IL-17A and GFAP, Iba1, NeuN, and CD3). RESULTS: The ELISA study data showed a significant increase in IL-17A concentrations in the 7-, 15-, 30-, and 60-day exposure groups, with regard to the control group (P<.05). Furthermore, they indicate that hippocampal neurons were the cells showing greatest immunoreactivity against IL-17A between 60 and 90 days of exposure to ozone; we also observed an increase in activated astrocytes in the 30- and 60-day exposure groups. CONCLUSION: Exposure to ozone in rats induces an increase in IL-17A expression, mainly in hippocampal neurons, accompanied by hippocampal astrocyte activation during chronic neurodegeneration, similar to that observed in Alzheimer disease in humans. PMID- 30447856 TI - MRI findings in pediatric neuromyelitis optica spectrum disorder with MOG antibody: Four cases and review of the literature. AB - BACKGROUND: Myelin oligodendrocyte glycoprotein antibodies (MOG Abs) are frequently detected in pediatric acquired demyelinating syndrome (ADS), and MOG Ab-positive ADS differs from multiple sclerosis (MS) and aquaporin-4 (AQP4)-Ab positive neuromyelitis optica spectrum disorder (NMOSD) in terms of age distribution, therapeutic response, and prognosis. METHODS: Based on medical records, we retrospectively evaluated patients with MOG-Ab-positive NMOSD treated in the acute phase who were followed up in the chronic phase at our hospital from January 2011 to December 2017. RESULTS: The patients comprised two boys and two girls aged 3-12 (median, 8) years. Peak MOG-Ab titers were 1:2048 to 1:32768 (median, 1:10240), and the relapse rate ranged from 0 to 1.25 times/year (median, 0.59 times/year); no sequelae were observed in any cases. Lesions other than those of optic neuritis were distributed at the cortex in one patient, subcortical white matter in four, deep white matter in three, and brainstem in one, all of which were disseminated lesions. No lesions were found in the corpus callosum, periventricular white matter, diencephalon, and regions adjacent to the third and fourth ventricles. The lesions tended to be asymptomatic, and two patients aged >5 years had well-demarcated lesions. CONCLUSION: All the patients showed disseminated lesions in the subcortical region to deep white matter, which were different from those found in MS and AQP4-Ab-positive NMOSD and were consistent with the characteristics of brain lesions in MOG-Ab-positive ADS, including other disease types. PMID- 30447857 TI - Types of antiseptics, presentations and rules of use. AB - Antiseptics are chemical substances that when applied topically onto intact skin, mucous membranes or wounds partially or completely reduces the population of living microorganisms in those tissues. Different types of antiseptics are available - those most commonly used in clinical practice being alcohols, iodinated compounds and chlorhexidine. When using an antiseptic, consideration is required of its spectrum of antimicrobial activity, latency, residual effects, possible interferences of the presence of organic material with the activity of the antiseptic, its side effects, compatibility with other antiseptics, and cost. PMID- 30447858 TI - Neuroprotective and antihyperalgesic effects of orexin-A in rats with painful diabetic neuropathy. AB - AIM OF STUDY: Diabetes mellitus is related to the development of neuronal tissue injury in different peripheral and central nervous system regions. A common complication of diabetes is painful diabetic peripheral neuropathy (PDN). We have studied the neuroprotective and anti-nociceptive properties of neuropeptide orexin-A in an animal experimental model of diabetic neuropathy. METHODS: All experiments were carried out on male Wistar rats (220-250 g). Diabetes was induced by a single intraperitoneal injection of 55 mg/kg (i.p.) streptozotocin (STZ). Orexin-A was chronically administrated into the implanted intrathecal catheter (0.6, 2.5 and 5 nM/L, daily, 4 weeks). The tail-flick and rotarod treadmill tests were used to evaluate the nociceptive threshold and motor coordination of these diabetic rats, respectively. Cleaved caspase-3, Bax, Bcl2 and the Bax/Bcl-2 ratio, as the biochemical indicators of apoptosis, were investigated in the dorsal half of the lumbar spinal cord tissue by western blotting method. RESULTS: Treatment of the diabetic rats with orexin-A (5 nM/L) significantly attenuated the hyperalgesia and motor deficit in diabetic animals. Furthermore, orexin-A (5 nM/L) administration suppressed pro-apoptotic cleaved caspase-3 and Bax proteins. Also, orexin-A (5 nM/L) reduced the expression of Bax/Bcl-2 ratio in spinal cord dorsal half of rats with PDN. CONCLUSIONS: Altogether our data suggest that the orexin-A has anti-hyperalgesic and neuroprotective effects in rats with PDN. Cellular mechanisms underlying the observed effects may, at least partially, be related to reducing the neuronal apoptosis. PMID- 30447859 TI - Guidelines of the Polish Medical Society of radiology for the routinely used MRI protocol in patients with multiple sclerosis. AB - Magnetic resonance imaging is widely used in diagnosing multiple sclerosis as a basic method for detecting and monitoring the disease. INTRODUCTION: Polish Medical Society of Radiology presents the second version of the recommendations for the routinely conducted MRI in multiple sclerosis, which include new data and practical remarks for radiographers and radiologists. The recommended protocol aims to improve the imaging procedure and, most importantly, to standardize conducting MRI scans in all MRI departments. This is crucial for monitoring the patients with MS, which directly contributes to essential clinical decisions. AIM OF THE GUIDELINES: Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disease of the central nervous system (CNS) with its etiology still unknown. The fundamental requirement of the disease is the CNS destruction process disseminated in time (DIT) and space (DIS). MR imaging detects focal lesions in white and gray matter with high sensitivity and is the best way to assess brain atrophy in MS patients. It is unquestionably the best diagnostic tool to follow-up the clinical course of the disease and treatment of MS patients. However, to achieve a diagnosis based on MRI scans, and follow-up MS patients according to the latest standards, an MRI scan has to meet certain quality criteria that are the subject of this work. PMID- 30447860 TI - Determination of residual poly diallyldimethylammonium chloride (pDADMAC) in monoclonal antibody formulations by size exclusion chromatography and evaporative light scattering detector. AB - The cationic polyelectrolyte pDADMAC is widely used in biopharmaceutical industry as a flocculating agent to enhance clarification throughput and downstream filtration operations. Due to the possible toxicity, pDADMAC should be assessed for an acceptable residual level to ascertain the safety of the product to patients. The strong protein-polyelectrolyte interaction, however, can negatively affect sensitivity and accuracy of measurements. This paper reports on the application of size exclusion (SE) chromatography coupled to evaporative light scattering detector (ELSD) to the quantitative determination of pDADMAC in monoclonal antibody formulations and in process intermediates during downstream purification. The SE chromatography was performed under isocratic condition with a mobile phase consisting of 0.1% TFA in water (90%) and acetonitrile (10%) at a flow rate of 0.4 ml/min. A quantification limit (S/N = 10) of 0.85 ppm was achieved in sample matrix, which is sufficiently low for the trace analysis of this compound in protein-containing samples. PMID- 30447862 TI - Aging bodies, minds and selves: Representations of senile dementia in Japanese film. AB - This paper examines depictions of senility and related forms of age-related decline in Japanese film, literature, and other media, relative to their popular representation in North America. While medicalized concepts of senile dementia, especially Alzheimer's disease (Arutsuhaima sho), are well known in Japan, symptoms of deterioration among the elderly are still commonly framed as "boke"-a folk-medical category associated more with a loss of social graces than with cognitive decline. Whereas senile dementia has most often been depicted in North America as a condition entailing a horrifying "loss of self," or even a loss of humanity, responses in Japan point to a different range of concerns. Japanese discourse on senility has commonly expressed anxieties over the difficulties faced by caregivers or the potential for senile elders to engage in socially disruptive behavior, but representations of senility that call into question the selfhood or humanity of the elder are exceedingly rare. I argue that social and cultural factors can help explain why people in Japan might be less inclined to interpret the kinds of changes wrought by dementing diseases in terms of a diminishment of self. PMID- 30447861 TI - Smart eldercare in Singapore: Negotiating agency and apathy at the margins. AB - Around the world, smart technologies are being embraced as a cost-efficient means of enabling the elderly to be cared for in new, more non-proximate ways. They can facilitate ageing-in-place, and have the potential to relieve pressure on the providers of care. Yet, the fact is that the interface of technology and society is a negotiated one. These negotiations are most acutely felt when technology is used to supplement the hitherto human-centred process of caregiving, especially amongst "marginalised" societal cohorts, like the elderly. With this, there is a need to better understand the ways in which smart eldercare technologies are used, misused, or not used by those that they are designed to benefit. Drawing on qualitative data derived from triallists of three smart eldercare technologies in Singapore, this paper explores how the lived experience of smart eldercare can cause agentic and apathetic behaviours towards technology to manifest. Specifically, we identify four expectations - of understanding, response, compliance and appreciation - that undermine the potential beneficence of smart eldercare. To conclude, we emphasise the need for more collaborative, and more contextually-sensitive, approaches to the design, development and implementation of smart eldercare solutions. PMID- 30447863 TI - A comparison of stepgrandchildren's perceptions of long-term and later-life stepgrandparents. AB - BACKGROUND: Multi-generational steprelationships are relatively common, and yet little is known about stepgrandparent-stepgrandchild relationships. The quality of steprelationships is relevant to understanding intergenerational support for older divorced and remarried adults. OBJECTIVES: The purpose of this study is to examine and compare stepgrandchildren's perceptions of two types of intergenerational step-relationships - long-term stepgrandparents who joined the stepfamily before stepgrandchildren were born and later-life stepgrandparents who joined stepfamilies when they were older. RESEARCH DESIGN AND METHODS: Grounded theory methods were used to interview 48 adult stepgrandchildren who had 44 long term stepgrandparents and 28 later-life stepgrandparents. RESULTS: Long-term stepgrandparents more closely resembled biological grandparents' relationships with stepgrandchildren than did later-life stepgrandparents, largely because of conditions attributable to intergenerational dynamics associated with remarriage timing, shared histories, and linked lives with other kin. Middle-generation parents gatekept more in long-term stepfamilies - later-life stepgrandchildren had greater autonomy in relationships with new stepgrandparents and everyone in later-life stepfamilies experienced family structural changes concurrently. Long term stepgrandparents were defined as kin more often than later-life stepgrandparents. Long-term relationships were often perceived as positive and emotionally close. DISCUSSION AND IMPLICATIONS: Later-life stepgrandchildren experience more intergenerational transitions than long-term stepgrandchildren. Appreciating and understanding the implications of different pathways to stepgrandparenthood will enhance science and practice with older stepfamily couples and intergenerational stepfamilies. PMID- 30447864 TI - Making meaning of financial scarcity in old age. AB - The purpose of this paper is twofold: first, we explore how older people (aged 69 to 85 years) living on the edge of relative poverty experience their everyday lives, and second, we investigate how they cope with their financial situation. We examine these aspects through 16 life story interviews to understand which paths these older people believe have led them to where they are today. First, we show how the older people highlight events or decisions in their life that mainly have an individual origin placing the responsibility of their current financial situation on themselves. We argue that these accounts reflect a change in the discourse on poverty; a transformation from poverty as collective destiny to poverty as the result of individual failure. Second, we show how these older people's control strategies vary across their life spans. In earlier phases of their lives, these older people attempted actively to improve their financial situation; however, in their old age, they focus more on adapting to and accepting the situation because their advanced age makes it difficult for them to use active coping strategies to overcome financial scarcity. Third, we argue that the imprints the interviewees received growing up in financial scarcity during the Second World War and the postwar years may have instilled them with silence and modesty, thus they are likely to adjust stoically. PMID- 30447865 TI - Unequal access: Applying Bourdieu's practice theory to illuminate the challenges of ICT use among senior citizens in Singapore. AB - The following article examines the application of Pierre Bourdieu's Practice Theory in accounting for ongoing disparities in accessing information and communications technology (ICT) in Singapore among senior citizens. As the relevance of Practice Theory is increasingly recognized among both scholars of ICT and ageing studies in modern societies, this article seeks to further contextualize and demonstrate its theoretical relevance and explanatory potential within developed, multicultural and rapidly ageing societies such as Singapore. Qualitative data collected from focus group discussions and personal in-depth interviews are analyzed to gain insights into how older adults above the age of 55 in Singapore perceive and use ICT. While it is argued that unequal access to forms of capital - be they social, cultural, economic, symbolic or bodily - has an obvious role in impacting the construction of one's habitus within the field of ICT usage, our findings reveal that not all forms of capital exert a similar impact on the accessibility of ICT. The discussions and interviews suggest that social and cultural capital play a relatively more fundamental role. While the increasingly easy-to-use and economically affordable nature of ICT has made it more accessible, our findings indicate that many older persons in Singapore still lack the necessary educational backgrounds, linguistic skills and supportive social networks that facilitate easier access. Such insights ultimately have implications on the nature of efforts by the state to create a more digitally inclusive society in Singapore. PMID- 30447866 TI - Health, illness and frailty in old age: a phenomenological exploration. AB - The aim of this paper is to subject the clinical classification of frailty to scrutiny through exploring, via a phenomenological lens, the lived experiences of older people who meet the objective, or clinical, criteria of frailty. Drawing on a range of published research that explores the heterogeneous experiences of embodied ageing, the paper highlights the continuity of phenomenological structures of experience across successful ageing, normal ageing and frailty, suggesting the permeability and contestability of the boundaries between them and highlighting the complexity of health and illness in old age. Such data suggests a need to question the perception of frailty as something both apart from 'normal' ageing, and constitutive of frailed or failed ageing, and challenges the construction of the third age/fourth age polarity that underpins much of the meaning accorded to old age today. PMID- 30447867 TI - Unyielding selflessness: Relational negotiations, dementia and care. AB - This article addresses how couples within care relationships engage in negotiations when mutual selflessness is the relational starting point. Evaluation of hypothetical dementia care scenarios offers insights into pressures upon joint decision-making. Strategic interaction models such as 'the prisoner's dilemma' focus on how a person's pursuit of self-interested preferences might be impeded by the self-interest of another person. Scrutiny of negotiations within care relationships demonstrates that selflessness can also present significant challenges, as combined strategies of altruistic intent mean that neither party is able to prioritise the other person successfully. Moreover, sociocultural pressures associated with illness and care mean that alternative strategic options are difficult to pursue. Care deliberations, predicated on mutual selflessness, can therefore present a static and unyielding interactional context for both parties to endure. The exploration of relational negotiations highlights the requirement to understand the complex breadth of factors that shape experience. This can accordingly enhance academic understandings of the relational basis of dementia and care, as well as informing the approaches of policymakers. PMID- 30447868 TI - 'Third Age' under neoliberalism: From risky subjects to human capital. AB - In this paper, I trace the discursive evolution of the phrase 'Third Age.' Focusing on its increasing appearances in lifestyle articles within popular Anglo American print media during the past three decades, I argue that 'Third Age' operates as a category of neoliberal governance. More specifically, through the analysis of 'Third Age' I uncover a shift in the kind of subjectivity ageing subjects are called upon to cultivate-from subjects imbued with risk for themselves and for society to savvy entrepreneurs who take risks and diligently maximize their self-worth. This shift from risk-oriented to entrepreneurial subjects, I suggest, is accompanied by a temporal modification relating to the neoliberal imperative to invest in oneself. One of the ways neoliberal governance operates is through a cost-benefit calculus where subjects are encouraged to make investments in the present with the promise of future returns. My analysis reveals that from the mid-2000s onwards this future-oriented approach is replaced with a 'here and now' temporality, whereby ageing subjects are incited to make investments in the present as a form of living in the moment, rendering the future less relevant. This finding challenges existing literature on neoliberal rationality that underscores its future-oriented temporality. PMID- 30447869 TI - Problematizing the age friendly cities and communities program in Toronto. AB - This article contributes to the literature on Age Friendly Cities and Communities (AFCC) through a poststructural policy analysis of the program in Toronto. The purpose is to propose an approach, rooted in the study of public policy, that can offer a political interrogation into the problems plaguing AFCCs in practice. The approach centres on a basic question: what problem are AFCCs in Toronto intended to solve? A discourse analysis is undertaken on this problematization, using Toronto's age-friendly policy and 77 qualitative interview transcripts with policy actors as key texts. The findings suggest a dominant discursive practice where AFCCs are used to address the problem of costly seniors rather than the problem of inaccessible environments. However, alternative discursive practices rooted in the rights of senior citizens to access services and amenities in environments are also highlighted through the analysis. AFCC policy is thus flexible enough to be used by different political projects and poststructural policy analysis is useful for teasing out these projects, for understanding the problems that plague AFCCs, as well as for informing rights-based alternatives. PMID- 30447870 TI - "Small places" of ageing in a high-rise housing neighbourhood. PMID- 30447871 TI - The dog that didn't bark: The challenge of cross-cultural qualitative research on aging. AB - The paper addresses the problem of cultural proximity in qualitative cross cultural research on aging, presenting insights into a methodology of systematic 'estrangement'. Based on interdisciplinary research on the social time orientations of elderly people in Germany, Hong Kong, and the US, we discuss the question of how shared identities and taken-for-granted assumptions may bias the findings in comparative aging studies. With Alfred Schutz's phenomenological concept of 'lifeworld' as a methodological device, we focus on the issue of the diverging 'systems of relevance' that each of the national project teams obviously referred to when gathering and interpreting the data. The paper suggests that, by way of organizing an interactive research setting that is open for the reciprocity of perspectives, one of the major problems for cross-cultural research on aging may be overcome or at least mitigated. PMID- 30447873 TI - Longevity narratives: Darwinism and beyond. AB - The essay looks at longevity narratives as an important configuration of old age, which is closely related to evolutionary theories of ageing. In order to analyse two case studies of longevity published in the early twentieth century, the American psychologist G. Stanley Hall's book Senescence (1922) and the British dramatist Bernard Shaw's play cycle Back to Methuselah (1921), the essay draws on an outline of theories of longevity from the Enlightenment to the present. The analysis of the two case studies illustrates that evolutionary and cultural perspectives on ageing and longevity are ambivalent and problematic. In Hall's and Shaw's texts this is related to a crisis narrative of culture and civilization against which both writers place their specific solutions of individual and species longevity. Whereas Hall employs autobiographical accounts of artists as examples of longevity to strengthen his argument about wise old men as exclusive repositories of knowledge, Shaw in his vision of longevity as an extended form of midlife for both genders encounters the limits of age representation. PMID- 30447872 TI - Contours of "here": Phenomenology of space for assisted living residents approaching end of life. AB - Informed by theory from environmental gerontology, this study investigates how assisted living residents who are approaching end of life navigate and experience space. Since its development, environmental gerontology has moved beyond the concept of person-environment fit to encompass aspects of place attachment and place integration, processes by which inhabited impersonal space becomes a place of individual personal meaning and this person-place relationship evolves with changing needs. Our study is a secondary data analysis of in-depth interviews completed with the first 15 residents (mean age 88, range 65-103; 8 white and 7 black) recruited from four diverse assisted living communities in metropolitan Atlanta. Using interpretative phenomenological analysis, we identify five overarching themes within and across assisted living communities and their subthemes. Findings show that participants experience a neutral theme of shrinking space, negative themes of confinement and vulnerability, and positive themes of safety and intimacy. Results dovetail with other phenomenologically based environmental gerontology research from community-dwelling populations that indicate behavioral changes to accommodate aging and health decline. Findings have implications for interventions to improve place integration in AL and enhance residents' quality of life at end of life, including developing strategies to promote small meaningful journeys within context of shrinking life space. PMID- 30447874 TI - Imagining the 'baffling geography' of age. AB - This article explores later life as a special moment for the imagination, for persons of all ages. If we were to routinely ask ourselves what is the life we hope to be able to look back on, we would increase the likelihood that our ultimate life review would bring us deeper satisfaction. Why, then, do we not devote more attention to imagining our future lives and inviting that vision to help guide us, without which we deprive ourselves of contemplating a life of other possibilities. The article reviews the limited research which has been done on imagining old age, and relates this to data gathered over a twenty year period with an East German actress and activist, who engages with the study of her own aging as "reading a crime novel." PMID- 30447875 TI - Pushing for miracles, pulling away from risk: An ethnographic analysis of the force dynamics at Senior Summer Camps in Sweden. AB - With an ageing population and a discourse of active ageing guiding welfare policies, initiatives to engage older people in health promoting activities have been established. One growing phenomenon is Senior Summer Camps, arranged all over Sweden in beautiful natural environments close to water. Their main purpose is to enable older people to participate in outdoor activities in an institutionalized setting. Although many professionals consider acts of infantilization as highly inappropriate, research has shown that still this is frequently done in institutional settings targeting older people. This paper wish to contribute to this field of research. The objective is to study how the camp leaders handle the dilemma of on the one hand, wanting to push senior campers into participating in challenging activities, and on the other, needing to pull them away, to reduce risk and ensure their safety, as well as how senior campers experience alternately being pushed into and pulled away from activities. What strategies are used by the camp leaders to push the campers to challenge themselves without taking unnecessary risks, and what consequences do these strategies have for the campers? The study was conducted in the form of ethnographic observations at two different camps. During one week at each camp we stayed with the participants, alternately being a silent observer and listener in the background, and an active participant in conversations and activities. Narratives, direct quotes, descriptions and reflections were written down in a field diary that forms the empirical basis for the analysis. Various modes of pushing and pulling were identified and defined as cheering, tricking, compelling, monitoring and restricting. These different modes of pushing and pulling were analyzed as manifestations of force, exerted by the camp leaders within a certain age-based force dynamic that resulted in different responses among the campers, especially in terms of how they "did age" in relation to notions on autonomy and vulnerability. It is shown that manifestations of force involve the risk of putting the campers in a position of vulnerability, regardless of whether or not they are actually vulnerable. The main argument in this paper is that initiatives that in an institutionalized context aim to promote a prolonged health and well-being, targeting "older people" in a general sense, run the risk of getting the exact opposite result, namely instead learned vulnerability is implicitly promoted by removing or downplaying the agency and autonomy of the campers. PMID- 30447876 TI - Salvage surgery for a locally persistent or recurrent tumour in maxillary cancer patients who have undergone radiotherapy and concomitant intra-arterial cisplatin: implications for surgical margin assessment. AB - Limited information about salvage surgery is available for locally persistent and recurrent maxillary sinus cancers after the completion of chemoradiation therapy. Seventy-six maxillary sinus cancer patients who had undergone chemoradioselection using initial radiotherapy and concomitant intra-arterial cisplatin were screened retrospectively. Twenty-four of these patients who had a locally persistent or recurrent tumour were investigated. The 2-year overall survival rate of patients with maxillary sinus cancer of all types was 39.0% for those who underwent salvage surgery and 10.0% for those who did not. The 2-year overall survival rate of patients with maxillary sinus squamous cell carcinoma was 45.8% for those who underwent salvage surgery and 11.1% for those who did not. Furthermore, the 2 year local control and overall survival rates of patients with positive and negative surgical margins were 14.3% and 83.3% and 14.3% and 66.7%, respectively. There were significant differences in local control (P=0.004) and overall survival (P=0.005) regarding surgical margin status. Although salvage surgery for a locally persistent or recurrent maxillary sinus cancer is a feasible treatment, patients with positive surgical margins are more prone to local relapse. Therefore, surgical safety margins should be assessed thoroughly. PMID- 30447877 TI - Novel Biomedical Applications of Crosslinked Collagen. AB - Collagen is one of the most useful biopolymers because of its low immunogenicity and biocompatibility. The biomedical potential of natural collagen is limited by its poor mechanical strength, thermal stability, and enzyme resistance, but exogenous chemical, physical, or biological crosslinks have been used to modify the molecular structure of collagen to minimize degradation and enhance mechanical stability. Although crosslinked collagen-based materials have been widely used in biomedicine, there is no standard crosslinking protocol that can achieve a perfect balance between stability and functional remodeling of collagen. Understanding the role of crosslinking agents in the modification of collagen performance and their potential biomedical applications are crucial for developing novel collagen-based biopolymers for therapeutic gain. PMID- 30447878 TI - Engineering Microorganisms for Enhanced CO2 Sequestration. AB - Microbial CO2 sequestration not only provides a green and sustainable approach for ameliorating global warming but also simultaneously produces biofuels and chemicals. However, the efficiency of microbial CO2 fixation is still very low. In addition, concomitant microbial CO2 emission decreases the carbon yield of desired chemicals. To address these issues, strategies including engineering CO2 fixing pathways and energy-harvesting systems have been developed to improve the efficiency of CO2 fixation in autotrophic and heterotrophic microorganisms. Furthermore, metabolic pathways and energy metabolism can be rewired to reduce microbial CO2 emissions and increase the carbon yield of value-added products. This review highlights the potential of biotechnology to promote microbial CO2 sequestration and provides guidance for the broader use of microorganisms as attractive carbon sinks. PMID- 30447879 TI - Is a "watch and wait strategy" safe to manage clinically N0 squamous cell carcinoma of the upper jaw? AB - PURPOSE: The main aim of the present study is to analyze the behavior of squamous cell carcinoma (SCC) of maxillary gingiva, alveolus, and hard palate and to determine the utility of selective neck dissection in clinically N0 patients at early stages. MATERIAL AND METHOD: Twenty-nine previously untreated patients with SCC of maxillary gingiva, alveolus, and hard palate were diagnosed and treated with at least a tumorectomy and selective neck dissection at HUVN and included in the study. RESULTS: A total of 34.4% of patients (10/29) showed nodal involvement at postoperative histopathologic exam. Several pathologic features such as N involvement, N stage, T stage, and locoregional failure all have a negative impact on overall survival. DISCUSSION: SCC of maxillary gingiva, alveolus, and hard palate shows an aggressive behavior that is comparable with other oral cavity cancers. A more aggressive treatment is thus required for improving locoregional control and overall survival. Supraomohyoid neck dissection may be useful in cT2N0M0. PMID- 30447880 TI - Enhancing Checkpoint Inhibitor Therapy with Ultrasound Stimulated Microbubbles. AB - Checkpoint inhibitor (CI) immunotherapy is playing an increasingly prominent role in the treatment of cancer but is effective and durable in only a subset of patients. There are concerted efforts to improve CI therapy through the use of multiple CIs or use of CIs in combination with other anti-cancer agents. Here we investigate the use of "anti-vascular" ultrasound-stimulated microbubble (USMB) treatments in combination with anti-PD-1 CI therapy. The colorectal cancer cell line CT26 was used to conduct longitudinal growth studies along with acute experiments to assess ultrasound-induced anti-tumor immune responses using flow cytometry and enzyme-linked immunospot (ELISPOT) analysis. Longitudinal experiments indicated that USMB + anti-PD-1 treatments significantly enhanced tumor growth inhibition and animal survival relative to monotherapies. Flow cytometry and ELISPOT data did not clearly support a T cell-dependent mechanism for the enhancement. Therefore, the results indicate the ability of anti-vascular USMBs to increase the anti-tumor effects of CI therapy; the specific mechanisms of enhancement remain to be established. PMID- 30447881 TI - Adult moyamoya angiopathy in Bourgogne-Franche-Comte: Epidemiology, diagnosis and management. AB - INTRODUCTION: Moyamoya angiopathy (MMA) is a progressive steno-occlusive disease of the distal internal carotid arteries mainly described in Asia. It induces the development of collateral vascular networks to reduce chronic cerebral hypoperfusion. Symptoms depend on the patient's age in Asia: children are at greater risk of transient or constituted ischemic events, whereas adults are more exposed to hemorrhagic stroke. Data from the literature seem to show that the pattern of MMA in western countries differs from that in Asia. MATERIAL AND METHODS: A retrospective study of patients with MMA was conducted in Bourgogne Franche-Comte (mid-eastern France). Clinical data (symptoms, risk factors, age at diagnosis, number and timing of recurrences, type of treatment) as well as radiological data (angiographic findings, Suzuki's grade) were analyzed. RESULTS: Seventeen adult patients (9 men, 53%) were followed at the university hospitals of Besancon and Dijon from 2009 to 2016. Fourteen patients (83%) had bilateral disease. The mean age at diagnosis was 49 years (+/-16), 83% of the patients were Caucasian and 17% originated from Maghreb. Only 17% of the hemispheres had a hemorrhagic form. Ischemic form was more frequent before diagnosis with transient ischemic attack (24% of patients) and stroke (83% of patients). With medical treatment, 9 patients suffered from stroke recurrence (53% of patients) with an average delay of 22.7+/-34 months. Three patients (18%) had combined surgical management by encephelo-synangiosis and superficial temporal artery-to-middle cerebral artery (STA-MCA) anastomosis, without symptom recurrence after treatment with an average follow up of 14 months. CONCLUSION: MMA remains a rare cerebrovascular disease in Europe and requires multidisciplinary care. Epidemiological analysis showed differences with the Asian population, especially the predominance of ischemic forms in adults. PMID- 30447882 TI - Antimicrobial susceptibility testing of Mycobacteroides (Mycobacterium) abscessus complex, Mycolicibacterium (Mycobacterium) fortuitum, and Mycobacteroides (Mycobacterium) chelonae. AB - The drug susceptibility of rapidly growing mycobacteria (RGM) varies among isolates. Treatment strategies similarly differ depending on the isolate, and for some, no clear strategy has been identified. This complicates clinical management of RGM. Following Clinical and Laboratory Standards Institute standard M24-A2, we assessed the susceptibility of 140 RGM isolates to 14 different antimicrobial drugs by measuring their minimal inhibitory concentrations (MICs). We also investigated the correlation of clarithromycin (CAM) MICs with the erm(41) and rrl gene mutations in the Mycobacteroides (Mycobacterium) abscessus complex, the rrl mutation in Mycobacteroides (Mycobacterium) chelonae, and the erm(39) mutation in Mycolicibacterium (Mycobacterium) fortuitum to determine the contribution of these mutations to CAM susceptibility. The five species and subspecies examined included 48 M. abscessus subsp. abscessus isolates (34.3%), 35 (25.0%) being M. abscessus subsp. massiliense, and two (1.4%) being M. abscessus subsp. bolletii. The M. abscessus complex accounted for 85 isolates (60.7%) in total, whereas 43 isolates (30.7%) were M. fortuitum, and 12 (8.6%) were M. chelonae. Our results demonstrated species-specific susceptibility to antimicrobials. In most cases, susceptibility to CAM could be predicted based on genetic pattern, but since one isolate did not fit that pattern, MIC values needed to be measured. Some isolates also exhibited rates of resistance to other drugs that differed from those previously reported in other locations, indicating that accurate identification of the bacterial isolate and use of the correct method for determining MIC are both important for the diagnosis of RGM. PMID- 30447883 TI - PACAP deficiency aggravates atherosclerosis in ApoE deficient mice. AB - Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays an important role in cytoprotection, inflammation and cardiovascular regulation. Thus, we studied the involvement of PACAP in atherogenesis. Differentiated human THP-1 macrophages (MPhi) were stimulated with oxidized low-density lipoproteins (oxLDL) and the influence of PACAP38 treatment on lipid content and TNF release was determined. To test the effect of PACAP deficiency (PACAP-/-) on the development of atherosclerosis under standard chow (SC) or cholesterol-enriched diet (CED) in vivo, PACAP-/- mice were crossbred with ApoE-/- to generate PACAP-/-/ApoE-/- mice. Blood cholesterol and triglyceride levels were quantified. Lumen stenosis in the brachiocephalic trunk, cellularity and amounts of pro-inflammatory as well as autophagy-, apoptosis- and necroptosis-relevant proteins were analysed in atherosclerotic plaques by quantitative immunohistochemistry. In vitro, PACAP38 inhibited oxLDL-induced intracellular lipid storage as well as TNF release in MF. In vivo, after SC, but not under CED, PACAP-/-/ApoE-/- mice showed an increased lumen stenosis compared to ApoE-/- mice. In atherosclerotic plaques of PACAP-/ /ApoE-/- mice, the immunoreactive areas of TNF+, IL-1beta+, autophagic, apoptotic and necroptotic cells were increased. In contrast, the overall cell density was decreased compared to ApoE-/- under SC, while no differences were seen under CED. Similar plasma cholesterol levels were observed in PACAP-/-/ApoE-/- and ApoE-/- mice under the respective feeding regime. Thus, PACAP-/-/ApoE-/- mice represent a novel mouse model of accelerated atherosclerosis where CED is not required. Our data indicate that PACAP acts as an endogenous atheroprotective neuropeptide. Thus, stable PACAP agonists may have potential as anti-atherosclerotic therapeutics. The specific PACAP receptor(s) mediating atheroprotection remain(s) to be identified. PMID- 30447884 TI - Skills training for operative vaginal birth. AB - Skilled, safe operative vaginal birth can substantially improve maternal and neonatal outcomes arising from complications in the second stage of labour and should be available in a diverse range of maternity settings for women across the world. Operative vaginal births are complex, requiring a combination of good technical skills, non-technical skills as well as sensitivity from the accoucher. It is axiomatic that accouchers should be adequately trained and simulation-based training is a promising strategy to improve outcomes and increase the rates of operative vaginal birth. However, not all training is effective and although there are likely to be important lessons from other areas of simulation-based obstetric emergencies training that are generalisable, more research is required to identify effective training interventions for operative vaginal birth. Training for operative vaginal birth should also be operationalised for maximum spread and benefit. PMID- 30447885 TI - Anatomical study of length and branching pattern of main trunk of the left coronary artery. AB - The left coronary artery is responsible for the irrigation of important heart structures. The objective of this study was to analyze the morphological characteristics of the main trunk of left coronary artery in the Brazilian population and its clinical implications. The study was carried out by using 63 adult human hearts of the human anatomy laboratory of the Federal university of Ceara, Brazil. The hearts were dissected for exposure and analysis of the left coronary artery and its branches. The data collected were statistically analyzed. The main trunk arose from the left aortic sinus under the left atrial auricle in all the 63 hearts. The mean length of the main trunk was 8.53+/-4.03mm. According to the criteria for the classification of the main trunk length, about 78% were medium-sized. The majority of the hearts (52.38%) showed trifurcation of the main trunk. Anova test followed by the Tukey's post hoc test showed that the main trunk length of hearts with trifurcation was significantly longer when compared with hearts with bifurcation (9.77+/-4.31mm vs. 6.44+/-3.01mm; P=0.0029). Similar findings were observed in the main trunk length of the hearts with tetrafurcation in comparison with hearts with bifurcation (10.78+/-1.4mm vs. 6.44+/-3.01mm; P=0.0387). This study showed that there is a correlation between the branching pattern and the length of the main trunk. Additionally, we showed that the most common branching pattern of the main trunk is the trifurcation, differing from other Brazilian studies and providing additional information to professionals of cardiology, cardiovascular surgery, and radiology. PMID- 30447886 TI - Reorganising the order Bacillales through phylogenomics. AB - Bacterial classification at higher taxonomic ranks such as the order and family levels is currently reliant on phylogenetic analysis of 16S rRNA and the presence of shared phenotypic characteristics. However, these may not be reflective of the true genotypic and phenotypic relationships of taxa. This is evident in the order Bacillales, members of which are defined as aerobic, spore-forming and rod-shaped bacteria. However, some taxa are anaerobic, asporogenic and coccoid. 16S rRNA gene phylogeny is also unable to elucidate the taxonomic positions of several families incertae sedis within this order. Whole genome-based phylogenetic approaches may provide a more accurate means to resolve higher taxonomic levels. A suite of phylogenomic approaches were applied to re-evaluate the taxonomy of 80 representative taxa of eight families (and six family incertae sedis taxa) within the order Bacillales. This showed several anomalies in the current family and order level classifications including the existence of four Bacillaceae and two Paenibacillaceae "family" clades. Furthermore, the families Staphylococcaceae and Listeriaceae belong to the sister order Lactobacillales. Finally, we propose a consensus phylogenomic approach which may diminish algorithmic biases associated with single approaches and facilitate more accurate classification of a broad range of taxa at the higher taxonomic levels. PMID- 30447887 TI - Re: [177Lu]-PSMA-617 Radionuclide Treatment in Patients with Metastatic Castration-resistant Prostate Cancer (LuPSMA Trial): A Single-centre, Single-arm, Phase 2 Study. PMID- 30447888 TI - Towards lead compounds as anti-cancer agents via new phaeosphaeride A derivatives. AB - New derivatives of phaeosphaeride A (PPA) were synthesized and characterized. Anti-tumor studies were carried out on the U937, HCT-116, PC3, MCF-7, A549, K562, NCI-H929, Jurkat, THP-1, RPMI8228 tumor cell lines, and on the HEF cell line. All the compounds synthesized were found to have better efficacy than PPA towards the tumor cell lines mentioned. Compound 6 (IC50 = 0.59 +/- 0.27 uM) was observed to be 11 times more active than PPA (IC50 = 6.5 +/- 0.30 uM) towards the NCI-H929 cell line, with a therapeutic index of 18. Compound 6 was determined to be over half and 16 times more active than etoposide towards the NCI-H929 (IC50 = 0.9 +/- 0.05 uM) and A549 (IC50 = 100 +/- 7.0 uM) cell lines, respectively. PMID- 30447889 TI - Discovery and SAR studies of novel 2-anilinopyrimidine-based selective inhibitors against triple-negative breast cancer cell line MDA-MB-468. AB - Triple-negative breast cancers (TNBCs) are characterized as an invasive and intractable subtype of breast cancers. Overexpression of epidermal growth factor receptor (EGFR) has been considered to be an important target for TNBC therapy, but efficacies of EGFR inhibitors in clinical trials are elusive. In this study, novel series of 2-anilinopyrimidines were synthesized in an effort to identify selective inhibitors against an EGFR-overexpressing TNBC cell line. Biological evaluation demonstrated that compounds 21 and 38, with a 4-methylpiperidine group and a high ClogP value, exhibited good potency and selectivity for the TNBC cell line. This study has provided evidence to support further development of 2 anilinopyrimidine-based TNBC selective inhibitors and investigation of the targets of compounds 21 and 38. PMID- 30447890 TI - Factors affecting side of ovulation in heifers and mares-A comparative study. AB - Effect of side (left ovary, LO; right ovary, RO) and intraovarian presence of the regressing corpus luteum (CL) on the preovulatory follicle (PF) and ovulation were studied using ultrasonic- records of complete interovulatory intervals (IOI) for 500 IOI in heifers and 485 IOI in mares. Only IOI with a recording of side of a single PF and a single CL at each end of the IOI were used. In heifers, ovulation at the end of the IOI occurred more frequently (P < 0.0001) from RO (n = 285, 57%) than LO (n = 215, 43%). In mares, frequency of ovulation did not differ between RO (n = 250. 52%) and LO (n = 235, 48%). In heifers but not in mares, the number of predeviation follicles has been reported to be greater in RO than LO. In heifers, RO ovulation was more frequent when CL was in PF ovary (66%) than when CL was in opposite ovary (50%). There was no difference in side of ovulation (RO, 50%, LO, 50%). In mares, there were no significant main effects or interactions for frequency of ovulation involving side and intraovarian presence of the CL. On a species comparative basis, the present and reported results supported hypothesis 1 that a greater number of predeviation follicles in RO than in LO is associated with the predilection for RO ovulation. Results also supported hypothesis 2 that ovulation from RO in heifers is more frequent when RO contains the regressed CL than when the CL is in LO. PMID- 30447891 TI - Effect of Bismuth Subsalicylate on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral Delayed-Release Dimethyl Fumarate: PREVENT, a Randomized, Multicenter, Double-Blind, Placebo-Controlled Study. AB - PURPOSE: Flushing and gastrointestinal (GI) events are commonly associated with the use of delayed-release dimethyl fumarate (DMF) treatment for relapsing multiple sclerosis. METHODS: PREVENT (A Multicenter, Double-Blind, Placebo Controlled Study of Pepto-Bismol [Bismuth Subsalicylate] on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral TECFIDERA [Dimethyl Fumarate] Delayed-Release Capsules Twice Daily) is a double-blind, placebo-controlled, 8 week study that evaluated the effect of bismuth subsalicylate on DMF-related GI events. Bismuth subsalicylate 524 mg or placebo were administered 30 min before DMF (weeks 1-4). DMF was dosed twice-daily (BID) at 120 mg (week 1) and 240 mg (weeks 2-8). Using an e-diary device, participants recorded GI and flushing events on the Modified Overall Gastrointestinal Symptom Scale once daily for the preceding 24 h. The primary end point was time to first GI-related event. Secondary end points included frequency and severity of GI-related events. FINDINGS: A total of 175 participants were enrolled (placebo, n = 87; bismuth subsalicylate, n = 88), and 17 discontinued treatment (placebo, n = 8; bismuth subsalicylate n = 9). A total of 146 participants reported >=1 GI event: placebo, n = 72 (82.8%); and bismuth subsalicylate, n = 74 (84.1%). There was no statistical difference in risk of a GI event between the groups (P = 0.8292). Mean (SD) time from DMF initiation to first GI event was similar: placebo, 5.4 (8.73) days; and bismuth subsalicylate, 5.6 (10.87) days. Incidence of flatulence (38.6% vs 50.6%) and diarrhea (36.4% vs 48.2%) during weeks 1-4 was numerically lower in the bismuth subsalicylate group compared with the placebo group. Mean worst severity scores for flatulence (1.1 vs 1.8; P = 0.0219) and diarrhea (1.0 vs 1.6; P = 0.0500) were lower with bismuth subsalicylate than with placebo. IMPLICATIONS: Although coadministration of bismuth subsalicylate did not affect the occurrence of DMF-related GI events overall, it reduced the severity and incidence of flatulence and diarrhea. ClinicalTrials.gov identifier: NCT01915901. PMID- 30447892 TI - TEMPORARY REMOVAL: Importance of diastolic arterial pressure in septic shock: PRO. AB - The article has been temporarily removed as a rebuttal in this PRO-CON debate has yet to be added. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 30447893 TI - Population genomic footprints of environmental pollution pressure in natural populations of the Mediterranean mussel. AB - Bivalve molluscs of the genus Mytilus are considered a model organism in ecotoxicology and are known to be well adapted to marine ecosystems affected by multiple anthropogenic factors, including pollution. In order to assess whether pollution interferes with the reproductive success of Mytilus and affects the diversity within and between populations, we sequenced the transcriptomes of 72 individuals from 9 populations of Mytilus galloprovincialis collected along a ca. 130-km north-south transect on the Western coast of the Iberian Peninsula. We found that polluted areas are acting as a barrier to gene flow, potentially because of the detrimental effect of anthropogenic chemicals on larvae carried from more pristine environments. Furthermore, we observed an increase in genetic diversity in populations from polluted site, which could be indicative of higher mutagenicity driven by the environment. We propose that a microevolutionary perspective is essential for a full characterization of human activities on the dispersal of M. galloprovincialis and that it should be incorporated into management, and conservation plans and policies in the context of the effects of pollution on populations. PMID- 30447894 TI - Clinical practice guideline. Unintentional perioperative hypothermia. AB - The importance of the safety of our patients in the surgical theatre, has driven many projects. The majority of them aimed at better control and clinical performance; mainly of the variables that intervene or modulate the results of surgical procedures, and have a direct relationship with them. The Spanish Society of Anesthesiology, Critical Care and Therapeutic Pain (SEDAR), maintains a constant concern for a variable that clearly determines the outcomes of our clinical processes, "unintentional hypothermia" that develops in all patients undergoing an anesthetic or surgical procedure. SEDAR has promoted, in collaboration with other scientific Societies and patient Associations, the elaboration of this clinical practice guideline, which aims to answer clinical questions not yet resolved and for which, up to now, there are no documents based in the best scientific evidence available. With GRADE methodology and technical assistance from the Ibero-American Cochrane Collaboration office, this clinical practice guideline presents three recommendations (weak in favor) for active heating methods for the prevention of hypothermia (skin, fluid or gas); three for the prioritization of strategies for the prevention of hypothermia (too weak in favor and one strongly in favor); two of preheating strategies prior to anesthetic induction (both weak in favor); and two for research. PMID- 30447895 TI - Reversion algorithm for patients anticoagulated with dabigatran in urgent surgery. PMID- 30447896 TI - Marfan syndrome in a term-pregnant woman with aortic root dilatation between 40 and 45 mm. AB - Marfan syndrome is a hereditary connective tissue disorder. The main cause of mortality in these patients is due to cardiovascular complications related to dilation of an aneurysm and dissection of the aortic root, a situation that increases their risk due to the physiological changes that occur during pregnancy, childbirth and puerperium. The case is presented of a pregnant woman with Marfan syndrome and aortic root dilatation of 42mm. The issues are discussed, such as the mode of delivery (vaginal delivery vs. caesarean section) depending on the aortic root diameter or the choice of type of anaesthesia (general vs. neuraxial) in these cases. PMID- 30447897 TI - Perioperative management of a female diagnosed with heterozygous X-linked adrenoleukodystrophy for shoulder arthroscopy. AB - X-linked adrenoleukodystrophy (X-ALD) belongs to a family of rare diseases due to inborn errors of metabolism. It has a wide spectrum of clinical manifestations that anaesthesiologists should recognise during the perioperative period (respiratory centre dysfunction, hypotonia, adrenal or hepatic failure, gastroesophageal reflux disease, osteopenia, seizures).The case is presented of a 42-year-old X-linked adrenoleukodystrophy female carrier, who underwent combined general and an ultrasound-guided interscalene brachial plexus block anaesthesia for shoulder arthroscopy. Induction was performed with thiopentone and fentanyl, and sevoflurane was used as inhaled maintenance agent. No events were recorded during the procedure. Her post-operative recovery was satisfactory and she was later discharged home. PMID- 30447898 TI - Endovascular management of femoropopliteal in-stent restenosis: A systematic review. AB - Despite the development of new therapies for the treatment of femoropopliteal disease, nitinol stents remain a mainstay of therapy following balloon angioplasty. Consequently, femoropopliteal in-stent restenosis (FP-ISR) remains an important clinical problem. Interventions used to treat de novo lesions of the femoropopliteal segment have been used to treat ISR lesions, with disappointing outcomes. Early interventions focused on repeat balloon angioplasty, cryoplasty, and various debulking therapies. Recently, treatment has shifted towards the use of stent-grafts, drug-eluting therapies, and combination therapies. This review analyzes the evidence behind each treatment modality and provides insight into future directions for optimal endovascular management of FP-ISR. PMID- 30447899 TI - Cardiovascular effects of marijuana. AB - More than four decades ago, the United States Surgeon General issued a warning regarding the medical problems of marijuana smoking, including cardiac toxicity. Since then, many reports have described atrial fibrillation, ventricular tachycardia, acute coronary syndromes, and cardiac arrest temporally related to marijuana use. The subjects were quite young, with no significant cardiovascular risk factors, with the only obvious trigger being marijuana use. Despite these strong signals, the drug is now legalized for recreational use in many states. We believe the time has come to conduct definitive studies about the safety of marijuana before this trend moves to the rest of the nation. PMID- 30447900 TI - Which patients are satisfied with their overall outcome but dissatisfied with their return to recreational activities after total knee arthroplasty? AB - BACKGROUND: The primary aim of this study was to assess whether patients dissatisfied with both recreational activities and overall outcome were different to those dissatisfied with recreational activities but satisfied with their overall outcome one year after total knee arthroplasty (TKA). METHODS: A retrospective cohort consisting of 3324 primary TKA were identified from an established arthroplasty database. Patient demographics, comorbidities, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form (SF) 12 scores were collected pre-operatively and one year post-operatively. Overall patient satisfaction and satisfaction with recreational activities were assessed at one year. RESULTS: The rate of patient satisfaction with recreational activities (n = 2672, 80.4%) was significantly (odds ratio (OR) 0.47, 95% confidence intervals (CI) 0.41 to 0.54, p < 0.001) lower than satisfaction with the overall outcome (n = 2982, 89.7%). When adjusting for confounding variables older age (OR 1.03, p = 0.008), increasing BMI (OR 1.05, p = 0.01) and absence of hypertension (OR 0.66, p = 0.02) were independent predictors of being dissatisfied with recreational activities in isolation. The one-year components and total WOMAC scores were significant (p < 0.001) predictors of satisfaction with recreational activities and were reliable with an area under the curve of >=0.82 CONCLUSION: Patients of older age, higher BMI and without hypertension are more likely to be dissatisfied with recreational activities despite being satisfied with their overall outcome. PMID- 30447901 TI - Levels of IL-17F and IL-33 correlate with HLA-DR activation in clinical-grade human bone marrow-derived multipotent mesenchymal stromal cell expansion cultures. AB - BACKGROUND AIMS: Multipotent mesenchymal stromal cell (MSC)-based medicines are extensively investigated for use in regenerative medicine and immunotherapy applications. The International Society for Cell and Gene Therapy (ISCT) proposed a panel of cell surface molecules for MSC identification that includes human leukocyte antigen (HLA)-DR as a negative marker. However, its expression is largely unpredictable despite production under tightly controlled conditions and compliance with current Good Manufacturing Practices. Herein, we report the frequency of HLA-DR expression in 81 batches of clinical grade bone marrow (BM) derived MSCs and investigated its impact on cell attributes and culture environment. METHODS: The levels of 15 cytokines (interleukin [IL]-1beta, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, interferon gamma, soluble CD40 ligand and tumor necrosis factor-alpha) were determined in sera supplements and supernatants of BM-MSC cultures. Identity, multipotentiality and immunopotency assays were performed on high (>20% of cells) and low (<=20% of cells) HLA-DR+ cultures. RESULTS: A correlation was found between HLA-DR expression and levels of IL-17F and IL-33. Expression of HLA-DR did neither affect MSC identity, in vitro tri-lineage differentiation potential (into osteogenic, chondrogenic and adipogenic lineages), nor their ability to inhibit the proliferation of stimulated lymphocytes. DISCUSSION: Out of 81 batches of BM MSCs for autologous use analyzed, only three batches would have passed the ISCT criteria (<2%), whereas 60.5% of batches were compliant with low HLA-DR values (<=20%). Although a cause-effect relationship cannot be drawn, we have provided a better understanding of signaling events and cellular responses in expansion culture conditions relating with HLA-DR expression. PMID- 30447902 TI - Predictors of postpartum diabetes mellitus in patients with gestational diabetes. AB - INTRODUCTION: Gestational diabetes (GD) is related to development of diabetes mellitus (DM) after delivery. The predictive factors in this association are not yet well defined. Objetive: to study the predictive factors of dysglucosis in the postpartum period in a sample of patients with GD. MATERIAL AND METHODS: A total of 1765 women with DG were studied. Variables analyzed: anthropometric data and maternal history. Glycemia in OGTT with 100g (basal: 1, 2 and 3h) and HbA1c. Use of insulin in pregnancy. The OGTT with 75g and HbA1c at 3 months after delivery. RESULTS: Postpartum DM prevalence 2.1%. Among these patients, there was a higher percentage of patients with a history of GD (25.9 vs. 12.9%; P<.05), pre pregnancy obesity (20.8 vs. 14.9%; P<.05) and insulin use during pregnancy (79.2 vs. 20%; P<.01). In the OGTT with 100g, the number of pathological points was higher (3.18+/-0.69 in DM vs. 2.3+/-0.28 normal, 2.6+/-0.47 IFG, 2.5+/-0.32 IGT; P<.001). In the OGTT 100g, the blood glucose level above which the diagnosis of postpartum DM is most likely is 189mg/dl in the 2h determination (S: 86.2%, E: 72%). A level of HbA1c>5.9% during pregnancy has a specificity of 95.9% for the diagnosis of postpartum DM in our sample. CONCLUSION: We show factors associated with the diagnosis of postpartum DM, among which are quantitative determinations such as glycemia at 2h of the OGTT with 100g and HbA1c during pregnancy in patients with DG. PMID- 30447903 TI - Reprint of: Circulating cell-free DNA mutation patterns in early and late stage colon and pancreatic cancer. AB - Cancer is a heterogeneous disease harboring diverse subclonal populations that can be discriminated by their DNA mutations. Environmental pressure selects subclones that ultimately drive disease progression and tumor relapse. Circulating cell-free DNA (ccfDNA) can be used to approximate the mutational makeup of cancer lesions and can serve as a marker for monitoring disease progression at the molecular level without the need for invasively acquired samples from primary or metastatic lesions. This potential for molecular analysis makes ccfDNA attractive for the study of clonal evolution and for uncovering emerging therapeutic resistance or sensitivity. We assessed ccfDNA from colon and pancreatic adenocarcinoma patients using next generation sequencing of 56 cancer associated genes at the time of primary resectable disease and metastatic progression and compared this to the mutational patterns of the primary tumor. 28%-47% of non-synonymous mutations in the primary tumors were also detected in the ccfDNA while 71%-78% mutations found in ccfDNA were not detected in the primary tumors. ccfDNA collected at the time of progression harbored 3-5 new mutations not detected in ccfDNA at the earlier collection time points. We conclude that incorporation of ccfDNA analysis provides crucial insights into the changing molecular makeup of progressive colon and pancreatic cancer. PMID- 30447904 TI - Treating Brain Disorders by Targeting Adult Neural Stem Cells. AB - Adult neurogenesis, a developmental process of generating functionally integrated neurons from neural stem cells, occurs throughout life in the hippocampus of the mammalian brain and highlights the plastic nature of the mature central nervous system. Substantial evidence suggests that new neurons participate in cognitive and affective brain functions and aberrant adult neurogenesis contributes to various brain disorders. Focusing on adult hippocampal neurogenesis, we review recent findings that advance our understanding of the key properties and potential functions of adult neural stem cells. We further discuss the key evidence demonstrating the causal role of aberrant hippocampal neurogenesis and various brain disorders. Finally, we propose strategies aimed at simultaneously correcting stem cells and their niche for treating brain disorders. PMID- 30447905 TI - Are there variations in adherence to colorectal cancer clinical guidelines depending on treatment place and recommendation novelty? The French EvaCCoR observational study. AB - BACKGROUND: Studies have shown clinical practices variation between centers in colorectal cancer (CRC) management. After the implementation of national cancer plans, we tested for differences in center and patients' socioeconomic position (SEP)-related variation in CRC guidelines. METHODS: All patients aged 18 years and over, cared for a first CRC in 2010 in Southwest of France. We used mixed effect model to test for center-related heterogeneity (CRH) in recommendation, from the oldest to the more recent: (1) at least 12 lymph nodes analysed for stage II, (2) the prescription of adjuvant chemotherapy stage III and (3) the assessment of CRC molecular phenotype regarding KRAS status for stage IV. Patients' SEP was approached by an ecological social deprivation index. RESULTS: We found: higher adherence for the oldest than for the most recent recommendations; no CRH in recommendation No. 2 but lower adherence in academic centers; a CRH for recommendations No. 1 and 3; no SEP-related differences in clinical practices. CONCLUSION: Results showed that older recommendations have higher adherence but did not support increasing influence of centers characteristics and CRH as recommendations are more recent. PMID- 30447906 TI - Genetic variant of TMBIM1 is associated with the susceptibility of colorectal cancer in the Chinese population. AB - BACKGROUND AND AIMS: Recent meta-analysis of genome-wide association studies (GWASs) identified a novel variant rs992157 at 2q35 that was associated with colorectal cancer (CRC) in the population of European ancestry. We aimed to replicate the association of rs992157 with CRC in the Chinese population and to further determine the real susceptible gene of CRC as indicated by this variant. METHODS: 824 CRC patients and 1063 healthy controls were included. The frequency of the genotype and the allele of rs992157 were compared between the patients and the controls and between different subgroups of patients classified by status of metastasis. Expression level of TMBIM1 was compared between the tumor tissue and the adjacent normal tissues collected from 43 patients during surgery. Besides, the relationship between genotypes of rs992157 and the tissue expression of TMBIM1 was analyzed. RESULTS: Patients were found to have significantly higher frequency of allele G than the controls (44.2% vs. 40.0%, P = 0.009; OR = 1.18). Moreover, allele G was associated with an increased risk of lymph node metastasis (P = 0.02) and distant metastasis of CRC (P = 0.04). The mean expression level of TMBIM1 was significantly higher in tumor tissue than in the adjacent normal tissues (0.0019 +/- 0.00068 vs. 0.00041 +/- 0.00024, P < 0.001). In addition, patients with genotype GG were found to have remarkably higher TMBIM1 expression in the tumors than those with genotype AA (0.0024 +/- 0.00052 vs. 0.0015 +/- 0.00078, P = 0.005). CONCLUSION: Variant rs992157 is significantly associated with the susceptibility and progression of CRC. It can increase the risk of CRC possibly via up-regulation of TMBIM1. PMID- 30447907 TI - Hyperammonemic encephalopathy associated with hereditary hemorrhagic telangiectasia. PMID- 30447908 TI - A melanosis coli associated with a large flat adenoma of the cecum. PMID- 30447909 TI - Radiofrequency ablation versus resection for resectable liver metastases of gastrointestinal stromal tumours: Results from three national centres in China. AB - OBJECTIVE: The aim of the present study was to compare outcomes after curative intent radiofrequency ablation and resection in patients with resectable liver metastases of Gastrointestinal Stromal Tumours (GISTs) after pre-operative tyrosine kinase inhibitor (TKI) treatment. METHODS: We retrospectively analysed data from 25 patients diagnosed with resectable liver metastases from GISTs who received pre-operative TKI treatment, who received radiofrequency ablation or resection and post-operative TKI treatment, and who were admitted to 3 institutions from January 2009 to December 2017. RESULTS: Ten patients (10/25, 40.00%) underwent RFA combined with post-operative TKI treatment, and 15 (15/25, 60.00%) patients were treated with hepatic resection combined with post-operative TKI treatment. There were fewer post-operative complications (10.00% vs. 53.33%, P = 0.04) and shorter length of stay (4 vs. 9 days, P = 0.00) in the RFA group. After a median follow-up of 26 months, the 1-, 3-, and 5-year survival rates were 100.00%, 75.00%, 55.00%, respectively. The RFA group had a lower median PFS (P = 0.007, mPFS: 9 months versus 29 months), but overall survival was not influenced by the treatment modality compared with the resection group (P = 0.413, mOS: 47 months versus not reached).Hepatic resection combined with post-operative TKI treatment was the only prognostic factor for PFS in univariate analysis (HR = 0.071, 95% CI: 0.007-0.759, P = 0.029). CONCLUSIONS: For patients with resectable liver metastases from GISTs after receiving pre-operative TKI treatment, compared with resection, ablation seemed to be associated with shorter progression-free survival, but RFA offered comparable overall survival, and the post- procedure morbidity and lengths of stay were significantly lower. With complete ablation of the targeted tumours, our results suggest that RFA is an acceptable option in selected patients. PMID- 30447910 TI - Probing Brain Developmental Patterns of Myelination and Associations With Psychopathology in Youths UsingGray/White Matter Contrast. AB - BACKGROUND: Cerebral myeloarchitecture shows substantial development across childhood and adolescence, and aberrations in these trajectories are relevant for a range of mental disorders. Differential myelination between intracortical and subjacent white matter can be approximated using signal intensities in T1 weighted magnetic resonance imaging. METHODS: To test the sensitivity of gray/white matter contrast (GWC) to age and individual differences in psychopathology and general cognitive ability in youths (8-23 years), we formed data-driven psychopathology and cognitive components using a large population based sample, the Philadelphia Neurodevelopmental Cohort (N = 6487, 52% female). We then tested for associations with regional GWC defined by an independent component analysis in a subsample with available magnetic resonance imaging data (n = 1467, 53% female). RESULTS: The analyses revealed a global GWC component, which showed an age-related decrease from late childhood and across adolescence. In addition, we found regional anatomically meaningful components with differential age associations explaining variance beyond the global component. When accounting for age and sex, both higher symptom levels of anxiety or prodromal psychosis and lower cognitive ability were associated with higher GWC in insula and cingulate cortices and with lower GWC in pre- and postcentral cortices. We also found several additional regional associations with anxiety, prodromal psychosis, and cognitive ability. CONCLUSIONS: Independent modes of GWC variation are sensitive to global and regional brain developmental processes, possibly related to differences between intracortical and subjacent white matter myelination, and individual differences in regional GWC are associated with both mental health and general cognitive functioning. PMID- 30447911 TI - Interleukin-6 Induced by Social Stress Promotes a Unique Transcriptional Signature in the Monocytes That Facilitate Anxiety. AB - BACKGROUND: Interleukin-6 (IL-6) is elevated in circulation with chronic stress and may contribute to neurobehavioral complications. We have reported that repeated social defeat stress in mice caused recruitment of proinflammatory monocytes to the brain and triggered the onset of anxiety-like behavior. Therefore, the purpose of this study was to determine the role of IL-6 signaling in the peripheral immune response, neuroinflammation, and anxiety following stress. METHODS: Wild-type and IL-6 knockout mice were subjected to repeated social defeat, and immune and behavioral parameters were determined 14 hours later. RESULTS: Although monocyte release and recruitment to the brain during stress were maintained in the IL-6 knockout mice, anxiety and social avoidance were prevented. NanoString analysis of fluorescence-activated cell-sorted blood monocytes (CD11b+/Ly6Chi) and brain monocytes (CD11b+/CD45hi) revealed a unique pattern of immune-related gene expression that was dependent on stress and IL-6. For instance, blood monocytes after stress had a transcriptional signature and immune profile consistent with priming, which was attenuated in monocytes from IL 6 knockout stress mice. Moreover, the monocytes recruited to the brain and associated with the development of anxiety had a transcriptional signature (enhanced IL-1beta, CD14, Mmp9, Myd88, Ager, and Stat3) that was dependent on IL 6. CONCLUSIONS: Here, we show the effects of IL-6 on the transcriptional signature of monocytes in circulation and brain after stress. Overall, robust increases in IL-6 after stress induced a primed profile in monocytes that were recruited to the brain and propagated IL-1-mediated inflammation and anxiety. PMID- 30447912 TI - Early Parenting Intervention and Adverse Family Environments Affect Neural Function in Middle Childhood. AB - BACKGROUND: Growing work points to the negative impact of early adverse experiences on the developing brain. An outstanding question concerns the extent to which early intervention can normalize trajectories of brain development in at risk children. We tested this within the context of a randomized clinical trial of an early parenting program, the Attachment and Biobehavioral Catch-up (ABC), delivered to parents and infants monitored for maltreatment by Child Protective Services. METHODS: Families participated in the randomized clinical trial when children were 2.5 years of age or younger. Parenting and home adversity was measured at baseline. Children were followed longitudinally, and resting brain activity was measured electrophysiologically (n = 106) when children reached 8 years of age. Spectral power was quantified and compared across children assigned to the experimental intervention (ABC), a control intervention, and a low-risk comparison group (n = 76) recruited at the follow-up assessment. RESULTS: Higher early home adversity was associated with electrophysiological profiles indicative of cortical delays/immaturity in middle childhood, based on relatively greater power in lower frequency bands (theta, 4-6 Hz, and low alpha, 6-9 Hz) and lower power in a higher frequency band (high alpha, 9-12 Hz). Children assigned to ABC showed relatively greater high-frequency power (beta, 12-20 Hz) than children assigned to the control intervention. Beta power in the ABC did not differ from that of the low-risk comparison group. CONCLUSIONS: Maltreatment risk and home adversity can affect indicators of middle childhood brain maturation. Early parenting programs can support more normative patterns of neural function during middle childhood. PMID- 30447913 TI - One step ahead: miRNA-34 in colon cancer-future diagnostic and therapeutic tool? AB - The discovery that microRNAs (miRNAs) - short, non-coding RNA molecules which regulate gene expression - are implicated in many types of cancer has revolutionised cancer research, giving hope for a new perspective in diagnostics and treatment. Dysregulation of miRNAs occurs in various malignancies, including colorectal cancer (CRC). CRC is one of the leading causes of cancer-related death and in most countries its incidence is still rising. Among several miRNAs which have been linked to CRC, miR-34 has attracted particular attention. This miRNA is involved in the regulation of cell cycle and apoptosis through multiple signaling pathways such as p53, Ra and Wnt signaling. Understanding its role in CRC may facilitate its future use as a diagnostic tool and therapeutic target. PMID- 30447914 TI - Polymorphisms in non-coding RNAs and risk of colorectal cancer: A systematic review and meta-analysis. AB - Colorectal cancer (CRC) has been regarded as a common cancer due to its prevailing incidence in both males and females. Recently, non-coding RNAs used as biomarkers for screening, diagnosis and prognosis of different cancers have been under the focus of attention. As a result of this, the aim of this study was to systematically review articles that investigated the SNPs in genes related to microRNAs and long non-coding RNAs to assess the genetic susceptibility of colorectal cancer risk. The outcome is presented as the results of a meta analysis. We systematically searched PubMed, Web of Science, and Scopus to identify relevant studies published up to 20/5/2017. These included eligible studies consisting of 23,581 patients and 22,697 controls. The conferred risk was estimated and presented using odds ratios (ORs) and 95% confidence intervals (CI). The Hardy-Weinberg equilibrium (HWE) was assessed by the goodness-of-fit chi-square test in all studies. The power of each study was also calculated based on the available results. Out of 27 different microRNAs which had published results, although most of the studies were under powered, miR-146a and miR-196a were amongst the most studied microRNAs. For five miRNAs (miR-196a, miR-146a, miR 27a, miR-499 and miR-149) which we performed a meta-analysis, miR-27a and miR-149 gene polymorphisms were associated with susceptibility to CRC. Other miRNAs did not show any effect on the CRC risk. Overall, significant association between miR 149 rs2292832 and susceptibility to cancer was identified in a recessive genetic model, TT/ (TC + CC) (OR = 1.19, 95% CI = 1.02-1.39, P = 0.02). On the other hand, rs895819 (miR-27a) GG carriers were more susceptible to CRC (OR = 1.47, 95% CI = 1.21-1.78, P = <0.05) in a recessive genetic model. Analysis of the data based on race revealed that rs2910164 (miR-146a) polymorphism may decrease the risk of CRC among Europeans, in a co dominant model [OR = 0.81, 95% CI 0.66-0.99, p = 0.04], but not among Asians. In conclusion, certain miRNAs (miR-27a and miR 149) may affect the CRC risk and can be regarded as genetic markers amongst different populations. LncRNAs still have to be studied more to reach a conclusion for their association with CRC risk. PMID- 30447915 TI - Hormone replacement therapy after prophylactic risk-reducing salpingo oophorectomy and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A meta analysis. AB - BACKGROUND: Hormone replacement therapy (HRT) has been tested in women with BRCA1 and BRCA2 mutations who underwent risk-reducing salpingo-oophorectomy (RRSO), but its effect on breast cancer (BC) risk has never been appraised using meta analysis comparison. We performed the first meta-analysis aimed to clarify whether HRT after RRSO could negatively impact on BC risk in women carriers of BRCA1 and BRCA2 mutations. METHODS AND MATERIAL: Pubmed and Scopus databases were searched to retrieve articles written in the English language. Trials comparing RRSO with or without HRT were identified and only those trials with available BC events were included. BC risk was the main endpoint. RESULTS: Three trials with 1100 patients were included. There was not a significantly higher BC risk in BRCA1 and BRCA2 mutation carriers receiving HRT after RRSO (HR = 0.98; 95% CI 0.63-1.52). There was a slightly but not significantly, benefit in BC risk reduction in favor of estrogen alone HRT versus estrogen plus progesterone HRT formulation (OR = 0.53; 95% CI 0.25-1.15). CONCLUSION: HRT use after RRSO in BRCA 1 and BRCA2 mutation carries does not affect BC risk. Comparison of the different HRT types suggests that estrogen alone should be related to lowest BC risk. PMID- 30447916 TI - Fertility preserving options for gynecologic malignancies: A review of current understanding and future directions. AB - Gynecological malignancies affect significant proportion of women in whom fertility preservation is a priority. Advancing reproductive technology and modern surgical techniques are changing the way young women with cancer are counseled regarding their fertility plans at time of cancer diagnosis. This review article provides the reader with fertility preserving updates in gynecologic malignancies as well as those with genetic predisposition for gynecologic malignancies. The different types of gynecologic malignancies including cervical, endometrial, and ovarian cancers and their unique obstacles are addressed separately. New insights into conservative cervical cancer surgery and fertility preserving neoadjuvant chemotherapy followed by fertility preserving surgery for cervical cancer are discussed. Hormonal management of endometrial cancer are highlighted. Additionally, better understanding of ovarian failure with modern chemotherapy/radiation therapy is summarized. Finally, modern reproductive techniques such as ovarian cryopreservation are reviewed as well as those in early stages are development such as artificial ovarian tissue are previewed. PMID- 30447917 TI - Liver toxicity in the era of immune checkpoint inhibitors: A practical approach. AB - Immune checkpoint inhibitors have revolutionized the cancer treatment with an approved efficacy in different solid tumors and hematologic malignancies. These agents are increasing the indication in cancer treatment, but can be associated with serious immune-related adverse effects (IRAEs). Dermatologic and gastrointestinal toxicities are the most common IRAE followed by endocrinopathies with a different time of occurrence. Rarely cases of gastrointestinal toxicities are observed almost 2 years after initiation of the therapy. In this review we focus on liver toxicity related to these immunotherapeutic agents for which the largest amount of safety data is available. The management of drug-induced liver toxicity is very complicated and in same cases may take a long period of time to be resolved. A prompt recognition of liver IRAEs and an appropriate management of this event, requiring close collaboration with other specialist figures, could improve its treatment with evident implication on the efficacy of the therapy. PMID- 30447918 TI - The prognostic value of the systemic inflammatory response in randomised clinical trials in cancer: A systematic review. AB - BACKGROUND: The prognostic value of the systemic inflammatory response in cancer has been well established in observational studies. This review aims to examine and rationalise the evidence for the role of systemic inflammation based prognostic scores in randomised clinical trials. METHOD: An extensive literature review using targeted medical subject headings was carried out in the MEDLINE, EMBASE, and CDSR databases until January 2018. Titles were examined for relevance and after exclusions bibliographies were hand searched to identify additional trials. RESULTS: There were 29 trials containing data on 37,020 patients presented in full paper form and 8 trials containing data on 3805 patients presented in abstract form. Most trials were published within the last three years. Seven trials containing data on 6044 patients were published in 2015. Eight trials containing data on 4384 patients were published in 2016. Twelve trials containing data on 27,228 patients were published in 2017. The majority of trials were in advanced inoperable cancer and colorectal cancer was the most common cancer type with 11 articles containing data on 27,909 patients. The GPS/mGPS was shown to have prognostic value in randomised clinical trials in NSCLC, oesophageal cancer, pancreatic cancer, prostate cancer and breast cancer. The NLR/dNLR was shown to have prognostic value in randomised clinical trials in nasopharyngeal cancer, oesophageal cancer, pancreatic cancer, biliary cancer, prostate cancer and multiple cancer types. CONCLUSION: The prognostic value of systemic inflammation based prognostic scores has been confirmed in multiple trials and should be incorporated into future prospective randomised clinical trials. PMID- 30447919 TI - Prevalence of pathogenic variants and variants of unknown significance in patients at high risk of breast cancer: A systematic review and meta-analysis of gene-panel data. AB - BACKGROUND: Gene-panels are used to assess predisposition to breast cancer by simultaneous testing of multiple susceptibility genes. This approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We performed a systematic review of published studies to calculate the prevalence of VUS and pathogenic variants (PV) in routinely tested breast cancer susceptibility genes in patients at high risk of breast cancer. METHODS: We comprehensively searched the literature using Medline through May 23, 2017 for studies conducting gene-panel testing on germline DNA of women with familial breast cancer and reporting on both PVs and VUSs. A meta analysis of the collected data was carried out to obtain pooled VUS and PV prevalence estimates per gene using a generalized linear mixed model with logit link for binomial distribution. RESULTS: Of 602 publications, 4 were eligible and included 1870 patients. The panels encompassed 4-27 considered genes. Overall, the estimated probability per gene of a PV and VUS was 55% (95% confidence interval (CI) 26%-81%) and 91% (95% CI 78%-97%), respectively (p = 0.0066). The estimated probability per patient of a PV and VUS was 8% (95% CI 1%-34%) and 23% (95% CI 7%-52%), respectively (p = 0.0052). The ratio of VUS to PV was highest in the mismatch repair genes MLH1, MSH2, MSH6, PMS2 (18.7), CDH1 (13.4) and ATM (9.5). Amongst the 1468 patients tested for BRCA1 and BRCA2, only these two genes had a VUS to PV ratio of less than one (0.2 and 0.6, respectively). CONCLUSION: With the current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a PV. Better classification of VUSs is therefore critical and requires gene-specific VUS-assessment in every future study of gene-panel testing in patients at high risk of breast cancer. PMID- 30447920 TI - Crosstalk in cancer resistance and metastasis. AB - The main obstacles that lead to clinical failure in cancer treatment are the development of resistant to chemotherapy and a rise in invasive characteristics in cancer tumor cells due to prolonged chemotherapeutic processes. Recent studies have revealed some evidence about the existence of a direct relationship between development of drug resistance and triggering of invasive capability in tumor cells. Therefore, devising and application of chemotherapeutic procedures that are not prone to the development of chemotherapy resistance are necessary. Here, we focus on CD147, CD44, ANAX2, P-gp, MMPs, and UCH-L1 proteins involved in the crosstalk between metastasis and cancer treatment. We think that further structural and functional analysis of these proteins may direct scientists towards designing highly effective chemotherapy procedures. PMID- 30447921 TI - To resect or not to resect: The hamletic dilemma of primary tumor resection in patients with asymptomatic stage IV colorectal cancer. AB - Primary tumor resection (PTR) in advanced asymptomatic colorectal cancer (CRC) has been a matter of intense debate for long time. With the advances in systemic treatments, this practice has decreased over the years, although it remains still pervasive. Although the removal of primary tumor has been extensively interrogated both in retrospective and prospective studies, it still remains a clinical conundrum. There are many arguments for and against PTR in CRC both from the preclinical and the clinical point of view. Two scoring models have been published aiming at identifying patients who are suitable candidate for PTR, but they deserve further investigations in larger datasets. While awaiting the results of ongoing randomized clinical trials (RCTs) on this controversial topic, both upfront systemic treatment and PTR followed by chemotherapy should be considered valid options in patients with asymptomatic mCRC. Clinical selection and a shared-decision making approach are the keys to success. PMID- 30447922 TI - A rationale multidisciplinary approach for treatment of esophageal and gastroesophageal junction cancer: Accurate review of management and perspectives. AB - Cancer of the esophagus and of gastroesophageal junction can be cured, even if with lacking cure rate. Different approaches have been developed, mostly when carcinoma has loco-regional pattern. Multimodality therapy showed a survival rate superior than 10% if compared to a single approach. This is a systematic review, carried to assess the following matters: Which therapeutic opportunities are available? Who could benefit of them? Which adverse reactions could possibly verify? How can physicians definitely choose the proper strategy? Which is the role of surgery? We mean to give either General Practitioner or specialists clear and efficient updates about current treatment of this tumour, starting from physical examination. Four eminent guidelines were consulted for our study: Cancer Care Ontario's Program in Evidence-Based Care, NCCN, Belgian Health Care Knowledge Centre and Esmo. PMID- 30447923 TI - Direct oral anticoagulants for the treatment of venous thromboembolism in cancer patients: Potential for drug-drug interactions. AB - Patients with cancer are at high risk of developing venous thromboembolism (VTE). Although the recommended low molecular weight heparins (LMWHs) are more effective than vitamin K antagonists in treating VTE in patients with cancer, they have limitations and contraindications. Direct oral anticoagulants (DOACs) circumvent some of these limitations. Here, DOAC use for VTE treatment in patients receiving anticancer therapy is reviewed, focusing on metabolic and elimination pathways, potential drug-drug interactions and practical considerations. DOACs are typically substrates of the cytochrome P450-based metabolic pathways and/or ATP binding cassette transporters. Although many cancer therapies influence these pathways, only a minority of these drugs interact with DOACs. Phase III DOAC trials provided encouraging safety and efficacy data for their use in cancer associated thrombosis. Furthermore, numerous ongoing DOAC trials strive to gain a better understanding of the treatment of cancer-associated thrombosis and continue to support a role for DOACs in this setting. PMID- 30447924 TI - The role of Cancer/Testis Antigens in Multiple Myeloma pathogenesis and their application in disease monitoring and therapy. AB - A unique group of genes, encoding tumour associated antigens, known as the Cancer/Testis Antigens (CTAs), have been explored as novel markers of disease progression and as targets of immunotherapy in several cancers, including the haematological malignancy Multiple Myeloma (MM). This review aims to update the knowledge of CTA involvement in MM pathogenesis and how their potential as biomarkers for disease monitoring and targets of immunotherapy has been explored in the MM disease arena. Despite the initial promise of these antigens, their use as immunotherapy targets has not been successful, yet with a greater understanding of their role in disease pathogenesis they may still have a significant role to play as biomarkers of disease and therapeutic targets. PMID- 30447925 TI - Performance of advanced imaging modalities at diagnosis and treatment response evaluation of patients with post-transplant lymphoproliferative disorder: A systematic review and meta-analysis. AB - INTRODUCTION AND AIM: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, associated with significant morbidity and mortality. In this systematic review we evaluated the clinical performance of advanced imaging modalities at diagnosis and treatment response evaluation of PTLD patients after solid organ and hematopoietic stem cell transplantation. METHODS: We have carried out a literature search until December 15, 2017 using PubMed/Medline, Embase, "Web of Science" and Cochrane Library databases concerning the performance of computed tomography (CT), magnetic resonance imaging (MRI) and 18F flurodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) at diagnosis or treatment response evaluation of PTLD patients. RESULTS: A total of 11 studies were included comprising 368 patients, from which FDG-PET(/CT) was the primary imaging modality investigated. The methodological quality according to QUADAS-2 of the reviewed studies was moderate-poor. Subgroup analysis of imaging results for detection and staging in patients with PTLD indicated that FDG-PET/(CT) identified additional lesions not detected by CT and/or MRI in 27.8%, (95% confidence interval [95%CI]) 17.0%-42.0% (I2 = 51.1%), from which extra-nodal sites in 23.6% (95%CI: 7.9%-52.4%) (I2 = 76.6%). False negative results occurred in 11.5% (95%CI: 4.9%-24.5%) (I2 = 73.4%), predominantly in physiological high background activity regions and in early PTLD lesions. False positive results occurred in 4.8% (95%CI: 2.6%-8.6%) (I2 = 0%) predominantly due to inflammatory conditions. Subgroup analysis of imaging results at treatment response evaluation indicated that FDG-PET(/CT) findings altered or guided treatment in 29.0% (95%CI: 14.0%-50.5%) (I2 = 40.1%). False positive results during treatment response evaluation were reported in 20.0% (95%CI: 10.7%-34.2%) (I2 = 0%), predominantly due to inflammatory conditions. CONCLUSION: FDG-PET(/CT) is currently the most frequently investigated imaging modality in PTLD patients. Available studies report promising results in detection, staging and therapy evaluation but suffer from methodological shortcomings. Concerns remain with regard to occurrence of false negatives due to physiological high background activity and early PTLD lesions as well as false positives due to inflammatory conditions. PMID- 30447926 TI - Emerging paradigms in the treatment of liver metastases in colorectal cancer. AB - Efforts to combat colorectal cancer have benefited from improved screening and surveillance, which facilitates early detection. The survival rate associated with diagnosis at stage I is approximately 90%. However, progress in improving survival in metastatic colorectal cancer (mCRC) has been minimal. This review focuses on mCRC with special emphasis on the molecular aspects of liver metastases, which is one of the most frequently involved organ site. Better molecular evidence is required to guide the decisions for surgical and other interventions used in the clinical management of mCRC. Results from different treatment modalities have exposed significant gaps in the existing paradigms of the mCRC management. Indeed there is a critical need to better understand molecular events and pathways that lead to colorectal cancer liver metastasis. Such a focused approach may help identify biomarkers and drug targets that can be useful in the clinical applications. With this focus, we provide an account of the molecular pathways involved in the spread of CRC to the liver. Specifically, the molecular changes at the DNA and RNA levels that are associated with liver metastases are discussed. Similarly, we describe relevant microRNAs that are identified as regulators of gene expression and can also serve as biomarkers. Conventionally applied biomarkers are not yet specific and sensitive enough to be relied in routine clinical decision making. Hence search for novel biomarkers is critically needed especially if these can be utilized using liquid biopsies. This review provides a comprehensive analysis of current molecular evidence along with potential future directions that could reshape the diagnostic and management paradigms and thus mitigate the devastating impact of colorectal cancer metastasis to the liver. PMID- 30447927 TI - Magnetic resonance imaging in breast cancer management in the context of neo adjuvant chemotherapy. AB - This review discusses the clinical applications of magnetic resonance imaging (MRI) for the assessment of neo-adjuvant chemotherapy (NAC) indication, axillary lymph node status, preNAC cancer prognosis, early and intermediate response to NAC, and post-NAC residual disease in patients with breast cancer. Contrast enhanced MRI with analysis of the tumor morphological features and qualitative enhancement kinetics must be considered as the standard method for pre-NAC breast cancer staging and post-NAC residual disease assessment. Diffusion-weighted imaging (DWI) is easy to perform and may increase the specificity of breast MRI for tumor staging, and also for the assessment of tumor multifocality and multicentricity and lymph node status. It also provides an ancillary added value in the early and post-NAC response evaluation. Changes in the functional tumor volume are the main criterion for the early response analysis. Other MRI methods, such as quantitative perfusion analysis, MR spectroscopy and texture analysis, are still under study. PMID- 30447928 TI - Effect of long term aspirin use on the incidence of prostate cancer: A systematic review and meta-analysis. AB - BACKGROUND: Previous studies found divergent effects of aspirin use on prostate cancer incidence, potentially due to studies with short durations of aspirin use and insufficient adjustment for screening. METHODS: A systematic review on the association between aspirin use >=3 years and incident prostate cancer was performed in accordance with the PRISMA and MOOSE criteria. RESULTS: In the cohort studies, aspirin use for at least 3 years was associated with a lower incidence rate of prostate cancer (Odds ratio (OR) 0.88, 95% CI 0.80-0.97). No protective association was established for the case-control studies (OR 0.92, 95% CI 0.68-1.23). Subgroup analysis of advanced and aggressive cancers showed a protective association (OR 0.82, 95% CI 0.71-0.94 and OR 0.75, 95% CI 0.61-0.97). CONCLUSION: This synthesis of observational studies suggests a potential protective association between long term aspirin use and incident prostate cancer. The current literature is highly heterogenous and suffers from inconsistent aspirin dose definition and measurement. PMID- 30447929 TI - Antithrombotic medication in cancer-associated thrombocytopenia: Current evidence and knowledge gaps. AB - In cancer patients, antithrombotic medications (i.e. anticoagulation or antiplatelet therapy) are frequently prescribed for prior or new indications such as venous thromboembolism or stoke prevention in atrial fibrillation. Balancing the risks of bleeding and thrombosis during periods of thrombocytopenia represents a significant challenge. Management is informed mainly by expert opinion and several recent retrospective studies on venous thromboembolism. The main management options include no change, temporarily withholding antithrombotic therapy, reducing dose, changing the regimen, and increasing the platelet transfusion threshold. Important recent advances in knowledge include the prognostic importance and apparent safety of aspirin in acute myocardial infarction and thrombocytopenia and data suggesting a low risk of recurrent venous thromboembolism in autologous stem cell transplantation patients who had anticoagulation withheld. This paper will review the literature on antithrombotic medication in thrombocytopenic patients with cancer. The significant knowledge gaps will be summarized and considerations for practice and research will be provided. PMID- 30447930 TI - The role of endothelial colony forming cells in kidney cancer's pathogenesis, and in resistance to anti-VEGFR agents and mTOR inhibitors: A speculative review. AB - Renal cell carcinoma (RCC) is highly dependent on angiogenesis, due to the overactivation of the VHL/HIF/VEGF/VEGFRs axis; this justifies the marked sensitivity of this neoplasm to antiangiogenic agents which, however, ultimately fail to control tumor growth. RCC also frequently shows alterations in the mTOR signaling pathway, and mTOR inhibitors have shown a similar pattern of initial activity/late failure as pure antiangiogenic agents. Understanding mechanisms of resistance to these agents would be key to improve the outcome of our patients. Circulating endothelial cells are a family of mainly bone marrow-derived progenitors, which have been postulated to be responsible of the reactivation of angiogenesis in different tumors. In this review, we shall discuss the complex nature and function of these cells, the evidence pro and contra their contribution to tumor vascularization, especially as far as RCC is concerned, and their possible role in determining resistance to presently available treatments. PMID- 30447932 TI - Case Studies in Clinical Practice Management: Patient Demographics and Referral Patterns for [F-18]Fluciclovine-PET Imaging at a Tertiary Academic Medical Center. PMID- 30447933 TI - Simplifying Complexity: Lessons for Radiology From a New Type of Stock Exchange. PMID- 30447931 TI - Continuous therapy in standard- and high-risk newly-diagnosed multiple myeloma: A pooled analysis of 2 phase III trials. AB - BACKGROUND: Risk-adapted therapy is a common strategy in curable hematologic malignancies: standard-risk patients receive less intensive treatment, whereas high-risk patients require a more intensive approach. This model cannot be applied in multiple myeloma (MM), which is still incurable. Continuous treatment (CT) is a key strategy for MM treatment, since it improves duration of remission. However, the role of CT according to standard- or high-risk baseline prognosis remains an open question. PATIENTS AND METHODS: We performed a pooled analysis of 2 phase III trials (GIMEMA-MM-03-05 and RV-MM-PI-209) that randomized patients to CT vs fixed-duration therapy (FDT). RESULTS: In the overall patient population (n = 550), CT improved progression-free survival1 (PFS1) (HR 0.54), PFS2 (HR 0.61) and overall survival (OS) (HR 0.71) vs FDT. CT improved PFS1 both in R-ISS I (HR 0.49) and R-ISS II/III patients (HR 0.55). Four-year PFS1 was 38% in R-ISS II/III patients receiving CT and 25% in R-ISS I patients receiving FDT, with similar trends for PFS2 and OS. High-risk patients benefited more from proteasome inhibitor plus immunomodulatory-based CT than immunomodulatory alone. CONCLUSION: Good prognosis patients receiving FDT lose their prognostic advantage over high risk patients receiving CT and high-risk patients may benefit from more intensive maintenance including proteasome inhibitors and immunomodulators. PMID- 30447934 TI - Canonical BMP signaling in tubular cells mediates recovery after acute kidney injury. AB - Bone morphogenetic protein (BMP) signaling has been shown to modulate the development of renal fibrosis in animal models of kidney injury, but the downstream mediators are incompletely understood. In wild-type mice, canonical BMP signaling mediated by SMAD1/5/8 transcription factors was constitutively active in healthy renal tubules, transiently down-regulated after ischemia reperfusion injury (IRI), and reactivated during successful tubular regeneration. We then induced IRI in mice with a tubular-specific BMP receptor 1A (BMPR1A) deletion. These mice failed to reactivate SMAD1/5/8 signaling in the post ischemic phase and developed renal fibrosis after injury. Using unbiased genomic analyses, we identified three genes encoding inhibitor of DNA-binding (ID) proteins (Id1, Id2, and Id4) as key targets of BMPR1A-SMAD1/5/8 signaling. BMPR1A deficient mice failed to re-induce these targets following IRI. Instead, BMPR1A deficiency resulted in activation of pro-fibrotic signaling proteins that are normally repressed by ID proteins, namely, p38 mitogen-activated protein kinase and cell cycle inhibitor p27. These data indicate that the post-ischemic activation of canonical BMP signaling acts endogenously to repress pro-fibrotic signaling in tubular cells and may help to prevent the progression of acute kidney injury to chronic kidney disease. PMID- 30447936 TI - Enhanced recovery after liver surgery. AB - INTRODUCTION: In a majority of cases, enhanced recovery after surgery program (ERP) leads to a reduced rate of postoperative complications and shortened hospital stays following digestive surgery. The program's preoperative, perioperative and postoperative measures are implemented by the members of a motivated multidisciplinary team. Having shown its merits in digestive surgery, ERP would be particularly useful in liver surgery due to the elevated rates of morbidity and mortality this type of operation continues to entail. The objective of this review was to evaluate the efficacy of ERP in liver surgery. METHOD: This is a systematic narrative review of the literature on the efficacy of ERP in liver surgery by laparotomy or laparoscopy. RESULTS: Notwithstanding a number of studies (n=30: 5 randomized trials, 14 cohort studies and 11 meta-analyses) less sizable than with regard to digestive surgery in general and colorectal surgery in particular, analysis of the literature confirms that in liver surgery, ERP is associated with an overall decrease in complications by 30 to 60%, but without improvement in the rates of hospital readmission and postoperative mortality. All of the studies report a reduction in average length of stay (ALOS) by 2.3 days and in functional recovery, a more objective indicator than ALOS, by 2.5 days. As of now, the economic impact of the ERP programs in liver surgery is neither positive nor negative, the above-mentioned savings being counterbalanced by heightened costs for material and equipment. Laparoscopic surgery is independently associated with better outcomes in terms of complications, functional recovery and ALOS; that is why it is important to incorporate this surgical approach in ERP as often as possible. Given a lack of robust evidence, Prehabilitation, which is a preoperative optimization process leading to improved functional reserve, has yet to be assigned a place in ERP programs pertaining to liver surgery. Possible roadblocks to application of an ERP program can be overcome through coordination by a team leader, a motivated multidisciplinary team, training courses and dedicated teaching sessions. CONCLUSION: ERP is a care improvement process that has a major play to play in organization of liver surgery, and its large-scale application is to be recommended. PMID- 30447935 TI - Phthalates exposure and uterine fibroid burden among women undergoing surgical treatment for fibroids: a preliminary study. AB - OBJECTIVES: To examine the association between phthalate exposure and two measures of uterine fibroid burden: diameter of largest fibroid and uterine volume. DESIGN: Pilot, cross-sectional study. SETTING: Academic medical center. PATIENT(S): Fifty-seven premenopausal women undergoing either hysterectomy or myomectomy for fibroids. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The diameter of the largest fibroid and uterine dimensions were abstracted from medical records. Spot urine samples were analyzed for 14 phthalate biomarkers using mass spectrometry. We estimated associations between fibroid outcomes and individual phthalate metabolites, sum of di(2-ethylhexyl) phthalate metabolites (?DEHP), and a weighted sum of anti-androgenic phthalate metabolites (?AA Phthalates) using linear regression, adjusting for age, race/ethnicity, and body mass index. Fibroid outcomes were also examined dichotomously (divided at the median) using logistic regression. RESULTS: Most women were of black ethnicity, overweight or obese, and college educated. In multivariable models, higher levels of mono-hydroxyisobutyl phthalate, monocarboxyoctyl phthalate, monocarboxynonyl phthalate, mono(2-ethylhexyl) phthalate, mono(2-ethyl-5-hydroxyhexyl phthalate) (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5 carboxypentyl) phthalate (MECPP), ?DEHP, and ?AA Phthalates were positively associated with uterine volume. Associations were most pronounced for individual DEHP metabolites (MEHHP, MEOHP, MECPP), ?DEHP, and ?AA Phthalates. For example, a doubling in ?DEHP and ?AA Phthalates was associated with 33.2% (95% confidence interval 6.6-66.5) and 26.8% (95% confidence interval 2.2-57.4) increase in uterine volume, respectively. There were few associations between phthalate biomarkers and fibroid size. CONCLUSIONS: Exposure to some phthalate biomarkers was positively associated with uterine volume, which further supports the hypothesis that phthalate exposures may be associated with fibroid outcomes. Additional studies are needed to confirm these relationships. PMID- 30447937 TI - A meta-analysis on salvage surgery as a potentially curative procedure in patients with isolated local recurrent or persistent esophageal cancer after chemoradiotherapy. AB - BACKGROUND: Isolated local recurrent or persistent esophageal cancer (EC) after curative intended definitive (dCRT) or neoadjuvant chemoradiotherapy (nCRT) with initially omitted surgery, is a potential indication for salvage surgery. We aimed to evaluate safety and efficacy of salvage surgery in these patients. MATERIAL AND METHODS: A systematic literature search following PRISMA guidelines was performed using databases of PubMed/Medline. All included studies were performed in patients with persistent or recurrent EC after initial treatment with dCRT or nCRT, between 2007 and 2017. Survival analysis was performed with an inverse-variance weighting method. RESULTS: Of the 278 identified studies, 28 were eligible, including a total of 1076 patients. Postoperative complications after salvage esophagectomy were significantly more common among patients with isolated persistent than in those with locoregional recurrent EC, including respiratory (36.6% versus 22.7%; difference in proportion 10.9 with 95% confidence interval (CI) [3.1; 18.7]) and cardiovascular complications (10.4% versus 4.5%; difference in proportion 5.9 with 95% CI [1.5; 10.2]). The pooled estimated 30- and 90-day mortality was 2.6% [1.6; 3.6] and 8.0% [6.3; 9.8], respectively. The pooled estimated 3-year and 5-year overall survival (OS) were 39.0% (95% CI: [35.8; 42.2]) and 19.4% [95% CI:16.5; 22.4], respectively. Patients with isolated persistent or recurrent EC after initial CRT had similar 5 year OS (14.0% versus 19.7%, difference in proportion -5.7, 95% CI [-13.7; 2.3]). CONCLUSIONS: Salvage surgery is a potentially curative procedure in patients with locally recurrent or persistent esophageal cancer and can be performed safely after definitive or neoadjuvant chemoradiotherapy when surgery was initially omitted. PMID- 30447938 TI - When Short Stature Is an Asset in Trees. AB - With their imposing grandeur, the small number of very tall tree species attract a disproportionate amount of scientific study. We right this bias by focusing here on the shorter trees, which often grow in the shade of the giants and many other places besides. That tall trees are so restricted in distribution indicates that there are far more habitats available for small trees. We discuss some leading candidates for the mechanisms that limit maximum plant height in any given habitat, as well as why every habitat has a range of plant sizes. At least two attributes - greater adaptation capacity and higher drought resistance - suggest that the forests of the future belong to short trees. PMID- 30447939 TI - Finding Common Ground between Adaptive Management and Evidence-Based Approaches to Biodiversity Conservation. AB - Adaptive management (AM) and evidence-based conservation (EBC) have emerged as major decision-making frameworks for conservation management. AM deals with complexity and the importance of local context in making conservation decisions under conditions of high variability, uncertainty, and rapid environmental and social change. EBC seeks for generality from empirical data and aims to develop and enhance best practice. The goal of this review is to explore opportunities for finding common ground between AM and EBC. We propose a framework for distinguishing the subset of conservation problems that are amenable to an evidence-based approach, based on levels of uncertainty, complexity, and social agreement. We then suggest ways for combining multiple lines of evidence and developing greater opportunities for iteration and co-learning in EBC. PMID- 30447940 TI - Postoperative Delirium After Noncardiac Surgery. PMID- 30447941 TI - Pearl millet stress-responsive NAC transcription factor PgNAC21 enhances salinity stress tolerance in Arabidopsis. AB - Pearl millet (Pennisetum glaucum) is the sixth-leading cereal crop and a staple food crop. It is known for its high tolerance to abiotic stress and good nutrient profile. NAC (NAM, ATAF1/2 and CUC) transcription factors (TFs) play an important role in abiotic stress tolerance. In our study, the pearl millet stress responsive NAC TF gene PgNAC21 was characterized. Gene expression analysis revealed that PgNAC21 expression is induced by salinity stress and abscisic acid (ABA) treatment. In silico promoter analysis showed the presence of ABA response elements (ABREs) and MYB TF binding sites. A yeast one-hybrid assay indicated that a putative MYB TF in pearl millet, PgMYB1, binds to the promoter of PgNAC21. A transactivation assay in yeast cells revealed that PgNAC21 functions as a transcription activator and that its activation domain is located in its C terminus. Relative to control plants, Arabidopsis plants overexpressing PgNAC21 exhibited better seed germination, heavier fresh weight and greater root length under salinity stress. Overexpression of PgNAC21 in Arabidopsis plants also enhanced the expression of stress-responsive genes such as GSTF6 (GLUTATHIONE S TRANSFERASE 6), COR47 (COLD-REGULATED 47) and RD20 (RESPONSIVE TO DEHYDRATION 20). Our data demonstrate that PgNAC21 functions as a stress-responsive NAC TF and can be utilized in transgenic approaches for developing salinity stress tolerance in crop plants. PMID- 30447942 TI - The synergistic effects of sodium and potassium on the xerophyte Apocynum venetum in response to drought stress. AB - Apocynum venetum is an eco-economic plant species with high adaptability to saline and arid environments. Our previous work has found that A. venetum could absorb large amount of Na+ and maintain high K+ level under saline conditions. To investigate whether K+ and Na+ could simultaneously enhance drought resistance in A. venetum, seedlings were exposed to osmotic stress (-0.2 MPa) in the presence or absence of additional 25 mM NaCl under low (0.01 mM) and normal (2.5 mM) K+ supplying conditions, respectively. The results showed that A. venetum should be considered as a typical K+-efficient species since its growth was unimpaired and possessed a strong K+ uptake and prominent K+ utilization efficiency under K+ deficiency condition. Leaf K+ concentration remained stable or was even significantly increased under osmotic stress in the presence or absence of NaCl, compared with that under control condition, regardless of whether the K+ supply was sufficient or not, and the contribution of K+ to leaf osmotic potential consistently exceeded 37%, indicating K+ is the uppermost contributor to osmotic adjustment of A. venetum. Under osmotic stress, the addition of 25 mM NaCl significantly increase Na+ accumulation in leaves and the contribution of Na+ to osmotic adjustment, thus improving the relative water content, concomitantly, promoting the photosynthetic activity resulting in an enhancement of overall plant growth. These findings suggested that, K+ and Na+ simultaneously play crucial roles in the osmotic adjustment and the maintenance of water status and photosynthetic activity, which is beneficial for A. venetum to cope with drought stress. PMID- 30447943 TI - It's Time to Wake Up to the Use of Pharmacologic Sleep Aids by Emergency Physicians. PMID- 30447944 TI - Oral Ondansetron to Reduce Intravenous Fluid Rehydration: Context Matters. PMID- 30447945 TI - Age-Related Characteristics and Outcomes for Patients With Severe Trauma: Analysis of Japan's Nationwide Trauma Registry. AB - STUDY OBJECTIVE: Although geriatric trauma patients are becoming more common, few large-scale analyses have comprehensively evaluated geriatric-specific characteristics in trauma. This study aims to clarify the age-specific characteristics, outcomes, and predictive accuracy of current trauma scoring systems among geriatric trauma patients. METHODS: Patients with severe trauma, with an Abbreviated Injury Scale score greater than or equal to 3, and registered in the Japan Trauma Data Bank during 2004 to 2015 were retrospectively reviewed. Age-related differences were assessed for injury mechanism, injured region, anatomic and physiologic severity, and inhospital mortality. The mortality risk was evaluated with multivariate mixed-effect models adjusted for Injury Severity Score, Revised Trauma Score, year of injury, and treating facility. Age-related differences in the accuracy of the Injury Severity Score and Revised Trauma Score for predicting inhospital mortality were evaluated with an area under the receiver operating characteristic curve. RESULTS: We identified 127,303 patients, including 67,316 geriatric patients (52.9%) who were aged 60 years or older. The percentage of geriatric patients increased from 31.9% to 59.7% during the study period. The most frequent injury mechanism was ground-level falls (55.2%) and the most frequently injured region was the pelvis and lower extremities (43.7%). Severity-adjusted mixed-effects models revealed a marked age-dependent increase in mortality. Although the Injury Severity Score had similar predictive accuracy among all generations, the accuracy of the Revised Trauma Score decreased with increasing age. CONCLUSION: The characteristics of trauma patients varied widely according to age, and mortality risk increased steadily with increasing age, despite a decrease in anatomic injury severity. The Revised Trauma Score had decreasing predictive accuracy at older ages, suggesting that an alternative measure is needed. PMID- 30447947 TI - A Cost-Effectiveness Analysis Comparing Clinical Decision Rules PECARN, CATCH, and CHALICE With Usual Care for the Management of Pediatric Head Injury. AB - STUDY OBJECTIVE: To determine the cost-effectiveness of 3 clinical decision rules in comparison to Australian and New Zealand usual care: the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE), the Pediatric Emergency Care Applied Research Network (PECARN), and the Canadian Assessment of Tomography for Childhood Head Injury (CATCH). METHODS: A decision analytic model was constructed from the Australian health care system perspective to compare costs and outcomes of the 3 clinical decision rules compared with Australian and New Zealand usual care. The study involved multicenter recruitment from 10 Australian and New Zealand hospitals; recruitment was based on the Australian Pediatric Head Injury Rules Study involving 18,913 children younger than 18 years and with a head injury, and with Glasgow Coma Scale score 13 to 15 on presentation to emergency departments (EDs). We determined the cost effectiveness of the 3 clinical decision rules compared with usual care. RESULTS: Usual care, CHALICE, PECARN, and CATCH strategies cost on average AUD $6,390, $6,423, $6,433, and $6,457 per patient, respectively. Usual care was more effective and less costly than all other strategies and is therefore the dominant strategy. Probabilistic sensitivity analyses showed that when simulated 1,000 times, usual care dominated all clinical decision rules in 61%, 62%, and 60% of simulations (CHALICE, PECARN, and CATCH, respectively). The difference in cost between all rules was less than $36 (95% confidence interval -$7 to $77) and the difference in quality-adjusted life-years was less than 0.00097 (95% confidence interval 0.0015 to 0.00044). Results remained robust under sensitivity analyses. CONCLUSION: This evaluation demonstrated that the 3 published international pediatric head injury clinical decision rules were not more cost-effective than usual care in Australian and New Zealand tertiary EDs. Understanding the usual care context and the likely cost-effectiveness is useful before investing in implementation of clinical decision rules or incorporation into a guideline. PMID- 30447948 TI - Ebstein's anomaly with imperforate tricuspid valve: An extremely rare congenital anomaly. PMID- 30447949 TI - Effect of image reconstruction algorithms on volumetric and radiomic parameters of coronary plaques. AB - BACKGROUND: Volumetric and radiomic analysis of atherosclerotic plaques on coronary CT angiography have been shown to predict high-risk plaque morphology and to predict patient outcomes. However, there is limited information whether image reconstruction algorithms and preprocessing steps (type of binning, number of bins used for discretization) may influence parameter values. METHODS: We retrospectively identified 60 coronary lesions on coronary CT angiography (CTA). All images were reconstructed using filtered back projection (FBP), hybrid (HIR) and model-based (MIR) iterative reconstruction. Plaques were segmented manually on HIR images and copied to FBP and MIR images to ensure identical voxels were analyzed. Overall, 4 volumetric and 169 radiomic parameters were calculated. Intra-class correlation coefficient (ICC) was used to assess reproducibility between image reconstructions, while linear regression analysis was used to assess the effect of preprocessing steps done before calculating radiomic metrics. RESULTS: All volumetric and radiomic metrics had ICC>0.90 except for first-order statistics: mode, harmonic mean, minimum (0.45, 0.76, 0.84; respectively) and gray level co-occurrence (GLCM) parameters: inverse difference sum and sum variance (0.01, 0.04; respectively). Among GLCM parameters 90% were significantly affected by the type of binning and 100% by the number of bins. In case of gray level run length matrix parameters 100% of metrics were affected by both preprocessing steps. CONCLUSIONS: Volumetric and radiomic statistics are robust to image reconstruction algorithms. However, all radiomic variables were affected by preprocessing steps therefore, showing the need for standardization before being implemented into everyday clinical practice. PMID- 30447950 TI - Severe chronic blepharitis. Torpid evolution of several years. PMID- 30447946 TI - Older Blood Is Associated With Increased Mortality and Adverse Events in Massively Transfused Trauma Patients: Secondary Analysis of the PROPPR Trial. AB - STUDY OBJECTIVE: The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion. METHODS: We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial. Subjects in the parent trial included critically injured adult patients admitted to 1 of 12 North American Level I trauma centers who received at least 1 unit of packed RBCs and were predicted to require massive blood transfusion. The primary exposure was volume of packed RBC units transfused during the first 24 hours of hospitalization, stratified by packed RBC age category: 0 to 7 days, 8 to 14 days, 15 to 21 days, and greater than or equal to 22 days. The primary outcome was 24-hour mortality. We evaluated the association between transfused volume of each packed RBC age category and 24-hour survival, using random-effects logistic regression, adjusting for total packed RBC volume, patient age, sex, race, mechanism of injury, Injury Severity Score, Revised Trauma Score, clinical site, and trial treatment group. RESULTS: The 678 patients included in the analysis received a total of 8,830 packed RBC units. One hundred patients (14.8%) died within the first 24 hours. On multivariable analysis, the number of packed RBCs greater than or equal to 22 days old was independently associated with increased 24-hour mortality (adjusted odds ratio [OR] 1.05 per packed RBC unit; 95% confidence interval [CI] 1.01 to 1.08): OR 0.97 for 0 to 7 days old (95% CI 0.88 to 1.08), OR 1.04 for 8 to 14 days old (95% CI 0.99 to 1.09), and OR 1.02 for 15 to 21 days old (95% CI 0.98 to 1.06). Results of sensitivity analyses were similar only among patients who received greater than or equal to 10 packed RBC units. CONCLUSION: Increasing quantities of older packed RBCs are associated with increased likelihood of 24-hour mortality in trauma patients receiving massive packed RBC transfusion (>=10 units), but not in those who receive fewer than 10 units. PMID- 30447951 TI - Prognostic impact of regression in patients with primary cutaneous melanoma >1 mm in thickness. AB - BACKGROUND: The impact of histologic regression on sentinel lymph node biopsy (SLNB) status and on clinical outcome is uncertain. OBJECTIVE: To investigate whether and to what extent regression <75% is able to predict SLNB status and clinical outcome of patients with melanoma >1-mm thick. METHODS: The study included patients with diagnoses given at 4 centers of the Italian Melanoma Intergroup. Univariate and multivariate Cox proportional hazard models stratified by center were used to analyze the effect of regression on disease-free interval and melanoma-specific survival. RESULTS: Out of 1182 patients given primary cutaneous melanoma diagnoses during 1998-2015 with a Breslow thickness >1 mm, 954 (304 with and 650 without regression) were included in the analysis. The proportion of patients with a positive SLNB was lower in patients with regression than without (24.4% vs 31.6%, chi-squared test P = .0368). At multivariate analysis, no association was detected between regression and disease-free interval (hazard ratio 1.11, 95% confidence interval 0.85-1.46; P = .4509) or melanoma-specific survival (hazard ratio 1.05, 95% confidence interval 0.77-1.44; P = .7600). LIMITATION: Retrospective analysis. CONCLUSION: In our series, regression was not an independent prognostic factor in primary cutaneous melanoma patients with Breslow thickness >1 mm whereas it was associated with a lower incidence of SLNB positivity. PMID- 30447952 TI - Prevalences of Stages of Change for Smoking Cessation in Adolescents and Associated Factors: Systematic Review and Meta-Analysis. AB - PURPOSE: To synthesize evidence on the prevalences of stages of change (Transtheoretical Model) for smoking cessation in adolescents and associated factors. METHODS: A systematic search of Web of Science (Thomson Reuters), SCOPUS (Elsevier), MEDLINE/PubMed, CINAHL (EBSCO) and PsycINFO (APA) was conducted to identify eligible studies. Two calibrated reviewers selected studies independently, extracted data, and appraised studies. A qualitative synthesis of the findings and meta-analysis of the prevalences of the stages of change for smoking cessation were carried out. A quality effects model was used to estimate the pooled prevalences. RESULTS: Eleven studies (N = 6469 adolescents) from five middle- to high-income countries were included in the review. Precontemplators accounted for 41% of smokers in earlier stages of change (95%CI: 34%-49%). In such a group, a lowered decisional balance, the lowest self-efficacy, and highest nicotine dependence were found (p < .05). CONCLUSIONS: A higher overall prevalence of adolescents in precontemplation stage for smoking cessation was observed. Such group displayed more unfavorable smoking-related behaviors and characteristics than adolescents in other stages. The evidence is limited due to the lack of studies in adolescents living in low-income countries. PMID- 30447953 TI - Identifying Syndemics for Sexually Transmitted Infections Among Young Adults in the United States: A Latent Class Analysis. AB - PURPOSE: Syndemic theory suggests that the convergence of social, environmental, and ecological factors can interact to exacerbate behavioral health problems and are often intensified by social conditions and disparities. This study used latent class analysis (LCA) to determine gender and racial/ethnic specific classes for sexually transmitted infection (STI) risk. METHODS: LCA included 18 measured socioeconomic, depression, substance use, and sexual behavioral variables from 1,664 young adults ages 18-25 in the NHANES. Models were stratified by gender and then by race/ethnicity. Logistic regression determined associations between latent class membership and testing positive for one or more STIs (Chlamydia trachomatis, HIV or herpes simplex virus-II). For each stratified analysis, classes with the lowest probability of reported risk factors in the LCA were the reference groups. RESULTS: Class 3 in females (highest probability of reporting both socioeconomic and behavioral factors) and class 3 in males (majority behavioral factors) had increased odds of STI (females: OR = 2.7, 95% CI 1.6-4.5; males: OR 2.5, 95% CI 1.3-4.6). By race for females, depression (highest in Hispanics), poverty, and less educated households (highest in blacks and Hispanics) were evident in classes associated with STI. Class 1 black males (majority behavioral factors) had a higher odds of STI compared with low risk white males (OR = 16.4 95% CI 3.7-72.0) However, no other associations were observed among males. CONCLUSIONS: Risk patterns for STI differed by gender and race/ethnicity. Consistent with syndemic theory, effective STI interventions need to address socioeconomic factors and mental health rather than individual behaviors, particularly for minority women. PMID- 30447954 TI - Prevalence and Prognostic Significance of Negative U-waves in a 12-lead Electrocardiogram in the General Population. AB - Negative U-waves are a relatively rare finding in an electrocardiogram (ECG), but are often associated with cardiac disease. The prognostic significance of negative U-waves in the general population is unknown. We evaluated 12-lead ECGs of 6,518 adults (45% male, mean age 50.9 +/- 13.8 years) for the presence of U waves, and followed the subjects for 24.5 +/- 10.3 years. Primary end points were all-cause mortality, cardiac mortality, and sudden cardiac death; secondary end point was hospitalization due to cardiac causes. Negative U-waves (amplitude >=0.05 mV) were present in 231 subjects (3.5%), minor negative (amplitude <0.05 mV) or discordant U-waves in 1,004 subjects (15.4%), normal positive U-waves in 3,950 (60.6%) subjects, and no U-waves were observed in 603 subjects (9.3%). In 730 subjects (11.2%), U-waves were unassessable. When adjusted for age and gender, negative U-waves were associated with all end points (p <0.01). In an analysis adjusted for multiple demographic and clinical factors, in men, negative U-waves were associated with increased risk of all-cause mortality (hazard ratio [HR] 1.60; 95% confidence interval [CI] 1.26 to 2.03; p <0.001), cardiac mortality (HR 1.74; 95% CI 1.26 to 2.39; p = 0.001), and cardiac hospitalization (HR 1.67; 95% CI 1.27 to 2.18; p <0.001), but not with sudden cardiac death, whereas women did not show a significant association to any of the end points (p >0.30). In conclusion, negative U-waves are associated with adverse events in the general population. In men, this association is independent of cardiovascular risk factors. PMID- 30447955 TI - Association of Electronic Cigarette Use With Myocardial Infarction: Persistent Uncertainty. PMID- 30447956 TI - Moth-eaten appearance of the iris in Fuchs heterochromic iridocyclitis. PMID- 30447957 TI - [Orbital fat prolapse]. PMID- 30447958 TI - Nitric oxide provides myocardial protection when added to the cardiopulmonary bypass circuit during cardiac surgery: Randomized trial. AB - OBJECTIVES: The aim of this pilot study was to elucidate the effects of exogenous nitric oxide (NO) supply to the extracorporeal circulation circuit for cardioprotection against ischemia-reperfusion injury during coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB). METHODS: A total of 60 patients with coronary artery disease scheduled for CABG with CPB were enrolled in a prospective randomized study. Patients were allocated randomly to receive treatment according to standard or modified CPB protocol where 40-ppm NO was added to the CPB circuit during cardiac surgery. The primary endpoint was the measurement of cardiac troponin I (cTnI). The secondary end points consisted in the measurements of creatine kinase-muscle/brain fraction (CK-MB) and vasoactive inotropic score (VIS). RESULTS: NO delivered into the CPB circuit had a cardioprotective effect. The level of cTnI was significantly lower in NO-treated group compared with the control group 6 hours after surgery: 1.79 +/- 0.39 ng/mL versus 2.41 +/- 0.55 ng/mL, respectively (P = .001). The CK-MB value was significantly lower in NO-treated group compared with the control group 24 hours after surgery: 47.69 +/- 8.08 U/L versus 62.25 +/- 9.78 U/L, respectively (P = .001); and the VIS was significantly lower in the NO-treated group 6 hours after the intervention. CONCLUSIONS: NO supply to the CPB circuit during CABG exerted a cardioprotective effect and was associated with lower levels of VIS and cardiospecific blood markers cTnI and CK-MB. PMID- 30447959 TI - Papillary fibroelastoma: A unique case of distant recurrence. PMID- 30447960 TI - Pathologic complete response after esophagectomy following neoadjuvant chemoradiation therapy for esophageal carcinoma: A cure sometimes? PMID- 30447961 TI - Balloon protection of the left subclavian artery in debranching thoracic endovascular aortic repair. AB - OBJECTIVES: Since 2012, we have routinely applied balloon protection of the proximal left subclavian artery to prevent embolic events through the left vertebral artery during debranching thoracic endovascular aortic repair. This study aimed to study the effectiveness of balloon protection of the proximal left subclavian artery. METHODS: We reviewed the medical records of 157 patients who underwent debranching thoracic endovascular aortic repair between 2007 and 2017. Of these, 71 patients for whom balloon protection of the proximal left subclavian artery was used were assigned to the balloon protection of the proximal left subclavian artery group (58 men; age: 78 +/- 6.7 years), and 86 patients were assigned to the control group (66 men; age: 78 +/- 8.9 years). A total of 51 patients from each group were matched by their propensity scores to adjust for differences in the patients' characteristics. RESULTS: Perioperative stroke was significantly lower in the balloon protection of the proximal left subclavian artery group than in the control group (0%: 0/71 vs 7.9%: 7/86, P = .014). Freedom from all causes of mortality at 2 and 4 years was significantly higher in the balloon protection of the proximal left subclavian artery group compared with the control group (93%/76% vs 77%/59%, P = .015). Freedom from aortic death at 2 and 4 years was similar in both groups (97%/97% vs 91%/86%, P = .094). Propensity score matching yielded similar results of better freedom from all causes of mortality in the balloon protection of the proximal left subclavian artery group (93%/93% vs 81%/63%, P = .017) and equivalent aortic death in both groups (95%/95% vs 92%/88%, P = .30). CONCLUSIONS: Debranching thoracic endovascular aortic repair using balloon protection of the proximal left subclavian artery demonstrated more appropriate early and late outcomes. Evaluation using propensity score matching enhanced the efficacy of balloon protection of the proximal left subclavian artery. PMID- 30447962 TI - MicroRNA-145-loaded poly(lactic-co-glycolic acid) nanoparticles attenuate venous intimal hyperplasia in a rabbit model. AB - BACKGROUND: MicroRNA-145 (miR-145) reportedly alters the phenotype of vascular smooth muscle cells (VSMCs) from a proliferative to a contractile state. So far, viral or plasmid vectors have been experimentally used to transduce microRNAs into VSMCs. We hypothesized that a simple ex vivo microRNA delivery system using miR-145-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA NPs) could control the VSMC phenotype and prevent intimal hyperplasia. METHODS: Jugular vein grafts of male Japanese white rabbits were soaked in phosphate buffered saline, control microRNA (cont-miR)-loaded PLGA NP solution or miR-145 loaded PLGA NP solution for 30 minutes (n = 8 for each). Vein grafts were implanted in the ipsilateral carotid artery and assessed 2 weeks after the implantation. RESULTS: Quantitative polymerase chain reaction analysis showed significantly higher miR-145 expression in the miR-145-treated group. The neointimal area was significantly smaller in the miR-145-treated group (phosphate buffered saline-treated vs cont-miR-treated vs miR-145-treated group; 1.63 +/- 0.52 mm2 vs 1.67 +/- 0.49 mm2 vs 0.88 +/- 0.34 mm2, respectively; P < .01 for the miR-145-treated vs the cont-miR-treated group). In the miR-145-treated group, Ki 67-positive cells were significantly fewer, indicating lower VSMC proliferation. An inflammation-related molecule, CD40 expression was significantly reduced by miR-145-loaded PLGA NP treatment. CONCLUSIONS: Local and sustained release of miR 145 by PLGA NPs attenuated intimal hyperplasia in the rabbit model by maintaining VSMCs in a contractile state. This simple ex vivo miR-145 delivery system would be promising toward broader clinical application. PMID- 30447963 TI - The fenestrated frozen elephant trunk technique: A not-all-comers strategy. PMID- 30447964 TI - Coronary artery arteriovenous malformation. PMID- 30447965 TI - Characterization of 3-dimensional papillary muscle displacement in in vivo ovine models of ischemic/functional mitral regurgitation. AB - OBJECTIVE: Papillary muscle (PM) displacement contributes to ischemic/functional mitral regurgitation (IMR/FMR). The displaced PMs pull the mitral leaflets into the left ventricle (ie, toward the apex) thus hampering leaflet coaptation. Intuitively apical leaflet tethering results from apical PM displacement. The 3 dimensional directions of PM displacement are, however, incompletely characterized. METHODS: Data from in vivo ovine models of IMR (6-8 weeks of posterolateral infarction, n = 12) and FMR (9-21 days of rapid left ventricular pacing, n = 11) were analyzed. All sheep had radiopaque markers implanted on the anterior and posterior PM (PPM) tips, around the mitral annulus, and on the left ventricular apex. To explore 3-dimensional PM displacement directions, differences in marker coordinates were calculated at end-systole before and during IMR/FMR using a right-handed coordinate system centered on the mitral annular "saddle horn" with the y-axis passing through the apical marker. RESULTS: No apical PM displacement was observed during either IMR or FMR. The anterior PM displaced laterally during FMR. Posterolateral PPM displacement was observed during IMR and FMR. CONCLUSIONS: Experimental in vivo ovine models suggest posterolateral PPM displacement as a predominant pathomechanism leading to apical leaflet tethering during IMR/FMR. PMID- 30447966 TI - MI VII: Cardiac tumor; CMRI I: The solution. PMID- 30447967 TI - Looking to prevent acute kidney injury after cardiac surgery? Just check the urine. PMID- 30447968 TI - Totally endoscopic bypass grafting: Hunting for a Norwegian mushroom. PMID- 30447970 TI - Competing to raise awareness of rare diseases. PMID- 30447971 TI - "No, actually it is not a headache". PMID- 30447972 TI - Towards faster studies of neonatal encephalopathy. PMID- 30447969 TI - Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. AB - BACKGROUND: In neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy. METHODS: We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4-14 days after birth. Clinical neurodevelopmental tests were done 18-24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711. FINDINGS: Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5-10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20-25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0.99 [95% CI 0.94-1.00]; sensitivity 100% [74 100]; specificity 97% [90-100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0.72 (0.65-0.78) and 0.60 (0.53-0.68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0.73 (0.65-0.79). On conventional MRI (n=190), cortical injury had an AUC of 0.67 (0.60-0.73), basal ganglia or thalamic injury had an AUC of 0.81 (0.75-0.87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0.82 (0.76-0.87). Fractional anisotropy of PLIC (n=65) had an AUC of 0.82 (0.76 0.87). MRS metabolite peak-area ratios (n=160) of NAA-creatine (<1.29) had an AUC of 0.79 (0.72-0.85), of NAA-choline had an AUC of 0.74 (0.66-0.80), and of lactate-NAA (>0.22) had an AUC of 0.94 (0.89-0.97). INTERPRETATION: Thalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration. FUNDING: National Institute for Health Research UK. PMID- 30447973 TI - Local Food Sources to Promote Community Nutrition and Health: Storefront Businesses, Farmers' Markets, and a Case for Mobile Food Vending. PMID- 30447974 TI - Interactions of human chorionic gonadotropin with genotype and parity on fertility responses of lactating dairy cows. AB - Fertility-promoting effects of treatment of lactating dairy cattle with human chorionic gonadotropin (hCG) after artificial insemination (AI) have been variable. Here, we tested whether fertility response to hCG in lactating Holstein cows interacts with genotype and parity. Primiparous (n = 538) and multiparous (n = 613) cows were treated with hCG (3,300 IU) or vehicle 5 d after AI. Pregnancy was diagnosed on d 32 and 60 after AI. A subset of cows (n = 593-701) was genotyped for 4 single nucleotide polymorphisms (SNP) previously associated with fertility. Treatment with hCG increased progesterone concentration on d 12 after AI regardless of genotype or parity. Pregnancy per AI was improved by hCG in primiparous cows but not in multiparous cows. Moreover, hCG treatment interacted with a SNP in coenzyme Q9 (COQ9) to affect fertility. Fertility of cows treated with vehicle was greatest for the AA allele, whereas fertility was lowest for the same genotype among cows treated with hCG. Pregnancy per AI was also affected by genotype for heat shock protein A1-like (HSPA1L) and progesterone receptor (PGR), but no interactions were observed with treatment. Genotype for a SNP in prostate androgen-regulated mucin-like protein 1 (PARM1) was not associated with fertility. Overall, results show that variation in response to hCG treatment on fertility depends on parity and interacts with a SNP in COQ9. PMID- 30447975 TI - Systemic and skin-targeting beneficial effects of lycopene-enriched ice cream: A pilot study. AB - The health-promoting dietary antioxidant lycopene has limited natural bioavailability, but lycopene-rich functional foods can improve its bioavailability. We assessed a new lycopene-enriched ice cream for systemic antioxidant effects and influence on morphological characteristics of facial skin surface in healthy volunteers. In a randomized crossover study, we used 4-wk dietary interventions with either control or lycopene-enriched ice cream. Samples of serum and residual skin surface components (RSSC) from facial skin were taken before interventions, at 2 wk, and at intervention end. Lycopene concentration, conventional blood biochemistry, and oxidative stress biomarkers comprising inflammatory oxidative damage and low-density lipoprotein peroxidase proteins were assessed in the serum. Lycopene-associated immunofluorescence, lipid droplet size, corneocyte desquamation, and microbial presence were measured in the RSSC. The results show that lycopene concentrations in the serum and skin steadily increased during lycopene-enriched ice cream consumption. Whereas we found no intervention-dependent changes in conventional biochemical parameters, both inflammatory oxidative damage and low-density lipoprotein peroxidase protein values significantly decreased by the end of intervention with lycopene-enriched ice cream, but remained unchanged during control ice cream consumption. Control ice cream significantly increased corneocyte desquamation and bacterial presence in the RSSC. These adverse effects, which could potentially predispose consumers to acne development, were absent when volunteers consumed lycopene-enriched ice cream. We concluded that lycopene-enriched ice cream is a new functional food with clear antioxidant properties. In addition, enrichment with lycopene may alleviate proinflammatory action of ice cream at the level of facial skin, thus decreasing diet-associated acne development risk in young consumers. PMID- 30447976 TI - A survey on the incidence of Prototheca mastitis in dairy herds in Lublin province, Poland. AB - Prototheca mastitis has recently become an emerging disease; although its incidence is increasing steadily, its epidemiology remains largely understudied. The aim of this work was to investigate the prevalence of Prototheca spp. in dairy cows and their environment in Lublin province, covering most of southeastern Poland. Between December 2015 and July 2016, a total of 172 milking cows from 10 dairy farms were inspected for mastitis using clinical examination and the California Mastitis Test (CMT). Quarter milk samples (QMS, n = 179) and body site swabs (n = 151) from CMT-positive cows were collected for microbiological culture. In addition, we evaluated QMS and body site swabs from 23 healthy cows, along with 91 environmental samples. Of 100 CMT-positive cows, 71 had at least one QMS positive for microbial growth. In 8 (11.3%) of these cows, originating from 7 dairy farms, Prototheca spp. were cultured. The average somatic cell count of the Prototheca-containing milk was 4.02 * 106 cells/mL compared with 0.13 * 106 cells/mL of the Prototheca-free milk (collected from control animals). No significant differences were observed between mastitis and control cows with respect to counts of total white blood cells, lymphocytes, neutrophils, and eosinophils. Half of the cows with Prototheca spp. in their milk did not yield the algae from other anatomical sites. Eight cows were negative for the presence of Prototheca spp. in their milk but positive for the algae in swabs from anatomical sites. Among the environmental sources that were positive for Prototheca growth were watering troughs, manure, feed, and mud. All (45) Prototheca isolates recovered in this study were subjected to species- and genotype-level molecular identification. All QMS and most of the animal swabs (90%) yielded Prototheca zopfii genotype (gen.) 2. Of the animal samples, P. zopfii gen. 1 and Prototheca blaschkeae were isolated only from feces and rectum. Environmental samples grew either P. zopfii gen. 2 (67%) or P. zopfii gen. 1 (33%). This study demonstrates that P. zopfii gen. 2 is the third most common pathogen of mastitis in cattle in southeast Poland, with an overall incidence of 4.6%. Finding Prototheca spp., including P. zopfii gen. 1 and 2 and P. blaschkeae, in stool and rectal swabs from healthy animals may suggest their role as nonpathogenic microflora of bovine gut. PMID- 30447977 TI - Dry inoculation methods for nonfat milk powder. AB - Carriers with inoculated microorganisms are often used to validate low-moisture food safety interventions. In this study, we evaluated dry inoculation methods using silicon dioxide (SiO2) and a small portion of nonfat milk powder (NFMP) as dry carriers for NFMP. Silicon dioxide was characterized by vapor sorption analysis. One milliliter of inoculum of a 5-strain Salmonella cocktail (serovars Agona, Reading, Tennessee, Montevideo, and Mbandaka) or Enterococcus faecium NRRL B-2354 was inoculated onto 1 g of SiO2 or 10 g of NFMP as carriers. Both inoculated carriers were air-dried for 72 h [22 degrees C, relative humidity (RH) ~30%], equilibrated to water activity (aw) 0.25 +/- 0.02 (24 h at 22 degrees C, RH 25%), and mixed with preconditioned NFMP (aw = 0.25 +/- 0.02) to reach an inoculation level of 8.2 +/- 0.2 log cfu/g. Inoculated NFMP was stored at 22 degrees C, RH 25%, and its bacterial populations were monitored for 30 d. Both sets in equilibrated NFMP were subjected to isothermal treatments in closed aluminum cells at 85, 90, and 95 degrees C. Silicon dioxide maintained moisture content (0.29 +/- 0.03%, dry basis) at different water activities. The NFMP inoculated with both carriers exhibited stable bacterial populations over 30 d at 22 degrees C. Strains in NFMP inoculated with SiO2 showed equal or higher D values but equal z-values compared with those inoculated with a small portion of NFMP. Enterococcus faecium exhibited comparable thermal resistance to Salmonella under all tested conditions. This study supports E. faecium as a Salmonella surrogate in thermal processing of NFMP and the use of SiO2 to inoculate NFMP. PMID- 30447978 TI - Effect of a whey protein and rapeseed oil gel feed supplement on milk fatty acid composition of Holstein cows. AB - Isoenergetic replacement of dietary saturated fatty acids (SFA) with cis monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) can reduce cardiovascular disease risk. Supplementing dairy cow diets with plant oils lowers milk fat SFA concentrations. However, this feeding strategy can also increase milk fat trans fatty acids (FA) and negatively affect rumen fermentation. Protection of oil supplements from the rumen environment is therefore needed. In the present study a whey protein gel (WPG) of rapeseed oil (RO) was produced for feeding to dairy cows, in 2 experiments. In experiment 1, four multiparous Holstein-Friesian cows in mid-lactation were used in a change over experiment, with 8-d treatment periods separated by a 5-d washout period. Total mixed ration diets containing 420 g of RO or WPG providing 420 g of RO were fed and the effects on milk production, composition, and FA concentration were measured. Experiment 2 involved 4 multiparous mid-lactation Holstein-Friesian cows in a 4 * 4 Latin square design experiment, with 28-d periods, to investigate the effect of incremental dietary inclusion (0, 271, 617, and 814 g/d supplemental oil) of WPG on milk production, composition, and FA concentration in the last week of each period. Whey protein gel had minimal effects on milk FA profile in experiment 1, but trans-18:1 and total trans-MUFA were higher after 8 d of supplementation with RO than with WPG. Incremental diet inclusion of WPG in experiment 2 resulted in linear increases in milk yield, cis- and trans-MUFA and PUFA, and linear decreases in SFA (from 73 to 58 g/100 g of FA) and milk fat concentration. The WPG supplement was effective at decreasing milk SFA concentration by replacement with MUFA and PUFA in experiment 2, but the increase in trans FA suggested that protection was incomplete. PMID- 30447979 TI - Development of a mathematical model to predict pool sizes and rates of digestion of 2 pools of digestible neutral detergent fiber and an undigested neutral detergent fiber fraction within various forages. AB - The digestion of neutral detergent fiber treated with amylase and sodium sulfite and ash corrected (aNDFom) has been described as a single digestible pool and a fraction undigested in ruminants. Further, most models that predict rate and extent of digestion of aNDFom in the rumen assume first-order processes, in which the rates of digestion and passage are proportional to the pool size of aNDFom consumed and digested. Data exist demonstrating that the undigested fraction of aNDFom is not well described by a fixed coefficient and varies by maturity and agronomic growing conditions of the plant. Thus, our objective was to improve the prediction of digestible aNDFom (pdNDF) and to quantify, using a minimum number of fermentation time points, 2 pools of digestible aNDFom, pdNDF1 and pdNDF2, and their respective rates. Based on fermentations from 0 to 240 h among 34 forages (grasses, conventional and brown midrib corn silages, and alfalfas), 3 pools were described by aNDFomt = pdNDF1 * e-k1(t-L) + pdNDF2 * e-k2(t-L) + uNDF, where aNDFomt is the residue at time t; L is the lag; k1 is the rate of digestion of pdNDF1; k2 is the rate of digestion of pdNDF2; and uNDF the unavailable NDF on an aNDFom basis. A nonlinear estimation allowed the computation of the pool size and respective digestion rates. Using 3 time points from the digestion curve, 30, 120, and 240 h, as the fermentation endpoints to represent uNDF, we optimized the same model in Vensim (Ventana Simulation Environment; Ventana Systems Inc., Belmont, MA) to obtain rates and pool sizes of aNDFom. In addition, the same optimization was also performed with 2 timepoints and a forage type-specific range for uNDF. Parameters (with and without uNDF) obtained per forage using Vensim were compared by fitting kinetics data from the nonlinear calculations, using coefficients of determination and residual mean squares at convergence for ranking purposes for the whole equation and mean squared prediction errors for specific parameters. The highest coefficient of determination (0.98) and lowest mean square prediction error [0.0927 (NDF-1)2] were obtained when using 48, 120, and 240 h of aNDFom residues or when using 30 and 120 h and a range for the forage-specific uNDFom. Correlations were in all cases consistently high for all kinetic parameters, ranging from 0.76 to 0.99. Results demonstrated that an adequate description of the heterogeneity of aNDFom disappearance was possible without multiple fermentation time points. The equation was fit to all data generated; however, because of the variable nature of pool sizes and rates, forage-specific equations should be developed for better estimations of the forage specific pool sizes and uNDF estimation. This study further describes the heterogeneous nature of aNDFom disappearance and provides an approach for estimating the individual pool sizes and rates of digestion for application for diet formulation. PMID- 30447980 TI - Short communication: Risk of subacute ruminal acidosis affects the feed sorting behavior and milk production of early lactation cows. AB - The objective of this study was to determine if the risk of developing subacute ruminal acidosis, as potentially affected by dietary straw particle size, influenced the feed sorting, rumination behavior, and milk production of early lactation dairy cows. Upon calving, 41 multiparous Holstein cows were fed a total mixed ration with 9% wheat straw (dry matter basis) chopped (1) using a 2.54-cm screen (short; n = 21) or (2) using a 5.08-cm screen (long; n = 20). For the first 4 wk following calving, rumination behavior (recorded using data loggers attached to neck collars) and reticulorumen pH (recorded using wireless telemetry boluses) were monitored 24 h/d. Due to technical failures, analyses were conducted on 38 cows (n = 19 per treatment). Total mixed ration and orts samples were collected every 3 d to determine feed sorting. Based on an acidosis index, created using area under the curve data (reticulorumen pH < 5.8) normalized for dry matter intake, cows were categorized as either low (LR) or high (HR) risk for developing subacute ruminal acidosis (SARA). Low risk cows had higher mean (6.3 vs. 6.1), minimum (6.0 vs. 5.7), and maximum (6.7 vs. 6.5) reticulorumen pH than HR cows. Low risk cows also had less severe area under the curve values (1.5 vs. 49.4 pH * min/d) and spent less time below a reticulorumen pH threshold of 5.8 (21.9 vs. 309.2 min/d). Although total milk yield was unaffected by SARA risk, LR cows produced more 4% fat-corrected milk (47.2 vs. 41.9 kg/d) and milk fat (2.1 vs. 1.8 kg/d) than HR cows. A SARA risk category * treatment interaction was detected for sorting all fractions of the diet; HR cows on the long treatment sorted against the longest particles in the diet, whereas LR cows on the same treatment did not sort this fraction, suggesting that SARA risk may be mitigated by a more balanced intake of physically effective fiber. High risk cows on the short treatment consumed the longest dietary particles as predicted, and sorted in favor of the physically effective medium and short particles. A SARA risk category * treatment interaction was detected for rumination behavior; within the long treatment, HR cows tended to ruminate less than LR cows (432.3 vs. 493.2 min/d). Overall, these results suggest that LR cows consumed a more balanced diet, whereas HR cows sorted their feed more, particularly when fed the diet containing long straw particles, which may have led to reduced rumination activity and yield of milk fat and fat-corrected milk. PMID- 30447981 TI - Annual rhythms of milk and milk fat and protein production in dairy cattle in the United States. AB - An annual pattern of milk composition has been well recognized in dairy cattle, with the highest milk fat and protein concentration observed during the winter and lowest occurring in the summer; however, rhythms of milk yield and composition have not been well quantified. Cosinor rhythmometry is commonly used to model repeating daily and annual rhythms and allows determination of the amplitude (peak to mean), acrophase (time at peak), and period (time between peaks) of the rhythm. The objective of this study was to use cosinor rhythmometry to characterize the annual rhythms of milk yield and milk fat and protein concentration and yield using both national milk market and cow-level data. First, 10 yr of monthly average milk butterfat and protein concentration for each Federal Milk Marketing Order were obtained from the US Department of Agriculture Agricultural Marketing Service database. Fat and protein concentration fit a cosine function with a 12-mo period in all milk markets. We noted an interaction between milk marketing order and milk fat and protein concentration. The acrophase (time at peak) of the fat concentration rhythm ranged from December 4 to January 19 in all regions, whereas the rhythm of protein concentration peaked between December 27 and January 6. The amplitude (peak to mean) of the annual rhythm ranged from 0.07 to 0.14 percentage points for milk fat and from 0.08 to 0.12 percentage points for milk protein. The amplitude of the milk fat rhythm generally was lower in southern markets and higher in northern markets. Second, the annual rhythm of milk yield and milk fat and protein yield and concentration were analyzed in monthly test day data from 1,684 cows from 11 tiestall herds in Pennsylvania. Fat and protein concentration fit an annual rhythm in all herds, whereas milk and milk fat and protein yield only fit rhythms in 8 of the 11 herds. On average, milk yield peaked in April, fat and protein yield peaked in February, fat concentration peaked in January, and protein concentration peaked in December. Amplitudes of milk, fat, and protein yield averaged 0.82 kg, 55.3 g, and 30.4 g, respectively. Milk fat and protein concentration had average amplitudes of 0.12 and 0.07, respectively, similar to the results of the milk market data. Generally, milk yield and milk components fit annual rhythm regardless of parity or diacylglycerol O-acyltransferase 1 (DGAT1) K232A polymorphism, with only cows of the low-frequency AA genotype (5.2% of total cows) failing to fit rhythm of milk yield. In conclusion, the yearly rhythms of milk yield and fat and protein concentration and yield consistently occur regardless of region, herd, parity, or DGAT1 genotype and supports generation by a conserved endogenous annual rhythm. PMID- 30447982 TI - Influence of protein concentration and coagulation temperature on rennet-induced gelation characteristics and curd microstructure. AB - This study characterized the coagulation properties and defined the cutting window (CW; time between storage modulus values of 35 and 70 Pa) using rheometry for milk standardized to 4, 5, or 6% protein and set at 28, 32, or 36 degrees C. Milks were standardized to a protein-to-fat ratio of approximately 1 by blending ultrafiltration retentate, skim milk, and whole milk. The internal curd microstructure for selected curd samples was analyzed with transmission electron microscopy and scanning electron microscopy. Lowering the coagulation temperature caused longer rennet coagulation time and time to reach storage modulus of 35 Pa, translating into a wider CW. It also led to a lower maximum curd-firming rate (MCFR) with lower firmness at 40 min at a given protein level. Increasing protein levels resulted in the opposite effect, although without an effect on rennet coagulation time at a given temperature. On coagulation at 28 degrees C, milk with 5% protein resulted in a similar MCFR (~4 Pa/min) and CW (~8.25 min) compared with milk with 4% protein at 32 degrees C, which reflects more standard conditions, whereas increasing milk to 6% protein resulted in more than doubling of the curd-firming rate (MCFR = 9.20 Pa/min) and a shorter CW (4.60 min). Gels set at 28 degrees C had lower levels of rearrangement of protein network after 40 min compared with those set at 36 degrees C. Protein levels, on the other hand, had no influence on the levels of protein network rearrangement, as indicated by loss tangent values. The internal structure of curd particles, as investigated by both scanning electron microscopy and transmission electron microscopy, appeared to have less cross-linking and smaller casein aggregates when coagulated at 28 degrees C compared with 36 degrees C, whereas varying protein levels did not show a marked effect on aggregate formation. Overall, this study showed a marked interactive effect between coagulation temperature and protein standardization of milk on coagulation properties, which subsequently requires adjustment of the CW during cheesemaking. Lowering of the coagulation temperature greatly altered the curd microstructure, with a tendency for less syneresis during cutting. Further research is required to quantify the changes in syneresis and in fat and protein losses to whey due to changes in the microstructure of curd particles arising from the different coagulation conditions applied to the protein-fortified milk. PMID- 30447983 TI - The microbiome of Escherichia coli and culture-negative nonsevere clinical mastitis: Characterization and associations with linear score and milk production. AB - Culture-negative and Escherichia coli cases are uncommonly treated in pathogen based protocols for nonsevere mastitis. High-throughput 16S rRNA sequencing might reveal the presence of other pathogens and can provide information on microbial diversity. The objective was to explore the milk microbiome at the time of the mastitis event (enrollment) and its association with survival in the herd, milk production, and postevent linear score (LS) for cows with clinical mastitis characterized as negative or E. coli by culture. Fifty E. coli-positive and 35 culture-negative samples from cases were enrolled. No cases were treated with antimicrobials. All E. coli-positive quarters were characterized as transient; microbiological culture of samples taken 15 d postmastitis were negative for this organism. However, a difference in alpha-diversity (Shannon index) was present between enrollment and follow-up samples (3.8 vs. 5.1). When alpha-diversity was explored for enrollment E. coli samples, no relationship was observed between the Shannon indices of these samples and postmastitis LS. Alpha-diversity of the enrollment samples was lower for E. coli-positive cows that subsequently had greater losses in milk production. This difference was explained by a greater relative abundance of the family Enterobacteriaceae (67.8 vs. 38.4%) for cows that dropped in production. Analysis of composition of the microbiome identified one phylum, Proteobacteria, that differed between E. coli-positive cows that dropped in production and those that did not. Evaluation of beta-diversity found no statistical relationship between postmastitis LS and the microbiome. When evaluating alpha- and beta-diversities and composition of the microbiomes for culture-negative quarters, no associations were found for milk production changes and postmastitis LS. Three cows did not remain in the herd, limiting the ability to analyze survival. The findings suggest that a contributing factor to negative outcomes in E. coli-positive cows is relative abundance of this pathogen, and that no single or collective group of bacterial families is associated with milk production changes or postmastitis LS in culture-negative quarters. Although additional studies should be performed, the absence of associations between outcomes explored and microbial profiles in this study suggests that we are not missing opportunities by not treating nonsevere E. coli or culture-negative mastitis cases. PMID- 30447984 TI - A biomechanical study comparing minimally invasive anterior pelvic ring fixation techniques to external fixation. AB - INTRODUCTION: INFIX and Pelvic Bridge are two new minimally invasive surgical techniques for unstable pelvic ring injuries, and they have demonstrated early clinical success in small, single-center case-series. The primary objective of this study is to gather evidence speaking to the biomechanical stability of internal bridging methods relative to external fixation, with the expectation of biomechanical equivalence. METHODS: Ten human cadaveric pelvic specimens were dissected free of all skin, fat, organs, and musculature and were prepared with a partially unstable pelvic ring injury (OTA/AO 61-B). The specimens were randomized to two groups and were repaired and tested with anterior pelvic external fixation (APEF) and INFIX sequentially, or APEF and Pelvic Bridge sequentially. Testing was performed with each specimen mounted onto a servo hydraulic testing frame with axial compression applied to the superior base of the sacrum under five axial loading/unloading sinusoidal cycles between 10 N and 1000 N at 0.1 Hz. Relative translational motion and rotation across the osteotomy site was reported as our primary outcome measures. Outcome measures were further analyzed using a Wilcoxon signed-rank test to determine differences between non parametric data sets with significance defined as a p value < 0.05. RESULTS: We found no statistical difference in translation (p = 0.237, 0.228) or rotation (p = 0.278, 0.873) at the fracture site when comparing both new constructs to external fixation. Under the imposed loading protocol, no episodes of implant failure or failure at the bone-implant interface occurred. DISCUSSION: Our study provides the biomechanical foundation necessary to support future clinical trial implementation for pelvic fracture patients. While biomechanical stability of these newer, subcutaneous techniques is equivalent to APEF, the surgeon must take into account their technical abilities and knowledge of pelvic anatomy, patient specific factors including body habitus, and the potential complications associated with each implant and the ability to avoid them. PMID- 30447985 TI - Comparison of the use of antibiotic-loaded calcium sulphate and wound irrigation suction in the treatment of lower limb chronic osteomyelitis. AB - AIMS: We sought to compare the efficacy of antibiotic-loaded calcium sulphate with wound irrigation-suction in patients with lower limb chronic osteomyelitis. PATIENTS AND METHODS: Adult patients with lower limb chronic osteomyelitis treated at our hospital by means of segmental bone resection, antibiotic-loaded calcium sulphate implantation or wound irrigation-suction, followed by bone transport with external fixator from January 2011 to July 2015 were retrospectively evaluated. The clinical presentation, laboratory results, complications, docking obstruction, infection recurrence were compared. RESULTS: There were totally 74 patients met the inclusion criteria. Docking obstruction rate and infection recurrence were higher in the irrigation group with significant difference. The success rate of the first operation was 90.74% in the calcium sulphate group compared with 45% in the irrigation group. Postoperaton leakage of the incision happened more in the calcium sulphate group, but it wasn't a risk factor for docking obstruction and infection recurrence. Patients in the calcium sulphate group had shorter hospital stay and systemic antibiotic treatment, also with less external fixator index. CONCLUSIONS: The findings of our study suggest that antibiotic-loaded calcium sulphate implantation for lower chronic limb osteomyelitis was a more successful method than wound irrigation suction, it greatly decreased infection recurrence and docking obstruction. Postoperative leakage after implantation didn't worsen patient's outcome. PMID- 30447986 TI - Arthroscopic reduction of posterior cruciate ligament tibial avulsion fracture using two cross-linked pull-out sutures: A surgical technique and case series. AB - Surgical treatment of the posterior cruciate ligament (PCL) tibial avulsion fracture is challenging due to the deep-seated location of the lesion with complex adjacent anatomy and usually with small-sized bone fragment. We introduce a novel arthroscopic reduction technique using two cross-linked pull-out sutures (2XLPOS) through triple bone tunnels in posterior cruciate ligament (PCL) tibial avulsion fracture. Posterior trans-septal portal was established following the four standard arthroscopic portals. Bilateral margins of the PCL with 1~2 mm margin from the border were penetrated using suture hook. Fiberwire sling tied with a No. 0 PDS knot was introduced anterior to the PCL by the two posteriorly pulled shuttle sutures. Three bone tunnels were drilled in the inferomedial, inferolateral, and apex edge of the avulsed tibial crater. Each end of the Fiberwire was drawn out through the inferomedial and inferolateral bone tunnel, respectively. Two ends of the No. 0 PDS were drawn out through the apex tunnel by the same manner. Fiberwire was tied on the anteromedial aspect of the proximal tibia with one strand of the No. 0 PDS placed underneath the Fiberwire knot. And, the No. 0 PDS loop was tied to complete cross-linking of pull-out construct. Arthroscopic reduction of PCL tibial insertion avulsion fracture using 2XLPOS technique was performed in eleven patients. Mean range of motion at the first postoperative year was 126.8 degrees . Mean Lysholm score, Tegner activity scale, and IKDC was 69.2, 4.2, and 58.1, respectively. Posterior instability decreased from mean 12.6 mm preoperatively to 3.2 mm at 1-year postoperative follow up. Radiographic union of the fracture site was confirmed in 11 cases. Our new surgical technique yielded good clinical and radiological outcome, and we consider it is unique in utilizing two cross-linked sling type pull-out suture constructs and triple bone tunnels for their passage. PMID- 30447987 TI - Real-time augmented model guidance for mandibular proximal segment repositioning in orthognathic surgery, using electromagnetic tracking. AB - It is essential to reposition the mandibular proximal segment (MPS) as close to its original position as possible during orthognathic surgery. Conventional methods cannot pinpoint the exact position of the condyle in the fossa in real time during repositioning. In this study, based on an improved registration method and a separable electromagnetic tracking tool, we developed a real-time, augmented, model-guided method for MPS surgery to reposition the condyle into its original position more accurately. After virtual surgery planning, using a complex maxillomandibular model, the final position of the virtual MPS model was simulated via 3D rotations. The displacements resulting from the MPS simulation were applied to the MPS landmarks to indicate their final postoperative positions. We designed a new registration body with 24 fiducial points for registration, and determined the optimal point group on the registration body through a phantom study. The registration between the patient's CT image and physical spaces was performed preoperatively using the optimal points. We also developed a separable frame for installing the electromagnetic tracking tool on the patient's MPS. During MPS surgery, the electromagnetic tracking tool was repeatedly attached to, and separated from, the MPS using the separable frame. The MPS movement resulting from the surgeon's manipulation was tracked by the electromagnetic tracking system. The augmented condyle model and its landmarks were visualized continuously in real time with respect to the simulated model and landmarks. Our method also provides augmented 3D coronal and sagittal views of the fossa and condyle, to allow the surgeon to examine the 3D condyle-fossa positional relationship more accurately. The root mean square differences between the simulated and intraoperative MPS models, and between the simulated and postoperative CT models, were 1.71 +/- 0.63 mm and 1.89 +/- 0.22 mm respectively at three condylar landmarks. Thus, the surgeons could perform MPS repositioning conveniently and accurately based on real-time augmented model guidance on the 3D condyle positional relationship with respect to the glenoid fossa, using augmented and simulated models and landmarks. PMID- 30447988 TI - ATP Release by Red Blood Cells under Flow: Model and Simulations. AB - ATP is a major player as a signaling molecule in blood microcirculation. It is released by red blood cells (RBCs) when they are subjected to shear stresses large enough to induce a sufficient shape deformation. This prominent feature of chemical response to shear stress and RBC deformation constitutes an important link between vessel geometry, flow conditions, and the mechanical properties of RBCs, which are all contributing factors affecting the chemical signals in the process of vasomotor modulation of the precapillary vessel networks. Several in vitro experiments have reported on ATP release by RBCs due to mechanical stress. These studies have considered both intact RBCs as well as cells within which suspected pathways of ATP release have been inhibited. This has provided profound insights to help elucidate the basic governing key elements, yet how the ATP release process takes place in the (intermediate) microcirculation zone is not well understood. We propose here an analytical model of ATP release. The ATP concentration is coupled in a consistent way to RBC dynamics. The release of ATP, or the lack thereof, is assumed to depend on both the local shear stress and the shape change of the membrane. The full chemo-mechanical coupling problem is written in a lattice-Boltzmann formulation and solved numerically in different geometries (straight channels and bifurcations mimicking vessel networks) and under two kinds of imposed flows (shear and Poiseuille flows). Our model remarkably reproduces existing experimental results. It also pinpoints the major contribution of ATP release when cells traverse network bifurcations. This study may aid in further identifying the interplay between mechanical properties and chemical signaling processes involved in blood microcirculation. PMID- 30447989 TI - CellSpecks: A Software for Automated Detection and Analysis of Calcium Channels in Live Cells. AB - To couple the fidelity of patch-clamp recording with a more high-throughput screening capability, we pioneered a, to our knowledge, novel approach to single channel recording that we named "optical patch clamp." By using highly sensitive fluorescent Ca2+ indicator dyes in conjunction with total internal fluorescence microscopy techniques, we monitor Ca2+ flux through individual Ca2+-permeable channels. This approach provides information about channel gating analogous to patch-clamp recording at a time resolution of ~2 ms with the additional advantage of being massively parallel, providing simultaneous and independent recording from thousands of channels in the native environment. However, manual analysis of the data generated by this technique presents severe challenges because a video recording can include many thousands of frames. To overcome this bottleneck, we developed an image processing and analysis framework called CellSpecks capable of detecting and fully analyzing the kinetics of ion channels within a video sequence. By using randomly generated synthetic data, we tested the ability of CellSpecks to rapidly and efficiently detect and analyze the activity of thousands of ion channels, including openings for a few milliseconds. Here, we report the use of CellSpecks for the analysis of experimental data acquired by imaging muscle nicotinic acetylcholine receptors and the Alzheimer's disease associated amyloid beta pores with multiconductance levels in the plasma membrane of Xenopus laevis oocytes. We show that CellSpecks can accurately and efficiently generate location maps and create raw and processed fluorescence time traces; histograms of mean open times, mean close times, open probabilities, durations, and maximal amplitudes; and a "channel chip" showing the activity of all channels as a function of time. Although we specifically illustrate the application of CellSpecks for analyzing data from Ca2+ channels, it can be easily customized to analyze other spatially and temporally localized signals. PMID- 30447990 TI - Dissociation of the Dimer of the Intrinsically Disordered Domain of RNase Y upon Antibody Binding. AB - Although RNase Y acts as the key enzyme initiating messenger RNA decay in Bacillus subtilis and likely in many other Gram-positive bacteria, its three dimensional structure remains unknown. An antibody belonging to the rare immunoglobulin G (IgG) 2b lambdax isotype was raised against a 12-residue conserved peptide from the N-terminal noncatalytic domain of B. subtilis RNase Y (BsRNaseY) that is predicted to be intrinsically disordered. Here, we show that this domain can be produced as a stand-alone protein called Nter-BsRNaseY that undergoes conformational changes between monomeric and dimeric forms. Circular dichroism and size exclusion chromatography coupled with multiangle light scattering or with small angle x-ray scattering indicate that the Nter-BsRNaseY dimer displays an elongated form and a high content of alpha-helices, in agreement with the existence of a central coiled-coil structure appended with flexible ends, and that the monomeric state of Nter-BsRNaseY is favored upon binding the fragment antigen binding (Fab) of the antibody. The dissociation constants of the IgG/BsRNaseY, IgG/Nter-BsRNaseY, and IgG/peptide complexes indicate that the affinity of the IgG for Nter-BsRNaseY is in the nM range and suggest that the peptide is less accessible in BsRNaseY than in Nter-BsRNaseY. The crystal structure of the Fab in complex with the peptide antigen shows that the peptide adopts an elongated U-shaped conformation in which the unique hydrophobic residue of the peptide, Leu6, is completely buried. The peptide/Fab complex may mimic the interaction of a microdomain of the N-terminal domain of BsRNaseY with one of its cellular partners within the degradosome complex. Altogether, our results suggest that BsRNaseY may become accessible for protein interaction upon dissociation of its N-terminal domain into the monomeric form. PMID- 30447991 TI - Force Spectroscopy and Beyond: Innovations and Opportunities. AB - Life operates at the intersection of chemistry and mechanics. Over the years, we have made remarkable progress in understanding life from a biochemical perspective and the mechanics of life at the single-molecule scale. Yet the full integration of physical and mechanical models into mainstream biology has been impeded by technical and conceptual barriers, including limitations in our ability to 1) easily measure and apply mechanical forces to biological systems, 2) scale these measurements from single-molecule characterization to more complex biomolecular systems, and 3) model and interpret biophysical data in a coherent way across length scales that span single molecules to cells to multicellular organisms. In this manuscript, through a look at historical and recent developments in force spectroscopy techniques and a discussion of a few exemplary open problems in cellular biomechanics, we aim to identify research opportunities that will help us reach our goal of a more complete and integrated understanding of the role of force and mechanics in biological systems. PMID- 30447992 TI - Microtubule Feedback and LET-99-Dependent Control of Pulling Forces Ensure Robust Spindle Position. AB - During asymmetric division of the Caenorhabditis elegans zygote, to properly distribute cell fate determinants, the mitotic spindle is asymmetrically localized by a combination of centering and cortical-pulling microtubule-mediated forces, the dynamics of the latter being regulated by mitotic progression. Here, we show a, to our knowledge, novel and additional regulation of these forces by spindle position itself. For that, we observed the onset of transverse spindle oscillations, which reflects the burst of anaphase pulling forces. After delaying anaphase onset, we found that the position at which the spindle starts to oscillate was unchanged compared to control embryos and uncorrelated to anaphase onset. In mapping the cortical microtubule dynamics, we measured a steep increase in microtubule contact density after the posterior centrosome reached the critical position of 70% of embryo length, strongly suggesting the presence of a positional switch for spindle oscillations. Expanding a previous model based on a force-generator temporal control, we implemented this positional switch and observed that the large increase in microtubule density accounted for the pulling force burst. Thus, we propose that the spindle position influences the cortical availability of microtubules on which the active force generators, controlled by cell cycle progression, can pull. Importantly, we found that this positional control relies on the polarity-dependent LET-99 cortical band, the boundary of which could be probed by microtubules. This dual positional and temporal control well accounted for our observation that the oscillation onset position resists changes in cellular geometry and moderate variations in the active force generator number. Finally, our model suggests that spindle position at mitosis end is more sensitive to the polarity factor LET-99, which restricts the region of active force generators to a posterior-most region, than to microtubule number or force generator number/activity. Overall, we show that robustness in spindle positioning originates in cell mechanics rather than biochemical networks. PMID- 30447993 TI - The Second Messenger c-di-GMP Adjusts Motility and Promotes Surface Aggregation of Bacteria. AB - Bacteria can use the second messenger c-di-GMP to adjust their motility in response to environmental cues. The protein YcgR, upon binding of c-di-GMP, interacts with the flagellar motor to affect the motor behavior. However, the full feature of the effects of c-di-GMP::YcgR on the flagellar motor remains unclear, and its interacting partners on the motor is still controversial. Here, we characterized the effects of c-di-GMP::YcgR on the torque-speed curve of the flagellar motor, one of the most important properties of the motor, finding that it affects the motor behavior throughout the full range of load conditions from zero to high loads by shifting the motor torque-speed curve downward. We also investigated the interacting partner on the motor through dynamical fluorescent studies, finding that c-di-GMP::YcgR mainly interacts with the motor-switch complex instead of the torque-generating units (stators). To directly test the behavioral consequence of elevated c-di-GMP levels, we measured the distribution of bacteria swimming near a surface, finding that elevated c-di-GMP levels promote bacterial aggregation on surfaces. The effects of c-di-GMP on bacterial motile behavior that we characterized here are consistent with the key role that c-di-GMP plays in the transition between motile and sedentary forms of bacterial life. PMID- 30447994 TI - Light-Activated Dynamic Clamp Using iPSC-Derived Cardiomyocytes. AB - iPSC-derived cardiomyocytes (iPSC-CMs) are a potentially advantageous platform for drug screening because they provide a renewable source of human cardiomyocytes. One obstacle to their implementation is their immature electrophysiology, which reduces relevance to adult arrhythmogenesis. To address this, dynamic clamp is used to inject current representing the insufficient potassium current, IK1, thereby producing more adult-like electrophysiology. However, dynamic clamp requires patch clamp and is therefore low throughput and ill-suited for large-scale drug screening. Here, we use optogenetics to generate such a dynamic-clamp current. The optical dynamic clamp (ODC) uses outward current-generating opsin, ArchT, to mimic IK1, resulting in more adult-like action potential morphology, similar to IK1 injection via classic dynamic clamp. Furthermore, in the presence of an IKr blocker, ODC revealed expected action potential prolongation and reduced spontaneous excitation. The ODC presented here still requires an electrode to measure Vm but provides a first step toward contactless dynamic clamp, which will not only enable high-throughput screening but may also allow control within multicellular iPSC-CM formats to better recapitulate adult in vivo physiology. PMID- 30447995 TI - Can a Charged Surfactant Unfold an Uncharged Protein? AB - Does sodium dodecyl sulfate (SDS) denature proteins through electrostatic SDS protein interactions? We show that a protein completely lacking charged side chains is unfolded by SDS in a manner similar to charged proteins, revealing that formal protein charges are not required for SDS-induced protein unfolding or binding. PMID- 30447996 TI - Spatially Resolving the Condensing Effect of Cholesterol in Lipid Bilayers. AB - We study the effect of cholesterol on the structure of dipalmitoylphosphatidylcholine phospholipid bilayers. Using extensive molecular dynamics computer simulations at atomistic resolution, we observe and quantify several structural changes upon increasing cholesterol content that are collectively known as the condensing effect: a thickening of the bilayer, an increase in lipid tail order, and a decrease in lateral area. We also observe a change in leaflet interdigitation and a lack thereof in the distributions of dipalmitoylphosphatidylcholine headgroup orientations. These results, obtained over a wide range of cholesterol mole fractions, are then used to calibrate the analysis of phospholipid properties in bilayers containing a single cholesterol molecule per leaflet, which we perform in a spatially resolved way. We find that a single cholesterol molecule affects phospholipids in its first and second solvation shells, which puts the range of this effective interaction to be on the order of 1-2 nm. We also observe a tendency of phospholipids to orient their polar headgroups toward the cholesterol, which provides additional support for the umbrella model of bilayer organization. PMID- 30447997 TI - Local control, safety, and survival following image-guided percutaneous microwave thermal ablation in primary lung malignancy. AB - AIM: To determine local control, safety, and survival following percutaneous computed tomography (CT)-guided high-power microwave ablation (MWA) in the treatment of primary lung malignancy at a single institution. MATERIAL AND METHODS: From July 2010 to June 2016, 52 patients (mean age 76.3 years, range 55 91 years) with 61 unresectable primary lung cancers of mean diameter 23.8 mm (range 26-55 mm) underwent MWA in 55 ablation sessions. Tumours were diagnosed at biopsy, or positron-emission tomography (PET) avidity (mean SUV max = 10.51) and interval growth. Statistical analysis was performed by Kaplan-Meier modelling and Cox and logistic regression. RESULTS: Local tumour progression (LTP) was diagnosed in six lesions (10%). Median time to local recurrence was 3 months (range 2-14 months). There was a near 12-fold increased odds of local recurrence if the lesion size was >3 cm (95% confidence interval [CI]: 1.84-75.14; p=0.009). The median inpatient stay was 1 day, with no intra-procedural deaths and a 0% 30 day post-ablation mortality rate. Pneumothorax requiring drain was the most serious complication, occurring in 22% (n=12) of patients. Presence of severe emphysema and predicted forced expiratory volume in 1 second (FEV1) of <50% were found to predict future requirement of a drain (odds ratio [OR] 8.17, 95% CI: 1.62-41.37, p=0.01 and OR: 5.14, 95% CI: 1.28-20.68, p=0.02 respectively), when adjusted for age and gender. Tumour size >3 cm had a hazard ratio of 4.37 compared with tumour size <=3 cm (95% CI: 1.45-13.17, p=0.009) of risk of cancer death at any time, by Cox regression. CONCLUSION: MWA for primary lung malignancy is a safe and effective treatment for primary lung tumours with outcomes that may be comparable to stereotactic body radiation therapy. PMID- 30447998 TI - BioJupies: Automated Generation of Interactive Notebooks for RNA-Seq Data Analysis in the Cloud. AB - BioJupies is a web application that enables the automated creation, storage, and deployment of Jupyter Notebooks containing RNA-seq data analyses. Through an intuitive interface, novice users can rapidly generate tailored reports to analyze and visualize their own raw sequencing files, gene expression tables, or fetch data from >9,000 published studies containing >300,000 preprocessed RNA-seq samples. Generated notebooks have the executable code of the entire pipeline, rich narrative text, interactive data visualizations, differential expression, and enrichment analyses. The notebooks are permanently stored in the cloud and made available online through a persistent URL. The notebooks are downloadable, customizable, and can run within a Docker container. By providing an intuitive user interface for notebook generation for RNA-seq data analysis, starting from the raw reads all the way to a complete interactive and reproducible report, BioJupies is a useful resource for experimental and computational biologists. BioJupies is freely available as a web-based application from http://biojupies.cloud. PMID- 30447999 TI - Production of Spliced Long Noncoding RNAs Specifies Regions with Increased Enhancer Activity. AB - Active enhancers in mammals produce enhancer RNAs (eRNAs) that are bidirectionally transcribed, unspliced, and unstable. Enhancer regions are also enriched with long noncoding RNA (lncRNA) transcripts, which are typically spliced and substantially more stable. In order to explore the relationship between these two classes of RNAs, we analyzed DNase hypersensitive sites with evidence of bidirectional transcription, which we termed eRNA-producing centers (EPCs). EPCs found very close to transcription start sites of lncRNAs exhibit attributes of both enhancers and promoters, including distinctive DNA motifs and a characteristic chromatin landscape. These EPCs are associated with higher enhancer activity, driven at least in part by the presence of conserved, directional splicing signals that promote lncRNA production, pointing at a causal role of lncRNA processing in enhancer activity. Together, our results suggest that the conserved ability of some enhancers to produce lncRNAs augments their activity in a manner likely mediated through lncRNA maturation. PMID- 30448000 TI - Mapping Cellular Reprogramming via Pooled Overexpression Screens with Paired Fitness and Single-Cell RNA-Sequencing Readout. AB - Understanding the effects of genetic perturbations on the cellular state has been challenging using traditional pooled screens, which typically rely on the delivery of a single perturbation per cell and unidimensional phenotypic readouts. Here, we use barcoded open reading frame overexpression libraries coupled with single-cell RNA sequencing to assay cell state and fitness, a technique we call SEUSS (scalable functional screening by sequencing). Using SEUSS, we perturbed hPSCs with a library of developmentally critical transcription factors (TFs) and assayed the impact of TF overexpression on fitness and transcriptomic states. We further leveraged the versatility of the ORF library approach to assay mutant genes and whole gene families. From the transcriptomic responses, we built genetic co-regulatory networks to identify altered gene modules and found that KLF4 and SNAI2 drive opposing effects along the epithelial-mesenchymal transition axis. From the fitness responses, we identified ETV2 as a driver of reprogramming toward an endothelial-like state. PMID- 30448001 TI - Independent knowledge-based treatment planning QA to audit Pinnacle autoplanning. AB - BACKGROUND AND PURPOSE: With the advent of automatic treatment planning options like Pinnacle's Autoplanning (PAP), the challenge arises how to assess the quality of a plan that no dosimetrist did work on. The aim of this study was to assess plan quality consistency of PAP prostate cancer patients in clinical practice. MATERIALS AND METHODS: 100 prostate cancer patients were included from NKI and 129 from RadboudUMC (RUMC). Per institute a previously developed [1] treatment planning QA model, based on overlap volume histograms, was trained on PAP plans to predict achievable dose metrics which were then compared to the clinical PAP plans. A threshold of 3 Gy (DVH dose parameters)/3% (DVH volume parameters) was used to detect outliers. For the outlier plans, the PAP technique was adjusted with the aim of meeting the threshold. RESULTS: The average difference between the prediction and the clinically achieved value was <0.5 Gy (mean dose parameters) and <1.2% (volume parameters), with standard deviation of 1.9 Gy/1.5% respectively. We found 8% (NKI)/25% (RUMC) of patients to exceed the 3 Gy/3% threshold, with deviations up to 6.7 Gy (mean dose rectum) and 6% (rectal wall V64Gy). In all cases the plans could be improved to fall within the thresholds, without compromising the other dose metrics. CONCLUSION: Independent treatment planning QA was used successfully to assess the quality of clinical PAP in a multi-institutional setting. Respectively 8% and 25% suboptimal clinical PAP plans were detected that all could be improved with replanning. Therefore we recommend the use of independent treatment plan QA in combination with PAP for prostate cancer patients. PMID- 30448002 TI - Survival impact of radiotherapy interruption in nasopharyngeal carcinoma in the intensity-modulated radiotherapy era: A big-data intelligence platform-based analysis. AB - PURPOSE: To evaluate the effect of radiotherapy interruption (RTI) in patients with nasopharyngeal carcinoma (NPC) receiving intensity-modulated radiotherapy (IMRT). PATIENTS AND METHODS: A total of 7826 patients using the well-established big-data intelligence platform were identified. Computer-generated random numbers were used to assign these patients into a training cohort (n = 3913 patients) and an internal validation cohort (n = 3913 patients). RTI was defined as the difference between radiation treatment time and planned radiation time (assuming a Monday start). Survival analysis was performed using the Kaplan-Meier method for survival, and log-rank test to evaluate difference. Optimal RTI threshold was identified using the recursive partitioning analyses (RPAs). Multivariate analysis was performed using the Weibull model. The primary endpoint was overall survival (OS). RESULTS: The optimal threshold of RTI with respect to OS in the training cohort was 6.5 d based on RPAs. Therefore, a uniform threshold of 7 d (<7 vs. >=7 d) was selected to classify both training and validation cohorts into high and low RTI groups for survival analysis. RTI of >=7 d showed significant detrimental effects on OS in both training (5-y OS, 82.4% vs 86.5%; P = 0.001) and validation cohorts (5-y OS, 85.2% vs 86.7%; P = 0.013) than those patients with RTI of <7 d. Consistent with results of the univariate analysis, RTI of >=7 d was found to be an independent unfavorable prognostic factor for OS in both training (HR, 1.49; 95% CI, 1.14-1.95; P = 0.003) and validation cohort (HR, 1.37; 95% CI, 1.07-1.65; P = 0.031). Subgroup analysis showed that RTI of >=7 d had significant adverse effects on prognosis of NPC patients receiving IMRT, regardless of TNM stage and chemotherapy (P < 0.05 for all). CONCLUSIONS: In the IMRT era, RTI independently influences survival. Raising RTI >= 7 d was consistently unfavorable for NPC survival. Medical practitioners must remind patients on the importance of minimizing RT interruptions. PMID- 30448003 TI - 4D liver tumor localization using cone-beam projections and a biomechanical model. AB - PURPOSE: To improve the accuracy of liver tumor localization, this study tests a biomechanical modeling-guided liver cone-beam CT (CBCT) estimation (Bio-CBCT-est) technique, which generates new CBCTs by deforming a prior high-quality CT or CBCT image using deformation vector fields (DVFs). The DVFs can be used to propagate tumor contours from the prior image to new CBCTs for automatic 4D tumor localization. METHODS/MATERIALS: To solve the DVFs, the Bio-CBCT-est technique employs an iterative scheme that alternates between intensity-driven 2D-3D deformation and biomechanical modeling-guided DVF regularization and optimization. The 2D-3D deformation step solves DVFs by matching digitally reconstructed radiographs of the 3D deformed prior image to 2D phase-sorted on board projections according to imaging intensities. This step's accuracy is limited at low-contrast intra-liver regions without sufficient intensity variations. To boost the DVF accuracy in these regions, we use the intensity driven DVFs solved at higher-contrast liver boundaries to fine-tune the intra liver DVFs by finite element analysis-based biomechanical modeling. We evaluated Bio-CBCT-est's accuracy with seven liver cancer patient cases. For each patient, we simulated 4D cone-beam projections from 4D-CT images, and used these projections for Bio-CBCT-est based image estimations. After Bio-CBCT-est, the DVF propagated liver tumor/cyst contours were quantitatively compared with the manual contours on the original 4D-CT 'reference' images, using the DICE similarity index, the center-of-mass-error (COME), the Hausdorff distance (HD) and the voxel wise cross-correlation (CC) metrics. In addition to simulation, we also performed a preliminary study to qualitatively evaluate the Bio-CBCT-est technique via clinically acquired cone beam projections. A quantitative study using an in-house deformable liver phantom was also performed. RESULTS: Using 20 projections for image estimation, the average (+/-s.d.) DICE index increased from 0.48 +/- 0.13 (by 2D-3D deformation) to 0.77 +/- 0.08 (by Bio-CBCT-est), the average COME decreased from 7.7 +/- 1.5 mm to 2.2 +/- 1.2 mm, the average HD decreased from 10.6 +/- 2.2 mm to 5.9 +/- 2.0 mm, and the average CC increased from -0.004 +/- 0.216 to 0.422 +/- 0.206. The tumor/cyst trajectory solved by Bio-CBCT-est matched well with that manually obtained from 4D-CT reference images. CONCLUSIONS: Bio-CBCT-est substantially improves the accuracy of 4D liver tumor localization via cone-beam projections and a biomechanical model. PMID- 30448005 TI - Late-onset progression of keratoconus after therapy with selective tissue estrogenic activity regulator. AB - We describe the association of rapid progression of keratoconus in a 49-year-old woman on selective tissue estrogenic activity regulator (STEAR) therapy for endometriosis. Approximately 4 months after initiation of therapy with STEAR therapy and 3 months after ovariectomy, Scheimpflug images showed a massive increase in the previously stable ectasia. During this period, the maximum increase in the keratometry values was 2.7 diopters (D) in the right eye and 3.8 D in the left eye. Corneal crosslinking (CXL) was performed in both eyes. This resulted in excessive flattening of 5.5 D in the right eye and 6.1 D in the left eye at 9 months postoperatively. Patients having STEAR therapy must be monitored closely for corneal changes. PMID- 30448006 TI - Bone manifestations in neuronopathic Gaucher disease while receiving high-dose enzyme replacement therapy. AB - Avascular necrosis (AVN), one type of bone infarction, is a major irreversible complication of Gaucher disease (GD). In this report, two pediatric patients with GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), developed AVN despite treatment on long-term, high-dose enzyme replacement therapy (ERT). ERT was initiated in both patients, who had intact spleens, shortly after diagnosis with an initial dramatic response. However, both patients exhibited AVN after 5.5 and 11 years on high-dose ERT, respectively, despite good compliance and normalized hematological findings and visceral symptoms. This report demonstrates the importance of careful, regular surveillance of the musculoskeletal system in addition to monitoring the neurological symptoms associated with neuronopathic GD. Additionally, it highlights the limitations of ERT in terms of targeting certain sanctuary sites such as bone marrow and suggests the need for new treatment modalities other than ERT monotherapy to address these limitations. PMID- 30448004 TI - A comprehensive screening of copy number variability in dementia with Lewy bodies. AB - The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk. PMID- 30448007 TI - Elevated methylmalonic acidemia (MMA) screening markers in Hispanic and preterm newborns. AB - Analysis of California newborn screening (NBS) data revealed a high prevalence of Hispanic infants testing positive for methylmalonic acidemia (MMA), a trend seen for both true- and false-positive cases. Here we show that Hispanic infants have significantly higher levels of MMA screening markers than non-Hispanics. Preterm birth and increased birth weight were found to be associated with elevated MMA marker levels but could not entirely explain these differences. While the preterm birth rate was higher in Blacks than Hispanics, Black infants had on average the lowest MMA marker levels. Preterm birth was associated with lower birth weight and increased MMA marker levels suggesting that gestational age is the stronger predictive covariate compared to birth weight. These findings could help explain why MMA false-positive results are more likely in Hispanic than in Black infants, which could inform screening and diagnostic procedures for MMA and potentially other disorders in newborns. PMID- 30448008 TI - International survey of orthokeratology contact lens fitting. AB - PURPOSE: . To determine the extent of orthokeratology (OK) contact lens fitting worldwide and to characterize associated demographics and fitting patterns. METHODS: . Survey forms were sent to contact lens fitters in 45 countries between January and March every year for 14 consecutive years (2004 - 2017, inclusive). Practitioners were asked to record data relating to the first 10 contact lens fits or refits performed after receiving the survey form. RESULTS: . Data were obtained for 295,044 contact lens fits, of which 2,702 were with OK lenses and 292,342 were with other lens types (non-OK). Overall, OK lenses represented 1.2% of all contact lens fits, with significant differences between nations (p < 0.0001), ranging from no fits recorded in Brazil, Egypt, Indonesia, Iran, Lithuania, Nepal and the United Arab Emirates, to 6.0% in The Netherlands. There has been a slight overall increase in OK lens fitting over the survey period (p < 0.0001). OK lenses were fitted to younger persons (OK, 25.0 +/- 12.8 years vs. non-OK, 39.8 +/- 14.9 years) (p < 0.0001). A higher proportion of males (55%) were fitted with OK lenses versus non-OK lenses (30%) (p < 0.0009). There was a skewed distribution towards OK lenses being fit with higher oxygen permeable materials (p < 0.0001) and on a planned replacement basis (p < 0.0001). CONCLUSIONS: . OK contact lens prescribing is a niche activity, with this lens type typically being fitted in high oxygen permeable materials on a planned replacement basis to younger males. The slightly increasing rate of OK fitting, albeit at a very low level, may be attributed to practitioner interest in the reported myopia control properties of this lens type. PMID- 30448009 TI - Reply to the comments on: Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: Meta-analysis of 153 cohorts with 15,713 patients: Meta-analysis of incidence and risk factors of EGFR TKI pneumonitis in NSCLC. PMID- 30448011 TI - Citation for the 2017 BAOMS Surgery prize - Rajiv Anand. PMID- 30448010 TI - [Medico-legal risk in urology: Analysis of a portfolio of insured persons by a French insurance company between 2009 and 2018]. AB - OBJECTIVE: Presentation of data collected on urology claims from the register of a French insurance company. MATERIAL AND METHOD: Compensation claims involving urologists covering the period 2009-2018 were identified and analyzed. RESULTS: A total of 37 files were found. Oncological and functional surgical interventions accounts for 78% of repair claims. Postoperative complications represent 76% of the cases. The most represented acts are total prostatectomy (5) and promonto fixation (4). The average time of complaint is 28.6 months [1-144 months], the average duration of a procedure (opening-closing) is 32.8 months [12-72 months]. The Conciliation and Compensation Commissions (CCC) and the High Court Courts (HCC) were solicited respectively in 51% and 33% of the proceedings. An amicable agreement is found in 16% of cases. There was no criminal or disciplinary proceedings. The average cost of a closed urology file is 7836 ? [0-31,120 ?]. In total, 64.8% of the expertises confirm practices in the respect of the rules of the art. CONCLUSION: This series presents the first forensic analysis of a portfolio of urologists on a period of 9 years in French urology. There is a rate of responsibility retained against the practitioner in only 27% of cases. The low rate of faulty files, the absence of a conviction for breach of the duty to provide information and in connection with antibiotic prophylaxis seem to confirm that the practice of urology in France is of good quality, a further study on a longer period of time and on a larger cohort of urologists would allow a finer medico-legal approach. LEVEL OF EVIDENCE: 3. PMID- 30448012 TI - Blended learning modules for lectures on oral and maxillofacial surgery. AB - Over the last couple of years, new teaching methods have been developed and implemented in German universities, but only rarely in dental schools. The aim of this project therefore was to implement students' requests for such methods to be used in dental education. In 2012, based on an analysis of both quantitative and qualitative requirements, we designed a questionnaire for quantitative analysis, and evaluated a series of lectures on oral and maxillofacial surgery. Based on our findings, we then designed a blended learning module that was gradually integrated into the series. In 2017 we again evaluated the lectures, and rated the module. The two evaluations were then compared using a two-sample z-test. The results showed that students were very satisfied with the approach. They were particularly happy with the surgical videos, which were shown during the lectures and also included in the module, as they helped them to understand the surgical technique. Our survey showed that most of the students were using the online learning program and that it was the resource they preferred. Application of a blended learning approach could satisfy the requirements of the new generation of students, and transform traditional lectures into modern, sustainable, and technology-enhanced learning experiences. PMID- 30448013 TI - Influence of Fathers' Early Parenting on the Development of Children Born Very Preterm and Full Term. AB - OBJECTIVES: To examine factors associated with fathers' early parenting behaviors (including very preterm [VPT] birth, familial social risk, child sex, and child medical risk), and the relationship between fathers' early parenting behaviors and later child development. STUDY DESIGN: Participants were 81 VPT (born <30 weeks of gestation) and 39 full-term father-child dyads. Parenting behaviors (sensitivity, structuring, nonintrusiveness, nonhostility) were assessed at 12 months of corrected age using the Emotional Availability Scales, with scores ranging from 1 (low) to 7 (high). At 24 months of corrected age, child cognitive, language, motor, and social-emotional development were assessed. Results are presented as (regression coefficients; 95% CIs). RESULTS: There was little evidence that VPT birth, familial social risk, or child medical risk were associated with fathers' parenting behaviors. Fathers of girls tended to be more sensitive (0.42; 0.18, 0.65), less intrusive (0.36; 0.04, 0.70), and less hostile (0.26; 0.01, 0.50) compared with fathers of boys. Higher structuring was associated with more optimal cognitive (3.29; 1.25, 5.34), and language development (4.69; 2.26, 7.14). Higher sensitivity was associated with more optimal language development 3.35 (0.95, 5.75), and more intrusive behavior was associated with more externalizing symptoms (-1.68; -3.06, -0.31). CONCLUSIONS: Early parenting did not differ between fathers with VPT and full-term children, but fathers' parenting did vary according to child sex. Fathers' early parenting was associated with future neurodevelopment, reinforcing the need to support fathers' parenting, and include fathers in early intervention programs. PMID- 30448014 TI - Physiological Effect of Prone Position in Children with Severe Bronchiolitis: A Randomized Cross-Over Study (BRONCHIO-DV). AB - OBJECTIVE: To assess the effect of the prone position on physiological measures, including inspiratory effort, metabolic cost of breathing, and neural drive to the diaphragm as compared with the supine position in infants with severe bronchiolitis requiring noninvasive ventilation. STUDY DESIGN: Fourteen infants, median age 33 days (IQR [first and third quartiles], 25-58) were randomized to receive 7 cmH2O continuous positive airway pressure for 1 hour in the prone position or in the supine position, which was followed by cross-over to the supine position and the prone position for 1 hour, respectively. Flow, esophageal, airway, gastric, and transdiaphragmatic pressures, as well as electrical activity of the diaphragm were simultaneously recorded. The modified Wood clinical asthma score was also assessed. RESULTS: Median esophageal pressure time product per minute was significantly lower in the prone position than in the supine position (227 cmH2O*s/minute [IQR, 156-282] cmH2O*s/minute vs 353 cmH2O*s/minute [IQR, 249-386 cmH2O*s/minute]; P = .048), as were the modified Wood clinical asthma score (P = .033) and electrical activity of the diaphragm (P = .006). The neuromechanical efficiency of the diaphragm, as assessed by transdiaphramagtic pressure to electrical activity of the diaphragm swing ratio, was significantly higher in the prone position than in the supine position (1.1 cmH2O/uV [IQR, 0.9-1.3 cmH2O/uV] vs 0.7 cmH2O/uV [IQR, 0.6-1.2 cmH2O/uV], respectively; P = .022). CONCLUSIONS: This study suggests a benefit of the prone position for infants with severe bronchiolitis requiring noninvasive ventilation by significantly decreasing the inspiratory effort and the metabolic cost of breathing. Further studies are needed to evaluate the potential impact of these physiological findings in a larger population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02602678. PMID- 30448015 TI - The health of Palestinians. PMID- 30448016 TI - Anthropogenic nutrient inputs in the NW Iberian Peninsula estuaries determined by nitrogen and carbon isotopic signatures of Zostera noltei seagrass meadows. AB - Coastal watersheds of the NW Iberian Peninsula have undergone increases in population densities and urbanization over the past decades. However, the effect of altered nutrient inputs to estuarine Zostera noltei ecosystems associated to these anthropogenic pressures remains largely unknown. Eleven Zostera noltei meadows located in the NW Iberian Peninsula were studied to assess the relationship between the anthropogenic pressure over coastal watersheds and the nitrogen and carbon isotopic signatures of Z. noltei meadows. Anthropogenic pressure on the watersheds was estimated from human population data and land cover classes. Carbon and nitrogen stable isotopic analyses were performed on Z. noltei leaves and in the sediments surrounding the rhizospheres. Our results indicate that the N and C isotopic signatures of Z. noltei meadows from the NW Iberian Peninsula reflect the impact of anthropogenic pressures. Nevertheless, these relationships are complex due to several processes acting simultaneously altering the expected isotopic responses. PMID- 30448017 TI - Processing of N5-substituted formamidopyrimidine DNA adducts by DNA glycosylases NEIL1 and NEIL3. AB - A variety of agents cause DNA base alkylation damage, including the known hepatocarcinogen aflatoxin B1 (AFB1) and chemotherapeutic drugs derived from nitrogen mustard (NM). The N7 site of guanine is the primary site of alkylation, with some N7-deoxyguanosine adducts undergoing imidazole ring-opening to stable mutagenic N5-alkyl formamidopyrimidine (Fapy-dG) adducts. These adducts exist as a mixture of canonical beta- and unnatural alpha-anomeric forms. The beta species are predominant in double-stranded (ds) DNA. Recently, we have demonstrated that the DNA glycosylase NEIL1 can initiate repair of AFB1-Fapy-dG adducts both in vitro and in vivo, with Neil1-/- mice showing an increased susceptibility to AFB1 induced hepatocellular carcinoma. Here, we hypothesized that NEIL1 could excise NM-Fapy-dG and that NEIL3, a closely related DNA glycosylase, could excise both NM-Fapy-dG and AFB1-Fapy-dG. Product formation from the reaction of human NEIL1 with ds oligodeoxynucleotides containing a unique NM-Fapy-dG followed a bi component exponential function under single turnover conditions. Thus, two adduct conformations were differentially recognized by hNEIL1. The excision rate of the major form (~13.0 min-1), presumed to be the beta-anomer, was significantly higher than that previously reported for 5-hydroxycytosine, 5-hydroxyuracil, thymine glycol (Tg), and AFB1-Fapy-dG. Product generation from the minor form was much slower (~0.4 min-1), likely reflecting the rate of conversion of the alpha anomer into the beta anomer. Mus musculus NEIL3 (MmuNEIL3Delta324) excised NM Fapy-dG from single-stranded (ss) DNA (turnover rate of ~0.4 min-1), but not from ds DNA. Product formation from ss substrate was incomplete, presumably because of a substantial presence of the alpha anomer. MmuNEIL3Delta324 could not initiate repair of AFB1-Fapy-dG in either ds or ss DNA. Overall, the data suggest that both NEIL1 and NEIL3 may protect cells against cytotoxic and mutagenic effects of NM-Fapy-dG, but NEIL1 may have a unique role in initiation of base excision repair of AFB1-Fapy-dG. PMID- 30448018 TI - Incidence, mortality and bleeding rates associated with pulmonary embolism in England between 1997 and 2015. AB - BACKGROUND: Improvements in availability and accuracy of diagnostic testing in pulmonary embolism (PE) in the last 20 years have more recently been paralleled by the introduction of additional anticoagulation agents and treatment strategies. These developments are likely to shape potentially important changes in PE incidence, associated mortality and treatment complications. METHODS: We investigated trends in PE incidence, PE-related mortality and bleeding risk by analysing Hospital Episodes Statistics for England. RESULTS: Between 1997 and 2015, 464,046 patients (53.9% female) were hospitalized with PE in England. The annual number of hospitalizations with an associated diagnosis of PE more than doubled over this period (24,366 in 1998 vs. 53,108 in 2014), with a corresponding increase in PE hospitalization rate (50.2 to 97.8 per 100,000 population/year), evident in all age categories. Mortality at 1 and 3 months decreased over the study period and was significantly associated with age, treatment era and comorbidities. The risk of bleeding resulting in hospitalization or death within 3 and 12 months after the index PE admission increased over the study period (4.3%/5.1% for 1998-2004 versus 6.1%/7.2% for 2010-2014, p < 0.001 for both comparisons). CONCLUSIONS: The incidence of PE doubled in England between 1997 and 2015, likely attributable to raised awareness and ability to diagnose less severe cases. While PE-associated mortality decreased, there was an increase in bleeding risk. Renewed efforts directed at reducing the incidence of bleeding, including consideration of anticoagulation regimens and investigation of anticoagulation requirement in patients with low risk features, are needed. PMID- 30448019 TI - Sirtuin 5 promotes ischemia/reperfusion-induced blood-brain barrier damage after stroke. PMID- 30448020 TI - Biomimetic Conditioning of Human Dentin Using Citric Acid. AB - INTRODUCTION: In carious teeth, transforming growth factor beta 1 (TGF-beta1) is released from the dentin matrix and possibly activated in an acidic environment. Conversely, EDTA solutions with a neutral to slightly alkaline pH are used in clinics to promote cell homing in regenerative endodontic procedures. We hypothesized that citric acid (CA) might be more beneficial. METHODS: TGF-beta1 release from human dentin disks conditioned with either 10% CA (pH = 2) or 17% EDTA (pH = 8) and the behavior of human stem cells toward such pretreated dentin were studied. The protein concentration in conditioning solutions after 10 minutes of dentin exposure was determined using a pH-independent slot blot technique. RESULTS: There was a 5-fold higher concentration of the target protein in CA (382 +/- 30 ng/disk) compared with EDTA (66 +/- 3 ng/disk, P < .005). Using confocal laser scanning microscopy on immunofluorescent-labeled disks, we identified a high density of TGF-beta1 in peritubular dentin after CA treatment. A migration assay showed that CA conditioning attracted significantly more stem cells toward the dentin after 24 hours compared with EDTA (P < .05) or phosphate buffered saline (P < .005). To investigate whether the cell response to these dentin surfaces could be affected by different pretreatments, we cultured stem cells on conditioned dentin disks and found that CA had a significantly (P < .05) better effect than EDTA on cell attachment and cell survival. CONCLUSIONS: CA conditioning could be useful and may have significant benefits over current treatments. PMID- 30448021 TI - Presence of N-acetylglucosamine residues on the surface coating of bronchioloalveolar cells during rat postnatal development: What is their purpose? AB - Mammalian lung development is a complex process that is partially accomplished during the postnatal period. Surface carbohydrates are crucial in many biological and pathological phenomena and are key partners during development. The outer surface of lung epithelial cells, which is rich in carbohydrate components, plays a pivotal role throughout the developmental process. However, systematic studies on the sugar residue content of the cell surface coating during postnatal rat lung development are scarce. The aim of the present study was to identify and determine the localization of N-acetylglucosamine residues on the bronchioloalveolar cell surface during rat lung development using light and pre embedding transmission electron microscopy methodologies, and to associate these data with the components underlying postnatal lung growth. Strong binding sites for the lectin Triticum vulgare (common name Wheat Germ, WGA) are present on the luminal surface of adult rat bronchioloalveolar cells throughout the entire postnatal period and have been identified as N-acetylglucosamine residues. The consistent positive reaction observed on the surface coating of bronchioloalveolar lining cells before and after neuraminidase treatment suggests that aside from possible terminal sialic acids, the lectin specificity for N acetylglucosamine residues is still evident. Our results also suggest a stronger positive reaction on the bronchioloalveolar cell surface when compared with endothelial cell surface. N-acetylglucosamine residues for lectin binding can be present in glycoproteins in the membrane and also within heparin sulfate chains of glycosaminoglycans, which are crucial for lung development. The work described here has sought to highlight the presence and possible importance of N acetylglucosamine residues on the glycocalyx of bronchioloalveolar cells, during postnatal lung development. PMID- 30448022 TI - Family presence during resuscitation (FPDR): A qualitative descriptive study exploring the experiences of emergency personnel post resuscitation. AB - INTRODUCTION: Family presence during resuscitation (FPDR), remains inconsistently implemented by emergency personnel. The benefits for family members is well documented, providing opportunities for family to say goodbye, facilitates closure and enables family to provide emotional support to the patient. The aim of this study was to explore the experiences and attitudes of emergency personnel towards FPDR immediately post resuscitation events. METHOD: A descriptive qualitative design was used to explore the experiences of emergency personnel with FPDR. Data was collected from single rural and metropolitan emergency departments in the state of Victoria, Australia. The participants consisted of nurses and doctors who took active roles during resuscitation events. Following transcription of the audiotaped interviews Creswell's (2003) six step analysis process was employed. RESULT: A total of 29 interviews of key personnel, following 6 paediatric and 18 adult resuscitation events. Interviews were conducted over a period of two weeks in each venue. The data was organised into six themes following analysis including: care coordinators inconsistently called, gate keepers to implementation, effective communication strategies helping to deliver bad news, life experience generates confidence, allocation of family support person, and family members roles dependent on age of patient. CONCLUSION: FPDR is common practice in paediatric events however remains inconsistently implemented during adult resuscitations. A designated family support person is essential to successful implementation of FPDR and should be incorporated in to the allocation of the resuscitation team roles during both adult and paediatric resuscitation events. Education and training is important for clinicians to learn essential communication skills, building practice confidence, which is required to successfully implement FPDR. PMID- 30448023 TI - Changes in the secretome of Vitis vinifera cv. Monastrell cell cultures treated with cyclodextrins and methyl jasmonate. AB - Elicitors induce defense responses that resemble those triggered by pathogen attack, including the synthesis of phytoalexins and pathogen-related proteins, which are accumulated in the extracellular space. In this work we analyze the changes in the secretome of Vitis vinifera cv. Monastrell cell cultures. This refers to the secreted proteome obtained from cell suspension cultures, in response to treatment with cyclodextrins and methyl jasmonate, separately or in combination using label-free quantitative approaches. Of the proteins found, thirty-three did not show significant differences in response to the different treatments carried out, indicating that these proteins were expressed in a constitutive way in both control and elicited grapevine cell cultures. These proteins included pathogenesis-related proteins 4 and 5, class III peroxidases, NtPRp-27, chitinases and class IV endochitinases, among others. Moreover, eleven proteins were differentially expressed in the presence of cyclodextrins and/or methyl jasmonate: three different peroxidases, two pathogenesis related protein 1, LysM domain-containing GPI-anchored protein 1, glycerophosphoryl diester phosphodiesterase, reticulin oxidase, heparanase, beta-1,3-glucanase and xyloglucan endotransglycosylase. Treatments with cyclodextrins reinforced the defensive arsenal and induced the accumulation of peroxidase V and xyloglucan endotransglycosylase. However, elicitation with methyl jasmonate decreased the levels of several proteins such as pathogenesis related protein 1, LysM domain containing GPI-anchored protein 1, cationic peroxidase, and glycerophosphoryl diester phosphodiesterase, but increased the levels of new gene products such as heparanase, beta-1,3 glucanase, reticulin oxidase, and peroxidase IV, all of which could be used as potential biomarkers in the grapevine defense responses. PMID- 30448024 TI - Transcriptional profiling and physiological analysis reveal the critical roles of ROS-scavenging system in the Antarctic moss Pohlia nutans under Ultraviolet-B radiation. AB - Organisms suffer more harmful ultraviolet radiation in the Antarctica due to the ozone layer destruction. Bryophytes are the dominant flora in the Antarctic continent. However, the molecular mechanism of Antarctic moss adaptation to UV-B radiation remains unclear. In the research, the transcriptional profiling of the Antarctic moss Pohlia nutans under UV-B radiation was conducted by Illumina HiSeq2500 platform. Totally, 72,922 unigenes with N50 length of 1434 bp were generated. Differential expression analysis demonstrated that 581 unigenes were markedly up-regulated and 249 unigenes were significantly down-regulated. The gene clustering analysis showed that these differentially expressed genes (DEGs) includes several transcription factors, photolyases, antioxidant enzymes, and flavonoid biosynthesis-related genes. Further analyses suggested that the content of malondialdehyde (MDA), the activities of several antioxidant enzymes (i.e., catalase, peroxidase, and glutathione reductase) were significantly enhanced upon UV-B treatment. Furthermore, the content of flavonoids and the gene expression levels of their synthesis-related enzymes were also markedly increased when plants were exposed to UV-B light. Therefore, these results suggested that the pathways of antioxidant enzymes, flavonoid synthesis and photolyases were the main defense systems that contributed to the adaption of Pohlia nutans to the enhanced UV-B radiation in Antarctica. PMID- 30448025 TI - Beyond the reminder: The next steps in pharmacist-driven, mHealth patient engagement. AB - OBJECTIVE: To describe opportunities for pharmacists to use mobile messaging and real-time monitoring to engage with patients taking long-term medications. SUMMARY: The proliferation of mobile phone use across the United States has been met with increased application of these devices by the medical community. However, beyond simple text messages and app-based functions, use of these devices by pharmacies and pharmacists has not been leveraged to improve patient outcomes, such as medication adherence. Resources now exist that can facilitate more advanced mobile communication between patients and pharmacists, which can be managed and informed by data available in most pharmacies. Such tailored messaging can be personalized further by being reactive to patient behavior using real-time medication use monitoring tools, facilitating low-cost, high-reach interventions for patients in need of ongoing guidance. CONCLUSION: Mechanisms now exist for pharmacies to engage patients more proactively with their prescribed therapy using mobile communication and devices. By facilitating such engagement, pharmacists can remain connected with patients throughout their care, better interpret their needs, navigate adherence-related issues, and more holistically counsel patients based on observed behaviors. Community pharmacy leadership should pursue the use of these advanced mobile messaging techniques as another tool in their arsenal to improve patient outcomes. PMID- 30448026 TI - Prescription and over-the-counter medication record integration: A holistic patient-centered approach. AB - OBJECTIVE: Nonprescription or over-the-counter (OTC) medications play a crucial role in a patient's ability to make choices to manage his or her own health care. Often these nonprescription choices are unknown to health care practitioners and thus are often not included as part of patients' health records. The exclusion of these therapies can pose risks to patient safety. There is a significant need to address the capture of OTC medication use in both the physician and pharmacy electronic health records (EHRs) and during the practitioner-patient medication history and reconciliation process. DATA SOURCES: On October 26, 2016, the National Association of Chain Drug Stores Foundation hosted a forum for a select group of health care industry professionals to work on a series of recommendations to improve the documentation of OTC medication use by patients. This diverse group of more than a dozen stakeholders included community pharmacy leaders from multiple chain pharmacies, pharmacy system vendors, e-prescribing vendors, health information technology experts, and multiple industry representatives, including individuals from the public sector. This commentary is a summary of the insights and suggestions where the group was in general agreement. SUMMARY: Successful OTC medication EHR integration will require system level buy-in across multiple layers of the health care industry to improve patient safety. Forum participants suggested incremental steps that could be taken by multiple stakeholders to lay the foundation for integration within an appropriate regulatory structure. CONCLUSION: Based on the results of the stakeholder forum, an agreement formed around one approach that the group supported as feasible: the creation of a consistent and uniform identification method for OTC medications in cooperation with government regulatory authorities. PMID- 30448027 TI - In-hospital Mortality Due to Acute Myocardial Infarction in the Canary Islands. PMID- 30448028 TI - Is There a Gender Gap in Spanish Cardiology? PMID- 30448029 TI - In-hospital Mortality Due to Acute Myocardial Infarction in the Canary Islands. Response. PMID- 30448030 TI - The value of immediate postoperative intravesical epirubicin instillation as an adjunct to standard adjuvant treatment in intermediate and high-risk non-muscle invasive bladder cancer: A preliminary results of randomized controlled trial. AB - PURPOSE: We aimed at this study to test the value of immediate postoperative intravesical epirubicin instillation in intermediate and high-risk non-muscle invasive bladder cancer patients. MATERIALS AND METHODS: After approval of Institutional Review Board, 260 patients were randomly allocated into 2 groups, including transurethral resection of bladder tumor (TURBT) alone in control group and TURBT plus immediate postoperative epirubicin (50 mg) in test group. Patients were monitored for postoperative complications. Adjuvant instillation therapy was administered according to risk categorization. Patients were followed every 3 months by cystourethroscopy and urine cytology. The primary end points were recurrence, progression, and/or death from cancer. RESULTS: Of the 260 patients, 236 were eligible and followed for a mean of 29 months. The 2 study groups were comparable regarding perioperative baseline demographic criteria. There was no statistically significant difference between the 2 groups regarding recurrence rate (27.1% vs. 26.2%), interval to first recurrence (16.3 +/- 6.6 vs. 16.4 +/- 6.4 months) or progression rate to muscle invasion (8.5% vs. 5.9%). Site, size, and number of recurrences were also comparable between the 2 groups. Recurrences and progression-free survival were comparable between the 2 groups (Log-rank P = 0.88 and 0.47, respectively). Postoperative complications were all low-grade according to modified Dindo-Clavian system, with no significant difference in their rate between the 2 groups. CONCLUSIONS: Immediate post-TURBT epirubicin instillation is ineffective in intermediate and high-risk non-muscle-invasive bladder cancer. It neither prolongs time to recurrence and/or progression nor reduces number of recurrences. We advocate strict specification of patient and tumor criteria in which immediate instillation is indicated. PMID- 30448031 TI - Impact on confidence and practice: How the ADAPT online patient care skills program made a difference for pharmacists. AB - BACKGROUND: The ADAPT "ADapting pharmacists' skills and Approaches to maximize Patients' drug Therapy effectiveness" online education program was developed to enable pharmacists to overcome a lack of confidence in patient care and collaborative skills, enabling successful adoption of expanded scope of pharmacist practice. OBJECTIVES: This study examined responses of ADAPT participants, to determine if acquisition of knowledge, skill, and confidence is retained and translated into adoption of expanded scope of practice and billable services, perceived improvement in quality of patient care, and increased professional satisfaction. METHODS: A sequential exploratory mixed methods approach was used for this study. RESULTS: Fifty-four surveys were completed and 13 interviews were conducted. Greater than 86% agreed or strongly agreed that their confidence in their ability to perform ADAPT skills had improved. Billing for services varied based on province. Four themes emerged through the interview process: confidence, change, impact and barriers/facilitators. CONCLUSIONS: Respondents described confidence in their ability to use ADAPT skills to make changes in personal practice activities, and this appeared to lead to taking on new roles that provided both professional satisfaction and improved patient care and professional relations. However, some barriers remained in providing or billing for certain practice activities. PMID- 30448033 TI - Small, however significant differences in the definition of physical frailty, and sarcopenia. PMID- 30448032 TI - Validation of giant cell arteritis diagnosis code in the French hospital electronic database. PMID- 30448034 TI - Impact of Cognitive Impairment in Patients with Gliomas. AB - OBJECTIVES: To address the estimated rates of incidence, potential underlying etiologies, and cognitive domains affected from diagnosis and treatment. To describe potential cognitive function interventions. DATA SOURCES: PubMed. CONCLUSION: Adults with gliomas report that the most distressing, persistent, and greatest negative impact on their lives relates to the cognitive impairment they experience. However, there are several potential interventions that may prevent cognitive decline during treatment or maintain cognitive function long term. IMPLICATIONS FOR NURSING PRACTICE: Awareness of cognitive sequela that adults with gliomas face can lead to early identification, full neurocognitive profiling, and implementation of evidence-based interventions for those experiencing cognitive impairments following cancer treatment. PMID- 30448035 TI - Corrigendum to "Subchronic reproductive effects of 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFAES), an alternative to PFOS, on adult male mice" [J. Hazard. Mater. 358 (September) (2018) 256-264]. PMID- 30448036 TI - Comparison of the strength of two multi-strand tendon repair configurations in a chicken model. AB - We sought to investigate the strength of two multi-strand tendon repair configurations in a chicken model. Fifty-six chicken flexor tendons were repaired with one to two different four-strand configurations: 1) a four-strand repair consisting of a two-strand core modified Kessler suture with a circle loop repair and 2) a four-strand core Kessler suture repair with three separate peripheral suture points. The strength of the repaired tendons were measured 2, 3 and 4 weeks after the surgical repair and were analyzed statistically. The strength of the two repair methods was not statistically different 2 weeks after surgery. The tendons repaired with the four-strand core Kessler suture repair and three separate peripheral suture points were significantly stronger than those repaired with a two-strand core modified Kessler suture and a circle loop repair at 3 weeks (P = 0.033) and 4 weeks (P = 0.039). The four-strand repair with three separate peripheral suture points had greater strength than a two-strand repair with one circle loop suture based on an in vivo chicken flexor tendon model. PMID- 30448037 TI - Dual Role of the C-Terminal Domain in Osmosensing by Bacterial Osmolyte Transporter ProP. AB - ProP is a member of the major facilitator superfamily, a proton-osmolyte symporter, and an osmosensing transporter. ProP proteins share extended cytoplasmic carboxyl terminal domains (CTDs) implicated in osmosensing. The CTDs of the best characterized, group A ProP orthologs, terminate in sequences that form intermolecular, antiparallel alpha-helical coiled coils (e.g., ProPEc, from Escherichia coli). Group B orthologs lack that feature (e.g., ProPXc, from Xanthomonas campestris). ProPXc was expressed and characterized in E. coli to further elucidate the role of the coiled coil in osmosensing. The activity of ProPXc was a sigmoid function of the osmolality in cells and proteoliposomes. ProPEc and ProPXc attained similar activities at the same expression level in E. coli. ProPEc transports proline and glycine betaine with comparable high affinities at low osmolality. In contrast, proline weakly inhibited high-affinity glycine-betaine uptake via ProPXc. The KM for proline uptake via ProPEc increases dramatically with the osmolality. The KM for glycine-betaine uptake via ProPXc did not. Thus, ProPXc is an osmosensing transporter, and the C-terminal coiled coil is not essential for osmosensing. The role of CTD-membrane interaction in osmosensing was examined further. As for ProPEc, the ProPXc CTD co-sedimented with liposomes comprising E. coli phospholipid. Molecular dynamics simulations illustrated association of the monomeric ProPEc CTD with the membrane surface. Comparison with the available NMR structure for the homodimeric coiled coil formed by the ProPEc-CTD suggested that membrane association and homodimeric coiled-coil formation by that peptide are mutually exclusive. The membrane fluidity in liposomes comprising E. coli phospholipid decreased with increasing osmolality in the range relevant for ProP activation. These data support the proposal that ProP activates as cellular dehydration increases cytoplasmic cation concentration, releasing the CTD from the membrane surface. For group A orthologs, this also favors alpha-helical coiled-coil formation that stabilizes the transporter in an active form. PMID- 30448038 TI - Bacterial Cohesion Predicts Spatial Distribution in the Larval Zebrafish Intestine. AB - Are there general biophysical relationships governing the spatial organization of the gut microbiome? Despite growing realization that spatial structure is important for population stability, interbacterial competition, and host functions, it is unclear in any animal gut whether such structure is subject to predictive, unifying rules or if it results from contextual, species-specific behaviors. To explore this, we used light sheet fluorescence microscopy to conduct a high-resolution comparative study of bacterial distribution patterns throughout the entire intestinal volume of live, larval zebrafish. Fluorescently tagged strains of seven bacterial symbionts, representing six different species native to zebrafish, were each separately monoassociated with animals that had been raised initially germ-free. The strains showed large differences in both cohesion-the degree to which they auto-aggregate-and spatial distribution. We uncovered a striking correlation between each strain's mean position and its cohesion, whether quantified as the fraction of cells existing as planktonic individuals, the average aggregate size, or the total number of aggregates. Moreover, these correlations held within species as well; aggregates of different sizes localized as predicted from the pan-species observations. Together, our findings indicate that bacteria within the zebrafish intestine are subject to generic processes that organize populations by their cohesive properties. The likely drivers of this relationship-peristaltic fluid flow, tubular anatomy, and bacterial growth and aggregation kinetics-are common throughout animals. We therefore suggest that the framework introduced here of biophysical links between bacterial cohesion and spatial organization should be useful for directing explorations in other host-microbe systems, formulating detailed models that can quantitatively map onto experimental data, and developing new tools that manipulate cohesion to engineer microbiome function. PMID- 30448039 TI - Optical Recording of Action Potential Initiation and Propagation in Mouse Skeletal Muscle Fibers. AB - Skeletal muscle fibers have been used to examine a variety of cellular functions and pathologies. Among other parameters, skeletal muscle action potential (AP) propagation has been measured to assess the integrity and function of skeletal muscle. In this work, we utilize 1-(3-sulfonatopropyl)-4[beta[2-(Di-n-octylamino) 6-naphtyl]vinyl]pyridinium betaine, a potentiometric dye, and mag-fluo-4, a low affinity intracellular Ca2+indicator, to noninvasively and reliably measure AP conduction velocity in skeletal muscle. We used remote extracellular bipolar electrodes to generate an alternating polarity electric field that initiates an AP at either end of the fiber. Using enzymatically dissociated flexor digitorum brevis (FDB) fibers and high-speed line scans, we determine the conduction velocity to be ~0.4 m/s. We applied these methodologies to FDB fibers under elevated extracellular potassium conditions and confirmed that the conduction velocity is significantly reduced in elevated [K+]o. Because our recorded velocities for FDB fibers were much slower than previously reported for other muscle groups, we compared the conduction velocity in FDB fibers to that of extensor digitorum longus (EDL) fibers and measured a significantly faster velocity in EDL fibers than FDB fibers. As a basis for this difference in conduction velocity, we found a similarly higher level of expression of Na+ channels in EDL than in FDB fibers. In addition to measuring the conduction velocity, we can also measure the passive electrotonic potentials elicited by pulses by applying tetrodotoxin and have constructed a circuit model of a skeletal muscle fiber to predict passive polarization of the fiber by the field stimuli. Our predictions from the model fiber closely resemble the recordings acquired from in vitro assays. With these techniques, we can examine how various pathologies and mutations affect skeletal muscle AP propagation. Our work demonstrates the utility of using 1-(3-sulfonatopropyl)-4[beta[2-(Di-n octylamino)-6-naphtyl]vinyl]pyridinium betaine or mag-fluo-4 to noninvasively measure AP initiation and conduction. PMID- 30448040 TI - Evaluating the use of text message communication in a postpartum patient navigation program for publicly insured women. AB - OBJECTIVE: To compare communication between navigators and women according to follow-up status in a postpartum patient navigation program ("Navigating New Motherhood" [NNM]). METHODS: This is a mixed methods secondary analysis of text message and email transcripts from NNM. Transcripts were analyzed by number of messages sent, received, and unanswered. Message themes were qualitatively analyzed using constant comparative technique. Bivariable and multivariable tests were conducted. RESULTS: Most women (98.2%) communicated with navigators via text message. Women who completed postpartum follow-up sent and received more texts than women who did not (7.8 vs. 3.7, p < 0.001 and 11.5 vs. 8.0, p < 0.05, respectively); exchange of >=6 messages was associated with greater odds of follow-up (adjusted odds ratio 2.89, 95% CI1.13-7.41). Lack of patient response was also associated with lack of follow-up (p < 0.001). Four categories of message themes were identified: Rapport-building, Postpartum Care Coordination, Maternal Health, and Motherhood. Message threads with more Rapport-building or Maternal Health messages were associated with more frequent patient follow-up (p < 0.01 and p < 0.05, respectively), as was average number of emoticons per message thread (2.1 vs. 1.2, p = 0.01). CONCLUSION: More frequent and multidimensional communication was associated with follow-up in a postpartum patient navigation program. PRACTICE IMPLICATIONS: Text messaging can serve as a favorable communication platform within patient navigation. PMID- 30448041 TI - Analyzing paths from online health information seeking to colorectal cancer screening using health literacy skills frame and cognitive mediation model. AB - OBJECTIVE: To test the hypothesized paths for Online Health Information Seeking (OHIS) behaviors in developing health literacy, leading to colorectal cancer (CRC) screening among Korean Americans (KAs) using Health Literacy Skills Frameworks (HLSF) and Cognitive Mediation Model (CMM). METHODS: A total of 433 KAs aged 50 through 75 in a metropolitan area in the Southeastern U.S. completed a cross-sectional survey regarding sociodemographics, OHIS behaviors, information overload, health literacy, decisional balance, and CRC screening history. Path analyses were implemented to assess the hypothesized causal models by examining the relationships among these variables. RESULTS: OHIS was positively associated with information overload and health literacy; information overload was negatively associated with health literacy. Health literacy was positively associated with decisional balance; decisional balance was positively associated with uptake of sigmoidoscopy and colonoscopy. CONCLUSION: The findings supported both theoretical frameworks, HLSF and CMM, for OHIS to develop health literacy, leading to CRC screening. These findings highlight the significant roles of information overload and attitudes and beliefs about screening in enhancing health literacy and CRC screening among KAs. PRACTICE IMPLICATIONS: Practice efforts for facilitating CRC screening among medically underserved older KAs should target improving access to and use of OHIS and culturally-tailored health information delivery. PMID- 30448042 TI - The effects of persuasive messages on cancer patients' attitudes, norms and intention to express concerns. AB - OBJECTIVE: To examine whether the use of persuasive messages in which cancer patients' attitudes and perceived social norms were either simultaneously or exclusively targeted can positively change patients' attitudes, perceived social norms and the intention to express concerns in consultations. METHODS: Two online experiments were conducted. The first experiment had a pre-test and post-test measurements design with 4 conditions (attitudes message, social norms message, combined message, control message). The second experiment had a pre-test and post test measurements design with 2 conditions (message and no message group). RESULTS: The results of the first study showed small positive changes for patients who could potentially change, but there were no differences in effects between conditions. A second study was conducted to determine whether these effects could be attributed to exposure to the message or to the pre-test questionnaire. There were no differences between the conditions. CONCLUSION: The results indicate that paying attention to the expression of concerns by patients might increase patients' intention to express further concerns. PRACTICE IMPLICATIONS: Providers might be able to support patients' in their sharing of concerns through simple communication strategies such as explicitly mentioning that the expression of concerns is possible during a consultation. PMID- 30448043 TI - "A change would do you good": Training medical students in Motivational Interviewing using a blended-learning approach - A pilot evaluation. AB - Objectives This study aims to assess medical students' interest in a Motivational Interviewing (MI), the objective need for a special training, and students' satisfaction with and the effectiveness of such a course. Methods A mandatory MI course was implemented for sixth-semester medical students. Their interest in learning MI was evaluated, along with their satisfaction with the course, which was delivered in a blended-learning teaching approach. Participants' baseline MI skills and general communication skills were assessed. MI non-adherent behavior, like persuading and confronting patients, was noted. Successful learning was measured with a multiple-choice test administered before and after the course that assessed subjective knowledge and skills. Results Students were highly interested in learning MI. At baseline, they showed good communication skills but moderate MI skills. Satisfaction with the course was high. The course was effective, as subjective and objective knowledge and skills improved significantly. Conclusions This pilot study suggests that basic MI skills can be successfully taught in a blended-learning teaching approach. Further research should investigate sustainability and transfer to clinical practice. Practice implications Medical schools should consider providing students with special training in MI to help students counsel patients towards behavioral changes. PMID- 30448044 TI - Patient-led decision making: Measuring autonomy and respect in Canadian maternity care. AB - OBJECTIVE: The Changing Childbirth in British Columbia study explored women's preferences and experiences of maternity care, including women's role in decision making. METHODS: Following content validation by community members, we administered a cross-sectional online survey exploring novel topics, including drivers for interventions, and experiences of autonomy, respect, or mistreatment during maternity care. Using the Mothers Autonomy in Decision-Making (MADM) scale as an outcome measure in a mixed-effects analysis, we examined differential experiences by socio-demographic and prenatal risk profile, type of care provider, interventions received, and nature of communication with care providers. RESULTS: A geographically representative sample of Canadian women (n = 2051) reported on 3400 pregnancies. Most women (95.2%) preferred to be the lead decision-maker during care. Patients of physicians had significantly lower autonomy (MADM) scores than midwifery clients as did women who felt pressured to accept interventions. Women who had a difference in opinion with their provider, and those who felt their provider seemed rushed reported the lowest MADM scores. CONCLUSION: Women's autonomy is significantly altered by model of maternity care, the nature of interactions with care providers, and women's ability for self determination. PRACTICE IMPLICATIONS: If health professionals acquire skills in person-centred decision-making experience of autonomy among pregnant women may improve. PMID- 30448045 TI - Phosphorylated ERM Mediates Lipopolysaccharide Induced Pulmonary Microvascular Endothelial Cells Permeability Through Negatively Regulating Rac1 Activity. AB - INTRODUCTION: The endotoxin lipopolysaccharide (LPS)-induced pulmonary endothelial barrier disruption is a key pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, the molecular mechanisms underlying LPS-impaired permeability of pulmonary microvascular endothelial cells (PMVECs) are not fully understood. METHODS: Rat PMVECs were isolated and monolayered cultured, then challenged with different doses of LPS (0.1mg/L, 1mg/L, and 10mg/L). Trans-endothelial electrical resistance (TER) was utilized to measure the integrity of the endothelial barrier. Ras-related C3 botulinum toxin substrate 1 (Rac1) activity and the phosphorylation of Ezrin/Radixin/Moesin proteins (ERM) were assessed by pulldown assay and Western Blotting. Small interfering RNA (siRNA) inhibition of Rac1 and Moesin were applied to evaluate the effect of PMVEs permeability and related pathway. RESULTS: LPS induced dose and time-dependent decreases in TER and increase in ERM threonine phosphorylation, while inactivated Rac1 activity in PMVEC. siRNA study demonstrated that both Rac1 and Moesin were involved in the mediation of the LPS induced hyperpermeability in PMVECs monolayers, and Rac1 and Moesin could regulate each other. CONCLUSION: Phosphorylated ERM mediates LPS induced PMVECs permeability through negatively regulating Rac1 activity. PMID- 30448046 TI - Paying attention to relatives of cancer patients: What can we learn from their online writings? AB - OBJECTIVE: Relatives of cancer patients often play a crucial role in care, while their own needs generally receive scant attention. We investigate those topics on which relatives share information online. METHODS: We coded user-generated content written by 185 relatives on a major Dutch cancer site (kanker.nl), into three main categories: 'Disease', 'Well-being' and 'Other subjects'. In addition, we analysed five websites (from five countries) for which content they provide that is relevant for relatives. RESULTS: Our analysis showed that across cancer types, relatives share online information and emotions. Quantitative analysis showed that they mainly write about topics related to their own well-being (blog posters: 45% of the posts and group posters 64%). Blog posters found the disease related topics more important than the group posters (45% and 29%). CONCLUSIONS: This study has shown that relatives share different kinds of user generatedcontent related to their own situation. This could be a valuable resource for further research into the needs of relatives, and a very useful source for identification of emotional and informational topics. PRACTICE IMPLICATIONS: It is crucial that relatives are enabled to occupy their own space in the disease-and-treatment process appropriate to their needs and to help avoid caregiver burden. PMID- 30448047 TI - Measuring shared decision-making in the pediatric outpatient setting: Psychometric performance of the SDM-Q-9 and CollaboRATE among English and Spanish speaking parents in the US Midwest. AB - OBJECTIVE: Shared decision-making (SDM) measures have never been assessed for validity and feasibility in pediatric outpatient settings. We compared psychometric performance of parent adaptations of a well-established measure (SDM Q-9) to a newer measure focusing on provider effort in facilitating SDM (CollaboRATE) in two clinics. METHODS: English (n = 955) and Spanish (n = 58) speaking parents of children ages 1-5 years with symptoms of acute respiratory tract infections (ARTI) completed post-visit SDM-Q-9, CollaboRATE, satisfaction items (visit, provider communication, and study participation), and qualitative feedback. RESULTS: Parents felt CollaboRATE was more comprehensible and relevant than SDM-Q-9, which refers to decision-making actions difficult to define in ARTI visits. Among English-speakers, both measures showed high internal consistency (alpha = 0.91, alpha = 0.97). SDM-Q-9 reliability was strong (split-half, r = 0.83) and CollaboRATE weak-to-moderate (two-week test-retest, rho = 0.41-0.66). Convergent validity with communication and visit satisfaction was poor for SDM-Q 9 (r=0.38, r=0.34) but higher for CollaboRATE (r=0.59, r = 0.52). Both showed divergent validity with study participation satisfaction (r=0.08, r=0.13). Spanish versions demonstrated similar results. CONCLUSIONS: Parent preference and correlations with satisfaction support CollaboRATE over SDM-Q-9, however psychometrics were borderline acceptable. PRACTICE IMPLICATIONS: Tools like CollaboRATE that focus on provider effort appear more appropriate for routine pediatric visits where SDM outcomes may be difficult to identify, yet additional validation research is needed. PMID- 30448048 TI - Bexarotene in Patients With Peripheral T-cell Lymphomas: Results of a Retrospective Study. AB - BACKGROUND: Peripheral T-cell lymphomas (PTCLs) are generally aggressive non Hodgkin lymphomas that portend poor prognosis with currently available therapies. Bexarotene, a retinoic acid derivative, has efficacy in cutaneous T-cell lymphomas, but its activity in PTCL is unknown. PATIENTS AND METHODS: We conducted a retrospective, single-institution, review of off-label bexarotene therapy in patients with PTCL between 2005 and 2016. RESULTS: Twelve patients were treated with bexarotene as monotherapy: 3 patients with PTCL, not otherwise specified, and 9 patients with angioimmunoblastic T-cell lymphoma. Bexarotene doses of 300 mg/m2 daily or 150 mg/m2 were used for all patients. The treatment was well-tolerated. The most common toxicities included hypothyroidism and hyperlipidemia, which were effectively managed. The overall response rate for all patients was 58% with a median duration of response of 11 months (95% confidence interval [CI], 1.3 months to not estimable). Among patients with angioimmunoblastic T-cell lymphoma, there was a 44% overall response rate. The median progression-free survival for all patients was 2.1 months (95% CI, 1.1 months to not estimable), and the median overall survival was 14.9 months (95% CI, 2.1-73.1 months). CONCLUSION: Bexarotene monotherapy is well-tolerated and has encouraging activity in PTCL that warrants further investigation in prospective clinical trials. PMID- 30448049 TI - Feasibility of 4DCBCT-based proton dose calculation: An ex vivo porcine lung phantom study. AB - Inter-fractional variations of breathing pattern and patient anatomy introduce dose uncertainties in proton therapy. One approach to monitor these variations is to utilize the cone-beam computed tomography (CT, CBCT) scans routinely taken for patient positioning, reconstruct them as 4DCBCTs, and generate 'virtual CTs' (vCTs), combining the accurate CT numbers of the diagnostic 4DCT and the geometry of the daily 4DCBCT by using deformable image registration (DIR). In this study different algorithms for 4DCBCT reconstruction and DIR were evaluated. For this purpose, CBCT scans of a moving ex vivo porcine lung phantom with 663 and 2350 projections respectively were acquired, accompanied by an additional 4DCT as reference. The CBCT projections were sorted in 10 phase bins with the Amsterdam shroud method and reconstructed phase-by-phase using first a FDK reconstruction from the Reconstruction Toolkit (RTK) and again an iterative reconstruction algorithm implemented in the Gadgetron Toolkit. The resulting 4DCBCTs were corrected by DIR of the corresponding 4DCT phases, using both a morphons algorithm from REGGUI and a b-spline deformation from Plastimatch. The resulting 4DvCTs were compared to the 4DCT by visual inspection and by calculating water equivalent thickness (WET) maps from the phantom's surface to the distal edge of a target from various angles. The optimized procedure was successfully repeated with mismatched input phases and on a clinical patient dataset. Proton treatment plans were simulated on the 4DvCTs and the dose distributions compared to the reference based on the 4DCT via gamma pass rate analysis. A combination of iterative reconstruction and morphons DIR yielded the most accurate 4DvCTs, with median WET differences under 2mm and 3%/3mm gamma pass rates per phase between 89% and 99%. These results suggest that image correction of iteratively reconstructed 4DCBCTs with a morphons DIR of the planning CT may yield sufficiently accurate 4DvCTs for daily time resolved proton dose calculations. PMID- 30448050 TI - Infection control in patients with myelodysplastic syndromes who are candidates for active treatment: Expert panel consensus-based recommendations. AB - The improvement in supportive care and the introduction of new therapeutic agents, including lenalidomide and hypomethylating agents, in myelodysplastic syndromes have improved patients' outcomes; however, at the same time, the frequency and epidemiology of infections have changed. Therefore, the great strides in the indications and use of new treatment strategies for myelodysplastic syndromes need a parallel progress in the best approach to prophylaxis and supportive therapy for infections. Based on the recognition that the above issues represent an unmet clinical need in myelodysplastic syndromes, an Italian expert panel performed a review of the literature and composed a framework of the best recommendations for optimal infection control in patient candidates to receive active treatment for myelodysplastic syndromes. In this consensus document we report the outcomes of that review and of the consensus meetings held during 2017. The issues tackled in the project dealt with: information to be collected from candidates for active treatment for myelodysplastic syndromes; how to monitor the risk of infection; antimicrobial prophylaxis; the role of iron chelation and antiviral/antibacterial vaccinations. For each of these issues, practice recommendations are provided. PMID- 30448051 TI - Management of Urosepsis in 2018. AB - Despite optimal treatment, urosepsis has still high morbidity and mortality rates. An updated definition and classification system for sepsis have recently been introduced. Management of urosepsis comprises four major aspects: (1) early diagnosis, (2) early empiric intravenous antimicrobial treatment, (3) identification and control of complicating factors, and (4) specific sepsis therapy. The quick sequential organ failure assessment is replacing the systemic inflammatory response syndrome scoring for rapid identification of patients with urosepsis. PATIENT SUMMARY: Urosepsis is a serious, life-threatening complication of infections originating from the urinary tract. As urosepsis has a very high mortality rate, it is important that is quickly spotted and that appropriate treatment is swiftly begun. Imaging of urinary tract disorders has been shown to be useful in decreasing mortality from urosepsis, and in the future microbiology techniques may also prove useful. Given the severity of urosepsis and the associated risks, large efforts need to be made to prevent high-risk infections in hospitals with appropriate prevention measures, such as the early removal of catheters used whenever possible. PMID- 30448052 TI - Effects of sodium chloride and sodium perchlorate on properties and partition behavior of solutes in aqueous dextran-polyethylene glycol and polyethylene glycol-sodium sulfate two-phase systems. AB - Effects of two salt additives, NaCl and NaClO4, at the fixed concentrations of 0.215 M on the properties of aqueous two-phase systems (ATPSs) formed by dextran (Dex) and polyethylene glycol (PEG), and the effects of NaClO4 at the same concentration on the properties of ATPS formed by PEG and Na2SO4 were examined. The effects of these salt additives on partitioning of 12 small organic compounds and five proteins in the above ATPSs were studied. In each system with a given salt additive, 0.5 M sorbitol, 0.5 M sucrose, and 0.5 M and 1.5 M trimethylamine N-oxide (TMAO) were also used as additives. The results obtained were compared with those reported previously for the Dex-PEG ATPS without salt additives and PEG-Na2SO4 ATPS without salt additives and in the presence of 0.215 M NaCl. It is shown that the differences between the solvent properties of the phases in the systems formed by polymer and salt exceed those observed in the systems formed by two polymers. The three most significant solvent features of the systems are hydrophobic and electrostatic properties and hydrogen bonding donor acidity of the solvent media. Osmolyte additives were found to have a significant effect on the differences between the electrostatic properties of the phases. Analysis of the partition coefficients of 12 organic compounds and five proteins showed that the osmolyte additives may affect the partition behavior of compounds in a compound-specific manner. The relative contributions of different types of interactions of a given compound with aqueous media change in the presence of salt and osmolyte additives. Analysis of the variability ranges of partition coefficient, K, in the systems studied showed that for small organic compounds, the ranges of K-values observed in the PEG-Na2SO4 ATPSs exceed those determined in the Dex-PEG ATPSs quite significantly, whereas for proteins, the range of K values in Dex-PEG ATPSs exceeded those in PEG-Na2SO4 ATPSs for three proteins, and were very similar for two proteins. This observation supported the notion that the ATPSs formed by two polymers are more suitable for protein analysis than those formed by a single polymer and a salt. The single polymer-salt ATPSs have an advantage for protein isolation/separation. PMID- 30448053 TI - Analysis of 6- and 7-ring PAH and other non-EPA PAH by atmospheric pressure laser ionization - mass spectrometry (APLI-MS) in environmental certified reference materials NIST 1941b, NIST 1649b, BAM CC013a and IRMM BCR 535. AB - Proceedings in environmental analytical chemistry of polycyclic aromatic hydrocarbons (PAH) in the past decades cover improvements in laboratory methods as well as new insights in the toxicology of single PAH compounds. A re evaluation of the established list of 16 priority PAH published by the U. S. Environmental Protection Agency seems overdue. In this study we have applied PAH analysis by atmospheric pressure laser ionization - mass spectrometry (APLI-MS) to NIST 1941b, NIST 1649b, BAM CC013a and IRMM BCR 535 giving further references in addition to the certificates of analysis. Gas chromatography enables to distinguish between different alkylated PAH derivatives whereas liquid chromatography additionally allows detection of PAH tentatively with six or more aromatic rings on the level of chemical formula. For an optimal isomer-specific differentiation, LC-APLI-MS should be used in combination with fluorescence detection. Distribution patterns of 6 and 7-ring PAH are presented for urban dust, marine and harbor sediments and the soil sample. Additionally, a set of 14 nitrogen, sulfur and oxygen-containing polycyclic aromatic compounds were analyzed by APLI and quantified in all reference materials for the first time. PMID- 30448054 TI - [A necessary reflection on the legal framework of biomedical scientific research]. PMID- 30448055 TI - AtMYB44 interacts with TOPLESS-RELATED corepressors to suppress protein phosphatase 2C gene transcription. AB - AtMYB44 has been described in diverse hormonal signaling processes including abscisic acid (ABA)-mediated tolerance to abiotic stress; however, its function as a transcription factor is controversial. AtMYB44 contains the amino acid sequence LSLSL, a putative ETHYLENE-RESPONSIVE ELEMENT BINDING FACTOR-ASSOCIATED AMPHIPHILIC REPRESSION (EAR) motif. In yeast two-hybrid assay, physical interaction between AtMYB44 and a TOPLESS-RELATED (TPR) corepressor was observed, but abolished by mutation of the EAR motif. We performed bimolecular fluorescence complementation assay to confirm their interaction in planta. Chromatin immunoprecipitation assay revealed binding of AtMYB44 to the promoter regions of clade A protein phosphatase 2C (PP2C) genes (e.g., ABI1, ABI2, and HAI1), implying putative targets. Levels of histone H3 acetylation around the promoter regions were markedly lower in AtMYB44-overexpressing (35S:AtMYB44) plants than in wild-type plants. These results suggest that AtMYB44 forms a complex with TPR corepressors and recruits histone deacetylase(s) to suppress PP2C gene transcription in a signal-independent manner. PMID- 30448056 TI - LncRNA ZEB1-AS1/miR-409-3p/ZEB1 feedback loop is involved in the progression of non-small cell lung cancer. AB - Emerging evidence has illustrated that long noncoding RNA (LncRNA) ZEB1 antisense RNA 1 (ZEB1-AS1) involved in the development of various type of human cancers. However, the role of ZEB1-AS1 in non-small cell lung cancer (NSCLC) is still elusive and poorly understood. The present study aimed to provide functional evidence and elucidate the molecular mechanisms by which the ZEB1-AS1 promotes oncogenesis of NSCLC. Our study found that ZEB1-AS1 was upregulated in NSCLC cells and knockdown of ZEB1-AS1 significantly inhibited cell growth and induced cell apoptosis. Mechanically, miR-409-3p was confirmed as a direct target of ZEB1 AS1 and negatively regulated by ZEB1-AS1 via competing endogenous RNA (ceRNA) mechanism; miR-409-3p inhibited ZEB1 expression by directly binding to the 3'UTR. Importantly, as predicted by JASPAR and further confirmed by luciferase reporter gene and ChIP assays, we found ZEB1 could bind to the promoter region of ZEB1-AS1 to activate its expression. Restoration of ZEB1 could partially abolished the action of ZEB1-AS1 silencing on cell proliferation and apoptosis. Collectively, the results suggested that ZEB1-AS1/miR-409-3p/ZEB1 constitutes a positive feedback loop to promote the tumorigenesis of NSCLC, highlighting the possibility of improving NSCLC treatment by targeting the ZEB1-AS1 signaling pathway. PMID- 30448057 TI - Soybean CCA1-like MYB transcription factor GmMYB133 modulates isoflavonoid biosynthesis. AB - MYB transcription factors play important roles in the regulation of phenylpropanoid biosynthesis. However, the knowledge regarding the roles of CCA1 like MYBs in phenylpropanoid pathway is limited in plants. Previously, we identified 54 CCA1-like proteins in soybean. In the study, a CCA1-like MYB (GmMYB133) was functionally characterized as a positive regulator in isoflavonoid synthesis. GmMYB133 encodes a 330 aa protein featured with one CCA1 conserved motif. Further analysis indicated that the expression pattern of GmMYB133 was near-perfectly correlated with isoflavonoid accumulation as soybean embryos develop. GmMYB133 over-expression promoted the expression of two key isoflavonoid biosynthetic genes (GmCHS8 and GmIFS2) and increased total isoflavonoid content in hairy roots. Protein-protein interaction assays indicated that GmMYB133 might form hetero- and homodimers with an isoflavonoid regulator GmMYB176 and itself, respectively, while the subcellular localization of GmMYB133 can be altered by its interaction with 14-3-3 protein. These findings provided new insights into the functional roles of CCA1-like MYB proteins in the regulation of phenylpropanoid pathway, and will contribute to the future genetic engineering in the improvement of soybean seed quality. PMID- 30448058 TI - KATNAL1 is a more active and stable isoform of katanin, and is expressed dominantly in neurons. AB - Microtubule severing is essential for reorganization of microtubules during neuronal migration and process elongation. Katanin is a microtubule-severing enzyme, of which the major catalytic subunits are katanin A1 (KATNA1) and katanin A-like 1 (KATNAL1). The domain organization of the two subunits are almost the same; however, little is known about their functional difference. Here, we compared the expression pattern, microtubule-severing activity, intracellular degradation and knockdown phenotype in cultured cells of the two subunits. While KATNA1 was expressed ubiquitously among tissues of young adult mice, KATNAL1 was highly expressed in the brain and the testis. Neurons expressed almost only KATNAL1. When introduced into Neuro2a cells, KATNAL1 showed higher microtubule severing activity. Cycloheximide chase analysis revealed that KATNAL1 is more stable in cells. To elucidate which part of the molecules are responsible for these characteristics, we generated chimeric molecules by swapping the amino terminal and carboxyl-terminal halves between the two subunits. Experiments using these chimeras revealed that the amino-terminal half region is the determinant for their characteristics. Furthermore, KATNAL1 knockdown in Neuro2a cells resulted in enhancement of process elongation, while KATNA1 knockdown showed no effect. These data suggest that more active and more stable katanin subunit, KATNAL1, plays more important role in process elongation. PMID- 30448059 TI - DPY30 functions in glucose homeostasis via integrating activated histone epigenetic modifications. AB - Glucose homeostasis is a key event during many physiological and pathological processes. Histone modifications have emerged as vital factors influencing this process. DPY30, a core subunit of SET1/MLL family histone H3K4 methyltransferase complexes, has been reported to be amplified in cancers. However, the role of DPY30 in glucose homeostasis remains unclear. Here we reported that DPY30 regulated H3K4me3 recruitment to control the expression of Hif1alpha and its targeted glycolytic genes. Specifically, DPY30 promoted H3K9Ac recruitment via inhibiting SIRT6 occupancy on these gene promoters. Finally, we observed significant upregulation of DPY30 mRNA expression in hepatocellular carcinoma samples from datasets. Taken together, our results reveal a critical role of DPY30 in glucose homeostasis and might offer new therapeutic and diagnostic opportunities for cancers. PMID- 30448060 TI - Long noncoding RNA LINC00165-induced by STAT3 exerts oncogenic properties via interaction with Polycomb Repressive Complex 2 to promote EMT in gastric cancer. AB - Long non-coding RNAs (lncRNAs) are a crucial member of the non-coding RNA family, and increasing evidence demonstrates that lncRNAs participate in the initiation and progression of cancers. Our study aimed to explore the role of the lncRNA LINC00165 in gastric cancer (GC) development. In the present study, our results showed that LINC00165 was upregulated in GC tissues and cell lines and high expression of LINC00165 was correlated with tumor-node-metastasis stage, invasion depth, and overall survival of GC patients. Functional assays showed that LINC00165 knockdown inhibited the proliferation, migration and invasion of GC cells and LINC00165 overexpression stimulated their proliferation, migration and invasion. Online transcription factor binding site prediction analysis showed that there were STAT3 binding sites in the LINC00165 promoter region. Furthermore, luciferase reporter and chromatin immunoprecipitation assays provided evidence that STAT3 could bind directly to the region between -547 bp to -537 bp (ATGTTGGGAAA) of LINC00165 promoter and activate its transcription. Then GC cells were partitioned into nuclear and cytoplasmic fractions and we found that LINC00165 was localized preferentially to the nucleus. Mechanistically, we revealed that LINC00165 functioned as a scaffold for interaction with Polycomb Repressive Complex 2 to promote the epithelial-mesenchymal transition in GC cells. Taken together, our study revealed that LINC00165 was involved in the progression and poor prognosis of GC as an oncogenic role. Therefore, LINC00165 might become a new potential target for GC chemotherapy and further predict prognosis of patients. PMID- 30448062 TI - Communicating vessels volumeter to measure upper extremity in lymphedema after breast cancer: reliability and criterion validity compared to the gold standard. AB - BACKGROUND: The traditional overflow method for measuring limb volume remains the gold standard, but many disadvantages still inhibit its routine use in clinical practice. OBJECTIVE: To assess the intra-rater and inter-rater reliability and criterion validity of the 'communicating vessels volumeter' (CVV) for volume measurement of lymphedematous upper extremities (LUE) by using the overflow volumeter (OV) as the reference standard. METHODS: Twelve LUE of 12 women undergoing mastectomy for breast cancer were measured three times each by three raters using both methods, totaling 216 volume measurements. Criterion validity was estimated by 33 volume measurements of one cylinder of known volume by three raters using both methods, totaling 198 measurements. RESULTS: Measurement time was short with both CVV and OV. The intraclass correlation coefficient3,1 was high for both CVV and OV in intra-rater (0.99 vs 0.99) and inter-rater (0.99 vs 0.99) analyses. The bias between methods was low (7.50mL; 0.40%) and the limits of agreement were narrow (-5.80 to 6.50%). The volumes were statistically equal with a strong correlation (R2=0.98) between methods. CVV was more accurate than OV (0.00 vs 0.02%) in cylinder measurements. CONCLUSION: The high intra-rater and inter-rater reliability rates of CVV were comparable to those of OV, and the volumes resulting from LUE measurements were statistically equal in the two methods. Criterion validity rates indicated that CVV measurements were closer to the actual value of the cylinder than those obtained with the OV. PMID- 30448061 TI - Dll4-Notch1 signaling but not VEGF-A is essential for hyperoxia induced vessel regression in retina. AB - It is well recognized that decreased vascular endothelial growth factor A (VEGF A) mRNA plays an important role in retinal vessel regression induced by hyperoxia. However, this concept has been challenged by increasing new evidence. Furthermore, VEGF-A strongly enhances Dll4 expression and inhibition of Dll4 Notch signaling leads to excessive sprouting angiogenesis. Recently, it is shown that inactivation of Dll4-Notch1 signaling reduce hyperoxia induced vessel regression. It is unknown whether sprouting angiogenesis contributes to the protective effect or not and further investigations are needed. Moreover, the expression of Dll4 or Notch1 activation in the regressing plexus remains elucidated. To determine the role of VEGF-A and Dll4-Notch1 signaling in hyperoxia induced vascular regression in the retina, we used mice at postnatal day 5 (P5) - P7. Hyperoxia induced massive vascular regression in the central plexus but not in the angiogenic plexus and had no effect on sprouting angiogenesis. Immunostaining showed that VEGF-A was significantly repressed in the angiogenic front region after hyperoxia exposure but not detectable in the central area of both normoxia and hyperoxia treated retinas. In contrast, Notch ligand Delta-like 4 (Dll4) and Notch1 intracellular domain (N1-ICD) expression were inhibited in the regressing capillaries of central retina but comparable in the angiogenic plexus after high oxygen treatment. Moreover, administration of Dll4 neutralizing antibody or gamma-Secretase inhibitor DAPT significantly aggravated vessel regression induced by short-time hyperoxia administration. Our data show that repressed Dll4-Notch1 signaling pathway but not downregulation of VEGF-A expression are responsible for hyperoxia induced pervasive vessel regression. PMID- 30448063 TI - Association between patient reminders and influenza vaccination status among children. AB - BACKGROUND: Patient reminders are recommended to increase vaccination rates. The objectives of this study were to estimate the percentage of children 6 months-17 years for whom a patient reminder for influenza vaccination was received by a child's parent or guardian, estimate influenza vaccination coverage by receipt of a patient reminder, and identify factors associated with receipt of a patient reminder. METHODS: National Immunization Survey-Flu (NIS-Flu) data for the 2013 14 influenza season were analyzed. Tests of association between patient reminders and demographic characteristics were conducted using Wald chi-square tests and pairwise comparison t-tests. Multivariable logistic regression was used to determine variables independently associated with receiving a patient reminder. RESULTS: Approximately 22% of children had a parent or guardian report receiving a patient reminder for influenza vaccination for their child, ranging from 12.9% in Idaho to 41.2% in Mississippi. Children with a patient reminder were more likely to be vaccinated compared with children without a patient reminder (73.7% versus 55.5%). In the multivariable model, reminder receipt was higher for children 6-23 months compared with children 13-17 years, black children compared with white children, and children whose parent completed the survey in English compared with children whose parent completed the survey in a language other than English or Spanish. CONCLUSIONS: Although patient reminders are associated with a higher likelihood of influenza vaccination, nationally, less than one-fourth of children had a parent report receiving one. Despite being based on parental report, with its limitations, this study suggests that increasing the number of parents who receive patient reminders for their children may improve vaccination coverage among children. PMID- 30448064 TI - Characterization of the innate stimulatory capacity of plant-derived virus-like particles bearing influenza hemagglutinin. AB - Cell-mediated immunity is an important component of immediate and long-term anti viral protection. Dendritic cells (DCs) are essential for the induction of cell mediated immunity by instructing the activation and differentiation of antigen specific T cell responses. Activated DCs that express co-stimulatory molecules and pro-inflammatory cytokines are necessary to promote the development of type 1 immune responses required for viral control. Here we report that plant-derived virus-like particles (VLPs) bearing influenza hemagglutinins (HA) directly stimulate mouse and human DCs. DCs exposed to H1- and, to a lesser extent, H5 VLPs in vitro rapidly express co-stimulatory molecules and produce pro inflammatory cytokines including IL-12, IL-6 and TNFalpha. Furthermore, these VLPs support the activation and differentiation of antigen-specific T cell responses. Mechanistically, H1-VLPs stimulate the activation of kinases typically activated downstream of pattern recognition receptors including AKT, p38, and p42/44 ERK. In vivo, immunization with plant-derived VLPs induce the accumulation of both cDC1s and cDC2 in the draining lymph node and a corresponding increase in T and B cells. VLPs devoid of HA protein activate DCs, suggesting they are intrinsically immunostimulatory. Together, the results demonstrate that these candidate plant-derived VLP vaccines have an inherent and direct stimulatory effect on DCs and can enhance the ability of DCs to promote Type 1 immune responses. PMID- 30448065 TI - Monocyte-activation test to reliably measure the pyrogenic content of a vaccine: An in vitro pyrogen test to overcome in vivo limitations. AB - Pyrogen content is one of the critical quality attributes impacting the safety of a product, and there is an increasing need for assays that can reliably measure this attribute in vaccines. The Limulus amebocyte lysate (LAL) assay and the rabbit pyrogen test (RPT) are the canonical animal-based pyrogen tests currently used to release vaccines; however, there are several drawbacks associated with these tests when applied to Bexsero, intrinsically pyrogenic product, containing a meningococcal Outer Membrane Vesicle component. While the RPT, as applied to Bexsero at its given dilution, ensures safe vaccine, it is highly variable and prone to false positive results. On the other hand, the LAL assay although quantitative, can detect only endotoxin pyrogens and is not sufficient for monitoring the safety of Bexsero, which contains both LPS and non-endotoxin pyrogens. Being aware of these limitations of the RPT and LAL when applied to Bexsero, the Monocyte Activation Test (MAT) which is sensitive to both endotoxin and non-endotoxin based pyrogens has been developed as an alternative pyrogen test. Here, the development and the validation of a MAT assay adapted from the European pharmacopoeia for Bexsero, is described. The MAT assay is then used for monitoring the safety and consistency of Bexsero vaccines at release, providing great advantages in terms of reduced variability with respect to RPT, reduction of animal use, in line with the 3Rs principle concerning the protection of animals and faster time to market. In addition the correlation of the MAT to the RPT has been demonstrated supporting the replacement of the in vivo method and the potential application of the assay to other intrinsically pyrogenic vaccines. PMID- 30448066 TI - Influenza vaccination among adults living with persons at high-risk for complications from influenza during early 2016-17 influenza season. AB - BACKGROUND: The Advisory Committee on Immunization Practices (ACIP) recommends all persons aged >=6 months get vaccinated for influenza annually, placing particular emphasis on persons who are at increased risk for influenza-related complications and persons living with or caring for them. METHODS: Data from the 2016 National Internet Flu Survey (NIFS), a nationally representative, probability-based Internet panel survey of the noninstitutionalized U.S. civilian population aged >=18 years, was used to compare influenza vaccination coverage among adults who live with household members at high-risk for complications from influenza with those who do not. Logistic regression was used to evaluate the difference in the adjusted vaccination coverage prevalence between persons living with and without high-risk household members. RESULTS: From the 2016 NIFS (n = 4,113), we estimated that 29.2% of noninstitutionalized U.S. adults had at least one household member at increased risk for influenza-related complications. Unadjusted influenza vaccination coverage was significantly higher for adults with a high-risk household member compared with those without (46.7% vs 38.6%, respectively). After adjustment for demographic and access-to-care factors, adults with high-risk household members were more likely to be vaccinated than those without (adjusted prevalence difference = 5.3 [0.3, 10.3]). Among vaccinated respondents with high-risk household members, 88.7% reported that protection of their family and close contacts was one of the reasons they were vaccinated. CONCLUSION: Approximately half of adults living with someone at increased risk of complications from influenza did not report receiving an influenza vaccination. Vaccination reminder/recall for persons at increased risk should include reminders for their household contacts. PMID- 30448067 TI - Mechanochemical-assisted hydrolysis of pretreated rice straw into glucose and xylose in water by weakly acidic solid catalyst. AB - In this work, carbonaceous materials bearing only weakly acidic COOH and phenolic OH groups were directly prepared by the pyrolysis of lignin and KOH in black liquor generating from rice straw that was pretreated with KOH aqueous solution. The synthesized carbon materials were used for the hydrolysis of cellulose or the alkali pretreated rice straw in water, after mixed ball-milling pretreatment, and provided a high glucose yield of 76.3% for cellulose, high yields of 52.1% glucose and 66.5% xylose for alkali pretreated rice straw, respectively, in 0.015 wt% HCl aqueous solution at 200 degrees C for 60 min. The weakly acidic catalyst showed good stability and recyclability in the aqueous reaction system. This work provides an efficient process for the hydrolysis of lignocellulose by biomass derived weakly acidic catalysts in water and should have wide applications in biomass utilization. PMID- 30448068 TI - BHLHA15-positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice. AB - BACKGROUND & AIMS: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. METHODS: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apcflox/flox, LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5 mRNA positive cells, irradiated, or given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues we analyzed the fate of progeny that expressed Bhlha15 mRNA. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using the TCGA dataset. RESULTS: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15+ cells had no plasticity after loss of Lgr5 positive cells or irradiation. However, Bhlha15+ secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15+ secretory precursors to long-lived enterocyte progenitors (EPs). Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with EPs, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15+ precursors, towards that of ISCs. Bhlha15+ EPs with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells following dextran sodium sulfate-induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. CONCLUSION: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation, in addition to traditional ISCs. PMID- 30448070 TI - History of Cardiac Anesthesia in India. PMID- 30448069 TI - A Tale as Old as Time: Higher-Quality Evidence Needed for the Ross Procedure. PMID- 30448071 TI - Echocardiographic Assessment of Biventricular Function in 249 Patients During the Peri-Extracorporeal Membrane Oxygenation Period: Procedural and Ethical Questions. PMID- 30448072 TI - Differences in Two- and Three-Dimensional Assessment of the Mitral Valve by Novices and Experts, Illustrated Using Anterior Mitral Valve Leaflet Length. AB - OBJECTIVES: In this measurement validation study, the authors evaluated agreement between 2-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE), measuring anterior mitral valve leaflet length by both novice and experienced echocardiographers. DESIGN: This was a retrospective, observational study. SETTING: Single university hospital. PARTICIPANTS: Analyses on datasets from 44 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty datasets from 44 patients with mitral regurgitation were analyzed by 4 observers (2 novices, 2 experts). All observers measured the anterior mitral valve leaflet length from end-systolic 2D TEE images from the midesophageal longitudinal axis view and 3D software-augmented TEE images. The overall mean anterior mitral valve leaflet length was significantly shorter with 3D versus 2D TEE measurements (24.6 +/- 4.5 mm v 26.2 +/- 5.3 mm; p < 0.001), with novices measuring shorter leaflets than experts for both techniques (p < 0.001 and p = 0.005, respectively). Bland-Altman plots of 3D and 2D TEE measurements showed mean biases (95% limits of agreement) of -1.6 mm (-9.0 to 5.9 mm), -1.8 mm (-9.6 to 6.0 mm), and -1.3 mm (-8.4 to 5.7 mm) for all observers, novices, and experts, respectively. For 2D measurements, interobserver reliability was very strong among experts and strong among novices (Pearson's r = 0.83 v 0.66; p = 0.055). For 3D measurements, interobserver reliability was strong in experts and moderate in novices (Pearson's r = 0.69 v 0.51; p = 0.168). CONCLUSION: For both novices and experts, 3D TEE measurements of the anterior mitral valve leaflet were significantly shorter than 2D measurements. Interobserver reliability was lowest for novices making 3D TEE measurements, indicating that reliable, quantitative evaluation of 3D TEE may require a greater amount of practice. PMID- 30448073 TI - The expanding field of neuromuscular ultrasound. PMID- 30448074 TI - Does creating a trough on the anterior glenoid rim make a difference in Arthroscopic Bankart repair using suture anchors? A mid-term follow-up retrospective study. AB - PURPOSE: Creating a trough on the anterior glenoid rim is one of the methods used for arthroscopic Bankart repair with suture anchors. The purpose of this study was to analyze clinical and radiological outcomes of arthroscopic Bankart repair with suture anchors; to compare between the outcomes of surgical procedures with and without trough. METHODS: Clinical and radiological outcomes were evaluated for 116 patients who underwent arthroscopic Bankart repair at our institute from 2005 to 2011. The mean follow-up was 5.2 years (range, 2-8.8 years). All data were divided into trough group (n = 62) and non-trough group (n = 71). Clinical and functional outcomes were assessed pre- and postoperatively as range of motion (ROM), pain on the visual analog scale (p-VAS), function on the visual analog scale (f-VAS), and Rowe score. Radiological outcomes were also evaluated. RESULTS: The overall postoperative clinical and functional outcomes improved significantly (P < .001). A total of 8 patients (6.8%) showed recurrent instability. Radiologic findings showed mild arthritis in 27 cases (23.1%), moderate arthritis in 6 cases (5.1%), and no severe arthritis. 32 patients showed anterior apprehension after surgery, and 22 out of those 32 patients were from non-trough group. However, no significant difference between the trough and non trough groups was found with respect to clinical and functional outcomes (P > .05). CONCLUSION: The additional procedure of creating a trough did not improve clinical outcomes in terms of frank dislocation; however, at the final follow-up, patients with the trough showed less anterior apprehension. Overall, arthroscopic Bankart repair using suture anchors had relatively good clinical outcome, with a redislocation rate of 6.8%. LEVEL OF EVIDENCE: Level III, Case series. PMID- 30448075 TI - Early response assessment of re-ossification after palliative conventional radiotherapy for vertebral bone metastases. AB - BACKGROUND: To evaluate the therapeutic outcomes in patients with bone metastases receiving radiotherapy (RT), it is important to use objective radiological response criteria. The aim of this study was to investigate the changes in pain and re-ossification after RT for painful vertebral bone metastases without paralysis by malignant spinal cord compression. METHODS: The participants included 55 patients who received RT for painful vertebral bone metastases without paralysis in our institution between 2012 and 2016. Bone modifying agents (BMAs) were administered in all patients. Follow-up assessments were done just before the start of RT and at 1, 2, 3, 4, and 6 months after RT. Radiological responses of irradiated vertebrae by RT were assessed by computed tomography (CT) using MD Anderson response classification criteria (MDA criteria) and the pain response was assessed by Numeric Rating Scale (NRS). Response was classified as complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD). RESULTS: The rates of CR were 2%, 7%, 20%, 30%, and 56% at 1, 2, 3, 4, and 6 months, respectively. The rates of CR or PR were 15%, 49%, 77%, 91%, and 91% at 1, 2, 3, 4, and 6 months, respectively. The rates of CR or PR were significantly higher in patients with breast cancer than in patients with lung cancer (p = 0.043). At one month, there was an association between the NRS and radiological response assessed by MDA criteria. There was a significant trend that, with a better response, there were more patients without pain (p = 0.021). CONCLUSIONS: Under BMAs administration, successful RT for vertebral bone metastases decreased pain and caused re-ossification. The MD Anderson criteria could be useful for assessment of radiological responses of irradiated vertebrae. PMID- 30448076 TI - Corrigendum to "Limitations in electrophysiological model development and validation caused by differences between simulations and experimental protocols" [Prog. Biophys. Mol. Biol. 129 (2017) 53-64]. PMID- 30448077 TI - Real-world anti-viral treatment decisions among chronic hepatitis C patients in Taiwan: The INITIATE study. AB - BACKGROUND/PURPOSE: While direct-acting antiviral regimens have been approved for chronic hepatitis C (CHC) patients in Taiwan, reimbursement is limited to certain populations. Thus, pegylated interferon plus ribavirin (PEG-IFN/RBV) remains the standard of care for many patients. The aim of this study was to investigate the percentage of CHC patients who were recommended and willing to receive PEG IFN/RBV, and to identify reasons why patients were not recommended or unwilling to receive treatment. METHODS: 822 Taiwanese CHC patients were enrolled from May August 2016 in this cross-sectional study. PEG-IFN/RBV recommendation and patient willingness to receive treatment were evaluated through surveys. Patient characteristics associated with treatment recommendation and willingness were assessed. RESULTS: 311 (37.8%) patients were recommended PEG-IFN/RBV while 102 (12.4%) were willing to follow treatment recommendation. Rates of recommendation and willingness were lower in treatment-experienced, hepatitis C virus genotype 1 (GT1) and cirrhotic patients, and those treated in Northern Taiwan. Multivariate analyses found factors such as prior treatment experience, GT1, cirrhosis and low hemoglobin levels to be associated with lower recommendation rates while advanced age, GT1 and low baseline viral loads were associated with lower willingness rates. Physicians' top reasons for not recommending PEG-IFN/RBV included the wish to wait for better treatment options (60.3%), prior treatment failure (21.3%) and patients' advanced age (20.9%). Patients were unwilling to receive treatment mainly due to concerns about side effects (91.4%), the wish to wait for better treatment options (71.3%) and inconvenience (25.4%). CONCLUSION: A minority of Taiwanese CHC patients were recommended PEG-IFN/RBV, of which few were willing to receive treatment. PMID- 30448078 TI - Are EMG and visual observation comparable in determining resting motor threshold? A reexamination after twenty years. PMID- 30448080 TI - Report of the 2018 meeting of the German Society for Protozoology. PMID- 30448079 TI - Appropriateness for testis-sparing surgery based on the testicular tumor size in a pediatric and adolescent population. AB - INTRODUCTION: In children, most small testicular tumors are benign, and testicular-sparing surgery (TSS) is a viable treatment option. OBJECTIVE: The objective of this study is to assess for correlation between the tumor size and final pathologic diagnoses appropriate for TSS for pediatric and adolescent patients with an intratesticular mass and negative serum tumor markers (STMs). MATERIALS AND METHODS: A retrospective review of 24 patients (aged 0-18 years) who underwent radical or partial orchiectomy between 2003 and 2015. Patients with unifocal, unilateral intratesticular tumors and negative STMs were included. Tumors with benign and non-germ cell histology were considered appropriate for TSS, and active germ cell tumor elements on final histology were categorized as inappropriate for TSS. Baseline characteristics, tumor size, and frozen section results were evaluated for association, for the entire cohort and then for a subset of pubertal and postpubertal patients (defined as >=10 years old). RESULTS: Patients with testicular tumor pathology inappropriate for TSS were significantly older (median age 17.1 years, P = 0.03). A 2-cm size cutoff did not accurately predict pathology for the entire cohort, or for just pubertal and postpubertal patients (P = 0.132, P = 0.154, respectively). Frozen section and final pathology demonstrated good agreement (kappa = 0.826, P < 0.001) as did pre operative and final pathologic size measurement (kappa = 0.703, P < 0.001). Frozen section analysis did not miss a TSS inappropriate pathology. DISCUSSION: The present data refute the finding in adults that a 2-cm cutoff accurately predicts pathology in pediatric patients with an intratesticular mass and normal STMs. These data suggest that TSS should still be offered, regardless of the tumor size alone, but frozen section appears to more accurately predict pathology than the tumor size, and its use should, thus, be emphasized. There are several limitations of this study to mention. First, this is a retrospective review of a small cohort of patients with a rare clinical scenario, which necessitated the combination of pediatric and adolescent patients. The study did not evaluate oncologic outcomes. CONCLUSIONS: In children with an intratesticular tumor and normal STMs, a tumor size cutoff of 2 cm does not appear to accurately predict the final pathology. However, the data presented support the continued use intra operative frozen section analysis in both children and adolescents undergoing TSS. PMID- 30448081 TI - [The new reference equations of the Global Lung function Initiative (GLI) for pulmonary function tests]. AB - Until recently, the reference equations available for pulmonary function tests (PFTs) have had several weaknesses: they have often been based on relatively weak samples of normal subjects; they used mathematical models that are not very efficient in describing the evolution of PFTs over age; there were different equations for children/adolescents and for adults; the expression of the results solely as a percentage of the predicted value did not provide a good indication of the statistical significance of any difference that may exist between a measured value and its reference value. The Global Lung Initiative (GLI) aimed to establish new reference equations for PFTs that do not have these disadvantages. Based on large, representative, reference populations and allowing individualization of homogeneous ethnic groups over a wide age range, the GLI uses a statistical model that does not have any a priori hypothesis regarding the evolution of PFTs as a function of age (these models therefore make it possible to describe, in a very precise manner, the PFTs over all age ranges). For a given PFT, the equation is the same regardless of age (no discontinuity on transition to adulthood). The GLI equations are used to define a reference value, a threshold value (lower limit of the normal) and a z-score that take into account age, sex, size and, for some PFTs, ethnicity. The reference equations of the GLI were established in 2012 for spirometry, in 2017 for the TLCO and will soon be established for lung volumes. Already the representation of ethnic groups not identified by the GLI and of subjects with extreme values of age and size is being questioned. PMID- 30448082 TI - Clonal relationship and the association of the ST218 strain harboring blaOXA-72 gene to mortality in carbapenem-resistant Acinetobacter baumannii bacteremia. AB - BACKGROUND/PURPOSE: In 2017, the World Health Organization categorized carbapenem resistant Acinetobacter baumannii (CRAB) as a priority 1, critical antibiotic resistant bacteria. This study analyzed the clinical outcomes and investigated the molecular epidemiology of CRAB bacteremia in a medical center in Northern Taiwan. METHODS: We collected 62 blood isolates from patients with CRAB bacteremia from January 2014 to December 2015 at MacKay Memorial Hospital and determined the clonal relationship using the PCR-based technique for molecular epidemiology. Medical charts were reviewed for clinical outcomes. RESULTS: Fifty six isolates harbored the blaOXA-51-like and blaOXA-23-like carbapenemase genes, 4 isolates harbor the blaOXA-51-like and blaOXA-24-like carbapenemase genes and 2 isolates harbored only the blaOXA-51-like gene. After sequencing, all four isolates of blaOXA-24-like carbapenemase gene were confirmed to be isolates of blaOXA-72 carbapenemase genes. In multivariate analysis in the 60 patients, the independent mortality risk factors of CRAB bacteremia included >=65 years (elderly) (Odds ratio, 4.04, 95% CI, 1.10-14.83, p = 0.035), chronic kidney disease (4.36, 1.14-16.72, p = 0.032). Isolates harboring the blaOXA-72 gene had the same sequence type (ST218) and PFGE pulsotype raising the possibility of intra-hospital transmission, and all infected patients died. CONCLUSION: This study showed the clonal relationship of isolates harboring the carbapenemase gene in CRAB bacteremia. Patients with the ST218 strain harboring blaOXA-72 gene had high mortality. This warrants further research to determine the mechanism of virulence and risk factors in order to reduce mortality. PMID- 30448083 TI - The effects of grounding (earthing) on bodyworkers' pain and overall quality of life: A randomized controlled trial. AB - BACKGROUND: It is well known that massage therapists routinely develop a number of health problems related to their profession. PURPOSE: To determine the effects of grounding on massage therapists' quality of life and pain. Grounding, refers to being in direct body contact with the ground, such as walking barefoot on humid soil or on grass. SETTING: The Chopra Center for Well-Being in Carlsbad, California, USA. PARTICIPANTS: Sixteen massage therapists (mean age 42.8 years). RESEARCH DESIGN AND INTERVENTION: A stepped wedge cluster design was incorporated into a 6-week double-blind Randomized Controlled Trial (RCT) procedure with massage therapists assigned randomly into one of two cohorts. Therapists were not grounded for the first week, were grounded while working on clients and at home while sleeping for the next four weeks, and then ungrounded for the last week. OUTCOME MEASURES: Prior to, during, and immediately following the intervention, participants completed standardized questionnaires reporting on pain, physical function, anxiety, depression, fatigue/tiredness, sleep disturbance and number of hours of sleep, number of clients worked on per working day, energy, and emotional and mental stress. RESULTS: As a group, therapists experienced significant increases in physical function and energy and significant decreases in fatigue, depressed mood, tiredness and pain while grounded as compared to not being grounded. At one-month following the study, physical function was also increased and depressed mood and fatigue were decreased. CONCLUSIONS: We observed consistent beneficial effects of grounding in domains highly relevant to massage therapists, namely pain, physical function, and mood. These findings, combined with prior results from this trial indicating improvements in inflammatory biomarkers, blood viscosity and heart rate variability (HRV), suggest that grounding is beneficial to massage therapists in multiple domains relevant to their occupation, supporting overall health and quality of life. PMID- 30448084 TI - Parents' and carers' experiences of transition and aftercare following a child's discharge from a paediatric intensive care unit to an in-patient ward setting: A qualitative systematic review. AB - OBJECTIVES: To explore parents' experiences of transition and aftercare following their child's discharge from a paediatric intensive care unit to an in-patient ward. METHODS: A qualitative systematic review was conducted. Electronic databases CINAHL, MEDLINE, EMBASE, Psych INFO, and ASSIA were searched for qualitative studies with no date limits imposed. Methodological quality was assessed using the JBI QARI standardised critical appraisal instrument. Data were extracted into a standardised data extraction tool. Findings were pooled using a meta-aggregative approach. RESULTS: Four studies were included in the final review that included a total of 95 participants. Forty-nine findings were extracted and through an iterative process resulting in four synthesised findings being developed. These included: (1) Dynamic emotional response pre, peri and post-transfer; (2) Involvement in care absent but fundamental to functioning; (3) Changes in care delivery and environment provoking adverse emotions and (4) Transition as a physical, emotional and social balancing act. CONCLUSION: Transitioning from the paediatric intensive care unit to an in-patient ward can be a challenging time for parents, exposing them to a turbulent emotional and social status, and depleting their personal resources. Parents are aware of differences in the organisation and delivery of care between clinical areas which can compound the adversity experienced. Health professionals need to provide targeted support in order to mitigate these negative emotional, physical and social effects experienced. PMID- 30448085 TI - A steady decline in pancreas transplantation rates. AB - BACKGROUND/OBJECTIVES: After years of growth in many pancreas transplant programs, UNOS has reported declining transplant numbers in the USA. This precipitating trend urges for an evaluation of the transplant numbers and scientific productivity in the Eurotransplant region and the UK. METHODS: We performed a trend analysis of pancreas transplantation rates, between 1997 and 2016, adjusting for changes in population size, and an analysis of scientific publications in this field. We used information from the UNOS, Eurotransplant, and UK transplant registry and bibliometric information from the Web of Science database. RESULTS: Between 2004 and 2016 there was an average annual decline in pancreas transplantation rates per million inhabitants of 3.3% in the USA and 2.5% in the Eurotransplant region. In the UK, transplant numbers showed an average annual decline of 1.0% from 2009 to 2016. Publications in Q1 journals showed an annual change of -2.1% and +20.1%, before 2004, and a change of -3.8% and -5.5%, between 2004 and 2016, for USA and Eurotransplant publications, respectively. CONCLUSIONS: Adjusting pancreas transplantation rates for changes in population size showed a clear decline in transplant numbers in both the USA and Eurotransplant region, with first signs of decline in the UK. Following this trend, the number of scientific publications in this field have declined worldwide. PMID- 30448086 TI - pH/NIR-responsive semiconducting polymer nanoparticles for highly effective photoacoustic image guided chemo-photothermal synergistic therapy. AB - Multifunctional drug delivery nanoplatform (PDPP3T@PSNiAA NPs) based on NIR absorbing semiconducting polymer nanoparticles for pH/NIR light-controllably regulated drug release has been successfully prepared. In this strategy, pH/thermal-sensitive multifunctional polymer polystyrene-b-poly(N isopropylacrylamide-co-acrylic acid) (PSNiAA) was meticulously designed and synthesized using the reversible addition fragmentation chain transfer (RAFT) polymerization method. Furthermore, PSNiAA was used to functionalize diketopyrrolopyrrole-based semiconducting polymer (PDPP3T) to combine photothermal capacity and pH/thermo-responsive drug release in one entity. The prepared PDPP3T@PSNiAA NPs exhibited high photothermal conversion efficiency (eta = 34.1%) and excellent photoacoustic (PA) brightness. Meanwhile, benefiting from the photothermal effect of PDPP3T and the pH/thermal-responsive properties of PSNiAA, Dox-loaded PDPP3T@PSNiAA NPs (PDPP3T@PSNiAA-Dox NPs) were able to controllably regulate the release of Dox by pH/NIR light, in which the enhanced drug release at acidic condition upon NIR irradiation phenomenon would minimize unnecessary drug release in normal tissues and was highly beneficial for precise synergistic chemo- and photothermal therapy. PMID- 30448087 TI - Fight load index and body composition are most associated with combat fitness in female Marines. AB - : Optimizing tactical fitness is important for combat readiness and injury prevention, especially as women have entered ground combat military occupational specialties. OBJECTIVES: To assess characteristics of male and female Marines by Combat Fitness Test (CFT) performance clusters. DESIGN: Cross-sectional study. METHODS: Anthropometric, body composition (BF%, fat and fat-free mass [FM and FFM], and Fight load index [FLI], physiological (maximal oxygen uptake, lactate threshold and anaerobic power/capacity), and musculoskeletal (isokinetic strength of the knee, shoulder, torso, and isometric strength of the ankle) assessments were obtained from 294 male (M) and female (F) Marines. Hierarchical cluster analysis classified Marines based on performance of two CFT events (sec): Maneuver Under Fire (MANUF) and Movement to Contact (MTC). Following tests for normality, one-way ANOVA or Kruskal Wallis tests, followed by Bonferroni post-hoc tests, assessed characteristics across clusters and sex (alpha=0.05). RESULTS: Two clusters (C) were determined: C1: N=66F, 16M and C2: N=18F, 194M, with C2 demonstrating better performance on the MANUF and MTC. C1F demonstrated significantly greater BF% and FLI than C1M, C2F, and C2M. C2M demonstrated significantly greater knee flexion strength than C1F and C2F, but C1M was only significantly greater than C1F. C2M demonstrated significantly greater ankle eversion and inversion strength than C1F. CONCLUSIONS: Women with increased BF%, increased FM and reduced FFM relative to a fighting load may have decreased performance in combat-related tasks. Training programs based on an individual Marine's baseline body composition and fitness characteristics can enhance combat fitness and force readiness. PMID- 30448088 TI - Impact of Chemotherapy-induced Menopause in Women of Childbearing Age With Non metastatic Breast Cancer - Preliminary Results From the MENOCOR Study. AB - BACKGROUND: Young patients with breast cancer treated with chemotherapy can experience ovarian failure, which can lead to chemotherapy-induced menopause (CIM) impacting the quality of life (QoL). A prospective study was set out to evaluate the impact of CIM on QoL in women of childbearing age with non metastatic breast cancer, and this article reports results of the interim analysis conducted to evaluate feasibility and to see preliminary results. PATIENTS AND METHODS: A total of 58 women (age, 18-46 years) with newly diagnosed breast cancer and treated with chemotherapy were eligible. QoL was assessed by self-administered questionnaires (Quality of Life Questionnaire-Core 30 [QLQ C30], Quality of Life Questionnaire-Breast 23 [QLQ-BR23], and Kupperman index) and hormonal variations (anti-Mullerian hormone [AMH], follicle-stimulating hormone, and estradiol) were explored. We compared patients with >= 12 months amenorrhea (CIM) (n = 41) to patients with < 12 months of amenorrhea (non-CIM) (n = 17). RESULTS: A good inclusion rate (approximately 4/month) and sufficient data enabled us to perform this analysis. QLQ-C30 failed to show any difference between CIM and non-CIM patients (P = .5). In contrast, at 6 months post chemotherapy, CIM patients tended to have lower QoL as shown by QLQ-BR23 (P = .16) and more severe climacteric symptoms (P = .01). Regarding hormonal variations, AMH pre-treatment level was higher in non-CIM patients (P = .0032). We also noted that CIM patients were older (P = .00013), had shorter menstruation cycle (P = .082), and experienced faster amenorrhea (P = .088). CONCLUSIONS: The study is technically feasible, and our preliminary results underline that age in association with pre-treatment AMH level could be helpful to predict ovarian function. QLQ-BR23 seemed to be stronger, more precise, and appropriate to evaluate QoL changes in patients with breast cancer than the QLQ-C30. PMID- 30448089 TI - Neutral supporting mandibular advancement device with tongue bead for passive myofunctional therapy: a long term follow-up study. AB - BACKGROUNDS: Myofunctional therapy has been reported to be a valid adjunct treatment to OSA, but compliance was mentioned as an issue. We performed a prospective study on age matched randomized children submitted to myofunctional therapy (MFT) or to a functional device used during sleep (passive MFT). METHODS: 110 children 4 to 16 were recruited for the study, 54 children were in the MFT group [A] while 56 were in the "nocturnal device" group [B]. Clinical evaluation, polysomnography and cephalometric X-Rays were performed at baseline, 6 months and 12 months, with clinical follow-up at 3 months. RESULTS: MFT group show very important absence of compliance, at six months only 23 subjects participated and only 10/23 had been compliant with treatment. None came back for research investigation at 12 months. 48/56 of passive MFT children ended the research protocol at 12 months. Comparison of baseline to 6 and 12 months data showed that all children with passive MFT improved (PSG and cephalometrics) and had nasal breathing during sleep at 1 year, and no negative effect of device were noted. The 10 children compliant with MFT showed clear improvement of sleep related breathing with also changes at cephalometric -X-rays. CONCLUSION: Compliance is a major problem of MFT, and MFT will have to take into consideration the absolute need to have continuous parental involvement in the procedure. Passive MFT gives many more positive results, but potential negative effects of device on other jaw will have to be continuously evaluated. PMID- 30448090 TI - Pre-Existing Renal Failure Increases In-Hospital Mortality in Patients with Intracerebral Hemorrhage. AB - BACKGROUND: To determine the clinical outcome for intracerebral hemorrhage (ICH) patients with pre-existing renal failure in the United States. METHODS: We analyzed the data from Nationwide Inpatient Sample (2008-2012) for all ICH patients with or without pre-existing renal failure. Patients were identified using the International Classification of Disease, Ninth Revision, Clinical Modification codes. Baseline characteristics, in-hospital complications, and exposure to invasive procedures were compared between groups. Discharge outcomes (mortality, minimal disability, and moderate-to-severe disability) were compared between the two groups, before and after adjusting for the presence of other medical comorbidities, in-hospital complications, and exposure to invasive procedures. RESULTS: Of the 328,728 patients with ICH, 36,067 (11.8%) had pre existing renal failure as a comorbidity. There were higher rates for in-hospital complications like myocardial infarction (3.5% versus 1.9%, P <= .0001), sepsis (5.4% versus 3.0%, P <= .0001), pneumonia (7.1% versus 5.3%, P <= .0001), deep venous thrombosis (1.6% versus 1.2%, P = .0041), urinary tract infections (16.9% versus 15.1%, P = .0101), and gastrointestinal bleeding (0.4% versus 0.2%, P <= .0154), longer hospital stay (9.4 +/- 14.4 versus 7.7 +/- 11.4; P < .0001), and higher mean hospital charges ($86497.9 +/- 131708.1 versus $69583.4 +/- 110629.1; P < .0001) in patients with pre-existing renal failure . The in-hospital mortality was also higher among patients with pre-existing renal failure as comorbidity in both univariate (26.4% versus 25.3 %, P = .0010) and multivariate analysis (odds ratio [OR] = 1.124 [1.042-1.213], P = .0025). There was no statistically significant difference for in terms of moderate to severe disability between 2 groups (OR = 1.030 [0.962-1.104], P value: .3953 in multivariate analysis when analysis was limited to alive patients. CONCLUSIONS: Patients with ICH, who present with pre-existing renal failure, have higher rates of in-hospital mortality but not for disability, the difference remained significant after adjusting for the presence of other medical comorbidities, in hospital complications or exposure to invasive procedures. PMID- 30448091 TI - The relationship between sperm DNA fragmentation, free radicals and antioxidant capacity with idiopathic repeated pregnancy loss. AB - More than two consecutive miscarriages in less than 20 weeks of gestation is defined as recurrent spontaneous miscarriage. Various causes such as uterine anatomical anomalies, genetic factors, and infectious and endocrine disorders have been reported for RPL. However, approximately 50% of the causes are unknown, which can be due to male factors. Several studies have been done on semen parameters to determine the unknown causes and risk factors for miscarriages, however, only studying common semen parameters have not been sufficient. In this study, the relationship between sperm DNA fragmentation, the amount of free radicals, and total antioxidant capacity (TAC) in semen have been considered as a risk factor for spontaneous miscarriage. Semen samples were collected from 42 men whose partners had a history of spontaneous miscarriage and 42 fertile men as the control group. Volume, pH, viscosity, concentration, and motility of semen, as well as sperm morphology were measured. Sperm DNA fragmentation was analyzed by the sperm chromatin structure assay (SCSA) and TUNEL methods, the amount of sperm free radicals was measured by the luminescence method and the total amount of semen antioxidant was measured using the TAC kit. The results have shown that sperm motility in the experimental group was significantly less than the control group (P = 0.001). The percentage of sperm DNA fragmentation and the amount of free radicals in the experimental group were significantly higher than the control group (P < 0.001). The total amount of antioxidant was lower in the experimental group compared to the control. Spouses of men with lower sperm motility and higher DNA fragmentation had a higher chance of spontaneous miscarriage when compared to the control group. The results of this study support the hypothesis that sperm DNA fragmentation is a major contributor to spontaneous miscarriage. The relationship between SDF, ROS and TAC with RPL. PMID- 30448092 TI - Frequency of alcohol consumption and risk of type 2 diabetes mellitus: A nationwide cohort study. AB - BACKGROUND & AIMS: Alcohol consumption correlates with type 2 diabetes through its effects on insulin resistance, changes in alcohol metabolite levels, and anti inflammatory effects. We aim to clarify association between frequency of alcohol consumption and risk of diabetes in Taiwanese population. METHODS: The National Health Interview Survey (NHIS) in 2001, 2005, and 2009 selected a representative sample of Taiwan population using a multistage sampling design. Information was collected by standardized face to face interview. Study subjects were connected to the Taiwan National Health Insurance claims dataset and National Register of Deaths Dataset from 2000 to 2013. Kaplan-Meier curve with log rank test was employed to assess the influence of alcohol drinking on incidence of diabetes. Univariate and multivariate Cox proportional regression were used to recognize risk factors of diabetes. RESULTS: A total of 43,000 participants were included (49.65% male; mean age, 41.79 +/- 16.31 years). During the 9-year follow-up period, 3650 incident diabetes cases were recognized. Kaplan-Meier curves comparing the four groups of alcohol consumption frequency showed significant differences (p < 0.01). After adjustment for potentially confounding variables, compared to social drinkers, the risks of diabetes were significantly higher for non-drinkers (adjusted hazard ratio [AHR] = 1.21; 95% confidence interval [CI], 1.09-1.34; p < 0.01), regular drinkers (AHR = 1.19; 95% CI, 1.06-1.35; p < 0.01), and heavy drinkers (AHR = 2.21, 95% CI, 1.56-3.13, p < 0.01). CONCLUSIONS: Social drinkers have a significantly decreased risk of new-onset diabetes compared with non-, regular, and heavy drinkers. PMID- 30448093 TI - [Use of human papilloma virus testing in primary cervical cancer screening in rural Madagascar]. AB - BACKGROUND: Testing for high-risk human papilloma virus (HR-HPV) is an effective approach to the prevention of cervical cancer. This study in the Atsinanana area of Madagascar aimed to compare the management of women screened by visual inspection after coloration with acetic acid (VIA) and the management of women screened by HPV with VIA as a triage test. METHOD: During the last two screening campaigns, the first patients (between 28 and 120 women par center) were sampled using a dry swab, just before the acetic acid application, to test 14 genotypes of HR-HPV using Roche Diagnostics Cobas(r) Test. We compared current management practices based on primary VIA to those that would have been implemented if the clinician had followed the recommendations of the World Health Organization for HPV-based primary screening. We used a regression Poisson model with random effect and robust variance. RESULTS: Among the 250 screened-women, 28 (11.2%) had acidophilic lesions of the uterine cervix or suspected lesions of invasive cancer (IVA +). The HPV test was positive in 62 cases (24.8%). The HPV-based screening strategy would have reduced by 52% the number of women needing thermo-coagulation treatment: 24 women (9.6%) with primary VIA-based screening vs. 13 women (5.2%) with primary HPV-based screening; RR: 0.52 and 95%CI: 0.27-1.02. The diagnosis of severe dysplastic lesion or invasive cancer would not have changed. CONCLUSION: Primary HPV-based screening is a strategy that could be useful for low-resource countries like Madagascar. It would reduce the rate of false positives and unnecessary treatments compared to the current strategy based on primary IVA. The questions of the feasibility and cost-benefit of this strategy should be further explored. PMID- 30448094 TI - [The effects of crystalloid warming on maternal body temperature and fetal outcomes: a randomized controlled trial]. AB - BACKGROUND AND OBJECTIVES: Hypothermia occurs in about 60% of patients under anesthesia and is generally not managed properly during short lasting surgical procedures. Hypothermia is associated with adverse clinical outcomes. The current study is designed to assess the effects of crystalloid warming on maternal and fetal outcomes in patients undergoing elective cesarean section with spinal anesthesia. METHODS: In this prospective randomized controlled trial, sixty parturients scheduled for elective cesarean section with spinal anesthesia were randomly allocated to receive crystalloid at room temperature or warmed at 37 degrees C. Spinal anesthesia was performed at L3-L4 interspace with 10mg of hyperbaric bupivacaine without adding opioids. Core temperature, shivering, and hemodynamic parameters were measured every minute until 10th minute and 5-min intervals until the end of operation. The primary outcome was maternal core temperature at the end of cesarean section. RESULTS: There was no difference for baseline tympanic temperature measurements but the difference was significant at the end of the operation (p=0.004). Core temperature was 36.8+/-0.5 degrees C at baseline and decreased to 36.3+/-0.5 degrees C for isothermic warmed crystalloid group and baseline tympanic core temperature was 36.9+/-0.4 degrees C and decreased to 35.8+/-0.7 degrees C for room temperature group at the end of the operation. Shivering was observed in 43.3% in the control group. Hemodynamic parameter changes and demographic data were not significant between groups. CONCLUSIONS: Isothermic warming crystalloid prevents the decrease in core temperature during cesarean section with spinal anesthesia in full-term parturients. Fetal Apgar scores at first and fifth minute are higher with isothermic warming. PMID- 30448095 TI - [Harmonization of data coding in post-transplant follow-up - "GVHD, complications and additional treatments": Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. AB - The quality of the information provided in post-transplant follow-up is necessary to obtain a coherent and exploitable database. Since the beginning of 2017, three forms (Med-B-allograft) have been available: the first month (Day 0), Day 100 (second report) and an annual follow-up report. Recommendations for follow-up were addressed in the 2014 harmonization workshop, "Harmonization of Data Coding...". However, it is sometimes difficult to determine which data to specify in ProMISe for post-transplantation. The objective of this workshop was to clarify certain situations and/or items. PMID- 30448096 TI - Brain atrophy and strategic lesion location increases risk of parkinsonism in cerebral small vessel disease. AB - INTRODUCTION: Incident parkinsonism in patients with comparable cerebral small vessel disease (SVD) burden is not fully explained by presence of SVD alone. We therefore investigated if severity of SVD, SVD location, incidence of SVD and/or brain atrophy plays a role in this distinct development of parkinsonism. METHODS: Participants were from the RUN DMC study, a prospective cohort of 503 individuals with SVD. Parkinsonism was diagnosed according to the UKPDS brain bank criteria. Fine and Gray method was used to assess the association between SVD and incident parkinsonism. Differences in white matter hyperintensities (WMH) progression and brain atrophy were calculated with a linear mixed effect analysis. RESULTS: After a median follow-up of 8.6 years, 32 of 501 participants developed parkinsonism (6.4%). The highest WMH load was found in the frontal lobe for both groups. Presence of more than one lacune at baseline was higher in the group who developed parkinsonism, especially in the frontal lobe (22% versus 3%, p < 0.001) and basal ganglia (12.5% versus 1%, p-value <0.001). The annual rate of total brain atrophy was significantly higher for those who developed parkinsonism compared to those who did not (8.7 ml [95%CI 7.1-10.3] and 4.9 ml [95%CI 4.5 5.3], respectively). While WMH progression was not different, incidence of lacunes and microbleeds was higher in the group with parkinsonism. CONCLUSION: The risk of parkinsonism in patients with SVD is especially increased when WMH and lacunes are present in the frontal lobe. A higher brain atrophy rate might further increase this risk. PMID- 30448098 TI - Development of a positron emission tomography risks map. AB - Patient safety is an essential component of quality of care, especially when the complexity of care has reached extreme levels. Currently achieving this safety is considered a basic strategy of the National Health System. Nuclear Medicine departments have certain peculiarities that make them special in terms of patient safety, with situations that go beyond the common healthcare practice of other departments. Namely, that both encapsulated and non-encapsulated ionizing radiation is used in daily practice, and numerous groups of professionals must be coordinated to undertake positron emission tomography (PET) specifically, from the clinical management unit itself, and from other departments of the hospital (as well as companies outside the hospital itself and the Public Health System). The objective of this paper was to identify the risks to which a patient who is to be explored through PET can be exposed in a Nuclear Medicine department and draw up a risk map for the PET process. The methodology used is part of the proposal of the Ministry of Health (2007), and its practical implementation (given the limited literature available on Nuclear Medicine), follows as far as possible that of related care areas (radiodiagnosis and radiotherapy). For this purpose, a multidisciplinary team of professionals directly related to the PET process was created, using the modal analysis of faults and effects methodology to identify possible failures, their causes and the potential adverse events causing each. As a final step, a risk map was created, locating the previously identified faults at each stage of the process. This paper exposes the PET process, and describes the risks that patients might run when a PET scan is required, as well as the adverse events deriving from it. All this is shown in a risk map of the PET process. PMID- 30448097 TI - Medical and surgical co-management - A strategy of improving the quality and outcomes of perioperative care. AB - With the increase of ageing population, rates of chronic diseases and complex medical conditions, the management of high-risk surgical patients is likely to become a great concern in most countries. Considering all these factors, it is certainly rational and intuitive that internists should be included into a collaborative model of medical and surgical co-management, where their multi potentiality and synthesis capacity require them to coordinate the multidisciplinary team and to be the leading agent of change. In this regard, our aim was to present the official position and approach of the Working Group on Professional Issues and Quality of Care of the European Federation of Internal Medicine (EFIM), for implementation of this strategy of care, encouraging internists to assume an important role and to provide continuity of multidisciplinary care, from the decision to operate through to rehabilitation and recovery. Moving from the traditional model of medical care of the surgical patients to the co-management model, from a reactive simple consultation to a new pro-active continued service, may optimize the quality and perioperative care, improving the survival, shortening hospital stays, replacing the old strategy of late and complication treatment to an early and preventive one. PMID- 30448099 TI - Can the gut be the missing piece in uncovering PD pathogenesis? AB - It is now well established that Parkinson's disease (PD) is not only a movement disorder of the CNS but also a gastrointestinal disorder affecting the enteric nervous system (ENS). The gut-brain axis is a bidirectional communication between the brain and the gastrointestinal tract, which comprises besides the CNS and the ENS, the intestinal epithelial barrier, the intestinal microbiota and the enteroendocrine systems. In this review, we present the clinical and pathological evidence suggesting that the gut-brain axis is dysfunctional in PD by discussing the possible role of gut microbiota, inflammation and permeability in the development of the disease. PMID- 30448100 TI - Prognostic Effect of Tumor Sidedness in Colorectal Cancer: A SEER-Based Analysis. AB - BACKGROUND: The prognostic value of tumor sidedness in metastatic colorectal cancer (CRC) has been established, but its impact on nonmetastatic disease remains unclear. Our study aimed to explore the prognostic effect of tumor sidedness by subgroup survival analyses, according to histology and tumor grade in stage I-IV CRCs. METHODS: A retrospective population-based study was conducted based on Surveillance, Epidemiology and End Results (SEER) data. Population data in the SEER 9 registry (1975-2014) were used to determine survival trends of CRCs, and associated population data in the SEER 18 registry (2000 to 2014) were used to assess the prognostic impact of tumor sidedness on CRCs. RESULTS: The 5 year cause-specific survival for all subgroups of CRCs improved from 1975 to 2014. Of 238,826 patients, 44.2% had right-sided cancer. Patients with right sided cancer were more likely to be older, to be women, to have disease of mucinous or signet-ring cell histology, to have more poorly differentiated tumors, and to be diagnosed with a more advanced disease stage. Multivariate Cox regression showed stage I-II right-sided cancers had better cause-specific survival than the left-sided cancers (left colon: hazard ratio [HR] = 1.091, 95% confidence interval [CI], 1.052-1.132; rectum: HR = 1.363; 95% CI, 1.304-1.425; P < .001), while stage III and IV right-sided cancers had worse cause-specific survival. In subgroup analyses by histology and tumor grade within stage III CRCs, right-sided poorly differentiated mucinous adenocarcinoma showed significantly better survival (left colon: HR = 1.352; 95% CI, 1.145-1.596; rectum: HR = 1.125; 95% CI, 0.916-1.381; P = .002). CONCLUSION: The relationship between sidedness and prognosis in CRCs depends on stage and histopathologic characteristics, especially for stage III disease. PMID- 30448101 TI - Disability, sexual orientation, and the mental health outcomes of intimate partner violence: A comparative study of women in the U.S. AB - BACKGROUND: Research on disabled non-heterosexual women's post-intimate partner violence mental health outcomes-such as anxiety, depression, suicidal ideation, and alcohol use-is lacking. OBJECTIVE: To examine the impact of the intersection of disability and sexual orientation on women's post-intimate partner violence mental health outcomes: including difficulty sleeping, missing school or work, or reporting some post-traumatic stress disorder symptomology and a self-reported subjective measure of overall wellbeing. METHODS: Data come from the National Intimate Partner and Sexual Violence Survey (2010). A series of chi-square analyses were conducted (applying standardized sample weights and adjusting standard errors for both clustering and stratification for survey data). RESULTS: Bisexual women are significantly more likely than straight women to report being disabled prior to victimization, but all disabled women-regardless of sexual orientation-are equivalently likely to rate their mental health as poor and/or actively experience difficulty sleeping, difficulty going to work or school, and/or PTSD. CONCLUSIONS: Aligned with previous work, this study finds that bisexual women are significantly more likely than straight women to be disabled prior to experiencing all forms of intimate partner violence; and that disabled women, generally, are significantly more likely than not-disabled women to experience the negative mental health consequences of that violence. However, contrary to previous work, there are no sexual orientation disparities in said mental health outcomes among disabled women. Clinically, it is important for health care providers to be aware of the significant impact of intimate partner violence on the disabled women they regularly provide care to. PMID- 30448102 TI - Participating more, participating better: Health benefits of adaptive leisure for people with disabilities. AB - BACKGROUND: Increasing participation in recreational leisure activities (RLA) could be an effective vehicle for social inclusion and improvement - people's with disabilities health. Unfortunately, many barriers limit their participation in RLA. Interventions to improve access to RLA are often limited to therapeutic or adaptive sports in rehabilitation. Knowledge about the benefits of adaptive RLA in the community is still needed. OBJECTIVE/HYPOTHESIS: The aim of this study was to assess the benefits of adaptive RLA offered in the community for people with disabilities, and to document the facilitators and barriers to participation. METHODS: This paper presents the qualitative results of a mixed methods study. The participants were members with disabilities (n = 19), volunteers (n = 9), and staff members (n = 8) of an organization offering various adaptive RLA in the community. Semi-structured interviews, focus groups, and naturalistic observations were conducted. The data were analyzed using an inductive content analysis approach. RESULTS: Three overarching themes emerged from the analysis: 1) "Personal enrichment" illustrated the individual benefits experienced by the member with disabilities; 2) "Collective impact" represented the social benefits for the members and their communities; and 3) "Contributors to the RLA experience" concerned the facilitators and barriers to participation. CONCLUSIONS: Considering the numerous benefits of adaptive RLA, it is necessary to implement specific policies to support integrated community programs or accessible public transports to allow full participation of people with disabilities, thereby increasing their social inclusion. PMID- 30448103 TI - Transformation of quality of life in prenatal women with nausea and vomiting. AB - PROBLEM: Nausea and vomiting not only cause physical discomfort in pregnant women but also impact their quality of life. BACKGROUND: Few longitudinal studies have been conducted to investigate QOL of women over the course of pregnancy. AIM: To examine the transformation of health-related QOL and related factors among pregnant women with NV during three trimesters. METHODS: A longitudinal research design with convenience sampling was used. A structural questionnaire was used to repeatedly measure the data of 101 pregnant women with NV during the first, second, and third trimesters. A generalized estimating equation (GEE) was used to analyze the collecting data. FINDINGS: The results showed significant differences in symptom distress, prenatal stress, and health-related QOL among the three trimesters in pregnant women with NV (p<0.001). The scores of symptom distress, prenatal stress, and health-related QOL in the first trimester were significantly higher than those in the second and third trimesters (p<0.001). The GEE indicated that the trimester of pregnancy, severity of NV, symptom distress, and prenatal stress were key factors for the transformation of health-related QOL of women with NV during pregnancy. DISCUSSION: The findings of this study are seminal in terms of understanding the relationships between symptom distress, prenatal stress and health-related QOL in pregnant women with NV over the course of a pregnancy. CONCLUSION: This study can serve as a reference for designing interventions (i.e., professional support) for women in different pregnancy stages to improve their health-related QOL during pregnancy. PMID- 30448104 TI - Karyopherin Alpha 2 Is an Adverse Prognostic Factor in Clear-Cell and Papillary Renal-Cell Carcinoma. AB - BACKGROUND: Karyopherin alpha2 (KPNA2) is involved in the nucleocytoplasmic transport system and is functionally involved in the pathogenesis of various solid tumors by the translocation of cancer associated cargo proteins. However, the role of KPNA2 in renal-cell carcinoma (RCC) is still unknown. The aim of the present study was to investigate the protein expression of KPNA2 in cancerous and healthy renal tissues to evaluate its prognostic value in RCC. PATIENTS AND METHODS: We assessed KPNA2 protein expression via immunohistochemistry in a well characterized cohort of 240 RCC patients by using a quantitative image analysis software. In addition, we analyzed publicly available gene expression data from The Cancer Genome Atlas (TCGA). RESULTS: A subgroup of clear-cell RCC (ccRCC) showed elevated protein expression levels of KPNA2. Most remarkably, we detected a correlation between high KPNA2 protein expression and shorter overall survival times as well as higher tumor stage and International Society of Urologic Pathology grade in ccRCC. However, the prognostic value of KPNA2 was not confirmed by multivariate Cox regression analysis when tested together with strong prognostic factors like tumor stage, lymph node metastasis, International Society of Urologic Pathology grade, and resection status. The results of the TCGA gene expression data analysis confirmed the prognostic value of KPNA2 in ccRCC. Additionally, KPNA2 expression was identified as an adverse factor in papillary RCC at the transcript level. CONCLUSION: KPNA2 appears to be involved in the carcinogenesis of RCC and functions as a novel prognostic indicator. PMID- 30448105 TI - Pathologic Nodal Involvement in Patients With Penile Cancer With Cavernosal Versus Spongiosal Involvement. AB - BACKGROUND: The American Joint Committee on Cancer recently proposed new TNM staging for penile cancer, with proposed T2 as spongiosal invasion and T3 as cavernosal invasion. We sought to validate the proposed staging system for predicting pathologic nodal involvement using the National Cancer Data Base. PATIENTS AND METHODS: Invasive penile cancer cases from 2010 to 2012 were identified. Differences in demographic and pathologic factors between T2 and T3 tumors were compared using chi2 and t tests. Logistic regression was performed to determine the odds of pathologically involved lymph nodes (pN+) by T classification. RESULTS: There were 378 T2 and 524 T3 patients with penile cancer. Compared with T2 tumors, T3 tumors were larger (mean size, 5.8 cm vs. 4.3 cm), had higher positive surgical margin rates (12% vs. 9%), and were more likely to have lymphovascular invasion (42% vs. 31%) (all P < .05). In multivariable analysis, both T2 (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.3) and T3 (OR, 2.3; 95% CI, 1.4-3.6) remained significantly associated with risk of positive lymph nodes compared with T1 disease, but there was no increase in risk between T2 and T3 disease (OR, 1.1; 95% CI, 0.7-1.8; P = .56). CONCLUSION: The proposed new American Joint Committee on Cancer staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement. There does not appear to be a difference in positive lymph node status between the 2 grades when other clinical and pathologic variables are considered. PMID- 30448106 TI - Results From a Large, Multicenter, Retrospective Analysis On Radium223 Use in Metastatic Castration-resistant Prostate Cancer (mCRPC) in the Triveneto Italian Region. AB - BACKGROUND: Radium 223 was introduced for metastatic castration-resistant prostate cancer based on the results of a randomized controlled trial showing risk reduction for death and skeletal events. Our aim was to evaluate the outcome of patients receiving radium 223 in a real-world setting. PATIENTS AND METHODS: We conducted a multicenter retrospective analysis in the Triveneto region of Italy. RESULTS: One hundred fifty-eight patients received radium 223 in our region. After a median follow-up of 9.5 months, 75 patients died. The median overall survival (OS) was 14.2 months, and the median progression-free survival (PFS) was 6.2 months. Seventy-one (45%) patients achieved progression as best response. Thirty-seven (23%) patients stopped the treatment early because of progression. Eastern Cooperative Oncology Group performance status was prognostic for OS (18.4 vs. 12.3 vs. 7.5 months; 0 vs. 1, P = .0062; 0 vs. 2, P = .0002), whereas previous prostatectomy or docetaxel exposure were not. A neutrophil to lymphocytes ratio >= 3 significantly impacted OS (18.1 vs. 9.7 months; P < .001) and slightly impacted PFS (6.6 vs. 5.6 months; P = .05). Patients with a baseline alkaline phosphatase (ALP) value >= 220 U/L had worse OS and PFS (24.1 vs. 10.5 months; 7.2 vs. 5.5 months; P < .001). Patients with changes in ALP value achieved better OS (P = .029) and PFS (P = .002). There was no difference according to the line of therapy (0 vs. >= 1; P = .490). The main grade 3/4 toxicities were anemia, asthenia, and thrombocytopenia. CONCLUSION: This large real-world report confirms comparable OS and PFS data when compared with the pivotal study, as well as the predictive role of ALP and neutrophil to lymphocytes ratio. The definition of the optimal position of radium 223 in the treatment of metastatic castration-resistant prostate cancer has still to be defined. PMID- 30448107 TI - Cannabis Abuse or Dependence During Pregnancy: A Population-Based Cohort Study on 12 Million Births. AB - OBJECTIVE: Cannabis is the most commonly used recreational drug during pregnancy in the United States. This study aimed to describe the rate of cannabis dependence or abuse use during pregnancy and its effect on obstetrical and neonatal outcomes. METHODS: A retrospective population-based cohort of births in the United States between 1999 and 2013 was created using data from the National Inpatient Sample. Births to mothers who reported cannabis dependence or abuse were identified using ICD-9 codes, and the effect on various obstetrical and neonatal outcomes was assessed using logistic regression, adjusting for relevant confounders (Canadian Task Force Classification II-2). RESULTS: A total of 12 578 557 births were included in our analysis. The incidence of cannabis abuse or dependence rose from 3.22 in 1000 births in 1999 to 8.55 in 1000 births in 2013 (P < 0.0001). Women reporting cannabis dependence or abuse were more likely to have a preterm premature rupture of membranes (OR 1.46; 95% CI 1.35-1.58), a hospital stay of >7 days (OR 1.17; 95% CI 1.11-1.23), and an intrauterine fetal demise (OR 1.50; 95% CI 1.39-1.62). Neonates born to exposed mothers had a higher risk of prematurity (OR 1.40; 95% CI 1.36-1.43) and growth restriction (OR 1.35; 95% CI 1.30-1.41). CONCLUSION: Cannabis use during pregnancy steadily increased over the study period. Users of cannabis during gestation were more likely to have adverse outcomes during delivery and require longer periods of hospitalization. Neonates born to exposed mothers were more likely to be born preterm and underweight. PMID- 30448108 TI - [Evaluation of pain in children of 2, 4 and 6 months after the application of non pharmacological analgesia methods during vaccination]. AB - INTRODUCTION: Young children perceive pain as much, or even more than adults, and the pain may have short- and long-term consequences. The literature describes the use of non-pharmacological interventions to alleviate pain during vaccination. The aim of this study was to assess 3such interventions for analgesia during vaccination: non-nutritive sucking (NNS), breastfeeding (BF), and administration of a 50% dextrose solution (D50W). MATERIALS AND METHODS: A prospective, non randomised cohort study was carried out on infants aged 2, 4 and 6 months that received 1, 2, or 3 vaccines, respectively, according to the routine immunisation schedule. There were 3treatments: NNS, BF, and 2mL of D50W combined with NNS. Pain was assessed using the LLANTO scale, and the duration of crying. RESULTS: The study included 387 infants. The mean scores in the LLANTO scale at ages 2 and 6 months were significantly lower in breastfed infants compared to infants managed with NNS (P=.025 and P<.001, respectively), or infants given D50W (P=.025 and P=.001), and the difference was not statistically significant at age 4 months (P=.21 and P=.27). There were no significant differences between infants managed with NNS and D50W at 2, 4, and 6 months (P=.66, P=.93 and P=.45, respectively). The duration of crying was significantly lower at age 6 months in breastfeed infants compared to infants managed with NNS or D50W (P=.013 and P=.017). No breastfed child (n=129) experienced side effects. CONCLUSIONS: In infants born to term with adequate weight for gestational age, breastfeeding reduces pain on the administration of 1 or 2 vaccines. When 3 vaccines are given, the reduction is minimal. Administration of D50W does not have any additional analgesic effect in infants compared to being held by a parent combined with NNS during vaccination. BF during vaccination is not associated with any side effects. PMID- 30448109 TI - Females are more vulnerable to Internet gaming disorder than males: Evidence from cortical thickness abnormalities. AB - BACKGROUND: Male predominance is a well-known feature of Internet gaming disorder (IGD), with a reported male to female ratio of 3:1. Because of the overwhelming focus on males, little is known about the neural basis of sex differences in IGD, especially neuroanatomical features. Thus, investigations on sex differences with an adequate sample size are critical for improving the understanding of biological mechanisms underlying IGD. METHODS: Structural magnetic resonance imaging data were acquired from 62 IGD subjects (29 males, 33 females) and 71 recreational game users (RGUs) (37 males, 34 females) with well-matched age and education levels. Group-by-sex interaction in cortical thickness was analyzed, and the correlations between cortical thickness and addiction severity were calculated. RESULTS: We detected a group-by-sex interaction in the bilateral rostral middle frontal gyri (MFG), left superior frontal gyrus (SFG), left supramarginal gyrus (SMG), right posterior cingulate cortex (PCC), and right superior parietal lobule (SPL). Post-hoc analyses revealed that, compared with same-sex RGUs, male IGD subjects had increased cortical thickness and female IGD subjects had reduced cortical thickness beside their right PCC. By contrast, male IGD subjects had reduced cortical thickness and female IGD subjects had increased cortical thickness in their right PCC. Moreover, only females showed significant negative correlations between the cortical thickness and their self-reported cravings and Internet addiction test scores. CONCLUSIONS: For female IGD subjects, the reduced cortical thickness, combined with the negative correlations of addiction severities, suggests the great effect created by IGD in the brain regions. Males and females may be affected differently by IGD, with females being more vulnerable to it. PMID- 30448110 TI - Controversies in Allergy: Is Asthma Chronic Obstructive Pulmonary Disease Overlap a Distinct Syndrome That Changes Treatment and Patient Outcomes? PMID- 30448111 TI - Cryostorage of testicular tissue and retransplantation of spermatogonial stem cells in the infertile male. AB - Transplantation of own cryostored spermatogonial stem cells (SSCs) is a promising technique for fertility restoration when the SSC pool has been depleted. In this regard, cryopreservation of pre-pubertal testicular tissue or SSCs suspensions before gonadotoxic therapies is ethically accepted and increasingly proposed. SSC transplantation has also been considered to treat other causes of infertility relying on the possibility of propagating SSCs retrieved in the testes of infertile men before autologous re-transplantation. Although encouraging results were achieved in animals and in preclinical experiments, clinical perspectives are still limited by a number of unresolved technical and safety issues, such as the risk of cancer cell contamination of cells intended for transplantation and the genetic and epigenetic stability of SCCs when cultured before re transplantation. Moreover, while genome editing techniques raise the hope of modifying the SSCs genome before re-transplantation, their application for reproductive purposes might be a step too far for the moment. PMID- 30448112 TI - Prolonged QRS duration as a predictor of right ventricular dysfunction after balloon pulmonary angioplasty. AB - BACKGROUND: Balloon pulmonary angioplasty (BPA) has shown beneficial effects for chronic thromboembolic pulmonary hypertension (CTEPH). However, previous studies have shown less cardiac output improvement and symptoms remaining after BPA, implying poor right ventricular (RV) function recovery. Therefore, we investigated the residual RV dysfunction after BPA to reveal risk factors, clinical effects, and possible underlying histopathological mechanisms. METHODS AND RESULTS: We investigated 61 consecutive CTEPH patients who underwent cardiovascular magnetic resonance before and 3 and 12 months after BPA series. Residual dysfunction (RD) of RV was defined as RV end-diastolic volume index >100 ml/m2 or RV ejection fraction (EF) <45% at 12-month follow-up. Patients were divided into RD (44%) and normalized dysfunction (ND) (56%) groups. Compared with the ND group, the RD group had significantly worse World Health Organization (WHO) functional class at follow-up. No significant hemodynamic differences were observed between the groups. On multivariable logistic regression analysis, male sex (odds ratio [OR] 12.5, p = 0.004) and prolonged QRS duration (OR 1.08, p = 0.029) were independently associated with residual RV dysfunction. Additionally, RV histopathology in 11 CTEPH autopsy cases showed that QRS duration was correlated with RV fibrosis area. CONCLUSIONS: Relatively high percentage (44%) of residual RV dysfunction with worse WHO functional class was observed in CTEPH patients even after BPA. Prolonged QRS duration may predict poor recovery in RV function after BPA. PMID- 30448113 TI - Spontaneous coronary artery dissections and fibromuscular dysplasia: Current insights on pathophysiology, sex and gender. AB - Spontaneous coronary artery dissections (SCADs) are increasingly recognized as an important cause of acute coronary syndromes in predominantly women below 60 years of age. SCAD patients comprise a heterogeneous group, in which it is estimated that a quarter to one third have underlying fibromuscular dysplasia (FMD). Although the mutual relationship of SCAD and FMD is complex and only partly understood, there seems to be some overlap in genetic background and interaction with endogenous sex-steroids. In this review we provide an update of our current knowledge on these intriguing emerging arteriopathies. PMID- 30448114 TI - Relationship Between Left Ventricular Ejection Fraction and Mortality in Asymptomatic and Minimally Symptomatic Patients With Severe Aortic Stenosis. AB - OBJECTIVES: This study sought to determine the best left ventricular ejection fraction (LVEF) cutoff value to predict long-term mortality in patients with asymptomatic or minimally symptomatic severe aortic stenosis (AS) and LVEF >=50% under conservative management and after surgical correction of AS. BACKGROUND: Aortic valve replacement (AVR) is a Class I indication in asymptomatic patients with severe AS and LVEF <50%. However, this is an uncommon situation in asymptomatic severe AS (<1% of patients), usually occurring late in the course of the disease. No data are available concerning the prognostic value of LVEF in asymptomatic or minimally symptomatic AS patients with preserved LVEF (>=50%) in order to identify a LVEF threshold value associated with increased mortality. METHODS: This analysis included 1,678 patients with preserved LVEF and no or minimal symptoms, with a diagnosis of severe AS. The population was divided into 3 groups: LVEF <55%, LVEF 55% to 59%, and LVEF >=60%. RESULTS: Five-year survival rate was 72 +/- 2% for patients with LVEF >=60%, 74 +/- 2% for patients with LVEF between 55% and 59%, and 59 +/- 4% for patients with LVEF <55% (p < 0.001). Under initially conservative or initially surgical management (surgery within 3 months after baseline echocardiography), patients with LVEF <55% displayed significant excess mortality compared to patients with LVEF>= 60% (adjusted hazard ratio [HR]: 2.44 [95% confidence interval: 1.51 to 3.94]; p < 0.001 and 2.51 [95% confidence interval: 1.58 to 4.00]; p < 0.001, respectively), whereas patients with LVEF between 55% and 59% had comparable prognosis to those with LVEF >=60% (p = 0.53 and p = 0.36, respectively). In patients with LVEF <55%, initial conservative management was associated with increased mortality compared to initial surgical management, even after covariate adjustment (adjusted hazard ratio [HR]: 2.70 [95% confidence interval: 1.98 to 3.67]; p < 0.001). CONCLUSIONS: In patients with severe AS, preserved LVEF and no or minimal symptoms at the time of diagnosis, LVEF <55% is a marker of poor outcome, with medical or surgical management suggesting that these patients should be considered for surgery before this stage. PMID- 30448115 TI - High-Sensitivity Troponin and Coronary Artery Disease Severity: A Bridge Too Far? PMID- 30448116 TI - Self-Expanding Transcatheter Aortic Valve Replacement in Patients With Low Gradient Aortic Stenosis. AB - OBJECTIVES: The authors sought to compare clinical and hemodynamic outcomes in patients receiving transcatheter aortic valve replacement (TAVR) for low-gradient (LG) aortic stenosis in the CoreValve EUS (Expanded Use Study) versus those with high-gradient (HG) aortic stenosis from the CoreValve U.S. Pivotal Extreme Risk Trial and CAS (Continued Access Study). BACKGROUND: The EUS examined the impact of TAVR in patients unsuitable for surgical aortic valve replacement who were excluded from the U.S. Pivotal Extreme Risk Trial due to LG aortic stenosis. METHODS: EUS patients were stratified by left ventricular ejection fraction: normal (>=50%, LG-normal ejection fraction), and low (<50%, did not respond to dobutamine by generating a mean gradient >40 mm Hg and/or velocity >4.0 m/s, "nonresponders"), and compared with extreme-risk patients from U.S. Pivotal and CAS that had either low resting gradient and responded to dobutamine ("responders"), or a high resting gradient (HG) or velocity. The primary endpoint was all-cause mortality or major stroke at 1 year. Hemodynamics and quality of life are reported at 30 days and 1 year. RESULTS: At 30 days, patients with LG/low left ventricular ejection fraction (nonresponders and responders) had significantly higher rates of all-cause mortality or major stroke, all-cause mortality, and cardiovascular mortality than both HG and LG-normal ejection fraction patients. At 1 year, only the responders had higher rates of these outcomes in comparison to the other 3 groups. Mean gradient and effective orifice area improved significantly in all patients and were maintained through 1 year. New York Heart Association functional classification and Kansas City Cardiomyopathy Questionnaire overall summary scores improved (p < 0.05) in all cohorts through 1 year. When all 4 subgroups were pooled, both decreasing mean gradient and stroke volume index were associated with increased mortality. Pre procedural mean gradient was the only hemodynamic independent predictor of 1-year mortality by multivariate analysis. CONCLUSIONS: In this study, TAVR provided EUS patients significant hemodynamic relief with both 1-year survival and quality of life outcomes comparable to Pivotal and CAS patients (Safety & Efficacy Study of the Medtronic CoreValve System-Treatment of Symptomatic Severe Aortic Stenosis With Significant Comorbidities in Extreme Risk Subjects Who Need Aortic Valve Replacement, NCT01675440; Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement, NCT01240902; Safety and Efficacy Continued Access Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in Very High Risk Subjects and High Risk Subjects Who Need Aortic Valve Replacement, NCT01531374). PMID- 30448117 TI - Diagnostic and Prognostic Utility of Cardiac Magnetic Resonance Imaging in Aortic Regurgitation. AB - OBJECTIVES: This study investigated the diagnostic and prognostic value of cardiac magnetic resonance (CMR) imaging in chronic aortic regurgitation (AR). BACKGROUND: Accurate quantification of AR severity by echocardiography frequently remains difficult. CMR is recommended as the complementary method; however, its accuracy and prognostic utility remain unknown. METHODS: A total of 232 consecutive patients (34.5% were females 55.5 +/- 19.8 years of age) with chronic AR (including 40 with moderate to severe and 44 with severe AR on echocardiography) underwent CMR within 4 weeks of echocardiography. CMR included phase-contrast velocity-encoded imaging for the measurement of regurgitant volume and fraction at the sinotubular junction and assessment of holodiastolic retrograde flow (HRF) in the descending aorta. Significant AR was defined as the presence of HRF on CMR. Patients were followed prospectively, and multivariate Cox regression was applied for outcome analysis using a combination of heart failure, hospitalization, and cardiovascular death as primary endpoint. RESULTS: AR severity on the basis of echo was reclassified in a significant number of patients according to CMR: 6.8% with mild AR on echo had HRF on CMR, whereas 34.1% with severe AR on echo did not have HRF on CMR and were reclassified as having nonsignificant AR. In 40 patients with uncertain AR severity (moderate to severe) on echo, 45.0% had HRF on CMR, indicating severe AR. Patients were followed for 35.3 +/- 26.6 months. During that period, 63 patients (27.2%) reached the combined endpoint, including 43 (18.5%) with heart failure hospitalizations and 20 (8.6%) with cardiovascular deaths. By multivariate regression analysis, including clinical as well as imaging parameters, only N terminal pro-B-type natriuretic peptide concentration (hazard ratio: 2.184 [95% confidence interval: 1.468 to 3.248]; p < 0.001) and HRF on CMR (hazard ratio: 2.774 [95% confidence interval: 1.131 to 6.802]; p = 0.026) remained significantly associated with outcome. CONCLUSIONS: In chronic AR, CMR has the potential to add important diagnostic and prognostic information. PMID- 30448118 TI - First-Phase Ejection Fraction Is a Powerful Predictor of Adverse Events in Asymptomatic Patients With Aortic Stenosis and Preserved Total Ejection Fraction. AB - OBJECTIVES: This study investigated the prognostic value of first-phase ejection fraction (EF1) in patients with aortic stenosis (AS), a condition in which left ventricular dysfunction as measured by conventional indices is an indication for valve replacement. BACKGROUND: EF1, the ejection fraction up to the time of maximal ventricular contraction may be more sensitive than existing markers in detecting early systolic dysfunction. METHODS: The predictive value of EF1 compared to that of conventional echocardiographic indices for outcomes was assessed in 218 asymptomatic patients with at least moderate AS, including 73 with moderate, 50 with severe, and 96 with "discordant" (aortic area <1.0 cm2 and gradient < 40 mm Hg) AS, all with preserved EF, followed for at least 2 years. EF1 was measured retrospectively from archived echocardiographic images by wall tracking of the endocardium. The primary outcome was a combination of aortic valve intervention, hospitalization for heart failure, and death from any cause. RESULTS: EF1 was the most powerful predictor of events in the total population and all subgroups. A cutoff value of 25% (or EF1 of <25% compared to >=25%) gave hazard ratios of 27.7 (95% confidence interval [CI]: 13.1 to 58.7; p < 0.001) unadjusted and 24.4 (95% CI: 11.3 to 52.7; p < 0.001) adjusted for other echocardiographic measurements including global longitudinal strain, for events at 2 years in all patients with asymptomatic AS. Corresponding hazard ratios for all-cause mortality in the total population were 17.5 (95% CI: 5.7 to 53.3) and 17.4 (95% CI: 5.5 to 55.2) unadjusted and adjusted, respectively. CONCLUSIONS: EF1 may be potentially valuable in the clinical management of patients with AS and other conditions in which there is progression from early to late systolic dysfunction. PMID- 30448119 TI - A New Threshold for Intervention Based on Left Ventricular Ejection Fraction in Subclinical, Severe Aortic Stenosis: Is 55 the New 50? PMID- 30448120 TI - Diffuse Myocardial Fibrosis in Aortic Stenosis: Time to Act? PMID- 30448121 TI - Low Gradient Aortic Stenosis: Who Benefits from Intervention? PMID- 30448122 TI - Transcatheter Aortic Heart Valves: Histological Analysis Providing Insight to Leaflet Thickening and Structural Valve Degeneration. AB - OBJECTIVES: This study investigated processes causing leaflet thickening and structural valve degeneration (SVD). BACKGROUND: Although transcatheter aortic valve replacement (TAVR) has changed the treatment of aortic stenosis, concerns remain regarding SVD, potentially related to valve thrombosis and thickening, based on studies using computed tomography (CT). Detailed histological analyses are provided to help attain insights into these processes. METHODS: Explanted transcatheter heart valves (THVs) were evaluated for thrombosis, fibrosis, and calcification for quantification of leaflet thickness. Immunohistochemical and microscopy approaches were used to investigate SVD-associated mechanisms. RESULTS: THVs (n = 23) were obtained from 22 patients (median 81 years of age; 50% male) from 0 to 2,583 days post TAVR. Maximal leaflet thickness increased relative to implant duration (rho = 0.427; p = 0.027). THVs explanted after >2 years were thicker than those explanted after <2 years (p = 0.007). All THVs had adherent thrombus on both aortic and ventricular sides, which beyond 60 days was seen in combination with fibrosis and beyond 4 years had calcification. Early thrombus formation (<60 days) occurred despite rapid endothelialization with an abnormal hyperplastic phenotype. Fibrosis was observed in 6 patients on both the aortic and the ventricular THV surfaces, remodeled over time, and was associated with matrix metalloproteinase-1 expression. Five THVs showed overt calcification associated with adherent thrombus and fibrosis. CONCLUSIONS: There is a time dependent degeneration of THVs consisting of thrombus formation, endothelial hyperplasia, fibrosis, tissue remodeling, proteinase expression, and calcification. Future investigation is needed to further understand these mechanisms contributing to leaflet thickening and SVD. PMID- 30448123 TI - Diastolic Function Assessment Revisited: Is Big Data Analysis Going to be a Big Hit? PMID- 30448124 TI - Insights From Autopsies: Potential Role of Thrombus in Structural Valve Deterioration. PMID- 30448125 TI - First-Phase Ejection Fraction: The FEV1 of the Heart? PMID- 30448126 TI - Incremental Predictive Value of Left Atrial Parameters Over Clinical Risk Scores for Subsequent Atrial Fibrillation: Function Beyond Size. PMID- 30448127 TI - Optimizing the Assessment of Aortic Regurgitation: The Importance of Quantity and Quality. PMID- 30448128 TI - Assessment of Cardiac Iron Overload in Thalassemia With MRI on 3.0-T: High-Field T1, T2, and T2* Quantitative Parametric Mapping in Comparison to T2* on 1.5-T. PMID- 30448129 TI - Multiorgan Imaging of Comorbidity and Cardiovascular Risk. PMID- 30448130 TI - Comparing CMR Mapping Methods and Myocardial Patterns Toward Heart Failure Outcomes in Nonischemic Dilated Cardiomyopathy. AB - OBJECTIVES: In patients with nonischemic dilated cardiomyopathy (NIDCM), native T1, partition coefficient (lambdaGd), and extracellular volume fraction (ECV) mapping may offer prognostic values beyond late gadolinium enhancement (LGE), by scaling the range of myocardial changes. BACKGROUND: In patients with NIDCM, LGE is seen in 30% of patients and it indicates adverse prognosis. METHODS: The study mapped 6 anatomical locations using all 4 cardiac magnetic resonance (CMR) tissue characterizing methods and associated with outcome. The authors performed T1 mapping of the myocardium and the blood pool, before and serially after contrast injection, using a Look-Locker cine gradient-echo technique to obtain T1 and the corresponding reciprocal R1 values. lambdaGd values were derived from the slopes of the least-squares regression lines for myocardial versus blood R1, then adjusted to serum hematocrit to yield ECV. RESULTS: Consecutive 240 NIDCM patients (49 +/- 16 years of age; 38% women) underwent CMR for cardiac function, LGE, native T1, lambdaGd, and ECV. After a median of 3.8 years, 36 (15%) experienced major adverse cardiac events (MACE), including 22 heart failure hospitalizations and 14 deaths. Nonischemic LGE was detected in 34%, whereas ECV was elevated (>=1 location) in 58%. Comparing the 4 methods, mean ECV and lambdaGd both demonstrated strong association with MACE (both p < 0.001). In contrast to native T1 and LGE, ECV values from all 6 locations were associated with MACE and death, with the anteroseptum being the most significant (p < 0.0001). The number of abnormal ECV locations correlated linearly with annual MACE rates (p = 0.0003). Mean ECV was the only predictor to enter a prognostic model that contained age, sex, New York Heart Association functional class, and left ventricular ejection fraction. For every 10% increase, mean ECV portended to a 2.8-fold adjusted increase risk to MACE (p < 0.001). CONCLUSIONS: In this study of patients with NIDCM, mapping the myocardial extent of abnormality using ECV offers prognostication toward heart failure outcomes incremental to LGE or native T1 mapping. PMID- 30448132 TI - Association Between TTE Appropriateness, Echocardiographic Findings, and Clinical Outcomes. PMID- 30448131 TI - Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study. AB - OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-flourodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: beta = 0.20, p = 0.01) and subclinical CVD (VI: beta = 0.31, p < 0.001; NCB: beta = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact. PMID- 30448133 TI - Prognostic Value of Thoracic Aorta Calcification Burden in Patients Treated With TAVR. PMID- 30448134 TI - Epicardial Adipose Tissue and Myocardial Fibrosis in Aortic Stenosis Relationship With Symptoms and Outcomes: A Study Using Cardiac Magnetic Resonance Imaging. PMID- 30448135 TI - A Hyperdynamic RV Is an Early Marker of Clinical Decompensation and Cardiac Recovery in Aortic Stenosis With Normal LV Ejection Fraction. PMID- 30448136 TI - Comparison of Insonation-Augmented Physical Examination With Standard Physical Examination in Detecting Severe Left-Sided Valve Disease. PMID- 30448137 TI - Contrast Echocardiographic Perfusion Imaging in Clinical Decision-Making for Cardiac Masses in Patients With a History of Extracardiac Malignant Tumor. PMID- 30448138 TI - Transcatheter Repair of Severe Functional Tricuspid Insufficiency Using Mitraclip System: Transgastric Views Are the Key for an Effective Guide. PMID- 30448139 TI - Do 2-Dimensional Speckle Tracking Indexes Have Sufficient Reproducibility to Be Used in Clinical Practice When Image Acquisition and Severity of LV Dysfunction Are Taken Into Account? PMID- 30448140 TI - T1 or ECV?: Depends on the Methods. PMID- 30448141 TI - Echocardiographic Assessment of Transcatheter Aortic Valve Hemodynamics: More Tools for the Toolbox. PMID- 30448142 TI - Reclassifying Risk in Familial Hypercholesterolemia: The Power of a Coronary Artery Calcium Score of Zero. PMID- 30448143 TI - Noninvasive Assessment of Hemodynamics in Left Ventricular Assist Device Patients: Echocardiographic Accuracy and Clinical Outcome Implications. PMID- 30448144 TI - Right Ventricular Function in TAVR: The Right Hand Knows What the Left Hand Is Doing. PMID- 30448145 TI - Coronary Artery Calcium and Cardiovascular Events in Patients With Familial Hypercholesterolemia Receiving Standard Lipid-Lowering Therapy. AB - OBJECTIVES: The aim of this study was to evaluate the role of coronary artery calcium (CAC) as a predictor of atherosclerotic cardiovascular disease (ASCVD) (fatal or not myocardial infarction, stroke, unstable angina requiring revascularization, and elective myocardial revascularization) events in asymptomatic primary prevention molecularly proven heterozygous familial hypercholesterolemia (FH) subjects receiving standard lipid-lowering therapy. BACKGROUND: FH is associated with premature ASCVD. However, the clinical course of ASCVD in subjects with FH is heterogeneous. CAC score, a marker of subclinical atherosclerosis burden, may optimize ASCVD risk stratification in FH. METHODS: Subjects with FH underwent CAC measurement and were followed prospectively. The association of CAC with ASCVD was evaluated using multivariate analysis. RESULTS: A total of 206 subjects (mean age 45 +/- 14 years, 36.4% men, baseline and on treatment low-density lipoprotein cholesterol 269 +/- 70 mg/dl and 150 +/- 56 mg/dl, respectively) were followed for a median of 3.7 years (interquartile range: 2.7 to 6.8 years). CAC was present in 105 (51%), and 15 ASCVD events (7.2%) were documented. Almost half of events were hard outcomes, and the others were elective myocardial revascularizations. The annualized rates of events per 1,000 patients for CAC scores of 0 (n = 101 [49%]), 1 to 100 (n = 62 [30%]) and >100 (n = 43 [21%]) were, respectively, 0, 26.4 (95% confidence interval: 12.9 to 51.8), and 44.1 (95% confidence interval, 26.0 to 104.1). In multivariate Cox regression analysis, log(CAC score + 1) was independently associated with incident ASCVD events (hazard ratio: 3.33; 95% CI: 1.635 to 6.790; p = 0.001). CONCLUSIONS: CAC was independently associated with ASCVD events in patients with FH receiving standard lipid-lowering therapy. This may help further stratify near term risk in patients who might be candidates for further treatment with newer therapies. PMID- 30448146 TI - The "Native T1 Versus Extracellular Volume Fraction Paradox" in Cardiac Amyloidosis: Answer to the Million-Dollar Question? PMID- 30448147 TI - Coronary Calcium and Selection for Risk Reduction: Reverend Bayes Has His Say. PMID- 30448148 TI - Assessment of Myocardial Fibrosis Using Multimodality Imaging in Severe Aortic Stenosis: Comparison With Histologic Fibrosis. AB - OBJECTIVES: This study assessed diffuse myocardial fibrosis (MF) by cardiac magnetic resonance (CMR) imaging and speckle-tracking echocardiography (STE) in patients with severe aortic stenosis (AS) and validated findings by using histologic confirmation of MF. BACKGROUND: MF is a concomitant pathologic finding related to hypertrophic response in severe AS. It would be beneficial to have reliable imaging methods to assess MF. METHODS: CMR and STE were performed in 71 consecutive patients with severe AS before aortic valve replacement. The extracellular volume (ECV) and native T1 values obtained by CMR and global longitudinal strain (GLS) values by STE were measured. The degree of MF was quantified by using Masson trichrome stain in myocardial biopsy specimens obtained intraoperatively. The study population was divided into 3 groups according to the degree of MF on histology (mild, moderate, and severe MF). RESULTS: The severe MF group had a higher incidence of heart failure (HF) and diastolic dysfunction than the mild and moderate MF groups. The ECV (r = 0.465; p < 0.0001), GLS (r = 0.421; p = 0.0003), and native T1 (r = 0.429; p = 0.0002) values were significantly correlated with the degree of MF. GLS was moderately correlated with ECV (r = 0.455; p = 0.0001) and less with the native T1 (r = 0.372; p = 0.0014) value. The model using ECV (R2 = 0.44; Akaike Information Criterion [AIC] = 55.8) was found to predict the degree of MF most accurately than that with GLS (R2 = 0.35; AIC = 66.84) and the native T1 (R2 = 0.36; AIC = 66.18) value. The secondary endpoint of interest was clinical outcome of a composite of total mortality, admission for HF, or development of HF symptoms. During follow-up (median: 4.6 years), and there were 16 clinical events. Although statistically insignificant, ECV is more closely related to prediction of the clinical outcome than native T1 or GLS. CONCLUSIONS: ECV as assessed by CMR could be an ideal surrogate marker for diffuse MF in patients with severe AS among all 3 models considered. PMID- 30448149 TI - Assessing health effects of air quality actions: what's next? PMID- 30448150 TI - Impact of London's low emission zone on air quality and children's respiratory health: a sequential annual cross-sectional study. AB - BACKGROUND: Low emission zones (LEZ) are an increasingly common, but unevaluated, intervention aimed at improving urban air quality and public health. We investigated the impact of London's LEZ on air quality and children's respiratory health. METHODS: We did a sequential annual cross-sectional study of 2164 children aged 8-9 years attending primary schools between 2009-10 and 2013-14 in central London, UK, following the introduction of London's LEZ in February, 2008. We examined the association between modelled pollutant exposures of nitrogen oxides (including nitrogen dioxide [NO2]) and particulate matter with a diameter of less than 2.5 MUm (PM2.5) and less than 10 MUm (PM10) and lung function: postbronchodilator forced expiratory volume in 1 s (FEV1, primary outcome), forced vital capacity (FVC), and respiratory or allergic symptoms. We assigned annual exposures by each child's home and school address, as well as spatially resolved estimates for the 3 h (0600-0900 h), 24 h, and 7 days before each child's assessment, to isolate long-term from short-term effects. FINDINGS: The percentage of children living at addresses exceeding the EU limit value for annual NO2 (40 MUg/m3) fell from 99% (444/450) in 2009 to 34% (150/441) in 2013. Over this period, we identified a reduction in NO2 at both roadside (median -1.35 MUg/m3 per year; 95% CI -2.09 to -0.61; p=0.0004) and background locations ( 0.97; -1.56 to -0.38; p=0.0013), but not for PM10. The effect on PM2.5 was equivocal. We found no association between postbronchodilator FEV1 and annual residential pollutant attributions. By contrast, FVC was inversely correlated with annual NO2 (-0.0023 L/MUg per m3; -0.0044 to -0.0002; p=0.033) and PM10 ( 0.0090 L/MUg per m3; -0.0175 to -0.0005; p=0.038). INTERPRETATION: Within London's LEZ, a smaller lung volume in children was associated with higher annual air pollutant exposures. We found no evidence of a reduction in the proportion of children with small lungs over this period, despite small improvements in air quality in highly polluted urban areas during the implementation of London's LEZ. Interventions that deliver larger reductions in emissions might yield improvements in children's health. FUNDING: National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' National Health Service (NHS) Foundation Trust and King's College London, NHS Hackney, Lee Him donation, and Felicity Wilde Charitable Trust. PMID- 30448151 TI - Anastomotic reconstruction and external drainage of Wirsung's duct as treatment for pancreaticojejunal stenosis following pancreaticoduodenectomy. AB - Stenosis of the pancreaticodigestive anastomosis (pancreaticogastrostomy and pancreaticojejunostomy) is a very rare complication that usually develops several years after pancreaticoduodenectomy (PD). Only a few cases have been previously reported. We have reviewed the literature and present 2 more cases of pancreaticojejunostomy stenosis that started with episodes of recurrent acute pancreatitis 6 years and 1 year after PD, respectively. Diagnosis was based on symptoms of pancreatitis (12-15 episodes between 5 and 20 months after PD) and CT and MRI scans. Both patients were treated by resection of the pancreaticojejunostomy stenosis, including a 1-cm slice of pancreatic parenchyma in contact with the jejunum, followed by a new well-vascularized two-layer end-to side PJ with external drainage of the Wirsung duct. Catheter drainage was exteriorized through a jejunal limb using the Witzel technique. Postsurgical course was uneventful in both cases, and after a follow-up period of 3 and 2.5 years, respectively, the patients remain asymptomatic but with endocrine and exocrine insufficiency. Resection of the PJ and construction of a new PJ with external stent drainage of the Wirsung duct is our preferred surgical option in the rare cases of PJ stenosis after a Whipple procedure. PMID- 30448152 TI - The relative roles of power, linear endovenous energy density, and pullback velocity in determining short-term success after endovenous laser ablation of the truncal saphenous veins. AB - OBJECTIVE: The objective of this study was to describe the relative contributions of power output, linear endovenous energy density (LEED), and pullback rate (PBR) in determining successful long-term occlusion of the truncal saphenous veins after endovenous laser ablation (EVLA). METHODS: A consecutive 203 patients (336 ablated veins) with reflux of the great saphenous vein or small saphenous vein (Clinical, Etiology, Anatomy, and Pathophysiology class C2-C6) defined by duplex ultrasound and clinical criteria were treated with 1470-nm EVLA at a power of 6 to 12 W. Prospective outcomes were evaluated in serial clinical and duplex ultrasound follow-up. Univariate logistic regression (ULR) and multivariable logistic regression modeling assessed LEED, power output, and PBR as success predictors and optimal settings for sustained closure. RESULTS: Higher power outputs (8-12 W) were significantly better than lower outputs (6-7 W) for successful closure. ULR suggested a >=90% probability of success for power output >10.34 W (P < .001) and LEED >26.56 J/cm (P = .001). Power output was foremost (P < .001) and LEED second (P < .001), and PBR was insignificant overall (P = .38), becoming significant only at LEED values >26 J/cm (P < .001). Multivariable logistic regression confirmed both power (P < .040) and LEED (P < .008) but not PBR (P = .69) as significant determinants. Clinical side effects were not associated by ULR with power output (P = .14), LEED (P = .71), or PBR (P = .39). CONCLUSIONS: Power and LEED are separate but important determinants of short-term EVLA success. Threshold-dependent effects are observed for PBR (LEED <=26 J/cm or >=26 J/cm), with significant PBR correlation seen only at higher LEED values. Whereas ideal values for power and LEED differ according to the clinical scenario, our findings suggest that use of higher power outputs and greater LEED values (>=90% success probability achieved with power >10.34 W or LEED >26.56 J/cm) may yield optimal results. PMID- 30448153 TI - Systematic review and meta-analysis of the anatomic variants of the saphenofemoral junction. AB - BACKGROUND: The aim of this systematic review was to provide comprehensive data on the prevalence of variations of the saphenofemoral junction (SFJ) to prevent misidentification of the SFJ or the incomplete ligation of the tributaries of the great saphenous vein. METHODS: A systematic review was conducted using the PubMed, Embase, and Cochrane Library databases through September 14, 2017. To be included in the meta-analysis, a study had to report prevalence data on the morphology of the SFJ or the presence of venous tributaries. RESULTS: A total of 16 studies (7433 legs) were included. The majority of studies were performed during varicose vein surgery (74.14%), with fewer studies by means of computed tomography venography and cadaveric dissection. The pooled prevalence estimate (PPE) for a duplication of the SFJ with a bifid junction was 9.6% (P = .001). The PPE for a duplication of the SFJ with two separate junctions was 1.7%. The PPE for ectasia of the SFJ was 2.3% in type 1, 1.2% in type 2, and 1.7% in type 3. The distribution of the PPE for the number of venous SFJ tributaries was approximately normal with a slight right skew; a higher rate was observed in the group with four venous tributaries to the SFJ. CONCLUSIONS: This analysis found high heterogeneity in the prevalence of SFJ anatomic variants and the number of venous SFJ tributaries. For this reason, it is highly recommended that a preoperative Doppler ultrasound assessment of the SFJ and great saphenous vein be performed. PMID- 30448154 TI - Upregulating brain activity using non-drug reward imagery and real-time fMRI neurofeedback-A new treatment approach for addiction? PMID- 30448156 TI - Examining Black-White Disparities Among Medicare Beneficiaries in Assisted Living Settings in 2014. AB - OBJECTIVE: Assisted living (AL) provides housing and personal care to residents who need assistance with daily activities. Few studies have examined black-white disparities in larger (25 + beds) ALs; therefore, little is known about black residents, their prior residential settings, and how they compare to whites in AL. We examined racial differences among a national cohort of AL residents and how the racial variation among AL Medicare Fee-For-Service (FFS) beneficiaries compared to differences among community-dwelling and nursing home cohorts. STUDY DESIGN: Retrospective cohort study. PARTICIPANTS: We included (1) a prevalence sample of 442,018 white and black Medicare beneficiaries residing in large AL settings, (2) an incidence sample of new residents (n = 94,741), and (3) 10% random samples of Medicare FFS community-dwelling and nursing home beneficiaries in 2014. MEASURES: The Medicare Master Summary Beneficiary File was used to identify AL residents and provided demographic, entitlement, chronic condition, and health care utilization information. We used the American Community Survey and prior ZIP code tabulation areas of residents to examine differences in prior neighborhoods. Medicare claims and the Minimum Data Set yielded samples of Medicare FFS community-dwelling older adults and nursing home residents. RESULTS: Blacks were disproportionately represented in AL, younger, more likely to be Medicaid eligible, had higher levels of acuity, and more often lived in ALs with fewer whites and more duals. New black residents entered AL with higher rates of acute care hospitalizations and skilled nursing facility utilization. Across the 3 cohorts, blacks had higher rates of dual-eligibility. CONCLUSIONS: Black-white differences observed among AL residents indicate a need for future work to examine how disparities manifest in differences in care received and residents' outcomes, as well as the pathways to AL. More research is needed to understand the implications of inequities in AL as they relate to quality and experiences of residents. PMID- 30448155 TI - A large HCV transmission network enabled a fast-growing HIV outbreak in rural Indiana, 2015. AB - BACKGROUND: A high prevalence (92.3%) of hepatitis C virus (HCV) co-infection among HIV patients identified during a large HIV outbreak associated with injection of oxymorphone in Indiana prompted genetic analysis of HCV strains. METHODS: Molecular epidemiological analysis of HCV-positive samples included genotyping, sampling intra-host HVR1 variants by next-generation sequencing (NGS) and constructing transmission networks using Global Hepatitis Outbreak and Surveillance Technology (GHOST). FINDINGS: Results from the 492 samples indicate predominance of HCV genotypes 1a (72.2%) and 3a (20.4%), and existence of 2 major endemic NS5B clusters involving 49.8% of the sequenced strains. Among 76 HIV co infected patients, 60.5% segregated into 2 endemic clusters. NGS analyses of 281 cases identified 826,917 unique HVR1 sequences and 51 cases of mixed subtype/genotype infections. GHOST mapped 23 transmission clusters. One large cluster (n = 130) included 50 cases infected with >=2 subtypes/genotypes and 43 cases co-infected with HIV. Rapid strain replacement and superinfection with different strains were found among 7 of 12 cases who were followed up. INTERPRETATION: GHOST enabled mapping of HCV transmission networks among persons who inject drugs (PWID). Findings of numerous transmission clusters, mixed genotype infections and rapid succession of infections with different HCV strains indicate a high rate of HCV spread. Co-localization of HIV co-infected patients in the major HCV clusters suggests that HIV dissemination was enabled by existing HCV transmission networks that likely perpetuated HCV in the community for years. Identification of transmission networks is an important step to guiding efficient public health interventions for preventing and interrupting HCV and HIV transmission among PWID. FUND: US Centers for Disease Control and Prevention, and US state and local public health departments. PMID- 30448157 TI - Bingo Candies in Long-term Care: A Quality Improvement Project. PMID- 30448158 TI - Patient Characteristics as Indicator for Care Dependence after Hip Fracture: A Retrospective Cohort Study Using Health Insurance Claims Data From Germany. AB - OBJECTIVES: Hip fractures are common consequences of falls in older adults and, among other negative health outcomes, often lead to care dependence in the long term. Until 2016, the German long-term care insurance classified care recipients according to a standardized classification system consisting of 3 care levels. It was based on required assistance in performing activities of daily living and assessed by a qualified physician or nurse. Thus, care level reflects the degree of care dependence. The aim of this study was to determine relevant patient characteristics, which are related to the likelihood of increasing care dependence in terms of worsening care level after hip fracture. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Statutory health insurance claims data including 122,922 insured individuals living in Germany and aged 65 years or older, who sustained a hip fracture from 2009 through 2011. MEASURES: The association of patient characteristics with worsening care level in the quarterly period after hip fracture was investigated by means of multinomial logit regression analysis. Death constitutes a competing risk and was modeled as additional nominal outcome. RESULTS: Among all patients, crude rates were 30.9% for worsening care level, 54.8% for unchanged care level, and 14.4% for death after hip fracture. The multivariate analysis revealed that patient factors male sex, increasing age, increasing comorbidity, increasing inpatient length of stay, and a lack of inpatient rehabilitation were significantly associated with a worsening care level. CONCLUSIONS/IMPLICATIONS: This study uses the German standardized measurement of care dependence in terms of worsening care level after hip fracture and finds various related patient characteristics. Knowledge of these characteristics helps to identify possible risk groups for care dependence after hip fracture, for which special attention can be provided regarding treatment and prevention of hip fractures. PMID- 30448159 TI - IBS clinical management in Italy: The AIGO survey. AB - BACKGROUND: Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder, both in primary and secondary care. AIMS: (1) To describe diagnostic tools and treatments suggested to IBS patients by Italian gastroenterologists; (2) To evaluate patients' quality of life and psychological involvement and the relationship of these factors with symptom severity. METHODS: Twenty-six gastroenterologists recorded the demographic and clinical data of 677 IBS patients. Diagnostic and treatment measures taken in the previous year and those suggested by gastroenterologists were analysed. RESULTS: IBS with constipation was found in 43.4%, with diarrhoea in 21.6%, mixed-IBS in 35.0%. Routine blood tests, ultrasonography, colonoscopy, barium enema and CT were more frequently requested in the previous year than by the gastroenterologists (p < 0.001). Colonoscopy (11%), and ultrasonography (20.4%) were also suggested by the gastroenterologists in a non-negligible number of patients. Abdominal pain and distension, bowel dissatisfaction, anxiety and depression were more severe in females than in males. Quality of life decreased with increasing IBS-symptom severity. CONCLUSIONS: IBS diagnosis is still largely based on exclusion criteria even if gastroenterologists try to improve diagnostic appropriateness. However, therapy remains symptom-based also in the gastroenterological setting even if gastroenterologists use a wide variety of approaches, including innovative therapies such as linaclotide and psychotherapy. PMID- 30448160 TI - To STABILISE or not: Is the additive time of additive benefit? PMID- 30448161 TI - A paradox of remote ischemic preconditioning: Remote understanding, remote relevance, and remote future? PMID- 30448163 TI - General thoracic surgery as a subspecialty in Colombia. PMID- 30448162 TI - Open surgery for descending thoracic aorta in an endovascular era. AB - BACKGROUND: Thoracic endovascular aortic repair has become the preferred treatment for a variety of descending thoracic aortic pathologies. However, there are unresolved issues such as morphologic appearance of chronic dissection, persistent false lumen perfusion, and adequacy of landing zone. Enthusiasm for improving the technique of open aortic repair and perioperative management is fading. In this study, we would like to demonstrate how we improve our surgical outcomes by establishing a dedicated aortic multidisciplinary team at the Kawasaki Aortic Center. METHOD: We performed a single-center retrospective study from January 2015 to December 2016. All patients with open descending thoracic aortic replacement were recruited. Preoperative patient demographic data, bypass strategies, operative details, and postoperative outcomes were reviewed. RESULT: From January 2015 to December 2016, we treated 168 cases of descending thoracic aortic repair using a left thoracotomy. Median age was 69.0 +/- 21.8 years old, and 63.1% were aortic dissection (acute, 4.8%; chronic, 58.3%); 81.3% patients underwent elective operations. Left heart bypass, deep hypothermic circulatory arrest, and partial cardiopulmonary bypass were performed in 88.6%, 9.0%, and 2.4% of patients, respectively. Mean operative time was 312 +/- 94 minutes. In hospital mortality in total was 0.6%. The rate of transient spinal cord injury was 4.7%. CONCLUSIONS: Under a dedicated aortic multidisciplinary team, we demonstrated that open descending thoracic aorta replacement can be performed with excellent early outcomes with low reintervention rates, regardless of the nature of the aortic pathologies. PMID- 30448164 TI - What makes a cardiac surgical intensive care unit safe after midnight? PMID- 30448165 TI - The young surgeons' page. PMID- 30448167 TI - A Rapid Inflation and Deflation Technique in Digital Subtraction Angiography for Improved Visualization of Expansion of a Balloon Catheter. PMID- 30448166 TI - Impact of remote ischemic preconditioning preceding coronary artery bypass grafting on inducing neuroprotection. AB - BACKGROUND: Neurological complications after coronary artery bypass grafting (CABG) reduce quality of life, increase mortality, and inflate resource utilization. The risk of postoperative neurological complications parallels the increasing risk burden of the contemporary patient population. We evaluated the efficacy of remote ischemic preconditioning (RIPC) on inducing neuroprotection. METHODS: Seventy patients undergoing first-time CABG were randomly assigned to RIPC or a sham procedure. Structural brain magnetic resonance imaging (MRI) was complemented with functional connectivity MRI to gain a whole-brain global connectivity analysis. Paired neurocognitive and MRI data were acquired pre- and postoperatively. The primary end point was a composite of new ischemic brain lesions and neurocognitive impairment. Secondary end points included brain connectivity profiles, pooled ischemic volumes, and individual components of the primary outcome. The Shapiro-Wilk test was used to determine whether a data set followed a normal distribution. The Fisher exact test was used to calculate the measures of association for categorical variables, whereas continuous data were tested with either the Mann-Whitney U test or the Student t test. RESULTS: There was no between-group difference in the incidence of the primary end point (9 [27%] in the RIPC group vs 8 [24%] in the control group, odds ratio, 1.17 [95% confidence interval, 0.34-4.06]; P = 1.0). Although RIPC did not reduce the incidence of brain ischemia (8/33 [24%] vs 7/33 [21%]; P = 1.0), the pooled ischemic volume was lower in the RIPC group (157 [interquartile range, 125-231] vs 777 [interquartile range, 564-965] mm3; P = .004). Postoperative neurocognition was marginally superior in the RIPC group as evidenced by a lower absolute number of abnormal neurocognitive tests in the RIPC group (7/99 [7%] vs 16/99 [16%]; odds ratio, 0.40 [95% confidence interval, 0.14-1.09]; P = .074). Robust reductions of functional connectivity profiles for the associative thalamus were documented in both groups, irrespective of RIPC (RIPC group, t = 3.31; P < .01; and the control group, t = 3.52; P < .01). CONCLUSIONS: Silent brain ischemia occurs frequently after CABG. RIPC did not reduce the incidence of the primary outcome. However, RIPC significantly reduced the pooled volume of ischemic brain lesions. Surgery adversely affected global brain connectivity, with RIPC conferring no demonstrable protection. The association of RIPC with superior neurocognitive test scores failed to cross the threshold for significance. PMID- 30448168 TI - "Baumkuchen" Structure Assessed by Optical Coherence Tomography After 15 Years of Bare-Metal Stent Implantation. PMID- 30448169 TI - An Unexpected Origin of Fluctuating Pulsatile Tinnitus. PMID- 30448170 TI - Drug-Coated Balloon Angioplasty Compared With Uncoated Balloons in the Treatment of 200 Chinese Patients With Severe Femoropopliteal Lesions: 24-Month Results of AcoArt I. AB - OBJECTIVES: The authors sought to investigate the midterm efficacy and safety of drug-coated balloon (DCB) in the treatment of severe femoropopliteal artery disease (FPAD). BACKGROUND: The midterm outcome of DCB versus uncoated balloon percutaneous transluminal angioplasty (PTA) for FPAD are still debated. METHODS: A total of 200 Chinese patients with FPAD were prospectively randomized into treatment with DCB or with PTA. The primary efficacy endpoints were primary patency of the target lesion, freedom from clinically driven target lesion revascularization, improved ankle-brachial index, and improved Rutherford class at 24 months. The primary safety endpoint was the rate of major adverse events. RESULTS: The DCB group and PTA group were comparable in demographic characteristics and clinical severity at baseline. At 24-month follow-up, primary patency was better in the DCB group versus PTA group (64.6% vs. 31.4%; p < 0.001). The DCB group had a higher rate of freedom from clinically driven target lesion revascularization than the PTA group (86.5% vs. 58.9%; p < 0.001). Rutherford class and ankle-brachial index also confirmed more improvements in the DCB group (p < 0.01 and p < 0.05, respectively). There was no significant difference in major adverse events. CONCLUSIONS: The superiority of DCB versus PTA in the efficacy of FPAD treatment persists at 24-month follow-up and the safety of DCB is equivalent to that of PTA. PMID- 30448171 TI - Simple Treatment for Complex Femoropopliteal Disease?: Midterm Drug-Coated Balloon Results From the AcoArt I Trial. PMID- 30448172 TI - Spontaneous Coronary Artery Dissection in a Man With a Novel Missense Mutation in SMAD2 Treated by Optical Coherence Tomography-Guided Percutaneous Coronary Intervention. PMID- 30448173 TI - Coronary Sinus Reducer Implantation to Reduce the Ischemic Burden in Refractory Angina. PMID- 30448174 TI - Aberrant Vertebral Artery: An Intruder into the Aortic Arch (Atypical Bow Hunter's Syndrome). PMID- 30448175 TI - Thioredoxin-interacting protein-derived peptide (TN13) inhibits LPS-induced inflammation by inhibiting p38 MAPK signaling. AB - Inflammation comprises an innate immune response, and is mainly induced by macrophages to protect the host from pathogens and mechanical injuries. The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammatory responses in macrophages. Here, we investigated the anti inflammatory effects of thioredoxin-interacting protein-derived peptide (TN13) in macrophages in vitro and in vivo. Human immunodeficiency virus (HIV) trans activator protein (TAT)-conjugated TN13 (TAT-TN13) was found to penetrate RAW 264.7 cells and decrease p38 MAPK activation in a dose-dependent manner. We also showed that TAT-TN13 could significantly inhibit lipopolysaccharide (LPS)-induced expression of macrophage activation-related receptors including CD80, CD86, and MHC II, as well as the transcriptional activation of nuclear factor-kappa B (NF kappaB) and activator protein-1 (AP-1) in RAW 264.7 cells and primary mouse splenic macrophages. Furthermore, TAT-TN13 decreased the LPS-induced production of proinflammatory cytokines and mediators such as tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), nitric oxide (NO), inducible NO synthase (iNOS), and cyclooxygenase 2 (COX-2) in RAW 264.7 cells and mice. These results indicate that TAT-TN13 can inhibit macrophage derived inflammation by inhibiting p38 MAPK activity and might represent a potential novel drug for the treatment of inflammation-related diseases. PMID- 30448176 TI - CD44v-dependent upregulation of xCT is involved in the acquisition of cisplatin resistance in human lung cancer A549 cells. AB - Cisplatin (CDDP) is widely used as an anti-cancer platinum agent but its therapeutic efficacy is limited by acquired drug resistance. To develop a new therapeutic strategy that could overcome this resistance, it is important to characterize CDDP-resistant cancer cells. Here we established human lung cancer A549 cell-derived low- and high-grade CDDP-resistant sublines, termed ACR4 and ACR20 cells, by stepwise increasing CDDP concentrations up to 4 and 20 MUM, respectively. ACR4 and ACR20 cells showed 6- and 16-fold higher resistance to CDDP than A549 cells, respectively. Cell migration, invasion, and sphere formation were significantly decreased, whereas expression of the stem cell marker CD44v was increased in order of A549, ACR4, and ACR20 cells. The expression of the cystine-glutamate transporter xCT, which is encoded by SLC7A11, was upregulated because of the increased cell surface expression of CD44v in ACR20 cells. Treatment with the xCT inhibitor salazosulfapyridine and knockdown of SLC7A11 mRNA by a specific siRNA significantly improved sensitivity to CDDP in A549, ACR4, and ACR20 cells. Thus, our results suggest that CD44v overexpression is not involved in cancer stem cell properties but increases xCT expression, which leads to the acquisition of CDDP-resistance. This mechanism may contribute to the development of a new therapeutic strategy that can overcome resistance. PMID- 30448177 TI - Hydrogen sulfide ameliorated lipopolysaccharide-induced acute lung injury by inhibiting autophagy through PI3K/Akt/mTOR pathway in mice. AB - OBJECTIVE: Recent studies reported that hydrogen sulfide (H2S) is an effective agent for the prevention and treatment of acute lung injury (ALI). But the underlying mechanisms have not been understood clearly. In this study, we explored the possible mechanism from the perspective of autophagy regulation. METHODS: A mouse model of ALI and alveolar type II epithelial cells (MLE-12 cells) injury was induced using lipopolysaccharide (LPS). Expression of Beclin 1 and the conversion of LC3I to LC3II were detected to evaluate the activity of autophagy. Lung histopathological changes, wet/dry (W/D) ratio, pro-inflammatory cytokines TNF-alpha, IL-1beta and protein content in bronchoalveolar lavage fluid (BALF), cell viability and lactic dehydrogenase (LDH) in the culture medium were determined to evaluate the severity of ALI. The activity of PI3K/Akt/mTOR pathway was detected to explore the possible mechanisms involved in the regulation of autophagy by H2S. RESULTS: The expression of Beclin 1 and the conversion of LC3I to LC3II were significantly increased after LPS treatment and reversed by H2S both in vivo and in vitro. Lung histopathological changes, W/D ratio, TNF-alpha, IL-1beta and protein content in BALF induced by LPS were effectively ameliorated by H2S and autophagy inhibitor 3-methyladenine. The in vitro results showed that H2S and 3-methyladenine also attenuated LPS-induced cell viability decrease and LDH release. Furthermore, H2S effectively reversed LPS-induced PI3K/Akt/mTOR signaling pathway inhibition. CONCLUSION: Autophagy inhibition through PI3K/Akt/mTOR pathway was involved in H2S prevention of LPS-induced ALI in mice. PMID- 30448178 TI - Management of incidental discovery of microscopic squamous cell carcinoma in zones of osteoradionecrosis of the mandible. AB - OBJECTIVES: Osteoradionecrosis (ORN) of the mandible is a common complication of head and neck radiotherapy and often requires surgical treatment. Squamous cell carcinoma (SCC) can be exceptionally discovered within zones of ORN on histological examination of the operative specimen. The authors discuss the management of these lesions based on a short patient series. MATERIALS AND METHODS: This single-centre retrospective study was based on patients managed between 2012 and 2014 for ORN with incidental discovery of microscopic SCC. RESULTS: Five patients with incidental discovery of microscopic SCC in a zone of ORN of the mandible were included in this study. The mean time to onset of ORN after the end of radiotherapy for locally advanced SCC of the oral cavity or oropharynx was 42 months. Surgical treatment consisted of marginal or segmental mandibulectomy with free flap reconstruction. No recurrence was observed with a mean follow-up of 35 months [24-46]. CONCLUSION: The incidental discovery of microscopic SCC in a zone of ORN of the mandible is a rare event and has not been reported in the literature. Optimal management cannot be reliably defined due to the lack of data in the literature, but the present study supports careful histological examination of ORN specimens. Treatment must be as conservative as possible to avoid excessively invasive surgery. PMID- 30448179 TI - Factors influencing pupil behaviour during femtosecond laser assisted cataract surgery. AB - AIM: Femtosecond laser assisted cataract surgery is associated with pupillary constriction. This study aims to look at patient and surgical factors predisposing to abnormal pupil behaviour during FLACS. METHODS: This prospective observational study included all patients undergoing FLACS in the Princess of Wales Hospital, Bridgend, UK between February and June 2017. Pupils were measured at three time points; immediately before and after laser pre-treatment, and at the start of surgery. Pupil behaviour during surgery was noted in descriptive terms, patient demographic, co-morbidities, eye measurements, suction on time, shifting time and laser energy levels were recorded. RESULTS: Seventy-three eyes were included. Average patient age was 74.84 +/- 9.1 years. Mean horizontal pupil sizes immediately before and after femto pre-treatment were 7.87 +/- 0.87 mm and 7.7 +/- 0.89 mm respectively (P < 0.0005). Mean horizontal pupil size at the start of surgery was 6.83 +/- 1.43 mm (P < 0.0005). Short capsulotomy-pupil distance (P = 0.01), shallower anterior chamber (P = 0.0012), smaller pre operative pupil size (P = 0.045) and longer suction on time (P = 0.0019) were significantly associated with intra-operative miosis during FLACS. Sustained mydriasis was observed in eyes in whom topical diclofenac was used within 2 h of surgery. CONCLUSIONS: FLACS can result in significant pupil miosis. Eyes particularly at risk are ones with smaller pre-operative pupils and shallower anterior chambers and those subjected to longer suction on time. Well-timed NSAIDs application could be protective against this phenomenon. PMID- 30448180 TI - Light disturbance analysis in the controlled randomized clinical trial MiSight(r) Assessment Study Spain (MASS). AB - PURPOSE: To evaluate the perception of light disturbances (LD) in children wearing Dual Focus (DF) MiSight(r) contact lenses (CLs) for myopia control compared with children wearing single vision spectacles (SV). METHODS: This was a randomized, controlled clinical trial involving subjects aged 8-12 with myopia of -0.75 to -4.00D and astigmatism <1.00D allocated to MiSight(r) study CLs group or control group wearing SV. LD was determined at baseline, 12 and 24 months visit with a validated device, Light Disturbance Analyzer (LDA) to determine the shape, size and regularity of the LD phenomena with parameters of Light Disturbance Index (LDI) Best Fit Circle (BFC) and Standard Deviation between LD and BFC (BFCIrreg.SD). RESULTS: 74 children completed the study, 41 in the CL group and 33 in the SV group. SV group didn't show any significant differences between monocular and binocular LD measurements throughout the study. Binocular BFCRadius was smaller at 24 months visit compared with 12 month visit (p < 0.05) and for BFCIrreg.SD was significantly smaller at 24 month visit compared with baseline (p < 0.05). In MiSight(r) group, binocular and monocular LDI, BFCRadius and BFCIrreg.SD measurements didn't show any significant change between 12 and 24 month visits (p > 0.05). However, monocular BFCIrreg. as well as monocular and binocular BFCIrreg.SD showed a significant decrease at 24 month visit compared with 12 month visit. CONCLUSIONS: DF lenses increase the monocular light disturbance perception compared with a single vision spectacle correction. However, this effect decreased over the follow-up time and presented a significant binocular attenuation effect. PMID- 30448181 TI - Biologically Enhanced Hamstring Tendon Transfer for Treatment of Acute Rupture of Posterior Tibialis Tendon in an Athlete: Case Report. AB - We report the case of a 32-year-old basketball player who presented with an acute flatfoot deformity after performing a unipodal power jump. Rupture of the posterior tibial tendon within the foot was diagnosed and then treated by hamstring tendon transfer combined with application of autologous biologic preparations. The functional outcome at 18 months was good. To our knowledge, this is the first reported case of posterior tibial tendon rupture treated by hamstring tendon transfer. PMID- 30448182 TI - Accurate Osteotomy for the Treatment of a Rare Case of Postaxial Polydactyly of the Foot That Originated From a Deformed Calcaneus Using a 3D-Printed Guiding Plate. AB - Polydactyly is a common congenital deformity of the foot that can be categorized as preaxial, central, or postaxial. Current treatments involve resecting the supernumerary toe(s) and repairing the normal toe(s) and soft tissue. Here, we present the first published report describing a very rare case of polydactyly of the foot, in which the supernumerary toe originated from a deformed calcaneus, which formed an abnormal bony bump. Preoperatively, 3-dimensional (3D) computed tomography reconstruction images revealed the morphology of the deformed toe and calcaneus, and gait analysis showed an abnormal weightbearing zone in the left foot. The 3D printing technology and a specially designed 3D-printed guiding plate were used for osteotomy. Postoperatively, x-ray showed that the calcaneus had a normal shape and surface, whereas gait analysis showed that the left foot was uniformly loaded and the area of pain was eliminated. Our findings should raise awareness among clinicians that a 3D-printed guiding plate is useful in the treatment of such an unusual deformity. PMID- 30448183 TI - Platelet-Rich Plasma Has Better Long-Term Results Than Corticosteroids or Placebo for Chronic Plantar Fasciitis: Randomized Control Trial. AB - Plantar fasciitis is the most common cause of heel pain. Platelet-rich plasma (PRP) is a supersaturated concentration of autologous platelets that augments the natural healing response of fascia. Previous studies have shown the superiority of PRP over corticosteroids (CS) for chronic plantar fasciitis. The aim of this study was to compare the pain and functional outcomes of PRP with CS and placebo injections for the treatment of chronic plantar fasciitis. We conducted a 3-arm randomized controlled trial of 90 patients: PRP (n = 30 patients), CS (n = 30 patients), and placebo (n = 30 patients). The patients were followed at regular intervals until 18 months postinjection using validated instruments. The mean visual analog scale score showed significant improvement in all groups between baseline and 18-month follow-up (PRP: 8.2 vs 2.1; CS: 8.8 vs 3.6; placebo: 8.1 vs 5.4), with CS showing significantly better improvement than PRP in the short term, whereas longer-term PRP was significantly better than CS. The mean Roles and Maudley score showed significant improvement in all groups between baseline and 18-month follow-up (PRP: 1.7 vs 3.7; CS: 1.2 vs 3.1; placebo: 1.2 vs 2.0), with CS showing significantly better improvement than PRP in the short term, whereas longer-term PRP was significantly better than CS. The mean Short Form 12 score showed significant improvement in all groups between baseline and 18-month follow-up (PRP: 55.4 vs 80.2; CS: 56.2 vs 76.2; placebo: 54.1 vs 62.4). We found that all 3 groups showed significant improvement between baseline and end of the follow-up period with regard to pain, function, and general health. The CS arm showed better improvement in the short term, whereas the PRP arm showed better results in the long term. In contrast to previous studies, we found no significant drop-off effect of CS in the long term, which may be owing to background natural healing process of the disease. In summary, both PRP and CS are safe and effective treatment options for chronic plantar fasciitis, showing superior results to placebo treatment. The longer-term results and less reinjection and/or surgery rate of PRP makes it more attractive as an injection treatment option versus CS injection. PMID- 30448184 TI - Use of Metatarsophalangeal Joint Dorsal Subluxation in the Diagnosis of Plantar Plate Rupture. AB - A dorsal drawer exam, also known as a modified Lachman's test, is a common clinical test for plantar plate insufficiency. This disorder presents as a dislocated metatarsophalangeal joint. The aim of this cadaveric case study was to quantify the degree of the plantar plate pathology necessary to correlate with a positive Lachman's test. The second metatarsophalangeal joint was tested on 18 cadaveric lower extremities. Limbs with previous digital surgery or with an obvious digital deformity were excluded from this study. A plantar linear incision over the plantar aspect of the second metatarsophalangeal joint was performed, and the flexor tendons were retracted to expose the plantar plate. After evaluating the plantar plate's integrity and measuring its width, a Lachman's test was then performed under fluoroscopy. The plantar plate was subsequently severed in a serial manner in 2-mm increments. A modified Lachman's test was performed with the different levels of rupture to assess the degree of dislocation. We found that a tear as small as 2 mm, detected in 12 (66.7%) of 18 specimens, produced gross instability in the second metatarsophalangeal joint. We also showed that a simulated plantar plate tear >=4 mm but <6 mm resulted in joint subluxation (positive modified Lachman's test) with a sensitivity of 90.3%. This study reinforces the finding that a modified Lachman's test is a clinical exam that demonstrates high sensitivity in diagnosing plantar plate insufficiency. PMID- 30448185 TI - Hallux Valgus Surgery in the Athlete: Current Evidence. AB - Hallux valgus is a common disorder characterized by a medial deviation of the 1st metatarsal, eventually leading to subluxation and pain of the 1st metatarsophalangeal joint. This can inhibit sports activity. Despite being a common forefoot pathology, debate exists regarding the appropriate surgical approach in the athletic population. Paucity in literature exists with reporting of outcomes of 1st metatarsal procedures leading to best outcomes. This review was able to identify 5 studies of surgical correction of hallux valgus in athletes published to date. The aim is to guide the physician in treating athletes with hallux valgus deformity. Currently, the literature supports distal 1st metatarsal osteotomy (Chevron) with a return to activity of approximately 3 months for mild to moderate deformity, and the Ludloff osteotomy for moderate to severe deformity at a slightly slower time frame of return to sports. At best, the Lapidus procedure allows approximately 80% of patients to return to activity. Studies need to document activity level and return to sport in order to help guide treatment. PMID- 30448186 TI - Hallux Valgus Correction With Rotational Scarf Combined With Adductor Hallucis Tendon Transposition. AB - Hallux valgus affects 23% of people older than 40 years, and there are hundreds of methods dealing with this pathology, which have their advantages and disadvantages. The aim of the present prospective cohort study was to report our experience in treating the patients with hallux valgus and to perform a comparative analysis of the outcomes of the innovative and standard methods of surgical correction. Data on 78 patients (113 feet) with hallux valgus operated on between March 2010 and December 2015 using either an innovative method, which included rotational scarf osteotomy with bone fragment impaction and adductor hallucis tendon reinsertion, or the classical scarf osteotomy were analyzed. X ray examination was performed preoperatively and 3 and 36 months after the procedure. A comparative analysis of the outcomes between the groups was carried out. No significant difference in mean radiographic data (p > .05) was found between these 2 groups preoperatively and 3 months after surgery. Nevertheless, the mean intermetatarsal angle 36 months after surgery in standard and innovative groups was 9.7 +/- 0.7 degrees and 9.0 +/- 0.8 degrees (p < .01) and the mean metatarsophalangeal angle 13.6 +/- 0.9 degrees and 13.2 +/- 1.1 degrees (p = .01), respectively. The innovative method of surgical correction of hallux valgus was seen to produce improved radiographic results. PMID- 30448187 TI - Reliability and Validity of the Turkish Version of Foot and Ankle Ability Measure for Patients With Chronic Ankle Disability. AB - The Foot and Ankle Ability Measure is a valid, reliable, and widely used self reported questionnaire for the foot. It has been adapted and validated for a Turkish-speaking population. The purpose of this study was to provide evidence for validity and reliability of the Turkish version of the Foot and Ankle Measure (FAAM-T) in patients with chronic ankle instability (CAI). A total of 316 patients with CAI were enrolled. The internal consistency and test-retest reliability were evaluated. Validity was examined using correlations with the Short Form Health Survey version 2.0 (SF-36v2) questionnaire. Cronbach's alpha scores were 0.94 and 0.96 for the the FAAM-T ADL (Activities of Daily Living) and FAAM-T Sports subscales, respectively, indicating high internal consistency. For the second administration, Cronbach's alpha was found to be 0.96 for both subscales of the FAAM-T. The test-retest reliability of the FAAM-T was very high for both subscales with an intraclass correlation coefficient of 0.97 and 0.94, respectively (p < .001). The standard error of the mean and minimal detectable change were determined to be 2.5 and 6.7 for the FAAM-T ADL and 6.9 and 18.5 for the FAAM-T Sport. The FAAM-T ADL and Sport subscales were strongly correlated with the SF-36v2 PF (physical functioning; r = 0.51, r = 0.40, respectively; p = .001) and SF-36v2 PCS (physical component scale; r = 0.64, r = 0.55, respectively; p = .001). The weakest associations between the FAAM-T ADL and Sport and the SF-36v2 were noted for the mental health subscale (r = 0.08 and r = 0.03) and the SF-36v2 MCS (mental component scale; r = .05 and r = .006, respectively). This study provides evidence for validity, internal consistency, and test-retest reliability for the FAAM-T to evaluate patients with CAI. PMID- 30448188 TI - Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells. AB - Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC50 of 0.6 ug/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC50 of 20 nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC50 of only 4.4 uM, a semisynthetic pyrazole-derivative P5b, has ~10-fold improved potency (IC50, 0.49 MUM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G0-G1 phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents. PMID- 30448189 TI - Design, synthesis and in vitro evaluation of stilbene derivatives as novel LSD1 inhibitors for AML therapy. AB - LSD1 is implicated in a number of malignancies and has emerged as an exciting target. As part of our sustained efforts to develop novel reversible LSD1 inhibitors for epigenetic therapy of cancers, in this study, we reported a series of stilbene derivatives and evaluated their LSD1 inhibitory activities, obtaining several compounds as potent LSD1 inhibitors with IC50 values in submicromolar range. Enzyme kinetics studies and SPR assay suggested that compound 8c, the most active LSD1 inhibitor (IC50 = 283 nM), potently inhibited LSD1 in a reversible and FAD competitive manner. Consistent with the kinetics data, molecular docking showed that compound 8c can be well docked into the FAD binding site of LSD1. Flow cytometry analysis showed that compound 8c was capable of up-regulating the expression of the surrogate cellular biomarker CD86 in THP-1 human leukemia cells, suggesting the ability to block LSD1 activity in cells. Compound 8c showed good inhibition against THP-1 and MOLM-13 cells with IC50 values of 5.76 and 8.34 MUM, respectively. Moreover, compound 8c significantly inhibited colony formation of THP-1 cells dose dependently. PMID- 30448190 TI - Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites. AB - The function of acid ceramidase (ACDase), whose congenital deficiency leads to Farber disease, has been recognized to be vital to tumor cell biology, and inhibition of its activity may be beneficial in cancer therapy. Therefore, manipulation of the activity of this enzyme may have significant effect, especially on cancer cells. LCL521, Di-DMG-B13, is a lysosomotropic inhibitor of ACDase. Here we define complexities in the actions of LCL521 on ACDase. Systematic studies in MCF7 cells showed dose and time divergent action of LCL521 on ACDase protein expression and sphingolipid levels. Low dose of LCL521 (1 uM) effectively inhibited ACDase in cells, but the effects were transient. A higher dose of LCL521 (10 uM) caused a profound decrease of sphingosine and increase of ceramide, but additionally affected the processing and regeneration of the ACDase protein, with biphasic and reversible effects on the expression of ACDase, which paralleled the long term changes of cellular sphingosine and ceramide. Finally, the higher concentrations of LCL521 also inhibited Dihydroceramide desaturase (DES-1). In summary, LCL521 exhibits significant effects on ACDase in a dose and time dependent manner, but dose range and treatment time need to be paid attention to specify its future exploration on ACDase targeted cancer treatment. PMID- 30448191 TI - Screening and Audit as Service-Level Strategies to Support Implementation of Australian Guidelines for Cancer Pain Management in Adults: A Feasibility Study. AB - BACKGROUND: Pain in people with cancer is common but often under-recognized and under-treated. Guidelines can improve the quality of pain care, but need targeted strategies to support implementation. AIM: To test the feasibility of two service level strategies for supporting guideline implementation: a screening system and medical record audit. DESIGN: Multimethods. SETTING: One oncology outpatient service, and one palliative care outpatient and inpatient service. PARTICIPANTS: Patients with advanced cancer. METHODS: Patients were screened in the waiting room with a modified version of the Edmonton Symptom Assessment System-revised either electronically or in paper-based format. Feasibility indicated the percentage of patients successfully screened from the total number attending the services. An audit assessed adherence to key indicators of pain assessment and management. Feasibility thresholds were set at 75% incidence for screening and a median of 30 minutes per patient for audit. RESULTS: Of 452 patient visits, 95% (n = 429) were successfully screened, 34% (n = 155) electronically and 61% (n = 274) paper-based. Electronic pain screening was technically challenging and time intensive for nurses. Thirty-one patients consented to have their records audited. The median audit time was 37.5 minutes (range 10-120 minutes). Variability arose from the number and type of record (outpatient or inpatient). Adherence to indicators varied from 63% (pain assessment at first presentation) to 94% (regular pain assessment and medication prescribed at regular intervals). CONCLUSIONS: This study confirmed the need to implement evidence-based guidelines for cancer pain and generated useful insights into the feasibility of pain screening and audit. PMID- 30448192 TI - Lower-limb muscle function during sidestep cutting. AB - To investigate lower-limb muscle function during sidestep cutting, prior studies have analysed electromyography (EMG) data together with three dimensional motion analysis. Such an approach does not directly quantify the biomechanical role of individual lower-limb muscles during a sidestep cut. This study recorded three dimensional motion analysis, ground reaction force (GRF) and EMG data for eight healthy males executing an unanticipated sidestep cut. Using a musculoskeletal modelling approach, muscle function was determined by computing the muscle contributions to the GRFs and lower-limb joint moments. We found that bodyweight support (vertical GRF) was primarily provided by the vasti, gluteus maximus, soleus and gastrocnemius. These same muscles, along with the hamstrings, were also primarily responsible for modulating braking and propulsion (anteroposterior GRF). The vasti, gluteus maximus and gluteus medius were the key muscles for accelerating the centre-of-mass towards the desired cutting direction by generating a medially-directed GRF. Our findings have implications for designing retraining programs to improve sidestep cutting technique. PMID- 30448193 TI - Supplemental parenteral nutrition improves immunity with unchanged carbohydrate and protein metabolism in critically ill patients: The SPN2 randomized tracer study. AB - BACKGROUND & AIMS: Individualized supplemental parenteral nutrition (SPN) providing measured energy expenditure from day 4 reduced infectious complications in a previous study including 305 intensive care (ICU) patients. The study aimed at investigating the metabolic, and immune responses underlying the clinical response of the previous trial. METHODS: Randomized controlled trial enrolling 23 critically ill patients on day 3 (D3) of admission to the ICU who were fed less than 60% of their energy target by the enteral nutrition (EN) alone: allocation to either continued EN or to SPN to a target validated by indirect calorimetry. Protein and glucose metabolism (primary endpoint) were investigated with tracer isotopes on D4 and D9. Secondary endpoints: 1) immune response, investigated in serum and in stimulated peripheral blood mononuclear cells (PMBC), by dosing a panel of cytokines (infectious complications were recorded), and 2) Muscle mass was assessed by ultrasound of the thigh. RESULTS: Comparable at baseline, the SPN group (n = 11) received more energy (median 24.3 versus 17.8 kcal/kg/day: p < 0.001) and proteins (1.11 versus 0.69 g/kg/day: p < 0.001) than the control group during the five days' intervention, resulting in a less negative energy balance by D9 (p = 0.0027). Net protein breakdown and Glucose kinetics on D9 did not differ, within or between groups. In agreement with a decrease in infection rate, immune response in the SPN group showed decreased serum IL-6 (p = 0.024), IL 1beta, IL-10 levels and TNF-alpha secretion by PBMC (p = 0.018) at D9. Muscle mass loss from D4 to D15 tended to be less in the SPN group (-16% versus -23%: p = 0.06). Clinical course by D28 did not differ. CONCLUSIONS: Feeding patients to cover an individualised measured energy target with SPN from D4 to cover needs, was associated with improved immunity, less systemic inflammation and a trend to less muscle mass loss. CLINICAL TRIAL REGISTRY: NCT02022813 at https://clinicaltrials.gov/. PMID- 30448194 TI - Prevalence of malnutrition using harmonized definitions in older adults from different settings - A MaNuEL study. AB - BACKGROUND & AIMS: Malnutrition is widespread among older people and related to poor outcome. Reported prevalences vary widely, also because of different diagnostic criteria used. This study aimed to describe prevalences in several populations of older persons in different settings using harmonized definitions. METHODS: Available studies within the Joint Programming Initiative (JPI) Knowledge Hub 'Malnutrition in the Elderly' (MaNuEL) were used to calculate and compare prevalences of malnutrition indicators: low BMI (<20 kg/m2; age-specific BMI <20 if age 65-<70 and <22 kg/m2 if age >=70 years), previous weight loss (WL), moderate and severe decrease in food intake, and combined BMI <20 kg/m2 and/or WL in participants aged >=65 years. RESULTS: Fifteen samples with in total 5956 participants (59.3% women) were included: 7 consisting of community-dwelling persons, 2 studies in geriatric day hospitals, 3 studies in hospitalized patients and 3 in nursing homes. Mean age of participants ranged between 67 and 87 years. Up to 4.2% of community-dwelling persons had a BMI <20 kg/m2, 1.6 and 9% of geriatric day hospital patients, 4.5-9.4% of hospital patients and 3.8-18.2% of nursing home residents. Using age-specific cut-offs doubled these prevalences. WL was reported in 2.3-10.5% of community-dwelling persons, 6% and 12.6% of geriatric day hospital patients, 5-14% of hospitalized patients and 4.5-7.7% of nursing home residents. Severe decrease in food intake was recorded in up to 9.6% of community-dwelling persons, 1.5% and 12% of geriatric day hospital patients, 3.4-34.2% of hospitalized patients and 1.5-8.2% of nursing home residents. The criteria age-specific BMI and WL showed opposing prevalences across all settings. Compared to women, low BMI and moderate decrease in food intake showed low prevalences in men but similar prevalences were observed for weight loss and severe decrease in food intake. In half of the study samples, participants in a younger age group had a higher prevalence of WL compared to those of an older age group. Prevalence of BMI <20 kg/m2 and WL at the same time did not exceed 2.6% in all samples. The highest prevalences were observed based on combined definitions when only one of the three criteria had to be present. CONCLUSIONS: Prevalences for different criteria vary between and within the settings which might be explained by varying functional status. The criteria used strongly affect prevalence and it may be preferable to look at each criterion separately as each may indicate a nutritional problem. PMID- 30448195 TI - The Cost-effectiveness of Corticosteroids for the treatment of Community-Acquired Pneumonia. AB - BACKGROUND: The use of corticosteroids as adjunct treatment for community acquired pneumonia (CAP) is associated with potential clinical benefits and the aim of this study was to evaluate the cost-effectiveness of this approach. METHODS: We constructed a decision-analytic model comparing the use of corticosteroids+antibiotics to that of placebo+antibiotics for the treatment of CAP. Cost-effectiveness was determined by calculating deaths averted and incremental cost-effectiveness ratios (ICER). Uncertainty was addressed by plotting cost-effectiveness planes and acceptability curves for various willingness-to-pay thresholds. RESULTS: In the base-case analysis, corticosteroids with antibiotics resulted in savings of $142,795 per death averted (ICER: $-142,795/death averted). In the probabilistic analysis, at a willingness-to-pay of $50,000, corticosteroids with antibiotics had a 86.4% chance of being cost-effective compared to placebo with antibiotics. In cost effectiveness acceptability curves, the corticosteroids+antibiotics strategy was cost-effective in 87.6% to 94.3% of simulations compared to the placebo with antibiotics strategy for a willingness-to-pay ranging from $0 to $50,000. In patients with severe CAP (PSI classes IV/V) the corticosteroids+antibiotics strategy resulted in savings of $70,587 and had a 82.6% chance of being cost effective compared to the placebo+antibiotics strategy. CONCLUSIONS: The use of corticosteroids with antibiotics is a cost-effective strategy and results in considerable health care cost-savings, especially among patients with severe CAP (PSI classes IV/V). PMID- 30448196 TI - RNA-Modified T Cells Mediate Effective Delivery of Immunomodulatory Cytokines to Brain Tumors. AB - With the presence of the blood-brain barrier (BBB), successful immunotherapeutic drug delivery to CNS malignancies remains a challenge. Immunomodulatory agents, such as cytokines, can reprogram the intratumoral microenvironment; however, systemic cytokine delivery has limited access to the CNS. To bypass the limitations of systemically administered cytokines, we investigated if RNA modified T cells could deliver macromolecules directly to brain tumors. The abilities of T cells to cross the BBB and mediate direct cytotoxic killing of intracranial tumors make them an attractive tool as biological carriers. Using T cell mRNA electroporation, we demonstrated that activated T cells can be modified to secrete granulocyte macrophage colony-stimulating factor (GM-CSF) protein while retaining their inherent effector functions in vitro. GM-CSF RNA-modified T cells effectively delivered GM-CSF to intracranial tumors in vivo and significantly extended overall survival in an orthotopic treatment model. Importantly, GM-CSF RNA-modified T cells demonstrated superior anti-tumor efficacy as compared to unmodified T cells alone or in combination with systemic administration of recombinant GM-CSF. Anti-tumor effects were associated with increased IFN-gamma secretion locally within the tumor microenvironment and systemic antigen-specific T cell expansion. These findings demonstrate that RNA modified T cells may serve as a versatile platform for the effective delivery of biological agents to CNS tumors. PMID- 30448197 TI - Efficacy of Multi-exon Skipping Treatment in Duchenne Muscular Dystrophy Dog Model Neonates. AB - Duchenne muscular dystrophy (DMD) is caused by mutations in DMD, which codes for dystrophin. Because the progressive and irreversible degeneration of muscle occurs from childhood, earlier therapy is required to prevent dystrophic progression. Exon skipping by antisense oligonucleotides called phosphorodiamidate morpholino oligomers (PMOs), which restores the DMD reading frame and dystrophin expression, is a promising candidate for use in neonatal patients, yet the potential remains unclear. Here, we investigate the systemic efficacy and safety of early exon skipping in dystrophic dog neonates. Intravenous treatment of canine X-linked muscular dystrophy in Japan dogs with a 4-PMO cocktail resulted in ~3%-27% in-frame exon 6-9 skipping and dystrophin restoration across skeletal muscles up to 14% of healthy levels. Histopathology was ameliorated with the reduction of fibrosis and/or necrosis area and centrally nucleated fibers, significantly in the diaphragm. Treatment induced cardiac multi exon skipping, though dystrophin rescue was not detected. Functionally, treatment led to significant improvement in the standing test. Toxicity was not observed from blood tests. This is the first study to demonstrate successful multi-exon skipping treatment and significant functional improvement in dystrophic dogs. Early treatment was most beneficial for respiratory muscles, with implications for addressing pulmonary malfunction in patients. PMID- 30448198 TI - The Eagle Effect and Antibiotic-Induced Persistence: Two Sides of the Same Coin? AB - The Eagle effect describes a phenomenon in which bacteria or fungi exposed to concentrations of antibiotic higher than an optimal bactericidal concentration (OBC) have paradoxically improved levels of survival than at the OBC due to a decreased net rate of cell death. Despite extensive observational reports of this effect in different microorganisms, its underlying mode of action is not well understood. Although aspects of the Eagle effect resemble persistence, there is strong evidence that these phenomena are substantially different phenotypic responses to antibiotic treatment. We present an overview of the microorganism and antimicrobial combinations in which the Eagle effect has been observed. Proposed underlying mechanism(s) are assessed, and the Eagle effect and microbial persistence are compared and contrasted. The clinical relevance of the Eagle effect is reviewed, incorporating evidence from experimental in vitro and in vivo studies, as well as clinical reports. PMID- 30448199 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 30448200 TI - The Prevalence of Mitral Valve Prolapse in Panic Disorder: A Meta-Analysis. AB - BACKGROUND: Although most studies have suggested that mitral valve prolapse (MVP) is more prevalent in patients with panic disorder (PD) than in healthy controls, there is a substantial uncertainty in the rates of MVP across studies. OBJECTIVE: To investigate, through systematic review and meta-analysis, the relative risk of MVP in patients with PD compared to controls. METHODS: Embase, Proquest, Pubmed, and Google Scholar electronic databases were searched up to September 2018. All studies published in peer-reviewed journals, which included both PD and controls groups, were selected. Events (presence of MVP) and nonevents (absence of MVP) in PD and control groups were recorded. The main outcome was the measure of relative risk (RR) pooled with 95% confidence intervals, using fixed-effects model. Heterogeneity, small publication effect, and publication bias were evaluated. RESULTS: Fourteen studies, including 1146 participants, met eligibility criteria. There was no significant heterogeneity or publication bias. The prevalence of MVP in PD and healthy controls was 27.20% and 9.21%, respectively. Patients with PD had a significantly increased relative risk of MVP compared to controls in the pooled sample (RR = 2.469, 95% confidence interval = 1.848-3.300). Age did not significantly modify the RR. CONCLUSIONS: MVP is significantly more prevalent in patients with PD than in controls. This meta-analysis of published studies is sufficient to establish an association between PD and MVP; nevertheless, it is not clear that the association is specific to PD. Patients with PD should be evaluated for MVP to decrease possible negative adverse consequences of MVP. PMID- 30448201 TI - Heteroatom-doped carbon dots based catalysts for oxygen reduction reactions. AB - Carbon materials doped with heteroatoms are a class of cost-effective and stable electrocatalysts for oxygen reduction reactions (ORR), whose activities are mainly based on the heteroatom-related active sites. Besides the widely reported one-dimensional carbon nanotubes and two-dimensional graphene materials, carbon dots (CDs), as a new kind of zero-dimensional carbon materials, exhibit a range of unique structures and promising catalytic activities for ORR. In order to optimize the complex conditions of carbon-based catalysts, composites consisting of doped CDs and reduced graphene oxide (rGO) (designated as CD/rGO) are prepared hydrothermally, in comparison with directly doped rGO. All produced composites outperform their corresponding directly doped rGO counterparts in ORR measurements. It is noted that nitrogen and sulfur co-doped samples perform better than those doped by individual N or S. Mechanistic relationships between the ORR catalytic activities and the catalyst features are proposed, including type, location, bonding, fraction and synergistic effects of dopants, as well as the composition and structure of the carbon substrates. It is apparent that doping heteroatoms and constructing carbon substrates play a synergistic role in yielding high-performance carbon based catalysts. PMID- 30448202 TI - Self-reported walking difficulty and knee osteoarthritis influences limb dynamics and muscle co-contraction during gait. AB - Knee osteoarthritis (OA) gait is characterized by simultaneous flexor and extensor use, or co-contraction. Co-contraction can stabilize and redirect joint forces. However, co-contraction can push and pull on the femur and tibia that exacerbate OA symptoms and make walking difficult. Such movements are quantifiable by limb dynamics (i.e., linear acceleration and jerk); thus, this study examines limb dynamics and its relationship with co-contraction and OA related walking difficulty. Three groups of age-and-sex-matched subjects with and without OA and walking difficulty (N = 13 per group) walked with electromyography (EMG) on the knee extensors and flexors and inertial measurement units (IMUs) at the femur and tibia. We calculated co-contraction from antagonistic EMG signals and linear acceleration and its derivative jerk from IMUs. We determined group differences using one-way ANOVAs, nonparametric equivalence, and effect sizes, and main and interaction effects of walking difficulty with regression modeling. Medium effect sizes and differences for femoral acceleration (d = 0.64; P = .02) and jerk (d = 0.51; P = .01) were observed between with and without knee OA. Medium to large effect sizes (r = 0.33 to 0.51 and d = 0.81 to 0.97) and differences (P = .01 to 0.05) for tibial acceleration and jerk were obsevered between with and without walking difficulty. Walking difficulty moderated the relationship between tibial jerk and co-contraction (p < .05). Tibial jerk differences were observed based on walking difficulty. The significant interaction effect suggested that walking difficulty explained the relationship between limb dynamics and co-contraction. Perhaps co-contraction levels used by those with knee OA and no walking difficulty are optimal as compared to those with walking difficulty. PMID- 30448203 TI - Support for and interest in alternative models of medication abortion provision among a national probability sample of U.S. women. AB - OBJECTIVE: The objective was to assess women's personal interest in and support for three alternative models of medication abortion (MA) provision. STUDY DESIGN: Using an online survey of a U.S. national, probability-based representative sample of women ages 18-49, we gauged personal interest in and general support for three alternative models for accessing abortion pills: (1) in advance from a doctor for future use, (2) over-the-counter (OTC) from a drugstore and (3) online without a prescription. We conducted multivariable analyses to identify characteristics associated with support for these provision models. RESULTS: Fifty percent (n=7022) of eligible women invited completed the survey. Nearly half (49%) supported and 30% were personally interested in one or more of the three access models; 44% supported advance provision, 37% supported OTC access, and 29% supported online access. Common advantages reported for advance provision, OTC and online access included privacy (49%, 29% and 46%, respectively), convenience (38%, 44% and 38%) and being able to end the pregnancy earlier (48%, 40% and 29%). Common disadvantages included concern that women might take the pills incorrectly (55%, 53% and 57%), not seeing a clinician before the abortion (52%, 54% and 53%) and safety (42%, 43% and 60%). History of abortion and experiencing barriers accessing reproductive health services were associated with greater support for the alternative models. CONCLUSION: Women are interested in and support alternative models of MA provision, in particular, advance provision. However, they also reported concerns about incorrect pill use and not seeing a clinician beforehand. IMPLICATIONS: Offering women more choices in how they access medication abortion, including options where they can safely self-manage their own care, has the potential to expand access to care. PMID- 30448204 TI - Atrioventricular nodal reentrant tachycardia and cannon A waves: A case report. AB - Regular, narrow complex tachycardia with a ventricular rate around 150 can be challenging. The differential includes sinus tachycardia, atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular reentrant tachycardia (AVRT), and atrial tachycardia (focal or macro re-entrant - i.e. flutter). We present a case of a 90-year-old woman presenting with shortness of breath in which the ECG was not diagnostic, but the presence of regular neck pulsations helped secure the diagnosis of AVNRT. In AVNRT, atria and ventricular contractions occur nearly simultaneously. When the right atrium attempts to contract against a closed tricuspid valve, an abrupt increase in venous pressure is encountered. This increase in venous pressure manifests as prominent neck pulsations termed "cannon A waves." The patient was ultimately successfully electrically cardioverted resulting in resolution of her presenting symptoms, neck pulsations, and tachycardia. While irregular "cannon A waves" can be seen in conditions of AV dissociation, regular "cannon A waves" strongly favor the diagnosis of AVNRT. PMID- 30448205 TI - Real-world cell phone radiofrequency electromagnetic field exposures. AB - In 2011 the International Agency for Research on Cancer classified radiofrequency electromagnetic fields (RF EMF) from cell phones as possibly carcinogenic to humans. The National Toxicology Program and the Ramazzini Institute have both reported that RF EMF exposures significantly increase gliomas and Schwannomas of the heart in rodent studies. Recent studies indicate that RF EMF exposures from cell phones have negative impacts on animal cells and cognitive and/or behavioral development in children. Case-control epidemiological studies have found evidence for cell phone use and increased risk for glioma and localization of the glioma associated with the consistent exposure site of regular cell phone use. Understanding the exposure level, or power density, from RF EMF emitted by cell phones under real-world usage and signal reception conditions, as distinct from the published measurements of maximum Specific Absorption Rate values, may help cell phone users decide whether to take behavioral steps to reduce RF EMF exposure. Exposure measurements were conducted on phone models from four major mobile network operators (MNOs) in the USA for calls received under strong and weak reception signal conditions, near the phone face and at several distances up to 48 cm. RF EMF exposure from all phones was found to be greater under weak (1-2 display bars) than under strong (4-5 display bars) reception signal conditions by up to four orders of magnitude. Notably, RF EMF exposure levels under weak reception signal conditions at a distance of 48 cm from the phone were similar to or greater than those detected under strong reception signal conditions at a distance of 4 cm. Under weak reception signal conditions, power density reductions of up to 90% occurred at 16 cm typical for speaker phone or texting over the 4 cm near-ear exposure. The results of this investigation of second generation (2G) technology suggest that reduced and precautionary use of cell phones under weak signal conditions could lower a user's RF EMF exposure by up to several orders of magnitude. Bluetooth headset power density exposures were 10 400 times lower than those of the cell phones to which they were connected and dependent on the headset rather than the connected phone. The results of this study informed the development of public health guidance regarding cell phone use. PMID- 30448206 TI - Sporadic pancreatic neuroendocrine tumor: Surgery of the primary tumor. AB - The management of patients with sporadic pancreatic neuroendocrine tumors (PNET) is multi-disciplinary and often, multimodal. Surgery has a large part in treatment because it is the only potentially curative therapeutic modality if resection can be complete. The update reviews the operative indications and the different surgical techniques available (including parenchymal-sparing surgery) to treat the primary lesion according to patient status, preoperative work-up and whether the tumor is functioning or not. The place of observation for "small" non functional sporadic PNET is also discussed. PMID- 30448207 TI - Correlations between self-reported and psychiatrist assessments of well-being among patients with schizophrenia. PMID- 30448208 TI - Architects meets Repairers: The interplay between homeobox genes and DNA repair. AB - Homeobox genes are widely considered the major protagonists of embryonic development and tissue formation. For the past decades, it was established that the deregulation of these genes is intimately related to developmental abnormalities and a broad range of diseases in adults. Since the proper regulation and expression of homeobox genes are necessary for a successful developmental program and tissue function, their relation to DNA repair mechanisms become a necessary discussion. However, important as it is, studies focused on the interplay between homeobox genes and DNA repair are scarce, and there is no critical discussion on the subject. Hence, in this work, I aim to provide the first review of the current knowledge of the interplay between homeobox genes and DNA repair mechanisms, and offer future perspectives on this, yet, young ground for new researches. Critical discussion is conducted, together with a careful assessment of each reviewed topic. PMID- 30448209 TI - Outcomes following laparoscopic Roux-en-Y gastric bypass (LRYGB) vary by sex: Analysis of 83,059 women and men with morbid obesity. AB - BACKGROUND: Previously we have reported variation in pre-operative clinical characteristics between women and men undergoing laparoscopic roux-en-Y gastric bypass (LRYGB). However, variation by sex in post-operative outcomes following LRYGB has not been investigated. METHODS: Pre-operative data was compared to follow-up data at 12 months after surgery on 83,059 patients from the Surgical Review Corporation's BOLD database. Data included age, weight, BMI, and 31 obesity-related medical conditions. RESULTS: Men had increased weight, actual weight lost, and BMI. Women had higher rates of gastrointestinal and mental health disorders. Men failed to resolve cardiopulmonary/vascular and metabolic derangements, abdominal hernia, and were more functionally impaired than women. CONCLUSIONS: Overall, women may benefit more from LRYG than men, as their pre operative conditions showed greater improvement at 12 months post-op. This advance knowledge may aid LRYGB planning and improve outcomes. PMID- 30448210 TI - Impact of the Affordable Care Act on elective general surgery clinical practice. AB - BACKGROUND: The Affordable Care Act (ACA) dramatically changed the healthcare system in the United States. This study aims to analyze the impact of the ACA on general surgery clinic visits and resultant procedures. METHODS: A retrospective review was conducted on new patients who presented to the elective general surgery clinic at an academic medical center between Jan. 1, 2012 and Dec. 31, 2015. Based on the open enrollment start date of Jan.1, 2014 patients were divided into pre-ACA and post-ACA periods. Data on demographics, type of insurance, missed appointments, and elective surgical procedures performed were collected. RESULTS: Medi-Cal insurance coverage increased post-ACA from 20.9% to 56.7%, p < 0.001; self-pay status went from 9.8% to 0%. There were 296 (35.4%) surgical procedures performed pre-ACA and 347 (37.1%) post-ACA (p = 0.445). Missed clinic visits decreased after implementation of the ACA, with 26.8% no shows pre-ACA and 20.7% no-shows post-ACA (p = 0.003). CONCLUSION: The ACA had a profound impact on the general surgery clinic with fewer uninsured patients, fewer no-shows and a modest increase in the number of procedures performed. SUMMARY: In 2014 the Affordable Care Act mandate was implemented. This legislation impacted healthcare by significantly decreasing the number of uninsured patients and increasing overall volume in one general surgery clinic. PMID- 30448211 TI - Realistic Exposure Study Assists Risk Assessments of ZnO Nanoparticle Sunscreens and Allays Safety Concerns. AB - The findings of a new study by Mohammed et al. show that after repeated hourly or daily topical applications typically used for sunscreens, zinc oxide nanoparticles do not penetrate into the viable epidermis or cause toxicity in human skin. This important study confirms that the known benefits of using zinc oxide nanoparticles in sunscreen clearly outweigh the perceived risks of using nanosunscreens. PMID- 30448212 TI - Support for the Safe Use of Zinc Oxide Nanoparticle Sunscreens: Lack of Skin Penetration or Cellular Toxicity after Repeated Application in Volunteers. AB - Zinc oxide is a widely used broad-spectrum sunscreen, but concerns have been raised about the safety of its nanoparticle (NP) form. We studied the safety of repeated application of agglomerated zinc oxide (ZnO) NPs applied to human volunteers over 5 days by assessing the skin penetration of intact ZnO-NPs and zinc ions and measuring local skin toxicity. Multiphoton tomography with fluorescence lifetime imaging microscopy was used to directly visualize ZnO-NP skin penetration and viable epidermal metabolic changes in human volunteers. The fate of ZnO-NPs was also characterized in excised human skin in vitro. ZnO-NPs accumulated on the skin surface and within the skin furrows but did not enter or cause cellular toxicity in the viable epidermis. Zinc ion concentrations in the viable epidermis of excised human skin were slightly elevated. In conclusion, repeated application of ZnO-NPs to the skin, as used in global sunscreen products, appears to be safe, with no evidence of ZnO-NP penetration into the viable epidermis nor toxicity in the underlying viable epidermis. It was associated with the release and penetration of zinc ions into the skin, but this did not appear to cause local toxicity. PMID- 30448213 TI - Arterial stiffness and white matter integrity in the elderly: A diffusion tensor and magnetization transfer imaging study. AB - BACKGROUND AND PURPOSE: The stiffness of large arteries and increased pulsatility can have an impact on the brain white matter (WM) microstructure, however those mechanisms are still poorly understood. The aim of this study was to investigate the association between central artery stiffness, axonal and myelin integrity in 54 cognitively unimpaired elderly subjects (65-75 years old). METHODS: The neuronal fiber integrity of brain WM was assessed using diffusion tensor metrics and magnetization transfer imaging as measures of axonal organization (Fractional anisotropy, Radial diffusivity) and state of myelination (Myelin volume fraction). Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Statistical analyses included 4 regions (the corpus callosum, the internal capsule, the corona radiata and the superior longitudinal fasciculus) which have been previously denoted as vulnerable to increased central artery stiffness. RESULTS: cfPWV was significantly associated with fractional anisotropy and radial diffusivity (p < 0.05, corrected for multiple comparisons) but not with myelin volume fraction. Findings from this study also show that improved executive function performance correlates with Fractional anisotropy positively (p < 0.05 corrected) as well as with myelin volume fraction and radial diffusivity negatively (p < 0.05 corrected). CONCLUSIONS: These findings suggest that arterial stiffness is associated with axon degeneration rather than demyelination. Controlling arterial stiffness may play a role in maintaining the health of WM axons in the aging brain. PMID- 30448214 TI - Partial liquid ventilation for bronchopulmonary dysplasia: Visualizing ventilation patterns on chest radiographs. PMID- 30448215 TI - Use of syringe filters to isolate Campylobacter species from stool samples. AB - We investigated the efficacy of syringe filters and membrane filters with different pore sizes for recovering Campylobacter. A syringe filter with a 0.45 MUm pore size achieved the highest recovery rate (0.29%), while polycarbonate membrane filters with pore sizes of 0.6 MUm and 0.4 MUm recovered less Campylobacter, at 0.01% and 1.3 * 10-3%, respectively. We also tested 601 diarrheic stool samples using membrane and syringe filtration methods. A total of 23 Campylobacter jejuni/coli were isolated from both syringe and membrane filtration; nine and one were isolated from only syringe or only membrane filtration, respectively (p < .05). The syringe filtration technique was better than membrane filtration for the isolation of Campylobacter. PMID- 30448216 TI - Morphokinetic characteristics of embryos derived from in-vitro-matured oocytes and their in-vivo-matured siblings after ovarian stimulation. AB - RESEARCH QUESTION: Does delayed maturation of aspirated metaphase I (MI) oocytes, completed in vitro, adversely affect early embryo development? DESIGN: Time-lapse microscopy was used to compare morphokinetic variables between embryos derived from oocytes with delayed maturation after ovarian stimulation and from in-vivo matured metaphase II (MII) sibling oocytes from the same IVF and intracytoplasmic sperm injection cycle. RESULTS: A total of 1545 injected oocytes in 169 cycles from 149 patients were included. The in-vitro-matured oocytes had lower normal fertilization rates than the MII aspirated oocytes (50.2% versus 68.0%; P < 0.001). Early key developmental events were significantly delayed in the normally fertilized in-vitro-matured compared with in-vivo-matured oocytes (polar body extrusion: 5.4 +/- 3 versus 3.9 +/- 1.8 h; P < 0.001; pronuclear fading: 27.2 +/- 4.7 versus 25.1 +/- 4.2 h; P < 0.001, respectively) and synchrony of the second cell cycle was adversely affected. The proportions of embryos with optimal second cell cycle length and second cell cycle were similar but with fewer top-quality embryos, based on an algorithm, for the delayed in-vitro-matured oocytes compared with their in-vivo-matured sibling oocytes (14% versus 29.1%; P < 0.001). CONCLUSIONS: Embryos derived from oocytes that failed to mature in-vivo in standard treatment after ovarian stimulation may show a different morphokinetic profile from their sibling oocytes aspirated at the MII stage after completing maturation in-vivo. PMID- 30448217 TI - An enriched granger causal model allowing variable static anatomical constraints. AB - The anatomical connectivity constrains but does not fully determine functional connectivity, especially when one explores into the dynamics over the course of a trial. Therefore, an enriched granger causal model (GCM) integrated with anatomical prior information is proposed in this study, to describe the dynamic effective connectivity to distinguish the depression and explore the pathogenesis of depression. In the proposed frame, the anatomical information was converted via an optimized transformation model, which was then integrated into the normal GCM by variational bayesian model. Magnetoencephalography (MEG) signals and diffusion tensor imaging (DTI) of 24 depressive patients and 24 matched controls were utilized for performance comparison. Together with the sliding windowed MEG signals under sad facial stimuli, the enriched GCM was applied to calculate the regional-pair dynamic effective connectivity, which were repeatedly sifted via feature selection and fed into different classifiers. From the aspects of model errors and recognition accuracy rates, results supported the superiority of the enriched GCM with anatomical priors over the normal GCM. For the effective connectivity with anatomical priors, the best subject discrimination accuracy of SVM was 85.42% (the sensitivity was 87.50% and the specificity was 83.33%). Furthermore, discriminative feature analysis suggested that the enriched GCM that detect the variable anatomical constraint on function could better detect more stringent and less dynamic brain function in depression. The proposed approach is valuable in dynamic functional dysfunction exploration in depression and could be useful for depression recognition. PMID- 30448218 TI - Immunophenotypic profile as predictor of prognosis in advanced ovarian carcinoma. AB - Although proteomic profiles for ovarian epithelial carcinoma (OECa) have been widely investigated, no single marker or set of predictors has been clinically implemented mainly because their reliability and validity have not yet been well established. To establish immunohistochemical (IHC) panels for prognosis prediction of OECa for use in daily pathology practice, the expression patterns of 12 IHC markers, p53, HNF-1beta, ARID1A, estrogen receptor-alpha, progesterone receptor, vimentin, PTEN, PIK3CA, WT1, left-right determination factor, beta catenin, and Ki-67, were investigated using 282 OECas. Hierarchical clustering analysis revealed seven major immunoprofile groups (IPGs I-VII) that could be used to categorize OECa tumors independent of histotypes. Based on the results of the cluster analysis and protein expression statuses, we further demonstrated the effective classification of OECa tumors into simplified immunoprofile panels using only 4 IHC markers including HNF-1beta, p53, ARID1A, and WT1. The tumors in IPG VII with HNF1beta+/p53+/ARID1A+ immunophenotype demonstrated a significantly worse overall survival (OS) and progression-free survival (PFS) as compared to the other IPGs. Multivariate Cox regression analysis also revealed that the immunophenotype (HNF1beta+/p53+/ARID1A+), as well as clinical stage, were significant and independent prognostic factors for OS and PFS in advanced OECa. In conclusion, we identified immunoprofiles in OECa using a panel of four IHC markers, which could identify tumors by the immunophenotype that is associated with the most unfavorable prognosis, and thus, facilitate prognosis prediction of advanced OECa. PMID- 30448219 TI - High frequency of POLE mutations in synchronous endometrial and ovarian carcinoma. AB - Synchronous endometrial and ovarian carcinomas (SEOs) represent 5% to 10% of endometrial or ovarian carcinomas. We assessed genetic alterations (in PTEN, CTNNB1, POLE, etc.) and evaluated correlations with patient outcomes to determine the utility of clonality analyses for differentiating between metastases and concurrent primary tumors and for determining whether genetic alterations in synchronous tumors are predictive of biological behavior. Genomic DNA was isolated from formalin-fixed paraffin-embedded tissues and frozen tissues from patients with SEOs. Samples were obtained from the Department of Obstetrics and Gynecology at the Shimane University School of Medicine between 2003 and 2017. Sanger sequencing was used to analyze the mutational status of the coding exons in TP53, PTEN, POLE, PIK3CA, KRAS, and CTNNB1 using previously published primers. All patients lived, and three had disease recurrence. The frequencies of somatic mutations in TP53, PTEN, CTNNB1, KRAS, and POLE were 3/8 (37.5%), 2/8 (25.0%), 3/8 (37.5%), 0/8 (0.0%), and 5/8 (62.5%) in ovarian tumors and 3/8 (37.5%), 2/8 (25.0%), 3/8(37.5%), 1/8 (12.5%), and 5/8 (62.5%) in endometrial tumors, respectively. The frequencies of POLE and CTNNB1 mutations were higher than those in previous reports. A clonal relationship was determined by genomic analyses in three of six cases that were initially diagnosed as primary independent tumors. We confirmed that these three cases were indicated metastatic tumors because the lesion of mutation was the same. This information, provided by the sequencing based strategy, could be useful for hypothesizing a patient's prognosis and deciding on treatment. PMID- 30448220 TI - Spindle assembly checkpoint MAD2 and CDC20 overexpressions and cell-in-cell formation in gastric cancer and its precursor lesions. AB - Overexpression of mitotic arrest deficient 2 (MAD2) and/or cell division cycle 20 (CDC20) in the spindle assembly checkpoint (SAC) leads to chromosomal instability (CIN) and aneuploidy. Cell-in-cell (CIC) structures are formed by the process that cancer or immune cells are internalized into adjacent host cancer cells. Here, we investigated the clinicopathologic significances of SAC protein overexpression and CIC structures in 829 cases of normal, premalignant, and gastric cancer (GC) lesions. MAD2 and CDC20 expressions were significantly increased in intestinal metaplasia (IM), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and early gastric cancer (EGC) than normal mucosa and their expression levels were the highest in HGD. Interestingly, CDC20 immunohistochemistry specifically stained the outer cells of CIC structures, which were the most frequently observed in EGC. In univariate analyses, MAD2 and CDC20 overexpressions and CIC formation were associated with older age, intestinal histology, lower tumor-node-metastasis stage, and longer recurrence free survival (RFS) and cancer-specific survival (CSS) of GC patients. In multivariate survival analyses, MAD2 and CDC20 overexpressions were associated with better RFS (hazard ratio=0.61, P=.012) and CSS (hazard ratio=0.63, P=.043), respectively. In conclusion, MAD2 and CDC20 are the most expressed in HGD, suggesting their roles in the early stage of gastric carcinogenesis, whereas their overexpressions in GC are associated with intestinal histology and favorable clinicopathologic parameters, which may be useful for immunohistochemical classification of CIN-type GC. Moreover, CDC20 is a novel immunohistochemical marker for highlighting CIC structures. PMID- 30448221 TI - The implication of tumor infiltrating lymphocytes in Epstein-Barr virus associated gastric carcinoma. AB - EBV-associated gastric carcinoma (EBVaGC) is a distinct entity which has conspicuously inflammatory infiltration compared with EBV-negative gastric carcinoma (EBVnGC). To date, the local immune status in EBVaGC and its relationship with patient prognosis and apoptosis of tumor cells is largely unknown. In this study, we evaluated the density of different types of tumor infiltrating lymphocytes (TILs) in 53 EBVaGCs and 67 EBVnGCs and analyzed its relationship with patient outcomes and apoptosis of tumor cells in EBVaGC. The average number of CD3+ total T cells, CD8+ T cells, CD79alpha+ B cells, CD56+ NK cells, Fascin+ dendritic cells (DCs), FoxP3+ Tregs and the average proportions of Ki-67, IL-1beta, Granzyme B, IFN-gamma, IL-10 in TILs were higher in EBVaGC, and CD8+ T cells were the predominant constituent cells of TIL in EBVaGC. Patients with higher numbers of CD3+ total T cells,CD8+ T cells, CD79alpha+ B cells, Fascin+ DCs survived longer in EBVaGC, and CD8+ T cells and Fascin+ DCs were independent prognostic factors for patient survival. Besides, CD8+ T cells were positively correlated with apoptotic index of tumor cells. However, the apoptosis of tumor cells were lower and the expression of survivin and NF-kappaBp65 in tumor cells were up-regulated in EBVaGC. These findings suggested that CD3+ total T cells,CD8+ T cells, CD79alpha+ B cells, Fascin+ DCs predict a better prognosis in EBVaGC; CD8+ T cells might through a non-apoptotic pathway to eliminate tumor cells, thereby improving the patient prognosis. PMID- 30448222 TI - Immunohistochemical pattern of c-MYC protein judged as '+/(weak)+/-' by a new notation correlates with MYC gene non-translocation in large B-cell lymphoma. AB - Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill-defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma (DLBCL) or DLBCL coexisting with grade 3A to 3B follicular lymphoma. The most common notation was '+ / (weak) +/-' [49/82 cases (59.8%)]; cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively. PMID- 30448223 TI - Donor-related diabetic nephropathy: a comprehensive Clinicopathologic study. AB - Knowledge on renal involvement in kidney donors with diabetes i.e., diabetic nephropathy (DN), is limited. During the 7years (2010-2017), 921 post-perfusion biopsies were performed for living donors (14%) or deceased donors (86%). The Renal Pathology Society Classification schema for DN (Class 0-IV) was used. Biopsies with light microscopic changes of DN (at least Class IIa) were selected for study. Eleven biopsies (1.2%) showed DN, all from deceased donors (Class IIa in 8, Class IIb in 2, and Class III in 1 biopsy). The glomerular basement membrane thickness ranged from 439+/-52 to 725+/- 82 nanometers. These biopsies also displayed arterionephrosclerosis. They were from 9 deceased donors [fulfilling clinical criteria for acceptance in all, diabetes (> 6years) in 8, hypertension in 6, and proteinuria (1+) in all]. Follow-up biopsies (5-342weeks post-transplant) showed DN of the same class (7 biopsies), probably progression (1), or progression (3). At follow-up (15-416weeks), all recipients were alive. One graft was lost at 76weeks due to progressive DN. The other 10 grafts were functioning, but the serum creatinine reached 2.0-2.7mg/dL in five of them. Although diabetes is frequent in kidney donors, donor-related DN is unusual. It is observed only in deceased donors, but the risk factors for its development are not known. Donor-related DN may be stable or progress. Whether it resolves, especially for DN in early phase, remains unknown. It may adversely impact the graft outcome with a magnitude proportional to the severity of the tissue injury in the post-perfusion biopsies. PMID- 30448224 TI - I Stay-Swedish Specialist Nurses in the Perioperative Context and Their Reasons to Stay at Their Workplace. AB - PURPOSE: To investigate why nurse anesthetists and operating room nurses choose to stay in the same workplace. DESIGN: Qualitative design. METHODS: Individual interviews were conducted with 15 nurse specialists from four hospitals in Sweden. Two men and 13 women aged between 43 and 63 participated. Data were analyzed with systematic text condensation according to Malterud. FINDINGS: Three themes were identified. (1) Organizational stability contributed to low staff turnover, with good spirits between colleagues, representing everyone's equal value and resulting in a feeling of homelikeness. (2) Sustained development in one's own profession. (3) A humane head nurse who was at hand, who was a facilitator, who knew staff members, and eliminated obstacles for them. CONCLUSIONS: In a nonhierarchical and stable organization with a head nurse with caritative leadership skills, a welcoming working environment with opportunities for professional development is created. Thus, nurse specialists choose to stay, contributing to organizational development. PMID- 30448226 TI - The paradox of tegumentary leishmaniasis diagnosis: How the need for accurate and modern techniques is being addressed in low income areas. PMID- 30448225 TI - Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection. AB - BACKGROUND: Total anomalous pulmonary venous connection (TAPVC) is recognized as a rare congenital heart defect (CHD). With a high mortality rate of approximately 80%, the survival rate and outcomes of TAPVC patients are not satisfactory. However, the genetic aetiology and mechanism of TAPVC remain elusive. This study aimed to investigate the underlying genomic risks of TAPVC through next generation sequencing (NGS). METHODS: Rare variants were identified through whole exome sequencing (WES) of 78 sporadic TAPVC cases and 100 healthy controls using Fisher's exact test and gene-based burden test. We then detected candidate gene expression patterns in cells, pulmonary vein tissues, and embryos. Finally, we validated these genes using target sequencing (TS) in another 100 TAPVC cases. FINDINGS: We identified 42 rare variants of 7 genes (CLTCL1, CST3, GXYLT1, HMGA2, SNAI1, VAV2, ZDHHC8) in TAPVC cases compared with controls. These genes were highly expressed in human umbilical vein endothelial cells (HUVECs), mouse pulmonary veins and human embryonic hearts. mRNA levels of these genes in human pulmonary vein samples were significantly different between cases and controls. Through network analysis and expression patterns in zebrafish embryos, we revealed that SNAI1, HMGA2 and VAV2 are the most important genes for TAPVC. INTERPRETATION: Our study identifies novel candidate genes potentially related to TAPVC and elucidates the possible molecular pathogenesis of this rare congenital birth defect. Furthermore, SNAI1, HMGA2 and VAV2 are novel TAPVC candidate genes that have not been reported previously in either humans or animals. FUND: National Natural Science Foundation of China. PMID- 30448227 TI - Gut microbiota in diabetes and HIV: Inflammation is the link. PMID- 30448229 TI - Mechanobiology to repair the herniated disc. PMID- 30448228 TI - The enhancer RNA lnc-SLC4A1-1 epigenetically regulates unexplained recurrent pregnancy loss (URPL) by activating CXCL8 and NF-kB pathway. AB - BACKGROUND: Enhancer RNAs (eRNAs) are a group of lncRNAs transcribed from enhancers, whose regulatory effects on gene expression are an emerging area of interest. However, the role of eRNAs in regulating trophoblast cells and unexplained recurrent pregnancy loss (URPL) remains elusive. METHODS: We profiled eRNAs in villi from URPL patients and matched controls by RNA-seq. Functions of URPL-related eRNAs were further investigated in vitro. RESULTS: We identified lnc SLC4A1-1, which was transcribed from an active enhancer marked with H3K27ac and H3K4me1 and so-called eRNA, highly expressed in URPL patients. Gain-of-function experiments indicated that lnc-SLC4A1-1 facilitated trophoblast cell migration and apoptosis. Mechanistically, as an eRNA, lnc-SLC4A1-1 was retained in the nuclei and recruited transcription factor NF-kappaB to bind to CXCL8, resulting in increased H3K27ac in the CXCL8 promoter and subsequent elevation of CXCL8 expression. Activation of CXCL8 exacerbated inflammatory reactions in trophoblast cells by inducing TNF-alpha and IL-1beta, which could be blocked by an antagonist of lnc-SLC4A1-1. INTERPRETATION: These findings indicate that an eRNA, lnc-SLC4A1 1, alters trophoblast function via activation of immune responses and by regulating the NF-kappaB/CXCL8 axis. Our study provides new insights in understanding lncRNA/eRNA function in pathological pregnancy, potentially informing on therapeutic strategies for URPL. FUND: National Natural Science Foundation of China, Natural Science Foundation of Jiangsu Province, National Key Research and Development Program, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions. PMID- 30448230 TI - Local Auxin Biosynthesis Mediates Plant Growth and Development. AB - Auxin is one of the most important plant hormones controlling various aspects of plant growth and development. Here, we highlight three recent papers that shed light on how local auxin biosynthesis contributes to plant growth and development in response to endogenous developmental signals and exogenous environmental cues, such as shade and aluminum stress. PMID- 30448231 TI - Odontogenic tumors and lesions treated in a single specialist oral and maxillofacial pathology unit in the United Kingdom in 1992-2016. AB - OBJECTIVES: Odontogenic tumors (ODTs) are a heterogeneous group of lesions derived from elements of tooth-forming tissues. No detailed data on the incidence of odontogenic tumors in the United Kingdom have been published. The aim of this study was to retrospectively describe the range and incidence of odontogenic tumors from 1992 to 2016 in a single specialist unit and to compare this population with others. STUDY DESIGN: By using the Oral and Maxillofacial Pathology database, Sheffield (UK), we included both local and referred consultation cases. A proportion of diagnoses were reclassified in accordance with the 2017 World Health Organization classification. RESULTS: In total, 559 odontogenic tumors were diagnosed. Overall, the most common lesions were ameloblastoma (196 [33.8%]), odontoma (148 [25.5%]), and odontogenic myxoma (37 [6.3%]), but this varied between local and referral case populations, with odontomas being most common in the local population (43%). The sites affected and the gender and age of patients were similar to other Western populations. Malignant ODTs comprised 33 cases (5.7%), of which 9 (27.3%) were ameloblastic carcinoma. The majority of the malignant ODTs comprised referral cases. CONCLUSIONS: Here, we present the first detailed data on ODTs within a UK population, and the pattern of incidence from the local population is similar to other Western populations. The exceptional rarity of malignant ODTs emphasizes the need for specialist centers for their treatment to gain diagnostic experience. PMID- 30448232 TI - Selection of Protein-Protein Interactions of Desired Affinities with a Bandpass Circuit. AB - We have developed a genetic circuit in Escherichia coli that can be used to select for protein-protein interactions of different strengths by changing antibiotic concentrations in the media. The genetic circuit links protein-protein interaction strength to beta-lactamase activity while simultaneously imposing tuneable positive and negative selection pressure for beta-lactamase activity. Cells only survive if they express interacting proteins with affinities that fall within set high- and low-pass thresholds; i.e. the circuit therefore acts as a bandpass filter for protein-protein interactions. We show that the circuit can be used to recover protein-protein interactions of desired affinity from a mixed population with a range of affinities. The circuit can also be used to select for inhibitors of protein-protein interactions of defined strength. PMID- 30448233 TI - Synthesis and biological evaluation of Ginsenoside Compound K analogues as a novel class of anti-asthmatic agents. AB - Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti asthmatic effects (IgE value = 1237.11 +/- 106.28, 975.82 +/- 160.32, 1136.96 +/- 121.85, 1191.08 +/- 107.59 and 1258.27 +/- 148.70 ng/mL, respectively) in comparison with CK (1501.85 +/- 184.66 ng/mL). These potent compounds could serve as leads for further development. PMID- 30448234 TI - Discovery and optimization of 3,4,5-trimethoxyphenyl substituted triazolylthioacetamides as potent tubulin polymerization inhibitors. AB - Based on our previous research, three series of new triazolylthioacetamides possessing 3,4,5-trimethoxyphenyl moiety were synthesized, and evaluated for antiproliferative activities and inhibition of tubulin polymerization. The most promising compounds 8b and 8j demonstrated more significant antiproliferative activities against MCF-7, HeLa, and HT-29 cell lines than our lead compound 6. Moreover, analogues 8f, 8j, and 8o manifested more potent antiproliferative activities against HeLa cell line with IC50 values of 0.04, 0.05 and 0.16 MUM, respectively, representing 100-, 82-, and 25-fold improvements of the activity compared to compound 6. Furthermore, the representative compound, 8j, was found to induce significant cell cycle arrest at the G2/M phase in HeLa cell lines via a concentration-dependent manner. Meanwhile, compound 8b exhibited the most potent tubulin polymerization inhibitory activity with an IC50 value of 5.9 MUM, which was almost as active as that of CA-4 (IC50 = 4.2 MUM). Additionally, molecular docking analysis suggested that 8b formed stable interactions in the colchicine-binding site of tubulin. PMID- 30448235 TI - Synthesis, antituberculosis studies and biological evaluation of new quinoline derivatives carrying 1,2,4-oxadiazole moiety. AB - Tuberculosis is the infectious disease caused by mycobacterium tuberculosis (Mtb), responsible for the utmost number of deaths annually across the world. Herein, twenty-one new substituted 1,2,4-oxadiazol-3-ylmethyl-piperazin-1-yl quinoline derivatives were designed and synthesized through multistep synthesis followed by in vitro evaluation of their antitubercular potential against Mtb WT H37Rv. The compound QD-18 was found to be promising with MIC value of 0.5 ug/ml and QD-19 to QD-21 were also remarkable with MIC value of 0.25 ug/ml. Additionally, we have carried out experiments to confirm the metabolic stability, cytotoxicity and pharmacokinetics of these compounds along with kill kinetics of QD-18. These compounds were found to be orally bioavailable and highly effective. Altogether, these results indicate that QD-18, QD-19, QD-20 and QD-21 are promising lead compounds for the development of a novel chemical class of antitubercular drugs. PMID- 30448236 TI - Inhibition of SphK2 Stimulated Hepatic Gluconeogenesis Associated with Dephosphorylation and Deacetylation of STAT3. AB - BACKGROUND: Sphingosine kinase (SphK) is considered as a potential target for developing novel therapeutics of cancer and other diseases including diabetes. As the major SphK isoform in the liver, much less is known the role of SphK2 involved in regulating hepatic glucose metabolism. METHOD: In this study, RNA interference, real time RT-PCR, western blot and immunoprecipitation method was used to investigate the regulation of SphK2 in hepatic glucose metabolism. RESULTS: Both siRNA and SphK2 inhibitor ABC294640 stimulated expression of gluconeogenetic gene PEPCK and G6Pase but not enzymes of hepatic glycogenolysis, glycolysis and glycogen synthesis. Inhibition of SphK2 also prevented insulin repressed PEPCK and G6Pase expression as well as glucose production levels. Furtherly, inhibition of SphK2 inactivated STAT3 by decreasing both phosphorylation on Tyr705 and acetylation on lysine residue, and led to stimulation of PEPCK and G6Pase expression. Inhibition of SphK2 also prevented IL 6 dependent activation of STAT3 and suppression of PEPCK and G6pase expression both in vitro and in vivo. CONCLUSION: Our study suggests that SphK2 participates in hepatic glucose metabolism related to activation of STAT3. PMID- 30448237 TI - Layer-by-layer adsorption: Factors affecting the choice of substrates and polymers. AB - The electrostatic layer-by-layer technique for fabrication of multi-layered structures of various sizes and shapes using flat and colloidal templates coupled with polyelectrolyte layer-forming materials has attracted significant interest among both academic and industrial researchers due to its versatility and relative simplicity of the procedures involved in its execution. Fabrication of the multi-layered structures using the electrostatic layer-by-layer method involves several distinct stages each of which holds great importance when considering the production of a high-quality product. These stages include selection of materials (both template and a pair of construction polyelectrolytes), adsorption of the first polyelectrolyte layer onto the selected templates, formation of the second layer comprised of the oppositely charged polyelectrolyte and guided by the interactions between the two chosen polyelectrolytes, and multi-layering, where a selected number of layers are produced, and which is conditioned by both intrinsic properties of the involved construction materials and external fabrication conditions such as temperature, pH and ionic strength. The current review summarises the most important aspects of each stage mentioned above and gives examples of the materials suitable for utilization of the technique and describes the underlying physics involved. PMID- 30448238 TI - Seasonal transcriptomes of the Antarctic pteropod, Limacina helicina antarctica. AB - High latitude seas will be among the first marine systems to be impacted by ocean acidification (OA). Previous research studying the effects of OA on the pteropod, Limacina helicina antarctica, has led this species to be identified as a sentinel organism for OA in polar oceans. Here, we present gene expression data on L. h. antarctica, collected in situ during the seasonal transition from early spring to early summer. Our findings suggest that after over-wintering under seasonal sea ice, pteropods progress toward full maturity in the early summer when food becomes increasingly available. This progression is highlighted by a dramatic shift in gene expression that supports the development of cytoskeletal structures, membrane ion transportation, and metabolically important enzymes associated with glycolysis. In addition, we observed signs of defense of genomic integrity and maturation as evidenced by an up-regulation of genes involved in DNA replication, DNA repair, and gametogenesis. These data contribute to a broader understanding of the life-cycle dynamics for L. h. antarctica and provide key insights into the transcriptomic signals of pteropod maturation and growth during this key seasonal transition. PMID- 30448239 TI - Condition of pteropod shells near a volcanic CO2 vent region. AB - Natural gradients of pH in the ocean are useful analogues for studying the projected impacts of Ocean Acidification (OA) on marine ecosystems. Here we document the in situ impact of submarine CO2 volcanic emissions (CO2 vents) on live shelled-pteropods (planktonic gastropods) species Creseis conica in the Gulf of Naples (Tyrrhenian Sea, Mediterranean). Since the currents inside the Gulf will likely drive those pelagic calcifying organisms into and out of the CO2 vent zones, we assume that pteropods will be occasionally exposed to the vents during their life cycle. Shell degradation and biomass were investigated in the stations located within and nearby the CO2 vent emission in relation to the variability of sea water carbonate chemistry. A relative decrease in shell biomass (22%), increase in incidence of shell fractures (38%) and extent of dissolution were observed in Creseis conica collected in the Gulf of Naples compared to those from the Northern Tyrrhenian Sea (control stations). These results suggest that discontinuous but recurrent exposure to highly variable carbonate chemistry could consistently affect the characteristic of the pteropod shells. PMID- 30448240 TI - Response to the letter entitled "Extremely high levels of high-density lipoprotein cholesterol and increased risk of cardiovascular mortality" by Dr Kawada. PMID- 30448241 TI - Extremely high levels of high-density lipoprotein cholesterol and increased risk of cardiovascular mortality. PMID- 30448242 TI - KDM5B is a master regulator of the H3K4-methylome in stem cells, development and cancer. AB - Epigenetic regulation of chromatin plays a critical role in controlling stem cell function and tumorigenesis. The histone lysine demethylase, KDM5B, which catalyzes the demethylation of histone 3 lysine 4 (H3K4), is important for embryonic stem (ES) cell differentiation, and is a critical regulator of the H3K4 methylome during early mouse embryonic pre-implantation stage development. KDM5B is also overexpressed, amplified, or mutated in many cancer types. In cancer cells, KDM5B regulates expression of oncogenes and tumor suppressors by modulating H3K4 methylation levels. In this review, we examine how KDM5B regulates gene expression and cellular fates of stem cells and cancer cells by temporally and spatially controlling H3K4 methylation levels. PMID- 30448243 TI - The clinical features of older patients with lung cancer in comparison with their younger counterparts. AB - BACKGROUND: Older patients with lung cancer have increased over the past decades. Several standard treatments for older patients were established, but their clinical features in real world clinics remain unknown. Thus, we performed a retrospective study to clarify the clinical features of them. METHODS: The patients with lung cancer who were admitted to our hospital between April 1, 2012 and March 31, 2015 were retrospectively analyzed. Patients older than 75 years were defined as older patients. Standard treatments were based on the guidelines. RESULTS: In total, 333 patients were analyzed. The older patients had a poor performance status (PS), more comorbidities, and fewer opportunities to receive standard treatments. The prognosis of the older patients who received standard treatments was superior to that of those who did not. The therapeutic efficacy of standard treatments for older patients with stages I and II diseases was similar to their younger counterparts. However, the prognosis of older patients with advanced stage, especially stage III disease, was poor. The tolerability of first line chemotherapy by older patients was comparable with their younger counterparts, but the older patients had fewer opportunities to receive several chemotherapy regimens, even second line chemotherapy. CONCLUSIONS: We should positively consider standard treatments for older patients. However, not only their shorter life expectancy but also their poor PS and multiple comorbidities that sometimes render patients unable to receive standard treatments and several chemotherapy regimens, make their prognosis poor. The standard treatments for older patients, especially in locally advanced stages, require modification. PMID- 30448244 TI - Responding to violence against women: A qualitative study with midwives in Timor Leste. AB - PROBLEM: The health sector is a critical partner in the response to violence against women, but little is known about how to translate international guidelines and sustainable good practice in remote and under-resourced health systems. AIM: This research explores the barriers and enablers that midwives report in responding to domestic and sexual violence in Timor-Leste, a country with a very high rate of violence against women. The aim is to inform a systems approach to health provider training and engagement applicable to Timor-Leste and other low-resource settings. METHODS: In 2016 we conducted qualitative interviews and group discussions with 36 midwives from rural health settings, community health centres and hospitals in three municipalities of Timor-Leste. FINDINGS: A range of individual, health system and societal factors shape midwives' practice. While training provided the foundation for knowing how to respond to cases of violence, midwives still faced significant health system barriers such as lack of time, privacy and a supportive environment. Key enablers were support from colleagues and health centre managers. CONCLUSION: Health provider training to address violence against women is important but tends to focus on individual knowledge and skills. There is a need to shift toward systems-based approaches that engage all staff and managers within a health facility, work creatively to overcome barriers to implementation, and link them with wider community-based resources. PMID- 30448245 TI - Evaluating awareness of Cultural Safety in the Australian midwifery workforce: A snapshot. AB - PROBLEM: There are no validated tools to measure midwives' awareness of Cultural Safety. BACKGROUND: Cultural Safety is an important component of midwifery practice. Measurement can inform practice and evaluate professional development strategies. AIM: To adapt and evaluate the Awareness of Cultural Safety Scale with the midwifery workforce. METHODS: An online survey was distributed to members of Australian College of Midwives and Congress of Aboriginal and Torres Strait Islander Nurses and Midwives. Measures included the Awareness of Cultural Safety Scale - Revised, Self-assessment of Cultural Knowledge and Perceptions of Racism scales. FINDINGS: The revised Awareness scale had a Cronbach's alpha of 0.87. Principal Component Analysis with varimax rotation produced a three-factor structure accounting for 67% of variance. Awareness scores correlated with Self assessment of Cultural Knowledge (r=0.22 p<0.03) and Perceptions of Racism (r=0.62 p<0.001) scales. Educators scored significantly higher on awareness compared to clinicians (t (1,80)=-3.09, p=0.003). Perceptions of Racism predicted Awareness of Cultural Safety scores (F (2,87) 29.25, adjusted r square=0.39 p<0.001 95% Confidence Interval=1.09, 1.93). DISCUSSION: The revised scale was a reliable and valid measure of Cultural Safety across a diverse sample of midwives. Midwives working in education settings have a higher awareness of Cultural Safety than clinical peers. CONCLUSION: The Awareness of Cultural Safety Scale can be used with midwives across practice settings. Professional organisations and education providers need to promote the professional responsibilities of midwives towards Cultural Safety in clinical practice and education. PMID- 30448246 TI - Treatment of keloid scars with intralesional triamcinolone and 5-fluorouracil injections - a randomized controlled trial. AB - Keloids have high recurrence rates. Current first-line therapy is triamcinolone (TAC) injection, but it has been suggested that approximately 50% of keloids are steroid resistant. We compared the efficacy of intralesional 5-fluorouracil (5 FU) and triamcinalone injections in a double-blind randomized controlled trial. Forty-three patients with 50 keloid scars were treated with either intralesional TAC or 5-FU-injections over 6 months. There was no statistically significant difference in the remission rate at 6 months between the 5-FU and TAC groups (46% vs 60%, respectively). Local adverse effects were higher in the TAC group compared to the 5-FU group. Occurrence of skin atrophy in TAC group was 44% and in the 5-FU group 8% (p < 0.05). Also the occurrence of telangiectasia in the TAC group was 50% and in the 5-FU 21% (p < 0.05). Vascularity of the keloids, assessed by spectral imaging and immunohistochemical staining for blood vessels, after treatment decreased in the TAC group, but not in the 5-FU group (p < 0.05). Fibroblast proliferation evaluated by Ki-67 staining significantly decreased in the TAC group (p < 0.05) but increased in the 5-FU group (p < 0.05). TAC and 5-FU injections did not differ in their clinical effectivity in this randomized study, but 5-FU injections lead to increased proliferation rate and did not affect vascular density in histological assessment. Due to the greater number of adverse effects observed after TAC treatment, 5-FU injections may be preferable for cosmetically sensitive skin areas. PMID- 30448247 TI - Perovskite Photovoltaic Modules: Life Cycle Assessment of Pre-industrial Production Process. AB - Photovoltaic devices based on perovskite materials have a great potential to become an exceptional source of energy while preserving the environment. However, to enter the global market, they require further development to achieve the necessary performance requirements. The environmental performance of a pre industrial process of production of a large-area carbon stack perovskite module is analyzed in this work through life cycle assessment (LCA). From the pre industrial process an ideal process is simulated to establish a benchmark for pre industrial and laboratory-scale processes. Perovskite is shown to be the most harmful layer of the carbon stack module because of the energy consumed in the preparation and annealing of the precursor solution, and not because of its Pb content. This work stresses the necessity of decreasing energy consumption during module preparation as the most effective way to reduce environmental impacts of perovskite solar cells. PMID- 30448249 TI - Glucocorticoids and resilience. AB - All organisms endure frequent challenges to homeostasis, or stressors, that require adaptation. Depending on the individual, the context, and the magnitude of stress, this active adaptation can lead to behavioral susceptibility or resilience. The latter is an under-appreciated consequence of stress, as the damaging effects of chronic stress and chronically elevated glucocorticoids have received much more attention. We suggest here that neural pathways promoting resilience are initiated at the time of stress, and that they involve glucocorticoid signaling. By focusing on the neurobiology of resilience induction and the identification of vulnerable individuals, we may be able to intervene in the future at the time of stress to promote positive adaptation. PMID- 30448248 TI - Prevalence of five lifestyle risk factors among U.S. adults with and without stroke. AB - BACKGROUND: History of stroke increases cardiometabolic risk, which can be exacerbated by the presence of unhealthy lifestyle factors. Population-based estimates of lifestyle risk factors in people with stroke are lacking but could be used to inform research, policy, and healthcare practice. OBJECTIVE: To compare population-based estimates of the prevalence of five lifestyle risk factors-low fruit and vegetable consumption, insufficient physical activity, smoking, heavy alcohol consumption, and overweight/obesity-among U.S. adults with and without stroke. METHODS: Representative data from noninstitutionalized adults aged >=18 years (stroke, n = 37,225; no stroke, n = 851,607) from the 2015 and 2017 Behavioral Risk Factor Surveillance System (BRFSS) were used to estimate prevalence of individual and total number of risk factors. Logistic regression models were used to determine the odds of lifestyle risk factors in adults with stroke, adjusting for sex, age, ethnicity, marital status, education, income, and disability. RESULTS: Prevalence and adjusted odds ratios (AOR) were higher in individuals with stroke compared to those without stroke for insufficient physical activity (56.5% vs. 49.5%, AOR: 1.14) and smoking (30.1% vs. 16.6%, AOR: 1.16), but lower for heavy alcohol consumption (5.4% vs. 6.1%, AOR: 0.76). Prevalence for low fruit and vegetable consumption (51.7% vs. 46.0%) and overweight/obesity (70.2% vs. 64.5%) was higher among adults with stroke, but differences were attenuated by demographic characteristics. Additionally, clustering of 4-5 lifestyle risk factors was higher in adults with stroke (9.0% vs. 5.3%, AOR: 1.12). CONCLUSION: Additional research and healthcare interventions are needed to improve lifestyle risk factors in adults with stroke. PMID- 30448250 TI - Robust cubature Kalman filter based on variational Bayesian and transformed posterior sigma points error. AB - An improved robust cubature Kalman filter (RCKF) based on variational Bayesian (VB) and transformed posterior sigma points error is proposed in this paper, which not only retains the robustness of RCKF, but also exhibits adaptivity in the presence of time-varying noise. First, a novel sigma-point update framework with uncertainties reduction is developed by employing the transformed posterior sigma points error. Then the VB is used to estimate the time-varying measurement noise, where the state-dependent noise is addressed in the iteratively parameter estimation. The new filter not only reduces the uncertainty on sigma points generation but also accelerates the convergence of VB-based noise estimation. The effectiveness of the proposed filter is verified on integrated navigation, and numerical simulations demonstrate that VB-RCKF outperforms VB-CKF and RCKF. PMID- 30448251 TI - Loss model based efficiency optimized control of brushless DC motor drive. AB - Energy efficiency improvement of electrical motor drives has recently become a very interesting subject. Several methods have been proposed in the literature to improve the efficiency of permanent magnet synchronous machine (PMSM) with sinusoidal back-EMF. These methods are not precise and appropriate for brushless DC machine (BLDCM) with trapezoidal back-EMF. As a unique solution, this work introduces a flux controlled based loss minimization algorithm suitable for BLDCM that considers iron loss as well as influence of back-EMF harmonics; consequently promotes efficiency of machine. In this regard, the loss model of PMSM is extended based on multiple reference frame analysis to include back-EMF harmonics of BLDCM. As an advantage, proposed modified loss model does not require any additional data about the dimensions of machine that makes it suitable for industrial motor drive applications. The Proposed loss model is validated through experimental tests in different operating conditions. Afterward, by applying direct torque and indirect flux control of BLDCM as the control technique, d-axis current in the rotor reference frame is controlled to reduce the air gap flux and consequently iron loss of the machine. Finally, a procedure is presented to determine the optimum d-axis current which maximizes the efficiency. Effectiveness of proposed control system is evaluated using simulation results in MATLAB/Simulink and experimental results on a practical prototype. It is indicated that depending on the operating conditions, about 2% to 11% of efficiency improvement would be achieved in the proposed method. PMID- 30448252 TI - Rapid estimation of PID minimum variance. AB - PID controllers are the most common type of controllers used in industry. However, to find the best PID performance is a challenging task. Assessment of the best PID performance leads to the minimization of the deviation from set point as indicated by closed loop transfer function. This is a non-convex optimization problem and there is no direct solution for finding this benchmark. Solving this problem iteratively as proposed in literature requires long calculation times. Furthermore, iterative methods are not guaranteed to find the minimum value. Using as many as possible infinite impulse response coefficients, or increasing the number of finite impulse coefficients gradually, causes undesirably large calculation times. We propose a fast method to evaluate the minimum variance by a fixed number of finite impulse response coefficients. This finite impulse model is double the size of the stable system impulse response (it contains the transient response and the same duration of steady state). Thus it avoids undesired iteration, and consequently, the PID minimum variance is quickly evaluated. Time is a critical factor as the purpose to assess this index is for use in online monitoring. The proposed method is tested on benchmark simulation examples from literature. PMID- 30448253 TI - Paradoxical evolution of rickettsial genomes. AB - Rickettsia species are strictly intracellular bacteria that evolved approximately 150 million years ago from a presumably free-living common ancestor from the order Rickettsiales that followed a transition to an obligate intracellular lifestyle. Rickettsiae are best known as human pathogens vectored by various arthropods causing a range of mild to severe human diseases. As part of their obligate intracellular lifestyle, rickettsial genomes have undergone a convergent evolution that includes a strong genomic reduction resulting from progressive gene degradation, genomic rearrangements as well as a paradoxical expansion of various genetic elements, notably small RNAs and short palindromic elements whose role remains unknown. This reductive evolutionary process is not unique to members of the Rickettsia genus but is common to several human pathogenic bacteria. Gene loss, gene duplication, DNA repeat duplication and horizontal gene transfer all have shaped rickettsial genome evolution. Gene loss mostly involved amino-acid, ATP, LPS and cell wall component biosynthesis and transcriptional regulators, but with a high preservation of toxin-antitoxin (TA) modules, recombination and DNA repair proteins. Surprisingly the most virulent Rickettsia species were shown to have the most drastically reduced and degraded genomes compared to closely related species of milder pathogenesis. In contrast, the less pathogenic species harbored the greatest number of mobile genetic elements. Thus, this distinct evolutionary process observed in Rickettsia species may be correlated with the differences in virulence and pathogenicity observed in these obligate intracellular bacteria. However, future investigations are needed to provide novel insights into the evolution of genome sizes and content, for that a better understanding of the balance between proliferation and elimination of genetic material in these intracellular bacteria is required. PMID- 30448254 TI - Sequencing and genetic characterization of two strains Paramushir virus obtained from the Tyuleniy Island in the Okhotsk Sea (2015). AB - Paramushir virus belongs to Sakhalin virus genogroup within Orthonairovirus genus and is one of the poorly studied viruses with unknown pathogenicity. At the moment, only one nearly complete sequence of Paramushir virus genome, isolated in 1972, is available. Two new strains of PARV were isolated in 2015 from a sample collected at the Tyuleniy Island in the Okhotsk Sea and sequenced using a combination of high throughput sequencing and specific multiplex PCR. Both strains are closely related to the early sequenced PARV strain LEIV-1149 K. The signs of intersegment reassortment and probable recombination were revealed, which point to a high variability potential of Paramushir virus and may lead to the formation of strains with novel properties, different from those of the predecessors. The new data regarding Paramushir virus can promote a better understanding of the diversity and relations within Orthonairovirus genus and help define intragenic demarcation criteria, which have not yet been established. PMID- 30448255 TI - 5'-triphosphate siRNA targeting HBx elicits a potent anti-HBV immune response in pAAV-HBV transfected mice. AB - RNA with 5'-triphosphate (3p-RNA) is recognized by RNA sensor RIG-I (retinoic acid-inducible gene I protein). Previously, we reported that small interfering RNA targeting HBx (3p-siHBx) could confer potent anti-hepatitis B virus (HBV) efficacy via HBx silencing and RIG-I activation. However, the characteristics of innate and adaptive immunity especially exhaustion profiles in the liver microenvironment in response to 3p-siHBx therapy have not been fully elucidated. Here, we observed that 3p-siHBx more significantly inhibited HBV replication in vivo. 3p-siHBx enhanced natural killer (NK) cell activation with KLRG1 and CD69 upregulation and interferon (IFN)-gamma secretion. 3p-siHBx significantly reversed the exhaustion phenotype of CD8+ T cells, and augmented CD8+ T cell activation and function. Importantly, 3p-siHBx disrupted the differentiation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), accompanied by the reduction of the immunosuppressive cytokines interleukin (IL) 10 and transforming growth factor (TGF)-beta. 3p-siHBx also enhanced dendritic cell maturation. Further investigation showed that RIG-I was involved in 3p-siHBx induced IFN-alpha, IFN-beta, and IFN-lambda production. Moreover, RIG-I activation in HBV+ hepatocytes would improve the recruitment of CD8+ T cells and NK cells. These results reveal that 3p-siHBx therapy can improve the immune microenvironment in HBV-carrier liver and inhibit HBV replication, indicating the potential utility of RIG-I ligands as molecular adjuvants for viral vaccines or candidate drugs. PMID- 30448256 TI - Optimization and preclinical evaluation of novel histamine H3receptor ligands: Acetyl and propionyl phenoxyalkyl piperazine derivatives. AB - As a continuation of our search for novel histamine H3 receptor ligands, a series of new acetyl and propionyl phenoxyalkylamine derivatives (2-25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer, composed of six various 4N-substituted piperazine moieties were evaluated for their binding properties at human histamine H3 receptors (hH3R). In vitro test results proved the 4-pyridylpiperazine moiety as crucial element for high hH3R affinity (hH3R Ki = 5.2-115 nM). Moreover introduction of carbonyl group containing residues in the lipophilic part of molecules instead of branched alkyl substituents resulted in increased affinity in correlation to previously described series, whereas propionyl derivatives showed slightly higher affinities than those of acetyl (16 and 22vs.4 and 10; hH3R Ki = 5.2 and 15.4 nM vs. 10.2 and 115 nM, respectively). These findings were confirmed by molecular modelling studies, demonstrating multiple ligand-receptor interactions. Furthermore, pharmacological in vivo test results of compound 4 clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound. Likewise, its protective action against hyperglycemia and the development of overweight has been shown. In order to estimate drug-likeness of compound 4, in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. PMID- 30448257 TI - Isolation and structure determination of a new lasso peptide specialicin based on genome mining. AB - Based on genome mining, a new lasso peptide specialicin was isolated from the extract of Streptomyces specialis. The structure of specialicin was established by ESI-MS and NMR analyses to be a lasso peptide with the length of 21 amino acids, containing an isopeptide bond and two disulfide bonds in the molecule. The stereochemistries of the constituent amino acids except for Trp were determined to be L and the stereochemistry of Trp at C-terminus was determined to be D. Three dimensional structure of specialicin was determined based on NOE experimental data, which indicated that specialicin possessed the similar conformational structure with siamycin I. Specialicin showed the antibacterial activity against Micrococcus luteus and the moderate anti-HIV activity against HIV-1 NL4-3. The biosynthetic gene cluster of specialicin was proposed from the genome sequence data of S. specialis. PMID- 30448258 TI - Ameliorative effect of Argyreia boseana Sant. & Pat. on stress in Caenorhabditis elegans. AB - BACKGROUND: Argyreia boseana Santapau and Patel commonly known as Kumbharao belongs to the family of Convolvulaceae. The plant is rare in distribution and found chiefly in the dediapada region of Gujarat. Traditionally it is used by the tribals of south Gujarat forest region in the treatment of various diseases of the nervous system. In order to study the scientific basis of the plants effect we set out to investigate the effect of the plant on ageing organisms and used Caenorhabditis elegans as a model. OBJECTIVE: In the present study the objective is to evaluate the effect of crude extract of leaves, prepared from A. boseana on oxidative stress, thermal stress, longevity and in vivo gene expression of C. elegans. MATERIAL AND METHODS: Plant extracts was prepared by sonication based method using solvent ethanol:water. Longevity experiments were carried out in liquid S media. Oxidative stress was induced by paraquat. RESULT: Results indicate no increase in the normal life span of C. elegans. However, A. boseana significantly induces stress tolerance and increased the mean lifespan of worms during thermal and oxidative stress. Additionally A. boseana was also able to up regulate the stress associated gene gst-4. CONCLUSION: Thus the present study, for the first time, unravels the anti-stress and ROS modulating effect of A. boseana. PMID- 30448259 TI - A track of the clones: new developments in cellular barcoding. AB - International experts from multiple disciplines gathered at Homerton College in Cambridge, UK from September 12-14, 2018 to consider recent advances and emerging opportunities in the clonal tracking of hematopoiesis in one of a series of StemCellMathLab workshops. The group included 35 participants with experience in the fields of theoretical and experimental aspects of clonal tracking, and ranged from doctoral students to senior professors. Data from a variety of model systems and from clinical gene therapy trials were discussed, along with strategies for data analysis and sharing and challenges arising due to underlying assumptions in data interpretation and communication. Recognizing the power of this technology underpinned a group consensus of a need for improved mechanisms for sharing data and analytical protocols to maintain reproducibility and rigor in its application to complex tissues. PMID- 30448260 TI - Cancer-associated stroma significantly contributes to the mesenchymal subtype signature of serous ovarian cancer. AB - OBJECTIVE: Mesenchymal (MES) subtype of high-grade serous ovarian cancer (HGSOC) is associated with worse outcomes including survival and resectability compared with other molecular subtypes. Molecular subtypes have historically been derived from 'tumor', consisting of both cancer and stromal cells. We sought to determine the origins of multiple MES subtype gene signatures in HGSOC. METHODS: Fifteen patients with MES subtype of HGSOC diagnosed between 2010 and 2013 were identified. Formalin-fixed paraffin-embedded (FFPE) blocks from primary surgery were sectioned for immunohistochemistry (IHC) staining of relevant proteins. Eight genes (ACTA2, COL5A1, COL11A1, FAP, POSTN, VCAN, ZEB1 and p-SMAD2) were selected for IHC staining based on their differential expression in MES vs. non MES subtypes of HGSOC. Slides were scored for intensity and localization and simple statistics were used to compare expression results in cancer vs. stroma and between primary and metastatic sites. RESULTS: COL5A1, VCAN, FAP, and ZEB1 proteins were almost exclusively expressed by stroma as opposed to cancer cells. In addition, stromal expression was dominant for ACTA2, COL11A1, POSTN and p SMAD2. In general there were minimal differences in expression of proteins between primary and metastatic sites, exceptions being COL5A1 (reduced in metastases) and COL11A1 (increased in metastases). Nuclear p-SMAD2 expression was more common in metastatic stroma. CONCLUSIONS: The existing molecular classification of HGSOC MES subtype reflects a significant stromal contribution, suggesting an important role in HGSOC behavior and thus stroma may be a relevant therapeutic target. Specific patterns of expression indicate that collagens and TGF-beta signaling are involved in the metastatic process. PMID- 30448261 TI - Soluble AXL is ubiquitously present in malignant serous effusions. AB - OBJECTIVE: The objective of this study was to analyze the expression level and clinical role of soluble AXL (sAXL) in cancers affecting the serosal surfaces, with focus on ovarian carcinoma. METHODS: sAXL protein expression by ELISA was analyzed in 572 effusion supernatants, including 424 peritoneal, 147 pleural and 1 pericardial specimens. RESULTS: sAXL was overexpressed in peritoneal effusions compared to pleural and pericardial specimens (p < 0.001). sAXL levels were additionally significantly higher in effusions from patients with ovarian carcinoma, malignant mesothelioma and breast carcinoma compared to specimens from patients with other cancers (predominantly carcinomas of lung, gastrointestinal or uterine corpus/cervix origin) or benign reactive effusions (p < 0.001). sAXL was further overexpressed in high-grade serous carcinoma (HGSC; n = 373) compared to low-grade serous carcinoma (LGSC; n = 32; p = 0.036). In HGSC, sAXL levels were significantly lower in post-chemotherapy effusions compared to primary diagnosis pre-chemotherapy specimens (p = 0.002). sAXL levels in HGSC were unrelated to chemoresponse at diagnosis, progression-free survival or overall survival. Levels were similarly unrelated to survival in LGSC and breast carcinoma. CONCLUSIONS: sAXL is widely expressed in malignant effusions, particularly in ovarian and breast carcinoma and in malignant mesothelioma. sAXL is overexpressed in HGSC compared to LGSC and its levels are lower following exposure to chemotherapy. However, sAXL levels are not informative of chemoresponse or survival. PMID- 30448262 TI - Evaluation of Outcomes of the Busan Community-based Palliative Care Project in Korea. AB - PURPOSE: We evaluated the outcomes of a community-based palliative care project conducted in Busan City, Korea from 2013 to 2015. METHODS: We selected 4 outcome indices based on the project's outcomes derived from a logic model and used a longitudinal and cross-sectional comparative design approach depending on the outcome index. RESULTS: The utilization rate of palliative care increased from 9.2% in 2012 to 41.9% in 2015. Regarding symptom changes in 65 patients receiving palliative care at 3 and 6 months (mean age=72 years, SD=9.64, 55.4% women), pain, anxiety, and depression had improved. Quality of life (QOL) was higher among palliative care patients compared to patients who did not receive palliative care (t = 2.09, p = .039). Regarding recognition of palliative care, civil servants at public health centers who participated in the pilot project (2013-2014) scored higher than those at public health centers who began participation in 2015 (t = 2.67, p = .008). CONCLUSION: This is the first study in Korea that systematically evaluated community-based palliative care. The Busan Community-based Palliative Care Project improved the QOL of palliative care patients by providing services at an appropriate level and by raising the recognition of palliative care in the community. To increase the utilization ratio of palliative care and the quality of service, strategies should be developed to supplement medical support systems. PMID- 30448263 TI - Who comes to the emergency room with an infection from a long-term care hospital? A retrospective study based on a medical record review. AB - PURPOSE: Healthcare-associated infections increase disease prevalence and mortality and are the main reason for the hospitalization of the elderly. However, the management of underlying infections in patients hospitalized in long term care hospitals (LTCHs) is insufficient, and the transfer of these poorly managed patients to the emergency room (ER) of an acute-care hospital can lead to rapid spread of infection. This study investigated the risk factors associated with an ER visit due to infections that developed in LTCHs. METHODS: The electronic medical records of patients who were transferred to the ER of a university hospital in South Korea, were used. Infection prevalence, causative infectious agent, and antibiotic sensitivity were assessed. The associations between patient characteristics and hospital-associated infections were examined using multiple logistic regression analyses. RESULTS: Among the 483 patients transferred to the ER during the study period, the number of infection cases was 197, and 171 individuals (35.4%) had one or more infections, with pneumonia being the most common (52.8%), followed by urinary tract (21.3%) and bloodstream (17.8%) infections. Patients with bedsores, fever, an indwelling catheter, and with a higher nursing need were more likely to be seen in the ER due to infectious disease from an LTCH. CONCLUSIONS: Both an intensive care system and surveillance support should be established to prevent infections, particularly in high-risk patients at LTCHs. PMID- 30448264 TI - Alpinumisoflavone causes DNA damage in Colorectal Cancer Cells via blocking DNA repair mediated by RAD51. AB - AIMS: Colorectal Cancer (CRC) accounts for 6.1% incidence and 9.2% mortality worldwide. The current study aimed to investigate the effect of alpinumisoflavone (AIF) on CRC and its possible molecular mechanism. METHODS: HCT-116 and SW480 cells were chosen as cell model to study the anti-cancer activity of AIF in vitro experiments. Cells proliferative capacity and clonogenicity were examined by CCK 8 assay and colony formation assay, while cell apoptosis was detected by Hoechst 33258 staining and Flow cytometer. The protein expression levels of related gene were examined by western blotting. Transcriptome analyses were conducted to identify the differentially expressed genes in CRC cells, following AIF treatment. DNA damage was examined by gammaH2AX foci assay. The anti-cancer effect of AIF in vivo was validated in CRC xenograft model. KEY FINDINGS: We found that AIF inhibited CRC cell proliferation and promoted apoptosis in a dose dependent manner, as well as increased the number of gamma-H2AX foci. In addition, microarray analysis showed that the DNA-double strand break (DSB) repair gene RAD51 was aberrantly overexpressed in CRC tissues, and was positively correlated with lymph node metastasis, TNM stage and poor outcomes. Both in vitro and in vivo experiments confirm that AIF treatment significantly decreased RAD51 levels. Knockdown RAD51 could enhance the anti-cancer activity of AIF against CRC, while abrogated by RAD51 overexpression. SIGNIFICANCE: These findings suggest that AIF can be regarded as a potential anti-cancer drug and provide new insights into CRC treatment. PMID- 30448265 TI - Eugenol ameliorates insulin resistance, oxidative stress and inflammation in high fat-diet/streptozotocin-induced diabetic rat. AB - BACKGROUND: Eugenol, a phenolic compound present in many plant essential oils, demonstrated anti-diabetic activity but the underlying mechanisms are not fully understood. The aim of the present study was to examine the anti-diabetic, anti oxidative and the anti-inflammatory effect of eugenol in high-fat-diet (HFD) and streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of eugenol on the insulin sensitivity and on skeletal muscle protein contents of glucose transporter-4 (GLUT4) and AMP-activated protein kinase (AMPK) was investigated. MATERIALS AND METHODS: HFD/STZ-induced diabetic rats were treated orally with eugenol (10 mg/kg) for 45 days. After the end of the experiment, blood and skeletal muscle samples were collected. Metformin was used as positive control. RESULTS: The anti-diabetic effects of eugenol were demonstrated by the significant reduction in the levels of serum glucose, triglyceride, cholesterol, Low-density lipoprotein, malondialdehyde and interleukin-6 in the treated group compared to the diabetic group. Additionally, eugenol treatment significantly restored the decreased serum levels of insulin and glutathione when compared to that of the diabetic control rats. The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower in rats treated with eugenol than in the diabetic rats. The skeletal muscle protein contents of GLUT4 and AMPK were higher in the eugenol treated groups than in the diabetic control group. CONCLUSION: Eugenol possesses potent anti-oxidative and anti-inflammatory effect in HFD/STZ-induced diabetic rats. Moreover, eugenol facilitates insulin sensitivity and stimulate skeletal muscle glucose uptake via activation of the GLUT4-AMPK signaling pathway. Eugenol could represent a promising therapeutic agent to prevent type 2 diabetes. PMID- 30448266 TI - [MRgRT: Magnetic Resonance guided Radiation Therapy]. PMID- 30448267 TI - A behavior-theoretic evaluation of values clarification on parental beliefs and intentions toward genomic sequencing for newborns. AB - Decision aids commonly include values clarification exercises to help people consider which aspects of a choice matter most to them, and to help them make decisions that are congruent with their personal values and preferences. Using a randomized online experiment, we examined the influence of values clarification on parental beliefs and intentions about having genomic sequencing for newborns. We recruited 1186 women and men ages 18-44 who were pregnant or whose partner was pregnant or planning to become pregnant in the next two years. Participants (N = 1000) completed one of two versions of an online decision aid developed as part of a larger project examining the technical, clinical, and social aspects of using exome sequencing to screen newborns for rare genetic conditions. The education-only version provided information about using genomic sequencing to screen newborns for medically treatable conditions. The education-plus-values clarification version included the same information, along with a values clarification exercise in which participants classified as important or unimportant five reasons in support of having and five reasons against having their newborn undergo genomic sequencing. We conducted partial correlations, regression analysis, and MANCOVAs with sex, health literacy, and experience with genetic testing as covariates. Participants who completed the decision aid with the values clarification exercise agreed less strongly with four of the five statements against sequencing compared to participants who viewed the education only decision aid. The groups did not differ on agreement with reasons in support of sequencing. Agreement with four of five reasons against genomic sequencing was negatively associated with intentions to have their newborn sequenced, whereas agreement with all five reasons in support of sequencing were positively associated with intentions. PMID- 30448268 TI - Brief measures of physical and psychological distance to suicide methods as correlates and predictors of suicide risk: A multi-study prospective investigation. AB - A core component of suicide risk assessment and management is determining one's physical proximity to specific suicide means and counseling individuals to minimize their physical access to these means. However, this approach ignores other potentially relevant parameters, such as perceptions of how psychologically close/distant one feels to a particular suicide method. The present study examined the degree to which novel, brief measures of physical and psychological distance to suicide methods were associated with and prospectively predicted suicide-related outcomes at (1) two-month follow-up among 121 students with current/recent suicidality; and (2) one-week follow-up among 91 community dwelling adults at high suicide risk. Results indicated that both physical and psychological distance to means were related to suicidal intent at baseline. Additionally, in Study 2, lower psychological distance, but not physical distance, predicted suicidal intent and increased likelihood of having made suicide plans and suicide preparations at one-week follow-up. Overall, these findings highlight the importance of considering not only physical proximity to suicide means, but also psychological distance, pointing to the potential import of assessing and intervening upon psychological distance during lethal means counseling. Our findings also highlight the potential clinical utility of two brief measures of physical and psychological closeness to suicide means. PMID- 30448269 TI - Molecular dynamics and structural models of the cyanobacterial NDH-1 complex. AB - NDH-1 is a gigantic redox-driven proton pump linked with respiration and cyclic electron flow in cyanobacterial cells. Based on experimentally resolved X-ray and cryo-EM structures of the respiratory complex I, we derive here molecular models of two isoforms of the cyanobacterial NDH-1 complex involved in redox-driven proton pumping (NDH-1L) and CO2-fixation (NDH-1MS). Our models show distinct structural and dynamic similarities to the core architecture of the bacterial and mammalian respiratory complex I. We identify putative plastoquinone-binding sites that are coupled by an electrostatic wire to the proton pumping elements in the membrane domain of the enzyme. Molecular simulations suggest that the NDH-1L isoform undergoes large-scale hydration changes that support proton-pumping within antiporter-like subunits, whereas the terminal subunit of the NDH-1MS isoform lacks such structural motifs. Our work provides a putative molecular blueprint for the complex I-analogue in the photosynthetic energy transduction machinery and demonstrates that general mechanistic features of the long-range proton-pumping machinery are evolutionary conserved in the complex I-superfamily. PMID- 30448270 TI - Association of Provider Recommendation and Human Papillomavirus Vaccination Initiation among Male Adolescents Aged 13-17 Years-United States. AB - OBJECTIVE: To assess human papillomavirus (HPV) vaccination coverage among adolescents by provider recommendation status. STUDY DESIGN: The 2011-2016 National Immunization Survey-Teen data were used to assess HPV vaccination coverage among male adolescents by provider recommendation status. Multivariable logistic analyses were conducted to evaluate associations between HPV vaccination and provider recommendation status. RESULTS: HPV vaccination coverage among male adolescents increased from 8.3% in 2011 to 57.3% in 2016. Likewise, the prevalence of provider recommendation increased from 14.2% in 2011 to 65.5% in 2016. In 2016, HPV coverage was higher in male adolescents with a provider recommendation than in those without a provider recommendation (68.8% vs 35.4%). In multivariable logistic regression, characteristics independently associated with a higher likelihood of HPV vaccination included receipt of a provider recommendation, age 16-17 years, black or Hispanic race/ethnicity, any Medicaid insurance, >=2 physician contacts in the previous 12 months, and urban or suburban residence. Participants with a mother with some college or a college degree, those with a mother aged 35-44 years, and those who did not have a well child visit at age 11-12 years had a lower likelihood of HPV vaccination. CONCLUSIONS: Receiving a provider recommendation for vaccination was significantly associated with receipt of HPV vaccine among male adolescents, indicating that a provider recommendation for vaccination is an important approach to increase vaccination coverage. Evidence-based strategies, such as standing orders and provider reminders, alone or in combination with health system interventions, are useful for increasing provider recommendations and HPV vaccination coverage among male adolescents. PMID- 30448271 TI - Identifying and Managing Developmental and Behavioral Health Concerns within Primary Care: A Push for Change. PMID- 30448272 TI - Trends and Predictors of Clostridium difficile Infection among Children: A Canadian Population-Based Study. AB - OBJECTIVE: To assess time trends in Clostridium difficile infection (CDI) rates, and predictors of CDIs, including recurrent CDIs, in children. STUDY DESIGN: Data were extracted from Manitoba Health Provider Claims, and other population registry datasets from 2005 to 2015. CDI was identified from the Manitoba Health Public Health Branch Epidemiology and Surveillance population-based laboratory confirmed CDI dataset. Children aged 2-17 years with CDI were matched by age, sex, area of residence, and duration of residence in Manitoba with children without CDI. The rates and time trends of CDIs using previously recommended definitions were determined. Predictors of CDI subtypes were determined using multivariable logistic regression models. Cox regression analysis was used to assess for the potential predictors of recurrent CDI. RESULTS: Children with and without CDI were followed for 828 and 2753 persons-years, respectively. The overall CDI rate during the study period was 7.8 per 100 000 person-years. There was no significant change in CDI rates over the observation period. Comorbid conditions, more prevalent among children with CDI than matched controls, included Hirschsprung disease (P < .001) and inflammatory bowel disease (P < .0001). Recurrent CDIs (>2 occurrences) were responsible for 10% of CDI episodes (range, 2-6 infections). Predictors of recurrence included malignancy (hazard ratio, 3.0, 95% CI, 1.1-8.8), diabetes (hazard ratio, 4.8; 95% CI, 1.1-21.4), and neurodegenerative diseases (hazard ratio, 8.4; 95% CI, 1.9-37.5). CONCLUSIONS: The incidence of CDI is stable among children in Manitoba. Children with Hirschsprung disease and inflammatory bowel disease are more susceptible to CDI, and those with malignancy, diabetes. and neurodegenerative disorders are more likely to develop recurrent CDI. PMID- 30448273 TI - Reply. PMID- 30448274 TI - Practice Variation in Umbilical Hernia Repair Demonstrates a Need for Best Practice Guidelines. AB - OBJECTIVE: To evaluate and better understand variations in practice patterns, we analyzed ambulatory surgery claims data from 3 demographically diverse states to assess the relationship between age at umbilical hernia repair and patient, hospital, and geographic characteristics. STUDY DESIGN: We performed a cross sectional descriptive study of uncomplicated hernia repairs performed as a single procedure in 2012-2014, using the State Ambulatory Surgery and Services Database for Wisconsin, New York, and Florida. Age and demographic characteristics of umbilical hernia repair patients are described. RESULTS: The State Ambulatory Surgery and Services Database analysis included 6551 patients. Across 3 states, 8.2% of hernia repairs were performed in children <2 years, 18.7% in children age 2-3 years, and 73.0% in children age >=4 years, but there was significant variability (P < .001) in practice patterns by state. In regression analysis, race, Medicaid insurance and rural residence were predictive of early repair, with African American patients less likely to have a repair before age 2 (OR 0.62, P = .046) and rural children (OR 1.53, P = .009) and Medicaid patients (OR 2.01, P < .001) more likely to do so. State of residence predicted early repair even when holding these variables constant. CONCLUSIONS: The age of pediatric umbilical hernia repair varies widely. As hernias may resolve over time and can be safely monitored with watchful waiting, formal guidelines are needed to support delayed repair and prevent unnecessary operations. PMID- 30448275 TI - Autism Spectrum Disorder Severity, Developmental Delays, and Overweight/Obese Weight Status. PMID- 30448276 TI - HLA genotype and response to nivolumab therapy in relapsed refractory primary mediastinal B-cell lymphoma. PMID- 30448277 TI - Staphylococcus aureus meningitis in adults: A comparative cohort study of infections caused by methicillin-resistant and methicillin-susceptible strains. AB - BACKGROUND: Staphylococcus aureus meningitis is an uncommon nosocomial infection usually associated with neurosurgical procedures but spontaneous infections may occasionally appear. AIMS: To compare the features of meningitis caused by methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) S. aureus and examine the prognostic factors for mortality, including MRSA infection and combined antimicrobial therapy. METHODS: Retrospective cohort study of 350 adults with S. aureus meningitis admitted to 11 hospitals in Spain (1981-2015). Logistic regression and propensity score matching were used to analyze prognostic factors. RESULTS: There were 118 patients (34%) with MRSA and 232 (66%) with MSSA. Postoperative infection (91% vs. 73%) and nosocomial acquisition (93% vs. 74%) were significantly more frequent in MRSA than in MSSA meningitis (P<0.001). Combined therapy was given to 118 (34%) patients. Overall 30-day mortality rate was 23%. On multivariate analysis, mortality was associated with severe sepsis or shock (odds ratio [OR], 9.9 [95% CI, 4.5-22.0], P<0.001), spontaneous meningitis (OR, 4.2 [95% CI, 1.9-9.1], P<0.001), McCabe-Jackson score rapidly or ultimately fatal (OR, 2.8 [95% CI, 1.4-5.4], P=0.002), MRSA infection (OR, 2.6 [95% CI, 1.3 5.3], P=0.006), and coma (OR, 2.6 [95% CI, 1.1-6.1], P<0.029). In postoperative cases, mortality was related to retention of cerebrospinal devices (OR, 7.9 [95% CI, 3.1-20.3], P<0.001). CONCLUSIONS: Clinical and epidemiological differences between MRSA and MSSA meningitis may be explained by the different pathogenesis of postoperative and spontaneous infection. In addition to the severity of meningitis and underlying diseases, MRSA infection was associated with increased mortality. Combined antimicrobial therapy was not associated with increased survival. PMID- 30448278 TI - Glucagon-like peptide 1 (GLP-1) drives postprandial hyperinsulinemic hypoglycemia in pregnant women with a history of roux-en-Y gastric bypass operation. AB - BACKGROUND: The influential role of incretin hormones on glucose metabolism in patients with a history of Roux-en-Y gastric bypass (RYGB) has been investigated thoroughly, but there has been little examination of the effect of incretins and ectopic lipids on altered glucose profiles, especially severe hypoglycemia in pregnant women with RYGB. METHODS: In this prospective clinical study, an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and continuous glucose monitoring (CGM) were conducted in 25 women with RYGB during pregnancy, 19 of normal weight (NW) and 19 with obesity (OB) between the 24th and the 28th weeks of pregnancy, and 3 to 6 months post-partum. Post-partum, the ectopic lipid content in the liver, heart, and skeletal muscle was analyzed using 1H-magnetic resonance spectroscopy (1H-MRS). RESULTS: RYGB patients presented with major fluctuations in glucose profiles, including a high occurrence of postprandial hyperglycemic spikes and hypoglycemic events during the day, as well as a high risk of hypoglycemic periods during the night (2.9 +/- 1.1% vs. 0.1 +/- 0.2% in the OB and vs. 0.8 +/- 0.6% in the NW groups, p < 0.001). During the extended OGTT, RYGB patients presented with exaggerated expression of GLP-1, which was the main driver of the exaggerated risk of postprandial hypoglycemia in a time-lagged correlation analysis. Basal and dynamic GLP-1 levels were not related to insulin sensitivity, insulin secretion, or beta cell function and did not differ between pregnant women with and without GDM. A lower amount of liver fat (2.34 +/- 5.22% vs.5.68 +/- 4.42%, p = 0.015), which was positively related to insulin resistance (homeostasis model assessment of insulin resistance, HOMA IR: rho = 0.61, p = 0.002) and beta-cell function (insulinogenic index: rho = 0.65, p = 0.001), was observed in the RYGB group after delivery in comparison to the OB group. CONCLUSION: GLP-1 is mainly involved in the regulation of postprandial glucose metabolism and therefore especially in the development of postprandial hypoglycemia in pregnant RYGB patients, who are characterized by major alterations in glucose profiles, and thus in long-term regulation, multiple organ-related mechanisms, such as the lipid content in the liver, must be involved. Clinical Trials Registration Number: NCT03190148. PMID- 30448279 TI - Fetal midline anomalies: Diagnosis and counselling Part 1: Corpus callosum anomalies. AB - Midline anomalies encompasses a heterogeneous group of conditions caused by an abnormal process of ventral induction after the end of primary neurulation. Advances in prenatal imaging techniques have led to an increase in the detection rate of such anomalies since the first trimester of pregnancy although a significant proportion of them remain undiagnosed until birth. Ultrasound is the primary technique in detecting such anomalies while fetal magnetic resonance imaging (MRI) is commonly performed to confirm the diagnosis and detect additional anomalies, especially those involving the cortical surface of the brain, which may potentially impact post-natal outcome. Neurodevelopmental outcome of cerebral anomalies involving the midline is directly related to the type of anomaly, cause and presence of associated anomalies. However, even in case of isolated anomalies prenatal counselling is challenging. The aim of this review is to provide an up to date on the diagnosis, counselling and management of the most common supra-tentorial anomalies involving the midline and diagnosed on prenatal ultrasound. PMID- 30448280 TI - Prenatal diagnosis of brainstem anomalies. AB - Prenatal diagnosis of brainstem anomalies is important due to the usually associated neurodevelopmental impairment and genetic implications. The extreme developmental changes that the brainstem and cerebellum undergo during fetal life pose a challenge for the characterization and definition of the different malformations. The present review aims to demonstrate the normal development of the fetal brainstem and to present the main features required for diagnosis of its anomalies according to available data in the medical literature. PMID- 30448281 TI - Soluble LR11 competes with amyloid beta in binding to cerebrospinal fluid-high density lipoprotein. AB - BACKGROUND: LR11 is a member of the low-density lipoprotein (LDL) receptor family with high expression in neurons. Some cell surface LR11 is cleaved and secreted into the cerebrospinal fluid (CSF) as soluble LR11 (sLR11). Patients with Alzheimer's disease (AD), particularly apolipoprotein E4 carriers, have high CSF sLR11 and low CSF-amyloid beta (Abeta) concentrations. Therefore, we assessed whether sLR11 is bound to CSF-high-density lipoprotein (HDL) and whether sLR11 competes with Abeta in binding to apoE in CSF-HDL. METHODS: We measured CSF-sLR11 concentrations (50 controls and 16 patients with AD) using enzyme immunoassay. sLR11 and apoE distribution in the CSF was evaluated using non-denaturing two dimensional gel electrophoresis (N-2DGE). ApoE bound to sLR11 or Abeta was identified using co-immunoprecipitation assay. RESULTS: CSF-sLR11 concentrations were higher in patients with AD than controls (adjusted for sLR11 using phospholipid). N-2DGE analysis showed that sLR11 and Abeta comigrated with a large apoE-containing CSF-HDL. Moreover, fewer apoE was bound to Abeta when a higher amount of apoE was bound to sLR11 in patients with AD who presented with epsilon4/4. CONCLUSION: sLR11 binds to CSF-HDL and competes with Abeta in binding to apoE in CSF-HDL, indicating that sLR11 affects Abeta clearance via CSF-HDL. PMID- 30448282 TI - Deep neural network for estimating low density lipoprotein cholesterol. AB - BACKGROUND: LDL cholesterol (LDL-C) has been mainly estimated using the Friedewald equation, and other equations have recently been developed to complement the Friedewald equation. The present study aims to employ a deep neural network (DNN) to improve LDL-C estimation. METHODS: We used two independent datasets obtained from the Korean National Health and Nutrition Examination Survey and the Wonju Severance Christian Hospital as training and test datasets, respectively. We used the training dataset to construct the DNN architecture, which takes three input values of total cholesterol, HDL cholesterol, and triglyceride, and estimates LDL-C as the output. The model consists of six hidden layers, and each hidden layer has 30 nodes. The performance of the DNN model constructed by the training dataset was measured using the test dataset. RESULTS: In fivefold cross-validation using the training dataset, the DNN model showed the lowest mean and median squared errors compared to the Friedewald equation and Novel method. For the independent test dataset, our DNN model outperformed other existing methods on the basis of mean and median squared errors. CONCLUSIONS: The DNN model provided the most accurate estimation of LDL-C compared to other existing methods including the Friedewald and Novel methods. PMID- 30448283 TI - Contextualizing study drugs - An exploratory study of perceptions and practices among study counselors, general practitioners, psychiatrists and from student polls. AB - BACKGROUND: Recent decades have revealed a growing use of medicines for non disease conditions, especially among university students. The prevalence rates for the use of study drugs (SDs), i.e. prescription stimulants and beta-blockers, range from 2 to 20% among students worldwide. However, SD use does not take place in a vacuum. Like any other health-related behavior, medicine use takes place in specific social and cultural contexts, and there is very little scholarly work on these contextual aspects of SD use. OBJECTIVE: This article aims to explore university students' use of SDs through the perceptions and practices of university counselors, general practitioners (GPs), psychiatrists, and from student polls in Denmark, in order to advocate for a contextual approach to SD use. METHODS: The article relies on data from three different data sets involving a total of 18 semi-structured interviews, seven study counselors, nine GPs, and two psychiatrists, as well as votes from eight in-class polls conducted among approximately 300 university students in total. Data were collected between 2012 and 2017 and analyzed through meaning condensation and categorization. RESULTS: The study shows that a great variety of perceptions and practices concerning SDs exists. While study counselors generally do not hear much about SDs from students, except for those seeking help with regard to beta-blockers, they link the pressure, competition and perfectionism among students to a more general explanation of why some students may feel the need to use SDs. GPs meet students seeking SDs, but differ significantly in how they align their perceptions with their prescribing practices. The psychiatrists who participated in the study expressed widely different perceptions and practices regarding SDs. Finally, student polls indicate that students' opinions on SDs are also highly divided. CONCLUSION: The lack of consensus on SDs among professionals in health and education may contribute to students' divided opinions about SDs, just as it provides students with an opportunity to legitimize their use of SDs. PMID- 30448284 TI - The role of monogenic genes in idiopathic Parkinson's disease. AB - In the past two decades, mutations in multiple genes have been linked to autosomal dominant or recessive forms of monogenic Parkinson's disease (PD). Collectively, these monogenic (often familial) cases account for less than 5% of all PD, the majority being apparently sporadic cases. More recently, large-scale genome-wide association studies have identified over 40 loci that increase risk of PD. Importantly, there is overlap between monogenic and sporadic PD genes, particularly for the loci that contain the genes SNCA and LRRK2, which are mutated in monogenic dominant PD. There have also been reports of idiopathic PD cases with heterozygous variants in autosomal recessive genes suggesting that these mutations may increase risk of PD. These observations suggest that monogenic and idiopathic PD may have shared pathogenic mechanisms. Here, we focus mainly on the role of monogenic PD genes that represent pleomorphic risk loci for idiopathic PD. We also discuss the functional mechanisms that may play a role in increasing risk of disease in both monogenic and idiopathic forms. PMID- 30448285 TI - Reduction of microglial progranulin does not exacerbate pathology or behavioral deficits in neuronal progranulin-insufficient mice. AB - Loss-of-function mutations in progranulin (GRN), most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Individuals with loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Progranulin is a secreted glycoprotein expressed by a variety of cell types throughout the body, including neurons and microglia in the brain. Understanding the relative importance of neuronal and microglial progranulin insufficiency in FTD pathogenesis may guide development of therapies. In this study, we used mouse models to investigate the role of neuronal and microglial progranulin insufficiency in the development of FTD-like pathology and behavioral deficits. Grn-/- mice model aspects of FTD and NCL, developing lipofuscinosis and gliosis throughout the brain, as well as deficits in social behavior. We have previously shown that selective depletion of neuronal progranulin disrupts social behavior, but does not produce lipofuscinosis or gliosis. We hypothesized that reduction of microglial progranulin would induce lipofuscinosis and gliosis, and exacerbate behavioral deficits, in neuronal progranulin-deficient mice. To test this hypothesis, we crossed Grnfl/fl mice with mice expressing Cre transgenes targeting neurons (CaMKII-Cre) and myeloid cells/microglia (LysM-Cre). CaMKII Cre, which is expressed in forebrain excitatory neurons, reduced cortical progranulin protein levels by around 50%. LysM-Cre strongly reduced progranulin immunolabeling in many microglia, but did not reduce total brain progranulin levels, suggesting that, at least under resting conditions, microglia contribute less than neurons to overall brain progranulin levels. Mice with depletion of both neuronal and microglial progranulin failed to develop lipofuscinosis or gliosis, suggesting that progranulin from extracellular sources prevented pathology in cells targeted by the Cre transgenes. Reduction of microglial progranulin also did not exacerbate the social deficits of neuronal progranulin insufficient mice. These results do not support the hypothesis of synergistic effects between progranulin-deficient neurons and microglia. Nearly complete progranulin deficiency appears to be required to induce lipofuscinosis and gliosis in mice, while partial progranulin insufficiency is sufficient to produce behavioral deficits. PMID- 30448286 TI - Effects of acute waterborne exposure to harmful algal toxin domoic acid on foraging and swimming behaviours of fish early stages. AB - Domoic acid (DA) is a neurotoxin naturally produced by Pseudo-nitzschia diatoms that may be transferred through the marine food web and cause mass mortality events at higher trophic levels. Yet, the effects of the dissolved marine toxin on foraging responses and swimming performances of fish early stages are poorly known. Here we evaluated the effects of short-term exposure (24 h) to a single dose of domoic acid (136 MUg DA L-1) on larvae (15-20 days post-hatch) of three commercially important fish species (the sea breams Diplodus sargus and Sparus aurata and the meagre Argyrosomus regius). Although DA exposure did not elicit significant effects on larval survival (p > 0.05) and swimming performance (p > 0.05), the toxin significantly affected the fish capture success (p < 0.001). Our findings suggest that toxigenic Pseudo-nitzschia blooms may compromise fish early stages, in particular larvae feeding behaviours, leading to complications in the development and increasing fish vulnerability and mortality. PMID- 30448287 TI - First observation of microcystin- and anatoxin-a-producing cyanobacteria in the easternmost part of the Gulf of Finland (the Baltic Sea). AB - The aim of this study was to obtain the first data on the occurrence and distribution of potentially toxic cyanobacteria and cyanotoxins in the Russian Easternmost part of the Gulf of Finland of the Baltic Sea. Studied samples were collected from 2012 to 2017 and three independent approaches - HPLC-HRMS, PCR and light microscopy were applied for cyanotoxins analysis and detection of toxigenic cyanobacteria. Aphanizomenon flos-aquae Ralfs ex Born. et Flah., Planktothrix agardhii (Gom.) Anag. et Kom., Microcystis aeruginosa (Kutz.) Kutz. and Dolichospermum spp. dominated among cyanobacteria in collected samples. In 2012 2013 during research cruises, microcystins concentrations varied from below detection levels to low (0.01-0.6 MUg L-1) values. In the autumn of 2015 and 2017, during cyanobacterial bloom events very high concentrations of microcystins (dissolved up to 49 MUg L-1, intracellular up to 466 MUg g-1) and dissolved anatoxin-a (1.4 MUg L-1) were detected. The evaluated toxin profile was represented by most common arginine-containing variants of microcystins (MC-LR, MC-RR, MC-YR) and their desmethylated forms. Leucine-containing congeners (MC-LF; MC-LY; MC-LW for the biomass sample from the coast of Komarovo, 2015) were found at low concentrations. In environmental DNA from bloom samples, we identified mcy genes regions responsible for MC biosynthesis that are specific for Dolichospermum, Microcystis, and Planktothrix. This study is the first molecular evidence the ability of Microcystis aeruginosa and Planktothrix agardhii from the Gulf of Finland to produce microcystins. On the basis of the obtained data of genus-specific PCR and microscopy, we suppose the presence of anatoxin-a producing Apanizomenon flos-aquae population in the phytoplankton of Russian part of the Gulf of Finland. PMID- 30448288 TI - An unusual case of gross myoglobinuria in a child following Russell's viper (Daboia russelii) envenomation. AB - Overt myoglobinuria associated with myotoxicity is a classic feature of sea snake envenomation. Russell's viper bites usually result in coagulopathy, neurotoxicity and nephrotoxicity but rarely myotoxicity has been reported, especially in the Sri Lankan variety (Daboia russelii). All those studies have demonstrated mild degree myotoxicity with microscopic level myoglobinuria. We report what is probably the first case of gross myoglobinuria in a child following a Russell's viper bite with biochemical evidence of significant myotoxicity well beyond the levels that have been previously reported. PMID- 30448289 TI - Protective effects of kefir against zearalenone toxicity mediated by oxidative stress in cultured HCT-116 cells. AB - Kefir is a fermented milk with numerous health favors counting restorative properties of bacterial flora, reduction of the symptoms of lactose intolerance, immune system stimulation, cholesterol reduction, as well as anti-mutagenic and anti-tumor properties. Zearalenone (ZEN) is a mycotoxin produced by some Fusarium species. ZEN often occurs as a contaminant in cereal grains and animal feeds. Human exposure occurs by ingestion of mycotoxin-contaminated products and can cause serious health problems. This study aimed to assess the preventive effect of kefir against ZEN toxicity in cultured HCT-116 colorectal carcinoma cells; by the evaluation of cell viability, oxidative stress status and the initiation of apoptotic cell death pathway. Our results demonstrated that ZEN inhibits cell proliferation which was accompanied by an increase in the generation of free radicals as measured by fluorescent 2,7-dichlorofluorescein (DCF) and Malondialdehyde (MDA). As an adaptive response to this redox status, we showed an induction of heat shock protein expression (Hsp 70) and an activation of antioxidant enzymes; catalase and Superoxide Dismutase (SOD). Moreover, a loss of mitochondrial membrane potential (Delta?m) was observed. The co-treatment as well as the pre-treatment by kefir showed a reduction of ZEN induced damages for all tested markers. However, the pre-treatment seems to be the most efficient, it prevented almost all ZEN hazards. Consequently, oxidative damage appears to be a key determinant of ZEN induced toxicity in cultured HCT-116 cells. In conclusion, we showed that kefir may better exert its virtue on preventive mode rather than on curative one. By this way, kefir as a beverage with highly antioxidant properties could be relevant particularly with the emergent demand for natural products which may counteract the detrimental effects of oxidative stress and therefore prevent multiple human diseases. PMID- 30448290 TI - Systemic lupus erythematosus: Diagnosis and clinical management. AB - Systemic lupus erythematosus (SLE) is a worldwide chronic autoimmune disease which may affect every organ and tissue. Genetic predisposition, environmental triggers, and the hormonal milieu, interplay in disease development and activity. Clinical manifestations and the pattern of organ involvement are widely heterogenous, reflecting the complex mosaic of disrupted molecular pathways converging into the SLE clinical phenotype. The SLE complex pathogenesis involves multiple cellular components of the innate and immune systems, presence of autoantibodies and immunocomplexes, engagement of the complement system, dysregulation of several cytokines including type I interferons, and disruption of the clearance of nucleic acids after cell death. Use of immunomodulators and immunosuppression has altered the natural course of SLE. In addition, morbidity and mortality in SLE not only derive from direct immune mediated tissue damage but also from SLE and treatment associated complications such as accelerated coronary artery disease and increased infection risk. Here, we review the diagnostic approach as well as the etiopathogenetic rationale and clinical evidence for the management of SLE. This includes 1) lifestyle changes such as avoidance of ultraviolet light; 2) prevention of comorbidities including coronary artery disease, osteoporosis, infections, and drug toxicities; 3) use of immunomodulators (i.e. hydroxychloroquine and vitamin D); and 4) immunosuppressants and targeted therapy. We also review new upcoming agents and regimens currently under study. PMID- 30448291 TI - Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, and consequently, effective antifibrotic drugs are strongly desired. Although we have previously reported a validated Col1a1-Luc Tg rat model for fibrosis, there are only a few mouse models that enable the evaluation of fibrosis in a short time period and with high sensitivity. Therefore, we generated a Col1a1-internal ribosome entry site (IRES)-Luc knock-in (KI) mouse in which the IRES-luciferase gene construct was inserted into the 3'-UTR of the type I collagen alpha 1 gene (Col1a1). There was a high correlation between luciferase activity and hydroxyproline content in the KI mice, which is similar to the result that we have previously reported for the Col1a1-Luc Tg rat model. In a bleomycin (BLM) induced lung fibrosis model, luciferase activity in the lung showed a significant increase 3 days after BLM treatment, while only a slight increase was observed in the hydroxyproline content. An ALK-5 inhibitor-R-268712-was effective in inhibiting the luciferase activity in both the in vivo BLM-induced lung fibrosis model and in vitro primary mouse lung fibroblasts. This suggests that fibroblasts are the major collagen-producing cells in lung fibrosis. In human lung fibroblasts, TGF-beta stimulation induced alpha-smooth muscle actin as observed by immunostaining, suggesting that myofibroblast transdifferentiation (MTD) plays an important role in lung fibrosis. Together, these results indicated that ALK-5 inhibitors might affect lung fibrosis mainly via the inhibition of MTD. Thus, the Col1a1-IRES-Luc KI mouse might be useful for the evaluation of antifibrotic effects and their underlying mechanisms. PMID- 30448292 TI - Chemokine CXCL10/CXCR3 signaling contributes to neuropathic pain in spinal cord and dorsal root ganglia after chronic constriction injury in rats. AB - Inflammatory cytokines and chemokines play essential roles in the occurrence and persistence of neuropathic pain (NP). Chronic constriction injury (CCI) enhances the activation of p-ERK, which is involved in neuropathic pain. Although the chemokine CXCL10 and its receptor CXCR3 are implicated in the pathophysiology of itch, it is largely unexplored for neuropathic pain. In this study, we determined the role of the CXCL10-CXCR3 axis in NP using a well-established CCI model. CCI significantly induced mechanical allodynia and thermal hyperalgesia. Following the pain course, a significant increase of CXCL10 and CXCR3 in both dorsal root ganglion (DRG) neurons and spinal cord (SC) neurons was detected in rats. Furthermore, intrathecal injection of CXCR3 inhibitor AMG487 was found to attenuate pain hypersensitivity in a dose-dependent manner in CCI. The expression of p-ERK was also depressed after intrathecal injection of AMG487 associated with a significant laxation of hyperalgesia, which demonstrated that the interaction of CXCL10/CXCR3 possibly took part in neuropathic pain by regulating p-ERK signaling in the SC. Overall, these findings demonstrate that the CXCL10/CXCR3 signaling pathway is critical in CCI. PMID- 30448293 TI - Endogenous hydrogen peroxide affects antidiuresis to cholinergic activation in the medial septal area. AB - Cholinergic activation of the medial septal area (MSA) with carbachol produces thirst, natriuresis and antidiuresis. Hydrogen peroxide (H2O2) injected into the medial septal area (MSA) impairs behavioral and renal responses induced by carbachol at the same site, suggesting the exogenous H2O2 may modulate the responses to cholinergic activation in the MSA. In the present study, we investigated if the accumulation of endogenous H2O2 in the MSA after the injection of the catalase inhibitor 3-amino-1,2,4-triazole (ATZ) also affects cholinergic responses. In addition, the effects of the combination of ATZ with a non-effective dose of H2O2 in the MSA were also tested. Male Holtzman rats (280 320 g) with stainless steel cannulas implanted in the MSA were used. The treatment with ATZ (10 nmol) into the MSA partially reverted the antidiuretic effect of carbachol (10.5 +/- 0.7, vs. saline + carbachol: 7.3 +/- 0.6 ml/120 min), without changing carbachol-induced water intake (9.5 +/- 1.9, vs. saline + carbachol: 10.7 +/- 1.6 ml/60 min). The combination of a low dose of ATZ (2.5 nmol) with an ineffective dose of H2O2 (0.5 MUmol) into the MSA reduced carbachol induced thirst (7.5 +/- 2.0, vs. saline + carbachol: 14.9 +/- 1.2 ml/15 min) and reverted the antidiuresis (8.1 +/- 1.1, vs. saline + carbachol: 5.3 +/- 0.9 ml/120 min). Sodium and potassium excretion were not modified regardless the treatment. Although exogenous H2O2 injected in the MSA may affect most of the responses to cholinergic activation of the MSA, the antidiuresis is the response clearly modulated by endogenous H2O2. PMID- 30448295 TI - Response to the editorial comment. PMID- 30448294 TI - IL-15 improves skeletal muscle oxidative metabolism and glucose uptake in association with increased respiratory chain supercomplex formation and AMPK pathway activation. AB - BACKGROUND: IL-15 is believed to play a role in the beneficial impact of exercise on muscle energy metabolism. However, previous studies have generally used supraphysiological levels of IL-15 that do not represent contraction-induced IL 15 secretion. METHODS: L6 myotubes were treated acutely (3 h) and chronically (48 h) with concentrations of IL-15 mimicking circulating (1-10 pg/ml) and muscle interstitial (100 pg/ml -20 ng/ml) IL-15 levels with the aim to better understand its autocrine/paracrine role on muscle glucose uptake and mitochondrial function. RESULTS: Acute exposure to IL-15 levels representing muscle interstitial IL-15 increased basal glucose uptake without affecting insulin sensitivity. This was accompanied by increased mitochondrial oxidative functions in association with increased AMPK pathway and formation of complex III-containing supercomplexes. Conversely, chronic IL-15 exposure resulted in a biphasic effect on mitochondrial oxidative functions and ETC supercomplex formation was increased with low IL-15 levels but decreased with higher IL-15 concentrations. The AMPK pathway was activated only by high levels of chronic IL-15 treatment. Similar results were obtained in skeletal muscle from muscle-specific IL-15 overexpressing mice that show very high circulating IL-15 levels. CONCLUSIONS: Acute IL-15 treatment that mimics local IL-15 concentrations enhances muscle glucose uptake and mitochondrial oxidative functions. That mitochondria respond differently to different levels of IL-15 during chronic treatments indicates that IL-15 might activate two different pathways in muscle depending on IL-15 concentrations. GENERAL SIGNIFICANCE: Our results suggest that IL-15 may act in an autocrine/paracrine fashion and be, at least in part, involved in the positive effect of exercise on muscle energy metabolism. PMID- 30448296 TI - Spetzler-Martin grade IV and V arteriovenous malformations: Treatment outcomes and risk factors for negative outcomes after surgical resection. AB - OBJECTIVE: Microsurgical resection may be recommended for high grade brain arteriovenous malformations (BAVMs) (HBAVMs) in individualized patients. Careful case selection is necessary to minimize postoperative complications. The aim of this study was to determine the surgical outcomes in patients with HBAVMs and to identify their risk factors associated with postoperative negative outcomes. PATIENTS AND METHODS: We retrospectively studied 53 consecutive patients with HBAVMs. All patients had undergone preoperative diffusion tensor imaging (DTI), MRI, 3D time-of-flight MRA (3D TOF-MRA) and digital subtraction angiography (DSA) followed by resection. White matter (WM) eloquent fibre tracts, including the corticospinal tract (CST), optic radiation (OR) and arcuate fasciculus (AF), were tract. Both functional, angioarchitectural and operative factors were analyzed with respect to the surgical outcomes. RESULTS: Nineteen (35.8%) patients suffered from negative surgical outcomes (MRS > 2) one week after surgery. At the last clinic visit, 10 patients (18.9%) suffered from negative surgical outcomes. Diffuse nidus (P = 0.018), Perforating arteries (PA) supplying (P = 0.009) and CST involving (P = 0.001) were independent risk factors for negative short-term outcomes. PA supplying (P = 0.039), CST involving (P = 0.026) and postoperative intracranial haemorrhage (ICH) (P = 0.014) were independent risk factors for negative long-term neurological outcomes. Larger nidus size (P = 0.024) was predictor of postoperative ICH. The cut-off point was 6.8 cm. CONCLUSIONS: This study identified that diffuse nidus, PA supplying and CST involving are risk factors for negative short-term outcomes in patients with HBAVMs. PA supplying, CST involving and postoperative ICH are risk factors for negative long-term outcomes. Larger nidus size was risk factor for postoperative ICH. PMID- 30448297 TI - C5 pure motor spinal cord injury: A case with a rare manifestation of cervical spinal cord injury. AB - We report an extremely rare case showing a fifth cervical spine (C5) level pure motor cervical spinal cord injury (SCI). A 55-year-old-man lost consciousness and fell into a bathtub. Immediately after regaining consciousness, the patient had right arm drop alone. He was referred to our department for investigation of right arm drop 4 months later. Neurological examination revealed motor weakness of the right deltoid muscle. MRI of the cervical spine revealed a C3-4 level central disc herniation compressing the spinal cord. An electromyogram study revealed bilateral neurogenic discharges in the deltoid, supraspinatus and infraspinatus muscles. We diagnosed a C5 segmental pure motor SCI. We chose conservative therapy for the present patient. At the latest follow-up visit, the patient showed modest recovery of motor weakness. Although it is unusual, this case illustrates the possibility that C5 segmental pure motor palsy can occur as one of the manifestations of cervical SCI. PMID- 30448298 TI - Autonomic nervous system assessment by pupillary response as a potential biomarker for cardiovascular risk: A pilot study. AB - BACKGROUND: Cardiovascular risk (CVR) biomarkers are of increasing interest because of their potential utility in management of cardiovascular diseases. The activity of the autonomic nervous system (ANS) is known to be highly correlated with CVR and therefore, is a putative biomarker. Common ANS measurement tools have several technological limitations and high-variance signals. The pupillary responses (PR) is controlled by both components of the ANS, and recent advances in pupillometry are making this measurement, easy and reliable. Thus, PR assessment could become a useful clinical tool to measure the ANS modulation and its relation to CVR. Here, we aimed to evaluate differences in PR between low CVR and moderate/high CVR individuals. METHODS: We performed a cross-sectional study. We recruited voluntaries with low CVR (group 1, n = 12) and patients with moderate/high CVR (group 2, n = 7). An eye tracker was used to measure PR to different visual stimulus that included colors (white, black, gray) and images with known emotional valence (pleasant, unpleasant and neutrals), which were intercalated by pink "noise" images. Differences in PR between both CVR groups were assessed by Mann Whitney U test of different epochs of the PR. RESULTS: PR was significantly different between both CVR groups (p-value < 0,05) when the observed images were unpleasant, neutral, and pink noise, for different epochs of the PR. CONCLUSIONS: This is the first study that demonstrates that PR is different according to CVR. Thus, PR could be considered as a novel biomarker of CVR to be tested in prospective studies. PMID- 30448299 TI - Young and Aged Blunt Trauma Patients Display Major Differences in Circulating Inflammatory Mediator Profiles after Severe Injury. AB - BACKGROUND: Aging is accompanied by alterations in immune functions. How these changes translate into levels of circulating inflammatory mediators and network expression after severe trauma is not well characterized. To address this, we compared time-dependent changes in the levels of an extensive biomarker panel in cohorts of severely injured young and aged adults. STUDY DESIGN: Cohorts of young (18-30 years old, n=115) and aged (65-90 years old, n=101) blunt trauma patients admitted to the intensive care unit (ICU) with plasma sampled 3 times within the first 24 hours and daily from day (D)1 to D7 were assayed for 30 inflammatory biomarkers using LuminexTM. Stringently matched groups controlling for sex ratio and injury severity score [ISS] (n = 56 young vs. n = 56 aged) were generated. Data were analyzed using 2-way ANOVA, area under the curve (AUC) analysis, Dynamic Bayesian Network (DyBN) inference, and Dynamic Network Analysis (DyNA). RESULTS: In the overall cohorts, the young group had a significantly higher ISS, which was associated with higher circulating levels of 18 inflammatory mediators from admission to D7. The aged group had higher levels of C-X-C motif chemokine 10/interferon gamma-induced protein 10 (CXCL10/IP-10) and chemokine ligand 9/monokine induced by gamma interferon (CXCL9/MIG). In groups that were matched for ISS, the significantly higher levels of IP-10 and MIG persisted in the aged. DyBN revealed IP-10 and MIG as key mediators in the aged, while DyNA revealed higher network complexity in the aged. CONCLUSIONS: These findings indicate that differences in the early inflammatory networks between young and aged trauma patients are not simply a suppression of pro-inflammatory responses in the aged, but are characterized by a major shift in the mediator profile patterns with high levels of CXC chemokines in the aged. PMID- 30448300 TI - Impact of Autologous Blood Transfusion on Survival and Recurrence Among Patients Undergoing Partial Hepatectomy for Colorectal Cancer Liver Metastases. AB - BACKGROUND: Autologous transfusion has long been considered unsafe in major oncologic surgery due to a theoretic risk of spreading metastatic disease, however, little data supports this assumption. STUDY DESIGN: Retrospective analysis of 147 patients who underwent partial hepatectomy for colorectal cancer metastases at a single institution. 74 patients received only an autologous transfusion (AT) and 73 received no transfusion (NT). We compared the overall survival (OS) and recurrence-free survival (RFS) of these groups using Kaplan Meier survival curves and adjusted Hazard Ratios. RESULTS: Patients who received autologous transfusion had greater blood loss, more extensive resections, and longer procedures. There were no differences in age, sex, proportion colon vs. rectal cancer or Fong clinical risk score. Mean follow-up was 54 months. Median OS in the autologous transfusion group was 59 months compared to 54 months in the no transfusion group, p=0.69 on log-rank test. After adjusting for age, gender, Fong score, type of cancer (colon vs. rectal), receipt of neoadjuvant therapy, receipt of adjuvant therapy, extent of resection and blood loss, no difference in OS was noted: hazard ratio AT vs. NT 0.58 (95% confidence interval (CI): 0.31 1.11; p=0.10). RFS was also similar in the AT and NT groups (27% vs. 37%, p=0.22). The adjusted hazard ratio for RFS was 0.95 (95% CI: 0.54-1.65; p=0.85). CONCLUSIONS: Autologous blood transfusion is not associated with an increased recurrence risk or a higher mortality rate. Surgeons performing liver resections for patients with colorectal cancer metastases can safely transfuse filtered autologous blood. PMID- 30448301 TI - Otilonium and pinaverium trigger mitochondrial-mediated apoptosis in rat embryo cortical neurons in vitro. AB - In the frame of a repositioning programme with cholinergic medicines in clinical use searching for neuroprotective properties, we surprisingly found that spasmolytic antimuscarinics otilonium and pinaverium exhibited neurotoxic effects in neuronal cultures. We decided to characterize such unexpected action in primary cultures of rat embryo cortical neurons. Neurotoxicity was time- and concentration-dependent, exhibiting approximate EC50 values of 5 MUM for both drugs. Seven antimuscarinic drugs endowed with a quaternary ammonium, and another 10 drugs with different cholinergic activities, carrying in their molecule a ternary ammonium did not exhibit neurotoxicity. Both drugs caused a concentration dependent blockade of whole-cell inward currents through voltage-activated calcium channels (VACCs). Consistent with this, they also blocked the K+-elicited [Ca2+]c transients. Neither antioxidant catalase, glutathione, n-acetylcysteine, nor melatonin protected against neurotoxicity of otilonium or pinaverium. However cyclosporine A, a blocker of the mitochondrial permeability transition pore, prevented the neurotoxic effects of otilonium and pinaverium monitored as the fraction of cells undergoing apoptosis. Furthermore, the caspase-9 and caspase-3 inhibitor Ac-LEHD-CHO mitigated the apoptotic neuronal death of both drugs by around 50%. Data are compatible with the hypothesis that otilonium and pinaverium elicit neuronal death by activating the intrinsic mitochondrial-mediated signaling pathway of apoptosis. This may have its origin in the mitigation of Ca2+ entry and the uncoupling of the Ca2+-dependent generation of mitochondrial bioenergetics, thus causing the opening of the mitochondrial mPTP to elicit apoptotic neuronal death. PMID- 30448302 TI - Abnormal cortical activation during silent reading in adolescents with autism spectrum disorder. AB - OBJECTIVE: Autism spectrum disorder (ASD) is a developmental disorder characterized by communication deficits and social difficulties, and individuals with ASD frequently exhibit varied levels of language abilities. However, the neurophysiological mechanisms underlying their language deficits remain unclear. To gain insight into the neurophysiological mechanisms of receptive language deficits, we assessed cortical activation patterns in adolescents with ASD during silent word-reading. METHODS: We used magnetoencephalography to measure cortical activation during a silent word-reading task in 14 adolescent boys with high functioning ASD and 17 adolescent boys with typical development (TD). RESULTS: Compared with participants with TD, those with ASD exhibited significantly decreased cortical activation in the left middle temporal gyrus, left temporoparietal junction, bilateral superior temporal gyrus, left posterior insula, and right occipitotemporal gyrus, and increased activation in the right anterior insula. Participants with ASD also exhibited a lack of left lateralization in the central sulcus and abnormal right-lateralization in the anterior insula area. Furthermore, in participants with ASD, we found that abnormal activation of the right central sulcus correlated significantly with lower visual word comprehension scores, and that decreased activation of the right anterior insula correlated significantly with the severity of social interaction difficulties. CONCLUSION: Our findings suggest that atypical cortical activation and lateralization in the temporal-frontal area, which is associated with higher-order language processing functions, such as semantic analysis, may play a crucial role in visual word comprehension and social interaction difficulties in adolescents with ASD. PMID- 30448304 TI - Association of bone mineral density with hemoglobin and change in hemoglobin among older men and women: The Cardiovascular Health Study. AB - PURPOSE: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD). METHODS: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged >65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb <13 g/dL in men; <12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use. RESULTS: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10-2 g/cm2per 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = -0.49 [x 10-2 g/cm2per 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10-2 g/cm2per 1 g/dL annualized Hgb change], 95% CI: 4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women. CONCLUSIONS: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement. PMID- 30448305 TI - Antibiotic Resistance Induction in Eyes With Boston Type I Keratoprosthesis. PMID- 30448303 TI - Lamin B receptor-related disorder is associated with a spectrum of skeletal dysplasia phenotypes. AB - LBR (Lamin B Receptor) encodes a bifunctional protein important for cholesterol biosynthesis and heterochromatin organization on the inner nuclear membrane. Pathogenic variants in LBR are associated with marked phenotypic variability, ranging from the benign Pelger-Huet anomaly to lethal Greenberg Dysplasia. We performed trio exome sequencing (ES) on two patients with atypical variants of skeletal dysplasia and their unaffected parents. Patient 1 exhibited frontal bossing, mid-face hypoplasia, short stature with rhizomelic limb shortening, and relative macrocephaly at birth. Although remained short, Patient 1 later showed spontaneous improvement in her skeletal findings. Exome sequencing revealed two novel variants in LBR, c.1504C > G (p.Arg502Gly) in exon 12 and c.1748G > T (p.Arg583Leu) in exon 14, which were inherited from her unaffected father and mother, respectively. Sterol analysis revealed an increased level of cholesta 8,14-dien-3beta-ol to 2.9% of total sterols, consistent with a functional deficiency of 3beta-hydroxysterol Delta14-reductase. Patient 2 presented at birth with short stature and marked rhizomelic limb shortening but later exhibited decreasing severity of shortening of the long bones and improvement in the radiographic skeletal abnormalities although he continued to be significantly short at age 10 years. Exome sequencing revealed that Patient 2 is homozygous for a pathogenic variant c.1534C > T (p.Arg512Trp) in exon 12 of LBR, which was inherited from his unaffected consanguineous parents. This report provides further evidence for a phenotypic spectrum of LBR-associated disorders and expands the genotypic spectrum by describing 3 novel disease-causing variants that have not been previously associated with a disease. Moreover, our data on Patient 1 demonstrate that variants throughout the gene appear to influence both the sterol reductase and nuclear functions of LBR. PMID- 30448306 TI - Boston Type I Keratoprosthesis: Antibacterial Resistance and Microbiota Evaluation of Soft Contact Lenses. PMID- 30448307 TI - Predicted amorphous solubility and dissolution rate advantages following moisture sorption: Case studies of indomethacin and felodipine. AB - Water is often readily absorbed by amorphous compounds, lowering their glass transition temperature (Tg) and facilitating their recrystallization (via nucleation-and-growth). At the same time, the increase in moisture content translates to a decrease in both the thermodynamic solubility and intrinsic dissolution rate, as compared to the corresponding dry (pure) amorphous phase, e.g. see [Murdande SB, Pikal MJ, Shanker RM, Bogner RH. 2010. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci 99:1254-1264.]. In the case of pure indomethacin and felodipine, the solubility advantage of each amorphous phase over its crystalline counterpart were previously determined to be 7.6 and 4.7, respectively, using a new methodology together with basic calorimetric data taken from the literature. Herein, we demonstrate that, theoretically, following the uptake of just ~0.5% w/w water, the solubility ratios decrease to 6.9 and 4.5, in the same order. Moreover, as the predicted intrinsic dissolution rate (based on the Noyes-Whitney equation) is directly proportional to the solubility advantage of a given amorphous crystalline pair, it decreases proportionately upon moisture uptake. Applying the methodology presented herein, one can directly predict the extent of Tg-lowering observed at any moisture content, for a given amorphous phase. Knowing that value, it is possible to estimate the relative decrease in the solubility and/or intrinsic dissolution rate of the plasticized phase compared to the pure glass, and vice-versa. PMID- 30448308 TI - 'Dendrimer-Cationized-Albumin' encrusted polymeric nanoparticle improves BBB penetration and anticancer activity of doxorubicin. AB - Glioblastoma is one of the most rapaciously growing cancer within the brain with an average lifespan of 12-15 months (5-year survival <3-4%). Doxorubicin (DOX) is clinically utilized as a first line drug in the treatment of Glioblastoma, however, its restricted entry into the brain via the blood-brain barrier (BBB), limited blood-tumor barrier (BTB) permeability, hemotoxicity, short mean half life of 1-3 hr as well as rapid body clearance results in tremendously diminished bioactivity in glioblastoma. Dendrimer-Cationized-Albumin (dCatAlb) was synthesized following the carboxyl activation technique and the synthesized biopolymer was characterized by FTIR, MALDI-TOF and zeta potential. The prepared dCatAlb was encrusted on DOX-loaded PLGA nanoparticle core to develop a novel hybrid DOX nanoformulation (dCatAlb-pDNP; particle size: 156 +/- 10.85 nm; e: 10.0 +/- 2.1 mV surface charge). The formulated dCatAlb-pDNP showed a unique pH dependent DOX release profile, diminished hemolytic toxicity, higher drug uptake (<0.001) and cytotoxicity in U87MG glioblastoma cells, increase levels of caspase 3 gene in U87MG cells (approximately 5.35-fold higher) inferred that anticancer activity is primarily taking place through caspase-mediated apoptosis mechanism. The developed novel DOX nanoformulation also showed superior trans-epithelial permeation transport across monolayer bEnd.3 cells as well as notable biocompatibility and stability. The dCatAlb-pDNP showed enhanced BBB permeation efficacy as confirmed permeation assay in bEnd.3 cell-based model. The long-term formulation stability of developed nanoformulations was studied by storing them at 5 +/- 2 degrees C and 30 +/- 2 degrees C/60 +/- 5% Relative Humidity (% RH) in the stability chamber for a period of 60 days (ICHQ1A (R2)). The outcomes of this investigation evidently indicate that dCatAlb-pDNP offers superior anticancer activity of DOX in glioblastoma cells while significantly improving its BBB permeation. The developed formulation is a biocompatible, safer and commercially viable approach to delivering DOX selectively in sustained manner glioblastoma while countering its hemolytic toxic effect, which is a major ongoing issue with conventional DOX injectable available in the market today. PMID- 30448309 TI - Biocompatible nanoparticles and vesicular systems in transdermal drug delivery for various skin diseases. AB - Transdermal drug delivery (TDDS) has been highly explored in the past couple of decades due to benefits such as increased patient compliance, improved drug release, tissue targeting, avoiding the presystemic metabolism in the liver etc. However, the stratum corneum poses as the rate limiting barrier to the permeation of drugs through the skin, which has been a continuous challenge in TDDS. This review covers the various types of nanoparticles and nanoemulsions that are currently being investigated for TDDS applications, desirable physical and chemical characteristics of these systems, their routes of penetration through the skin, and summarizes recent advances using these systems in treating conditions such as alopecia, wound healing, psoriasis, and melanoma. Additionally, synergistic effect of iontophoresis and mechanical force mediated drug delivery will be reviewed. PMID- 30448310 TI - Tailoring microstructural, drug release properties, and antichagasic efficacy of biocompatible oil-in-water benznidazol-loaded nanoemulsions. AB - This study explored the transition of lamellar-type liquid crystal (LLC) to biocompatible oil-in-water nanoemulsions able to modify benznidazole (BNZ) release and target the drug to cells infected with the T. cruzi parasite. Three cosolvents (2methylpyrrolidone [NMP], polyethylene glycol [POL], and propylene glycol [PRO] were tested to induce the transition of anisotropic LLC systems to isotropic nanoemulsions. Mixtures of soy phosphatidylcholine with sodium oleate stabilized the dispersions of medium chain triglyceride in water. Rheological measurements, polarized microscopy, and small angle X-ray scattering demonstrated that there is a phase transition from LLC to desired nanoemulsions. These small and narrow droplet-sized nanocarriers exhibited some advantages and promising features, such as the enhanced BNZ aqueous solubility and slow drug release rate. In vitro cell biocompatibility of formulations was assessed in the Vero E6 and SiHa cell lines. Drug-loaded nanoemulsions inhibited the epimastigote growth of the T. cruzi parasite (IC50 0.208 +/- 0.052 MUg mL-1) and reduced its infective life form trypomastigote (IC50 0.392 +/- 0.107 MUg mL-1). The oil-in-water nanoemulsions were demonstrated as promising biocompatible liquid drug delivery systems capable of improving the BNZ trypanocidal activity for the treatment of Chagas disease. PMID- 30448311 TI - Theoretical and practical evaluation of lowly hydrolyzed polyvinyl alcohol as a potential carrier for hot-melt extrusion. AB - Polyvinyl alcohol (PVA) is considered to be an unsuitable carrier for hot-melt extrusion (HME) due to its low processability. In this study, we focused on a lowly hydrolyzed PVA (JR-05, 70.0-74.0% hydrolyzed, L-PVA) to evaluate the potential use of L-PVA as a carrier for HME using the Hoftyzer and Krevelen method and thermodynamic models. These evaluations for drug-polymer systems based on the Flory-Huggins theory predicted the physicochemical properties of the solubility and miscibility between indomethacin (IND) and PVAs. Prior to initiating formulation studies, construction of IND and PVA phase diagrams provided guidance for design process conditions in HME. On the basis of the results of the validation studies, a conventional grade of PVA (JP-05, 87.0-89.0% hydrolyzed) is unlikely to be suitable as a carrier of HME due to its low plasticity, resulting in rapid recrystallization in the evaluation of in vitro dissolution and stability caused by poor miscibility. On the other hand, JR-05 demonstrated high processability, leading to the preparation of miscible extrudate with a high stability and an excellent in vitro dissolution profile due to its unique micelle-forming capability. These findings suggest that L-PVA brings about new carrier options among non-ionic polymers for HME. PMID- 30448312 TI - Synthesis and modification of crystalline SBA-15 nanowhiskers as a pH-sensitive metronidazole nanocarrier system. AB - Clinical resistance to drugs and diminution in their side effects have become great issues for pharmacologists. In veterinary medicine, parasites like Trichomonas gallinae are of veterinary, hygienic and economic importance and can be treated by metronidazole. Unfortunately, scientific evidence has been reported about its resistance and serious side effects in trichomoniasis. In this research, it was attempted to introduce a new procedure to lower side effects of the drug molecules and also, enhance the treatment of disease. Whisker-formed SBA 15 nanoparticles were utilized for the first time in this issue. They had mesoporous structures which metronidazole molecules could be trapped in them. Additionally, these crystalline nanowhiskers were modified with tannic acid to make the release process better. The branches of tannic acid covered the opening of pores in crystalline SBA-15 nanowhiskers and restricted the drug from fast release. It caused a controlled metronidazole release in the smart drug delivery. These nanocarriers were completely tested by several experiments. Whisker-like SBA-15 nanocrystals had a mesopore volume of 0.5931 cm3/g, pore diameter of 6.06 nm and surface area of 491.38 m2/g. Based on TGA analysis, 10% of tannic acid was coated on the crystalline nanowhiskers during the modification. The metronidazole content and entrapment efficiency of final nanocarriers was 28.56% and 71.40%, respectively. The decomposition of tannic acid in lower pHs made whisker-like SBA 15@tannic acid nanocrystals be pH-responsive which can be used for other applications in the pharmacology. In-vitro study revealed that the minimal lethal concentration of nanocarriers was 0.5 mg/mL for 180 min. PMID- 30448313 TI - A novel composition of ticagrelor by solid dispersion technique for increasing solubility and intestinal permeability. AB - The aim of this study is to improve the bioavailability of ticagrelor, BCS class 4 drug, using solid dispersion technique, and to evaluate the potential of ticagrelor loaded-solid dispersion, as a new formulation. The solid dispersion formulation was prepared via solvent evaporation method using ethanol. TPGS and Neusilin(r) US2 selected via screening studies were used for preparing formulation. The results of scanning electron microscopy, differential scanning calorimetry and powder X-ray diffraction showed that the crystallinity of the ticagrelor was completely transformed to an amorphous form and maintained in the solid dispersion formulation. The released amount of the optimized solid dispersion significantly increased by 2.2- and 34-fold in comparison with physical mixture (Ticagrelor:TPGS:Neusilin(r) US2 = 1:2:2, w/w/w) and commercial product (Brilinta(r)) in distilled water at 90 min, respectively. The absorptive permeability was improved (1.4-fold) and the efflux ratio was decreased (0.45 fold) by formulation containing TPGS acting as a P-gp inhibitor compared to pure drug. The solid dispersion formulation improved the peak plasma concentration (Cmax) and relative bioavailability compared to that of pure drug as 238.09 +/- 25.96% and 219.78 +/- 36.33%, respectively, after oral administration in rats. Thus, we successfully prepared the solid dispersion formulation for enhancing oral bioavailability of ticagrelor, and then this formulation would be recommended as a practical oral pharmaceutical product. PMID- 30448314 TI - Magnetic-silk/polyethyleneimine core-shell nanoparticles for targeted gene delivery into human breast cancer cells. AB - The lack of efficient and cost-effective methods for gene delivery has significantly hindered the applications of gene therapy. In this paper, a simple one step and cost effective salting-out method has been explored to fabricate silk-PEI nanoparticles (SPPs) and magnetic-silk/PEI core-shell nanoparticles (MSPPs) for targeted delivery of c-myc antisense oligodeoxynucleotides (ODNs) into MDA-MB-231 breast cancer cells. The size and zeta potential of the particles were controlled by adjusting the amount of silk fibroin in particle synthesis. Lower surface charges and reduced cytotoxicity were achieved for MSPPs compared with PEI coated magnetic nanoparticles (MPPs). Both SPPs and MSPPs were capable of delivering the ODNs into MDA-MB-231 cells and significantly inhibited the cell growth. Through magnetofection, high ODN uptake efficiencies (over 70%) were achieved within 20 min using MSPPs as carriers, exhibiting a significantly enhanced uptake effect compared to the same carriers via non-magnetofection. Both SPPs and MSPPs exhibited a significantly higher inhibition effect against MDA-MB 231 breast cancer cells compared to human dermal fibroblast (HDF) cells. Targeted ODN delivery was achieved using MSPPs with the help of a magnet, making them promising candidates for targeted gene therapy applications. PMID- 30448315 TI - Formulation and biopharmaceutical evaluation of supersaturatable self nanoemulsifying drug delivery systems containing silymarin. AB - The first objective of this study was to optimize a supersaturatable self nanoemulsifying drug delivery system (S-SNEDDS) containing silymarin through the investigation of the single and synergistic effect of either SNEDDS or a precipitation inhibitor on dissolution efficiency (DE) of silymarin. The bioavailability and hepatoprotective activity of S-SNEDDS were then compared to those of a branded product (Legalon(r), Meda). SNEDDS containing silymarin was developed by titration technique, and Poloxamer 407 was selected as the optimal precipitation inhibitor by using casting film and solvent-shift method. The interaction of silybin (the major active constituent of silymarin) and the polymer was then determined by differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transforms infrared spectroscopy and 1H NMR analysis. The combination of two techniques including SNEDDS and addition of 10% of Poloxamer 407 remarkably increased DE4h (88.28%) compared to the reference product (6.41%). The relative bioavailability of S-SNEDDS versus Legalon(r) was about 760%. The hepatoprotective activity of S-SNEDDS in CCl4-induced mice was also superior to the commercial product in declining both the levels of serum transaminases (ALT, AST) and lipid peroxidation as well as glutathione and superoxide dismutase (SOD) activities under tested doses calculated as silybin (10, 25 and 50 mg/kg). These biopharmaceutical and pharmacological advantages of S-SNEDDS indicated prospects in the development of a novel product that offers lower strength of silymarin while enhancing therapeutic outcomes. PMID- 30448316 TI - Adjustment of Vocal Tract Shape via Biofeedback: Influence on Vowels. AB - The study assessed 30 nonprofessional singers to evaluate the effects of vocal tract shape adjustment via increased resonance toward an externally applied sinusoidal frequency of 900 Hz without phonation. The amplification of the sound wave was used as biofeedback signal and the intensity and the formant position of the basic vowels /a/, /e/, /i/, /o/, and /u/ were compared before and after a vocal tract adjustment period. After the adjustment period, the intensities for all vowels increased and the measured changes correlated with the participants' self-perception.The diferences between the second formant position of the vowels and the applied frequency influences the changes in amplitude and in formant frequencies. The most significant changes in formant frequency occurred with vowels that did not include a formant frequency of 900 Hz, while the increase in amplitude was the strongest for vowels with a formant frequency of about 900 Hz. PMID- 30448317 TI - Laryngostroboscopic Exploration of Rough Vocal Effects in Singing and their Statistical Recognizability: An Anatomical and Physiological Description and Visual Recognizability Study of Distortion, Growl, Rattle, and Grunt using laryngostroboscopic Imaging and Panel Assessment. AB - OBJECTIVES: To study vocal effects in singing from the pedagogical method complete vocal technique as related to specific and discrete supraglottic structures and activities by means of laryngostroboscopic imaging and panel testing. STUDY DESIGN: This is a case-control study with a double-panel assessment. METHODS: Twenty singers were recorded performing four of the rough vocal effects from the method Complete Vocal Technique. Two studies were performed: (1) Laryngostroboscopic examination using a videonasoendoscopic camera system and the Laryngostrobe program; (2) two blind-panel assessments with (a) voice clinicians and (b) singing teachers to investigate the recognizability of the vocal effects in supraglottic structures. RESULTS: The four investigated vocal effects could be related to particular and discrete vibratory pattern of supraglottic structures; Distortion as vibrations of the ventricular folds, Growl as vibrations of the arytenoid cartilages against the epiglottis, Rattle as the vibration of the arytenoid cartilages against one another, and Grunt as the vibrations of the whole supraglottic structure from level 1-4 at low frequencies with a large amplitude in the vibration of the vocal folds, with particular movement of the aryepiglottic folds. The two panels recognized the vocal effects with 91%/96% accuracy for Distortion, 91%/74% accuracy for Rattle, 90%/66% accuracy for Grunt, and 83%/99% accuracy for Growl, with an overall accuracy of 91%/84%. CONCLUSION: Vocal effects can be performed, identified, and recognized as particular vibratory patterns of supraglottic structures with no visible pathology in subjects performing the effects. PMID- 30448318 TI - Analysis of the first 2645 registrations at the research registry(r): A global repository for all study types involving human participants. AB - BACKGROUND: The Declaration of Helsinki has called for the registration of all research studies involving human participants. Despite this, prior registries did not allow registration certain study types, or retrospective registration. The Research Registry(r) (www.researchregistry.com) was established in 2015 to provide a venue of registration for any study involving human participants. METHODS: and analysis: This retrospective database analysis describes the first 3000 registrations received by the Research Registry(r). Since the launch of the Registry in 2015, we have collected data on each registration and excluded inappropriate registrations through a weekly curation process. The characteristics of all studies registered is presented. Each registration was marked against a quality score by two researchers acting independently, and we describe how this has changed over time. No ethical approval was required for this data only study including no human participants. RESULTS: Of 3000 registrations, we included 2645 that were submitted to the registry between February 2015 and October 2017. The number of registrations increased year on year, and we now receive between 60 and 80 registrations per month. One fifth of registrations were from China (537 [20.3%]). Retrospective observational studies were most commonly registered (1125 [42.5%]), and studies included in excess of 20 million patients (median 80 [IQR:25-200]). The quality score of registrations improved over the time (Kruskal-Wallis p < 0.05), and the 'control/comparator' component of the quality score was most poorly completed (completed by 1199 [54%]). CONCLUSION: The Research Registry(r) has received registrations on over 2500 registrations, including in excess of 20 million patients, with the quality of registrations improving over time. Retrospective observational studies and case series are the most commonly registered. PMID- 30448319 TI - Verification of the rabies virus glycoprotein lower limit of immunogenicity by serological assay. AB - Rabies lethality is close to 100% and annually 15 million people receive post exposure prophylaxis. Testing for vaccines against this zoonosis should ensure its quality. A standardized test by the National Institutes of Health (NIH) test, based on mice immunization and challenge, has been used to determine the potency of vaccine lots. It has several disadvantages, the main one being its significant variability. Several in vitro methods like an Enzyme-linked immunosorbent assay (ELISA) have been proposed based on the quality and quantity of glycoprotein (Glptn) of rabies virus, but may also present limitations such as low sensitivity, instability and imprecision. The estimate of immunogenicity based on neutralizing antibody titer (Nab) evaluated by a serological test (ST) such as the Modified Rapid Fluorescent Focus Inhibition Test (mRFFIT), is not yet efectively applied for human vaccine. Nevertheless, a Nab concentration can be used as a predictor of clinical efficacy of this product in vaccinated humans, so, that can be applied in estimating the vaccine potency. The aim of this study was to verify the lower limit of immunogenicity of the viral Glptn content in mice using mRFFIT. The lower Glptn content by ELISA able to induce Nab response was determined. The results were correlated and demonstrated that ST was able to determine the Glptn immunogenicity lower limit. Our findings suggest that a test based on rabies Nabs may represent an additional alternative for the evaluation of rabies vaccines. PMID- 30448320 TI - Molecular characterization of two novel proteins All1122 and Alr0750 of Anabaena PCC 7120 conferring tolerance to multiple abiotic stresses in Escherichia coli. AB - In- silico and functional genomics approaches have been used to determine cellular functions of two hypothetical proteins All1122 and Alr0750 of Anabaena sp. PCC 7120. Motif analysis and multiple sequence alignment predicted them as typical alpha/beta ATP binding universal stress family protein-A (UspA) with G (2*)-G-(9*)-G(S/T) as conserved motif. qRT-PCR data under UV-B, NaCl, heat, As, CdCl2, mannitol and methyl viologen registered approximately 1.4 to 4.3 fold induction of all1122 and alr0750 thus confirming their multiple abiotic stress tolerance potential. The recombinant E. coli (BL21) cells harboring All1122 and Alr0750 showed 12-41% and 23-41% better growth respectively over wild type control under said abiotic stresses thus revalidating their stress coping ability. Functional complementation on heterologous expression in UspA mutant E. coli strain LN29MG1655 (DeltauspA::Kan) attested their UspA family membership. This study tempted us to suggest that recombinant Anabaena PCC 7120 over expressing all1122 and alr0750 might contribute to the nitrogen economy in paddy fields experiencing array of abiotic stresses including drought and nutrient limitation. PMID- 30448321 TI - Longitudinal changes in vigorous intensity physical activity from childhood to adolescence: Gateshead Millennium Study. AB - OBJECTIVE: The aims of our study were to quantify levels and investigate sex specific changes and trajectories in VPA longitudinally from age 7 to 15 years. DESIGN: Longitudinal observational study. METHODS: Participants were part of the Gateshead Millennium Study. Measures were taken at age 7 (n=507), 9 (n=510), 12 (n=425) and 15 years (n=310). Vigorous physical activity was quantified objectively using ActiGraph GT1M accelerometers over 5-7days at the four time points. Multilevel linear spline random-effects model and trajectory analysis to identify sub-groups were performed. RESULTS: In boys, average VPA declined across childhood followed by an increase at adolescence, while in girls, average VPA declined across the 8-year study period. In boys, daily VPA decreased from 9-12 years (1.70minutes/year) and increased from 12-15 years (1.99minutes/year) (all p <0.05). In girls daily VPA decreased from 7-9 years (1.70minutes/year) (p <0.05). Three VPA trajectories were identified which differed between the sexes. In boys, one group decreased from an initial relatively high level, one group, initially relatively low, increased, whereas the third one was stable over the 8-year period. In girls, all three groups declined from baseline. CONCLUSIONS: Marked sex and age-specific trajectories in VPA change were observed. These novel findings should help sports and exercise medicine specialists, as well as policy makers, in their effort to maintain or increase VPA in childhood and adolescence. PMID- 30448322 TI - Association between musculoskeletal pain at multiple sites and objectively measured physical activity and work capacity: Results from UK Biobank study. AB - OBJECTIVES: To describe the cross-sectional association between musculoskeletal pain at multiple sites and physical work capacity (PWC) and objectively measured physical activity (PA). DESIGN: Observational study. METHODS: Data from a subsample of the UK Biobank were utilised (n=9856; mean age 58.5 years, mean body mass index 30.2kg/m2, 62% female). PWC was measured by a bicycle ergometer and PA by an accelerometer. Pain experienced in hip, knee, back and neck/shoulder was collected by questionnaire. Linear regression modelling was used with adjustment for potential confounders to estimate the association between pain and PWC and PA. RESULTS: Increase in number of painful sites was associated with lower PWC, moderate and vigorous PA and increased low intensity PA in a dose-response relationship (all p-values for trend <=0.001) before and after adjustment for confounders. In site specific analyses, hip pain was associated with an increased low intensity PA (beta 52.8min/week, 95% CI 2.3-103.2) and reduced moderate PA (beta -50.1min/week, 95% CI -98.5 to -1.8). Knee pain was only associated with vigorous PA (beta -5.7min/week, 95% CI -10.0 to -1.3). Pain at neck/shoulder pain and back were not independently associated with PWC and PA. CONCLUSIONS: Greater number of painful sites is consistently associated with poorer PWC, increased low intensity PA and reduced moderate to vigorous PA. Clinicians should address the critical role of being physically active in managing chronic musculoskeletal pain and interventions targeting musculoskeletal pain may be needed to increase PA levels. PMID- 30448323 TI - Occult Left Common Iliac Vein Compression Increases Postoperative Venous Thromboembolism Risk Following Total Hip Arthroplasty. AB - BACKGROUND: Left common iliac vein (LCIV) compression by the right or left common iliac artery (RCIA, LCIA) is known to cause venous thromboembolism (VTE), but the extent to which occult LCIV compression synergizes with lower extremity orthopedic surgery is unknown. We hypothesize that occult LCIV compression is associated with increased VTE risk following total hip or knee arthroplasty (THA, TKA). METHODS: This case-control study involves all patients at our institution who underwent primary or revision THA or TKA from 2009 to 2017 who had computed tomography or magnetic resonance imaging of the abdomen or pelvis available preoperatively. VTE cases (pulmonary embolism or left-sided deep vein thrombosis) within 30 days of surgery were matched to a control by age, gender, body mass index, Charlson Comorbidity Index, surgical site, and hypercoagulable risk factors. LCIV compression by the right common iliac artery and/or the left common iliac artery was measured in a blinded fashion and was considered present at 50% diameter reduction. RESULTS: One hundred twelve patients (22 cases, 90 controls) were included for analysis. Nineteen (86.4%) cases and 46 (51.1%) controls demonstrated LCIV compression. The overall sample odds ratio of postoperative VTE in the presence of LCIV compression was 5.97 (95% confidence interval 1.59-33.67, P = .003). In patients who underwent THA (n = 75), LCIV compression was highly predictive of VTE (odds ratio infinity, 95% confidence interval 2.83-infinity, P < .001). Compression in the TKA patients did not significantly predict VTE. CONCLUSION: Compression of the LCIV significantly increases odds of developing postoperative VTE following THA. This effect may suggest a new method of stratifying VTE risk in the orthopedic population to reduce VTE-associated morbidity and mortality. PMID- 30448324 TI - Bundled Payment "Creep": Institutional Redesign for Primary Arthroplasty Positively Affects Revision Arthroplasty. AB - BACKGROUND: Revision total joint arthroplasty (TJA) is associated with increased readmissions, complications, and expense compared to primary TJA. Bundled payment methods have been used to improve value of care in primary TJA, but little is known of their impact in revision TJA patients. The purpose of this study is to evaluate the impact of a care redesign for a bundled payment model for primary TJA on quality metrics for revision patients, despite absence of a targeted intervention for revisions. METHODS: We compared quality metrics for all revision TJA patients including readmission rate, use of post-acute care facility after discharge, length of stay, and cost, between the year leading up to the redesign and the 2 years following its implementation. Changes in the primary TJA group over the same time period were also assessed for comparison. RESULTS: Despite a volume increase of 37% over the study period, readmissions declined from 8.9% to 5.8%. Use of post-acute care facilities decreased from 42% to 24%. Length of stay went from 4.84 to 3.92 days. Cost of the hospital episode declined by 5%. CONCLUSION: Our health system experienced a halo effect from our bundled payment influenced care redesign, with revision TJA patients experiencing notable improvements in several quality metrics, though not as pronounced as in the primary TJA population. These changes benefitted the patients, the health system, and the payers. We attribute these positive changes to an altered institutional mindset, resulting from an invested and aligned care team, with active physician oversight over the care episode. PMID- 30448325 TI - Topical Tranexamic Acid in Revision Total Knee Arthroplasty Reduces Transfusion Rates and May Be Associated With Earlier Recovery. AB - BACKGROUND: The use of tranexamic acid (TXA) has been proved to be effective in reducing blood loss and transfusion requirements after primary total knee arthroplasty (TKA). However, the evidence for its use in revision surgery is scant. We assessed the safety and efficacy of topical TXA in revision TKA. METHODS: We retrospectively compared 76 revision TKA patients who received topical TXA (3 g before tourniquet deflation) "study group" with a historic control group of 205 revision TKA patients in which TXA was not used. Each group was further stratified into subgroups according to the type of revision. All patients were followed for a minimum of 6 weeks. Blood loss, transfusion requirements, changes in hemoglobin-hematocrit levels, Knee Society Score, and complications were recorded. RESULTS: The mean estimated blood loss, hemoglobin drop, and transfusion rate were significantly lower in the study group than in the control group (P = .008, P < .001, P < .001, respectively). Hidden blood loss was similar between the 2 groups (P = .12). Six weeks postoperatively, the improvement in the knee-specific Knee Society Score was significantly higher in the study group than in the control group (P < .001). No significant differences were found in thromboembolic complications between the 2 groups (P = .92). In the subgroup analysis, when both components (femur and tibia) were revised, the relative risk of transfusion was significantly lower with the use of TXA (relative risk 0.227, confidence interval 0.0593-0.860, P = .004). CONCLUSION: Topical TXA in revision TKA is safe and effective in reducing blood loss and transfusions. This effect is enhanced when both components are revised. Additionally, the use of TXA may improve early outcomes. PMID- 30448326 TI - Direct Anterior Approach Total Hip Arthroplasty Using a Morphometrically Optimized Femoral Stem, a Conventional Operating Table, Without Fluoroscopy. AB - BACKGROUND: Our experience with direct anterior approach total hip arthroplasty (THA) suggests that it can be performed successfully with a morphometrically optimized metaphyseal-diaphyseal engaging femoral stem (NOT a short stem), a regular operating room table (NOT a special custom table), and WITHOUT intraoperative fluoroscopy. We report our minimum 2-year results. METHODS: A retrospective review of a single-surgeon series of primary direct anterior approach THAs was performed. All procedures were performed on a regular table, without fluoroscopy, using a cementless tapered femoral stem. Clinical, functional, and radiographic outcomes were evaluated at a minimum of 2 years. RESULTS: In total, 1017 primary THAs were performed. The preoperative Harris Hip Score was 40.7 +/- 5.1 and improved to 95.3 +/- 4.2 at minimum 2-year follow-up. There were 3 dislocations (0.3%) and 15 revisions (1.5%): 7 for infection (0.7%), 4 for periprosthetic fractures (0.4%), 2 for instability (0.2%), 1 for loosening (0.1%), and 1 for pain (0.1%). Five patients (0.5%) required blood transfusion. One patient developed deep vein thrombosis and pulmonary embolism. No intraoperative fractures, perforation, or THA-related mortality occurred. Neutral stem alignment was confirmed in 98.3%. Mean cup inclination was 38.8 degrees +/- 5.1 degrees and anteversion was 16.2 degrees +/- 3.5 degrees . The mean leg length discrepancy was corrected from 1.2 +/- 0.2 cm preoperatively to 0.2 +/- 0.1 cm postoperatively. CONCLUSION: Using a morphometrically optimized metaphyseal-diaphyseal engaging tapered femoral stem instead of a short stem reduces component malposition and minimizes risk of loosening. Combining the use of this implant design and the technique and elements described in our cohort demonstrated to have excellent results at 2 years. The patients will need continued follow-up to demonstrate further durability of this device and technique compared to others performing direct anterior THA. PMID- 30448327 TI - Frailty as a predictor of complications after radical cystectomy: A prospective study of various preoperative assessments. AB - PURPOSE: Frailty has been correlated with worse postoperative outcomes. Prospective studies examining frailty and bladder cancer are lacking. We aimed to determine whether a prospective frailty assessment or traditional risk indices can identify patients undergoing radical cystectomy (RC) at risk for complications. MATERIALS AND METHODS: Patients >=65 years undergoing RC were preoperatively assessed using Fried Frailty Criteria (FFC; grip strength, gait speed, exhaustion, physical activity, shrinking), Charlson Comorbidity Index, American Society of Anesthesiologists score, Katz Index of Independence in Activities of Daily Living, Karnofsky Performance Scale, Eastern Cooperative Oncology Group performance status, and Center for Epidemiological Studies Depression scale. Thirty-day and 90-day postoperative complications were recorded. Univariate and multivariate analyses were performed. RESULTS: One hundred and twenty three patients were assessed with median age of 74 years. Fifty-nine patients (48.0%) had >=1 complication within 30 days and 72 (58.5%) within 90 days. Center for Epidemiological Studies Depression scale (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.01-1.17, P = 0.027) and shrinking (OR 3.79, 95% CI 1.64-9.26, P = 0.0024) were significant for any 30-day complication, while physical activity was protective (OR 0.84, 95% CI 0.69-1.00, P = 0.072) for any 90-day complication. Being intermediately frail or frail was associated with high-grade 30-day (OR 4.87, 95% CI 1.39-22.77, P = 0.022) and 90-day complications (OR 3.01, 95% CI 1.05-9.37, P = 0.045), along with Eastern Cooperative Oncology Group score >=3 (OR 45.00, 95% CI 6.92-437.69, P = 0.0010 and OR 17.85, 95% CI 3.21-143.26, P = 0.0079, respectively). CONCLUSIONS: Fried Frailty Criteria were predictive of high-grade complications, while individual components were predictive of having any complication. Elderly patients should be routinely assessed prior to RC to guide postoperative care. PMID- 30448328 TI - Outcomes of midfoot and hindfoot fractures in multitrauma patients. AB - INTRODUCTION: Multitrauma patients suffering hindfoot fractures, including calcaneal and talar fractures, often result in poor outcomes. However, less is known about the outcomes following midfoot fracture in the mutitrauma population. This study aims to describe the epidemiology of midfoot fractures in multitrauma patients and to compare the outcomes of midfoot and hindfoot fractures in this population. METHODS: Data about multitrauma patients (Injury Severity Score >12) sustaining a unilateral midfoot or hindfoot fracture were obtained from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR) and from retrospective review of medical records at a major trauma centre. Further outcome data were obtained via a survey using the American Academy of Orthopedic Surgeons Foot and Ankle Score (AAOS FAS) and the 12-item Short Form Health Survey (SF-12). RESULTS: 122 multitrauma patients were included; 81 with hindfoot fractures and 41 with midfoot fractures. The median ISS (IQR) was 22 (17-29) and 27 (17-24) for the hindfoot and midfoot groups, respectively (p = 0.23). Hindfoot and midfoot fractures were commonly associated with intracranial injuries (80.3%), spine injuries (60.7%), ipsilateral lower extremity injuries (24.6%) and pelvic injuries (16.4%). The mean (SD) time to follow up was 4.5 (+/-2.7) years. There were no differences in mean SF-12 physical (37.97 vs 35.22, p = 0.33) or mental (46.90 vs 46.67, p = 0.94) component summary scores between the groups. There were no differences in mean AAOS FAS standard scores (69.3 vs 69.1, p = 0.97) or shoe comfort scores (median 40 vs 40 p = 0.18) between the groups. CONCLUSION: Functional outcomes in multitrauma patients with midfoot or hindfoot fractures were comparable. These findings suggest that midfoot fractures should be treated with the same degree of due diligence as hindfoot fractures in the multitrauma patient. PMID- 30448329 TI - Fixator-assisted nailing of tibial fractures: New surgical technique and presentation of first 30 cases. AB - BACKGROUND: Intramedullary nailing is considered a "gold standard" for treatment of tibial shaft fractures. However, some types of fractures are typically considered as "difficult for nailing". This group includes the periarticular fractures, fractures of both bones at the same level, comminuted and segmental fractures of the tibia. Fixator-assisted nailing (FAN) is an effective method treatment of these types of fractures. The main requirements for the ideal reduction device are an ease of its installation and an ability of multiplanar fracture reduction. Fixator-assisted nailing (FAN) with the use of two perpendicular to each other monolateral tubular frames perfectly meets these requirements. In this study we present this new surgical technique and the analysis of first 30 cases. METHODS: A prospective analysis was conducted for 30 patients with "difficult for nailing" tibial fractures treated with fixator assisted nailing in our institution between September 1st, 2017, and March 1st, 2018. The duration of surgery and its different stages, the time of fluoroscopy, difficulties encountered during surgery, were analyzed. Clinical and radiological methods were used to evaluated reduction quality. RESULTS: In all 30 cases the acceptable reduction was achieved. The mean duration of the surgical procedure was 73.7 +/- 3 min. The mean duration of fluoroscopy 85.9 +/- 4.8 s. In 7 cases we faced with technical difficulties, which were successfully addressed. CONCLUSION: The described technique of FAN is an effective method for the treatment of "difficult for nailing" tibial fractures. Future multi-centered studies with a larger number of patients are needed to validate our results. PMID- 30448330 TI - Accuracy of massive transfusion as a surrogate for significant traumatic bleeding in health administrative datasets. AB - BACKGROUND: Due to the challenge of identifying need for intervention in bleeding patients, there is a growing interest in prediction modeling. Massive transfusion (MT; 10 or more packed red cells in 24 h) is the most commonly studied dependent variable, serving as a surrogate for severe bleeding and its prediction guides the need for intervention. The critical administration threshold (CAT; 3 packed red cells in 1 h) has been proposed as an alternative. In this study, we aim to compare the classification accuracy of these two surrogates for hemorrhage related outcomes in health administrative datasets. METHODS: We performed a secondary analysis of major trauma patients from the prospectively collected Ottawa Trauma Registry, from September 2014 to September 2017. We conducted a logistic regression analysis utilizing need for hemostasis or hemorrhagic death as dependent variables. We compared classification accuracy in terms of sensitivity, specificity, positive predictive value, negative predictive value and AUC. CAT + and MT + status is not mutually exclusive. RESULTS: We studied 890 major trauma patients, including 145 CAT + and 48 MT + patients. CAT + demonstrated a superior association for the composite outcome of 24-hour hemorrhage-related mortality and need for hemostasis (AUC 0.815 vs. 0.644, p < 0.0001). This performance was driven by a substantial difference in sensitivity, noted to be 70.0% (95% CI 62.1-77.9%) for CAT + but only 30.0% (95% CI 22.1 37.9%) for MT+. CAT + and MT + demonstrated specificities of 92.9% (95% CI 91.1 94.7%) and 98.9% (98.1-99.6%) respectively. CONCLUSION: This study illustrates the concepts of survivorship and competing risk bias for massive transfusion. Utilizing a composite outcome of need for hemostasis and early hemorrhagic death, we demonstrate that CAT + is more accurate for identifying significantly bleeding patients. PMID- 30448331 TI - Fluoroquinolones versus trimethoprim-sulfamethoxazole for the treatment of Stenotrophomonas maltophilia infections: A systematic review and meta-analysis. AB - BACKGROUND: Fluoroquinolones (FQs) are a popular alternative to trimethoprim sulfamethoxazole (STX) for Stenotrophomonas maltophilia infections. OBJECTIVES: To compare the effects of FQs and STX on mortality of S. maltophilia infections DATA SOURCES: PubMed and EMBASE STUDY ELIGIBILITY CRITERIA: Clinical studies reporting mortality outcomes of S. maltophilia infections PARTICIPANTS: Patients with clinical infections caused by S. maltophilia INTERVENTIONS: FQ monotherapy in comparison with STX monotherapy METHODS: Systematic review with meta-analysis technique RESULTS: Seven retrospective cohort and seven case-control studies were included. Three cohort studies were designed to compare the two drugs, while others for other purposes. A total of 663 patients were identified, 332 of which were treated with STX (50.1%) and 331 with FQs (49.9%). Three cohort studies were designed to compare the effect of the two drugs, while others for other purposes. Levofloxacin was most frequently used among FQs (187/331, 56.5%), followed by ciprofloxacin (114/331, 34.4%). The overall mortality rate was 29.6%. Using pooled ORs for the mortality of each study, FQ treatment (OR 0.62, 95% CI 0.39 0.99) was associated with survival benefit over STX treatment, with low heterogeneity (I2 = 18%). Specific FQs such as ciprofloxacin (OR 0.44, 95% CI 0.17-1.12) and levofloxacin (OR 0.78, 95% CI 0.48-1.26) did not show significant difference in comparison with STX. In the sub-group analyses of adult and bacteremic patients, significant differences in mortality were not observed between FQs and STX. CONCLUSIONS: Based on a meta-analysis of non-randomized studies, FQs demonstrated comparable effects on mortality of S. maltophilia infection to STX, supporting the use of FQs in clinical S. maltophilia infections. Although the pooled analysis of overall studies favored FQs over STX, the studies included were observational and sub-group analyses of certain FQ agents did not show statistical differences with STX. Randomized clinical studies need to be conducted to address these issues. PMID- 30448332 TI - Recombinant infectious laryngotracheitis virus expressing Newcastle disease virus F protein protects chickens against infectious laryngotracheitis virus and Newcastle disease virus challenge. AB - In this study, we isolated and identified an infectious laryngotracheitis virus (ILTV) that was naturally avirulent in specific pathogen-free (SPF) chickens, with the aim of developing a more efficacious vaccine against ILTV and Newcastle disease virus (NDV). We constructed a US9-deleted ILTV mutant based on this avirulent ILTV, and then constructed a recombinant ILTV (designated ILTV-DeltaUS9 F) expressing the fusion protein (F) of the genotype VII NDV based on the US9 deleted ILTV mutant. Expression of the F protein in ILTV-DeltaUS9-F-infected cells was confirmed by indirect immunofluorescence assay and western blotting. The inserted F gene was stably expressed in ILTV-DeltaUS9-F. The growth kinetics of ILTV-DeltaUS9-F were comparable to those of the wild-type ILTV strain. Vaccination of SPF chickens with ILTV-DeltaUS9-F produced no clinical signs but did induce low levels of NDV-specific enzyme-linked immunosorbent assay and neutralizing antibodies. A single vaccination with 104 plaque-forming units (PFU) of ILTV-DeltaUS9-F provided good protection against both genotype VII and IX NDVs based on clinical signs, similar to the protection provided by the commercial live La Sota vaccine. Notably, ILTV-DeltaUS9-F limited the replication and shedding of genotype VII NDV from oropharyngeal swabs more efficiently than the La Sota vaccine. In addition, vaccination with lower doses (103 and 102 PFU) of ILTV-DeltaUS9-F also provided sufficient clinical protection. These results indicated that ILTV-DeltaUS9-F may be a bivalent vaccine candidate against both ILTV and NDV. PMID- 30448334 TI - A cross-sectional study of Bordetella pertussis seroprevalence and estimated duration of vaccine protection against pertussis in St. Petersburg, Russia. AB - BACKGROUND: In Russia as in other countries introduction of infant vaccination against pertussis in 1950s led to dramatic decrease of whooping cough. The current vaccination schedule includes a 3-dose infant series and toddler booster; the pre-school booster was cancelled in 1980s and never reintroduced. Whole-cell vaccines, and in a smaller proportion acellular vaccines are used for all doses. However, pertussis incidence in urban settings is high with highest burden in school children. We conducted a study of seroprevalence of recent pertussis infection to estimate the duration of protection from the 4-dose series. MATERIALS AND METHODS: Sera sample from 395 St Petersburg children aged >=3 years and <14 years were tested for pertussis toxin antibodies using a commercial PT ELISA test. Only children with completed 4-dose vaccination course were included in the study. Age-specific seroprevalence of recent pertussis infection was analyzed for trends. RESULTS: Children fully vaccinated against pertussis at 3 years old had significant delays in infant vaccination schedule: only 83.5% received at least one dose of pertussis vaccine at 6 months of age and 25.6% received their toddler booster before 24 months-old. Overall, 10.6% of children demonstrated the serological signs of the infection in the last 12 months. A clear trend (r2 = 0.692) of increasing proportion of infection in the last 12 months was observed in children who had received their last dose of vaccine 6 years and more prior to the study. CONCLUSION: Our study demonstrates that Russian children become susceptible to infection at or soon after entering school. The results confirm the waning of vaccine-elicited immunity around school age and support the need for a booster dose at that age. PMID- 30448333 TI - Sero-prevalence of rubella among pregnant women in India, 2017. AB - BACKGROUND: We conducted a sero-survey among pregnant women attending antenatal clinics of six hospitals which also function as sentinel sites for CRS surveillance, to estimate the prevalence of IgG antibodies against rubella. METHODS: We systematically sampled 1800 pregnant women attending antenatal clinics and tested their sera for IgG antibodies against rubella. We classified sera as seropositive (titre >=10 IU/ml), sero-negative (titre <8 IU/ml) or indeterminate (titre 8-9.9 IU/ml) per manufacturer's instructions. In a sub sample, we estimated the titers of IgG antibodies against rubella. IgG titer of >=10 IU/mL was considered protective. RESULTS: Of 1800 sera tested, 1502 (83.4%) were seropositive and 24 (1.3%) were indeterminate and 274 (15.2%) were sero negative. Rubella sero-positivity did not differ by age group, educational status or place of residence. Three hundred and eighty three (87.8%) of the 436 sera had IgG concentrations >=10 IU/mL. CONCLUSION: The results of the serosurvey indicate high levels of rubella sero-positivity in pregnant women. High sero-prevalence in the absence of routine childhood immunization indicates continued transmission of rubella virus in cities where sentinel sites are located. PMID- 30448335 TI - Incidence of outcomes relevant to vaccine safety monitoring in a US commercially insured population. AB - BACKGROUND: Background incidence rates (IRs) of potential safety outcomes among vaccine eligible individuals can inform assessment of vaccine safety. Vaccine safety surveillance often uses claims databases, but the impact of outcome definitions on background IR estimates is largely unexplored. Using two definitions for each outcome, we estimated background IRs of 32 cardiac, metabolic, allergic, autoimmune, neurologic, hematologic and nephrologic outcomes among individuals eligible to receive pneumococcal vaccination. METHODS: We defined a cohort of individuals aged 6-100 years in US commercial health plans who had >=12 months of health plan enrollment between January 2007 and August 2014 and no previous record of conjugate or simple polysaccharide pneumococcal vaccination. We developed a sensitive and a specific definition for each outcome, with the specific definition requiring evidence of additional care consistent with the outcome. IRs per 100,000 person-years for each outcome were presented overall and stratified by age, gender, and invasive pneumococcal disease (IPD) risk category. RESULTS: We followed 19.9 million individuals for a median of 2.5 years. Wide variation was seen in IRs across different definitions of the 32 outcomes, with 19 (59%) outcomes having a specific definition IR less than half of the sensitive definition IR. IRs were particularly variable by definition for outcomes categorized as either hematologic/nephrologic or neurologic (mean ratio of specific IR to sensitive IR = 0.26 and 0.30, respectively). Across definitions, the IRs of the 32 outcomes were often highest in females, adults >=65, and those at higher IPD risk. CONCLUSIONS: Background IRs of safety outcomes relevant to populations indicated for pneumococcal vaccine varied by outcome definitions and population subgroups in this large US commercially insured population. Given large differences in estimated IRs using sensitive versus specific case definitions, neurologic, and hematologic/nephrologic safety outcomes as compared to allergic and autoimmune outcomes may warrant more refined definitions and medical record validation. PMID- 30448336 TI - Low uptake of nasal influenza vaccine in Polish and other ethnic minority children in Edinburgh, Scotland. AB - Failure to vaccinate is well-recognised in Europe as a contributing factor to outbreaks of infectious diseases. Low immunisation rates are often associated with religious, social and ethnic minorities, including refugees or migrant groups. Polish people form Scotland's newest and largest migrant group. They have moved to Scotland since 2004, joining established ethnic minorities from China, the Indian subcontinent and Africa. Scotland has had a seasonal influenza nasal vaccination programme for all primary school children since 2013. We investigated three primary schools in Edinburgh, which had reported low influenza vaccination uptake rates in 2016 and 2017 and found that these schools contained many pupils from ethnic minorities, the majority of whom were Polish. Pupils were categorized as one of three ethnic groupings: White British, Polish and Other Identified Ethnic Minority (OIEM). We ascertained ethnicity using NHS and Education Department information sources and name recognition. We examined vaccine acceptance, declination and non-return of consent forms. In 2017, nasal influenza vaccine uptake was 70.7% (65.2-75.6%, p < 0.001) in White British, 60.9% (53.9 67.6%%, p < 0.001) in other identified ethnic minorities and 25.0% (20.9-29.6%, p > 0.001) in Polish children. White British children were more likely to return completed forms (78.9%) than other groups (OIEM 68.2% and Polish 61.8%). 36.8% of Polish families completed a consent form declining vaccination compared to 6.2% of White British families. These findings demonstrate that significant differences exist in nasal influenza vaccination uptake rates, which have important implications for the trans-national study of vaccine hesitancy. Further qualitative work and an investigation of uptake rates of other childhood immunisations in Polish and other migrant groups is required to assess differences in uptake and behaviours. PMID- 30448337 TI - Defining a correlate of protection for chikungunya virus vaccines. AB - Chikungunya virus infection causes a debilitating febrile illness that in many affected individuals is associated with long-term sequelae that can persist for months or years. Over the past decade a large number of candidate vaccines have been developed, several of which have now entered clinical trials. The rapid and sporadic nature of chikungunya outbreaks poses challenges for planning of large clinical efficacy trials suggesting that licensure of chikungunya vaccines may utilize non-traditional approval pathways based on identification of immunological endpoint(s) predictive of clinical benefit. This report reviews the current status of nonclinical and clinical testing and potential challenges for defining a suitable surrogate or correlate of protection. PMID- 30448338 TI - Measurement Properties of the Barthel Index in Geriatric Rehabilitation. AB - OBJECTIVE: The Barthel index (BI) is a widely used observer-based instrument to measure physical function. Our objective is to assess the structural validity, reliability, and interpretability of the BI in the geriatric rehabilitation setting. DESIGN: Two studies were performed. First, a prospective cohort study was performed in which the attending nurses completed the BI at admittance and discharge (n = 207). At discharge, patients rated their change in physical function on a 5-point Likert rating scale. To assess the internal structure of the BI, a confirmatory factor analysis was performed. Unidimensionality was defined by comparative fit index and Tucker-Lewis index of >0.95, and root mean square error of approximation of <0.06. To evaluate interpretability, floor/ceiling effects and the minimal important change (MIC) were assessed. Predictive modeling was used to calculate the MIC. The MIC was defined as going home and minimal patient-reported improvement defined as slightly or much improved physical function, which served as anchors to obtain a clinical- and patient-based MIC. A second group of 37 geriatric rehabilitation patients were repeatedly assessed by 2 attending nurses to assess reliability of the BI. The intraclass correlation coefficient, standard error of measurement, and smallest detectable change were calculated. SETTING AND PARTICIPANTS: Patients receiving inpatient geriatric rehabilitation admitted to 11 Dutch nursing homes (n = 244). RESULTS: Confirmatory factor analysis showed partly acceptable fit of a unidimensional model (comparative fit index 0.96, Tucker-Lewis index 0.95, and root mean square error of approximation 0.12). The clinical-based MIC was 3.1 [95% confidence interval (CI) 2.0-4.2] and the patient-based MIC was 3.6 (95% CI 2.8-4.3). The intraclass correlation coefficient was 0.96 (95% CI 0.93-0.98). The standard error of measurement and smallest detectable change were 1.1 and 3.0 points, respectively. CONCLUSIONS/IMPLICATIONS: The structural validity, reliability, and interpretability of the BI are considered sufficient for measuring and interpreting changes in physical function of geriatric rehabilitation patients. PMID- 30448339 TI - The Incidence of Recorded Delirium Episodes Before and After Dementia Diagnosis: Differences Between Dementia With Lewy Bodies and Alzheimer's Disease. AB - OBJECTIVES: To describe the incidence of delirium recording before and after a diagnosis of dementia is established in patients with dementia with Lewy bodies (DLB) and compare findings to a matched cohort of patients with Alzheimer's disease (AD). DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: A cohort of patients with dementia from a large mental health and dementia care database in South London, linked to hospitalization and mortality data. We identified 194 patients with DLB and 1:4 matched these with 776 patients diagnosed with AD on age, gender, and cognitive status. MEASURES: We identified delirium episodes recorded in mental health and hospital records from 1 year before to 1 year after dementia diagnosis. Using dementia diagnosis as an index date we additionally followed patients until first episode of delirium, death or a censoring point without restricting the observation period. RESULTS: Patients with DLB had significantly more episodes of delirium recorded in the year before dementia diagnosis than patients with AD (incidence rate 17.6 vs 3.2 per 100 person-years; P < .001). Whereas the incidence of recording of delirium episodes reduced substantially in patients with DLB after dementia diagnosis, it remained significantly higher than in patients with AD (incidence rate 6.2 vs 2.3 per 100 person-years; P = .032). Cox regression models indicate that patients with DLB remain at a higher risk of delirium than patients with AD after a dementia diagnosis. CONCLUSIONS/RELEVANCE: Establishing a diagnosis of dementia reduces episodes classified as delirium in patients with DLB and might lead to fewer potentially harmful interventions such as hospitalization or use of antipsychotic medication. PMID- 30448340 TI - Comparative limitations and benefits of liquid chromatography - mass spectrometry techniques for analysis of sex steroids in tears. AB - Sex steroids impact regulation of the ocular surface tissues and thus influence dry eye. Most tissues in the human body synthesise and metabolise active sex steroids at levels required by the tissue. This is likely to also be the case for humans in ocular surface tissues. This study investigated the presence and quantities of selected sex steroids, in addition to sex steroid precursors and metabolites, in human tears. Detection of sex steroids in tears is challenging due to trace level analyte concentrations and low volumes of available tears. Immunoassays have previously been employed to assess sex steroids in tears, however, this approach only allows a single analyte to be measured and can overestimate concentrations. This study evaluated ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS) and tandem mass spectrometry (MS/MS) methods for the concurrent detection and estimation of fourteen sex steroid and metabolite compounds in human tears. Basal tears were collected and pooled from 5 healthy pre-menopausal women (total 100 MUL). Following protein precipitation and centrifuging, extract volumes equivalent to 14 MUL of pooled tears were analysed. A Thermo Scientific Q ExactiveTM Plus MS was used to compare novel high-resolution MS atmospheric pressure chemical ionization (APCI) and electrospray ionisation (ESI) methods for detection of fourteen target sex steroids, including dehydroepiandrosterone-sulphate (DHEAS), testosterone, oestradiol and their metabolites, using standards and pooled tears. The MS was programmed to switch between positive and negative polarity ionization modes at designated times through the UPLC run, in order to detect each analyte at optimal sensitivity. Analytes were analysed using APCI in standard mixtures at concentrations of 0.1, 0.3, 1, 3, 10, 30, 100 and 1000 pg/mL, per component, to determine the limits of detection (LOD) and quantification. Both parallel reaction monitoring (PRM) MS/MS and selected ion monitoring (SIM) MS, were evaluated by plotting narrow range mass-to-charge ratio (m/z) chromatograms for each analyte. An APCI UPLC-MS method to simultaneously measure 14 sex steroids using standards was successfully developed following comparative evaluation of all available LC-MS techniques. Preliminary experiments found APCI to be more sensitive than ESI using standards. Narrow m/z range SIM MS resulted in better sensitivity, in tear samples, than PRM. One sex steroid and two androgen metabolites were detected, with the developed APCI UPLC-MS method, and their concentrations estimated in human tears that had been extracted with a protein crash. Progesterone, androsterone-glucuronide (ADT-G) and 3alphaDiol-G were successfully detected in the tear extract and their concentrations in the pooled tear sample were estimated (with 95% confidence intervals) to be 0.10 +/- 0.03 pg/MUL, 30.9 +/- 18.3 pg/MUL and 9.8 +/- 4.3 pg/MUL respectively. The concentrations of the remaining 11 sex steroids in the tear sample were below the LODs of the method. This work shows that high mass resolution UPLC-MS can detect certain sex steroids and metabolites in tears, but that sensitivity of the technique and the low available tear volumes limit its application to a broader range of sex steroids. The investigation of sex steroids in tears and ocular surface tissue will aid understanding of the influence of sex steroids on ocular surface tissues facilitating better targeted treatment for dry eye. PMID- 30448341 TI - Peptide-induced formation of protein aggregates and amyloid fibrils in human and Guinea pig alphaA-crystallins under physiological conditions of temperature and pH. AB - alphaA66-80 peptide forms with age in the lens nucleus of humans and guinea pigs, and binds to alphaA-crystallin by hydrophobic bonds to produce protein aggregates. The purpose of the present study was to use negative-stain transmission electron microscopy (TEM) to investigate peptide/crystallin structures that form when alphaA66-80 peptide is incubated with recombinant human (HU) and guinea pig (GP) alphaA-crystallin, and GP alphaAins-crystallin, under physiological conditions of temperature and pH. HU and GP alphaA-crystallin each consists of 173 amino acid residues with only eight differences. GP alphaAins crystallin contains an insertion of 23 amino acids into the sequence for normal GP alphaA-crystallin. Synthetic alphaA66-80 peptide was incubated with each crystallin for 24 h in phosphate buffered saline at 37o C, pH 7.4. Samples were loaded onto electron microscopy grids and analyzed by TEM. With GP alphaA crystallin, the alphaA66-80 peptide appeared to first form up to 700 nm long, independent peptide fibrils, which subsequently bound numerous alphaA-crystallin oligomers along the entire length of the fibril to form up to 30 nm thick peptide/oligomer fibril structures. In contrast, HU alphaA-crystallin somehow prevented independent alphaA66-80 peptide fibrillation, and instead joined with the peptides to form amorphous aggregates and linear chains of alphaA oligomers. When incubated alone, GP alphaAins-crystallin eventually lost all oligomeric structure and formed amorphous aggregates. However, addition of alphaA66-80 peptide to the incubation medium resulted in the formation of highly-organized peptide/alphaAins oligomer amyloid fibrils, nearly 400 nm in length, with oligomer dimers appearing to stack one on top of another. Mature peptide/alphaAins oligomer fibrils were highly compressed and 40% thicker than observed protofibrils (17 nm vs. 12 nm thickness). Use of a control V72P alphaA crystallin peptide, as well as addition of the disulfide bond reducing agent DTT to the incubation medium, prevented fibril formation. Turbidity and Thioflavin T fluorescence analyses confirmed the observed peptide-induced fibril formation. This study represents the first time that fibrillation of alphaA-crystallin has been accomplished under physiological conditions of temperature and pH without use of denaturants. Fibrillation of GP alphaAins-crystallin was linked with possible intermolecular disulfide-crosslinking of oligomers. The finding that alphaA66-80 peptide induces aggregate formation with HU alphaA-crystallin supports a role for this peptide in the development of HU nuclear cataract. PMID- 30448342 TI - Laparoscopic sleeve gastrectomy versus Roux-en-Y gastric bypass in cardiovascular risk reduction: A match control study. AB - BACKGROUND: There is a paucity of studies comparing risk reduction of the atherosclerotic cardiovascular disease (ASCVD) and Framingham-body mass index (BMI) Coronary Heart risk score after a laparoscopic Roux-en-Y gastric bypass (RYGB), and few studies have assessed the efficacy of laparoscopic sleeve gastrectomy (SG) in reducing cardiovascular risk. OBJECTIVE: Our goal in this study was to compare the impact of SG and RYGB on cardiovascular risk reduction. SETTING: U.S. university hospital. METHODS: We retrospectively reviewed the records of all SG or RYGB cases at our institution between 2010 and 2015. Patients who met the criteria for calculating the ASCVD 10-year and Framingham BMI score were included in the study. Propensity score matching was used to match SG and RYGB on demographic characteristics and co-morbidities. RESULTS: Of the 1330 bariatric patients reviewed in the study period, 219 (19.3%) patients met the criteria for risk score calculation. SG was the most prevalent surgery in 72.6% (N = 159) of cases compared with RYGB in 27.4% (N = 60) of cases. At 12 month follow-up, ASCVD 10-year score had an absolute risk reduction of 3.9 +/- 6.5% in SG patients and 2.9 +/- 5.8% in RYGB patients (P = .3). Framingham-BMI score absolute risk reduction was 11.0 +/- 12.0% in SG and 9.0 +/- 11.0% in RYGB patients (P = .4), and the decrease in estimated heart age was 12.1 +/- 15.6 years in SG versus 9.2 +/- 9.6 years in RYGB (P = .1). The percentage of estimated BMI loss at 1 year was 68.1 +/- 23.3% in SG versus 74.2 +/- 24.8% in RYGB (P = .1). CONCLUSION: Our results suggest that SG and RYGB are equally effective in improving cardiovascular risk and decreasing the estimated vascular/heart age at 12-month follow-up. PMID- 30448343 TI - Oligometastatic gastric cancer: An emerging clinical entity with distinct therapeutic implications. AB - Gastric cancer (GC) remains responsible for a high burden worldwide being the third leading cause of cancer-related mortality. Most of patients present at an advanced stage at diagnosis and are thus candidates to standard chemotherapy resulting in median survival of less than 1 year. Oligometastatic gastric cancer is an increasingly recognized clinical entity characterized by limited metastatic spread that has been showing to benefit from aggressive multimodality strategies encompassing chemotherapy and surgery. The ongoing RENAISSANCE/AIO-FLOT5 (NCT02578368) phase III trial is aimed at evaluating if perioperative chemotherapy with FLOT in combination with surgical resection of the primary tumour and metastases could become the new standard of care for oligometastatic GC. In the meantime, in addition to currently available clinical parameters, the emerging predictive/prognostic role of biomarkers such mismatch repair deficiency/microsatellite instability high status needs to be specifically addressed also in this subgroup of GC to assist in patient selection. PMID- 30448344 TI - Social media, social mania. PMID- 30448345 TI - Phosphorylation and inhibition of ceramide kinase by protein kinase C-beta: Their changes by serine residue mutations. AB - Ceramide kinase (CerK) phosphorylates ceramide to ceramide-1-phosphate (C1P), and various roles for the CerK/C1P pathway in the regulation of cellular/biological functions have been demonstrated. CerK is constitutively phosphorylated at several serine (Ser, S) residues, however, the roles of Ser residues, including their phosphorylation, in CerK activity, have not yet been elucidated in detail. Therefore, we conducted the present study to investigate this issue. In A549 cells expressing wild-type CerK, a treatment with phorbol 12-myristate 13-acetate (PMA) decreased the formation of C1P in a protein kinase C (PKC)-betaI/II mediated manner. In the Phos-tag SDS-PAGE analysis, CerK existed in its phosphorylated form and was further phosphorylated by the PMA treatment in a PKC betaI/II-mediated manner. We examined the effects of the displacement of Ser residues (72/300/340/403/408/427) in CerK by alanine (Ala, A) on its activity and phosphorylation. Triple mutations (S340/408/427A), but not a single or double mutations (S340/408A), in CerK significantly decreased the formation of C1P. PMA induced phosphorylation levels in S340/408A- and S340/408/427A-CerK were significantly and maximally reduced, respectively, but were similar in CerK with a single mutation and wild-type CerK. Ser residue mutations tested, including six mutations, did not affect PMA-induced decreases in C1P formation more than expected. Treatments with the protein phosphatase inhibitors, okadaic acid and cyclosporine A, decreased the formation of C1P. These results demonstrated that the activity of CerK was regulated in a phosphorylation-dependent manner in cells. PMID- 30448346 TI - ACTL6A interacts with p53 in acute promyelocytic leukemia cell lines to affect differentiation via the Sox2/Notch1 signaling pathway. AB - Actin-like 6A (ACTL6A), a component of BAF chromatin remodeling complexes, is important for cell differentiation. Nevertheless, its role and mechanism in acute promyelocytic leukemia (APL) has not been reported. To identify the genes that may participate in the development of APL, we analyzed data from an APL cDNA microarray (GSE12662) in the NCBI database, and found that ACTL6A was up regulated in APL patients. Subsequently, we investigated the function and mechanisms of ACTL6A in myeloid cell development. The expression of ACTL6A was gradually decreased during granulocytic differentiation in all-trans retinoic acid-treated NB4 and HL-60 cells, and phorbol myristate acetate-treated HL-60 cells. We also found that knockdown of ACTL6A promoted differentiation in NB4 and HL-60 cells, and decreased the levels of Sox2 and Notch1. Mechanistically, ACTL6A interacted with and was co-localized with Sox2 and p53. Meanwhile, CBL0137, an activator of p53, decreased the expression of ACTL6A and promoted differentiation in NB4 and HL-60 cells. These findings suggest that the inhibition of ACTL6A promotes differentiation via the Sox2 and Notch1 signaling pathways. Furthermore, the differentiation promoted by inhibiting ACTL6A could be regulated by p53 via its physical interaction with ACTL6A. PMID- 30448347 TI - Fatigue failure load and finite element analysis of multilayer ceramic restorations. AB - OBJECTIVE: To evaluate the fatigue failure load via staircase approach and stress distribution via FEA of different ceramic configurations arranged in multilayers composed of ceramic materials with different elastic moduli and compare them to monolayer models. METHODS: CAD-CAM ceramic blocks were used to shape 0.3mm and 1.5mm thick discs, corresponding to: feldspathic (F), 64GPa; lithium disilicate (L), 95GPa; and Yttrium-partially stabilized tetragonal zirconia (Y-TZP) (Y), 209.3GPa. The 0.3mm discs were arranged in 4 layers cemented with resin cement (Multilink N), and the 1.5mm discs were not treated, in such a way that the final thickness of all specimens was 1.5mm (+/-0.15mm). The following 6 groups were tested: F (F: monolithic); L (L: monolithic); LLFF (L+L+F+F); FFLL (F+F+L+L); YLFF (Y+L+F+F); YLLF (Y+L+L+F). The loads-to-fracture were obtained using the biaxial flexural strength test until failure and the data were run using one-way ANOVA and Tukey's multiple comparisons (alpha=0.05) tests. The biaxial bending test was also simulated through finite element analysis (FEA) to identify the tensile stress generated at each layer of the groups. Mean fatigue failure load (100,000 cycles; 20Hz) was determined using the staircase approach. The fracture analysis was performed by stereomicroscope and scanning electron microscopy. RESULTS: The load to fracture (N) were obtained as follows: L (592.9+/ 73.8)D>FFLL (319.78+/-43.59)C>YLLF (246.75+/-24.89)B>F (167.13+/-9.84)A>YLFF (166.51+/-15.24)A>LLFF (165.46+/-22.75)A; and the fatigue failure load (N): L (310.92+/-26.73)F>FFLL (190.17+/-8.32)E>F (106.21+/-2.81)D>YLLF (96.48+/ 5.73)C>YLFF (89.56+/-2.38)B>LLFF (77.23+/-6.33)A. The origin of all of the tested specimens was located at the tensile region of the discs, as encountered in FEA. SIGNIFICANCE: The material under tensile stress is determinant for the restoration's strength and the adhesive interface negatively influenced the mechanical behavior of the multilayer structures. PMID- 30448348 TI - Channeling of newly synthesized fatty acids to cholesterol esterification limits triglyceride synthesis in SND1-overexpressing hepatoma cells. AB - SND1 is a putative oncoprotein whose molecular function remains unclear. Its overexpression in hepatocellular carcinoma impairs cholesterol homeostasis due to the altered activation of the sterol regulatory element-binding protein (SREBP) 2, which results in the accumulation of cellular cholesteryl esters (CE). In this work, we explored whether high cholesterol synthesis and esterification originates changes in glycerolipid metabolism that might affect cell growth, given that acetyl-coenzyme A is required for cholesterogenesis and fatty acids (FA) are the substrates of acyl-coenzyme A:cholesterol acyltransferase (ACAT). SND1-overexpressing hepatoma cells show low triglyceride (TG) synthesis, but phospholipid biosynthesis or cell growth is not affected. Limited TG synthesis is not due to low acetyl-coenzyme A or NADPH availability. We demonstrate that the main factor limiting TG synthesis is the utilization of FAs for cholesterol esterification. These metabolic adaptations are linked to high Scd1 expression, needed for the de novo production of oleic acid, the main FA used by ACAT. We conclude that high cholesterogenesis due to SND1 overexpression might determine the channeling of FAs to CEs. PMID- 30448349 TI - The expansion of genes encoding soluble silk components in the greater wax moth, Galleria mellonella. AB - Lepidopteran silk is a complex assembly of proteins produced by a pair of highly specialized labial glands called silk glands. Silk composition has been examined only in a handful of species. Here we report on the analysis of silk gland specific transcriptomes from three developmental stages of the greater wax moth, Galleria mellonella, combined with proteomics, Edman microsequencing and northern blot analysis. In addition to the genes known earlier, we identified twenty seven candidate cDNAs predicted to encode secretory proteins, which may represent novel silk components. Eight were verified by proteomic analysis or microsequencing, and several others were confirmed by similarity with known silk genes and their expression patterns. Our results revealed that most candidates encode abundant secreted proteins produced by middle silk glands including ten sericins, two seroins, one or more mucins, and several sequences share no apparent similarity to known proteins. Our data not only show that the number of sericin genes in the greater wax moth is higher than in other species thus far examined, but also the total content of soluble proteins in silk is twice as high in G. mellonella as in B. mori or A. yamamai. Our data will serve as a foundation for future identification and evolutionary analysis of silk proteins in the Lepidoptera. PMID- 30448350 TI - Exploring determinants of behavioral chronotype in a diurnal-rodent model of human physiology. AB - Numerous studies conducted with human participants have shown that differences in chronotype, defined as individual patterns of early or late beginning of daily activity, have implications for many biobehavioral processes, such as cognitive performance, mood, impulsivity, academic achievement of college students, and mental health. However, the determinants of individual variation in chronotype have not been investigated. Basic research on circadian rhythms has provided a basis for investigating the causes of chronotype variation, but experimental tests of pertinent hypotheses are difficult to conduct with human subjects. This limitation can be overcome by use of animal models. This study was conducted with a rodent species, the antelope ground squirrel (Ammospermophilus leucurus), that, like humans, is active during the daytime, exhibits a spread of chronotypes, and has a similar average free-running circadian period. We found chronotype to be a stable trait within individuals based on strong consistency of separate determinations made six months apart (correlation r = 0.91). We also found a moderate correlation of chronotype with the duration of the active phase (r = 0.51) and with free running period (r = 0.34), but weak correlation with rhythm robustness (r = 0.16), and no correlation with photic responsiveness or with masking responses. The best multiple regression model, incorporating the duration of the active phase, free-running period, and rhythm robustness, explained 38% of the variance in chronotype. Although 62% of the variance in chronotype remained unaccounted for, the results are encouraging because they document the possibility of using a diurnal rodent as a model for the investigation of the determinants of chronotype variation in humans. PMID- 30448351 TI - Visceral-afferent signals from the cardiovascular system, but not urinary urge, affect startle eye blink. AB - The aim of the current study was to investigate if startle methodology is suitable to reflect urinary urgency. Eighteen healthy men were tested on two separate days, each including an ingestion of fluid until 80% of the subjective urge to micturate was reached. EMG responses to acoustic startle stimuli were assessed before and after micturition, as well as in the early and late cardiac cycle phases (230 vs. 530 ms after a cardiac R-wave). Sonographic assessment confirmed bladder-filling status. Emotional arousal, stress, urge and unpleasantness ratings, as well as mean blood pressure were higher before than after micturition. Startle eye blink responses were lower during the early than during the late cardiac cycle phase, but were not affected by bladder filling status. We conclude that startle methodology is suitable for the investigation of afferent signals from the cardiovascular system, but not to reflect urinary urgency. This result may be due to different neurophysiological mechanisms underlying afferent signals from the bladder compared to other visceral organs or interference with affective states or sympathetic activation associated with bladder filling. Notwithstanding, the present research protocol of fluid intake, sonographic assessment of the bladder, and subjective reports, can be applied to examine effects of urinary urge on physiological and psychological processes. PMID- 30448352 TI - Impact of dosing schedule in animal experiments on compound progression decisions. AB - Low pipeline output is a major problem for the pharmaceutical industry. Many compounds fail to enter clinical development, owing to toxicities in animals. Using pharmacology principles, this paper argues that the often-infrequent dosing in animal experiments despite a drug's short half-life produces a large fluctuation in drug concentration, which can severely erode the therapeutic index and safety margin for the anticipated clinical dose, consequently preventing potentially effective treatments from entering human trials. Aided by computer simulations under generalised conditions, the analysis was conducted in a quantitative framework with broad relevance. The findings call for more translatable dosing practices through closer collaboration among scientists in multiple disciplines and better regulatory guidance for animal studies to better inform compound progression decisions. PMID- 30448353 TI - Accelerating pharmaceutical structure-guided drug design: a successful model. AB - The impact and value of structure-based drug design to pharmaceutical discovery across the industry are now undeniable, with many break-through therapies on the market that are structure based in nature. Enabling the structural research is the Industrial Macromolecular Crystallography Association-Collaborative Access Team (IMCA-CAT), formed over 25 years ago as a world-class research facility at the synchrotron at Argonne National Laboratory. What makes IMCA-CAT unique is the strategy of the founding consortium to comprehensively provide for the evolving needs of industry in one facility. This includes year-round high-quality data, capabilities that match target portfolios, throughput and capacity that are never limiting, and unfailing security. Here, we illuminate the unique capabilities offered by IMCA-CAT and instruct how all industrial organizations can access this facility. PMID- 30448354 TI - The legacy of redlining in the effect of foreclosures on Detroit residents' self rated health. AB - Historical practices, such as housing discrimination in Detroit, have been shown to have lasting impacts on communities. Perhaps the most explicit example is the practice of redlining in the 1930s, whereby lenders outlined financially undesirable neighborhoods, populated by minority families, on maps and prevented residents from moving to better resourced neighborhoods. Awareness of historical housing discrimination may improve research assessing the impacts of current neighborhood characteristics on health. Using the Detroit Neighborhood Health Study (DNHS), we assessed the association between two-year changes in home foreclosure rates following the 2007-2008 Great Recession, and residents' five year self-rated health trajectories (2008-2013); and estimated the confounding bias introduced by ignoring historical redlining practices in the city. We used both ecological and multilevel models to make inference about person- and community-level processes. In a neighborhood-level linear regression adjusted for confounders (including percent redlined); a 10%-point slower foreclosure rate recovery was associated with an increase in prevalence of poor self-rated health of 0.31 (95% CI:-0.02 to 0.64). At the individual level, it was associated with a within-person increase in probability of poor health of 0.45 (95% CI:0.15-0.72). Removing redlining from the model biased the estimated effect upward to 0.38 (95% CI:0.07-0.69) and 0.56 (95% CI:0.21-0.84) in the neighborhood and individual level models, respectively. Stratum-specific foreclosure recovery effects indicate stronger influence in neighborhoods with a greater proportion of residents identifying as white and a greater degree of historic redlining. These findings support earlier theory suggesting a historical influence of structural discrimination on the association between current neighborhood characteristics and health, and suggests that historical redlining specifically may increase vulnerability to contemporary neighborhood foreclosures. Community interventions should consider historical discrimination in conjunction with current place-based indicators to more equitably improve population health. PMID- 30448355 TI - Design and rationale of the B-lines lung ultrasound guided emergency department management of acute heart failure (BLUSHED-AHF) pilot trial. AB - BACKGROUND: Medical treatment for acute heart failure (AHF) has not changed substantially over the last four decades. Emergency department (ED)-based evidence for treatment is limited. Outcomes remain poor, with a 25% mortality or re-admission rate within 30 days post discharge. Targeting pulmonary congestion, which can be objectively assessed using lung ultrasound (LUS), may be associated with improved outcomes. METHODS: BLUSHED-AHF is a multicenter, randomized, pilot trial designed to test whether a strategy of care that utilizes a LUS-driven treatment protocol outperforms usual care for reducing pulmonary congestion in the ED. We will randomize 130 ED patients with AHF across five sites to, a) a structured treatment strategy guided by LUS vs. b) a structured treatment strategy guided by usual care. LUS-guided care will continue until there are <=15 B-lines on LUS or 6h post enrollment. The primary outcome is the proportion of patients with B-lines <= 15 at the conclusion of 6 h of management. Patients will continue to undergo serial LUS exams during hospitalization, to better understand the time course of pulmonary congestion. Follow up will occur through 90 days, exploring days-alive-and-out-of-hospital between the two arms. The study is registered on ClinicalTrials.gov (NCT03136198). CONCLUSION: If successful, this pilot study will inform future, larger trial design on LUS driven therapy aimed at guiding treatment and improving outcomes in patients with AHF. PMID- 30448356 TI - Trimester-specific association between antibiotics exposure during pregnancy and childhood asthma or wheeze: the role of confounding. AB - PURPOSE: We conducted the meta-analysis to respectively evaluate the risk of prenatal antibiotics use during specific trimesters (first, second, and third trimester) on childhood asthma or wheeze and to explore whether the association was biased by potential confounding. METHODS: The quality of included articles was assessed according to Newcastle-Ottawa Quality Assessment Scale and the Strengthening the Reporting of Observational Studies in Epidemiology. A random effects model was used to calculate pooled risk ratios and corresponding 95% confidence interval (CI), and publication bias was tested by Egger statistical test. RESULTS: Eight studies were included finally. We found a crude positive association of prenatal antibiotics use during each pregnancy trimester and risk of childhood asthma or wheeze with RRs of 1.28 (95% CI, 1.09-1.51) for the first trimester of pregnancy, 1.25 (95% CI, 1.02-1.52) for the second trimester, and 1.25 (95% CI, 1.05-1.49) for the third trimester. However, when considering potential factors of maternal infections and presence of siblings, the relationship for each trimester was insignificant. CONCLUSIONS: This systemic review and meta-analysis proposed a crude positive association between prenatal antibiotic use in every specific trimester and risk of childhood asthma or wheeze. However, adjustment for confounders decreased the relative risk estimates, supporting the concept that these associations are, at least in part, because of confounding by indication. PMID- 30448358 TI - Citation for the 2017 Down Surgical Prize - Paul Johnson. PMID- 30448357 TI - Association between impacted third molars and position of the mandibular canal: a morphological analysis using cone-beam computed tomography. AB - Our aim was to assess the association between the angle of impaction of the third molar and the position of the mandibular canal on cone-beam computed tomography (CT). We designed a retrospective study of 100 cone-beam CT images of 173 mandibular third molars that were obtained between January 2012 and December 2015, and recorded the angle of impaction of the third molar, the position of the mandibular canal in relation to the impacted tooth, and the potential contact between the roots of the tooth and the mandibular canal. Most third molars tilted mesially (n=33), while the mandibular canal was positioned below the roots of the third molar in most cases (n=73). Contact between the two was most likely when the mandibular canal was between (RR=1.49; 95% CI 1.27 to 1.75, p<0.001), or to the lingual side (RR=1.49; 95% CI 1.27 to 1.75, p<0.001) of the roots of the tooth. These outcomes indicate a greater likelihood of contact between the canal and the roots when the canal is between, and to the lingual side, of the roots. We found no association between the angle of impaction and the position of the canal. These findings illustrate the importance of surgical planning using complementary imaging tests such as cone-beam CT. PMID- 30448359 TI - Multicopy integrants of crt genes and co-expression of AMP deaminase improve lycopene production in Yarrowia lipolytica. AB - Lycopene has been broadly studied in recent decades due to its health benefits including cancer prevention, anti-atherogenic and anti-obesity effects, and modulation of the immune system. To obtain efficient synthesis of lycopene, extensive researches have been conducted in various microbial cells, including Yarrowia lipolytica, to heterologously produce lycopene using various genetic and metabolic engineering methods. In this study, the effects of copy numbers of lycopene synthesis genes, a variety of key central metabolic genes (especially AMP deaminase-encoding gene AMPD), and 5-L fermenter cultivation on lycopene production in Y. lipolytica were investigated and the engineered strains with significantly enhanced lycopene content (46-60 mg/g DCW) were achieved. It is therefore possible to make use of the obtained strains to meet the industrial demand of lycopene production on the basis of further genetic and process optimization. PMID- 30448360 TI - A case of bilateral emphysematous pyelonephritis caused by Candida albicans. AB - Emphysematous pyelonephritis (EPN) is a life-threatening renal infection characterized by the formation of gas within the renal parenchyma and collecting duct system, as well as perinephric tissues. We herein report a case of bilateral EPN accompanied by the urinary tract infection caused by spherical growth of Candida albicans in a patient with underlying diabetes mellitus and prostate cancer. The diagnosis was assisted by computed tomography, urography, and gram staining. Despite immediate percutaneous catheter drainage and a 4-week course of antifungal treatment, the C. albicans infection was refractory, as indicated by continuous isolation from the urine, and the patient eventually died. A local autopsy of urinary organs revealed C. albicans in the renal tissue. EPN caused by Candida species frequently occurs in men, and almost all cases have underlying poorly controlled diabetes. This condition is subject to delayed diagnosis, which may lead to extended disease and high mortality. Candida species should be considered as causative microorganism for refractory EPN in patients with poorly controlled diabetes who are receiving antibiotic treatment. Gram staining may contribute to an early diagnosis of EPN caused by Candida species, which may require long-term antifungal therapy. PMID- 30448361 TI - Community-acquired bacterial co-infection predicts severity and mortality in influenza-associated pneumonia admitted patients. AB - BACKGROUND: Influenza is frequently complicated by bacterial co-infection, causing additional hospitalization and mortality. We determined the incidence, risk factors and outcomes of patients with influenza-associated community acquired bacterial co-infection. METHOD: This was a retrospective, observational study. Influenza was diagnosed using the polymerase chain reaction. Co-infection had to be confirmed using standard bacteriological tests. The primary endpoint was presence of community-acquired co-infection, and the secondary endpoint was in-hospital mortality. RESULTS: During the 8 influenza seasons from 2010 to 2018, of the 209 influenza-associated pneumonia admitted patients, 41 (19.6%) were identified with community-acquired bacterial co-infections and Staphylococcus aureus was the predominant strain. Compared with patients without co-infection, patients with co-infection had similar demographic characteristics and co morbidities, obtained a higher APACHE II score and a higher SOFA score, and had higher ratio of sepsis shock, invasive mechanical ventilation, and ICU requirement. In-hospital mortality independently associated with bacterial co infection (adjusted hazard ratio (aHR) 2.619; 95%CI 1.252-5.480; p = 0.011); in subgroup S. aureus (aHR 6.267; 95%CI 2.679-14.662; p < 0.001) and other pathogens (aHR 2.964; 95%CI 1.160-7.577; p = 0.023); and in subgroup positive findings in bloodstream (aHR 7.420; 95%CI 2.712-20.302; p < 0.001) and positive findings in other site (aHR 3.427; 95%CI 1.514-7.757; p = 0.003). CONCLUSION: Community acquired bacterial co-infection was frequent in influenza-associated pneumonia, without risk factor identified yet. Bacterial co-infection was likely to predict severity, and was an independent risk factor for in-hospital mortality. Co infection of Staphylococcus aureus with influenza was identified as a lethal synergism, and should be targeted when developing clinical antibiotic strategies. PMID- 30448362 TI - The History of the Dioxin issue in Brazil: From citrus pulp crisis to food monitoring (REVIEW). AB - Dioxins and furans are ubiquitous, anthropogenic environmental contaminants which can be found even in isolated places. Exposition to these chemicals poses several risks to humans such as thyroid dysfunction, cardiovascular diseases, and even cancer. In this review, the dioxin issue is analyzed in the light of the events that brought the World's attention to these pollutants, and the evolution of Brazilian scientific data on this matter since the citrus pulp crisis in 1998. Soil and air have been the main environmental matrices studied in Brazil. However, most of the research focuses on contaminated areas, with few or no data available on background levels. With the ratification of the Stockholm Convention in 2010, Brazil started to implement some measures to monitor the release of dioxins to the environment, such as the national inventory of sources. Still, the country lacks specific legislation stating acceptable limits for some industrial processes known to be source of dioxins emissions. Likewise, food monitoring has grown in recent years with the expansion of food groups monitored in the National Control Plan for Residues and Contaminants, but the available data do not allow affirming whether Brazilian residents are safe, as regard to exposure via food consumption. The implementation of a systemic survey such as a Total Diet Study would be a good strategy for a long-term monitoring not only for dioxins but also for other contaminants. Unfortunately, progressive cuts in science funds are holding back the scientific production in Brazil, whereas worldwide new emerging contaminants are being monitored and included in National Monitoring Plans both on food and environment matrices. PMID- 30448363 TI - Comments on "Chiral pharmaceuticals: Environment sources, potential human health impacts, remediation technologies and future perspective". PMID- 30448364 TI - Investigating landfill leachate toxicity in vitro: A review of cell models and endpoints. AB - Landfill leachate is a complex mixture characterized by high toxicity and able to contaminate soils and waters surrounding the dumpsite, especially in developing countries where engineered landfills are still rare. Leachate pollution can severely damage natural ecosystems and harm human health. Traditionally, the hazard assessment of leachate is based on physicochemical characterization but the toxicity is not considered. In the last few decades, different bioassays have been used to assess the toxicity of this complex matrix, including human-related in vitro models. This article reviews the cell bioassays successfully used for the risk assessment of leachate and to evaluate the efficiency of toxicity removal of several processes for detoxification of this wastewater. Articles from 2003 to 2018 are covered, focusing mainly on studies that used human cell lines, highlighting the usefulness and adequacy of in vitro models for assessing the hazard involved with exposure to leachate, particularly as an integrative supporting tool for chemical-based risk assessment. Leachate is generally toxic, mutagenic, genotoxic and estrogenic in vitro, and these effects can be measured in the cells exposed to already low concentrations, confirming the serious hazard of this wastewater for human health. PMID- 30448365 TI - Polybrominated diphenyl ethers and novel brominated flame retardants in indoor dust of different microenvironments in Beijing, China. AB - The occurrence levels of eight polybrominated diphenyl ethers (PBDEs) and four novel brominated flame retardants (NBFRs) were determined and compared in indoor dust from different microenvironments (21 homes, 23 offices and 16 day care centers) in Beijing, China. Concentrations of ?8PBDEs in dust were 430-17,000 ng/g, 690-8600 ng/g, and 90-2300 ng/g for homes, offices, and day care centers, respectively, and were dominated by BDE-209. Concentrations of ?4NBFRs ranged from 310 to 17,000 ng/g, 300 to 4300 ng/g, and not detected to 500 ng/g for homes, offices, and day care centers, respectively, and were dominated by bis(2 ethylhexyl)-3,4,5,6-tetrabromophthalate (BEH-TEBP) and decabromodiphenylethane (DBDPE) across microenvironments. The results showed an increasing detection and elevated concentration of NBFRs (especially BEH-TEBP), indicating that monitoring of NBFRs in dust samples should be of concern in future studies. A notable finding was that the BFR concentrations in dust samples from day care centers were generally one order of magnitude lower than those from homes and offices in the present study. This implies that previous estimates of toddler exposure via dust ingestion on data from homes may be overestimated. Concentrations of BDE-209 and ?8PBDEs were found to be significantly higher in elevated surface dust than floor dust from day care centers. The estimates of daily intakes of BFRs via dust ingestion for Chinese adults and toddlers using Monte Carlo analysis were 2-5 orders of magnitude lower than the corresponding reference daily intakes. PMID- 30448366 TI - Calcium phosphate buffer formed in the mitochondrial matrix during preconditioning supports DeltapH formation and ischemic ATP production and prolongs cell survival -A hypothesis. AB - Ischemic preconditioning makes cells less sensitive to oxygen deprivation. A similar effect can be achieved by increasing the calcium concentration and applying potassium channel openers. A hypothetical mechanism of preconditioning is presented. In the mitochondrial matrix, there is a calcium hydroxide buffer consisting of a few insoluble calcium phosphate minerals. During ischemia, calcium ions stored in the matrix buffer start to leak out, forming an electric potential difference, while hydroxyl ions remain in the matrix, maintaining its pH and the matrix volume. Preconditioning factors increase the matrix buffer capacity. Production of ATP during ischemia might be the relic of a pre endosymbiotic past. PMID- 30448367 TI - Diabetic retinopathy techniques in retinal images: A review. AB - The diabetic retinopathy is the main reason of vision loss in people. Medical experts recognize some clinical, geometrical and haemodynamic features of diabetic retinopathy. These features include the blood vessel area, exudates, microaneurysm, hemorrhages and neovascularization, etc. In Computer Aided Diagnosis (CAD) systems, these features are detected in fundus images using computer vision techniques. In this paper, we review the methods of low, middle and high level vision for automatic detection and classification of diabetic retinopathy.We give a detailed review of 79 algorithms for detecting different features of diabetic retinopathy during the last eight years. PMID- 30448368 TI - Effect of the Need for Pre-operative Dialysis on Peri-operative Outcomes on Patients Undergoing Laparoscopic Nephrectomy: An Analysis of the NSQIP Database. AB - OBJECTIVE: To investigate whether patients requiring dialysis are a higher risk surgical population and would experience more peri-operative adverse events even when undergoing a perceived less invasive operation as a laparoscopic radical nephrectomy (LRN). LRN is generally a well-tolerated surgical procedure with minimal morbidity and mortality. Prior to transplantation, dialysis patients will often have to undergo a LRN to remove a native kidney with a suspicious mass. MATERIALS AND METHODS: Patients in the American College of Surgeons National Surgical Quality Improvement Program who underwent a laparoscopic radical nephrectomy between 2011 and 2016 were included. Patients were stratified by the need for pre-operative dialysis two weeks prior to surgery, and peri-operative outcomes were compared. A multivariable logistic regression analysis was performed to test the association between the need for pre-operative dialysis and peri-operative risk. RESULTS: There were 8,315 patients included in this analysis of which 445 (5.4%) patients required pre-operative dialysis. Patients who required pre-operative dialysis had more minor (p < .0001) and major (p=.0025) complications, a higher rate of return to the operating room (p=0.002), and a longer length of stay (LOS) (p < 0.0001) than those patients not requiring pre operative dialysis. In a multivariate analysis, the need for pre-operative dialysis was independently associated with adverse peri-operative outcomes (OR=1.45, CI=1.08-1.95, p=.015). CONCLUSIONS: Patients requiring pre-operative dialysis were more likely to experience a peri-operative complication and have a longer LOS. For LRNs performed prior to transplantation, further risk stratification is needed, and treatment sequencing may need to be reconsidered. PMID- 30448369 TI - Ambulatory Tubeless Mini-PCNL using Moses Technology and Dusting Technique. AB - OBJECTIVE: To demonstrate the use of the Moses technology for holmium laser lithotripsy in conjunction with mini-PCNL to treat a lower pole stone. The Moses technology is a pulse modulation method that can reduce stone retropulsion, which may have advantages when used during mini-PCNL. METHODS: A 63-year-old patient with a right-sided 1.5 cm lower pole stone (1300 Hounsfield Unit) underwent mini PCNL using a 120W holmium laser (MosesP120, Lumenis). Moses has two modes - "Contact" and "Distance" - optimized for operation at 0-1 and 2-3 mm from the stone surface, respectively. Percutaneous access was obtained into the lower pole while the patient was in prone position. Using the medium (17.5F) mini-PCNL set (Karl Storz), the stone was fragmented using dusting settings with a 230 um Moses fiber (0.3Jx20-30Hz; Moses Contact and Distance modes). RESULTS: The video demonstrates the capabilities of treating a lower pole stone with a dusting technique using Moses modes. Dusting, to decrease the stone size so that it can fit within the sheath, in combination with fragment expulsion with the Venturi effect, as well as extraction with graspers/baskets resulted in complete stone removal. Following placement of an antegrade ureteral stent (tubeless technique) and sealing of the tract with FloSeal, the patient was discharged from the recovery unit. There were no adverse events. The stent was removed after 7 days, and follow-up KUB at 2 weeks showed no residual fragment. CONCLUSION: Due to the miniaturization of equipment, the holmium laser serves as an ideal energy source for fragmentation. In our early experience, the Moses technology with mini-PCNL allows a combination of dusting and stone extraction. As mini-PCNL offers smaller tract dilatation, for lower pole stones it can be performed in an ambulatory setting and is an alternative to ureteroscopy or shockwave lithotripsy with the potential for complete stone clearance. PMID- 30448370 TI - Serological and molecular analysis for brucellosis in selected swine herds from Southern India. AB - BACKGROUND: Swine brucellosis is a zoonotic disease caused by Brucella suis. The study describes the occurrence of brucellosis in two organized piggeries in Southern India. METHODS: A total of 585 serum samples comprising 575 from pigs and 10 from animal handlers were collected and tested by serological tests and PCR. Tissue samples were collected for isolation of the pathogen. RESULTS: Out of 575 serum samples screened, 236 (41.04%) were positive for brucellosis by both Rose Bengal plate test (RBPT) and indirect ELISA (iELISA) and 47 (8.17) samples showed Brucella DNA amplification by genus specific PCR. The sows those aborted and 19 boars with orchitis were seropositive for brucellosis indicating association of clinical symptoms with brucellosis seropositivity. Two of 10 pig handlers were positive by RBPT and showed significant serum agglutination test (SAT) titres of >1:160 and 1:320. B. suis bvI was isolated and identified by biochemical tests and confirmed by amplification Brucella genus and Bruce ladder PCRs from vaginal and testicular samples. CONCLUSIONS: The introduction of untested breeding boars in the farms might have resulted in the disease transmission and spread. The present study highlighted the diagnosis of B. suis bvI as a cause of abortions in the pigs and occupational exposure to farm personnel. PMID- 30448371 TI - CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity. AB - OBJECTIVE: Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity. METHODS: CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed. RESULTS: Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype. CONCLUSION: CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity. PMID- 30448372 TI - Light Bulb Procedure for the Treatment of Tarsal Navicular Osteonecrosis After Failed Percutaneous Decompression: A Case Report. AB - Tarsal navicular osteonecrosis in adults is a rare condition with unclear etiology, and the optimal treatment has not been established. Here we report a case of tarsal navicular osteonecrosis with a complete course of treatment and comprehensive imaging studies starting at an early stage. A 37-year-old female diagnosed with tarsal navicular osteonecrosis was first treated with percutaneous decompression, but her symptoms persisted postoperatively. The tarsal navicular showed no further collapse, but follow-up magnetic resonance imaging (MRI) at 6 months postoperatively revealed persistent osteonecrotic changes. Debridement of the necrotic bone with preservation of the cortical shell and bone substitute packing for the defect (light bulb procedure) were performed. The symptoms resolved by 3 months postoperatively, and the patient could return to work. At a 6-year follow-up visit, the patient was free of symptoms, and MRI showed remodeling of the tarsal navicular without further collapse. PMID- 30448373 TI - Ankle Stabilization With Arthroscopic Versus Open With Suture Tape Augmentation Techniques. AB - Ankle instability is a common problem that often leads to surgery to stabilize the ankle if conservative methods are unsuccessful in returning the patient to full activity. Surgical ankle stabilization, including arthroscopic and open methods, has been performed with overall excellent results reported. Although initial ligament strength after repair is weaker than the native ligament, new methods of augmentation with suture tape have yielded initial strength comparable to native ligament. The present study compares arthroscopic ankle stabilization and open stabilization with suture tape augmentation. A retrospective comparative trial was undertaken with a follow-up satisfaction survey. A total of 55 patients were ultimately included, consisting of 43 arthroscopic patients and 12 open with suture tape augmentation patients. Ancillary procedures are reported. The mean follow-up duration was 24.2 months in the arthroscopic group and 21 months in the open group. There was a statistically significantly faster return to activity/sports in the arthroscopic group (127.2 days vs 170 days; p = .008). Although not statistically significant, there was a trend toward favoring the open group in terms of revision surgery and patient satisfaction. Our data indicate that both methods of stabilization are reasonable for ankle instability repair. PMID- 30448374 TI - Reliability, Surgeon Preferences, and Eye-Tracking Assessment of the Stress Examination of the Tarsometatarsal (Lisfranc) Joint Complex. AB - The primary objective of this investigation was to determine the level of agreement and reliability of the stress examination of the Lisfranc tarsometatarsal joint complex. Secondary objectives were to determine surgeon preferences with respect to this testing and to use gaze recognition software to perform an eye-tracking assessment during the performance of the test. Twelve foot and ankle surgeons, 12 residents, and 12 students were shown 2 intraoperative fluoroscopic still images and 1 video of the stress examination of the tarsometatarsal joint complex using stress abduction of the forefoot on the rearfoot. Participants were asked to evaluate the result as being "positive" or "negative" for tarsometatarsal joint stability. The overall reliability of the interpretation of the stress examination was a kappa of 0.281 (surgeons 0.182; residents 0.423; students 0.256) indicating "fair" agreement. Survey results indicated wide variability in the perioperative preferences and protocols of surgeons dealing with the evaluation and treatment of the tarsometatarsal joint. Eye-tracking results also demonstrated variability in the anatomic structures of interest focused on during performance of this testing. The results of this investigation provide evidence of reliability well below what would be expected of a gold standard test during stress examination of the Lisfranc tarsometatarsal joint complex. These results indicate that future scientific endeavors are required to standardize the performance and interpretation of this testing. PMID- 30448375 TI - Delayed Allergic Reaction to ChloraPrepTM in Foot and Ankle Surgery. AB - Chlorhexidine-based skin preparations are frequently used in orthopaedic surgery. We report 2 recent cases of patients suffering significant allergic reactions to ChloraPrepTM complicating routine foot and ankle surgery. We advise vigilance for this possible issue and recommend thorough removal of all preparation at the end of the procedure. PMID- 30448376 TI - Results of Achilles Tendon Excision for Purpose of Wound Closure: Case Series. AB - The loss of Achilles tendon results in reduced plantar flexion strength; however, in patients who are not fit for major reconstructive surgery, with soft-tissue defects overlying the tendon, Achilles tendon excision is a useful adjunct procedure for wound closure. We report 3 patients with infections around the Achilles tendons needing debridement procedures who underwent Achilles tendon excision for the purpose of wound closure. Local healing was achieved in all patients; all returned to their premorbid ambulatory status, and 2 could perform heel raise. Our series showed that Achilles tendon excision eases soft-tissue reconstruction around it and that the primary aim of wound closure was met with a reasonable functional outcome. As such, it is a viable option for selected patients with infections around the Achilles tendon who are poor candidates for flaps. PMID- 30448377 TI - Ankle Fracture Fixation: Medial or Lateral First? AB - In unstable ankle fractures, the importance of reducing the lateral malleolus first to obtain an anatomic reduction of the talus is well established. Although this is a time-tested and common surgical approach, current surgical practice does not always follow the established dogma. Medial-first fixation may be a worthwhile alternative to lateral-first fixation in select instances. We performed a retrospective, cohort study in an urban level I trauma center to compare medial malleolus-first fixation of unstable ankle fractures with lateral malleolus-first fixation. Patient demographics, injury characteristics, and radiographic metrics including pre-, intra-, and final postoperative talocrural angles, medial clear space, and tibiofibular overlap were assessed. Complications were also reviewed. A total of 280 adult patients with operative bimalleolar ankle fractures from January 2010 to January 2015 met inclusion criteria. There were more open fractures (23.2% vs 9.4%, p = .01) and less isolated injuries in the medial-first group (59.2% vs 71.0%, p = .02). There were less isolated operative procedures (80.3% vs 89.1%, p = .04) and more intramedullary screw placement of the lateral malleolus (11.2% vs 4.3% p = .02) in the medial-first fixation group. There was also a strong trend in identifying more posterior tibial tendon injuries in the medial-first group compared with the lateral-first group (3.5% vs 0%, p = .06). There were no significant differences in fluoroscopy times or radiographic variables in the preoperative, intraoperative, or most recent postoperative images between either group. This approach demonstrates equivalent radiographic outcomes to lateral-first fixation and may be appropriate in select cases. PMID- 30448378 TI - Structures at Risk From an Intermetatarsal Screw for Lapidus Bunionectomy: A Cadaveric Study. AB - The Lapidus bunionectomy is performed to treat hallux valgus. Recurrence of the deformity remains a concern. A transverse intermetatarsal screw spanning the base of the first metatarsal to the base of the second can increase stability. The neurovascular bundle is located within the proximity of this screw. In this study, we assessed the structures at risks with the use of this technique. In 10 specimens, a guide wire was placed, and a 4.0-mm cannulated screw was inserted. The neurovascular bundle was dissected and inspected for direct trauma to the neurovascular bundle, and the proximity of the screw was measured using a digital caliper. Ten cadaveric specimens were used. The dorsalis pedis artery and deep peroneal nerve were free from injury in 9 of 10 specimens. In those 9 specimens, the neurovascular bundle was located dorsal in relation to the screw. The mean distance of the screw to the neurovascular bundle was 7.1 +/- 3.3 mm. The mean distance from the screw to the first tarsometatarsal joint (TMTJ) was 14.7 +/- 4.3 mm. The mean distance from the screw as it entered the second metatarsal to the second TMTJ was 18.0 +/- 7.2 mm. In 1 specimen, the screw was found to be traversing through the neurovascular bundle. The distance from the screw to the first TMTJ was 15.0 mm. The distance of the screw from where it entered the second metatarsal to the second TMTJ was 24.0 mm. Although the intermetatarsal screw avoided the neurovascular cases in most instances, there is some anatomic risk to the neurovascular bundle. Further study is warranted to evaluate clinical results using the intermetatarsal screw for the modified Lapidus procedure. PMID- 30448379 TI - Identifying Risk Factors for 30-Day Readmissions After Triple Arthrodesis Surgery. AB - Rigid flatfoot deformity is a debilitating condition that can be managed by triple arthrodesis surgery. Triple arthrodesis has the potential to restore health-related quality of life, but it is also associated with several complications. Few studies have examined the 30-day readmission rates after triple arthrodesis. The objective of this study was to investigate risk factors for 30-day all-cause readmissions after triple arthrodesis. The nationwide readmission database was queried from 2013. By using International Classification of Disease, Ninth Revision, procedure codes, all triple arthrodesis procedures were identified. Demographic factors, comorbidities, insurance status, and hospital characteristics were statistically compared between patients who experienced a 30-day readmission and those who did not. Multivariable logistic regression was used to identify independent risk factors for 30-day readmission. Overall, 1916 triple arthrodesis cases were identified. The overall 30-day readmission rate after triple arthrodesis was 4.6%. Univariate analysis revealed a statistically higher proportion of patients with electrolyte abnormalities (13.8% vs 4.6%; p < .01) in the patients who were readmitted within 30 days compared with those who were not. Multivariable analysis demonstrated Medicaid insurance, relative to private insurance, as the only statistically significant predictor of 30-day readmission with an odds ratio of 4.43 (p < .05). These results suggest that patients of lower socioeconomic status may be at a greater risk for development of a short-term readmission after triple arthrodesis surgery. These findings are important for surgeon and patient communication, counseling, and postoperative care when choosing to pursue triple arthrodesis surgery. PMID- 30448380 TI - Open Talus Fractures: Early Infection and Its Epidemiological Characteristics. AB - Open talus fractures are relatively rare and severe open injuries with a high risk of severe infection. To better understand the epidemiological characteristics of this kind of injury, a monocentric case review was conducted among open talus fracture patients admitted in West China Hospital of Sichuan University between January 2010 and December 2014. Fifty-one (N = 51) patients were recruited to the study, including 44 (86.3%) males and 7 (13.7%) females. Fifty-two cases of open talus fractures were diagnosed among the patients (1 patient had bilateral fractures). The primary cause of open talus fracture was a fall from a height. The rate of concurrent injuries associated with open talus fracture was 84.3%. The overall infection rate was 41.2%, rising with the increase of injury severity classified by Gustilo-Anderson classification and the existence of peritalar dislocation. Therefore, it can be concluded that open talus fractures are at high risk of concurrent complications and early infection. It is necessary to perform a complete physical examination to search for possible concurrent injuries. When evaluating the risk of infection, in addition to the severity of open talus fracture, the existence and severity of peritalar dislocation should also be taken into consideration. PMID- 30448381 TI - Effects of thyroid hormone disruption on the ontogenetic expression of thyroid hormone signaling genes in developing zebrafish (Danio rerio). AB - Thyroid hormones (THs) regulate neurodevelopment, thus TH disruption is widely posited as a mechanism of developmental neurotoxicity for diverse environmental chemicals. Zebrafish have been proposed as an alternative model for studying the role of TH in developmental neurotoxicity. To realize this goal, it is critical to characterize the normal ontogenetic expression profile of TH signaling molecules in the developing zebrafish and determine the sensitivity of these molecules to perturbations in TH levels. To address these gaps in the existing database, we characterized the transcriptional profiles of TH transporters, deiodinases (DIOs), receptors (TRs), nuclear coactivators (NCOAs), nuclear corepressors (NCORs), and retinoid X receptors (RXRs) in parallel with measurements of endogenous TH concentrations and tshbeta mRNA expression throughout the first five days of zebrafish development. Transcripts encoding these TH signaling components were identified and observed to be upregulated around 48-72 h post fertilization (hpf) concurrent with the onset of larval production of T4. Exposure to exogenous T4 and T3 upregulated mct8, dio3-b, tralpha-a, trbeta, and mbp-a levels, and downregulated expression of oatp1c1. Morpholino knockdown of TH transporter mct8 and treatment with 6-propyl-2 thiouracil (PTU) was used to reduce cellular uptake and production of TH, an effect that was associated with downregulation of dio3-b at 120 hpf. Collectively, these data confirm that larval zebrafish express orthologs of TH signaling molecules important in mammalian development and suggest that there may be species differences with respect to impacts of TH disruption on gene transcription. PMID- 30448382 TI - IGFBP-rP1, a strongly conserved member of the androgenic hormone signalling pathway in Isopoda. AB - The first protein which has been described to interact with the malacostracan Androgenic Gland Hormone (AGH) is a binding protein called IGFBP-rP1. It has been identified and studied in several species of decapods, in which its interaction with the masculinizing hormone and its expression patterns have been established in several ways. However, this protein remains uncharacterised to date in the other malacostracan orders, like Amphipoda and Isopoda, although they were historically the first ones in which the androgenic gland and the corresponding hormone were respectively described. In this article, we identified the IGFBP-rP1 of isopods and established its implication in the pathway of the AGH with a silencing approach in the model species Armadillidium vulgare. We also showed that this gene is expressed in all the tissues of males and females, with a similar pattern in animals infected with Wolbachia, a feminizing endosymbiont of several isopod species. The expression pattern did not differ during the development of uninfected and infected animals either. We finally studied the evolution of the IGFBP-rP1 in 68 isopod species, looking for conserved motifs and evidence of natural selection. Altogether, our results showed that this gene is constitutively expressed and strongly conserved in isopods, in which it likely constitutes a key element of the insulin/IGF signalling pathway. However, we also illustrated that IGFBP-rP1 is not sufficient on its own to explain the different developmental paths taken by the males and the females or feminized genetic males. PMID- 30448383 TI - Transglutaminase 1 Replacement Therapy Successfully Mitigates the ARCI Phenotype in Full-Thickness Skin Disease Equivalents. PMID- 30448384 TI - Epidermal barrier function is impaired in Langerhans cell-depleted mice. PMID- 30448385 TI - Can scalar timing explain variability in scanning patterns? AB - Why are scanning patterns so variable? Theory predicts that for prey species facing non-stalking predators scans to monitor predators should occur at fixed rather than unpredictable times. Yet, empirical distributions of inter-scan intervals (ISIs) are very variable. One hypothesis to explain variability is that animals initiate several of their scans in response to external disturbances that occur at random times. I propose, instead, that animals actually aim to initiate scans at fixed times, which are adjusted to perceived predation risk, but well established cognitive processes on interval timing induce variability in ISIs. Signatures associated with scalar timing, a leading theory of interval timing in animals, include a linear increase in the standard deviation of ISIs as a function of mean ISI duration. The increase is expected to be proportional to mean ISI duration, which implies that the CV (SD*100/Mean) of ISIs is unrelated to mean ISI duration. Finally, the distribution of ISIs should be gamma-like with right skew. I tested these predictions in groups of domestic fowls (Gallus gallus domesticus) under controlled conditions and in groups of American flamingos (Phoenicopterus ruber) in the field. I found support for most but not all predictions in these two species. In particular, CV of ISIs increased with the mean, a deviation that I attribute to non-independent vigilance amongst group members. Cognitive processes associated with scanning patterns warrant further empirical testing. PMID- 30448386 TI - Trigeminal nerve stimulation successfully awakened an unconscious patient. PMID- 30448387 TI - Development of covalent NLRP3 inflammasome inhibitors: Chemistry and biological activity. AB - The NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome is the best recognized and most widely implicated regulator of caspase-1 activation. It is a key regulator of innate immune response and is involved in many pathophysiological processes. Recent evidences for its inappropriate activation in autoinflammatory, autoimmune, as well as in neurodegenerative diseases attract a growing interest toward the development of small molecules NLRP3 inhibitors. Based on the knowledge of biochemical and structural aspects of NLRP3 activation, one successful strategy in the identification of NLRP3 inhibitors relies on the development of covalent irreversible inhibitors. Covalent inhibitors are reactive electrophilic molecules able to alkylate nucleophiles in the target protein. These inhibitors could ensure good efficacy and prolonged duration of action both in vitro and in vivo. In spite of these advantages, effects on other signalling pathways, prone to alkylation, may occur. In this review, we will illustrate the chemistry and the biological action of the most studied covalent NLRP3 inhibitors developed so far. A description of what we know about their mechanism of action will address the reader toward a critical understanding of NLRP3 inhibition by electrophilic compounds. PMID- 30448389 TI - Biopiracy in India: Seed diversity and the scramble for knowledge. AB - BACKGROUND: Biopiracy has usually been discussed mostly in the context of the life sciences, sometimes in dialogue with legal debates or political implications. This paper provides a humanities perspective on contemporary discussions of biopiracy and biopatenting. HYPOTHESIS: It proceeds from the hypothesis that contemporary debates and practices of biopiracy can be understood as harking back to colonial legacies, which systematically disregard "native" knowledge or seek to appropriate it for their own purposes. RESULTS: Drawing on the work of Vandana Shiva, the present article seeks to redefine the notion of ownership of knowledge from a cultural studies perspective. Exploring the 2016 documentary film Seed: The Untold Story, it analyses counter-discourses to practices of biopiracy. CONCLUSION: The paper concludes that given the roots of biopiracy in colonial legacies, forms of resistance may need to appropriate colonialist epistemologies. One example of such appropriation is Vandana Shiva's own campaign, which casts seed ownership in the imagery and rhetoric of Mahatma Gandhi's fight against British colonialism in India. Finally, the article ends by suggesting that issues of biopiracy need to be seen in larger context. Drawing on the work of cultural philosopher Hans-Ulrich Gumbrecht, it argues that the problem of the twenty-first century may be a scramble for natural resources such as the right for clean water. Biopiracy is hence far from a debate linked only to specific cases in particular locales, but is part of a global epistemological and political framework, which has systematically disenfranchised communities of color and countries of the global South. PMID- 30448388 TI - Decomposition of Piloty's acid derivatives - Toward the understanding of factors controlling HNO release. AB - The recent interest in the clinical applications of Piloty's acid derivatives as HNO donors for the treatment of cardiovascular system dysfunction has led us to the examination of factors controlling HNO release from selected ortho substituted N-hydroxysulfonamides. Here we present the kinetic and quantum mechanical studies on the mechanism of HNO release from selected ortho substituted N-hydroxysulfonamides and in vivo examination of the antiaggregatory properties of N-hydroxy-(2-bromobenzene)sulfonamide complex with sodium salt of beta-cyclodextrin sulfobutyl ethers-ethyl ethers as compared with Angeli's salt. PMID- 30448390 TI - A hepatitis B vaccine booster shot at age 10 could be cost-saving in China: But is it too soon to tell? PMID- 30448391 TI - Cilostamide affects in a concentration and exposure time-dependent manner the viability and the kinetics of in vitro maturation of caprine and bovine oocytes. AB - This study investigated: 1) the kinetics of oocyte chromatin configuration during in vitro maturation (IVM) of caprine and bovine oocytes; and 2) the effect of in vitro pre-maturation (IVPM) with cilostamide with or without association of the follicular wall (FW) on the same parameters. In experiment I, cumulus-oocyte complexes (COCs) were cultured in vitro in a standard maturation medium for 6, 12, 18 or 30 h. For experiment II, the COCs were cultured for 30 h, either in a standard IVM medium or in IVPM containing cilostamide (10 or 20 MUM) and FW alone or in combination, for 6 or 12 h before the onset of maturation. The MII rate was similar (P > .05) between 18 and 30 h of maturation, both of which were higher (P < .05) than 6 and 12 h IVM in both species (Experiment I). Contrary to caprine, all IVPM treatments presented a higher (P < .05) percentage of bovine oocytes arrested at the GV stage than the control treatment after 6 h of culture. The percentage of MII oocytes after 30 h (IVPM+IVM) of culture in bovine oocytes treated with 10 MUM cilostamide associated with FW and FW alone cultured for 6 h presented MII percentages similar to the control. However, in caprine, these treatments significantly reduced the percentages of MII in relation to the control treatment (Experiment II). In conclusion, the combination of concentration-exposure time to cilostamide during IVPM delayed meiotic progression in bovine after 6 and 12 h of culture. However, overall the culture period (IVPM+IVM) influenced the oocyte chromatin configuration and kinetics in both species. PMID- 30448392 TI - Role of homocysteine metabolism in animal reproduction: A review. AB - Homocysteine (Hcy) is a thiol-containing essential amino acid, important for the growth of cells and tissues. Several hypotheses exist regarding Hcy toxicity in humans; Hcy is involved in protein structural modifications, oxidative stress, and neurotoxicity induction and is therefore associated with several pathological conditions in humans. In veterinary science, knowledge regarding Hcy has increased recently due to several studies; however, many aspects remain undiscovered. Many details remain unknown regarding the effect of Hcy levels on pregnancy and the optimal management of pathological conditions associated with Hcy levels during pregnancy in various species. In this review, we aimed to compile various studies on Hcy metabolism to elucidate its current status in the veterinary field, particularly for ovine, bovine, equine, porcine, canine, and feline species. PMID- 30448394 TI - Obesity and Mortality in End-Stage Renal Disease. Is It Time to Reverse the "Reverse Epidemiology"-at Least in Peritoneal Dialysis? AB - With the rising incidence of chronic kidney disease, there has been a steady growth of the hemodialysis (HD) and peritoneal dialysis (PD) population. Prevalence of obesity has also been on the rise. It has been proposed by some that obesity helps with survival in HD and possibly in PD patients-a concept called "Reverse Epidemiology." Here, we attempt to explore this phenomenon in the HD and PD populations and see specifically if it is time to reverse this concept. A MEDLINE search was performed using search terms: obesity, body mass index, end stage renal disease, HD, PD, renal dialysis, mortality, survival, and reverse epidemiology. Review of recent literature questions the benefit of obesity on survival in the dialysis population-more specifically in PD. Patients on PD with higher muscle mass seem to have the best survival. There should be more focus on malnutrition among such patients. PMID- 30448393 TI - Glycemic Status and Mortality in Chronic Kidney Disease According to Transition Versus Nontransition to Dialysis. AB - OBJECTIVE: The impact of glycemic control in diabetic patients with chronic kidney disease (CKD) who may or may not transition to dialysis remains uncertain, given recent interest in the conservative management of advanced CKD without dialysis therapy, which may benefit from alternative glycemic control strategies. DESIGN AND METHODS: Among a national cohort of US Veterans, we examined the association of glycemic status, defined by averaged random blood glucose and hemoglobin A1c (HbA1c), with mortality after transitioning to dialysis over 2007 2011 (Transition Cohort) compared with patients in a one-to-one matched cohort of CKD patients with diabetes who did not transition to dialysis (Nontransition Cohort). RESULTS: Among 17,121 patients in the Transition Cohort, averaged random glucose >=200 mg/dL was associated with higher mortality in expanded case-mix analyses (reference: 100-<120 mg/dL): adjusted hazard ratio (95% confidence interval) 1.26 (1.13-1.40). In the transition cohort, HbA1c 8-<10% and >=10% were associated with higher mortality (reference: 6-<8%): adjusted hazard ratios (95% confidence interval) 1.21 (1.11-1.33) and 1.43 (1.21-1.69), respectively. Among 8,711 patients in the Nontransition Cohort, averaged random glucose <100 mg/dl and >=160 mg/dl were associated with higher death risk, whereas HbA1c was not associated with mortality. CONCLUSION: In diabetic CKD patients transitioning to dialysis, higher averaged random glucose and HbA1c were associated with early dialysis mortality, whereas in matched CKD patients who did not transition, both lower and higher glucose levels were associated with higher mortality. These data suggest the need for different glycemic strategies based on whether there are plans to transition to dialysis versus pursue conservative management among diabetic patients with CKD. PMID- 30448395 TI - Relationships between craniofacial morphology and masticatory muscle activity during isometric contraction at different interocclusal distances. AB - OBJECTIVE: The aim was to investigate relationships amongst interocclusal distances, masticatory muscle electromyographic (EMG) activity during isometric contraction of masticatory muscles, and craniofacial morphology. DESIGN: Twenty eight women and 12 men (25.3 +/- 3.8 years old) participated. After measuring maximal voluntary occlusal bite force (MVOBF) between the right-first premolars, the participants were asked to bite at submaximal levels of 0 (= holding the bite force transducer), 15, 22.5, and 30% MVOBF with the use of visual feedback. The thickness of a bite force transducer was set at 10, 12, 13, 14, 16, 17, 18, 19, 20, 22, and 24 mm (= interocclusal distance: IOD). Nine soft tissue craniofacial factors were assessed through digital photograph: face height, middle face height, lower face height, face width, inter-pupil distance and mandibular plane angle, lower face height / face height ratio, inter-pupil distance / facial width ratio and face width / face height ratio. RESULTS: In the masseter muscle, EMG activity decreased with increased IODs. The participants with higher mandibular plane angle had more negative slope coefficients of IOD-EMG graphs at 0% MVOBF especially in male temporalis and female masseter and temporalis muscles, suggesting that a greater mandibular plane angle is associated with lower EMG activity at longer IOD. CONCLUSIONS: Overall the findings support the notion that craniofacial morphology is associated with differences in neuromuscular activity of the masticatory muscles, and suggest that the neuromuscular effects of oral appliances may be dependent on patients' craniofacial morphology and the thickness of the device. (247/250 words). PMID- 30448396 TI - Lipid Mediators, M2 Macrophages, and Pathological Neovascularization. AB - Sasaki and colleagues [1] (JCI Insight 2018;3,e96902) identified the leukocyte inflammatory lipid mediator leukotriene B4 (LTB4)/LTB4 receptor 1 receptor signaling axis in M2 macrophages as a causal pathway for the vascular endothelial growth factor-dependent pathological neovascularization in a mouse model that mimics wet age-related macular degeneration. This observation provides a novel mechanism by which an eicosanoid lipid mediator drives retinal vascular pathology and suggests a novel therapeutic target for proliferative retinal vascular diseases. PMID- 30448397 TI - Effects of hindlimb suspension and reloading on gastrocnemius and soleus muscle mass and function in geriatric mice. AB - Reloading of atrophied muscles after hindlimb suspension (HLS) can induce muscle injury and prolong recovery after disuse in old rats, especially in fast contracting muscles. Less is known about the responses in mice and whether fast and slow muscles from geriatric mice will respond in a similar fashion to HLS unloading and recovery (HLS + R). Furthermore, while slow muscles undergo atrophy with disuse, they typically are more resistant to sarcopenia than fast contracting muscles. Geriatric (28 mo. of age) male C57BL/6 mice were randomly placed into 3 groups. These included HLS for 14 days n = 9, and HLS followed by 14 days of reloading recovery (HLS + R; n = 9), or normal ambulatory cage controls (n = 9). Control mice were not exposed to unloading. Electrically evoked maximal muscle function was assessed in vivo in anesthetized mice at baseline, after 14 days of HLS or HLS + R. As expected, HLS significantly reduced body weight, wet weight of gastrocnemius and soleus muscles and in vivo maximal force. There were no differences in vivo fatigability of the plantar flexor muscles and overall fiber size. There were only minor fiber type distribution and frequency distribution of fiber sizes that differ between HLS + R and control gastrocnemius and soleus muscles. Soleus muscle wet weight had recovered to control levels after reloading, but type I/IIA fibers in the soleus muscles were significantly smaller after HLS + R than control muscles. In contrast, gastrocnemius muscle wet weight did not recover to control levels after reloading. Plantar flexion muscle force (primarily influenced by the gastrocnemius muscles) did not recover in HLS + R conditions as compared to HLS conditions and both were lower than control force production signaling for apoptosis, autophagy and anabolic markers were not different between control and HLS + R gastrocnemius and soleus muscles in geriatric mice. These results suggest that molecular signaling does not explain attenuated ability to regain muscle wet weight, fiber size or muscle force production after HLS in geriatric mice. It is possible that fluid shifts, reduced blood flow, or shortened muscle fibers which failed to regain control lengths contributed to the attenuation of muscle wet weight after HLS and reloading and this affected force production. Further work is needed to determine if altered/loss of neural activity contributed to the inability of geriatric mice to regain gastrocnemius muscle weight and function after HLS and reloading. PMID- 30448398 TI - Lipid composition and salt concentration as regulatory factors of the anion selectivity of VDAC studied by coarse-grained molecular dynamics simulations. AB - The voltage-dependent anion channel (VDAC) is a mitochondrial outer membrane protein whose fundamental function is to facilitate and regulate the flow of metabolites between the cytosol and the mitochondrial intermembrane space. Using coarse-grained molecular dynamics simulations, we investigated the dependence of VDAC selectivity towards small inorganic anions on two factors: the ionic strength and the lipid composition. In agreement with experimental data we found that VDAC becomes less anion selective with increasing salt concentration due to the screening of a few basic residues that point into the pore lumen. The molecular dynamics simulations provide insight into the regulation mechanism of VDAC selectivity by the composition in the lipid membrane and suggest that the ion distribution is differently modulated by POPE compared to the POPC bilayer. This occurs through the more persistent interactions of acidic residues located at both rims of the beta-barrel with head groups of POPE which in turn impact the electrostatic potential and thereby the selectivity of the pore. This mechanism occurs not only in POPE single component membranes but also in a mixed POPE/POPC bilayer by an enrichment of POPE over POPC lipids on the surface of VDAC. Thus we show here that computationally-inexpensive coarse-grained simulations are able to capture, in a semi-quantitative way, essential features of VDAC anion selectivity and could pave the way toward a molecular level understanding of metabolite transport in natural membranes. PMID- 30448399 TI - Differences in capillary recruitment between cardiac surgery and septic patients after fluid resuscitation. AB - BACKGROUND: Clinical evaluation of the effects of fluid therapy remains cumbersome and strategies are based on the assumption that normalization of macrohemodynamic variables will result in parallel improvement in organ perfusion. Recently, we and others suggested the use of direct in-vivo observation of the microcirculation to evaluate the effects of fluid therapy. METHODS: A single-centre observational study, using in-vivo microscopy to assess total vessel density (TVD) in two subsets of ICU patients. RESULTS: After fluid resuscitation TVD showed no difference between sepsis patients (N = 47) and cardiac surgery patients (N = 52): 18.4[16.8-20.8] vs 18.7[16.8-20.9] mm/mm2, p = 0.59. In cardiac surgery patients there was a significant correlation between the amount of fluids administered and TVD, with an optimum in the third quartile. However, such correlation was absent in septic patients. CONCLUSIONS: TVD after fluid administration is not different between 2 subtypes of intensive care patients. However, only in septic patients we observed a lack of coherence between the amount of fluids administered and TVD. Further research is needed to determine if TVD may serve as potential endpoint for fluid administration. PMID- 30448400 TI - Numerical simulations of the microvascular fluid balance with a non-linear model of the lymphatic system. AB - Fluid homeostasis is required for life. Processes involved in fluid balance are strongly related to exchanges at the microvascular level. Computational models have been presented in the literature to analyze the microvascular-interstitial interactions. As far as we know, none of those models consider a physiological description for the lymphatic drainage-interstitial pressure relation. We develop a computational model that consists of a network of straight cylindrical vessels and an isotropic porous media with a uniformly distributed sink term acting as the lymphatic system. In order to describe the lymphatic flow rate, a non-linear function of the interstitial pressure is defined, based on literature data on the lymphatic system. The proposed model of lymphatic drainage is compared to a linear one, as is typically used in computational models. To evaluate the response of the model, the two are compared with reference to both physiological and pathological conditions. Differences in the local fluid dynamic description have been observed using the non-linear model. In particular, the distribution of interstitial pressure is heterogeneous in all the cases analyzed. The resulting averaged values of the interstitial pressure are also different, and they agree with literature data when using the non-linear model. This work highlights the key role of lymphatic drainage and its modeling when studying the fluid balance in microcirculation for both to physiological and pathological conditions, e.g. uremia. PMID- 30448401 TI - Inflammatory stress causes N-glycan processing deficiency in ocular autoimmune disease. AB - High levels of proinflammatory cytokines have been associated with loss of tissue function in ocular autoimmune diseases but the basis for this relationship remains poorly understood. Here we investigated a new role for tumor necrosis factor (TNF)-alpha in promoting N-glycan processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were detected between the efficacies of cytokines in regulating the expression of glycogenes responsible for the biosynthesis of N-glycans. TNFalpha but not interleukin-1beta had a profound effect in suppressing the expression of enzymes involved in the Golgi branching pathway, including MGAT1 and 2, which are required for the formation of biantennary structures. This decrease in gene expression correlated with a reduction in enzymatic activity and impaired N-glycan branching. Moreover, patients with ocular mucous membrane pemphigoid were characterized by marginal N acetylglucosaminyltransferase expression and decreased N-glycan branching in conjunctiva. Together, these data indicate that proinflammatory cytokines differentially influence the expression of N-glycan processing enzymes in the Golgi and set the stage for future studies to explore the pathophysiology of ocular autoimmune diseases. PMID- 30448402 TI - Tyrosinase is a novel endogenous regulator of developmental and inflammatory lymphangiogenesis. AB - Lymphangiogenesis is critically involved in tissue fluid balance, graft rejection, and tumor metastasis. Endogenous regulation of lymphangiogenesis is poorly understood. Here we use the lymphatic vessel architecture at the limbal border of the normally avascular cornea, a quantitative trait under strong genetic influence, as a model system to identify new candidate genes regulating lymphangiogenesis. Comparing low-lymphangiogenic BALB/cN versus high lymphangiogenic C57BL/6N mice, we performed quantitative trait loci analysis of five phenotypes in a large BALB/cN x C57BL/6N intercross (n=795) and identified three to eight genome-wide significant loci, the strongest on chromosome 7 containing Tyrosinase (Tyr). Tyrosinase-negative mice showed significantly increased limbal lymphvascularized areas, a higher number of lymphatic vessel endpoints, and branching points and increased inflammation-induced lymphangiogenesis. These findings confirm that tyrosinase is a novel lymphangiogenesis regulator in developmental and inflammatory lymphangiogenesis. Our findings link melanin synthesis with lymphangiogenesis and open new treatment options in lymphangiogenesis-related diseases. PMID- 30448403 TI - Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in CYP46A1-Mediated Cholesterol Removal. AB - CYP46A1 is the cytochrome P450 enzyme that converts cholesterol to 24 hydroxycholesterol, a cholesterol elimination product and a potent liver X receptor (LXR) ligand. We conducted retinal characterizations of Cyp46a1-/- mice that had normal fasting blood glucose levels but up to 1.8-fold increase in retinal cholesterol. The retina of Cyp46a1-/- mice exhibited venous beading and tortuosity, microglia/macrophage activation, and increased vascular permeability, features commonly associated with diabetic retinopathy. The expression of Lxralpha and Lxrbeta was increased in both the whole Cyp46a1-/- retina and retinal macroglia/macrophages. The LXR-target genes were affected as well, primarily in activated microglial cells and macrophages. In the latter, the LXR transactivated genes (Abca1, Abcg1, Apod, Apoe, Mylip, and Arg2) were up regulated; similarly, there was an up-regulation of the LXR-transrepressed genes (Ccl2, Ptgs2, Cxcl1, Il1b, Il6, Nos2, and Tnfa). For comparison, gene expression was investigated in bone marrow-derived macrophages from Cyp46a1-/- mice as well as retinal and bone marrow-derived macrophages from Cyp27a1-/- and Cyp27a1-/ Cyp46a1-/- mice. CYP46A1 expression was detected in retinal endothelial cells, and this expression was increased in pro-inflammatory environment. Retinal Cyp46a1-/- phosphoproteome revealed altered phosphorylation of 30 different proteins, including tight junction protein ZO-1 and aquaporin 4. Collectively, the data obtained establish metabolic and regulatory significance of CYP46A1 for the retina and suggest pharmacological activation of CYP46A1 as potential therapeutic approach to dyslipidemia-induced retinal damage. PMID- 30448404 TI - Fibrosis rescue improves cardiac function in dystrophin-deficient mice and Duchenne patient-specific cardiomyocytes by immunoproteasome modulation. AB - Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of beta-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific towards DMD disease. Medications that target DMD cardiac fibrosis are in early stages of development. Here, we demonstrated immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of DMD patients. Interestingly, immunoproteasome inhibition ameliorated cardiomyopathy in mdx mice and reduced the development of cardiac fibrosis. Establishing the immunoproteasome inhibition dependent cardioprotective role suggests the possibility to modulate the immunoproteasome as novel and clinically relevant treatment to rescue dilated cardiomyopathy in DMD patients. PMID- 30448405 TI - Hepatocyte PPARalpha enhances liver regeneration after partial hepatectomy in mice. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPARalpha is also a potent hepaticmitogen. Hepatocyte-specific disruption of PPARalpha inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPARalpha in partial hepatectomy (PHx)-induced liver regeneration. Here, using hepatocyte-specific PPARalpha-deficient (Ppara?Hep) mice, the function of hepatocyte PPARalpha in PHx-induced liver regeneration was investigated. PPARalpha protein level and transcriptional activity were increased in the liver after PHx. Compared with the Pparafl/fl mice, Ppara?Hep mice exhibited significantly reduced hepatocyte proliferation at 32 hours after PHx. Consistently, reduced Ccnd1 and Pcna mRNA and CYCD1 and PCNA protein were observed at 32 hours after PHx in PparaDeltaHep mice. Furthermore, PparaDeltaHep mice showed increased hepatic lipid accumulation, and enhanced hepatic triglyceride contents due to impaired hepatic fatty acid beta-oxidation when compared with that observed in Pparafl/fl mice. These results indicate that PPARalpha promotes liver regeneration after PHx, at least partially via regulating the cell cycle and lipid metabolism. PMID- 30448406 TI - Role of endoplasmic reticulum stress in pro-inflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy. AB - Shallow extravillous trophoblast (EVT) invasion is central to the pathophysiology of many pregnancy complications. Invasion is mediated partially by matrix metalloproteinases (MMPs). MMP-2 is highly expressed in early pregnancy. MMP activity can be regulated by pro-inflammatory cytokines, which also induce endoplasmic reticulum (ER) stress in other cells. We investigated whether pro inflammatory cytokines regulate MMP-2 activity through ER stress response pathways in trophoblast, before exploring potential regulatory mechanisms. There was increased immunoreactivity of HSPA5, also known as GRP78, in cells of the placental bed, including EVTs, in cases of early-onset preeclampsia compared to normotensive controls. Treating EVT-like JEG3 and HTR8/SVneo cells with ER stress inducers, tunicamycin and thapsigargin, suppressed MMP2 mRNA and protein expression, secretion, activity, and reduced their invasiveness. A cocktail of pro-inflammatory cytokines, interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma, suppressed MMP-2 activity in JEG-3 cells, and was accompanied by activation of the PERK-EIF2A arm of the ER stress pathway. Knockdown of ATF4, a downstream transcriptional factor of the PERK-EIF2A pathway, by small interference RNA, restored MMP2 expression but not cellular proteins. However, suppression of EIF2A phosphorylation with a PERK inhibitor, GSK2606414, under ER stress, restored MMP-2 protein. ER stress regulates MMP-2 expression at both the transcriptional and translational levels. This study provides the first mechanistic linkage by which pro-inflammatory cytokines may modulate trophoblast invasion through ER stress pathways. PMID- 30448407 TI - Elevated membrane cholesterol disrupts lysosomal degradation to induce Abeta accumulation: the potential mechanism underlying augmentation of Abeta pathology by type 2 diabetes mellitus. AB - Endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of beta-amyloid protein (Abeta), a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the strongest risk factors for development of AD. Supporting this link, experimentally induced T2DM enhances AD pathology in various animal models. Spontaneous T2DM also enhances Abeta pathology with severe endocytic pathology, even in nonhuman primate brains. However, it remains unclear how T2DM accelerates Abeta pathology. Here, we demonstrate that cholesterol metabolism-related protein levels are increased and that membrane cholesterol level is elevated in spontaneous T2DM-affected cynomolgus monkey brains. Moreover, in vitro studies that manipulate cellular cholesterol reveal that elevated membrane cholesterol disrupts lysosomal degradation and enhances chemical-induced endocytic disturbance, resulting in great accumulation of Abeta in Neuro2a cells. These findings suggest that an alteration of cerebral cholesterol metabolism may be responsible for augmentation of Abeta pathology in T2DM-affected brains, which in turn may increase the risk for developing AD. PMID- 30448408 TI - The atypical chemokine receptor 2 limits progressive fibrosis after acute ischemic kidney injury. AB - Following renal ischemia-reperfusion injury (IRI) resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. The atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor, that binds and scavenges inflammatory CC-chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared to wild type, Ackr2 deficiency increased CC chemokine ligand 2 levels in tumor necrosis factor-stimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI one or five days after transient renal pedicle clamping tubular injury was similar to wild-type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2-/- kidneys. Regarding long-term outcomes, Ackr2-/ kidneys displayed more tubular injury five weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6Chigh inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency resulted in substantially aggravated renal fibrosis in Ackr2-/- kidneys five weeks after IRI, as revealed by increased expression of matrix molecules, renal accumulation of alphaSMA+ myofibroblasts, and bone marrow-derived fibrocytes. ACKR2 plays an important role in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury, and thus can prevent progression to chronic renal disease. PMID- 30448409 TI - Loss of integrin alphavbeta8 in murine hepatocytes accelerates liver regeneration. AB - Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes following liver injury. In other systems, integrin alphavbeta8 has a major role in activating transforming growth factor beta (TGFbeta), a potent inhibitor of hepatocyte proliferation. We hypothesized that depletion of hepatocyte integrin alphavbeta8 would increase hepatocyte proliferation and accelerate liver regeneration following injury. Using Itgb8flox/flox;Alb-Cre mice to deplete hepatocyte alphavbeta8, following partial hepatectomy, hepatocyte proliferation and liver-to body weight ratio were significantly increased in Itgb8flox/flox;Alb-Cre mice compared to control. Antibody-mediated blockade of hepatocyte alphavbeta8 in vitro, with assessment of TGFbeta signaling pathways by qPCR array, supported the hypothesis that integrin alphavbeta8 inhibition alters hepatocyte TGFbeta signaling towards a pro-regenerative phenotype. A diethylnitrosamine-induced model of hepatocellular carcinoma, employed to examine the possibility that this pro-proliferative phenotype might be oncogenic, revealed no difference in either tumor number or size between Itgb8flox/flox;Alb-Cre and control mice. Immunohistochemistry for integrin alphavbeta8 in healthy and injured human liver demonstrated that human hepatocytes express integrin alphavbeta8. Depletion of hepatocyte integrin alphavbeta8 results in increased hepatocyte proliferation and accelerated liver regeneration following partial hepatectomy in mice. These data demonstrate that targeting integrin alphavbeta8 may represent a promising therapeutic strategy to drive liver regeneration in patients with a broad range of liver diseases. PMID- 30448411 TI - Hyperosmotic low-volume bowel preparations: Is NER1006 safe? PMID- 30448410 TI - The danger signal extracellular ATP is involved in the immuno-mediated damage of alpha-sarcoglycan deficient muscular dystrophy. AB - In muscular dystrophies the muscle membrane fragility results in a tissue specific increase of danger-associated molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular adenosine triphosphate (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the "triggering" of the immune response and inhibition of regulatory T cells. Accordingly, pharmacological and genetic inhibition of eATP signaling improves the phenotype in models of chronic inflammatory diseases. In alpha sarcoglycanopathy (LGMD2D), eATP effects may be further amplified since alpha sarcoglycan extracellular domain binds eATP and displays an ecto-ATPase activity, thus controlling eATP concentration at the cell surface and attenuating the magnitude and/or the duration of eATP-induced signals. Here we show that in vivo blockade of the eATP/P2X purinergic pathway by a broad spectrum P2XR-antagonist delayed the progression of the dystrophic phenotype in alpha-sarcoglycan null mice. eATP blockade dampened the muscular inflammatory response and enhanced the recruitment of Foxp3+ immunosuppressive regulatory CD4+ T cells. The improvement of the inflammatory features was associated with increased strength, reduced necrosis and limited expression of pro-fibrotic factors, suggesting that pharmacologic purinergic antagonism, altering the innate and adaptive immune component in the muscle infiltrates, might provide a therapeutic approach to slow disease progression in LGMD2D. PMID- 30448412 TI - GooD4Mum: A general practice-based quality improvement collaborative for diabetes prevention in women with previous gestational diabetes. AB - AIMS: Gestational diabetes (GDM) and Type 2 diabetes pose tremendous health and economic burdens as worldwide incidence increases. Primary care-based systematic diabetes screening and prevention programs could be effective in women with previous GDM. GooD4Mum aimed to determine whether a Quality Improvement Collaborative (QIC) would improve postpartum diabetes screening and prevention planning in women with previous GDM in general practice. METHODS: Fifteen general practices within Victoria (Australia) participated in a 12-month QIC, consisting of baseline and four quarterly audits, guideline-led workshops and Plan-Do-Study Act feedback cycles after each audit. The primary outcome measures were the proportion of women on local GDM registers completing a diabetes screening test and a diabetes prevention planning consultation within the previous 15 months. RESULTS: Diabetes screening increased with rates more than doubled from 26% to 61% and postpartum screening increased from 43%-60%. Diabetes prevention planning consultations did not show the same level of increase (0%-10%). The recording of body mass index improved overall (51%-69%) but the number of women with normal body mass index did not. CONCLUSIONS: GooD4Mum supported increased diabetes screening and the monitoring of high risk women with previous GDM in general practice. PMID- 30448413 TI - Children eat more food when they prepare it themselves. AB - Encouraging children to participate in food preparation is recommended by pediatric guidelines and has been included in public health interventions. However, little is known about whether the act of preparing a food specifically increases children's intake of that food, nor is it known whether this effect might differ for healthy and familiar unhealthy foods. The present study examines whether 5- to 7-year-old children eat more of a food they prepared themselves compared to the same food prepared by someone else. Children participated in a laboratory study in which they prepared either a salad or a dessert and then had the opportunity to eat the food they prepared and/or a nearly identical food prepared by someone else. We found that children ate more of a food they prepared themselves, but no significant difference was observed in children's ratings of each food. In addition to eating more healthy foods they prepared themselves, children ate more unhealthy foods they prepared themselves, including familiar and well-liked desserts. More specific recommendations are needed if the goal of involving children in food preparation is to promote health. PMID- 30448414 TI - Small molecules as inhibitors of PCSK9: Current status and future challenges. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed. PMID- 30448415 TI - Design, synthesis and biological evaluation of novel, orally bioavailable pyrimidine-fused heterocycles as influenza PB2 inhibitors. AB - With the aim to identify novel influenza PB2 inhibitors with high potency and excellent pharmacokinetic parameters, we have designed and synthesized two new series of pyrimidine-fused heterocycle derivatives based on two generations of co crystal structures. Docking studies with the newly disclosed PDB structure guided the second round of rational design and led to the discovery of 25m, 25o and 25p as representative compounds with improved potency (EC50 < 1 nM). After pinpointing the metabolic labile site, the CN replacement of compound 25p successfully produced compound 29c, which demonstrated highly improved PK properties (Cl = 1.3 mL/min/kg, PO AUC = 152 MUM h at 10 mpk in mouse, F = 57%) and improved potency, emerging as a promising lead compound for the treatment of influenza A infection. PMID- 30448416 TI - Benzofuran derivatives and their anti-tubercular, anti-bacterial activities. AB - Benzofuran is a fundamental structural unit in a variety of biologically active natural products, and its derivatives display various biological properties. Some benzofuran derivatives possess unique anti-tubercular and anti-bacterial action mechanism, and exhibit excellent in vitro and in vivo activities against both drug-sensitive and drug-resistant pathogens. Moreover, several benzofuran derivatives have already used in clinics for the treatment of various diseases. Thus, benzofuran is a useful pharmacophore to develop new anti-tubercular and anti-bacterial drugs. This review covers the recent advances of benzofuran derivatives as potential anti-tubercular and anti-bacterial agents, and the structure-activity relationship is also discussed to pave the way for the further rational development of this kind of derivatives. PMID- 30448417 TI - N-Substituted aminoquinoline-pyrimidine hybrids: Synthesis, in vitro antimalarial activity evaluation and docking studies. AB - A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC50 values in the range 0.0189-0.945 MUM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction. PMID- 30448418 TI - Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents. AB - Microtubule-targeting agents (MTAs) are a class of clinically successful anti cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors. PMID- 30448419 TI - Highly fluorescent and HDAC6 selective scriptaid analogues. AB - Fluorescent scriptaid analogues with excellent HDAC6 selectivity (HDAC1/6 > 500) and potency (HDAC6 IC50 < 5 nM) have been synthesised and evaluated. The highly fluorescent nature of the compounds (up to PhiF = 0.83 in DMSO and 0.38 in aqueous buffer) makes them ideally suited for cellular imaging and visualisation of their cytoplasmic localisation was readily accomplished. Whole organism imaging in zebrafish confirmed both the vascular localisation of the new inhibitors and the impact of HDAC6 inhibition on in vivo development. PMID- 30448420 TI - Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase. AB - Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (Ki) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5 10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best Ki of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target. PMID- 30448421 TI - Opioid system modulators buprenorphine and samidorphan alter behavior and extracellular neurotransmitter concentrations in the Wistar Kyoto rat. AB - Approximately two-thirds of major depressive disorder (MDD) patients do not respond adequately to current therapies. BUP/SAM (ALKS 5461), a combination of buprenorphine (BUP) and samidorphan (SAM), is a novel opioid system modulator in development as an adjunct treatment for MDD. Using a rat strain (Wistar Kyoto rat) that is predisposed to stress and has an inadequate response to selective serotonin reuptake inhibitors (SSRIs), we investigated the effect of BUP and SAM, individually and in combination, in established nonclinical assays used to study antidepressants (the forced swim test, FST) and anxiolytics (marble burying test). As opioids and their receptors are expressed in mesocorticolimbic regions of the brain, we analyzed extracellular concentrations of dopamine, serotonin, and/or their metabolites in brain areas associated with mood and motivation. BUP alone and in combination with SAM significantly reduced immobility in the FST. Similarly, the BUP/SAM combination significantly reduced immobility in SSRI (escitalopram)-treated rats. BUP/SAM also decreased burying behavior. SAM attenuated BUP-induced changes of extracellular levels of serotonin and dopamine in the medial prefrontal cortex and nucleus accumbens shell. The latter suggests that the addition of SAM to BUP may limit activation of the mesolimbic dopamine reward pathway and thereby reduce BUP's reinforcing properties. SAM alone had no effect on neurochemistry or immobility in the FST. Collectively, these data indicate that opioid system modulation may offer an alternative mechanism that does not rely on enhanced serotonergic neurotransmission in neurocircuits associated with antidepressant and anxiolytic activity in nonclinical models. PMID- 30448422 TI - Evaluation of ultrasonic vocalizations in a neurodevelopmental model of schizophrenia during the early life stages of rats. AB - In an animal neurodevelopmental model of schizophrenia, we investigated ultrasonic communication and social behavior in male and female rats. Pregnant dams were treated with methylazoxymethanol acetate (MAM; 22 mg/kg) at 17 days of gestation. First, we examined the ultrasonic vocalizations (USVs) emitted by 8 day-old pups isolated from their mothers and placed in a familiar or an unfamiliar environment. Second, we assessed tickling-induced USVs, social play (SP) behavior and accompanying USVs in 30-day-old juveniles. Independent of the prenatal treatment, sex differences were noted at both ages. In the pups isolated from their mothers, compared to the females, the males produced flatter calls with a lower frequency. Compared to the females, the tickling-induced male USVs were characterized by a higher frequency, and the male SP-induced USVs showed a broader bandwidth and more modulated structure. Additionally, the numbers of both SP-induced USVs and SP episodes in the males were higher than those in the females. In contrast, the MAM exposure reduced the ultrasonic communication and social behavior independent of age almost equally in the male and female rats. The MAM-exposed isolated pups and juveniles experiencing tickling and social interaction displayed lower USV bandwidths, suggesting that the complexity of their ultrasonic communication was reduced. In addition, the MAM-exposed juveniles demonstrated a lower number of 50-kHz "happy calls" and decreased SP duration, which is suggestive of social withdrawal or negative-like symptoms. These data demonstrate that young MAM-exposed rats display an atypical repertoire of USVs and reduced play behavior suggestive of communication deficits associated with schizophrenia. PMID- 30448423 TI - Oxytocin prevents the increase of cocaine-related responses produced by social defeat. AB - The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (RSD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 min before each episode of RSD. Three weeks after the last defeat, the effects of cocaine on the conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigms were evaluated. The influence of OXT on the levels of BDNF in the prefrontal cortex (PFC), striatum and hippocampus was also measured. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by social defeat and modifies BDNF levels in all the structures we have studied. Moreover, OXT prevents RSD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the social defeat-induced increment in the conditioned rewarding effects of cocaine in the CPP, favored the extinction of cocaine-associated memories in both the CPP and SA, and decreased reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of RSD are counteracted by administering OXT prior to stress, and changes in BDNF expression may underlie these protective effects. PMID- 30448424 TI - RIFM fragrance ingredient safety assessment, 10-undecenoic acid, heptyl ester, CAS Registry Number 68141-27-5. PMID- 30448425 TI - Inhibition of HSP90beta by ganetespib blocks the microglial signalling of evoked pro-inflammatory responses to heat shock. AB - Although microglial reaction to heat shock is considered to be protective, heat shock is still a potential hazard caused by high temperatures. Recent studies indicate that the inhibition of the 90-kDa heat shock protein (HSP90) increasing the protective heat shock response and suppressing inflammatory signalling pathways in several diseases. Nevertheless, the effects of heat shock on microglial pro-inflammatory responses are not completely identical. Here, we aim to investigate the effect of the HSP90 inhibitor ganetespib on microglial pro inflammatory responses following heat shock. HSP90 isoforms were determined by transfecting N9 microglial cells (N9 cells) with enzymatically prepared siRNA (esiRNAs). We found that heat shock significantly increased the secretion of tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and nitric oxide (NO), and the phosphorylation of extracellular signal-regulated kinase (ERK), Janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IkappaB-alpha) and p65 nuclear factor kappa-light chain-enhancer of activated B cells (p65 NF-kappaB) in N9 cells. These increases, except for phospho-p65, were attenuated efficiently in a dose-dependent manner by ganetespib pretreatment. Furthermore, the suppression of heat shock-evoked cytokines and NO production, and the phosphorylation of ERK, JAK2 and STAT3 in cytosols and/or nuclei were also observed by administering esiRNA HSP90beta, but not HSP90alpha, in heat shock-treated N9 cells. Taken together, our findings demonstrate that the HSP90 inhibitor ganetespib blocks pro-inflammatory responses in heat shock-treated N9 cells via a signalling mechanism involving HSP90beta and STAT3. PMID- 30448426 TI - Expression and functional analysis of flotillins in Dugesia japonica. AB - FLOTILLIN-1 and FLOTILLIN-2 are membrane rafts associated proteins that have been implicated in insulin and growth factor signaling, endocytosis, cell migration, proliferation, differentiation, cytoskeleton remodeling and membrane trafficking. Furthermore, FLOTILLINs also play important roles in the progression of cancer and neurodegenerative diseases. In this study, the roles of flotillins are investigated in planarian Dugesia japonica. The results show that Djflotillin-1 and Djflotillin-2 play a key role in homeostasis maintenance and regeneration process by regulating the proliferation of the neoblast cells, they are not involved in the maintenance and regeneration of the central nervous system in planarians. PMID- 30448427 TI - Brain embolization of a healthy artery fragment as a complication of a cardiac catheterization. AB - Ischemic stroke is the most common neurological complication of cardiac catheterization resulting in a high morbidity and mortality. We present a 44-year old man admitted for vasospastic angina that suffered a right middle cerebral artery (MCA) occlusion after a cardiac catheterization. Mechanical thrombectomy was indicated and complete arterial recanalization was achieved. The material obtained showed a fragment of a healthy artery. Partial radial endarterectomy and cerebral embolization may be a rare complication of cardiac catheterization. PMID- 30448428 TI - Congenital Zika syndrome associated with findings of cerebellar cortical dysplasia - Broadening the spectrum of presentation of the syndrome. PMID- 30448429 TI - Endovascular management of multiple intracranial dural arteriovenous fistulas. AB - BACKGROUND AND PURPOSE: Multiply occurring intracranial dural arteriovenous fistulas (dAVFs) have been documented but rarely occur, and neither pathogenesis nor prognosis is clearly understood. This study was conducted to analyze angiographic characteristics of multiple dAVFs and to chronicle our treatment experience. METHODS: Between April, 2002 and January, 2018, data prospectively collected from 310 patients with intracranial dAVFs were systematically reviewed, assessing clinical and anatomic outcomes of endovascular treatment in 32 patients with multiple dAVFs (>= 2 fistulas each). Lesions were categorized as multifocal or diffuse type, depending on presentation, and further characterized as progressive or non-progressive disease. RESULTS: Overall, 18 patients (56.3%) experienced aggressive presentations, including intracerebral hemorrhage or venous infarction. Cortical venous reflux (CVR) was observed in 26 patients (81.3%), and sinus thrombosis or occlusion was seen in 24 (75.0%). Clinical outcomes in patients with multifocal fistulas (n = 11) were excellent (100%), marked by a moderately high rate of complete occlusion (54.5%). Those with progressive disease (n = 10) regularly displayed certain angiographic findings, namely diffuse configuration (100%), sinus thrombosis (100%), and CVR (100%). Complete anatomic obliteration was achieved in 12 patients (37.5%), and in 26 patients (81.3%), clinical outcomes were favorable. CONCLUSION: Multiple dAVFs are typically aggressive at presentation, given strong associations with CVR and sinus thrombosis. In diffuse-type fistulas, the potential to recur or progress is high. Although definitive treatment poses a challenge, outcomes of endovascular therapeutics may be still optimized in this setting through strategic procedural modifications and careful follow-up monitoring. PMID- 30448430 TI - Juice Displaces Milk and Fruit in High School Lunches. AB - OBJECTIVE: To compare beverages and foods selected by high school students on days when juice was offered (juice days) and not offered (non-juice days) with the reimbursable school meal. METHODS: Lunch register data from 386 days across 3 low-income Northeast high schools were used to compare juice and non-juice days for average daily selections of meal components and a la carte water and 100% juice sales. RESULTS: On juice days, 9.9% fewer milks (P < .01) and 7.4% fewer fruits (P < .01) were selected with lunches. In addition, on juice days, 8.2% fewer bottles of water and 24.4% fewer bottles of 100% juice were sold a la carte (P < .05). CONCLUSIONS AND IMPLICATIONS: Reducing juice availability in the reimbursable school lunch may increase selection of milk and fruit. Future research is warranted to assess how juice availability influences selection of milk, fruit, and water across a range of student populations. PMID- 30448431 TI - Fungus Ball of the Maxillary Sinus-Modern Treatment by Osteoplastic Approach and Functional Endoscopic Sinus Surgery. AB - PURPOSE: Functional endoscopic sinus surgery (FESS) is considered standard surgical therapy for fungus ball of the maxillary sinus. However, recent findings have indicated an odontogenic etiology, which requires simultaneous treatment of the dental origin. This study presents the authors' treatment results of fungus ball of the maxillary sinus using a combination of FESS and an endoscopically assisted osteoplastic approach through the anterior wall of the maxillary sinus, enabling simultaneous treatment of the dental origin. MATERIALS AND METHODS: A cohort of 22 patients with histopathologically confirmed fungus ball of the maxillary sinus was retrospectively analyzed. Clinical records and medical imaging data were reviewed to evaluate the etiology, clinical and radiologic findings, and postoperative outcome. RESULTS: Only 15 patients presented nonspecific clinical symptoms compatible with chronic unilateral maxillary sinusitis. Computed tomography visualized complete opacity of the maxillary sinus in 11 patients and intralesional hyperdensity in 12 patients. An odontogenic association was verified in 18 patients. Twenty-one patients underwent endoscopically assisted osteoplastic surgery through the anterior maxillary sinus wall. In 12 cases, the assumed persistent odontogenic source was treated simultaneously. Depending on the patency of the ostiomeatal complex, the accompanying chronic sinusitis was treated by FESS. CONCLUSIONS: The present data support the assumption of an odontogenic etiology of fungus ball of the maxillary sinus. Hence, surgical management requires simultaneous treatment of the fungal mass, the odontogenic origin of the disease, and the accompanying chronic sinusitis. To properly treat fungus ball, the authors present a modern treatment concept, using a minimally invasive endoscopically assisted osteoplastic approach through the anterior maxillary wall, for sufficient and necessary surgical treatment. PMID- 30448432 TI - Pyoderma Gangrenosum After Facelift and Otoplasty Surgery: Case Presentations and Literature Review. AB - PURPOSE: Pyoderma gangrenosum (PG) is an uncommon autoimmune, neutrophilic, ulcerative skin condition of uncertain etiology believed to result from dysregulation of the immune system. Although this entity is well recognized by dermatologists, other specialists are less familiar with diagnosis and treatment. This report describes a severe PG reaction to an elective cosmetic facelift, which is believed to be the second reported case of PG after facelift surgery. A second case after otoplasty surgery is described. MATERIALS AND METHODS: An unusual presentation of PG after cervicofacial rhytidectomy (facelift) is presented and discussed with a review of the literature. RESULTS: The present case was a rare complication after facelift surgery and followed the natural progression of PG. Delayed diagnosis and treatment extended the disease process. CONCLUSIONS: PG can mimic other surgical complications and delay diagnosis and treatment. This case is believed to represent the second reported incidence of PG after elective facelift surgery. PMID- 30448433 TI - Associations Between Poor Oral Health and Risk of Squamous Cell Carcinoma of the Head and Neck: A Meta-Analysis of Observational Studies. AB - PURPOSE: Many epidemiologic studies have reported an association of poor oral health, especially periodontal disease (PD) and tooth loss, with the risk of squamous cell carcinoma of the head and neck (SCCHN). However, these studies have yielded inconsistent results. Therefore, the present study investigated whether poor oral health is an independent predictor of SCCHN through a meta-analysis of observational studies. MATERIALS AND METHODS: The PubMed, EMBASE, and Cochrane Library databases were systematically searched for relevant observational studies of the association between oral health and risk of SCCHN conducted up to October 2017. The meta-analysis was conducted using STATA 12.0 (StataCorp, College Station, TX). A fixed- or random-effects model was applied to evaluate pooled risk estimates, and sensitivity and subgroup analyses were performed to identify sources of heterogeneity and pooled estimation. Publication bias was assessed using the Begg test, the Egger test, and funnel plots. RESULTS: Twenty-seven relevant observational studies were identified, consisting of 24 case-and-control studies, 2 prospective studies, and 1 cross-sectional study, with 26,750 participants. Notably, oral health correlated meaningfully with SCCHN (odds ratio [OR] = 2.24; 95% confidence interval [CI], 1.77-2.82). In subgroup analyses, participants with PD (OR = 2.52; 95% CI, 1.43-4.44) had a higher risk of developing SCCHN than those with tooth loss (OR = 2.13; 95% CI, 1.63-2.78). The risk estimates exhibited substantial heterogeneity. Evidence of publication bias was limited. CONCLUSIONS: The results of this meta-analysis suggest that patients with tooth loss or PD might face a substantial and independent risk of SCCHN, even after adjusting for smoking and alcohol consumption. However, the pooled estimates from observational studies could not establish a causative relation among PD, tooth loss, and SCCHN. Additional investigations of this correlation are warranted. PMID- 30448434 TI - Bioinspired hydrogels for drug-eluting contact lenses. AB - Efficient ocular drug delivery that can overcome the challenges of topical application has been largely pursued. Contact lenses (CLs) may act as light transparent cornea/sclera bandages for prolonged drug release towards the post lens tear fluid, if their composition and inner architecture are fitted to the features of the drug molecules. In this review, first the foundations and advantages of using CLs as ocular drug depots are revisited. Then, pros and cons of common strategies to prepare drug-loaded CLs are analyzed on the basis of recent examples, and finally the main section focuses on bioinspired strategies that can overcome some limitations of current designs. Most bioinspired strategies resemble a reverse engineering process to create artificial receptors for the drug inside the CL network by mimicking the human natural binding site of the drug. Related bioinspired strategies are being also tested for designing CLs that elute comfort ingredients mimicking the blinking-associated renewal of eye mucins. Other bioinspired approaches exploit the natural eye variables as stimuli to trigger drug release or take benefit of bio-glues to specifically bind active components to the CL surface. Overall, biomimicking approaches are being revealed as valuable tools to fit the amounts loaded and the release profiles to the therapeutic demands of each pathology. STATEMENT OF SIGNIFICANCE: Biomimetic and bioinspired strategies are remarkable tools for the optimization of drug delivery systems. Translation of the knowledge about how drugs interact with the natural pharmacological receptor and about components and dynamics of anterior eye segment may shed light on the design criteria for obtaining efficient drug eluting CLs. Current strategies for endowing CLs with controlled drug release performance still require optimization regarding amount loaded, drug retained in the CL structure during storage, regulation of drug release once applied onto the eye, and maintenance of CL physical properties. All these limitations may be addressed through a variety of recently growing bioinspired approaches, which are expected to pave the way of medicated CLs towards the clinics. PMID- 30448435 TI - Alum-functionalized graphene oxide nanocomplexes for effective anticancer vaccination. AB - Aluminum-based adjuvant (e.g., aluminum oxyhydroxide (AlO(OH), known as the commercial Alhydrogel(r) (Alum)) is the first adjuvant to be used in human vaccines. Although Alum shows a robust induction of antibody-mediated immunity, its weak stimulation of cell-mediated immunity makes it a questionable adjuvant for cancer immunotherapy. Herein, we described a novel formulation of Alum-based adjuvant by preparing AlO(OH)-modified graphene oxide (GO) nanosheets (GO AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. Similar to Alum, GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. Antigen loaded GO-AlO(OH) nanocomplexes facilitated cellular uptake and cytosolic release of antigens and promoted DC maturation, thereby eliciting higher antigen-specific IgG titers, inducing robust CD4+ and CD8+ T lymphocyte response, and inhibiting tumor growth in vivo. Furthermore, by employing tumor cell lysate-based cancer vaccines, GO-AlO(OH) nanocomplexes led to significant inhibition of tumor growth and can be implemented as a personalized treatment strategy for cancer vaccine development. Overall, GO-AlO(OH) nanocomplexes described herein may serve as a facile and efficient approach for effective anticancer vaccination. STATEMENT OF SIGNIFICANCE: Herein, we described a novel formulation of aluminum-based adjuvant by preparing aluminum oxyhydroxide (AlO(OH)) (known as "Alum")-modified graphene oxide (GO) nanocomplexes (GO-AlO(OH)), which, in addition to maintaining the induction of humoral immune response by AlO(OH), could further elicit the cellular immune response by GO. GO-AlO(OH) nanocomplexes can be prepared easily and in large scale by a chemical precipitation method. Similar to "Alum," antigen loaded GO-AlO(OH) vaccine formulation could be constructed by the incorporation of antigen using a facile mixing/adsorption approach. The very simple and reproductive preparation process of vaccines and the powerful ability to raise both humoral and cellular immune responses provide a novel approach for improving cancer immunotherapy efficacy. PMID- 30448436 TI - Study on the effectiveness of ligand reversible shielding strategy in targeted delivery and tumor therapy. AB - We previously proved the superiority of the ligand reversible shielding strategy based on the pH-responsive self-assembly/disassembly of gold nanoparticles through computed tomography imaging in vivo. Herein, the practicality of this strategy in tumor therapy was investigated by a ligand reversible shielding system based on a temperature-responsive polymer. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt, and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAAm-co-AAm)) were co-modified onto the surface of gold nanostars. In the blood circulation (37 degrees C), the ligand was shielded by the extension of P(NIPAAm-co-AAm), whose lower critical solution temperature (LCST) is approximately 39 degrees C. After the nanoparticles accumulate at the tumor site by the enhanced permeability and retention (EPR) effect, the heat generated from gold nanostars upon near-infrared light irradiation would trigger the contraction of P(NIPAAm-co-AAm), thus deshielding the ligand for enhanced tumor cellular uptake. Owing to the reversible extension-contraction transformation change of P(NIPAAm-co-AAm), the reversible shielding effect on the ligand could be accomplished even if the nanoparticles return to the blood circulation. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower), and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. This strategy showed significantly superior tumor inhibition (11% higher) than the irreversible system. All these results make clear that the ligand reversible shielding strategy is effective and offers important references for the design of nanomaterials for improving tumor accumulation. STATEMENT OF SIGNIFICANCE: Herein, the practicality of the ligand reversible shielding strategy in tumor therapy was investigated. The ligand biotin, cisplatin loaded chain poly(acrylic acid)-Pt and the shielding segment thermo-sensitive poly(N-isopropylacrylamide-co acrylamide) (P(NIPAAm-co-AAm) which LCST is about 39 degrees C) were co-modified onto the surface of gold nanostars. This well-designed NPs could shield target ligand in blood circulation (37 degrees C) and deshield it at tumor site (40-41 degrees C) reversibly. The results indicated that the system could extend blood circulation (1.6-fold at 24 h), reduce immune system clearance (28% lower) and enhance tumor accumulation (37% higher) effectively compared with the irreversible ligand shielding system by analysis of platinum. Significantly, the strategy showed superior tumor inhibition than the irreversible system (11% higher). PMID- 30448437 TI - Characterization of stm3030 and stm3031 genes of Salmonella enterica serovar Typhimurium in relation to cephalosporin resistance. AB - BACKGROUND/PURPOSE: The outer membrane protein STM3031 had been shown to confer Salmonella enterica serovar Typhimurium resistance to ceftriaxone. In this study, the STM3030 was increased in strain R200 and decreased in strain R200(Deltastm3031). How stm3030 and stm3031 contributing to antibiotic resistance was investigated. METHODS: The level of STM3030 protein in R200(Deltastm3031) were compared between 01-4, R200, and R200(Deltastm3031) by 2-DE analysis. The stm3030 gene deleted strain, R200(Deltastm3030), was generated by the one-step inactivation chromosome gene method. The various antibiotic susceptibility of strains 01-4, R200, R200(Deltastm3031) and R200(Deltastm3030) were determined by agar dilutions assays and E-test. The co-transcription of stm3031 and stm3030 were determined by RT-PCR. The promoter activities of these two genes fused with LacZ were determined. The binding of the regulatory protein BaeR on the promoter of both genes was detected by EMSA. The interaction between STM3030 and STM3031 proteins was determined by GST pull-down assay. RESULTS: Strain R200(Deltastm3030) displayed a 32- to 64-fold reduction in resistance to cephalosporin drugs. Transcription analyses revealed that stm3030 and stm3031 are independent genes and that the promoter of stm3030 is stronger than that of stm3031. The regulator BaeR binds to the promoter region of stm3031 but not that of stm3030. The STM3031 decreased in R200(Deltastm3030) compared to R200 by western blot analysis. The pull-down assay revealed that STM3030 and STM3031 bind to each other. CONCLUSION: Our data indicate that STM3030 has a chaperone-like activity and may modulate or stabilize STM3031, leading to resistance of S. enterica serovar Typhimurium to cephalosporin drugs. PMID- 30448438 TI - Cytokine profiles in cerebrospinal fluid of patients with meningitis at a tertiary general hospital in China. AB - BACKGROUND: There has been a great deal of evidence indicating that cytokines participate in meningeal inflammation. Different cytokine profiles may be presented in central nervous system (CNS) infection due to different pathogens. We have attempted to investigate cytokine profiles in cerebrospinal fluid (CSF) of patients with CNS infection. METHODS: Forty-three patients with CNS infection including tuberculous meningitis, purulent meningitis and cryptococcal meningitis were enrolled and 11 patients with normal CSF were enrolled as control group. The concentrations of Th1-, Th2- and Th17-type cytokines in CSF were detected using multiplex cytokine assay. Furthermore, the correlation between CSF cytokines and CSF parameters in CNS infection was analyzed. RESULTS: The CSF levels of IL 1beta, IL-4, IL-6, IL-10, IL-17, IL-23, IL-33, IFN-gamma, TNF-alpha and sCD40L among the patients with CNS infection were all higher than control group (all P < 0.05). A remarkable elevation of CSF IL-6 in the patients with CNS infection was observed with the least overlap of the CSF concentrations compared to controls. Moreover, CSF IL-6 levels were strongly negatively correlated with CSF glucose and the CSF/blood glucose ratio (r = -0.4375, P = 0.0042; r = -0.4991, P = 0.0009). CONCLUSIONS: The excessive activation of immune response characterized by elevated levels of CSF Th1-, Th2- and Th17-type cytokines has been observed during CNS infection. Furthermore, we observed negative correlations between CSF IL-6 levels and CSF glucose and CSF/blood glucose ratio in CNS infection. And we suggested that combined CSF IL-6 levels with CSF glucose may serve as a novel biomarker pool for the differential of CNS infection. PMID- 30448439 TI - Fine scale differences within the vagal neural crest for enteric nervous system formation. AB - The enteric nervous system is mostly derived from vagal neural crest (NC) cells adjacent to somites (s)1-7. We used in ovo focal fluorescent vital dyes and focal electroporation of fluorophore-encoding plasmids in quail embryos to investigate NC cell migration to the foregut initially and later throughout the entire gut. NC cells of different somite-level origins were largely separate until reaching the foregut at about QE2.5, when all routes converged. By QE3.5, NC cells of different somite-levels became mixed, although s1-s2 NC cells were mainly confined to rostral foregut. Mid-vagal NC-derived cells (s3 and s4 level) arrived earliest at the foregut, and occurred in greatest number. By QE6.5 ENS was present from foregut to hindgut. Mid-vagal NC-derived cells occurred in greatest numbers from foregut to distal hindgut. NC-derived cells of s2, s5, and s6 levels were fewer and were widely distributed but were never observed in the distal hindgut. Rostro-vagal (s1) and caudo-vagal (s7) levels were few and restricted to the foregut. Single somite levels of quail neural tube/NC from s1 to s8 were combined with chick aneural ChE4.5 midgut and hindgut and the ensemble was grown on the chorio-allantoic membrane for 6 days. This tests ENS-forming competence in the absence of intra-segmental competition between NC cells, of differential influences of segmental paraxial tissues, and of positional advantage. All vagal NC-levels, but not s8 level, furnished enteric plexuses in the recipient gut, but the density of both ENS cells in total and neurons was highest from mid-vagal level donors, as was the length colonised. We conclude that the fate and competence for ENS formation of vagal NC sub-levels is not uniform over the vagal level but is biased to favour mid-vagal levels. Overviewing this and prior studies suggests the vagal region is, as in its traditional sense, a natural unit but with complex sub-divisions. PMID- 30448440 TI - Molecular mechanism of mammary gland involution: An update. AB - The mammary gland (MG) is a unique organ responsible for milk synthesis, secretion, and involution to prepare the gland for subsequent lactation. The mammary epithelial cells (MECs), which are the milk synthesizing units of the MG, proliferate, differentiate, undergo apoptosis and regenerate following a cyclic pathway of lactation - involution - lactation, fine-tuning these molecular events through hormones, growth factors and other regulatory molecules. The developmental stages of the MG are embryonic, prepubertal, pubertal, pregnancy, lactation and involution, with major developmental processes occurring after puberty. The involution stage includes interesting physiological processes such as MEC apoptosis, matrix remodeling, and the generation of cells regaining the shape of a virgin MG. Signal transducer and activator of transcription 3 (STAT3) is the established master regulator of this process and aberrant expression of STAT3 leads to subnormal involution and may induce neoplasia. Several studies have reported on the molecular mechanism of MG involution with substantial knowledge being gained about this process; however, a deep understanding of this phenomenon has yet to be attained. This review focuses deeply on the molecular details of post-lactational regression, the signaling pathways involved in the lactation-involution cycle, and the latest developments in STAT3-associated MG neoplasia. Deep insight into the involution process will pave the way towards understanding the biology, apoptosis, and oncogenesis of the MG. PMID- 30448441 TI - Music Therapy and Pain Management in Patients with End-Stage Liver Disease: An Evidence-Based Practice Quality Improvement Project. AB - BACKGROUND: Pain can negatively affect the inpatient hospitalization experience; however, in patients with compromised metabolic pathways who are more vulnerable to medication side effects, pain control becomes even more challenging. AIMS: This evidence-based practice quality improvement project explored the feasibility of implementing a music therapy intervention for improved pain management (pain intensity, analgesic volume) and patient satisfaction among patients with a diagnosis of cirrhotic end-stage liver disease in the acute care setting. DESIGN: The plan-do-check-act cycle served as the implementation framework. Four nurse champions were trained to implement a 30-minute music intervention. Self-selected musical selections were delivered via unit-based iPads with earbud headphones during 3 consecutive days. METHODS: Data collection was performed using unit based measures for pain and patient satisfaction and an investigator-developed audit tool. Bivariate analyses and descriptive statistics were used to assess the effect of the intervention on the three outcomes of interest. RESULTS: Overall results from data collected with eight participants during a 6-week period indicated a 10% reduction in pain intensity and a 30% improvement in patient satisfaction with pain management care. CONCLUSIONS: Findings from this evidence based practice quality improvement project provide support for the effectiveness of music therapy as an adjunct to traditional pharmacologic modalities for pain management of the end-stage liver disease patient population. PMID- 30448442 TI - SLAMF receptors on normal and malignant B cells. AB - The Signaling Lymphocyte Activation Molecule family (SLAMF) is a collection of nine surface receptors expressed mainly on hematopoietic cells, and was found to modulate the behavior of immune cells. SLAMF receptors are expressed on B cells in health and disease. Each SLAM receptor has a unique differential expression pattern during the development and activation of B cells. Furthermore, recent findings have revealed a principal role for this family of receptors in B cell malignancies, emphasizing their importance in the control of malignant cell survival, cell to cell communication within the tumor microenvironment, retention in the supporting niches and regulation of T cell anti-tumor response. This review summarizes the latest studies regarding SLAMF expression and behavior in B cells and in B cell pathologies, and discusses the therapeutic potential of these receptors. PMID- 30448443 TI - Neonatal hypoxia-ischemia caused mild motor dysfunction, recovered by acrobatic training, without affecting morphological structures involved in motor control in rats. AB - The aim of this study was to evaluated motor function and morphological aspects of the components involved in motor control (sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle) in male Wistar rats exposed to a model of neonatal hypoxic-ischemic encephalopathy (HIE) and the possible influence of different physical exercise protocols - treadmill and acrobatic. Male Wistar rats at the 7th post-natal day (PND) were submitted to the HIE model and from the 22nd until 60nd PND the exercise protocols (treadmill or acrobatic training) were running. After the training, the animals were evaluated in Open Field, Ladder Rung Walking and Rotarod tasks and after samples of the motor control components were collected. Our results evidenced that the acrobatic training reversed the hyperactivity and anxiety, caused locomotion improvement and decreased brain atrophy in HIE animals. We did not find morphological differences on sensorimotor cortex, spinal cord, sciatic nerve, neuromuscular junctions and skeletal muscle in the animals submitted to HIE model. These intriguing data support the statement of the Rice-Vannucci model does not seem to reproduce, in structures involved in control function, the damage found in humans that suffer HIE. Regarding the protocols of exercise, we proposed that the acrobatic exercise could be a good therapeutic option especially in children affected by neonatal HIE and can be responsible for good results in cognitive and motor aspects. PMID- 30448444 TI - Bone marrow mesenchymal stem cell transplantation exerts neuroprotective effects following cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt pathway. AB - Although cerebral ischemia itself is associated with a high rate of disability, secondary cerebral ischemia/reperfusion (I/R) injury following recanalization is associated with much more severe outcomes. The mechanisms underlying cerebral I/R injury are complex, involving neuronal death caused by apoptosis and autophagy. Autophagy is critical for cell survival and plays an important role in the pathogenesis of cerebral I/R injury. Research has indicated that transplantation of bone marrow mesenchymal stem cells (BMSCs) is effective in repairing and reconstructing brain tissue, and that this effect may be associated with the regulation of autophagy. To explore this hypothesis, we intravenously transplanted BMSCs into a rat model of cerebral I/R injury (middle cerebral artery occlusion [MCAO]). Our results indicated that BMSCs transplantation promoted behavioral recovery, reduced cerebral infarction volume, and decreased the number of apoptotic cells in rats exposed to cerebral I/R injury. Moreover, this effect was associated with reduced expression of the autophagy-associated proteins microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1. Furthermore, BMSCs remarkably increased the expression of p-Akt and p-mTOR following cerebral I/R injury. Expression of LC3 also increased when the PI3K pathway was blocked using LY294002. In summary, our results indicated that the protective effects of BMSCs in cerebral I/R injury may be associated with the inhibition of autophagy via the activation of the PI3K/Akt/mTOR signaling pathway. PMID- 30448445 TI - Characterization and function of a group II type I interferon in the perciform fish, large yellow croaker (Larimichthys crocea). AB - Teleost fish possess two groups of type I interferons (IFNs) with two (group I IFNs) or four (group II IFNs) conserved cysteines, which are further classified into seven subgroups. In our previous study, two group I type I IFNs, LcIFNd and LcIFNh (a new subgroup member), were identified in the perciform fish, large yellow croaker (Larimichthys crocea). Here, we identified a group II type I IFN, LcIFNc, in this species. The deduced LcIFNc contained six cysteines, four of which are highly conserved (C1: C28, C2:C53, C3: C130, and C4:C159) in the fish group II type I IFNs, and a typical type I IFN signature motif was also found in it. Phylogenetic analysis indicated that LcIFNc belongs to the IFNc subgroup of fish group II type I IFNs. LcIFNc was constitutively expressed in all examined tissues, and was rapidly up-regulated in spleen and head kidney by poly(I:C) and Aeromonas hydrophila. Recombinant LcIFNc protein (rLcIFNc) could increase the expression of antiviral genes, Mx1, PKR and ISG15, in large yellow croaker peripheral blood leukocytes (PBLs). The rLcIFNc also exhibited obvious antiviral activity based on less cytopathic effect (CPE) and decreased expression levels of several viral genes in the rLcIFNc-treated grouper spleen (GS) cells following Singapore grouper iridovirus (SGIV) infection. Additionally, rLcIFNc was able to induce the expression of LcIFNc, as well as LcIFNd and LcIFNh in the PBLs and primary head kidney cells (HKCs) from large yellow croaker. These results therefore indicated that LcIFNc not only had antiviral activity, but also mediated the regulation of type I IFN response. PMID- 30448446 TI - Role of teleost B cells in viral immunity. AB - Teleost fish possess all the necessary elements to mount an adaptive immune response. Despite this, the important physiological and structural differences between the mammalian and the teleost fish immune system, anticipate significant changes regarding how this response is coordinated and executed. B cells are key players in adaptive immune responses through the production of antibodies. However, recent studies performed in mammals and other species including fish point to many additional functions of B cells within both the adaptive and the innate immune system, in many occasions taking part in the crosstalk between these two arms of the immune response. Furthermore, it should be taken into account that fish B cells share many functional and phenotypical features with innate B cell populations from mammals, which will surely condition their response to antigens. Concerning viral infections, although most studies undertaken to date in fish have been focused on characterizing antibody production, some recent studies have demonstrated that fish B cells are able to interact with viruses at different levels. In this sense, in the current review, we have tried to provide an overview of what is currently known regarding the role of teleost B cells in antiviral immunity. PMID- 30448447 TI - Astaxanthin protects lipopolysaccharide-induced inflammatory response in Channa argus through inhibiting NF-kappaB and MAPKs signaling pathways. AB - The present study was conducted to evaluate the protective effects of astaxanthin against lipopolysaccharide (LPS)-induced inflammatory responses in Channa argus in vivo and ex vivo. Primary hepatocytes were exposed to different concentrations of LPS for 24 h to induce an inflammatory response, and the protective effects of astaxanthin against LPS-induced inflammation were studied ex vivo and in vivo. Hepatocytes exposed to LPS (5-20 MUg mL-1) alone for 24 h resulted in a significant increase in lactate dehydrogenase release (LDH), Nitric oxide (NO) production and Malondialdehyde (MDA) content, 10 MUg mL-1 LPS could induced inflammatory response in hepatocytes. Gene expression of TLR4, NFkBp65, MAPKp38, TNF-alpha, IL-6 and IL-1beta mRNA expression were also enhanced ex vivo (p < 0.05). In vivo test demonstrated that pretreatment with astaxanthin prevented the LPS-induced upregulation of pro-inflammatory cytokines TNF-alpha, IL-6 and IL 1beta. Besides, astaxanthin blocked the expression of Toll-like receptor 4 (TLR4) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-kappaB) p65 and degradation inhibitor of NF-kappaBalpha (IkappaBalpha). Further study showed that astaxanthin could suppress the phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in mitogen-activated protein kinase (MAPK) signal pathway. In conclusion, our results suggest that astaxanthin played an anti-inflammatory role by regulating TLR4 and the NF-kappaB and MAPK signaling pathways in C. argus. PMID- 30448448 TI - Cytokine gene expression profiles in goldfish (Carassius auratus) during Gyrodactylus kobayashii infection. AB - Monogeneans of the genus Gyrodactylus are well-known pathogens causing huge mortalities in wild and cultured fish. Cytokine expression is one of most important host defense mechanisms against parasite infections. In this study, the expression pattern of the key pro-inflammatory (IL-1beta, IL-8, IFN-gamma, TNF alpha, IL-12 and iNOS) and anti-inflammatory cytokine genes (IL-10, TGFbeta and IL-4) of Gyrodactylus kobayashii infected goldfish (Carassius auratus) were determined by real-time quantitative PCR analysis. Our results showed that G. kobayashii infection caused increased expression of the pro-inflammatory cytokines including IFN-gamma, TNF-alpha and iNOS in all detected tissues throughout the infection period. Among these genes, iNOS has the highest transcript level accompanied with increased nitric oxide (NO) concentration in the serum of all infected goldfish. The mRNA level of IL-1beta in the liver, spleen and head kidney was significantly up-regulated during the early stage of infection (days 2-8). While high expression level of IL-8 and IL-12 was observed during the elimination phase of infection (days 10-14). As for anti-inflammatory cytokines, the expression profiles of IL-10 were distinct from those of TGF-beta and IL-4. Specifically, the mRNA level of IL-10 did not increase in the spleen and head kidney during the early stage of infection, while increased expression of TGF-beta and IL-4 were likewise seen. Besides, all infected fish had significantly higher complement C3 but lower IgM levels than the non-infected fish. The results provide insights into the interaction between gyrodactylids and the fish host, and indicate that systemic cytokine responses are critical for controlling parasite infection in fish. PMID- 30448449 TI - Clinical significance of neutrophil-lymphocyte and platelet-lymphocyte ratios in bipolar patients: An 18-month prospective study. AB - Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have recently been investigated as inexpensive and reproducible markers of systemic inflammation in many diseases. However, few studies evaluate clinical and prognostic value of NLR and PLR in psychiatric patients. The objective of this study is to investigate the clinical repercussions of NLR and PLR in patients with bipolar disorder (BD). An 18-month prospective study followed up eighty euthymic BD outpatients. Baseline data included an interviewer-administered questionnaire, behavioral scales and a blood count to calculate NLR and PLR. The occurrence of mood episodes and hospitalizations was assessed monthly for 18 months. Higher NLR and PRL were associated with more anxious symptoms and poorer functioning. BD patients with Night Eating Syndrome (NES) had higher PLR and tended to higher NLR. No association with other sleep parameters was evidenced. Higher NLR and PRL were also associated with more episodes and hospitalizations after 18 months. However, only higher baseline NLR was related to more (hypo)mania episodes. NLR and PLR are important prognostic factor for BD. This study suggested the importance of a simple blood count, an inexpensive and reproducible exam, in evaluating the course of the BD. Further studies must be performed to confirm these results. PMID- 30448450 TI - Non-high-density lipoprotein cholesterol and risk of cardiovascular disease in the general population and patients with type 2 diabetes: A systematic review and meta-analysis. AB - AIMS: To examine the relationship of non-high-density lipoprotein cholesterol (non-HDL-C) level with cardiovascular disease (CVD) risk in type 2 diabetes patients and the general population by conducting a meta-analysis. METHODS: We made a comprehensive literature search for relevant observational studies investigating the relationship of non-HDL-C level with CVD risk in the general population and type 2 diabetes patients using the PubMed and Embase databases. Pooled risk ratio (RR) with 95% confidence intervals (CI) was calculated for the highest versus the reference lower non-HDL-Cl. RESULTS: A total of 13 studies with 156,381 individuals were included. The pooled RR of CVD was 1.59 (95% CI 1.46-1.72) in the general population and 1.99 (95% CI 1.57-2.51) in type 2 diabetes patients. Subgroup analysis showed the similar effect of non-HDL-C on CVD risk between men (RR1.98; 95% CI 1.70-2.30) and women (RR 1.63; 95% CI 1.35 1.96). However, elevated non-HDL-C was not associated with higher risk of cardiovascular mortality in the general population (RR 1.64; 95% CI 0.96-2.80) and type 2 diabetes patients (RR 1.08; 95% CI 0.57-2.07). CONCLUSIONS: Elevated non-HDL-C level is associated with an increased risk of CVD in the general population and type 2 diabetes patients. PMID- 30448452 TI - Subregion-specific Protective Effects of Fluoxetine and Clozapine on Parvalbumin Expression in Medial Prefrontal Cortex of Chronically Isolated Rats. AB - Dysregulation of GABAergic system is becoming increasingly associated with depression, psychiatric disorder that imposes severe clinical, social and economic burden. Special attention is paid to the fast-spiking parvalbumin positive (PV+) interneurons, GABAergic neurons which are highly susceptible to redox dysregulation and oxidative stress and implicated in a variety of psychiatric diseases. Here we analyzed the number of PV+ and cleaved caspase-3 positive (CC3+) cells in the rat medial prefrontal cortical (mPFC) subregions following chronic social isolation (CSIS), an animal model of depression and schizophrenia. Also, we examined potential protective effects of antidepressant fluoxetine (FLX) and atypical antipsychotic clozapine (CLZ) on the number of these cells in mPFC subregions, when applied parallel with CSIS in doses that correspond to therapeutically effective ones in patients. Immunofluorescence analysis revealed decreased number of PV+ cells in cingulate cortex area 1, prelimbic area (PrL), infralimbic area (IL) and dorsal peduncular cortex of the mPFC in isolated rats, which coincided with depressive- and anxiety-like behaviors. In addition, CSIS-induced increase in the number of CC3+ cells was detected in aforementioned subregions of mPFC. Treatments with either FLX or CLZ prevented behavioral changes, decrease in PV+ and increase in CC3+ cell numbers in PrL and IL subregions in isolated rats. These results indicate the importance of intact GABAergic signaling in these areas for resistance against CSIS-induced behavioral changes, as well as subregion-specific protective effects of FLX and CLZ in mPFC of CSIS rats. PMID- 30448451 TI - Similar glycaemic control with less nocturnal hypoglycaemia in a 38-week trial comparing the IDegAsp co-formulation with insulin glargine U100 and insulin aspart in basal insulin-treated subjects with type 2 diabetes mellitus. AB - AIMS: To confirm non-inferiority of insulin degludec/insulin aspart (IDegAsp) once-daily (OD) versus insulin glargine (IGlar) U100 OD+insulin aspart (IAsp) OD for HbA1c after 26 weeks, and compare efficacy and safety between groups at W26+W38. METHODS: A 38-week, randomised, open-label, treat-to-target (HbA1c <7.0%) trial in adults with type 2 diabetes mellitus (on basal insulin +/-oral antidiabetic drugs; HbA1c 7.0-10.0%). Randomisation (1:1): IDegAsp or IGlar U100 + IAsp. Intensification to IDegAsp twice daily (BID) was permitted at W26+W32, or with additional IAsp injections at W26 (maximum IAsp BID) or W32 (maximum IAsp three-times daily). RESULTS: For W0-W26, mean percentage-change (standard deviation) HbA1c was: IDegAsp, -1.1 (0.9); IGlar U100+IAsp, -1.1 (0.8); estimated treatment difference: 0.07% (95% confidence interval [CI]: -0.06; 0.21) confirmed non-inferiority. At W26 and W38, target HbA1c achievement, and mean fasting and postprandial glucose were similar across groups. At W38, more subjects achieved target HbA1c without hypoglycaemia with IDegAsp (22.5%) than with IGlar U100+IAsp (21.1%), with significantly fewer nocturnal episodes (W0-W38, estimated rate ratio: 0.61 [95% CI: 0.40; 0.93]). Safety profiles were similar across treatment groups throughout. CONCLUSIONS: IDegAsp OD/BID are effective treatment intensification options versus multiple injection basal-bolus therapies, achieving similar glycaemic control, with significantly less nocturnal hypoglycaemia. PMID- 30448453 TI - New progress in the approaches for blood-brain barrier protection in acute ischemic stroke. AB - Ischemic stroke is a disease with high morbidity and mortality worldwide, which often places an additional strain on families and society due to the poor prognosis. Blood brain-barrier (BBB) damage is the critical pathological process, which contributes to hemorrhagic transformation (HT) and poor prognosis in cerebral ischemia. Thus, there is a pressing need to seek an approach to ameliorate BBB damage and reduce the HT that can be induced by fibrinolytic therapy involving recombinant tissue plasminogen activator (rtPA) in clinical practice. This review provides an overview of the recent scientific reports to improve our understanding of new approaches to ameliorating BBB damage in ischemic stroke, including physical approaches, chemical agents, traditional Chinese medicine and its extracts, neural stem cell therapy and microRNA intervention. Inhibiting matrix metalloproteinases (MMP) is possibly the main functional mechanism of these BBB protectants, along with anti-oxidative and anti inflammatory effects. Other significant mechanisms for BBB protection have been studied recently, such as anti-apoptosis, extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/ Akt pathways and so on. An in depth understanding of the related mechanisms contributes to finding potential approaches for BBB protection, and a deeper understanding of the emerging BBB protectants offers opportunities to seek a promising adjuvant therapy to prevent HT in the post-stroke brain. PMID- 30448454 TI - Analysis of the neuronal network of the medullary respiratory center in transgenic rats expressing archaerhodopsin-3 in Phox2b-expressing cells. AB - Preinspiratory (Pre-I) neurons in the parafacial respiratory group (pFRG) comprise one of the respiratory rhythm generators in the medulla of the neonatal rat. A subgroup of pFRG/Pre-I neurons expresses the transcription factor Phox2b. To further analyze detailed neuronal mechanisms of respiratory rhythm generation in the neonatal rat, we developed a transgenic (Tg) rat line in which Phox2b positive cells expressed archaerhodopsin-3 (Arch). Brainstem-spinal cord preparations were isolated from 0-2-day-old Tg newborn rats and were superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25-26 degrees C. Inspiratory fourth cervical ventral root (C4) activity was monitored, and membrane potentials of neurons in the pFRG including Pre-I and inspiratory neurons were recorded. Phox2b-positive cells in the Tg rats were essentially positive for enhanced green fluorescent protein (EGFP) signals (reporter for Arch) in the pFRG. Continuous photo-stimulation of the rostral ventral medulla for up to 90 s by covering the pFRG with green laser light (532 nm) induced a decrease of respiratory rate measured at C4 accompanied by membrane hyperpolarization of Phox2b-positive pFRG/Pre-I neurons. In contrast, Phox2b negative inspiratory neurons were not hyperpolarized during the photo stimulation. Our findings showed that Phox2b-expressing pFRG/Pre-I neurons are involved in the maintenance of the basic respiratory rhythm in neonatal rat. PMID- 30448455 TI - Effects of Weight Loss in Outpatients with Mild Chronic Heart Failure: Findings from the J-MELODIC Study. AB - BACKGROUND: Weight loss is a strong prognostic factor in chronic heart failure (CHF); however, little is known about its effects in patients with mild CHF. Therefore, we investigated the effects of weight loss in patients with mild CHF. METHODS AND RESULTS: We analyzed a total of 242 outpatients with mild CHF from J MELODIC study cohort. Weight loss was defined as >=5% weight loss at 1 year. Twenty-seven (11.2%) patients lost >=5% weight in 1 year. Patients with weight loss was associated with higher rate of underweight and worsening renal function in 1 year compared with those without >=5% weight loss. The predictors of weight loss included edema, BNP, and DM at baseline. While weight loss was significantly associated with subsequent cardiovascular death or hospitalization for HF (log rank, p = 0.002) and subsequent death from any cause (log-rank, p = 0.002), underweight was not associated with these outcomes (log-rank, p = 0.356 and 0.168, respectively). Even after adjusting for covariates, weight loss was a significant and independent risk factor for subsequent cardiovascular death or hospitalization for HF (HR, 3.22; 95% CI, 1.10-8.41; p = 0.034). CONCLUSIONS: In patients with mild CHF, >=5% weight loss was a significant predictor for subsequent cardiovascular death or hospitalization for HF. PMID- 30448456 TI - Impact of empiric treatment for vancomycin-resistant Enterococcus (VRE) in colonized patients early after allogeneic hematopoietic stem cell transplantation. AB - In recent years, vancomycin-resistant Enterococcus (VRE) colonization is increasingly being encountered among transplant populations, and VRE has become one of the leading causes of bacteremia early after allogeneic hematopoietic stem cell transplantation (allo-HSCT). There are sparse data regarding the effect of empiric VRE therapy for febrile, neutropenic allo-HSCT recipients colonized with VRE. All allo-HSCT patients aged 18 years and older who developed VRE bacteremia (VREB) between 2005-2014 were identified and categorized as to whether they received empiric versus (vs) directed VRE therapy. There were 434 (33%) VRE colonized and 872 (67%) non-VRE-colonized patients during the study period, and 172 of 434 (40%) VRE-colonized patients received empiric therapy. There was no significant difference in incidence of VREB among colonized patients who did or did not receive empiric therapy (28/172, 16% vs 55/262, 21%; P=0.22). There was a total of 95 patients with VREB, of which the majority (83/95, 87%) was known to be VRE-colonized. Of the 95 VREB episodes, 29 (31%) received empiric VRE therapy, whereas 66 (69%) received directed therapy. No significant differences in clinical outcome, including median duration of bacteremia (2 vs 2 days, P=0.39), recurrent VREB (3/29, 10% vs 5/66, 8%, P=0.65), 30-day all-cause mortality (1/29, 3% vs 4/66, 6%, P=0.62), or VRE-attributable mortality (1/29, 3% vs 1/66, 2%, P=0.55) were observed between the empiric- and directed-therapy groups. Kaplan Meier curve showed no significant difference in survival at 30 days in allo-HSCT recipients with VREB who received empiric vs directed therapy (97% vs 94%, P=0.62). We recommend against empiric use of VRE-active agents for fever and neutropenia in VRE-colonized patients undergoing allo-HSCT. PMID- 30448457 TI - The Future of Chimeric Antigen Receptor T Cell Therapy for the Treatment of Multiple Myeloma. PMID- 30448458 TI - Capsule endoscopy in suspected small bowel Crohn's disease - Is it worth repeating a negative study? PMID- 30448459 TI - Coronary flow reserve in patients with primary biliary cholangitis. AB - BACKGROUND: It is still not clear whether primary biliary cholangitis (PBC) is associated with abnormalities of the cardiovascular system. We aimed to assess the relationship between PBC and coronary flow reserve (CFR). METHODS: Our inclusion criterion was a diagnosis of PBC with no clinical evidence of heart disease or metabolic syndrome. Coronary flow velocity in the left anterior descending coronary artery was measured using transthoracic Doppler echocardiography at rest (DFVr), and during adenosine infusion (DFVh). The corrected CFR (cCFR) was defined as the ratio of DFVh to DFVr corrected for cardiac workload (cDFVr). Microvascular resistance was also assessed in baseline (BMR) and hyperemic conditions (HMR). RESULTS: 37 PBC patients and 37 sex- and age-matched controls were considered. The cCFR was significantly lower in PBC patients (2.8 +/- 0.7 vs. 3.7 +/- 0.7, p < 0.0001), and abnormal (<=2.5) in 13 (35%) of them, but in none of the controls (p < 0.0001). The cDFVr was higher in patients with abnormal cCFR (29.0 +/- 6.0 vs. 20.4 +/- 4.5 cm/sec, p < 0.0001). The CFR and cCFR did not correlate with any characteristics of PBC, comorbidities or Framingham risk scores. The BMR and HMR correlated with time since PBC diagnosis and duration of symptoms. CONCLUSION: The CFR is reduced in PBC, apparently due to mechanisms correlating with the time since diagnosis. In particular, the higher cDFVr with a lower basal resistance in patients with cCFR <= 2.5 suggests a compensatory mechanism against any cardiomyocyte bioenergetics impairment. PMID- 30448460 TI - Duodenal tumor risk in Lynch syndrome. AB - BACKGROUND AND AIMS: Lynch syndrome (LS) is associated with an increased risk of small bowel tumors but routine screening is not recommended in international guidelines. The aim of our study was to determinate the prevalence of duodenal tumors in a French cohort of LS patients. METHODS: Patients carrying a germline pathogenic variant in a MMR gene, supported by our local network, in which at least one upper endoscopy had been performed, were included. We registered the occurrence of duodenal lesions in those patients. RESULTS: 154 LS patients were identified including respectively 85 MSH2 and 41 MLH1 mutated patients respectively. Seven out of 154 (4.5%) had at least one duodenal lesion. Median age at diagnosis was 58 years (range: 49-73). The twelve lesions locations were: descending duodenum (n = 7), genu inferius (n = 2), duodenal bulb (n = 1), ampulla (n = 1), fourth duodenum (n = 1). Three lesions were invasive adenocarcinomas. The incidence rate of duodenal lesions in patients with MSH2 or MLH1 pathogenic variants was respectively 7.1% (6 out of 85) and 2.4% (1 out of 41) emphasizing a trend toward increased risk of developing duodenal lesion in MSH2 mutated patients: OR: 5.17, IC95% (0.8-60.07), p = 0.1307. CONCLUSION: Regarding this high prevalence rate, especially in MSH2 patients, regular duodenal screening during upper endoscopy should be considered in routine in LS patients. PMID- 30448461 TI - ADAR2-dependent A-to-I RNA editing in the extracellular linear and circular RNAs. AB - Currently, no reliable biomarkers of amyotrophic lateral sclerosis (ALS) exist. In sporadic ALS, RNA editing at the glutamine/arginine site of GluA2 mRNA is specifically reduced in the motor neurons due to the downregulation of adenosine deaminase acting on RNA 2 (ADAR2). Furthermore, TDP-43 pathology, the pathological hallmark of ALS, is observed in the ADAR2-lacking motor neurons in ALS patients and conditional ADAR2 knockout mice, suggesting a pivotal role of ADAR2 downregulation in the ALS pathogenesis. Extracellular RNAs were shown to represent potential disease biomarkers and the editing efficiencies at their ADAR2-dependent sites may reflect cellular ADAR2 activity, suggesting that these RNAs isolated from the body fluids may represent the biomarkers of ALS. We searched for ADAR2-dependent sites in the mouse motor neurons and human-derived cultured cells and found 10 sites in five host RNAs expressed in SH-SY5Y cells and their culture medium. Of these, the arginine/glycine site of SON mRNA was newly identified as an ADAR2-dependent site. Furthermore, we detected a circular RNA with an ADAR2-dependent site in the SH-SY5Y cells and their culture medium. Therefore, the changes in the editing efficiencies at the identified host RNA sites isolated from the body fluids may represent potential biomarkers of ALS. PMID- 30448462 TI - Wolbachia spread dynamics in multi-regimes of environmental conditions. AB - Mosquito-borne diseases such as dengue fever and Zika kill more than 700,000 people each year in the world. A novel strategy to control these diseases employs the bacterium Wolbachia whose infection in mosquitoes blocks virus replication. The prerequisite for this measure is to release Wolbachia -infected mosquitoes to replace wild population. Due to the fluctuation of environmental conditions for mosquito growth, we develop and analyze a model of differential equations with parameters randomly changing over multiple environmental regimes. By comparing the dynamics between the stochastic system and constructed auxiliary systems, combined with other techniques, we provide sharp estimates on the threshold releasing level for Wolbachia fixation. We define the alarm period of disease transmission to measure the risk of mosquito-borne diseases. Our numerical simulations suggest that more frequent inter-regime transitions help reduce the alarm period, and the disease transmission is more sensitive to the average climatic conditions than the number of sub-regimes over a given time period. Further numerical examples also indicate that the reduction in the waiting time to suppress 95% of wild population is more evident when the releasing amount is increased up to a double of the wild population. PMID- 30448463 TI - En Face Optical Coherence Tomography Imaging of the Photoreceptor Layers in Hydroxychloroquine Retinopathy. AB - OBJECTIVE: To investigate the application of en face optical coherence tomography (OCT) imaging in eyes with hydroxychloroquine (HCQ) retinopathy. DESIGN: Retrospective case series METHODS: SETTING: Institutional PATIENT POPULATION: Sixty-two eyes of 31 Asian patients with HCQ retinopathy. OBSERVATION PROCEDURES: Macular volume scanning using swept-source OCT was performed in 6 * 6 and 9 * 9 mm areas centered on the fovea. Segmentation of the photoreceptor layers was automatically performed between the inner border of the ellipsoid zone and that of the retinal pigment epithelium-Bruch's membrane complex to obtain en face OCT images. Findings from the en face images were qualitatively and quantitatively evaluated; they were analyzed and correlated with the fundus autofluorescence and visual field findings. MAIN OUTCOME MEASURES: En face OCT findings RESULTS: All eyes with HCQ retinopathy had a beaten-bronze appearance in the areas with photoreceptor defects, whereas those with intact photoreceptors had areas with smooth surfaces, which were occasionally demarcated by hyporeflective margins, on the en face OCT images. The presence and extent of the retinopathy could be quickly determined using the images. They also provided quantitative information on the progression based on the areas of intact photoreceptors compared over several visits. Furthermore, the area of central intact photoreceptors significantly correlated with the mean deviation, pattern standard deviation, and visual field index of 30-2 visual field examinations (all P < .001). CONCLUSIONS: En face OCT may be useful for visualizing the presence and extent of HCQ retinopathy and its progression. The area of central intact photoreceptors measured on en face OCT images showed a significant association with functional visual field defects. This imaging may be a helpful adjunct for screening and follow-up examinations of HCQ retinopathy. PMID- 30448464 TI - IP3 receptors and Ca2+ entry. AB - Inositol 1,4,5-trisphosphate receptors (IP3R) are the most widely expressed intracellular Ca2+ release channels. Their activation by IP3 and Ca2+ allows Ca2+ to pass rapidly from the ER lumen to the cytosol. The resulting increase in cytosolic [Ca2+] may directly regulate cytosolic effectors or fuel Ca2+ uptake by other organelles, while the decrease in ER luminal [Ca2+] stimulates store operated Ca2+ entry (SOCE). We are close to understanding the structural basis of both IP3R activation, and the interactions between the ER Ca2+-sensor, STIM, and the plasma membrane Ca2+ channel, Orai, that lead to SOCE. IP3Rs are the usual means through which extracellular stimuli, through ER Ca2+ release, stimulate SOCE. Here, we review evidence that the IP3Rs most likely to respond to IP3 are optimally placed to allow regulation of SOCE. We also consider evidence that IP3Rs may regulate SOCE downstream of their ability to deplete ER Ca2+ stores. Finally, we review evidence that IP3Rs in the plasma membrane can also directly mediate Ca2+ entry in some cells. PMID- 30448465 TI - Pore-former enabled seeding of tau in rats: Alleviation by memantine and lithium chloride. AB - Background Tauopathies, including Alzheimer's disease (AD), are multifactorial diseases with strong phenotypic and genetic heterogeneity. Recent evidence revealed that mechanisms of pathogenesis of early (hereditary) and late (sporadic) forms of AD are different. This is not properly reflected in current experimental models, especially when it comes to sporadic forms of AD. Here, we present novel seeding based model and explore its suitability for therapeutic intervention. New method We validate novel region specific approach to modelling Tau pathology reported by Koss and co-authors (2015). Wistar rats 3, 9 and 15 month-old were surgically prepared for hippocampal loading with pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) and recombinant human tau including pharmacological inhibition of phosphatase activity by okadaic acid co administration. We explored whether tau seeding caused molecular and behavioural traits reminiscent of AD and explored their reversibility/prevention by administration of either memantine or lithium. Results The presented model emulates several changes observed in progressive dementia such as: heightened levels of tau and its hyperphosphorylation, changes in tau compartmentalization, breakdown of the cytoskeleton, cognitive impairments, and sensitivity for anti dementia treatment. Comparison with existing methods Seeding has been achieved in transgenic mouse models, but this is the first rat model significantly mimicking cognitive and neuronal changes akin to tauopathies. Moreover, we have successfully included the factor age in our model and can show sensitivity to drug treatment. Conclusions These data validate a novel model of locally infused recombinant human Tau as an inducer of tauopathy in rats and holds the potential for development of novel therapies. PMID- 30448466 TI - 15-year follow-up of short dental implants placed in the partially edentulous patient: Mandible Vs maxilla. AB - There is paucity of the studies that assess the outcomes of short dental implants with a follow-up time higher than 10years. This study aims to evaluate the long term (15years) survival and marginal bone loss around short dental implants and assess the influence of the anatomical location (mandible or maxilla) on these outcomes. A clinical retrospective study of short dental implants (<=8.5mm) was conducted in a single private dental clinic. The predictor variable was the anatomical location (mandible or maxilla). The primary outcome was the dental implant survival rate. The secondary outcomes were the marginal bone loss, the prosthesis failures and the influence of anatomical location, the antagonist type, and the clinical/anatomical crown-to-implant ratio (CIR) on the marginal bone loss and implant success rate. Descriptive analysis was performed for patients' demographic data, implant details, and prosthetic variables. Kaplan Meier method was used to assess the implant survival rate. Fifty patients with a mean age of 59+/-10years had a mean follow-up time of 15years. Seventy five implants were placed being 30 in the maxilla and 45 in the mandible. The implant position did not affect significantly the implant survival. The marginal bone loss has been significantly higher in the maxilla than the mandible. The implant survival rate was 93.3%. Short dental implants could be indicated to support fixed partial prosthesis in the mandible and the maxilla. Implant position may affect the marginal bone loss around the short dental implants. PMID- 30448467 TI - Expression and localization of VIAAT in distal uriniferous tubular epithelium of mouse. AB - Vesicular inhibitory amino acid transporter (VIAAT) is a transmembrane transporter which is responsible for the storage of gamma-aminobutyric acid (GABA) or glycine in synaptic vesicles. According to recent studies, GABA is known to be expressed in the kidney. For clear understanding of the intra-renal GABA signaling, the localization of VIAAT was examined in the present study. Intense immunoreactivity was found largely confined to the distal tubule epithelia, especially distinct in the inner medulla, although the immunoreactivity was discerned more or less in all tubules and glomeruli. No distinct immunoreactivity was seen in capillary endothelia or interstitial fibroblasts. In immuno-DAB and immuno-gold electron microscopy, the immunoreaction was found at the basal infoldings of plasma membranes and basal portions of the lateral plasma membranes, but not in any vesicles or vacuoles within the distal tubular cells. The significance of the enigmatic finding, localization of a vesicular molecule on selected portions of the plasma membrane of distal tubular cells, was discussed in view of the possibility of paracrine or autocrine effects of GABA on some other uriniferous tubular cells or interstitial cells. PMID- 30448468 TI - Acute epileptic seizures in myelin oligodendrocyte glycoprotein encephalomyelitis and neuromyelitis optica spectrum disorder: A comparative cohort study. AB - BACKGROUND: Little is known about the incidence and characteristics of acute epileptic seizures in myelin oligodendrocyte glycoprotein encephalomyelitis (MOG EM) and neuromyelitis optica spectrum disorder (NMOSD). In this study, we compared the incidence and characteristics of acute epileptic seizures in MOG-EM and NMOSD patients. METHODS: MOG-EM (n = 61) and NMOSD (n = 565) cases obtained from the MSNMOBase (2011-2018) were retrospectively reviewed. RESULTS: Acute epileptic seizures were observed in 13 (21.3%) patients with MOG-EM and two (0.4%) patients with NMOSD (P < 0.001). In both MOG-EM and NMOSD patients, more than half of seizures were single and of focal onset; slow wave and cortical/subcortical lesions were the most common abnormalities. In MOG-EM patients, no difference was found in the proportion of single seizure with and without anti-epileptic drugs (AEDs; 64.3% vs. 45.5%, P = 0.435). Long-term AED use did not significantly reduce the occurrence of acute epileptic seizures, which was 66.7% before and after treatment. In patients with MOG-EM and NMOSD, mycophenolate mofetil significantly reduced acute epileptic seizure occurrence (P = 0.024). CONCLUSION: Acute epileptic seizures were more common in MOG-EM patients than in NMOSD patients. The long-term use of AEDs might be unnecessary given the use of immunotherapy in cases of MOG-EM. PMID- 30448469 TI - HIV infection associated neuromyelitis optica spectrum disorder: Clinical features, imaging findings, management and outcomes. AB - INTRODUCTION: HIV Infection associated NMOSD (HIV-NMOSD) is a recently recognized entity. Management of patients with HIV-NMOSD is a challenge. Here we report our own experience of HIV-NMOSD along with a complete review of all the cases of HIV NMOSD reported in literature. OBJECTIVE: Describe the clinical features, radiological findings, treatment patterns and outcomes in patients with HIV NMOSD. METHODS: The details of all cases of HIV- NMOSD were searched from our NMOSD registry. A literature search was also done using the terms NMO, NMOSD and HIV infection in PUBMED, Google Scholar and EMBASE. The details of all the reported cases and cases from our registry were collected and analyzed. RESULTS: Six cases of HIV-NMOSD were identified from the literature and one from our registry. There were four males and three females with age ranging from 8 years to 49 years. Duration of HIV infection ranged from newly detected to 15 years. Optic neuritis followed by myelitis was the commonest presentation, occurring in 5 out of 7 patients. 3 patients were anti-aquaporin 4 antibody positive while 3 were negative and in one anti- aquaporin 4 antibody assay was not done. All patients received immunomodulatory treatment. 5/7 patients had poor recovery from acute attacks but no patient had further relapses while on immunomodulatory treatment and antiretroviral therapy. CONCLUSION: HIV associated NMOSD is a recently recognized entity. A high index of suspicion is needed to diagnose these patients. In all patients with HIV infection presenting with optic neuritis or/and myelitis, anti aquaporin 4 antibody status should be checked and in all patients of NMOSD, HIV infection should be ruled out. PMID- 30448470 TI - Peak width of skeletonized mean diffusivity (PSMD) as marker of widespread white matter tissue damage in multiple sclerosis. AB - BACKGROUND: Peak width of skeletonized mean diffusivity (PSMD) is a novel and fully automated, MRI biomarker, which has shown clinical relevance in cerebral small vessel diseases (SVD). We aimed here to assess PSMD levels across the brain of patients with multiple sclerosis (MS), in comparison to normal controls (NC) and patients with CADASIL, a genetically defined form of severe SVD. METHODS: We assessed PSMD in relapsing-remitting (RR) MS patients (n = 47) in comparison to age-matched CADASIL patients (n = 25) and NC (n = 28). Diffusion Tensor Imaging data were acquired on 1.5T MR clinical scanner to automatically compute PSMD through "skeletonization" of WM tracts and diffusion histograms. RESULTS: RRMS had lower WM lesion volume (LV) than CADASIL (8.6 +/- 8.2 vs 24.4 +/- 17.4 cm3, p < 0.001). After correction for LV, PSMD values in MS were higher than in CADASIL patients (adjusted mean values: 4.5 vs 3.9 * 10-4 mm2/s, p = 0.03) and in both patient groups were higher than in NC (2.8 +/- 0.3 * 10-4 mm2/s, p < 0.001). PSMD values correlated with LV in both patient groups (r = 0.8, p < 0.001 in MS; r = 0.6, p = 0.002 in CADASIL). CONCLUSIONS: In both patient groups, PSMD was higher than in NC and closely correlated with LV, suggesting sensitivity in assessing brain tissue damage in these disorders. In MS patients, PSMD levels were higher than in CADASIL patients, despite the lower LV. This might be related to more severe normal-appearing WM abnormalities occurring in the MS brains. This novel, fully automated, MRI metric may represent a useful marker for a robust quantification of the diffuse WM tissue damage in MS. PMID- 30448471 TI - Schistosomiasis in Malaysia: A review. AB - Schistosomiasis, a neglected tropical parasitic disease caused by the trematode flatworms of the genus Schistosoma, affects approximately 207 million people worldwide. Among the five main species infecting humans, Schistosoma mansoni and S. japonicum are responsible for the majority of hepatointestinal schistosomiasis. Human settlements near fresh water sites that lack proper sanitary systems often contribute to the transmission of disease. This risk particularly impacts on travellers or immigrants who come into contact with larvae-contaminated water. This review discusses the central features of schistosomiasis; including clinical manifestations, diagnosis, treatments, and the preventive measures available for the control of this disease. The description of the Malaysian schistosome species Schistosoma malayensis and the current status of schistosomiasis in Malaysia including the compilation of cases diagnosed from 1904 to 2015 are also discussed in this paper. PMID- 30448472 TI - Consumers' preferences for freezing of meat to prevent toxoplasmosis- A stated preference approach. AB - Consumption of raw or undercooked meat increases the risk of infection with Toxoplasma gondii. Freezing meat products can eliminate this risk. Freezing of meat may affect consumers' valuation of meat products in two different ways: it may be valued positively because of increased food safety or valued negatively because of (perceived) loss of quality. In a Discrete Choice Experiment on four different meat products we studied the difference in willingness to pay for frozen and non-frozen meat products in the Netherlands. Analyses revealed that most Dutch consumer groups prefer non-frozen meat. Price was important in consumer decisions, whereas the meat being frozen appeared to play a minor role in the decision to purchase meat products. Even though it may seem obvious that people would prefer safe food to unsafe food, in a context where consumers presume food being safe, many consumers appear unwilling to pay for freezing of meat as additional measure to reduce the risk of food borne infections such as toxoplasmosis. PMID- 30448473 TI - Supranutritional doses of vitamin E to improve lamb meat quality. AB - Vitamin E is a fat-soluble antioxidant, therefore, it can be stored in any fat depot in the body, where it exerts a potent chain-breaking antioxidant effect. Moreover, the antioxidant activity of vitamin E-like compounds is also present in meat post mortem. The deposition of tocopherol in the muscle depends on the dosage, the source, and the period of supplementation, so different dosage-time combinations have been developed. Vitamin E does not affect production parameters if minimum requirements for function and growth are satisfied, but it could influence lamb fatty acid profile. During display, it protects PUFA from degradation, reducing lipid oxidation and, therefore, delaying discolouration. Furthermore, vitamin E would indirectly affect the development of lamb aroma by reducing protein and lipid oxidation. To facilitate optimal supplementation rates by producers and retailers, the present paper reviews vitamin E chemistry, biochemistry, nutrition and its ability to maintain lamb quality. PMID- 30448474 TI - Contrasting the quality traits of aged bolar blade, topside and striploin cuts sourced from dark cutting and control Australian beef carcasses. AB - The bolar blade, striploin and topside cuts from dark cutting (DC) and normal (nDC) beef carcasses were compared in terms of their eating quality, oxidation and colour traits. Carcass grades were assigned so that striploins assessed to have pH > 5.7 were classified DC. Cuts were aged (14 and 28 d) before their shear force, sarcomere length, ultimate pH, particle size, TBARS, drip and cooking losses, and colour stability traits were analysed. DC effects on tenderness traits were not uniform across all cuts. Only TBARS was influenced by grade and ageing period interactions. Colorimetric variation due to grade was more evident in the striploin than the other cuts, although this was independent to ageing or display. Cuts themselves differed and were impacted by ageing and display periods. It was concluded that unlike the topside and striploin, the bolar blade from DC carcasses had comparable quality to nDC and could therefore retain its value if priced independent to the entire carcasses. PMID- 30448475 TI - Organogels use in meat processing - Effects of fat/oil type and heating rate. AB - The effects of fat/oil type (regular and rendered beef fat, canola, soy and flaxseed oils), form (native or organogel), and heating rate (0.7 and 3.5 degrees C/min) were investigated in a comminuted meat system. Converting beef fat to organogel resulted in higher hardness values of the cooked meat products, but the opposite was observed with the vegetable oils. Springiness was lower for all organogels compared to the native fat/oil used. Fat globule size was larger in the organogels prepared from vegetable oils compared to the native oils, but that was not the case for beef fat. Increasing heating rate reduced cooking loss, and while employing organogels did not affect the regular beef fat, it significantly increases losses from the vegetable oil treatments. Overall, using the organogel technology should be attractive to processors and consumers alike as products with high unsaturated fatty acids can be produced. PMID- 30448477 TI - Round optimization for improved discovery of native bispecific antibodies. AB - The assembly of bispecific antibodies (bsAb) that retain the structure of a standard IgG can be challenging as the correct pairing of the different heavy and light chains has to be ensured while unwanted side products kept to a minimum. The use of antibodies sharing a common chain facilitates assembly of such bsAb formats but requires additional efforts during the initial discovery phase. We have developed a native bsAb format called kappalambda body based on antibodies that, while being specific for different antigens, share the same heavy chain. Such antibodies can readily be isolated from antibody libraries incorporating a single VH combined with light chain diversity. However, in order to improve the discovery process of such fixed VH antibodies, we developed a method to optimize populations of light chains by recovering and shuffling CDRL3 sequences that have been enriched for antigen binding by phage display selection. This approach allowed for the isolation of a more diverse and potent panel of antibodies blocking the interaction between PD-1 and PD-L1 when compared to our standard in vitro selection approach, thus providing better building blocks for subsequent bsAb generation. PMID- 30448476 TI - The Relapsing Polychondritis Damage Index (RPDAM): development of a disease specific damage score for relapsing polychondritis. AB - OBJECTIVES: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM). METHODS: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert scale. The selection of items for each subsequent round was based on the median rating of each item. RESULTS: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items. CONCLUSION: We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. Following its validation, the RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials. PMID- 30448478 TI - Analysis of post-transcriptional RNA metabolism in prokaryotes. AB - Post-transcriptional RNA metabolic pathways play important roles in permitting prokaryotes to operate under a variety of environmental conditions. Although significant progress has been made during the last decade in deciphering RNA processing pathways in a number of bacteria, a complete understanding of post transcriptional RNA metabolism in any single microorganism is far from reality. Here we describe multiple experimental approaches that can be used to study mRNA stability, tRNA and rRNA processing, sRNA metabolism, and polyadenylation in prokaryotes. The methods described here can be readily utilized in both Gram negative and Gram-positive bacteria with simple modifications. PMID- 30448479 TI - Phosphorylation of Cx43 residue Y313 by Src contributes to blocking the interaction with Drebrin and disassembling gap junctions. AB - Phosphorylation regulates connexin43 (Cx43) function from assembly/disassembly to coupling at the plaque. Src is a tyrosine kinase known to both phosphorylate Cx43 (residues Y247 and Y265) and affect gap junction intercellular communication. However, the Cx43 carboxyl-terminal (CT) domain contains additional tyrosine residues and proteomic discovery mass spectrometry data identified Y313 as a potential phosphorylation target. Based upon the study of Lin et al. (2001) J. Cell Biol., which still observed tyrosine phosphorylation by Src when using a Cx43 Y247/Y265F mutant, we addressed the possibility of Y313 phosphorylation (pY313) by Src. In vitro Src phosphorylation of purified Cx43CT followed by mass spectroscopy revealed that Src also phosphorylates Y313. This observation was confirmed by repeating the in vitro phosphorylation using different combinations of Cx43CT Y -> F mutants and a general anti-pTyr antibody. Next, a phospho specific antibody was generated to help characterize the importance of pY313. We established an in cyto experimental system by stably expressing Cx43 WT and mutants (Y247F, Y265F, Y313F, Y247/265F, Y247/313F, Y265/313F, or Y247/265/313F) in Cx43-deficient HeLa cells. Cx43 WT and mutants, in the absence of v-Src, localized to the plasma membrane and formed gap junctions. When v-Src was over expressed, Cx43 WT localized intracellularly, while all of the single and double mutants remained able to form plaques and transfer dye, albeit variable in number and amount, respectively. Complete Src-resistance was only achieved with the Cx43 Y247/265/313F mutant. Furthermore, Cx43 Y265F inhibited the ability of v-Src to phosphorylate Y247 and Y313 as well as phosphorylation at both Y265 and Y313 was necessary to inhibit the Cx43 interaction with Drebrin. Finally, we observed in diseased cardiac tissue, in which Src is active, an increase in intercalated disc and intracellular localized Cx43 pY313. PMID- 30448480 TI - The SCFFBXO3 ubiquitin E3 ligase regulates inflammation in atherosclerosis. AB - Inflammation is critical in the pathobiology of atherosclerosis. An essential player in the inflammatory process in atherosclerosis are macrophages that scavenge oxidatively modified low-density lipoproteins (OxLDL) deposited in the subendothelium of systemic arteries that secrete a myriad of pro-inflammatory mediators. Here, we identified that a subunit of the Skp-Cullin-F-box ubiquitin E3 ligase apparatus, termed FBXO3, modulates the inflammatory response in atherosclerosis. Specifically, individuals with a hypofunctioning genetic variant of FBXO3 develop less atherosclerosis. FBXO3 protein is present in cells of monocytic lineage within carotid plaques and its levels increase in those with symptomatic compared with asymptomatic atherosclerosis. Further, cellular depletion or small molecule inhibition of FBXO3 significantly reduced the inflammatory response to OxLDL by macrophages without altering OxLDL uptake. Thus, FBXO3 potentiates vascular inflammation and atherosclerosis that can be effectively mitigated by a small molecule inhibitor. PMID- 30448481 TI - Emergency surgery for acute type A aortic dissection in octogenarians without patient selection. AB - BACKGROUND: Octogenarians are often declined emergent surgery for acute type A aortic dissection on grounds of high mortality rate and short life expectancy. Our policy is to accept all patients at any time and never to refuse an emergency operation, even for octogenarians. METHODS: From April 2004 to September 2017, 319 patients underwent surgical repair for acute type A aortic dissection at our institution. We compared the clinical results between the fifty-five elderly patients (>=80 years old; older group) and the 264 non-elderly patients (<=79 years old; younger group). The primary endpoint was early mortality and the secondary endpoint long-term mortality. RESULTS: The older group had a higher proportion of females (74.5% vs. 46.6%), a lower body mass index (21.4 vs. 23.8), and a lower proportion of smokers (20.0% vs. 46.2%). In the two groups (older vs. younger), postoperative stroke and hospital mortality occurred in 12.7% vs. 11.4 % and 10.2% vs. 10.9%, respectively, with no significantly statistical difference. In multivariate analysis, older age of 80 years or more was not a significant risk factor for hospital mortality. Among the hospital survivors, the actuarial survival rate at 8 years was 52.5% in the older group and 85.0% in the younger group (p=0.005). CONCLUSIONS: Emergency surgery for type A aortic dissection in octogenarians without patient selection resulted in similar rates of mortality and morbidity to younger patients. Octogenarians should not be refused this life-saving emergent surgery. PMID- 30448482 TI - Right-sided vs Left-sided Pneumonectomy after Induction Therapy for Non-small cell Lung Cancer. AB - BACKGROUND: A right-sided pneumonectomy after induction therapy for non-small cell lung cancer (NSCLC) has been shown to be associated with significant perioperative risk. We examined the impact of laterality on long-term survival after induction therapy and pneumonectomy using the National Cancer Data Base (NCDB). METHODS: Perioperative and long-term outcomes of patients who underwent pneumonectomy following induction chemotherapy with or without radiation from 2004-2014 in the NCDB were evaluated using multivariable Cox proportional hazards modeling and propensity score-matched analysis. RESULTS: During the study period, 1465 patients (right n=693 [47.3%], left n=772 [52.7%]) met inclusion criteria. Right-sided pneumonectomy was associated with significantly higher 30-day (8.2% [57/693] vs 4.2% [32/772], p< 0.01) and 90-day mortality (13.6% [94/693] vs 7.9% [61/772], p<0.01), and right-sided pneumonectomy was a predictor of higher 90-day mortality (OR 2.23, p<0.01). However, overall survival between right and left pneumonectomy was not significantly different in univariate (5-year survival 37.6% [95% CI: 0.34-0.42] vs 35% [95% CI: 0.32-0.39], log-rank p=0.94) or multivariable analysis (hazard ratio, 1.07 [95% CI: 0.92-1.25], p=0.40). In a propensity score-matched analysis of 810 patients, there were no significant differences in 5-year survival between the right- vs left-sided groups (34.7% [95% CI: 0.30-0.40] vs 34.1%, [95% CI: 0.29-0.39], log-rank p =0.86). CONCLUSIONS: In this national analysis, right-sided pneumonectomy after induction therapy was associated with a significantly higher perioperative but not worse long-term mortality compared to a left-sided procedure. PMID- 30448483 TI - Surgical repair of distal aortic arch aneurysm with distal extension: sternotomy versus thoracotomy. AB - BACKGROUND: There is no consensus as to whether a median approach or lateral approach is better for distal aortic arch aneurysms with distal extensions. The aim of this study was to compare clinical outcomes of these two approaches for distal aortic arch aneurysms with distal extensions. METHODS: From January 2001 to December 2017, 212 consecutive patients with distal aortic arch aneurysms with distal extensions underwent surgery using different approaches: hemiarch and descending thoracic aneurysm (DTA) replacement via thoracotomy (group 1, n=91), and total arch and DTA replacement via sternotomy (group 2, n=121). Early and late outcomes were compared using scores and inverse-probability-of-treatment adjustments to reduce treatment selection bias. RESULTS: The in-hospital mortality was 9.89% (9/91) in the thoracotomy group and 2.48% (3/121) in the sternotomy group (p=0.02). The sternotomy group had a lower incidence of permanent stroke (2.48%, 3/121) compared with thoracotomy (10.99%, 10/91) (p=0.01). After adjustment, patients who underwent thoracotomy were at a greater risk of hospital mortality [odds ratio (OR), 5.00; p=0.01)], permanent stroke (OR, 6.83; p<0.01), and pneumonia (2.99; p=0.04), compared to those who underwent sternotomy. The overall survival at 10 years was 69.8+/-7.0% for the thoracotomy group and 83.0+/-5.5.0% for the sternotomy group (unadjusted; p=0.049; adjusted; p=0.034). CONCLUSIONS: The sternotomy approach showed better outcomes in terms of operative mortality, stroke, and pneumonia, as well as long-term survival compared to thoractomy. These results suggested that the sternotomy approach was more appropriate for patients with distal aortic arch aneurysms with distal extensions. PMID- 30448484 TI - Deep Hypothermia + Retrograde Cerebral Perfusion vs. Moderate Hypothermia + Antegrade Cerebral Perfusion for Arch Surgery. AB - BACKGROUND: Patients undergoing aortic arch replacement are at high risk for neurologic injury. The purpose of this study was to compare two different established neuroprotective strategies in patients undergoing elective transverse hemiarch replacement. METHODS: Twenty patients undergoing hemiarch replacement were prospectively randomized to receive either: Deep Hypothermic Circulatory Arrest + Retrograde Cerebral Perfusion(DHCA+RCP) or Moderate Hypothermic Circulatory Arrest + Antegrade Cerebral Perfusion(MHCA+ACP). All patients received Neurologist-adjudicated exams and MRI's prior to discharge. The primary endpoint was a composite of stroke, transient ischemic attack and MRI-adjudicated injury. Secondary endpoints were transient neurologic dysfunction(TND), and the NIH stroke scale and neurocognitive scores. RESULTS: Randomization resulted in 11 DHCA+RCP patients, and 9 MHCA+ACP patients. There was no difference in cardiopulmonary bypass, cross-clamp or circulatory arrest times. MHCA+ACP patients underwent circulatory arrest at significantly warmer temperatures (MHCA+ACP 26.3+/-1.8 degrees C vs. DHCA+RCP 19.9+/-0.1 degrees C,p<0.0001). There were no deaths or renal failure in either group. There was 1 stroke in each group. NIH stroke scale scores and neurocognitive test results were equivalent. Diffusion weighted imaging MRI demonstrated lesions in 100%(9/9) of MHCA+ACP patients compared to 45%(5/11) of DHCA+RCP patients(p<0.01). MHCA+ACP patients had a significantly higher number of lesions compared to DHCA+RCP(p<0.01). The primary endpoint was achieved in 100% of MHCA+ACP patients compared to 45% of DHCA+RCP patients(p<0.01). CONCLUSIONS: Although there was no significant difference in clinically evident neurologic injury, this pilot study suggests that MHCA+ACP may be associated with a higher incidence of radiographic neurologic injury than DHCA+RCP in patients undergoing elective hemiarch replacement. PMID- 30448485 TI - Heparin-Induced Thrombocytopenia and Cardiac Surgery. AB - Heparin-induced thrombocytopenia (HIT), is an immune-mediated condition characterized by thrombocytopenia with possible arterial and/or venous thrombosis. The overall incidence of HIT is low but ranges from 0.1% to 5%.1,2 The incidence can be as high as 3% in patients undergoing cardiac surgery. The use of unfractionated heparin is ubiquitous in patients who undergo cardiac procedures and carries a ten-fold higher incidence of HIT over low molecular weight heparin. Patients undergoing cardiac surgery thus form a unique group that warrants specific attention to this clinicopathological entity considering the relatively high incidence and associated morbidity and mortality with a delay in diagnosis. In this article, we will discuss five clinical aspects pertinent to the diagnosis and management of HIT in cardiac surgery patients and review the current literature. PMID- 30448486 TI - Effect of anti-solvents on the characteristics of regenerated cellulose from 1 ethyl-3-methylimidazolium acetate ionic liquid. AB - This work investigates the effect of different anti-solvents (water, ethanol, or both water and ethanol) on the characteristics of cellulose dissolved and then generated from 1-ethyl-3-methylimidazolium acetate ([Emim][OAc]). Compared with original microcrystalline cellulose (MCC) granules, all regenerated celluloses showed a homogeneous, agglomerated macromorphology and had its crystalline structure transformed from original cellulose I to cellulose II. The regenerated cellulose using water (43.3%) had a higher degree of crystallinity than that using ethanol (13.5%), and a degree of crystallinity of 21.3% was obtained when an ethanol-water-ethanol treatment method was used. SAXS and FTIR results indicate that water as an anti-solvent could promote the rearrangement of cellulose molecular chains and the rebuilding of an ordered aggregated structure. Moreover, the regenerated cellulose with water showed better thermal stability than that of the samples regenerated using ethanol. Thus, our results suggest that the reconstitution of cellulose molecules during regeneration with various anti-solvents can affect the multiscale structures and properties of cellulose. PMID- 30448487 TI - New glucose oxidase-immobilized stimuli-responsive dextran nanoparticles for insulin delivery. AB - Designing strategies for the use of biopolymer-based nanoparticles as drug delivery carriers is a considerable challenge in pharmaceutical science. Present study reports synthesis of a novel glucose responsive and in-vitro pH triggered insulin delivery system comprised of glucose oxidase immobilized on acryloyl crosslinked dextran dialdehyde (ACDD) nanoparticles. Scanning electron microscopy, transmission electron microscopy and particle size analysis data revealed that these carriers possess nanosize which is an important parameter for drug delivery applications. In-vitro insulin release studies were performed under artificial gastric fluid (AGF, pH 1.2) and artificial intestinal fluid conditions (AIF, pH 7.4) at physiological temperature (37 degrees C). Insulin release profile showed controlled release of about 70% under AIF conditions for 24 h. Insulin release mechanism studied using different kinetic models revealed that Korsmeyer-Peppas model appropriately explained the mechanism as 'non-Fickian' diffusion release of insulin. These glucose responsive stimuli sensitive nanocarriers exhibited controlled release of about 90% under AIF conditions in the presence of glucose. These findings revealed that these nanoparticles are promising and reliable delivery systems to overcome problems related with subcutaneous insulin therapy. PMID- 30448488 TI - Protective effects of a Lachnum polysaccharide against liver and kidney injury induced by lead exposure in mice. AB - This study was designed to investigate the liver and kidney protective efficacy of a Lachnum polysaccharide (LEP) against Pb-induced toxicity in mice. The results showed that LEP decreased the Pb-induced bodyweight loss and organ index. Moreover, biochemical analysis showed that treatment of LEP could improve antioxidant status (CAT, GSH-Px and MDA) and the injury of tissues (liver and kidney). In addition, the histopathological observations indicated that LEP could attenuate liver and kidney cell injury induced by Pb. For further studies, key proteins involved in hepatic and kidney apoptosis, including cleaved caspase-3, Bax, Bcl-2, TGF-beta1 and alpha-SMA, were quantified. The present findings demonstrated that LEP is strongly effective in protecting against the liver and kidney injury induced by Pb. We hope this research can offer a theoretical base for development of polysaccharide based on nutraceutical food in future. PMID- 30448490 TI - Effect of ZnO nanoparticles on the mechanical, barrier and optical properties of thermoplastic cationic starch/montmorillonite biodegradable films. AB - In this study, various amounts of nanoclay montmorillonite (MMT) and ZnO nanopowders were used to analyze the properties of biodegradable nanocomposites of cationic starch (CS). Nanocomposites are produced by solvent casting method. The structure of CS-MMT nanocomposite films that contain 3% montmorillonite was exfoliated and was proved by XRD test. New hydrogen bonds were successfully formed between the CS hydroxyl groups and nanofillers and this was proved by FTIR test. The water vapor permeability and the UV light transmittance of the nanocomposites reduced after the contents of MMT and ZnO increased. ?E and opacity of the nanocomposites enhanced after the amount of ZnO increased. Tensile strength (TS) of nanocomposites increased after the incorporation of ZnO and MMT nanoparticles although the elongation at break was diminished. Results showed that the 3 and 0.7 wt% amounts of montmorillonite and ZnO nanopowders were sufficient in order to acquire a well-moderated mechanical behavior in plastic and elastic regions, and they also cause good improvements in barrier and optical properties. PMID- 30448489 TI - The first mitogenomes of the superfamily Pamphilioidea (Hymenoptera: Symphyta): Mitogenome architecture and phylogenetic inference. AB - The Pamphilioidea represents a small superfamily of the phytophagous suborder Symphyta (Hymenoptera). Here, nearly complete mitochondrial genomes (mitogenomes) of three pamphilioid species: Chinolyda flagellicornis (Pamphiliidae), Megalodontes spiraeae and M. cephalotes (Megalodontesidae) were newly sequenced using next generation sequencing and comparatively analysed with the previously reported symphytan mitogenomes. A positive AT skew (0.013) and a negative GC skew (-0.194) were found in pamphilioid mitogenome, and a deviation from strand asymmetry was also observed in the PCGs encoded on both strands. Several gene rearrangement events were observed in four tRNA gene clusters (WCY, IQM, ARNS1EF and TP clusters), which have not been reported from symphytan mitogenomes to date. As the most parsimonious explanation, compared with the inferred insect ancestral mitogenome architecture, the occurrence of gene rearrangements in pamphilioid mitogenomes requires totally five evolutionary steps, including four transpositions and one inversion. The predicted secondary structures of tRNAs, rrnS and rrnL genes are mostly consistent with reported hymenopteran species. Phylogenetic analyses recovered the monophyly of superfamily Pamphilioidea and indicated the relationship Tenthredinoidea + (Pamphilioidea + (Cephoidea + (Orussoidea + Apocrita))) with strong nodal supports. PMID- 30448491 TI - Physical, thermal, mechanical and barrier properties of pearl millet starch films as affected by levels of acetylation and hydroxypropylation. AB - Starch-based films possess potential application in food packaging, due to their biodegradability, lower cost, stretchability and clarity. The aim of this work was to develop novel edible films from native, acetylated and hydroxypropylated pearl millet starches with improved flexibility, transparency and water barrier properties. Each film contained a fixed concentration of starch (3 g/100 g) and glycerol (30%, w/w based on starch weight). The effect of levels of acetylation (4% and 8%, w/w) and hydroxypropylation (10% and 30%, w/v) on the rheological, physical, thermal, mechanical and barrier properties of films was investigated. SEM results showed that modified starch films possessed smoother surface in comparison to native starch film (NF). Rheological evaluation depicted that filmogenic solution of 30% hydroxypropylated starch was more viscous than other solutions. Films containing 4% and 8% acetylated starches showed excellent moisture barrier property as depicted by their low water vapor permeability (WVP) and water solubility (WS). The extent of these improvements depended on the levels of acetylation. Elongation at break (%EAB) and transparency (%T) of 10% and 30% hydroxypropylated starch films were higher than NF and increased with increasing amount of propylene oxide. Glass transition temperature (Tg) was lowered by addition of modified starches in film formulation. PMID- 30448492 TI - Dual functional jute fabric biocomposite with chitosan and phosphorylated nano cellulose (antimicrobial and thermal stability). AB - In the present study, phosphorylated nanocellulose (P-NC) has been prepared from date palm sheath fibers by a solvent-free acid hydrolysis procedure. Eighteen different treatment procedures were employed for the composite treatment of jute fabric. Different fractions of phosphorylated nanocellulose (1-4%) and chitosan (0.5-2%) were used to examine the effects of treatment procedures on the resulting jute fabric composites. Weight uptake, phosphorus content and tensile properties of the treated jute fabrics have been reported. ATR-FTIR spectroscopy, X-ray diffractometer, transmission electron microscopy, environmental scanning electron microscopy, energy-dispersive X-ray spectroscopy and thermo-gravimetric analysis were used to gain insight into the mechanism of interaction between jute fabric, CS macromolecules, and P-NCs. In addition, the development of antimicrobial and thermal stability properties on jute fabric has been investigated. PMID- 30448493 TI - Solvent exchange and drug release characteristics of doxycycline hyclate-loaded bleached shellac in situ-forming gel and -microparticle. AB - Doxycycline hyclate (DX)-loaded bleached shellac (BS) in situ forming gel (isg) and in situ microparticle (ism) were prepared using dimethyl sulfoxide (DMSO), N methyl pyrrolidone (NMP) and 2-pyrrolidone (PYR) as solvents. Solvent and drug release characteristics of them were investigated. Diffusion rate of solvent applied in formulation was as following: DMSO > NMP > PYR. In situ forming systems comprising PYR had the slowest release rate of solvent and drug while water flowed into system in rank of solvent order as following: DMSO > NMP > PYR. Size and density of pores were increased by time similarly to release rate of solvent and drug. At steady state, total mass loss converted to PYR ? NMP > DMSO similarly to water content pattern. The solvent and DX release from ism were apparently slower than those from isg owing to barrier effect from oil component. The isg and ism prepared from DMSO exhibited the highly sponge-like structure than that using PYR which the later matrices eventually dissipated due to hydrolysis of BS which was accelerated by PYR-induced water accumulation. PYR was the most appropriated solvent for BS isg and ism because their formulations demonstrated the proper sustained drug release and preferable self-degradation. PMID- 30448494 TI - Characterization of hydroxyapatite-containing alginate-gelatin composite films as a potential wound dressing. AB - In this study, hydroxyapatite (HA)-containing alginate-gelatin films were prepared by solution casting method by blending alginate (A) and gelatin (G) solutions, followed by crosslinking with calcium chloride. HA (1, 2, 5, 10, 20% w/w) was added to film solutions prepared at different ratios (A:G = 40:60, 50:50, and 60:40) and the swelling and degradation behavior, mechanical, antimicrobial and thermal properties, and morphologies of the obtained films were examined. The release of tetracycline hydrochloride (TH), selected as a model drug, from the prepared films was studied. It was observed that the swelling ratio and weight loss of the films decreased as the amounts of alginate and HA increased. Scanning electron microscopy analysis indicated that as the amount of HA in the films increased, the film surface becomes rougher. The mechanical properties of the films were affected by the amount of HA and the A:G ratio. Incorporation of HA increased the thermal stability of films. The amount of TH released from the films within 15 min decreased as the amounts of alginate and hydroxyapatite increased. It was found that films containing TH showed slightly higher antimicrobial activity against Staphylococcus aureus than Escherichia coli. PMID- 30448495 TI - Formulation development and characterization of cefazolin nanoparticles-loaded cross-linked films of sodium alginate and pectin as wound dressings. AB - The present study focuses on the preparation of nanoparticles-loaded ionic cross linked films for the topical delivery of cefazolin. The aim of the study was to prepare a dosage form which can provide local effect of cefazolin along with sustained delivery at the site of application. Cefazolin was loaded into chitosan nanoparticles to mask the burst release of the drug and they were optimized based on particle size, PDI, % EE and zeta potential. Finally, the prepared nanoparticles were loaded into the films comprising of sodium alginate and pectin which were then subjected to cross-linking via calcium chloride to improve the mechanical strength of the hydrogel films upon exposure to wound fluid. The films were assessed for physical and mechanical properties, swelling behavior, water transmission rate, mucoadhesion, FTIR, DSC, percent inhibition assay and in vitro release profile. Optimized formulation with Cefazolin nanoparticles in the size range of 227 nm and 0.5% CL films showed significantly better results (p < 0.05) as compared to the films with increased cross-linker concentration. Therefore, 0.5% CL films were considered more suitable for the treatment of infections when applied as wound dressing. PMID- 30448496 TI - Investigation of accelerated aging of lignin-containing polymer materials. AB - This paper presents the results of an accelerated aging test of biocomposites containing kraft lignin, where the resistance of the materials against humidity and light exposure was investigated. Low molecular weight lignin, modified with methacrylic anhydride (LWL-Met), was copolymerized with two commercial monomers: styrene (St) and methyl methacrylate (MMA). The biocomposites were obtained by a bulk polymerization method using alpha,alpha'-azoiso-bis-butyronitrile (AIBN) as a free radical polymerization initiator. The Shore D hardness of the obtained materials was determined before and after aging test. The changes in the chemical structures of polymers, as the result of aging were analyzed by using the attenuated total reflection Fourier transform infrared (ATR/FT-IR) spectroscopy method. The thermal behavior and stability of the obtained materials were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The surface topography was determined using the optical topography method to evaluate the changes on the surface of synthesized materials resulted from accelerated aging. Application of modified lignin as a biocomponent in the polymerization process and its influence on the properties of the obtained materials before and after the accelerated aging test are discussed. PMID- 30448497 TI - Thermoalkaliphilic laccase treatment for enhanced production of high-value benzaldehyde chemicals from lignin. AB - Enzymatic conversion of lignin into high-value chemicals is a key step in sustainable and eco-friendly development of lignin valorization strategies. In the present study, a novel thermoalkaliphilic laccase, CtLac, from Caldalkalibacillus thermarum strain TA2.A1 was tested for the depolymerization of lignin and the production of value-added chemicals, using three different lignocellulosic biomass, organosolv lignin (OSL), and Kraft lignin. Seven valuable lignin monomers were identified from the CtLac-treated samples using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Remarkably, increases of 22.0%, 65.6%, and 27.3% of p-hydroxybenzaldehyde and increases of 111.1%, 93.5%, and 238.1% of vanillin were observed from rice straw, corn stover, and reed, respectively. Comparative analysis of lignin monomers released from rice straw, using Trametes versicolor laccase (TvL) and CtLac indicated efficient depolymerization of lignin by CtLac. CtLac treatment resulted in 2.3 fold and 5.6 fold, and 1.9 fold and 2.8 fold higher amounts of p hydroxybenzaldehyde and vanillin from OSL and Kraft lignin, respectively, compared to CtLac-treated rice straw samples after 12 h reaction. OSL was the best substrate for the production of benzaldehyde chemicals using CtLac treatment. The results demonstrated potential application of bacterial laccase CtLac for valorization of biomass lignin into high-value benzaldehyde chemicals under thermoalkaliphilic conditions. PMID- 30448498 TI - Effect of lignin on the release rate of acetylsalicylic acid tablets. AB - The main focus of this paper is on the improvement of formulations utilising non conventional bio-based excipients to improve tablet release rates. Two different formulations were considered. The first formulation contains Alcell lignin, lactose monohydrate and microcrystalline cellulose as excipients and acetylsalicylic acid (aspirin) as active pharmaceutical ingredient (API). The second formulation contains lactose monohydrate and microcrystalline cellulose as excipients and aspirin as API. The prepared formulations were roller compacted followed by milling, sieving, and tableting. The tablets were then characterised in terms of dissolution rate in order to compare the release rates. Results indicated that tablets containing Alcell lignin have quicker release, faster disintegration times and higher tablet hardness for all samples with differing process parameters. Higher API dissolution has been attributed to the amorphous structure of lignin and its interaction with aspirin, which increases dissolution of the API. PMID- 30448499 TI - Antitumor and anti-inflammatory effects of oligosaccharides from Cistanche deserticola extract on spinal cord injury. AB - In the present study, the pharmacological effects of oligosaccharides from Cistanche deserticola extract on inflammation, oxidative stress, and apoptosis in male albino rats with spinal cord injury were investigated. Lipid peroxidation, GSH, catalase, superoxide dismutase, acetylcholine esterase, GPx, ROS, and nitric acid were significantly altered in the rats with spinal cord injury. The mRNA expression levels of IL-6, TNF-alpha, cyclooxygenase-2, iNOS, p53, caspase-3, bax, and pro-NGF were reduced by >20% following extract supplementation. Protein expression levels of caspase-3 and pro-NGF were also reduced by >20%. The number of p53 positive cells was 1, 79, 54, 33, and 19 in groups GI-GV, respectively, and the corresponding numbers of caspase-3 positive cells were 2, 87, 51, 23, and 14. Based on the present results, the use of oligosaccharides from Cistanche deserticola extract was effective against inflammation, oxidative stress, and apoptosis in spinal cord injury male albino rats. PMID- 30448500 TI - Structure and gene cluster of the O antigen of Escherichia coli F17, a candidate for a new O-serogroup. AB - Escherichia coli F17 isolated from horse feces was studied in respect to the O antigen (O polysaccharide) structure and genetics. The lipopolysaccharide was isolated by phenol-water extraction of bacterial cells and cleaved by mild acid hydrolysis to yield the O polysaccharide, which was studied by sugar analysis and selective solvolysis with CF3CO2H along with one- and two-dimensional 1H and 13C NMR spectroscopy. The O polysaccharide was found to have a branched pentasaccharide repeat (O-unit) containing one residue each of d-galactose, d mannose, l-rhamnose, d-glucuronic acid, and N-acetyl-d-glucosamine; about 2/3 units bear a side-chain glucose residue. To our knowledge, the F17 O polysaccharide structure established is unique among known bacterial polysaccharide structures. The O-antigen gene cluster of E. coli F17 between the conserved genes galF and gnd was sequenced and found to be 99% identical to that of E. coli 102,755 assigned to a novel OgN8 genotype (A. Iguchi, S. Iyoda, K. Seto, H. Nishii, M. Ohnishi, H. Mekata, Y. Ogura, T. Hayashi, Front. Microbiol. 7 (2016) 765). Genes in the cluster were annotated taking into account the F17 O polysaccharide structure. The data obtained confirm that E. coli F17 and E. coli strains belonging to the OgN8 genotype can be considered as a candidate to a new E. coli O-serogroup. The O antigen of this novel type was demonstrated to make for an effective shield protecting the intimate outer membrane surface of bacteria from direct interaction with bacteriophages. PMID- 30448501 TI - Hypersensitivity Pneumonitis: A Fibrosing Alveolitis Produced by Inhalation of Diverse Antigens. AB - Hypersensitivity pneumonitis (HP) is a TH1 lymphocyte biased fibrosing alveolitis that is caused by antigens ranging from avian excreta, fungi, thermophilic bacteria, and protozoa to reactive chemicals found in the workplace. Mimicking a viral syndrome, acute exposures to inciting antigens cause abrupt onset of non productive cough, dyspnea, chills, with arthralgias or malaise usually from 4-8 hours later so that the temporal relationship between antigen exposure and symptoms may be unsuspected. The histology of HP reveals prominent lymphocyte infiltrates that thicken the alveolar septa with poorly formed granulomas or giant cells. Broncholalveolar lavage demonstrates > 20% lymphocytes in nearly all patients. Abnormalities on high resolution computerized tomography examinations range from nodular, centrilobular opacities in acute/subacute disease to increased reticular markings and honeycombing fibrosis, which typically are predominant in the upper lobes, in advanced disease. Descriptors include "mosaic attenuation" and "ground-glass" opacities. Repeated episodes can result in nodular pulmonary infiltrates and suspected nonspecific interstitial pneumonia or idiopathic pulmonary fibrosis. Clinicians require a high level of suspicion to make an early diagnosis of HP before extensive pulmonary fibrosis or restrictive lung disease has occurred. PMID- 30448502 TI - Lower-than-predicted mortality in a predominantly HIV-infected population with epidermal necrolysis regardless of HIV status. Implications and challenges for interventional studies. PMID- 30448503 TI - Impact of prehospital physician-led cardiopulmonary resuscitation on neurologically intact survival after out-of-hospital cardiac arrest: a nationwide population-based observational study. AB - AIM: The impact of prehospital physician care for out-of-hospital cardiac arrest (OHCA) on long-term neurological outcome is unclear. We aimed to determine the association between emergency medical services (EMS) physician-led cardiopulmonary resuscitation (CPR) versus paramedic-led CPR and neurologically intact survival after OHCA. METHODS: We assessed 613,251 patients using All-Japan Utstein Registry data from 2011 to 2015 retrospectively. The main outcome measure was 1-month neurologically intact survival after OHCA, defined as Cerebral Performance Category 1 or 2 (CPC 1-2). RESULTS: Before propensity score matching, the 1-month CPC 1-2 rate was significantly higher in EMS physician-led CPR than in paramedic-led CPR [5.7% (1114/19,551) vs. 2.5% (14,859/593,700), P < 0.001; adjusted odds ratio (aOR), 1.50; 95% confidence interval (CI), 1.40-1.61]. After propensity score matching, EMS physician-led CPR showed more favourable neurological outcomes than paramedic-led CPR [6.0% (996/16,612) vs. 4.6% (766/16,612), P < 0.001; aOR, 1.44; 95% CI, 1.29-1.60]. In most subgroup analyses after matching, physician-led CPR had higher 1-month CPC 1-2 rates than paramedic led CPR did; however, 1-month CPC 1-2 rates were similar between the two CPR configurations for patients aged <18 years (5.6% vs. 8.2%, P = 0.10; aOR, 0.82; 95% CI, 0.46-1.47) and those who received bystander defibrillation (26.3% vs. 21.5%; P = 0.10; aOR, 1.07; 95% CI, 0.74-1.53). CONCLUSION: Within the limitations of this retrospective observational research, EMS physician-led CPR for OHCA was associated with improved 1-month neurologically intact survival compared with paramedic-led CPR. However, neurologically intact survival was similar for patients aged <18 years and those receiving bystander defibrillation. PMID- 30448504 TI - Distributions of organophosphate flame retardants (OPFRs) in three dust size fractions from homes and building material markets. AB - The distributions of organophosphate flame retardants (OPFRs) in various size fractions of indoor dust samples from homes (H; n = 18) and building material markets (B; n = 7) in the Rhine/Main region of Germany were investigated. Three particle size fractions (F1: 150-200 MUm, F2: 63-150 MUm, and F3: <63 MUm) and bulk dust (BD) subsamples (<200 MUm) of each sample were analyzed for 10 OPFRs. On average, the total OPFR concentrations (?10OPFR) in bulk dust and all three size fractions from building material markets were 133, 153, 196, and 88.0 MUg/g in subsamples B-BD, B-F1, B-F2, and B-F3. These concentrations were at least five times higher than those in bulk dust and all three size fractions from homes, with values of 19.3, 17.2, 19.5, and 18.7 MUg/g for subsamples H-BD, H-F1, H-F2, and H-F3, respectively. Tris(2-chloroisopropyl)phosphate (TCIPP) was the dominant congener in dust from building material markets, contributing over 91% to the ?10OPFR of B-BD and all particle size fractions. Meanwhile, both tris(2 butoxyethyl)phosphate (TBOEP) and TCIPP were abundant in dust from homes, respectively contributing 28%-41% and 31%-43% to the ?10OPFR of H-BD and all particle size fractions. Most of the OPFR concentrations showed no consistent trend with particle size. However, TCIPP was more likely to be enriched in F2. Microscopic examination indicated that TCIPP in indoor dust mainly originated from abraded fragments of commercial products. In contrast, TBOEP accumulated in F3, related to direct transfer of floor-care products to fine dust particles. The concentrations of OPFRs were not significantly correlated with total organic carbon contents in any particle size fraction. However, evaluation of their mass contributions showed that more than 85% of OPFRs accumulated in particles smaller than 150 MUm, indicating that this particle size fraction is most suitable for monitoring of OPFRs. PMID- 30448505 TI - Fate of microbial pollutants and evolution of antibiotic resistance in three types of soil amended with swine slurry. AB - Swine waste is a reservoir of microbial pollutants, including pathogens, antibiotic resistance genes (ARGs) and antibiotic resistant bacteria (ARB); therefore, soil fertilized with swine waste is an essential pathway for the dissemination of microbial pollutants from concentrated swine farms to the public. To rationalize the intervals of swine wastes application and investigate the effects of soil type on the occurrences of microbial pollutants and antibiotic resistance, pot experiments were conducted with three typical soils, humic acrisol, calcaric cambisols and histosols, being collected from south, northwest and northeast China (soil-R, soil-Y and soil-B, respectively). The soils were amended with swine slurry, digestate and chemical fertilizers and then conducted for 172 days. The influence of microbial pollutants and antibiotic resistance in soil posed by digestate application was similar to that of the chemical fertilizers, while swine slurry posed high risks to the soil. Soil-B which had the highest organic matter and neutral pH was least influenced by the swine slurry amendment. tetG, tetM and ermF were persistent ARGs in the slurry treated soil, and their decay rates fitted to first-order kinetics in the order soil-B> soil-Y > soil-R. Putative pathogens showed strong correlations with ARGs, suggesting a risk of dissemination. The initial 43-82 days was the active phase of microbial pollution in slurry treated soil, during which time heavy metals, moisture content, total organic carbon and the microbial community were key factors contributing to changes in antibiotic resistance. Fertilization intervals of livestock wastes should be lengthened over the ARG active phase. PMID- 30448507 TI - Trace metals in polyethylene debris from the North Atlantic subtropical gyre. AB - Plastic pollution in the marine environment poses threats to wildlife and habitats through varied mechanisms, among which are the transport and transfer to the food web of hazardous substances. Still, very little is known about the metal content of plastic debris and about sorption/desorption processes, especially with respect to weathering. In this study, plastic debris collected from the North Atlantic subtropical gyre was analyzed for trace metals; as a comparison, new packaging materials were also analyzed. Both the new items and plastic debris showed very scattered concentrations. The new items contained significant amounts of trace metals introduced as additives, but globally, metal concentrations were higher in the plastic debris. The results provide evidence that enhanced metal concentrations increase with the plastic state of oxidation for some elements, such as As, Ti, Ni, and Cd. Transmission electron microscopy showed the presence of mineral particles on the surface of the plastic debris. This work demonstrates that marine plastic debris carries complex mixtures of heavy metals. Such materials not only behave as a source of metals resulting from intrinsic plastic additives but also are able to concentrate metals from ocean water as mineral nanoparticles or adsorbed species. PMID- 30448506 TI - Spatial distribution of lead contamination in soil and equipment dust at children's playgrounds in Beijing, China. AB - Lead contamination is widespread across China, posing a serious public health concern. In quantifying child lead exposure, established health risk assessment (HRA) approaches often take into account residential soil lead levels. However, this may not constitute a significant exposure source for children in urban mainland China, where the population mainly dwell in high-rise buildings without back or front yards. In this setting, children's playgrounds may represent a more probable exposure source. The present study analyzed lead levels in settled dust on playground equipment and in surficial soils at 71 playgrounds in Beijing, China. Our results reveal that the average playground dust lead concentration was 80.5 mg/kg, more than twice the average soil lead concentration of 36.2 mg/kg. It was found that there are differences in statistical and spatial distributions for lead in playground dust and soils. Lead levels in equipment dust were largely consistent across Beijing, with elevated levels detected at locations in the main city area, the newly developed Tongzhou District, and the rural counties. Whereas average soil lead concentrations were higher at playgrounds in the main city area than other areas of Beijing. Statistical analysis suggests that the lead content in dust and soil may derive from different natural and anthropogenic sources. Equipment dust lead may be associated with long-distance atmospheric transportation and deposition. Whereas lead in soil is more likely to be associated with local traffic. This study also found that, in certain areas of Beijing, the risk of blood lead levels (BLLs) exceeding safe levels was up to 6 times higher when based on dust exposure than when based on playground soil exposure. The results of this study suggests that HRA undertaken for children in urban mainland China should pay closer attention to children's playgrounds as a lead exposure source, and, in particular, playground equipment dust. PMID- 30448508 TI - Increase of apoplastic ascorbate induced by ozone is insufficient to remove the negative effects in tobacco, soybean and poplar. AB - Apoplastic ascorbate (ASCapo) is an important contributor to the detoxification of ozone (O3). The objective of the study is to explore whether ASCapo is stimulated by elevated O3 concentrations. The detoxification of O3 by ASCapo was quantified in tobacco (Nicotiana L), soybean (Glycine max (L.) Merr.) and poplar (Populus L), which were exposed to charcoal-filtered air (CF) and elevated O3 treatments (E-O3). ASCapo in the three species were significantly increased by E O3 compared with the values in the filtered treatment. For all three species, E O3 significantly increased the malondialdehyde (MDA) content and decreased light saturated rate of photosynthesis (Asat), suggesting that high O3 has induced injury/damage to plants. E-O3 significantly increased redox state in the apoplast (redox stateapo) for all species, whereas no effect on the apoplastic dehydroascorbate (DHAapo) was observed. In leaf tissues, E-O3 significantly enhanced reduced-ascorbate (ASC) and total ascorbate (ASC+DHA) in soybean and poplar, but significantly reduced these in tobacco, indicating different antioxidative capacity to the high O3 levels among the three species. Total antioxidant capacity in the apoplast (TACapo) was significantly increased by E-O3 in tobacco and poplar, but leaf tissue TAC was significantly enhanced only in tobacco. Leaf tissue superoxide anion (O2*-) in poplar and hydrogen peroxide (H2O2) in tobacco and soybean were significantly increased by E-O3. The diurnal variation of ASCapo, with maximum values occurring in the late morning and lower values experienced in the afternoon, appeared to play an important role in the harmful effects of O3 on tobacco, soybean and poplar. PMID- 30448509 TI - A beta-defensin gene of Trachinotus ovatus might be involved in the antimicrobial and antiviral immune response. AB - Defensins are a group of small cationic and cysteine-rich peptides that are important components of the innate immune system. However, studies on defensins in teleosts are very limited, particularly studies on defensin functions through in vivo assays. In this study, we cloned and identified one beta-defensin (TroBD) the golden pompano, Trachinotus ovatus, and analyzed the functions of TroBD in both in vivo and in vitro assays. TroBD is composed of 63 amino acids and shares high sequence identities (27.27-98.41%) with known beta-defensins of other teleosts. The protein has a signature motif of six conserved cysteine residues within the mature peptide. The expression of TroBD was most abundant in the head kidney and spleen and was significantly upregulated following infection by Vibrio harveyi and viral nervous necrosis virus (VNNV). Purified recombinant TroBD (rTroBD) inhibited the growth of V. harveyi, and its antimicrobial activity was influenced by salt concentration. TroBD was found to have a chemotactic effect on macrophages in vitro. The results of an in vivo study demonstrated that TroBD overexpression/knockdown in T. ovatus significantly reduced/increased bacterial colonization or viral copy numbers in tissues. Taken together, these results indicate that TroBD plays a significant role in both antibacterial and antiviral immunity and provide new avenues for protection against pathogen infection in the aquaculture industry. PMID- 30448510 TI - Detection of Lotmaria passim in Africanized and European honey bees from Uruguay, Argentina and Chile. AB - Trypanosomatids affecting honey bees, Crithidia mellificae and Lotmaria passim, have been poorly studied in South America. We therefore analyzed their presence in Africanized and European honeybees from Uruguay, Argentina and Chile collected between 1990 and 2011 and assessed their association with other bee parasites and pathogens. Crithidia mellificae was not detected while L. passim was wide-spread. This report shows that L. passim has been present in this region at least since 2007 and it infects both Africanized and European honey bees. L. passim infected colonies showed high V. destructor parasitization levels, suggesting an association between them. PMID- 30448511 TI - Discovery and characterization of a novel picorna-like RNA virus in the cotton bollworm Helicoverpa armigera. AB - We characterize a novel picorna-like virus, named Helicoverpa armigera Nora virus (HaNV), with a genome length of 11,200 nts, the sequence of which was isolated from the lepidopteran host cotton bollworm Helicoverpa armigera, using RNA-Seq. Phylogenetic analysis, using the putative amino acid sequence of the conserved RNA-dependent RNA polymerase (RdRp) domain, indicated that HaNV clustered with Spodoptera exigua Nora virus, Drosophila Nora virus and Nasonia vitripennis virus 3 with a high bootstrap value (100%), which might indicate a new viral family within the order Picornavirales. HaNV was efficiently horizontally transmitted between hosts via contaminated food, and transmission was found to be dose dependent (up to 100% efficiency with 109 viral copy number/ul). HaNV was also found to be transmitted vertically from parent to offspring, mainly through transovum transmission (virus contamination on the surface of the eggs), but having a lower transmission efficiency (around 43%). Infection distribution within the host was also investigated, with HaNV mainly found in only the gut of both adult moths and larvae (>90%). Moreover, our results showed that HaNV appears not to be an overtly pathogenic virus to its host. PMID- 30448513 TI - Accumulation of PtdIns(4)P at the Golgi mediated by reversible oxidation of the PtdIns(4)P phosphatase Sac1 by H2O2. AB - Phosphatidylinositol 4-phosphate [PtdIns(4)P] plays a key role in the biogenesis of transport vesicles at the Golgi complex by recruiting coat proteins and their accessory factors. The PtdIns(4)P content of the Golgi is determined by the concerted action of PtdIns 4-kinase (PI4K) and PtdIns(4)P phosphatase enzymes. Sac1 (suppressor of actin 1) is the major PtdIns(4)P phosphatase and is localized to the Golgi and endoplasmic reticulum. The targeting of both PI4Ks and Sac1 to the Golgi membrane is extensively regulated, as is the catalytic activity of PI4Ks at the Golgi. However, regulation of the catalytic activity of Sac1 has been largely unexplored. Here we show that Sac1undergoes reversible inactivation in mammalian cells when its catalytic Cys389 residue is oxidized by exogenous H2O2 to form an intramolecular disulfide with Cys392. The oxidative inactivation of Sac1 results in the accumulation of PtdIns(4)P at the Golgi, with this effect also being supported by the H2O2-induced activation of p38 mitogen-activated protein kinase (MAPK), which was previously shown to promote the translocation of Sac1 from the Golgi to the endoplasmic reticulum. The increase in Golgi PtdIns(4)P due to Sac1 inactivation, however, is faster than that due to Sac1 translocation. Exposure of cells to H2O2 also increased membrane protein trafficking from the Golgi to the plasma membrane as well as protein secretion. PMID- 30448514 TI - Fundamentals of fetal toxicity relevant to sevoflurane exposures during pregnancy. AB - Over the last three decades, advances in medical and surgical techniques have proven life saving and life-improving for young children. Consequently, early and repeated exposure to general anesthetics in childhood has increased. However, accumulating evidence suggests that general anesthetics may be neurotoxic in children. Of particular concern is the neurotoxicity fetuses may suffer from maternal exposure to sevoflurane during surgeries and fetal intervention procedures performed during the second trimester, as this can cause neurodevelopmental impairment in offspring. In this review we demonstrate that the pathology associated with fetal toxicity resulting from exposure to sevoflurane during pregnancy involves oxidative stress, neuroinflammation, neuroapoptosis, and alteration of synaptic properties. The mechanisms remain to be elucidated, but may include increased tau protein phosphorylation and abnormal methylation. These findings highlight the need for a global and comprehensive understanding of the potential neurotoxicity of anesthetic exposure in fetuses and its long-term effects. PMID- 30448515 TI - Seminars in cell and developmental biology. PMID- 30448512 TI - Using the synthesized peptide HAYED (5) to protect the brain against iron catalyzed radical attack in a naturally senescence Kunming mouse model. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Abeta42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia. PMID- 30448516 TI - Safety and efficacy of iron therapy on reducing red blood cell transfusion requirements and treating anaemia in critically ill adults: A systematic review with meta-analysis and trial sequential analysis. AB - PURPOSE: To evaluate the safety (risk of infection) and efficacy (transfusion requirements, changes in haemoglobin (Hb)) of iron therapy in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: We systematically searched seven databases for all relevant studies until January 2018 and included randomized (RCT) studies comparing iron, by any route, with placebo/no iron. RESULTS: 805 participants from 6 RCTs were included. Iron therapy, by any route, did not decrease the risk of requirement for a red blood cell (RBC) transfusion (Risk ratio (RR) 0.91, 95% CI 0.80 to 1.04, p = 0.15) or mean number of RBCs transfused per participant (mean difference (MD) -0.30, 95% CI -0.68 to 0.07, p = 0.15). Iron therapy did increase mean Hb concentration (MD 0.31 g/dL, 95% CI 0.04 to 0.59, p = 0.03). There was no difference in infection (RR 0.95, 95% CI 0.79 to 1.19, p = 0.44). Trial Sequential Analysis suggests that the required participant numbers to detect or reject a clinically important effect of iron therapy on transfusion requirements or infection in ICU patients has not yet been reached. CONCLUSION: Iron therapy results in a modest increase in Hb. The current evidence is inadequate to exclude an important effect on transfusion requirements or infection. PMID- 30448518 TI - Bacterial Resistance in the Intensive Care Unit of developing countries: report from a tertiary hospital in Kazakhstan. AB - OBJECTIVES: Describing the patterns of antimicrobial resistance causing hospital acquired infections (HAIs), in the Intensive Care Unit (ICU) of a tertiary hospital in Kazakhstan. METHODS: Retrospective analysis of the resistance to antibiotics in the ICU of the National Research Center for Oncology and Transplantation (NRCOT), Astana (KZ), in the period from January 1st till December 31st, 2015. RESULTS: During the study period, 546 patients were admitted to ICU and 135 developed at least one HAI, corresponding to 24.7%. Most HAIs sustained by gram-positive bacteria were caused by Enterococcus faecalis, being resistant to aminoglycosides in more than 70% cases. Gram-negative bacteria were isolated in around 50% cases, thus representing the greatest burden of HAIs. Here, we showed a very high resistance rates to ceftriaxone, cefotaxime and cefuroxime. Moreover, Pseudomonas aeruginosa and Acinetobacter baumannii resulted to be resistant to carbapenems in less than 20% and in around 45% of cases, respectively. CONCLUSIONS: our study evidenced the urgent need to implement a more rationale use of antimicrobial drugs in Kazakhstan, which could be done only by establishing a proactive surveillance system along with an appropriate program of infection control. PMID- 30448517 TI - Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study. AB - BACKGROUND: The aim of this proof of concept, prospective, randomized pilot trial was to investigate the effects of extracorporeal cytokine removal (CytoSorb(r)) applied as a standalone treatment in patients with septic shock. METHODS: 20 patients with early (<24 h) onset of septic shock of medical origin, on mechanical ventilation, norepinephrine>10 MUg/min, procalcitonin (PCT) > 3 ng/mL without the need for renal replacement therapy were randomized into CytoSorb (n = 10) and Control groups (n = 10). CytoSorb therapy lasted for 24 h. Clinical and laboratory data were recorded at baseline (T0), T12, T24, and T48 hours. RESULTS: Overall SOFA scores did not differ between the groups. In the CytoSorb-group norepinephrine requirements and PCT concentration decreased significantly (norepinephrine: CytoSorb: T0 = 0.54[IQR:0.20-1.22], T48 = 0.16[IQR:0.07-0.48], p = .016; Controls: T0 = 0.43[IQR:0.19-0.64], T48 = 0.25[IQR:0.08-0.65] MUg/kg/min; PCT: CytoSorb: T0 median = 20.6[IQR: 6.5-144.5], T48 = 5.6[1.9-54.4], p = .004; Control: T0 = 13.2[7.6-47.8], T48 = 9.2[3.8-44.2]ng/mL). Big-endothelin-1 concentrations were also significantly lower in the CytoSorb group (CytoSorb: T0 = 1.3 +/- 0.6, *T24 = 1.0 +/- 0.4, T48 = 1.4 +/- 0.8, *p = .003; Control: T0 = 1.1 +/- 0.7, T24 = 1.1 +/- 0.6, T48 = 1.2 +/- 0.6 pmol/L, p = .115). There were no CytoSorb therapy-related adverse events. CONCLUSIONS: This is the first trial to investigate the effects of early extracorporeal cytokine adsorption treatment in septic shock applied without renal replacement therapy. It was found to be safe with significant effects on norepinephrine requirements, PCT and Big endothelin-1 concentrations compared to controls. TRIAL REGISTRATION: The study has been registered on ClinicalTrials.gov, under the registration number of NCT02288975, registered 13 November 2014. PMID- 30448519 TI - Antimicrobial resistance and molecular characterization of Neisseria gonorrhoeae isolates in Fukuoka, Japan, from 1996 to 2016. AB - OBJECTIVES: We examined the antimicrobial resistance and molecular characteristics of Neisseria gonorrhoeae isolates obtained from 1996 -2005 (n=200) and 2008-2016 (n=200) in Fukuoka, Japan. METHODS: MICs were determined by agar dilution and sequence types (STs) were examined using N. gonorrhoeae multi antigen sequence typing (NG-MAST). Sequencing of the major extended-spectrum cephalosporin (ESC) resistance determinants (penA, mtrR, and ponA) was performed. RESULTS: Increases in the proportion of gonococci with decreased susceptibility or resistance to cefixime (from 18% in 1996-2005 to 46% in 2008-2016) and ceftriaxone (from 2.5% to 4%) were observed. Gonococcal isolates also showed increases in resistance to ciprofloxacin and azithromycin. The 4 most prevalent NG-MAST STs with a multi-drug resistance phenotype were ST2958 (n=18), ST1407 (n=14), ST 6798 (n=12), and ST4015 (n=10). The number of isolates belonging to the 4 STs rose from the first to the second period. Among the 54 isolates belonging to the 4 major STs, 42 (77.8%) contained a penA mosaic allele and 12 (22.2%) a penA non-mosaic allele. The sequence pattern types in the 42 isolates with a penA mosaic allele included type X (64.3%), type XXXIV (33.3%), and a novel pattern type (2.4%). In contrast, all 12 isolates with the penA non-mosaic allele included the sequence pattern type V (100%). CONCLUSION: N. gonorrhoeae isolates with decreased susceptibilities or resistance to ESC have increased over the years, in Fukuoka, Japan. Four major STs with a multi-drug resistance phenotype were identified. These isolates contained a penA mosaic allele or a non mosaic allele in PBP2. PMID- 30448520 TI - Genomic features of a multidrug-resistant Enterobacter cloacae ST279 producing CTX-M-15 and AAC(6')-Ib-cr isolated from fatal infectious stomatitis in a crossed pit viper (Bothrops alternatus). AB - OBJECTIVES: The widespread dissemination of extended-spectrum beta-lactamase producing Enterobacteriaceae has become a major issue in veterinary medicine. However, until now, there has been no report of bacteria with such a phenotype in infected snakes. The aim of this study was to report the first draft genome sequence of an Enterobacter cloacae isolate (SERP1) recovered from a snake with infectious stomatitis. METHODS: The whole genome of E. cloacae strain SERP1 was sequenced on an Illumina NextSeq platform and was de novo assembled using CLC NGS Cell v.10. Data analysis was performed using online tools from the Center of Genomic Epidemiology. RESULTS: The genome size was calculated at 4966856bp, containing a total of 4796 protein-coding sequences. The strain was assigned to sequence type 279 (ST279) and, besides the clinically relevant blaCTX-M-15 and aac(6')-Ib-cr genes, it also presented resistance genes to beta-lactams, aminoglycosides, phenicols, sulphonamides, tetracyclines, trimethoprim, quinolones and fosfomycin. CONCLUSION: These data offer novel information regarding multidrug-resistant E. cloacae dissemination in wild animals and might contribute to further comparative genomic analysis. PMID- 30448521 TI - Co-occurrence of antibiotic resistance and virulence determinants in enterococci isolated from traditionally fermented fish products. AB - OBJECTIVE: Fermented foods frequently consumed in Northeast India can act as reservoir for disseminating pathogenic organisms complicating the treatment option. Enterococci are often responsible for contamination of food products. The present study dealt with investigation on antibiotic resistance in enterococci found in traditionally processed foods and their co-existing virulence determinants. METHOD: Thirty-eight enterococci isolates identified as Enterococcus faecalis isolated from fermented fish were selected for screening of the pathogenic traits. RESULTS: Twenty three percent of the isolates were able to hydrolyse gelatinase and thirty four percent showed protease activity. Haemolytic activity of the isolates had no positive test on sheep blood. The presence virulence genes (gelE, agg, esp, cpd, efaAfs and cyl) were investigated by PCR. gelE, agg and esp were present in 17, 13 and 4 isolates respectively. cpd and efaAfs were found in all the isolates whereas cyl was not detected. Resistance percentage detected to different antibiotics at higher incidence included kanamycin (63%), vancomycin and gentamycin (57.8%), tetracyclin (52.6%) and rifampicin (50%). VanA genotype was confirmed in 15 multidrug and vancomycin resistant strains. CONCLUSION: The simultaneous occurrence of virulence determinants and antibiotic resistance in enterococci prevalent in the studied fermented fish product pose a potential threat of transmission to humans through the food chain. This study highlights the importance of E. faecalis as a reservoir of antibiotic resistance and virulence factors and their potential transfer to humans. The findings reopen the issue of food safety of enterococci prevalent in traditionally processed fish products in the region. PMID- 30448522 TI - The effect of practice on inhibition in task switching: Controlling for episodic retrieval. AB - Previous work has shown that extended practice leads to a reduction in a key measure of cognitive inhibition during task switching: The n-2 task repetition cost. However, it has been demonstrated that this n-2 task repetition cost is increased by a non-inhibitory process-namely episodic retrieval-raising the question of whether the observed reduction of the cost with practice is driven by a reduction in inhibition, episodic retrieval effects, or a combination of both. The current study addresses this question by utilising a practice protocol using a task switching paradigm capable of controlling for episodic retrieval. The results showed a reduction in the n-2 task repetition cost with extended practice. The results also showed a clear increase of the n-2 task repetition cost due to episodic retrieval effects. The reduction of the cost with practice was driven by a reduction in inhibition and episodic retrieval contributions to the cost with practice, although there was a larger reduction in the episodic retrieval contribution with practice. The results are discussed with reference to current theoretical models of inhibition in task switching, which need to accommodate episodic retrieval and practice effects. PMID- 30448523 TI - Direct compression tablet containing 99% active ingredient - a tale of spherical crystallization. AB - Direct compression (DC) is the easiest and most cost-effective process for tablet manufacturing, since it only involves blending and compression. However, active pharmaceutical ingredients (API) generally exhibit poor mechanical and micromeritic properties, which necessitate dilution and the use of high percentage of excipients to enable a robust DC manufacturing process. Consequently, drug loading in DC tablets is usually low (typically < 30%, w/w). In this study, spherical crystallization by the quasi-emulsion solvent diffusion method was used to engineer a poorly flowing model compound, ferulic acid (FA), to attain superior mechanical properties, particle size distribution, and morphology. The engineered FA particles enabled the successful development of DC tablets containing 99% FA, which is in sharp contrast to the maximum 10% FA loading using as-received FA. The record high API loading in this work illustrates the potential for spherical crystallization to overcome low drug loading when developing a tablet product using the DC manufacturing process. PMID- 30448524 TI - Evaluation of Cytochrome P450 Selectivity for Hydralazine as an Aldehyde Oxidase Inhibitor for Reaction Phenotyping. AB - Hydralazine has been reported as a selective mechanism-based inactivator of aldehyde oxidase (AO) and it is widely used in the pharmaceutical industry for reaction phenotyping to estimate fraction metabolized by AO and to identify AO substrates. In this study, however, hydralazine was found to inhibit CYP1A2, 2B6, 2D6 and 3A, in human suspension hepatocytes under reaction phenotyping assay conditions, at concentrations that chemically knocked out most of the AO activities (>= 50 MUM). Furthermore, hydralazine is a time-dependent inhibitor of CYP1A2. Based upon these findings, precautions need to be taken when using hydralazine as an AO inhibitor for in vitro studies since fraction metabolized by AO is likely to be overestimated and the likelihood of false positives in identifying AO substrates increases. PMID- 30448525 TI - ParStream-seq: An improved method of handling next generation sequence data. AB - The exponential growth of next generation sequencing (NGS) data has put forward the challenge for its storage as well as its efficient and faster analysis. Storing the entire amount of data for a particular experiment and its alignment to the reference genome is an essential step for any quantitative analysis of NGS data. Here, we introduce streaming access technique 'ParStream-seq' that splits the bulk sequence data, accessed from a remote repository into short manageable packets followed by executing their alignment process in parallel in each of the compute core. The optimal packet size with fixed number of reads is determined in the stream that maximizes system utilization. Result shows a reduction in the execution time and improvement in the memory footprint. Overall, this streaming access technique provides means to overcome the hurdle of storing the entire volume of sequence data corresponding to a particular experiment, prior to its analysis. PMID- 30448526 TI - Improved cellular uptake of perfluorocarbon nanoparticles for in vivo murine cardiac 19F MRS/MRI and temporal tracking of progenitor cells. AB - Herein, we maximize the labeling efficiency of cardiac progenitor cells (CPCs) using perfluorocarbon nanoparticles (PFCE-NP) and 19F MRI detectability, determine the temporal dynamics of single-cell label uptake, quantify the temporal viability/fluorescence persistence of labeled CPCs in vitro, and implement in vivo, murine cardiac CPC MRI/tracking that could be translatable to humans. FuGENEHD-mediated CPC PFCE-NP uptake is confirmed with flow cytometry/confocal microscopy. Epifluorescence imaging assessed temporal viability/fluorescence (up to 7days [D]). Nonlocalized murine 19F MRS and cardiac MRI studied label localization in terminal/longitudinal tracking studies at 9.4 T (D1-D8). A 4-8 fold 19F concentration increase is evidenced in CPCs for FuGENE vs. directly labeled cells. Cardiac 19F signals post-CPC injections diminished in vivo to ~31% of their values on D1 by D7/D8. Histology confirmed CPC retention, dispersion, and macrophage-induced infiltration. Intra-cardiac injections of PFCE NP-labeled CPCs with FuGENE can be visualized/tracked in vivo for the first time with 19F MRI. PMID- 30448527 TI - Nanonized tetracycline cures deadly diarrheal disease 'shigellosis' in mice, caused by multidrug-resistant Shigella flexneri 2a bacterial infection. AB - We reported earlier about nano-formulation of tetracycline through its entrapment within calcium-phosphate nano-particle (CPNP) and about killing of pathogenic bacterium Shigella flexnari 2a, resistant to tetracycline (and 9 other antibiotics), by the nanonized antibiotic (Tet-CPNP). Here, we report on therapeutic role of Tet-CPNP against deadly diarrheal disease 'shigellosis' in mice, caused by Shigella infection. Our findings revealed that occurrence of mushy-stool excretion, colon-length shortening, weight-loss and bacterial colonization in gastrointestinal tract of mice due to shigellosis was significantly reduced by Tet-CPNP treatment. Histo- and immuno-logical studies showed that changes in morphology and level of inflammatory cytokines TNF-alpha, IL-1beta and IFN-gamma in intestinal tissue of Shigella-infected mice were reverted to almost normal features by Tet-CPNP treatment. Bulk tetracycline had no anti-shigellosis action. Thus, nanonization of tetracycline rejuvenated the old, cheap, broad-spectrum antibiotic from obsolescence (due to resistance generation), making it highly beneficial for diarrhea-prone developing countries with limited health-care budgets. PMID- 30448528 TI - Forensic tri-allelic SNP genotyping using nanopore sequencing. AB - The potential and current state-of-the-art of forensic SNP genotyping using nanopore sequencing was investigated with a panel of 16 tri-allelic single nucleotide polymorphisms (SNPs), multiplexing five samples per sequencing run. The sample set consisted of three single-source human genomic reference control DNA samples and two GEDNAP samples, simulating casework samples. The primers for the multiplex SNP-loci PCR were taken from a study which researched their value in a forensic setting using conventional single-base extension technology. Workflows for multiplexed Oxford Nanopore Technologies' 1D and 1D2 sequencing were developed that provide correct genotyping of most SNP loci. Loci that are problematic for nanopore sequencing were characterized. When such loci are avoided, nanopore sequencing of forensic tri-allelic SNPs is technically feasible. PMID- 30448529 TI - Estimating the postmortem interval using microbes: Knowledge gaps and a path to technology adoption. AB - Microbes have potential to be used as physical evidence for forensic science because they are ubiquitous and have predictable ecologies. With the advent of next generation sequencing technology and the subsequent boost to microbiome science (study of the genes and molecules of microbial communities), it has become possible to develop new microbial-based tools for forensic science. One promising approach is the use of microbial succession during the ecological process of decomposition to estimate the time since death, or postmortem interval (PMI). This microbial clock of death is developed by building a regression model using microbiome data collected from postmortem samples (e.g. swab of skin) with known PMIs. In a death investigation, a similar sample type (e.g. swab of skin) would be collected, the microbes profiled using DNA sequencing, and the microbes would be matched to a point on the clock (i.e. the regression model). Recent research by several independent scientific teams has provided a proof of concept for this new microbiome forensic tool. However, developing and transitioning new forensic science technologies into the justice system requires overcoming scientific, investigative, and legal hurdles. In this article, I address the apparent knowledge gaps in the science of microbiome technology to estimate PMI, and discuss a path for bringing this technology into the justice system. PMID- 30448530 TI - Preference for speech in infancy differentially predicts language skills and autism-like behaviors. AB - Early emerging biases for conspecific vocalizations are a hallmark of early development. Typically developing neonates listen to speech more than many other sounds, including non-biological non-speech sounds, but listen equally to speech and monkey calls. By 3 months of age, however, infants prefer speech over both non-biological non-speech sounds and monkey calls. We examined whether different listening preferences continue to develop along different developmental trajectories and whether listening preferences are related to developmental outcomes. Given the static preference for speech over non-biological non-speech sounds and the dynamic preference for speech over monkey calls between birth and 3 months, we examined whether 9-month-olds prefer speech over non-biological non speech sounds (Experiment 1) and prefer speech over monkey calls (Experiment 2). We compared preferences for sounds in infants at low risk (SIBS-TD) and infants at high risk (SIBS-A) of autism spectrum disorder (ASD), a heterogeneous population who differ from typically developing infants in their preferences for speech, and examined whether listening preferences predict vocabulary and autism like behaviors at 12 months for both groups. At 9 months, SIBS-TD listened longer to speech than to non-speech sounds and listened longer to monkey calls than to speech, whereas SIBS-A listened longer to speech than to non-speech sounds but listened equally to speech and monkey calls. SIBS-TD's preferences did not predict immediate developmental outcomes. In contrast, SIBS-A who preferred speech over non-speech or monkey calls had larger vocabularies and fewer markers of autism-like behaviors at 12 months, which could have positive developmental implications. PMID- 30448531 TI - Thresholds of ultrasound synovial abnormalities for knee osteoarthritis - a cross sectional study in the general population. AB - OBJECTIVE: To establish "normal" ranges for synovial thickness and effusion detected by ultrasound (US) and to determine cut-offs associated with knee pain (KP) and radiographic knee osteoarthritis (RKOA) in the community. METHODS: 147 women and 152 men >=40 years old were randomly selected from the Nottingham KP and Related Health in the Community (KPIC) cohort (n = 9506). The "normal" range was established using the percentile method in 163 participants who had no KP and no RKOA. Optimal (maximum sensitivity and specificity) and high specificity (90%) cut-offs were established using receiver operating characteristic (ROC) curve analysis in a comparison between people with both KP and RKOA and normal controls. RESULTS: Effusion and synovial hypertrophy differed by gender but not by age or laterality, therefore gender-specific reference limits were estimated. However, the "normal" ranges between men and women were similar for effusion (0 10.3 mm vs 0-9.8 mm), but different for synovial hypertrophy (0-6.8 mm vs 0-5.4 mm). Power Doppler Signal (PDS) in the healthy controls was uncommon (1.2% in men and 0.0% in women). The optimal cut-off was 7.4 mm for men and 5.3 mm for women for effusion, and 3.7 and 1.6 for hypertrophy respectively. The high specificity cut-off was 8.9 for men and 7.8 for women for effusion, and 5.8 and 4.2 for hypertrophy respectively. CONCLUSIONS: US effusion and synovial hypertrophy but not PDS are common, but differ by gender, in community-derived people without painful knee OA. Currently used cut-offs for abnormality need reappraisal. PMID- 30448532 TI - Exploring longitudinal associations of histologically assessed inflammation with symptoms and radiographic damage in knee osteoarthritis: combined results of three prospective cohort studies. AB - OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment. PMID- 30448533 TI - Regional gene expression analysis of multiple tissues in an experimental animal model of post-traumatic osteoarthritis. AB - OBJECTIVE: To characterize local disease progression of the medial meniscus transection (MMT) model of post-traumatic osteoarthritis (OA) at the molecular level, in order to establish a baseline for therapeutic testing at the preclinical stage. DESIGN: Weight-matched male Lewis rats underwent MMT or sham surgery on the left limb with the right leg as contralateral control. At 1 and 3 weeks post-surgery, tissues were harvested from different areas of the articular cartilage (medial and lateral tibial plateaus, and medial osteophyte region) and synovium (medial and lateral), and analyzed separately. RNA was extracted and used for microarray (RT-PCR) analysis. RESULTS: Gene expression changes due to surgery were isolated to the medial side of the joint. Gene changes in chondrocyte phenotype of the medial tibial plateau cartilage preceded changes in tissue composition genes. Differences in inflammatory markers were only observed at the osteophyte region at 3 weeks post-surgery. There was surgical noise in the synovium at week 1, which dissipated at week 3. At this later timepoint, meniscal instability resulted in elevated expression of matrix degradation proteins and osteogenic markers in the synovium and cartilage. CONCLUSION: These results suggest feedback interactions between joint tissues during disease progression. Regional tissue expression differences found in MMT joints indicated similar pathophysiology to human OA, and provided novel insights about this degeneration model. The examination of gene expression at a localized level in multiple tissues provides a well-characterized baseline to evaluate mechanistic effects of potential therapeutic agents on OA disease progression in the MMT model. PMID- 30448534 TI - Independent contribution of perceptual experience and social cognition to face recognition. AB - Faces convey rich perceptual and social information. The contribution of perceptual and social information to face recognition has been typically examined in separate experiments. Here, we take a comprehensive approach by studying the contributions of both perceptual experience and social-conceptual information to face learning within the same experimental design. The effect of perceptual experience was examined by systematically varying the similarity between the learned and test face views. Social information was manipulated by asking participants to make social, perceptual, or no evaluations on faces during learning. Results show better recognition for the learned views, which declines as a function of the dissimilarity between the learned and unlearned views. Additionally, processing faces as social concepts produced a general gain in performance of a similar magnitude for both the learned and unlearned views. We concluded that both social-conceptual and perceptual information contribute to face recognition but through complementary, independent mechanisms. These findings highlight the importance of considering both cognition and perception to obtain comprehensive understanding of face recognition. PMID- 30448536 TI - Pseudoacromegaly. AB - Individuals with acromegaloid physical appearance or tall stature may be referred to endocrinologists to exclude growth hormone (GH) excess. While some of these subjects could be healthy individuals with normal variants of growth or physical traits, others will have acromegaly or pituitary gigantism, which are, in general, straightforward diagnoses upon assessment of the GH/IGF-1 axis. However, some patients with physical features resembling acromegaly - usually affecting the face and extremities -, or gigantism - accelerated growth/tall stature - will have no abnormalities in the GH axis. This scenario is termed pseudoacromegaly, and its correct diagnosis can be challenging due to the rarity and variability of these conditions, as well as due to significant overlap in their characteristics. In this review we aim to provide a comprehensive overview of pseudoacromegaly conditions, highlighting their similarities and differences with acromegaly and pituitary gigantism, to aid physicians with the diagnosis of patients with pseudoacromegaly. PMID- 30448535 TI - N6-Methyladenine DNA Methylation in Japonica and Indica Rice Genomes and Its Association with Gene Expression, Plant Development, and Stress Responses. AB - N6-Methyladenine (6mA) DNA methylation has recently been implicated as a potential new epigenetic marker in eukaryotes, including the dicot model Arabidopsis thaliana. However, the conservation and divergence of 6mA distribution patterns and functions in plants remain elusive. Here we report high quality 6mA methylomes at single-nucleotide resolution in rice based on substantially improved genome sequences of two rice cultivars, Nipponbare (Nip; Japonica) and 93-11 (Indica). Analysis of 6mA genomic distribution and its association with transcription suggest that 6mA distribution and function is rather conserved between rice and Arabidopsis. We found that 6mA levels are positively correlated with the expression of key stress-related genes, which may be responsible for the difference in stress tolerance between Nip and 93-11. Moreover, we showed that mutations in DDM1 cause defects in plant growth and decreased 6mA level. Our results reveal that 6mA is a conserved DNA modification that is positively associated with gene expression and contributes to key agronomic traits in plants. PMID- 30448537 TI - MATHEMATICAL PRINCIPLES AND METHODS OF BIOLOGICAL SURFACE LUBRICATION WITH PHOSPHOLIPIDS BILAYERS. AB - This paper presents a mini-review of investigations performed by the authors in the field of hydrodynamic theory of lubrication of biological systems and synthetic processing of results to indicate the influence of biologically live material properties on biological liquid viscosity variations. The goal of the presented study was to demonstrate a new principle of a general mathematical theory applied to the mechanism of hydrodynamic lubrication of human joint cartilage surfaces with phospholipids bilayer and to indicate analytical solutions of hydrodynamic pressure, temperature and bio-fluid velocity components. Moreover, 3D variations of dynamic synovial fluid viscosity are assessed, particularly its variations across the entire film thickness. A new 3D analytical and numerical model has been elaborated on the basis of tribology methods, based on the assumptions of an ultra-thin boundary layer of non Newtonian fluid. The analysed elements also included phospholipid concentrations, power hydrogen ion and collagen fiber concentrations in synovial, biological fluids, as well as electrostatic field, cartilage or biological surface wettability. The obtained results of our analysis demonstrate relationships which occur among hydrodynamic pressure, human joint load carrying capacity and phospholipid bilayer in the cartilage superficial layer. According to the best knowledge of the Authors, the obtained results may find applications in a broad scope of spatiotemporal models in biology and health science. PMID- 30448538 TI - Discovering significantly different metabolites between Han and Uygur two racial groups using urinary metabolomics in Xinjiang, China. AB - The main object of the study was to discover the associated significantly different metabolites between Han and Uygur, two main racial groups in Xinjiang, China with urinary metabolomics. Urine samples from 96 Han and 96 Uygur were analyzed using gas chromatography coupled to mass spectrometry (GCMS). Multivariate analysis was used to investigate the effect of race, age and gender on the urinary metabolomic profiles. Totally eight metabolites are identified contributed to the discrimination between Han and Uygur, including phenylacetylglutamine, myoinositol, d-galactose, ribonolactone, octadecanoic acid, galactitol, threonic acid and succinic acid. The metabolic pathways of them are mainly involved in carbohydrate, TCA cycle, fatty acid and mammalian gut microbial-related metabolism. Importantly, three metabolites, being used as biomarkers in clinic, are also differentially expressed in urine samples of two races. It suggests that the race effect should be critically considered prior to make diagnostic result in multi-race coexisted areas to decrease the false positive rate caused by above biomarkers. Moreover, the results show that the age period and the gender also affect the urinary metabolomics profiles, but with different levels compared to race. We hope that the work can provide some help for developing novel diagnostic tests, understanding the mechanism of disease, designing clinical trials and refining precision medicine in multi-race coexisted areas. PMID- 30448540 TI - Incidence of snakebites in 3 different geographic regions in Thua Thien Hue province, central Vietnam: Green pit vipers and cobras cause the majority of bites. AB - BACKGROUND: The annual incidence of snakebites in Vietnam is not known and only few publications about snakebite envenoming and medically relevant snakes can be found in English language literature. The present community-based surveys provide data on incidence of snakebites in three different geographic regions of Thua Thien Hue (TT Hue) province, central Vietnam and snake species responsible for bites in this region. METHODOLOGY/RESULTS: The cross-sectional community based surveys were conducted from March to July 2017. Multistage cluster sampling was applied and snakebite incidence was calculated at 58 snakebites per 100,000 person-years for the entire province, and 172, 69 and 10 snakebites per 100,000 person-years in the mountainous, coastal and urban region of TT Hue province, respectively. Thirty-one snakebite victims interviewed during the surveys reported 18 (58%) green pit viper bites (Trimeresurus species), 5 (16%) cobra bites (Naja kaouthia, Naja siamensis), 2 (7%) krait bites (Bungarus candidus, Bungarus fasciatus), 2 (7%) red-necked keelback bites (Rhabdophis subminiatus) and 4 bites from unidentified snakes (13%). The outcome was favourable for 28 snakebite victims (90%), two (6%) had minor sequelae and one (3%) victim died after a Malayan krait bite. Two hundred and twenty-one snakebite patients were treated in 9 district hospitals and one central hospital in TT Hue between 2014 and 2016. Eighty green pit vipers (84%), 12 cobras (13%) and 3 kraits (3%) were responsible for bites in 95 patients where snake identification was documented. CONCLUSIONS: Incidence of snakebites is surprisingly low in TT Hue province in central Vietnam in comparison to other regions in Asia, particularly to neighbouring Lao PDR. However, snakebites are still a significant health problem in the mountainous region and green pit vipers and cobras cause the vast majority of bites. PMID- 30448539 TI - Non-targeted metabolomic analysis on multidrug resistance hepatocellular carcinoma cell and reversal effect of annonaceous acetogenins. AB - Multidrug-resistance (MDR) has been shown to play a critical role in the development of many diseases. In this study, we used metabolomic method to evaluate the MDR in hepatocellular carcinoma, and investigate regulatory of annonaceous acetogenins on MDR of hepatocellular carcinoma. Multivariate statistical analysis revealed that the MDR of SMMC 7721 together with changes in glutathione metabolism, arginine and proline metabolism, sphingolipid metabolism. Annonaceous acetogenins impact these metabolism pathways. Metabolic pathway analysis coupled with stoichiometry analysis can be an effective tool to understand MDR mechanism and to potentially find new MDR reversal agents. PMID- 30448541 TI - Identification and development of amino acid oxidases. AB - Amino acid oxidases are an important class of enzymes that mostly participate in the oxidation of amino acids using FAD as a cofactor. Many of them function in the catabolism of amino acids with wider substrate specificities. On the other hand, based on the recent, successful use of the enzymes for diagnoses with new cofactor and mechanism, highly selective enzymes have been screened from Nature, and many new enzymes have been discovered and further characterized by X-ray crystallography. As a result of the screening for amino acid oxidases with biosynthetic or antibiotic functions, l-Trp oxidase, l-Lys oxidases, and Gly oxidase have been found. The pyridoxal phosphate-dependent l-Arg oxidase has the intriguing new activity of hydroxylating unactivated CC bonds. A new amine oxidase was created by the protein engineering of d-amino acid oxidase. Recent developments in the characterization of amino acid oxidases and their applications are summarized. PMID- 30448542 TI - Proteoglycan 4 deficiency protects against glucose intolerance and fatty liver disease in diet-induced obese mice. AB - OBJECTIVE: Proteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. METHODS: Prg4 knockout (KO) mice and wild type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructose water was provided starting from week 13. RESULTS: Prg4 deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: -29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (-49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: -30%; p < 0.05) and lipogenesis (Acc: -21%; p < 0.05 and Scd1: -38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (-56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (-29%; p < 0.01), Pfkm (-21%; p < 0.05) and Hk2 (-39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids ( 46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfalpha (-65%, -81% and -63%, respectively; p < 0.01) than WT mice. CONCLUSION: Prg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease. PMID- 30448543 TI - Androgen receptor (AR)/miR-520f-3p/SOX9 signaling is involved in the altering hepatocellular carcinoma (HCC) cell sensitivity to the Sorafenib therapy under hypoxia via increasing cancer stem cells phenotype. AB - Early studies indicated that the androgen receptor (AR) might play key roles to impact hepatocellular carcinoma (HCC) progression at different stages. Its linkage to hypoxia, a condition that occurrs frequently during the HCC progression, however, remains unclear. Here we found that AR/miR-520f-3p/SOX9 signaling is involved in the altering HCC cells sensitivity to the Sorafenib therapy under hypoxia via increasing the cancer stem cells (CSCs) population. Mechanism dissection revealed that AR might alter the miR-520f-3p/SOX9 signaling through transcriptional regulation via binding to the androgen-response-elements (AREs) on the promoter region of miR-520f, which could then suppress SOX9 mRNA translation via targeting its 3' untranslated region (3'UTR). The in vivo mouse model with orthotopic xenografts of HCC cells also validated the in vitro data, and a human HCC sample survey confirmed the positive linkage of AR/miR-520f 3p/SOX9 signaling to the CSCs population during HCC progression. Together, these preclinical findings suggest that hypoxia may increase the HCC CSCs population via altering the AR/miR-520f-3p/SOX9 signaling, and targeting this newly identified signaling with small molecule of miR-520f-3p may help in the development of the novel therapy to better suppress the HCC progression. PMID- 30448544 TI - Comparison decompression by duraplasty or cerebellar tonsillectomy for Chiari malformation-I complicated with syringomyelia. AB - OBJECTIVE: The current study aimed to assess the two surgical procedures of posterior fossa decompression (PDF) in treating Chiari malformation type I (CM-1) complicated by syringomyelia (SM), and to evaluate the postoperative complications, surgical effects and prognosis. PATIENTS AND METHODS: A retrospective study was performed on 115 adult CM-I patients undergoing surgical treatment from November 2013 to November 2016 in a single comprehensive hospital. These patients underwent the surgical procedure of either posterior fossa decompression with duraplasty (PFDD) or posterior fossa decompression combined with the resection of tonsils (PFDRT) by five experienced neurosurgeon in a single center. The clinical outcomes of these two surgical procedures were evaluated through comparing the clinical data before and 6 months after the operation. RESULTS: A total of 115 patients, including 35 men and 80 women with the mean age of 43.4 +/- 10.1 years (range, 16-60 years), were enrolled in the current study. 37 out of the 115 patients underwent PFDD, while the remaining 78 received PFDRT according to the surgical assessment. The operation time in PFDRT group (159.3 +/- 40.0 min) was higher than that in PFDD group (134.1 +/- 30.8 min) (P < 0.05). Besides, 20 cases in PFDRT group (20/78) developed postoperative dizziness and headache, and such incidence was higher than that in PFDD group (3/37) (P < 0.05). After 6 months of follow-up, a total of 69 patients (88.4%) in PFDRT group had alleviated symptoms, while 31 (83.8%) patients in PFDD group had improved symptoms. Altogether, the SM cavity was reduced in 54 patients (69.2%) in PFDRT group and 29 (78.4%) in PFDD group, respectively, after the operation. No statistical differences in symptom improvement and cavity reduction rate could be witnessed between the two groups. CONCLUSION: Our study suggests that both PFDRT and PFDD can achieve comparable short-term clinical outcomes for adult CM-I patients. Surgical treatment is considered to be a reliable choice for the treatment of adult CM-I patients. Typically, PFDRT may lead to a higher risk of aseptic inflammatory complication. The precise surgical procedure should be selected based on detailed conditions of patients. PMID- 30448545 TI - B cell activation and proliferation increase intracellular zinc levels. AB - Zinc ions serve as second messengers in major cellular pathways, including the regulation pathways of proliferation and their proper regulation is necessary for homeostasis and a healthy organism. Accordingly, expression of zinc transporters can be altered in various cancer cell lines and is often involved in producing elevated intracellular zinc levels. In this study, human B cells were infected with Epstein-Barr virus (EBV) to generate immortalized cells, which revealed traits of tumor cells, such as high proliferation rates and an extended lifespan. These cells showed differentially altered zinc transporter expression with ZIP7 RNA and protein expression being especially increased as well as a corresponding increased phosphorylation of ZIP7 in EBV-transformed B cells. Accordingly, free zinc levels were elevated within these cells. To prove whether the observed changes resulted from immortalization or rather high proliferation, free zinc levels in in vitro activated B cells and in freshly isolated B cells expressing the activation marker CD69 were determined. Here, comparatively increased zinc levels were found, suggesting that activation and proliferation, but not immortalization, act as crucial factors for the elevation of intracellular free zinc. PMID- 30448546 TI - Thermally and photocatalytically active multifunctional porous coatings for high temperature applications. AB - In this study, the thermal catalytic powder mixtures of Mn, Ce and Co oxides supported on Al2O3 were synthesized. In order to obtain thermally active porous coating on the steel substrate, a binder solution produced via sol-gel method was used to bind the synthesized powder. Additionally by incorporation of TiO2 nanoparticles to previously described thermally active coating, both thermally and photocatalytically active multifunctional surfaces were obtained. The self cleaning property and the rate of volatile organic compounds (VOC) degradation of the coatings were studied, in which pyrazine, thiazole, maltol, vanillin and toluene were applied as VOC. In TiO2 applications UV illuminations were applied. In the self-cleaning performance tests using soybean oil, the thermally active coating was slightly better than the TiO2 containing coatings. Under UV illumination, the high rates of VOC (photo) degradation was achieved with the thermally and photocatalytically active coating. PMID- 30448547 TI - Profiling of intracellular and extracellular antibiotic resistance genes in tap water. AB - Antibiotic resistance genes (ARGs) have gained global attention due to their public health threat. Extracelluar ARGs (eARGs) can result in the dissemination of antibiotic resistance via free-living ARGs in natural environments, where they promote ARB transmission in drinking water distribution systems. However, eARG pollution in tap water has not been well researched. In this study, concentrations of eARGs and intracellular ARGs (iARGs) in tap water, sampled at Tianjin, China, were investigated for one year. Fourteen eARG types were found at the highest concentration of 1.3 * 105 gene copies (GC)/L. TetC was detected in 66.7% of samples, followed by sul1, sul2, and qnrA with the same detection frequency of 41.7%. Fifteen iARGs (including tetA, tetB, tetM, tetQ, tetX, sul1, sul2, sul3, ermB, blaTEM, and qnrA) were continuously detected in all collected tap water samples with sul1 and sul2 the most abundant. Additionally, both eARG and iARG concentrations in tap water presented a seasonal pattern with most abundant prevalence in summer. The concentration of observed intracellular sulfonamide resistance genes showed a significantly positive correlation with total nitrogen concentrations. This study suggested that eARG and iARG pollution of drinking water systems pose a potential risk to human public health. PMID- 30448548 TI - Neurotoxin BMAA and its isomeric amino acids in cyanobacteria and cyanobacteria based food supplements. AB - Cyanobacteria are photosynthetic microorganisms distributed globally in aquatic and terrestrial environments. They are also industrially cultivated to be used as dietary supplements, as they have a high nutritional value; however, they are also known to produce a wide range of toxic secondary metabolites, called cyanotoxins. BMAA (beta-methylamino-l-alanine) and its most common structural isomers, DAB (2,4-diaminobutyric acid) and AEG (N-2-aminoethylglycine) produced by cyanobacteria, are non-proteinogenic amino acids that have been associated with neurodegenerative diseases. A possible route of exposure to those amino acids is through consumption of food supplements based on cyanobacteria. The review critically discusses existing reports regarding the occurrence of BMAA, DAB and AEG in cyanobacteria and cyanobacteria-based food supplements. It is shown that inconsistencies in reported results could be attributed to performance of different methods of extraction and analysis applied and in ambiguities regarding determination of soluble and bound fractions of the compounds. The critical aspect of this review aims to grow awareness of human intake of neurotoxic amino acids, while results presented in literature concerning dietary supplements aim to promote further research, quality control as well as development of guidelines for cyanotoxins in food products. PMID- 30448549 TI - Intra-NAPL diffusion and dissolution of a MGP NAPL exposed to persulfate in a flow-through system. AB - Intra-NAPL diffusion is a critical process that can influence NAPL/water mass transfer. A series of physical model experiments was performed to investigate the role of intra-NAPL diffusion on the transient dissolution of a complex multicomponent NAPL subjected to persulfate treatment. To support these observations, a diffusion-based model was developed and calibrated using the experimental data. The experimental results indicated that while persulfate was able to completely degrade dissolved phase components, mass loss after ~410 pore volumes of persulfate flushing was less than the no-treatment system. Intra-NAPL diffusion limitations were not observed in the physical model experiments. A comparison of experimental and simulated results indicated that processes related to persulfate/NAPL interactions restricted mass transfer, and yielded multicomponent mass transfer rate coefficients that were ~30% of those estimated from an equivalent water-flushing experiment. Simulation results showed that a combination of NAPL composition and geometry, and interphase mass transfer rate can yield intra-NAPL diffusion limitations. Remedial technologies that rely on the aggressive flushing of reagents into NAPL zones may give rise to intra-NAPL diffusion limitations, which will directly affect treatment efficiency. PMID- 30448550 TI - Suppression effects of micro-fin surface on the explosive boiling of liquefied gas under rapid depressurization. AB - The boiling liquid expanding vapor explosion (BLEVE) is a most severe hazard in liquefied gas storage and transportation, and its prevention depends on the suppression of the explosive boiling during tank depressurization. This paper proposes an idea of using micro-fin type surface to suppress the explosive boiling, and experimentally investigates the suppression mechanisms and quantitative effects on the explosive boiling. In the experiments, the bubble behaviors on a micro-fin and a smooth surface are observed for phenomenal analysis, and the explosive boiling consequences of the two surfaces are measured for quantitative evaluation. The results show that, the micro-fin surface brings forward the nucleation onset and reduces the boiling region, resulting in a weakened explosive boiling process. Among release pressures of 200 kPa-500 kPa and vent areas of 1.8 cm2-5.3 cm2, the adopted micro-fin surface reduces the boiling-induced pressure rise and the released energy by up to 24.5% and 35.6%, respectively. PMID- 30448551 TI - The capability of commercial CFD code to predict organic peroxide fireball characteristics. AB - Fireballs of liquid organic peroxides differ from those of liquid hydrocarbon fuels. Modified equations for predicting the fireball diameter, height, surface emissive power and the duration in dependence of the fuel mass are presented for di-tert-butyl peroxide. They base on 13 steel drum tests with fuel masses from 10 kg to 168 kg. Moreover, computational fluid dynamics simulations are performed using the laminar flamelet approach and a statistically turbulence treatment. Fireballs involving peroxide from 10 kg to 80 kg were simulated and their properties compared to the experimentally developed models. The deviations of each property are partially compensating each other leading to an adequate prediction of thermal safety distances for both, a time-independent and a time averaged treatment. Simulations prove to be a good tool for predicting thermal radiation hazards of fireball scenarios. PMID- 30448552 TI - Combustion behaviour and dominant shrinkage mechanism of flexible polyurethane foam in the cone calorimeter test. AB - The shrinkage is an important thermal response of flexible polyurethane foam (FPUF) in fire, which couples its first combustion stage and influences the initial fire spread. In this paper the combustion and shrinkage behaviours are quantitatively investigated and the shrinkage mechanisms are discussed. The critical heat flux for the shrinkage is about 13 kW/m2, between the critical heat flux for piloted ignition and that for non-piloted ignition. Above the critical value the shrinkage rate increases linearly with increasing the heat flux. As the foam density decreases both the shrinkage rate and the first peak of Figra curve which reflects the initial fire spread rate increase. The perceptible shrinkage originates from the decomposition via which the struts convert to the melts. Both the shrinking of struts and the gasification play a minor role. The collapse of porous structure, namely the melts filling into the pores to form the tar layer, dominates the shrinkage. The tar is composed of polyols produced after the first decomposition stage. Beneath the tar layer the porous structure is unchanged. To reduce the fire hazards of FPUF by its heat insulation merit it needs to maintain the porous structure at the first decomposition stage. PMID- 30448553 TI - Physical, morphological and chemical modification of Al-based nanofillers in by products of incinerated nanocomposites and related biological outcome. AB - The number of products containing nanomaterials is increasing this last ten years. Information and literature about the end-of-life of nanocomposites often remains partial and does not address the overall fate and transformations of nanoparticles that may affect biological responses. This paper underlines that the physico-chemical features of nanoparticles can be modified by the incineration process and the available toxicological data on pristine nanofillers might not be relevant to assess the modified nanoparticles included in soot. Combustion tests have been performed at lab-scale using a cone calorimeter modified to collect fumes (particulate matter and gas phase) and have been characterized using various techniques. Nanocomposites selected were poly(ethylene vinyl acetate) containing Al-based nanoparticles, i.e. boehmites or alumina. Evaluations of in vitro cytotoxicity responses on pristine nanofillers, soot and residual ash, show that safe boehmite nanoparticles, become toxic due to a chemical modification after incineration process. PMID- 30448554 TI - Ignition sensitivity and flame propagation of zirconium powder clouds. AB - The ignition sensitivity and flame propagation of zirconium powder clouds are investigated with the influence of initial turbulence. The effect of initial turbulence on the zirconium powder explosion is studied by the change of ignition delay time and dispersion pressure. Hartmann apparatus and Godbert-Greenwald furnace are used to evaluate the minimum ignition energy and minimum ignition temperature, respectively. The high-speed camera is used to analyze the flame propagation behaviors of zirconium powder cloud. The experimental results show that the minimum ignition energy is between 1 mJ and 3 mJ and minimum ignition temperature is 503 K. The ignition energy reaches the minimum value of 30 mJ at the 0.7 MPa. The ignition energy with the effect of ignition delay time has revealed the similar rule. The maximum flame speed increases with the increase of dispersion pressure. Although, the instantaneous flame speed with the lowest dispersion pressure (0.4 MPa) is significantly higher than two others in the early stage of flame propagation. PMID- 30448555 TI - MDMA modulates 5-HT1-mediated contractile response of the human internal thoracic artery in vitro. AB - 3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is a popular recreational drug of abuse. In addition to its characteristic psychotropic effects, important cardiovascular effects have been described such as increased blood pressure and heart rate. MDMA was previously shown to behave as a partial agonist on 5 hydroxytryptamine (5-HT) receptors in the human internal thoracic artery in vitro, involving the 5-HT2A subtype. Here, we studied the interaction of MDMA (400, 800 and 1600 MUM) with the following 5-HT receptor agonists: 5 carboxamidotryptamine (5-CT, full agonist for the 5-HT1, 5-HT2, 5-HT5, 5-HT6 and 5-HT7 receptors) and sumatriptan (selective 5-HT1B/1D receptors agonist). The results showed the ability of MDMA to influence the concentration-dependent response of 5-CT (97.3% of maximal reduction for 1600 MUM of MDMA) and sumatriptan (72.43% of maximal reduction for 1600 MUM of MDMA). The lower concentration of MDMA (400 MUM) produced a significant potentiation of the response to sumatriptan thus suggesting an interaction of MDMA with the activation of 5-HT receptors, namely of the 5-HT1 subtype, in the peripheral vasculature. Together our results further support the importance of the affinity of MDMA to 5-HT receptors in the vascular effects of this drug. PMID- 30448556 TI - Overexpression of HIF-1a could partially protect K562 cells from 1,4-benzoquinone induced toxicity by inhibiting ROS, apoptosis and enhancing glycolysis. AB - Benzene is an environmental contaminant which causes hematological diseases. Previously, hypoxia inducible factor-1a (HIF-1a) was found to be involved in benzene-induced hematotoxicity. This study aims to explore whether overexpression of HIF-1a in K562 cell line could influence the toxicity caused by 1,4-BQ. HIF-1a overexpression K562 cell line was constructed with a lentiviral vector. Results showed that HIF-1a was significantly elevated in control K562 cells and HIF-1a overexpression cells exposed to 1,4-BQ. Compared with 1,4-BQ exposed control cells, HIF-1a overexpression blocked cell cycle at G2/M phase, remarkably reduced apoptosis and ROS level. And HIF-1a overexpression caused downregulation of Nox4 and upregulation of Bcl-2. In addition, the lactic acid (LD)/pyruvic acid (PA) ratio was significantly higher in HIF-1a overexpression cells than that in control cells at the same 1,4-BQ dose. Furthermore, significant increases in Glut1, Ldha, Pkm2, Pgk1, Pdk1, Pfkl, Pfkfb3 protein levels was also observed in HIF-1a overexpression cells. Overall, our results indicated that HIF-1a overexpression could alleviate ROS and apoptosis caused by 1,4-BQ through targeting Nox4, Bcl-2 and key enzymes in glycolysis. PMID- 30448557 TI - Poly(ADP-ribose) polymerase-1 promotes expression of miR-155 by the up-regulation of methyl-CpG binding domain protein 2 in TK6 cells exposed to hydroquinone. AB - Hydroquinone (HQ), one of the major metabolites of benzene, can induce aberrant gene expression. MiR-155, a tumor activator, participates in various biological processes, including DNA damage response. However, the molecular mechanism of aberrant miR-155 expression is still not completely elucidated. Here, we investigated the mechanism of abnormal expression of miR-155 induced by poly(ADP ribose)polymerase-1 (PARP-1) expression in HQ-treated TK6 lymphoblastoid cells. We examined the expression of genes related to abnormal expression of miR-155 to explore the reason for this phenomenon. The results of the present study showed that miR-155 was significantly increased and reactive oxygen species (ROS) were decreased in cells treated with HQ for 72 h compared with PBS-treated cells. Meanwhile, E4F1, PARP-1 and PARP-1 related co-regulators (NF-kappaB, HDAC1, and HDAC2), acetylated histone H3 (H3Ac) were increased in a concentration-dependent manner. Experiments for treatment with 5-AzaC (DNMTs inhibitor), TSA (HDACs inhibitor), DOX (to activate PARP-1) or MG132 (proteasome inhibitor) revealed that the MBDs and PARP-1 was positively associated with miR-155 expression. Moreover, in cells treated with HQ in conjunction with PARP-1 knockdown, expression of miR-155, H3Ac and MBD2 protein were decreased, compared with negative control. In conclusion, PARP-1 activates expression of miR-155 via acetylation by regulating MBD2 in TK6 cells exposed to HQ. PMID- 30448558 TI - Dynamics of a capsule flowing in a tube under pulsatile flow. AB - We analyze numerically the behavior of a deformable micro-capsule confined in a pipe under a pulsatile flow. The capsule moves and is deformed by the action of a pulsatile flow inside the tube with a non-null mean velocity. This configuration can be found in the nature and in many bioengineering systems where artificial capsules are driven by micro-pumps through micro-channels. The capsule is considered as a thin hyperelastic membrane, which encloses an internal fluid. As it has been demonstrated in the literature, this model represents a wide range of artificial capsules, for example, the alginate-based capsules, typically used in bioengineering applications. A hybrid isogeometric finite element method and boundary element method based on a T-spline discretization and formulated in the time domain is used to solve the mechanical and hydrodynamical equations. The influence of the relative rigidity of the membrane, frequency and amplitude of the pulsatile flow is studied. Results show that the behavior of the capsule differs from steady flows and it depends strongly on the frequency of the flow and mechanical characteristic of the capsule. PMID- 30448559 TI - Designed for resistance to puncture: The dynamic response of fish scales. AB - Natural dermal armors are serving as a source of inspiration in the pursuit of "next-generation" structural materials. Although the dynamic strain response of these materials is arguably the most relevant to their performance as armors, limited work has been performed in this area. Here, uniaxial tension and transverse puncture tests were performed on specimens obtained from the scales of Asian carp over strain rates spanning seven decades, from 10-4 to 103 s-1. The importance of anatomical variations was explored by comparing the performance of scales from the head, middle and tail regions. In both loading orientations, the scales exhibited a significant increase in the resistance to failure with loading rate. The rate sensitivity was substantially higher for transverse loading than for in-plane tension, with average strain rate sensitivity exponents for measures of the toughness of 0.35 and 0.08, respectively. Spatial variations in the properties were largest in the puncture responses, and scales from the head region exhibited the greatest resistance to puncture overall. The results suggest that the layered microstructure of fish scales is most effective at resisting puncture, rather than in-plane tension, and its effectiveness increases with rate of loading. X-ray microCT showed that delamination of plies in the internal elasmodine and stretching of the fibrils were key mechanisms of energy dissipation in response to puncture loading. Understanding contributions from the microstructure to this behavior could guide the development of flexible engineered laminates for penetration resistance and other related applications. PMID- 30448560 TI - Tribological behavior of Ti-6Al-4V against cortical bone in different biolubricants. AB - Titanium alloys (Ti-6Al-4V) are promising materials as bone implants in clinical surgeries owing to their excellent performances. However, wear debris caused by the tribological behavior of the cortical bone and titanium alloy interface were found to be paramount for implant stability. The contact environment between the cortical bone and Ti-6Al-4V in vivo has been considered to affect the tribological behavior. Currently, the tribological behaviors of bone and Ti-6Al 4V in different biolubricants remain elusive. Therefore, in this work, the tribological behaviors of Ti-6Al-4V plates sliding against bovine cortical bone were investigated in dry sliding and in biolubricants of physiological saline (PS), simulated body fluids (SBF), and fetal bovine serum (FBS). Results show that the friction coefficient and wear rate of the bovine cortical bone and Ti 6Al-4V interface exhibit the same sequence as follows: FBS > SBF > PS > dry sliding. These results are attributed to bone hardness variation and corrosion of different biolubricants. Meanwhile, the effects of normal load and velocity on the tribological behavior of bone and Ti-6Al-4V interface were also investigated in dry sliding and three different biolubricants. Results show that as the normal load is increased and the sliding velocity is decreased, the friction coefficient decreases in dry condition, adhering to the Hertz contact theory. However, according to the boundary lubrication theory, the friction coefficient in three biolubricants correlates positively to the normal load and negatively to the sliding velocity. Moreover, the wear rates of the bone samples increase with the increase in normal load and sliding velocity under dry and biolubrication conditions. Finally, the characterization results indicate that the wear mechanisms of the cortical bone and Ti-6Al-4V interface in dry friction are primarily adhesive and abrasive wear. Further, corrosive wear occurs in biolubrications, apart from adhesive and abrasive wear. PMID- 30448561 TI - Surface functionalization of polylactic acid fibers with alendronate groups does not improve the mechanical properties of fiber-reinforced calcium phosphate cements. AB - Calcium phosphate cements (CPCs) are frequently used as synthetic bone substitute, but their intrinsic low fracture toughness impedes their application in highly loaded skeletal sites. However, fibers can be used to reduce the brittleness of these CPCs provided that the affinity between the fibers and cement matrix facilitates the transfer of loads from the matrix to the fibers. The aim of the present work was to improve the interface between hydrophobic polylactic acid (PLA) microfibers and hydrophilic CPC. To this end, calcium binding alendronate groups were conjugated onto the surface of PLA microfibers via different strategies to immobilize a tunable amount of alendronate onto the fiber surface. CPCs reinforced with PLA fibers revealed toughness values which were up to 50-fold higher than unreinforced CPCs. Nevertheless, surface functionalization of PLA microfibers with alendronate groups did not improve the mechanical properties of fiber-reinforced CPCs. PMID- 30448562 TI - Effect of carbon fiber type on monotonic and fatigue properties of orthopedic grade PEEK. AB - Carbon-fiber reinforced (CFR) PEEK implants are used in orthopedic applications ranging from fracture fixation plates to spinal fusion cages. Documented implant failures and increasing volume and variety of CFR PEEK implants warrant a clearer understanding of material behavior under monotonic and cyclic loading. To address this issue, we conducted monotonic and fatigue crack propagation (FCP) experiments on orthopedic grade unfilled PEEK and two formulations of CFR PEEK (PAN- and pitch-based carbon fibers). The effect of annealing on FCP behavior was also studied. Under monotonic loading, fiber type had a statistically significant effect on elastic modulus (12.5 +/- 1.3 versus 18.5 +/- 2.3 GPa, pitch versus PAN CFR PEEK, AVG +/- SD) and on ultimate tensile strength (145 +/- 9 versus 192 +/- 17 MPa, pitch versus PAN CFR PEEK, AVG +/- SD). Fiber type did not have a significant effect on failure strain. Under cyclic loading, PAN CFR PEEK demonstrated an increased resistance to FCP compared with unfilled and pitch CFR PEEK, and this improvement was enhanced following annealing. Pitch CFR PEEK exhibited FCP behavior similar to unfilled PEEK, and neither material was appreciably affected by annealing. The improvements in monotonic and FCP behavior of PAN CFR PEEK is attributed to a compound effect of inherent fiber properties, increased fiber number for an equivalent wt% reinforcement, and fiber aspect ratio. FCP was shown to proceed via cyclic modes during stable crack growth, which transitioned to static modes (more akin to monotonic fracture) at longer crack lengths. The mechanisms of fatigue crack propagation appear similar between carbon-fiber types. PMID- 30448563 TI - The effect of different preconditioning protocols on repeatability of bovine ACL stress-relaxation response in tension. AB - Mechanical characterization of soft tissues such as ligaments remains challenging. There is variability in the measured material parameters of ligaments, most of which is related to natural tissue variability, but some of it can be a result of using different testing protocols. Generally preconditioning (cyclic loading-unloading) is performed prior to actual tests to reduce the experimental variability. Commonly, preconditioning protocols for ligaments with a small strain level and 10 sinusoidal loading-unloading cycles are used. The effect of preconditioning and its parameters including strain level, number of cycles and number of preconditioning repetitions on the repeatability of tensile stress-relaxation tests are poorly known for knee ligaments. In the present study, forty-eight dumbbell-shaped bovine anterior cruciate ligament (ACL) samples were used to evaluate the repeatability of stress-relaxation response. Different preconditioning protocols with 2% and 6% strain levels and 1, 5 or 10 preconditioning repetitions were applied. After preconditioning, one-step stress relaxation test was carried out twice with an hour resting period in between the tests. The equilibrium stress showed no systematic bias when only one preconditioning repetition was applied (2.0 +/- 3.1% difference and p > 0.05 between repeated tests). Systematic bias in the peak-to-equilibrium stress ratio was not observed when higher strain level and number of repetitions were used (0.5 +/- 1.6% difference and p > 0.05 between repeated tests). In conclusion, the commonly used preconditioning protocol is capable of producing repeatable equilibrium stress levels of bovine ACLs from stress-relaxation tests in tension. However, if repeatable peak-to-equilibrium stress ratio is desirable, higher strain and number of preconditioning repetitions are recommended. PMID- 30448564 TI - The prion protein in neuroimmune crosstalk. AB - The cellular prion protein (PrPC) is a medium-sized glycoprotein, attached to the cell surface by a glycosylphosphatidylinositol anchor. PrPC is encoded by a single-copy gene, PRNP, which is abundantly expressed in the central nervous system and at lower levels in non-neuronal cells, including those of the immune system. Evidence from experimental knockout of PRNP in rodents, goats, and cattle and the occurrence of a nonsense mutation in goat that prevents synthesis of PrPC, have shown that the molecule is non-essential for life. Indeed, no easily recognizable phenotypes are associate with a lack of PrPC, except the potentially advantageous trait that animals without PrPC cannot develop prion disease. This is because, in prion diseases, PrPC converts to a pathogenic "scrapie" conformer, PrPSc, which aggregates and eventually induces neurodegeneration. In addition, endogenous neuronal PrPC serves as a toxic receptor to mediate prion-induced neurotoxicity. Thus, PrPC is an interesting target for treatment of prion diseases. Although loss of PrPC has no discernable effect, alteration of its normal physiological function can have very harmful consequences. It is therefore important to understand cellular processes involving PrPC, and research of this topic has advanced considerably in the past decade. Here, we summarize data that indicate the role of PrPC in modulating immune signaling, with emphasis on neuroimmune crosstalk both under basal conditions and during inflammatory stress. PMID- 30448565 TI - Enhanced AMPA receptor-mediated excitatory transmission in the rodent rostromedial tegmental nucleus following lesion of the nigrostriatal pathway. AB - The GABAergic rostromedial tegmental nucleus (RMTg) has reciprocal connections with the dopaminergic ventral tegmental area and substantia nigra pars compacta (SNc), and is involved in inhibitory control of monoaminergic nuclei. At present, it is not clear whether unilateral 6-hydroxydopamine lesions of the SNc in rats affect AMPA receptor-mediated excitatory transmission in the RMTg. Here we found that lesions of the SNc in rats increased the firing rate of GABAergic neurons and the level of glutamate in the RMTg compared to sham-operated rats. Intra-RMTg injection of AMPA receptor agonist (S)-AMPA increased the firing rate of the GABAergic neurons in both sham-operated and the lesioned rats, while AMPA receptor antagonist NBQX decreased the firing rate of the neurons. Further, intra RMTg injection of (S)-AMPA decreased the levels of dopamine and serotonin in the medial prefrontal cortex (mPFC) in the two groups of rats; conversely, NBQX increased the levels of dopamine and serotonin. Compared to sham-operated rats, the duration of (S)-AMPA and NBQX action on the firing rate of GABAergic neurons in the RMTg and release of doapmine and serotonin in the mPFC was prolonged in the lesioned rats. In addition, lesions of the SNc in rats increased protein expression of t-GluR1 and p-GluR1-S831 subunits compared to sham-operated rats. Therefore, these changes in the lesioned rats are associated with increased release of glutamate and up-regulated expression of GluR1 subunit-containing AMPA receptors in the RMTg, which suggest that degeneration of the nigrostriatal pathway enhances AMPA receptor-mediated excitatory transmission in the RMTg. PMID- 30448566 TI - Impact of C57BL/6 substrain on sex-dependent differences in mouse stroke models. AB - We have recently found significant variation in stroke vulnerability among substrains of C57BL/6 mice, observing that commonly used N-lineage substrains exhibit larger infarcts than C57BL/6J and related substrains. Parallel variation was also seen with respect to sex differences in stroke vulnerability, in that C57BL/6 mice of the N-lineage exhibited comparable infarct sizes in males and females, whereas infarcts tended to be smaller in females than in males of J lineage substrains. This adds to the growing list of recognized phenotypic and genetic differences among C57BL/6 substrains. Although no previous studies have explicitly compared substrains with respect to sex differences in stroke vulnerability, unrecognized background mismatch has occurred in some studies involving control and genetically modified mice. The aims of this review are to: present the evidence for associated substrain- and sex-dependent differences in a mouse permanent occlusion stroke model; examine the extent to which the published literature in other models compares with these recent results; and consider the potential impact of unrecognized heterogeneity in substrain background on the interpretation of studies investigating the impact of genetic modifications on sex differences in stroke outcome. Substrain emerges as a critical variable to be documented in any experimental stroke study in mice. PMID- 30448567 TI - Incidence of cardiovascular disease in familial combined hyperlipidemia: A 15 year follow-up study. AB - BACKGROUND AND AIMS: Familial combined hyperlipidemia (FCHL) is a complex dyslipidemia associated with premature cardiovascular disease (CVD). The present study was conducted to 1) determine the incidence of CVD in FCHL in this era of protocolled, primary prevention; and 2) examine whether cardiovascular risk estimation based on the Systemic Coronary Risk Estimation (SCORE) chart, as proposed in the 2016 ESC/EAS guidelines for the management of dyslipidemia, is justified in FCHL. METHODS: FCHL patients, their normolipidemic (NL) relatives and spouses originally included in our baseline cohort in 1998-2005 (n = 596) were invited for a follow-up visit to determine the incidence of CVD, defined as (non-)fatal coronary artery disease, ischemic stroke and peripheral artery disease requiring invasive treatment. RESULTS: Follow-up data (median: 15 years) was acquired for 85% of the original cohort. The cumulative incidence of CVD was significantly higher in FCHL patients than in spouses (23.6% versus 4.7%; hazard ratio (HR): 5.4, 95%CI: 2.0-14.6; HR after adjustment for risk factors included in SCORE: 4.7, 95%CI: 1.6-13.8), but not in NL relatives compared to spouses (5.8% versus 4.7%). The SCORE chart tended to overestimate CVD risk in the spouses (observed [O]/expected [E] ratio:0.2, p = 0.01), but not in FCHL patients (O/E:1.3, p = 0.50). CONCLUSIONS: Risk of primary CVD is still substantially increased in FCHL patients, despite preventive measures. The overestimation of CVD risk by the SCORE chart - a nowadays frequently observed phenomenon thanks to improved primary prevention - was not seen in FCHL. These results suggest that more aggressive treatment is justified to avoid excessive CVD in FCHL. PMID- 30448568 TI - The combined utility of myeloperoxidase (MPO) and paraoxonase 1 (PON1) as two important HDL-associated enzymes in coronary artery disease: Which has a stronger predictive role? AB - BACKGROUND AND AIMS: Serum paraoxonase 1 (PON1) and myeloperoxidase (MPO) are HDL associated enzymes that contribute significantly to the formation of dysfunctional HDL. The present study thus seeks to comparatively analyze the predictive role of PON1, MPO and the MPO/PON1 ratio and to also evaluate which one has a stronger predictive role in their combined utility as an MPO/PON1 ratio in coronary artery disease (CAD). METHODS: PON1 activity and MPO concentrations were determined in patients with established CAD and those without significant CAD. Receiver operating characteristic (ROC) curves were drawn by plotting true positivity versus false positivity. RESULTS: The ROC curve analyses showed that PON1 (AUC = 61%, p = 0.003) and MPO/PON1 (AUC = 60%, p = 0.01) have a better diagnostic performance than MPO (AUC = 50%, p = 0.42) in detecting patients with CAD. PON1 and MPO/PON1 were found to have a significantly stronger discriminatory power for the age range >=52 and < 60 years (AUC = 69%, p = 0.008 for PON1; AUC = 66%, p = 0.022 for MPO/PON1). The multivariate analysis revealed PON1 as an independent variable that was significantly associated with the multi-vessel disease [odds ratio (OR) = 0.98; p = 0.017]. At the cutoff point of 30 MUmol/mL/min for PON1 and 1.85 for MPO/PON1, specificities were 97% and 73% and sensitivities 30% and 54% for discriminating patients with single-vessel disease from non-CAD subjects. CONCLUSIONS: The diagnostic performance of PON1 alone was comparable to that of the MPO/PON1 ratio for CAD risk assessment; however, MPO may increase the true positive rate. A larger number of blocked vessels seems to be associated with an increased predictive power for both PON1 and MPO/PON1. Recent data support the fact that PON1 and MPO may potentially be appropriate therapeutic targets for preventing CAD. PMID- 30448569 TI - Deep Brain Stimulation of Nucleus Accumbens for Methamphetamine Addiction: Two Case Reports. AB - Methamphetamine (MA) addiction is one of the most prevalent socioeconomic and health problems worldwide. In recent years, deep brain stimulation (DBS) has increasingly been used for the treatment of addiction. This study reports on two MA-dependent patients who received DBS of the nucleus accumbens (NAc). During the approximately two-year follow-up period, one patient (A) remained abstinent and presented with positive emotional experiences, while the other (B) had no significant psychobehavioral changes during stimulation at low to moderate voltages and subsequently relapsed. Through co-registration of preoperative MRI with postoperative CT/MRI, the DBS electrode of patient (A) was confirmed to be accurately implanted in the NAc, while one side of the electrode of patient (B) deviated from the target. These case reports demonstrate that NAc-DBS maybe a possible treatment option for MA addiction. PMID- 30448570 TI - A bibliometric analysis of the top 100 influential papers on carotid artery stenting. AB - BACKGROUND: Artery stenting is an effective therapy for carotid artery stenosis to prevent ischemic stroke. We aimed to identify and analyze the 100 top-cited papers published on carotid artery stenting (CAS), to provide the achievements and development in this field. METHODS: Web of Knowledge (WoS) was searched up to May 3, 2018, using the terms "carotid artery stenting" or "CAS". Top 100 cited papers were extracted to analyze their characteristics. RESULTS: Citation number of top 100 cited papers ranged from 120 to 1,813, with an accumulated citation of 26,265. They were from 13 countries, with USA owning the most publications (n = 62), followed by UK (n = 11), Germany (n = 6) and Italy (n = 6). Stroke (n = 21) is the leading producing journal, followed by Journal of Vascular Surgery (n = 11) and Journal of the American College of Cardiology (n = 10). Papers with higher impact factor were likely to be cited more (P ? 0.0001). These publications were categorized in: clinical trials (n = 74), review (n = 13), basic study (n = 5), guideline (n = 5), commentary (n = 1), expert consensus (n = 1) and protocol (n = 1). CONCLUSIONS: This study provides the scientific performances in CAS. USA contributed to the most publications. Stroke was the leading productive journal. Papers with higher impact factor were likely to be cited more. PMID- 30448571 TI - The effect of re-neurorrhaphy of the distal coaptation on nerve regeneration after nerve grafting:an animal experimental study. AB - INTRODUCTION: Previous studies have shown that re-neurorrhaphy of a distal coaptation at an appropriate time after nerve grafting can upregulate neurotrophins in rat spinal cord neurons. The objective of the present study was to evaluate the effect this procedure has on peripheral nerve regeneration. METHODS: Fifteen Wistar rats were randomly assigned to sham-surgery, control, or experimental (transection and re-repair of the distal coaptation of the grafting nerve) groups. The sciatic nerve was evaluated via electromyogram (EMG) and histology at 20 weeks. RESULTS: When crossing the proximal coaptation of the grafting nerve, the EMG and histological evaluations did not significantly differ between experimental and control groups (P > 0.05). In contrast, crossing the distal coaptation yielded significantly better values (P < 0.05) in the experimental group. CONCLUSION: These results indicate that re-neurorrhaphy of the distal coaptation at an appropriate time after nerve grafting can improve nerve function and facilitate the regeneration of axons. PMID- 30448572 TI - The Honest Palm Sign: Detecting Incomplete Effort on Physical Exam. AB - OBJECTIVE: We investigated a simple, novel diagnostic test for detecting incomplete effort during the motor portion of the neurologic examination. METHODS: The Honest Palm Sign (HPS) was evaluated in 162 consecutive neuro oncology patients undergoing upper extremity strength testing. Deltoid, bicep, and wrist extensor strength were assessed in all patients. During the exam, patients were repeatedly encouraged to "try as hard as possible", and to "resist with all your strength". The absence of nail prints on the palms constituted a positive HPS test result (indicative of incomplete effort). The presence of nail prints constituted a negative HPS test result (indicative of full effort). RESULTS: One hundred and sixty-two patients were tested. Mean age was 55.5 years (SD 14.9), median Karnofsky Performance Score was 80 (60-100), and 63 patients (39%) were male. One hundred and two patients (63%) had malignant gliomas, 28 (17%) had brain metastases, 21 (13%) had other primary brain tumors, and 11 (6.8%) had primary central nervous system lymphomas. Forty-eight patients (30%) had a positive HPS. Test sensitivity (84.6%), specificity (75.2%), positive likelihood ratio (3.41) and negative likelihood ratio (0.205) were good. After excluding 33 patients with characteristics that made them unsuitable for testing, results from the remaining 129 patients were analyzed. Sensitivity was unchanged (84.6%), but specificity (96.6%), positive likelihood ratio (24.5), and negative likelihood ratio (0.16) improved dramatically. CONCLUSIONS: The Honest Palm Sign test is a simple, sensitive, very specific test for detecting incomplete effort during the motor portion of the neurologic evaluation. PMID- 30448573 TI - Predictors of failure of non-operative management following subaxial spine trauma and creation of the modified subaxial injury classification (mSLIC) system. AB - INTRODUCTION: Subaxial cervical spine injuries may be treated with either non operative stabilization or surgical fixation. The subaxial injury classification (SLIC) provides one method for suggesting degree of necessity for surgery. In the current study, we examined if the SLIC score, or other pre-operative metrics, can predict failure of non-operative management. METHODS: We performed a retrospective chart review to identify patients that presented with acute non penetrating subaxial cervical spine injury within our health system between 2007 2016. Patient demographics, medical co-morbidities, injuries, and treatments were collected. Logistic regression analysis was used to determine potential predictors of failure of non-operative management. RESULTS: During the study period, 40 patients met the inclusion criteria. A small subset of patients failed non-operative management (n=5,12.5%). The mean SLIC score was 3.9+/-1.9, however 14 (35%) patients had scores greater than 4. Neither total SLIC score (p=0.68) nor SLIC sub-scores (morphology [p=0.96], discoligamentous complex [p=0.83], neurological status [p=0.60]) predicted failure of non-operative treatment. Time to evaluation/treatment did predict failure of non-operative management. Evaluation within 8h of injury was a negative predictor of failure (OR=0.03,p=0.001) and evaluation 24h or more after injury was a positive predictor of failure (OR=66.00,p<0.001). We created a modified SLIC score (mSLIC) based on these findings. mSLIC significantly predicted failure of non-operative management (p=0.044). CONCLUSION: The management of subaxial spine injuries is complex. In our cohort, SLIC scoring did not adequately predict odds of failure of non-operative management. Time to evaluation, however, did. We created a modified SLIC score that significantly predicted failure of non-operative management. PMID- 30448574 TI - Anterior transcorporeal approach to percutaneous endoscopic cervical discectomy for single-level cervical intervertebral disc herniation:a case series with 2 year follow up. AB - OBJECTIVE: To examine the effects of anterior transcorporeal percutaneous endoscopic cervical discectomy (ATPECD) for the treatment of single-level CIDH with a focus on its safety, feasibility, clinical efficacy, and specific possible complications. METHODS: A series of 35 patients with symptomatic single-level cervical intervertebral disc herniation (CIDH) were enrolled to be treated with ATPECD. Neck and arm pain was measured using the visual analog scale (VAS). The quality of life was measured using the bodily pain and physical function on the SF-36. The average disc height and the vertical vertebral body height were recorded. Bone healing was evaluated based on postoperative computed tomography. RESULTS: Successful removal of the herniated disc was confirmed in all 35 cases. At 2 years, the patients showed a significant treatment effect in the VAS and the body pain and physical function portions of the SF-36 (1.14+/-0.60 vs. 7.62+/ 0.61, 63.92+/-6.74 vs. 32.55+/-6.80, and 82.14+/-6.22 vs. 34.43+/-4.50, respectively, p<0.01). Mean pre-operative disc height was 6.79 +/- 0.37 mm, which decreased to 6.34 +/- 0.46 mm at 2 years post-operation (6.6% decrease). Pre operative surgical VB height also decreased from pre-operation (15.79 +/- 0.52 mm) to 2 years post-operation (15.12 +/- 0.38 mm) (4.2% decrease). 3 surgery related complications were observed (8.6%). CONCLUSION: Preliminary clinical experience with ATPECD shows that it is safe, effective, feasible, and minimally invasive. Although it has some disadvantages, such as the need for repeated fluoroscopy, some minor complications, and non-symptomatic disc height decreases, ATPECD can supplement minimally invasive surgeries in selected cases of CIDH. PMID- 30448575 TI - Bullough's lesion: an unexpected diagnosis after the resection of a slowly growing osseous-like retroauricular bump. Case report and review of the literature. AB - We describe the case of a 33 years old woman with a history of over 15 years of a slow growing firm osseous-like right retroauricular mass. Surgical resection was easily performed using a sharp technique, due to a clear cleavage plane. The histological diagnosis was a rare, unexpected, protuberant fibro-osseous lesion named "Bullough lesion". Only few cases of this benign pathological entity have been described in English literature. Clinical differential diagnosis must be done with osteoma, periosteal chondroma, and other fibro-osseous lesions such as fibrodysplasia and ossifying fibroma and. Due to the paucity of data, natural history of this lesion is unknown and serial clinical and radiological follow-up is advised. PMID- 30448576 TI - Use of Recombinant Human Bone Morphogenetic Protein-2 at the C1-2 Lateral Articulation Without Posterior Structural Bone Graft in Posterior Atlantoaxial Fusion in Adult Patients. AB - INTRODUCTION: Posterior atlantoaxial fusion is an important armamentarium for neurosurgeons to treat several pathologies involving the craniovertebral junction. Although the potential advantages of recombinant human bone morphogenetic protein -2 (rhBMP-2) are well-documented in the lumbar spine, its indication in C1-2 fusion has not been well-characterized. In our institution, we apply rhBMP-2 to the C1-2 joint either alone or with hydroxyapatite, locally harvested autograft chips, and/or morselized allogenic bone graft for selected cases - without conventional posterior structural bone graft. Here, we will report the clinical outcomes of the surgical technique to elucidate its feasibility. METHODS: Single-center, retrospective data review from 2008 to 2016 identified 69 patients who underwent posterior atlantoaxial fusion with rhBMP-2. Clinical records of these patients were reviewed and clinical data such as baseline characteristics, operative data, and postoperative complications were collected and statistically analyzed. RESULTS: The average age of 69 patients was 60.8 +/- 4.5 (female: 55.1%). With the average follow-up period of 21.1 +/- 4.2 months, C1-2 fusion rate was 94.3% (65/69), and the time-to-fusion was 11.4 +/- 2.6 on average [range: 5-23]. The overall reoperation rate was 10.1% (7/69), which was attributed to instrumentation failure (seven patients, 10.1%), adjacent segment disease (two patients, 2.9%), and postoperative dysphagia and dyspnea (two patients, 2.9%). No ectopic bone formation or soft-tissue edema was observed in our cohort. CONCLUSIONS: Albeit retrospective, single-center nature of the study, the use of rhBMP-2 at the C1-2 joint without posterior structural bone graft was deemed a safe, reasonable surgical option. PMID- 30448577 TI - Neuroendoscopic intraoperative ultrasound-guided ("nius") technique for paraventricular tumors biopsy: technical note. AB - Different tumors can be encountered in the paraventricular regions and while their deep location often make these lesions difficult to access surgically, they may be amenable to chemotherapy and/or radiotherapy. Therefore, tumor biopsy and histologic diagnosis are mandatory to optimize treatment. Different technical procedures have been recommended, being the neuroendoscopic approach an accepted and diffused one, in particular in a context of enlarged ventricular system. However, when dealing specifically with paraventricular tumors, tissue sampling may be challenging hence, in such scenario, the use of intraoperative ultrasound technique could add some advantages regarding diagnostic accuracy and procedure safety. Accordingly, in this study we described a novel technical procedure in 7 selected patients consisting in performing tumor tissue biopsy in a coupled neuroendoscopic and ultrasound-guided environment; we defined a so-called "NIUS" technique (Neuroendoscopic Intraoperative UltraSound technique). The main advantages of this technique involved the identification of the tumor that may not been clearly identified underneath the ventricular ependymal through the neuroendoscopic window alone; further, such technique gives the possibility to detect the depth of the needle advance in the selected tissue while labeling the lesion beneath the ventricular ependyma. Moreover, intraoperative ultrasonography could reveal in a real-time fashion intracranial hemorrhages that may occur after tissue biopsy therefore providing a useful tool to achieve a valid and directed hemostasis when needed. PMID- 30448578 TI - Utility of video ICG to detect the cortical entry point of a draining vein with a superficial vein during AVM surgery. AB - Resection of brain arteriovenous malformation is challenging particularly if the feeder arteries and draining vein are not directly visible on the surface. Indocyanine green video angiography can assist detection of the connecting point of the draining vein with the superficial vein and can thus localise the cortical entry point for AVM resection. Here, we present a case of a 27-year-old man with headache. CT scan showed right occipital atypical bleeding. CTA and DSA confirmed the cortical AVM fed by the posterior cerebral artery (PCA) branches. We decided on surgical treatment because the small PCA feeders were not easily accessible for endovascular treatment. We used an OPMI PENTERO 900 microscope (Carl Zeiss, Germany) to perform microsurgical resection of AVM. We present an illustrative video showing the surgical approach, microsurgical anatomy, and technical aspects of the utility of video ICG in deep cortical small AVM surgery. Video ICG assisted detection of the cortical arterialised draining vein that was anasthamosed with a sprawled superficial vein. This enabled a customised approach for the AVM resection. Post-surgical video ICG showed normalised flow in the superficial vein supporting the complete resection of AVM. Indocyanine angiography is potentially helpful for detecting the cortical entry point of a deep draining vein with a sprawled superficial vein. ICG should be used as an adjunct to better understand the microvascular anatomy that may aid decision making during AVM surgery. PMID- 30448579 TI - Challenges in the management of a ruptured bihemispheric posterior inferior cerebellar artery aneurysm. AB - BACKGROUND: Bihemispheric posterior inferior cerebellar artery (PICA) is a rare anatomical variant, wherein a single PICA supplies both cerebellar hemispheres. Being the only PICA, treatment of aneurysms arising from this anatomical variant is more complex. We present a case of a ruptured bihemispheric PICA aneurysm and the challenges encountered in its management. CASE DESCRIPTION: A 54-year-old man presented with giddiness and nausea. Otherwise, he was neurologically intact. CT brain showed a right cerebellar hematoma and intraventricular hemorrhage. Cerebral angiogram revealed a dissecting aneurysm in the retromedullary segment of a right- bihemispheric PICA with a prominent saccular component. Initially, the patient refused to undergo any invasive treatment. However, when a follow-up angiogram showed increase in the aneurysm-sac size, he consented for treatment. Although parent vessel occlusion (PVO) was the clinical recommendation, in view of the patient's apprehensions, only the saccular component of the aneurysm was coil-embolized without parent vessel sacrifice. Fifteen days from the coiling, there was a rebleed from this dissecting aneurysm that was treated with PVO followed by suboccipital craniectomy. He made a reasonable recovery and was MRS1 at 6-month follow-up. CONCLUSION: In dissecting aneurysms of a bihemispheric PICA, isolated endosaccular occlusion provides uncertain protection from a rebleed while a more reliable treatment with PVO carries unpredictable risk of ischemic complications. The risks of a PVO may be rationalized as a life-saving measure; however, subsequent threshold for posterior fossa decompression should be low. PMID- 30448580 TI - Neuroprotective Effects of Hesperidin on Cerebral Vasospasm Following Experimental Subarachnoid Haemorrhage in Rats: Biochemical, Pathological and Histomorphometric Analysis. AB - We examined the protective effects of hesperidin on cerebral vasospasm by establishing an experimental rat model of subarachnoid haemorrhage and performing biochemical, pathological and histomorphometric analysis on these data. Forty albino Wistar rats were randomly divided into five groups of n = 8 in each: Group (G)1, no experimental interventions; G2, subjected to subarachnoid haemorrhage; G3, subjected to subarachnoid haemorrhage and administered saline (100 mg/kg); G4, subjected to subarachnoid haemorrhage and treated with low dose hesperidin (50 mg/kg); G5, subjected to subarachnoid haemorrhage and treated with high dose hesperidin (100 mg/kg). Subarachnoid haemorrhage was created by injecting 0.15 cc of autologous blood taken from the rat-tail artery and injected into the cisterna magna from the craniocervical junction. Drugs were administered intraperitoneally as twice daily doses for 48 h. Rats were sacrificed at the end of this period. No statistically significant decrease was observed in malondialdehyde levels, which is the end-product of lipid peroxidation, among the drug groups (G4 and G5). Thin sections prepared from the basilar artery were examined morphologically. Severe luminal narrowing and vessel-wall thickening were observed in the subarachnoid haemorrhage groups (G2, G3). In the hesperidin-administered groups (G4, G5), it was determined that vessel-wall-thickness measurements revealed thinner walls than in the subarachnoid-haemorrhage groups (G2, G3) and the luminal diameters were significantly larger than in the subarachnoid-haemorrhage groups (G2, G3). These findings suggest that hesperidin has no effect on malondialdehyde associated lipid-peroxidation activity; however, it might be useful in subarachnoid-haemorrhage therapy because of its beneficial effects on vessel-wall thickness and luminal diameters. PMID- 30448581 TI - Long-term Supratentorial Radiological Effects of Surgery and Local Radiation in Children with Infratentorial Ependymoma. AB - OBJECT: Current standard of care for children with infratentorial ependymoma includes maximal safe resection and local radiation of 54-59gy. High-dose local radiation has been associated with declines in multiple cognitive domains. The anatomic and physiologic correlates of this cognitive decline remain undefined and there have been no radiographic studies on the long-term effects of this treatment paradigm. METHODS: A comprehensive database of pediatric brain tumor patients treated at Stanford Children's from 2004-2016 was queried. Seven patients with posterior fossa ependymoma were identified who were treated with surgery and local radiation alone, who had no evidence of recurrent disease, and had imaging suitable for analysis. Diffusion-weighted MRI (DWI) datasets were used to calculate apparent diffusion coefficient (ADC) maps for each subject, while arterial spin labeling (ASL) datasets were used to calculated maps of cerebral blood flow (CBF). DWI and ASL datasets of 52 age-matched healthy children were a analyzed in the same fashion to enable group comparisons. RESULTS: Several statistically significant differences were detected between the two groups. CBF was lower in the caudate and pallidum and higher in the nucleus accumbens in the ependymoma cohort compared to controls. ADC was increased in the thalamus and trended towards decreased in the amygdala. CONCLUSIONS: Surgery and local radiation for posterior fossa ependymoma are associated with supratentorial ADC and CBF alterations, which may represent an anatomic and physiologic correlate to the previously published decline in neurocognitive outcomes in this population. PMID- 30448582 TI - Long-term efficacy and tolerability of gamma knife radiosurgery for growth hormone-secreting adenoma: A retrospective multi-center study (MERGE -001). AB - OBJECTIVE: Little is known about the long-term efficacy, prognostic factors and tolerability of gamma knife radiosurgery (GKS) for acromegaly. The aim of this study is to investigate long-term hormonal effects, prognostic factors and tolerability of GKS in patients with GH-secreting adenoma. METHODS: Retrospective multi-center study over 25 years with a median follow-up of 85.2 months was performed. A total of 138 patients from three tertiary referral centers in South Korea were included in this study between 1991 and 2017. Main outcome measures were endocrine remission, endocrine control under somatostatin analogues, and hypopituitarism. RESULTS: With a mean follow-up period of 85.2 months (range, 12 304 months), overall median time to the endocrine remission and control under long-acting somatostatin analogues was 138 months and 96 months, respectively. Female sex, normal age-adjusted IGF-I <=2 and GKS as an adjuvant treatment were significantly favorable factors for remission (P = 0.004, P = 0.001, P = 0.010, respectively). Early response group had a significantly lower proportion of normal age-adjusted IGF-I level >2 than did late response group (22.2% vs. 51.7%, P = 0.035), even though lower radiation dose (24.3 Gy vs. 27.0 Gy, P = 0.003). The incidence of GKS-induced hypopituitarism (one or more) was 12 of 138 patients (8.6%) at the last follow-up. CONCLUSIONS: In acromegalic patients, women with normal age-adjusted IGF-I <=2 and GKS as an adjuvant treatment have a better response to GKS. We should take into account the variability of radiosensitivity of the tumor according to the gender and IGF-I level. PMID- 30448583 TI - "Temporary " short segment fixation in treating Adolescent lumbar spondylolysis. AB - OBJECTIVE: To introduce a new operation for isthmic spondylolysis in teenagers and to evaluate its clinical efficacy. METHODS: Thirty cases of teenage isthmic spondylolysis patients with chronic low back pain underwent "temporary" short segmental pedicle screw combined with transverse device fixation and isthmic bone graft repair treatment. X-ray and CT images were evaluated during the regular follow-up to confirm successful bone graft fusion, after which the fixation was removed. Lumbar MRI examination was performed before and 1 year after the fixation operation and 1 year after the removal operation. Modic grading and Pfirrmann grading standards were used to observe the effect of "temporary" fixation on the corresponding vertebral endplate and the intervertebral disc. RESULTS: Thirty cases have complete follow-up, on average 2 years. The low back pain symptoms disappeared completely, and X-ray and CT imaging showed that the isthmuses in all patients achieved bony fusion. As internal fixation was removed, the fixed segment motion recovered. "Temporary" rigid internal fixation did not increase the corresponding vertebral endplate or intervertebral disc degeneration. CONCLUSION: "Temporary" short-segmental pedicle screw combined with transverse device fixation is a simple and effective method for teenage isthmic spondylolysis with rigid internal fixation and accelerated bone graft fusion. PMID- 30448584 TI - The relationship between colloid transfusion during surgical decompression hemicraniectomy period and post-operative pneumonia or long-term outcome after space-occupying cerebral infarction: A retrospective study. AB - BACKGROUND: The colloid transfusion during surgical decompressive hemicraniectomy (DHC) after space-occupying cerebral infarction induced by middle cerebral artery (MCA), is controversial. A multicenter retrospective study was conducted to determine whether or not an increased colloid transfusion during surgery is associated with lower incidence of post-operative pneumonia and better long-term outcomes after space-occupying cerebral infarction. METHOD: Data from surgical DHC within 48 h to treat space-occupying cerebral infarction that took place between Nov. 30th 2013 and Nov. 30th 2016 were collected in a multicenter chart. Univariate analysis, spearman correlation, chi-square test, bivariate and multivariate logistic regression, were performed to account for the associations between colloid transfusion and post-operative pneumonia or long-term outcomes (indicated by Modified Rankin scores [MRS]). RESULTS: Univariate analysis showed that surgical duration and MRS were significantly difference between the subjects older and younger than 60 years who underwent surgical DHC (P<0.05). In the entire population studied, increased National Institutes of Health stroke scale (NIHSS) was associated with higher incidence of post-operative pneumonia (OR =1.255, P=0.003) and increased MRS (OR =1.229, P=0.014). In the population aged greater than 60 years, it was revealed that increased colloid transfusion was associated with lower incidence of post-operative pneumonia (OR =0.761, P=0.030) or better outcomes indicated with lower MRS (OR =0.837, P=0.045). CONCLUSION: Our retrospective study demonstrated that there is a robust association between increased peri-operative colloid transfusion and lower incidence of post operative pneumonia and better outcomes among the patients older than 60 years after space-occupying cerebral infarction. PMID- 30448585 TI - Spondylocostal dysostosis (Jarcho-Levin syndrome) in an adult patient with consanguineous parents, in long-term follow-up. AB - A 24-year-old female presented to neurosurgical consultation for chronic back pain. The patient was long-term in wheelchair for vertebral deformity. She was the third child of first-degree consanguineous parents. The two older brothers had also vertebral malformations. The radiological images showed butterfly vertebra, vertebral fusion, hemivertebrae, scoliosis, rib malformation. The patient was in follow-up for restrictive lung disease. Motor evoked potentials and lower limbs electromyography were normal. We recommended conservative treatment for the back pain with antalgic and physical therapy. Diagnosis of spondylocostal dysostosis (SCD), or Jarcho-Levin syndrome was made based on radiological features. Radiological mages are pathognomonic. SCD is a rare hereditary disorder associated with multiple vertebral and rib anomalies. The entity is distinct from spondylothoracic dysostosis, which has a higher mortality due to respiratory complications. The patient was not compliant for genetic familiar counseling. At 12-years follow-up, the patient was in periodic respiratory and motor rehabilitation therapy. PMID- 30448586 TI - Intraspinal inclusion tumor after myelomeningocele repair. A long-term single center experience. AB - OBJECTS: Given the lack of significant responses to many queries regarding behavior, treatment options and possible preventions of iatrogenic intraspinal inclusion tumors (IITs), we think that further clinical, radiological and follow up data are mandatory to better characterize this entity. We retrospectively reviewed a series of 14 consecutive patients affected by IIT occurred after myelomeningocele repair. The long follow-up is a mainstay of this series, that may help to better understand the history of this slow-growing disease. To date, this is the largest series of IITs after myelomeningocele repair reported in the literature. METHODS: A retrospective chart review was performed to identify all cases of surgically repaired myelomeningocele at the Department of Neurosurgery of G. Gaslini Children's Hospital in Genoa, from January 1993 to January 2018. Among them, data regarding patients who developed a IIT were recovered. The medical records of these patients and clinical history, neurological examination, and diagnostic workup were reviewed. RESULTS: From January 1993 to January 2018, 160 cases of myelomeningocele were surgically treated. Among them, 14 cases of IIT developed. The mean time between myelomeningocele repair and IIT diagnosis was 94,7 months. The mean follow-up time was 60,1 months. CONCLUSIONS: It is well documented that IITs may be discovered in patients who had previously undergone myelomeningocele repair. In our series, we report with a long follow up time, the possible range of behavior of such lesions and the utility of surgical treatment of primary therapy. Our series confirms that residual IIT show marked stability during our long follow-up. PMID- 30448587 TI - Kidney and thyroid cancer-specific treatment algorithm for spinal metastases: a validation study. PMID- 30448588 TI - Pneumoventricle of Unknown Origin: A Personal Experience and Literature Review of a Clinical Enigma. AB - Pneumocephalus (PC) is an uncommon and life-threatening neurological condition. Air within the ventricular system of the brain is also known as Pneumoventricle (PV). It requires emergency treatments to prevent catastrophic neurological outcomes. Head injury is the most common cause of PV, but there are other well recognized etiologies in case there is no clear radiological evidence of skull discontinuity. Although this clinical entity has been well described in Literature, our report presents the unique feature of describing a purely ventricular PC without evidence of skull base or cranial vault fracture. Therefore, this case presentation explores mysterious causes of fistulous connections with the atmosphere that may lead to air trapped in and around the cranial vault. The aim of the present paper is to report a case of post-traumatic PV without radiological signs of skull base or convexity fracture in a 72-years old man, underlining the diagnostic and clinical features, and review the relevant Literature. PMID- 30448589 TI - Transclinoid-Transcavernous Approach to A Giant Cavernous Sinus Hemangioma: 2 Dimensional Operative Video. AB - This operative video demonstrates a transclinoid-transcavernous approach for the resection of a cavernous sinus hemangioma. The patient is a 42-yr-old female who presented with headache and blurred vision. Magnetic resonance imaging (MRI) demonstrated an enhancing mass in the right-side cavernous sinus and sella. The patient underwent an orbito-zygomatic craniotomy, extradural anterior clinoidectomy and transcavernous approach for tumor resection. Removal of the orbital roof, lateral orbital wall, zygomatic arch and anterior clinoid process with a high-speed drill was performed. Lateral wall of cavernous sinus was opened via interdural dissection and a large reddish tumor was encountered. The tumor was resected after circumferential dissection and coagulation. The cranial nerve III, IV, and V were found and preserved. The surgical cavity was closed with abdominal fat to prevent cerebral-spinal fluid leak. The bone flap was put back and fixed with titanium mesh, plates and screws, the wound was closed in layers using sutures. The blurred vision relieved immediately after surgery. The patient got temporary right-side oculomotor nerve palsy which was partially resolved after 6 months. There were no other complications. Final pathology was consistent with a cavernous sinus hemangioma. Postoperative MRI demonstrated near total resection except for a small piece of residual in the sella, which was stable in 6-months follow-up MRI scan without further treatment. The patient has been back to normal life and work. PMID- 30448590 TI - Understanding toxicological implications of accidents with caterpillars Megalopyge lanata and Podalia orsilochus (Lepidoptera: Megalopygidae). AB - Megalopygids Megalopyge lanata and Podalia orsilochus are common causative agents of accidents in agricultural workers. These accidents are provoked by dermal contact at their larval stage and are characterized by cutaneous reactions, such as burning pain, edema and erythema, typically mild and self-limited. There is very little information about their venoms and their toxicological implications on human health. Thus, we employed proteomic techniques and biological assays to characterize venoms (bristle extracts) from caterpillars of both species collected from Misiones, Argentina. The electrophoretic profiles of both venoms were substantially different, and they presented proteins related to toxicity, such as serinepeptidases, serpins and lectins. P. orsilochus venom exhibited higher caseinolytic activity than M. lanata venom, agreeing with the fact that only P. orsilochus venom hydrolyzed human fibrin(ogen). In addition, the latter shortened the clotting time triggered by calcium. While the venom of M. lanata induced a mild inflammatory lesion in mouse skin, P. orsilochus venom caused prominent necrosis, inflammatory infiltration and hemorrhage at the site of venom injection. On the other hand, P. orsilochus venom was better recognized by Lonomia obliqua antivenom, although many of its proteins could not be cross reacted, what may explain the difference in the clinical manifestations between accidents by Podalia and those by Lonomia. Altogether, this study provides relevant information about the pathophysiological mechanisms whereby both caterpillars can induce toxicity on human beings, and paves the way for novel discovery of naturally occurring bioactive compounds. PMID- 30448591 TI - The effects of bacterial endotoxin (LPS) on cardiac function in a medicinal blow fly (Phaenicia sericata) and a fruit fly (Drosophila melanogaster). AB - The bacterial endotoxins, lipopolysaccharides (LPS), are known to have direct effects on mammalian heart cells; thus, LPS is likely to have some effects in other cardiac models. Drosophila melanogaster was used since it serves as a model for cardiac physiology. Larvae of blow flies (Phaenicia sericata) commonly used as therapy for debriding dead tissue, are exposed to high levels of bacterial endotoxins, but their mechanisms of LPS resistance are not entirely understood. Comparative effects of LPS on heart rate (HR) were examined for both Drosophila and blowfly larvae. Acute 10-min direct exposure of in situ heart tubes with saline containing 1, 100, and 500 MUg/ml LPS from two common bacterial stains (Pseudomonas aeruginosa and Serratia marcescens) revealed a dose-dependent effect. The effects differed between the two fly models. Larval hearts of Drosophila stopped rapidly in low Ca2+ containing saline, but the hearts of blow flies appear unaffected for >30 min. S. marcescens increased HR initially in Drosophila followed by a reduction for low and high doses, but no change was observed in larvae of blow flies. Whereas P. aeruginosa at a high dose decreased HR in larvae of Drosophila but increased HR in larvae of blow flies. The goal of this study is to better the understanding in the direct action of LPS on HR. Knowing the acute and direct actions of LPS exposure on HR in different species of larvae may aid in understanding the underlying mechanisms in other animals during septicemia. PMID- 30448592 TI - Phylogenetic Analysis Reveals that the 'Radial Centric' Diatom Orthoseira Thwaites (Orthoseiraceae, Bacillariophyta) is a Member of a 'Multipolar' Diatom Lineage. AB - The diatom genus Orthoseira Thwaites (Bacillariophyta) is a ubiquitous taxon in aerial diatom assemblages, with species found globally. Cylindrical cell shape and radial symmetry of this genus has led to its historical placement in the Coscinodiscophyceae ('radial centric' diatoms), but its systematic relationships have remained uncertain. We present a five-gene phylogeny, based on nuclear (nSSU rDNA) and chloroplast (rbcL, psbC, psbA, and psaB) genes to determine the phylogenetic placement of Orthoseira among the diatoms. The concatenated multi gene phylogenies and nSSU-only gene tree demonstrate that Orthoseira is deeply embedded within a clade of the Mediophyceae ('multipolar centric' diatoms). Throughout all phylogenetic analyses, Orthoseira was shown to be sister to the genera Terpsinoe and Hydrosera. Through comparison of topologies reflecting competing hypotheses about the placement of Orthoseira, it was determined that the hypothesis that Orthoseira, represented here by O. dendroteres and O. roeseana, is a member of the Melosirales should be rejected. Therefore, lack of morphological similarity between Hydrosera, Orthoseira, and Terpsinoe is hypothesized to be the result of changes in habitat preferences that lead to an ancient divergence event between the Orthoseirales and the Hydrosera, Terpsinoe clade. PMID- 30448593 TI - Sex Difference in Celiac Disease in Undiagnosed Populations - a Systematic Review and Meta-Analsysis. AB - BACKGROUND AND AIMS: A higher proportion of female vs male patients receive a diagnosis of celiac disease. Little is known about sex-based differences in the prevalence of celiac disease in undiagnosed populations. We aimed to address this knowledge gap with a systematic review and meta-analysis. METHODS: We searched MEDLINE, Embase, Cochrane, and Scopus databases through 2017 for studies of screen-detected or undiagnosed celiac disease. Our final analysis included studies that included screening and confirmatory tests (either second serologic analysis or a small intestine biopsy) and provided information on sex of participants. Studies were excluded if they were performed with specific, high risk, or referral populations. The primary outcome was percentage of undetected celiac disease among female and male patients. RESULTS: We identified 4070 articles and analyzed data from 87. Our meta-analysis comprised data from 291,969 study participants. The pooled prevalence of undetected celiac disease in female participants was 0.589% (95% CI, 0.549%-0.629%) and in male participants was 0.415% (95% CI, 0.343%-0.487%). The risk of undetected celiac disease was higher among female than male participants (relative risk [RR] 1.42, 95% CI, 1.27-1.57; P<0.00001). The I2 was 5% (low heterogeneity among studies). In subgroup analyses, the RR of celiac disease for girls vs boys was 1.79 (95% CI, 1.44-2.22; P<0.00001; I2 = 18%), the RR for female vs male blood donors was 1.13 (95% CI, 0.76-1.69; P=0.54; I2 = 0), and the RR for women vs men with villous atrophy was 1.38 (95% CI, 1.07-1.79; P=0.01; I2 = 0). CONCLUSION: In a systematic review and meta-analysis, we found a higher risk for celiac disease in women than men in undiagnosed populations (identified through general population screening). The increased risk for celiac disease among girls and women should be considered for screening, diagnosis, and management strategies. PMID- 30448594 TI - Validation of Serum Test for Advanced Liver Fibrosis in Patients with Nonalcoholic Steatohepatitis. AB - BACKGROUND & AIMS: We analyzed markers of fibrosis in serum samples from patients with nonalcoholic fatty liver disease (NAFLD), assessed by liver biopsy. We used serum levels of markers to develop an algorithm to discriminate patients with advanced fibrosis from those with mild or moderate fibrosis and validated its performance in 2 independent cohorts of patients with NAFLD. METHODS: We performed a retrospective analysis of serum samples from 396 patients with NAFLD and different stages of fibrosis (F0-F4), collected from 2007 through 2017 on the day of liver biopsy (training cohort 1). We measured serum concentrations of alpha-2 macroglobulin (A2M), hyaluronic acid (HA), and TIMP metallopeptidase inhibitor 1 (TIMP1), and used measurements to develop an algorithm that could discriminate patients with NAFLD with advanced fibrosis (F3-F4; 24.1% of cohort) from those with mild or moderate fibrosis (F0-F2; 79.5% of cohort). We validated the algorithm using serum samples collected from a separate 396 patients from the same time period and location (validation cohort 1), as well as 244 patients with NAFLD evaluated at a separate location, from 2011 through 2017, within a median of 11 days of liver biopsy (cohort 2). RESULTS: The algorithm identified patients with advanced fibrosis vs mild or moderate fibrosis in training cohort 1 with an area under the receiver operating characteristic (AUROC) curve of 0.867 (95% CI, 0.827-0.907), 84.8% sensitivity (95% CI, 75.5%-91.0%), and 72.3% specificity (95% CI, 66.9%-77.3%), at a cutoff score of 17. The AUROC for the combined validation cohorts 1 and 2 (n=640) was 0.856 (95% CI, 0.820-0.892), identifying patients with 79.7% sensitivity (95% CI, 71.9%-86.2%) and 75.7% specificity (95% CI, 71.8% 79.4%) at the predetermined cutoff score of 17. The algorithm had negative predictive values that ranged from 92.5% to 94.7% in the validation cohorts; it correctly classified 90.0% of F0 samples, 75.0% of F1 samples, 77.4% of F3 samples, and 94.4% of F4 samples. CONCLUSION: We developed an algorithm that identifies patients with advanced fibrosis from those with mild to moderate fibrosis in patients with NAFLD with an AUROC value of approximately 0.86, based on levels of serum biomarkers. We validated the findings in two separate sets of patients with biopsy-proven NAFLD. The algorithm can be used non-invasively to determine risk of advanced fibrosis in patients with NAFLD. PMID- 30448595 TI - An intramucosal buried clip after endoscopic submucosal dissection. PMID- 30448596 TI - Pathology characterization and detection of human papillomavirus type 16 in rectal squamous cell carcinomas. PMID- 30448597 TI - Serum Concentrations of 7alpha-hydroxy-4-cholesten-3-one are Associated with Bile Acid Diarrhea in Patients with Crohn's Disease. AB - BACKGROUND & AIMS: Patients with Crohn's disease (CD) often have bile acid diarrhea (BAD), due to bile acid malabsorption following ileal resection (IR). Bile acid malabsorption increases production of 7alpha-hydroxy-4-cholesten-3-one (C4), a bile acid precursor. We investigated relationships between serum concentrations of C4 and BAD in patients with CD. METHODS: We collected demographic data, serum samples, and information on the presence of diarrhea (>3 liquid bowel movements/day), as well as clinical, endoscopic, and histologic scores from 26 patients with CD and IR, 21 patients with CD without IR, and 37 patients with ulcerative colitis (UC). We compared serum concentrations of C4 and fibroblast growth factor 19 (FGF19) between groups. We performed area under the receiver operating characteristic curve (AUROC) analysis to identify the optimal cutoff C4 concentrations for the diagnosis of diarrhea attributable to bile acid malabsorption (BAD), defined as diarrhea and a serum concentration of FGF19 <60 pg/mL. RESULTS: Patients with UC had a median serum C4 concentration of 11.8 ng/mL, whereas patients with CD and IR with ileitis (documented endoscopically) had a median concentration of 100.0 ng/mL (P compared to UC<.0001) and patients with CD and IR without ileitis had a median concentration of 51.6 ng/mL (P compared to UC<.001). Patients with CD without IR did not have a significantly higher median concentration of C4 than patients with UC (P=.71), regardless of ileitis (P=.34). When endoscopic findings were confirmed histologically, similar results were found to analyses using endoscopic findings alone. A higher proportion of patients with active UC had diarrhea (72.0% vs 0 patients with inactive UC; P<.001), but their median concentrations of C4 did not differ significantly from that of patients with inactive UC (12.1 ng/mL vs 9.7 ng/mL; P=.3). A cutoff concentration of C4 of 48.3 ng/mL or greater identified patients with diarrhea attributable to bile acid malabsorption with 90.9% sensitivity, 84.4% specificity, and an AUROC 0.94. A significantly higher proportion of patients with concentrations of C4 above this cutoff had BAD (50.0%) than below this cutoff (1.8%) (P<.001). When we analyzed only patients with diarrhea, a C4 cutoff of 48.3 ng/mL identified those with low FGF19 concentrations (<60 pg/mL) with 91% sensitivity and 95.5% specificity (AUROC, 0.99). Above this cutoff, 83.3% of patients had a serum concentration of FGF19 <60 pg/mL compared to 4.5% below this threshold (P<.0001). C4 concentrations correlated with the number of daily bowel movements (r=0.41; P=.004) and correlated inversely with FGF19 concentrations (r= -0.72; P<.0001). CONCLUSION: We observed significantly increased serum concentrations of C4 in patients with CD with IR, compared to patients with UC. A cutoff concentration of C4 above 48.3 ng/mL identifies patients with diarrhea likely attributable to bile acid malabsorption (BAD) with an AUROC value of 0.94. Increased serum levels of bile acid precursors identify patients with diarrhea and a low serum concentration of FGF19, and concentrations of C4 correlate with daily liquid bowel movements and correlate inversely with FGF19 concentrations. C4 may be a biomarker to identify patients with diarrhea attributable to bile acid malabsorption. PMID- 30448599 TI - Upfront Combination Therapy, Compared with Monotherapy, for Patients Not Previously Treated with a Biologic Agent Associates With Reduced Risk of Inflammatory Bowel Disease-related Complications in a Population-based Cohort Study. AB - BACKGROUND & AIMS: Although guidelines recommend inclusion of immune modulators in anti-tumor necrosis factor (TNF) initiation therapy for Crohn's disease (CD) or ulcerative colitis (UC), there are limited data on the incremental effectiveness of this treatment strategy from the real world. METHODS: We collected data from the Manitoba Inflammatory Bowel Disease (IBD) Epidemiology database on persons with CD (n=852) or UC (n=303), from 2001 through 2016, who began treatment with a TNF antagonist. New and/or continuing users of immunomodulators at the time anti-TNF therapy began were considered recipients of combination therapy. The main outcome was treatment ineffectiveness (IBD-related hospitalization, intestinal resection, corticosteroid use, or change of anti-TNF agent) during TNF antagonist-based therapy or within 90 days after the anti-TNF agent was discontinued. We used Cox proportional hazards models to assess the association between concomitant use of immunomodulators and treatment ineffectiveness RESULTS: In patients with CD, combination therapy was associated with a significant decrease in likelihood of treatment ineffectiveness (adjusted hazard ratio [aHR] for ineffectiveness, 0.62; 95% CI, 0.49-0.79). However, this association was not significant in patients with UC (aHR, 0.82; 95% CI, 0.56 1.20). In patients with CD, combination therapy was also associated with increased time to first IBD-related hospitalization (aHR 0.53; 95% CI, 0.36-0.80) and switching anti-TNF agents (aHR, 0.63; 95% CI, 0.41-0.97), but not associated with IBD-related surgery (aHR, 0.76; 95% CI, 0.51-1.12) or new or recurrent use of corticosteroids (aHR, 0.75; 95% CI, 0.55-1.04). CONCLUSION: In an analysis of a database of real-world patients with IBD, we associated initiation therapy with a combination immune modulators and anti-TNF agents with a decreased likelihood of treatment ineffectiveness for patients with CD but not UC. PMID- 30448598 TI - Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic HBV Infection. AB - BACKGROUND & AIMS: Besifovir dipivoxil maleate (BSV) has activity against hepatitis B virus (HBV). We performed a phase 3 study to compare the antiviral efficacy and safety of BSV vs tenofovir disoproxil fumarate (TDF) in patients with chronic HBV infection in Korea. METHODS: We conducted a double-blind, non inferiority trial of 197 patients with chronic HBV infection at 22 sites in South Korea, from November 2013 through February 2016. Patients were randomly assigned to groups given BSV (150 mg, n = 99) or TDF (300 mg, n = 98) for 48 weeks. We evaluated virologic responses to therapy (HBV DNA <69 IU/mL or 400 copies/ml), bone mineral density (BMD), and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks. RESULTS: After 48 weeks of treatment, 80.9% of patients given BSV and 84.9% of patients given TDF met the efficacy endpoint, indicating the non inferiority of BSV to TDF. At week 96, 87.2% of patients in the BSV-BSV and 85.7% of patients in the TDF-BSV had a virologic response. At week 48, changes in hip and spine BMD differed significantly between the BSV and TDF groups, whereas the estimated glomerular filtration rate in the TDF group was significantly lower than that in the BSV group. However, at 96 weeks, there were no significant differences in BMD and estimated glomerular filtration rate between the BSV-BSV and TDF-BSV groups. CONCLUSIONS: BSV has antiviral efficacy comparable to that of TDF after 48 weeks of treatment, with durable effects for 96 weeks. BSV has a better safety profile than TDF, in terms of bone and renal outcomes. ClinicalTrials.gov no: NCT01937806. PMID- 30448601 TI - Statin Use is Associated with Improved Outcomes of Patients With Primary Sclerosing Cholangitis. AB - BACKGROUND & AIMS: There is increasing evidence that statins can benefit patients with chronic liver diseases, but their effects have not been studied in patients with primary sclerosing cholangitis (PSC). We performed a nationwide study in Sweden to determine the effects of exposure to drugs, including statins, in patients with PSC. METHODS: We studied a population-based cohort of patients in Sweden with PSC and concomitant ulcerative colitis or Crohn's disease from 2005 through 2014 (n=2914), followed through 2016. We collected analyzed data from the patient register, the prescribed drug register, the death certificate register and the cancer register. We calculated risk or death, liver transplantation, bleeding of esophageal varices, and cancer in relation to drug exposure. RESULTS: The mean age of patients at the time of diagnosis with PSC was 41.4 years (inter quartile range [IQR], 25.6-56.1 years). The total follow-up time was 11769 person years, during which 3.4% of patients received liver transplants and 19.9% died. Proportions of patients exposed to drugs were: ursodeoxycholic acid, 60.2%; 5 aminosalicylic acid, 74.4%; azathioprine or mercaptopurins, 33.7%; and statins, 13.9%. Statin use was associated with a reduced risk of all-cause mortality (hazard ratio [HR], 0.68; 95% CI, 0.54-0.88) and death or liver transplantation (HR, 0.50; 95% CI, 0.28-0.66). Use of azathioprine was also associated with reduced mortality (HR, 0.66; 95% CI, 0.52-0.84) and risk of death or liver transplantation (HR, 0.65; 95% CI, 0.50-0.83). Exposure to ursodeoxycholic acid did not affect mortality (HR, 1.04; 95% CI, 0.87-1.25). CONCLUSION: In a population-based cohort of patients in Sweden with PSC, we associated use of statins and azathioprine with decreased risks of death and death or liver transplantation. Exposure to ursodeoxycholic acid was not associated with reduced mortality. PMID- 30448600 TI - Prevalence and Severity of Nonalcoholic Fatty Liver Disease (NAFLD) Among Caregivers of Patients with NAFLD Cirrhosis. PMID- 30448602 TI - Fatal accidental asphyxia in the reverse jack-knife position on a chair with wheels. PMID- 30448603 TI - Extensive gastric necrosis secondary to acute gastric dilatation: A case report. AB - We report a case of sudden death in a patient who developed extensive gastric necrosis secondary to acute gastric dilatation. A 36-year-old man with mental retardation (but without difficulties in activities of daily living), developed an illness after a meal out with friends, necessitating 3 hospital visits. He returned home after receiving drug therapy; however, his condition deteriorated, and he was transferred to our hospital via ambulance. Whole-body computed tomography performed upon admission revealed gastric dilatation. A stomach tube was inserted, and 2000 mL of gastric aspirate was obtained. The patient died approximately 5 h later despite receiving treatment. Autopsy revealed 1000 mL of gastric contents and extensive gastric necrosis. He was diagnosed with extensive gastric necrosis secondary to acute gastric dilatation. PMID- 30448604 TI - Dietary replacement of fish-meal impaired protein synthesis and immune response of juvenile Pacific white shrimp, Litopenaeus vannamei at low salinity. AB - An 8-week feeding trial was conducted to evaluate the effect of fish-meal replacement on growth performance, protein synthesis and immune response of juvenile Pacific white shrimp, Litopenaeus vannamei reared at low salinity (70/00). Five isonitrogenous and isolipidic diets were formulated to contain graded levels (25, 20, 15, 10 and 5%) of fish-meal. High quality alternative solutions were performed, crystalline amino acids, phytase, mannan oligosaccharides and some micro-nutrients were supplemented in the low fish-meal diets. Each diet was randomly assigned to triplicate tanks, each tank with 30 shrimp (mean weight 0.3 g), the shrimp were fed 3 times a day. Weight gain and survival were decreased with the decreasing dietary fish meal levels. When dietary fish-meal decreased, the gene expression of TOR, Raptor and eIF4E2 in hepatopancreas were decreased with the decreasing fish meal levels, eIF4E2 in intestine was decreased while 4E-BP was increased with the decreasing fish meal levels. The mRNA level of SOD in hepatopancreas decreased, and the expression of GPx and CAT increased with the decreasing FM levels. The Toll pathway was affected by dietary FM levels, the expression of Toll2, TNFSF, MyD88, Rho and p38 in intestine were increased with the decreasing FM levels. The results indicated that at low salinity condition, fish meal level lower than 15% would inhibit the protein synthesis and harm to the health of shrimp. PMID- 30448605 TI - Correction. PMID- 30448606 TI - Reproductive factors, obesity and risk of colorectal cancer in a cohort of Asian women. AB - BACKGROUND: This study evaluated reproductive factors and obesity in relation to colorectal cancer (CRC) in Asian women. METHODS: The study cohort comprised 28191 women who were recruited between 1994 and 1997. During 18 years of prospective follow-up, 404 and 212 women developed colon cancer (CC) and rectal cancer (RC) respectively. Cox proportional hazards regression was used. RESULTS: Menstrual factors were not related to the risk of CRC, CC and RC. Gravidity and parity were not associated with CRC or RC, but women who were ever pregnant had a HR of 1.87 (95%CI 1.12-3.14) compared to those never pregnant, and parous women had a HR of 1.79 (95% CI 1.10-2.92) compared to nulliparous women for CC. Use of oral contraceptives and hormone replacement therapy were not associated with CRC, CC or RC. Compared to women with normal BMI, women who were obese had HRs of 1.39 (95%CI 1.12-1.74) and 1.64 (95%CI 1.24-2.16) for CRC and CC respectively. No increased risk was seen for RC. Adjusted for BMI, for colonic cancer, women in the highest quartile for Waist Circumference had a HR of 2.14 (95%CI 1.42-3.25) compared to the lowest quartile, for Waist Hip Ratio, a HR of 1.74 (95%CI 1.30 2.34), and for Waist-Height ratio, a HR of 1.80 (1.26-2.57). None of these measures were significantly associated with RC. CONCLUSIONS: Obesity is positively associated with CC but not RC, and abdominal obesity exerts an independent effect. Reproductive factors had at best a weak effect on CC and RC. PMID- 30448607 TI - Phosphatidylinositol 3-Kinase/Akt signal pathway resists the apoptosis and inflammation in human extravillous trophoblasts induced by Porphyromonas gingivalis. AB - Epidemiological studies suggested that periodontitis is a risk factor for pregnancy complications including preterm birth. Porphyromonas gingivalis, a vital periodontal pathogen found in amniotic fluid and intact membranes of women who deliver preterm low birth weight infants, is thought to contribute to preterm labor. However, molecular and cellular interactions between P. gingivalis and placental cells are not clear. In this study, we investigated the effect of P. gingivalis on human extravillous trophoblasts and observed that it triggered apoptosis and inflammation and that Akt was activated in this process. In addition, when Akt activation was inhibited, apoptosis and inflammation was significantly increased. Thus, P. gingivalis infection contributes to preterm low birth weight infants by triggering excessive inflammation and increasing apoptosis in trophoblasts and that the Phosphatidylinositol 3-Kinase/Akt signaling pathway is involved in the regulation of Pg-induced apoptosis and inflammation. PMID- 30448608 TI - HLA-G, -E and -F regulatory and coding region variability and haplotypes in the Beninese Toffin population sample. AB - HLA-G/E/F genes exhibit immunomodulatory properties and are expressed in placenta. Little attention has been devoted to the study of these genes in sub Saharan African populations, which are yet the most diverse. To fill this gap, we evaluated the complete gene variability, approximately 5.1 kb for HLA-G (n = 149), 7.7 kb for HLA-E (n = 150) and 6.2 kb for HLA-F (n = 152) in the remote Beninese Toffin population, using massive parallel sequencing. Overall, 96, 37 and 68 variable sites were detected along the entire HLA-G, -E and -F, respectively, arranged into region-specific haplotypes; i.e., promoter haplotypes (16, 19, and 15 respectively), coding haplotypes (19, 15, and 29 respectively), 3' untranslated region (3'UTR) haplotypes (12, 7 and 2, respectively) and extended haplotypes (33, 31 and 32 respectively). All promoter/coding/3'UTR haplotypes followed the patterns already described in worldwide populations. HLA E was the most conserved, exhibiting mainly two full-length encoded-molecules (E*01:01 and E*01:03), followed by HLA-F, three full-length proteins (F*01:01, F*01:02 and F*01:03) and HLA-G, four proteins: three full-length (G*01:01, G*01:03 and G*01:04) and one truncated (G*01:05N). Although HLA-G/E/F alleles in the Toffin population were the most frequently observed worldwide, the frequencies of the coding haplotypes were closely similar to those described for other African populations (Guinea-Conakry and Burkina-Faso), when compared to non African ones (Brazilian), indicating that variable sites along these genes were present in Africa before human dispersion. PMID- 30448609 TI - Immuno-informatics based approaches to design a novel multi epitope-based vaccine for immune response reinforcement against Leptospirosis. AB - Leptospirosis is known as a zoonotic disease of global importance originated from infection with the spirochete bacterium Leptospira. Although several leptospirosis vaccines have been tested, the vaccination is relatively unsuccessful in clinical application despite decades of research. Therefore, this study was conducted to construct a novel multi-epitope based vaccine against leptospirosis by using Hap1, LigA, LAg42, SphH and HSP58 antigens. T cell and IFN gamma epitopes were predicted from these antigens. In addition, to induce strong CD4+ helper T lymphocytes (HTLs) responses, Pan HLA DR-binding epitope (PADRE) and helper epitopes selected from Tetanus toxin fragment C (TTFrC) were applied. Moreover, for boosting immune response, Heparin-Binding Hemagglutinin (HBHA), a novel TLR4 agonist was added to the construct as an adjuvant. Finally, selected epitopes were linked together using EAAAK, GPGPG, AAY and HEYGAEALERAG linkers. Based on the predicted epitopes, a multi-epitope vaccine was construct with 490 amino acids. Physico-chemical properties, secondary and tertiary structures, stability, intrinsic protein disorder, solubility, and allergenicity of this vaccine construct were assessed by applying immunoinformatics analyses. A soluble, and non-allergic protein with a molecular weight of 53.476 kDa was obtained. Further analyses validated the stability of the chimeric protein and the predicted epitopes in the chimeric vaccine indicated strong potential to induce B-cell and T-cell mediated immune response. Therefore, immunoinformatics analysis showed that the modeled multi-epitope vaccine can properly stimulate the both T and B cells immune responses and could potentially be used for prophylactic or therapeutic usages. PMID- 30448610 TI - Mechanisms and functions of IL-17 signaling in renal autoimmune diseases. AB - Immune-mediated glomerular diseases (glomerulonephritis) encompass a heterogeneous collection of diseases that cause inflammation within the glomerulus and other renal compartments with significant morbidity and mortality. In general, CD4+ T cells orchestrate the immune response and play a unique role in autoimmune and chronic inflammatory diseases. In particular, the characterization of a distinct, IL-17 cytokines producing CD4+ T cell subset named TH17 cells has significantly advanced the current understanding of the pathogenic mechanisms of organ-specific immunity. Our group and others have shown that the recruitment of TH17 cells to the inflamed kidney drives renal tissue injury in experimental and possibly human crescentic glomerulonephritis (GN), but much remains to be understood about the biological functions, regulation, and signaling pathways of the TH17/IL-17 axis leading to organ damage. Here we review our current knowledge about the mechanisms and functions of IL-17 signaling in renal autoimmune diseases, with a special focus on experimental and human crescentic GN. PMID- 30448611 TI - Brain age from the electroencephalogram of sleep. AB - The human electroencephalogram (EEG) of sleep undergoes profound changes with age. These changes can be conceptualized as "brain age (BA)," which can be compared to chronological age to reflect the degree of deviation from normal aging. Here, we develop an interpretable machine learning model to predict BA based on 2 large sleep EEG data sets: the Massachusetts General Hospital (MGH) sleep lab data set (N = 2532; ages 18-80); and the Sleep Heart Health Study (SHHS, N = 1974; ages 40-80). The model obtains a mean absolute deviation of 7.6 years between BA and chronological age (CA) in healthy participants in the MGH data set. As validation, a subset of SHHS containing longitudinal EEGs 5.2 years apart shows an average of 5.4 years increase in BA. Participants with significant neurological or psychiatric disease exhibit a mean excess BA, or "brain age index" (BAI = BA-CA) of 4 years relative to healthy controls. Participants with hypertension and diabetes have a mean excess BA of 3.5 years. The findings raise the prospect of using the sleep EEG as a potential biomarker for healthy brain aging. PMID- 30448612 TI - High-fat diet worsens the impact of aging on microglial function and morphology in a region-specific manner. AB - Hippocampal microglia are vulnerable to the effects of aging, displaying a primed phenotype and hyper-responsiveness to various stimuli. We have previously shown that short-term high-fat diet (HFD) significantly impairs hippocampal- and amygdala-based cognitive function in the aged without affecting it in the young. Here, we assessed if morphological and functional changes in microglia might be responsible for this. We analyzed hippocampus and amygdala from young and aging rats that had been given three days HFD, a treatment sufficient to cause both hippocampal- and amygdala-dependent cognitive and neuroinflammatory differences in the aged. Aging led to the expected priming of hippocampal microglia in that it increased microglial numbers and reduced branching in this region. Aging also increased microglial phagocytosis of microbeads in the hippocampus, but the only effect of HFD in this region was to increase the presence of enlarged synaptophysin boutons in the aged, indicative of neurodegeneration. In the amygdala, HFD exacerbated the effects of aging on microglial priming (morphology) and markedly suppressed phagocytosis without notably affecting synaptophysin. These data reveal that, like the hippocampus, the amygdala displays aging-related microglial priming. However, the microglia in this region are also uniquely vulnerable to the detrimental effects of short-term HFD in aging. PMID- 30448613 TI - Translating Alzheimer's disease-associated polymorphisms into functional candidates: a survey of IGAP genes and SNPs. AB - The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels. For (1), we confirmed that 12 AD-associated coding common SNPs and five nonsynonymous rare variants are in linkage disequilibrium with the IGAP SNPs. For (2), the IGAP SNPs in CELF1 and MS4A6A were associated with expression of their neighboring genes, MYBPC3 and MS4A6A, respectively, in blood. The IGAP SNP in DSG2 was an expression quantitative trait loci (eQTL) for DLGAP1 and NETO1 in the human frontal cortex. The IGAP SNPs in ABCA7, CD2AP, and CD33 each acted as eQTL for AD-associated genes in brain. Our approach for identifying proxies and examining eQTL highlighted potentially impactful, novel gene regulatory phenomena pertinent to the AD phenotype. PMID- 30448614 TI - Postmitotic cell longevity-associated genes: a transcriptional signature of postmitotic maintenance in neural tissues. AB - Different cell types have different postmitotic maintenance requirements. Nerve cells, however, are unique in this respect as they need to survive and preserve their functional complexity for the entire lifetime of the organism, and failure at any level of their supporting mechanisms leads to a wide range of neurodegenerative conditions. Whether these differences across tissues arise from the activation of distinct cell type-specific maintenance mechanisms or the differential activation of a common molecular repertoire is not known. To identify the transcriptional signature of postmitotic cellular longevity (PMCL), we compared whole-genome transcriptome data from human tissues ranging in longevity from 120 days to over 70 years and found a set of 81 genes whose expression levels are closely associated with increased cell longevity. Using expression data from 10 independent sources, we found that these genes are more highly coexpressed in longer-living tissues and are enriched in specific biological processes and transcription factor targets compared with randomly selected gene samples. Crucially, we found that PMCL-associated genes are downregulated in the cerebral cortex and substantia nigra of patients with Alzheimer's and Parkinson's disease, respectively, as well as Hutchinson-Gilford progeria-derived fibroblasts, and that this downregulation is specifically linked to their underlying association with cellular longevity. Moreover, we found that sexually dimorphic brain expression of PMCL-associated genes reflects sexual differences in lifespan in humans and macaques. Taken together, our results suggest that PMCL-associated genes are part of a generalized machinery of postmitotic maintenance and functional stability in both neural and non-neural cells and support the notion of a common molecular repertoire differentially engaged in different cell types with different survival requirements. PMID- 30448615 TI - Sex-dependent effect of the BDNF Val66Met polymorphism on executive functioning and processing speed in older adults: evidence from the health ABC study. AB - Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i.e., estimated baseline DSST) and change in DSST over 9 years, adjusted for covariates. Sex interacted with BDNF genotype to predict DSST intercept (F[1,1599] = 7.4, p < 0.01) and 9-year change (F[1,1183] = 4.1, p = 0.04) in white participants only. Initially, white male Val/Val carriers had lower DSST scores (37.6, SE = 0.8) in comparison with male Met carriers (difference, -1.7; 95% CI, -3.2 to -0.3) and female Val/Val carriers (difference, -5.6; 95% CI, -6.8 to -4.3). White female Met carriers showed a slower rate of change (annual rate of change = -0.6, SE = 0.1) in comparison with female Val/Val carriers (difference, -0.2; 95% CI, -0.4 to -0.02) and male Met carriers (difference, -0.3; 95% CI, -0.5 to -0.02). Our findings suggest that BDNF Val66Met and sex should be considered in future endeavors aimed at treating or preventing neurodegenerative disorders. PMID- 30448616 TI - The potential nutrigeroprotective role of Mediterranean diet and its functional components on telomere length dynamics. AB - The Mediterranean diet (MD) is a gold standard for nutrition and the most evidence-based diet to delay the onset of age-associated pathologies. Telomeres are the heterochromatic repeat regions found at the ends of eukaryotic chromosomes, whose length is considered a reliable hallmark of biological ageing. Telomere shortening is, at least in part, a modifiable factor and there is evidence that adherence to the MD is associated with longer telomeres. Data from several studies indicate an association between "inflammatory/oxidative status" and telomere length (TL). The MD, as a complex exposome with thousands of nutrients and phytochemicals, may positively influence telomere attrition by reducing inflammation and oxidative stress. However, it is unclear whether the protective effects on TL provided by the MD result from its individual constituents or some combination of these. Furthermore, these properties of the MD and its components are not yet fully validated by clinical endpoints in randomized trials or observational studies. Here, we summarize the data from experimental and population-based studies on the effects of the MD on TL maintenance. We will both highlight the possible role of the MD in the prevention of age-associated diseases, and attempt to identify certain aspects of the diet that are particularly important for telomere maintenance. PMID- 30448617 TI - The evolving field of non-pharmacological therapies to improve functional capacity in chronic heart failure. AB - Clinical investigations in chronic heart failure (HF) have been increasingly including endpoints related to functional and exercise capacity. Noninvasive ventilation support (NIVS) constitutes a therapeutic option that could improve several markers of cardiovascular performance and functional capacity along with improvements in HF symptoms such as dyspnea. NIVS with bilevel positive airway pressure (BiPAP) is a therapeutic option that can be better tolerated by patients compared to continuous positive airway pressure (cPAP) and potentially improve heart failure patients' adherence. Future investigations should improve our understanding as to how to select the HF patients most amenable to respond favorably, elucidate the frequency and duration of NIVS session required to maintain the observed short-term beneficial effects for a long period of time and also shed additional light on the mechanisms associated with these benefits. In summary, NIVS appears to be a promising non-pharmacological therapy to improve exercise capacity and quality of life in chronic HF. PMID- 30448618 TI - Understanding the anatomy of a perforated mitral valve: From 2D echocardiography to 3D printing. PMID- 30448619 TI - Myocardial performance versus exercise tolerance: What matters the most in patients with heart failure? PMID- 30448620 TI - Transthoracic 3D echocardiography used as a low-cost and precise technique to facilitate ablation of ventricular tachycardia from the left posteromedial papillary muscle. PMID- 30448621 TI - Ischemia-reperfusion injury: Complex pathophysiology with elusive treatment. PMID- 30448622 TI - A reversible cause of hypoxaemia in a patient with acute right ventricular infarction. PMID- 30448623 TI - 50th Anniversary Retrospective: Computers and Biomedical Research and Journal of Biomedical Informatics. PMID- 30448624 TI - Estrogen receptor-alpha (ESR1) polymorphism rs1999805 associates with asthma. PMID- 30448625 TI - Enhancing the social capital in industrial workplaces: Developing workplace interventions using intervention mapping. AB - Social capital in the workplace has been found to be associated with employee wellbeing and work engagement. Yet, evidence of effects of interventions to enhance the social capital are lacking. The intervention mapping method has been described as a useful tool for developing workplace interventions but it is very resource consuming. We aimed to develop an adapted version of the intervention mapping method which is more practically feasible to apply. To get insight into strengths and weaknesses of the adapted method, we applied it and conducted interviews with staff at six companies. The interviews revealed that the action plans developed using the adapted intervention mapping method were generally perceived as relevant and that the action plans had a positive effect on the social capital. However, the implementation of the action plans had been a challenge. In conclusion, the adapted intervention mapping method appears to be suitable for developing interventions to enhance the social capital in the workplace. However, more attention to the implementation of the action plans needs to be incorporated into the method. Suggestions to enhance the implementation included the involvement of the management in the implementation and monitoring of the implementation of the action plans as well as integrating the action plans into existing procedures in the workplace. PMID- 30448626 TI - Preterm birth in relation to the bisphenol A replacement, bisphenol S, and other phenols and parabens. AB - INTRODUCTION: Preterm birth continues to be a significant public heath concern and is a leading cause of perinatal and infant mortality. Environmental exposures to phenols and parabens are suspected to potentially contribute to the pathology of preterm birth, yet limited human studies have characterized the extent to which these toxicants are associated with birth outcomes. METHODS: We examined the associations between phenols, parabens, and preterm birth, within pregnant women who were recruited early in gestation into the LIFECODES cohort at Brigham and Women's Hospital in Boston, Massachusetts. Urine samples were collected at up to 4 time points in pregnancy and analyzed for phenols and parabens. We selected 130 cases of preterm birth (defined as delivery before 37 weeks gestation), and 350 random controls. We categorized preterm birth subtypes based on clinical presentation and identified 75 cases of spontaneous preterm birth (characterized by spontaneous preterm labor and/or preterm premature rupture of membranes), and 37 cases of placental preterm birth (characterized by preeclampsia and/or intrauterine growth restriction). We used multivariate logistic regression with visit specific and geometric averages of phenols and parabens to determine associations with preterm birth. RESULTS: We observed moderate variability in urinary phenol and paraben concentrations over pregnancy with intraclass correlation coefficients ranging between 0.45 and 0.68. Regression analyses indicated mostly null associations. We observed inverse associations, notably between 2,5-dichlorophenol and overall preterm birth (adjusted odds ratio [95% confidence interval, CI]: 0.79 [0.67 - 0.94]), and this relationship was consistent by study visit. Conversely, ethyl paraben was associated with increased risk for placental preterm birth (adjusted odds ratio [95% CI]: 1.47 [1.14 - 1.91]). Bisphenol-S detection at visit 4 was associated with overall preterm birth (adjusted odds ratio [95% CI]: 2.05 [1.09, 3.89]). CONCLUSIONS: While the findings from this study largely indicate null associations, we observed some relationships between select phenols, parabens and preterm birth, which warrants further investigation of these toxicants and birth outcomes. PMID- 30448627 TI - The maximum entropy production requirement for proton transfers enhances catalytic efficiency for beta-lactamases. AB - Movement of charges during enzyme catalytic cycle may be due to conformational changes, or to fast electron or proton transfer, or to both events. In each case, entropy production can be calculated using Terrel L. Hill's method, if relevant microscopic rate constants are known. When ranked by their evolutionary distance from putative common ancestor, three beta-lactamases considered in this study show correspondingly increased catalytic constant, catalytic efficiency, and overall entropy production. The acylation and deacylation steps with concomitant proton shuttles are the most important contributors to overall entropy production. The maximal entropy production requirement for the ES<->EP or EP<->E + P step leads to optimal rate constants, performance parameters, and entropy production values, which are close to those extracted from experiments and also rank in accordance with evolutionary distances. Concurrent maximization of entropy productions for both proton transfer steps revealed that evolvability potential of different beta-lactamases is similarly high. These results may have implications in particular for latent potential of beta-lactamases to evolve further and in general for selection of optimized enzymes through natural or directed evolution. PMID- 30448628 TI - Preparation of micro-cell membrane chromatographic columns with polyvinyl alcohol modified polyether ether ketone tube as cellular membrane carrier. AB - Cell membrane chromatography is a promising technique for screening active components from complex matrices. Unfortunately, the large consumption of cells and low resolutions of analytes limit the applications of this method. Herein, we report polyether ether ketone tube as a novel cellular membrane carrier for cell membrane chromatography. Its inner surface is firstly coated by polyvinyl alcohol and then cell membranes are physically adsorbed onto the polyvinyl alcohol layer. To verify this approach, osteoclast and osteoblast micro-column were prepared and characterized by calcitonin and verapamil, respectively. Comparing with common cell membrane chromatographic column, the micro-cell membrane chromatographic columns showed about 1000-fold decrease of cell consumption and satisfactory retention behavior. The developed column was applied to screen potential active components from Cortex Phellodendri Chinensis. A total of 18 components in Cortex Phellodendri Chinensis extract were observed as having retention property of osteoclast micro-cell membrane chromatographic column, while 10 components retained on osteoblast micro-cell membrane chromatographic column. The results of in vitro assay showed that berberine, obacunoic acid and phellodendrine had an obvious inhibitory effect on osteoclast differentiation and function. Berberine and tetrahydropalmatine increased the osteoblast proliferations and mineralized nodules density. This cell membrane/polyvinyl alcohol column can be applied to various biological chromatography models. PMID- 30448629 TI - Optimization and validation of extraction and quantification methods of antimalarial triterpenic esters in Keetia leucantha plant and plasma. AB - The aim of this study is to develop validated methods for the extraction and quantification of antimalarial triterpene esters from Keetia leucantha and from plasma samples. These compounds, showing in vitro and in vivo antiplasmodial activities, were optimally extracted from Keetia leucantha twigs using ultrasounds with dichloromethane and from plasma using protein precipitation with acetonitrile. We then developed and validated HPLC-UV quantification methods, which proved to be selective, accurate, linear, true and precise, both in plant and plasma samples for the eight triterpenic esters in mixture. Based on the total error concept as decision criteria, the validated dosage ranges of the triterpene esters mixture were set between 14.68 and 73.37 MUg/mL in plants and 15.90 and 106.01 MUg/mL in plasma injected solutions, corresponding to 7.95 and 53.01 MUg/mL in plasma. These reliable methods were used to determine effectively triterpene esters content in collected samples, that seems highly variable in plant extracts, and will be helpful to further investigate pharmacokinetics parameters of these interesting bioactive compounds. PMID- 30448630 TI - The application of 'valence' to the idea of household food insecurity in Canada. AB - Household food insecurity (HFI), lack of access to adequate food due to financial constraint, has been studied extensively in Canada and is well-recognized for its negative impacts on population health. Despite considerable high-level political recognition, the issue has evoked little substantive policy deliberation. We suggest that Beland and Cox's recently articulated construct of 'valence' may be useful in examining why the idea of HFI has motivated little policy response. Valence is defined as the emotional quality of an idea. According to valence theory, ideas with a high emotional intensity, positive valence acquire importance in policy debate, and those with high intensity, negative valence are 'unthinkable' as a policy idea. We compiled four datasets in which HFI was discussed (verbatim legislative excerpts, parliamentary committee proceedings, government reports, interviews with HFI policy entrepreneurs), representing different kinds of political forums for debate. We analyzed what was said with respect to the valence of the idea of HFI. We found that discussions about HFI were on the whole generally subdued and of low emotional intensity. High intensity negative valence pronouncements were found among legislators' statements and parliamentary committee evidence. Regardless of emotional intensity level, speakers usually talked about the idea of HFI in ways that elicited a negative valence. Positive valence in discussion of the idea of HFI was limited and invoked comments about individual aspiration, prosperity, and community spirit. Our findings suggest that the negative valence of HFI is an inherent trait of the idea that makes it unattractive to policy makers. We suggest that HFI may be a better metric than a policy problem and that aspirational goals with positive valence related to poverty alleviation might better use HFI as an outcome rather than the focus of action. PMID- 30448631 TI - The multi-factorial determinism of forensic expertise regarding sentence interruption on medical grounds and decision. AB - The topic proposed by this research is the complex determinism or requesting forensic expertise for the purpose of postponing or interrupting a sentence in medical ground. Within the topic, it was necessary to perform a complex analysis on several aspects of inmate life, from the point of view of their rights and especially the right to medical assistance. We have included aspects related to the evolution of the legal framework and current regulations, to the status of medical assistance in the penitentiary environment (illustrating realities related to morbidity and mortality) and to the doctor-patient relationship during a forensic expertise. To this end, this paper aims to reveal the realities of how inmates are informed about the framework in which the institution of forensic expertise operates, as well as to analyse the inmates' perception on the accessibility and usability of this type of expertise. At the same time, we aimed to identify cases which abusively exceed the boundaries of requesting sentence interruption on medical grounds and the causes of these situations. In the first part, a retrospective statistical study was performed in mortality within the penitentiary population in the area included in the study. The characteristics particular to the doctor-inmate patient relationship were also explored. PMID- 30448632 TI - Walking more than 90 minutes/week was associated with a lower risk of self reported low back pain in persons over 50 years of age: a cross-sectional study using the Korean National Health and Nutrition Examination Surveys. AB - BACKGROUND CONTEXT: Physical activity, such as muscle strengthening and aerobic exercise, has been found to be effective for low back pain (LBP). However, the association between weekly walking duration and LBP in the general population remains poorly understood. OBJECT: This study aimed (1) to analyze the association between walking and LBP and (2) to examine this association according to walking duration and overall walking days per week in a general population over 50 years of age using a representative sample of Korean adults. STUDY DESIGN: Cross-sectional study. PATIENT SAMPLE: Data from the Korea National Health and Nutrition Examination Surveys V and VI, performed from 2010 to 2015. OUTCOME MEASURES: Multiple logistic regression analysis was performed to determine the association between walking days and duration and LBP. Analysis was restricted to participants aged over 50 years who responded to surveys on LBP and walking activity. METHODS: National health and nutrition examination surveys were performed in the Korean general population (N=48,482) from 2010 to 2015. LBP status was surveyed using a self-reported questionnaire form ("Have you complained of LBP for more than 30 days during the past 3 months?"). Daily walking activity (low-intensity activity) was evaluated using the following two questions: (1) "During the last 7 days, on how many days did you walk for at least 10 minutes at a time? This includes at work and at home, walking to travel from place to place, and any other walking that you have done solely for recreation, sport, exercise, or leisure." (2) "How much time did you usually spend walking on each of those days?" Walking duration per day was classified into two categories: over 30 min/day and over 1 h/day. Overall walking days per week were categorized into <3, 3-4, and >=5 days/week. Basic characteristics, comorbidities, socioeconomic status, and other variables were used to create multiple logistic regression models. No sources of funding and no conflicts of interest were associated with this study. RESULTS: Walking for more than 3 days per week for over 30 minutes at a time was negatively associated with LBP in the unadjusted (adjusted odds ratio [aOR]: 0.65, p<.001) and fully adjusted logistic regression models (aOR: 0.79, p<.001). Similarly, walking for more than 5 days per week for over 1 hour at a time was negatively associated with LBP in the unadjusted (aOR: 0.62, p<.001) and fully adjusted logistic regression models (aOR: 0.76, p<.001). The risk of LBP decreased with increasing walking days and duration. CONCLUSIONS: Our study showed that longer walking duration was associated with a lower risk of LBP using a cross-sectional health survey in the Korean general population. Regular walking with a longer duration for more than 3 days/week is significantly associated with a lower risk of LBP in the general population aged over 50 years. PMID- 30448633 TI - Novel manipulations of ratio spectra as powerful tools for resolution and quantitative determination of Pyridostigmine bromide and its' related substances; A comparative study. AB - Resolution and quantitative determination of ternary mixture with severely overlapped spectra without any preliminary separation steps represents a big challenge for any analyst. Smart and novel spectrophotometric methods are continuously innovated for achieving the above mentioned target. Novel applications of ratio difference spectrophotometric technique utilizing ratio spectra and derivative ratio spectra are applied in presented work. The proposed methods included derivative ratio difference (DRD) and ratio subtraction ratio difference (RSRD) methods. Comparative study was achieved between the proposed methods and the recently developed induced ratio difference (IRD) method. The developed methods were assessed through the analysis of ternary mixtures with different ratios of Pyridostigmine bromide (PR) and its related substances; impurity a (IMP A) and impurity b (IMP B). Analysis of PR in a pharmaceutical dosage form without any interference from other inactive ingredients was also a successful application of the proposed methods. As per ICH guidelines, the proposed methods were validated ensuring their accuracy, precision and specificity. Statistical comparison between the developed methods and the reference method was done, where calculated F and t values were less than the theoretical ones in regards to accuracy and precision. PMID- 30448634 TI - A dansyl-appended N-heterocycle for Cu2+ and S2- recognition via a displacement mode. AB - A novel l-proline based heterocycle 3 of C2 symmetry has been designed and synthesized for cation and anion recognition in aqueous solution. Ligand 3 shows a strong affinity to Cu2+ ion, and their interaction induces a remarkable fluorescence quenching in DMSO:H2O = 9:1 (HEPES buffer, 0.01 M, pH 7.4) among various metal ions. Both the in-situ generated and isolated 3-Cu2+ complex exhibit specific fluorescence recovery upon addition of S2-, even in the presence of S2O32-, L-histidine, and thiol-containing amino acids. For this dual functional switch, a combination of 1H NMR titration, ESI mass and FT-IR spectra suggest that its sensing behavior is via a displacement mode. Sequential "on-off on" fluorescence bio-imaging of the heterocycle 3 to Cu2+ and S2- was carried out in HeLa cells. PMID- 30448635 TI - PD-1 blockade augments humoral immunity through ICOS-mediated CD4+ T cell instruction. AB - Successful applications of PD-1/PD-L1 blockade in multiple cancers highlight the efficacy of immunotherapy mediated by enhancing CD8+ T cell immunity both in mouse and human. How PD-1 blockade affects humoral immunity remains unclear. Herein we demonstrated that treatment of anti-PD-1 antibody led to the increase in both total IgG and OVA-specific IgG in OVA-immunized mice. However, no effect was observed on Ab affinity maturation. Accumulation of germinal center (GC) and memory B cells was observed in the spleens together with elevated percentages of plasma cells in the spleens and bone marrow. More interestingly, dramatic infiltration of CD4+ T cells was apparent in GCs after PD-1 blockade with a significant increase in the expression of ICOS. When CD4+ T cells and B cells from OVA-immunized mice were co-cultured with neutralizing anti-PD-1 Ab in vitro, PD-1 blockade recapitulated the up-regulation of ICOS expression on CD4+ T cells with the activation of ERK signaling. Suppression of ERK activation not only reduced ICOS expression on CD4+ T cells but also attenuated IgG production upon PD-1 blockade. Taken together, PD-1 blockade enhances humoral immunity. This process partially relies on more accumulation of CD4+ T cells in GCs with the up regulation of ICOS expression and the promotion of B cell terminal differentiation. The regulatory pattern of PD-1 blockade illustrated here provides a new mechanism of how immune checkpoint molecules regulating humoral immune responses. PMID- 30448636 TI - A surgical case of aortic stenosis with recurrent gastrointestinal bleeding: Heyde syndrome. AB - INTRODUCTION: The combination of aortic stenosis, acquired coagulopathy, and anemia due to gastrointestinal (GI) bleeding is described as Heyde syndrome. PRESENTATION OF CASE: We report a surgical case of a 77-year-old man who was admitted because of melena and exertional chest compression. GI endoscopy could not reveal the origin of the GI bleeding. Conservative therapy including fasting and transfusion improved the anemia. Echocardiography demonstrated severe aortic stenosis (AS) with a hypertrophied left ventricle. Hematologic examination by gel electrophoresis showed deficiency of high-molecular-weight multimers of von Willebrand factor (vWF), resulting in the diagnosis of Heyde syndrome. He electively underwent aortic valve replacement (AVR) with a bioprosthesis using standard cardiopulmonary bypass. In the perioperative period, the patient had no recurrent anemia. He was discharged without subjective symptoms on postoperative day 18. The 20-month follow-up was unremarkable, with no episode of recurrent GI bleeding. DISCUSSION: Heyde syndrome is associated with acquired von Willebrand disease type IIA and AS. The true characteristic of von Willebrand disease type IIA is hemorrhagic diathesis caused by deficiency of high-molecular-weight multimers of vWF. Under the influence of high shear stress caused by AS, vWF is stretched and easily cleaved by vWF-cleaving protease. Consequently, it causes deficiency of high-molecular-weight multimers of vWF and primary hemostasis impairment. Therefore, the most effective treatment for Heyde syndrome is correction of AS. AVR can improve not only the hemodynamic status but also coagulopathy. CONCLUSION: The differential diagnosis of patients with recurrent GI bleeding with concurrent systolic murmur should include Heyde syndrome. PMID- 30448637 TI - Zancolli procedure and nerve repair with sural graft as a treatment for patient with claw hand due to complete rupture of ulnar and median nerve: A case report. AB - INTRODUCTION: Combined injuries of peripheral nerve of upper extremity are usually the result of severe trauma to the extremity, and are often associated with substantial soft tissue, vascular, and bony injuries. The most common form of such combined injury is a low median-ulnar palsy, usually due to laceration of the volar wrist. It is a devastating injury, and with delayed presentation the injury is going to be more difficult to reconstruct. PRESENTATION OF CASE: Ten year-old girl was admitted to hospital with numbness of her left palm and fingers, 5 months before admission. She was hit by a car while riding a bicycle from opposite direction from she was heading and cut her left forearm by licensed plate. Initially treated at nearby clinic but later couldn't extend her fingers after the pain subsided and left untreated for 5 months. DISCUSSION: Traditionally, number of static procedures have been described to correct the claw hand deformity by preventing MCP joint hyperextension. Nevertheless, these procedures are reserved for those having ability to extend IP joints while MCP joint hyperextension were prevented. Conversely, static procedure like Zancolli capsulodesis is simple and do not sacrifice any motors in an already compromised extremity. Combined with sural graft, the outcome for the patient is hopefully better than Zancolli procedure alone. CONCLUSION: Zancolli procedure along with nerve repair with sural graft as a treatment of claw hand due to complete rupture of ulnar and median nerve is one of feasible treatment options to correct claw hand deformity with such combined palsy. PMID- 30448638 TI - Mediastinal mature teratoma perforating the right lung that was successfully resected with complete thoracoscopic surgery: A case report. AB - INTRODUCTION: A perforating mediastinal mature teratoma can cause severe inflammation and adhesion; therefore, open surgery is usually performed. Asymptomatic perforation involving a teratoma is very rare. Complete thoracoscopic surgery is often difficult because of inflammation associated with perforation and the frequently large size of a mediastinal mature teratoma. We report a rare case of an asymptomatic perforating mediastinal mature teratoma successfully treated with complete thoracoscopic surgery. PRESENTATION OF CASE: The patient was a 15-year-old girl with an abnormal shadow at the mediastinum seen on chest radiography at a health examination performed at her junior high school; an asymptomatic mediastinal tumour was suspected. Enhanced computed tomography revealed a 6.5 * 3.5-cm tumour associated with the right upper lobe. Thoracoscopic surgery was performed using 4 access ports. Although there were inflammatory changes, hemi-thymectomy and right upper lobectomy were achieved with complete thoracoscopic surgery. The tumour included the skin, sebaceous glands, hair, and pancreatic tissue and was diagnosed as a mature teratoma perforating the right upper lobe. DISCUSSION: There might be limited inflammatory changes if the patient has few or no symptoms, as in our case. In such cases, the tumour may be excised even if it is large. CONCLUSION: We report a rare case of an asymptomatic perforating mediastinal mature teratoma that was successfully treated with complete thoracoscopic surgery. Although infection, inflammatory adhesion, large tumour size, and the need for radical cure are concerns, complete thoracoscopic surgery might be helpful. In cases of few or no symptoms, thoracoscopic surgery is worth challenging. PMID- 30448639 TI - WDR68 is essential for the transcriptional activation of the PRC1-AUTS2 complex and neuronal differentiation of mouse embryonic stem cells. AB - Recent studies on Polycomb repressive complexes (PRC) reveal a surprising role in transcriptional activation, yet the underlying mechanism remains poorly understood. We previously identified a type 1 PRC (PRC1) that contains Autism Susceptibility Candidate 2 (AUTS2), which positively regulates transcription of neuronal genes. However, the mechanism by which the PRC1-AUTS2 complex influences neurodevelopment is unclear. Here we demonstrate that WDR68 is not only an integral component of the PRC1-AUTS2 complex, but it is also required for PRC1 AUTS2-mediated transcription activation. Furthermore, deletion of Wdr68 in mouse embryonic stem cells leads to defects in neuronal differentiation without affecting self-renewal. Through transcriptomic analysis, we found that many genes responsible for neuronal differentiation are down-regulated in Wdr68 deficient neural progenitors. These genes include those targeted by the PRC1-AUTS2 complex. In summary, our studies uncovered a previously unknown but essential component of the active PRC1 complex and evidence of its role in regulating the expression of genes that are important for neuronal differentiation. PMID- 30448640 TI - Polymorphisms of the cytidine deaminase APOBEC3F have different HIV-1 restriction efficiencies. AB - The APOBEC3 enzyme family are host restriction factors that induce mutagenesis of HIV-1 proviral genomes through the deamination of cytosine to form uracil in nascent single-stranded (-)DNA. HIV-1 suppresses APOBEC3 activity through the HIV 1 protein Vif that induces APOBEC3 degradation. Here we compared two common polymorphisms of APOBEC3F. We found that although both polymorphisms have HIV-1 restriction activity, APOBEC3F 108 A/231V can restrict HIV-1 DeltaVif up to 4 fold more than APOBEC3F 108 S/231I and is partially protected from Vif-mediated degradation. This resulted from higher levels of steady state expression of APOBEC3F 108 A/231 V. Individuals are commonly heterozygous for the APOBEC3F polymorphisms and these polymorphisms formed in cells, independent of RNA, hetero oligomers between each other and with APOBEC3G. Hetero-oligomerization with APOBEC3F 108 A/231V resulted in partial stabilization of APOBEC3F 108 S/231I and APOBEC3G in the presence of Vif. These data demonstrate functional outcomes of APOBEC3 polymorphisms and hetero-oligomerization that affect HIV-1 restriction. PMID- 30448641 TI - The effects of cognitive load and optical flow on antagonist leg muscle coactivation during walking for young and older adults. AB - The purpose of this study was to compare how healthy aging interacts with environments that challenge cognitive load and optical flow to affect antagonist leg muscle coactivation during walking. We measured leg muscle activity in sixteen older adults (70.4 +/- 4.2 years) and twelve young adults (23.6 +/- 3.9 years) walking on a treadmill at their preferred speed while watching a speed matched virtual hallway. Cognitive load was challenged using a dual-task to interfere with available attentional resources. Optical flow was challenged using perturbations designed to create a perception of lateral imbalance. We found antagonist coactivation increased with aging, independent of condition. We also found that, compared to unperturbed walking, only in the presence of optical flow perturbations did the older adults increase their antagonist coactivation. Antagonist coactivation in the young adults was not affected by either condition. Our findings provide evidence that antagonist leg muscle coactivation in healthy older adults is more sensitive to walking environments that challenge optical flow than environments that challenge cognitive load. As increased antagonist coactivation may indicate compromised balance, these findings may be relevant in the design of living environments to reduce falls risk. PMID- 30448642 TI - Spanking and young children's socioemotional development in low- and middle income countries. AB - Spanking is one of the most common forms of child discipline used by parents around the world. Research on children in high-income countries has shown that parental spanking is associated with adverse child outcomes, yet less is known about how spanking is related to child well-being in low- and middle-income countries. This study uses data from 215,885 children in 62 countries from the fourth and fifth rounds of UNICEF's Multiple Indicator Cluster Surveys (MICS) to examine the relationship between spanking and child well-being. In this large international sample which includes data from nearly one-third of the world's countries, 43% of children were spanked, or resided in a household where another child was spanked, in the past month. Results from multilevel models show that reports of spanking of children in the household were associated with lower scores on a 3-item socioemotional development index among 3- and 4-year-old children. Country-level results from the multilevel model showed 59 countries (95%) had a negative relationship between spanking and socioemotional development and 3 countries (5%) had a null relationship. Spanking was not associated with higher socioemotional development for children in any country. While the cross sectional association between spanking and socioemotional development is small, findings suggest that spanking may be harmful for children on a more global scale than was previously known. PMID- 30448643 TI - Zika virus disease-knowledge, attitudes and practices among pregnant women implications for public health practice. AB - OBJECTIVE: Mosquito-borne diseases continue to pose a threat to Latin America and the Caribbean. Zika virus disease entered the Caribbean in 2013 with increased reporting of cases across the region in 2016, affecting more than 50 countries. This study aimed to ascertain the knowledge of, attitudes and practices towards Zika virus disease among antenatal clinic attenders in Trinidad and Tobago during the 2016 outbreak. STUDY DESIGN: A cross-sectional questionnaire survey was undertaken. METHODS: A knowledge attitudes and practices survey was conducted among antenatal clinic attenders at publicly funded primary care health centres. All counties of Trinidad (except St Patrick, Caroni and Victoria) and Tobago were included in the study. Within each county, three health centres were selected at random. At the antenatal clinic of each selected health centre, antenatal clients were selected by randomly selecting their patient file from that day's antenatal clinic patient files. Data collection occurred from September to November 2016. The knowledge, attitudes and practice survey was administered by an interviewer administered questionnaire. The World Health Organization Knowledge, Attitudes and Practice surveys Zika virus disease and potential complications Resource pack was adapted for use as the data collection tool. All data collected were analysed using SPSS software, version 23. Tests with P-values less than 0.05 were deemed significant. RESULTS: Seventy-four percent (74%) of responders did not think there was a link between sexual transmission and Zika. About 19% stated that abstaining could prevent Zika but only 6.6% actually practiced this. Seventy-six percent knew the risk of microcephaly, and this knowledge of the risk of microcephaly was found to be significantly associated with the number of weeks' gestation. Less than 40% knew the risk of Guillain-Barre syndrome. Doctors at health centres followed by private doctors were the top two trusted information sources for responders. Responders thought that the government could spray insecticide, clean drains, educate community members and clean overgrown vacant lots of land. CONCLUSION: The government and healthcare workers need to reach specific target groups with accurate messages to minimize the associated morbidity and thereby safeguarding national and global health security. PMID- 30448644 TI - Neural measures of anticipatory bodily attention in children: Relations with executive function. AB - The ability to selectively direct attention to a certain location or modality is a key neurocognitive skill. One important facet of selective attention is anticipation, a foundational biological construct that bridges basic perceptual processes and higher-order cognition. The current study focuses on the neural correlates of bodily anticipation in 6- to 8-year-old children using a task involving tactile stimulation. Electroencephalographic (EEG) activity over sensorimotor cortex was measured after a visual cue directed children to monitor their right or left hand in anticipation of tactile stimulation. Prior to delivery of the tactile stimulus, a regionally-specific desynchronization of the alpha-range mu rhythm occurred over central electrode sites (C3/C4) contralateral to the cue direction. The magnitude of anticipatory mu rhythm desynchronization was associated with children's performance on two executive function tasks (Flanker and Card Sort). We suggest that anticipatory mu desynchronization has utility as a specific neural marker of attention focusing in young children, which in turn may be implicated in the development of executive function. PMID- 30448645 TI - Capacitative deionization using commercial activated carbon fiber decorated with polyaniline. AB - Capacitive deionization (CDI) has become a promising technology for water desalination due to its remarkable advantages including low operation cost, no secondary pollution and high rate of ion recovery. However, the majority of commercial CDI electrode materials are carbonaceous materials such as activated carbon with limited capacitance and high charge transfer resistance, which significantly hinders the wide application of CDI. Herein, we demonstrate a N doped carbonaceous CDI electrode with a maximum ion electrosorption capacity of 19.9 mg/g, a low charge transfer resistance (1.17 Omega) and a robust regeneration performance (2800 min for 28 circles). The N-doped carbonaceous CDI electrode is the commercial activated carbon fiber (ACF) decorated with polyaniline (PANI) (ACF/PANI) electrode fabricated by in-situ electrochemical polymerization. The ACF/PANI electrode was characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), and fourier transform infrared spectroscopy (FTIR), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The pseudocapacitance of ACF/PANI electrode significantly contributed to the effectively improved CDI performance that 90.0% of sodium storage was attributed to the capacitive process and the unique porous structure of ACF/PANI electrode contributed to the other 10.0% diffusion-controlled capacity. PMID- 30448646 TI - Photocatalytic reduction of Cr (VI) on nano-sized red phosphorus under visible light irradiation. AB - Red phosphorus as a novel visible-light-responsive and metal-free photocatalyst has attracted extensive attention in the area of energy conversion and environmental remediation. Herein, nano-sized red phosphorus photocatalyst was synthesized via a hydrothermal and ultrasonic method and used for reduction of Cr (VI) for the first time. The as-prepared photocatalysts were characterized by XRD, UV-Vis-DRS, XPS, SEM, TEM and photoelectrochemical measurements. Compared to bulk red phosphorus, nano-sized red phosphorus exhibit a significantly enhanced photocatalytic activity for reduction of Cr (VI) due to the greatly reduced charge transfer resistance and enhanced adsorption capability of Cr (VI). PMID- 30448647 TI - Controlled synthesis of metal-organic frameworks coated with noble metal nanoparticles and conducting polymer for enhanced catalysis. AB - The combination of noble metal nanoparticles (NM NPs) and metal-organic frameworks (MOFs) for enhanced properties in catalysis is a rapidly developing interdisciplinary research field. Herein we report a facile one-step approach to the deposition of functional nanocomposite shell composed of NM NPs and conducting polymer on the surface of particulate UiO-66. Our approach is based on the recently developed double solvents method involving a hydrophobic solvent (n hexane) and a hydrophilic solvent (water). Particularly, the n-hexane was used in a large amount to suspend the UiO-66 particles with hydrophilic inner pores and promoted the enrichment of the water containing the palladium chloride (PdCl2) inside the pores of UiO-66 particles, because these two solvents are immiscible and the volume of water is smaller than the pore volume of the UiO-66 particles. After the introduction of hydrophobic pyrrole into the n-hexane, the UiO-66 particles are successfully coated with a nanocomposite shell, composed of Pd NPs and polypyrrole (PPy) resulting from the interfacial polymerization of pyrrole on the external surface of UiO-66 particles initiated by PdCl2 presented within the UiO-66 particles. Significantly, in such a unique structure, the prepared hybrid particles noted as UiO-66/Pd@PPy nanocomposite particles are demonstrated to be an excellent catalyst with both high activity and stability in the reduction reaction of p-nitrophenol and sodium borohydride. Furthermore, this synthetic method not only effectively controls the mass loading of Pd NPs and PPy on the UiO-66 particles but also enables the deposition of Au@PPy and Ag@PPy nanocomposite shells onto the surface of the UiO-66 particles. PMID- 30448648 TI - Colloidal systems chemistry. Replication, reproduction and selection at nanoscale. AB - Development of synthetic systems carrying life-like features is a long-standing challenge in chemistry and material science. Poor understanding of mechanisms ruling the emergence of life-like features in an inanimate matter makes the challenge even more exciting. The growing field of systems chemistry takes the lead in defining life-like dynamic signatures in minimalistic (macro)molecular systems through the development of multicomponent synthetic models using tools from organic and supramolecular chemistry. Recent progress in nanoscience makes available a range of novel materials that can undoubtedly enrich systems chemistry. Therefore, with the aim of placing nano- and colloidal science within the context of systems chemistry, the recent experimental and theoretical developments dealing with the use of nanoparticles and their assemblies in the realisation of the concepts such as replication, reproduction and selection are discussed. PMID- 30448649 TI - Designing transition metal alloy nanoparticles embedded hierarchically porous carbon nanosheets as high-efficiency electrocatalysts toward full water splitting. AB - Developing high-efficiency catalysis electrodes towards both HER (hydrogen evolution reaction) and OER (oxygen evolution reaction) is critical to the popularity and practical application of devices for conversion and storage of clean and renewable hydrogen energy by overall water splitting. In this paper, a series of transition metal alloy nanoparticles embedded hierarchically porous carbon nanosheets (denoted as FexCoy@PCNSs) have been successfully designed and synthesized. After optimizing the metallic contents in FexCoy alloy, Fe3Co7@PCNSs displays superior water electrolysis performances compared to other control samples and previously reported non-noble metal catalysts. This advance is mainly due to the synergistic effect of increased carbon edges exposure, abundant accessible active sites, and improved electron/mass transport capability of 3D hierarchically porous architecture. More importantly, when Fe3Co7@PCNSs is applied as both cathode and anode in a two-electrode cell for carrying out the overall water splitting process, it just needs the corresponding cell voltages of 1.667 and 1.707 V to attain the 10 and 20 mA cm-2 current densities respectively. The synthesis of Fe3Co7@PCNSs confirms the importance of Fe and Co elements in designing catalyst structures. The electrochemical measurements further display the key roles of structural features and metal alloy@C active sites for boosting water splitting performances. PMID- 30448650 TI - Investigating the redox behavior of activated carbon supercapacitors with hydroquinone and p-phenylenediamine dual redox additives in the electrolyte. AB - Activated carbon (AC) with large surface area and high electrical conductivity is widely applied on supercapacitors (SC), but the energy storage mechanism for the pure electrical double layer capacitor of carbon leads to a low energy density. Developing stable aqueous electrolytes with abundant redox reactions via incorporating more than one redox additive in the electrolyte is one of the efficient strategies to improve the energy storage capacity of the AC-based SC. In this study, the dual redox additives of hydroquinone (HQ) and p phenylenediamine (PPD) are incorporated in the aqueous solution as the electrolyte for SC. The effects of the aqueous solution type as well as the total redox additive concentration and the relative amounts of HQ and PPD on the electrochemical performance of SC are carefully studied. Two binders are used for assembling the AC electrodes, and the binder-dependent electrochemical behaviors and energy storage capabilities for SC are obtained. The symmetric SC assembled with the optimized electrolyte and the AC electrode prepared using the LA132 binder shows the potential window of 1.6 V, the specific capacitance of 116.23 F/g at 2 A/g, and the maximum energy density of 1.85 W h/kg at the power density of 0.15 kW/kg. PMID- 30448651 TI - Ultra-efficient electromagnetic wave absorption with ethanol-thermally treated two-dimensional Nb2CTx nanosheets. AB - Nb2CTx, an emerging type of MXene, should be a promising electromagnetic wave (EMW) absorbing material to overcome the EMW pollution nowadays due to its unique layered structure and extremely thin monolayer thickness, but was lack of systematic study till now. Meanwhile, Nb2CTx nanosheets obtained upon HF etching of Nb2AlC MAX was unfortunately found with limited absorption performance due to its mainly dielectric loss mechanism herein. Therefore, the Nb2CTx nanosheets were further treated with solvothermal strategy in various solvents. As a result, the absorption performance of the as-treated Nb2CTx nanosheets could be significantly improved, while the ones in ethanol showed much more superior absorption capability, especially in the low-frequency band (2.0-4.0 GHz). The minimum reflection loss value could reach -52.2 dB at 3.93 GHz with the thickness of only 2.90 mm, indicating more than 99.999% EMW was absorbed. These should be due to the multi-loss mechanism including dielectric, interfacial, and multiple reflection ones resulting from the enlarged interlayer spacing, and increased surface functional groups on the Nb2CTx nanosheets upon the ethanol-based solvothermal treatment. PMID- 30448652 TI - Nanodiamonds conjugated upconversion nanoparticles for bio-imaging and drug delivery. AB - A multifunctional nanoplatform with simultaneous imaging and therapeutic capacities has been fabricated by covalently conjugating nanodiamonds (NDs) with upconversion NaYF4:Yb,Er nanoparticles (UCNPs). Green emission can be observed for the UCNP-NDs composites under 980 nm excitation, and in vitro imaging was carried out towards HeLa cells. The UCNP-NDs also shows good drug storage capability toward anticancer drug doxorubicin (Dox) and exhibits significant pH dependent drug-release behavior. Dox-loaded UCNP-NDs shows higher therapy efficiency towards Hela cells than free Dox when the equivalent concentration of the Dox is more than 10 MUg/mL. Thus, a favorable strategy may be provided to decrease the side effects of Dox, minimize drug dose, and improve its efficacy. These findings highlight the fascinating features of UCNP-NDs nanocomposites as upconversion fluorescence imaging contrast agents and doxorubicin loading carrier. In addition, this work may also provide a novel strategy for the design of multifunctional nanoplatforms. PMID- 30448653 TI - Terrain-influenced incremental watchtower expansion for wildfire detection. AB - Optimizing the effectiveness of early wildfire detection systems is of significant interest to the community. To this end, watchtower-based wildfire observations are continuing to be practical, often in conjunction with state-of the-art technologies, such as automated vision systems and sensor networks. One of the major challenges that the community faces is the optimal expansion of existing systems, particularly in multiple stages due to various practical, political and financial constraints. The notion of incremental watchtower expansion while preserving or making minimal changes to an existing system is a challenging task, particularly while meeting coverage and financial constraints. Conventionally and historically, this problem has been treated as a multi objective optimization problem, and as such, currently employed methods are predominantly focused on the full-fledged optimization problem, where the problem is re-solved every time during the expansion process. In this paper, for the first time, we propose an alternative approach, by treating the expansion as a submodular set-function maximization problem. By theoretically proving that the expansion problem is a submodular set-function maximization problem, we provide four different models and matching algorithms to handle various cases that arise during the incremental expansion process. Our evaluation of the proposed approach on a practical dataset from a forest park in China, namely, the NanJing forest park, shows that our algorithms can provide an excellent coverage by integrating visibility analysis and location allocation while meeting the stringent budgetary requirements. The proposed approach can be adapted to areas of other countries. PMID- 30448654 TI - Pharmaceuticals in freshwater aquatic environments: A comparison of the African and European challenge. AB - Hundreds of tons of pharmaceutical compounds are annually dispensed and consumed worldwide. Pharmaceuticals are an important class of emerging environmental micropollutants: their presence in water bodies is an increasing environmental concern. The aim of this review paper is to provide a comprehensive review of the occurrence of pharmaceuticals in freshwater aquatic environments in the African and European context. A literature survey has been performed, resulting in 3024 data points related to environmental occurrence. The concentration levels of 71 pharmaceuticals were assessed. The top ten most frequently detected and quantified compounds in both continents were sulfamethoxazole, carbamazepine, diclofenac, trimethoprim, ibuprofen, naproxen, paracetamol (acetaminophen), ketoprofen, venlafaxine and clarithromycin. The maximum concentrations of 17beta estradiol, estriol, ciprofloxacin, sulfamethoxazole, paracetamol, naproxen reported in African aquatic environments were ~3140, ~20,000, ~125, ~100, ~215 and ~171 times higher, respectively, than the concentrations reported in European based studies. The variation in pharmaceutical consumption, partial removal of pharmaceuticals in wastewater treatment processes, and the direct discharge of livestock animal farm wastewater were identified among the major reasons for the observed differences. Several pharmaceuticals were found in aquatic environments of both continents in concentration levels higher than their ecotoxicity endpoints. In Europe, compounds such as diclofenac, ibuprofen, triclosan, sulfadimidine, carbamazepine and fluoxetine were reported in a concentration higher than the available ecotoxicity endpoints. In Africa, much more compounds reached concentrations more than the ecotoxicity endpoints, including diclofenac, ibuprofen, paracetamol, naproxen, ciprofloxacin, triclosan, trimethoprim, sulfamethoxazole, carbamazepine and fluoxetine, estriol and 17beta-estradiol. Details for each therapeutic group are presented in this review. PMID- 30448655 TI - Temperature and precipitation change in Malawi: Evaluation of CORDEX-Africa climate simulations for climate change impact assessments and adaptation planning. AB - Malawi is highlighted as one of the most vulnerable countries in the world to the effects of climate change. The large uncertainty around future climate change in the region remains a barrier to adaptation planning. Despite this high potential vulnerability, relatively little research has gone into determining how well available models represent this country's climate. This work therefore evaluates the ability of existing General Circulation Models (GCMs) and Regional Climate Models (RCMs) to hindcast climatic variables in Malawi at a resolution appropriate for climate change impact assessment and adaptation planning. We focus on monthly precipitation rate, and mean, maximum and minimum surface air temperature. This assessment compares available observed datasets against the outputs of six ERA-interim driven RCMs and 21 GCM-driven RCMs from the Coordinated Regional Climate Downscaling Experiment (CORDEX) initiative, and the 11 GCMs which form their boundary conditions. It was found that the performance of the RCMs is highly influenced by their boundary conditions. None of the individual or ensemble RCMs or GCMs assessed in this paper correlate well with the observed datasets for any of the assessed climatic variables. While, they do simulate the trending change in temperature variables well, the simulated outputs for precipitation are highly divergent. Based on these findings we suggest that either the ensemble RCMs or ensemble GCMs would be suitable for understanding projected temperature trends, with the RCMs providing better spatial resolution. However, none of the assessed models provide certainty over future precipitation trends in Malawi. As such we suggest that impact assessments and adaptation plans in Malawi will need to be designed and tested against a range of future precipitation scenarios. To improve modelling for Malawi it is recommended that regional climate models be improved for higher spatial resolution and inclusion of the impacts from large water bodies, including Lake Malawi. PMID- 30448656 TI - Methane emissions in grazing systems in grassland regions of China: A synthesis. AB - The effects of grazing on methane (CH4) budgets are important for understanding the balance of greenhouse gas emissions and removals in grassland ecosystems. However, the CH4 budgets of grazing systems, that is simultaneously considering CH4 uptake by grassland soils and emissions from ruminant enteric fermentation, livestock folds and animal feces, are poorly investigated, particularly for Chinese grasslands, and thus, remained unclear currently. Here, a synthesis of 43 individual studies was carried out to assess the grazing season/annual CH4 budgets and their responses to grazing in grassland ecosystems of China. The results showed that heavy grazing (HG) significantly decreased, while light grazing (LG) and moderate grazing (MG) had no significant effects soil CH4 uptake, as compared to un-grazing sites. Grazing has shifted Chinese grasslands from a sink to source for atmospheric CH4, and the grazing season/annual CH4 budgets increased with increasing grazing intensity, while the offset of CH4 uptake by grassland soils to total CH4 emissions from sheep, sheepfolds and feces were exponentially decreased with increasing grazing intensity. Moreover, the herbage biomass (HBM), organic matter intake (OMI) and live weight gain (LWG) were decreased while CH4 emission intensities (i.e., CH4 emission per HBM, OMI, and LWG) were linearly increased with increasing grazing intensity. Our results demonstrate that mediating grazing intensity, e.g., from HG to LG, could yield the optimal balance between maintaining productive grasslands and meanwhile mitigating CH4 emissions. This study could help for building strategies with implications for grassland management in China with similar CH4 emission problems. PMID- 30448657 TI - The emission of PM2.5 in respiratory zone from Chinese family cooking and its health effect. AB - To investigate the PM2.5 emission in the direct exposed area from Chinese family cooking, eleven kinds of Chinese ordinary family cooking dishes were designed including frying, quick-frying, stewing, deep-frying, boiling and steaming according to the results of questionnaire survey. The results showed that the intensity sequence for PM2.5 emissions decreased as follows in general: deep frying (0.709-2.731 mg/m3) > stir-frying (0.700-0.958 mg/m3) > stewing (~0.573 mg/m3) > quick-frying (0.140-0.433 mg/m3) > boiling (0.004-0.247 mg/m3) > steaming (0.011-0.088 mg/m3), most of them exceeded the national indoor air standard. The average concentration of PM2.5 in the direct respiratory zone from family cooking was determined to be 0.599 mg/m3, which was about 8 times higher than the national indoor air standard of China and lower than that from commercial restaurants. The annual PM2.5 inhalation exposure in the direct exposed area from family cooking for male and female was 346.30 mg/year and 309.59 mg/year, respectively. Although the annual PM2.5 inhalation exposure of male operators in general ordinary family cooking was about 11.8% higher than that of females, the pregnant women, children and the elderly are not encouraged to prepare ordinary family cooking for a long time due to their sensitive to PM2.5 emission. Selecting ventilator with high wind speed can reduce PM2.5 emission more than 65% when compared to medium wind speed. Improvement of ventilator wind speed is considered to be an effect way to reduce PM2.5 emission for cooking. PMID- 30448658 TI - Association of prenatal exposure to organochlorine pesticides and birth size. AB - There has been substantial evidence showing the adverse effects of organochlorine pesticide (OCP) exposure on human, but studies focused on the prenatal exposure effects at low OCP levels on infant birth size were scarce and controversial. In this study, cord serum samples were collected at the delivery from 1028 pairs of mothers and newborns in Wuhan, China and investigated the associations of prenatal exposure to OCPs and birth size. The prenatal exposure of hexachlorocyclohexane isomers (HCHs), p,p'-dichlorodiphenyltrichloroethane (p,p' DDT) and its metabolites were analyzed. The associations between birth size and prenatal OCP exposure were examined by multiple linear regressions. A sex specific relationship between the OCP exposure and birth size was observed. beta HCH was negatively associated with birth weight and ponderal index for boys [adjusted beta = -28.61; 95% confidence interval (CI): -54.84, -4.37 and adjusted beta = -0.17; 95% CI: -0.32, -0.01, respectively], whilst no significant associations with prenatal exposure of OCPs were found among girls. The inverse association of prenatal exposure to low levels of beta-HCH was shown sex-specific difference, which was only observed significantly in boys. The findings strengthened the evidence that the fetal development was influenced by prenatal exposure to certain OCPs and the effects might be different in the newborn sex. PMID- 30448659 TI - Drivers of tree carbon storage in subtropical forests. AB - Tropical and subtropical forest ecosystems play an important role in the global carbon regulation. Despite increasing evidence for effects of biodiversity (species diversity, functional diversity and functional dominance), stand structural attributes, stand age and environmental conditions (climate and topography) on tree carbon storage, the relative importance of these drivers at large scale is poorly understood. It is also still unclear whether biodiversity effects on tree carbon storage work through niche complementarity (i.e. increased tree carbon storage due to interspecific resource partitioning) or through the mass-ratio effect (tree carbon storage regulated by dominant traits within communities). Here we analyze tree carbon storage and its drivers using data of 480 plots sampled across subtropical forests in China. We use multiple regression models to test the relative effects of biodiversity, stand structural attributes, stand age and environmental conditions on tree carbon storage, and use a partial least squares path model to test how these variables directly and/or indirectly affect tree carbon storage. Our results show that tree carbon storage is most strongly affected by stand age, followed by climate, biodiversity and stand structural attributes. Stand age and climate had both direct and indirect (through species diversity, functional dominance and stand structural attributes) effects. We find that tree carbon storage correlates with both species diversity and functional dominance after stand age and environmental drivers are accounted for. Our results suggest that niche complementarity and the mass-ratio effect, not necessarily mutually exclusive, both play a role in maintaining ecosystem functioning. Our results further indicate that biodiversity conservation might be an effective way for enhancing tree carbon storage in natural, species-rich forest ecosystems. PMID- 30448660 TI - An integrated risk-based assessment of the North Sea to guide ecosystem-based management. AB - This study provides an integrated perspective to ecosystem based management (EBM) by considering a diverse array of societal goals, i.e. sustainable food supply, clean energy and a healthy marine ecosystem, and a selection of management measures to achieve them. The primary aim of this exercise is to provide guidance for (more) integrated EBM in the North Sea based on an evaluation of the effectiveness of those management measures in contributing to the conservation of marine biodiversity. A secondary aim is to identify the requirements of the knowledge base to guide such future EBM initiatives. Starting from the societal goals we performed a scoping exercise to identify a "focal social-ecological system" which is a subset of the full social-ecological system but considered adequate to guide EBM towards the achievement of those societal goals. A semi quantitative risk assessment including all the relevant human activities, their pressures and the impacted ecosystem components was then applied to identify the main threats to the North Sea biodiversity and evaluate the effectiveness of the management measures to mitigate those threats. This exercise revealed the need for such risk-based approaches in providing a more integrated perspective but also the trade-off between being comprehensive but qualitative versus quantitative but limited in terms of the "focal" part of the SES that can be covered. The findings in this paper provide direction to the (further) development of EBM and its knowledge base that should ultimately allow an integrated perspective while maintaining its capacity to deliver the accuracy and detail needed for decision-making. PMID- 30448661 TI - Selecting lichen functional traits as ecological indicators of the effects of urban environment. AB - Air pollution and the urban heat island effect are known to directly affect ecosystems in urban areas. Lichens, which are widely known as good ecological indicators of air quality and of climatic conditions, can be a valuable tool to monitor environmental changes in urban environments. The objective of this work was to select lichen functional traits and functional groups that can be used as ecological indicators of the effects of urbanization, with emphasis in the Southern subtropics, where this had never been done. For that, we assessed lichen functional composition in urban sites with different population density, which was considered as proxy for grouping sites in two levels of urbanization (low and medium/high). This a priori grouping was based on their significantly differences on air pollutants and land cover. Urbanization and air pollution showed to affect all lichen functional traits, with different responses depending on the functional group. Medium/high density urbanization was associated to an increase on the mean relative abundance of lichens with chlorococcoid green algae, foliose narrow lobes, soredia as the main reproduction strategy, pruinose thallus and containing secondary metabolites for chemical protection. Lower density urbanization showed a higher relative frequency of cyanolichens and lichens with Trentepohlia as the main algae, loosely attached crustose thallus and isidia as the main reproductive structure. The differences found on photobiont and growth form traits in response to the environmental variables used as proxies of microclimatic conditions (forest cover and number of trees around the sampling units), enabled us to detect the urban heat island effect (drier conditions in more urbanized sites). PMID- 30448662 TI - Dose-dependent effects of flufenoxuron on thyroid system of mature female lizards (Eremias argus) and their offspring. AB - More and more studies are focusing on toxic effect of pesticides on lizards. However, the responses of different life-stage lizards to pesticides have not been reported. In this study, according to RNA-seq library data, thyroxine 5' deiodinase activity showed significant difference between mature and immature lizard liver. In addition, triiodothyronine (T3) level in immature lizard serum was higher than that in mature lizard serum. Thus, we investigated the thyroid disruption of flufenoxuron with different concentrations (0, 5, 20 mg/kg) to both mature lizards and their offspring. No significant differences were observed in immature lizard body weight compared between control and exposure groups while the body weight of mature lizards was significantly decreased after flufenoxuron exposure. Moreover, the levels of thyroid hormones and the expression of thyroid related genes changed with exposure concentration of flufenoxuron and exhibited different regulation mechanism between mature and immature lizards. In immature lizard liver, tralpha, trbeta, dio1 and ugt genes controlled the thyroid hormone levels interfered by flufenoxuron. In contrast, the thyroxine (T4) pathway in mature lizard liver was significantly disrupted especially by 20 mg/kg flufenoxuron exposure. This study elucidated the different thyroid disruption effects of flufenoxuron to lizards based on different exposure doses and lizard life stages. PMID- 30448663 TI - Mercury pollution in modern times and its socio-medical consequences. AB - Mercury plays a critical role in serious health problems due to environmental or occupational exposures. Aquatic ecosystems are an essential component of the global biogeochemical cycle of mercury, as inorganic mercury can5 be converted to toxic methyl mercury in these environments and reemissions of elemental mercury rival anthropogenic mercury releases on a global scale. The history of the Minamata disease, a typical example of industrial pollution, has shown how corporate secrecy and ignorance on part of the health authorities may influence the devastating spread of environmental contamination and the progress of disease. While the Minamata Convention, in place since 2017, is aiming to lower mercury exposure and to prevent adverse effects, there are still knowledge gaps in the areas of global environmental mercury exposure. Areas of uncertainty in the global biogeochemical cycle of mercury include oxidation processes in the atmosphere, land-atmosphere and ocean-atmosphere cycling, and methylation processes in the ocean. Pollution related to climate change (especially in boreal and arctic regions), bioaccumulation and biomagnification of methyl mercury in the food chain, especially in fish and marine mammals, needs to be addressed in more detail. Information is lacking on numerous hidden contaminant exposures i.e. from globally applied traditional medicine, mercury containing skin creams and soaps, dental amalgam, ethyl mercury containing vaccines and latex paint additives, as well as on mercury releases from power plants, e-waste/fluorescent lamps, wildfire emissions, and global artisanal small-scale gold mining activities. Mercury occurs in various forms with different levels of toxicity. While much is already known and documented on the health effects of mercury, present knowledge and translation into preventive actions is still incomplete. Risks for long term health effects trough prolonged low dose exposure and trough cumulative exposures of various mercury forms should be further addressed. Preventive actions should include adequate human biomonitoring programs. Research data should be translated swiftly into management tools for local policy makers and health professionals, also paying attention at the major differences in mercury contamination across the globe. PMID- 30448664 TI - Pollution characteristics of ambient PM2.5-bound benzo[a]pyrene and its cancer risks in Beijing. AB - The purpose of this study was to reveal the pollution characteristics of ambient PM2.5-bound benzo[a]pyrene (B[a]P) in Beijing and to assess the lifetime cancer risk from respiratory pathway exposure. The average daily dose was evaluated by the annual concentrations of ambient PM2.5-bound B[a]P, combined with Chinese human exposure factors and the age sensitivity factors. The 70-year lifetime cancer risks of different groups were assessed by the exposure assessment and stochastic analysis method recommended by California Environmental Protection Agency. The groups were divided by age and gender. The results showed that the ambient PM2.5-bound B[a]P concentration during the cold season was 15.7 times greater than that during the warm season in Beijing. The annual average concentrations of PM2.5-bound B[a]P in outdoors and indoors were 1.67 ng/m3 and 1.04 ng/m3, respectively, which exceeded the limit of Chinese National Ambient Air Quality Standard. The cancer risks of PM2.5-bound B[a]P in males, females, and the general population were 9.085 * 10-6, 8.050 * 10-6, and 8.740 * 10-6, respectively. The cancer risk constituent ratios of ambient PM2.5-bound B[a]P in early life (<=16 years of age) for males, females, and the general population were 70.9%, 71.4%, and 71.3%, respectively. The males' cancer risk of PM2.5-bound B[a]P in Beijing was higher than that of the females. The early life cancer risk exposure to PM2.5-bound B[a]P should be paid more attention. PMID- 30448665 TI - What are the root causes hindering the implementation of green roofs in urban China? AB - It is worldwide accepted that green roofs have a variety of environmental, economic, and social benefits. China, which is experiencing rapid urbanization, has great potential to gain the benefits of green roofs, yet which are not commonly seen in the existing or new buildings. Understanding its root causes is important for promoting the larger-scale implementation of green roofs. Previous studies have studied the barriers of implementing green roofs in developed urban areas but ignored developing countries or regions, whose implementation of green roofs is still at the initial stage. To fill the research gap, this study aims to investigate the root causes that impede the implementation of green roofs in urban China through a practical survey and case study. The root causes are identified as the increase of maintenance cost, increase of design and construction cost, poor arrangement of the use of green roofs, and lack of incentives towards developers. Policy implications are proposed, which provide valuable references for decision-makers to improve the green-roof-related codes, policies and incentives. PMID- 30448666 TI - How could phytoextraction reduce Cd content in soils under annual crops? Simulations in the French context. AB - Human populations are threatened by chronic exposure to the Cd accumulated in foods after being taken up from soils by crops. To evaluate how phytoextraction with the hyperaccumulator Noccaea caerulescens as an annual crop or as a cover crop could modify the Cd mass balance in French agricultural soils, we simulated this process according to two scenarios. If current practices are maintained (first scenario), the average soil Cd content will increase by 2.9% after a century. If Cd content in P fertilizers is limited according to the European regulation project (second scenario), the decrease will be of about 4%. A phytoextraction crop with a 10 t dry matter (DM) ha-1 yield every 25 years would bring down the soil Cd content from 0.31 mg kg-1 to around 0.11 mg kg-1. However, this scenario is relatively unrealistic, because high dry matter yield is unlikely and the cost of the process is elevated. Phytoextraction as a cover crop every four to five years would decrease the soil Cd content more quickly. This requires a 2.5 t DM ha-1 yield, which appears realistic. This cover crop phytoextraction would be cheaper. It would need annual sowing of 4 million ha and the production of around 10 million t of dry biomass. To meet such a requirement, any breeding of the hyperaccumulator should favour traits allowing a 3-4 month cultivation period in the autumn. Processes also have to be developed to recover energy, metal or beneficial compounds from the biomass produced by phytoextraction. PMID- 30448667 TI - Identification of conservation and restoration priority areas in the Danube River based on the multi-functionality of river-floodplain systems. AB - Large river-floodplain systems are hotspots of biodiversity and ecosystem services but are also used for multiple human activities, making them one of the most threatened ecosystems worldwide. There is wide evidence that reconnecting river channels with their floodplains is an effective measure to increase their multi-functionality, i.e., ecological integrity, habitats for multiple species and the multiple functions and services of river-floodplain systems, although, the selection of promising sites for restoration projects can be a demanding task. In the case of the Danube River in Europe, planning and implementation of restoration projects is substantially hampered by the complexity and heterogeneity of the environmental problems, lack of data and strong differences in socio-economic conditions as well as inconsistencies in legislation related to river management. We take a quantitative approach based on best-available data to assess biodiversity using selected species and three ecosystem services (flood regulation, crop pollination, and recreation), focused on the navigable main stem of the Danube River and its floodplains. We spatially prioritize river-floodplain segments for conservation and restoration based on (1) multi-functionality related to biodiversity and ecosystem services, (2) availability of remaining semi-natural areas and (3) reversibility as it relates to multiple human activities (e.g. flood protection, hydropower and navigation). Our approach can thus serve as a strategic planning tool for the Danube and provide a method for similar analyses in other large river-floodplain systems. PMID- 30448668 TI - Horizontal vs vertical growth: Understanding latent patterns of urban expansion in large metropolitan regions. AB - Building activity at the metropolitan scale reflects socioeconomic transformations increasingly dependent on place-specific factors. The present study investigates height profile and age of buildings over 12 time intervals (1910s-2010s) in Greece, a country experiencing particularly complex urban cycles in the last century, with the aim to identify distinctive forces fueling vertical and horizontal urban expansion. To discriminate vertical from horizontal expansion, a new indicator of urban growth ('Vertical-to-Horizontal Growth' ratio, VHG) was proposed and used to identify the dominant socioeconomic profile underlying local-scale urbanization processes. Results of this study contribute to discriminate intense vertical expansion coinciding with population growth in large urban areas (Athens, Salonika, Iraklio) from moderate horizontal expansion around medium-rank cities, along coastal areas and in internal lowlands with small compact towns. Greek municipalities display spatial patterns of building activity that reflect the distinct impact of geographical gradients, divergent responses to market stimuli and planning constraints. As in other European countries, urban cycles in Greece were heterogeneous over space, justifying a joint analysis of intensity and spatial direction of metropolitan growth. PMID- 30448669 TI - Interregional carbon compensation cost forecast and priority index calculation based on the theoretical carbon deficit: China as a case. AB - Interregional carbon compensation is an important part of ecological compensation. An accurate accounting of the interregional carbon compensation cost is the foundation for establishing a carbon compensation mechanism. Corresponding to the actual carbon deficit, this paper advances, for the first time, the concept of the theoretical carbon deficit and, improves the calculation method of the interregional carbon compensation cost based on the theoretical carbon deficit. Additionally, this paper, forecasts the carbon compensation cost among 30 provinces in China from 2017 to 2026 by using the Stochastic Impacts by Regression on Population, Affluence, and Technology (STIRPAT) model and the gray prediction model GM (1, 1). Finally, this paper calculates the priority indexes of the carbon compensation among provinces. The results indicate that, first, from 2017 to 2026, the carbon emissions and carbon absorption in 30 provinces in China are generally on the rise, and the increase rate of carbon absorption is less than the increase rate of carbon emissions. Second, from 2017 to 2026, China's carbon compensation cost payment provinces and carbon compensation cost recipient provinces do not change position, and the flow of the carbon compensation cost is stable. The carbon compensation cost payment provinces are mainly located in the central and eastern regions, and the carbon compensation cost recipient provinces are mainly located in the northwestern region. Third, the priority indexes of carbon compensation in China's provinces are all small and declining, and the carbon compensation among regions has little impact on regional economic development. The research results in this paper can provide a reasonable reference for the cost calculation of interregional carbon compensation and the establishment and improvement of an interregional carbon compensation mechanism. PMID- 30448670 TI - Increase in anthropogenic mercury in marginal sea sediments of the Northwest Pacific Ocean. AB - Over the past century, the addition of anthropogenic mercury (HgANTH) to vast areas of North Pacific marginal seas adjacent to the northeast Asian continent has tripled. Analysis of sediment cores showed that the rate of HgANTH addition (HgANTH flux) was greatest in the East China and Yellow Seas (9.1 MUg m-2 yr-1) in the vicinity of China (the source continent), but was small in the Bering and western Arctic Ocean (Chukchi Sea) (0.9 MUg m-2 yr-1; the regions furthest from China). Our results show that HgANTH has reached open ocean sedimentary environments over extended areas of the northwestern Pacific Ocean, via the formation of organic-mercury complexes and deposition. The implication of these findings is that the addition of HgANTH (via atmospheric deposition and riverine input) to the ocean environment is responsible for elevated Hg flux into sedimentary environments in the northwest Pacific Ocean. PMID- 30448671 TI - Crop yield sensitivity of global major agricultural countries to droughts and the projected changes in the future. AB - Understanding the potential drought impacts on agricultural production is critical for ensuring global food security. Instead of providing a deterministic estimate, this study investigates the likelihood of yield loss of wheat, maize, rice and soybeans in response to droughts of various intensities in the 10 largest producing countries. We use crop-country specific standardized precipitation index (SPI) and census yield data for 1961-2016 to build a probabilistic modeling framework for estimating yield loss risk under a moderate (-1.2 < SPI < -0.8), severe (-1.5 < SPI < -1.3), extreme (-1.9 < SPI < -1.6) and exceptional (SPI < -2.0) drought. Results show that there is >80% probability that wheat production will fall below its long-term average when experiencing an exceptional drought, especially in USA and Canada. As for maize, India shows the highest risk of yield reduction under droughts, while rice is the crop that is most vulnerable to droughts in Vietnam and Thailand. Risk of drought-driven soybean yield loss is the highest in USA, Russian and India. Yield loss risk tends to grow faster when experiencing a shift in drought severity from moderate to severe than that from extreme to the exceptional category, demonstrating the non-linear response of yield to the increase in drought severity. Sensitivity analysis shows that temperature plays an important role in determining drought impacts, through reducing or amplifying drought-driven yield loss risk. Compared to present conditions, an ensemble of 11 crop models simulated an increase in yield loss risk by 9%-12%, 5.6%-6.3%, 18.1%-19.4% and 15.1%-16.1 for wheat, maize, rice and soybeans by the end of 21st century, respectively, without considering the benefits of CO2 fertilization and adaptations. This study highlights the non-linear response of yield loss risk to the increase in drought severity. This implies that adaptations should be more targeted, considering not only the crop type and region but also the specific drought severity of interest. PMID- 30448672 TI - Framework for determining optimal strategy for sustainable remediation of contaminated sediment: A case study in Northern Taiwan. AB - Contaminated sediment may pose a serious threat to human health and ecosystems. However, sediment remediation is typically an expensive and time-consuming process. Therefore, an effective decision-making process for the remediation of contaminated sediment is essential for identifying the optimal approach. Since a single assessment for sediment remediation may be insufficient, combining different analytical approaches is highly recommended. The objective of this study was to develop a comprehensive assessment framework based on the concept of green and sustainable remediation that considers various environmental, economic, and social aspects for the management of contaminated sediment. We propose a framework based on human health risk assessment (HHRA) and cost-benefit analysis (CBA) and apply the multicriteria decision analysis (MCDA) technique to implement integrated and sustainable strategies for sediment management. We used the framework to determine the best alternative for managing heavy-metal-contaminated sediment in a river in Northern Taiwan. The results of the pre-remediation HHRA indicated an unacceptably high cancer risk to children, while the CBA revealed that a remediation project was economically feasible. Moreover, the results of the MCDA revealed that a strategy involving in-situ capping with anthracite-based activated carbon would be relatively inexpensive and result in low risk to human health. In addition, this strategy would have a higher environmental impact and greater public acceptance as compared to a method involving the dredging and washing of soil. Thus, in this case study, in-situ capping using anthracite-based activated carbon was identified as the preferable remediation alternative from multiple perspectives. The proposed framework should allow decision-makers to choose the optimal integrated management strategy for similar river sites with contaminated sediment. PMID- 30448674 TI - Spatial distribution and temporal variation of drought in Inner Mongolia during 1901-2014 using Standardized Precipitation Evapotranspiration Index. AB - With intensification of climate change and human activities, warming and drying trend has brought severe challenges to pastoral areas in arid and semi-arid regions. Consequently, it becomes imperative to explore non-stationarity features of drought in such regions. In this research, the SPEIbase v2.4 datasets with a 0.5 degree spatial resolution was employed to extract Standardized Precipitation Evapotranspiration Index (SPEI) in Inner Mongolia, China. We explored non stationarity characteristics of drought using Breaks For Additive Seasonal and Trend (BFAST) method, investigated the variation characteristics of drought intensity in each time interval using intensity analysis method, and finally assessed the spatial and temporal gathering characteristics of drought with Empirical Orthogonal Function (EOF). The results showed that trend of regional drought had a tendency towards drought conditions, which is particularly significant from the year 1945 onwards in the overall Inner Mongolia. We have explored a long behavior of drought in semiarid and central regions of cold semihumid climate zone throughout the whole study period, and detected a drying trend in northeastern regions of Inner Mongolia at the latter decades. The overall drought intensity displayed an increasing trend first, which was followed by a decreasing trend, among which the extreme drought was dominant in period of 1960-1970. EOF mode1 showed that variation intensity of drought showed a not significantly increasing trend in the entire region, and the drought with high amplitude was likely to occur in the central region. EOF mode2 showed that variation intensity of drought displayed the opposite phases between the eastern and the western regions. The northeastern regions were prone to display a high amplitude of drought. PMID- 30448673 TI - Spatial analysis of energy use and GHG emissions from cereal production in India. AB - Agriculture contributes 18% of India's greenhouse gas (GHG) emissions. Yet, little is known about the energy requirements of individual crops, making it difficult to link nutrition-enhancing dietary changes to energy consumption and climate change. We estimate the energy and CO2 intensity of food grains (rice, wheat, sorghum, maize, pearl millet and finger millet) taking into account their irrigation requirements, water source, dependence on groundwater, yields, fertilizer and machinery inputs. Rice is the most energy-intensive cereal, while millets are the least. Total energy use contributes 16% of GHG emissions for rice, due to its high methane emissions, and 56% for wheat. Fertilizer production and use dominates GHG emissions from all crops, contributing 52% of GHGs from cereals. Energy intensities vary by up to a factor of four across the country, due to varying water requirements, irrigation sources and groundwater table depths. The results suggest that replacing rice with other cereals has the potential to reduce energy consumption and GHGs, though the spatial variation of production shifts would influence the extent of this reduction and the possible trade-offs with total production. PMID- 30448675 TI - Community composition, structure and productivity in response to nitrogen and phosphorus additions in a temperate meadow. AB - Global nitrogen (N) enrichment likely alters plant community composition and increases productivity, consequently affecting ecosystem stability. Meanwhile, the effects of N addition on plant community composition and productivity are often influenced by phosphorus (P) nutrition, as the effects of N and P addition and interactions between N and P on plant community structure and productivity are still not well understood. An in situ experiment with N and P addition was conducted in a temperate meadow in northeastern China from 2013 to 2016. The responses of plant community composition, structure, functional group cover, richness and productivity to N and P additions were examined. N addition significantly reduced species richness and diversity but increased aboveground net primary productivity (ANPP) during the four-study-year period. P addition exerted no significant impact on species richness, diversity or ANPP but reduced cover of grasses and increased legume cover. Under N plus P addition, P addition alleviated the negative effects of N addition on community structure by increasing species richness and covers of legume and forbs. N and P additions significantly altered plant community structure and productivity in the functional groups. N addition significantly increased the cover of gramineous and reduced the cover of legume, P addition significantly increased legume cover. Our observations revealed that soil nutrient availability regulates plant community structure and ANPP in response to nutrient enrichment caused by anthropogenic activities in the temperate meadow. Our results highlight that the negative influence of N deposition on plant community composition might be alleviated by P input in the future. PMID- 30448677 TI - Additional reduction of antibiotic resistance genes and human bacterial pathogens via thermophilic aerobic digestion of anaerobically digested sludge. AB - Thermophilic aerobic digestion (TAD) was applied to further reduce ARGs and heavy metal resistance genes (HMRGs) as well as class 1 integrons (intI1) in sludge from anaerobic digestion (AnD). Unlike after AnD, there was no enrichment of ARGs, HMRGs and intI1 after TAD. Residual gene fractions of intI1 and total ARGs (sum of targeted ARGs) were 0.03 and 0.08, respectively. Two kinetic models (Collins-Selleck and first-order) described the decay patterns of targeted genes, revealing rapid removal of intI1 during TAD. After TAD, the relative abundance of human bacterial pathogens (HBPs) and the numbers of HBPs species decreased to approximately 68% and 64% compared to anaerobically digested sludge, respectively. Thus, TAD, subsequent to AnD, may possess high potential for reducing biological risks resulting from ARGs, HMRGs, intI1 and HBPs in sewage sludge. PMID- 30448676 TI - Microwave-assisted low-temperature hydrothermal treatment of red seaweed (Gracilaria lemaneiformis) for production of levulinic acid and algae hydrochar. AB - In this study, red seaweed (Gracilaria lemaneiformis) food waste with high carbohydrate content was valorized into levulinic acid (LA) and algae hydrochar through microwave-assisted low-temperature hydrothermal treatment in dilute acid solution. Various parameters including treatment temperature (160-200 degrees C), reaction time (1-40 min), acid concentration (0-0.6 M), and biomass-to-liquid ratio (1%-10%, w/v) were examined. The energy efficiency and carbon recovery of the proposed process were investigated. Under the experimental conditions of 5% (w/v) biomass loading, 0.2 M H2SO4, 180 degrees C, and 20 min, the highest levulinic acid yield of 16.3 wt% was produced. The resulting hydrochar showed approximately 45-55% energy yield and higher heating values of 19-25 MJ kg-1. The energy efficiency of the present study (1.31 * 10-6 g LA/J) was comparable to those of the conventional hydrothermal treatment of lignocellulosic biomass, while the reaction time (20 min) was much shorter with a high carbon recovery (73.3%). PMID- 30448678 TI - Simultaneous fermentation of biomass-derived sugars to ethanol by a co-culture of an engineered Escherichia coli and Saccharomyces cerevisiae. AB - Microorganisms ferment xylose at high rate only when glucose concentration in the medium falls below a critical level. Since the specific productivity of product is highest during exponential to early stationary phase of growth, a glucose utilization negative ethanologenic E. coli (strain LW419a) was constructed for high rate of xylose fermentation in combination with Turbo yeast. This co-culture fermented all the released sugars in an acid/enzyme-treated sugar cane bagasse slurry (10% solids) to an ethanol titer of 24.9 +/- 0.8 g.L-1 (70% of the theoretical yield) in <30 h. Ethanol titer increased to 48.6 +/- 1.04 g.L-1 (yield, 0.45 g.g-1 sugars) at a solids content of 20% and the highest rate of xylose consumption was 1.58 +/- 0.21 g.L-1.h-1. This study demonstrates the potential of a co-culture of strain LW419a and yeast to rapidly ferment all the sugars in pretreated biomass slurries to ethanol at their respective highest rates. PMID- 30448679 TI - Increased carbohydrate production from carbon dioxide in randomly mutated cells of cyanobacterial strain Synechocystis sp. PCC 6714: Bioprocess understanding and evaluation of productivities. AB - Recently, several mutants of Synechocystis sp. PCC 6714 were obtained showing superior PHB content and productivities. Here, the most promising mutant named MT_a24 is compared in detail with the wild-type in controlled photobioreactors. In order to provide an easily scalable and alternative approach to the normally done two-step process -comprising of growth phase and limitation phase- a one step cultivation was optimized. The multivariate experimental design approach was used for the optimization of the one-step, self-limiting media. During one-step cultivation of MT_a24 with optimized media 30 +/- 4% (DCW) corresponding to 1.16 g L-1 PHB was obtained. Using pulse experiments it was demonstrated that phosphate is the key driver of glycogen synthesis in Synechocystis sp. PCC 6714 and it can be used to boost glycogen productivity. The maximum glycogen content acquired was 2.6 g L-1 (76.2% DCW) for mutant MT_a24 using phosphate feeding and carbon dioxide as carbon source. PMID- 30448680 TI - Economical lipid production from Trichosporon oleaginosus via dissolved oxygen adjustment and crude glycerol addition. AB - The effect of dissolved oxygen concentration on lipid accumulation in Trichosporon oleaginosus has been investigated. The experiment was performed in 15 L fermenters. The dissolved oxygen concentration varied by adjusting the agitation and aeration. High dissolved oxygen level at 50%-60% enhanced cell growth. Maintaining low dissolved oxygen concentration at 20%-30% during lipogenesis phase led to high final lipid content (51%) in Trichosporon oleaginosus. The consumptions of energy and cost of the process were evaluated. The energy consumption in the dissolved oxygen level optimized process was 41% less than that with dissolved oxygen level at 50%-60%. In addition, the cost was also reduced around one time in the dissolved oxygen level optimized process compared to the one with dissolved oxygen level at 50%-60%. The study provided a feasible way of enhancing lipid accumulation in Trichosporon oleaginosus and reducing the consumption of energy and cost of lipid production from Trichosporon oleaginosus. PMID- 30448681 TI - Cost-effective wastewater treatment in a continuous manner by a novel bio photoelectrolysis cell (BPE) system. AB - Approaches to improve wastewater treatment by microalgae have objectives of greater culture control, efficient nutrient removal and increased lipid content. This work designed a bio-photoelectrolysis cell (BPE) system to modulate wastewater treatment by electric current. The electric current had the capacity to enrich entrapped cell weight with a 0.72-fold increase, which resulted in high daily nutrient removal, with 6.78 mg/L/d for nitrogen and 2.14 mg/L/d for phosphorus at 0.6 A/m2. As the nutrient removal was mostly dependent on cell growth, the 1.17-fold increase of lipid productivity was achieved. The harvesting at 6 A/m2 required lower energy input of 1.77 KWh/kg. For the recyclability of treatment, BPE system could continuously treat the fresh wastewater for at least three cycles with biomass and lipid productivities of 68.67 and 22.04 mg/L/d, respectively. The nitrogen removal model of Cst = 45.52-5.52exp(0.45 t) and phosphorus removal model of Cst = 12.54-1.48exp(0.45 t) were established to evaluate the stability of BPE system. PMID- 30448682 TI - Quantitation of fast hydrolysis of cellulose catalyzed by its substituents for potential biomass conversion. AB - This paper investigates the accelerated acidic hydrolysis of cellulose by its substituents for potential biomass conversion. Insufficient pretreatments and slow cellulose hydrolysis are major obstacles that impede efficient hydrolysis of cellulose. Substituted cellulose, such as dyed cotton, has large availability. It is susceptible to acidic hydrolysis and can be used for biomass conversion without any pretreatments. To understand the mechanism of accelerated hydrolysis of cellulose by its substituents is a prerequisite for cellulosic biomass conversion with high efficiency. Substituents with different charge properties were synthesized and their interactions with oxocarbenium ions were studied based on Density Functional Theory. Results indicate that hydrolysis rate is affected by field effect from substituents. Such field effect is dominated by amounts of negative charges on substituents and distance between negatively charged groups and oxocarbenium. Hydrolysis rate of dye-substituted cotton is higher than or comparable to that applied with other catalytic approaches. PMID- 30448684 TI - From batch to fed-batch and to continuous packed-bed reactors: Lipase-catalyzed esterifications in low viscous deep-eutectic-solvents with buffer as cosolvent. AB - This work explores for the first time the use of Deep Eutectic Solvents (DES) with phosphate buffer 100 mM pH 7 as cosolvent (10% v/v) in biocatalytic reactions in fed-batch and packed-bed bioreactors. The lipase-catalyzed esterification of glycerol and benzoic acid is studied, as it involves two substrates with different polarities (for which DES are needed). In the fed-batch bioreactor, the highest conversion (90%) was obtained at a substrate flow rate of 0.01 mL/min. The fed-batch operation increased the conversion by 59% compared to the batch mode. Regarding productivity, semi-continuous and continuous bioreactors showed analogous results. Upon recirculation of the reaction media in the continuous bioreactor, a conversion of 67% was achieved in 7 cycles of operation. The stability of the biocatalyst in the packed-bed bioreactor decreased only 2% in 10 days, demonstrating the attractiveness that low viscous DES-water mixtures with continuous processes may have. PMID- 30448683 TI - Photosystem I fluorescence as a physiological indicator of hydrogen production in Chlamydomonas reinhardtii. AB - This study investigated the interrelations between hydrogen synthesis and Photosystem I electron transport rate in Chlamydomonas reinhardtii. The fluorescence of both photosystems (PS I and PS II) was monitored using a Dual Pulse Amplitude Modulated (PAM) Fluorometer. Hydrogen synthesis was induced by eliminating sulphur from the growth media (TAP-S). Multiple physiological parameters [rETR, Y (I), Y (II), NPQ, alpha, Fv/Fm and YI:YII] were recorded using the Dual PAM and correlated to hydrogen produced. There was a 66% increase in Photosystem I rETRmax during hydrogen production. A significant direct correlation existed between PS 1 rETRmax and hydrogen evolution values over the ten-day period (r = 0.895, p < 0.01) indicating that PS I can be considered as a driver of H2 production. Significant correlations between rETRmax of PS I and H2 evolution suggest a novel physiological indicator to monitor H2 production during the three critical phases identified in this study. PMID- 30448685 TI - Triacylglycerols accumulation and glycolipids secretion by the oleaginous yeast Rhodotorula babjevae Y-SL7: Structural identification and biotechnological applications. AB - The newly isolated oleaginous yeast, Rhodotorula babjevae Y-SL7, was shown to accumulate high intracellular content of microbial oil (mainly triacylglycerols) and to secret, under the same culture conditions, an atypical glycolipid. This unusual behavior was induced when the strain was subjected to nitrogen limitation and high amount of carbon. A series of analytical methods was adopted in order to structurally characterize the secreted glycolipid. The latter consists of a mixture of 9 molecules formed by a polyol head group, bound through the carboxyl end of an acetylated 3-hydroxy fatty acid with C18 or C16 chain length. In addition of their physicochemical properties such as emulsifying activity on hydrophobic substrates, Y-SL7 glycolipids have shown a therapeutically promising cytotoxic effect against different cancer cell lines. In fact, Y-SL7 strain can be used for the production of triacylglycerols as energetic molecules and for the secretion of a biosurfactant of therapeutic and environmental interest. PMID- 30448687 TI - Performance and potential appraisal of various microalgae as direct combustion fuel. AB - Direct combustion of biomass is considered the most effective and simple means to contribute to CO2 reduction. In this context, the life-cycle potential of microalgal solid fuel, which has been overlooked so far, was comprehensively scrutinized ranging from cultivation to direct combustion. According to the quantitative data, using the raw fuel was confirmed to offer great benefits over the conventional lipid-targeted microalgal fuel systems through exploiting all of the biomass' energy potential, thereby being able to significantly increase the energy yield from biomass. The solid fuel is shown to exhibit diverse positive aspects owing to its remarkable calorific value, productivity and CO2 fixation ability. The combustion test reveals coal-microalgae co-combustion brings beneficial consequences on combustibility and environmental impacts with no notable thermal efficiency drop. This holistic appraisal shows microalgae patently possess high potential as a direct combustion fuel, even outperforming that of extensively used woody fuels. PMID- 30448686 TI - High-efficiency removal of Pb(II) and humate by a CeO2-MoS2 hybrid magnetic biochar. AB - This work prepares a novel CeO2-MoS2 hybrid magnetic biochar (CMMB) for the adsorptive removal of Pb(II) and humate from aqueous solution. The CMMB was evaluated against magnetic biochar (MB). The results showed that CMMB exhibited strong magnetic separation ability. Hybridization of CMMB greatly improved Pb(II) and humate removal compared to MB, with >99% Pb(II) and humate removed within 6 h. Pb(II) and humate removal capacities of CMMB were 263.6 mg/g and 218.0 mg/g, respectively, with negligible influence of ion strength in the range of 0-0.1 mol/L NaNO3. Pb(II) removal mechanism involved predominately with electrostatic attraction, Cpi-Pb(II) bond interaction, and surface adsorption and complexation combined processes; while pore-filling, partition effect and pi-pi interaction contributed to the adsorption of humate. Overall, the introduction of graphene like MoS2 materials into biochar benefits both of the biomass resources recovery and environmental protection. PMID- 30448688 TI - Piggery wastewater treatment by aerobic granular sludge: Granulation process and antibiotics and antibiotic-resistant bacteria removal and transport. AB - The aim of this work was to study the responses of aerobic granulation process to antibiotics and investigate the antibiotics and antibiotic-resistant bacteria (ARB) removal and transport. Results showed that aerobic granular sludge (AGS) was dominant in the bioreactor at day 45, and the relatively high protein content from tightly bound extracellular polymeric substances (TB-EPS) facilitated aerobic granulation and maintained biomass stabilization. The protein contents in EPS and TB-EPS were positively correlated with relative hydrophobicity, thereby improving the adsorption capacity among hydrophobic particles. The chemical oxygen demand (COD), NH3-N, and total N removal efficiencies were 98.0%, 97.0%, and 92.4%, respectively. Five antibiotics, including kanamycin, tetracycline, ciprofloxacin, ampicillin, and erythromycin, were examined in piggery wastewater, with concentrations up to the concentration range of 29.4-44.1 ug/l, and the total antibiotics removal rate reached up to 88.4% +/- 4.5%. A total of 5.2% of the total antibiotics were discharged from bioreactor, and 62.5% of the total antibiotics were degraded, and 32.3% of total antibiotics were adsorbed by aerobic granules. The presence of antibiotics rarely exhibited an influence on AGS formation, and the relatively high microbial activity of aerobic granules was beneficial to antibiotics removal. The ARB removal rate increased up to 89.4% +/- 3.3%, but a large amount of ARB was enriched in aerobic granules. PMID- 30448689 TI - Same fear responses, less avoidance: Rewards competing with aversive outcomes do not buffer fear acquisition, but attenuate avoidance to accelerate subsequent fear extinction. AB - Rewards for approaching a feared stimulus may compete with fear reduction inherent to avoidance and thereby alter fear and avoidance learning. However, the impact of such competing rewards on fear and avoidance acquisition has rarely been investigated. During acquisition, participants chose between one option (CS+ option) associated with a neutral stimulus followed by an aversive unconditioned stimulus (US) and another option (CS- option) associated with another neutral stimulus followed by no US (N = 223 randomized into three groups). In a subsequent test, no more USs occurred. In one group, competing rewards were established by linking the CS+ option to high rewards and the CS- option to low rewards during acquisition and test (Reward Group). In a second group, rewards were present during acquisition, but discontinued during test (Initial-Reward Group). In a third group, rewards were completely absent (No-Reward Group). Without competing rewards, significant avoidance was acquired and persisted in the absence of the US. Competing rewards attenuated avoidance acquisition already after the first experience of the aversive US. Avoidance remained attenuated even when rewards were discontinued during test. Rewards did, however, not change the level of fear responses to the CS+ (US expectancy, skin conductance). Finally, rewards did not change the level of fear reduction during test, which was, however, experienced earlier. Summarized, rewards for approaching aversive events do not buffer fear acquisition, but can prevent avoidance. This damping of avoidance may initiate fear extinction. PMID- 30448690 TI - The frequency-following response (FFR) to speech stimuli: A normative dataset in healthy newborns. AB - The Frequency-Following Response (FFR) is a neurophonic auditory evoked potential that reflects the efficient encoding of speech sounds and is disrupted in a range of speech and language disorders. This raises the possibility to use it as a potential biomarker for literacy impairment. However, reference values for comparison with the normal population are not yet established. The present study pursues the collection of a normative database depicting the standard variability of the newborn FFR. FFRs were recorded to /da/ and /ga/ syllables in 46 neonates born at term. Seven parameters were retrieved in the time and frequency domains, and analyzed for normality and differences between stimuli. A comprehensive normative database of the newborn FFR is offered, with most parameters showing normal distributions and similar robust responses for /da/ and /ga/ stimuli. This is the first normative database of the FFR to characterize normal speech sound processing during the immediate postnatal days, and corroborates the possibility to record the FFRs in neonates at the maternity hospital room. This normative database constitutes the first step towards the detection of early FFR abnormalities in newborns that would announce later language impairment, allowing early preventive measures from the first days of life. PMID- 30448691 TI - Outcomes and costs of single-step hepatitis C testing in primary care, Birmingham, United Kingdom. AB - OBJECTIVES: In UK laboratories, the diagnostic algorithm for chronic hepatitis C (HCV) infection commonly requires two serological assays to confirm anti-HCV antibody positivity in a serum sample followed by HCV RNA detection in a second whole-blood sample (two-step testing algorithm). A single-step algorithm (both anti-HCV antibodies and RNA tested on an initial serum specimen) has been advocated to reduce attrition rates from the care pathway. STUDY DESIGN: To investigate the feasibility, clinical impact and relative costs of switching from a two-step to single-step testing algorithm in the laboratory, a pilot study on unselected primary care requests was undertaken. METHODS: All primary care patients tested for HCV infection from December 2013 to April 2016 were included. The single-step testing algorithm was introduced in March 2015. Before this, the two-step algorithm was used. Patients were followed up until August 2016. RESULTS: RNA quantitation in plasma was within one log of serum values for 21 paired samples. Although all patients in the single-step algorithm received an RNA test, only 70% completed the two-step testing algorithm; differences in referral rates to specialist care was due to 30% of HCV antibody-positive patients in the two-step algorithm not having follow-up whole-blood sampling for HCV RNA testing. Costs per new diagnosis and new diagnosis referred to specialist care were lower in single-step testing by L94.32 and L144.25, respectively. CONCLUSION: This study provides further evidence that a single-step testing algorithm, as recommended in the UK Standards for Microbiology Investigation, works in practice and should be the standard of care for screening for chronic HCV. PMID- 30448692 TI - Psychological distress among primary school teachers: a comparison with clinical and population samples. AB - OBJECTIVES: This analysis explored the level of psychological distress among primary school teachers in the South West of England as compared with clinical and general population samples. STUDY DESIGN: Secondary analysis of data from the Supporting Teachers and Children in Schools (STARS) trial completed by up to 90 teachers at baseline, 9, 18 and 30 months of follow-up. METHODS: We used the Everyday Feelings Questionnaire (EFQ) as a measure of psychological distress. Baseline data on teachers were compared with a population sample of professionals and a clinical sample of patients attending a depression clinic. RESULTS: Our teacher cohort experienced higher levels of psychological distress than comparable professionals from the general population, which were sustained over 30 months of follow-up. Levels of psychological distress were lower than those found in the clinical sample. Using a cut-point indicative of moderate depression, our data suggest that between 19% and 29% of teachers experienced clinically significant distress at each time-point. CONCLUSIONS: We detected high and sustained levels of psychological distress among primary school teachers, which suggests an urgent need for intervention. Effective support for teachers' mental health is particularly important given the potential impact of poor teacher mental health on pupil well-being, pupil attainment and teacher-pupil relationships. PMID- 30448694 TI - Frailty phenotype, frailty index and risk of mortality in Chinese elderly population- Rugao longevity and ageing study. AB - BACKGROUND: To explore the associations of frailty phenotype and frailty index (FI) defined frailty and pre-frailty with mortality in a Chinese elderly population. METHODS: Data of 1788 community-dwelling elders aged 70-84 years from the ageing arm of Rugao Longevity and Ageing Study, a prospective cohort study, were used. Frailty phenotype was defined using modified Fried's phenotype (FP) criteria and FI was constructed using 45 health deficits. Mortality was ascertained using the Death Registry of Rugao's Civil Affairs Bureau. RESULTS: During 3-year follow-up, 149 (8.3%) of the 1788 elderly subjects died. For frailty phenotype, about 9.5% of the elderly were frail and 43% were pre-frail. For FI, frail (FI > 0.21) was approximately 27.5%, and pre-frail (FI: 0.1-0.21) was approximately 51.3%. Highest mortality was observed among frail participants defined by both FP and FI criteria (all Log Rank P < 0.05). Frailty defined by the frailty index was associated with a 2.31 fold (95% CI 1.16-4.6) risk of all cause death compared with robust elderly. Compared with the robust elderly, not only frailty (HR 2.24, 95% CI 1.31-3.83) defined by frailty phenotype but also pre-frailty (HR 1.51, 95% CI 1.03-2.21) was associated with risk of all-cause mortality. CONCLUSIONS: Frailty, defined by either phenotype or index, is associated with increased risks of mortality in elderly Chinese community population. PMID- 30448693 TI - Which frailty scale for patients admitted via Emergency Department? A cohort study. AB - OBJECTIVES: To determine the prevalence of frailty in Emergency Departments (EDs); examine the ability of frailty to predict poor outcomes post-discharge; and identify the most appropriate instrument for routine ED use. METHODS: In this prospective study we simultaneously assessed adults 65+yrs admitted and/or spent one night in the ED using Fried, the Clinical Frailty Scale (CFS), and SUHB (Stable, Unstable, Help to walk, Bedbound) scales in four Australian EDs for rapid recognition of frailty between June 2015 and March 2016. RESULTS: 899 adults with complete follow-up data (mean (SD) age 80.0 (8.3) years; female 51.4%) were screened for frailty. Although different scales yielded vastly different frailty prevalence (SUHB 9.7%, Fried 30.4%, CFS 43.7%), predictive discrimination of poor discharge outcomes (death, poor self-reported health/quality of life, need for community services post-discharge, or reattendance to ED after the index hospitalization) for all identical final models was equivalent across all scales (AUROC 0.735 for Fried, 0.730 for CFS and 0.720 for SUHB). CONCLUSION: This study confirms that screening for frailty in older ED patients can inform prognosis and target discharge planning including community services required. The CFS was as accurate as the Fried and SUHB in predicting poor outcomes, but more practical for use in busy clinical environments with lower level of disruption. Given the limitations of objectively measuring frailty parameters, self-report and clinical judgment can reliably substitute the assessment in EDs. We propose that in a busy ED environment, frailty scores could be used as a red flag for poor follow-up outcome. PMID- 30448695 TI - Brain arousal regulation in SSRI-medicated patients with major depression. AB - EEG measures of arousal have been suggested as diagnostic and predictive biomarkers for major depression. The aim of the present study was to examine whether self-rated depression severity in SSRI-medicated patients with major depression (MD) is associated with EEG measures of brain arousal. Based on previous studies, we expected that a higher level of brain arousal and a slower arousal decline during a 15-min EEG recording are associated with higher symptom severity as assessed with the Beck Depression Inventory (BDI) at the time of the EEG recording. EEGs of 78 MD patients and 46 healthy controls were analyzed. Brain arousal was assessed using the Vigilance Algorithm Leipzig (VIGALL 2.1). Based on automatically classified 1-s segments (EEG-vigilance Stages 0, A1, A2, A3, B1, B2/3 or C) we computed indices to assess the level (mean EEG-vigilance) and the decline of arousal (slope index) during the 15-min resting state EEG under eyes-closed condition. We found that a higher arousal level and a slower arousal decline corresponded to higher severity of depressive symptoms (rho = 0.238, p = .018; and rho = 0.236; p = .019). Self-rated non-remitters (BDI>12) had a higher arousal level (mean EEG-vigilance: t76 = -2.19, p = .016) and slower arousal decline (slope index: Z = -2.08, p = .019) during the 15-min recording as compared to remitters. Similar results were obtained between non-remitters and healthy controls (mean EEG-vigilance: t102 = -2.75, p = .004; slope index: Z = 1.92, p = .028), but not between remitters and controls (p > .260). The findings support the model that brain arousal regulation plays an important role in the pathophysiology and treatment of MD. PMID- 30448696 TI - Prefabrication of a large pedicled bone graft by engineering the germ for de novo vascularization and osteoinduction. AB - Large and complex bone defects represent challenging clinical scenarios, typically requiring autologous vascularized bone transplants. In order to bypass the numerous associated limitations, here we aimed at ectopically prefabricating a bone graft surrogate with vascular pedicle. A hollow cylinder of devitalized cancellous bone was used to define the space of a large bone substitute. This space was filled with devitalized pellets of engineered hypertrophic cartilage as bone-inducing material, in combination or not with stromal vascular fraction (SVF) of adipose tissue as source of osteoprogenitors and endothelial cells. Vascularization of the space was targeted through axial insertion of an arterio venous (AV) bundle. Constructs were subcutaneously implanted in nude rats for 12 weeks and analyzed for bone formation and vascularization by histology and microtomography. Retrieved constructs were extensively vascularized in all conditions, with vessels sprouting from the AV bundle and reaching a higher density in the axially central volume. Bone tissue was formed through remodeling of hypertrophic cartilage, and quantitatively correlated with de novo vascularization. Our study demonstrates feasibility to prefabricate large, pedicled bone grafts in predefined shapes. The combination of an AV bundle with engineered hypertrophic cartilage provided a germ for the coupled processes of vascularization and bone formation. The demonstrated osteoinductivity of devitalized hypertrophic cartilage offers the opportunity of implementing the proposed regenerative surgery strategy through off-the-shelf materials. PMID- 30448697 TI - Autophagy inhibitor enhance ZnPc/BSA nanoparticle induced photodynamic therapy by suppressing PD-L1 expression in osteosarcoma immunotherapy. AB - Elevated expression of programmed death ligand-1 (PD-L1) on the surface of tumor cells can exhaust cytotoxic T lymphocyte cells and lead to the failure of anti tumor immunity during the course of tumor treatment. Here, we implemented a combined regimen of tumor resection and bovine serum albumin-Zinc phthalocyanine induced photodynamic therapy (PDT). To overcome the long-distance metastasis of osteosarcoma, we also explored the effects of PD-L1 down-regulation with PDT and the autophagy inhibitor 3-MA on osteosarcoma treatment. A dramatic anti-tumor effect induced by PDT was observed in a partial resection model, which revealed the potential clinical application of PDT during tumor resection. Meanwhile, we also confirmed the down-regulation of PD-L1 in osteosarcoma in response to PDT and 3-MA treatment, which significantly inhibited tumor growth in a model of tumor metastasis. The immunological response induced by the combination of the autophagy inhibitor and PDT suppressed osteosarcoma in vitro and in vivo, which indicated the potential application of this regimen for preventing tumor metastasis. The combination of PDT with multiple therapies has a potentially bright future as an osteosarcoma treatment strategy. PMID- 30448698 TI - In vitro placenta barrier model using primary human trophoblasts, underlying connective tissue and vascular endothelium. AB - Fetal development may be compromised by adverse events at the placental interface between mother and fetus. However, it is still unclear how the communication between mother and fetus occurs through the placenta. In vitro - models of the human placental barrier, which could help our understanding and which recreate three-dimensional (3D) structures with biological functionalities and vasculatures, have not been reported yet. Here we present a 3D-vascularized human primary placental barrier model which can be constructed in 1 day. We illustrate the similarity of our model to first trimester human placenta, both in its structure and in its ability to respond to altered oxygen and to secrete factors that cause damage cells across the barrier including embryonic cortical neurons. We use this model to highlight the possibility that both the trophoblast and the endothelium within the placenta might play a role in the fetomaternal dialogue. PMID- 30448699 TI - An injectable continuous stratified structurally and functionally biomimetic construct for enhancing osteochondral regeneration. AB - Osteochondral regeneration with the formation of hyaline cartilage and subchondral bone as well as the integration between the newly formed tissues with the host tissue still remains a great challenge. In this study, a construct containing an injectable continuous stratified scaffold and multiple cell systems was designed for enhancing osteochondral regeneration. Briefly, an injectable sodium alginate(SA)/bioglass (BG) composite hydrogel containing bone marrow stem cells (BMSCs) (SA/BG + BMSCs) was used for subchondral bone regeneration and an injectable thermosensitive SA/agarose (AG) composite hydrogel with co-culture of BMSCs and articular chondrocytes (ACs) (SA/AG + ACs/BMSCs) was applied for articular cartilage regeneration. The continuous SA phase and the stratified structure enable the scaffold to mimic the natural osteochondral structure. In addition, the SA/BG + BMSCs hydrogel could enhance the osteoblast differentiation of BMSCs by upregulating their alkaline phosphatase and collagen I gene expressions, and the SA/AG + ACs/BMSCs hydrogel could promote the chondrocyte differentiation of BMSCs by upregulating their Acan and collagen II gene expressions, which indicated that this stratified scaffold could mimic the natural osteochondral function. Furthermore, after the stratified construct was injected into a rat osteochondral defect model, obvious neonatal articular cartilage tissues and subchondral bone tissues with regular surface and highly integration with normal tissues could be observed. This structural and functional biomimetic construct, together with its proper swelling ratio, could not only stimulate the hyaline cartilage and subchondral bone regeneration in an entire osteochondral unit but also promote the integration between the newly formed tissues and the host tissue. PMID- 30448700 TI - Health implication of heavy metals exposure via multiple pathways for residents living near a former e-waste recycling area in China: A comparative study. AB - Herein, crop (vegetables and rice, n = 30), soil (n = 14), dust (n = 12), and PM10 (n = 25) samples were collected to assess the environmental quality of a former e-waste recycling area and evaluate the related health risks. In dust and PM10, the concentrations of heavy metals (Cd, Cu, Ni, Pb, and Zn) were lower than previously reported values, although the numbers for soil, vegetables, and rice remained high. The average accumulation factors of heavy metals in crops decreased in the order of Zn > Cd > Ni > Cu > Pb, and soil was identified as the largest contributor to crop pollution. Heavy metal ingestion largely occurred via rice consumption, which accounted for a significant fraction of the total average daily dose (ADD; 75.2-86.7% in children and 78.0-91.7% in adults), especially for Cd, Cu, Ni, and Zn. However, in the case of Pb, soil ingestion accounted for 48.9% of the ADD in adults, while in children, vegetable, rice, and dust ingestion accounted for 44.7%, 28.6%, and 23.7% of the ADD, respectively. The combined exposure hazard indices at the fifth, median, and 95th percentiles for all heavy metals were determined as 2.54, 9.40, and 40.1 for adults and as 3.75, 13.7, and 58.4 for children, respectively. In terms of health risk, crop consumption was identified as the major exposure pathway for both children and adults, featuring a contribution of 99.9%. In addition, the 95th percentile carcinogenic risks for Pb exceeded the acceptable level. Thus, this work shows that to reduce the health risk for local residents in the former e-waste area, more attention should be paid to soil repair. PMID- 30448701 TI - Bulk/wet deposition of trace metals to rural, industrial, and urban areas in the Yangtze River Delta, China. AB - The bulk depositions of trace metals to three land uses in the Yangtze River Delta are investigated based on the collected 154 precipitation samples from August 2015 to May 2017. The volume-weighted mean (VWM) concentrations of Ni, Cu, Zn, Cd, and Pb were 13.28, 5.32, 13.02, 0.33, and 10.53 MUg L-1, and 12%, 16%, 3%, 11%, and 26% of precipitation events exceeded the limits in the Central Drinking-Water Source Area (GB3838-2002), respectively. Furthermore, the five metals varied significantly under urban, industrial, and rural land use conditions, indicating that these metal concentrations were greatly determined by local sources; lower concentrations were found in sea and local air masses than in air masses from inland trajectories. Combining the precipitation amounts, the bulk deposition fluxes of the five metals were 25.99, 25.47, 20.60, 10.40, 0.64 mg m-2 yr-1. By comparing the metal deposition fluxes in 98 studies across China, Ni and Pb deposition in the Yangtze River Delta was higher, while that of Cd and Zn was lower than their respective averages across China, indicating that Ni and Pb pollution should receive more attention in the study area. CAPSULE: Bulk/wet deposition fluxes of trace metals varied greatly among rural, industrial, and urban areas, and Pb and Ni showed severe pollution levels in the Yangtze River Delta. PMID- 30448702 TI - Comparative extraction of Salmonella bongori derived metabolites and their toxicity on bacterial pathogens, mosquito-larvae, zebrafish-embryo and brine shrimp: A modified approach. AB - The present study pertains to two different (standard and adapted) extraction procedures to extract bacterial extracellular metabolites from the cell-free supernatant (CFS) of S. bongori. Metabolites were extracted with the different polarity solvents using lyophilized-CFS mediated procedure, which revealed more number of compounds than standard procedure. The crude-extracts (CEs) were characterized using FTIR, HPLC and GC-MS analyses. The commonly presented compounds in standard (ME, EA & HE) and lyophilization-mediated extracts (LME, LEA & LHE) were identified through Heat-map analysis. Antibacterial assay: all CEs showed considerable activity on tested MTCC-strains, in which, LME and LEA were found preponderant. Larvicidal bioassay: LME resulted maximum mortality than other CEs on Culex-larvae. Zebrafish embryo-toxicity assay: except HE, all CEs exhibited toxicity at 100 ppm after 96 hpf. Brine shrimp-toxicity assay: ME, LME, EA and LEA have shown significant mortality after 24 h. With these observations, the adapted-extraction-procedure could form significance in the drug development process. PMID- 30448703 TI - Evaluation of cytotoxicity, genotoxicity and ecotoxicity of nanoemulsions containing Mancozeb and Eugenol. AB - Mancozeb is a fungicide widely used in agriculture, mostly against the pathogen Glomerella cingulata responsible for the rot of ripe grape, but presents high toxicity. Strategies are sought to reduce the toxicity of this fungicide and alternative treatments are welcome. An alternative could be the use of clove oil, which has Eugenol as its major compound, and has antifungal potential against G. cingulata, however, Eugenol is susceptible to degradation processes which may compromise its efficacy. The nanoencapsulation of Mancozeb and Eugenol is a possible strategy to overcome the limitations of toxicity, solubility and instability of these compounds. Therefore, the objective of this study is to develop nanoemulsions containing Mancozeb (0.1 mg/mL) and Eugenol (33 mg/mL), isolated or associated, and evaluate the safety of these formulations through cytotoxicity, genotoxicity and ecotoxicity tests. Nanoemulsions were developed by the spontaneous emulsification method, cytotoxicity and genotoxicity were evaluated in healthy human cells through MTT, Dichlorofluorescein diacetate and Picogreen tests, and ecotoxicity assessment was carried out using the chronic toxicity test in springtails. After preparation, the physicochemical characterization of the nanoemulsions were performed which presented mean particle size between 200 and 300 nm, polydispersity index less than 0.3, negative zeta potential and acid pH. The nanoencapsulation was able to avoid the reduction of the cell viability caused by Mancozeb, while Eugenol was shown to be safe for cell use in both free and nanostructured forms, however the association of the two active compounds showed toxicity in the higher doses of Mancozeb. In the ecotoxicity tests, both free Mancozeb and Eugenol forms presented high toxic potential for soil, whereas the nanoencapsulation of these compounds did not cause a reduction in number of springtails. Therefore, from the tests performed, it was possible to observe that nanoencapsulation of Mancozeb and Eugenol is a safe alternative for the application of these compounds mainly in agriculture. PMID- 30448704 TI - Modelling the mitigation speeds of 137Cs, 90Sr and 131I in the topsoils and assessment of the radiological hazards. AB - Fate modelling of artificial radionuclides (ARs) in top soils are necessary to assess the radiological effects to population. Among ARs, 137Cs, 90Sr and 131I are very important since the large abundances in the environment. In this study, the fates of 137Cs, 90Sr and 131I in the surface soil layers were simulated by the soil model which was developed by the Canadian Centre for Environmental Modelling and Chemistry (CEMC). The scenario that 137Cs, 90Sr and 131I contaminated in topsoil in the exclusion of Fukushima Daiichi nuclear power plant (NPP) accident was evaluated. The results show the expected time for the minimum hazardous level of exposure. It is 115.5 days after the exposure, when the total effective dose is 1 mSv y-1 in which 0.46 mSv y-1 from ingestion and 0.54 mSv y-1 from gamma exposure. Hazard levels due to exposure progresses are varied in order gamma exposure (82.14%) > ingestion (17.47%) > inhalation (0.39%). The hazard levels from radionuclides are varied in order 137Cs (63.34%) > 131I (33.48%) > 90Sr (3.18%). PMID- 30448705 TI - Impacts of the mycotoxin zearalenone on growth and photosynthetic responses in laboratory populations of freshwater macrophytes (Lemna minor) and microalgae (Pseudokirchneriella subcapitata). AB - Mycotoxins are an important class of chemicals of emerging concern, recently detected in aquatic environments, potentially reflecting the influence of fungicide resistance and climatic factors on fungal diseases in agricultural crops. Zearalenone (ZON) is a mycotoxin formed by Fusarium spp. and is known for its biological activity in animal tissues; both in vitro and in vivo. ZON has been reported in US and Polish surface waters at 0.7 - 96 ng/L, with agricultural run-off and wastewater treatment plants being the likely sources of mycotoxins. As some mycotoxins can induce phytotoxicity, laboratory studies were conducted to evaluate the toxicity of ZON (as measured concentrations) to freshwater algae (Pseudokirchneriella subcapitata) and macrophytes (Lemna minor) following OECD test guidelines 201 and 221, respectively. Zinc sulphate was used as a positive control. In the OECD 201 algal static study (72 h at 24 +/- 1 degrees C), exposure to ZON gave average specific growth rate (cell density) EC50 and yield (cell density) EC50 values of > 3.1 and 0.92 (0.74 - 1.8) mg/L, respectively. ZON was less toxic in the OECD 221 static study and after 7 d at 24 +/- 1 degrees C. L. minor growth was significantly reduced based on frond number and frond area at 11.4 mg ZON/L, showing a higher tolerance than reported for other mycotoxins with Lemna spp. Chlorophyll fluorescence parameters were used as biomarkers of impacts on photosystem II efficiency, with no effect seen in algae but, with responses being observed in L. minor between 5.2 - 14.4 mg ZON/L. ZON toxicity seen here is not of immediate concern in context with environmental levels, but this study highlights that other freshwater organisms including algae are more sensitive to mycotoxins than Lemna sp., the only current source of toxicity data for freshwater plants. PMID- 30448706 TI - The impact of chronic environmental metal and benzene exposure on human urinary metabolome among Chinese children and the elderly population. AB - The health effects of metals and benzene exposure have been extensively investigated; however, information on the impact of chronic environmental metal and benzene exposure on human urinary metabolome is limited. In this study, a total of 566 participants, including 352 elderly and 214 children, were split into the "exposed" and "control" groups. The urine samples of all the participants were collected and stored at - 80 degrees C until analysis. The urinary levels of 17 metals and S-phenylmercapturic acid (S-PMA) were determined by the ICP-MS and LC-MS/MS methods to comprehensively assess the personal metal and benzene exposure levels, respectively. Then, the individual levels of metal and benzene exposure were correlated to the metabolic consequences of ambient pollutant exposure, which were previously observed in our metabolomics study. As a result, multiple metals, including Cd, Co, Cr, Cu, Fe, Hg, Li, Mo, Ni, Pb, Se, and Zn, exhibited a significant linear dose-dependent association with one or more urinary metabolites, including two amino acids (pyroglutamic acid and 3 methylhistidine), three organic acids (azelaic acid, decenedioic acid, and hydroxytetradecanedioic acid), ten medium-chainacylcarnitines (heptenedioylcarnitine, octenedioylcarnitine, nonenedioylcarnitine, decenedioylglucuronide, 3-hydroxydecanoylcarnitine, dodecanedioylcarnitine, nonanoylcarnitine, decadienylcarnitine, hydroxydodecenoylcarnitine, dodecadienylcarnitine, and dodecenoylcarnitine), and one glucuronide conjugate (decenedioylglucuronide). These observations indicate that the increased environmental metal exposure has caused various oxidative stress-related effects, including the depletion of antioxidants, accelerated muscle proteolysis, elevated activity of UGTs, increased lipid peroxidation, and the disorder of mitochondrial lipid metabolism among exposed children and the elderly. The current study provides new insights into the biological effects induced by metal exposure in the environment. PMID- 30448707 TI - Educational achievement of children with congenital heart disease: Promising results from a survey by the German National Register of Congenital Heart Defects. AB - BACKGROUND: Survival rates of children with congenital heart disease (CHD) have increased significantly in the decade. There is now increased interest in the long-term outcome and quality of life of these children. AIMS: To assess the educational achievement of patients with CHD in Germany. STUDY DESIGN: Cross sectional study using an online survey. The recruitment of study participants was carried out via the database of the German National Register for Congenital Heart Defects (NRCHD). SUBJECTS: Patients born between 1992 and 2011 were enrolled in the study. For 2609 study participants (female = 1870 (71.7%); 1072 (41.1%) patients; 1537 (58.9%) parents), who participated in the survey, detailed information regarding the underlying CHD diagnosis and clinical data was available. OUTCOME MEASURES: Age at enrollment, secondary school form, school year repetition, school degree. RESULTS: The large majority of study participants were enrolled at a conventional elementary school (83.4%) and started school at the age of 6 years or below (73.3%). In total 45.7% of graduated study participants graduated with the qualification necessary to study at any university. In terms of analysis of the different CHD severity subgroups 57.3% of patients with a mild CHD, 47.5% with a moderate CHD and only 35.1% suffering from a severe CHD attained a high school diploma. CONCLUSIONS: In our study, the majority of participating CHD patients had a standard school career. These initial results are of great importance to affected families and treating physicians as they show that, in general, a normal school career is possible for all CHD patients. PMID- 30448708 TI - Factors affecting motorcyclists' injury severities: An empirical assessment using random parameters logit model with heterogeneity in means and variances. AB - Motorcycles constitute 61% of the total registered vehicles in Pakistan and there has been a 371% growth in motorcycles in the country from year 2005-2015. Motorcycle is an essential and popular mode of transportation in Pakistan, therefore, the present study estimated a random parameters logit model to investigate the factors influencing the motorcycle injury severity using motorcycle crash data of Rawalpindi city collected by the Provincial Emergency Response Service. No injury, minor injury, severe injury and fatal injury are used as four categories of motorcyclist injury severity levels to calibrate the model. Mainly the effects of speed limits, crash-specific factors, rider attributes, roadway characteristics, weather and socio-demographics factors are considered for motorcycle-injury severity analysis. It was revealed that probability of fatal/severe injury increases for crashes: involving middle-aged riders (25-50 years) and riders with no education, occurring on roads with posted speed limit of 70 kms per hour or higher, crashes involving a motorcycle and a heavy vehicle, involving collision of a motorcycle with a fixed object and occurring during dry weather conditions. Also, the probability of minor injury increases for crashes: occurring on divided streets and road segments with a posted speed limit of less than 50 kms per hour, involving Chinese brand motorcycles, involving registered motorcycles, and where at least one motorcycle and auto rickshaw is involved. The research findings suggest that besides measures to control/ reduce the risky motorcyclists behavior there is a need to lower speed limits on roads with a higher motorcycle proportion, separate motorcycles from heavy vehicles and removal of fixed objects from the roadside. Besides data limitations, results are expected to generate more discussion and interest in motorcycle safety in the country and can be used by the enforcement agencies to improve/ enhance the current state of motorcycle safety in the country. PMID- 30448709 TI - The association of self-regulation, habit, and mindfulness with texting while driving. AB - The saturation of mobile phones throughout Australia has led to some individuals being unable to regulate their use within situations that are inappropriate or risky. One of the most prevalent risky mobile phone use behaviours is texting while driving. Attempts to explain texting while driving suggest cognitive variables and personality characteristics are key factors. This study explored relationships between trait self-regulation, habitual text messaging, trait mindfulness, and texting while driving. One hundred and seventy participants comprising Australian undergraduate psychology students and members of the public completed an online survey measuring trait self-regulation, habitual text messaging behaviour, trait mindfulness, and frequency of texting while driving. It was found that habitual texting behaviour mediated the relationship between trait self-regulation and frequency of texting while driving. Additionally, trait mindfulness moderated the relationship between habit and texting while driving, such that habitual texting was significantly, positively related to texting while driving, but only for individuals with low to moderate trait mindfulness. These results suggest personality constructs related to attention, awareness, and control of behaviour play a significant role in counteracting the association that habitual texting behaviour has with the frequency of texting while driving. As these traits are considered malleable, this association may be applicable in future development of intervention programs aimed at increasing control over mobile phone use and reducing the frequency with which people text while driving. PMID- 30448710 TI - Adjuvant radiation therapy in small ductal carcinoma in situ. AB - BACKGROUND: The objective of this study was to evaluate ipsilateral breast tumor recurrence (IBTR) rates in patients with small (<=1 cm) ductal carcinoma in situ (DCIS) who were followed up for more than 15 years. METHODS: We identified 209 patients with primary small (<=1 cm) DCIS without invasion who received curative excision with and without adjuvant radiation therapy (RT) from 1996 to 2009. IBTR rates and prognostic factors in all patients were estimated by univariate and multivariate analyses. RESULTS: With a median follow-up of 104 months, eight (53.3%) had DCIS recurrence and seven (46.7%) had recurrence of invasive ductal carcinoma. IBTR rate of all patients was 7.5% at 10 years and 12.1% at 15 years. In univariate analysis, age and subtypes were significant factors for IBTR. In multivariate analysis, resection margin, adjuvant RT, and endocrine therapy were significant factors for IBTR. CONCLUSIONS: IBTR rate of small (<=1 cm) DCIS following excision with or without adjuvant RT was 12.1% at 15 years. Adjuvant RT and endocrine therapy were associated with lower IBTR rate in small DCIS. PMID- 30448711 TI - Effect of a lipopeptide biosurfactant on the precipitation of calcium carbonate. AB - Observing flora and fauna, it can be said that nature is a great architect. Nature can create amazing structures with unique properties that may find potential applications in industry. This phenomenon is why the biomimetic synthesis of calcium carbonate with various polymorphs, sizes and morphologies using natural biomolecules, such as proteins and polysaccharides, has become an interesting topic in recent years. This novel work uses natural surfactants produced by Bacillus species (surfactins) in the formation of calcium carbonate particles. Calcium carbonate was synthesized by the reaction of Na2CO3 and CaCl2. The effects of surfactin concentration and pH on calcium carbonate crystal growth were investigated. Precipitated calcium carbonate was characterized by powder X ray diffraction (XRD), Fourier transform infrared (FTIR) analysis, scanning electron microscopy (SEM) and atomic force microscopy (AFM). The pore size and specific surface area were measured via the BET isotherm method. Surfactin molecules were observed to prevent the transformation of vaterite into calcite in the reaction system, especially at pH 8. Surfactin possesses two negatively charged groups (COO-), which have strong affinity towards metal ions at pH 8. When the surfactin concentration was 20 ppm, the surfaces of calcite crystals were punctuated by spherical and oval depressions. Surface roughness may substantially improve the properties of the obtained structures, for example, as inorganic templates for polymeric capsules. PMID- 30448712 TI - Synthesis and characterization of magnetic hybrid nanomaterials via RAFT polymerization: A pH sensitive drug delivery system. AB - Herein, a facile and versatile method for the synthesis of a novel magnetic nanocarrier via surface- initiated reversible addition-fragmentation chain transfer (RAFT) polymerization is introduced. At first, RAFT agent was successfully attached to the surface of Fe3O4 nanoparticles and, then, poly (glycidyl methacrylate) (PGMA) chains were grown and anchored onto the surface of Fe3O4 nanoparticles. At the end, hydrazine (Hy) groups were introduced to the PGMA chains via reaction between epoxy rings and hydrazine molecules. Doxorubicin (DOX) was covalently conjugated to the prepared nanocarrier (Fe3O4@PGMA@Hy) through a hydrazone linkage. The in vitro drug release of Fe3O4@PGMA@Hy@DOX examined in buffers with pH 7.4 and pH 5.4 exhibited a strong pH-sensitive behavior. The results showed that Fe3O4@PGMA@Hy@DOX successfully performed the delivery and controlled release of doxorubicin (DOX) anticancer drug. PMID- 30448713 TI - Novel Enteromorpha Prolifera based carbon dots: Probing the radical scavenging of natural phenolic compounds. AB - Phenolic compounds can act as protective agents against free radical oxidation. It is desirable to develop simple and efficient analytical techniques to measure the phenolic content and their antioxidant capacity. Using Enteromorpha prolifera (EP) as the carbon source, novel fluorescent carbon dots (EP-CDs) were synthesized through a facile microwave-assisted hydrothermal method. EP-CDs exhibit high mono-dispersity in aqueous solution, low cytotoxicity, and dual fluorescence emission in the visible and near-infrared range. The fluorescence of EP-CDs is inert to phenolic compounds and hydroxyl free radicals, but could be rapidly and efficiently quenched by the quinoid oxidation products. By monitoring the fluorescence quenching of EP-CDs, it is demonstrated that the radical scavenging processes of different natural phenolic compounds could be sensitively detected. By employing this eco-friendly and economic analytical method, phenols with different structure or concentration could be rapidly detected and determined. EP-CDs also have potential for additional applications, such as hydrogen peroxide and iron analysis. PMID- 30448714 TI - Predictive value of intraoperative bulbocavernosus reflex during untethering surgery for post-operative voiding function. AB - OBJECTIVE: To evaluate the clinical significance of intraoperative bulbocavernosus reflex (BCR) during untethering surgery in predicting post operative voiding function. METHODS: We conducted a retrospective review of pediatric patients who underwent untethering surgery with available intraoperative baseline BCR. BCR response during surgery was classified into loss or maintenance. Post-operative voiding function was determined as worsened or maintained based on history, postvoid residual urine measurement, and urodynamic study (UDS). Data regarding demographics, diagnosis, pre-operative voiding difficulty, re-untethering, syrinx, and abnormalities in electromyography were collected for analysis. RESULTS: We included 106 patients, with a mean age of 3.3 years, and 49 patients were male. BCR was lost in 15 patients during surgery and voiding function worsened in 14 patients after surgery. Lumbosacral lipoma was the most common diagnosis, and 16 patients were diagnosed with lipomyelomeningocele (LMMC). The sensitivity and specificity of intraoperative BCR for post-operative worsening of voiding function were 35.7%, and 88.5% at 6 months, respectively. The diagnosis of LMMC was statistically significant in a logistic regression analysis. The specificity of BCR at 6 months in patients with diagnosis other than LMMC was 93.4%, and intraoperative BCR was significant in a logistic regression analysis. CONCLUSIONS: Intraoperative BCR during untethering could predict bladder function 6 months post-operatively with high specificity (88.5%), particularly in cases other than LMMC (93.4%), indicating that voiding function deterioration will not occur if intraoperative BCR is preserved. SIGNIFICANCE: Intraoperative BCR during untethering surgery is a useful tool to predict post-operative voiding outcome. PMID- 30448715 TI - Novel Co(II) and Cu(II) coordination complexes constructed from pyrazole acetamide: Effect of hydrogen bonding on the self assembly process and antioxidant activity. AB - In the present study, two pyrazole-acetamide derivatives namely N-(2-aminophenyl) 2-(5-methyl-1H-pyrazol-3-yl) acetamide (L1) and (E)-N-(2-(1-(2-hydroxy-6-methyl-4 oxo-4H-pyran-3-yl)ethylideneamino)phenyl)-2-(5-methyl-1H-pyrazol-3-yl) acetamide (L2) have been synthesized and characterized by infrared spectrophotometry (IR), nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization-mass spectrometry (ESI-MS). Two coordination complexes of L1 and L2, namely [Co(L1)2(EtOH)2].Cl2 (1) and [Cu(L2)].H2O (2), respectively have been synthesized and characterized by elemental analysis and spectroscopic studies. The solid state structure of these two complexes was established by single crystal X-ray crystallography. In complex 1, the amide O and pyrazole N atoms of two molecules of L1 take part in coordination with octahedral Co(II) ions, the remaining two coordination sites being occupied by two EtOH molecules leading to a N2O4 coordination environment. On the other hand, the imine N atoms, pyrazole N and O atoms of the 2-hydroxy-6-methyl-4H-pyran-4-one function present in L2 are involved in coordination with Cu(II) ions, resulting in a distorted square planar geometry displaying a N2O4 chromophore, in complex 2. The crystal packing analysis of 1 and 2, revealed 1D and 2D supramolecular architectures respectively, via various hydrogen bonding interactions, which are discussed in the present account. Furthermore, the antioxidant activity of the ligands and their complexes were determined in vitro by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and ferric reducing antioxidant power(FRAP), showing that the ligands L1 and L2 and complexes 1 and 2 present significant antioxidant activity. PMID- 30448716 TI - Synthesis and structural characterization of antimicrobial binuclear copper(II) coordination compounds bridged by hydroxy- and/or thiodipropionic acid. AB - In the present study, two binuclear copper(II) coordination compounds bridged by hydroxy- and thiodipropionic acid have been synthesized. The structure of compounds was determined by X-ray crystallography. The central copper atoms exist in square pyramidal surroundings. Basal plane is formed by nitrogen atoms of amines and oxygen atoms of bridges, whereas apical positions are occupied by oxygen atoms of coordinated water molecules. Temperature dependence study of magnetic susceptibility proved strong antiferromagnetic exchange between copper atoms in hydroxy-bridged complex. These coordination compounds were also tested for their biological activities in vitro. Both coordination compounds exhibit pronounced cytocompatibility in mammalian epithelial cells with no induction of oxidative stress and DNA fragmentation. Moreover, synthesized compounds are hemocompatible and do not alter expression of a marker of multiple cellular stress, p53. On the other hand, both compounds had stimulatory effect on expression of metallothioneins (MT-1/2 and MT-3). Antimicrobial testing on Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus revealed that both copper compounds exhibit antibacterial activity regardless the cell wall composition. Overall, current work presents a synthesis of Cu(II) coordination compounds with interesting biological behavior and with a promising potential to be further tested in pre-clinical models. PMID- 30448717 TI - Cerebral folate deficiency in adults: A heterogeneous potentially treatable condition. AB - OBJECTIVE: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases. METHODS: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data. RESULTS: 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; <=25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7+/-1.6 vs 3.4+/-1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement. CONCLUSION: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient. PMID- 30448718 TI - Treatment of intractable resting tremor of spinocerebellar ataxia 42 with zonisamide. PMID- 30448719 TI - Disk-based one-dimensional photonic crystal slabs for label-free immunosensing. AB - One-dimensional photonic crystal slabs are periodic optical nanostructures that produce guided-mode resonance. They couple part of the incident light into the waveguide generating bandgaps in the transmittance spectrum, whose position is sensitive to refractive index variations on their surface. In this study, we present one-dimensional photonic crystal slab biosensors based on the internal nanogrooved structure of Blu-ray disks for label-free immunosensing. We demonstrated that this polycarbonate structure coated with a critical thickness of TiO2 generates guided-mode resonance. Its optical behavior was established comparing it with other compact disk structures. The results were theoretically calculated and experimentally demonstrated, all them being in agreement. The bioanalytical performance of these photonic crystals was experimentally demonstrated in a model assay to quantify IgGs as well as in two immunoassays to determine the biomarkers C-reactive protein and lactate dehydrogenase (detection limits of 0.1, 87, and 13 nM, respectively). The results are promising towards the development of new low-cost, portable, and label-free optical biosensors that join these photonic crystals with dedicated bioanalytical scanners based on compact disk drives. PMID- 30448720 TI - Analysis of stage-specific expression of the toll-like receptor family in the porcine endometrium throughout the estrous cycle and pregnancy. AB - Toll-like receptors (TLRs) play critical roles in innate immunity by regulating antimicrobial responses in mucosal tissues. The expression and function of TLRs in female reproductive tissues have been studied in several species, but the expression and function of TLRs and MYD88, an adaptor molecule in the TLR signaling pathway, at the maternal-conceptus interface are not well understood in pigs. Thus, we determined the expression of TLR1 - TLR10 and MYD88 in the endometrium, conceptus, and chorioallantoic tissues of pigs. TLR1 - TLR10 and MYD88 mRNAs were expressed in the endometrium during the estrous cycle and pregnancy in a stage-dependent manner. TLR and MYD88 mRNAs were also detected in early stage conceptuses and chorioallantoic tissues from Day 30 to term pregnancy. The expression of TLR2, TLR4, TLR5, and TLR7 was localized to epithelial and stromal cells in endometrial and chorioallantoic tissues. Increasing doses of P4, but not E2, induced the expression of TLR4, TLR5, TLR6, TLR7, and TLR8, while interferon-gamma increased the expression of TLR2 and TLR7 in endometrial explant tissues. Expression of TLR3, TLR5, TLR6, TLR7, and MYD88 was higher in the endometrium with somatic cell nucleus transfer-derived conceptuses than conceptuses derived from natural mating on Day 12. These results indicate that the expression of TLR1 - TLR10 and MYD88 is dynamically regulated at the maternal-conceptus interface in pigs, suggesting that TLRs expressed in the endometrium and the placenta may play a critical role in regulating mucosal immune responses to support the establishment and maintenance of pregnancy. PMID- 30448721 TI - A comprehensive service delivery model for preschoolers with special educational needs: Its characteristics and effectiveness. AB - BACKGROUND: The compartmentalization between early intervention services and early childhood special education programs is a worldwide phenomenon, which results in the fragmentation of services for preschoolers with special educational needs (SEN). AIMS: To address this fragmentation of services, an intervention program in Hong Kong adopted a comprehensive service delivery model with six characteristics: 1) multidisciplinary approach, 2) integration of services across different contexts, 3) multimodal intervention with direct and indirect services, 4) capacity building for systems, 5) inclusive environment, and 6) high program intensity. METHODS: The program evaluation was a quasi experiment with a control group (n = 60) matched to the experimental group (n = 60). RESULTS: At the end of the school year, the experimental group made significant improvement in most measures including cognitive skills, receptive language skills, expressive language skills, gross-motor skills, fine-motor skills, and self-direction skills. School heads in the experimental group also agreed that the program had empowered their teachers and reinforced their school systems. CONCLUSION: Despite its exploratory nature, the study has shed light on the future directions of services for preschoolers with SEN. The comprehensive service delivery model offers a response to the fragmentation of services and reveals the importance of integration of services across different contexts with multidisciplinary approach. PMID- 30448722 TI - Design, synthesis, and biological activities of 1-aryl-(3-(2-styryl)phenyl)prop-2 en-1-ones. AB - A moderate elevation in reactive oxygen species (ROS) levels can generally be controlled in normal cells, but may lead to death of cancer cells as the ROS level in cancer cells is already elevated. Therefore, a ROS-generating compound can act as a selective chemotherapeutic agent for cancer cells that does not affect normal cells. In our previous study, a compound containing a Michael acceptor was selectively cytotoxic to cancer cells without affecting normal cells; therefore, we designed and synthesized 26 compounds containing a Michael acceptor. Their cytotoxicities against HCT116 human colon cancer cell lines were measured by using a clonogenic long-term survival assay. To derive the structural conditions required to obtain stronger cytotoxicity against cancer cells, the relationships between the half-maximal cell growth inhibitory concentration values of the synthesized compounds and their physicochemical properties were evaluated by Comparative Molecular Field Analysis and Comparative Molecular Similarity Indices Analysis. It was confirmed that the compound with the best half-maximal cell growth inhibitory concentration triggered apoptosis through ROS generation, which then led to stimulation of the caspase pathway. PMID- 30448723 TI - Novel dauricine derivatives suppress cancer via autophagy-dependent cell death. AB - Eleven dauricine derivatives were synthesized and evaluated for their anti-cancer effect in different cancer cells and their autophagic activity in HeLa model cell. Among these newly synthesized compounds, carbamates 2a, 2b, carbonyl ester 3a and sulfonyl ester 4a exhibited potent cytotoxic effects on tested cancer cells with IC50 values ranged from 2.72 to 12.53 MUM, which were more potent than that of dauricine (higher than 15.53 MUM). The above four derivatives are validated to induce autophagy-dependent cell death in HeLa cancer cells. These findings offer us a promising source for generating novel autophagic enhancers for anti-cancer therapy. PMID- 30448724 TI - Introduction of Z-GP scaffold into procarbazine reduces spermatoxicity and myelosuppression. AB - Incorporation of carbobenzoxy-glycylprolyl (Z-GP) to either alpha or beta position of the hydrazine moiety in procarbazine (Pcb) has been carried on in 5 steps process. The overall yield was 32.7%. The new entity Z-GP-Pcb was confirmed targeting to fibroblast activation protein-alpha (FAPalpha). Z-GP-Pcb may be hydrolyzed by either isolated rhFAPalpha or tumor homogenate. It was shown far less cytotoxicity against NCI-H460 cell line than Pcb. Z-GP-Pcb was displayed the potency to reduce spermatoxcity in H22-bearing mice. The mechanism may be ascribed to the blockade of dehydrogenation by alpha-glycerolphosphate dehydrogenase. This candidate was further proved equal antitumor activity to Pcb. However, the introduction of Z-GP scaffold decreased myelosuppression. All the evidences support that Z-GP-Pcb is a better antitumor agent than Pcb. PMID- 30448725 TI - Neuroprotective effects of triterpenoid saponins from Medicago sativa L. against H2O2-induced oxidative stress in SH-SY5Y cells. AB - Medicago sativa L. is a forage legume plant widely distributed in all continents. Six new triterpenoid saponins, Medicagosides A-F (1-6) and five known ones (7-11) were isolated from M. sativa. Their structures were determined via HRESIMS, 1D and 2D NMR analysis. Biologically, all the isolates displayed neuroprotective activities against H2O2-induced damage in SH-SY5Y cells. Among them, compounds 1, 3-5 and 10 exhibited striking neuroprotective activities at 100 MUM, restoring cell viability range from 79.66% to 89.03%, relative to 79.46% (100 MUM) of Trolox used as the positive control. PMID- 30448726 TI - Assessment of novel azaanthraquinone derivatives as potent multi-target inhibitors of inflammation and amyloid-beta aggregation in Alzheimer's disease. AB - A series of 6-substituted azaanthraquinone derivatives have been designed, synthesized, and their anti-inflammatory activities, antiaggregation effects on beta-amyloid proteins, anticholinesterase and neuroprotective activity were tested. The new derivatives strongly suppressed NO and iNOS production and modulate the production of cytokines by decreasing TNF-a, IL-1beta and IL-6 formation in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Meanwhile, the derivatives exhibited a significant in vitro inhibitory activity toward the self-induced Abeta aggregation. While, treatment of SH-SY5Y cells overexpressing the Swedish mutant form of human b-amyloid precursor protein (APPsw) with derivatives was associated with significant reduction of Abeta42 secretion levels. Moreover, the derivatives exhibited moderate inhibitory potency toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Further investigations indicated that compound 7b could attenuate H2O2-induced neurotoxicity toward SH-SY5Y neuroblastoma cells and half of the synthetic compounds were predicted to be able to cross the blood-brain barrier (BBB) to reach their targets in the central nervous system (CNS) according to a parallel artificial membrane permeation assay for BBB. Taken together, azaanthraquinone derivatives targeting multiple pathogenetic factors deserves further investigation for prevention and treatment of AD. PMID- 30448727 TI - In vitro toxicological activity of particulate matter generated by coal combustion. AB - Herein, the toxicity of particles generated from the complete combustion of 1 g coal at 500, 700, and 900 degrees C were compared, and combustion at 700 degrees C generated the most toxins. Chemical analyses revealed that all components except catechol, resorcinol, and aromatic amines were most abundant at 700 degrees C. Toxicity results confirmed that the relative mutagenicity, cytotoxicity, redox cycling, and production of reactive oxygen species was highest for particles generated at 700 degrees C. Particles generated during combustion at 700 degrees C exhibited higher toxicity toward biological systems due to a higher content of toxic compounds. PMID- 30448728 TI - Low vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses. AB - The two stress-responsive physiological systems, autonomic nervous system (ANS) and hypothalamus-pituitary-adrenal (HPA) axis exert complementary and interrelated actions in the organism. Individuals that suffer stress-related psychopathologies frequently present simultaneous alterations -i.e., either low or high- responsiveness- in both systems. However, there is scarce evidence establishing whether a priori alterations in these systems -i.e., independent of previous stress exposure- may predispose to the development of psychopathologies possibly due to the lack of animal models simultaneously involving aberrant HPA and SNS responses. In this study, we describe two animal models selectively bred according to their differential (either high, 'High', or low, 'Low') glucocorticoid responsiveness to stress, in comparison to a third line of rats that displays intermediate ('Inter') glucocorticoid responses. The two extreme lines may be considered distinct models of psychopathology; the High line representing a model of constitutive mood alterations while the Low line a model of vulnerability to develop stress-induced psychopathologies. We recorded the electrocardiogram in rats from the three lines and quantified heart rate variability and vagal tone indexes during rest and stress challenges. Rats from both High and Low lines displayed higher heart rate and lower basal vagal tone than the Inter group, both at resting and following stress exposure. Specific pharmacological manipulations probing the relative contribution of sympathetic and parasympathetic components on HR modulation confirmed a relative lower vagal tone in High and Low lines and discarded differences in the sympathetic regulation of heart rate between the lines. Therefore, the two genetically selected High and Low glucocorticoid rat lines emerge as two valuable preclinical models of psychopathology involving two key risk factors for psychiatric and cardiovascular disorders, namely dysregulations in the HPA axis and cardiac vagal functioning. PMID- 30448729 TI - Coarse-grained molecular dynamics of membrane semitoroidal pore formation in model lipid-peptide systems. AB - Transmembrane pores play an important role in various cell processes. However, the detailed structures of these pores and their influence on the membrane properties remain undetermined. We performed microsecond coarse-grained molecular dynamics simulations to study the interaction of cationic beta-structural peptides with multicomponent lipid bilayers consisting of two types of anionic (POPS, POPI) and two types of zwitterionic (POPE, POPC) lipids. The formation of semitoroidal pores was analyzed from a standpoint of self-organization of lipids and peptides. Our results showed that semitoroidal pores were mainly formed by POPI molecules with a strong negative charge. We found that peptide aggregation is a necessary step of pore formation; single peptide is unable to stabilize the semitoroidal pore. To characterize the influence of semitoroidal pores on membrane properties, we evaluated the bilayer thickness, the two-dimensional density maps of lipids, the deuterium order parameters, and the lateral diffusion coefficients of lipids. The pore formation induced perturbation of the phospholipid organization in membrane and facilitated the organization of zones with different electrostatic potential. PMID- 30448730 TI - Isotope Tracing Untargeted Metabolomics Reveals Macrophage Polarization-State Specific Metabolic Coordination across Intracellular Compartments. AB - We apply stable isotope tracing, mass-spectrometry-based untargeted metabolomics, to reveal the biochemical space labeled by 13C-substrates in bone-marrow-derived macrophages. At the pathway level, classically (lipopolysaccharide [LPS] polarized, M1) and alternatively (interleukin [IL]-4-polarized, M2) polarized macrophages were 13C-labeled with surprising concordance. Total pools of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), an intermediate in the hexosamine biosynthetic pathway, were equally abundant in LPS- and IL-4-polarized macrophages. Informatic scrutiny of 13C-isotopologues revealed that LPS-polarized macrophages leverage the pentose phosphate pathway to generate UDP-GlcNAc, whereas IL-4-polarized macrophages rely on intact glucose and mitochondrial metabolism of glucose carbon. Labeling from [13C]glucose is competed by unlabeled fatty acids and acetoacetate, underscoring the broad roles for substrate metabolism beyond energy conversion. Finally, the LPS-polarized macrophage metabolite itaconate is imported into IL-4-polarized macrophages, in which it reprograms [13C]glucose metabolism. Thus, use of fully unsupervised isotope tracing metabolomics in macrophages reveals polarization-state-specific metabolic pathway connectivity, substrate competition, and metabolite allocation among cellular compartments. PMID- 30448731 TI - Nuclear Actin Polymerized by mDia2 Confines Centromere Movement during CENP-A Loading. AB - Centromeres are specialized chromosomal regions epigenetically defined by the histone H3 variant centromere protein A (CENP-A). CENP-A needs to be replenished in every cell cycle, but how new CENP-A is stably incorporated into centromeric chromatin remains unclear. We have discovered that a cytoskeletal protein, diaphanous formin mDia2, is essential for the stable incorporation of new CENP-A proteins into centromeric nucleosomes. Here we report that mDia2-mediated formation of dynamic and short nuclear actin filaments in G1 nucleus is required to maintain CENP-A levels at the centromere. Importantly, mDia2 and nuclear actin are required for constrained centromere movement during CENP-A loading, and depleting nuclear actin or MgcRacGAP, which lies upstream of mDia2, extends centromeric association of the CENP-A loading chaperone Holliday junction recognition protein (HJURP). Our findings thus suggest that nuclear actin polymerized by mDia2 contributes to the physical confinement of G1 centromeres so that HJURP-mediated CENP-A loading reactions can be productive, and centromere's epigenetic identity can be stably maintained. PMID- 30448732 TI - Synthesis of 3-Substituted Pyrrolidines via Palladium-Catalyzed Hydroarylation. AB - Metal-catalyzed reactions have revolutionized synthetic chemistry, allowing access to unprecedented molecular architectures with powerful properties and activities. Nonetheless, some transformations remain sparse in number, or out of reach, even with the diverse modern catalytic chemical arsenal, including bimolecular alkene hydroarylation reactions. We report here a broad-scope, palladium-catalyzed pyrroline hydroarylation process that gives 3-aryl pyrrolidines, a class of small molecules with potency in a diverse range of biological scenarios. Thus, whereas N-acyl pyrrolines usually undergo palladium catalyzed arylation to give alkene products, the corresponding reactions of N alkyl pyrrolines deliver products of hydroarylation, pyrrolidines. The process has broad substrate scope and can be used to directly deliver drug-like molecules in a single step from readily available precursors. PMID- 30448734 TI - A Deep Learning-Based Radiomics Model for Differentiating Benign and Malignant Renal Tumors. AB - OBJECTIVES: To investigate the effect of transfer learning on computed tomography (CT) images for the benign and malignant classification on renal tumors and to attempt to improve the classification accuracy by building patient-level models. METHODS: One hundred ninety-two cases of renal tumors were collected and identified by pathologic diagnosis within 15 days after enhanced CT examination (66% male, 70% malignant renal tumors, average age of 62.27 +/- 12.26 years). The InceptionV3 model pretrained by the ImageNet dataset was cross-trained to perform this classification. Five image-level models were established for each of the Slice, region of interest (ROI), and rectangular box region (RBR) datasets. Then, two patient-level models were built based on the optimal image-level models. The network's performance was evaluated through analysis of the receiver operating characteristic (ROC) and five-fold cross-validation. RESULTS: In the image-level models, the test results of model trained on the Slice dataset [accuracy (ACC) = 0.69 and Matthews correlation coefficient (MCC) = 0.45] were the worst. The corresponding results on the ROI dataset (ACC = 0.97 and MCC = 0.93) were slightly better than those on the RBR dataset (ACC = 0.93 and MCC = 0.85) when freezing the weights before the mixed6 layer. Compared with the image-level models, both patient-level models could discriminate better (ACC increased by 2% 5%) on the RBR and Slice datasets. CONCLUSIONS: Deep learning can be used to classify benign and malignant renal tumors from CT images. Our patient-level models could benefit from 3D data to improve the accuracy. PMID- 30448733 TI - miR-224 Is Significantly Upregulated and Targets Caspase-3 and Caspase-7 During Colorectal Carcinogenesis. AB - miR-224 has recently emerged as a driver oncomiR in sporadic colorectal carcinogenesis, but its pathogenetic role is still controversial. A large phenotypical and molecularly characterized series of preinvasive and invasive colorectal lesions was investigated for miR-224 expression by qRT-PCR and in situ hybridization. The caspase-3 and caspase-7 status was also assessed and correlated to miR-224 dysregulation. miR-224 was significantly upregulated during the adenoma-carcinoma sequence and in the context of inflammatory bowel disease dysplastic lesions, whereas its expression was significantly downregulated among BRAF-mutated tumors and in the presence of a DNA mismatch repair deficiency. miR 224 targets caspase-3 and caspase-7 in colorectal cancer, and this inverse relation was already evident from the earliest phases of transformation in intestinal mucosa. The miR-224/caspases axis may represent an interesting field of study for innovative biomarkers/therapeutics for BRAF-mutated/DNA mismatch repair-deficient tumors. PMID- 30448735 TI - A Pilot Prospective Study of Refractory Solid Tumor Patients for NGS-Based Targeted Anticancer Therapy. AB - With the advent of next-generation sequencing (NGS), targeted sequencing is now contributing to decision making for which chemotherapeutics to administer to cancer patients, especially in refractory and metastatic cancer. Given that most patients with refractory cancer develop resistance to chemotherapy and have few treatment options, we performed NGS test to evaluate the efficacy and clinical feasibility of NGS-based targeted anticancer therapy. We used a gene panel for capturing target regions covering 83 cancer-related genes. A total of 25 refractory metastatic solid tumor patients were enrolled in this study. Among the 25 patients, 7 had FDA-approved drug-responsive or -resistant alterations. However, the effectiveness of targeted therapy was assessed by follow-up in three patients (12%). These included crizotinib for ALK-EML4 fusion in a malignancy of undefined origin patient and everolimus for AKT3 amplification in a uterine sarcoma patient. In addition, we identified a KRAS codon 146 mutation (A146V), which is associated with resistance to anti-EGFR, in a cetuximab-resistant colon cancer patient with wild-type KRAS exons 2 and 12, and EGFR amplification. He received bevacizumab therapy. All three patients showed partial response after targeted therapy. Furthermore, we characterized KRAS A146V biologically using colon cancer cells. In conclusion, this study suggests that targeted therapy based on NGS test may be a good choice for improving the care of patients with refractory solid tumors. PMID- 30448736 TI - The importance of reactive oxygen species on the aqueous phototransformation of sulfonamide antibiotics: kinetics, pathways, and comparisons with direct photolysis. AB - Sulfonamide antibiotics (SAs) are increasingly detected as aquatic contaminants and exist as different dissociated species depending on the pH of the water. Their removal in sunlit surface waters is governed by photochemical transformation. Here we report a detailed examination of the hydroxyl radical (*OH) and singlet oxygen (1O2) mediated photooxidation of nine SAs: sulfamethoxazole, sulfisoxazole, sulfamethizole, sulfathiazole, sulfamethazine, sulfamerazine, sulfadiazine, sulfachloropyridazine and sulfadimethoxine. Both *OH and 1O2 oxidation kinetics varied depending on the dominant protonated states of the SA in question (H2SAs+, HSAs0 and SAs-) as a function of pH. Based on competition kinetic experiments and matrix deconvolution calculations, HSAs0 or SAs- (pH ~5-8) were observed to be more highly reactive towards *OH, while SAs- (pH ~8) react the fastest with 1O2 for most of the SAs tested. Using the empirically derived rates of reaction for the speciated forms at different pHs, the environmental half-lives were determined using typical 1O2 and *OH concentrations observed in the environment. This approach suggests that photochemical 1O2 oxidation contributes more than *OH oxidation and direct photolysis to the overall phototransformation of SAs in sunlit waters. Based on the identification of key photointermediates using tandem mass spectrometry, 1O2 oxidation generally occurred at the amino moiety on the molecule, whereas *OH reaction experienced multi-site hydroxylation. Both these reactions preserve the basic parent structure of the compounds and raise concerns that the routes of phototransformation give rise to intermediates with similar antimicrobial potency as the parent SAs. We therefore recommend that these phototransformation pathways are included in risk assessments concerning the presence and fate of SAs in waste and surface waters. PMID- 30448737 TI - Interactions between suspended particulate matter and algal cells contributed to the reconstruction of phytoplankton communities in turbulent waters. AB - The effect of turbulence on phytoplankton growth has been widely studied; however, its effects with respects to suspended particulate matter (SPM) on the development of phytoplankton communities and the behavioral responses of phytoplankton to turbulence and SPM are poorly understood. Here, an approximately homogeneous turbulence simulation system (AHTS, mainly consisting of an oscillating-grid apparatus) was established to gain insight into the mechanisms underlying phytoplankton community responses in turbid, well-mixed waters. The results revealed that maintaining the turbulence dissipation rates (E) of 2.25 * 10-3 and 1.80 * 10-2 m2/s3 caused significant reductions in algal density, and the effects could be substantially enhanced when 500 mg/L of SPM were added before day 12. In contrast to the constant decrease of algal density for the E of 2.25 * 10-3 m2/s3, a dramatic increase in the phytoplankton density occurred after 16 days of incubation for a E of 1.80 * 10-2 m2/s3, irrespective of SPM. Addition of SPM in the E of 1.80 * 10-2 m2/s3 treatments did not considerably affect the algal density profile compared to that without SPM, of which unicellular algae decreased and colonial algae dominated the phytoplankton community. On the other hand, the phytoplankton can regulate the SPM properties. During the 18 days' coincubation, extracellular polymeric substances (EPS) released from algal cells induced larger particle sizes and round surfaces of SPM, which can reduce the damage received to algal cells. Here we demonstrated that the phytoplankton communities could actively counteract the effects of turbulence + SPM and adapt the couple stress, jointly through the release of EPS, the modification of SPM surface properties and the conversion of their assemblage pattern, thereby contributing to rebalance the ecosystem. These findings highlight the strategies employed during the reconstruction of phytoplankton under the dual effects of turbulence and SPM for the first time, consequently enabling the forecasting of the dominant species of phytoplankton in turbulent waters. PMID- 30448738 TI - Genome-resolved metagenomic analysis reveals roles of microbial community members in full-scale seawater reverse osmosis plant. AB - Biofouling of Reverse Osmosis (RO) membrane is a significant issue for the water treatment industry. In this study, we apply the metagenomic shot-gun sequencing technology to characterise the composition and functional potential of the microbial community in a full-scale RO plant, at different stages of seawater treatment. We find Proteobacteria, Bacteroidetes and Planctomycetes to be the most abundant bacterial phyla. The genetic potential of the RO membrane microbial community shows the enrichment of genes involved in biofilm formation, representing the selective pressure of the biofilm formation process. We recover 31 metagenome-assembled genomes (MAGs) from intake (raw seawater), fouled RO membranes (leading and middle RO module) and brine reject water. A total of 25 MAGs are recovered from the biofilm samples (leading and middle RO modules), with 9 of them (36%) belonging to Planctomycetes. We investigate all 25 MAGs for genes (pili, flagella, quorum sensing, quorum quenching and nitrate reduction) that play an important role in biofilm formation and sustenance of cells. We show that Planctomycetes contain genes for the formation of flagella and pili, and the reduction of nitrate. Although genes for quorum sensing are not detected, quorum quenching genes are identified in the biofilm MAGs. Our results show that Planctomycetes, along with other microbes, play an important role in the formation and sustenance of biofilms on seawater RO membranes. PMID- 30448739 TI - Rare dimeric guaianes from Xylopia vielana and their multidrug resistance reversal activity. AB - Thirteen undescribed dimeric guaianes were isolated from the leaves of Xylopia vielana Pierre. Their structures were elucidated by NMR spectroscopy and mass spectrometry, and the absolute configurations of vielanins G-Q were determined by a combination of the circular dichroism (CD) exciton chirality method, chemical conversion, and electronic CD (ECD) spectroscopy analysis. Vielaninors A and B are the first examples of trinor-guaiane-dimers. Multidrug resistance reversal activity assay of the isolates was evaluated in doxorubicin-resistant human breast cancer cells. Vielanins H, K-M, P, and Q were noncytotoxic and enhanced the cytotoxicity of doxorubicin by 2.1-41.6-fold at 10 MUM. PMID- 30448740 TI - Functional characterization and correlation analysis of phenylalanine ammonia lyase (PAL) in coumarin biosynthesis from Peucedanum praeruptorum Dunn. AB - Coumarins exhibit many biological activities and are the main specialised metabolites of Peucedanum praeruptorum Dunn, an important plant used in traditional Chinese medicine. In preliminary studies, we cloned several genes involved in coumarin biosynthesis in P. praeruptorum, such as 4-coumarate: CoA ligase (4CL), p-coumaroyl CoA 2'-hydroxylase (C2'H), feruloyl CoA 6'-hydroxylase (F6'H) and bergaptol O-methyltransferase (BMT). However, phenylalanine ammonia lyase (PAL) in P. praeruptorum (PpPAL) has not yet been studied. In the present study, we cloned one novel PpPAL gene. Subsequently, the relationship between gene and compounds was studied using quantitative real-time PCR (qRT-PCR) and High Performance Liquid Chromatography (HPLC) analysis. Then, enzyme function was analyzed with L-phenylalanine (L-Phe) as substrate. These experiments showed that the coumarin content could be upregulated by methyl jasmonate (MeJA), UV irradiation and cold, which was consistent with increased expression levels of PpPAL. In addition, correlation analysis indicated that coumarins were partially related to PpPAL. And the recombinant protein could catalyze the conversion of L Phe to trans-cinnamic acid (t-CA) with a Km of 120 +/- 33 MUM and a Kcat of 117 +/- 32 min-1. Besides, Tyr110, Phe116, Gly117, Ser206, Leu209, Leu259, Tyr354, Arg357, Asn387 and Phe403 were essential for enzymatic activity based on three dimensional modeling and site-directed mutagenesis experiments. Altogether these results highlight the importance of PpPAL in abiotically induced coumarin biosynthesis and provide further insights regarding the structure-function relationships of this protein. PMID- 30448741 TI - Machine learning to predict lung nodule biopsy method using CT image features: A pilot study. AB - Computed tomography (CT)-based screening on lung cancer mortality is poised to make lung nodule management a growing public health problem. Biopsy and pathologic analysis of suspicious nodules is necessary to ensure accurate diagnosis and appropriate intervention. Biopsy techniques vary as do the specialists that perform them and the ways lung nodule patients are referred and triaged. The largest dichotomy is between minimally invasive biopsy (MIB) and surgical biopsy (SB). Cases of unsuccessful MIB preceding a SB can result in considerable delay in definitive care with potentially an adverse impact on prognosis besides potentially avoidable healthcare expenditures. An automated method that predicts the optimal biopsy method for a given lung nodule could save time and healthcare costs by facilitating referral and triage patterns. To our knowledge, no such method has been published. Here, we used CT image features and radiologist-annotated semantic features to predict successful MIB in a way that has not been described before. Using data from the Lung Image Database Consortium image collection (LIDC-IDRI), we trained a logistic regression model to determine whether a MIB or SB procedure was used to diagnose lung cancer in a patient presenting with lung nodules. We found that in successful MIB cases, the nodules were significantly larger and more spiculated. Our model illustrates that using robust machine learning tools on easily accessible semantic and image data can predict whether a patient's nodule is best biopsied by MIB or SB. Pending further validation and optimization, clinicians could use our publicly accessible model to aid clinical decision-making. PMID- 30448742 TI - Examining associations between sleep disturbance and distress tolerance in trauma exposed psychiatric inpatients. PMID- 30448743 TI - The relationship between the frequency of suicidal ideation and sleep disturbance factors among adolescent earthquake victims in China. AB - OBJECTIVE: This study aimed to examine the frequency of suicidal ideation (SI) and identify exposure variables, mental health, and sleep-related risk factors of SI among adolescents following the 2013 Ya'an earthquake. METHODS: Participants consisted of 5563 adolescent students selected through random sampling from 11 primary and high schools in the counties most severely affected by the earthquake. They were asked to complete the Pittsburgh Sleep Quality Index, Children's Revised Impact of Event Scale-13, Short Mood and Feelings Questionnaire, and Screen for Child Anxiety-Related Emotional Disorders. Multinomial logistic analysis was used to identify possible relationships between SI and psychopathology, sleep problems, earthquake exposures or demographic characteristics. The mediation analysis was used to identify direct and indirect effects among sleep problems, psychopathology, earthquake exposures and SI. RESULTS: Our findings suggest that 29.5% of the sample experienced SI during the past year (12.9% once, 11.9% twice, 2.6% on 3-4 occasions and 2.1% on at least 5 occasions). Multiple sleeping problems, including trouble falling asleep, shorter sleep duration, and daytime dysfunction, showed independent associations with SI. The mediation analysis suggested that depression and anxiety mainly mediated the association of sleep with SI. LIMITATIONS: This study was cross-sectional and did not include controls. No baseline data were collected prior to the earthquake. CONCLUSION: SI can be a serious problem among adolescents following a major earthquake, especially those who are older, who live in one-child households, or who are female. Years after a disaster, we found that exposure severity, psychopathology and sleep impairment all contributed to SI, and that earthquake exposure may have disrupted sleep and worsened mood, which in turn may have impacted SI. By enhancing teenagers' sleep management and shaping their activities, post-disaster intervention programs may help prevent SI among Chinese adolescents. PMID- 30448744 TI - Response of natural phytoplankton communities exposed to crude oil and chemical dispersants during a mesocosm experiment. AB - During the 2010 Deepwater Horizon oil spill, the chemical dispersant Corexit was applied over vast areas of the Gulf of Mexico. Marine phytoplankton play a key role in aggregate formation through the production of extracellular polymeric materials (EPS), an important step in the biological carbon pump. This study examined the impacts of oil and dispersants on the composition and physiology of natural marine phytoplankton communities from the Gulf of Mexico during a 72-hour mesocosm experiment and consequences to carbon export. The communities were treated using the water accommodated fraction (WAF) of oil, which was produced by adding Macondo surrogate oil to natural seawater and mixed for 24 h in the dark. A chemically enhanced WAF (CEWAF) was made in a similar manner, but using a mixture of oil and the dispersant Corexit in a 20:1 ratio as well as a diluted CEWAF (DCEWAF). Phytoplankton communities exposed to WAF showed no significant changes in PSII quantum yield (Fv/Fm) or electron transfer rates (ETRmax) compared to Control communities. In contrast, both Fv/Fm and ETRmax declined rapidly in communities treated with either CEWAF or DCEWAF. Analysis of other photophysiological parameters showed that photosystem II (PSII) antenna size and PSII connectivity factor were not altered by exposure to DCEWAF, suggesting that processes downstream of PSII were affected. The eukaryote community composition in each experimental tank was characterized at the end of the 72 h exposure time using 18S rRNA sequencing. Diatoms dominated the communities in both the control and WAF treatments (52 and 56% relative abundance respectively), while in CEWAF and DCEWAF treatments were dominated by heterotrophic Euglenozoa (51 and 84% respectively). Diatoms made up the largest relative contribution to the autotrophic eukaryote community in all treatments. EPS concentration was four times higher in CEWAF tanks compared to other treatments. Changes in particle size distributions (a proxy for aggregates) over time indicated that a higher degree of particle aggregation occurred in both the CEWAF and DCEWAF treatments than the WAF or Controls. Our results demonstrate that chemically dispersed oil has more negative impacts on photophysiology, phytoplankton community structure and aggregation dynamics than oil alone, with potential implications for export processes that affect the distribution and turnover of carbon and oil in the water column. PMID- 30448745 TI - Dichlorprop induced structural changes of LHCII chiral macroaggregates associated with enantioselective toxicity to Scnedesmus obliquus. AB - The enantioselective toxic mechanisms of chiral herbicides in photosynthetic organisms are closely related to the production of reactive oxygen species (ROS) production, however, there are few reports on how the enantioselective production of ROS can be triggered. In suboptimal conditions, photosynthesis is one of the most important processes in the production of ROS, especially in the process of light utilization and electron transfer. In this study, we investigated the interactions between chiral herbicide dichlorprop (DCPP) enantiomers and the chiral macroaggregates of the photosynthetic light-harvesting chlorophyll a/b pigment-protein complexes (LHCII) in Scenedesmus obliquus, which is of great significance in capturing and utilizing sun light, and also in dissipating the excess excitation energy. The results of the circular dichroism indicated that DCPP induced the structural changes of the LHCII chiral macroaggregates in an enantioselective manner and that the (R)-DCPP treated-group showed a bigger change accompanied by a changed enantioselective dissipation of the excitation energy. The excitation energy was excessed in DCPP treated-groups and the degree of excess was enantioselective and the detrimental non-chemical energy triggered the enantioselective production of ROS, that induced the enantioselective toxicity to green algae S. obliquus. Overall, this study has identified that how the enantioselective production of ROS can be triggered in chloroplasts; this can help to reveal the enantioselective mechanisms of chiral herbicides to photosynthetic organisms. PMID- 30448746 TI - Smoking cessation support and obstetric outcomes in an Irish maternity hospital. AB - OBJECTIVE: Maternal cigarette smoking is a recognised risk factor for maternal and fetal morbidity and mortality and remains a significant problem in the Irish maternity system. Approximately 11% of Irish women will continue to smoke in pregnancy, despite awareness of the negative impact on their pregnancy. Although recommendations exist for the management of pregnant smokers, information on the antenatal care of Irish smokers in pregnancy has not been described. We reviewed the care given to smokers in a large urban maternity hospital. STUDY DESIGN: This is a retrospective cohort study of 100 consecutive smokers and 110 contemporaneous non-smokers who delivered at a large urban maternity hospital of over 8200 births per year in Oct-Nov 2017. Data were obtained from both electronic patient records and chart review to ensure comprehensive capture of outcomes. RESULTS: In general, mothers who smoked were younger (29yrs vs 33yrs p < 0.001) and of higher parity (1.4 vs. 1.0 p < 0.001) than non-smokers. They were less likely to have a planned pregnancy (44.4% vs 79.6%, p < 0.001) and less likely to have taken pre-conceptual folic acid (22.2% vs 58.3%, p < 0.001). These mothers also had a higher rate of history of illicit drug use, particularly cannabis (19.1% vs 0.9%, p < 0.001) and opiates (16.1% vs 0.9%, p < 0.001). Mental health issues were commoner in smokers with 36.3% describing depression, postnatal depression or bipolar disorder and 34.3% experiencing anxiety disorder or panic attacks. Smoking cessation advice was identified in only 36.5% of smokers and no smokers were referred for smoking cessation interventions. Two thirds of smokers were referred for an additional ultrasound, largely due to suspected fetal growth restriction. Infants of smoking mothers had lower mean birthweights (3.16 kg vs 3.47 kg p < 0.001) and mean birth centile (27th vs 47th p < 0.001) than non-smokers. Twenty eight percent of these infants were small for gestational age, an incidence significantly higher than non-smokers at 13% (p < 0.001). CONCLUSION: Maternal cigarette smoking appears to be a largely tolerated risk factor in the population studied, despite being associated with poor obstetric outcomes. We identified an absence of smoking cessation services and a lack of intervention and structure around care pathways. PMID- 30448747 TI - Effects of polystyrene microplastics on the composition of the microbiome and metabolism in larval zebrafish. AB - Microplastics are major pollutants in marine environment and may have health effects on aquatic organisms. In this study, we used two sizes (5 and 50 MUm diameter) of fluorescent and virgin polystyrene microplastics to analyze the adverse effects on larval zebrafish. In our study, we evaluated the effects on larval zebrafish after exposure to 100 and 1000 MUg/L of two sizes of polystyrene microplastics for 7 days. Our results show that polystyrene microplastics could cause alterations in the microbiome at the phylum and genus levels in larval zebrafish, including changes in abundance and diversity of the microbiome. In addition, metabolomic analysis suggested that exposure to polystyrene microplastics induced alterations of metabolic profiles in larval zebrafish, and differential metabolites were involved in energy metabolism, glycolipid metabolism, inflammatory response, neurotoxic response, nucleic acid metabolism, oxidative stress. Polystyrene microplastics also significantly decreased the activities of catalase and the content of glutathione. In addition, the results of gene transcription analysis showed that exposure to polystyrene microplastics induced changes in glycolysis-related genes and lipid metabolism-related genes, confirming that polystyrene microplastics disturbed glycolipid and energy metabolism. Taken together, the results obtained in the present study indicated that the potential effects of environmental microplastics on aquatic organisms should not be ignored. PMID- 30448748 TI - A novel biochar supported CMC stabilized nano zero-valent iron composite for hexavalent chromium removal from water. AB - In this study, novel biochar supported nano-scale zero-valent iron (biochar-CMC nZVI) stabilized by carboxymethyl cellulose (CMC) was developed and used for the removal of hexavalent chromium (Cr(VI) from aqueous solution. With the stabilization of CMC, nZVI particles (about 80 nm) were effectively dispersed onto the surface of biochar, which inhibited the aggregation of nZVI and resulted in the smaller particle size of nZVI on the surface of biochar. The results showed that the specific surface area of the composite was 11.1 m2/g, lower than that of pristine biochar. The basic element composition was C, O, and Fe with a large number of oxygen-containing functional groups (-COOH, OH, and OCO) observed on the surface. Cr(VI) was reduced to Cr(III) by the composite material, mainly due to the reduction of nZVI on the biochar surface. Upon reaction with Cr(VI), CrxFe1-x(OH)3 and FexCryO4 were deposited on the surface of biochar-CMC-nZVI composite. Electrostatic attraction, reduction, and surface complexation were the dominant removal mechanisms. The results showed that the 100 mg/L Cr(VI) could be removed completely by biochar-CMC-nZVI within 18 h, at a dosage of 1.25 g/L and an initial pH of 5.6. Cr(VI) removal by biochar-CMC-nZVI was favored by lower pH. The pseudo-second-order kinetic model and the Langmuir isothermal adsorption model fitted well with the sorption kinetic and isotherm data, indicated Cr(VI) adsorption mechanism was a chemisorption based multi-layer adsorption. The present study demonstrated the promise of biochar-CMC-nZVI composite as a low cost, "green", and effective sorbent for removal of Cr(VI) in the environment. PMID- 30448749 TI - Environmental impact assessment of industrial activities on heavy metals distribution in street dust and soil. AB - Street dust and soil are important materials for evaluating the contaminants level in industrial areas. Detailed size-resolved distribution of metal(loid)s in street dusts and soils influenced by industrial activities has rarely been investigated. This study was carried out to understand how industrialization might affect the size distribution of metal(loid)s concentration and contamination level in the street dust and soil from Murcia, southern Spain. An industrial and a natural areas were selected and surface soil and street dust samples were taken. They were fractionated into eleven size classes and total concentrations of Pb, Zn, Cu, Cd, Cr, Ni, As and Fe were determined in both the bulk samples and their fractions. Enrichment factor, geoaccumulation index, and mass loading of different heavy metal(loids) were calculated. The results indicated that the street dust from natural and industrial areas had almost the same particle size distribution, both containing higher percentage of coarse sized particles than the soil. Industrialization seems to have only slightly affected the concentration of most elements studied in the soil. In contrast, the concentrations of the heavy elements in bulk industrial dust samples and all their size fractions were extremely higher than those from the natural area. This means that the industrial activities only affected the size dependency of the concentration (contamination level) of certain elements (Pb, Zn, Cu, Cd, and Cr) in the street dust, but not in the soil. PMID- 30448750 TI - Effects of ion species on the disinfection byproduct formation in artificial and real water. AB - Disinfection byproducts (DBPs) have attracted extensive attention due to their cytotoxicity and genotoxicity. This study investigates the effects of different ions on DBP formation during chlorination and chloramination in artificial and real water samples. Compared with chlorination, chloramination can reduce the formation of DBPs. K+ only reduce the formation of DBPs during chloramination. Ca2+ forms less DBPs than Mg2+ does during chlorination and chloramination due to the stronger binding effect. Al3+ and their hydroxide colloids have a significant effect on DBP formation. Anions have no significant effect on DBP formation. Due to the difference between the real and artificial water samples, the large amount of NH4+ in the real water will form chloramine during chlorination. Furthermore, the effects of different ion in the chlorination will have the same tendency during chlorination. In the wastewater with high ionic strength, the effects of salts are mostly ignored. Studying the effects of different ions on DBP formation is important in controlling the content of DBPs in the disinfection process. PMID- 30448751 TI - Aqueous- and solid-phase molybdenum geochemistry of oil sands fluid petroleum coke deposits, Alberta, Canada. AB - Fluid petroleum coke generated at oil sands operations in the Athabasca Oil Sands Region of northern Alberta, Canada, contains elevated concentrations of molybdenum (Mo) and other metals including nickel (Ni) and vanadium (V). Solid phase Mo concentrations in fluid petroleum coke are typically 10 to 100 times lower than V and Ni, yet dissolved Mo concentrations in associated pore waters are often comparable with these metals. We collected pore water and solids from fluid petroleum coke deposits in the AOSR to examine geochemical controls on Mo mobility. Dissolved Mo concentrations increased with depth below the water table, reaching maxima of 1.4-2.2 mg L-1, within a mixing zone between slightly acidic and oxic meteoric water and mildly alkaline and anoxic oil sands process-affected water (OSPW). Dissolved Mo concentrations decreased slightly with depth below the mixing zone. X-ray absorption spectroscopy revealed that Mo(VI) and Mo(IV) species were present in coke solids. The Mo(VI) occurred as tetrahedrally coordinated MoO42- adsorbed via inner- and outer-sphere complexation, and was coordinated in an environment similar to Fe-(hydr)oxide surface complexes. The OSPW likely promoted desorption of outer-sphere Mo(VI) complexes, resulting in higher dissolved Mo concentrations in the mixing zone. The principal Mo(IV) species was MoS2, which originated as a catalyst added upstream of the fluid coking process. Although MoS2 is likely stable under anoxic conditions below the mixing zone, oxidative weathering in the presence of meteoric water may promote long-term Mo release. PMID- 30448752 TI - Adsorption and photocatalytic removal of Ibuprofen by activated carbon impregnated with TiO2 by UV-Vis monitoring. AB - The removal of Ibuprofen was investigated by activated carbon impregnated with TiO2. Emphasis was given on the effect of different parameters, such as composite type, initial Ibuprofen concentration (5-25 mg/L), temperature (22-28 degrees C) and pH (acidic and alkaline solution). The experiment was carried out in a self made tubular flow reactor, with one 15 W monochromatic UV lamp (254 nm). The composite AC90T10 gives the highest removal degree of 92% of Ibuprofen solution under UV light within 4 h, due to synergy of adsorption and photodegradation. It was found that weight ratio of composite/Ibuprofen has limited effect on the removal degree within the concentration range (5-25 mg/L), but reaction time under UV light (4 h) and pH (acidic solution) are very important. The kinetic experimental data obtained at pH 4.3 at 25 degrees C on different composites were fitted to pseudo-first, pseudo-second and Elovich models, obtaining a high accuracy based on R2 values. From the results, composites of granular activated carbon and TiO2 can enhance removal of Ibuprofen effectively, making recycle process much easier and less costly, which can be a promising method in future water treatment. PMID- 30448753 TI - TiO2 nanoparticles and BPA are combined to impair the development of offspring zebrafish after parental coexposure. AB - Titanium dioxide (TiO2) nanoparticles and bisphenol A (BPA) in aquatic environments interact reciprocally to enhance the maternal transfer of pollutants to offspring, thus varying the innate toxicities during early embryonic development. However, it remains unexplored regarding the molecular mechanisms of developmental toxicity in offspring after parental coexposure. In the present study, adult zebrafish were exposed to TiO2 nanoparticles (100 MUg/L), BPA (20 MUg/L) or their binary mixture for four months. Then, eggs of F1 generation were collected and reared in clean water until 5 days post-fertilization. In characteristic of larval survival and growth, parental coexposure to TiO2 particles and BPA caused a severer inhibition of F1 offspring larvae compared with single exposure. Mechanistic investigation by shotgun proteomics found that development of larval offspring from coexposed parents was impaired through a distinct mode of toxicity, that is, specifically altering the activity of phagosome and lysosome. Single exposure of adult zebrafish to TiO2 mainly affected insulin-responsive compartment; and BPA parental exposure mainly affected carbohydrate metabolism and calcium signaling of larval offspring. Furthermore, considering the tight regulation of sex hormones in the expression of vitellogenin (VTG), addition of nanoparticles during parental exposure led to inconsistencies between VTG induction and endogenous levels of sex hormones (estradiol and testosterone) in F1 offspring fish. This implied that transfer of nanoparticles to offspring larvae may change the availability of hormonal molecules and BPA at target tissues. Overall, current results provided mechanistic clues into the multigenerational developmental toxicity by parental coexposure to TiO2 particles and BPA. PMID- 30448754 TI - Liquid phase catalytic hydrogenation reduction of Cr(VI) using highly stable and active Pd/CNT catalysts coated by N-doped carbon. AB - Liquid catalytic hydrogenation is a green and cost-effective technique for the reductive removal of pollutants in water. Supported noble metals are the most frequently used catalysts in liquid phase catalytic hydrogenation, whereas marked catalyst deactivation is commonly identified. In this study, we coated supported Pd catalyst on carbon nanotube (denoted as Pd/CNT) by different overcoatings (including SiO2, carbon and N-doped carbon) to prevent catalyst deactivation. The activities of the coated catalysts for liquid phase catalytic hydrogenation reduction of hexavalent chromium (Cr(VI)) differed with the overcoating properties. Negligible Cr(VI) conversion was observed on SiO2 coated Pd/CNT, while feasible Cr(VI) reduction was identified on carbon coated (denoted as Pd/CNT@C) and N-doped carbon coated catalysts (denoted as Pd/CNT@CN). Pd/CNT@CN exhibited a much higher catalytic activity than Pd/CNT@C, which was ascribed to the stronger Cr(VI) adsorption on CN overcoating. The catalytic activity of Pd/CNT@CN was positively correlated with the conductivity and hydrophilicity of CN overcoating, which could be optimized by varying carbonization temperature. Furthermore, Pd/CNT@CN retained its initial activity after ten consecutive catalyst cycles without any deactivation, whereas Pd/CNT only retained 8.2% of its initial activity, reflecting much higher catalytic stability of Pd/CNT@CN than Pd/CNT. The findings in the present study highlight that liquid catalytic reduction using Pd/CNT@CN as the catalyst is a highly stable and effective method to remove Cr(VI) in water. PMID- 30448755 TI - Metal subcellular partitioning determines excretion pathways and sensitivity to cadmium toxicity in two marine fish species. AB - Subcellular cadmium (Cd) partitioning was investigated in the liver of two marine fish species, the European sea bass Dicentrarchus labrax and the Senegalese sole Solea senegalensis, dietary exposed to an environmentally realistic Cd dose for two months followed by a two-month depuration. The two species displayed different handling strategies during the depuration period. Cd was largely bound to detoxifying fractions such as heat stable proteins (HSP) including metallothioneins (MT) in sea bass, while Cd was more linked to sensitive fractions such as organelles in sole. Whole liver concentrations and subcellular partitioning were also determined for essential elements. The greatest impairment of essential metal homeostasis due to Cd exposure was found in sole. These elements followed the Cd partitioning pattern, suggesting that they are involved in antioxidant responses against Cd toxicity. Cd consumption diminished sole growth in terms of body weight, probably due to lipid storage impairment. The contrasting partitioning patterns showed by the two species might imply different pathways for Cd elimination from the liver. In sea bass, MT-bound Cd would be excreted through bile or released into blood, crossing the cell membrane via a protein transporter. In sole, MRG-bound Cd would be sequestered by organelles before being released into the blood via vesicular exocytosis. These distinct strategies in cellular Cd handling in the liver might account for differential sensitivity to Cd toxicity and differential Cd excretion pathways between the two marine fish species. PMID- 30448756 TI - Treatment of low-level Cu(II) wastewater and regeneration through a novel capacitive deionization-electrodeionization (CDI-EDI) technology. AB - It was difficult for mature technologies to manage the low-level heavy metal wastewater due to low efficiency, secondary pollution and difficult enrichment. In this study, a novel capacitive deionization-electrodeionization (CDI-EDI) technology was developed through coordination mechanism of electromigration, electro-adsorption and ion exchange. Based on this technique, the low-content heavy metal ions in high-salinity wastewater could be removed efficiently. Moreover, a higher electro-adsorption CDI electrode was applied in the CDI-EDI stack. EDI device was optimized by decreasing ion exchange membranes from 4 to 2, thus reduced the stack cost. Based on the CDI-EDI stack, the simulated Cu(II) wastewater (C0 = 42.9 mg/L) was treated, and its average removal rate in 1st cycle cathode- and anode-effluent was 95.7% and 87.6%, respectively, under optimal direct current (DC) of 1.5 mA for 1.5 min, followed by electroregeneration of resin and electrode. Besides, the actual electroplating wastewater containing Ni(II) (389.4 mg/L) was treated via this device after precipitation to verify its feasibility. The results indicated that Ni(II) in the anode- and cathode-compartments were removed by 1.61 mg/L and 2.01 mg/L, respectively, only via one-stage CDI-EDI device under the operating voltage (0.10 0.20 V) and direct current (2.0-4.0 mA). It was possible to improve desalination efficiency of low-concentration heavy metal using tandem-type multistage devices. The CDI-EDI technique could not only ensure stable effluent and lower regenerations cost, but also enrich heavy metal from regeneration fluid to achieve resource recovery. This study would have obvious implications in treatment of low-content and salt-containing heavy metal wastewater with high efficiency and low energy consumption. PMID- 30448757 TI - Enhanced phytoremediation of uranium-contaminated soils by arbuscular mycorrhiza and rhizobium. AB - Uranium phytoextraction is a promising technology, however, facing difficult that limited plant biomass due to nutrient deficiency in the contaminated sites. The aim of this study is to evaluate the potential of a symbiotic associations of a legume Sesbania rostrata, rhizobia and arbuscular mycorrhiza fungi (AMF) for reclamation of uranium contaminated soils. Results showed AMF and rhizobia had a mutual beneficial relations in the triple symbiosis, which significantly increased plant biomass and uranium accumulation in S. rostrata plant. The highest uranium removal rates was observed in plant-AMF-rhizobia treated soils, in which 50.5-73.2% had been extracted, whereas 7.2-23.3% had been extracted in plant-treated soil. Also, the S. rostrata phytochelatin synthase (PCS) genes expression were increased in AMF and rhizobia plants compared with the plants. Meantime, content of malic acid, succinic acid and citric acid were elevated in S. rostrata root exudates of AMF and rhizobia inoculated plants. The facts suggest that the mutual interactions in the triple symbiosis help to improve phytoremediation efficiency of uranium by S. rostrata. PMID- 30448758 TI - Non-Suicidal self-injury and suicide in depressed Adolescents: Impact of peer victimization and bullying. AB - BACKGROUND: While prior research has demonstrated that peer victimization and bully perpetration contribute to non-suicidal self-injury (NSSI) and suicidal thoughts and behaviors (STBs), it remains unclear whether these interpersonal processes differentiate self-injuring adolescent suicide ideators and attempters. METHODS: The study included adolescents aged 13-18 years (n = 223; M = 15.31, SD = 1.34) recruited from an acute inpatient program. Participants were divided into two groups: (1) NSSISI (n = 106): endorsed past year NSSI, current suicide ideation, and no lifetime suicide attempts and (2) NSSISI+SA (n = 117): endorsed past year NSSI, current suicide ideation, and lifetime suicide attempts. Adolescents completed clinical interviews (i.e., mental disorders, NSSI, and STBs) and self-report measures assessing peer victimization, bully perpetration, and depression severity. RESULTS: NSSISI+SA youth reported higher levels of peer victimization and bully perpetration than NSSISI youth (ps < 0.01, ds = 0.36 0.37). Among the NSSISI+SA youth, bully perpetration was associated with a greater number of past month suicide attempts (p = 0.02, RR = 1.07). Only peer victimization was associated with greater NSSI behaviors in the past month (p = 0.04, RR = 1.01). LIMITATIONS: The study is cross-sectional, and reports of peer victimization and bully perpetration rely on self-report assessment. CONCLUSIONS: Peer victimization and bully perpetration differentiated adolescent suicide ideators and attempters, highlighting the need to address bully perpetration in addition to peer victimization in suicide interventions and research. PMID- 30448759 TI - Prevalence and related influencing factors of depressive symptoms among empty nest elderly in Shanxi, China. AB - BACKGROUND: In China, aging has become a serious social problem, and the number of empty-nest elderly is on the rise. The aim of this study is to clarify the prevalence of depressive symptoms among empty-nest elderly in Shanxi province and evaluate the effects of sociodemographic factors and health-promoting lifestyles so as to provide a scientific reference for preventing and intervening their depression. METHODS: A cross-sectional study, which used a multi-stage random cluster sampling way, was conducted among 4901 empty-nest elderly in Shanxi. An independent t-test and a chi square test were used to compare the sociodemographic factors, depression scores, and health-promoting lifestyle scores of the empty-nest elderly. Multinomial logistic regression was used to analyze the potential influencing factors for depression. RESULTS: The prevalence of depressive symptoms in the population was 64.2%. Among all participants 1,776 (36.2%) had mild depression, 1,236 (25.2%) had moderate depression, and 135 (2.8%) had severe depression. The health-promoting lifestyle of the empty nesters in this study was at the medium level (2.51 +/- 0.47). Gender, education level, old-age provision model, exercise frequency, chronic disease, relationships with children, self-care ability, and health-promoting lifestyles were found to be influencing factors of depression and all variables had different effects on different degrees of depression. LIMITATIONS: This was a cross-sectional study, so the results cannot establish causal relationships among the study variables. CONCLUSIONS: Depression was prevalent among the empty-nest elderly in Shanxi. Maintaining good interpersonal relationships, developing extensive interests, and maintaining healthy lifestyles including good nutrition habits and regular exercises can reduce the incidence of depression among empty nesters. PMID- 30448760 TI - REM sleep fragmentation associated with depressive symptoms and genetic risk for depression in a community-based sample of adolescents. AB - INTRODUCTION: Fragmented REM sleep may impede overnight resolution of distress and increase depressive symptoms. Furthermore, both fragmented REM and depressive symptoms may share a common genetic factor. We explored the associations between REM sleep fragmentation, depressive symptoms, and a polygenic risk score (PRS) for depression among adolescents. METHODS: About 161 adolescents (mean age 16.9 +/- 0.1 years) from a birth cohort underwent a sleep EEG and completed the Beck Depression Inventory-II the same day. We calculated PRSes for depressive symptoms with PRSice 1.25 software using weights from a recent genome-wide association study for dimensions of depressive symptoms (negative emotion, lack of positive emotion and somatic complaints). REM fragmentation in relation to entire REM duration was manually calculated from all REM epochs. REM latency and density were derived using SomnoMedics DOMINO software. RESULTS: PRSes for somatic complaints and lack of positive emotions were associated with higher REM fragmentation percent. A higher level of depressive symptoms was associated with increased percent of REM fragmentation and higher REM density, independently of the genetic risks. Belonging to the highest decile in depressive symptoms was associated with a 2.9- and 7.6-fold risk of belonging to the highest tertile in REM fragmentation and density. In addition, higher PRS for somatic complaints had an independent, additive effect on increased REM fragmentation. LIMITATION: A single night's sleep EEG was measured, thus the night-to-night stability of the REM fragmentation-depressive symptom link is unclear. CONCLUSION: Depressive symptoms and genetic risk score for somatic complaints are independently associated with more fragmented REM sleep. This offers new insights on the quality of sleep and its relation to adolescents' mood. PMID- 30448761 TI - HCN channels: New targets for the design of an antidepressant with rapid effects. AB - BACKGROUND: Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that carries a staggering global burden. Although numerous antidepressants are available on the market, unfortunately, many patients die by committing suicide as a result of the therapeutic lag between treatment initiation and the improvement of depressive symptoms. This therapeutic lag highlights the need for new antidepressants that provide rapid relief of depressive symptoms. METHOD: In this review, we discuss the seminal researches on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in animal models of depression and highlight the substantial evidence supporting the development of rapid-acting antidepressants targeting HCN channels. RESULTS: HCN channels are associated with the risk of depression and targeting HCN channels or its auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) function may exert a rapid antidepressant-like effect. CONCLUSIONS: Compounds acting on HCN subunits or the TRIP8b-HCN interaction site may be excellent candidates for development into effective drugs with rapid antidepressant action. PMID- 30448762 TI - Predictors of change in depressive symptoms over time: Results from the Australian Longitudinal Study on Women's Health. AB - BACKGROUND: Depressive symptoms fluctuate over time, and are most common amongst women in early adulthood. Understanding predictors of changes in depressive symptoms among young women may inform health promotion and early intervention. METHODS: Data were collected at three-yearly intervals from 2000 (Survey 2) to 2012 (Survey 6) from the Australian Longitudinal Study on Women's Health. The sample comprised 7663 women, aged 22-27 in 2000, who reported any indicator of poor mental health at any wave. Generalised linear mixed models identified predictors of change in depressive symptoms (CESD-10) over each three-year period. RESULTS: Depressive symptoms reduced over time. In a fully adjusted model, greater reduction in symptoms was predicted by higher initial symptoms, time, higher social support, and higher self-rated general health. Slower reduction was predicted by lower education, difficulty managing on income, high or zero alcohol consumption, stress, and history of childhood sexual assault or partner violence. Motherhood predicted an increase in depressive symptoms at Survey 2 (2000), but a decrease at Survey 5 (2009). LIMITATIONS: Although sampling was nationally representative, there is a slight bias towards Australian born and more educated women. Further, although validated measures are used, all data are self-report. CONCLUSIONS: Fluctuations in depressive symptoms among young women are related to fixed and time-varying factors spanning multiple health and social domains. A range of factors, including education and financial resources, promotion of positive social support systems, and encouragement of health promoting lifestyles, might serve to promote young women's mental health and thus to reduce pressure on clinical services. PMID- 30448763 TI - The Self-Hate Scale: Development and validation of a brief measure and its relationship to suicidal ideation. AB - BACKGROUND: The "self" has been implicated in the development of a range of psychological disorders. While a growing body of literature has emerged exploring the Interpersonal Psychological Theory of Suicide (IPTS), little research has been conducted on the construct of self-hate and its relationship with suicidal ideation. The aims of this study were to: 1) develop and validate a brief self report instrument of self-hate; and, 2) explore the relationship between self hate, suicidal ideation, and the two main factors of the IPTS, perceived burdensomeness and thwarted belongingness. METHODS: Initial development of the item pool involved an expert panel and the development of the Self-Hate Scale included exploratory and confirmatory factor analyses using a large community sample. RESULTS: A 7-item Self-Hate Scale was developed, which exhibited a reliable unidimensional factor structure. High self-hate was found to predict suicidal ideation, while the relationship between low/moderate self-hate and suicidal ideation was partially moderated by the level of thwarted belongingness. The study provided limited evidence for the IPTS' main predictions. LIMITATIONS: While the current study provided support for the psychometric properties of the Self-Hate Scale, the scale will need to be replicated and validated using clinical populations. CONCLUSIONS: The Self-Hate Scale is a brief, psychometrically valid measure of self-hate that has the potential to be useful in suicide risk assessment. PMID- 30448765 TI - Novel method for analyzing transport parameters in through-diffusion tests. AB - Buffer materials such as bentonite are vital for absorbing radionuclide leakage and retarding migration from radioactive waste canisters. The diffusion coefficient and the retardation factor are the predominant properties controlling the diffusion-reaction process in a buffer material. Diffusion experiments combined with Crank's graphical method are a well-established process for determining asymptotic diffusion coefficients. However, the inaccuracy of the diffusion coefficient that results from the subjective judgement of the late-time linear part of the cumulative concentration data in Crank's graphical method will deteriorate the estimate of the retardation factor. A novel parameter identification process based on an iterative and analytical method (PIPIAM) is proposed here to obtain the diffusion coefficients and porosity of bentonite using concentration data. The results of PIPIAM and the graphical method are compared through an error analysis of concentration. The results show that PIPIAM outperforms the graphical method in terms of the error reduction of the concentration and the uncertainty decrease of the estimated parameters. The proposed method is thus a good alternative for acquiring transport parameters for use in safety assessments of nuclear waste repositories. PMID- 30448764 TI - The role of childhood abuse for suicidality in the context of the interpersonal theory of suicide: An investigation in German psychiatric inpatients with depression. AB - BACKGROUND: Several studies provide evidence for a relationship between childhood abuse and suicidality across the lifespan. To examine this association in the context of the Interpersonal Psychological Theory of Suicide (IPTS), we investigated whether its constructs thwarted belongingness, perceived burdensomeness and capability for suicide are potential mediators. METHODS: Eighty-four German psychiatric inpatients with unipolar depression (M = 37.6 years, 69% female) and current or lifetime suicidal ideation were included. For the assessment we used the Childhood Trauma Screener (CTS), the Rasch-based Screening for Depression (DESC-I), the Interpersonal Needs Questionnaire (INQ), the German Capability for Suicide Questionnaire (GCSQ), the Beck Scale for Suicide Ideation (BSS) and the Suicide Behaviors Questionnaire-Revised (SBQ-R). Simple and multiple mediator analyses were applied. RESULTS: Most patients (70%) had experienced childhood abuse. Emotional abuse showed an indirect association with suicidal ideation via thwarted belongingness and perceived burdensomeness, whereas physical and sexual abuse were indirectly related to suicide risk via capability for suicide. LIMITATIONS: The small sample size and the cross sectional design are limiting factors of the present study. CONCLUSIONS: Childhood abuse is a common experience of inpatients with unipolar depression. This study showed its indirect effects on suicidal ideation and risk for suicide, mediated by the constructs of the IPTS. Further research should investigate this issue in other populations and clinicians should be aware of the devastating effects of childhood abuse. PMID- 30448766 TI - A treatable hypertrophic neuropathy. PMID- 30448767 TI - Response to: 'ANA testing in "real life"' by Infantino et al. PMID- 30448768 TI - ANA testing in 'real life'. PMID- 30448769 TI - Visualisation of interstitial lung disease by molecular imaging of integrin alphavbeta3 and somatostatin receptor 2. AB - OBJECTIVE: To evaluate integrin alphavbeta3 (alpha-v-beta-3)-targeted and somatostatin receptor 2 (SSTR2)-targeted nuclear imaging for the visualisation of interstitial lung disease (ILD). METHODS: The pulmonary expression of integrin alphavbeta3 and SSTR2 was analysed in patients with different forms of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. Single photon emission CT/CT (SPECT/CT) was performed on days 3, 7 and 14 after BLM instillation using the integrin alphavbeta3-targeting 177Lu-DOTA-RGD and the SSTR2-targeting 177Lu-DOTA-NOC radiotracer. The specific pulmonary accumulation of the radiotracers over time was assessed by in vivo and ex vivo SPECT/CT scans and by biodistribution studies. RESULTS: Expression of integrin alphavbeta3 and SSTR2 was substantially increased in human ILD regardless of the subtype. Similarly, in lungs of BLM-challenged mice, but not of controls, both imaging targets were stage-specifically overexpressed. While integrin alphavbeta3 was most abundantly upregulated on day 7, the inflammatory stage of BLM-induced lung fibrosis, SSTR2 expression peaked on day 14, the established fibrotic stage. In agreement with the findings on tissue level, targeted nuclear imaging using SPECT/CT specifically detected both imaging targets ex vivo and in vivo, and thus visualised different stages of experimental ILD. CONCLUSION: Our preclinical proof-of-concept study suggests that specific visualisation of molecular processes in ILD by targeted nuclear imaging is feasible. If transferred into clinics, where imaging is considered an integral part of patients' management, the additional information derived from specific imaging tools could represent a first step towards precision medicine in ILD. PMID- 30448770 TI - Effect of seawalls on tsunami evacuation departure in the 2011 Great East Japan Earthquake. AB - OBJECTIVE: To quantitatively evaluate the effect of seawalls on tsunami evacuation departure. METHODS: A mixed-effect Cox proportional-hazards regression model was applied to evacuation behavioural data obtained from a probability survey of survivors of the 2011 Great East Japan Earthquake and Tsunami in Iwate and Miyagi prefectures. FINDINGS: Presence of a seawall higher than the forecast tsunami height at any given time reduces the likelihood of prompt evacuation by 30%. Findings suggest the existence of a false sense of security among residents deriving from the presence of seawalls. CONCLUSION: Prompt evacuation is a key factor affecting survival. The effect of seawalls on evacuation decisions is an important policy consideration. More work is needed in disaster preparedness education and in the way tsunami warnings are given, taking into consideration the risk of forecast error. Priority should be given to promoting prompt evacuation and educating residents as to the uncertainty of tsunami forecasting, to ensure that residents do not ignore evacuation warnings due to false impressions of the safety provided by seawalls. PMID- 30448771 TI - Incorrect policy interpretation affects conclusion on SO2 emissions by coal-fired power plants in China. PMID- 30448773 TI - Authors reply: treatment strategy for necrotising pancreatitis. PMID- 30448774 TI - Statin use and reduced risk of biliary tract cancers in the UK Clinical Practice Research Datalink. AB - OBJECTIVE: To evaluate the association between statin use and risk of biliary tract cancers (BTC). DESIGN: This is a nested case-control study conducted in the UK Clinical Practice Research Datalink. We included cases diagnosed with incident primary BTCs, including cancers of the gall bladder, bile duct (ie, both intrahepatic and extrahepatic cholangiocarcinoma), ampulla of Vater and mixed type, between 1990 and 2017. For each case, we selected five controls who did not develop BTCs at the time of case diagnosis, matched by sex, year of birth, calendar time and years of enrolment in the general practice using incidence density sampling. Exposures were defined as two or more prescription records of statins 1 year prior to BTC diagnosis or control selection. ORs and 95% CIs for associations between statins and BTC overall and by subtypes were estimated using conditional logistic regression, adjusted for relevant confounders. RESULTS: We included 3118 BTC cases and 15 519 cancer-free controls. Current statin use versus non-use was associated with a reduced risk of all BTCs combined (adjusted OR=0.88, 95% CI 0.79 to 0.98). The reduced risks were most pronounced among long term users, as indicated by increasing number of prescriptions (ptrend=0.016) and cumulative dose of statins (ptrend=0.008). The magnitude of association was similar for statin use and risk of individual types of BTCs. The reduced risk of BTCs associated with a record of current statin use versus non-use was more pronounced among persons with diabetes (adjusted OR=0.72, 95% CI 0.57 to 0.91). Among non-diabetics, the adjusted OR for current statin use versus non-use was 0.91 (95% CI 0.81 to 1.03, pheterogeneity=0.007). CONCLUSION: Compared with non use of statins, current statin use is associated with 12% lower risk of BTCs; no association found with former statin use. If replicated, particularly in countries with a high incidence of BTCs, our findings could pave the way for evaluating the value of statins for BTC chemoprevention. PMID- 30448775 TI - Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. AB - OBJECTIVE: Antimicrobial C-type lectin regenerating islet-derived 3 gamma (REG3G) is suppressed in the small intestine during chronic ethanol feeding. Our aim was to determine the mechanism that underlies REG3G suppression during experimental alcoholic liver disease. DESIGN: Interleukin 22 (IL-22) regulates expression of REG3G. Therefore, we investigated the role of IL-22 in mice subjected to chronic binge ethanol feeding (NIAAA model). RESULTS: In a mouse model of alcoholic liver disease, we found that type 3 innate lymphoid cells produce lower levels of IL 22. Reduced IL-22 production was the result of ethanol-induced dysbiosis and lower intestinal levels of indole-3-acetic acid (IAA), a microbiota-derived ligand of the aryl hydrocarbon receptor (AHR), which regulates expression of IL 22. Importantly, faecal levels of IAA were also found to be lower in patients with alcoholic hepatitis compared with healthy controls. Supplementation to restore intestinal levels of IAA protected mice from ethanol-induced steatohepatitis by inducing intestinal expression of IL-22 and REG3G, which prevented translocation of bacteria to liver. We engineered Lactobacillus reuteri to produce IL-22 (L. reuteri/IL-22) and fed them to mice along with the ethanol diet; these mice had reduced liver damage, inflammation and bacterial translocation to the liver compared with mice fed an isogenic control strain and upregulated expression of REG3G in intestine. However, L. reuteri/IL-22 did not reduce ethanol-induced liver disease in Reg3g-/- mice. CONCLUSION: Ethanol associated dysbiosis reduces levels of IAA and activation of the AHR to decrease expression of IL-22 in the intestine, leading to reduced expression of REG3G; this results in bacterial translocation to the liver and steatohepatitis. Bacteria engineered to produce IL-22 induce expression of REG3G to reduce ethanol induced steatohepatitis. PMID- 30448772 TI - NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study. AB - OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46 PBD as a promising therapy for RCDII, EATL and MEITL. PMID- 30448777 TI - Too many rib ticklers? Injuries in Australian women's cricket (PhD Academy Award). PMID- 30448776 TI - Iron-containing micronutrient powders modify the effect of oral antibiotics on the infant gut microbiome and increase post-antibiotic diarrhoea risk: a controlled study in Kenya. AB - OBJECTIVE: Many African infants receiving iron fortificants also receive antibiotics. Antibiotic efficacy against enteropathogens may be modified by high colonic iron concentrations. In this study, we evaluated the effect of antibiotics on the infant gut microbiome and diarrhoea when given with or without iron-containing micronutrient powders (MNPs). DESIGN: In a controlled intervention trial, four groups of community-dwelling infants (n=28; aged 8-10 months) received either: (A) antibiotics for 5 days and iron-MNPs for 40 days (Fe+Ab+); (B) antibiotics and no-iron-MNPs (Fe-Ab+); (C) no antibiotics and iron MNPs (Fe+Ab-); or (D) no antibiotics and no-iron-MNPs (Fe-Ab-). We collected a faecal sample before the first antibiotic dose (D0) and after 5, 10, 20 and 40 days (D5-D40) to assess the gut microbiome composition by 16S profiling, enteropathogens by quantitative PCR, faecal calprotectin and pH and assessed morbidity over the 40-day study period. RESULTS: In Fe+Ab+, there was a decrease in Bifidobacterium abundances (p<0.05), but no decrease in Fe-Ab+. In Fe-Ab+, there was a decrease in abundances of pathogenic Escherichia coli (p<0.05), but no decrease in Fe+Ab+. In Fe-Ab+, there was a decrease in pH (p<0.05), but no decrease in Fe+Ab+. Longitudinal prevalence of diarrhoea was higher in Fe+Ab+ (19.6%) compared with Fe-Ab+ (12.4%) (p=0.04) and compared with Fe+Ab- (5.2%) (p=0.00). CONCLUSION: Our findings need confirmation in a larger study but suggest that, in African infants, iron fortification modifies the response to broad-spectrum antibiotics: iron may reduce their efficacy against potential enteropathogens, particularly pathogenic E. coli, and may increase risk for diarrhoea. TRIAL REGISTRATION NUMBER: NCT02118402; Pre-results. PMID- 30448778 TI - Benefits and challenges of serial sports training risk assessment and counselling in kids: the T.R.A.C.K. randomised intervention study. AB - BACKGROUND: Published training recommendations exist for youth athletes aimed at reducing injury risk. No studies have assessed the impact of counselling interventions using training recommendations on risk of injury in young athletes. OBJECTIVES: To determine if online training counselling regarding safe sport participation can reduce injury risk in youth athletes and to assess recommendation compliance, including barriers to compliance. METHODS: A multicentre randomised intervention trial was performed at two Midwestern academic institutions with expertise in treating young athletes. Enrolled subjects ages 8-17 completed a baseline risk assessment survey and were randomised to a control or intervention group. Both groups completed exposure surveys every 3 months for 1 year. The intervention group also received online training counselling on safe sport participation every 3 months. Training characteristics including training volume, degree of specialisation and adherence to recommendations were captured. Differences in self-reported injury between groups, compliance to recommendations and barriers to compliance were evaluated. RESULTS: At baseline, n=357 subjects were enrolled (n=172 control and n=185 intervention). Controls were nearly twice as likely to be injured during the intervention period after controlling for age, sex, baseline injury and level of specialisation. No improvement in recommendation compliance was detected among intervention subjects. Primary barriers to compliance were no prior knowledge of recommendations, personal choice and following coaches' recommendations. CONCLUSIONS: In this convenience sample of youth athletes, electronic training counselling surrounding safe sports participation was not determined to affect injury risk. Lack of knowledge and adherence to appropriate training recommendations is evident and barriers to compliance exist. PMID- 30448779 TI - Injuries in male and female elite Korean wrestling athletes: a 10-year epidemiological study. AB - OBJECTIVES: To report injury patterns associated with the training activities of elite male and female South Korean wrestling athletes preparing for the Olympic Games. METHODS: From 2008 to 2017, we prospectively collected data on elite wrestling athletes at the Korea National Training Center. Athletes were assessed by two sports medicine doctors, and data were stratified according to sex, wrestling style, weight class, injury location and injury severity. Chi2tests were used to compare groups. Injury risk was expressed in relative ratios with 95% confidence intervals (RR, 95% CI). RESULTS: There were 238 male and 75 female elite wrestlers. Training time totalled 382 800 hours. We recorded 1779 injuries in 313 athletes aged >18 years (annual average, 4.04 injuries/athlete); 59% of these were mild injuries. When all athletes were considered, most injuries occurred in the lower extremities (37.5%), followed by the upper extremities (27.4%), trunk (25.4%) and the head and neck area (9.7%). Weight class significantly influenced injury severity for both wrestling styles among male athletes (Greco-Roman, P=0.031; freestyle, P=0.028), as well as among female freestyle wrestling athletes (P=0.013). The relative ratio of injury incidence for the lightweight class compared with the heavyweight class was high for Greco Roman style compared with freestyle (RR 1.13, 95% CI 1.03 to 1.27; P=0.011). CONCLUSIONS: Among male and female South Korean elite wrestling athletes training for the Olympic Games, most injuries were mild and occurred in the lower extremities. Weight class influenced injury severity in both wrestling styles, and lightweight athletes had higher injury rates. PMID- 30448780 TI - Rating of perceived challenge as a measure of internal load for technical skill performance. PMID- 30448781 TI - Pre-participation health evaluation in adolescent athletes competing at Youth Olympic Games: proposal for a tailored protocol. AB - OBJECTIVE: To promote sports participation in young people, the International Olympic Committee (IOC) introduced the Youth Olympic Games (YOG) in 2007. In 2009, the IOC Consensus Statement was published, which highlighted the value of periodic health evaluation in elite athletes. The objective of this study was to assess the efficacy of a comprehensive protocol for illness and injury detection, tailored for adolescent athletes participating in Summer or Winter YOG. METHODS: Between 2010 and 2014, a total of 247 unique adolescent elite Italian athletes (53% females), mean age 16+/-1,0 years, competing in 22 summer or 15 winter sport disciplines, were evaluated through a tailored pre-participation health evaluation protocol, at the Sports Medicine and Science Institute of the Italian Olympic Committee. RESULTS: In 30 of the 247 athletes (12%), the pre participation evaluation led to the final diagnosis of pathological conditions warranting treatment and/or surveillance, including cardiovascular in 11 (4.5%), pulmonary in 11 (4.5%), endocrine in five (2.0%), infectious, neurological and psychiatric disorders in one each (0.4%). Based on National and International Guidelines and Recommendations, none of the athletes was considered at high risk for acute events and all were judged eligible to compete at the YOG. Athletes with abnormal conditions were required to undergo a periodic follow-up. CONCLUSIONS: The Youth Pre-Participation Health Evaluation proved to be effective in identifying a wide range of disorders, allowing prompt treatment, appropriate surveillance and avoidance of potential long-term consequences, in a significant proportion (12%) of adolescent Italian Olympic athletes. PMID- 30448782 TI - Computational methods to model complex systems in sports injury research: agent based modelling (ABM) and systems dynamics (SD) modelling. PMID- 30448783 TI - Public mobilisation in implementation of smoke-free Beijing: a social media complaint platform. AB - In November 2014, Beijing People's Congress adopted the Beijing Smoking Control Ordinance and a key provision bans smoking in all indoor public places, workplaces and on public transport. To ensure effective implementation of the ordinance, the government calls on the whole society to take part. In response, Beijing Tobacco Control Association, with the support of a local technology company, developed the Beijing Tobacco Control Map, a digital system that enables comprehensive tobacco control information collection, data visualisation and mapping. A key component of the Beijing Tobacco Control Map is the Complaint Map which is generated by the data of reported violations of the smoke-free provisions by the general public through a social media platform. The Complaint Map visually displays the reported violations on a map of Beijing in real time. The general public can access the Complaint Map at any time to see which venues and locations have been reported. It is used by tobacco control volunteers, who are recruited and trained to address complaints and promote compliance. It is also used by the government's enforcement team for targeted inspections. The Complaint Map has effectively engaged the public and promoted a smoke-free Beijing. Beijing's innovative and systematic approach that involves the Complaint Map, volunteer management, coordination with the enforcement team, and media exposure can be replicated or adapted in other cities in China and abroad that are implementing smoke-free laws or tobacco control laws in general. PMID- 30448784 TI - The problem of miscarriage in multiple pregnancy. AB - OBJECTIVE: Introduction: We present the results of the combined method of treatment and prevention of miscarriage in women with a multiple pregnancy and a high risk of the threat of terminating the pregnancy because of using the obstetric unloading pessaries, combined with micronized progesterone. The efficiency of this method of treatment is evidenced by the rapid elimination of clinical symptoms of threatened abortion, accelerating the regression of ultrasound markers, reducing the number of complications in of pregnant women and reducing the time of their stay in hospital. The aim: To evaluate the effectiveness of the handling the obstetric pessary in combination with micronized progesterone at women with multiple pregnancies and a high risk of miscarriage. PATIENTS AND METHODS: Materials and methods: We analyzed 120 cases of multiple pregnancies with signs of miscarriage within the terms from 16 to 28 weeks. The first group of surveyed were 40 pregnant women with twins and signs of miscarriage, who in the scheme of treatment and prophylactic measures were proposed to use the unloading obstetric pessaries in combination with continuous therapy by natural micronized progesterone until 36 weeks of pregnancy. The second group included 40 pregnant women with twins, who were laid seam on the cervix because of cervical incompetence and were applied short-term courses of therapy by gestagens. The control group comprised 40 pregnant women with twins at the age of 16-28 weeks of pregnancy who were conducted the therapy about the threat of miscarriage according to the current clinical protocols (Order of the Ministry of Health of Ukraine No. 624). It was carried out the analysis of the course of pregnancy, childbirth, the postpartum period and the state of neonatal adaptation in the surveyed groups. RESULTS: Results: In the first group, urgent childbirth occurred in 34 (85%) cases, in group II in 29 (72.5%) cases, in control group - 25 (62.5%) cases. Cesarean delivery was performed in 7 (17.5%) of Group I pregnant women, in 9 (22.5%) of Group II patients and in 11 (27.5%) in the pregnant group. When studying the state of neonatal adaptation of newborns in the examined groups, the following results were obtained. The average weight of the newborns in group I was 3245 +/- 280 g, in group II 2865 +/- 365 g, in the control group - 2975 +/- 325 g (p> 0.05). The evaluation of the state of newborns on the Apgar scale, respectively at the 1st and 5th minutes, was respectively: in newborns of the I group, 7.5 +/- 1.4 and 8.4 +/- 1.3 points, in group II - 7.3 +/ 1.6 and 8.2 +/- 1.1 points, in the control group - 7.2 +/- 1.6 and 8.6 +/- 1.2 (r 1-r 2> 0.05). CONCLUSION: Conclusions: Comprehensive prophylaxis of non pregnancy in multiple pregnancies, combining the use of a traumatic cardiac cervix with the help of unloading obstetric pussies with progesterone preparations, allows prolonging pregnancy, preventing the development of prematurity, contributes to the improvement of perinatal indicators. PMID- 30448785 TI - [An assessment of medical rescue actions performed by the students in the sixth year of medicine at the national medical universities in Lviv and ivano-frankivsk in an out-of-hospital cardiac arrest (ohca) patient. a simulation study]. AB - OBJECTIVE: Introduction: Sudden cardiac arrest is a condition that requires the implementation of advanced emergency medical procedures. It constitutes a significant medical, economic and social issue. The aim: To assess the medical rescue actions performed by the students in the sixth year of medicine at the National Medical Universities in Lviv and Ivano-Frankivsk in an out-of-hospital cardiac arrest (OHCA) patient. PATIENTS AND METHODS: Material and methods: The research involved students in the sixth year of medicine at the National Medical Universities in Lviv and Ivano-Frankivsk. Participation was voluntary and all students were adult. Consequently, no written parental consent was required. The number of participating students amounted to 17 in Lviv and 16 in Ivano Frankivsk. There were two stages of the study. The research was conducted in compliance with the 2015 guidelines formulated by the European Resuscitation Council. The adopted level of statistical significance was p<0.05. RESULTS: Results: The pre-test percent average amounted to 60.27% whereas the final test average values were 82.39% in the first stage and 77.96% in the second stage. Higher scores were reported in the case of Lviv students which especially refers to the final tests (p< 0.001). The most important element influencing the effectiveness of the procedures is chest compression (compression location, depth, frequency and relaxation). A higher chest compression effectiveness was reported in each subsequent stage of the research. A higher effectiveness rate was observed in students in Ivano-Frankivsk (p<0.028). The other element with a significant impact on the effectiveness of procedures is ventilation. A higher rate of successful ventilation (breath frequency, volume and strength) was noted in Ivano-Frankivsk, especially as far as the first stage after training was concerned (p<0.038). CONCLUSION: Conclusion: The education of students of medicine in Ukraine is insufficient. The results of the effectiveness of resuscitation are not satisfactory and do not prepare future doctors to perform high quality resuscitation procedures. PMID- 30448786 TI - The results of cephalometric analysis in the dynamics of orthodontic treatment of patients with transversal anomalies of occlusion. AB - OBJECTIVE: Introduction: This article discusses the problems of the current issue of modern orthodontics aimed at increasing the effectiveness of diagnosis and treatment of transversal anomalies of occlusion in patients in periods of alternating and permanent bites by using standard orthodontic equipment in combination with orthopedic treatment by physical rehabilitation methods. In this work, the features of cephalometric indices in patients with transversal anomalies of occlusion have been studied, which make it possible to approach the choice of orthodontic treatment method in a comprehensive way. The aim was to prove the efficiency of the combination of standard orthodontic equipment with orthopedic treatment by physical rehabilitation methods. PATIENTS AND METHODS: Materials and methods: In order to study the characteristics of cephalometric indices in 9-15 years old patients with transversal anomalies of occlusion and to determine the criteria for the treatment effectiveness. Depending on the method of treatment, the patients were further divided into 2 subgroups: A and B. The method of treatment of subgroup A consisted of orthodontic treatment, which was carried out simultaneously with osteopathic correction of postural muscle imbalance by physical rehabilitation methods. Patients of subgroup B were treated exclusively by orthodontic treatment. The analysis of teleradiograms in the frontal projection was carried out using Dolphin software. RESULTS: Results: The effectiveness of the proposed regimens was carried out with the help of clinical and cephalometric indices which were studied before and after the orthodontic intervention. Clinical effectiveness of the performed orthodontic treatment was established in the absence of aesthetic disorders of facial features, normalisation and synchronization of the sizes of the upper and lower dentition, physiological positioning of the mandible, restoration of nasal breathing, disappearance of difficulties while chewing. CONCLUSION: Conclusions: When using proposed method (complex orthodontic treatment combined with physical rehabilitation methods) of orthodontic treatment, cephalometric analysis indices showed better dynamics, especially with unilateral cross-bite. PMID- 30448787 TI - [Knowledge on cardiovascular risk factors and symptoms of stroke among inhabitants of rural communite]. AB - OBJECTIVE: Introduction: Stroke is one of the leading causes of mortality and disability in the world. A wide knowledge of risk factors for cerebrovascular diseases is one of the main elements of primary prevention, while knowledge of stroke symptoms can significantly speed up treatment and reduce negative health effects. The aim: To assess the knowledge about stroke and risk factors of cerebrovascular diseases among the inhabitants of the randomly selected rural community (in Lodz Province). PATIENTS AND METHODS: Material and methods: The study included 143 adult residents of Rzasnia. The research was carried out using a self-constructed questionnaire, prepared on the basis of available literature. RESULTS: Results: The average score obtained from the knowledge survey on stroke was 5.79 +/- 3.47 (maximum number of points - 14). The average number of points in people with a family history of stroke was statistically significantly higher (7.46+/-3.31) than in those with no stroke in the family (4.20+/-2.98 ) (p <0.001). There was no statistically significant difference between the average number of points and gender (women - 6.13+/-3.55 points, men - 5.64+/-3.55, NS) and age (R = -0.1, NS ). However, the positive correlation between educational level and the score obtained in our questionnaire was found (R =0.4, p <0.05). The average number of correctly listed risk factors was: 0.6 +/- 1.6. At least one risk factor was reported by only 34% of respondents. Respondents most often mentioned: excessive alcohol consumption (18%), smoking (18%), hypertension (14%), atherosclerosis (11%). The average number of correctly listed symptoms of stroke was: 1.2+/-1.3. At least one symptom of stroke was reported by only 58% of respondents. The respondents most often reported: headache (29%), speech disorders (22%), gait disturbances (13%), and sensory disorders (13%). If a stroke was suspected, the majority of respondents would call an ambulance (94%). CONCLUSION: Conclusions: Knowledge of the residents of the chosen rural commune about the stroke is not satisfactory and should be supplemented with an educational program that would include as many people as possible. PMID- 30448788 TI - [Morphometrical evaluation of fetuses and newborns kidneys status developing under maternal iron deficiency anemaia conditions]. AB - OBJECTIVE: Introduction: Kidneys in fetuses and newborns play an important role in the homeostasis regulation and are the most vulnerable to the action of damaging factors from the mother organism, therefore it is important to timely assess their morphofunctional state. The aim: The purpose of the study was to reveal the morphometrical features of fetuses and newborns kidneys from mothers, whose pregnancy was complicated by iron deficiency anemia of varying degrees of severity. PATIENTS AND METHODS: Materials and methods: The material of the study was the tissue of kidneys of mature fetuses and newborns from mothers with physiological pregnancy (28 cases), as well as from mothers whose pregnancy was complicated by iron deficiency anemia of varying degrees of severity (85 cases). Morphometrical examination was performed during which the nephrogenic zone thickness, the specific volumes of renal corpuscles, tubules and stroma were determined. The absolute number of renal corpuscles, the specific volumes of immature and mature renal corpuscles and tubules were counted. RESULTS: Results: Maternal iron deficiency anemia of mild degree of severity in the offspring kidneys leads to an increase of the nephrogenic zone thickness; does not affect the absolute number of renal corpuscles; in fetuses in the cortical layer does not affect the specific volume of renal corpuscles, in the cortical and medullary layers decreases the specific volume of tubules and increases the specific volume of stroma, while in newborns in the cortical layer does not affect the specific volumes of renal corpuscles and tubules, increases the specific volume of stroma, in the medullary layer reduces the specific volume of tubules and increases the specific volume of stroma; increases the specific volumes of immature renal corpuscles, tubules and reduces the specific volumes of mature renal corpuscles, tubules. Maternal iron deficiency anemia of moderate and severe degree of severity in the offspring kidneys leads to an increase of the nephrogenic zone thickness; reduces the absolute number of renal corpuscles; decreases the specific volume of renal corpuscles in the cortical layer, reduces the specific volume of tubules and increases the specific volume of stroma in the cortical and medullary layers; increases the specific volumes of immature renal corpuscles, tubules and decreases the specific volumes of mature renal corpuscles and tubules. CONCLUSION: Conclusions: Quantitative changes of the structural elements in the fetuses and newborns kidneys from mothers with iron deficiency anemia, characterized by a decrease of the parenchymal component with the presence a significant number of immature structures in it and an increase of the stromal component, will lead to kidneys dysfunction in such children. PMID- 30448789 TI - Latent forms of the carious lesion of human lower third molars. AB - OBJECTIVE: Introduction: The most pronounced thinning of the enamel is in the intercuspal fissures of the third molars, which are characterized by a wide variety of shapes and sizes up to the abnormal disruption of their development and teething, which often causes all kinds of clinical complications. The aim: The purpose of the paper was to obtain the data on the structural state of the third molars and identify their most damaged areas in the latent form of dental caries. PATIENTS AND METHODS: Materials and Methods: 10 lower third molars with an intact crown without clear external signs of tooth decay have been examined. The teeth were embedded into epoxy resin, using the "Himkontakt-Epoxy" glue. Upon the completion of full polymerization, the resulting epoxy blocks were cut by the separation disk. Afterwards, the cross-cut ends with the naked tooth tissues were grinded and polished to obtain even unscratched slice, which was subsequently etched in Trilon-B (disodium salt EDTA) with the follow up staining in 1% borax methylene blue solution. Epoxy tooth slices were studied with the light optics in the reflected light using the MBS-9 binocular loupe, equipped with a digital camera adapter. RESULTS: Results: The process of tooth decay is of endogenous origin. The specimen of the third lower molar shows all pathomorphological signs of the latent carious lesions. Impacted lower third molar with deep carious was detected. It is obvious that, being in the subcortical zone of the alveolar ridge of the lower jaw, this abnormally developed tooth could not be exposed to any external effects. CONCLUSION: Conclusions: The microscopic study of the tooth, found in the ovarian dermoid cysts, showed that it was affected by caries that completely excludes the exogenous factors in its origination. We hypothesize that the mechanism of tooth decay directly involves the immune responses, antigens of which are (in certain circumstances) proteins of the dentin and enamel. This is the rationale for introduction into the current nosology the term "carious disease" instead of "dental caries". PMID- 30448790 TI - Experimental study of the liver ultrastructure in the presence of infection with herpes simplex virus 1. AB - OBJECTIVE: Introduction: Understanding of HSV-1liver infection pathogenesis is of great scientific, social and economic significance, since this is one of the main latent infections in population. However reactivation of this infection remains understudied. The aim: This experimental research aimed at studying the ultrastructure changes occurring in the liver in the presence of HSV-1infection. PATIENTS AND METHODS: Materials and methods: Experiments were conducted on 12 BALB/c line mice weighing 18-20 g. They were divided into 2 groups: experimental, and control. Experimental animals were infected with the attenuated HSV-1. On day 40 the animals were withdrawn from the experiment by decapitation. Liver fragments were excised and studied ultramicroscopically. RESULTS: Results: Liver disorders were represented by the focal damage of hepatic lobuli cells. Ultrastructure changes were found both in the microvascular endothelium and hepatocytes. The vascular disorders included swelling of endotheliocytes, their demise and desquamation into the lumen, disruption of the basal lamina integrity and diapedesis of blood cells into the subendothelial space. Finding virions in the endotheliocytes allowed to explain the possible pathway of the infection into the interstitium and hepatocytes via systemic circulation from the primary source of infection. Electron microscopy has not revealed any virions in hepatocytes, with only the following changes: significant cytosole density of the osmiophylic granules, lisosomes and lamellar bodies found. These were considered to be the consequence of the infectious process. Findings of the experimental study enable understanding of the causal relationship between the acute infection and liver damage. CONCLUSION: Conclusions: Ultrastructure changes in the liver of mice infected with HSV-1 were focal, and more rarely diffuse in nature. Non-specific cytopathological changes (swelling of the cytoplasm and reduction of the endoplasmatic reticulum, and mitochondria) were found both in the endotheliocytes of the sinusoid capillaries and hepatocytes. Endotheliocytes of the sinusoid liver capillaries in mice infected with HSV-1 lose their barrier function, which leads to direct and indirect damage of hepatocytes and development of dystrophic changes in the liver. PMID- 30448791 TI - Association of metabolic syndrome components with the genotypes of the S825T polymorphism in the g protein beta3-subunit gene (GNB3). AB - OBJECTIVE: Introduction: All components of the metabolic syndrome (MS) are the risk factors for the cardiovascular diseases, and their combination a great deal accelerates and complicates development of the diseases. Phenotypic expression of MS depends on the interaction of genetic and environmental factors. The aim: The aim is to study the association of metabolic syndrome components with the genotypes of the C825T polymorphism in the GNB3 gene, which allows predicting the risks and determining individual lifestyle and treatment program for the future. PATIENTS AND METHODS: Materials and methods: The patients were analyzed for anthropomorphic data and abdominal obesity. Presence of MS criteria was assessed in the patients in accordance with the consensus of International Diabetes Federation (2009). Hypertension diagnosis is based on the recommendations of adapted Clinical Practice Guidelines "Arterial Hypertension" (2012). The study of the S825T polymorphism in the G protein beta3-subunit gene was conducted at molecular-genetic research laboratory of Sumy State University with subsequent analysis of restriction fragment length polymorphism. The data were statistically processed using SPSS Statistics 21.0 program on PC. RESULTS: Results: T-allele carriers had 1.6 times higher risk of obesity than C-allele homozygotes ( r=0.034). T825T genotype carriers were 2.7 times higher risk of hypertension compared the carriers of S825S genotype of the S825T polymorphism of the GNB3 gene ( r = 0.002). The risk of increased LDL cholesterol level in the minor allele carriers is 3.9 times higher than that in the major allele carriers. ( r = 0.002). CONCLUSION: Conclusions: The results of our study concerning the association of the minor allele and T825 + C825T genotypes with the risk of components of the MS. PMID- 30448792 TI - Concomitant ascariasis as a factor in reducing the quality of life of patients with chronic pancreatitis. AB - OBJECTIVE: Inroduction: The urgency of the problem of chronic pancreatitis is increasing due to the fact that in 70.0% - 90.0% of cases of diseases of the digestive system are accompanied by pathology of other organs and systems, also including helminthiasis, especially ascariasis. The aim: to study and compare the quality of life of patients with chronic pancreatitis in regarding to patients with comorbidity of chronic pancreatitis and ascariasis. PATIENTS AND METHODS: Materials and methods: the study included 53 patients with chronic pancreatitis with ascariasis and 30 patients with isolated chronic pancreatitis. The quality of life of all patients were evaluated by using a common medical questionnaire - the Medical Outcomes Study 36-Item, and a specialized gastroenterological questionnaire the Gastrointestinal Symptom Rating Scale. RESULTS: Results: during the study, in patients with comorbidity of chronic pancreatitis with ascariasis a lower quality of life was established. The quality of life in patients with chronic pancreatitis and ascariasis was significantly reduced by both the general questionnaire SF-36 and the specific questionnaire GSRS in comparison with patients with isolated chronic pancreatitis. CONCLUSION: Conclusions: patients with chronic pancreatitis concomitant with ascariasis had a significantly lower level of quality of life scores on all scales as by a questionnaire Medical Outcomes Study 36-Item and by gastroenterological questionnaire the Gastrointestinal Symptom Rating Scale in regarding to the group of patients with chronic pancreatitis. PMID- 30448793 TI - [Maternal occupational hazards during pregnancy and allergy in the first year of life as risk factors of laryngotracheitis recurrence in shildren]. AB - OBJECTIVE: Introduction: Some studies have found associations between maternal occupational hazards during pregnancy and allergy in children. The role of allergy and maternal occupational hazards in predisposition to laryngotracheitis (LT) needs to be clarified. The aim: Objective of the research was to evaluate the possibility of relationship between maternal occupational hazards during pregnancy and allergy in the first year of life in children with LT and recurrent laryngotracheitis (RLT), as well as the debut timing of LT and RLT depending on allergy. PATIENTS AND METHODS: Materials and methods: A questionnaire was used to obtain life history of 405 children aged 6-14 years: 133 children with LT (1-3 episodes of LT), 74 children with RLT (4 or more episodes of LT) and 198 age matched children of control group. RESULTS: Results: The percentage of children with allergy in case of RLT was 48,6% and exceeded the percentage of children with allergy in case of LT and control group in 1,7 and 2,1 times, correspondingly (p<0,01). The tendency (p=0,06) towards increase of the percentage of children with allergy among children with RLT in case of maternal occupational health hazards has been revealed. Among children with RLT percentage of those who had allergy and the debut timing in the first year of life exceeded 3 times the corresponding percentage in children with LT (p<0,01). There was no difference in the debut timing of LT and RLT between children with and without allergu. CONCLUSION: Conclusions: Maternal occupational health hazards during pregnancy and allergy in the first year of life may be considered as risk factors of RLT in children. PMID- 30448794 TI - Effect of brassica oleracea extract on the erythron state during chronic yttrium salt intake. AB - OBJECTIVE: Introduction: Yttrium compounds are known to be able to produce toxic effects on the body. This fact brings up the question of the development of preventive healthcare measures for those who can be exposed to the chemical element. The aim: The purpose of this work is to study the effect of broccoli extract on the state of erythron in animals exposed to chronic intake of a water soluble yttrium compound. PATIENTS AND METHODS: Materials and methods: The series of experiments involved 16 white male rats, divided into 3 groups: intact rats; animals, which were administered yttrium acetate in a daily dose of 175 mg / kg body weight for 10 days; animals, which were given yttrium salt and dry extract of broccoli (Brassica oleracea L. var Italica Plenck) in a dose of 25 mg / kg body weight with food for 10 days. RESULTS: Results: Blood samples obtained were studied to evaluate red blood cells (RBC) count, hematocrit, total hemoglobin, RBC indices and reticulocyte content (Rt). The total number of karyocytes in the bone marrow of the femoral bone of the rats and their myelogram were investigated. The administration of yttrium acetate to the animals did not cause significant changes in "red" blood, but resulted in decreased Rt content compared with the intact control. There was a decrease in the karyocyte count in the bone marrow, the count of normoblasts and the total count of all erythroid cells. The use of the broccoli extract resulted in an increase in the blood Rt content in 1.4 times compared with the same level of yttrium loading without pharmacological correction. In the bone marrow of the animals of this group, the number of erythroid cells increased as well as the number of pro-normoblasts. CONCLUSION: Conclusions: The broccoli extract is able to reduce the negative effects produced by excess yttrium on erythropoiesis, contributing to the restoration of normal formation of reticulocytes and their release into the blood. PMID- 30448795 TI - [Public knowledge of the infertility and legal aspects of infertility treatment in Poland]. AB - OBJECTIVE: Introduction: The awareness of infertility is limited in Polish society despite the fact that this problem affects around one million couples in our country. Some of them decide to undergo specialistic treatment. Issues pertaining techniques of contributed reproduction are strictly regulated by Polish law. PATIENTS AND METHODS: Material and methods: The study was conducted among the residents of Lublin in the period from October 1, 2017 to May 1, 2018. The research tool was an original, anonymous questionnaire containing 24 questions. The study group consisted of 164 people. Statistical analysis was performed using T-student test for non-parametric variables. RESULTS: Results: The majority of the examined group were people who worked the medical profession (71%). It is significant that as much as 79.3% of respondents are religious. Only 8,5% of respondents know that the Polish law on infertility treatment is regulated in Act on the treatment of infertility of 25 June 2015. Almost half of the respondents (44.2%) answered correctly to the question regarding the treatment of infertility according to the binding Act. Only 28,5% of respondents were able to give the definition of embryo included in the Act. Moreover, almost all respondents (92.1%) never met with lectures about legal aspects in the treatment of infertility. Half of the respondents (47.3%) correctly indicated the most common cause of female infertility, the reason of men infertility was correctly indicated more respondents (65.5%). CONCLUSION: Conclusions: The respondents knowledge of infertility is more extensive than their knowledge of the legal regulations about infertility treatment. Respondents asked about regulations included in the Act on the treatment of infertility of June 25, 2015 mostly did not answer questions or gave wrong answers. The respondents whose field of study was related to medicine gave more correct answers compared to people who study non-medical fields. Practicing Catholic (45%) more often gave wrong answers. PMID- 30448796 TI - Experimental study on the carcinogenic effects of pesticides with ascertained carcinogenic activity under the conditions of its simultaneous influence on the organism of laboratory animals. AB - OBJECTIVE: Introduction: It is known that pesticides have both short-term and long-term effects of the action on the human body. Today, taking into account the growth rate of the agricultural crops protection means' market and the expansion of the range of pesticide mixtures and combined formulations, there is a need for a more in-depth study of its possible effects on the environment and the human body. Recently, a new fungicide containing a mixture of two active substances, benthiavalicarb isopropyl and folpet, was introduced for application in Ukraine. Considering the possible influence of both substances on the enzyme systems involved in the xenobiotic metabolism, potentiation of its carcinogenic action in the formulation can be expected. No genotoxic effect was revealed studying in vivo studies the mutagenic activity of both substances isolated. Therefore, both substances are epigenetic carcinogens with a promoter threshold mechanism of action. In this regard, the promoter action of these substances was studied by us in the mid-term test on a multi-organ model. The aim: The purpose of our work was an experimental study of the carcinogenic action of benthiavalicarb-isopropyl and folpet - substances with ascertained carcinogenic activity, under the conditions of its simultaneous influence on the organism of laboratory animals (rats and mice). PATIENTS AND METHODS: Materials and methods: Toxicological, toxicometric (weight of animals, absolute, relative mass of internal organs) histological, microscopic, histochemical, and statistical methods were used in the study. RESULTS: Results and conclusions: No combined action of folpet and benthiavalicarb-isopropyl on the proliferation of carcinogen-transformed hepatocytes and the formation of hyperplastic nodules expressing gamma glutamyltranspeptidases (gamma-GTP) as markers of pre-tumor changes in hepatocarcinogenesis was revealed. This allows us to conclude that there is no modifying effect of the folpet on carcinogenicity. PMID- 30448797 TI - Morphological dynamics of bone tissue reparative regeneration during the implantation of biocomposite "syntekost" into the cavity of the traumatic defect of the iliac crest of a rabbit in the experiment. AB - OBJECTIVE: Introduction: The problem of bone tissue regeneration and the development of the methods of directional influence on bone healing processes are one of the most urgent problems of modern medicine. The question of bone tissue posttraumatic regeneration is particularly important with regard to military conflicts, ecological and technological disasters, and has social and economic relevance, connected with the necessity of long-term treatment and medical rehabilitation. The aim: The objective of the work is the experimental evaluation of bone tissue reparative regeneration during the implantation of biocomposite "Syntekost" (patent for invention No98573 dated 25.05.2012 Ukraine), and also dynamics determination of bone tissue reparative regeneration after its application during a year. PATIENTS AND METHODS: Materials and methods: The experiment was carried out on 24 rabbits. All the rabbits were divided into three groups. Penetrating bone damages on the edge of the proximal tibial metaphysis and diaphysis with the diameter of 2,2 mm were formed in the rabbits of the first group using intravenous anesthetic and the dynamics of the reparative regeneration of bone tissue of the iliac crest was studied in 6, 9 and 12 months, without using composite "Syntekost" (control group - 8 rabbits). Penetrating bone damageson the edge of the proximal tibial metaphysis and diaphysis with the diameter of 2,2 mm were formed in the rabbits of the second group and biocomposite "Syntekost" was implantated into them (8 rabbits). Penetrating bone damages on the edge of the proximal tibial metaphysis and diaphysis with the diameter of 2,2 mm were formed in the rabbits of the third group and biocomposite "Syntekost" was implantated into them together with blood plasma and ossein hydroxyapatite (8 rabbits). RESULTS: Results: In all stages the research showed the significantly higher percentage of splenial bone tissue both in the rabbits that had biocomposite "Syntekost" implanted withoutblood plasma and ossein hydroxyapatite and in the rabbits that had biocomposite "Syntekost" implanted with blood plasma and ossein-hydroxyapatite in comparison with the one of the rabbits that didn't have biocomposite "Syntekost" implanted after having been injured (r < 0,05). In all stages of the research the rabbits that had biocomposite "Biokost" implanted together with blood plasma and ossein hydroxyapatite had the significantly higher percentage of neogenic splenial bone tissue and the significantly lower percentage of biocomposite "Syntekost" comparing to the ones of the rabbits that had biocomposite "Syntekost" implanted without blood plasma and ossein-hydroxyapatite (r < 0,05). CONCLUSION: Conclusions: The application of blood plasma and ossein-hydroxyapatite accelerates bone tissue regeneration and the process of biodegradation of biocomposite "Syntekost" throughout the experiment. In all stages of the experiment no toxic influence of biocomposite "Syntekost" on the surrounding bone tissue was found. PMID- 30448798 TI - Ukrainian priorities for herpesvirus infections that affect the central nervous system. AB - OBJECTIVE: Introduction: Herpesviruses (HVs) are ubiquitous pathogens that infect humans usually during childhood, followed by a life-long persistence in a latent state in many sites of a body including the nerve cells. After reactivation HVs can affect the Central Nervous System (CNS) becoming a major cause of morbidity and mortality worldwide as well as long-term neurological sequelae. Despite being an important public health problem very few population-based studies were conducted so far in the world and none in Ukraine. The aim: to explore the clinical features and etiology of herpesvirus encephalitis (HVE) in a prospective single center study from January 2014 to January 2017. PATIENTS AND METHODS: Materials and methods: 107 adult patients with confirmed herpesvirus infection and symptoms of possible encephalitis (CNS lesion) were analyzed in the study. CSF and blood contents, antibody for HVs M and G classes, and MRI scans have been studied, but the crucial diagnostic sign was the presence of specific viral DNA in the CSF or blood. RESULTS: Results: 74 (69.3%) out of 107 patients were females, the male to female ratio was 1:2.2. The median age of patients was 36.9 years (range 20-65 years). Most common clinical features were fever, meningism (stiff neck), and focal neurological signs. The genome of HVs was detected in CSF samples obtained from all patients as follows: Herpes simplex virus 1 and 2 - 13 (12.1 %), Varicella zoster virus - 2 (1.8), Cytomegalovirus - 14 (13 %), Epstein Barr virus - 22 (20.5 %), Human herpesvirus 6 - 5 (4.7 %), Human herpesvirus 7 - 13 (12.1 %). Co-infection (>= 2 HVs) was observed in 38 patients (35.5 %). CSF of 27 patients contained two viral DNA, and 11 - three one in various combination. Human herpesvirus 8 was not found. CONCLUSION: Conclusions: The most frequently diagnosed infections in hospital based study were Human herpesvirus 5 (EBV), followed by HSV-1/2, CMV, and HHV-7. Significant part of patients (35.5 %) were co-infected with two or three HVs. Predisposing factor for Ukrainian population is sex. PMID- 30448799 TI - Analysis of knowledge of students of higher educational institutions of poltava about the harmfulness of drug use. AB - OBJECTIVE: Introduction: The urgency of the topic is due to the fact that in recent years in Ukraine a part of youth who use narcotic drugs and psychoactive substances is growing. Today there are more than a quarter of billion drug addicts in the world. This number includes those who have tried drugs at least once. Among them - about 27 million drug addicts that are in need of treatment. The aim: to analyze the knowledge of the students of higher educational institutions of Poltava about various issues related to drug addiction. PATIENTS AND METHODS: Materials and method: 600 questionnaires of students who study at the universities (Poltava). The following methods were used: historical - analytical and bibliosemantic, medico-statistical, sociological, system approach and system analysis. RESULTS: Results: Student youth responded to various questions that were presented in the questionnaire, about various issues related to drug addiction. 26 % of respondents indicated that they know places where drugs can be purchased. To the question "Do you know what drugs are?" only 7 % answered "No". 2, 5 % of those surveyed met with drug users on the street. 13 +/- 1, 51 % (r<0, 05) of the respondents admitted that they were irritated when they were criticized for using narcotic drugs and only 9 +/- 1, 25 % (r<0, 05) felt guilty about abuse. CONCLUSION: Sonclusions: Students should be aware of the problem of the use of psychoactive substances, be aware of the legislative framework for the prevention of consumption, turnover and any manipulations with psychoactive substances. PMID- 30448800 TI - [Polish researchers on the traditional culture of nutrition of the peoples of Yakutia and its transformation at the present time]. AB - OBJECTIVE: Introduction: The article shows a valuable contribution of Polish researchers, political exiles V.L. Seroshevsky and E.K. Pekarsky in a thorough study of customs, life and epic of the peoples of Yakutia. The authors carry out a comparative analysis of traditional ideas about the nutrition of the inhabitants of Yakutia and modern trends in the culture of nutrition in the North. The aim: to conduct a comparative analysis of the daily diet of the Yakuts in the 17th-19th centuries and modern residents of the region. PATIENTS AND METHODS: Materials and methods: A questionnaire was conducted using the sampling method for quota sampling (n = 870) in 26 settlements of various regions of Yakutia with a total population of 55188 in July-August of 2017th within the framework of the project "The Problem of Valorization and Popularization of the Nutrition Culture of the Peoples of the North in Modern Conditions (for the Example of Yakutia)" (Application No. 17-21-08001 was supported by Russian Foundation for Basic Research). RESULTS: Results: Among the respondents, youth aged 18-19 (17, 1%), women (65, 4%), Sakha (82, 5%) and residents of the Suntar ulus (29, 6 %) predominated. The survey results showed that the majority of respondents prefer national traditional dishes (50, 3%). New recipes for cooking unusual dishes are used infrequently (52, 5%). Currently, residents of Yakutia prefer to cook in the microwave oven (53, 7%). Most of the surveyed (61, 4%) consider, that "fast food, semi-finished products are convenient, they can be quickly prepared". CONCLUSION: Conclusions: In general, the modern population of Yakutia adheres to traditional food, prefers meat dishes. PMID- 30448801 TI - Consideration of childhood psychological factors at dental appointment. AB - OBJECTIVE: Introduction: Paediatric dentistry is a special field of dental practice. The scope of professional activities within this field covers not only high level of expertise and technical skills tailored to the needs of young patients, but requires searching and creating positive psychological environment and communicative management of each child in order to improve daily service methods. The aim of this study is to identify and describe the main psychological characteristics of the age developmental periods of child's personality that dental professionals should regard dealing with the paediatric patients. PATIENTS AND METHODS: Materials and methods: The study involved 124 paediatric participants aged 2,5 - 15 years, who were referred to get specialized dental care at the Department of Paediatric Dentistry at the Municipal Paediatric Dentistry Hospital, Poltava. We have collected and identified behavioural patterns of children of all age groups during their contacts with dentists at the dental offices as well as studied the characteristics of childhood psyche age periods through the available literature. The data obtained were thoroughly As a result of the analysis of the obtained data, the principles for managing paediatric patients' behaviour at the dental office have been elaborated and introduced into the practice. RESULTS: Results: Outer evaluation of the children's activities performed is perceived by children as an assessment of personality, so any negative doctor's remark can provoke anxiety, irritability, and discomfort, apathy. Therefore, the paediatric specialists should remain attentive to physical and emotional indicators of stress when dealing with young patients. CONCLUSION: Conclusions: Hence, among the key tasks of a paediatric dentist is to create the friendliest and most comfortable conditions for small patients, where they have the opportunity to play toys and receive little gifts for patience and courage. PMID- 30448802 TI - Efficiency of hyperuricemia correction by low level laser therapy in the treatment of arterial hypertension. AB - OBJECTIVE: Introduction: Uric acid (UA) is the risk factors for the development of arterial hypertension (AH). Development of alternative methods of UA level reduction becomes relevant. The aim - to determine the correlation between UA and endothelial dysfunction and blood pressure level (BP), and to evaluate the effectiveness of low level laser therapy (LLLT). PATIENTS AND METHODS: Material and methods: Patients were divided according to the BP level: the first group included 30 patients with the hyperuricemia and normal BP; the second group - 34 patients with hyperuricemia and AH. Endothelium function was evaluated by test with reactive hyperemia. LLLT was provided by using of the apparatus "Mustang 2000" with wavelength 635 nm. RESULTS: Results: There is a mean value negative correlation on the Chaddock's scale r = - 0,6209 between UA and ED; a mean value positive correlation r = 0,48 between UA and daySBP; a weak positive correlation r = 0,33 between UA and DayDBP. LLLT reduces UA level by 4,7% more effective in patients with hyperuricemia without AH than in patients with AH combined with hyperuricemia. LLLT can increase EDVD by 9,87%, reduce UA level by 15,4%, DaySBP and DayDBP - about 7% in patients with AH combined with hyperuricemia than in patients with hyperuricemia along. CONCLUSION: Conclusion: Decreasing of DayDBP in hyperuricemia group and both DaySBP and DayDBP in the group of patients with AH combined with hyperuricemia demonstrated the influence of UA on EDVD and AH and the possibility to correct these cardiovascular risk factors with the using of LLLT. PMID- 30448803 TI - Evaluation of influence of infusion therapy on the dynamics of acid alkaline balance indices in patients with acute ischemic stroke. AB - OBJECTIVE: Introduction: The problem of the influence of infusion solutions on the correction of acid alkaline balance disorders in acute ischemic stroke (AIS) remains unclear. The aim: Compare the dynamics of changes acid alkaline balance (AAB) in the application of isosmolar 0.9% NaCl solution and hyperosmolar solution of mannitol in patients with acute ischemic stroke. PATIENTS AND METHODS: Materials and methods: The study included 50 patients with AIS. As the investigated solutions were used: hyperosmolar mannitol 15% and isosmolar 0.9% NaCl. The control group received only 0.9% NaCl, compared with main group of 0.9% NaCl+mannitol. The research was carried out at 1, 4 and 7 day, a number of indicators were determined: rN, RaO2, RaSO2, AV, SB, VV, VE. RESULTS: Results: The conducted research showed that in all observation groups, on 1st day, manifestations of mixed acidosis were observed. On the 7th day of observation the group of 0.9% NaCl showed results close to the norm of the studied parameters, indicating the leveling of acidosis developed in this group on the 1st day of stroke. Somewhat worse correction of metabolic acidosis was in the group of mannitol, on the 7th day of observation the manifestations of acidosis were not significantly different from the 1st day and were respectively: pH = 7.33 (7.24; 7.36); pO2 = 36 (33; 39); AB = 23 (15; 26); BE = -3.4 (-13.5, 0.2), SB = 22.9 (18.0, 25.4). CONCLUSION: Conclusions: Analysis of changes in the parameters of AAB in the application of different circuits of infusion therapy in patients with acute ischemic stroke showed that all the observation groups had manifestations of metabolic acidosis on the first day of AIS. The ability to normalize the disturbances of acid alkaline balance did not differ significantly (p>0.05) for patients of group 0.9% NaCl solution and mannitol. PMID- 30448804 TI - Major trends of the last decade in the number of icu beds, the number of icu patients, and the rates of icu mortality in Ukraine. AB - OBJECTIVE: Introduction: At present, the world faces an extremely heterogeneous situation in providing population with access to intensive care. In healthcare systems of different countries, there are significant differences in the number of available ICU beds per 10 thousand population. Even in the united Europe, the indicator is extremely variable and ranges from 0.42 ICU beds per 10.000 population in Portugal to 2.92 ICU beds per 10.000 population in Germany (a difference of almost 7 times), amounting to an average of 1.15 ICU beds per 10 thousand population The aim: To identify major trends in the number of ICU beds, the number of ICU patients and the rates of ICU mortality in Ukraine over the period of time from 2007 to 2015 based on the analysis of available data on the national intensive care service. PATIENTS AND METHODS: Materials and methods: The data from the 2007 nationwide audit of the domestic intensive care service and the summarized 2015 annual reports from the regional intensive care services, encompassing all the healthcare facilities that provide intensive care to population (819 hospitals in total) and represent 22 out of 26 administrative territories (regions) of the country, have been used to carry out comparative, 2015 vs. 2007, analysis and establish major trends in the indicators of interest. RESULTS: Results: The negligible increase in the number of ICU beds on referential territories in absolute (from 4.765 to 5.049) and relative (from 1.4 to 1.5 per 10 thousand population) figures have been found within the period of time from 2007 to 2015. In contrast, more prominent increase in the number of ICU patients (from 385.068 to 462.395 in absolute figures and from 111.6 to 138.2 per 10 thousand population) and in ICU mortality rates (from 8.4% to 8.7%) have been established. The average Ukrainian figure of the number of ICU beds per 10 thousand population for the year 2015 (1.5) seems to be roughly comparable with the corresponding European one for the year 2012 (1.15). CONCLUSION: Conclusions: The inclining trends in the number of ICU patients and ICU mortality rates, against the background of negligible growth in the bed capacity of the national intensive care service, indicate the need in the increase in the number of ICU beds in Ukraine. PMID- 30448805 TI - [Optimization of the system of prophylaxis congenital pathology in providing primary health care]. AB - OBJECTIVE: Introduction: reforming primary health care in Ukraine requires the provision of general practitioners - family medicine with prophylactic technologies. Among the last important place is the prevention of the implementation of the risk factors of congenital pathology. This requires thorough study and use of research results to optimize the existing prevention system. The aim: to substantiate and develop an optimized functional and organizational model of the system of the prevention of congenital pathology in the provision of primary care. PATIENTS AND METHODS: Materials and methods: methods of system approach, system analysis, medical-statistical, experimental, graphic modeling are used in the work. Materials: scientific sources on the subject (6 units), normative-legal documents (5 units), forms of state medical statistical reporting (24 units), data of an experimental study conducted in 62 rats in accordance with the requirements of the Helsinki Declaration of 1975, revised in 2000. RESULTS: Results: it was found that the frequency of thyroid gland diseases that complicated pregnancy, childbirth and postpartum period was 66.99 +/- 0.09 per 1000 pregnant women; at the same time, the frequency of diabetes mellitus was 0.99 +/- 0.01 per 1000 pregnant women. The cytogenetic effect of the food concentrate of polyphenols of the Enoant grape variety in the experiment with mutagenesis caused by thyroxine has been proved in the experiment. The increased risk of involuntary miscarriage and birth of a child with congenital pathology during the use of pregnant drugs has been confirmed. The limited organizational and preventive technologies in the existing system of the prevention of congenital pathology have been proved. The functional and organizational model of the system of prophylaxis of congenital pathology in the provision of primary care, in which the targeted prophylactic strategies are replaced by the generalized approaches, was substantiated and developed for all components (subject, object of management, block of scientific regulation). CONCLUSION: Conclusions: the results of the conducted research are the basis of system optimization of existing technologies for the prevention of congenital pathology, which allows recommending the proposed model for implementation in the conditions of primary medical care in Ukraine. PMID- 30448806 TI - Circadian characteristic of kidney excretory function influenced by nitrogen monoxide synthesis blockade under conditions of pineal gland normal with peculiarities of melatonin effect. AB - OBJECTIVE: The features of shronorhythmic alterations of excretory renal function under the physiological conditions of the pineal gland (PG) under the influence of a blockade of synthesis of nitrogen monoxide (NO) and melatonin correction were investigated. The aim: Aim of our work was to investigate circadian characteristic of kidney excretory function influenced by nitrogen monoxide synthesis blockade under conditions of pineal gland normal with peguliarities of melatonin effect. PATIENTS AND METHODS: Materials and methods: The experiments were conducted on 72 mature non-linear albino male rats with their body mass 0,15 0,18 kg. The animals were kept under vivarium conditions at a stable temperature and air humidity fed on a standard dietary intake. RESULTS: Results and conclusions: Based on a series of studies, the blockade of NO synthesis and melatonin correction resulted in a decrease in the average daily urinary output and a decrease in the removal of potassium ions from urine, relative to control, during the observation period. Therefore, the clarification of the features of shronorhythmic alterations of the excretory renal function under the physiological conditions of the PG under the influence of blockade of NO synthesis and melatonin correction is important for the knowledge of the mechanisms of occurrence and development of pathological conditions, which will enable to improve the early diagnosis, improve the treatment of renal pathology and timely preventative measures. PMID- 30448807 TI - [Methodological approaches to upgrading public health professionals training competency-based model in Kkraine]. AB - OBJECTIVE: Introduction: Training programs for workforce in health area considered as a topical issue and regulates by numerous international and national standards and guidance. In public health system development circumstances the issue of enhance competences for doctors becomes particularly important. Modern achievements of andragogy, sociology and psychology can greatly improve the educational processes in training personnel for public health needs. The aim: to rationalize methodological approaches for efficiency improvement of the competency model for training public health experts in a reforming environment of the healthcare service in Ukraine. PATIENTS AND METHODS: Materials and methods: semantic, systemic and biostatistical analyses, modelling peer review. RESULTS: Results: improvement in medical competency becomes increasingly relevant under the developing public health sector. The postgraduate training model is reviewed for improvement in its efficiency. Driving forces, analyzed and identified for the model establishment, are educational process regulation, logistics and staffing development status, opportunity to consider needs of educational service consumers. Possibilities of improving the postgraduate educational process are rationalized by the survey among physicians and heads of preventive medicine as an example, principal organizational forms and methods are defined as well. CONCLUSION: Conclusions: The provision of education demands further improvement and development in a reforming and more competitive environment. Curriculums, programmes and their organizational forms planning, use of a variety of pedagogical tools are unachievable without considering attitudes of educational service consumers ( by peer review), that provides higher efficiency and quality of educational activities aiming for improvement in competency of public health experts. Improving the regulation, professionalization of scholars, by means of present-day advances in information technology, turn crucial elements of the competency model of postgraduate education. PMID- 30448808 TI - [Efficiency predicate speech at work with hypertension patients in combination with comorbid diseases]. AB - The article presents statistical data concerning the effectiveness of antihypertensive therapy in Ukraine and in the world and presents the data of own research on the use of language predicates as part of complex therapy of patients with arterial hypertension in combination with comorbid pathology in order to increase the level of compliance. The survey examined 127 patients with arterial hypertension combined with comorbid disorders. The purpose of this publication is to inform physicians about the psychological peculiarities of patients with cardiovascular pathology and about the ways to increase the effectiveness of antihypertensive therapy and to emphasize the need for systematization and standardization of psychotherapeutic methods of elementary level in the work of cardiologists with the aim of both increasing the effectiveness of therapy and reducing the level of psychoemotional burnout of doctors. PMID- 30448809 TI - [The role of medical dispatchers in the prehospital management of patients with ST-segment elevation myocardial infarction]. AB - OBJECTIVE: Introduction: Cardiovascular diseases are the leading cause of mortality worldwide. Acute coronary syndromes are diagnosed in 1.5 million patients, in Poland about 140,000 patients per year. A medical dispatcher who has first contact with the patient or a witness of the accident plays a very important role. The aim: To analyze the quality indicators of the State Emergency Medical System, including the role of the medical dispatcher diling with patients with STEMI. PATIENTS AND METHODS: Material and methods: The medical documentation of the Voivodeship Emergency Medical Service in Katowice for the years 2013-2016 (n =915345)was analized a retrospective analysis. The study included those causes that ended with the diagnosed STEMI (870 cases). The final diagnosis was based on the data of the Polish Registry of Acute Coronary Syndromes PL-ACS and AMI-PL. RESULTS: Results: STEMI was diagnosed in 870 visits (0.095%) causes. More often in men than in women (63.8% vs. 36.2%, p <0.001). The average age of the patients was 65 years +/- 11.3. Most frequent STEMI occurred during the day (p <0.001). Patients either smoke or smoked in the past, a small proportion never smoked (78.3% vs 31.7%, p <0.001). The most frequent place occurrence of STEMI was the victim's home (p <0.001). The average time in the emergency code (K-1) was 6 min 29 seconds. It is worth noting that changing the code causes a dramatic increase in the time of a team reaching the place of an accident (p <0.001). The time of giving help is related to the time of day and the light of a conversation (p <0.001). CONCLUSION: Conclusions: Medical dispatcher and Emergency Medical Teams play a key role diling with patients with STEMI. Conducting activities in accordance with the current medical knowledge leads to much lower mortality and results in a better quality of life for the patient and his family. PMID- 30448810 TI - The state of the health of the oral cavity and health behaviors. AB - OBJECTIVE: The aim: To compare the patients' self-evaluations of oral hygiene and oral health with the results of the clinical examination expressed using both the DMFT index (DT, MT, FT) and the API index; and to evaluate the relationship between the patients' general health behaviors and their oral health status. PATIENTS AND METHODS: Material and Methods: 78 first-time dental patients (40 females, 38 males; Mage=40,7, SD=14.4) participated in the study. Prior to the initial dental visit, a questionnaire consisting of statements measuring self rated oral health, hygiene and the patient's knowledge about the oral cavity and the Health Behaviour Questionnaire (HBI) was administered. DMFT index, dental treatment index (DTI), and Approximal Plaque Index (API) were assessed upon intraoral examination. RESULTS: Results: The analyses revealed that the self declared level of knowledge about the oral cavity was significantly related to the API (p=0.004), to the number of DT (p<0.001) and to the number of FT (p<0.001). There was a correlation between the patients' declared state of the oral cavity and number of DT (p<0.001) and FT (p<0.001). The total HBI score correlated positively with FT (p=0.049). Health behaviours were related to the self-evaluation of oral care (p<=0.19), oral condition (p<=0.001), and knowledge of the oral cavity (p<=0.008). CONCLUSION: Conclusions: There is a significant relationship between the self-declared condition of the patients' oral cavity and their oral care and DMFT index. The higher the level of a patient's declared health behaviours, the better both the self-evaluated, and objectively assessed, state of the oral cavity. PMID- 30448811 TI - Review of treatment methods of patients with uncomplicated teeth fractures. AB - OBJECTIVE: Introduction: Taking into consideration the high prevalence of dental trauma, the issue dental trauma management in the frontal dentition is relevant, considering the principles of biological, economical feasibility and clinical features of each case. The aim: The purpose of this review article is to draw dentists' attention to the high prevalence of uncomplicated fractures of teeth (without pulp chamber exposure) and to highlight the most effective methods for their managment. PATIENTS AND METHODS: Materials and methods: We have processed about 50 scientific sources devoted to the treatment of traumatic lesions of teeth. Among them are articles, scientific researches, clinical cases, laboratory researches. CONCLUSION: Conclusions: The most appropriate method for teeth restoration in a case of uncomplicated fracture is to preserve the fragment of the tooth with its further reattachment applying an adhesion protocol with the preliminary preparation of hard tissues of teeth. To achieve the best aesthetic results and increase the endurance of restoration it is expedient to cover the repartitioned fragment of a tooth with ceramic veneers. PMID- 30448812 TI - [Review of diagnostic criteria for multiple sclerosis]. AB - Multiple sclerosis (MS) is a chronic, autoimmune disease of the central nervous system, leading to inflammatory demyelination and damage to neurons and their axons. The essence of MS is the occurrence of neurological symptoms associated with the occurance of demyelinating lesions disseminated in time (DIT) and space (DIS) (i.e. occurring within various CNS structures, in particular: pyramidal and cerebellar pathways). The aim of the article was to present the evolution of diagnostic criteria of multiple sclerosis in the years 1965-2017. Analysis of the changing criteria reveal that over the last several years, the time necessary to diagnose the disease, previously associated with the anticipation of subsequent symptoms of MS, now is definitely shorter, and the diagnosis can be made before the next relapse of MS, including cerebrospinal fluid examination. PMID- 30448813 TI - [Current treatment of neuroendocrine tumors]. AB - Neuroendocrine neoplasms (NEN) are group of rare neoplasms, which frequency is estimated on about 35 cases/100000. Though, during last 30 years the number of NEN new cases increased five-times. Nowadays the only method which allows to cure NEN is surgical treatment. Laparoscopic surgery and endoscopic treatment are also used. These neoplasms are usually diagnosed in advanced stadium, with distant metastases, when surgery is not an option. In this group of patients systemic and local therapies are used, such as somatostatin analogues, chemotherapy or targeted therapy. The choice of proper method is determined not only by neoplasm's localization or its size, but also clinical symptoms caused by tumor itself or by substations released by it. One place hopes in novel molecular-based therapies and currently investigated therapies using i.a. oncolytic viruses. PMID- 30448814 TI - [Characteristics of stress resistance and adaptive potential in the training of doctors in the system of postgraduate education]. AB - OBJECTIVE: Introduction: The article deals with the peculiarities of physicians' stress in conditions of exam stress in postgraduate education as a structural functional, dynamic, integrative property of the person, as a result of transactional process of collision of an individual with with the individual stress factors, which includes cognitive representation, the objective characterization of the situation and requirements for the individual. The course of diagnosis and adaptive capacity is considered in terms of physical, emotional and mental capacity, ability for social adaptation, to ensure the successful fulfillment, achievement of life goals, maintain homeostasis, efficiency and health. The aim of the research is to determine the impact of the development of teaching and exam stress on the process of adaptation of doctors in postgraduate education during continuous professional development; to study measures that will prevent the development of stress. PATIENTS AND METHODS: Materials and methods: In the work is used a range of methods: content analysis, bibliosemantic, systematic approach, analysis of products of activity. RESULTS: Review: In the human body there is a mechanism that promotes adaptation to various traumatic environmental factors that can lead to changes in the functioning of the organism. This response to the body is called a general adaptive syndrome or stress response, the main issues of which were worked out by the founder of the theory of stress Hans Sielie. Significant increase in the harmful effects of various factors on the body disturbs its livelihoods and causes the stress of all adaptation systems and in the future can lead to significant damage to the body. At present, scientists are considering several types of stress: biological, psychological, professional, emotional, sports, educational, exam and others. Academic and exam stress is one of the leading places among the causes that cause psychological stress in doctors in postgraduate education. Not successful in building exam can become a psycho-traumatic factors and create a trigger mechanism for reactive depression. Training stress refers to chronic stress while examinations can be attributed to acute stress. CONCLUSION: Conclusion: Therefore, it should be noted that frequent and prolonged stresses are gradually accumulating and may cause health problems. Any stressful situation causes changes in hemodynamics. In general, according to scientists, those people who are able to cope with stress have fewer health problems than those who are too stressed out of stress. Therefore, to manage stress, you need to learn how to control yourself and your emotions and more confidently approach non-standard situations. PMID- 30448815 TI - [Physicians induced demand in the primary health care level]. AB - Spending on health care in developed countries with the market economics has been growing over the past few years. Health care economists, along with other professionals, are constantly looking for new ways to control these costs. In this publication, an analysis of the theory of physicians induced demand (PID) at the primary level of medical care in Denmark, France and the Netherlands is presented the analysis of available literature data. Also we discussed the possibilities of conducting this study in the countries of Eastern Europe, taking Ukraine as an example. The phenomenon of physicians induced demand depends primarily on the asymmetry of information between the medical sector workers and patients, as well as on the possibility of choosing the programme of actions for the latter. The topic is relevant in order to reflect on how we will control the rapid growth of expenditures in the health sector in future, as this growth is caused by the rapid development of modern expensive technologies and by aging of the population. PMID- 30448816 TI - [Peculiarities of suicidal behavior of patients with paranoid schizophrenia with various clinical symptoms]. AB - OBJECTIVE: Introduction: Suicidal behavior in schizophrenia is one of the most urgent problems of modern psychiatry. The aim of the study was to study the suicidal activity of patients with paranoid schizophrenia in the context of clinical symptoms. PATIENTS AND METHODS: Materials and methods: The medical documentation of 407 men and 409 women who were diagnosed as "paranoid schizophrenia" in the period 1967-2017 on the basis of the Vinnytsia Regional Psychoneurological Hospital was studied by the method of continuous analysis; the prevalence of separate symptoms was analyzed in accordance with the standard ICD 10 criteria in the context of the presence of suicidal thoughts and suicidal actions. RESULTS: Review and conclusions: The main clinical symptoms of paranoid schizophrenia, as well as certain additional symptoms (chronic hallucinatory and delusional symptoms, negative symptoms and behavioral changes) are associated with suicidal thoughts and suicidal actions; while in men with suicidal actions, a disturbance of the speech function and catatonic symptomatology are more often detected. PMID- 30448817 TI - Comparative histological structure of the gastrointestinal mucosa in human and white rat: a bibliographic analysis. AB - OBJECTIVE: Introduction: According to numerous domestic and foreign researchers, morphofunctional structure of the digestive system of humans and rats have much in common, therefore, rats are used as the laboratory animals during the experiments. The aim of the paper was the comparative study of the histological structure of the gastrointestinal mucosa in human and white rat through the bibliographic analysis of the publications. PATIENTS AND METHODS: Materials and methods: The material for the investigation was current publications on the study of the histological structure of the intestine mucosa in human and white rat by analyzing, synthesizing and generalizing the resulting data. RESULTS: Review and discussion: Histologically, the gastrointestinal mucosa in white rat is similar to the human one. The gastrointestinal mucosa in white rats (with the exception of the generic difference in the structure of the stomach and the caecum), in its histological structure, is quite similar to the human one, to be studied in the experimental simulation of the specific lesions of the digestive system. PMID- 30448819 TI - [Does the morbidity on pertussis depend on the type and number of vaccines used to immunize? analysis of data from epidemiological surveillance in 2012-2016]. AB - Pertussis is an acute infectious disease that occurs with a chronic, extremely tiring paroxysmal cough. The interest of pertussis observed among clinicians, epidemiologists and public health specialists around the world caused from the fact that despite well-known mechanisms of disease pathogenesis, epidemic process and prevention methods, the disease still "surprises" with the increasing number of cases. Medical literature provides new data demonstrating the dynamically changing epidemiological situation of this disease. So far, few studies have been carried out to assess the effectiveness of Polish whole-cell vaccine. The following study is an attempt to answer the question whether pertussis occurs more common in people vaccinated against pertussis with the DTwP or DTaP vaccine? PMID- 30448818 TI - Pharmaceutical markets regulation overview of the selected European Union countries. AB - OBJECTIVE: Introduction: Pharmacy markets, operating in the European Union are regulated by national laws. In many of them, the main restrictions concern the process of creating a new pharmacy - institutions. They are basic criteria for entities that can carry out this form of business, as well as demographic and geographic factors regulating the possible location of a new pharmacy. In Poland, the Act of from the 7th of April 2017 has changed the pharmaceutical law and introduced new legal restrictions so far unknown on the Polish market. The aim: To analyze the main changes in the Polish legal requirements focused on opening process of new pharmacies and review of regulations on European markets. PATIENTS AND METHODS: Materials and Methods: The materials used in the study were concentrating on legal acts regulating the pharmacy markets of the European Community countries, as well as EU directives issued by the European Union Parliament. The analysis of the Polish market took place on the basis of the adopted amendment to the Pharmaceutical Law in the Act from April 7th 2017 (Journal of Laws 2017, No. 0, item 1015). CONCLUSION: Conclusions: The amendment to the Pharmaceutical Law, brings the Polish pharmaceutical market standard to European conditions. The introduction of the restrictions on the pharmaceutical market in Polish will contribute to the fulfillment of the obligation to guarantee permanent and equal access to benefits for all citizens. PMID- 30448820 TI - [Narrow-band imaging endoscopy for diagnosis of adult laryngeal papillomatosis - case raports]. AB - The laryngeal papillomas belong to the group of non-malignant tumours. The risk of getting sick increases with the number of contingent sexual contacts, smoking, alcohol abuse and untreated gastro-oesophageal reflux. This paper describes five cases presenting different levels of exposure to the risk factors and variable course of adult laryngeal papillomatosis. These people, in addition to routine diagnostics, were examined using endoscopy with the use of narrow beam of light, which turns out to be a useful diagnostic tool in the case of laryngeal papillomatosis. PMID- 30448821 TI - [Emphysematous cystitis in a patient with type-1diabetes mellitus - diagnostic difficulties]. AB - A case report of 28 year old female with medical history of bed controlled type 1 diabetes mellitus complicated by autonomic neuropathy in the form of gastroparesis, suffered by emphysematous cystitis caused by Escherichia coli was described. Emphysematous cystitis is a rare urinary tract infection connected with the presence of gas in the bladder lumen or/and within the bladder wall, which occurs mainly in women, in older age, suffering from type 2 diabetes, complicated by microangiopathy, neuropathy, with urinary tract obstruction and weakness of immunity system. Diagnostic difficulties and the delay in correct diagnosis in described case were caused by the dominated complaint of the upper gastrointestinal tract and difficulties in interpretation of imaging methods, such as abdominal X-ray and ultrasound scan. Eventually the use of computed tomography allowed to achieved an accurate diagnosis and choose appropriate treatment. It is possible that this is the first case of emphysematous cystitis described in Poland. PMID- 30448822 TI - Long-term follow-up of a Schwartz-Jampel syndrome case. AB - Schwartz-Jampel syndrome (SJS) is a rare genetic disorder characterised by myotonia and bone dysplasia. It is inherited as an autosomal recessive trait and caused by mutations in the perlecan-encoding gene HSPG2. Its symptoms include muscular stiffness and hypertrophy. The aim of the study was to analyse the clinical presentation as well as the physical therapy and rehabilitation in a patient with SJS. A 20-year-old male patient with SJS was followed up by the authors for the past 3 years. The paper assesses the physical therapy and rehabilitation conducted at home and presents the possibilities of an extended programme that can be implemented at the multi-field Division of Physical Medicine. Patients with SJS represent an extremely difficult clinical and therapeutic problem. PMID- 30448823 TI - Disease or not, aging is easily treatable. AB - Is aging a disease? It does not matter because aging is already treated using a combination of several clinically-available drugs, including rapamycin. Whether aging is a disease depends on arbitrary definitions of both disease and aging. For treatment purposes, aging is a deadly disease (or more generally, pre disease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated, thereby delaying classic age related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration. PMID- 30448824 TI - Adipose TSHB in Humans and Serum TSH in Hypothyroid Rats Inform About Cellular Senescence. AB - BACKGROUND/AIMS: Thyroid hormones have been recently linked to senescence and longevity. Given the recent description of TSHB mRNA in human adipose tissue (AT), we aimed to investigate the relationship between local AT TSH and adipose tissue senescence. METHODS: TSHB mRNA (measured by real-time PCR) and markers of adipose tissue senescence [BAX, DBC1, TP53, TNF (real-time PCR), telomere length (Telo TAGGG Telomere Length Assay) and lipidomics (liquid chromatography mass spectrometry)] were analysed in subcutaneous (SAT) and visceral (VAT) AT from euthyroid subjects. The chronic effects of TSH were also investigated in AT from hypothyroid rats and after recombinant human TSH (rhTSH) administration in human adipocytes. RESULTS: Both VAT and SAT TSHB gene expression negatively correlated with markers of AT cellular senescence (BAX, DBC1, TP53, TNF gene expression and specific glucosylceramides) and positively associated with telomere length. Supporting these observations, both rhTSH administration in human adipocytes and increased TSH in hypothyroid rats resulted in decreased markers of cellular senescence (Bax and Tp53 mRNA) in both gonadal and subcutaneous white adipose tissue. CONCLUSION: These data point to a possible role of TSH in AT cellular senescence. PMID- 30448825 TI - Cycles, Arrows and Turbulence: Time Patterns in Renal Disease, a Path from Epidemiology to Personalized Medicine? AB - Patients with end-stage renal disease (ESRD) experience unique patterns in their lifetime, such as the start of dialysis and renal transplantation. In addition, there is also an intricate link between ESRD and biological time patterns. In terms of cyclic patterns, the circadian blood pressure (BP) rhythm can be flattened, contributing to allostatic load, whereas the circadian temperature rhythm is related to the decline in BP during hemodialysis (HD). Seasonal variations in BP and interdialytic-weight gain have been observed in ESRD patients in addition to a profound relative increase in mortality during the winter period. Moreover, nonphysiological treatment patters are imposed in HD patients, leading to an excess mortality at the end of the long interdialytic interval. Recently, new evidence has emerged on the prognostic impact of trajectories of common clinical and laboratory parameters such as BP, body temperature, and serum albumin, in addition to single point in time measurements. Backward analysis of changes in cardiovascular, nutritional, and inflammatory parameters before the occurrence as hospitalization or death has shown that changes may already occur within months to even 1-2 years before the event, possibly providing a window of opportunity for earlier interventions. Disturbances in physiological variability, such as in heart rate, characterized by a loss of fractal patterns, are associated with increased mortality. In addition, an increase in random variability in different parameters such as BP and sodium is also associated with adverse outcomes. Novel techniques, based on time-dependent analysis of variability and trends and interactions of multiple physiological and laboratory parameters, for which machine-learning -approaches may be necessary, are likely of help to the clinician in the future. However, upcoming research should also evaluate whether dynamic patterns observed in large epidemiological studies have relevance for the individual risk profile of the patient. PMID- 30448826 TI - Investigating Sex-Specific Characteristics of Nicotine Addiction Using Metabolic and Structural Magnetic Resonance Imaging. AB - Nicotine addiction is known to modulate neurotransmission and alter the brain structure. The detrimental effect of nicotine is more prominent in females as compared to males. This study sought to examine the sex-specific influence of nicotine addiction on gamma amino butyric acid (GABA) and the white matter (WM) microstructure. Sixty healthy subjects (smokers/non-smokers) underwent structural and metabolic magnetic resonance imaging scans. Results showed alterations in WM integrity (measured as changes in fractional anisotropy [FA] and GABA in smokers versus non-smokers and females versus males. No overall significant smoking and sex-specific interactions were observed in this study. However, on comparing female smokers with female non-smokers, significantly higher GABA and FA values were observed in female smokers. However, GABA and FA values did not differ significantly when male smokers were compared against male non-smokers. Our results provide a further rationale to investigate the impact of nicotine on central GABAergic function and WM integrity, in particular due to the potential risk for females to experience depressive/anxiety symptoms during smoking cessation. PMID- 30448827 TI - Butyrate Modulates Inflammation in Chondrocytes via GPR43 Receptor. AB - BACKGROUND/AIMS: Osteoarthritis (OA) is a joint degenerative biomechanical disorder involving immunity, metabolic alterations, inflammation, and cartilage degradation, where chondrocytes play a pivotal role. OA has not effective pharmacological treatments and new therapeutic targets are needed. Adipokines contribute to the low-grade systemic inflammation in OA. Here, we explored novel molecular mechanisms of sodium butyrate (BuNa) in modulating inflammation and chemotaxis in chondrocytes, demonstrating the direct involvement of its G protein coupled receptor (GPR)-43. METHODS: ATDC5 murine chondrocytes were stimulated with interleukin (IL)-1beta, in the presence or not of BuNa, for 24 h. RT-PCR and Western blot analysis was performed to evaluate the expression of inflammatory mediators and structural proteins. RESULTS: Butyrate reduced the expression of canonic pro-inflammatory mediators (Nos2, COX-2, IL-6), pro-inflammatory adipokines (lipocalin-2 and nesfatin-1) and adhesion molecule (VCAM-1 and ICAM-1) in IL-1beta-stimulated chondrocytes, inhibiting several inflammatory signalling pathways (NFkappaB, MAPKinase, AMPK-alpha, PI3K/Akt). Butyrate also reduced metalloproteinase production and limited the loss of type II collagen in IL-1beta inflamed chondrocytes. The chemoattractant effect of butyrate, after different inflammatory challenges, was revealed by increased annexin (AnxA)1 levels and chemokines expression. The chemoattractant and anti-inflammatory activities of butyrate were completely blunted by GPR43 silencing using RNA interference. CONCLUSION: Taken together, our data suggest the potential application of sodium butyrate as a novel candidate in a multi-target approach for the treatment of chondrocyte inflammation and cartilage degenerative process. PMID- 30448828 TI - Clinical and Ultrasound Predictors of Placenta Accreta in Pregnant Women with Antepartum Diagnosis of Placenta Previa: A Multicenter Study. AB - BACKGROUND/AIMS: Abnormally invasive placenta (AIP) includes placenta accreta, increta, and percreta and represents major complications of pregnancy. This study was designed to assess the role of ultrasonography in the identification of AIP among pregnant women with antepartum diagnosis of placenta previa. METHODS: A cross-sectional study was performed between May 2015 and April 2016 in 11 centers, including 242 women with antepartum diagnosis of placenta previa. RESULTS: Ninety-eight out of 242 (40.49%) women had a histological diagnosis of placenta accreta. A higher number of caesarean deliveries (p = 0.001) and curettages (p = 0.027) and older age of the woman at the delivery (p = 0.031) were identified as risk factors for placenta accreta. The presence of irregularly shaped placental lacunae (vascular spaces) within the placenta (p = 0.008), protrusion of the placenta into the bladder (p < 0.0001), and turbulent blood flow through the lacunae on Doppler ultrasonography (p = 0.008) were predictors of placenta accreta. CONCLUSIONS: Women with a prior delivery by caesarean section have a high incidence of placenta accreta among women with antepartum diagnosis of placenta previa. PMID- 30448829 TI - Impact of Locoregional Treatment on Prognosis of de novo Stage IV Breast Cancer: A Retrospective Long-Term Study of Chinese Population. AB - OBJECTIVES: This study aimed to evaluate the impact of locoregional resection and radiotherapy on the prognosis of Chinese women with stage IV breast cancer. METHODS: The retrospective study included Chinese patients with de novo stage IV breast cancer in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, between January 1, 2001, and December 31, 2016. The patients were classified into surgery and nonsurgery groups. Overall survival (OS) and distant progression-free survival (DPFS) were evaluated at the last follow-up. RESULTS: Of the 157 patients, 66 (42.0%) underwent surgery and 52 (33.1%) received locoregional radiotherapy. The follow-up time ranged from 3 to 180 months. The median patient follow-up was 54.5 months. The patients in the surgery group had longer 5-year OS and 5-year DPFS compared with the patients in the nonsurgery group. DPFS was also significantly longer in patients who received radiotherapy. Two factors proved to be associated with survival: response to systemic therapy and surgical treatment. Multivariate analysis also showed that the progestogen receptor status significantly influenced the DPFS. CONCLUSION: Locoregional surgery and radiotherapy of primary tumor might be beneficial for Chinese patients with stage IV breast cancer. It proposed that surgical resection for selected stage IV breast cancer patients. PMID- 30448830 TI - Risk Factors for Delayed Hemorrhage after Colonic Endoscopic Mucosal Resection in Patients Not on Antithrombotic Therapy: Retrospective Analysis of 3,844 Polyps of 1,660 Patients. AB - BACKGROUND/AIMS: Colonic endoscopic mucosal resection (EMR) is safe for patients without antithrombotic therapy; however, EMR is associated with several risks. This study was performed to evaluate the risk of delayed hemorrhage in patients undergoing EMR without antithrombotic therapy. METHODS: In the present retrospective single-center study, 1,792 patients without antithrombotic therapy underwent colonic EMR from March 2012 to December 2016 at the Saga Medical Centre Koseikan. Risk factors were evaluated with respect to patient and lesion characteristics, the endoscopist's experience, and preventive hemoclips. Delayed hemorrhage was defined as bleeding for which emergency endoscopic hemostasis was applied >24 h after EMR. RESULTS: Among the 1,792 patients, 1,660 with 3,844 tumors were evaluated. Delayed hemorrhage occurred in 43 patients (2.6%) and 46 polyps (1.2%). Preventive hemoclips were applied in 996 patients (60.0%). Univariate analysis indicated that delayed hemorrhage occurred more frequently in young patients (3-39 years, p < 0.001, 40-59 years, p = 0.005) compared to > 60 years and in association with large polyps (> 10 mm, p = 0.003), hemoclip (p = 0.019), and pedunculated polyps (p = 0.024). Multivariate analysis indicated that risk factors for hemorrhage were young age (age of 3-39 years p < 0.001, 40-59 years, p = 0.005) and large polyps (> 10 mm, p < 0.001). The risk of delayed hemorrhage was increased by an estimated 8% with a 1-mm increase in polyp size. CONCLUSION: The present study suggests that young age (under 60 years old) and large polyp size are risk factors for causing delayed hemorrhage after colonic EMR in patients without antithrombotic therapy. PMID- 30448831 TI - Modified Laparoscopic Partial Ureterectomy for Adult Ureteral Fibroepithelial Polyp: Technique and Initial Experience. AB - OBJECTIVES: To present our modified laparoscopic partial ureterectomy technique for adult ureteral fibroepithelial polyp (FEP) and initial experience. METHODS: Between August 2009 and October 2017, 22 patients with ureteral FEP underwent modified laparoscopic partial ureterectomy by an experienced surgeon. In our method, a stay suture passing through the upper ureter was fixed to the abdominal wall to keep the ureter from twisting. The ureter was not completely dismembered until the first stitch, which was placed between the lowest points of the upper ureter and lower ureter end faces, was finished. Besides, we used a 3-step method to locate the polyp. Surgical success was defined as improved hydronephrosis and alleviated symptoms. RESULTS: The mean operative time was 152.18 min. The mean estimated blood loss was 22.73 mL. One patient complained of urinary tract infection postoperatively. The mean times to remove the drainage tube and catheter were 2.64 and 3.73 days respectively. The double-J tube was removed at 1 3 months after surgery. At a mean follow-up of 47.04 months, no patient experienced disease recurrence, and the operative success rate was 100%. CONCLUSIONS: Modified laparoscopic partial ureterectomy, with a high success rate, could be considered a safe and efficient treatment option for ureteral FEP. PMID- 30448832 TI - Propranolol Suppresses Cobalt Chloride-Induced Hypoxic Proliferation in Human Umbilical Vein Endothelial Cells in vitro. AB - BACKGROUND/AIMS: To investigate the effect of propranolol on cobalt chloride (CoCl2)-induced hypoxic proliferation in human umbilical vein endothelial cells (HUVECs). METHODS: CoCl2 was administrated to HUVECs to mimic hypoxic proliferation in infantile hemangioma. The proliferation of HUVECs was detected by Cell Counting Kit-8. Effects of propranolol on apoptosis and expressions of cell cycle-related genes, CDK4 and cyclin D1, were detected by flow cytometry and RT-PCR respectively. The release of vascular endothelial growth factor (VEGF) and lactate dehydrogenase (LDH) was measured by enzyme-linked immunosorbent assay. RESULTS: Propranolol significantly inhibited the CoCl2-induced hypoxic proliferation of HUVECs in a dose-dependent manner, and also induced apoptosis and suppressed the expression of CDK4 and cyclin D1. Propranolol also decreased the release of VEGF and LDH in the supernatant. CONCLUSIONS: Propranolol could inhibit CoCl2-induced hypoxic proliferation of HUVECs through inducing apoptosis and cell cycle arrest. PMID- 30448833 TI - New Insights into Kleefstra Syndrome: Report of Two Novel Cases with Previously Unreported Features and Literature Review. AB - Kleefstra syndrome (KS) is a rare genetic condition resulting from either 9q34.3 microdeletions or mutations in the EHMT1 gene located in the same genomic region. To date, approximately 100 patients have been reported, thereby allowing the core phenotype of KS to be defined as developmental delay/intellectual disability, generalized hypotonia, neuropsychiatric anomalies, and a distinctive facial appearance. Here, to further expand the knowledge on genotype and phenotype of this condition, we report 2 novel cases: one patient carrying a 46-kb 9q34.3 deletion and showing macrocephaly never described in KS, and a second patient carrying a classic 9q34.3 deletion, presenting with a previously unreported skeletal feature (postaxial polydactyly of the right foot) and an unusual brain anomaly (olfactory bulb hypoplasia) observed via magnetic resonance imaging. Further, we provide a review of the current literature regarding KS and compare these 2 patients with those previously described, thereby confirming that the genotype-phenotype correlation in KS remains difficult to determine. PMID- 30448835 TI - Mechanisms of Hydrogen Sulfide against the Progression of Severe Alzheimer's Disease in Transgenic Mice at Different Ages. AB - : Backgroud: Alzheimer disease is an age-related severe neurodegenerative pathology. The level of the third endogenous gas, hydrogen sulfide (H2S), is decreased in the brain of Alzheimer's disease (AD) patients compared with the brain of the age-matched normal individuals; also, plasma H2S levels are negatively correlated with the severity of AD. Recently, we have demonstrated that systemic H2S injections are neuroprotective in an early phase of preclinical AD. OBJECTIVES: This study focuses on the possible neuroprotection of a chronic treatment with an H2S donor and sulfurous water (rich of H2S) in a severe transgenic 3*Tg-AD mice model. METHOD: 3*Tg-AD mice at 2 different ages (6 and 12 months) were daily treated intraperitoneally with an H2S donor and sulfurous water (rich of H2S) for 3 months consecutively. We investigated the cognitive ability, brain morphological alterations, amyloid/tau cascade, excitotoxic, inflammatory and apoptotic responses. RESULTS: Three months of treatments with H2S significantly protected against impairment in learning and memory in a severe 3*Tg-AD mice model, at both ages studied, and reduced the size of Amyloid beta plaques with preservation of the morphological picture. This neuroprotection appeared mainly in the cortex and hippocampus, associated with reduction in activity of c-jun N-terminal kinases, extracellular signal-regulated kinases and p38, which have an established role not only in the phosphorylation of tau protein but also in the inflammatory and excitotoxic response. CONCLUSION: Our findings indicate that appropriate treatments with various sources of H2S, might represent an innovative approach to counteract early and severe AD progression in humans. PMID- 30448834 TI - High Herpesvirus Diversity in Wild Rodent and Shrew Species in Central Africa. AB - OBJECTIVE: Herpesviruses belong to a diverse order of large DNA viruses that can cause diseases in humans and animals. With the goal of gathering information about the distribution and diversity of herpesviruses in wild rodent and shrew species in central Africa, animals in Cameroon and the Democratic Republic of the Congo were sampled and tested by PCR for the presence of herpesvirus DNA. METHODS: A broad range PCRs targeting either the Polymerase or the terminase gene were used for virus detection. Amplified products from PCR were sequenced and isolates analysed for phylogenetic placement. RESULTS: Overall, samples of 1,004 animals of various rodent and shrew species were tested and 24 were found to be positive for herpesvirus DNA. Six of these samples contained strains of known viruses, while the other positive samples revealed DNA sequences putatively belonging to 11 previously undescribed herpesviruses. The new isolates are beta- and gammaherpesviruses and the shrew isolates appear to form a separate cluster within the Betaherpesvirinae subfamily. CONCLUSION: The diversity of viruses detected is higher than in similar studies in Europe and Asia. The high diversity of rodent and shrew species occurring in central Africa may be the reason for a higher diversity in herpesviruses in this area. PMID- 30448836 TI - An Objective, Comprehensive and Flexible Statistical Framework for Detecting Early Warning Signs of Mental Health Problems. PMID- 30448837 TI - Contents Vol. 98, 2018. PMID- 30448838 TI - Cytoprotective Effects of N-Acetylcysteine on Streptozotocin- Induced Oxidative Stress and Apoptosis in RIN-5F Pancreatic beta-Cells. AB - BACKGROUND/AIMS: Numerous studies have reported overproduction of reactive oxygen species (ROS) and alterations in mitochondrial energy metabolism in the development of diabetes and its complications. The potential protective effects of N-acetylcysteine (NAC) in diabetes have been reported in many therapeutic studies. NAC has been shown to reduce oxidative stress and enhance redox potential in tissues protecting them against oxidative stress associated complications in diabetes. In the current study, we aimed to investigate the molecular mechanisms of the protective action of NAC on STZ-induced toxicity in insulin secreting Rin-5F pancreatic beta-cells. METHODS: Rin-5F cells were grown to 80% confluence and then treated with 10mM STZ for 24h in the presence or absence of 10mM NAC. After sub-cellular fractionation, oxidative stress, GSH dependent metabolism and mitochondrial respiratory functions were studied using spectrophotometric, flow cytometric and Western blotting techniques. RESULTS: Our results showed that STZ-induced oxidative stress and apoptosis caused inhibition in insulin secretion while NAC treatment restored the redox homeostasis, enhanced insulin secretion in control cells and prevented apoptosis in STZ-treated cells. Moreover, NAC attenuated the inhibition of mitochondrial functions induced by STZ through partial recovery of the mitochondrial enzymes and restoration of membrane potential. STZ-induced DNA damage and expression of apoptotic proteins were significantly inhibited in NAC-treated cells. CONCLUSION: Our results suggest that the cytoprotective action of NAC is mediated via suppression of oxidative stress and apoptosis and restoration of GSH homeostasis and mitochondrial bioenergetics. This study may, thus, help in better understanding the cellular defense mechanisms of pancreatic beta-cells against STZ-induced cytotoxicity. PMID- 30448839 TI - Associate Editor Diana Rubin. PMID- 30448840 TI - Evaluation of the Potential Risk Factors for Drug-Induced Anaphylaxis in Adult Patients. AB - AIM: To investigate the potential risk factors in patients who have experienced anaphylaxis from drugs. METHOD: The study included 281 adult patients (median age 40 years; 76.5% female) who experienced immediate types of hypersensitivity reaction to a drug. The patients were divided into an anaphylaxis group and a nonanaphylaxis group. The anaphylaxis group was diagnosed according to the criteria of the World Allergy Organization. Skin testing with culprit drugs was performed. In the nonanaphylaxis group, drug provocation tests were performed with culprit drugs, including aspirin or diclofenac, to determine nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity. Atopy was determined by skin prick tests with the common inhalant allergens. Patients' demographics, clinical features, and baseline tryptase and total IgE levels were compared between the 2 groups. RESULTS: The median interval between the last reaction in the patient's history and the study evaluation was 7 months (range 1-120 months). In 52.3% of the patients, reactions were defined as anaphylaxis. The most common culprit drugs were NSAIDs (56.9%) and beta-lactams (34.7%). The culprit drugs were used parenterally in 13.2% of the patients. 34.9% of the patients had comorbid diseases and 24.6% used additional drugs, the most common being antihypertensives (10%). Atopy was determined in 28.8% and 28.1% of the patients were smokers. The median serum level of baseline tryptase and total IgE was 3.5 ug/L and 77 kU/L, respectively. In 46.3% of the patients, skin tests with culprit drugs were positive and the positivity ratio was higher in the anaphylaxis group (p = 0.002). Anapyhlaxis was more common in patients who were: hypertensive, atopic, using angio-tensin-converting enzyme inhibitors/angiotensin receptor blockers, and received the culprit drug parenterally (p = 0.034, p = 0.04, p = 0.03, p = 0.035, p = 0.013, and p < 0.001). In the multivariate analysis, it was observed that the parenteral usage of the drug and the presence of atopy were significantly higher in the anaphylaxis group (p < 0.001, odds ratio [OR] = 20.05, confidence interval [CI] 4.75-88.64; p = 0.012, OR = 2.1, CI 1.17-3.74). Age, smoking, family history, and serum levels of baseline tryptase and total IgE did not differ between groups. CONCLUSION: The parenteral route and atopy increase the risk of drug-induced anaphylaxis. IgE-mediated sensitivity to the culprit drug seems to facilitate anaphylaxis. PMID- 30448841 TI - The Impact of Childhood Maltreatment on Age of Onset of Alcohol Use Disorder in Women. AB - It is unclear whether exposure to childhood maltreatment is associated with the age of onset of alcohol use disorder (AUD). A group of socially stable women with AUD seeking treatment (n = 75) were interviewed using the Addiction Severity Index and the Mini International Neuropsychiatric Interview. They also filled out the Childhood Trauma Questionnaire-short form. Emotional abuse, sexual abuse and multiple childhood traumas were found to be associated with earlier onset of AUD. Multivariable linear regression analysis showed that independent predictors for an earlier onset of AUD were exposure to emotional abuse (beta = -7.44, SE = 2.83, adjusted p = 0.010) and mother's alcohol/substance problems (beta = -7.87, SE = 3.45, adjusted p = 0.026). These variables explained 18.9% of the variance of age of onset of AUD. These findings highlight a need for increased clinical attention to AUD subgroups who have experienced childhood maltreatment, especially emotional abuse, as well as a need for including support in the patient's own parental role in the treatment. PMID- 30448842 TI - Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage. AB - BACKGROUND/AIMS: Podocyte damage is associated with proteinuria, glomerulosclerosis and decline of renal function. This study aimed to screen critical genes associated with podocyte injury in chronic kidney disease (CKD) by weighted gene correlation network analysis (WGCNA), and explore related functions. METHODS: GSE66107, GSE93798, GSE30528, GSE32591 gene expression data including podocyte injury models or glomeruli in CKD patients were downloaded from the GEO database. R was used for data analysis. Differentially expressed genes (DEGs) (FDR< 0.05 or |Fold Change|>=1.5) in GSE993395 were assessed by WGCNA. According to Gene Ontology (GO) and known podocyte standard genes (PSGs), podocyte injury-associated modules were defined, with hub genes selected based on average intramodular connectivity. The Cytoscape software was used for network visualization. Nephroseq was used to assess the clinical significance of hub genes. Small interfering RNA (siRNA) was used to evaluate the roles of hub genes in podocyte injury Results: Totally 7957 DEGs were screened, with 15 (co.DEGs) altered in all 4 datasets; 4031 DEGs were used for WGCNA, encompassing 12 modules. Green modules (most PSGs and co.DEGs) were significantly enriched in glomerular development, and considered podocyte injury-associated modules. Furthermore, MAGI2 (a hub gene) was also a co.DEG and PSG. Glomerular MAGI2 levels were reduced in various kidney diseases, and positively and negatively associated with glomerular filtration rate and urinary protein levels in CKD patients. Moreover, MAIG2 knockdown reduced NPHS2, CD2AP and SYNPO levels, and induced podocyte rearrangement and apoptosis. CONCLUSION: MAGI2 identified by WGCNA regulates cytoskeletal rearrangement in podocytes, with its loss predisposing to proteinuria and CKD. PMID- 30448843 TI - Hepatitis B Virus X Protein Increases 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine (8 Oxodg) Level via Repressing MTH1/ MTH2 Expression in Hepatocytes. AB - BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection markedly increases the risk of development of hepatocellular carcinoma (HCC). Among the seven viral proteins that HBV encodes, HBV X protein (HBx) appears to have the most oncogenic potential. The mitochondria-associated HBx can induce oxidative stress in hepatocytes, leading to the production of abundant reactive oxygen species (ROS). High levels of ROS usually induce oxidative DNA damage and 8-hydroxy-2 deoxyguanosine (8-OHdG), also known as 8-oxo-7,8-dihydro-2-deoxyguanosine (8 oxodG), which is one of the major products of DNA oxidation and an important biomarker for oxidative stress and carcinogenesis. Cells have evolved a mechanism to prevent oxidized nucleotides from their incorporation into DNA through nucleotide pool sanitization enzymes of MTH1 (NUDT1), MTH2 (NUDT15), MTH3 (NUDT18) and NUDT5. However, little is known as to whether HBx can regulate the expression of those enzymes and modulate the formation and accumulation of 8 oxodG in hepatocytes. METHODS: The level of 8-oxodG was assessed by ELISA in stable HBV-producing hepatoma cell lines, an HBV infectious mouse model, HBV and HBx transgenic mice and HBV-infected patients versus their respective controls. Expression of MTH1, MTH2, MTH3 and NUDT5 was determined by a real-time quantitative PCR and western blot analysis. Transcriptional regulation of MTH1 and MTH2 expression by HBx and the effect of HBx on MTH1 and MTH2 promoter hypermethylation were examined using a luciferase reporter assay and bisulfite sequencing analysis. RESULTS: In comparison with controls, significantly higher levels of 8-oxodG were detected in the genome and culture supernatant of stable HBV-producing HepG2.2.15 cells, in the sera and liver tissues of HBV infectious mice and HBV or HBx transgenic mice, and in the sera of HBV-infected patients. Expression of HBx in hepatocytes significantly increased 8-oxodG level and reduced the expression of MTH1 and MTH2 at both mRNA and protein levels. It was also demonstrated that HBx markedly attenuated the MTH1 or MTH2 promoter activities through hypermethylation. Furthermore, enhancement of 8-oxodG production by HBx was reversible by overexpression of MTH1 and MTH2. CONCLUSION: Our data show that HBx expression results in the accumulation of 8-oxodG in hepatocytes through inhibiting the expression of MTH1 and MTH2. This may implicate that HBx may act as a tumor promoter through facilitating the mutational potential of 8-oxodG thus connecting a possible link between HBV infection and liver carcinogenesis. PMID- 30448844 TI - Dandy-Walker Malformation-Like Condition Revealed by Refractory Schizophrenia: A Case Report and Literature Review. AB - INTRODUCTION: Dandy-Walker malformation is a rare congenital malformation involving cystic dilatation of the fourth ventricle, enlarged posterior fossa, complete or partial agenesis of the cerebellar vermis, elevated tentorium cerebelli, and hydrocephalus. Previous research highlighted a possible role for the cerebellum in schizophrenia as well as the contribution of underlying brain malformations to treatment resistance. Here, we present a case of a Dandy-Walker malformation-like condition revealed by a refractory schizophrenia in a 24-year old male patient. We also conduct a literature review of all previously published case reports or case series of co-occurring posterior fossa abnormalities and schizophrenia or psychosis using a PubMed search query to better understand the potential link between these two disorders. CASE PRESENTATION: A 9-month hospital stay was needed to address the treatment-resistant psychotic symptoms, and the patient continued to experience moderate symptoms despite the prescription of various antipsychotic and antidepressant medications. After an irregular initial medical follow-up, the patient is currently treated with 350 mg daily clozapine and 20 mg daily prazepam and still exhibits moderate anxiety without delirious thoughts, however allowing him to re-enroll at the university. Regarding the literature, 24 cases published between 1996 and 2017 were identified, reviewed and compared to the present case report. DISCUSSION: This case report and literature review further illuminates the pathophysiology of psychotic disorders including the potential role of the cerebellum, reinforces the importance of a multidisciplinary approach for the neurological and psychiatric management of patients with schizophrenia, and highlights optimal pharmacological management strategies for treatment-resistant schizophrenia. PMID- 30448845 TI - Aldehyde Dehydrogenase 1 (ALDH1) Promotes the Toxicity of TRAIL in Non-Small Cell Lung Cancer Cells via Post-Transcriptional Regulation of MEK-1 Expression. AB - BACKGROUND/AIM: Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) based therapies have been used in many human cancers. However, some tumors are resistant to TRAIL-induced cell death. Aldehyde dehydrogenase 1 (ALDH1) is a functional marker for identification of CSCs. METHODS: In this study, we used the colony formation assay, AnnexinV/ PI double staining and PI staining to detect proliferation, apoptosis and cell cycle in ALDH1+ non-small cell lung cancer (NSCLC) cells with TRAIL treatment. In addition, we established xenograft mouse models to confirm the anti-tumor roles of TRAIL in vivo. Finally, gene array and western blot were used to detect the deeper mechanism of the susceptibility of ALDH1+ NSCLC cells to TRAIL. RESULTS: We confirmed that TRAIL could inhibit proliferation, and induce apoptosis and G1 arrest in ALDH1+ NSCLC cells. Correspondingly, TRAIL was associated with decreased tumor size and the favorable survival rate of ALDH1+ cells established xenograft mouse models. ALDH1 could increase the death receptors (DR) 4 and DR5 expression in ALDH1+ NSCLC cells via activating MEK/ERK signaling pathway. CONCLUSION: ALDH1 protein induced MEK-1 mRNA stability and promoted its translation via its 3'UTR. PMID- 30448846 TI - Candida albicans Increases Dentine Demineralization Provoked by Streptococcus mutans Biofilm. AB - Streptococcus mutans are considered the most cariogenic bacteria, but it has been suggested that Candida albicans could increase their cariogenicity. However, the effect of this dual-species microorganisms' combination on dentine caries has not been experimentally evaluated. Biofilms of C. albicans, S. mutans and C. albicans + S. mutans (n = 12/biofilm) were grown in ultra-filtered tryptone yeast extract broth culture medium for 96 h on root dentine slabs of known surface hardness and exposed 8 times per day for 3 min to 10% sucrose. The medium was changed 2 times per day (after the 8 cariogenic challenges and after the overnight period of famine), and aliquots were analyzed to determinate the pH (indicator of biofilm acidogenicity). After 96 h, the biofilms were collected to determine the wet weight, colony-forming units, and the amounts of extracellular polysaccharides (soluble and insoluble). Dentine demineralization was assessed by surface hardness loss (% SHL). The architecture of the biofilms was analyzed by confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM). Data were analyzed by ANOVA followed by Tukey's test (alpha = 0.05). The dual-species C. albicans + S. mutans biofilm provoked higher % SHL on dentine (p < 0.05) than the S. mutans and C. albicans biofilm. This was supported by the results of biofilm acidogenicity and the amounts of soluble (6.4 +/- 2.14 vs. 4.0 +/- 0.94 and 1.9 +/- 0.97, respectively) and insoluble extracellular polysaccharides (24.9 +/- 9.22 vs. 18.9 +/- 5.92 and 0.7 +/- 0.48, respectively) (p < 0.05). The C. albicans biofilm alone presented low cariogenicity. The images by CLSM and TEM, respectively, suggest that the C. albicans + S. mutans biofilm is more voluminous than the S. mutans biofilm, and S. mutans cells interact with C. albicans throughout polysaccharides from the biofilm matrix. These findings show that C. albicans enhances the cariogenic potential of the S. mutans biofilm, increasing dentine demineralization. PMID- 30448847 TI - Optimized Calcium Supplementation Approach for Regional Citrate Anticoagulation. AB - BACKGROUND: It has been confirmed that regional citrate anticoagulation (RCA) plays an effective role in extracorporeal anticoagulation. The current trial-and error calcium supplementation approach, with intensive monitoring of calcium levels, restricts the widespread use of RCA. Therefore, this study aimed to optimize the calcium supplementation approach for RCA. METHODS: Patients requiring RCA treatment for various reasons were included. Citrate was infused into the arterial port, and the ionized calcium levels in the extracorporeal circulation tubes and body were monitored to maintain them within the target range. Linear regression equations between the clearance of non-protein bound calcium (n-Ca) and prescribed effluent rate were determined; the ratio of the n Ca concentration to total calcium concentration (fa) after the infusion of citrate was also calculated. Then, we estimated a simplified calcium supplementation approach. RESULTS: Positive correlations were found between the clearance of n-Ca and effluent rate both during continuous veno-venous hemodialysis (CVVHD) and continuous veno-venous hemofiltration (CVVH; R2: 0.66 and 0.65, respectively, p < 0.01). The fa values at the pre-filter point and after infusion of citrate were constants, but the values differed from CVVHD to CVVH. For CVVHD, fa was 0.93, and for CVVH, fa was 0.80. Using the extracorporeal removal characteristics of n-Ca, the amount of extracorporeally removed calcium per mmol per hour can be quantified with a simplified equation. CONCLUSION: The optimized calcium supplementation approach could provide a more precise and practical method to estimate the amount of extracorporeal calcium removal with regard to different modalities and dosages of RCA. PMID- 30448848 TI - Inflammatory Signaling in Post-Stroke Fatigue and Depression. AB - BACKGROUND: In the United States, stroke continues to be the cause for long-term disability. Of the patients with a first stroke, up to 75% will experience post stroke fatigue (PSF) in the first year following stroke. PSF is one of the most disabling symptoms in stroke survivors; it decreases quality of life, increases mortality, and is a barrier to stroke rehabilitation. Given the incidence of stroke and the prevalence and detrimental impact of PSF on quality of life, independent living, and overall survival, efficient management of PSF must be a priority in stroke rehabilitation. The cause of PSF remains unknown. The burden of fatigue in stroke survivors is influenced by other stroke-related symptoms, most notably post-stroke depression (PSD). It is well known that stroke induces a systemic inflammatory response that is the trigger for sickness behavior, of which fatigue and depression are predominant symptoms. SUMMARY: To date, only a handful of studies have sought to explore the relationship between stroke-induced inflammation and PSF and PSD. In this review, we describe this evidence, highlight the strengths and weaknesses of these existing studies, and suggest further experiments that may further support the association between stroke related inflammatory processes and stroke-related symptoms. Key Messages: The current concept and further research are important for a more specific therapeutic intervention for PSF and PSD. PMID- 30448849 TI - The Association of the CHA2DS2VASc Score with Acute Stent Thrombosis in Patients with an ST Elevation Myocardial Infarction Who Underwent a Primary Percutaneous Coronary Intervention. AB - OBJECTIVE: In this study, we aimed to determine the predictive value of the CHA2DS2VASc score for acute stent thrombosis (ST) in patients with an ST elevation myocardial infarction (STEMI) treated with a primary percutaneous coronary intervention (pPCI). METHODS: This was a retrospective study conducted among 3,460 consecutive patients with STEMI patients who underwent pPCIs. Acute ST was considered as a definite or confirmed event in the presence of symptoms suggestive of acute coronary syndrome and angiographic confirmation of ST based on the diagnostic guidelines of the Academic Research Consortium. The ST was classified as acute if it developed within 24 h. RESULTS: The mean CHA2DS2VASc score was 3.29 +/- 1.73 in the ST group, whereas it was 2.06 +/- 1.14 in the control group (p < 0.001). In multivariable logistic regression analysis, the CHA2DS2VASc score >= 4 was independently associated with acute ST (odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.54-1.71, p < 0.001). In a receiver operating characteristic curve analysis, the best cut-off value for the CHA2DS2VASc score was >= 4, with 60% sensitivity and 73% specificity. Of note, patients with a CHA2DS2VASc score of 4 had a 4.3 times higher risk of acute ST compared to those with CHA2DS2VASc score of 1. CONCLUSIONS: The CHA2DS2VASc score may be a significant independent predictor of acute ST in patients with STEMI treated with a pPCI. Therefore, the CHA2DS2VASc score may be used to assess the risk of acute ST in patients with STEMI following a pPCI.
. PMID- 30448850 TI - Dynamic Evaluation of Orthodontically-Induced Tooth Movement, Root Resorption, and Alveolar Bone Remodeling in Rats by in Vivo Micro-Computed Tomography. AB - BACKGROUND The aim of this study was to dynamically evaluate tooth movement, root resorption, and remodeling of alveolar bone using different forces to cause tooth movement in rats. MATERIAL AND METHODS 12-week-old male Sprague-Dawley rats were selected. Nickel-titanium (Ni-Ti) coil springs (20 g, 50 g, and 100 g forces) were placed for mesial movement of the left first maxillary molar teeth. Tooth movement, root resorption, and microarchitectural parameters of the trabecular bone were evaluated by in vivo micro-CT. Histological examination was used to observe the root resorption, alveolar bone remodeling, and changes in osteoclasts from day 0 to day 14. RESULTS The tooth movement distance increased significantly over the initial 3 days in the 3 groups. The 20 g force group showed more tooth movement than in the 50 and 100 g force groups after 14 days (P<0.05). From days 7 to 10, root resorption lacunae appeared in the 3 groups and then stabilized, and the 100 g force group produced more lacunar resorption than in the anther 2 groups (P<0.05). Compared to day 0, the trabecular thickness and bone volume fraction on the pressure side gradually decreased from day 7 to day 14. The structure model index increased significantly from day 3 to day 14. Histological examination showed remarkable root resorption craters and osteoclasts positive for tartrate-resistant acid phosphatase in the root resorption lacunae in the 50 g and 100 g groups from day 7 to day 14. CONCLUSIONS A 100 g heavy force can be used to establish a root resorption model in rats. PMID- 30448851 TI - Comparison of Combination Stereotactic Body Radiotherapy Plus High-Intensity Focused Ultrasound Ablation Versus Stereotactic Body Radiotherapy Alone for Massive Hepatocellular Carcinoma. AB - BACKGROUND Thermal high-intensity focused ultrasound ablation is a non-invasive treatment of massive hepatocellular carcinomas. In stereotactic body radiotherapy, ablative radiotherapy is administered to tumors in targeted, limited doses to minimize damage to nearby tissues. We evaluated the outcomes and survival of patients receiving stereotactic body radiotherapy (singular therapy) versus those receiving combination thermal high-intensity focused ultrasound ablation plus stereotactic body radiotherapy (combination therapy). MATERIAL AND METHODS We compared data of 160 patients with massive hepatocellular carcinomas (12.5-18 cm) who were treated with combination therapy to those treated with singular therapy between January 2009 and February 2016. RESULTS Eighty-four patients were treated with single therapy while 76 were treated with combination therapy. Comparison of short-term outcomes and long-term survival between the groups revealed no significant differences in adverse events. In the combination group, the proportions of patients with complete response, partial response, stable disease, and progressive disease were 52.6%, 21.1%, 21.1%, and 5.3%, respectively; in the single therapy group, the corresponding rates were 0%, 23.8%, 50%, and 26.2%, respectively (P<0.0001). The 1-year, 3-year, and 5-year survival rates in the combination group were 33%, 20%, and 13%, respectively, while those in the single therapy group were 21%, 14%, and 1%, respectively. These data indicated no differences in complications between the groups except for a significantly higher level of skin edema in the combination group (P=0.015). CONCLUSIONS Combination therapy is more effective than single therapy for the treatment of massive hepatocellular carcinomas, although rates of most complications appear to be similar. PMID- 30448853 TI - Let's get moving. PMID- 30448852 TI - Carvedilol Ameliorates Intrahepatic Angiogenesis, Sinusoidal Remodeling and Portal Pressure in Cirrhotic Rats. AB - BACKGROUND Carvedilol is the first-line drug for the primary prophylaxis of variceal bleeding due to portal hypertension (PHT) in liver cirrhosis. This study aimed to investigate the effects of carvedilol on intrahepatic angiogenesis and sinusoidal remodeling in cirrhotic rats and explore the underlying mechanisms of carvedilol in PHT. MATERIAL AND METHODS For in vivo experiments, carbon tetrachloride was used to induce liver cirrhosis in rats, and carvedilol was simultaneously administered by gavage. The portal pressure was measured in rats, and liver tissues were examined by immunohistochemistry. Sinusoidal remodeling was observed by transmission electron microscopy. For in vitro experiments, the effects of carvedilol on fibronectin (FN) synthesis in human umbilical vein endothelial cells (HUVECs) were explored by quantitative real-time polymerase chain reaction and western blot analysis. RESULTS Portal vein pressure measurements showed that carvedilol reduced portal pressure in cirrhotic rats. Immunohistochemistry assays indicated that carvedilol ameliorated intrahepatic angiogenesis. Transmission electron microscopy examination demonstrated that carvedilol improved sinusoidal remodeling. In the in vitro experiments, carvedilol suppressed transforming growth factor beta1 (TGFbeta1)-induced FN synthesis in HUVECs by inhibition of the TGFbeta1/Smads pathway. CONCLUSIONS Carvedilol ameliorated intrahepatic angiogenesis, sinusoidal remodeling and portal pressure in cirrhotic rats. Carvedilol improved sinusoidal remodeling by suppressing FN synthesis in endothelial cells. Carvedilol has potential utility for treating early-stage liver cirrhosis. PMID- 30448854 TI - Decomposition responses to climate. PMID- 30448855 TI - Growth capacity and cell size. PMID- 30448856 TI - Publisher Correction: An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. AB - In the version of this article initially published, in the legend to Fig. 1b, the description of the frequency of TH17-IL-10+ clones was incomplete for the first group; this should read as follows: "...13 experiments with clones isolated from CCR6+CCR4+CXCR3- T cells...". Also, the label along the vertical axis of the bottom right plot in Figure 5b was incomplete; the correct label is 'IFN-gamma+ cells (%)'. Finally, in the first sentence of the final paragraph of the final Results subsection, the description of the regions analyzed was incorrect; that sentence should begin: "DNA motif-enrichment analysis of the subset-specific H3K27ac-positive regions...". The errors have been corrected in the HTML and PDF versions of the article. PMID- 30448857 TI - From molecules to medicines: the dawn of targeted therapies for genetic epilepsies. AB - Precision medicine is the treatment of patients with therapy targeted to their specific pathophysiology. This lofty ideal currently has limited application in clinical practice. However, new technological advances in epilepsy models and genomics suggest that the precision medicine revolution is closer than ever before. We are gaining an improved understanding of the true complexity underlying the pathophysiology of genetic epilepsies and the sources of phenotypic variation that continue to frustrate efforts at genotype-phenotype correlation. Conventional experimental models of epilepsy, such as mouse models and heterologous expression systems, have provided many of the advances in our understanding of genetic epilepsies, but fail to account for some of these complexities. Novel high-throughput models of epilepsy such as zebrafish and induced pluripotent stems cells can be combined with CRISPR-Cas9 gene editing techniques to explore the pathogenesis of a specific gene change and rapidly screen drug libraries for potential therapeutics. The knowledge gained from these models must be combined with thorough natural history studies to determine appropriate patient populations for pragmatic clinical trials. Advances in the 'omics', genetic epilepsy models and deep-phenotyping techniques have revolutionary translational research potential that can bring precision medicine to the forefront of clinical practice in the coming decade. PMID- 30448858 TI - Biological insights from the premonitory symptoms of migraine. AB - Migraine is a common neurological disorder with a diverse clinical phenotype that comprises more than just head pain. Premonitory (prodromal) symptoms can start hours to days before the onset of a migraine headache and can predict its onset in some individuals. Such symptomatology can include lethargy, yawning, light and sound sensitivity, thirst and cravings. This earliest phase of the migraine attack provides valuable insights into the neurobiology of the disorder, furthering our understanding of how and why these phenotypically heterogeneous symptoms are mediated. Improvements in our understanding of migraine could provide novel therapeutic opportunities, with the possibility of closing the therapeutic gap that remains owing to a lack of sufficiently effective and well tolerated acute and preventive treatments. Improved understanding of disease mechanisms and potential therapeutic targets through bench-to-bedside research into the premonitory phase is an exciting and emerging means of achieving this aim going forward. In this Review, we discuss the current evidence in the literature in relation to the phenotype and mediation of premonitory symptoms in migraine, and discuss the neurobiological insights gained from these studies. PMID- 30448859 TI - Occupational and leisure-time physical activity differentially predict 6-year incidence of stroke and transient ischemic attack in women. AB - Objectives Recent meta-analyses suggest a physical activity health paradox: high levels of occupational physical activity (OPA) increase cardiovascular disease (CVD) risk, while leisure-time physical activity (LTPA) decreases risk. However, studies of women and cerebrovascular disease are limited. This report examines physical activity effects on stroke and transient ischemic attack (TIA) among working women in the United States. Methods OPA history, health status, and lifestyle were assessed by baseline interviews of 31 270 employed Sister Study participants aged 35-74 years. OPA was assessed at six intensity levels (lowest: "mostly sitting"); the highest three were combined as "high intensity work." Independent OPA and LTPA effects on 6-year cerebrovascular disease incidence were estimated in adjusted Cox proportional hazard models. Results Stroke (N=441) and TIA (N=274) risk increased with more standing and higher intensity work at current and longest held job. Compared with mostly sitting, high intensity work at the current job increased TIA risk by 57% [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.04-2.38]. High intensity OPA at the longest held job increased risk for stroke by 44% (HR 1.44; 95% CI 1.08-1.93). Among women with CVD, sitting and standing equally, especially at the current job, increased risks up to two-fold (TIA HR 1.98, 95% CI 1.10-3.55) compared with mostly sitting at work. LTPA showed inverse associations. Conclusions Higher intensity levels of OPA increased stroke and TIA risks, while LTPA decreased risks; results corroborate the physical activity health paradox for women and cerebrovascular disease. More standing at work increased cerebrovascular disease risks, especially for women with CVD. PMID- 30448860 TI - Exposure-response relationships for silicosis and its progression in industrial sand workers. AB - Objectives This study aimed to characterize the relationship between radiographic silicosis and exposure to respirable quartz and determine how exposure affects disease progression. Methods Surveillance chest radiographs from a cohort of 1902 workers were examined to identify 67 cases of radiographic silicosis and 167 matched controls. Exposures were estimated by linking work histories to a job exposure matrix (JEM) based on samples collected by the participating companies and historical estimates. Conditional logistic regression was used to examine exposure-response relationships. Sequential radiographs from silicosis cases were used to assess associations between exposure and disease progression. Results Risk of silicosis increased with cumulative exposure [odds ratio (OR) 1.43 per 1 mg/m 3years, 95% confidence interval (CI) 1.23-1.66], average exposure concentration (OR 1.30 per 0.10 mg/m 3, 95% CI 1.11-1.51) and net exposure duration (OR 1.10 per year, 95% CI 1.05-1.16). Multivariate analyses indicated that the risk associated with cumulative exposure varied depending on exposure duration and concentration. Analysis of the time worked at differing exposure levels indicated that exposures <=0.05 mg/m 3were not significantly associated with silicosis risk after adjustment for years worked at higher concentrations. Disease progression was related to subsequent exposure concentration, with a yearly increase in small opacity profusion of 0.052 subcategory per each 0.10 mg/m 3increase in concentration. Conclusions Workers with longer exposure at lower concentrations were at higher risk for silicosis than those with the same cumulative exposure who worked for a shorter time at higher concentrations. The rate of silicosis progression was related to subsequent exposure concentration. PMID- 30448862 TI - Single-repeat R3 MYB transcription factors from Platanus acerifolia negatively regulate trichome formation in Arabidopsis. AB - MAIN CONCLUSION: Four R3 MYB genes were cloned and identified from Platanus acerifolia and analysed according to endogenous gene expression profiles, protein protein interaction patterns, phenotypic effects and related gene expression profiles in transgenic Arabidopsis, suggesting that London plane R3 MYB genes inhibit trichome formation in Arabidopsis. The CPC-like MYB transcription factors including CAPRICE (CPC), TRIPTYCHON (TRY), ENHANCER OF TRY AND CPC 1, 2 and 3 (ETC1, ETC2 and ETC3), TRICHOMELESS1 (TCL1) and TRICHOMELESS2(TCL2) play important roles in controlling trichome patterning in Arabidopsis. In this study, four sequences homologous with the Arabidopsis CPC family were identified from London plane and named PaTRY, PaCPC-like1, PaCPC-like2 and PaCPC-like3. Over expression of PaTRY, PaCPC-like1, PaCPC-like2 and PaCPC-like3 in Arabidopsis resulted in glabrous phenotypes. In addition, expression of endogenous GL2, GL1, MYB23, TTG2 and a set of R3 MYB-encoding genes was markedly reduced. Furthermore, the protein products of PaTRY, PaCPC-like1, PaCPC-like2 and PaCPC-like3 were shown to interact with PaGL3 in yeast two-hybrid assays. Together, these results likely suggest that the mechanisms of trichome regulation in London plane have similarities with those in Arabidopsis. PMID- 30448861 TI - Chromosome 18 gene dosage map 2.0. AB - In 2009, we described the first generation of the chromosome 18 gene dosage maps. This tool included the annotation of each gene as well as each phenotype associated region. The goal of these annotated genetic maps is to provide clinicians with a tool to appreciate the potential clinical impact of a chromosome 18 deletion or duplication. These maps are continually updated with the most recent and relevant data regarding chromosome 18. Over the course of the past decade, there have also been advances in our understanding of the molecular mechanisms underpinning genetic disease. Therefore, we have updated the maps to more accurately reflect this knowledge. Our Gene Dosage Map 2.0 has expanded from the gene and phenotype maps to also include a pair of maps specific to hemizygosity and suprazygosity. Moreover, we have revamped our classification from mechanistic definitions (e.g., haplosufficient, haploinsufficient) to clinically oriented classifications (e.g., risk factor, conditional, low penetrance, causal). This creates a map with gradient of classifications that more accurately represents the spectrum between the two poles of pathogenic and benign. While the data included in this manuscript are specific to chromosome 18, they may serve as a clinically relevant model that can be applied to the rest of the genome. PMID- 30448863 TI - Russeting partially restores apple skin permeability to water vapour. AB - MAIN CONCLUSION: The higher water loss of russeted fruit results from the higher permeance of the periderm of the russeted skin as compared to that of the intact cuticle and epidermis. Apple fruit surfaces are often in-parallel composites, comprising areas of intact cuticle (atop a healthy epidermis) adjacent to areas covered by periderm (so-called russet). The occurrence of non-russeting and russeting genotypes makes this species an ideal model to study the barrier properties of its composite skin. The objective was to quantify the water vapour permeances of non-russeted ([Formula: see text]) and russeted fruit skins ([Formula: see text]). Rates of water loss from whole fruit ([Formula: see text]) and excised epidermal skin segments (ES) or peridermal skin segments (PS) were quantified gravimetrically. The [Formula: see text] was larger in russeting than in non-russeting genotypes because [Formula: see text] exceeded [Formula: see text] by about twofold. Also, the [Formula: see text] of russeting genotypes was larger than that of non-russeting genotypes. Generally, [Formula: see text] was more variable than [Formula: see text]. These differences were consistent across seasons and genotypes. The lower [Formula: see text] as compared to [Formula: see text] resulted primarily from the higher wax content of the cuticle of the [Formula: see text]. For non-russeted genotypes, the value of [Formula: see text] was significantly related to the permeance determined on the same intact fruit ([Formula: see text]). Close relationships were also found between the [Formula: see text] calculated from [Formula: see text] determined on the same fruit and the measured [Formula: see text]. For russeting genotypes, the [Formula: see text] or [Formula: see text] were not correlated with [Formula: see text]. The [Formula: see text] calculated from [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] (all determined on an individual fruit basis) was significantly correlated with the measured [Formula: see text]. Our results demonstrate that the periderm permeance exceeds the cuticle permeance and that permeances of non-russeted surfaces of russeting genotypes exceed those of non-russeting genotypes. PMID- 30448864 TI - Connecting genome structural variation with complex traits in crop plants. AB - KEY MESSAGE: Structural genome variation is a major determinant of useful trait diversity. We describe how genome analysis methods are enabling discovery of trait-associated structural variants and their potential impact on breeding. As our understanding of complex crop genomes continues to grow, there is growing evidence that structural genome variation plays a major role in determining traits important for breeding and agriculture. Identifying the extent and impact of structural variants in crop genomes is becoming increasingly feasible with ongoing advances in the sophistication of genome sequencing technologies, particularly as it becomes easier to generate accurate long sequence reads on a genome-wide scale. In this article, we discuss the origins of structural genome variation in crops from ancient and recent genome duplication and polyploidization events and review high-throughput methods to assay such variants in crop populations in order to find associations with phenotypic traits. There is increasing evidence from such studies that gene presence-absence and copy number variation resulting from segmental chromosome exchanges may be at the heart of adaptive variation of crops to counter abiotic and biotic stress factors. We present examples from major crops that demonstrate the potential of pangenomic diversity as a key resource for future plant breeding for resilience and sustainability. PMID- 30448865 TI - The protective role of liver X receptor (LXR) during fumonisin B1-induced hepatotoxicity. AB - Fumonisin B1 (FB1), a congener of fumonisins produced by Fusarium species, is the most abundant and most toxicologically active fumonisin. FB1 causes severe mycotoxicosis in animals, including nephrotoxicity, hepatotoxicity, and disruption of the intestinal barrier. However, mechanisms associated with FB1 toxicity are still unclear. Preliminary studies have highlighted the role of liver X receptors (LXRs) during FB1 exposure. LXRs belong to the nuclear receptor family and control the expression of genes involved in cholesterol and lipid homeostasis. In this context, the toxicity of FB1 was compared in female wild type (LXR+/+) and LXRalpha,beta double knockout (LXR-/-) mice in the absence or presence of FB1 (10 mg/kg body weight/day) for 28 days. Exposure to FB1 supplemented in the mice's drinking water resulted in more pronounced hepatotoxicity in LXR-/- mice compared to LXR+/+ mice, as indicated by hepatic transaminase levels (ALT, AST) and hepatic inflammatory and fibrotic lesions. Next, the effect of FB1 exposure on the liver transcriptome was investigated. FB1 exposure led to a specific transcriptional response in LXR-/- mice that included altered cholesterol and bile acid homeostasis. ELISA showed that these effects were associated with an elevated FB1 concentration in the plasma of LXR-/- mice, suggesting that LXRs participate in intestinal absorption and/or clearance of the toxin. In summary, this study demonstrates an important role of LXRs in protecting the liver against FB1-induced toxicity, suggesting an alternative mechanism not related to the inhibition of sphingolipid synthesis for mycotoxin toxicity. PMID- 30448866 TI - The effect of repeated methotrexate injections on the quality of life of children with rheumatic diseases. AB - In clinical practice, the burden of repeated injections in children with rheumatic disease receiving disease-modifying anti-rheumatic drugs is significant. To investigate the nature and extent of impact on the quality of life after repeated injections, we conducted a literature review. Two relevant papers were identified, both about children with juvenile idiopathic arthritis (JIA) being administered methotrexate. The results suggest that the combination of needle fear, impact of methotrexate treatment, and procedural consequences, e.g., blood sampling, all contribute to the distress and the loss of quality of life of children with JIA. Remarkably, no studies examining fear of injections or injection pain in children with rheumatic diseases receiving biologicals were identified.Conclusion: Strategies to optimize administration of disease modifying anti-rheumatic drugs should be systematically investigated. What is Known: * Repeated parenteral administration of drugs is burdensome for children with rheumatic diseases. What is New: * Needle fear should be investigated systematically to optimize administration of disease-modifying anti-rheumatic drugs. PMID- 30448867 TI - Injection site reactions after long-term subcutaneous delivery of drisapersen: a retrospective study. AB - A retrospective study in which we reviewed the hospital files of a subset of 7 patients with Duchenne muscular dystrophy participating in the open-label phase I/II PRO051-02 study in Leuven. The objective of this study was to describe in detail the injection site reactions in these children treated with drisapersen (PRO-051), a 2'-O-methyl phosphorothioate RNA antisense oligonucleotide, that induces exon 51 skipping in Duchenne muscular dystrophy. Antisense oligonucleotides, restoring the reading frame by skipping of exons, have become a potential treatment of Duchenne muscular dystrophy and other monogenetic diseases. Erythema followed by hyperpigmentation, fibrosis, and calcification were seen at the injection sites in all children. Ulcerations, which were difficult to heal, occurred in 5 of 7 children. Progression still occurred after switching to intravenous administration of drisapersen or even after stopping therapy. Systemic reactions included a reversible proteinuria and alpha1 microglobulinuria. Moreover, hypotrichosis was a common feature.Conclusion: Subcutaneous administration of drisapersen causes severe and progressive injection site effects. What is known: * Antisense oligonucleotides offer the possibility to convert Duchenne muscular dystrophy to the less severe Becker type. This can potentially be achieved by targeting and skipping specific exons of the Duchenne muscular dystrophy gene to restore the disrupted reading frame and to induce the production of a semi functional dystrophin protein. * Drisapersen is such an antisense oligonucleotides which can be administered subcutaneously. Its use has been tested extensively in the escalating dose pilot study (PRO051-02). What is new: * This report describes the injection site reactions caused by this type of agent in detail which has never been done before. We therefore reviewed the hospital files of 7 patients with Duchenne muscular dystrophy participating in the phase I/II open-label, escalating dose pilot study (PRO051-02) with drisapersen. * Severe side effects starting with erythema, hyperpigmentation, and later fibrosis, calcification, and difficult to treat ulcerations developed in all patients, and these continued to progress even after cessation of drisapersen. We discuss some possible underlying mechanisms. The exact mechanism however is still not known. PMID- 30448868 TI - Added value of arterial spin labeling magnetic resonance imaging in pediatric neuroradiology: pitfalls and applications. AB - Arterial spin labeling is a noninvasive, non-gadolinium-dependent magnetic resonance imaging (MRI) technique to assess cerebral blood flow. It provides insight into both tissue metabolic activity and vascular supply. Because of its non-sensitivity toward blood-brain barrier leakage, arterial spin labeling is also more accurate in cerebral blood flow quantification than gadolinium dependent methods. The aim of this pictorial essay is to promote the application of arterial spin labeling in pediatric neuroradiology. The authors provide information on artifacts and pitfalls as well as numerous fields of application based on pediatric cases. PMID- 30448869 TI - Factors affecting infectious complications following flexible ureterorenoscopy. AB - In the present study, we aimed to clarify predictive factors that may cause postoperative infectious complications after flexible ureterorenoscopy (f-URS). In a 4-year prospective study, charts of patients who underwent f-URS between January 2014 and January 2018 for renal stone(s) in a tertiary academic center were reviewed. A standardized f-URS procedure was performed for all patients. Post-operative infectious complications including fever, sepsis and septic shock were categorized into same group. Patients with and without infectious complications were compared in the terms of preoperative, operative and post operative characteristics. In total, 463 patients who did not face infectious complications and 31 patients who faced infectious complications were enrolled into the study. The mean age was significantly lower in patients who did face infectious complications (34.8 vs 44.7 years old, p < 0.001). On the other hand, presence of renal abnormality was significantly more common in patients with infectious complications (12.3% vs 35.5%, p < 0.001). The mean operation time was 65.3 min in patients with infectious complications and significantly longer when compared with patients who did not face infectious complication (47.8 min, p < 0.001). Stone-free rate was significantly higher in patients without infectious complications (85.3% vs 77.5, p = 0.009). Multivariate regression analysis revealed that longer operation time >= 60 min, presence of renal abnormality and age <= 40 years were predictive factors for infectious complications following f URS. The present study has demonstrated that operation time >= 60 min, presence of renal abnormality and patients with <= 40 years were significantly associated with infectious complications following f-URS. PMID- 30448870 TI - Modulation of nitrogen metabolism of maize plants inoculated with Azospirillum brasilense and Herbaspirillum seropedicae. AB - Maize is highly responsive to the application of nitrogen to achieve high productivity. Inoculation with diazotrophic bacteria can improve plant growth with low N fertilization. The objective was to evaluate the inoculation of two species of diazotrophs on N metabolism in maize plants, in the presence of two concentrations of nitrogen in a hydroponic system. A factorial arrangement composed of two N levels (3.0 and 0.3 mM), with the presence of Hs-Herbaspirillum seropedicae, and Ab-Azospirillum brasilense or not. The parameters used were dry mass; N, P, and K accumulation; nitrate reductase activity; soluble fractions in roots and leaves. The inoculation altered the N metabolism and promoted greater development of maize plants, as well as a higher accumulation of P and K in the shoots. A more intensive process of N assimilation was evidenced when the plants were inoculated with H. seropedicae, leading to increased levels of NO3- and reduced N-amino, sugars, and NH4+ in leaves associated with high N level, opposite of A. brasilense. PMID- 30448871 TI - Transcriptomic analysis of Campylobacter jejuni grown in a medium containing serine as the main energy source. AB - Campylobacter jejuni is one of the most important causes of food-borne diseases in industrialized countries. Amino acids are an important nutrient source for this pathogen because it lacks enzymes related to glycolysis. However, the metabolic characteristics of C. jejuni grown in a nutrient-restricted medium with specific amino acids have not been fully elucidated. This study shows that C. jejuni NCTC 11168 grows well in a nutrient-restricted medium containing serine, aspartate, glutamate, and proline. Subtracting serine significantly reduced growth, but the removal of the three other amino acids did not, suggesting that serine is a priority among the four amino acids. A transcriptomic analysis of C. jejuni NCTC 11168 grown in a medium with serine as the main energy source was then performed. Serine seemed to be sensed by some chemoreceptors, and C. jejuni reached an adaptation stage with active growth in which the expression of flagellar assembly components was downregulated and the biosyntheses of multiple amino acids and nucleotide sugars were upregulated. These data suggest that C. jejuni NCTC 11168 requires serine as a nutrient. PMID- 30448872 TI - Exploring the genome of Arctic Psychrobacter sp. DAB_AL32B and construction of novel Psychrobacter-specific cloning vectors of an increased carrying capacity. AB - Cold-active bacteria are currently of great interest in biotechnology, and their genomic and physiological features have been extensively studied. One of the model psychrotolerant bacteria are Psychrobacter spp. Analysis of Arctic psychrophilic Psychrobacter sp. DAB_AL32B genome content provided an insight into its overall stress response, and genes conferring protection against various life limiting factors (i.e., low temperature, increased ultraviolet radiation, oxidative stress and osmotic pressure) were recognized and described. Moreover, it was revealed that the strain carries a large plasmid pP32BP2. Its replication system was used for the construction of two novel shuttle vectors (pPS-NR Psychrobacter-Escherichia coli-specific plasmid and pPS-BR-Psychrobacter-various Proteobacteria-specific plasmid) of an increased carrying capacity, which may be used for genetic engineering of Psychrobacter spp. PMID- 30448873 TI - Available ablation energies to treat cT1 renal cell cancer: emerging technologies. AB - PURPOSE: An increasing interest in percutaneous ablation of renal tumors has been caused by the increasing incidence of SRMs, the trend toward minimally invasive nephron-sparing treatments and the rapid development of local ablative technologies. In the era of shared decision making, patient preference for non invasive treatments also leads to an increasing demand for image-guided ablation. Although some guidelines still reserve ablation for poor surgical candidates, indications may soon expand as evidence for the use of the two most validated local ablative techniques, cryoablation (CA) and radiofrequency ablation (RFA), is accumulating. Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades, resulting in some new emerging types of ablations. METHODS: A literature search was conducted to identify original research articles investigating the clinical outcomes of new emerging technologies, percutaneous MWA, percutaneous IRE and SABR, in patients with primary cT1 localized renal cell cancer. RESULTS: Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades. New emerging technologies such as microwave ablation (MWA), irreversible electroporation (IRE) and stereotactic ablative radiotherapy (SABR) seem to be getting ready for prime time. CONCLUSION: This topical paper describes the new emerging technologies for cT1 localized renal cell cancer and investigates how they compare to CA and RFA. PMID- 30448874 TI - Academic achievement in children with chronic kidney disease: a report from the CKiD cohort. AB - BACKGROUND: There are limited data to describe academic achievement outcomes for children with mild to moderate pediatric chronic kidney disease (CKD). The objective of this study was to describe the prevalence of low academic achievement in patients with mild to moderate CKD. METHODS: Wechsler Individual Achievement Test, Second Edition, Abbreviated (WIAT-II-A) data were collected at entry into the Chronic Kidney Disease in Children (CKiD) study. Achievement in basic reading, spelling, mathematics, and total achievement was evaluated with a focus on the effects of comorbid CKD-related variables, neurocognitive, and school-based characteristics on academic achievement. RESULTS: WIAT-II-A data were available for 319 children in the CKiD cohort. Low total academic achievement was present in 34% percent of the sample. There was no significant effect of CKD-related medical variables on academic achievement. Mathematics had the lowest distribution of achievement scores. In univariate models, low achievement was significantly related to days of missed school (p = 0.006) and presence of individualized education plan (p < 0.0001). CONCLUSIONS: Low academic achievement was seen in over one-third of children with CKD, with the most difficulty observed in the domain of mathematics. Providers and educators should monitor for academic difficulties in this population in order to facilitate early educational assistance and promote positive educational outcomes. PMID- 30448875 TI - Correction to: Tyrosine-hydroxylase immunoreactivity in the mouse transparent brain and adrenal glands. AB - Unfortunately, the given name and family name of the fourth author was incorrectly tagged in the xml data, therefore it is abbreviated wrongly as ''Goazigo AR'' in Pubmed. The correct given name is Annabelle and family name is Reaux-Le Goazigo. PMID- 30448876 TI - Pseudocavernoma-a new diagnosis? PMID- 30448877 TI - Foods and Drinks Available from Urban Food Pantries: Nutritional Quality by Item Type, Sourcing, and Distribution Method. AB - The overall nutritional quality of foods/drinks available at urban food pantries is not well established. In a study of 50 pantries listed as operating in the Bronx, NY, data on food/drink type (fresh, shelf-stable, refrigerated/frozen) came from direct observation. Data on food/drink sourcing (food bank or other) and distribution (prefilled bag vs. client choice for a given client's position in line) came from semi-structured interviews with pantry workers. Overall nutritional quality was determined using NuVal(r) scores (range 1-100; higher score indicates higher nutritional quality). Twenty-nine pantries offered zero nutrition at listed times (actually being closed or having no food/drinks in stock). Of the 21 pantries that were open as listed and had foods/drinks to offer, 12 distributed items in prefilled bags (traditional pantries), 9 allowed for client choice. Mean NuVal(r) scores were higher for foods/drinks available from client-choice pantries than traditional pantries (69.3 vs. 57.4), driven mostly by sourcing fresh items (at 28.3% of client-choice pantries vs. 4.8% of traditional pantries). For a hypothetical 'balanced basket' of one of each fruit, vegetable, grain, dairy and protein item, highest-NuVal(r) items had a mean score of 98.8 across client-choice pantries versus 96.6 across traditional pantries; lowest-NuVal(r) items had mean scores of 16.4 and 35.4 respectively. Pantry workers reported lower-scoring items (e.g., white rice) were more popular appeared in early bags or were selected first-leaving higher-scoring items (e.g., brown rice) for clients later in line. Fewer than 50% of sampled pantries were open and had food/drink to offer at listed times. Nutritional quality varied by item type and sourcing and could also vary by distribution method and client position in line. Findings suggest opportunities for pantry operation, client and staff education, and additional research. PMID- 30448878 TI - Consumption of a dark roast coffee blend reduces DNA damage in humans: results from a 4-week randomised controlled study. AB - PURPOSE: To determine the DNA protective effects of a standard coffee beverage in comparison to water consumption. METHODS: The single-blind, randomised controlled study with parallel design included healthy women (n = 50) and men (n = 50) recruited from the general Central European population. The subjects were randomised in a coffee and a control group, with stratification for sex and body mass index. The study comprised two periods of 4 weeks: a preconditioning period, with daily consumption of at least 500 ml water but no coffee, nor tea, nor any other caffeine-containing product. During the subsequent intervention period the coffee group consumed 500 ml of freshly brewed dark roast coffee blend per day, the control group consumed water instead. On the last day of each period, blood was drawn and analysed by comet assay (single-cell gel electrophoresis) to assess the level of DNA damage (strand breakage). RESULTS: At the end of the intervention period the mean level of DNA strand breaks in the coffee group has decreased in comparison to the control group [difference in means 0.23% TI (tail intensity), p = 0.028]. The mean change from baseline (delta value) was - 23% in the coffee group (p = 0.0012). Effects of coffee intake were similar for men and women. During intervention, neither group showed any significant change in body weight or calorie intake. CONCLUSIONS: Our results indicate that regular consumption of a dark roast coffee blend has a beneficial protective effect on human DNA integrity in both, men and women. PMID- 30448879 TI - Carbohydrate nutrition variables and risk of disability in instrumental activities of daily living. AB - PURPOSE: We aimed to examine the prospective association between dietary glycemic index (GI) and glycemic load (GL) of foods consumed, intakes of carbohydrates and fiber, and the ability to perform activities of daily living (ADL) in older adults. METHODS: A total of 844 participants from the Blue Mountains Eye Study aged 60 years or older were examined from 2002-2004 to 2007-2009. Dietary information was collected using a validated, semi-quantitative food-frequency questionnaire. The Older Americans Resources and Services activities of daily living scale were administered to assess the functional status of participants. Multivariable logistic regression analysis was performed. RESULTS: After multivariable adjustment, participants who were in the second and third quartiles of energy-adjusted total fiber intake compared to those in the first quartile of intake (reference group) at baseline had reduced risk of incident impaired instrumental activities of daily living (IADL) 5 years later: OR, 0.39 (95% CI 0.22-0.70) and OR 0.54 (95% CI 0.30-0.95), respectively. Analyses that involved dichotomized total fiber intake showed that participants in the upper three quartiles of total fiber intake (> 19 g/day), compared to those in the lowest quartile of intake (<= 19 g/day) or reference group, had reduced IADL disability risk 5 years later: OR 0.49 (95% CI 0.31-0.79). Non-significant associations were observed with total carbohydrates, GI, and GL and with risk of impaired total and basic ADL at 5-year follow-up. CONCLUSIONS: Habitual fiber consumption might be beneficial in leading to improved health status subserving performance of instrumental daily activities, needed to function in the community. PMID- 30448880 TI - Dietary intake of (poly)phenols in children and adults: cross-sectional analysis of UK National Diet and Nutrition Survey Rolling Programme (2008-2014). AB - PURPOSE: Current evidence accounts for the role of (poly)phenolic compounds in the prevention of non-communicable diseases. Detailed information on population level intakes is required to translate these findings into recommendations. This work aimed to estimate (poly)phenol intake in the UK population using data from a nationally representative survey. METHODS: Data from 9374 participants (4636 children aged 1.5-18 years and 4738 adults aged 19 years and over) from the National Diet and Nutrition Survey Rolling Programme (NDNS RP) 2008-2014 was used. (Poly)phenol content of foods consumed in the NDNS RP was identified using Phenol-Explorer and through literature searches. Data on flavonoids, phenolic acids, and stilbenes were collected. Total (poly)phenol content was also assessed. RESULTS: Mean total (poly)phenol intake ranged from 266.6 +/- 166.1 mg/day in children aged 1.5-3 years to 1035.1 +/- 544.3 mg/day in adults aged 65 years and over, with flavan-3-ols and hydroxycinnamic acids being the most consumed (poly)phenols across all age groups. (Poly)phenol intake was higher in males in all age groups except for adults aged 19-34 and 50-64 years, where intakes were marginally higher in females. Energy-adjusted intakes accounted for the pattern of increasing (poly)phenol intakes with age and a higher intake was observed in females across all age groups, with the exception of children aged 1.5-3 years. The main food sources were non-alcoholic beverages and fruits, being the main compounds flavan-3-ols and caffeoylquinic acids. CONCLUSIONS: This analysis provides estimates of (poly)phenol intake from a representative sample of the UK general population, which can help inform the health implications of (poly)phenol intake. PMID- 30448881 TI - Metabolic reprogramming of mitochondrial respiration in metastatic cancer. AB - Tumor initiation, progression, and metastasis are tissue context-dependent processes. Cellular and non-cellular factors provide the selective microenvironment that determines the fate of the evolving tumor through mechanisms that include metabolic reprogramming. Genetic and epigenetic changes contribute to this reprogramming process, which is orchestrated through ongoing communication between the mitochondrial and nuclear genomes. Metabolic flexibility, in particular the ability to rapidly adjust the balance between glycolytic and mitochondrial energy production, is a hallmark of aggressive, invasive, and metastatic cancers. Tumor cells sustain damage to both nuclear and mitochondrial DNA during tumorigenesis and as a consequence of anticancer treatments. Nuclear and mitochondrial DNA mutations and polymorphisms are increasingly recognized as factors that influence metabolic reprogramming, tumorigenesis, and tumor progression. Severe mitochondrial DNA damage compromises mitochondrial respiration. When mitochondrial respiration drops below a cell specific threshold, metabolic reprogramming and plasticity fail to compensate and tumor formation is compromised. In these scenarios, tumorigenesis can be restored by acquisition of respiring mitochondria from surrounding stromal cells. Thus, intercellular mitochondrial transfer has the potential to confer treatment resistance and to promote tumor progression and metastasis. Understanding the constraints of metabolic, and in particular bioenergetic reprogramming, and the role of intercellular mitochondrial transfer in tumorigenesis provides new insights into addressing tumor progression and treatment resistance in highly aggressive cancers. PMID- 30448882 TI - Calpain system protein expression and activity in ovarian cancer. AB - PURPOSE: Expression of members of the calpain system are associated with clinical outcome of patients with, amongst others, breast and ovarian cancers, with calpain-2 expression in ovarian cancer being implicated in chemo-resistance and survival. This study aimed, using a large patient cohort and in vitro models, to verify its importance and further investigate the role in ovarian cancer chemoresponse. METHODS: Calpain-1, calpain-2, calpain-4 and calpastatin expression were evaluated in primary ovarian carcinomas (n = 575) by immunohistochemistry. Protein expression was assessed, via western blotting, in five ovarian cancer cell lines with various sensitivities towards cisplatin/carboplatin. In vitro calpain activity was inhibited by calpeptin treatment to assess changes in platinum sensitivity by proliferation assay, with expression of genes associated with epithelial-mesenchymal transition being examined by RT2 ProfilerTM PCR Array. RESULTS: The current study confirmed previous data that high calpain-2 expression is associated with poor overall survival (P = 0.026) and that calpain-1 was not associated with overall survival or progression-free survival. Low expression of calpastatin (P = 0.010) and calpain-4 (P = 0.003) were also associated with adverse survival. Such prognostic associations do not seem to be linked with altered tumour sensitivity towards platinum-based chemotherapy. Interestingly, low calpain-1 expression was more frequent in patients with confined tumours (stage 1) (chi2 = 11.310, df = 1, P = 0.001). Calpain and calpastatin expression varied among ovarian cancer cell lines yet their expression levels were similar between chemo-sensitive cells and resistant counterparts. Moreover, calpeptin treatment did not alter cellular response to platinum-based chemotherapy or epithelial-mesenchymal transition related gene expression. CONCLUSIONS: The conventional calpains and calpastatin have been confirmed to play an important role in ovarian cancer; however, the precise mechanisms whereby they exert effects remain to be elucidated. PMID- 30448883 TI - Molecular cloning and functional characterization of multiple geranylgeranyl pyrophosphate synthases (ApGGPPS) from Andrographis paniculata. AB - KEY MESSAGE: We found that ApGGPPS1, ApGGPPS2, and ApGGPPS3 can convert IPP and DMAPP to GGPP. ApGGPPS2 is probably involved in andrographolide biosynthesis. ApGGPPS3 may be responsible for the synthesis of the cytosolic GGPP. Andrographis paniculata is a traditional herb for the treatment of sore throat, flu, upper respiratory tract infections and other disorders. In A. paniculata, GGPP is not only the precursor of andrographolide and its primary bioactive compounds, but also the precursor of chlorophylls, carotenoids, gibberellins, and abscisic acid, which are the biomolecules of photosynthesis, growth regulation and other physiological and ecological processes. In this study, four cDNAs (named ApGGPPS1, ApGGPPS2, ApGGPPS3 and ApGGPPS4) encoding geranylgeranyl pyrophosphate synthases from A. paniculata were putatively isolated. Bioinformatic and phylogenetic analyses suggested that these ApGGPPS are highly similar to the geranylgeranyl pyrophosphate synthases in other plants. Prokaryotic expression showed that ApGGPPS1, ApGGPPS2 and ApGGPPS3 could convert IPP and DMAPP to GGPP, although ApGGPPS4 lacks a similar function. The expression of ApGGPPS2 was similar as ApCPS2 under MeJA treatment, ApCPS2 involved in the biosynthesis pathway of andrographolide (Shen et al., Biotechnol Lett 38:131-137, 2016a), has been proven through Virus-induced Gene Siliencing (VIGS) (Shen et al., Acta Bot Boreal 36:17-22, 2016b), and the subcellular localization of ApGGPPS2 was shown to localize in the plastid, suggested that ApGGPPS2 could be the key synthase in the biosynthesis pathway of andrographolide. In addition, ApGGPPS3 was shown to localize in the cytoplasm, suggested that ApGGPPS3 may be responsible for the synthesis of cytosolic GGPP, which may participate in the synthesis of cytosolic oligoprenols as side chains to produce ubiquinone, dolichols or other isoprenoids, in the synthesis of polyisoprenoids, and in protein prenylation. PMID- 30448884 TI - Discrepant hypoxia tolerance aggravates subchondral delamination in osteonecrosis of the femoral head. PMID- 30448885 TI - Cyclodestructive Procedures in Glaucoma: A Review of Current and Emerging Options. AB - The first surgical modalities to reduce aqueous humor production by damaging the ciliary body date back to the early twentieth century. Until recently, however, cyclodestructive procedures (e.g., cyclocryotherapy and transscleral diode laser photocoagulation) have been reserved as last option procedures in refractory glaucoma patients with poor visual potential. Emerging technologic innovation has led to the development of promising, safer and less destructive techniques, such as micropulse diode cyclophotocoagulation, endoscopic cyclophotocoagulation and ultrasound cyclodestruction. Consequently, an emerging paradigm shift is under way with the selection of these surgical options in eyes with less severe glaucoma and good visual potential. Although existing evidence has not, as yet, adequately defined the role and value of these procedures, their emergence is a welcome expansion of available options for patients with moderate-to-severe glaucoma. This article reviews the pertinent evidence on both established and evolving cyclodestructive techniques and describes their growing role in the management of glaucoma. PMID- 30448887 TI - The effect of overactive bladder treatment with anticholinergics on female sexual function in women: a prospective observational study. AB - PURPOSE: The aim of the study was to determine the effect of anticholinergics used for overactive bladder treatment on the sexual function of women. METHODS: Between January 2016 and August 2018, over 18 years old, 216 sexual active women with OAB and 165 healthy women as control group were prospectively enrolled in the study. Five different anticholinergics were used for the treatment. Female Sexual Function Index (FSFI), eight-item overactive bladder awareness tool (OAB V8), and Beck Depression Inventory form were completed before and after 3 months. Baseline and post-treatment scores were compared with a control group of age matched healthy women. RESULTS: Patients with OAB reported at baseline significantly worse sexual function in all FSFI domains compared to healthy control group (21.47 +/- 3.22 vs. 26.79 +/- 5.56, p < 0.01). Three months after treatment, over 85% of participants reported clinically relevant improvements in sexual function, with statistically significant changes in mean FSFI scores. CONCLUSIONS: Treatment of OAB with anticholinergics can improve sexual function of sexual active women with OAB. Patients may be informed about this potential benefit of anticholinergic treatment, to improve their sexual function. PMID- 30448886 TI - A Randomized Controlled Clinical Trial Comparing 20 Gauge and 23 Gauge Vitrectomy for Patients with Macular Hole or Macular Pucker. AB - INTRODUCTION: To compare the transconjunctival sutureless 23 gauge (G) pars plana vitrectomy (PPV) with 20 G PPV regarding inflammation, safety, visual outcome and patient comfort. METHODS: We included 103 patients with symptomatic macular hole or macular pucker, scheduled for vitrectomy in this prospective, randomized, controlled, mono-center clinical trial. Patients were randomized 1:1 to either 20G PPV (n = 51) or 23G PPV (n = 52). All eyes underwent standard 20G or 23G PPV with membrane peeling. Primary outcome measure was change in aqueous humor flare 3 weeks after surgery compared with baseline. Secondary outcome measures were flare values 2 days and 26 weeks after surgery, subjective discomforts measured with a visual analog scale, best-corrected visual acuity, duration of surgery, intraocular pressure (IOP) and adverse events. RESULTS: There was no significant difference in change of flare 3 weeks after PPV [- 1.7, 95% CI (- 6.3 to 2.9), p = 0.466]. Both groups showed a significant increase in flare 2 days after surgery (20G: p < 0.001, 23G: p = 0.002), but only the 20G group after 3 weeks (p = 0.011). The gain in visual acuity after 3 weeks was higher after 23G PPV (4.2 95% CI (0.4-8.0, p = 0.029), but without a difference after 6 months. The duration of surgery was shorter in the 23G group (p < 0.001). Patient comfort 3 weeks after surgery was greater after 23G PPV (foreign body sensation p = 0.002; itching: p = 0.021). However, the rate of complications did not differ between the groups. CONCLUSION: The primary aim, showing the superiority of the 23G group regarding the change of flare value from baseline to 3 weeks after surgery, was not met, but the level of inflammation decreased faster after 23G PPV. Clear advantages of the 23G PPV were a lower risk of postoperative IOP elevation, a shorter surgery time, faster visual recovery and greater patient comfort in the early postoperative phase. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01969929. PMID- 30448888 TI - Gastroduodenal perforation in the pediatric population: a retrospective analysis of 20 cases. AB - OBJECTIVE: The aim of this study was to investigate the pathogenesis, symptoms and individualized surgical management in pediatrics with gastroduodenal perforation (GDP). METHODS: Patients diagnosed with GDP from January 2013 to December 2016 in our hospital were collected and divided into gastric perforation (GP) group and duodenal perforation (DP) group. Demographics, clinical events, etiological factors, symptoms, the time from symptom onset to operation, intraoperative findings and surgical procedures were analyzed. Follow-ups including ulcer, perforations occurrence, and digestive symptoms were carried out by out-patient review or telephones. RESULTS: A total of 20 patients aged from 3 months to 14 years were enrolled in this study. The average age, main clinical presentations, size of perforations and operating time between two groups had no difference. The male to female ratio in DP group was higher than GP (P < 0.05). The high risk factor for DP was the use of dexamethasone, and for GP was HP infection. The most common site of perforation in DP group was duodenal bulb, and in GP group was pylorus area. Simple suture is the main management for both DP and GP, but distal gastrectomy combined with gastrojejunal Roux-en-Y anastomosis may be an alternative procedure for large perforation with diameter > 2 cm. The length of hospital days in GP group is shorter than DP group (P < 0.05). For follow-up, no patients had digestive symptoms. CONCLUSIONS: The general condition had no difference between GP and DP patients. But the risk factors and surgical repair differ depending on the patient's fundamental illness and the complexity of the perforation. PMID- 30448889 TI - Early Aberrant Growth of Mossy Fibers after Status Epilepticus in the Immature Rat Brain. AB - Axonal sprouting is recognized to be an important mean of repair after neurologic injury. Some characteristic aftermaths of pilocarpine-induced status epilepticus (SE) in the immature rat are nerve cell loss and rearrangement of neuronal fibers. SE induced cell degeneration exclusively in the hippocampal CA1 subfield. Development of neuronal death becomes evident within hours after SE, following a delayed time course ranging from 6 to 48 h post-SE. An incidental finding is that pilocarpine induces within 48 h an aberrant growth of hippocampal mossy fibers in the hippocampus, especially in the infrapyramidal region of the CA3-subfield. We found a strong infrapyramidal band of mossy fibers along the entire stratum oriens of the CA3-region. No mossy fibers sprouting into the inner molecular layer of the dentate gyrus, or CA1 sprouting into the stratum moleculare of CA1 were noted. Signs of aberrant connectivity were found in six of the 10 pilocarpine-treated animals. This study provides the demonstration that pilocarpine within 48 h consistently results in the formation of ectopic hippocampal mossy fibers in a 2-week-old pup. This indicates a high degree of axonal reorganization in the hippocampus. It remains controversial whether such reorganization is the cause or consequence of chronic seizures. We assume that these additional infrapyramidal mossy fibers may influence the way in which granule cells drive pyramidal cells in CA3. PMID- 30448890 TI - Post Hoc Analysis of the CONFIDENCE II, PROTECT I, SHAKE THE HABIT I and SHAKE THE HABIT II Observational Studies in Mild to Moderate Hypertensive Patients Treated with Perindopril and Atorvastatin Concomitantly. AB - BACKGROUND AND OBJECTIVES: Management of hypertension and dyslipidemia is important when considering cardiovascular disease risk; however, achievement of optimal lipid and blood pressure (BP) targets in clinical practice remains inadequate. This analysis sought to estimate the frequency, effectiveness, and safety of co-administrated atorvastatin and perindopril in routine care. METHODS: We conducted a post hoc analysis of four Canadian, prospective, multi-center, observational studies assessing real-life effectiveness and safety of perindopril + atorvastatin in mild-to-moderate hypertensive patients with concomitant dyslipidemia over 16 weeks. The safety population comprised patients receiving one or more doses of free combination perindopril + atorvastatin; the full analysis set (FAS) received perindopril + atorvastatin at baseline, with one or more post-baseline systolic BP measurements while on treatment. RESULTS: A total of 3541 and 3172 patients were included in the safety population and FAS, respectively. At the last observation carried forward, significant reductions in mean systolic BP (- 18.0 mmHg; p < 0.001) and diastolic BP (- 8.9 mmHg; p < 0.001) were observed; target BP was achieved by 73.1% of patients. Emergent adverse events (AEs) were reported in 8.0% of patients, the most common being cough (4.5% of patients), headache (0.9%), and dizziness (0.8%). Four serious AEs were reported among three (0.1%) patients. No differences were observed in effectiveness or safety between studies. CONCLUSIONS: Concomitant perindopril + atorvastatin therapy demonstrated similar efficacy across all studies, with significant reductions in BP and achievement of target BP levels observed in a real-world setting. Results align with known safety profiles of atorvastatin and perindopril, with no unexpected AEs observed when compared with data from treatment with the individual drugs. PMID- 30448891 TI - Developmental and functional characteristics of the thoracic aorta perivascular adipocyte. AB - Thoracic aorta perivascular adipose tissue (T-PVAT) has critical roles in regulating vascular homeostasis. However, the developmental characteristics and cellular lineage of adipocyte in the T-PVAT remain unclear. We show that T-PVAT contains three long strip-shaped fat depots, anterior T-PVAT (A-T-PVAT), left lateral T-PVAT (LL-T-PVAT), and right lateral T-PVAT (RL-T-PVAT). A-T-PVAT displays a distinct transcriptional profile and developmental origin compared to the two lateral T-PVATs (L-T-PVAT). Lineage tracing studies indicate that A-T PVAT adipocytes are primarily derived from SM22alpha+ progenitors, whereas L-T PVAT contains both SM22alpha+ and Myf5+ cells. We also show that L-T-PVAT contains more UCP1+ brown adipocytes than A-T-PVAT, and L-T-PVAT exerts a greater relaxing effect on aorta than A-T-PVAT. Angiotensin II-infused hypertensive mice display greater macrophage infiltration into A-T-PVAT than L-T-PVAT. These combined results indicate that L-T-PVAT has a distinct development from A-T-PVAT with different cellular lineage, and suggest that L-T-PVAT and A-T-PVAT have different physiological and pathological functions. PMID- 30448892 TI - The non-canonical functions of telomerase: to turn off or not to turn off. AB - Telomerase is perceived as an immortality enzyme that enables passing the Hayflick limit. Its main function is telomere restoration but only in a limited group of cells, including cancer cells. Since it is found in a vast majority of cancer cells, it became a natural target for cancer therapy. However, it has much more functions than just altering the metabolism of telomeres-it also reveals numerous so-called non-canonical functions. Thus, a question arises whether it is always beneficial to turn it off when planning a cancer strategy and considering potential side effects? The purpose of this review is to discuss some of the recent discoveries about telomere-independent functions of telomerase in the context of cancer therapy and potential side effects. PMID- 30448893 TI - Resistance determination of the ACCase-inhibiting herbicide of clodinafop propargyl in Avena ludoviciana (Durieu), and study of their interaction using molecular docking and simulation. AB - Structural mutations providing herbicide resistance may cause a modification of the three dimensional structure of a protein which will lead to a decrease in the herbicide efficacy. Wild oat (Avena ludoviciana Durieu.) is an increasingly disruptive weed in areas of intensive cereal production, thus the aim of this research was to identify mutations conferring resistance to ACCase-inhibitor herbicides at greenhouse, laboratory and in silico scales. Among the selected biotypes, No. 3 in the position 1781 (Ile1781-Leu) and No. 14 in the position 2041 (Ile2041-Asn), showed resistance to ACCase-inhibitor. The above mutations were confirmed using the specific primers and PCR-based methods. Analysis of molecular docking indicated that residues of Trp1948 and Pro2001 are important in the binding site and showed remarkable variation in the mutation types. Using molecular dynamic simulation analysis, we demonstrated that mutation types changed the conformation of the enzyme. These changes resulted in compressed conformation in the active site, which limited the availability of binding herbicide-enzyme. In present, no crystallography molecular structure and modeling reported on the ACCase of plants and this study investigated interactions of clodinafop propargyl and ACCase CT domain in A. ludoviciana by modeling, docking and simulations for the first time. Totally, bioinformatics analysis as well as PCR-based method confirmed that herbicide resistance conferred by nucleotide mutations in the gene sequence. PMID- 30448894 TI - Antimicrobial activity of bacteriocin-like inhibitory substance produced by Pediococcus pentosaceus: from shake flasks to bioreactor. AB - Bacteriocins are peptides produced by various species of bacteria, especially lactic acid bacteria (LAB), which have a large spectrum of action against spoilage bacteria and foodborne pathogens. However, when not entirely characterized, they are alternatively called bacteriocin-like inhibitory substances (BLIS). Pediococcus pentosaceus ATCC 43200 grew and produced BLIS optimally when cultivated anaerobically in bioreactor for 24 h at 30 degrees C and 200 rpm in De Man, Rogosa and Sharp (MRS) medium supplemented with 1.5% peptone. Under such optimal conditions, the cell mass concentration (3.41 g/L) was 66% higher, the generation time (1.28 h) 38% shorter and the BLIS activity against different indicator strains significantly higher than in MRS medium without any supplement taken as a control, and the exponential phase started 4 h before. The agar diffusion method showed BLIS inhibition halos against LAB strains with diameter in the range 11.0-19.5 mm and specific areas between 377.1 and 2654.6 mm2/mL, while BLIS activity against Listeria strains was better quantified by the liquid medium assay that showed, for the fermented broth without any dilution, 100 and 50% inhibition of Listeria innocua and Listeria seeligeri growth, respectively. These results highlight the potential of P. pentosaceus BLIS as a natural antimicrobial for application in the food industry. PMID- 30448895 TI - Human astroviruses: in silico analysis of the untranslated region and putative binding sites of cellular proteins. AB - Human astrovirus (HAstV) constitutes a major cause of acute gastroenteritis in children. The viral 5' and 3' untranslated regions (UTR) have been involved in the regulation of several molecular mechanisms. However, in astrovirues have been less characterized. Here, we analyzed the secondary structures of the 5' and 3' UTR of HAstV, as well as their putative target sites that might be recognized by cellular factors. To our knowledge, this is the first bioinformatic analysis that predicts the HAstV 5' UTR secondary structure. The analysis showed that both the UTR sequence and secondary structure are highly conserved in all HAstVs analyzed, suggesting their regulatory role of viral activities. Notably, the UTRs of HAstVs contain putative binding sites for the serine/arginine-rich factors SRSF2, SRSF5, SRSF6, SRSF3, and the multifunctional hnRNPE2 protein. More importantly, putative binding sites for PTB were localized in single-stranded RNA sequences, while hnRNPE2 sites were localized in double-stranded sequence of the HAstV 5' and 3' UTR structures. These analyses suggest that the combination of SRSF proteins, hnRNPE2 and PTB described here could be involved in the maintenance of the secondary structure of the HAstVs, possibly allowing the recruitment of the replication complex that selects and recruits viral RNA replication templates. PMID- 30448896 TI - Development of microsatellite markers for the seagrass Zostera japonica using next-generation sequencing. AB - The seagrass Zostera japonica Asch. & Graebn. is among the few seagrass species that thrive both in temperate and tropical intertidal zones. The degradation of Z. japonica in its native range and continued expansion in some localities have raised concerns with regard to its conservation and management. Population genetic studies of Z. japonica across its biogeographic range and within meadows are scarce. Previously developed microsatellites via traditional methods are not sufficient in quantity and perform inconsistently between the temperate and tropical populations. Thus, this study aimed to develop more reliable polymorphic markers for Z. japonica using next generation sequencing. In total, 6479 sequences containing loci were identified and 1619 pairs of primers were successfully designed. Of these, 63 loci were selected for primary validation in 16 individuals from four populations, with 48 (76.2%) polymorphic loci detected. Seventeen polymorphic loci were selected for further evaluation in 62 individuals from one temperate and one tropical population. The overall probability of identity (PID) for both populations was 2.375e-22 (PIDsib = 3.557e-08). The number of alleles, and expected and observed heterozygosity in the two populations were both relatively high and not significantly different from each other. The pairwise FST = 0.232 (p < 0.0001) and Principal Coordinates Analysis both suggested a large and significant genetic divergence between the two populations. This study makes abundant molecular markers available for genetic studies in Z. japonica, and facilitates its conservation and management strategies. PMID- 30448897 TI - Time-varying risks of second events following a DCIS diagnosis in the population based Vermont DCIS cohort. AB - PURPOSE: Long-term disease-free survival patterns following surgical, radiation, and endocrine therapy treatments for ductal carcinoma in situ (DCIS) are not well characterized in general US practice. METHODS: We identified 1252 women diagnosed with DCIS in Vermont during 1994-2012 using data from the Vermont Breast Cancer Surveillance System, a statewide registry of breast imaging and pathology records. Poisson regression and Cox regression with time-varying hazards were used to evaluate disease-free survival among self-selected treatment groups. RESULTS: With 7.8 years median follow-up, 192 cases experienced a second breast cancer diagnosis. For women treated with breast-conserving surgery (BCS) alone, the annual rate of second events decreased from 3.1% (95% CI 2.2-4.2%) during follow-up years 1-5 to 1.7% (95% CI 0.7-3.5%) after 10 years. In contrast, the annual rate of second events among women treated with BCS plus adjuvant radiation therapy increased from 1.8% (95% CI 1.1-2.6%) during years 1-5 to 2.8% (95% CI 1.6-4.7%) after 10 years (P < 0.05 for difference in trend compared to BCS alone). Annual rates of second events also increased over time among women treated with BCS plus adjuvant radiation and endocrine therapy (P = 0.01 for difference in trend compared to BCS alone). The rate of contralateral events increased after 10 years for all groups with adjuvant treatments. The rate of second events did not vary over time among women who underwent ipsilateral mastectomy (P = 0.62). CONCLUSIONS: Long-term risk of a second event after DCIS varies over time in a manner dependent on initial treatment. PMID- 30448898 TI - Clinical implication of E-cadherin deficiency in lobular breast cancer. PMID- 30448899 TI - Size of Protein is a Major Factor that Affects Retention on Preparative IMAC Columns. AB - Immobilized metal affinity chromatography (IMAC) is a specific high-capacity technique used in large-scale purification of proteins. IMAC exploits the ability of immobilized metal ions to form coordination bonds with atoms in the side chains of certain amino acids. The technique is generally robust. However, several factors still affect column binding capacity, retention, yield and purity of proteins during IMAC. It was observed that the recovery of 6* histidine, (His)6-tagged proteins from metal affinity columns differ significantly depending on the size of the protein. To test this observation, we determined the effect of protein size, flow-rate, number and position of (His)6 tag on the retention of highly expressing proteins on commercial Ni2+ and Co2+ IMAC columns. All experiments were performed in phosphate buffer to eliminate interference of amine containing buffers with the binding of the (His)6 tag to the columns. Column retention was determined as the ratio of protein of interest in the supernatant (input) to flow-through (output). Data obtained suggest that regardless of the flow-rate, (His)6 tag position and number, the size of protein is a major factor affecting column retention and therefore recovery during column IMAC purification. Small and medium-sized proteins (~ 50 kDa) have higher column retention than bigger proteins, resulting in higher recovery. These outcomes provide important information to consider when performing IMAC. PMID- 30448900 TI - Low-dose CT imaging of the acute abdomen using model-based iterative reconstruction: a prospective study. AB - OBJECTIVES: Performance of a modified abdominopelvic CT protocol reconstructed using full iterative reconstruction (IR) was assessed for imaging patients presenting with acute abdominal symptoms. MATERIALS AND METHODS: Fifty-seven patients (17 male, 40 female; mean age of 56.5 +/- 8 years) were prospectively studied. Low-dose (LD) and conventional-dose (CD) CTs were contemporaneously acquired between November 2015 and March 2016. The LD and CD protocols imparted radiation exposures approximating 10-20% and 80-90% those of routine abdominopelvic CT, respectively. The LD images were reconstructed with model based iterative reconstruction (MBIR), and CD images with hybrid IR (40% adaptive statistical iterative reconstruction (ASIR)). Image quality was assessed quantitatively and qualitatively. Independent clinical interpretations were performed with a 6-week delay between reviews. RESULTS: A 74.7% mean radiation dose reduction was achieved: LD effective dose (ED) 2.38 +/- 1.78 mSv (size specific dose estimate (SSDE) 3.77 +/- 1.97 mGy); CD ED 7.04 +/- 4.89 mSv (SSDE 10.74 +/- 5.5 mGy). LD-MBIR images had significantly lower objective and subjective image noise compared with CD-ASIR (p < 0.0001). Noise reduction for LD MBIR studies was greater for patients with BMI < 25 kg/m2 than those with BMI >= 25 kg/m2 (5.36 +/- 3.2 Hounsfield units (HU) vs. 4.05 +/- 3.1 HU, p < 0.0001). CD ASIR studies had significantly better contrast resolution, and diagnostic acceptability (p < 0.0001 for all). LD-MBIR studies had significantly lower streak artifact (p < 0.0001). There was no difference in sensitivity for primary findings between the low-dose and conventional protocols with the exception of one case of enteritis. CONCLUSIONS: Low-dose abdominopelvic CT performed with MBIR is a feasible radiation dose reduction strategy for imaging patients presenting with acute abdominal pain. PMID- 30448901 TI - Solubilized eggshell membrane supplies a type III collagen-rich elastic dermal papilla. AB - Signs of aging in facial skin correlate with lifespan and chronic disease; however, the health of aging skin has not been extensively studied. In healthy young skin, the dermis forms a type III collagen-rich dermal papilla, where capillary vessels supply oxygen and nutrients to basal epidermal cells. Chicken eggshell membranes (ESMs) have been used as traditional medicines to promote skin wound healing in Asian countries for many years. Previously, we designed an experimental system in which human dermal fibroblasts (HDFs) were cultured on a dish with a solubilized ESM (S-ESM) bound to an artificial phosphorylcholine polymer; we found that genes that promoted the health of the papillary dermis, such as those encoding type III collagen, were induced in the S-ESM environment. The present study found that a gel with a ratio of 20% type III/80% type I collagen, similar to that of the baby skin, resulted in a higher elasticity than 100% type I collagen (p < 0.05) and that HDFs in the gel showed high mitochondrial activity. Thus, we decided to perform further evaluations to identify the effects of S-ESM on gene expression in the skin of hairless mice and found a significant increase of type III collagen in S-ESM. Picrosirius Red staining showed that type III collagen significantly increased in the papillary dermis after S-ESM treatment. Moreover, S-ESM application significantly improved human arm elasticity and reduced facial wrinkles. ESMs may have applications in extending lifespan by reducing the loss of tissue elasticity through the increase of type III collagen. PMID- 30448902 TI - Sasa quelpaertensis leaf extract mitigates fatigue and regulates the transcriptome profile in mice. AB - INTRODUCTION: It has been reported that various plant species may enhance the elimination of fatigue-related metabolites. However, relatively few studies have directly addressed the potential anti-fatigue effects. OBJECTIVE: The objective of this study was to investigate the anti-fatigue potential of a hot water extract of Sasa quelpaertensis Nakai leaf (SQH) in male ICR mice. METHODS: The animals were divided into three groups. The normal control (NC) group was administered saline without exercise every day for 7 days. The exercise control (EC) and exercise with SQH (ES) groups were administered saline and SQH (50 mg/kg of body weight), respectively, every day for 7 days and underwent swimming exercise. RNA sequencing technology was used to analyze the transcriptome profiles of muscle. RESULTS: Swimming times were prolonged in the ES group compared with the EC group. The ES group had higher blood glucose and lower blood lactate levels, and higher muscular glycogen and lower muscular lactate levels, compared with the EC group. The groups did not differ in histopathological parameters of the muscle and liver, but muscle cell sizes were smaller in the EC group than in the ES and NC groups. RNA sequencing analysis revealed that SQH administration regulated genes associated with energy-generating metabolic pathways in skeletal muscle. CONCLUSION: These results suggest that SQH exerts anti-fatigue properties by balancing various biological systems and helping maintain the basic harmonious pattern of the body. PMID- 30448903 TI - Dietary regulation of metastasis. AB - The impact of diet and associated lifestyle choices on the risk of developing cancer is well established. However, whether these parameters also affect cancer recurrence and survival is less well investigated. Virtually nothing is known about the impact of diet on the development of metastases. It is therefore significant that a study in this issue of Clinical and experimental metastasis reports that breast cancer-bearing mice fed on a diet rich in long-chain omega-3 fatty acids had a lower incidence of metastasis than control mice, which was associated with modified infiltration of immune cells into the tumors. These findings should form the basis of further pre-clinical evaluation with a view to clinical application. PMID- 30448904 TI - Triptolide modulates tumour-colonisation and anti-tumour effect of attenuated Salmonella encoding DNase I. AB - The strong human immunity and the associated toxicities of attenuated Salmonella severely limit the clinical use of Salmonella in tumour suppression. In the present study, we constructed an engineered VNP20009-DNase I strain and evaluated the synergistic effects of triptolide (TPL) and VNP20009-DNase I against melanoma in mice. Our results indicated that TPL could significantly inhibit the cell growth and cell migration and significantly enhanced the apoptosis rate of B16F10 cells in vitro. The in vivo results indicated that TPL markedly improved tumour colonisation of VNP20009-DNase I and led to a larger necrotic area in the melanoma. Moreover, the combination therapy significantly suppressed tumour volume and prolonged the life span of mice (P < 0.05) by upregulating the expression of Bcl-2/Bax and Caspase-3 and by downregulating the TLR4/NF-kappaB signalling, the expression of p-AKT/AKT and the production of proinflammatory factors. Therefore, the sound synergistic anti-tumour effects of TPL and VNP20009 DNase I indicate that the unconventional application of TPL and biological agents, approved by the China Food and Drug Administration (CFDA), can result in improved anti-cancer therapeutic outcomes. PMID- 30448905 TI - Insights into regulatory roles of MAPK-cascaded pathways in multiple stress responses and life cycles of insect and nematode mycopathogens. AB - Fungal entomopathogenicity may have evolved at least 200 million years later than carnivorism of nematophagous fungi on Earth. This mini-review focuses on the composition and regulatory roles of mitogen-activated protein kinase (MAPK) cascades, which act as stress-responsive signaling pathways. Unveiled by genomic comparison, three MAPK cascades of these mycopathogens consist of singular MAPKs (Fus3/Hog1/Slt2), MAPK kinases (Ste7/Pbs2/Mkk1), and MAPK kinase kinases (Ste11/Ssk2/Bck1). All cascaded components characterized in fungal entomopathogens play conserved and special roles in regulating multiple stress responses and phenotypes associated with biological control potential. Fus3 cascaded components are indispensable for fungal growth on oligotrophic substrata and virulence, and mediate cell tolerance to Na+/K+ toxicity, which is often misinterpreted as hyperosmotic effect but readily clarified by transcriptional changes of Na+/K+ ATPase genes and/or cell responses to osmotic polyols. Hog1 cascaded components regulate osmotolerance positively and phenylpyrrole-type fungicide resistance negatively, and also play differential roles in cell growth, conidiation, virulence, and responses to other stress cues. Ste11 has no stress responsive role in the Beauveria Hog1 cascade despite an essential role in branched yeast Hog1 cascade. Slt2-cascaded components are required for mediation of cell wall integrity and repair of cell wall damage. A crosstalk between Hog1 and Slt2 cascades ensures fungal osmotolerance inside or outside insect. In nematode-trapping fungi, Slt2 is indispensable for cell wall integrity, conidiation, and mycelial trap formation, suggesting that the Slt2 cascade could have evolved along a distinct trajectory required for fungal carnivorism and dispersal/survival in nematode habitats. Altogether, the MAPK cascades are major parts of signaling network that regulate fungal adaptation to insects and nematodes and their habitats. PMID- 30448906 TI - Sustainable production of glutathione from lignocellulose-derived sugars using engineered Saccharomyces cerevisiae. AB - Glutathione has diverse physiological functions, and therefore, the demand for it has increased recently. Currently, industrial mass production of glutathione is performed from D-glucose via fermentation by the budding yeast Saccharomyces cerevisiae. However, use of D-glucose often competes with demands for various other industries, leading to high production costs. To affordably produce glutathione, we aimed to produce high amounts of glutathione from D-glucose and D xylose, which are the main constituents of lignocellulosic biomass pre-treated with acids. Genetically engineered S. cerevisiae strains that can produce high amounts of glutathione and assimilate D-xylose were constructed and cultured in media containing D-xylose. Among these recombinant strains, a S. cerevisiae GCI (XR/XDH/XK) strain over-expressing gamma-glutamylcysteine synthetase, glutathione synthetase, D-xylose reductase, xylitol dehydrogenase, and xylulokinase genes successfully consumed D-xylose in the medium and produced the highest amount of glutathione. When strains were grown in media containing D-glucose and D-xylose, the GCI (XR/XDH/XK) strain showed 4.6-fold higher volumetric glutathione production (mg/L-broth), 2.2-fold higher glutathione content (%), and 2.1-fold higher cell growth (g-cell/L-broth) than the vector control strain of YPH499 (Vector). Furthermore, when recombinant S. cerevisiae strains were grown in medium containing fermentation inhibitory materials, the GCI (XR/XDH/XK) strain produced 5.8- and higher volumetric glutathione, 2.6-fold higher intracellular glutathione, and 2.9-fold higher cell growth than the vector control YPH499 (Vector) strain. The gradual sugar consumption by recombinant S. cerevisiae strains in medium containing D-glucose and D-xylose leads to high yields of glutathione. These results indicate the potential for glutathione production from lignocellulosic materials. PMID- 30448907 TI - The Constitutive Expression of a Chrysanthemum ERF Transcription Factor Influences Flowering Time in Arabidopsis thaliana. AB - AP2/ERF transcription factors (TFs) represent valuable targets for the genetic manipulation of crop plants, as they participate in the control of metabolism, growth and development, as well as in the plants' response to environmental stimuli. Here, an ERF TF encoded by the chrysanthemum (Chrysanthemum morifolium) genome, designated CmERF110, was cloned and functionally characterized. The predicted CmERF110 polypeptide included a conserved DNA-binding AP2/ERF domain. A transient expression experiment revealed that the protein was deposited in the nucleus, and a transactivation experiment in yeast suggested that it had no transcriptional activity. The gene was transcribed in the chrysanthemum root, stem and leaf, with its transcript level following a circadian rhythm under both long and short days. The effect of constitutively expressing the gene in Arabidopsis thaliana was to accelerate flowering. Transcriptional profiling implied that its effect on floral initiation operated through the photoperiod pathway. PMID- 30448908 TI - DNA Vaccine Targeting Gonadotropin-Releasing Hormone Receptor and Its Application in Animal Contraception. AB - Overpopulation of free-roaming and wildlife animals negatively affects economy and public health in many parts of the world. Contraceptive vaccines are viewed as a valuable option for reducing numbers of unwanted animals. This study develops vaccines for potential use in animal contraception exploiting a DNA platform. Objectives of the study were to generate DNA constructs directed against gonadotropin-releasing hormone receptor (GnRHR), a crucial molecular player in animal reproduction, and characterize them for ability to promote immune responses and suppression of reproductive parameters in vivo. DNA constructs were created to encode for a recombinant protein composed of two domains: GnRHR, the target antigen, and ubiquitin (Ub), a support protein. Ub GnRHR constructs administered intramuscularly or intradermally or containing different promoters were compared. CMV and EF1alpha promoters were shown to be superior to CAG. In fertility trials, mice immunized intradermally with Ub-GnRHR construct driven by EF1alpha had a significantly lower number of fetuses. Importantly, the impaired fertility was achieved with a single DNA immunization and without the use of adjuvants. The study demonstrated for the first time that targeting the GnRH receptor with DNA-based vaccines could be a viable option for animal contraception. PMID- 30448909 TI - Psychometric Testing of the Chinese Version of Supportive Care Needs Survey for Partners and Caregivers of Cancer Patients. AB - The objective of this study was to test the psychometric properties of the Chinese version of the Supportive Care Needs Survey for Partners and Caregivers (SCNS-P&C-C) among the caregivers of Chinese patients with cancer. The original English version of SCNS-P&C was translated into Chinese using a forward and backward translation approach. The psychometric properties of the SCNS-P&C-C including factor structure, convergent, and discriminative validities and internal consistency were then tested. A convenience sample of 498 caregivers of hospitalized patients with cancer was recruited from oncology units in three tertiary public hospitals in Hefei city, mainland China. Exploratory factor analysis revealed four domains of the SCNS-P&C-C, which resemble the original English version scale. The convergent validity of the SCNS-P&C-C has established with statistically significant correlations between the SCNS-P&C-C and the Chinese version of Kessler Psychological Distress Scale (r = 0.327, P < 0.01). The SCNS-P&C-C has also good internal consistency with Cronbach's alpha coefficients ranging from 0.79 to 0.89 for the four subscales and 0.94 for the total scale. The Chinese version of the SCNS-P&C was found to be reliable and valid to assess the supportive care needs for partners and caregivers of Chinese patients with cancer. The SCNS-P&C-C can be used to assess and understand the supportive care needs of Chinese caregivers of patients with cancer. Such information will help the healthcare professionals to formulate tailored supportive care services for the caregivers of Chinese patients with cancer. PMID- 30448910 TI - A new scale for measuring quality of life in acquired brain injury. AB - PURPOSE: A common and frequent consequence of an acquired brain injury (ABI) is the diminished quality of life (QoL) of affected people. Because the majority of existing QoL instruments assess health-related domains, new instruments that allow for the evaluation of the QoL from an integral perspective that considers the context and personal factors of the individual are warranted. Hence, the purpose of this study is to develop and validate an instrument with these characteristics. METHODS: The CAVIDACE scale is a new 64-item specific instrument to assess QoL in people with ABI based on a third-person perspective. The validation sample comprises 421 adults with ABI, with ages ranging from 17 to 90 years (M = 53.12; SD = 14.87). The scale was completed by 97 professionals and 58 family members. Validity evidence based on the internal structure of the scale was provided through confirmatory factor analyses. Reliability was analyzed in terms of internal consistency and inter-rater reliability. RESULTS: The results supported the internal structure of the scale, based on the theoretical and assessment framework in which QoL is composed of eight intercorrelated first order domains (CFI = 0.890, RMSEA = 0.065, SRMR = 0.071). The internal consistency was good or excellent for the eight domains (ordinal alpha ranging from 0.77 to 0.93). The inter-rater reliability was very high (0.97). CONCLUSIONS: The CAVIDACE scale is found to be a specific instrument with excellent psychometric properties that is helpful for the assessment of QoL in people with ABI, both in clinical practice and for research purposes. PMID- 30448911 TI - Implementing patient-reported outcome measures in clinical practice: a companion guide to the ISOQOL user's guide. AB - PURPOSE: The use of patient-reported outcome (PRO) measures in clinical practice is increasing. Following the creation of a 'User's Guide to Implementing PRO Assessment in Clinical Practice' by the International Society for Quality of Life Research (ISOQOL), volunteers from ISOQOL sought to create a Companion Guide to assist health care providers with the scientific and practical considerations involved in implementing and using PRO measures in clinical care by using information from real-world case studies. This paper summarizes the key issues presented in the Companion Guide. METHODS: Ten respondents, who were members of the ISOQOL's CP-SIG and worked in various clinical areas, participated in a survey or telephone interview. Participants were from Canada (n = 2), Denmark (n = 1), England (n = 2), Holland (n = 1), and the United States (n = 4). RESULTS: Based on the information provided by respondents, a Companion Guide was produced, organized according to the nine questions presented in the User's Guide. An additional section for key take-home messages was also provided. This guide provides examples of issues and considerations related to the implementation of PRO measures in clinical practice. CONCLUSIONS: Respondents provided insight into their experiences and emphasized that PRO initiatives were likely to be more successful if there is purposeful, designed integration into clinical practice, meaningful substantive engagement with all stakeholders and access to necessary organizational resources. The ability to leverage existing technology as well as realistic and stakeholder consensus-driven expectations for planning and timing were also key to the successful implementation of PRO measures. PMID- 30448912 TI - Assessment of TILs, IDO-1, and PD-L1 in resected non-small cell lung cancer: an immunohistochemical study with clinicopathological and prognostic implications. AB - Several cancers, especially non-small cell lung cancer (NSCLC), are able to escape the immunosurveillance of tumor-infiltrating lymphocytes (TILs); among the molecules involved, the indoleamine 2,3-dioxygenase 1 (IDO-1) and the programmed cell death ligand-1 (PD-L1) play a crucial role. These aspects are of great interest in the current immunotherapeutic era, therefore the current study analyses the TILs, IDO-1, and PD-L1 interactions and their correlations with clinicopathological parameters and prognosis in NSCLC. One hundred ninety-three NSCLC surgical specimens, formalin-fixed, and paraffin-embedded were assessed for TILs density, TILs localization, IDO-1 (clone 4.16H1), and PD-L1 (clone E1L3N) immunohistochemical expressions. This data was correlated with clinicopathological parameters, disease free, and overall survivals. IDO-1 and PD L1 high expressions were related to the solid pattern of adenocarcinomas (respectively p = 0.036 and p = 0.026); high PD-L1 expression was correlated with squamous histotype (p = 0.048). IDO-1 overexpression correlated with former smokers (p = 0.041), higher adenocarcinoma stages (p = 0.039), and with both higher TILs density and PD-L1 expression (respectively p = 0.025 and p = 0.0003). A better prognosis was associated with TILs intratumoral or mixed localizations (p = 0.029). TILs localization affects NSCLC prognosis; the higher expression of IDO-1 and PD-L1 in poorly differentiated and more aggressive lung adenocarcinomas, as well as the correlation between high PD-L1 expression and squamous cell histotype, confirm the more efficient immunoescaping of these NSCLC subgroups. PMID- 30448913 TI - Midline preperitoneal repair for incarcerated and strangulated femoral hernia. AB - OBJECTIVE: Femoral hernias constantly present as incarceration or strangulation and require emergency surgery. Incarcerated and strangulated femoral hernia repair remains challenging and controversial. The aim of our study was to analyze the efficacy of preperitoneal tension-free hernioplasty via lower abdominal midline incision for incarcerated and strangulated femoral hernia. METHODS: Data of 47 patients who underwent emergency surgery for incarcerated or strangulated femoral hernias from January 2009 to December 2017 were retrospectively analyzed. According to the surgical incisions, they were divided into two groups: the observation group (21 cases) had a lower abdominal midline incision, and the control group (26 cases) had a traditional inguinal incision. General data of patients, intraoperative findings, operative time and postoperative complications were compared. RESULTS: Patient characteristics showed that the two groups were comparable.15 cases (31.9%) underwent intestinal resection, and 32 cases (68.1%) underwent first-stage tension-free repair in total. The rate of first-stage tension-free hernioplasty was significantly higher in the observation group (18/21, 85.7% vs 14/26 53.8%, P = 0.020). No additional incision was required in the observation group, while six cases of the control group (23.1%) had an additional incision for intestinal resection and anastomosis (P = 0.026). Mean operative time (53.6 +/- 24.7 min vs 77.9 +/- 36.5 min, P = 0.012) and the length of hospital stay (6.3 +/- 4.2 days vs 10.3 +/- 6.9 days, P = 0.020) were significantly shorter in the observation group. The time of return to normal physical activity resulted significantly reduced compared to the control group (9.2 +/- 4.1 days vs 13.3 +/- 6.6 days, P = 0.017). The total incidence of postoperative complication (including chronic pain, foreign body sensation, hernia recurrence, wound infection and seroma/hematomas) in the observation group was lower (14.3% vs 42.3% P = 0.037). There were two recurrences in the control group. No mesh-related infection and no mortalities in two groups. CONCLUSIONS: Midline preperitoneal approach for incarcerated and strangulated femoral hernia is a convenient and effective technique. It can improve the rate of first-stage tension-free repair of incarcerated femoral hernia and allow intestinal resection through the same incision, and with lower rate of postoperative complications. PMID- 30448915 TI - Abstracts of the XXXIX Congress of the Spanish Society of Physiological Sciences (SECF), 18-21 September 2018, Cadiz, Spain. PMID- 30448914 TI - Nano-medicine and Vascular Endothelial Dysfunction: Options and Delivery Strategies. AB - The endothelium is a thin innermost layer of flat cells which release various mediators including endothelin-1 (ET-1), prostanoids, von Willebrand factor (vWF) and endothelium-derived relaxing factor (EDRF; nitric oxide) to regulate vascular tone. Endothelial nitric oxide synthase (eNOS) is a key enzyme that generates nitric oxide (NO). NO maintains vascular homeostasis and cardiac functions by influencing major vascular protective properties such as anti-platelet, anti proliferative, anti-migratory, antioxidant and anti-inflammatory action in vessels. Abnormal endothelial production and release of NO lead to vascular endothelial dysfunction (VED) and further leads to pathogenesis in myocardial and other tissues. Numerous pharmacological agents such as angiotensin-converting enzyme inhibitors, statins, calcium channel blockers, ET-1 receptor antagonists, insulin sensitizers, antioxidants and supplements like tetrahydrobiopterin, arginine and folate have been implicated in the treatment of VED, but their therapeutic potency was restricted due to some unavoidable adverse effects. The new era with advances in nanotechnology and its ability to target a specific disease, nano-medicine explored an innovative gateway for advanced therapy for VED. The present commentary reveals the various available, pipeline nano medicine, their interaction with endothelium and in other associated pathological conditions and their delivery strategies for target-specific treatment of VED. PMID- 30448916 TI - Diagnostic performance of MRI- versus MDCT-categorized T3cd/T4 for identifying high-risk stage II or stage III colon cancers: a pilot study. AB - PURPOSE: The aim of this study was to determine the diagnostic performance of magnetic resonance imaging (MRI)-categorized T3cd/T4 tumors for identifying high risk stage II or stage III cancer in patients with curatively resectable colon cancer in comparison to that of multidetector computed tomography (MDCT). MATERIALS AND METHODS: Thirty-eight patients with histopathologically indicated adenocarcinomas prospectively underwent MRI of the colon. Two radiologists independently and retrospectively assessed for T-category, including T3 substage (<= T3ab vs. >= T3cd). The diagnostic accuracies and interreader agreements between assessments using each modality were compared using a pairwise comparison of receiver-operating characteristic curves and a weighted kappa statistic, respectively. RESULTS: Twenty-nine patients (76.3%) were histopathologically diagnosed with high-risk stage II or stage III colon cancer. The false-positive rate with MRI was lower than that with MDCT (0% vs. 7.9% for reader 1, 2.6% vs. 10.6% for reader 2). The diagnostic performance of MRI was better than that of MDCT across both readers (AUC: 0.707 vs. 0.506 [P = 0.032] for reader 1, 0.651 vs. 0.485 [P = 0.055] for reader 2). Moreover, MRI interreader agreement for the assessment of T3cd/T4 was significantly better than that of MDCT (kappa = 0.821 vs. 0.391 [P = 0.017]). CONCLUSION: The diagnostic performance of MR imaging of the colon may be better than that of MDCT for identifying high-risk stage II or stage III cases. Particularly, colon MRI reduced the false-positive rate and improved the interreader agreement, although further studies with a larger sample size are required. PMID- 30448917 TI - The hepatoduodenal ligament revisited: cross-sectional imaging spectrum of non neoplastic conditions. AB - INTRODUCTION: The hepatoduodenal ligament is frequently involved by conditions affecting the portal triad and surrounding structures, including a vast array of non-neoplastic conditions. Due its unique location between the retroperitoneum and the peritoneal space, the hepatoduodenal ligament is also targeted by inflammatory conditions involving the retroperitoneum and the liver. Finally, the presence of lymphatics and of the biliary tracts makes the hepatoduodenal ligament a route of spread for a variety of infections. The purpose of this pictorial essay is twofold: to review the cross-sectional radiological anatomy and variants of the structures within the hepatoduodenal ligament, and to illustrate the non-neoplastic conditions that may arise within the hepatoduodenal ligament. CONCLUSION: Familiarity with these specific entities and their cross sectional imaging findings is fundamental for a more accurate diagnosis. PMID- 30448918 TI - Evaluation of biliary anatomy in the caudate lobe using drip infusion cholangiography-computed tomography. AB - PURPOSE: This study aimed to retrospectively evaluate the caudate branches (CBs), which are bile ducts originating from the caudate lobe (CL), using drip infusion cholangiography with computed tomography (DIC-CT). METHODS: The confluence patterns of CBs were evaluated in 185 adult patients undergoing DIC-CT. The following bile duct features were evaluated: (a) number of depicted CBs; (b) identification of the caudate portion from which the CBs were derived; (c) identification of the confluence site of a CB; and (d) whether there was a difference in the confluence site of the CBs depending on the position of the right posterior hepatic duct (RPHD) and the portal vein (PV). RESULTS: DIC-CT enabled detection of a total of 640 bile ducts from the CL in 185 patients, and the total number of CBs from the Spiegel lobe (SP), the paracaval portion, and the caudate process (CP) were 347 (54.2%), 112 (17.5%), and 181 (28.2%), respectively. In the SP, over 60% of CBs joined the left hepatic duct system (LHDS). The positional relationship between the RPHD and the PV was divided into a supra-portal course (n = 168) and an infra-portal course (n = 17). The number of CBs joining the LHDS was significantly different between a supra-portal course and an infra-portal course (p = 0.0484). CONCLUSION: CBs were depicted by DIC-CT in 98.9% of the subjects, and a detailed evaluation was possible. The number of CBs joining the LHDS was associated with the position of the RPHD and the PV. PMID- 30448919 TI - The ovarian "string-of-pearls" sign. PMID- 30448920 TI - A review of the principles of texture analysis and its role in imaging of genitourinary neoplasms. AB - Advances in the management of genitourinary neoplasms have resulted in a trend towards providing patients with personalized care. Texture analysis of medical images, is one of the tools that is being explored to provide information such as detection and characterization of tumors, determining their aggressiveness including grade and metastatic potential and for prediction of survival rates and risk of recurrence. In this article we review the basic principles of texture analysis and then detail its current role in imaging of individual neoplasms of the genitourinary system. PMID- 30448922 TI - Differential Response of Cafeteria roenbergensis to Different Bacterial and Archaeal Prey Characteristics. AB - In the marine environment, the abundance of Bacteria and Archaea is either controlled bottom-up via nutrient availability or top-down via grazing. Heterotrophic nanoflagellates (HNF) are mainly responsible for prokaryotic grazing losses besides viral lysis. However, the grazing specificity of HNF on specific bacterial and archaeal taxa is under debate. Bacteria and Archaea might have different nutritive values and surface properties affecting the growth rates of HNF. In this study, we offered different bacterial and archaeal strains with different morphologic and physiologic characteristics to Cafeteria roenbergensis, one of the most abundant and ubiquitous species of HNF in the ocean. Two Nitrosopumilus maritimus-related strains isolated from the northern Adriatic Sea (Nitrosopumilus adriaticus, Nitrosopumilus piranensis), two Nitrosococcus strains, and two fast growing marine Bacteria (Pseudoalteromonas sp. and Marinobacter sp.) were fed to Cafeteria cultures. Cafeteria roenbergensis exhibited high growth rates when feeding on Pseudoalteromonas sp., Marinobacter sp., and Nitrosopumilus adriaticus, while the addition of the other strains resulted in minimal growth. Taken together, our data suggest that the differences in growth of Cafeteria roenbergensis associated to grazing on different thaumarchaeal and bacterial strains are likely due to the subtle metabolic, cell size, and physiological differences between different bacterial and thaumarchaeal taxa. Moreover, Nitrosopumilus adriaticus experienced a similar grazing pressure by Cafeteria roenbergensis as compared to the other strains, suggesting that other HNF may also prey on Archaea which might have important consequences on the global biogeochemical cycles. PMID- 30448923 TI - Right colectomy: consecutive 100 patients treated with laparoscopic and robotic technique for malignancy. Cumulative experience in a single centre. AB - Robotic-assisted resections prove beneficial in overcoming potential limitation of laparoscopy, but clear evidences on patient's benefits are still lacking. We report our experience on 100 consecutive patients who underwent right colectomy with either robotic or laparoscopic approaches. Data were prospectively collected on a dedicated database (ASA score, age, operative time, conversion rate, re operation rate, early complications, length of stay, and pathological results). Median total operative time was 160 min in LS group (IQR = 140-180) and 204 min for RS group (IQR = 180-230). Median time to first flatus was 2.5 days for LS group (IQR = 2 - 3) and 2 days for RS group (IQR = 1-2). Length of stay (median) was 8 days in LS group (IQR = 6-10) and 5 days in RS group (IQR = 5-7). No statistically significant difference was found between the 2 groups when the number of harvested nodes, the anastomotic leakage and the postoperative bleeding were analyzed. The 30-day mortality was 0% in LS and RS groups. Conversion rate for LS group was 14% (7/50 pts) and for RS group was 0% (0/50). Minimally invasive surgery is a feasible and safe technique. The RS may overcome some technical limitations of laparoscopic surgery and it achieves the same oncological results compared to LS but with higher costs. The lower conversion rate allows to expect better clinical outcomes and lower complication rate. PMID- 30448921 TI - Probing the mechanism of SIRT1 activation by a 1,4-dihydropyridine. AB - The NAD+-dependent deacetylase SIRT1 plays important roles in several physiological processes such as transcription, genome stability, stress responses, and aging. Due to its diverse role in metabolisms, SIRT1 has emerged as a potential therapeutic target in many human disorders such as type II diabetes, cardiovascular and neurodegenerative diseases, and cancer. Recent studies have reported that modulation of SIRT1 activity by phenolic activators like resveratrol and some 1,4-dihydropyridines (1,4-DHPs) can inhibit tumor growth by promoting apoptosis in cancer cells. However, the mechanism of SIRT1 activation is still not clear. In this report, we have tried to elucidate the mechanism of SIRT1 activation from studies on its interaction with a synthetic 1,4-DHP derivative (DHP-8; 3,5-diethoxy carbonyl-4-(4-nitrophenyl)-2,6-dimethyl 1,4-dihydropyridine) using molecular modeling, docking, simulation, and free energy analyses. Owing to the absence of full-length human SIRT1 structure, multi template based modeling approach was opted followed by docking of DHP-8 at its allosteric site. In presence of DHP-8, the overall conformation of SIRT1 was found to be more stable (especially at its substrate binding sites) with a large structural variation at its N-terminal domain while bound to substrate p53 or p53 W. Determination of the MM/PBSA free energy indicated that the binding of DHP-8 to SIRT1 significantly increased the binding affinity of SIRT1 to its substrate p53-W as well as to NAD+. Overall, this study depicts the atomistic detailed mechanism for the direct activation of SIRT1 by a 1,4-DHP. This would serve to develop new SIRT1 activators for future therapeutic perspectives. PMID- 30448924 TI - Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers. AB - The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-gamma (IFN-gamma) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN gamma before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p < 0.001). Furthermore, in the pN+ population, patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year DFS and OS. PD-L1 and IFN-gamma upregulation increased in tumor tissues after neoCRT, and patients with high PD-L1 and high IFN-gamma exhibit improved 5-year DFS and OS (p = 0.04 and p = 0.001, respectively). To the best of our knowledge, this study is the first to demonstrate that PD-L1 upregulation in a pN+ cohort correlates with improved prognosis, which is similar to that in patients without nodal metastasis. Moreover, this study verified that PD-L1 and IFN-gamma were upregulated by neoCRT treatment in LARC patients and demonstrated that neoCRT may be useful not only for immune checkpoint inhibitor treatment but also for reinvigorating preexisting anti-cancer immunity. PMID- 30448925 TI - Patterns of microchromosome organization remain highly conserved throughout avian evolution. AB - The structure and organization of a species genome at a karyotypic level, and in interphase nuclei, have broad functional significance. Although regular sized chromosomes are studied extensively in this regard, microchromosomes, which are present in many terrestrial vertebrates, remain poorly explored. Birds have more cytologically indistinguishable microchromosomes (~ 30 pairs) than other vertebrates; however, the degree to which genome organization patterns at a karyotypic and interphase level differ between species is unknown. In species where microchromosomes have fused to other chromosomes, they retain genomic features such as gene density and GC content; however, the extent to which they retain a central nuclear position has not been investigated. In studying 22 avian species from 10 orders, we established that, other than in species where microchromosomal fusion is obvious (Falconiformes and Psittaciformes), there was no evidence of microchromosomal rearrangement, suggesting an evolutionarily stable avian genome (karyotypic) organization. Moreover, in species where microchromosomal fusion has occurred, they retain a central nuclear location, suggesting that the nuclear position of microchromosomes is a function of their genomic features rather than their physical size. PMID- 30448926 TI - Casticin inhibits esophageal cancer cell proliferation and promotes apoptosis by regulating mitochondrial apoptotic and JNK signaling pathways. AB - Casticin, a flavonoid isolated from Vitex species, has been found to have anti tumor property in multiple human cancers. The present study aimed to investigate the effect of casticin on the proliferation and apoptosis of esophageal cancer (EC) cells, and further illustrate the underlying mechanisms. In in vitro studies, human EC cell lines TE-1 and ECA-109 were treated with various concentrations of casticin (low-, middle-, and high-dose groups). The results showed that casticin dose-dependently inhibited the proliferation and clonogenicity of EC cells and induced cell cycle arrest in sub-G1 and G2 phases. Furthermore, casticin markedly enhanced EC cell apoptosis as detected by flow cytometry and Hoechst 33342 staining. The level of anti-apoptotic Bcl-2 protein was decreased, while the levels of pro-apoptotic Bax, cleaved-caspase-3, cleaved caspase-9, and cleaved-PARP were conversely increased in casticin-treated TE-1 and ECA-109 cells. Moreover, casticin decreased the mitochondrial membrane potential and increased the release of mitochondrial cytochrome C into cytoplasm. In addition, the JNK signaling pathway was involved in casticin-medicated anti proliferation and pro-apoptosis. Cells pretreated with SP600125, a JNK pathway inhibitor, partially abolished the effect of casticin. Finally, the anti-tumor property of casticin was confirmed in in vivo xenograft models. Overall, we provided both in vitro and in vivo evidences that casticin inhibited the proliferation and induced apoptosis of EC cells, and the anti-tumor action of casticin was mediated, in part, by the mitochondrial-dependent apoptosis and the activation of JNK signaling pathway. PMID- 30448927 TI - Interactions between mitochondria and endoplasmic reticulum in demyelinated axons. AB - Demyelination leads to axonal changes that involve the functions and dynamics of axonal mitochondria supporting metabolism and survival of axons. However, the changes in the physical interactions between mitochondria and endoplasmic reticulum, called mitochondria-associated membranes, are poorly understood in demyelinated axons. In this study, we investigated the three-dimensional ultrastructural changes in membrane juxtapositions between mitochondria and endoplasmic reticulum in axons of a chronic progressive demyelination mouse model caused by extra copies of proteolipid protein (PLP4e). In the optic nerve of PLP4e mice, most axons were ensheathed by myelin by age 1 month, but were demyelinated by age 5 months. At age 1 month, mitochondria in PLP4e mice were slightly larger than those in wild-type mice, while the size and frequency of juxtaposition were similar. At age 5 months, the sizes of mitochondria and size of juxtaposition in PLP4e mice were prominently larger than those in wild-type mice. In degenerating axons under demyelination, the enlargement of mitochondria was diminished, while the density and frequency of juxtaposition were similar to those of non-degenerating axons. These results suggest that interactions between mitochondria and ER are enhanced in chronically demyelinated axons and maintained during axonal degeneration in hereditary myelin diseases. PMID- 30448928 TI - Neuroprotective Mechanism of Hypoxic Post-conditioning Involves HIF1-Associated Regulation of the Pentose Phosphate Pathway in Rat Brain. AB - Post-conditioning is exposure of an injured organism to the same harmful factors but of milder intensity which mobilizes endogenous protective mechanisms. Recently, we have developed a novel noninvasive post-conditioning (PostC) protocol involving three sequential episodes of mild hypobaric hypoxia which exerts pronounced neuroprotective action. In particular, it prevents development of pathological cascades caused by severe hypobaric hypoxia (SH) such as cellular loss, lipid peroxidation, abnormal neuroendocrine responses and behavioural deficit in experimental animals. Development of these post-hypoxic pathological effects has been associated with the delayed reduction of hypoxia-inducible factor 1 (HIF1) regulatory alpha-subunit levels in rat hippocampus, whereas PostC up-regulated it. The present study has been aimed at experimental examination of the hypothesis that intrinsic mechanisms underlying the neuroprotective and antioxidant effects of PostC involves HIF1-dependent stimulation of the pentose phosphate pathway (PPP). We have observed that SH leads to a decrease of glucose 6-phosphate dehydrogenase (G6PD) activity in the hippocampus and neocortex of rats as well as to a reduction in NADPH and total glutathione levels. This depletion of the antioxidant defense system together with excessive lipid peroxidation during the reoxygenation phase resulted in increased oxidative stress and massive cellular death observed after SH. In contrast, PostC led to normalization of G6PD activity, stabilization of the NADPH and total glutathione levels and thereby resulted in recovery of the cellular redox state and prevention of neuronal death. Our data suggest that stabilization of the antioxidant system via HIF1-associated PPP regulation represents an important neuroprotective mechanism enabled by PostC. PMID- 30448929 TI - The use of steroids to reduce complications after tonsillectomy: a systematic review and meta-analysis of randomized controlled studies. AB - OBJECTIVES: To systemically review and compare the efficacy of intravenous, local, and oral steroids in decreasing post-tonsillectomy pain, nausea, and vomiting, and its risk of causing hemorrhage. METHODS: We searched electronic databases (PubMed, Scopus, Cochrane Library) and additional sources. The date of the most recent search was June 20th, 2018. We selected RCTs of steroids in all routes of administration, in all age groups who underwent tonsillectomy or adenotonsillectomy and studied the results of nausea/vomiting, pain, and hemorrhage. Data analysis was done using Review Manager 5.3.5 software. RESULTS: We included 64 studies (6,327 participants) with variety quality assessed by the Cochrane Handbook for Systematic Reviews of Interventions. IV steroids statistically and clinically significant decrease post-tonsillectomy nausea/vomiting in children and adult, with superior effect to local steroids (Children: OR 0.21; 95% CI 0.15-0.30; P < 0.001, I2 = 67%, Adult: OR 0.32; 95% CI 0.16-0.67; P = 0.002, I2 = 40%). In the analysis of local steroids studies, there was only evidence in children that local steroids decrease post-tonsillectomy nausea/vomiting (OR 0.54; 95% CI 0.33-0.88; P = 0.01, I2 = 32%). IV and local steroids statistically significant decrease immediate post-operative pain severity. Local steroids had extended effect in reducing pain scores on the first day after tonsillectomy. However, the clinical significance of pain relief had to be concerned due to decreasing VAS only about 1 out of 10. Adding oral steroids to IV steroids gave no difference in effect from IV steroids alone. There are very few local steroids studies in adults and oral steroids studies to show the significant effects. Steroids have no statistically significant effect in reducing pain severity after a 1-day period. Steroids in all routes had no statistically significant effects on post-operative hemorrhage (primary hemorrhage: OR 0.96; 95% CI 0.55-1.67; P = 0.88, I2 = 0%; secondary hemorrhage: OR 1.05; 95% CI 0.74-1.51; P = 0.79, I2 = 0%). CONCLUSION: Intravenous steroids statistically significantly decrease post-tonsillectomy nausea/vomiting, and immediate pain scores (< 24 h) in children and adults. There is evidence in only children that local steroids statistically significantly decreases post tonsillectomy nausea/vomiting, and pain scores during the 0-h to 1-day period. PMID- 30448930 TI - Support for Autonomy at School Predicts Immigrant Adolescents' Psychological Well being. AB - We investigated the relationship between teacher support at school intended to promote students' autonomy and immigrant adolescents' psychological well-being. A structural equation model was tested on 3130 immigrant adolescents who attended a representative sample of 654 Italian high schools. Gender, socioeconomic status, previous school achievement and immigrant generation were included in the analysis as control variables. Results showed that when teachers are perceived as adopting an approach that is supportive of autonomy, immigrant adolescents report significantly higher levels of psychological well-being. Gender appears to be the most relevant background factor, with girls being more at risk than boys as regards mental health. Overall, our findings suggest that interventions of enacted support by teachers at school that aim to foster students' autonomy would be an effective approach for protecting against mental illness in immigrant adolescents. PMID- 30448931 TI - Rapid detection of OXA-48-like, KPC, NDM, and VIM carbapenemases in Enterobacterales by a new multiplex immunochromatographic test. AB - The rapid detection of carbapenemase-producing Gram-negative bacteria is indispensable to optimize treatment and avoid the further spread of these organisms. While phenotypic tests are time-consuming and PCR is expensive and not available in many routine laboratories, immunochromatographic tests (ICT) can provide rapid results at moderate cost. The aim of this study was to determine the performance of the new ICT RESIST-4 O.K.N.V. K-SeT (Coris BioConcept, Gembloux, Belgium) which can detect the four most prevalent carbapenemases: OXA 48-like, KPC, NDM, and VIM. Additionally, we analyzed the impact of different culture conditions on the sensitivity. The new ICT was challenged with 169 carbapenem-resistant isolates. Of these, 125 were carbapenemase producers: 43 OXA 48-like, 15 KPC, 29 NDM, and 43 VIM. The ICT correctly detected 129 of the 130 carbapenemases resulting in a sensitivity of 99.2% and specificity of 100% when tested from Mueller-Hinton agar (MHA). The sensitivity of the assay increased to 100% when performed from zinc-supplemented MHA and sheep blood agar (SBA) or when the inoculum was harvested from the inhibition zone of an ertapenem disk. All carbapenemase-negative carbapenem-resistant bacteria tested negative and no cross reaction was observed. The new ICT is an excellent test for rapid diagnostic of carbapenemase-producing Gram-negatives in the routine laboratory. It is easy to handle and provides rapid results with a high sensitivity. For best results, we recommend to obtain the inoculum from a medium with sufficient zinc or from the inhibition zone of an ertapenem disk. PMID- 30448932 TI - Potential uses of an infodemiology approach for health-care services for rheumatology. AB - OBJECTIVES: This is a demand-based infodemiology study using the Google Trends and AdWords tools to illustrate infodemiology's potential use in rheumatology. The study investigates three questions in North American countries: (1) What terms associated with "rheumatology" and "arthritis" do people search for on Google? (2) What is the search volume for disease-modifying antirheumatic drugs (DMARDs)? and (3) What is the search volume for the term "arthritis" compared with for "hepatitis C" and "breast cancer"? METHODS: We conducted independent searches by country and search term for 2015-2017. Seventeen DMARDs were searched for 2015 through May 2018, with the turmeric remedy included for comparison. Data were exported to Excel for further analysis, adjusted by country population, and expressed as searches per 100,000 inhabitants (SpTh). RESULTS: There were approximately 550 associated terms for "arthritis" in each country, and 5679 SpTh for DMARDs across the three countries. Searches for turmeric numbered slightly lower than for all DMARDs together in Canada and the USA, but were 70% higher in Mexico. Turmeric was also searched four times more than the most-searched biological DMARD in Canada and the USA, and 60 times more in Mexico. Arthritis was more commonly searched for in Canada than hepatitis C and breast cancer, but hepatitis C was highest in the USA and breast cancer in Mexico. Monthly trends did not show expected peaks associated with arthritis awareness campaigns. CONCLUSION: Infodemiology provides preliminary information that could help in generating hypotheses, assessing health-care interventions, or even in providing patient-centered care. PMID- 30448933 TI - Optimal care for systemic sclerosis patients: recommendations from a patient centered and multidisciplinary mixed-method study and working conference. AB - INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune disease with multiorgan involvement. OBJECTIVE: Identify preferences and priorities among patients and health care professionals regarding care for SSc patients in The Netherlands. Develop ideas to improve quality of care. METHODS: A structured approach was followed to collect information from different perspectives to prepare a working conference. Qualitative and quantitative data from patients (n = 650), rheumatologists (n = 167), nurses (n = 51), and health professionals (n = 85) from regional centers and university hospitals were collected. In February 2018, a working conference was organized. Seventy-seven persons (including 10 SSc patients) from different backgrounds discussed the identified themes and survey results. Ideas to improve health care were formulated and prioritized using nominal group technique. RESULTS: Five key themes were identified: (1) shared care and multidisciplinary collaboration, (2) medical data exchange, (3) information for both patients and health care professionals, (4) patient empowerment, and (5) non-pharmacological care. Shared care was the preferred model of care in 49% of patients and 82% of physicians. However, current collaboration structures, especially between hospitals, should be improved. Suggestions for improvements were explicitly formulated agreements about referral, clear task division, treatment coordination, and exploration of novel ways to exchange medical records. The creation of a national web-based information hub was highly prioritized. CONCLUSION: In this mixed-method study, broad-based consensus was achieved and recommendations were developed to improve health care for SSc patients. The approach, recommendations, and challenges summarized in this paper can be of use for health care professionals and other actors involved in patients with rare, chronic, and multisystem conditions. PMID- 30448934 TI - Association of work instability with fatigue and emotional status in patients with ankylosing spondylitis: comparison with healthy controls. AB - INTRODUCTION/OBJECTIVE: Ankylosing spondylitis (AS) is usually seen in among younger person of working age and carries a significant economic burden. It was aimed to explore the relation of work instability with fatigue, depression, and anxiety in working AS patients comparing with healthy controls. METHOD: This case control study was conducted on working 61 AS patients and 40 sex-age-matched working healthy controls. The data were collected using Visual analogue scale pain, Bath AS Disease Activity Index, Bath AS Functional Index, Bath AS Metrology Index in patients; and Beck Depression Inventory, Beck Anxiety Inventory, Multidimensional Assessment of Fatigue, AS Work Instability Scale in all participants. Data were analyzed by SPSS, using chi-squared test, Mann-Whitney U test, Kruskal-Wallis test, Spearman correlation analysis, and multivariate linear regression analysis. RESULTS: Depression, fatigue, and work instability scores were significantly higher in patients than controls (p < 0.05). Clinical parameters (except spinal mobility) showed a significant worsening across the levels of work instability in patients (p < 0.05) and work instability scores were positively correlated with all clinical parameters except spinal mobility (p < 0.001). There was a weak correlation between work instability and spinal mobility (p < 0.05). Fatigue (p < 0.001), pain, and functional capacity scores (p < 0.05) were found to be influential variables on work instability scores. CONCLUSION: The results of this study demonstrated that fatigue and depressive symptoms had negative effect on work instability beside pain, disease activity, and functionality in patients with AS. The recognition and improvement of fatigue and depression may lead to reduced risk of job loss in these patients. PMID- 30448935 TI - The frequency of infections in patients with juvenile idiopathic arthritis on biologic agents: 1-year prospective study. AB - INTRODUCTION: The most effective and concurrently the safest treatment regimen selection is important to provide early control of juvenile idiopathic arthritis (JIA) and to have an acceptable quality of life. The effectivity of biologic agents as well as standard disease-modifying drugs is well documented in treatment of JIA. In spite of their high benefit, these drugs have the risk of serious infections. Herein, we conducted a prospective study to investigate the infectious complications of biologic agents in patients diagnosed with JIA. METHODS: Patients on biologic treatment regimen were examined by the pediatric infectious disease specialist in every 2 months during 1-year long. RESULTS: Throughout the study period, 57% (n:175) of the patients developed infection and 43% (n:132) of them completed this period without any infection. Upper respiratory tract infections which were treated in outpatient clinic were the most common infection. Only three serious infections (two pneumonia, one pleural effusion), which required hospitalization, developed. The infection rate was highest in systemic JIA and lowest in enthesitis-related arthritis (p < 0.001). The total rate of infection development after 1-year period was lowest for etanercept; it was highest for the patients on infliximab treatment (p < 0.001). CONCLUSION: We comment that the altered immune system of JIA can be responsible from the serious infections irrespective of immunosuppressive therapy. Biologic agents can be safely used in JIA evaluating the loss and benefit statement. PMID- 30448936 TI - The influence of exercise training dose on fasting acylated ghrelin concentration in older women. AB - This study investigated if exercise dose affected acylated ghrelin response to exercise training, and how body weight or fat mass changes might affect the responses. Non-obese older women (n = 49) were randomly assigned to 4-month moderate-intensity aerobic exercise of one of two doses (8 or 14 kcal kg-1 body weight weekly). Following exercise training, fasting acylated ghrelin concentrations changed differently between the two groups (p for group * time interaction = 0.050). It decreased in the moderate-dose (Cohen's d = 0.52, p = 0.019), but did not change in the low-dose exercise group. Adjustment for weight or fat changes did not affect these results. Therefore, exercise training dose can have specific effects on acylated ghrelin that are not dependent on weight or fat loss. However, whether the different acylated ghrelin changes are associated with differing degree of subsequent weight maintenance worth further investigation. PMID- 30448937 TI - Low occurrence of hemosporidian parasites in the Neotropic cormorant (Phalacrocorax brasilianus) in Chile. AB - Hemosporidian parasites rarely infect aquatic birds. Few studies have been conducted in South America identifying some lineages of the genera Plasmodium, Leucocytozoon, and Haemoproteus, but none has been done in the Neotropic cormorant (Phalacrocorax brasilianus). This species is widely distributed through the American continent, from Southern USA to Tierra del Fuego, using a wide range of aquatic habitats. We molecularly studied the occurrence and diversity of hemosporidian lineages infecting individuals of Neotropic cormorant across a broad latitudinal gradient in Chile (Arica to Tierra del Fuego). As expected, a very low occurrence of individuals infected by Plasmodium sp. (4/123, 3.3%) and Leucocytozoon sp. (2/123, 1.6%) was detected. We found no evidence of Haemoproteus sp. We identified one lineage of Plasmodium (ZEMAC01) and one new lineage of Leucocytozoon (PHABRA01) infecting cormorants. Individuals infected by Plasmodium sp. were birds from only one site (i.e., Chillan), whereas Leucocytozoon sp. was found in one bird from Valdivia and another one from Tierra del Fuego. Our results expand the known range of hemosporidian parasite lineages in aquatic birds providing an essential baseline data that contribute to a better understanding of the geographic range of hemosporidian parasites infecting Phalacrocoracidae in South America. PMID- 30448938 TI - Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation. AB - A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m2), intravenous BU (12.8 mg/kg), and melphalan (100 mg/m2) (FLU/BU4/MEL) and conducted retrospective analyses of treatment outcomes at our institute. Forty-two patients with myeloid malignancies received allogeneic bone-marrow transplantation or peripheral blood stem-cell transplantation (allo-BMT/PBSCT) with FLU/BU4/MEL regimen. The median age of patients was 46.5 years (20-63 years). Thirteen patients (31%) did not achieve complete hematological remission at transplantation. All patients examined achieved complete whole and T-cell chimerism within 1 month after allo-HCT. The 4 year overall survival and disease-free survival rates were 66.0% [95% confidence interval (CI) 49.4-78.3%] and 59.5% (95% CI 43.2-72.6%) in all patients, and 49.4% (95% CI 19.7-73.6%) and 38.5% (95% CI 14.1-62.8%) in patients who were not in remission. In conclusion, FLU/BU4/MEL showed curative potential, even in patients with advanced myeloid malignancies, accompanied by achievement of rapid complete chimerism after allo-BMT/PBSCT. PMID- 30448939 TI - Q-switched 1064-nm dymium-doped yttrium aluminum garnet laser irradiation induces skin collagen synthesis by stimulating MAPKs pathway. AB - The 1064-nm Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is widely used in clinical practice. However, the effects of 1064-nm Q-switched Nd:YAG laser on skin collagen generation have not been fully elucidated. The objectives of the present study were to investigate whether the 1064-nm Q switched Nd:YAG laser can be used for non-ablative rejuvenation and to explore the possible mechanism underlying the effects. Six-week-old SKH-1 hairless mice were irradiated by the 1064-nm Nd:YAG laser at fluences of 0, 0.5, 1, 1.5, and 2 J/cm2, respectively. The contents of hydroxyproline and hydration were detected after laser irradiation. Moreover, hematoxylin-eosin (HE) staining was preformed to evaluate the dermal thickness. Immunofluorescence was used to detect the expressions of MMP-2 and TIMP-1 in the skin after laser irradiation. Furthermore, qRT-PCR was performed to determine the expressions of TGF-beta1 and Smad3. In addition, the expressions of ERK1/2, p-ERK1/2, p38, p-p38, JNK, ERK5, and collagen were evaluated by Western blotting. The results indicated that the levels of hydroxyproline, hydration, and collagen were markedly increased; both the thickness of dermal was enhanced after low dose of laser treatment. Moreover, the expression of TIMP-1 was significantly increased, whereas the expression of MMP-2 was remarkably decreased after laser irradiation. Meanwhile, TGF-beta1, Smad3, p-ERK1/2, p-P38, and JNK productions were significantly enhanced in irradiated group compared with the ones non-irradiated. Nevertheless, no significant changes were observed in the expression of ERK5 after irradiation. In summary, our study demonstrated that Q-switched 1064-nm Nd:YAG laser can induce collagen generation, at least in part, through activating TGF-beta1/Smad3/MAPK signaling pathway. PMID- 30448940 TI - Effects of UVB and UVC irradiation on cariogenic bacteria in vitro. AB - The aim of this study was to evaluate the bactericidal effect of ultraviolet (UV) light at 265-nm (UVC) and 310-nm (UVB) wavelengths from a newly developed UV light-emitting diode (LED) device against cariogenic bacteria in vitro. Suspensions of Streptococcus mutans (S. mutans) and Streptococcus sobrinus were directly irradiated by UVB or UVC for 2.5 min or 5 min. Numbers of colonies were counted and calculated as colony forming units (CFU) per milliliter. Fluorescence microscopy (FM) and optical density measurements at 490 nm (OD490) were also taken after irradiation. In addition, the bactericidal effects of irradiation against S. mutans under 0.5 mm-thick dentin were compared using culture tests and OD490 measurements. Direct UV-LED irradiation with both UVB and UVC showed strong bactericidal effects. UVB showed superior bactericidal effect through 0.5-mm thick dentin than did UVC, especially after demineralization. These results suggest that UVB irradiation could be utilized for the prevention and management of dental caries. PMID- 30448941 TI - Does self-organized criticality drive leading edge protrusion? AB - Arp2/3 complex nucleates dendritic actin networks and plays a pivotal role in the formation of lamellipodia at the leading edge of motile cells. Mouse fibroblasts lacking functional Arp2/3 complex have the characteristic smooth, veil-like lamellipodial leading edge of wild-type cells replaced by a massive, bifurcating filopodia-like protrusions (FLPs) with fractal geometry. The nanometer-scale actin-network organization of these FLPs can be linked to the fractal geometry of the cell boundary by a self-organized criticality through the bifurcation behavior of cross-linked actin bundles. Despite the pivotal role of the Arp2/3 complex in cell migration, the cells lacking functional Arp2/3 complex migrate at rates similar to wild-type cells. However, these cells display defects in the persistence of a directional movement. We suggest that Arp2/3 complex suppresses the formation of FLPs by locally fine-tuning actin networks and favoring dendritic geometry over bifurcating bundles, giving cells a distinct evolutionary edge by providing the means for a directed movement. PMID- 30448942 TI - Building the contractile ring from the ground up: a lesson in perseverance and scientific creativity. AB - This contribution to the Festschrift for Professor Thomas (Tom) D. Pollard focuses on his work on the elucidation of the protein organization within the cytokinetic nodes, protein assemblies, precursors to the contractile ring. In particular, this work highlights recent discoveries in the molecular organization of the proteins that make the contractile machine in fission yeast using advanced microscopy techniques. One of the main aspects of Tom's research philosophy that marked my career as one of his trainees is his embrace of interdisciplinary approaches to research. The cost of interdisciplinary research is to be willing to step out of our technical comfort zone to learn a new set of tools. The payoff of interdisciplinary research is the expansion our realm of possibilities by bringing new creative tools and ideas to push our research program forward. The rewarding outcomes of this work under Tom's mentorship were the molecular model of the cytokinetic node and the development of new techniques to unravel the structure of multi-protein complexes in live cells. Together, these findings open a new set of questions about the mechanism of cytokinesis and provide creative tools to address them. PMID- 30448944 TI - Evolution of a Dedicated Emergency Surgery and Trauma (ESAT) unit over 3 years: sustained improved outcomes. AB - INTRODUCTION: The traditional 24-h call model faces pressure from competing needs between emergency and elective services. Recognizing this, a dedicated ESAT service was developed in Khoo Teck Puat Hospital in Singapore, with improved clinical outcomes. It was initially led by a single consultant (SC) in 2014, and subsequently evolved to a weekly consultant rotation (WC) roster in 2017 to achieve sustainability. METHODS: Each consultant led the ESAT WC service for a week and maintained ownership of their patients thereafter. All emergency surgical admissions between two distinct 6-month periods were reviewed, from May to October 2014 (pre-ESAT) and January to June 2017 (ESAT WC). Patient demographics, diagnoses, and operations were compared. Efficiency and clinical outcomes were evaluated. RESULTS: There were 1248 and 1284 patients in the pre ESAT and ESAT WC group, respectively. Majority were males and in their 50s. Acute appendicitis, gallstone conditions, and soft-tissue infections made up half of the admissions. Trauma workload was comparable (7.8% pre-ESAT vs 9.5% ESAT WC). Cholecystectomies doubled during the ESAT period, 14.2% vs 7.2%, (p = 0.01). More consultants were involved in major cases (95.9% vs 86%), (p = 0.01) and more operations were performed during the day (52.1% vs 47.9%), (p = 0.01). Average time to OT was shorter and there were less major surgical complications (p = 0.02). Mortality (p = 0.08) and length of stay were reduced (4 vs 4.5 days), (p = 0.01). CONCLUSION: The ESAT WC service has sustained improved outcomes in our institution. PMID- 30448943 TI - Molecular mechanisms of contractile-ring constriction and membrane trafficking in cytokinesis. AB - In this review, we discuss the molecular mechanisms of cytokinesis from plants to humans, with a focus on contribution of membrane trafficking to cytokinesis. Selection of the division site in fungi, metazoans, and plants is reviewed, as well as the assembly and constriction of a contractile ring in fungi and metazoans. We also provide an introduction to exocytosis and endocytosis, and discuss how they contribute to successful cytokinesis in eukaryotic cells. The conservation in the coordination of membrane deposition and cytoskeleton during cytokinesis in fungi, metazoans, and plants is highlighted. PMID- 30448945 TI - Structural modules of the stress-induced protein HflX: an outlook on its evolution and biological role. AB - Multifunctional proteins often show modular structures. A functional domain and the structural modules within the domain show evolutionary conservation of their spatial arrangement since that gives the protein its functionality. However, the question remains as to how members of different domains of life (Archaea, Bacteria, Eukarya), polish and perfect these modules within conserved multidomain proteins, to tailor functional proteins according to their specific requirements. In the quest for plausible answers to this question, we studied the bacterial protein HflX. HflX is a universally conserved member of the Obg-GTPase superfamily but its functional role in Archaea and Eukarya is barely known. It is a multidomain protein and possesses, in addition to its conserved GTPase domain, an ATP-binding N-terminal domain. It is involved in heat stress response in Escherichia coli and our laboratory recently identified an ATP-dependent RNA helicase activity of E. coli HflX, which is likely instrumental in rescuing ribosomes during heat stress. Because perception and response to stress is expected to be different in different life forms, the question is whether this activity is preserved in higher organisms or not. Thus, we explored the evolution pattern of different structural modules of HflX, with particular emphasis on the ATP-binding domain, to understand plausible biological role of HflX in other forms of life. Our analyses indicate that, while the evolutionary pattern of the GTPase domain follows a conserved phylogeny, conservation of the ATP-binding domain shows a complicated pattern. The limited analysis described here hints towards possible evolutionary adaptations and modifications of the domain, something which needs to be investigated in more depth in homologs from other life forms. Deciphering how nature 'tweaks' such modules, both structurally and functionally, may help in understanding the evolution of such proteins, and, on a large-scale, of stress-related proteins in general as well. PMID- 30448946 TI - Assessment of occupational exposure to pesticide mixtures with endocrine disrupting activity. AB - Occupational exposure to pesticide mixtures comprising active substance(s) and/or co-formulant(s) with known/possible endocrine-disrupting activity was assessed using long-term activity records for 50 professional operators representing arable and orchard cropping systems in Greece, Lithuania, and the UK. Exposure was estimated using the harmonised Agricultural Operator Exposure Model, and risk was quantified as a point of departure index (PODI) using the lowest no observed (adverse) effect level. Use of substances with known/possible endocrine activity was common, with 43 of the 50 operators applying at least one such active substance on more than 50% of spray days; at maximum, one UK operator sprayed five such active substances and 10 such co-formulants in a single day. At 95th percentile, total exposure was largest in the UK orchard system (0.041 * 10-2 mg kg bw-1 day-1) whereas risk was largest in the Greek cropping systems (PODI 0.053 * 10-1). All five cropping systems had instances indicating potential for risk when expressed at a daily resolution (maximum PODI 1.2-10.7). Toxicological data are sparse for co-formulants, so combined risk from complex mixtures of active substances and co-formulants may be larger in reality. PMID- 30448947 TI - Locating and eliminating feral swine from a large area of fragmented mixed forest and agriculture habitats in north-central USA. AB - Illinois is one of the US states where elimination of feral swine (Sus scrofa) was determined practical, as only a few isolated populations were established. A particularly important step towards feral swine elimination from Illinois was to eliminate the population in Fulton County. We describe the approaches applied to systematically detect, locate, and eliminate feral swine in a successful county wide elimination. Detecting and locating feral swine was facilitated by extensive outreach activities, aerial surveys to locate crop damage, and use of camera traps placed over bait in areas where reports, sign, or crop damage occurred. The population was eliminated after 376 feral swine were removed from 2009 to 2016 by trapping, sharpshooting over bait, and aerial shooting. Aerial surveys efficiently located feral swine activity over wide areas during times of the crop cycle when damage would occur and would be most distinguishable from other damage sources. Two applications of aerial shooting in 2014 were particularly efficient for rapidly eliminating most remaining feral swine after they had become difficult to locate and remove. Persistent efforts thereafter led to the successful elimination of feral swine in Fulton County by 2016. We believe this is the first documentation of a widespread feral swine elimination in mixed agriculture and forest habitats. PMID- 30448948 TI - Effect of n-butanol/diesel blends and piston bowl geometry on combustion and emission characteristics of CI engine. AB - The present study describes the experimental and numerical analysis of the combustion and emission characteristics of CI engine operated with diesel-butanol blends. Experiments were carried with neat diesel fuel (i.e., Bu00) and its blends of n-butanol, 10%, 20% and 30% by volume (Bu10, Bu20 and Bu30) at a constant speed and rated load. From the experimental results, it is observed that CO, NOx and smoke emissions decreased, whereas the unburned hydrocarbon (UBHC) emission increased with increasing butanol content, as compared to Bu00. From the experimental analysis, it is also observed that Bu20 blend gives higher brake thermal efficiency (BTE) and lower brake specific energy consumption (BSEC) as compared to Bu00, Bu10 and Bu30, but produces higher UBHC. In order to decrease the UBHC emission, different piston bowl geometries were analysed using simulation studies. The combustion and emission characteristics of the CI engine operating with Bu20 blend for three different piston bowl geometries viz., hemispherical combustion chamber (HCC), shallow combustion chamber (SCC) and toroidal combustion chamber (TCC), were studied using CONVERGE CFD code. The simulation model was validated with experimental results of the baseline engine configuration (HCC) for diesel fuel as well as Bu20 blend. The results showed that there is a significant reduction in UBHC and improvement of performance for SCC and TCC piston geometry compared to HCC piston geometry. However, a slight increment of NOx emissions was observed. PMID- 30448949 TI - The influence of local emissions and regional air pollution transport on a European air pollution hot spot. AB - The EU air quality standards have been frequently exceeded in one of the European air pollution hot spots: Ostrava. The aim of this study was to perform an air quality comparison between an urban site (Radvanice), which has a nearby metallurgical complex, and a suburban site (Plesna) to estimate air pollution sources and determine their local and/or regional origins. Twenty-four hour PM1 and PM10 (particular matter) concentrations, detailed mass size distributions (MSDs) to distinguish the sources of the fine and coarse PM, and their chemical compositions were investigated in parallel at both sites during the winter of 2014. Positive matrix factorization (PMF) was applied to the PM1 and PM10 chemical compositions to investigate their sources. During the measurement campaign, prevailing northeastern-southwestern (NE-SW) wind directions (WDs) were recorded. Higher average PM10 concentration was measured in Radvanice than in Plesna, whereas PM1 concentrations were similar at both sites. A source apportionment analysis revealed six and five sources for PM10 and PM1, respectively. In Radvanice, the amount of PM and the most chemical species were similar under SW and NE WD conditions. The dominant sources were industrial (43% for PM10 and 27% for PM1), which were caused by a large metallurgical complex located to the SW, and biomass burning (25% for PM10 and 36% for PM1). In Plesna, the concentrations of PM and all species significantly increased under NE WD conditions. Secondary inorganic aerosols were dominant, with the highest contributions deriving from the NE WD. Therefore, regional pollution transport from the industrial sector in Silesian Province (Poland) was evident. Biomass burning contributed 22% and 24% to PM10 and PM1, respectively. The air quality in Ostrava was influenced by local sources and regional pollution transport. The issue of poor air quality in this region is complex. Therefore, international cooperation from both states (the Czech Republic and Poland) is needed to achieve a reduction in air pollution levels. PMID- 30448950 TI - Aging as the main factor controlling PAH and polar-PAC (polycyclic aromatic compound) release mechanisms in historically coal-tar-contaminated soils. AB - In industrial sites, historically contaminated by coal tar (abandoned coking and manufactured gas plants), other families of organic pollutants than the 16 PAHs (polycyclic aromatic hydrocarbons) classified by the US-EPA can occur and induce potential risk for groundwater resources. Polar PACs (polycyclic aromatic compounds), especially oxygenated and nitrogenated PACs (O-PACs and N-PACs), are present in the initial pollution and can also be generated over time (i.e., O PACs). Their aqueous solubilities are much greater than those of the PAHs. For these reasons, we need to increase our knowledge on polar PACs in order to better predict their behavior and the potential on-site risk. Batch leaching tests were carried out under various conditions of temperature, ionic strength, and availability of pollutants to determine the mechanisms and key parameters controlling their release. The results show a release of low-molecular-weight PAHs and polar PACs mainly by dissolution, while higher molecular weight PAHs are mainly released in association with colloids. Aging mainly controls the former mechanism, and ionic strength mainly controls the latter. Temperature increased both dissolution and colloidal mobilization. The Raoult law predicts the PAC equilibrium concentration for soils presenting high pollutant availability, but this law overestimates PAC concentration in aged soils (low pollutant availability). This is mainly due to limitation of PAC diffusion within coal-tar particles with aging. The most soluble PACs (especially polar PACs) are the most sensitive to aging. For better prediction of the PAC behavior in soils and water resources management, aging needs to be taken into account. PMID- 30448951 TI - Effect of iron loading on the performance and structure of Fe/ZSM-5 catalyst for the selective catalytic reduction of NO with NH3. AB - A series of Fe/ZSM-5 catalysts with different Fe contents were prepared by impregnation method. The catalysts were characterized by TEM, XRD, H2 temperature programed reduction (H2-TPR), temperature-programed desorption of ammonia (NH3 TPD), and in situ diffuse-reflectance infrared Fourier transform spectroscopy (DRIFTS), and the catalytic activity test was also carried out on selective catalytic reduction (SCR) denitration device. Results showed that the single metal iron-supported ZSM-5 catalyst has high deNOx activity in the medium-high temperature range, and the optimal loading of Fe active component is 10 wt%; the deNOx efficiency over 80% at the range of 350-450 degrees C and 431 degrees C reaches the maximum of 96.91%. Iron species can be finely dispersed on the surface of the carrier as amorphous oxides, and the crystalline structure of zeolite is retained. The significant redox performance, highly dispersed nanoparticles, and rich Lewis acid sites on the surface of catalyst are favorable for the SCR denitration reaction. Fe/ZSM-5 10 wt% catalyst has rich Lewis acid sites and less B acid sites and Lewis acidic sites play an important role during the reaction. Only Eley-Rideal (E-R) mechanism existed during the NH3-SCR reaction process, and there is no denitration reaction being accomplished by L-H mechanism at 150 degrees C. PMID- 30448952 TI - Sorption and immobilization of Cu and Pb in a red soil (Ultisol) after different long-term fertilizations. AB - The sorption and immobilization of Cu and Pb in a red soil (Ultisol) treated by no fertilizer (Ck), chemical fertilizer (NPK), a mixture of chemical fertilizer and straw (NPKS), and animal manure (AM) from a long-term fertilization experimental site were studied. Compared to the sorption on Ck soil, the maximum amount of Cu and Pb sorption increased by 16% and 31%, 19% and 42%, and 30% and 45% on NPK, NPKS, and AM soil, respectively. The removal of organic matter from soils decreased the sorption of Cu but increased the sorption of Pb. The sorption of Cu and Pb on the examined soils was reduced by the presence of Ca. However, the inhibition was smaller on the fertilized soils than on non-fertilized soil and was weaker for Pb than for Cu. After the aging of Cu and Pb in the examined soils for 2 months, the proportion of reducible Pb was much higher than that of reducible Cu, whereas that of acid-soluble Cu was much higher than that of acid soluble Pb in the corresponding soils. The fertilization, especially AM treatment, decreased the percentage of the acid-soluble fraction of Cu and Pb but increased the proportion of the reducible fraction, suggesting that the immobilization of Cu and Pb in the Ultisol was strengthened by the fertilization, especially by the animal manure treatment. These findings could be useful in assessing and controlling heavy metal pollution in Ultisols. PMID- 30448953 TI - Effects of modified sediments from a eutrophic lake in removing phosphorus and inhibiting phosphatase activity. AB - Phosphorus is one of the main limiting and strong influencing factors of eutrophication, and phosphorus controlling in lake is of great significance for eutrophication. To do this, sediment materials were taken from Dianchi Lake, a typically eutrophic lake, and modified by hexadecyltrimethylammonium bromide (CTAB) and ZnSO4 to remove phosphorus and inhibit alkaline phosphatase activity (APA). Results indicated that phosphorus removal efficiencies of sediments modified by CTAB (S-CTAB), ZnSO4 (S-Zn), and oxidized sediments (OS) were higher than that of the raw sediment (RS). Ability to absorb phosphorus varied, following the order S-Zn>S-CTAB>OS>RS. Sorption was influenced by ionic strength, with the former decreasing with the increase of the latter. Freundlich model well described the sorption isotherm, with an R2 ranging from 0.9168 to 0.9958. Furthermore, compared with the raw sediments, the maximum phosphorus sorption capacities of S-Zn and S-CTAB increased by 12.2% and 124.5%, respectively. Results of desorption studies suggest that the desorption rate of S-Zn was from 3.88 to 13.76%, lower than that of other sediment materials. APA was inhibited by S-CTAB and S-Zn at the same time, with inhibition rates from 29.6% and 61.0% when the concentrations of S-CTAB and S-Zn were 10 nmol L-1 and 0.2 nmol L-1, respectively. This study provides new insights into phosphorus removal and phosphatase activity inhibition in water treatment. PMID- 30448954 TI - What determines compliance with cleaner production? An appraisal of the tanning industry in Sialkot, Pakistan. AB - Leather tanneries which produce significant amounts of solid waste, effluents, and emissions are a major contributor to industrial waste. A cleaner production program was launched by the government of Pakistan to implement the cleaner production measures for tanneries of Sialkot from 1999 to 2005. The main objective of this study is to identify the impact of a cleaner production program, along with other determinants of a cleaner production in the leather industry. The study analyses firm-level primary data collected from leather tanneries in Sialkot. The primary data were collected from tanneries in Sialkot. The econometric analysis is conducted using the Poisson regression analysis. Overall results show that there is no significant impact of cleaner production in 2015, while the panel data results indicate that the effect of cleaner production support by CPC on cleaner production practices diminished once the support came to an end. The other main factor is firm size, which indicates the financial position of the firm; international and regulator pressures are major determinants of the adoption of cleaner production measures. The analysis also indicates that there is higher probability of large firms adopting a cleaner production in comparison with small ones. Export orientation of firms is another important determinant of cleaner production. The enforcement of the environment compliance laws also has positive effect. The compliance with cleaner production measures is quite low, at 6.4 out of 19 cleaner production practice measures. There is a need to adopt measures that are environmentally friendly and are favorable towards both labor health and product quality, which are important for the sustainable growth of the tanning industry. PMID- 30448955 TI - Flavonoid glucosides from the flowers of Trollius chinensis Bunge. AB - Four new flavonoid glucosides, 2"-O-(6'''-O-caffeoyl)-galactopyranosylvitexin (1), 2"-O-(6'''-O-veratroyl)-galactopyranosylvitexin (2), 2"-O-(6'''-O-feruloyl) galactopyranosylorientin (3), 2"-O-(2'''-O-methylbutyryl) glucopyranosylisoswertisin (4), along with three known compounds were isolated from the flowers of Trollius chinensis Bunge. Their structures were determined by extensive spectroscopic analyses. PMID- 30448956 TI - Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis. AB - PURPOSE: Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance. METHODS: We retrospectively collected data on 270 patients [median age 76 (range 48-92) years, M/F 204/66, PS 0 (27)/1 (110)/>= 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously. RESULTS: Patients received an overall median of 6 (range 1-25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1-21) months [T1 7 (1-21), T2 5.5 (1-19) and T3 4 (1-19) months] and median overall survival 9 (range 1-36) months [T1 10 (1-31), T2 8 (1-36) and T3 6.5 (2-29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7-36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine. CONCLUSION: We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy. PMID- 30448957 TI - Diagnostic performance of 18F-choline PET-CT in prostate cancer. AB - OBJECTIVES: To evaluate the diagnostic performance of 18F-choline PETCT in staging prostate cancer (PC) and whether the use of this imaging modality changes the therapeutic decision in patients previously staged by conventional imaging. The secondary aim was to determine the prognostic factors associated with positive choline PETCT findings in both detection of disseminated disease and in changes in the therapeutic indication. MATERIALS AND METHODS: Multicentre, retrospective, observational study of 269 patients diagnosed with PC. Mean age was 69 +/- 9.2 years. Of the 269 patients, 62 (23%) had high-risk localized PC (group 1), 118 (43.9%) biochemical failure after radical prostatectomy (group 2), and 89 (33.1%) biochemical failure after radiotherapy (group 3). None of the patients showed clear evidence of distant disease on computed tomography or bone scans. The following potential prognostic factors were assessed: PSA level at diagnosis; primary and secondary Gleason; Gleason score (GS); clinical and pathologic T and N stage; number of positive cylinders in the biopsy; presence of vascular or lymphatic invasion; status of surgical margins; androgen deprivation therapy (ADT); time to biochemical recurrence; and PSA, PSA doubling time (PSADT), and PSA velocity (PSAV) at failure. Univariate and multivariate analyses were performed, and receiver-operating curves calculated. RESULTS: The mean PSA by groups was, group 1: 31.22 ng/ml, group 2: 2.52 ng/ml and group 3: 5.85 ng/ml. The tumor detection rate with 18F-choline PETCT was 74% (group 1: 85.5%, group 2: 55.1% and group 3: 91%). Prognostic factors for positive 18F-choline PETCT were identified only in group 2: PSA at failure and PSADT. 18F-choline PETCT changed the therapeutic indication in 62.8% (group 1: 71%, group 2: 55.2% and group 3: 70.1%). The prognostic factors for a change in treatment were identified only in group 1: secondary Gleason <= 4 and GS <= 7 and in group 2: PSA at failure, PSA nadir after surgery and pathologic stage N0. 18F-choline PETCT identified lymph node and/or metastatic disease in 32.7% (group 1: 25.8%, group 2: 29.7% and group 3: 41.6%). Prognostic factors for detecting lymph node/metastasis were identified in the group 2: PSA failure >= 1.37 ng/ml and PSADT < 4 months and in the group 3: PSADT < 4.6 months and time to failure < 5 years. CONCLUSION: These findings support the clinical use de 18F-choline PET-CT in staging high-risk patients with a secondary Gleason <= 4 and GS <= 7, in restaging patients with biochemical recurrence after RP if PSA at failure >= 1.37 ng/ml or PSADT <= 4 months and in patients with biochemical failure after RT, if PSADT <= 4.6 months and time to failure < 5 years, because it determines a change in the therapeutic indication. PMID- 30448958 TI - Ligustrazine attenuates inflammation and oxidative stress in a rat model of arthritis via the Sirt1/NF-kappaB and Nrf-2/HO-1 pathways. AB - Inflammation responses and oxidative stress are closely involved in the pathogenesis of arthritis. Ligustrazine (Lig), a natural four methyl which is isolated from Chinese herb ligusticum chuanxiong hort, has been proved significantly anti-inflammation and anti-oxidative stress effects. The present study aimed to evaluate the effect of Lig on inflammation and oxidative stress in Freund's complete adjuvant (FCA)-induced arthritis in rats. The treatment of Lig significantly decreased the hind-paw volume change and alleviated the histopathological changes in sections of rat paws induced by arthritis. Lig also reduced the serum levels of pro-inflammatory cytokines (interleukin [IL]-6, IL-1 beta, and tumor necrosis factor-alpha), increased the activity of superoxide dismutase (SOD) and reduced the concentration of malondialdehyde (MDA). Besides that, the protein expressions of the sirtuin 1 (Sirt1)/nuclear factor kappa B (NF kappaB) and nuclear factor (erythroid-derived 2)-like-2 factor (Nrf-2)/heme oxygenase (HO)-1 pathways determined by western bolt further confirmed that Lig effectively inhibited the Sirt1/NF-kappaB pathway and activated the Nrf-2/HO-1 pathway. Taken together, our results suggest Lig has therapeutic potential for arthritis, which might be via the regulation of Sirt1/NF-kappaB and Nrf-2/HO-1 pathways. PMID- 30448959 TI - Do femoral fractures in adult patients with osteogenesis imperfecta imitate atypical femoral fractures? A case series. AB - Atypical femoral fractures (AFFs) are low-energy femoral fractures with characteristic radiological features and a suspected relation to treatment with bisphosphonate (BP) or denosumab. In osteogenesis imperfecta (OI), BP is currently the drug of choice when medical treatment is indicated. Due to bone deformities, the radiologic appearance of femoral fractures may be different in patients with OI and patients with osteoporosis. We investigated the prevalence and appearance of femoral fractures in a cohort of adult patients with confirmed OI (55 patients, age range 19-69 years, 26 women (47%) and 35 patients (64%) had received BP treatment), who attended the outpatient clinic at Aarhus University Hospital. The fractures were evaluated according to major and minor AFF criteria. In our OI cohort, we found that eight out of 55 patients had suffered a femoral fracture in adult year: five women and three men, aged 25 to 54 years. One patient had OI type I, two had OI type III, four had OI type IV, and one had OI type V. All fractures were associated with no or minimal trauma. Four patients had fractures that fulfilled the criteria of AFFs. Two of the four patients had received long-term BP treatment prior to the fracture and three patients had severe deformities of the femur. Femoral fractures in OI imitate AFFs. This suggests that bone deformity, collagen deficiencies, and alterations in mineralization of bone may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. Bone deformities should be monitored as part of the management of adult patients with OI. Continuous dull or aching pain in the groin or thigh should lead to radiographic examination. The radiologic appearance of femoral fractures may be different in patients with osteogenesis imperfecta (OI) and patients with osteoporosis, thus imitate atypical femoral fractures (AFF). We found that bone deformity, collagen deficiencies, and alterations in bone mineralization may cause femoral fractures that imitate AFFs even in the absence of antiresorptive treatment. PMID- 30448960 TI - Prevalence of osteoporosis with the World Health Organization diagnostic criteria in the Eastern Mediterranean Region: a systematic review and meta-analysis. AB - : A systematic review and meta-analysis was conducted on the prevalence of osteoporosis in the Eastern Mediterranean Region. The overall pooled prevalence of osteoporosis was 24.4%. The prevalence has increased significantly over the recent years. The highest pooled prevalence was in Saudi Arabia (32.7%), and the lowest was in Kuwait (15.1%). PURPOSE: To conduct a systematic review and meta analysis on the prevalence of osteoporosis in the Eastern Mediterranean Region (EMR), as defined by the World Health Organization. METHODS: We included all observational studies reporting the prevalence of osteoporosis among general population. We searched literatures from the databases of PubMed, Scopus, Web of Science, and Index Medicus for the EMR published between January 2000 and December 2017 with no restriction of language. Two reviewers independently contributed in study selection and data extraction. STATA software was used for analyzing the collected data. RESULTS: A total of 1692 citations were retrieved. After excluding the irrelevant articles, 36 eligible studies were included. The overall pooled prevalence rate of osteoporosis in the EMR on 31,593 participants was 24.4% (95% confidence interval [CI], 20.4-28.4). Based on femoral densitometry, the prevalence of osteoporosis was 16.8% (95% CI, 9.5-24.2), and based on spinal densitometry, it was 24.3% (95% CI, 19.4-29.2). The pooled prevalence in males was 20.5% (95% CI, 10.5-30.5), compared with 24.4% (95% CI, 20.2-28.6) in females. The prevalence rate was significantly higher in 2007-2015 (32.7%; 95% CI, 25.1-40.3) than in 2000-2006 (19.8%; 95% CI, 12.5-27). CONCLUSIONS: Our findings indicate a considerable prevalence of osteoporosis among the people of the EMR. The prevalence has increased during recent years, showing that osteoporosis is becoming a critical health problem in this region. Prevention and control measures need to be implemented by health service authorities. PMID- 30448961 TI - Health Risks Associated with Heavy Metals in Imported Fish in a Coastal City in Colombia. AB - Colombia is a fish exporter and consumer country because of its geographical location. Since 2012, imported fish have become a more economical option than domestic species due to free trade agreements. Concentrations of Pb, Cd, and Zn were evaluated in three imported and highly commercialized fish species in a city on the Caribbean coast of Colombia: Prochilodus lineatus, Prochilodus reticulatus, and Pangasianodon hypophthalmus, plus one brand of canned tuna and one brand of sardines. The canned species showed the highest values for Pb, Cd, and Zn; canned tuna (oil-packed) contained 0.189 +/- 0.047 mg/kg Pb and 238.93 +/ 76.43 mg/kg Zn, while canned sardines contained 0.111 +/- 0.099 mg/kg Cd, suggesting a relationship between the canning process and the metal concentrations. The estimated daily intake (EDI) and hazard quotient (HQ) suggested that there is no risk for consumer health in the short term, but the presence of these heavy metals certainly should be a concern in the long term because of the bioaccumulation phenomenon due to the high intake of these fish species in this coastal and tourist community. It is recommended that continuous monitoring of heavy metal concentrations take place to protect communities in a local and global context. PMID- 30448962 TI - Draft Genome Sequences of Proteus mirabilis K1609 and K670: A Model Strains for Territoriality Examination. AB - Proteus mirabilis is a pathogenic Gram-negative bacterium characterized by its ability to swarm across surfaces, which frequently leads to colonization of the urinary tract and causes severe infections. P. mirabilis strains are also well known from their self-recognition phenomenon, referred to as Dienes phenomenon. In this study, we present novel aspect of self-recognition, which is a hierarchy in terms of strains territoriality. We report the draft genome sequences of P. mirabilis K1609 and K670 strains exhibiting the strongest and the weakest territoriality, respectively. Our results indicated that K1609 is closely related to strain BB2000, a model system for self-recognition, comparing with the K670. We annotated genes associated with recognition of kin and swarming initiation control and indicated polymorphisms by which observed differences in territoriality might results from. The phenotypic and genomic features of both strains reveal their application as a model organisms for studying not only the mechanisms of kin-recognition but also strains territoriality, thus providing new approach to the phenomenon. Availability of these genome sequences may facilitate understanding of the interactions between P. mirabilis strains. PMID- 30448963 TI - A validation study on three screening questionnaires for obstructive sleep apnea in a Korean community sample. AB - PURPOSE: Obstructive sleep apnea (OSA) is highly prevalent and causes serious cardiovascular complications. Several screening questionnaires for OSA have been introduced, but only few validation studies have been conducted in general population. The aim of the present study was to assess the diagnostic value of three OSA screening questionnaires (Berlin Questionnaire, BQ; STOP-Bang Questionnaire, STOP-B; Four-Variable Screening Tool, Four-V) in a Korean community sample. METHODS: A total of 1148 community-dwelling participants completed the BQ, STOP-B, and Four-V. An overnight in-laboratory polysomnography (PSG) was conducted in randomly selected 116 participants. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and area under the curve (AUC) were calculated. RESULTS: The Four-V with cutoff >= 8 showed high sensitivity for overall OSA (69.4%), and the Four-V with cutoff >= 9 showed high specificity for both overall OSA (81.5%) and moderate to severe OSA (69.0%). On the other hand, the STOP-B showed acceptable sensitivity and specificity for both overall OSA (61.3 and 79.6%, respectively) and moderate to severe OSA (72.4 and 67.8%, respectively). The STOP-Bang also showed the largest area under the receiver operator characteristic curve for both overall OSA (0.752) and moderate to severe OSA (0.750). The BQ showed the lowest performance in predicting OSA. CONCLUSIONS: Among the three questionnaires, the STOP-B was revealed as the most useful screening tool for OSA in terms of sensitivity, specificity, and area under the receiver-operator characteristic curve in the population of South Korea. PMID- 30448964 TI - Bacterial indoleacetic acid-induced synthesis of colloidal Ag2O nanocrystals and their biological activities. AB - The biosynthesis and biological activity of colloidal Ag2O nanocrystals have not been well studied, although they have potential applications in many fields. For the first time, we developed a reducing agent free, cost-effective technique for Ag2O biosynthesis using Xanthomonas sp. P5. The optimal conditions for Ag2O synthesis were 50 degrees C, pH 8, and 2.5 mM AgNO3. Using these conditions the yield of Ag2O obtained at 10 h was about five times higher than that obtained at 12 h under unoptimized conditions. Ag2O was characterized by FESEM-EDS, TEM, dynamic light scattering, XRD, and UV-Visible spectroscopy. Indoleacetic acid produced by the strain P2 was involved in the synthesis of Ag2O. Ag2O exhibited a broad antimicrobial spectrum against several human pathogens. Furthermore, Ag2O exhibited 1,1-diphenyl-2-picrylhydrazyl (IC50 = 25.1 ug/ml) and 2,2'-azinobis-3 ethylbenzothiazoline-6-sulfonate (IC50 = 16.8 ug/ml) radical scavenging activities, and inhibited collagenase (IC50 = 27.9 mg/ml). Cytotoxicity of Ag2O was tested in fibroblast cells and found to be non-toxic, demonstrating biocompatibility. PMID- 30448965 TI - Observing movement disorders: best practice proposal in the use of video recording in clinical practice. AB - Clinical evaluation is of utmost importance in the semeiological description of motor disorders which often require video recording to highlight subtle signs and their subsequent evolution. After reviewing 1858 video recordings, we composed a suitable list of video-documentation maneuvers, classified semeiologically in the form of a "video recording protocol", to guarantee appropriate documentation when filming movement disorders. Aware that our proposed filming protocol is far from being exhaustive, by suggesting a more detailed documenting approach, it could help not only to achieve a better definition of some disorders, but also to guide neurologists towards the correct subsequent examinations. Moreover, it could be an important tool for the longitudinal evaluation of patients and their response to therapy. Finally, video recording is a powerful teaching tool as visual teaching highly improves educational training. PMID- 30448966 TI - Disturbed effective connectivity patterns in an intrinsic triple network model are associated with posttraumatic stress disorder. AB - BACKGROUND: Disturbance of the triple network model was recently proposed to be associated with the occurrence of posttraumatic stress disorder (PTSD) symptoms. Based on resting-state dynamic causal modeling (rs-DCM) analysis, we investigated the neurobiological model at a neuronal level along with potential neuroimaging biomarkers for identifying individuals with PTSD. METHODS: We recruited survivors of a devastating typhoon including 27 PTSD patients, 33 trauma-exposed controls (TECs), and 30 healthy controls without trauma exposure. All subjects underwent resting-state functional magnetic resonance imaging. Independent components analysis was used to identify triple networks. Detailed effective connectivity patterns were estimated by rs-DCM analysis. Spearman correlation analysis was performed on aberrant DCM parameters with clinical assessment results relevant to PTSD diagnosis. We also carried out step-wise binary logistic regression and receiver operating characteristic curve (ROC) analysis to confirm the capacity of altered effective connectivity parameters to distinguish PTSD patients. RESULTS: Within the executive control network, enhanced positive connectivity from the left posterior parietal cortex to the left dorsolateral prefrontal cortex was correlated with intrusion symptoms and showed good performance (area under the receiver operating characteristic curve = 0.879) in detecting PTSD patients. In the salience network, we observed a decreased causal flow from the right amygdala to the right insula and a lower transit value for the right amygdala in PTSD patients relative to TECs. CONCLUSION: Altered effective connectivity patterns in the triple network may reflect the occurrence of PTSD symptoms, providing a potential biomarker for detecting patients. Our findings shed new insight into the neural pathophysiology of PTSD. PMID- 30448967 TI - Genotype-phenotype associations in atrial fibrillation: meta-analysis. AB - PURPOSE: Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with atrial fibrillation (AF). The relationship between SNPs and the incidence of stroke, heart failure, and the recurrence rate of AF after cardioversion has been reported. This meta-analysis focuses on the genotype-phenotype associations in AF. METHODS: We searched PubMed/Medline and Embase for literature providing the phenotypic parameters and genotypes of RS10033464, RS13376333, RS2106261, RS2200733, and RS7193343. We selected literature published in English and reviewed the full text of included studies to perform a meta-analysis. RESULTS: Fifteen papers, and 7034 patients with AF, were included. The mean risk gene frequency of the investigated variants was between 12 and 43%. The mean age of patients was between 50 and 70 and 70-80% of them were male. The stroke and heart failure frequencies in AF patients with RS2200733 were 10 and 7%, respectively. There was no significant difference in left ventricular ejection fraction and left ventricular end-diastolic diameter for all risk genotypes. For the AF recurrence after cardioversion treatment with direct current electric conversion, catheter ablation therapy, and anti arrhythmic drugs. The early AF recurrence rate was 46% in RS10033464 and RS13376333 patients, and the late AF recurrence rate was 53% in RS2200733 patients. CONCLUSIONS: Pooled analysis showed a significantly high prevalence of stroke (10%) in RS2200733 AF patients. AF patients with the studied SNPs had preserved left ventricular systolic function (i.e., ejection fraction greater than 50%). AF patients with RS10033464 presented larger left atrium diameter (44 mm (95% CI 42.02-45.98)) than those with other SNPs. The late AF recurrence rate was highest in RS2200733 patients (53% (95% CI 0.43-0.64)). This study aids our understanding of the existing genetic findings and the function-altering "strongest" SNPs. PMID- 30448968 TI - Demonstration of an adjacent conduction gaps-derived left atrial and pulmonary vein flutter by high-density mapping. PMID- 30448969 TI - Association between sex and body mass index as mediated by temperament in a nonclinical adult sample. AB - PURPOSE: The main purpose of the present study was to investigate the association between sex and body mass index (BMI) as mediated by the temperament traits postulated by the regulative theory of temperament. METHODS: A group of 317 subjects, including 122 men and 195 women 18-82 years old (M = 31.93; SD = 12.64 years), was recruited from the general population to participate in the study. A cross-sectional design was applied in this study. Temperament was assessed using the formal characteristics of behaviour-temperament inventory revised version (FCB-TIR). In the sample, BMIs ranged from 16.51 to 35.56 kg/m2 (M = 23.31 kg/m2; SD = 3.61 kg/m2). RESULTS: The male group had significantly higher BMI, briskness and endurance levels and significantly lower perseveration, sensory sensitivity and emotional reactivity levels compared to the female group. No significant differences between these groups were noted in terms of activity and rhythmicity. The correlations between BMI and briskness and between BMI and endurance were positive, while the correlations between BMI and perseveration and between BMI and activity were negative. The correlations among BMI, sensory sensitivity, emotional reactivity and rhythmicity were not statistically significant. The mediation analysis showed that briskness and endurance were significant partial mediators of the relationship between sex and BMI. CONCLUSIONS: Sex and two temperament traits, briskness and endurance, were the best predictors of BMI. Briskness and endurance partially mediated the relationship between sex and BMI. LEVEL OF EVIDENCE: Descriptive cross-sectional study. Level V. PMID- 30448970 TI - Dealing with death when studying disease or physiological marker: the stochastic system approach to causality. AB - The stochastic system approach to causality is applied to situations where the risk of death is not negligible. This approach grounds causality on physical laws, distinguishes system and observation and represents the system by multivariate stochastic processes. The particular role of death is highlighted, and it is shown that local influences must be defined on the random horizon of time of death. We particularly study the problem of estimating the effect of a factor V on a process of interest Y, taking death into account. We unify the cases where Y is a counting process (describing an event) and the case where Y is quantitative; we examine the case of observations in continuous and discrete time and we study the issue of whether the mechanism leading to incomplete data can be ignored. Finally, we give an example of a situation where we are interested in estimating the effect of a factor (blood pressure) on cognitive ability in elderly. PMID- 30448971 TI - Leopard (Panthera pardus) predation on a red-tailed monkey (Cercopithecus ascanius) in the Issa Valley, western Tanzania. AB - Predation is predicted to be an important selection pressure for primates. Evidence for this hypothesis is rare, however, due to the scarcity of direct observations of primate predation. We describe an observation of leopard (Panthera pardus) predation on a red-tailed monkey (Cercopithecus ascanius schmidti) at the Issa Valley, a savanna-woodland mosaic landscape in western Tanzania. We compare rates of evidence of leopard presence between Issa and other primate study sites in sub-Saharan Africa. An increase in direct observations of leopards at Issa in recent years suggests that leopards may be habituating to researcher presence. PMID- 30448972 TI - Extended pleurectomy decortication for thymoma with pleural dissemination. AB - Complete resection is the mainstay of treatment for thymoma. Even for advanced stage thymoma with pleural dissemination, complete resection with extrapleural pneumonectomy may provide a favorable prognosis. Pleurectomy decortication, a lung-sparing surgery, has been preferably employed in recent years as an alternative surgical procedure for malignant pleural mesothelioma. However, little has been reported about pleurectomy decortication for other malignant tumors with pleural dissemination. Here, we present the first case of thymoma with pleural dissemination for which complete en bloc resection was achieved with extended pleurectomy decortication. PMID- 30448974 TI - Author Index Volume 41. PMID- 30448973 TI - Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis. AB - Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials. PMID- 30448975 TI - Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. AB - Inflammation is the body's response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia. PMID- 30448976 TI - Effects of hypothermia during propofol anesthesia on learning and memory ability and hippocampal apoptosis in neonatal rats. AB - OBJECTIVE: At present, the harm of hypothermia to the central nervous system has received a great attention from scholars. The present study aimed to investigate the effects of hypothermia on learning and memory abilities and hippocampal apoptosis in neonatal rats and the role of p-ERK and p-CREB in anesthesia. METHODS: In this study, 60 Sprague Dawley newborn rats (age 7-day-old) were randomly divided into 3 groups (n = 20), including Control Group (Group C), Anesthesia Group (Group A), and Anesthesia Hypothermia Group (Group AH). Group C was intraperitoneally injected with 0.1 ml saline, and rectal temperature was maintained in the range of 38-39 degrees C; Group A was intraperitoneally injected with 25 mg/kg of propofol (0.1 ml), the 1/2 initial dose was added per each period of 20 min, anesthesia was maintained for 2 h, and rectal temperature was kept in the range of 38-39 degrees C. The anesthesia mode and duration of Group AH were as same as Group A, room temperature was set to 23 degrees C, which caused body's temperature naturally dropped down. After the anesthesia recovered, each group randomly involved five rats for analyzing by Western blot to detect the expression level of p-ERK and p-CREB, and other five rates were also analyzed by flow cytometry assay to detect hippocampal apoptosis rate. The remaining 10 rats in each group were kept up to 30 days for conducting the Morris water maze test, five rats were tested for detecting the expression level of p ERK and p-CREB, as well as hippocampal apoptosis rate in each group. RESULTS: Compared with Group C and Group A, the rectal temperature of Group AH was decreased significantly (P < 0.05); At the age of 7 days, compared with Group C and Group A, apoptosis rate of hippocampal tissue in Group AH was increased (P < 0.05), the expression level of p-ERK and p-CREB proteins in Group AH was significantly reduced (P < 0.05), and there were no significant differences between Group C and Group A. At the age of 36 days, there were no significant differences in the results of behavioral test, apoptotic rates, and expression level of the proteins. CONCLUSION: Our findings suggest that hypothermia during anesthesia can increase the apoptosis rate in the hippocampus of neonatal rats, whose mechanism may be related to the downward adjustment of p-ERK and p-CREB. However, it has no obvious influence on the long-term learning and memory abilities. PMID- 30448977 TI - The BDNF Val66Met Polymorphism Promotes Changes in the Neuronal Integrity and Alters the Time Perception. AB - Studies at the molecular level aim to integrate genetic and neurobiological data to provide an increasingly detailed understanding of phenotypes related to the synchronization ability and brain oscillations in time perception. Genetic variation as a modifying factor at cellular and neurochemical levels permeates several neurofunctional aspects in time-lapse duration concentrating from milliseconds to hours. Thus, the review presents the BDNF Val66Met polymorphism association in a dynamic frame of brain neurotrophic factor expression in the adaptation, integrity, and neuronal synchronism processes in the ability to estimate multisensory stimuli at different time intervals. Our study aims to understand the molecular aspects involved in a neurobiological domain pertinent to the time judgment, tracing a genetic profile of association with psychometric functions and behavioral performances related to timing stimuli. PMID- 30448978 TI - Light-use efficiency and energy partitioning in rice is cultivar dependent. AB - One of the main limitations of rice yield in regions of high productive performance is the light-use efficiency (LUE). LUE can be determined at the whole plant level or at the photosynthetic apparatus level (quantum yield). Both vary according to the intensity and spectral quality of light. The aim of this study was to analyze the cultivar dependence regarding LUE at the plant level and quantum yield using four rice cultivars and four light environments. To achieve this, two in-house Light Systems were developed: Light System I which generates white light environments (spectral quality of 400-700 nm band) and Light System II which generates a blue-red light environment (spectral quality of 400-500 nm and 600-700 nm bands). Light environment conditioned the LUE and quantum yield in PSII of all evaluated cultivars. In white environments, LUE decreased when light intensity duplicated, while in blue-red environments no differences on LUE were observed. Energy partition in PSII was determined by the quantum yield of three de-excitation processes using chlorophyll fluorescence parameters. For this purpose, a quenching analysis followed by a relaxation analysis was performed. The damage of PSII was only increased by low levels of energy in white environments, leading to a decrease in photochemical processes due to the closure of the reaction centers. In conclusion, all rice cultivars evaluated in this study were sensible to low levels of radiation, but the response was cultivar dependent. There was not a clear genotypic relation between LUE and quantum yield. PMID- 30448979 TI - Autonomic nervous system dysfunction and fatigue in multiple sclerosis: common pathophysiology or spurious association? PMID- 30448980 TI - Lithium Toxicity with Severe Bradycardia Post Sleeve Gastrectomy: a Case Report and Review of the Literature. AB - Lithium is one of the major treatment options in bipolar disorder. Bariatric surgery can significantly modify the oral bioavailability of drugs, and lithium is no exception; although in most cases drug absorption seems to decrease, in the case of lithium, toxicity is the risk. In this article, we describe a 61-year-old male patient presented with lithium toxicity, including newly diagnosed severe bradycardia requiring a permanent pacemaker, after undergoing sleeve gastrectomy. We discuss the mechanisms behind this case, provide potential solutions for clinicians treating bariatric patients with lithium, and review previous reports of lithium toxicity post bariatric surgery. Awareness of changes in drug absorption, particularly lithium, following bariatric surgery, is prudent and essential for optimal patient care. Close clinical and drug levels monitoring is strongly advised. PMID- 30448981 TI - Metabolic Effects of Sleeve Gastrectomy with Transit Bipartition in Obese Females with Type 2 Diabetes Mellitus: Results After 1-Year Follow-up. AB - PURPOSE: To present the early metabolic effects of sleeve gastrectomy with transit bipartition (SG + TB) procedure in female obese patients with type 2 diabetes mellitus (T2DM). METHODS: This prospective clinical study was carried out between January 2016 and June 2017. Inclusion criteria were female participants under 60 years old with T2DM, body mass index >= 40 kg/m2 and HbA1c level >= 8%. All patients underwent to SG + TB procedure. Primary outcomes were the glycemic control variables, and the secondary outcomes were weight loss and dyslipidemia levels up to the last follow-up point. RESULTS: A total of 35 female participants with an average age of 48.8 +/- 6.0 years old and a mean preoperative BMI of 42.0 +/- 1.3 kg/m2 were included during the study period. Diabetic remission was achieved in 88.6% of patients (n = 31) on the third month without any antidiabetic medications. The mean postoperative BMI of patients was 24.8 +/- 1.6 kg/m2, and dyslipidemia levels were significiantly lower at the last follow-up point of all patients. CONCLUSIONS: SG + TB procedure may be a potent therapeutic option for the treatment of obese patients with T2DM. PMID- 30448982 TI - Laparoscopic Roux-En-Y Gastric Bypass Versus Sleeve Gastrectomy on Pelvic Floor Disorders in Morbidly Obese Women: a Prospective Monocentric Pilot Study. AB - BACKGROUND: Obesity is a well-known risk factor for female pelvic floor disorders (PFD). This study assessed the effects of bariatric surgery (BS) on pelvic organ prolapse symptoms (POPs) and urinary (UI) and anal incontinence (AI) in morbidly obese women undergoing either sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). METHODS: Morbidly obese women undergoing BS from June 2016 to May 2017 were prospectively included. POPs, UI, and AI were compared at baseline and at 1 year after surgery using validated questionnaires. RESULTS: Seventy-two consecutive women were enrolled, 54 (75%) (30 (56%) RYBP and 24 (44%) SG) completed the study at 1 year and were considered for the final analysis. The mean age and mean preoperative BMI were 43 +/- 11.8 years (range, 20-65) and 41 +/- 5.4 kg/m2 (range, 35-56), respectively. At baseline, 30 (56%), 32 (59%), and 27 (50%) patients, respectively, had AI (flatus only 72%), UI, and POPs. The mean TBWL% at 1 year was 33%. In the whole study population, weight loss was associated with a significant improvement in UI (p < 0.001) but there was no significant difference in terms of AI and POPs. In the subgroups analysis, AI increased significantly 1 year after the RYGB (p = 0.02) due to an increase in flatus incontinence (p = 0.04). No significant difference in AI was found 1 year after the SG. CONCLUSION: BS is associated with a significant improvement in UI but not in POPs. RYBP seems to increase AI, mainly flatus incontinence, compared to SG. PMID- 30448983 TI - Incidence of Diabetes Mellitus, Cardiovascular Diseases, and Cancer in Patients Undergoing Malabsorptive Surgery (Biliopancreatic Diversion and Biliointestinal Bypass) vs Medical Treatment. AB - BACKGROUND AND AIMS: Bariatric surgeries such as gastric banding (LAGB), gastric bypass (RYGB), vertical banded gastroplasty (VBG), and sleeve gastrectomy (LSG) decrease body weight in morbid obesity, leading to the resolution of coexisting diabetes mellitus and arterial hypertension in the majority of cases as well as improvements of renal function and liver steatosis. BS (LAGB, RYGB, VBG, and LSG) also reduce incident cases of diabetes, of cardiovascular diseases, and of cancer; these therapeutic and preventive effects on comorbidities of obesity have not been analyzed for malabsorptive surgeries such as biliopancreatic diversion (BPD) or biliointestinal bypass (BIBP). The aim of this study was to analyze the incidence of comorbidities, i.e., diabetes, cardiovascular diseases, and cancer, in obese subjects undergoing BPD and BIBP, in comparison with standard medical treatment of obesity. PATIENTS AND METHODS: Medical records of 1983 obese patients (body mass index (BMI) > 35 kg/m2, aged 18-65 years, undergoing surgery (n = 472, of which 111 with diabetes) or medical treatment (n = 1511, of which 422 with diabetes), during the period 1999-2008 (visit 1)) were collected; incident cases of comorbidities were ascertained through December 31, 2016. RESULTS: Observation period was 12.0 +/- 3.48 years (mean +/- SD). Compared to non-surgical patients matched for age, body mass index, and blood pressure, malabsorptive surgeries were associated with reduced new incident cases of diabetes (p = 0.001), cardiovascular diseases (p = 0.001), hyperlipidemia (p = 0.001), oculopathy (p = 0.021), and cancer (p = 0.001). The preventive effect of BS was similar in both nondiabetic and diabetic patients for cardiovascular diseases and hyperlipidemia (both p = 0.001). The preventive effect was significant in nondiabetic subjects for coronary heart disease and for cancer, not significant in diabetic subjects. CONCLUSION: Patients undergoing malabsorptive bariatric surgery show less incident cases of diabetes, cardiovascular diseases, hyperlipidemia, oculopathy, and cancer than controls receiving medical treatment. PMID- 30448984 TI - Psychological Support and Well-being in Post-Bariatric Surgery Patients. AB - Bariatric surgery research has focused predominantly on weight loss outcomes and complications of surgery in relation to the type of surgical procedure. The psychological impact of having bariatric surgery has received less attention. This study investigated whether patients who receive psychological counselling have better physical and mental well-being post-bariatric surgery. Eighty-eight persons (81 female, 7 male, M age 43.99 years) who had undergone weight loss surgery were recruited from bariatric surgery and obesity online support groups to answer an electronic survey which included the Health Survey Short Form (SF 12) to assess mental and physical well-being. Patients who had attended >= 6 counselling sessions after gastric sleeve surgery had better physical well-being, compared to those who attended < 6 sessions. Patients who attended between one and four psychological counselling sessions had significantly higher mental well being. Psychological support for the mental health needs of obese patients post surgery requires more attention. PMID- 30448985 TI - Evaluation of bony fusion after anterior cervical discectomy: a systematic literature review. AB - PURPOSE: Anterior cervical discectomy and fusion (ACDF) has proven effective in treating radicular arm pain. Post-operatively, cervical spine stability is temporarily challenged, but data on bony fusion and speed of fusion are ambiguous; optimum evaluation method and criteria are debated. AIM: To study bony fusion accomplishment and to obtain an overview of methods to evaluate fusion. METHODS: A literature search was performed in PubMed and Embase. Included studies had to report original data concerning 1- or 2-level ACDF with intervertebral device or bone graft, where bony fusion was assessed using CT scans or X-rays. RESULTS: A total of 146 articles comprising 10,208 patients were included. Bony fusion was generally defined as "the presence of trabecular bridging" and/or "the absence of motion". Fusion was accomplished in 90.1% of patients at the final follow-up. No gold standard for assessment could be derived from the results. Addition of plates and/or cages with screws resulted in slightly higher accomplishment of fusion, but differences were not clinically relevant. Eighteen studies correlated clinical outcome with bony fusion, and 3 found a significant correlation between accomplishment and better clinical outcome. CONCLUSIONS: In approximately 90% of patients, bony fusion is accomplished one year after ACDF. As there is no generally accepted definition of bony fusion, different measuring techniques cannot be compared to a gold standard and it is impossible to determine the most accurate method. Variations in study design hamper conclusions on optimising the rate of bony fusion by choice of material and/or additives. Insufficient attention is paid to correlation between bony fusion and clinical outcome. These slides can be retrieved from electronic supplementary material. PMID- 30448986 TI - Low back pain patients and controls display functional differences in endplates and vertebrae measured with T2-mapping. AB - PURPOSE: The aim was to (1) verify our previous finding that endplates (EPs) display load-induced T2-changes, (2) investigate whether vertebrae display load induced T2-changes and (3) investigate whether EPs and vertebrae in LBP patients and controls display T2-differences during conventional unloaded MRI and axial loaded MRI (alMRI). METHODS: Twenty-seven patients (mean 39 years) and 12 (mean 38 years) controls were examined with T2-mapping on a 1.5 T scanner during conventional unloaded MRI and subsequently during alMRI (Dynawell(r) loading device), separated by approximately 20 min. For determination of EP and vertebral T2-values, volumetric regions of interest were manually segmented. Each vertebra was then divided into half to obtain superior and inferior units. The presence of EP changes (visual inhomogeneity in the EP zone), Schmorl's nodules and Modic changes were registered. RESULTS: For conventional unloaded MRI, the T2-values in the superior and inferior vertebral units and the EPs were significantly higher in the patients compared with controls (p < 0.03, p < 0.006) even when adjusted for the presence of Modic changes, Schmorl's nodules and EP signal changes. alMRI induced significant changes in the superior EPs of the patients (p < 0.001). Additionally, the T2-value differed significantly between the superior and inferior EP, as well as between the superior and inferior vertebra with higher values in the inferior units (p < 0.001). CONCLUSION: This study demonstrated significantly higher EP and vertebral T2-values in LBP patients in comparison with controls. In addition, alMRI induced significant T2-changes in the superior EPs for patients but not for controls. Importantly, the T2-differences between the groups may indicate that EPs and vertebrae in LBP patients have altered biodynamical characteristics compared to controls and the higher T2-values measured in patients may represent early inflammation or impaired nutritional transport. These slides can be retrieved from electronic supplementary material. PMID- 30448987 TI - Intermediate screws or kyphoplasty: Which method of posterior short-segment fixation is better for treating single-level thoracolumbar burst fractures? AB - PURPOSE: To compare intermediate screws (IS) with kyphoplasty (KP) in posterior short-segment fixation (PSSF) for patients with single-level thoracolumbar burst fractures. METHODS: Between 2010 and 2016, 1465 patients were retrospectively reviewed; 48 patients were enrolled with a minimal follow-up of 2 years. Perioperative and functional outcomes were compared. The regional Cobb angle (CA) was included in radiographic analysis. Implant failures or CA correction loss over 10 degrees were regarded as surgical failures. Multiple linear regression was performed to investigate the risk factors of kyphosis recurrence. RESULTS: Fluoroscopic time (23.7 +/- 3.6 vs. 79.3 +/- 12.1 s, p < 0.001), operative time (109.6 +/- 13.1 vs. 123.8 +/- 19.0 min, p = 0.006) and blood loss (104.6 +/- 34.9 vs. 129.1 +/- 21.7 ml, p = 0.005) were all lower in the IS group. The KP group had lower Visual Analogue Scale scores (3.3 +/- 0.9 vs. 2.7 +/- 0.8, p = 0.028) and greater anterior body height (ABH) (30.3 +/- 9.0 vs. 36.3 +/- 11.0%, p = 0.044) after surgery, and less correction loss (5.6 +/- 2.7 vs. 0.4 +/- 1.2%, p < 0.001). Both groups had a CA correction loss of 4 degrees with a 10% failure rate. The A3 Magerl subclassification, smaller preoperative ABH and smaller postoperative CA had positive correlations with CA correction loss. CONCLUSION: PSSF with KP provides better back pain relief, greater ABH reduction and less correction loss, while IS has the advantages of less operative time, fluoroscopic time and blood loss. Magerl subclassification of burst fracture is a potential predictor for recurrent kyphosis. Reducing fractured vertebral body height rather than segmental curvature may be more important in PSSF. STUDY DESIGN: Retrospective, non-randomized controlled study. These slides can be retrieved under Electronic Supplementary Material. PMID- 30448988 TI - Posterior atlantoaxial dislocation without fracture or neurological symptoms treated by transoral-posterior approach surgery: a case report and literature review. AB - BACKGROUND: Atlantoaxial dislocation usually results from hyperextension trauma and is almost always accompanied by odontoid fracture and neurological symptoms. In most cases, patients with atlantoaxial dislocation die instantly. This is a rare report of posterior atlantoaxial dislocation without fracture and neurological symptoms effectively treated by transoral-posterior approach surgery, and only eleven similar cases have been previously reported. OBJECTIVE: To describe the very rare case of an adult posterior atlantoaxial dislocation patient without fracture who was neurologically treated using transoral-posterior approach surgery and to review the relevant literature. METHOD: A 52-year-old man riding a motorcycle was rear-ended by a car. Using X-ray, computed tomography (CT) scan and magnetic resonance imaging (MRI), he was diagnosed with posterior atlantoaxial dislocation without a related fracture or a significant change in spinal cord signal. Transoral-posterior approach surgery with sustained skull traction was used after failed closed reduction. RESULT: During a 6-month follow up observation, the lateral cervical spine radiography and sagittal reconstructions of CT scans demonstrated no instability of the atlantoaxial complex. Few patients experience posterior atlantoaxial dislocation without a related fracture or spinal cord deficit. For a patient who experiences trauma with hyperextension, such as in rear-end collisions, X-ray, CT scan and MRI should be performed to ensure that this injury is diagnosed. It is necessary to perform surgery to recover atlantoaxial stability, even in the absence of fracture or neurological symptoms. CONCLUSION: Transoral-posterior approach surgery is a safe and effective way to manage irreducible posterior atlantoaxial dislocation. PMID- 30448989 TI - Using Ca2+-channel biosensors to profile amphetamines and cathinones at monoamine transporters: electro-engineering cells to detect potential new psychoactive substances. AB - BACKGROUND: The appearance of stimulant-class new psychoactive substances (NPS) is a frequent and significant problem in our society. Cathinone variants are often sold illegally as 3,4-methylenedioxy methamphetamine ("ecstasy") or disguised for legal sale using misleading names such as "bath salts" and carry the risk of promoting disruptive mental states, addiction, and fatal overdose. The principal targets of these recreational drugs are monoamine transporters expressed in catecholaminergic and serotonergic neurons. Some transporter ligands can be transported into cells, where they can promote a massive release of neurotransmitters through reverse transport, and others can block uptake. A ligand's dopamine vs. serotonin transporter selectivity, potency, and activity as a substrate or blocker can help elucidate the abuse liability and subjective effects of a drug. OBJECTIVES: Here, we describe the discovery, development, and validation of an emerging methodology for compound activity assessment at monoamine transporters. KEY FINDINGS: Substrates generate inward electrical currents through transporters and can depolarize the plasma membrane, whereas blockers work as a "cork in a bottle" and function as antagonists. Voltage-gated Ca2+ channels were co-expressed with monoamine transporters in cultured cells and used to measure fluctuations of the membrane electrical potential. In this system, substrates of monoamine transporters produce reliable dose-dependent Ca2+ signals, while blockers hinder them. DISCUSSION: This system constitutes a novel use of voltage-gated Ca2+ channels as biosensors for the purpose of characterizing ligand activity at monoamine transporters using fluorimetry. This approach in combination with in vivo evaluations of drugs' abuse-related effects is a powerful strategy for anticipating potential stimulant-class NPS. PMID- 30448990 TI - Chronic treatment with a metabotropic mGlu2/3 receptor agonist diminishes behavioral response to a phenethylamine hallucinogen. AB - BACKGROUND: There is evidence that mGlu2/3 receptors regulate 5-HT2A signaling, interactions that have been theorized to play a role in the antipsychotic-like effects of mGlu2/3 agonists as well as the hallucinogenic effects of 5-HT2A agonists. One approach to unraveling this interaction is through the chronic administration of agonists at the two receptors, which should influence the functional properties of the targeted receptor due to receptor downregulation or desensitization and thereby alter crosstalk between the two receptors. In this study, we investigated whether chronic treatment with the mGlu2/3 agonist LY379268 would alter the behavioral response to a phenethylamine hallucinogen, 25CN-NBOH, which acts as a selective 5-HT2A agonist. METHODS: We first conducted a dose response of 25CN-NBOH (0.1, 0.3, 1, 3, or 10 mg/kg) to confirm the effects on head-twitch response (HTR) and then blockade studies with either the M100907 (0.1 mg/kg) or SB242084 (0.1, 0.3, or 1 mg/kg) to determine the contribution of 5 HT2A and 5-HT2C to 25CN-NBOH-induced HTR, respectively. To determine whether an mGlu2/3 agonist could block 25CN-NBOH-induced HTR, mice were pretreated with vehicle or LY379268 (0.1, 1, or 10 mg/kg) prior to 25CN-NBOH, and HTR was assessed. The effects of chronic LY379268 on 5-HT2A agonist-induced HTR were evaluated by treating mice with either vehicle or LY379268 (10 mg/kg) for 21 days and measuring 25CN-NBOH-induced HTR 48 h after the final LY379268 treatment. The following day (72 h after the final LY379268 treatment), the ability of acute LY379268 to block PCP-induced locomotor activity was assessed. RESULTS: 25CN-NBOH dose-dependently increased the HTR, a 5-HT2A-mediated behavior, in mice. The selective 5-HT2A antagonist M100907 completely blocked the HTR induced by 25CN NBOH, whereas the selective 5-HT2C antagonist SB242084 had no effect on the HTR. Administration of LY379268 (10 mg/kg SC) attenuated the HTR induced by 1 mg/kg 25CN-NBOH by ~ 50%. Chronic treatment (21 days) with LY379268 also attenuated the HTR response to 25CN-NBOH when tested 48 h after the last dose of LY379268. In locomotor tests, acute LY379268 significantly attenuated PCP-induced locomotor activity in the chronic vehicle treatment group; by contrast, there was only a trend for an overall interaction in the chronic LY379268 group, with LY379268 blocking the locomotor-stimulating effects of PCP only during the last 20 min. CONCLUSIONS: These data are consistent with a functional interaction between mGlu2/3 and 5-HT2A receptors, although the specific mechanism for the interaction is not known. These data support the hypothesis that mGlu2/3 receptors play a prominent role in modulating the behavioral response to 5-HT2A receptor activation. PMID- 30448991 TI - Effects of cocaine on the discriminative stimulus and reinforcing effects of mephedrone in male rats. AB - RATIONALE: Abuse of cathinones has been a worldwide health concern for some time. Their chemical structures and wide variation in pharmacodynamic effects have led to clinical and preclinical effects that can be both similar to and different from other psychoactive substances such as methylenedioxymethamphetamine (MDMA), methamphetamine, and cocaine. OBJECTIVE: The present study examined the discriminative stimulus and reinforcing effects of mephedrone to further characterize the behavioral and pharmacological profile of this first-generation substituted methcathinone. METHODS: Rats were trained to discriminate mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 (FR-20) schedule of food presentation. After establishing dose-effect curves for increasing cumulative doses of mephedrone, substitution tests were conducted with bupropion (5.6-32 mg/kg), cocaine (1.8-18 mg/kg), morphine (0.56-10 mg/kg), and amitriptyline (3.2 32 mg/kg). In addition, cocaine (3.2-18 mg/kg) and the serotonin type-2 (5-HT2) receptor antagonist ritanserin (1, 3.2, and 10 mg/kg) were administered prior to the cumulative doses of mephedrone. Lastly, varying infusion doses of cocaine were substituted for mephedrone in subjects trained to self-administer mephedrone, and varying infusion doses of mephedrone were substituted for cocaine in subjects trained to self-administer cocaine to assess the importance of drug history on the reinforcing effects of mephedrone. RESULTS: Of the drugs tested, cocaine had the highest level of mephedrone-lever responding when administered alone (73.5%). In combination with mephedrone, cocaine shifted the mephedrone dose-effect curve upwards in an infra-additive manner. Ritanserin had a small, but non-significant, effect on mephedrone's discriminative stimulus effects. An extensive history (baseline) of cocaine self-administration increased mephedrone self-administration compared to that obtained in mephedrone-trained subjects, whereas a baseline of mephedrone self-administration decreased cocaine self administration compared to that obtained in cocaine-trained subjects. CONCLUSION: The similarity between the discriminative stimulus effects of cocaine and mephedrone in male rats suggests an important overlap and the relative importance of the dopamine (DAT) and serotonin (SERT) transporters. The self-administration data suggest that mephedrone is less reinforcing than cocaine, but that a history of responding for cocaine can increase the reinforcing effects of mephedrone. PMID- 30448992 TI - Metabolomics signature associated with circulating serum selenoprotein P levels. AB - PURPOSE: Selenoprotein P (SELENOP) has been previously related to various metabolic traits with partially conflicting results. The identification of SELENOP-associated metabolites, using an untargeted metabolomics approach, may provide novel biological insights relevant to disentangle the role of SELENOP in human health. METHODS: In this cross-sectional study, 572 serum metabolites were identified by comparing the obtained LC-MS/MS spectra with spectra stored in Metabolon's spectra library. Serum SELENOP levels were measured in 832 men and women using an ELISA kit. RESULTS: Circulating SELENOP levels were associated with 24 out of 572 metabolites after accounting for the number of independent dimensions in the metabolomics data, including inverse associations with alanine, glutamate, leucine, isoleucine and valine, an unknown compound X-12063, urate and the peptides gamma-glutamyl-leucine, and N-acetylcarnosine. Positive associations were observed between SELENOP and several lipid compounds. Of the identified metabolites, each standard deviation increase in the branched-chain amino acids (isoleucine, leucine, valine), alanine and gamma-glutamyl-leucine was related to higher odds of having T2DM [OR (95% CI): 1.96 (1.41-2.73); 1.62 (1.15-2.28); 1.94 (1.45-2.60), 1.57 (1.17-2.11), and 1.52 (1.13-2.05), respectively]. CONCLUSIONS: Higher serum SELENOP levels were associated with an overall healthy metabolomics profile, which may provide further insights into potential mechanisms of SELENOP associated metabolic disorders. PMID- 30448993 TI - Student monitoring of the ecological quality of neotropical urban streams. AB - Most Latin American demands for drinking water are in or near urban areas. However, population growth and untreated sewage disposal degrade water quality, with negative effects for biodiversity and ecosystem services. Mobilizing society to monitor quality of urban watercourses facilitates training and allows diagnosis that may further help implement mitigation and management strategies. Therefore, our research was conducted in a > 4000 km2 metropolitan region of high human influence. Urban water body assessments were conducted by 1965 teachers and students and their consistency validated by rigorous scientific methods. The assessments revealed degradation of physical habitat, water quality, or biology in 91% of the evaluated urban stream sites. Increased knowledge concerning environmental stressors and biological responses by local citizens may increase their participation in public policy development and implementation. We conclude that participatory scientific monitoring is a viable way for improving science education, increasing social participation, and improving the ecosystem services provided by urban watercourses. PMID- 30448994 TI - Setting priorities in biodiversity conservation: An exercise with students, recent graduates, and environmental managers in Brazil. AB - Facing a global biodiversity conservation crisis, urgent decisions are needed but prioritization is challenging. We analyzed how students, recent graduates of Biology, Law, and Engineering, and environmental managers in Brazil ranked ten conservation actions. Reduction in habitat loss and in overexploitation, and in situ protection were consensual top priorities. Freshmen students have similar priorities, which change as their courses advance. Biologists, engineers, and lawyers agree about only two priorities, but not in a consensual order. Biologists gave little importance to financial resources; managers much higher, and lower to action plans. Flagship species and ex situ protection were least priorities for all. Prioritization was influenced by educational level and experience and some priorities are counterintuitive. Our study reinforces the need to assess inter-groups differences, so conservationists could anticipate tendencies of single group decisions. Gaps in the conservation-oriented education of potential decision-makers must be filled, so their decisions could be more effective. PMID- 30448995 TI - Towards future-oriented conservation: Managing protected areas in an era of climate change. AB - Management of protected areas must adapt to climate impacts, and prepare for ongoing ecological transformation. Future-Proofing Conservation is a dialogue based, multi-stakeholder learning process that supports conservation managers to consider the implications of climate change for governance and management. It takes participants through a series of conceptual transitions to identify new management options that are robust to a range of possible biophysical futures, and steps that they can take now to prepare for ecological transformation. We outline the Future-Proofing Conservation process, and demonstrate its application in a pilot programme in Colombia. This process can be applied and adapted to a wide range of climate adaptation contexts, to support practitioners in developing positive ways forward for management and decision-making. By acknowledging scientific uncertainty, considering social values, and rethinking the rules that shape conservation governance, participants can identify new strategies towards "future-oriented conservation" over the long term. PMID- 30448996 TI - Embracing an interdisciplinary approach to plastics pollution awareness and action. AB - This paper considers how an interdisciplinary approach to the "wicked problem" of plastics pollution offers unique and important collaborative possibilities. Specially, the paper considers the approach of the Synthetic Collective, a group comprising artists, humanities scholars, and scientists. Considering first how artists and scientists might respond differently to tracking, mapping, understanding, and representing plastics pollution, we then look for potential points of commonality across disciplinary difference. In respect to the urgent and multifaceted problem of marine plastics pollution in the Great Lakes region, we ask what are some of the successes and pitfalls of bringing together diverse approaches and interests? The paper concludes with a clear strategy: a set of instructions geared towards building successful interdisciplinary collaborations. Ultimately, we conclude that a strong relationship amongst scientists and artists is possible, fruitful, and indeed warranted when shared goals are the driving principle of the group. PMID- 30448997 TI - Building actor-centric transformative capacity through city-university partnerships. AB - Cities worldwide are rising to the challenge of sustainable development, calling for large-scale and fast-paced transformations towards sustainability. Urban sustainability challenges are now being reframed as a lack of capacity of individuals and organizations to carry out such socio-technical transformations. This article expands on transformative capacity literature by elucidating the concept of actor-centric transformative capacity. It focuses on the unique role city-university partnerships (CUPs) can play in catalyzing and supporting effective urban sustainability transformations. Two case studies on CUPs in Portland, Oregon and Tempe, Arizona are used to identify determinants of actor centric transformative capacity, their role in the transformative capacity of urban systems, and how they are built through CUPs. The article concludes with strategies for building effective CUPs capable of building actor-centric transformative capacity among university actors and city administrators. PMID- 30448998 TI - Urban Growth, Land-use Efficiency and Local Socioeconomic Context: A Comparative Analysis of 417 Metropolitan Regions in Europe. AB - The present study presents a multidimensional analysis of land-use efficiency in terms of per-capita built-up area over 417 metropolitan regions from 27 European countries. The study period encompasses two urban phases including economic expansion (2000-2007) and crisis (2008-2015). Multiple geographical gradients were identified as relevant predictors of land-use efficiency across Europe. The socioeconomic variables most associated with high land-use efficiency were per capita disposable income (in Western, Atlantic and Central Europe) and income growth during 2000-2007 (in Eastern Europe), indicating that wealthier cities are characterized by higher land-use efficiency. Land-use efficiency increased in contexts with diversified urban landscapes. PMID- 30448999 TI - Comorbid cancer and use of thrombolysis in acute pulmonary embolism. AB - Guidelines suggest the use of thrombolytic therapy for acute pulmonary embolism (PE) patients with hypotension who are not at high-risk of bleeding. Data describing the use of thrombolysis in patients with cancer are scarce. The aim of this study was to evaluate the relationship between cancer and the use of thrombolysis for acute PE. The 2013 and 2014 US National Inpatient Sample was used to identify admissions for acute PE. Identified admissions were stratified based on the presence or absence of cancer. Multivariable logistic regression was performed to determine the association between comorbid cancer and the odds of receiving thrombolysis after adjustment for patient- and hospital-level covariates. In those receiving thrombolysis, the association between cancer and in-hospital mortality was determined using logistic regression after adjusting for age >= 65 years and sex. We identified 72,546 admissions for acute PE; of which, 14.7% (n = 10,673) had comorbid cancer. A total of 3.4% (n = 2439) of patients received thrombolysis. Upon multivariable adjustment, cancer was associated with decreased odds of receiving thrombolysis (odds ratio = 0.55; 95% confidence interval = 0.48-0.64). When the population was restricted to PE admissions receiving thrombolysis, mortality occurred in 315 (12.9%) admissions; with no difference in in-hospital mortality observed between those with versus without cancer (p = 0.11). In this study of admissions for acute PE, comorbid cancer was associated with decreased odds of receiving thrombolysis. As PE is a common complication among patients with cancer, the risk-benefit profile of thrombolysis in this patient population should be determined. PMID- 30449001 TI - Bleeding rates of Veterans taking apixaban or rivaroxaban for atrial fibrillation or venous thromboembolism. AB - This study examined potential differences in bleeding between apixaban and rivaroxaban, the most commonly utilized direct oral anticoagulants at the Richard L. Roudebush VA Medical Center. Additionally, the analysis included a comparison between observed and literature-reported bleeding rates. This retrospective chart review examined 452 (39%) Veterans receiving rivaroxaban and 716 (61%) Veterans receiving apixaban. Bleeding rates were expressed per 100 patient-years and the overall rates were analyzed as the primary analysis. Secondary objectives included comparisons based on indication and severity, as well as comparisons to literature-reported bleed rates, time to bleeding event, and location of the bleed. The analysis did not detect any statistically significant differences between apixaban and rivaroxaban in terms of overall, (ARR 0.90% per 100 patient years, 95% CI - 0.58 to 2.38%, p > 0.05) major, (ARR 0.22% per 100 patient-years, 95% CI - 0.74 to 1.17%, p > 0.05) or non-major clinically relevant (ARR 0.35% per 100 patient-years, 95% CI - 0.57 to 1.27%, p > 0.05) bleeding. Observed bleeding for both rivaroxaban and apixaban in the Veteran population exceeded the rates reported by the literature when used for atrial fibrillation (1.96% vs. 0.15%, p < 0.05; 1.08% vs. 0.16%, p < 0.05) but the opposite was seen for long term venous thromboembolism (VTE) treatment (3.97% vs. 8.03%, p < 0.0001; 0.14% vs. 15.51%, p < 0.0001) or extended VTE prophylaxis (0.07% vs 5.98%, p < 0.0001; 0.07% vs 1.88%, p < 0.01). Results from this study suggest these agents impart similar levels of risk, but variations in bleeding risk between the Veteran population and the patients in the original clinical trials may exist. PMID- 30449000 TI - Fatal warfarin-associated intracranial hemorrhage in atrial fibrillation inpatients. AB - Ischemic stroke and major bleeding, mostly due to intracranial hemorrhage (ICH), cause about the same rates of death in pivotal randomized trials of direct oral anticoagulants (DOACs) versus warfarin for stroke prevention in atrial fibrillation (AF). We analyzed our AF inpatient database to determine whether any ICH-related deaths were potentially preventable. Among 5008 patients admitted to our institution between May 2008 and September 2014 with a diagnosis of AF, eight had fatal ICH between admission and 90 days follow-up. The mean age of these patients was 85 years; 62% were male. Localization of the ICH was intraparenchymal in 62% and subdural in 38%. CHA2DS2-VASc scores ranged from 4 to 7, and the HAS-BLED scores ranged from 3 to 7. Three of the eight fatal ICHs were directly due to falls. All 8 patients were taking warfarin. One was taking concomitant aspirin. At the time ICH was diagnosed, one patient had an INR of 5.4. Five patients had an INR within the target therapeutic range of 2.0-3.0, and two had an INR less than 2.0. After multivariate adjustment, a history of falls was the sole independent predictor of fatal ICH (OR 22.3; 95% CI 2.5-60.3). In conclusion, most patients had achieved the target INR at the time of ICH, and the primary precipitant of fatal ICH was often a fall. Using DOACs instead of warfarin and implementing structured fall-prevention programs in high-risk patients could further reduce mortality from ICH in AF. PMID- 30449002 TI - The synthetic peptide LyeTxI-b derived from Lycosa erythrognatha spider venom is cytotoxic to U-87 MG glioblastoma cells. AB - Antimicrobial peptides present a broad spectrum of therapeutic applications, including their use as anticancer peptides. These peptides have as target microbial, normal, and cancerous cells. The oncological properties of these peptides may occur by membranolytic mechanisms or non-membranolytics. In this work, we demonstrate for the first time the cytotoxic effects of the cationic alpha-helical antimicrobial peptide LyeTx I-b on glioblastoma lineage U87-MG. The anticancer property of this peptide was associated with a membranolytic mechanism. Loss of membrane integrity occurred after incubation with the peptide for 15 min, as shown by trypan blue uptake, reduction of calcein-AM conversion, and LDH release. Morphological studies using scanning electron microscopy demonstrated disruption of the plasma membrane from cells treated with LyeTx I-b, including the formation of holes or pores. Transmission electron microscopy analyses showed swollen nuclei with mild DNA condensation, cell volume increase with an electron-lucent cytoplasm and organelle vacuolization, but without the rupture of nuclear or plasmatic membranes. Morphometric analyses revealed a high percentage of cells in necroptosis stages, followed by necrosis and apoptosis at lower levels. Necrostatin-1, a known inhibitor of necroptosis, partially protected the cells from the toxicity of the peptide in a concentration-dependent manner. Imaging flow cytometry confirmed that 59% of the cells underwent necroptosis after 3-h incubation with the peptide. It is noteworthy that LyeTx I b showed only mild cytotoxicity against normal fibroblasts of human and monkey cell lines and low hemolytic activity in human erythrocytes. All data together point out the anticancer potential of this peptide. PMID- 30449003 TI - Correction to: Metabolic relevance for N-hydroxy L-arginine reduction in estrogen negative breast cancer cells. AB - We found a unit error with our LC-MS lower limit of quantitation (LLOQ) measurement in the Amino Acids Journal. PMID- 30449004 TI - Asymmetric synthesis of (2S,3S)-3-Me-glutamine and (R)-allo-threonine derivatives proper for solid-phase peptide coupling. AB - Practical new routes for preparation of (2S,3S)-3-Me-glutamine and (R)-allo threonine derivatives, the key structural components of cytotoxic marine peptides callipeltin O and Q, suitable for the Fmoc-SPPS, were developed. (2S,3S)-Fmoc-3 Me-Gln(Xan)-OH was synthesized via Michael addition reactions of Ni (II) complex of chiral Gly-Schiff base; while Fmoc-(R)-allo-Thr-OH was prepared using chiral Ni (II) complex-assisted alpha-epimerization methodology, starting form (S) Thr(tBu)-OH. PMID- 30449005 TI - Exogenous glutamine impairs neutrophils migration into infections sites elicited by lipopolysaccharide by a multistep mechanism. AB - Glutamine (GLN) is the most abundant free amino acid in the body, and is considered as a conditionally essential amino acid under stress conditions, acting as an important modulator of the immune response. We here investigated the role of exogenous GLN treatment on leukocyte migration after the onset of endotoxemia and the intracellular mechanisms of GLN actions on neutrophils. Two in vivo models of endotoxemia caused by lipopolysaccharide of Escherichia coli (LPS) injection were carried out in male outbred Balb/C mice 2-3 months old, as follow: (1) LPS (50 MUg/kg) was intravenously injected 1 h prior to intravenous injection of GLN (0.75 mg/kg) and samples were collected 2 h later to investigate the role of GLN on the acute lung inflammation; (2) LPS (1 mg/kg) was intraperitoneally injected 1 h prior to intravenous injection of GLN (0.75 mg/kg) and samples were collected 18 h later to measure the effects of GLN on local and later phases of inflammation in the peritoneum. Results showed that GLN administration reduced the number of neutrophils in the inflamed lungs, partially recovery of the reduced number of leukocytes in the blood; reduced adhesion molecules on lung endothelium and on circulating neutrophils. Moreover, GLN treatment diminished the number of neutrophils, levels of chemotactic cytokine CXCL2 in the inflamed peritoneum, and neutrophils collected from the peritoneum of GLN-treated mice presented lower levels of Rho, Rac, and JNK. Together, our data show novel mechanisms involved in the actions of GLN on neutrophils migration. PMID- 30449006 TI - Carnosine protects cardiac myocytes against lipid peroxidation products. AB - Endogenous histidyl dipeptides such as carnosine (beta-alanine-L-histidine) form conjugates with lipid peroxidation products such as 4-hydroxy-trans-2-nonenal (HNE and acrolein), chelate metals, and protect against myocardial ischemic injury. Nevertheless, it is unclear whether these peptides protect against cardiac injury by directly reacting with lipid peroxidation products. Hence, to examine whether changes in the structure of carnosine could affect its aldehyde reactivity and metal chelating ability, we synthesized methylated analogs of carnosine, balenine (beta-alanine-Ntau-methylhistidine) and dimethyl balenine (DMB), and measured their aldehyde reactivity and metal chelating properties. We found that methylation of Ntau residue of imidazole ring (balenine) or trimethylation of carnosine backbone at Ntau residue of imidazole ring and terminal amine group dimethyl balenine (DMB) abolishes the ability of these peptides to react with HNE. Incubation of balenine with acrolein resulted in the formation of single product (m/z 297), whereas DMB did not react with acrolein. In comparison with carnosine, balenine exhibited moderate acrolein quenching capacity. The Fe2+ chelating ability of balenine was higher than that of carnosine, whereas DMB lacked chelating capacity. Pretreatment of cardiac myocytes with carnosine increased the mean lifetime of myocytes superfused with HNE or acrolein compared with balenine or DMB. Collectively, these results suggest that carnosine protects cardiac myocytes against HNE and acrolein toxicity by directly reacting with these aldehydes. This reaction involves both the amino group of beta-alanyl residue and the imidazole residue of L-histidine. Methylation of these sites prevents or abolishes the aldehyde reactivity of carnosine, alters its metal-chelating property, and diminishes its ability to prevent electrophilic injury. PMID- 30449007 TI - A Simulation-Based Workshop to Improve Dermatologists' Communication Skills: A Pilot for Continuing Medical Education. AB - INTRODUCTION: Communication skills influence the quality of health care and patient experience; both may affect provider reimbursement. There are few opportunities available for practicing physicians to receive direct feedback on communication in patient encounters. The purpose of this simulation-based patient encounter workshop was for dermatologists to practice and obtain feedback on their communication skills. METHODS: In March 2016, dermatologists participated in a workshop with four simulated patient encounters. Cases were developed based on a prior needs assessment. Standardized patient educators evaluated participants' communication using the Master Interview Rating Scale and provided verbal feedback. Physicians rated the usefulness of the simulation and the feedback received through a survey upon workshop completion. RESULTS: Of the 170 physicians who registered, 103 participated in the simulation. The workshop was highly rated in meeting its three learning objectives (score of 4.5-4.6 out of a maximum score of 5). The lowest-rated communication skills were as follows: allowing the patient to share their narrative thread (3.1), summarizing the patient's history from the provider (3.8), and assessing patient understanding (3.8). CONCLUSIONS: Participants reported that this communication workshop effectively satisfied its learning objectives. Opportunities to practice and improve communication skills as part of continuing medical education will benefit the clinical experience of patients and physicians alike, and the workshop may be formatted to serve physicians of other specialties. The lowest-scoring communication areas identified in this study present an opportunity to develop a tailored curriculum for physician-patient communication in the future. PMID- 30449008 TI - Laparoscopic assisted insertion of a colonic self-expandable metallic stent. PMID- 30449009 TI - Periodic vicissitudes of different concentrations of a developed prototype killed S. aureus mastitis vaccine on immune modulators, mediators and immunoglobulins in cows. AB - Mastitis is the inflammation of the mammary gland due to microbial infiltration causing a reduced mammary function. This study aims at developing a vaccine using Malaysian local isolate of Staphylococcus aureus and evaluating serum amyloid A, Interleukin-10, IgM and IgG responses periodically. Four bacterin concentrations (106, 107, 108 and 109 cfu/ml of the local isolate of S. aureus) were adjuvanted with aluminium potassium sulphate. Thirty cows grouped into 4 treatment groups (G ) were vaccinated (2 ml) intramuscularly, with a fifth G-A as control. The mean concentration (MC) of serum amyloid A (SAA) was significantly different (sig-d) (p ? 0.05) in G-D at 0 h post vaccination (PV), 3 h PV, 24 h PV, weeks 1, 2, 3 and 4 PV (6-, 15-, 5-, 12-, 11-, 4- and 11-fold increased (FI) respectively). The MC of serum amyloid A was also sig-d in G-E at 0 h PV, weeks 1, 2 and 4 PV (3, 8, 5 and 8 FI respectively). The MC of IL-10 was sig-d in G-D and C at 3 h PV and week 2 PV (5 and 2 FI respectively). The IgM MC was sig-d in G-B and C at 3 h PV (5 and 6 FI respectively), at 24 h PV (5 and 9 FI respectively), at week 3 PV(2 and 2 FI respectively) and week 4 PV (3 and 4 FI respectively). The MC of IgG was sig-d in G-E at 0 h, 3 h and week 3 PV(5, 6 and 2 FI respectively) and in G-D at weeks 1-4 (3, 3, 3 and 5 FI respectively). In conclusion, elevated levels of SAA, IgG and IL-10 in G-D(108) informed our choice of best dosage which can be used to evoke immunity in cows. PMID- 30449010 TI - Feeding balanced ration can improve the productivity and economics of milk production in dairy cattle: a comprehensive field study. PMID- 30449011 TI - Fatty acid profile and carcass characteristics in castrated and uncastrated hair lambs. AB - The aim of this study was to investigate the effects of castration on carcass characteristics and fatty acid profile of visceral fat and meat from lambs. Eighteen six-month-old Santa Ines male lambs (18.9 +/- 2.4 kg of body weight (BW)) were used. Animals were assigned to two treatments according to their sexual condition: uncastrated (U) or castrated (C). During a 98-day experimental period, animals were kept on an Andropogon gayanus grass pasture area of 1 ha and supplemented with 200 g/animal/day of concentrate mixture. Water and mineral salt were available ad libitum. The lambs were weighed fortnightly, and at the last day of the trial, they were slaughtered for evaluation of carcass characteristics and fatty acids profile of perirenal fat and longissimus lumborum muscle samples. Castrated lambs showed higher BW than U during most part of the experiment (p < 0.05). Fat deposition was higher in C lambs as evidenced by their increased carcass fat cover. Meat from U lambs showed lower content of C16:0 and higher polyunsaturated fatty acids (PUFA) (p < 0.05) than that from C (U, 14.3 and C, 10.5%). Conjugated linoleic acid (CLA) content was not affected by castration (p > 0.05) (U, 0.74 and C, 0.76%). The cis-9, cis-12 C18:2n-6 (U, 10.6 and C, 6.86%) fatty acid and the PUFA:SFA (saturated fatty acids) ratio (U, 0.36 and C, 0.25) were higher in the muscle of U lambs (p < 0.05), indicating that the meat from U animals may provide more benefits to human health than that of C. PMID- 30449013 TI - Nitroxoline: an option for the treatment of urinary tract infection with multi resistant uropathogenic bacteria. AB - The number of multi-resistant uropathogens is increasing. A multi-morbid patient developed a symptomatic urinary tract infection with two multi-resistant bacteria, namely Klebsiella pneumoniae and Proteus mirabilis. Nitroxoline was the only drug active against both uropathogens. Obviously, nitroxoline can be an option for the therapy of a urinary tract infection with multi-resistant uropathogens. PMID- 30449012 TI - Increased implantation rate after intrauterine infusion of a small volume of human chorionic gonadotropin at the time of embryo transfer: a randomized, double blind controlled study. AB - PURPOSE: Intrauterine human chorionic gonadotropin (hCG) infusion at the time of embryo transfer (ET) has resulted in controversial results. We evaluated the effects of intrauterine infusion of a small volume of hCG at the time of ET in fresh and frozen-thawed cycles. METHODS: Infertile women scheduled for ET with either fresh or frozen-thawed cycles were enrolled and randomized into two groups (n = 100 each): an hCG group, who received 500 IU of hCG in 10 uL culture medium infused into the uterine cavity using a soft catheter 4 min before ET; and a control group, who received 10 uL of culture medium alone by the same technique. The primary outcome was the implantation rate. The secondary outcomes were clinical pregnancy and live birth rate. RESULTS: Two hundred infertile women aged 18-43 years, undergoing fresh or frozen-thawed ET were enrolled, regardless of any previous transfer cycles. The implantation rate was significantly higher in the hCG group compared with the control group (28.8% vs. 18.2%, p = 0.030). The clinical pregnancy rates were similar in both groups (42% vs. 30%, p = 0.077). The live birth rates were also similar (29% and 23% in the hCG and control group, respectively). CONCLUSIONS: Intrauterine infusion of a small volume of hCG at the time of ET can significantly improve the implantation rate, while the clinical pregnancy rate may only be improved in younger patients (aged < 40 years). This technique may thus be of benefit to patients undergoing clinical infertility treatment. PMID- 30449014 TI - Regulatory T Cell Plasticity and Stability and Autoimmune Diseases. AB - CD4+CD25+ regulatory T cells (Tregs) are a class of CD4+ T cells with immunosuppressive functions that play a critical role in maintaining immune homeostasis. However, in certain disease settings, Tregs demonstrate plastic differentiation, and the stability of these Tregs, which is characterized by the stable expression or protective epigenetic modifications of the transcription factor Foxp3, becomes abnormal. Plastic Tregs have some features of helper T (Th) cells, such as the secretion of Th-related cytokines and the expression of specific transcription factors in Th cells, but also still retain the expression of Foxp3, a feature of Tregs. Although such Th-like Tregs can secrete pro inflammatory cytokines, they still possess a strong ability to inhibit specific Th cell responses. Therefore, the plastic differentiation of Tregs not only increases the complexity of the immune circumstances under pathological conditions, especially autoimmune diseases, but also shows an association with changes in the stability of Tregs. The plastic differentiation and stability change of Tregs play vital roles in the progression of diseases. This review focuses on the phenotypic characteristics, functions, and formation conditions of several plastic Tregs and also summarizes the changes of Treg stability and their effects on inhibitory function. Additionally, the effects of Treg plasticity and stability on disease prognosis for several autoimmune diseases were also investigated in order to better understand the relationship between Tregs and autoimmune diseases. PMID- 30449015 TI - Association of tenacious goal pursuit and flexible goal adjustment with out-of home mobility among community-dwelling older people. AB - BACKGROUND: As people age, functional losses may limit the potential to get outside the home and participate in desired activities and community life. Coping with age-related losses has been reported to be important for psychological well being. Hitherto is not known whether active use of coping strategies also helps maintain out-of-home mobility. AIMS: We investigated how two coping strategies, tenacious goal pursuit (TGP; persistency in reaching one's goals) and flexible goal adjustment (FGA; adjusting one's goals to changed circumstances), are associated with life-space mobility and perceived autonomy in participation outdoors among community-dwelling older people. METHODS: Participants (n = 186) were aged 79-93 years. TGP and FGA were self-reported using separate scales. Perceived autonomy in participation was assessed with the Impact on Participation and Autonomy Outdoors-subscale, and life-space mobility with the Life-Space Assessment. Two-step cluster analysis was used to create data-driven coping profiles of TGP and FGA. RESULTS: General linear model analyses showed that the profile including highly tenacious and flexible older people had the highest life space mobility and perceived autonomy outdoors, whereas the profile including people with low TGP and low FGA showed the lowest scores. Depressive symptoms attenuated the associations. CONCLUSIONS: Active use of both TGP and FGA is favorable for out-of-home mobility and enables more active participation in society in later life. PMID- 30449016 TI - Intensive formation of coccoid forms as a feature strongly associated with highly pathogenic Helicobacter pylori strains. AB - The variability of Helicobacter pylori morphology and the heterogeneity of virulence factors expressed by these bacteria play a key role as a driving force for adaptation to the hostile stomach environment. The aim of the study was to determine the relationship between the presence of certain genes encoding virulence factors and H. pylori morphology. One reference and 13 clinical H. pylori strains with a known virulence profile (vacA, cagA, babA2, dupA, and iceA) were used in this study. Bacteria were cultured for 1 h and 24 h in stressogenic culture conditions, i.e., serum-free BHI broths at suboptimal conditions (room temperature and atmosphere, without shaking). H. pylori cell morphology was observed by light and scanning electron microscopy. The vacA polymorphism and the cagA and babA2 presence were positively correlated with the reduction in cell size. Exposure to short-time stressogenic conditions caused more intense transformation to coccoid forms in highly pathogenic H. pylori type I strains (35.83% and 47.5% for type I s1m2 and I s1m1, respectively) than in intermediate pathogenic type III (8.17%) and low pathogenic type II (9.92%) strains. The inverse relationship was observed for the number of rods, which were more common in type III (46.83%) and II (48.42%) strains than in type I s1m2 (19.25%) or I s1m1 (6.58%) strains. Our results suggest that there is a close relationship between the presence of virulence genes of H. pylori strains and their adaptive morphological features. PMID- 30449017 TI - Rationale and methods of an observational study to support the design of a nationwide surgical registry: the MIDAS study. AB - BACKGROUNDSurgical registries are becoming increasingly popular. In addition, Swiss legislation requires data on therapeutic outcome quality. The Swiss Association of Surgeons (Schweizerische Gesellschaft Chirurgie, SGC-SCC) has already agreed on a first minimum data set. However, in the long run the scope and content of the registry should be evidence-based and not only accepted by professional stakeholders. The MIDAS study aims at providing such evidence for the example population of patients undergoing emergency or elective hip surgery. Five relevant aspects are considered: (1) choice of instruments for assessing health related quality of life (HRQoL); (2) optimal time-point for assessment; (3) use of proxy assessments; (4) choice of pre-surgery risk factors; and (5) assessment of peri- and postoperative variables.METHODSMIDAS is a longitudinal observational multicentre study. All patients suffering from a femoral neck fracture or from arthritis of the hip joint with an indication for prosthetic joint replacement surgery will be offered participation. The study is based on a combination of routine data from clinical standard practice with specifically documented data to be reported by the treating clinician and data to be collected in cooperation with the patient - in particular patient-reported outcome measures (PROMs). The latter include the Health Utility Index Mark 3 (HUI3) and Euro-Qol 5D (EQ-5D) as generic instruments, Hip Disability and Osteoarthritis Outcome Score (HOOS) as a disease specific instrument for the assessment of HRQoL, and two performance-based functional tests. Data will be collected at baseline, during hospitalisation/at discharge and at three routine follow-up visits. All patients will be asked to name a person for assessing proxy-perceived HRQoL.DISCUSSIONTo the best of our knowledge, this is the first study explicitly addressing questions about the design of a national surgical registry in an empirical manner. The study aims at providing a scientific base for decisions regarding scope and content of a potential national Swiss surgical registry. We designed a pragmatic study to envision data collection in a national registry with the option of specifying isolated research questions of interest. One focus of the study is the use of PROMs, and we hope that our study and their results will inspire also other surgical registries to take this important step forward.Trial registrationRegistered at the "Deutsches Register Klinischer Studien (DRKS)", the German Clinical Trials Registry, since this registry meets the scope and methodology of the proposed study. Registration no.: DRKS00012991 PMID- 30449018 TI - Clinical presentation of 54 patients with endogenous hyperinsulinaemic hypoglycaemia: a neurological chameleon (observational study). AB - BACKGROUNDImportant causes of endogenous hyperinsulinaemic hypoglycaemia (EHH) in adult patients are insulinoma and adult nesidioblastosis. Data on main symptoms in EHH are scarce and controversial. We analysed main symptoms of patients with EHH in the framework of two prospective studies investigating glucagon-like peptide-1 receptor imaging.METHODSPatients were referred from secondary European endocrine centres and endocrinologists. Inclusion criteria were biochemically proven EHH (glucose <2.5 mmol/l in the presence of inadequate insulin and C peptide levels) with neurological hypoglycaemic symptoms. Demographic characteristics and aetiologies of the patients with EHH were retrieved. Main symptoms were categorised into neurological, sympathicoadrenal (sweating, tremor, palpitation, hunger, shivering and pallor) and nonspecific other symptoms (nonspecific asthenia, weight gain, gastrointestinal symptoms and headaches). Neurological symptoms were subdivided into moderately impaired consciousness (confusion, dizziness, somnolence and delirium), visual, speech and sensorimotor impairment, severely impaired consciousness (loss of consciousness and apathy), attention deficit, seizures and personality changes. Biochemical assessment and duration of EHH at the end of a fasting test were recorded.RESULTSFifty-four patients with full documentation were included in the analysis (74% female; mean age 54 years, range 22-84). Median duration from onset of symptoms to diagnosis of EHH was 12 months (range 0-120). Fifty (92.6%) patients had neurological symptoms, including moderately impaired consciousness (46.3%), visual, speech and sensorimotor function impairment (44.4%), severely impaired consciousness (37%), attention deficit (31.5%), seizures (16.7%) and personality change (13%). Sympathicoadrenal symptoms were present in 33 (61.1%) patients. Nonspecific other symptoms occurred in 36 (66.7%) patients. 43 patients (79.6%) suffered from symptoms of at least two different categories.CONCLUSIONSClinical symptoms of EHH are characterised by a wide variety of mainly different neurological symptoms ("neurological chameleon"). EHH should be considered as a differential diagnosis in many neurological disorders.Trial registration numbersNCT00937079 & NCT02127541 PMID- 30449019 TI - What is the profile of older drivers considered medically unfit to drive? A cross sectional survey in Western Switzerland. AB - OBJECTIVE: We aimed to assess how often and for what reasons general practitioners (GPs) consider older drivers medically unfit to drive. METHODS: All GPs certified to carry out fitness-to-drive assessments in Geneva (medical assessors, n = 69), as well as a random sample of 500 GPs practising in Vaud, Neuchatel and Jura, were asked to complete a questionnaire about the mean number of assessments per week, the number of negative decisions in the previous year and the main reason for the most recent negative decision. RESULTS: Completed questionnaires were returned by 268 respondents (45 medical assessors and 223 other GPs, participation rate: 47%). The mean proportion of drivers with a negative decision was 2.2% (standard deviation [SD] 3.3). The proportion was slightly lower among medical assessors (1.1%, SD 1.3) compared to other GPs (2.3%, SD 3.3, p <0.001). The main reasons for being considered medically unfit to drive were cognitive (64%) and visual acuity impairments (18%). CONCLUSIONS: GPs in this survey reported considering approximately 2% of older drivers as medically unfit to drive, mainly because of cognitive and visual acuity impairments. Further research should identify how GPs decide if older drivers are fit or unfit, and assess the effectiveness of medical screening in reducing car crashes involving older drivers. PMID- 30449020 TI - Demographics and Clinical Outcomes of Patients Undergoing Anterior Cruciate Ligament Reconstruction with a Planned or Unplanned Hybrid Graft. AB - The purpose of this study was to report the demographics and clinical outcomes of patients at our institution following anterior cruciate ligament reconstruction (ACLR) with a planned or unplanned hybrid autograft-allograft. At a minimum 2 year follow-up, patients at our institution who had undergone primary ACLR with a planned (P) or unplanned (U) hybrid graft using fresh-frozen allografts were contacted to complete a survey containing the Knee Injury and Osteoarthritis Outcome Score, Subjective International Knee Documentation Committee score, Single Assessment Numeric Evaluation, 12-Item Short Form Health Survey, and visual analog scale for activity level. Demographics were compared between groups. Patient-reported outcomes (PROs) and a revision rate were reported for each group. Mean follow-up among all patients was 3.3 years. Revision rate at follow-up was 0.8 and 6.3% in the P and U groups, respectively (p = 0.03). Among patients reached for follow-up (90 P, 30 U), a lower proportion of males was found in the unplanned hybrid graft group (P: 52%, U: 23%, p < 0.01). Unplanned hybrid graft patients were significantly younger at the time of surgery (P: 41.0 years, U: 31.0 years, p < 0.0001). Graft size did not differ between groups (P: 9.1 mm, U: 8.9 mm, p = 0.11). Patients in both groups achieved moderate to high PROs. Demographics differ between patients undergoing ACLR with a planned or unplanned hybrid graft. Patients with a planned hybrid graft are at a significantly reduced risk of postoperative graft failure, likely due to the older age of this group. PMID- 30449021 TI - Correlation of Meniscal Tear with Timing of Anterior Cruciate Ligament Reconstruction in Patients without Initially Concurrent Meniscal Tear. AB - The incidence of meniscal tear was reported to increase with the delay of anterior cruciate ligament reconstruction (ACLR). The tear may occur concurrently with the ACL injury or after the ACL injury. Few studies had focused on the patients whose meniscus is intact during ACL injury. We determined the correlation between timing of surgery and incidence of meniscal tears in ACL deficient knees with initially intact meniscus. We retrospectively reviewed 387 patients who had undergone primary ACLR. Time of initial ACL injury, magnetic resonance imaging (MRI) examination, and surgery was recorded. The MRI was reviewed by experienced radiologic and orthopaedic doctors. Intraoperative arthroscopic images were also obtained and reviewed. The type of tear noted during surgery was classified according to the modification of International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine classification of meniscal tears. Patients were divided into early (surgery within 12 months from injury) and late surgery group (surgery at more than 12 months from injury). There were 216 patients with intact medial meniscus and 257 patients with intact lateral meniscus on the postinjury MRI study. The incidence of medial meniscus tear (MMT) was significantly higher than lateral meniscus tear (LMT) during the ACLR (33.8 vs. 19.8%, p < 0.001). The incidence of MMT is higher in late group than in early group (53.7 vs. 29.1%, p = 0.004, odds ratio= 2.815). The incidence of LMT is mildly higher in late group but without statistics significance (23.8 vs. 18.6%, p = 0.364). In both MMT and LMT, the most common injury pattern observed was a longitudinal tear. The incidence of each type is not different between early and late group. For patients without concurrent meniscal injuries with the ACL tear, the incidence of MMT significantly increased if ACLR was performed more than 12 months after injury. The medial meniscus was more prone to injury than the lateral meniscus in chronic ACL-deficient knee. ACLR should be performed earlier to reduce the risk of meniscal tears for patients without initially concurrent meniscal tear. PMID- 30449022 TI - Posteromedial versus Anteromedial Hamstring Tendon Harvest for Anterior Cruciate Ligament Reconstruction: A Retrospective Comparison of Accidental Gracilis Harvests, Outcomes, and Operative Times. AB - Hamstring autografts are frequently harvested for anterior cruciate ligament reconstruction (ACLR), traditionally through the anteromedial (AM) approach. Recently, a posteromedial (PM) approach has been described. The primary purpose of this study was to compare rates of unintentional gracilis (Gr) harvest or premature tendon amputation with these approaches. We also sought to compare operative times and patient-reported outcome measures (PROMs) between both groups and between those with only semitendinosus (ST) grafts or with combined ST and Gr grafts. Patients who underwent ACLR with hamstring autograft by a single surgeon from 2014 to 2016 were retrospectively reviewed. An accidental harvest was identified as an unintentional Gr harvest or premature graft amputation. PROMs included the Knee Osteoarthritis and Outcomes Score, Western Ontario and McMaster Universities Osteoarthritis Index, and International Knee Documentation Committee score. Two out of 22 (9.1%) patients in the AM group had unintentional Gr tendon harvests, while none (out of 29) were identified in the PM group (p = 0.101). Group mean PROMs were not significantly different between patients in either group or patients with either ST-only grafts and those with combined ST + Gr. Average operative times and tourniquet times were significantly shorter with the PM approach versus the AM approach (101 +/- 18.2 vs 129 +/- 25.6 minutes, p = 0.002; 68 +/- 14.8 vs 90 +/- 28.9 minutes, p = 0.005). The PM approach was associated with a trend toward decreased risk of unintentional harvest of the Gr tendon and significantly decreased operative and tourniquet times without affecting knee outcomes compared with the traditional AM approach. Accidental Gr harvest was not associated with worse outcomes. PMID- 30449023 TI - Diagnostic Imaging and Management of Common Intra-articular and Peri-articular Soft Tissue Tumors and Tumorlike Conditions of the Knee. AB - Intra-articular (IA) and peri-articular (PA) tumors of the knee are frequently encountered by orthopaedic surgeons. Nonetheless, due to the possibility of great morbidity and potential mortality, it is important to recognize and differentiate between benign and malignant lesions in a timely manner. Therefore, the purpose of this article is to provide a concise, practical, and updated review of commonly encountered IA and PA tumors including intratendinous gout, synovial chondromatosis, schwannoma, pigmented villonodular synovitis, and synovial sarcoma, and a detailed description of differentiating features to include various imaging modalities. PMID- 30449024 TI - Giant Cell Tumor of Bone: Review of Current Literature, Evaluation, and Treatment Options. AB - Giant cell tumor of bone is a benign albeit aggressive tumor commonly affecting the bones of the knee. Patients with these tumors present with pain, swelling, and inability to bear weight on the involved extremity. These destructive tumors typically arise in the metaphyseal region of the long bones in individuals in the second, third, and fourth generations of life. Histologically, the multinucleated giant cells are the hallmark of the lesion, easily recognized on histological review, which recently have become therapeutic targets for medical management of the disease. For decades, surgical management has been the primary treatment for giant cell tumor of the bone. Some tumors can be treated with excision and filling of the osseous void with bone cement or allograft. This is an effective treatment option with a low to moderate risk of local recurrence while preserving limb function. For more destructive tumors, wide excision and reconstruction with prosthetic, structural allograft or combined allograft prosthetic components are utilized. Advances in medical management of the disease have also demonstrated promise as an effective treatment; however, its use has usually been limited to the treatment of metastatic disease, recurrent disease or when advanced local disease would require surgical treatment felt to be overly morbid. PMID- 30449025 TI - Malignant Bone Tumors of the Knee: How to Identify and Treat. AB - Malignant bone tumors are rare conditions that may be encountered by nononcologic surgeons only a few times in their careers, but a delay in diagnosis or a misinterpretation of data can have limb and life-threatening consequences. Prior literature suggests that unplanned resection of sarcoma was associated with an increased risk of local recurrence, decreased 10-year survival, and increased amputation rate compared with planned resection. In addition to patient morbidity, missed diagnoses and unplanned excisions of malignant tumors lead to increased cost of treatment and higher likelihood of subsequent medicolegal action. According to the American Cancer Society, the 5-year survival of all combined cases of malignant bone tumors is approximately 70%. However, the survival rate of each type of malignant bone tumor varies, with multiple myeloma survival rates being much lower and lymphoma somewhat higher. These rates depend on many factors including grade, stage, and chemotherapy response. For example, the 10-year survival of localized osteosarcoma is almost 70%, yet rapidly declines to 20 to 30% in patients with metastases. This further emphasizes the elevated importance of prompt recognition and treatment of malignant bone tumors. PMID- 30449026 TI - High macrophage activities are associated with advanced periductal fibrosis in chronic Opisthorchis viverrini infection. AB - Liver fluke infection caused by Opisthorchis viverrini induces several hepatobiliary conditions including advanced periductal fibrosis (APF) and cholangiocarcinoma (CCA), but >25% of the infected population develops APF and 1% develop CCA. The innate immune response is the first line of defence, and macrophages are critical regulators of fibrosis. We hypothesized that macrophages from infected individuals have different capacities to either promote or suppress periductal fibrosis. We compared phagocytic activities of macrophages of healthy individuals and O viverrini-infected individuals +/- APF, and found that macrophages from infected individuals with APF ingested significantly higher numbers of beads compared with healthy controls and O viverrini-infected individuals without APF. To further investigate proteolytic activity, we monitored real-time phagosomal proteolysis of beads conjugated to DQ-BODIPY-BSA using live cell imaging. We show that macrophages from O viverrini-infected individuals with APF also have elevated phagosomal proteolysis activity, which is consistent with their increased phagocytic activity. Additionally, stimulated ROS production by blood monocytes was higher in individuals with APF compared with healthy controls and infected individuals without APF. These results suggest that during O viverrini infection, macrophages with high phagocytic and proteolytic activities together with elevated ROS production are the phenotypes that can promote tissue damage, which results in periductal fibrosis. PMID- 30449028 TI - Use of curcumin solution for probe-based confocal laser endomicroscopy of squamous cell carcinoma of the esophagus. PMID- 30449027 TI - Inhaled nitric oxide dependency at the end of double-lung transplantation: A boosted propensity score cohort analysis. AB - OBJECTIVE: Inhaled nitric oxide (iNO) is usually used during lung transplantation despite controversial postoperative benefits. Our group chose to administer iNO systematically during the procedure and stop at end of surgery. This study aims to describe the features of patients who cannot be weaned from iNO, the reasons for this and its impact on postoperative outcomes. METHODS: This is a monocentric cohort study comprised all consecutive patients who underwent double-lung transplantation (DLT) between January 1st, 2012 and January 1, 2016. The impact of iNO dependency on postoperative outcomes was estimated using a boosted inverse probability of treatment weighting estimator. RESULTS: 9.8% of the 173 patients included in the study could not be weaned from iNO at end-surgery stage. Body mass index (OR=2.03, 95%CI=1.14-3.29, p=0.02) and intraoperative extracorporeal membrane oxygenation (OR=1.80, 95%CI=1.02-2.72, p=0.04) were risk factors for iNO dependency In the weighted population, iNO dependency was associated with an increased prevalence of grade 3 primary graft dysfunction (adjusted RR=4.20, 95%CI=1.75-10.09, p < 0.001) and decreased postoperative survival during the first 1500 days of follow up (adjusted HR = 5.0, 95%CI = 1.86-13.48, p < 0.001). CONCLUSIONS: iNO dependency is an early marker of a poor prognosis following DLT. This article is protected by copyright. All rights reserved. PMID- 30449029 TI - Size scaling of photophysiology and growth in four freshly isolated diatom species from Ryder Bay, western Antarctic peninsula. AB - Diatoms are one of the dominant groups in phytoplankton communities of the western Antarctic Peninsula (WAP). Although generally well-studied, little is known about size dependent photophysiological responses in diatom bloom formation and succession. To increase this understanding, four Antarctic diatom species covering two orders of magnitude in cell size were isolated in northern Marguerite Bay (WAP). Fragilariopsis sp., Pseudo-nitzschia cf. subcurvata, Thalassiosira cf. antarctica, and Proboscia cf. alata were acclimated to three different irradiances after which photophysiology, electron transport, carbon fixation and growth were assessed. The small species Fragilariopsis sp., Pseudo nitzschia cf. subcurvata, and large species Proboscia cf. alata showed similar photoacclimation to higher irradiances with a decrease in cellular chlorophyll a and an increase in chlorophyll a specific absorption and xanthophyll cycle pigments and activity. In contrast, pigment concentrations and absorption remained unaffected by higher irradiances in the large species Thalassiosira cf. antarctica. Overall, the small species showed significantly higher growth rates compared to the large species, which was related to relatively high light harvesting capacity and electron transport rates in the smaller species. However, photophysiological responses related to photoinhibition and photoprotection and carbon fixation showed no relationship to cell size. The present study supports the dominance of small diatoms at low irradiances during winter and early spring, but does not provide photophysiological evidence for the dominance of large diatoms during the phytoplankton bloom in the WAP. This suggests that other factors such as grazing and nutrient availability are likely to play a major role in diatom bloom formation. This article is protected by copyright. All rights reserved. PMID- 30449030 TI - Diffusion of enrofloxacin to pregnancy fluids and effects on foetal cartilage after intravenous administration to late pregnant mares. AB - BACKGROUND: In select cases, enrofloxacin may be an alternative antibacterial agent to treat unresponsive infections in pregnant mares. Supratherapeutic doses of enrofloxacin are toxic to adult horses and also to newborn foals, however, it is unknown if enrofloxacin crosses the equine placenta or if it is toxic to the foetus. OBJECTIVES: To assess the diffusion of enrofloxacin and its metabolite to foetal fluids and its effects on foetal cartilage when administered to pregnant mares. STUDY DESIGN: In vivo and terminal experiment. METHODS: Healthy mares at 260 days gestation were allocated into three groups: untreated (n = 3), therapeutic treatment (5 mg/kg enrofloxacin, i.v., n = 7), or supratherapeutic treatment (10 mg/kg, i.v., n = 6) for 11 days. Foetal fluids were collected on days 1, 5, and 11 of treatment. Premature delivery was induced on day 11 with oxytocin and foetal plasma was collected at delivery. Plasma and foetal fluid enrofloxacin and ciprofloxacin concentrations were measured by liquid chromatography-mass spectrometry. Foetal articular cartilage was examined macroscopically and histologically for lesions. RESULTS: Enrofloxacin and ciprofloxacin reached the minimum inhibitory concentrations for common pathogens in all fluids. Ciprofloxacin did not increase with the double enrofloxacin dose in maternal plasma, but allantoic fluid showed a 10-fold increase relative to foetal trough plasma concentrations. Administration of enrofloxacin at recommended doses did not result in cartilaginous lesions in foetuses. MAIN LIMITATIONS: Only one time point in gestation was evaluated and mares treated in the study were healthy at time of treatment. It remains to be determined if enrofloxacin shows toxicity at other stages of pregnancy, after a longer duration of treatment, or once the foals are delivered and articular surfaces are weight bearing. CONCLUSIONS: Short-term administration of enrofloxacin to late gestation mares resulted in detectable enrofloxacin and ciprofloxacin concentrations in foetal fluids and did not result in macroscopic or microscopic lesions in the foetus. While further research is needed to address long term foal outcomes, enrofloxacin may be useful for select bacterial infections in pregnant mares. This article is protected by copyright. All rights reserved. PMID- 30449031 TI - Occurrence of Pathogenic Vibrio parahaemolyticus in Seafood Distribution Channels and Their Antibiotic Resistance Profiles in S. Korea. AB - This study investigated the occurrence of Vibrio parahaemolyticus in seafood distribution channels, and the incidence of pathogenic and antibiotic resistant strains. One hundred sixty seven samples (126 fishery samples and 41 environmental samples) were collected from fishery auction markets, fish markets, and online markets in S. Korea from March to September, 2017. The samples were enriched in polymyxin broth and plated on CHROM agar Vibrio to isolate typical colonies. These were analyzed by PCR to identify V. parahaemolyticus strains containing the hns gene and to examine the presence of pathogenic genes (tdh and trh). The isolates were screened for antibiotic susceptibility (amoxycillin/clavulanic acid, ampicillin, ampicillin sulbactam, chloramphenicol, ciprofloxacin, erythromycin, gentamicin, and tetracycline). Twenty eight samples (16.8%) were V. parahaemolyticus-positive, andfrom the positive samples three isolates (SMFM201708-OY1, SMFM201709-CO2-2 and SMFM201709-CO1-2) were pathogenic which contained thermostable direct hemolysin (TDH) or thermostable direct related hemolysin (TRH). These are virulence factors associated with gastrointestinal symptoms. These three isolates were also resistant to ampicillin. These results indicate that there is high incidence of V. parahaemolyticus; less than 10%. These were pathogenic, and the pathogenic strains showed ampicillin resistance. Therefore, food safety measures are necessary in a seafood distribution channel. This article is protected by copyright. All rights reserved. PMID- 30449032 TI - Abemaciclib inhibits renal tubular secretion without changing glomerular filtration rate. AB - Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6, is indicated for metastatic breast cancer treatment. Reversible increases in serum creatinine levels of approximately 15%-40% over baseline have been observed following abemaciclib dosing. This study assessed the in vitro and clinical inhibition of renal transporters by abemaciclib and its metabolites using metformin (a clinically relevant transporter substrate), in a clinical study that quantified glomerular filtration and iohexol clearance, In vitro, abemaciclib inhibited metformin uptake by OCT2, MATE1 and MATE2-K transporters with an IC50 of 0.4-3.8 MUM. Clinically abemaciclib significantly increased metformin exposure but did not significantly affect measured glomerular filtration rate, serum NGAL, serum cystatin C or the urinary markers of kidney tubular injury, NGAL and KIM-1,. This article is protected by copyright. All rights reserved. PMID- 30449033 TI - EUS-guided coil and cyanoacrylate embolization for gastric varices and the roles of endoscopic Doppler and Endosonographic varicealography in vascular targeting. AB - OBJECTIVES: To report the results of endoscopic-ultrasound guided injection of coils with cyanoacrylate using a less-expensive coil, with an emphasis on the roles of Doppler and Endosonographic varicealography in identifying the feeder vessel in gastric varix treatment. METHODS: An observational, descriptive study with prospectively collected data. Patients with gastric varices were included and were treated by the endoscopic-ultrasound guided injection of cyanoacrylate and a less-expensive coil. Technical success, complete and immediate variceal obliteration, rebleeding, complication and survival rates were evaluated. RESULTS: Thirty patients with gastric varices, with a mean age of 62 years (range 44-76 years), were treated. The median number of coils used was 2 (range 1-3), and the median volume of cyanoacrylate was 1.8 ml (1.2-2.4 ml). The technical success rate was 100%. Endosonographic varicealography technical success was observed in 26/30 patients. Complete variceal obliteration was observed in 96.6%of patients, and the immediate disappearance of the varix was observed in 24 (80%) patients. The complication rate was 6.7%. CONCLUSIONS: Endoscopic ultrasound guidance for gastric varix treatment with the addition of endosonographic varicealography and the use of a less-expensive coil is a safe and effective technique that results in the immediate disappearance of gastric varices after targeting the feeding vessel. This article is protected by copyright. All rights reserved. PMID- 30449034 TI - DNA damage and reactive oxygen species cause cell death in the rice local lesions 1 mutant under high light and high temperature. AB - * High light and high temperature (HLHT) stress may become more frequent and severe as the climate changes, affecting crop growth and resulting in reduced production. However, the mechanism of the response to HLHT stress in rice is not yet fully understood. * In the present study, we screened a rice mutant library using HLHT conditions and isolated a HLHT-sensitive mutant, local lesions 1 (ls1), which showed decreased pigment contents, defective stomata and chloroplasts, and a local lesions phenotype under HLHT. * We characterized and cloned LS1 by map-based cloning and genetic complementation. LS1 encodes the A subunit of the RNase H2 complex (RNASEH2A). TUNEL and comet assays indicated that mutation of LS1 led to severe DNA damage under HLHT stress. Furthermore, we found excessive reactive oxygen species (ROS) accumulation in the ls1 mutant under HLHT stress. Exogenous antioxidants eased the local lesions phenotype of the ls1 mutant under HLHT. DNA damage caused by HLHT stress induces ROS accumulation, which causes the injury and apoptosis of leaf cells in the ls1 mutant. * These results enhance our understanding of the regulatory mechanism the response to HLHT stress in higher plants. This article is protected by copyright. All rights reserved. PMID- 30449035 TI - Community Response to Extreme Drought (CRED): a framework for drought-induced shifts in plant-plant interactions. AB - As climate changes, many regions of the world are projected to experience more intense droughts, which can drive changes in plant community composition through a variety of mechanisms. During drought, community composition can respond directly to resource limitation, but biotic interactions modify the availability of these resources. Here, we develop the Community Response to Extreme Drought framework (CRED), which organizes the temporal progression of mechanisms and plant-plant interactions that may lead to community changes during and after a drought. The CRED framework applies some principles of the stress gradient hypothesis (SGH), which proposes that the balance between competition and facilitation changes with increasing stress. The CRED framework suggests that net biotic interactions (NBI), the relative frequency and intensity of facilitative (+) and competitive (-) interactions between plants, will change temporally, becoming more positive under increasing drought stress and more negative as drought stress decreases. Further, we suggest that rewetting rates affect the rate of resource amelioration, specifically water and nitrogen, altering productivity responses and the intensity and importance of NBI, all of which will influence drought-induced compositional changes. System-specific variables and the intensity of drought influence the strength of these interactions, and ultimately the system's resistance and resilience to drought. This article is protected by copyright. All rights reserved. PMID- 30449036 TI - Comparison of regulatory B cells in asthma and allergic rhinitis. PMID- 30449037 TI - Moderate heritability and low evolvability of sperm morphology in a species with high risk of sperm competition, the collared flycatcher Ficedula albicollis. AB - Spermatozoa represent the morphologically most diverse type of animal cells and show remarkable variation in size across and also within species. To understand the evolution of this diversity, it is important to reveal to what degree this variation is genetic or environmental in origin and whether this depends on species' life-histories. Here we applied quantitative genetic methods to a pedigreed multigenerational data set of the collared flycatcher Ficedula albicollis, a passerine bird with high levels of extra-pair paternity, to partition genetic and environmental sources of phenotypic variation in sperm dimensions for the first time in a natural population. Narrow-sense heritability (h2 ) of total sperm length amounted to 0.44+/-0.14 SE while the corresponding figure for evolvability (estimated as coefficient of additive genetic variation, CVa ) was 0.02+/-0.003 SE. We also found an increase in total sperm length within individual males between the arrival and nestling period. This seasonal variation may reflect constraints in the production of fully elongated spermatozoa shortly after arrival at the breeding grounds. There was no evidence of an effect of male age on sperm dimensions. In many previous studies on laboratory populations of several insect, mammal and avian species, heritabilities of sperm morphology were higher while evolvabilities were similar. Explanations for the differences in heritability may include variation in the environment (laboratory vs. wild), intensity of sexual selection via sperm competition (high vs. low) and genetic architecture that involves unusual linkage disequilibrium coupled with overdominance in one of the studied species. This article is protected by copyright. All rights reserved. PMID- 30449038 TI - Nurse leaders' strategies to foster nurse resilience. AB - AIM: To identify nurse leaders' strategies to cultivate nurse resilience. BACKGROUND: High nursing turnover rates and nursing shortages are prominent phenomena in healthcare. Finding ways to promote nurse resilience and reduce nurse burnout is imperative for nursing leaders. METHODS: This is a qualitative descriptive study that occurred from November 2017 to June 2018. This study explored strategies to foster nurse resilience from nurse leaders who in this study were defined as charge nurses, nurse managers, and nurse executives of a tertiary hospital in the United States. A purposive sampling method was used to have recruited 20 nurse leaders. RESULTS: Seven strategies are identified to cultivate nurse resilience: facilitating social connections, promoting positivity, capitalizing on nurses' strengths, nurturing nurses' growth, encouraging nurses' self-care, fostering mindfulness practice, and conveying altruism. CONCLUSIONS: Fostering nurse resilience is an ongoing effort. Nurse leaders are instrumental in building a resilient nursing workforce. The strategies identified to foster nurse resilience will not only impact the nursing staff but also improve patients' outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: The strategies presented are simple and can be easily implemented in any settings. Nurse leaders have an obligation to model and enable evidence-based strategies to promote nurses' resilience. This article is protected by copyright. All rights reserved. PMID- 30449039 TI - Progressive behavioral, physiological, and transcriptomic shifts over the course of prolonged starvation in ticks. AB - Ticks are obligatorily hematophagous but spend the majority of their lives off host in an unfed state where they must resist starvation between bouts of blood feeding. Survival during these extended off-host periods is critical to the success of these arthropods as vectors of disease; however, little is known about the underlying physiological and molecular mechanisms of starvation tolerance in ticks. We examined the bioenergetic, transcriptomic, and behavioral changes of female American dog ticks, Dermacentor variabilis, throughout starvation (up to nine-months post blood meal). As starvation progressed, ticks utilized glycogen and lipid, and later protein as energy reserves with proteolysis and autophagy facilitating the mobilization of endogenous nutrients. The metabolic rate of the ticks was expectedly low, but showed a slight increase as starvation progressed possibly reflecting the up-regulation of several energetically costly processes such as transcription/translation and/or increases in host-seeking behaviors. Starved ticks had higher activity levels, increased questing behavior, and augmented expression of genes related to chemosensing, immunity, and salivary gland proteins. The shifts in gene expression and associated behavioral and physiological processes are critical to allowing these parasites to exploit their ecological niche as extreme sit-and-wait parasites. The overall responses of ticks to starvation were similar to other blood-feeding arthropods, but we identified unique responses that could have epidemiological and ecological significance for ticks as ectoparasites that must be tolerant of sporadic feeding. This article is protected by copyright. All rights reserved. PMID- 30449041 TI - Strictures after endoscopic submucosal dissection of the esophagus: Are the histopathological findings the same between human and porcine models? AB - Since the composition of the muscularis propria of the esophagus is different between porcine models and humans (mainly skeletal muscle in the former, and smooth muscle in the latter), it is not clear as to whether the histological findings of strictures after ESD are similar between the two models. In the present study, we performed a retrospective analysis of one case that required surgery for severe strictures after ESD of the entire circumference of the esophagus. This article is protected by copyright. All rights reserved. PMID- 30449040 TI - VMAT and IMRT plan-specific correction factors for linac-based ionization chamber dosimetry. AB - PURPOSE: The determination of absorbed dose to water from external beam radiotherapy using radiation detectors is currently rooted in calibration protocols that do not account for modulations encountered in patient-specific deliveries. Detector response in composite clinical fields has not been extensively studied due to the time and effort required to determine these corrections on a case-by-case basis. To help bridge this gap in knowledge, corrections for the Exradin A1SL scanning chamber were determined in a large number of composite clinical fields using Monte Carlo methods. The chamber specific perturbations that contribute the most to the overall correction factor were also determined. METHODS: A total of 131 patient deliveries comprised of 834 beams from a Varian C-arm linear accelerator were converted to EGSnrc Monte Carlo inputs. A validated BEAMnrc 21EX linear accelerator model was used as a particle source throughout the EGSnrc simulations. Composite field dose distributions were compared against a commercial treatment planning system for validation. The simulation geometry consisted of a cylindrically symmetric water-equivalent phantom with the Exradin A1SL scanning chamber embedded inside. Various chamber perturbation factors were investigated in the egs_chamber user code of EGSnrc and were compared to reference field conditions to determine the plan-specific correction factor. RESULTS: The simulation results indicated that the Exradin A1SL scanning chamber is suitable to use as an absolute dosimeter within a high dose and low-gradient target region in most nonstandard composite fields; however, there are still individual cases that require larger delivery-specific corrections. The volume averaging and replacement perturbations showed the largest impact on the overall plan-specific correction factor for the Exradin A1SL scanning chamber, and both volumetric modulated arc therapy (VMAT) and step and-shoot beams demonstrated similar correction factor magnitudes among the data investigated. Total correction magnitudes greater than 2% were required by 9.1% of step-and-shoot beams and 14.5% of VMAT beams. When examining full composite plan deliveries as opposed to individual beams, 0.0% of composite step-and-shoot plans and 2.6% of composite VMAT plans required correction magnitudes greater than 2%. CONCLUSIONS: The A1SL scanning chamber was found to be suitable to use for absolute dosimetry in high-dose and low-gradient dose regions of composite IMRT plans but even if a composite dose distribution is large compared to the detector used, a correction-free absorbed dose-to-water measurement is not guaranteed. PMID- 30449042 TI - Migratory plasticity is not ubiquitous among large herbivores. AB - 1.The migratory movements of wild animals can promote abundance and support ecosystem functioning. For large herbivores, mounting evidence suggests that migratory behavior is an individually variable trait, where individuals can easily switch between migrant and resident tactics. The degree of migratory plasticity, including whether and where to migrate, has important implications for the ecology and conservation of large herbivores in a changing world. 2.Mule deer (Odocoileus hemionus) are an iconic species of western North America, but are notably absent from the body of literature that suggests large herbivore migrations are highly plastic. We evaluated plasticity of migration in female mule deer using longitudinal GPS data collected from 312 individuals across 9 populations in the western US, including 882 animal-years (801 migrants and 81 residents). 3.We followed both resident and migratory mule deer through time to determine if individual animals switched migratory behaviors (i.e., whether to migrate) from migratory to residency, or vice versa. Additionally, we examined the fidelity of individuals to their migration routes (i.e., where to migrate) to determine if they used the same routes year after year. We also evaluated if age and reproductive status affected propensity to migrate or fidelity to migratory routes. 4. Our results indicate that mule deer, unlike other large herbivores, have little or no plasticity in terms of whether or where they migrate. Resident deer remained residents, and migrant deer remained migrants, regardless of age, reproductive status, or number of years monitored. Further, migratory individuals showed strong fidelity (>80%) to their migration routes year after year. 5. Our study clearly shows that migration plasticity is not ubiquitous among large herbivores. Because of their rigid migratory behavior, mule deer may not adapt to changing environmental conditions as readily as large herbivores with more plastic migratory behavior (e.g., elk). The fixed migratory behaviors of mule deer make clear that conservation efforts aimed at traditional seasonal ranges and migration routes are warranted for sustaining this iconic species that continues to decline across its range. This article is protected by copyright. All rights reserved. PMID- 30449043 TI - 'Candy Sign' in EUS guided cysto-gastrostomy of pancreatic fluid collection with metal stent. AB - A 40-year-old male underwent EUS guided drainage for symptomatic large WON (15 x 9 cm) due severe acute pancreatitis 6 months ago. The initial steps of EUS guided cysto-gastrostomy with BFMS (needle puncture, passage of guidewire, creation of fistula using co-axial 6Fr cystotome and dilation of track with 4mm balloon) were uneventful. However, there was significant resistance to cross the wall of WON while passing the stent assembly (NAGI stent, Taewoong Medical) over the guidewire. Subsequently, the stent assembly was withdrawn and its inspection revealed that conical plastic tip was loose and migrated within the blunt sheath of the delivery system. This article is protected by copyright. All rights reserved. PMID- 30449044 TI - Restless legs syndrome and its variants in acute ischemic stroke. AB - BACKGROUND: The clinical-radiological correlation between restless legs syndrome (RLS) or its variants and acute ischemic stroke remains unclear. METHODS: This study prospectively included 104 consecutive patients with acute ischemic stroke, confirmed by diffusion-weighted imaging. The frequency and clinical characteristics of RLS or RLS variants were evaluated according to the International RLS Study Group criteria, as was the topography of the associated lesions. RESULTS: Among 104 patients with acute ischemic stroke, 6 (5.8%) and 2 patients (1.9%) had RLS and RLS variants, respectively, for a total of 8 patients (7.7%). Three (3.3%) had poststroke RLS/RLS variants: 2 (66.7%) had bilateral symptoms and 1 (33.3%) had unilateral symptoms contralateral to the lesion. RLS symptoms developed within 2 days after the onset of stroke. Forty percent of prestroke RLS/RLS variant patients experienced exacerbation of their symptoms after stroke onset, and two-thirds of poststroke RLS/RLS variant patients required treatment for their RLS/RLS variants. Patients positive for RLS/RLS variants tended to have difficulty falling asleep, but there was no difference in daytime sleepiness, sleep quality, depressive symptoms, stroke subtypes, comorbid diseases, laboratory data, or modified Rankin Scale scores at admission or discharge between patients with and without RLS/RLS variants. RLS/RLS variants were most frequently observed to accompany lesions in the medulla (25%), followed by the pons (15.4%), the corona radiata (14.8%), the basal ganglia (3.8%), and the cortex (3.8%). CONCLUSION: RLS/RLS variants were found in 8% of acute ischemic stroke patients. Adequate screening and management are needed to improve patients' quality of life. PMID- 30449045 TI - Linking leaf hydraulic properties, photosynthetic rates, and leaf lifespan in xerophytic species: a test of global hypotheses. AB - PREMISE OF THE STUDY: Leaf venation and its hierarchal traits are crucial to the hydraulic and mechanical properties of leaves, reflecting plant life-history strategies. However, there is an extremely limited understanding of how variation in leaf hydraulics affects the leaf economic spectrum (LES) or whether venation correlates more strongly with hydraulic conductance or biomechanical support among hierarchal orders. METHODS: We examined correlations of leaf hydraulics, indicated by vein density, conduit diameter, and stomatal density with light saturated photosynthetic rates, leaf lifespan (LLS), and leaf morpho-anatomical traits of 39 xerophytic species grown in a common garden. KEY RESULTS: We found positive relationships between light-saturated, area-based photosynthetic rates, and vein densities, regardless of vein orders. Densities of leaf veins had positive correlations with stomatal density. We also found positive relationships between LLS and vein densities. Leaf area was negatively correlated with the density of major veins but not with minor veins. Most anatomical traits were not related to vein densities. CONCLUSIONS: We developed a network diagram of the correlations among leaf hydraulics and leaf economics, which suggests functional trade-offs between hydraulic costs and lifetime carbon gain. Leaf hydraulics efficiency and carbon assimilation were coupled across species. Vein construction costs directly coordinated with the LLS. Our findings indicate that hierarchal orders of leaf veins did not differ in the strength of their correlations between hydraulic conductance and biomechanical support. These findings clarify how leaf hydraulics contributes to the LES and provide new insight into life-history strategies of these xerophytic species. PMID- 30449046 TI - Behavioural plasticity modulates temperature-related constraints on foraging time for a montane mammal. AB - 1.Contemporary climate change is altering temperature profiles across the globe. Increasing temperatures can reduce the amount of time during which conditions are suitable for animals to engage in essential activities, such as securing food. Behavioural plasticity, the ability to alter behaviour in response to the environment, may provide animals with a tool to adjust to changes in the availability of suitable thermal conditions. The extent to which individuals can alter fitness-enhancing behaviours, such as food collection, to proximately buffer variation in temperature, however, remains unclear. Even less well understood are the potential performance advantages of flexible strategies among endotherms. 2.We examined the degree to which individuals altered rates of food collection in response to temperature, and two potential benefits, using the American pika (Ochotona princeps), a temperature-sensitive, food-hoarding mammal, as a model. 3.From July - Sept, 2013-2015, we used motion-activated cameras and in situ temperature loggers to examine pika food-caching activity for 72 individuals across 10 sites in the central Rocky Mountains, USA. We quantified % nitrogen by cache volume as a metric of cache quality, and the number of events during which pikas were active in temperatures > 25 degrees C as a measure of potential thermoregulatory stress. 4.We found a strong negative effect of temperature on the rate at which pikas cached food. Individual responses to temperature varied substantially in both the level of food-collecting activity and in the degree to which individuals shifted activity with warming temperature. After accounting for available foraging time, individuals that exhibited greater plasticity collected a comparable amount of nitrogen, while simultaneously experiencing fewer occasions in which temperatures eclipsed estimated thermal tolerances. 5.By varying food-collection norms of reaction, individuals were able to plastically respond to temperature-driven reductions in foraging time. Through this increased flexibility individuals amassed food caches of comparable quality, while minimizing exposure to potentially stressful thermal conditions. Our results suggest that, given sufficient resource quality and availability, plasticity in foraging activity may help temperature-limited endotherms adjust to climate-related constraints on foraging time. This article is protected by copyright. All rights reserved. PMID- 30449047 TI - Feedback-informed treatment and autonomy supportiveness: Effects on children s psychological outcomes. AB - PURPOSE: Examine the importance of feedback, specifically the perception of parental autonomy support, to reduce youths' premature treatment dropout. DESIGN AND METHODS: A retrospective chart review was conducted, utilizing the convenience-purposive sample of 60 patient charts. Individuals were seen between October 2014 and July 2015 in a community clinic utilizing a treatment approach known as feedback-informed treatment (FIT). FINDINGS: Clients found to have high paternal involvement reported better overall well-being and lower levels of distress. CONCLUSIONS: The construct of parental autonomy support, when combined with a FIT treatment model, is a promising approach to lower the rate of early treatment termination. PMID- 30449048 TI - Endoscopic submucosal dissection of superficial esophageal cancer expanding into the diverticulum. AB - Endoscopic submucosal dissection (ESD) is standard treatment for early esophageal cancer (EEC). Cancer located within the diverticulum, which has a thin or nonexistent muscular coating, is extremely rare. We describe successful ESD of esophageal diverticular cancer with a high risk of perforation. A 20-mm EEC lesion expanding into the diverticulum was detected in the middle thoracic esophagus of a 73-year-old man. Positive-pressure ventilation under general anesthesia and carbon dioxide insufflation were performed. This article is protected by copyright. All rights reserved. PMID- 30449049 TI - Cystic neutrophilic granulomatous mastitis: The Cleveland Clinic experience with diagnosis and management. AB - Granulomatous mastitis is an uncommon inflammatory disease that typically presents with painful breast lesions. Recent publications have brought to light a specific subset of granulomatous mastitis patients with a distinct histological pattern of disease termed, "cystic neutrophilic granulomatous mastitis" (CNGM). Although many cases of granulomatous lobular mastitis have been thought to be idiopathic, this rare subset of an uncommon disease has been linked to infections with Corynebacterium species. Herein, a cohort of CNGM patients from a large, tertiary care, North-American, academic medical center is presented. Correlative demographic, clinical, radiographic, pathologic, microbiologic, management, and outcomes data are provided. Collaborative communication between specialists to accurately diagnose and manage these patients is essential to decreasing potential morbidity. PMID- 30449050 TI - Detecting gastric cancer from video images using convolutional neural networks. AB - Early detection of gastric cancer is one of the most important factors for improving the prognosis of patients. However, the detection rate for gastric cancer differs depending on the endoscopist's experience. In the last decade, new deep-learning-based machine learning methods have shown significant improvements in image recognition and have therefore been applied to various medical fields. Previously, we have reported the efficacy of our deep learning-based convolutional neural network (CNN) system for detecting gastric cancer in still images. This CNN system achieved a high detection rate (overall: 92.2%, diameter greater than 6 mm: 98.6%) with a high processing speed (2296 images/47 sec.) [5], and it is expected to help endoscopists increase diagnostic yields. This article is protected by copyright. All rights reserved. PMID- 30449051 TI - Multi-tasking epidermal stem cells: Beyond epidermal maintenance. AB - Over the past decade, multiple stem cell compartments have been identified within the epidermis. These stem cell pools have different transcriptional properties, proliferative modes and anatomical locations, and they maintain distinct epidermal compartments. The importance of this stem cell heterogeneity and compartmentalization has been understood as a key feature in epidermal homeostasis. However, recent studies have revealed that these heterogeneous stem cells themselves act as a niche for neighboring cells, thereby establishing spatially and temporally patterned epidermal-dermal functional units. These studies provide a new perspective for interpreting the biological significance of stem cell heterogeneity and compartmentalization beyond their role in epidermal maintenance. PMID- 30449052 TI - Transient liver toxicity as a result of the oral administration of 5 aminolevulinic acid for photodynamic diagnosis in patients with bladder cancer. PMID- 30449053 TI - Linking Relational Coordination to Nurses' Job Satisfaction, Affective Commitment, and Turnover Intention in Saudi Arabia. AB - AIM: To examine the association between relational coordination, job satisfaction, affective commitment and turnover intention. BACKGROUND: While there is a substantial body of literature that examines how relational coordination influences outcomes among nurses in western societies, there is no known study that examines the impact of relational coordination on outcomes in a non-western healthcare system. As many of the factors associated with nursing turnover in Saudi Arabia are uniquely complex and challenging, a focus on relational coordination in this context is particularly worthy of investigation. METHOD: The study utilized a cross-sectional online survey. A total of 180 nurses participated in the study. RESULTS: The results indicated that the relationship between relational coordination and turnover intention is mediated by job satisfaction. The results further show that the relationship between relational coordination and turnover intention is mediated by affective commitment. CONCLUSION: High levels of relational coordination can give rise to various outcomes of relevance to nurses, allied health professionals, and patients. IMPLICATIONS FOR NURSING MANAGEMENT: Re-configured job designs to build and cultivate links between nurses and other clinical disciplines will be necessary to enhance job satisfaction and commitment levels and to reduce turnover intention. This article is protected by copyright. All rights reserved. PMID- 30449054 TI - Language counts: Early language mediates the relationship between parent education and children's math ability. AB - Children's early math skills have been hailed as a powerful predictor of academic success. Disparities in socioeconomic context, however, also have dramatic consequences on children's learning. It is therefore critical to investigate both of these distinct contributors in order to better understand the early foundations of children's academic outcomes. The current study tests an integrated model of children's developing math ability so as to 1) identify the specific skills and abilities most clearly linked to early math achievement and 2) measure the influence of children's socioeconomic context on each of these skills. We first evaluated the early vocabulary, number word knowledge (knower level), and Approximate Number System (ANS) acuity of a diverse group of preschoolers. Then, approximately one year later as they entered Kindergarten, we administered a test of early math achievement. We find that children's early language (general vocabulary and number word knowledge) fully mediates the relationship between parent education and math ability. Additionally, number word knowledge mediates the relationship between ANS acuity and early math. We argue that increased focus on number word knowledge, as well as general vocabulary, may help to minimize disparities in math ability as children enter kindergarten. We also highlight the role of parent education on children's learning and note that this may be an important locus for intervention. This article is protected by copyright. All rights reserved. PMID- 30449055 TI - Cycle Consistent Adversarial Denoising Network for Multiphase Coronary CT Angiography. AB - PURPOSE: In multiphase coronary CT angiography (CTA), a series of CT images are taken at different levels of radiation dose during the examination. Although this reduces the total radiation dose, the image quality during the low-dose phases is significantly degraded. Recently, deep neural network approaches based on supervised learning technique have demonstrated impressive performance improvement over conventional model-based iterative methods for low-dose CT. However, matched low- and routine- dose CT image pairs are difficult to obtain in multiphase CT. To address this problem, we aim at developing a new deep learning framework. METHOD: We propose an unsupervised learning technique that can remove the noise of the CT images in the low-dose phases by learning from the CT images in the routine dose phases. Although a supervised learning approach is not applicable due to the differences in the underlying heart structure in two phases, the images are closely related in two phases, so we propose a cycleconsistent adversarial denoising network to learn the mapping between the low and high dose cardiac phases. RESULTS: Experimental results showed that the proposed method effectively reduces the noise in the low-dose CT image while preserving detailed texture and edge information. Moreover, thanks to the cyclic consistency and identity loss, the proposed network does not create any artificial features that are not present in the input images. Visual grading and quality evaluation also confirm that the proposed method provides significant improvement in diagnostic quality. CONCLUSIONS: The proposed network can learn the image distributions from the routine-dose cardiac phases, which is a big advantages over the existing supervised learning networks that need exactly matched low- and routine- dose CT images. Considering the effectiveness and practicability of the proposed method, we believe that the proposed can be applied for many other CT acquisition protocols. This article is protected by copyright. All rights reserved. PMID- 30449056 TI - Short-term neurological outcomes in ischemic and hemorrhagic pediatric stroke. AB - BACKGROUND: Our aim is to retrospectively assess short-term neurological outcomes in pediatric stroke with patient features. METHODS: Children aged 28 days-18 years with arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT), and hemorrhagic stroke (HS) between 2007 and 2013 were evaluated. Neurological findings within the first three months were accepted as short-term prognosis and modified Rankin scale was used. RESULTS: In the study, 33 patients (62%) with AIS, 12 (23%) with HS, and 8 (15%) with CSVT were included. Moya moya syndrome was the most common new diagnosis in AIS. Stroke recurred in 5 (15%), one AIS patient with posterior circulation infarct died (3%). Prognosis in AIS was favorable for 20 patients (61%) and poor for 13 patients (39%). Fourty two percent of HS were of vascular origin. Seven patients (70%) with HS had good prognosis and 3 (30%) patients had poor prognosis with no death. Homocysteine related hypercoagulability was most frequently detected in the etiology CSVT. Synchronous systemic thrombosis was observed in 3 (37.5%) and death occurred in two (25%) CSVT patients. Prognosis was evaluated as favorable for 3 (37.5%) and poor for 5 of CSVT patients (62.5%). For thrombophilia, thrombosis panel was performed fully in 83% of AIS and CSVT patients. CONCLUSIONS: Pediatric stroke is associated with poor prognosis in a substantial number of patients in short term, with CSVT having the worst prognosis. Not only ischemic but also hemorrhagic stroke were presented with detailed patient characteristics, with a full thrombosis panel achieved for most ischemic stroke patients. This article is protected by copyright. All rights reserved. PMID- 30449057 TI - High Frequency of Multiple HPV Types Detection in Fanconi Anemia Patients Oral Swabs. AB - BACKGROUND: Fanconi anemia (FA) is a rare genetic disease usually characterized by bone marrow failure and congenital malformations. The risk of development of malignancies in the oral cavity of FA patients, such as squamous cell carcinoma (SCC), increases significantly after a hematopoietic stem cells transplant (HSCT), and may also be linked with the presence of human papillomavirus (HPV) infections in the oral cavity. We investigated the prevalence and the HPV genotypes in oral mucosa of Brazilian FA patients. METHODS AND RESULTS: Oral swabs of 49 FA patients were collected. The median age of patients was 20 years old (range 5-44) and 57% were over 18y. Oral lesions were present in 20% of all patients, being 90% leukoplakia. HPV DNA was detected in 28% (14/49) of patients, one of which also reported genital HPV lesions. Sixty-seven percent of all patients had undergone HSCT, including twelve patients (86%) of those with HPV+ results. Multiple HPV types were detected in 78% and 71% of HPV+ samples by Sanger sequencing and reverse hybridization methods, respectively. The most prevalent HPV types detected were 6, 11, 18 and 68. CONCLUSIONS: HPV prevalence in the oral mucosa of the assessed FA patients was higher than reported in the general population. Additional studies with collection of sequential samples are needed to know the natural history of the presence of multiple HPV types in these individuals and its association with the development of tumors, to evaluate the implementation of preventive measures, such as vaccination, and to guide early treatment. This article is protected by copyright. All rights reserved. PMID- 30449058 TI - Limited potential of harvest index improvement to reduce methane emissions from rice paddies. AB - Rice is a staple food for nearly half of the world's population, but rice paddies constitute a major source of anthropogenic CH4 emissions. Root exudates from growing rice plants are an important substrate for methane-producing microorganisms. Therefore, breeding efforts optimizing rice plant photosynthate allocation to grains, i.e., increasing harvest index (HI), are widely expected to reduce CH4 emissions with higher yield. Here we show, by combining a series of experiments, meta-analyses and an expert survey, that the potential of CH4 mitigation from rice paddies through HI improvement is in fact small. Whereas HI improvement reduced CH4 emissions under continuously flooded (CF) irrigation, it did not affect CH4 emissions in systems with intermittent irrigation (II). We estimate that future plant breeding efforts aimed at HI improvement to the theoretical maximum value will reduce CH4 emissions in CF systems by 4.4%. However, CF systems currently make up only a small fraction of the total rice growing area (i.e. 27% of the Chinese rice paddy area). Thus, to achieve substantial CH4 mitigation from rice agriculture, alternative plant breeding strategies may be needed, along with alternative management. This article is protected by copyright. All rights reserved. PMID- 30449059 TI - d2-R Test for Japanese Adolescents: Concurrent Validity with ADHD-RS. AB - BACKGROUND: The d2-R test is a cancellation test developed in Germany and plays a prominent role in measuring subjects' concentration and attention. This study examined the validity of the d2-R test for Japanese adolescents and made the comparison with German standardized data. METHODS: Japanese junior high school students (n=121, 61 females and 60 males) participated in this study. The students' performance scores in the d2-R test were compared with their daily attentiveness and hyperactivity/impulsiveness assessments conducted by their teachers. The assessments were evaluated using the attention deficit hyperactivity disorder rating scale (ADHD-RS) -IV. The comparison with German counterparts were also made. RESULTS: Results indicated that students who were rated as less attentive and more hyperactive/impulsive performed more slowly and committed more errors in the d2-R test. Although there were no sex differences in any of the d2-R parameters, male students were rated higher than females in all of the ADHD-RS-IV scores. Japanese adolescents outscored German counterparts on speed, concentration, and carefulness. CONCLUSION: Our results confirm the concurrent validity of the d2-R test and suggest that it is appropriate as an index to measure the sustained and focused attention of Japanese adolescents. The present research merits attention as the first investigation of the d2-R test conducted for Japanese adolescents. This article is protected by copyright. All rights reserved. PMID- 30449060 TI - Characterization of chylomicron in preterm infants. AB - OBJECTIVES: The aim of this study was to investigate cholesterol and triglyceride levels in the chylomicron fraction of preterm infants at birth and during the early postnatal period. METHODS: A total of 133 infants (81 boys and 52 girls) were included; 74 were term infants born at 37-41 wk gestation and 59 were preterm infants born at 29-36 wk gestation. Cholesterol and triglyceride levels in the chylomicron fraction were measured by high-performance liquid chromatography. RESULTS: Compared to term infants, preterm infants had higher cholesterol and lower triglyceride levels in the chylomicron fraction, both in cord blood and at 1 mo after birth. Thus, the chylomicron triglyceride/cholesterol ratio was significantly lower in preterm infants than in term infants in cord blood and at 1 mo of age. Single regression analyses demonstrated that the chylomicron triglyceride/cholesterol ratio correlated positively with gestational age at birth (r = 0.331, p = 0.0003) and at 1 mo (r = 0.221, p = 0.0119). CONCLUSIONS: Preterm infants exhibited a less-lipidated chylomicron composition at birth and at 1 mo of age. Some prenatal factors may persist to influence chylomicron lipidation during the early postnatal period. This article is protected by copyright. All rights reserved. PMID- 30449062 TI - Transplantation of kidneys from HCV viremic donors to HCV viremic recipients followed by early direct acting anti-viral therapy without ribavirin. AB - BACKGROUND: Direct acting anti-viral drugs (DAA) have led to a paradigm shift in the approach to hepatitis C virus (HCV) positive organs. In this study, we report our experience with HCV viremic recipients undergoing kidney transplantation (KT) from HCV viremic donors, followed by the initiation of DAA therapy without ribavirin METHODS: We conducted a single center, retrospective review of patients who underwent deceased donor KT from March 2015 to February 2017. HCV viremic patients who received an HCV viremic kidney and were then treated with DAAs were included. The primary outcome was determination of sustained virologic response (SVR) 12 weeks after completion of DAA therapy. Results Twelve HCV viremic patients received viremic kidneys. The average age of the recipient was 63.7 years. Nine patients (75%) were genotype 1a and seven (58.3%) were treatment naive. The median time on the waitlist was 74 days, and the median time from transplant to initiation of DAA was 119 days. All were treated with sofosbuvir 400 mg and ledipasvir 90 mg daily and none received ribavirin. The majority (83.3%) were treated for 12 weeks and the remainder for 24 weeks. All achieved SVR at 12 weeks with no significant adverse events or rejection observed CONCLUSION: We observed that HCV viremic recipients undergoing KT from a viremic donor followed by the initiation of DAA therapy without ribavirin was safe and efficacious. In the DAA era, the utilization of HCV positive organs has the potential to decrease waitlist times, expand the donor pool, and improve survival. This article is protected by copyright. All rights reserved. PMID- 30449063 TI - High Frequency Supraorbital Nerve Stimulation with a Novel Wireless Minimally Invasive Device for Post-traumatic Neuralgia: A Case Report. AB - BACKGROUND: Post-traumatic neuropathic pain in the head and face is a condition which is often refractory to medical management. Peripheral Nerve Stimulation (PNS) can be an effective treatment. A successful implant of a novel minimally invasive wireless device is reported here. OBJECTIVE: To assess analgesic effects of a minimally invasive wireless PNS device in the treatment of post-traumatic supraorbital neuralgia (SON). CASE SUMMARY: The patient presented with SON following multiple post-traumatic cranioplasty surgeries, which were complicated by infections. Medical and interventional management failed, and the patient reported a Numeric Rating Scale (NRS) pain score of 8 out of 10. Two octopolar implantable neural stimulators (INS) (StimRelieve LLC, Pompano Beach, FL, USA) were implanted with a minimally invasive, percutaneous technique to stimulate the supraorbital nerves. Stimulation parameters were set at a frequency of 10 kHz and a pulse width of 30 MUs. RESULTS: At 12- and 24-month follow-up evaluations, the patient's NRS was only 2 out of 10, and the patient occasionally required 1 g of Paracetamol to control the pain. Stimulation was reported to be paresthesia-free. There were no adverse events related to the procedure or the treatment until today. CONCLUSIONS: High frequency stimulation with an external pulse generator and minimally invasive, percutaneous, and bilateral placement of two passive INSs on the supraorbital nerves resulted in a significant pain relief in this patient with post-traumatic SON. The device was safe and effective, and the cosmesis was satisfactory. This article is protected by copyright. All rights reserved. PMID- 30449061 TI - A niche for ecosystem multifunctionality in global change research. AB - Concern about human modification of Earth's ecosystems has recently motivated ecologists to address how global change drivers will impact the simultaneous provisioning of multiple functions, or ecosystem multifunctionality (EMF). However, metrics of EMF have often been applied in global change studies with little consideration of the information they provide beyond single functions, or how and why EMF may respond to global change drivers. Here, we critically review the current state of this rapidly expanding field and provide a conceptual framework to guide the effective incorporation of EMF in global change research. In particular, we emphasize the need for a priori identification and explicit testing of the biotic and abiotic mechanisms through which global change drivers impact EMF, as well as assessing correlations among multiple single functions because these patterns underlie shifts in EMF. While the role of biodiversity in mediating global change effects on EMF has justifiably received much attention, empirical support for effects via other biotic and physicochemical mechanisms are also needed. Studies also frequently stated the importance of measuring EMF responses to global change drivers to understand the potential consequences for multiple ecosystem services, but explicit links between measured functions and ecosystem services were missing from many such studies. While there is clear potential for EMF to provide novel insights to global change research, predictive understanding will be greatly improved by ensuring future research is strongly hypothesis-driven, is designed to explicitly test multiple abiotic and biotic mechanisms, and assesses how single functions and their covariation drive emergent EMF responses to global change drivers. This article is protected by copyright. All rights reserved. PMID- 30449064 TI - Accumulation patterns of endogenous beta-aminobutyric acid during plant development and defense in Arabidopsis thaliana. AB - We have recently discovered that beta-aminobutyric acid (BABA), a molecule known for its ability to prime defenses in plants, is a natural plant metabolite. However, the role played by endogenous BABA in plants is currently unknown. In this study we investigated the systemic accumulation of BABA during pathogen infection, the levels of BABA during plant growth and development, and analyzed mutants possibly involved in BABA transport or regulation. BABA was quantified by LC-MS using an improved method adapted from a previously published protocol. Systemic accumulation of BABA was determined by analyzing non-infected leaves and roots after localized infections with Plectosphaerella cucumerina or Pseudomonas syringae pv. tomato (Pst) DC3000 avrRpt2. The levels of BABA were also quantified in different plant tissues and organs during normal plant growth, and in leaves during senescence. Mutants affecting amino acid transport (aap6, aap3, prot1, and gat1), gamma-aminobutyric acid levels (pop2), and senescence/defense (cpr5-2) were analyzed. BABA was found to accumulate only locally after bacterial or fungal infection, with no detectable increase in non-infected systemic plant parts. In leaves, the BABA content increased during natural and induced senescence. Reproductive organs were found to show the highest levels of BABA, and the mutant cpr5-2 was found to produce constitutively high levels of BABA. Synthetic BABA is highly mobile in the receiving plant, whereas endogenous BABA appears to be produced and accumulated locally in a tissue-specific way. We discuss a possible role for BABA in the age-related resistance, and propose a comprehensive model for endogenous and synthetic BABA. This article is protected by copyright. All rights reserved. PMID- 30449065 TI - Reply to the Letter to the Editor - "Live Donor Liver Transplantation Using Selected Grafts with Two Bile Ducts compared to One Bile Duct Does Not Impact on Patient Outcome". AB - We thank Sapana et al. for their thoughtful comments on our recent publication on the use of live donor grafts with multiple bile ducts (BD). 1 As discussed, we agree that it is always better to use grafts with a single BD in LDLT. However, driven by organ scarcity, institutions performing this type of procedure often find the need to expand donor selection criteria to those grafts with 2 or more BD. In our study, we demonstrate that patients who received a live donor liver graft with two BD (n=169) showed comparable outcome to those who received a live donor liver graft with only one BD (n=320). Therefore, we are convinced that these types of grafts should not be declined solely based on the presence of more than 1 BD to reconstruct. This article is protected by copyright. All rights reserved. PMID- 30449066 TI - Evaluation of DNA damage in spinal cord and mutagenic effect of a Phalpha1beta recombinant toxin with analgesic properties from the Phoneutria nigriventer spider. AB - Phalpha1beta peptide isolated from the venom of the Phoneutria nigriventer spider has shown higher analgesic action in pre-clinical studies than omega-conotoxin MVIIA peptide used to treat severe chronic pain. In view of the great potential for the development of a new Phalpha1beta-based drug, a Phalpha1beta recombinant form (CTK 01512-2) has been studied for efficacy and safety. The aim of this study was to evaluate cytotoxic, genotoxic and mutagenic effects of a Phalpha1beta recombinant form and compare it with native Phalpha1beta and omega conotoxin MVIIA. Cytotoxicity was evaluated using the MTT (3-[4,5-dimethylthiazol 2-yl]-2,5-diphenyltetrazolium bromide) colourimetric assay in L929 mouse fibroblast cells (0.5 - 10.0 MUmol/L). Genotoxic and mutagenic activities were analysed using the alkaline comet assay in peripheral blood and spinal cord and the micronucleus test in bone marrow from Wistar rats treated by intrathecal injection of CTK 01512-2 (200, 500 and 1000 pmol/site), native Phalpha1beta (500 pmol/site) and omega-conotoxin MVIIA (200 pmol/site). CTK 01512-2 decreased the cell viability of the L929, showing IC50 of 3.3 +/- 0.1 MUmol/L, while the Phalpha1beta and omega-conotoxin MVIIA did not show cytotoxicity (IC50 > 5.0 MUmol/L). Native and recombinant Phalpha1beta forms induced DNA damage in the spinal cord, but not in peripheral blood. CTK 01512-2 at 1000 pmol/site increased the micronucleus frequency suggesting mutagenic effects. In conclusion, the recombinant form has cytotoxic, genotoxic and mutagenic effects, evidenced in doses five time above the therapeutic dose. This article is protected by copyright. All rights reserved. PMID- 30449067 TI - A multi-institutional retrospective study of carbon-ion radiotherapy for non squamous cell malignant tumors of the nasopharynx: Subanalysis of Japan Carbon Ion Radiation Oncology Study Group study 1402 HN. AB - BACKGROUND: This multi-institutional retrospective study focused on the clinical outcome of carbon-ion radiotherapy (C-ion RT) for non-squamous cell malignant tumors of the nasopharynx. METHODS: The Japan Carbon-ion Radiation Oncology Study Group collected and analyzed data for 43 patients with non-squamous cell malignant tumors of the nasopharynx treated with C-ion RT at four institutions in Japan. RESULTS: Twenty-nine patients had adenoid cystic carcinomas, seven had malignant melanomas, three had adenocarcinomas, two had mucoepidermoid carcinomas, and two had other pathologies. Twenty-six of the 43 patients (61%) had T4 tumors. The most common dose-fractionation schedule was 64 Gy (relative biological effectiveness) in 16 fractions. The median follow-up period was 30 months. The 2-year local control (LC) and overall survival (OS) rates were 88% and 84%, respectively. For late toxicity, one patient developed grade 4 optic nerve disorder and two developed grade 5 pharyngeal hemorrhage. Actual incidence of grade 3 or higher late adverse events was 19%, and included cranial nerve dysfunction, jaw bone necrosis, central nervous system necrosis, and ear inflammation. CONCLUSIONS: C-ion RT provided good LC and OS rates with acceptable toxicity for treatment of non-squamous cell malignant tumors of the nasopharynx. PMID- 30449068 TI - Clinicopathological analysis of primary intestinal diffuse large B-cell lymphoma: Prognostic evaluation of CD5, PD-L1, and Epstein-Barr virus on tumor cells. AB - BACKGROUND: Primary intestinal diffuse large B-cell lymphoma (iDLBCL) is rare. In this study, we investigated the clinicopathological features of this disease to further understand the prognostic value of CD5, programmed cell death ligand 1 (PD-L1), and Epstein-Barr virus (EBV) on tumor cells. METHODS: Tumor specimens from 62 patients consecutively diagnosed with primary iDLBCL at a single institution were analyzed. RESULTS: Our series consisted of EBV-positive (EBV+ ) iDLBCL (n = 10), de novo CD5+ iDLBCL (n = 4), and DLBCL, not otherwise specified (DLBCL-NOS; n = 48). Notably, seven of 10 EBV+ cases had treated lymphoma associated (n = 4) or iatrogenic immunodeficiency (n = 3). Two of 10 EBV+ cases expressed PD-L1 on tumor cells, whereas the remaining eight were positive for PD L1 on microenvironment immune cells. Only one DLBCL-NOS case had neoplastic PD-L1 expression with a giant cell-rich appearance. Both EBV-harboring and PD-L1 expression on tumor cells, but not CD5, were associated with worse overall survival (OS) in iDLBCL patients receiving rituximab-containing chemotherapy (P = 0.0354, P = 0.0092, and P = 0.1097, respectively). Multivariate analysis identified PD-L1 positivity on tumor cells (P = 0.0106), PD-L1 negativity on microenvironment immune cells (P = 0.0193), and EBV positivity (P = 0.0324) as poor independent prognostic factors for OS. Among iDLBCL cases without any EBV association, CD5 positivity, or neoplastic PD-L1 expression, high PD-L1 expression (>=40%) on microenvironment immune cells predicted an extremely favorable outcome. CONCLUSION: EBV+ iDLBCL mainly comprised immunodeficiency associated patients, which may highlight the specificity of the intestine. PD-L1 expression on tumor cells or microenvironment immune cells was found to have an opposite prognostic impact in iDLBCL. PMID- 30449069 TI - Establishment of a highly efficient conjugation protocol for Streptomyces kanamyceticus ATCC12853. AB - Kanamycin B as the secondary metabolite of wild-type Streptomyces kanamyceticus (S. kanamyceticus) ATCC12853 is often used for the synthesis of dibekacin and arbekacin. To construct the strain has the ability for kanamycin B production; the pSET152 derivatives from Escherichia coli ET12567 were introduced to S. kanamyceticus by intergeneric conjugal transfer. In this study, we established a reliable genetic manipulation system for S. kanamyceticus. The key factors of conjugal transfer were evaluated, including donor-to-recipient ratio, heat-shock, and the overlaying time of antibiotics. When spores were used as recipient, the optimal conjugation frequency was up to 6.7 * 10-6 . And mycelia were used as an alternative recipient for conjugation instead of spores; the most suitable donor to-recipient ratio is 1:1 (107 :107 ). After incubated for only 10-12 hr and overlaid with antibiotics subsequently, the conjugation frequency can reach to 6.2 * 10-5 which is sufficient for gene knockout and other genetic operation. Based on the optimized conjugal transfer condition, kanJ was knocked out successfully. The kanamycin B yield of kanJ-disruption strain can reach to 543.18 +/- 42 mg/L while the kanamycin B yield of wild-type strain was only 46.57 +/- 12 mg/L. The current work helps improve the content of kanamycin B in the fermentation broth of S. kanamyceticus effectively to ensure the supply for the synthesis of several critical semisynthetic antibiotics. PMID- 30449070 TI - Three-dimensional prediction of roots position through Cone-Beam Computed Tomography scans-digital model superimposition: a novel method. AB - OBJECTIVES: To introduce a new, fast, reliable, and free from software-related bias method to predict three-dimensionally the root position and angulation during and after orthodontic treatment. The final goal is to keep to a minimum the use of ionizing radiation by eliminating the necessity of multiple radiation exposure for checking root alignment. SETTING AND SAMPLE POPULATION: Pre- and post-treatment digital models and CBCT scans from a patient were retrieved. MATERIAL AND METHODS: The post-treatment digital model (post-model) was set as the reference; pre- and post-treatment CBCT scans were pre-aligned to the post model with a point set registration; iterative closest point algorithm was then employed for final adjustments. The accuracy of the proposed method was assessed by comparing the average distance between the expected root position setup with the true position of the roots, as from the post-treatment CBCT. RESULTS: After crown superimposition, 3D color maps showed that the accuracy of the root prediction was below 0.1 mm. CONCLUSION: The proposed digital workflow allows to predict in an accurate and truly three-dimensional way the final position of roots, when an initial CBCT is available, without the need of an extra X-ray examination for the patient at the end of treatment. The limitation of the exposure to mid- and post- treatment x-rays is in accordance with the ALARA (As Low As Reasonably Achievable) principle and it is even more relevant in growing patients. This article is protected by copyright. All rights reserved. PMID- 30449071 TI - Ewing's Sarcoma of the Head and Neck: Margins are not just for surgeons. AB - BACKGROUND, METHODS: To describe the characteristics, treatments (systemic/local), and outcome (oncological/functional) of French patients with head and neck Ewing's sarcomas (HNES) registered in the Euro-Ewing 99 (EE99) database. Specific patient-level data were reviewed retrospective. RESULTS: Forty seven HNES patients in the EE99 database had a median age of 11 years, 89% had bone tumors (skull 55%, mandible 21%, maxilla 11%), 89% had small tumors (<200 mL), and they were rarely metastatic (9%). Local treatment was surgery radiotherapy (55%), exclusively surgery (28%), or radiotherapy (17%). Metastatic relapses occurred in five patients with high relapse risk factors (metastasis at diagnosis, poor histological response, large tumors). Local progression/relapses (LR) after exclusive radiotherapy occurred in three patients with persistent extra-osseous residue and in four patients considered R0 margins (postchemotherapy surgery, without postoperative radiotherapy [PORT]), reclassified by pathological review as R1a. Pathological review reclassified 72% of R0 margins: 11/18 to R1a and 2/18 to R2. Five patients had confirmed R0 margins after postchemotherapy surgery without PORT and had no LR Eight patients had R2 margins (initial surgery without previous chemotherapy, with PORT) and had no LR With a median follow-up of 9.3 years, the 3-year LR rate, EFS, and OS were 84.8%, 78.6%, and 89.3%, respectively. Among the 5-year survivors, 88% had long term sequelae. CONCLUSION: To optimize HNES management, patients should be treated from diagnosis in expert centers with multidisciplinary committees to discuss treatment strategy (type of surgery, need for PORT) and validate surgical margins. PMID- 30449072 TI - Using magnetic core-shell nanoparticles coated with an ionic liquid dispersion assisted by effervescence powder for the micro-solid-phase extraction of four beta blockers from human plasma by ultra high performance liquid chromatography with mass spectrometry detection. AB - In this work, a novel, efficient, and green sorbent, SiO2 @Fe3 O4 has been created and functionalized with 1-butyl-3-methylimidazolium hexafluorophosphate as an ionic liquid. This sorbent was applied for microextraction of four beta blockers, propranolol, metoprolol, atenolol, and alprenolol with bupivacaine as internal standard from human plasma followed by liquid chromatography with mass spectrometric detection. A mixture of sodium bicarbonate and sodium dihydrogen phosphate was used as an extractant dispersive agent (effervescent power) to enhance the interaction between the magnetic sorbent and analytes. Main affecting parameters on microextraction and elution were optimized. Figures of merit for dispersive solid phase extraction with ionic liquid coated magnetic nanoparticles assisted by effervescent powder were calculated under the optimized conditions. The detection limits for propranolol, metoprolol, atenolol, and alprenolol were found at 0.33, 0.62, 0.03, and 0.44 ng/mL, respectively. For all analytes, good linearity was obtained. Intra- (n = 5) and interday (n = 10) precision were both under 6.3% while the preconcentration factors were obtained in the range between 15-18. The extraction efficiencies for each analyte ranged from 75 to 91%. The method was successfully applied for determination of trace amounts of the beta blockers in human plasma samples. PMID- 30449073 TI - A field investigation of an African horse sickness outbreak in the controlled area of South Africa in 2016. AB - An outbreak of African horse sickness (AHS) caused by AHS virus type 1 occurred within the South African AHS surveillance zone during April and May 2016. The index case was detected by a private veterinarian through passive surveillance. There were 21 cases in total, which is relatively low compared to case totals during prior AHS outbreaks in the same region (and of the same AHS virus type) in 2004, 2011 and 2014. The affected proportion of horses on affected properties was 0.07 (95% CI 0.04, 0.11). Weather conditions were conducive to high midge activity immediately prior to the outbreak but midge numbers decreased rapidly with the advent of winter. The outbreak was localized, with 18 of the 21 cases occurring within 8 km of the index property and the three remaining cases on two properties within 21 km of the index property, with direction of spread consistent with wind-borne dispersion of infected midges. Control measures included implementation of a containment zone with movement restrictions on equids. The outbreak was attributed to a reversion to virulence of a live attenuated vaccine used extensively in South Africa. Outbreaks in the AHS control zones have a major detrimental impact on the direct export of horses from South Africa, notably to the European Union. PMID- 30449074 TI - A high-quality chromosome-level genome assembly of a generalist herbivore, Trichoplusia ni. AB - The cabbage looper, Trichoplusia ni, is a globally distributed highly polyphagous herbivore and an important agricultural pest. T. ni has evolved resistance to various chemical insecticides, and is one of the only two insect species that have evolved resistance to the biopesticide Bacillus thuringiensis (Bt) in agricultural systems and has been selected for resistance to baculovirus infections. We report a 333-Mb high-quality T. ni genome assembly, which has N50 lengths of scaffolds and contigs of 4.6 Mb and 140 Kb, respectively, and contains 14,384 protein-coding genes. High-density genetic maps were constructed to anchor 305 Mb (91.7%) of the assembly to 31 chromosomes. Comparative genomic analysis of T. ni with Bombyx mori showed enrichment of tandemly duplicated genes in T. ni in families involved in detoxification and digestion, consistent with the broad host range of T. ni. High levels of genome synteny were found between T. ni and other sequenced lepidopterans. However, genome synteny analysis of T. ni and the T. ni derived cell line High Five (Hi5) indicated extensive genome rearrangements in the cell line. These results provided the first genomic evidence revealing the high instability of chromosomes in lepidopteran cell lines known from karyotypic observations. The high-quality T. ni genome sequence provides a valuable resource for research in a broad range of areas including fundamental insect biology, insect-plant interactions and co-evolution, mechanisms and evolution of insect resistance to chemical and biological pesticides, and technology development for insect pest management. This article is protected by copyright. All rights reserved. PMID- 30449075 TI - Suramin, screened from an approved drug library, inhibits HuR functions and attenuates malignant phenotype of oral cancer cells. AB - AU-rich elements (ARE) exist in the 3'-untranslated regions of the mRNA transcribed from cell growth-related genes such as proto-oncogenes, cyclin related genes, and growth factors. HuR binds and stabilizes ARE-mRNA. HuR is expressed abundantly in cancer cells and related malignant phenotypes. HuR knockdown attenuates the malignant phenotype of oral cancer cells. In this study, we screened 1570 compounds in the approved drug library by differential scanning fluorimetry (DSF) to discover a HuR-targeted compound. Firstly, 55 compounds were selected by DSF. Then, 8 compounds that showed a shift in the melting temperature value in a concentration-dependent manner were selected by DSF. Of them, suramin, an anti-trypanosomal drug, binds to HuR, exhibiting fast-on and fast-off kinetic behavior on surface plasmon resonance (SPR). We confirmed that suramin significantly decreased mRNA and protein expression of cyclin A2 and cyclin B1. The cyclin A2 and cyclin B1 mRNAs were destabilized by suramin. Furthermore, the motile and invasive activities of a tongue carcinoma cell line treated with suramin were markedly lower than those of control cells. The above findings suggest that suramin binds to HuR and inhibits its function. We also showed that the anticancer effects of suramin were caused by the inhibition of HuR function, indicating its potential as a novel therapeutic agent in the treatment of oral cancer. Our results suggest that suramin, via its different mechanism, may effectively suppress progressive oral cancer that cannot be controlled using other anticancer agents. PMID- 30449076 TI - Direct-acting antivirals-based therapy decreases hepatic fibrosis serum biomarker microfibrillar-associated protein 4 in hepatitis C patients. AB - Background/Aims: An estimated 80 million people worldwide are infected with viremic hepatitis C virus (HCV). Even after eradication of HCV with direct acting antivirals (DAAs), hepatic fibrosis remains a risk factor for hepatocarcinogenesis. Recently, we confirmed the applicability of microfibrillar associated protein 4 (MFAP4) as a serum biomarker for the assessment of hepatic fibrosis. The aim of the present study was to assess the usefulness of MFAP4 as a biomarker of liver fibrosis after HCV eliminating therapy with DAAs. Methods: MFAP4 was measured using an immunoassay in 50 hepatitis C patients at baseline (BL), the end-of-therapy (EoT), and the 12-week follow-up visit (FU). Changes in MFAP4 from BL to FU and their association with laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelets, the AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4), and albumin were analyzed. Results: MFAP4 serum levels were representative of the severity of hepatic fibrosis at BL and correlated well with laboratory parameters, especially APRI (Spearman correlation, R2=0.80). Laboratory parameters decreased significantly from BL to EoT. MFAP4 serum levels were found to decrease from BL and EoT to FU with high statistical significance (Wilcoxon P<0.001 for both). Conclusions: Our findings indicate that viral eradication resulted in reduced MFAP4 serum levels, presumably representing a decrease in hepatic fibrogenesis or fibrosis. Hence, MFAP4 may be a useful tool for risk assessment in hepatitis C patients with advanced fibrosis after eradication of the virus. PMID- 30449077 TI - The Usefulness of New-Generation Capsule Endoscopy in Patients with Portal Hypertensive Enteropathy. PMID- 30449078 TI - Efficacy of fecal microbiota therapy in steroid dependent ulcerative colitis: a real world intention-to-treat analysis. AB - Background/Aims: Four high-quality randomized controlled trials have proven the efficacy of fecal microbiota transplantation (FMT) in active ulcerative colitis (UC). We assessed the efficacy of FMT in a real-world setting involving steroid dependent patients with UC. Methods: This was a single-center prospective analysis of data from steroid-dependent patients with UC treated with FMT from September 2015 to September 2017 at the Dayanand Medical College, a tertiary care center in India. Fecal samples from random unrelated donors were administered through colonoscopy at weeks 0, 2, 6, 10, 14, 18, and 22. The primary outcome was achievement of steroid-free clinical remission, and the secondary outcomes were clinical response and endoscopic remission at 24 weeks. Modified intention-to treat analysis was performed, which included subjects who underwent at least 1 FMT. Results: Of 345 patients with UC treated during the study period, 49 (14.2%) had steroid-dependent UC. Of these 49 patients, 41 underwent FMT: 33 completed 7 sessions over 22 weeks according to the protocol, and 8 discontinued treatment (non-response, 5; lost to follow-up, 2; and fear of adverse effects, 1). At week 24, steroid-free clinical remission was achieved in 19 out of 41 (46.3%) patients, whereas clinical response and endoscopic remission were achieved in 31 out of 41 (75.6%) and 26 out of 41 (63.4%) patients, respectively. All patients with clinical response were able to withdraw steroids. There were no serious adverse events necessitating discontinuation. Conclusions: A multisession FMT via the colonoscopic route is a promising therapeutic option for patients with steroid-dependent UC, as it can induce clinical remission and aid in steroid withdrawal. PMID- 30449079 TI - Epidemiological trend in inflammatory bowel disease in Taiwan from 2001 to 2015: a nationwide populationbased study. AB - Background/Aims: Incidences of inflammatory bowel diseases (IBDs), ulcerative colitis (UC), and Crohn's disease (CD), have been increasing in Asia. In this study, we report the relevant clinical characteristics and determined the epidemiological trend of IBD in Taiwan from 2001 to 2015. Methods: A retrospective study was conducted to analyze data recorded from January 2001 through December 2015 in the registered database compiled by the National Health Insurance and provided by the Ministry of Health and Welfare, Taiwan. Results: A total of 3,806 patients with catastrophic IBD illness were registered from 2001 to 2015 in Taiwan (CD, 919; UC, 2,887). The crude incidence of CD increased from 0.17/100,000 in 2001 to 0.47/100,000 in 2015, whereas that of UC increased from 0.54/100,000 in 2001 to 0.95/100,000 in 2015. The prevalence of CD increased from 0.6/100,000 in 2001 to 3.9/100,000 in 2015, whereas that of UC increased from 2.1/100,000 in 2001 to 12.8/100,000 in 2015. The male-to-female ratio in the study sample was 2.19 for CD and 1.62 for UC. The median age of those registered with CD was lower than that of those registered for UC: 38.86 and 44.86 years, respectively. A significantly greater increase in CD incidence rate was identified among 20 to 39-year-old compared with other age groups. Conclusions: Using Taiwan's nationwide insurance database, we determined that the number of patients with CD increased more rapidly during the study period than the number of patients with UC, especially among age 20 to 39-year-old, resulting in a decreased UC-to-CD ratio. PMID- 30449080 TI - Development and validation of a scoring system for advanced colorectal neoplasm in young Korean subjects less than age 50 years. AB - Background/Aims: Colorectal cancer incidence among patients aged <=50 years is increasing. This study aimed to develop and validate an advanced colorectal neoplasm (ACRN) screening model for young adults aged <50 years in Korea. Methods: This retrospective cross-sectional study included 59,575 consecutive asymptomatic Koreans who underwent screening colonoscopy between 2003 and 2012 at a single comprehensive health care center. Young Adult Colorectal Screening (YCS) score was developed as an optimized risk stratification model for ACRN using multivariate analysis and was internally validated. The predictive power and diagnostic performance of YCS score was compared with those of Asia-Pacific Colorectal Screening (APCS) and Korean Colorectal Screening (KCS) scores. Results: 41,702 and 17,873 subjects were randomly allocated into the derivation and validation cohorts, respectively, by examination year. ACRN prevalence was 0.9% in both cohorts. YCS score comprised sex, age, alcohol, smoking, obesity, glucose metabolism abnormality, and family history of CRC, with score ranges of 0 to 10. In the validation cohort, ACRN prevalence was 0.6% in the low-risk tier (score, 0-4), 1.5% in the moderate-risk tier (score, 5-7), and 3.4% in the high risk tier (score, 8-10). ACRN risk increased 2.5-fold (95%CI, 1.8-3.4) in the moderate-risk tier and 5.8-fold (95%CI, 3.4-9.8) in the high-risk tier compared with the low-risk tier. YCS score identified better balanced accuracy (53.9%) than APCS (51.5%) and KCS (50.7%) scores and had relatively good discriminative power (area under the curve=0.660). Conclusions: YCS score based on clinical and laboratory risk factors was clinically effective and beneficial for predicting ACRN risk and targeting screening colonoscopy in adults aged <50 years. PMID- 30449081 TI - Improving the quality of care for inflammatory bowel disease. AB - Great strides have been achieved in the development of quality-of-care measures and standards for inflammatory bowel disease (IBD) over the last decade. The central structural component of care in IBD revolves around the multidisciplinary team, which should be equipped with the necessary resources to operate and implement decisions. Process measures have been defined by interest groups and can be adapted into process tools for the delivery of care for various patient subgroups and clinical scenarios. The emerging treat-to-target approach to IBD management may be used to achieve optimal long-term and holistic patient-centred outcomes, such as survival, control of inflammation and disease progression, symptomatic remission, quality of life and complications. Other important quality of-care outcome measures for IBD include disutility of care, healthcare utilization and other patient-reported outcomes such as nutritional status and impact of fistulae. The current challenge for healthcare providers and health systems is the integration of quality-of-care structures and processes into clinical practice, and the consistent delivery of updated evidence-based quality IBD care to various patient populations by individual health care providers. Finally, the awareness and appreciation for quality of care in IBD is increasing in Asia, and Asian healthcare institutions should be encouraged to take the lead in improving the quality of care in IBD. PMID- 30449082 TI - In Situ FTIR Reactor for Monitoring Gas-Phase Products during a (Photo)catalytic Reaction in the Liquid Phase. AB - Various catalytic and photocatalytic reactions in the liquid phase give rise to gas products. Therefore, the identification and quantification of these products are of high importance and are even essential for some reactions. In this paper, a new in situ FTIR reactor is designed and used for analyzing the gas headspace of a (photo)catalytic reaction in solution. It allows the identification and quantification of the gas-phase products of a liquid reaction under operating conditions and in real time. The new reactor has been tested in three representative photocatalytic reactions widely studied as model reactions in the liquid phase: i.e., (i) decomposition of formic acid, (ii) oxidation of methylene blue, and (iii) reduction of CO2. The validity of the results has been confirmed by analyzing the headspace at the end of the reaction using gas chromatography technique. The new reactor opens the possibility to follow online the (photo)catalyst activity. This is useful for ensuring the stability of the catalyst and studying the evolution of the selectivity during the reaction. The nondestructive behavior of the FTIR technique allows its coupling with other techniques for obtaining complementary results. The new reactor setup is easy to handle and to ship and is very efficient, which makes it very suitable for performing complementary, fast and/or preliminary studies. PMID- 30449083 TI - The molecular fingerprint of fluorescent natural organic matter offers insight into biogeochemical sources and diagenetic state. AB - Investigating the biogeochemistry of dissolved organic matter (DOM) requires the synthesis of data from several complementary analytical techniques. In contrast to subjective post-hoc correlation analysis, a robust integration requires data fusion, capable of simultaneously decomposing data from multiple instruments while identifying linked and unrelated signals. Here, Advanced Coupled Matrix and Tensor Factorization (ACMTF) was used to identify the molecular fingerprint of DOM fluorescence fractions in Arctic fjords. ACMTF explained 99.84 % of the variability with six fully shared components. Individual molecular formulas were linked to multiple fluorescence components and vice versa. Molecular fingerprints differed in diversity and oceanographic patterns, suggesting a link to the biogeochemical sources and diagenetic state of DOM. The fingerprints obtained through ACMTF were more specific compared to traditional correlation analysis and yielded greater compositional insight. Multivariate data fusion aligns extremely complex, heterogeneous DOM datasets, and thus facilitates a more holistic understanding of DOM biogeochemistry. PMID- 30449084 TI - Mesoporous Cages in Chemically Robust MOFs Created by a Large Number of Vertices with Reduced Connectivity. AB - We report the design and synthesis of two metal-organic frameworks (MOFs) with permanent porosity, MOF-818 and MOF-919, us-ing a small di-topic organic linker, 1H-pyrazole-4-carboxylic acid (H2PyC), 0.4 nm in length. Three mesoporous cages of unprecedent-ed polyhedra are identified in these MOFs, wuh cage in MOF-818, yys and liu cages in MOF-919, with the diameter of 3.8, 4.9 and 6.0 nm, respectively. The di-topic H2PyC linker functions as the edge in the structure, while two types of metal-containing second building units (SBUs) function as the vertices. 28 vertices present in wuh cage; 50 in yys cage; and 70 in liu cage. Systematic analysis of these cages along with other mesoporous cages in supramolecules and MOFs constructed by di-topic linkers reveals that the exten sion of cage size is dictated by both the number and connectivity of the vertices. The increase in cage size is proportional to the num-ber of vertices, while the growth rate is determined by their connectivity. The reduction in connectivity is found to be an effective way to create large cages. All three cages in this report are constructed by three-connecting (3-c) vertices and two connecting (2-c) vertices. This [2-c, 3-c] connectivity represents the least connectivity required for the construction of cage and the most effective one for cage size expansion. The largest cage liu, exhibits a cage size to linker size ratio of 15, outstanding in supramolecules and MOFs. MOF-818 is stable in water with a wide pH range (pH = 2-12) and the wuh cage is big enough for the inclusion of biomolecules such as vitamin-B12 and insulin. PMID- 30449085 TI - Green Synthesis of Porous Cocoon-like rGO for Enhanced Microwave-Absorbing Performances. AB - A novel porous cocoon-like reduced graphene oxide (rGO) with high porosity and low density was fabricated by a simple and green reduction reaction using ascorbic acid as the reductant in combination with a freeze-drying process without annealing. The bulk density of porous cocoon-like rGO is only 28.49 mg/cm3, and the porosity reaches 94.57%. The reaction times have an important influence on the formation of porous cocoon-like rGO and the reduction degree of rGO. The porous cocoon-like rGO exhibits an excellent microwave-absorbing property with a low mass filling ratio of 7.0 wt %; its minimum reflection loss (RL) is -29.05 dB at 15.96 GHz with a sample thickness of 2.0 mm and the effective absorption bandwidth (RL < -10 dB) is 5.27 GHz. The microwave-absorbing property of porous cocoon-like rGO is much better than that of GO and other porous rGO. The in-depth analyses of the reduction degree, porosity, and microwave-absorbing performance illustrate that the microwave-absorbing performance of rGO is significantly related to the reduction degree and porosity. In addition, the synthetic route for porous cocoon-like rGO is simple, has low energy consumption, and is environmentally friendly. Our work demonstrates that the porous cocoon-like rGO is a promising lightweight microwave absorber with high performance. PMID- 30449086 TI - Untargeted Molecular Discovery in Primary Metabolism: Collision Cross Section as a Molecular Descriptor in Ion Mobility-Mass Spectrometry. AB - In this work, we established a collision cross section (CCS) library of primary metabolites based on analytical standards in the Mass Spectrometry Metabolite Library of Standards (MSMLS) using a commercially available ion mobility-mass spectrometer (IM-MS). From the 554 unique compounds in the MSMLS plate library, we obtained a total of 1246 CCS measurements over a wide range of biochemical classes and adduct types. Resulting data analysis demonstrated that the curated CCS library provides broad molecular coverage of metabolic pathways and highlights intrinsic mass-mobility relationships for specific metabolite superclasses. The separation and characterization of isomeric metabolites were assessed, and all molecular species contained within the plate library, including isomers, were critically evaluated to determine the analytical separation efficiency in both the mass ( m/ z) and mobility (CCS/DeltaCCS) dimension required for untargeted metabolomic analyses. To further demonstrate the analytical utility of CCS as an additional molecular descriptor, a well characterized biological sample of human plasma serum (NIST SRM 1950) was examined by LC-IM-MS and used to provide a detailed isomeric analysis of carbohydrate constituents by ion mobility. PMID- 30449087 TI - Monitoring Early Life Mycotoxin Exposures via LC-MS/MS Breast Milk Analysis. AB - Infants are particularly susceptible toward the toxic effects of food contaminants, including mycotoxins. However, multimycotoxin exposure assessment in breast milk has received very limited attention so far, resulting in a poor understanding of coexposures during early life. Here, we present the development and application of a highly sensitive, specific, and quantitative assay assessing up to 28 mycotoxins, including regulated (aflatoxins, ochratoxin A, deoxynivalenol, zearalenone) and emerging mycotoxins as well as key metabolites by LC-MS/MS. After careful optimization of the sample preparation procedure, a QuEChERS protocol combined with a freeze-out step was validated in-house. The limits of quantification varied between 0.009 and 2.9 ng/mL, and for most analytes extraction recovery (74-116%) and intermediate precision (2-20%) were satisfactory. The method was applied to examine multiple breast milk samples obtained from 22 women ( n = 75 in total) from Ogun State, Nigeria. Most samples were either entirely free of mycotoxins or contaminated to a minimal extent with beauvericin (56%), enniatin B (9%), ochratoxin A (15%), and aflatoxin M1 (1%). The most abundant mycotoxin was beauvericin, which was not reported in this biological fluid before, with concentrations up to 0.019 ng/mL. In conclusion, the method demonstrated to be fit for purpose to determine and quantify low background contaminations in human breast milk. On the basis of the high sensitivity of the novel analytical method, it was possible to deduce that tolerable daily intake values were not exceeded by breastfeeding in the examined infants. PMID- 30449088 TI - Photon-Only Molecular Motor with Reverse Temperature-Dependent Efficiency. AB - Light-driven molecular motors are archetypal molecular machines and enable fast and efficient unidirectional motions under photoirradiation. Their common working mechanism contains thermal ratcheting steps leading to slowed-down and even halted directional movement at lower temperatures. In this work, an alternative type of molecular motor is presented, which operates without thermal ratcheting in the ground state. Instead, three consecutive and different photoreactions lead to a directional stepwise rotation of one molecular fragment with respect to the other. This motion is increased in speed and directionality at lower temperatures and at the same time allows a considerably larger fraction of the supplied photon energy to be used for performing work. PMID- 30449089 TI - Linear scanning ATR-FTIR for chemical mapping and high-throughput studies of Pseudomonas sp. biofilms in microfluidic channels. AB - A fully automated linear scanning attenuated total reflection (ATR) accessory is presented for Fourier transform infrared (FTIR) spectrosco-py. The approach is based on the accurate displacement of a multi-bounce ATR crystal relative to a stationary infrared beam. To ensure accu-rate positioning and to provide a second sample characterization mode, a custom-built microscope was integrated into the system and the computerized work flow. Custom software includes automated control and measurement routines with a straightforward user interface for selecting parameters and monitoring experimental progress. This cost-effective modular system can be implemented on any research-grade spectrometer with a standard sample compartment for new bioanalytical chemistry studies. The system was validated and optimized for use with microfluidic flow cells containing growing Pseudomonas sp. bacterial biofilms. The complementarity among the scan positioning accu-racy, measurement spatial resolution and the microchannel dimensions paves the way for parallel biological assays with real-time control over environmental parameters and minimal manual labor. By rotating the channel orientation relative to the beam path, the system could also be used for acquisition of linear biochemical maps and stitched microscope images along the channel length. PMID- 30449090 TI - An Intrinsically Disordered Peptide-Peptide Stapler for Highly Efficient Protein Ligation Both in vivo and in vitro. AB - Herein, we report an intrinsically disordered protein SpyStapler that can catalyze the isopeptide bond formation between two pep-tide tags, i.e. SpyTag and BDTag, both in vitro and in vivo. SpyStapler and BDTag are developed by splitting SpyCatcher-the cog-nate protein partner of SpyTag-at the more solvent exposed second loop region. Regardless of their locations in protein constructs, SpyStapler enables efficient covalent coupling of SpyTag and BDTag under a variety of mild conditions in vitro (yield ~80%). Co-expression of SpyStapler with telechelic dihydrofolate reductase (DHFR) bearing a SpyTag at N-terminus and a BDTag at C-terminus leads to direct cellular synthesis of a circular DHFR. Mechanistic studies involving circular dichroism (CD) and nuclear magnetic resonance (NMR) spectrometry reveal that SpyStapler alone is disordered in solution and forms a stable folded structure (Tm ~55 oC) in the presence of both SpyTag and BDTag upon isopeptide bonding. No ordered structure can be formed in the ab-sence of either tag. The catalytically inactive SpyStapler-EQ mutant cannot form a stable physical complex with SpyTag and BDTag, but it can fold into ordered structure in the presence of the ligated product (SpyTag-BDTag). It suggests that the isopeptide bond is important in stabilizing the complex. Given its efficiency, resilience, and robustness, SpyStapler provides new opportunities for bioconjugation and creation of complex protein architectures. PMID- 30449091 TI - Spiroborate-Based Double-Stranded Helicates: Meso-to-Racemo Isomerization and Ion Triggered Spring-Like Motion of the Racemo-Helicate. AB - A one-handed double-stranded spiroborate helicate exhibits a unique reversible extension-contraction motion coupled with a twisting motion in one direction triggered by binding and release of a Na+ ion while retaining its handedness. Here we report that an extended meso-helicate was also produced together with the racemo-helicate, and the meso-helicate was readily con-verted to the racemo helicate assisted by a Na+ ion as a template in the presence of water. The thermodynamic analyses of the ion-triggered spring-like motion of the racemo helicate using a series of monovalent cations with different sizes revealed that the association constants of the extended racemo-helicate decreased in the following order: Li+ > Na+ > NH4+ > Ag+ >= K+ > Cs+ > Rb+, which roughly agrees with the reverse order of their ionic radii except for the NH4+ ion due to the more elongated contracted helicates when complexed with larger cations as supported by the crystal and DFT calculated structures. The one-handed contracted helicates showed characteristic CD spectra depending on the cation species due to the differences in their contracted helical structures and its absolute handedness of the spiroborate helicate was determined by X-ray crystallography. The kinetic studies of the spring-like motions of the racemo-helicate showed that the exchange rate between the extended and contracted helicates tend to increase in the following order: Li+ < Na+ < K+ <= NH4+ < Rb+ < Cs+ < Ag+ as anticipated from the association constants, being in good agreement with the order of the cation sizes except for Ag+. PMID- 30449092 TI - Resveratrol protects porcine intestinal epithelial cells from deoxynivalenol induced damage via the Nrf2 signaling pathway. AB - Deoxynivalenol (DON) is a common mycotoxin that induces oxidative stress and affects intestinal health of humans and animals. This study was carried out to investigate the potential protective effect of resveratrol (RES) as a natural antioxidant on the alleviation of cytotoxicity induced by DON using an established intestinal porcine epithelial cell line (IPEC-J2). Pre-treatment of cells with 15 uM RES improved cell viability and proliferation, and attenuated cell cycle arrest induced by DON. Pre-treatment with RES also decreased accumulation of intracellular reactive oxygen species (ROS), stabilized mitochondrial membrane potential (MMP), and prevented apoptosis induced by DON. RES activated the nuclear factor-erythroid 2-related factor-2 (Nrf2) signaling pathway, while knockdown of Nrf2 expression by siRNA abrogated the protective effects of RES on DON-induced cytotoxicity, oxidative stress, and mitochondria dependent apoptosis. These results suggest that RES protects IPEC-J2 cells against DON-induced damage at least partly via the Nrf2 signaling pathway. PMID- 30449093 TI - Ultrasensitive Fluorescence Detection of Peroxymonosulfate Based on a Sulfate Radical-Mediated Aromatic Hydroxylation. AB - Recently, peroxymonosulfate (PMS)-based advanced oxidation processes have exhibited broad application prospects in the environment field. Accordingly, a simple, rapid, and ultrasensitive method is highly desired for the specific recognition and accurate quantification of PMS in various aqueous solutions. In this work, SO4*--induced aromatic hydroxylation was explored, and based on that, for the first time, a novel fluorescence method was developed for the PMS determination using Co2+ as a PMS activator and benzoic acid (BA) as a chemical probe. Through a suite of spectral, chromatographic, and mass spectrometric analyses, SO4*- was proven to be the dominant radical species, and salicylic acid was identified as the fluorescent molecule. As a result, a whole radical chain reaction mechanism for the generation of salicylic acid in the BA/PMS/Co2+ system was proposed. This fluorescence method possessed a rapid reaction equilibrium (<1 min), an ultrahigh sensitivity (detection limit = 10 nM; quantification limit = 33 nM), an excellent specificity, and a wide detection range (0-100 MUM). Moreover, it performed well in the presence of possible interfering substances, including two other peroxides (i.e., peroxydisulfate and hydrogen peroxide), some common ions, and organics. The detection results for real water samples further validated the practical utility of the developed fluorescence method. This work provides a new method for the specific recognition and sensitive determination of PMS in complex aqueous solutions. PMID- 30449094 TI - Tailored Phase Conversion under Conjugated Polymer Enables Thermally Stable Perovskite Solar Cells with Efficiency Exceeding 21. AB - The precise control of stoichiometric balance and ionic defects on the surface of solution-processed perovskite is critical to the performance and stability of perovskite solar cells (pero-SCs). Here, we introduce a low-cost and stable conjugated donor polymer (PTQ10) as interfacial layer in the planar n-i-p structured pero-SCs. The polymer was applied to the perovskite intermediate phase before the thermal annealing. This treatment significantly reduced the loss of surface organic cation during thermal annealing. Importantly, the kinetics of phase conversion of perovskite was influenced, and perovskite crystal showed a more preferential orientation. Moreover, the polymer proved to be an effective hole extraction layer due to the proper energy alignment with perovskite. Finally, a champion power conversion efficiency of the planar pero-SCs was achieved at 21.2% with a high fill factor of 81.6%. The devices also showed great ambient and thermal stability. This work presents a facile way of perovskite surface control to achieve high-performance pero-SCs. PMID- 30449096 TI - Direct Catalytic Enantioselective Benzylation from Aryl Acetic Acids. AB - We demonstrate that metal-catalyzed enantioselective benzylation reactions of allylic electrophiles can occur directly from aryl acetic acids. The reaction proceeds via a pathway in which decarboxylation is the terminal event, occurring after stereoselective carbon-carbon bond formation. This mechanistic feature enables enantioselective benzylation without the generation of a highly basic nucleophile. Thus, the process has broad functional group compatibility that would not be possible employing established protocols. PMID- 30449095 TI - Chemical Compositions, Antiobesity, and Antioxidant Effects of Proanthocyanidins from Lotus Seed Epicarp and Lotus Seed Pot. AB - Lotus seed epicarp (LSE) and lotus seed pot (LSP) were characterized, and a total of 5 and 7 proanthocyanidins (PAs) were identified in purified LSE and LSP extract, respectively. Purified LSE and LSP PAs significantly suppressed the body weight and weight gain of white adipose tissue (WAT) and decreased the WAT cell size in high-fat diet-induced obese mice regardless of the daily food intake. LSE or LSP administration significantly lowered the serum leptin level and improved the serum and liver lipid profiles (including total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) levels), increased activities of antioxidant enzymes (superoxide dismutase (SOD) and glutathione transferase (GST)) and reduced glutathione (GSH) concentration, and suppressed lipid peroxidation in hepatic tissue. LSP PAs were generally more effective than LSE PAs. Both extracts ameliorated obesity, insulin resistance, and oxidative damage in obese mice, suggesting they are good candidates for value-added functional food and nutraceutical ingredients. PMID- 30449097 TI - Flexoelectricity in Monolayer Transition Metal Dichalcogenides. AB - Flexoelectricity, the coupling effect of the strain gradient and charge polarization, is an important route to tune electronic properties of low dimensional materials. Here our extensive first-principles calculations reveal that structural wrinkling and corrugation will cause significant flexoelectricity in transition metal dichalcogenide (TMD) monolayers. The flexoelectricity is induced by the strain gradients created along the finite thickness of the wrinkled TMD monolayers and becomes more dominant in determining out-of-plane polarizations with decreasing wavelengths of the TMD wrinkles. According to the first-principles calculations and whole structural symmetry, a theoretical model is developed to describe the total out-of-plane polarizations and flexoelectric effect of the wrinkled TMD monolayers. The unveiled flexoelectricity in monolayer TMDs highlights a potential for their application in energy conversion devices. PMID- 30449098 TI - Coupling to Charge Transfer States is the Key to Modulate the Optical Bands for Efficient Light Harvesting in Purple Bacteria. AB - The photosynthetic apparatus of purple bacteria uses exciton delocalization and static disorder to modulate the position and broadening of its absorption bands, leading to efficient light harvesting. Its main antenna complex, LH2, contains two rings of identical bacteriochlorophyll pigments, B800 and B850, absorbing at 800 and 850 nm, respectively. It has been an unsolved problem why static disorder of the strongly coupled B850 ring is several times larger than that of the B800 ring. Here we show that mixing between excitons and charge transfer states in the B850 ring is responsible for the effect. The linear absorption spectrum of the LH2 system is simulated by using a multiscale approach with an exciton Hamiltonian generalized to include the charge transfer states that involve adjacent pigment pairs, with static disorder modeled microscopically by molecular dynamics simulations. Our results show that sufficient inhomogeneous broadening of the B850 band, needed for efficient light harvesting, is only obtained by utilizing static disorder in the coupling between local excited and interpigment charge transfer states. PMID- 30449099 TI - Plant Resources, Chemical Constituents and Bioactivities of Tea Plants from the Genus Camellia Section Thea. AB - Tea, as one of the most popular beverages with various bioactivities, is commonly produced from the fresh leaves of two widely cultivated tea plants, C. sinensis and C. sinensis var. assamica. Both plants belong to the genus Camellia section Thea, which was considered to have 12 species and 6 varieties according to Min's taxonomic system. Most species except the cultivated ones are known as wild tea plants and have been exploited and utilized to producing teas by the local people of its growing areas. So far, six species and varieties have been phytochemically studied, leading to the identification of 398 compounds, including hydrolyzable tannins, flavan-3-ols, flavonoids, terpenoids, alkaloids and other phenolics and related compounds. Various health beneficial effects were reported for tea and its components, involving antioxidant, anti-tumor and antimutagenic, anti diabetic, hypolipidemic, anti-inflammatory, anti-microbial, antiviral, antifungal, neuro-protective, hepatoprotective and so on. In this review, the geographical distribution of tea plants and the chemical constituents (1-398) reported from the genus Camellia section Thea and some tea products (green, black, oolong and Pu-er teas) ever been studied between 1970 and 2018 have been summarized, taking species as the main hint, and the main biological activities are also discussed. PMID- 30449100 TI - Computational Investigation of RO2 + HO2 and RO2 + RO2 Reactions of Monoterpene Derived First-Generation Peroxy Radicals Leading to Radical Recycling. AB - The oxidation of biogenically emitted volatile organic compounds (BVOC) plays an important role in the formation of secondary organic aerosols (SOA) in the atmosphere. Peroxy radicals (RO2) are central intermediates in the BVOC oxidation process. Under clean (low-NOX) conditions, the main bimolecular sink reactions for RO2 are with the hydroperoxy radical (HO2) and with other RO2 radicals. Especially for small RO2, the RO2 + HO2 reaction mainly leads to closed-shell hydroperoxide products. However, there exist other known RO2 + HO2 and RO2 + RO2 reaction channels that can recycle radicals and oxidants in the atmosphere, potentially leading to lower-volatility products and enhancing SOA formation. In this work, we present a thermodynamic overview of two such reactions: a) RO2 + HO2 -> RO + OH + O2 and b) RO'2 + RO2 -> R'O + RO + O2 for selected monoterpene + oxidant derived systems. The monoterpenes considered are alpha-pinene, beta pinene, limonene, trans-beta-ocimene, and delta3-carene. The oxidants considered are the hydroxyl radical (OH), nitrate radical (NO3), and ozone (O3). The reaction Gibbs energies were calculated at the DLPNO-CCSD(T)/def2 QZVPP//omegaB97X-D/aug-cc-pVTZ level of theory. All reactions studied here were found to be exergonic in terms of Gibbs energy. Based on a comparison with previous mechanistic studies, we predict that reaction a and reaction b are likely most important for first-generation peroxy radicals from O3 oxidation (especially for beta-pinene), while less so for most first-generation peroxy radicals from OH and NO3 oxidation. This is because both reactions are comparatively more exothermic for the O3 oxidized systems than their OH and NO3 oxidized counterparts. Our results indicate that certain complex RO2 may contribute to an increase in radical and oxidant recycling under high HO2 conditions in the atmosphere, which can potentially enhance SOA formation. PMID- 30449101 TI - Watching an Engineered Calcium Biosensor Glow: Altered Reaction Pathways before Emission. AB - Biosensors have become an indispensable tool set in life sciences. Among them, fluorescent protein-based biosensors have great biocompatibility and tunable emission properties but their development is largely on trial and error. To facilitate a rational design, we implement tunable femtosecond stimulated Raman spectroscopy, aided by transient absorption and quantum calculations, to elucidate the working mechanisms of a single-site Pro377Arg mutant of an emission ratiometric Ca2+ biosensor based on a green fluorescent protein-calmodulin complex. Comparisons with the parent protein and the Ca2+-free/bound states unveil more structural inhomogeneity yet an overall faster excited-state proton transfer (ESPT) reaction inside the Ca2+-bound biosensor. The correlated photoreactant and photoproduct vibrational modes in the excited state reveal more chromophore twisting and trapping in the Ca2+-bound state during ESPT and the largely conserved chromophore dynamics in the Ca2+-free state from parent protein. The uncovered structural dynamics insights throughout an ESPT reaction inside a calcium biosensor provide important design principles in maintaining a hydrophilic, less compact, and more homogeneous environment with directional H bonding (from the chromophore to surrounding protein residues) via bioengineering methods to improve the ESPT efficiency and quantum yield while maintaining photostability. PMID- 30449102 TI - Pentacene Crystal Growth on Silica and Layer-Dependent Step-Edge Barrier from Atomistic Simulations. AB - Understanding and controlling the growth of organic crystals deposited from the vapor phase is important for fundamental materials science and necessary for applications in pharmaceutical and organic electronics industries. Here, this process is studied for the paradigmatic case of pentacene on silica by means of a specifically tailored computational approach inspired by the experimental vapor deposition process. This scheme is able to reproduce the early stages of the thin film formation, characterized by a quasi layer-by-layer growth, thus showcasing its potential as a tool complementary to experimental techniques for investigating organic crystals. Crystalline islands of standing molecules are formed at a critical coverage, as a result of a collective reorientation of disordered aggregates of flat-lying molecules. The growth then proceeds by sequential attachment of molecules at the cluster and then terrace edges. Free energy calculations allowed us to characterize the step-edge barrier for descending the terraces, a fundamental parameter for growth models for which only indirect experimental measurements are available. The barrier is found to be layer-dependent (approximately 1 kcal/mol for the first monolayer on silica, 2 kcal/mol for the second monolayer) and to extend over a distance comparable with the molecular length. PMID- 30449103 TI - Phenol Molecular Sheets Woven by Water Cavities in Hydrophobic Slit Nanospaces. AB - Despite extensive research over the last several decades, the microscopic characterization of topological phases of adsorbed phenol from aqueous solutions in carbon micropores (pore size < 2.0 nm), which are believed to exhibit a solid and quasi-solid character, has not been reported. Here, we present a combined experimental and molecular level study of phenol adsorption from neutral water solutions in graphitic carbon micropores. Theoretical and experimental results show high adsorption of phenol and negligible coadsorption of water in hydrophobic graphitic micropores (super-sieving effect). Graphic processing unit accelerated molecular dynamics simulation of phenol adsorption from water solutions in a realistic model of carbon micropores reveal the formation of two dimensional phenol crystals with a peculiar pattern of hydrophilic-hydrophobic stripes in 0.8 nm supermicropores. In wider micropores, disordered phenol assemblies with water clusters, linear chains, and cavities of various sizes are found. The highest surface density of phenol is computed in 1.8 nm supermicropores. The percolating water cluster spanning the entire pore space is found in 2.0 nm supermicropores. Our findings open the door for the design of better materials for purification of aqueous solutions from nonelectrolyte micropollution. PMID- 30449104 TI - Shortening Nucleation Time to Enable Ultrafast Phase Transition in Zn1Sb7Te12 Pseudo-Binary Alloy. AB - Zn1Sb7Te12 thin films have been deposited by magnetron co-sputtering of ZnTe and Sb2Te3 targets. The microstructure, phase-change speed, optical cycling stability, and crystallization kinetics have been investigated during thermal annealing and laser irradiation. The thermal-annealed and laser-irradiated films give a clear evidence of the coexistence of trigonal Sb2Te3 and cubic ZnTe phases, which are homogeneously distributed in a single alloy as confirmed by advanced scanning transmission electron microscopy. The formation of both phases increases the initial nucleation sites, leading to the rapid phase-change speed in the Zn1Sb7Te12 film. The film has a minimum crystallization time of ~3 ns at 70 mW with almost no incubation period for the formation of critical nuclei compared to Ge2Sb2Te5 and other Zn-based films. Moreover, the complete crystallization of Zn1Sb7Te12 thin films is achieved within 10 ns. The ultrafast two-dimensional nucleation and crystal growth speed in Zn1Sb7Te12 obtained from the laser-irradiated system is almost 7 times faster compared to that in Ge2Sb2Te5 film. Controlling the crystallization process through doping ZnTe into Sb2Te3 is thus promising for the development of high-speed optical switching technology. PMID- 30449105 TI - Apo-12'-lycopenal, a Lycopene Metabolite, Promotes Adipocyte Differentiation via Peroxisome Proliferator-activated Receptor Gamma Activation. AB - Apo-lycopenals, lycopene metabolites produced by an initial cleavage by beta,beta carotene-9',10'-oxygenase, exhibit diverse biologically active effects. In this study, we investigated the effect of apo-lycopenals on the activation of nuclear receptors involved in glucose and lipid metabolism. Only apo-12'-lycopenal exhibited selective and dose-dependent transactivation activity for peroxisome proliferator-activated receptor gamma (PPARgamma), whereas neither apo-6'- nor 8' lycopenals displayed this activity (7.83 +/- 0.66-, 1.32 +/- 0.10-, 1.31 +/- 0.37 fold higher activity relative to control, respectively). Additionally, apo-12' lycopenal promoted adipocyte differentiation of 3T3-L1 cells and subsequently increased the mRNA levels of PPARgamma (a 2.36 +/- 0.07-fold increase relative to control; p < 0.01) and its target genes, as well as enhanced adiponectin secretion (a 3.25 +/- 0.27-fold increase relative to control; p < 0.01) and insulin-stimulated glucose uptake (1486 +/- 85 pmol/well; p < 0.001) in 3T3-L1 cells. Our results indicated that apo-12'-lycopenal promoted adipocyte differentiation by direct binding and activation of PPARgamma. PMID- 30449106 TI - Frequency Range Selection Method for Vibrational Spectra. AB - Theoretical calculations of vibrational properties are widely used to explain and predict experimental spectra. However, with standard quantum chemical methods all molecular motions are considered, which is rather time-consuming for large molecules. Because typically only a specific spectral region is of experimental interest, we propose here an efficient method that allows calculation of only a selected frequency interval. After a computationally cheap low-level estimate of the molecular motions, the computational time is proportional to the number of normal modes needed to describe this frequency range. Results for a medium-sized molecule show a reduction in computational time of up to 1 order of magnitude with negligible loss in accuracy. We also show that still larger computational savings are possible by using an additional intensity-selection procedure. PMID- 30449107 TI - Highly Promoted Carrier Mobility and Intrinsic Stability by Rolling Up Monolayer Black Phosphorus into Nanoscrolls. AB - Rolling up two-dimensional (2D) materials into nanoscrolls could not only retain the excellent properties of their 2D hosts but also display intriguing physical and chemical properties that arise from their 1D tubular structures. Here, we report a new class of black phosphorus nanoscrolls (bPNSs), which are stable at room-temperature and energetically more favorable than 2D bP. Most strikingly, these bPNSs hold tunable direct band gaps and extremely high mobilities (e.g., the mobility of the double-layer bPNS is about 20-fold higher than that of 2D bP monolayer). Their unique self-encapsulation structure and layer-dependent conduction band minimum can largely prevent the entrance of O2 and the production of O2- and thereby suppress the possible environmental degradation as well. The enhanced intrinsic stability and promoted electronic properties render bPNSs great promise in many advanced electronics or optoelectronics applications. PMID- 30449108 TI - Non-monotonous wetting of graphene-mica and MoS2-mica interfaces with a molecular layer of water. AB - Hydration of interfaces with a layer of water is a ubiquitous phenomenon, which has important implications for numerous natural and technologically important processes. Nevertheless, at the nanoscale the understanding of the wetting process is still limited, since it is experimentally difficult to follow. Here, graphene and monolayers of MoS2 deposited on dry mica are used to investigate wetting of the 2D material-mica interfaces with a molecularly thin layer of water employing scanning force microscopy in different modes. Wetting occurs non monotonously in time and space for both types of interfaces. It starts at relative humidities (RH) of 10-17 % for graphenes and 8-9 % for MoS2, and it concludes with a homogeneous layer at 25-30 % and 15-20 %, respectively. Investigation of the process at the graphene-mica interface indicates that up to about 25 % RH, initially a highly compliant and unstable layer of water spreads, which subsequently stabilizes by developing labyrinthine nanostructures. Moreover, these nanostructures exhibit distinct mechanical deformability and dissipation, which is ascribed to different densities of the confined water layer. The laterally structured morphology is explained by the interplay of counteracting long-range dipole-dipole repulsion and short-range line tension, with the latter caused at least in part by the mechanical deformation of the 2D material. The proposed origins of the interactions are common for thin layers of polar molecules at interfaces, implying that the lateral structuring of thin wetting layers at sub-monolayer concentrations may also be a quite general phenomenon. PMID- 30449110 TI - Nanosafety Research-An Ongoing Story. PMID- 30449109 TI - Sub-20 fs All-Optical Switching in a Single Au-Clad Si Nanodisk. AB - Dielectric nanoantennas have recently emerged as promising elements for nonlinear and ultrafast nanophotonics due to their ability to concentrate light on the nanometer scale with low losses, while exhibiting large nonlinear susceptibilities. In this work, we demonstrate that single Si nanodisks covered with a thin 30 nm thick layer of Au can generate positive and negative sub-20 fs reflectivity modulations of ~0.3% in the vicinity of the first-order anapole mode, when excited around the second-order anapole mode. The experimental results, characterized in the visible to near-infrared spectral range, suggest that the nonlinear optical Kerr effect is the responsible mechanism for the observed all-optical switching phenomena. These findings represent an important step toward nanoscale ultrafast all-optical signal processing. PMID- 30449111 TI - Egg yolk immunoglobulins supplementation prevents rat liver from aflatoxin B1 induced oxidative damage and genotoxicity. AB - Egg yolk immunoglobulins (IgY), as nutraceutical supplement for therapeutic or prophylactic intervention, has been extensively studied. The effects of IgY on small molecular toxin-induced toxicity in animals is unclear. In the present study, the protection of highly purified and specific anti-AFB1 IgY against AFB1 induced genotoxicity and oxidative damage on the rat liver model were investigated. Our results revealed that AFB1 induced significant oxidative damage markers, as well as AFB1-induced protein expression in antioxidant, pro- and anti apoptosis processes in rat liver. These effects could be significantly inhibited by co-gavage with anti-AFB1 IgY in a dose-dependent manner. However, anti-AFB1 IgY did not significantly induce hepatic CAT and SOD1. To explore mechanisms, metabolite experiments were established to evaluate the influence of anti-AFB1 IgY on the absorption of AFB1 in rats. Middle and high dose of anti-AFB1 IgY reduced hepatic AFB1-DNA adducts by 43.3% and 52.9%, AFB1-N7-guanine urinary adducts by 19.6% and 34.4%, and AFB1-albumin adducts by 10.5% and 21.1%, respectively. The feces of high dose anti-AFB1 IgY co-gavaged rats contained approximately 2-fold higher AFB1 equivalents at 3-6 h after ingestion than AFB1 group feces, indicating IgY inhibited AFB1 uptake. These results had provided insight that anti-AFB1 IgY could prevent animal organs from damage caused by AFB1, and will be beneficial for the application of detoxication antibody as a supplement in food. PMID- 30449112 TI - Guided by Light: Optical Control of Microtubule Gliding Assays. AB - Force generation by molecular motors drives biological processes such as asymmetric cell division and cell migration. Microtubule gliding assays in which surface-immobilized motor proteins drive microtubule propulsion are widely used to study basic motor properties as well as the collective behavior of active self organized systems. Additionally, these assays can be employed for nanotechnological applications such as analyte detection, biocomputation, and mechanical sensing. While such assays allow tight control over the experimental conditions, spatiotemporal control of force generation has remained underdeveloped. Here we use light-inducible protein-protein interactions to recruit molecular motors to the surface to control microtubule gliding activity in vitro. We show that using these light-inducible interactions, proteins can be recruited to the surface in patterns, reaching a ~5-fold enrichment within 6 s upon illumination. Subsequently, proteins are released with a half-life of 13 s when the illumination is stopped. We furthermore demonstrate that light controlled kinesin recruitment results in reversible activation of microtubule gliding along the surface, enabling efficient control over local microtubule motility. Our approach to locally control force generation offers a way to study the effects of nonuniform pulling forces on different microtubule arrays and also provides novel strategies for local control in nanotechnological applications. PMID- 30449113 TI - Black stomach: acute gastric wall ischemia due to polycythemia of an unknown origin. AB - Acute ischemia of the gastric mucosa, resulting in a black stomach, is a very rare event given the blood supply of the stomach, with a rich collateral blood flow system. We present the case of a 65-year-old man, with polycythemia of unknown origin under investigation, presented to the emergency department with a history of diffuse abdominal pain and hematemesis. Blood tests revealed a hemoglobin level of 22 g/dL.Upper endoscopy revealed a black ulcerated gastric mucosa compatible with acute necrosis of the corpus and antrum of the stomach . Despite few cases described in the literature, many etiologic factors have been suggested. In this particular case, given the severe polycythemia and associated hyperviscosity, vascular compromise of the gastric blood vessels might have played a major role in the pathogenesis of the ischemic process. PMID- 30449114 TI - A foreign body in the small bowel: a rare entity of acute abdomen. AB - Acute abdomen secondary to intestinal impactation due to ingestion of foreign body is a rare entity. We report a 73-year-old male patient who presented ileal perforation due to ingestion of a fishbone. PMID- 30449115 TI - Treatment of gastric GIST using endoscopic techniques combined with the application of endoloop and intralesional cyanoacrylate in a non-surgical patient. AB - We present the case of a 79-year-old patient with multiple cardiovascular morbidities, classified as ASA III (American Society of Anesthesiology). An upper digestive endoscopy was performed due to chronic anemia and a subepithelial lesion was identified in the subcardial region of 30 x 25 mm, without other relevant findings. PMID- 30449116 TI - Influence of infant feeding on the excretion of gluten immunopeptides in feces. AB - INTRODUCTION: the secretion of antigens from the diet into breast milk has been extensively documented. The transfer of gliadin could be critical for the development of an immune response. OBJECTIVES: to investigate the presence of immunogenic gluten peptides in the feces of infants fed with different diets. MATERIAL AND METHODS: a blind, prospective, controlled, collaborative study was performed in three hospitals, between September 2016 and January 2017. The study protocol was approved by the Ethics Committee of the hospitals in Seville prior to starting the study. RESULTS: the cohort was divided into three groups of 30 infants: an experimental group (average age 9.2 +/- 2.8 weeks) with exclusive breastfeeding, a control group 1 (average age 10.3 +/- 3.3 weeks) exclusively fed with onset formula and a control group 2 (average age 56 +/- 3.7 weeks) with infants that consumed gluten on a regular basis. The peptide 33-mer of gliadin was negative in all feces samples from both the experimental and control group 1. With regard to control group 2, the peptide 33-mer of gliadin was negative in 23% of cases (seven children). There was no difference in the amount of gluten ingested by these children compared to those who excreted the 33-mer peptide. CONCLUSIONS: the failure to detect gluten in the feces of infants that were exclusively breastfed indicates that it is probably below the limits of detection. Healthy children who consume gluten may not excrete it in feces. PMID- 30449117 TI - Supraumbilical skin necrosis after repeat transarterial chemoembolization. AB - Transcatheter arterial chemoembolization TACE is an effective treatment for stage BCLC-B hepatocellular carcinoma (1). The development of skin lesions in the supraumbilical region is an unusual complication following this procedure. We report the case of an 80-year-old male with alcoholic liver cirrhosis, portal hypertension PHT (Child-Pugh A) and multifocal hepatocellular carcinoma. The patient had already undergone four radiofrequency ablations, one alcoholization procedure and four TACEs via femoral access. PMID- 30449118 TI - Prognostic differences between lymphoepithelioma-like colon carcinoma and colon adenocarcinoma. AB - Lymphoepithelioma-like colon carcinoma (LELC) is rare. The Epstein-Barr virus (EBV) hasn't been implicated in the pathogenesis of LELC of the colon, but they may in fact be more strongly associated with MSI. Its treatment is identical to adenocarcinoma. However, lymphocyte infiltration and microsatellite instability have been associated with better prognosis. PMID- 30449119 TI - Evaluation of the medical economics and safety: two methods for the endoscopic removal of jujube pits. AB - OBJECTIVE: to evaluate the medical economics and safety of two methods for the endoscopic removal of jujube pits, one with a transparent cap combined with a stone basket and the other with a transparent cap combined with foreign body forceps. METHODS: consecutive patients with a suspected jujube pit ingestion in the esophagus between January 2008 and December 2017 were enrolled into the study. Fifty-three patients who met the criteria were divided into two groups. Group A patients were treated by a transparent cap combined with a stone basket and group B patients were treated by a transparent cap combined with foreign body forceps. The following clinical data were collected: age, sex, location of jujube pits, complications, operation time, extraction success and average hospital costs. RESULTS: a total of 53 patients who met the criteria were enrolled into the study; 29 cases in group A and 24 cases in group B. Endoscopic removal was successful in 98.1% (52/53) of the patients and the remaining 1.9% (1/53) required surgery. Severe complications were less frequent in group A than in group B (p = 0.017). Surgery time was not significantly different between the two groups (p = 0.647). The extraction success in group A was higher than in group B (p = 0.001). The medical costs including the total cost, inspection, treatment, radiation and drug cost were not significantly different between the two groups (p > 0.05 in all cases). CONCLUSION: endoscopic baskets are suitable for cases of jujube pit ingestion and have a higher extraction success and a lower proportion of severe complications. Surgery time was not significantly extended and the medical costs did not increase. PMID- 30449120 TI - Colon perforation due to fistulization of a pancreatic pseudocyst. AB - We present a computed tomography image of a patient with acute necrotizing pancreatitis due to alcohol, who developed several pseudocysts, one of which fistulized into the colon. PMID- 30449122 TI - Healing of autoimmune hepatitis associated with hepatitis C virus infection treated with direct-acting antivirals. AB - The use of direct-acting antivirals (DAA) for the hepatitis C virus (HCV) has yielded a significant improvement in the treatment of autoimmune hepatitis (AIH) associated with HCV infection. Interferon was the cornerstone of HCV therapy before the introduction of these agents into the clinical practice. Herein, we report the case of an HCV-infected patient who developed an interferon-induced AIH and since then, has received immunosuppressive therapy. Administration of DAA resulted in a sustained virologic response (SVR) and clinical AIH remission which allowed a discontinuation of immunosuppressive treatment. PMID- 30449121 TI - Subtotal cholecystectomy versus cholecystostomy. AB - Emergency laparoscopic cholecystectomy (LC) is associated with a higher morbidity and mortality, as compared to elective LC. A two-fold increase in 30-day re admission after LC was associated with two or more pre-operative admissions with symptoms of cholecystitis, as opposed to index-admission-LC (IALC). This was presumably because of more inflammation due to repeated attacks of cholecystitis in the former cohort, making gallbladders more "difficult". Inflamed gallbladders with higher Nassar-scores (scores 3 and 4) also have significantly raised complication rates. PMID- 30449123 TI - Pelvic hydatidosis: an exceptional location. AB - Hydatid disease is a zoonosis, still endemic in some Spanish geographical areas. Extrahepatic-extrapulmonary lesions account for only 10%, with pelvic lesions being exceptional. We present two patients with pelvic hydatidosis, with or without concomitant liver injury. Treatment depends on the cyst, location and symptoms. Surgery is mandatory if there is any complication. PMID- 30449124 TI - Expanding the mutational spectrum of the ABCB4 gene in inherited adult cholestatic liver disorders with four novel pathogenic variants: case reports. AB - Low phospholipid-associated cholelithiasis and intrahepatic cholestasis of pregnancy are two MDR3-related inherited liver disorders caused by biallelic or monoallelic ABCB4 loss-of-function variants. Low phospholipid-associated cholelithiasis is clinically characterized by the early onset of symptomatic cholelithiasis in young adults while intrahepatic cholestasis of pregnancy is a distinct clinical entity associated with adverse fetal outcomes. Of note, patients carrying ABCB4 sequence variations commonly exhibit phenotypic expression over a wide continuum due to environmental and hormonal contributing factors and genetic modifiers. Patients with an early diagnosis of MDR3-related diseases could benefit from ursodeoxycholic acid treatment in order to prevent acute and chronic complications as well as adverse pregnancy outcomes. We herein report five patients with an overlapping phenotype from low phospholipid associated cholelithiasis to intrahepatic cholestasis of pregnancy, harboring five ABCB4 missense variants, four of which were novel. Our study highlights the phenotypic and genetic heterogeneity of inherited cholestatic liver diseases and also expands the mutation spectrum of ABCB4 sequence variations in adult cholestatic liver diseases. PMID- 30449125 TI - Primary Palliative Care Education Programs: Review and Characterization. AB - BACKGROUND:: Primary palliative care (PPC) education programs have arisen in response to the recognition that all clinicians need to have a basic set of knowledge and skills to provide excellent care to all patients. PPC education programs appear to vary widely, making it difficult for potential learners to find the right program to fit their needs. We have cataloged and categorized a snapshot of PPC education programs across the United States to serve as a resource for those seeking training, and for educators interested in starting or optimizing such programs. METHODS:: Medical and commercial search engines (MSEs and CSEs, respectively) were used to generate a list of PPC education programs in the United States. Programs were contacted to supplement information available online, and then categorized based on intended learner, certification/degree conferred upon completion, and other characteristics. RESULTS:: There was little overlap between the PPC education programs found through MSEs and CSEs. Programs found via CSEs varied with respect to intended learners, pedagogy, content, and cost. Among the minority of programs that confer a certification/degree upon completion, there is no consensus as to what these signify. CONCLUSIONS:: The wide variety of PPC education programs is both a challenge to and strength of the field. We hope that this report will serve as a call to develop a standard PPC education taxonomy to help define essential components of all PPC programs, while also leaving sufficient room for programs to serve the unique needs of their local learners and patient populations. PMID- 30449126 TI - A case of recurrent seizures: Drug-drug interaction between low-dose clozapine and extended-release bupropion. PMID- 30449127 TI - Nebivolol/Valsartan: A Novel Antihypertensive Fixed-Dose Combination Tablet. AB - DATA SOURCES: A PubMed (1966 to October 2018) search was conducted using the following keywords: nebivolol, valsartan, and hypertension (HTN). Additional sources were identified by references. STUDY SELECTION AND DATA EXTRACTION: Articles written in English were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or place in therapy of nebivolol/valsartan in human subjects. DATA SYNTHESIS: Most patients with HTN require combination therapy; however, beta-adrenergic antagonists and AII type 1 receptor blockers have been considered less effective because of overlapping mechanisms of action. A phase III, randomized trial demonstrated that nebivolol/valsartan produced statistically significant blood pressure (BP) lowering as compared with monotherapy with the individual components or placebo. Substudy analyses confirmed this among subgroups and demonstrated that nebivolol/valsartan decreased plasma renin and aldosterone levels. One trial reported continued BP lowering at 52 weeks. Another study showed that nebivolol/valsartan had similar additivity scores as compared with other antihypertensive combinations. Relevance to Patient Care and Clinical Practice: This review discusses drug information, efficacy, and safety of nebivolol/valsartan and discusses its clinical relevance as a novel combination product in managing patients with HTN. CONCLUSION: Nebivolol/valsartan combination may offer a benefit to patients with an indication for both classes who desire to decrease pill burden. Although BP lowering was statistically significant in comparison to the individual components as monotherapy, the combination does not offer clinically significant benefits that would elevate its place in HTN management. PMID- 30449128 TI - That Was Easy! Expectancy Violations During Exposure and Response Prevention for Childhood Obsessive-Compulsive Disorder. AB - Violating expectancies during exposure therapy is proposed to promote inhibitory learning and improved treatment outcomes. Because people tend to overestimate how distressing emotionally challenging situations will be, violating expectations of distress may be an intuitive way to promote treatment outcome during exposure based cognitive-behavioral therapy (CBT). This study evaluated overpredictions of distress during exposure tasks in 33 youth with obsessive-compulsive disorder (OCD; ages 8-17) participating in CBT. Youth with more variable prediction accuracy and a higher proportion of overpredictions experienced more rapid symptom reduction, b = -0.29, p = .002. Underpredictions were less common toward the end of therapy as youth experienced less severe OCD, b = 0.12, p= .001. Findings suggest that although youth often accurately predict the intensity of exposure, overpredictions are common as well. The frequency of these overpredictions promoted treatment outcome, supporting expectancy violations as one indicator of inhibitory learning during exposure therapy. PMID- 30449129 TI - Positive and detached reappraisal in older adulthood: A temporal examination of gaze patterns. AB - OBJECTIVES: Cognitive reappraisal is an emotion regulation strategy that involves the adaptive restructuring of one's thoughts surrounding an emotionally evocative stimulus. Previous studies have produced mixed results on how distinct reappraisal and attentional processes are, but few studies have teased apart specific reappraisal methods. This is of particular interest in aging as older adults' regulation success may vary by reappraisal type. The current study examined whether detached and positive reappraisal are associated with distinct temporal patterns of attention in a sample of older adults. METHOD: 29 older adult participants viewed negative IAPS images and were instructed to implement both positive and detached reappraisal while eye movements were monitored. Participants also reported on their mood before and after viewing the images. RESULTS: Participants fixated on negative areas early on and looked at them less over time, however their attention was oriented specifically towards the most negative region during reappraisal. They also re-fixated on the negative areas of the images during the last second of viewing during detached reappraisal, and reported feeling best while using this strategy. CONCLUSION: These findings provide information about the temporal nature of visual attention while utilizing distinct cognitive reappraisal strategies. Results highlight the importance of further teasing apart differences between detached and positive reappraisal as regulatory success and attentional shifts differ between these reappraisal types in older adulthood. PMID- 30449130 TI - National Guideline Clearinghouse Is No More: Keep Calm and Search On. AB - In July 2018, the National Guideline Clearinghouse lost funding, leaving fewer freely available online guideline collections. Based on the authors' experience of the 3 major guideline-focused databases that are currently available (Guidelines International Network, the Turning Research into Practice database, and Guideline Central) an easy to use resource with stringent inclusion criteria is currently lacking, though new resources are in development. These 3 resources vary in scope, and none stood out as an all-encompassing favorite. Regardless of the source used to find and access guidelines, clinicians must evaluate guideline quality and currency before using them in clinical practice. PMID- 30449132 TI - Does legislative change affect the use and duration of compulsory treatment orders? AB - OBJECTIVE:: Victoria, Australia, introduced reformed mental health legislation in 2014. The Act was based on a policy platform of recovery-oriented services, supported decision-making and minimisation of the use and duration of compulsory orders. This paper compares service utilisation and legal status after being on a community treatment order under the Mental Health Act 1986 (Vic) with that under the Mental Health Act 2014 (Vic). METHODS:: We obtained two distinct data sets of persons who had been on a community treatment order for at least 3 months and their subsequent treatment episodes over 2 years under the Mental Health Act and/or as an inpatient for the periods 2008-2010 (Mental Health Act 1986) and 2014-2016 (Mental Health Act 2014). The two sets were compared to assess the difference in use, duration and odds of having a further admission over 2 years. We also considered the mode of discharge - whether by the treating psychiatrist, external body or through expiry. RESULTS:: Compared with the Mental Health Act 1986, under the Mental Health Act 2014, index community treatment orders were shorter (mean 227 days compared with 335 days); there was a reduction in the mean number of community treatment orders in the 2 years following the index discharge - 1.1 compared with 1.5 (incidence rate ratio (IRR) = 0.71, 95% confidence interval = [0.63, 0.80]) - and a 51% reduction in days on an order over 2 years. There was a reduction in the number of subsequent orders for those whose order expired or was revoked by the psychiatrist under the Mental Health Act 2014 compared to those under the Mental Health Act 1986. The number of orders which were varied to an inpatient order by the authorised psychiatrist was notably greater under the Mental Health Act 2014. CONCLUSION:: The reformed Mental Health Act has been successful in its intent to reduce the use and duration of compulsory orders in the community. The apparent increase in return to inpatient orders raises questions regarding the intensity and effectiveness of community treatment and context of service delivery. PMID- 30449133 TI - Evaluation of Targeted Pharmacist Interventions to Reduce Length of Stay in an Acute Care Practice Model. AB - BACKGROUND: Despite widespread recognition of the need for innovative pharmacy practice approaches, the development and implementation of value-based outcomes remains difficult to achieve. Furthermore, gaps in the literature persist because the majority of available literature is retrospective in nature and describes only the clinical impact of pharmacists' interventions. OBJECTIVE: Length of stay (LOS) is a clinical outcome metric used to represent efficiency in health care. The objective of this study was to evaluate the impact of pharmacist-driven interventions on LOS in the acute care setting. METHODS: A separate samples pretest-posttest design was utilized to compare the effect of pharmacist interventions across 3 practice areas (medicine, hematology/oncology, and pediatrics). Two time periods were evaluated: preimplementation (PRE) and a pilot period, postimplementation of interventions (POST). Interventions included targeted discharge services, such as discharge prescription writing (with provider cosignature). Participating pharmacists completed semistructured interviews following the pilot. RESULTS: A total of 924 patients (466 PRE and 458 POST) were included in the analysis. The median LOS decreased from 4.95 (interquartile range = 3.24-8.5) to 4.12 (2.21-7.96) days from the PRE versus POST groups, respectively ( P < 0.011). There was no difference in readmission rates between groups (21% vs 19.1%, P = 0.7). Interviews revealed several themes, including positive impact on professional development. Conclusion and Relevance: This pilot study demonstrated the ability of pharmacist interventions to reduce LOS. Pharmacists identified time as the primary barrier and acknowledged the importance of leaders prioritizing pharmacists' responsibilities. This study is novel in targeting LOS, providing a value-based outcome for clinical pharmacy services. PMID- 30449134 TI - Atherosclerosis and Arrhythmias in Patients With HIV. PMID- 30449135 TI - Myeloid-Derived Suppressor Cells and Costimulatory Molecules in Children With Allergic Rhinitis. AB - OBJECTIVES:: The aim of this study is to assess the level of myeloid-derived suppressor cells (MDSCs) and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T-lymphocytes in children with allergic rhinitis (AR). METHODS:: The study included 60 children with AR and 50 controls. Flow cytometry was performed to analyze MDSCs and the expression of costimulatory molecules CD80 and CD86 on monocytes and their ligands (CD28) on T lymphocytes. RESULTS:: The percentages of total and monocytic MDSCs and the expression of costimulatory molecule CD86 on monocytes were significantly higher in children with AR than in healthy controls. In addition, the expressions of CD28 on CD4+ and CD8+ were significantly elevated in AR patients. CONCLUSION:: The present study demonstrated that the percentages of MDSCs were significantly elevated in AR children. Moreover, the expressions of CD28 on CD4+ and CD8+ were significantly higher in children with AR. PMID- 30449136 TI - Serum neprilysin and the risk of death in patients with out-of-hospital cardiac arrest of non-traumatic origin. AB - BACKGROUND:: Early risk stratification remains an unmet clinical need in patients with in out-of-hospital cardiac arrest. We hypothesised that soluble neprilysin may represent a promising biomarker in patients with out-of-hospital cardiac arrest of non-traumatic origin and provide new pathobiological insight. METHODS:: This pilot study was a biomarker analysis from the Heidelberg Resuscitation Registry. Serum soluble neprilysin levels on admission were measured in 144 patients with successful return of spontaneous circulation after out-of-hospital cardiac arrest of non-traumatic origin. The primary endpoint was time to all cause mortality. KM Event Rates are reported. Cox models were adjusted for age, bystander resuscitation, initial ECG rhythm, baseline estimated glomerular filtration rate, baseline lactate, left ventricular function at baseline, and targeted temperature management. RESULTS:: In total, 90 (62.5%) patients died over a follow-up of at least 30 days. Soluble neprilysin correlated weakly with high-sensitivity troponin T ( r=0.18, P=0.032) but did not correlate significantly with estimated glomerular filtration rate ( r=-0.12) or lactate ( r=0.11). Patients with elevated soluble neprilysin levels on admission were at significantly higher risk of all-cause mortality (Q4 69.1% vs. Q1 48.4%). After multivariable adjustment, soluble neprilysin in the top quartile (Q4) was significantly associated with all-cause mortality (Q4 vs. Q1: adjusted hazard ratio 2.48 (1.20-5.12)). In an adjusted multimarker model including high sensitivity troponin T and high-sensitivity C-reactive protein, soluble neprilysin and high-sensitivity troponin T remained independently associated with all-cause mortality (soluble neprilysin: adjusted hazard ratio 2.27 (1.08-4.78); high-sensitivity troponin T: adjusted hazard ratio 3.40 (1.63-7.09)). CONCLUSION:: Soluble neprilysin, measured as early as on hospital admission, was independently associated with all-cause mortality in patients with out-of hospital cardiac arrest of non-traumatic origin and may prove to be useful in the estimation of risk in these patients. PMID- 30449137 TI - Correlates of same-sex behavior disclosure to health care providers among Black MSM in the United States: implications for HIV prevention. AB - Disclosure of same-sex behavior to health care providers (HCPs) by men who have sex with men (MSM) has been argued to be an important aspect of HIV prevention. However, Black MSM are less likely to disclose compared to white MSM. This analysis of data collected in the United States from 2006-2009 identified individual and social network characteristics of Black MSM (n = 226) that are associated with disclosure that may be leveraged to increase disclosure. Over two thirds (68.1%) of the sample had ever disclosed to HCPs. Part-time employment (AOR = 0.32, 95% CI = 0.11-0.95), bisexual identity (AOR = 0.29, 95% CI = 0.12 0.70), and meeting criteria for alcohol use disorders (AOR = 0.32, 95% CI = 0.14 0.75) were negatively associated with disclosure. Disclosers were more likely to self-report being HIV-positive (AOR = 4.47, 95% CI = 1.54-12.98), having more frequent network socialization (AOR = 2.15, 95% CI = 1.24-3.73), and having a social network where all members knew the participant had sex with men (AOR = 4.94, 95% CI = 2.06-11.86). These associations were not moderated by self reported HIV status. Future interventions to help MSM identify social network members to safely disclose their same-sex behavior may also help disclosure of same-sex behavior to HCPs among Black MSM. PMID- 30449138 TI - The effect of educational attainment on cognition of older adults: results from the Mexican Health and Aging Study 2001 and 2012. AB - OBJECTIVE: This paper seeks to document changes in the effect of educational attainment on cognitive function of older adults in Mexico, and measure gender differences using data from two time periods. METHODS: The data come from the Mexican Health and Aging Study (MHAS), taking the cross-sections of adults aged 60 years or older interviewed in 2001 and 2012. We perform an OLS regression using standardized z-scores for five individual cognitive domains and for total cognition. RESULTS: Total cognitive scores and educational attainment were higher for men than women in both years. When cognitive components were analyzed separately, women had higher verbal memory and verbal recall scores than men. The gender gap in overall cognition score was smaller in 2012 compared to 2001, while the gender gap in educational attainment was larger in 2012 than in 2001. Even though men had higher educational attainment than women, the effect of educational attainment on cognition was higher for women. Similarly, the difference between total scores for each task for men compared to women decreased between 2012 and 2001, except for verbal learning and verbal recall where the gender difference widened. CONCLUSIONS: If younger cohorts of women continue to progressively achieve higher levels of education, the gender gap in old-age cognition should close. Additional work should determine the mechanisms through which added formal education seems to translate into higher cognitive gains for women compared to men. PMID- 30449139 TI - CASPR2 encephalitis presenting as post-partum psychosis. PMID- 30449140 TI - How does carer resilience change over time and care status? A qualitative longitudinal study. AB - OBJECTIVES: Little research examines trajectories of carer resilience or the factors that facilitate or hinder resilience over time. We use qualitative longitudinal methods to examine trajectories of resilience and which assets and resources are associated with resilience and care status transitions in spousal dementia carers. METHOD: Based on an original sample of 23 spousal dementia carers (Donnellan, Bennett, & Soulsby, 2015 ), we conducted 13 follow-up interviews, including: 5 continuing home carers, 3 former carers (institutionalised), and 5 former carers (widowed). RESULTS: Five participants remained resilient (stable resilient), three remained non-resilient (stable non resilient) and four participants became resilient (non-resilient to resilient). Only one participant became non-resilient (resilient to non-resilient). Stable resilience was characterised by continuing individual assets and community resources. Carers who became resilient returned to previous resources, or gained new resources. CONCLUSION: Institutionalisation and widowhood are not always barriers to resilience; spousal dementia carers can remain or even become resilient over time despite deteriorating health, institutionalisation, or death of the care recipient. PMID- 30449141 TI - Natural course of neuropsychiatric symptoms in nursing home patients with mental physical multimorbidity in the first eight months after admission. AB - OBJECTIVE: Aging societies will bring an increase in the number of long-term care patients with mental-physical multimorbidity (MPM). This paper aimed to describe the natural course of neuropsychiatric symptoms (NPS) in patients with MPM in the first 8 months after admission to a geronto-psychiatric nursing home (GP-NH) unit. METHODS: Longitudinal cohort study among 63 patients with MPM no dementia living in 17 GP-NH units across the Netherlands. Data collection consisted of chart review, semi-structured interviews, and brief neuropsychological testing, among which our primary outcome measure the Neuropsychiatric Inventory (NPI). Descriptive and bivariate analyses were conducted. RESULTS: Our study showed a significant increase of the NPI total score (from 25.3 to 29.3, p = 0.045), and the total scores of a NPI hyperactivity cluster (from 9.7 to 11.8, p = 0.039), and a NPI mood/apathy cluster (from 7.7 to 10.1, p = 0.008). Just over 95% had any clinically relevant symptom at baseline and/or six months later, of which irritability was the most prevalent and persistent symptom and the symptom with the highest incidence. Hyperactivity was the most prevalent and persistent symptom cluster. Also, depression had a high persistence. CONCLUSIONS: Our results indicate the omnipresence of NPS of which most were found to be persistent. Therefore, we recommend to explore opportunities to reduce NPS in NH patients with MPM, such as creating a therapeutic milieu, educating the staff, and evaluating patient's psychotropic drug use. PMID- 30449142 TI - Biological markers of aging and mental health: A seed and soil model of neurocognitive disorders. AB - As the population of the world gets older, cognitive and mental health decline in older adults has become one of the most pressing scientific problems of the 21st century. It has been well-established that multiple pathways exist that can lead to future cognitive decline and the development of age-related mental health conditions. Making matters more complicated is the fact that aging is not a homogenous or simple process; rather, each person brings a diverse set of circumstances to the table, leading to differences in biologically aging. Research is needed to identify how the intersection of environmental and biological factors may protect older adults or put them at future risk for cognitive decline and the development of age-related mental health conditions. Furthermore, each potential factor may impact different domains of cognition and mental health or may impact individuals differentially based on genetic, environmental, social, emotional, and behavioral factors. Neuroimaging is one key tool that can be used to discover and assess markers of cognitive and mental health. The goal of this special issue is to expand the science on how biological markers can aid the understanding of aging and mental health through the lens of the individual from an international perspective, representing Germany, Taiwan, Thailand, the United Kingdom, and the United States. Common themes from these articles are used to support the new Seed and Soil Model of Neurocognitive Disorders. PMID- 30449143 TI - Physical health burdens and emotional distress in later life: the mediating effects of self-rated health. AB - Physical health burdens have been shown to predict geriatric depression and anxiety, but there is scarce knowledge about the mechanism by which these occur. This study examined the extent to which self-rated health (SRH) mediated the associations between physical health burdens and anxiety/depression in a sample of 465 older adults between ages 60-93 residing in Ekiti State Senatorial Districts, Nigeria. The number of medical diagnoses and physical impairments significantly predicted both anxiety and depression. SRH was significantly and negatively associated with medical diagnoses, physical impairments, anxiety and depression. Furthermore, SRH was found to fully mediate the relationship between medical diagnoses and anxiety/depression. While a full mediation was found for SRH in the relationship between physical impairments and anxiety, a partial mediation was found between impairments and depression. Collectively, these results suggest that SRH may be a necessary link between physical health burdens and emotional distress at old age. PMID- 30449144 TI - Educational level and its Association with the domains of the Montreal Cognitive Assessment Test. AB - OBJECTIVE: To explore the association between educational level and the scores obtained in each of the domains of the Montreal Cognitive Assessment test. METHODS: This is a secondary analysis of the SABE/2012 Bogota survey; a cross sectional study including 2000 subjects aged >=60years. The MoCA test was the dependent variable and was stratified by cognitive domains, incorrect answers and scores were considered. Educational level was assessed through years of formal education. Age, sex and selected medical conditions were also included to adjust the multivariate models. Bivariate analyses, fitted logistic and linear regression models were employed for analyzing association between these variables. RESULTS: The proportion of incorrect answers increased as schooling years decreased and as age increased. In the multivariate analysis, visuospatial and executive function were the most affected domains. Educational level displayed less influence than age on short memory-recall task (standardized beta 0.19 vs -0.24). Educational level showed a greater influence than age on no memory tasks (the sum of all other domains; standardized beta 0.50 vs -0.29). CONCLUSIONS: It seems logical to consider that performance in most domains of the MoCA is influenced by years of education. Therefore, low scores on these tasks could lead to low total MoCA scores and thus to bias and over diagnosis of cognitive impairment in patients with lower educational levels. Memory-recall domain is not affected much by education and applying it separately could be useful in patients with low educational level in whom we suspect memory impairment. PMID- 30449131 TI - Cyclophilin A as a target in the treatment of cytomegalovirus infections. AB - BACKGROUND: Viruses are obligate parasites that depend on the cellular machinery of the host to regenerate and manufacture their proteins. Most antiviral drugs on the market today target viral proteins. However, the more recent strategies involve targeting the host cell proteins or pathways that mediate viral replication. This new approach would be effective for most viruses while minimizing drug resistance and toxicity. METHODS: Cytomegalovirus replication, latency, and immune response are mediated by the intermediate early protein 2, the main protein that determines the effectiveness of drugs in cytomegalovirus inhibition. This review explains how intermediate early protein 2 can modify the action of cyclosporin A, an immunosuppressive, and antiviral drug. It also links all the pathways mediated by cyclosporin A, cytomegalovirus replication, and its encoded proteins. RESULTS: Intermediate early protein 2 can influence the cellular cyclophilin A pathway, affecting cyclosporin A as a mediator of viral replication or anti-cytomegalovirus drug. CONCLUSION: Cyclosporin A has a dual function in cytomegalovirus pathogenesis. It has the immunosuppressive effect that establishes virus replication through the inhibition of T-cell function. It also has an anti-cytomegalovirus effect mediated by intermediate early protein 2. Both of these functions involve cyclophilin A pathway. PMID- 30449145 TI - Development of a Computer-Assisted Adverse Drug Events Alarm and Assessment System for Hospital Inpatients in China. AB - BACKGROUND:: Computerized detection is a promising method for monitoring adverse drug events (ADEs); however, this method is currently in its infancy and is a new area of exploration in China. This study aimed to develop a computerized ADE alarm and assessment system to help pharmacists effectively detect, assess, and analyze possible ADEs in patients in China. METHODS:: Based on the clinical characteristics of these adverse drug events, we designed combined multiparameters as ADE alert rules to be assembled into detection configurations. We also developed system function modules by extracting data from the People's Liberation Army (PLA) general hospital information system (electronic medical records). Positive predictive values were calculated for the alert. RESULTS:: Five function modules were created in this platform: automatic screening, assisted evaluation, risk characteristic analysis, report generation into SRS (spontaneous reporting system), and a dictionary database. Four ADE alert configurations were set in our ADE alarm and assessment system: drug-related thrombocytopenia, anemia, liver injury, and kidney injury. The positive predictive values of the 4 monitored ADEs were approximately 44.4% to 95.8%. CONCLUSIONS:: An automatic ADE screening system was established for hospitalized patients in Chinese medical institutions. Compared with previous studies, combined drug-event alerts and a system-assisted assessment interface performed better than alerts based only on laboratory values. Furthermore, this platform's assisted-layered evaluation and risk factor analysis functions could save considerable time for professionals and improve early prevention of potentially serious ADEs. To date, this system has been applied in 10 large-scale medical institutions. PMID- 30449146 TI - Ixekizumab (Interleukin 17A Antagonist): 12-week Efficacy and Safety Outcomes in Real-world Clinical Practice. AB - BACKGROUND:: Current knowledge of the efficacy and safety of ixekizumab is limited to data from phase III randomized controlled trials (RCTs). A gap exists in our understanding of treatment outcomes of this newly available biologic in real-world clinical practice. OBJECTIVE:: This study explores the efficacy and safety of ixekizumab in non-RCT patients to compare real-world outcomes to those reported in RCTs. METHODS:: We conducted a multicentre, retrospective chart review of patients treated with ixekizumab therapy for moderate-to-severe plaque psoriasis. Efficacy (Psoriasis Area and Severity Index score of 75 or Physician Global Assessment of 0 or 1) and safety (reported adverse events [AEs]) were assessed following a 12-week treatment period. RESULTS:: Of the 60 patients included, 45 (75.0%) achieved efficacious outcomes after 12 weeks of ixekizumab treatment. Twenty-two (36.7%) patients experienced one or more AEs, of whom only 3 (5.0%) withdrew from treatment as a result. Common AEs included injection site reaction/erythema/pain (13.3%) and dermatitis (5.0%). CONCLUSION:: Ixekizumab has shown to be a safe and effective therapeutic option for plaque psoriasis in real world practice. It does not appear that patients experience more AEs in real world clinics than those in clinical trials. PMID- 30449147 TI - The Protective Roles of Urinary Trypsin Inhibitor in Brain Injury Following Fat Embolism Syndrome in a Rat Model. AB - Fat embolism syndrome (FES) is a common complication following long bone fracture; fat droplets are released into the blood circulation and form embolisms, mainly in lung and brain. However, the potential mechanisms involved remain to be clarified. In this study, the mechanism of brain injury following FES and the protective effects of urinary trypsin inhibitor (UTI)-a serine protease inhibitor-were investigated. Sixty male Sprague-Dawley rats were divided randomly into sham, FES and FES+UTI treatment groups. The FES model was established using tail vein injection of glycerol trioleate, and UTI was administered by intraperitoneal injection immediately following FES. Brain/lung water content evaluation, Evans blue content and magnetic resonance imaging examination were used to assess the effects of UTI. Furthermore, immunohistochemistry and western blot were also applied to explore the protective mechanism of UTI following FES. The results of oil red O staining indicated that the FES model was successfully established. UTI could significantly attenuate blood-brain-barrier (BBB) disruption, as seen through brain edema evaluation and Evans blue content examination. Immunofluorescence staining results indicated that the TLR4-JNK pathway was involved in brain injury after FES; this effect could be quenched by UTI treatment. Furthermore, UTI could decrease the levels of downstream target proteins of the TLR4-JNK pathway, phosphorylated-NF- kappaB (p65) and p53 in brain. Our results showed that UTI could alleviate BBB injury after FES through blocking activity of the TLR4-JNK pathway. PMID- 30449148 TI - Anatomical Significance of the Spatial Distribution of the Palatopharyngeus With Regard to Velopharyngeal Closure. AB - OBJECTIVE:: Coordination of the various soft palate and pharyngeal muscles should be considered while evaluating velopharyngeal closure. However, it remains unclear whether different muscle bundles have specific functions during velopharyngeal closure. We macroscopically and microscopically examined these muscles in detail and particularly clarified the morphology of the palatopharyngeus (PP) in velopharyngeal closure. DESIGN:: Forty halves of 21 heads from Japanese cadavers (average: 83.9 years) were used for analysis; 37 halves of 19 heads were macroscopically examined and 3 halves of 2 heads were histologically examined. RESULTS:: The PP consisted of muscle bundles originating from the superior and inferior surfaces of the palatine aponeurosis. The most superior part of the superior constrictor (SC) and most lateral part of PP on the palatine aponeurosis initially ran in parallel and subsequently, in superoposterior and inferoposterior directions, respectively. The PP appeared as a single continuous sheet that was radially spread as a whole. Its medial margins, located superior and inferior to the aponeurosis, formed a fold that established the palatopharyngeal arch. The stylopharyngeus (StP) adjoined the base of this arch. CONCLUSIONS:: Since PP consisted of muscle bundles running in various directions, various functions of these bundles should be considered during velopharyngeal closure. The PP can function as a sphincter with SC and as an elevator with StP. In addition, PP forms the medial protrusion in collaboration with StP and SC. Thus, PP plays an important role in velopharyngeal closure with the coordination of various muscles. PMID- 30449149 TI - Higher Levels of Intelligence and Executive Functioning Protect Maltreated Children Against Adult Arrests: A Prospective Study. AB - Research shows that maltreated children are at elevated risk of arrest as adults and that higher verbal intelligence, reading ability, and executive functioning (abstract reasoning and cognitive flexibility) may be protective against criminal behavior. The current study examines this hypothesis using data from court substantiated cases of child abuse and neglect and demographically matched controls followed prospectively into middle adulthood ( N = 1,196). At age 29, verbal intelligence was assessed with the Quick Test and reading ability with the Wide Range Achievement Test-Revised. At age 41, abstract reasoning was assessed with the Matrix Reasoning Test and cognitive flexibility with the Trail Making Test-B. Arrest records were gathered from law enforcement agencies through mean age 51. Data were analyzed with binomial logistic regressions. The results indicated that maltreated children were at increased risk of arrest for nonviolent and violent crime. Higher verbal intelligence, reading ability, nonverbal reasoning, and cognitive flexibility were protective against arrest for violent crime. The protective effects of neuropsychological functions were more pronounced for violent than nonviolent crime, for the control than maltreated children, and differed by gender and race. These results suggest that interventions targeting improved cognitive and neuropsychological functions may serve an important role in reducing risk of crime. PMID- 30449150 TI - Altered speech with migraine attacks: A prospective, longitudinal study of episodic migraine without aura. AB - BACKGROUND AND OBJECTIVE: Some individuals with migraine report the presence of speech changes during their migraine attacks. The goal of this study was to compare objective features of speech during the migraine pre-attack, the migraine attack, and during the interictal period. METHODS: This was a prospective, longitudinal, observational study of adults with episodic migraine and healthy non-migraine controls. Participants provided speech samples three times per day using a speech elicitation tool included within a mobile app. Six complementary speech features that capture articulation and prosody were extracted from speech samples. Participants with migraine maintained a daily headache diary using the same app. A mixed effects model and t-tests were used to investigate differences in speech features between controls, the migraine pre-attack phase, the migraine attack, and the interictal period. RESULTS: In total, 56,767 speech samples were collected, including 43,102 from 15 individuals with migraine and 13,665 from matched healthy controls. Significant group-level differences in speech features were identified between those with migraine and healthy controls and within the migraine group during the pre-attack vs. attack vs. interictal periods (all p < .05). Most consistently, speech changes occurred in the speaking rate, articulation rate and precision, and phonatory duration. Within-subject analysis revealed that seven of 15 individuals with migraine showed significant change in at least one speech feature when comparing the migraine attack vs. interictal phase and four showed similar changes when comparing the pre-attack vs. interictal phases. CONCLUSIONS: Changes in speech occurred in almost half of the individuals during migraine attacks. Once confirmed in subsequent studies, speech changes could be considered a feature of the migraine attack. PMID- 30449151 TI - Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial. AB - OBJECTIVE: To assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial. METHODS: This was a double-blind, randomized, sham controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline. RESULTS: A total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: -3.46 +/- 2.32 versus -1.78 +/- 1.89 ( p < 0.0001), or -59% versus -30% ( p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for 'migraine without aura' attacks: mean visual analogue scale reduction at 1 hour was -3.3 +/- 2.4 for the verum group versus -1.7 +/- 1.9 for the sham group ( p = 0.0006). For 'migraine with aura' attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was -4.3 +/- 1.8 for the verum group versus -2.6 +/- 1.9 for the sham group ( p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group. CONCLUSION: One-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks. STUDY PROTOCOL: ClinicalTrials.gov Identifier: NCT02590939. PMID- 30449152 TI - User perspective on receiving adaptive equipment after stroke: A mixed-methods study. AB - BACKGROUND.: Adaptive equipment (AE) is frequently provided during stroke rehabilitation by occupational therapists. PURPOSE.: This study aimed to identify the AE that people typically use after a stroke and the outcomes achieved as a result, and to explore people's experiences obtaining and using AE, to inform both practice and policy in this field. METHOD.: A mixed-methods study, involving a postal questionnaire and interviews, used descriptive statistics and grounded theory to analyze the quantitative and qualitative data, respectively. FINDINGS.: Questionnaire data ( n = 258) revealed mobility AE was issued most frequently, with increased safety as the primary reported outcome. Interview data ( n = 15) indicated relationships with health professionals and the hospital environment shaped early AE selection and use. Once home, making sense of AE and community participation were more influential. IMPLICATIONS.: Therapeutic relationships and reflection time are critical to maximize AE use after stroke. Policy and related funding for AE need to prioritize community participation. PMID- 30449153 TI - Leptin induces the expression of tumorigenic genes in the gastric mucosa of male Sprague-Dawley rats. AB - IMPACT STATEMENT: Gastric cancer is the third most common cause of death due to cancer in the world. Obese individuals are at risk of developing gastric cancer, and the reason for this is unknown. Serum leptin levels are high in obese individuals and leptin is known to induce proliferation of gastric cancer cells in vitro. However, to date, no reports exist on the tumorigenic effects of leptin on the stomach in vivo. This study therefore determines if chronic leptin administration induces gastric carcinogenesis in non-obese rats, which might serve as a useful animal model for future studies. Although the findings are somewhat inconclusive, to our knowledge, however, this is the first study to show the up-regulation of numerous potential driver genes that highlight the potential role of leptin in the higher prevalence of gastric cancer among obese individuals. The findings certainly necessitate further scrutiny of leptin gastric cancer. PMID- 30449154 TI - Developing facilitation skills amongst undergraduate nursing students to promote dementia awareness with children in a higher education institution (innovative practice). AB - Final year students on a BSc Hons Nursing programme in Scotland were supported to become Dementia Friends facilitators and develop interactive dementia awareness sessions for children from local schools. The children were invited to indicate phrases and images they associated with 'dementia' at the outset and end of the session. Analysis of the responses suggested that there were positive changes in the children's values and beliefs when thinking about a person living with dementia during the sessions. We suggest that peer learning is a valuable strategy to increase public and professional awareness about dementia and supports the development of graduate attributes. PMID- 30449155 TI - Association Between the Medical Home Model of Care and Demographic Characteristics in US Children. AB - Given the medical home model of care's (MHMOC) potential to reduce disparities in health care, this study determined the relationship between MHMOC, MHMOC indicators, and (1) demographic characteristics and (2) health outcomes in US children. Caregivers (n = 50 212) of children 0 to 17 years completed the 2016 National Survey of Children's Health. The MHMOC measure comprised 5 indicators (e.g., having a personal doctor/nurse and receiving family-centered care). Bivariate and multiple logistic regressions assessed the relationships between MHMOC, MHMOC indicators, and (1) demographic characteristics and (2) health outcomes. Approximately 49% of the children were served in a MHMOC. MHMOC and MHMOC indicators were related to race, ethnicity, nativity, caregiver education, federal poverty level, insurance type, and predicted health outcomes. These findings suggest that children most in need of MHMOC are less likely to be served in them. Thus, the current distribution of MHMOC likely contributes to greater disparities in care. PMID- 30449156 TI - Low income as a determinant of exercise capacity in COPD. AB - Exercise capacity (EC) is a critical outcome in chronic obstructive lung disease (chronic obstructive pulmonary disease (COPD)). It measures the impact of the disease and the effect of specific interventions like pulmonary rehabilitation (PR). EC determines COPD prognosis and is associated with health-care utilization and quality of life. Field walking tests and cardiopulmonary exercise test (CPET) are two ways to measure EC. The 6-minute walking test (6MWT) is the commonest and easiest field test. CPET has the advantage of assessing maximal aerobic capacity. Determinants of EC include age, gender, breathlessness, and lung function. Previous research suggests that socioeconomic status (SES), a meaningful factor in COPD, may also be associated with EC. However, those findings have not been replicated. We aimed to determine whether SES is an independent factor associated with EC in COPD. For this analysis, we used the National Emphysema Treatment Trial (NETT) database. NETT was a multicenter clinical trial where severe COPD patients were randomized to lung volume reduction surgery or medical therapy. Measures used were taken at baseline, postrehabilitation. Patients self-reported their income and were divided in two groups whether it was less or above US$30,000. Patients with a lower income had worse results in 6MWT ( p < 0.0001). We found an independent association between income and the 6MWT in patients with severe COPD after adjusting for age, gender, lung function, dyspnea, and living conditions ( p < 0.0007). One previous publication stated the relationship between income and EC. Our research confirms and extends previous publications associating EC with income by studying a large and well characterized cohort of severe COPD patients, also addressing EC by two different methods (maximal watts and 6MWT). Our results highlight the importance of addressing social determinants of health such as income when assessing COPD patients. PMID- 30449157 TI - Assessing the potential of the qualitative trajectory calculus to detect gait pathologies: a case study of children with developmental coordination disorder. AB - The Qualitative Trajectory Calculus (QTC) is a qualitative spatio-temporal calculus for describing interactions between moving point objects. So far, it remained unclear whether QTC is useful for describing subtle differences, such as between the movements of different parts of a human body. We tested the applicability of QTC to detect differences in the gait patterns of children with or without Developmental Coordination Disorder (DCD). We found that using a combination of three markers (i.e. ankle, toe and trochanter), QTC can achieve a high classification accuracy (i.e. 83.3%) of classifying subjects correctly to either the DCD group or the control group. PMID- 30449158 TI - Evaluating the inhibitory effect of eight compounds from Daphne papyracea against the NS3/4A protease of hepatitis C virus. AB - Hepatitis C virus (HCV) infection is a global threat to human health with an estimated 1.75 million new cases in 2015. Our previous studies showed that the ethyl acetate extraction of Daphne papyracea exhibited an inhibitory effect towards the HCV NS3/4A protease and eight compounds were identified from the extract. In this study, we investigated which of the eight compounds was responsible for the inhibitory effect of the extract against the HCV NS3/4A protease. From both molecular docking and enzyme inhibition studies, (+)-usnic acid was shown to be the most active compound and could be used as a lead compound in developing novel anti-HCV agents. PMID- 30449159 TI - Synthesis of different metallochlorophyllins and quantification in food samples by reversed phase - high performance liquid chromatography. AB - The complex formation between metals (Ni, Co, Zn, Fe, Pb, Sn and Ag) and natural chlorophyll extracted from green leaves was monitored in the present study. The respective metallochlorophyllin was prepared by the reaction of metal chloride or nitrate (1M) to chlorophyll extracted from Ficus leaves extract. All synthesized metallochlorophyllins were stable and Na-Cu-chlorohyllin (E141) which is permitted to add in food and are listed in European Directive 94/36/EC on food colouring materials, was identified in commercially available food commodities (candies). In this study different synthesized metallochlorophyllins were characterised by using UV-Vis, FT-IR, HPLC, AAS and HR-MS techniques. Many food commodities (i.e. candy, chips, drink, and cream biscuits) were monitored for metallochlorophyllins and Na-Cu-Chlorophyllin was detected only in real candy samples. PMID- 30449160 TI - Calibration of crushable foam plasticity models for synthetic bone material for use in finite element analysis of acetabular cup deformation and primary stability. AB - Polyurethane (PU) foam is a material often used in biomechanical experiments and demands for the definition of crushable foam plasticity (CFP) in numerical simulations of the primary stability and deformation of implants, to describe the crushing behaviour appropriately. Material data of PU foams with five different densities (10-40 pounds per cubic foot were ascertained experimentally in uniaxial compression test and used to calibrate CFP models for finite element modelling. Additionally, experimental and numerical deformation, push-out and lever-out tests of press-fit acetabular cups were carried out to assess the influence of the chosen material definition (linear elastic and CFP) on the numerical results. Comparison of the experimentally and numerically determined force-displacement curves of the uniaxial compression test showed a mean deviation of less than 3%. In primary stability testing, the deviation between the experimental and numerical results was in a range of 0%-27% for CFP modelling and 64%-341% for the linear elastic model. The material definition selected, highly influenced the numerical results in the current study. The use of a CFP model is recommended for further numerical simulations, when a deformation of the foam beyond the yield strength is likely to occur. PMID- 30449161 TI - Comparative study of the phenolic profile, antioxidant and antimicrobial activities of leaf extracts of five Juniperus L. (Cupressaceae) taxa growing in Turkey. AB - The purpose of this study was to conduct a comparative evaluation of some biological properties of methanol and water extracts of leaves of five Juniperus taxa growing in Turkey: J. communis L. var. communis (Jcc), J. communis L. var. saxatilis Pall. (Jcs), J. drupacea Labill. (Jd), J. oxycedrus L. subsp. oxycedrus (Joo), J. oxycedrus L. subsp. macrocarpa (Sibth. & Sm.) Ball. (Jom). The antioxidant properties were examined in vitro; both in the DPPH and in the reducing power tests, Joo methanol extract resulted the most active (IC50 = 0.09 +/- 0.01mg/mL and ASE/mL = 2.56 +/- 0.06). In the TBA assay, Jcs methanol extract exhibited the highest activity (IC50 = 4.39 +/- 0.47 MUg/mL). The extracts displayed bacteriostatic activity against Staphylococcus aureus, and Jd methanol extract resulted the most effective (MIC = 19.53 MUg/mL); no effect on the S. aureus biofilm formation was observed. The extracts resulted non-toxic in the Artemia salina lethality bioassay. Finally, the phenolic profile of the methanol extracts was characterized by HPLC-PDA/ESI-MS. PMID- 30449162 TI - Influence of morphology and material properties on the range of motion of the costovertebral joint - a probabilistic finite element analysis. AB - The motion of the costovertebral joint (CVJ) is governed by the material properties and its morphology. The goal of this numerical study was to identify the material and morphology parameters with the greatest influence on the motion of the CVJ. A fully parametric finite element model of the anatomy and material properties of the CVJ was developed. The impact of five morphology and thirteen material parameters was investigated and compared to in vitro data. The motion was influenced in particular by the rotational stiffness of the articulatio capitis costae and the lateral position of the fovea costalis transveralis. PMID- 30449163 TI - Assessment of chemically characterised Myristica fragrans essential oil against fungi contaminating stored scented rice and its mode of action as novel aflatoxin inhibitor. AB - The study reports chemically characterised Myristica fragrans essential oil (MFEO) as plant based food preservative against fungal and aflatoxin B1 (AFB1) contamination of scented rice varieties. The chemical profile of MFEO revealed elemicin (27.08%), myristicine (21.29%) and thujanol (18.55%) as major components. The minimum inhibitory and minimum aflatoxin inhibitory concentrations of MFEO were 2.75 and 1.5 mg/ml, respectively. The MFEO was efficacious against a broad spectrum of food deteriorating fungi. MFEO caused decrease in ergosterol content of fungal plasma membrane and enhanced leakage of cellular ions, depicting plasma membrane as the site of action. The MFEO caused reduction in cellular methylglyoxal content, the aflatoxin inducer. This is the first report on MFEO as aflatoxin suppressor. The essential oil may be recommended as plant based food preservative after large scale trials and reduction in methylglyoxal suggests its application for development of aflatoxin resistant varieties through green transgenics. PMID- 30449164 TI - Fabrication of peptide-linked albumin nanoconstructs for receptor-mediated delivery of asiatic acid to the brain as a preventive measure in cognitive impairment: optimization, in-vitro and in-vivo evaluation. AB - The aim of the study was to evaluate the neuroprotective activity of glutathione (GU)-conjugated asiatic acid (AA) loaded albumin nanoparticles and establishing the drug targeting efficiency (DTE) of GU as a selective ligand for brain targeted delivery. Albumin nanoparticles were prepared by desolvation technique and optimized using quality by design (QbD) approach. GU was conjugated with nanoparticles by carbodiimide reaction and characterized by its size and zeta potential using dynamic light scattering phenomenon. Dialysis bag technique was employed for in-vitro release study and in-vivo brain targeting efficiency was evaluated in Sprague-Dawley rats (75 mg/kg, i.p.). Neuroprotective activity was evaluated against scopolamine-induced dementia in rats. Resultant brain bioavailability of nanoparticles with 100.2 nm size and 71.59% entrapment efficiency (EE), was found 7-fold higher than AA dispersion with 293% DTE for the brain. Conjugated nanoparticles showed significantly high percentage correct alternation (p < .05), low escape latency time (p < .01), cholinesterase inhibition (p < .01) and ameliorated GU levels (p < .01) as compared to diseased animals. GU showed potential to enhance the brain delivery of AA with ameliorated neuroprotective activity due to enhanced bioavailability. This concept can serve as a platform technology for similar potential neurotherapeutics, whose clinical efficacy is still challenging owing to poor bioavailability. [Formula: see text]. PMID- 30449165 TI - Microbial transformation of the anti-aging agent cycloastragenol by Mucor racemosus. AB - The microbial transformation of cycloastragenol (CA) by Mucor racemosus AS 3.20 was investigated. Seven isolated products were identified as (20R,24S) 3beta,6alpha,16beta,25- tetrahydroxy-20,24-epoxy-9,10-seco-cycloartan 9(11),10(19)-diene (1), (20R,24S)- 3beta,6alpha,16beta,25-tetrahydroxy-20,24 epoxy-9,10-seco-cycloartan-1(10),9(11)-diene (2), (20R,24S)-3beta,16beta,25 trihydroxy-6alpha,19alpha;20,24-diepoxy-9,10-seco-cycloartan-9(11)-ene (3), (20R,24S)-6alpha,16beta,25-trihydroxy-3beta,10beta;20,24-diepoxy-9,10-seco- cycloartan-11-one (4), (20R,24S)-16beta,25-dihydroxy-6alpha-methoxy 3beta,10beta;20,24- diepoxy-9,10-seco-cycloartan-7(8),9(11)-diene (5), (20R,24S) 6alpha,16beta,25-trihydroxy-3beta,10beta;20,24-diepoxy-9,10-seco-cycloartan-9(11) ene (6), and (20R,24S)-3beta,6alpha,16beta,25-tetrahydroxy-19-acetoxy-ranunculan 9(10)-ene (7) by spectroscopic analysis. Among them, compounds 2 and 5 were new compounds. M. racemosus could catalyze ring expansion and epoxidation reactions to form 3beta,10beta-epoxy- or 6alpha,19alpha-epoxy-9,10-seco-cycloartane structures. These regio- and stereo-selective reactions are difficult to achieve by chemical means. In addition, the biological effects of isolated metabolites on increasing the lifespan of Caenorhabditis elegans were evaluated. Most of the metabolites could significantly extend the lifespan of C. elegans at 50 MUM. PMID- 30449166 TI - Capsaicinoids from hot pepper (Capsicum annuum L.) and their phytotoxic effect on seedling growth of lettuce (Lactuca sativa L.). AB - One new capsaicinoid, N-vanillyl-4E,6E-dien-8-methylnonanamide (4), along with nine known capsaicinoids, capsaicin (1), dihydrocapsaicin (2), N vanillyloctanamide (3), nordihydrocapsaicin (5), N-vanillyldecanamide (6), homocapsaicin (7), N-vanillyl-4,8-dimethylnonanamide (8), homodihydrocapsaicin II (9), and homodihydrocapsaicin I (10) were isolated from the fruits of Capsicum annuum using semi-preparative high-performance liquid chromatography. The structural characterizations of the isolated compounds were elucidated by spectroscopic data and comparison with the literatures. Bioassays showed that the isolated capsaicinoids significantly reduced the radical length of Lactuca sativa seedling, this inhibition being dose-dependent. [Formula: see text]. PMID- 30449167 TI - Bioactive xanthoquinodins and epipolythiodioxopiperazines from Chaetomium globosum 7s-1, an endophytic fungus isolated from Rhapis cochinchinensis (Lour.) Mart. AB - A new xanthoquinodin B9 (1), together with two known xanthoquinodins, xanthoquinodin A1 (2) and xanthoquinodin A3 (3), three epipolythiodioxopiperazines, chetomin (4), chaetocochin C (5) and dethio tetra(methylthio)chetomin (6), and four other compounds, chrysophanol (7), emodin (8), alatinone (9), and ergosterol (10) were isolated from the endophytic fungus Chaetomium globosum 7s-1, isolated from Rhapis cochinchinensis (Lour.) Mart. All isolated structures were established based on their spectroscopic data analyses. Compounds 1-6 showed antibacterial activity against Gram positive bacteria with MICs ranging from 0.02 pM to 10.81 uM. Compounds 1-6 also exhibited cytotoxicity against KB, MCF-7 and NCI-H187 cancer cell lines (IC50 0.04-18.40 uM). However, they were cytotoxic towards a normal cell line (Vero cell) with IC50 values ranging from 0.04 to 3.86 uM. PMID- 30449168 TI - Bioactive Eudesmane sesquiterpenes from Artabotrys hongkongensis Hance. AB - A new naturally occurring trinoreudesmane sesquiterpene, artahongkongol A (1), together with seven known eudesmane sesquiterpenes (2-8), was isolated from the stems and leaves of Artabotrys hongkongensis Hance. Among them, 1 is a rare trinoreudesmane sesquiterpene containing 12 carbon atoms on the carbon skeleton. All known compounds (2-8) were isolated from the genus Artabotrys for the first time. The structure of 1 was elucidated by extensive spectroscopic methods and the known compounds were identified by comparisons with data reported in the literature. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1-8 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.57 to 15.68 MUM. PMID- 30449169 TI - Gakolanone: a new benzophenone derivative from Garcinia kola Heckel stem-bark. AB - Gakolanone (3',5'-digeranyl-2',4',6',3-tetrahydroxybenzophenone; 1), a novel benzophenone derivative was isolated from the hexane extract of Garcinia kola Heckel stem-bark along with three known 3-8'' linked biflavonoids: 3'',4',4''',5,5'',7,7''-heptahydroxy-3,8''-biflavanone (2); 3'',4',5,5'',5''',7,7''-heptahydroxy-4-methoxy-3,8''-biflavanone (3) and 4',4''',5,5'',7,7''-hexahydroxy-3,8''-biflavanone (4) from the ethanol extract. The compounds were characterized primarily using 1 D and 2 D nuclear magnetic resonance spectroscopy and mass spectrometry and by comparing with literature. The compounds were subjected to in-vitro alpha-amylase enzyme inhibitory assay using DNSA (3,5-dinitrosalicylic acid) reagent with acarbose used as the standard drug. All the compounds were found to show alpha-amylase inhibitory activities with IC50 of 21.4 +/- 1.5, 9.9 +/- 0.2, 15.3 +/- 2.3, 12.9 +/- 2.3 ug/mL respectively. All the compounds exhibited better alpha-amylase inhibitory activities than the standard drug, acarbose (IC50= 38.1 +/- 8.3 ug/mL). PMID- 30449170 TI - Neoclerodane diterpenoids from Scutellaria barbata with cytotoxic activities. AB - Two new neoclerodane diterpenoids, barbatin F (1), barbatin G (2) together with four known compounds, scutebata A (3), scutebata B (4), scutebata C (5) and scutebata P (6) were isolated from the whole plant of Scutellaria barbata D.Don. Their structures were elucidated on the basis of spectroscopic studies. In vitro cytotoxicity of selected compounds against cancer cell lines LoVo, SMMC-7721, HCT 116, and MCF-7 were evaluated, compound 1 and 2 showed weak cytotoxic activities against HCT-116 colon cancer cell lines with IC50 value of 44.3, 32.3 MUM, respectively, while compound 3 and 4 exhibited moderate cytotoxic activities against four tested human cancer cell lines with IC50 values of 5.31~28.5 MUM. PMID- 30449171 TI - Randomized Study of the Effect of Dietary Counseling During Adjuvant Chemotherapy on Chemotherapy Induced Nausea and Vomiting, and Quality of Life in Patients With Breast Cancer. AB - Patients with breast cancer (PsBC) usually face with chemotherapy induced nausea and vomiting (CINV). The aim of this study was to assess the impact of nutritional counseling on CINV and quality of life (QoL) of PsBC. 150 PsBC were randomly assigned for receiving a personalized diet, which contained 1.2-1.5 g/kg of protein, 30% of energy from fat and 55-60% of energy from carbohydrate, a face to face nutrition education, and a pamphlet which contained beneficial nutrition information to reduce the severity of CINV before each chemotherapy session for three times (n = 75) or regular care (n = 75). CINV, QoL, and dietary intake were evaluated after each chemotherapy session. Nausea rating index, overall nausea index, and visual analog scale (P < 0.001) were dramatically lower in the intervention group. Global health status/QoL as well as physical functioning, role functioning, emotional functioning, and cognitive functioning (P < 0.001) were significantly better in the intervention group. Patients in the control group experienced more fatigue, nausea and vomiting, pain, dyspnea, loss of appetite, constipation, and diarrhea (P < 0.001). Nutrition counseling during adjuvant chemotherapy among PsBC reduced the occurrence of CINV and led to significant improvements in the QoL. PMID- 30449172 TI - HPLC analysis, optimization of extraction and purification conditions, biological evaluation of total protoflavones from Macrothelypteris viridifrons. AB - The present study aims to evaluate phytochemical and pharmacological potential of total protoflavones from Macrothelypteris viridifrons. In the phytochemical study, an HPLC analysis method was established, and the optimal extraction and purification conditions were analyzed. The extractive condition was optimized as follows: the backflow extraction with 20 folds of 70% ethanol at 80?C for 1 h twice. Moreover, by combining the alkali-extraction and acid-precipitation method with the macroporous resin purification technology, the final purity rate of total protoflavones was no less than 54.85%. In the pharmacological study, the total protoflavones from M. viridifrons showed a significant tumor-inhibitory effect in the H22 hepatoma cells transplantation model with a higher inhibitory rate of 55.76% in high dosage (100mg/kg) treatment group compared with the positive control group (20 mg/kg cyclophosphamide). Taken of all, these results support that protoflavones are the material basis of M. viridifrons as an anticancer folk medicine. PMID- 30449173 TI - Cytotoxic naphthoquinones from Arnebia densiflora (Nordm.) Ledeb and determining new apoptosis inducers. AB - In this study, phytochemical composition of Arnebia densiflora (AD) was determined and cytotoxic effects of the n-hexane extract and compounds isolated from this species on various cell lines were investigated. By means of serial chromatographic studies, 6 naphthoquinone derivatives were yielded, which are isovalerylalkannin, alpha-methyl-n-butyl alkannin, acetylalkannin, beta-acetoxy isovalerylalkannin, alkannin and a new compound: 4-hydroxy 4-methyl valeryl alkannin. Structures of the isolated compounds were elucidated using UV, IR, 1D 2D NMR, MS and CD methods. Cytotoxic effects of the extract and isolated alkannins were investigated on L929, HeLa, HEp-2 cells. AD and the isolated compounds demonstrated moderate to strong cytotoxic effects (IC50 range: 4.92 172.35 ug/ml). The results of DNA fragmentation and caspase-3 activity studies on HeLa cells exhibited that AD and the naphthoquinones isolated from it caused cytotoxicity through induction of apoptosis. PMID- 30449174 TI - Amelioration of ischaemia reperfusion-induced cerebral injury in mice by liposomes containing Allium cepa fraction administered intranasally. AB - Neuroprotection in ischaemic stroke prevents neuronal injury and subsequent death. Our earlier work revealed the neuroprotective effect of ethylacetate fraction (EF) obtained from Allium cepa outer scales in a mouse model of cerebral ischaemia-reperfusion (I-R) injury. The present study was designed to develop and optimize a liposomal delivery system for EF, along with its biological assessment. Thin film hydration method was used for the preparation of liposomal formulation. The prepared liposomes were optimized with respect to particle size, size distribution and encapsulation efficiency (EE) and characterised on the basis of zeta potential, in vitro release, morphology (TEM) and physical stability. The biological activity of the optimized liposomal formulation (EF-L; 8.5 mg/kg, intra-nasal) was evaluated after induction of cerebral injury in the experimental animals. Neuroprotective effects were assessed in terms of improvement of cognitive/sensorimotor functions and reduction of cerebral infarct size and brain oxidative stress. EF-L (particle size of 204.93 +/- 7.96 nm; EE of 88.02 +/- 2.09%; zeta potential of -20.8 +/- 1.24 mV) showed controlled release pattern; spherical shape and were physically stable for 60 days at 4 degrees C. Intra-nasal administration of EF-L produced significant neuroprotection in mice at 1/10th the oral dose. Thus, EF-L may be developed as a neuroprotective formulation. PMID- 30449175 TI - In loco retention effect of magnetic core mesoporous silica nanoparticles doped with trastuzumab as intralesional nanodrug for breast cancer. AB - Breast cancer is women's most common type of cancer, with a global rate of over 522,000 deaths per year. One of the main problems related to breast cancer relies in the early detection, as the specialized treatment. In this direction was developed, characterized and tested in vivo a smart delivery system, based on radiolabelled magnetic core mesoporous silica doped with trastuzumab as intralesional nanodrug for breast cancer imaging and possible therapy. The results showed that nanoparticles had a size of 58.9 +/- 8.1 nm, with specific surface area of 872 m2/g and pore volume of 0.85 cm3/g with a pore diameter of 3.15 nm. The magnetic core mesoporous silica was efficiently labelled with 99mTc (97.5% +/-0.8) and doped >98%. The cytotoxicity assay, demonstrated they are safe to use. The data were corroborated with the IC50 result of: 829.6 ug +/- 43.2. The biodistribution showed an uptake by the tumour of 7.5% (systemic via) and 97.37% (intralesional) with less than 3% of these nanoparticles absorbed by healthy tissues. In a period 6-h post-injection, no barrier delimited by the tumour was crossed, corroborating the use as intralesional nanodrug. [Formula: see text]. PMID- 30449176 TI - Promising positive liver targeting delivery system based on arabinogalactan anchored polymeric micelles of norcantharidin. AB - Liver cancer is the third most common cause of global cancer-related deaths. This study focused on newly developed drug delivery systems with hepatocyte asialoglycoprotein receptor binding targeting the liver. Although norcantharidin (NCTD) is effective in primary liver cancer treatment, its toxicity in the urinary system remains. Positive liver-targeting effect could be achieved by preparing polymer micelles by arabinogalactan on the surface of N-(4 methylimidazole)-hydroxyethyl-chitosan (MHC). HepG2 cells were used to analyze the cytotoxicity, invasion, apoptosis and uptake of NCTD-loaded micelles. The in vivo antitumor efficacy of NCTD-M was evaluated using tumor-bearing nude mice. Successful preparation of NCTD-M was shown. In vivo imaging showed that micelles significantly increased positive liver drug targeting. Laser confocal microscopy showed increased cellular uptake of micelles. NCTD-M also enhanced cell invasion and the proportion of apoptotic cells. Compared with the other groups, the micelles showed better antitumor effects in vivo. Therefore, the positive liver targeting NCTD-M, which can enhance antitumor efficacy and reduce toxicity, could be a promising and effective therapeutic agent for liver cancer treatment. PMID- 30449177 TI - Research progress of novel inorganic nanometre materials carriers in nanomedicine for cancer diagnosis and treatment. AB - Nanomedicine, as the new achievement in combination of nanotechnology and medical science, has the potential to accurately monitor tumor for early diagnosis and dramatically improve the targeted, long-lasting and combinational therapy. Compared with traditional chemotheraphy, nanomedicine would effectively improve the drug accumulation and controlled release in the tumor sites to improve the therapeutic effect. Recently, all kinds of nanomedicines are designed and synthesized for tumor diagnosis and treatment based on inorganic nanocarriers, such as quantum dots, gold nanoparticles, silicon nanoparticles and so on. They might be adjusted and promoted their properties by core-shell structure, surface modification and other strategies. In this review, the inorganic nanometre materials as nanodrug carriers applied in tumor diagnosis and treatment were summarized; nanodrug carriers design strategies and mechanisms of tumor diagnosis and treatment were introduced in detail, the future and several questions still need to resolve about inorganic nanodrugs in tumor diagnosis and treatment of clinical application was prospected. PMID- 30449178 TI - A comparative study of stability, antioxidant, DNA cleavage and antibacterial activities of green and chemically synthesized silver nanoparticles. AB - Silver nanoparticles have a wide range of research, industrial and biomedical applications that make it essential to develop a low cost and eco-friendly approach with scaling up potential. Green synthesis of nanoparticles through bio reactions leads to a reduction of silver ions to particles could be an acceptable selection using no additional reducing chemicals. Moreover, the simplicity of scale-up processes of the method makes it more efficient than chemical and physical synthesis methods. In this study, Datura stramonium leaf extract and sodium citrate were used as biological and chemical reducing and stabilizing agents to make silver nanoparticles. The main goal is to comprise properties and evaluate antibacterial activity of nanoparticles synthesized through two approaches. Size and morphology compared between the two types of the synthesized nanoparticle by UV-Visible spectroscopy, DLS, AFM, TEM and their antibacterial effects were evaluated through growth inhibition MIC and MBC methods. The results showed narrow size range, spherical shape, high anti-oxidant, antibacterial and DNA cleavage activities of green synthesized silver nanoparticles comparing to less average size, wider range of nanoparticle size, no anti-oxidant activity and less antibacterial and DNA cleavage activities of chemically synthesized nanoparticles. The green synthesized silver nanoparticles had more desirable characteristics and biological activities compared to chemically synthesized nanoparticles. For instance, the green nanoparticles showed narrow size range, spherical shape, high anti-oxidant, antibacterial and DNA cleavage activities versus the chemically synthesized which had less average size, higher range of nanoparticles size, no anti-oxidant activity and less antibacterial and DNA cleavage activities. PMID- 30449179 TI - Development and characterization of folic acid-functionalized apoferritin as a delivery vehicle for epirubicin against MCF-7 breast cancer cells. AB - Epirubicin (Epr) is an effective chemotherapeutic drug; however, the clinical amenability of Epr is limited by its highly toxic interaction with normal cells. This toxicity can be decreased by utilizing nanocarriers and targeted drug delivery systems. This work describes an approach for the delivery of Epr via encapsulation in the horse spleen apoferritin (HsAFr) cavity. The encapsulation was achieved by the disassembling of apoferritin into subunits at pH 2 followed by its reformation at pH 7.4 in the presence of Epr. The surface of HsAFr encapsulated Epr was modified with folic acid (FA) for optimal targeting of breast cancer cells (MCF-7). The use of FA to functionalize HsAFr could enhance the cellular uptake efficiency via FA-receptor-mediated endocytosis. UV-vis spectroscopy, fluorescence spectroscopy, circular dichroism (CD) and transmission electron microscopy (TEM) were utilized for structural characterization of the HsAFr-Epr and HsAFr-Epr-FA complexes. The comparison of the anti-cancer activities across the HsAFr-Epr-FA complex and the free Epr drug was performed using the MTT viability assay on MCF-7. PMID- 30449180 TI - Optimization of Ag2O nanostructures with strontium for biological and therapeutic potential. AB - Pristine- and strontium-doped Ag2O nanoparticles (NPs) were synthesized utilizing the symbolic co-precipitation method, in which sodium hydroxide was used as a precipitating agent. Various instrumentation methods were employed to get an inside view of the synthesized NPs. Powdered X-ray diffraction (PXRD) analysis revealed the existence of high crystallinity and small-sized NPs (an average diameter range of 35-48 nm). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) displayed spherical and circular disc-shaped morphology of the particles. Energy-dispersive X-ray spectroscopy (EDX) showed the purity of NPs. All the screened metal functionalized Ag2O NPs exhibited excellent cytotoxicity and antibacterial activities, moderate to good antioxidant and antifungal activities in comparison to Ag2O NPs. Furthermore, nanomaterials were evaluated for DNA interaction studies. The results illustrated that by increasing the concentration of dopant, i.e. strontium up to 5%, the binding affinity of the NPs effectively increased, hence causing the structural changes in DNA. PMID- 30449181 TI - Adsorption of cadmium from aqueous solutions by novel Fe3O4- newly isolated Actinomucor sp. bio-nanoadsorbent: functional group study. AB - A novel bio-nanocomposite was prepared by the combination of fungal biomass and Fe3O4 magnetic nanoparticles. The result of XRD and EDAX analysis indicated that Fe3O4 Actinomucor sp. bio-nanoadsorbent was prepared. Our experiments showed that the adsorption kinetics and isotherm of this material comply with the pseudo second-order and the Langmuir models, respectively. The maximum adsorption capacity (qmax) of this novel bio-nanoadsorbent was obtained as 29.49 mg/g. The thermodynamic analysis revealed that the adsorption of Cd2+ is spontaneous and exothermic. The optimum temperature, initial concentration, contact time and pH for adsorption system of cadmium were about 45 degrees C, 400 mg/L, 120 min and 7, respectively. Pretreatment of adsorbent by NaOH and SDS significantly increased cadmium adsorption capacity. SEM images showed that Fe3O4 nanoparticles were immobilized successfully on the fungus cell surface. Contribution of the carboxyl, hydroxyl, amine and Fe-O functional groups of the bio-nanoadsorbent in the binding to cadmium ions was revealed by FTIR analysis. Results from regeneration studies indicated reusability of the adsorbent up to 91%. According to experimental results, it could be claimed that bio-nanocomposite of Fe3O4 Actinomucor sp. is a novel efficient adsorbent for removal of metal ions from aqueous solutions, and hence it has potential to be used in the environmental pollution cleanup programs. PMID- 30449182 TI - Practitioners' opinions on traumatic brain injury care pathways in Finland and France: different organizations, common issues. AB - OBJECTIVE: In traumatic brain injury (TBI), differences in health-care contexts have profound effects on care pathways. Objectives were to compare TBI pathways of care and practitioners' views on quality of care issues in two large European areas: Varsinais-Suomi, Finland and Ile-de-France, France. METHODS: Thematic analysis of semi-structured interviews was conducted with TBI practitioners (n = 10) from all stages of TBI care. Interviews addressed organization and financing of care, decision-making on care transitions, and perceived issues. The structure process-outcome model of Donabedian was used to classify findings related to quality of care issues. RESULTS: Main differences in organization of care pathways for people with TBI were related to financing modalities, number of pathway alternatives, inpatient versus outpatient rehabilitation, and indirect versus direct referrals to rehabilitation. Similar categories of issues were raised in the two settings. Issues in structures involved availability of services, financial access, and heterogeneity of expertise. Issues in processes involved diagnosis and follow-up, training regarding cognitive impairments, decision-making for referrals, transition delays, and care pathways of very severely affected patients. CONCLUSIONS: These findings provide clues to address care pathways in further comparative studies. Determinants of care pathway quality could be classified as direct or indirect, binding or adaptive organizational factors. PMID- 30449183 TI - miR-219a-5p represses migration and invasion of osteosarcoma cells via targeting EYA2. AB - EYA2 is the developmental transcription factor and phosphatase, playing an important role in numerous species in regulating cell death and differentiation. Recent studies showed that EYA2 is dysregulated and involved in the progression of various cancers. However, the expression and role of EYA2 in osteosarcoma remains unclear. Here, we found that EYA2 expression was evidently upregulated osteosarcoma (OS) tissue and cell lines. Next, we predicted EYA2-targeting miRNAs, which was further evaluated using a dual luciferase reporter assay. We found that miR-219a-5p significantly repressed EYA2 expression via binding to the 3'-UTR of EYA2. Furthermore, overexpressed miR-219a-5p significantly repressed OS cell invasion and migration, which was reversed by overexpressed EYA2. While silenced miR-219a-5p induced OS cell invasion and migration, which was reversed by silenced EYA2. In conclusion, our study revealed that miR-219a-5p function as tumour suppressor regulates OS cell invasiveness by repressing EYA2 expression. PMID- 30449184 TI - Management of severe pain after dermal contact with caterpillars (erucism): a prospective case series. AB - CONTEXT: Erucism, envenomation caused by dermal contact with larval forms of moths, may result in intense local pain, mainly after contact with puss caterpillars (family Megalopygidae). OBJECTIVE: To evaluate the response to different treatments for controlling severe pain in a case series of erucism in Campinas, southeastern Brazil. PATIENTS AND METHODS: Prospective cohort study. A Numeric Pain Rating Scale (NPRS 0-10) was used to assess pain intensity in the Emergency Department (ED). Pain was considered as severe upon ED admission (T0) when the NPRS was >=8. INCLUSION CRITERIA: age >=8 years old, severe pain at T0, with continuous assessment of pain intensity in all patients using the NPRS during the ED stay (T5, T15, T30, T60 min and at discharge). RESULTS: Fifty-five patients fulfilled the inclusion criteria and were divided into three groups according to the initial treatment at T0: local anesthesia alone with 2% lidocaine (group 1, n = 15), local anesthesia and analgesics (group 2, n = 26) and analgesics without local anesthesia (group 3, n = 14). Most patients were admitted within 2 h after dermal contact with the stinging bristles of caterpillars (median =90 min, IQR: 40-125 min). In 22 cases (40%), the caterpillar was brought for identification (Podalia spp., n = 18; Megalopyge spp., n = 4). There was a significant decrease in pain from T5 onwards with all of the treatments. When the short-term response (T5 and T15) was considered, analgesia was more effective in groups 1 and 2 compared to group 3 (p < .01). Additional analgesia (from T5 until discharge) was frequently required (n = 25/55), mainly in group 1 (n = 11/15). The median length of stay in the ED was 120 min (IQR: 80-173 min). CONCLUSIONS: The association of local anesthesia with analgesics was apparently a good combination for the rapid management of severe pain in the ED. PMID- 30449185 TI - Neuregulin 1 treatment improves glucose tolerance in diabetic db/db mice, but not in healthy mice. AB - CONTEXT: Neuregulin 1 (NRG1) and ErbB receptors are involved in glucose homeostasis. However, the effects of the neuregulin 1-ErbB pathway activation on glucose metabolism in liver are controversial. OBJECTIVE: Assess NRG1 and ErbB signalling in liver and the effects of 8-week treatment with NRG1 on glucose homeostasis in diabetic db/db mice and in control healthy mice. RESULTS: NRG1 improved glucose, insulin and insulin sensitivity index during OGTT in db/db mice, but not in control mice. Compared with healthy mice, phosphorylation of p38, ErbB-1 and ErbB-3 was increased in diabetic mice, and neuregulin 1 treatment increased phosphorylation of p38 and ErbB-4. Conversely, the AKT/FOXO1 pathway was not affected by the 8-week treatment with NRG1. CONCLUSION: Diabetic mice showed altered NRG1-ErbB pathway in the liver compared with healthy mice. Moreover, chronic NRG1 treatment increased p38 phosphorylation in liver and improved glucose tolerance in diabetic mice, but not in control mice. PMID- 30449186 TI - Effects of subacute 3-monochloropropane-1,2-diol treatment on the kidney of male albino rats. AB - 3-Monochloropropane-1,2-diol (3-MCPD) is a well-known food contaminant. Although the kidney is thought to be a target organ for 3-MCPD toxicity, nephrotoxic structural changes are relatively unstudied. We investigated the renal alterations caused by 3-MCPD in male albino rats. 3-MCPD was administered orally, at a dose of 60 mg/kg for 7 days. 3-MCPD caused significant elevation of serum creatinine and urea levels together with hydropic degeneration, necrosis and shedding of the cells of the proximal convoluted tubules, urinary casts in the distal convoluted tubules and interstitial inflammatory cell infiltration. Administration of 3-MCPD for a period as short as 7 days causes acute renal failure in male albino rats. PMID- 30449187 TI - Risperidone medication errors in children: an analysis of French poison centres data. AB - OBJECTIVES: To describe clinical consequences of risperidone medication errors in children of less than 13 years and to estimate a clinically relevant toxic dose. METHODS: All cases of risperidone medication errors managed by French Poison Centres from 2001 to 2012 were analyzed. Inclusion criteria were a delay of at least 2 hours between ingestion and request to the FPC in asymptomatic children, an ingested dose above two-fold the maximal daily dose for children above 5 years or any symptomatic patient at the time of first contact. RESULTS: One hundred and sixty cases met our criteria. Median age was 8 years (range 0.9-12) and 28.1% were aged 5 years or less. Causes of the error were an incorrect dose in treated children (84.2%) or a dose given to a wrong child (15.8%). The median ingested dose was 0.1 mg/kg or 3.3-fold the maximum recommended dose. Overall, 59 children had no symptoms, 95 experienced minor symptoms and six moderate symptoms. Somnolence/sedation was the most common (73.3%). Of the 17 children who developed extrapyramidal disorders, all had minor or moderate symptoms and only five required a symptomatic treatment. CONCLUSIONS: Risperidone medication errors in children cause minimal effects. Somnolence and mild to moderate extrapyramidal reactions were the main features of toxicity, and significant cardiac or other neurological features were not observed. No case with severe toxicity was noted. At home surveillance can be proposed for children exposed to a dose <=0.15 mg/kg. PMID- 30449188 TI - Accidental inoculation of humans with veterinary vaccines: there is no such thing as zero risk, a better understanding is needed. PMID- 30449190 TI - Correction. PMID- 30449189 TI - An overview of neural networks for drug discovery and the inputs used. AB - INTRODUCTION: Artificial intelligence systems based on neural networks (NNs) find rules for drug discovery according to training molecules, but first, the molecules need to be represented in certain ways. Molecular descriptors and fingerprints have been used as inputs for artificial neural networks (ANNs) for a long time, while other ways for describing molecules are used only for storing and presenting molecules. With the development of deep learning, variants of ANNs are now able to use different kinds of inputs, which provide researchers with more choices for drug discovery. Areas covered: The authors provide a brief overview of the applications of NNs in drug discovery. Combined with the characteristics of different ways for describing molecules, corresponding methods based on NNs provide new choices for drug discovery, including de novo drug design, ligand-based drug design, and receptor-based drug design. Expert opinion: Various ways for describing molecules can be inputs of NN-based models, and these models achieve satisfactory results in metrics. Although most of the models have not been widely applied and tested in practice, they can be the basis for automatic drug discovery in the future. PMID- 30449191 TI - Effects of nicotine on rat adrenal gland: crosstalk between oxidative and inflammatory markers, and amelioration by melatonin. AB - Although the risks of smoking are well known, the effects of exposure to nicotine on endocrine functions remain unclear. We investigated the deleterious effects of nicotine on the adrenal gland and the mechanisms of these changes in rats. The role of melatonin in ameliorating pathological changes also was investigated. We used 24 rats divided into four groups of six: group 1, control; group 2, nicotine treated; group 3, nicotine and melatonin treated; group 4, melatonin treated. We used histology; immunohistochemistry of inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF) and tyrosine hydroxylase (TH); measured oxidative and antioxidative markers, malondialdehyde (MDA) and glutathione (GSH); and performed real-time PCR for NF-kappaB 65, IL1-B and IL6. We also performed histomorphometric analysis. Indentation and lamellar separation of the adrenal capsule, vacuolated degenerated cells and lymphocytic infiltration were observed in group 2. Vacuolated cells and cells with pyknotic nuclei also were detected in the zona reticularis and medulla of the same group. We observed improved shape and cellular lining of the gland in groups 3 and 4. Widespread expression of iNOS, VEGF and TH, increased area percent collagen, decreased GSH (56%) and increased MDA, NF-kappaB, IL1-B and IL-6 were observed in group 2. All parameters were ameliorated in groups 3 and 4. The effects of nicotine on the adrenal gland can be attributed to oxidative and inflammatory stress; melatonin ameliorates these effects. PMID- 30449192 TI - Encapsulation of S-nitrosoglutathione: a transcriptomic validation. AB - OBJECTIVE: S-nitrosogluthatione (GSNO), a S-nitrosothiol, is a commonly used as nitric oxide (NO*) donor. However, its half-life is too short for a direct therapeutic use. To protect and ensure a sustained release of NO*, the encapsulation of GSNO into nanoparticles may be an interesting option. METHODS: In this work, we have investigated the early (4 h) and late (24 h) transcriptomic response of THP-1 human monocytes cells to two doses (1.4 and 6 uM) of either free or Eudragit(r) nano-encapsulated GSNO using RNA microarray. RESULTS: After exposure to free GSNO, genes mainly involved in apoptosis, cell differentiation, immune response and metabolic processes were differentially expressed. Although, cells exposed to free or encapsulated GSNO behave differently, activation of genes involved in blood coagulation, immune response and cell cycle was observed in both conditions. CONCLUSIONS: These results suggest that the encapsulation of low doses of GSNO into Eudragit(r) nanoparticles leads to a progressive release of GSNO making this compound a possible oral therapy for several biomedical applications like inflammatory bowel diseases. PMID- 30449193 TI - Osteogenic differentiation of Wharton's jelly-derived mesenchymal stem cells cultured on WJ-scaffold through conventional signalling mechanism. AB - Wharton's jelly-derived extracellular matrix (WJ-ECM) has attracted researcher's attention for its biomedical applications. Previously, we fabricated a biomimetic spongy scaffold from decellularized WJ-ECM and, in this study, we sought to examine the osteogenic inductive potential of this scaffold and its underlying mechanism. To address this question, mesenchymal stem cells (MSCs) were isolated from WJ using a mechanical method and cultured on the scaffold, under dynamic condition, for over 21 days in the presence or absence of osteogenic medium. The status of signalling pathways involved in the osteogenic differentiation and the expression profile of integrins in the WJ-derived MSCs (WJ-MSCs) were examined. WJ-MSCs displayed differentiation capacities and expressed surface antigens, characteristics of MSCs. Histologically, WJ-MSCs seeded on the scaffold showed a proper cellular attachment, penetration and migration. They also exhibited a higher degree of alkaline phosphatase activity, calcium deposition and osteogenic gene expression, than those cultured in 2D condition. The expression of Wnt, BMP and TGF-beta signalling target genes together with that of alpha2, alphav and beta1 integrins was increased in WJ-MSCs in both presence and absence of osteogenic induction medium. Taken together, our results demonstrate that WJ derived scaffold induces osteogenic differentiation of WJ-MSCs, possibly through activating integrins and subsequently conventional intracellular signalling pathways. PMID- 30449194 TI - Short-term exposure to titanium, aluminum and niobium (Ti-6Al-4Nb) alloy powder can disturb the serum low-density lipoprotein concentrations and antioxidant profile in vital organs but not the behavior of male albino mice. AB - A group of seven-week-old albino mice of both genders were orally administered with a suspension of 25 mg Ti-6Al-4Nb/ml of saline/kg body weight and evaluated in comparison with a control group of animals treated with saline. Evaluation of both the groups was conducted through behavioral tests (Rota rod, open field, novel object and light dark box test), blood biochemical tests [complete blood count and selected serum parameters ([cholesterol, high-density lipoproteins, low density lipoproteins, creatinine and triglycerides)] and on the basis of measured concentration of antioxidant metabolites (superoxide dismutase, catalase and lipid peroxidation) in vital organs (brain, heart, liver, kidney and lungs). Based upon the results of these tests, it has been found that the applied dose of Ti-6Al-4Nb alloy powder has not effect on physical and neurological outcome of these animals. However, it can increase low-density lipoprotein concentrations as well as disturb the H2O2 and lipid peroxidation associated metabolic pathways, especially in male albino mice. Whereas all other hematological indices and antioxidative stress parameters were unaffected. PMID- 30449195 TI - Clinical pharmacokinetics of drugs in cardiopulmonary associated cachexia without hepatorenal pathology: a systematic review. AB - Cachexia not only has a dramatically harmful impact on a patient's life, but also a poor response to therapeutic agents. The purpose of the present review is to provide updated information concerning the pharmacokinetic aspects of drugs used to treat cardiopulmonary cachexia in patients with no signs of hepatic or renal pathology. A systematic search of PubMed, the Cochrane Central Register of Control Trials, Science Direct, and Clinical Trials Registry (ClinicalTrials.gov), encompassing the period between 2000 and 2017, was conducted in accordance to PRISMA guidelines. Seven studies were identified. Collectively, these studies included a total of 196 individuals (19 healthy subjects and 177 diseased patients). This data review found no differences in bisoprolol and prothionamide absorption in cachectic patients with chronic heart failure and tuberculosis, but higher absorption of oflaxocin in the same set of patients was observed. The distribution of bisoprolol, prothionmaide, ceftazidime, and cefipirome was reduced in cardiopulmonary cachexia patients. Hepatic clearance of rifampin was equivalent in cachectic and non-cachectic patients that had normal hepatic function. Similarly in cardiopulmonary cachexia patients, renal clearance of ceftazidime was reduced by 19% but no significant differences in bisorpolol and prothionamide clearance were observed. In the case of cefipirome, both renal clearance and creatinine clearance were higher in cachectic patients with cystic fibrosis. From the limited evidence available, the main drug pharmacokinetic changes seen in cardiopulmonary cachexia patients were a reduction in the volume of distribution and impairment of clearance. PMID- 30449196 TI - Photodynamic application of protoporphyrin IX as a photosensitizer encapsulated by silica nanoparticles. AB - BACKGROUND: Achieved Silica Nanoparticles (SiNPs) to encapsulate the photosensitizer [Protoporphyrin IX (PpIX)] in photodynamic therapy (PDT) application was reported in this research. MATERIALS AND METHODS: Cytotoxicity for five different concentrations of encapsulated and naked PpIX was measured. Optimum concentration and optimum exposure time of encapsulated and naked PpIX that needed to destroy the cells (Osteosarcoma cells) was measured. RESULTS: The results showed that the encapsulated PpIX has more efficacy compared to the naked PpIX and the applicability of the encapsulated PpIX-SiNPs was proved on osteosarcoma cells. CONCLUSION: The results established the important in-vitro photodynamic effectiveness of PpIX-SiNP, which may open a new application for PpIX in its clinical and in-vitro studies. PMID- 30449197 TI - Modified Internal Mammary Artery Perforator Flap in Treatment of Sternal Wound Complications. AB - Objectivs There are multiple treatment strategies and flap options to cover defects after deep sternal wound infections and other similar sternal defects. The choice of flap is made according to surgeons' preferences and the size and location of the defect. Our aim is to introduce a new option to cover these kinds of defects with an internal mammary artery perforator flap combined with a pectoralis major muscle flap mostly raised with a muscle-sparing technique. Design We treated 13 patients with a sternal defect after cardiothoracic operations with this technique between 2010-2016. Ten patients had a deep sternal wound infection, two had an infection of the prosthesis after carotico-subclavian bypass and one had a fragmented sternum. Nine patients were treated with an internal mammary artery perforator fasciocutaneous flap with a muscle-sparing pectoralis major muscle flap and four patients with an internal mammary artery perforator fasciocutaneous flap combined with a right pectoralis major muscle flap. Results Three patients (23%) experienced major complications and four patients (31%) had conservatively treated minor complications. There were no flap losses. Conclusion This combination of flaps is a suitable option for patients with large defects in whom direct skin closure is not possible. It can be utilized for defects comprising the entire vertical length of the sternum. These are local flaps with a short operation time and are therefore most suitable for patients with comorbidities in whom major surgery is not an option. PMID- 30449199 TI - Letter in response to: "No influence of initial naloxone dosage: a significant misunderstanding". PMID- 30449198 TI - Neurophysiological responses in the brain tissues of rainbow trout (Oncorhynchus mykiss) treated with bio-pesticide. AB - The aim of this study was to investigate neurophysiological responses in rainbow trout brain tissue exposed to natural/botanical pesticides. Fish were exposed to botanical and synthetic pesticides over a 21-day period. At the end of the treatment period, oxidative DNA damage (indicated by 8-OHdG (8-hydroxy-2' deoxyguanosine), AChE activity (acetylcholinesterase) and transcriptional parameters (gpx (glutathione peroxidase), sod (superoxide dismutase), cat (catalase), HSP70 (heat shock protein 70) and CYP1A (cytochromes P450)) was investigated in control and application groups. Our results indicated that brain AChE activities decreased very significantly in fish treated with both insecticide types when compared with control (p < 0.05). 8-OHdG activity increased in a dose/time-dependent situation in the brain tissues of Oncorhynchus mykiss (p < 0.05). In addition, with regards to gene expression, gpx sod and, cat expressions were down-regulated, whereas CYP1A and HSP70 gene expression were up regulated in fish treated with both insecticides when compared to the control group (p < 0.05). The data for this study suggests that bio-pesticides can cause neurophysiological changes in fish brain tissue. PMID- 30449200 TI - Systems pharmacology approach to investigate the molecular mechanisms of herb Rhodiola rosea L. radix. AB - Rhodiola rosea L. radix (RRL) is one of the most popular medical herb which has been widely used for the treatment of different diseases effectively, including cardiovascular diseases and nerve system diseases. However, due to the multiple compounds in RRL, the underlying molecular mechanisms of RRL are remained unclear. To decipher the action mechanisms of RRL from a systematic perspective, a systems pharmacology approach integrated absorption, distribution, metabolism, and excretion (ADME) system, drug targeting, and network analysis was introduced. First, by the ADME screening system and the target fishing process, 56 potential active compounds and 62 targets were obtained, respectively. In addition, compound-target network demonstrated that most compounds interacted with multiple targets, indicating that RRL may enhance its therapeutic effects probably through hitting on multiple targets in a holistic level. Moreover, target-pathway network and gene ontology analysis showed that multiple targets of RRL were involved in several biological pathways, i.e. Neuroactive ligand-receptor interaction, calcium signaling pathway, adrenergic signaling in cardiomyocytes, and VEGF signaling pathway, which dissecting the therapeutic effects of RRL on various diseases, such as cardiovascular diseases, depression, adaptation diseases, etc. In summary, this work successfully explains the potential active compounds and the multi-scale curative action mechanisms of RRL for treating various diseases; meanwhile, it implies that RRL could be applied as a novel therapeutic agent in arthritic diseases. Most importantly, this work provides an in silico strategy to understand the action mechanisms of herbal medicines from molecular/system levels, which will promote the new drug development of traditional Chinese medicine. PMID- 30449201 TI - Incretin-based therapy for diabetic ulcers: from bench to bedside. AB - INTRODUCTION: Diabetic foot ulcers are a serious complication of diabetes and are associated with pain, disability, and poor quality of life. Incretin-based therapy is available for type-2 diabetes. Aside from glucose control, such treatment can impart numerous beneficial effects. Areas covered: This review summarizes the preclinical and clinical evidence supporting incretin-based treatment approaches for diabetic ulcers. Expert opinion: Incretin-based therapy may have a role in the treatment of diabetic foot ulcers; the benefits of such treatment arise from attenuation of inflammatory response, improvement of keratinocyte migration, induction of angiogenesis, and the enhancement of tissue remodeling. Large-scale clinical trials are required to determine the advantages of GLP-1 receptor agonists and DPP4 inhibitors. Future research on the topical application of incretin-based therapy is necessary. Such therapeutic approaches may provide new hope in improving the treatment of impaired diabetic foot ulcers. PMID- 30449202 TI - Acute skeletal fluorosis in the setting of 1,1-difluoroethane abuse. PMID- 30449203 TI - Effect of amylin on memory and central insulin resistance in a rat model of Alzheimer's disease. AB - CONTEXT: Alzheimer's disease is strongly associated with brain insulin signalling. OBJECTIVE: Investigating the effect of amylin as a novel treatment in streptozotocin (STZ) rat model of AD. MATERIALS AND METHODS: Alzheimer's disease (AD) was induced in albino rats by intracerebroventricular injection of STZ (3 mg/kg). Rats received either amylin analogue (Pramlintide 200 MUg/kg/day) or Metformin (30 mg/kg/day) for 5 weeks. RESULTS: Both Pramlintide and Metformin improve learning and memory through enhancing insulin signalling (p-IR and p PI3K) which lead to lowering level of CSF glucose, phosphorylated tau proteins, and amyloid-beta peptide (Abeta) in hippocampus. CONCLUSIONS: Insulin sensitisers as Metformin and Pramlintide can improve learning and memory and decrease the pathological changes in STZ induced rat model of AD. However, Pramlintide is superior to Metformin in some memory tests which related to its action as an amylin analogue. Amylin improves learning and memory through an independent effect other than insulin sensitisation. PMID- 30449204 TI - Effects of activity pacing in patients with chronic conditions associated with fatigue complaints: a meta-analysis. AB - A meta-analysis was conducted to (1) determine the effect of activity pacing interventions on fatigue, physical functioning and physical activity among patients with chronic conditions associated with fatigue complaints, and to (2) examine potential moderator effects of trial characteristics (components of intervention and amount of patient-provider contact). Six studies were included in the meta-analysis. Relevant content of the studies was extracted and rated on methodological quality. Random-effects modeling was used to pool data across studies. Medium (standardized mean difference =0.50) and marginal (standardized mean difference =0.34) effects were found for fatigue at post-treatment and follow-up respectively. Inconsequential effects were found for physical functioning and activity (standardized mean difference =0.08-0.30) at both assessment points. Subgroup analyses revealed components of intervention and amount of patient-provider contact were not the source of variance. Minimal patient-provider contact had an effect on fatigue comparable in magnitude to more intensive contact. This meta-analysis of activity pacing in patients with fatigue complaints suggests that activity pacing might have sustained beneficial effects on fatigue management, in particular on fatigue reduction. The divergence in effects for all outcomes suggests that alternative ways such as tailoring advice to individual's behavior toward physical activity may be more successful. Implications for rehabilitation In a relatively small sample this meta-analysis shows fatigue severity improved after activity pacing interventions and provides a basis to integrate activity pacing in activity stimulation programs for persons with chronic conditions. Activity pacing can feasibly be implemented within standard health care to manage fatigue and physical activity behaviors in persons with chronic conditions. PMID- 30449205 TI - Domain-specific deficits in self-awareness and relationship to psychosocial outcomes after severe traumatic brain injury. AB - PURPOSE: To investigate the evidence for domain-specific deficits in self awareness on the Patient Competency Rating Scale (PCRS) and the relationship to psychosocial outcomes after severe traumatic brain injury (TBI). METHODS: Fifty six adults with severe TBI (75% males, M age =36.96, SD = 12.96), and 50 age- and gender-matched controls (72% male, M age =34.12, SD = 11.43) were administered the PCRS self-report form, and the Depression, Anxiety, Stress Scales. Relatives of TBI and control participants completed the PCRS informant version. Relatives of the TBI group also completed the Sydney Psychosocial Rating Scale. RESULTS: A within-group analysis indicated that self-awareness varied according to PCRS domain (p <.01). Relative to their own profile, TBI participants displayed significantly poorer self-awareness on the activities of daily living (ADLs) domain than on the interpersonal and emotional domains (p < 0.01). Further, TBI participants displayed significantly poorer self-awareness of ADLs than controls (p < 0.001), but there were no significant between-group differences in other domains. Hierarchical regression analyses revealed that poorer self-awareness of cognitive difficulties was related to lower occupational functioning (p = 0.01), whereas poorer self-awareness of difficulties with ADLs was related to lower independent living skills (p < 0.001). CONCLUSIONS: The results provide only limited support for domain-specific deficits in self-awareness after severe TBI, with impairment most evident for ADLs. Poorer self-awareness in the ADLs and cognitive domains were associated with lower independence and occupational functioning, respectively. The findings highlight the potential benefits of targeting self-awareness related to difficulties with ADLs in the rehabilitation of people with severe TBI. Implications for rehabilitation People with severe traumatic brain injury had poorest self-awareness of difficulties regarding activities of daily living, which was related to less independence Difficulties with complex activities of daily living were more likely to be under-reported than difficulties with basic self-care It may be beneficial to target self awareness of difficulties relating to complex activities of daily living in rehabilitation. PMID- 30449206 TI - A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone. AB - INTRODUCTION: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections. Areas covered: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from 3 steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in 3 patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data has been published. Expert Commentary: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the 9th injection (8 months). PP3M may take >1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers). PMID- 30449207 TI - Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs. AB - OBJECTIVE: Recent randomized and controlled trials of drugs derived from the gut hormone glucagon-like peptide-1 (GLP-1) show that the most frequent adverse symptoms are gastrointestinal, including gallbladder-related side effects such as cholithiasis and cholecystitis. Since the gut hormone cholecystokinin (CCK) stimulates bile secretion and regulates gallbladder motility and emptying, we examined the effect of GLP-1 on the secretion of CCK in normal subjects and patients with type 1 diabetes mellitus. MATERIALS AND METHODS: Plasma was sampled from 10 healthy subjects and 10 patients with diabetes. With plasma glucose concentrations clamped between 6 and 9 nmol/l, GLP-1 or saline was infused for 240 min during and after a meal. The plasma concentrations of CCK were measured with a highly specific radioimmunoassay. RESULTS: Basal plasma concentrations of CCK were similar in the normal subjects and in the diabetes patients. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the diabetes patients. CONCLUSIONS: The results show that GLP-1 suppresses the secretion of CCK after a meal in normal and diabetic subjects. The suppression attenuates the gallbladder contractility. Our data, therefore, offer an explanation for the increased risk of adverse gallbladder events during treatment with GLP-1-derived drugs. PMID- 30449208 TI - Bone protection for early menopausal women in China: standard or half-dose estrogen with progestin? A one-year prospective randomized trail. AB - The aim of the study is to compare the bone sparing effect of half-dose with standard-dose conjugated equine estrogen (CEE) combined with progestin. A total of 123 participants were administrated with 0.625 mg of CEE and 100 mg of micronized progesterone (MP) in group A, 0.3 mg of CEE and 100 mg of MP in group B, 0.625 mg of CEE and 10 mg of dydrogesterone (DDG) in group C for one year. Percent changes from baseline in BMD at lumbar spine and fracture rate were primary outcomes. Secondary endpoints included changes of BMD at femoral neck, total hip and arm, bone markers (alkaline phosphatase, calcium and phosphorus), serum alanine aminotransferase (ALT) and endometrial thickness. No fractures occurred during the treatment. Standard dose of CEE leads to significant changes in lumbar spine and arm. The 3.78% growth of BMD at femoral neck in group C marked a statistically difference. There was no statistically remarkable bone loss at hip in all three groups. Bone turnover markers and ALT significantly decreased from basic values. Endometrium thickened more with traditional dose of CEE. Both the half and standard dose CEE are effective in BMD preservation among early menopausal women with subtle side effects. Low-dose estrogen is less efficacious than traditional one. PMID- 30449209 TI - Developing a vaccine for type 1 diabetes by targeting coxsackievirus B. AB - INTRODUCTION: Virus infections have long been considered as a possible cause of type 1 diabetes (T1D). One virus group, enteroviruses (EVs), has been studied extensively, and clinical development of a vaccine against T1D-associated EV types has started. Areas covered: Epidemiological studies have indicated an association between EVs and T1D. These viruses have a strong tropism for insulin producing beta-cells; the destruction of these cells leads to T1D. The exact mechanisms by which EVs could cause T1D are not known, but direct infection of beta-cells and virus-induced inflammation may play a role. Recent studies have narrowed down the epidemiological association to a subset of EVs: group B coxsackieviruses (CVBs). These findings have prompted efforts to develop vaccines against CVBs. Prototype CVB vaccines have prevented both infection and CVB induced diabetes in mice. This review summarizes recent progress in the field and the specifics of what could constitute the first human vaccine developed for a chronic autoimmune disease. Expert commentary: Manufacturing of a clinical CVB vaccine as well as preclinical studies are currently in progress in order to enable clinical testing of the first CVB vaccine. Ongoing scientific research projects can significantly facilitate this effort by providing insights into the mechanisms of the CVB-T1D association. PMID- 30449210 TI - How safe is rucaparib in ovarian cancer? AB - INTRODUCTION: Rucaparib is increasingly being utilized for women with recurrent ovarian cancer both as treatment and maintenance therapy. PARP inhibitors like rucaparib are daily oral medication that exploit the DNA repair pathway. The most significant clinical benefit is in those tumors exhibiting deficiency in their homologous recombination pathway. Areas covered: This review will discuss the mechanism of action, clinical efficacy data and safety of rucaparib as presented from phase 1, 2, and phase 3 clinical trials. Expert opinion: Rucaparib is a promising therapeutic option for women where prolongation of survival with favorable side effects is the goal. The side effect profile is similar or more favorable when evaluating it against other PARP inhibitors. Physicians will likely need to have increasing comfort with unique side effects like transaminitis and serum creatinine increases. Clinicians should be prepared for not only increasing utilization of PARP inhibitors in the recurrent setting but upfront usage may be on the horizon. As >50% of high grade serous ovarian cancers likely have the predictive biomarker, HRD, for PARP inhibition a substantial group of patients stand to have PARP inhibitors as part of their oncologic care. PMID- 30449211 TI - Current pharmacological treatment guidelines for psoriasis and psoriatic arthritis. AB - INTRODUCTION: Psoriasis is a common chronic skin condition that is prevalent worldwide. Despite the numerous treatment options available, discrepancies exist between international guidelines. Areas Covered: This review aims to evaluate the current international guidelines for the systemic treatment of psoriasis and psoriatic arthritis. Expert Commentary: Most guidelines are unanimous on medication dosing and laboratory monitoring. However, even the most up to date guidelines do not include many of the new biologic medications. Guidelines will require frequent updates to include the newer treatments and will soon need to state a recommendation on the use of biosimilars. PMID- 30449212 TI - Malignant endometrial polyp in woman with the levonorgestrel intrauterine system a case report. AB - The levonorgestrel-releasing intrauterine system (LNG-IUS) is widely used and recommended as a reliable contraceptive. It also acts by opposing the effects of estrogen on the endometrium, thereby preventing development of endometrial hyperplasia and its possible malignant transformation. This case describes a 52 year-old multiparous amenorrhoeic patient who was seen in the gynecology outpatient department for a routine control 46 months after the insertion LNG-IUS as contraception. Hysteroscopy with a target biopsy following suspicious ultrasound scan confirmed well-differentiated endometrioid adenocarcinoma. Ultrasound scan prior to inserting LNG-IUS revealed normal 5 mm thin endometrium with the sharp edges. Uterine bleeding before the LNG-IUS insertion was regular and not excessive and the woman has remained amenorrhoeic after the LNG-IUS insertion. We present a case of the growth of a polyp-shaped endometrial carcinoma in a LNG-IUS asymptomatic user. PMID- 30449214 TI - Defining the toxicity of current regimens for extranodal NK/T cell lymphoma: a systematic review and metaproportion. AB - OBJECTIVES: The aim of this study is to compare the toxicity profiles of SMILE versus less intense L-asparaginase-containing regimens, CCRT or "sandwich" RT+CT regimens. METHODS: PRISMA protocol was used to search Pubmed and Embase for studies of treatment regimens for extranodal NK/T-cell lymphoma, nasal type (ENKTL) in English published before March 2018. Pooled data were grouped into five categories: A) CHOP-like regimens; B) Gemcitabine-based regimens; C) SMILE like regimens; D) Concurrent and "sandwich" RT + CT; and E) Methotrexate-based combinations. We pooled prevalence of selected adverse events from each study to calculate the weighted overall prevalence using meta-proportion in Stata. RESULTS: Group C was the most toxic with the pooled neutropenia 72% (95 CI 64;80) and thrombocytopenia 48% (95% CI 40;55) prevalence. The use of Group D treatment regimens was associated with the lowest anemia (10% (95% CI 1;19)) prevalence. Group E was the least toxic with regard to thrombocytopenia (6% (95% CI 1;11). CONCLUSION: Our analysis confirms that SMILE regimen, which is current standard to treat advanced-stage ENKTL may be associated with more severe hematological toxicity compared to other L-asparaginase combinations, including methotrexate based (AspaMetDex, MESA and MEDA) or gemcitabine-based (GELOX, PGEMOX, DDGP, GDL, GOLD, GLIDE) or CCRT-based regimens. PMID- 30449213 TI - Chinese version of the Recovery Self-Assessment scale: psychometric evidence from Rasch analysis and reliability estimates. AB - BACKGROUND: The Recovery Self-Assessment (RSA) is a popular and well-validated instrument for assessing recovery-oriented service around the world. AIMS: This study aims to develop a Chinese version of the RSA, which assesses the recovery orientation of hospital-based mental health services. METHODS: We conducted forward and backward translations of the RSA and modify the translated Chinese based on comments by content experts. We recruited 350 people with mental illnesses who regularly attend hospital and community mental health services. The participants completed the Chinese Recovery Self-Assessment Service User version (CRSA-SU) and convergent measures on hope and mental well-being. RESULTS: The Rasch analysis supported five of the six factors in the instrument and suggests that the "Life Goal" factor could be further split into two factors. We identified three misfit items (items 6, 12 and 17) that could be considered for removal. Both the internal consistency and test-retest reliability are between satisfactory and very good within each subscale, with the exception of the Choice subscale. The seven subscales had low positive correlations with measures of hope and mental well-being, which supported the convergent validity of CRSA-SU. CONCLUSIONS: The results supported the factor structure, reliability and validity of the CRSA-SU. PMID- 30449215 TI - Supervision Strategies and Their Correlates: An Empirical Study of Chinese Community Correctional Staff. AB - While there are different approaches to dealing with offenders sentenced to community corrections, the three major ones are law enforcement (surveillance), therapeutic (rehabilitation), and crime opportunity prevention. Using the study of U.S. community corrections staff by Miller as a guide, the current study examined the supervision strategy used by Chinese community corrections staff in the Hubei province of China. Chinese community corrections staff were more likely to use the therapeutic and crime opportunity prevention approaches than the law enforcement model. Predictors of each of the three offender supervision approaches differed. The results from Chinese staff were similar in many ways to that found among U.S. staff reported by Miller but differed in some areas. PMID- 30449216 TI - Two Growth Patterns in One Melanoma Lung Metastasis. PMID- 30449217 TI - Real-world treatment patterns, resource use and costs of treating uncontrolled carcinoid syndrome and carcinoid heart disease: a retrospective Swedish study. AB - OBJECTIVES: To quantify healthcare resource use (HRU) and costs in relation to carcinoid syndrome (CS) and carcinoid heart disease (CHD) in a real-world setting, and to provide perspective on treatment patterns. MATERIALS AND METHODS: Patient data and HRU were collected retrospectively from three Swedish healthcare registers. Adult patients diagnosed with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) grade 1 or 2 and CS who purchased somatostatin analogs (SSAs), and experienced controlled (defined by SSAs use) and uncontrolled (defined by SSAs dose escalation) CS for >=8 months during the study period were included. Patients diagnosed with CHD from the date of the GEP-NET diagnosis were included in the CHD study group. RESULTS: Overall, total HRU cost increased with uncontrolled CS and CHD. Total resource cost was 15,500?/patient during controlled CS (8 months), rising to 21,700?/patient during uncontrolled CS (8 months), representing an increase of ~40% (6200?/patient). Costs/patient were driven mainly by SSA use, tumor-related medical interventions and examinations. The total mean cost/year of disease was 1100?/patient without CHD, compared to 4600?/patient with CHD, a difference of 3500?/patient. Excluding SSA cost burden, the main drivers of increased cost in CHD patients were surgical interventions and echocardiography. CONCLUSIONS: This study provides a comprehensive overview of the treatment patterns and burden of uncontrolled CS symptoms and CHD using Swedish national register data. Increases in medical interventions and examinations HRU and increased SSA use suggest that SSA dose escalation alone may not effectively control the symptoms associated with uncontrolled CS, highlighting an unmet treatment need in this patient group. PMID- 30449218 TI - NF-kappaB p65 Knock-down inhibits TF, PAI-1 and promotes activated protein C production in lipopolysaccharide-stimulated alveolar epithelial cells type II. AB - : Purpose/aim: Activated coagulation and reduced fibrinolysis in alveolar compartment are an important characteristics in acute respiratory distress syndrome (ARDS). Alveolar epithelial cell type II (AECII) participates in regulating the intra-alveolar abnormalities of coagulation and fibrinolysis mainly through adjusting the productions of tissue factor (TF), plasminogen activator inhibitor (PAI)-1 and activated protein C (APC) in ARDS. NF-kappaB signal pathway may be involved in coagulation regulation in sepsis-induced ALI. The purpose of this study was to testify the hypothesis that NF-kappaB p65 (p65) knock-down would improve the abnormalities of coagulation and fibrinolysis mediated by lipopolysaccharide (LPS) stimulation in AECII. MATERIALS AND METHODS: p65 gene knock-down in AECII was achieved by small interfering RNA (siRNA) transfection. Rat AECII (RLE-6TN) with or without p65 gene knock-down were stimulated by LPS for 24 hours. And then cytolysate was used for TF, PAI-1 expression examination, and supernatant was collected for TF, PAI-1 and PC concentrations determination. Activation of NF-kappaB canonical pathway was simultaneously checked by western-blotting, RT-PCR and immunofluorescence respectively. RESULTS: TF, PAI-1 expressions in normal cells obviously increased under LPS stimulation with NF-kappaB canonical pathway activation represented by high levels of p65, p-p65, p-IkappaB with increased nuclear translocation of p p65. Cells with NF-kappaB p65 knock-down, however, showed significant decreases in TF, PAI-1, p65, p-p65, p-IkappaB expressions following LPS stimulation with significant reduction in p-p65 nuclear translocation as compared to normal and siRNA control cells. The high concentrations of TF, PAI-1 and low level of APC in supernatant induced by LPS in normal cells were significantly reversed through p65 knock-down. CONCLUSIONS: The experimental findings demonstrate that NF-kB signaling pathway is involved in regulating the expressions of coagulation and fibrinolysis factors in LPS-stimulated AECII, which suggest that NF-kB signaling pathway may be a new target to correct intra-alveolar coagulation and fibrinolytic abnormalities in ARDS. PMID- 30449219 TI - Indoleamine 2,3-dioxygenase as a novel therapeutic target for Huntington's disease. AB - INTRODUCTION: Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder. Despite the severe motor, psychiatric and cognitive symptoms and the great socioeconomic burden caused by the disease, available treatment is mainly symptomatic. The kynurenine pathway (KP) is the main metabolic route of tryptophan degradation, in the course of which several neuroactive compounds are generated. The imbalance of the neurotoxic and neuroprotectant metabolites can lead to excitotoxicity and overproduction of reactive oxygen species, which both contribute to the progression of HD. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme of the KP that has various immune modulatory roles. Areas covered: Current knowledge of the involvement of KP in HD pathogenesis with a particular focus on IDO1. By reviewing the diverse roles of the enzyme in kynurenine production, immune modulation, and serotonin metabolism, we elucidate the factors that make this enzyme a therapeutic target. Expert opinion: Due to the complexity of HD and the various effects that IDO1 exerts, targeting this enzyme, while highly profitable, may be a great challenge. Through IDO1 activity, neurodegeneration, inflammatory processes and depressive symptoms, often related to HD, can be modulated. Ongoing trials of IDO1 inhibitors in other areas of medicine offer advantages for initiating approaches toward this enzyme as a therapeutic target. PMID- 30449220 TI - Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. AB - OBJECTIVE: To review glucose-lowering efficacy and changes in renal function associated with sodium-glucose co-transporter 2 (SGLT2) inhibitors among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). DATA SOURCES: A literature search of MEDLINE and Cochrane databases was performed from 2000 to August 2018 using search terms: SGLT2 inhibitors, sodium glucose co transporter 2, canagliflozin, empagliflozin, dapagliflozin, ertugliflozin, and chronic kidney disease. References of identified articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: English-language studies investigating glucose-lowering endpoints and/or changes in renal function with one of four U.S. approved SGLT2 inhibitors were included. A total of 10 studies met inclusion criteria and are included in this review. RESULTS: In patients with T2DM and CKD, SGLT2 inhibitors are modestly effective in lowering hemoglobin A1C and fasting plasma glucose compared to placebo. Small reductions in eGFR are seen shortly after initiating therapy with SGLT2 inhibitors, but return to baseline levels after discontinuation. SGLT2 inhibitors are associated with a substantial reduction in albuminuria and reduced risk of progression to albuminuria. CONCLUSIONS: In patients with T2DM and CKD, SGLT2 inhibitors have a decreased glucose-lowering effect compared to patients without CKD. Renal benefits among patients with CKD are similar to those without CKD and include a significant reduction in albuminuria and reduced incidence of worsening albuminuria. Given that CKD and T2DM are both associated with increased cardiovascular risk, we believe these agents should considered as preferred add-on agents in most patients with uncontrolled T2DM and eGFR >30 ml/min/1.73 m2. Ongoing studies will provide additional information as to whether these agents should be added to the current standard of care for CKD patients, with and without T2DM. PMID- 30449221 TI - A patent review of the ubiquitin ligase system: 2015-2018. AB - INTRODUCTION: Ubiquitin-proteasome system (UPS) has been validated as a novel anticancer drug target in the past 20 years. The UPS contains two distinct steps: ubiquitination of a substrate protein by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3), and substrate degradation by the 26S proteasome complex. The E3 enzyme is the central player in the ubiquitination step and has a wide range of specific substrates in cancer cells, offering great opportunities for discovery and development of selective drugs. Areas covered: This review summarizes the recent advances in small molecule inhibitors of E1s, E2s, and E3s, with a focus on the latest patents (from 2015 to 2018) of E3 inhibitors and modulators. Expert opinion: One strategy to overcome limitations of current 20S proteasome inhibitors is to discover inhibitors of the upstream key components of the UPS, such as E3 enzymes. E3s play important roles in cancer development and determine the specificity of substrate ubiquitination, offering novel target opportunities. E3 modulators could be developed by rational design, natural compound or library screening, old drug repurposes, and application of other novel technologies. Further understanding of mechanisms of E3-substrate interaction will be essential for discovering and developing next-generation E3 inhibitors as effective anticancer drugs. PMID- 30449222 TI - Intrapartum cardiotocography with and without computer analysis: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate whether intrapartum cardiotocography with computer analysis decreases the incidence of newborn metabolic acidosis or obstetric intervention when compared with visual analysis through a systematic review with meta-analysis of randomized controlled trials. METHODS: The research was conducted using Medline, Embase, Web of Science, Scopus, ClinicalTrial.gov, Ovid and Cochrane Library as electronic databases from the inception of each database to May 2018. Selection criteria included randomized trial evaluating women with cephalic presentation at term or late preterm term during labor who were randomized to electronic fetal heart rate monitoring with either computer analysis (i.e. intervention group) or standard visual analysis (i.e. control group). Trials evaluating antenatal fetal heart rate monitoring in women not in labor were excluded. The primary outcome was incidence of newborn metabolic acidosis, defined as pH less than 7.05 and base deficit greater than 12 mmol/L. Secondary outcomes were mode of delivery, admission to neonatal intensive care unit, hypoxic-ischemic encephalopathy, and perinatal death. The summary measures were reported as relative risk (RR) with 95% confidence interval (CI). RESULTS: Three randomized controlled trials (RCTs), including 54,492 participants, which met inclusion criteria for this meta-analysis, were analyzed. All the included trials enrolled women with cephalic presentation at term or late preterm. Women were randomized in the active first stage of labor and all of them received continuous cardiotocography (CTG) from randomization until delivery. Women who received continuous CTG during labor with computerized analysis had similar risk of newborn metabolic acidosis. No between group differences were found in the secondary outcomes. CONCLUSIONS: Compared with visual analysis, use of computer analysis of fetal monitoring signals during labor did not significantly reduce the rate of metabolic acidosis or obstetric intervention. PMID- 30449223 TI - rFVIIIFC for hemophilia A prophylaxis. AB - INTRODUCTION: rFVIIIFC was the first extended half-life product to complete the phase 3 development program and be registered. It was developed to reduce the high treatment burden imposed by prophylaxis. It is now one of four extended half life products available for a variety of indications in hemophilia A. This article focus on the efficacy use of rFVIIIFC in the prevention of bleeds in hemophilia A. Areas covered: This article provides an update on efficacy data from three clinical studies describing the use of rFVIIIFC in the treatment and prevention of bleeds in hemophilia A. The update includes the efficacy use of rFVIII in all age groups, in the perisurgical setting, in immune tolerance induction and in improving the quality of life of patients. The role of rFVIIIFC prophylaxis in the face of rapidly evolving non-replacement therapy and gene therapy is summarized. Expert commentary: The role of rFVIIIFC in hemophilia A prophylaxis is uncertain in the light of development of newer prophylaxis agents with better route of administration, improved pharmacokinetic and superior efficacy profiles. Whilst rFVIIIFC was primarily developed for prophylaxis in hemophilia A, this role may change in the face of competitive extended half-life products and non-replacement therapies. PMID- 30449224 TI - New mutation causing androgen insensitivity syndrome - a case report and review of literature. AB - Androgen insensitivity syndrome (AIS) is a congenital disorder in which a defect in the androgen receptor (AR) gene leads to cellular resistance to androgens. Defects in the AR gene, located on the X chromosome, result in the development of a feminine phenotype in chromosomally male (46, XY) individuals. In this case report, we present a 44 years old patient with complete androgen insensitivity syndrome (CAIS) initially presenting with primary amenorrhea. The patient underwent a full clinical evaluation, revealing hypoplastic vagina and a lack of uterus and ovaries. Hormonal evaluation revealed markedly elevated testosterone, FSH, and LH serum concentrations. Diagnostic imaging, including pelvic MRI, confirmed the presence of two solid masses in the inguinal canals (right 26 * 13 mm, left 25 * 15 mm). The patient underwent genetic testing, revealing a 46 XY karyotype and an as of yet unprecedented androgen receptor mutation. The type of the mutation was a single-base exchange - the substitution from cytosine to thymine in chromosome X:66942710 position (referred to human reference genome GRCh37), which has resulted in an amino acid changes from leucine (CTT) to phenyloalanine (TTT) in ligand-binding domain. PMID- 30449226 TI - Teixobactin: a novel anti-infective agent. PMID- 30449225 TI - Halfway Out: An Examination of the Effects of Halfway Houses on Criminal Recidivism. AB - Halfway houses are a form of community supervision and correctional programming that have become a staple intervention in recent years. Despite the ingrained belief in their benefits with respect to successful reintegration, this assumption may not be justified based on the existing literature. The current study provides a systematic review and meta-analysis of nine studies examining the effects of halfway houses on recidivism. Overall, the findings suggest that halfway houses are an effective correctional strategy for successful reentry (log odds ratio [LOR] = 0.236, z = 9.27, p < .001). Further work is needed to determine best practices for programming and meeting the needs of different participants. PMID- 30449227 TI - Distress and resilience associated with workload of medical students. AB - BACKGROUND: University students face numerous stressors during their study curricula, which require adequate resilience to ensure healthy adaptation. AIMS: To examine how relationships between study workload and mental health problems are moderated by resilience. Secondly, to compare our findings with other studies and assess differences in resilience and distress between medical and non-medical students. METHODS: A prospective quantitative design was used. Participants completed a questionnaire package assessing resilience resources (Resilience Scale for Adults) and mental health (Core-OM: Clinical outcomes in routine evaluation - outcome measure) under three different conditions: heavy, low or regular workload. RESULTS: During heavy workload, significantly higher distress score was found among medical students compared to other students (1.46 vs. 1.25; p < 0.05). Medical students had slightly higher overall resilience scores (5.21 vs. 4.94; p > 0.05). During heavy workload up to 20% of the participants had higher distress score than clinical samples' average from other studies. RSA score and Core-OM scores were inversely dependent (p < 0.0001; r= -0.434). CONCLUSION: Findings suggest that distress mediated by heavy workload does not significantly affect resilience. Many students, especially medical, are experiencing high levels of distress. Resilience is associated with the decrease in distress. PMID- 30449228 TI - Serum neopterin as well as ferritin, soluble interleukin 2 receptor, KL-6 and anti-MDA5 antibody titer provide markers of the response to therapy in patients with interstitial lung disease complicating anti-MDA5 antibody positive dermatomyositis. AB - OBJECTIVE: This study identified biomarkers that can be used to assess disease activity and response to therapy in patients with interstitial lung disease complicating anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab) positive clinically amyopathic dermatomyositis (CADM). METHODS: In 15 patients with interstitial lung disease complicating anti-MDA5 Ab-positive CADM, anti-MDA5 Ab, neopterin, interleukin (IL)-18, ferritin, and soluble interleukin 2 receptor (sIL-2R) levels were measured in cryopreserved serum specimens before and at multiple times after remission induction therapy, and their correlations were assessed. RESULTS: Anti-MDA5 Ab, neopterin, IL-18, ferritin, and sIL-2R levels did not differ significantly between patients who survived and those who succumbed to the disease. In many cases, serum anti-MDA5 Ab titers were over the upper limit (over 150 index value) before treatment in the usual measuring method, and gradually decreased to the normal range at stable phase. Meanwhile, serum neopterin levels (21.6 [15.3-48.3] nmol/L) were significantly elevated in newly diagnosed patients and fell to 6.8 (5-11.4) nmol/L at 6 months after treatment introduction. CONCLUSIONS: Elevated serum neopterin as well as ferritin, sIL-2R, KL-6, and anti-MDA5 Ab titer might help identify patients with interstitial lung disease complicated with DM and might be useful in monitoring response to therapy. PMID- 30449229 TI - Breast metastasis two years after pelvic surgery and adjuvant chemotherapy for serous ovarian cancer. AB - Ovarian cancer is considered the leading cause of death among gynecologic neoplasias. Breast metastases from primary ovarian cancer have been reported in only 0.03-0.6% of all breast cancers. A 38-year-old female, multipara, affected by advanced ovarian cancer and undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and pelvic peritonectomy two years earlier, was discovered to have a breast metastasis. She underwent a quadrantectomy (QSI) with an open biopsy of nodularity attached to the pectoral muscle fascia: on definitive histological characterization the breast lesions showed a high-grade invasive carcinoma, with papillary serum differentiation, and the immunohistochemistry study of breast lesion showed positivity for cytokeratin 7 and an extensive positivity for Wilm's tumor (WT)-1 and paired box 8 (PAX8). These aspects are indicative of mammary metastasis from carcinoma of ovarian origin. Despite their rarity, metastases to breast from ovarian cancer should be considered possible because their recognition and differentiation compared to primary tumors are crucial for prognosis. Future clinical studies on MOCB should be performed to discover new specific markers for a more accurate histopathological diagnosis and to establish the real need of surgical treatment. PMID- 30449230 TI - Age and Gender Measurement Noninvariance of the Adult ADHD Self-Report Scale Screener. AB - OBJECTIVE: The nature and form of demographics-related differences in ADHD self reported symptoms across adulthood is currently poorly understood. This study explored the psychometrics of the Adult ADHD Self-Report Scale Screener (ASRS-6), including its age- and gender-related measurement invariance. METHOD: Structural equation models were used to analyze adult data-aged 16 to 95 years-from the 2007 British Adult Psychiatric Morbidity Survey. RESULTS: The three-factor model (disorganization, inattention, hyperactivity) outperformed one- and two-factor models. Self-reported attentional deficits may be more pathognomonic of overall self-reported ADHD in adults than other symptoms. All items exhibited age measurement noninvariance while only a subset exhibited gender measurement noninvariance. Individuals who are male and younger tend to have lower thresholds for endorsement for ASRS-6 items than individuals who are female and older. CONCLUSION: The ASRS-6 does not appear to be unidimensional, and self-reported ASRS-6 symptomatology changes in meaning with age. PMID- 30449232 TI - Who Supports Honor-Based Violence in the Middle East? Findings From a National Survey of Kuwait. AB - This study reports findings from what is, to the authors' knowledge, the first nationally representative survey of public attitudes toward honor-based violence (HBV) in a Middle East country affected by such violence, and one of very few if any such national surveys undertaken in any context. In a telephone survey of 1,050 adult citizens of the Arab Gulf state of Kuwait, we collect attitudinal and behavioral measures of support for HBV. Facilitated by vignettes, item order randomization, and other survey best practices designed to reduce social desirability bias, the survey measures both support for HBV in principle and support for legislation permitting it. We also assess the correlates of views toward honor-based crimes, including demographic attributes (age, sex, and education), social indicators (economic status, religiosity, and tribal attachment), and political indicators (political interest, engagement, and ideology). These unique data permit investigation into the individual-level predictors of support for HBV among citizens of a country that has experience with HBV and laws that afford reduced punishment for perpetrators of honor killing. Results reveal, first, considerable levels of public support in Kuwait for HBV. Half of citizens report agreement that physical violence is justified as punishment for female adultery, whereas a third of both men and women say they would support a law permitting violence against a female adulterer. The strongest positive predictors of individual support for HBV are tribal attachment, religiosity, and support for political Islam. Surprisingly perhaps, permissive views of HBV are most likely among the youngest generation of Kuwaitis. The findings have important implications for understanding the factors that help explain the existence and persistence of HBV in the Middle East, in Islamic contexts, and elsewhere where it occurs. PMID- 30449231 TI - Short-term effects of surgical weight loss after sleeve gastrectomy on sex steroids plasma levels and PSA concentration in men with severe obesity. AB - Male obesity is known to be associated with hypogonadism, which can be reverted after surgical weight reduction. However, the evidence about how rapidly this effect rises after surgery and what consequences each procedure have on prostate function and prostatic-specific antigen (PSA) concentration is scarce. So, we evaluated total testosterone, estradiol, luteinizing hormone, follicle stimulating hormone and PSA plasma levels in a group of 29 Caucasian obese men (BMI - 43.4 +/- 8.5 kg/m2) before and one month after sleeve gastrectomy. 19 lean healthy male subjects were considered as controls. As expected, obese patients showed a high prevalence of hypogonadism (51.6%) at baseline, with reduced total testosterone compared to lean controls (10.8 +/- 3.5 vs 15.7 +/- 4.2 nmol/l, p < .01), higher estradiol (124.4 +/- 46.5 vs 78.7 +/- 39.6 pmol/l, p < .01), lower luteinizing hormone and follicle stimulating hormone (3.6 +/- 1.3 and 2.5 +/- 0.9 vs 5.2 +/- 2.4 and 5.9 +/- 3.8 U/L, respectively, p < .05) plasma levels. One month after surgery, patients showed a significant body weight reduction (-17.2 +/- 6.7 kg) with increased total testosterone (from 10.8 +/- 3.5 to 18.9 +/- 4.9 nmol/l, p < .001), reduced estradiol (from 124.4 +/- 46.5 to 96.1 +/- 34.3 pmol/l, p < .05) and increased PSA (from 0.74 +/- 0.38 to 1.0 +/- 0.51 MUg/l, p < .001). These results confirm that hypogonadism is highly prevalent in obese males, but they also show that it can be early reversed after sleeve gastrectomy, further confirming the strong indication to surgery of hypogonadal patients with severely reduced quality of life. Higher testosterone levels may be responsible for the increase of PSA observed after surgery; however, PSA concentration has to be monitored over time to avoid underrating of potential severe prostate diseases. PMID- 30449233 TI - Oral Desensitization to Peanuts. PMID- 30449235 TI - Temporal variations of nucleosides and nucleotides in rabbit milk. AB - Nucleotides and nucleosides have a preeminent role in physiological and biochemical processes for newborns, the major source of these during early development is the breast milk. Different biomolecules exhibit daily fluctuations in maternal milk that could transfer temporal information that synchronize newborn circadian system. As a first approach, we characterized the diurnal profile of nucleotides and nucleosides contained in maternal milk of rabbits during the first week of lactation. It is possible that some nucleosides, such as adenosine, play a relevant role in setting up the emerging circadian rhythmicity, whereas uridine and guanosine could participate in the maintenance of rhythmicity. PMID- 30449236 TI - Commentary on infected penile prosthesis: literature review highlighting the status quo of prevention and management. PMID- 30449237 TI - Sex-Specific Longitudinal Modeling of Youth Peak Oxygen Uptake. AB - PURPOSE: To investigate peak oxygen uptake ([Formula: see text]) in relation to sex, age, body mass, fat-free mass (FFM), maturity, and overweight status. METHODS: Multiplicative, allometric models of 10- to 18-year-olds were founded on 1057 determinations of peak [Formula: see text] supported by anthropometry and estimates of maturity status. RESULTS: Baseline models with body mass controlled for showed age to exert a positive effect on peak [Formula: see text], with negative estimates for age2, sex, and a sex-by-age interaction. Sex-specific models showed maturity status to have a positive effect on peak [Formula: see text] in addition to the effects of age and body mass. Introducing skinfold thicknesses to provide, with body mass, a surrogate for FFM explained maturity effects and yielded a significantly (P < .05) better statistical fit in all models compared with those based on FFM estimated from youth-specific skinfold equations. With girls only, the introduction of overweight, defined by body mass index, resulted in a small but significant (P < .05) negative effect, with an age by-overweight status interaction. CONCLUSIONS: FFM has a powerful influence on peak [Formula: see text] in both sexes. Interpretation of the development of youth aerobic fitness and its application to health should reflect the sex- and maturity-associated variation in FFM. PMID- 30449234 TI - AR101 Oral Immunotherapy for Peanut Allergy. AB - BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .). PMID- 30449238 TI - Effects of RhoA and RhoC upon the sensitivity of prostate cancer cells to glutamine deprivation. AB - RhoA and RhoC contribute to the regulation of glutamine metabolism, which is a crucial determinant of cell growth in some types of cancer. Here we investigated the participation of RhoA and RhoC in the response of prostate cancer cells to glutamine deprivation. We found that RhoA and RhoC activities were up- or downregulated by glutamine reduction in PC3 and LNCaP cell lines, which was concomitant to a reduction in cell number and proliferation. Stable overexpression of wild type RhoA or RhoC did not alter the sensitivity to glutamine deprivation. However, PC3 cells expressing dominant negative RhoAN19 or RhoCN19 mutants were more resistant to glutamine deprivation. Our results indicate that RhoA and RhoC activities could affect cancer treatments targeting the glutamine pathway. PMID- 30449239 TI - Majority group children expect that ethnic out-group peers feel fewer positive but more negative emotions than in-group peers. AB - Across two studies majority group children's (8-13 years) perception of positive and negative emotions in ethnic in-group and disadvantaged ethnic out-group peers was examined. Study 1 (N = 302) showed that children expected in-group peers to feel better in a positive situation compared to out-group peers. Whereas, in a negative situation, children expected in-group peers to feel less bad compared to out-group peers, particularly when they evaluated the in-group as very positive. Study 2 (N = 201) replicates these findings across multiple positive and negative situations, and additionally shows that in very negative situations children expect in-group and out-group peers to feel equally bad. These results suggest that children's perception of emotions in others is influenced by ethnic group membership. PMID- 30449240 TI - Techniques and considerations for monitoring swimmers' passive drag. AB - Drag is the resistant force that opposes a swimmer displacing through water and significantly affects swimming performance. Drag experienced during active swimming is called active drag (Da), and its direct determination is still controversial. By contrast, drag experienced while gliding in a stable streamlined body position is defined as passive drag (Dp), and its assessment is widely agreed upon. Dp reduction preserves the high velocity gained with the push off from the starting block or wall after starting and turning or improves the gliding phase of the breaststroke cycle. Hence, this paper reviewed studies on swimming that measured Dp under different conditions of gliding. In the present research, accurate descriptions of the main methods used to directly or indirectly determine Dp are provided and the main advantages, limitations and critical features of each method are discussed. Since Dp differs in methods but not in reported values and is consistent regardless of the measuring method, the information provided in this paper might allow coaches and practitioners to identify the most suitable method for assessing and determining the drag of their swimmers. PMID- 30449241 TI - The bacterial siderophore enterobactin confers survival advantage to Salmonella in macrophages. AB - Enterobactin (Ent), a prototypical bacterial siderophore known for its unparalleled affinity for iron, is widely conserved among members of the Enterobacteriaceae family of Gram-negative bacteria. In this study, we demonstrated that, aside from mediating iron acquisition, Ent also dampened the macrophages (MPhis) antimicrobial responses against intracellular infection by Salmonella enterica serovar Typhimurium. Accordingly, the loss of Ent expression (DeltaentB) in Salmonella demoted their survivability against MPhis. Addition of exogenous Ent not only rescued the survival of DeltaentB Salmonella, but also augmented WT Salmonella to better withstand the microbicidal activity of MPhis. The protection conferred to WT Salmonella was observed only when Ent was administered as iron-free, thus indicating the requirement of iron chelation in this context. In contrast, the exogenous iron-bound Ent retained its ability to promote the survival of DeltaentB Salmonella, albeit modestly. Assessment on MPhis labile iron pool (LIP) revealed that iron-free Ent is able to permeate into MPhis, chelate the intracellular LIP, and regulate the expression of several key iron-regulatory proteins, i.e., divalent metal transporter 1, ferroportin, and hepcidin. Chelation of iron by Ent was also observed to promote the MPhis towards M2 polarization. Collectively, our findings demonstrated that Ent not only facilitates bacterial iron uptake but also disrupts MPhis iron homeostasis and M1/M2 polarization to safeguard intracellular bacteria against the anti-bacterial effects of their host. PMID- 30449242 TI - Length of Women's Stays in Domestic Violence Shelters: Examining the Contribution of Background Variables, Level of Violence, Reasons for Entering Shelters, and Expectations. AB - Women's shelters are one of the most important services established for women who are victims of intimate partner violence against women (IPVAW). Studies indicate that women undergo positive processes in shelters, and the longer the stay in the shelter, the more successful the woman will be in leaving the cycle of violence. However, the literature also reveals a remarkable variance in the length of women's shelter stays, and very little research has been conducted to understand the factors contributing to this variance. The current research focused on the contribution of demographics (ethnic origin, age, education, number of children, and employment situation), history of violence (level of violence, characteristics of violence, and separation attempts from the partner), reasons for entering the shelter, and expectations of the shelter framework to the length of women's shelter stays. Research participants consisted of 506 women living in 12 shelters in Israel. The findings revealed a variance in the length of the women's stays in accordance with their ethnic origins. Women who had immigrated to Israel from Ethiopia or from the former Soviet Union (FSU) stayed in shelters for longer periods of time than did Israeli-born Arab women, who stayed in shelters for significantly shorter periods of time than did Israeli-born Jewish women. There was no contribution of the demographic variables to the variance of length of the woman's shelter stay. In addition, previous separations, emotional abuse, and applying to the shelter following the decision of a child protection worker explained 12% of the variance in the length of the woman's shelter stay. The findings point to a specific profile that seems to predict a woman's longer stay in shelters for women who are victims of intimate partner violence. PMID- 30449243 TI - Telehealth model of care for routine follow up of renal transplant recipients in a tertiary centre: A case study. AB - Royal Melbourne Hospital (RMH) performs over 140 kidney transplant operations annually. Kidney transplant recipients require regular medical review, which results in loss of time and costs from travel, particularly for regional patients, and places high demand on the hospital outpatient service. The RMH renal transplant unit initiated a telehealth service in 2016 to provide cost effective, patient-centred clinical care for regional patients. To date, 263 clinical reviews have been conducted via telehealth, potentially saving 203,202 kilometres in travel distance; 2771 hours in car travel time; an estimated AUD $31,048 in petrol savings and 51 tonnes CO2 equivalents of greenhouse gas emissions. Lessons learnt have included the importance of using technology that allows patients to access telehealth from their place of choice. The option of a joint consultation with local healthcare providers has facilitated the development of extended care networks for our patients. Incorporation of telehealth into our outpatient system has been achieved with the existing nephrology workforce, making it a sustainable long-term review option. Our renal transplant telehealth outpatient clinic has been a successful change in the way we provide care to regional patients. Formal comparison of clinical outcomes and the patient experience of telehealth versus in person reviews are underway. PMID- 30449244 TI - Immune/microbial interface perturbation in human IgA deficiency. AB - In a recently published article we report the metagenomic analysis of human gut microbiomes evolved in the absence of immunoglobulin A (IgA). We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. While our study underlines a rather expected pathobiont expansion, we at the same time highlight a less expected depletion in some typically beneficial symbionts. We also show that IgM partially supply IgA deficiency, explaining the relatively mild clinical phenotype associated with the early steps of this condition. Microbiome studies in patients should consider potential issues such as cohort size, human genetic polymorphism and treatments. In this commentary, we discuss how such issues were taken into account in our own study. PMID- 30449245 TI - Risk stratification in breast screening: A word of caution. PMID- 30449246 TI - In response to: New data for venous thromboembolism in patients with small cell lung cancer: A review. PMID- 30449247 TI - Association of physical activity on the functional connectivity of the hippocampal-orbitofrontal pathway. AB - OBJECTIVE: The objective of the study is to examine the association between physical activity and hippocampal-orbitofrontal functional connectivity. METHODS: Data from the Nathan Kline Institute-Rockland Sample was utilized, which consisted of 366 participants (Mage = 43 years; 63% female). Physical activity was self-reported using the International Physical Activity Questionnaire. Hippocampal-orbitofrontal functional connectivity was assessed from magnetic resonance imaging. RESULTS: Moderate-intensity physical activity was not statistically significantly associated with left hippocampal-orbitofrontal connectivity (beta = 0.001; 95% CI: -0.02, 0.03; P = 0.90) or right hippocampal orbitofrontal connectivity (beta = 0.01; 95% CI: -0.01, 0.04; P = 0.22). However, vigorous-intensity physical activity was statistically significantly associated with right hippocampal-orbitofrontal connectivity (beta = 0.01; 95% CI: 0.004, 0.02; P = 0.002). DISCUSSION: Habitual engagement in intense physical activity was associated with greater hippocampal-orbitofrontal connectivity, while moderate activity engagement was not. This may have important implications for the exercise neurobiology field in the context of exercise and memory function, suggesting that intense activity may facilitate cognitive/memory functions. However, our findings should be interpreted with caution given the relatively weak associations that were observed. PMID- 30449248 TI - Criterion-related validity of self-report walking time from the EPIC questionnaire in older adults. AB - Tools for measuring walking time make use of objective and subjective methods. One subjective approach is to administer physical activity questionnaires (PAQ), mainly because they are inexpensive and easy to give to large groups. The European Prospective Investigation into Cancer and Nutrition (EPIC) study has a brief PAQ (EPIC-PAQ) and includes one question referencing walking time. The objective of this study was to assess the validity of the question about time spent walking included in the EPIC-PAQ. The sample included 200 older adults (113 women). To assess daily walking time, participants responded to the EPIC-PAQ in an interview and wore a portable gait analysis system and physical activity monitor for 48 consecutive hours in free-living condition. Results indicated that the mean of bias between the EPIC-PAQ and objetive measurement was -64.6 min/day. Also, the correlation was low compared to an objective measurement (rho = 0.196) and was positively correlated with the time spent at speeds below 2.5 mph but the correlation was low (slow walking rho = 0.154 and pace walking rho = 0.163). The EPIC-PAQ shows low correlations with the objective measurement of walking time, that suggests it may be inaccurate and affecting the estimate of the EPIC-PAQ's PA energy expenditure in this age group. PMID- 30449249 TI - Reply to the Editor. PMID- 30449250 TI - Clinical outcomes and survival rate of cementless modular distal fixation femoral stem for revision hip arthroplasty: A minimum 6-year follow-up. AB - PURPOSE:: Revision hip arthroplasty is a very challenging procedure. Use of a modular distal fixation stem is one of the available options for revision arthroplasty in patients with proximal femoral bone deficiency. The purpose of this study was to evaluate mid- to long-term outcomes of cementless modular distal fixation femoral stem implantation in revision hip surgery. METHODS:: Clinical and radiological findings, complications, and stem survival rate were analyzed for 46 patients (48 hips) who underwent revision hip arthroplasty using a cementless modular distal fixation femoral stem. The mean patient age was 58.8 years (range 31-82 years) and the mean follow-up period was 95 months (72-122 months). The preoperative diagnoses were aseptic loosening (36 hips), infection (4 hips), ceramic fracture (4 hips), and femoral periprosthetic fracture (4 hips). RESULTS:: The mean Harris hip score improved from 56.6 preoperatively to 88.2 postoperatively at the last follow-up. All hips showed stable osteointegration and firm fixation. Complications involved four hips (8.3%); there was one case each of periprosthetic fracture, delayed union of osteotomy site, femoral perforation, and infection. One stem re-revision was performed for deep infection of the femoral side. The Kaplan-Meier survival rate was 97.6% at the final follow-up. CONCLUSION:: Revision hip arthroplasty using a cementless modular distal fixation femoral stem showed satisfactory initial firm fixation and mid- to long-term survival rate. Complications can be minimized by careful surgical planning and meticulous procedure. PMID- 30449251 TI - The circulation of penicillin in Spain: health, wealth and authority. PMID- 30449252 TI - Different visual stimuli affect muscle activation at the knee during sidestepping. AB - Increasing knee stability via appropriate muscle activation could reduce anterior cruciate ligament (ACL) injury risk during unplanned sidestepping. High-level athletes may activate their knee muscles differently from low-level athletes when responding to quasi-game realistic versus non game-realistic stimuli. Eleven high level and 10 low-level soccer players responded to a non game-realistic arrow planned condition (AP), a quasi game-realistic one-defender scenario (1DS) and two-defender scenario (2DS), and an arrow-unplanned condition (AUNP), that imposed increasing time constraints to sidestep. Activation from eight knee muscles during sidestepping was measured during pre-contact and weight acceptance. Knee flexor-extensor co-activation ratios were established. Muscle activation levels increased by approximately 27% solely in the 1DS in both sidestepping phases. In the 2DS, the shift from a flexor dominant co-activation strategy in pre-contact toward extensor dominance in weight-acceptance commenced earlier for the high-level players. Quasi game-realistic information allowed for anticipatory increases in knee muscle activation regardless of expertise levels but only when the time demands to respond were low (1DS). High-level players were better at interpreting complex game-realistic information (2DS) to activate their knee extensors earlier in preparation for single-leg landing during weight acceptance. PMID- 30449253 TI - Dissection of binding of trypsin to its natural inhibitor Gensenoside-Rg1 using spectroscopic methods and molecular modeling. AB - The interaction of trypsin with Gensenoside-Rg1 (G-Rg1) was studied using fluorescence, ultraviolet-visible (UV-vis), and circular dichroism (CD) spectroscopies along with enzyme activity assay and molecular docking. The enzyme activity assays showed that G-Rg1 inhibited the activity of trypsin effectively. The fluorescence experiments indicated that a complex of G-Rg1-trypsin was formed and that the fluorescence of trypsin was quenched by G-Rg1 via a mixed-quenching mechanism (both static and dynamic quenching). The thermodynamic analysis suggested that hydrophobic interaction and hydrogen bond were the major forces between G-Rg1 and trypsin. According to the theory of Forster's non-radiation energy transfer, the binding distance between trypsin and G-Rg1 was calculated to be 2.01 nm, which implies that energy transfer occurred within the complex. The experimental results obtained from UV-vis absorption spectra, synchronous fluorescence spectra, and CD spectra indicated that G-Rg1 was mainly located on tryptophan moiety and that the interaction between G-Rg1 and trypsin led to conformational changes of trypsin with some alpha-helix and unordered coil structures being transformed into beta-sheet structures. In addition, docking results supported the above experimental findings and suggested the possible binding location of G-Rg1 on trypsin along with the possible hydrogen bonds and hydrophobic interactions between G-Rg1 and trypsin. The experimental results from this study should be useful to minimize the antinutritional effects and make full use of Genseng extracts in the food industry and also be helpful to the design of the drugs for the diseases related to overexpression of trypsin. Communicated by Ramaswamy H. Sarma. PMID- 30449254 TI - DPSCs seeded in acellular nerve grafts processed by Myroilysin improve nerve regeneration. AB - Since synthetic nerve conduits do not exhibit ideal regeneration characteristics, they are generally inadequate substitutes for autologous nerve grafts in the repair of long peripheral nerve defects. To resolve this problem, in this study, a nerve regeneration acellular nerve graft (ANG) with homologous dental pulp stem cells (DPSCs) was constructed. Xenogeneic ANG was processed by Myroilysin to completely remove cells and myelin sheath, while preserving extracellular matrix (ECM) microstructure of the natural nerve. The study revealed that ANG could support cell attachment and proliferation and did not stimulate a vigorous host rejection response. After inoculation of rabbit DPSCs (r-DPSCs) onto ANG, cells were observed to align along the longitudinal axis of the acellular nerve matrix (ANM) and persistently express NGF and BDNF. Undifferentiated r-DPSCs also presented glial cell characteristics and promoted nerve regeneration after transplantation in vivo. We repaired 1 cm purebred New Zealand White Rabbits sciatic nerve defects using this nerve graft construction, and nerve gap regeneration was indicated by electrophysiological and histological analysis. Therefore, we conclude that the combination of an ANG processed by Myroilysin with DPSCs providing a microenvironment that increases nerve regeneration for repairing peripheral nerve defects. PMID- 30449255 TI - Long-Term clinical and radiographic outcomes and patient satisfaction after adult spinal deformity correction. AB - BACKGROUND AND AIMS:: Adult spinal deformity surgery has increased with the aging population and modern surgical approaches, although it has high complication and reoperation rates. The permanence of radiographic correction, mechanical complications, predictive factors for poor patient-reported outcomes, and patient satisfaction were analyzed. MATERIAL AND METHODS:: A total of 79 adult patients were retrospectively analyzed at baseline and 1-9 years after adult spinal deformity correction between 2007 and 2016. Patient-reported outcomes (Oswestry Disability Index, visual analog scale, and Scoliosis Research Society-30 scores), changes in radiographic alignment, indications for reoperation, predictors of poor outcomes according to the Oswestry Disability Index and Scoliosis Research Society-30 scores, and patient satisfaction with management were studied. RESULTS:: Oswestry Disability Index and visual analog scale scores (p = 0.001), radiographic correction of thoracic kyphosis, lumbar lordosis, and pelvic retroversion (p ? 0.001) and sagittal vertical axis (p = 0.043) were significantly better at 4-5 years of follow-up than at baseline. The risk for the first reoperation owing to mechanical failure of instrumentation or bone was highest within the first year, at 13.9% (95% confidence interval = 8.0%-23.7%), and 29.8% (95% confidence interval = 19.4%-43.9%) at the 5-year follow-up. Oswestry Disability Index and Scoliosis Research Society-30 total scores had a good correlation (r = -0.78; 95% CI = -0.86 to -0.68; p < 0.001). Satisfaction with management was correlated with patient-reported outcomes. Male sex and depression (p = 0.021 and 0.018, respectively) predicted poor outcomes according to the Oswestry Disability Index and/or Scoliosis Research Society-30 score. CONCLUSION:: The achieved significant radiographic correction was maintained 5 years postoperatively. Despite reoperations, patient satisfaction and clinical outcomes were good. Depression and male sex predicted poor clinical outcomes. PMID- 30449256 TI - Synthesis and in vitro evaluation of antiviral and cytostatic properties of novel 8-triazolyl acyclovir derivatives. AB - As a part of the research aimed on identification of new nucleobase derivatives with improved biological properties, a series of novel 8-substituted acyclovir derivatives were synthesized. The 8-azidoguanosine 4 and novel 8-azidoacyclovir 9 were synthesized from commercially available guanosine 1 and acyclovir 6 which were transformed into 8-bromopurine derivatives 2 and 7 and hydrazine derivatives 3 and 8, respectively. 8-Triazolylguanosine 5 and 8-triazolylacyclovir analogs 10 12 were successfully synthesized via the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of azides 4 and 9 with propargyl alcohol, 4-pentyn-1-ol and 5-hexyn-1-ol. The novel 1,4-disubstituted 1,2,3-triazolyl compounds 5, 10-12 were evaluated for antiviral activity against selected DNA and RNA viruses and cytostatic activity against normal Madine Darby canine kidney (MDCK I) cells, and seven tumor cell lines (HeLa, CaCo-2, NCI-H358, Jurkat, K562, Raji and HuT78). While tested compounds exerted no antiviral activity at nontoxic concentrations, the 8-triazolyl acyclovir derivative 10, with the shortest alkyl substituent at the C-4 of triazole ring, was found to be the most active against the CaCo-2 cell line. PMID- 30449257 TI - Returning to Social Life: Development of Social Identity for Adolescent and Young Adult Survivors of Leukemia in Korea. AB - OBJECTIVE: The purpose of this study is to investigate the life experiences and processes that occur as adolescent and young adult leukemia survivors return to social life using grounded theory. METHOD: This study comprised 14 adolescents and young adults who visited a hospital for follow-up care after treatment of leukemia. We used in-depth interviews to examine the participants' experiences in returning to social life. The semistructured questionnaire examined "good and bad experiences in returning to social life," "sources of happiness and stress," and "strategies for managing stressful events." RESULTS: We extracted 6 categories and 21 concepts from the interviews. We grouped the 6 categories into a core category and three phases: "catching up with others," "discovering myself," and "planning my future." A core category shown through all phases was "fear of recurrence." The "catching up with others" phase included themes of "feeling different from others" and "wanting to be like others." The "discovering myself" phase included "completing one thing at a time" and "recognizing myself as special." The "planning my future" phase included "looking for things I can do." CONCLUSIONS: Self-esteem was an important issue for adolescent leukemia survivors; negative illness perception affected self-esteem in both adolescents and young adults. It is important for health care providers to develop programs to help adolescent and young adult leukemia survivors to perceive their disease experiences more positively and to take part in social life, including school life. PMID- 30449258 TI - Pharmacoinformatics-based identification of chemically active molecules against Ebola virus. AB - Ebola is a dangerous virus transmitted by animals and humans and to date there is no curable agent for such a deadly infectious disease. In this study, pharmacoinformatics-based methods were adopted to find effective novel chemical entities against Ebola virus. A well predictive and statistical robust pharmacophore model was developed from known Ebola virus inhibitors collected from the literature. The model explained the significance of each of hydrogen bond acceptor and donor, and two hydrophobic regions for activity. The National Cancer Institute and Asinex (Antiviral library) databases were screened using the final validated pharmacophore model. Initial hits were further screened with a set of criteria and finally eight molecules from both databases were proposed as promising anti Ebola agents. Further molecular docking and molecular dynamics studies were carried out and it was found that the proposed molecules possessed capability to interact with amino residues of Ebola protein as well as retaining equilibrium of protein-ligand systems. Finally, the binding energies were calculated using MM-GBSA approach and all proposed molecules showed strong binding affinity towards the Ebola protein receptor. PMID- 30449259 TI - Dual controlled release nanomicelle-in-nanofiber system for long-term antibacterial medical dressings. AB - Long-term antibacterial medical dressings can prevent infection as skin wounds heal. In this study, we used the hydrophobic antibacterial drug amoxicillin as a model to prepare drug-loaded nanomicelles using a film dispersion-hydration method, and drug-loaded nanomicelles were coaxially electrospun into nanofiber to create a novel nanomicelle-in-nanofiber (NM-in-NF) drug delivery system. Scanning electron microscopy and transmission electron microscopy were used to characterize the morphology of nanomicelles and nanofibers. Thermal property of as-prepared samples was tested using differential scanning calorimetry. The drug release behavior, cytotoxicity, and antibacterial properties of NM-in-NFs were examined in vitro to evaluate the system's potential to be used in the treatment of skin wounds. Experimental results indicated that the novel NM-in-NF system had dual controlled release effect, which greatly reduced burst release and prolonged effective drug duration. Moreover, NM-in-NFs was also found to be safe and non toxic, with a broad-spectrum antibacterial activity. It thus could potentially be used in long-term antibacterial medical dressings to treat skin wounds. PMID- 30449260 TI - Postoperative opioid prescribing patterns and use after vascular surgery. AB - The aim of this study was to assess postoperative opioid prescribing patterns, usage, and pain control after common vascular surgery procedures in order to develop patient centered best-practice guidelines. We performed a prospective review of opioid prescribing after seven common vascular surgeries at a rural, academic medical center from December 2016 to July 2017. A standardized telephone questionnaire was prospectively administered to patients ( n = 110) about opioid use and pain management perceptions. For comparison we retrospectively assessed opioid prescribing patterns ( n = 939) from July 2014 to June 2016 normalized into morphine milligram equivalents (MME). Prescribers were surveyed regarding opioid prescription attitudes, perceptions, and practices. Opioids were prescribed for 78% of procedures, and 70% of patients reported using opioid analgesia. In the prospective group, the median MMEs prescribed were: VEIN (31, n = 16), CEA (40, n = 14), DIAL (60, n = 17), EVAR (108, n = 8), INFRA (160, n = 16), FEM TEA (200, n = 11), and OA (273, n = 4). The median proportion of opioids used by patients across all procedures was only 30% of the amount prescribed across all procedures (range 14-64%). Patients rated the opioid prescribed as appropriate (59%), insufficient (16%), and overprescribed (25%), and pain as very well controlled (47%), well controlled (47%), poorly controlled (4%), and very poorly controlled (2%). In conclusion, we observed significant variability in opioid prescribing after vascular procedures. The overall opioid use was substantially lower than the amount prescribed. These data enabled us to develop guidelines for opioid prescribing practice for our patients. PMID- 30449261 TI - Theoretical Advancements in mHealth: A Systematic Review of Mobile Apps. AB - There are now few hundred thousand healthcare apps, yet there is a gap in our understanding of the theoretical mechanisms for which, and how, technological features translate into improved healthcare outcomes. In particular, the technological convergence, within mobile health (mHealth) apps, of the processes of mass and interpersonal communication, and human-computer interaction requires greater parsing in the literature. This paper analyzed 85 empirical studies on mHealth apps using the Input-Mechanism-Output model. We found in the literature that, firstly, there is a greater emphasis on technological inputs (87%) of accessibility, usability, usage, and data quality, than health outputs (52%) such as system process efficiencies and individual level behavioral or health outcomes. Secondly, there is little evidence of explanatory mechanisms (19%) of how the effects of mHealth apps are achieved. While we believe that successful apps would require research that incorporates technological inputs, theoretical mechanisms and health outputs, such studies are a rarity (n = 3). There is a minor increase in rigor with randomized control trials (n = 5), and a preponderance of discussion around social influence (n = 8) and gamification (n = 7), albeit in a scattered manner. We discuss the implications of the trend towards socialization and gamification findings in terms of future research, particularly in terms of study design guided by theoretical mechanisms. PMID- 30449262 TI - Opioids in vascular surgery: A call to action. PMID- 30449263 TI - Job satisfaction and stress among healthcare workers in public hospitals in Qatar. AB - This article explores predictors of job satisfaction and stress among clinicians and administrative staff at the public health sector in the State of Qatar. This is a rapidly growing sector, aiming for excellence in service, education and research. The vast majority of the staff are expatriates with different cultural backgrounds, and varying qualifications. After obtaining ethical approvals to conduct the study, the target population were asked to complete an anonymous online survey, that included sociodemographic data followed by the National Institute for Occupational Safety and Health (NIOSH) generic Job Stress questionnaire. Total number included in the analysis is 1260, female, married with children. Role ambiguity, conflict, skill underutilization and workload were associated with job dissatisfaction. Role and job future ambiguity were significantly associated with depression. PMID- 30449265 TI - No more donor secrets in the genomic age. PMID- 30449264 TI - Kinetic studies on oxygen releasing of HBOC and red blood cells as fluids and factors affecting the process. AB - Red blood cells (RBCs) possess intact cyto-architectures while haemoglobin (Hb) is a cell-free, homogeneous solution. Both RBCs and Hb are generalized oxygen carriers. In this paper, kinetic studies on oxygen-releasing of high concentration of Hb and RBCs under various conditions were carried out regarding Hb and RBCs as fluids. Among them, Hb under specific conditions was seen as the simplest Hb-based oxygen carrier (HBOC), Also, factors affecting the oxygen releasing of Hb and RBCs, including osmotic pressure, viscosity and allosteric agent, have been well studied. Analysis of the results from the measurement above showed that kinetics of oxygen releasing of either pure Hb or the simplest HBOCs was obviously different from that of RBCs. The oxygen-releasing time of Hb was shorter and the oxygen-releasing rates of Hb were quicker than those of RBCs under various conditions. Therefore, as fluids, only by changing the milieus it exists in, Hb could not achieve the expected oxygen-releasing effect on the microcirculation so well as RBCs do in the same system, irrespective of the interaction between the fluids and blood vessels. Furthermore, kinetic properties of HBOCs must be considered and matched with those of RBCs in the study of HBOCs. PMID- 30449266 TI - Exploring the Role of Race and Gender on Perceived Bystander Ability and Intent: Findings Before and After Exposure to an Online Training Program to Prevent Sexual Assault on Campus. AB - The current study explores the significance of race and gender on bystander attitudes before and after an online bystander intervention program to prevent sexual assault. A diverse sample of 750 college students participated in an online intervention and participants' perceived bystander intervention ability and intent were assessed. The interaction of participant race and gender had a marginally significant impact on bystander ability and intent baseline scores. Furthermore, when analyzing gain scores from pre- to posttest, there was a significant race by gender interaction. Specifically, Latinx and Black men had higher preintervention scores, and White men had higher gains postintervention. Relevant cultural and social factors and directions for future research are discussed. PMID- 30449267 TI - Some recent applications of rabbit biotechnology - a review. AB - The rabbit is gaining attention in the biotechnology field because it offers several advantages as a specific experimental model. Both wild and domestic rabbits exist. They are prey, browsers and ecosystem keystone species, and they also exhibit high production. Rabbit biotechnology is a branch of animal biotechnology in which molecular biology techniques are used to modify living organisms and make products. The advances in biotechnology have created new applications in rabbit genetics. These applications have moved from measuring the phenotype to assessing the genotype and are now based on the science of genetic engineering. The novel aspect introduced by biotechnology is the modification of gene sequences that influence the traits of interest. This review integrates recent developments in biotechnology that influence traits of interest in rabbits. PMID- 30449269 TI - The role of veterinary diagnostic laboratories in the fight against antimicrobial resistance. PMID- 30449268 TI - Long-Term Effectiveness of Guided Self-Help for Parents of Children With ADHD in Routine Care-An Observational Study. AB - OBJECTIVE: To assess long-term effectiveness of guided self-help for parents of children with ADHD under routine care conditions. METHOD: 6- to 12-year-old children diagnosed with ADHD were enrolled in an observational study on a 1-year telephone-assisted parent-administered behavioral intervention. N = 136 families who completed the intervention participated in a follow-up assessment. Pre-, post , and follow-up data were analyzed by repeated measures ANOVA with planned contrasts. Clinical significance was analyzed according to the reliable change index. RESULTS: Child ADHD symptoms (primary outcome), oppositional defiant disorder (ODD) symptoms, overall behavioral problems, and quality of life improved during the intervention. There was a further improvement in ADHD symptoms at follow-up, with a medium effect size. Improvements during treatment in ODD symptoms, overall behavioral problems, and quality of life were maintained at follow-up. CONCLUSION: The findings suggest that telephone-assisted self-help interventions may result in a long-term reduction of child behavior problems. PMID- 30449270 TI - Pediatric oncology social workers' experience of compassion fatigue. AB - Pediatric oncology social workers play an important role in supporting cancer patients and their families as they learn to talk about and cope with the physical and psychological impacts of cancer. As a result, social workers are particularly vulnerable to compassion fatigue and the associated psychological and physical impacts. The purpose of this qualitative study was to understand the experience of compassion fatigue among 27 pediatric oncology social workers. Four main themes emerged throughout the five focus groups: Conditions that contribute to compassion fatigue; the influence of compassion fatigue; coping strategies to alleviate compassion fatigue; and desire for systematic support to prevent compassion fatigue. Our study findings emphasize the importance of developing programs, policies and research geared toward the prevention of compassion fatigue, in addition to coping with symptoms. Further, this study brings attention to the importance of including pediatric oncology social workers in efforts to develop and implement systemic supports. PMID- 30449272 TI - Efficacy of fluralaner plus moxidectin (Bravecto(r) Plus spot-on solution for cats) against Otodectes cynotis infestations in cats. AB - BACKGROUND: The efficacy of the fixed combination of fluralaner plus moxidectin for the treatment of Otodectes cynotis infestations was evaluated in cats after topical application. METHODS: Sixteen cats experimentally infested with O. cynotis were allocated randomly to two groups of 8 cats each. One group was treated topically with the fixed combination of fluralaner plus moxidectin at the minimum dose rate of 40 mg fluralaner and 2 mg moxidectin/kg body weight. The other group was treated with physiological saline solution. Before and 14 and 28 days after treatment the ears of all cats were examined otoscopically for live mites and for the amount of debris and cerumen. Twenty-eight days after treatment, the cats were sedated and had both ears flushed to obtain the total number of live mites per animal. Efficacy was calculated, based on the results of the ear flushing, by comparing mean live mite counts in the fluralaner plus moxidectin treated group versus the saline group. RESULTS: A single topical application of the fixed combination of fluralaner plus moxidectin to cats reduced the mean mite counts by 100% (P < 0.001) by 28 days after treatment. No mites were visible during otoscopic examination at either 14 or 28 days after treatment. All fluralaner plus moxidectin treated cats had less ceruminous exudate 28 days after treatment compared to pre-treatment and 14 days after treatment. No treatment related adverse events were observed in any cats enrolled in the study. CONCLUSIONS: Single topical application of the fixed combination of fluralaner plus moxidectin was highly effective against O. cynotis infestations in cats. PMID- 30449273 TI - Q&A: Scaling up delivery of mental health treatments in low and middle income countries: interviews with Retha Arjadi and Vikram Patel. AB - In this Q&A, we talk with Retha Arjadi and Vikram Patel about using new technologies and lay-counselor support for scalable delivery of mental health treatment in low and middle-income countries. PMID- 30449274 TI - Outbreak of Crimean-Congo haemorrhagic fever with atypical clinical presentation in the Karak District of Khyber Pakhtunkhwa, Pakistan. AB - BACKGROUND: Crimean-Congo haemorrhagic fever (CCHF) is a potentially fatal disease endemic in Pakistan. The causative virus is transmitted by the bite of Hyalomma ticks or by contact with infected blood or tissue. First cases of the disease were reported in Pakistan in 1976 but regular outbreaks have been observed since the year 2000. A huge agricultural base with more than 175 million livestock, the concomitant presence of Hyalomma ticks and a lack of precautionary measures to prevent transmission lead to a considerable risk for exposed populations to contract CCHF in Pakistan. At the same time, secondary cases contracted by nosocomial transmission are reported from hospitals. CASE PRESENTATION: Here we present an outbreak of CCHF with four of six patients succumbing to the disease before the suspicion for CCHF was raised. Importantly, the main clinical features of these cases were gastrointestinal symptoms without any clinical signs of bleeding. Only the last two patients in this outbreak presented with typical signs of bleeding disorder and were then confirmed being infected by CCHF. Confirmation of diagnosis was done at the National Institute of Health by real-time RT-PCR. CONCLUSIONS: This case series highlights the importance of early clinical suspicion for CCHF in exposed individuals and the need for improved precautionary measures against the spread of CCHF within the Pakistani population and hospitals. PMID- 30449275 TI - A randomized, blinded, controlled, multi-centered field study assessing the treatment of gastrointestinal nematode infections in cats with fluralaner plus moxidectin spot-on solution (Bravecto(r) Plus). AB - BACKGROUND: A spot-on formulation containing fluralaner (280 mg/ml) plus moxidectin (14 mg/ml) (Bravecto(r) Plus) was developed for the treatment of nematode infections as well as providing 12 weeks of protection against insect and acarine parasites in cats. The effectiveness and safety of this product against feline gastrointestinal nematodes was assessed in naturally-infested, client-owned cats under field conditions in Albania, Bulgaria, Germany and Hungary. METHODS: To be eligible for enrollment in this investigator-blinded study cats had to be at least 10 weeks-old, weigh at least 1.2 kg, be clinically healthy, and have a faecal sample testing positive for nematodes no more than eight days prior to treatment. Cats were stratified into blocks of three in order of presentation at each center and randomly allocated in a 2:1 ratio to be treated topically on Day 0 with fluralaner plus moxidectin (minimum dose rates 40 mg/kg and 2 mg/kg, respectively) or emodepside plus praziquantel (minimum dose rates 3 mg/kg and 12 mg/kg, respectively) (Profender(r)). Faecal samples were collected from cats prior to treatment and 14 +/- 4 days later. RESULTS: There were 182 cats randomized to the fluralaner plus moxidectin group, and 91 to the emodepside plus praziquantel group. Prior to treatment the most commonly identified nematode egg was Toxocara cati, found in 79.1 and 82.4% of cats in the fluralaner plus moxidectin and emodepside plus praziquantel groups, respectively. Eggs of Toxascaris leonina were found in 8.2 and 6.6% of cats; of hookworms in 30.8 and 24.2%; and of Capillaria spp. in 7.1 and 4.3%, respectively. After treatment, faecal samples from 98.3% of fluralaner plus moxidectin treated and 96.6% of emodepside plus praziquantel-treated cats were free of nematode ova. Geometric mean faecal egg count reductions for T. cati, the only eggs found in post-treatment faecal samples, were 99.97% and 99.93%, respectively. Treatment with fluralaner plus moxidectin was non-inferior to emodepside plus praziquantel. Both products were safe and well tolerated by cats treated under field conditions. CONCLUSIONS: This field study confirms that, in addition to 12-week extended duration flea and tick control, fluralaner plus moxidectin provides broad spectrum treatment of nematodes in cats. PMID- 30449277 TI - Patterns of homozygosity in insular and continental goat breeds. AB - BACKGROUND: Genetic isolation of breeds may result in a significant loss of diversity and have consequences on health and performance. In this study, we examined the effect of geographic isolation on caprine genetic diversity patterns by genotyping 480 individuals from 25 European and African breeds with the Goat SNP50 BeadChip and comparing patterns of homozygosity of insular and nearby continental breeds. RESULTS: Among the breeds analysed, number and total length of ROH varied considerably and depending on breeds, ROH could cover a substantial fraction of the genome (up to 1.6 Gb in Icelandic goats). When compared with their continental counterparts, goats from Iceland, Madagascar, La Palma and Ireland (Bilberry and Arran) displayed a significant increase in ROH coverage, ROH number and FROH values (P value < 0.05). Goats from Mediterranean islands represent a more complex case because certain populations displayed a significantly increased level of homozygosity (e.g. Girgentana) and others did not (e.g. Corse and Sarda). Correlations of number and total length of ROH for insular goat populations with the distance between islands and the nearest continental locations revealed an effect of extremely long distances on the patterns of homozygosity. CONCLUSIONS: These results indicate that the effects of insularization on the patterns of homozygosity are variable. Goats raised in Madagascar, Iceland, Ireland (Bilberry and Arran) and La Palma, show high levels of homozygosity, whereas those bred in Mediterranean islands display patterns of homozygosity that are similar to those found in continental populations. These results indicate that the diversity of insular goat populations is modulated by multiple factors such as geographic distribution, population size, demographic history, trading and breed management. PMID- 30449276 TI - Signatures of selection and environmental adaptation across the goat genome post domestication. AB - BACKGROUND: Since goat was domesticated 10,000 years ago, many factors have contributed to the differentiation of goat breeds and these are classified mainly into two types: (i) adaptation to different breeding systems and/or purposes and (ii) adaptation to different environments. As a result, approximately 600 goat breeds have developed worldwide; they differ considerably from one another in terms of phenotypic characteristics and are adapted to a wide range of climatic conditions. In this work, we analyzed the AdaptMap goat dataset, which is composed of data from more than 3000 animals collected worldwide and genotyped with the CaprineSNP50 BeadChip. These animals were partitioned into groups based on geographical area, production uses, available records on solid coat color and environmental variables including the sampling geographical coordinates, to investigate the role of natural and/or artificial selection in shaping the genome of goat breeds. RESULTS: Several signatures of selection on different chromosomal regions were detected across the different breeds, sub-geographical clusters, phenotypic and climatic groups. These regions contain genes that are involved in important biological processes, such as milk-, meat- or fiber-related production, coat color, glucose pathway, oxidative stress response, size, and circadian clock differences. Our results confirm previous findings in other species on adaptation to extreme environments and human purposes and provide new genes that could explain some of the differences between goat breeds according to their geographical distribution and adaptation to different environments. CONCLUSIONS: These analyses of signatures of selection provide a comprehensive first picture of the global domestication process and adaptation of goat breeds and highlight possible genes that may have contributed to the differentiation of this species worldwide. PMID- 30449279 TI - Genome-wide patterns of homozygosity provide clues about the population history and adaptation of goats. AB - BACKGROUND: Patterns of homozygosity can be influenced by several factors, such as demography, recombination, and selection. Using the goat SNP50 BeadChip, we genotyped 3171 goats belonging to 117 populations with a worldwide distribution. Our objectives were to characterize the number and length of runs of homozygosity (ROH) and to detect ROH hotspots in order to gain new insights into the consequences of neutral and selection processes on the genome-wide homozygosity patterns of goats. RESULTS: The proportion of the goat genome covered by ROH is, in general, less than 15% with an inverse relationship between ROH length and frequency i.e. short ROH (< 3 Mb) are the most frequent ones. Our data also indicate that ~ 60% of the breeds display low FROH coefficients (< 0.10), while ~ 30 and ~ 10% of the goat populations show moderate (0.10 < FROH < 0.20) or high (> 0.20) FROH values. For populations from Asia, the average number of ROH is smaller and their coverage is lower in goats from the Near East than in goats from Central Asia, which is consistent with the role of the Fertile Crescent as the primary centre of goat domestication. We also observed that local breeds with small population sizes tend to have a larger fraction of the genome covered by ROH compared to breeds with tens or hundreds of thousands of individuals. Five regions on three goat chromosomes i.e. 11, 12 and 18, contain ROH hotspots that overlap with signatures of selection. CONCLUSIONS: Patterns of homozygosity (average number of ROH of 77 and genome coverage of 248 Mb; FROH < 0.15) are similar in goats from different geographic areas. The increased homozygosity in local breeds is the consequence of their small population size and geographic isolation as well as of founder effects and recent inbreeding. The existence of three ROH hotspots that co-localize with signatures of selection demonstrates that selection has also played an important role in increasing the homozygosity of specific regions in the goat genome. Finally, most of the goat breeds analysed in this work display low levels of homozygosity, which is favourable for their genetic management and viability. PMID- 30449280 TI - Mathematical model of the life cycle of taenia-cysticercosis: transmission dynamics and chemotherapy (Part 1). AB - BACKGROUND: Taenia solium is the aetiological agent of human taeniasis, pig cysticercosis and human neurocysticercosis, which are serious public health problems, especially in developing countries. METHODS: A mathematical model of the transmission dynamics of taeniasis-cysticercosis is formulated. The model consists of a coupled system of differential equations, which are density dependent equations for describing the flow of the parasite through the life cycle. The model is hybrid since it comprises deterministic equations with stochastic elements which describe changes in the mean parasite burden and incorporates the overall pattern of the parasites' distribution. RESULTS: Sensitivity and bifurcation analyses were carried out to determine the range of values of the model. The model can reproduce the observed epidemiological patterns of human taeniasis, pig and human cysticercosis. For example, for a wide range of parameter values, the mean intensity of adult worms tends to rapidly stabilize in one parasite per individual host. From this model, we also derived a Susceptible-Infected model to describe the prevalence of infection in humans and pigs. Chemotherapeutic interventions against pig cysticercosis or human taeniasis may reduce rapidly and effectively the mean intensity of human taeniasis, pig cysticercosis and human cysticercosis. This effect can be achieved even if the protective efficacy of the drug is of the order of 90% and the coverage rate is 90%. This means that health in humans infected either with adult worms or cysticerci may be achieved by the application of anthelmintic drugs against pig cysticercosis. However, treatment against human cysticercosis alone, does not influence neither human teniasis nor pig cysticercosis. This is because human cysticercosis infection does not influence the value of the basic reproductive number (Ro). CONCLUSIONS: Even coverage of 100% in the administration of anthelmintics did not eliminate the infection. Then elimination of the infection in all hosts does not seem a feasible goal to achieve by administering only chemotherapeutic interventions. Throughout the manuscript a discussion of our model in the context of other models of taeniasis-cysticercosis is presented. PMID- 30449282 TI - Functional SNP panel for parentage assessment and assignment in worldwide goat breeds. AB - BACKGROUND: International standard panels of single nucleotide polymorphisms (SNPs) have replaced microsatellites in several species for parentage assessment and assignment (PA) purposes. However, such a resource is still lacking in goats. The application of a cheap tool for PA would help the management of goat populations by improving the reliability of pedigree registration and, consequently, allow a better implementation of breeding schemes or conservation programs. RESULTS: Using data from the current GoatSNP50 chip, starting from a worldwide dataset of more than 4000 animals belonging to more than 140 breeds and populations from the AdaptMap initiative, we selected a panel of 195 SNPs. The assignment rate of this panel was up to 100% on an additional dataset that included 2000 Alpine and Saanen animals and highly related candidate sires. CONCLUSIONS: In this study, we defined a highly informative SNP panel, which will be publicly available to worldwide breeders and laboratories. Its development on such a large number of breeds and populations, together with validation on a second set of cosmopolitan breeds, makes it a promising and important genomic tool for the goat species. PMID- 30449278 TI - A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases. AB - Pancreatic ribonuclease is known to participate in host defense system against pathogens, such as parasites, bacteria, and virus, which results in innate immune response. Nevertheless, its potential impact to host cells remains unclear. Of interest, several ribonucleases do not act as catalytically competent enzymes, suggesting that ribonucleases may be associated with certain intrinsic functions other than their ribonucleolytic activities. Most recently, human pancreatic ribonuclease 5 (hRNase5; also named angiogenin; hereinafter referred to as hRNase5/ANG), which belongs to the human ribonuclease A superfamily, has been demonstrated to function as a ligand of epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family. As a newly identified EGFR ligand, hRNase5/ANG associates with EGFR and stimulates EGFR and the downstream signaling in a catalytic-independent manner. Notably, hRNase5/ANG, whose level in sera of pancreatic cancer patients, serves as a non-invasive serum biomarker to stratify patients for predicting the sensitivity to EGFR-targeted therapy. Here, we describe the hRNase5/ANG-EGFR pair as an example to highlight a ligand receptor relationship between families of ribonucleases and receptor tyrosine kinases, which are thought as two unrelated protein families associated with distinct biological functions. The notion of serum biomarker-guided EGFR-targeted therapies will also be discussed. Furthering our understanding of this novel ligand-receptor interaction will shed new light on the search of ligands for their cognate receptors, especially those orphan receptors without known ligands, and deepen our knowledge of the fundamental research in membrane receptor biology and the translational application toward the development of precision medicine. PMID- 30449283 TI - How culturally competent are hospitals in Israel? AB - BACKGROUND: Cultural competence (CC) in health systems is the ability to provide care to patients with different values, beliefs and behaviors, and to match the care to their social, cultural and linguistic needs. In 2011, the Director General of Israel's Ministry of Health issued a cultural competence directive to health care providers that sought to minimize health inequalities caused by cultural and linguistic gaps. This study assesses the status of organizational CC in Israeli general hospitals in the wake of the 2011 directive. METHOD: Organizational CC was assessed using a 75-item structured questionnaire based on the 2011 directive and on international standards. Data were gathered via interviews conducted between December 2012 and February 2014. 35 of Israel's 36 general hospitals participated in the study, for a response rate of 97%. A composite CC score was calculated for each hospital as the average of the 75 items in the questionnaire. RESULTS: The average composite score of all the hospitals was low to moderate (2.3 on a scale of 0-4), the median score was 2.4, and the range of composite scores was large, 0.7-3.2. The interquartile range was [1.94, 2.57]. Hospital CC is positively associated with non-private ownership status and location in the southern or central districts. Still, these differences are not statistically significant and immutable hospital characteristics such as ownership status and location account for only 21% of the inter-hospital variation in CC. This suggests that hospital leaders have significant discretion in the priority to be given to CC. Dimensions of CC with relatively low average scores include hospital connections with the community (1.28), staff training on CC (1.35), oral translation (i.e. interpreting) during treatment (1.62), and CC adaptation of human resources recruitment and evaluation (1.64). These areas appear to be particularly in need of improvement. CONCLUSION: The study findings suggest that hospitals and policy-makers can take significant steps to improve CC; these include setting more concrete and measurable implementation guidelines. We conclude with suggestions for policy and practices to improve cultural competence in the health system. PMID- 30449281 TI - Sport, doping and female fertility. AB - This article is a review that addresses the following topics, divided by paragraphs. The first paragraph investigates the effects of physical activity on ovarian function, analyzing in particular the changes concerning the serum concentrations of follicle-stimulating hormone, luteinizing hormone, prolactin, growth hormone, thyroid hormones, leptin, ghrelin, neuropeptide Y. The second paragraph analyzes the effects of doping on the hypothalamic-pituitary-ovarian axis. Finally, the last paragraph analyzes the PCOS category, evaluating the effects of hyperandrogenism in relation to athletic performance. PMID- 30449285 TI - Posterior interosseous nerve palsy caused by synovial osteochondromatosis of the elbow analyzed by three-dimensional reconstruction: a case report. AB - BACKGROUND: Synovial osteochondromatosis, a benign tumor consisting of cartilage and bone, generally presents as multiple osteochondral or chondral nodules. Peripheral nerve palsy caused by synovial osteochondromatosis is rare. Three dimensional reconstruction based on magnetic resonance imaging shows the specific shape and location of the tumor and its relation to the nerve. CASE PRESENTATION: We describe a case of posterior interosseous nerve palsy caused by synovial osteochondromatosis of the elbow in a 66-year-old Japanese man. A three dimensional reconstructed image based on magnetic resonance imaging was used to determine the location and shape of the giant tumor, which was composed of bone and cartilage. After surgical resection of the giant tumor and neurolysis of the posterior interosseous nerve, he fully recovered from nerve palsy 9 months postoperatively. There was no recurrence of the lesion 1 year postoperatively. CONCLUSION: Synovial osteochondromatosis that causes posterior interosseous nerve palsy has a characteristic morphology and location, that is, a giant tumor located anterior to the humeroradial joint, as revealed by three-dimensional magnetic resonance image reconstruction. PMID- 30449286 TI - Evidence of Concomitantly Increasing Stroke and Dementia Prevalence among those 80 Years and Older in Ontario, Canada, 2003-04 to 2012-13. AB - Among those aged 80 years and older in Ontario, Canada, stroke and dementia incidence declined concomitantly from 2002-03 to 2013-14. This study aimed to report the concurrent temporal trends of stroke and dementia prevalence in Ontario among the same age demographic. The prevalence of both stroke and dementia increased from 2003-04 to 2012-13 in both sexes and the magnitude in which prevalence of dementia increased over time exceeded that of stroke. The substantial increase in the prevalence of dementia may be because of increased recognition and diagnoses of dementia and increased survival of stroke patients who are at higher risk of developing dementia. PMID- 30449284 TI - Genome-wide SNP profiling of worldwide goat populations reveals strong partitioning of diversity and highlights post-domestication migration routes. AB - BACKGROUND: Goat populations that are characterized within the AdaptMap project cover a large part of the worldwide distribution of this species and provide the opportunity to assess their diversity at a global scale. We analysed genome-wide 50 K single nucleotide polymorphism (SNP) data from 144 populations to describe the global patterns of molecular variation, compare them to those observed in other livestock species, and identify the drivers that led to the current distribution of goats. RESULTS: A high degree of genetic variability exists among the goat populations studied. Our results highlight a strong partitioning of molecular diversity between and within continents. Three major gene pools correspond to goats from Europe, Africa and West Asia. Dissection of sub structures disclosed regional gene pools, which reflect the main post domestication migration routes. We also identified several exchanges, mainly in African populations, and which often involve admixed and cosmopolitan breeds. Extensive gene flow has taken place within specific areas (e.g., south Europe, Morocco and Mali-Burkina Faso-Nigeria), whereas elsewhere isolation due to geographical barriers (e.g., seas or mountains) or human management has decreased local gene flows. CONCLUSIONS: After domestication in the Fertile Crescent in the early Neolithic era (ca. 12,000 YBP), domestic goats that already carried differentiated gene pools spread to Europe, Africa and Asia. The spread of these populations determined the major genomic background of the continental populations, which currently have a more marked subdivision than that observed in other ruminant livestock species. Subsequently, further diversification occurred at the regional level due to geographical and reproductive isolation, which was accompanied by additional migrations and/or importations, the traces of which are still detectable today. The effects of breed formation were clearly detected, particularly in Central and North Europe. Overall, our results highlight a remarkable diversity that occurs at the global scale and is locally partitioned and often affected by introgression from cosmopolitan breeds. These findings support the importance of long-term preservation of goat diversity, and provide a useful framework for investigating adaptive introgression, directing genetic improvement and choosing breeding targets. PMID- 30449287 TI - Morphology and morphometry of preantral follicles, and immunolocalization of angiogenic factors in ovarian tissue from the neotropical primate Sapajus apella. AB - SummaryOvarian biopsies from five health adult monkeys were collected by exploratory laparotomy. Preantral follicles (primordial, primary, and secondary) were classified as normal or degenerated and submitted to morphometric analysis in which granulosa cell counts and the areas of follicles, oocytes, and oocyte nuclei were measured. Ovarian fragments were also immunolabelled for the quantitative analysis of VEGFA and CD31 protein expression in the ovarian tissue and in the preantral follicles. In total, 213 preantral follicles was examined for morphometry and morphological classification. From this total, 20 (9.4%) were follicles enclosing two or more oocytes, i.e. multi-oocyte follicles (MOFs). From the 193 follicles enclosing only one oocyte, 46.3% were classified as primordial, 24,1% as transition, 23.3% as primary, and 6.3% as secondary follicles. The mean number of granulosa cells surrounding primordial, transition, primary, and secondary follicles was 9.2, 12.1, 18.7, and 45.3, respectively. Increase in oocyte diameter was observed from primary to secondary follicles, while the oocyte nucleus increased only when follicles reached the secondary stage. The expression of CD31 was strong in vessels, corpus luteum, and in normal oocytes and granulosa cells from preantral follicles at all developmental stages. Likewise, VEGFA expression was observed in vessels and preantral follicles (granulosa cells, the oocyte and the oocyte nucleus). We characterized the morphology, and morphometry and expression of angiogenic factors in normal and atretic preantral follicles from Sapajus apella. This description can support the analysis of follicular quality and survival after procedures such as transplantation and cryopreservation. PMID- 30449288 TI - Leucine promotes porcine myofibre type transformation from fast-twitch to slow twitch through the protein kinase B (Akt)/forkhead box 1 signalling pathway and microRNA-27a. AB - Muscle fibre types can transform from slow-twitch (slow myosin heavy chain (MyHC)) to fast-twitch (fast MyHC) or vice versa. Leucine plays a vital effect in the development of skeletal muscle. However, the role of leucine in porcine myofibre type transformation and its mechanism are still unclear. In this study, effects of leucine and microRNA-27a (miR-27a) on the transformation of porcine myofibre type were investigated in vitro. We found that leucine increased slow MyHC protein level and decreased fast MyHC protein level, increased the levels of phospho-protein kinase B (Akt)/Akt and phospho-forkhead box 1 (FoxO1)/FoxO1 and decreased the FoxO1 protein level. However, blocking the Akt/FoxO1 signalling pathway by wortmannin attenuated the role of leucine in porcine myofibre type transformation. Over-expression of miR-27a decreased slow MyHC protein level and increased fast MyHC protein level, whereas inhibition of miR-27a had an opposite effect. We also found that expression of miR-27a was down-regulated following leucine treatment. Moreover, over-expression of miR-27a repressed transformation from fast MyHC to slow MyHC caused by leucine, suggesting that miR-27a is interdicted by leucine and then contributes to porcine muscle fibre type transformation. Our finding provided the first evidence that leucine promotes porcine myofibre type transformation from fast MyHC to slow MyHC via the Akt/FoxO1 signalling pathway and miR-27a. PMID- 30449289 TI - Validation of a Short Form of Job Crafting Scale in a Spanish Sample. AB - Applications of job crafting are widespread in the professional practice. In an attempt to measure this phenomenon, Tims, Bakker and Derks (2012) developed a Job Crafting Scale based on the Job Demand-Resources model (JD-R) and validated it in a Dutch sample. However, its application to other cultural contexts presented some difficulties. The present work aimed to validate a shorter version of scale by Tims et al. (2012) in a Spanish sample (n = 1,647). The data were randomly split in two independent subsamples (Sample 1: Explorative; Sample 2: Confirmative). The exploratory factor analysis showed a three-factor structure. Through a confirmatory factor analysis, the four-dimensionality structure of the original scale was replicated. In fact, the four-factor solution presented better goodness of fit indices than the alternative one-factor model, chi2(48) = 192.70, p < .01; AGFI = .94; NNFI = .93; RMR = .05; RMSEA = .06. Alpha reliabilities were acceptable for increasing structural job resources (alpha = .75), decreasing hindering job demands (alpha = .64), increasing social job resources (alpha = .78) and increasing challenging job demands (alpha = .77). Convergent validity was appropriate for three of the four dimensions, because each construct's AVE were around .50 and each construct's Composite Reliability were around .70. Decreasing hindering job demands presented more limited values (CR = .65; AVE = .40). In addition, the four job crafting dimensions presented significant correlations with job performance (range -.09 to .42) and personal growth (ranging from -.09 to .45). Finally, the squared correlations between factors were lower than the square root of AVE, which confirmed discriminant validity. PMID- 30449290 TI - A Quality Control Circle Process to Reduce Blood Culture Contamination Rates. PMID- 30449291 TI - Sugar-sweetened beverage taxes in 2018: a year of reflections and consolidation. PMID- 30449292 TI - Morphological Properties of the Two Types of Caudate Interneurons: Kohonen Self Organizing Maps and Correlation-Comparison Analysis. AB - Our previous study found that caudate and putaminal interneurons are morphologically very different, and that accordingly they could be divided in two separate clusters. In addition, it also demonstrated, as a collateral result, that the caudate cluster itself consists of two clusters of morphologically different interneurons. Hence, the objective of this study is a morphological description and subtle differing of morphologies of these two types of caudate interneurons, i.e., an investigation of those morphological traits which characterize them uniquely, and which would distinguish them. Binary two dimensional images of caudate interneurons, taken from deceased adult human subjects, were analyzed by using 46 parameters, describing the morphology of interneurons. The parameters can be divided in the following classes: size (surface) of a neuron, neuronal shape, length of neuronal morphological compartments, dendritic branching, morphological organization, and complexity. The morphological determination of caudate interneurons was performed in a step wise manner. The first step was the assignment of each individual neuron to an adequate cluster where it belonged according to morphological criteria. This was done by using the trained artificial neural network, Kohonen self-organizing map. After the clusters were formed, the analysis is further continued by the precise, feature-wise determination of morphological differences found between clusters of caudate interneurons and then finished by defining correlation-based, mutual, inter-parametric relations for each of the clusters. The first was performed by using single-factor analysis, and the second by correlation-comparison analysis. Single-factor analysis showed significance for 34 parameters (morphological features) that distinguish between the clusters. Correlation-comparison analysis extended the results of single-factor analysis by demonstrating significance for 198 inter-parametric correlation pairs that represent 19.13% of mismatched correlations of the first kind among the total number of correlations. This represents a significant inter-cluster separation zone. In addition, the analysis extracted one correlation of the second kind, namely, the DO-MDCBO, very highly significant (p<0.001), positive (r=0.45) in the cluster I, while negative (r= 0.13), also significant (p<0.05) in the cluster II. The two clusters of caudate interneurons were found to be significantly morphologically different. These differences, albeit not strong as the caudate-putaminal differences, are more numerous with respect to significant morphological properties defining them. They probably underlie, influence, and modulate different neurofunctional behavior of the two types of interneurons, which need to be further investigated by future studies. PMID- 30449293 TI - Effects of prenatal alcohol exposure on language, speech and communication outcomes: a review longitudinal studies. AB - OBJECTIVE: The aim of this paper was to provide a systematic review and update on the available longitudinal studies on the impact of prenatal alcohol exposure (PAE) on language, speech and communication development, as well as associated potential environmental confounders during the preschool period. METHODS: A literature search was restricted to English, full-text, peer-reviewed, longitudinal studies in from 1970 until present: PUBMed, Scopus, Web of Science {C-e Collection, Biological Abstracts, KCI-Kean Journal Database, Russian Science Citation Index, SciELO Citation Index, Zoological Rec-d}, Academic Search Premier (Africa-Wide Information, CINAHL, MEDLINE, PsycINFO. Keywords included: prenatal alcohol exposure (PAE); speech or language or communication outcomes; neurocognitive or neurodevelopment or neurobehavioral or neurobehavioural; infant or baby or toddler or preschooler; longitudinal or follow-up. The inclusion criteria included (i) longitudinal cohorts with at least 2 time-points; (ii) association of light, moderate or heavy PAE on language, speech or communication delay, development or disorder; (iii) environmental confounders; (iv) infants up to preschool age. RESULTS: Six studies satisfied the threshold for inclusion. Three studies reported that PAE was significantly associated with receptive or expressive delay. These studies demonstrated lower scores on either receptive or expressive communication in the alcohol group in comparison to the non-alcohol group, even after controlling for environmental factors up to 36 months. CONCLUSION: Evidence from the longitudinal studies reviewed suggest that PAE influenced delays in receptive and expressive communication up to 36 months. Contextual risk factors played a significant role in language development over time and especially as children approached school age. PMID- 30449294 TI - Accuracy of self-reported weight in the Women's Health Initiative. AB - OBJECTIVE: To assess the extent of error present in self-reported weight data in the Women's Health Initiative, variables that may be associated with error, and to develop methods to reduce any identified error. DESIGN: Prospective cohort study. SETTING: Forty clinical centres in the USA.ParticipantsWomen (n 75 336) participating in the Women's Health Initiative Observational Study (WHI-OS) and women (n 6236) participating in the WHI Long Life Study (LLS) with self-reported and measured weight collected about 20 years later (2013-2014). RESULTS: The correlation between self-reported and measured weights was 0.97. On average, women under-reported their weight by about 2 lb (0.91 kg). The discrepancies varied by age, race/ethnicity, education and BMI. Compared with normal-weight women, underweight women over-reported their weight by 3.86 lb (1.75 kg) and obese women under-reported their weight by 4.18 lb (1.90 kg) on average. The higher the degree of excess weight, the greater the under-reporting of weight. Adjusting self-reported weight for an individual's age, race/ethnicity and education yielded an identical average weight to that measured. CONCLUSIONS: Correlations between self-reported and measured weights in the WHI are high. Discrepancies varied by different sociodemographic characteristics, especially an individual's BMI. Correction of self-reported weight for individual characteristics could improve the accuracy of assessment of obesity status in postmenopausal women. PMID- 30449295 TI - Determination of Phthalic Acid, 2-(3',5'-Dibromo-2',4'-Dihydroxybenzoyl)Benzoic Acid, and Tribromoresorcinol in the Color Additives D&C Red No. 21, D&C Red No. 22 (Eosin Y), and Their Lakes Using UHPLC. AB - Background: Certain impurities in the color additives drug and cosmetic (D&C) Red No. 21 (R21), D&C Red No. 22 (R22), and their lakes are limited to levels specified in the Code of Federal Regulations (CFR) and are quantified by the U.S. Food and Drug Administration in batches of these color additives submitted for certification. Currently, a lengthy and tedious method based on gravity flow elution column chromatography is used to quantify the following CFR-specified impurities: the intermediate, phthalic acid (PhthAc); the manufacturing by-products, 2-(3',5'-dibromo-2',4'-dihydroxybenzoyl)benzoic acid (Br2BBA); and brominated resorcinol. "Brominated resorcinol" implies the sum of all possible brominated resorcinols, but the current work focused on 2,4,6 tribromoresorcinol (Br3R) as the most probable side-reaction product. Objective: An improved method was needed to quantify PhthAc, Br2BBA, and Br3R in R21, R22, and their lakes. Methods: A rapid ultra-HPLC (UHPLC) method was developed to replace the gravity flow method for quantitative determination of PhthAc, Br2BBA, and Br3R. Results: PhthAc, Br2BBA, and Br3R were quantified by using five-point calibration curves with data point ranges of 0.11-1.55, 0.06-0.77, and 0.04-0.61% by weight, respectively. LODs for the analytes ranged from 0.01 to 0.03%. Recoveries of the analytes ranged from 90.6 to 99.9%. Conclusions: The UHPLC method is accurate and significantly more rapid than the gravity -flow method, requiring approximately 7 min as compared with 6 h to detect PhthAc, Br2BBA, and Br3R in one sample. Highlights: A rapid UHPLC method was developed to determine CFR-specified impurities in the color additives D&C Red Nos. 21 and 22 and their lakes. PMID- 30449296 TI - Association of steroid 17-alpha-hydroxylase/17,20 lyase (CYP17) single nucleotide polymorphism (SNP) 628 and dopamine receptor D2 (DRD2) SNP939 genotypes with sheep reproductive performance. AB - In a previous study we investigated the association between two single nucleotide polymorphism (SNP) genotypes, namely steroid 17-alpha-hydroxylase/17,20 lyase (CYP17) SNP628 and dopamine receptor D2 (DRD2) SNP939, with two temperaments (calm and nervous) in Australian Merino sheep and concluded that the DRD2 SNP939 T/T genotype combined with the CYP17 SNP628 G/G genotype is associated with a calm temperament and could be used as a potential marker for calm sheep, whereas the DRD2 SNP939 C allele combined with the CYP17 SNP628 A/A genotype is associated with a nervous temperament and could be used as a potential marker for nervous sheep. In sheep, the association between temperament and reproductive performance has been determined, but the association of these two SNP genotypes with sheep reproduction has not been investigated. Therefore, using Chinese Sinkiang Merino sheep, the present study investigated the association of the two CYP17 SNP628 and DRD2 SNP939 genotypes with sheep reproductive performance. Sheep with the DRD2 SNP939 T/T genotype combined with the CYP17 SNP628 G/G genotype had a higher ovulation rate, multiple gestation rate, better maternal behaviour and lower lamb mortality. Thus, the results of this study contribute to our knowledge of the association between genotypes and reproduction in sheep, which is beneficial for sheep genetics and breeding. PMID- 30449297 TI - Testicular hyperthermia increases blood flow that maintains aerobic metabolism in rams. AB - There is a paradigm that testicular hyperthermia fails to increase testicular blood flow and that an ensuing hypoxia impairs spermatogenesis. However, in our previous studies, decreases in normal and motile spermatozoa after testicular warming were neither prevented by concurrent hyperoxia nor replicated by hypoxia. The objective of the present study was to determine the effects of increasing testicular temperature on testicular blood flow and O2 delivery and uptake and to detect evidence of anaerobic metabolism. Under general anaesthesia, the testicular temperature of nine crossbred rams was sequentially maintained at ~33 degrees C, 37 degrees C and 40 degrees C (+/-0.5 degrees C; 45 min per temperature). As testicular temperature increased from 33 degrees C to 40 degrees C there were increases in testicular blood flow (13.2 +/- 2.7 vs 17.7 +/- 3.2 mL min-1 per 100 g of testes, mean +/- s.e.m.; P < 0.05), O2 extraction (31.2 +/- 5.0 vs 47.3 +/- 3.1%; P < 0.0001) and O2 consumption (0.35 +/- 0.04 vs 0.64 +/- 0.06 mL min-1 per 100 g of testes; P < 0.0001). There was no evidence of anaerobic metabolism, based on a lack of change in lactate, pH, HCO3- and base excess. In conclusion, these data challenge the paradigm regarding scrotal testicular thermoregulation, as acute testicular hyperthermia increased blood flow and tended to increase O2 delivery and uptake, with no indication of hypoxia or anaerobic metabolism. PMID- 30449298 TI - 2-Methoxyoestradiol impairs mouse embryo implantation via F-spondin. AB - The anti-implantation effects of high oestradiol (E2) concentrations could be mediated by E2 metabolites. Herein, we examined whether 2-methoxyoestradiol (2ME) impairs embryo implantation via its target protein F-spondin. Mice on Day 3 of pregnancy were treated with E2 concomitantly with the cathecol-O-methyl transferase inhibitor OR486 and the number of implanted embryos was recorded 5 days later. The effect of 2ME or 4-methoxyoestradiol (4ME) on embryo implantation was also investigated. Plasma and uterine levels of 2ME were measured 0.5, 1 or 3 h after E2 treatment while the mRNA for spondin 1 (Spon1) and F-spondin were determined in the uterus 3, 6, 12 or 24 h after 2ME treatment. Finally, the effect of a neutralising F-spondin antibody on the anti-implantation effect of 2ME was explored. OR486 blocked the anti-implantation effect of E2; 2ME, but not 4ME, affected embryo implantation. The 2ME concentration was increased after 0.5 and 1 h in plasma and 3 h in uterine fluid following E2 treatment. 2ME increased levels of Spon1 at 12 and 24 h although F-spondin was increased at 12 h. F spondin antibody blocked the effect of 2ME on embryo implantation. We conclude that 2ME impairs mouse embryo implantation via activation of F-spondin in the uterus. PMID- 30449300 TI - Correction to Lancet Child Adolesc Health 2018; 2: 245-54. PMID- 30449299 TI - Sex steroids influence the plasma membrane transformation in the uterus of the fat-tailed dunnart (Sminthopsis crassicaudata, Marsupialia). AB - The uterine epithelium undergoes remodelling to become receptive to blastocyst implantation during pregnancy in a process known as the plasma membrane transformation. There are commonalities in ultrastructural changes to the epithelium, which, in eutherian, pregnancies are controlled by maternal hormones, progesterone and oestrogens. The aim of this study was to determine the effects that sex steroids have on the uterine epithelium in the fat-tailed dunnart Sminthopsis crassicaudata, the first such study in a marsupial. Females were exposed to exogenous hormones while they were reproductively quiescent, thus not producing physiological concentrations of ovarian hormones. We found that changes to the protein E-cadherin, which forms part of the adherens junction, are controlled by progesterone and that changes to the desmoglein-2 protein, which forms part of desmosomes, are controlled by 17beta-oestradiol. Exposure to a combination of progesterone and 17beta-oestradiol causes changes to the microvilli on the apical surface and to the ultrastructure of the uterine epithelium. There is a decrease in lateral adhesion when the uterus is exposed to progesterone and 17beta-oestradiol that mimics the hormone environment of uterine receptivity. We conclude that uterine receptivity and the plasma membrane transformation in marsupial and eutherian pregnancies are under the same endocrine control and may be an ancestral feature of therian mammals. PMID- 30449301 TI - Risk of invasive species spread by recreational boaters remains high despite widespread adoption of conservation behaviors. AB - The spread of non-native aquatic species among waterbodies has become a major social, environmental, and economic concern. An important mechanism of this spread is the inadvertent transport of organisms on recreational boats as they are moved among waterbodies. Organisms can survive on the exterior of the boat, the interior, attached to fishing tackle, and can be intentionally moved by boaters. In response, local, state, and federal U.S. agencies have invested in outreach campaigns to educate boaters about the impacts of invasive aquatic species and the ways that boaters can reduce the risk of spread. We surveyed boaters in the U.S. state of Illinois to determine their travel patterns and how frequently they clean different parts of their boats. A majority of boaters reported that they always take recommended actions to clean their boat exterior (72% of respondents), boat interior (78%), and fishing tackle (55%), and only 4% reported that they intentionally move organisms. We used network methods to analyze the movement of recreational boaters and found strong connections among 28 highly visited waterbodies. When we removed the 38% of respondents who Always take recommended actions to reduce risk of species spread by all four mechanisms this network was minimally altered and still contained all 28 waterbodies. This indicates that despite high adoption of conservation behaviors there is a continuing risk of non-native species transport among all waterbodies. This work shows that further action is necessary if the impacts of invasive aquatic species are to be reduced in the future. PMID- 30449302 TI - From killing lists to healthy country: Aboriginal approaches to weed control in the Kimberley, Western Australia. AB - The Australian Government's funding of land management by Aboriginal communities aims to enable them to manage natural and cultural resources according to their values and aspirations. But this approach is countered in the case of weed management, where the emphasis is on killing plants that are identified on invasive alien species lists prepared by government agencies. Based on field research with Bardi-Jawi, Bunuba, Ngurrara, Nyikina Mangala and Wunggurr land managers in the Kimberley region of Western Australia, we observed that 27 of 35 weed control projects followed the government agency weed lists for species-led control. Of these 27 projects, only two were considered successful in meeting Aboriginal cultural aspirations. In most of the other cases, the list-based approach generated frustration among Aboriginal rangers who felt they were engaged in purposeless killing. In contrast, we found that elders and rangers preferred site-based approaches that considered landscape and vegetation management from their culturally specific and highly contextual geographies of 'healthy country'. We outline instances where ranger groups have adopted site based management that has been informed by geographies of healthy country and argue that such an approach offers a better alternative to current list-based weed control and produces positive outcomes for Aboriginal communities. PMID- 30449303 TI - The impact of cold stress on genes expression pattern of mono- and sesquiterpene biosynthesis and their contents in Ocimum basilicum L. AB - Basil (Ocimum basilicum L.) contains valuable monoterpene and sesquiterpene compounds used for medical purposes. Environmental stresses are suggested to change the essential oil composition in medicinal plants. In the current investigation, an experiment was arranged in greenhouse to study the effect of cold stress on genes expression patterns of linalool synthase (LIS), beta-myrcene synthase (MYS), gamma-cadinene synthase (CDS), germacrene D synthase (GDS) and geraniol synthase (GES) which is involved in monoterpenes and sesquiterpenes biosynthesis in O. basilicum. The monoterpenes and sesquiterpenes composition and content were also investigated. Plants were exposed to temperatures 22 (control), 4 and 10 degrees C at 6 to 8 leaf stage for 12, 24 and 48 h. The genes expression levels were determined by real time PCR in plant leaves. Essential oil was extracted at flowering stage by distillation using Clevenger apparatus and its compounds were identified using gas chromatography/mass spectrometry (GC-MS). The results revealed that the LIS expression increasingly occurred to 4.86 fold at 10 degrees C after 12 h while that of GES reached to 5.7 fold at 10 degrees C after 48 h. Temperature 4 degrees C for 12 h increased the expression levels of MYS and GDS genes to 41.5 and 14.2 fold, respectively, while the expression level of CDS increased to 25.5 fold at 4 degrees C for 48 h. Significant differences (P <= 0.01) were observed among treatments with respect to all compounds except alpha-pinene and camphene. The maximum proportion of geraniol and gamma-cadinene were observed at 4 degrees C for 24 h, while the maximum proportion of germacrene D and alpha-bergamotene obtained at 10 degrees C for 12 h. The highest proportion of 1, 8-cineole was achieved at 4 degrees C for 48 h. Positive associations between germacrene D content and GDS expression (r = 0.8, P <= 0.05) and gamma-cadinene and CDS expression (r = 0.78, P <= 0.05) proposed that the content of terpenoid compounds in basil can be enhanced through increasing the expression levels of genes involved in their biosynthesis. PMID- 30449304 TI - Personalised Ecology. AB - The field of ecology has focused on understanding characteristics of natural systems in a manner as free as possible from biases of human observers. However, demand is growing for knowledge of human-nature interactions at the level of individual people. This is particularly driven by concerns around human health consequences due to changes in positive and negative interactions. This requires attention to the biased ways in which people encounter and experience other organisms. Here we define such a 'personalised ecology', and discuss its connections to other aspects of the field. We propose a framework of focal research topics, shaped by whether the unit of analysis is a single person, a single population, or multiple populations, and whether a human or nature perspective is foremost. PMID- 30449305 TI - Corrigendum to "A network analysis of DSM-5 posttraumatic stress disorder and functional impairment in UK treatment-seeking veterans" [J. Anxiety Disord. 57 (2018) 7-15]. PMID- 30449306 TI - Interexaminer Reliability of Seated Motion Palpation for the Stiffest Spinal Site. AB - OBJECTIVES: The purpose of this study was to assess the interexaminer reliability of palpation for stiffness in the cervical, thoracic, and lumbar spinal regions. METHODS: In this secondary data analysis, data from 70 patients from a chiropractic college outpatient clinic were analyzed. Two doctors of chiropractic palpated for the stiffest site within each spinal region. Each were asked to select the stiffest segment and to rate their confidence in their palpation findings. Reliability between examiners was calculated as Median Absolute Examiner Differences (MedianAED) and data dispersion as Median Absolute Deviation (MAD). Interquartile analysis of the paired examiner differences was performed. RESULTS: In total, 210 paired observations were analyzed. Nonparametric data precluded reliability determination using intraclass correlation. Findings included lumbar MedianAED = 0.5 vertebral equivalents (VE), thoracic = 1.7 VE, and cervical = 1.4 VE. For the combined dataset, the findings were MedianAED = 1.1 VE; MAD was lowest in the lumbar spine (0.3 VE) and highest in thoracic spine (1.4 VE), and for the combined dataset, MAD = 1.1 VE. Examiners agreed on the segment or the motion segment containing the stiffest site in 54% of the observations. CONCLUSIONS: Interexaminer reliability for palpation was good between 2 clinicians for the stiffest site in each region of the spine and in the combined dataset. This is consistent with previous studies of motion palpation using continuous analysis. PMID- 30449307 TI - Regarding the Suture Annuloplasty in Bicuspid Aortic Valve. PMID- 30449309 TI - Complement C3a receptor modulates embryonic neural progenitor cell proliferation and cognitive performance. AB - The complement system of innate immunity is emerging as a novel player in neurodevelopmental processes. The receptor for C3a, C3aR, shares a close evolutionary and functional relationship with C5a receptors. Whilst the C5a receptor, C5aR1, has been demonstrated to promote embryonic neural stem cell proliferation, little is known about the role of C3aR in this process. Here we show that C3aR is expressed in a similar manner to C5aR1 in mice, at the apical pole of the embryonic ventricular zone, though it has an opposing function. Using in utero delivery of C3aR agonist and antagonist compounds to the embryonic ventricle, we demonstrate that C3aR functions to decrease proliferation of apical neural progenitor cells (NPC). Intriguingly, C3aR-/- animals also have altered NPC proliferation, but demonstrate an opposing phenotype to animals subjected to pharmacological blockade of C3aR. Finally, despite a grossly normal development of C3aR-/- animals, cognitive behavioural testing of adult mice showed subtle deficits in recall memory. These data demonstrate that in addition to C5a, C3a also has a critical role in the normal development of the mammalian brain. PMID- 30449310 TI - Corrigendum to "Anti-neuroinflammatory effects of 20C from Gastrodia elata via regulating autophagy in LPS-activated BV-2 cells through MAPKs and TLR4/Akt/mTOR signaling pathways" [Molecular Immunology 99 (2018) 115-123]. PMID- 30449311 TI - Thermogenic fat. PMID- 30449312 TI - Chinese national policy initiative for the management of childhood myopia. PMID- 30449314 TI - Mitochondria-Derived Vesicles Deliver Antimicrobial Reactive Oxygen Species to Control Phagosome-Localized Staphylococcus aureus. AB - Pathogenic bacteria taken up into the macrophage phagosome are the target of many anti-microbial mechanisms. Although mitochondria-derived antimicrobial effectors like reactive oxygen species (mROS) aid in bacterial killing, it is unclear how these effectors reach bacteria within the phagosomal lumen. We show here that endoplasmic reticulum stress triggered upon methicillin-resistant Staphylococcus aureus (MRSA) infection induces mROS that are delivered to bacteria-containing phagosomes via mitochondria-derived vesicles (MDVs). The endoplasmic reticulum stress sensor IRE1alpha induces mROS, specifically hydrogen peroxide (mH2O2), upon MRSA infection. MRSA infection also stimulates the generation of MDVs, which require the mitochondrial stress response factor Parkin, and contributes to mH2O2 accumulation in bacteria-containing phagosomes. Accumulation of phagosomal H2O2 requires Toll-like receptor signaling and the mitochondrial enzyme superoxide dismutase-2 (Sod2), which is delivered to phagosomes by MDVs. Sod2 depletion compromises mH2O2 production and bacterial killing. Thus, mitochondrial redox capacity enhances macrophage antimicrobial function by delivering mitochondria derived effector molecules into bacteria-containing phagosomes. PMID- 30449313 TI - Environmental risk assessment of metformin and its transformation product guanylurea. I. Environmental fate. AB - Metformin (MET) is a pharmaceutical with very high use worldwide that is excreted in unchanged form, leading to concern about potential aquatic life impacts associated with MET, and its primary transformation product guanylurea (GUU). This study presents, in two companion papers, a risk assessment following internationally accepted guidelines of MET and GUU in surface water based on literature data, previously unpublished studies, and a new degradation test that resolves conflicting earlier results. Previous studies have shown that MET is removed during sewage treatment, primarily through transformation to GUU. In addition, measurements in WWTPs suggest that MET is not only transformed to GUU, but that GUU is further biodegraded. A prolonged inherent biodegradation test strongly suggests not only primary transformation of MET to GUU, but also subsequent full mineralization of GUU, with both degradation phases starting after a clear lag phase. MET may partition from surface water to sediment, where both transformation to GUU and in part mineralization is possible, depending on the presence of competent degrading microorganisms. In addition, MET may form non extractable residues in sediments (12.8-73.5%). Both MET and GUU may be anaerobically degraded during sludge digestion, in soils or in sediments. Bioconcentration factor (BCF) values in crops and most plants are close to 1 suggesting low bioaccumulation potential, moreover, at least some plants can metabolize MET to GUU; however, in aquatic plants higher BCFs were found, up to 53. Similarly, neither MET nor GUU are expected to bioaccumulate in fish based on estimated values of BCFs <=3.16. PMID- 30449315 TI - Plant-Derived Exosomal MicroRNAs Shape the Gut Microbiota. AB - The gut microbiota can be altered by dietary interventions to prevent and treat various diseases. However, the mechanisms by which food products modulate commensals remain largely unknown. We demonstrate that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNAs that alter microbiome composition and host physiology. Ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs that target various genes in Lactobacillus rhamnosus (LGG). Among these, GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN-RNAs or I3A, a ligand for aryl hydrocarbon receptor, are sufficient to induce production of IL-22, which is linked to barrier function improvement. These functions of GELN-RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. These findings reveal how plant products and their effects on the microbiome may be used to target specific host processes to alleviate disease. PMID- 30449317 TI - Ecological Validity in Bilingualism Research and the Bilingual Advantage. AB - Traditional research in bilingualism has consistently found that switching languages is effortful, placing demands on neural systems of cognitive control. This finding runs counter to most bilinguals' intuitive experience. We review a body of recent work showing that, in fact, when bilinguals switch languages voluntarily, both the behavioral cost of switching and the associated recruitment of cognitive control areas are greatly reduced or completely eliminated. This suggests that switching languages is not inherently effortful, but rather, particular communicative demands may make it costly. The new evidence also challenges the basic premise underlying the bilingual advantage hypothesis. We articulate a more nuanced version of it, in which the advantage is limited to bilinguals who frequently switch languages based on external constraints. PMID- 30449316 TI - Biology and Taxonomy of crAss-like Bacteriophages, the Most Abundant Virus in the Human Gut. AB - CrAssphages represent the most abundant virus in the human gut microbiota, but the lack of available genome sequences for comparison has kept them enigmatic. Recently, sequence-based classification of distantly related crAss-like phages from multiple environments was reported, leading to a proposed familial-level taxonomic group. Here, we assembled the metagenomic sequencing reads from 702 human fecal virome/phageome samples and analyzed 99 complete circular crAss-like phage genomes and 150 contigs >=70 kb. In silico comparative genomics and taxonomic analysis enabled a classification scheme of crAss-like phages from human fecal microbiomes into four candidate subfamilies composed of ten candidate genera. Laboratory analysis was performed on fecal samples from an individual harboring seven distinct crAss-like phages. We achieved crAss-like phage propagation in ex vivo human fecal fermentations and visualized short-tailed podoviruses by electron microscopy. Mass spectrometry of a crAss-like phage capsid protein could be linked to metagenomic sequencing data, confirming crAss like phage structural annotations. PMID- 30449318 TI - Spatial Embedding Imposes Constraints on Neuronal Network Architectures. AB - Recent progress towards understanding circuit function has capitalized on tools from network science to parsimoniously describe the spatiotemporal architecture of neural systems. Such tools often address systems topology divorced from its physical instantiation. Nevertheless, for embedded systems such as the brain, physical laws directly constrain the processes of network growth, development, and function. We review here the rules imposed by the space and volume of the brain on the development of neuronal networks, and show that these rules give rise to a specific set of complex topologies. These rules also affect the repertoire of neural dynamics that can emerge from the system, and thereby inform our understanding of network dysfunction in disease. We close by discussing new tools and models to delineate the effects of spatial embedding. PMID- 30449319 TI - Early Human Hemogenic Endothelium Generates Primitive and Definitive Hematopoiesis In Vitro. AB - The differentiation of human embryonic stem cells (hESCs) to hematopoietic lineages initiates with the specification of hemogenic endothelium, a transient specialized endothelial precursor of all blood cells. This in vitro system provides an invaluable model to dissect the emergence of hematopoiesis in humans. However, the study of hematopoiesis specification is hampered by a lack of consensus in the timing of hemogenic endothelium analysis and the full hematopoietic potential of this population. Here, our data reveal a sharp decline in the hemogenic potential of endothelium populations isolated over the course of hESC differentiation. Furthermore, by tracking the dynamic expression of CD31 and CD235a at the onset of hematopoiesis, we identified three populations of hematopoietic progenitors, representing primitive and definitive subsets that all emerge from the earliest specified hemogenic endothelium. Our data establish that hemogenic endothelium populations endowed with primitive and definitive hematopoietic potential are specified simultaneously from the mesoderm in differentiating hESCs. PMID- 30449320 TI - Studies in an Early Development Window Unveils a Severe HSC Defect in both Murine and Human Fanconi Anemia. AB - Fanconi anemia (FA) causes bone marrow failure early during childhood, and recent studies indicate that a hematopoietic defect could begin in utero. We performed a unique kinetics study of hematopoiesis in Fancg-/- mouse embryos, between the early embryonic day 11.5 (E11.5) to E12.5 developmental window (when the highest level of hematopoietic stem cells [HSC] amplification takes place) and E14.5. This study reveals a deep HSC defect with exhaustion of proliferative and self renewal capacities very early during development, together with severe FA clinical and biological manifestations, which are mitigated at E14.5 due to compensatory mechanisms that help to ensure survival of Fancg-/- embryos. It also reports that a deep HSC defect is also observed during human FA development, and that human FA fetal liver (FL) HSCs present a transcriptome profile similar to that of mouse E12.5 Fancg-/- FL HSCs. Altogether, our results highlight that early mouse FL could represent a good alternative model for studying Fanconi pathology. PMID- 30449322 TI - From the Editor's desk....: December 2018. PMID- 30449321 TI - Genetic Engineering of Human Embryonic Stem Cells for Precise Cell Fate Tracing during Human Lineage Development. AB - It is highly desirable to specify human developmental principles in an appropriate human model with advanced genetic tools. However, genetically engineering human cells with lineage-tracing systems has not been achieved. Here we introduce strategies to construct lineage-tracing systems in human embryonic stem cells (hESCs). The AAVS1 locus was suitable for the integration of the conditional reporter. The Cre-LoxP and Flp-FRT systems were highly sensitive, which may cause inaccurate lineage labeling in human cells. The recombination sensitivity and tracing fidelity could be finely tuned by modification of the LoxP recombination site. Moreover, tamoxifen-controllable CreERT2-LoxP and FlpERT2-FRT systems showed compelling advantages in tightly tracing human lineages temporally. In proof-of-principle experiments, we traced human PAX6+ neuroectoderm cells and revealed their full neural lineage differentiation potency both in vitro and in vivo. Devising and optimizing of lineage-tracing systems in hESCs will thus set up a solid foundation for human developmental studies. PMID- 30449323 TI - Functionalized carbon nanotube adsorption interfaces for electron transfer studies of galactose oxidase. AB - Modified electrodes featuring specific adsorption platforms able to access the electrochemistry of the copper containing enzyme galactose oxidase (GaOx) were explored, including interfaces featuring nanomaterials such as nanoparticles and carbon nanotubes (CNTs). Electrodes modified with various self-assembled monolayers (SAMs) including those with attached nanoparticles or amide-coupled functionalized CNTs were examined for their ability to effectively immobilize GaOx and study the redox activity related to its copper core. While stable GaOx electrochemistry has been notoriously difficult to achieve at modified electrodes, strategically designed functionalized CNT-based interfaces, cysteamine SAM-modified electrode subsequently amide-coupled to carboxylic acid functionalized single wall CNTs, were significantly more effective with high GaOx surface adsorption along with well-defined, more reversible, stable (>= 8 days) voltammetry and an average ET rate constant of 0.74 s-1 in spite of increased ET distance - a result attributed to effective electronic coupling at the GaOx active site. Both amperometric and fluorescence assay results suggest embedded GaOx remains active. Fundamental ET properties of GaOx may be relevant to biosensor development targeting galactosemia while the use functionalized CNT platforms for adsorption/electrochemistry of electroactive enzymes/proteins may present an approach for fundamental protein electrochemistry and their future use in both direct and indirect biosensor schemes. PMID- 30449324 TI - Coalesced thermal and electrotransfer mediated delivery of plasmid DNA to the skin. AB - Efficient gene delivery and expression in the skin can be a promising minimally invasive technique for therapeutic clinical applications for immunotherapy, vaccinations, wound healing, cancer, and peripheral artery disease. One of the challenges for efficient gene electrotransfer (GET) to skin in vivo is confinement of expression to the epithelium. Another challenge involves tissue damage. Optimizing gene expression profiles, while minimizing tissue damage are necessary for therapeutic applications. Previously, we established that heating pretreatment to 43 degrees C enhances GET in vitro. We observed a similar trend in vivo, with an IR-pretreatment for skin heating prior to GET. Currently, we tested a range of GET conditions in vivo in guinea pigs with and without preheating the skin to ~43 degrees C. IR-laser heating and conduction heating were tested in conjunction with GET. In vivo electrotransfer to the skin by moderately elevating tissue temperature can lead to enhanced gene expression, as well as achieve gene transfer in epidermal, dermal, hypodermal and muscle tissue layers. PMID- 30449326 TI - Outcomes and Long-term Effects of Pregnancy in Women With Biologic and Mechanical Valve Prostheses. AB - The optimal choice of prosthetic heart valve for women of child-bearing age is not well established. We conducted this retrospective cohort study to compare pregnancy outcomes and maternal mortality and morbidity, including long-term valve reoperation, between women with biologic and mechanical valve replacements. Women <=50 years of age with prosthetic heart valve implantation and subsequent pregnancy in California, New Jersey, and New York State between 1990 to 2015 were identified using mandatory state inpatient databases. Average follow-up time was 9.4 years (SD 6.7 years). Of 11,930 women who underwent 14,017 valve replacements, pregnancies in 417 women with 241 biologic valves, and 217 mechanical valves were identified. Women with mechanical prostheses experienced significantly higher rates of pregnancy loss, with almost 2/3 of pregnancies ending in either spontaneous or induced abortion, and hemorrhage and thromboembolic events during delivery. Delivery was a significant risk factor for reoperation for both biologic (hazard ratio 2.5, 95% confidence interval 1.6 to 3.8 after time-dependent propensity matching) and mechanical (hazard ratio 2.3, 95% confidence interval 1.3 to 4.1 after time-dependent propensity matching) prostheses. Half of reoperations in women with mechanical valves who experienced pregnancy occurred within 1 year after delivery, and most were associated with mitral valve thrombosis. In conclusion, pregnancy accelerates time to reoperation for both biologic and mechanical prostheses. Mechanical valves are at particular risk for near-term valve failure after delivery, and compared with bioprostheses, are associated with higher rates of adverse events during pregnancy. PMID- 30449327 TI - Assessment of medication management capacity in a predominantly African American and Caribbean American sample of adults with intractable epilepsy. AB - INTRODUCTION: Suboptimal or partial adherence to antiepileptic drugs (AEDs) is an avoidable cause of seizures and deleterious outcomes in epilepsy. As self-rated adherence may be unreliable, suboptimal adherence may go undetected. This study assessed generalizability of a performance-based measure of medication management to patients with intractable epilepsy. MATERIALS AND METHODS: Participants were 50 adults (age = 42 +/- 14 years, 60% female, 82% Black, 20% Hispanic/Latino) with >=2 seizures in the preceding 6 months. Antiepileptic drug adherence was electronically monitored for one month via Medication Event Monitoring Systems (MEMS) and self-rated (1 = very poor to 6 = excellent). The Medication Management Ability Assessment (MMAA) was administered at follow-up and scored by raters blind to adherence results. Spearman correlations and Poisson regressions assessed their associations. RESULTS: On average, participants self-reported good to-very good adherence. According to MEMS, participants took AEDs as prescribed 73% of the time; most participants (58%) missed >=3 doses. The MMAA demonstrated strong internal consistency (Kuder-Richardson 20 = 0.81) and was associated with MEMS: percentage of days doses were taken correctly (rs = 0.29, p = 0.04) and frequency of missed doses (rs = -0.31, p = 0.03). The MMAA was not associated with self-rated adherence. Poisson regressions showed that self-ratings and MMAA performance accounted for unique variance in frequency of missed AED doses. CONCLUSIONS: These findings provide evidence of the MMAA's criterion validity as a measure of capacity to manage AEDs. It may prove useful in cases where suboptimal adherence is suspected but unreported by patients. Its lack of significant association with self-rated adherence is consistent with prior reports; however, future studies should replicate these findings with larger samples. PMID- 30449328 TI - Does memantine improve memory in subjects with focal-onset epilepsy and memory dysfunction? A randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: Excitotoxic injury involving N-methyl-d-aspartate (NMDA) receptor hyperactivity contributes to epilepsy-related memory dysfunction (ERMD). Current treatment strategies for ERMD have limited efficacy and fail to target the underlying pathophysiology. The present pilot study evaluated the efficacy of memantine, an NMDA receptor antagonist, for the treatment of ERMD in adults with focal-onset seizures. METHODS: Subjects underwent cognitive testing at baseline, after a 13-week randomized, parallel-group, double-blinded phase (of memantine titrated to 10 mg bid or placebo), and following a 13-week open-label extension phase (of memantine titrated to 10 mg bid). The selective reminding test (SRT) continuous long-term retrieval (CLTR) score and 7/24 Spatial Recall Test learning score served as the primary outcome measures. Secondary measures included tests of attention span, fluency, visual construction, and response inhibition, as well as assessments of quality of life, depression, sleepiness, and side effects. RESULTS: Seventeen subjects contributed data to the blinded phase (n = 8 memantine, n = 9 placebo). No significant differences were seen between groups on the primary or secondary outcome measures. Pooled data at the end of the open label phase from 10 subjects (initially randomized to memantine n = 3 or placebo n = 7) demonstrated statistically significant improvement from baseline in CLTR score, memory-related quality of life, spatial span, and response inhibition. No significant changes were evident in depression, sleepiness, side effects, or seizure frequency throughout the trial. SIGNIFICANCE: Results demonstrated no significant effect of memantine on cognition when assessed at the end of the blinded period. Pooled data at the end of the open-label phase showed significant improvement over baseline performance in measures of verbal memory, frontal executive function, and memory-related quality of life. These improvements, however, may be due to practice effects and should be interpreted cautiously. Findings suggest a favorable safety profile of memantine in the setting of epilepsy. PMID- 30449329 TI - Trimethylamine N-oxide: A new therapeutic target for atrial fibrillation? PMID- 30449330 TI - The challenge of heart failure diagnosis and management in primary care in elderly population: Mere illusion or concrete opportunity? PMID- 30449325 TI - Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations. AB - Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) that include G660D, R678Q, E693K, and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the TMD/JMD mutations function by improving the active dimer interface or stabilizing an activating conformation. Further, we found that HER2 G660D employed asymmetric kinase dimerization for activation and signaling. Importantly, anti-HER2 antibodies and small-molecule kinase inhibitors blocked the activity of TMD/JMD mutants. Consistent with this, a G660D germline mutant lung cancer patient showed remarkable clinical response to HER2 blockade. PMID- 30449331 TI - Genome-edited MSCs that express GCP-2 and SDF-1alpha might be a novel therapeutic strategy for the treatment of ischemic vascular disease. PMID- 30449332 TI - Inhibition of HMGB1 ameliorates cardiac fibrosis through regulation of endothelial-to-mesenchymal transition. PMID- 30449333 TI - Human adipose-derived stem cells combined with high mobility group box protein 1 might be a novel therapeutic strategy for the treatment of peripheral arterial disease. PMID- 30449334 TI - Usefulness of red blood cell distribution width to stratify individuals with elevated homocysteine levels: Implications in the general population. PMID- 30449335 TI - Soluble regulators of Interleukin-1 signaling: Novel biomarkers for early acute myocardial infarction diagnosis and to predict ischemia/reperfusion injury? PMID- 30449336 TI - Letter regarding Groves et al. "Feasibility of low radiation dose retrospectively gated cardiac CT for functional analysis in adult congenital heart disease". PMID- 30449337 TI - Retraction notice to "Enhanced IL-17 signalling following myocardial ischaemia/reperfusion injury" [Int. J. Cardiol. 163 (2013) 326-334]. PMID- 30449338 TI - Diagnostic performance of cCTA derived stenosis predictors to detect hemodynamic significant coronary stenosis. PMID- 30449339 TI - Response to letter from Madias regarding our article "Admission heart rate and in hospital course of patients with Takotsubo syndrome". PMID- 30449340 TI - Corrigendum to "Effects of gradual and later weaning ages when feeding high milk replacer rates on growth, textured starter digestibility, and behavior in Holstein calves from 0 to 4 months of age" (J. Dairy Sci. 101:9863-9875). PMID- 30449341 TI - Letter From the Editor: Thinking Pink. PMID- 30449342 TI - Low-grade Adenosquamous Carcinoma of the Breast: A Case Report. PMID- 30449343 TI - High-Risk Breast Lesions and Current Management. PMID- 30449344 TI - Advances in Breast MRI in the Setting of Ductal Carcinoma In Situ. PMID- 30449345 TI - Advances in Breast Localization Techniques: An Opportunity to Improve Quality of Care and Patient Satisfaction. PMID- 30449346 TI - Breast Cancer Screening and Optimizing Recommendations. PMID- 30449347 TI - Contrast-Enhanced Spectral Mammography in Breast Imaging. PMID- 30449348 TI - Molecular Imaging in Management of Breast Cancer. PMID- 30449349 TI - Role of Magnetic Resonance Image in Children with Lumbosacral and Perineal Hemangiomas: Case Reports and Review of the Literature. AB - Cutaneous hemangiomas are the most frequent benign tumors in children. When they affect the lumbar and perineal area some cases can be associated with an occult spinal dysraphism. The management of these hemangiomas lack consensus. We report 3 cases of children with lumbosacral and perineal hemangiomas with magnetic resonance image abnormalities and we review the literature to find out the type and timing of tests that should be performed to complete the study in these patients. Ultrasound is typically requested as young as possible, as this imaging technique is not possible 11the posterior spinal elements have ossified. MRI is the gold standard for diagnosing occult spinal dysraphism. According to the literature, the mean age for MRI screening should be around 6 months, when the fat formation in the filum terminale is expanded. In our opinion, an MRI scan should be performed at 6 months of age in every children with lumbar or perineal hemangioma regardless the lesion size, neurological symptoms or the ultrasound results. PMID- 30449350 TI - Up-regulated RxLR effector genes of Plasmopara viticola in synchronized host-free stages and infected leaves of hosts with different susceptibility. AB - Fast recognition of host signals and early activation of infection mechanisms in Plasmopara viticola are decisive for successful infestation of Vitis vinifera. To better understand interactive processes at the first front line of combat between the pathogen and its host, a specific pre-infective stage was generated in a host free system. Zoospore encystment was triggered within minutes after treatment with CaCl2. Subsequently, high rates of germ tube formation occurred in a synchronized manner. This method was employed to compare development-related gene expression in strains of different virulence. Soon after germination, spores showed strong up-regulation of two effector genes, PvRxLR18 and PvRxLR28, particularly in the high virulence strain. On infected grapevine leaf-discs of cultivars with different susceptibility, a similar up-regulation was found at 6 hours post inoculation (hpi). This effect was much more evident in the high virulence than in the low virulence strain and was significantly higher on leaves of the tolerant cultivar Regent than on Muller-Thurgau. In addition, PvRxLR67 was up-regulated 24 hpi in the high virulence strain indicating that different effectors are active in later infection stages. Differences in the expression pattern of RxLR effector genes between the two strains corroborated with infection symptoms visible by sporulation. PMID- 30449351 TI - Microbial and pigment profile of the reddish patch occurring within Tuber magnatum ascomata. AB - Tuber magnatum Pico, the delectable white truffle, is the most prized truffle species. In this study, we examined the reddish pigmentation that frequently occurs in T. magnatum ascomata for the presence of pigment-producing bacteria. The inner part of the reddish-pigmented region of three T. magnatum ascomata collected in North-Central Italy was analysed. This reddish part was used to establish a bacterial culture collection and to extract the total genomic DNA in order to obtain a library of 16S rRNA genes representative of the bacterial community. The molecular approach revealed limited microbial diversity within the reddish-pigmented regions compared to the wider range of bacterial species commonly found at the same maturation stage and season in T. magnatum ascomata. The pigmented regions showed a prevalence of specific bacterial species belonging to alpha-, beta- and gamma- Proteobacteria, Actinobacteria and Firmicutes. From the tandem mass spectrometry analysis of the extracted pigment, four compounds were identified: i) bixin, ii) beta-carotene, iii) cis-1-glycosyl-apo-8'- lycopene and iv) the fucoxanthin. Carotenoid producing species such as Microbacterium and Chryseobacterium emerged as the most likely cause of the peculiar reddish pigment production. Indeed, our findings suggest that the peculiar reddish pigment might be produced by these bacterial species. PMID- 30449352 TI - Four new Ophiostoma species associated with hardwood-infesting bark beetles in Norway and Poland. AB - Ophiostoma spp. (Ophiostomatales, Ascomycota) are well-known fungi associated with bark and ambrosia beetles (Curculionidae: Scolytinae, Platypodinae). Fungi in the Ophiostomatales include serious tree pathogens as well as agents of timber blue-stain. Although these fungi have been extensively studied in the northern hemisphere, very little is known regarding their occurrence on hardwoods in Europe. The aims of the present study were to identify and characterize new Ophiostoma spp. associated with bark and ambrosia beetles infesting hardwoods in Norway and Poland, and to resolve phylogenetic relationships of Ophiostoma spp. related to the Norwegian and Polish isolates, using multigene phylogenetic analyses. Results obtained from five gene regions (ITS, LSU, beta-tubulin, calmodulin, translation elongation factor 1-alpha) revealed four new Ophiostoma spp. These include Ophiostoma hylesinum sp. nov., O. signatum sp. nov., and O. villosum sp. nov. that phylogenetically are positioned within the Ophiostoma ulmi complex. The other new species, Ophiostoma pseudokarelicum sp. nov. reside along with Ophiostoma karelicum in a discrete, well-supported phylogenetic group in Ophiostoma s. stricto. The results of this study clearly show that the diversity and ecology of Ophiostoma spp. on hardwoods in Europe is poorly understood and that further studies are required to enrich our knowledge about these fungi. PMID- 30449353 TI - A mid-Cretaceous ambrosia fungus, Paleoambrosia entomophila gen. nov. et sp. nov. (Ascomycota: Ophiostomatales) in Burmese (Myanmar) amber, and evidence for a femoral mycangium. AB - An ambrosia fungus is described from filamentous sporodochia adjacent to a wood boring ambrosia beetle (Coleoptera: Curculionidae: Platypodinae) in mid Cretaceous Burmese amber. Yeast-like propagules and hyphal fragments of Paleoambrosia entomophila gen. nov. et sp. nov. occur in glandular sac mycangia located inside the femur of the beetle. This is the first record of a fossil ambrosia fungus, showing that symbiotic associations between wood-boring insects and ectosymbiotic fungi date back some 100 million years ago. The present finding moves the origin of fungus-growing by insects from the Oligocene to the mid Cretaceous and suggests a Gondwanan origin. PMID- 30449354 TI - Sporothrix brasiliensis induces a more severe disease associated with sustained Th17 and regulatory T cells responses than Sporothrix schenckii sensu stricto in mice. AB - Little is known about the differences in the CD4+ T-cell response induced by Sporothrix schenckii and Sporothrix brasiliensis, the most virulent species that cause sporotrichosis. Here, the helper (Th) and regulatory T cells (Tregs) responses were evaluated comparatively in a murine model of sporotrichosis on days 7, 21 and 35 after subcutaneous infection with either S. schenckii or S. brasiliensis conidia. The fungal load was measured at the site of infection, as well as in the liver and spleen. The Th1/Th17/Tregs responses were analyzed in the spleen, while the level of IL-2, IL-4, IL-6, TNF-alpha, IFN-gamma, IL-17A and IL-10 cytokines were measured at the local site of infection on 24 h postinfections and in sera on the indicated days. S. brasiliensis caused a longer lasting infection in the skin and chronic systemic dissemination associated to more severe granulomatous lesions. Similar Th1/Th1-Th17/Tregs responses were induced by both S. brasiliensis and S. schenckii on 7th and 21st d.p.i but on 35 d.p.i a reduction of Th1 and Th1-Th17 cells, associated to higher values of Th17/Tregs cells was observed only in S. brasiliensis-infected mice. In summary, S. brasiliensis caused a more severe disease associated with sustained Th17/Tregs responses than S. schenckii in mice. PMID- 30449355 TI - Morphology, zoospore ultrastructure, and phylogenetic position of Polyphlyctis willoughbyi, a new species in Chytridiales (Chytridiomycota). AB - The purpose of our research is to investigate the morphology, zoospore ultrastructure, and molecular phylogenetic placement of a chytrid from Australia. From a survey of chytrid fungi in New South Wales, Australia, we isolated strain PL AUS 026 and putatively identified it as Polyphlyctis unispina. Light microscopic evaluation determined strain PL AUS 026 to be similar to two other strains of P. unispina characterized in the literature but to have a more complex thallus than that of the type. Molecular phylogenetic analyses placed our strain as sister of or basal to Chytridiaceae, Chytridiales. Ultrastructural analysis of the zoospore of strain PL AUS 026 revealed unique features. On the basis of our analyses we designate strain PL AUS 026 as a new species, Polyphlyctis willoughbyi. This research extends our concept of Chytridiaceae systematics and ultrastructural variation in the Chytridiales zoospore. PMID- 30449356 TI - Ceratocystidaceae exhibit high levels of recombination at the mating-type (MAT) locus. AB - Mating is central to many fungal life cycles and is controlled by genes at the mating-type (MAT) locus. These genes determine whether the fungus will be self sterile (heterothallic) or self-fertile (homothallic). Species in the ascomycete family Ceratocystidaceae have different mating strategies, making them interesting to consider with regards to their MAT loci. The aim of this study was to compare the composition of the MAT locus flanking regions in 11 species of Ceratocystidaceae representing four genera. Genome assemblies for each species were examined to identify the MAT locus and determine the structure of the flanking regions. Large contigs containing the MAT locus were then functionally annotated and analysed for the presence of transposable elements. Genes typically flanking the MAT locus in sordariomycetes were found to be highly conserved in the Ceratocystidaceae. The different genera in the Ceratocystidaceae displayed little synteny outside of the immediate MAT locus flanking genes. Even though species ofCeratocystis did not show much synteny outside of the immediate MAT locus flanking genes, species of Huntiella and Endoconidiophora were comparatively syntenic. Due to the high number of transposable elements present in Ceratocystis MAT flanking regions, we hypothesise that Ceratocystis species may have undergone recombination in this region. PMID- 30449357 TI - Cell wall structure of secreted laccase-silenced strain in Lentinula edodes. AB - Laccase1 (Lcc1) is abundantly secreted from vegetative mycelia into culture medium by Lentinula edodes. Down-regulation of lcc1 in L. edodes results in abnormal hyphal structure and thinner cell wall in mycelia. In this study, we observed the effects of Lcc1 on the hyphal morphology and cell wall structure of L. edodes. A thick cell wall and fibrous layer were clearly observed in the lcc1 silenced strain ivrL1#32, when purified Lcc1 (0.1 mU/mL) was added to the culture medium. The ratio of cell wall polysaccharide contents was compared between the ivrL1#32 strain and the wild-type (WT) strain SR-1, revealing that levels of the alkali soluble beta-1,3-1,6-glucan were significantly lower in the lcc1-silenced strain than in the WT strain. Chronological analysis revealed that chitin content in the cell wall did not increase over time, but that the alkali soluble beta-1,3 1,6-glucan content increased after Lcc1 secretion in the WT. Taken together, these data suggest that the increased level of beta-1,3-1,6-glucan induced by Lcc1 in the mycelial cell wall contributes to increased cell wall thickness and strength. PMID- 30449358 TI - Genomic overview of closely related fungi with different Protea host ranges. AB - Genome comparisons of species with distinctive ecological traits can elucidate genetic divergence that influenced their differentiation. The interaction of a microorganism with its biotic environment is largely regulated by secreted compounds, and these can be predicted from genome sequences. In this study, we considered Knoxdaviesia capensis and Knoxdaviesia proteae, two closely related saprotrophic fungi found exclusively in Protea plants. We investigated their genome structure to compare their potential inter-specific interactions based on gene content. Their genomes displayed macrosynteny and were approximately 10 % repetitive. Both species had fewer secreted proteins than pathogens and other saprotrophs, reflecting their specialized habitat. The bulk of the predicted species-specific and secreted proteins coded for carbohydrate metabolism, with a slightly higher number of unique carbohydrate-degrading proteins in the broad host-range K. capensis. These fungi have few secondary metabolite gene clusters, suggesting minimal competition with other microbes and symbiosis with antibiotic producing bacteria common in this niche. Secreted proteins associated with detoxification and iron sequestration likely enable these Knoxdaviesia species to tolerate antifungal compounds and compete for resources, facilitating their unusual dominance. This study confirms the genetic cohesion between Protea associated Knoxdaviesia species and reveals aspects of their ecology that have likely evolved in response to their specialist niche. PMID- 30449359 TI - A Fusarium solani endophyte vs fungicides: Compatibility in a Fusarium oxysporum f.sp. radicis-lycopersici - tomato pathosystem. AB - The potential of FsK, a non-pathogenic endophytic Fusarium solani strain, to be utilized as a biocontrol agent in combination with nine selected fungicides registered in tomato crops in Greece was evaluated. In vitro fungitoxicity tests revealed that FsK was insensitive to doses exceeding 100 MUg/mL of thiophanate methyl, fenhexamid, cyprodinil, boscalid and mancozeb. On the contrary, prochloraz, fludioxonil, pyraclostrobin and difenoconazole were most toxic to FsK. None of the later fungicides affected conidial production in an adverse way. Drenching of tomato plants with the above fungicides at recommended doses did not significantly affect colonization of tomato roots by FsK as revealed by in vitro isolation and Real Time PCR quantification. The disease suppressive ability of FsK against Fusarium oxysporum f.sp.radicis lycopersici (FORL) was not adversely affected by the post-inoculation application of commercial formulations of fludioxonil (Switch) and pyraclostrobin (Comet) at the recommended doses. Even more, the Comet-FsK combination resulted in enhanced disease suppression compared to either of the two treatments applied individually. In conclusion, not only biocontrol agent FsK is suitable for use in tomato integrated disease management programs that include all tested fungicides but also, some FsK -fungicide combinations can have additive effect against FORL disease incidence. PMID- 30449360 TI - Survival and redox activity of Friedmanniomyces endolithicus, an Antarctic endemic black meristematic fungus, after gamma rays exposure. AB - Despite living organisms are not exposed to acute ionizing radiation under natural conditions, some exhibit a high radiation resistance. Understanding this phenomenon is important for assessing the impact of radiation-related accidents, occupational exposures and space missions. In this context, in this study we analyzed the effect of gamma rays on the Antarctic cryptoendolithic melanized fungus Friedmanniomyces endolithicus CCFEE 5208 and demonstrated its resistance to acute doses of gamma radiation (up to 400 Gy), accompanied by increase in metabolic activity. PMID- 30449361 TI - Corrigendum to "PsAAT3, an oomycete-specific aspartate aminotransferase, is required for full pathogenicity of the oomycete pathogen Phytophthora sojae" [FUNBIO 122/4 (2016) 620-630]. PMID- 30449362 TI - ? PMID- 30449363 TI - ? PMID- 30449364 TI - [Old age in Medieval times]. AB - Europe in the Middle Ages had no experience of gerontology as we know it today. The categorisation of old age was based on symbolic relationships with the world, inherited from Antiquity, and resulted in an ambivalent image of this age. Our knowledge in the area is derived mainly from fiction, from scholarly texts of a philosophical, moralising or medical nature, each interacting with the other. This observation is backed up by a moral treatise on the 'four ages of man' written in the 13th century by Philip of Novara. PMID- 30449365 TI - [The adaptation of society to ageing today]. AB - Living at home as long as possible, adapting 'old age' policies to dependent elderly people, using new technologies to enable elderly people to remain at home and funding dependence are just some of the challenges facing today's society. The law relating to the adaptation of society to ageing was constructed around the notion of autonomy. This article presents an overview of this complex patient management. PMID- 30449366 TI - [The adaptation of society to ageing today]. AB - Living at home as long as possible, adapting 'old age' policies to dependent elderly people, using new technologies to enable elderly people to remain at home and funding dependence are just some of the challenges facing today's society. The law relating to the adaptation of society to ageing was constructed around the notion of autonomy. This article presents an overview of this complex patient management. PMID- 30449367 TI - [Evolution of the status of family carers]. AB - Family carers play a key and indispensable role in today's society. What is their legal status and what have been the stages of their recognition? It would appear that their situation fluctuates between a status in the process of being constructed and the temptation of self-sacrifice. PMID- 30449368 TI - [Non-pharmacological therapies and neuropsychological disorders in institutions]. AB - Non-pharmacological therapies are now used in many nursing homes often with residents presenting a risk of behavioural disorders. They include music therapy, animal-assisted therapy, physical activity as well as other approaches such as light therapy or aromatherapy. It requires rigorous assessment, the permanent involvement and engagement of residents as well as the staff as part of a compassionate and participative approach. PMID- 30449369 TI - [Fragilty of elderly people in Quebec, the role of the nurse]. AB - The ageing of the population is an issue which concerns the whole planet and Quebec is no exception. When caring for fragil elderly people, the nurse's role is deployed in different contexts. Care in the home is often prioritised and innovations are emerging to promote professionals in this area. In the hospital setting, notably, there is a programme in which the nurse is given a central role. This article presents an overview of the challenges in terms of training and long-term care. PMID- 30449371 TI - ? PMID- 30449370 TI - ? PMID- 30449372 TI - ? PMID- 30449373 TI - Sex-Specific Differences in Risk Factors for Development of Heart Failure in Women. AB - Sex specific differences exist in the impact of risk factors for the development of heart failure (HF). Addressing these differences can have an impact on prevention of HF. This article reviews sex-specific risk factors associated with development of HF. These risk factors include current smoking, diabetes, hypertension, and myocardial infarction. Other risks for HF are toxins, inflammation, and other chronic conditions, such as sleep breathing disorders, anemia, obesity, and renal insufficiency. Some of these risks factors present risk reduction opportunities that may improve outcomes. PMID- 30449374 TI - Implantable Cardioverter-Defibrillators and Cardiac Resynchronization Therapy in Women. AB - Implantable cardioverter-defibrillator and cardiac resynchronization therapy devices have been prescribed for patients with heart failure for several decades. Factors leading to increased usage include significant enhancements in technology and availability of multiple randomized clinical trials demonstrating their benefit with improved implementation of evidence-based guidelines. Despite these advances, gaps still exist in the utilization and referral of these devices, particularly among women. This article reviews the literature on these devices with a focus on gender differences and proposes reasons for why they exist. PMID- 30449376 TI - Pulmonary Hypertension in Women. AB - Prevalence of pulmonary arterial hypertension (PAH) is higher in women, and the mechanism remains unclear. Prognosis is overall better for female compared with male patients with PAH. Pregnancy is associated with significant risk, mortality, and morbidity in patients with PAH; consensus guidelines recommend against pregnancy and counsel about early termination in these patients. Recent advances in treatment showed improvement in prognosis in small case reports of pregnant patients with PAH, particularly with the early use of parental prostacyclin. Education remains fundamental for women with PAH of childbearing age for pregnancy prevention as well as discussion about birth control methods. PMID- 30449375 TI - Heart Transplantation in Women. AB - Over the past 5 decades, heart transplantation has become an established therapy with greater quality of life and survival than expected from end-stage heart failure. Nonetheless, challenges still exist, especially for women undergoing heart transplantation. Women have greater post-transplant survival than their male counterparts but worse quality of life. Pregnancy may occur, especially because more women are reaching child-bearing age after transplantation. Successful outcomes have been reported but require a systematic multidisciplinary approach. Women are more likely to be sensitized, with preformed anti-human leukocyte antigens antibodies related to prior pregnancies, posing challenges for their pretransplant and post-transplant management. PMID- 30449377 TI - Heart Failure with Reduced Ejection Fraction in Women: Epidemiology, Outcomes, and Treatment. AB - There are millions of people affected by heart failure with reduced ejection fraction (HFrEF) as diagnosed with ejection fraction 40% or less by imaging. Established therapies have been proven through clinical trials on lifestyle interventions, medications, and devices for HFrEF to improve quality of life, heart function, and survival. Although there are more men than women suffering with HFrEF, there are no prospectively proven, sex-specific guideline therapies because women have been underrepresented in clinical trials. Current recommendations for medications in women with HFrEF are described in this article. PMID- 30449378 TI - Peripartum Cardiomyopathy: Progress in Understanding the Etiology, Management, and Prognosis. AB - Occurring in approximately 1 in 1000 live births in the United States, peripartum cardiomyopathy (PPCM) is characterized by left ventricular ejection fraction reduced to less than 45% near the end of pregnancy or within the first 5 months after delivery. Although the cause of PPCM remains unclear, increasing evidence supports a complex interaction of genetic and environmental factors contributing to angiogenic imbalance, which may lead to myocardial dysfunction in a susceptible woman. This article reviews the progress that has been made regarding understanding of the cause, management, and natural history of PPCM. PMID- 30449379 TI - Stress-Induced Cardiomyopathy. AB - Stress-induced cardiomyopathy is characterized by reversible myocardial injury with distinctive regional wall motion abnormalities of the left ventricle, usually precipitated by an emotional or physical stressor. This condition has a strong predilection for older women and has a trend of increasing incidence. The diagnosis can be made based on symptoms, biomarkers, electrocardiogram, coronary angiogram, and noninvasive imaging. It is frequently complicated by acute heart failure, cardiogenic shock, arrhythmias, left ventricular outflow tract obstruction, and ventricular thrombi. Evidence of the treatment of stress-induced cardiomyopathy is limited. Prognosis is not benign; it carries substantial mortality, similar to that of acute coronary syndrome. PMID- 30449380 TI - Atrial Fibrillation and Heart Failure in Women. AB - Atrial fibrillation often occurs as a cause or consequence of heart failure. Clinical outcomes are worse when atrial fibrillation and heart failure coexist. There are important sex-related differences in the incidence, prevalence, pathophysiology, treatment, and outcomes of these patients. Women with heart failure are at greater risk of developing atrial fibrillation than men, and more women with atrial fibrillation develop heart failure. More women die of atrial fibrillation-related strokes. Despite significant morbidity and mortality, current treatments for women are inadequate. This review explores sex differences in atrial fibrillation and heart failure, emphasizing risk stratification and treatments to improve clinical outcomes. PMID- 30449382 TI - Valvular Heart Disease and Heart Failure in Women. AB - Valvular heart disease and heart failure remain important causes of cardiovascular disease among women in the United States. Mitral regurgitation, aortic stenosis, and tricuspid regurgitation are the most common valvular lesions among men and women. This review focuses on gender differences in the epidemiology, treatment, and outcomes of mitral regurgitation, aortic stenosis, and tricuspid regurgitation. The authors also review the unique management of valvular heart disease in pregnancy. PMID- 30449381 TI - Breast Cancer and Heart Failure. AB - Heart failure and breast cancer have shared risks and morbidities. Multimodality therapies for breast cancer, including conventional chemotherapy, targeted therapeutics, radiation therapy, and hormonal agents, may make patients more susceptible to asymptomatic left ventricular dysfunction and clinical heart failure during and after treatment. New or preexisting left ventricular dysfunction may lead to interruptions in cancer treatment and limit options of breast cancer systemic therapy, leading to adverse outcomes. Early recognition and management of cardiovascular risk factors before, during, and after cancer treatment are of utmost importance. This review presents advances, challenges, and opportunities for cardiovascular care in contemporary breast cancer treatment. PMID- 30449383 TI - Heart Failure in Women with Congenital Heart Disease. AB - Heart failure remains the most common cause of morbidity and mortality in adults with congenital heart disease (CHD). Although gender-specific outcomes are not robust, it seems that women with CHD may be more affected by late heart failure (HF) than men. A specialized and experienced adult CHD team is required to care for these women as they age, including assessment for reversible causes of HF and in the management of pregnancy, labor, and delivery. PMID- 30449384 TI - Heart Failure with Preserved Ejection Fraction in Women. AB - Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent condition, particularly in women. Comorbidities, including older age, obesity, diabetes mellitus, hypertension, and hyperlipidemia, are risk factors and define phenotypic profiles of HFpEF in women. The condition has a relatively high burden of morbidity and mortality, with phenotypic profiles potentially characterizing risk of hospitalization and mortality. Based on limited data, nonpharmacologic and pharmacologic treatments may provide benefit; however, compelling evidence-based, disease-modifying treatments are needed. Many unanswered questions about HFpEF in women warrant further investigation to improve understanding of the disease and provide better patient care. PMID- 30449386 TI - Heart Failure in Women: An Increasing Health Concern. PMID- 30449385 TI - Advanced Therapies for Advanced Heart Failure in Women. AB - Women with advanced heart failure (HF) are underrepresented in trials of short term and durable mechanical circulatory support although they derive similar benefit. In acute HF, intensive medical and interventional therapies are effective but underutilized. The smaller, newer generation, left ventricular assist devices (LVADs) have increased the feasibility of durable support in women. Women frequently present late, with more comorbidities, emphasizing the need for timely referral. Compared with men, the stroke risk is higher in women with an LVAD. Increased representation in clinical trials and a better understanding of the psychosocial issues affecting women is essential. PMID- 30449387 TI - Self-plagiarism is not easily defined, but should be avoided. PMID- 30449388 TI - Clinical relevance commentary in response to: Intrarater and inter-rater reliability of a handheld dynamometric technique to quantify palmar thumb abduction strength in individuals with and without carpal tunnel syndrome. PMID- 30449389 TI - ? PMID- 30449390 TI - ? PMID- 30449391 TI - [Temporalities of care for obese teenagers]. AB - Obesity in adolescents is a common reason for consulting a physician for angst associated with a need to lose weight. The multidisciplinary treatment takes into account the teenager's temporality. The duration of the initial treatment must be optimised in order to construct, with the teenager, a project which corresponds to his or her particular difficulties. PMID- 30449392 TI - [Physical training for overweight teenagers]. AB - Physical activity is essential in the treatment of overweight teenagers. High Intensity Interval Circuit Training, consisting of a series of high intensity physical exercises, seems effective in this context. Offered in day hospitals, it can be easily reproduced after discharge. PMID- 30449393 TI - [Photolangage(r) workshops in the therapeutic education of obese teenagers]. AB - A photolanguage workshop was organised as part of a therapeutic education day for obese teenagers. It is a valuable way of establishing links between their eating habits and their emotions, and to help them become aware of the benefit of psychotherapy. In addition this workshop helps to remove the common inhibitions of these young people, helping them to express themselves around the often painful experience of being overweight and their relational and family difficulties. PMID- 30449394 TI - [Obese teenagers and food, between experiences and sensations]. AB - Several types of nutrition workshops can be organised in day hospitals for obese teenagers. This support enables young patients to develop a better perception of the sensations they get from food, to improve their relationship with food and to adopt healthy behaviour. This dietetic approach is part of a multi-disciplinary project. The parents play a key role and are involved on the psychological and educational levels. PMID- 30449395 TI - [A contact nurse coordinator for obese teenagers in the day hospital]. AB - The putting in place of a cross-disciplinary therapeutic education programme for teenagers with obesity requires coordination between all those concerned: patients, parents and caregivers. Specially trained, the contact nurse coordinators put in place the shared educational assessment, evaluate the levers and the obstacles to providing the necessary support, and lead the care project with the teenager and his or her parents. PMID- 30449396 TI - [Psychomotricity and socio-aesthetics, physical therapy interventions for obese teenagers]. AB - The project to lose weight is not simply a matter of changing behaviour. Obese teenagers must draw on other strategies, including those which require them to learn to love their body. In this respect, psychomotricity and socio-aesthetics are two complementary approaches which can be used as part of a teenager's care in the day hospital. PMID- 30449397 TI - [The relational issues surrounding food in obese teenagers and their family]. AB - Several qualitative studies have been carried out into the relational issues in families where a teenager is suffering from obesity. Power struggles, issues related to love, relational distance and family organisation must be taken into account in the care of these teenagers. Work on the intrafamily relational aspects can help to improve the effectiveness of standard treatments. PMID- 30449398 TI - [Training in distraction and hypnosis for pain relief in paediatrics]. AB - The use of psychophysical techniques such as distraction and hypnosis for pain relief is becoming more common in order to reduce the pain and anxiety associated with care procedures in paediatrics. A training programme in supporting painful care procedures was implemented in a paediatrics unit. Running since 2013, it has already trained more than 150 caregivers. It lies at the heart of a philosophy of care. PMID- 30449399 TI - [Autism spectrum disorders, a pilot parent-child unit]. AB - Today, it is possible to work on the developmental trajectory of autism spectrum disorders. Due to brain plasticity, the earlier the treatment, the greater the benefits. A pilot unit has been created in a day hospital, offering a quick and intensive approach, between 18 and 36 months, focused on parental skills. PMID- 30449400 TI - [Assistance with parenthood for new mothers with mental health problems]. AB - Women with mental health problems during the perinatal period need support with parenthood. Guidance from professionals providing the paediatric nursing care must favour the baby's development, but also help the mother assume her role and support the establishment of the mother-baby bond. Mediation when providing paediatric nursing care is a means of supporting parenthood. PMID- 30449401 TI - [The psychologist in paediatric intensive care, liaison and separation]. AB - The relationship between the interventions of liaison psychiatry and those of general medicine is essential. The psychologist, notably, plays an important role in a paediatric intensive care unit. A double temporality, somatic and psychological, is to be taken into account in order to hear, beyond the individual, what the subjet has to say. PMID- 30449402 TI - Primary and Specialized Care: a necessary relationship for the implementation of a Heart Failure program. PMID- 30449403 TI - Endoscopic balloon dilation for benign gastric outlet obstruction: Does etiology matter? PMID- 30449404 TI - Impact of preoperative EUS-guided FNA for pancreatic cancer on overall and cancer free survival: Is the jury still out? PMID- 30449405 TI - Concerns about transplantation of autologous esophageal mucosa to prevent stricture after circumferential endoscopic submucosal dissection. PMID- 30449406 TI - Cytomegalovirus infection in an immunocompetent patient. PMID- 30449407 TI - Intestinal IgA tTG deposits in the duodenal bulb in patients with celiac disease: light at the beginning of the tunnel! PMID- 30449409 TI - Screening for pancreatic cancer and... scientific integrity. PMID- 30449408 TI - Optimal interval of additional endoscopic re-intervention for noncurative cases via endoscopic submucosal dissection. PMID- 30449410 TI - Response. PMID- 30449411 TI - Earlier use of capsule endoscopy in clinical practice: don't hold back the scouts. PMID- 30449412 TI - Response. PMID- 30449413 TI - The utility of intravenous heparin to aid diagnosis and intervention in obscure GI bleeding. PMID- 30449414 TI - Response. PMID- 30449415 TI - Editorial Overview: Developmental neuroscience (2018). PMID- 30449416 TI - Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg Cinotti Syndrome. AB - We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation. In three of the families, affected individuals comprise singleton adult individuals, and parental samples were not available for verification of the de novo occurrence of the DDR2 variants. In the fourth family, a mother and two of her children were affected, and the c.2219A>G missense variant was proven to be de novo in the mother. Phosphorylation of DDR2 was increased in fibroblasts from affected individuals, suggesting reduced receptor autoinhibition and ligand-independent kinase activation. Evidence for activation of other growth-regulatory signaling pathways was not found. Finally, we found that the protein kinase inhibitor dasatinib prevented DDR2 autophosphorylation in fibroblasts, suggesting an approach to treatment. We propose this progressive, fibrotic condition should be designated as Warburg-Cinotti syndrome. PMID- 30449417 TI - Ventricular Septal Defect Closure Devices, Techniques, and Outcomes. AB - Transcatheter closure of ventricular septal defects (VSDs) was first documented in 1988. The early studies of VSD closure were successful but there were high complication rates, particularly early and late-onset complete heart block. However, the development and use of new vascular occlusion devices in an off label fashion has improved the range of patients who can be treated and reduced the complication rates. In particular, the rate of complete heart block documented in contemporary studies of VSD closure has fallen to levels at or below those documented in the surgical VSD closure literature. PMID- 30449418 TI - State-of-the-Art Atrial Septal Defect Closure Devices for Congenital Heart. AB - This article describes current devices and indications for transcatheter device closure of atrial septal defect (TC-ASD) and patent foramen ovale in children and young adults. TC-ASD has a proven record of efficacy and safety, but device erosion raises questions about the relative safety of TC-ASD versus operative open heart surgical ASD closure. New devices for ASD closure with properties to reduce risk of erosion are being developed. Recent studies demonstrating superiority of patent foramen ovale device closure over medical therapy for cryptogenic stroke may lead to changes in practice for structural/interventional cardiologists. Care should be taken in extrapolating data to children and younger adults. PMID- 30449419 TI - New Patent Ductus Arteriosus Closure Devices and Techniques. AB - Patent ductus arteriosus (PDA) in extremely low-birth-weight infants puts this vulnerable population at high risks of morbidity and mortality. Inclusion of a multidisciplinary team and newly available transcatheter PDA occlusion devices in the management of these infants can mitigate those risks and promote better long term outcomes. It is important that specific techniques with venous-only approach outlined in this article be followed to achieve optimal results. PMID- 30449421 TI - Current Transcatheter Approaches for the Treatment of Aortic Coarctation in Children and Adults. AB - Coarctation of the aorta is a common congenital heart defect and can present at any age. Infants may carry a fetal diagnosis, or are generally diagnosed after auscultation of a murmur, although rarely present in shock. Those that escape early childhood detection typically present in adolescence and adulthood, generally with upper-extremity hypertension. Percutaneous therapies have evolved to include balloon angioplasty and stent placement, and generally are the preferred first-line therapy for most adolescent/adult patients. Percutaneous interventions are now viable options in younger and smaller patients. The advent of bioresorbable stents may provide further expansion of treatment options to very small patients. PMID- 30449420 TI - Pulmonary Artery Stenting. AB - Stent implantation for pulmonary artery stenosis has advanced. Newer generations of stents allow confidence in long-term results, even in pediatric interventions. Primary intravascular stent implantation is recommended in significant branch pulmonary artery stenosis when the vessel or patient is large enough to accommodate a stent that can be dilated to an adult diameter. A variety of specialized stents are now available, improving applicability despite complex vessel size characteristics. Developments in bioresorbable stents and patient specific rapid prototyping are anticipated. PMID- 30449422 TI - Transcatheter Pulmonary Valve Replacement in Congenital Heart Disease. AB - Patients with dysfunctional right ventricular outflow tracks comprise a large portion of patients with severe congenital heart disease. Transcatheter pulmonary valve replacement in patients with dysfunctional right ventricular outflow tracks is feasible, safe, and efficacious. This article reviews current transcatheter valve replacement technology for dysfunctional right ventricular outflow tract and pulmonary valvular disease and its applications to patients with congenital heart disease. Discussed are the approach and preprocedural planning, current options, and applications of transcatheter pulmonary valve therapy. Also considered are future directions in this field as the technologies begin to develop further. PMID- 30449423 TI - Self-Expanding Pulmonary Valves for Large Diameter Right Ventricular Outflow Tracts. AB - Congenital heart defects that involve obstruction to the right ventricular outflow tract are common. Surgical repair involves early relief of right ventricular outflow tract obstruction, which typically results in pulmonary regurgitation and large irregularly shaped "native" right ventricular outflow tract. This type of anatomy represents the majority of patients who could potentially benefit from transcatheter pulmonary valve therapy. Currently approved balloon-expandable devices were not designed for this application and the unique anatomy of these patients presents tremendous challenges for designing a valve that is. This article explores those challenges and the newest self expanding devices designed to treat this challenging population. PMID- 30449425 TI - Update in Congenital Interventions. PMID- 30449424 TI - Biodegradable Stents for Congenital Heart Disease. AB - The quest for an ideal biodegradable stent for both adult coronary and pediatric congenital heart disease applications continues. Over the past few years, a lot of progress has been made toward development of a dedicated pediatric biodegradable stent that can be used for congenital heart disease applications. At present, there are no biodegradable stents available for use in congenital heart disease. In this article, the authors review the different biodegradable materials and their limitations and provide an overview of the current biodegradable stents being evaluated for congenital heart disease applications. PMID- 30449426 TI - Synthesis and biological evaluation of a trisaccharide repeating unit derivative of Streptococcus pneumoniae 19A capsular polysaccharide. AB - Streptococcus pneumoniae (SP) is a common human pathogen associated with a broad spectrum of diseases and it is still a leading cause of mortality and morbidity worldwide, especially in children. Moreover, SP is increasingly associated with drug resistance. Vaccination against the pathogen may thus represent an important strategy to overcome its threats to human health. In this context, revealing the molecular determinants of SP immunoreactivity may be relevant for the development of novel molecules with therapeutic perspectives as vaccine components. Serogroup 19 comprises the immune-cross reactive types 19F, 19A, 19B and 19C and it accounts for a high percentage of invasive pneumococcal diseases, mainly caused by serotypes 19F and 19A. Herein, we report the synthesis and biological evaluation of an aminopropyl derivative of the trisaccharide repeating unit of SP 19A. We compare two different synthetic strategies, based on different disconnections between the three monosaccharides which make up the final trisaccharide, to define the best approach for the preparation of the trisaccharide. Synthetic accessibility to the trisaccharide repeating unit lays the basis for the development of more complex biopolymer as well as saccharide conjugates. We also evaluate the binding affinity of the trisaccharide for anti 19A and anti-19F sera and discuss the relationship between the chemical properties of the trisaccharide unit and biological activity. PMID- 30449428 TI - Local Anesthetic Systemic Toxicity: Reviewing Updates From the American Society of Regional Anesthesia and Pain Medicine Practice Advisory. PMID- 30449427 TI - Identification of N-benzyltetrahydroisoquinolines as novel anti-neuroinflammatory agents. AB - A series of simplified berberine analogs was designed, synthesized, and evaluated for anti-inflammatory activity. SAR studies identified N benzyltetrahydroisoquinoline 7d as a potent berberine analog. 7d suppressed LPS induced inflammatory cytokine levels in both BV2 cells and primary microglia. Taken together, our results suggest that simplified BB analogs have therapeutic potential as a novel class of anti-neuroinflammatory agents. PMID- 30449429 TI - Preoperative Optimization. PMID- 30449430 TI - Considering Randomness. PMID- 30449431 TI - Transforming Perianesthesia Clinical Practice Through Dissemination and Implementation Science. PMID- 30449432 TI - A Healthier You for Christmas. PMID- 30449433 TI - Patients Scheduled for General Anesthesia: Betwixt and Between Worrying Thoughts and Keeping Focus. AB - PURPOSE: The purpose of the research was to explore the interaction between cancer patients and Registered Nurse Anesthetists (RNAs) before general anesthesia from the patients' perspective. DESIGN: Focused ethnography was used as method for data collection. METHODS: Surgical patients' interactions with the RNAs were observed during preparations for general anesthesia and further explored during an interview on the first or second postoperative day. Methodological concepts of Grounded Theory structured the analysis. FINDINGS: The core variable describes patients being in an intermediate position, not knowing the outcome of the anesthetic and surgical procedures. The core variable is elaborated by subcore variables describing patients' coping strategies and need for care. CONCLUSIONS: Patients' experiences of being cared for and supported in their coping strategies by RNAs will substantiate patients' predisposed confidence in the RNA and the anesthetic procedure. This will support patients in keeping focus in a highly technological environment. PMID- 30449434 TI - Examination of the Relationship Between Elective Surgical Patients' Methods for Coping With Stress and Sleeping Status the Night Before an Operation. AB - PURPOSE: This study was conducted to examine the relationship between elective surgical patients' methods for coping with stress and sleeping status the night before an operation. DESIGN: This research was a descriptive and correlational study. METHODS: The study was conducted between November 2016 and February 2017 with 132 patients who were waiting to undergo elective surgery in the surgery clinics of a university hospital. The data were collected using a personal information form, the Richards-Campbell Sleep Questionnaire (RCSQ), and the Ways of Coping Inventory (WOC). FINDINGS: This study indicated that the mean RCSQ score of the male patients and patients who were hospitalized at a cardiology clinic and experienced no situation that interrupted sleep the night before the operation was higher, and the difference was statistically significant (P < .05). Patients obtained a mean score of 46.31 +/- 32.21 on the RCSQ. A positive significant relationship was found between the mean scores of the self-confident approach, optimistic approach, and receiving social support, which are subscales of the WOC, and the total mean score on the RCSQ (P < .01). A negative significant relationship was found between the mean scores of the helpless approach and the submissive approach subscales of the WOC, and the total mean score on the RCSQ (P < .01). CONCLUSIONS: The results of this study showed that the approaches that the patients waiting for elective surgery used to cope with stress affected their nocturnal sleep status. PMID- 30449435 TI - The Effectiveness of Intravenous Oxycodone in the Treatment of Acute Postoperative Pain: A Systematic Review. AB - PURPOSE: Intravenous (IV) opioids are administered for management of acute postoperative pain in the postanesthesia care unit. The benefits of parenteral oxycodone for acute pain management are understudied. The purpose of this review was to evaluate the effectiveness of IV oxycodone for acute postoperative pain. DESIGN: A systematic review of quantitative studies using the Joanna Briggs Institute approach. METHODS: A search for randomized controlled trials was conducted, revealing 314 potentially relevant studies. These were compared with the inclusion criteria. Those that met these criteria were critically appraised. FINDINGS: Participants (N = 506) in eight trials were included in this review. Four studies supported the use of IV oxycodone as patient-controlled analgesia and IV bolus. The remaining studies showed equipotent effects between oxycodone and control. Higher incidences of adverse effects were associated with IV oxycodone. CONCLUSIONS: IV oxycodone can be considered as effective analgesia for acute postoperative pain with careful regards to its adverse effects. PMID- 30449436 TI - The Power of Topical Anesthetics and Distraction for Peripheral Intravenous Catheter Placement in the Pediatric Perianesthesia Area. AB - Placing a peripheral intravenous catheter is a painful procedure and produces much anxiety for the pediatric patient, as well as for their parents and nursing staff. There is a heightened need for having effective pain control during this process, which will lead to increased cooperation and decreased anxiety for the patient, making the placement of a peripheral intravenous catheter successful. Topical analgesics and distraction are powerful tools that can make inserting a peripheral intravenous catheter easier for the patient, and also easier for a nurse with limited pediatric experience. The purpose of this article is to educate nursing staff of the importance of using topical analgesics such as LMX4 and EMLA, needle free lidocaine injections, as well as different methods of distraction to successfully place a peripheral intravenous catheter in a pediatric patient on first attempt. PMID- 30449437 TI - Nurse Practitioner-Driven Optimization of Presurgical Testing. AB - Nurse practitioners play a pivotal role as members of the perioperative team. This article outlines the evolution of presurgical testing from the vantage of generic testing to one that is tailored to the patient's clinical presentation and the type of surgery to be performed, whether it is high, intermediate, or low risk. Emphasis is placed on indicated testing, screening tools to identify patients at risk for perioperative complications, the optimization of patients before undergoing major cancer surgery, and enhanced recovery after surgery. The goal was to bring awareness to our colleagues that evidence-based practice defines the present role of the nurse practitioner in this setting and evidence will shape its future direction. PMID- 30449438 TI - Scale Development and Psychometric Evaluation of the Preoperative Assessment of Readiness Tool. AB - PURPOSE: Technology has greatly advanced surgical capacity; however, the patient's perspective of surgical readiness remains unexplored. There is also a paucity of psychometrically sound instruments quantifying surgical readiness. Hence, this study developed and psychometrically evaluated the Preoperative Assessment of Readiness Tool (PART). DESIGN: A methodological study. METHODS: An initial 25-item questionnaire was developed after preliminary interviews and literature review. Psychometrics included content and construct validity and internal consistency. PART was tested on 210 purposively selected preoperative patients and preliminary factor analyses examined two random halves of the sample. FINDINGS: The questionnaire was reduced to 21 items after content validation and was further reduced to 15 items after preliminary factor analyses. Final factor analysis extracted two factors: quality information acquisition and supportive interpersonal care assimilation. Scale reliability was 0.97 with acceptable subscale reliability. CONCLUSIONS: The 15-item Preoperative Assessment of Readiness Tool demonstrated satisfactory psychometrics in assessing perceived surgical readiness. Nonetheless, further analysis is warranted to guarantee robust cross-cultural and cross-geographical comparisons. PMID- 30449439 TI - A Comprehensive Protocol to Prevent Brachial Plexus Injury During Ankylosing Spondylitis Surgery. AB - PURPOSE: This article describes a comprehensive protocol to protect the brachial plexus when performing pedicle subtraction osteotomy for ankylosing spondylitis patients with thoracolumbar kyphosis. DESIGN: A descriptive study was conducted. METHODS: Records of 101 cases from October 2013 to December 2016 were retrospectively audited. The protocol included five items: (1) preoperative assessment of motion range and nerve function of limbs and trunks; (2) preoperative positioning according to the assessment results; (3) intra-operative somatosensory evoked potential and blood pressure monitoring; (4) intra-operative repositioning according to the monitoring alarm signals; and (5) postoperative neurological function check. FINDINGS: Five patients showed impending brachial plexus injury indicators, including two who had a decrease in blood pressure and three who had a decrease in the amplitude of somatosensory evoked potential. After adjustment of position and soft pads, one patient had brachial plexus injury (0.99%) and the recovery time was 2 weeks. CONCLUSIONS: With this comprehensive strategy, the brachial plexus could be effectively protected during the surgery. PMID- 30449440 TI - The Effect of Neiguan Point (P6) Acupressure With Wristband on Postoperative Nausea, Vomiting, and Comfort Level: A Randomized Controlled Study. AB - PURPOSE: To determine how usage of wristband acupressure at pericardium 6 (P6) Neiguan point application affects nausea, vomiting, and comfort level in the postoperative period. DESIGN: A randomized controlled experimental study. METHODS: The study was implemented at an obstetrics hospital. The study was conducted on 97 patients (47 experimental and 50 control subjects) who underwent gynecologic surgery other than caesarian section. In the experimental group, wristband acupressure was applied during the first 12 hours after operation. The control group received antiemetics during and after operation. FINDINGS: Although P6 acupressure application was effective at preventing vomiting, its effect on nausea intensity was even better. Also, the P6 acupressure application enhanced patient comfort. CONCLUSIONS: Because of its effectiveness and feasibility, wristband P6 acupuncture point acupressure application is a great alternative to pharmacologic methods in the gynecologic surgery population. PMID- 30449441 TI - Benefits of Passive Warming on Surgical Patients Undergoing Regional Anesthetic Procedures. AB - PURPOSE: The purpose of this quality improvement project was to determine if application of preoperative passive warming methods would maintain body temperature in patients receiving regional anesthetic procedures (RAPs). DESIGN: A nonrandomized quasi-experimental design was used. METHODS: A passive warming trial using a convenience sample of 53 RAP patients warmed with passive measures was compared with data collected from 67 retrospective chart reviews of RAP patients warmed per standard unit policy-typically active forced warm air. Passive measures included a thermal reflective surgical cap and an activated chemical warmer. FINDINGS: Passive warming methods maintained temperatures throughout the perioperative process. No significant variations in mean temperatures were noted. As age increased, the difference in temperature from admit to transfer to operating room also increased (P = .0182). CONCLUSIONS: Passive warming is a suitable cost-effective alternative when forced-air warming is not feasible. Additional inquiry into the use of passive warming is warranted. PMID- 30449442 TI - The Swedish Safety Attitudes Questionnaire-Operating Room Version: Psychometric Properties in the Surgical Team. AB - PURPOSE: To validate the Swedish Safety Attitudes Questionnaire-operating room (SAQ-OR) version by re-evaluating its psychometric properties for the surgical team. DESIGN: Cross-sectional questionnaire study. METHODS: 541 surgical team members including perioperative nurses, physicians, and licensed practical nurses at three Swedish hospitals were included. FINDINGS: For the total sample, the Cronbach's alpha for the six factors ranged from 0.51 to 0.76. Goodness-of-fit analyses indicated that the six-factor model was acceptable and the factor loadings were statistically significant. The test of the hypothesized relationships among the factors showed a correlation from 0.936 to 0.042. CONCLUSIONS: The refined Swedish version of the SAQ-OR is a reasonably reliable and acceptably valid instrument for the measurement of patient safety climate in the surgical team. However, the results related to the different analyses varied among the different professionals and further research, using larger samples, is needed to explore these differences, especially among the physicians. PMID- 30449443 TI - Patients' Experiences During Carotid Endarterectomy Performed Under Local Anesthesia. AB - PURPOSE: To describe patients' experiences undergoing a carotid endarterectomy (CEA) under local anesthesia. DESIGN: Explorative qualitative design. METHODS: Semistructured interviews with 15 participants who had undergone CEA under local anesthesia, analyzed by content analysis. FINDINGS: Undergoing CEA under local anesthesia entails enduring stress with no possibility of withdrawal. Patients' lack of understanding of local anesthesia and experiencing pain and discomfort caused feelings of stress. The surgery resulted in a loss of control; patients had to surrender their autonomy to someone else. The nurse anesthetist was the link to the world outside the operating room (OR), and that nurse conveyed feelings of safety and security during the surgery. CONCLUSIONS: Patients' experiences ranged from being pleased with the surgical procedure and local anesthesia to vowing never to undergo such a procedure again. It is important to focus on the patients' experiences and feelings when choosing a method of anesthesia. PMID- 30449444 TI - Preoperative Pain Management Education: An Evidence-Based Practice Project. AB - PURPOSE: The purpose of this evidence-based practice project was to evaluate the effectiveness of a preoperative pain management patient education intervention on improving patients' pain management outcomes. DESIGN: The project was conducted in an outpatient general surgery service at a teaching institution for patients undergoing same-day surgery. Intervention patients received one-on-one education on postoperative pain management including how to take medications, managing medication side effects, using nonpharmacologic methods, and reporting inadequate postoperative pain control. Comparison patients received general education from multiple health care providers, and this information may not have been consistent. METHODS: Intervention patients received education at the first preoperative clinic visit. Patients in the intervention and comparison groups completed the Revised American Pain Society Patient Outcome Questionnaire during their first postoperative clinic visit. Results were analyzed by the Mann-Whitney U test/Wilcoxon rank sum test. FINDINGS: A 12-month project (N = 99) showed statistically significant results (P = .020 and P = .001, respectively) in questions about side effects and whether the patient was encouraged to use nonpharmacologic methods to reduce pain. The intervention group reported the effects of pain on mood (P = .067) and use of nonpharmacologic methods (P = .052); however, these results were not statistically significant. CONCLUSIONS: More intervention patients than comparison patients reported medication side effects and were encouraged to use nonpharmacologic methods for reducing postoperative pain. Intervention patients also reported the effects of pain on mood and the use of nonpharmacologic methods more frequently than comparison patients. Preoperative pain management education may increase patients' knowledge in key areas of postoperative pain management to prevent negative outcomes. PMID- 30449445 TI - Effectiveness of a Preoperative Preparation Program on Children's Emotional States and Parental Anxiety. AB - PURPOSE: The study was conducted to examine the effects of a preoperative preparation program on children and their parents in a pediatric surgery outpatient clinic. DESIGN: A quasiexperimental design was used. METHODS: Seventy three children and their primary caregivers were included in the study (intervention = 36, control = 37). Data collection tools included the Characteristics of Children and Caregivers Data Form, the PedsQL Health Care Parental Satisfaction Scale, the State Anxiety Inventory, and the children's Koppitz Human Figure Drawing Test. Data were collected on the day before surgery and the day of surgery. The program comprised verbal and written information about the process that was given to families and children, and a medical play doll was used for therapeutic communication with children in the intervention group. FINDINGS: The satisfaction level of parents in the intervention group was found to be significantly higher than in the control group (intervention = 100, control = 50; P < .05). During the preoperative and discharge periods, the anxiety scores of parents in the intervention group were significantly lower than the control group (P < .05). According to the Koppitz Drawing Test, the children in the control group's emotional state was higher than the intervention group regarding impulsiveness, anxiety, and anger on discharge (P < .05). CONCLUSIONS: The preoperative preparation program was found to have a positive effect on the children and their parents. Nurses should use drawings of children as a therapeutic communication technique to evaluate the emotions of children. PMID- 30449447 TI - Ending the Silence for Second Victims in Health Care. PMID- 30449446 TI - Delirium: Are We Doing Enough? PMID- 30449448 TI - ASPAN Legacy Recognition of Esther Watson, BSN, RN, ASPAN Historian. PMID- 30449449 TI - Structural and functional aspects of P-glycoprotein and its inhibitors. AB - P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity has been the subject of numerous attempts to develop P-gp inhibitors. The aim of this review is to present up-to-date information on the structural and functional aspects of P-gp and its known inhibitors. The data presented also provide some information on drug discovery approaches for candidate P-gp inhibitors. Nucleotide-binding domains (NBDs) and drug-binding domains (DBDs) have been extensively studied to gain more information about P-gp inhibition and it looks that the ATPase activity of this pump has been the most attractive target for designing inhibitors. Hydrophobic and pi-pi (aromatic) interactions between P-gp binding domains and inhibitors are dominant intermolecular forces that have been reported in many studies using different methods. Many synthetic and natural products have been found to possess inhibitory or modulatory effects on drug transporter proteins. Log P value is an important factor in studying these inhibitors and has a crucial role on absorption, distribution, metabolism, and excretion (ADME) properties of candidate P-gp inhibitors. PMID- 30449450 TI - Matrikines for therapeutic and biomedical applications. AB - Matrikines, peptides originating from the fragmentation of extracellular matrix proteins are identified to play important role in both health and disease. They possess biological activities, much different from their parent protein. Identification of such bioactive cryptic regions in the extracellular matrix proteins has attracted the researchers all over the world in the recent decade. These bioactive peptides could find use in preparation of biomaterials and tissue engineering applications. Matrikines identified in major extracellular matrix (ECM) proteins like collagen, elastin, fibronectin, and laminin are being extensively studied for use in tissue engineering and regenerative medicine. They are identified to modulate cellular activity like cell growth, proliferation, migration and may induce apoptosis. RGD, a well-known peptide identified in fibronectin with cell adhesive property is being investigated in designing biomaterials. Collagen hexapeptide GFOGER was found to promote cell adhesion and differentiation. Laminin also possesses regions with strong cell adhesion property. Recently, cell-penetrating peptides from elastin are used as a targeted delivery system for therapeutic drugs. The continued search for cryptic sequences in the extracellular matrix proteins along with advanced peptide coupling chemistries would lead to biomaterials with improved surface properties. This review article outlines the peptides derived from extracellular matrix and some of the possible applications of these peptides in therapeutics and tissue engineering applications. PMID- 30449451 TI - Testosterone mediates hyperthermic response of mice to heat exposure. AB - AIMS: Testosterone is implicated as a potential contributing factor to heat induced injury. We examined effects of testosterone on thermal response of mice to heat exposure. MAIN METHODS: Adult C57BL/6J male mice received gonadectomy or sham surgery subsequent vehicle (Gnx) or testosterone implants (Gnx+T). Body core temperature (Tc) of mice was recorded telemetrically during acute heat exposure. Thermal responses to heat exposure were also examined in age-matched female mice at each stage of the estrous cycle. KEY FINDINGS: Basal Tc was lower in sham male mice than females, but did not differ among sham, Gnx or Gnx+T males. No alterations in expression of uncoupling proteins 2 and 3 in the gastrocnemius muscle were found in either Gnx or Gnx+T mice compared to sham males. During heat exposure, sham male mice had a faster and greater rise in Tc, compared to females. This rapid hyperthermic response to heat was abolished in Gnx males, but not in Gnx+T males. No significant correlation was revealed between peak Tc values and plasma testosterone concentrations in Gnx+T males treated with either low- or high-dose testosterone. No effects of estrous cycle phase on the thermal response to heat exposure were detected in female mice. SIGNIFICANCE: We found that male mice were more susceptible to development of heat-induced hyperthermia than females and this was prevented by castration, not by castration with testosterone replacement. These results suggest that testosterone mediates heat induced hyperthermia and is a heat stress susceptibility factor. PMID- 30449452 TI - CRTC2 suppresses BMP2-induced osteoblastic differentiation via Smurf1 expression in MC3T3-E1 cells. AB - AIMS: CREB (cAMP response element-binding protein)-regulated transcription coactivator (CRTC2) has been reported to act as a coactivator of CREB during gluconeogenesis. The role of CRTC2 in osteoblastic differentiation has not yet been elucidated. The aim of this study is to identify the mechanism of CRTC2 in osteoblast differentiation. MAIN METHODS: The mRNA expression was determined by RT-PCR and qPCR. Protein levels were measured using Western blot assay. Alkaline phosphatase (ALP) staining was performed to evaluate ALP activity. Alizarin red S (ARS) staining was performed to measure extracellular mineralization. Transcriptional activity was detected using a luciferase assay. KEY FINDINGS: In the present study, TNF-alpha was found to stimulate CRTC2 expression. However, TNF-alpha did not increase the gene expression of osteoblast differentiation markers and inhibited BMP2-induced osteoblastic differentiation. Overexpression of CRTC2 decreased the expression of osteogenic genes, ALP activity and extracellular matrix mineralization. Knockdown of CRTC2 restored BMP2-induced osteogenic gene expression and ALP activity. CRTC2 increased Smurf1 mRNA expression, Smurf 1 promoter activity, and protein level. Furthermore, Smurf 1 decreased Smad 1/5/9 protein levels. These results suggest that CRTC2 decreased BMP2-induced osteoblastic differentiation via Smurf 1 expression. SIGNIFICANCE: Our results indicate that CRTC2 regulates the expression of Smurf1 in osteoblast differentiation. PMID- 30449453 TI - Evaluation of disinfectants and wiping substrates combinations to inactivate Staphylococcus aureus on Formica coupons. AB - Effective disinfection in health care facilities prevents health care-associated infections. This study evaluated the ability of Environmental Protection Agency approved disinfectants (quaternary ammonium compound, QAC; sodium hypochlorite, and hydrogen peroxide) applied with 3 wiping substrates (microfiber, nonwoven, and cotton) to remove Staphylococcus aureus from Formica surfaces. All treatments reduced S aureus on Formica squares with the exception of QAC applied with cotton and QAC, nondisinfectant, and control applied with a nonwoven cloth. Sodium hypochlorite or hydrogen peroxide applied with cotton or microfiber, respectively, may be the best choice for disinfection of Formica surfaces in health care settings. PMID- 30449454 TI - The Safe Hands Study: Implementing aseptic techniques in the operating room: Facilitating mechanisms for contextual negotiation and collective action. AB - BACKGROUND: Even though hand hygiene and aseptic techniques are essential to provide safe care in the operating room, several studies have found a lack of successful implementation. The aim of this study was to describe facilitative mechanisms supporting the implementation of hand hygiene and aseptic techniques. METHODS: This study was set in a large operating room suite in a Swedish university hospital. The theory-driven implementation process was informed by the literature on organizational change and dialogue. Data were collected using interviews and participant observations and analyzed using a thematic approach. The normalization process theory served as a frame of interpretation during the analysis. RESULTS: Three facilitating mechanisms were identified: (1) commitment through a sense of urgency, requiring extensive communication between the managers, operating room professionals, and facilitators in building commitment to change and putting the issues on the agenda; (2) dialogue for co-creation, increasing and sustaining commitment and resource mobilization; and (3) tailored management support, including helping managers to develop their leadership role, progressively involving staff, and retaining focus during the implementation process. CONCLUSIONS: The facilitating mechanisms can be used in organizing implementation processes. Putting the emphasis on help and support to managers seems to be a crucial condition in complex implementation processes, from preparation of the change process to stabilization of the new practice. PMID- 30449455 TI - The American Association of Hip and Knee Surgeons, Hip Society, Knee Society, and American Academy of Orthopaedic Surgeons Position Statement on Outpatient Joint Replacement. PMID- 30449456 TI - Pharmacokinetic/pharmacodynamic analysis as a tool for surveillance of the activity of antimicrobials against Pseudomonas aeruginosa strains isolated in critically ill patients. AB - INTRODUCTION: To evaluate the changes in the susceptibility of Pseudomonas aeruginosa over time (2000-2017) against antimicrobials used in an intensive care unit of a Spanish tertiary hospital, and to compare them with the antimicrobial activity considering theoretical pharmacokinetic/pharmacodynamic (PK/PD) criteria. The influence of the method for handling duplicate isolates to quantify susceptibility rates was also evaluated. METHODS: The susceptibility was studied considering the Clinical and Laboratory Standards Institute (CLSI) breakpoints. Monte Carlo simulations were conducted to calculate the cumulative fraction of response (CFR). Linear regression analysis was applied to determine the trends in susceptibility and in the CFR. RESULTS: A significant decrease in the susceptibility to gentamicin and imipenem was observed, and more recently the highest percentages of susceptible strains were found for amikacin, cephalosporins and piperacillin/tazobactam (>80%). The probability of success of an empiric treatment or CFR for most of the evaluated antimicrobials was lower than 70% during the last two-year period. Only meropenem provided high probabilities (>90%) to achieve the PK/PD target. Cephalosporins provided moderate probabilities (>80%) although for ceftazidime, the highest dose (2g/8h) was required. Moreover, a significant decrease in the CFR trend for ciprofloxacin, imipenem and levofloxacin was observed. CONCLUSIONS: Both susceptibility rates and CFR values have to be considered together to optimize the antimicrobial dose regimen for clinical making-decisions. They are complementary tools and, they should be used jointly in surveillance programmes. In fact, susceptibility data are not always useful to detect changes in the CFR. No relevant differences were observed among the methods for handling repeated isolates. PMID- 30449458 TI - Achieving hepatitis C elimination in Taiwan-Overcoming barriers by setting feasible strategies. PMID- 30449457 TI - Down-regulation of miR-200b-targeting Slug axis by cyclosporine A in human gingival fibroblasts. AB - BACKGROUND/PURPOSE: Cyclosporine A (CsA) has been used as an immunosuppressive agent with a side effect of gingival overgrowth. It has been known that CsA induced epithelial-mesenchymal transition (EMT) in gingiva, but the molecular mechanism has not been fully unveiled. The purpose of the study is to investigate functional roles of microRNAs in gingival overgrowth. METHODS: The effect of CsA on the expression of microRNA-200b (miR-200b) in normal human gingival fibroblasts (HGFs) was determined using qRT-PCR. Luciferase reporter assay and Western blot were utilized to examine the relationship between miR-200b and EMT inducer Slug. Cell proliferation was assessed by MTT assay. RESULTS: CsA was found to downregulate the miR-200b transcript in HGFs in a dose-dependent manner. Luciferase reporter assay confirmed that Slug was a direct target of miR-200b, and the CsA-induced cell proliferation and Slug upregulation were inhibited by overexpression of miR-200b. Additionally, the silence of Slug reversed the increased proliferation of HGFs by miR-200b inhibitor. CONCLUSION: Repression of miR-200b after CsA administration led to an increase in Slug expression. Our results suggested that miR-200b was an upstream effector of the CsA-induced EMT and may act as a therapeutic target for CsA-induced gingival overgrowth. PMID- 30449459 TI - Massive hemorrhage protocol survey: Marked variability and absent in one-third of hospitals in Ontario, Canada. AB - BACKGROUND: Massive hemorrhage protocols (MHP) are critical to standardized delivery of timely, safe, and resource-effective coordinated care for patients with life-threatening bleeding. METHODS: A standardized MHP survey was sent to all hospitals (n = 150) in Ontario with a transfusion service. This study aim was to determine the proportion of hospitals with an MHP and assess for variability. RESULTS: The overall survey completion rate was 133 of 150 hospitals (89%) (remaining 17 providing negative affirmation that they did not have an MHP). An MHP was in place at 97 of 150 (65%) hospitals (60% of small (<5000 red cell units/year) vs. 91% of medium/large). A total of 10 different names of protocols were reported, with "Massive Transfusion Protocol" (68%) predominating. Activation criteria were present in 82 of 97 (85%); commonly activated based on volume of blood loss (70%). Blood work was drawn at the discretion of the physician (37%) or at predefined intervals (31%; majority every 60 min). Common routine laboratory tests performed were CBC (87%) and INR (84%). Fibrinogen testing was available at 88 (66%) of 133 reporting hospitals and part of the standard testing at 73 of 97 (75%) hospitals with an MHP. Median targets of hemostatic resuscitations, stated in the protocol at 49% of hospitals with an MHP, were: platelets >50 * 109/L, INR < 1.8, fibrinogen >1.5 g/L, and hemoglobin >70 g/L. Protocol required patient temperature monitoring in 65% and specified a reversal plan for patients on anticoagulants in 59%. At 36% of sites all patients are initially managed with O RhD negative blood. Overall, 61% of sites issue blood in predefined packs (vs. on demand). Hemostatic agents in protocols included: tranexamic acid (70%), prothombin complex concentrate (14%), fibrinogen concentrate (13%), and recombinant FVIIa (4%). Quality metrics were tracked in 32% of hospitals. CONCLUSIONS: A third of hospitals lack formal MHPs, with the majority lacking in smaller hospitals. The survey results indicate that there is marked variability in all key aspects of the reported MHPs. This may be due to differences in hospital resources and personnel, lack of supporting evidence to dictate requirements, and differences in knowledge base of the individuals involved in protocol setting. PMID- 30449461 TI - ? PMID- 30449460 TI - Traction radiographs versus CT in the evaluation of fracture morphology and consecutive treatment decisions in OTA/AO 43C3 fractures. AB - BACKGROUND: Standard radiographs are limited in the evaluation of fracture characteristics and preoperative planning of OTA/AO 43C3 fractures. Therefore, CT imaging is an accepted as a useful method. CT is however expensive and has high radiation, and traction radiographs could be an alternative. This study aimed to compare fracture fragment and comminution zone visualization between traction radiographs and CT and any potentially resulting differences in consecutive treatment and surgical approach recommendations. METHODS: Twenty orthopaedic surgeons assessed traction radiographs and CT images of 12 OTA/AO 43C3 type fractures. Each observer was required to identify the anterolateral, posterolateral, and medial malleolus fragments and the lateral, central, and medial shoulder comminution zones. They then had to recommend treatment (nonoperative, ORIF, closed reduction and external fixation, percutaneous screw fixation, or primary tibiotalar arthrodesis) with the best surgical approach (medial, anterolateral, posterolateral, posteromedial, or combined). Intra- and interobserver reliability, correct identification of fracture fragments and comminution zones on both images, and consistency of treatment recommendations and surgical approaches were analyzed. RESULTS: The agreement of each observer's assessment of the presence or absence of specific fracture fragments and comminution zones was substantially increased for CT as compared to traction radiographs, particularly for the posterolateral (p = 0.000) and anterolateral fragment (p = 0.000), and the lateral (p = 0.000), central (p = 0.000), and medial shoulder comminution zone (p = 0.000). The interobserver reliability when assessing the three fracture fragments and comminution zones on the traction radiographs was moderate, whereas it was substantial when assessing these characteristics on CT. The medial malleolus fragment was more often correctly identified on traction radiographs than CT images (p = 0.001). The ability to correctly identify lateral, central, and medial shoulder comminution zones was higher for CT than traction radiographs (p = 0.000). The treatment and surgical approach recommendations after traction radiograph and CT evaluation were similar (p < 0.05). CONCLUSIONS: Traction radiographs may be a useful alternative to CT imaging in the preoperative planning of pilon fracture repair. Despite less reliable fracture fragment and comminution zone identification on traction radiographs, treatment recommendations and surgical approach were not influenced. PMID- 30449462 TI - [An interview guide for screening for psychological pain in oncology]. AB - An interview guide has been introduced with patients treated in oncology in order to assess their psychological pain. It helps to structure the nurse interview. It also combines the identification of the patient's psychological needs with the creation of an opportunity to talk, thereby initiating a help relationship. PMID- 30449463 TI - ? PMID- 30449464 TI - [Work related stress, sociological analysis]. AB - Experienced on a personal and psychological level, work related stress nevertheless has social causes. New forms of management demand from staff an ever greater personal investment, but the growing intensification of the work often makes the missions they are given impossible to fulfil. This results in a feeling of having failed and of not being up to the job, which are in turn sources of suffering and stress. PMID- 30449466 TI - [Moral harassment in the workplace and work related stress]. AB - Work related stress may be caused by moral harassment or not. The law gives a precise definition of harassment, which constitutes a civil and criminal offence. This situation requires proof to be gathered and those responsible to be identified. In all cases, employees can protect themselves from harassment and seek help. PMID- 30449465 TI - [Psychosocial risks and work related stress]. AB - Psychosocial risks threaten employees' physical and mental health. Their causes are rooted among numerous factors, including interpersonal relationships and the mismatch between the 'prescribed' work and that which can be achieved. A preventive attitude is the first shield against work related stress. PMID- 30449467 TI - [Symptoms and characteristics of burnout]. AB - For several years, the use of the term 'burnout' has been applied to clinical situations inappropriately and often excessively. The complexity of the approach to work related stress could explain this. It is important to understand the clinical bases which constitute this occupational exhaustion syndrome. PMID- 30449468 TI - [Work related stress in caregivers]. AB - Health professionals have to endure the full force of the fast paced and sometimes paradoxical transformations of care facilities. Economic reasoning, standardisation and industrial management now govern the work of caregivers. They are sources of stress and destabilisation whereas caring is first and foremost an act of humanity. PMID- 30449469 TI - [Angst and suffering among student nurses]. AB - Nurse training constitutes a radical personal change for most students, heading for a profession deemed difficult by many. A study into student nurses' stress, carried out in 2017, identifies several types of issues. PMID- 30449470 TI - [Clinical approach to stress in occupational psychopathology]. AB - In the workplace, everyone is aware of the constraints of an organisation, but often, work related stress is refuted. However, the employer must take the necessary measures to ensure its employees' safety. Occupational psychopathology consultations constitute a resource for supporting people with stress and carrying out preventive actions. PMID- 30449471 TI - [The prevention of psychosocial risks in hospital]. AB - The best way to prevent psychosocial risk is to support the teams in terms of their dynamics and their difficulties. We need to take care of caregivers and other hospital staff. Management has an essential role to play to achieve this objective. PMID- 30449472 TI - [Difficulties and stress of the anaesthetist-intensive care doctor]. AB - Anaesthetist-intensive care doctors are trained and experienced in stress management. However, they experience, in their complex professional practice, productivity constraints which undermine their own values and their everyday practice. This is a feeling shared with other health professionals. Awareness of the issue must enable these doctors to regain the composure needed for practising their profession. PMID- 30449473 TI - [Keys for well-being and fulfilment at work]. AB - If organizations seek to be profitable, they have no choice but to help their employees live in harmony, to be serene and creative. Well-being at work is largely linked to our ability to adapt to the moving reality of the company, without losing ourselves. Guides and methods help to live this reality as well as possible. PMID- 30449474 TI - [Reconstructing the relationship in health facilities]. AB - Health facilities are today subjected to a drive for profitability, efficiency and performance which go against caregivers' core values of providing help and support. To maintain the necessary focus on care and its difficulties, health managers must favour and reinforce relations between colleagues, and involve teams in the decisions and projects concerning their care activity. Working on the relationship is an essential part of this approach. PMID- 30449475 TI - [Emotional and social robots for care, ethical challenges and issues]. AB - The arrival of robots in our society often arouses fantasies and fears. Emotional and social robots are already being used in healthcare. Ethical analysis is necessary to regulate the use of these objects which are able to simulate dialogues, appearing to feel emotions and to be capable of learning. PMID- 30449476 TI - ? PMID- 30449477 TI - Association Between Childhood and Adolescent Sexual Abuse Experiences and High Risk Sexual Behaviors Among Chinese Youth. AB - INTRODUCTION: Adolescents are at high risk for negative health outcomes associated with high-risk sexual behaviors (HRSBs), and researchers have attempted to identify factors that influence such behavior so that meaningful prevention and intervention programs may be developed. AIM: To investigate the associations between CSA experience and HRSBs in Chinese youth aged 15-24 years old. METHODS: Data were from the Survey of Youth Access to Reproductive Health in China, a national sample survey conducted in 2009. The following behaviors were classified as HRSBs: condom non-use during the first sexual experience, having sex with multiple partners, taking part in casual sex, engaging in commercial sex, taking part in anal sex, and condom non-use during the most recent sexual encounter. Differences in HRSBs between the sexes were examined. The chi2 test and binary logistic regression were used to estimate the association between CSA experience and HRSBs. MAIN OUTCOME MEASURE: The sexual behaviors of condom non use during the first sexual experience, sexual activity with multiple partners, taking part in casual sex, engaging in commercial sex (defined as paying or receiving money/gifts in exchange for sex), taking part in anal sex, and condom non-using during the most recent sexual intercourse were classified as HRSBs. RESULTS: 4,974 Sexually active youth were included in this study, 150 respondents (3.0%) reported CSA experience, and 3,950 (79.4%) sexually active youth had engaged in at least 1 type of HRSBs. The odds of having sex with multiple partners (odds ratio [OR] 4.31, 95% CI 3.07-6.07), casual sex (OR 3.65, 95% CI 2.55-5.24), commercial sex (OR 7.43, 95% CI 5.13-10.77), anal copulation (OR 2.54, 95% CI 1.57-4.12), or any of these HRSBs (OR 5.02, 95% CI 2.33-10.80) were significantly higher among those who had experienced CSA. There was a gender specific difference in the associations of CSA with different types of HRSBs. CONCLUSION: Sexual abuse experience in childhood is highly correlated with HRSBs among Chinese youth, and the pattern of this association differs between males and females. Public knowledge and social assistance systems needs to be improved for children and youth in China. Gender-specific counter-measures may be more efficient for interventions. Ding R, Wen X, He P, et al. Association Between Childhood and Adolescent Sexual Abuse Experiences and High-Risk Sexual Behaviors Among Chinese Youth. Sex Med 2018;6:273-281. PMID- 30449478 TI - The excess mortality risk associated with anticholinergic burden among older patients discharged from acute care hospital with depressive symptoms. AB - BACKGROUND: The relationship between anticholinergic burden and mortality is controversial, and the impact of anticholinergic burden on prognosis may vary in presence of other conditions common in old age. We aimed at investigating the role of depressive symptoms as potential effect modifiers in the association between anticholinergic burden and 1-year mortality in older patients discharged from hospital. METHODS: Our series consisted of 576 older patients consecutively admitted to seven geriatric and internal medicine acute care wards in the context of a prospective multicenter observational study. Overall anticholinergic burden was assessed by Anticholinergic Cognitive Burden (ACB) score. Depressive symptoms were assessed by 15-item Geriatric Depression Scale (GDS). The study outcome was all-cause mortality during 12-months follow-up. Statistical analysis was carried out by Cox regression analysis. RESULTS: After adjusting for potential confounders, discharge ACB score = 2 or more was significantly associated with the outcome among patients with GDS > 5 (HR = 3.70; 95%CI = 1.18-11.6), but not among those with GDS <= 5 (HR = 2.32; 95%CI = 0.90-6.24). The association was confirmed among depressed patients after adjusting for ACB score at 3-month follow-up (HR = 3.58; 95%CI = 1.21-10.7), as well as when considering ACB score as a continuous variable (HR = 1.42; 95%CI = 1.10-1.91). The interaction between ACB score at discharge and BADL dependency was statistically significant (p < .005). CONCLUSIONS: ACB score at discharge may predict mortality among older patients discharged from acute care hospital carrying high GDS score e. Hospital physician should be aware that prescribing anticholinergic medications in such a vulnerable population may have negative prognostic implications. PMID- 30449479 TI - Prognostic factors for survival in Ewing sarcoma: A systematic review. AB - Development of a prognostic model for survival can assist in stratifying treatment according to the individual patients' risk, leading to risk- and response adaptive treatment strategies which allow for early decision making. The aim of this systematic review is to provide an overview of prognostic factors for overall survival (OS) and event-free survival (EFS) in Ewing sarcoma to be used in the development of prediction models and clinical trial design. A literature search was performed using Pubmed, Embase, Web of Science, Academic search premier and Cochrane databases. Studies were eligible if: 1) Sample size >=100; 2) Follow-up >=2 years or dead within 2 years; 3) Recruitment after 1975; 4) Outcome measure OS or EFS; 5) Multivariate analysis to assess the effect of prognostic factors on survival outcomes; 6) Study published in English. In case studies were derived from the same database the most all-embracing was selected. Study selection and quality assessment was performed by two reviewers independently. For each risk factor a level of evidence synthesis was performed. Kappa-statistic was used to determine inter-observer agreement. A total of 149 full-text articles were found, 21 eligible for inclusion. 24 prognostic factors were investigated, 14 relevant for this review. Prognostic factors associated with survival include metastasis at diagnosis, large tumors (volume >= 200 ml or largest diameter >= 8 cm), primary tumors located in the axial skeleton, especially pelvic and a histological response of less than 100%. These factors should be included as risk factors in the development of prediction models for ES. PMID- 30449480 TI - Histone deacetylase inhibitors in hepatocellular carcinoma: A therapeutic perspective. AB - Hepatocellular carcinoma (HCC) is a major contributor to the global cancer burden. Given the current limited options to treat advanced HCC, understanding the molecular basis of HCC carcinogenesis and pinpointing druggable targets will be important to identify future HCC treatments. Epigenetic modification by inhibiting histone deacetylases (HDAC) is an emerging approach with promising results in cancer treatment. In the preclinical setting, HDAC inhibitors such as valproic acid sodium, panobinostat, vorinostat, trichostatin A, sodium butyrate, belinostat and romidepsin have demonstrated antitumor efficacy via activation of classic and alternative cell death molecular cascades. Combination regimens with the tyrosine kinase inhibitor sorafenib, poly(ADP-ribose) polymerases, proteasome and mammalian target of rapamycin inhibitors have shown promise. Phase I/II clinical studies with belinostat monotherapy and the combination of resminostat with sorafenib have suggested response and survival benefits. The safety profile was favorable with manageable adverse events and a low incidence of grade 3/4 toxicity. We herein review the role and potential therapeutic impact of epigenetic regulation through histone deacetylase inhibitors (HDACi) in the treatment of HCC. PMID- 30449481 TI - Patients with resectable pancreatic adenocarcinoma: A 15-years single tertiary cancer center study of laparotomy findings, treatments and outcomes. AB - BACKGROUND: To describe, in patients with resectable pancreatic ductal adenocarcinoma (PDAC), the laparotomy findings, treatments and outcomes before (period 1) and after 2010 (period 2). METHODS: From 2000 to 2015, patients newly diagnosed with resectable PDAC at Paoli-Calmettes Institute, France, were evaluated. Survival was examined using the Kaplan-Meier method, and statistical comparisons were conducted using log rank tests. RESULTS: Among 1175 patients diagnosed with pancreatic mass, 164 underwent laparotomy with an intention of pancreatic resection. Some of them did not undergo pancreatic resection due to peroperative discovery of advanced disease. For those who were finally resected (n = 119), there were fewer pancreaticoduodenectomies (p = 0.045), shorter operation times (p < 0.01), lower mortality rates (p = 0.02), more advanced-stage tumors (T3), more frequent perineural invasion and R1 resection in period 2. This group had a trend of better outcomes after 2010 (51 months vs. 36 months (p = 0.065)). CONCLUSION: Improvement in surgical procedures and postoperative management led to prolonged survival of those who underwent surgery for resectable pancreatic cancer since 2010, despite a higher frequency of advanced tumors at the diagnosis in our institution. PMID- 30449482 TI - High-dose rate intraluminal brachytherapy: An effective palliation for cholangiocarcinoma causing bile duct obstruction. PMID- 30449483 TI - Half the deaths after surgery for lung cancer occur after discharge. AB - INTRODUCTION: Mortality following surgery for lung cancer increases at 90 days. The objective of this study was to determine the rate, factors, time to death, hospital stay until discharge, time to death after discharge and causes of mortality at 90 days following surgery for lung cancer. METHODS: A prospective follow-up study was performed in a cohort of 378 patients who underwent surgery for lung cancer between January 2012 and December 2016. Data on preoperative status, postoperative complications, and mortality were collected. RESULTS: Rates of mortality were 1.6% vs. 3.2% at 30 and 90 days, respectively. Half of deaths occurred between 31 and 90 postoperative days following discharge. The variables found to be related to mortality at 90 days were a Charlson Index >3 (p < 0.001), a history of stroke (p = 0.036), postoperative pneumonia (p = 0.001), postoperative pulmonary or lobar collapse (p = 0.001), reintubation (p < 0.001) and postoperative arrhythmia (p = 0.0029). The risk of mortality was also observed to be associated with the type of surgical technique -being higher for thoracotomy as compared to video-assisted thoracoscopy (VATS) (p = 0.011) -, and hospital readmission after discharge (p < 0.001). Adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. Multivariate analysis revealed that a Charlson Index >3 (p = 0.001) OR 2.0 (1.55,2.78), a history of stroke (p = 0.018) OR 5.1 (1.81, 32.96) and postoperative pulmonary or lobar collapse (p = 0.001) OR 8.5 (2.41,30.22) were independent prognostic factors of mortality. The most common causes of death were related to respiratory (58.3%) and cardiovascular (33.2%) complications. CONCLUSIONS: Mortality at 90 days following surgery for lung cancer doubles 30-day mortality, which is a relevant finding of which both, patients and healthcare should be aware. Half the deaths within 90 days after surgery for lung cancer occur after discharge. Specific outpatient follow-up programs should be designed for patients at a higher risk of 90-day mortality. PMID- 30449484 TI - Robotic pancreatoduodenectomy for a solid pseudopapillary tumor in a ten-year-old child. AB - BACKGROUND: Pancreatoduodenectomy (Whipple resection) in children is feasible though rarely indicated. In several pediatric malignancies of the pancreas, however, it may be the only curative strategy [1]. With the emergence of robotic pancreatoduodenectomy as at least a clinically equivalent alternative to open surgery [2], it remains to be determined whether the pediatric population may potentially benefit from this minimally invasive procedure. Here we present, for the first time, a video of setup and surgical technique of robotic pancreatoduodenectomy in a child. METHODS: A 10-year-old girl presented with complaints of fullness and abdominal pain in the upper quadrants. Investigations including a diffusion-weighted, pancreatic MR scan suggested the diagnosis of solid pseudopapillary tumor (Frantz's tumor). The patient was considered for robotic pancreatoduodenectomy. RESULTS: After anesthesia, the patient was placed supine on a split-leg table. Trocar placement was adjusted to accommodate the child's length and body weight, according to pre-operatively calculated positions that would allow for maximum working space and minimize inadvertent collision between the robotic arms. The da Vinci Si surgical robot was positioned in-line towards the surgical target and all four robotic arms were docked, while two additional laparoscopic ports were placed for tableside assistance. After standard pancreatoduodenectomy, a conventional loop reconstruction was performed including an end-to-side pancreaticojejunostomy with duct-to-mucosa technique and stapled side-to-side gastrojejunostomy. We suggest that in this patient group, pylorus preserving pancreatoduodenectomy with end-to-side duodenojejunostomy may be a suitable alternative. Postoperative recovery was complicated by delayed gastric emptying but otherwise unremarkable. Hospital length of stay was 12 days. Final pathology demonstrated a solid pseudopapillary tumor with negative surgical margins. CONCLUSION: This case illustrates the feasibility of robotic pancreatoduodenectomy in children. Essential elements of this procedure are a well-running robotic pancreatic surgery program as well as careful preoperative port placement planning. PMID- 30449485 TI - Differences in PD-L1 expression on tumor and immune cells between lung metastases and corresponding primary tumors. AB - BACKGROUND: It has been reported that the tumor microenvironment, including tumor associated immune cells (ICs) and programmed cell death-ligand 1 (PD-L1) expression, differs between primary and metastatic tumors. This study aimed to elucidate the differences in PD-L1 expression on tumor cells (TCs) and ICs between lung metastases and corresponding primary tumors. METHODS: We analyzed paired lesions from 44 patients diagnosed with lung metastases between 2005 and 2017 at Kyushu University. The percentages of PD-L1-positive TCs and ICs in lung metastases and the primary tumor were classified into five categories (0: <1%; 1: 1%-4%; 2: 5%-9%; 3: 10%-49%; and 4: >=50%). Lesions in which >=1% of the TCs and ICs were PD-L1-positive were considered positive. RESULTS: The primary cancers included rectal (n = 19), colon (n = 10), liver (n = 10), bile duct (n = 2), stomach (n = 1), gall bladder (n = 1) and breast (n = 1). Discrepancies in PD-L1 expression on TCs and ICs between lung metastases and primary lesions were observed in 5 (11.4%, kappa = 0.23) and 9 (20.5%, kappa = 0.11) of the 44 cases, respectively. PD-L1 expression on ICs was higher in lung metastases than paired primary tumors (p = 0.026), although the percentage of PD-L1-positive TCs was not significantly different between lung metastases and primary tumors (p = 0.767). CONCLUSIONS: There were significant differences in PD-L1 expression on TCs and ICs between lung metastases and primary tumors. Clinicians should be aware of these differences in the tumor microenvironment when treating patients with immunotherapy. PMID- 30449486 TI - Laparoscopic intragastric resection of melanoma cardial lesion. AB - BACKGROUND: Gastrointestinal tract involvements of metastatic melanoma are rare; 7% of gastrointestinal tract metastases of melanoma concerns the stomach [1]. Actually, bleeding from gastric melanoma metastasis is very rare. For the first time in Literature, this video shows a laparoscopic intragastric resection [2] of a cardial lesion of melanoma. A 64-year old patient with history of a skin melanoma resection with lung and liver metastatic disease confirmed by FDG PET, stable after repeated cycles of Pembrolizumab, presented anemia with gastrointestinal bleeding signs. Endoscopy and CT scans documented a 4-cm subcardial metastatic melanoma lesion. Endoscopic ultrasound evaluation confirmed no full-thickness involvement of gastric wall. Patient refused blood transfusions because Jehovah's Witness. Since the tumor position so close to the cardias contraindicated both typical endoscopic and laparoscopic approaches, we proposed laparoscopic intragastric solution in order to avoid risk related to a total gastrectomy. METHODS: Procedure was performed by 3 intragastric trocars placed under endoscopic view. The primary surgical intent was to excise the tumor in order to avoid further bleeding. Actually, during dissection we verified the possibility to radically resect the lesion. After removal (with partial fragmentation) of the lesion, residual free fragments have been accurately removed to reduce the risks of tumor implantation on gastric mucosa and a mucosal suture was completed. Two-layer running sutures were applied on gastric holes. After completion of procedure, suture and cardial gastric wall were tested for leakage with satisfying result. Finally, lesser sac was opened up to expose the right diaphragmatic pillar in order to exclude eventual posterior gastric wall damage. RESULTS: Pathologic evaluation demonstrated a diffuse submucosal invasion by melanoma, confirming that R0 resection was achieved. CONCLUSIONS: In the general strategy of a palliation treatment of a largely metastastic tumor, the specific aim of this procedure was to stop gastric bleeding and to allow the continuation of systemic therapies effective in the disease control. After 6 months from surgery, patient resumed chemotherapy without any documented gastric recurrence. PMID- 30449487 TI - Transoral surgery (TOS) in oropharyngeal cancer: Different tools, a single mini invasive philosophy. AB - Surgery with or without adjuvant therapy and radiotherapy with or without chemotherapy have traditionally represented the possible treatment options for oropharyngeal cancer. The adverse effects of non-surgical treatments and recent technical innovations have prompted a new interest in the surgical approach. However, in parallel to the possibility of achieving radical cancer clearance, we should remember the impact that traditional open surgery has on the patient's cosmesis, functionality and quality of life. As a result, transoral surgery is an attractive option for oropharyngeal tumors. The term "transoral surgery" only indicates that the tumor is accessed and resected via the oral cavity, but the surgeon can choose among different resection methods, such as transoral laser microsurgery, transoral robotic surgery, transoral videolaryngoscopic surgery, endoscopic laryngo-pharyngeal surgery, and transoral ultrasound surgery. The aim of this paper is to review the recent literature on the transoral treatment of oropharyngeal cancer, to standardize the terminology of transoral procedures, analyzing the common aspects, main differences and future perspectives of the various forms of transoral surgery. PMID- 30449488 TI - Current challenges in gastric cancer surgery: European perspective. AB - Gastric cancer (GC) remains one of the most common causes of cancer death worldwide with expected 5-year survival rates around 25% in Western countries. In order to improve treatment strategy, a most effective staging process should be completed. A novel TNM staging for GC has been proposed recently, along with a separate staging system for GC patients who underwent preoperative therapy (ypStage). Availability of high-quality imaging and access to diagnostic laparoscopy with lavage cytology should be applied while planning the multimodal therapy. In the European setting, GC treatment is based on a combination of surgery and perioperative chemotherapy. However, in selected groups of patients with high risk of locoregional recurrence, adjuvant chemoradiotherapy should be considered. New epidemiological trends of GC in the Western countries include an upward shift in the location of the primary tumour and a relative increase of advanced and diffuse type tumours. These trends dictate modification of surgical techniques towards a more individualized GC treatment approach. PMID- 30449489 TI - Sclerosing encapsulating peritonitis as a potential complication of cytoreductive surgery and HIPEC: Clinical features and results of treatment in 4 patients. AB - Sclerosing encapsulating peritonitis (SEP) is a rare entity characterized by encapsulation of the small bowel and/or the colon by a fibrous tissue that forms a shell. Intraperitoneal chemotherapy (IPC) has been reported to be a potential causative factor of secondary SEP. However, few studies have reported on secondary SEP related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Here, we review results from four clinical cases of SEP associated with CRS and HIPEC. In all four patients, additional surgery was necessary to alleviate recurrent episodes of small bowel obstruction. These obstructions can occur as early as several weeks after CRS plus HIPEC or as late as 3 years after treatment. Of utmost importance is the prevention of fistulization which can result in enteric contamination of the peritoneal space. To date, no solution to SEP has been identified except additional surgery but it is evident that these reoperative experiences are difficult for both surgeon and patient. The etiopathogenesis of SEP in this setting remains unknown but it is clear that it is related to chronic inflammation of the peritoneum. Large studies are needed to identify the incidence and potential common causes of SEP after CRS and HIPEC. PMID- 30449490 TI - Development of novel biological resection criteria for safe and oncologically satisfying resection of hepatocellular carcinoma. AB - OBJECTIVE: To develop criteria for safe and oncologically satisfying liver resection in case of early hepatocellular carcinoma with a 5-year overall survival (OS) similar to liver transplantation. SUMMARY BACKGROUND DATA: Liver resection (LR) and liver transplantation (LT) are potentially curative treatment options for hepatocellular carcinoma. Generally, LT achieves better OS. Due to organ shortage, however not all patients can receive a LT. METHODS: To decide which patients to resect and which to transplant we have developed biological resection criteria (BRC) as a compound out of mGPS (modified Glascow Prognostic Scale) and the Kings-Score (for HCV cirrhosis). These are based on routine clinical values that reflect both liver function and tumor biology/immunology. RESULTS: 276 patients were analyzed. Patients undergoing LR within BRC (inBRC) had a significantly better overall (73.6% vs. 35.4%, (p < 0.001)) and disease free survival (54.7% vs. 17.2%, (p < 0.001)) as compared to patients outside the BRC (outBRC). The predictive value of BRC was independent of tumor burden. In a subgroup analysis outBRC patients had significantly worse outcome after major resection. In LT patients BRC had no predictive value. CONCLUSIONS: BRC may be a valuable tool to predict survival after LR for HCC. Patients resected inBRC may achieve comparable survival as LT. LR in outBRC patients are unlikely to be curative. All outBRC patients should be monitored closely for salvage LT. PMID- 30449491 TI - Laparoscopic resection of caudate lobe. Technical strategies for a difficult liver segment - Video article. PMID- 30449492 TI - Primary sarcomas of the pancreas: A review of 253 patients from the National Cancer Data Base. AB - INTRODUCTION: Primary sarcomas of the pancreas are rare, and the limited data regarding their presentation, oncologic profile, and survival have been derived from small case series. METHODS: The National Cancer Data Base (1998-2012) was queried for patients with primary sarcomas of the pancreas. Demographic and clinical features at the time of diagnosis were evaluated for all patients. Subjects who underwent surgical resection were identified, and logistic regression was used to identify variables associated with resection. A Cox proportional hazards model was developed to identify factors associated with survival. RESULTS: In total, 253 patients were identified. The mean age at diagnosis was 63 years, with tumors occurring more frequently in women (57.3%) and those of white race (79.8%). Tumors in the head of the pancreas were most common (63.3%). The mean size was 7.5 cm. Only 100 patients (39.5%) underwent resection, with younger age (OR = 0.763, p = 0.04) and smaller tumor size (OR = 0.978, p < 0.01) associated with resection. Chemotherapy and radiation therapy use were similar in patients who underwent resection and those who did not. Patients who underwent resection had a median survival of 17 months, compared to 6 months for patients who were not resected (p < 0.01). Following adjustment, only older age (HR 1.257, p = 0.03) and higher tumor grade (HR 1.997, p = 0.01) were associated with an increased risk of death in resected patients. CONCLUSIONS: Primary pancreatic sarcomas are rare and the majority of patients do not undergo resection; thus, little is known about their oncologic profile or outcomes following pancreatectomy. Patients who undergo resection have markedly improved survival; older age and higher tumor grade are associated with decreased survival. PMID- 30449493 TI - A scoring system to predict recurrence in breast cancer patients. AB - OBJECTIVE: Current breast cancer recurrence prediction models have limitations for clinical practice (statistical methodology, simplicity and specific populations). We therefore developed a new model that overcomes these limitations. METHODS: This cohort study comprised 272 patients with breast cancer followed between 2003 and 2016. The main variable was time-to-recurrence (locoregional and/or metastasis) and secondary variables were its risk factors: age, postmenopause, grade, oestrogen receptor, progesterone receptor, c-erbB2 status, stage, multicentricity, diagnosis and treatment. A Cox model to predict recurrence was estimated with the secondary variables, and this was adapted to a points system to predict risk at 5 and 10 years from diagnosis. The model was validated internally by bootstrapping, calculating the C statistic and smooth calibration (splines). The system was integrated into a mobile application for Android. RESULTS: Of the 272 patients with breast cancer, 47 (17.3%) developed recurrence in a mean time of 8.6 +/- 3.5 years. The system variables were: age, grade, multicentricity and stage. Validation by bootstrapping showed good discrimination and calibration. CONCLUSIONS: A points system has been developed to predict breast cancer recurrence at 5 and 10 years. PMID- 30449494 TI - The role of hepatectomy for synchronous liver metastases from pancreatic adenocarcinoma. AB - BACKGROUND: The role of hepatectomy for patients with liver metastases from ductal adenocarcinoma of the pancreas (PLM) remains controversial. Therefore, the aim of our study was to examine the postoperative morbidity, mortality, and long term survivals after liver resection for synchronous PLM. METHODS: Clinicopathological data of patients who underwent hepatectomy for PLM between 1993 and 2015 were assessed. Major endpoint of this study was to identify predictors of overall survival (OS). RESULTS: During the study period, 76 patients underwent resection for pancreatic cancer and concomitant hepatectomy for synchronous PLM. Pancreatoduodenectomy, distal pancreatectomy, and total pancreatectomy were performed in 67%, 25%, and 8% of the patients, respectively. The median PLM size was 1 (1-13) cm and 36% of patients had multiple PLM. The majority of patients (96%) underwent a minor liver resection. After a median follow-up time of 130 months, 1-, 3-, and 5-year OS rates were 41%, 13%, and 7%, respectively. Postoperative morbidity and mortality rates were 50% and 5%, respectively. Preoperative and postoperative chemotherapy was administered to 5% and 72% of patients, respectively. In univariate analysis, type of pancreatic procedure (P = .020), resection and reconstruction of the superior mesenteric artery (P = .016), T4 stage (P = .086), R1 margin status at liver resection (P = .001), lymph node metastases (P = .016), poorly differentiated cancer (G3) (P = .037), no preoperative chemotherapy (P = .013), and no postoperative chemotherapy (P = .005) were significantly associated with worse OS. In the multivariate analysis, poorly differentiated cancer (G3) (hazard ratio [HR] = 1.87; 95% confidence interval [CI] = 1.08-3.24; P = .026), R1 margin status at liver resection (HR = 4.97; 95% CI = 1.46-16.86; P = .010), no preoperative chemotherapy (HR = 4.07; 95% CI = 1.40-11.83; P = .010), and no postoperative chemotherapy (HR = 1.88; 95% CI = 1.06-3.29; P = .030) independently predicted worse OS. CONCLUSIONS: Liver resection for PLM is feasible and safe and may be recommended within the framework of an individualized cancer therapy. Multimodal treatment strategy including perioperative chemotherapy and hepatectomy may provide prolonged survival in selected patients with metastatic pancreatic cancer. PMID- 30449497 TI - Overall survival prediction in glioblastoma multiforme patients from volumetric, shape and texture features using machine learning. AB - Glioblastoma multiforme (GBM) are aggressive brain tumors, which lead to poor overall survival (OS) of patients. OS prediction of GBM patients provides useful information for surgical and treatment planning. Radiomics research attempts at predicting disease prognosis, thus providing beneficial information for personalized treatment from a variety of imaging features extracted from multiple MR images. In this study, MR image derived texture features, tumor shape and volumetric features, and patient age were obtained for 163 patients. OS group prediction was performed for both 2-class (short and long) and 3-class (short, medium and long) survival groups. Support vector machine classification based recursive feature elimination method was used to perform feature selection. The performance of the classification model was assessed using 5-fold cross validation. The 2-class and 3-class OS group prediction accuracy obtained were 98.7% and 88.95% respectively. The shape features used in this work have been evaluated for OS prediction of GBM patients for the first time. The feature selection and prediction scheme implemented in this study yielded high accuracy for both 2-class and 3-class OS group predictions. This study was performed using routinely acquired MR images for GBM patients, thus making the translation of this work into a clinical setup convenient. PMID- 30449496 TI - The expression profile of integrin receptors and osteopontin in thyroid malignancies varies depending on the tumor progression rate and presence of BRAF V600E mutation. AB - : Thyroid cancer (TC) is one of the most common malignancy of the human endocrine system. BRAF V600E mutation is the most frequent genetic alteration of papillary carcinoma, the most frequent TC, which effects RAS-RAF-MEK intracellular signaling pathway. These alterations in RAS-RAF-MEK pathway lead to changes in expression levels of cell membrane integrin receptors and their ligand - extracellular matrix protein osteopontin, which in turn increases the metastatic potential of tumor cells. Thus, integrins and their ligand osteopontin can be considered as potential biomarkers of tumor progression and aggressive tumor phenotypes. The aim of the study was to evaluate the expression levels of integrin receptors ITGA2, ITGA3, ITGAV, ITGA6, ITGA9, ITGB1, ITGB3 and their ligands OPNa, OPNb in the thyroid cancer with different BRAF V600E mutation status. METHODS: Thyroid tumor samples of 70 patients obtained during surgical treatment were analyzed. Expression levels of the investigated genes were evaluated by real time RT-PCR. Fluorescent immunohistochemistry (IHC) was used to confirm the PCR results and to estimate the amount of protein levels. For IHC frozen sections were used. BRAF V600E mutation was determined using allele specific amplification. Nonparametric criteria (Kruskal Wallis, Wilcoxon and Mann Whitney tests) were used to evaluate group differences. P values of less than 0.05 were considered as statistically significant. RESULTS: A higher gene expression level of ITGA2 (1.9-fold, p = 0.037), ITGA3 (21.1-fold, p = 0.041) and ITGA5 (2.08-fold, p = 0.048) was observed in papillary thyroid cancer (PTC) tissue in comparison with median expression level in control samples (conventionally normal tissue of thyroid gland). These changes were confirmed by IHC (significant changes for alpha2 integrin). ITGAV expression level was statistically significantly higher in follicular thyroid cancer (FTC) (2.0-fold, p = 0.040). Next, high gene expression levels in tissue samples of lymph node metastases were observed for ITGA5 (2.92-fold, p = 0.015), OPNb (4.36-fold, p = 0.037). For genes ITGA3 (37.48-fold, p = 0.017790), ITGA6 (18.76-fold, p = 0.028921) and ITGA9 (12.52-fold, p = 0.026710) higher expression level was detected in T3-4 tumors (TNM) compared to tumors classified as T1-2. Presence of BRAF V600E mutation was identified in 20 samples of PTC of 40 (50%). A significant increase of the expression level only of ITGA3 (3.1-fold, p = 0. 0422) was observed in BRAF V600E positive samples. Further, changes in expression levels of integrins and osteopontin were assessed in benign and malignant neoplasms. In PTC samples higher expression of ITGA2 (2.8-fold, p = 0.005), ITGA6 (2.11, p = 0.03) and ITGB1 (2.32-fold, p = 0.02) was detected. In FTC expression level of ITGA6 (2.67, p = 0.007) was higher than in benign thyroid nodules. CONCLUSION: Identified changes in expression levels of the studied genes indicate that they could play an important role in tumor progression, and their expression could be affected by the product of mutant BRAF gene. Integrins and their ligand osteopontin might be considered as potential markers in determining prognosis and treatment of TC. PMID- 30449495 TI - Dynamic prediction of overall survival for patients with high-grade extremity soft tissue sarcoma. AB - PURPOSE: There is increasing interest in personalized prediction of disease progression for soft tissue sarcoma patients. Currently, available prediction models are limited to predictions from time of surgery or diagnosis. This study updates predictions of overall survival at different times during follow-up by using the concept of dynamic prediction. PATIENTS AND METHODS: Information from 2232 patients with high-grade extremity soft tissue sarcoma, who underwent surgery at 14 specialized sarcoma centers, was used to develop a dynamic prediction model. The model provides updated 5-year survival probabilities from different prediction time points during follow-up. Baseline covariates as well as time-dependent covariates, such as status of local recurrence and distant metastases, were included in the model. In addition, the effect of covariates over time was investigated and modelled accordingly in the prediction model. RESULTS: Surgical margin and tumor histology show a significant time-varying effect on overall survival. The effect of margin is strongest shortly after surgery and diminishes slightly over time. Development of local recurrence and distant metastases during follow-up have a strong effect on overall survival and updated predictions must account for their occurrence. CONCLUSION: The presence of time-varying effects, as well as the effect of local recurrence and distant metastases on survival, suggest the importance of updating predictions during follow-up. This newly developed dynamic prediction model which updates survival probabilities over time can be used to make better individualized treatment decisions based on a dynamic assessment of a patient's prognosis. PMID- 30449498 TI - Are elderly patients presenting with squamous cell carcinoma of the oral cavity given the appropriate treatment? AB - OBJECTIVES: There is no consensus for the specific management of elderly patients presenting with oral cavity squamous cell carcinomas (OC SCC). We report our findings in the treatment of primary OC SCC, for patients of 70 years of age or more, in a French university hospital center. PATIENTS AND METHODS: One hundred and twenty five patients diagnosed between 2000 and 2010, were included retrospectively. Independent risk factors of post-operative complications were identified using a logistic regression. The overall survival (OS) was estimated using the Kaplan Meier method. Independent factors of survival were calculated using a Cox model. RESULTS: The patient's median age was 78. Women presented significantly more premalignant lesions, less alcohol intoxication, and less tobacco consumption. Half of the population sample was staged T4 in the TNM classification. Eighty eight percent of the patients received a curative treatment. The independent risk factors for post-operative complications were T3/T4 stages (OR 4.3 [1.3-14.4]), lymph node metastasis (OR 6.9 [2.1-22.7]), and alcohol abuse (OR 3.5 [1.1-11.0]). The median OS was 14.0 months. The independent negative prognostic factors for OS for patients treated curatively were: age >79 years (HR 1.9 [1.2-3.2]), stage T2/T3/T4 tumor vs. T1 (HR = 3.0 [1.5-6.0], P = 0.001) and substandard surgery (HR = 1.8 [1.1-2.9], P = 0.03). CONCLUSIONS: The management of OC SCC in elderly patients is complex and requires collaboration among gerontologists, surgeons and oncologists. The treatment choice is related to the disease extent and preoperative morbid conditions. PMID- 30449499 TI - Minor laparoscopic liver resection for Hepatocellular Carcinoma is safer than minor open resection, especially for less compensated cirrhotic patients: Propensity score analysis. AB - BACKGROUND: Laparoscopic liver resection (LLR) has gained significant popularity over the last 10 years. First experiences of LLR compared to open liver resection (OLR) reported a similar survival and a better safety profile for LLR. MATERIALS AND METHODS: This is a retrospective analysis of prospectively collected data of all consecutive patients treated by liver resection for HCC on liver cirrhosis between January 2005 and March 2017. The choice of procedure (LLR vs OLR) was generally based on tumor localization, history of previous upper abdominal surgery and patient's preference. The type of resection and indication for surgery were unrelated to the adopted technique. Based on pre-operative variables and confirmed cirrhosis, a 1:1 propensity score matching (PSM) model was developed to compare outcomes of LLR and OLR in patients with HCC. Outcomes of interest included morbidity, mortality and long-term cure potential. RESULTS: After-PSM, the LLR group demonstrated better perioperative results including: lower complication rate (50.7% in OLR vs 29.3% in LLR, p = 0.0035), significantly lower intra-operative blood loss (200 ml in OLR vs 150 ml in LLR, p = 0.007) and shorter hospital length of stay (median 9 days in OLR vs 7 days in LLR, p = 0.0018). Moreover there was no significant difference between the two groups in 3 year survival (76%, CI: 60%-86% in LLR vs 68%, CI: 55%-79% in OLR, p = 0.32) or recurrence-free survival rates (44%, CI: 28%-58%, vs 44%, CI: 31%-57%, p = 0.94). CONCLUSIONS: Minor LLR appeared significantly safer compared to minor OLR for HCC. LLR was associated with fewer post-operative complication, lower operative blood loss and a shorter hospital stay along with similar survival and recurrence free survival rates. PMID- 30449500 TI - Oncologic outcome and recurrence rate following anastomotic leakage after curative resection for colorectal cancer. AB - INTRODUCTION: Anastomotic leakage is one of the most severe early complications after colorectal surgery, and it is associated with a high reoperation rate-, and increased in short-term morbidity and mortality rates. It remains unclear whether anastomotic leakage is associated with poor oncologic outcomes. The aim of this study was to determine the impacts of anastomotic leakage on long-term oncologic outcomes, disease-free survival and overall mortality in patients who underwent curative surgery for colorectal cancer. METHODS: This single-centre, retrospective, observational cohort study included patients who underwent curative surgery for colorectal cancer between 2005 and 2015 and who had a primary anastomosis. Survival- and multivariate cox regression analyses were performed to adjust for confounding. RESULTS: A total of 1984 patients had a primary anastomosis after surgery. The overall incidence of anastomotic leakage was 7.5%; 19 patients were excluded because they were lost to follow-up. Of the remaining 1965 patients, 41 (2.1%) developed local recurrence associated with anastomotic leakage [adjusted hazard ratio (HR) = 2.25; 95% confidence interval (CI) 1.14-5.29; P = 0.03]. Distant recurrence developed in 291(14.8%) patients with no association with anastomotic leakage [adjusted HR = 1.30 (95% CI: 0.85 1.97) P = 0.23]. Anastomotic leakage was associated with increased long-term mortality [adjusted HR = 1.69 (95% CI 1.32-2.18) P < 0.01]. Five year disease free survival was significantly decreased in patients with anastomotic leakage, (log rank test P < 0.01). CONCLUSION: Anastomotic leakage was significantly associated with increased rates of local recurrence, disease free-survival and overall mortality. Associations of anastomotic leakage with distant recurrence was not found. PMID- 30449501 TI - Comparison of treatment outcomes between laparoscopic and endoscopic surgeries for relatively small gastric gastrointestinal stromal tumors. AB - BACKGROUND: Complete surgical resection remains the predominant treatment modality for primary gastrointestinal stromal tumors (GISTs). No therapeutic consensus exists for 2-5 cm gastric GISTs. We compared the efficacy, safety, and prognosis of laparoscopic and endoscopic surgeries in the treatment of relatively small (2-5 cm) intraluminal gastric GISTs. METHODS: We collected 101 patients with relatively small intraluminal gastric GISTs who had integrated clinicopathological data and underwent laparoscopic or endoscopic resection (laparoscopic group n = 66; endoscopic group n = 35). Clinicopathological characteristics, perioperative data, and long-term oncological outcomes were retrospectively analyzed. Comparative analysis of clinicopathological data in the two groups was performed by using a chi-square test, Fisher's exact test, and Student's t-test. Recurrence-free survival (RFS) was analyzed by the log-rank test. RESULTS: All clinicopathological characteristics had no significant difference between the two groups. Patients in the endoscopic group had shorter operation time (P < 0.001), postoperative hospital stay (P < 0.001), time to a liquid diet (P < 0.01), and time to a semi-liquid diet (P < 0.01), and lower hospital charges (P < 0.001), compared to those in the laparoscopic group. Four patients (6.1%) in the laparoscopic group and one patient (2.9%) in the endoscopic group had perioperative complications, but with no significant difference. Recurrence occurred in 6 patients (9.1%) and 2 patients (5.7%) in the laparoscopic and endoscopic groups, respectively. There was no significant difference in RFS between the two groups. CONCLUSION: Endoscopic resection is a feasible and safe treatment modality for patients with relatively small (2-5 cm) intraluminal gastric GISTs. Due to faster recovery and lower cost, endoscopic resection is more suitable for elderly and weak patients, or patients with a poor financial situation. PMID- 30449502 TI - Patterns of lymphatic drainage after axillary node dissection impact arm lymphoedema severity: A review of animal and clinical imaging studies. AB - Upper extremity lymphoedema after axillary node dissection is an iatrogenic disease particularly associated with treatment for breast or skin cancer. Anatomical studies and lymphangiography in healthy subjects identified that axillary node dissection removes a segment of the lymphatic drainage pathway running from the upper limb to the sub-clavicular vein, creating a surgical break. It is reasonable to infer that different patterns of lymphatic drainage may occur in the upper limb following surgery and contribute to the various presentations of lymphoedema from none to severe. Firstly, we reviewed animal imaging studies that investigated the repair of lymphatic drainage pathways from the limb after lymph node dissection. Secondly, we examined clinical imaging studies of lymphatic drainage pathways after axillary node dissection, including lymphangiography, lymphoscintigraphy and indocyanine green fluorescence lymphography. Finally, based on the gathered data, we devised a set of general principles for the restoration of lymphatic pathways after surgery. Lymphoscintigraphy shows that restoration of the original lymphatic pathway to the axilla after its initial disruption by nodal dissection was not uncommon and may prevent lymphoedema. We found that regenerated lymphatic vessels and dermal backflow (the reflux of lymph to the skin) contributed to either restoration of the original pathway or rerouting of the lymphatic pathway to other regional nodes. Variation in the lymphatic drainage pathway and the mechanisms of fluid drainage itself are the foundation of new lymphatic drainage patterns considered to be significant in determining the severity with which lymphoedema develops. PMID- 30449503 TI - Minimal-invasive versus open hepatectomy for hepatocellular carcinoma: Comparison of postoperative outcomes and long-term survivals using propensity score matching analysis. AB - BACKGROUND: Minimal-invasive hepatectomy (MIH) has been increasingly performed for benign and malignant liver lesions with most promising results. However, the role of MIH for the treatment of patients with hepatocellular carcinoma (HCC) needs further investigation. METHODS: Clinicopathological data of patients who underwent liver resection for HCC between 2005 and 2016 were assessed. Postoperative outcomes und long-term survivals of patients following MIH were compared with those of patients undergoing conventional open hepatectomy (OH) after 1:1 propensity score matching. RESULTS: During the study period, 407 patients underwent liver resection for HCC with curative intent. Fifty-six patients underwent MIH and were compared with a matched cohort of 56 patients who underwent OH. The rate of patients with fibrosis/cirrhosis (82% vs. 86%, p = 0.959), multiple lesions (32% vs. 32%, p = 1.00), tumor size >30 mm (61% vs. 55%, p = 0.566), and major resection (16% vs. 16%, p = 1.00) was comparable between the two groups (MIH vs. OH). MIH was associated with lower 90-day complication rate (32% vs. 54%, p = 0.022), lower postoperative major complication rate (14% vs. 30%, p = 0.041), lower liver failure rate (0% vs. 7%, p = 0.042), lower 90 day mortality rate (0 vs. 7%, p = 0.042), and shorter length of hospital stay (9 vs. 12 days, p = 0.009) compared to OH. After a median follow-up time of 51 months, MIH and OH showed comparable 5-year overall survival (54% vs. 41%, p = 0.151), and 5-year disease-free survival rates (50% vs. 38%, p = 0.956). CONCLUSIONS: MIH for HCC is associated with lower postoperative morbidity and mortality and shorter length of hospital stay, resulting in oncologic outcomes similar to those achieved with the established OH. Our findings suggest that MIH should be considered as the preferred method for the treatment of curatively resectable HCC. PMID- 30449504 TI - Socioeconomic status impacts survival and access to resection in pancreatic adenocarcinoma: A high-resolution population-based cancer registry study. AB - BACKGROUND: Survival of patients with pancreatic adenocarcinoma (PA) is very poor. Resection status is highly associated with prognosis but only 15%-20% are resectable. The aim of this study was to analyse the impact of socioeconomic deprivation on PA survival and to define which management steps are affected. METHODS: Between 01/01/2000 and 31/12/2014, 1451 incident cases of PA recorded in the digestive cancer registry of the French department of Calvados were included. The population was divided between less deprived areas (quintile 1) and more deprived areas (quintile 2,3,4,5 aggregated). RESULTS: Patients from less deprived areas were younger at diagnosis than those from more deprived areas (69.9 vs 72.3 years, p = 0.01). There was no difference in stage or comorbidities. Three- and 5-year survival rates were significantly higher for less deprived areas than more deprived areas: 10.5% vs 5.15% and 4.7% vs 1.7% respectively (p = 0.01). In univariate analysis, those living in less deprived areas had a better survival than those in more deprived areas (HR = 0.81 [0.69 0.95], p = 0.009) but not in multivariable analysis (HRa = 0.93 [0.79-1.11], p = 0.383) or analysis stratified on resection. In multivariable regression, less deprived areas had more access to surgery than more deprived areas (ORa = 1.73 [1.08-2.47], p = 0.013). No difference was observed on access to adjuvant chemotherapy (ORa = 0.95 [0.38-2.34], p = 0.681). CONCLUSION: The key to reducing survival inequalities in PA is access to resection, so future studies should investigate the factors impacting this issue. PMID- 30449505 TI - Total pharyngolaryngectomy in the elderly: The impact of age on postoperative complications and oncologic and functional outcomes. AB - OBJECTIVES: To evaluate the clinical outcomes of total pharyngolaryngectomy (TPL) in the elderly and to analyze the impact of age on postoperative complications and oncologic and functional outcomes. METHODS: We conducted a retrospective review of the medical records of all patients who underwent TPL for a laryngeal or hypopharyngeal squamous cell carcinoma, between 2000 and 2015. The impact of advanced age (>70 years) on clinical outcomes was assessed in univariate and multivariate analyses. RESULTS: A total of 245 patients (mean age = 66.4 years) were enrolled in this study including 91 (37%) patients aged over 70 years. In patients aged over 70 years, local and general complication rates were 36% and 10%, respectively. Five-year overall, cause-specific and recurrence-free survival rates were 36%, 52% and 31%, respectively. Satisfactory swallowing (swallowing score >= 1; i.e. no enteral feeding) and speech (speech score >= 1; i.e. intelligible speech) functions were recovered by 94% and 70% of elderly patients. In multivariate analysis, older age had no significant impact on postoperative complications, oncologic outcomes and swallowing function. Compared to younger patients, elderly patients achieved significantly lower speech scores (p = 0.05). CONCLUSION: TPL is associated with favorable clinical outcomes in patients aged over 70 years and can therefore be considered a reliable therapeutic option. However, compared to younger patients, a lower level of recovery regarding speech function is expected in the elderly, and particular attention should be paid to the postoperative speech rehabilitation program in this population of patients. PMID- 30449507 TI - Comment on: Current role of staple line reinforcement in 30-day outcomes of primary laparoscopic sleeve gastrectomy: An analysis of MBSAQIP data, 2015-2016 PUF. PMID- 30449506 TI - Pituicyte Cues Regulate the Development of Permeable Neuro-Vascular Interfaces. AB - The hypothalamo-neurohypophyseal system (HNS) regulates homeostasis through the passage of neurohormones and blood-borne proteins via permeable blood capillaries that lack the blood-brain barrier (BBB). Why neurohypophyseal capillaries become permeable while the neighboring vasculature of the brain forms BBB remains unclear. We show that pituicytes, the resident astroglial cells of the neurohypophysis, express genes that are associated with BBB breakdown during neuroinflammation. Pituicyte-enriched factors provide a local microenvironment that instructs a permeable neurovascular conduit. Thus, genetic and pharmacological perturbations of Vegfa and Tgfbeta3 affected HNS vascular morphogenesis and permeability and impaired the expression of the fenestral marker plvap. The anti-inflammatory agent dexamethasone decreased HNS permeability and downregulated the pituicyte-specific cyp26b gene, encoding a retinoic acid catabolic enzyme. Inhibition of Cyp26b activity led to upregulation of tight junction protein Claudin-5 and decreased permeability. We conclude that pituicyte-derived factors regulate the "decision" of endothelial cells to adopt a permeable endothelial fate instead of forming a BBB. PMID- 30449508 TI - Increased adverse outcomes after laparoscopic sleeve gastrectomy in older super obese patients: analysis of American College of Surgeons National Surgical Quality Improvement Program Database. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (SG) has become the most popular bariatric operation over the last decade. Extreme obesity and increasing age have been generally associated with higher risks of complications after bariatric surgery. The postoperative risk for complications after SG has not been previously presented according to simultaneous grouping of body mass index (BMI) and age. OBJECTIVE: We aim to explore the association of age and BMI in determining the postoperative risk of SG from a national perspective. SETTING: The American College of Surgeons National Surgical Quality Improvement Program database. METHODS: We analyzed patient characteristics and operative outcomes of the 2010 to 2013 SG cohort available in the American College of Surgeons National Surgical Quality Improvement Program (N = 21,131). Patients were grouped based on age and BMI: young-obese (N = 10,291; <50 yr, BMI <0 kg/m2; reference group), young-super-obese (N = 3594; <50 yr and BMI >=50 kg/m2), older-obese (N = 5636; >=50 yr, BMI <0 kg/m2), and older-super-obese (N = 1610; >=50 yr, BMI >=50 kg/m2). Composite morbidity and/or mortality (M&M) was used as the primary outcome and risk-adjusted odds ratios (AOR[M&M]) were derived by logistic regression. M&M was a composite of surgical site, renal, neurologic, cardiac, thromboembolic, respiratory, septic and bleeding complications, unplanned readmissions, prolonged stay, and death. RESULTS: Overall operative mortality was low (.1%) but significantly worse in older-super-obese patients (.37%; P = .005). M&M rates were lowest in young-obese (5.8%), similarly worse in young-super-obese (7.0%) and older-obese (7.0%), and highest for older-super-obese (10.1%; P < .001). After comprehensive covariate risk adjustment, the composite M&M outcome after SG was significantly increased (42%) only in older-super-obese patients (AOR = 1.42 [1.16-1.73]), while older age alone (AOR = 1.09 [.94-1.25]) and super obesity alone (AOR = 1.09 [.93-1.28]) did not. CONCLUSIONS: Analysis of the American College of Surgeons National Surgical Quality Improvement Program showed that super obesity is associated with increased complications in older patients undergoing SG. Older-super-obese patients should be appropriately counseled about increased SG perioperative risks within the context of expected long-term benefits. PMID- 30449509 TI - Effect of laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy on fasting gastrointestinal and pancreatic peptide hormones: A prospective nonrandomized trial. AB - BACKGROUND: Changes in gastrointestinal and pancreatic hormones may play a role in promoting long-term weight reduction and improved glucose metabolism after sleeve gastrectomy and Roux-en-Y gastric bypass. However, few studies have examined the metabolic and endocrine effects of these procedures in Mainland China. OBJECTIVES: To compare the effects of laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB) on gastrointestinal and pancreatic peptide hormones. SETTING: University hospital, China. METHODS: A nonrandomized prospective study was conducted in Chinese obese patients undergoing LSG or LRYGB. Of 20 patients in this study, 10 underwent LSG, and 10 underwent LRYGB. Fasting plasma levels of insulin, glucagon, ghrelin, gastric inhibitory peptide, peptide YY, glucagon-like peptide (GLP)-1, and GLP-2 were measured preoperatively and at 1, 3, 6, and 12 months after surgery. This trial was registered at www.clinicaltrials.gov (NCT02963662). RESULTS: During the first year after both operations, mean body mass index and fasting insulin levels steadily decreased at all intervals. Fasting plasma glucose levels significantly decreased at 1 month after surgery, then remained stable in both groups. Glucagon levels significantly decreased at 1, 3, and 6 months after surgery in both groups, but returned to baseline at 12 months. Fasting GLP-1 and peptide YY significantly increased in both groups, but more so after LRYGB. However, GLP-2 did not change in either group. Ghrelin levels significantly decreased after LSG, but not after LRYGB. Gastric inhibitory peptide levels decreased after LRYGB but not after LSG. CONCLUSIONS: LSG and LRYGB resulted in significant and distinct changes in multiple gastrointestinal and pancreatic peptide hormones that are important regulators of obesity and metabolic health. PMID- 30449510 TI - Gastric band conversion to Roux-en-Y gastric bypass shows greater weight loss than conversion to sleeve gastrectomy: 5-year outcomes. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (LSG) are often used as revisional surgeries for a failed laparoscopic adjustable gastric band (LAGB). There is debate over which procedure provides better long term weight loss. OBJECTIVE: To compare the weight loss results of these 2 surgeries. SETTING: University hospital, United States. METHODS: A retrospective review was conducted of all LAGB to RYGB and LAGB to LSG surgeries performed at a single institution. Primary outcomes were change in body mass index (BMI), percent excess BMI lost, and percent weight loss. Secondary outcomes included 30 day complications and reoperations. RESULTS: The cohort included 192 conversions from LAGB to RYGB and 283 LAGB to LSG. The baseline age and BMI were similar in the 2 groups. Statistical comparisons made between the 2 groups at 24 months postconversion were significant for BMI (RYGB = 32.93, LSG = 38.34, P = .0004), percent excess BMI lost (RYGB = 57.8%, LSG = 29.3%, P < .0001), and percent weight loss (RYGB = 23.4%, LSG = 12.6%, P < .0001). However, the conversion to RYGB group had a higher rate of reoperation (7.3% versus 1.4%, P = .0022), longer operating room time (RYGB = 120.1 min versus LSG = 115.5 min, P < .0001), and longer length of stay (RYGB = 3.33 d versus LSG = 2.11 d, P < .0001) than the LAGB to LSG group. Although not significant, the conversion to RYGB group had a higher rate of readmission (7.3% versus 3.5%, P = .087). CONCLUSION: Weight loss is significantly greater for patients undergoing LAGB conversion to RYGB than LAGB to LSG. However, those undergoing LAGB conversion to RYGB had higher rates of reoperation and readmission. Patients looking for the most effective weight loss surgery after failed LAGB should be advised to have RYGB performed, while also understanding the increased risks of the procedure. PMID- 30449511 TI - Diagnosis and treatment of chronic abdominal pain 5 years after Roux-en-Y gastric bypass. AB - BACKGROUND: Knowledge of optimal diagnostic workup, etiology, and response to treatment of chronic abdominal pain after Roux-en-Y gastric bypass (RYGB) is limited. OBJECTIVE: To define the etiology of chronic abdominal pain presenting at the 5-year follow-up after RYGB and to evaluate response to treatment. SETTING: Oslo University Hospital (tertiary referral center for obesity surgery). METHODS: Of 234 patients operated during a randomly selected 12-month period, 165 (71%) returned for 5-year follow-up, and 160 responded to study questionnaires. Of these, 54 (34%) reported chronic abdominal pain and were invited to participate in a structured diagnostic and treatment algorithm. These patients were contacted for the evaluation of their response to treatment. RESULTS: Fifty one of 54 patients (94%) reporting chronic abdominal pain at the 5-year follow-up were included in the study. Of the 45 patients with onset of symptoms post-RYGB, 28 (62%) underwent one or more radiologic evaluations, 10 (22%) underwent endoscopy, and 13 (29%) underwent laparoscopy. Diagnosis and treatment were established for 34 patients (76%), whereas 11 (24%) had abdominal pain of unknown cause. The most common etiology was internal herniation (n = 6), dumping (n = 6), food intolerance (n = 6), gallstones (n = 5), and irritable bowel syndrome (n = 4). After a median follow-up of 13.0 months (standard deviation, 11.5), 37 (82%) patients reported remission or improvement of symptoms, 6 had unchanged symptoms, and 2 patients were lost to follow-up. CONCLUSIONS: The etiology of long-term chronic abdominal pain post-RYGB is diverse. A multidisciplinary team can help most patients with dedicated follow-up, but a subset of patients has symptoms of unknown etiology. PMID- 30449512 TI - Long-term effects of proximal small bowel exclusion by duodenal-jejunal bypass liner on weight reduction and glycemic control in diabetic patients. AB - BACKGROUND: Exclusion of the proximal gut from nutrient absorption entails significant metabolic benefits. The duodenal-jejunal bypass liner (DJBL) is the first endoscopic device that excludes the first part of the gut by covering it. OBJECTIVES: To assess weight and glycemic control at the end of treatment and after 1 year of follow-up. SETTING: Bariatric endoscopy service in a tertiary medical center. METHODS: Diabetic patients were treated with DJBL and followed prospectively between 2013 and 2016. Data were collected during scheduled visits. RESULTS: Out of 51 patients treated, 39 completed at least 9 months with the device. Complications were recorded for the entire cohort. Percent of total weight loss was 15.05% +/- 6.0% after 12 months of treatment (P < .001 versus baseline). Twelve months postretrieval, percent of total weight loss decreased to 8.75% +/- 5.07% (P < .001 versus baseline). Patients with baseline body mass index >=35 kg/m2 experienced greater percent total weight loss changes over time (P < .001). There was a significant effect on hemoglobin A1C levels over time (P = .003), and the nadir was reached at 9 months of treatment (median 6.05% versus 7.20% at baseline, P < .001). Insulin users had consistently higher median hemoglobin A1C values compared with insulin nonusers (P < .001). Adverse events were experienced by 12 of 51 patients (23.5%), of which 4 cases (7.8%) were severe. CONCLUSIONS: Proximal bowel bypass by DJBL is an effective tool for weight reduction and glycemic control. Metabolic achievements are partially preserved at 1 year after device removal. Because DJBL entails a considerable rate of side effects, strategies to mitigate them are warranted. PMID- 30449513 TI - Second-stage duodenal switch for sleeve gastrectomy failure: A matched controlled trial. AB - BACKGROUND: Sleeve gastrectomy (SG) has become the predominant bariatric surgery worldwide. However, the surgical management in case of failure is still debated. OBJECTIVES: To evaluate the risks and benefits of converting SG to biliopancreatic diversion with duodenal switch (BPD-DS) for suboptimal outcome after SG. SETTING: University-affiliated tertiary care center. METHODS: We included all patients who underwent a laparoscopic second-stage duodenal switch (DS) for weight loss failure after SG and had a minimal follow-up of 2 years. Patients were matched 1:1 for age, sex, body mass index, and year of surgery with a group of patients who underwent a single-stage laparoscopic BPD-DS. Data were obtained from our prospective electronic database and are reported as the mean +/ standard deviation, comparing 2- versus 1-stage BPD-DS. RESULTS: A total of 118 patients were included (59 in each group). There was no significant difference in initial body mass index (53.8 +/- 9.7 versus 52.7 +/- 7.8 kg/m2, P = .4), age (44.0 +/- 10.2 versus 43.4 +/- 9.6 yr, P = .5), and sex ratio (37 female/22 male, P > .9) between the 2 groups. Mean follow-up was 59.9 +/- 27 months, with an 85% (n = 100) follow-up rate. Patients were converted to BPD-DS after a mean 24.4 +/- 10.2 months. There was no short- or long-term mortality. Major 90-days complications occurred in 2%, 5%, and 5% after SG, second-stage DS and single stage BPD-DS, respectively (P > .05). At the time of conversion, the excess weight loss for SG was 39 +/- 17% and total weight loss was 20 +/- 9%. After DS or single-stage BPD-DS, the excess weight loss was 74.8 +/- 18% versus 87.9 +/- 18% at 1 year (n = 107, P = .00021), 80.2 +/- 17% versus 92.3 +/- 14% at 2 years (n = 100, P = .002), and 80.2 +/- 18% versus 87.2 +/- 16% at 3 years (n = 70, P = .6). Total weight loss was 38.7 +/- 9% versus 44.5 +/- 8% at 1 year (P = .0004), 41.2 +/- 9% versus 46.8 +/- 7% at 2 years (P = .001), and 42.3 +/- 9% versus 45.1 +/- 9% at 3 years (P = .2). The incidence of type 2 diabetes and hypertension before surgery were 61% versus 54% and 58% versus 47%. Remission rate for type 2 diabetes increased from 59% to 94% after second-stage DS (P = .001), which is identical to first-stage BPD-DS (94%). Remission of hypertension increased from 42% to 77% after second-stage DS (P = .03) and was 71% after first-stage BPD-DS (P = .8). CONCLUSION: Second-stage DS is an effective option for the management of suboptimal outcomes of SG, with an additional 41% excess weight loss and 35% remission rate for type 2 diabetes. At 3 years, the global outcomes of staged approach did not significantly differ from single-stage BPD-DS; however, longer term outcomes are still needed. PMID- 30449516 TI - SOARD Category 1 CME Credit Featured Articles, Volume 14, September 2018. PMID- 30449514 TI - Bariatric surgery in patients with pulmonary hypertension. AB - BACKGROUND: Data regarding the outcomes of bariatric surgery in patients with pulmonary hypertension (PH) is limited. The aim of this study was to review our experience on bariatric surgery in patients with PH. SETTING: An academic medical center. METHODS: Patients with PH who underwent either a primary or revisional bariatric surgery between 2005 and 2015 and had a preoperative right ventricle systolic pressure (RVSP) >=35 mm Hg were included. RESULTS: Sixty-one patients met the inclusion criteria. Fifty (82%) were female with the median age of 58 years (interquartile range [IQR] 49-63). The median body mass index was 49 kg/m2 (IQR 43-54). Procedures performed included the following: Roux-en-Y gastric bypass (n = 33, 54%), sleeve gastrectomy (n = 24, 39%), adjustable gastric banding (n = 3, 5%), and banded gastric plication (n = 1, 2%). Four patients (7%) underwent revisional bariatric procedures. Median operative time and length of stay was 130 minutes (IQR 110-186) and 3 days (IQR 2-5), respectively. The 30-day complication rate was 16% (n = 10) with pulmonary complications noted in 4 patients. There was no 30-day mortality. One-year follow-up was available in 93% patients (n = 57). At 1 year, median body mass index and excess weight loss were 36 kg/m2 (IQR 33-41) and 51% (IQR 33-68), respectively. There was significant improvement in the RVSP after bariatric surgery at a median follow-up of 22 months (IQR 10-41). The median RVSP decreased from 44 (IQR 38-53) to 40 mm Hg (IQR 28-54) (P = .03). CONCLUSION: Bariatric surgery can be performed without prohibitive complication rates in patients with PH. In our experience, bariatric patients with PH achieved significant weight loss and improvement in RVSP. PMID- 30449515 TI - Laparoscopic vertical clip gastroplasty - quality of life. AB - BACKGROUND: Over the last decade, several techniques have emerged and the bariatric trends have changed. A new bariatric procedure that has been proposed is laparoscopic vertical clip gastroplasty (LVCG), which mimics the principle of laparoscopic sleeve gastrectomy, but with a completely reversible mechanism. The introduction of a new procedure in the bariatric armamentarium necessitated a period of preclinical and clinical studies and a validation of the procedure concerning the quality of life. SETTING: Private hospital, Dominican Republic. OBJECTIVES: The purpose of this manuscript was to evaluate patient satisfaction, measured by various questionnaires after LVCG. METHODS: From November 2012 to February 2017, 138 patients underwent LVCG and demographic data were collected prospectively. A total of 82 were evaluated for quality of life with a minimum follow-up of 6 months after the procedure. The quality of life was also analyzed regarding the complications and resolution of different medical conditions included in the Bariatric Analysis and Reporting Outcome System score. RESULTS: Eighty-five patients (73.9%) agreed to participate in the study and a total of 82 patients completed the questionnaires at all points in time. Seventy-one patients were female, with an average age of 34 (19-38). Mean body mass index before operation was 42.4 kg/m2 and declined significantly in both the first and second year postoperatively to 33.7 kg/m2 (1-year follow-up) in 65 patients and 34.3 kg/m2 (2-year follow-up) in 37 patients. The results showed failure for 1.2% of patients and were fair for 6.1% of cases. Quality of life was assessed as good for 26 patients (31.8%), as very good for 39 patients (47.5%), and as excellent for 11 patients (13.4%). CONCLUSIONS: LVCG represents a new bariatric procedure that mimics the principle of laparoscopic sleeve gastrectomy, but with a completely reversible mechanism. The procedure consists of a nonadjustable clip that is vertically placed parallel to the lesser curvature. After >3 years of clinical use, the weight loss results seem to be encouraging and up to 92.7% of patients have an improved quality of life. PMID- 30449517 TI - Dialysis Modality and Incident Atrial Fibrillation in Older Patients With ESRD. AB - RATIONALE & OBJECTIVE: Atrial fibrillation (AF) is common in patients with kidney failure treated by maintenance dialysis. Whether the incidence of AF differs between patients receiving hemodialysis and peritoneal dialysis is uncertain. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Using the US Renal Data System, we identified older patients (>=67 years) with Medicare Parts A and B who initiated dialysis therapy (1996-2011) without a diagnosis of AF during the prior 2 years. EXPOSURE: Dialysis modality at incident end-stage renal disease (ESRD) and maintained for at least 90 days. OUTCOME: Patients were followed up for 36 months or less for a new diagnosis of AF. ANALYTICAL APPROACH: Time-to-event analysis using multivariable Cox proportional hazards regression to estimate cause-specific HRs while censoring at modality switch, kidney transplantation, or death. RESULTS: Overall, 271,722 older patients were eligible; 17,487 (6.9%) were treated with peritoneal dialysis, and 254,235 (93.1%), with hemodialysis, at the onset of ESRD. During 406,225 person-years of follow-up, 69,705 patients had AF newly diagnosed. Because the proportionality assumption was violated, we introduced an interaction term between time (first 90 days vs thereafter) and modality. The AF incidence during the first 90 days was 187/1,000 person-years on peritoneal dialysis therapy and 372/1,000 person-years on hemodialysis therapy. Patients on peritoneal dialysis therapy had an adjusted 39% (95% CI, 34%-43%) lower incidence of AF than those on hemodialysis therapy. From day 91 onward, AF incidence was ~140/1,000 person-years with no major difference between modalities. LIMITATIONS: Residual confounding from unobserved differences between exposure groups; ascertainment of AF from billing claims; study of first modality may not generalize to patients switching modalities; uncertain generalizability to younger patients. CONCLUSIONS: Although patients initiating dialysis therapy using peritoneal dialysis had a lower AF incidence during the first 90 days of ESRD, there was no major difference in AF incidence thereafter. The value of interventions to reduce the early excess AF risk in patients receiving hemodialysis may warrant further study. PMID- 30449518 TI - Regional Prefrontal Resting-State Functional Connectivity in Posttraumatic Stress Disorder. AB - BACKGROUND: Prefrontal subregions, including the ventromedial prefrontal cortex (PFC), dorsomedial PFC, and dorsolateral PFC (DLPFC), are differentially implicated in the pathophysiology of posttraumatic stress disorder (PTSD), though few existing studies have examined subregional differences in resting-state functional connectivity (rsFC). We hypothesized that PTSD would involve weaker positive rsFC between ventromedial PFC, dorsomedial PFC, and other default mode network regions and increased negative rsFC between DLPFC and posterior default mode network regions. Additionally, we hypothesized that prefrontal regions exhibiting group differences in rsFC would be characterized by alterations in cortical thickness. METHODS: Participants included 36 healthy control subjects, 30 trauma-exposed control subjects, and 21 individuals with current DSM-IV PTSD resulting from community-acquired trauma. Participants completed the Clinician Administered PTSD Scale, questionnaires (Childhood Trauma Questionnaire, Adverse Childhood Events, Life Events Checklist, Beck Depression Inventory), structural neuroimaging, and resting-state functional magnetic resonance imaging. rsFC of DLPFC, ventromedial PFC, and dorsomedial PFC seeds was evaluated in SPM12 and CONN. Cortical thickness for regions with significant rsFC findings was assessed using FreeSurfer. RESULTS: Relative to both healthy control and trauma-exposed control subjects, individuals with PTSD showed increased negative rsFC between the DLPFC and a region of precuneus. This finding was associated with increased overall symptom severity but not with trauma load or childhood trauma exposure. Greater negative DLPFC-precuneus connectivity was associated with greater bilateral precuneus thickness. CONCLUSIONS: Given participation of precuneus subregions in the central executive network, increased anticorrelation between right DLPFC and precuneus in this sample may reflect increased opposition between anterior and posterior central executive network hubs in PTSD. PMID- 30449519 TI - Harmonized Outcome Measures for Use in Atrial Fibrillation Patient Registries and Clinical Practice: Endorsed by the Heart Rhythm Society Board of Trustees. AB - BACKGROUND: Atrial fibrillation (AF) affects an estimated 33 million people worldwide, leading to increased mortality and an increased risk of heart failure and stroke. Many AF patient registries exist, but the ability to link and compare data across registries is hindered by differences in the outcome measures collected by each registry and a lack of harmonization. OBJECTIVES: The purpose of this project was to develop a minimum set of standardized outcome measures that could be collected in AF patient registries and clinical practice. METHODS: AF patient registries were identified through multiple sources and invited to join the workgroup and submit outcome measures. Additional measures were identified through literature searches and reviews of consensus statements. Outcome measures were categorized using the Agency for Healthcare Research and Quality's supported Outcome Measures Framework (OMF). A minimum set of broadly relevant measures was identified. Measure definitions were harmonized through in person and virtual meetings. RESULTS: One hundred twelve outcome measures, including those from thirteen registries, were curated according to the OMF and then harmonized into a minimum set of measures in the OMF categories of survival (3 measures), clinical response (3 measures), events of interest (9 measures), patient-reported outcomes (2 measures), and resource utilization (3 measures). The harmonized definitions build on existing consensus statements. CONCLUSIONS: The harmonized measures represent a minimum set of outcomes that are relevant in AF research and clinical practice. Routine and consistent collection of these measures in registries and in other systems would support creation of a research infrastructure to efficiently address new questions and improve patient outcomes. PMID- 30449520 TI - Genetic effects and gene-by-education interactions on episodic memory performance and decline in an aging population. AB - Both social and genetic factors contribute to cognitive impairment and decline, yet genetic factors identified through genome-wide association studies (GWAS) explain only a small portion of trait variability. This "missing heritability" may be due to rare, potentially functional, genetic variants not assessed by GWAS, as well as gene-by-social factor interactions not explicitly modeled. Gene by-social factor interactions may also operate differently across race/ethnic groups. We selected 39 genes that had significant, replicated associations with cognition, dementia, and related traits in published GWAS. Using gene-based analysis (SKAT/iSKAT), we tested whether common and/or rare variants were associated with episodic memory performance and decline either alone or through interaction with education in >10,000 European ancestry (EA) and >2200 African ancestry (AA) respondents from the Health and Retirement Study (HRS). Nine genes in EA and five genes in AA were associated with memory performance or decline (p < 0.05), and these effects did not attenuate after adjusting for education. Interaction between education and CLPTM1 on memory performance was significant in AA (p = 0.003; FDR-adjusted p = 0.038) and nominally significant in EA (p = 0.026). In both ethnicities, low memory performance was associated with CLPTM1 genotype (rs10416261) only for those with less than high school education, and effects persisted after adjusting for APOE epsilon4. For over 70% of gene-by education interactions across the genome that were at least nominally significant in either ethnic group (p < 0.05), genetic effects were only observed for those with less than high school education. These results suggest that genetic effects on memory identified in this study are not mediated by education, but there may be important gene-by-education interactions across the genome, including in the broader APOE genomic region, which operate independently of APOE epsilon4. This work illustrates the importance of developing theoretical frameworks and methodological approaches for integrating social and genomic data to study cognition across ethnic groups. PMID- 30449521 TI - Comparison of Traditional and Web-Based Medical Student Teaching by Radiology Residents. AB - PURPOSE: Web-based learning tools are increasingly available for use and have been described in the pedagogical literature. However, rigorous comparisons between traditional learning methods and newer collaborative online tools have not been performed. Herein, we describe a web-based curriculum hosted on the collaborative Radiopaedia.org website. This curriculum was compared with traditional learning tools in a randomized, controlled fashion. MATERIALS AND METHODS: Medical students rotating through inpatient pediatrics were offered a 1 hour case-based learning session led by radiology residents. Students were randomized to receive online (Radiopaedia.org) versus traditional supplemental educational materials (reading material covering the same content) for review before the in-class session. A 15-point questionnaire was administered at two different points during the rotation: at the beginning of the clinical rotation and at the end of the classroom session. RESULTS: Fifty-eight students were approached for enrollment and a total of 47 (81%) consented to participation and completed the study requirements. Students who completed the web-based module had higher mean knowledge scores (74%) compared with those who were provided the traditional learning material (68%) (P = .06). Specifically, they demonstrated increased knowledge of the ACR Appropriateness Criteria and the "silhouette sign." CONCLUSIONS: A randomized, controlled, nonblinded evaluation of a novel radiology curriculum intervention hosted on Radiopaedia.org demonstrates improved test scores compared with traditional teaching methods. PMID- 30449522 TI - The Treatment of Laryngeal Cancer. AB - Successful management of laryngeal cancer depends on careful pretreatment evaluation of patient and disease factors to arrive at accurate staging, leading to appropriate treatment selection for patients with this highly impacting disease. Surgical modalities, including transoral laser microsurgery, open partial laryngectomy, and total laryngectomy, offer options, alone or in combination with radiation and chemotherapy. Treatment strategy for laryngeal cancer should strive for cure while maintaining the best quality of life possible for the patient. Achieving the goals of initial and salvage treatment for laryngeal cancer depends on executing a plan of care determined by the expertise of the multidisciplinary team. PMID- 30449523 TI - Contemporary Osseous Reconstruction of the Mandible and the Maxilla. AB - Cancers of the oral cavity and paranasal sinuses often require ablative surgery with adjuvant therapy in most cases. Large, postablative defects of the mandible and the maxilla present several challenges to the reconstructive surgeon. Functional and cosmetically satisfactory restoration requires a thorough understanding of the underlying disease process, a firm grasp of the nuances of head and neck anatomy, and an ability to plan and execute a reconstruction with the most suitable tissue for each particular patient. The authors outline the components of osseous reconstruction of the facial skeleton with a bias toward techniques and approaches that are particularly useful. PMID- 30449524 TI - Salivary Gland Malignancies. AB - Salivary gland tumors are rare pathologic entities that are derived from major and minor salivary gland tissue located throughout the head and neck region. These tumors are distinctly heterogenous, comprising numerous cell types, especially those deemed malignant. The incidence of malignant salivary gland tumors is widely distributed in both adult and pediatric patient populations. Accurate diagnosis and optimal treatment of these tumors pose challenges to both interpreting pathologists and ablative surgeons. This article examines the epidemiology and pathology of malignant tumors of the major and minor salivary glands and provides recommendations for the most successful treatment approaches. PMID- 30449525 TI - Current Concepts in Chemotherapy for Head and Neck Cancer. AB - This article highlights the evidence-based data to support systemic treatment options for patients with head and neck squamous cell carcinoma (HNSCC). The discovery of the human papillomavirus epidemic in HNSCC and its favorable prognosis has led to a major focus of research. Patients are stratified into clinical or pathologic risk categories and enrolled in trials comparing standard treatment paradigms with deintensification, in low-risk disease, or to intensification, in intermediate-risk or high-risk disease. Immunotherapy has proven beneficial in second-line palliative therapy and is under investigation in first-line palliative therapy and as a component of definitive, multimodality therapy for high-risk patients. PMID- 30449526 TI - Soft Tissue Reconstruction for Head and Neck Ablative Defects. AB - Soft tissue reconstruction of head and neck ablative defects is a broad, challenging, and subjective topic. The authors outline goals to keep in mind when deciding on a primary reconstructive option for defects created by oncologic resection. Factors considered in local, regional, and distant flap selection are discussed. Based on the goals of reconstruction and factors involved in flap selection, a defect-based reconstructive algorithm is developed to help choose the ideal reconstructive option. The authors also discuss indications, pearls, pitfalls, and challenges in the harvest and inset of commonly used soft tissue flaps for head and neck reconstructive surgery. PMID- 30449527 TI - Management of the Neck in Oral Squamous Cell Carcinoma: Background, Classification, and Current Philosophy. AB - Nodal metastasis is the single most prognostic determinant in patients with oral squamous cell carcinoma (OSCC). Since its inception more than a century ago, the management of the neck has led to decreased surgical morbidity, with continued preservation of oncologic safety for OSCC. Nodal metastasis is the single most prognostic determinant in patients with OSCC. The decision for the extent of the neck dissection is tailored to tumor-specific characteristics, which dictate the probability and extent of nodal metastasis, including tumor size, location, histopathologic characteristics, and the presence or absence of clinical nodal disease. These factors are tools to aid diagnosticians in their decision making for individual patients. PMID- 30449529 TI - The Head and Neck Cancer Patient: Neoplasm Management. PMID- 30449528 TI - Immunotherapy for Head and Neck Cancer. AB - The immune system has a vital role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). Immune evasion of cancer cells leads to progression of HNSCC. An understanding of this mechanism provides the basis for improved therapies and outcomes for patients. Through the tumor's influence on the microenvironment, the immune system can be exploited to promote metastasis, angiogenesis, and growth. This article provides an overview of the interaction between immune infiltrating cells in the tumor microenvironment, and the immunologic principles related to HNSCC. Current immunotherapeutic strategies and emerging results from ongoing clinical trials are presented. PMID- 30449530 TI - The Role of Dendritic Brain-Derived Neurotrophic Factor Transcripts on Altered Inhibitory Circuitry in Depression. AB - BACKGROUND: A parallel downregulation of brain-derived neurotrophic factor (BDNF) and somatostatin (SST), a marker of inhibitory gamma-aminobutyric acid interneurons that target pyramidal cell dendrites, has been reported in several brain areas of subjects with major depressive disorder (MDD). Rodent genetic studies suggest that they are linked and that both contribute to the illness. However, the mechanism by which they contribute to the pathophysiology of the illness has remained elusive. METHODS: With quantitative polymerase chain reaction, we determined the expression level of BDNF transcript variants and synaptic markers in the prefrontal cortex of patients with MDD and matched control subjects (n = 19/group) and of C57BL/6J mice exposed to chronic stress or control conditions (n = 12/group). We next suppressed Bdnf transcripts with long 3' untranslated region (L-3'-UTR) using short hairpin RNA and investigated changes in cell morphology, gene expression, and behavior. RESULTS: L-3'-UTRs containing BDNF messenger RNAs, which migrate to distal dendrites of pyramidal neurons, are selectively reduced, and their expression was highly correlated with SST expression in the prefrontal cortex of subjects with MDD. A similar downregulation occurs in mice submitted to chronic stress. We next show that Bdnf L-3'-UTR knockdown is sufficient to induce 1) dendritic shrinkage in cortical neurons, 2) cell-specific MDD-like gene changes (including Sst downregulation), and 3) depressive- and anxiety-like behaviors. The translational validity of the Bdnf L-3'-UTR short hairpin RNA-treated mice was confirmed by significant cross species correlation of changes in MDD-associated gene expression. CONCLUSIONS: These findings provide evidence for a novel MDD-related pathological mechanism linking local neurotrophic support, pyramidal cell structure, dendritic inhibition, and mood regulation. PMID- 30449531 TI - Computational Modeling Applied to the Dot-Probe Task Yields Improved Reliability and Mechanistic Insights. AB - BACKGROUND: Biased patterns of attention are implicated as key mechanisms across many forms of psychopathology and have given rise to automated mechanistic interventions designed to modify such attentional preferences. However, progress is substantially hindered by limitations in widely used methods to quantify attention, bias leading to imprecision of measurement. METHODS: In a sample of patients who were clinically anxious (n = 70), we applied a well-validated form of computational modeling (drift-diffusion model) to trial-level reaction time data from a two-choice "dot-probe task"-the dominant paradigm used in hundreds of attention bias studies to date-in order to model distinct components of task performance. RESULTS: While drift-diffusion model-derived attention bias indices exhibited convergent validity with previous approaches (e.g., conventional bias scores, eye tracking), our novel analytic approach yielded substantially improved split-half reliability, modestly improved test-retest reliability, and revealed novel mechanistic insights regarding neural substrates of attention bias and the impact of an automated attention retraining procedure. CONCLUSIONS: Computational modeling of attention bias task data may represent a new way forward to improve precision. PMID- 30449532 TI - Adiposity, history of diabetes, and risk of pancreatic cancer in postmenopausal women. AB - PURPOSE: The purpose of this study was to examine the association of type II diabetes and anthropometric variables with risk of pancreatic cancer among postmenopausal women. METHODS: Weight, height, waist circumference, and hip circumference were measured by trained personnel, whereas history of diabetes and weight earlier in life were self-reported. Pancreatic cancer was ascertained via central review of medical records by physician adjudicators. After exclusions, 1045 cases of pancreatic cancer were diagnosed among 156,218 women over a median follow-up of approximately 18 years. Cox proportional hazards models were used to estimate the associations of study factors with pancreatic cancer risk. RESULTS: Diabetes (hazards ratio (HR): 1.30; 95% confidence intervals (95% CI): 1.01 1.66), and in particular, waist circumference, waist-to-hip ratio, and waist-to height ratio showed positive associations with pancreatic cancer risk (HRs for highest vs. lowest level 1.38; 95% CI: 1.14-1.66, 1.40; 1.17-1.68; and 1.36; 1.13 1.64, respectively). Body mass index at the baseline showed only a borderline positive association with risk (HR: 1.21; 95% CI: 0.97-1.51). Body mass index at age 50 years, but not at ages 18 and 35 years, was also associated with increased pancreatic cancer risk. CONCLUSIONS: In this study of postmenopausal women, central adiposity and, to a lesser extent, general adiposity and a history of diabetes, were associated with increased pancreatic cancer risk. PMID- 30449533 TI - The use of proteomics to understand antiviral immunity. AB - Viruses are intracellular pathogens that cause a vast array of diseases, which are often severe and typified by high morbidity and mortality rates. Viral infections continue to be a global health burden and effective vaccines and therapeutics are constantly sought to prevent and treat these infections. The development of such treatments generally relies on understanding the mechanisms that underpin efficient host antiviral immune responses. This review summarises recent developments in our understanding of antiviral adaptive immunity and in particular, highlights the use of mass spectrometry to elucidate viral antigens and their processing and presentation to T cells and other immune effectors. These processed peptides serve as potential vaccine candidates or may facilitate clinical monitoring, diagnosis and immunotherapy of infectious diseases. PMID- 30449534 TI - The intersection of affinity and specificity in the development and optimization of T cell receptor based therapeutics. AB - The role of the alphabeta T cell receptor (TCR) in identifying immunological targets and signaling appropriate responses provides for exciting translational opportunities. Yet TCRs mediate one of the most complex protein-protein interactions in biology, with intricate signaling and selection mechanisms adding additional layers of sophistication. In this review, we discuss how these complexities influence the development and optimization of TCR-based therapeutics, focusing on the intersection between structure, affinity, and specificity. We highlight similarities between TCRs and germline antibodies in molecular recognition, but emphasize that engineering TCRs by mimicking antibody maturation may not translate into improved biological outcomes. A key point is the need to distinguish TCR biochemical recognition from T cell functional recognition and the complications this distinction has for efforts in TCR engineering. We suggest learning from natural immunity and taking advantage of structural features and state-of-the-art protein design principles as a means to optimize TCRs for therapeutic use. PMID- 30449535 TI - MR1-dependent antigen presentation. AB - MR1 is a non-classical class I molecule that is highly conserved among mammals. Though discovered in 1995, only recently have MR1 ligands and antigens for MR1 restricted T cells been described. Unlike the traditional class I molecules HLA A, -B, and -C, little MR1 is on the cell surface. Rather, MR1 resides in discrete intracellular vesicles and the endoplasmic reticulum, and can present non peptidic small molecules such as those found in the riboflavin biosynthesis pathway. Since mammals do not synthesize riboflavin, MR1 can serve as a sensor of the microbial metabolome and could be key to the early detection of intracellular infection. This review will summarize the current understanding of MR1-dependent antigen presentation. PMID- 30449536 TI - A Randomized Trial of a Long-Acting Depot Corticosteroid Versus Dexamethasone to Prevent Headache Recurrence Among Patients With Acute Migraine Who Are Discharged From an Emergency Department. AB - STUDY OBJECTIVE: Migraine patients continue to report headache during the days and weeks after emergency department (ED) discharge. Dexamethasone is an evidence based treatment of acute migraine that decreases the frequency of moderate or severe headache within 72 hours of ED discharge. We hypothesize that intramuscular methylprednisolone acetate, a long-acting steroid that remains biologically active for 14 days, will decrease the number of days with headache during the week after ED discharge by at least 1 day compared with intramuscular dexamethasone. METHODS: We conducted a randomized, blinded clinical trial comparing intravenous metoclopramide at 10 mg+intramuscular dexamethasone at 10 mg with intravenous metoclopramide at 10 mg+intramuscular methylprednisolone acetate at a dose of 160 mg for patients presenting to 2 different EDs with moderate or severe migraine. Outcomes were assessed by telephone with a standardized instrument. The primary outcome was number of days with headache during the week after ED discharge. Secondary outcomes were complete freedom from headache, without the necessity of additional headache medication for the entire week after ED discharge, and medication preference, as determined by asking the patient whether he or she would want to receive the same medication again. RESULTS: One hundred nine patients received dexamethasone and 111 received methylprednisolone acetate. We obtained primary outcome data from 101 dexamethasone patients and 106 methylprednisolone acetate patients. Dexamethasone patients reported 3.0 headache days and methylprednisolone acetate 3.3 headache days (95% confidence interval for rounded mean difference of 0.4 days: -0.4 to 1.1). Of 107 dexamethasone patients with analyzable data, 10 (9%) reported complete freedom from headache at 1 week versus 6 of 110 (5%) methylprednisolone acetate patients (95% confidence interval for difference of 4%: -3% to 11%). In the dexamethasone group, 76 of 101 (75%) patients would want the same medication again versus 75 of 106 (71%) of methylprednisolone acetate patients (95% confidence interval for difference of 4%: -8% to 17%). Other than injection site reactions, which were more common in the methylprednisolone acetate group, there were no substantial differences in frequency of adverse events. CONCLUSION: Methylprednisolone acetate does not decrease the frequency of post-ED discharge headache days compared with dexamethasone. Most migraine patients are likely to continue to experience headache during the week after ED discharge. PMID- 30449537 TI - Update on prevention and treatment of sudden cardiac arrest. AB - Sudden cardiac arrest is the leading cause of cardiovascular mortality, posing a substantial public health burden. The incidence and epidemiology of sudden death are a function of age, with primary arrhythmia syndromes and inherited cardiomyopathies representing the predominant causes in younger patients, while coronary artery disease being the leading etiology in those who are 35 years of age and older. Internal cardioverter defibrillators remain the mainstay of primary and secondary prevention of sudden cardiac arrest. In the acute phase, cardiac chain of survival, early reperfusion, and therapeutic hypothermia are the key steps in improving outcomes. In the chronic settings, ventricular tachycardia ablation has been shown to improve patients' quality of life by reducing frequency of defibrillator shocks. Moreover, recent studies have suggested that it may increase survival. Neuromodulation represents a novel therapeutic modality that has a great potential for improving treatment of ventricular arrhythmias. PMID- 30449538 TI - Retrospective and perspective of rice breeding in China. AB - Breeding is the art and science of selecting and changing crop traits for the benefit of human beings. For several decades, tremendous efforts have been made by Chinese scientists in rice breeding in improving grain yield, nutrition quality, and environmental performance, achieving substantial progress for global food security. Several generations of crop breeding technologies have been developed, for example, selection of better performance in the field among variants (conventional breeding), application of molecular markers for precise selection (molecular marker assisted breeding), and development of molecular design (molecular breeding by rational design). In this review, we briefly summarize the advances in conventional breeding, functional genomics for genes and networks in rice that regulate important agronomic traits, and molecular breeding in China with focuses on high yield, good quality, stress tolerance, and high nutrient-use efficiency. These findings have paved a new avenue for rational design of crops to develop ideal varieties with super performance and productivity. PMID- 30449539 TI - Big ideas: New metaphors for nursing (2): The nurse as bricoleur. PMID- 30449540 TI - Nonhuman biota dose rate estimation from liquid effluent releases during normal operations of light water reactors using the LADTAP II computer code. AB - The LADTAP II computer code was used to estimate the dose rates to seven nonhuman biota (fish, algae, invertebrate, muskrat, raccoon, heron, and duck) from liquid effluent releases during the normal operations of new light water reactor facilities in the United States. The estimated dose rates to nonhuman biota depended on the nuclear power plant design but were orders of magnitude less than the 'derived consideration reference levels' (DCRL) in International Commission on Radiological Protection (ICRP) Publication 108. The estimated dose rates were at least three orders of magnitude lower than the guideline values identified by the International Atomic Energy Agency (IAEA) and the National Council on Radiation Protection and Measurements to cause observable changes in populations of biota. Radionuclides that contributed most of the dose rates for seven nonhuman biota depended on the nuclear power plant design. The differences in the estimated dose rates to seven nonhuman biota calculated from the default bioaccumulation factors used in the LADTAP II computer code and the dose rates calculated from the concentration ratios of radionuclides in the IAEA Technical Report Series (TRS) wildlife handbook were less than one order of magnitude for most default biota in LADTAP. The concentration ratios for some radionuclides in liquid effluent releases from nuclear power plant designs that contributed more than 5% of the internal dose rates for invertebrates (P, and Ru) and algae (La and Pr) were not available in the IAEA TRS wildlife handbook. PMID- 30449541 TI - Reply to the comments on: Erlotinib in combination with bevacizumab has potential benefit in non small cell lung cancer: A systematic review and meta-analysis of randomized clinical trials. PMID- 30449542 TI - Long-term Outcomes for Teen Mothers Who Participated in a Mentoring Program to Prevent Repeat Teen Pregnancy. AB - BACKGROUND: Each year in the United States (US), one million adolescents are pregnant, of which approximately 20% are repeat pregnancies. Adolescent motherhood is associated with lower educational attainment, socioeconomic status and poorer health outcomes. A mentoring program called the Maikuru Program conducted from 2011 to 2015, was designed to teach young mothers under 20 years old how to face daily life challenges, to support them by pairing them with an adult mentor, and prevent a subsequent pregnancy during their teens. The goal of the present study was to examine educational attainment, employment and pregnancies of these adolescent mothers 1-5 years post program. METHODS: Former participants of the Maikuru Program were contacted by telephone and/or Facebook in 2016 to conduct a survey about education attainment, employment status, number of subsequent children delivered, and satisfaction with the program. RESULTS: Nineteen of 51 participants (37%) were reached to complete the survey. Of those who responded, all were in high school or had graduated, nearly half were pursuing some form of higher education and 12 (63%) were currently employed. Nine mothers had given birth to another child; only two (10.5%) were known to be less than 20 years old at the time. All participants reported positive perceptions of the program and would recommend it to other adolescent mothers. CONCLUSION: Educational achievement and employment were high among a modest proportion of adolescent mothers who had participated in a culturally tailored, teen mother adult mentoring program. Repeat teen pregnancy was infrequent and the mentoring program was perceived as contributing to the success of those who responded to the follow-up. A future randomized trial based on this model may confirm these findings. PMID- 30449544 TI - Familial hypocalciuric hypercalcemia and related disorders. AB - Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit alpha11, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH. PMID- 30449543 TI - Primary hyperparathyroidism. AB - Primary hyperparathyroidism (PHPT), the most common cause of hypercalcemia, is most often identified in postmenopausal women with hypercalcemia and parathyroid hormone (PTH) levels that are either frankly elevated or inappropriately normal. The clinical presentation of PHPT includes three phenotypes: target organ involvement of the renal and skeletal systems; mild asymptomatic hypercalcemia; and more recently, high PTH levels in the context of persistently normal albumin corrected and ionized serum calcium values. The factors that determine which of these three clinical presentations is more likely to predominate in a given country include the extent to which biochemical screening is employed, the prevalence of vitamin D deficiency, and whether a medical center or practitioner tends to routinely measure PTH levels in the evaluation of low bone density or frank osteoporosis. When biochemical screening is common, asymptomatic primary hyperparathyroidism is the most likely form of the disease. In countries where vitamin D deficiency is prevalent and biochemical screening is not a feature of the health care system, symptomatic disease with skeletal abnormalities is likely to predominate. Finally, when PTH levels are part of the evaluation for low bone mass, the normocalcemic variant is seen. Guidelines for surgical removal of hyperfunctioning parathyroid tissue apply to all three clinical forms of the disease. If guidelines for surgery are not met, parathyroidectomy can also be an appropriate option if there are no medical contraindications to surgery. In settings where either the serum calcium or bone mineral density is of concern, and surgery is not an option, pharmacological approaches are available and effective. Referencing in this article the most current published articles, we review the different presentations of PHPT, with particular emphasis on recent advances in our understanding of target organ involvement and management. PMID- 30449545 TI - Parathyroid hormone independent hypercalcemia in adults. AB - Parathyroid independent hypercalcemia is characterized by suppressed parathyroid hormone (PTH) in the presence of hypercalcemia. Well known causes and mechanisms are redistribution of calcium from the skeleton, by malignant diseases; inadequately increased intestinal calcium uptake mediated by increased vitamin D activity, and reduced renal elimination due to medications. Frequent and infrequent causes are discussed, and more recent mechanistic models presented in this review. Most hypercalcemic conditions are stable and in equilibrium between the different organs, whereas the utmost severe cases are characterized by rapid rising calcium levels and renal failure, resulting in a vicious circle where a disequilibrium state is developed. Management and treatment depends on the underlying condition and severity. The aim of this review is to discuss non parathyroid hypercalcemic conditions as seen in the modern clinic, with a focus on areas where recent gain of knowledge has been achieved. PMID- 30449546 TI - Hypocalcemic disorders. AB - Calcium is vital for life, and extracellular calcium concentrations must constantly be maintained within a precise concentration range. Low serum calcium (hypocalcemia) occurs in conjunction with multiple disorders and can be life threatening if severe. Symptoms of acute hypocalcemia include neuromuscular irritability, tetany, and seizures, which are rapidly resolved with intravenous administration of calcium gluconate. However, disorders that lead to chronic hypocalcemia often have more subtle manifestations. Hypoparathyroidism, characterized by impaired secretion of parathyroid hormone (PTH), a key regulatory hormone for maintaining calcium homeostasis, is a classic cause of chronic hypocalcemia. Disorders that disrupt the metabolism of vitamin D can also lead to chronic hypocalcemia, as vitamin D is responsible for increasing the gut absorption of dietary calcium. Treatment and management options for chronic hypocalcemia vary depending on the underlying disorder. For example, in patients with hypoparathyroidism, calcium and vitamin D supplementation must be carefully titrated to avoid symptoms of hypocalcemia while keeping serum calcium in the low normal range to minimize hypercalciuria, which can lead to renal dysfunction. Management of chronic hypocalcemia requires knowledge of the factors that influence the complex regulatory axes of calcium homeostasis in a given disorder. This chapter discusses common and rare disorders of hypocalcemia, symptoms and workup, and management options including replacement of PTH in hypoparathyroidism. PMID- 30449547 TI - Paget's disease of bone. AB - Paget's disease of bone is a focal disorder of bone remodelling that progresses slowly and leads to changes in the shape and size of affected bones and to skeletal, articular and vascular complications. In some parts of the world it is the second most common bone disorder after osteoporosis though in recent years its prevalence and severity appear to decrease. The disease is easily diagnosed and effectively treated but its pathogenesis remains incompletely understood. PMID- 30449548 TI - Vitamin D insufficiency: Definition, diagnosis and management. AB - Severe vitamin D deficiency can be defined as the dose of vitamin D or serum 25OHD concentrations needed to prevent nutritional rickets or osteomalacia. There is large international consensus that these diseases can be prevented by 400 IU of vitamin D/d and 25OHD above 30 nmol/l (12 ng/ml). Vitamin D deficiency can also accelerate the risk of fractures and probably also of falls in elderly subjects but there is no consensus on the required daily doses or minimal 25OHD threshold for these endpoints. The majority of experts consider 800 IU/d and serum 25OHD above 50 nmol/l (20 ng/ml) as sufficient, with a minority opinion aiming for 75 nmol/l or even higher. For other extra-skeletal endpoints, no hard evidence is available to define whether or not this is causally related to vitamin D status. Therefore, for these endpoints no minimal dosage or 25OHD threshold can be defined. PMID- 30449550 TI - Sclerosing bone dysplasias. AB - The group of sclerosing bone dysplasia's is a clinically and genetically heterogeneous group of rare bone disorders which, according to the latest Nosology and classification of genetic skeletal disorders (2015), can be subdivided in three subgroups; the neonatal osteosclerotic dysplasias, the osteopetroses and related disorders and the other sclerosing bone disorders. Here, we give an overview of the most important radiographic and clinical symptoms, the underlying genetic defect and potential treatment options of the different sclerosing dysplasias included in these subgroups. PMID- 30449549 TI - Phosphate homeostasis disorders. AB - Our understanding of the regulation of phosphate balance has benefited tremendously from the molecular identification and characterization of genetic defects leading to a number of rare inherited or acquired disorders affecting phosphate homeostasis. The identification of the key phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), as well as other molecules that control its production, such as the glycosyltransferase GALNT3, the endopeptidase PHEX, and the matrix protein DMP1, and molecules that function as downstream effectors of FGF23 such as the longevity factor Klotho and the phosphate transporters NPT2a and NPT2c, has permitted us to understand the complex interplay that exists between the kidneys, bone, parathyroid, and gut. Such insights from genetic disorders have allowed not only the design of potent targeted treatment of FGF23-dependent hypophosphatemic conditions, but also provide clinically relevant observations related to the dysregulation of mineral ion homeostasis in health and disease. PMID- 30449551 TI - Bone turnover: Biology and assessment tools. AB - Bone turnover includes two processes: resorption (removal of old bone) and formation (laying down of new bone). N-terminal propeptide of type I procollagen (PINP) and C-telopeptide of type I collagen (CTX-I) are markers of bone formation and resorption, respectively, that the International Osteoporosis Foundation and the International Federation of Clinical Chemistry recommend for clinical use. Bone turnover markers (BTM) are subject to sources of variability, including feeding (lower resorption) and recent fracture (increased levels of all markers). Controllable patient-related factors should be adapted as much as possible (eg blood collection after an overnight fast) to minimize pre-analytical variability. Uncontrollable factors should be considered in the interpretation of the BTM measurements. BTM do not improve prediction of bone loss or fracture within an individual. In osteoporotic patients, BTM may help to assess the response to anabolic and antiresorptive therapies, to assess compliance to the treatment, or to indicate possible secondary causes of osteoporosis. BTM reflect changes in bone metabolism induced by anti-osteoporotic treatment. Anti-resorptive drugs induce a rapid dose-dependent decrease in bone resorption, whereas bone formation stimulating medications increase the levels of bone formations markers. BTM may be used for monitoring anti-osteoporosis therapy. The expected effect during the anti-resorptive therapy is to decrease the PINP by at least 10 ng/mL and to attain the target level of less than 35 ng/mL. The expected effect during the bone formation-stimulating therapy is to increase the PINP by at least 10 ng/mL and to attain the target level of more than 69 ng/mL. PMID- 30449552 TI - Postmenopausal osteoporosis: Assessment and management. AB - Osteoporosis increases the risk of fractures, which are associated with increased mortality and lower quality of life. Patients with prevalent fracture are at high risk to of sustaining another one. Optimal protein and calcium intakes, and vitamin D supplies, together with regular weight bearing physical exercise are the corner stones of fracture prevention. Evidence for anti-fracture efficacy of pharmacological interventions relies on results from randomised controlled trials in postmenopausal women with fractures as the primary outcome. Treatments with bone resorption inhibitors, like bisphosphonates or denosumab, and bone formation stimulator like teriparatide, reduce vertebral and non-vertebral fracture risk. A reduction in vertebral fracture risk can already be detected within a year after starting therapy. PMID- 30449553 TI - Update on osteoporosis in men. AB - Osteoporosis in men remains under-diagnosed and under-appreciated. After a low trauma fracture, a man is less likely to have evaluation and treatment. The lifetime risk for osteoporotic fracture in older men may range from 13 to 25%, and as men live longer, there will be more fractures. Newer strategies for determining which men should have bone density testing are emerging. Information from observational studies are providing insights that allow targeted testing and treatment of those men at the highest risk for fracture. Treatment with most of the same medications used in women is efficacious and generally safe. Nonetheless, the fear of side effects of treatments for an asymptomatic disorder (before a fracture) and other barriers have made management challenging in men at risk for fracture. This review provides updates on epidemiology, pathophysiology, evaluation and treatment of male osteoporosis. PMID- 30449568 TI - Differential diagnosis of a hepatic mass by 99mTc-labelled red cells and octreotide scintigraphy. PMID- 30449569 TI - It's the beans that count. PMID- 30449570 TI - Aortic valve therapies: Different approaches and outcomes. PMID- 30449571 TI - Transcatheter aortic valve replacement and surgical aortic valve replacement: Both excellent therapies. PMID- 30449572 TI - Only quality can save surgery. PMID- 30449573 TI - Innovative valve disease therapies, a potential benefit for patients but calling for more clinical evaluation. PMID- 30449574 TI - Tailored approach for severe aortic stenosis. PMID- 30449575 TI - Progression of cardiac surgery-associated acute kidney injury into acute kidney disease: A case for enhanced early kidney diagnostic fine-tuning implementation? PMID- 30449577 TI - The 2018 Thoracic Surgery Residents Association and Society of Thoracic Surgeons traveling fellowship: Total arterial grafting in Calgary. PMID- 30449576 TI - Mentoring never ends. PMID- 30449578 TI - Reminder: Tetralogy of Fallot is not just a right-sided cardiac problem. PMID- 30449580 TI - The aorta in repaired tetralogy of Fallot: A potential source of late danger? PMID- 30449579 TI - Reduced proximal aortic compliance and elevated wall shear stress after early repair of tetralogy of Fallot. AB - OBJECTIVE: Patients with tetralogy of Fallot are at risk for late aortic complications due to progressive aortic root dilation and decreased aortic compliance. Early repair normalizes aortic dimensions by preadolescence. It is not known if early repair normalizes aortic wall histology and compliance or reduces late aortic complications. We used 4-dimensional flow magnetic resonance imaging to determine if children with tetralogy of Fallot repaired in infancy had normal aortic dimensions and to characterize the aortic wall hemodynamic state and luminal flow parameters in these patients. METHODS: Comprehensive aortic analysis with 4-dimensional flow magnetic resonance imaging was performed in 18 patients with tetralogy of Fallot who were repaired in infancy and compared with 18 normal volunteers. Peak systolic and time-averaged wall shear stress, relative area change, and distensibility were evaluated in standardized aortic planes. Qualitative grade scale flow analysis with interactive pathline visualization was used to detect pathologic flow patterns. RESULTS: Thoracic aortic dimensions did not differ between groups, and all tetralogy of Fallot aortas were in normal range. In the tetralogy of Fallot group, ascending and descending aortic relative area change and distensibility were significantly reduced, and both peak systolic and time-averaged wall shear stress were elevated throughout the aorta. Supra physiologic systolic helical formations occurred in the ascending aorta of 14 patients with tetralogy of Fallot (78%) versus 0 controls. CONCLUSIONS: Despite early repair and normal aortic dimensions, preadolescents and adolescents with tetralogy of Fallot had elevated wall shear stress, increased stiffness, and pathologic systolic flow formations in the proximal aorta. Although early repair normalizes aortic dimensions in childhood, our findings suggest that patients with tetralogy of Fallot remain at risk for late aortic complications. PMID- 30449582 TI - Lymph node dissection during sublobar resection, quantitative or qualitative? PMID- 30449583 TI - Lymph Node Assessment Adequacy and First Amendment Jurisprudence: Can We Do Better Than Just "Knowing it When We See it"? PMID- 30449581 TI - Markers of peripheral perfusion during high-flow regional cerebral perfusion for aortic arch repair. AB - OBJECTIVES: High-flow regional cerebral perfusion (HFRCP) provides cerebral and somatic oxygen delivery through collateral vessels during aortic arch repair in small children; however, optimal flow conditions during HFRCP have not been established. We sought to identify markers of peripheral perfusion during HFRCP. METHODS: Between 2009 and 2016, in total 20 consecutive pediatric patients undergoing aortic arch repair with HFRCP were enrolled in this prospective, observational study. Median age was 20 days (range, 6-116 days); median body weight was 2.77 kg (range, 1.8-4.98 kg). Oxygen delivery ratio (Do2R) was calculated as the oxygen delivery during HFRCP divided by the oxygen delivery before HFRCP. Regional oxygen saturations on the forehead and on the thigh (rSo2T) were monitored during HFRCP, and postoperative creatinine kinase and lactate concentrations were measured as postoperative outcomes. Multivariate analyses were performed to clarify the effectiveness of Do2R and rSo2T as markers of peripheral perfusion during HFRCP. RESULTS: No deaths or neurologic impairments occurred. Multivariate analysis showed that the lowest rSo2T (P = .005) and cardiopulmonary bypass time (P = .012) predicted postoperative creatinine kinase concentration. Do2R was the only factor to predict postoperative lactate concentration (P < .001). Receiver operating characteristic analysis showed that Do2R less than 0.66 predicted risk of high postoperative lactate concentration (>5.0 mmol/L), with area under the curve of 0.95. CONCLUSIONS: For aortic arch repair in small children, rSo2T and Do2R during HFRCP are useful markers for predicting peripheral perfusion. Maintaining higher Do2R during HFRCP minimizes postoperative increases in lactate and creatinine kinase concentrations. PMID- 30449584 TI - Going home after esophagectomy: The story is not over yet. PMID- 30449585 TI - A first start for lung transplantation? PMID- 30449586 TI - Delving into the details of postpneumonectomy prognosis. PMID- 30449588 TI - Notice of Correction. PMID- 30449589 TI - Esophagectomy via upper partial sternotomy for esophageal cancer after previous right pneumonectomy: A case report. PMID- 30449587 TI - Patients experiencing early acute respiratory failure have high postoperative mortality after pneumonectomy. AB - OBJECTIVE: Post-pneumonectomy acute respiratory failure leading to invasive mechanical ventilation carries a severe prognosis especially when acute respiratory distress syndrome occurs. The aim of this study was to describe risk factors and outcome of acute respiratory failure. METHODS: We retrospectively reviewed clinical files of all patients who underwent pneumonectomy in a single center between 2005 and 2015. Risk factors and outcome of acute respiratory failure were assessed in univariate and multivariate analysis. RESULTS: Among the 543 patients who underwent pneumonectomy in the period of study, 89 (16.4%) needed reintubation within the 30th postoperative day and 60 of these (11% of all pneumonectomies) developed acute respiratory distress syndrome. In multivariate analysis, right-side of pneumonectomy (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.24-4.22), chronic cardiac disease (OR, 2.15; 95% CI, 1.08-4.25), Charlson Comorbidity Index (OR, 1.35; 95% CI, 1.14-1.61), carinal resection (OR, 3.23; 95% CI, 1.26-8.29), and extrapleural pneumonectomy (OR, 8.36; 95% CI, 3.31 21.11) were identified as independent risk factors of reintubation. Thirty-day mortality was 7.7% for all pneumonectomies, 41.6% (37/89) in the invasive ventilation group, and 53.3% (32/60) in patients with acute respiratory distress syndrome. In non-reintubated patients, 30-day mortality was 1.1% (5/454). In reintubated patients, 5-year survival was 27.1% (95% CI, 17.8-41.4). CONCLUSIONS: Early acute respiratory failure requiring reintubation remains a severe complication of pneumonectomy with a poor outcome. PMID- 30449590 TI - A new MR radiological sign in HaNDL syndrome. A case report. AB - BACKGROUND: One of the classical diagnostic criteria of the syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) is the normality of imaging studies except from some reversible alterations as leptomeningeal enhancement or focal hypoperfusion. CASE: We present a 41 year-old man who abruptly started with a set of right parietal symptoms, meeting the diagnostic criteria for HaNDL syndrome. An electroencephalographic record showed a slowing of the right hemisphere. MR susceptibility weighted sequences demonstrated a reduced venous signal in the symptomatic hemisphere, unlike other transient disorders as migraine aura where an opposite pattern with prominence of the venous structures in the symptomatic hemisphere has been reported. This sign could reflect a decrease in metabolic demands or a fail in oxygen employment by the affected tissue. CONCLUSION: To our knowledge, this finding has not been described yet, and it may provide a new insight on the pathogenesis of HaNDL syndrome. PMID- 30449591 TI - ? PMID- 30449593 TI - WITHDRAWN: corrigendum to "Effectiveness of complementary pain treatment for women with deep endometriosis through Transcutaneous Electrical Nerve Stimulation (TENS): Randomized controlled trial" [Eur. J. Obstet. Gynecol. Reprod. Biol. 194 (2015) 1-6]. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. PMID- 30449592 TI - The role of symptoms and insight in mediating cognition and functioning in first episode psychosis. AB - INTRODUCTION: Achieving functional recovery in patients with psychosis is a challenge in clinical practice. Investigating the complex interplay between cognition, symptoms, insight and functional outcome in first episode psychosis will be crucial to understanding the factors leading to better functioning. METHODS: In this 12-month prospective follow-up study, we investigated how cognition, clinical symptoms, and insight into illness affected overall functioning in 160 patients with first episode psychosis recruited from the Early Assessment Service for Young People with Psychosis (EASY) in Hong Kong from July 1, 2014 to June 30, 2016. Cognition was assessed at baseline while symptoms, insight, and functioning were assessed at 12-month follow-up. Structural equation modelling was used to examine the direct and indirect relationships between functioning and other latent constructs. RESULTS: Symptoms (negative symptoms and general psychopathology) and insight were shown to be significant mediators between cognition and functioning. The significant direct relationship between cognition and functioning (beta = 0.387; p < 0.001) became insignificant (beta = 0.079; p = 0.578) after including symptoms and insight in the model. Symptoms and insight were significantly associated with cognition (symptoms, beta = -0.469; p < 0.001; insight, beta = -0.372; p < 0.001) and predicted functioning (symptoms, beta = -0.558; p < 0.001; insight, beta = -0.264; p < 0.01). CONCLUSION: Symptoms and insight mediated the effects of cognition on functioning. Interventions for improving functioning in patients with first episode psychosis should target not only cognition but also symptoms and insight. PMID- 30449594 TI - Hop/STIP1 depletion alters nuclear structure via depletion of nuclear structural protein emerin. AB - Hop/STIP1 is a co-chaperone of Hsp70 and Hsp90 that regulates a number of cell biology processes via interactions with cellular proteins. Here we report a new relationship between Hop and the nuclear structural protein emerin in maintenance of nuclear morphology. Depletion or overexpression of Hop resulted in the reduction of emerin protein levels via proteasomal and lysosomal pathways. Co immunoprecipitation assays confirmed that Hop and emerin are in a common complex, which could accommodate Hsp70 but not Hsp90, and that TPR2AB is required for the association. Loss of Hop or emerin led to a deformation of nuclear structure, a statistically significant decrease in nuclear size, and was associated with changes in the levels of nuclear proteins, lamin A-C and fibrillarin. The nuclear defects upon Hop loss could be rescued by emerin overexpression. Taken together, these data suggest that Hop stabilises emerin and that loss of Hop alters nuclear structure via emerin degradation. PMID- 30449595 TI - MicroRNA-98-5p ameliorates oxygen-glucose deprivation/reoxygenation (OGD/R) induced neuronal injury by inhibiting Bach1 and promoting Nrf2/ARE signaling. AB - MicroRNA-98-5p (miR-98-5p) is a stress-related microRNA (miRNA) that plays an important role in regulating cell survival, apoptosis, and oxidative stress in multiple cell types and diseases. However, little is known about the role of miR 98-5p in cerebral ischemia/reperfusion injury. In this study, we investigated the role and mechanism of miR-98-5p in regulating neuronal injury induced by oxygen glucose deprivation/reoxygenation (OGD/R), an in vitro model of cerebral ischemia/reperfusion injury. We found that miR-98 expression was significantly altered in neurons in response to OGD/R treatment. Functional experiments showed that overexpression of miR-98-5p inhibited OGD/R-induced apoptosis and reactive oxygen species (ROS) production in neurons, whereas inhibition of miR-98-5p showed the opposite effect. Interestingly, bioinformatics analysis predicted that BTB and CNC homology 1 (Bach1) was a potential target gene of miR-98-5p, that was verified by dual-luciferase reporter assay. Moreover, overexpression of miR-98-5p inhibited Bach1 expression while suppression of miR-98-5p promoted Bach1 expression in neurons. Notably, miR-98-5p was shown to regulate the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the activity of the antioxidant response element (ARE). However, overexpression of Bach1 or silencing of Nrf2 significantly abolished the miR-98-5p-mediated neuroprotective effect. Overall, these results demonstrate that miR-98-5p ameliorates OGD/R-induced neuronal injury in vitro through targeting to promote activation of Nrf2/ARE signaling. Our study suggests that miR-98-5p may play a potential role in cerebral ischemia/reperfusion injury and represents a potential therapeutic target for neuroprotection. PMID- 30449596 TI - SmpB down-regulates proton-motive force for the persister tolerance to aminoglycosides in Aeromonas veronii. AB - Bacterial persisters comprise a small fraction of phenotypically heterogeneous variants with transient capability for survival when exposed to high concentrations of antibiotic. In aquatic pathogenic bacteria Aeromonas veronii, Small Protein B (SmpB), the core factor of trans-translation system, was identified as a new persistence-related gene. The SmpB deletion exhibited a higher susceptibility and lower persister cell formation under aminoglycosides antibiotics pressure compared with wild type. The transcriptional and translational activities of smpB gene were significantly enhanced by the gentamicin challenge in exponential phase, but not changed in stationary phase. The transcriptomic analysis revealed that the smpB deletion stimulated the production of proton-motive force (PMF). The cell survival induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) further verified that SmpB variation affected the quantities of PMF. Taken together, these results uncovered a novel mechanism of persister formation mediated by SmpB under aminoglycosides treatments. PMID- 30449597 TI - AUX1 acts upstream of PIN2 in regulating root gravitropism. AB - AUX1 and PIN2 auxin transporter are required for the asymmetric distribution of auxin for root gravitropic response. However, the relationship between AUX1 and PIN2 in root gravitropism is unclear. Here, we report that aux1-T mutant show stronger defects in root gravitropism than pin2-T, and aux1-T pin2-T double mutants display similar agravitropic phenotype to aux1-T. The gravity-induced asymmetric distribution of auxin responses could not be established in pin2-T, aux1-T and aux1-T pin2-T mutants; whereas aux1-T pin2-T double mutants showed similar auxin responses to aux1-T mutant. These findings support AUX1 plays a role in root gravitropism upstream of PIN2. PMID- 30449598 TI - IFN-gamma, IL-17A, or zonulin rapidly increase the permeability of the blood brain and small intestinal epithelial barriers: Relevance for neuro-inflammatory diseases. AB - Breakdown of the blood-brain barrier (BBB) precedes lesion formation in the brains of multiple sclerosis (MS) patients. Since recent data implicate disruption of the small intestinal epithelial barrier (IEB) in the pathogenesis of MS, we hypothesized that the increased permeability of the BBB and IEB are mechanistically linked. Zonulin, a protein produced by small intestine epithelium, can rapidly increase small intestinal permeability. Zonulin blood levels are elevated in MS, but it is unknown whether zonulin can also disrupt the BBB. Increased production of IL-17A and IFN-gamma has been implicated in the pathogenesis of MS, epilepsy, and stroke, and these cytokines impact BBB integrity after 24 h. We here report that primary human brain microvascular endothelial cells expressed the EGFR and PAR2 receptors necessary to respond to zonulin, and that zonulin increased BBB permeability to a 40 kDa dextran tracer within 1 h. Moreover, both IL-17A and IFN-gamma also rapidly increased BBB and IEB permeability. By using confocal microscopy, we found that exposure of the IEB to zonulin, IFN-gamma, or IL-17A in vitro rapidly modified the localization of the TJ proteins, ZO-1, claudin-5, and occludin. TJ disassembly was accompanied by marked depolymerization of the peri-junctional F-actin cytoskeleton. Our data indicate that IFN-gamma, IL-17A, or zonulin can increase the permeability of the IEB and BBB rapidly in vitro, by modifying TJs and the underlying actin cytoskeleton. These observations may help clarify how the gut-brain axis mediates the pathogenesis of neuro-inflammatory diseases. PMID- 30449599 TI - Sonic Hedgehog signaling and Gli-1 during embryonic chick myogenesis. AB - The Sonic Hedgehog signaling (Shh) pathway has been implicated in both proliferation of myoblast cells and terminal differentiation of muscle fibers, and contradictory results of these effects have been described. To clarify the role of Shh during myogenesis, we decided to study the effects of recombinant Shh and the distribution of Gli-1 during in vitro and in situ embryonic chick skeletal muscle differentiation at later stages of development. Gli-1 was found in small aggregates near the nucleus in mononucleated myoblasts and in multinucleated myotubes both in vitro and in situ chick muscle cells. Some Gli-1 aggregates colocalized with gamma-tubulin positive-centrosomes. Gli-1 was also found in striations and at the subsarcolemmal membrane in muscle fibers in situ. Recombinant Shh added to in vitro grown muscle cells induced the nuclear translocation of Gli-1, as well as an increase in the number of myoblasts and in the number of nuclei within myotubes. We suggest that Gli-1 aggregates observed in chick muscle cells near the nuclei of myoblasts and myotubes could be a storage site for the rapid cellular redistribution of Gli-1 upon specific signals during muscle differentiation. PMID- 30449600 TI - Inhibition of Drp1 hyperactivation reduces neuropathology and behavioral deficits in zQ175 knock-in mouse model of Huntington's disease. AB - Mitochondrial dysfunction manifests in the pathogenesis of Huntington's disease (HD), a fatal and inherited neurodegenerative disease. Dynamin-related protein 1 (Drp1) is the primary component of mitochondrial fission and becomes hyperactivated in various models of HD. We previously reported that inhibition of Drp1 hyperactivation by P110, a rationally designed peptide inhibitor of Drp1 Fis1 interaction, is protective in the HD R6/2 mouse model, which expresses a fragment of mutant Huntingtin (mHtt). In this study, we expand our work to test the effect of P110 treatment in HD knock-in (zQ175 KI) mice that express full length mtHtt and exhibit progressive disease symptoms, reminiscent of human HD. We find that subcutaneously sustained treatment with P110 reduces movement deficits of mice. Moreover, the treatment attenuates striatal neuronal loss, microglial hyperactivity and white matter disorganization in zQ175 KI mice. These findings provide an additional line of evidence that inhibition of Drp1 hyperactivation is sufficient to reduce HD-associated neuropathology and behavioral deficits. We propose that manipulation of Drp1 hyperactivation might be a useful strategy to develop therapeutics for treating HD. PMID- 30449601 TI - Short- and long-term effects of high-fat diet feeding and voluntary exercise on hepatic lipid metabolism in mice. AB - Exercise is an effective tool for improving high-fat diet induced fat accumulation in the liver. However, the process of fat accumulation in the liver and the efficacy of early intervention with exercise remain unclear. The aim of this study was to investigate the short- and long-term effects of high-fat diet feeding and voluntary exercise on hepatic lipid metabolism in mice. Male C57BL/6J mice aged 6 weeks were randomly divided into two groups, the control group and high-fat diet feeding group, and fed a normal or high-fat diet for 12 weeks. After 6 weeks, mice in the high-fat diet feeding group were further divided into no exercise group and voluntary exercise training group, with mice in the exercise group provided a running wheel for 6 weeks. Body weight, food intake, and wheel rotation counts were measured every second day for 12 weeks. We found that voluntary exercise for 1 week (short-term exercise) significantly reduced fat accumulation in the liver by downregulating the expression of hepatic lipogenesis-associated proteins and upregulating the expression of hepatic lipolysis-associated proteins, as determined through western blotting and histology. Further, voluntary exercise for 6 weeks (long-term exercise) downregulated the expression of hepatic lipogenesis-associated proteins. These results suggest that hepatic lipogenesis and/or hepatic lipolysis mediate the beneficial effects of voluntary exercise on hepatic fat accumulation. PMID- 30449602 TI - Behavioral and Physiological Signs for Pain Assessment in Preterm and Term Neonates During a Nociception-Specific Response: A Systematic Review. AB - BACKGROUND/GOAL: Assessment and treatment of neonatal pain is difficult because current scales are rarely validated against brain-based evidence. We sought to systematically evaluate published evidence to extract validation of the most promising markers of neonatal pain. METHODS: We searched four databases using germane MeSH terms. We focused on assessments of pain and/or nociception that had at least two measures among behavioral, physiological, or cortical components in preterm and/or term neonates. We evaluated studies for quality of evidence and strength of recommendations using standardized tools. RESULTS: Fifteen articles met our inclusion criteria. Among the behavioral components uncovered in this review, the withdrawal reflex and changes in facial expression are the most strongly associated with nociception-specific brain activity. These associations may be influenced by gestational age and change over time. Physiological signs, such heart rate and oxygen saturation, have little to no association with this type of response. CONCLUSIONS: Current assessments of neonatal pain include behavioral components that are associated with nociceptive processing, but also other less valid components, while omitting newer measures based on neuroscientific research. PMID- 30449603 TI - Legal liabilities of BCI-users: Responsibility gaps at the intersection of mind and machine? PMID- 30449604 TI - Dietary intake, body composition and metabolic parameters in women with polycystic ovary syndrome. AB - BACKGROUND & AIMS: Overweight polycystic ovary syndrome (PCOS) patients present exacerbation of clinical symptoms and increased risk for chronic diseases. The effects of inadequate dietary intake have been investigated in body weight gain in PCOS women. The aim of this study was to evaluate the dietary pattern and to analyze possible associations with the metabolism and body composition in PCOS women. METHODS: A case-control study was performed with thirty-nine women diagnosed with PCOS and thirty-five control women, matched by age and body mass index. A body composition assessment was performed by Dual-energy X-ray absorptiometry (DXA) and food intake was assessed using the seven-day food record. The metabolic parameters evaluated were fasting glucose, insulin, Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) index and oral glucose tolerance test (OGTT). RESULTS: No significant differences were observed in dietary intake of women with or without PCOS. In the analysis of the associations between dietary intake, metabolic parameters and body composition, PCOS women showed an inverse correlation between dietetic fiber intake and HOMA IR index (r = -0.365; p = 0.024). Also in PCOS group, dietary fiber intake presented an inverse correlation with total body fat (r = -0.401; p = 0.011), trunk fat (r = -0.388; p = 0.015), and android fat (r = -0.431; p = 0.006). PCOS women group had higher glucose 120', compared to those without PCOS (p = 0.015). CONCLUSION: These results provide evidence that the adequate intake of dietary fiber contributes to more appropriate body composition and glucose metabolism in PCOS women and possibly toward the prevention of chronic non-communicable diseases. PMID- 30449605 TI - Home parenteral nutrition and employment in patients with intestinal failure: Factors associated with return to employment. AB - BACKGROUND & AIMS: Home parenteral nutrition (HPN) is provided to patients with intestinal failure (IF). HPN can however affect the patients' quality of life and ability to remain in employment. The aim of this study was to determine the effect of HPN on employment and factors associated with the likelihood of maintaining or returning to employment while on HPN. METHODS: Patients with chronic IF were identified from a prospectively maintained IF Unit database. A structured questionnaire was designed to probe employment both before and after starting HPN, intention to work and social welfare status (benefits & pensions). RESULTS: A total of 196 (62.8% females, median age 53 years) patients participated in the study of which 184 (94%) patients were in full or part time employment before their illness. At the time of starting HPN, 102 (52%) patients had the desire to return to work with 19 (18%) and 48 (47%) patients returning to full time or part time employment respectively. Multivariate analysis demonstrated that the frequency of the HPN infusion per week (p = 0.045) and intention to work after starting HPN (p = 0.001) were significantly associated with returning to work. CONCLUSIONS: Patients on HPN can have their employment status affected. The number of days per week on HPN and the desire of the patient to return to employment are significantly associated with employment. PMID- 30449606 TI - Letter to the Editor. PMID- 30449607 TI - Genome-wide characterization of aberrant DNA methylation patterns and the potential clinical implications in patients with endometrial cancer. AB - Aberrant DNA methylation has been implicated in the development of the majority of human cancers. However, the association of aberrant DNA methylation with the clinical characteristics of uterine corpus endometrial carcinoma (UCEC) has not been fully explored. We performed an integrative analysis in order to examine the genome-wide DNA methylation profile and the gene expression profile of 432 UCEC samples and 46 normal tissue samples. A total of 793 differentially methylated regions (DMRs) that were associated with 472 protein-coding genes were identified, including 622 hypermethylated DMRs and 171 hypomethylated DMRs. These DMRs were capable of differentiating UCEC from normal tissues with an accuracy of 99.07% using an unsupervised hierarchical clustering method. The genomic analysis suggested that the hypermethylated DMRs were located in CpG island regions nearer to the transcription start site (TSS) compared with the hypomethylated DMRs. Functional analysis for genes associated with DMRs revealed an enrichment of methylated genes that were involved in key cancer-related biological processes and pathways, such as cell adhesion, cell differentiation and the cAMP signaling pathway. Finally, we performed a correlation analysis of the methylation levels of DMRs and patient survival time, and identified 130 DMRs. These molecular markers could classify patients into high-risk and low-risk groups with significantly different overall survival. Taken together, the present study revealed the potential applications of the detection of aberrant DNA methylation as a valuable prognostic marker for UCEC. The current findings may aid the therapeutic exploitation of UCEC treatment strategies and improve our understanding regarding the regulation of methylation in UCEC. PMID- 30449608 TI - Colorectal cancer screening: The surgery rates they are a-changing. A nationwide study on surgical resections in Italy. AB - BACKGROUND: Growing evidence suggests that colorectal cancer (CRC) screening based on the fecal immunochemical test (FIT) reduces CRC incidence and surgical resection rates. AIMS: To compare trends in surgery for proximal and distal CRC among Italian regions at different stages of screening implementation. METHODS: From the National Hospital Discharge Database we selected hospitalizations with CRC resection of residents aged 50-74 years during 2002-2014, and computed surgery rates for the 8 most populous Italian regions with/without a screening program. RESULTS: In regions with screening, implemented around 2006-2007, the annual percent change (APC) of distal CRC resection was +1.7 (95% confidence interval -1.0, 4.4) during 2002-2007 and -9.1 (-10.6, -7.7) during 2007-2014. No significant change was observed in regions without screening. The APC for proximal colon resection in regions with screening was +5.8 (2.5, 9.0) during 2002-2007 and -4.1 (-5.8, -2.4) during 2007-2014, while in regions without screening surgical rates increased through the whole study period. Compared to 2002, in 2014 distal CRC resection rates were greatly reduced in regions with screening, reaching values similar to proximal CRC resection. CONCLUSION: Following the implementation of screening programs surgery rates steeply decreased, confirming the deep impact of FIT-based screening on the burden of CRC. PMID- 30449609 TI - Turner syndrome and pregnancy: A multidisciplinary approach. PMID- 30449610 TI - Left main and/or three-vessel disease in patients with non-ST-segment elevation myocardial infarction and low-risk GRACE score: Prevalence, clinical outcomes and predictors. AB - INTRODUCTION: A low-risk GRACE score identifies patients with a lower incidence of major cardiac events, however it can erroneously classify patients with severe coronary artery disease as low-risk. We assessed the prevalence, clinical outcomes and predictors of left main and/or three-vessel disease (LM/3VD) in non ST-elevation acute myocardial infarction (NSTEMI) patients with a GRACE score of <=108 at admission. METHODS: Using data from the Portuguese Registry on Acute Coronary Syndromes, 1196 patients with NSTEMI and a GRACE score of <=108 who underwent coronary angiography were studied. Independent predictors of LM/3VD and its impact on in-hospital complications and one-year mortality were retrospectively analyzed. RESULTS: LM/3VD was present in 18.2% of patients. Its prevalence was higher in males and associated with hypertension, diabetes, previous myocardial infarction, heart failure and peripheral arterial disease (PAD). Although there were no differences in in-hospital complications, these patients had higher mortality (0.9 vs. 0.0%) and more major adverse cardiac and cerebrovascular events (MACCE) (4.1 vs. 2.5%, p=0.172), and higher one-year mortality (2.4 vs. 0.5%, p=0.005). Independent predictors of LM/3VD were age (OR 1.03; 95% CI 1.01-1.0, p=0.003), male gender (OR 2.56; 95% CI 1.56-4.17, p<0.001), heart rate (1.02; 95% CI 1.01-1.03, p<0.001), PAD (OR 3.21; 95% CI 1.47 7.00, p<0.001) and heart failure (OR 3.38; 95% CI 1.02-11.15, p=0.046). CONCLUSIONS: LM/3VD was found in one in five patients. These patients had a tendency for higher in-hospital mortality and more MACCE, and higher one-year mortality. Simple clinical variables could help predict this severe coronary anatomy. PMID- 30449611 TI - The dilemma of beta-blocker use after acute coronary syndrome: To support the dogma or to embrace the paradigm shift? PMID- 30449612 TI - Reply to Letter to the Editor "Focus on spontaneous coronary artery dissection: Where are we now?" PMID- 30449613 TI - Chorea following extracorporeal circulation in adults: A case report and brief literature review. PMID- 30449614 TI - Asthma, rhinitis, and nasal polyp multimorbidities. AB - The aim of this review is to assist pulmonologists in the management of diseases involving both the upper and lower respiratory tract that are linked by a common, interrelated epidemiology, clinical signs and symptoms, and inflammatory mechanism - asthma, in particular. The document discusses the definitions of the various sinonasal phenotypes associated with asthma: allergic and non-allergic rhinitis and chronic rhinosinusitis with or without nasal polyps. Diagnostic criteria and severity levels are also listed. Particular attention has been given to the 2 main syndromes associated with asthma: (i)allergic rhinitis, the most common, and (ii)chronic rhinosinusitis with nasal polyps, the disease most closely associated with severe asthma. To summarize, the upper respiratory tract should always be evaluated in order to achieve a single diagnosis and comprehensive treatment of the "united airway". PMID- 30449616 TI - Response to: A need to apply unified criteria to choreoballism associated with glycemic derangement. PMID- 30449615 TI - The negative impact of anterior cruciate ligament reconstruction in professional male footballers. AB - BACKGROUND: Soccer is one of the most common international sports in which ACL injuries occur, with previous studies reporting high return-to-play rates following ACL reconstruction (ACLR). Return-to-play analysis fails to take into consideration how effective a player remains once returning to competition. The aims of this study are to provide a large-scale international analysis of return to-play and player performance statistics among professional soccer athletes following ACLR. METHODS: Using publicly available sources, professional soccer athletes who have undergone ACLR between the 1996 and 2015 seasons were identified. Player metrics including statistical performance, recovery time, and return-to-play rates were analyzed both before and after reconstruction. Furthermore, player performance statistics during each of three consecutive seasons post-ACLR were compared. RESULTS: A total of 176 athletes who underwent ACLR were included in this study. The return-to-play rate was 93.2% (164 athletes). Cumulative post-surgical statistical analysis of ACLR players demonstrated fewer games/season, minutes/season, minutes/game, goals/season, and more fouls/season following ACLR (p < 0.04). Analysis of player performance statistics suggests that athletes do not return to their baseline number of games/season and minutes/game until two and three seasons post-ACLR, respectively. At three seasons post-ACLR, athletes are still starting fewer games/season and scoring fewer goals/90 min (p < 0.04). CONCLUSION: Return-to play rate is high following ACLR; however, athletes exhibit poorer statistical performance, especially in the first few seasons upon return. Our data shows that athletes continue to start fewer games/season and score fewer goals/90 min at three seasons post-ACLR. PMID- 30449617 TI - A Membraneless Organelle Associated with the Endoplasmic Reticulum Enables 3'UTR Mediated Protein-Protein Interactions. AB - Approximately half of human genes generate mRNAs with alternative 3' untranslated regions (3'UTRs). Through 3'UTR-mediated protein-protein interactions, alternative 3'UTRs enable multi-functionality of proteins with identical amino acid sequence. While studying how information on protein features is transferred from 3'UTRs to proteins, we discovered that the broadly expressed RNA-binding protein TIS11B forms a membraneless organelle, called TIS granule, that enriches membrane protein-encoding mRNAs with multiple AU-rich elements. TIS granules form a reticular meshwork intertwined with the endoplasmic reticulum (ER). The association between TIS granules and the ER creates a subcellular compartment-the TIGER domain-with a biophysically and biochemically distinct environment from the cytoplasm. This compartment promotes 3'UTR-mediated interaction of SET with membrane proteins, thus allowing increased surface expression and functional diversity of proteins, including CD47 and PD-L1. The TIGER domain is a subcellular compartment that enables formation of specific and functionally relevant protein-protein interactions that cannot be established outside. PMID- 30449618 TI - Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains. AB - Gene expression is controlled by transcription factors (TFs) that consist of DNA binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation. PMID- 30449619 TI - Genome-wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function. AB - Human T cells are central effectors of immunity and cancer immunotherapy. CRISPR based functional studies in T cells could prioritize novel targets for drug development and improve the design of genetically reprogrammed cell-based therapies. However, large-scale CRISPR screens have been challenging in primary human cells. We developed a new method, single guide RNA (sgRNA) lentiviral infection with Cas9 protein electroporation (SLICE), to identify regulators of stimulation responses in primary human T cells. Genome-wide loss-of-function screens identified essential T cell receptor signaling components and genes that negatively tune proliferation following stimulation. Targeted ablation of individual candidate genes characterized hits and identified perturbations that enhanced cancer cell killing. SLICE coupled with single-cell RNA sequencing (RNA seq) revealed signature stimulation-response gene programs altered by key genetic perturbations. SLICE genome-wide screening was also adaptable to identify mediators of immunosuppression, revealing genes controlling responses to adenosine signaling. The SLICE platform enables unbiased discovery and characterization of functional gene targets in primary cells. PMID- 30449620 TI - Secretin-Activated Brown Fat Mediates Prandial Thermogenesis to Induce Satiation. AB - The molecular mediator and functional significance of meal-associated brown fat (BAT) thermogenesis remains elusive. Here, we identified the gut hormone secretin as a non-sympathetic BAT activator mediating prandial thermogenesis, which consequentially induces satiation, thereby establishing a gut-secretin-BAT-brain axis in mammals with a physiological role of prandial thermogenesis in the control of satiation. Mechanistically, meal-associated rise in circulating secretin activates BAT thermogenesis by stimulating lipolysis upon binding to secretin receptors in brown adipocytes, which is sensed in the brain and promotes satiation. Chronic infusion of a modified human secretin transiently elevates energy expenditure in diet-induced obese mice. Clinical trials with human subjects showed that thermogenesis after a single-meal ingestion correlated with postprandial secretin levels and that secretin infusions increased glucose uptake in BAT. Collectively, our findings highlight the largely unappreciated function of BAT in the control of satiation and qualify BAT as an even more attractive target for treating obesity. PMID- 30449621 TI - Acetylation of Cytidine in mRNA Promotes Translation Efficiency. AB - Generation of the "epitranscriptome" through post-transcriptional ribonucleoside modification embeds a layer of regulatory complexity into RNA structure and function. Here, we describe N4-acetylcytidine (ac4C) as an mRNA modification that is catalyzed by the acetyltransferase NAT10. Transcriptome-wide mapping of ac4C revealed discretely acetylated regions that were enriched within coding sequences. Ablation of NAT10 reduced ac4C detection at the mapped mRNA sites and was globally associated with target mRNA downregulation. Analysis of mRNA half lives revealed a NAT10-dependent increase in stability in the cohort of acetylated mRNAs. mRNA acetylation was further demonstrated to enhance substrate translation in vitro and in vivo. Codon content analysis within ac4C peaks uncovered a biased representation of cytidine within wobble sites that was empirically determined to influence mRNA decoding efficiency. These findings expand the repertoire of mRNA modifications to include an acetylated residue and establish a role for ac4C in the regulation of mRNA translation. PMID- 30449622 TI - Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. AB - While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci [eQTLs], and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org). PMID- 30449624 TI - De-intensified treatment in human papillomavirus-positive oropharyngeal cancer. PMID- 30449623 TI - Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. AB - BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3 5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3 5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4.8 [95% CI 4.2-5.4] with cisplatin vs 4.8 [4.2-5.4] with cetuximab; p=0.98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29.2 [95% CI 27.3-31.0] with cisplatin vs 30.1 [28.3-31.9] with cetuximab; p=0.49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97.5% vs 89.4%, hazard ratio 5.0 [95% CI 1.7-14.7]; p=0.001) and 2-year recurrence (6.0% vs 16.1%, 3.4 [1.6-7.2]; p=0.0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK. PMID- 30449626 TI - Fatal cholestatic hepatitis after a single dose of celecoxib. PMID- 30449625 TI - Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non inferiority trial. AB - BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity. METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (<=10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1.45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834. FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4.5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1.45, one-sided 95% upper CI 1.94; p=0.5056 for non-inferiority; one-sided log-rank p=0.0163). Estimated 5-year overall survival was 77.9% (95% CI 73.4-82.5) in the cetuximab group versus 84.6% (80.6-88.6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1.72, 95% CI 1.29-2.29; p=0.0002; 5-year progression-free survival 67.3%, 95% CI 62.4-72.2 vs 78.4%, 73.8-83.0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2.05, 95% CI 1.35-3.10; 5 year proportions 17.3%, 95% CI 13.7-21.4 vs 9.9%, 6.9-13.6). Proportions of acute moderate to severe toxicity (77.4%, 95% CI 73.0-81.5 vs 81.7%, 77.5-85.3; p=0.1586) and late moderate to severe toxicity (16.5%, 95% CI 12.9-20.7 vs 20.4%, 16.4-24.8; p=0.1904) were similar between the cetuximab and cisplatin groups. INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation. PMID- 30449627 TI - Human exposure to antibiotic resistant-Escherichia coli through irrigated lettuce. AB - Antibiotic resistant bacteria (ARB) have been found on fresh fruit and vegetables globally. These types of ARB infections are spreading rapidly and are a major human health threat. A quantitative human exposure assessment model was created using scenario analysis to investigate the potential human exposure to antibiotic resistant Escherichia coli (AR-E. coli) through the consumption of lettuce irrigated with surface water. Scientific literature and site specific data were collected to model each process from farm to fork to calculate the concentration of AR-E. coli on the lettuce at the point of human consumption. The processes examined were the adhesion, colonisation and viability of bacteria on the lettuce; the effect of different post-harvest cleaning processes; the effect of consuming the lettuce before, on or after the expiry date; and the effect of the consumer washing the lettuce. The results show the mean human exposure levels ranged between 1.00 * 10-2 and 1.35 * 106 colony forming units (CFU) of AR-E. coli per 100 g of surface water irrigated lettuce for the different scenarios investigated. The mean probability of illness from consuming 100 g of lettuce contaminated with potential pathogenic antibiotic-sensitive E. coli was between 1.46 * 10-9 to 1.88 * 10-2. A back calculation revealed that in order for the EC No 1441/2007 regulation to be exceeded (>=1000 CFU/g of E. coli on lettuce at the manufacturing stage), the mean contamination levels required in the irrigation water would need to be 2.7, 3.1 or 4.8 log CFU/ml using the post-harvest treatments of washing with water, rapid cooling with water and washing with a chlorine solution respectively. The information generated from this model could help to set guidelines for producers on maximum permissible AR-E. coli contamination levels in irrigation water and provides recommendations on the best post-harvest treatment to use. PMID- 30449628 TI - Metabolites of organophosphate esters in urine from the United States: Concentrations, temporal variability, and exposure assessment. AB - Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers in consumer products, which contributes to widespread exposure of humans. OPE diester metabolites in urine have been used as biomarkers of human exposure to these chemicals. Little is known, however, about occurrence and temporal variability in urinary concentrations of OPE metabolites in humans. In this study, 11 OPE metabolites were measured in 213 urine samples collected from 19 volunteers from Albany, New York, United States, at 3-day intervals for five weeks to investigate temporal variability in urinary concentrations. Diphenyl phosphate (DPHP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the major OPE metabolites, detected in all urine samples at specific gravity (SG)-adjusted concentrations (geometric mean, GM) of 1060 and 414 pg/mL and creatinine (Cr) adjusted concentration (GM) of 404 and 156 ng/g, respectively. Inter-day variability in urinary OPE metabolite concentrations in 19 individuals was evaluated by intraclass correlation coefficients (ICCs). The inter-day variability in Cr-adjusted OPE metabolite concentrations (ICC: 0.31-0.67) was lower than those of SG-adjusted (ICC: 0.19-0.71) and unadjusted urinary concentrations (ICC: 0.24-0.74). BDCIPP (ICC: 0.68) and bis(2-chloroethyl) phosphate (BCEP) (ICC: 0.67) concentrations showed a moderate-to-high reliability over the sampling period, whereas the other nine OPE metabolites exhibited a moderate reliability (ICC: 0.31-0.55). Urine samples were further stratified by gender, age, ethnicity, and body mass index (BMI). The concentrations of BDCIPP and DPHP were significantly lower in males with normal BMI (BMI: 18.5-25 kg/m2) than in females and other BMI categories (p < 0.01). Relatively high ICCs, indicating low inter-day variability, were observed for males (ICC: 0.35-0.71) of 30-40 years of age (ICC: 0.34-0.87) with normal BMI (ICC: 0.28-0.64). The daily exposure doses to OPEs were estimated from urinary concentrations of corresponding OPE metabolites. The estimated doses of triphenyl phosphate (TPHP) and triethyl phosphate (TEP), based on median urinary concentrations of their metabolites, were 19.4 and 24.0 ng/kg bw/day, and the exposure dose to ?OPEs was estimated at 65.3 ng/kg bw/day. Overall, our results indicate a high ICC for Cr adjusted urinary concentrations of 11 OPE metabolites in urine. PMID- 30449629 TI - People, place and pollution: Investigating relationships between air quality perceptions, health concerns, exposure, and individual- and area-level characteristics. AB - An extensive body of research has demonstrated that air pollution exposure is associated with adverse health outcomes. Urban air quality remains a major concern for both public health officials and the general public. In the United States, air quality public awareness campaigns are major efforts of governments at every level. Yet, our understanding of relationships between ambient air pollution exposure, public perceptions of air quality, and concerns about associated health risks is incomplete. We examined 2869 individual responses to annual air quality public awareness surveys administered between 2009 and 2012 in the Kansas City metropolitan area. Our study had three objectives: 1) examine the spatial distribution of PM2.5 and O3 exposures, pollution perceptions, and pollution health concerns; 2) explore relationships between individual- and area level characteristics and PM2.5 and O3 exposure; 3) and examine cross-sectional associations between individual- and area-level characteristics, as well as PM2.5 and O3 exposures, and pollution perception and pollution health concerns. We found inverse spatial patterns between the distribution of O3 and PM2.5 exposure levels as well as between areas where respondents perceived air pollution as worsening and areas where residents had higher concern about the health effects of pollution exposure. We also found inverse relationships between individual- and area-level demographic and socioeconomic characteristics and O3 and PM2.5 exposure. Individual-level characteristics were significantly related to pollution perceptions, while both individual- and area-level characteristics were significantly related to pollution health concerns. Public awareness campaigns should be combined with education on ways the public can protect themselves and tailored explicitly for targeting vulnerable populations (e.g., elderly, and persons with respiratory problems) and areas both socioeconomically vulnerable (e.g., higher racial segregation and poverty) and experiencing higher pollution exposure (e.g., O3 and PM2.5). PMID- 30449630 TI - An apple a day? Assessing gardeners' lead exposure in urban agriculture sites to improve the derivation of soil assessment criteria. AB - Globally, many of our urban agriculture sites (UAS) contain high levels of lead (Pb), a contaminant of toxicological concern to humans. To improve the derivation of soil assessment criteria at UAS, and avoid inappropriate closure of these valuable community spaces, we sampled nearly 280 paired soil and crop samples across 31 UAS gardens. This sampling was coupled with an exposure and food frequency questionnaire and participants blood Pb levels (BLL), (43 gardeners and 29 non-gardening neighbours). In 98% of the sampled soils, Pb concentrations were above the current UK soil guideline for UAS (80 mg/kg), however despite the high soil Pb (geometric mean: 324 mg/kg), and high soil bioaccessible Pb (geometric mean: 58.7%), all participants BLL were <4.1 MUg/dL (range: 0.6-4.1 MUg/dL). Indeed, there was no statistically significant difference between the BLL of the UAS gardeners and those of their non-gardening neighbours (p = 0.569). Pb uptake, however, varied with crop type and our study highlights the suitability of certain crops for growing at UAS with elevated Pb (e.g. tubers, shrub and tree fruit), whilst limiting the consumption of others (selected root vegetables, such as rhubarb, beetroot, parsnips and carrots, with observed Pb concentrations > 0.1 mg/kg FW). The importance of defining the exposure scenario of a specific sub population (i.e. UAS gardeners) is highlighted. Our preferred models predict site specific assessment criteria (SSAC) of 722-1634 mg/kg. We found fruit and vegetable consumption rates by all participants, and not just the UAS gardeners, to be considerably higher than those currently used to derive the UK's category 4 screening levels (C4SLs). Furthermore, the soil to plant concentration factors (SPCFs) used to derive the UAS C4SL significantly over predict Pb uptake. Our study indicates it may be appropriate to develop a distinct exposure dataset for UAS. In particular we recommend the derivation of SPCFs that are reflective of urban soils, both in terms of the range of soil Pb concentrations typically observed, but also the sources (and hence human oral bioaccessibility and plant availability) of this Pb. PMID- 30449631 TI - Genome-wide interaction study of gene-by-occupational exposures on respiratory symptoms. AB - Respiratory symptoms are important indicators of respiratory diseases. Both genetic and environmental factors contribute to respiratory symptoms development but less is known about gene-environment interactions. We aimed to assess interactions between single nucleotide polymorphisms (SNPs) and occupational exposures on respiratory symptoms cough, dyspnea and phlegm. As identification cohort LifeLines I (n = 7976 subjects) was used. Job-specific exposure was estimated using the ALOHA + job exposure matrix. SNP-by-occupational exposure interactions on respiratory symptoms were tested using logistic regression adjusted for gender, age, and current smoking. SNP-by-exposure interactions with a p-value <10-4 were tested for replication in two independent cohorts: LifeLines II (n = 5260) and the Vlagtwedde-Vlaardingen cohort (n = 1529). The interaction estimates of the replication cohorts were meta-analyzed using PLINK. Replication was achieved when the meta-analysis p-value was <0.05 and the interaction effect had the same direction as in the identification cohort. Additionally, we assessed whether replicated SNPs associated with gene expression by analyzing if they were cis-acting expression quantitative trait loci (eQTL) in lung tissue. In the replication meta-analysis, sixteen out of 477 identified SNP-by-occupational exposure interactions had a p-value <0.05 and 9 of these interactions had the same direction as in the identification cohort. Several identified loci were plausible candidates for respiratory symptoms, such as TMPRSS9, SERPINH1, TOX3, and ARHGAP18. Three replicated SNPs were cis-eQTLs for FCER1A, CHN1, and TIMM13 in lung tissue. Taken together, this genome-wide SNP-by-occupational exposure interaction study in relation to cough, dyspnea, and phlegm identified several suggestive susceptibility genes. Further research should determine if these genes are true susceptibility loci for respiratory symptoms in relation to occupational exposures. PMID- 30449632 TI - Acquisition rate of antibody to hepatitis B surface antigen among medical and dental students in Japan after three-dose hepatitis B vaccination. AB - BACKGROUND: Health care workers (HCWs) are at high risk of contracting blood borne infections including hepatitis B virus (HBV) infection. In Japan, all HCWs are required to receive HB vaccination before beginning work. This study aimed to investigate the dynamics of the HB surface antibody (anti-HBs) titer after a three-dose HB vaccination in HCWs and to determine effective scheduling of HB vaccination for non-responders. METHODS: Subjects included 832 medical and dental students who had received a three-dose HB vaccination (Bimmugen(r) 0.5 ml/vial). Anti-HBs was measured three times (before the third dose and 1 and 5 months after the third dose) using the CLIA method. The cut-off value of anti-HBs acquisition was 10 mIU/mL. After booster doses (three maximum) were administered to non responders, the anti-HBs titers were measured again. RESULTS: Out of 832 students, 491 were analyzed, of which 58.9% (289) were male. Anti-HBs-positive rates before the third dose and 1 and 5 months later were 47.9%, 95.9%, and 89.0%, respectively. The relationship between the antibody titer at one month (x) and 5 months (y) was estimated by log10y = log10x - 0.134 (P < 0.0001). Twelve non-responders were followed-up, all of which acquired a protective anti-HBs titer after revaccination with a three-dose booster. CONCLUSION: Anti-HBs titer decreases by an average of 20% within 4 months between the 1st and 5th month after the third dose. Therefore, anti-HBs titer should be measured periodically after completing the three-dose vaccination. Additionally, results suggested that booster doses are effective if administered with the same schedule as primary vaccination. PMID- 30449633 TI - Anti-glioma effect of intracranial vaccination with tumor cell lysate plus flagellin in mice. AB - The adjuvant effects of flagellin on regulation of immune response have been proved; whether flagellin could assist tumor cell lysate (TCL) to enhance anti glioma immunity remains to be investigated. This study tests a hypothesis that therapeuticly intracranial administration with flagellin plus TCL enhances the effects of specific immunotherapy on glioma in mice. In this study, GL261 cells were transferred into C57BL/6 mice and the GL261-bearing mice were subcutaneously or intracranially inoculated with flagellin plus TCL, flagellin, TCL or saline. Our results showed that prophylacticly subcutaneous administration with TCL and flagellin could induce potent cytotoxic T lymphocyte (CTL) and prolong the survival of GL261-bearing mice significantly, but therapeuticly subcutaneous administration failed to. However, therapeuticly intracranial administration of TCL plus flagellin could prolong the survival. Moreover, intracranial administration of flagellin could recruit CD4+ T cells and CD8+ T cells to brain tissues, induce proliferation of natural killer (NK) cells, CD4+ T cells and CD8+ T cells in peripheral blood mononuclear cells and induce to splenomegaly. The results suggested that flagellin could be acted as an efficient adjuvant for TCL based vaccine. PMID- 30449634 TI - Serotypes and genotypes of S. pneumoniae isolates from adult invasive disease in Spain: A 5-year prospective surveillance after pediatric PCV13 licensure. The ODIN study. AB - Serotypes/genotypes causing invasive pneumococcal disease (IPD) in adults are determined by vaccination strategies. The aim of this study was to assess the epidemiology of IPD in adults (>=18 years) after PCV13 introduction for children: serotypes, clonal complexes, antibiotic non-susceptibility and clinical presentations. We performed a prospective, clinical surveillance of hospitalized culture-confirmed IPDs in adults in nine Spanish hospitals (August 2010-June 2015). A total of 1087 culture-confirmed IPD episodes were included, of which 772 (71.0%) had bacteremic pneumonia (401 complicated/371 uncomplicated pneumonia), 122 (11.2%) meningitis, 102 (9.4%) non-focal bacteremia, 34 (3.1%) peritonitis and 57 (5.3%) others. The most common serotypes were: 3 (12.7%), 19A (8.5%), 8 (7.7%), 7F (6.3%), 1 (4.2%), 6C (4.2%), 11A (4.2%), 22F (4.2%) and 14 (4.0%). Vaccine types (PCV13 + 6C) caused 49.8% of IPD episodes, with a significant decrease over the 5-year period, and significant decreases in serotypes 6C and 7F. The most common genotypes were: CC180 (8.4%), CC191 (6.0%), and CC53 (5.0%). Vaccine types caused 53.9% (414/768) pneumonia episodes and 58.9% (235/399) complicated pneumonia, 53.4% IPD in adults <50 years (143/268), and 54.7% IPD in immunocompetent patients (337/616). Overall non-susceptibility was 25.9% to penicillin (1.1% for parenteral criteria), 24.9% to erythromycin and 2.7% to levofloxacin. CONCLUSIONS: Although the percentage of vaccine-types causing IPDs in adults significantly decreased, it remained high. Associations of vaccine types with pneumonia (with complicated pneumonia for specific serotypes), and immunocompetent patients point to the burden of IPD caused by PCV13 serotypes. PMID- 30449635 TI - Relation between the electric field and activation of cortical neurons in transcranial electrical stimulation. AB - BACKGROUND: To address the brain areas and circuits affected by transcranial electrical stimulation (tES), which had been used widely to treat psychiatric and neurological diseases, the stimulus-induced electric field in the cortex was calculated using a head model that reflects anatomical information. To obtain detailed information at the macroscopic and microscopic levels, multi-scale modeling was proposed that integrates the head model with multi-compartmental models of cortical neurons. OBJECTIVE: Our goal was to use multi-scale modeling to describe the relation between the stimulus-induced electric field and neuronal responses during tES. METHODS: We simulated sub- and supra-threshold neuronal responses to stimulus-induced uniform and realistic electric fields. For the realistic electric field, multi-scale models that combined the head model derived from structural MRIs and multi-compartmental models of neurons were constructed. Then, we simulated the steady-state membrane polarization for sub-threshold stimulation and the excitation threshold for supra-threshold stimulation by varying the tES montages. The electric field calculated was decomposed into two orthogonal components, the radial and tangential fields, which were compared to the neuronal responses. RESULTS: The stimulus-induced electric field depended strongly on stimulus parameters, and neuronal excitability showed a higher correlation with the radial field. We demonstrated that neurons exhibited linear polarization during sub-threshold stimulation depending on the local radial field intensity that resulted in a significant relation regardless of the tES montage. Supra-threshold stimulation showed a stronger relation with the radial field, but rather complex patterns of excitation thresholds depending on neurons' morphological features. CONCLUSION: Our results indicated that cortical neurons are affected greatly by the relative direction of the stimulus-induced electric field, which may be a necessary step toward a detailed understanding of tES' potential mechanisms. PMID- 30449636 TI - Giant cell tumour of frontal bone in a patient with bilateral retinoblastoma. AB - A case is presented of a 5 year-old patient with bilateral hereditary retinoblastoma treated with radiotherapy in the right eye and enucleation of the left eye. After three years without evidence of progression, the patient presented with a right orbital mass that compromised the frontal bone. After surgical excision, the histology analysis was consistent with a diagnosis of giant cell tumour. Primary orbital bone neoplasms, such as giant cell tumours, are extremely rare. Both radiological and histopathology studies are essential to establish the differential diagnosis of orbital mass lesions. PMID- 30449637 TI - Schwannoma of the eyelid. A case report. AB - The case is presented of a 57 year-old man with a one-year history of enlargement of the left upper eyelid. An excisional biopsy was performed, and the histological and immunohistochemical study confirmed the diagnosis of schwannoma. Schwannomas are benign peripheral nerve sheath tumours, derived from a Schwann cells proliferation. Eyelid involvement is extremely uncommon. To make the diagnosis, a detailed histopathological and immunohistochemical study is essential. This case suggests that schwannomas should be included within the differential diagnosis of any solid eyelid lesion. PMID- 30449638 TI - The 2016 World Health Organization classification of tumours of the central nervous system. AB - The 2016 WHO classification of tumours of the central nervous system represents the new paradigm among the specialists in the brain tumours and proposes a new approach combining histopathological and molecular features into diagnosis named 'integrated diagnosis'. The aim of this challenge is to overstep the interobserver variability of diagnosis based on previous classifications in order to ensure homogenous biological entities with a more accurate clinical significance. Over the last two decades, several molecular aberrations into gliomagenesis were highlighted and then confirmed as emerging biomarkers through prognostic stratification. In particular, IDH1/IDH2 genes mutations, 1p/19q codeletion and mutations in genes encoding histone H3 variants drastically changed the knowledge about diffuse gliomas inducing the WHO working group to consider the phenotype-genotype approach. In the present review, the historical development of the diagnosis of brain tumours from the 3D spatial configuration to the integration of multidisciplinary data up to recent molecular alterations is discussed. At the national level, the RENOCLIP network (supported by the National Cancer Institute) contributes to improve the standardization of histological diagnosis and the facilitation of access to molecular biology platforms for the detection of genetic aberrations necessary for integrated diagnosis. Importantly, the French POLA cohort allowed to test the clinical impact of the new criteria introduced by 2016 WHO classification of CNS tumours confirming the high accuracy in predicting clinical behaviour for diffuse gliomas. PMID- 30449639 TI - Management of meningioma. AB - Meningiomas are the most frequent primary brain tumors, accounting for ~37% of central nervous systems tumors. Despite being largely benign, clinicians frequently face difficult treatment decisions in cases with complex morphology or localisation, near vital brain structures such as the optic nerve or in the case of incidental tumors. Here, we review current concepts of diagnosis, treatment and follow-up with clinical decision-making informed by multimodal imaging, histology, and molecular biology. PMID- 30449640 TI - Outcomes of nurse vs. anesthesiologist monitoring during cataract surgery under topical anesthesia. PMID- 30449641 TI - [Mantle cell lymphoma of the iris treated by ibrutinib]. PMID- 30449642 TI - [Prepapillary vascular loop with vitreous traction]. PMID- 30449643 TI - Sarcoidosis. AB - Sarcoidosis is a systemic granulomatosis characterized by the formation of epithelioid and giant cell granulomas without caseous necrosis. To make the diagnosis, it is necessary to prove systemic granulomatosis involving at least two organs; but in practice, a combination of clinical, paraclinical and histologic findings is used. It affects predominantly women with a bimodal age distribution: 25-29 years and 65-69 years. The most commonly affected organs are the mediastinal lymphatic system, lungs, skin and eyes. Ophthalmological involvement is present in 20 to 50% of cases. The typical ocular presentation is that of granulomatous uveitis associated with venous retinal vasculitis and lesions of peripheral multifocal choroiditis. This ophthalmological presentation, although very evocative, is not always associated with systemic disease. The diagnosis of ocular sarcoidosis is then presumed in the absence of histological evidence. Algorithms combining ophthalmological and systemic signs have been proposed in cases of isolated uveitis. They make it possible to establish the diagnosis of ocular sarcoidosis with various levels of probability. The absence of significant granulomas on a systemic level during primary ocular involvement remains the main hypothesis to explain these diagnostic difficulties. Treatment is well described, as the uveitis of sarcoidosis is most often steroid responsive. In the case of corticosteroid-dependent uveitis, the first-line immunosuppressant remains methotrexate. The use of anti-tumor necrosis factor alpha is an interesting alternative in patients whose ocular sarcoidosis is refractory to conventional immunosuppressants. PMID- 30449644 TI - [Dislocation of the crystalline lens into the anterior chamber]. PMID- 30449645 TI - [Brainstem anesthesia after a peribulbar injection of ropivacaine]. PMID- 30449646 TI - [Traumatic homonymous hemianopsia and ganglion cell complex changes: Report of 3 cases]. AB - Homonymous lateral hemianopia follows an attack on the contralateral retrochiasmal visual pathways. In three patients with post-traumatic homonymous hemianopia, optical coherence tomographic (OCT) study of the ganglion cell layer thickness showed hemiretinal thinning contralateral to the visual field defect. This involvement could be explained by trans-synaptic degeneration of the pre geniculate visual pathways, whose cell nuclei correspond to ganglion cells, which synapse with the damaged retrogeniculate visual pathways. PMID- 30449647 TI - Satisfaction With Care Coordination for Families of Children With Disabilities. AB - INTRODUCTION: Children with disabilities have significant health care needs, and receipt of care coordinator services may reduce caregiver burdens. The present study assessed caregivers' experience and satisfaction with care coordination. METHOD: Caregivers of Medicaid-enrolled children with disabilities (n = 2,061) completed a survey (online or by telephone) collecting information on the caregivers' experiences and satisfaction with care coordination using the Family Experiences with Coordination of Care questionnaire. RESULTS: Eighty percent of caregivers with a care coordinator reported receiving help making specialist appointments, and 71% reported help obtaining community services. Caregivers who reported that the care coordinator helped with specialist appointments or was knowledgeable, supportive, and advocating for children had increased odds of satisfaction (odds ratio = 3.46, 95% confidence interval = [1.01, 11.77] and odds ratio = 1.07, 95% confidence interval = [1.03, 1.11], respectively). DISCUSSION: Findings show opportunities for improving care coordination in Medicaid-enrolled children with disabilities and that some specific elements of care coordination may enhance caregiver satisfaction with care. PMID- 30449648 TI - Pediatric Delirium: Early Identification of Barriers to Optimize Success of Screening and Prevention. AB - INTRODUCTION: Pediatric delirium has a 25% prevalence rate in the pediatric intensive care unit. The purpose of this project was to evaluate the impact/effect of implementing nonpharmacologic nursing bundles on the incidence of pediatric delirium. It is not yet known whether or not bundles consistently reduce the incidence of delirium. METHOD: A nonpharmacologic nursing bundle was implemented for pediatric intensive care unit patients, 2 to 18 years of age, admitted to an Arizona metropolitan children's hospital. Data were collected using the Cornell Assessment of Pediatric Delirium (CAP-D) screening tool. RESULTS: Control group scores and post-bundle CAP-D scores (mean = 5.57, standard deviation = 5.78 and mean = 7.10, standard deviation = 5.61, respectively) did not differ among the participants. Control participants required an intervention 26.7% of the time for delirium compared with 31.6% in the post-bundle population. No statistical significance was seen between the control group and the post bundle CAP-D scores t(59) = 7.46; t(205) = 18.17 (p = .08, Fisher exact test). DISCUSSION: The use of nonpharmacologic bundles for delirium prevention have shown some promising results in helping with delirium reduction. Whether they consistently reduce the incidence has yet to be fully proven. This project shows that significant barriers exist when implementing them in a complex pediatric intensive care environment. PMID- 30449649 TI - Infant Immunizations in Pediatric Critical Care: A Quality Improvement Project. AB - INTRODUCTION: Infants with congenital heart disease can be critically ill; prolonged hospitalization is common. The purpose of this project was to create and then evaluate the efficacy of education programs for staff nurses and medical providers aimed at improving infant immunization administration during hospitalization for congenital heart disease. METHODS: This project used pre- and post-education program chart review to evaluate infant immunization rates at discharge. Pretests and posttests were administered to cardiac care staff to determine knowledge change. Paired t test, chi-square test, and descriptive statistics were used. RESULTS: The pretest and posttest surrounding the education programs indicated significant knowledge change for both groups. Immunization rates were improved before compared with after the education program (60% vs. 88%, respectively). There was significant improvement in immunization documentation on the discharge summary (p < .001). DISCUSSION: The findings suggest that customized education presentations to cardiac care staff can increase the administration of recommended immunizations to hospitalized infants and documentation on discharge summaries. PMID- 30449650 TI - Pneumocystis jirovecii pneumonia (PJP) prophylaxis patterns among patients with rheumatic diseases receiving high-risk immunosuppressant drugs. AB - INTRODUCTION/OBJECTIVES: Pneumocystis jirovecii pneumonia (PJP) is a rare but potentially fatal opportunistic infection; however, consensus varies around which conditions or medications confer a level of risk sufficient to justify antibiotic prophylaxis for PJP. We used electronic health record (EHR) data to assess the current patterns of PJP prophylaxis, PJP outcomes, and prophylaxis-related adverse events among patients with rheumatic diseases who were receiving high risk immunosuppressant drugs. METHODS: Data derive from the EHR of a large health system. We included new immunosuppressant users with diagnoses of vasculitis, myositis, or systemic lupus erythematosus. We calculated the proportion of patients who received PJP prophylaxis for each diagnosis and drug combination. We also calculated the number of PJP infections and the number of antibiotic adverse drug events (ADEs) per patient-year of exposure. RESULTS: We followed 316 patients for 23.2 + /- 14.2 months. Overall, 124 (39%) of patients received prophylactic antibiotics for PJP. At least 25% of patients with the highest risk conditions (e.g. vasculitis) or highest risk immunosuppressants (e.g. cyclophosphamide) did not receive PJP prophylaxis. We found no cases of PJP infection over 640 patient-years of follow up, including among those not receiving prophylaxis, and an overall incidence rate of ADEs of 2.2% per patient year. CONCLUSIONS: PJP prophylaxis for patients with rheumatic conditions is inconsistent, with one quarter of patients who have high risk conditions or high risk immunosuppressants not receiving prophylaxis. However, given extremely low rates of PJP infection, but detectable ADEs to prophylactic antibiotics, our findings suggest that evidence to guide more personalized risk assessments are needed to inform PJP prophylaxis. PMID- 30449651 TI - Antiphospholipid antibodies and renal transplant: A systematic review and meta analysis. AB - OBJECTIVE: To evaluate the effect of antiphospholipid antibodies (aPL) on renal allograft outcome after kidney transplantation. METHODS: A systematic search of EMBASE and PubMed databases from inception to July 2018 was run according to PRISMA guidelines; Peto's odds ratio (OR) for rare events was used for the meta analysis. RESULTS: Our inclusion/exclusion criteria were met by 22 cohort studies having different outcomes: allograft thrombosis (n = 9) and thromboprophylaxis (n = 3), allograft loss from any cause (n = 9), allograft malfunction (n = 3), duration (n = 2), glomerular filtration rate at 1 year (n = 3) and allograft rejection (n = 5). The pooled prevalence of allograft thrombosis and of thrombotic microangiopathy was greater in aPL+ve than negative recipients (10.4% vs 1.7%, p < 0.0001 and 10.2% vs 0%, p = 0.005, respectively). The pooled prevalence of allograft thrombosis was 75% in patients not taking anticoagulation whereas none of the anticoagulated recipients developed thrombosis (p < 0.0001). The pooled prevalence of allograft loss was greater in aPL+ve recipients (28% vs 18% respectively, p < 0.0001); the pooled prevalence of aPL was greater in allograft loss recipients compared to those who did not lose it (51% vs 33%, p < 0.0001). The pooled prevalence of allograft malfunction and rejection was similar in aPL-ve and aPL+ve recipients (32.2% vs 40.3% and 14.9% vs 14.4%, respectively) but graft duration was shorter in aPL+ve than aPL-ve recipients (p = 0.001) and glomerular filtration rate at 1 year was lower in aPL + ve than aPL-ve recipients (p < 0.0001). CONCLUSION: APL relate strongly to allograft thrombosis, loss and duration but not to allograft malfunction and rejection. Oral antivitamin K anticoagulants effectively prevent allograft thrombosis in aPL recipients. The debate on the role of aPL in renal transplant is limited by the expression of data as percentage of recipients positive for aPL rather than aPL titres in many studies. PMID- 30449652 TI - Palliative and end-of-life care in rheumatology: High symptom prevalence and unmet needs. AB - OBJECTIVES: To determine the extent of end-of-life suffering and predictors of high symptom prevalence in the last one year of life in patients with systemic rheumatic diseases (SRDs) and the extent of supportive care received. METHODS: We identified adult patients with SRDs who died between 1 April 2006 and 1 April 2016. We collected data within 1 year before their death, on the following: (i) cumulative symptom prevalence, (ii) rates of Advance Care Planning (ACP), Do-Not Resuscitate (DNR) orders and referral to a palliative physician. We analyzed the predictors of total symptom prevalence and palliative physician referral. RESULTS: Of the 161 patients studied, 34.2% had rheumatoid arthritis and 21.6% had systemic lupus erythematosus. Pain (81.4%), anorexia (80.1%) and dyspnea (77%) afflicted the majority of patients. On multivariate analysis, patients of the following profile had higher total symptom prevalence: (i) older age (beta = 0.027, SE = 0.013, p = 0.044); (ii) more comorbidities measured by the Charlson Comorbidity Index (beta = 0.192, SE = 0.159, p = 0.044); (iii) more admissions (beta = 0.263, SE = 0.090, p = 0.004) and (iv) recurrent infections (beta = 0.923, SE = 0.423, p = 0.031). Five patients (3.1%) received ACP and 25 (15.5%) were referred to a palliative physician. The median time between referral to palliative medicine and death was 8 days (IQR0-19). Of the 106 (67.5%) who had DNR orders, the median time between DNR and death was 3 days (IQR 0-10). CONCLUSIONS: Palliative and supportive care is relevant to patients with SRDs at the end-of-life. These patients experienced high physical suffering, particularly those who were elderly, with more comorbidities, hospital admissions and recurrent infections. Rheumatologists and physicians caring for patients with SRDs must be empowered to provide supportive care to these patients at the last phase of life, particularly by facilitating early ACP. PMID- 30449653 TI - The European Federation of Organisations for Medical Physics (EFOMP) White Paper: Big data and deep learning in medical imaging and in relation to medical physics profession. AB - Big data and deep learning will profoundly change various areas of professions and research in the future. This will also happen in medicine and medical imaging in particular. As medical physicists, we should pursue beyond the concept of technical quality to extend our methodology and competence towards measuring and optimising the diagnostic value in terms of how it is connected to care outcome. Functional implementation of such methodology requires data processing utilities starting from data collection and management and culminating in the data analysis methods. Data quality control and validation are prerequisites for the deep learning application in order to provide reliable further analysis, classification, interpretation, probabilistic and predictive modelling from the vast heterogeneous big data. Challenges in practical data analytics relate to both horizontal and longitudinal analysis aspects. Quantitative aspects of data validation, quality control, physically meaningful measures, parameter connections and system modelling for the future artificial intelligence (AI) methods are positioned firmly in the field of Medical Physics profession. It is our interest to ensure that our professional education, continuous training and competence will follow this significant global development. PMID- 30449654 TI - Goals matter: Amplification of the motivational significance of the feedback when goal impact is increased. AB - Performance monitoring (PM) entails the continuous evaluation of actions and their outcomes. At the electrophysiological level, PM has been consistently related to two event-related brain potentials (ERPs): the Feedback-Related Negativity (FRN) and the P3. In a previous within-subject crossover design study, we showed that feedback's goal impact (i.e., its importance to one's goal) modulated these ERP components, yet in opposing directions. Although high goal impact was associated with a larger P3, the preceding FRN had a lower amplitude than in the low impact condition. We sought to extend these findings here by adopting a between-subjects design for a pure goal impact manipulation. Sixty eight participants completed a Go/No Go Task while 64-channel electroencephalography was recorded concurrently. They were randomly assigned to either a high or low goal impact condition, manipulated through instructions on the supposed task's diagnosticity, while reward probability was kept similar between conditions. Replicating our previous results, we found that high goal impact yielded a marginally lower FRN, but substantially larger P3 during PM than low goal impact, without arousal or performance differences. Moreover, a principal component analysis confirmed these opposing directions of goal impact modulation. Overall, these results dovetail with the assumption that goal impact influences PM processes. PMID- 30449655 TI - A Brainstem-Spinal Circuit Controlling Nocifensive Behavior. AB - Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNl), and reticular formation (MdD). A combination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNlTac1 neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdDTac1 neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNlTac1 neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli. PMID- 30449656 TI - Whole-Brain Neuronal Activity Displays Crackling Noise Dynamics. AB - Previous studies suggest that the brain operates at a critical point in which phases of order and disorder coexist, producing emergent patterned dynamics at all scales and optimizing several brain functions. Here, we combined light-sheet microscopy with GCaMP zebrafish larvae to study whole-brain dynamics in vivo at near single-cell resolution. We show that spontaneous activity propagates in the brain's three-dimensional space, generating scale-invariant neuronal avalanches with time courses and recurrence times that exhibit statistical self-similarity at different magnitude, temporal, and frequency scales. This suggests that the nervous system operates close to a non-equilibrium phase transition, where a large repertoire of spatial, temporal, and interactive modes can be supported. Finally, we show that gap junctions contribute to the maintenance of criticality and that, during interactions with the environment (sensory inputs and self generated behaviors), the system is transiently displaced to a more ordered regime, conceivably to limit the potential sensory representations and motor outcomes. PMID- 30449659 TI - Mandatory bundled payment model for US cancer patients. PMID- 30449658 TI - Immunotherapy toxicity predicted by circulating cytokines. PMID- 30449660 TI - Elotuzumab in multiple myeloma. PMID- 30449661 TI - Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in Switzerland. PMID- 30449657 TI - Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations. AB - Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule associated protein that is predominantly expressed in post-mitotic neurons and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions, we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant-negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases. PMID- 30449662 TI - Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics. AB - Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 MUg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect. PMID- 30449663 TI - Two-minute versus 6-minute walk distances during 6-minute walk test in neuromuscular disease: Is the 2-minute walk test an effective alternative to a 6 minute walk test? AB - Functional tests such as Motor Function Measure-32 (MFM-32), supine to stand, ascend/descend stairs permit the assessment of task-specific motor function in neuromuscular disease (NMD). The 6-min walk test (6MWT), though functional, is primarily used to assess endurance and disease progression in children with neuromuscular disorders. Barriers to 6MWT administration, in this population, can include reduced attention span due to age and inability to tolerate test length due to weakness. We propose task-specific functional deficits are related to endurance. Additionally, the 2-min walk test (2MWT) could effectively replace the 6MWT in this population. Seventy-seven participants, ages 5-18, with a variety of neuromuscular disorders performed the 6MWT, timed functional tests (TFT), and the MFM-32. Correlation and paired t-test analyses were used to compare the distance walked in the first 2 min (2MWD) to the distance walked in the entire 6 min (6MWD) and to the functional outcome measures above. The 2MWD strongly correlated with 6MWD and the other outcome measures. Paired t-test analysis also showed that the 2MWD did not differ from the distance walked in the last 2 min of the 6MWT. Although equivalence testing could not reject the claim that this difference exceeded the upper practical limit of 9.5 m, it only showed a modest overestimation of the 4-6MWD compared with the 2MWD. Together, our results support the ability of the 2MWD to predict the 6MWD, specifically in the pediatric neuromuscular disease population. PMID- 30449664 TI - Extreme Enlargement of the Cerebellum in a Clade of Teleost Fishes that Evolved a Novel Active Sensory System. AB - Brains, and the distinct regions that make up brains, vary widely in size across vertebrates [1, 2]. Two prominent hypotheses have been proposed to explain brain region scaling evolution. The mosaic hypothesis proposes that changes in the relative sizes of particular brain regions are the result of selection acting independently on those regions [2, 3]. The concerted hypothesis proposes that the brain evolves as a coordinated structure due to developmental constraints [4]. These hypotheses have been widely debated [3-7], and recent studies suggest a combination of the two best describes vertebrate brain region scaling [8-10]. However, no study has addressed how the mosaic and concerted models relate to the evolution of novel behavioral phenotypes. We addressed this question using African mormyroid fishes. The mormyroids have evolved a novel active electrosensory system and are well known for having extreme encephalization [11] and a large cerebellum [2, 12], which is cited as a possible example of mosaic evolution [2]. We found that compared to outgroups without active electrosensing, mormyroids experienced mosaic increases in the sizes of the cerebellum and hindbrain, and mosaic decreases in the sizes of the telencephalon, optic tectum, and olfactory bulb. However, the evolution of extreme encephalization within mormyroids was associated with concerted changes in the sizes of all brain regions. This suggests that mosaic evolutionary change in the regional composition of the brain is most likely to occur alongside the evolution of novel behavioral functions, but not with the evolution of extreme encephalization. PMID- 30449665 TI - Cellular-Resolution Imaging of Vestibular Processing across the Larval Zebrafish Brain. AB - The vestibular system, which reports on motion and gravity, is essential to postural control, balance, and egocentric representations of movement and space. The motion needed to stimulate the vestibular system complicates studying its circuitry, so we previously developed a method for fictive vestibular stimulation in zebrafish, using optical trapping to apply physical forces to the otoliths. Here, we combine this approach with whole-brain calcium imaging at cellular resolution, delivering a comprehensive map of the brain regions and cellular responses involved in basic vestibular processing. We find responses broadly distributed across the brain, with unique profiles of cellular responses and topography in each region. The most widespread and abundant responses involve excitation that is graded to the stimulus strength. Other responses, localized to the telencephalon and habenulae, show excitation that is only weakly correlated to stimulus strength and that is sensitive to weak stimuli. Finally, numerous brain regions contain neurons that are inhibited by vestibular stimuli, and these neurons are often tightly localized spatially within their regions. By exerting separate control over the left and right otoliths, we explore the laterality of brain-wide vestibular processing, distinguishing between neurons with unilateral and bilateral vestibular sensitivity and revealing patterns whereby conflicting signals from the ears mutually cancel. Our results confirm previously identified vestibular responses in specific regions of the larval zebrafish brain while revealing a broader and more extensive network of vestibular responsive neurons than has previously been described. This provides a departure point for more targeted studies of the underlying functional circuits. PMID- 30449666 TI - Whole-Brain Calcium Imaging during Physiological Vestibular Stimulation in Larval Zebrafish. AB - The vestibular apparatus provides animals with postural and movement-related information that is essential to adequately execute numerous sensorimotor tasks. In order to activate this sensory system in a physiological manner, one needs to macroscopically rotate or translate the animal's head, which in turn renders simultaneous neural recordings highly challenging. Here we report on a novel miniaturized, light-sheet microscope that can be dynamically co-rotated with a head-restrained zebrafish larva, enabling controlled vestibular stimulation. The mechanical rigidity of the microscope allows one to perform whole-brain functional imaging with state-of-the-art resolution and signal-to-noise ratio while imposing up to 25 degrees in angular position and 6,000 degrees /s2 in rotational acceleration. We illustrate the potential of this novel setup by producing the first whole-brain response maps to sinusoidal and stepwise vestibular stimulation. The responsive population spans multiple brain areas and displays bilateral symmetry, and its organization is highly stereotypic across individuals. Using Fourier and regression analysis, we identified three major functional clusters that exhibit well-defined phasic and tonic response patterns to vestibular stimulation. Our rotatable light-sheet microscope provides a unique tool for systematically studying vestibular processing in the vertebrate brain and extends the potential of virtual-reality systems to explore complex multisensory and motor integration during simulated 3D navigation. PMID- 30449667 TI - Narrow Acoustic Field of View Drives Frequency Scaling in Toothed Whale Biosonar. AB - Toothed whales are apex predators varying in size from 40-kg porpoises to 50-ton sperm whales that all forage by emitting high-amplitude ultrasonic clicks and listening for weak returning echoes [1, 2]. The sensory field of view of these echolocating animals depends on the characteristics of the biosonar signals and the morphology of the sound generator, yet it is poorly understood how these biophysical relationships have shaped the evolution of biosonar parameters as toothed whales adapted to different foraging niches. Here we test how biosonar output, frequency, and directivity vary with body size to understand the co evolution of biosonar signals and sound-generating structures. We show that the radiated power increases twice as steeply with body mass (P ? M1.47 +/- 0.25) than expected from typical scaling laws of call intensity [3], indicating an evolutionary hyperallometric investment into sound production structures that may be driven by a strong selective pressure for long-range biosonar. We find that biosonar frequency scales inversely with body size (F ? M-0.19 +/- 0.03), resulting in remarkably stable biosonar beamwidth that is independent of body size. We discuss why the three main hypotheses for inverse frequency scaling in animal communication signals [3-5] do not explain frequency scaling in toothed whale biosonar. We instead propose that a narrow acoustic field of view, analogous to the fovea of many visual predators, is the primary evolutionary driver of biosonar frequency in toothed whales, serving as a spatial filter to reduce clutter levels and facilitate long-range prey detection. PMID- 30449668 TI - Two Interlinked Bistable Switches Govern Mitotic Control in Mammalian Cells. AB - Distinct protein phosphorylation levels in interphase and M phase require tight regulation of Cdk1 activity [1, 2]. A bistable switch, based on positive feedback in the Cdk1 activation loop, has been proposed to generate different thresholds for transitions between these cell-cycle states [3-5]. Recently, the activity of the major Cdk1-counteracting phosphatase, PP2A:B55, has also been found to be bistable due to Greatwall kinase-dependent regulation [6]. However, the interplay of the regulation of Cdk1 and PP2A:B55 in vivo remains unexplored. Here, we combine quantitative cell biology assays with mathematical modeling to explore the interplay of mitotic kinase activation and phosphatase inactivation in human cells. By measuring mitotic entry and exit thresholds using ATP-analog-sensitive Cdk1 mutants, we find evidence that the mitotic switch displays hysteresis and bistability, responding differentially to Cdk1 inhibition in the mitotic and interphase states. Cdk1 activation by Wee1/Cdc25 feedback loops and PP2A:B55 inactivation by Greatwall independently contributes to this hysteretic switch system. However, elimination of both Cdk1 and PP2A:B55 inactivation fully abrogates bistability, suggesting that hysteresis is an emergent property of mutual inhibition between the Cdk1 and PP2A:B55 feedback loops. Our model of the two interlinked feedback systems predicts an intermediate but hidden steady state between interphase and M phase. This could be verified experimentally by Cdk1 inhibition during mitotic entry, supporting the predictive value of our model. Furthermore, we demonstrate that dual inhibition of Wee1 and Gwl kinases causes loss of cell-cycle memory and synthetic lethality, which could be further exploited therapeutically. PMID- 30449670 TI - Genetics and Genomics of an Unusual Selfish Sex Ratio Distortion in an Insect. AB - Diverse selfish genetic elements have evolved the ability to manipulate reproduction to increase their transmission, and this can result in highly distorted sex ratios [1]. Indeed, one of the major explanations for why sex determination systems are so dynamic is because they are shaped by ongoing coevolutionary arms races between sex-ratio-distorting elements and the rest of the genome [2]. Here, we use genetic crosses and genome analysis to describe an unusual sex ratio distortion with striking consequences on genome organization in a booklouse species, Liposcelis sp. (Insecta: Psocodea), in which two types of females coexist. Distorter females never produce sons but must mate with males (the sons of nondistorting females) to reproduce [3]. Although they are diploid and express the genes inherited from their fathers in somatic tissues, distorter females only ever transmit genes inherited from their mothers. As a result, distorter females have unusual chimeric genomes, with distorter-restricted chromosomes diverging from their nondistorting counterparts and exhibiting features of a giant non-recombining sex chromosome. The distorter-restricted genome has also acquired a gene from the bacterium Wolbachia, a well-known insect reproductive manipulator; we found that this gene has independently colonized the genomes of two other insect species with unusual reproductive systems, suggesting possible roles in sex ratio distortion in this remarkable genetic system. PMID- 30449669 TI - Luck in Food Finding Affects Individual Performance and Population Trajectories. AB - Energy harvesting by animals is important because it provides the power needed for all metabolic processes. Beyond this, efficient food finding enhances individual fitness [1] and population viability [2], although rates of energy accumulation are affected by the environment and food distribution. Typically, differences between individuals in the rate of food acquisition are attributed to varying competencies [3], even though food-encounter rates are known to be probabilistic [4]. We used animal-attached technology to quantify food intake in four disparate free-living vertebrates (condors, cheetahs, penguins, and sheep) and found that inter-individual variability depended critically on the probability of food encounter. We modeled this to reveal that animals taking rarer food, such as apex predators and scavengers, are particularly susceptible to breeding failure because this variability results in larger proportions of the population failing to accrue the necessary resources for their young before they starve and because even small changes in food abundance can affect this variability disproportionately. A test of our model on wild animals indicated why Magellanic penguins have a stable population while the congeneric African penguin population has declined for decades. We suggest that such models predicting probabilistic ruin can help predict the fortunes of species operating under globally changing conditions. PMID- 30449671 TI - A Grow-and-Lock Model for the Control of Flagellum Length in Trypanosomes. AB - Several models have been proposed to explain how eukaryotic cells control the length of their cilia and flagella. Here, we investigated this process in the protist Trypanosoma brucei, an excellent model system for cells with stable cilia like photoreceptors or spermatozoa. We show that the total amount of intraflagellar transport material (IFT, the machinery responsible for flagellum construction) increases during flagellum elongation, consistent with constant delivery of precursors and the previously reported linear growth. Reducing the IFT frequency by RNAi knockdown of the IFT kinesin motors slows down the elongation rate and results in the assembly of shorter flagella. These keep on elongating after cell division but fail to reach the normal length. This failure is neither due to an absence of precursors nor to a morphogenetic control by the cell body. We propose that the flagellum is locked after cell division, preventing further elongation or shortening. This is supported by the fact that subsequent increase in the IFT rate does not lead to further elongation. The distal tip FLAM8 protein was identified as a marker for the locking event. It is initiated prior to cell division, leading to an arrest of elongation in the daughter cell. Here, we propose a new model termed "grow and lock" where the flagellum elongates until a locking event takes place in a timely defined manner, hence fixing length. Alteration in the growth rate and/or in the timing of the locking event would lead to the formation of flagella of different lengths. PMID- 30449672 TI - Geographically Resolved Rhythms in Twitter Use Reveal Social Pressures on Daily Activity Patterns. AB - Daily rhythms in human physiology and behavior are driven by the interplay of circadian rhythms, environmental cycles, and social schedules. Much research has focused on the mechanism and function of circadian rhythms in constant conditions or in idealized light-dark environments. There have been comparatively few studies into how social pressures, such as work and school schedules, affect human activity rhythms day to day and season to season. To address this issue, we analyzed activity on Twitter in >1,500 US counties throughout the 2012-2013 calendar years in 15-min intervals using geographically tagged tweets representing ~0.1% of the total population each day. We find that sustained periods of low Twitter activity are correlated with sufficient sleep as measured by conventional surveys. We show that this nighttime lull in Twitter activity is shifted to later times on weekends relative to weekdays, a phenomenon we term "Twitter social jet lag." The magnitude of this social jet lag varies seasonally and geographically-with the West Coast experiencing less Twitter social jet lag compared to the Central and Eastern US-and is correlated with average commuting schedules and disease risk factors such as obesity. Most counties experience the largest amount of Twitter social jet lag in February and the lowest in June or July. We present evidence that these shifts in weekday activity coincide with relaxed social pressures due to local K-12 school holidays and that the direct seasonal effect of altered day length is comparatively weaker. PMID- 30449673 TI - Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor. AB - The c-Jun NH2-terminal kinase (JNK) signaling pathway is central to the cell response to stress, inflammatory signals, and toxins. While selective inhibitors are known for JNKs and for various upstream MAP3Ks, no selective inhibitor is reported for MKK7--one of two direct MAP2Ks that activate JNK. Here, using covalent virtual screening, we identify selective MKK7 covalent inhibitors. We optimized these compounds to low-micromolar inhibitors of JNK phosphorylation in cells. The crystal structure of a lead compound bound to MKK7 demonstrated that the binding mode was correctly predicted by docking. We asserted the selectivity of our inhibitors on a proteomic level and against a panel of 76 kinases, and validated an on-target effect using knockout cell lines. Lastly, we show that the inhibitors block activation of primary mouse B cells by lipopolysaccharide. These MKK7 tool compounds will enable better investigation of JNK signaling and may serve as starting points for therapeutics. PMID- 30449675 TI - Perturbation of Iron Metabolism by Cisplatin through Inhibition of Iron Regulatory Protein 2. AB - Cisplatin is classically known to exhibit anticancer activity through DNA damage in the nucleus. Here we found a mechanism by which cisplatin affects iron metabolism, leading to toxicity and cell death. Cisplatin causes intracellular iron deficiency through direct inhibition of the master regulator of iron metabolism, iron regulatory protein 2 (IRP2) with marginal effects on IRP1. Cisplatin, but not carboplatin or transplatin, binds human IRP2 at Cys512 and Cys516 and impairs IRP2 binding to iron-responsive elements of ferritin and transferrin receptor-1 (TfR1) mRNAs. IRP2 inhibition by cisplatin caused ferritin upregulation and TfR1 downregulation leading to sustained intracellular iron deficiency. Cys512/516Ala mutant IRP2 made cells more resistant to cisplatin. Furthermore, combination of cisplatin and the iron chelator desferrioxamine enhanced cytotoxicity through augmented iron depletion in culture and xenograft mouse model. Collectively, cisplatin is an inhibitor of IRP2 that induces intracellular iron deficiency. PMID- 30449674 TI - Perturbation-Based Proteomic Correlation Profiling as a Target Deconvolution Methodology. AB - Molecular target identification of small molecules, so-called target deconvolution, is a major obstacle to phenotype-based drug discovery. Here, we developed an approach called perturbation-based proteomic correlation profiling (PPCP) utilizing the correlation between protein quantity and binding activity of compounds under cellular perturbation by gene silencing and successfully identified lanosterol synthase as a molecular target of TGF-beta pathway inhibitor. This PPCP concept was extended to the use of a cell line panel and provides a new option for target deconvolution. PMID- 30449676 TI - Recycling full thickness skin graft from failing free flaps in salvage procedures. PMID- 30449677 TI - Challenges for school-based, anti-smoking education in China. PMID- 30449678 TI - Scrotal injuries during neonatal circumcision. AB - OBJECTIVE: To report very rarely encountered scrotal injuries during neonatal circumcision. Hospitals and physicians in the authors' country are mandated to report circumcision complications to the Ministry of Health. Those reports include the discharge summary from the emergency room or the admitting department. This is believed to be the first case series describing scrotal injuries during ritual circumcision. PATIENTS AND METHODS: Reports of all circumcision complications between 2007 and 2014 were evaluated. Retrieved data on cases of scrotal injuries included patient's age, time between injury and hospital admission, nature of the injury, and administered treatment. RESULTS: Twelve of a total of 489 reports of circumcision injuries involved the scrotum (2.5%). All circumcisions were performed during the neonatal period, and the infants were admitted on the day of injury. The only related genital injury was significant shortage of penile skin reported in six patients. Scrotal exploration and skin closure in the operating room was undertaken in six cases, five under general anesthesia. Suture closure in the emergency department was performed in three patients, and the scrotal skin was left to heal with secondary intention in three other patients. Scrotal content injury that extended to the tunica vaginalis of the testis was noted in one exploration. DISCUSSION: The injuries sustained by the 12 study infants were mostly superficial and are not expected to cause long-term damage, although half of the patients required treatment under general anesthesia in the operating room or under sedation in the emergency department. While all reported patients emerged unscathed from the anesthetic procedures, the possible immediate complications of anesthesia as well as its long-term effects are not to be taken lightly, especially when treating a newborn. Further education of medical providers as well as performers of ritual circumcisions may help lower the risk of this rare injury as well as other more severe complications. CONCLUSION: Scrotal injury during neonatal circumcision is rare. While half of the 12 reported patients required exploration in the operating room, the injuries were mostly superficial and did not involve scrotal content, although they often involved extensive resection of penile skin. PMID- 30449679 TI - An evaluation of the readability, quality, and accuracy of online health information regarding the treatment of hypospadias. AB - BACKGROUND: Hypospadias is one of the most common genital anomalies. Treatment of hypospadias requires surgical repair, usually in childhood. Patients are increasingly using the internet to learn more about their health or that of their children, which can often empower patients to make well-informed healthcare decisions. OBJECTIVE: The objective of this study was to evaluate not only the readability but also the quality and accuracy of available online health information for the treatment of hypospadias. STUDY DESIGN: Search terms for hypospadias treatment were queried on major search engines. Each website was classified into one of four categories: institutional, commercial, charitable organization, or personal website. Content on each website discussing treatment options was analyzed for readability using three readability formulas. A validated tool, the DISCERN instrument, was used to measure the quality of online health information regarding hypospadias treatment. Accuracy was independently assessed by two pediatric urologists on a 1-5 scale, in which 1 and 5 correspond to 0% and 100% of the information in the text being accurate, respectively. RESULTS: A total of 150 search engine results were acquired, of which 46 were analyzed for readability, quality, and accuracy. The mean readability scores across all websites were 14.89 (Gunning-Fog), 11.01 Simple Measure of Goddledygook (SMOG), and 8.44 (Dale-Chall), which correspond to an 11th- to 12th grade reading level. Most websites (65.2%) were considered of 'good' quality. Readability and quality scores were not statistically different between website categories. Institutional and charitable websites had the highest mean accuracy scores (3.91 and 3.50, respectively), with institutional websites proving to have significantly more accurate information regarding hypospadias treatment than commercial websites (3.91 and 3.42, respectively; P = 0.001). DISCUSSION: Pediatric urologists should know what information about hypospadias and its treatment exists on the Internet and understand if it is accurate and of good quality and, more importantly, if the material is written at a reading level comprehensible by the majority of parents. Limitations included analysis of only English-written websites regarding hypospadias treatment specifically, using search engines alone rather than other online resources, not evaluating online videos or illustrations, and not using more than two pediatric urologists for determining content accuracy. CONCLUSION: This study demonstrates that online health materials regarding hypospadias and its treatment are written at a level far greater than the reading level of most adults. Most websites were considered of adequate quality, and websites from institutions or references had significantly more accurate information than those from commercial websites. PMID- 30449680 TI - Hemiarthroplasty or total hip arthroplasty in recent femoral neck fractures? AB - The optimal treatment of recent femoral neck fractures remains debated. The available options are internal fixation, hemiarthroplasty (HA) and total hip arthroplasty (THA). There is a consensus in favour of internal fixation in younger patients. In elderly individuals who are institutionalised and have limited physical activity, HA is usually performed when the joint line is intact. Whether HA or THA deserves preference in patients aged 60 years or over is unclear. In addition, there are two types of HA, unipolar and bipolar, and two types of THA, conventional and dual-mobility. Both HA types provide similar outcomes with satisfactory stability but a risk of acetabular wear that may eventually require conversion to THA. THA is associated with better functional outcomes and a lower risk of revision surgery in self-sufficient, physically active patients. Instability is the leading complication of conventional THA and occurs with a higher incidence compared to HA. With all implant types, preoperative factors associated with mortality and complications include walking ability and level of self-sufficiency, nutritional status, and haematocrit. An evaluation of these factors before surgery is of paramount importance. Factors amenable to treatment should be corrected by working jointly with geriatricians to develop a preoperative management strategy. In patients who are self sufficient, physically active, and free of risk factors, THA remains the option of choice, as it provides better functional outcomes. A dual-mobility implant deserves preference to prevent instability. HA is indicated in patients whose self-sufficiency and physical activity are limited. A unipolar implant should be used, as no evidence exists that bipolar implants provide additional benefits. When performing HA, the posterior approach should be avoided given the risk of instability. For THA, in contrast, the posterior approach is a reliable option in the hands of an experienced surgeon using a dual-mobility cup. Cement fixation of the stem is recommended to minimise the risk of peri-prosthetic fracture. PMID- 30449681 TI - Preclinical Models for Studying NASH-Driven HCC: How Useful Are They? AB - Hepatocellular carcinoma (HCC) is one of the most fatal and fastest-growing cancers. Recently, non-alcoholic steatohepatitis (NASH) has been recognized as a major HCC catalyst. However, it is difficult to decipher the molecular mechanisms underlying the pathogenesis of NASH and understand how it progresses to HCC by studying humans. Progress in this field depends on the availability of reliable preclinical models amenable to genetic and functional analyses and exhibiting robust NASH-to-HCC progression. Although numerous mouse models of NASH have been described, many do not faithfully mimic the human disease and few reliably progress to HCC. Here, we review current literature on the molecular etiology of NASH-related HCC and critically evaluate existing mouse models and their suitability for studying this malignancy. We also compare human transcriptomic and histopathological profiles with data from MUP-uPA mice, a reliable model of NASH-driven HCC that has been useful for evaluation of HCC-targeting immunotherapies. PMID- 30449683 TI - Neuromedin U Does Not Act as a Decretin in Rats. AB - Studies on isolated pancreatic islets suggest that neuromedin U (NMU), a brain and gastrointestinal peptide, acts as a decretin hormone, inhibiting glucose stimulated insulin secretion. We investigated whether this effect could be reproduced in vivo and in isolated perfused rat pancreas. Unlike the incretin hormone, glucagon-like peptide 1 (GLP-1), intravenous NMU administration had no effects on blood glucose and plasma insulin and glucagon in vivo. Moreover, NMU neither changed insulin, glucagon, or somatostatin secretion from isolated perfused rat pancreas, nor affected GLP-1-stimulated insulin and somatostatin secretion. For NMU to act as a decretin hormone, its secretion should increase following glucose ingestion; however, glucose did not affect NMU secretion from isolated perfused rat small intestine, which contained extractable NMU. Furthermore, the two NMU receptors were not detected in endocrine rat or human pancreas. We conclude that NMU does not act as a decretin hormone in rats. PMID- 30449682 TI - Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells. AB - Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents. PMID- 30449684 TI - Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids. AB - Elevations in branched-chain amino acids (BCAAs) associate with numerous systemic diseases, including cancer, diabetes, and heart failure. However, an integrated understanding of whole-body BCAA metabolism remains lacking. Here, we employ in vivo isotopic tracing to systemically quantify BCAA oxidation in healthy and insulin-resistant mice. We find that most tissues rapidly oxidize BCAAs into the tricarboxylic acid (TCA) cycle, with the greatest quantity occurring in muscle, brown fat, liver, kidneys, and heart. Notably, pancreas supplies 20% of its TCA carbons from BCAAs. Genetic and pharmacologic suppression of branched-chain alpha ketoacid dehydrogenase kinase, a clinically targeted regulatory kinase, induces BCAA oxidation primarily in skeletal muscle of healthy mice. While insulin acutely increases BCAA oxidation in cardiac and skeletal muscle, chronically insulin-resistant mice show blunted BCAA oxidation in adipose tissues and liver, shifting BCAA oxidation toward muscle. Together, this work provides a quantitative framework for understanding systemic BCAA oxidation in health and insulin resistance. PMID- 30449685 TI - Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic beta Cells for In Vitro and In Vivo Analysis. AB - Identification of cell-surface markers specific to human pancreatic beta cells would allow in vivo analysis and imaging. Here we introduce a biomarker, ectonucleoside triphosphate diphosphohydrolase-3 (NTPDase3), that is expressed on the cell surface of essentially all adult human beta cells, including those from individuals with type 1 or type 2 diabetes. NTPDase3 is expressed dynamically during postnatal human pancreas development, appearing first in acinar cells at birth, but several months later its expression declines in acinar cells while concurrently emerging in islet beta cells. Given its specificity and membrane localization, we utilized an NTPDase3 antibody for purification of live human beta cells as confirmed by transcriptional profiling, and, in addition, for in vivo imaging of transplanted human beta cells. Thus, NTPDase3 is a cell-surface biomarker of adult human beta cells, and the antibody directed to this protein should be a useful new reagent for beta cell sorting, in vivo imaging, and targeting. PMID- 30449686 TI - Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis. AB - Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ~200 chemical features, but its reduced form D-[13C]beta-hydroxybutyrate (D-betaOHB) labeled almost none. [13C]glucose labeled ~500 features, and while unlabeled AcAc competed with only ~15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-betaOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte macrophage ketone shuttle that segregates AcAc from D-betaOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages. PMID- 30449687 TI - A Multi-model Approach to Assessing Local and Global Cryo-EM Map Quality. AB - There does not currently exist a standardized indicator of how well cryo-EM derived models represent the density from which they were generated. We present a straightforward methodology that utilizes freely available tools to generate a suite of independent models and to evaluate their convergence in an EM density. These analyses provide both a quantitative and qualitative assessment of the precision of the models and their representation of the density, respectively, while concurrently providing a platform for assessing both global and local EM map quality. We further use standardized datasets to provide an expected deviation within a suite of models refined against EM maps reported to be at 5 A resolution or better. Associating multiple atomic models with a deposited EM map provides a rapid and accessible reporter of convergence, a strong indicator of highly resolved molecular detail, and is an important step toward an FSC independent assessment of map and model quality. PMID- 30449688 TI - Structural Basis of H+-Dependent Conformational Change in a Bacterial MATE Transporter. AB - Multidrug and toxic compound extrusion (MATE) transporters efflux toxic compounds using a Na+ or H+ gradient across the membrane. Although the structures of MATE transporters have been reported, the cation-coupled substrate transport mechanism remains controversial. Here we report crystal structures of VcmN, a Vibrio cholerae MATE transporter driven by the H+ gradient. High-resolution structures in two distinct conformations associated with different pHs revealed that the rearrangement of the hydrogen-bonding network around the conserved Asp35 induces the bending of transmembrane helix 1, as in the case of the H+-coupled Pyrococcus furiosus MATE transporter. We also determined the crystal structure of the D35N mutant, which captured a unique conformation of TM1 facilitated by an altered hydrogen-bonding network. Based on the present results, we propose a common step in the transport cycle shared among prokaryotic H+-coupled MATE transporters. PMID- 30449689 TI - The Structure of the SPOP-Pdx1 Interface Reveals Insights into the Phosphorylation-Dependent Binding Regulation. AB - Pdx1 is a transcription factor crucial for development and maintenance of a functional pancreas. It regulates insulin expression and glucose homeostasis. SPOP is an E3-ubiquitin ligase adaptor protein that binds Pdx1, thus triggering its ubiquitination and proteasomal degradation. However, the underlying mechanisms are not well understood. Here, we present the crystal structure of the SPOP-Pdx1 complex. We show that Pdx1 residues 223-233 bind to SPOP MATH domain with low micromolar affinity. The interface is extended compared to other SPOP client proteins. Previously, Pdx1 phosphorylation has been proposed to have a regulatory function. In this respect we show that phosphorylation lowers the affinity of Pdx1 to SPOP by isothermal titration calorimetry and nuclear magnetic resonance data. Our data provide insights into a critical protein-protein interaction that regulates cellular Pdx1 levels by SPOP-mediated decay. A reduction of Pdx1 levels in beta cells is linked to apoptosis and considered a hallmark of type 2 diabetes. PMID- 30449690 TI - Comorbid conditions are a risk for osteonecrosis of the jaw unrelated to antiresorptive therapy. AB - OBJECTIVE: Osteonecrosis of the jaw (ONJ) is commonly associated with antiresorptive therapy. There have been numerous reports of ONJ unrelated to antiresorptive therapy (ONJuat), confounding risk assessment. This study aimed to determine if ONJuat is associated with one or more particular comorbidities. STUDY DESIGN: This was a retrospective case-control study of patients with ONJuat and delayed healing (DH). Each case was matched for patient age and gender, as well as location of ONJuat or DH lesion to a control patient who had a history of dentoalveolar surgery with uneventful healing and no history of antiresorptive therapy. Comorbidity data included medical conditions and smoking. RESULTS: Of the 92 patients identified, 67 (73%) met the criteria for ONJuat and 25 (27%) for DH. The most common trigger for ONJ and DH was extraction (50%). The presence of any comorbidity (i.e., at least 1) was more prevalent in ONJuat than among controls (P = .04), and there were more comorbidities in patients with ONJuat and DH than in controls [M(SD) = 1.94 (1.2) and 2.0 (1.3) vs 1.26 (0.89); both P < .001]. CONCLUSIONS: ONJ and DH are not limited to patients with a history of antiresorptive therapy. More comorbidities may signal increased risk for ONJuat and DH. PMID- 30449691 TI - Effectiveness of platelet-rich plasma injection in patients with temporomandibular joint osteoarthritis: a systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of platelet rich plasma (PRP) injection after arthrocentesis or arthroscopy in patients with temporomandibular joint osteoarthritis. STUDY DESIGN: Electronic databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched for reports up to July 30, 2018. We included all published or unpublished randomized controlled trials (RCTs). The primary outcome was pain reduction, and the secondary outcome was the improvement of maximal mouth opening. Weighted mean differences were utilized for random-effect meta-analysis. RESULTS: Five RCTs were enrolled in the meta-analysis, comparing PRP injection to placebo (hyaluronic acid [HA] injection, saline injection, or no injection). The results revealed that PRP injection was more effective than placebo in pain reduction, but no in the improvement of maximal mouth opening, in the long term. In the subgroup analysis, PRP injection yielded better outcome only in pain reduction comparing to HA injection (Weighted mean difference 1.34, 95% confidence interval [CI] 0.95 1.73). CONCLUSIONS: This meta-analysis demonstrated that PRP injection provided adjuvant efficacy to arthrocentesis or arthroscopy in pain reduction for temporomandibular joint osteoarthritis in the long term. Furthermore, PRP injection significantly reduced pain better compared with HA injection, saline injection, or no injection. PMID- 30449692 TI - Long-term clinical outcomes of valsartan in patients with a systemic right ventricle: Follow-up of a multicenter randomized controlled trial. AB - OBJECTIVES: In the VAL-SERVE (Valsartan in Systemic Right Ventricle) trial, three year valsartan treatment improved systemic ventricular function only in symptomatic patients with congenitally or with an atrial switch corrected transposition of the great arteries. The aim of the current study was to investigate the longer-term clinical outcomes after valsartan treatment. METHODS: From 2006 to 2009, 88 adults were randomly allocated 1:1 to either valsartan or placebo for three consecutive years. Endpoints were defined as overall survival and freedom from clinical events (arrhythmia, heart failure, tricuspid valve surgery, death). RESULTS: Cardiac drug use and median follow-up after trial close out (8.3 years) was similar between the randomization groups. Six patients (valsartan n = 3, placebo n = 3) died in 364 and 365 person-years (P = 0.999). No difference in the composite or separate clinical endpoints was found between the randomization groups, with corresponding long-term event-free survival rates of 50% and 34%. Nevertheless, in symptomatic patients valsartan significantly reduced the risk for events compared to placebo (HR 0.37, 95% CI 0.17-0.92). Analysis for repeated events and on-treatment analysis with any renin-angiotensin aldosterone-system-inhibitor did not alter these results. CONCLUSIONS: Valsartan treatment in systemic RV patients did not result in improved survival at longer term follow-up, but was associated with decreased risk of events in symptomatic patients. PMID- 30449693 TI - Implementing a minimally invasive approach (combining radial approach, small guiding catheters and minimization of double access) for coronary chronic total occlusion intervention according to the hybrid algorithm: The Minimalistic Hybrid Algorithm. AB - Percutaneous recanalization of coronary chronic total occlusions (CTOs) traditionally relies on the use of dual access and large bore catheters, with trans-femoral approach adoption in most of the cases. Aim of this manuscript is to describe an alternative algorithm, that we called "Minimalistic Hybrid Algorithm", in order to minimize the use of double access, large bore catheters, and femoral approach thus reducing patient's discomfort and possibly procedural complications. This algorithm can be interpreted as an evolution of the classic "Hybrid Algorithm" and requires the operator to be confident with all techniques known in this conventional algorithm. Indeed, all possible techniques and approaches of the conventional hybrid approach to treat CTOs are included in a novel diagram for procedural strategy, which offers an alternative sequence of steps to limit, whenever possible, the invasiveness of the procedure. After dividing the cases in "simple" or "complex" CTO lesions according to the available complexity scores and to the "feeling", knowledge and expertise of the operator, a systematic description of the procedural steps is provided. This includes antegrade and retrograde approaches, as well as sub-intimal and intra luminal techniques, in order to maintain the simpler single-catheter transradial strategies in the first line for the simple CTO, and the adoption of more complex, double access and transfemoral ones in the further steps. The minimalistic hybrid algorithm herein described is a possible alternative sequence of steps in the setting of CTO recanalization, with the potential of limiting the use of double access, large bore catheters, and femoral approach. PMID- 30449694 TI - Cross-sectional associations between Ideal Cardiovascular Health scores and vascular phenotypes in 11- to 12-year-olds and their parents: The Longitudinal Study of Australian Children. AB - BACKGROUND: Understanding early-life relationships between the Ideal Cardiovascular Health (ICVH) score and vascular phenotypes could inform likely effectiveness and timing of cardiovascular disease prevention strategies. We aimed to describe associations between ICVH scores and vascular phenotypes in 11- to 12-year-old children and their parents. METHODS AND RESULTS: Cross-sectional ICVH scores (range 0-7, higher indicating better health), derived by summing dichotomized metrics for cholesterol, glucose, blood pressure (BP), body mass index (BMI), diet, physical activity and smoking, were constructed for 1235 adults (89% female, mean age 43 years) and 1028 children (48% female, 12 years). The median scores were 4 and 5 for adults and children respectively. Child ICVH scores were associated with parent scores (0.18 higher child score per additional point in parent's score, 95% CI 0.12 to 0.22, P < 0.001). Each additional point in the adult ICVH score was associated with slower carotid-femoral pulse wave velocity (PWV, -0.32 m/s, 95% CI -0.37 to -0.27), greater carotid elasticity (0.017%/mm Hg, 95% CI 0.014 to 0.020) and reduced carotid intima-media thickness (IMT, -7.3 MUm, 95% CI -12.0 to -2.5). An additional point in the child score was associated with functional phenotypes (PWV -0.07 m/s, 95% CI -0.11 to -0.03; carotid elasticity 0.009%/mm Hg, 95% CI 0.004 to 0.015) but not structural phenotypes (IMT -1.8 MUm, 95% CI -5.2 to 1.5). CONCLUSION: Few Australian children and even fewer parents have ideal cardiovascular health. Lower ICVH scores were associated with adverse adult vascular phenotypes and adverse child vascular function. Family-based interventions optimizing ICVH metrics may delay onset and progression of subclinical atherosclerosis and later cardiovascular disease. PMID- 30449695 TI - Are we ready for a gender-specific approach in interventional cardiology? AB - Gender differences in the pathophysiology of atherosclerosis, cardiovascular risk factors, and diagnosis of coronary artery disease and valvular heart disease are well known. Such differences have also been outlined in the management and outcomes after acute coronary syndromes and valvular repair. Regarding the atherosclerotic process, pathological experimental studies suggest that plaque composition and burden may differ by gender. Female gender is associated with worse outcomes in the case of ischemic heart disease and, compared with men, women are less likely to undergo interventional cardiac procedures and sustain worse outcomes. In the setting of valvular heart disease (VHD), transcatheter aortic valve implantation (TAVI) and percutaneous edge-to-edge mitral valve repair are now well-established procedures with high success rates. In women with moderate to severe aortic stenosis, subgroup analyses in TAVI trials have demonstrated gender-related differences suggesting female gender as beneficial in terms of short-, mid-, and long-term outcomes. Similarly, several studies reported different procedural challenges and outcomes in males and females following surgical and percutaneous mitral valve repair. These diverse findings emphasize the necessity to provide gender-specific analyses of interventional methods. This review highlights gender differences in the epidemiology, pathophysiology, treatment options and clinical outcomes of the conditions mentioned above. PMID- 30449696 TI - Long-term assessment of surgical and quality-of-life outcomes between lightweight and standard (heavyweight) three-dimensional contoured mesh in laparoscopic inguinal hernia repair. AB - BACKGROUND: Mesh weight is a possible contributor to quality-of-life outcomes after inguinal hernia repair. This study compares lightweight mesh versus heavyweight mesh in laparoscopic inguinal hernia repair. METHODS: A prospective, single-center, hernia-specific database was queried for all adult laparoscopic inguinal hernia repair with three-dimensional contoured mesh (3-D Max, Bard, Inc, New Providence, NJ) from 1999 to June 2016. Demographics and outcomes were analyzed. Quality of life was evaluated preoperatively and after 2 weeks, 4 weeks, 6 months, 12 months, and 24 months, using the Carolinas Comfort Scale. Univariate analysis and multivariate logistic regression were performed. RESULTS: A total of 1,424 laparoscopic inguinal hernia repair were performed with three dimensional contoured mesh, with 804 patients receiving lightweight mesh and 620 receiving heavyweight mesh. Patients receiving lightweight mesh were somewhat younger (52.6 +/- 14.8 years vs 56.3 +/- 13.7 years, P < .0001), with slightly lower body mass indices (26.4 +/- 9.9 vs 27.1 +/- 4.3, P < .0001). Lightweight mesh was used less often in incarcerated hernias (12.5% vs 16.8%, P = .02). There were a total of 3 surgical site infections. There were no differences in complications between groups except for seroma. Although on univariate analysis, seromas appeared to occur more frequently with heavyweight mesh (21.5% vs 7.9%). On multivariate analysis, heavyweight mesh was not independently associated with seroma formation. Average follow-up was 20 months. Recurrence rates were similar between lightweight mesh and heavyweight mesh (0.7 vs 0.6% P > .05). At all points of follow-up (4 week to 3 years), quality-of-life outcomes of discomfort, mesh sensation, and movement limitation scores were similar between lightweight mesh and heavyweight mesh. CONCLUSION: Contoured lightweight mesh and heavyweight mesh in laparoscopic inguinal hernia repair yield excellent recurrence rates and no difference in postoperative complications or quality of life. Considering the lack of outcome difference with long-term follow-up, heavyweight mesh may be considered for use in laparoscopic inguinal hernia repair patients. PMID- 30449697 TI - Two-stage hepatectomy for colorectal liver metastases: Pathologic response to preoperative chemotherapy is associated with second-stage completion and longer survival. AB - BACKGROUND: Two-stage hepatectomy of bilobar colorectal liver metastases is widely used and shows encouraging survival results. However, the risk of dropout after the first stage remains high and is associated with poor survival. The objective of our study was to evaluate the factors associated with long-term survival based on the pathologic response to preoperative systemic chemotherapy in colorectal liver metastases patients who underwent two-stage hepatectomy. METHODS: The pathologic response to preoperative chemotherapy and its effect on second-stage completion and survival were retrospectively evaluated in 67 patients treated between 2003 and 2013. RESULTS: A total of 56 patients underwent two-stage hepatectomy for initially nonresectable colorectal liver metastases. Chemotherapy was combined with a biotherapy in 32 cases. The tumor regression grade, modified tumor regression grade, and Blazer grade were used to classify patients as responders (tumor regression grade and modified tumor regression grade 1-3, Blazer 0-1) or nonresponders (tumor regression grade and modified tumor regression grade 4-5, Blazer 2) after the first stage. Tumor response in the three classifications was associated with second-stage completion (tumor regression grade 1-3: OR = 4.01, 95% CI: 1.12-14.36, P = .033; modified tumor regression grade 1-3: OR = 3.8, 95% CI: 1.13-12.6, P = .03; Blazer 0-1: OR = 5.45, 95% CI: 1.66-17.85, P = .005). Triple chemotherapy was also associated with responders. The median overall survival of responders was significantly higher (Blazer 0-1: 42.9 months versus Blazer 2: 20.1 months, P = .018; tumor regression grade 1-3: 42.9 months versus tumor regression grade 4-5: 25.1 months, P = .04). CONCLUSION: A pathologic response to chemotherapy is associated with second-stage completion and longer survival. Further studies are needed to achieve the early identification of patients for whom the benefit of the second surgical stage is less straightforward. PMID- 30449698 TI - The neuroscience of adaptive thermoregulation. AB - The nervous system acts as a biological thermostat by controlling behaviors that regulate the warming and cooling of animals. We review the structures responsible for thermoregulation in three model species: roundworms (Caenorhabditis elegans), flies (Drosophila melanogaster), and rats (Rattus novegicus). We then consider additional features of the nervous system required to explain adaptive plasticity of the set-point temperature and the precision of thermoregulation. Because animals use resources such as energy, water, and oxygen to thermoregulate, the nervous system monitors the abundance of these resources and adjusts the strategy of thermoregulation accordingly. Starvation, dehydration, or hypoxemia alter the activity of temperature-sensitive neurons in the pre-optic area of the hypothalamus. Other regions of the brain work in conjunction with the hypothalamus to promote adaptive plasticity of thermoregulation. For example, the amygdala likely inhibits neurons of the pre-optic area, overriding thermoregulation when a risk of predation or a threat of aggression exists. Moreover, the hippocampus enables an animal to remember microhabitats that enable safe and effective thermoregulation. In ectothermic animals, such as C. elegans and D. melanogaster, the nervous system can alter set-point temperatures as the environmental temperatures change. To build on this knowledge, neuroscientists can use experimental evolution to study adaptation of neural phenotypes in controlled thermal environments. A microevolutionary perspective would leverage our understanding of ecological processes to predict the origin and maintenance of neural phenotypes by natural selection. PMID- 30449699 TI - Re: Geobiology Reveals How Human Kidney Stones Dissolve In Vivo. PMID- 30449700 TI - Do men with normal testosterone-oestradiol ratios benefit from letrozole for the treatment of male infertility? AB - RESEARCH QUESTION: Previous studies of aromatase inhibitors on male infertility have focused on men with low testosterone-oestradiol ratio of less than 10. Can aromatase inhibitors improve spermatogenesis in men with idiopathic male infertility with normal testosterone-oestradiol ratio? DESIGN: Prospective study of men with idiopathic severe oligozoospermia (sperm concentration <5 million/ml) carried out between February 2015 and March 2017. The objective was to assess if semen-analysis parameters improved after treatment with letrozole. Secondary objectives were to monitor the safety of letrozole in men, and to measure the alterations in serum FSH, LH, oestradiol and testosterone levels. RESULTS: Fifteen men with normal testosterone-oestradiol ratio (>10) were treated with letrozole 2.5 mg daily for 4 months. This produced a 5.5-fold increase in sperm concentration (P = 0.0068). All men had increased total serum testosterone and suppressed oestradiol levels after treatment, thus raising the overall testosterone-oestradiol ratio (P < 0.0001). Adverse effects from letrozole were relatively minor and included loss of libido (54%), headaches (25%), fatigue (21%), weakness (13%), loss of hair (8%) and dry mouth (8%). CONCLUSIONS: Letrozole improves sperm concentration and increases testosterone-oestradiol ratio for men with oligozoospermia who have normal testosterone-oestradiol ratio; its role in the treatment of male infertility may be extended to this group of patients. In addition, it is a relatively well-tolerated drug with no serious adverse effects. PMID- 30449702 TI - Mother smoking leads to methylation anomalies on 'smoke' genes in the offspring: Indelible traces of previous injuries. PMID- 30449701 TI - CHAF1A interacts with TCF4 to promote gastric carcinogenesis via upregulation of c-MYC and CCND1 expression. AB - BACKGROUND: Histones chaperones have been found to play critical roles in tumor development and progression. However, the role of histone chaperone CHAF1A in gastric carcinogenesis and its underlying mechanisms remain elusive. METHODS: CHAF1A expression in gastric cancer (GC) was analyzed in GEO datasets and clinical specimens. CHAF1A knockdown and overexpression were used to explore its functions in gastric cancer cells. The regulation and potential molecular mechanism of CHAF1A expression in gastric cancer cells were studied by using cell and molecular biological methods. FINDINGS: CHAF1A was upregulated in GC tissues and its high expression predicted poor prognosis in GC patients. Overexpression of CHAF1A promoted gastric cancer cell proliferation both in vitro and in vivo, whereas CHAF1A suppression exhibited the opposite effects. Mechanistically, CHAF1A acted as a co-activator in the Wnt pathway. CHAF1A directly interacted with TCF4 to enhance the expression of c-MYC and CCND1 through binding to their promoter regions. In addition, the overexpression of CHAF1A was modulated by specificity protein 1 (Sp1) in GC. Sp1 transcriptionally enhanced the expression of CHAF1A in GC. Furthermore, CHAF1A expression induced by Helicobacter pylori was Sp1 dependent. INTERPRETATION: CHAF1A is a potential oncogene in GC, and may serve as a novel therapeutic target for GC treatment. PMID- 30449703 TI - Genome Toxicity and Impaired Stem Cell Function after Conditional Activation of CreERT2 in the Intestine. AB - With the tamoxifen-inducible CreERT2 system, genetic recombination can be temporally controlled in a cell-type-specific manner in intact animals, permitting dissection of the molecular underpinnings of mammalian physiology. Here we present a significant drawback to CreERT2 technology for analysis of intestinal stem cells. Using the intestine-specific Villin-CreERT2 mouse strain, we observed delayed intestinal regeneration post irradiation. Villin-CreERT2 activation was associated with DNA damage and cryptic loxP site cleavage. Analysis of stem cell-specific CreERT2 strains showed that the genome toxicity impairs function of crypt base columnar stem cells, resulting in loss of organoid initiating activity. Importantly, the stem cell impairment is short-lived, with return to normal by 7 days post tamoxifen treatment. Our findings demonstrate that mouse genetic experiments that utilize CreERT2 should consider the confounding effects of enhanced stem cell sensitivity to genome toxicity resulting from CreERT2 activation. PMID- 30449704 TI - Enhancement of Sensitivity to Chemo/Radiation Therapy by Using miR-15b against DCLK1 in Colorectal Cancer. AB - Chemo-/radiotherapy resistance is the main cause accounting for most treatment failure in colorectal cancer (CRC). Tumor-initiating cells (TICs) are the culprit leading to CRC chemo-/radiotherapy resistance. The underlying regulation mechanism of TICs in CRC remains unclear. Here we discovered that miR-15b expression positively correlated with therapeutic outcome in CRC. Expression of miR-15b in pretreatment biopsy tissue samples predicted tumor regression grade (TRG) in rectal cancer patients after receiving neoadjuvant radiotherapy (nRT). Expression of miR-15b in post-nRT tissue samples was associated with therapeutic outcome. DCLK1 was identified as the direct target gene for miR-15b and its suppression was associated with self-renewal and tumorigenic properties of DCLK1+ TICs. We identified B lymphoma Mo-MLV insertion region l homolog (BMI1) as a downstream target regulated by miR-15b/DCLK1 signaling. Thus, miR-15b may serve as a valuable marker for prognosis and therapeutic outcome prediction. DCLK1 could be a potential therapeutic target to overcome chemo-/radioresistance in CRC. PMID- 30449705 TI - Specifying the Anterior Primitive Streak by Modulating YAP1 Levels in Human Pluripotent Stem Cells. AB - Specifying the primitive streak (PS) guides stem cell differentiation in vitro; however, much remains to be learned about the transcription networks that direct anterior and posterior PS cells (APS and PPS, respectively) to differentiate to distinct mesendodermal subpopulations. Here, we show that APS genes are predominantly induced in YAP1-/- human embryonic stem cells (hESCs) in response to ACTIVIN. This finding establishes the Hippo effector YAP1 as a master regulator of PS specification, functioning to repress ACTIVIN-regulated APS genes in hESCs. Moreover, transient exposure of wild-type hESCs to dasatinib, a potent C-SRC/YAP1 inhibitor, enables differentiation to APS-derived endoderm and cardiac mesoderm in response to ACTIVIN. Importantly, these cells can differentiate efficiently to normal beating cardiomyocytes without the cytoskeletal defect seen in YAP1-/- hESC-derived cardiomyocytes. Overall, we uncovered an induction mechanism to generate APS cells using a cocktail of ACTIVIN and YAP1i molecules that holds practical implications for hESC and induced pluripotent stem cell differentiation into distinct mesendodermal lineages. PMID- 30449706 TI - Immunotherapy for anti-NMDA receptor encephalitis: Experience from a single center in Taiwan. AB - BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an anti neuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurological deficits in previously healthy patients. The aims of this study were to demonstrate the clinical characteristics of patients diagnosed with anti-NMDA receptor encephalitis and to compare the different treatment strategies among these patients. METHODS: Patients presenting with newly acquired psychiatric and/or neurological deficits were studied retrospectively from 2009 to 2017. Patients with evidence of anti-NMDA receptor antibodies in serum and/or cerebrospinal fluid were enrolled. The modified Rankin scale was used to assess the initial status and outcomes of the enrolled patients. Details of the clinical presentations and results of investigations were analyzed. RESULTS: All (n = 24) of the patients received first-line immunotherapy (steroids, and/or intravenous immunoglobulin, and/or plasma exchange), and 14 patients received second-line immunotherapy (rituximab and/or cyclophosphamide). The mean time between the first- and second-line treatment was 13 days. During the first 6 months, 20 patients (20/24, 83%) achieved a good outcome (modified Rankin Scale score <=2) and 15 patients (15/24, 62.5%) completely recovered. Four patients (17.7%) relapsed, and three patients (12.5%) had associated tumors. CONCLUSION: Immunotherapy is an effective treatment for anti-NMDA receptor encephalitis. Rituximab and/or cyclophosphamide are treatment options for those who cannot tolerate or do not respond to first-line immunotherapy. Prospective studies are necessary to investigate the role of rituximab and cyclophosphamide in anti-NMDA receptor encephalitis. PMID- 30449707 TI - Role of cAMP modulator supplementations during oocyte in vitro maturation in domestic animals. AB - Cyclic adenosine monophosphate (cAMP) is an important molecule in signal transduction within the cell, functioning as a second cell messenger of gonadotrophin stimulation. The concentration of cAMP in cumulus-oocyte complexes (COCs) is known to be controlled through modulation of its synthesis by adenylyl cyclase (AC) and by degradation through the cyclic nucleotide phosphodiesterase (PDE) enzymes. One of the main obstacles for in vitro embryo production is the optimization of reproduction processes that occur in oocyte maturation. The function of cAMP is important in maintaining meiotic arrest in mammalian oocytes. When the oocyte is physically removed from the antral follicle for in vitro maturation (IVM), intra-oocyte cAMP concentrations decrease and spontaneous meiotic resumption begins, due to the depletion of inhibitory factors from the follicle. In many studies, relatively greater cAMP concentrations before IVM has been reported to improve oocyte competence, leading to subsequent benefits in embryonic development in different species. There, therefore, has been an increase in oocyte cAMP concentrations with several treatments and different approaches, such as invasive AC, stimulators of AC activity, PDE inhibitors, and cAMP analogs. The aim of this review is to comprehensively evaluate and provide data related to (i) the use of cAMP modulators during IVM and the effects on completion of meiosis and cytoplasmic reorganization, which are required for development of oocytes with the capacity to contribute to fertilization and subsequent embryonic development; and (ii) the main cAMP modulators and the effects when used in oocyte IVM. PMID- 30449708 TI - Intracranial hypertension caused by superior sagittal sinus stenosis secondary to a depressed skull fracture: Case report and review of the literature. AB - Depressed fractures that occur on the superior sagittal sinus (SSS) cause stenosis or thrombosis of the sinus in 11.5% of cases. Despite this, the appearance of signs and symptoms derived from high intracranial pressure is an infrequent event. So far, only 17 cases of venous sinus injury causing intracranial hypertension have been documented. It is necessary to establish treatment immediately before clinical suspicion. Surgical treatment by craniectomy is a fast, effective and safe alternative according to the series. However, it is necessary to anticipate the possibility of haemorrhage in the operating room. The case of a 7-year-old girl admitted for traumatic brain injury (TBI) with the diagnosis of a left parasagittal occipital sinus fracture that stenosed the posterior third of the superior sagittal sinus is presented. Upon arrival, she was asymptomatic, and conservative management was selected. Subsequently, the patient began to present with headache, nausea, vomiting and diplopia associated with bradycardia and apnoea pauses of central origin. She underwent surgery with a craniectomy with satisfactory clinical and radiological evolution and normalization of the intracranial pressure (ICP) registry. PMID- 30449709 TI - Non-dysraphic intramedullary lipoma of the craniocervical region in an adult: Case report. AB - Intradural spinal lipomas with intracranial extension are very rare and are typically diagnosed in childhood. Radical surgical excision usually causes a high rate of morbidity because of the firm adherence between the lipoma and neural tissues. In this report, we present a case of craniocervical intradural intramedullary lipoma in an adult patient. The patient underwent surgery with excision of the mass, leaving a sheet of lipoma on the tumor bed. PMID- 30449710 TI - Transcendental Meditation and treatment for post-traumatic stress disorder. PMID- 30449711 TI - Integrated care for people with long-term mental and physical health conditions in low-income and middle-income countries. AB - Integrated care is defined as health services that are managed and delivered such that people receive a continuum of health promotion, disease prevention, diagnosis, treatment, disease management, rehabilitation, and palliative care services, coordinated across the different levels and sites of care within and beyond the health sector and, according to their needs, throughout the life course. In this Review, we describe the most relevant concepts and models of integrated care for people with chronic (or recurring) mental illness and comorbid physical health conditions, provide a conceptual overview and a narrative review of the strength of the evidence base for these models in high income countries and in low-income and middle-income countries, and identify opportunities to test the feasibility and effects of such integrated care models. We discuss the rationale for integrating care for people with mental disorders into chronic care; the models of integrated care; the evidence of the effects of integrating care in high-income countries and in low-income and middle-income countries; the key organisational challenges to implementing integrated chronic care in low-income and middle-income countries; and the practical steps to realising a vision of integrated care in the future. PMID- 30449712 TI - Non-trauma-focused meditation versus exposure therapy in veterans with post traumatic stress disorder: a randomised controlled trial. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a complex and difficult-to treat disorder, affecting 10-20% of military veterans. Previous research has raised the question of whether a non-trauma-focused treatment can be as effective as trauma exposure therapy in reducing PTSD symptoms. This study aimed to compare the non-trauma-focused practice of Transcendental Meditation (TM) with prolonged exposure therapy (PE) in a non-inferiority clinical trial, and to compare both therapies with a control of PTSD health education (HE). METHODS: We did a randomised controlled trial at the Department of Veterans Affairs San Diego Healthcare System in CA, USA. We included 203 veterans with a current diagnosis of PTSD resulting from active military service randomly assigned to a TM or PE group, or an active control group of HE, using stratified block randomisation. Each treatment provided 12 sessions over 12 weeks, with daily home practice. TM and HE were mainly given in a group setting and PE was given individually. The primary outcome was change in PTSD symptom severity over 3 months, assessed by the Clinician-Administered PTSD Scale (CAPS). Analysis was by intention to treat. We hypothesised that TM would show non-inferiority to PE in improvement of CAPS score (Delta=10), with TM and PE superior to PTSD HE. This study is registered with ClinicalTrials.gov, number NCT01865123. FINDINGS: Between June 10, 2013, and Oct 7, 2016, 203 veterans were randomly assigned to an intervention group (68 to the TM group, 68 to the PE group, and 67 to the PTSD HE group). TM was significantly non-inferior to PE on change in CAPS score from baseline to 3-month post-test (difference between groups in mean change -5.9, 95% CI -14.3 to 2.4, p=0.0002). In standard superiority comparisons, significant reductions in CAPS scores were found for TM versus PTSD HE (-14.6 95% CI, -23.3 to -5.9, p=0.0009), and PE versus PTSD HE (-8.7 95% CI, -17.0 to -0.32, p=0.041). 61% of those receiving TM, 42% of those receiving PE, and 32% of those receiving HE showed clinically significant improvements on the CAPS score. INTERPRETATION: A non trauma-focused-therapy, TM, might be a viable option for decreasing the severity of PTSD symptoms in veterans and represents an efficacious alternative for veterans who prefer not to receive or who do not respond to traditional exposure based treatments of PTSD. FUNDING: Department of Defense, US Army Medical Research. PMID- 30449713 TI - Comparative Analysis and Refinement of Human PSC-Derived Kidney Organoid Differentiation with Single-Cell Transcriptomics. AB - Kidney organoids derived from human pluripotent stem cells have great utility for investigating organogenesis and disease mechanisms and, potentially, as a replacement tissue source, but how closely organoids derived from current protocols replicate adult human kidney is undefined. We compared two directed differentiation protocols by single-cell transcriptomics of 83,130 cells from 65 organoids with single-cell transcriptomes of fetal and adult kidney cells. Both protocols generate a diverse range of kidney cells with differing ratios, but organoid-derived cell types are immature, and 10%-20% of cells are non-renal. Reconstructing lineage relationships by pseudotemporal ordering identified ligands, receptors, and transcription factor networks associated with fate decisions. Brain-derived neurotrophic factor (BDNF) and its cognate receptor NTRK2 were expressed in the neuronal lineage during organoid differentiation. Inhibiting this pathway improved organoid formation by reducing neurons by 90% without affecting kidney differentiation, highlighting the power of single-cell technologies to characterize and improve organoid differentiation. PMID- 30449714 TI - Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy. AB - Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8alphabeta T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) alpha chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8alphabeta T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8alphabeta T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies. PMID- 30449715 TI - Oncogenic Amplification of Zygotic Dux Factors in Regenerating p53-Deficient Muscle Stem Cells Defines a Molecular Cancer Subtype. AB - The identity of tumor-initiating cells in many cancer types is unknown. Tumors often express genes associated with embryonic development, although the contributions of zygotic programs to tumor initiation and formation are poorly understood. Here, we show that regeneration-induced loss of quiescence in p53 deficient muscle stem cells (MuSCs) results in rhabdomyosarcoma formation with 100% penetrance. Genomic analyses of purified tumor cells revealed spontaneous and discrete oncogenic amplifications in MuSCs that drive tumorigenesis, including, but not limited to, the amplification of the cleavage-stage Dux transcription factor (TF) Duxbl. We further found that Dux factors drive an early embryonic gene signature that defines a molecular subtype across a broad range of human cancers. Duxbl initiates tumorigenesis by enforcing a mesenchymal-to epithelial transition, and targeted inactivation of Duxbl specifically in Duxbl expressing tumor cells abolishes their expansion. These findings reveal how regeneration and genomic instability can interact to activate zygotic genes that drive tumor initiation and growth. PMID- 30449716 TI - People got lost in solving a set of similar problems. AB - A mental set generally refers to the human brain's tendency to persist with a familiar solution and stubbornly ignore alternatives. However, if a familiar solution is unable to solve a problem similar to a previous problem, does it continue to hinder alternative solutions, and if so, how and why? To answer these questions, a Chinese character decomposition task was adopted in this study. Participants were asked to perform a practice problem that could be solved by a familiar loose chunk decomposition (LCD) solution followed by a test problem that was similar to the practice problem but could only be solved by an unfamiliar tight chunk decomposition (TCD) solution or were asked to repeatedly perform 3-5 practice problems followed by a test problem; the former is the base-set condition, and the latter is the enhanced-set condition. The results showed that the test problem recruited more activation of the inferior frontal gyrus (IFG), middle occipital cortex (MOG), superior parietal lobule (SPL) and dorsal anterior cingulate cortex (dACC) than the practice problem in the latter operation and verification stage, but almost equal activation of the dACC occurred in the early exploration stage. This likely implied that people did not think that the familiar but currently invalid LCD solution could not be used to solve the test problem; thus, it continuously competed for attention with the unfamiliar TCD solution, which required more executive control to suppress. Moreover, compared with the base-set condition, the test problem in the enhanced-set condition recruited greater activations of the IFG, SPL and dACC in the latter verification stage but less activations of regions in the left IFG and MOG in the early exploration stage. These results revealed that people less actively explored and had to work harder to operate the unfamiliar TCD solution, particularly to resolve competition from the familiar but currently invalid LCD solution. In conclusion, people lost the ability to identify errors in the familiar but currently invalid solution, which in turn decreased the exploration efforts and increased the processing demands associated with alternative solutions in the form of attentional bias and competition. This finding broadly explains the dilemma of creative problem solving. PMID- 30449717 TI - Phylogeography and evolution of infectious hematopoietic necrosis virus in China. AB - Infectious hematopoietic necrosis virus (IHNV) is a well-known rhabdoviral pathogen of salmonid fish. In this study, a comprehensive analysis of 40 IHNV viruses isolated from thirteen fish farms in nine geographically dispersed Chinese provinces during 2012 to 2017 is presented. Identity of nucleotide and amino acid sequences among all the complete glycoprotein (G) genes from Chinese isolates was 98.0-100% and 96.7-100%, respectively. Coalescent phylogenetic analyses revealed that all the Chinese IHN virus characterized in this study were in a monophyletic clade that had a most recent common ancestor with the J Nagano (JN) subgroup within the J genogroup of IHNV. Within the Chinese IHNV clade isolates obtained over successive years from the same salmon fish farm clustered in strongly supported subclades, suggesting maintenance and diversification of virus over time within individual farms. There was also evidence for regional virus transmission within provinces, and some cases of longer distance transmission between distant provinces, such as Gansu and Yunnan. The data demonstrated that IHNV has evolved into a new subgroup in salmon farm environments in China, and IHNV isolates are undergoing molecular evolution within fish farms. We suggest that Chinese IHNV comprises a separate JC subgroup within the J genogroup of IHNV. PMID- 30449718 TI - Is VLSM a valid tool for determining the functional anatomy of the brain? Usefulness of additional Bayesian network analysis. AB - OBJECTIVES: The ability of voxel-based lesion-symptom mapping (VLSM) to define the functional anatomy of the human brain has not been fully assessed. With a view to assessing VLSM's validity, the present study analyzed the technique's ability to determine the known clinical-anatomic correlates of hemiparesis in stroke patients. DESIGN: Lesions (damaged in at least 5 patients) associated with transformed limb motor score (after adjustment on lesion volume) at 6 months were examined in 272 patients using VLSM. The value of additional multivariable linear, logistic and Bayesian analyses was examined. RESULTS: We first checked that motor hemiparesis was fully accounted for by corticospinal tract (CST) lesions (sensitivity = 100%; p = 0.0001). Conventional VLSM analysis flagged up 2 regions corresponding to the CST, but also 8 regions located outside the CST. All 10 brain regions achieving statistical significance in the VLSM analysis were submitted to 3 additional analyses. The backward linear regression analysis selected 5 regions, one only corresponding to the CST (R2: 0.03, p = 0.0008). The logistic regression analysis selected correctly the CST (OR: 2.39, 95%CI: 1.44 3.96; 0.001). The Bayesian network analysis selected regions including the CST (in 92% of 3000 bootstrap replications) and identified the source of multicollinearity. These lesions evaluated by structural equation modeling resulted in an excellent fit (p-value = 0.228, chi/df = 1.19, RMSEA = 0.032, CFI = 0.999). Analyses of confusion factors showed that conventional VLSM analyses were strongly influenced by lesion frequency (R2 = 0.377; p = 0.0001) and multicollinearity. CONCLUSIONS: Conventional VLSM analyses are sensitive but weakened by a type I error due to the combined effects of multicollinearity and lesion frequency. We demonstrate that the addition of a Bayesian network analysis, and to a lesser extent of logistic regression, controlled for this type I error and constituted a reliable means of defining the functional anatomy of the motor system in stroke patients. PMID- 30449719 TI - Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer. AB - OBJECTIVE: In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. METHODS: Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage I-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed. RESULTS: The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. CONCLUSIONS: Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored. PMID- 30449720 TI - Inversely and adaptively planned interstitial brachytherapy: A single implant approach. AB - OBJECTIVE: To evaluate the efficacy, feasibility and safety of image-based, inversely and adaptively planned high-dose rate interstitial brachytherapy (HDR ISBT) to treat advanced primary or recurrent gynecologic malignancy in a single implant, three-consecutive-day regimen. METHODS: Clinical demographics and outcome data were abstracted from all patients with primary and recurrent gynecologic malignancies who received HDR-ISBT boost from 2014 to 2017. Treatment consisted of a single implant (~7 Gy * 4 fractions) of interstitial needles using the Syed-Neblett template over a three-day hospital admission. CT-based (3D) simulation with inverse and adaptive planning was utilized for each fraction. MR prior to and MR immediately after external beam therapy were fused for HDR-ISBT target delineation. RESULTS: Forty women with an overall median follow-up of 18 months (range: 6-54 months) received an HDR-ISBT boost. Of the 30 primary cases (83% cervix, 10% vaginal, 7% uterine), 44% had organ invasion (bladder, rectal or both) on MRI. Median coverage and dose are reported (V100: 98%, HR-CTV EQD2: 85.1 Gy, D90: 92 Gy). A significant association existed between rectal doses exceeding GEC-ESTRO recommendations (D2cc < 75 Gy) and the development of grade 3 gastrointestinal toxicity with a relative risk of 1.4 [1.1-1.8] (p = .046). Actuarial two-year overall survival (OS), local control (LC) and progression-free survival (PFS) were 81%, 81% and 64%, respectively. CONCLUSIONS: A four fraction, inversely and adaptively planned, single-implant approach of image-based HDR-ISBT provides excellent coverage, minimal toxicity and effective local control in patients with advanced and recurrent disease. PMID- 30449721 TI - Breathe New Life Into Your Chest CT Exams: Using Advanced Acquisition and Postprocessing Techniques. AB - OBJECTIVE: Chest computed tomography (CT) imaging enables detailed visualization of the pulmonary structures and diseases. This article reviews how continued innovation and improvements in modern CT system hardware and software now facilitate a wider range of image acquisition options and generate unique qualitative and quantitative information that can benefit patients RESULTS: Dual energy imaging utilizes two x-ray energies to highlight differences in tissue properties and increase iodine signal to improve diagnosis or reduce metal artifacts. Ultra-low dose imaging can be performed by using additional x-ray beam filtration, such as a tin filter, combined with iterative reconstruction algorithms to benefit lung cancer screening or pediatric imaging. Ultra-fast pitch spiral acquisition improves temporal resolution and reduces motion artifacts. Higher spatial resolution acquisition and reconstruction methods permit improved visualization of small structures. Radiomic analysis of chest CT image features permits risk stratification of pulmonary nodules and masses and reliable measures of change in pulmonary architecture and disease. CONCLUSIONS: Multiple new CT acquisition and reconstruction techniques, along with advanced post processing methods permit detailed analysis of changes in pulmonary architecture and function, and an expanded ability to adapt chest CT to the unique needs of different patients. PMID- 30449722 TI - Cryo-EM Structures of MDA5-dsRNA Filaments at Different Stages of ATP Hydrolysis. AB - Double-stranded RNA (dsRNA) is a potent proinflammatory signature of viral infection. Long cytosolic dsRNA is recognized by MDA5. The cooperative assembly of MDA5 into helical filaments on dsRNA nucleates the assembly of a multiprotein type I interferon signaling platform. Here, we determined cryoelectron microscopy (cryo-EM) structures of MDA5-dsRNA filaments with different helical twists and bound nucleotide analogs at resolutions sufficient to build and refine atomic models. The structures identify the filament-forming interfaces, which encode the dsRNA binding cooperativity and length specificity of MDA5. The predominantly hydrophobic interface contacts confer flexibility, reflected in the variable helical twist within filaments. Mutation of filament-forming residues can result in loss or gain of signaling activity. Each MDA5 molecule spans 14 or 15 RNA base pairs, depending on the twist. Variations in twist also correlate with variations in the occupancy and type of nucleotide in the active site, providing insights on how ATP hydrolysis contributes to MDA5-dsRNA recognition. PMID- 30449723 TI - Deregulated Expression of Mammalian lncRNA through Loss of SPT6 Induces R-Loop Formation, Replication Stress, and Cellular Senescence. AB - Extensive tracts of the mammalian genome that lack protein-coding function are still transcribed into long noncoding RNA. While these lncRNAs are generally short lived, length restricted, and non-polyadenylated, how their expression is distinguished from protein-coding genes remains enigmatic. Surprisingly, depletion of the ubiquitous Pol-II-associated transcription elongation factor SPT6 promotes a redistribution of H3K36me3 histone marks from active protein coding to lncRNA genes, which correlates with increased lncRNA transcription. SPT6 knockdown also impairs the recruitment of the Integrator complex to chromatin, which results in a transcriptional termination defect for lncRNA genes. This leads to the formation of extended, polyadenylated lncRNAs that are both chromatin restricted and form increased levels of RNA:DNA hybrid (R-loops) that are associated with DNA damage. Additionally, these deregulated lncRNAs overlap with DNA replication origins leading to localized DNA replication stress and a cellular senescence phenotype. Overall, our results underline the importance of restricting lncRNA expression. PMID- 30449724 TI - Inhibiting the Evolution of Antibiotic Resistance. AB - Efforts to battle antimicrobial resistance (AMR) are generally focused on developing novel antibiotics. However, history shows that resistance arises regardless of the nature or potency of new drugs. Here, we propose and provide evidence for an alternate strategy to resolve this problem: inhibiting evolution. We determined that the DNA translocase Mfd is an "evolvability factor" that promotes mutagenesis and is required for rapid resistance development to all antibiotics tested across highly divergent bacterial species. Importantly, hypermutator alleles that accelerate AMR development did not arise without Mfd, at least during evolution of trimethoprim resistance. We also show that Mfd's role in AMR development depends on its interactions with the RNA polymerase subunit RpoB and the nucleotide excision repair protein UvrA. Our findings suggest that AMR development can be inhibited through inactivation of evolvability factors (potentially with "anti-evolution" drugs)-in particular, Mfd providing an unexplored route toward battling the AMR crisis. PMID- 30449725 TI - A B-Cell-Specific Enhancer Orchestrates Nuclear Architecture to Generate a Diverse Antigen Receptor Repertoire. AB - The genome is organized into topologically associated domains (TADs) that enclose smaller subTADs. Here, we identify and characterize an enhancer that is located in the middle of the V gene region of the immunoglobulin kappa light chain (Igkappa) locus that becomes active preceding the stage at which this locus undergoes V(D)J recombination. This enhancer is a hub of long-range chromatin interactions connecting subTADs in the V gene region with the recombination center at the J genes. Deletion of this element results in a highly altered long range chromatin interaction pattern across the locus and, importantly, affects individual V gene utilization locus-wide. These results indicate the existence of an enhancer-dependent framework in the Igkappa locus and further suggest that the composition of the diverse antibody repertoire is regulated in a subTAD-specific manner. This enhancer thus plays a structural role in orchestrating the proper folding of the Igkappa locus in preparation for V(D)J recombination. PMID- 30449726 TI - Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase Guanylate Cyclase. AB - Apicomplexan parasites rely on cyclic nucleotide-dependent kinases for host cell infection, yet the mechanisms that control their activation remain unknown. Here we show that an apically localized guanylate cyclase (GC) controls microneme secretion and lytic growth in the model apicomplexan Toxoplasma gondii. Cell permeable cGMP reversed the block in microneme secretion seen in a knockdown of TgGC, linking its function to production of cGMP. TgGC possesses an N-terminal P type ATPase domain fused to a C-terminal heterodimeric guanylate cyclase domain, an architecture found only in Apicomplexa and related protists. Complementation with a panel of mutants revealed a critical requirement for the P-type ATPase domain for maximum GC function. We further demonstrate that knockdown of TgGC in vivo protects mice from lethal infection by blocking parasite expansion and dissemination. Collectively, this work demonstrates that cGMP-mediated signaling in Toxoplasma relies on a multi-domain architecture, which may serve a conserved role in related parasites. PMID- 30449727 TI - Ubiquitin-conjugating enzyme E2 B regulates the ubiquitination of O6 methylguanine-DNA methyltransferase and BCNU sensitivity in human nasopharyngeal carcinoma cells. AB - O6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes the alkyl groups from the O6 position of guanine and is then degraded via ubiquitin-mediated degradation. Previous studies indicated that 1,3-bis(2 chloroethyl)-1-nitrosourea (BCNU) facilitates the ubiquitination and degradation of MGMT in several types of cancer cells. However, the underlying mechanism of MGMT ubiquitination remains unclear. In this study, we demonstrated for the first time that ubiquitin-conjugating enzyme E2 B (UBE2B) is a novel regulator of MGMT ubiquitination mediated by BCNU in nasopharyngeal carcinoma (NPC) cells. The E3 ubiquitin ligase RAD18, a partner of UBE2B, is also involved in BCNU-mediated MGMT ubiquitination. Overexpression/knockdown of UBE2B enhanced/reduced BCNU mediated MGMT ubiquitination. Surprisingly, UBE2B knockdown significantly increased BCNU cytotoxicity in NPC cells. Therefore, loss of UBE2B seems to disrupt ubiquitin-mediated degradation of alkylated MGMT. We found that UBE2B knockdown reduced MGMT activity, suggesting that loss of UBE2B leads to the accumulation of deactivated MGMT and suppresses MGMT protein turnover in BCNU treated cells. These findings indicate that UBE2B modulates sensitivity to BCNU in NPC cells by regulating MGMT ubiquitination. PMID- 30449728 TI - Epidemiology and diagnosis of pleural tuberculosis in a low incidence country with high rate of immigrant population: A retrospective study. AB - BACKGROUND: The confirmatory diagnosis of pleural tuberculosis (pTB) remains challenging. The aim of this study was to describe the clinical and epidemiological characteristics of pTB patients and assess the yield of different diagnostic procedures in a low burden country with a high rate of immigrant population. METHODS: All adult patients with pTB between 2007 and 2014 were studied retrospectively. RESULTS: One hundred and three out of 843 patients with tuberculosis had pTB. Fifty-three (54.1%) were male, and the median age was 45years (range 18-87years). Fifty-two (50.49%) patients were immigrants. A confirmed diagnosis was reached in 16 patients (15.5%) by microbiological studies of pleural effusion. Lung involvement was demonstrated by sputum smear microscopy in 13/49 (26.5%), sputum GeneXpert MTB/RIF test in 13/20 (65%), and sputum culture in 16/37 (43.2%). High-resolution computed tomography (CT) showed lung involvement in 47.7% of the patients. The cure rate was 91.3% at the 1-year follow-up. Three patients died, all of them within the first month after diagnosis. CONCLUSIONS: The detection of lung involvement increased by two-fold when lung CT was used; this correlated with the likelihood of finding a positive microbiological result on sputum sample testing. Pleural microbiological studies had a low diagnostic yield, and sputum could have a complementary role. PMID- 30449729 TI - Representation of spatial sequences using nested rules in human prefrontal cortex. AB - Memory for spatial sequences does not depend solely on the number of locations to be stored, but also on the presence of spatial regularities. Here, we show that the human brain quickly stores spatial sequences by detecting geometrical regularities at multiple time scales and encoding them in a format akin to a programming language. We measured gaze-anticipation behavior while spatial sequences of variable regularity were repeated. Participants' behavior suggested that they quickly discovered the most compact description of each sequence in a language comprising nested rules, and used these rules to compress the sequence in memory and predict the next items. Activity in dorsal inferior prefrontal cortex correlated with the amount of compression, while right dorsolateral prefrontal cortex encoded the presence of embedded structures. Sequence learning was accompanied by a progressive differentiation of multi-voxel activity patterns in these regions. We propose that humans are endowed with a simple "language of geometry" which recruits a dorsal prefrontal circuit for geometrical rules, distinct from but close to areas involved in natural language processing. PMID- 30449730 TI - Sex-dependent gene expression after ochratoxin A insult in F344 rat kidney. AB - Ochratoxin A (OTA) is a potent rodent nephrocarcinogen; being males more sensitive than females. The objective was to study the response between sexes at gene expression level (whole genome transcriptomics) in kidneys of F344 rats treated with 0.21 or 0.50 mg/kg bw OTA for 21 days. DNA methylation analysis of selected genes was also studied (MALDI-TOF mass spectrometry). OTA-induced response was dose-dependent in males and females, although clearer in males. Females showed a higher number of altered genes than males but functional analysis revealed a higher number of significantly enriched toxicity lists in 0.21 mg/kg treated males. OTA modulated damage, signaling and metabolism related lists, as well as inflammation, proliferation and oxidative stress in both sexes. Eleven toxicity lists (damage, fibrosis, cell signaling and metabolism) were exclusively altered in males while renal safety biomarker and biogenesis of mitochondria lists were exclusively enriched in females. A high number of lists (39) were significantly enriched in both sexes. However, they contained many sex biased OTA-modulated genes, mainly phase I and II, transporters and nuclear receptors, but also others related to cell proliferation/apoptosis. No biologically relevant changes were observed in the methylation of selected genes. PMID- 30449731 TI - Evaluation of intranasal delivery route of drug administration for brain targeting. AB - The acute or chronic drug treatments for different neurodegenerative and psychiatric disorders are challenging from several aspects. The low bioavailability and limited brain exposure of oral drugs, the rapid metabolism, elimination, the unwanted side effects and also the high dose to be added mean both inconvenience for the patients and high costs for the patients, their family and the society. The reason of low brain penetration of the compounds is that they have to overcome the blood-brain barrier which protects the brain against xenobiotics. Intranasal drug administration is one of the promising options to bypass blood-brain barrier, to reduce the systemic adverse effects of the drugs and to lower the doses to be administered. Furthermore, the drugs administered using nasal route have usually higher bioavailability, less side effects and result in higher brain exposure at similar dosage than the oral drugs. In this review the focus is on giving an overview on the anatomical and cellular structure of nasal cavity and absorption surface. It presents some possibilities to enhance the drug penetration through the nasal barrier and summarizes some in vitro, ex vivo and in vivo technologies to test the drug delivery across the nasal epithelium into the brain. Finally, the authors give a critical evaluation of the nasal route of administration showing its main advantages and limitations of this delivery route for CNS drug targeting. PMID- 30449732 TI - Role of calcium-permeable AMPA receptors in memory consolidation, retrieval and updating. AB - The role of the calcium-permeable AMPA receptor (CP-AMPAR) in synaptic plasticity is well established. CP-AMPAR is believed to be recruited to synapse when the memory trace is in a plastic state; however, the direct implications of its expression for memory processes is less known. Here, we investigated the contribution of CP-AMPAR expressed in the basolateral amygdala (BLA) and hippocampus (HPC) in consolidation of different types of memory, retrieval and memory update. We showed that CP-AMPAR blockade by NASPM in the BLA and HPC impaired fear memory consolidation. NASPM infusion in the HPC also impaired spatial memory consolidation in the water maze, whereas consolidation of object location memory was not affected. We found evidence of the CP-AMPAR involvement in the BLA and in the HPC upon memory retrieval. Furthermore, memory update was affected by NASPM infusion in the HPC in both immediate shock deficit and water maze reversal learning tasks. Our data indicate that the activity of CP-AMPAR in the BLA and HPC is required for the consolidation of emotional memories. Moreover, this receptor activity is required for memory retrieval in the BLA and HPC. These findings support that CP-AMPAR has a key function in memory states in which plastic changes are presumably higher, such as the beginning of memory consolidation, and retrieval-induced updating. PMID- 30449734 TI - Noise pollution in hospitals. PMID- 30449735 TI - Post-fracture care gap: a retrospective population-based analysis of Hong Kong from 2009 to 2012. AB - INTRODUCTION: Patients who sustain an osteoporotic fracture are at increased risk of sustaining further osteoporotic fracture. The risk can be reduced by prescription of anti-osteoporosis medication. The aim of the present study was to determine the current practice in Hong Kong regarding secondary drug prevention of fragility fractures after osteoporotic hip fracture. METHODS: Dispensation of anti-osteoporosis medication records from patients with new fragility hip fractures aged >=65 years were retrieved using the Hospital Authority Clinical Data Analysis and Reporting System from 2009 to 2012. The intervention rate each year was determined from the percentage of patients receiving anti-osteoporosis medication within 1 year after hip fracture. RESULTS: A total of 15 866 patients with osteoporotic hip fracture who met the criteria were included. The intervention rate differed each year from 2009 to 2012, ranging between 9% and 15%. Orthopaedic surgeons initiated 63% of anti-osteoporosis medication, whereas physicians initiated 37%. The anti-osteoporosis drugs being prescribed included alendronic acid (76%), ibandronic acid (12%), strontium ranelate (5%), and zoledronic acid (4%). CONCLUSION: Most patients with hip fracture remained untreated for 1 year after the osteoporotic hip fracture. The Hospital Authority should allocate more resources to implement a best practice framework for treatment of patients with hip fracture at high risk of secondary fracture. PMID- 30449733 TI - An Oncolytic Virus Expressing a T-cell Engager Simultaneously Targets Cancer and Immunosuppressive Stromal Cells. AB - Effective immunotherapy of stromal-rich tumors requires simultaneous targeting of cancer cells and immunosuppressive elements of the microenvironment. Here, we modified the oncolytic group B adenovirus enadenotucirev to express a stroma targeted bispecific T-cell engager (BiTE). This BiTE bound fibroblast activation protein on cancer-associated fibroblasts (CAF) and CD3epsilon on T cells, leading to potent T-cell activation and fibroblast death. Treatment of fresh clinical biopsies, including malignant ascites and solid prostate cancer tissue, with FAP BiTE-encoding virus induced activation of tumor-infiltrating PD1+ T cells to kill CAFs. In ascites, this led to depletion of CAF-associated immunosuppressive factors, upregulation of proinflammatory cytokines, and increased gene expression of markers of antigen presentation, T-cell function, and trafficking. M2-like ascites macrophages exhibited a proinflammatory repolarization, indicating spectrum-wide alteration of the tumor microenvironment. With this approach, we have actively killed both cancer cells and tumor fibroblasts, reversing CAF mediated immunosuppression and yielding a potent single-agent therapeutic that is ready for clinical assessment.Significance: An engineered oncolytic adenovirus that encodes a bispecific antibody combines direct virolysis with endogenous T cell activation to attack stromal fibroblasts, providing a multimodal treatment strategy within a single therapeutic agent. Cancer Res; 1-14. (c)2018 AACR. PMID- 30449736 TI - Oxidative muscles have better mitochondrial homeostasis than glycolytic muscles throughout life and maintain mitochondrial function during aging. AB - Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis ab initio and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia. PMID- 30449738 TI - Errata. PMID- 30449737 TI - Effects of milrinone on inflammatory response-related gene expressions in cultured rat cardiomyocytes. AB - Congestive heart failure (CHF) is defined as a cardiac dysfunction leading to low cardiac output and inadequate tissue perfusion. Intravenous positive inotropes are used to increase myocardial contractility in hospitalized patients with advanced heart failure. Milrinone is a phosphodiesterase III inhibitor and used most commonly for inotropic effect. The well-known PROMISE study investigated the effects of milrinone on mortality in patients with severe CHF, and concluded that long-term therapy with milrinone increased morbidity and mortality among patients with advanced CHF. Previous studies have suggested that phosphodiesterase inhibitors can have potential effects on inflammatory pathways. Hence, we hypothesized that milrinone may alter inflammatory gene expressions in cardiomyocytes, thus leading to adverse clinical outcomes. We used rat cardiomyocyte cell line H9C2 and studied the impact of exposing cardiomyocytes to milrinone (10 MUmol/L) for 24 hours on inflammatory gene expressions. RNA extracted from cultured cardiomyocytes was used for whole rat genome gene expression assay (41,000 genes). The following changes in inflammatory response related gene expressions were discovered. Genes with increased expressions included: THBS2 (+9.98), MMP2 (+3.47), DDIT3 (+2.39), and ADORA3 (+3.5). Genes with decreased expressions were: SPP1 (-5.28) and CD14 (-2.05). We found that the above mentioned gene expression changes seem to indicate that milrinone may hinder the inflammatory process which may potentially lead to adverse clinical outcomes. However, further in vivo and clinical investigations will be needed to illustrate the clinical relevance of these gene expression changes induced by milrinone. PMID- 30449739 TI - Change and Constancy. PMID- 30449740 TI - Meeting Health Care Needs in Rural Alabama: The Power of Partnerships. AB - Recruiting and retaining rural primary care providers is challenging. The Graduate Nursing Education Primary Care Scholars (GNEPCS) is a partnership between a philanthropic organization and a school of nursing to recruit, educate, train, and retain primary care advanced practice registered nurses (APRNs) for practice in rural Alabama with a focus on improving the state's health outcomes. In its initial four years, the GNEPCS partnership has been successful in identifying 60 registered nurses interested in becoming rural primary care APRNs. These students have received mentoring, individualized content on rural health, preceptorships with rural providers, and opportunities for professional and leadership development. Pilot philanthropic funding has allowed us to develop sustainable curricula, attract additional complementary federal funds, and create a critical mass of practice-ready APRNs who are improving primary care access for some of the state's most rural and underserved populations. PMID- 30449741 TI - Dietary Inadequacies Among US Homeless Families: An Enduring Problem. AB - We reviewed the literature on eating patterns, prevalent diet-related illnesses, barriers to healthy eating, and interventions to improve diet among the U.S. homeless family population. Our search returned 17 articles and one literature review. We found that families experiencing homelessness tend to have poor diets, lacking healthy foods such as fruits and vegetables, but high in intake of unhealthy sugars and fats. Barriers to healthy eating included lack of access to cooking and storage resources in the shelter environment, the high cost of healthy foods, and little access to healthy eating options. Interventions to address dietary inadequacies were limited to nutrition education programs, and did not show any significant change in eating behaviors. With the recent increase in family homelessness in several states, namely in the sheltered homeless family population, we propose a need for greater research and interventions that address structural barriers to healthy eating for this underserved population. PMID- 30449742 TI - The Evidence Base for Social Determinants of Health as Risk Factors for Infant Mortality: A Systematic Scoping Review. AB - The objectives of this study were to identify social determinants of health as risk factors for infant mortality, particularly among African Americans, and to determine the extent to which research has demonstrated an association between each social determinant of health and infant mortality. A systematic scoping review was conducted following PRISMA guidelines. Databases searched include: EBSCOhost, CINAHL Plus, PsycINFO, SocINDEX, Social Work Abstracts, and Sociological Collection. Following a three-step selection process conducted by two reviewers, 89 studies were included. The social ecological model was used to categorize both the search terms and the findings. Findings revealed that the majority of studies focused on the individual and public policy levels, and most failed to account for the complexity of the issue. Additional research is needed to explore the social determinants of health that are hypothesized to affect infant mortality across all levels, applying more complex, system-level approaches. PMID- 30449743 TI - The Use of Traditional and Complementary Medicine for Diabetes in Rural Guatemala. AB - OBJECTIVES: The global burden of type 2 diabetes mellitus is increasing, especially in Central America. In resource-limited settings, such as Guatemala, there are significant barriers to diabetes care and many Guatemalans use medicinal plants as treatment. The purpose of this study is to understand the use of medicinal plants in an indigenous population with diabetes in rural Guatemala. METHODS: Semi-structured interviews were conducted in communities around San Lucas Toliman, Guatemala with people with diabetes, health promoters, and traditional healers. RESULTS: Out of the 55 people with diabetes interviewed, 35 (63.6%) had used medicinal plants, most frequently using Artemisia absinthium, Moringa oleifera, Carica papaya, and Neurolaena lobata. The majority of participants cited lack of access to medications as the reason for their use of medicinal plants. CONCLUSION: There is widespread use of medicinal plants in San Lucas Toliman. More research is needed to understand the degree of glycemic control in these communities. PMID- 30449744 TI - Non-profit hospital community benefit spending based on local sociodemographics. AB - Non-profit hospitals are facing greater pressure to address the social determinants of health. Since 2012, with new requirements for greater transparency and community health needs assessments, non-profit tax exemption requirements are believed to incentivize investments in the community, particularly for vulnerable populations. We conducted a cross-sectional analysis of community benefit spending by private, acute care, non-profit hospitals from 2012-2014 to measure if hospitals have begun to address local community needs. We measured total community benefit spending and two subsets of spending-health care related expenditures and community-directed contributions-as the proportion of their total expenditure. We obtained sociodemographic characteristics for their community, defined by ZIP code. In unadjusted and adjusted analyses using hospital-level and community-level covariates, community benefit spending has not varied and community-directed contribution amounts did not reflect local needs. Stronger incentives-tax-based or otherwise-are needed to steer non-profit hospitals to invest in community health. PMID- 30449745 TI - Increased Health and Social Vulnerability Among Hepatitis C Infected Individuals Co-infected with Hepatitis B. AB - Hepatitis B (HBV) and hepatitis C (HCV) infections contribute significant morbidity in the United States, particularly among those with a history of incarceration, homeless-ness, and/or co-morbid mental illness. Data from the Philadelphia Department of Public Health's viral hepatitis registry were matched at the person-level to the city's shelter, jail, and mental health system datasets (vulnerability datasets), and descriptive statistics were calculated. Between January 2010 and December 2014, 29,807 cases of HCV and 133 cases of HBV/HCV were reported. Fifty-eight percent of HCV cases and 70% of HBV/HCV cases were found in at least one vulnerability dataset. Compared with HCV cases, HBV/HCV cases were more likely to have a mental health diagnosis and history of incarceration, and to have spent more days in jail, and were less likely to be receiving treatment for HCV. Data are needed to describe more adequately the trajectory of HBV/HCV co-infected individuals to improve health service planning and policy. PMID- 30449746 TI - Impact of Nurses' Strike in Kenya on Number of Fully Immunized Infants in 18 County Referral Hospitals. AB - INTRODUCTION: Nurses in Kenya provide significant health care including immunization in government-run health facilities. Nurses' went on strike for 150 days in 2017. This study sought to determine the strike's effect on immunization services. METHODS: Data on number of fully immunized infants reported in 18 county referral hospitals was extracted from the Kenya Health Information System and analyzed for strike and similar non-strike months. A similar analysis was conducted for 14 faith-based health facilities that were not affected by the strike. RESULTS: A Mann-Whitney U Test revealed significant difference in the mean number of fully immunized infants during the strike period (Md= 111, n=18) and non-strike period (Md=289, n=18), U=37, z= -4.0, p= .000, r=.6. A decline of 56.9% was reported during the strike. Faith-based health facilities reported an increase of 251.6% during the strike periodConclusion. This nurses' strike may have adversely affected immunization services. PMID- 30449747 TI - Using Post-discharge Home Visitation to Improve Cultural Sensitivity and Patient centered Discharge Planning by Internal Medicine Trainees. AB - BACKGROUND: Patient-centered discharge planning improves transitional care and health outcomes for vulnerable adults. The HOME Initiative was an educational intervention aiming to improve trainees' patient-centered discharge planning skills. METHODS: Using a quasi-experimental design, 52 internal medicine residents at an academic medical center were randomized to intervention or control in 2014-2015. Intervention interns visited recently discharged patients during inpatient rotations. Interns addressed patient deficits in understanding, rectified medication errors, and provided health education. RESULTS: Over three quarters (77%) of intervention interns completed pre-and post-tests. Intervention interns reported significant improvements in patient-centered discharge planning skills and delivery of culturally sensitive care. Through improved communication skills, residents more effectively elicited patients' illness narratives and assessed their patients' safety (0.65; p=.05), functional status (0.79; p=.02) and health literacy (0.70; p=.01). CONCLUSION: Structured home visitation with recently discharged patients is a valuable tool for medical residents to learn patient-centered discharge planning and improve delivery of culturally sensitive care. PMID- 30449748 TI - Transgender and Genderqueer Individuals' Experiences with Health Care Providers: What's Working, What's Not, and Where Do We Go from Here? AB - Research demonstrates health disparities between gender-minority individuals and cisgender individuals. These disparities arise from multiple sources, including negative health care experiences. This study examines interactions between transgender and gender non-binary (TGGNB) individuals and their health care providers. We analyzed 119 participants' descriptions of positive and negative health care experiences, and what they wish providers knew about caring for TGGNB patients. Health care experiences went well when providers and staff used inclusive language, demonstrated their experience and education, and treated identity disclosure as routine. Negative interactions were characterized by misgendering, unfamiliarity with TGGNB people and health issues, and transphobic practices. Participants wished providers understood their health concerns, did not expect their patients to educate them, and created a welcoming clinical environment. Medical educators, administrators, and providers share responsibility for improving TGGNB patient experiences. Through a framework of cultural safety, we recommend several changes to ensure more equitable treatment in health care. PMID- 30449749 TI - Failure to Thrive among Immigrant and Refugee Children: A Quality Improvement Project to Innovate a Primary Care Approach. AB - OBJECTIVE: This quality improvement (QI) project aimed to improve primary care for immigrant and refugee children with failure to thrive (FTT) in a diverse clinic where elevated rates of FTT were noted. METHODS: The QI intervention included a patient registry managed by a care coordinator, a manual to educate providers, and group visits for patients with shared primary language. Rates of clinical follow-up, growth parameters of children in group visits versus standard care, and provider confidence/satisfaction were evaluated. RESULTS: Follow-up rates improved for all patients post-intervention (p=.002). There was no significant difference in growth parameters for group visit children (n=12) compared with standard care children (n=56). Providers (n=16) reported improved confidence/satisfaction post-intervention. CONCLUSION: This initiative employs an innovative model to improve primary care for children with FTT. Improved patient follow-up and provider confidence/satisfaction were observed. Patient numbers were too small to assess meaningful changes in growth parameters, necessitating further research. PMID- 30449750 TI - "Feastworthy is Something That Gives Us Our Dignity Back:" Feasibility of A Delivered Prepared Meal Program for Families in Motel-Shelters. AB - Families experiencing homelessness struggle with food access and face a high burden of nutrition-related diseases. We assessed feasibility of Feastworthy, a prepared meal delivery program for families in motel-shelters with meals made from surplus food from local colleges. We used pre-and post-program surveys and semi-structured interviews, comparing participating families with families in a nearby shelter. During the three-month pilot, Feastworthy delivered 4,875 meals to 38 families; 33 families participated in the study (20 intervention and 13 control). Families reported that the motel-shelter worsened their diet and health, and reported increased food security and healthier diets with Feastworthy. In difference-in-differences analyses, vegetable intake trended upward by 0.6 servings/day (p=.08) among participants relative to comparison-site individuals. Changes in food security scores and out-of-pocket food expenses were no different. A delivered meal program was feasible and may provide health benefits for homeless families. Future larger-scale, longer-term studies will clarify its befits. PMID- 30449751 TI - An Emergency Department Pilot Study to Save Money for Patients through use of Retail Pharmacy Generic Drug Discount Programs. AB - OBJECTIVE: The objective was to assess the number of emergency department patients with selected chronic medical conditions having medicine on a generic drug discount program list (GDDP), and to see if providing information about GDDPs would lead to cost savings. METHODS: A survey was given to consenting patients with at least one of 16 chronic medical conditions. Participants were offered education, which provided information about the three pharmacies closest to the participant. Participants were called after 30 days after to assess GDDP use and money saved. RESULTS: Nearly all (96%) of the 116 participants had at least one medicine on a GDDP list; 80% were unaware of GDDPs. Of the 45 participants enrolled in the intervention component, 37 patients were reached for 30-day follow-up. Of those reached, 26 (70%) reported switching to a GDDP and saving money. CONCLUSION: Discussing GDDPs with patients in the ED may produce cost-savings. PMID- 30449752 TI - Cervical Cancer Screening Behaviors and Perceptions of Medical Mistrust among Rural Black and White Women. AB - BACKGROUND: This study examined the relationship of medical mistrust using the Group-based Medical Mistrust Scale (GBMMS), and Papanicolaou testing behaviors among rural Black and White women. METHODS: Utilizing a convenience sample, a cross-sectional study was performed. Inclusion criteria included self identification as a non-Hispanic Black or White woman, at least 21 years of age, and a resident of one of the selected counties in the region. Analyses conducted were two-sample t-tests, Fisher's exact tests, Spearman's rho, and logistical regression. RESULTS: Among 338 women, four GBMMS items had statistically significant outcomes using multiple significance tests; significance remained when adjusting for demographic variables. Analyses indicated that Whites were dissatisfied with the health care system to a greater extent than Blacks. CONCLUSIONS: The impact of medical mistrust should be explored beyond individuals of a racial/ethnic minority group. Future directions include the development of a community-informed screening intervention to foster adherence among diverse rural populations. PMID- 30449753 TI - Alumni Perspectives on the Role of Medical School Service Learning Experiences in Their Professional Development and Practice. AB - PURPOSE: Understand how participation in service-learning activities in medical school influenced physicians' early careers. METHODS: Researchers conducted semi structured interviews with physicians who had completed residency training and held leadership positions within an established medical-student-run, service learning initiative. The research team analyzed the interviews iteratively, using an editing coding strategy to identify categories, and identified themes by prolonged data immersion. The team sought disconfirming evidence and conducted member-checking. Researchers stopped interviews after no new themes emerged (saturation). RESULTS: The research team identified four main themes: service learning activities provided an outlet for individuals predisposed to service; participants reported actively seeking underserved populations in their practice; participants described increased sensitivity towards the underserved; and participants reported gaining leadership, organizational, and administrative skills. CONCLUSIONS: Physicians who participated in medical school service learning activities indicated these experiences influenced their professional development and approach to practice. Future studies may consider these outcomes when evaluating service-learning projects. PMID- 30449754 TI - Philadelphia Telemedicine Glaucoma Detection and Follow-up Study: Ocular Findings at Two Health Centers. AB - Blindness from glaucoma can be prevented by early detection and treatment. Telemedicine improves access to treatment in high-risk populations that face barriers to receiving adequate ophthalmic care. We used a practice-based telemedicine screening model at two health centers. Telemedicine imaging of the fundus and optic nerve, followed by a complete eye exam at the same location for participants with abnormal findings, unreadable images, or ocular hypertension (OHTN), was performed. A total of 182 participants were screened, of whom 108 qualified for a complete eye exam. Of these, 62 (34.1%) had abnormal images, 12 (6.6%) had OHTN, and 34 (18.7%) had unreadable images. Eighty-nine of the 108 (82%) returned for the complete eye exam. Predominantly, participants were African American with glaucoma suspect and cataract. Screening location was an important factor for follow-up. Assessment of the fundus and optic disc using telemedicine resulted in early detection of glaucoma and other ocular pathology. PMID- 30449755 TI - Colorectal Cancer Screening Among South Asians: Focus Group Findings on Attitudes, Knowledge, Barriers and Facilitators. AB - BACKGROUND: Colorectal cancer (CRC) screening rates are low among South Asians. Understanding barriers and facilitators about CRC screening among South Asians may inform effective messaging and interventions. METHODS: We conducted eight focus groups (FGs) among South Asians to gather contextual information about CRC causes, screening barriers and facilitators, and cultural factors affecting screening. FINDINGS: An overarching sentiment across Asian Indian and Bangladeshi FGs was that cancer is considered a death sentence. However, many participants were unaware that CRC was a problem in their communities, and considered CRC screening as a low priority. Women often thought of CRC as mostly affecting men. Physician influence on screening decisions was most frequently discussed among Bangladeshis, as were sentiments of shame and modesty that may prevent screening. CONCLUSION: Findings highlight that physicians should provide culturally appropriate CRC information for South Asian patients, and the importance of access to CRC screening for South Asians. PMID- 30449756 TI - Defining "Community" from the Perspectives of Individuals with Sickle Cell Disease in Rural Georgia. AB - Individuals with sickle cell disease (SCD) often struggle to transition from pediatric to adult-centered medical environments. One probable cause is that many transition programs do not focus on what happens when patients leave the medical environment and return to their communities. Little is known about how individuals with SCD define community. Therefore, we worked with health care providers at four rural Georgia SCD outreach clinics to conduct qualitative interviews with 21 individuals who had transitioned to adult SCD care. The biopsychosocial ecological model was the framework for the study. Findings indicated that individuals with SCD describe five aspects of community that span across the family, community, and society-levels of the biopsychosocial ecological model: 1) immediate family, friends, and social circle; 2) relationships with medical providers; 3) geographic community/neighbors; 4) church/spiritual support; and 5) society. Interventions designed to improve SCD in rural communities may be most effective if they include not only support from family but also enhanced neighborhood supports and links between adults with SCD and relevant community organizations. PMID- 30449757 TI - Exploring the Relationship between Maternal Health Literacy, Parenting Self Efficacy, and Early Parenting Practices among Low-Income Mothers with Infants. AB - OBJECTIVE: To explore the association of maternal health literacy (MHL), parenting self-efficacy and early parenting practices among low-income mothers with infants. DESIGN: A cross-sectional, descriptive correlational design. PARTICIPANTS: Low-income mothers (N=186) with infants. METHODS: Face-to-face interviews were conducted using English and Spanish versions of questionnaires by trained bilingual research assistants. The Newest Vital Sign (NVS) screening tool was used to measure MHL. RESULTS: Nearly three-quarters (72%) of mothers were rated as having low MHL. In the bivariate analysis, MHL was positively correlated with education, household income, language, social support, parenting self efficacy, and early parenting practices, but negatively correlated with number of children. The study findings demonstrate that parenting self-efficacy had a mediating effect on MHL and early parenting practices among mothers with infants. CONCLUSION: Results suggest that future research is needed to advance MHL in low income mothers and to inform potential HL interventions for this target population. PMID- 30449758 TI - Gaining Medicaid Coverage During ACA Implementation: Effects on Access to Care and Preventive Services. AB - OBJECTIVE: The continued expansion of Medicaid is under debate; it is critical to evaluate the effect of obtaining Medicaid on access to preventive care. METHODS: We analyzed longitudinal data from the 2013-2014 Medical Expenditure Panel Survey and applied a difference-in-differences approach. Our treatment group included low-income, non-pregnant, non-disabled adults aged 18-64 with no insurance in 2013 who received Medicaid in 2014; the comparison group included individuals who did not have insurance in either year. RESULTS: Gaining Medicaid increased the likelihood of having a usual source of care, at least one office visit, annual checkup, annual cholesterol and blood pressure tests by 13 (CI: 2-24), 14 (CI: 2 27), 11 (CI: 1-21), 29 (CI: 20-39), and 13 (CI: 1-25) percentage points, respectively. Receipt of flu vaccine increased by eight (CI: -3-19) percentage points (insignificant). CONCLUSIONS: Medicaid coverage improved use of evidence based preventive services at a national level among uninsured, non-pregnant, low income adults. PMID- 30449759 TI - Tobacco Use Patterns among GED Recipients. AB - : U.S. General Educational Development diploma (GED) recipients have the highest smoking prevalence of any education level. This paper describes demographic characteristics and tobacco use patterns and examines effect modification and confounding as potential explanations for higher crude prevalence of smoking. METHODS: The study population included adults aged 25 and older in the 2013 National Health Interview Survey. We estimated adjusted prevalence ratios and 95% CIs for smoking and quitting behaviors using weighted multivariable logistic regression. RESULTS: Among women with a GED, adjusted prevalence of ever use (58.7%) and smoking (32.4%) was 1.50 and 1.52 times the prevalence among high school dropouts (39.1%, 21.3%). Female GED recipients had a significantly higher prevalence of ever smoking compared with dropouts. We found no significant educational differences in smoking prevalence among men or quit behaviors for either sex. CONCLUSIONS: More research is needed to identify targeted interventions to prevent smoking in this disparate population. PMID- 30449760 TI - Does Medicaid Coverage Modify the Relationship between Glycemic Status and Teeth Present in Older Adults? AB - Understanding the relationships among diabetes, teeth present, and dental insurance is essential to improving primary and oral health care. Participants were older adults who attended senior centers in northern Manhattan (New York, N.Y.). Sociodemographic, health, and health care information were obtained via intake interviews, number of teeth present via clinical dental examinations, and glycemic status via measurement of glycosylated hemoglobin (HbA1c). Complete data on dental insurance coverage status for 785 participants were available for analysis (1,015 after multiple imputation). For participants with no dental insurance and any private/other dental insurance, number of teeth present is less for participants with diabetes than for participants without diabetes; however, for participants with Medicaid coverage only, the relationship is reversed. Potential explanations include the limited range of dental services covered under the Medicaid program, inadequate diabetes screening and monitoring of Medicaid recipients, and the poor oral and general health of Medicaid recipients. PMID- 30449761 TI - Perspectives of Community Advisory Board Members in a Community-Academic Partnership. AB - BACKGROUND: Community-academic partnerships are increasingly used to engage community members and researchers in research activities; however, little is known about the motivations and perceptions of community members to participate in such projects. OBJECTIVES: The overall goal was to elicit Community Advisory Board (CAB) members' motivations and perceptions of involvement in a community academic partnership about cancer prevention. METHODS: An external evaluator conducted 15 one-on-one semi-structured interviews with CAB members of the project. Coders conducted a conventional content analysis to derive themes from the interview data. RESULTS: Emergent themes were grouped into four categories: CAB members' 1) motivation to participate in the project, 2) perceptions that they had insider information, 3) views of roles and responsibilities in project planning and implementation, and 4) challenges and suggestions to improve the community-academic relationship. CONCLUSIONS: This study found substantial evidence that CAB members perceived they were working to involve the Hispanic community in health promotion. PMID- 30449762 TI - The New Mexico Peer Education Project: Filling a Critical Gap in HCV Prison Education. AB - INTRODUCTION: Hepatitis C (HCV) is an epidemic in the incarcerated population in the United States. In New Mexico, more than 40% of people entering the prison systems test positive for HCV antibodies. Project ECHO's New Mexico Peer Education Project (NMPEP) was developed to educate prisoners about HCV and impact the cycle of HCV transmission in the prison system. METHODS: Evaluation of NMPEP included multiple methods. Surveys focused on the short-term impact of training. Focus groups and post-release interviews were conducted to assess the intermediate impact of training on peer educators. RESULTS: Significant changes were observed in knowledge, attitudes, behavioral intention and self-efficacy. The program had a powerful positive impact on peer educators giving them a unique skill set, a sense of agency and a passion to help others. CONCLUSIONS: Prison peer educators can learn to effectively teach HCV prevention and harm reduction strategies and disease specific information to their peers. PMID- 30449763 TI - Understanding the Needs of Older (Mature) Black Men who have Sex with Men: Results of a Community-based Survey. AB - Older (mature) Black men who have sex with men (BMSM) are an understudied group disproportionately affected by HIV/AIDS and experience competing priorities such as medical comorbidities, social isolation, and financial stressors. The purpose of this study was to assess the needs and priorities of a sample of urban mature BMSM to inform HIV prevention programming. A cross-sectional survey of BMSM ages 40 and older was conducted among men recruited from community-based organizations. Men ranked priorities from seven domains: financial and housing stability, physical health, mental health, relationships with family, relationships with partners, HIV prevention. Men were also asked whether mature BMSM should mentor younger BMSM. Financial and housing stability and HIV prevention were ranked in the top three by a majority. Desired program features included a safe physical space for socializing that provides information and aid. The majority of the sample agreed that mature BMSM should mentor younger BMSM. PMID- 30449764 TI - The Impact of Federal and State Policy on Oral Health Care Delivery in Long-Term Care Settings. AB - Residents of long-term care (LTC) facilities have a significantly higher risk of poor oral health status compared with those living independently; moreover, the provision of oral health services to LTC residents is often limited. This study identifies and classifies state-level policies and funding sources for dental services that are available to LTC residents. The research details variability in coverage levels, payment sources, workforce capacity, and care delivery configuration, finding little coherence between policy and the needs of patients or providers. Reforms to address the oral health care needs of vulnerable populations in LTC settings should start with defining a clearer standard of oral care required for this population. This will allow best practices in policy, practice, and accountability to be structured around care that improves patients' oral health. PMID- 30449765 TI - Assessing the Impact of Electronic Health Record Interventions on Hepatitis B Screening and Vaccination. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major health disparity between Asian Americans, Native Hawaiians, and Pacific Islanders compared with other racial/ethnic groups in the U.S. AIMS: Our aims were to determine the effectiveness of an electronic health record (EHR) data-driven clinical intervention to improve HBV screening and vaccination rates at a community health center primarily serving Asian American patients. METHODS: Using a community engaged approach, we conducted a study to compare the differences in screening and vaccination rates for 6,429 patient encounters before and after implementation of the EHR intervention. A multivariable logistic regression analysis was conducted to estimate the effect of the intervention. RESULTS: Analyses indicated that patients who visited the clinic after implementing the EHR intervention were more likely to be screened (OR=1.8, p<.001) and vaccinated (OR=2.8, p<.001) for hepatitis B. CONCLUSIONS: Electronic health record interventions implemented using a community-engaged approach may improve delivery of appropriate care to patients at risk for hepatitis B in a community health setting. PMID- 30449766 TI - Microbial Diversity in Actively Forming Iron Oxides from Weathered Banded Iron Formation Systems. AB - The surface crust that caps highly weathered banded iron formations (BIFs) supports a unique ecosystem that is a post-mining restoration priority in iron ore areas. Geochemical evidence indicates that biological processes drive the dissolution of iron oxide minerals and contribute to the ongoing evolution of this duricrust. However, limited information is available on present-day biogeochemical processes in these systems, particularly those that contribute to the precipitation of iron oxides and, thus, the cementation and stabilization of duricrusts. Freshly formed iron precipitates in water bodies perched on cangas in Karijini National Park, Western Australia, were sampled for microscopic and molecular analyses to understand currently active microbial contributions to iron precipitation in these areas. Microscopy revealed sheaths and stalks associated with iron-oxidizing bacteria. The iron-oxidizing lineages Sphaerotilus, Sideroxydans, and Pedomicrobium were identified in various samples and Leptothrix was common in four out of five samples. The iron-reducing bacteria Anaeromyxobacter dehalogens and Geobacter lovleyi were identified in the same four samples, with various heterotrophs and diverse cyanobacteria. Given this arid, deeply weathered environment, the driver of contemporary iron cycling in Karijini National Park appears to be iron-reducing bacteria, which may exist in anaerobic niches through associations with aerobic heterotrophs. Overall oxidizing conditions and Leptothrix iron-oxidizers contribute to net iron oxide precipitation in our sampes, rather than a closed biogeochemical cycle, which would result in net iron oxide dissolution as has been suggested for canga caves in Brazil. Enhancements in microbial iron oxide dissolution and subsequent reprecipitation have potential as a surface-crust-ecosystem remediation strategy at mine sites. PMID- 30449767 TI - Genetic analysis of suppressor mutants of a pho84 disruptant in the search for genes involved in intracellular inorganic phosphate sensing in Saccharomyces cerevisiae. AB - To achieve inorganic phosphate (Pi) homeostasis, cells must be able to sense intracellular and extracellular Pi concentrations. In the Pi signaling (PHO) pathway in Saccharomyces cerevisiae, high Pi represses genes involved in Pi uptake (e.g., PHO84) and Pi utilization (PHO5); conversely, the cyclin-dependent kinase inhibitor Pho81 inhibits the activity of the Pho80-Pho85 cyclin-cyclin dependent kinase complex in low-Pi conditions, leading to induction of these genes. However, how yeast senses Pi availability remains unresolved. To identify factors involved in Pi sensing upstream of the Pho81-Pho80-Pho85 complex, we generated and screened suppressor mutants of a Deltapho84 strain that shows constitutive PHO5 expression. By a series of genetic tests, including dominance recessiveness, complementation and tetrad analyses, three sef (suppressor of pho84 [pho eighty-four]) mutants (sef8, sef9 and sef10) were shown to contain a novel single mutation. The sef mutants suppressed the phenotype of constitutive PHO5 expression at the transcriptional level, but did not show restored Pi uptake capacity. An epistasis-hypostasis test revealed that the sef mutations were hypostatic to pho80 mutation, indicating that their gene products function upstream of the Pho81-Pho80-Pho85 complex in the PHO pathway. The sef mutations identified are associated with gene(s) that may be involved in the homeostasis of an intracellular Pi level-sensing mechanism in S. cerevisiae. PMID- 30449768 TI - Frequency of Balanced-Meal Consumption and Frailty in Community-Dwelling Older Japanese: A Cross-Sectional Study. AB - BACKGROUND: Although meals that combine a staple food, main dish, and side dish (balanced meals) are recommended in Japan, the health effects of such meals are unclear. We investigated the association of frequency of eating balanced meals with frailty among community-dwelling older Japanese. METHODS: We analyzed data from 912 persons aged 65 years or older who participated in the Hatoyama Cohort Study or Kusatsu Longitudinal Study. The frequency of eating two or more balanced meals daily was self-reported as <=1 day/week, 2 or 3 days/week, 4 or 5 days/week, and daily. Frailty was defined as the presence of at least three, and pre-frailty as the presence of one or two, of the following criteria: weight loss, muscle weakness, exhaustion, slowness, and low physical activity. Adjusted logistic regression was used to study associations of frequency of balanced-meal consumption with frailty (prefrailty and frailty combined) and frailty criteria. RESULTS: Participants reporting a frequency of balanced-meal consumption of <=2 or 3 days/week had a higher prevalence of frailty (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.21-2.64) than did those reporting a frequency of daily. Lower frequency of balanced-meal consumption was also associated with higher prevalences of weight loss (OR, 4.10; 95% CI, 1.90-8.85), exhaustion (OR, 6.35; 95% CI, 2.49-16.17), and low physical activity (OR, 1.92; 95% CI, 1.22 3.01). CONCLUSIONS: Our findings suggest that more frequent twice daily consumption of meals with a staple food, main dish, and side dish decreases the risks of prefrailty and frailty. PMID- 30449769 TI - Socioeconomic Disparity in the Prevalence of Objectively Evaluated Diabetes Among Older Japanese Adults: JAGES Cross-Sectional Data in 2010. AB - BACKGROUND: Studies on sex-specific socioeconomic gradients in objectively evaluated diabetes among older adults are scarce. METHODS: We used cross sectional data of 9,893 adults aged 65 years and older in Aichi Prefecture without long-term care insurance from the Japan Gerontological Evaluation Study (JAGES) in 2010 (Response rate: 66.3%). We collected demographic, socioeconomic (income, years of education, and longest occupation) and behavioral information using a mail-in self-reported survey. Blood samples for the objectively evaluated diabetes and self-reported medical history were collected at annual municipal health checkups. Poisson regression analysis stratified by sex with multiple imputations was conducted to calculate prevalence ratio and 95% confidence interval. RESULTS: A clear income gradient in diabetes prevalence was observed among women, from 11.7% in the lowest income quartile (Q1) to 7.8% in the highest (Q4). Among men, the findings were 17.6% in Q1 to 15.1% in Q4. The prevalence ratios for diabetes with incomes Q1 to Q4 were 1.43 (95% confidence interval [CI], 1.07-1.90) for women and 1.16 (95% CI, 0.90-1.50) for men after adjusting for age and other socioeconomic factors. Even after adjusting for marital status, body mass index, other metabolic risk factors, and lifestyle factors, the income based gradient remained among women. Education and occupation were not significantly associated with diabetes in the study population. CONCLUSIONS: Only women showed an income-based gradient in diabetes. Monitoring income gradient in diabetes is important in public health actions, even in older populations. Future longitudinal and intervention studies should evaluate the causal link of income to diabetes onset, determine the mechanisms of the potential sex differences in the income/diabetes association, and identify ways to mitigate the income-based inequality. PMID- 30449770 TI - Trends in Small-Cell Lung Cancer Survival in 1993-2006 Based on Population-Based Cancer Registry Data in Japan. AB - BACKGROUND: Lung cancers are classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer due to their different treatment and prognosis. Although many studies have reported the specific survival of SCLC patients treated at cancer hospitals, survival from population-based data has rarely been reported. METHODS: We analyzed survival of SCLC cases diagnosed from 1993 through 2006 from a population-based cancer registry of six prefectures. To assess trends in SCLC survival, we defined three periods that mirrored developments in SCLC treatment: period 1, 1993-1998; period 2, 1999-2001; and period 3, 2002-2006. Assessments were based on relative survival (RS), excess hazard, and conditional survival. RESULTS: A total of 10,911 SCLC patients were analyzed. Five-year RS among limited disease SCLC (LD-SCLC) in periods 1 to 3 was 16.8%, 21.1%, and 21.4%, respectively. Five-year RS among extensive disease SCLC (ED-SCLC) in periods 1 to 3 was 2.3%, 2.8%, and 2.7%, respectively. Improvement in 5-year RS in periods 2 and 3 compared with period 1 was significant among both LD- and ED SCLC patients (all P < 0.001). Conditional 5-year RS of LD-SCLC increased from 21% at year 0 to 73% at year 5, while that of ED-SCLC was 3% at year 0 and 53% at year 5. CONCLUSIONS: The prognosis of SCLC patients improved from 1999-2001 but plateaued in 2002-2006, after which no further significant improvement was seen. Continuous survey based on population-based data is helpful in monitoring the impact of developments in treatment. PMID- 30449771 TI - A Case of Amelanotic Malignant Melanoma with Dense Pleural Thickening Mimicking Malignant Mesothelioma. AB - A 51-year-old man was diagnosed with stage IIC nodular malignant melanoma (T4bN0M0) of the right upper arm. The tumor was treatment-refractory, and left sided pleural effusion emerged 1.5 years later. Aspiration of pleural fluid revealed abundant amelanotic, atypical cells that resembled epithelial malignant mesothelioma or lung adenocarcinoma cells; these cells were positive for melanoma associated antigen recognized by T cells (MART-1)/Melan-A, HMB-45, and S-100 on immunocytochemistry. Thoracic computed tomography (CT) revealed marked diffuse pleural thickening in the left hemithorax that mimicked malignant mesothelioma; thus, the present report describes the unique cytological and radiological findings of this case. PMID- 30449772 TI - Hydrocele Due to Wuchereria bancrofti Infection. PMID- 30449773 TI - Gastric Xanthoma is a Predictive Marker for Early Gastric Cancer Detected after Helicobacter pylori Eradication. AB - BACKGROUND: The detection of early gastric cancer (GC) after Helicobacter pylori eradication is expected to increase in Japan. However, the predictive markers for early GC detected after H. pylori eradication have not been extensively studied. We conducted a retrospective, single-center observational study to investigate the predictive markers for early GC detected after H. pylori eradiation. METHODS: A total of 421 patients underwent endoscopic submucosal dissection for early GC at NTT West Osaka Hospital between June 2006 and August 2017. Data from patients with GC (Group C; n=70) and without GC (Group NC; n=114) after H. pylori eradication were analyzed. RESULTS: The proportion of men was significantly higher in Group C than in Group NC (92.9% vs. 65.8%; p<0.0001). Complications with other malignant diseases were more prevalent in Group C than in Group NC. A significantly greater proportion of patients had gastric xanthoma (GX) in Group C than in Group NC (64.3% vs. 14.9%; p<0.0001). Regarding scores for endoscopic findings related to the risk of GC, the atrophy score, intestinal metaplasia score and total score were significantly higher in Group C than in Group NC. A multivariate logistic regression analysis identified male sex, atrophy (open type), the presence of intestinal metaplasia and GX as independent predictors for early GC detected after H. pylori eradication. An atrophy-matched control analysis also identified GX as an independent predictor. CONCLUSION: GX is a novel predictive marker for early GC detected after H. pylori eradication. PMID- 30449775 TI - Tolvaptan Efficiently Reduces Intracellular Fluid: Working Toward a Potential Treatment Option for Cellular Edema. AB - Objective Tolvaptan is a class of diuretics that reduce body water through aquaresis. One of the most prominent characteristics of these agents is that worsening of the renal function is less likely to occur. We investigated the underlying mechanism concerning the change in the intracellular fluid (ICF) when the body fluid is reduced. Methods In this retrospective observational study, five overhydrated CKD patients with edema or pleural effusion treated with tolvaptan were assessed by the bioelectrical impedance method twice: once before and once after tolvaptan therapy. The changes in the ICF rate were compared with those in 11 hemodialysis patients undergoing body fluid reduction by hemodialysis. Results Removal of the body fluid either by tolvaptan or by hemodialysis increased the post/pre-ratio of ICW/total body water (TBW). Tolvaptan reduced the ICF more efficiently than hemodialysis. Conclusion Tolvaptan treatment lessens body fluid by the efficient reduction of the ICF. PMID- 30449774 TI - Hepatocellular Carcinoma Arising in a Non-cirrhotic Liver with Secondary Hemochromatosis. AB - A 70-year-old man was admitted for treatment of a single liver nodule that was detected by contrast-enhanced computed tomography. Twenty years earlier, the patient had been diagnosed with myelodysplastic syndrome-refractory anemia and secondary hemochromatosis but had not received erythrocyte transfusions. The current histological, computed tomography, and magnetic resonance imaging findings revealed hepatocellular carcinoma (HCC) and non-cirrhotic liver hemochromatosis. The liver tumor was treated using radiofrequency ablation therapy. Secondary hemochromatosis may be a risk factor for HCC, even if the liver is not cirrhotic. In such cases, additional surveillance may be required to detect the development of HCC. PMID- 30449776 TI - Transient Lesion of the Splenium of the Corpus Callosum after Acute Ischemic Stroke: A Report of Two Cases. AB - Two patients who showed transient lesions in the splenium of the corpus callosum (SCC) secondary to acute ischemic stroke are reported. Both patients had embolic strokes and showed an isolated lesion in the SCC on magnetic resonance imaging (MRI) 1-2 weeks after the onset of stroke, with a hyperintense lesion on DWI and decreased apparent diffusion coefficient (ADC) values, with no symptoms related to the lesion. In both cases, the lesion disappeared on MRI approximately 1 week later. Clinicians should note that transient SCC lesions can occur following acute ischemic stroke and avoid misdiagnosing them and performing unnecessary examinations or treatment. PMID- 30449777 TI - Bicytopenia in Primary Lung Melanoma Treated with Nivolumab: A Case Report. AB - A 73-year-old man who was a current smoker complained of weakness in his limbs and slow movement and was diagnosed with primary lung melanoma with brain metastases. Following stereotactic brain radiotherapy, nivolumab was administrated. After the first cycle of nivolumab, his blood neutrophil count and hemoglobin levels started to decline. Excluding other possible causes, nivolumab was considered the most probable cause of bicytopenia. Nivolumab was not restarted, and the bicytopenia gradually recovered with no corticosteroid administration for this event. While serious hematological adverse events regarding immune checkpoint inhibitors have been assumed to be rare, severe neutropenia and anemia should be considered in patients receiving immune checkpoint therapy. PMID- 30449779 TI - An Atypical Case of Non-asthmatic Eosinophilic Granulomatosis with Polyangiitis Finally Diagnosed by Tissue Biopsy. AB - A 78-year-old woman with fever of unknown origin that had persisted for 3 months, systemic edema, and cervical lymphadenopathy was admitted to our hospital. Skin purpura and jaw claudication were subsequently observed. Histopathological examinations of the lymph nodes, skin, and temporal artery revealed findings characteristic of eosinophilic granulomatosis with polyangiitis (EGPA). However, she had no past medical history of asthma with modest eosinophilia. Although EGPA is a systemic vasculitis characterized by asthma and eosinophilia, various limited forms have been described. This was therefore considered to be an atypical form of non-asthmatic EGPA complicating with temporal arteritis (TA) diagnosed by tissue biopsy. PMID- 30449778 TI - Rapid Progression of Lung Cancer Following Emergency Caesarean Section Led to Postpartum Acute Respiratory Failure. AB - Our case patient was a 38-year-old pregnant Japanese woman who underwent emergency Caesarean section because of massive vaginal bleeding due to a low lying placenta. Immediately after delivery, she presented with rapidly progressive dyspnea. Contrast-enhanced computed tomography revealed bilateral pleural effusion, lung nodules, multiple liver tumors, and multiple osteolytic lesions. Accordingly, epidermal growth factor receptor-mutant advanced lung adenocarcinoma was diagnosed. This report highlights the occurrence of rapid progression of lung cancer following delivery that led to postpartum acute respiratory failure, rather than due to pulmonary thromboembolism associated with the existing deep venous thrombosis of the inferior vena cava. PMID- 30449780 TI - Autoimmune Encephalitis as an Extra-articular Manifestation of Rheumatoid Arthritis: A Case Report. AB - Autoimmune encephalitis (AE) is an immune-mediated encephalitis characterized by the subacute onset of memory deficits, altered mental status, or psychiatric symptoms. Limbic encephalitis associated with rheumatoid arthritis (RA) has not been reported yet. A 57-year-old man presented with the subacute onset of headache, depression, and anorexia 7 months before the onset of RA. Brain magnetic resonance imaging showed symmetric parenchymal lesions involving the medial temporal lobes. He was diagnosed with RA and AE, but no autoantibodies to neuronal intracellular or cell-surface antigens were identified in either the serum or cerebrospinal fluid. His symptoms improved with immunotherapy. AE can develop as an extra-articular manifestation of RA. PMID- 30449781 TI - Hyperammonemia in a Woman with Late-onset Ornithine Transcarbamylase Deficiency. AB - A 52-year-old woman developed vomiting and disturbance of consciousness after consuming raw fish and sushi on a trip. A blood test showed hyperammonemia (310 MUg/dL) with a normal liver function. She fell into a deep coma, and her serum ammonia level increased to 684 MUg/dL. L-arginine was administered as a diagnostic treatment for urea cycle disorder (UCD) and serum ammonia, and her consciousness levels improved. She was diagnosed with ornithine transcarbamylase deficiency (OTCD) by analyses of plasma amino acids, urinary orotic acid, and the OTC gene mutation. UCD should be considered for patients with hyperammonemia without severe liver function abnormalities. PMID- 30449783 TI - Osteitis Condensans Ilii. PMID- 30449782 TI - Sick Sinus Syndrome Observed in a Patient with Cholinesterase Deficiency. AB - A 58-year-old woman complained of general fatigue and was diagnosed with sick sinus syndrome (SSS) by ambulatory electrocardiogram, which demonstrated sinus arrest at midnight and paroxysmal atrial fibrillation (AF) at nighttime. Since her plasma cholinesterase (ChE) activity had been persistently zero, she was diagnosed with ChE deficiency. She refused permanent pacemaker implantation, and treatment with positive chronotropic drugs is ongoing. A novel association of ChE deficiency with SSS is theoretically possible rather than coincident, considering that ChE plays a key role in cholinergic influences on the sinus node leading to sinus bradyarrhythmia and on the atria, causing vagally mediated AF. PMID- 30449784 TI - Successful Bridging Chemotherapy with Gemcitabine, Carboplatin, and Dexamethasone before Unrelated Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma. AB - A 45-year-old woman was diagnosed with hepatosplenic T-cell lymphoma (HSTCL), a rare subtype of peripheral T-cell lymphoma. She received different types of chemotherapy, but disease progression was observed. To reduce the tumor burden before an unrelated bone marrow transplantation, combination chemotherapy consisting of the gemcitabine, carboplatin, and dexamethasone (GCD) was administered as bridging therapy, resulting in a reduction in the number of lymphoma cells. We were then able to perform bone marrow transplantation. Although she experienced some adverse events, she successfully achieved long-term remission. We herein report a successful case of HSTCL treated with unrelated stem cell transplantation following the GCD regimen as bridging chemotherapy. PMID- 30449785 TI - Severe Chronic Inflammatory Demyelinating Polyneuropathy Ameliorated following High-dose (3 g/kg) Intravenous Immunoglobulin Therapy. AB - We report the case of a 53-year-old woman with severe chronic inflammatory demyelinating polyneuropathy (CIDP) who developed progressive tetraplegia with respiratory failure despite receiving a standard dose of intravenous immunoglobulin therapy (IVIg), steroid pulse therapy, plasma exchange, and cyclosporine. We administered high-dose IVIg (3 g/kg; 0.6 g/kg/day for 5 consecutive days at monthly intervals). The patient's muscle weakness gradually improved after IVIg. She recovered completely 2 years after the onset of symptoms. The effects of IVIg treatment in individuals with CIDP may vary in each patient. In patients with refractory CIDP receiving standard-dose IVIg, repeated high-dose IVIg treatment can be considered. PMID- 30449786 TI - Nivolumab-induced Hypophysitis, Secondary Adrenal Insufficiency and Destructive Thyroiditis in a Patient with Lung Adenocarcinoma: A Case Report. AB - Nivolumab-induced multiple organ immune-related adverse events (irAEs) have been described in some case reports. The symptoms of endocrinological irAEs are especially nonspecific. A 63-year-old man with a postoperative recurrence of pulmonary adenocarcinoma who was treated with nivolumab presented fever, anorexia and fatigue after the 7th cycle. He underwent a rapid adrenocorticotrophic hormone test, four-hormone tolerance test and thyroid gland scintigraphy. The results were consistent with destructive thyroiditis, hypophysitis and secondary adrenal insufficiency. Nivolumab was restarted following glucocorticoid and thyroid hormone replacement treatment. When a patient presents nonspecific symptoms, the possibility of endocrinological irAEs should be considered as it may enable their early detection. PMID- 30449788 TI - Symmetric Ventral Brainstem Lesion in Leptomeningeal Carcinomatosis. PMID- 30449787 TI - Bronchoscopy as a Useful Examination for Determining Surgical Treatment Indications in Refractory Mycobacterium avium Complex Lung Disease Patients with Bilateral Lesions. AB - We herein report three cases of refractory Mycobacterium avium complex (MAC) disease successfully treated surgically despite the MAC lesions being present bilaterally. Of note, although two patients did not present with any respiratory symptom, bronchoscopy clearly revealed a major excretory lesion with a large amount of purulent sputum in all patients. Because an excretory lesion was localized, surgical resection was performed, and the mycobacterial sputum smear became negative in all patients. Bronchoscopy may be a useful examination for detecting major excretory lesions with purulent sputum, which can disseminate to other lobes, and for determining the surgical indications of refractory MAC patients, regardless of the presence of respiratory symptoms. PMID- 30449789 TI - Clinical Features of anti-MDA5 Antibody-positive Rapidly Progressive Interstitial Lung Disease without Signs of Dermatomyositis: A Case Series. AB - Anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody is associated with rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) or dermatomyositis (DM). We herein report three Japanese cases of anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM. High-resolution computed tomography revealed patchy or subpleural distribution of consolidations and/or ground-glass opacities accompanied by traction bronchiectasis. All patients succumbed to respiratory failure within two months. Anti-MDA5 antibody-positive RP-ILD without signs of CADM or DM should be included in the differential diagnosis of acute/subacute ILD. Measurement of anti-MDA5 antibody and an intensive immunosuppressive regimen might rescue these patients from RP-ILD. PMID- 30449790 TI - Treatment Results of Endoscopic Mucosal Resection with a Ligation Device for Duodenal Neuroendocrine Tumors. AB - Objective The vertical margin of neuroendocrine tumors (NETs) removed by endoscopic mucosal resection (EMR) is often tumor-positive. We examine the treatment results of endoscopic mucosal resection with a ligation device (EMR-L) for the removal of duodenal NETs located in the submucosal layer without metastasis. EMR-L can be performed with less technical skill, and the ligation device reduces the rate of positive vertical margin. Methods Ten consecutive patients with 10 duodenal NETs resected by EMR-L were enrolled. All of the lesions were located in the submucosal layer, were assessed to be free of metastasis, and were confirmed to be NETs pathologically by an endoscopic biopsy. The endoscopic results, pathological results, and prognosis were all examined. Results The enbloc resection rate and endoscopic complete resection rate were both 100%. Complete resection was achieved pathologically in 7 lesions (70.0%). The vertical margins were negative in all cases. Lymphatic vessel invasion was observed in three patients, all of whom underwent additional surgery with lymph node dissection (one of them also exhibited blood vessel invasion and a positive horizontal margin). No evidence of residual tumors or lymph node metastasis was observed in any of the patients. No recurrence was observed in any of the 10 patients (mean follow-up period: 18.6 months). One patient (10.0%) experienced intraoperative bleeding. Perforation occurred in 1 patient (10.0%), but the condition was managed well by conservative therapy. Conclusion EMR-L was an acceptable method for endoscopically resecting submucosal duodenal NETs, and the NETs resected by EMR-L were tumor-negative in the vertical margins. PMID- 30449791 TI - A Case of Systemic Sarcoidosis Presenting with Renal Involvement Caused by Various Sarcoidosis-associated Pathophysiological Conditions. AB - A 61-year-old man was diagnosed with sarcoidosis involving the lungs, eyes, parotid gland and extrathoracic lymph nodes complicated by chronic kidney injury and hypercalcemia. Kidney biopsy showed non-specific interstitial nephritis and nephrosclerosis. However, immunohistochemical staining of cell surface markers revealed a multinucleated giant macrophage surrounded by T-cells, suggesting granulomatous interstitial nephritis. Corticosteroid improved the kidney function, and reduced the serum levels of calcium and angiotensin-converting enzyme. Sarcoid nephropathy may be caused by the combination of several sarcoidosis-associated pathophysiological conditions and a comprehensive kidney examination should be performed to assess the type of injury when determining a treatment strategy. PMID- 30449792 TI - A Case of Plummer-Vinson Syndrome with Esophageal Web Formation in which Detailed Endoscopic Images Were Obtained. AB - Plummer-Vinson syndrome is a rare entity, characterized by dysphagia, esophageal web formation, and iron deficiency anemia. The patient was a 63-year-old woman with a clinical history of iron deficiency anemia and glossitis in her 20s to 40s and who had experienced swallowing difficulties for the past 20 years. A membranous stricture was found in the cervical esophagus during a fluoroscopic examination. An endoscopic examination conducted under general anesthesia revealed an oblique linear scar on the proximal surface of the stricture. Sequential balloon dilation was performed successfully. We suggest that the esophageal web formation might have been related to the healing of an esophageal ulcer. PMID- 30449793 TI - Eosinophilic Esophagitis Mimicking Candida Esophagitis. PMID- 30449794 TI - Effectiveness of Crizotinib for Inflammatory Myofibroblastic Tumor with ALK mutation: A Case Report. AB - Inflammatory myofibroblastic tumor (IMT), a rare sarcoma, is primarily treated via resection of the mass. However, in cases of recurrence or unresectable tumors, no standard care exists. While crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is only approved for non-small-cell lung cancer with ALK mutation, it is reportedly effective for other malignant tumors with ALK mutation. We herein report a case involving a 37-year-old woman with retroperitoneal IMT with ALK mutation, who experienced recurrence after complete resection, in whom crizotinib treatment resulted in complete response. ALK inhibitor efficacy against malignancies with ALK mutations should be investigated in future. PMID- 30449795 TI - Pyogenic Ventriculitis Secondary to Liver Abscess. PMID- 30449796 TI - A Long Interval from a Spinal Cord Lesion to a Subsequent Brain Lesion in Primary Central Nervous System Vasculitis: A Case Report. AB - Primary central nervous system vasculitis (PCNSV) is an uncommon vasculitis restricted to the small- and medium-sized vessels in the brain and spinal cord. Previously, only 9 cases have been reported that initially manifested as an isolated spinal cord lesion with subsequent brain involvement, where the longest interval from the onset to brain involvement was 1 year and 11 months. We herein report the case of an isolated spinal cord lesion with subsequent brain involvement appearing seven years and five months later. This case shows that brain lesions can develop after an extended interval from spinal onset in PCNSV. PMID- 30449797 TI - Repeated Left Upper Abdominal Pain. PMID- 30449798 TI - Necrotizing Otitis Externa. PMID- 30449799 TI - Community-acquired Disseminated Exophiala dermatitidis Mycosis with Necrotizing Fasciitis in Chronic Graft-versus-host Disease. AB - We herein report a case of systemic phaeohyphomycosis by Exophiala dermatitidis (E. dermatitidis) with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient had been taking oral corticosteroids for years to control the GVHD. Yeast-like fungi were identified in a blood culture, so treatment with micafungin (150 mg/day) was begun, with no improvement. The patient passed away on hospital Day 12. A sequence analysis of rRNA revealed the isolate to be E. dermatitidis. This report brings attention to an emerging mycosis of community-acquired Exophiala species infection in the very late phase after allogenic HSCT in patients with chronic GVHD. PMID- 30449800 TI - Relationship of Helicobacter pylori Infection with Gastric Black Spots Shown by Endoscopy. AB - Objective The recently reported endoscopic finding of black spots is defined as black pigmentation in gastric mucosa. We attempted to clarify the relationship between the Helicobacter pylori infection status and black spot occurrence. Subjects and methods The study subjects were 1,600 individuals who underwent an annual medical checkup and whose H. pylori status could be determined. Upper endoscopic examinations were performed in all, and the presence of black spots in the stomach as well as the degree of gastric mucosal atrophy were determined. Results Among the 1,600 enrolled subjects, 784 underwent eradication for H. pylori, of whom 144 were originally H. pylori-positive and 672 H. pylori negative. Black spots in the stomach were observed in 156 (9.8%). The rate of prevalence of black spots in the H. pylori-positive and H. pylori-negative subjects was 2.1% and 1.5%, respectively, while that in subjects after undergoing eradication of H. pylori was 18.2%. A multiple logistic regression analysis demonstrated that an older age and post-eradication status were significant factors for black spot occurrence, while proton pump inhibitor treatment showed a tendency to be a risk factor. In subjects with post-eradication status, a higher grade of gastric mucosal atrophy was a significant risk factor for the occurrence of black spots. Conclusion H. pylori post-eradication status and an older age were significant factors related to the appearance of black spots, and a higher grade of gastric mucosal atrophy was also a significant risk factor in subjects who had undergone successful eradication. PMID- 30449801 TI - Disseminated Cryptococcosis in a Patient with Multiple Myeloma Treated with Daratumumab, Lenalidomide, and Dexamethasone. AB - We report a case of disseminated cryptococcosis in a patient with multiple myeloma (MM) during treatment with daratumumab, lenalidomide, and dexamethasone (DRd). A 62-year-old woman, who was diagnosed with IgGlambda type MM, was treated with three cycles of bortezomib and dexamethasone and subsequently treated with three cycles of DRd before admission. She reached a stringent complete response and presented with lethargy and seizure. Laboratory findings revealed severe CD4 lymphopenia, and Cryptococcus neoformans was detected in her cerebrospinal fluid and blood culture. The risk of developing an opportunistic infection should be considered in patients treated with daratumumab. PMID- 30449802 TI - Pleural Mucosa-associated Lymphoid Tissue Lymphoma with Trisomy 18. PMID- 30449803 TI - Early Detection of Inflammation and Joint Destruction Revealed by Ultrasound in a Patient with Sternoclavicular Septic Arthritis. AB - A 53-year-old Japanese man experienced fever/neck pain, and neck magnetic resonance imaging revealed a spinal epidural abscess. The following day, he developed a palpable mass with evident inflammatory signs in the right sternoclavicular joint (SCJ) with severe pain. Ultrasound revealed synovitis with remarkable power Doppler signals in the right SCJ. Blood cultures yielded Streptococcus agalactiae growth. After 12 days, ultrasound showed right distal clavicle bone erosion. His symptoms improved with long-term parenteral antibiotic treatment, but the right SCJ joint destruction progressed for several months. We diagnosed him with sternoclavicular septic arthritis complicated with a spinal epidural abscess and bacteremia. PMID- 30449804 TI - An Unusual Case of Acute Cholecystitis with Amyloidosis: A Case Report and Literature Review. AB - We present an extremely rare case of amyloid A (AA) deposition in the gallbladder and review the literature on similar cases. The patient was a 76-year-old man who had been diagnosed with mild bronchiectasis three years previously, who was admitted to the hospital with right upper quadrant pain and fever. Computed tomography revealed swelling and wall thickening of the gallbladder with a small gallstone. The patient was diagnosed with acute cholecystitis and cholelithiasis and underwent open cholecystectomy. A postoperative histological examination revealed extensive AA deposition in the gallbladder wall. Thus, the definitive diagnosis was acute cholecystitis with AA amyloidosis. PMID- 30449805 TI - Infectious Aneurysm Caused by Citrobacter koseri in an Immunocompetent Patient. AB - Citrobacter species can cause severe infection in immunocompetent patients. A 78 year-old man visited our hospital because he had had a fever lasting one day each month for the past 3 months. Antibiotics were initiated for suspected bronchial pneumonia, but the C-reactive protein level remained high. Contrast-enhanced computed tomography revealed saccular brachiocephalic artery aneurysm. Citrobacter koseri was isolated from a blood culture, and he was diagnosed with infectious brachiocephalic artery aneurysm. He underwent endovascular aneurysm repair after one month of intravenous cefepime and metronidazole. We herein report for the first time an immunocompetent patient with infectious aneurysm caused by C. koseri periodontal infection. PMID- 30449807 TI - Myocardial Infarction Potentially Caused by Erosion and Spasm. PMID- 30449806 TI - Paraneoplastic Syndrome Presenting with Polymyalgia Rheumatica-like Accumulations on 18F-fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography. AB - A 70-year-old woman presented with a fever and pain in both lower extremities and the right shoulder and right upper arm continuously for approximately 3 months. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F FDG/PET-CT) revealed the accumulation of FDG in the right shoulder, lumbar spinous processes, both ischial tuberosities, and both hips and greater trochanters, indicating polymyalgia rheumatica (PMR). In addition, upper gastrointestinal endoscopy revealed esophageal carcinoma. After endoscopic submucosal dissection was performed, her musculoskeletal symptoms spontaneously improved, and the 18F-FDG/PET-CT findings decreased. In light of these findings, she was diagnosed with paraneoplastic syndrome. When atypical features of PMR, such as asymmetric symptoms occur, we should search for malignancies. PMID- 30449808 TI - Glecaprevir and Pibrentasvir for Japanese Patients with Human Immunodeficiency Virus and Genotype 3 Hepatitis C Virus Coinfection: A Report of Three Cases. AB - The efficacy and safety of glecaprevir and pibrentasvir in Japanese patients with human immunodeficiency virus (HIV) and/or genotype 3 hepatitis C virus (HCV) infection is yet to be clarified. This is because no or only a few patients have been included in Japanese phase 3 trials. We herein report for the first time the successful treatment of glecaprevir and pibrentasvir in three Japanese patients with HIV and genotype 3 HCV coinfection as well as hemophilia. Glecaprevir and pibrentasvir treatment is safe and effective for Japanese patients with genotype 3 HCV and HIV coinfection. PMID- 30449809 TI - Ceritinib Aggravates Glycemic Control in Insulin-treated Patients with Diabetes and Metastatic ALK-positive Lung Cancer. AB - We herein report a 75-year-old woman with insulin-treated diabetes and metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who received ceritinib, a second-generation ALK inhibitor, and achieved dramatic tumor reduction. However, her fasting blood glucose increased, particularly markedly in the first two weeks after ceritinib administration, and did not normalize even increasing the total insulin dose. After discontinuing ceritinib, her glucose levels rapidly reduced. Ceritinib can aggravate hyperglycemia in patients with diabetes who lack compensatory insulin secretion, due to its inhibitory effects on the insulin receptor. Careful monitoring for ceritinib induced hyperglycemia should be performed, especially in the first two weeks after ceritinib administration. PMID- 30449810 TI - Multiple Pulmonary Metastases of Cutaneous Squamous Cell Carcinoma. AB - We herein report a rare case of diffuse pulmonary metastasis occurring approximately one year after surgical excision of cutaneous squamous cell carcinoma that had been thought to be stage I with a free margin of healthy tissue. In addition, this case had chest imaging findings unusual for a skin cancer patient, showing a miliary pattern on computed tomography. Distant metastases may develop even if early-stage cutaneous squamous cell carcinoma is completely resected. When observing a miliary shadow on chest computed tomography, metastatic lung tumor from skin cancer should be considered as a differential diagnosis. PMID- 30449811 TI - A Rare Case Involving the Inability to Belch. AB - A 17-year-old girl was referred to our hospital with an inability to belch, while experiencing chest gurgling noises, and severe abdominal bloating. She reported having these symptoms all her life. A timed barium esophagogram revealed a moderate amount of bubbles in the esophagus and gastric fundus, which significantly increased after the examination. High resolution manometry revealed that the basal upper esophageal sphincter pressure increased with a rise in the cervical esophageal pressure. A pathological inability to belch is rare; at present, no specific name exists to describe the disorder. Further research is needed in this unexplored field. PMID- 30449812 TI - Efficacy of Combined Thrombomodulin and Antithrombin in Anticoagulant Therapy for Acute Cholangitis-induced Disseminated Intravascular Coagulation. AB - Objective The efficacy and safety of concomitant use of antithrombin (AT) with recombinant soluble human thrombomodulin (rTM) for acute cholangitis-induced disseminated intravascular coagulation (AC-induced DIC) remains unclear. This study was conducted to investigate the efficacy of AT combined with rTM as anticoagulant therapy for AC-induced DIC. Methods One hundred patients with AC induced DIC received anticoagulant therapy using rTM from April 2010 to December 2017. Of the 83 patients treated with rTM immediately after the diagnosis of DIC, excluding those who had not undergone biliary drainage or who had malignancies or a serum AT III level >70%, 56 patients were studied. Outcomes and adverse events (AEs) were retrospectively compared between the 16 patients treated with rTM alone (rTM group) and the 40 patients treated with rTM and AT (rTM+AT group). Results Patients' background characteristics did not differ markedly, except for a significantly higher serum D-dimer level in the rTM group than in the rTM+AT group (p=0.038). The DIC resolution rates on day 9 were 100% and 95.1% in the rTM and rTM+AT groups, respectively (p=0.909). The mean DIC scores were significantly lower in the rTM group than in the rTM+AT group on days 3 (p=0.012), 5 (p<0.001), 7 (p=0.033), and 9 (p=0.007). The incidence of AEs was 6.3% and 10.0% (p=0.941), and the in-hospital mortality rates was 0% and 5.0% (p=0.909) in the rTM and rTM+AT groups, respectively. Conclusions The concomitant use of AT with anticoagulant therapy using rTM for AC-induced DIC may not help improve the treatment outcome. PMID- 30449813 TI - Pancreaticopleural Fistula Resulting in Formation of Mediastinal Pseudocysts. PMID- 30449814 TI - Isolated Orbital Myeloid Sarcoma as a Therapy-related Myeloid Neoplasm. PMID- 30449815 TI - Characteristics of self-reported daily life note (LN) users in return-to-work judgment for workers on sick leave due to mental health conditions, and usefulness of the tool. AB - A self-reported daily life note (LN) is an effective tool used by occupational physicians to assess the capacity of workers on sick leave due to mental illness to return to work (RTW). We aimed to clarify whether there were differences in the criteria used to define recovery for RTW between LN users and non-users, whether LN users were satisfied with LN, and whether non-users wanted to use LN. In total, 363 occupational physicians (238 LN users, 125 non-users) completed self-reported questionnaires covering demographic and occupational variables, and RTW assessment criteria. We investigated which of the 10 assessment criteria were considered most important for RTW. The proportion of LN users was higher among women, younger physicians, and occupational physicians with more working days per month. LN users emphasized four criteria in assessing RTW: 1) constant wake-up time, 2) constant bedtime, 3) no midnight waking, and 4) no feeling of drowsiness during the day. LN users regard regular sleep rhythm and the absence of drowsiness during the day as important criteria for RTW. 97% of users regarded LN as useful. 74% of non-users had interest in using LN. PMID- 30449816 TI - Synergistic Effects of 1 h Post-Load Plasma Glucose and Smoking on Arterial Stiffness in Apparently Healthy Men: A Cross-sectional Study. AB - AIM: One-hour post-load plasma glucose (1h-PG) during an oral glucose tolerance test and smoking are associated with arterial stiffness. However, it remains unknown whether there are synergistic effects of these two factors on arterial stiffness. This study aimed to investigate the interaction between 1h-PG and smoking in relation to brachial-ankle pulse wave velocity (baPWV) in young men with normal glucose tolerance (NGT). METHODS: The study included 25-, 30-, 35-, 40-, and 45-year-old non-industrial male workers (n=2189) who underwent a detailed health check-up. Normotensive participants with NGT and taking no medication were included. RESULTS: A univariate linear regression analysis showed that 1h-PG correlated with baPWV (r=0.13, p<0.001), but the correlation was not significant in the multivariate analysis (beta=0.02, p=0.24). However, we found a significant interaction between 1h-PG levels and smoking status in relation to baPWV (p=0.048). Therefore, further analyses were conducted in nonsmokers and smokers. A multivariate linear regression analysis revealed that 1h-PG significantly correlated with baPWV in smokers (beta=0.11, p=0.02), but not in nonsmokers (beta=0.01, p=0.79). The correlation remained significant even after adjustment for the number of cigarettes smoked per day (beta=0.096, p=0.048) or the Brinkman index (beta=0.097, p=0.043). CONCLUSION: A significant interaction between 1h-PG and smoking in relation to baPWV was found in apparently healthy men younger than 50 years old. PMID- 30449817 TI - Common venous renal trunk in two dogs: multidetector computed tomographic imaging findings. AB - In dogs, variation in the branching pattern of renal veins is rare with only few patterns reported. This report describes two unusual anomalies of the renal vein branching patterns in two dogs. In dog 1, a common renal trunk drained both kidneys, in a T-shape pattern, in the caudal vena cava after a long right perirenal course. In dog 2, a common venous trunk branched cranially from the pre renal segment of an azygos-caudal vena cava venous trunk and divided into the renal veins in a Y-shape pattern. Proper knowledge of the possible anatomical variations in renal venous drainage may be helpful during imaging assessment and surgical planning of several canine diseases involving the abdominal vasculature and retroperitoneal space. PMID- 30449818 TI - The effect of environmental and biological factors on STT I and normal total tear protein concentration in Japanese black calves. AB - To identify reference values for the Schirmer tear test I (STT I) in Japanese black cattle, investigate the effects of variables (sex, age, time of day, and environment in the barn including environmental temperature, humidity, illuminance, and ammonia concentration) on tear production, and determine total tear protein concentration. One-hundred-and-thirty-seven Japanese black cattle (67 females and 70 males, age 3-90 days) were evaluated. The mean STT I values was 18.9 +/- 2.9 mm/min (n=263) and significant effects were age and ammonia concentration in the barn. Mean total tear protein concentration was 1.18 +/- 0.30 mg/ml in healthy cattle older than 15 days (n=38). It was suggested that age and ammonia concentration are related to fluctuation of tear volume. PMID- 30449819 TI - Long-term management and postmortem examination in a diabetic cat with acromegaly treated with two courses of radiation therapy. AB - A 12-year-old, castrated male cat with diabetes mellitus was diagnosed with acromegaly and examined with magnetic resonance imaging (enlarged pituitary gland, 8 mm); serum hormone concentrations were measured. After the first course of radiation therapy (4 Gy, 12 fractions), insulin administration was not required from day 420 after diagnosis. Enlarged pituitary tumor (8 mm) recurred, and insulin dosage amount of the cat was increased on day 1,065. The second course of radiation therapy (6 Gy, 4 fractions) was performed on day 1,201 and insulin administration was again discontinued. However, the cat died from lymphoma on day 1,397. Postmortem examination revealed pituitary adenoma. Most tumor cells were positive for chromogranin A, synaptophysin, and growth hormone immunohistochemistry. The pancreatic islet cells revealed diffuse hyperplasia. We achieved long-term successful management of an acromegalic cat with two courses of RT. However, a protocol for a second course of RT for feline recurrent pituitary tumor should be further discussed. PMID- 30449820 TI - Anatomical variations of the arterial branches from the rat iliac arteries. AB - Animal disease models contribute to a better understanding of the pathogenic mechanisms of human and animal diseases and help develop treatments for them. Ligation of the rat iliac arteries is performed to reproduce erectile dysfunction and peripheral arterial disease. Although knowledge of the ramification of branches from the rat iliac artery is important to perform such surgery, descriptions in previous studies are insufficient. Therefore, 17 male and 18 female Wistar rats were observed to elucidate the detailed ramification patterns of branches from the iliac arteries with the latex injection method. The iliac arteries branched off the umbilical, cranial gluteal, lateral and medial circumflex femoral, external pudendal, and caudal epigastric arteries, and the common trunk of the caudal gluteal and internal pudendal arteries. The branching pattern of the umbilical, cranial and caudal gluteal, and internal pudendal arteries varied greatly and was categorized as Types 1 to 3 based on the number of branching levels along the proximodistal axis of the iliac arteries. Based on the same criteria, the ramification patterns of the lateral and medial circumflex femoral arteries were also divided into Groups 1 and 2. The external pudendal and caudal epigastric arteries originated from the external iliac artery mainly as a common trunk or less frequently as independent arteries in this order. The detailed branching patterns of the rat iliac arteries elucidated in the present study are beneficial for the refinement of surgical procedures. PMID- 30449821 TI - Evidence for the involvement of FXR signaling in ovarian granulosa cell function. AB - FXR (farnesoid X receptor) is mainly present in enterohepatic tissues and regulates cholesterol, lipid, and glucose homeostasis in coordination with target genes such as SHP and FABP6. Although FXR has been revealed to be expressed in reproductive tissues, FXR function and expression levels in the ovary remain unknown. In this study, we investigated FXR expression in mouse ovaries and its target genes in ovarian granulosa cells. In situ hybridization and immunohistochemical staining showed that FXR was mainly distributed in secondary and tertiary follicles. The agonist-induced activation of FXR in cultured granulosa cells induced the expression of SHP and FABP6, while siRNA targeting of FXR decreased CYP19a1 and HSD17b1 expression. Upon examination of the roles of SHP and FABP6 in granulosa cells, we found that SHP overexpression significantly decreased StAR, CYP11a1, and HSD3b gene expression. In addition, siRNA targeting of FABP6 decreased CYP19a1 and HSD17b1 expression, while FABP6 overexpression increased CYP19a1 expression. In conclusion, the present study demonstrates the presence of FXR signaling in the ovary and reveals that FXR signaling may have a role in function of granulosa cells. PMID- 30449822 TI - T2 Distribution in the Forearm Muscles and the T2 Threshold for Defining Activated Muscle. AB - PURPOSE: In order to detect exercised muscles by the increase in T2, we have defined a Gaussian T2 distribution and reference values (T2r and SDr) in resting state muscles, and a threshold for detecting exercised muscles. METHODS: The subjects were healthy adult volunteers (14 males and 12 females). Multiple-spin echo (MSE) MR images were obtained with 10 TE values from 10 to 100 ms using a 0.2T MRI system. T2 values for 10 forearm muscles were obtained in the resting state and after isometric wrist flexion exercise with 5%, 15%, and 25% of the maximum voluntary contraction (MVC). Z values were obtained by (T2e - T2r)/SDr, where T2e was T2 after exercise. Based on sample size calculations, three thresholds (ZT = 1.00, 2.56, and 3.07) were applied to agonist and antagonist muscles. RESULTS: A normal distribution of T2 was detected in resting muscles at 34 +/- 3 ms (mean +/- standard deviation [SD]) in 26 subjects using the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the Jarque-Bera test (P > 0.05). No gender differences were shown between the T2 or SD, and a similar result was obtained in 12 measurements on a single subject (P < 0.01). The T2r and SDr were used for reference values. The threshold ZT = 1.00 showed the highest sensitivity (0.86) even with 5% MVC, but it showed a lower specificity (0.85) than the other thresholds. ZT = 3.07 showed the highest specificity (1.0), but it showed a lower sensitivity (0.36) with the 5% MVC, compared with ZT = 2.56 (0.50). The receiver operating characteristics analysis also supported these results. CONCLUSION: We found that the T2 distribution in muscles was Gaussian, suggesting that a one-sample t-test can be applied, and that ZT = 2.56 could cover low-intensity exercise with high specificity and a low false-positive rate. PMID- 30449823 TI - Erythroblastic sarcoma in the thoracic cavity of a cow. AB - Erythroblastic sarcoma in a 10-year-old Japanese Black cow with anemia is described. Tumor masses or nodules were located mainly in the thoracic cavity, and some lymph nodes were slightly enlarged. Although neoplastic involvement of the bone marrow was detected, the cow was not leukemic. The diagnosis was made based on the localized distribution of neoplastic lesions, no increase of intravascular nucleated cell number, deeply eosinophilic cytoplasm in some tumor cells, and frequent immunoreactivity of the tumor cells for hemoglobin. The tumor cells were characterized by marked pleomorphism and atypia; such morphological deviation from their normal counterparts may be connected with functional deviation resulting in the sarcomatous growth of these erythroid cells. PMID- 30449824 TI - L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma. AB - L-type amino acid transporter 1 (LAT1) functions to transport large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. These amino acids are essential for cell growth and proliferation. Many studies have demonstrated LAT1 expression in various types of cancer, and its high expression level was associated with poor prognosis. However, the significance of LAT1 expression in thymic epithelial tumors is controversial. We conducted this retrospective study to investigate the LAT1 immunoreactivity in thymic epithelial tumors and its impact on prognosis. We analyzed 32 patients with thymoma and 14 patients with thymic carcinoma who underwent surgery at our institute. Immunohistochemical analysis was performed using formalin-fixed paraffin-embedded surgical tissues and an anti-LAT1 polyclonal antibody. We thus found that LAT1 immunoreactivity was undetectable in all of the thymoma specimens, regardless of the subtypes of thymoma. By contrast, LAT1 immunoreactivity was consistently detected in the cytosol of thymic carcinoma cells; namely, all 14 thymic carcinoma specimens demonstrated LAT1 immunoreactivity in the cytosol. Among these 14 thymic carcinoma specimens, four carcinoma specimens also showed LAT1 immunoreactivity in the cell membrane. Survival analysis indicated that the thymic carcinoma with the LAT1 membrane signal was associated with poor prognosis, compared with the specimens with the LAT1 cytosol signal. We therefore propose that LAT1 is expressed in the cytosol of thymic carcinoma cells, which could be a diagnostic marker of thymic carcinoma. Moreover, LAT1 expression in the cell membrane is a prognostic marker of thymic carcinoma. PMID- 30449825 TI - Development of the gall bladder, and caudate and quadrate lobes of the liver: A fetal morphometric study. AB - INTRODUCTION: The gall bladder (GB) is a storage reservoir that allows bile acids to be delivered in a high concentration. The quadrate (QL) and caudate lobes (CL) are functional parts of the liver. The knowledge of the gross and developmental anatomy of GB and CL and QL of liver is important for surgeons who operate in this region. The present study was conducted to examine the developmental sequence and morphometry of the GB, and CL and QL of liver. MATERIALS AND METHODS: In the present cross sectional study the parameters measured were length of GB from the neck to the lowest point on the fundus, and the length and width of QL and CL measured at the midpoint. The data was analyzed statistically and the various parameters were correlated using Pearson's correlation. RESULTS: There was a statistically significant correlation indicating that the growth of GB, QL and CL was proportional to the gestational age (GA). The variations in the morphology of the GB were also noted. In two specimens it was found that the GB was embedded partially in the substance of the liver and failed to reach the inferior border of the liver. CONCLUSION: The regression equations calculated in the study provide a tool to estimate the lengths of GB, QL and CL prenatally. PMID- 30449826 TI - In vitro evaluation of visible light-activated titanium dioxide photocatalysis for in-office dental bleaching. AB - The evaluation of the photocatalysis of visible light activated titanium dioxide employed in hydrogen peroxide (H2O2) was carried using seven H2O2 solutions (3.5 and 35%) and/or methylene blue (MB), with or without light irradiation (LI); the absorbance of MB was the bleaching indicator. Color analysis was performed on bovine teeth (n=12) using two different concentrations of H2O2, 6 and 35% associated with titanium dioxide (TiO2). Data were analyzed with one and two-way ANOVA, and significance level of p<0.05. Solutions containing MB, H2O2 at 3.5 or 35%, and TiO2, followed by LI, showed significant difference when compared with other groups. Greater MB reduction was found in 35% concentration. H2O2 35%+TiO2 gel showed no difference in comparison to control group. All groups for the color analysis assay showed DeltaE higher than 3.3. In conclusion, TiO2 and H2O2 association is a promisor alternative for reducing the clinical time of in-office dental bleaching. PMID- 30449827 TI - Toxicity of functionalized multi-walled carbon nanotubes on bone mesenchymal stem cell in rats. AB - Carbon nanotubes (CNTs) are promising biomaterials in the medical field, especially in tissue engineering of bone. However, the use of CNTs is largely confined by its unfavorable solubility and toxicity. To improve solubility and biocompatibility of CNTs, functionalization has been proven to be an effective strategy. Although various functionalized CNTs have been extensively studied, only few CNTs have the desired qualities. We compared the toxicity of several promising functionalized multi-walled carbon nanotubes (MWCNTs) on rat bone marrow derived stem cells (BMSCs). Cell experiments showed that while acid oxidation (AO)MWCNTs and Raw-MWCNTs exhibited significant toxicity on BMSCs, polyethylene glycols (PEG)-MWCNTs and hydroxyapatit (HA)-MWCNTs had favorable biocompatibility and a trivial effect on BMSCs. Possible mechanisms for the cytotoxicity on BMSCs included mitochondrisome and deoxyribonucleic acid damage, increased oxidative stress and damaging of cellular membranes. Our data indicated that PEG-MWCNTs and HA-MWCNTs may be promising materials for bio-related applications. PMID- 30449828 TI - Influence of the difference between implant body and screw materials on abutment screw loosening. AB - The purpose of this study was to investigate how differences in dental implant and screw materials affected screw loosening. Screws (pure titanium; Ti4S, titanium alloy; TiAS), blocks (Y-TZP; ZrB, pure titanium; Ti4B) and plates (Y TZP; ZrP), representing abutment screws, implant bodies and superstructures, respectably, were used. Plates were fastened to blocks by screws using a torque of 20 N*cm, and the loosening torque was measured after cyclic loading. Tests was performed on 13 specimens per group, with four groups for loading at the eccentric point (9 mm from screw center) and one group at the centric point (3 mm from screw center). In eccentric point tests, Ti4S screws led to significantly more loosening than TiAS screws (p<0.01). The block material had no effect. For ZrBTi4S, there was no difference in loosening before and after the centric point tests. More loosening occurred for eccentric point than for centric point tests (p<0.05). PMID- 30449829 TI - The repair bond strength to resin matrix in cured resin composites after water aging. AB - The repair microshear bond strengths (uSBSs) to resin matrices in 4 different cured-composites after water storage (0, 60 s, 1 week, 1 month) were evaluated. Three different adhesive application methods to the cured-composites were performed; (1) none, (2) onestep self-etch adhesive application, and (3) one-step self-etch adhesive application with a silane coupling agent. Degree of conversion (DC) of the composite discs was determined using ATR/FT-IR with a time-based spectrum analysis. Initially, the amount of unreacted resin monomers in the repaired cured-composite contributed to the bonding performance of newly-filled uncured-composite to resin matrix of the cured-composite. Adhesive application could not improve their repair uSBS. After 1-month of water-storage, the repair uSBS was dependent on material, which either reduced or did not and was not influenced by their amount of un-reacted resin monomers. When repairing aged composite resin, the appropriate adhesive application procedures were different among resin composites. PMID- 30449830 TI - Mechanical properties and radiopacity of flowable fiber-reinforced composite. AB - The aim was to evaluate the effect of different zirconia discontinuous fiber fractions on radiopacity and other selected properties of glass discontinuous fiber-reinforced flowable composite (Exp-SFRC). Exp-SFRC was prepared by mixing 30 wt% of resin-matrix and 45 wt% of particulate-fillers to 25 wt% of various weight-fractions of E-glass/zirconia discontinuous fiber-fillers (25:0, 20:5, 15:10, 10:15, 0:25 wt%). Flexural strength and fracture toughness were determined for each experimental material. Radiograph of each ExpSFRC and aluminium step wedge were taken to determine the radiopacity. Degree of conversion and light transmission were also measured. Scanning electron microscopy was used to evaluate the microstructure of the Exp-SFRC. Analysis of variance (ANOVA) revealed that fractions of E-glass/zirconia discontinuous fiber-fillers had significant effect (p<0.05) on radiopacity and other tested properties of the Exp SFRCs. Replacing low fraction of E-glass fiber with zirconia fiber-fillers can increase the radiopacity of the fiberreinforced composite without deteriorating the mechanical properties, although, degree of conversion was decreased. PMID- 30449831 TI - Dynamics of Sulfate-Reducing Bacteria Community Structure in Surface Sediment of a Seasonally Hypoxic Enclosed Bay. AB - We herein report on the dynamics of a sulfate-reducing bacteria (SRB) community structure in the surface sediment of a seasonally hypoxic enclosed bay for two consecutive years (2012 and 2013). The uppermost (0-5 mm) and subsurface (5-10 mm) layers of sediment were examined with a terminal-restriction fragment length polymorphism (T-RFLP) analysis based on the dissimilatory sulfite reductase (dsrA) gene. The SRB community significantly differed between the two sediment layers over the sampling period. This difference was mainly attributed to operational taxonomic units (OTUs) that were unique to either of the sediment layers. However, nearly 70% of total OTUs were shared between the two layers, with a few predominating. Therefore, no significant shift was observed in the SRB community structure under varying dissolved oxygen (DO) conditions in bottom water overlying the sediment surface. An additional analysis of 16S rRNA gene amplicon sequences, conducted for three uppermost sediment samples (July, August, and September in 2012), revealed that Desulfococcus, a member of SRB with high tolerance to oxygen, was the predominant Deltaproteobacteria across the uppermost sediment samples. Based on the predominance of shared OTUs across the SRB community in the sediment (0-10 mm) regardless of bottom-water DO, some SRB that are physiologically tolerant of a wide range of DO conditions may have dominated and masked changes in responsive SRB to DO concentrations. These results suggest that the SRB community structure in the enclosed bay became stable under repeated cycles of seasonal hypoxia, but may be compromised if the severity of hypoxia increases in the future. PMID- 30449832 TI - PM2.5 Particle Detection in a Microfluidic Device by Using Ionic Current Sensing. PMID- 30449833 TI - A Simplified Method Using a Single TODGA Resin Column for the Purification of Sr, Nd and Hf in Geological Materials and the Determination of their Isotopic Ratios by Multi-collector Inductively Coupled Plasma-mass Spectrometry. PMID- 30449834 TI - Quantifying redox dynamics of c-type cytochromes in a living cell suspension of dissimilatory metal-reducing bacteria. PMID- 30449835 TI - On-Site Method for Beef Detection Based on Strand Exchange Amplification. PMID- 30449837 TI - Tyrosinase-mediated peptide conjugation with chitosan-coated gold nanoparticles. PMID- 30449836 TI - Successful mesoporous silica encapsulation of optimally functional EcDOS, a heme based O2-sensing phosphodiesterase. PMID- 30449838 TI - [Randomized Phase II Trial Designs in Oncology]. AB - In recent years, a clinical trial design called randomized phase II is often applied in cancer clinical trials. Among them, some trials are planned based on clinical trial designs, which are different from conventional one. As those conventionally used, there is a Simon's selection design, randomized screening design with concurrent control, and dose-finding randomized design. However, recently, many clinical trials corresponding to more complicated purposes different from these are often planned and conducted. Inherently, it is essential that trial designs that match the characteristics of the therapies or drugs to be developed are required, especially in phase II trial. Unlike phase I or phase III trials, which often remain in conservative designs, it is also natural that different phase II trials have different objectives. There should be various design options according to each trial objective. Considering the current applications, the randomized phase II design is a collection of heterogeneous designs. Researchers are required to refine properly in choosing an appropriate design for their clinical trials. Furthermore, depending on the needs of researchers, it is also necessary for biostatistician to develop a new design according to the present and coming era of medicine, for example, the era of molecular targeted therapeutic drugs and immune-oncology. PMID- 30449840 TI - [Diagnosis and Treatment of MSI-H Cancer in the Urological Malignancy]. AB - In May 2017, the Food and DrugAdministration granted accelerated approval to pembrolizumab for microsatellite instability- high(MSI-H)or deficient mismatch repair(dMMR)solid tumors irrespective to tumor origins. Lynch syndrome is one of the diseases causingMSI -H tumor, however some sporadic cancers have MSI-H. We focus on the frequency of Lynch syndrome and sporadic MSI-H tumor in urological cancer. PMID- 30449839 TI - [MSI Status in Colorectal Cancer]. AB - In recent years, immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration(FDA)for adult patients with microsatellite instability-high(MSI-high)or mismatch repair deficient(dMMR)solid tumors. In addition, FDA approves nivolumabfor MSI-high or dMMR colorectal cancer. MSI status has an important role in colorectal cancer management. PMID- 30449842 TI - [Pathological Diagnosis of MSI-H Tumors]. AB - MSI-H tumors are drove with molecular mechanism different from ordinary carcinoma, and thus the morphological features could be distinct. Particularly, MSI-H colorectal carcinoma has peculiar morphological characteristics, which are listed as one of the criteria to recommend MSI-testing. In this article, morphological characteristics and immunohistological detection of MSI-H colorectal cancer are reviewed, with contrasting to those of gynecological tumors. PMID- 30449841 TI - [Diagnosis and Treatment of MSI-H Cancer in Gynecological Cancer]. AB - Among gynecological cancers, microsatellite instability(MSI)is most commonly found in endometrial carcinoma. When an allelic variation is observed in multiple microsatellite regions, it is called MSI-high(MSI-H). Hereditary MSI-H endometrial cancer develops through a germline mutation ofthe mismatch repair(MMR)gene, resulting in Lynch syndrome, and increased risk ofsporadic MSI-H endometrial cancer is caused by somatic lineage mutations or methylation abnormalities. Clinical characteristics ofendometrial cancer involved in Lynch syndrome include symptoms such as onset at a younger age, a lower corpus segment at the site, earlier stage cancer, and varied histology, when compared with those ofthe sporadic cancer. Alternatively, somatic mutations ofthe MMR gene are highly heterogeneous; however, a meta-analysis showed no difference in prognosis between with and without MSI-H. MSI-H is considered to be a biomarker, showing the therapeutic effects of an immune checkpoint inhibitor. A recent randomized controlled trial(RCT)demonstrated that an immune checkpoint inhibitor was effective against colorectal cancer with MSI-H. An additional RCT proved its effectiveness for MSI-H solid cancers, regardless oforgan type, including endometrial cancer. As the number ofcases ofendometrial cancer is increasing in Japan, MSI-H may hold utility as a biomarker for new molecular-target drugs, including immune checkpoint inhibitors. Ongoing surveillance ofcarcinomas in patients and family members is important because endometrial carcinoma associated with Lynch syndrome is a hereditary tumor. However, there is currently no established surveillance method for endometrial cancer. To improve the overall prognosis ofpatients with Lynch syndrome, genetic counseling and cross-division management are necessary, and also establishing the system is urgently required. PMID- 30449844 TI - [I. Chemotherapy for Small Bowel Adenocarcinoma]. PMID- 30449843 TI - [Lower G. I./Colon and Rectum Cancer Lower G. I. Tumor - Treatment for Rare Fraction in Lower G. I. Tumor]. PMID- 30449845 TI - [II. Chemotherapy for Appendiceal Epithelial Neoplasms]. PMID- 30449846 TI - [III. Treatment Strategy for Squamous Cell Carcinoma of the Anus]. PMID- 30449847 TI - [IV. dMMR or MSI-H Colorectal Cancer]. PMID- 30449848 TI - [Pemetrexed for Treatment of Nonsquamous Non-Small-Cell Lung Cancer]. AB - Pemetrexed(Alimta(r))is a multi-targeted antifolate that shows antitumor effects by inhibiting enzymes in the folate metabolic pathway essential for cell replication. Pemetrexed is a standard treatment for Japanese patients with nonsquamous, non-small-cell lung cancer. In this review, we summarize the evidence of clinical studies for the efficacy and safety of pemetrexed in the treatment of nonsquamous non-small-cell lung cancer as first-line chemotherapy and continuation maintenance therapy. In addition, we describe future prospects for pemetrexed in combination with a recent approved PD-1 path- way inhibitor. PMID- 30449850 TI - [Survey of Cholinergic Symptoms in Patients with Colorectal Cancer Who Were Receiving Irinotecan Hydrochloride Combination Chemotherapy]. AB - We investigated the incidence of cholinergic symptoms related to irinotecan hydrochloride(CPT-11)and examined their association with clinical factors. The subjects were 61 patients with colorectal cancer for whom combination chemotherapy with CPT-11 was indicated between May 2008 and December 2014. The incidence of CPT-11-related cholinergic symptoms was investigated. Cholinergic symptoms were observed in 46 patients(75.4%), of whom 29(47.5%)showed Grade 2 or higher symptoms as follows: nasal discharge(47.5%), lacrimation(39.3%), nausea/vomiting(29.5%), and watery stool (26.2%). The results of the multivariate analysis showed that high-dose CPT-11 administration(150mg/m2)was a significant risk factor for the appearance of cholinergic symptoms and that PS 0 was a significant factor for reducing the onset of symptoms. It is important to adequately manage cholinergic symptoms, considering these clinical factors. PMID- 30449849 TI - [CapeOX Therapy as a Salvage Treatment for Advanced Gastric Cancer Refractory to S-1, Cisplatin, Irinotecan, and Taxanes]. AB - AIM: This study aimed to retrospectively evaluate the efficacy and safety of capecitabine plus oxaliplatin(CapeOX)for heavily pretreated advanced gastric cancer(AGC)refractory to S-1, cisplatin, irinotecan, and taxanes. METHODS: Twelve patients with AGC refractory to S-1, cisplatin, irinotecan, and taxanes were enrolled in this study.Treatment comprised capecitabine(1,000mg/m / 2 twice a day on days 1-14)and oxaliplatin(130mg/m2 on day 1).Cycles were repeated at 3- week intervals. RESULTS: The overall response rate was 16.7%, and the disease control rate at 6 weeks was 75.0%. The progression free survival was 3.1 months, and the overall survival was 8.3 months after initiation of CapeOX therapy. The most common hematological toxicity was grade 3 neutropenia(50%).Peripheral neuropathy of Grade 1 or 2 was found in 50%of cases, but no Grade 3 or 4 neuropathy was found. CONCLUSIONS: CapeOX showed some activities as salvage therapy for heavily pretreated AGC patients.We suggest that CapeOX therapy should be considered a treatment option for pretreated AGC with good performance status. PMID- 30449851 TI - [The Incidence and Management of Hypersensitivity and Infusion Reactions in an Outpatient Chemotherapy Center]. AB - Hypersensitivity reactions(HSRs)are adverse events that are potentially caused by all anticancer agents. HSRs are unpredictable and can occur at any time, and prompt intervention is needed when symptoms occur. The types of symptoms and their degrees vary with the anticancer agent used and the number of chemotherapy cycles. Here, we evaluated the degree of HSRs and their frequencies in the outpatient chemotherapy center of Gunma University Hospital. Among 55,046 patients, 141 (0.26%)cases of HSRs and 70(0.13%)cases of infusion reactions were identified. Oxaliplatin and docetaxel conferred higher incidences of HRSs, whereas infliximab and rituximab conferred higher incidences of infusion reactions. The most common symptoms were skin reactions. HSRs to oxaliplatin were observed after a median of 7 cycles of chemotherapy, and the number of the patients developing HSRs was the highest during the second cycle of chemotherapy. The incidences of HSRs and the profiles of the anticancer drugs exhibiting higher frequencies of HSRs were similar to those in previous reports. The present study provides valuable information about appropriate management for HSRs depending on the anticancer agents used. PMID- 30449852 TI - [Physicians' Directions about Artificial Hydration and Nutrition at End-of-Life]. AB - PURPOSE: To conduct a questionnaire survey to elicit physicians' directions about artificialhydration and nutrition at end-oflife. METHODS: A questionnaire was sent to 2,773 randomly selected Japanese physicians who were registrants of Rakuten Research Inc.(Tokyo, Japan). Of the respondents, 500 returned the questionnaire, and their reposes were analyzed. The Fisher's exact test was used to compare the respective responses. RESULTS: Of the 500 physicians, 22.4%(112)chose to discontinue artificialhydration and nutrition for those who are at terminalstage and could no longer communicate. On the other hand, 20.8%(104/500)of the physicians chose to continue artificialhydration and nutrition for those who were confined to bed and had the tendency to self-remove drip infusion or other tubes. Significantly more physicians who were working in hospitals than in private clinics chose to continue artificial hydration and nutrition(27% vs 3%; p<0.00001). CONCLUSION: Our findings revealed that 20.8% of physicians did not know about the latest evidence of end-of-life care to uphold patient dignity until the end-of-life. As our results might be different from the practice in other facilities located abroad, we must adopt prudent guidelines for palliative and end-of-life care and enlighten physicians and medical students regarding the current guidelines. PMID- 30449853 TI - [A Super-Aged Patient with Advanced ALK-Positive NSCLC and Malignant Pericardial Effusion Causing Cardiac Tamponade]. AB - Here we report the case of an 88-year-old female with serious respiratory discomfort who exhibited significant heart enlargement and left pleural effusion in her chest X-ray. She developed cardiac tamponade with massive pericardial effusion, and the cytological analysis and diagnostic imaging revealed adenocarcinoma of an unknown primary site. Although supportive care was offered, due to her super-age and malignant pericardial effusion presenting cardiac tamponade, she and her family requested a detailed examination and active treatment. She was enrolled into our medical oncology department, and we immediately performed a cell block cytological examination procedure and drained the pleural effusion. The immunohistochemical and FISH analyses revealed anaplastic lymphoma kinase(ALK)-rearranged non-small cell lung cancer. An ALK tyrosine kinase inhibitor, alectinib, was administered and resulted in a prompt and effective improvement in clinical outcome. This case indicates that we should attempt to achieve an accurate diagnosis, even when patients are super-aged and exhibit serious progress disease conditions. The pleural effusion cell block analysis may be highly useful for the prompt and precise diagnosis of malignancies. PMID- 30449854 TI - [A Case in Which Toxic Epidermal Necrosis Developed during Treatment with the Immune Checkpoint Inhibitor Pembrolizumab for Recurrent Patients Following Lung Cancer Surgery]. AB - The patient was a 66-year-old male. Following surgery for pulmonary adenocarcinoma in the upper right lobe and adjuvant chemotherapy, the patient relapsed. We carried out treatment using the immune checkpoint inhibitor pembrolizumab (KEYTRUDA(r))for high expression of PD-L1. Following the first administration, severe drug eruption occurred and despite temporary improvement seen by intravenous infusion of steroids in combination with oral administration and external use thereof, it relapsed in the early stages and toxic epidermal necrosis developed. Skin problems were improved by multidisciplinary treatments such as gammaglobulin therapy, systemic steroid administration, and broad spectrum antibiotics. There were no reports oftoxic epidermal necrosis occurring during pembrolizumab administration for lung cancer. This case went through a unique course in which the disease relapsed into a more severe condition at an early stage following temporary remission. PMID- 30449855 TI - [Significance of Endocrine Therapy for Unresected Primary Breast Cancer]. AB - At present, surgery is still the recommended principal treatment for breast cancer. However, there are conditions in which surgery is not suitable, for example in elderly or high-risk patients and those who do not wish to undergo the procedure. This study presents a case series of 8 patients with unresected breast cancer who were administered hormonal therapy as an optional treatment. Patients included in the study were diagnosed with Stage I-III breast cancer from 2012 to 2015 at our institution. The patients were administered hormonal therapy for an average duration of 20.1 months. Complete responses were seen in 4 patients, while 1 and 3 patients were noted to have a partial response and stable disease, respectively. No disease progression was seen in any patients during the study period. Endocrine therapy may be an effective and safe option for patients with unresected breast cancer. PMID- 30449856 TI - [A Case of Sarcoidosis Associated with Esophageal Cancer]. AB - A 67-year-old man was diagnosed with esophageal cancer. Computed tomography(CT)revealed multiple sites of bilateral mediastinal lymph node swelling. Serum levels of soluble interleukin-2 receptor(sIL-2R)were elevated; however, serum levels of angiotensin-converting enzyme(ACE)were normal. Thus, we could not confirm a diagnosis of sarcoidosis. Esophagectomy with neck lymph node dissection was performed. The resected specimen, comprising the mediastinal lymph nodes, showed noncaseating epithelioid cell granuloma; this supported the diagnosis of sarcoidosis. Cases of sarcoidosis associated with esophageal cancer are rare. It is difficult to distinguish between metastasis and sarcoid-like reactions from swollen lymph nodes using preoperative CT or positron emission tomography(PET). It is possible to differentiate lymph node metastasis from its sarcoid reaction it the patient received. PMID- 30449857 TI - [The Case of a Patient with Gastric Cancer Who Showed No Neutropenia Only When Using the Generic S-1 Adjuvant Chemotherapy Formulation]. AB - We report the case of a 72-year-old female who underwent laparoscopic total gastrectomy for gastric cancer. The pathological diagnosis was pT3, N1, M0, pStage II B. She received adjuvant chemotherapy with the TS-1(r)combination OD tablet, beginning 48 days after gastrectomy. The first course was stopped at day 7 because of neutropenia. The dose was decreased, a second course was started, and the patient completed her second course without neutropenia. After completion of the second course, we discovered that she had taken generic drugs(NKS 1(r)combination OD tablet)during the second course. She was enrolled in a clinical trial in which the administration of generic drugs was not permitted, as per the protocol. Beginning with the third course, we once again treated her with TS-1, and we observed a return of neutropenia in every subsequent course. We decreased the dose of TS-1 and changed the administration schedule each time. She exhibited no neutropenia only when using the generic S-1 formulation. It is possible that the anti-tumor effect of the generic S-1 formulation, and its associated adverse events, are not identical to the innovator formulation. PMID- 30449858 TI - [A Case of Cecal Cancer with Liver and Lung Metastases That Maintained Long Stable Disease by TFTD and Bevacizumab Chemotherapy]. AB - The patient was a 69-year-old female diagnosed with cecum cancer, pMP, pN1, sH1, sP0, cM0, fStage IV. A laparoscopic cecal resection with D3 dissection was performed against the primary cecal cancer in January 2015. The histological diagnosis was moderately differentiated adenocarcinoma>mucinous adenocarcinoma, ly1, v0, RAS wild type(not known to start chemotherapy for primary treatment). Liver metastasis is very likely to invade the inferior vena cava, so the liver metastasis was judged unresectable, and mFOLFOX6 and bevacizumab(Bmab)chemotherapy was performed. After 4 courses of chemotherapy, the patient exhibited progressive disease(PD)and was transitioned to a secondary treatment with FOLFIRI plus panitumumab(Pmab)therapy. Lung metastases was observed(PD)upon computed tomography after 16 courses. Therefore, salvage line chemotherapy with TFTD and Bmab was performed. Long stable disease(SD)was obtained by the salvage line chemotherapy with TFTD and Bmab. We suspect that the effects of TFID increased in combination with Bmab. Moreover, the TFTD and Bmab chemotherapy was performed relatively safely. PMID- 30449859 TI - [A Case of Colon Cancer with DPD Deficiency That Showed Severe Myelosuppression by CapeOX Adjuvant Chemotherapy after Colon Resection]. AB - A 57-year-old female patient received ileocecal colon resection because of colon cancer. Pathological findings showed pSSN2M0(pStage III b). After surgery, CapeOX was administered as an adjuvant chemotherapy. On day 13 of CapeOX treatment, severe oral mucositis and Grade 4 myelosuppression appeared, and the CapeOX treatment was immediately stopped. However, these adverse effects continued for 19 days, and she gradually recovered. The severe myelosuppression was caused bydeficiencyof DPD, which is a keyenzy me that metabolizes 5-FU. While DPD deficiencyis veryrare, we need to consider that 5-FU causes severe adverse events in patients with DPD deficiency. PMID- 30449860 TI - [A Case of Recurrent Hyperammonemic Encephalopathy during Adjuvant Chemotherapy(Modified FOLFOX6)for Colorectal Cancer]. AB - A 60-year-old woman was administered mFOLFOX6 therapy as postoperative adjuvant chemotherapy for fStage III a ascending colon cancer. The patient developed a disorder of consciousness(Japan Coma Scale[JCS]III-200)immediately after the completion of the therapy. Blood ammonia levels were high at 319 mg/dL, and a diagnosis of disturbance of consciousness due to hyperammonemia was made. The patient's state of consciousness improved on the following day as blood ammonia levels decreased due to treatment with branched chain amino acid(BCAA)formulation and oxygen. Two months later, mFOLFOX6 therapy was again administered with strengthening measures for side effects to nausea and vomiting and reducing 5-FU, but the patient again developed a disorder of consciousness(JCS III-200). The 5 FU administration rate was considered as a potential cause of hyperammonemia. Hyperammonemia induced by 5-FU is relatively rare, with a reported incidence of 5 9%; however, caution is required with high dosage regimens of 5-FU that are currently recommended for colorectal cancer therapy because hyperammonemia is an important side effect. PMID- 30449861 TI - [A Case of a Patient with Rectum Cancer with Multiple Metastases, Who Was Able to Undergo Conversion Therapy Using Alternating mFOLFOX6 and FOLFIRI Regimens in Combination with Alternating Cetuximab and Bevacizumab]. AB - In order to reduce the frequency and the severity of oxaliplatin-related sensory neuropathy and preserve antitumor efficacy, we performed alternating 4 mFOLFOX6 and 4 FOLFIRI cycles, in combination with bevacizumab, in patients with metastatic colorectal cancer. The response rate of alternating mFOLFOX6 and FOLFIRI regimens(FIREFOX)plus bevacizumab was 100%. However, during neoadjuvant chemotherapy for colon cancer, we cannot use bevacizumab due to the concern of adverse events, such as bleeding and perforation. Therefore, we used cetuximab in 8 courses of FIREFOX. As a result, the volumes of the rectum cancers and liver metastases decreased. Thereafter, we used bevacizumab in another 8 courses of FIREFOX. A 77- year-old woman suffered from II type rectum cancer, which was localized 7 cm from the anal verge, with multiple liver metastases. We performed 8 courses of FIREFOX plus cetuximab. After observing a decrease in tumor burden, we performed another 8 courses FIREFOX plus bevacizumab. As a result, CEA and CA19-9 decreased to the normal range, and the size of the rectum cancer and liver metastases decreased. She underwent laparoscopic lower anterior and liver resections in the highvolume center. She presently remains alive with no sighs of recurrence, 18 months after resection. PMID- 30449862 TI - [Seven Cases of Metastatic Colorectal Cancer Treated with Dose-Reduced and Duration-Reduced Regorafenib Treatment]. AB - Regorafenib is widely used for patients with metastatic colorectal cancer, following disease progression with standard therapies.However, regorafenib has severe toxicities; therefore, careful monitoring and treatment are necessary.Several studies have investigated the efficacy of initial dose reductions.We started regorafenib doses from 80 mg, with a duration of 1 week on and 1 week off, after which we gradually increased the dosage and duration.From September 2015 to March 2017, we treated 7 consecutive patients who received regorafenib following standard chemotherapy for metastatic colorectal cancer.The average age was 73 years and average BMI was 23.3.The average total dose was 15,960(2,240-28,000)mg, and the average treatment duration was 243(50 379)days.The mean survival from the start of regorafenib was 399(median 407, 262 622)days.Adverse events of Grade 3 or higher were observed in 1 patient(14%). PMID- 30449863 TI - [Clinical Experience of Aortic Valve Replacement Using the New Stentless Bioprosthesis]. AB - BACKGROUND: The SOLO SMART valve is a bovine pericardial stentless bioprosthesis which shows superior hemodynamic performance compared to the stented valves. It is designed for supraannular and subcoronary implantation. We report our surgical experience and results in patients undergoing aortic valve replacement(AVR) with this new bioprosthesis. METHODS: Since June 2016, 19 patients with various types of aortic valve disease (mean age:72+/-7 years, 58% males) have undergone AVR with a SOLO SMART stentless bioprosthesis. Fourteen patients(74%)showed aortic stenosis( AS) and 9 patients(47%)had concomitant procedures;coronary bypass grafting (n=4), mitral valve surgery (n=3), total arch replacement (n=1), and pulmonary venous isolation( n=1). There was 1 patient with active infective valve endocarditis( IE) complicated with annular abscess and 1 patient was a redo AVR case. Surgical results of these patients were evaluated retrospectively. The hemodynamic performance was investigated with transthoracic echocardiography in pre and postoperative period. RESULTS: There was no operative death and 1 hospital death (postoperative subdural hematoma;Heyde syndrome). One patient showed a mild trans-prosthetic valve leak. No patient required reoperation. Although postoperative transient thrombocytopenia was noted, it had cured at the time of discharge. At the last echocardiographic evaluation, the peak and mean gradients in the patients undergoing AVR for AS were 17+/-7 and 9+/-5 mmHg, respectively. No prosthesis-patient mismatch (PPM) occurred in any patient. CONCLUSIONS: AVR using a SOLO SMART stentless bioprosthesis was performed with acceptable morbidity and mortality. The SOLO SMART stentless bioprosthesis showed excellent hemodynamic performance and early results. Because of favorable effective orifice area, the valve is attractive for patients at risk for PPM. Furthermore, it is expected to contribute to more complex AVR with concomitant mitral valve surgery, active IE or redo situation. PMID- 30449864 TI - [Surgical Experience of Total Arch Replacement Using Frozen Elephant Trunk, for Type B Acute Aortic Dissection]. AB - Recently, advanced technique and device of thoracic endovascular aortic repair (TEVAR) enabled surgical intervention for type B acute aortic dissection (BAD). However, BAD have often serious complications;cerebral infarction, spinal cord infarction, multi-organ ischemia or necrosis, and retrograde type A acute aortic dissection. TEVAR is performed for complicated BAD for the aim of life saving in such a failure case of conservative treatment. Here we reported our surgical experience of total arch replacement using frozen elephant trunk (FET) by median sternotomy, for BAD with failed conservative treatment. There are 3 advantages;brain protection using selective cerebral perfusion, main entry closure using FET, and prevention of retrograde type A acute aortic dissection following prosthetic graft replacement. We examined how to select a FET product size and described operative procedures. PMID- 30449865 TI - [Clinical Assessment of Spontaneous Hemopneumothorax]. AB - We experienced 25 cases of spontaneous hemopneumothorax, in which 9 were defined as occult cases on chest X-ray at the time of visit. All 9 cases visited our hospital within 12 hours after the onset. Of these, 5 were done chest computed tomography (CT) and 3 could be diagnosed as hemopneumothorax. Emergency surgery were necessary in 4 of 9. Chest CT and careful observation is thought to be essential in case of suspiciously combined hemothorax in pneumothorax cases. PMID- 30449866 TI - [Surgical Management of a Severely Calcified Ascending Aorta Using Intra-Aortic Balloon Occlusion]. AB - A severely calcified ascending aorta increases the risk of perioperative cerebral damage in cardiac surgery. Conventional aortic valve replacement using an external aortic cross clamp may be dangerous in patients with this morbidity. We used an intra-aortic balloon occlusion catheter(IABOC)to minimize risks of aortic valve replacement(AVR) in an 81-year-old man with severe aortic stenosis combined with a severely calcified aorta. IABOC was introduced to the ascending aorta via the right femoral artery by esophageal echocardiography. The precise site of the inflated balloon was confirmed by the pressure of the right radial artery and was secured by 2 tourniquets around the ascending aorta. The postoperative course was uneventful. Our technique can contribute to prevention of embolic complications in some patients with a severely calcified ascending aorta. PMID- 30449867 TI - [Successful Treatment with Aortic Stent Graft and Transcatheter Embolization for Bronchial Artery Aneurysm]. AB - We report a case of bronchial artery aneurysm (BAA) successfully treated with a combination of transcatheter embolization and stent graft. A 50-year-old woman was referred to our hospital for further examination of a hemispherical bulging lesion on the middle esophagus detected by gastroscopy. Computed tomography (CT) revealed BAA with a 15 mm-diameter arising from the descending aorta on the left side of the esophagus. We performed transcatheter embolization combined with a stent graft because of a short neck. Postoperative course was uneventful. Follow up CT showed complete isolation of the blood flow into the BAA. BAA is rare and often found incidentally by diagnostic imaging as shown in our case. Prompt treatment with complete isolation of blood inflow is required because the rupture of BAA is life-threatening. PMID- 30449868 TI - [Surgical Treatment of Giant Coronary Artery Aneurysm Presented as Acute Coronary Syndrome]. AB - Coronary artery aneurysm is rare disease, usually asymptomatic and is often found by chance by echocardiography, computed tomography(CT) and coronary angiography. However, its rupture or thrombotic obstruction to the periphery of the coronary artery leads to cardiac tamponade, angina pectoris, or myocardial infarction. We describe 2 cases of giant coronary artery aneurysm presented as acute coronary syndrome. Surgical resection of the aneurysm and coronary artery bypass grafting were successfully carried out under cardiopulmonary bypass. Postoperative courses of both cases were uneventful, and the patients were free of symptoms. PMID- 30449869 TI - [Primary Lung Cancer Initially Suspected of Pulmonary Extranodal Marginal Zone Lymphoma of Mucosa Associated Lymphoid Tissue(MALT)]. AB - Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is associated with pre-existing infections or autoimmune disorders. We report a case of lung cancer initially suspected of MALT lymphoma. The patient was a 73-year-old woman. Complete screening examinations identified a tumor in the right middle lobe. Transbronchial lung biopsy revealed the infiltration of CD20+/CD79a+ lymphocytes invading the structure of the alveolus. MALT lymphoma was suspected, and the middle lobe was resected. The tumor was primarily invasive mucinous carcinoma, and lymphocytic infiltration was observed around the tumor. The monoclonal expansion of B cells and genetic and chromosomal abnormalities which are criteria for the diagnosis of MALT lymphoma were not demonstrated and the lesion was diagnosed as reactive lymphoid infiltrates. Marked lymphocytic infiltration regardless of neoplastic or reactive may suggest the presence of latent lesions. PMID- 30449870 TI - [Successful Treatment of a Patient with Idiopathic Subglottic Stenosis]. AB - Idiopathic subglottic stenosis (ISS) is defined as the narrowing of the upper airway without any known cause. A 40-year-old female was referred to our hospital with the complaint of exacerbation of dyspnea causing difficulty in going out. Chest computed tomography (CT) scan and bronchoscopy revealed subglottic tracheal stenosis with a luminal diameter of 5 mm at the narrowest part. Tracheal mucosa of the stenotic lesion was smooth, and the patient had no previous medical history. Subglottic tracheal resection of the stenotic lesion and reconstruction were performed. The postoperative course was good, and the symptom of dyspnea improved significantly. Recently, some reports have suggested conservative treatments such as laser and balloon dilation for ISS, but the recurrence rate after these treatments is still high. Surgery is recommended rather than conservative treatments for patients with less severe inflammation of tracheal mucosa and other comorbidities like present case. PMID- 30449871 TI - [Infected Thoracic Aortic Aneurysm Secondary to the Purulent Pericarditis;Report of a Case]. AB - A 69-year-old man was hospitalized urgently to the department of cardiology, with the progressive general malaise. On admission, his blood pressure was 80/42 mmHg, his white cell count 13,700/ul, and C-reactive protein 25.55 mg/dl suggesting existence of aggressive infection with impaired circulation. Massive pericardial effusion was detected in echocardiography. Pericardial drainage was undergone promptly. There was drainage of 700 ml and the property was purulent. Pneumococcus was detected by the culture test of the pericardial fluid. Antibiotic administration was started by a diagnosis of the purulent pericarditis. His general condition was improved. However, a rapidly expanding saccular aneurysm was found in a descending thoracic aorta by computed tomography( CT). As an infected thoracic aortic aneurysm secondary to the purulent pericarditis, we performed thoracic endovascular aneurysm repair (TEVAR). The intravenous administration of antibiotics was continued for 2 weeks after TEVAR, which was followed by oral antibiotic administration for 1 year. The aneurysm completely disappeared by CT, 10 months after TEVAR. In case with an infected thoracic aortic aneurysm, TEVAR can be a 1st choice of treatment, depending on a causative organism and the morphology of the aneurysm. PMID- 30449872 TI - [Aortic Root Pseudoaneurysm due to Avulsion of Aortic Valve Commissure Following to Infective Endocarditis;Report of a case]. AB - A 40-year-old man presented to our hospital with fever and slight palpitation. The echocardiogram revealed bicuspid aortic valve, massive aortic regurgitation, and aneurysm of Valsalva sinus. Operative findings showed an aortic root pseudoaneurysm originating just below the avulsion of the right to left commissure. The orifice was closed with a part of a woven vascular graft, and the aortic valve was replaced with a mechanical valve. There was no sign of marked inflammation, although pathophysiologic findings indicated infective endocarditis. His postoperative course was uneventful. PMID- 30449873 TI - [Valve-sparing Aortic Root Replacement in Patient with Dissecting Ascending Aortic Aneurysm Complicated with Hemorrhagic Moyamoya Disease;Report of a Case]. AB - A 62-year-old female with Moyamoya disease (MMD) had cardiomegaly pointed out by chest X-ray and was admitted to our hospital. Chest computed tomography (CT) scan and echocardiography revealed a large dissecting ascending aortic aneurysm 78 mm in diameter combined with severe aortic regurgitation and mild mitral regurgitation. She had a history of intracranial hemorrhage related with MMD twice. Considering her relatively young age and risk of intracranial hemorrhage, valve-sparing aortic root replacement was planned to avoid anticoagulant therapy. Operation was performed keeping intra-operative blood pressure, perfusion pressure, Paco2 and activating clotting time in appropriate ranges. The postoperative course was uneventful without cerebral complication. No clinical symptom related with MMD was observed in 4 years after the operation. PMID- 30449874 TI - [Surgery for Left Main Coronary Artery Aneurysm with Severe Triple Vessel Disease;Report of a Case]. AB - Coronary artery aneurysm is a rare disease and its surgical indication is still controversial. We present a 63-year-old male having left main coronary artery aneurysm with 6 mm in diameter and symptomatic severe triple vessel disease. It was saccular and expanding into the myocardium. The patient successfully underwent off-pump quadruple coronary artery bypass and suture ligation of the aneurysmal neck. We believe that this technique is effective and less invasive to manage small or medium-sized coronary artery aneurysm in case aneurysmal shape, size, and location should be fitting for it. PMID- 30449875 TI - [Angina Pectoris due to Anomalous Aortic Origin of the Right Coronary Artery;Report of a Case]. AB - A 45-year-old woman was admitted to our hospital because of chest pain on exertion. She was diagnosed to have an anomalous aortic origin of the right coronary artery(RCA) arising from the left sinus of Valsalva, passing between the aorta and the main pulmonary artery. Exercise treadmill test demonstrated significant depression of ST segments in leads II, III and aVF.Because medical treatment was ineffective, reimplantation of the RCA was performed. Dysfunction of the reimplanted RCA occurred, however 3 hours after surgery, and emergency coronary artery bypass grafting was performed using a saphenous vein graft to the RCA. After the 2nd operation, postoperative course was uneventful and multidetector row computed tomographic angiography revealed the patent vein graft and narrowing of the relocated site of RCA. PMID- 30449877 TI - [ST Segment Elevation on Electrocardiogram (ECG) during Pleural Lavage with Distilled Water;Report of a Case]. AB - Pleural lavage with distilled water is often employed in lung resection to eliminate malignant cells. Here we report a case of transient ST segment elevation on electrocardiogram (ECG) during pleural lavage with distilled water. A 73-year-old female was referred to our hospital because of an abnormal shadow on a chest roentogenogram. Chest computed tomography scan revealed a mass in left S4+5 segment of left upper lobe. It was proved to be adenocarcinoma of the lung by transbronchial lung biopsy and she underwent left upper lobectomy. During pleural lavage with distilled water, ST segment was elevated on ECG. In this case, it was because that the pericardium was excised and the myocardium was exposed to distilled water during pleural lavage. PMID- 30449876 TI - [Aorta-left Main Trunk Interposition for Adult Anomalous Origin of the Left Coronary Artery from the Pulmonary Artery Using a Prosthetic Graft;Report of a Case]. AB - A 70-year-old woman with back pain was diagnosed with adult anomalous origin of the left coronary artery from the pulmonary artery [Bland-White-Garland (BWG) syndrome]. Preoperative transthoracic echocardiography showed diffuse hypokinesia of the left ventricle and mild mitral valve regurgitation. Coronary angiography revealed dilatation of both coronary arteries, but no aneurysms. The left coronary ostium was removed as buttons of the pulmonary arterial wall, and a prosthetic graft (8 mm ePTFE graft) was interposed between the ascending aorta and coronary button. The pulmonary arterial wall was repaired with a bovine pericardium. Postoperative angiography showed good flow of the graft. The antegrade flow provided by this simple technique will allow feasible percutaneous coronary intervention in the future. PMID- 30449878 TI - [Late-onset Chylothorax after Right Upper Lobectomy;Report of a Case]. AB - Chylothorax after pulmonary resection is diagnosed usually within a few days after surgery, hence late-onset chylothorax is relatively rare complication. A 79 year-old woman underwent right upper lobectomy and mediastinal dissection for lung cancer. A chest tube was removed on postoperative day (POD)3, and she was discharged on POD 8. Fifty days after an operation, the patient developed a dyspnea on effort, and chest radiography revealed a right-sided pleural effusion, which we diagnosed as chylothorax. Because the treatments of a fat-free diet and subcutaneous octreotide acetate administration were ineffective, thoracic duct ligation was finally performed. The post-reoperative course was uneventful. PMID- 30449879 TI - [Pulmonary Nontuberculous Mycobacteriosis Appeared at the Surgical Margin of the Lung Cancer Surgery;Report of a Case]. AB - A 70-year-old woman had undergone right S8+9 segmentectomy for stage I A lung cancer. Surgical staplers were used for an intersegmental line. Two years after surgery, routine chest computed tomography(CT) showed a 40-mm mass around the staple line in the right lower lobe, and positron emission tomography (PET) was positive. The mass was suspected to be local recurrence of lung cancer, and she was done additional surgery for resection of the remaining right lower lobe. The pathologic diagnosis was lung nontuberculous mycobacteriosis. It was suggested that nontuberculous mycobacteriosis developed at the atelectasis around the staple line. In addition to local recurrence, the possibility of nontuberculous mycobacteriosis should be considered in cases of pulmonary nodules appearing at the staple line after pulmonary resection. PMID- 30449880 TI - Assessment of the Dental Age of Children in the Polish Population with Comparison of the Demirjian and the Willems Methods. AB - BACKGROUND Dental age is less affected than the bone age by nutritional and hormonal factors. The assessment of dental age in children is of value in clinical and forensic practice. The aims of this study were to compare the Demirjian method and the Willems method in the assessment of dental age in children in Poland and to consider the need to standardize dental age assessment. MATERIAL AND METHODS Polish children of Caucasian ethnicity (n=1,002) who were treated at a single orthodontic center between 1994-2016 included girls (n-540) and boys (n=462) aged between 4-17 years, and 1,002 panoramic radiographs were reviewed. Dental age was assessed using the Demirjian method and the Willems method, the findings of the two methods were compared with the chronological age of the study participants. RESULTS Following statistical analysis, both the Demirjian method and the Willems method overestimated the dental age of the younger study participants, and underestimated the dental age of the older study participants. Both the Demirjian method and the Willems method had similar accuracy in estimating the chronological and dental age in the Polish population. CONCLUSIONS In the assessment of dental age in Polish children from panoramic radiographs, both the Demirjian method and the Willems method were accurate and should still be used as a method of choice. However, it seems reasonable to create international standards for the assessment of dentition maturity for this population to obtain a more acceptable range of error values between the dental age and chronological age. PMID- 30449881 TI - Sleep Quality, Depression, and Quality of Life After Bilateral Anodal Transcranial Direct Current Stimulation in Patients with Parkinson's Disease. AB - BACKGROUND Sleep dysfunctions impose a large burden on quality of life for patients with Parkinson's disease (PD). Several studies on PD reported potential therapeutic effects of transcranial direct current stimulation (tDCS) on motor and non-motor functions, but not related to sleep quality. Therefore, the present study examined sleep quality, depression perception, and quality of life changes after bilateral anodal tDCS in patients with PD. MATERIAL AND METHODS Twenty-one patients (n=21) with PD underwent 10 sessions (20 min each, 5 per week) of bilateral anodal tDCS stimulation applied simultaneously over the left and right prefrontal and motor areas. The Pittsburgh Sleep Quality Index (PSQI) total score and sub-scores, Geriatric Depression Scale (GDS), and Health-related quality of life questionnaire (SF-36) were measured pre/post bilateral tDCS anodal stimulation. RESULTS PSQI total score (P=0.045), sleep latency sub-score (P=0.02), and GDS total score (P=0.016) significantly decreased, and physical and mental components scores of SF-36 (P=0.018 and P=0.001, respectively) significantly increased after bilateral anodal tDCS stimulation. The GDS score decrease was directly correlated with decrease in PSQI total score (P=0.01), sleep latency sub-score (P=0.002), and sleep disturbance sub-score (P=0.003). In addition, the GDS score decrease was inversely correlated with increasing mental component score of SF-36 (P=0.001), which was directly correlated with an increase in sleep efficiency sub-score (P=0.03) and the physical component score of SF-36 (P=0.0001). CONCLUSIONS Bilateral anodal tDCS stimulation showed potential therapeutic effects in patients with PD in terms of sleep quality and depression level improvement, which together improved mental and physical quality of life in patients with PD. PMID- 30449882 TI - Chronic Pain Rehabilitation for Upper Extremity Pain Following Stimulator Removal. AB - BACKGROUND Both spinal cord stimulators (SCS) and interdisciplinary chronic pain rehabilitation program (CPRP) are evidence-based treatments for chronic pain but differ on treatment foci. SCS focuses on decreasing the subjective pain experience as a means of improving function and quality of life. CPRP focuses on addressing the cognitive, emotional, and behavioral factors associated with chronic pain to improve function. Due to experimental constraints, these 2 treatment options are difficult to compare; however, this case report offers a unique opportunity to examine outcomes for both interventions in a sequential manner for changes in pain, function, and mood. CASE REPORT This single case study examined the separate and sequential outcomes of SCS and CPRP in a 26-year old patient with a work-related injury resulting in chronic upper extremity pain. This patient was treated within an interdisciplinary CPRP following failure and removal of an SCS. Outcomes were measured by psychological assessments and return to-work through a 6-month post-CPRP follow-up. CONCLUSIONS Pain intensity decreased following SCS placement and CPRP, while pain-related distress, pain interference, and overall affect improved only after CPRP, with sustained improvements at 6-month follow-up. Patient evidenced improvement following treatment with SCS and CPRP. SCS resulted in improvement in subjective pain and modest improved self-reported activity. CPRP demonstrated marked improvement in pain, self-reported function, and mood with patient eventually returning to work and maintaining most of these gains 6-months after completing CPRP treatment. PMID- 30449883 TI - Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia. AB - Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia. PMID- 30449884 TI - Killing the Buzetazeta: accumbal PKMzeta blunts cocaine seeking and reward. PMID- 30449885 TI - Exploring the transcriptome of hormone-naive multifocal prostate cancer and matched lymph node metastases. AB - BACKGROUND: The current inability to predict whether a primary prostate cancer (PC) will progress to metastatic disease leads to overtreatment of indolent PCs as well as undertreatment of aggressive PCs. Here, we explored the transcriptional changes associated with metastatic progression of multifocal hormone-naive PC. METHODS: Using total RNA-sequencing, we analysed laser micro dissected primary PC foci (n = 23), adjacent normal prostate tissue samples (n = 23) and lymph node metastases (n = 9) from ten hormone-naive PC patients. Genes important for PC progression were identified using differential gene expression and clustering analysis. From these, two multi-gene-based expression signatures (models) were developed, and their prognostic potential was evaluated using Cox regression and Kaplan-Meier analyses in three independent radical prostatectomy (RP) cohorts (>650 patients). RESULTS: We identified several novel PC-associated transcripts deregulated during PC progression, and these transcripts were used to develop two novel gene-expression-based prognostic models. The models showed independent prognostic potential in three RP cohorts (n = 405, n = 107 and n = 91), using biochemical recurrence after RP as the primary clinical endpoint. CONCLUSIONS: We identified several transcripts deregulated during PC progression and developed two new prognostic models for PC risk stratification, each of which showed independent prognostic value beyond routine clinicopathological factors in three independent RP cohorts. PMID- 30449886 TI - Probiotics can Cause D-Lactic Acidosis and Brain Fogginess: Reply to Quigley et al. PMID- 30449887 TI - Haploseek: a 24-hour all-in-one method for preimplantation genetic diagnosis (PGD) of monogenic disease and aneuploidy. AB - PURPOSE: To develop an economical, user-friendly, and accurate all-in-one next generation sequencing (NGS)-based workflow for single-cell gene variant detection combined with comprehensive chromosome screening in a 24-hour workflow protocol. METHODS: We subjected single lymphoblast cells or blastomere/blastocyst biopsies from four different families to low coverage (0.3*-1.4*) genome sequencing. We combined copy-number variant (CNV) detection and whole-genome haplotype phase prediction via Haploseek, a novel, user-friendly analysis pipeline. We validated haplotype predictions for each sample by comparing with clinical preimplantation genetic diagnosis (PGD) case results or by single-nucleotide polymorphism (SNP) microarray analysis of bulk DNA from each respective lymphoblast culture donor. CNV predictions were validated by established commercial kits for single-cell CNV prediction. RESULTS: Haplotype phasing of the single lymphoblast/embryo biopsy sequencing data was highly concordant with relevant ground truth haplotypes in all samples/biopsies from all four families. In addition, whole-genome copy number assessments were concordant with the results of a commercial kit. CONCLUSION: Our results demonstrate the establishment of a reliable method for all-in-one molecular and chromosomal diagnosis of single cells. Important features of the Haploseek pipeline include rapid sample processing, rapid sequencing, streamlined analysis, and user-friendly reporting, so as to expedite clinical PGD implementation. PMID- 30449888 TI - Trajectory of exonic variant discovery in a large clinical population: implications for variant curation. AB - PURPOSE: Precision health initiatives and reduced sequencing costs are driving large-scale human genome analyses. Genetic variant curation is a bottleneck in clinical applications. The burden of variant curation can be high for newly discovered variants because they are less likely to have undergone previous clinical annotation; the rate of discovery of genetic variants in large clinical populations has not been empirically determined. METHODS: We determined the rate of accrual of unique sequence variants in 90,000 exome sequences. Separate analyses were done for 17,267 autosomal genes and a subset of 74 actionable genes; the effect of relatedness in the cohort was also determined. RESULTS: Variant discovery showed a nonlinear growth pattern. The rate of unique variant accrual decreased as the database size increased; by 90,000 exomes 97% of all projected coding and splicing variants had been observed. Variants in 74 actionable genes showed a similar pattern. Family relatedness slightly reduced the rate of discovery of unique variants. CONCLUSION: The heaviest burden of interpretation for genetic variants occurs early and diminishes as the database size increases. Our data provide a framework for scaling pathogenic genetic variant discovery and curation, a critical element of patient care in the era of precision health. PMID- 30449889 TI - Genetics influences development of AD pathology. PMID- 30449891 TI - Azolylthioacetamides as potential inhibitors of New Delhi metallo-beta-lactamase 1 (NDM-1). AB - Thirteen azolylthioacetamides was synthesized and characterized. Biological activity assays with MbetaLs revealed that all of these compounds (except 3 and 6) gained exhibited inhibitory activity on NDM-1, with an IC50 value ranging from 3.8 to 26.4 MUM. Inhibitors 11 and 13, in combination with cefazolin, resulted in a four-fold decrease in MIC of the antibiotic against Escherichia coli cells expressing NDM-1. Docking studies revealed that the inhibitors 7, 9, and 13 bound to active site of NDM-1. PMID- 30449890 TI - Gelatinase B/Matrix Metalloproteinase-9 as Innate Immune Effector Molecule in Achalasia. AB - OBJECTIVES: Achalasia is a primary esophageal motility disorder resulting from selective loss of inhibitory neurons in the esophageal myenteric plexus, likely due to an autoimmune response with involvement of the adaptive immune system. Innate immune processes of the host constitute the bridge between environmental etiological factors and the adaptive immune system. Although these remain poorly investigated, they might be of diagnostic and therapeutic relevance. In view of the role of extracellular proteolysis in organ-specific autoimmunity, we studied gelatinases of the matrix metalloproteinase (MMP) family in achalasia patients. METHODS: The presence of MMP-2 and MMP-9 proteoforms was analyzed in sera of two cohorts of achalasia patients. Additionally, with the use of immunohistopathological analysis, in situ MMP-2 and MMP-9 expression was investigated. Finally, we tested the paradigm of remnant epitopes generating autoimmunity (REGA) for achalasia-associated autoantigens by evaluating whether autoantigenic proteins are cleaved by MMP-9 into remnant epitopes. RESULTS: We showed significantly increased ratios of MMP-9/MMP-2 and activated MMP-9/proMMP-9 in sera of achalasia patients (n = 88) versus controls (n = 60). MMP-9-positive and MMP-2-positive cells were more abundant in achalasia (n = 49) versus control biopsies from transplant donors (n = 10). Furthermore, extensive damage within the plexus was found in the tissues with more MMP-9-positive cells. Additionally, we documented achalasia-associated autoantigens PNMA2, Ri, GAD65, and VIP as novel MMP-9 substrates. CONCLUSIONS: We provide new biomarkers and insights into innate immune mechanisms in the autoimmune pathology of achalasia. Our results imply that extracellular protease inhibition is worthwhile to test as therapeutic intervention in achalasia. PMID- 30449892 TI - Paradoxical growth effect of caspofungin on Candida spp. sessile cells not only at high drug concentrations. AB - According to the available literature, echinocandins display high anti-Candida spp. activity. Paradoxical growth (PG) of Candida spp. planktonic cells promoted by echinocandins is widely reported. Here we report on the ability of Candida spp. sessile cells to display PG when they are exposed to caspofungin in vitro, even at relatively low drug concentrations. Clinical significance of PG during echinocandin therapy of candidiasis remains uncertain. We assessed in vitro susceptibilities of Candida spp. sessile cells to caspofungin and analyzed the frequency of PG. The minimum inhibitory concentrations of caspofungin for sessile cells (SMICs) were determined for 70 clinical Candida spp. isolates (29 Candida albicans, 26 Candida parapsilosis, and 15 Candida glabrata isolates) and were defined as the lowest drug concentrations that resulted in at least 50% reduction in metabolic activity. PG was defined as a resurgence of growth (>50% of that in the drug-free growth control well) at drug concentrations above the MIC. The caspofungin SMICs ranged from <=0.015 to >256 ug ml-1. We observed PG in 26.9 93.1% of isolates tested, depending on the Candida species and age of sessile cells. Antibiofilm activity of caspofungin is species-specific, and strongly strain-depending among C. albicans and C. parapsilosis isolates. Interestingly, PG was present also at relatively low caspofungin concentrations. PMID- 30449893 TI - Synthetic Bessel light needle for extended depth-of-field microscopy. AB - An ultra-long light needle is highly desired in optical microscopy for its ability to improve the lateral resolution over a large depth of field (DOF). However, its use in image acquisition usually relies on mechanical raster scanning, which compromises between imaging speed and stability and thereby restricts imaging performance. Here, we propose a synthetic Bessel light needle (SBLN) that can be generated and scanned digitally by complex field modulation using a digital micromirror device. In particular, the SBLN achieves a 45-fold improvement in DOF over its counterpart Gaussian focus. Further, we apply the SBLN to perform motionless two-dimensional and three-dimensional microscopic imaging, achieving both improved resolution and extended DOF. Our work is expected to open up opportunities for potential biomedical applications. PMID- 30449894 TI - Energy Deposition by Energetic Electrons in a Diffusive Collisional Transport Model. AB - A considerable fraction of the energy in a solar flare is released as suprathermal electrons; such electrons play a major role in energy deposition in the ambient atmosphere, and hence the atmospheric response to flare heating. Historically, the transport of these particles has been approximated through a deterministic approach in which first-order secular energy loss to electrons in the ambient target is treated as the dominant effect, with second-order diffusive terms (in both energy and angle) being generally either treated as a small correction or neglected. However, it has recently been pointed out that while neglect of diffusion in energy may indeed be negligible, diffusion in angle is of the same order as deterministic scattering and hence must be included. Here we therefore investigate the effect of angular scattering on the energy deposition profile in the flaring atmosphere. A relatively simple compact expression for the spatial distribution of energy deposition into the ambient plasma is presented and compared with the corresponding deterministic result. For unidirectional injection there is a significant shift in heating from the lower corona to the upper corona; this shift is much smaller for isotropic injection. We also compare the heating profiles due to return current ohmic heating in the diffusional and deterministic models. PMID- 30449895 TI - Re-approaching community development through the arts: a 'critical mixed methods' study of social circus in Quebec. AB - Community arts projects have long been used in community development. Nevertheless, despite many liberatory tales that have emerged, scholars caution that well-meaning organizations and artists may inadvertently become complicit in efforts that distract from fundamental inequities, instrumentalizing creative expression as a means to transform potentially dissident youth into productive and cooperative 'citizens'. This article examines how social circus - using circus arts with equity-seeking communities - has been affecting personal and community development among youth with marginalized lifestyles in Quebec, Canada. Employing a 'critical mixed methods' design, we analysed the impacts of the social circus methodology and partnership model deployed on transformation at the personal and community level. Our analysis suggests that transformation in this context is grounded in principles of using embodied play to re-forge habits and fortify an identity within community and societal acceptance through recognizing individual and collective creative contributions. The disciplinary dimension of the programme, however, equally suggests an imprinting of values of 'productivity' by putting marginality 'to work'. In the social circus programmes studied, tensions between the goal of better coping within the existing socioeconomic system and building skills to transform inequitable dynamics within dominant social and cultural processes, are navigated by carving out a space in society that offers alternative ways of seeing and engaging. PMID- 30449896 TI - Influence of larval density and dietary nutrient concentration on performance, body protein, and fat contents of black soldier fly larvae (Hermetia illucens). AB - Performance and body composition of insect larvae depend on quality and quantity of their diet, and on biotic factors such as larval density. We investigated the effect of dietary nutrient concentration and larval rearing density on survival, development, growth, and protein and fat contents of larvae of the black soldier fly (BSF), Hermetia illucens L. (Diptera: Stratiomyidae). Neonate larvae were fed with a low (NC1), intermediate (NC2), or high nutrient concentration (NC3), and with four rearing densities (50, 100, 200, or 400 larvae per container). Two feeding regimes (FR) were tested: in FR1, the amount of diet added during the experiment was based on the visually estimated larval mass present, whereas in FR2, a fixed feeding ration of 0.6 g of food per larva was applied at the start. FR1 resulted in food limitation, resulting in significantly lower body crude protein content on diet NC1 than on NC2 at larval densities 100 and 200. Larval crude fat content was higher on diets with higher nutrient concentration and at lower larval densities. For FR2, development time was shorter on diets with higher nutrient concentration and at lower larval densities. Individual larval weight and total larval yield increased with higher nutrient concentration at all four larval densities. At lower nutrient concentration, higher larval density resulted in higher individual larval weight and total larval yield, revealing an interaction between larval density and dietary quality. Larval crude protein content was higher at lower densities and lower nutrient concentration. Larval crude fat was higher at higher larval densities and nutrient concentrations. This study indicates that larval protein content is regulated within narrow limits, whereas larval crude fat content is strongly affected by nutrient concentration and by larval density. PMID- 30449897 TI - Enhanced pool-boiling heat transfer and critical heat flux on femtosecond laser processed stainless steel surfaces. AB - In this paper, we present an experimental investigation of pool boiling heat transfer on multiscale (micro/nano) functionalized metallic surfaces. Heat transfer enhancement in metallic surfaces is very important for large scale high heat flux applications like in the nuclear power industry. The multiscale structures were fabricated via a femtosecond laser surface process (FLSP) technique, which forms self-organized mound-like microstructures covered by layers of nanoparticles. Using a pool boiling experimental setup with deionized water as the working fluid, both the heat transfer coefficients and critical heat flux were investigated. A polished reference sample was found to have a critical heat flux of 91 W/cm2 at 40 degrees C of superheat and a maximum heat transfer coefficient of 23,000 W/m2 K. The processed samples were found to have a maximum critical heat flux of 142 W/cm2 at 29 degrees C and a maximum heat transfer coefficient of 67,400 W/m2 K. It was found that the enhancement of the critical heat flux was directly related to the wetting and wicking ability of the surface which acts to replenish the evaporating liquid and delay critical heat flux. The heat transfer coefficients were also found to increase when the surface area ratio was increased as well as the microstructure peak-to-valley height. Enhanced nucleate boiling is the main heat transfer mechanism, and is attributed to an increase in surface area and nucleation site density. PMID- 30449898 TI - Bumble-BEEHAVE: A systems model for exploring multifactorial causes of bumblebee decline at individual, colony, population and community level. AB - World-wide declines in pollinators, including bumblebees, are attributed to a multitude of stressors such as habitat loss, resource availability, emerging viruses and parasites, exposure to pesticides, and climate change, operating at various spatial and temporal scales. Disentangling individual and interacting effects of these stressors, and understanding their impact at the individual, colony and population level are a challenge for systems ecology. Empirical testing of all combinations and contexts is not feasible. A mechanistic multilevel systems model (individual-colony-population-community) is required to explore resilience mechanisms of populations and communities under stress.We present a model which can simulate the growth, behaviour and survival of six UK bumblebee species living in any mapped landscape. Bumble-BEEHAVE simulates, in an agent-based approach, the colony development of bumblebees in a realistic landscape to study how multiple stressors affect bee numbers and population dynamics. We provide extensive documentation, including sensitivity analysis and validation, based on data from literature. The model is freely available, has flexible settings and includes a user manual to ensure it can be used by researchers, farmers, policy-makers, NGOs or other interested parties.Model outcomes compare well with empirical data for individual foraging behaviour, colony growth and reproduction, and estimated nest densities.Simulating the impact of reproductive depression caused by pesticide exposure shows that the complex feedback mechanisms captured in this model predict higher colony resilience to stress than suggested by a previous, simpler model. Synthesis and applications. The Bumble-BEEHAVE model represents a significant step towards predicting bumblebee population dynamics in a spatially explicit way. It enables researchers to understand the individual and interacting effects of the multiple stressors affecting bumblebee survival and the feedback mechanisms that may buffer a colony against environmental stress, or indeed lead to spiralling colony collapse. The model can be used to aid the design of field experiments, for risk assessments, to inform conservation and farming decisions and for assigning bespoke management recommendations at a landscape scale. PMID- 30449899 TI - Quantifying the impact of pesticides on learning and memory in bees. AB - Most insecticides are insect neurotoxins. Evidence is emerging that sublethal doses of these neurotoxins are affecting the learning and memory of both wild and managed bee colonies, exacerbating the negative effects of pesticide exposure and reducing individual foraging efficiency.Variation in methodologies and interpretation of results across studies has precluded the quantitative evaluation of these impacts that is needed to make recommendations for policy change. It is not clear whether robust effects occur under acute exposure regimes (often argued to be more field-realistic than the chronic regimes upon which many studies are based), for field-realistic dosages, and for pesticides other than neonicotinoids.Here we use meta-analysis to examine the impact of pesticides on bee performance in proboscis extension-based learning assays, the paradigm most commonly used to assess learning and memory in bees. We draw together 104 (learning) and 167 (memory) estimated effect sizes across a diverse range of studies.We detected significant negative effects of pesticides on learning and memory (i) at field realistic dosages, (ii) under both chronic and acute application, and (iii) for both neonicotinoid and non-neonicotinoid pesticides groups.We also expose key gaps in the literature that include a critical lack of studies on non-Apis bees, on larval exposure (potentially one of the major exposure routes), and on performance in alternative learning paradigms. Policy implications. Procedures for the registration of new pesticides within EU member states now typically require assessment of risks to pollinators if potential target crops are attractive to bees. However, our results provide robust quantitative evidence for subtle, sublethal effects, the consequences of which are unlikely to be detected within small-scale prelicensing laboratory or field trials, but can be critical when pesticides are used at a landscape scale. Our findings highlight the need for long-term postlicensing environmental safety monitoring as a requirement within licensing policy for plant protection products. PMID- 30449900 TI - Pathogen dynamics under both bottom-up host resistance and top-down hyperparasite attack. AB - The relative importance of bottom-up versus top-down control of population dynamics has been the focus of much debate. In infectious disease biology, research is typically focused on the bottom-up process of host resistance, wherein the direction of control flows from the lower to the higher trophic level to impact on pathogen population size and epidemiology. However, the importance of top-down control by a pathogen's natural enemies has been mostly overlooked.Here, we explore the effects of, and interaction between, host genotype (i.e., genetic susceptibility to pathogen infection) and infection by a hyperparasitic fungus, Ampelomyces spp., on the establishment and early epidemic growth and transmission of a powdery mildew plant pathogen (Podosphaera plantaginis). We used a semi-natural field experiment to contrast the impacts of hyperparasite infection, host-plant resistance and spatial structure to reveal the key factors that determine pathogen spread. We then used a laboratory-based inoculation approach to test whether the field experiment results hold across multiple pathogen-host genetic combinations and to explore hyperparasite effects on the pathogen's later life-history stages.We found that hyperparasite infection had a negligible effect on within-host infection development and between-host spread of the pathogen during the onset of epidemics. In contrast, host-plant resistance was the major determinant of whether plants became infected, and host genotype and proximity to an infection source determined infection severity.Our laboratory study showed that, while the interaction between host and pathogen genotypes was the key determinant of infection outcome, hyperparasitism did, on average, reduce the severity of infection. Moreover, hyperparasite infection negatively influenced the production of the pathogen's overwintering structures. Synthesis and applications. Our results suggest that bottom-up host resistance affects pathogen spread, but top-down control of powdery mildew pathogens is likely more effective against later life-history stages. Further, while hyperparasitism in this system can reduce early pathogen growth under stable laboratory conditions, this effect is not detectable in a semi-natural environment. Considering the effects of hyperparasites at multiple points in pathogen's life history will be important when considering hyperparasite-derived biocontrol measures in other natural and agricultural systems. PMID- 30449901 TI - Critical Dependence of Molecular Weight on Thermoresponsive Behavior of Diblock Copolymer Worm Gels in Aqueous Solution. AB - Reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization of 2-hydroxypropyl methacrylate was used to prepare three poly(glycerol monomethacrylate) x -poly(2-hydroxypropyl methacrylate) y (denoted G x -H y or PGMA-PHPMA) diblock copolymers, namely G37-H80, G54-H140, and G71 H200. A master phase diagram was used to select each copolymer composition to ensure that a pure worm phase was obtained in each case, as confirmed by transmission electron microscopy (TEM) and small-angle x-ray scattering (SAXS) studies. The latter technique indicated a mean worm cross-sectional diameter (or worm width) ranging from 11 to 20 nm as the mean degree of polymerization (DP) of the hydrophobic PHPMA block was increased from 80 to 200. These copolymer worms form soft hydrogels at 20 degrees C that undergo degelation on cooling. This thermoresponsive behavior was examined using variable temperature DLS, oscillatory rheology, and SAXS. A 10% w/w G37-H80 worm dispersion dissociated to afford an aqueous solution of molecularly dissolved copolymer chains at 2 degrees C; on returning to ambient temperature, these chains aggregated to form first spheres and then worms, with the original gel strength being recovered. In contrast, the G54-H140 and G71-H200 worms each only formed spheres on cooling to 2 degrees C, with thermoreversible (de)gelation being observed in the former case. The sphere-to-worm transition for G54-H140 was monitored by variable temperature SAXS: these experiments indicated the gradual formation of longer worms at higher temperature, with a concomitant reduction in the number of spheres, suggesting worm growth via multiple 1D sphere-sphere fusion events. DLS studies indicated that a 0.1% w/w aqueous dispersion of G71-H200 worms underwent an irreversible worm-to-sphere transition on cooling to 2 degrees C. Furthermore, irreversible degelation over the time scale of the experiment was also observed during rheological studies of a 10% w/w G71-H200 worm dispersion. Shear-induced polarized light imaging (SIPLI) studies revealed qualitatively different thermoreversible behavior for these three copolymer worm dispersions, although worm alignment was observed at a shear rate of 10 s-1 in each case. Subsequently conducting this technique at a lower shear rate of 1 s-1 combined with ultra small-angle x-ray scattering (USAXS) also indicated that worm branching occurred at a certain critical temperature since an upturn in viscosity, distortion in the birefringence, and a characteristic feature in the USAXS pattern were observed. Finally, SIPLI studies indicated that the characteristic relaxation times required for loss of worm alignment after cessation of shear depended markedly on the copolymer molecular weight. PMID- 30449902 TI - Effect of Intra- versus Intermolecular Cross-Linking on the Supramolecular Folding of a Polymer Chain. AB - Anfinsen's famous experiment showed that the restoration of catalytic activity of a completely unfolded ribonuclease A is only possible when the correct order of events is followed during the refolding process. Inspired by this work, the effect of structural constraints induced by covalent cross-links on the folding of a synthetic polymer chain via hydrogen-bonding interactions is investigated. Hereto, methacrylate-based monomers comprising either benzene-1,3,5 tricarboxamide (BTA)-based or coumarin-based pendants are copolymerized with n butyl methacrylate in various ratios via reversible addition-fragmentation chain transfer (RAFT) polymerization. To assess whether the folding and single-chain polymeric nanoparticle (SCPN) formation depend on the order of events, we compare two folding pathways. In the one case, we first covalently cross-link the coumarin pendants within the polymers in a solvent that prevents hydrogen bonding, after which hydrogen bonding is activated, inducing folding of the polymer. In the other case, we induce hydrogen-bonding interactions between tethered BTAs prior to covalent cross-linking of the coumarin pendants. A combination of circular dichroism (CD) spectroscopy, UV-vis spectroscopy, size exclusion chromatography (SEC), and dynamic light scattering (DLS) is employed to understand the effect of the structural constraints on the folding behavior of these synthetic polymers. The results show that like in ribonuclease A, the order of events matters greatly and determines the outcome. Importantly, a hydrogen bond-promoting solvent prevents the formation of SCPNs upon covalent cross linking and results in multichain aggregates. In contrast, covalently cross linking the polymer when no hydrogen bonds are present followed by inducing hydrogen bonding favors the formation of SCPNs above the UCST of the methacrylate based polymer. To our surprise, the two systems show a fundamentally different response to changes in temperature, indicating that also in synthetic polymers differences in the folding pathway induce differences in the properties of the resultant nanostructures. PMID- 30449904 TI - Stereoselective Synthesis of the C11-N26 Fragment of Griseoviridin. AB - The C11-N26 fragment of griseoviridin has been prepared enantioselectively. The 1,3-syn diol synthon was derived from lipase-catalyzed selective acylation of(+/ )-1-(benzyloxy)pent-4-en-2-ol. The conjugated (E,E)-dienylmethyl azide functionality was installed by a Pd-catalyzed allylic azidation reaction. PMID- 30449903 TI - How Political Cultures Produce Different Antibiotic Policies in Agriculture: A Historical Comparative Case Study between the United Kingdom and Sweden. AB - The purpose of this article is to provide an understanding of how different countries formulate and regulate antibiotic use in animals raised for human consumption. A comparative case study was undertaken, analysing historical documents from the 1950s to the 1990s from the UK, the first country to produce a scientific report on the public health risks of agricultural antibiotic use; and Sweden, the first country to produce legislation on the growth promotor use of antibiotics in food animals. Sheila Jasanoff's concepts of 'co-production' and 'political cultures' have been used to explore how both countries used different styles of scientific reasoning and justification of the risks of agricultural antibiotic use. It will be argued that national dynamics between policy, science and public knowledges co-produced different risk classifications and patterns of agricultural antibiotic use between both countries. UK's political culture used 'expert committees' to remove the issue from public debate and to inform agricultural antibiotic policies. In contrast, the Swedish 'consensus-oriented' political culture made concerns related to agricultural antibiotic use into a cooperative debate that included multiple discourses. Understanding how national policies, science and public knowledges interact with the risks related to agricultural antibiotic use can provide valuable insights in understanding and addressing countries agricultural use of antibiotics. PMID- 30449905 TI - Diastereoselective Synthesis of Substituted Tetrahydropyrans by Copper(II) Bisphosphine-Catalyzed Olefin Migration and Prins Cyclization. AB - We developed a copper(II) triflate-bisphosphine complex catalyzed olefin migration and Prins cyclization which lead to the synthesis of substituted tetrahydropyran derivatives. The protocol is convenient and a variety of substituted tetrahydropyrans were obtained in good to excellent yields with excellent diastereoselectivities. PMID- 30449906 TI - A stereoselective synthesis of (+)-boronolide. AB - A stereoselective synthesis of (+)-boronolide is described. The key steps involve a stereoselective reduction of an alpha-hydroxy ketone, allylation of an alpha hydroxy aldehyde and a ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester utilizing Grubbs' catalyst. PMID- 30449907 TI - Chelation-controlled ester-derived titanium enolate aldol reaction: diastereoselective syn-aldols with mono- and bidentate aldehydes. AB - A chelation-controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of (S)-valinol-derived ester with a variety of aldehydes proceeded with high syn-diastereoselectivities (up to 99:1) and isolated yields (94%). PMID- 30449908 TI - Imidazolidin-4-ones via (3+2) cycloadditions of aza-oxyallyl cations onto (E) Narylideneanilines. AB - In the course of our studies on the chemistry of oxyallyl species we uncovered a new (3+2) cycloaddition of aza-oxyallyl systems, generated in situ from N benzyloxy-2-chloroamides in the presence of NEt3, onto N-arylimines yielding imidazolidin-4-ones in moderate to good yields. The cycloadditions are regioselective. Computational modelling using DFT at the M062*/6-311+G** level is in support the observed regioselectivities. Although the path to the trans imidazolin-4-one is favored, the cis product is preferred by almost 8 kcal/mol and could be formed by base-catalyzed epimerization. All products were isolated by chromatography and characterized by means of their FTIR, NMR and HRMS data. PMID- 30449909 TI - Separation of Scales in Transpiration Effects on Low Flows: A Spatial Analysis in the Hydrological Open Air Laboratory. AB - The objective of this study was to understand whether spatial differences in runoff generation mechanisms affect the magnitudes of diurnal streamflow fluctuations during low flow periods and which part of the catchment induces the diurnal streamflow signal. The spatiotemporal variability of the streamflow fluctuations observed at 12 locations in the 66-ha Hydrological Open Air Laboratory experimental catchment in Austria was explained by differences in the vegetation cover and runoff generation mechanisms. Almost a quarter of the volume associated with diurnal streamflow fluctuations at the catchment outlet was explained by transpiration from vegetation along the tributaries; more than three quarters was due to transpiration by the riparian forest along the main stream. The lag times between radiative forcing and evapotranspiration estimated by a solar radiation-driven model increased from 3 to 11 hr from spring to autumn. The recession time scales increased from 21 days in spring to 54 days in autumn. Observations and model simulations suggest that a separation of scales in transpiration effects on low flows exists both in time and space; that is, the diurnal streamflow fluctuations are induced by transpiration from the riparian vegetation, while most of the catchment evapotranspiration, such as evapotranspiration from the crop fields further away from the stream, do not influence the diurnal signal in streamflow. PMID- 30449910 TI - Estimating snow mass in North America through assimilation of AMSR-E brightness temperature observations using the Catchment land surface model and support vector machines. AB - To estimate snow mass across North America, brightness temperature observations collected by the Advanced Microwave Scanning Radiometer from 2002 to 2011 were assimilated into the Catchment model using a support vector machine (SVM) as the observation operator and a one-dimensional ensemble Kalman filter. The performance of the assimilation system is evaluated through comparisons against ground-based measurements and reference snow products. In general, there are no statistically significant skill differences between the domain-averaged, model only ("open loop", or OL) snow estimates and assimilation estimates. The assessment of improvements (or degradations) in snow estimates is difficult because of limitations in the measurements (or products) used for evaluation. It is found that assimilation estimates agree slightly better in terms of root-mean square error (RMSE) and Nash-Sutcliffe model efficiency with ground-based snow depth measurements than OL estimates in 82% (56 out of 62) of pixels that are colocated with at least two ground-based stations. Assimilation estimates tend to agree slightly better in terms of mean difference with reference snow products over tun-dra snow, alpine snow, maritime snow, and sparsely-vegetated, snow covered pixels. Changes in snow mass via assimilation translate into improvements (e.g.,by 22% on average in terms of RMSE, relative to OL) in cumulative runoff estimates when compared against discharge measurements in 11 out of 13 snow dominated basins in Alaska. These results suggest that a SVM can potentially serve as an effective observation operator for snow mass estimation within a radiance assimilation system, but a better observational baseline is required to document a statistically significant improvement. PMID- 30449911 TI - Design of a spaceflight biofilm experiment. AB - Biofilm growth has been observed in Soviet/Russian (Salyuts and Mir), American (Skylab), and International (ISS) Space Stations, sometimes jeopardizing key equipment like spacesuits, water recycling units, radiators, and navigation windows. Biofilm formation also increases the risk of human illnesses and therefore needs to be well understood to enable safe, long-duration, human space missions. Here, the design of a NASA-supported biofilm in space project is reported. This new project aims to characterize biofilm inside the International Space Station in a controlled fashion, assessing changes in mass, thickness, and morphology. The space-based experiment also aims at elucidating the biomechanical and transcriptomic mechanisms involved in the formation of a "column-and-canopy" biofilm architecture that has previously been observed in space. To search for potential solutions, different materials and surface topologies will be used as the substrata for microbial growth. The adhesion of bacteria to surfaces and therefore the initial biofilm formation is strongly governed by topographical surface features of about the bacterial scale. Thus, using Direct Laser Interference Patterning, some material coupons will have surface patterns with periodicities equal, above or below the size of bacteria. Additionally, a novel lubricant-impregnated surface will be assessed for potential Earth and spaceflight anti-biofilm applications. This paper describes the current experiment design including microbial strains and substrata materials and nanotopographies being considered, constraints and limitations that arise from performing experiments in space, and the next steps needed to mature the design to be spaceflight-ready. PMID- 30449912 TI - Food safety in Brazilian popular public restaurants: Food handlers' knowledge and practices. AB - : This study aims to assess food safety knowledge and practices of food handlers in popular public restaurants in Brazil. A questionnaire has been applied with 70 food handlers in different municipalities, with questions related to food safety knowledge and food safety self-reported practices, and observed practices. To check hygienic-sanitary conditions of restaurants, a checklist has been applied. Regarding food safety knowledge, an average of 72.64% of correct answers has been observed. Food safety self-reported practices presented 80.71% of adequacy, while observed practices were 75.40%. A positive correlation has been observed between food safety knowledge and self-reported practices of handlers. The observed food safety practice of handlers presented no correlation with food safety knowledge and self-reported practices. The average adequacy of hygienic-sanitary conditions was 68.08%, classifying the units as "regular." Despite satisfactory results related to the handlers' food safety knowledge and practices, the hygienic sanitary conditions of the restaurants are of concern. Practical applications: The Popular Restaurant Program in Brazil aims to provide proper food from a nutritional and hygienic-sanitary aspect at affordable prices. The assessment of food handlers' food safety knowledge and practices and the assessment of hygienic sanitary conditions of these units are key in supporting actions aimed at improving the quality of the meals served, as food handlers are the essential agents in the production of meals and can become a source for food contamination if necessary care is not taken. Therefore, conducting this assessment can be an important tool for quality management in these units and can provide improvements in the process of food handling, in addition to ensuring compliance with the objectives proposed by the Popular Restaurant Program. PMID- 30449913 TI - On-farm evaluation and determination of sources of variability of soybean response to Bradyrhizobium inoculation and phosphorus fertilizer in northern Ghana. AB - Soybean yields on smallholder farms in sub-Sahara Africa (SSA) are far below the potential yield thus creating a huge yield gap. Interventions are thus needed to bridge this yield gap and ascertain the factors influencing the yield variation. This study evaluated the on farm response of soybean to rhizobia inoculation and or mineral P fertilizer in Northern and Upper West regions of Ghana in a single non-replicate trial using four treatments: no input (control), TSP fertilizer (P), rhizobia inoculant (I) and TSP plus inoculant (P + I). In addition, the study sought to develop a robust approach for determining responsiveness and non responsiveness using agronomic and economic indices. The results showed that the average grain yield of plots that received P or I were higher than control plots. Higher grain yield responses were however, obtained by the plots that received combined application of P and Bradyrhizobium inoculant. Grain yield response in the Northern region was higher than in the Upper West region. Response to P and or I were highly variable within and between locations. The cumulative rainfall and some soil factors including soil nitrogen, phosphorus, soil type, organic carbon, pH and texture explained about 42-79% of these variations in soybean grain yield. The agronomic approach for determining responsive and non responsiveness revealed that 17-40 % and 6-17% of the locations within the Northern and Upper West regions, respectively were responsive to P fertilization and/ or Bradyrhizobium inoculation. However, the economic approach indicated that 64-75% and 14-24% of the locations within the Northern and Upper West regions, respectively were responsive to P fertilization and Bradyrhizobium inoculation. The results imply that rhizobia inoculation is an effective strategy for increasing soybean yield and improving livelihood of smallholder farmers. PMID- 30449914 TI - Rhodium(III) and Iridium(III) Complexes of a NHC-Based Macrocycle: Persistent Weak Agostic Interactions and Reactions with Dihydrogen. AB - The synthesis and characterization of five-coordinate rhodium(III) and iridium(III) 2,2'-biphenyl complexes [M(CNC-12)(biph)][BArF 4] (M = Rh (1a), Ir (1b)), featuring the macrocyclic lutidine- and NHC-based pincer ligand CNC-12 are reported. In the solid state these complexes are notable for the adoption of weak epsilon-agostic interactions that are characterized by M...H-C contacts of ca. 3.0 A by X-ray crystallography and nu(CH) bands of reduced wavenumber by ATR IR spectroscopy. Remarkably, these interactions persist on dissolution and were observed at room temperature using NMR spectroscopy (CD2Cl2) and solution-phase IR spectroscopy (CCl4). The associated metrics point toward a stronger M...H-C interaction in the iridium congener, and this conclusion is borne out on interrogation of 1 in silico using DFT-based NBO and QTAIM analyses. Reaction of 1 with dihydrogen resulted in hydrogenolysis of the biaryl and formation of fluxional hydride complexes, whose ground state formulations as [Rh(CNC 12)H2][BArF 4] (2a") and [Ir(CNC-12)H2(H2)][BArF 4] (2b''') are proposed on the basis of inversion recovery and variable-temperature NMR experiments, alongside a computational analysis. Reactions of 1 and 2 with carbon monoxide help support their respective structural properties. PMID- 30449915 TI - Prospective applications of induced pluripotent stem cells in military medicine. AB - Soldiers involved in combat operations worldwide may be subjected to a wide array of tissue-specific injuries of varying degrees, thereby undergoing complicated medical treatments and prolonged rehabilitations. In many cases involving inadequate recovery, soldiers are further mentally traumatized as they can no longer serve their beloved country. In addition, many severe injuries can lead to soldiers being incapacitated for life and unable to perform even the most basic day-to-day activities. Present therapy for combat injuries is majorly aimed at alleviating pain and limiting further tissue damage from secondary infections. Cell-based therapy using stem cells is a promising tissue regenerative source, which will help our soldiers to recuperate from the severe injuries, and in some cases, even continue their service for the country after complete recovery. In this context, we would like to discuss the yet fully untapped potential of induced pluripotent stem cells (iPSCs) in regenerative medicine on the battlefield. In this review, we shall try to explore the rationale behind the use of these cells for military medicine, as well as the conventional and novel approaches to produce them for therapeutic applications. We shall also attempt to elucidate the evolving trends of battlefield injuries throughout history and the ongoing research on regeneration of tissues of specific interest using iPSCs and their potential role in combat medicine in the future. Additionally, we shall also discuss the concept of stem cell bio-banking for military personnel as a personalized safeguard against crippling and traumatic combat injuries. PMID- 30449916 TI - Is 400 IU per day of Vitamin-D given to healthy well-nourished mothers antenatally enough to prevent neonatal Vitamin-D deficiency? AB - Background: The incidence of Vitamin D deficiency (VDD) among newborns is very high in India, this is usually secondary to maternal deficiency. Currently Vitamin D at the dose of 400-600 IU/day is being prescribed during pregnancy for prevention. There is paucity of data regarding efficacy of current recommendations in preventing neonatal hypovitaminosis D.Our aim was to determine if good nutritional status of the mother and regular calcium and Vitamin D supplementation during pregnancy in the currently recommended doses help prevent or reduce VDD in neonates. Methods: Cord blood Serum 25(OH)D levels were studied in 342 neonates born to 323 healthy mothers at a tertiary care center in Mumbai. All the mothers were on regular antenatal follow up and received Vitamin D and calcium supplements as per current recommendations. Results: Mean umbilical cord blood 25(OH)D level was 12.088 ng/ml (SD 3.349, range 31.1-5.1). Out of 342 neonates, 335 (97.95%) had Vitamin D deficiency [cord blood 25(OH)D level <20 mg/ml] 1.75% had cord blood 25(OH)D level between 21 and 29 ng/ml in the insufficiency range and only 0.29% of the subjects had 'normal' cord blood 25(OH)D levels of >30 ng/ml. However, none of the neonates in the study were found to have severe VDD (<5 ng/ml). Conclusion: Antenatal supplementation of well nourished, socioeconomically better off mothers in our population with 400 IU/day of Vitamin D3 is ineffective in preventing VDD in neonates. PMID- 30449917 TI - A study of clinical, radiological and etiological profile of cerebral venous sinus thrombosis at a tertiary care center. AB - Background: A prospective, observational study was done at a tertiary care hospital in Western Maharashtra to describe the etiologies, clinical features, diagnosis and prognosis of cerebral venous sinus thrombosis in an Indian population. Methods: 54 patients with clinical and MRI features suggestive of cerebral venous sinus thrombosis (CVST), were studied with detailed clinical evaluation and pro-thrombotic work up. All were followed up monthly for 6 months, to assess the response to therapy and clinical outcomes. Results: The mean age of presentation was 35 years. Headache was the most common presenting symptom (94%) and hemi paresis (22%) was the most common neurological sign. The most common sinus involved was transverse sinus in 77% of cases. In the unprovoked CVST subset (n = 29), elevated factor VIII (72%) and protein C deficiency (24%) were the common prothrombotic states identified. In the provoked CVST subset (n = 18), puerperium (44%) and para-infectious (22%) accounted for majority cases. Idiopathic CVST accounted for 13% (7/54) in this study. A Modified Rankin Scale (MRS) of 0-1 was achieved in 96% of patients at the end of 6 months follow up with no mortality in this study. Conclusion: CVST is an important yet under recognized cause of intracranial hypertension and stroke in young. Clinical presentation is extremely varied and a high index of suspicion is needed. Magnetic Resonance Imaging (MRI) brain with Magnetic Resonance Venography (MRV) is the current diagnostic modality of choice. Elevated factor VIII and puerperium are the common etiologies in an Indian population. Management with anticoagulants is safe and has excellent clinical outcomes. PMID- 30449918 TI - Evaluation of three DNA extraction methods from fungal cultures. AB - Polymerase chain reaction (PCR) based assays have been developed to amplify DNA of fungal pathogens as culture-based detection methods show low sensitivity. In order to perform a sensitive, specific, and reliable PCR based assay, the availability of pure DNA as well as an easy-to-perform DNA extraction protocol is essential. The existing protocols for DNA extraction used for bacteria or viruses show poor release of fungal DNA. In this study, we evaluated three different methods of DNA extraction and compared their efficacy in the extraction of DNA from filamentous fungi, yeasts, and dermatophytes commonly isolated in our laboratory. It was found that the Fungi/Yeast Genomic DNA Isolation Kit (Norgen Biotek Corp, Ontario, Canada) demonstrated satisfactory extraction of DNA from all the fungi analyzed as compared to that of the Qiamp DNA extraction kit (Qiagen GmbH, Dusseldorf, Germany) or the Phenol Chloroform Isoamyl alcohol extraction method which failed to extract amplifiable DNA from many of the fungal species. Thus, we recommend the use of Fungi/Yeast Genomic DNA Isolation Kit (Norgen) with modifications for the extraction of DNA from fungal cultures. PMID- 30449919 TI - Revisiting anatomical variants on screening chest radiographs in Indian adolescents: A cross sectional observational pilot study. AB - Background: Knowledge of normal variation and measurements on a chest radiograph is essential to interpret any abnormality. There is paucity of information about normal measurement ranges and variations in young adolescents, particularly from Indian subcontinent. The aim of this study was to analyze certain normal variations on screening chest radiographs of healthy Indian adolescents and the objectives were to measure/assess (1) degree of inspiration, (2) cardiothoracic ratio (CTR), (3) presence of gastric fundic bubble, (4) fundocupolic distance, (5) presence of splenic flexure, (6) difference in height of diaphragmatic domes and (7) effect of inspiration on the CTR. Methods: Digital chest radiographs obtained during routine medical examinations for all consecutive medical graduate aspirants in the year 2016 at a medical college, were analyzed for the above mentioned parameters using DICOM viewing software. Result: A total of 558 chest radiographs were analyzed. The mean age of the subjects was 18.50 (SD = 1.002) (range: 17-22 years). There were 497 (89.1%) male and 61 (10.9%) female. Degree of inspiration was at 5th, 6th, 7th and 8th ribs in 29 (5.1%), 259 (46.4%), 264 (47.3%) and 6 (1%) respectively. Mean maximum transverse cardiac diameter, internal thoracic diameter, CTR were 1153.22 +/- 120.01, 2935.24 +/- 224.86 and 0.39 +/- 0.03 respectively. Females had slightly higher CTR (0.40 +/- 0.035) as compared to the males (0.39 +/- 0.032) (p = 0.009). Gastric fundic bubble was visualized in 91% subjects. Mean fundo-cupolic distance was 8.75 +/- 8.00. Mean value for difference in the level of two domes of diaphragm was 15.28 +/- 5.38. Conclusion: The study highlights normal range of inspiration, CT ratio, fundocupolic distance and diaphragmatic dome level difference on screening chest radiographs in healthy Indian adolescents. PMID- 30449920 TI - 'Health, Environment and Training': Guidance on conduct of physical exertion in hot and humid climates. AB - Background: Military operations and training in hot environments present a special set of challenges to medical personnel who must support them. Methods: Various meteorological parameters such as relative humidity (RH), ambient air temperature (Ta) and radiant temperature (Tg), were evaluated at training sites in a desert region. Development of a colour coded Heat Stress Prevention Decision Aid Tool was done using an existing guideline chart. Results: Temperatures were being recorded routinely by ordinary meteorological instruments mounted within a Stevenson Screen. Onsite measurements with a USB datalogger was found to be relevant in making a decision on suitability of weather for conduct of training. Heat casualties occur when the stresses imposed by some combination of environment, work, and clothing combine to exceed individual tolerance limits. Personnel may encounter high environmental heat loads while working outdoors; during road marches; and while carrying loads or undertaking mechanical maintenance activities. Preventive strategies cannot be expected to eliminate heat stress but should minimize its impact on training while preserving the health of personnel to the extent possible. Conclusion: It is recommended that onsite measurement of meteorological parameters should be done, and a decision tool should be utilized for arriving at a spot decision by junior leaders. PMID- 30449921 TI - Bronchial artery embolization in treatment of hemoptysis: Treatment efficacy and complications at a tertiary care chest centre. AB - Background: Hemoptysis is one of the most alarming condition to both the patients suffering from it and the treating physicians. It is caused due to varied etiologies. One of the emergent and at times life-saving treatment option is by minimally invasive interventional radiological technique of Bronchial Atery Embolization (BAE). The authors aimed to carry out a retrospective analysis of short term efficacy and safety of all patients treated by this technique at a tertiary care thoracic centre. Methods: A total of 52 patients were included in the study who had a median follow up of 35 days. All these patients were referred for hemoptysis, intractable hemoptysis not controlled by conservative management or massive hemoptysis. An analysis of the underlying etiology, immediate and short term outcomes and complications was made. Results: The study showed Tuberculosis and its sequel (bronchiectasis and chronic fibrotic changes) as the commonest etiology (65%). The BAE showed high short term efficacy (92%) in stopping the hemoptysis with a relatively low complication rate especially of major complications such as spinal cord ischemia (1.9%). The study strengthens the limited Indian data available on the subject and based on its outcome, BAE should be tried in all patients presenting with uncontrollable or massive hemoptysis not getting relief by conservative management alone. Conclusion: BAE is a very effective procedure with very less complications for management of massive or uncontrollable hemoptysis. PMID- 30449922 TI - Outbreak of Prototheca wickerhamii algaemia and sepsis in a tertiary care chemotherapy oncology unit. AB - Background: Prototheca is an emerging, opportunistic, pathogenic, zoonotic achlorophyllous green alga, expanding in pathogenicity and host range, causing localized and disseminated infections. This outbreak of Prototheca wickerhamii algaemia and sepsis in a tertiary care 30-bedded chemotherapy oncology unit is the first human outbreak to the best of our knowledge. Methods: P. wickerhamii algaemia was confirmed on consecutive isolation. Person to person transmission was hypothesized considering all patients in the unit at risk. Clinico demographic, diagnostic and treatment profile were correlated. Both manual and automated systems were used for blood culture, isolation, identification and susceptibility of Prototheca. Liposomal amphotericin B was given. Outbreak surveillance of faeces, fingertips and environmental reservoirs, retrospective surveillance during past 15 years and prospective surveillance was continued for two years. Results: The outbreak affected 12 neutropenic patients over 50 days. No specific clinical features were noted. The hypothesis could not be substantiated. P. wickerhamii was isolated as yeast-like colonies revealing Gram positive yeast-like cells without budding and pseudohyphae which were confirmed by automated system. Post amphotericin B blood cultures were negative for Prototheca. Surveillance studies were not contributory. Conclusion: P. wickerhamii has no documented reservoirs or transmission. Endogenous colonization in the gut followed by translocation during chemotherapy induced immunosuppression is likely to cause algaemia and sepsis. Outbreaks are difficult to detect and control as incubation period is variable and clinical presentation is muted, emphasizing the need to strengthen hospital and laboratory based surveillance systems to ensure adequate preparedness, rapid detection and response to outbreaks. PMID- 30449923 TI - A descriptive study of clinico-hematological profile of megaloblastic anemia in a tertiary care hospital. AB - Background: Megaloblastic Anemia (MA) is a relatively common disease, yet the data on prevalence of MA remains scarce. This study was conducted to study the prevalence and clinico-hematological profile of MA. Methods: This was a cross sectional study done on 1150 adult anemic patients. All patients diagnosed to have MA were studied for clinico-hematological and etiological profile. Nerve conduction studies (NCS) were done in all. Results: MA was present in 3.6% cases of anemia. Severe anemia was seen in 9.7% of anemic patients and 75% of MA cases (p < 0.05). Forty five percent of MA patients presented with pancytopenia. Vitamin B12 and folic acid deficiency were documented in 40% and 25% cases respectively while combined deficiency was noted in 35% of all MA cases. There was no co-relation between severity of anemia and deficiency of either of the vitamins (Fischer exact test: 0.530). Among MA patients, 35% were vegetarians while 65% consumed mixed diet. There was no association between vegetarian diet and Vit B12 deficiency (p = 0.3137). An additional etiology was more commonly found in patients on mixed diet [92%; 24/26] as compared to those on vegetarian diet [50%; 7/14] (p = 0.04). NCS was abnormal in 14 patients (35%). Overt clinical neuropathy was present in 12 cases of MA, while subclinical neuropathy was seen in 2 cases. Conclusion: MA is one of common causes of pancytopenia and severe anemia. Diet plays an important role in causation of MA in vegetarians. An alternative etiology is however, more likely to be found in patients on mixed diet. While overt neurological abnormalities are common in MA, subclinical neuropathy is uncommon. PMID- 30449924 TI - Gallstone ileus: A diagnostic and therapeutic challenge. PMID- 30449925 TI - The Currarino Triad. PMID- 30449926 TI - Giant omental lipoma in an elderly female patient. PMID- 30449927 TI - Waardenburg syndrome type 2. PMID- 30449928 TI - Pseudohemoptysis in an elderly due to Serratia marcescens pneumonitis. PMID- 30449929 TI - Sclerosing stromal cell tumor of ovary. PMID- 30449930 TI - A case of adenocarcinoma in a tail gut cyst and review of literature. PMID- 30449931 TI - Alkaptonuria. PMID- 30449932 TI - Pneumocephalus after lumbar epidural. PMID- 30449933 TI - Amenorrhea along with renal and thyroid metastasis: Unusual presentation of pancreatic adenocarcinoma. PMID- 30449934 TI - Reversible myelofibrosis due to severe Vitamin D deficiency rickets. PMID- 30449935 TI - A case of neurofibromatosis type 2 (NF2) with classic imaging and skin findings. AB - Neurofibromatosis is a neurocutaneous, tumor predisposing, inheritable disorder characterized by tumors of the brain and spine and the presence of skin lesions. The most important tumors associated with neurofibromatosis are vestibular nerve schwannomas, with others being meningiomas and ependymomas. The cord is also affected by tumors, ependymoma being the commonest, besides meningiomas and schwannomas. We present a case with cafe au lait macules, neurofibromas in the skin, bilateral VIII cranial nerve schwannomas, multiple meningiomas in the brain and spine, ependymomas in the brain and spine, and schwannomas in the cauda equina nerve roots. PMID- 30449936 TI - Neglected posterior urethral valve: Cause of irreversible renal damage and end stage renal disease. PMID- 30449937 TI - Association between vitamin D status and testosterone and cortisol in ice hockey players. AB - The identification of the vitamin D receptor in tissues related to testosterone and cortisol production, in conjunction with the observed correlations between vitamin D levels and these hormones in the general population, suggest vitamin D may influence testosterone and cortisol concentrations in athletes. A cross sectional study design was used to evaluate the association between 25(OH)D and testosterone and cortisol concentrations in young male ice hockey players (n = 50). All athletes were recruited during October from the Sosnowiec area, Poland (50 degrees N). Commercially available ELISA kits were used to determine total serum 25(OH)D, testosterone and cortisol concentrations. Serum 25(OH)D concentration was analyzed as both a continuous and dichotomous variable, binned at the criteria for deficiency (< 20 ng.ml-1), to investigate a threshold effect. Neither continuous (r = 0.18, p = 0.20) nor dichotomous (r = 0.16, p = 0.27) 25(OH)D concentration was significantly correlated with testosterone concentration. A small, inverse correlation (r = -0.30, p = 0.04) was detected between 25(OH)D and cortisol concentrations when analyzed as a dichotomous variable only. Serum 25(OH)D concentration was neither associated with testosterone (p = 0.09) nor cortisol concentrations (p = 0.11) after adjusting for age, fat free mass and fat mass in sequential linear regression. The inability of vitamin D status to independently predict testosterone and cortisol concentrations suggests that any performance-enhancing effects of vitamin D in athletes are unlikely to be mediated primarily through these hormones, at least amongst young male ice-hockey players. PMID- 30449938 TI - Serum cortisol as a moderator of the relationship between serum testosterone and Olympic weightlifting performance in real and simulated competitions. AB - Some equivocality exists regarding the effect of testosterone (T) on competitive performance with cortisol (C) implicated as a moderating factor. This study investigated whether C is moderating the T relationship with Olympic weightlifting (OWL) performance during real and simulated competitions. We monitored 105 male athletes (age 19.3+/-3.7 years); 46 during real OWL competitions (e.g., national age championships) and 59 across simulated events (e.g., talent identification). Serum T and C were assessed before warming up and within 15 minutes of event completion. Performance was indexed by the total combined load across the snatch and clean and jerk exercises. Hierarchical linear regression and simple slopes were employed to test the hormone and performance relationships. Pre-competition T (pre-T) and C (pre-C) were unrelated to OWL performance when controlling for competition type, time of day, age, and body mass (model=75.6% variance). However, the pre-T * pre-C interaction was significant (model=77% variance). Upon exploring this interaction, different pre T and performance relationships emerged for males with high pre-C (beta=-9.96) and low pre-C levels (beta=9.04), with diverging slopes (p=0.006). The assessment of T changes and pre-C produced similar results. The association between male T and performance during OWL competition was determined by C activity, which could explain conflicting reports of T as a correlate of competitive abilities. Our results imply that T and C are not strictly anabolic and catabolic biomarkers of performance, respectively, but rather they exert complementary actions that could depend on task, situational and environmental needs. PMID- 30449939 TI - Effects of work-matched moderate- and high-intensity warm-up on power output during 2-min supramaximal cycling. AB - We tested the hypothesis that compared with a moderate-intensity warm-up, a work matched high-intensity warm-up improves final-sprint power output during the last 30 s of a 120-s supramaximal exercise that mimics the final sprint during events such as the 800-m run, 1,500-m speed skate, or Keirin (cycling race). Nine active young males performed a 120-s supramaximal cycling exercise consisting of 90 s of constant-workload cycling at a workload that corresponds to 110% peak oxygen uptake (VO2peak) followed by 30 s of maximal cycling. This exercise was preceded by 1) no warm-up (control), 2) a 10-min cycling warm-up at a workload of 40% VO2peak (moderate-intensity), or 3) a 5-min cycling warm-up at a workload of 80% VO2peak (high-intensity). Total work was matched between the two warm-up conditions. Both warm-ups increased 5-s peak (observed within 10 s at the beginning of maximal cycling) and 30-s mean power output during the final 30-s maximal cycling compared to no warm-up. Moreover, the high-intensity warm-up provided a greater peak (577+/-169 vs. 541+/-175 W, P=0.01) but not mean (482+/ 109 vs. 470+/-135W, P=1.00) power output than the moderate-intensity warm-up. Both VO2 during the 90-s constant workload cycling and the post-warm-up blood lactate concentration were higher following the high-intensity than moderate intensity warm-up (all P<=0.05). We show that work-matched moderate- (~40% VO2peak) and high- (~80% VO2peak) intensity warm-ups both improve final sprint (~30 s) performance during the late stage of a 120-s supramaximal exercise bout, and that a high-intensity warm-up provides greater improvement of short-duration (<10 s) maximal sprinting performance. PMID- 30449940 TI - Effect of the 11+ injury prevention programme on fundamental movement patterns in soccer players. AB - No studies have assessed whether changes in an individual's fundamental movement patterns can be achieved with the 11+ prevention programme in soccer players. The aim of this study was to assess the effect of the 11+ compared with a standard warm-up on fundamental movement patterns using the Functional Movement Screen (FMS) in amateur male soccer players. Twenty-three male soccer players (age: 24.7+/-.3.8 years; height: 1.77+/-0.58 m; body mass: 73.9+/-6.2 kg) were randomly assigned to the 11+ (n= 12) or control (n= 11) group. The intervention programme had to be carried out 3 times a week over 6 weeks. The 11+ warm-up lasted ~25 minutes and was conducted before starting regular practice, replacing the team's standard warm-up. The control group warmed up with standard jogging, ball exercises, and active stretching to match the duration of the 11+. Within-group analysis revealed significant improvements in the FMS total score in the 11+ (+10.51%; d= 0.83) and control group (+7.99%; d= 0.68) from pre-test to post test. In the between-group analysis, there were no significant differences between groups. At the post-test a significantly greater number of players in the 11+ group exhibited a score that improved to above the injury threshold (<=14) (p= 0.046). This study suggests that regular implementation of the 11+ injury prevention programme may not produce additional improvements in fundamental movement patterns other than those produced by a standard warm-up. PMID- 30449942 TI - Oxygen consumption during concurrent training: influence of intra-session exercise sequence and aerobic exercise modality. AB - To compare the acute effects of different intra-session exercise sequences and aerobic exercise modalities during concurrent training sessions on oxygen consumption (VO2) and energy expenditure (EE) in young women. Eleven young women volunteered to participate in this study and underwent tests of their dynamic strength and a maximal incremental test on both the treadmill and cycle ergometer. Four concurrent training sessions were performed: resistance-running (RRu), resistance-cycling (RC), running-resistance (RuR) and cycling-resistance (CR). The aerobic exercise lasted 30 minutes and was performed at a heart rate equivalent to 95% of the second ventilatory threshold. The resistance exercise lasted approximately 21 minutes and consisted of 4 sets of 10 RM in each exercise. The VO2 was continuously evaluated through the portable gas analyser. No differences were found in the VO2 between the intra-session exercise sequence independently of aerobic modality (i.e., RRu vs. RuR, and RC vs. CR), and the sessions with the running aerobic exercise showed greater VO2 than sessions using cycling aerobic exercise in both exercise sequences (VO2aerobic (ml . kg-1 . min 1) - RRu: 27.5; RuR: 27.1; RC: 20.2; CR: 20.8). The present study showed that the intra-session exercise sequence during concurrent training does not influence VO2. However, the optimal combination of resistance and aerobic exercise should include running in order to increase VO2 and optimize EE. PMID- 30449941 TI - Repeated-sprints exercise in daylight fasting: carbohydrate mouth rinsing does not affect sprint and reaction time performance. AB - To determine the effect of carbohydrate mouth rinsing (CHO-MR) on physical and cognitive performance during repeated-sprints (RS) after 3 days of intermittent fasting (abstaining from food and fluid 14 h per day). In a randomized and counter-balanced manner 15 active healthy males in a fasted state performed a RS protocol [RSP; 2 sets (SET1 and SET2) of 5*5 s maximal sprints, with each sprint interspersed with 25 s rest and 3 min of recovery between SET1 and SET2] on an instrumented non-motorized treadmill with embedded force sensors under three conditions: i) Control (CON; no-MR), ii) Placebo-MR (PLA-MR; 0% maltodextrin) and iii) CHO-MR (10% maltodextrin). Participants rinsed their mouth with either 10 mL of PLA-MR or CHO-MR solution for 5 s before each sprint. Sprint kinetics were measured for each sprint and reaction time (RTI) tasks (simple and complex) were assessed pre-, during- and post-RSP. There was no statistical main effect of CHO MR on mean power, mean speed, and vertical stiffness during the sprints between the PLA-MR and CON condition. Additionally, no statistical main effect for CHO-MR on accuracy, movement time and reaction time during the RTI tasks was seen. CHO MR did not affect physical (RSP) or cognitive (RTI) performance in participants who had observed 3 days of intermittent fasting (abstaining from food and fluid 14 h per day). PMID- 30449944 TI - Updated analysis of changes in locomotor activities across periods in an international ice hockey game. AB - The aim of this study was to examine changes in time-motion patterns of elite male ice hockey players during an international game with special reference to the development of fatigue. Ten elite male ice hockey players were filmed during an official international game. Detailed time-motion patterns and behaviours (effective playing, stoppage and resting times, number of shifts, low- and high intensity skating activities across periods as well as passing, shooting and body checking) were analysed during the three game periods. Shift duration averaged 85.72+/-4.89 s (44.01+/-5.71 s of effective playing time and 41.71+/-4.07 s of stoppage) and was repeated ~7.4+/-1.8 times per period. Mean effective playing time and effective time per shift decreased over the periods (-6.8+/-17.3%, P = 0.18, d = 0.71 and -8.5+/-12.7%, P = 0.20, d = 0.24, respectively), resulting in a shorter distance covered (-12.8+/-5.7%, P = 0.16, d = 0.46) from period 1 to 3. At similar time intervals, stoppage (+8.2+/-9.8%, P<0.05, d = 0.78) and bench resting period (+35.6+/-34.0%, P<0.05, d = 1.26) also increased. The number of sprints performed in period 3 was significantly lower than in period 1 (-46.7+/ 32.1%, P<0.01, d = 1.12). This was accompanied by a lower effective time (-16.8+/ 24.9%, P<0.05, d = 0.82) spent in high-intensity activities (fast forward skating, forward sprinting and fast backward and sprinting) - particularly in forward sprints (-54.8+/-20.7%, P<0.01, d = 1.07) - in period 3 vs. 1. Detailed analysis of players' time-motion patterns of an international ice hockey game indicates that the capacity to perform intense actions is impeded towards the end of the match (period 3). Assessing performance fatigability may help practitioners to tailor ice hockey-specific training routines to help prevent in game premature and/or excessive fatigue development. PMID- 30449943 TI - Functional movement screen and Y-Balance test scores across levels of American football players. AB - Few studies have investigated differences in functional movement assessment performance across scholastic levels of competition. This study examined Functional Movement Screen (FMS) performance in middle school (MS), high school (HS) and collegiate (COL) American football players and Y-Balance test (YBT) scores in MS and HS players. Functional movement measurements were collected for MS (N = 29; age = 12.8 +/- 0.7 years), HS (N =52; age = 15.7 +/- 1.2 years), and COL (N =77; age = 19.9 +/- 1.4 years) football players prior to each group's competitive season. Differences in composite FMS and YBT measurements were examined using Welch's ANOVA and Mann-Whitney U-tests, respectively. Chi-square analyses examined normality of score distributions for individual FMS tests. The MS group displayed a lower composite FMS (12.9 +/- 1.9) than both HS (14.0 +/- 1.7) and COL (14.1 +/- 2.1) groups (p = 0.019). COL players scored significantly lower on the Shoulder Mobility (SM) but higher on the Deep Squat (DS), In-line Lunge (ILL), Active Straight-Leg Raise (ASLR) and Push-Up (PU) than both HS and MS groups. No differences were found between MS and HS groups for any YBT normalized reach distances and side-to-side reach distance differences. FMS performance varied with football competition level whereas YBT performance did not. The results suggest that football competition levels normative data and injury-risk thresholds should be established when using FMS scores to guide performance and injury prevention programming. PMID- 30449945 TI - Effects of preconditioning hamstring resistance exercises on repeated sprinting induced muscle damage in female soccer players. AB - To examine whether adding preconditioning hamstring resistance exercises to a regular warm-up prior to a repeated sprinting exercise provides protection against the sprinting-induced muscle damage. Ten female soccer players (mean +/- SD age: 21.3 +/- 4.5yrs; height: 171.34 +/- 8.29 cm; weight: 68.53 +/- 11.27 kg) participated in this study. After the familiarization visit, the subjects completed three separate randomly sequenced experimental visits, during which three different warm-up interventions were performed before the muscle-damaging protocol (12 sets of 30-m maximal repeated sprints): 1. Regular running and static stretching (Control); 2. Control with hyperextensions (HE); 3. Control with single leg Romanian deadlift (SLRD). Before (Pre), immediately (Post0), 24 hours (24hr), and 48 hours after (48hr) the sprints, hamstring muscle thickness, muscle stiffness, knee flexion eccentric peak torque, knee extension concentric peak torque, and functional hamstring to quadriceps ratios were measured. Repeated sprints have induced muscle damage (e.g., an average of 42% knee flexion eccentric strength reduction) in all three conditions. After the SLRD, hamstring muscle thickness decreased from 24hr to 48hr (p < 0.001). Additionally, muscle stiffness and eccentric strength for the SLRD showed no difference from baseline at 24hr and 48hr, respectively. When compared with the SLRD at 48hr, the muscle stiffness and the eccentric strength were greater and lower, respectively, in other protocols. The SLRD protocol had protective effect on sprinting-induced muscle damage markers than other protocols. Athletes whose competitions/training are densely scheduled may take advantage of this strategy to facilitate muscle recovery. PMID- 30449946 TI - Intensity-dependent gene expression after aerobic exercise in endurance-trained skeletal muscle. AB - We investigated acute exercise-induced gene expression in skeletal muscle adapted to aerobic training. Vastus lateralis muscle samples were taken in ten endurance trained males prior to, and just after, 4 h, and 8 h after acute cycling sessions with different intensities, 70% and 50% VO2max . High-throughput RNA sequencing was applied in samples from two subjects to evaluate differentially expressed genes after intensive exercise (70% VO2max ), and then the changes in expression for selected genes were validated by quantitative PCR (qPCR). To define exercise induced genes, we compared gene expression after acute exercise with different intensities, 70% and 50% VO2max , by qPCR. The transcriptome is dynamically changed during the first hours of recovery after intensive exercise (70% VO2max ). A computational approach revealed that the changes might be related to up- and down-regulation of the activity of transcription activators and repressors, respectively. The exercise increased expression of many genes encoding protein kinases, while genes encoding transcriptional regulators were both up- and down regulated. Evaluation of the gene expression after exercise with different intensities revealed that some genes changed expression in an intensity-dependent manner, but others did not: the majority of genes encoding protein kinases, oxidative phosphorylation and activator protein (AP)-1-related genes significantly correlated with markers of exercise stress (power, blood lactate during exercise and post-exercise blood cortisol), while transcriptional repressors and circadian-related genes did not. Some of the changes in gene expression after exercise seemingly may be modulated by circadian rhythm. PMID- 30449947 TI - Physiological responses, fatigue and perception of female soccer players in small sided games with different pitch size and sport surfaces. AB - The aim of this research was to evaluate the influence of game surface and pitch size on the physiological responses, jump performance and perceptions of sub elite female soccer players playing four-a-side games. Sixteen sub-elite female soccer players were divided into four groups of four players each. Three small sided games (SSGs; pitch size: 400 m2, 600 m2 and 800 m2) were played on three surfaces (dirt [DT], artificial turf [AT] and natural grass [NG]). Players' heart rate (HR) was monitored during each game. Before and after each SSG, participants performed two counter-movement jumps (CMJs) and answered a questionnaire based on visual analogue scales (VASs) to indicate their perception of the effort required on each surface. DT obtained lower outputs for most variables. In the SSG 600 mean HR was higher on NG than AT (+3.31 %HRmax; p = 0.029), but players' overall satisfaction with both surfaces was similar (p>0.05). The SSG 400 received the lowest ratings for most variables, whereas the SSG 600 resulted in higher mean HR than SSG 800 [NG (+9.14 b.p.m.; p = 0.001); AT (+7.32 b.p.m.; p = 0.014)]. No surface differences in CMJ performance were found. In conclusion, a higher internal load can be achieved on NG, whereas DT is not recommended for playing soccer. Moreover, the internal load on players in SSGs can be controlled by manipulating pitch size, but over-large pitches may entail a reduction in the physiological profile of female soccer players. PMID- 30449949 TI - Rigid Body Dynamics Algorithm for Modeling Random Packing Structures of Nonspherical and Nonconvex Pellets. AB - Despite the common use of nonspherical catalyst pellets in chemical engineering applications, the packing structures of such pellets have not been as systematically studied and characterized as spherical packings. We propose a packing algorithm based on rigid body dynamics to simulate packing of nonspherical and possibly nonconvex pellets. The algorithm exerts a hard-body approach to model collision phenomena. The novelty is that the transition between moving and resting particles is controlled by a cutoff on the relative contact velocities, instead of artificially damping linear and angular velocities to stabilize the algorithm. The algorithm is used to synthesize packings of spheres, cylinders, and Raschig rings with tube-to-pellet diameter ratios 3-9.16. The packings are validated in terms of bulk porosity and radial void fraction distribution, finding satisfactory agreement with literature data. Denser packing structures are generated with high restitution coefficients and low friction coefficients. The confining tube walls play an important role, with highly fluctuating bulk porosities in narrow tubes. PMID- 30449948 TI - Acute effects of whole body vibration combined with blood restriction on electromyography amplitude and hormonal responses. AB - The purpose of this study was to investigate the effects of whole body vibration (WBV) exercise with and without blood flow restriction (BFR) on electromyography (EMG) amplitude and hormonal responses. Eight healthy male adults who lacked physical activity participated in this study and completed 10 sets of WBV and WBV + BFR sessions in a repeated measures crossover design. In the WBV + BFR session, the participants wore a BFR device inflated to 140 mmHg around the proximal region of the thigh muscles. The results indicated that the EMG values from the rectus femoris and vastus lateralis during the WBV + BFR session were significantly higher than those during the WBV session (p < 0.05). Two-way analysis of variance with repeated measures showed that the WBV + BFR and WBV exercise sessions induced a significant (simple main effect for time) increase in lactate (LA) (0.61-4.68 vs. 0.46-3.44 mmol/L) and growth hormone (GH) (0.48-3.85 vs. 0.47-0.82 ng/mL) responses after some of the post-exercise time points (p < 0.05). WBV + BFR elicited significantly higher LA and GH (simple main effect for trial) responses than did WBV after exercise (p < 0.05). Although no significant time * trial interactions were observed for testosterone (T) (604.5-677.75 vs. 545.75-593.88 ng/dL), main effects for trial (p < 0.05) and for time (p < 0.05) were observed. In conclusion, WBV + BFR produced an additive effect of exercise on EMG amplitude and LA and GH responses, but it did not further induce T responses compared to those with WBV alone. PMID- 30449950 TI - Chemical Recovery of gamma-Valerolactone/Water Biorefinery. AB - We introduce the optimization of the pulping conditions and propose different chemical recovery options for a proven biorefinery concept based on gamma valerolactone (GVL)/water fractionation. The pulping process has been optimized whereby the liquor-to-wood (L:W) ratio could be reduced to 3 L/kg without compromising the pulp properties as raw material for textile fibers production. The recovery of the pulping solvent was performed through combinations of lignin precipitation by water addition, distillation at reduced pressure, and liquid CO2 extraction. With a two-step lignin precipitation coupled with vacuum distillation, more than 90% of lignin and GVL could be recovered from the spent liquor. However, a significant part of GVL remained unrecoverable in the residue, which was a highly viscous liquid with complicated phase behavior. The recovery by lignin precipitation combined with liquid CO2 extraction could recover more than 85% GVL and 90% lignin without forming any problematic residue as in the distillation process. The remaining GVL remained in the raffinate containing a low amount of lignin and other compounds, which can be further processed to isolate the GVL and improve the recovery rate. PMID- 30449951 TI - Precipitation, temperature, and teleconnection signals across the combined North American, Monsoon Asia, and Old World Drought Atlases. AB - The tree-ring-based North American Drought Atlas (NADA), Monsoon Asia Drought Atlas (MADA), and Old World Drought Atlas (OWDA) collectively yield a near hemispheric gridded reconstruction of hydroclimate variability over the last millennium. To test the robustness of the large-scale representation of hydroclimate variability across the drought atlases, the joint expression of seasonal climate variability and teleconnections in the NADA, MADA, and OWDA are compared against two global, observation-based PDSI products. Predominantly positive (negative) correlations are determined between seasonal precipitation (surface air temperature) and collocated tree-ring-based PDSI, with average Pearson's correlation coefficients increasing in magnitude from boreal winter to summer. For precipitation, these correlations tend to be stronger in the boreal winter and summer when calculated for the observed PDSI record, while remaining similar for temperature. Notwithstanding these differences, the drought atlases robustly express teleconnection patterns associated with the El Nino-Southern Oscillation (ENSO), North Atlantic Oscillation (NAO), Pacific Decadal Oscillation (PDO), and Atlantic Multidecadal Oscillation (AMO). These expressions exist in the drought atlas estimates of boreal summer PDSI despite the fact that these modes of climate variability are dominant in boreal winter, with the exception of the Atlantic Multidecadal Oscillation. ENSO and NAO teleconnection patterns in the drought atlases are particularly consistent with their well-known dominant expressions in boreal winter and over the OWDA domain, respectively. Collectively, our findings confirm that the joint Northern Hemisphere drought atlases robustly reflect large-scale patterns of hydroclimate variability on seasonal to multidecadal timescales over the 20th century and are likely to provide similarly robust estimates of hydroclimate variability prior to the existence of widespread instrumental data. PMID- 30449952 TI - Bis(oxazoline) derived cationic aqua complexes: highly effective catalysts for enantioselective Diels-Alder reactions. AB - Cationic aqua complex derived from bidentate inda-box ligand and Cu(ClO4)2.6H2O is an excellent catalyst (5-10 mol%) for enantioselective (92-99% ee) Diels-Alder reactions of cyclopentadiene and various bidentate dienophiles. PMID- 30449953 TI - Bayesian Additive Regression Trees using Bayesian Model Averaging. AB - Bayesian Additive Regression Trees (BART) is a statistical sum of trees model. It can be considered a Bayesian version of machine learning tree ensemble methods where the individual trees are the base learners. However for datasets where the number of variables p is large the algorithm can become inefficient and computationally expensive. Another method which is popular for high dimensional data is random forests, a machine learning algorithm which grows trees using a greedy search for the best split points. However its default implementation does not produce probabilistic estimates or predictions. We propose an alternative fitting algorithm for BART called BART-BMA, which uses Bayesian Model Averaging and a greedy search algorithm to obtain a posterior distribution more efficiently than BART for datasets with large p. BART-BMA incorporates elements of both BART and random forests to offer a model-based algorithm which can deal with high dimensional data. We have found that BART-BMA can be run in a reasonable time on a standard laptop for the "small n large p" scenario which is common in many areas of bioinformatics. We showcase this method using simulated data and data from two real proteomic experiments, one to distinguish between patients with cardiovascular disease and controls and another to classify aggressive from non aggressive prostate cancer. We compare our results to their main competitors. Open source code written in R and Rcpp to run BART-BMA can be found at: https://github.com/BelindaHernandez/BART-BMA.git. PMID- 30449955 TI - Characterization of dental materials. PMID- 30449954 TI - Sensitivity of treatment recommendations to bias in network meta-analysis. AB - Network meta-analysis (NMA) pools evidence on multiple treatments to estimate relative treatment effects. Included studies are typically assessed for risk of bias; however, this provides no indication of the impact of potential bias on a decision based on the NMA. We propose methods to derive bias adjustment thresholds which measure the smallest changes to the data that result in a change of treatment decision. The methods use efficient matrix operations and can be applied to explore the consequences of bias in individual studies or aggregate treatment contrasts, in both fixed and random-effects NMA models. Complex models with multiple types of data input are handled by using an approximation to the hypothetical aggregate likelihood. The methods are illustrated with a simple NMA of thrombolytic treatments and a more complex example comparing social anxiety interventions. An accompanying R package is provided. PMID- 30449956 TI - An in vitro study to evaluate and compare the surface roughness in heat-cured denture-based resin and injection-molded resin system as affected by two commercially available denture cleansers. AB - Background: Denture hygiene is of utmost importance to maintain the dentures as well as the underlying tissues in appropriate health. Various denture cleansers as well as denture-based materials have evolved in the market; however, the effect of denture cleansers on different types of denture-based materials has not been very well documented. Aim: The purpose of this in vitro study was to evaluate and compare the surface roughness in heat-cured denture-based resin and injection-molded resin system as affected by two commercially available denture cleansers for a period of 15, 30, and 45 days. Methodology: A standardized metal die was fabricated to make 120 denture-based resin discs of uniform dimensions. The samples of heat-cured denture-based resin and injection-molded thermoplastic denture-based resin were immersed in the two denture cleansing solutions for a period of 15, 30, and 45 days, respectively. The surface roughness was evaluated by surface profilometer TR200. The data were subjected to statistical analysis and the comparison of quantitative data was done using unpaired t-test and repeated-measures ANOVA test. Results: The surface roughness values (Ra) of heat cured denture base resin samples when immersed in two denture cleansers were 0.22 MUm at 0 days, 0.27 and 0.29 MUm at 15 days, 0.29 and 0.31 MUm at 30 days, 0.30 and 0.31 MUm at 45 days whereas for injection moulded samples surface roughness values were 1.31 & 1.27 MUm at 0 days, 1.46 & 1.66 MUm at 15 days, 1.50 & 1.69 MUm at 30 days, and 1.50 & 1.69 MUm at 45 days. Conclusion: The surface roughness (Ra) increased significantly in injection-molded polyamide denture-based resin samples when immersed in both the denture cleansers. Whereas, heat-cured denture based resin samples did not reveal any significant surface changes at the various time intervals. Hence, the use of denture cleansers is questionable in thermoplastic resins. PMID- 30449957 TI - A cephalometric analysis to establish a correlation of different ridge relations to three levels of camper's line in edentulous patients: An in vivo study. AB - Aim: This study was undertaken with an aim to establish a relationship between normognathic (Class I), retrognathic (Class II), and prognathic (Class III) ridge relation and superior, middle, and inferior levels of the ala-tragus line in edentulous individuals, by utilizing arbitrary and cephalometric methods. Methodology: Ninety edentulous male patients were selected for the study, and after establishing tentative jaw relation, radiopaque ball bearings were attached on three levels of the tragus and inferior part of the ala of the nose. Furthermore, orthodontic wire was attached to maxillary occlusal rims. Lateral cephalometric radiographs were taken, and tracings were carried out to compare and to evaluate the cephalometrically derived ridge relations with that of the visually analyzed ridge relations based on the mounted casts in relation to the ala-tragus line. The results obtained were statistically analyzed using one-way ANOVA test, and multiple comparisons were carried out using the Bonferroni tests. The interoperator variability for obtaining ridge relations using visual analysis and the cephalometrically obtained ridge relations were analyzed using the Kappa statistics. Results: The result obtained states that 78 participants out of 90 participants are in total agreement with the Kappa value of 0.8. Conclusion: The study concluded that for Class I and Class III, the inferior part of the tragus forming the ala-tragus line, and for Class II, the middle part of the tragus should be considered for establishing the occlusal plane. PMID- 30449958 TI - Effect of the simulated Indian and Mediterranean climates on the Shore A hardness of maxillofacial silicone. AB - Purpose: The purpose of this study was to assess and compare the effect of the simulated Indian and Mediterranean climates on the Shore A hardness of a commercially available nonpigmented room temperature vulcanizing maxillofacial silicone. Materials and Methods: Sixty specimens were fabricated from A-2000 silicone material (Factor II), using a stainless steel mold of dimension 20 mm * 2 mm. The initial Shore A hardness was noted using a digital durometer. Thirty samples were subjected to the simulated Mediterranean climate (Group I), and the remaining thirty samples were subjected to the Indian tropical climate (Group II) in an accelerated weather chamber to simulate 1 year of clinical use. Final Shore A hardness was noted. A one-way ANOVA and Bonferroni post hoc tests were performed for the Shore A hardness at P < 0.05. Results: The mean initial Shore A hardness for both the groups was 24.9833. After accelerated weathering, Group I showed mean Shore A hardness of 33.0000 whereas Group II showed mean Shore A hardness of 38.0000. Conclusions: The Shore A hardness of Factor II, before and after accelerated artificial weathering, was statistically significant at 0.05 level (P < 0.05). The change in Shore A hardness was greater in the simulated tropical climate group (Group II) as compared to the simulated Mediterranean climate group (Group I) but within clinical limits. PMID- 30449959 TI - A comparative evaluation of vertical marginal fit of provisional crowns fabricated by computer-aided design/computer-aided manufacturing technique and direct (intraoral technique) and flexural strength of the materials: An in vitro study. AB - Background: With the advent of new provisional crown materials, it has become imperative to evaluate their marginal fit and strength to select the ideal provisional crown material. Aim: The purpose of this in vitro study was to evaluate and compare the vertical marginal fit and flexural strength of provisional crowns prepared using computer-aided design-computer-aided manufacturing (CAD-CAM) temporary material versus those fabricated using bis acrylic composite-based autopolymerizing resin material. Materials and Methods: Eighty samples were divided into two equal Groups (I and II). Group I consisted of forty samples that were evaluated for flexural strength and Group II consisted of forty samples that were evaluated for their vertical marginal fit. Group I was subdivided as Group IA, i.e., bis-acrylic composite-based autopolymerizing resin material (ProtempTM 4) blocks and Group IB, i.e., CAD/CAM provisional material blocks. Similarly, Group II was subdivided as Group IIA, i.e., bis-acrylic composite-based autopolymerizing resin material (ProtempTM 4) crowns and Group IIB, i.e., CAD/CAM provisional material crowns. Marginal adaptation was evaluated using stereomicroscope and image analyzing software to measure the amount of marginal gap. For flexural strength, all specimens were subjected to a standard compression load in the universal testing machine until fracture occurred. Data were analyzed using Student's t-test (P = 0.001). Results: CAD/CAM provisional crowns showed better marginal adaptation (34.34 MUm) as compared to bis-acrylic composite-based autopolymerizing resin material (ProtempTM 4) crowns (63.42 MUm) (P < 0.001). The flexural strength of CAD/CAM blocks (94.06 megapascals [MPa]) was not statistically different from bis-acrylic composite-based autopolymerizing resin material (ProtempTM 4) blocks (101.41 MPa) (P > 0.001). Conclusion: ProtempTM 4 and CAD/CAM provisional materials have comparable flexural strength. However, the marginal fit of temporary crowns fabricated by CAD/CAM was found to be superior to the ones fabricated using bis-acrylic composite-based autopolymerizing resin material (ProtempTM 4). PMID- 30449960 TI - Determination of the center of anteroposterior curve of occlusion in a selected local population: A cross-sectional cephalometric study. AB - Objective: The objective of this paper was to cephalometrically determine the center of the anteroposterior curve of occlusion, and its relation to standardized landmarks, to establish a suitable occlusal curve for the restoration of maxillary and mandibular arches in a selected local population. To the best of the authors' knowledge, this was the first cephalometric study identifying variations occurring in the anteroposterior curve in this population. Materials and Methods: A total of 80 patients (40 males and 40 females) with Angle's Class I occlusion and normal growth pattern were selected. Landmarks were established following tracings on standardized lateral cephalograms. The center of the occlusal curve was determined, and its distance from the nasion, lachryma, and orbitale was statistically compared using ANOVA, post hoc and proximal matrix tests in males and females. In addition, a relationship between the depth of occlusal curve and the condyle was established. Results: The mean distances of the center from nasion, lachryma, and orbitale (statistically significant) were 11.15 mm +/- 5.65 mm, 18.68 mm +/- 8.6 mm and 33.10 mm +/- 10.13 mm for females (P < 0.001) and 9.7 mm +/- 4.69 mm, 16.80 mm +/- 6.45 mm and 31.22 mm +/- 8.51 mm (P < 0.001) for males, respectively. Depth of the curve and distance from the condyle had an inverse corelation. Conclusion: Nasion is closest to the center of the curve of occlusion in both females and males followed by lachryma and orbitale. Hence, nasion can be considered as a point of reference clinically while determining anteroposterior curve of occlusion. PMID- 30449961 TI - Computer-aided design finite element modeling of different approaches to rehabilitate endodontically treated teeth. AB - Background: Carious lesions and dental fractures cause weakening in the dental structure. In these situations, endodontic treatment and prosthetic rehabilitation using an intraradicular post are indicated. However, the postspace preparation of the root canal further weakens the dental remnant, especially if there is no ferrule present. This study aimed to evaluate the stress distribution in endodontically treated upper premolars treated with different rehabilitation approaches. Materials and Methods: An endodontically treated first upper premolar was modeled for finite element analysis. Three different approaches were carried out on this model: rehabilitation with fiberglass post (FCP), endocrown (ECW), or buildup. The models were exported in STEP format to the analysis software (ANSYS 17.2, ANSYS Inc., Houston, TX, USA). The solids were considered isotropic, homogeneous, and linearly elastic. A mechanical, structural static analysis was used as the criterion of maximum principal stress to show regions under tensile stress to evaluate the stress distribution in the restoration, cementation line, and root. A load of 400 N (90 degrees ) was applied to the lingual triangular ridge. The values of maximum principal stress in MPa were evaluated through colorimetric graphs. Results: Similar stress concentration was observed for all groups. However, the ECW group presented higher values in the restoration/cement interface and root dentin. Conclusions: All the treatment modalities had favorable mechanical behavior to support the masticatory loads; nevertheless, the ECW group presented a higher risk of detachment failure. PMID- 30449962 TI - Comparison of the effect of monolithic and layered zirconia on natural teeth wear: An in vitro study. AB - Aim: The aim of this study is to compare wear of the natural teeth against monolithic zirconia and layered zirconia with different surface finishing procedures such as unpolished unglazed, polished unglazed, and polished glazed. Materials and Methods: The two-bodied wear test was carried out in a custom-made oral wear simulator with a sample size of 60 zirconia specimen opposing natural teeth. Zirconia specimen was divided into two groups layered and monolithic which further subdivided into unpolished unglazed, polished unglazed, and polished glazed groups (n = 10). The amount of enamel wear occurred for 250,000 cycles when opposed by monolithic and layered zirconia with different surface finishing methods was measured by loss of height of each tooth using three-dimensional scanning and loss of weight using sensitive balance at specified time intervals of 50,000 cycles during masticatory test considering baseline measurement as control. The data were statistically analyzed to compare the enamel wear against layered and monolithic zirconia with different surface finishing protocols by repeated ANOVA test. Results: Monolithic polished unglazed zirconia showed least tooth wear followed by monolithic polished glazed zirconia, monolithic unpolished unglazed zirconia, and layered unpolished unglazed zirconia showed highest tooth wear in terms of both height loss and weight loss (P < 0.01). Conclusion: Within the limitations of the study, monolithic polished unglazed zirconia is wear friendly to the opposing natural teeth, and polished surfaces in both the groups showed less tooth wear compared to the glazed surface of zirconia specimen. PMID- 30449963 TI - A study on the evaluation of bite force, prosthetic and nutritional status in adult cleft patients in Kolkata. AB - Context: Altered orofacial morphology and poor dental status affects the dietary intake of cleft patient, making susceptible to nutritional imbalance. Oral health care planning for this population is impossible without the evaluation of stomatognathic functional status as well as prosthetic and nutritional status and need. Aims: The aim of this study was to evaluate prosthetic status and prosthetic treatment need, bite force and nutritional status, in adult cleft patients and to compare them with the adult noncleft population of similar definition. Settings and Design: Cleft (n = 250) and noncleft (n = 250) individuals of either sex, aged 18 years or above, excluding severe medically compromised and differently abled, were examined and individual biteforce was measured after obtaining written consent and ethical clearance from the two institutions in Kolkata. Subjects and Methods: A "raw data sheet" was prepared according to the parameters of the "Oral Health Surveys: Basic methods," World Health Organization (1997) for evaluation of prosthetic status and need, dentition status and Mini-Nutritional Assessment, Nestle (1994) for the evaluation nutritional status. A Gnathodynamometer was used to record bite force. Statistical Analysis Used: Statistical analysis was performed using SPSS 20.0.1, Graph Pad Prism version 5, Student's t-test, and Chi-square test. Results: The mean bite force of frontal area in cleft group (3.4356 +/- 0.9457 kgf) was found to be significantly lower (P < 0.0001) than in noncleft (22.8749 +/- 5.3644 kgf) group. The difference of mean bite force in the right side (2.4576 +/- 0.6131 kgf) and left side (1.2708 +/- 0.1036 kgf) in cleft group was found to be statistically significant (P < 0.0001). Prosthetic need in maxillary arch was found to be significantly (chi2: 490.0000; P < 0.0001) higher in cleft than in noncleft group. Nutritional status was observed to be significantly (chi2: 179.4049; P < 0.0001) higher "at risk" in cleft than in noncleft group. Conclusions: Lack of adequate Government concern leading to significantly higher prosthetic need and lower prosthetic status, hence lower bite force resulting lower nutritional status in adult cleft patients in Kolkata. PMID- 30449964 TI - Cone beam computerized tomography evaluation of incisive canal and anterior maxillary bone thickness for placement of immediate implants. AB - Purpose: Variation of dimensions of the nasopalatine canal and anterior maxillary bone thickness vary in relation to age, gender, edentulism, and ethnicity; thorough knowledge with regard to these landmarks is of vital importance prior to surgical procedures such as implant placement and local anesthesia in the anterior maxilla. Cone beam computerized tomography (CBCT) aids in accurate treatment planning in such situations. Subjects and Methods: A total of 300 participants were selected by the inclusion and exclusion criteria. CBCT was performed with Hyperion X9 CBCT Scanner. Images were reconstructed from the CBCT data using NNT image reconstruction software and visualized using multi-planar resolution screen. The dimensions of the nasopalatine foramen (NPF), the incisive canal (IC) and foramen, and anterior maxillary bone thickness were measured. Results: The mean diameter of NPF was found to be 3.27 mm, incisive foramen (IF) was 3.62 mm, IC was 2.12 mm. The average length of the IC was 10.66 mm. The IF was located at a mean distance of 13.81 mm away from the most anteroinferior point of the cortical plate of the labial bone of the maxilla. The anterior maxillary bone was the thickest at the nasal spine level (10.94 mm), and was the narrowest at lower labial alveolus (7.16 mm). The average anterior maxillary bone thickness was found to be 8.36 mm. Conclusion: Within the limitations of the study, it was found that found that gender and age are important factors that affected the characteristics of the IC and the amount of bone anterior to it. PMID- 30449965 TI - Prosthetic rehabilitation of resected orbit in a case of mucormycosis. AB - The design of orbital prosthesis to rehabilitate patients with orbital exenteration depends on the underlying clinical condition, material chosen for prosthesis, method of retention of the prosthesis, and and preference of the patient. Rehabilitation of a patient with orbital exenteration due to mucormycosis has been described by fabricating a prosthesis that used polymethyl methacrylate (to fabricate a conformer) and silicone material (to fabricate prosthetic superstructure). The two-component prosthesis was designed to attain dual mechanical retention using an anatomic undercut (conformer) and manually created mechanical undercut (prosthetic superstructure). The objective was to maintain the biological health of the underlying postsurgical tissue, longevity of the prosthesis, optimal esthetics, and adequate retention. PMID- 30449966 TI - Prosthodontic rehabilitation of combined oronasal defect in patients with non Hodgkin's lymphoma using two different attachments: Two case reports. AB - Debridement of affected parts in patients with non-Hodgkin's lymphoma leads to large mid facial defects leading to poor quality of life due to cosmetic disfigurement and various functional comorbidities. Therefore, a surgeon should refer the patients to a prosthodontist for replacement of lost tissues to improve their function and esthetics. Two cases have been presented here with a history of non-Hodgkin's lymphoma having large, continuous defects involving nose, cheeks, and maxilla. Retaining large facial prosthesis and intraoral obturator was a challenge as supporting hard and soft tissues were less. Two-piece lightweight prostheses were fabricated and retained with the use of very economical titch buttons used (used in clothes) in case 1 due to financial constraints and slightly expensive iron boron neodymium magnets in case 2. Functional and esthetic rehabilitation was successfully achieved with intraoral and facial prostheses attached to each other. PMID- 30449968 TI - Implementation and scale-up of a biomass pellet and improved cookstove enterprise in Rwanda. AB - This paper reviews the experience of a for-profit firm in Rwanda promoting biomass pellets and a fan micro-gasification improved cookstove as a clean cooking alternative to charcoal. Consumers purchase locally produced biomass pellets and receive the improved cookstove on a lease basis. The cost of the pellets and stove(s) is lower than the cost of cooking with charcoal in the urban setting where our study takes place. Inyenyeri has been piloting its business model since 2012. Using data from an ongoing quantitative impact evaluation study, focus group discussions, and a series of key informant interviews, we chronicle the firm's experience with stove choice, pellet production, and marketing, highlighting lessons for the design of private sector led clean cooking interventions We find that 38% of households marketed to as part of our ongoing impact evaluation study adopted the pellet and stove system, but that approximately 45% of those who adopted suspended contracts after signing up. The firm's experience with stove choice, pellet production, pricing structures, and customer service strategies have influenced implementation, adoption rates, and scale-up. Customer preferences for specific stove attributes and willingness of stove manufacturers to modify stoves for local conditions have influenced both the firm's choice of stove and customer satisfaction. In 2015 the firm transitioned customers from the Philips stove to the Mimi Moto, a decision which created confusion among consumers, and affected adoption rates. Despite the challenge of establishing and scaling-up pellet production in central Africa, the firm increased production 400% between 2014 and 2017 to reach 800,000 kg/year. Importing and maintaining pelletizing equipment in Rwanda is costly, the supply of feedstock, and undercapitalization of the firm have affected production. With respect to marketing, after experimenting with a sign-up fee and a minimum monthly purchase of pellets, the firm has decided to transition to a pay-as-you go system to reduce perceived risk by consumers. A high-level of customer service including in home visits, free in-home repair, and home delivery of pellets are major innovations. The long pilot phase and the evolutionary nature of the firm's activities illustrate both the complexity of building a market for clean cooking, and the time required to understand nascent markets and consumer demand. PMID- 30449967 TI - Presentation of cysticercosis of the lateral pterygoid muscle as temporomandibular disorder: A diagnostic and therapeutic challenge. AB - Orofacial pain can often be the chief complaint of many systemic disorders. Cysticercosis involving the lateral pterygoids may cause limitation of mouth opening and may mimic clinical symptoms of a temporomandibular disorder. A 37 year-old female presented with 1-month-old complaint of limited mandibular range of motion. She reported a similar episode a year earlier and was diagnosed with a temporomandibular joint disorder by her primary dentist. Comprehensive intra- and extra-oral examinations were performed, which revealed a limitation of mouth opening accompanied by mild limitation of contralateral excursion. A magnetic resonance imaging revealed a ring-enhancing lesion within the left pterygoid muscle suggestive of cysticercosis. The patient was referred to her primary care physician for further treatment and given physical therapy (stretching exercises) to improve mouth opening. One week later, she developed lesions in the arm and trunk. Further ultrasound imaging of the abdomen and the forearms confirmed the diagnosis of cysticercosis. She was treated with albendazole, physiotherapy, joint stabilization appliance, and had eventual complete recovery. This case emphasizes the importance of diagnosis of a systemic condition that may have serious implications, if untreated, and the importance of a comprehensive evaluation, workup, and multidisciplinary management. PMID- 30449969 TI - A journey of the Journal of Clinical Orthopaedics and Trauma. PMID- 30449970 TI - Has the risk of dislocation after total hip arthroplasty performed for displaced femoral neck fracture improved with modern implants? AB - Background: Displaced femoral neck fractures (DFNF) in the elderly can be treated with hemiarthroplasty or total hip arthroplasty (THA). One concern with utilizing THA in this setting is post-operative dislocation. The purposes of this study were to determine the incidence of hip dislocation following THA for DFNF and to identify risk factors for dislocation. Methods: The charts of 66 posterior approach THA cases performed for DFNF with mean post-operative follow-up of 4.4 years were retrospectively reviewed. Pre-operative patient demographic data and intra-operative clinical data were recorded including age, race, gender, height, weight, body mass index (BMI), femoral head diameter, acetabular cup diameter, use of an elevated liner, and cementing of femoral component. For patients with available post-operative pelvis radiographs, acetabular cup inclination and version angles were also calculated. Results: Four dislocation (4/66, 6%) events occurred at an average of 51 days after surgery. No specific risk factors for dislocation were identified but the use of a cemented femoral stem did approach significance (p = 0.06). 47% of the acetabular cups were located outside of the Lewinnek safe zone. Although the dislocation rate of THAs with acetabular cups outside of the safe zone was higher than the dislocation rate for THAs with cups in the safe zone (12.5% vs 0%), placement of acetabular cups outside of the safe zone was not a risk factor for dislocation. Conclusions: Posterior THA with proper cup positioning and meticulous soft tissue repair is an effective treatment option for DFNF with low dislocation risk. PMID- 30449971 TI - Birmingham hip resurfacing versus cementless total hip arthroplasty in patients 55 years or younger: A minimum five-year follow-up. AB - Objective: The optimal reconstructive method for advanced degenerative hip disease in young adults is a topic of ongoing discussion. The purpose of this study is to report the largest single institution experience from the United States on the outcomes of Birmingham hip resurfacing (BHR) vs. cementless total hip arthroplasty (THA) in patients 55 years or younger at a minimum follow-up of five years. Currently, BHR is the only FDA-approved hip resurfacing implant available in the US. Methods: A cohort of 505 patients representing all BHR cases performed at our institution between 2006 and 2010 was compared with an identical size cohort of consecutive patients who underwent primary cementless THA. Exclusion criteria were age greater than 55 years, non-elective cases, revision procedures, and those performed for fractures, tumors, or by low-volume arthroplasty surgeons. THAs with metal on metal articulation were also excluded. Outcomes: assessed were all-cause reoperations, complications, patient satisfaction, and mortality. After exclusions, 442 patients with BHR and 327 with THA were included. Results: Mean follow-up was 73.2 months. After controlling for potential confounding factors, multivariate analyses showed significant increase in the rates of revision surgery (p < 0.001), overall complications (p < 0.001), all-cause reoperations (p = 0.014), and mortality (p < 0.001) in the THA cohort. Component loosening was the most common cause for revision in the THA group. Patients with THA were also less likely to be satisfied (p = 0.046). Conclusions: This is largest US study to report on the midterm outcomes of BHR vs. THA. The results demonstrate favorable results for BHR in patients 55 years or younger. Long-term multicenter studies are needed to better understand the optimal patient characteristics when deciding between THA versus BHR. PMID- 30449972 TI - Is the fracture pattern in periprosthetic fractures around the knee related with the anterior femoral notch? AB - Introduction: Periprosthetic fractures around the knee (PPF) are a devastating complication of total knee arthroplasty (TKA). Anterior femoral notching during TKA is considered a risk factor for PPF. The aim of this paper is to determine if an anterior femoral notch after total knee arthroplasty may affect the fracture pattern when a PPF appears postoperatively. Material and methods: 50 patients diagnosed in our centre of a PPF from January 2010 to December 2013 were retrospectively enrolled. 100 patients who underwent a total knee arthroplasty without fracture were randomly obtained as a control group. Evidence of the notch was searched in both groups in postoperative X-rays. In the PPF group, distance from the shield of the femoral component to the most distal (d) and proximal (D) point of the fracture were measured. Results: Two different groups were obtained: 1) d = 0 (33 out of 50 patients); the fracture is supposed to be related with the notch as it's a theoretically weaker area. 2) d > 0 (17 out of 50 patients); the fracture pattern has no relationship with the notch. Prevalence of patients suffering a fracture in the shield of the prosthesis (d = 0), was similar in both patients with notch (66,7%) and without it (68%). Conclusions: In conclusion, fracture pattern is not related with the existence of a femoral notch in the clinical setting. PMID- 30449973 TI - Which do patients prefer, unicompartmental or total knee arthroplasty? AB - Objective: Unicompartmental knee arthroplasty (UKA) is a viable option for relieving pain and improving function in patients with isolated compartment knee osteoarthritis (OA). Certain surgeons prefer total knee arthroplasty (TKA) over UKA even when patients are candidates for UKA. Therefore, the decision to perform a UKA or a TKA when both are indicated is not straightforward. The goal of this study was to compare pre-operative and post-operative patient-reported outcome (PRO) scores for patients who underwent both a UKA and a contralateral TKA. Methods: In this study, 17 patients were identified who underwent UKA in one knee and TKA in the contralateral knee either simultaneously or at different time points between 2003 and 2014. All procedures were performed by one of two fellowship trained surgeons at a large academic medical center. Patients were evaluated pre-operatively and then post-operatively using the validated PRO measurements Short Form 12 (SF12), Knee Society Functional Score (KSS), and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) questionnaires. Student's paired t-tests were conducted to compare PRO scores for UKA and TKA pre-operatively and post-operatively. Results: Post-operatively, mean follow-up was 2.5 years (range, 3 months to 9 years). There was no significant difference in PRO scores between pre-operative values for UKA and TKA, and no significant difference between post-operative values for UKA and TKA (e.g. SF12 pre-operative difference between UKA and TKA mean = 1.6, p = 0.57; SF12 post operative difference between UKA and TKA mean = 1.9, p = 0.51). Conclusion: UKA and TKA are comparable in terms of PROs at mid-term follow-up. When choosing between UKA and TKA, the surgeon should expect similar PROs for each, and can therefore take into account other considerations when making a selection. PMID- 30449975 TI - A critical appraisal of medial open wedge high tibial osteotomy for knee osteoarthritis. AB - A medial open wedge high tibial osteotomy (MOWHTO) is an effective surgical procedure to correct varus deformity related to Knee Osteoarthritis. It consistently provides relief in knee pain and improves knee function. This technique is recommended for active, middle and old aged individuals with an isolated medial compartment knee OA. The MOWHTO scores several advantages over lateral closed wedge osteotomy and hence is now a preferred choice of HTO. PMID- 30449974 TI - Knee manipulation for reduced flexion after Total Knee Arthroplasty. Is timing critical? AB - Background: Reduced flexion following knee arthroplasty (TKA) may compromise patient's function and outcome. The timing of manipulation under anaesthesia (MUA) has been controversial. We present our experience in a high volume practice and analyse the impact of timing. Methods: All TKA patients requiring MUA from February 1996 to June 2015 under the care of a single surgeon were analysed. MUA was offered to patients who had <= 75 degrees of flexion post-op, providing that they had 30 degrees more flexion preoperatively. To address the impact of timing from primary surgery to MUA on flexion gain we looked at 3 groups: Group I <= 90 days, Group II 91-180 days and Group III > 180 days. Results: Sixty two out of 7,423 (0.84%) underwent MUA. The MUA patients were significantly younger than the overall TKA cohort 61.2 vs 70.5 years (p = < 0.01). The median duration between arthroplasty and MUA was 3.9 months (IQR 3.4, Range 1.6-72.5 months). Overall flexion gained at 6-12 Weeks and 1 year post MUA showed significant improvements of 20.9 degrees (p = <0.01) and 25 degrees respectively (p = < 0.01). The flexion gain in group I (<= 90 days) was significantly better than group III ( > 180 days) both at 6 weeks and 1 year following MUA but not better than group II (90-180 days). Conclusions: MUA is an effective treatment for reduced flexion following TKA and should be the first line of management after failed physiotherapy. It can still have benefit beyond 6 months but the gains become less effective with time. PMID- 30449976 TI - Anterior knee pain following BPTB graft harvest. Reality or overhyped. AB - Introduction: The patellar tendon graft has long been the gold standard for ACL reconstruction. Recently semitendinosus and gracilis tendons graft have been used increasingly. We hypothetise that the Bone-Patella Tendon-Bone graft is a good and economical graft for the Indian population with no adverse effects of anterior knee pain or patellar tendon shortening. We believe that the early squatting and cross-legged sitting causes early and constant stretching of the tendon in our patients. This is responsible for the lesser incidences of adverse effects in the Indian population. Material and Method: In a retrospective study, the hospital database was scrutinized to shortlist patients who had undergone a bone-patella tendon-bone harvest for ACL or PCL reconstruction before 2013. Each patient was evaluated using the Lysholm score and the KOOS Score. VAS was also used, to evaluate for the amount of pain experienced by patients. The analysis of the quadriceps power along with the presence or absence of any extensor lag was made too. The modified Insall Salvati index was also calculated. Results: Forty seven patients were shortlisted of which 25 patients were followed up with an average follow up of 94.5 months. Although some patients did complain of occasional pain with the average VAS score of 1.45; on analyzing the data it was evident that all our patients had excellent quadriceps power (5/5) with no extensor lag. The mean Lysholm score was 95.55, while the mean KOOS score was 94.17. The mean Insall index of 1.05 showed no significant patella baja in any of our patients. Conclusion: It is ascertained that no significant retro-patellar pain or shortening of the patellar tendon occurs following a bone patella tendon bone harvest. The bone patella bone tendon graft is a suitable graft for ligament reconstruction with good functional outcome, and no significant adverse effect of patella baja or anterior knee pain in the Indian patients. Level of Evidence: Level IV. PMID- 30449977 TI - Anterolateral ligament injuries on magnetic resonance imaging and pivot-shift testing for rotational laxity. AB - Maintaining anterolateral rotational stability of the knee requires a complex set of structures, most notably the anterior cruciate ligament. However, lateral knee structures such as the anterolateral ligament (ALL) also play an important role. There has been controversy over the role the ALL plays in an ACL deficient knee to maintain rotational stability. In this study, we examined ACL deficient knees with and without intact ALLs, for rotatory laxity using a pivot shift examination. This was graded using International Knee Document Committee (IKDC) criteria. MRI was used to view the ALL and its status. We found no statistically significant difference in rotational stability of ACL deficient knees, with or without intact ALLs. We did however find a statistically significant association between injury to the ALL and other concomitant lateral structures such as the lateral collateral ligament, biceps femoris tendon, and iliotibial band. This supports that the ALL works in concert with the other lateral structures in the knee and the ACL, to provide rotational stability. This suggests that as an isolated structure, the ALL's contribution to clinical rotational stability is not significant, even in the presence of an ACL tear. PMID- 30449978 TI - What is the fracture displacement influence to fracture non-union in intramedullary nail treatment in subtrochanteric fracture? AB - Introduction: The fracture displacement in intramedullary nail in femoral subtrochanteric fracture may cause fracture non-union. We retrospectively analysed our recent experience to clear the influence about fracture displacement in intramedullary nail in femoral subtrochanteric fracture. Materials and methods: This study includes 36 patients in the intramedullary nail group followed up for more than 12 months; these patients suffered from femoral subtrochanteric fracture from 2009.1-2014.12 in our hospital. The operation time, amount of bleeding, length of hospital stay, fracture healing time, Harris function score of hip joint, fracture displacement, TAD and postoperative complications were summarized. Results: The average follow up time was 20.2 months, average operation time was 126 min, average amount of bleeding was 258 ml, average hospitalization was 13.1 days, average fracture healing time was 6.8 months, average fracture displacement was 1.23 cm, average TAD was 19.7 mm and average hip Harris function score was 82.5 points. Five cases suffered non-union. Only the fracture displacement degree made significant correlation with fracture non-union. All union patients had a fracture displacement less than 2.2 cm and all non-union patients had a fracture displacement more than 2.5 cm. Conclusion: Intramedullary nail treatment must focus on fracture reduction and recovery of femoral medial support with assisted incision technique or closed cerclage wire technique when necessary. In our opinions, only the fracture displacement degree made significant correlation with bone non-union and all cases achieved bone union when it less than 2.2 cm according to our statistics. But it still need further research to find out the displacement of fracture fragments could be tolerant. PMID- 30449979 TI - Is nail dynamization beneficial after twelve weeks - An analysis of 37 cases. AB - Purpose: Although nail dynamization in femoral and tibial fractures is an effective method of promoting healing, its role beyond twelve weeks is still not clear. It is usually done two to three months following interlocking nailing. This study was done to evaluate the efficacy of late dynamization (after 12 weeks) and factors affecting union. Materials and methods: In this retrospective study, thirty seven patients who underwent dynamization for reamed intramedullary interlocking nails of femur (18) and tibia (20) after twelve weeks from index surgery and with a minimum followup of six months were included. Fracture healing index was calculated using predynamization radiographs. Radiographic union was defined as osseous bridging of three cortices on followup radiographs. Dynamization failure was defined as fractures not showing progressive increase in callus on followup radiographs and those that required secondary intervention. Results: Mean age of patients at time of injury was 35.92 years (range: 16-63) with males (86.8%) predominating. Mean time to dynamization from index surgery was 19.11 weeks (range-12-36). Thirty one fractures (81.5%) went onto union after dynamization of which twelve were femoral and nineteen were tibial fractures. Mean time to union after dynamization was 6 months. Communited fractures (6-21) showed poor results with delayed dynamization compared to other anatomical types which was statistically significant (P = 0.05). Predynamization FHI of more than 1.18 had 83% sensitivity and 72% specificity in predicting fracture healing after dynamization. Conclusion: Late dynamization is still beneficial in promoting healing in femoral and tibial fractures. Communited fractures showed poor results with dynamization. Predynamization FHI was an important predictor of fracture healing. PMID- 30449980 TI - Growth modulation by hemi epiphysiodesis using eight-plate in Genu valgum in Paediatric population. AB - Introduction: Genu valgum is an angular deformity of the knee, often treated surgically by osteotomy or by growth modulation (using tension band, staples, transphyseal screws and eight-plate which require removal after correction). With this study, we attempt to evaluate the efficacy, rate of correction and complications with the use of 8-plate in the correction of genu valgum deformity in children. Material and method: In a retrospective study of 24 patients with 11 bilateral and 13 unilateral (35 knees) genu valgum deformity which required surgical corrections were included. There were 11 males, and 13 females and all of them were treated with Steven's technique (Stevens, 2006) using eight-plate and monitored closely. Result: Twenty-four patients with an average age of 10 years and 8 months (range: 5 yrs, 7 months-14 yrs, 2 months), with the mean preoperative & post-implant removal (Post-IR) tibiofemoral angle of 22.02 degrees +/- 5.15 degrees (range 14 degrees -31 degrees ) & 6.14 degrees +/- 1.92 degrees (range 2 degrees -10 degrees ) respectively, required an average time period of 1yr & 5m +/- 5 m (range 10 months-28 months) for correction after which implants were removed. Of the 35 limbs, we achieved excellent results in 91.6%. One case (4.16%) had a partial correction of the deformity, and one case (4.16%) had reported with a superficial infection which was taken care. There were 2 cases (8.33%) of over-correction, which was gradually self-corrected during follow-up. Conclusion: Our results reflect the efficacy of flexible titanium eight plate which corrects angular deformity by acting as a tension band on one side of the growth plate and offers the advantage of reversible Hemi epiphyseal growth modulation. Guided growth modulation is a best available alternative for the treatment of an angular deformity in the patients with open physis. PMID- 30449981 TI - Radiological evaluation of pelvic inlet and outlet radiographic view in Indian population. AB - Background: Pelvic fractures represent one of the most challenging clinical problems in which an urgent multidisciplinary approach is required. The early management in a suspected pelvic fracture starts with the good radiological evaluation. The standard radiographic view includes the anteroposterior, inlet and outlet views. The inlet and outlet views are taken with 45 degrees tilt from anteroposterior plane. However, recent studies have shown that there is significant individual variation within the population and these values should be redefined. Material and Methods: This is a retrospective study carried out in a tertiary care teaching institute. Total 110 patients (including 42 female and 68 male patients) of age older than 18 years, who had a routine pelvic Computed Tomography (CT) scan performed for any indications unrelated to pelvic pathologies were included. Statistical analysis: Mean and standard deviation were calculated. For each angle measured, the effect of age was determined and a comparison was made between male and female patients, p value <0.05 is considered significant. Results: The mean angle of caudal tilt for the ideal screening inlet view was 33 degrees +/-8 (16.3-31.3) and the mean angle of cephalic tilt for the ideal screening outlet view was 56 degrees +/-9 (51.6-81.8). Conclusion: This study re-evaluated the optimal inlet and outlet angles in Indians and demonstrated that the mean angles needed to create an ideal pelvic inlet and outlet views are 33 degrees and 56 degrees respectively. PMID- 30449984 TI - Brain Perfusion Matters: From Pituitary Function to Blood Pressure Control during Acute Ischemic Stroke. PMID- 30449983 TI - Autologous stem cell implantation with core decompression for avascular necrosis of the femoral head. AB - Objective: Avascular necrosis (AVN) of the femoral head is a painful, progressive disease that can lead to limited mobility and early hip replacement. Autologous stem cell implantation into the necrotic lesion of the femoral head has been described, on the basis that patients with AVN have a reduced number of stem cells in the marrow. In this study, we aim to describe our technique for decompression of the hip with autologous implantation of stem cells for AVN of the femoral head, as well as retrospectively analyze our results. Methods: The records and imaging of patients with avascular necrosis of the femoral head treated by a single surgeon were retrospectively reviewed. All patients were treated with the combination of core decompression with autologous stem cell implantation from the iliac crest. Preoperatively, demographic information, stage of AVN per Association Research Circulation Osseous (ARCO) classification on magnetic resonance imaging and radiograph, and visual analogue pain scores (VAS) of the hip were recorded. Postoperatively, VAS were recorded and imaging was reviewed for progression of AVN or evidence of femoral head collapse. Statistical analysis was conducted comparing pre and postoperative VAS scores. Results: Overall, we treated 43 hips in 28 patients with autologous stem cell implantation, with an average follow up of 16 months. Patients ranged from ARCO Ia to ARCO IIc classification of AVN. The average pre-operative visual analogue scale (VAS) of pain was 7.8. Post operatively, the average VAS score decreased to 2.5 (p < 0.0001), with 78% of patients reporting at least a 50% decrease in pain. 40 of the 43 operatively treated hips showed no radiologic progression of the disease during the follow up period, while 3 of the 43 hips had evidence of femoral head collapse and needed subsequent total hip arthroplasty at an average of 17 months after the initial decompression. Conclusion: Our findings indicate that hip compression with autologous stem cell implantation for AVN of the femoral head provides significant symptomatic relief and may be beneficial in arresting progression of disease. PMID- 30449982 TI - Current status of top 10 nutraceuticals used for Knee Osteoarthritis in India. AB - Knee Osteoarthritis (OA) is a progressive degenerative joint disease affecting the quality of life of the elderly population. There is considerable evidence that nutraceuticals from natural herbs may play a significant role in inflammation and joint destruction in OA. We review the current status of some of the commonly used nutraceuticals in Indian market - Boswellia, Aflapin, Chondroitin sulphate, Glucosamine sulphate, Collagen peptide, Curcumin, Fish Oil, Ginger, Green tea, and Rosehip extract. We have summarized their mechanism of action, biological effects, toxicities and efficacy in the management of Knee OA. These supplements have been found to be effective in knee OA in various studies. No serious side effects have been reported for any of these supplements. Overall, our study identifies and support the use of these nutraceuticals to provide symptomatic relief to patients with knee OA and justify their use as an adjunct therapy for the management. More good quality trials are needed to provide definitive answers to questions related to their efficacy and safety for OA prevention and treatment. PMID- 30449985 TI - Hyperhomocysteinemia Predicts the Severity of Coronary Artery Disease as Determined by the SYNTAX Score in Patients with Acute Coronary Syndrome. AB - Background: Hyperhomocysteinemia is a known risk factor for acute coronary syndrome (ACS) and is related with the severity of coronary artery disease (CAD). Previous studies have used less quantifiable scoring systems for assessing the severity of CAD. Therefore, we aimed to assess the relationship between homocysteine levels and SYNTAX score (SXscore), which is currently more widely used to grade the severity of CAD. Methods: A total of 503 patients with adiagnosis of ACS were examined angiographically with SXscore. The patients were divided into three groups according to SXscore; Group 1 a low SXscore (<= 22), Group 2 a moderate SXscore (23-32), and Group 3 a high SXscore (>= 33). Results: Plasma homocysteine levels were 16.3 +/- 6.2 nmol/mL in Group 1, 18.1 +/- 9.6 nmol/mL in Group 2, and 19.9 +/- 9.5 nmol/mL in Group 3. Homocysteine levels were significantly higher in Group 2, and Group 3 compared to Group 1 (p = 0.023 and 0.007, respectively). In the correlation analysis, homocysteine levels were correlated with SXscore (r: 0.166, p < 0.01). Conclusions: Serum homocysteine levels on admission were associated with an increased severity of CAD in the patients with ACS. PMID- 30449986 TI - Advantages of Transradial Rotational Atherectomy versus Transfemoral Approach in Elderly Patients with Hard-Handling Calcified Coronary Lesions - A Single Center Experience. AB - Background: Balloons cannot pass through severely calcified coronary lesion (SCCL), and sometimes they cannot be opened at a high pressure even if they can pass through the lesion. There are limited data on rotational atherectomy (RA) via transradial access (TRA) in this setting. The aim of this study was to evaluate in-hospital and 1-year outcomes in elderly patients with SCCL who underwent RA via TRA. Methods: Eighty-six consecutive elderly patients with de novo SCCL who underwent RA were enrolled and divided into TRA (n = 45) and transfemoral access (TFA, n = 41) groups in this retrospective analysis from 2008 to 2013. Baseline characteristics and in-hospital and 1-year endpoints were compared between both groups. Results: Compared to TFA, 6Fr guide catheters were used significantly more in the radial approach (p < 0.001). In the TRA group, the rate of burr size (1.25 mm) was higher and the mean burr size was smaller (p = 0.021) than that in the TFA group. Vascular access site complications, bed rest time and hospital stay were significantly lower in the TRA group compared with the TFA group (p = 0.029, < 0.001, < 0.001, respectively). However, there was no significant difference in major adverse cardiac events during hospitalization and after 1 year follow-up between both groups (p = 0.338, 1.000, respectively). Conclusions: TRA is a useful alternative to TFA in elderly patient with SCCL. The advantages of TRA over TFA include reduced time of bed rest and hospital stay and vascular complications at the puncture site. PMID- 30449987 TI - Improvement of Pituitary Function after Carotid Revascularization in Patients with Abnormal Cerebral Perfusion - A Pilot Study. AB - Background: Brain ischemia may affect hypothalamic-pituitary axis function, which may influence the outcomes of patients with internal carotid artery (ICA) stenosis/occlusion. The objective of this study was to determine the influence of successful carotid revascularization on pituitary function in patients with severe ICA stenosis/occlusion. Methods: This study was conducted from April 2009 to December 2014. Patients receiving successful endovascular interventions for severe ICA stenosis/occlusion were enrolled. The patients were divided into 2 groups: group 1 with abnormal ipsilateral cerebral perfusion, and group 2 without. Endocrine profiles were measured before and > 1 year after the procedure. Computed tomography perfusion studies were used to assess brain perfusion. Results: Thirty-seven patients received successful interventions. Three patients were excluded due to re-stenosis before 1 year. There were 23 and 11 patients in group 1 and 2, with mean ages of 68 and 69 years, respectively. In the female patients, follicular stimulating hormone (FSH) and luteinizing hormone (LH) increased significantly (p = 0.043) after the interventions with a stable estradiol level in group 1. In contrast, FSH, LH and estradiol showed a decreasing trend in group 2. In the male patients, FSH and LH increased significantly (p < 0.01) after the interventions with a stable testosterone level in group 1, while testosterone showed a decreasing trend in group 2. Thyroid stimulating hormone increased significantly in the women in both groups, and in the men in group 1. Conclusions: Successful revascularization for severe ICA stenosis/occlusion may improve their pituitary function, especially FSH and LH levels. PMID- 30449988 TI - Cardiac Catheterization in the Early Post-Operative Period after Congenital Heart Surgery. AB - Background: The number of diagnostic and interventional cardiac catheterization procedures are increasing in the post-operative period of congenital heart diseases (CHD). The aim of this study was to evaluate data of patients who underwent cardiac catheterization in the early post-operative period after congenital heart surgery (CHS). Methods: We retrospectively evaluated the data of patients who underwent cardiac catheterization within 30 days after CHS. Results: Between 2010 and 2016 in our hospital, 2584 children had operations, and 2911 children underwent cardiac catheterization due to CHD. Cardiac catheterization was performed in 50 (1.9% of the surgeries) of these patients during the early post-operative period. Twenty-nine (58%) of the patients were males. The median age was 7.5 months (range: 15 days-12.5 years), and the median body weight was 6 kg (range: 3-35 kg). Twenty-eight (56%) of the patients had two-ventricle, and 22 (44%) had single ventricle physiology. The median RACHS-1 score was 3 (range: 1 6). Cardiac catheterization was performed under extracorporeal membrane oxygenation (ECMO) support in 16 of the patients. Twenty-four (48%) patients underwent diagnostic catheterization, while 26 (52%) had interventional procedures. Fifteen (30%) patients had a reoperation due to anatomic problems identified during catheterization. Major complications developed in 4 (8%) patients. There was no cases of procedural mortality due to catheterization. Conclusions: Cardiac catheterization should be performed in post-operative cardiac patients without hesitation, even under ECMO, if significant hemodynamic or clinical problems cannot be identified clearly by other non- interventional diagnostic techniques. PMID- 30449989 TI - Fingertip Reactive Hyperemia Peripheral Arterial Tonometry Score Predicts Response to Biventricular Pacing. AB - Purpose: The objectives of this study were to: (i) evaluate endothelial function via fingertip reactive hyperemia peripheral arterial tonometry (RH-PAT) among heart failure (HF) patients receiving cardiac resynchronization therapy (CRT), (ii) assess the effects of CRT on RH-PAT score, and (iii) investigate whether RH PAT score can identify CRT response. Methods: A total of 63 patients (61.8 +/- 10.3 years; 50 males; left ventricular (LV) ejection fraction 24.3 +/- 3.9%) with HF who received CRT were enrolled. Endothelial function via RH-PAT was assessed 1 day before and 6 months after CRT. Minnesota Living with Heart Failure Questionnaire (MLWHFQ) was used to assess clinical improvements. CRT response was defined as a reduction in LV end-systolic volume >= 15% at 6 months. Results: A RH-PAT score of < 1.7 signified a cut-off for endothelial dysfunction (ED). Baseline ED was observed among 43 (68.3%) patients and was more prevalent in responders (76.1% vs. 47.1%, p = 0.037). RH-PAT score improved 6 months after CRT (1.58 +/- 0.35 vs. 1.71 +/- 0.31, p = 0.012). A RH-PAT score of < 1.7 was a significant independent predictor of CRT response in multivariate logistic regression analysis (beta = 1.275, OR = 3.512, 95% CI = 1.231-11.477, p = 0.032). The severity of ED was an independent predictor of LV reverse remodeling (beta = 8.873, p = 0.015). Spearman's correlation analysis revealed moderate positive correlations between an improvement in RH-PAT (DeltaRH-PAT) and LV reverse remodeling (r = 0.461, p = 0.001) and MLWHFQ score (r = 0.440, p = 0.001). Conclusions: ED detected via RH-PAT could predict the response to CRT. The RH-PAT score increased 6 months after CRT and was correlated with echocardiographic and clinical improvements. PMID- 30449990 TI - Association between Fragmented QRS and Left Ventricular Systolic Function in Patients with Erectile Dysfunction. AB - Purpose: The aim of this study was to investigate the association between fragmented QRS and left ventricular (LV) systolic function in patients with erectile dysfunction (ED). Methods: A total of 106 patients with ED and without a history of coronary artery disease (CAD) were compared with 54 age- and gender matched healthy controls. LV systolic function was evaluated using speckle tracking echocardiography via global longitudinal strain (GLS) and global circumferential strain (GCS). The patients with ED were compared with healthy controls. The study group was further subdivided into fQRS (+) and fQRS (-) groups and compared with each other. Results: The frequency of fQRS was significantly higher in the patients with ED (p = 0.01). The frequency of fQRS was higher in the patients with mild and moderate ED, and significantly higher in those with severe ED (p < 0.001). LV-GLS (%) was 17.46 +/- 1.37 and 20.05 +/- 1.42 in the fQRS (+) and fQRS (-) groups, respectively (p <= 0.001). LV-GCS (%) was 17.33 +/- 0.81 and 18.55 +/- 0.92 in the fQRS (+) and fQRS (-) groups, respectively (p <= 0.001). fQRS and age were independent predictors of LV-GLS. Conclusions: The frequency of fQRS was higher in the patients with ED even in the absence of overt CAD. In the patients with ED, the fQRS (+) group had significantly lower values of LV-GLS and LV-GCS. These results indicate that presence of fQRS is associated with subclinical LV dysfunction in patients with ED. PMID- 30449991 TI - Efficacy of Antihypertensive Therapy in the Acute Stage of Cerebral Infarction - A Prospective, Randomized Control Trial. AB - Background: This study investigated whether patients in the acute stage of cerebral infarction (ACI) might benefit from single-drug antihypertensive therapy (AT) without the use of preset target levels. Methods: A total of 320 ACI patients were randomly divided into an AT group and a control group (group C) (160 patients in each group). The AT group received single antihypertensive drug treatment after the first 48 hours of onset with 5 mg of amlodipine besylate or 150 mg of irbesartan once a day. The primary end-point event was mortality on the 14th day and in the 6th month after onset, significant dependent-survival status (SDS, Barthel Index <= 60), mortality/disability ratio (modified Rankin Scale >= 3), and recurrence rate of cardio-cerebral vascular events (RR-CVE). Results: The National Institutes of Health Stroke Scale (NIHSS) score was 8.39 +/- 3.21 vs. 8.16 +/- 3.27 in the AT and C groups on entry to the study. On day 14, there were no significant differences in mortality (2.5% vs. 3.1%, p = 0.9994), SDS (50.0% vs. 49.0%, p = 0.864), and mortality/disability ratio (61.3% vs. 66.3%, p = 0.352) between the two groups, however the RR-CVE in the AT group was lower than in group C (4.4% vs. 11.9%, p = 0.014). In month 6, there were no significant difference in mortality rate between the two groups (3.1% vs. 3.8%, p = 0.767), however the SDS (23.4% vs. 34.4%, p = 0.033), mortality/disability ratio (32.1% vs. 45.0%, p = 0.018), and RR-CVE in group AT were lower than in group C (10.7% vs. 19.4%, p = 0.030). Conclusions: Appropriate AT for patients with ACI does not worsen the disease condition and may improve the prognosis for the patients with moderate or mild stroke severity. PMID- 30449992 TI - MicroRNA-21 is Associated with the Severity of Right Ventricular Dysfunction in Patients with Hypoxia-Induced Pulmonary Hypertension. AB - Background: The outcome of pulmonary hypertension (PH) mainly depends on the development of right ventricular (RV) dysfunction, and survival among patients with different etiologies of PH varies. Chronic hypoxia is a major cause of secondary PH, however the mechanisms of its associated RV dysfunction are largely unknown. Herein, we studied the role of microRNA-21 (miR-21) in hypoxia-induced RV dysfunction. Methods: In this longitudinal, prospective study, we enrolled 41 patients with hypoxia-induced PH. Echocardiography was conducted and circulating miR-21 was measured. The expression of miR-21 was also evaluated in hypoxia treated human pulmonary microvascular endothelial cells (HPECs) and conditioned media. Through the over-expression of miR-21 in H9C2 cells, we further identified crosstalk between the pulmonary circulation and RV. Results: Among the studied patients, 10 developed RV dysfunction. Notably, the expression of circulating miR 21 was correlated with the severity of RV dysfunction. Likewise, miR-21 was up regulated in the hypoxia-treated HPECs and its conditioned media in a time dependent manner. I addition, hypertrophic changes were observed in the hypoxia treated HPECs. The up-regulation of heart failure-associated markers in H9C2 cells over-expressing miR-21 implied the influence of pulmonary circulatory miR 21 on RV function. Conclusions: The expression of systemic and pulmonary miR-21 is associated with the severity of RV dysfunction in patients with hypoxia induced PH. PMID- 30449995 TI - Percutaneous Coronary Intervention for Tortuous Left Anterior Descending Artery with Bioresorbable Vascular Scaffold via the Transradial Approach. PMID- 30449994 TI - A Reliable Method: Purse-String Hemostasis for Arteriovenous Fistula or Arteriovenous Graft Cannulation after Percutaneous Transluminal Angioplasty. AB - Percutaneous transluminal angioplasty (PTA) is the most common therapy used to treat dialysis patients with an occluded arteriovenous fistula (AVF) or arteriovenous graft (AVG). AVF or AVG hemostasis after PTA is time consuming, and it may be complicated with acute thrombosis of the AVF or AVG and re-bleeding from the puncture site. In this study, we prospectively studied 145 hemodialysis patients with occluded AVF or AVG using a modified purse-string suture with short tubing tourniquet technique for hemostasis following PTA, during which we used heparin and urokinase infusion. The results indicated that the modified technique for hemostasis of AVF orAVG was effective and safe in achieving immediate hemostasis withoutmanual compression in all patients. PMID- 30449993 TI - Bendopnea and Its Clinical Importance in Outpatient Patients with Pulmonary Arterial Hypertension. AB - Purpose: Bendopnea is a recently reported novel symptom in patients with heart failure (HF) defined as shortness of breath when bending forward. It has been demonstrated that bendopnea is associated with advanced symptoms and worse outcomes. The aim of this study was to assess the presence of bendopnea and its clinical importance with regards to functional status, hemodynamic and echocardiographic characteristics in outpatient pulmonary arterial hypertension (PAH) patients. Methods: We conducted this prospective observational study of 53 patients who were admitted to our PAH clinic for routine control visits. We determined the presence of bendopnea and analyzed hemodynamic parameters, World Heart Organization (WHO) functional class, transcutaneous oxygen saturation, 6 minute walking distance (6-MWD), N-terminal pro-brain natriuretic peptide (NT proBNP) and right ventricular (RV) function indicators in patients with and without bendopnea. Results: Bendopnea was present 33.9% of the PAH patients. The mean age was higher in the patients with bendopnea than in those without bendopnea, but the difference was not significant (p = 0.201). The patients with bendopnea had a lower 6-MWD and higher NT-proBNP level (p < 0.001), and worse WHO functional class symptoms (p = 0.010). Mean right atrial pressure, pulmonary artery pressure, and pulmonary vascular resistance were higher in the patients with bendopnea. The patients with bendopnea had a more dilated RV end-diastolic diameter and lower tricuspid annular plane systolic excursion value (p < 0.001 and p = 0.001, respectively). Conclusions: Bendopnea was associated with worse functional capacity status, hemodynamic characteristics and RV function in our outpatient PAH patients. PMID- 30449996 TI - Staged Endovascular Intervention with Ultrasound-Assisted Thrombolysis and Stent Placement for Spontaneous Isolated Superior Mesenteric Artery Dissection with Total Thrombotic Occlusion. PMID- 30449997 TI - Migration of a Pacemaker Lead to an Unusual Site. PMID- 30449998 TI - Microwave implementation of two-source energy balance approach for estimating evapotranspiration. AB - A newly developed microwave (MW) land surface temperature (LST) product is used to substitute thermal infrared (TIR) based LST in the Atmosphere Land Exchange Inverse (ALEXI) modelling framework for estimating ET from space. ALEXI implements a two-source energy balance (TSEB) land surface scheme in a time differential approach, designed to minimize sensitivity to absolute biases in input records of LST through the analysis of the rate of temperature change in the morning. Thermal infrared (TIR) retrievals of the diurnal LST curve, traditionally from geostationary platforms, are hindered by cloud cover, reducing model coverage on any given day. This study tests the utility of diurnal temperature information retrieved from a constellation of satellites with microwave radiometers that together provide 6-8 observations of Ka-band brightness temperature per location per day. This represents the first ever attempt at a global implementation of ALEXI with MW-based LST and is intended as the first step towards providing all-weather capability to the ALEXI framework. The analysis is based on 9-year long, global records of ALEXI ET generated using both MW and TIR based diurnal LST information as input. In this study, the MW-LST sampling is restricted to the same clear sky days as in the IR-based implementation to be able to analyse the impact of changing the LST dataset separately from the impact of sampling all-sky conditions. The results show that long-term bulk ET estimates from both LST sources agree well, with a spatial correlation of 92% for total ET in the Europe/Africa domain and agreement in seasonal (3-month) totals of 83-97 % depending on the time of year. Most importantly, the ALEXI-MW also matches ALEXI-IR very closely in terms of 3-month inter-annual anomalies, demonstrating its ability to capture the development and extent of drought conditions. Weekly ET output from the two parallel ALEXI implementations is further compared to a common ground measured reference provided by the FLUXNET consortium. Overall, the two model implementations generate similar performance metrics (correlation and RMSE) for all but the most challenging sites in terms of spatial heterogeneity and level of aridity. It is concluded that a constellation of MW satellites can effectively be used to provide LST for estimating ET through ALEXI, which is an important step towards all-sky satellite-based retrieval of ET using an energy balance framework. PMID- 30449999 TI - Patient-Oriented Policies To Reduce The Harmful Effects Of Medication On Seniors' Brain Function. PMID- 30450000 TI - Clinical Significance of Diminutive Colonic Polyps in Elderly Patients. AB - Background and Objectives: Colorectal cancer is the third leading cause of cancer related death. Excision of premalignant polyps has a significant impact on reducing colorectal cancer mortality and morbidity. Colonoscopy is considered to be the gold standard for the diagnosis and affords an opportunity for treatment of colonic polyps. In recent years, serious debates have taken place because of the biological characteristics of diminutive polyps (DPs), polypectomy complications, and serious costs. There has not yet been a consensus on the management of DPs. The objectives of this study were to demonstrate the real clinical importance of DPs smaller than 5 mm in diameter, which are frequently seen in geriatric patients by new endoscopic techniques, and to help in determining screening and surveillance programs. Methods: The patients who underwent colonoscopy and were found to have a diminutive colorectal polyp (<5 mm from September 1, 2016 through September 1, 2017), were classified into 3 groups according to the imaging method used: flexible spectral imaging color enhancement (FICE), narrow band imaging (NBI), or I-SCAN. In all groups, demographic data were compared according to Paris classification (morphologic) and Kudo classification (correlation between the prediction of endoscopic diagnosis and final pathological examination) in terms of sensitivity, specificity, and negative and positive predictive values. Results: Two hundred sixty-seven patients were included in the study: 97 in the NBI group, 83 in the FICE group, and 87 in the I-SCAN group. There were no statistically significant differences between NBI, FICE, and I-SCAN in differentiating neoplastic and nonneoplastic polyps, according to the Kruskal-Wallis test (P = .809). Conclusions: The estimated progression rates of DPs to advanced adenomas or colorectal cancer (CRC) are very low. Missing these polyps or not excising them may lead to failure to diagnose some cancers. There is a need for further comprehensive studies of removing all polyps to determine whether non-high-risk lesions require further pathologic examination and to re-examine routine surveillance programs. PMID- 30450001 TI - The cumene/O2 system: a very simple tool for the radical chain oxidation of some functional groups. AB - Due to the relative stability of the cumyl radical, cumenes and alpha-methyl styrenes are ideally structured to directly harvest the oxidizing reactivity of O2 and initiate radical chain reactions in catalyst-free conditions. In the absence of additional substrates, these processes can lead to acetophenones. In the presence of substrates, the cumene oxidation process can be intercepted in various chain reactions, affording very simple protocols for functional group oxidation. PMID- 30450002 TI - Imitating Pathologist Based Assessment With Interpretable and Context Based Neural Network Modeling of Histology Images. AB - Convolutional neural networks (CNNs) have gained steady popularity as a tool to perform automatic classification of whole slide histology images. While CNNs have proven to be powerful classifiers in this context, they fail to explain this classification, as the network engineered features used for modeling and classification are ONLY interpretable by the CNNs themselves. This work aims at enhancing a traditional neural network model to perform histology image modeling, patient classification, and interpretation of the distinctive features identified by the network within the histology whole slide images (WSIs). We synthesize a workflow which (a) intelligently samples the training data by automatically selecting only image areas that display visible disease-relevant tissue state and (b) isolates regions most pertinent to the trained CNN prediction and translates them to observable and qualitative features such as color, intensity, cell and tissue morphology and texture. We use the Cancer Genome Atlas's Breast Invasive Carcinoma (TCGA-BRCA) histology dataset to build a model predicting patient attributes (disease stage and node status) and the tumor proliferation challenge (TUPAC 2016) breast cancer histology image repository to help identify disease relevant tissue state (mitotic activity). We find that our enhanced CNN based workflow both increased patient attribute predictive accuracy (~2% increase for disease stage and ~10% increase for node status) and experimentally proved that a data-driven CNN histology model predicting breast invasive carcinoma stages is highly sensitive to features such as color, cell size, and shape, granularity, and uniformity. This work summarizes the need for understanding the widely trusted models built using deep learning and adds a layer of biological context to a technique that functioned as a classification only approach till now. PMID- 30450003 TI - Cerebellar Upregulation of Cell Surface Death Receptor-Mediated Apoptotic Factors in Harmaline-Induced Tremor: An Immunohistochemistry Study. AB - Active caspase-3-mediated apoptosis has been implicated in the pathogenesis of harmaline-induced tremor. The aim of this study is to illustrate the impact of tremor induction on the expression of factors mediating the cell surface death receptor-dependent apoptosis. A total of 20 normal Wistar rats were randomly selected and equally divided into control and experimental groups. Tremor was induced in the experimental group by injecting the rats with a single dose of harmaline (50 mg/kg). After that, cerebellar tissues were evaluated by immunohistochemistry to examine the expression of tumor necrosis factor alpha (TNF-alpha) and active caspase-8 in the 2 groups of animals. TNF-alpha and active caspase-8 expression was significantly higher in cerebella from experimental rats compared with that in those from the control rats (P value < .01). Thus, our present data suggest the association of tremor induction with the cerebellar overexpression of TNF-alpha and active caspase-8, correlative with Purkinje cell (PC) loss indicated by loss of calbindin immunoreactivity, indicating the induction of the cell surface death receptor-mediated apoptosis. PMID- 30450004 TI - A Particular Medullary-Spinal Inhibitory Pathway is Recruited for the Expression of Muscle Atonia During REM Sleep. AB - Muscle atonia is a major pathognomonic sign of paradoxical sleep (PS; coined REM Sleep), during which dreams mainly occur. In the 1980s, an idiopathic syndrome called REM sleep behavior disorder (RBD) was described in patients endowed with loss of PS paralysis concomitant to abnormal movements, suggesting a dysfunction of PS networks. Another major clinical RBD feature is its prevalent phenoconversion into synucleinopathies as Parkinson's disease in a delay of 10-15 years after diagnosis. Thus, we undertook experiments in rats to disentangle brainstem networks involved in PS, including atonia. We first identified a contingent of pontine glutamate neurons recruited during PS with inputs to the ventromedial medulla (vmM) where they contact gamma-aminobutyric acid (GABA)/glycine inhibitory neurons also activated during PS. Here, we further show that these vmM inhibitory neurons send efferents to somatic spinal motoneurons until lumbar levels. As reported for the pontine generator, the genetic inactivation of the vmM inhibitory neurons abolishes atonia during PS without effects on waking locomotion and is sufficient to recapitulate major RBD symptoms. These original data suggest that RBD may reflect a severe dysfunction and/or degeneration linked to a developing synucleinopathic attack targeting specifically neurons that generate PS-specific atonia. PMID- 30450005 TI - Towards Targeted Brain Stimulation in Stroke: Connectivity as a Biomarker of Response. AB - Stroke is a leading cause of adult disability. New treatments capable of assisting recovery hold significant potential to improve quality of life for many stroke survivors. Transcranial direct current stimulation is one technique that has received much attention due to its potential to promote neuroplasticity and enhance recovery. However, current evidence suggests this is not a one-size-fits all treatment with indication that responses are highly variable. Using electroencephalography, Hordacre et al recently demonstrated that connectivity between the ipsilesional motor cortex, ipsilesional parietal cortex, and contralesional frontotemporal cortex was a strong predictor of the neurophysiological response to anodal transcranial direct current stimulation applied to the ipsilesional motor cortex in people with chronic ischemic stroke. Based on this outcome, we discuss the potential for connectivity to be used as a biomarker to target transcranial direct current stimulation. This includes identification of a connectivity threshold which could be used to select stroke survivors who are likely to respond to this potentially beneficial neuromodulatory treatment. Furthermore, we discuss treatment approaches for those identified as unlikely to benefit from ipsilesional anodal transcranial direct current stimulation based on connectivity profile. This represents an important progression towards targeting transcranial direct current stimulation for best treatment outcome based on individual connectivity characteristics. PMID- 30450006 TI - The Cognitive Neuroscience of Design Creativity. AB - Design cognition is a human cognitive ability that is characterized by multi faceted skills and competencies. This skill requires finding solutions for a vague problem, where the end point is not specified and the transformations from the problem state to the solution state are also flexible. Designers solve such tasks regularly, but the mental processes involved in such a skill are not known completely. Design research has involved empirical studies and theoretical modeling to understand the cognitive processes underlying this skill. In lab based studies, a sub-class of problem-solving tasks called "ill-structured" tasks has been used to study the design process. However, the use of a cognitive neuroscience perspective has only been nascent. In this review, some defining features of design creativity will be elucidated and a few cognitive neuroscience studies of design creativity that shows the underlying brain networks will be highlighted. Results from these experiments using ill-structured tasks along with functional magnetic resonance imaging (fMRI) show that the brain networks underlying design creativity only partially overlap with brain networks underlying other kinds of creativity. This argues for studying design creativity as a unique subset of creativity using experiments that mimic the real-world design creative processes. PMID- 30450007 TI - CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies? AB - The CNTNAP2 gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is however highly controversial because numerous heterozygous missense variants have also been identified in control subjects. In a recent study, we set up a sensitive developmental in vitro cell assay to clarify the potential functional impact of these variants in a heterozygous Cntnap2 background relevant for CNTNAP2 heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by CNTNAP2 plays a dose-dependent role in cortical neuron axon growth and provided a proof of principle that some variants have functional consequences, either a loss of function or a dominant-negative effect. This indicates that phenotypes mimicking CNTNAP2 heterozygous and homozygous null mutation may exist in humans. Our observations further suggest that more variants than originally expected could be functionally deleterious and induce a high heterogeneity of phenotypes at the scale of the whole brain. This raises the interesting possibility that CNTNAP2 heterozygous missense variants could define an overall endophenotype shaping a risk for ASD and questions whether, beyond ASD, the variants could contribute to the development of other neurodevelopmental disorders and/or genetically less complex pathologies. PMID- 30450009 TI - Intrathecal Methotrexate-Induced Necrotizing Myelopathy: A Case Report and Review of Histologic Features. AB - Central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) is associated with a poor prognosis. However, prophylactic measures, including intrathecal (IT) methotrexate, reduce the incidence of CNS relapse in these patients considerably. Unfortunately, IT methotrexate can cause several neurologic complications, including transverse myelopathy; ie, the development of isolated spinal cord dysfunction over hours or days following the IT infusion of methotrexate, but in the absence of a compressive lesion. Transverse myelopathy following IT methotrexate is a well-established clinical phenomenon, but the histologic features have been described only very rarely. We report the autopsy findings from a 31-year-old man with a history of T-cell ALL who received prophylactic IT methotrexate in anticipation of a bone marrow transplant. Microscopic examination showed transverse necrosis of the thoracic cord, with massive infiltration by macrophages and lymphocytes, and perivascular lymphocytic infiltrates. There was cavitary necrosis of cervical and lumbar spinal cord involving the entire gray matter and focal white matter, as well as extensive subpial vacuolar degeneration of the dorsal and lateral columns. PMID- 30450008 TI - A Narrative Review on Avulsion Fractures of the Upper and Lower Limbs. AB - Avulsion fractures compromise function and movement at the affected joint. If left untreated, it can lead to deformity, nonunion, malunion, pain, and disability. The purpose of this review was to identify and describe the epidemiology and available treatment options for common avulsion fractures of the upper and lower extremities. Current evidence suggests that optimal treatment is dependent on the severity of the fracture. Conservative efforts generally include casting or splinting with a period of immobilization. Surgery is typically indicated for more severe cases or if nonoperative treatments fail; patient demographics or preferences and surgeon experience may also play a role in decision making. Some avulsion fractures can be surgically managed with any one of various techniques, each with their own pros and cons, and often there is no clear consensus on choosing one technique over another; however, there is some research suggesting that screw fixation, when possible, may offer the best stability and compression at the fracture site and earlier mobilization and return to function. Physicians should be mindful of the potential complications associated with each intervention. PMID- 30450011 TI - Bayesian projection of life expectancy accounting for the HIV/AIDS epidemic. AB - Background: While probabilistic projection methods for projecting life expectancy exist, few account for covariates related to life expectancy. Generalized HIV/AIDS epidemics have a large, immediate negative impact on the life expectancy in a country, but this impact can be mitigated by widespread use of antiretroviral therapy (ART). Thus, projection methods for countries with generalized HIV/AIDS epidemics could be improved by accounting for HIV prevalence, the future course of the epidemic, and ART coverage. Methods: We extend the current Bayesian probabilistic life expectancy projection methods of Raftery et al. (2013) to account for HIV prevalence and adult ART coverage in countries with generalized HIV/AIDS epidemics. Results: We evaluate our method using out-of-sample validation. We find that the proposed method performs better than the method that does not account for HIV prevalence or ART coverage for projections of life expectancy in countries with a generalized epidemic, while projections for countries without an epidemic remain essentially unchanged. Conclusions: In general, our projections show rapid recovery to pre-epidemic life expectancy levels in the presence of widespread ART coverage. After the initial life expectancy recovery, we project a steady rise in life expectancy until the end of the century. Contribution: We develop a simple Bayesian hierarchical model for long-term projections of life expectancy while accounting for HIV/AIDS prevalence and coverage of ART. The method produces well-calibrated projections for countries with generalized HIV/AIDS epidemics up to 2100 while having limited data demands. PMID- 30450010 TI - Three-dimensional Printing of Multilayered Tissue Engineering Scaffolds. AB - The field of tissue engineering has produced new therapies for the repair of damaged tissues and organs, utilizing biomimetic scaffolds that mirror the mechanical and biological properties of host tissue. The emergence of three dimensional printing (3DP) technologies has enabled the fabrication of highly complex scaffolds which offer a more accurate replication of native tissue properties and architecture than previously possible. Of strong interest to tissue engineers is the construction of multilayered scaffolds that target distinct regions of complex tissues. Musculoskeletal and dental tissues in particular, such as the osteochondral unit and periodontal complex, are composed of multiple interfacing tissue types, and thus benefit from the usage of multilayered scaffold fabrication. Traditional 3DP technologies such as extrusion printing and selective laser sintering have been used for the construction of scaffolds with gradient architectures and mixed material compositions. Additionally, emerging bioprinting strategies have been used for the direct printing and spatial patterning of cells and chemical factors, capturing the complex organization found in the body. To better replicate the varied and gradated properties of larger tissues, researchers have created scaffolds composed of multiple materials spanning natural polymers, synthetic polymers, and ceramics. By utilizing high precision 3DP techniques and judicious material selection, scaffolds can thus be designed to address the regeneration of previously challenging musculoskeletal, dental, and other heterogeneous target tissues. These multilayered 3DP strategies show great promise in the future of tissue engineering. PMID- 30450013 TI - A novel cancer syndrome caused by KCNQ1-deficiency in the golden Syrian hamster. AB - BACKGROUND: The golden Syrian hamster is an emerging model organism. To optimize its use, our group has made the first genetically engineered hamsters. One of the first genes that we investigated is KCNQ1 which encodes for the KCNQ1 potassium channel and also has been implicated as a tumor suppressor gene. MATERIALS AND METHODS: We generated KCNQ1 knockout (KO) hamsters by CRISPR/Cas9-mediated gene targeting and investigated the effects of KCNQ1-deficiency on tumorigenesis. RESULTS: By 70 days of age seven of the eight homozygous KCNQ1 KOs used in this study began showing signs of distress, and on necropsy six of the seven ill hamsters had visible cancers, including T-cell lymphomas, plasma cell tumors, hemangiosarcomas, and suspect myeloid leukemias. CONCLUSIONS: None of the hamsters in our colony that were wild-type or heterozygous for KCNQ1 mutations developed cancers indicating that the cancer phenotype is linked to KCNQ1 deficiency. This study is also the first evidence linking KCNQ1-deficiency to blood cancers. PMID- 30450012 TI - M3 muscarinic acetylcholine receptors regulate epithelial-mesenchymal transition, perineural invasion, and migration/metastasis in cholangiocarcinoma through the AKT pathway. AB - Background: Cholangiocarcinoma is a highly malignant tumor type that is not sensitive to radiotherapy or chemotherapy due to aggressive perineural invasion and metastasis. Unfortunately, the mechanisms underlying these processes and the signaling factors involved are largely unknown. In this study, we analyzed the role of M3 muscarinic acetylcholine receptors (M3-mAChR) in cell migration, perineural invasion, and metastasis during cholangiocarcinoma. Methods: We assessed 60 human cholangiocarcinoma tissue samples and 30 normal biliary tissues. Immunohistochemical staining was used to detect M3-mAChR expression and the relationship between expression and clinical prognosis was evaluated. The biological functions of M3-mAChR in cholangiocarcinoma cell migration, perineural invasion, and epithelial-mesenchymal transition (EMT) were investigated using the human cholangiocarcinoma cell lines FRH0201 and RBE in conjunction with various techniques, including agonist/antagonist treatment, RNA interference, M3-mAChR overexpression, dorsal root ganglion co-culturing, immunohistochemistry, western blotting, etc. Results: M3-mAChR were highly expressed in cholangiocarcinoma tissue and expression was closely related to differentiation and lymphatic metastasis, affecting patient survival. Treatment with the M3-mAChR agonist pilocarpine and M3-mAChR overexpression significantly promoted migration and perineural invasion, while the M3-mAChR antagonist atropine blocked these effects. Similarly, M3-mAChR knock-down also weakened cell migration and perineural invasion. The expression of phosphatase and tensin homolog, AKT, E cadherin, vimentin, and Snail, which are components of the phosphatidylinositol 3 kinase/AKT signaling pathway and EMT, were altered by pilocarpine, and these effects were again blocked by atropine. Notably, AKT knock-down decreased M3 mAChR expression and reversed the downstream effects of this receptor. Conclusions: M3-mAChR are involved in tumor cell migration, perineural invasion, and EMT during cholangiocarcinoma, and these effects are modulated via the AKT signaling pathway. PMID- 30450014 TI - Cost-effective interventions for breast cancer, cervical cancer, and colorectal cancer: new results from WHO-CHOICE. AB - Background: Following the adoption of the Global Action Plan for the Prevention and Control of NCDs 2013-2020, an update to the Appendix 3 of the action plan was requested by Member States in 2016, endorsed by the Seventieth World Health Assembly in May 2017 and provides a list of recommended NCD interventions. The main contribution of this paper is to present results of analyses identifying how decision makers can achieve maximum health gain using the cancer interventions listed in the Appendix 3. We also present methods used to calculate new WHO CHOICE cost-effectiveness results for breast cancer, cervical cancer, and colorectal cancer in Southeast Asia and eastern sub-Saharan Africa. Methods: We used "Generalized Cost-Effectiveness Analysis" for our analysis which uses a hypothetical null reference case, where the impacts of all current interventions are removed, in order to identify the optimal package of interventions. All health system costs, regardless of payer, were included. Health outcomes are reported as the gain in healthy life years due to a specific intervention scenario and were estimated using a deterministic state-transition cohort simulation (Markov model). Results: Vaccination against human papillomavirus (two doses) for 9-13-year-old girls (in eastern sub-Saharan Africa) and HPV vaccination combined with prevention of cervical cancer by screening of women aged 30-49 years through visual inspection with acetic acid linked with timely treatment of pre-cancerous lesions (in Southeast Asia) were found to be the most cost effective interventions. For breast cancer, in both regions the treatment of breast cancer, stages I and II, with surgery +/- systemic therapy, at 95% coverage, was found to be the most cost-effective intervention. For colorectal cancer, treatment of colorectal cancer, stages I and II, with surgery +/- chemotherapy and radiotherapy, at 95% coverage, was found to be the most cost effective intervention. Conclusion: The results demonstrate that cancer prevention and control interventions are cost-effective and can be implemented through a step-wise approach to achieve maximum health benefits. As the global community moves toward universal health coverage, this analysis can support decision makers in identifying a core package of cancer services, ensuring treatment and palliative care for all. PMID- 30450015 TI - Learned Labels Shape Pre-speech Infants' Object Representations. AB - Infants rapidly learn both linguistic and nonlinguistic representations of their environment and begin to link these from around 6 months. While there is an increasing body of evidence for the effect of labels heard in-task on infants' online processing, whether infants' learned linguistic representations shape learned nonlinguistic representations is unclear. In this study 10-month-old infants were trained over the course of a week with two 3D objects, one labeled, and one unlabeled. Infants then took part in a looking time task in which 2D images of the objects were presented individually in a silent familiarization phase, followed by a preferential looking trial. During the critical familiarization phase, infants looked for longer at the previously labeled stimulus than the unlabeled stimulus, suggesting that learning a label for an object had shaped infants' representations as indexed by looking times. We interpret these results in terms of label activation and novelty response accounts and discuss implications for our understanding of early representational development. PMID- 30450016 TI - Role of Additives during Deracemization Using Temperature Cycling. AB - Temperature cycling, alongside Viedma ripening, has been established as a reliable method for deracemizing racemic mixtures of chiral compounds that crystallize as a conglomerate. Here we report that the speed of temperature cycling can be increased by using chiral additives. We also demonstrate that the chirality of the additive determines the final enantiomeric state of the solid phase. Viedma ripening experiments using equivalent conditions, with and without chiral additives, are always found to be slower. PMID- 30450017 TI - History of High-Resolution Anoscopy. AB - High-resolution anoscopy (HRA) is a form of low-resolution anal microscopy currently utilized in the screening and management of anal squamous dysplasia. No randomized controlled trials, national or international guidelines exist on the use of HRA for this purpose. Much of our understanding of this entity has been adapted from the literature on cervical squamous dysplasia, including the technique of HRA itself. Epidemiologic evidence has shown that the prevalence and incidence of anal dysplasia is highest in HIV-positive populations. The history of this technique parallels the evolution of our understanding of anal dysplasia. To understand the history of the use of HRA and its place in the screening and management of anal squamous dysplasia, we discuss key advances in the understanding of human papillomavirus-related squamous dysplasia. We begin with early reports in the field establishing the link between this virus and squamous dysplasia, through the marked increase in anal cancer seen with the onset of the HIV epidemic, the identification of relevant populations at risk, the performance of the test itself, to its use today. PMID- 30450018 TI - RIGID GRAPH COMPRESSION: MOTIF-BASED RIGIDITY ANALYSIS FOR DISORDERED FIBER NETWORKS. AB - Using particle-scale models to accurately describe property enhancements and phase transitions in macroscopic behavior is a major engineering challenge in composite materials science. To address some of these challenges, we use the graph theoretic property of rigidity to model mechanical reinforcement in composites with stiff rod-like particles. We develop an efficient algorithmic approach called rigid graph compression (RGC) to describe the transition from floppy to rigid in disordered fiber networks ("rod-hinge systems"), which form the reinforcing phase in many composite systems. To establish RGC on a firm theoretical foundation, we adapt rigidity matroid theory to identify primitive topological network motifs that serve as rules for composing interacting rigid particles into larger rigid components. This approach is computationally efficient and stable, because RGC requires only topological information about rod interactions (encoded by a sparse unweighted network) rather than geometrical details such as rod locations or pairwise distances (as required in rigidity matroid theory). We conduct numerical experiments on simulated two-dimensional rod-hinge systems to demonstrate that RGC closely approximates the rigidity percolation threshold for such systems, through comparison with the pebble game algorithm (which is exact in two dimensions). Importantly, whereas the pebble game is derived from Laman's condition and is only valid in two dimensions, the RGC approach naturally extends to higher dimensions. PMID- 30450019 TI - Headwater gas exchange quantified from O2 mass balances at the reach scale. AB - Headwater streams are important in the carbon cycle and there is a need to better parametrize and quantify exchange of carbon-relevant gases. Thus, we characterized variability in the gas exchange coefficient (k 2) and dissolved oxygen (O2) gas transfer velocity (k) in two lowland headwaters of the River Avon (UK). The traditional one-station open-water method was complemented by in situ quantification of riverine sources and sinks of O2 (i.e., groundwater inflow, photosynthesis, and respiration in both the water column and benthic compartment) enabling direct hourly estimates of k 2 at the reach-scale (~ 150 m) without relying on the nighttime regression method. Obtained k 2 values ranged from 0.001 h-1 to 0.600 h-1. Average daytime k 2 were a factor two higher than values at night, likely due to diel changes in water temperature and wind. Temperature contributed up to 46% of the variability in k on an hourly scale, but clustering temperature incrementally strengthened the statistical relationship. Our analysis suggested that k variability is aligned with dominant temperature trends rather than with short-term changes. Similarly, wind correlation with k increased when clustering wind speeds in increments correspondent with dominant variations (1 m s-1). Time scale is thus an important consideration when resolving physical drivers of gas exchange. Mean estimates of k 600 from recent parametrizations proposed for upscaling, when applied to the settings of this study, were found to be in agreement with our independent O2 budget assessment (within < 10%), adding further support to the validity of upscaling efforts aiming at quantifying large scale riverine gas emissions. PMID- 30450020 TI - clustvarsel: A Package Implementing Variable Selection for Gaussian Model-Based Clustering in R. AB - Finite mixture modeling provides a framework for cluster analysis based on parsimonious Gaussian mixture models. Variable or feature selection is of particular importance in situations where only a subset of the available variables provide clustering information. This enables the selection of a more parsimonious model, yielding more efficient estimates, a clearer interpretation and, often, improved clustering partitions. This paper describes the R package clustvarsel which performs subset selection for model-based clustering. An improved version of the Raftery and Dean (2006) methodology is implemented in the new release of the package to find the (locally) optimal subset of variables with group/cluster information in a dataset. Search over the solution space is performed using either a step-wise greedy search or a headlong algorithm. Adjustments for speeding up these algorithms are discussed, as well as a parallel implementation of the stepwise search. Usage of the package is presented through the discussion of several data examples. PMID- 30450021 TI - MAESTROS: A Multiwavelength Time-Domain NIRS System to Monitor Changes in Oxygenation and Oxidation State of Cytochrome-C-Oxidase. AB - We present a multiwavelength, multichannel, time-domain near-infrared spectroscopy system named MAESTROS. This instrument can measure absorption and scattering coefficients and can quantify the concentrations of oxy- and deoxy haemoglobin ([HbO2], [HHb]), and oxidation state of cytochrome-c-oxidase ([oxCCO]). This system is composed of a supercontinuum laser source coupled with two acousto-optic tuneable filters. The light is collected by four photomultipliers tubes, connected to a router to redirect the signal to a single time-correlated single-photon counting card. The interface between the system and the tissue is based on optical fibres. This arrangement allows us to resolve up to 16 wavelengths, within the range of 650-900 nm, at a sampling rate compatible with the physiology (from 0.5 to 2 Hz). In this paper, we describe the system and assess its performance based on two specifically designed protocols for photon migration instruments, the basic instrument protocol and nEUROPt protocols, and on a well characterized liquid phantom based on Intralipid and water. Then, the ability to resolve [HbO2 ], [HHb], and [oxCCO] is demonstrated on a homogeneous liquid phantom, based on blood for [HbO2], [HHb], and yeast for [oxCCO]. In the future, the system could be used to monitor brain tissue physiology. PMID- 30450023 TI - Incidence of Active Tuberculosis within One Year after Tumor Necrosis Factor Inhibitor Treatment according to Latent Tuberculosis Infection Status in Patients with Inflammatory Bowel Disease. AB - Background: We investigated the incidence of active tuberculosis among patients with inflammatory bowel disease (IBD) treated with tumor necrosis factor (TNF) inhibitors, with or without latent tuberculosis infection (LTBI). Methods: The study was performed at a Korean tertiary referral center between January 2011 and June 2017. In total, 740 patients with IBD who underwent LTBI screening tests and were followed-up for >= 1 year after TNF inhibitor treatment initiation were enrolled. LTBI was detected on the basis of tuberculin skin test results, interferon-gamma release assay results, chest X-ray findings, and previous tuberculosis treatment history. The patients were classified into LTBI (n = 84) or non-LTBI (n = 656) group. The risk of developing tuberculosis in each group was assessed on the basis of standardized incidence ratio (SIR) and 95% confidence interval (CI) for active tuberculosis. Results: Mean patient age was 33.1 years, and patients with Crohn's disease were predominant (80.7%). Within 1 year after the initiation of TNF inhibitor treatment, 1 patient in the LTBI group (1/84; 1.2%) and 7 patients in the non-LTBI group (7/656; 1.1%) developed active tuberculosis. The overall 1-year incidence of tuberculosis among the patients was significantly higher than that among the general population (SIR, 14.0; 95% CI, 7.0-28.0), and SIR was not affected by LTBI status (LTBI group: 14.5, 95% CI, 2.0 102.6; non-LTBI group: 14.0, 95% CI, 6.7-29.4). Conclusion: Patients with IBD undergoing TNF inhibitor treatment showed a higher 1-year incidence of tuberculosis than the general population irrespective of LTBI status. PMID- 30450022 TI - The Role of Extremes in Interpregnancy Interval in Women at Increased Risk for Adverse Obstetric Outcomes Due to Health Disparities: ?A Literature Review. AB - Background: The interpregnancy interval (IPI) defines the time between two consecutive gestations. In the general population, women with IPIs that fall outside the recommended 18-24 month range appear to be at modestly increased risk for adverse obstetric outcomes. Objective: The aim of this review was to assess the impact of extremes in IPI in populations with an increased baseline risk for adverse obstetric outcomes due to disparities in health and health care, including racial and ethnic groups, adolescents, and those of lower socioeconomic status. Methods: We conducted a MEDLINE/Pubmed literature search in February 2016. Identified articles were reviewed and assigned a level of evidence. Results: The 24 studies included in our final review were mainly retrospective with considerable heterogeneity in definitions and outcomes that prevented a quantitative meta-analysis. Conclusion: The results of our review suggest that at risk populations may have an increased frequency of shortened IPIs though the impact appears to be moderate and inconsistent. There was insufficient evidence to draw meaningful conclusions regarding a prolonged IPI or the effect of interventions. Based on the current literature, under-served populations are more likely to have a shortened IPI which increased the incidence of prematurity and low birth weight in some groups though the effect on additional obstetric outcomes is difficult to assess. PMID- 30450024 TI - Pregnancy Rates and Outcomes of HIV-Infected Women in Korea. AB - Background: Antepartum, intrapartum, and postpartum preventive measures with antiretroviral drugs, appropriate delivery methods, and discouraging breastfeeding significantly decrease the risk of mother-to-child transmission of human immunodeficiency virus (HIV) infection. Herein, we investigated the pregnancy outcomes in HIV-infected Korean women. Methods: We retrospectively reviewed medical records of childbearing-age HIV-infected women between January 2005 and June 2017 at four tertiary care hospitals in Korea. Results: Among a total of 95 HIV infected women of child-bearing age with 587.61 years of follow up duration, 15 HIV-infected women experienced 21 pregnancies and delivered 16 infants. The pregnancy rate was 3.57 per 100 patient-years. Among the 21 pregnancies, five ended with an induced abortion, and 16 with childbirth including two preterm deliveries at 24 and 35 weeks of gestation, respectively. The two preterm infants had low birth weight and one of them died 10 days after delivery due to respiratory failure. Among the 14 full-term infants, one infant was small for gestational age. There were no HIV-infected infants. Conclusion: The pregnancy rate of HIV-infected women in Korea is lower than that of the general population. Although several adverse pregnancy outcomes were observed, mother-to-child transmission of HIV infection was successfully prevented with effective preventive measures. PMID- 30450025 TI - Psychiatric Manifestation in Patients with Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although its major manifestation is motor symptoms, resulting from the loss of dopaminergic neurons in the substantia nigra, psychiatric symptoms, such as depression, anxiety, hallucination, delusion, apathy and anhedonia, impulsive and compulsive behaviors, and cognitive dysfunction, may also manifest in most patients with PD. Given that the quality of life - and the need for institutionalization - is so highly dependent on the psychiatric well-being of patients with PD, psychiatric symptoms are of high clinical significance. We reviewed the prevalence, risk factors, pathophysiology, and treatment of psychiatric symptoms to get a better understanding of PD for improved management. PMID- 30450026 TI - Influences of Tobacco-Related Knowledge on Awareness and Behavior towards Smoking. AB - Background: A considerable amount of research has shown that knowledge and appropriate awareness are essential for encouraging positive behaviors and promoting health. In Korea, the roles that behavioral changes play in the prevention of cancer have been an important issue since the introduction of the 10 codes for cancer prevention in 2006. Thus, the present study investigated the associations of tobacco-related knowledge with awareness and attitudes towards positive smoking-cessation behaviors. Methods: The present study analyzed data from the 2010 national questionnaire survey (n = 1,006). This study evaluated sociodemographic characteristics, smoking status, self-rated health status, health-related interests, and the accuracy of 12 tobacco-related statements to determine knowledge level and to investigate its impact on awareness and behaviors related to smoking. These parameters were examined and staged using the Precaution Adoption Process Model. Results: A higher level of tobacco-related knowledge was significantly associated with a positive attitude towards smoking cessation (5-8 correct answers: odds ratio [OR], 2.53; 95% confidence interval [CI], 1.57-4.08; >= 9 correct answers: OR, 3.90; 95% CI, 2.22-6.82; reference: <= 4 correct answers). Interestingly, among current smokers, only those who correctly responded to >= 9 of 12 tobacco-related statements were significantly associated with a positive attitude towards smoking cessation. Conclusion: This study found that having a higher level of tobacco-related knowledge had a significant impact on positive attitudes towards smoking cessation. This suggests that there is a need to disseminate appropriate knowledge to the general population to encourage positive attitudes and promote healthful behaviors in terms of smoking. PMID- 30450027 TI - CDC6 mRNA Expression Is Associated with the Aggressiveness of Prostate Cancer. AB - Background: Cell division cycle 6 (CDC6) is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle. CDC6 has been associated with oncogenic activities in human cancers; however, the clinical significance of CDC6 in prostate cancer (PCa) remains unclear. Therefore, we investigated whether the CDC6 mRNA expression level is a diagnostic and prognostic marker in PCa. Methods: The study subjects included 121 PCa patients and 66 age-matched benign prostatic hyperplasia (BPH) patients. CDC6 expression was evaluated using real-time polymerase chain reaction and immunohistochemical (IH) staining, and then compared according to the clinicopathological characteristics of PCa. Results: CDC6 mRNA expression was significantly higher in PCa tissues than in BPH control tissues (P = 0.005). In addition, CDC6 expression was significantly higher in patients with elevated prostate-specific antigen (PSA) levels (> 20 ng/mL), a high Gleason score, and advanced stage than in those with low PSA levels, a low Gleason score, and earlier stage, respectively. Multivariate logistic regression analysis showed that high expression of CDC6 was significantly associated with advanced stage (>= T3b) (odds ratio [OR], 3.005; confidence interval [CI], 1.212 7.450; P = 0.018) and metastasis (OR, 4.192; CI, 1.079-16.286; P = 0.038). Intense IH staining for CDC6 was significantly associated with a high Gleason score and advanced tumor stage including lymph node metastasis stage (linear-by linear association, P = 0.044 and P = 0.003, respectively). Conclusion: CDC6 expression is associated with aggressive clinicopathological characteristics in PCa. CDC6 may be a potential diagnostic and prognostic marker in PCa patients. PMID- 30450028 TI - Optogenetic Light Sensors in Human Retinal Organoids. AB - Optogenetic technologies paved the way to dissect complex neural circuits and monitor neural activity using light in animals. In retinal disease, optogenetics has been used as a therapeutic modality to reanimate the retina after the loss of photoreceptor outer segments. However, it is not clear today which ones of the great diversity of microbial opsins are best suited for therapeutic applications in human retinas as cell lines, primary cell cultures and animal models do not predict expression patterns of microbial opsins in human retinal cells. Therefore, we sought to generate retinal organoids derived from human induced pluripotent stem cells (hiPSCs) as a screening tool to explore the membrane trafficking efficacy of some recently described microbial opsins. We tested both depolarizing and hyperpolarizing microbial opsins including CatCh, ChrimsonR, ReaChR, eNpHR 3.0, and Jaws. The membrane localization of eNpHR 3.0, ReaChR, and Jaws was the highest, likely due to their additional endoplasmic reticulum (ER) release and membrane trafficking signals. In the case of opsins that were not engineered to improve trafficking efficiency in mammalian cells such as CatCh and ChrimsonR, membrane localization was less efficient. Protein accumulation in organelles such as ER and Golgi was observed at high doses with CatCh and ER retention lead to an unfolded protein response. Also, cytoplasmic localization was observed at high doses of ChrimsonR. Our results collectively suggest that retinal organoids derived from hiPSCs can be used to predict the subcellular fate of optogenetic proteins in a human retinal context. Such organoids are also versatile tools to validate other gene therapy products and drug molecules. PMID- 30450029 TI - Altered Brain Fraction Amplitude of Low Frequency Fluctuation at Resting State in Patients With Early Left and Right Bell's Palsy: Do They Have Differences? AB - Purpose: Bell's palsy refers to acute idiopathic unilateral facial nerve palsy. It is a common disorder of the main motor pathway to the facial muscles. This study aimed to investigate the abnormal fraction amplitude of low frequency fluctuation (fALFF) of the brain in patients with early left and right Bell's palsy. Materials and Methods: Sixty-seven patients (left 33, right 34) and 37 age and sex-matched healthy controls underwent resting-state functional magnetic resonance imaging (R-fMRI) examination. The fALFF values were measured from all subjects and were compared among the left palsy, right palsy, and control groups. Then, correlations between the Toronto Facial Grading System (TFGS) scores of the patients and the fALFF values of abnormal brain regions were analyzed. Results: Significant group differences in fALFF values among the three groups were observed mainly in the cerebral cortical, subcortical, and deep gray matter regions. Compared with the right Bell's palsy group, the left Bell's palsy group showed significantly decreased fALFF values in the left temporal pole of the superior temporal gyrus (TPOsup), right supramarginal, left and right middle cingulate cortex (MCC), left superior frontal gyrus (SFG), and left precentral gyrus (PreCG), and increased fALFF values were observed in the right SFG and PreCG. Furthermore, altered fALFF values correlated positively with the TFGS scores in the left superior TPO, bilateral MCC, and right PreCG, and correlated negatively with the TFGS scores in the right SFG of the left Bell's palsy group. Altered fALFF values correlated positively with the TFGS scores in the bilateral MCC and right PreCG and correlated negatively with the TFGS scores in the left superior TPO and SFG of the right Bell's palsy group. Conclusion: Regulatory mechanisms seem to differ between patients with left and right early Bell's palsy. The severity of the disease is associated with these functional alterations. PMID- 30450031 TI - SIRT3 Regulation Under Cellular Stress: Making Sense of the Ups and Downs. AB - Sirtuin 3 (SIRT3) is an NAD+ dependent deacetylase that resides primarily in mitochondria and functions to maintain mitochondrial homeostasis under stress. SIRT3 expression has been observed to change under a number of different stresses in multiple tissues and model systems. Inconsistencies in the literature with regards to how and when SIRT3 protein levels change indicates that the mechanism of SIRT3 regulation is multi-faceted. Alterations in SIRT3 have been observed in experimental models of cellular stress, however, the effect these changes have on mitochondrial health remain unknown. Neurons are highly dependent on proper mitochondrial function for their survival. SIRT3 dynamics and function have been studied using models of genotoxic, metabolic, and oxidative stresses, although it remains unclear how SIRT3 is being regulated under these conditions. A closer look into SIRT3 regulation under stress conditions in various model systems will help incorporate the many SIRT3 regulatory mechanisms at play in disease states. In this review, we describe the observations that have been made about SIRT3 protein modulation under basic stress conditions. We then point out consistencies and contradictions in these observations and what they mean. Lastly, we present the observations made in the complicated neuronal stress of stroke. We hope that this review will help consolidate the ambiguous SIRT3 literature and provide a framework for investigation of SIRT3 regulation during stress response. PMID- 30450030 TI - Ten Years of Tau-Targeted Immunotherapy: The Path Walked and the Roads Ahead. AB - Neurofibrillary pathology comprised of pathological tau protein is closely tied to a range of neurodegenerative disorders, the most common of which is Alzheimer's disease. While they are individually rarer, a range of other disorders, the tauopathies (including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, primary progressive aphasia, and ~50% of behavioral variant frontotemporal dementia cases) display pronounced underlying tau pathology. In all cases, the distribution and amount of tau pathology closely correlates with the severity and phenotype of cognitive impairment, and with the pattern and degree of brain atrophy. Successfully counteracting tau pathology is likely to halt or slow the progression of these debilitating disorders. This makes tau a target of prime importance, yet an elusive one. The diversity of the tau proteome and post-translational modifications, as well as pathophysiology of tau are reviewed. Beginning 2013, a range of tau-targeted immunotherapies have entered clinical development; these therapies, and their common themes and differences are reviewed. The manuscript provides an extensive discussion on epitope selection for immunotherapies against tau pathology, on immunological mechanisms involved in their action, and challenges such as immune senescence, vaccine design, or evolution of epitopes. Furthermore, we provide methodological recommendations for the characterization of active vaccines and antibodies, animal models, and the target itself - the diseased tau proteome. PMID- 30450033 TI - METH-Induced Neurotoxicity Is Alleviated by Lactulose Pretreatment Through Suppressing Oxidative Stress and Neuroinflammation in Rat Striatum. AB - Abuse of methamphetamine (METH) results in neurological and psychiatric abnormalities. Lactulose is a poorly absorbed derivative of lactose and can effectively alleviate METH-induced neurotoxicity in rats. The present study was designed to investigate the effects of lactulose on METH-induced neurotoxicity. Rats received METH (15 mg/kg, 8 intraperitoneal injections, 12-h interval) or saline and received lactulose (5.3 g/kg, oral gavage, 12-h interval) or vehicle 2 days prior to the METH administration. Reactive oxygen species (ROS) and malondialdehyde (MDA) were measured. Protein levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6), nuclear factor kappaB (NFkappaB), interleukin (IL) 1beta, IL-6, TNF-alpha, cleaved caspase 3, and poly(ADP-ribose) polymerase-1 (PARP-1) were determined by western blotting. mRNA expressions of nuclear factor erythroid 2-relatted factor-2 (Nrf2), p62, and heme oxygenase-1 (HO-1) were assessed by RT-qPCR. The lactulose pretreatment decreased METH-induced cytoplasmic damage in rat livers according to histopathological observation. Compared to the control group, overproduction of ROS and MDA were observed in rat striatums in the METH alone-treated group, while the lactulose pretreatment significantly attenuated the METH-induced up-regulation of oxidative stress. The lactulose pretreatment significantly repressed over-expressions of proteins of TLR4, MyD88, TRAF6, NFkappaB, IL-1beta, IL-6, TNF-alpha, cleaved caspase 3, PARP 1. The lactulose pretreatment increased mRNA expressions of Nrf2, p62, and HO-1. These findings suggest that lactulose pretreatment can alleviate METH-induced neurotoxicity through suppressing neuroinflammation and oxidative stress, which might be attributed to the activation of the Nrf2/HO-1 axis. PMID- 30450032 TI - Regenerative Approaches in Huntington's Disease: From Mechanistic Insights to Therapeutic Protocols. AB - Huntington's Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the exon-1 of the IT15 gene encoding the protein Huntingtin. Expression of mutated Huntingtin in humans leads to dysfunction and ultimately degeneration of selected neuronal populations of the striatum and cerebral cortex. Current available HD therapy relies on drugs to treat chorea and control psychiatric symptoms, however, no therapy has been proven to slow down disease progression or prevent disease onset. Thus, although 24 years have passed since HD gene identification, HD remains a relentless progressive disease characterized by cognitive dysfunction and motor disability that leads to death of the majority of patients, on average 10-20 years after its onset. Up to now several molecular pathways have been implicated in the process of neurodegeneration involved in HD and have provided potential therapeutic targets. Based on these data, approaches currently under investigation for HD therapy aim on the one hand at getting insight into the mechanisms of disease progression in a human-based context and on the other hand at silencing mHTT expression by using antisense oligonucleotides. An innovative and still poorly investigated approach is to identify new factors that increase neurogenesis and/or induce reprogramming of endogenous neuroblasts and parenchymal astrocytes to generate new healthy neurons to replace lost ones and/or enforce neuroprotection of pre-existent striatal and cortical neurons. Here, we review studies that use human disease-in-a-dish models to recapitulate HD pathogenesis or are focused on promoting in vivo neurogenesis of endogenous striatal neuroblasts and direct neuronal reprogramming of parenchymal astrocytes, which combined with neuroprotective protocols bear the potential to re-establish brain homeostasis lost in HD. PMID- 30450034 TI - Investigating Gene Function for Neuronal Survival After Metabolic Stress Using Semi-Automated Fluorescence Microscopy and Automated Image Analysis. AB - Overexpression approaches and fluorescence microscopy techniques allow investigating important spatiotemporal aspects of gene regulation as well as quantifying gene function. Consequently, fluorescence microscopy techniques help answer important questions on gene regulation such as addressing the role of a specific gene product for neuronal survival under different treatments. Here, we describe a versatile tool to measure effects of a transfected gene of interest on neuronal survival upon metabolic stress. We focus on nutrient starvation of cultured rodent primary neurons as a model of metabolic stress but our approach can easily be generalized and adapted to other cell types or to investigate single gene function in regulating neuronal survival under various conditions. PMID- 30450035 TI - Dimerization of Neuronal Calcium Sensor Proteins. AB - Neuronal calcium sensor (NCS) proteins are EF-hand containing Ca2+ binding proteins that regulate sensory signal transduction. Many NCS proteins (recoverin, GCAPs, neurocalcin and visinin-like protein 1 (VILIP1)) form functional dimers under physiological conditions. The dimeric NCS proteins have similar amino acid sequences (50% homology) but each bind to and regulate very different physiological targets. Retinal recoverin binds to rhodopsin kinase and promotes Ca2+-dependent desensitization of light-excited rhodopsin during visual phototransduction. The guanylyl cyclase activating proteins (GCAP1-5) each bind and activate retinal guanylyl cyclases (RetGCs) in light-adapted photoreceptors. VILIP1 binds to membrane targets that modulate neuronal secretion. Here, I review atomic-level structures of dimeric forms of recoverin, GCAPs and VILIP1. The distinct dimeric structures in each case suggest that NCS dimerization may play a role in modulating specific target recognition. The dimerization of recoverin and VILIP1 is Ca2+-dependent and enhances their membrane-targeting Ca2+-myristoyl switch function. The dimerization of GCAP1 and GCAP2 facilitate their binding to dimeric RetGCs and may allosterically control the Ca2+-dependent activation of RetGCs. PMID- 30450037 TI - Upregulation of Cysteine Protease Cathepsin X in the 6-Hydroxydopamine Model of Parkinson's Disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic neurons in the substantia nigra pars compacta (SNc). In vitro, a contribution to neuroinflammation and neurotoxicity has been shown for the lysosomal protease cathepsin X; however, its expression and its role in PD remain unknown. Therefore, the current study was designed to address the regional, cellular, and subcellular localization and activity of cathepsin X in hemi-parkinsonian rats with 6-hydroxydopamine (6-OHDA)-induced excitotoxicity in the unilateral medial forebrain bundle (MFB) lesion. We report for the first time that cathepsin X expression and activity are rapidly increased in the ipsilateral SNc after injection of 6-OHDA into the MFB reaching a maximum after 12 h but seem to stay strongly upregulated after 4 weeks after injection. At early time points of 6-OHDA injection into the MFB, the increased cathepsin X is localized in the lysosomes in the neuronal, predominantly tyrosine hydroxylase-positive dopaminergic cells. After 12 h of 6-OHDA induced lesion, only a few activated microglial cells are positive for cathepsin X whereas, in 4 weeks post-lesion accompanied with complete loss of dopaminergic neurons, there is persistent cathepsin X upregulation restricted to activated glia cells. Taken together, our results demonstrate that cathepsin X upregulation in the lesioned dopaminergic system may play a role as a pathogenic factor in PD. Moreover, inhibition of cathepsin X expression or activity may be useful in protecting the nigrostriatal dopaminergic projection in the PD. PMID- 30450038 TI - Model for Coordination of Microtubule and Actin Dynamics in Growth Cone Turning. AB - In the developing nervous system, axons are guided to their synaptic targets by motile structures at the axon tip called growth cones, which reorganize their cytoskeleton in order to steer in response to chemotactic cues. Growth cone motility is mediated by an actin-adhesion "clutch" mechanism, in which mechanical attachment to a substrate, coupled with polarized actin growth, produces leading edge protrusion. Several studies suggest that dynamic microtubules (MTs) in the growth cone periphery play an essential role in growth cone steering. It is not yet well-understood how the MT cytoskeleton and the dynamic actin-adhesion clutch system are coordinated to promote growth cone navigation. I introduce an experimentally motivated stochastic model of the dynamic reorganization of the growth cone cytoskeleton in response to external guidance cues. According to this model, asymmetric decoupling of MTs from actin retrograde flow leads to a local influx of MTs to the growth cone leading edge, and the leading-edge MT accumulation is amplified by positive feedback between MTs and the actin-adhesion clutch system. Local accumulation of MTs at the leading edge is hypothesized to increase actin adhesion to the substrate, which attenuates actin retrograde flow and promotes leading-edge protrusion. Growth cone alignment with the chemotactic gradient is predicted to be most effective for intermediate levels of sensitivity of the adhesion strength to the presence of leading-edge MTs. Quantitative predictions of the MT distribution and the local rate of retrograde actin flow will allow the hypothetical positive feedback mechanism to be experimentally tested. PMID- 30450036 TI - Exploiting Post-mitotic Yeast Cultures to Model Neurodegeneration. AB - Over the last few decades, the budding yeast Saccharomyces cerevisiae has been extensively used as a valuable organism to explore mechanisms of aging and human age-associated neurodegenerative disorders. Yeast models can be used to study loss of function of disease-related conserved genes and to investigate gain of function activities, frequently proteotoxicity, exerted by non-conserved human mutant proteins responsible for neurodegeneration. Most published models of proteotoxicity have used rapidly dividing cells and suffer from a high level of protein expression resulting in acute growth arrest or cell death. This contrasts with the slow development of neurodegenerative proteotoxicity during aging and the characteristic post-mitotic state of the affected cell type, the neuron. Here, we will review the efforts to create and characterize yeast models of neurodegeneration using the chronological life span model of aging, and the specific information they can provide regarding the chronology of physiological events leading to neurotoxic proteotoxicity-induced cell death and the identification of new pathways involved. PMID- 30450040 TI - Automatic Mitochondria Segmentation for EM Data Using a 3D Supervised Convolutional Network. AB - Recent studies have supported the relation between mitochondrial functions and degenerative disorders related to ageing, such as Alzheimer's and Parkinson's diseases. Since these studies have exposed the need for detailed and high resolution analysis of physical alterations in mitochondria, it is necessary to be able to perform segmentation and 3D reconstruction of mitochondria. However, due to the variety of mitochondrial structures, automated mitochondria segmentation and reconstruction in electron microscopy (EM) images have proven to be a difficult and challenging task. This paper puts forward an effective and automated pipeline based on deep learning to realize mitochondria segmentation in different EM images. The proposed pipeline consists of three parts: (1) utilizing image registration and histogram equalization as image pre-processing steps to maintain the consistency of the dataset; (2) proposing an effective approach for 3D mitochondria segmentation based on a volumetric, residual convolutional and deeply supervised network; and (3) employing a 3D connection method to obtain the relationship of mitochondria and displaying the 3D reconstruction results. To our knowledge, we are the first researchers to utilize a 3D fully residual convolutional network with a deeply supervised strategy to improve the accuracy of mitochondria segmentation. The experimental results on anisotropic and isotropic EM volumes demonstrate the effectiveness of our method, and the Jaccard index of our segmentation (91.8% in anisotropy, 90.0% in isotropy) and F1 score of detection (92.2% in anisotropy, 90.9% in isotropy) suggest that our approach achieved state-of-the-art results. Our fully automated pipeline contributes to the development of neuroscience by providing neurologists with a rapid approach for obtaining rich mitochondria statistics and helping them elucidate the mechanism and function of mitochondria. PMID- 30450039 TI - Navigating the Murine Brain: Toward Best Practices for Determining and Documenting Neuroanatomical Locations in Experimental Studies. AB - In experimental neuroscientific research, anatomical location is a key attribute of experimental observations and critical for interpretation of results, replication of findings, and comparison of data across studies. With steadily rising numbers of publications reporting basic experimental results, there is an increasing need for integration and synthesis of data. Since comparison of data relies on consistently defined anatomical locations, it is a major concern that practices and precision in the reporting of location of observations from different types of experimental studies seem to vary considerably. To elucidate and possibly meet this challenge, we have evaluated and compared current practices for interpreting and documenting the anatomical location of measurements acquired from murine brains with different experimental methods. Our observations show substantial differences in approach, interpretation and reproducibility of anatomical locations among reports of different categories of experimental research, and strongly indicate that ambiguous reports of anatomical location can be attributed to missing descriptions. Based on these findings, we suggest a set of minimum requirements for documentation of anatomical location in experimental murine brain research. We furthermore demonstrate how these requirements have been applied in the EU Human Brain Project to optimize workflows for integration of heterogeneous data in common reference atlases. We propose broad adoption of some straightforward steps for improving the precision of location metadata and thereby facilitating interpretation, reuse and integration of data. PMID- 30450041 TI - Localization of Active Brain Sources From EEG Signals Using Empirical Mode Decomposition: A Comparative Study. AB - The localization of active brain sources from Electroencephalogram (EEG) is a useful method in clinical applications, such as the study of localized epilepsy, evoked-related-potentials, and attention deficit/hyperactivity disorder. The distributed-source model is a common method to estimate neural activity in the brain. The location and amplitude of each active source are estimated by solving the inverse problem by regularization or using Bayesian methods with spatio temporal constraints. Frequency and spatio-temporal constraints improve the quality of the reconstructed neural activity. However, separation into frequency bands is beneficial when the relevant information is in specific sub-bands. We improved frequency-band identification and preserved good temporal resolution using EEG pre-processing techniques with good frequency band separation and temporal resolution properties. The identified frequency bands were included as constraints in the solution of the inverse problem by decomposing the EEG signals into frequency bands through various methods that offer good frequency and temporal resolution, such as empirical mode decomposition (EMD) and wavelet transform (WT). We present a comparative analysis of the accuracy of brain-source reconstruction using these techniques. The accuracy of the spatial reconstruction was assessed using the Wasserstein metric for real and simulated signals. We approached the mode-mixing problem, inherent to EMD, by exploring three variants of EMD: masking EMD, Ensemble-EMD (EEMD), and multivariate EMD (MEMD). The results of the spatio-temporal brain source reconstruction using these techniques show that masking EMD and MEMD can largely mitigate the mode-mixing problem and achieve a good spatio-temporal reconstruction of the active sources. Masking EMD and EEMD achieved better reconstruction than standard EMD, Multiple Sparse Priors, or wavelet packet decomposition when EMD was used as a pre-processing tool for the spatial reconstruction (averaged over time) of the brain sources. The spatial resolution obtained using all three EMD variants was substantially better than the use of EMD alone, as the mode-mixing problem was mitigated, particularly with masking EMD and EEMD. These findings encourage further exploration into the use of EMD-based pre-processing, the mode-mixing problem, and its impact on the accuracy of brain source activity reconstruction. PMID- 30450042 TI - Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner. AB - Stress-related psychiatric disorders such as major depression are strongly associated with alcohol abuse and alcohol use disorder. Recently, many epidemiological and preclinical studies suggest that chronic stress prior to conception has cross-generational effects on the behavior and physiological response to stress in subsequent generations. Thus, we hypothesized that chronic stress may also affect ethanol drinking behaviors in the next generation. In the first cohort of mice, we found that paternal preconception chronic variable stress significantly reduced both two-bottle choice and binge-like ethanol drinking selectively in male offspring. However, these results were not replicated in a second cohort that were tested under experimental conditions that were nearly identical, except for one notable difference. Cohort 1 offspring were derived from in-house C57BL/6J sires that were born in the animal vivarium at the University of Pittsburgh whereas cohort 2 offspring were derived from C57BL/6J sires shipped directly from the vendor. Therefore, a third cohort that included both in-house and vendor born sires was analyzed. Consistent with the first two cohorts, we observed a significant interaction between chronic stress and sire source with only stressed sires that were born in-house able to impart reduced ethanol drinking behaviors to male offspring. Overall, these results demonstrate that paternal preconception stress can impact ethanol drinking behavior in males of the next generation. These studies provide additional support for a recently recognized role of the paternal preconception environment in shaping ethanol drinking behavior. PMID- 30450043 TI - Treating PTSD: A Review of Evidence-Based Psychotherapy Interventions. AB - Posttraumatic stress disorder (PTSD) is a chronic, often debilitating mental health disorder that may develop after a traumatic life event. Fortunately, effective psychological treatments for PTSD exist. In 2017, the Veterans Health Administration and Department of Defense (VA/DoD) and the American Psychological Association (APA) each published treatment guidelines for PTSD, which are a set of recommendations for providers who treat individuals with PTSD. The purpose of the current review article is to briefly review the methodology used in each set of 2017 guidelines and then discuss the psychological treatments of PTSD for adults that were strongly recommended by both sets of guidelines. Both guidelines strongly recommended use of Prolonged Exposure (PE), Cognitive Processing Therapy (CPT) and trauma-focused Cognitive Behavioral Therapy (CBT). Each of these treatments has a large evidence base and is trauma-focused, which means they directly address memories of the traumatic event or thoughts and feelings related to the traumatic event. Finally, we will discuss implications and future directions. PMID- 30450045 TI - Predicting Responses to Psychedelics: A Prospective Study. AB - Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points were N = 654, N = 535, N = 379, N = 315, and N = 212 respectively. Psychological well-being was increased 2 weeks after a psychedelic experience and remained at this level after 4 weeks. Higher ratings of a "mystical-type experience" had a positive effect on the change in well-being after a psychedelic experience, whereas the other acute psychedelic experience measures, i.e., "challenging experience" and "visual effects", did not influence the change in well-being after the psychedelic experience. Having "clear intentions" for the experience was conducive to mystical-type experiences. Having a positive "set" as well as having the experience with intentions related to "recreation" were both found to decrease the likelihood of having a challenging experience. The baseline trait "absorption" and higher drug doses promoted all aspects of the acute experience, i.e., mystical-type and challenging experiences, as well as visual effects. When comparing the relative contribution of different types of variables in explaining the variance in the change in well-being, it seemed that baseline trait variables had the strongest effect on the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding crucial clinical decisions about whether, when, where and how to dose with a psychedelic, thus helping to mitigate risks while maximizing potential benefits in an evidence-based manner. PMID- 30450046 TI - Notoginsenoside R1 Protects Against Diabetic Cardiomyopathy Through Activating Estrogen Receptor alpha and Its Downstream Signaling. AB - Diabetic cardiomyopathy (DCM) leads to heart failure and death in diabetic patients, no effective treatment is available. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and our previous studies have showed cardioprotective and neuroprotective effects of NGR1. However, its role in protecting against DCM remains unexplored. Herein, we examine potential effects of NGR1 on cardiac function of diabetic db/db mice and H9c2 cardiomyocytes treated by advanced glycation end products (AGEs). In vitro experiments revealed that pretreatment with NGR1 significantly decreased AGEs induced mitochondria injury, limited an increase in ROS, and reduced apoptosis in H9c2 cells. NGR1 eliminated ROS by promoting estrogen receptor alpha expression, which subsequently activated Akt and Nrf2-mediated anti-oxidant enzymes. In vivo investigation demonstrated that NGR1 significantly reduced serum lipid levels, insulin resistance, the expression of enzymes related to cardiomyopathy, and the expression of apoptotic proteins. Finally, NGR1 improved cardiac dysfunction and attenuated histological abnormalities, as evidenced by elevating ejection fraction and fractional shortening, and reducing cardiac fibrosis. Mechanistically, NGR1 promoted ERalpha expression, which led to the activation of Akt-Nrf2 signaling and the inhibition of the TGFbeta pathway. Collectively, these results strongly indicate that NGR1 exerts cardioprotective effects against DCM through its inhibition of oxidative stress and apoptosis, and eventually suppresses cardiac fibrosis and hypertrophy, which suggests that NGR1 is a potential therapeutic medicine for the treatment of DCM. PMID- 30450047 TI - Effect of Total Flavonoids of Rhizoma drynariae on Tibial Dyschondroplasia by Regulating BMP-2 and Runx2 Expression in Chickens. AB - Tibial dyschondroplasia (TD) is an abnormality of the growth cartilage that occurs in chickens and other rapidly growing avian species. This disease not only cause huge economic losses, but also greatly affects animal welfare. The total flavonoids of Rhizoma drynariae (TFRD) has been used to cure wide variety of diseases including bone fractures and osteoarthritis and osteoporosis. However, less information is available about the using of TFRD against the TD. The aim of this study was to determine the effect of TFRD on TD by regulating BMP-2 and Runx2 in chickens. A total of 200 birds were randomly divided into control, TD, TD recovery (TDR), and TFRD groups. All the groups were given standard diet with an addition of thiram (50 mg/kg) from days 3 to 7 in TD, TDR, and TFRD groups in order to induce TD in chickens. After the induction of TD, the birds of TFRD group were fed standard diet with the addition of TFRD at 20 mg/kg. Clinical results conveyed that TFRD can improve the growth performance of the TD chickens and recover normal activity, and it is more obvious than TDR. Gene expressions of BMP-2 and Runx2 were down-regulated during the development of the disease and were up-regulated obviously after TFRD treatment. In conclusion, TFRD not only decreased the mortality rate but also increased the growth performance of TD in chickens. In conclusion, TFRD plays important role in improving the growth performance, adjusting the relevant physiological indicators, and regulating BMP 2 and Runx2 in chickens. PMID- 30450048 TI - Development of Rifampicin-Indocyanine Green-Loaded Perfluorocarbon Nanodroplets for Photo-Chemo-Probiotic Antimicrobial Therapy. AB - Acne vulgaris, generally resulted from overgrowth of Propionibacterium acnes (P. acnes), is one of the most difficult-to-treat facial dermatoses and more than 90% of adolescents experienced the disease worldwide. Because the innate non-lymphoid immune system cannot effectively eliminate excessive P. acnes from the skin surface, so far the therapy of acne vulgaris is still mainly dependent on antibiotic treatment. However, long-term or overdose of antibiotics may initiate microbial drug resistance and/or generate unexpected side effects that seriously hamper the use of antibiotics in the clinic. To overcome the aforementioned challenges, the novel rifampicin (RIF)-indocyanine green (ICG)-loaded perfluorocarbon (PFC) nanodroplets (RIPNDs) that may offer combined photo-, chemo , and probiotic efficacies to P. acnes eradication were developed in this study. The RIPND was first characterized as a sphere-like nanoparticle with surface charge of -20.9 +/- 2.40 mV and size of 240.7 +/- 6.73 nm, in which the encapsulation efficiencies of RIF and ICG were 54.0 +/- 10.5% and 95.0 +/- 4.84%, respectively. In comparison to the freely dissolved ICG, the RIPNDs conferred an enhanced thermal stability to the entrapped ICG, and were able to provide a comparable hyperthermia effect and markedly increased production of singlet oxygen under near infrared (NIR; 808 nm, 6 W/cm2) exposure. Furthermore, the RIPNDs were able to induce fermentation of S. epidermidis but not P. acnes, indicating that the RIPNDs may serve as a selective fermentation initiator for the target probiotics. Based on the microbial population index analyses, P. acnes with 1 * 106 cells/mL can be completely eradicated by 12-h co-culture with S. epidermidis fermentation products followed by treatment of RIPNDs (>=20-MUM ICG/3.8-MUM RIF) + NIR for 5 min, whereby the resulted microbial mortality was even higher than that caused by using 16-fold enhanced amount of loaded RIF alone. Overall these efforts show that the RIPNDs were able to provide improved ICG stability, selective fermentability to S. epidermidis, and enhanced antimicrobial efficacy compared to equal dosage of free RIF and/or ICG, indicating that the developed nanodroplets are highly potential for use in the clinical anti-P. acne treatment with reduced chemotoxicity. PMID- 30450044 TI - Neurostimulation Combined With Cognitive Intervention in Alzheimer's Disease (NeuroAD): Study Protocol of Double-Blind, Randomized, Factorial Clinical Trial. AB - Despite advances in the treatment of Alzheimer's disease (AD), there is currently no prospect of a cure, and evidence shows that multifactorial interventions can benefit patients. A promising therapeutic alternative is the use of transcranial direct current stimulation (tDCS) simultaneously with cognitive intervention. The combination of these non-pharmacological techniques is apparently a safe and accessible approach. This study protocol aims to compare the efficacy of tDCS and cognitive intervention in a double-blind, randomized and factorial clinical trial. One hundred participants diagnosed with mild-stage AD will be randomized to receive both tDCS and cognitive intervention, tDCS, cognitive intervention, or placebo. The treatment will last 8 weeks, with a 12-month follow-up. The primary outcome will be the improvement of global cognitive functions, evaluated by the AD Assessment Scale, cognitive subscale (ADAS-Cog). The secondary outcomes will include measures of functional, affective, and behavioral components, as well as a neurophysiological marker (Brain-derived neurotrophic factor, BDNF). This study will enable us to assess, both in the short and long term, whether tDCS is more effective than the placebo and to examine the effects of combined therapy (tDCS and cognitive intervention) and isolated treatments (tDCS vs. cognitive intervention) on patients with AD. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02772185-May 5, 2016. PMID- 30450049 TI - Combined Metabolic Targeting With Metformin and the NSAIDs Diflunisal and Diclofenac Induces Apoptosis in Acute Myeloid Leukemia Cells. AB - The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid metabolism as well as mitochondrial activity have been shown in solid tumors but also in leukemic cells. As tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited. Here, we analyzed the impact of the anti-diabetic drug metformin alone or in combination with two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and diflunisal on acute myeloid leukemia (AML) cell lines and primary patient blasts. Diclofenac but not diflunisal reduced lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations. Despite these metabolic effects, both NSAIDs showed a limited effect on tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4-0.8 mM diflunisal alone exerted a clear effect on proliferation of AML cell lines and blocked respiration. Single treatment with the anti-diabetic drug metformin blocked mitochondrial respiration, but proliferation and viability were not affected. However, combining all three drugs exerted a strong cytostatic and cytotoxic effect on THP-1 cells. Comparable to the results obtained with THP-1 cells, the combination of all three drugs significantly reduced proliferation of primary leukemic blasts and induced apoptosis. Furthermore, NSAIDs supported the effect of low dose chemotherapy with cytarabine and reduced proliferation of primary AML blasts. Taken together we show that low concentrations of metformin and the two NSAIDs diclofenac and diflunisal exert a synergistic inhibitory effect on AML proliferation and induce apoptosis most likely by blocking tumor cell metabolism. Our results underline the feasibility of applying anti-metabolic drugs for AML therapy. PMID- 30450051 TI - Pre-treatment or Post-treatment of Human Glioma Cells With BIX01294, the Inhibitor of Histone Methyltransferase G9a, Sensitizes Cells to Temozolomide. AB - Glioblastoma (GBM) is a malignant, primary brain tumor, highly resistant to conventional therapies. Temozolomide (TMZ) is a first line therapeutic agent in GBM patients, however, survival of such patients is poor. High level of DNA repair protein, O6-methylguanine-DNA-methyltransferase (MGMT) and occurrence of glioma stem-like cells contribute to GBM resistance to the drug. Here, we explored a possibility of epigenetic reprograming of glioma cells to increase sensitivity to TMZ and restore apoptosis competence. We combined TMZ treatment with BIX01294, an inhibitor of histone methyltransferase G9a, known to be involved in cancerogenesis. Two treatment combinations were tested: BIX01294 was administered to human LN18 and U251 glioma cell cultures 48 h before TMZ or 48 h after TMZ treatment. Despite their different status of the MGMT gene promoter, there was no correlation with the response to TMZ. The analyses of cell viability, appearance of apoptotic alterations in morphology of cells and nuclei, and markers of apoptosis, such as levels of cleaved caspase 3, caspase 7 and PARP, revealed that both pre-treatment and post-treatment with BIX01294 sensitize glioma cells to TMZ. The additive effect was stronger in LN18 cells. Moreover, BIX01294 enhanced the cytotoxic effect of TMZ on glioma stem-like cells, although it was not associated with modulation of the pluripotency markers (NANOG, SOX2, CD133) expression or methylation of NANOG and SOX2 gene promoters. Accordingly, knockdown of methyltransferase G9a augments TMZ-induced cell death in LN18 cells. We found the significant increases of the LC3-II levels in LN18 cells treated with BIX01294 alone and with drug combination that suggests involvement of autophagy in enhancement of anti-tumor effect of TMZ. Treatment with BIX01294 did not affect methylation of the MGMT gene promoter. Altogether, our results suggest that G9a is a potential therapeutic target in malignant glioma and the treatment with the G9a inhibitor reprograms glioma cells and glioma stem-like cells to increase sensitivity to TMZ and restore apoptosis competence. PMID- 30450052 TI - Calcium-Mediated Oscillation in Membrane Potentials and Atrial-Triggered Activity in Atrial Cells of Casq2R33Q/R33Q Mutation Mice. AB - Aim: We investigated the underlying mechanisms in atrial fibrillation (AF) associated with R33Q mutation and Ca2+-triggered activity. Methods and Results: We examined AF susceptibility with intraesophageal burst pacing in the sarcoplasmic reticulum (SR) Ca2+ leak model calsequestrin 2 R33Q (Casq2R33Q/R33Q) mice. Atrial trigger appeared in R33Q mice but not WT mice (17.24%, 5/29 vs. 0.00%, 0/32, P < 0.05). AF was induced by 25 Hz pacing in R33Q mice (48.27%, 14/29 vs. 6.25%, 2/32, P < 0.01). The mice were given 1.5 mg/kg isoproterenol (Iso), and the incidences of AF increased (65.51%, 19/29 vs. 9.21%, 3/32, P < 0.01). Electrophysiology experiments and the recording of intracellular Ca2+ indicated significant increases in the Ca2+ sparks (5.24 +/- 0.75 100 MUM-1.s-1 vs. 0.29 +/- 0.04 100 MUM-1.s-1, n = 20, P < 0.05), intracellular free Ca2+ (0.238 +/- 0.009 MUM vs. 0.172 +/- 0.006 MUM, n = 20, P < 0.05), Ca2+ wave (11.74% vs. 2.24%, n = 20, P < 0.05), transient inward current (ITi) (-0.56 +/- 0.02 pA/pF vs. -0.42 +/- 0.01 pA/pF, n = 10, P < 0.05), and oscillation in membrane potentials (10.71%, 3/28 vs. 4.16%, 1/24, P < 0.05) in the R33Q group, but there was no significant difference in the L-type calcium current. These effects were enhanced by Iso, and the inhibition of calmodulin-dependent protein kinase II (CaMKII) by 1 MUM KN93 reversed the effects of Iso on Ca2+ sparks (5.01 +/- 0.66 100 MUm-1.s-1 vs. 11.33 +/- 1.63 100 MUm-1.s-1, P < 0.05), intracellular Ca2+ (0.245 +/- 0.005 MUM vs. 0.324 +/- 0.008 MUM, P < 0.05), Ca2+ wave (12.35% vs. 17.83%, P < 0.05), ITi (-0.61 +/- 0.02 pA/pF vs. -0.78 +/- 0.03 pA/pF, n = 10, P < 0.05), and oscillation in membrane potential (17.85% 5/28 vs. 32.17% 9/28, P < 0.05). The reduction of ryanodine receptor 2 (RyR2) stable subunits (Casq2, triadin, and junctin) rather than RYR2 and the increase in CaMKII, phosphor-CaMKII, phosphor-RyR2 (Ser 2814), SERCA, and NCX1.1 was reflected in the R33Q group. Conclusion: This study demonstrates that the increase in spontaneous calcium elevations corresponding to ITi that may trigger the oscillation in membrane potentials in the R33Q group, thereby increasing the risk of AF. The occurrence of spontaneous calcium elevations in R33Q atrial myocytes is due to the dysfunction of RyR2 stable subunits, CaMKII hyperactivity, and CaMKII mediated RyR phosphorylation. An effective therapeutic strategy to intervene in Ca2+-induced AF associated with the R33Q mutation may be through CaMKII inhibition. PMID- 30450054 TI - Editorial: Redox and Nitrosative Signaling in Cardiovascular System: From Physiological Response to Disease. PMID- 30450053 TI - Marker-Free Tracking for Motion Artifact Compensation and Deformation Measurements in Optical Mapping Videos of Contracting Hearts. AB - Optical mapping is a high-resolution fluorescence imaging technique, which provides highly detailed visualizations of the electrophysiological wave phenomena, which trigger the beating of the heart. Recent advancements in optical mapping have demonstrated that the technique can now be performed with moving and contracting hearts and that motion and motion artifacts, once a major limitation, can now be overcome by numerically tracking and stabilizing the heart's motion. As a result, the optical measurement of electrical activity can be obtained from the moving heart surface in a co-moving frame of reference and motion artifacts can be reduced substantially. The aim of this study is to assess and validate the performance of a 2D marker-free motion tracking algorithm, which tracks motion and non-rigid deformations in video images. Because the tracking algorithm does not require markers to be attached to the tissue, it is necessary to verify that it accurately tracks the displacements of the cardiac tissue surface, which not only contracts and deforms, but also fluoresces and exhibits spatio-temporal physiology-related intensity changes. We used computer simulations to generate synthetic optical mapping videos, which show the contracting and fluorescing ventricular heart surface. The synthetic data reproduces experimental data as closely as possible and shows electrical waves propagating across the deforming tissue surface, as seen during voltage-sensitive imaging. We then tested the motion tracking and motion-stabilization algorithm on the synthetic as well as on experimental data. The motion tracking and motion-stabilization algorithm decreases motion artifacts approximately by 80% and achieves sub-pixel precision when tracking motion of 1-10 pixels (in a video image with 100 by 100 pixels), effectively inhibiting motion such that little residual motion remains after tracking and motion-stabilization. To demonstrate the performance of the algorithm, we present optical maps with a substantial reduction in motion artifacts showing action potential waves propagating across the moving and strongly deforming ventricular heart surface. The tracking algorithm reliably tracks motion if the tissue surface is illuminated homogeneously and shows sufficient contrast or texture which can be tracked or if the contrast is artificially or numerically enhanced. In this study, we also show how a reduction in dissociation-related motion artifacts can be quantified and linked to tracking precision. Our results can be used to advance optical mapping techniques, enabling them to image contracting hearts, with the ultimate goal of studying the mutual coupling of electrical and mechanical phenomena in healthy and diseased hearts. PMID- 30450050 TI - PLGA-Based Nanoparticles in Cancer Treatment. AB - Nanomedicines can be used for a variety of cancer therapies including tumor targeted drug delivery, hyperthermia, and photodynamic therapy. Poly (lactic-co glycolic acid) (PLGA)-based materials are frequently used in such setups. This review article gives an overview of the properties of previously reported PLGA nanoparticles (NPs), their behavior in biological systems, and their use for cancer therapy. Strategies are emphasized to target PLGA NPs to the tumor site passively and actively. Furthermore, combination therapies are introduced that enhance the accumulation of NPs and, thereby, their therapeutic efficacy. In this context, the huge number of reports on PLGA NPs used as drug delivery systems in cancer treatment highlight the potential of PLGA NPs as drug carriers for cancer therapeutics and encourage further translational research. PMID- 30450055 TI - Pacing Strategies in the 'Athens Classic Marathon': Physiological and Psychological Aspects. AB - Despite the increased scientific interest in the relationship between pacing and performance in marathon running, little information is available about the association of pacing with physiological and psychological parameters. Therefore, the aim of the present study was to examine the role physical fitness and training characteristics on pacing in the 'Athens Classic Marathon.' Finishers in this race in 2017 (women, n = 26, age 40.8 +/- 9.4 years; men, n = 130, age 44.1 +/- 8.6 years) were analyzed for their pacing during the race, completed the Motivation of Marathon Scale (MOMS) and performed a series of physiological tests. Women and faster recreational runners adopted a more even pacing. A more even pacing was related with a higher aerobic capacity and lower muscle strength in men, but not in women. Men with more even pacing scored higher in psychological coping, self-esteem, life meaning, recognition and competition than their counterparts with less even pacing. Considering the increasing number of participants in marathon races, these findings might help a wide range of professionals (fitness trainers, physiologists, and psychologists) working with runners to optimize the pacing of their athletes. PMID- 30450056 TI - Acute Dehydration Impairs Endurance Without Modulating Neuromuscular Function. AB - Introduction/Purpose: This study examined the influence of acute dehydration on neuromuscular function. Methods: On separate days, combat sports athletes experienced in acute dehydration practices (n = 14) completed a 3 h passive heating intervention (40 degrees C, 63% relative humidity) to induce dehydration (DHY) or a thermoneutral euhydration control (25 degrees C, 50% relative humidity: CON). In the ensuing 3 h ad libitum fluid and food intake was allowed, after which participants performed fatiguing exercise consisting of repeated unilateral knee extensions at 85% of their maximal voluntary isometric contraction (MVIC) torque until task failure. Both before and after the fatiguing protocol participants performed six MVICs during which measures of central and peripheral neuromuscular function were made. Urine and whole blood samples to assess urine specific gravity, urine osmolality, haematocrit and serum osmolality were collected before, immediately and 3 h after intervention. Results: Body mass was reduced by 3.2 +/- 1.1% immediately after DHY (P < 0.001) but recovered by 3 h. Urine and whole blood markers indicated dehydration immediately after DHY, although blood markers were not different to CON at 3 h. Participants completed 28% fewer knee extensions at 85% MVIC (P < 0.001, g = 0.775) and reported a greater perception of fatigue (P = 0.012) 3 h after DHY than CON despite peak torque results being unaffected. No between-condition differences were observed in central or peripheral indicators of neuromuscular function at any timepoint. Conclusion: Results indicate that acute dehydration of 3.2% body mass followed by 3 h of recovery impairs muscular strength-endurance and increases fatigue perception without changes in markers of central or peripheral function. These findings suggest that altered fatigue perception underpins muscular performance decrements in recovery from acute dehydration. PMID- 30450057 TI - Force-Velocity Characteristics, Muscle Strength, and Flexibility in Female Recreational Marathon Runners. AB - Physical fitness components that relate with performance in marathon running, e.g., aerobic capacity and body composition, have been studied extensively. On the other hand, data on components of the health-related physical fitness, such as flexibility and muscle strength, were missing in this sport. Therefore, the aim of the present study was to profile force-velocity (F-v) characteristics, muscle strength and flexibility in female recreational marathon runners and to examine their relationship with age, race time and anthropometric characteristics (body fat percentage, fat-free mass - FFM, and total thigh muscle cross-sectional area - CSA). Thirty three female marathon runners (age 40.0 +/- 8.9 years, body fat percentage 19.5 +/- 4.6% and personal record 4:34 +/- 0:39 h:min), separated into three age groups (<35, 35-45 and >45 years) and three performance groups (race time <4:15 h:min, 4:15-4:45 h:min and >4:45 h:min), performed sit-and-reach test (SAR), isometric muscle strength tests, squat jump, countermovement jump and F-v test on a cycle ergometer. The main findings of the present study were that (i) participants had moderate scores of body composition and physical fitness considering norms of the general population, (ii) the <35 age group had better jumping ability than 35-45 and >45 age group, and the older age group had lower F0, Pmax and rPmax than their younger counterparts, (iii) the slowest performance group scored the highest in SAR, and (iv) isometric strength, F0 and Pmax correlated largely with body mass and FFM. Considering the lack of existing data on anaerobic power and neuromuscular fitness of female marathon runners, the findings reported in this study would be useful for strength and conditioning trainers to monitor the training of their athletes. Even if these parameters were not related to race time, they should be monitored regularly as they were either component of health-related physical fitness (muscle strength and flexibility) or could help runners (anaerobic power) under specific circumstances such as ascends during a race. PMID- 30450060 TI - Death Penalty and Psychiatric Evaluation in Japan. AB - Japan recently ordered a string of death sentences for offenders with mental illness. Based on the verdicts, we describe cases where one or more psychiatrists conducted psychiatric evaluations for several months and testified in lay judge courts. We compared these cases with those in which the death penalty was avoided, or the mandating treatment order was applied. Additionally, we discuss a trend toward more severe punishment and Japanese cultural background seen in a public opinion survey. Moreover, we introduce a research report that concluded a strong correlation between the number of victims and death penalty verdict. In Japan, lay judge trials determine the sentencing of the defendant and the verdict of guilty or not guilty, and it can be difficult for psychiatrists to help lay judges understand psychiatric symptoms and the relationship between symptoms and criminal responsibility through their testimony. We believe the right to life is the most fundamental of human rights and that the death penalty is inhumane. The death penalty also eliminates the possibility of treatment or rehabilitation, despite the fact that psychiatrists should support the possibility of treatment or rehabilitation in all cases. Further, the Japanese Penal Code does not permit execution for those mentally ill deemed unable to receive sentence; however, it is unclear who will conduct these evaluations and how they will do so. We describe our beliefs of how psychiatrists should act in these situations. PMID- 30450058 TI - Mechanisms of Moral Injury Following Military Sexual Trauma and Combat in Post 9/11 U.S. War Veterans. AB - Objective: Moral injury may result from perpetration-based and betrayal-based acts that violate deeply held norms; however, researchers and clinicians have little guidance about the moral injury syndrome's specific developmental pathways following morally injurious events. The present study's objective was to examine the direct and indirect pathways proposed in a frequently cited model of moral injury (1) in relation to two types of military-related traumas [experiencing military sexual trauma (MST) and combat exposure]. Methods: Secondary analyses were conducted within a sample of post-9/11 veterans at a Southwestern Veterans Health Care System (N = 310) across two time-points. Structural equation modeling tested the direct and indirect pathways from MST and combat to a PTSD-depression factor via betrayal, perpetration, guilt, and shame. Results: Betrayal accounted for the association between MST and PTSD-depression (beta = 0.10, p < 0.01, 95% CI = 0.01 - 0.11) and perpetration accounted for the association between combat and PTSD-depression (beta = 0.07, p < 0.05, 95% CI = 0.02 - 0.14). The indirect path from combat to shame to PTSD-depression was significant (beta = 0.16, p < 0.01, 95% CI = 0.07 - 0.28) but the path through guilt was not. The specific indirect paths through perpetration or betrayal to shame or guilt were non significant. Conclusions: Betrayal and perpetration are associated with PTSD depression following MST and combat. Results suggest multiple pathways of moral injury development following different military traumas and morally injurious events. Implications for moral injury conceptualization and treatment are discussed. PMID- 30450059 TI - Beyond the Walls: An Evaluation of a Pre-Release Planning (PReP) Programme for Sentenced Mentally Disordered Offenders. AB - Background: Prison mental health services have tended to focus on improving the quality of care provided to mentally disordered offenders at the initial point of contact with the prison system and within the prison environment itself. When these individuals reach the end of their sentence and return to the community, there is an increased risk of morbidity, mortality, homelessness and re imprisonment. New models of care have been developed to minimize these risks. Objectives: The objective of this project was to establish a Pre-Release Planning (PReP) Programme with social work expertise, to enhance interagency collaboration and improve continuity of care for mentally disordered offenders upon their release. We aimed to evaluate the first 2 years of the programme by measuring its success at improving the level of mental health support and the security and quality of accommodation achieved by participants upon release in comparison to that reported at time of imprisonment. Additionally, we aimed to explore the impact of these outcomes on rates of re-imprisonment. Methods: A process of participatory action research was used to develop and evaluate the first 2 years of the programme. This was a naturalistic prospective observational whole cohort study. Results: The PReP Programme supported 43 mentally disordered offenders, representing 13.7%, (43/313) of all new assessments by the prison's inreach mental health service during the 2 years study period. When compared with that reported at time of reception at the prison, gains were achieved in level of mental health support (FET p < 0.001) and security and quality of accommodation (FET p < 0.001) upon release. Of those participants seen by the PReP Programme, 20 (46.5%, 20/43) were returned to prison during the 2-years study period. There was no significant relationship between re-imprisonment and gains made in mental health support (FET p = 0.23) or accommodation (FET p = 0.23). Conclusions: We have shown that compared to that reported at time of reception at prison, the level of mental health support and the security of tenure and quality of accommodation both improved upon release following the intervention of the programme. Improved mental health support and accommodation were not associated with lower rates of re-imprisonment. PMID- 30450062 TI - A Daily Diary Study on Sleep Quality and Procrastination at Work: The Moderating Role of Trait Self-Control. AB - Background: This daily diary study investigates the relation between sleep quality during the night and its effect on procrastination at work during the next workday. Previous research has shown that sleep quality is an important variable for work behavior at the daily level, including employee performance, safety, health, and attitudes, such as work engagement. Also, sleep quality has been found to be negatively related to next-day work procrastination. However, these studies did not address trait differences that may be involved. In other words, they have not investigated whether all employees experience the effects of sleep quality on procrastination similarly. We explore the moderating effect of trait self-control. Methods: Seventy one full-time employees (51% male) working in various industries participated, including finance or banking (17%), government or education (13%), construction (7%), health care (7%), sales or marketing (6%), and others. Average age was 35.20 years (SD = 12.74), and average employment tenure was 13.3 years (SD = 13.16). Participants completed a one-shot general electronic questionnaire (to assess trait self-control, using a four-item scale adapted from Tangney et al., 2004). Subsequently, these employees received two daily electronic questionnaires to assess sleep quality (measured with one item from the Pittsburgh Sleep Quality Index (Buysse et al., 1989), and a three item scale of procrastination (adapted from Tuckman, 1991) over the course of 10 workdays, resulting in 465 pairs of matched morning-afternoon measurements (65% response). Results: Results of multilevel regression analyses showed that sleep quality was negatively related to work procrastination the next day. Sleep quality, however, also interacted with trait self-control in impacting work procrastination, such that low sleep quality affected employees low in trait self control, but not employees high in trait self-control. Conclusion: The findings of this study qualify earlier research showing the relation between procrastination and sleep quality. We show that the relation is only present for those who have low trait self-control; employees with high trait self-control tend to be immune to low sleep quality. Thus, general advice or interventions to improve sleep quality may be restricted to a selection of employees that are truly affected. PMID- 30450061 TI - There's a SNARC in the Size Congruity Task. AB - The size congruity effect involves interference between numerical magnitude and physical size of visually presented numbers: congruent numbers (either both small or both large in numerical magnitude and physical size) are responded to faster than incongruent ones (small numerical magnitude/large physical size or vice versa). Besides, numerical magnitude is associated with lateralized response codes, leading to the Spatial Numerical Association of Response Codes (SNARC) effect: small numerical magnitudes are preferably responded to on the left side and large ones on the right side. Whereas size congruity effects are ascribed to interference between stimulus dimensions in the decision stage, SNARC effects are understood as (in)compatibilities in stimulus-response combinations. Accordingly, size congruity and SNARC effects were previously found to be independent in parity and in physical size judgment tasks. We investigated their dependency in numerical magnitude judgment tasks. We obtained independent size congruity and SNARC effects in these tasks and replicated this observation for the parity judgment task. The results confirm and extend the notion that size congruity and SNARC effects operate in different representational spaces. We discuss possible implications for number representation. PMID- 30450063 TI - Decisional Dimensions in Expert Witness Testimony - A Structural Analysis. AB - The relationship between forensic science and legal adjudication is intricate mainly because the need to inform fact-finders on issues going beyond the layman's knowledge poses challenges both on empirical and normative dimensions, in particular with regards to the specific role and duties of the different participants in the legal process. While rationality is widely upheld as one of the aspirations of the legal process across many modern jurisdictions, a pending question is how to remedy the uneasy relationship between general propositions (and knowledge claims) conditioning expert witness testimony, and individualized decisions taken by fact-finders. The focus has hitherto been put on the utilization of model-based and formal methods of reasoning while, regrettably, the concepts of judgment and decision-making have not received equal attention. A first aspiration of our paper will thus be to further clarify the nature of this systemic relationship in the particular area of the legal process involving scientific experts, by conducting a critical transversal analysis of current empirical, normative and doctrinal understandings of expert witness testimony. As a second aim, we will use this insight to argue in favor of the view that structural features of expert witness testimony are embedded in a decision-making process, and that the understanding of this decisional dimension is important for clarifying the respective roles of expert witnesses and fact-finders, and for favoring their mutual understanding thereof. To substantiate this perspective, and attest to its growing recognition as a frontier understanding, we will provide real-world examples from forensic science reporting practice and policy documents of professional bodies. PMID- 30450064 TI - Consciousness as a Physical Process Caused by the Organization of Energy in the Brain. AB - To explain consciousness as a physical process we must acknowledge the role of energy in the brain. Energetic activity is fundamental to all physical processes and causally drives biological behavior. Recent neuroscientific evidence can be interpreted in a way that suggests consciousness is a product of the organization of energetic activity in the brain. The nature of energy itself, though, remains largely mysterious, and we do not fully understand how it contributes to brain function or consciousness. According to the principle outlined here, energy, along with forces and work, can be described as actualized differences of motion and tension. By observing physical systems, we can infer there is something it is like to undergo actualized difference from the intrinsic perspective of the system. Consciousness occurs because there is something it is like, intrinsically, to undergo a certain organization of actualized differences in the brain. PMID- 30450066 TI - Opposition to Inbreeding Between Close Kin Reflects Inclusive Fitness Costs. AB - Due to the intense selection pressure against inbreeding, humans are expected to possess psychological adaptations that regulate mate choice and avoid inbreeding. From a gene's-eye perspective, there is little difference in the evolutionary costs between situations where an individual him/herself is participating in inbreeding and inbreeding among other close relatives. The difference is merely quantitative, as fitness can be compromised via both routes. The question is whether humans are sensitive to the direct as well as indirect costs of inbreeding. Using responses from a large population-based sample (27,364 responses from 2,353 participants), we found that human motivations to avoid inbreeding closely track the theoretical costs of inbreeding as predicted by inclusive fitness theory. Participants were asked to select in a forced choice paradigm, which of two acts of inbreeding with actual family members they would want to avoid most. We found that the estimated fitness costs explained 83.6% of participant choices. Importantly, fitness costs explained choices also when the self was not involved. We conclude that humans intuit the indirect fitness costs of mating decisions made by close family members and that psychological inbreeding avoidance mechanisms extend beyond self-regulation. PMID- 30450065 TI - When Low Leisure-Time Physical Activity Meets Unsatisfied Psychological Needs: Insights From a Stress-Buffer Perspective. AB - Background: Few studies have tested whether the stress-buffering effects of leisure-time physical activity (LTPA) depend on other resources, such as the satisfaction of basic psychological needs. Therefore, the present study examines the interaction between perceived stress, LTPA and psychological need satisfaction (PNS) on occupational burnout symptoms in a sample of Swiss workers. Methods: The sample consisted of 306 employees (48% women; M age = 42.9 years, SD = 14.1). Perceived stress was assessed with the Perceived Stress Scale, LTPA with the International Physical Activity Questionnaire, PNS (autonomy, relatedness, and competence) with the Need Satisfaction Scale, and occupational burnout symptoms with the Shirom-Melamed Burnout Measure. A hierarchical regression analysis and single slopes tests were performed to examine two- and three-way interactions. Results: Stress was positively correlated with burnout, and negatively correlated with LTPA and PNS levels. LTPA was positively associated with PNS, and negatively correlated with burnout. A negative association existed between PNS and burnout. In the hierarchical regression analysis, all main effects, two- and three-way interactions were significant. People who engaged in more LTPA reported fewer burnout symptoms, if they reported high stress. However, the potential of LTPA to buffer stress was particularly evident in participants who reported low PNS. Conclusion: If adult workers are exposed to elevated stress, they are particularly likely to show increased burnout levels if they report low LTPA in combination with low PNS, specifically a lack of autonomy, competence and relatedness. PMID- 30450067 TI - Childbirth Related Post-traumatic Stress Symptoms and Maternal Sleep Difficulties: Associations With Parenting Stress. AB - In the literature, increasing evidence is showing the importance of sleep difficulties in the development or maintenance of posttraumatic stress (PTS) symptoms as well as the association between childbirth-related PTS symptoms and early maternal emotions and perceptions of their children. However, little is known regarding the effects of maternal sleep difficulties on parenting or about the mediational role of childbirth-related PTS symptoms in this association. The present study (pregnancy: T0; 1 month postpartum: T1; 3 months postpartum: T2) had two aims. The first one was to explore whether maternal sleep difficulties could contribute to the maintenance of PTS symptoms and whether PTS symptoms could contribute to the maintenance of maternal sleep difficulties. The second purpose was to explore, at 3 months (T2), the associations among childbirth related PTS symptoms, maternal sleep difficulties, and the three dimensions of parenting stress [parental distress (PD), parent-child dysfunctional interaction, and difficult child] by examining the mediational role of both maternal sleep difficulties and childbirth-related PTS symptoms. Self-report questionnaires were administered to 95 women at different times (T0, T1, and T2). Mediational results confirmed the bidirectional effects between maternal sleep difficulties and PTS symptoms and their reciprocal role of maintenance of symptoms. Moreover, at 3 months postpartum (T2), sleep difficulties mediated the association between PTS symptoms and the three dimensions of maternal parenting stress, while PTS symptoms mediated the associations among maternal sleep difficulties, PD, and difficult child dimensions of parenting stress. The study contributes to the understanding of the maintenance factors of childbirth-related PTS symptoms and of the relationships among PTS symptoms, maternal sleep difficulties, and parenting stress. PMID- 30450068 TI - The Interaction of TPH1 A779C Polymorphism and Maternal Authoritarianism on Creative Potential. AB - Exploring the possible mechanisms through which gene may interact with environment to influence creativity has been one of the leading issues in creativity research. In a sample of four hundred and twenty-one Chinese undergraduate students, the present study investigated for the first time the interaction of TPH1 A779C polymorphism and maternal parenting styles on creative potential. The results showed that there was a significant interaction of TPH1 A779C polymorphism and maternal authoritarianism on creative potential. Moreover, the analysis of regions of significance (Ros) provided supporting evidences for both the diathesis-stress model (flexibility) and the differential susceptibility model (originality). These findings extend our understanding concerning the mechanisms by which gene and environment may act in coordination to contribute to creativity. PMID- 30450070 TI - From Character Strengths to Children's Well-Being: Development and Validation of the Character Strengths Inventory for Elementary School Children. AB - Although research on character strengths has flourished in recent years, the paucity of suitable quantitative instruments for the assessment of children's character strengths limits the study of character development in childhood. The Character Strengths Inventory for Children (CSI-C) is a new self-report character inventory for children that was designed for easy administration directly to elementary school-aged children. The CSI-C provides an evaluation of 24 character strengths defined in Peterson and Seligman's Values in Action Classification of Strengths. Data from two samples of 2,061 Israeli children aged 7-12 support the constructs of the instrument. Principal component analysis and confirmatory factor analysis of the 96 CSI-C items revealed preliminary evidence for a hierarchical structure with 24 lower factors nested within four higher-order latent factors: interpersonal, transcendence, intellectual, and temperance strengths. Children's interpersonal and temperance strengths were negatively associated with mental health difficulties, and their temperance and transcendence strengths were positively associated with subjective well-being. The intellectual and temperance strengths were correlated with children's school functioning and grit. The potential uses of the CSI-C in research and practice are discussed. PMID- 30450069 TI - Virtual Reality as a Vehicle to Empower Motor-Cognitive Neurorehabilitation. AB - In this paper, we advocate the combination of four key ingredients that we believe are necessary to design long-lasting effective treatments for neurorehabilitation: (i) motor-cognitive training, (ii) evidence-based neuroscience principles, in particular those related to body perception, (iii) motivational games, and (iv) empowerment techniques. Then, we propose virtual reality (VR) as the appropriate medium to encompass all the requirements mentioned above. VR is arguably one of the most suitable technologies for neurorehabilitation able to integrate evidence-based neurorehabilitation techniques and neuroscience principles into motivating training approaches that promote self-management by empowering patients to own their recovery process. We discuss the advantages and challenges of such an approach on several exemplary applications and outline directions for future developments. We strongly believe that the combination of positive psychology and positive technology mediated by VR-based interventions can heavily impact the rehabilitation outcomes of motor cognitive functions along all the stages of the rehabilitation path. PMID- 30450071 TI - Improving Self-Esteem With Motivational Quotes: Opportunities for Digital Health Technologies for People With Chronic Disorders. PMID- 30450073 TI - Pros and Cons of 19 Sport-Related Concussion Educational Resources in Canada: Avenues for Better Care and Prevention. AB - Objective: The goal of this research was to assess the effectiveness of available concussion educational resources in Canada, the means used to disseminate this knowledge and the impact of these educational resources on players' concussion prevention knowledge. Methods: We assessed concussion knowledge before and after exposure to one or more of 19 resources introduced through a national program aimed to increase awareness and knowledge of concussion. The effectiveness of the mode of delivery was measured by changes in concussion knowledge scores (CKS) between pre and pro scores. Measures: Concussion knowledge scores (CKS) were calculated for pre- and post- exposure to concussion educational resources and used as a measure of both, the effectiveness of each resource as well as the effectiveness of the delivery method. The effectiveness of each educational resource was also measured by the respondents' rating of each concussion educational resource. Results: Respondents in post-survey had higher CKS than those in pre-survey. Two out of the 19 newly developed concussion educational resources were effective in improving the resource users' CKS. Linear regression showed that using more resources further increased CKS. Four out of six modes of delivery enhanced respondents' concussion knowledge. Conclusion: Our findings demonstrate that the newly developed Canadian concussion educational resources were effective at improving users' concussion knowledge. Our data demonstrates that using three or more resources further enhanced the users' concussion knowledge. Future research, however, is critical to assess whether concussion prevention knowledge is sufficient to reduce injuries and factors influencing it. PMID- 30450072 TI - Abnormal Global Brain Functional Connectivity in Primary Insomnia Patients: A Resting-State Functional MRI Study. AB - Background: Resting-state functional magnetic resonance imaging (fMRI) studies have uncovered the disruptions of functional brain networks in primary insomnia (PI) patients. However, the etiology and pathogenesis underlying this disorder remains ambiguous, and the insomnia related symptoms are influenced by a complex network organization in the brain. The purpose of this study was to explore the abnormal intrinsic functional hubs in PI patients using a voxel-wise degree centrality (DC) analysis and seed-based functional connectivity (FC) approach. Methods: A total of 26 PI patients and 28 healthy controls were enrolled, and they underwent resting-state fMRI. Degree centrality was measured across the whole brain, and group differences in DC were compared. The peak points, which significantly altered DC between the two groups, were defined as the seed regions and were further used to calculate FC of the whole brain. Later, correlation analyses were performed between the changes in brain function and clinical features. Results: Primary insomnia patients showed DC values lower than healthy controls in the left inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) and showed a higher DC value in the right precuneus. The seed-based analyses demonstrated decreased FC between the left MTG and the left posterior cingulate cortex (PCC), and decreased FC was observed between the right precuneus and the right lateral occipital cortex. Reduced DC in the left IFG and decreased FC in the left PCC were positively correlated with the Pittsburgh sleep quality index and the insomnia severity index. Conclusions: This study revealed that PI patients exhibited abnormal intrinsic functional hubs in the left IFG, MTG, and the right precuneus, as well as abnormal seed-based FC in these hubs. These results contribute to better understanding of how brain function influences the symptoms of PI. PMID- 30450074 TI - Longitudinal Associations of the Healthy Lifestyle Index Score With Quality of Life in People With Multiple Sclerosis: A Prospective Cohort Study. AB - Objective: To explore the association between combined lifestyle risk factors with quality of life in people with multiple sclerosis (MS) over 2.5 years. Methods: People with MS were recruited to participate in a comprehensive online survey regarding their demographic and clinical characteristics, health-related quality of life (HRQOL), and lifestyle behaviors including physical activity, alcohol consumption, cigarette smoking, body mass index, and dietary habits measured at baseline and 2.5-year follow-up. A combined healthy lifestyle index score (HLIS) was constructed by assigning scores of 0-4 to each of the lifestyle risk factors, for which higher values indicate healthier lifestyle behavior. Multivariable linear regression modeling was used to assess whether the HLIS at baseline was associated with the physical and mental HRQOL over the study period in this sample of people with MS. Results: Of 2,466 participants with confirmed MS, 1,401 (57%) completed the follow-up. Multivariable linear regression analyses demonstrated that every 5-point increase (of a possible total of 20) in the baseline HLIS was associated with 1.7 (95% CI: 0.2-3.2) and 2.5 (95% CI: 1.0-4.0) higher scores in the change in physical and mental HRQOL components from baseline to follow-up respectively. Conclusion: Findings suggest the importance of healthy lifestyle behavior in quality of life in MS. A healthy lifestyle program focusing on these behaviors has the potential to positively influence health-related quality of life for people with MS. PMID- 30450075 TI - Association Between Anxiety, Depression, and Post-traumatic Stress Disorder and Outcomes After Ischemic Stroke. AB - Background: Stroke patients are known to be at risk of developing anxiety, depression, and post-traumatic stress disorder (PTSD). Objective: To determine the overlap between anxiety, depression, and PTSD in patients after stroke and to determine the association between these disorders and quality of life, functional status, healthcare utilization, and return to work. Methods: A cross-sectional telephone survey was conducted to assess for depression, anxiety, PTSD, and health-related outcomes 6-12 months after first ischemic stroke in patients without prior psychiatric disease at a single stroke center. Results: Of 352 eligible subjects, 55 (16%) completed surveys. Seven subjects (13%) met criteria for probable anxiety, 6 (11%) for PTSD, and 11 for depression (20%). Of the 13 subjects (24%) who met criteria for any of these disorders, 6 (46%) met criteria for more than one, and 5 (39%) met criteria for all three. There were no significant differences in baseline characteristics, including stroke severity or neurologic symptoms, between those with or without any of these disorders. Those who had any of these disorders were less likely to be independent in their activities of daily living (ADLs) (54 vs. 95%, p < 0.001) and reported significantly worse quality of life (score of 0-100, median score of 50 vs. 80, p < 0.001) compared to those with none of these disorders. Conclusions: Anxiety, depression, and PTSD are common after stroke, have a high degree of co occurrence, and are associated with worse outcomes, including quality of life and functional status. PMID- 30450076 TI - Inherent vs. Induced Loop Gain Abnormalities in Obstructive Sleep Apnea. AB - Unstable ventilatory chemoreflex control, quantified as loop gain, is recognized as one of four key pathophysiological traits that contribute to cause obstructive sleep apnea (OSA). Novel treatments aimed at reducing loop gain are being investigated, with the intention that future OSA treatment may be tailored to the individual's specific cause of apnea. However, few studies have evaluated loop gain in OSA and non-OSA controls and those that have provide little evidence to support an inherent abnormality in either overall chemical loop gain in OSA patients vs. non-OSA controls, or its components (controller and plant gain). However, intermittent hypoxia may induce high controller gain through neuroplastic changes to chemoreflex control, and may also decrease plant gain via oxidative stress induced inflammation and reduced lung function. The inherent difficulties and limitations with loop gain measurements are discussed and areas where further research are required are highlighted, as only by understanding the mechanisms underlying OSA are new therapeutic approaches likely to emerge in OSA. PMID- 30450077 TI - Plasticity Induced in the Human Spinal Cord by Focal Muscle Vibration. AB - The spinal cord spinal cord has in the past been considered a hardwired system which responds to inputs in a stereotyped way. A growing body of data have instead demonstrated its ability to retain information and modify its effector capabilities, showing activity-dependent plasticity. Whereas, plasticity in the spinal cord is well documented after different forms of physical exercise, whether exogenous stimulation can induce similar changes is still a matter of debate. This issue is both of scientific and clinical relevance, since at least one form of stimulation, i.e., focal muscle vibration (fMV), is currently used as a treatment for spasticity. The aim of the present study was to assess whether fMV can induce plasticity at the SC level when applied to different muscles of the upper limb. Changes in different electrophysiological measures, such as H reflex testing homonymous and heteronymous pathways, reciprocal inhibition and somatosensory evoked potentials were used as outcomes. We found that fMV was able to induce long-term depression-like plasticity in specific spinal cord circuits depending on the muscle vibrated. These findings helped understand the basic mechanisms underlying the effects of fMV and might help to develop more advanced stimulation protocols. PMID- 30450078 TI - Recursive Partitioning Analysis of Fractional Low-Frequency Fluctuations in Narcolepsy With Cataplexy. AB - Objective: To identify narcolepsy related regional brain activity alterations compared with matched healthy controls. To determine whether these changes can be used to distinguish narcolepsy from healthy controls by recursive partitioning analysis (RPA) and receiver operating characteristic (ROC) curve analysis. Method: Fifty-one narcolepsy with cataplexy patients (26 adults and 25 juveniles) and sixty matched heathy controls (30 adults and 30 juveniles) were recruited. All subjects underwent a resting-state functional magnetic resonance imaging scan. Fractional low-frequency fluctuations (fALFF) was used to investigate narcolepsy induced regional brain activity alterations among adult and juveniles, respectively. Recursive partitioning analysis and Receiver operating curve analysis was used to seek the ability of fALFF values within brain regions in distinguishing narcolepsy from healthy controls. Results: Compared with healthy controls, both adult and juvenile narcolepsy had lower fALFF values in bilateral medial superior frontal gyrus, bilateral inferior parietal lobule and supra marginal gyrus. Compared with healthy controls, both adult and juvenile narcolepsy had higher fALFF values in bilateral sensorimotor cortex and middle temporal gyrus. Also juvenile narcolepsy had higher fALFF in right putamen and right thalamus compared with healthy controls. Based on RPA and ROC curve analysis, in adult participants, fALFF differences in right medial superior frontal gyrus can discriminate narcolepsy from healthy controls with high degree of sensitivity (100%) and specificity (88.9%). In juvenile participants, fALFF differences in left superior frontal gyrus can discriminate narcolepsy from healthy controls with moderate degree of sensitivity (57.1%) and specificity (88.9%). Conclusion: Compared with healthy controls, both the adult and juvenile narcolepsy showed overlap brain regions in fALFF differences after case-control comparison. Furthermore, we propose that fALFF value can be a helpful imaging biomarker in distinguishing narcolepsy from healthy controls among both adults and juveniles. PMID- 30450079 TI - Serum Insulin-Like Growth Factor-1 in Parkinson's Disease; Study of Cerebrospinal Fluid Biomarkers and White Matter Microstructure. AB - Background: Growing evidence shows that impaired signaling of Insulin-like Growth Factor-1 (IGF-1) is associated with neurodegenerative disorders, such as Parkinson's disease (PD). However, there is still controversy regarding its proinflammatory or neuroprotective function. In an attempt to elucidate the contribution of IGF-1 in PD, we aimed to discover the relation between serum IGF 1 levels in drug-naive early PD patients and cerebrospinal fluid (CSF) biomarkers as well as microstructural changes in brain white matter. Methods: The association between quartiles of serum IGF-1 levels and CSF biomarkers (alpha synuclein, dopamine, amyloid-beta1-42, total tau, and phosphorylated tau) was investigated using adjusted regression models in 404 drug-naive early PD patients with only mild motor manifestations and 188 age- and sex-matched healthy controls (HC) enrolled in the Parkinson's Progression Markers Initiative (PPMI). By using region of interest analysis and connectometry approach, we tracked the white matter microstructural integrity and diffusivity patterns in a subgroup of study participants with available diffusion MRI data to investigate the association between subcomponents of neural pathways with serum IGF-1 levels. Results: PD patients had higher levels of IGF-1 compared to HC, although not statistically significant (mean difference: 3.60, P = 0.44). However, after adjustment for possible confounders and correction for False Discovery Rate (FDR), IGF-1 was negatively correlated with CSF alpha-synuclein, total and phosphorylated tau levels only in PD subjects. The imaging analysis proved a significant negative correlation (FDR corrected P-value = 0.013) between continuous levels of serum IGF-1 in patients with PD and the connectivity, but not integrity, in following fibers while controlling for age, sex, body mass index, depressive symptoms, education years, cognitive status and disease duration: middle cerebellar peduncle, cingulum, genu and splenium of the corpus callosum. No significant association was found between brain white matter microstructral measures or CSF markers of healthy controls and levels of IGF-1. Conclusion: Altered connectivity in specific white matter structures, mainly involved in cognitive and motor deterioration, in association with higher serum IGF-1 levels might propose IGF-1 as a potential associate of worse outcome in response to higher burden of alpha synucleinopathy and tauopathy in PD. PMID- 30450082 TI - Preparation, Antidermatophyte Activity, and Mechanism of Methylphloroglucinol Derivatives. AB - In this study a variety of phloroglucinols were isolated from the plant, and the activity experiment showed that the phloroglucinols had strong antifungal activity, especially methylphloroglucinol derivatives such as aspidin PB, dryofragin, aspidinol, aspidin BB, aspidin AB, and albicanol, in which the hydroxyl group of methylphloroglucinol is the active group of compounds, and C-2 or C-6 is the active site. The introduction of different groups in this position could change the properties and bioactivity of the compounds. In this study, different functional groups were introduced to the structure of methylphloroglucinol to obtain methylphloroglucinol derivatives that were synthesized, and antidermatophyte activities on Trichophyton rubrum, Trichophyton mentagrophytes, Microsporum canis, and Gypsum microspore bacteria were evaluated. Molecular docking verified its ability to combine the protein binding site. The antidermatophyte mechanism of compounds on cytochrome P450 sterol 14a demethylase, squalene epoxidase, and beta-1,3-glucan synthase was investigated by the enzyme-linked immunosorbent assay. The results showed that compounds had an inhibitory effect on four kinds of common dermatophytes in varying degrees, in which compound g had the strongest activities, the binding mode of methylphloroglucinol and its derivatives were similar to those of three enzymes, and compounds e and g had significant effects on the activity of the three enzymes, and compound g had a slightly stronger effect than the blank group. Compounds e and g also had a significant effect on the ergosterol synthesis of M. canis. This study could supply some antidermatophyte leading structure and possible mechanism for studying and developing new antifungal agents. PMID- 30450080 TI - New Neuronal Subtypes With a "Pre-Pancreatic" Signature in the Sea Urchin Stongylocentrotus purpuratus. AB - Neurons and pancreatic endocrine cells have a common physiology and express a similar toolkit of transcription factors during development. To explain these common features, it has been hypothesized that pancreatic cells most likely co opted a pre-existing gene regulatory program from ancestral neurons. To test this idea, we looked for neurons with a "pre-pancreatic" program in an early-branched deuterostome, the sea urchin. Only vertebrates have a proper pancreas, however, our lab previously found that cells with a pancreatic-like signature are localized within the sea urchin embryonic gut. We also found that the pancreatic transcription factors Xlox/Pdx1 and Brn1/2/4 co-localize in a sub-population of ectodermal cells. Here, we find that the ectodermal SpLox+ SpBrn1/2/4 cells are specified as SpSoxC and SpPtf1a neuronal precursors that become the lateral ganglion and the apical organ neurons. Two of the SpLox+ SpBrn1/2/4 cells also express another pancreatic transcription factor, the LIM-homeodomain gene islet 1. Moreover, we find that SpLox neurons produce the neuropeptide SpANP2, and that SpLox regulates SpANP2 expression. Taken together, our data reveal that there is a subset of sea urchin larval neurons with a gene program that predated pancreatic cells. These findings suggest that pancreatic endocrine cells co-opted a regulatory signature from an ancestral neuron that was already present in an early-branched deuterostome. PMID- 30450081 TI - Intracellular Follicle-Stimulating Hormone Receptor Trafficking and Signaling. AB - Models of G protein-coupled receptor (GPCR) signaling have dramatically altered over the past two decades. Indeed, GPCRs such as the follicle-stimulating hormone receptor (FSHR) have contributed to these new emerging models. We now understand that receptor signaling is highly organized at a spatial level, whereby signaling not only occurs from the plasma membrane but distinct intracellular compartments. Recent studies in the role of membrane trafficking and spatial organization of GPCR signaling in regulating gonadotropin hormone receptor activity has identified novel intracellular compartments, which are tightly linked with receptor signaling and reciprocally regulated by the cellular trafficking machinery. Understanding the impact of these cell biological mechanisms to physiology and pathophysiology is emerging for certain GPCRs. However, for FSHR, the potential impact in both health and disease and the therapeutic possibilities of these newly identified systems is currently unknown, but offers the potential to reassess prior strategies, or unveil novel opportunities, in targeting this receptor. PMID- 30450083 TI - Strategies to Maintain Natural Biocontrol of Soil-Borne Crop Diseases During Severe Drought and Rainfall Events. AB - In many parts of the world, agricultural ecosystems are increasingly exposed to severe drought, and rainfall events due to climate changes. This coincides with a higher vulnerability of crops to soil-borne diseases, which is mostly ascribed to decreased resistance to pathogen attacks. However, loss of the natural capacity of soil microbes to suppress soil-borne plant pathogens may also contribute to increased disease outbreaks. In this perspectives paper, we will discuss the effect of extreme weather events on pathogen-antagonist interactions during drought and rainfall events and upon recovery. We will focus on diseases caused by root-infecting fungi and oomycetes. In addition, we will explore factors that affect restoration of the balance between pathogens and other soil microbes. Finally, we will indicate potential future avenues to improve the resistance and/or recovery of natural biocontrol during, and after water stresses. As such, our perspective paper will highlight a knowledge gap that needs to be bridged to adapt agricultural ecosystems to changing climate scenarios. PMID- 30450084 TI - Flexible Symbiotic Associations of Symbiodinium With Five Typical Coral Species in Tropical and Subtropical Reef Regions of the Northern South China Sea. AB - The coral symbiont Symbiodinium plays important roles in the adaptation of coral to environmental changes. However, coral-Symbiodinium symbiotic associations are not well-understood in the South China Sea (SCS) whilst considering environmental factors and host taxa. In this study, next-generation sequencing of the internal transcribed spacer region 2 (ITS2) marker gene was used to explore the symbiotic associations between Symbiodinium and five typical coral species across tropical and subtropical reef regions of the SCS. The results showed that Acropora sp., Galaxea fascicularis, Platygyra lamellina, and Sarcophyton glaucum exhibited distinct Symbiodinium compositions between tropical and subtropical reef regions, whereas Porites lutea had stable Symbiodinium compositions. More heterogeneous Symbiodinium compositions among different coral species were observed in the tropical region, but there were no statistically significant differences in Symbiodinium compositions among different coral species in subtropical reef regions. There was a correlation between the Symbiodinium compositions and environmental factors, except for the composition of P. lutea. Symbiodinium subclades D1, D2, C71, C71a, C21, C3b, and C161 were primarily explained by the seawater temperature, nitrate, ammonia, and phosphate. Several host-specific Symbiodinium subclades (e.g., C15, C15.6, and C91) were observed in P. lutea as well. The findings of this study demonstrate the relationship of Symbiodinium diversity with coral hosts and the environment are helpful for elucidating the adaptation of corals to global climate change and anthropogenic disturbance. PMID- 30450085 TI - Corrigendum: Staphylococcus aureus Bacteriophage Suppresses LPS-Induced Inflammation in MAC-T Bovine Mammary Epithelial Cells. AB - [This corrects the article DOI: 10.3389/fmicb.2018.01614.]. PMID- 30450086 TI - Causes and Consequences of a Variant Strain of Phaeobacter inhibens With Reduced Competition. AB - Phaeobacter inhibens 2.10 is an effective biofilm former and colonizer of marine surfaces and has the ability to outcompete other microbiota. During biofilm dispersal P. inhibens 2.10 produces heritable phenotypic variants, including those that have a reduced ability to inhibit the co-occurring bacterium Pseudoalteromonas tunicata. However, the genetic changes that underpin the phenotypic variation and what the ecological consequences are for variants within the population are unclear. To answer these questions we sequenced the genomes of strain NCV12a1, a biofilm variant of P. inhibens 2.10 with reduced inhibitory activity and the P. inhibens 2.10 WT parental strain. Genome wide analysis revealed point mutations in genes involved in synthesis of the antibacterial compound tropodithietic acid (TDA) and indirectly in extracellular polymeric substances (EPS) production. However, confocal laser scanning microscopy analyses found little differences in biofilm growth between P. inhibens 2.10 WT (parental) and NCV12a1. P. inhibens NCV12a1 was also not outcompeted in co-cultured biofilms with P. tunicata, despite its reduced inhibitory activity, rather these biofilms were thicker than those produced when the WT strain was co-cultured with P. tunicata. Notably, dispersal populations from biofilms of P. inhibens NCV12a1 had a higher proportion of WT-like morphotypes when co-cultured with P. tunicata. These observations may explain why the otherwise non-inhibiting variant persists in the presence of a natural competitor, adding to our understanding of the relative importance of genetic diversification in microbial biofilms. PMID- 30450087 TI - Stochastic and Deterministic Effects of a Moisture Gradient on Soil Microbial Communities in the McMurdo Dry Valleys of Antarctica. AB - Antarctic soil supports surface microbial communities that are dependent on ephemeral moisture. Understanding the response to availability of this resource is essential to predicting how the system will respond to climate change. The McMurdo Dry Valleys are the largest ice-free soil region in Antarctica. They are a hyper-arid polar desert with extremely limited moisture availability. Microbial colonization dominates this ecosystem but surprisingly little is known about how communities respond to changing moisture regimes. We utilized the natural model system provided by transiently wetted soil at lake margins in the Dry Valleys to interrogate microbial responses along a well-defined contiguous moisture gradient and disentangle responses between and within phyla. We identified a striking non linear response among bacteria where at low moisture levels small changes resulted in a large impact on diversity. At higher moister levels community responses were less pronounced, resulting in diversity asymptotes. We postulate that whilst the main drivers of observed community diversity were deterministic, a switch in the major influence occurred from abiotic factors at low moisture levels to biotic interactions at higher moisture. Response between and within phyla was markedly different, highlighting the importance of taxonomic resolution in community analysis. Furthermore, we resolved apparent stochasticity at high taxonomic ranks as the result of deterministic interactions taking place at finer taxonomic and spatial scales. Overall the findings provide new insight on the response to moisture and this will be useful in advancing understanding of potential ecosystem responses in the threatened McMurdo Dry Valleys system. PMID- 30450088 TI - Clinical Efficacy and Microbiome Changes Following Fecal Microbiota Transplantation in Children With Recurrent Clostridium Difficile Infection. AB - Fecal microbiota transplantation (FMT) has been shown as an effective treatment for recurrent clostridium difficile infection (RCDI) in adults. In this study, we aim to evaluate the clinical efficacy of FMT in treating children with RCDI, and explore fecal microbiota changes during FMT treatment. A total of 11 RCDI subjects with a median age of 3.5 years were enrolled in this single-center prospective pilot study. All patients were cured (11/11, 100%) by FMT either through upper gastrointestinal tract route with a nasointestinal tube (13/16, 81.2%) or lower gastrointestinal tract route with a rectal tube (3/16, 18.8%). The cure rate of single FMT was 63.6% (7/11), and 4 (4/11, 36.4%) cases were performed with 2 or 3 times of FMT. Mild adverse events were reported in 4 children (4/11, 36.4%), including transient diarrhea, mild abdominal pain, transient fever and vomit. Gut microbiota composition analysis of 59 fecal samples collected from 34 participants (9 RCDI children, 9 donors and 16 health controls) showed that the alpha diversity was lower in pediatric RCDI patients before FMT than the healthy controls and donors, and fecal microbial community of pre-FMT samples (beta diversity) was apart from that of healthy controls and donors. No significant differences in alpha diversity, beta diversity or phylogenetic distance were detected between donors and healthy controls. Both the richness and diversity of gut microbiota were improved in the pediatric RCDI patients after FMT, and the bacteria community was shifted closer to the donor and healthy control group. Furthermore, FMT re-directed gut microbiome functions of pediatric RCDI toward a health state. Our results indicate that it is safe and tolerant to use FMT in treating pediatric RCDI. FMT shifted the gut microbiome composition and function in children with RCDI toward a healthy state. PMID- 30450090 TI - Enhanced Expression of Pullulanase in Bacillus subtilis by New Strong Promoters Mined From Transcriptome Data, Both Alone and in Combination. AB - Pullulanase plays an important role as a starch hydrolysis enzyme in the production of bio-fuels and animal feed, and in the food industry. Compared to the methods currently used for pullulanase production, synthesis by Bacillus subtilis would be safer and easier. However, the current yield of pullulanase from B. subtilis is low to meet industrial requirements. Therefore, it is necessary to improve the yield of pullulanase by B. subtilis. In this study, we mined 10 highly active promoters from B. subtilis based on transcriptome and bioinformatic data. Individual promoters and combinations of promoters were used to improve the yield of pullulanase in B. subtilis BS001. Four recombinant strains with new promoters (Phag, PtufA, PsodA, and PfusA) had higher enzyme activity than the control (PamyE). The strain containing PsodA+fusA (163 U/mL) and the strain containing PsodA+fusA+amyE (336 U/mL) had the highest activity among the analyzed dual- and triple-promoter construct stains in shake flask, which were 2.29 and 4.73 times higher than that of the strain with PamyE, respectively. Moreover, the activity of the strain containing PsodA+fusA+amyE showed a maximum activity of 1,555 U/mL, which was 21.9 times higher than that of the flask-grown PamyE strain in a 50-liter fermenter. Our work showed that these four strong promoters mined from transcriptome data and their combinations could reliably increase the yield of pullulanase in quantities suitable for industrial applications. PMID- 30450089 TI - Catch Crop Residues Stimulate N2O Emissions During Spring, Without Affecting the Genetic Potential for Nitrite and N2O Reduction. AB - Agricultural soils are a significant source of anthropogenic nitrous oxide (N2O) emissions, because of fertilizer application and decomposition of crop residues. We studied interactions between nitrogen (N) amendments and soil conditions in a 2-year field experiment with or without catch crop incorporation before seeding of spring barley, and with or without application of N in the form of digested liquid manure or mineral N fertilizer. Weather conditions, soil inorganic N dynamics, and N2O emissions were monitored during spring, and soil samples were analyzed for abundances of nitrite reduction (nirK and nirS) and N2O reduction genes (nosZ clade I and II), and structure of nitrite- and N2O-reducing communities. Fertilization significantly enhanced soil mineral N accumulation compared to treatments with catch crop residues as the only N source. Nitrous oxide emissions, in contrast, were stimulated in rotations with catch crop residue incorporation, probably as a result of concurrent net N mineralization, and O2 depletion associated with residue degradation in organic hotspots. Emissions of N2O from digested manure were low in both years, while emissions from mineral N fertilizer were nearly absent in the first year, but comparable to emissions from catch crop residues in the second year with higher precipitation and delayed plant N uptake. Higher gene abundances, as well as shifts in community structure, were also observed in the second year, which were significantly correlated to NO3- availability. Both the size and structure of the nitrite- and N2O-reducing communities correlated to the difference in N2O emissions between years, while there were no consistent effects of management as represented by catch crops or fertilization. It is concluded that N2O emissions were constrained by environmental, rather than the genetic potential for nitrite and N2O reduction. PMID- 30450091 TI - HipA-Mediated Phosphorylation of SeqA Does not Affect Replication Initiation in Escherichia coli. AB - The SeqA protein of Escherichia coli is required to prevent immediate re initiation of chromosome replication from oriC. The SeqA protein is phosphorylated at the serine-36 (Ser36) residue by the HipA kinase. The role of phosphorylation was addressed by mutating the Ser36 residue to alanine, which cannot be phosphorylated and to aspartic acid, which mimics a phosphorylated serine residue. Both mutant strains were similar to wild-type with respect to origin concentration and initiation synchrony. The minimal time between successive initiations was also unchanged. We therefore suggest that SeqA phosphorylation at the Ser36 residue is silent, at least with respect to SeqA's role in replication initiation. PMID- 30450092 TI - Transcriptome and Proteome of Fish-Pathogenic Streptococcus agalactiae Are Modulated by Temperature. AB - Streptococcus agalactiae is one of the most important pathogens associated with streptococcosis outbreaks in Nile tilapia farms worldwide. High water temperature (above 27 degrees C) has been described as a predisposing factor for the disease in fish. At low temperatures (below 25 degrees C), fish mortalities are not usually observed in farms. Temperature variation can modulate the expression of genes and proteins involved in metabolism, adaptation, and bacterial pathogenicity, thus increasing or decreasing the ability to infect the host. This study aimed to evaluate the transcriptome and proteome of a fish-pathogenic S. agalactiae strain SA53 subjected to in vitro growth at different temperatures using a microarray and label-free shotgun LC-HDMSE approach. Biological triplicates of isolates were cultured in BHIT broth at 22 or 32 degrees C for RNA and protein isolation and submitted for transcriptomic and proteomic analyses. In total, 1,730 transcripts were identified in SA53, with 107 genes being differentially expressed between the temperatures evaluated. A higher number of genes related to metabolism, mainly from the phosphotransferase system (PTS) and ATP-binding cassette (ABC) transport system, were upregulated at 32 degrees C. In the proteome analysis, 1,046 proteins were identified in SA53, of which 81 were differentially regulated between 22 and 32 degrees C. Proteins involved in defense mechanisms, lipid transport and metabolism, and nucleotide transport and metabolism were upregulated at 32 degrees C. A higher number of interactions were observed in proteins involved in nucleotide transport and metabolism. We observed a low correlation between the transcriptome and proteome datasets. Our study indicates that the transcriptome and proteome of a fish-adapted S. agalactiae strain are modulated by temperature, particularly showing differential expression of genes/proteins involved in metabolism, virulence factors, and adaptation. PMID- 30450093 TI - Recent Advances in Our Understanding of the Biosynthesis of Sulfur Modifications in tRNAs. AB - Sulfur is an essential element in all living organisms. In tRNA molecules, there are many sulfur-containing nucleosides, introduced post-transcriptionally, that function to ensure proper codon recognition or stabilization of tRNA structure, thereby enabling accurate and efficient translation. The biosynthesis of tRNA sulfur modifications involves unique sulfur trafficking systems that are closely related to cellular sulfur metabolism, and "modification enzymes" that incorporate sulfur atoms into tRNA. Herein, recent biochemical and structural characterization of the biosynthesis of sulfur modifications in tRNA is reviewed, with special emphasis on the reaction mechanisms of modification enzymes. It was recently revealed that TtuA/Ncs6-type 2-thiouridylases from thermophilic bacteria/archaea/eukaryotes are oxygen-sensitive iron-sulfur proteins that utilize a quite different mechanism from other 2-thiouridylase subtypes lacking iron-sulfur clusters such as bacterial MnmA. The various reaction mechanisms of RNA sulfurtransferases are also discussed, including tRNA methylthiotransferase MiaB (a radical S-adenosylmethionine-type iron-sulfur enzyme) and other sulfurtransferases involved in both primary and secondary sulfur-containing metabolites. PMID- 30450095 TI - A Strong Humoral Immune Response Induced by a Vaccine Formulation Containing rSm29 Adsorbed to Alum Is Associated With Protection Against Schistosoma mansoni Reinfection in Mice. AB - The helminth Schistosoma mansoni is one of main causes of human schistosomiasis, a health and economic concern in some of the world's poorest countries. Current treatment regimens can lead to serious side effects and are not suitable for breastfeeding mothers. As such, efforts have been undertaken to develop a vaccine to prevent infection. Of these, Sm29 is a promising candidate that has been associated with resistance to infection/reinfection in humans and mice. Its ability to induce resistance to reinfection has also been recently demonstrated using a vaccine formulation containing Freund's adjuvant. However, Freund's adjuvant is unsuitable for use in human vaccines. We therefore evaluated the ability of Sm29 to induce protection against S. mansoni reinfection when formulated with either alum or MPLA as an adjuvant, both approved for human use. Our data demonstrate that, in contrast to Sm29 with MPLA, Sm29 with alum reduced parasite burden after reinfection compared to a control. We next investigated whether the immune response was involved in creating the differences between the protective (Sm29Alum) and non-protective (Sm29MPLA) vaccine formulations. We observed that both formulations induced a similar mixed-profile immune response, however, the Sm29 with alum formulation raised the levels of antibodies against Sm29. This suggests that there is an association between a reduction in worm burden and parasite-specific antibodies. In summary, our data show that Sm29 with an alum adjuvant can successfully protect against S. mansoni reinfection in mice, indicating a potentially effective vaccine formulation that could be applied in humans. PMID- 30450096 TI - Novel Antibody Drug Conjugates Targeting Tumor-Associated Receptor Tyrosine Kinase ROR2 by Functional Screening of Fully Human Antibody Libraries Using Transpo-mAb Display on Progenitor B Cells. AB - Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been identified as a highly relevant tumor-associated antigen in a variety of cancer indications of high unmet medical need, including renal cell carcinoma and osteosarcoma, making it an attractive target for targeted cancer therapy. Here, we describe the de novo discovery of fully human ROR2-specific antibodies and potent antibody drug conjugates (ADCs) derived thereof by combining antibody discovery from immune libraries of human immunoglobulin transgenic animals using the Transpo-mAb mammalian cell-based IgG display platform with functional screening for internalizing antibodies using a secondary ADC assay. The discovery strategy entailed immunization of transgenic mice with the cancer antigen ROR2, harboring transgenic IgH and IgL chain gene loci with limited number of fully human V, D, and J gene segments. This was followed by recovering antibody repertoires from the immunized animals, expressing and screening them as full-length human IgG libraries by transposon-mediated display in progenitor B lymphocytes ("Transpo mAb Display") for ROR2 binding. Individual cellular "Transpo-mAb" clones isolated by single cell sorting and capable of expressing membrane-bound as well as secreted human IgG were directly screened during antibody discovery, not only for high affinity binding to human ROR2, but also functionally as ADCs using a cytotoxicity assay with a secondary anti-human IgG-toxin-conjugate. Using this strategy, we identified and validated 12 fully human, monoclonal anti-human ROR2 antibodies with nanomolar affinities that are highly potent as ADCs and could be promising candidates for the therapy of human cancer. The screening for functional and internalizing antibodies during the early phase of antibody discovery demonstrates the utility of the mammalian cell-based Transpo-mAb Display platform to select for functional binders and as a powerful tool to improve the efficiency for the development of therapeutically relevant ADCs. PMID- 30450097 TI - Unravelling the Immunity of Poultry Against the Extracellular Protozoan Parasite Histomonas meleagridis Is a Cornerstone for Vaccine Development: A Review. AB - The protozoan parasite Histomonas meleagridis is the causative agent of histomonosis in gallinaceous birds, predominantly in turkeys and chickens. Depending on the host species the outcome of the disease can be very severe with high mortality as observed in turkeys, whereas in chickens the mortality rates are generally lower. The disease is known for more than 100 years when in vitro and in vivo investigations started to understand histomonosis and the causative pathogen. For decades histomonosis could be well-controlled by effective drugs for prevention and therapy until the withdrawal of such chemicals for reasons of consumer protection in Europe, the USA and additional countries worldwide. Consequently, research efforts also focused to find new strategies against the disease, resulting in the development of an efficacious live-attenuated vaccine. In addition to efficacy and safety several studies were performed to obtain a deeper understanding of the immune response of the host against H. meleagridis. It could be demonstrated that antibodies accumulate in different parts of the intestine of chickens following infection with H. meleagridis which was much pronounced in the ceca. Furthermore, expression profiles of various cytokines revealed that chickens mounted an effective cecal innate immune response during histomonosis compared to turkeys. Studying the cellular immune response following infection and/or vaccination of host birds showed a limitation of pronounced changes of B cells and T-cell subsets in vaccinated birds in comparison to non protected birds. Additionally, numbers of lymphocytes including cytotoxic T cells increased in the ceca of diseased turkeys compared to infected chickens suggesting an immunopathological impact on disease pathogenesis. The identification of type 1 and type 2 T-helper (Th) cells in infected and lymphoid organs by in situ hybridization did not show a clear separation of Th cells during infection but revealed a coherence of an increase of interferon (IFN) gamma mRNA positive cells in ceca and protection. The present review not only summarizes the research performed on the immune response of host birds in the course of histomonosis but also highlights the specific features of H. meleagridis as a model organism to study immunological principles of an extracellular organism in birds. PMID- 30450098 TI - Both Type I and Type II Interferons Can Activate Antitumor M1 Macrophages When Combined With TLR Stimulation. AB - Triggering or enhancing antitumor activity of tumor-associated macrophages is an attractive strategy for cancer treatment. We have previously shown that the cytokine interferon-gamma (IFN-gamma), a type II IFN, could synergize with toll like receptor (TLR) agonists for induction of antitumor M1 macrophages. However, the toxicity of IFN-gamma limits its clinical use. Here, we investigated whether the less toxic type I IFNs, IFN-alpha, and IFN-beta, could potentially replace IFN-gamma for induction of antitumor M1 macrophages. We measured in vitro the ability of type I and II IFNs to synergize with TLR agonists for transcription of inducible nitric oxide synthase (iNOS) mRNA and secretion of nitric oxide (NO) by mouse bone marrow-derived macrophages (BMDMs). An in vitro growth inhibition assay was used to measure both cytotoxic and cytostatic activity of activated macrophages against Lewis lung carcinoma (LLC) cancer cells. We found that both type I and II IFNs could synergize with TLR agonists in inducing macrophage mediated inhibition of cancer cell growth, which was dependent on NO. The ability of high dose lipopolysaccharide (LPS) to induce tumoricidal activity in macrophages in the absence of IFN-gamma was shown to depend on induction of autocrine type I IFNs. Antitumor M1 macrophages could also be generated in the absence of IFN-gamma by a combination of two TLR ligands when using the TLR3 agonist poly(I:C) which induces autocrine type I IFNs. Finally, we show that encapsulation of poly(I:C) into nanoparticles improved its potency to induce M1 macrophages up to 100-fold. This study reveals the potential of type I IFNs for activation of antitumor macrophages and indicates new avenues for cancer immunotherapy based on type I IFN signaling, including combination of TLR agonists. PMID- 30450100 TI - Dissecting the Immune Stimulation Promoted by CSF-470 Vaccine Plus Adjuvants in Cutaneous Melanoma Patients: Long Term Antitumor Immunity and Short Term Release of Acute Inflammatory Reactants. AB - As cutaneous melanoma (CM) currently remains with a bleak prognosis, thorough investigation of new treatment options are of utmost relevance. In the phase II/III randomized clinical trial (CASVAC-0401), the repeated immunization of stages IIB-III CM patients with the irradiated, allogeneic cellular CSF-470 vaccine plus the adjuvants bacillus Calmette-Guerin (BCG) and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) demonstrated a significant benefit over IFN-alpha2B treatment in distant metastasis-free survival. Here we present on the short and long term immune monitoring results after completing the 2-year protocol; a continuation of the previous report by Mordoh et al. (1). We demonstrate that the repeated CSF-470 vaccinations stimulated a long term cellular and humoral immunity response directed against the vaccine antigens. In the case of 2 patients, we are able to show that a similar immune response was generated against autologous antigens. Evaluation of inhibitory receptor co-expression on patient's T cells indicates that the vaccination protocol did not stimulate T cell exhaustion. In order to better understand the basis for the efficacious vaccine responses observed, we investigated the short term immune events following vaccine injection. A significant increase in C-reactive protein (CRP) and IL-6 was observed 24 h after vaccination, with in vitro studies suggesting IL-6 production occurs in the vaccine site. We demonstrate that CRP enhances the cytotoxicity of peripheral blood mononuclear cells (PBMC) against melanoma cells in an in vitro model. Additionally, CRP stimulates the release of pro and anti-inflammatory cytokines from PBMC. As our results demonstrate that successive vaccinations with CSF-470 plus adjuvants promoted an increase in both anti-tumor innate and adaptive immunity, we propose a subsequent model of action. PMID- 30450099 TI - Characterization of the TLR Family in Branchiostoma lanceolatum and Discovery of a Novel TLR22-Like Involved in dsRNA Recognition in Amphioxus. AB - Toll-like receptors (TLRs) are important for raising innate immune responses in both invertebrates and vertebrates. Amphioxus belongs to an ancient chordate lineage which shares key features with vertebrates. The genomic research on TLR genes in Branchiostoma floridae and Branchiostoma belcheri reveals the expansion of TLRs in amphioxus. However, the repertoire of TLRs in Branchiostoma lanceolatum has not been studied and the functionality of amphioxus TLRs has not been reported. We have identified from transcriptomic data 30 new putative TLRs in B. lanceolatum and all of them are transcribed in adult amphioxus. Phylogenetic analysis showed that the repertoire of TLRs consists of both non vertebrate and vertebrate-like TLRs. It also indicated a lineage-specific expansion in orthologous clusters of the vertebrate TLR11 family. We did not detect any representatives of the vertebrate TLR1, TLR3, TLR4, TLR5 and TLR7 families. To gain insight into these TLRs, we studied in depth a particular TLR highly similar to a B. belcheri gene annotated as bbtTLR1. The phylogenetic analysis of this novel BlTLR showed that it clusters with the vertebrate TLR11 family and it might be more related to TLR13 subfamily according to similar domain architecture. Transient and stable expression in HEK293 cells showed that the BlTLR localizes on the plasma membrane, but it did not respond to the most common mammalian TLR ligands. However, when the ectodomain of BlTLR is fused to the TIR domain of human TLR2, the chimeric protein could indeed induce NF-kappaB transactivation in response to the viral ligand Poly I:C, also indicating that in amphioxus, specific accessory proteins are needed for downstream activation. Based on the phylogenetic, subcellular localization and functional analysis, we propose that the novel BlTLR might be classified as an antiviral receptor sharing at least partly the functions performed by vertebrate TLR22. TLR22 is thought to be viral teleost-specific TLR but here we demonstrate that teleosts and amphioxus TLR22-like probably shared a common ancestor. Additional functional studies with other lancelet TLR genes will enrich our understanding of the immune response in amphioxus and will provide a unique perspective on the evolution of the immune system. PMID- 30450101 TI - Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcgammaR Expressing Mice. AB - There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-betaRII mice expressing hCD20 and human Fcgamma receptors (hFcgammaRs). Beginning at 4-6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks' treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC. PMID- 30450102 TI - Loss of Smad7 Promotes Inflammation in Rheumatoid Arthritis. AB - Objective: Smad7 is an inhibitory Smad and plays a protective role in many inflammatory diseases. However, the roles of Smad7 in rheumatoid arthritis (RA) remain unexplored, which were investigated in this study. Methods: The activation of TGF-beta/Smad signaling was examined in synovial tissues of patients with RA. The functional roles and mechanisms of Smad7 in RA were determined in a mouse model of collagen-induced arthritis (CIA) in Smad7 wild-type (WT) and knockout (KO) CD-1 mice, a strain resistant to autoimmune arthritis induction. Results: TGF-beta/Smad3 signaling was markedly activated in synovial tissues of patients with RA, which was associated with the loss of Smad7, and enhanced Th17 and Th1 immune response. The potential roles of Smad7 in RA were further investigated in a mouse model of CIA in Smad7 WT/KO CD-1 mice. As expected, Smad7-WT CD-1 mice did not develop CIA. Surprisingly, CD-1 mice with Smad7 deficiency developed severe arthritis including severe joint swelling, synovial hyperplasia, cartilage damage, massive infiltration of CD3+ T cells and F4/80+ macrophages, and upregulation of proinflammatory cytokines IL-1beta, TNFalpha, and MCP-1. Further studies revealed that enhanced arthritis in Smad7 KO CD-1 mice was associated with increased Th1, Th2 and, importantly, Th17 over the Treg immune response with overactive TGF-beta/Smad3 and proinflammatory IL-6 signaling in the joint tissues. Conclusions: Smad7 deficiency increases the susceptibility to autoimmune arthritis in CD-1 mice. Enhanced TGF-beta/Smad3-IL-6 signaling and Th17 immune response may be a mechanism through which disrupted Smad7 causes autoimmune arthritis in CD-1 mice. PMID- 30450104 TI - The Phenotype and Treatment of WIP Deficiency: Literature Synopsis and Review of a Patient With Pre-transplant Serial Donor Lymphocyte Infusions to Eliminate CMV. AB - Early diagnosis of primary immunodeficiency disorders (PID) is vital and allows directed treatment, especially in syndromes with severe or profound combined immunodeficiency. In PID patients with perinatal CMV or other opportunistic, invasive infections (e.g., Pneumocystis or Aspergillus), multi-organ morbidity may already arise within the first months of life, before hematopoietic stem cell transplantation (HSCT) or gene therapy can be undertaken, compromising the definitive treatment and outcome. Deficiency of Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP deficiency) causes an autosomal recessive, WAS like syndrome with early-onset combined immunodeficiency that has been described in three pedigrees to date. While WAS typically includes combined immunodeficiency, microthrombocytopenia, and eczema, the clinical and laboratory phenotypes of WIP-deficient patients-including lymphocyte subsets, platelets, lymphocyte proliferation in vitro, and IgE-varied widely and did not entirely recapitulate WAS, impeding early diagnosis in the reported patients. To elucidate the phenotype of WIP deficiency, we provide a comprehensive synopsis of clinical and laboratory features of all hitherto-described patients (n = 6) and WIP negative mice. Furthermore, we summarize the treatment modalities and outcomes of these patients and review in detail the course of one of them who was successfully treated with serial, unconditioned, maternal, HLA-identical donor lymphocyte infusions (DLI) against life-threatening, invasive CMV infection, followed by a TCRalphabeta/CD19-depleted, treosulfan/melphalan-conditioned, peripheral blood HSCT and repetitive, secondary-prophylactic, CMV-specific DLI with 1-year post-HSCT follow-up. This strategy could be useful in other patients with substantial premorbidity, considered "too bad to transplant," who have an HLA-identical family donor, to eliminate infections and bridge until definitive treatment. PMID- 30450094 TI - Improving Immunotherapy Through Glycodesign. AB - Immunotherapy is revolutionizing health care, with the majority of high impact "drugs" approved in the past decade falling into this category of therapy. Despite considerable success, glycosylation-a key design parameter that ensures safety, optimizes biological response, and influences the pharmacokinetic properties of an immunotherapeutic-has slowed the development of this class of drugs in the past and remains challenging at present. This article describes how optimizing glycosylation through a variety of glycoengineering strategies provides enticing opportunities to not only avoid past pitfalls, but also to substantially improve immunotherapies including antibodies and recombinant proteins, and cell-based therapies. We cover design principles important for early stage pre-clinical development and also discuss how various glycoengineering strategies can augment the biomanufacturing process to ensure the overall effectiveness of immunotherapeutics. PMID- 30450103 TI - Interplay Between the Unfolded Protein Response and Immune Function in the Development of Neurodegenerative Diseases. AB - Emerging evidence suggests that the immune and nervous systems are in close interaction in health and disease conditions. Protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER) are central contributors to neurodegenerative diseases. The unfolded protein response (UPR) is the main transduction pathway that maintains protein homeostasis under conditions of protein misfolding and aggregation. Brain inflammation often coexists with the degenerative process in different brain diseases. Interestingly, besides its well-described role in neuronal fitness, the UPR has also emerged as a key regulator of ontogeny and function of several immune cell types. Nevertheless, the contribution of the UPR to brain inflammation initiated by immune cells remains largely unexplored. In this review, we provide a perspective on the potential role of ER stress signaling in brain-associated immune cells and the possible implications to neuroinflammation and development of neurodegenerative diseases. PMID- 30450106 TI - Preferential Homologous Chromosome Pairing in a Tetraploid Intergeneric Somatic Hybrid (Citrus reticulata + Poncirus trifoliata) Revealed by Molecular Marker Inheritance. AB - The creation of intergeneric somatic hybrids between Citrus and Poncirus is an efficient approach for citrus rootstock breeding, offering the possibility of combining beneficial traits from both genera into novel rootstock lineages. These somatic hybrids are also used as parents for further tetraploid sexual breeding. In order to optimize these latter breeding schemes, it is essential to develop knowledge on the mode of inheritance in the intergeneric tetraploid hybrids. We assessed the meiotic behavior of an intergeneric tetraploid somatic hybrid resulting from symmetric protoplast fusion of diploid Citrus reticulata and diploid Poncirus trifoliata. The analysis was based on the segregation patterns of 16 SSR markers and 9 newly developed centromeric/pericentromeric SNP markers, representing all nine linkage groups of the Citrus genetic map. We found strong but incomplete preferential pairing between homologues of the same ancestral genome. The proportion of gametes that can be explained by random meiotic chromosome associations (tau) varied significantly between chromosomes, from 0.09 +/- 0.02 to 0.47 +/- 0.09, respectively, in chromosome 2 and 1. This intermediate inheritance between strict disomy and tetrasomy, with global preferential disomic tendency, resulted in a high level of intergeneric heterozygosity of the diploid gametes. Although limited, intergeneric recombinations occurred, whose observed rates, ranging from 0.09 to 0.29, respectively, in chromosome 2 and 1, were significantly correlated with tau. Such inheritance is of particular interest for rootstock breeding because a large part of the multi-trait value selected at the teraploid parent level is transmitted to the progeny, while the potential for some intergeneric recombination offers opportunities for generating plants with novel allelic combinations that can be targeted by selection. PMID- 30450105 TI - A Novel Reliable and Efficient Procedure for Purification of Mature Osteoclasts Allowing Functional Assays in Mouse Cells. AB - Osteoclasts (OCLs) are multinucleated phagocytes of monocytic origin responsible for physiological and pathological bone resorption including aging processes, chronic inflammation and cancer. Besides bone resorption, they are also involved in the modulation of immune responses and the regulation of hematopoietic niches. Accordingly, OCLs are the subject of an increasing number of studies. Due to their rarity and the difficulty to isolate them directly ex vivo, analyses on OCLs are usually performed on in vitro differentiated cells. In this state, however, OCLs represent a minority of differentiated cells. Since up to date a reliable purification procedure is still lacking for mature OCLs, all cells present in the culture are analyzed collectively to answer OCL-specific questions. With the development of in-depth transcriptomic and proteomic analyses, such global analyses on unsorted cells can induce severe bias effects in further results. In addition, for instance, analysis on OCL immune function requires working on purified OCLs to avoid contamination effects of monocytic precursors that may persist during the culture. This clearly highlights the need for a reliable OCL purification procedure. Here, we describe a novel and reliable method to sort OCLs based on cell multinucleation while preserving cell viability. Using this method, we successfully purified multinucleated murine cells. We showed that they expressed high levels of OCL markers and retained a high capacity of bone resorption, demonstrating that these are mature OCLs. The same approach was equally applied for the purification of human mature OCLs. Comparison of purified OCLs with mononucleated cells or unsorted cells revealed significant differences in the expression of OCL-specific markers at RNA and/or protein level. This exemplifies that substantially better outcomes for OCLs are achieved after the exclusion of mononucleated cells. Our results clearly demonstrate that the in here presented procedure for the analysis and sorting of pure OCLs represents a novel, robust and reliable method for the detailed examination of bona fide mature OCLs in a range that was previously impossible. Noteworthy, this procedure will open new perspectives into the biology of osteoclasts and osteoclast-related diseases. PMID- 30450107 TI - Transplants, Open Top Chambers (OTCs) and Gradient Studies Ask Different Questions in Climate Change Effects Studies. AB - Long-term monitoring, space-for-time substitutions along gradients, and in situ temperature manipulations are common approaches to understand effects of climate change on alpine and arctic plant communities. Although general patterns emerge from studies using different approaches, there are also some inconsistencies. To provide better estimates of plant community responses to future warming across a range of environments, there have been repeated calls for integrating different approaches within single studies. Thus, to examine how different methods in climate change effect studies may ask different questions, we combined three climate warming approaches in a single study in the Hengduan Mountains of southwestern China. We monitored plant communities along an elevation gradient using the space-for-time approach, and conducted warming experiments using open top chambers (OTCs) and plant community transplantation toward warmer climates along the same gradient. Plant species richness and abundances were monitored over 5 years addressing two questions: (1) how do plant communities respond to the different climate warming approaches? (2) how can the combined approaches improve predictions of plant community responses to climate change? The general trend across all three approaches was decreased species richness with climate warming at low elevations. This suggests increased competition from immigrating lowland species, and/or from the species already growing inside the plots, as indicated by increased biomass, vegetation height or proportion of graminoids. At the coldest sites, species richness decreased in OTCs and along the gradient, but increased in the transplants, suggesting that plant communities in colder climates are more open to invasion from lowland species, with slow species loss. This was only detected in the transplants, showing that different approaches, may yield different results. Whereas OTCs may constrain immigration of new species, transplanted communities are rapidly exposed to new neighbors that can easily colonize the small plots. Thus, different approaches ask slightly different questions, in particular regarding indirect climate change effects, such as biotic interactions. To better understand both direct and indirect effects of climate change on plant communities, we need to combine approaches in future studies, and if novel interactions are of particular interest, transplants may be a better approach than OTCs. PMID- 30450109 TI - Jasmonic Acid Seed Treatment Stimulates Insecticide Detoxification in Brassica juncea L. AB - The present study focused on assessing the effects of jasmonic acid (JA) seed treatment on the physiology of Brassica juncea seedlings grown under imidacloprid (IMI) toxicity. It has been observed that IMI application declined the chlorophyll content and growth of seedlings. However, JA seed treatment resulted in the significant recovery of chlorophyll content and seedling growth. Contents of oxidative stress markers like superoxide anion, hydrogen peroxide, and malondialdehyde were enhanced with IMI application, but JA seed treatment significantly reduced their contents. Antioxidative defense system was activated with IMI application which was further triggered after JA seed treatment. Activities of antioxidative enzymes and contents of non-enzymatic antioxidants were enhanced with the application of IMI as well as JA seed treatment. JA seed treatment also regulated the gene expression of various enzymes under IMI stress. These enzymes included respiratory burst oxidase (RBO), Ribulose-1,5-bisphosphate carboxylase/oxygenase (RUBISCO), NADH-ubiquinone oxidoreductase (NADH), carboxylesterase (CXE), chlorophyllase (CHLASE), cytochrome P450 monooxygenase (P450). JA seed treatment up-regulated the expressions of RUBISCO, NADH, CXE, and P450 under IMI toxicity. However, expressions of RBO and CHLASE were down regulated in seedlings germinated from JA seed treatment and grown in presence of IMI. Seed soaking with JA also resulted in a significant reduction of IMI residues in B. juncea seedlings. The present study concluded that seed soaking with JA could efficiently reduce the IMI toxicity by triggering the IMI detoxification system in intact plants. PMID- 30450111 TI - Influence of Fetal and Maternal Genetic Susceptibility to Obesity on Birthweight in African Ancestry Populations. AB - Fetal and maternal genetic propensity to obesity can influence birthweight. We investigated the effects of fetal and maternal genetic risk of obesity on birthweight and evaluated whether these genetic influences modify the well-known association between maternal pre-pregnancy body mass index (BMI) and birthweight. In 950 mother-baby pairs of African ancestry, a genetic risk score for adulthood obesity was generated for mothers (mGRS) and their babies (bGRS) as the weighted sum of BMI-increasing alleles of 97 single nucleotide polymorphisms known to be associated with BMI. The median GRS value was used as a cut-off to define high or low bGRS and mGRS. High bGRS was significantly associated with 70 g lower birthweight (95% Confidence Interval [CI] = -127.4 to -12.4) compared to low bGRS. mGRS was positively correlated with birthweight but the association was not significant. mGRS modified the significant birthweight-increasing effect of maternal pre-pregnancy BMI (P-for-interaction = 0.03); among mothers with low mGRS, those who were overweight or obese had 127.7 g heavier babies (95% CI = 27.1 to 228.2) compared to those who had normal weight. In summary, fetal obesity genetic risk loci exert direct influence on birthweight, and maternal loci modify the effect of pre-pregnancy BMI on birthweight. PMID- 30450108 TI - Exploring the Diversity of Mechanisms Associated With Plant Tolerance to Virus Infection. AB - Tolerance is defined as an interaction in which viruses accumulate to some degree without causing significant loss of vigor or fitness to their hosts. Tolerance can be described as a stable equilibrium between the virus and its host, an interaction in which each partner not only accommodate trade-offs for survival but also receive some benefits (e.g., protection of the plant against super infection by virulent viruses; virus invasion of meristem tissues allowing vertical transmission). This equilibrium, which would be associated with little selective pressure for the emergence of severe viral strains, is common in wild ecosystems and has important implications for the management of viral diseases in the field. Plant viruses are obligatory intracellular parasites that divert the host cellular machinery to complete their infection cycle. Highjacking/modification of plant factors can affect plant vigor and fitness. In addition, the toxic effects of viral proteins and the deployment of plant defense responses contribute to the induction of symptoms ranging in severity from tissue discoloration to malformation or tissue necrosis. The impact of viral infection is also influenced by the virulence of the specific virus strain (or strains for mixed infections), the host genotype and environmental conditions. Although plant resistance mechanisms that restrict virus accumulation or movement have received much attention, molecular mechanisms associated with tolerance are less well understood. We review the experimental evidence that supports the concept that tolerance can be achieved by reaching the proper balance between plant defense responses and virus counter-defenses. We also discuss plant translation repression mechanisms, plant protein degradation or modification pathways and viral self-attenuation strategies that regulate the accumulation or activity of viral proteins to mitigate their impact on the host. Finally, we discuss current progress and future opportunities toward the application of various tolerance mechanisms in the field. PMID- 30450112 TI - Robust Co-clustering to Discover Toxicogenomic Biomarkers and Their Regulatory Doses of Chemical Compounds Using Logistic Probabilistic Hidden Variable Model. AB - Detection of biomarker genes and their regulatory doses of chemical compounds (DCCs) is one of the most important tasks in toxicogenomic studies as well as in drug design and development. There is an online computational platform "Toxygates" to identify biomarker genes and their regulatory DCCs by co clustering approach. Nevertheless, the algorithm of that platform based on hierarchical clustering (HC) does not share gene-DCC two-way information simultaneously during co-clustering between genes and DCCs. Also it is sensitive to outlying observations. Thus, this platform may produce misleading results in some cases. The probabilistic hidden variable model (PHVM) is a more effective co clustering approach that share two-way information simultaneously, but it is also sensitive to outlying observations. Therefore, in this paper we have proposed logistic probabilistic hidden variable model (LPHVM) for robust co-clustering between genes and DCCs, since gene expression data are often contaminated by outlying observations. We have investigated the performance of the proposed LPHVM co-clustering approach in a comparison with the conventional PHVM and Toxygates co-clustering approaches using simulated and real life TGP gene expression datasets, respectively. Simulation results show that the proposed method improved the performance over the conventional PHVM in presence of outliers; otherwise, it keeps equal performance. In the case of real life TGP data analysis, three DCCs (glibenclamide-low, perhexilline-low, and hexachlorobenzene-medium) for glutathione metabolism pathway dataset as well as two DCCs (acetaminophen-medium and methapyrilene-low) for PPAR signaling pathway dataset were incorrectly co clustered by the Toxygates online platform, while only one DCC (hexachlorobenzene low) for glutathione metabolism pathway was incorrectly co-clustered by the proposed LPHVM approach. Our findings from the real data analysis are also supported by the other findings in the literature. PMID- 30450110 TI - FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene. AB - Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with one FXS child and another sibling presenting mild intellectual disability and behavioral features evocative of FXS. Genetic characterization of the undiagnosed sibling revealed mosaicism in both the CGG expansion size and the methylation levels in the different tissues analyzed. This report shows that in the same family, two siblings carrying different CGG repeats, one in the full mutation range and the other in the premutation range, present methylation mosaicism and consequent decreased FMRP production leading to FXS and FXS-like features, respectively. Decreased FMRP levels, more than the number of repeats seem to correlate with the severity of FXS clinical phenotypes. PMID- 30450113 TI - Bringing Light to Transcription: The Optogenetics Repertoire. AB - The ability to manipulate expression of exogenous genes in particular regions of living organisms has profoundly transformed the way we study biomolecular processes involved in both normal development and disease. Unfortunately, most of the classical inducible systems lack fine spatial and temporal accuracy, thereby limiting the study of molecular events that strongly depend on time, duration of activation, or cellular localization. By exploiting genetically engineered photo sensing proteins that respond to specific wavelengths, we can now provide acute control of numerous molecular activities with unprecedented precision. In this review, we present a comprehensive breakdown of all of the current optogenetic systems adapted to regulate gene expression in both unicellular and multicellular organisms. We focus on the advantages and disadvantages of these different tools and discuss current and future challenges in the successful translation to more complex organisms. PMID- 30450114 TI - Efficacy of sertraline against Trypanosoma cruzi: an in vitro and in silico study. AB - Background: Drug repurposing has been an interesting and cost-effective approach, especially for neglected diseases, such as Chagas disease. Methods: In this work, we studied the activity of the antidepressant drug sertraline against Trypanosoma cruzi trypomastigotes and intracellular amastigotes of the Y and Tulahuen strains, and investigated its action mode using cell biology and in silico approaches. Results: Sertraline demonstrated in vitro efficacy against intracellular amastigotes of both T. cruzi strains inside different host cells, including cardiomyocytes, with IC50 values between 1 to 10 MUM, and activity against bloodstream trypomastigotes, with IC50 of 14 MUM. Considering the mammalian cytotoxicity, the drug resulted in a selectivity index of 17.8. Sertraline induced a change in the mitochondrial integrity of T. cruzi, resulting in a decrease in ATP levels, but not affecting reactive oxygen levels or plasma membrane permeability. In silico approaches using chemogenomic target fishing, homology modeling and molecular docking suggested the enzyme isocitrate dehydrogenase 2 of T. cruzi (TcIDH2) as a potential target for sertraline. Conclusions: The present study demonstrated that sertraline had a lethal effect on different forms and strains of T. cruzi, by affecting the bioenergetic metabolism of the parasite. These findings provide a starting point for future experimental assays and may contribute to the development of new compounds. PMID- 30450115 TI - Modeled deposition of nitrogen and sulfur in Europe estimated by 14 air quality model systems: evaluation, effects of changes in emissions and implications for habitat protection. AB - The evaluation and intercomparison of air quality models is key to reducing model errors and uncertainty. The projects AQMEII3 and EURODELTA-Trends, in the framework of the Task Force on Hemispheric Transport of Air Pollutants and the Task Force on Measurements and Modelling, respectively (both task forces under the UNECE Convention on the Long Range Transport of Air Pollution, LTRAP), have brought together various regional air quality models to analyze their performance in terms of air concentrations and wet deposition, as well as to address other specific objectives. This paper jointly examines the results from both project communities by intercomparing and evaluating the deposition estimates of reduced and oxidized nitrogen (N) and sulfur (S) in Europe simulated by 14 air quality model systems for the year 2010. An accurate estimate of deposition is key to an accurate simulation of atmospheric concentrations. In addition, deposition fluxes are increasingly being used to estimate ecological impacts. It is therefore important to know by how much model results differ and how well they agree with observed values, at least when comparison with observations is possible, such as in the case of wet deposition. This study reveals a large variability between the wet deposition estimates of the models, with some performing acceptably (according to previously defined criteria) and others underestimating wet deposition rates. For dry deposition, there are also considerable differences between the model estimates. An ensemble of the models with the best performance for N wet deposition was made and used to explore the implications of N deposition in the conservation of protected European habitats. Exceedances of empirical critical loads were calculated for the most common habitats at a resolution of 100 * 100 m2 within the Natura 2000 network, and the habitats with the largest areas showing exceedances are determined. Moreover, simulations with reduced emissions in selected source areas indicated a fairly linear relationship between reductions in emissions and changes in the deposition rates of N and S. An approximate 20 % reduction in N and S deposition in Europe is found when emissions at a global scale are reduced by the same amount. European emissions are by far the main contributor to deposition in Europe, whereas the reduction in deposition due to a decrease in emissions in North America is very small and confined to the western part of the domain. Reductions in European emissions led to substantial decreases in the protected habitat areas with critical load exceedances (halving the exceeded area for certain habitats), whereas no change was found, on average, when reducing North American emissions in terms of average values per habitat. PMID- 30450116 TI - Rash induced by enteral vancomycin therapy in an older patient in a long-term care ventilator unit: case report and review of the literature. AB - Background: Oral vancomycin is a first-line treatment for severe Clostridium difficile colitis. Oral vancomycin is perceived to lack systemic absorption or systemic adverse effects; however, a few cases of hypersensitivity to oral vancomycin have been reported, all in hospitalized patients. Case presentation: In the present case, a 66-year-old woman with end-stage neurodegenerative disease residing in a long-term care facility developed a maculopapular rash following treatment with enteral vancomycin for recurrent C. difficile colitis. The rash resolved after withdrawal of the drug. Conclusion: Rashes associated with oral vancomycin treatment include maculopapular rash, urticaria, red man syndrome, and linear IgA bullous dermatitis. Risk factors for systemic vancomycin absorption include renal insufficiency, severe intestinal inflammation, and high vancomycin dose and duration. Routine serum testing of vancomycin levels, even in these high risk cases, is not recommended. Clinicians should be aware that enteral vancomycin can cause hypersensitivity reactions which may be serious. PMID- 30450117 TI - Crocetin attenuates inflammation and amyloid-beta accumulation in APPsw transgenic mice. AB - Background: Crocetin, an agent derived from saffron, has multiple pharmacological properties, such as neuroprotective, anti-oxidant, and anti-inflammatory actions. These properties might benefit the treatment of Alzheimer's disease (AD). In the present study, we tested whether crocetin attenuates inflammation and amyloid beta (Abeta) accumulation in APPsw transgenic mice, AD mouse models. Cell viability and the levels of Abeta40 and Abeta42 in HeLa cells stably transfected with Swedish mutant APP751 were evaluated. Mice with Swedish mutant APP751 transgene were used as transgenic mouse models of AD, and were orally administrated with crocetin. Abeta protein and inflammatory cytokines were measured with ELISA. NF-kappaB and P53 were measured with western blot assay. Learning and memory were analyzed with Morris water maze and novel object recognition tests. Results: Crocetin significantly reduced Abeta40 and Abeta42 secretion in Hela cells without effecting cell viability. In AD transgenic mice, crocetin significantly reduced the pro-inflammatory cytokines and enhanced anti inflammatory cytokine in plasma, suppressed NF-kappaB activation and P53 expression in the hippocampus, decreased Abeta in various brain areas, and improved learning and memory deficits. Conclusion: Crocetin improves Abeta accumulation-induced learning and memory deficit in AD transgenic mice, probably due to its anti-inflammatory and anti-apoptotic functions. PMID- 30450118 TI - Genetics of exceptional longevity: possible role of GM allotypes. PMID- 30450120 TI - Circulating glutamate concentration as a biomarker of visceral obesity and associated metabolic alterations. AB - Background: Visceral adipose tissue (VAT) area is a strong predictor of obesity related cardiometabolic alterations, but its measurement is costly, time consuming and, in some cases, involves radiation exposure. Glutamate, a by product of branched-chain-amino-acid (BCAA) catabolism, has been shown to be increased in visceral obese individuals. In this follow-up data analysis, we aimed to investigate the ability of plasma glutamate to identify individuals with visceral obesity and concomitant metabolic alterations. Methods: Measurements of adiposity, targeted blood metabolomics and cardiometabolic risk factors were performed in 59 healthy middle-aged women. Visceral and subcutaneous adipose tissue areas were measured by computed tomography (CT) whereas body fat and lean mass were assessed by dual-energy x-ray absorptiometry (DEXA). Results: The univariate Pearson correlation coefficient between glutamate and VAT area was r = 0.46 (p < 0.001) and it was r = 0.36 (p = 0.006) when adjusted for total body fat mass. Glutamate allowed to identify individuals with VAT areas >=100 cm2 (ROC_AUC: 0.78, 95% CI: 0.66-0.91) and VAT >=130 cm2 (ROC_AUC: 0.71, 95% CI: 0.56 0.87). The optimal glutamate concentration threshold determined from the ROC curve (glutamate >=34.6 MUmol/L) had a greater sensitivity than the metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTW) phenotype to identify individuals with VAT >=100 cm2 (83% for glutamate vs 52% for the MetS and 35% for the HTW). Variance analysis showed that women with a high circulating glutamate level (>=34.6 MUmol/L) had an altered metabolic profile, particularly regarding total triglyceride levels and the amount of triglycerides and cholesterol in very low-density lipoproteins (all p < 0.01). Conclusion: Circulating glutamate is strongly associated with VAT area and may represent a potential screening tool for visceral obesity and alterations of the metabolic profile. PMID- 30450119 TI - Association of immunoglobulin GM allotypes with longevity in long-living individuals from Southern Italy. AB - Background: The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity. The role played by immunoglobulin allotypes in the control of immune responses is well known as well as the role of an efficient immune response in longevity achievement. So, it is conceivable that particular GM allotypes may contribute to the generation of an efficient immune response that supports successful ageing, hence longevity. Methods: In order to show if GM allotypes play a role in the achievement of longevity, we typed the DNA of 95 Long-living individuals (LLIs) and 96 young control individuals (YCs) from South Italy for GM3/17 and GM23+/- alleles. Results: To demonstrate the role of GM allotypes in the attainment of longevity we compared genotype and allele frequencies of GM allotypes between LLIs and YCs. A global chi-square test (3 * 2) shows that the distribution of genotypes at the GM 3/17 locus is highly significantly different in LLIs from that observed in YCs (p < 0.0001). The 2 * 2 chi-square test shows that the carriers of the GM3 allele contribute to this highly significant difference. Accordingly, GM3 allele is significantly overrepresented in LLIs. No significant differences were instead observed regarding GM23 allele. Conclusion: These preliminary results show that GM3 allotype is significantly overrepresented in LLIs. To best of our knowledge, this is the first study performed to assess the role of GM allotypes in longevity. So, it should be necessary to verify the data in a larger sample of individuals to confirm GM role in the attainment of longevity. PMID- 30450121 TI - Comparison between the musician-specific seating position of high string bow players and their habitual seating position - a video raster stereographic study of the dorsal upper body posture. AB - Background: Effects of playing high stringed bow instruments on the upper body posture have not been analysed so far. The instrument-specific seating position when playing in an orchestra is compared to the habitual seating position. Methods: Three dimensional back scans were performed in 13 professional violinists and viola players of a radio orchestra (8 f / 5 m). Trunk position in their habitual seating position and in the instrument- specific seating position imitating playing was compared. Statistical differences were calculated using Wilcoxon Matched Pairs Test with Bonferroni Holm correction. Results: Significant differences were found between the seated position with instrument and without (p < 0.001, 0.03, 0.02 or 0.01) in the spine (trunk length, sagittal trunk decline, lumbar bending angle, maximal rotation, standard deviation rotation, lumbar lordosis), the shoulder (scapula distance, scapula rotation, scapula angle right) and pelvis distance. Conclusions: Playing an instrument changes the static seating position by increased rotation of the spine and specific shoulder adaptations holding the instrument (left arm) and the bow (right arm), with minor effects on the pelvis. This forced position may result in chronic health effects. The method used in this study is an approach to better understand the involved muscular structures and possible resulting health damages. PMID- 30450122 TI - Prevalence of hidden carbon monoxide poisoning in auto service workers; a prospective cohort study. AB - Background: Carbon monoxide (CO) is formed as a result of the incomplete burning of hydrocarbon-containing fuels such as natural gas, coal, liquid petroleum gas, and wood. CO is a colorless, odorless, and poisonous gas that produces various acute and chronic effects in CO-exposed people. In this study, we aimed to measure CO levels in auto care repairmen with chronic CO-related illnesses using a serial, non-invasive method.A prospective cohort study. Methods: A total of 99 people from six different auto-repair services were included in the study. Carboxyhemoglobin (COHb) levels were measured at four different times with 2-hour intervals starting at 08:00 AM. Data concerning employees' ages, working hours, smoking statuses, and types of home heating fuel were collected. A control group of 100 cases was created based on this data. The measurements were done on the control group in the morning with a Masimo Rad-57 CO-oximeter. Results: The highest mean (+/- SD) COHb value was 7.04% +/- 3.32% after the third measurement. The mean value for the control group was 1.61% +/- 1.43%. A statistically significant difference between the groups was found for each value. Discussion: We determined that the risk of being affected by CO is high in buildings in which the auto services were located. The effects of chronic or prolonged exposure to low amounts of CO were found to be ambiguous. However, in some studies, it was found that low-grade CO exposure could lead to coronary artery disease and some neurological complications. Therefore, it is necessary to be careful about the health of employees who have been exposed to CO. Conclusions: We concluded that there is a need for more detailed studies concerning chronic CO poisoning. Also, in workplaces in which there is high exposure to CO, proper workplace safety measures should be taken to reduce this gas's harmful effects to employees. PMID- 30450123 TI - Abdominopelvic trauma: from anatomical to anatomo-physiological classification. AB - Abdominopelvic trauma has been for decades classified with the AAST-OIS (American Association for the Surgery of Trauma-Organ Injury Scale) classification. It has represented a milestone. At present, the medical evolutions in trauma management allowed an incredible progress in trauma decision-making and treatment. Non operative trauma management has been widely applied. The interventional radiological procedures and the modern conception of Hybrid and Endovascular Trauma and Bleeding Management (EVTM) led to good results in increasing the rate of patients managed non-operatively, opening new scenarios and options. Even severe anatomical lesions in hemodynamically stable patients can be safely managed non-operatively. The driving issue in deciding for the best treatment is anatomy, as well as physiology, for the patient physiological derangement grade is even more important. The emergency general surgeon must be prepared in those pathophysiological issues that play the pivotal role in the team management of trauma patients. Moreover, the classification of trauma patients cannot only remain anchored to anatomical lesions. The necessity to follow the modern possibilities of treatment imposes addressing trauma using a classification based on anatomical lesions and on the physiological status of the patient. PMID- 30450124 TI - Neural correlates of body comparison and weight estimation in weight-recovered anorexia nervosa: a functional magnetic resonance imaging study. AB - Background: The neural mechanisms underlying body dissatisfaction and emotional problems evoked by social comparisons in patients with anorexia nervosa (AN) are currently unclear. Here, we elucidate patterns of brain activation among recovered patients with AN (recAN) during body comparison and weight estimation with functional magnetic resonance imaging (fMRI). Methods: We used fMRI to examine 12 patients with recAN and 13 healthy controls while they performed body comparison and weight estimation tasks with images of underweight, healthy weight, and overweight female bodies. In the body comparison task, participants rated their anxiety levels while comparing their own body with the presented image. In the weight estimation task, participants estimated the weight of the body in the presented image. We used between-group region of interest (ROI) analyses of the blood oxygen level dependent (BOLD) signal to analyze differences in brain activation patterns between the groups. In addition, to investigate activation outside predetermined ROIs, we performed an exploratory whole-brain analysis to identify group differences. Results: We found that, compared to healthy controls, patients with recAN exhibited significantly greater activation in the pregenual anterior cingulate cortex (pgACC) when comparing their own bodies with images of underweight female bodies. In addition, we found that, compared with healthy controls, patients with recAN exhibited significantly smaller activation in the middle temporal gyrus corresponding to the extrastriate body area (EBA) when comparing their own bodies, irrespective of weight, during self-other comparisons of body shape. Conclusions: Our findings from a group of patients with recAN suggest that the pathology of AN may lie in an inability to regulate negative affect in response to body images via pgACC activation during body comparisons. The findings also suggest that altered body image processing in the brain persists even after recovery from AN. PMID- 30450125 TI - Systematic review of pathways to mental health care in Brazil: narrative synthesis of quantitative and qualitative studies. AB - Background: Pathways to care are actions and strategies employed by individuals in order to get help for health-related distress and the related processes of care providers. On several systematic reviews regarding pathways to mental health care (PMHC), studies regarding South American countries were not present. This review synthesizes qualitative and quantitative research about PMHC in Brazil. Methods: LILACS, MEDLINE and SCIELO databases were searched for papers regarding PMHC in Brazil. The results were organized in pathway stages, based on Goldberg and Huxley's 'model of Levels and Filters' and on Kleinman's framework of 'Popular, Folk and Professional health sectors'. Analysis also considered the changes in national mental health policy over time. Results: 25 papers were found, with data ranging from 1989 to 2013. Complex social networks were involved in the initial recognition of MH issues. The preferred points of first contact also varied with the nature and severity of problems. A high proportion of patients is treated in specialized services, including mild cases. There is limited capacity of primary care professionals to identify and treat MH problems, with some improvement from collaborative care in the more recent years. The model for crisis management and acute care remains unclear: scarce evidence was found over the different arrangements used, mostly stressing lack of integration between emergency, hospital and community services and fragile continuity of care. Conclusions: The performance of primary care and the regulation of acute demands, especially crisis management, are the most critical aspects on PMHC. Although primary care performance seems to be improving, the balanced provision and integration between services for adequate acute and long-term care is yet to be achieved. PMID- 30450126 TI - Changes in lipid metabolism convey acid tolerance in Saccharomyces cerevisiae. AB - Background: The yeast Saccharomyces cerevisiae plays an essential role in the fermentation of lignocellulosic hydrolysates. Weak organic acids in lignocellulosic hydrolysate can hamper the use of this renewable resource for fuel and chemical production. Plasma-membrane remodeling has recently been found to be involved in acquiring tolerance to organic acids, but the mechanisms responsible remain largely unknown. Therefore, it is essential to understand the underlying mechanisms of acid tolerance of S. cerevisiae for developing robust industrial strains. Results: We have performed a comparative analysis of lipids and fatty acids in S. cerevisiae grown in the presence of four different weak acids. The general response of the yeast to acid stress was found to be the accumulation of triacylglycerols and the degradation of steryl esters. In addition, a decrease in phosphatidic acid, phosphatidylcholine, phosphatidylserine and phosphatidylethanolamine, and an increase in phosphatidylinositol were observed. Loss of cardiolipin in the mitochondria membrane may be responsible for the dysfunction of mitochondria and the dramatic decrease in the rate of respiration of S. cerevisiae under acid stress. Interestingly, the accumulation of ergosterol was found to be a protective mechanism of yeast exposed to organic acids, and the ERG1 gene in ergosterol biosynthesis played a key in ergosterol-mediated acid tolerance, as perturbing the expression of this gene caused rapid loss of viability. Interestingly, overexpressing OLE1 resulted in the increased levels of oleic acid (18:1n-9) and an increase in the unsaturation index of fatty acids in the plasma membrane, resulting in higher tolerance to acetic, formic and levulinic acid, while this change was found to be detrimental to cells exposed to lipophilic cinnamic acid. Conclusions: Comparison of lipid profiles revealed different remodeling of lipids, FAs and the unsaturation index of the FAs in the cell membrane in response of S. cerevisiae to acetic, formic, levulinic and cinnamic acid, depending on the properties of the acid. In future work, it will be necessary to combine lipidome and transcriptome analysis to gain a better understanding of the underlying regulation network and interactions between central carbon metabolism (e.g., glycolysis, TCA cycle) and lipid biosynthesis. PMID- 30450127 TI - Knomics-Biota - a system for exploratory analysis of human gut microbiota data. AB - Background: Metagenomic surveys of human microbiota are becoming increasingly widespread in academic research as well as in food and pharmaceutical industries and clinical context. Intuitive tools for investigating experimental data are of high interest to researchers. Results: Knomics-Biota is a web-based resource for exploratory analysis of human gut metagenomes. Users can generate and share analytical reports corresponding to common experimental schemes (like case control study or paired comparison). Interactive visualizations and statistical analysis are provided in association with the external factors and in the context of thousands of publicly available datasets arranged into thematic collections. The web-service is available at https://biota.knomics.ru. Conclusions: Knomics Biota web service is a comprehensive tool for interactive metagenomic data analysis. PMID- 30450128 TI - Calcitonin measurement in fine-needle aspirate washout fluid by electrochemiluminescence immunoassay for thyroid tumors. AB - Purpose: For the differential diagnosis of medullary thyroid carcinoma (MTC) on thyroid nodules, ultrasound-guided fine-needle aspiration cytology is a useful and safe procedure, but its diagnostic accuracy is not high enough. As an ancillary method to accurately diagnose MTC, the calcitonin in fine-needle aspirate washout fluid (FNA-Ct) is used. However, no data are available about cut off values of FNA-Ct using the currently available electrochemiluminescence immunoassay (ECLIA). Methods: We investigated 180 thyroid nodules in 141 patients. After smearing, the syringe and needle used for the FNA were rinsed with normal saline (0.5 mL). The calcitonin in the washout was measured by ECLIA. Results: The FNA-Ct in the non-MTC nodules of MTC patients, non-MTC nodules of non-MTC patients, and MTC nodules were 10.6-2100 pg/mL (median 24.6 pg/mL), < 0.5 21.0 pg/mL (median < 0.5 pg/mL), and 94.9-4,070,000 pg/mL (median 177,000 pg/mL), respectively. A receiver operating characteristic analysis of the MTC nodules and the non-MTC nodules of the non-MTC patients indicated that the cut-off value was 21.0 pg/mL, leading to 100% sensitivity and 100% specificity. Conclusions: This is the first study to determine the cut-off value of FNA-Ct with an ECLIA, and we propose that the optimal cut-off value is 21.0 pg/mL. PMID- 30450130 TI - An advanced enrichment method for rare somatic retroelement insertions sequencing. AB - Background: There is increasing evidence that the transpositional activity of retroelements (REs) is not limited to germ line cells, but often occurs in tumor and normal somatic cells. Somatic transpositions were found in several human tissues and are especially typical for the brain. Several computational and experimental approaches for detection of somatic retroelement insertions was developed in the past few years. These approaches were successfully applied to detect somatic insertions in clonally expanded tumor cells. At the same time, identification of somatic insertions presented in small proportion of cells, such as neurons, remains a considerable challenge. Results: In this study, we developed a normalization procedure for library enrichment by DNA sequences corresponding to rare somatic RE insertions. Two rounds of normalization increased the number of fragments adjacent to somatic REs in the sequenced sample by more than 26-fold, and the number of identified somatic REs was increased by 8 fold. Conclusions: The developed technique can be used in combination with vast majority of modern RE identification approaches and can dramatically increase their capacity to detect rare somatic RE insertions in different types of cells. PMID- 30450131 TI - Assessing snow extent data sets over North America to inform and improve trace gas retrievals from solar backscatter. AB - Accurate representation of surface reflectivity is essential to tropospheric trace gas retrievals from solar backscatter observations. Surface snow cover presents a significant challenge due to its variability and thus snow-covered scenes are often omitted from retrieval data sets; however, the high reflectance of snow is potentially advantageous for trace gas retrievals. We first examine the implications of surface snow on retrievals from the upcoming TEMPO geostationary instrument for North America. We use a radiative transfer model to examine how an increase in surface reflectivity due to snow cover changes the sensitivity of satellite retrievals to NO2 in the lower troposphere. We find that a substantial fraction (>50%) of the TEMPO field of regard can be snow covered in January, and that the average sensitivity to the tropospheric NO2 column substantially increases (doubles) when the surface is snow covered. We then evaluate seven existing satellite-derived or reanalysis snow extent products against ground station observations over North America to assess their capability of informing surface conditions for TEMPO retrievals. The Interactive Multisensor Snow and Ice Mapping System (IMS) had the best agreement with ground observations (accuracy of 93%, precision of 87%, recall of 83%). Multiangle Implementation of Atmospheric Correction (MAIAC) retrievals of MODIS-observed radiances had high precision (90% for Aqua and Terra), but underestimated the presence of snow (recall of 74% for Aqua, 75% for Terra). MAIAC generally outperforms the standard MODIS products (precision of 51%, recall of 43% for Aqua; precision of 69%, recall of 45% for Terra). The Near-real-time Ice and Snow Extent (NISE) product had good precision (83%) but missed a significant number of snow-covered pixels (recall of 45%). The Canadian Meteorological Centre (CMC) Daily Snow Depth Analysis Data set had strong performance metrics (accuracy of 91%, precision of 79%, recall of 82%). We use the F score, which balances precision and recall, to determine overall product performance (F = 85%, 82(82)%, 81%, 58%, 46(54)% for IMS, MAIAC Aqua(Terra), CMC, NISE, MODIS Aqua(Terra) respectively) for providing snow cover information for TEMPO retrievals from solar backscatter observations. We find that using IMS to identify snow cover and enable inclusion of snow covered scenes in clear-sky conditions across North America in January can increase both the number of observations by a factor of 2.1 and the average sensitivity to the tropospheric NO2 column by a factor of 2.7. PMID- 30450129 TI - Nonadiabatic dynamics: The SHARC approach. AB - We review the Surface Hopping including ARbitrary Couplings (SHARC) approach for excited-state nonadiabatic dynamics simulations. As a generalization of the popular surface hopping method, SHARC allows simulating the full-dimensional dynamics of molecules including any type of coupling terms beyond nonadiabatic couplings. Examples of these arbitrary couplings include spin-orbit couplings or dipole moment-laser field couplings, such that SHARC can describe ultrafast internal conversion, intersystem crossing, and radiative processes. The key step of the SHARC approach consists of a diagonalization of the Hamiltonian including these couplings, such that the nuclear dynamics is carried out on potential energy surfaces including the effects of the couplings-this is critical in any applications considering, for example, transition metal complexes or strong laser fields. We also give an overview over the new SHARC2.0 dynamics software package, released under the GNU General Public License, which implements the SHARC approach and several analysis tools. The review closes with a brief survey of applications where SHARC was employed to study the nonadiabatic dynamics of a wide range of molecular systems. This article is categorized under: Theoretical and Physical Chemistry > Reaction Dynamics and KineticsSoftware > Simulation MethodsSoftware > Quantum Chemistry. PMID- 30450132 TI - Selective Hydrogenation of Aldehydes Using a Well-Defined Fe(II) PNP Pincer Complex in Biphasic Medium. AB - A biphasic process for the hydrogenation of aldehydes was developed using a well defined iron (II) PNP pincer complex as model system to investigate the performance of various ionic liquids. A number of suitable hydrophobic ionic liquids based on the N(Tf)2 - anion were identified, allowing to immobilize the iron (II) catalyst in the ionic liquid layer and to facilitate the separation of the desired alcohols. Further studies showed that targeted Bronsted basic ionic liquids can eliminate the need of an external base to activate the catalyst. PMID- 30450133 TI - Energetic Effects of a Closed System Approach Including Explicit Proton and Electron Acceptors as Demonstrated by a Mononuclear Ruthenium Water Oxidation Catalyst. AB - When considering water oxidation catalysis theoretically, accounting for the transfer of protons and electrons from one catalytic intermediate to the next remains challenging: correction factors are usually employed to approximate the energetics of electron and proton transfer. Here these energetics were investigated using a closed system approach, which places the catalytic intermediate in a simulation box including proton and electron acceptors, as well as explicit solvent. As a proof of principle, the first two catalytic steps of the mononuclear ruthenium-based water oxidation catalyst [Ru(cy)(bpy)(H2O)]2+ were examined using Car-Parrinello Molecular Dynamics. This investigation shows that this approach offers added insight, not only into the free energy profile between two stable intermediates, but also into how the solvent environment impacts this dynamic evolution. PMID- 30450134 TI - Redox State of Human Serum Albumin and Inflammatory Biomarkers in Hemodialysis Patients with Secondary Hyperparathyroidism During Oral Calcitriol Supplementation for Vitamin D. AB - Background: Hemodialysis (HD) patients with secondary Hyperparathyroidism (s-HPT) are exposed to increased inflammation and oxidative stress. In HD patients, oxidized albumin is a reliable marker of oxidative stress and its clinical significance has been rarely studied. Objective: The objective of this study was to evaluate Cys34 Human Serum Albumin (HSA) as oxidative stress biomarker in HD patients with s-HPT and its relationship with inflammation on bone turnover markers during oral calcitriol supplementation for vitamin D. Patients and Methods: Fifteen stable hemodialysis patients with s-HPT (mean age 48.67+/-8.15, 11 males and 4 females) were used in the experiment to receive calcitriol treatment for 16 weeks (0.25mcg or 0.5 mcg once a day according to serum level of Ca and P for each). The changes in the serum biochemical parameters (Ca, P, ALP, and iPTH), inflammatory markers (CRP and IL-6 levels) and serum oxidative stress condition (SOD, IS and albumin ratio HNA/HMA) were evaluated before and at 8 and 16 weeks of calcitriol treatment. The correlations between those factors were studied. Results: All patients responded to oral calcitriol therapy, with a significant decrease in the serum iPTH. The results showed that calcitriol could effectively suppress iPTH secretion with a significant elevation of serum Ca and P but ALP remained unchanged during the study. It can also effectively reduce the inflammatory markers (CRP and IL-6), while increasing the oxidative markers (SOD and IS). Oxidative albumin ratio HNA/HMA showed a significant (p=0.001) reduction after 16 weeks of calcitriol treatment and the redox state of HSA showed a positive prediction for hyperparathyroidism and for inflammation. Conclusion: The redox state of HSA could be used as a predictor for monitoring hyperparathyroidism and inflammation during calcitriol treatment by retarding albumin oxidation in HD patients with secondary hyperparathyroidism. PMID- 30450136 TI - F.E.M. Stress-Investigation of Scolios Apex. PMID- 30450135 TI - Characterization of the F-box Proteins FBXW2 and FBXL14 in the Initiation of Bone Regeneration in Transplants given to Nude Mice. AB - Background: Cultured bovine-periosteum-derived cells can form three-dimensional structures on tissue culture dishes without artificial scaffolding material, can induce bone regeneration in vivo. The utility of cultured bovine-periosteum derived cells for bone tissue regeneration after their transplantation into nude mice has been reported, the precise F-box molecular mechanism was unclear. Objective: The aim of this study was to investigate the specific F-box proteins required for bone regeneration by cultured bovine-periosteum-derived cells in vitro. Methods: In the present study, periosteum tissue and cultured periosteum derived cells were cultured for 5 weeks in vitro and then embedded in collagen gel with a green tissue-marking dye. Electrophoresis and immunohistochemistry were used to identify the specific F-box proteins required for tissue bone regeneration. Results: The bovine-periosteum-derived cells were observed to form bone shortly after the expression of F-box proteins. After the initial phase of bone formation, the expression of the F-box proteins ceased. FBXW2 was shown to be expressed in the periosteum, but not in cultured periosteum-derived cells. Furthermore, FBXL14 disappeared during bone formation. Conclusions: Bone regeneration requires progenitor cells, such as bovine-periosteum-derived cells and the activation of the F-box Proteins FBXW2 and FBXL14, over time the expression of these proteins ceases. Further scientific and clinical trials are needed to investigate how the F-box Proteins can be used therapeutically to treat osteoporosis and osteonecrosis. PMID- 30450137 TI - Shade Stability of Polymer-Infiltrated and Resin Nano Ceramics. AB - Background: The esthetics plays an increasingly significant role in today's dentistry. Objective: The objective was to investigate the shade stability of a polymer-infiltrated and a resin nano ceramic in comparison to a conventional feldspar ceramic and an acrylate polymer. Methods: 20 specimens of each of the materials, CAD-Temp (CT), Mark II (M), VITA Enamic (VE) and Lava Ultimate (LU), were prepared using the standard method. These were divided into groups (n=5) and placed in the following stain solutions: Distilled water, coffee, Coca-Cola and red wine for 14 days. The shade of each specimen was measured before and after using a spectrophotometer (n=5). The data were analyzed using ANOVA and Tukey's test (p <= 0.05). Results: The largest DeltaE mean values were observed in CT by Coca-Cola (4.38 +/- 0.41), in M by coffee (5.95 +/- 0.62), in VE (6.02 +/- 0.78) and LU (8.61 +/- 0.30) by red wine. LU had the largest and strongest overall shade differences (total score: SSC=16.95) and CT the least (SSC=8.74). Overall shade differences of VE (SSC=12.03) and M (SSC=12.48) were statistically indistinguishable. After 14 days, only Coca-Cola caused clinically relevant shade differences in CT (DeltaE > 2.7); this was also caused by coffee, Coca-Cola and red wine in M and coffee and red wine in VE and LU. Conclusion: On average, VE showed fewer shade differences than LU. After 14 days of immersion, shade differences which exceeded the clinical acceptance threshold of DeltaE=2.7 were shown by CT in Coca-Cola, by M in coffee, Coca-Cola and red wine, and by VE and LU in coffee and red wine. PMID- 30450139 TI - First Molecular Identification of Symbiotic Archaea in a Sponge Collected from the Persian Gulf, Iran. AB - Background: Marine sponges are associated with numerically vast and phylogenetically diverse microbial communities at different geographical locations. However, little is known about the archaeal diversity of sponges in the Persian Gulf. The present study was aimed to identify the symbiotic archaea with a sponge species gathered from the Persian Gulf, Iran. Methods: Sponge sample was collected from a depth of 3 m offshore Bushehr, Persian Gulf, Iran. Metagenomic DNA was extracted using a hexadecyl trimethyl ammonium bromide (CTAB) method. The COI mtDNA marker was used for molecular taxonomy identification of sponge sample. Also, symbiotic archaea were identified using the culture independent analysis of the 16S rRNA gene and PCR- cloning. Results: In this study, analysis of multilocus DNA marker and morphological characteristics revealed that the sponge species belonged to Chondrilla australiensis isolate PG_BU4. PCR cloning and sequencing showed that all of the sequences of archaeal 16S rRNA gene libraries clustered into the uncultured archaeal group. Conclusion: The present study is the first report of the presence of the genus of Chondrilla in the Persian Gulf. Traditional taxonomy methods, when used along with molecular techniques, could play a significant role in the accurate taxonomy of sponges. Also, the uncultured archaea may promise a potential source for bioactive compounds. Further functional studies are needed to explore the role of the sponge-associated uncultured archaea as a part of the marine symbiosis. PMID- 30450138 TI - Using Resonance Frequency Analysis to Compare Delayed and Immediate Progressive Loading for Implants Placed in the Posterior Maxilla: A Pilot Study. AB - Objective: Implants placed in the posterior region of the maxilla have a high incidence of implant failure due to poor bone quality, especially when immediate implant loading is needed. Immediate Progressive Loading (IPL) can enhance bone quality and may offer an alternative solution when Immediate Implant loading is needed. Methods: Six patients (one male and five females; 34-62 years old) were included in this study. Twelve implants were inserted in the posterior region of the maxilla. Resonance Frequency Analysis (RFA) was performed at the time of implant placement and after 1, 2, 3 and 6 months. ISQ (Implant Stability Quotient) values were compared between the Delayed Loading (DL) group after 2 months and the Progressive Loading (PL) group and between different time points for each group. Results: At implant placement, the mean ISQ values for PL and DL implants were 63 and 57, respectively. One month after implant placement, the mean ISQ value for PL implants was 73.Two months after implant placement, the mean ISQ value for PL implants was 75. Three months after implant placement, the mean ISQ values for PL and DL implants were 76 and 69, respectively. Six months after implant placement, the mean ISQ values for PL and DL implants were 79 and 76, respectively. Conclusion: Despite its limitations, this pilot study indicated that compared to DL, PL can enhance bone density and implant stability, resulting in greater early functionality and fewer surgery sessions. PMID- 30450140 TI - Pulmonary Tuberculosis and Associated Factors Among Diabetic Patients Attending Hawassa Adare Hospital, Southern Ethiopia. AB - Background: Developing countries have a high burden of Tuberculosis (TB); although it is considered as a disease of the past in most developed countries. The end TB strategy was predicted to stabilize or drop the incidence of TB. However, the rising of the prevalence of immune-related diseases like Diabetes Mellitus (DM) are challenging the TB control strategy in high TB burden region. The objective of this study was to determine the prevalence and associated factors of pulmonary tuberculosis in DM patients attending Adare Hospital, south Ethiopia. Methods: A cross-sectional study was carried out on 207 randomly selected diabetic patients at the Adare hospital. A structured pre-tested questionnaire was used during the data collection from participants. Sputum concentration technique followed by Ziehl-Neelsen staining method was used to examine pulmonary tuberculosis. Logistic regression analysis was used to assess the association between various variables and pulmonary tuberculosis. Odds ratios and 95% CI were computed to determine the strength and presence of the association. Results: The prevalence of pulmonary tuberculosis among diabetics was 5.3% [95% CI: (2.2, 8.4)]. Diabetic patients who were underweight [AOR = 9.94, 95% CI: (1.51-80.89)], had more than 10 years duration with DM [AOR = 7.03 95% CI: (1.357, 73.6)], Alcohol drinking habit [AOR = 12.49, 95% CI: (3.28, 77.94)], and history of contact with TB [AOR = 5.35, 95% CI: (1.1-39.12)] were the factors positively associated with pulmonary TB infection while being HIV seronegative had a negative association with pulmonary TB infection [AOR =0.074, 95% CI: (0.001-0.29)]. Conclusion: High proportion of pulmonary TB was observed in diabetic patients as compared to the national estimated prevalence of TB in the total population. Duration of patient with DM, being underweight, alcohol consumption habit, and contact history with TB were positively associated with pulmonary TB infection while being HIV seronegative had a negative association with the infection in diabetic patients. PMID- 30450142 TI - Non-Antimicrobial Drugs: Etodolac as a Possible Antimicrobial or Adjuvant Agent Against ESKAPE Pathogens. PMID- 30450141 TI - First Detection of Chlamydia trachomatis 'Swedish' Variant (nvCT) in a Russian Couple with Infertility. AB - Background: Chronic asymptomatic chlamydial genital infection caused by the wild type of Chlamydia trachomatis (wtCT) is the most common bacterial infection causing human infertility. The novel 'Swedish' variant of S.trachomatis (nvCT) which contains a 377 bp deletion in a region that is specifically targeted in some nucleic acid amplification tests may impede diagnosis. Objective: The study aimed to investigate whether nvCT may be a possible cause of infertility in a couple undergoing in vitro fertilization (IVF). Method: Clinical specimens from both genital (urethra and cervix) and extra-genital sites (pharynx, conjunctive, blood) of a couple who experienced multiple unsuccessful attempts at pregnancy by natural fertilization and IVF procedures were analyzed before and after antibiotic therapy. Both partners had neither somatic nor endocrinal abnormality nor any clinically apparent genital manifestations of Chlamydia or other STIs. Results: Before antibiotic therapy all the samples of the Female Partner (FP) contained DNA of only the nvCT. After antibiotic therapy, additionally, DNA of wtCT of genovars E and D was detected in specimens from her conjunctiva and oropharynx. All samples of the Male Partner (MP) revealed co-infection of nvCT and wtCT. Identical SNP within the variable region 4 (VD4) of the ompA gene confirmed the identity of the wtCT strains found in both partners. The FP had a positive anti-chlamydial IgG titer. The sperm characteristics of the MP, motility (immotile spermatozoa was 51.1% versus 21.6%) and vitality (46% versus 68%) declined progressively, and the MP anti-chlamydial IgG titer was negative. Conclusion: Infertility in this couple may have been caused by chronic asymptomatic and persistent nvCT-associated infection that was complicated by re infection later with wtCT. This study illustrates the importance of including detection methods for nvCT strains in the investigation of infertility cases. PMID- 30450144 TI - Polymorphisms of Aldose Reductase (ALR2) Regulatory Gene are Risk Factors for Diabetic Retinopathy in Type-2 Diabetes Mellitus Patients in Bali, Indonesia. AB - Aim: The study aimed to elucidate whether the polymorphisms of the aldose reductase regulatory gene were risk factors for Diabetic Retinopathy (DR) in type 2 diabetes mellitus (T2DM) patients in Bali. Methods: This is a case-control study including 35 cases of T2DM patients with DR paired with 35 cases with non DR as controls. PCR analysis and DNA-sequencing were carried out to detect the C( 106)T and C(-12)G polymorphisms at the regulatory region of Aldose Reductase (ALR2) gene. Genotype and allele distributions were analyzed by Chi-squared test and independent t-and Mann-Whitney U tests were used to analyze other data. Results: Among all subjects in both groups, the baseline characteristics were homogenous except for systolic blood pressure, fasting blood glucose and 2-hours post-prandial blood glucose. This study found two polymorphisms, C(-104)T and C( 9)G, in the regulatory region of ALR2 gene. The result showed that the C(-104)T polymorphism was a risk factor for DR (OR=36; 95% CI = 4.43-292.85; p=0.001), but not the C(-9)G polymorphism (OR=1.28; 95% CI=0.48-3.38; p=0.621). Other findings in the study revealed that CC/CC haplotype is a protective factor for DR (OR=0.198; p=0.002), whereas CT/CC and CT/CG haplotypes as risk factors for DR with OR=15.58; p=0.002 and OR=2.29; p=0.005 respectively. Conclusion: It can be concluded that C(-104)T polymorphism in the regulatory region of Aldose Reductase (ALR2) gene was the risk factor for DR among T2DM patients in Bali, Indonesia. However, small sample size, systolic blood pressure, fasting blood glucose and 2 hours post-prandial blood glucose could affect our finding. PMID- 30450143 TI - Correlations between Capsular Changes and ROM Restriction in Frozen Shoulder Evaluated by Plain MRI and MR Arthrography. AB - Background: Evaluation of the Range Of Motion (ROM) is one of the important procedures for shoulder disorders. The purpose of this study was to investigate correlations between capsular changes and ROM restrictions evaluated by both plain magnetic resonance imaging (MRI) and Magnetic Resonance Arthrography (MRA) in the same patients with frozen shoulder. Methods: Between March 2015 and June 2016, 24 patients with frozen shoulders (13 male and 11 female patients, mean age 60.5) with severe ROM restriction who underwent both MRI and MRA on the same affected side were evaluated. We evaluated 1) ROM, 2) the coracohumeral ligament (CHL) thickness, 3) the joint capsule thickness in the axillary recess (humeral and glenoid sides), 4) the area of the axillary recess, and 5) the capsular area of the axillary recess. Results: Positive correlations were found between the axillary area and forward flexion (FF) (R = 0.43, P = 0.035), lateral elevation (LE) (R = 0.66, P<0.001), external rotation (ER)(R = 0.43, P = 0.035), 90 degrees abduction with external rotation (AER)(R = 0.56, P = 0.004), and hand behind the back (HBB)(R = 0.6, P = 0.002) on MRA. Negative correlations were found between the joint capsule at the glenoid side and ER and HBB in both MRI and MRA. Conclusion: The axillary area was significantly correlated with ROM restriction in FF, LE, ER, AER, and HBB on MRA. Thickness of the joint capsule at the glenoid side is an important factor for ROM restriction in frozen shoulder. Level of Evidence: Level 3, Study of Diagnostic Test. PMID- 30450145 TI - Depressive Symptoms and Complications Early after Acute Myocardial Infarction: Gender Differences. AB - Background: Cardiovascular disease is the first leading cause of death worldwide. Coronary heart disease is the most common manifestation of cardiovascular disease. Acute myocardial infarction is the primary manifestation of coronary heart disease. Depression is a common and predicted complication after acute myocardial infarction. Limited studies evaluated gender differences in depressive symptoms after acute myocardial infarction especially in developing countries. Objective: The study aimed to determine whether there was a difference in depression levels and rate of complications based on gender early after acute myocardial infarction. Method: This was a prospective comparative study on 230 patients (150 men and 80 women) with a confirmed diagnosis of acute myocardial infarction. All participants signed an informed consent, filled sociodemographic and clinical questionnaire and the Depression Subscale of the Hospital Anxiety and Depression Scale. Clinical data were abstracted from the participants' medical record after discharge. Results: Eighty-six participants (37.4%), 54 men and 32 women, developed 1 or more complications during hospitalization. Female patients were more depressed (14.4+/-3.5 vs. 8.3 +/- 2.6) and developed more complications (1.9 +/- 0.9 vs. 0.8 +/- 0.5) than male patients did. Depressive symptoms increased the occurrence of complication by 40% and 33% for female and male patients respectively after controlling for sociodemographic and clinical variables. Conclusion: Depressive symptoms independently predicted complications after acute myocardial infarction in both men and women. The inclusion of depression assessment tools in acute myocardial infarction treatment protocols is highly recommended. PMID- 30450146 TI - Magnetic Resonance Imaging Findings of Term and Preterm Hypoxic-Ischemic Encephalopathy: A Review of Relevant Animal Models and Correlation to Human Imaging. AB - Background: Neonatal hypoxic-ischemic encephalopathy is brain injury caused by decreased perfusion and oxygen delivery that most commonly occurs in the context of delivery complications such as umbilical cord compression or placental abruption. Imaging is a key component for guiding treatment and prediction of prognosis, and the most sensitive clinical imaging modality for the brain injury patterns seen in hypoxic-ischemic encephalopathy is magnetic resonance imaging. Objective: The goal of this review is to compare magnetic resonance imaging findings demonstrated in the available animal models of hypoxic-ischemic encephalopathy to those found in preterm (<= 36 weeks) and term (>36 weeks) human neonates with hypoxic-ischemic encephalopathy, with special attention to the strengths and weaknesses of each model. Methods: A structured literature search was performed independently by two authors and the results of the searches were compiled. Animal model, human brain age equivalency, mechanism of injury, and area of brain injury were recorded for comparison to imaging findings in preterm and term human neonates with hypoxic-ischemic encephalopathy. Conclusion: Numerous animal models have been developed to better elicit the expected findings that occur after HIE by allowing investigators to control many of the clinical variables that result in injury. Although modeling the same disease process, magnetic resonance imaging findings in the animal models vary with the species and methods used to induce hypoxia and ischemia. The further development of animal models of HIE should include a focus on comparing imaging findings, and not just pathologic findings, to human studies. PMID- 30450148 TI - Malignant optic glioma masked by suspected optic neuritis and central retinal vein occlusion. AB - Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity. PMID- 30450147 TI - Metabolic and Cardiovascular Comorbidities Among Clinically Stable HIV Patients on Long-Term ARV Therapy in Five Ambulatory Clinics in Lima-Callao, Peru. AB - Background: There is scarcity of data about the prevalence of non-AIDS defining comorbidities among stable HIV-infected patients in Peru. Objective: We aimed to describe the most frequent cardiometabolic comorbidities found among ambulatory adults on ARV in Peru. Methods: A review of records for patients attending regular visits at 5 clinics in Lima-Callao in January-February 2016 is presented. Patients were adults on ARV for >6 months, with no recent AIDS-defining condition. Results: Three hundred and five medical charts were reviewed. Most patients were male (73.1%, n=223) with a mean age of 46.0 years. Mean time from HIV diagnosis was 9.41 yrs. and mean duration of ARV was 7.78 yrs. Most patients were on an NNRTI-based first line regimen (76.4%, n=233), and 12.1% (n=37) were on rescue regimens. Median CD4 count was 614.2 cells/uL and the proportion of patients with viral load <40 c/mL was 90.8% (n=277). Most frequent metabolic diagnoses were dyslipidemia (51.5%, n=157), obesity (11.1%, n=34), and diabetes mellitus (7.2%, n=22). Hypertension was diagnosed in 8.9% (n=27). Other diagnoses of cardiovascular disease were documented in 3.3% (n=10). Pharmacologic treatment was prescribed in 91.3% of patients with diabetes or hypertension, but in only 29.3% of patients with dyslipidemia. Conclusion: A high proportion of metabolic comorbidities was found, with dyslipidemia being the most frequent, followed by obesity and diabetes. In contrast, cardiovascular disease was documented less frequently. Medical treatment was started for only a third of dyslipidemia patients. HIV care policies need to consider proper management of chronic comorbidities to optimize long-term outcomes. PMID- 30450149 TI - Ice Nucleation at the Water-Sapphire Interface: Transient Sum-Frequency Response without Evidence for Transient Ice Phase. AB - Heterogeneous ice nucleation at the water-sapphire interface is studied using sum frequency generation spectroscopy. We follow the response of the O-H stretch mode of interfacial water during ice nucleation as a function of time and temperature. The ice and liquid states each exhibit very distinct, largely temperature independent responses. However, at the moment of freezing, a transient response with a significantly different intensity is observed, with a lifetime between several seconds and several minutes. The presence of this transient signal has previously been attributed to a transient phase of ice. Here, we demonstrate that the transient signal can be explained without invoking a transient ice phase, as the transient signal can simply be accounted for by a linear combination of time dependent liquid and ice responses. PMID- 30450150 TI - Angle-Independent Polariton Emission Lifetime Shown by Perylene Hybridized to the Vacuum Field Inside a Fabry-Perot Cavity. AB - The formation of hybrid light-matter states in optical structures, manifested as a Rabi splitting of the eigenenergies of a coupled system, is one of the key effects in quantum optics. The hybrid states (exciton polaritons) have unique chemical and physical properties and can be viewed as a linear combination of light and matter. The optical properties of the exciton polaritons are dispersive by nature, a property inherited from the photonic contribution to the polariton. On the other hand, the polariton lifetime in organic molecular systems has recently been highly debated. The photonic contribution to the polariton would suggest a lifetime on the femtosecond time scale, much shorter than experimentally observed. Here, we increase the insights of light-mater states by showing that the polariton emission lifetime is nondispersive. A perylene derivative was strongly coupled to the vacuum field by incorporating the molecule into a Fabry-Perot cavity. The polariton emission from the cavity was shown to be dispersive, but the emission lifetime was nondispersive and on the time scale of the bare exciton. The results were rationalized by the exciton reservoir model, giving experimental evidence to currently used theories, thus improving our understanding of strong coupling phenomena in molecules. PMID- 30450151 TI - Nanoscale Investigation of Defects and Oxidation of HfSe2. AB - HfSe2 is a very good candidate for a transition metal dichalcogenide-based field effect transistor owing to its moderate band gap of about 1 eV and its high-kappa dielectric native oxide. Unfortunately, the experimentally determined charge carrier mobility is about 3 orders of magnitude lower than the theoretically predicted value. This strong deviation calls for a detailed investigation of the physical and electronic properties of HfSe2. Here, we have studied the structure, density, and density of states of several types of defects that are abundant on the HfSe2 surface using scanning tunneling microscopy and spectroscopy. Compared to MoS2 and WSe2, HfSe2 exhibits similar type of defects, albeit with a substantially higher density of 9 * 1011 cm-2. The most abundant defect is a subsurface defect, which shows up as a dim feature in scanning tunneling microscopy images. These dim dark defects have a substantially larger band gap (1.25 eV) than the pristine surface (1 eV), suggesting a substitution of the Hf atom by another atom. The high density of defects on the HfSe2 surface leads to very low Schottky barrier heights. Conductive atomic force microscopy measurements reveal a very small dependence of the Schottky barrier height on the work function of the metals, suggesting a strong Fermi-level pinning. We attribute the observed Fermi-level pinning (pinning factor ~0.1) to surface distortions and Se/Hf defects. In addition, we have also studied the HfSe2 surface after the exposure to air by scanning tunneling microscopy and conductive atomic force microscopy. Partly oxidized layers with band gaps of 2 eV and Schottky barrier heights of ~0.6 eV were readily found on the surface. Our experiments reveal that HfSe2 is very air-sensitive, implying that capping or encapsulating of HfSe2, in order to protect it against oxidation, is a necessity for technological applications. PMID- 30450152 TI - Estimating Evapotranspiration From Satellite Using Easily Obtainable Variables: A case study over the Southern Great Plains, U.S.A. AB - Evapotranspiration (ET) is a critical component of the Earth's water budget, a critical modulator of land-atmosphere (L-A) interactions, and also plays a crucial role in managing the Earth's energy balance. In this study, the feasibility of generating spatially-continuous daily evaporative fraction (EF) and ET from minimal remotely-sensed and meteorological inputs in a trapezoidal framework is demonstrated. A total of four variables, Normalized Difference Vegetation Index (NDVI), Land surface temperature (Ts ), gridded daily average temperature (Ta ) and elevation (z) are required to estimate EF. Then, ET can be estimated with the available soil heat flux (G) and net radiation (Rn) data. Firstly, the crucial model variable, Ts - Ta , is examined how well it characterizes the variation in EF using in situ data recorded at two eddy correlation flux towers in Southern Great Plains, U.S.A in 2011. Next, accuracy of satellite-based Ts are compared to ground-based Ts . Finally, EF and ET estimates are validated. The results reveal that the model performed satisfactorily in modeling EF and ET variation at winter wheat and deciduous forest during the high evaporative months. Even though the model works best with the observed MODIS-Ts as opposed to temporally interpolated Ts , results obtained from interpolated Ts are able to close the gaps with reasonable accuracy. Due to the fact that Ts - Ta , is not a good indicator of EF outside the growing season when deciduous forest is dormant, potential improvements to the model are proposed to improve accuracy in EF and ET estimates at the expense of adding more variables. PMID- 30450153 TI - EMPHYSEMA QUANTIFICATION ON SIMULATED X-RAYS THROUGH DEEP LEARNING TECHNIQUES. AB - Emphysema quantification techniques rely on the use of CT scans, but they are rarely used in the diagnosis and management of patients with COPD; X-ray films are the preferred method to do this. However, this diagnosis method is very controversial, as there are not established guidelines to define the disease, sensitivity is low, and quantification cannot be done. We developed a quantification method based on a CNN, capable of predicting the emphysema percentage of a patient based on an X-ray image. We used real CT scans to simulate X-ray films and to calculate emphysema percentage using the LAA%. The model developed was able to calculate emphysema percentage with an LAA% mean error of 3.96, and it obtained an AUC accuracy of 90.73% for an emphysema definition of >=10%, with a mean sensitivity of 85.68%, significantly improving X ray-based emphysema diagnosis. PMID- 30450155 TI - T-cell exhaustion in glioblastoma. PMID- 30450154 TI - ESTIMATION OF SHAPE AND GROWTH BRAIN NETWORK ATLASES FOR CONNECTOMIC BRAIN MAPPING IN DEVELOPING INFANTS. AB - In vivo brain connectomics have heavily relied on using functional and diffusion Magnetic Resonance Imaging (MRI) modalities to examine functional and structural relationships between pairs of anatomical regions in the brain. However, research work on brain morphological (i.e., shape-to-shape) connections, which can be derived from T1-w and T2-w MR images, in both typical and atypical development or ageing is very scarce. Furthermore, the brain cannot be only regarded as a static shape, since it is a dynamic complex system that changes at functional, structural and morphological levels. Hence, examining the 'connection' between brain shape and its changes with time (e.g., growth) may help advance our understanding of connectomic brain dynamics as well as disorders that may affect it. To address these limitations, we unprecedentedly introduce two population based shape and growth connectivity analysis tools that further extend the field of connectomics to brain morphology and dynamics: the morphome and the kinectome. Specifically, for a population of anatomically labelled shapes, the morphome identifies a network of anatomical shape regions that are connected when morphologically similar at a single timepoint, whereas the kinectome identifies anatomical shape regions that elicit similar evolution dynamics across successive timepoints. These proposed generic tools can be easily invested to examine how a baseline shape influences its deformation trajectory at later timepoints using any longitudinal shape data. We evaluated these tools on 23 infants, with right and left cortical surfaces reconstructed at birth, 3, 6, 9 and 12 months of age. Investigating the relationship between the neonatal morphome and the postnatal kinectome (from birth to 1 year of age) gave insights into brain connectivity at birth and how it develops over time. PMID- 30450156 TI - DNMT3a and TET2 in adipocyte insulin sensitivity. PMID- 30450157 TI - BH4-mimetics and -antagonists: an emerging class of Bcl-2 protein modulators for cancer therapy. PMID- 30450158 TI - Systemic immune-inflammation index, SII, for prognosis of elderly patients with newly diagnosed tumors. AB - Background: Cancer in the elderly has become a common problem due in part to the increase in life expectancy. Compared to younger counterparts, the biological characteristics of tumors and their responsiveness to therapy may differ in elderly patients, and the elderly also can have a decreased tolerance to anticancer therapy. In addition, there is less evidence from clinical trials to guide physicians in treating aged patients with solid tumors. Thus, we often face a dilemma as to how actively to treat these patients and it would be highly useful to have a simple and powerful indicator of their prognosis. In this paper we evaluated the predictive value of the Systemic Immune-inflammation Index, SII, in determining the one-year survival and tumor differentiation status in elderly patients with newly diagnosed solid tumors. Results: A high SII > 390*109 cells/L was correlated with poor tumor differentiation (chi2 = 9.791, P = 0.002) and poor one-year survival (chi2 = 7.658, P = 0.006). Patients with low SII had improved survival and better tumor differentiation (Stage I-II). The SII was not associated with Ki-67 expression. Materials and Methods: Data from 119 patients, 70 to 89 years of age with newly diagnosed solid tumors in 2014 were retrospectively analyzed. The patients were divided into two groups according to age: (1) 70-75 years of age and (2) over 75 years of age. We calculated SII from the equation, SII = P x N/L, where P, N and L are the preoperative peripheral blood platelet, neutrophil and lymphocyte counts per liter respectively. The optimum cutoff point for SII for a favorable prognosis was determined to be 390*109 cells/L. For evaluation of SII as a prognostic indicator, the patients were divided into high SII (> 390*109 cells/L) and low SII (<= 390*109 cells/L) groups. Individual values were used to determine the relationship between SII and one-year survival, tumor differentiation and Ki-67 expression in the two age groups. Conclusions: SII was a robust indicator of tumor differentiation and one year survival in elderly patients with newly diagnosed solid tumors. Patients in the high SII group showed poor tumor differentiation and poor prognosis compared to patients with a low SII score. PMID- 30450159 TI - Sex hormone receptor expression and survival in esophageal adenocarcinoma: a prospective cohort study. AB - Introduction: A striking epidemiological feature of esophageal adenocarcinoma (EAC) is its strong, unexplained male predominance but few studies have evaluated the prevalence of sex hormone receptor expression in EAC. Results: A low proportion of EAC tumors stained positive for ERalpha (4%) and AR (3%) while approximately one third stained positive for ERbeta (31%). After a mean follow-up of 3 years (max 9 years), no significant associations were seen for ERalpha, ERbeta or AR expression and EAC recurrence or survival. A non-significant reduction in mortality was observed for positive ERbeta tumor expression, when restricting to patients with gastro-esophageal junctional (GEJ) cancer (HR 0.58, 95% CI 0.33, 1.03, p = 0.06). Materials and Methods: We identified all EAC patients who underwent neo-adjuvant chemotherapy prior to surgical resection between 2004-2012 in the Northern Ireland Cancer Centre. Immunohistochemical expression of ERalpha, ERbeta and AR was scored on triplicate cores to generate H scores. Cox proportional hazards regression was used to evaluate the association between sex hormone receptor expression and overall, cancer-specific and recurrence-free survival. Conclusion: We found little evidence of ERalpha or AR expression in EAC. A moderate proportion expressed ERbeta and there was suggestive evidence that its expression was associated with improved survival in GEJ cancer patients. PMID- 30450160 TI - Knock-in of the Wt1 R394W mutation causes MDS and cooperates with Flt3/ITD to drive aggressive myeloid neoplasms in mice. AB - Wilms tumor 1 (WT1) is a zinc finger transcriptional regulator, and has been implicated as both a tumor suppressor and oncogene in various malignancies. Mutations in the DNA-binding domain of the WT1 gene are described in 10-15% of normal-karyotype AML (NK-AML) in pediatric and adult patients. Similar WT1 mutations have been reported in adult patients with myelodysplastic syndrome (MDS). WT1 mutations have been independently associated with treatment failure and poor prognosis in NK-AML. Internal tandem duplication (ITD) mutations of FMS like tyrosine kinase 3 (FLT3) commonly co-occur with WT1-mutant AML, suggesting a cooperative role in leukemogenesis. The functional role of WT1 mutations in hematologic malignancies appears to be complex and is not yet fully elucidated. Here, we describe the hematologic phenotype of a knock-in mouse model of a Wt1 mutation (R394W), described in cases of human leukemia. We show that Wt1 +/R394W mice develop MDS which becomes 100% penetrant in a transplant model, exhibit an aberrant expansion of myeloid progenitor cells, and demonstrate enhanced self renewal of hematopoietic progenitor cells in vitro. We crossbred Wt1 +/R394W mice with knock-in Flt3 +/ITD mice, and show that mice with both mutations (Flt3 +/ITD/Wt1 +/R394W) develop a transplantable MDS/MPN, with more aggressive features compared to either single mutant mouse model. PMID- 30450161 TI - Down-regulation of AR splice variants through XPO1 suppression contributes to the inhibition of prostate cancer progression. AB - Emerging studies have shown that the expression of AR splice variants (ARv) lacking ligand-binding domain is associated with castrate-resistant prostate cancer (CRPC) and higher risk of tumor metastasis and recurrence. Nuclear export protein XPO1 regulates the nuclear localization of many proteins including tumor suppressor proteins. Increased XPO1 in prostate cancer is associated with a high Gleason score and bone metastasis. In this study, we found that high expression of AR splice variant 7 (AR-v7) was correlated with increased XPO1 expression. Silencing of XPO1 by RNAi or treatment with Selective Inhibitor of Nuclear Export (SINE) compounds selinexor and eltanexor (KPT-8602) down-regulated the expression of AR, AR-v7 and ARv567es at mRNA and protein levels. XPO1 silencing also inhibited the expression of AR and ARv regulators including FOXA1, Src, Vav3, MED1 and Sam68, leading to the suppression of ARv and AR target genes, UBE2C and PSA. By targeting XPO1/ARv signaling, SINE suppressed prostate cancer (PCa) growth in vitro and in vivo and potentiated the anti-cancer activity of anti-AR agents, enzalutamide and abiraterone. Therefore, XPO1 inhibition could be a novel promising agent used in combination with conventional chemotherapeutics and AR targeted therapy for the better treatment of PCa, especially CRPC. PMID- 30450162 TI - Anti-PD-1 therapy for clinical treatment of lymphoma: a single-arm meta-analysis. AB - : Anti-PD1 antibodies exhibit satisfactory efficacy in treating certain types of lymphoma. We conducted this meta-analysis to explore subtypes benefiting from this treatment and the best anti-PD1 therapeutic modalities. Methods: A quantitative meta-analysis was performed via a systematic search in PubMed, Web of Science, and The Cochrane Library. The pooled overall response rate (ORR), progression-free survival (PFS), complete remission rate (CRR), overall survival (OS) and adverse events (AEs) were calculated and compared. Data were analyzed using a random-effects meta-analysis to determine risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. Results: Thirteen articles were selected, and 9 studies were included in the meta-analysis. There was evidence of significant heterogeneity among the studies. According to PD-L1 expression subgroup analysis, the PD-L1-positive group exhibited significantly better outcomes than the PD-L1-negative group (Z=5.481, p=0.000), with pooled ORRs of 0.74 (95% CI: 0.67-0.81) and 0.2 (95% CI: 0.11-0.3), respectively. For PD L1-positive and PD-L1-negative patients, the pooled CRRs, PFS and OS were 0.21 (95% CI: 0.14-0.29), 0.76 (95% CI: 0.71-0.81) and 1.0 (95% CI: 0.98-1.0) and 0.05 (95% CI: 0.01-0.11), 0.20 (95% CI: 0.09-0.39) and 0.64 (95% CI: 0.45-0.80), respectively; differences were all statistically significant (Z=2.248, p=0.025; Z=3.555, p=0.000; and Z=3.039, p=0.002, respectively). The pooled incidence of treatment-related all-grade AEs and grade-3/4 AEs was 0.84 (95% CI: 0.75-0.92) and 0.21 (95% CI: 0.15-0.29), respectively. Conclusion: Patients with PD-L1 overexpression in relapsed or refractory lymphoma benefited more from anti-PD-1 therapy. Moreover, treatment with approved PD-1 inhibitors was well tolerated. PMID- 30450163 TI - A phase I pilot study evaluating the beneficial effects of black raspberries in patients with Barrett's esophagus. AB - Black raspberries inhibit a broad range of cancers in preclinical models which has led to clinical evaluations targeting premalignant lesions of the colon, oral cavity and esophagus. A phase I pilot study was conducted in twenty Barrett's esophagus (BE) patients to investigate the effect of lyophilized black raspberries (LBR) on urinary metabolites and markers of lipid peroxidation, DNA damage and tissue markers of cellular proliferation, detoxification, and inflammation. Surveys, biopsies, blood and urine samples were collected before and after 6 months of LBR treatment (32 or 45 g). LBR significantly reduced urinary excretion of 8-epi-prostaglandin F2alpha, a marker of lipid peroxidation linked to oxidative stress and free radical damage. Urinary levels of the ellagitannin metabolites, urolithin A-glucuronide, urolithin A-sulfate and dimethylellagic acid glucuronide were significantly increased following 12 and 26 weeks of LBR consumption and may prove useful as indicators of compliance in future clinical studies. Immunohistochemical staining of BE biopsies following LBR treatment showed significant increases in mean GST-pi levels, with 55.6% of subjects responding favorably. In summary, LBR significantly decreased urinary lipid peroxidation levels and significantly increased GST-pi, a marker of detoxification, in BE epithelium. Still, LBR may need to be formulated differently, administered at higher concentrations or multiple times a day to increase efficacy. PMID- 30450164 TI - Correction: Development and validation of nomograms for predicting survival in patients with non-metastatic colorectal cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.16167.]. PMID- 30450166 TI - Towards good correlation between fragment molecular orbital interaction energies and experimental IC50 for ligand binding: A case study of p38 MAP kinase. AB - We describe several procedures for the preprocessing of fragment molecular orbital (FMO) calculations on p38 mitogen-activated protein (MAP) kinase and discuss the influence of the procedures on the protein-ligand interaction energies represented by inter-fragment interaction energies (IFIEs). The correlation between the summation of IFIEs for a ligand and amino acid residues of protein (IFIE-sum) and experimental affinity values (IC50) was poor when considered for the whole set of protein-ligand complexes. To improve the correlation for prediction of ligand binding affinity, we carefully classified data set by the ligand charge, the DFG-loop state (DFG-in/out loop), which is characteristic of kinase, and the scaffold of ligand. The correlation between IFIE-sums and the activity values was examined using the classified data set. As a result, it was confirmed that there was a selected data set that showed good correlation between IFIE-sum and activity value by appropriate classification. In addition, we found that the differences in protonation and hydrogen orientation caused by subtle differences in preprocessing led to a relatively large difference in IFIE values. Further, we also examined the effect of structure optimization with different force fields. It was confirmed that the difference in the force field had no significant effect on IFIE-sum. From the viewpoint of drug design using FMO calculations, various investigations on IFIE-sum in this research, such as those regarding several classifications of data set and the different procedures of structural preparation, would be expected to provide useful knowledge for improvement of prediction ability about the ligand binding affinity. PMID- 30450167 TI - Cytofast: A workflow for visual and quantitative analysis of flow and mass cytometry data to discover immune signatures and correlations. AB - Multi-parametric flow and mass cytometry allows exceptional high-resolution exploration of the cellular composition of the immune system. A large panel of computational tools have been developed to analyze the high-dimensional landscape of the data generated. Analysis frameworks such as FlowSOM or Cytosplore incorporate clustering and dimensionality reduction techniques and include algorithms allowing visualization of multi-parametric cytometric analysis. To additionally provide means to quantify specific cell clusters and correlations between samples, we developed an R-package, called cytofast, for further downstream analysis. Specifically, cytofast enables the visualization and quantification of cell clusters for an efficient discovery of cell populations associated with diseases or physiology. We used cytofast on mass and flow cytometry datasets based on the modulation of the immune system upon immunotherapy. With cytofast, we rapidly generated visual representations of group-related immune cell clusters and showed correlations with the immune system composition. We discovered macrophage subsets that significantly decrease upon cancer immunotherapy and distinct prime-boost effects of prophylactic vaccines on the myeloid compartment. Cytofast is a time-efficient tool for comprehensive cytometric analysis to reveal immune signatures and correlations. Cytofast is available at Bioconductor. PMID- 30450165 TI - Scavenging of reactive oxygen and nitrogen species with nanomaterials. AB - Reactive oxygen and nitrogen species (RONS) are essential for normal physiological processes and play important roles in cell signaling, immunity, and tissue homeostasis. However, excess radical species are implicated in the development and augmented pathogenesis of various diseases. Several antioxidants may restore the chemical balance, but their use is limited by disappointing results of clinical trials. Nanoparticles are an attractive therapeutic alternative because they can change the biodistribution profile of antioxidants, and possess intrinsic ability to scavenge RONS. Herein, we review the types of RONS, how they are implicated in several diseases, and the types of nanoparticles with inherent antioxidant capability, their mechanisms of action, and their biological applications. PMID- 30450168 TI - The Effects of Acorus calamus L. in Preventing Memory Loss, Anxiety, and Oxidative Stress on Lipopolysaccharide-induced Neuroinflammation Rat Models. AB - Objective: Several factors lead to memory loss, the most important of which is brain aging that is caused mostly by neuroinflammation and oxidative stress. The need of finding preventive treatments of memory impairment in elderly encouraged authors to assess the effect of Acorus calamus on memory loss, anxiety, and antioxidant indices on neuroinflammation rat models. Materials and Methods: Different fractions of A. calamus were prepared. The subject rats were grouped in 11 groups of 10 each. In the nine treated groups, the extract gavage began 1 week before intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) and continued for 2 weeks after the last injection of LPS. Behavioral tests, including passive avoidance and elevated plus-maze (EPM) tests, were run on days 24, 25, and 26 and the subjects were sacrificed on the day after the last behavioral test, and their hippocampus was isolated to measure the oxidative stress markers. Results: Assessment of oxidative stress markers in hippocampus samples revealed that the amounts of endogenous antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and total antioxidant activity) in the groups that received different fractions were less than their equivalent figures in LPS-control group, and levels of malondialdehyde (MDA) in treatment groups were less than MDA level in LPS-control group. Moreover, the treatment groups with different fractions of A. calamus revealed better performance compared to LPS-control group in shuttle-box test. In EPM test, the groups with different fractions revealed lower stress level in comparison with LPS-control group. The best performance in memory test and the lowest level of stress in EPM was observed in the group with aqueous fraction at 600 mg/kg dose, and the least figures of oxidative stress markers were of the group with aqueous fraction at 600 mg/kg dose. Conclusion: The oral administration of different fractions of A. calamus, especially aqueous fraction, prevented from memory deficits and stress through controlling oxidative stress and inflammation processes. PMID- 30450169 TI - Dark Chocolate Effect on Serum Adiponectin, Biochemical and Inflammatory Parameters in Diabetic Patients: A Randomized Clinical Trial. AB - Background: An appropriate snack for patients with diabetes mellitus should be considered to help them in their treatment due to their hard administrative diet. This study was conducted to evaluate the effect of dark chocolate on inflammatory markers, serum adiponectin, and certain biochemical factors in patients with type 2 diabetes (T2D). Methods: This study was a randomized parallel clinical trial. Thirty grams of 84% dark chocolate, along with therapeutic lifestyle changes (TLCs) guidelines, were administrated to patients with T2D. Control group received only TLC guidelines. The intervention period was 8 weeks. Twenty-one subjects in dark chocolate and 23 subjects in control group completed the study. Fasting blood samples were collected before and after the intervention period and inflammatory markers, biochemical factors, and adiponectin levels were assessed. Results: Fasting blood sugar, hemoglobin A1C, low-density lipoprotein and triglyceride levels declined significantly in the dark chocolate group and this decrease was significant between the intervention and control groups. Tumor necrosis factor-alpha, interleukin-6, and high sensitive C-reactive protein were significantly decreased in the dark chocolate group. Adiponectin levels were not significantly different between the two groups. Conclusions: In this study subjects who received dark chocolate along with TLC guidelines had lower levels of inflammatory markers such as hs-CRP, TNF-alpha, and IL-6, compared with the subjects who were devoid of dark chocolate and followed only the TLC guidelines. Other studies should be conducted to evaluate the most effective and administrative dosage of dark chocolate as a snack along with the common treatment of diabetes. PMID- 30450171 TI - A Randomized Controlled Trial of Zinc Supplementation as Adjuvant Therapy for Dengue Viral Infection in Thai Children. AB - Background: Zinc deficiency is common in developing countries and increases the risk for several infectious diseases. Low serum zinc levels have been reported in children with dengue virus infection (DVI). This study aimed to assess the effects of zinc supplementation on DVI outcomes. Methods: A double-blinded, randomized trial was conducted in 50 children with dengue fever (DF)/dengue hemorrhagic fever admitted to the pediatric unit of MSMC Srinakharinwirot University Hospital, Thailand, between January 2016 and April 2017. Bis-glycinate zinc or placebo was orally administered three times a day for 5 days or until defervescence. The primary outcome was to evaluate the DVI defervescence phase; the secondary outcome was to assess hospitalization length and presence of severe DVI and zinc deficiency. Results: The mean time of defervescence was 29.2 +/- 24.0 h in the supplementation group and 38.1 +/- 31.5 h in the placebo group (P = 0.270). Meantime of hospital staying was 62.5 +/- 23.8 h in the supplementation group and 84.7 +/- 34.0 h in placebo group with the mean difference of hospital staying between groups of 22.2 h (95% confidence interval [CI]: 5.5-38.5 h; P = 0.010). Overall prevalence of zinc deficiency was 46%. Serum zinc levels increased from baseline to the end of the study. the mean gain was 26.4 MUg/dL (95% CI: 13.6-39.1 MUg/dL) in the supplementation group and 14.4 MUg/dL (95% CI: 7.4-21.3 MUg/dL) in placebo group. No signs of severe DVI were observed in both groups. Zinc supplementation was well tolerated. Conclusions: Overcoming zinc deficiency among Thai children may reduce DF duration and limit the hospitalization, in addition to other advantages that normal serum zinc levels have on overall children health. PMID- 30450170 TI - The Importance of Sleep Hygiene in Polycystic Ovary Syndrome from the View of Iranian Traditional Medicine and Modern Medicine. AB - Polycystic ovary syndrome (PCOS) is known as the most common hormonal disorder in women at reproductive age. Recent studies have revealed a high prevalence of sleep disorders in PCOS, suggesting that it is an amendable factor for these patients; however, the sleep was not considered in their treatment plan. According to the Iranian traditional medicine (ITM), sleep is an important item in the lifestyle modification of all diseases. The aim of this study is to determine the importance of sleep hygiene in PCOS from the view of ITM and Modern Medicine. In this study, some keywords about "sleep and PCOS" were searched in medical databases and some ITM books. Lifestyle modification is one of the first steps in treatment of patients with PCOS in which the emphasis will be mainly on exercise and diet. Despite proof of the high prevalence of sleep disorders in these patients, modification of sleep is not considered in their lifestyle. ITM as a holistic medicine emphasizes on lifestyle modification under the title of "Settah-e-Zaruria" (In Persian), the six essential schemes for the prevention and treatment of all diseases. Management of sleep is one of these schemes. There are many advices about sleep hygiene in both ITM and modern medicine. It seems that lifestyle modification should be expanded in PCOS patients to include more options, and sleep hygiene should be considered in their lifestyle alongside food and exercise. PMID- 30450172 TI - The Association between Household Socioeconomic Status, Breastfeeding, and Infants' Anthropometric Indices. AB - Background: The growth, learning, and contribution to active life in the communities are better in well-nourished children, and various factors influence infants' feeding. In this study, we assessed whether household socioeconomic status (SES) affects infants' length-for-age, weight-for-age (indicators of health and nutritional status) and breastfeeding (BF) (a necessity for optimal growth and health) status. Methods: In this cross-sectional study, 150 households with infants of 1-1.5 years old were interviewed on these variables: family size, dwelling ownership, duration of BF, exclusive BF (EBF) for 6 months, parents' age, parents' ethnicity, birth order, delivery type, and parents' education. Weight and length at 4 and 12 months were obtained from centers' records. To determine SES, we assessed total years of parents' education and household asset ownership by an index of nine owned assets. Results: The average of 4-month length in the low SES group was significantly lower than the two others (P < 0.05). In middle socioeconomic group, duration of BF was significantly higher (19.5 +/- 7.3 months vs. 18.0 +/- 8.0 months in low and 17.5 +/- 7.9 months in high SES groups) (P < 0.05). Comparing illiterate mothers, university degree holders and university students were 73% less likely to not having EBF. Moreover, those with middle SES showed to be about 40% less likely to not having EBF. Conclusions: Nutritional status, duration of BF, and EBF might be determined by household SES and maternal education. Therefore, these findings can be used to decide how to focus on appropriate target groups in family education planning to improve children's development to its most possible. PMID- 30450173 TI - Effects of Isokinetic versus Isotonic Training and its Cessation on Total Leukocytes and Lymphocytes Count in Adolescent State-level Weightlifters. AB - Background: The study investigated the effects of isokinetic versus isotonic training among adolescent state-level weightlifters in terms of total leukocytes, total lymphocytes, and its subsets following 24 sessions of training program and a month following training program cessation. Methods: Nineteen adolescent state level weightlifters were assigned into isokinetic or isotonic groups. All participants were recruited from a pool of weightlifters with standardized training program provided by their coach. Series of immunological tests were carried out before the commencement, immediately upon the completion, and a month after the cessation of the additional training program to evaluate total leukocytes and lymphocytes count. Results: The results revealed a significant time and group interaction and main effects of time on mean total leukocytes (P < 0.05). Mean total leukocytes count at posttest decreased in both groups. In isotonic group, it was further decreased following 1 month of training cessation (P < 0.05) but not in the isokinetic group. However, the decrement was not high and the values were in the normal range. No significant time and group interaction was observed in total lymphocytes and its subsets count. Conclusions: Eight weeks of isokinetic and isotonic additional training with emphasis on shoulder joint only affect mean total leukocytes count in state-level adolescent weightlifters. PMID- 30450174 TI - The Relationship between Health Literacy and Stages of Change in Smoking Behavior among Employees of Educational Health Centers of Tabriz University of Medical Sciences (2016). AB - Background: Health literacy has been considered as a predictor of starting, maintaining, and stop smoking. However, such relations have not been well documented in previous texts. Therefore, the purpose of this study was to investigate the relation between health literacy and changes in the behavior of smoking in Tabriz University of Medical Sciences. Methods: In this correlational descriptive study, a total of 297 employees of Tabriz health centers were examined. To collect data, a demographic-social questionnaire, Iranian Health Literacy Questionnaire, and DiClemente's behavior change questionnaire were used. Besides, SPSS 13 software (significance level = 0.05) was employed to analyze the data. Results: The average health literacy rate of participants was 70, and most respondents had adequate health literacy. Nearly 41.1% were in the precontemplation phase which is one of the stages of behavior change. There was a positive and significant statistical relation between behavior change variable with all health literacy areas (except the scope of understanding) and total health literacy score (P = 0.011 and r = 0.147). The results of ordinal regression analysis demonstrated that there is a significant positive relationship between the score of health literacy and behavioral change (b = 0.019, 95% confidence interval = (0.010-0.029), P < 0.001). Conclusions: Improving the level of health literacy can lead to change people's behavior in relation to tobacco consumption. However, due to the lack of relevant texts, there is a need for further studies in this field. PMID- 30450177 TI - Death Outcome with Successful Treatment of Tuberculosis Patients. PMID- 30450175 TI - Preventive Effect of Hydroalcoholic Extract of Rosa damascena on Cardiovascular Parameters in Acute Hypertensive Rats Induced by Angiotensin II. AB - Background: Rosa damascena (R.D) is an aromatic plant with numerous therapeutic effects including cardiovascular effect. The mechanism cardiovascular effect of R.D is unclear and suggested mediated through renin-angiotensin system (RAS). Therefore, in this study, the role of hydroalcoholic extract of R.D on acute hypertension induced by AngII was evaluated. Methods: After anesthesia, femoral artery and vein of rats were cannulated for recording cardiovascular responses and drug injection, respectively. Systolic blood pressure (SBP), mean arterial blood pressure (MAP), and heart rate (HR) were recorded continuously by power lab software. Rats were divided into saline, AngII (50 ng/kg), AngII + Losartan (10 mg/kg), and three groups of R.D extract (250, 500, and 1000 mg/kg). Losartan and AngII were administered intravenously and the other ones intraperitoneal. In the R.D groups, 30 min after injection of the extract, AngII was injected and the maximum changes in SBP, MAP, and HR were calculated and compared to that in control and AngII groups. Results: Results show that AngII significantly increased SBP, MAP, and decreased HR than the control group which was blocked by losartan. SBP and MAP in R.D + AngII groups were significantly lower than AngII alone (P < 0.05 -P < 0.001). Only MAP in higher dose (1000 mg/kg) was significantly lower than low dose (250 mg/kg; P < 0.05). Two higher doses also significantly decreased bradycardia induced by AngII (P < 0. 01). Conclusions: The preventive effect of hydroalcoholic extract of R.D on cardiovascular parameters maybe is mediated by suppression of AngII activity. PMID- 30450176 TI - Oropharyngeal Irrigation to Prevent Ventilator-Associated-Pneumonia: Comparing Potassium Permangenate with Chlorhexidine. AB - Background: Pneumonia is one of the most common hospital-acquired infections among bedridden patients in Intensive Care Units (ICUs). Colonization of mouth and pharynx by pathogenic bacteria and their aspiration into the lower respiratory tract is an important step in pathogenesis of hospital-acquired pneumonia. The purpose of this study was to compare the effects of chlorhexidine and potassium permanganate mouthwashes in preventing incidence of hospital acquired pneumonia in hospitalized patients in the ICU. Methods: This study is a clinical trial, conducted on 150 patients on ventilator in ICU. Patients were divided into three groups: Chlorhexidine group, potassium permanganate group, and control group. Mouthwashing three times a day, each time 5 min for 1 week by sterile gas with 10 cc solution of chlorhexidine, potassium permanganate, or placebo, was performed. Finally, pneumonia incidence was recorded, according to the Center for Disease Control and Prevention criteria. The data were analyzed by SPSS software version 20. Results: In the present study, 28 cases of pneumonia among 150 patients on ventilator were investigated. There were 15 (30%), 6 (12%), and 7 (14%) incidences of pneumonia in control, chlorhexidine, and permanganate group, respectively. Pneumonia incidence in these groups differed significantly (P = 0.041). Conclusions: The use of common mouthwashes, especially chlorhexidine solution, for washing oropharynx of ICU patients, can decrease pneumonia incidence, especially in patients under ventilation. Thus, washing and sterilizing mouth of patients with mouthwashes is recommended due to the high risk of hospital-acquired pneumonia in these patients. PMID- 30450178 TI - Health-Promoting Lifestyle among People Without Heart Disease in Isfahan. AB - Background: The present research conducted with aim to determine the health promoting behaviors (HPBs) of public of Isfahan, and study the associations of HPBs with demographic characteristics. Methods: In a cross-sectional study conducted on 369 people without heart disease living in Isfahan, HPBs were assessed using a questionnaire which consists of two parts: personal information and Health-Promoting Lifestyle Profile II (HPLP-II). Data were analyzed by t-test and one-way analysis of variance. Results: The mean score for overall HPLP-II (158.30 +/- 19.38) indicated the acceptable level of performing HPBs in Isfahan. Physical activity got the lowest score (16.36 +/- 5.13), and the highest score was for interpersonal relations (53.16 +/- 5.59). There were significant differences on physical activity and interpersonal relation dimensions between males and females (P < 0.05). The mean score of physical activity was highest in single participants (P < 0.05). Mean score of physical activity for people with college education was greater than others (P < 0.05). Overall HPLP-II and its domains mean scores for people that received education about prevention of cardiovascular disease were greater than others (P < 0.05). Conclusions: Results showed HPBs in people of Isfahan society is acceptable but physical activity is in the worst condition. The role of physical activity in preventing and controlling cardiovascular disease is well established. Therefore, it seems that providing information about physical activity can lead to an improvement of health-promoting lifestyle. PMID- 30450179 TI - A cyclic peptide inhibitor of C-terminal binding protein dimerization links metabolism with mitotic fidelity in breast cancer cells. AB - Identification of direct modulators of transcription factor protein-protein interactions is a key challenge for ligand discovery that promises to significantly advance current approaches to cancer therapy. Here, we report an inhibitor of NADH-dependent dimerization of the C-terminal binding protein (CtBP) transcriptional repressor, identified by screening genetically encoded cyclic peptide libraries of up to 64 million members. CtBP dimers form the core of transcription complexes associated with epigenetic regulation of multiple genes that control many characteristics of cancer cells, including proliferation, survival and migration. CtBP monomers also have distinct and critical cellular function, thus current experimental tools that deplete all forms of a targeted protein (e.g. siRNA) do not allow the cellular consequences of this metabolically regulated transcription factor to be deciphered. The most potent inhibitor from our screen (cyclo-SGWTVVRMY) is demonstrated to disrupt CtBP dimerization in vitro and in cells. This compound is used as a chemical tool to establish that the NADH-dependent dimerization of CtBPs regulates the maintenance of mitotic fidelity in cancer cells. Treatment of highly glycolytic breast cancer cell lines with the identified inhibitor significantly reduced their mitotic fidelity, proliferation and colony forming potential, whereas the compound does not affect mitotic fidelity of cells with lower glycolytic flux. This work not only links the altered metabolic state of transformed cells to a key determinant of the tumor cell phenotype, but the uncovered compound also serves as the starting point for the development of potential therapeutic agents that target tumors by disrupting the CtBP chromatin-modifying complex. PMID- 30450180 TI - Dynamics of the excited-state hydrogen transfer in a (dG).(dC) homopolymer: intrinsic photostability of DNA. AB - The intrinsic photostability of nucleic acids is intimately related to evolution of life, while its understanding at the molecular and electronic levels remains a challenge for modern science. Among the different decay pathways proposed in the last two decades, the excited-state hydrogen transfer between guanine-cytosine base pairs has been identified as an efficient non-reactive channel to dissipate the excess of energy provided by light absorption. The present work studies the dynamics of such phenomena taking place in a (dG).(dC) B-DNA homopolymer in water solution using state-of-the-art molecular modelling and simulation methods. A dynamic effect that boosts the photostability of the inter-strand hydrogen atom transfers, inherent to the Watson-Crick base pairing, is unveiled and ascribed to the energy released during the proton transfer step. Our results also reveal a novel mechanism of DNA decay named four proton transfer (FPT), in which two protons of two adjacent G-C base pairs are transferred to form a biradical zwitterionic intermediate. Decay of the latter intermediate to the ground state triggers the transfer of the protons back to the guanine molecules recovering the Watson-Crick structure of the tetramer. This FPT process is activated by the close interaction of a nearby Na+ counterion with the oxygen atoms of the guanine nucleobases and hence represents a photostable channel operative in natural nucleic acids. PMID- 30450181 TI - Cu2+ selective chelators relieve copper-induced oxidative stress in vivo. AB - Copper ions are essential for biological function yet are severely detrimental when present in excess. At the molecular level, copper ions catalyze the production of hydroxyl radicals that can irreversibly alter essential bio molecules. Hence, selective copper chelators that can remove excess copper ions and alleviate oxidative stress will help assuage copper-overload diseases. However, most currently available chelators are non-specific leading to multiple undesirable side-effects. The challenge is to build chelators that can bind to copper ions with high affinity but leave the levels of essential metal ions unaltered. Here we report the design and development of redox-state selective Cu ion chelators that have 108 times higher conditional stability constants toward Cu2+ compared to both Cu+ and other biologically relevant metal ions. This unique selectivity allows the specific removal of Cu2+ ions that would be available only under pathophysiological metal overload and oxidative stress conditions and provides access to effective removal of the aberrant redox-cycling Cu ion pool without affecting the essential non-redox cycling Cu+ labile pool. We have shown that the chelators provide distinct protection against copper-induced oxidative stress in vitro and in live cells via selective Cu2+ ion chelation. Notably, the chelators afford significant reduction in Cu-induced oxidative damage in Atp7a-/- Menkes disease model cells that have endogenously high levels of Cu ions. Finally, in vivo testing of our chelators in a live zebrafish larval model demonstrate their protective properties against copper-induced oxidative stress. PMID- 30450182 TI - Reversible on-off switching of both spin crossover and single-molecule magnet behaviours via a crystal-to-crystal transformation. AB - The on-off switching of spin-crossover (SCO) and single-molecule magnetism (SMM) remains highly attractive, especially if it involves dynamic crystal-to-crystal transformation. Herein we report the first molecule, a mononuclear cobalt(ii) complex, that exhibits on-off switching between SCO and SMM reversibly during crystal-to-crystal transformation. Subtle structural transformation triggered by a simple dehydration-rehydration process induces significant geometrical changes of the CoII center and modification of the supramolecular interactions and switches its colour and magnetic properties (dark red/SCO-on/SMM-off <-> orange/SCO-off/SMM-on). This work suggests that modification of the weak supramolecular interactions could be very effective in achieving switchable materials involving both SCO and SMM properties. PMID- 30450183 TI - Transition metal-free direct dehydrogenative arylation of activated C(sp3)-H bonds: synthetic ambit and DFT reactivity predictions. AB - A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp3)-H bonds has been developed. This operationally simple and environmentally friendly aerobic arylation uses tert-BuOK as the base and nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of alpha-arylated esters, amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates containing a C(sp3)-H bond with a sufficiently low pK a value should readily undergo arylation. The DFT prediction was confirmed through experimental testing of nearly a dozen substrates containing activated C(sp3)-H bonds. This arylation method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers. PMID- 30450184 TI - Smart composite films of nanometric thickness based on copper-iodine coordination polymers. Toward sensors. AB - One-pot reactions between CuI and methyl or methyl 2-amino-isonicotinate give rise to the formation of two coordination polymers (CPs) based on double zig-zag Cu2I2 chains. The presence of a NH2 group in the isonicotinate ligand produces different supramolecular interactions affecting the Cu-Cu distances and symmetry of the Cu2I2 chains. These structural variations significantly modulate their physical properties. Thus, both CPs are semiconductors and also show reversible thermo/mechanoluminescence. X-ray diffraction studies carried out under different temperature and pressure conditions in combination with theoretical calculations have been used to rationalize the multi-stimuli-responsive properties. Importantly, a bottom-up procedure based on fast precipitation leads to nanofibers of both CPs. The dimensions of these nanofibres enable the preparation of thermo/mechanochromic film composites with polyvinylidene difluoride. These films are tens of nanometers in thickness while being centimeters in length, representing smaller thicknesses so far reported for thin-film composites. This nanomaterial integration of CPs could represent a source of alternative nanomaterials for opto-electronic device fabrication. PMID- 30450186 TI - Writing and erasing multicolored information in diarylethene-based supramolecular gels. AB - A facile cocktail approach implying the mixing of diarylethene (DAE) photoswitches and low molecular weight gelators (LMWG) is presented. The photoresponsive gels exhibit multicolored emission that can be precisely controlled by different light exposure schemes (wavelength and dose), applicable for fluorescence patterning/writing. Including also a blue-emitting fluorophore allows for tri-chromatic color tuning of the emission via multistep energy transfer reactions, which in turn yields a non-linear response between the emission spectra and the light dose. This feature is highly desired in data security and anti-counterfeiting contexts. The information written in the gels can be conveniently erased by light, mass diffusion, or shaking; the latter being due to the thixotropic properties of the gels. PMID- 30450185 TI - The special role of B(C6F5)3 in the single electron reduction of quinones by radicals. AB - In the presence of two molar equiv. of B(C6F5)3 p-benzoquinone reacts with persistent radicals TEMPO, trityl or decamethylferrocene by single electron transfer to give doubly O-borylated benzosemiquinone radical anions with TEMPO+, trityl or ferrocenium counter cations. All three [(C6F5)3B]2-semiquinone radical anion salts were characterized by X-ray diffraction. The addition of donor reagent THF or DMSO induced rapid back electron transfer, in the case of the [(C6F5)3B]2-semiquinone radical anion oxoammonium salt giving rise to the formation of the (C6F5)3B-DMSO (or THF) Lewis adduct, p-benzoquinone and the TEMPO radical. The reaction of 9,10-anthraquinone or acenaphthenequinone with either the Gomberg dimer or in 1 : 1 stoichiometry in the presence of two molar equiv. of B(C6F5)3 gave the respective two-fold O-B(C6F5)3 containing 9,10 anthrasemiquinone or acenaphthene-semiquinone radical anion salts with either Ph3C+ or counter cations. These products were also characterized by X-ray diffraction. The salts showed analogous back electron shuttling behavior upon treatment with DMSO. 9,10-Phenanthrenequinone reacted analogously with B(C6F5)3 and the electron rich ferrocene. The [(C6F5)3B]2-9,10-phenanthrene-semiquinone salt was characterized by X-ray diffraction. The radical anions were characterized by ESR spectroscopy. PMID- 30450189 TI - Awareness, adoption and implementation of the water safety plan methodology: insights from five Latin American and Caribbean experiences. AB - Considerable effort has been made worldwide to disseminate information and provide technical assistance to encourage the adoption and implementation of the water safety plan (WSP) methodology. Described since the third edition of the World Health Organization (WHO) Guidelines for Drinking-water Quality, a WSP provides guidance for water utilities to ensure the delivery of safe drinking water and protect health. Attention is now being given to understand the success of efforts to advance adoption of the WSP methodology in the Latin America and Caribbean (LAC) region. More specifically, there is interest in knowing how early adopters developed strategies to implement the WSP methodology and what challenges exist for further implementation. To better understand adoption and implementation trends, key informants from five LAC countries were interviewed and case studies were developed to reveal the diversity of WSP approaches applied in the region. Results indicate that WSP implementation is more widespread than previously reported. Respondents affirmed that the WHO Guidelines for Drinking water Quality are routinely used as a model for country-level drinking-water regulations, which has led to uptake of the WSP methodology. Interview respondents also revealed innovative national strategic approaches for WSP implementation. PMID- 30450188 TI - Equine lung decellularization: a potential approach for in vitro modeling the role of the extracellular matrix in asthma. AB - Contrary to conventional research animals, horses naturally develop asthma, a disease in which the extracellular matrix of the lung plays a significant role. Hence, the horse lung extracellular matrix appears to be an ideal candidate model for in vitro studying the mechanisms and potential treatments for asthma. However, so far, such model to study cell-extracellular matrix interactions in asthma has not been developed. The aim of this study was to establish a protocol for equine lung decellularization that maintains the architecture of the extracellular matrix and could be used in the future as an in vitro model for therapeutic treatment in asthma. For this the equine lungs were decellularized by sodium dodecyl sulfate detergent perfusion at constant gravitational pressure of 30 cmH2O. Lung scaffolds were assessed by immunohistochemistry (collagen I, III, IV, laminin, and fibronectin), scanning electron microscopy, and DNA quantification. Their mechanical property was assessed by measuring lung compliance using the super-syringe technique. The optimized protocol of lung equine decellularization was effective to remove cells (19.8 ng/mg) and to preserve collagen I, III, IV, laminin, and fibronectin. Moreover, scanning electron microscopy analysis demonstrated maintained microscopic lung structures. The decellularized lungs presented lower compliance compared to native lung. In conclusion we described a reproducible decellularization protocol that can produce an acellular equine lung feasible for the future development of novel treatment strategies in asthma. PMID- 30450187 TI - The role of extracellular vesicles in biomineralisation: current perspective and application in regenerative medicine. AB - Extracellular vesicles comprise a heterogenous population of exosomes and microvesicles that have critical roles in intercellular signalling and tissue development. These complex particles have been implicated as mediators of the therapeutic effects of stem cells via the transfer of an assorted cargo of proteins and nucleic acids, which can modulate inflammation and enhance endogenous regeneration in a range of tissues. In addition, extracellular vesicles have the capacity to be loaded with therapeutic molecules for targeted delivery of pharmaceuticals. The versatility, biostability and biocompatibility of extracellular vesicles make them appealing for regenerative medicine and may endow considerable advantages over single molecule approaches. Furthermore, since production can be optimised and assessed ex vivo, extracellular vesicles present a decreased risk of neoplastic transformation when compared with cell-based methods. To date, the contribution of vesicles to tissue development has perhaps been most comprehensively defined within hard tissues, such as endochondral bone, where they were first identified in 1969 and henceforth referred to as matrix vesicles. Within developing bone, vesicles function as vehicles for the delivery of pro-osteogenic factors and initiate early nucleational events necessary for matrix mineralisation. However, advancement in our understanding of the biogenesis and characterisation of matrix vesicles has occurred largely in parallel to associated developments in wider extracellular vesicle biology. As such, there is a requirement to align current understanding of matrix vesicle mediated mineralisation within the context of an evolving literature surrounding exosomes and microvesicles. In this review, we present an overview of current progress and opinion surrounding the application of vesicles in regenerative medicine with a primary focus on their potential as an acellular approach for enhancing hard tissue regeneration. This is balanced with an assessment of areas where further development is required to maximise their application for regenerative medicine. PMID- 30450190 TI - CITED1 promotes proliferation of papillary thyroid cancer cells via the regulation of p21 and p27. AB - Background: It has been reported that CBP/p300-Interacting Transactivator with glutamic acid [E]/aspartic acid [D]-rich C-terminal domain 1 (CITED1) is overexpressed in papillary thyroid cancer (PTC). However, the functional significance and underlying mechanisms of CITED1 in PTC are largely unknown. Methods: The Cancer Genome Atlas dataset and real-time PCR were used to determine the expression of CITED1 in PTC. The role of CITED1 in PTC cell proliferation was determined conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and flow cytometry assays in vitro, and a subcutaneous xenotransplantation tumor model in nude mice was established to analyze tumor growth in vivo. We studied the potential mechanisms underlying the contribution of CITED1 to PTC proliferation using western blotting and luciferase assays. Results: We found that CITED1 was highly expressed in PTC. In vitro and in vivo experiments demonstrated that CITED1 was involved in PTC cell proliferation and tumorigenesis. Then, gain- and loss-of-function experiments revealed that CITED1 decreased the expression of p21 and p27, and thereby increased the phosphorylation of pRb as well as E2F1 transcriptional activity. Conclusions: Our results suggest that CITED1 is overexpressed in PTC and that CITED1 promotes the proliferation of PTC cells via the regulation of p21 and p27, which indicates that CITED1 might be a potential therapeutic target in the treatment of PTC. PMID- 30450191 TI - Post-infectious ankylosis of the cervical spine in an army veteran: a case report. AB - Background: Vertebral osteomyelitis is a rare, life-threatening condition. Successful management is dependent on prompt diagnosis and management with intravenous antibiotic therapy or surgery in addition to antibiotics. Reoccurrence is minimal after 1 year. However, very little is reported in the conservative spine literature regarding the long-term follow-up and the changes to the spine following management of the spinal infection. We report the dramatic radiologic findings of the long-term sequela of a cervical spine infection following a gunshot wound from 1969. Most impressive to the spine specialist is this patient's ability to return to work despite significant alterations to spinal biomechanics. Case presentation: A 69 year-old caucasian male presented to the chiropractic clinic at a Veterans Affairs Medical Center with complaint of chronic left shoulder pain secondary to an associated full thickness tear of the left infraspinatus. An associated regional assessment of the cervical spine ensued. Radiological imaging on file revealed ankylosis C2/C3 to C7/T1. The patient reported a history of multiple fragment wounds in 1969 to the left anterior neck and shoulder 45 years earlier. Osteomyelitis of the cervical spine resulted from the wounds. Conclusion: Potential sequela of osteomyelitis is ankylosis of affected joints. In this particular case, imaging provides evidence of regional ankylosis of the cervical spine. Considering the patient did not complain of cervical pain or related symptoms apart from lack of cervical range of motion, and his Neck Disability Index score was 2 out of 50 (4%), no intervention was provided to the cervical spine. The patient reported he self managed well, worked full-time as a postal worker after he was discharged due to the injury to his neck, and planned to retire in less than one month at age 70. The patient demonstrates successful return to work with pending retirement at age 70 following spondylodiscitis and subsequent ankylosis of the cervical region. PMID- 30450192 TI - Development of superficial lung lesions monitored on farm by serial ultrasonographic examination in sheep with lesions confirmed as ovine pulmonary adenocarcinoma at necropsy. AB - Background: This ultrasonographic study monitored lesions involving the lung surface suspected to be the early stages of ovine pulmonary adenocarcinoma (OPA) tumours over 4 months in commercially farmed sheep. The enlargement of these lesions defined ultrasonographically, which likely represent the development of OPA tumours, have important implications for ultrasound screening schedules in veterinary management plans attempting to eliminate OPA by test-and-cull. Results: The lungs of 58 adult Scottish Blackface sheep with ultrasonographic changes at the lung surface consistent with early OPA tumours were examined two to six times over 40 to 290 days. Lesion development, represented in early video recordings by 2-3 mm lesions involving the visceral pleural and comet tails, then a decreasing length of the hyperechoic line representing the normal visceral pleura and increasing depth of the sharply-demarcated and largely uniform hypoechoic areas into the lung parenchyma, was found in 26 of the 58 sheep. The rate at which the sonographic lesions progressed varied considerably and in 10 of 17 Group 1 sheep developed quickly from an estimated depth of 2-30 mm up to 70 mm between 60 and 120 days later. These sonographic lesions were confirmed as OPA at necropsy; histological changes of concurrent bacterial infection were detected in one of these 10 Group 1 sheep. Thirty-one sheep had sonographic changes <=30 mm consistent with very early OPA at the first examination which had reduced or were not observed at subsequent examination. Five of these 31 sheep were necropsied, 3 had small OPA lesions while 2 had no significant pathology. Conclusion: Lesions involving the visceral pleura, with sonographic changes consistent with previous published findings of early OPA, developed over 40-120 days to large masses in 10 of 17 Group 1 sheep with the provisional sonographic diagnosis confirmed histologically at necropsy. While it is possible that atalectic lung could have caused some of the minor sonographic changes there was no microscopic evidence of pathologies other than OPA in nine of 10 Group 1 sheep. We conclude that some small tumours progress to large tumours within 3 months questioning the assumption that OPA is a slow growing tumour in adult sheep taking several years to cause clinical disease. The findings that a proportion of small ultrasonographic lesions are not found again at subsequent scanning illustrates the challenges of interpreting small (< 1-2 cm) lesions during rapid whole flock ultrasonographic examination and we continue to recommend re-scanning suspicious sonographic changes 2 months later. PMID- 30450193 TI - Making progress in a rare disease: emerging therapeutics in soft tissue sarcomas. AB - Sarcomas are rare tumors derived from mesenchymal connective tissues in the body. Because there are well over 50 histologic sarcoma subtypes, including malignant and non-malignant pathologies, clinical courses and therapeutic management are widely divergent. In general, therapeutic options across all soft tissue sarcomas are limited in number and are often generalized across multiple sarcoma histologies. The recent emergence of molecularly targeted therapies and immune based agents presents a future of refined systemic treatment practices that are rationally tailored to the tumor by histologic subtype and biologic mechanisms. PMID- 30450194 TI - Large-scale protein function prediction using heterogeneous ensembles. AB - Heterogeneous ensembles are an effective approach in scenarios where the ideal data type and/or individual predictor are unclear for a given problem. These ensembles have shown promise for protein function prediction (PFP), but their ability to improve PFP at a large scale is unclear. The overall goal of this study is to critically assess this ability of a variety of heterogeneous ensemble methods across a multitude of functional terms, proteins and organisms. Our results show that these methods, especially Stacking using Logistic Regression, indeed produce more accurate predictions for a variety of Gene Ontology terms differing in size and specificity. To enable the application of these methods to other related problems, we have publicly shared the HPC-enabled code underlying this work as LargeGOPred ( https://github.com/GauravPandeyLab/LargeGOPred). PMID- 30430004 TI - Crystal structures of a llama VHH antibody BCD090-M2 targeting human ErbB3 receptor. AB - Background: The ability of ErbB3 receptor to functionally complement ErbB1-2 and induce tumor resistance to their inhibitors makes it a unique target in cancer therapy by monoclonal antibodies. Here we report the expression, purification and structural analysis of a new anti-ErbB3 single-chain antibody. Methods: The VHH fragment of the antibody was expressed in E. coli SHuffle cells as a SUMO fusion, cleaved by TEV protease and purified to homogeneity. Binding to the extracellular domain of ErbB3 was studied by surface plasmon resonance. For structural studies, the antibody was crystallized by hanging-drop vapor diffusion in two different forms. Results: We developed a robust and efficient system for recombinant expression of single-domain antibodies. The purified antibody was functional and bound ErbB3 with K D =15+/-1 nM. The crystal structures of the VHH antibody in space groups C2 and P1 were solved by molecular replacement at 1.6 and 1.9 A resolution. The high-quality electron density maps allowed us to build precise atomic models of the antibody and the putative paratope. Surprisingly, the CDR H2 existed in multiple distant conformations in different crystal forms, while the more complex CDR H3 had a low structural variability. The structures were deposited under PDB entry codes 6EZW and 6F0D. Conclusions: Our results may facilitate further mechanistic studies of ErbB3 inhibition by single-chain antibodies. Besides, the solved structures will contribute to datasets required to develop new computational methods for antibody modeling and design. PMID- 30430005 TI - shinySISPA: A web tool for defining sample groups using gene sets from multiple omics data. AB - As opposed to genome-wide testing of several hundreds of thousands of genes on very few samples, gene panels target as few as tens of genes and enable the simultaneous testing of many samples. For example, some cancer gene panels test for 50 genes that can affect tumor growth and potentially identify treatment options directed against the genetic mutation. The increasing popularity of gene panel testing has spurred the technological development of panels that test for diverse data types such as expression and mutation. Once samples are tested, there is the desire to examine clinical associations based on the panel and for this purpose, one would like to identify, among the samples tested, which show support for a molecular profile (e.g., presence of mutation with increased expression) versus those samples that do not among the genes tested. With user specified molecular profile of interest, and gene panel data matrices (e.g., gene expression, variants, etc.) that define the profile, shinySISPA (Sample Integrated Set Profile Analysis) is a web-based shiny tool to define two sample groups with and without profile support based on our previously published method from which clinical associations may be readily examined. The shinySISPA can be accessed from http://shinygispa.winship.emory.edu/shinySISPA/. PMID- 30430006 TI - Enterobacter hormaechei subsp. hoffmannii subsp. nov., Enterobacter hormaechei subsp. xiangfangensis comb. nov., Enterobacter roggenkampii sp. nov., and Enterobacter muelleri is a later heterotypic synonym of Enterobacter asburiae based on computational analysis of sequenced Enterobacter genomes. AB - Background: The predominant species in clinical Enterobacter isolates is E. hormaechei. Many articles, clinicians, and GenBank submissions misname these strains as E. cloacae. The lack of sequenced type strains or named species/subspecies for some clades in the E. cloacae complex complicate the issue. Methods: The genomes of the type strains for Enterobacter hormaechei subsp. oharae, E. hormaechei subsp. steigerwaltii, and E. xiangfangensis, and two strains from Hoffmann clusters III and IV of the E. cloacae complex were sequenced. These genomes, the E. hormaechei subsp. hormaechei type strain, and other available Enterobacter type strains were analysed in conjunction with all extant Enterobacter genomes in NCBI's RefSeq using Average Nucleotide Identity (ANI). Results: There were five recognizable subspecies of E. hormaechei: E. hormaechei subsp. hoffmannii subsp. nov., E. hormaechei subsp. xiangfangensis comb. nov., and the three previously known subspecies. One of the strains sequenced from the E. cloacae complex was not a novel E. hormaechei subspecies but rather a member of a clade of a novel species: E. roggenkampii sp. nov.. E. muelleri was determined to be a later heterotypic synonym of E. asburiae which should take precedence. Conclusion: The phylogeny of the Enterobacter genus, particularly the cloacae complex, was re-evaluated based on the type strain genome sequences and all other available Enterobacter genomes in RefSeq. PMID- 30450199 TI - Could differences in implicit attitudes to sexual concurrency play a role in generalized HIV epidemics? AB - Background: Sexual partner concurrency has been implicated in the genesis of generalized HIV epidemic in South Africa. Most South Africans, however, disapprove of concurrency in surveys. These surveys test individuals' explicit attitudes which are susceptible to a number of important biases such as the social desirability bias. Assessment of implicit cognitions have been found to be better predictors of behaviour in socially sensitive domains. We hypothesized that South Africans may have implicit attitudes more tolerant of concurrency than lower concurrency prevalence populations. Methods: To test this hypothesis, we developed a concurrency-implicit association test (C-IAT) and compared the C-IATs of samples of South African and Belgian university students. Results: We found a large and statistically significant difference in the C-IAT between the South Africans (D600-score = -0.009, indicating absence of preference for concurrency or monogamy) and Belgians (D600-score = 0.783, indicating a strong preference for monogamy; t-test = 13.3; P < 0.0001). The effect size measure, Cohen's d, was found to be 0.88, which is considered a large effect size in this field. Conclusions: Our results are compatible with the thesis that differences in implicit attitudes to concurrency play a role in the genesis of generalised HIV epidemics. PMID- 30443344 TI - Association between intensity of STI screening and development of antimicrobial resistance in N. gonorrhoeae in 12 cities in the USA: An ecological study. AB - In this study, we assessed if there was a city-level association between sexually transmitted infection (STI) screening intensity in men who have sex with men and antimicrobial sensitivity in Neisseria gonorrhoeae in the United States, 2007 to 2013. We found positive associations between STI screening intensity and increases in minimum inhibitory concentrations for cefixime and azithromycin, but not ceftriaxone. PMID- 30450201 TI - Relationship between Candida albicans and Streptococcus mutans in early childhood caries, evaluated by quantitative PCR. AB - Background: The aim of this study was to analyze the synergistic relationship between Candida albicans and Streptococcus mutans in children with early childhood caries (ECC) experience. Methods: Dental plaque and unstimulated saliva samples were taken from 30 subjects aged 3-5 years old, half with (n=15, dmft > 4) and half without (n=15) ECC. The abundance of C. albicans and S. mutans and relative to total bacteria load were quantify by real-time PCR (qPCR). This method was also employed to investigate the mRNA expression of glycosyltransferase ( gtfB) gene in dental plaque. Student's t-test and Pearson's correlation were used to perform statistical analysis. Results: Within the ECC group, the quantity of both microorganisms were higher in the saliva than in dental plaque. The ratio of C. albicans to total bacteria was higher in saliva than in plaque samples (p < 0.05). We observed the opposite for S. mutans (p < 0.05). The different value of C. albicans and S. mutans in saliva was positively correlated, and negatively correlated in dental plaque. Transcription level of S. mutans gtfB showed a positive correlation with C. albicans concentration in dental plaque. Conclusion: C. albicans has a positive correlation with cariogenic traits of S. mutans in ECC-related biofilm of young children. PMID- 30450195 TI - Does cardiac development provide heart research with novel therapeutic approaches? AB - Embryonic heart progenitors arise at specific spatiotemporal periods that contribute to the formation of distinct cardiac structures. In mammals, the embryonic and fetal heart is hypoxic by comparison to the adult heart. In parallel, the cellular metabolism of the cardiac tissue, including progenitors, undergoes a glycolytic to oxidative switch that contributes to cardiac maturation. While oxidative metabolism is energy efficient, the glycolytic hypoxic state may serve to maintain cardiac progenitor potential. Consistent with this proposal, the adult epicardium has been shown to contain a reservoir of quiescent cardiac progenitors that are activated in response to heart injury and are hypoxic by comparison to adjacent cardiac tissues. In this review, we discuss the development and potential of the adult epicardium and how this knowledge may provide future therapeutic approaches for cardiac repair. PMID- 30450202 TI - Surgical management of metastatic lesions of proximal femur and the hip. AB - Metastatic bony lesions involving proximal femur and hip joint pose a challenge to orthopedic surgeons. Lesions in this important weight-bearing zone of the femur weaken its ability to sustain load causing pain and impending pathologic fracture. These Patients warrant multidisciplinary approach including orthopedic surgeons, oncologist and medical specialties. Management of these lesions has evolved over the last 60 years from benign neglect to internal fixation and recently to prosthetic reconstruction for optimum function. Decision for surgical approach requires consideration for location of the lesion, presence of a fracture, tumor type, cortical destruction, patient's life expectancy, patient preferences and the expected outcome. We aim to present a narrative review of the options and results of surgical management of these lesions in the light of literature. PMID- 30450203 TI - The use of a portable ultrasound system in the surgical assessment of rib fractures in an elderly patient. AB - Introduction: Portable ultrasound is a modality of medical ultrasonography that utilizes small and light devices, and is an established diagnostic method used in clinical settings such as Cardiology, Vascular Surgery, Radiology, Endocrinology, Pediatric and Obstetric & Gynecology. Presentation of cases: We present a case report of 86-years old patient who underwent surgical rib fixation for multiple rib fractures followed by falling from standing height and our management experience. Discussion: The use of portable ultrasound device in operation theatre demonstrates several advantages.We believe that Portable color doppler ultrasound system would be necessary in the management of rib fracture. Conclusion: This study demonstrates that the portable ultrasound system is a valuable method of imaging in the assessment of rib fractures, and which can save time, economically affordable for many patients, and allow surgeons to make a minor incision in order to avoid complications such as infection, particularly in this group of vulnerable patients. PMID- 30450205 TI - Correction to: Residual feed intake phenotype and gender affect the expression of key genes of the lipogenesis pathway in subcutaneous adipose tissue of beef cattle. AB - [This corrects the article DOI: 10.1186/s40104-018-0282-9.]. PMID- 30450204 TI - Hepatic echinococcosis: A review. AB - Cystic echinococcosis (CE) is a widely endemic helminthic disease caused by infection with metacestodes (larval stage) of the Echinococcus granulosus tapeworm and transmitted by dogs. E. granulosus are common parasites in certain parts of the world, and are present on every continent with the exception of Antarctica. As a result, a large number of people are affected by CE. In humans, the disease is characterized by slowly growing cyst commonly occurring in liver and lungs. Clinical features are mainly right upper quadrant pain, feeling of lump and enlarged tender liver. The cyst may be complicated by infection or rupture and may lead to anaphylactic reaction. The diagnosis depends on clinical suspicion. They appear in two ways as general (systemic) symptoms, and local symptoms based on the site and organ on which the larva settles. While cysts sometimes recover spontaneously, more severe clinical presentations are observed in immunosuppressed individuals. Ultrasonography supported by serology is the main diagnostic modality. The treatment varies from surgical intervention to minimally invasive treatments (percutaneous drainage) or medical therapies. Surgery is still the best treatment modality. Percutaneous drainage of the cyst is a good option in selected cases. New sensitive and specific diagnostic methods and effective therapeutic approaches against echinococcosis have been developed in the last 10 years. PMID- 30450206 TI - The revised short-form of the Eating Beliefs Questionnaire: Measuring positive, negative, and permissive beliefs about binge eating. AB - Background: The Eating Beliefs Questionnaire (EBQ) is a self-report assessment tool that measures positive and negative beliefs about food and eating that are believed to play a key role in maintaining binge eating behaviour that occurs in individuals with Bulimia Nervosa, Binge Eating Disorder and other atypical eating disorders. The present study aimed to further refine this measure with the addition of a third scale to assess permissive beliefs about eating, also thought to play a crucial role in the maintenance of binge eating. Permissive beliefs are defined as beliefs about eating that provide justification for the individual to engage in a binge eating episode. Methods: After consultation with the literature and endorsement from 10 experts in eating disorders, 19 permissive belief items were generated. Eight hundred eighty-three participants were recruited to complete a test battery online that included the EBQ and the new permissive items. Results: An exploratory factor analysis (n = 441) found a three-factor solution (positive, negative and permissive beliefs) explaining 63.4% of variance. A confirmatory factor analysis (n = 442) provided support for the three factor model, with the data best supporting a shorter 18-item questionnaire. The revised scale demonstrated good internal consistency, as well as good convergent validity with measures of related eating disorder symptoms, emotional regulation, mood and anxiety. Conclusions: With the addition of a third scale to measure permissive beliefs, the revised short-form of the EBQ offers clinicians and researchers a brief comprehensive tool for the measurement of positive, negative and permissive beliefs about binge eating. PMID- 30450207 TI - Selective extraction of supported Rh nanoparticles under mild, non-acidic conditions with carbon monoxide. AB - Owing to their limited supplies, recycling of precious metals, especially rhodium, is vital to sustain the growth of certain nanotechnologies. Here we report a mild, efficient, and selective method for rhodium recovery that relies on the use of carbon monoxide to extract rhodium nanoparticles on various supports in polar solvents. Unlike the traditional recycling technologies, this method operates at low temperature and does not require strong acids. Moreover, the CO-induced leaching is complimentary to leaching by acids in terms of selectivity toward rhodium versus other precious metals and results in metal recovery in the form of reduced metallic clusters. The method performs best on freshly reduced surfaces and can be promoted by the addition of tertiary amines. Besides CO gas, formic acid can also be used as a leachant by decomposition to produce CO by Rh catalysis. The concept of CO-induced leaching could be applied to the extraction of rhodium from nuclear waste and extended to modify rhodium nanoparticle size and composition. PMID- 30450208 TI - A highly hemocompatible erythrocyte membrane-coated ultrasmall selenium nanosystem for simultaneous cancer radiosensitization and precise antiangiogenesis. AB - Radiotherapy is a vitally important strategy for clinical treatment of malignant cancers. Therefore, rational design and development of radiosensitizers that could enhance radiotherapeutic efficacy has attracted tremendous attention. Antiangiogenesis therapy could be a potentially effective strategy to regulate tumor growth and metastasis due to angiogenesis plays a pivotal role for tumor growth, invasion and metastasis to other organs. Herein, we have rationally designed a smart and effective nanosystem by combining ultrasmall selenium nanoparticles and bevacizumab (AvastinTM, Av), for simultaneous radiotherapy and antiangiogenic therapy of cancer. The nanosystem was further coated with red blood cell (RBC) membranes to develop the final construct, RBCs@Se/Av. The RBC membrane coating effectively prolongs the blood circulation time and reduces the elimination of the nanosystem by autoimmune responses. As expected, RBCs@Se/Av, when irradiated with X-ray demonstrated potent anticancer and antiangiogenesis response in vitro and in vivo, as evidenced by strong inhibition of A375 tumor growth in nude mice, without causing any obvious histological damage to the non target major organs. Taken together, this study demonstrates an effective strategy for design of smart Se-based nanosystem decorated with RBC membrane for simultaneous cancer radiosensitization and precise antiangiogenesis. PMID- 30450209 TI - Overexpression and cytoplasmic localization of caspase-6 is associated with lamin A degradation in set of ovarian cancers. AB - Background: In most women with ovarian cancer, the diagnosis occurs after dissemination of tumor cells beyond ovaries. Several molecular perturbations occur ahead of tumor initiation including loss of lamin A/C. Our hypothesis was that the loss of nuclear structural proteins A type lamins (lamin A/C) transcribed from LMNA gene and substrate for active caspase-6 maybe one of the molecular perturbations. Our objective is to investigate the association between the loss of lamin A/C and the overexpression of caspase-6 in ovarian cancer cells. Method: Western blotting and immunofluorescence were used to analyze the expression of lamin A/C and active caspase-6 in normal human ovarian surface epithelial (HOSE) cells, immortalized human ovarian surface epithelial cells and a set of seven ovarian cancer cell lines (including OVCAR3, OVCAR5, and A2780). The activity of caspase-6 was measured by densitometry, fluorescence and flow cytometry. Immunohistochemistry was used to evaluate the expression of caspase-6 in set of ovarian cancer tissues previously reported to have lost lamin A/C. Results: The results showed that HOSE cells expressed lamin A/C and no or low level of active caspase-6 while cancer cells highly expressed caspase-6 and no or low level of lamin A/C. The inhibition of caspase-6 activity in OVCAR3 cells increased lamin A but has no effect on lamin C; active caspase-6 was localized in the cytoplasm associated with the loss of lamin A. Conclusion: Overexpression and cytoplasmic localization of caspase-6 in ovarian cancer cells may be involved in lamin A degradation and deficiency observed in some ovarian cancer cells. PMID- 30450210 TI - Heterogeneous expression of EPCAM in human circulating tumour cells from patient derived xenografts. AB - Background: We aim to characterize the heterogeneous circulating tumour cells (CTCs) in peripheral blood, independently of physical or immunological purification, by using patient-derived xenografts (PDXs) models. CTC studies from blood generally rely on enrichment or purification. Conversely, we devised a method for the inclusive study of human cells from blood of PDX models, without pre-selection or enrichment. Methods: A qRT-PCR assay was developed to detect human and cancer-related transcripts from CTCs in PDXs. We quantified the EPCAM and keratins CTC markers, in a PDX cohort of breast cancer. The murine beta actin gene was used for normalization. Spearman's rho coefficients were calculated for correlation. Results: We demonstrated, for the first time, that we can quantify the content of CTCs and the expression of human CTC markers in PDX blood using human-specific qRT-PCR. Our method holds strong potential for the study of CTC heterogeneity and for the identification of novel CTC markers. Conclusions: The identification and the relative quantification of the diverse spectrum of CTCs in patients, irrespective of EPCAM or other currently used markers, will have a great impact on personalized medicine: unrestricted CTCs characterization will allow the early detection of metastases in cancer patients and the assessment of personalized therapies. PMID- 30450211 TI - 3D mapping of nanoscale crosslink heterogeneities in microgels. AB - The majority of swollen polymer networks exhibit spatial variations in crosslink density. These spatial heterogeneities are particularly important in colloidal gel particles, or microgels, where they manifest themselves on the nanoscale and impact mechanical and transport properties. Despite their importance, the real space nanostructure of these heterogeneities at the individual particle level has remained elusive. Using state of the art super-resolution microscopy known as Whole cell 4Pi Single Molecule Switching Nanoscopy (W-4PiSMSN) we demonstrate 3D nanoscale mapping of spatial crosslink heterogeneities in a model system of poly(N-isopropylacrylamide) colloidal gel particles containing a novel fluorophore tagged crosslinker. We reveal the presence of higher crosslink density clusters embedded in a lower crosslink density matrix within the core of individual microgel particles, a phenomenon that has been predicted, but never been observed before in real space. The morphology of the clusters provides insight into the kinetics of microgel formation. This study also provides proof of-concept 3D super-resolution imaging of spatial heterogeneities in bulk hydrogels. PMID- 30450212 TI - Storage related haematological and biochemical changes in Plasmodium falciparum infected and sickle cell trait donor blood. AB - Background: In sub-Saharan Africa where sickle cell trait (SCT) and malaria is prevalent, significant proportions of blood donors may be affected by one or more of these abnormalities. The haemato-biochemical properties of SCT and asymptomatic malaria in donor blood have not been evaluated. This study evaluated the haemato-biochemical impact of SCT and asymptomatic malaria infections in citrate-phosphate-dextrose-adenine (CPDA-1) stored donor blood units. Methods: Fifty-milliliters of sterile CPDA-1 anti-coagulated blood were drained into the sample pouch attached to the main blood bag. Ten units each of sickle cell/malaria negative, sickle cell and malaria positive blood were analyzed. Baseline and weekly haematological profiling and week 1, 3 and 5 concentrations of plasma haemoglobin, % haemolysis, sodium, potassium and chloride and lactate dehydrogenase (LDH) were assayed. Differences between baseline and weekly data were determined using one-way analysis of variance (ANOVA) and Kruskal-Wallis test, whereas differences between baseline parameters and week 1-3 data pairs were determined using paired t-test. P-value < 0.05 was considered statistically significant. Results: Storage of SCT and malaria infected blood affected all haematological cell lines. In the SCT donors, red blood cells (RBC) (4.75 * 1012/L +/- 1.43baseline to 3.49 * 1012/L +/- 1.09week-5), haemoglobin (14.45 g/dl +/- 1.63baseline to 11.43 g/dl +/- 1.69week-5) and haematocrit (39.96% +/- 3.18baseline to 33.22% +/- 4.12week-5) were reduced. In the asymptomatic malaria group, reductions were observed in RBC (5.00 * 1012/L +/- 0.75baseline to 3.72 * 1012/L +/- 0.71week-5), haemoglobin (14.73 g/dl +/- 1.67baseline to 11.53 g/dl +/ 1.62week-5), haematocrit (42.72% +/- 5.16baseline to 33.38% +/- 5.80week-5), mean cell haemoglobin concentration (35.48 g/dl +/- 1.84baseline to 35.01 g/dl +/ 0.64week-5) and red cell distribution width coefficient of variation (14.81% +/- 1.54baseline to 16.26% +/- 1.37week-5). Biochemically, whereas plasma LDH levels significantly increased in asymptomatic malaria blood donors (319% increase at week 5 compared to baseline), SCT blood donors had the most significant increase in plasma potassium levels at week 5 (382% increase). Sodium ions significantly reduced in SCT/malaria negative and sickle cell trait blood at an average rate of 0.21 mmol/L per day. Moreover, elevations in lymphocytes-to-eosinophils and lymphocytes-to-neutrophils ratios were associated with SCT and malaria positive blood whilst elevation lymphocytes-to-basophils ratio was exclusive to malaria positive blood. Conclusion: Severe storage lesions were significant in SCT or malaria positive donor blood units. Proper clinical evaluation must be done in prospective blood donors to ensure deferral of such donors. PMID- 30450213 TI - Effects of high intensity interval training on exercise capacity in people with cystic fibrosis: study protocol for a randomised controlled trial. AB - Background: In people with cystic fibrosis (CF), higher exercise capacity is associated with better health-related quality of life (HRQoL), reduced risk of hospitalisation for a respiratory infection and survival. Therefore, optimisation of exercise capacity is an important treatment goal. The Australian and New Zealand clinical practice guidelines recommend that people with CF complete 30 to 60 min of moderate intensity aerobic exercise on most days of the week. This recommendation can be difficult to achieve by people with CF because of time constraints, and intolerable breathlessness and muscle fatigue during continuous exercise. In contrast, a low-volume, high intensity interval training (HIIT) program may be a more achievable and efficient training method to improve exercise capacity in people with CF. Methods: A randomised controlled trial will be undertaken. Forty people with CF (aged >=15 years) will be randomly allocated, on a 1:1 ratio, to either the experimental or control group. Regardless of their group allocation, all participants will be asked to continue with their usual daily treatment for the study duration. Those in the experimental group will complete 8 weeks of thrice weekly HIIT on a cycle ergometer. Those in the control group will receive weekly contact with the investigators. The primary outcome of this study is exercise capacity. Secondary outcomes are HRQoL, exercise self efficacy, feelings of anxiety, depression and enjoyment. These outcomes will be recorded at baseline (i.e. prior to randomisation) and following the 8-week intervention period. The study will also report other outcomes of the HIIT program (cardiovascular responses, symptom response, post-exercise muscle soreness and tolerance) and behaviour change techniques such as reinforcement, feedback and goal setting, used during the HIIT program. Discussion: This study will determine the effects of 8-weeks of supervised, low-volume HIIT, completed on a cycle ergometer on measures of exercise capacity, HRQoL, exercise self efficacy, feelings of anxiety, depression and enjoyment. If effective, this type of training could be an attractive alternative to traditional continuous training because it may be more achievable and time efficient. Trial registration: Australian and New Zealand Clinical Trials Registry (ANZCTR):12617001271392 (04/09/2017). PMID- 30450214 TI - Lived experiences of patients on hemodialytic treatment: A discursive perspective on fatigue and motivational issues. AB - Fatigue is an incapacitating symptom for patients on chronic hemodialysis treatment. This study explored the relationship between hemodialysis patients' subjective experience and motivation. The investigation of patients' narratives and fatigue-related factors was performed by holding semi-structured interviews with 31 hemodialysis patients. Fatigue Severity Scale and Behavioral Inhibition/Activation System questionnaire were used to assess fatigue severity and motivational mechanisms. Results showed significant differences in the use of specific topics and words (such as "family," "to manage," "dialysis," "psychological issues") depending on high, medium, and low Behavioral Inhibition System, Behavioral Activation System, and Fatigue Severity Scale scores, indicating that hemodialysis patients' narratives contain keywords related to the motivational sphere. PMID- 30450215 TI - The overlap of sense of coherence and the Big Five personality traits: A confirmatory study. AB - Sense of coherence is the perception of the world as coherent. Its conceptual similarities to the Big Five personality traits have been demonstrated. We therefore investigated the relationship between sense of coherence and the Big Five. In total, 1088 Japanese youths completed the 29-item Sense of Coherence Scale and the Ten-Item Personality Inventory. Neuroticism was negatively correlated and extraversion was positively correlated with comprehensibility (r = -.47, .35), manageability (r = -.44, .26), and meaningfulness (r = -.28, .30). These correlations were strong, and the overlap between the two scales was about 36 percent. While the Big Five are related to sense of coherence, their differences cannot be ignored. PMID- 30450217 TI - Unusual invasion of primary pulmonary adenocarcinoma in a cat. AB - Case summary: An 11-year-old female spayed domestic shorthair cat was referred to the Foster Hospital for Small Animals, USA for suspected dysautonomia based on weight loss, vomiting and referral radiographs that showed severe dilation of the esophagus, stomach and entire gastrointestinal tract. After recheck radiographs revealed a decrease in gas compared with the referral images, persistently reduced gastrointestinal motility was deemed less likely; however, cardiomegaly and a soft tissue opacity overlying the esophagus were noted. Echocardiogram identified a pulmonary mass either impinging on or invading the local organs. At necropsy, gross pathology and histopathology showed an aggressive pulmonary carcinoma invading the heart, trachea and esophagus, resulting in a focal esophageal stricture. Gastrointestinal gas dilation was most likely secondary to aerophagia as a result of chronic partial esophageal obstruction. Relevance and novel information: To our knowledge, this is the first reported feline case of invasion of the esophagus and heart by a pulmonary adenocarcinoma. Other than weight loss, the clinical signs for this invasive neoplasm were not evident until the cat was diagnosed with hyperthyroidism and prescribed oral medications. This reinforces the fact that pulmonary adenocarcinoma is difficult to detect clinically until secondary problems from the primary or metastatic neoplasm arise. PMID- 30450216 TI - Coping and adjustment in caregivers: A systematic review. AB - This systematic review assessed coping and adjustment in caregivers of all ages to provide a synthesis of existing literature in the context of methodological approaches and underlying theory. Four databases were searched. Reference lists, citations and experts were consulted. In total, 27 studies (13 quantitative and 14 qualitative) were included. Coping factors associated with adjustment (problem versus emotion-focussed coping and cognitive strategies) and psychosocial factors associated with physiological adjustment (trait anxiety, coping style and social support) were identified. Results raised methodological issues. Future research requires physiological adjustment measures and longitudinal assessment of the long-term impact of childhood caregiving. Findings inform future caregiver research and interventions. PMID- 30450218 TI - Invasive nasal histiocytic sarcoma as a cause of temporal lobe epilepsy in a cat. AB - Case summary: A 10-year-old neutered female domestic shorthair cat was presented with an acute onset of neurological signs suggestive of a right-sided forebrain lesion, temporal lobe epilepsy and generalised seizure activity. MRI of the head revealed an expansile soft tissue mass in the caudal nasal passages (both sides but predominantly right-sided) involving the ethmoid bone and extending through the cribriform plate into the cranial vault affecting predominantly the right frontal lobe and temporal lobe. Histopathological examination of the tumour revealed a histiocytic sarcoma. Relevance and novel information: This is the first report of a cat with clinical signs of temporal lobe epilepsy due to an invasive, histiocytic sarcoma. Histiocytic sarcoma, although rare, should be included in the list of differential diagnoses for soft tissue masses extending through the cribriform plate. Other differential diagnoses are primary nasal neoplasia (eg, adenocarcinoma, squamous cell carcinoma, chondrosarcoma and other types of sarcomas), lymphoma and olfactory neuroblastoma. Temporal lobe epilepsy in cats can be the consequence of primary pathology of temporal lobe structures, or it can be a consequence of pathology with an effect on these structures (eg, mass effect or disruption of interconnecting neuronal pathways). PMID- 30450219 TI - Granulomatous rhinitis secondary to feline leishmaniosis: report of an unusual presentation and therapeutic complications. AB - Case summary: A 12-year-old male neutered domestic shorthair cat underwent rhinoscopy due to inspiratory dyspnoea and stertor. Rhinoscopy showed signs of chronic rhinitis and a multinodular nasopharyngeal mucosa. A marked infiltrate of macrophages that contained intracellular parasitic forms morphologically compatible with Leishmania amastigotes were observed on histopathological examination of nasal and nasopharyngeal biopsies. PCR from nasal tissue was positive for Leishmania infantum DNA, confirming the diagnosis of granulomatous rhinitis secondary to this parasite. Two eyelid nodules were identified 2 weeks later. Fine-needle aspiration revealed Leishmania amastigotes within macrophages and in the background. Allopurinol therapy was started, but 5 days later the cat developed dermatological signs compatible with a cutaneous adverse drug reaction. The drug was discontinued and meglumine antimoniate prescribed. Twenty-five days later, the cat presented with acute kidney injury and meglumine antimoniate was discontinued. Despite clinical improvement after fluid therapy, mild azotaemia persisted. The cat was subsequently treated with nucleotides and active hexose correlated compounds (N-AHCC). Four months later upper respiratory signs were exacerbated. A relapse of granulomatous rhinitis was suspected and miltefosine therapy started. Chronic kidney disease (CKD) worsened during miltefosine treatment, having improved under fluid therapy. Since then, the cat has been treated with N-AHCC and renal diet and at the time of writing shows stable CKD with no recurrence of respiratory signs. Relevance and novel information: This case describes Leishmania infantum as a cause of granulomatous rhinitis in a cat without cutaneous lesions, reporting the alternative use of N-AHCC and miltefosine when allopurinol seemed to have induced a cutaneous rash and there was acute kidney injury (AKI) after meglumine antimoniate therapy. PMID- 30450220 TI - Reconfiguring in-patient services for adults with mental health problems: changing the balance of care. AB - Background: Research suggests that a significant minority of hospital in-patients could be more appropriately supported in the community if enhanced services were available. However, little is known about these individuals or the services they require. Aims: To identify which individuals require what services, at what cost. Method: A 'balance of care' (BoC) study was undertaken in northern England. Drawing on routine electronic data about 315 admissions categorised into patient groups, frontline practitioners identified patients whose needs could be met in alternative settings and specified the services they required, using a modified nominal group approach. Costing employed a public-sector approach. Results: Community care was deemed appropriate for approximately a quarter of admissions including people with mild-moderate depression, an eating disorder or personality disorder, and some people with schizophrenia. Proposed community alternatives drew heavily on carer support services, community mental health teams and consultants, and there was widespread consensus on the need to increase out-of hours community services. The costs of the proposed community care were relatively modest compared with hospital admission. On average social care costs increased by approximately L60 per week, but total costs fell by L1626 per week. Conclusions: The findings raise strategic issues for both national policymakers and local service planners. Patients who could be managed at home can be characterised by diagnosis. Although potential financial savings were identified, the reported cost differences do not directly equate to cost savings. It is not clear whether in-patient beds could be reduced. However, existing beds could be more efficiently used. Declaration of interest: None. PMID- 30450222 TI - Mental health in medical, dentistry and veterinary students: cross-sectional online survey. AB - Background: The mental health of university students, especially medical students, is of growing concern in the UK. Aim: To estimate the prevalence of mental disorder in health sciences students and investigate help-seeking behaviour. Method: An online survey from one English university (n = 1139; 53% response rate) collected data on depression (using the nine-item Patient Health Questionnaire), anxiety (seven-item Generalised Anxiety Disorder Assessment), alcohol use (Alcohol Use Disorders Identification Test), self-harm and well being, as well as help seeking. Results: A quarter of the students reported symptoms of moderate/severe depression and 27% reported symptoms of moderate/severe anxiety. Only 21% of students with symptoms of severe depression had sought professional help; the main reason for not seeking help was fear of documentation on academic records. Conclusions: The study highlights the extent of mental health problems faced by health science students. Barriers to help seeking due to concerns about fitness-to-practise procedures urgently need to be addressed to ensure that this population of students can access help in a timely fashion. Declaration of interest: None. PMID- 30450221 TI - Guidelines for the public on how to provide mental health first aid: narrative review. AB - Background: Expert-consensus guidelines have been developed for how members of the public should assist a person with a mental health problem or in a mental health crisis. Aims: This review aimed to examine the range of guidelines that have been developed and how these have been implemented in practice. Method: A narrative review was carried out based on a systematic search for literature on the development or implementation of the guidelines. Results: The Delphi method has been used to develop a wide range of guidelines for English-speaking countries, Asian countries and a number of other cultural groups. The primary implementation has been through informing the content of training courses. Conclusion: Further work is needed on guidelines for low- and middle-income countries. Declaration of interest: A.F.J. is an unpaid member of the Board of Mental Health First Aid International (trading as Mental Health First Aid Australia), which is a not-for-profit organisation. PMID- 30450223 TI - Understanding the role of the family physician in early psychosis intervention. AB - Background: The family physician is key to facilitating access to psychiatric treatment for young people with first-episode psychosis, and this involvement can reduce aversive events in pathways to care. Those who seek help from primary care tend to have longer intervals to psychiatric care, and some people receive ongoing psychiatric treatment from the family physician. Aims: Our objective is to understand the role of the family physician in help-seeking, recognition and ongoing management of first-episode psychosis. Method: We will use a mixed methods approach, incorporating health administrative data, electronic medical records (EMRs) and qualitative methodologies to study the role of the family physician at three points on the pathway to care. First, help-seeking: we will use health administrative data to examine access to a family physician and patterns of primary care use preceding the first diagnosis of psychosis; second, recognition: we will identify first-onset cases of psychosis in health administrative data, and look back at linked EMRs from primary care to define a risk profile for undetected cases; and third, management: we will examine service provision to identified patients through EMR data, including patterns of contacts, prescriptions and referrals to specialised care. We will then conduct qualitative interviews and focus groups with key stakeholders to better understand the trends observed in the quantitative data. Discussion: These findings will provide an in-depth description of first-episode psychosis in primary care, informing strategies to build linkages between family physicians and psychiatric services to improve transitions of care during the crucial early stages of psychosis. Declaration of interest: None. PMID- 30450225 TI - Neuropsychiatric profile and psychotropic medication use in adults with autism spectrum disorder: results from the Australian Longitudinal Study of Adults with Autism. AB - Background: Children and adolescents with autism spectrum disorder (ASD) are a highly medicated group. Few studies have examined the neuropsychiatric profile and patterns of psychotropic medication use among adults with ASD. Aims: To describe and compare the neuropsychiatric profile and psychotropic medication use in a cohort of adults with ASD and non-autistic controls. Method: Baseline data from a survey-based, longitudinal study of adults with ASD in Australia. Participants were 188 adults with ASD and 115 controls aged 25-80 years. Results: ASD was associated with increased odds of psychotropic medication use even when controlling for the presence of any neurological or psychiatric disorder. There were no corresponding indications for 14.4% of psychotropic medications prescribed to adults with ASD. Conclusions: This study found substantial psychotropic prescribing for adults with ASD. Patterns of psychotropic medication use may reflect prescribing for behavioural indications despite limited evidence to support this practice. Declaration of interest: None. PMID- 30450226 TI - Exploring the genetic correlations of antisocial behaviour and life history traits. AB - : Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviours in human and non-human species. Behavioural genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic aetiologies. We use genome-wide association study data to estimate the genetic correlations between various measures of reproductive development (N = 52 776-318 863) and antisocial behaviour (N = 31 968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, r g = 0.50, P = 0.0065) were positively correlated with alleles associated with antisocial behaviour, whereas alleles associated with more delayed reproductive onset (age at first birth, r g = -0.64, P = 0.0008) were negatively associated with alleles linked to antisocial behaviour. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviours may partly represent a faster life history approach, which may be significantly calibrated by genes. Declaration of interest: None. PMID- 30450224 TI - Predictive factors for hyperglycaemic progression in patients with schizophrenia or bipolar disorder. AB - Background: Patients with schizophrenia or bipolar disorder have a high risk of developing type 2 diabetes. Aims: To identify predictive factors for hyperglycaemic progression in individuals with schizophrenia or bipolar disorder and to determine whether hyperglycaemic progression rates differ among antipsychotics in regular clinical practice. Method: We recruited 1166 patients who initially had normal or prediabetic glucose levels for a nationwide, multisite, l-year prospective cohort study to determine predictive factors for hyperglycaemic progression. We also examined whether hyperglycaemic progression varied among patients receiving monotherapy with the six most frequently used antipsychotics. Results: High baseline serum triglycerides and coexisting hypertension significantly predicted hyperglycaemic progression. The six most frequently used antipsychotics did not significantly differ in their associated hyperglycaemic progression rates over the 1-year observation period. Conclusions: Clinicians should carefully evaluate baseline serum triglycerides and coexisting hypertension and perform strict longitudinal monitoring irrespective of the antipsychotic used. Declaration of interest: The authors report no financial or other relationship that is relevant to the subject of this article. Relevant financial activities outside the submitted work are as follows. I.K. has received honoraria from Astellas, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Nippon Chemiphar, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; has received research/grant support from AbbVie GK, Asahi Kasei Pharma, Astellas, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin; and is a member of the advisory boards of Dainippon Sumitomo Pharma and Tanabe Mitsubishi Pharma. Y.T. has received speaker's honoraria from Dainippon-Sumitomo Pharma, Otsuka, Meiji-Seika Pharma, Janssen Pharmaceutical, Daiichi-Sankyo Company, UCB Japan and Ono Pharmaceutical. K.U. has received honoraria from Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Takeda Pharmaceutical, Hisamitsu Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Tanabe Mitsubishi Pharma, Shionogi and Yoshitomiyakuhin. B.Y. has received speaker's honoraria from Otsuka Pharmaceutical and Janssen Pharmaceutical. J. I. has received honoraria from Dainippon Sumitomo Pharma, Eli Lilly, Janssen Pharmaceutical, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical and Mochida Pharma. PMID- 30450227 TI - The prognosis of out-patient alcohol treatment among parents with childcare responsibility. AB - Background: Despite expansive knowledge on the detrimental effects of growing up with parents with alcohol use disorders (AUDs), little is known about the prognosis of alcohol treatment among parents with childcare responsibility. Aims: This observational cohort study aimed to examine the prognosis of patients with and without childcare responsibility, in a conventional out-patient alcohol treatment clinic. Method: A consecutive AUD sample (N = 2201), based on ICD-10 Diagnostic Criteria for Research, was assessed with the European Addiction Severity Index during the clinical routine, at treatment entry and conclusion. Data on addiction severity, treatment course and drinking outcomes were derived, and adjusted odds ratios (AORs) were calculated with logistic-regression models. Drinking outcomes were compared in an intention-to-treat analysis, including all patients in a logistic regression with inverse probability weighting. Results: Patients with childcare responsibility (aged <18 years) had a less severe addiction profile and lower drop-out rate compared with patients without children or with children living out-of-home. They were also more likely to improve on all drinking-related outcomes, including abstinence (AOR 2.68, 95% CI 1.82-3.95), number of drinking days (AOR 2.45, 95% CI 1.50-4.03) and excessive drinking days (AOR 4.66, 95% CI 2.36-9.17); and those with children living out-of-home had better outcomes on abstinence (AOR 1.59, 95% CI 1.08-2.34) than patients without children. Conclusions: Childcare responsibility among out-patients was associated with better treatment course and outcomes than those without or not living with their children. This knowledge can help guide clinical practice, effectuate interventions and inform social authorities. PMID- 30450228 TI - Work-related variables associated with perceptions of recovery-oriented care among Quebec mental health professionals. AB - Background: Provider working conditions are important in mental health service delivery. Aims: To identify variables associated with perceived recovery-oriented care among mental health professionals. Method: A total of 315 mental health professionals and 41 managers across four Quebec service networks completed questionnaires. Univariate and multilevel mixed-effects linear regressions for bivariate and multivariate analyses were performed using independent variables from the input-mediator-output-input model and recovery-oriented care. Results: Recovery-oriented care related to: working in primary care or out-patient mental health services, team support, team interdependence, prevalence of individuals with suicide ideation, knowledge-sharing, team reflexivity, trust, vision (a subset of team climate), belief in multidisciplinary collaboration and frequency of interaction with other organisations. Conclusions: Optimising team processes (for example knowledge-sharing) and emergent states (for example trust) may enhance recovery-oriented care. Adequate financial and other resources, stable team composition, training on recovery best practices and use of standardised assessment tools should be promoted, while strengthening primary care and interactions with other organisations. Declaration of interest: None. PMID- 30450229 TI - Immunohistochemical characterization of stem cell and differentiation markers of the dental pulp of human natal teeth. AB - Aim: Dental pulp stem cells, which are primarily derived from the pulp tissues of human teeth, have rarely been obtained from natal teeth. This study investigated the stem cell and differentiation markers of the dental pulp of natal teeth using immunohistochemistry. Materials & Methods: The pulp tissue from extracted natal teeth (n = 2) of a 20-day-old healthy male was examined for immunohistochemical expression of stem cell (Oct-4 and SOX 2) and differentiation markers (Nestin, CD 44, desmin, osteopontin and Ki- 67). Results: The pulp tissue of the natal teeth expressed immunopositivity for nestin, CD 44 and SOX2. Conclusion: Natal teeth, if preserved properly, could serve as sources of dental pulp stem cells that are an improvement on deciduous teeth. PMID- 30450230 TI - Fertility status perception, fertility preservation and desire to have children in cancer survivors: French VICAN survey. AB - Aim: To report fertility status perception, fertility preservation and desire to have children in French cancer survivors 2 and 5 years after diagnosis. Methods: A total of 427 women and 115 men self-reported treatment-induced infertility, fertility status, access to gamete conservation, desire to have children and pregnancy/live births. Results: A total of 96.5% of men and 92.9% of women were thought to be fertile at diagnosis and 38% desired to have children. A total of 57.8% of men and 67.4% of women declared that no fertility preservation had been discussed before treatment. After 2 years, 26.8% of patients still desired to have children. After 5 years, 18 live births have been reported. Conclusion: Despite a legal obligation and technical progress, there is a lack of information given to patients. PMID- 30450231 TI - Is there a role for the platelet-to-lymphocyte ratio in chronic lymphocytic leukemia? AB - Aim: The rationale for platelet-to-lymphocyte ratio (PLR) in chronic lymphocytic leukemia (CLL) is that both the platelet and lymphocyte counts are affected by the CLL pathogenesis and could influence treatment decision-making. Methods: Demographic and clinical data of CLL patients diagnosed at our institution between 1989 and 2013 were collected. Cox regression models were used to evaluate the role of PLR in the duration of watchful waiting, postdiagnosis survival and postchemotherapy survival. Results: The data of 100 patients with CLL were reviewed for this study. The PLR correlated only to watchful waiting in the univariable analysis (Hazard ratio = 0.48 [0.32-0.73]; p = 0.018). In the multivariable analysis, the duration of watchful waiting was determined by Binet staging and lymphocyte count (p < 0.001). The postdiagnosis survival was determined by age (p = 0.002) and lymphocyte count (p = 0.010). Conclusion: The PLR did not seem to act as a prognostic biomarker for CLL. PMID- 30450232 TI - Spermidine/spermine N1-acetyltransferase-1 as a diagnostic biomarker in human cancer. AB - Aim: SSAT-1 is an enzyme that plays a critical role in cell growth. Amantadine, a FDA-approved antiviral drug, is a substrate for SSAT-1. The utility of amantadine as an agent to demonstrate elevated SSAT-1 activity linked to cancer was conducted. Results: High levels of SSAT-1 expression were measured in tumor human cell lines, and in breast, prostate and lung tumor tissue. An increase in the urinary levels of acetylated amantadine in cancer patients was observed. Conclusion: Increases in SSAT-1 contents in tumor tissue could be of value in targeting cancers with high SSAT-1 expression for confirmation/quantification. The high levels of acetylated amantadine could be used as a simple and useful screening test for the presence of cancer. PMID- 30450234 TI - A dozen years of clinical trials performing advanced cell therapy with perinatal cells. PMID- 30450235 TI - Foreword. PMID- 30450236 TI - Update on surgical and non-surgical management of COPD. PMID- 30450233 TI - Optimization of biomarkers-based classification scores as progression-free survival predictors: an intuitive graphical representation. AB - Aim: To construct classification scores based on a combination of cancer patient plasma biomarker levels, for predicting progression-free survival. Methods: The approach is based on the optimization of the biomarker cut-off values, which maximize the statistical differences between the groups with values lower or larger than the cut-offs, respectively. An intuitive visualization of the quality of the classification score is also proposed. Results: Even if there are only weak correlations between individual biomarker levels and progression-free survival, scores based on suitably chosen combination of three biomarkers have classification power comparable with the Response Evaluation Criteria in Solid Tumors criteria classification of response to treatments in solid tumors. Conclusion: Our approach has the potential to improve the selection of the patients who will benefit from a given anticancer treatment. PMID- 30450237 TI - Complications related to endoscopic lung volume reduction for emphysema with endobronchial valves: results of a multicenter study. AB - Background: Despite bronchoscopic lung volume reduction (BLVR) with valves is a minimally invasive treatment for emphysema, it can associate with some complications. We aimed at evaluating the rate and type of complications related to valve treatment and their impact on clinical outcomes. Methods: It is a retrospective multicenter study including all consecutive patients with severe heterogeneous emphysema undergoing BLVR with endobronchial valve treatment and developed any complications related to this procedure. The type of complication, the time of onset, the treatment required and the out-come were evaluated. Response to treatment was assessed according to the minimal clinically important difference (MCID) as follows: an improvement of >=15% in forced expiratory volume in one second (FEV1); of -8% in residual volume (RV); of >=26 m in 6-minnute walking distance (6MWD); and of >=4 points on the St. George's Respiratory Questionnaire (SGRQ). Target lobe volume reduction (TLVR) >=350 mL was considered significant. Results: One hundred and seven out of 423 (25.3%) treated patients had complications related to valve treatment including pneumothorax (17.3%); pneumonia (1.7%), chronic obstructive pulmonary disease (COPD) exacerbation (0.9%), respiratory failure (1.4%), valve migration (2.1%), and hemoptysis (1.9%). In all cases complications resolved with appropriate treatment including removal of valves in 21/107 cases (19.6%). Patients with TLVR >=350 mL (n=64) vs. those <350 mL (n=43) had a statistically significant higher improvement in FEV1 (19.0%+/-3.9% vs. 3.0%+/-0.9%; P=0.0003); in RV (-10.0%+/-4.8% vs. -4.0%+/-2.9%; P=0.002); in 6MWD (33.0+/-19.0 vs. 12.0+/-6.3 metres; P=0.001); and in SGRQ ( 15.0+/-2.9 vs. -8.0+/-3.5 points; P=0.01). Only patients with TLVR >=350 mL met or exceeded the MCID cut-off criteria for FEV1 (19.0%+/-3.9%), RV (-10.0%+/ 4.8%), 6MWT (33.0+/-19.0 metres), and SGQR (-15.0+/-2.9 points). Five patients (1.2%) died during follow-up for causes not related to valves treatment neither to any of the complications described. Conclusions: Valve treatment is a safe and reversible procedure. The presence of complications seems not to have a significant impact on clinical outcome in patients with lobar atelectasis. Due to poor clinical conditions and possible complications, BLVR should be performed in high volume centers with a multidisciplinary approach. PMID- 30450239 TI - The role of a multidisciplinary severe chronic obstructive pulmonary disease hyperinflation service in patient selection for lung volume reduction. AB - Chronic obstructive pulmonary disease (COPD) is a complex disease and the management is focused on improving breathlessness, quality of life and healthcare utilisation. Our understanding of COPD phenotypes has improved in recent years and there is an increased drive towards delivering phenotype-based therapies. Lung volume reduction can offer the prospect of life changing benefit in breathlessness and quality of life in a select group of patients with severe emphysema already receiving maximum medical treatment. In spite of the available evidence, very few procedures are being performed relative to the disease burden and prevalence of suitable individuals. Currently the major barriers to patient accessibility are lack in standardised multidisciplinary severe COPD services with easy access to lung volume reduction procedures, as well as poorly informed perceptions of healthcare professionals. There is a recognised need to improve such services in many healthcare systems. We share our experiences with setting up and running a successful regional multidisciplinary severe COPD hyperinflation service. PMID- 30450238 TI - History of lung volume reduction procedures. AB - Lung volume reduction (LVR) procedures for emphysematous patients were firstly introduced in the second half of the twentieth century. Over time, from the first invasive surgical procedures, new less invasive techniques have been conceived. In regards to the surgical approach, the adoption of VATS and the execution, in selected centers, of a non-resectional approach, with folding of less functional lung tissue, reduced mortality and adverse events risks. As regards to the bronchoscopic approach, endobronchial valves (EBV) and intrabronchial valves (IBV) were initially proposed in the early 2000s to obtain segmental or lobar atelectasis of the more compromised lung parenchyma. Despite showing promising results with respect to improvement of pulmonary function tests, particularly forced expiratory volume in 1st second (FEV1), and quality of life, and a good safety profile, valves showed disappointing results in presence of collateral ventilation, such as in cases of incomplete fissures. To overcome this technical issue, in the last 10 years, endobronchial coils have been designed and used. Having a compressive effect on the lung parenchyma where they are located, they are not affected by collateral ventilation. Randomized control trials (RCTs) on endobronchial coils showed a significant improvement in FEV1 and quality of life, however this technique was not immune to side effects, particularly low respiratory tract infections and pneumothoraces. Besides bronchial valves (BV) and coils, airway by-pass stents have also been evaluated in a RCT but without reaching the desired endpoints. Other innovative procedures recently considered and delivered through bronchoscopy regards thermal energy, with vapour therapy, to achieve a scarring reaction of the emphysematous lung parenchyma, and polymeric foams used as lung sealants to achieve absorptive atelectasis. In conclusion, LVR procedures may be considered in carefully selected patients with symptomatic emphysema and severe lung hyperinflation, and might be personalized according to the anatomical characteristics of emphysematous area. PMID- 30450240 TI - Surgical and endoscopic treatment for COPD: patients selection, techniques and results. AB - Chronic obstructive pulmonary disease (COPD) is a very heterogeneous disease characterised by an obstructive lung pattern that constitutes worldwide a major cause of high morbidity and mortality. In the last decades, lung volume reduction surgery (LVRS) has demonstrated to be a potential good alternative to transplantation in patients affected by COPD. The trend toward minimally invasive techniques resulted not only in surgical procedures better tolerated by the patients but also in several endoscopic treatments modality that are rapidly gaining ground. PMID- 30450241 TI - Bronchoscopic management of prolonged air leak. AB - Broncho-pleural fistula (BPF) is an atypical communication between the tracheobronchial tree and the alveolar/pleural space, with prolonged air leak (PAL). BPF is frequent and related to significant morbidity, prolonged length of hospital stay, and mortality. Nevertheless, in about 10%, more than 5 days of an air leak is considered a PAL, accounted for significant morbidity. Endobronchial valve is a novel device for the PAL management with minimal morbidity if related to surgical repairs. While it is suggested that surgical treatment should be undertaken when possible, endobronchial valves should be recommended as a therapeutic choice in high-risk patients. Placement techniques remain operator and patient friendly and allow the procedure to be performed with relative ease. Prospectively conducted, randomised, controlled clinical trials are needed where valve treatment is compared with other bronchoscopic techniques, surgical procedures, or both. PMID- 30450245 TI - Performance and safety in elite skiing sports: A big challenge on specificity, individuality, and complexity. PMID- 30450244 TI - Cellulose Acetate Phthalate and Antiretroviral Nanoparticle Fabrications for HIV Pre-Exposure Prophylaxis. AB - To adequately reduce new HIV infections, development of highly effective pre exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pH sensitive polymer with HIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, and morphological analyses illustrate that DTG-CAP-NPs were smooth and spherical, <=200 nm in size, and monodispersed with a polydispersity index PDI <= 0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be ~70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (>=80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 MUg/mL. Confocal microscopic studies illustrate that >=98% cells retained DTG-CAP NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV. PMID- 30450242 TI - Transplant options for end stage chronic obstructive pulmonary disease in the context of multidisciplinary treatments. AB - Lung transplantation (LTx) in advanced stage chronic obstructive pulmonary disease (COPD) patients is associated with significant improvement in lung function and exercise capacity. However, demonstration that the procedure also provides a survival benefit has been more elusive compared to other respiratory conditions. Identification of patients with increased risk of mortality is crucial: a low forced expiratory volume in 1 second (FEV1) is perhaps the most common reason for referral to a lung transplant center, but in itself is insufficient to identify which COPD patients will benefit from LTx. Many variables have to be considered in the selection of candidates, time for listing, and choice of procedure: age, patient comorbidities, secondary pulmonary hypertension, the balance between individual and community benefit. This review will discuss patient selection, transplant listing, potential benefits and critical issues of bilateral (BLTx) and single lung (SLTx) procedure, donor-to recipient organ size-matching; furthermore, it will describe LTx outcomes and its effects on recipient survival and quality of life. PMID- 30450243 TI - Lung volume reduction followed by lung transplantation-considerations on selection criteria and outcome. AB - Lung transplantation (LuTX) and lung volume reduction (LVR), either surgical (LVRS: lung volume reduction surgery) or endoscopic (ELVR: endoscopic lung volume reduction), are established therapies in the treatment of end-stage chronic obstructive pulmonary disease (COPD) patients. Careful patient selection is crucial for each intervention. If these techniques are sequentially applied there is a paucity of available data and individual center experiences vary depending on details in selection criteria and operative technique. This review aims to summarize the published data with a focus on LuTX after LVRS. This review covers patient selection for LuTX and LVR, technical considerations, limitations and outcomes. Published literature was identified by systematic search on Medline and appropriate papers were reviewed. Seven case reports/series, 7 comparative observational studies and one multicenter database analysis incorporating a total of 284 patients with LuTX and LVR were evaluated. Prior LVR can significantly affect intraoperative and postoperative risks after subsequent LuTX. Careful patient selection and timing and the choice of appropriate techniques such as minimal invasive LVRS and using ECMO as extracorporeal support during LuTX if required can minimize those risks, ultimately leading to very good postoperative outcomes in terms of lung function and survival. LVRS has the potential to delay listing and to bridge patients to LuTX by improving their physical condition while on the waiting list. After single lung transplantation (SLuTX) contralateral LVRS can counteract the deleterious effects of native lung hyperinflation (NLH). LVR and LuTX are adjunct therapies in the treatment of end stage COPD. The combination of both can safely be considered in selected patients. PMID- 30450246 TI - Pacing and predictors of performance during cross-country skiing races: A systematic review. AB - Background: Cross-country skiing (XCS) racing, a popular international winter sport, is complex and challenging from physical, technical, and tactical perspectives. Despite the vast amount of research focusing on this sport, no review has yet addressed the pacing strategies of elite XCS racers or the factors that influence their performance. The aim was to review the scientific literature in an attempt to determine the effects of pacing strategy on the performance of elite XCS racers. Methods: Four electronic databases were searched using relevant subject headings and keywords. Only original research articles published in peer reviewed journals and the English language and addressing performance, biomechanics, physiology, and anthropometry of XCS racers were reviewed. Results: All 27 included articles applied correlative designs to study the effectiveness of different pacing strategies. None of the articles involved the use of an experimental design. Furthermore, potential changes in external conditions (e.g., weather, ski properties) were not taken into consideration. A comparable number of studies focused on the skating or classical technique. In most cases, positive pacing was observed, with certain indications that higher-level athletes and those with more endurance and strength utilized a more even pacing strategy. The ability to achieve and maintain a long cycle length on all types of terrain was an important determinant of performance in all of the included studies, which was not the case for cycle rate. In general, uphill performance was closely related to overall race performance, with uphill performance being most closely correlated to the success of female skiers and performance on flat terrain being more important for male skiers. Moreover, pacing was coupled to the selection and distribution of technique during a race, with faster skiers employing more double poling and kick double poling, less diagonal stride, and more V2 (double dance) than V1 (single dance) skating across a race. Conclusion: We propose that skiers at all levels can improve their performance with more specific training in techniques (i.e., maintaining long cycles without compromising cycle rate and selecting appropriate techniques) in combination with training for endurance and more strength. Furthermore, we would advise less experienced skiers and/or those with lower levels of performance to apply a more even pacing strategy rather than a positive one (i.e., starting the race too fast). PMID- 30450247 TI - The influence of physiobiomechanical parameters, technical aspects of shooting, and psychophysiological factors on biathlon performance: A review. AB - The biathlon, an Olympic sporting discipline that combines cross-country skiing with rifle marksmanship, entails considerable physiological demands, as well as fine motor control while shooting after intense exercise and under mental pressure. Although much of our knowledge about cross-country skiing is probably also applicable to the biathlon, carrying the rifle and shooting under stress make this discipline somewhat unique. The present review summarizes and examines the scientific literature related to biathlon performance, with a focus on physiological and biomechanical factors and shooting technique, as well as psychophysiological aspects of shooting performance. We conclude with suggestions for future research designed to extend our knowledge about the biathlon, which is presently quite limited. PMID- 30450248 TI - Limb symmetry index in competitive alpine ski racers: Reference values and injury risk identification according to age-related performance levels. AB - Purpose: The aims of this study were to assess differences of limb symmetry index (LSI) in strength- and coordination-related tasks between high-level, competitive, noninjured ski racers of different age-related performance levels and to prospectively assess limb differences as a possible risk factor for traumatic and overuse injury in youth ski racers. Methods: The study (Study 1) included 285 high-level competitive ski racers (125 females, 160 males) of 3 age related performance levels and based on the school system: 95 youth (10-14 years, secondary modern school), 107 adolescent (15-19 years, grammar school), and 83 elite athletes (20-34 years). To investigate the second aim (Study 2), 67 of the 95 youth athletes were included and any traumatic or overuse injuries were prospectively recorded over 2 seasons. All athletes performed 4 unilateral tests (strength related: one-leg counter movement jump (OL-CMJ) and one-leg isometric/isokinetic press strength test (OL-ILS); coordination related: one-leg stability test (OL-ST) and one-leg speedy jump test (OL-SJ)). The LSI was calculated by dividing the dominant leg by the nondominant leg and multiplying by 100. Kruskal-Wallis H tests and binary logistic regression analyses were conducted. Results: There were significant differences between the LSI of the 3 age-related performance-level groups only in the strength-related tests: the OL CMJ (chi2(2, 285) = 9.09; p = 0.01) and the OL-ILS (chi2(2, 285) = 14.79; p < 0.01). The LSI for OL-ILS was found to be a significant risk factor for traumatic injury in youth ski racers (Wald = 7.08; p < 0.01). No significant risk factors were found for overuse injuries. Conclusion: Younger athletes display slightly greater LSI values only in the strength-related tests. The cut-off value of limb differences of <10% for return to sport decisions seems to be appropriate for elite athletes, but for youth and adolescent athletes it has to be critically discussed. It seems to be necessary to define thresholds based on specific performance tasks (strength vs. coordination related) rather than on generalizations, and age-related performance levels must be considered. Limb differences in unilateral leg extension strength represent a significant injury risk factor in youth ski racers. PMID- 30450250 TI - The BRICS Council for Exercise and Sport Science (BRICSCESS) - A new era has dawned. AB - *BRICS is the acronym for an international association of 5 major emerging national economies: Brazil, Russia, India, China, and South Africa.*The BRICS Council of Exercise and Sports Science was founded to address the specific concerns of these countries in respect to the health and wellness of the people in BRICS countries.*One recognized overwhelming need is the development of future leaders/volunteers.*BRICSCESS in conjunction with the FLV program are in part assembled to foster the development and evolution of junior professionals in respect to the health and wellness of people. PMID- 30450249 TI - A comparison of lower limb stiffness and mechanical muscle function in ACL reconstructed, elite, and adolescent alpine ski racers/ski cross athletes. AB - Purpose: The aim of this study was to compare mechanical muscle function in the eccentric/concentric phases of vertical bilateral jumping in anterior cruciate ligament-reconstructed (ACLR), elite (ELITE), and adolescent (ADOL) alpine ski racers and ski cross athletes. Methods: Alpine ski racers/ski crossers (ACLR: n = 12, age = 26.7 +/- 3.8 years; ELITE: n = 12, age = 23.9 +/- 3.0 years; ADOL: n = 12, age = 17.8 +/- 0.7 years; females: n = 6 per group, males: n = 6 per group) performed 5 maximal countermovement jumps (CMJs) and 5 squat jumps. The ground reaction forces for each limb were analyzed using dual force plate recording to obtain body center of mass (BCM) velocity, displacement, and power. The eccentric deceleration (ECC) and concentric phases were determined from BCM velocity. CMJ net concentric and ECC impulses were calculated (body mass normalized) along with the peak and mean BCM power and maximal vertical jump height. CMJ lower limb stiffness (LLS) was determined by the slope of the ground reaction forces vs. the BCM displacement curve over the ECC phase. Concentric and ECC asymmetry indices were calculated for each leg, and the left vs. right LLS was compared. Outcome measures (reported as mean +/- SD) calculated as a 5-jump mean were normalized to body mass and compared using an analysis of variance. Results: No between-group differences were found for peak and mean power or jump heights. There were no group differences for LLS or net concentric phase impulse, but the net ECC impulse was lower in the ADOL group compared with ELITE skiers (ADOL: 1.33 +/- 0.32 Ns/kg; ELITE: 1.59 +/- 0.16 Ns/kg; p < 0.05). Although no group differences were found for ECC asymmetry indices, a group * limb interaction was found for LLS (p < 0.01), which was systematically higher in the right vs. the left limb of ADOL skiers (right: 54.1 +/- 17.9 N/m/kg; left: 48.7 +/- 15.7 N/m/kg; p < 0.01). Conclusion: ADOL skiers demonstrated decreased ECC impulse and systematic right limb dominance in LLS compared with ACLR and ELITE skiers. The implication of these findings for injury and performance are unknown, but further investigation into these potential relationships is warranted. PMID- 30450251 TI - Battle of the sexes: Which is better for you, high- or low-intensity exercise? PMID- 30450253 TI - Association of traditional Chinese exercises with glycemic responses in people with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials. AB - Background: There is increasing evidence showing the health benefits of various forms of traditional Chinese exercises (TCEs) on the glycemic profile in people with type 2 diabetes. However, relatively little is known about the combined clinical effectiveness of these traditional exercises. This study was designed to perform a systematic review and meta-analysis of the overall effect of 3 common TCEs (Tai Ji Quan, Qigong, Ba Duan Jin) on glycemic control in adults with type 2 diabetes. Methods: We conducted an extensive database search in Cochrane Library, EMBASE, PubMed, Web of Science, EBSCO, and China National Knowledge Infrastructure on randomized controlled trials published between April 1967 and September 2017 that compared any of the 3 TCEs with a control or comparison group on glycemic control. Data extraction was performed by 2 independent reviewers. Study quality was evaluated using the Cochrane Handbook for Systematic Reviews of Interventions, which assessed the risk of bias, including sequence generation, allocation concealment, blinding, completeness of outcome data, and selective outcome reporting. The resulting quality of the reviewed studies was characterized in 3 grades representing the level of bias: low, unclear, and high. All analyses were performed using random effects models and heterogeneity was quantified. We a priori specified changes in biomarkers of hemoglobin A1c (in percentage) and fasting blood glucose (mmol/L) as the main outcomes and triglycerides, total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein-cholesterol, 2-h plasma glucose, and fasting plasma glucose as secondary outcomes. Results: A total of 39 randomized, controlled trials (Tai Ji Quan = 11; Qigong = 6; Ba Duan Jin = 22) with 2917 type 2 diabetic patients (aged 41-80 years) were identified. Compared with a control or comparison group, pooled meta-analyses of TCEs showed a significant decrease in hemoglobin A1c (mean difference (MD) = -0.67%; 95% confidence interval (CI): -0.86% to -0.48%; p < 0.00001) and fasting blood glucose (MD = -0.66 mmol/L; 95%CI: -0.95 to -0.37 mmol/L; p < 0.0001). The observed effect was more pronounced for interventions that were medium range in duration (i.e., >3-<12 months). TCE interventions also showed improvements in the secondary outcome measures. A high risk of bias was observed in the areas of blinding (i.e., study participants and personnel, and outcome assessment). Conclusion: Among patients with type 2 diabetes, TCEs were associated with significantly lower hemoglobin A1c and fasting blood glucose. Further studies to better understand the dose and duration of exposure to TCEs are warranted. PMID- 30450252 TI - MicroRNAs in heart and circulation during physical exercise. AB - Exercise training is beneficial to the cardiovascular system. MicroRNAs (miRNAs, miRs) are a class of conserved non-coding RNAs and play a wide-ranging role in the regulation of eukaryotic gene expression. Exercise training alters the expression levels of large amounts of miRNAs in the heart. In addition, circulating miRNAs appear to be regulated by exercise training. In this review, we will summarize recent advances in the regulation of miRNAs during physical exercise intervention in various cardiovascular diseases, including pathologic cardiac hypertrophy, myocardial fibrosis, ischemia-reperfusion injury, myocardial infarction, and heart failure. The regulatory role of circulating miRNAs after exercise training was also reviewed. In conclusion, miRNAs might be a valuable target for treatment of cardiovascular diseases and have great potential as biomarkers for assessment of physical performance. PMID- 30450254 TI - The effect of sex and performance level on pacing in cross-country skiers: Vasaloppet 2004-2017. AB - Background: Pacing, defined as percentage changes of speed between successive splits, has been extensively studied in running and cycling endurance sports; however, less information about the trends in change of speed during cross country (XC) ski racing is available. Therefore, the aim of the present study was to examine the effect of performance (quartiles of race time (Q), with Q1 the fastest and Q4 the slowest) level on pacing in the Vasaloppet ski race, the largest XC skiing race in the world. Methods: For this purpose, we analyzed female (n = 19,465) and male (n = 164,454) finishers in the Vasaloppet ski race from 2004 to 2017 using a one-way (2 sexes) analysis of variance with repeated measures to examine percentage changes of speed between 2 successive splits. Overall, the race consisted of 8 splits. Results: The race speeds of Q1, Q2, Q3, and Q4 were 13.6 +/- 1.8, 10.6 +/- 0.5, 9.2 +/- 0.3, and 8.1 +/- 0.4 km/h, respectively, among females and 16.7 +/- 1.7, 13.1 +/- 0.7, 10.9 +/- 0.6, and 8.9 +/- 0.7 km/h, respectively, among males. The overall pacing strategy of finishers was variable. A small sex * split interaction on speed was observed (eta 2 = 0.016, p < 0.001), with speed difference between sexes ranging from 14.9% (Split 7) to 27.0% (Split 1) and larger changes in speed between 2 successive splits being shown for females (p < 0.001, eta 2 = 0.004). A large performance * split interaction on speed, with Q1 presenting the smallest changes of speed between splits, was shown for females (eta 2 = 0.149, p < 0.001) and males (eta 2 = 0.169, p < 0.001). Conclusion: Male and fast XC skiers are more even pacers. Coaches and athletes should develop tailored sex- and performance-level pacing strategies; for instance, they should advise fast XC skiers to start fast and maintain their speed, rather than starting slowly and trying to make up time by going faster at times during the race. PMID- 30450255 TI - Assessing effect of interaction between the FTO A/T polymorphism (rs9939609) and physical activity on obesity-related traits. AB - Background: The first described obesity-susceptibility gene was the fat mass and obesity-associated (FTO) gene. However, knowledge about FTO's potential modifying effect on changes in body weight achieved through a training program is still limited. We decided to study the association between the FTO A/T polymorphism (rs9939609) and obesity-related traits. Additionally, we investigated whether body mass and body composition, as well as metabolic variables observed in physically active participants, are modulated by the FTO polymorphism. Methods: A group of 201 young Polish women were recruited for the study. The genotype distribution was examined in participants measured for selected changes before and after the completion of a 12-week training program. Results: Our results confirm the association between the common FTO A/T polymorphism and increased body mass index (BMI). Subjects with AA and AT genotypes had higher BMI during the entire study period compared with the TT genotype. Although parameters such as BMI, basal metabolism rate, tissue independence, fat mass percentage, fat mass, fat-free mass, total body water, high-density lipoprotein, and glucose changed significantly during the training program, none of the examined parameters changed significantly across the FTO genotypes (genotype * training interaction). Conclusion: We confirm an association between the FTO A/T polymorphism and increased BMI; this polymorphism is therefore a candidate for influencing obesity and other disease-related phenotypes. Although the gene * physical activity interaction was not shown, we want to point out that promoting physical activity is an important approach to controlling the increasing obesity epidemic. PMID- 30450256 TI - The effects of oral smokeless tobacco administration on endurance performance. AB - Background: Smokeless tobacco is widely used by athletes to enhance performance. Nicotine is a central nervous system stimulant and acts on cardiocirculatory and metabolic systems, involving tissue blood flow and circulatory vasoreactivity. The aim of this study was to investigate the effects of the oral smokeless tobacco (Swedish snus (SS)) on the perception of fatigue and time to exhaustion (TTE) during moderate-intensity aerobic exercise. Methods: Fourteen healthy non tobacco male users were recruited for a double-blind, controlled crossover design (SS vs. snus placebo (SP)). Subjects were tested for 3 sessions: experimental session 1 (Exp1) consisted of an incremental test to determine the maximal aerobic power output (Wmax), whereas Exp2 and Exp3 consisted of exercising at 65%Wmax until exhaustion in SS or SP conditions. During Exp2 and Exp3, muscle and cerebral oxygenation was assessed by means of near-infrared spectroscopy, and the rating of perceived exertion (RPE) was recorded. Results: Comparing SS with SP tests, significant differences (p < 0.05) were found in the values of cerebral (~3%) and muscular tissues oxygenation (~4%) in the first 30 min of exercise. The RPE values were not significantly different between the 2 conditions (SS vs. SP). No significant difference was found in TTE (SS: 54.25 +/- 21.84 min; SP: 50.01 +/ 17.03 min). Conclusion: This study showed that muscular and cerebral oxygenation increased significantly with snus administration during an endurance exercise until exhaustion, but this did not affect fatigue perception and TTE. The results showed that snus could not be considered an ergogenic substance in non-tobacco users. PMID- 30450257 TI - Effects of Rhodiola rosea supplementation on mental performance, physical capacity, and oxidative stress biomarkers in healthy men. AB - Purpose: The objective of this study was to investigate the effects of chronic Rhodiola rosea (R. rosea) supplementation on mental and physical performance, as well as hormonal and oxidative stress biomarkers. Methods: Twenty-six healthy male students received either R. rosea extract (600 mg/day; RR) or placebo (PL) in a randomized double-blind trial. Prior to supplementation (Term I) and following 4 weeks of supplementation (Term II), the students underwent psychomotor tests for simple and choice reaction time, included in the Vienna Test System. Also, the subjects performed VO2peak test. Blood samples were obtained before and after the test to measure the hormonal profile (cortisol, testosterone, and growth hormone), as well as the biomarkers of oxidative stress (lipid hydroperoxides, total antioxidant capacity, and superoxide dismutase) and muscle damage (creatine kinase). Results: R. rosea ingestion shortened reaction time and total response time. Moreover, a greater relative increase in the number of correct responses was observed in RR group as compared to the PL group. No changes in endurance exercise capacity and hormonal profile were observed after R. rosea ingestion. R. rosea ingestion raised plasma total antioxidant capacity. It did not, however, affect other measured parameters. Conclusion: Chronic R. rosea ingestion does not affect physical performance, but can improve the results of some psychomotor tests (simple and choice reaction time) in young, healthy, and physically active men. The improvements in mental performance, however, at least in our study, seem not to be related to changes in cortisol release or antioxidant activity of R. rosea extract. Thus, the specific mechanisms responsible for these effects still need to be elucidated. PMID- 30450258 TI - Intention and automaticity toward physical and sedentary screen-based leisure activities in adolescents: A profile perspective. AB - Purpose: Physical activity (PA) and sedentary behavior (SB) are increasingly considered independent health behaviors. Additionally, current research suggests that both controlled and automatic determinants account for their adoption. The purpose of this article was to identify intention-automaticity profiles toward PA and screen-based SB and to examine how those profiles are associated with different behavioral patterns. Method: Two cross-sectional studies based on self report questionnaires were conducted with French high school students (Study 1: n = 198; Study 2: n = 185). Results: In all, 4 distinct motivational profiles appeared. The first 3 clusters emerged in both studies: "PA" (high levels of automaticity and intention for PA, low levels of automaticity and intention for screen-based SB); "screen" (high levels of automaticity and intention for screen based SB, low levels of automaticity and intention for PA), and "mixed" (high levels of all variables), whereas the fourth cluster was observed only in Study 2: "high control" (below-mean levels of automaticity, high levels of intention toward both PA and screen-based SB). Adolescents with a screen profile displayed the least healthy behavioral pattern, whereas those in the PA profile demonstrated the most favorable behaviors. Conclusion: Future research is needed to extend these results to other populations using complementary assessment methods of automatic psychological processes and PA and SB behaviors. PMID- 30450259 TI - Sedentary behavior and physical activity predicting depressive symptoms in adolescents beyond attributes of health-related physical fitness. AB - Background: Sedentary behavior (SB), physical activity (PA), and attributes of physical fitness have been shown to be related to depressive symptoms in adolescents. The purpose of the present study was to investigate whether SB and fitness-producing activity predicted depression in active adolescents over and above gender and fitness attributes. Methods: Participants were 249 adolescents (age: 12.85 +/- 0.89 years, mean +/- SD) from 3 public middle schools who wore Actical accelerometers to assess their SB and PA. Participants also completed the FITNESSGRAM health-related fitness assessment and a brief depression questionnaire. A 3-step hierarchical regression analysis was conducted with gender and fitness attributes (i.e., body mass index (BMI), maximal volume oxygen uptake (VO2max), curlups, and pushups), moderate- and vigorous-intensity activity, and SB entered in respective steps. Results: Regression analysis indicated activity variables (i.e., moderate- and vigorous-intensity activity) significantly predicted depression (DeltaR 2 = 0.12, p < 0.01) beyond gender and fitness attributes. Overall, gender, fitness attributes, activity variables, SB explained 31% of the variance in depression. Structure coefficients revealed VO2max (r s = -0.77), moderate-intensity activity (r s = -0.67), vigorous intensity activity (r s = -0.81), and SB (r s = 0.57) were substantially correlated with the criterion variable; thus, they were the strongest predictors of depression. Conclusion: The findings of the current study indicated SB and PA were both significant predictors of depression; however, sufficient fitness producing activity and adequate cardiorespiratory fitness may nullify the negative influence of SB on depressive symptoms in active adolescents. PMID- 30450261 TI - What happened to USA health care on the way to socialism? PMID- 30450260 TI - Sport participation and vigilance in children: Influence of different sport expertise. AB - Purpose: The present study aimed to investigate the relationship between different types of sport expertise (externally-paced vs. self-paced sports) and vigilance performance in children by evaluating the cardiovascular fitness level of the participants. Methods: Three groups of children (11.0 +/- 0.2 years) differentiated in terms of their regular sport participation (football players, n = 20; track and field athletes, n = 20; non-athletic controls, n = 20) took part in the study. In one session, participants performed the Leger Multi-stage fitness test to estimate their aerobic fitness level. In another session, participants completed the Psychomotor Vigilance Task (PVT) to evaluate their vigilance performance under 2 conditions of velocity demands (normal vs. speed). Results: The results revealed that both groups of sport practitioners had higher cardiovascular fitness than non-athlete controls. In contrast, no significant differences in the performance PVT were found between track and field athletes and controls. Crucially, football players showed better performance in the PVT than track and field athletes and controls. These between-group differences were not modulated by the speed demands of the task. Conclusion: The major novel finding of this research points to a positive relationship between sport participation and vigilance performance during childhood. We discuss our results in terms of the different hypotheses put forward in the literature to explain the relationship between regular exercise and cognitive functioning: the "cardiovascular fitness" and the "cognitive component skills" hypotheses. PMID- 30450262 TI - Enlargement of Langerhans cell histiocytosis of the hypothalamus with progression into the basal ganglia and white matter. AB - Background: Langerhans cell histiocytosis (LCH) is a rare disease that may affect the central nervous system; it is caused by dendritic cell proliferation, and typically occurs in children. LCH frequently appears in the pituitary stalk and rarely results in multiple enhanced lesions in the brain parenchyma. Case Description: We present a case of a 40-year-old woman who deveolped panhypopituitarism and central diabetes insipidus in the postpartum period requiring hormone replacement therapy. At first, magnetic resonance imaging only revealed thickening of the pituitary stalk; while 6 months later, a single enhanced mass lesion was detected in the hypothalamus. Another 5 months later, the lesion had enlarged with appearance of multiple, enhanced satellite lesions in the basal ganglia and white matter. The patient underwent successful craniotomy to obtain a biopsy sample; LCH of the hypothalamus was definitively diagnosis by histopathological examination. Steroids were administrated and resulted in significant reduction of all lesions. Conclusions: Definitive histopathological diagnosis and subsequent appropriate therapy, such as steroid administration, are required when LCH lesions in the hypothalamus become progressively enlarged and new lesions appear in the brain parenchyma. PMID- 30450264 TI - Network Analysis of Autopsy Diagnoses: Insights into the "Cause of Death" from Unbiased Disease Clustering. AB - Background: Autopsies usually serve to inform specific "causes of death" and associated mechanisms. However, multiple diseases can co-exist and interact leading to a final demise. We approached autopsy-produced data using network analysis in an unbiased fashion to inform about interaction among different diseases and identify possible targets of system-level health care. Methods: Reports of 261 full autopsies from one institution between 2011 and 2013 were reviewed. Comorbidities were recorded and their Spearman's association coefficients were calculated. Highly associated comorbidities (P < 0.01) were selected to construct a network in which each disease is represented by a node, and each link between the nodes represents significant co-occurrence. Results: The network comprised 140 diseases connected by 419 links. The mean number of connections per node was 6. The most highly connected nodes ("hubs") represented infectious processes, whereas less connected nodes represented neoplasms and other chronic diseases. Eight clusters of biologically plausible associated diseases were identified. Conclusions: There is an unbiased relationship among autopsy-identified diseases. There were "hubs" (primarily infectious) with significantly more associations than others that could represent obligatory or important modulators of the final expression of other diseases. Clusters of co occurring diseases, or "modules," suggest the presence of clinically relevant presentations of pathobiologically related entities which are until now considered individual diseases. These modules may occur together prior to death and be amenable to interventions during life. PMID- 30450263 TI - Validation of Remote Digital Frozen Sections for Cancer and Transplant Intraoperative Services. AB - Introduction: Whole-slide imaging (WSI) technology can be used for primary diagnosis and consultation, including intraoperative (IO) frozen section (FS). We aimed to implement and validate a digital system for the FS evaluation of cancer and transplant specimens following recommendations of the College of American Pathologists. Materials and Methods: FS cases were routinely scanned at *20 employing the "Navigo" scanner system. IO diagnoses using glass versus digital slides after a 3-week washout period were recorded. Intraobserver concordance was evaluated using accuracy rate and kappa statistics. Feasibility of WSI diagnoses was assessed by the way of sensitivity, specificity, as well as positive and negative predictive values. Participants also completed a survey denoting scan time, time spent viewing cases, preference for glass versus WSI, image quality, interface experience, and any problems encountered. Results: Of the 125 cases submitted, 121 (436 slides) were successfully scanned including 93 oncological and 28 donor-organ FS biopsies. Four cases were excluded because of failed digitalization due to scanning problems or sample preparation artifacts. Full agreement between glass and digital-slide diagnosis was obtained in 90 of 93 (97%, kappa = 0.96) oncology and in 24 of 28 (86%, kappa = 0.91) transplant cases. There were two major and one minor discrepancy for cancer cases (sensitivity 100%, specificity 96%) and two major and two minor disagreements for transplant cases (sensitivity 96%, specificity 75%). Average scan and viewing/reporting time were 12 and 3 min for cancer cases, compared to 18 and 5 min for transplant cases. A high diagnostic comfort level among pathologists emerged from the survey. Conclusions: These data demonstrate that the "Navigo" digital WSI system can reliably support an IO FS service involving complicated cancer and transplant cases. PMID- 30450266 TI - Estimation of Pneumonic Plague Transmission in Madagascar, August-November 2017. AB - INTRODUCTION: Between August and November 2017, Madagascar reported nearly 2500 cases of plague; the vast majority of these cases were pneumonic, resulting in early exponential growth due to person-to-person transmission. Though plague is endemic in Madagascar, cases are usually bubonic and thus result in considerably smaller annual caseloads than those observed from August-November 2017. METHODS: In this study, we consider the transmission dynamics of pneumonic plague in Madagascar during this time period, as well as the role of control strategies that were deployed to curb the outbreak and their effectiveness. RESULTS: When using data from the beginning of the outbreak through late November 2017, our estimates for the basic reproduction number range from 1.6 to 3.6, with a mean of 2.4. We also find two distinctive periods of "control", which coincide with critical on-the-ground interventions, including contact tracing and delivery of antibiotics, among others. DISCUSSION: Given these results, we conclude that existing interventions remain effective against plague in Madagascar, despite the atypical size and spread of this particular outbreak. PMID- 30450268 TI - Establishing Health Biotech and Enhancing Local Manufacturing of Pharmaceuticals in Sub-Saharan Africa. AB - Although many nations in Sub-Saharan Africa (SSA) have recently recorded impressive economic growth, and several countries could attain middle-income status in the next decade, there is no or little concurrent advance in health biotech with little capabilities for manufacturing of medicines, medical supplies, and health commodities in the region. They import majority of medicines, medical supplies, and health commodities used in national programs including immunization, family planning, tuberculosis, HIV, and malaria that drive health outcomes and population-level impact with supports mainly obtained from high-income countries, multilateral agencies, or philanthropies. Nevertheless, there is a growing global debate that countries should graduate from receiving development assistance which goes to the most important health programs like immunization when nations transition from low-income to middle income economic status. Since sudden withdrawal of all or partial development assistance could send a shock to the health care and dent the trajectory toward achieving the health Sustainable Development Goal, it is imperative to urgently establish or strengthen health biotech and enhance manufacturing of pharmaceuticals in SSA. PMID- 30450265 TI - Computationally Assisted Mechanistic Investigation and Development of Pd Catalyzed Asymmetric Suzuki-Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis. AB - Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities. PMID- 30450269 TI - A Real Human Umbilical Cord Simulator Model for Emergency Umbilical Venous Catheter Placement Training. AB - Emergency umbilical venous catheter placement is a critical procedure during newborn resuscitation. Providing training in this high-acuity and low-frequency procedure is important to optimize the skills of newborn resuscitation teams. Available simulators use simulated umbilical cords which are lower in fidelity than real human umbilical cords and may not provide optimal training. This technical report describes the creation and use of a real human umbilical cord simulator model for emergency umbilical venous catheter placement training. This low-cost model provides learners the opportunity to experience placing an emergency umbilical venous catheter in a real umbilical cord, providing a more realistic training model than currently available commercial simulators. PMID- 30450267 TI - Comparison of Birth Outcomes by Gestational Diabetes Screening Criteria. AB - Objectives This study is to examine the association between different diagnostic criteria for gestational diabetes mellitus (GDM) and adverse birth outcomes. Study Design A retrospective cohort study of 5,937 women with a singleton pregnancy was conducted, who completed GDM screening between 24 to 32 weeks gestational age. Four nonoverlapping groups of women defined as: 1) Normal: glucose challenge test (GCT) <130 mg/dL, 2) elevated GCT + normal oral glucose tolerance test (OGTT): abnormal 1 hour GCT + normal 3 hour OGTT, 3) GDM/International Association of Diabetes in Pregnancy Study Group (IADPSG): abnormal 3 hour OGTT by the IADPSG criteria, and 4) GDM/Carpenter-Coustan (CC): diagnosis per CC criteria. We used logistic regression to examine the association between GDM group classification and main outcome of macrosomia and secondary birth outcomes. Results Prevalences were GDM/CC 4.6%, GDM/IADPSG 3.0, and 7.6% overall. GDM/IADPSG group was associated with increased macrosomia (adj OR [odd ratio] 1.87; 95% CI [confidence interval]: 1.08-3.25; p = 0.02), while GDM/CC group was associated with increased preterm birth (adj OR 1.75; 95% CI: 1.05 2.80; p = 0.03). Conclusion Little difference in birth outcomes was found between the two criteria, GDM/CC and GDM/IADPSG. Randomized controlled trials are needed to clarify the risks and benefits of these screening paradigms before their incorporation into clinical practice. PMID- 30450270 TI - Inhibition of crude viper venom action by silver nanoparticles: A biophysical and biochemical study. AB - This investigation understands the interaction between lyophilized crude Viper snake venom (Doboia russellie) and Silver nanoparticles (SNPs) using biophysical and biochemical approaches. SNPs were synthesized by chemical reduction method and characterized using UV-Visible spectroscopy, Dynamic Light Scattering (DLS) and Transmission electron microscope (TEM). The average hydrodynamic size of SNPs was found to be 52 nm with 0.261 PDI. TEM image revealed the spherical shape of SNP. Interaction of SNPs and viper venom was resulted in the formation of complex which was confirmed by using DLS technique. Spectroscopic results showed an increase in absorbance intensity of venom upon interaction with SNPs which indicated interaction with venom proteins. Fluorescence spectroscopic data revealed the quenching in the fluorescence intensity of viper venom upon incubation with varying concentration of SNPs. The results obtained by biochemical assays (Protease and whole blood clotting test) revealed the inhibition of venom action due to presence of silver nanoparticles. The activity of protease enzyme was found to be decreased (10-13% reduction) in presence of silver nanoparticles. Prolonged clotting time (two fold) of viper venom upon interaction with SNPs compared to native crude viper venom was observed. The overall results confirmed the inhibition action of silver nanoparticles against viper venom. PMID- 30450271 TI - Verification of the effect of the axon fluid as a highly dielectric medium in the high-speed conduction of action potentials using a novel axon equivalent circuit. AB - Both sensory neurons and motor neurons transfer signals rapidly through long pathways. Such signals propagate as action potentials through neurons. In myelinated neurons, high conduction velocities of 120 m/s have been reported, even for axons of just 20 MUm in diameter. Such a high conduction velocity is enabled by the characteristic morphology of a myelinated axon: repeated regions encased by long uniform myelin sheaths alternating with extremely short exposed regions of the axon called nodes of Ranvier, which generate extremely sharp action potentials. Although the need for the action potential to cross many nodes increases the relay time, it is still able to propagate rapidly. This phenomenon motivated us to derive a new mechanism of the action potential propagation. First, the dielectric effect of the axonal fluid was considered, and it was investigated whether the combination of the characteristic axonal morphology and the dielectric constant of the axonal fluid contributes significantly to the realization of high conduction velocities even with the inclusion of a large loss in the relay time. To this end, we propose a new axon equivalent circuit that incorporates the effect of the dielectric characteristics of the axonal fluid. It was confirmed that a realistically high conduction velocity could be calculated using the proposed circuit and that the dielectric constant calculated using the proposed circuit was in agreement with that of an ionic fluid similar to axonal fluid. Moreover, the contribution of the combination of the axonal morphology and axonal fluid to the conduction velocity was confirmed. PMID- 30450272 TI - Fluorescent nanodiamonds as a robust temperature sensor inside a single cell. AB - Thermometers play an important role to study the biological significance of temperature. Fluorescent nanodiamonds (FNDs) with negatively-charged nitrogen vacancy centers, a novel type of fluorescence-based temperature sensor, have physicochemical inertness, low cytotoxicity, extremely stable fluorescence, and unique magneto-optical properties that allow us to measure the temperature at the nanoscale level inside single cells. Here, we demonstrate that the thermosensing ability of FNDs is hardly influenced by environmental factors, such as pH, ion concentration, viscosity, molecular interaction, and organic solvent. This robustness renders FNDs reliable thermometers even under complex biological cellular environment. Moreover, the simple protocol developed here for measuring the absolute temperature inside a single cell using a single FND enables successful temperature measurement in a cell with an accuracy better than +/-1 degrees C. PMID- 30450273 TI - Management of Denys-Drash syndrome: A case series based on an international survey. AB - Denys-Drash syndrome (DDS), a condition caused by mutations in the tumor suppressor gene WT-1, is associated with a triad of disorders: ambiguous genitalia, nephrotic syndrome leading to end-stage renal disease (ESRD), and Wilms' tumor. Given the variable disease course, management is challenging. We aimed to describe the evolution of DDS and the range of management strategies by summarizing the clinical courses of cases collected from a questionnaire sent to the international pediatric nephrology community. 15 respondents provided information on 23 patients; 21 DDS cases were confirmed and analyzed. At DDS diagnosis, 6 patients had a Wilms' tumor (group A) and 15 had no Wilms' tumor (group B). Three group A patients had unilateral nephrectomy. Two of these still had renal function, with no second tumor, at 36 months and 16 years of age, and 1 progressed to ESRD. Three had bilateral nephrectomy before ESRD. Eight group B patients progressed to ESRD, all of whom later had all renal tissue removed. Two group B patients subsequently developed a unilateral Wilms' tumor and had bilateral nephrectomy pre-ESRD. Three had bilateral nephrectomy prior to reaching ESRD without ever having a Wilms' tumor. Two group B patients remained tumor-free with renal function at last follow-up. Two main management approaches were taken: pre-emptive nephrectomy prior to ESRD and conservative surveillance. Based on the known risks associated with ESRD in infants and young children, the variable course of DDS, and the relatively good prognosis associated with Wilms' tumor, a guiding principle of preservation of renal function is most logical. Most would advocate bilateral prophylactic nephrectomy after ESRD is reached due to the high tumor risk, which is likely heightened after transplant. PMID- 30450274 TI - Strong association between cervical and breast cancer screening behaviour among Danish women; A register-based cohort study. AB - High coverage is essential for the effectiveness of national screening programmes. Identifying non-screeners across different screening programmes may help inform strategies to improve uptake. This study aims to analyse the association between previous cervical cancer screening (CCS) coverage and participation in breast cancer screening (BCS). This historical register-based cohort study included 91,787 Danish women aged 50-64 years who were invited to participate in the first organised round of BCS in the Central Denmark Region (CDR) in 2008-09. CCS coverage was defined as having a smear registered in the 5 1/2 years preceding the BCS, and BCS participants were divided into participants and non-participants and further categorised as active non-participants (ANP) if they cancelled and passive non-participants (PNP) if they abstained from the appointment. Of all 91,787 women included in the study, 62,391 (68%) were covered both by CCS and participated in BCS. Women not covered by CCS were more likely to be non-participants in BCS than women covered by CCS (PRRadjusted = 2.80, 95% CI: 2.68-2.93). Both PNP (PRRadjusted = 3.99, 95% CI: 3.80-4.19) and ANP (PRRadjusted = 2.50, 95% CI: 2.34-2.68) were more likely not to be covered by the CCS. In conclusion, non-coverage by CCS was strongly associated with nonparticipation in BCS. Specific groups of women only participated in one screening programme. To increase uptake, future interventions may specifically target these groups. PMID- 30450275 TI - Invasive fungal infection by Aspergillus flavus in immunocompetent hosts: A case series and literature review. AB - Invasive aspergillosis usually affects immunocompromised hosts with variable manifestations depending on the site of infection. In this article, we present two cases of invasive Aspergillosis in two non-immunocompromised patients; both cases had a paranasal sinuses infection, with intraorbital and intracranial extension, requiring surgery and antifungal treatment with Voriconazole. These cases were initially diagnosed as paranasal sinus neoplasms. However, the pathology and microbiology studies revealed invasive fungal infection by Aspergillus flavus. PMID- 30450276 TI - Recurrent rheumatoid pleural effusions complicated by Mycobacterium heckeshornense infection. AB - A 41-year-old man with rheumatoid arthritis (RA) presented with worsening dyspnea and deconditioning. He had recently been treated with adalimumab for rheumatoid pleural effusions but developed non-tuberculous mycobacterial pleurisy due to Mycobacterium heckeshornense. Despite therapy with appropriate anti-mycobacterial agents, he ultimately required video assisted thoracoscopy for decortication. While Mycobacterium heckeshornense has been reported to cause infection in multiple sites including the lung, this is the first case to our knowledge of infection confined to the pleural space. Rheumatoid pleural effusions can be complex and difficult to treat, especially when complicated by mycobacterial infection. PMID- 30450278 TI - Improved quality of life associated with long-term use of guaifenesin in a patient with chronic obstructive pulmonary disease (COPD) & stable chronic bronchitis: A case report. AB - We read with interest the recent case reports in this journal on the apparent beneficial effects of long-term, high-dose guaifenesin in patients with chronic respiratory disease. This prompted us to review our own patient database as we also recommend daily guaifenesin to patients who report problems with mucociliary clearance. In our rural primary care practice, we currently have over 20 patients who have taken guaifenesin daily, for more than 3 years as an adjuvant to their prescribed medications for either chronic obstructive pulmonary disease (COPD) and/or stable chronic bronchitis. We report the long-term use of guaifenesin in one such patient with COPD, chronic bronchitis and seasonal allergies who presented with dyspnea and chronic, non-productive cough that impacted his activities of daily living. PMID- 30450277 TI - Acute respiratory distress syndrome after the use of gadolinium contrast agent. AB - Acute respiratory distress syndrome (ARDS) is a life-threatening medical emergency. The etiology of ARDS can involve various causes. ARDS associated with the use of iodinated contrast media is rarely reported, and the literature includes only one case of ARDS due to gadobutrol. A 46-year-old female patient presented to our emergency department with shortness of breath, wheezing, swelling of the lips, and difficulty swallowing about 30 minutes after undergoing magnetic resonance imaging with 6.5 ml (0.1 ml/kg) gadobutrol (Gadovist) contrast for a submandibular mass. She was treated for anaphylaxis, then immediately evaluated using chest x-ray and arterial blood gas analysis. Based on the findings, she was diagnosed with ARDS and started on continuous positive airway pressure (CPAP) ventilatory support and methylprednisolone at a dose of 1 mg/kg/day. On day 3 of follow-up, all symptoms had completely regressed. PMID- 30450279 TI - Ictal vomiting after cerebellar hemorrhage: A case report. AB - Vomiting is a typical symptom of cerebellar hemorrhage. Usually only supportive care such as antiemetic drugs are available. A 76-year-old woman presented in a light coma. A head CT demonstrated right cerebellar hemorrhage and the hematoma was surgically evacuated. Her intractable vomiting started 3 weeks after surgery. Because her vomiting was unexplained, we checked her EEG, which demonstrated generalized periodic discharges. We diagnosed her with ictal vomiting. Anti seizure medication was administered and vomiting was rapidly controlled. In conclusion, physicians must be aware that vomiting may rarely occur as a sign of seizures and status epilepticus. PMID- 30450280 TI - Absorption spectra of nanodiamond aqueous dispersions by optical absorption and optoacoustic spectroscopies. AB - The multispectral modality and technique for optically dense samples of optoacoustic spectroscopy were applied to measure spectra and high absorbances of concentrated aqueous dispersions of undoped nanodiamonds. The data from optoacoustic and optical transmission measurements and DSC data of the mean particle size by the Gibbs-Kelvin equation are compared to estimate the difference in composition of various nanodiamond trademarks. Optoacoustic spectra confirm the contribution of surface dimer chains into the absorption of nanodiamonds in the long wavelength range. Optoacoustic and conventional absorption spectra of aqueous solutions of nanodiamond fractions after centrifugation (15300g) and ultracentrifugation (130000g) revealed a separation of a highly absorbing non-diamond sp2 phase. The two-step separation by ultracentrifugation followed by extra centrifugation made it possible to isolate a highly absorbing and soluble nanodiamond phase with the particle size of 3.6 nm, showing a change in spectra compared to the starting nanodiamond material. PMID- 30450282 TI - Para testicular adult rhabdomyosarcoma: A case report and review of litterature. PMID- 30450283 TI - Bladder metastasis of gastric signet-ring cell carcinoma. PMID- 30450281 TI - Photoacoustic imaging for monitoring periodontal health: A first human study. AB - The gold-standard periodontal probe is an aging tool that can detect periodontitis and monitor gingival health but is highly error-prone, does not fully characterize the periodontal pocket, and causes pain. Photoacoustic imaging is a noninvasive technique that can address these limitations. Here, a range of ultrasound frequencies between 16-40 MHz were used to image the periodontium and a contrast medium based on cuttlefish ink was used to label the pockets. A 40 MHz ultrasound frequency could spatially resolve the periodontal anatomy, including tooth, gum, gingival margin, and gingival thickness of tooth numbers 7-10 and 22 27. The photoacoustic-ultrasound measurements were more precise (0.01 mm) than those taken with physical probes by a dental hygienist. Furthermore, the full geometry of the pockets could be visualized with relative standard deviations of 10% (n = 5). This study shows the potential for non-invasive monitoring of periodontal health with photoacoustic-ultrasound imaging in the dental clinic. PMID- 30450284 TI - Complete bladder eversion through a vesicovaginal fistula. PMID- 30450287 TI - Malignant pleural and peritoneal mesothelioma: clinical update 2018. PMID- 30450285 TI - The dose response principle from philosophy to modern toxicology: The impact of ancient philosophy and medicine in modern toxicology science. AB - Since ancient times the concept of dose response, from a toxicological perspective, has been a matter of concern. Already by the 8th century BC and over the years, many enlightened people have attempted to interpret this phenomenon, observing and coming across its results and practical implementation through exposure to chemical substances, either from natural or synthetic sources. Nowadays, the environmental exposure of human populations to chemicals in terms of quantity and quality might differ. Nevertheless, dose response still remains an issue joining hands with scientific and technological progress. The aim of the present review is not only to briefly recount the history of the dose response concept, from ancient time theories to novel approaches, but also to draw the outline of challenges and requirements toxicology science needs to fulfill. PMID- 30450286 TI - Cognition in schizophrenia improves with treatment of severe obstructive sleep apnoea: A pilot study. AB - Previous studies have shown that people with schizophrenia have high rates of Obstructive Sleep Apnoea (OSA). Despite this, intervention studies to treat OSA in this population have not been undertaken. The ASSET (Assessing Sleep in Schizophrenia and Evaluating Treatment) pilot study investigated Continuous Positive Airway Pressure (CPAP) treatment of severe OSA in participants recruited from a clozapine clinic in Adelaide. Participants with severe untreated OSA (Apnoea-Hypopnoea Index (AHI) > 30), were provided with CPAP treatment, and assessed at baseline and six months across the following domains: physical health, quality of sleep, sleepiness, cognition, psychiatric symptoms and CPAP adherence. Six of the eight ASSET participants with severe OSA accepted CPAP. At baseline, half of the cohort had hypertension, all were obese with a mean BMI of 45, and they scored on average 1.47 standard deviations below the normal population in cognitive testing. The mean AHI was 76.8 and sleep architecture was markedly impaired with mean rapid eye movement (REM) sleep 4.1% and mean slow wave sleep (SWS) 4.8%. After six months of treatment there were improvements in cognition (BACS Z score improved by an average of 0.59) and weight loss (mean weight loss 7.3 +/- 9 kg). Half of the participants no longer had hypertension and sleep architecture improved with mean REM sleep 31.4% of the night and mean SWS 24% of the night. Our data suggests CPAP may offer novel benefits to address cognitive impairment and sleep disturbance in people with schizophrenia. PMID- 30450288 TI - The use of patient-reported outcome measures (PROMs) in the management of malignant pleural mesothelioma: a descriptive literature survey. AB - Background: Malignant pleural mesothelioma (MPM) remains a highly symptomatic and aggressive malignancy. The treatment options are for most patients limited to palliative chemotherapy and best supportive care. Therefore, the use of patient reported outcome measures (PROMs) is recommended for the improvement of the quality of care. The aim of this literature survey is to provide an up to date review of the use of PROMs in mesothelioma. A concise comparison is made of the identified instruments. Methods: We searched PubMed, Web of Science and Google Scholar for the use of PROMs in MPM. Quality of the study and risk of bias were assessed using the appraisal tools recommended by the Dutch Cochrane Center. Results: A total of 31 articles on PROMs in MPM were identified that met the inclusion criteria and a total of 14 instruments. The instruments are categorized in generic (n=2), cancer-specific (n=4), lung cancer-specific (n=3), mesothelioma specific (n=2) and symptom-specific (n=3). They were mostly used in clinical trials. Conclusions: PROMs have the potential to improve the management of MPM. No particular instrument is specifically recommended, although there is a preference for patient-reported disease-specific instruments encompassing the concept of health-related quality of life (hrQoL) and relevant symptoms. Such instruments are the EORTC QLQ-LC13, LCSS-Meso and FACT-L, which measure the impact of malignant mesothelioma and its treatment on patients. Assessments should be made on baseline and post-treatment. The frequency of assessments should be further evaluated in this population. PMID- 30450289 TI - Hotspots of malignant pleural mesothelioma in Western Europe. AB - Malignant pleural mesothelioma, a highly invasive tumour, has been epidemiologically linked to an occupational or environmental exposure to asbestos. Although asbestos has been widely used in diverse industrial applications and in construction, some industrial sectors have been affected much more than others. The objective of this review was to describe the existence of clusters of malignant pleural mesothelioma in Western European countries, based on epidemiological studies published between 2000 and 2015. MEDLINE (PubMed) and Embase were searched for relevant studies on spatial clustering of mesothelioma in Western European countries. Eventually, 16 different studies published between 2000 and 2015 were selected for a comprehensive analysis. Relevant studies on spatial clustering of mesothelioma were found for Belgium, the Netherlands, the United Kingdom, Germany, France, Spain, Italy and Denmark. Clustering of pleural mesothelioma was found mainly around shipyards (16 studies) and asbestos cement industries (10 studies). Although malignant pleural mesothelioma may be found throughout Western Europe, the present study indicates specific areas with higher past and also probable future incidence. PMID- 30450291 TI - Malignant peritoneal mesothelioma: a review. AB - Malignant peritoneal mesothelioma (MPM) is a very rare malignancy of the peritoneum and has a poor prognosis. Of all mesotheliomas, pleural mesothelioma is more common than MPM. In comparison to pleural mesothelioma, the link with asbestos exposure is weaker (33-50% vs. >80%), but it is still the best-defined risk factor. MPM spreads predominantly expansive rather than infiltrative and symptoms are related to tumor spread within the abdominal cavity. Often, MPM is encountered incidentally by diagnostic imaging or by surgery. Computed tomography scan is widely accepted as a first line modality in diagnostic imaging. In diagnostic histopathology, MPM presents some challenges. Firstly, adequate clinical information is of utmost importance to consider the possibility of the diagnosis of MPM. Furthermore, a few morphological subtypes and variants exist. The most sensitive immunohistochemical markers are calretinin (100%), WT1 (94%) and CK5/6 (89%). The malignant character of immunohistochemically demonstrated mesothelial cells is not always obvious. This paradigm somewhat changed with the advent of immunohistochemical demonstration of BAP1 (BRCA-1 associated protein 1). Loss of BAP1 expression supports a diagnosis of malignancy. The gold standard in treatment remains cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Targetable molecular pathways in MPM are being identified. An exciting finding was the demonstration of ALK rearrangements in a small subset of patients with MPM and it is hoped for that at least this small subgroup of patients could benefit from treatment with ALK inhibitors. First-generation tyrosine kinase inhibitors against epidermal growth factor receptor (EGFR) did not show any significant activity in MPM. In contrast, nintedanib, an angiokinase inhibitor, improved progression-free survival and bevacizumab, a humanized anti-VEGF antibody increased overall survival in patients with MPM, when administered in combination with cisplatin and pemetrexed. Ongoing immunotherapy trials will offer a possible new treatment. PMID- 30450290 TI - Breath analysis as a diagnostic and screening tool for malignant pleural mesothelioma: a systematic review. AB - Malignant pleural mesothelioma (MPM) is a tumour related to a historical exposure to asbestos fibres. Currently, the definite diagnosis is made only by the histological examination of a biopsy obtained through an invasive thoracoscopy. However, diagnosis is made too late for curative treatment because of non specific symptoms mainly appearing at advanced stage disease. Hence, due to its biologic aggressiveness and the late diagnosis, survival rate is low and the patients' outcome poor. In addition, radiological imaging, like computed tomographic scans, and blood biomarkers are found not to be sensitive enough to be used as an early diagnostic tool. Detection in an early stage is assumed to improve the patients' outcome but is hampered due to non-specific and late symptomology. Hence, there is a need for a new screening and diagnostic test which could improve the patients' outcome. Despite extensive research has focused on blood biomarkers, not a single has been shown clinically useful, and therefore research recently shifted to "breathomics" techniques to recognize specific volatile organic compounds (VOCs) in the breath of the patient as potential non invasive biomarkers for disease. In this review, we summarize the acquired knowledge about using breath analysis for diagnosing and monitoring MPM and asbestos-related disorders (ARD). Gas chromatography-mass spectrometry (GC-MS), the gold standard of breath analysis, appears to be the method with the highest accuracy (97%) to differentiate MPM patients from at risk asbestos-exposed subjects. There have already been found some interesting biomarkers that are significantly elevated in asbestosis (NO, 8-isoprostane, leukotriene B4, alpha Pinene...) and MPM (cyclohexane) patients. Regrettably, the different techniques and the plethora of studies suffer some limitations. Most studies are pilot studies with the inclusion of a limited number of patients. Nevertheless, given the promising results and easy sampling methods, we can conclude that breath analysis may become a useful tool in the future to screen for MPM, but further research is warranted. PMID- 30450292 TI - The eighth TNM classification for malignant pleural mesothelioma. AB - In 2016, the International Association for the Study of Lung Cancer (IASLC) published a number of revisions of the seventh edition of the tumor, node and metastasis (TNM) classification for malignant pleural mesothelioma (MPM). The purpose was to establish a set of recommendations for the eighth edition of the TNM staging system. A large number of patients were included in the IASLC database and subsequently analysed to determine new definitions for the components of the TNM classification. A number of important changes were introduced for the T component. Survival analysis of the different T categories showed no significant difference in categories T1a and T1b. This has resulted in a collapse of categories T1a and T1b into one category T1. In addition, tumor thickness was also significantly associated with overall survival. The descriptors for the N components have been redefined as well for the eighth TNM classification. A major revision is the removal of category N3 in the N component. Both intrapleural and extrapleural (N1 and N2 in the seventh edition) are now combined into a single category N1. Lymph nodes that were previously categorized as N3 are now considered N2. For the M component, no redefinition has been published. However, a recommendation has been made to only consider M1 involvement as stage IV disease. This is in contrast to the seventh edition in which T4 and N3 disease were considered stage IV as well. In conclusion, a number of important revisions for the eighth TNM classification of MPM have been published as a result of this IASLC project. This type of large-scale and international joint efforts are key in establishing effective staging systems. Research into using tumor thickness as a prognostic instrument will be an important part of any future editions of the TNM classification. PMID- 30450293 TI - Extrapleural pneumonectomy: still indicated? AB - The optimal treatment of malignant pleural mesothelioma (MPM) has not yet been established and is still under investigation. Surgery is one of the pillars in the multimodality approach with the purpose of removing as much as visible tumor as possible and to relieve symptoms. To date, two major surgical procedures are available for removal or debulking of MPM that is considered to be resectable: [extended (e)] pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP). Historically, EPP was regarded as the only way to achieve a macroscopic complete resection. However, in the last years, there is a shift in literature towards (e)P/D as the preferred surgical procedure whenever possible as several retrospective studies and meta-analyses showed a similar or lower long-term survival and higher perioperative mortality and postoperative morbidity in patients who been treated with EPP. On the other hand, no randomized-controlled trials regarding surgical treatment with (e)P/D or EPP exist and therefore level A evidence favoring one surgical procedure is lacking. In this review we provide a nuanced and well-considered answer to the question whether EPP is still indicated in the surgical treatment of MPM. PMID- 30450294 TI - Extended pleurectomy decortication: the current role. AB - Extended pleurectomy/decortication (EPD) has been formally defined but there remain technical areas of debate between practitioners. This is partly attributable to the relative rarity of this operation which is largely confined to a small number of specialist centres. Nevertheless, there is a widespread acceptance that extended pleurectomy/decortication (P/D) is a realistic and favourable alternative to extrapleural pneumonectomy. There may, however, remain a small number of clinical cases where this more extensive operation may be indicated. Preservation of the lung has widened the selection criteria for this form of radical mesothelioma surgery but there remain important factors to consider when offering extended P/D. In many patients with poorer prognostic factors the less radical operation of video assisted partial pleurectomy may be preferable. However, a randomized trial showed no survival benefit for this operation over simple talc pleurodesis. The future for P/D may also lie in the outcome of the MARS2 randomized controlled trial which will report in the next few years. Meanwhile there is a clinical and ethical dilemma when asked to perform this operation outside of the context of a clinical trial in the face of the lack of high grade evidence. The role of P/D is in one respect expanding but this may be short lived pending the findings of its assessment against non surgical treatment. PMID- 30450295 TI - Combined modality treatment in mesothelioma: a systemic literature review with treatment recommendations. AB - In spite of recent progress, malignant pleural mesothelioma (MPM) remains synonymous with poor prognosis. A selected minority (<10%) of patients is eligible for a radical treatment with a combination of systemic chemotherapy (CT) and/or surgery and/or radiotherapy (RT), in an effort to maintain locoregional tumor control after achieving a macroscopically complete resection (MCR). However, as of yet there is no standard of care for this so-called multimodality treatment. As its potential gain is still limited (approximately one year added to overall survival), we must balance its efficacy with its cumulative toxicity. Several combined modality treatment trials are currently ongoing using novel techniques in surgery, RT and/or CT in an attempt to reduce the morbidity and mortality associated with older multimodality treatment protocols. Guidelines are following suit and are now including or mentioning this treatment option. In this systematic review, we analyze the available data in order to address the following questions: Is combined modality better than single modality? What is the optimal regimen within each modality? What is the optimal sequence of combined modality? PMID- 30450296 TI - Current chemotherapy strategies in malignant pleural mesothelioma. AB - Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a 5-year survival rate of ~10%. Since most patients present with irresectable disease, the vast majority is treated with chemotherapy. The only registered therapy for MPM is platinum-pemetrexed doublet therapy, although only up to half of patients have clinical benefit from this palliative treatment. Of the anti-angiogenesis agents, only bevacizumab and nintedanib have shown activity with platinum-pemetrexed doublet therapy. Other anti-angiogenesis agents like thalidomide did not prolong (progression free) survival or response rate. Eventually, all patients will get a recurrence and no active second line therapy has been identified to date. The clinical benefit of (switch) maintenance therapy after first line treatment and combination strategies of different chemotherapies with angiogenesis inhibitors are currently under investigation. The major challenges are finding optimal treatment combinations and to select the adequate treatment for an individual patient. This review focusses on the current standard of chemotherapy and new systemic therapy strategies under investigation. PMID- 30450297 TI - Is there a role for prophylactic radiotherapy to intervention tract sites in patients with malignant pleural mesothelioma? AB - Malignant pleural mesothelioma has a high morbidity and poor prognosis. Most patients undergo invasive pleural interventions to either facilitate diagnosis and/or alleviate symptoms from malignant pleural effusion. Procedure tract metastasis (PTM) are a well-known complication of pleural procedures in mesothelioma and there has been longstanding debate regarding the role of prophylactic irradiation of tracts in preventing them. This review summarises the existing evidence surrounding this controversial topic. Despite initial discrepancies amongst the results of 3 small, historical trials regarding the efficacy of prophylactic radiotherapy in mesothelioma, two large randomised control trials have recently provided more clarity. The SMART trial, which randomised over 200 patients, found no benefit of prophylactic radiotherapy in reducing PTM incidence in their primary analysis, with a number needed to treat (NNT) of 25.1 to prevent a single painful PTM. Additionally, there was no benefit in terms of symptomology, health-related quality of life parameters or cost effectiveness. This is supported by the preliminary results of the Prophylactic Irradiation of Tracts in Patients with Pleural Mesothelioma (PIT) trial, which randomised 375 patients and also found no evidence that prophylactic radiotherapy reduced PTM incidence, although the full results are still awaited. Combined analysis of these trials is planned, which will help clarify whether specific subpopulations may derive benefit from prophylactic radiotherapy, such as patients not receiving chemotherapy. Based on the currently available evidence there is no role for routine delivery of prophylactic radiotherapy to prevent PTM in mesothelioma. Instead holistic and vigilant follow-up of patients is recommended, aiming for adequate palliation of symptoms and support for patients. Should painful nodules develop these can be effectively treated with subsequent palliative radiotherapy. After years of uncertainty and debate, recent international guidelines have consistently advised against the use of prophylactic irradiation of tracts based on contemporary high-quality evidence. PMID- 30450298 TI - A randomized phase II study of pleurectomy/decortication preceded or followed by (neo-)adjuvant chemotherapy in patients with early stage malignant pleural mesothelioma (EORTC 1205). AB - Radical multimodality treatment for malignant pleural mesothelioma (MPM) is controversial, with intense debate (but lack of data) about which surgical procedure to perform [extrapleural pneumonectomy (EPP) or pleurectomy/decortication (PD)], if any. In order to perform a randomized comparison, the most optimal sequence of surgery and chemotherapy should be determined. EORTC 1205 is a clinical trial randomizing between upfront surgery, followed by chemotherapy (cisplatin plus pemetrexed) and deferred surgery, following neoadjuvant chemotherapy in early stage (T1-3 N0-2 M0) MPM (irrespective of histological subtype). The surgical procedure performed is (extended) pleurectomy/decortication (e-PD), which is promoted as an alternative for EPP, but lacks standardization. Primary outcome parameter is successful completion of multimodality treatment; secondary outcome parameters are surgical quality parameters (in order to standardize the procedure), progression free survival (PFS) and overall survival (OS), treatment-failure free survival, operative morbidity and mortality, toxicity and safety. PMID- 30450300 TI - Translational Lung Cancer Research, the 7th AME Journal indexed in SCIE. PMID- 30450299 TI - Update on the management of malignant peritoneal mesothelioma. AB - Malignant peritoneal mesothelioma (MPM) is a rare disease whose natural history is confined to the peritoneal space. Systemic chemotherapy has little impact on survival of patients with MPM. A surgical procedure with a goal of resection of all visible evidence of disease, called cytoreductive surgery (CRS) has been utilized in MPM patients. Also, regional chemotherapy with hyperthermic intraperitoneal chemotherapy (HIPEC) and normothermic intraperitoneal chemotherapy long-term (NIPEC-LT) have been effectively utilized in MPM patients. In the absence of CRS and HIPEC the median survival of MPM patients is approximately 1 year. The aggressive surgical approach plus regional chemotherapy has increased the median survival to more than 5 years. With NIPEC-LT added on, 70% 5-year survival has been reported. Knowledgeable patient selection for treatment is mandatory. The use of CRS, HIPEC and NIPEC-LT has greatly benefited patients with MPM. Global application of these treatments is indicated. PMID- 30450302 TI - Experimental study on the biocompatibility of keratoprosthesis with improved titanium implant. AB - AIM: To investigate whether hydroxyapatite (HAp) coating can improve keratoprosthesis (KPro) implant biointegration, ultimately to decrease the risk of implant-associated complications. METHODS: The modified titanium implant was designed and prepared for artificial cornea. The titanium implant was treated with sandblasting and hydroxyapatite coating by acid-base two-step method. Surface was analyzed by scanning electron microscopy (SEM), KPro implants coated with HAp and KPro implant sandblasted were implanted in rabbits. Tissue adhesion to the implant was assessed and compared to an unmodified implant by histopathology (HE), transmission electron microscopy (TEM) and SEM. RESULTS: SEM demonstrated successful deposition of HAp on titanium implant sandblasted (HA/SB Ti). The hydroxyapatite coatings caused enhancement of keratocyte proliferation compared with unmodified implant surfaces. HAp coating significantly increased adhesion forces. HAp coating of implants reduced the inflammatory response around the KPro implants in vivo. CONCLUSION: HAp-coated surfaces for use in titanium KPro implant greatly enhanced adherence of the titanium KPro implant in the rabbit cornea. PMID- 30450301 TI - Increased succinate receptor GPR91 involved in the pathogenesis of Mooren's ulcer. AB - AIM: To investigate the expression of succinate receptor GPR91 and its pathogenic roles in Mooren's ulcer (MU). METHODS: Biopsy specimens were obtained from 7 patients with MU and 6 healthy donors. The expression of GPR91 in MU tissues was evaluated using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). Succinate was used to activate GPR91 signaling, and the effect of GPR91 on the expression of interleukin-1beta (IL-1beta), NLRP3, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-13 (MMP-13) in human peripheral blood mononuclear cells (PBMCs) was determined. The influence of GPR91 on the nuclear factor-kappaB (NF-kappaB) signaling in PBMCs was investigated by detecting the phosphorylation of p65. Moreover, the expression of IL-1beta, VEGF, MMP-13 and phosphorylated p65 (p-p65) in the tissues of MU was examined by qRT-PCR or IHC. RESULTS: GPR91 mRNA expression showed a higher level in the MU group than in the healthy control group. IHC analysis also revealed that the expression of GPR91 was elevated in patients with MU compared with healthy controls. Moreover, ligation of GPR91 with succinate promoted the lipopolysaccharide-induced production of NLRP3, IL-1beta, VEGF and MMP-13 in PBMCs through increased phosphorylation of p65. Pharmacological inhibition of the NF-kappaB signaling reversed GPR91 induced production of NLRP3, IL-1beta, VEGF and MMP-13. These findings, coupled with the elevated amounts of IL-1beta, VEGF, MMP-13 and p-p65 observed in the MU biopsies, constituted a rational basis for the involvement of GPR91 in the pathogenesis of MU. CONCLUSION: This study indicates the increased succinate receptor GPR91 in conjunctival or corneal tissues is involved in the pathogenesis of MU through elevated NF-kappaB activity, which may provide a new therapeutic target for MU. PMID- 30450303 TI - Exploration of the glutamate-mediated retinal excitotoxic damage: a rat model of retinal neurodegeneration. AB - AIM: To explore the more suitable concentration of glutamate or N-methyl-D aspartic acid (NMDA) for intravitreal injection to establish a rat model of retinal neurodegeneration. METHODS: We injected different doses of glutamate (20 or 50 nmol) or NMDA (40 nmol) into the vitreous chambers of rats, then measured the concentration of glutamate and retinal thickness, quantified apoptotic cells and determined the degree of tau hyperphosphorylation at different time points. T test was used for comparison of two groups. One-way ANOVA and Turkey's multiple comparisons test were used for comparisons of different groups, and P values below 0.05 were considered statistically significant. RESULTS: The glutamate level in the rats treated with 50 nmol of glutamate was twice that of the control group and persisted two weeks. Seven days after intravitreal injection of 50 nmol of glutamate, three parameters [inner retinal thickness (IRT), retinal thickness (RT) and ganglion cell layer (GCL) cell number] were reduced significantly. Furthermore, numerous TUNEL-positive cells were observed in the GCL one day after intravitreal injection of 50 nmol of glutamate, the expression of the apoptosis related factor cleaved casepase-3 was markedly increased compared with the expression levels in the other treatment groups, and the expression levels of tau s396 and tau s404 were significantly increased compared with those in the control group. CONCLUSION: This study demonstrates that the intravitreal injection of 50 nmol of glutamate can establish the more effective retinal neurodegeneration animal model relative to other treatment groups. PMID- 30450304 TI - Effect of green flickering light on myopia development and expression of M1 muscarinic acetylcholine receptor in guinea pigs. AB - AIM: To investigate the effects of green flickering light on refractive development and expression of muscarinic acetylcholine receptor (mAChR) M1 in the eyes of guinea pigs. METHODS: Thirty guinea pigs (15-20 days old) were randomly divided into three groups (n=10/group). Animals in group I were raised in a completely closed carton with green flickering light illumination. Those in group II were kept in the open top closed carton under normal natural light. Guinea pigs were raised in a sight-widen cage under normal natural light in group III. The refractive status and axial length were measured before and after 8 weeks' illumination. Moreover, total RNA extracted from retinal, choroidal, and scleral tissues were determined by real-time reverse transcription polymerase chain reaction (RT-PCR). The expressions of the receptor M1 were also explored in the retina, choroid, and sclera using immunohistochemistry. RESULTS: There was a remarkable reduction in refractive error and increase in axial length after 8 weeks' green flickering light stimulation (P<0.001). The expression of M1 receptor mRNA in sclera and retina in myopia group were remarkably lower than that in group II and III (P<0.01). Significant reduced expression of M1 receptor stimulated by green flickering light in retina and sclera tissues were also observed (P<0.05). However, there was no M1 receptor expression in choroid in 3 groups. CONCLUSION: Myopia can be induced by 8 weeks' green flickering light exposure in the animal model. M1 receptor may be involved causally or protectively in myopia development. PMID- 30450306 TI - Endothelial parameters in central and peripheral cornea in patients wearing contact lenses. AB - AIM: To measure the parameters of endothelium in the central and peripheral parts of the cornea and evaluate the influence of wearing the hard and soft contact lenses on the mentioned parameters. METHODS: A specular microscope was used to measure the corneal endothelium parameters in both eyes of 139 Caucasians (a total of 278). All participants were divided into three groups: soft lens wearers, hard lens wearers and a control group. Factors, such as age, smoking, types of lens material, duration of lens wear and lens air permeability were assessed to determine their impact on the morphometric parameters of the endothelium. RESULTS: A lower percentage of hexagon-like cells and higher cell variation than in other groups were determined in hard contact lens wearers. The difference in density of endotheliocytes between the groups was not observed. The measurements of the morphometric parameters in soft contact lens wearers did not depend neither on the duration of lens wear, nor on air permeability. The relation between the patients' age and the variation of endothelium parameters was determined in the group of hard contact lens wearers. CONCLUSION: Wearing hard contact lenses provokes pleomorphism and polymegethism of the corneal endothelium, while soft contact lenses do not impact any parameters of the endothelium, most likely due to higher air permeability. PMID- 30450305 TI - Two-stage procedure in the management of selected cases of keratoconus: clear lens extraction with aspherical IOL implantation followed by WFG-PRK. AB - AIM: To assess the objective and subjective results of a two-stage procedure for management of keratoconus: clear lensectomy with aspherical intraocular lens (IOL) implantation followed by wave front-guided photorefractive keratotomy (WFG PRK). METHODS: This prospective interventional non-randomized study included patients aged 35 years old or more with grade I and II stable keratoconus, a clear visual axis, minimal corneal thickness (MCT) 420 um or more and average keratometric reading (K) less than 54 diopter (D). Refraction of all selected eyes should be -8.00 D sphere or more with less than -6.00 D cylinder and could be corrected two lines or more with spectacles or contact lenses. All studied eyes underwent a two-stage approach treatment: first refractive lens exchange and aspherical IOL implantation followed, after at least 3mo, by WFG-PRK. Pre and postoperative complete ophthalmological examination were performed. Topographical, visual and aberrometric results were recorded and evaluated during 6mo follow up period. Moreover, patient satisfaction and other subjective outcomes were also analyzed. RESULTS: The 13 eyes of 11 patients diagnosed with stable keratoconus and aged from 39 to 49y (42.4+/-6.2y) were enrolled in the study. At baseline, 8 eyes had grade I and 5 eyes had grade II keratoconus. The manifest sphere was -10.3+/-4.2 D (ranged from -8.0 to -14.0 D) and the manifest cylinder was -4.2+/-1.2 D (ranged from -1.75 to -5.50 D). After the two-stage procedure, sphere and cylinder reduced significantly to -0.43+/-0.22 D and -1.3+/ 0.72 D respectively (P<0.001). There was also a highly significant improvement in the mean uncorrected distance visual acuity (UDVA) from logMAR 1.41+/-0.49 preoperatively to 0.51+/-0.16 postoperatively (P<0.001) and the mean corrected distance visual acuity (CDVA) from 0.76+/-0.24 preoperatively to 0.49+/-0.13 after the operation (P<0.001). All aberrometric and mesopic vision parameters and most of the topographical indices demonstrated highly significant improvement that remains stable until the end of follow up. All recorded subjective data revealed a high degree of patient satisfaction. CONCLUSION: Two-stage approach (clear lens exchange with monofocal IOL followed by WFG-PRK) in selected cases of keratoconus is a safe, effective and highly predictable procedure with satisfactory visual and refractive results. PMID- 30450307 TI - Correlation between choroidal thickness and intraocular pressure after 23-gauge vitrectomy for idiopathic epiretinal membrane. AB - AIM: To determine the relationship between the subfoveal choroidal thickness (CT) and intraocular pressure (IOP) following idiopathic epiretinal membrane (ERM) surgery. METHODS: Retrospective observational case series of patients who had undergone 23-gauge vitrectomy for an ERM. The measurements of CT and IOP were done at the baseline and 1d, 1wk, 1, 3, 6, and 12mo after the surgery. RESULTS: Forty-four eyes of 43 patients with a mean age of 69.8+/-9.5y were studied. The CT was 200.8+/-86.3 um at the baseline, 210.1+/-83.5 um at 1d, 213.2+/-85.4 um at 1wk, 203.1+/-84.0 um at 1mo, 197.5+/-85.5 um at 3mo, 197.7+/-84.0 um at 6mo, and 191.2+/-86.8 um at 12mo after surgery. The CT on day 1 and week 1 after the surgery was significantly thicker than that at the baseline CT (P=0.0023 and P<0.0001). The CT at 12mo after surgery was significantly thinner than the baseline (P=0.0062). The IOP on day 1 and week 1 were significantly lower than the baseline (P<0.0001 and P=0.0042). The IOP at 1, 3, 6, and 12mo after surgery were significantly higher than the baseline IOP (P=0.0087, P=0.0023, P<0.00051, and P<0.0001). The rates of changes in the CT between baseline and day 1 and week 1 were significantly and negatively correlated with the rates of change in the IOP (P<0.0001 and P=0.046). In the group with the IOP change rate of -30% or less at 1d postoperatively, the change rate of CT was -21.1% to 31.2% (9.8%+/-12.4%) and in the group of -29% or more, it was -8.9% to 28.0% (2.6%+/-8.9%). The change rate of CT in the group with the IOP change rate of -30% or less was significantly higher than the group of -29% or more (P=0.016). CONCLUSION: CT increases soon after the ERM surgery which is probably due to the transient hypotony, showing that IOP may be a significant confounding factor for CT. PMID- 30450308 TI - Air tamponade and without heavy liquid usage in pars plana vitrectomy for rhegmatogenous retinal detachment repair. AB - AIM: To report the results of rhegmatogenous retinal detachment (RRD) repair after pars plana vitrectomy (PPV) without operative use of heavy liquid, and utilizing air tamponade in selected cases. METHODS: RRD patients without severity of proliferative vitreoretinopathy C2 or more underwent PPV without operative use of heavy liquid, and utilizing air tamponade were consecutively enrolled. Alternative postoperative facedown position or lateral position was required for 3-5d. RESULTS: Totally 36 eyes of 36 patients (24 males, 66.7%) aged 53.8+/-10.9y underwent this modified surgery. The mean number of retinal break was 2.1+/-1.3. Most of the eyes (29, 80.6%) had retinal detachment involving more than one quadrant. Twenty-two (61.1%) eyes with cataract had combined phacoemulsification and intraocular lens implantation. The mean follow up time was 4.6+/-1.8mo. Two eyes with retinal redetachment underwent a second retinal repair surgery with silicone oil tamponade, yielding the primary reattachment rate to 94.4% (34/36). Six (16.7%) eyes had intraocular pressure higher than 25 mm Hg. The visual acuity (logMAR) improved from 0.98+/-0.74 preoperatively to 0.52+/-0.31 postoperatively (P<0.001). CONCLUSION: The success rate of this modified retinal repair surgery is comparable with traditional surgery. This technique can be considered for certain retinal detachment patients, since its apparent advantages included lower surgical complications, reduced surgery expenditure, shorter time for postoperative facedown position, and avoiding silicone oil removal surgery. PMID- 30450310 TI - Comparison of persistent submacular fluid in different preoperative macular status after vitrectomy for rhegmatogenous retinal detachment. AB - AIM: To compare the incidence of persistent submacular fluid (SMF) and visual outcome after pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment (RRD) in different preoperative macular status according to optical coherence tomography (OCT). METHODS: A non-randomized, retrospective review was performed for patients who underwent successful PPV for RRD. OCT exams were taken preoperatively and 1mo after surgery, until SMF disappeared. According to the preoperative macular status on OCT, patients were divided into two groups: macula off RRD (Group A) and macula-on RRD (Group B). In Group A, there were two subgroups: macula partly detached (Group A1) and macula totally detached (Group A2). The main outcome measures were the presence of SMF on OCT 1mo after surgery, and the preoperative and postoperative best corrected visual acuities (BCVA), among the different groups and depending on the presence or absence of persistent SMF. RESULTS: A total of 139 eyes of 139 patients were included in the study. Persistent SMF at 1mo after surgery was 15.8% (22/139), all occurring in Group A (22/101); Group B had no SMF at 1mo after surgery (0/38, P=0.002). The incidence of persistent SMF at 1mo after surgery in Group A1 was 50% (14/28), and in Group A2 was 11.0% (8/73, P<0.001). Significant differences were shown between the presence and absence of persistent SMF on foveola-off RRD, the preoperative BCVA, the 1mo postoperative BCVA, and the degree of the BCVA improvement from 1mo postoperatively to the final follow-up (P<0.05). However, there were no significant differences in the final BCVA (P>0.05). CONCLUSION: Persistent SMF after PPV for retinal detachment is associated with preoperative macular status. Macula-uninvolving RRD shows no persistent SMF after PPV. Macular partly detached RRD has a higher incidence of SMF than macula totally detached RRD after PPV. The persistence of SMF may be responsible for the delayed visual recovery, whereas there were no significant differences in the final visual acuity. PMID- 30450309 TI - A quantitative comparison of five optical coherence tomography angiography systems in clinical performance. AB - AIM: To compare the clinical performance of 4 spectral-domain (SD) optical coherence tomography angiography (OCTA) systems: AngioVueTM, AngioPlexTM, Spectralis(r) OCTA, AngioScan, and 1 swept-source (SS) OCTA SS OCT AngioTM. METHODS: Twenty-seven undilated right eyes of 27 participants underwent OCTA examination using five different systems respectively for both 3*3 and 6*6 mm2 scan pattern (Spectralis OCTA for 3*3 mm2 scan only). Image quality, including vessel valid visibility and the number of motion artifacts, and acquisition time were evaluated. Repeated measures analysis of variance (ANOVA) with Bonferroni's post-test and Friedman test with Dunn's post-test were used to compare measurements. RESULTS: The age of the subjects was 28.19+/-5.55y (range, 23-49y). The spherical equivalent refraction was -2.55+/-1.84 D (range, 0.00 to -5.25 D). Significant difference was observed in the evaluation of vessel valid visibility (AngioVue the highest: 0.111+/-0.031 for 3*3 mm2 scan and 0.128+/-0.020 for 6*6 mm2 scan), number of motion artifacts (AngioVue the fewest: 0.778+/-1.086 for 3*3 mm2 scan and 0.333+/-0.620 for 6*6 mm2 scan) and acquisition time (AngioPlex the shortest: 8.537+/-1.921s for 3*3 mm2 scan and 8.298+/-1.741s for 6*6 mm2 scan; all P<0.001). CONCLUSION: There is poor agreement of measurements among systems. AngioVue provides images with the highest vessel valid visibility and the fewest motion artifacts. AngioPlex achieves the shortest acquisition. PMID- 30450311 TI - One-year real-world outcomes of ranibizumab 0.5 mg treatment in Taiwanese patients with polypoidal choroidal vasculopathy: a subgroup analysis of the REAL study. AB - AIM: To assess the effectiveness and safety of ranibizumab 0.5 mg in Taiwanese patients with polypoidal choroidal vasculopathy (PCV) by performing a retrospective exploratory subgroup analysis of the REAL study. METHODS: REAL was a 12-month, observational, prospective, non-interventional phase IV post marketing surveillance study conducted at 9 centers in Taiwan. The study collected data as part of the routine patient visits from the medical records of patients with neovascular age-related macular degeneration treated with ranibizumab 0.5 mg according to local standard medical practice and local label and/or reimbursement guidelines. The presence of PCV at baseline was determined using indocyanine green angiography. RESULTS: At baseline, PCV was diagnosed in 64 of the 303 enrolled patients (21.1%). Of these, 41 patients (64.1%) had received prior treatment; 15 (23.4%) patients had received ranibizumab. The intent-to-treat population included 58 patients; 47 (80%) who received ranibizumab and 11 (20%) who received ranibizumab plus photodynamic therapy (PDT; 9 patients received once, 2 patients received twice). Bevacizumab was used as a concomitant medication in a similar percentage of patients who received ranibizumab (43%, n=20) or ranibizumab plus PDT (45%, n=5). In patients who received ranibizumab, visual acuity (VA) at baseline was 50.1+/-12.9 Early Treatment Diabetic Retinopathy Study letters, and the gain at month 12 was 1.1+/ 17.8 letters. In patients who received ranibizumab plus PDT, VA at baseline was 51.4+/-15.9 letters, and there was a marked gain in VA at month 12 (14.0+/-9.2 letters, P=0.0009). In the intent-to-treat population, the reduction in central retinal subfield thickness from baseline at month 12 was 69.6+/-122.6 um (baseline: 310.8+/-109.8 um, P=0.0004). The safety results were consistent with the well-characterized safety profile of ranibizumab. CONCLUSION: In real-world settings, ranibizumab 0.5 mg treatment for 12mo results in maintenance of VA and reduction in central retinal subfield thickness in Taiwanese patients with PCV. Improvements in VA are observed in patients who received ranibizumab plus PDT. There are no new safety findings. PMID- 30450312 TI - Preventing condensation of objective lens in noncontact wide-angle viewing systems during vitrectomy. AB - AIM: To assess the optimal conditions for preventing condensation of objective lens during vitrectomy with noncontact wide-angle viewing systems (WAVSs). METHODS: We explored the effectiveness of the coating with ophthalmic viscoelastic device (OVDs) on the corneal surface and the soaking the objective lens in warm-saline for preventing condensation of objective lens. First, to find the optimal soaking time to keep the objective lens warm, we measured the temperature of objective lens every minute after soaking in warm saline. Second, to find optimal distance between cornea and objective lens, which provide as wide a view as possible and less condensation at the same time, we measured the condensation time with different distances. With the obtained optimal soaking time and distance, we explored the effect of coating cornea with OVDs and soaking objective lens in warm saline on condensation time. RESULTS: One and 5min of soaking in warm saline was most effective for keeping the lens warm enough (45.1 degrees C+/-2.1 degrees C for 1min and 46.4 degrees C +/-1.0 degrees C for 5min, P=0.109). The mean condensation times for the control group at 1, 3, and 5 mm from corneal surface to objective lens were 1+/-0.4, 4+/-1.4, 190+/-26.1s, respectively, thus 5 mm was most optimal distance for vitrectomy with WAVSs. For the OVD coating group, the mean condensation times were 1.5+/-0.3, 13+/-1.4, and 200+/-23.9s at 1, 3, and 5 mm distance and borderline significant compared with control group (P=0.068, 0.051, and 0.063, respectively). With the 1-minute warm saline soaking group, the mean condensation time were extended to 188+/-34.4, 416+/-65.7, and 600+/-121.3s at 1, 3, and 5 mm distance and statistically significant compared with control (P=0.043, 0.041 and 0.043, respectively). CONCLUSION: OVD coating on corneal surface shows no difference on condensation time with control group. However, soaking the objective lens in warm saline revealed statistically significant extension of condensation time compared to control group. Therefore, keeping the objective lens warm with soaking in warm saline is a simple but effective to prevent condensation of objective lens during vitrectomy. The thermodynamics between objective lens and cornea during vitrectomy warrants further investigation. PMID- 30450314 TI - Preliminary study on visual recognition under low visibility conditions caused by artificial dynamic smog. AB - AIM: To quantitatively evaluate the effect of a simulated smog environment on human visual function by psychophysical methods. METHODS: The smog environment was simulated in a 40*40*60 cm3 glass chamber filled with a PM2.5 aerosol, and 14 subjects with normal visual function were examined by psychophysical methods with the foggy smog box placed in front of their eyes. The transmission of light through the smog box, an indication of the percentage concentration of smog, was determined with a luminance meter. Visual function under different smog concentrations was evaluated by the E-visual acuity, crowded E-visual acuity and contrast sensitivity. RESULTS: E-visual acuity, crowded E-visual acuity and contrast sensitivity were all impaired with a decrease in the transmission rate (TR) according to power functions, with invariable exponents of -1.41, -1.62 and 0.7, respectively, and R2 values of 0.99 for E and crowded E-visual acuity, 0.96 for contrast sensitivity. Crowded E-visual acuity decreased faster than E-visual acuity. There was a good correlation between the TR, extinction coefficient and visibility under heavy-smog conditions. CONCLUSION: Increases in smog concentration have a strong effect on visual function. PMID- 30450313 TI - Abnormal resting-state functional network centrality in patients with high myopia: evidence from a voxel-wise degree centrality analysis. AB - AIM: To investigate the functional networks underlying the brain-activity changes of patients with high myopia using the voxel-wise degree centrality (DC) method. METHODS: In total, 38 patients with high myopia (HM) (17 males and 21 females), whose binocular refractive diopter were -6.00 to -7.00 D, and 38 healthy controls (17 males and 21 females), closely matched in age, sex, and education levels, participated in the study. Spontaneous brain activities were evaluated using the voxel-wise DC method. The receiver operating characteristic curve was measured to distinguish patients with HM from healthy controls. Correlation analysis was used to explore the relationship between the observed mean DC values of the different brain areas and the behavioral performance. RESULTS: Compared with healthy controls, HM patients had significantly decreased DC values in the right inferior frontal gyrus/insula, right middle frontal gyrus, and right supramarginal/inferior parietal lobule (P<0.05). In contrast, HM patients had significantly increased DC values in the right cerebellum posterior lobe, left precentral gyrus/postcentral gyrus, and right middle cingulate gyrus (P<0.05). However, no relationship was found between the observed mean DC values of the different brain areas and the behavioral performance (P>0.05). CONCLUSION: HM is associated with abnormalities in many brain regions, which may indicate the neural mechanisms of HM. The altered DC values may be used as a useful biomarker for the brain activity changes in HM patients. PMID- 30450315 TI - Clinical features of posterior microphthalmic and nanophthalmic eyes. AB - AIM: To clinically differentiate nanophthalmos (NO) and posterior microphthalmos (PM) and to explore the mechanisms related to papillomacular folds (PMF). METHODS: Medical records of 34 unrelated patients with microphthalmos (54 eyes) from April 2009 to October 2017 were retrospectively reviewed. RESULTS: Fourteen eyes of 7 unrelated patients with NO and PM were included in the study. The presenting age of the NO cohort was significantly higher compared with the PM cohort (NO: 27+/-16y; PM: 3.7+/-0.6y). PMF was more likely to occur in cases with PM than in NO (25% in NO, 100% in PM). The anatomic features of PMF from optical coherence tomography (OCT) included: ganglion cell layer, inner plexiform layer, inner nuclear layer, outer plexiform layer and outer nuclear layer. In eyes without an apparent PMF (these were all NO eyes), rudimentary fovea without a foveal pit was noted. Four eyes that were NO developed angle closure glaucoma. Three NO eyes developed exudative retinal detachment and were successfully treated with lamellar sclerectomy. CONCLUSION: Posterior segment changes are pervasive both in PM and NO. Complications like angle closure glaucoma and exudative retinal detachment are likely to occur in eyes with NO but not with PM. Detailed OCT analysis found that PMF was partially a neural retinal issue, suggesting that redundancy of retinal issues involved only inner retinal layers. PMID- 30450316 TI - A retrospective study of 2228 cases with eyelid tumors. AB - AIM: To describe the histopathologic and clinical features of eyelid tumor cases from Tianjin Eye Hospital during 2002 to 2015. METHODS: In this retrospective study, a total of 2228 cases of eyelid tumors with pathologic diagnoses were enrolled. The eyelid tumors were classified into three groups according to tumor origin: epidermal, adnexal and miscellaneous, including melanocytic, neural and vascular lesions. Inflammatory tumor-like lesions were excluded. The clinical characteristics of the eyelid tumors were analyzed, including age, gender and lesion location. RESULTS: Most eyelid tumors were epidermal in origin (1080, 48.5%), followed by miscellaneous (885, 39.7%) and adnexal tumors (263, 11.8%). Among all the tumors, 292 (13.1%) were malignant lesions, 1910 (85.7%) benign and 26 (1.1%) premalignant lesions. Most malignant tumors originated from epidermal cells (60.0%), followed by adnexal cells (34.6%). The most common malignant tumors were basal cell carcinomas (56.5%) followed by sebaceous carcinoma (34.6%), squamous cell carcinomas (3.8%) and lymphoma/plasmocytoma (1.7%). The benign and premalignant eyelid lesions mostly originated from epidermal cells (46.4%) followed by miscellaneous cell sources (45.2%), including melanocytic nevus (33.8%), seborrheic keratosis (13.7%), squamous cell papilloma (13.0%) and epidermal cysts (11.5%). CONCLUSION: Eyelid tumors are mostly epithelial in origin. Benign tumors are significantly more common than malignant tumors with an obvious female predominance, and the most frequent malignant tumor are basal cell carcinoma, sebaceous carcinoma and squamous cell carcinomas. The tumor clinical features varied among the different subtypes. PMID- 30450317 TI - Age related changes of the central lamina cribrosa thickness, depth and prelaminar tissue in healthy Chinese subjects. AB - AIM: To investigate the variation in the central lamina cribrosa thickness (cLCT), and the central anterior lamina cribrosa surface depth (cALCSD), as well as the central prelaminar tissue thickness (cPLTT) related to age in healthy Chinese subjects. METHODS: A total of 96 eyes from 96 Chinese healthy subjects were recruited. According to age, the 96 cases were divided into three groups: the young group (YG, 18-39y), middle-age group (MG, 40-59y) and older-age group (OG, 60y and above). Lamina cribrosa images were obtained from all participants using radial linear protocol by enhanced depth imaging spectral-domain optical coherence tomography. The cLCT, cALCSD and cPLTT were calculated from the average value of the lamina cribrosa thickness, anterior lamina cribrosa surface depth and prelaminar tissue thickness in the optic nerve head (ONH) centre point and paracentral points (150 um from the centre point in the horizontal and vertical directions). RESULTS: For the total subjects, the mean cLCT, cALCSD and cPLTT were 235.18+/-41.27, 358.02+/-93.80 and 182.02+/-92.11 um, respectively. No statistically significant differences in cLCT, cALCSD or cPLTT were found between gender and different eyes (P=0.27-0.92). The cLCT of the OG was the thickest among the three groups, while the cPLTT of the YG was the thickest among the three groups (P<0.05). Age was positively correlated with cLCT (r=0.42, P<0.001), and negatively correlated with cPLTT (r=-0.24, P=0.02). No significant correlation was found between the age and cALCSD (r=-0.06, P=0.55). And no correlation has been found between axial length and cLCT, cALCSD and cPLTT (P=0.11-0.81). CONCLUSION: The impact of age on the cLCT and the cPLLTT should be taken into account when analysing glaucoma and other diseases related to lamina cribrosa. PMID- 30450318 TI - Efficacy and safety of vitrectomy with internal limiting membrane peeling for diabetic macular edema: a Meta-analysis. AB - AIM: To evaluate the efficacy and safety of vitrectomy with internal limiting membrane (ILM) peeling for diabetic macular edema (DME). METHODS: The PubMed, Embase, Web of Science, Cochrane, SionMed, ClinicalTrials.gov, CNKI databases and Wanfang databases, published until Oct. 2017, were searched to identify studies comparing the clinical outcomes following vitrectomy with and without ILM peeling, for treating DME. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for vitrectomy with and without ILM peeling with regard to best corrected visual acuity (BCVA), central macular thickness (CMT), and complication incidents. RESULTS: A total of 14 studies involving 857 eyes were included of which three studies were Chinese and the rests were English literatures. Meta-analysis indicated that compared with vitrectomy alone, vitrectomy with ILM peeling could improve BCVA more obviously (OR=1.66, 95%CI: 1.12-2.46, P=0.01) and had higher rate of CMT reduction (OR=3.89, 95%CI: 1.37-11.11, P=0.01). There were significant statistical differences between the two surgical methods for both BCVA and CMT (P<0.05). For the incidence of intraoperative and postoperative complications, the incidence of epiretinal membrane (ERM) was slightly lower in the ILM peeling group than the group without ILM peeling (OR=0.38, 95%CI: 0.07-2.00, P=0.25), although insignificant statistically. Other incidences of overall complications, iatrogenic peripheral retinal break and increased intraocular pressure indicated no significant difference between two groups (OR=1.19, 95%CI: 0.82-1.73, P=0.36; OR=1.21, 95%CI: 0.66-2.21, P=0.53; OR=1.34, 95%CI: 0.75-2.40, P=0.32). CONCLUSION: Vitrectomy is effective for DME and the effect can be improved by additional ILM peeling, especially for anatomical efficacy, without increasing the incidence of intraoperative and postoperative complications. However, it is imperative to gain more evaluation in the future due to the paucity of prospective randomized study. PMID- 30450320 TI - Clinical and laboratory features of PCR-confirmed periocular tuberculosis in China. AB - Experts lack knowledge of periocular tuberculosis (TB) in China. Nested polymerase chain reaction (PCR) shows advantages in diagnosis of extrapulmonary TB. Our study aims to explore the clinical and laboratory features of PCR confirmed periocular TB. We retrospectively reviewed medical records of presumptive periocular TB and performed nested PCR test to confirm diagnosis. Nine cases were recruited. Clinical symptoms were chronic and insidious. Eight cases achieved favorable visual acuity, while one underwent enucleation due to fungal-TB panophthalmitis. Sensitivity of caseous necrosis, acid-fast bacilli (AFB) staining and interferon gamma release assay (T-SPOT) test are 33.3%, 44.4% and 85.7% respectively. Low lymphocyte percentage (P=0.019) and high monocyte lymphocyte ratio (P=0.042) positively correlate with AFB staining. Male gender (P=0.048) and Langhans giant cell (P=0.048) positively correlate with caseous necrosis. To conclude, traditional TB ancillary tests are not as sensitive as nested PCR technique. Several factors facilitate diagnosis including male gender, decreased lymphocytes, and typical Langhans giant cells. PMID- 30450319 TI - New insight into the role of the complement in the most common types of retinopathy-current literature review. AB - Pathological neovascularisation, which is a critical component of diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinopathy of prematurity (ROP), is a frequent cause of compromised vision or blindness. Researchers continuously investigate the role of the complement system in the pathogenesis of retinopathy. Studies have confirmed the role of factors H and I in the development of AMD, and factors H and B in the development of DR. Other components, such as C2, C3, and C5, have also been considered. However, findings on the involvement of the complement system in the pathogenesis of ROP are still inconclusive. This paper presents a review of the current literature data, pointing to the novel results and achievements from research into the role of complement components in the development of retinopathy. There is still a need to continue research in new directions, and to gather more detailed information about this problem which will be useful in the treatment of these diseases. PMID- 30450321 TI - Posterior chamber phakic intraocular lens for the correction of high myopic anisometropic amblyopia in adults. AB - This study aims to evaluate the clinical results of posterior chamber implantable collamer lens (ICL) implantation in adults with high myopic anisometropic amblyopia. Thirteen patients aged 27.04+/-7.24y (range 19.2 to 42.5) were studied. ICL implantation was performed in 13 amblyopic eyes. The mean myopic anisometropia was significantly dropped from -10.70+/-3.02 D preoperatively to +0.09+/-1.67 D at 1mo postoperatively. The logMAR CDVA at 3d, 1, 3 and mean 9mo postoperatively improved by a mean of 1.69, 2.50, 3.01 and 3.00 lines and gained more than 2 lines accounted for 23.08% (3 eyes), 41.67% (5 eyes), 63.63% (7 eyes) and 55.56% (5 eyes), respectively. The contrast sensitivity of amblyopic eyes was significantly increased after surgery. Four patients partially recovered near stereopsis (400" to 100"). There was no severe complications were observed. ICL implantation alone can improve vision, contrast sensitivity, and partial restoration of binocular vision in adult patients with high myopic anisometropia. PMID- 30450322 TI - X-linked juvenile retinoschisis: phenotypic and genetic characterization. AB - Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD OCT) images. The mean central foveal thickness was 569.7 um. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (<1.0) in all patients. RS1 (NM_000330.3) gene coding exons Sanger sequencing was performed. RS1 c.599G>T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits. PMID- 30450323 TI - Serous macular detachment due to nasally located optic disc pit-coloboma. PMID- 30450324 TI - Primary sino-orbital peripheral T-cell lymphoma presenting as unilateral periorbital swelling: a case report. PMID- 30450326 TI - Reader's Forum. PMID- 30450325 TI - Comment on "Assessment of the long-term visual and anatomical outcomes of ranibizumab to treat neovascular age-related macular degeneration". PMID- 30450327 TI - Assessment of lower incisor alveolar bone width using cone-beam computed tomography images in skeletal Class III adults of different vertical patterns. AB - Objective: This study was performed to investigate the alveolar bone of lower incisors in skeletal Class III adults of different vertical facial patterns and to compare it with that of Class I adults using cone-beam computed tomography (CBCT) images. Methods: CBCT images of 90 skeletal Class III and 29 Class I patients were evaluated. Class III subjects were divided by mandibular plane angle: high (SN-MP > 38.0 degrees ), normal (30.0 degrees < SN-MP < 37.0 degrees ), and low (SN-MP < 28.0 degrees ) groups. Buccolingual alveolar bone thickness was measured using CBCT images of mandibular incisors at alveolar crest and 3, 6, and 9 mm apical levels. Linear mixed model, Bonferroni post-hoc test, and Pearson correlation analysis were used for statistical significance. Results: Buccolingual alveolar bone in Class III high, normal and low angle subjects was not significantly different at alveolar crest and 3 mm apical level while lingual bone was thicker at 6 and 9 mm apical levels than on buccal side. Class III high angle group had thinner alveolar bone at all levels except at buccal alveolar crest and 9 mm apical level on lingual side compared to the Class I group. Class III high angle group showed thinner alveolar bone than the Class III normal or low angle groups in most regions. Mandibular plane angle showed negative correlations with mandibular anterior alveolar bone thickness. Conclusions: Skeletal Class III subjects with high mandibular plane angles showed thinner mandibular alveolar bone in most areas compared to normal or low angle subjects. Mandibular plane angle was negatively correlated with buccolingual alveolar bone thickness. PMID- 30450329 TI - Evaluation of changes in the maxillary alveolar bone after incisor intrusion. AB - Objective: This study was performed to investigate the changes in alveolar bone after maxillary incisor intrusion and to determine the related factors in deep bite patients. Methods: Fifty maxillary central incisors of 25 patients were evaluated retrospectively. The maxillary incisors in Group I (12 patients; mean age, 16.51 +/- 1.32 years) were intruded with a base-arch, while those in Group II (13 patients; mean age, 17.47 +/- 2.71 years) were intruded with miniscrews. Changes in the alveolar envelope were assessed using pre-intrusion and post intrusion cone-beam computed tomography images. Labial, palatal, and total bone thicknesses were evaluated at the crestal (3 mm), midroot (6 mm), and apical (9 mm) levels. Buccal and palatal alveolar crestal height, buccal bone height, and the prevalence of dehiscence were evaluated. Two-way repeated measure ANOVA was used to determine the significance of the changes. Pearson's correlation coefficient analysis was performed to assess the relationship between dental and alveolar bone measurement changes. Results: Upper incisor inclination and intrusion changes were significantly greater in Group II than in Group I. With treatment, the alveolar bone thickness at the labial bone thickness (LBT, 3 and 6 mm) decreased significantly in Group II (p < 0.001) as compared to Group I. The LBT change at 3 mm was strongly and positively correlated with the amount of upper incisor intrusion (r = 0.539; p = 0.005). Conclusions: Change in the labial inclination and the amount of intrusion should be considered during upper incisor intrusion, as these factors increase the risk of alveolar bone loss. PMID- 30450328 TI - Cone-beam computed tomography analysis of transverse dental compensation in patients with skeletal Class III malocclusion and facial asymmetry. AB - Objective: The purpose of this study was to analyze the transverse dental compensation in reference to the maxillary and mandibular basal bones using cone beam computed tomography (CBCT) and evaluate the correlations between transverse dental compensation and skeletal asymmetry variables in patients with skeletal Class III malocclusion and facial asymmetry. Methods: Thirty patients with skeletal Class I (control group; 15 men, 15 women) and 30 patients with skeletal Class III with menton deviation (asymmetry group; 16 men, 14 women) were included. Skeletal and dental measurements were acquired from reconstructed CBCT images using OnDemand3D 1.0 software. All measurements were compared between groups and between the deviated and nondeviated sides of the asymmetry group. Correlation coefficients for the association between skeletal and dental measurements were calculated. Results: Differences in the ramus inclination (p < 0.001), maxillary canine and first molar inclinations (p < 0.001), and distances from the canine and first molar cusp tips to the midmaxillary or midmandibular planes (p < 0.01) between the right and left sides were significantly greater in the asymmetry group than in the control group. In the asymmetry group, the ramus inclination difference (p < 0.05) and mandibular canting (p < 0.05) were correlated with the amount of menton deviation. In addition, dental measurements were positively correlated with the amount of menton deviation (p < 0.05). Conclusions: Transverse dental compensation was correlated with the maxillary and mandibular asymmetry patterns. These results would be helpful in understanding the pattern of transverse dental compensation and planning surgical procedure for patients with skeletal Class III malocclusion and facial asymmetry. PMID- 30450330 TI - Colorimetric evaluation of white spot lesions following external bleaching with fluoridation: An in-vitro study. AB - Objective: This study was performed to investigate the effects of external tooth bleaching with flouridation on the appearance of white spot lesions (WSLs) in vitro. Methods: In total, 125 bracket-bonded bovine incisor enamel blocks with artificial WSLs were randomly divided into a control group and four treatment groups (home bleaching, home bleaching + fluoridation, in-office bleaching, and in-office bleaching + fluoridation). A spectroradiometer (SR) and digital images (DIs) were used to evaluate colorimetric parameters (Commission Internationale l'Eclairage L*a*b*) for all specimens. Color measurements were obtained before WSL formation (T1), after WSL formation (T2), and after completion of the external tooth bleaching treatment (T3). Results: The SR-based color change after bleaching was significantly greater in the treatment groups than in the control group (p < 0.05). SR-based lightness (L*) and red-green (a*) values were significantly higher at T2 than at T1 (p < 0.001), with no significant changes in yellow-blue (b*) values. At T3, SR-based L* values had increased while a* and b* values had decreased in the treatment groups (p < 0.001). The DI-based color difference between the sound enamel and WSL areas (DeltaE*DI) increased significantly from T1 to T2 in all groups (p < 0.001) and significantly decreased from T2 to T3 in the treatment groups (p < 0.001). No significant differences in DeltaE*DI at T3 were shown between the four treatment groups (p > 0.05). Conclusions: The findings of this study suggested that external tooth bleaching with fluoridation can alleviate the conspicuity of WSLs. PMID- 30450331 TI - Effects of prestretch on stress relaxation and permanent deformation of orthodontic synthetic elastomeric chains. AB - Objective: This study was performed to investigate an appropriate degree of prestretch for orthodontic synthetic elastomeric chains focusing on time dependent viscoelastic properties. Methods: Orthodontic synthetic elastomeric chains of two brands were prestretched to 50, 100, 150, and 200% of the original length in one and three cycles, and the hysteresis areas of the obtained stress strain curves were determined. Acrylic plates were employed to maintain constant strain during the experiment. A total of 180 samples were classified into nine groups according to brand, and their stresses and permanent deformations were measured immediately after prestretch (0 hour), after 1 hour and 24 hours, and after 1, 2, 3, 4, 5, 6, 7, and 8 weeks. The relationship between stress relaxation and permanent deformation was investigated for various degrees of prestretch, and the estimated stress resulting from tooth movement was calculated. Results: The degree of prestretch and the stress relaxation ratio exhibited a strong negative correlation, whereas no correlation was found between the degree of prestretch and the average normalized permanent strain. The maximal estimated stress was observed when prestretch was performed in three cycles to 200% of the original length. Conclusions: Although prestretch benefited residual stress, it did not exhibit negative effects such as permanent deformation. The maximal estimated stress was observed at the maximal prestretch, but the difference between prestretch and control groups decreased with time. In general, higher residual stresses were observed for product B than for product A, but this difference was not clinically significant. PMID- 30450332 TI - Association between genetic polymorphisms and external apical root resorption: A systematic review and meta-analysis. AB - Objective: To date, only a few studies have investigated the relationships between genetic polymorphisms and external apical root resorption (EARR). Hence, the aim of this systematic review was to explore the relationship between different gene polymorphisms and their association with EARR. Methods: A complete literature search was conducted by two independent reviewers. The PubMed, Science Direct, and Scopus databases were searched. In addition, the bibliographies of all textbooks and relevant articles were searched manually. A meta-analysis was performed using data entered into the electronic databases until February 28, 2017. Results: On the basis of the search, we identified 17 and 7 publications for the systematic review and meta-analysis, respectively. Odds ratio (OR) was used to evaluate the association of the interleukin 1B (+3954) polymorphism and the risk of EARR. The overall OR from the studies was used to estimate the risk of EARR. However, no association was found and no publication bias was apparent for the risk of EARR in patients receiving orthodontic treatment. Conclusions: More research on the relationship between gene polymorphism and EARR is necessary to determine better specificity of possible interactions. PMID- 30450333 TI - Comparison of clinical and histological characteristics of orthodontic tooth movement into recent and healed extraction sites combined with corticotomy in rats. AB - Objective: This study was performed to investigate the rate of tooth movement and histological characteristics of extraction sockets those were subjected to corticotomy. Methods: A split-mouth randomized controlled trial experiment was designed. Thirty-two adult, male Wistar rats were divided into 2 groups: healing extraction socket (H) and recent extraction socket (R); these groups were randomly classified into 4 subgroups (0/7/21/60 days). The first maxillary molar was extracted on 1 side and 2 months were allowed for complete bone healing; then, the corresponding molar was extracted on the other side and surgical intervention was performed at the mid-alveolar point of the first maxillary molar. Ten grams of continuous force was applied. The outcomes measured were rate of tooth movement, percentage of periodontal space and histological evaluation. The rate of tooth movement was calculated as the measured distance divided by the duration of molar movement. Histomorphometric evaluations were performed on the second and third maxillary molars. The Wilcoxon signed rank test was used to compare differences between the two groups. Results: There were no significant differences in the rates of tooth movement between H and R groups at any of the 4 time points. The histological appearance and percentage of periodontal space between the R and H groups also demonstrated no significant differences. Conclusions: The rates of orthodontic tooth movement into recent and healed socket sites did not differ between the groups. Histological analysis of tooth movement revealed regional acceleration during every time period. PMID- 30450334 TI - List of the international reviewers in 2018. PMID- 30450336 TI - Metabolomics of Non-muscle Invasive Bladder Cancer: Biomarkers for Early Detection of Bladder Cancer. AB - Background: Clinical outcomes of bladder cancer (BC) are tightly associated with the stage and grade of the initial diagnosis of BC because early detection is clearly important for patients with BC. However, the diagnostic capability of current detection methods, such as urinary cytology, cystoscopy, imageology method, and several urine-based tests, is inadequate for early detection of BC. The objective of our study is to discover novel biomarkers for detecting BC at an early stage, called non-muscle invasive (NMI) BC, using liquid chromatography high resolution mass spectrometry (LC-HRMS)-based metabolomics. Methods: First, morning midstream urine samples were collected from healthy adult and NMIBC patients. The LC-HRMS-based metabolomics were applied to distinguish the NMIBC group without hematuria from the controls (gender- and age-matched volunteers with normal clinically healthy index), low-grade NMIBC from the controls, and high-grade from low-grade NMIBC. Results: A total of 284 subjects were enrolled in our study including 117 healthy adults, 80 NMIBC patients without hematuria, and 87 NMIBC patients with hematuria. The metabolite panel including dopamine 4 sulfate, MG00/1846Z,9Z,12Z,15Z/00, aspartyl-histidine, and tyrosyl-methionine was found in a discovery set, which showed the predictive ability to distinguish the NMIBC group from the control group with an area under the curve (AUC) of 0.838 in an external validation set. The AUC of the panel for low-grade NMIBC samples, which consisted of 3-hydroxy-cis-5-tetradecenoylcarnitine, 6-ketoestriol, beta cortolone, tetrahydrocorticosterone, and heptylmalonic acid, was 0.899. The sensitivity and specificity were 0.881 and 0.786, respectively. The AUC of the panel for distinction of low-grade NMIBC with and without hematuria against high grade NMIBC with and without hematuria were 0.827 and 0.755, respectively. In addition, metabolites involved in tryptophan metabolism were upregulated in the urine of high-grade NMIBC patients when compared with low-grade NMIBC patients with the presence or absence of hematuria. Conclusion: The NMIBC urine metabolic profiling was able to assist in the early detection of BC. Panels of metabolites were discovered to have a potential value for high-grade NMIBC and low-grade NMIBC diagnosis as well as for NMIBC grading distinction. PMID- 30450335 TI - The Identification of Immunological Biomarkers in Kidney Cancers. AB - The recent approval of several agents have revolutionized the scenario of therapeutic management of metastatic renal cell carcinoma (RCC) allowing us to reach important clinical end points with extended patients' survival. Actually, every new drug approved has represented an important step forward to the improvement of patient's survival. On the other hand, we now understand that RCC includes a large group of tumor entities, each of them with different genetic and mutational alterations, but also showing different clinical behavior; a reason behind the needs of subtype specific personalized approach to therapy of RCC. Immunotherapy is gradually becoming a key factor in the therapeutic algorithm for patients with locally advanced or metastatic RCC. Due to the combination of potent treatment success and potentially deadly adverse effects from immune checkpoint inhibitors (ICI), gathering prognostic and predictive information about FDA-indicated tumors seems to be prudent. Robust and reliable biomarkers are crucial for patient's selection of treatments with immunomodulatory drugs. PD L1 expression is a poor prognostic factor and predictive of better responses from both PD-1 and PD-L1 inhibitors in a variety of tumor types including RCC. Each FDA approved PD-1/PD-L1 drug is paired with a PD-L1 Immunohistochemistry (IHC) assay. Thus, there is need for improved knowledge and application of PD-1/PD-L1 IHC biomarkers in daily practice. IHC staining appears in membranous fashion. The atezolizumab approved IHC assay is unique in that only immune cell staining is quantified for the use of this assay in RCC. A single biomarker for patient selection may not be feasible, given that immune responses are dynamic and evolve over time. Biomarker development for ICI drugs will likely require integration of multiple biologic components like PD-L1 expression, TILs and mutational load. New methodological approaches based on digital pathology may be relevant since they will allow recognition of the biomarker and to objectively quantitate its expression, and therefore might produce objective and reproducible cut-off assessment. Multidisciplinary approach is very much needed to fully develop the current and future value of ICI in clinical practice. PMID- 30450337 TI - Targeted p53 on Small-Molecules-Induced Ferroptosis in Cancers. AB - Ferroptosis is a type of programmed cell death characterized by the accumulation of lipid reactive oxygen species (L-ROS) driven by the oxidative degeneration of lipids in an iron-dependent manner. The mechanism by which lipid oxidative degradation drives ROS-ferroptosis involves metabolic dysfunctions that result in impaired intracellular metabolic processes and ROS production. Recent studies have found that p53 acts as a positive regulator of ferroptosis by promoting ROS production. p53 directly regulates the metabolic versatility of cells by favoring mitochondrial respiration, leading to ROS-mediated ferroptosis. In mild stress, p53 protects cell survival via eliminating ROS; additionally, in human colorectal cancer, p53 antagonizes ferroptosis by formation of the DPP4-p53 complex. In short, the mechanisms of p53-mediated ROS production underlying cellular response are poorly understood. In the context of recent research results, the indistinct roles of p53 on ROS-mediated ferroptosis are scrutinized to understand the mechanism underlying p53-mediated tumor suppression. PMID- 30450340 TI - The Deep Circumflex Iliac Artery Perforator Flap for Breast Reconstruction: Un lambeau perforateur de l'artere iliaque circonflexe profonde pour la reconstruction mammaire. AB - Autologous breast reconstruction using abdominal-based perforator flaps produces excellent aesthetic results with minimal donor site morbidity. The superficial inferior epigastric artery and deep inferior epigastric perforator (DIEP) flaps reliably perfuse a hemi-abdomen, up to the anterior axillary line. Beyond this line laterally, the flank or "love handle" tissue is primarily perfused by the deep circumflex iliac artery (DCIA) or secondarily by the superficial circumflex iliac artery. The flank tissue is a valuable addition to increase flap size when harvested with a DIEP flap or to provide vascularized tissue when the abdomen has been previously harvested. Harvesting the flank tissue in combination with the anterior abdominal tissue improves the contour of the trunk, accentuates the waist, and minimizes secondary revisions to excise prominent "dogears." The DCIA flap is a novel technique for breast reconstruction. In this article, we describe our technique, pearls and pitfalls, and early results. PMID- 30450338 TI - Innate Immune Response of Primary Human Keratinocytes to West Nile Virus Infection and Its Modulation by Mosquito Saliva. AB - West Nile Virus (WNV) is a flavivirus involved in many human infections worldwide. This arthropod-borne virus is directly co-inoculated with mosquito saliva through the epidermis and the dermis during blood meal. WNV starts replicating in the skin before migrating to the draining lymph node, leading to widespread viremia and in some cases to neurological symptoms. Skin is a complex organ composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity. Keratinocytes, which represent 90% of the cells of the epidermis, are the organism's first line of defense, initiating innate immune response by recognizing pathogens through their pattern recognition receptors. Although WNV was previously known to replicate in human primary keratinocytes, the induced inflammatory response remains unknown. The aim of this study was first to characterize the inflammatory response of human primary keratinocytes to WNV infection and then, to assess the potential role of co-inoculated mosquito saliva on the keratinocyte immune response and viral replication. A type I and III interferon inflammatory response associated with an increase of IRF7 but not IRF3 mRNA expression, and dependent on infectious dose, was observed during keratinocyte infection with WNV. Expression of several interferon-stimulated gene mRNA was also increased at 24 h post infection (p.i.); they included CXCL10 and interferon-induced proteins with tetratricopeptide repeats (IFIT)-2 sustained up until 48 h p.i. Moreover, WNV infection of keratinocyte resulted in a significant increase of pro-inflammatory cytokines (TNFalpha, IL-6) and various chemokines (CXCL1, CXCL2, CXCL8 and CCL20) expression. The addition of Aedes aegypti or Culex quinquefasciatus mosquito saliva, two vectors of WNV infection, to infected keratinocytes led to a decrease of inflammatory response at 24 h p.i. However, only Ae. Aegypti saliva adjunction induced modulation of viral replication. In conclusion, this work describes for the first time the inflammatory response of human primary keratinocytes to WNV infection and its modulation in presence of vector mosquito saliva. The effects of mosquito saliva assessed in this work could be involved in the early steps of WNV replication in skin promoting viral spread through the body. PMID- 30450341 TI - Effect of Obesity on Complications in Short-Scar Breast Reduction: A Retrospective Study of 236 Consecutive Patients. AB - Background: Prior studies have examined the relationship between obesity and adverse outcomes after reduction mammaplasty, suggesting a correlation between increasing body mass index (BMI) and postoperative complications. However, there is little data published regarding such correlation with respect to short-scar technique. Methods: A total of 236 patients underwent short-scar mammaplasty with a superomedial pedicle from 2008 to 2014. The procedure was performed by a single surgeon at an academic medical center. Adverse outcomes included delayed healing, major wounds, nipple necrosis, fat necrosis, seroma, hematoma, infection, revision, and dog ear deformities. Univariate and multivariate logistic regression analyses were used to calculate crude and adjusted odds ratios for the association of BMI category with the development of any adverse outcome. Results: Patients were grouped by the following BMI categories: <25 kg/m2 (n = 27), 25 to <30 kg/m2 (n = 71), 30 to <35 kg/m2 (n = 73), 35 to <40 kg/m2 (n = 45), and >40 kg/m2 (n = 20). The mean follow-up period was 260 days. The total complication rate in each group was 22.2%, 23.9%, 27.4%, 33.3%, and 45.0%, respectively. Although the proportion of patients experiencing at least 1 adverse outcome increased across the ascending BMI categories (P trend = .145), there was no statistically significant difference between the groups. Conclusion: This study of 236 patients who underwent short-scar reduction mammaplasty found a positive trend in the incidence of adverse outcomes as BMI increased. However, this was not statistically significant. PMID- 30450342 TI - Tissue Expansion for Severe Foot and Ankle Deformities: A 16-Year Review. AB - Background: Tissue expansion in the lower extremity is controversial, with studies reporting complication rates as high as 83%. Few studies have looked at tissue expansion prior to orthopaedic correction of severe foot and ankle deformities, and those available are restricted to clubfoot in the pediatric population. Here, we report the largest case series on the use of tissue expanders for the reconstruction of severe foot and ankle deformity and the only report in adults. Methods: This is a retrospective chart review of the senior author's practice over a 16-year study period. All patients over 18 years of age who underwent tissue expansion prior to definitive orthopaedic correction of a severe foot and ankle deformity were included. Patient demographics, etiology of deformity, rate of expansion, and complications were recorded. Major complications were defined as those which required surgical intervention. Data were analyzed using descriptive statistics. Results: Nineteen cases were performed on 16 patients. Our overall complication rate was 31.6% (6/19), with major complications occurring in 21.1% (4/19) of cases, and minor complications occurring in 10.5% (2/19) of cases. Despite this, 94.7% (18/19) of cases went on to receive definitive orthopaedic correction after tissue expansion. No demographic parameters were associated with occurrence of complications. Conclusions: This represents the largest report on lower extremity tissue expansion for severe foot and ankle deformity correction. While we observed complications in 31.6% of patients, 94.7% of cases went on to receive definitive orthopaedic correction with successful primary closure. PMID- 30450339 TI - The Role of Host Cholesterol During Flavivirus Infection. AB - In recent years the emergence and resurgence of arboviruses have generated a global health alert. Among arboviruses, Dengue (DENV), Zika (ZIKV), Yellow Fever (YFV), and West Nile (WNV) virus, belong to the genus Flavivirus, cause high viremia and occasionally fatal clinical disease in humans. Given the genetic austerity of the virus, they depend on cellular factors and organelles to complete its replication. One of the cellular components required for flavivirus infection is cholesterol. Cholesterol is an abundant lipid in biomembranes of eukaryotes cells and is necessary to maintain the cellular homeostasis. Recently, it has been reported, that cholesterol is fundamental during flavivirus infection in both mammal and insect vector models. During infection with DENV, ZIKV, YFV, and WNV the modulation of levels of host-cholesterol facilitates viral entry, replicative complexes formation, assembly, egress, and control of the interferon type I response. This modulation involves changes in cholesterol uptake with the concomitant regulation of cholesterol receptors as well as changes in cholesterol synthesis related to important modifications in cellular metabolism pathways. In view of the flavivirus dependence of cholesterol and the lack of an effective anti-flaviviral treatment, this cellular lipid has been proposed as a therapeutic target to treat infection using FDA-approved cholesterol-lowering drugs. This review aims to address the dependence of cholesterol by flaviviruses as well as the basis for anti flaviviral therapy using drugs which target is cholesterol synthesis or uptake. PMID- 30450343 TI - Is There an Association Between Hyperbaric Oxygen Therapy and Improved Outcome of Deep Chemical Peeling? A Randomized Pilot Clinical Study. AB - Background: Phenol chemical peeling (PCP) treatment is associated with prolonged recovery and sustained adverse events. Hyperbaric oxygen therapy (HBOT) is known to accelerate wound healing. The purpose of the current study was to evaluate the effect of HBOT on PCP recovery period and adverse events. Methods: This is a pilot randomized controlled clinical study. Women following PCP underwent 5 consecutive daily HBOT sessions, compared with PCP alone. Pain, pruritus, erythema, crusting, scaling, and edema were daily evaluated up to 28 days following PCP. Photographs taken on days 14 and 35 following PCP were assessed. Confidence to appear in public was assessed 14 days following PCP. Results: Eight participants equally assigned to HBOT and control groups. Lower severity scores for erythema, scaling, and pruritus were documented in the HBOT group (mean difference 1.19, P = .006; .84, P = .04; and 2.19, P = .001, respectively). Photographic assessment severity score was higher for skin tightness, edema, erythema, crusting, and scaling in the control group on day 14 post PCP (P < .05) and for erythema on day 35 post PCP (P < .05). Epithelialization percentage was higher in the HBOT group on day 14 post PCP compared with controls (98.5% +/- 1% vs 94.2% +/- 1%; P = .021). The HBOT group scored higher in confidence to appear in public (20.8 +/- 1.7 vs 14.5 +/- 1.3; P = .029). Conclusion: Hyperbaric oxygen therapy following PCP is associated with faster recovery as assessed by both patients and caregivers. So far, HBOT was mainly used in the treatment of problematic or chronic wounds. Our study suggests expanding the indications in which hyperbaric oxygen treatment is applicable and recommended. PMID- 30450344 TI - Dog Bites in Children: A Descriptive Analysis. AB - Objective: To describe characteristics of dog bites and their treatment in a pediatric population including infection, medical specialties involved, rates of admission, and need for surgery. Method: Patients presenting with a dog bite to the emergency department of a tertiary care pediatric hospital between January 1, 2015, and June 30, 2017, were included. Details related to demographics, complications, consultations, and treatment were extracted from the patients' records. Descriptive statistics were performed and binary logistic regression was used to assess potential predictors of infection. Results: One hundred fifty eight dog bite patients were identified. Most patients were male (53.8%) and less than 5 years of age (50%). Bites occurred most frequently in June (13.3%) and July (16.5%). The face was most commonly involved (42.9%), followed by the hands (12.6%) and the scalp (26.6%). Pit bulls (11.4%), Labrador retrievers (7.0%), and German shepherds (4.4%) were the most common offending breeds. Most bites were superficial (91.1%). Half were treated conservatively with dressings and petrolatum-based ointment, with 41.1% requiring simple primary closure. Ten (6.3%) cases necessitated primary repair in the main operating room under general anesthesia. More than half of patients were treated with prophylactic systemic antibiotics (55.1%). Plastic surgery was the most common service involved (24.7%). Seven (4.4%) patients developed an infection and there were no mortalities or long-term complications. Rates of infection did not differ between patients who did or did not receive prophylactic systemic antibiotics (P = .88). Regression analysis revealed no significant predictors of infection. Conclusions: Most dog bites are superficial and involve the head and hands. Infection rate is low, with no significant difference in infection rates between patients treated with or without prophylactic antibiotics. PMID- 30450345 TI - Gender-Affirming Surgery for Transgender Individuals: Perceived Satisfaction and Barriers to Care. AB - Purpose: The purpose of this study was to examine the perceived satisfaction and barriers to care for transgender patients after they decide to undergo gender affirming surgery (GAS). Method: A survey consisting of 21 multiple-choice and short-answer questions was distributed to transgender organizations and online forums across Canada and the United States. The data were then analyzed using descriptive statistics. Results: There were 32 participants, 12 who identified as female to male and 20 as male to female. The mean age was 36 years, with a range of 18 to 81 years. The mean age of their first GAS was 33 years, and the range of wait time was 6 months to 7 years. Most of the participants received information about GAS from transgender websites and transgender surgery clinics (91% and 50%, respectively). Most participants (74%) felt like they had access to appropriate care and 89% felt like their surgeons provided enough information about GAS. There were 38% of participants who would change their experience with GAS. Participants stated several barriers toward receiving GAS: financial (73%), finding a physician (65%), and access to information (63%). Surgical transition was important to the quality of life for 91% of participants and 100% were happy with their decision to undergo GAS. Conclusions: Transgender participants demonstrated that GAS is important to their quality of life and this study showed significant barriers to GAS. PMID- 30450346 TI - The Canadian Plastic Surgery Workforce Analysis: Forecasting Future Need. AB - Background: Projecting the demand for plastic surgeons has become increasingly important in a climate of scarce public resource within a single payer health care system. The goal of this study is to provide a comprehensive workforce update and describe the perceptions of the workforce among Canadian Plastic Surgery residents and surgeons. Methods: Two questionnaires were developed by a national task force under the Canadian Plastic Surgery Research Collaborative. The surveys were distributed to residents and practicing surgeons, respectively. Results: Two-hundred fifteen (49%) surgeons responded, with a mean age of 51.4 years (standard deviation [SD] = 11.5); 78% were male. Thirty-three percent had been in practice for 25 years or longer. More than half of respondents were practicing in a large urban center. Fifty-nine percent believed their group was going to hire in the next 2 to 3 years; however, only 36% believed their health authority/provincial government had the necessary resources. The mean desired age of retirement was 67 years (SD = 6.4). We predict the surgeons-to-population ratio to be 1.55:100 000 and the graduate-to-retiree ratio to be 2.16:1 within the next 5 to 10 years. Seventy-seven (49%) residents responded. Most were "very satisfied" with their training (61%) and operative experience (90%). Eighty-nine percent of respondents planned to pursue addqitional training after residency, with 70% stating that the current job market was contributing to their decision. Most residents responded that they were concerned with the current job market. Conclusions: The results of this study predict an adequate number of plastic surgeons will be trained within the next 10 years to suit the population's requirements; however, there is concern that newly trained surgeons will not have access to the necessary resources to meet growing demands. Furthermore, there is an evident shortage of those practicing in rural areas. Many trainees worry about the availability of jobs, despite evidence of active recruitment. The workforce may benefit from structured career mentorship in residency and improved transparency in hiring practices, particularly to attract young surgeons to smaller communities. It may also benefit from a coordinated national approach to recruitment and succession planning. PMID- 30450347 TI - Smoking and Flap Survival. AB - Purpose: The aim of this study was to compare the complications of flap surgery in non-smokers and smokers and to determine how the incidence of complications was affected by the abstinence period from smoking before and after flap surgery. Methods: In PubMed and Scopus, terms "smoking" and "flap survival" were used, which resulted in 113 papers and 65 papers, respectively. After excluding 6 duplicate titles, 172 titles were reviewed. Among them, 45 abstracts were excluded, 20 full papers were reviewed, and finally 15 papers were analyzed. Results: Post-operative complications such as flap necrosis (P < .001), hematoma (P < .001), and fat necrosis (P = .003) occurred significantly more frequently in smokers than in non-smokers. The flap loss rate was significantly higher in smokers who were abstinent for 24 hours post-operatively than in non-smokers (n = 1464, odds ratio [OR] = 4.885, 95% confidence interval [CI] = 2.071-11.524, P < .001). The flap loss rate was significantly lower in smokers who were abstinent for 1 week post-operatively than in those who were abstinent for 24 hours post operatively (n = 131, OR = 0.252, 95% CI = 0.074-0.851, P = .027). No significant difference in flap loss was found between non-smokers and smokers who were abstinent for 1 week preoperatively (n = 1519, OR = 1.229, 95% CI = 0.482-3.134, P = .666) or for 4 weeks preoperatively (n = 1576, OR = 1.902, 95% CI = 0.383 2.119, P = .812). Conclusion: Since smoking decreases the alveolar oxygen pressure and subcutaneous wound tissue oxygen, and nicotine causes vasoconstriction, smokers are more likely to experience flap loss, hematoma, or fat necrosis than non-smokers. Preoperative and post-operative abstinence period of at least 1 week is necessary for smokers who undergo flap operations. PMID- 30450349 TI - Oral Examination. PMID- 30450348 TI - Diagnostic Performance of Plain Film, Ultrasonography, and Computed Tomography in Nasal Bone Fractures: A Systematic Review. AB - Purpose: The aim of this study was to compare the diagnostic performance (accuracy, sensitivity, specificity, positive predictive value, and negative predictive value) of plain film (PF), ultrasonography (USG), and computed tomography (CT) in diagnosing nasal bone fractures (NBFs). Methods: In a search of PubMed and Scopus, "nasal bone fracture" AND "X-ray OR CT OR USG OR MRI" were searched. Among the 369 titles from PubMed and 379 titles from Scopus, 257 duplicate titles were excluded and 491 titles were reviewed. Among them, 36 full articles were reviewed. From these, 21 were excluded and 1 mined article was added; thus, 16 articles were reviewed. Results: The accuracy of CT (94.4% +/- 2.3%) was significantly higher (P < .001) than that of USG (85.0% +/- 3.6%). The accuracy of USG was significantly higher (P < .001) than that of PF (67.7% +/- 4.7%). Computed tomography (89.3% +/- 3.1%) and USG (87.2% +/- 3.3%) were significantly more sensitive than PF (P < .001 and P < .001, respectively). The specificity of CT (94.2% +/- 2.3%) was significantly higher (P = .001) than that of USG (87.4% +/- 3.3%). The specificity of USG was significantly higher (P < .001) than that of PF (67.8% +/- 4.7%). Among the PF techniques, combining a lateral view and the Water's view (71.8% +/- 4.5%) had significantly higher accuracy than a lateral view alone (62.4% +/- 4.8%) or the Water's view alone (61.0% +/- 4.9%). In USG, there was no significant difference (P = .300) in accuracy among lateral and dorsal views (95.8% +/- 2.0%), a lateral view alone (84.2% +/- 3.7%), and a dorsal view alone (84.2% +/- 3.6%). Conclusion: The results of this review might be helpful in choosing the most appropriate diagnostic tool in patients suspected having NBF. PMID- 30450350 TI - Trump's Tariffs. PMID- 30450351 TI - Are Dog Bites a Problem of Nature or Nurture? PMID- 30450352 TI - The Role of Animal Assisted Intervention on Improving Self-Esteem in Children With Attention Deficit/Hyperactivity Disorder. AB - Attention Deficit/Hyperactivity Disorder (ADHD), the most ubiquitous mental health problem in children, has been associated with poor self-esteem. Psychosocial interventions have aimed to improve self-esteem among this group, with the aim of reducing the development of comorbid depression and anxiety. The present study implemented a randomized control design to examine the possibility of Animal Assisted Interventions (AAI) as a viable approach to improving self esteem among children with ADHD. Children's self-esteem across multiple domains as measured by the Self-Perception Profile for Children was evaluated (n = 80, ages 7-9, 71% male). To test the hypothesis that AAI improves self-esteem, stratified Wilcoxon Signed-Rank Tests (SAS NPAR1WAY procedure) were used to compare pre- to post-treatment ratings. Analyses indicated that scores of children's self-perceptions in the domains of behavioral conduct, social, and scholastic competence, were significantly increased from baseline to post treatment in the AAI group (z = 2.320, p = .021, z = 2.631, p = .008, and z = 2.541, p = .011, respectively), whereas pre-post-treatment differences in self perceptions were not found for the children in the control group without AAI. Findings suggest that AAI is a viable strategy for improving ratings of self perceived self-esteem in children with ADHD. PMID- 30450353 TI - Autonomy Benefits and Risks of Assistive Technologies for Persons With Intellectual and Developmental Disabilities. AB - This paper explores the ways in which assistive technologies (ATs) can both promote and undermine the autonomy of Persons with Intellectual and Developmental Disabilities (PIDD). Following an initial discussion of ATs for PIDD, I examine the specific issues of autonomy for PIDD. I outline the ways in which ATs can boost autonomy, of PIDD, focusing on knowledge, authenticity, and liberty. Following that I suggest that ATs are not necessarily beneficial in terms of autonomy and examine ways that they might be used to undermine the autonomy of PIDD, specifically the categories of knowledge, authenticity, and liberty. I conclude by suggesting that the development of ATs requires ethical oversight. PMID- 30450354 TI - Cannabis Use Among Remote Indigenous Australians: Opportunities to Support Change Identified in Two Waves of Sampling. AB - Background: Cannabis harms among Indigenous populations in Australia, New Zealand, Canada and the United States may be magnified by poorer health and heavy use. However, little direct evidence is available to evaluate cannabis' impacts. In communities in remote northern Queensland (Australia) where cannabis has become endemic, opportunities to support change were investigated. Methods: Opportunistically recruited participants (aged 15-49 years) discussed their cannabis use history in interviews in two waves of population sampling in Cape York (Queensland). Wave 1 included 429 people (235 males and 194 females); and wave 2 included 402 people (228 males and 174 females). Current users (used cannabis during the year before interview) described frequency of use, amount consumed, expenditure and dependence symptoms. Other substance use was recorded for 402 people at wave 2. Results: Wave 1: 69% reported lifetime use and 44% current use. Males (55%) were more likely than females (30%) to be current users (P < 0.001). Most (96%) current users described at least weekly use; nearly half (48%) were "heavy" users (>=6 cones/session at least once/week) and 77% met cannabis dependence criteria. Three communities spent up to $AUD14,200/week on cannabis, around $AUD2.0 million/year, or around 9% of community people's total income on cannabis. The majority (79%) of current users wanted to quit or reduce their cannabis use. Wave 2: no difference was observed in the proportion of lifetime (69%, |z| = 0.04, P = 0.968) or current cannabis users (39%, |z| = 1.39, P = 0.164); nor current use among males (71%, |z| = 0.91, P = 0.363) or females (62%, |z| = 0.36, P = 0.719). However, a significant reduction in current users by 15% (|z| = 2.36, P = 0.018) was observed in one community. Of 105 wave 1 current users re-assessed in 2, 29 (27%) had ceased use. These participants reported cost and family commitments as reasons to change and that social support and employment enabled abstinence. Current and lifetime cannabis use were closely associated with all other substance use, particularly tobacco and alcohol (both P > 0.001). Conclusions: High rates of heavy cannabis use in remote Australian Indigenous communities warrant action. Successful cessation among some individuals suggests that significant opportunities are available to support change even where cannabis use may be endemic. PMID- 30450355 TI - Applying Social Network Analysis to Evaluate Implementation of a Multisector Population Health Collaborative That Uses a Bridging Hub Organization. AB - Background: Multisector collaboratives are increasingly popular strategies for improving population health. To be comprehensive, collaboratives must coordinate the activities of many organizations across a geographic region. Many policy relevant models encourage creation and use of centralized hub organizations to do this work, yet there is little guidance on how to evaluate implementation of such hubs and track their network reach. We sought to demonstrate how social network analysis (SNA) could be used for this purpose. Methods: Through formative research, we defined and conceptualized key characteristics of a bridging hub network and identified a set of candidate measures-(1) network membership, (2) network interaction, (3) role and reach of the bridging hub, and (4) network collaboration-to evaluate its implementation within a pre-determined geographic region of Southeast Minnesota, USA. We then developed and administered a survey to assess outcomes as part of a SNA. We commented on the feasibility and usefulness of the methods. Results: The initial surveyed network consisted of 50 healthcare organizational sites and 50 community organizations representing sectors of public health, education, research, health promotion, social services, and long-term care and supports. Fifty-three of these organizations responded to the survey. The network's level of collaboration was "Cooperation" (level 2 of 5) and reported levels of collaboration varied by organization. Thirty-eight additional, unsurveyed organizations were identified as collaborators by respondents, pushing the theoretical network denominator up to 138 organizations. These additional organizations included grocery stores, ambulance services, and smaller, independent healthcare and community-based services focused on meeting the needs of underserved populations. The bridging hub organization had the highest betweenness centrality and was in good position to bridge healthcare and the community, although its organizational reach was estimated at only 51%. The SNA methods were feasible and useful for identifying opportunities and guiding implementation. Conclusions: Bridging hub organizations are not likely to link-or even be aware of-all relevant organizations in a geographic region at initial implementation. SNA may be a useful method for evaluating the value and reach of a bridging hub organization and guiding ongoing implementation efforts. Trial registration: http://ClinicalTrials.gov; #NCT03046498. PMID- 30450356 TI - A Molecular CO2 Reduction Catalyst Based on Giant Polyoxometalate {Mo368}. AB - Photocatalytic CO2 reduction in water is one of the most attractive research pursuits of our time. In this article we report a giant polyoxometalate {Mo368} based homogeneous catalytic system, which efficiently reduces CO2 to formic acid with a maximum turnover number (TON) of 27,666, turnover frequency (TOF) of 4,611 h-1 and external quantum efficiency of the reaction is 0.6%. The catalytic system oxidizes water and releases electrons, and these electrons are further utilized for the reduction of CO2 to formic acid. A maximum of 8.3 mmol of formic acid was observed with the loading of 0.3 MUmol of the catalyst. Our catalyst material is also stable throughout the reaction. The starting materials for this experiment are CO2 and H2O and the end products are HCOOH and O2. The formic acid formed in this reaction is an important H2 gas carrier and thus significant in renewable energy research. PMID- 30450357 TI - The Emerging Role of Lamin C as an Important LMNA Isoform in Mechanophenotype. AB - Lamin A and lamin C isoforms of the gene LMNA are major structural and mechanotransductive components of the nuclear lamina. Previous reports have proposed lamin A as the isoform with the most dominant contributions to cellular mechanophenotype. Recently, expression of lamin C has also been shown to strongly correlate to cellular elastic and viscoelastic properties. Nevertheless, LMNA isoforms exist as part of a network that collectively provides structural integrity to the nucleus and their expression is ultimately regulated in a cell specific manner. Thus, they have importance in mechanotransduction and structural integrity of the nucleus as well as potential candidates for biomarkers of whole cell mechanophenotype. Therefore, a fuller discussion of lamin isoforms as mechanophenotypic biomarkers should compare both individual and ratiometric isoform contributions toward whole-cell mechanophenotype across different cell types. In this perspective, we discuss the distinctions between the mechanophenotypic correlations of individual and ratiometric lamins A:B1, C:B1, (A + C):B1, and C:A across cells from different lineages, demonstrating that the collective contribution of ratiometric lamin (A + C):B1 isoforms exhibited the strongest correlation to whole-cell stiffness. Additionally, we highlight the potential roles of lamin isoform ratios as indicators of mechanophenotypic change in differentiation and disease to demonstrate that the contributions of individual and collective lamin isoforms can occur as both static and dynamic biomarkers of mechanophenotype. PMID- 30450359 TI - How Overweight and Obesity Relate to the Development of Functional Limitations among Filipino Women. AB - As life expectancy and obesity increase in low and middle-income countries, the relationship of weight status to functional outcomes in older adults in these settings requires attention. We examined how overweight (BMI > 25 kg/m2), obesity (BMI > 30 kg/m2), and high waist circumference (WC > 80 cm) related to grip strength, timed up-and-go, and development of limitations in mobility, activities of daily living (ADL), and instrumental activities of daily living (IADL) among Filipino women. We analyzed data from seven rounds of the Cebu Longitudinal Health and Nutrition Survey (1994, n = 2279 to 2015, n = 1568, age 49-78 years) to examine how women's reports of functional limitations related to their prior WC, and how their grip strength and timed up-and-go related to concurrently measured overweight and obesity, adjusted for age, socioeconomic status, and urbanicity. High WC was associated with higher odds of subsequent mobility and IADL limitations. Chronic disease morbidity (sum of self-reported arthritis, high blood pressure, heart disease, diabetes, and cancer) fully mediated the association of high WC with ADL and IADL limitations, but not physical/mobility limitations. Longer up-and-go times, and higher grip strength were related to overweight and obesity. Results emphasize the need for obesity prevention to reduce chronic diseases and maintain good functional status as women age. PMID- 30450360 TI - Healing Rates and Functional Outcomes After Triple-Loaded Single-Row Versus Transosseous-Equivalent Double-Row Rotator Cuff Tendon Repair. AB - Background: Although healing rates and outcomes of arthroscopic single-row rotator cuff repairs have been compared with double-row repairs, none have utilized triple-loaded anchors. Purpose: To compare healing and function after single-row repairs with triple-loaded anchors versus double-row repairs with a suture-bridge technique. Study Design: Cohort study; Level of evidence, 3. Methods: A single surgeon performed arthroscopic rotator cuff repair on 47 consecutive patients with an easily reducible full-thickness rotator cuff tear of medium size (1-3 cm). A retrospective cohort study was performed in which the first 25 patients underwent repair with a double-row suture-bridge (DRSB) technique. The next 22 patients underwent repair with a single-row technique with triple-loaded anchors and simple stitches (SRTL) after a change in technique by the surgeon. Twenty-one DRSB and 18 SRTL repairs were evaluated preoperatively and at a minimum of 12 months postoperatively with a visual analog scale for pain, the American Shoulder and Elbow Surgeons form, and the Simple Shoulder Test. Healing was evaluated with magnetic resonance imaging at a minimum of 12 months. Results: When DRSB repairs were compared with SRTL repairs, there were no significant differences in patient age (61 vs 65 years), tear size (2.3 vs 2.1 in the sagittal plane; 2.0 vs 1.8 cm in the coronal plane), Goutallier fatty infiltration (supraspinatus grade: stage 0, 38%; stage 1, 38%; stage 2, 19%; stage 3, 5%; vs stage 0, 56%; stage 1, 39%; stage 2, 5%; stage 3, 0%), tendon healing (71% vs 78%), improvement in visual analog scale pain score (3.7 vs 3.2), or improvement in American Shoulder and Elbow Surgeons scores (34.6 vs 36.9), with P > .05 in all cases. SRTL repairs had significantly greater improvement in Simple Shoulder Test scores versus DRSB repairs (6.6 vs 4.5; P = .03). Conclusion: DRSB and SRTL repairs have similar improvements in pain and function with equivalent healing rates for arthroscopic repair of mobile full-thickness rotator cuff tears of medium size (1-3 cm). PMID- 30450361 TI - Medial Elbow Pain During the Return-to-Throwing Period After Ulnar Collateral Ligament Reconstruction in Pitchers. AB - Background: Ulnar collateral ligament reconstruction (UCLR) is common in the sport of baseball, particularly among pitchers. Postoperative return-to-sport protocols have many players beginning to throw at 4 to 5 months and returning to full competition between 12 and 16 months after surgery. Medial elbow pain during the return-to-throwing period often occurs and can be difficult to manage. Purpose: To evaluate the incidence of medial elbow pain and associations with outcomes and revision surgery during the return-to-throwing period after UCLR. Study Design: Case-control study; Level of evidence, 3. Methods: Between the years of 2002 and 2014, all pitchers who underwent UCLR at a single institution were identified. Charts were reviewed for incidence of medial elbow pain during return to throwing, return to sport, and subsequent operative interventions, including revision ulnar collateral ligament surgery. Results: Of a total of 616 pitchers who underwent UCLR during the study period, 317 were included in this study. Medial elbow pain was experienced by 45.1% (143 of 317), with a mean time of complaint of 9.75 months after surgery. The groups with and without pain did not differ statistically with regard to age (pain, 20.6 years; no pain, 20.9 years) or level of competition. Of those who experienced medial elbow pain, 10.5% did not return to sport; 5.6% underwent revision UCLR; and 19.6% underwent other operative procedures at the elbow. Among those who did not experience medial elbow pain when returning to throw, 8.7% did not return to sport, with only 1.7% undergoing revision UCLR and 6.9% undergoing other operative elbow procedures. Conclusion: Of the pitchers evaluated in the study, approximately half reported pain during the return-to-throwing phase after UCLR. Those who experienced medial elbow pain had a higher rate of subsequent surgical intervention. PMID- 30450358 TI - Diagnosis of Autoimmune Blistering Diseases. AB - Autoimmune skin blistering diseases (AIBD) are characterized by autoantibodies that are directed against structural proteins in the skin and adjacent mucous membranes. Some clinical signs are typical for a specific AIBD, however, correct diagnosis requires the detection of tissue-bound or circulating autoantibodies. The gold standard for diagnosis of AIBD is the detection of autoantibodies or complement component 3 by direct immunofluorescence (DIF) microscopy of a perilesional biopsy. Circulating antibodies can be detected via indirect immunofluorescence (IIF) microscopy of different tissue substrates including human skin, monkey esophagus, and more recently, recombinant forms of the different target antigens. Latter are also employed in various commercial ELISA systems and by immunoblotting in in-house assays available in specialized laboratories. ELISA systems are also particularly valuable for monitoring of the disease activity during the disease course which can be helpful for treatment decisions. Exact diagnosis is essential for both treatment and prognosis, since some AIBD are associated with malign tumors such as paraneoplastic pemphigus and anti-laminin 332 mucous membrane pemphigoid. This review presents clinical and immunopathological features of AIBD for the state-of the art diagnosis of these disorders. PMID- 30450362 TI - Challenges and opportunities in neurophotonics discussed at the International Conference on Biophotonics 2017. AB - Neurophotonics is an exploding field that spans the intersection of light and neurons for fundamental discovery and clinical translation. Optical technologies have significantly impacted brain research by probing into the mysteries of the brain, modulating brain activity, and improving patient care. Based on a discussion held at the International Conference on Biophotonics 2017, a group of leading researchers brainstormed to identify areas of unmet need in neuroscience and medicine, where biophotonics research could have the highest affect. We present two areas of future growth that spans basic research and clinical needs: management of chronic pain and interventional neuroimmunology. There are many directions within these areas that could be pursued for the ultimate goal of improved understanding of the brain and enhanced care of patients with neurological disorders. PMID- 30450364 TI - Erratum: Adaptive algorithm utilizing acceptance rate for eliminating noisy epochs in block-design functional near-infrared spectroscopy data: application to study in attention deficit/hyperactivity disorder children. AB - [This corrects the article DOI: 10.1117/1.NPh.5.4.045001.]. PMID- 30450365 TI - Filter Retardation Assay for Detecting and Quantifying Polyglutamine Aggregates Using Caenorhabditis elegans Lysates. AB - Protein aggregation is a hallmark of several neurodegenerative diseases and is associated with impaired protein homeostasis. This imbalance is caused by the loss of the protein's native conformation, which ultimately results in its aggregation or abnormal localization within the cell. Using a C. elegans model of polyglutamine diseases, we describe in detail the filter retardation assay, a method that captures protein aggregates in a cellulose acetate membrane and allows its detection and quantification by immunoblotting. PMID- 30450363 TI - Prolonged monitoring of cerebral blood flow and autoregulation with diffuse correlation spectroscopy in neurocritical care patients. AB - Monitoring of cerebral blood flow (CBF) and autoregulation are essential components of neurocritical care, but continuous noninvasive methods for CBF monitoring are lacking. Diffuse correlation spectroscopy (DCS) is a noninvasive diffuse optical modality that measures a CBF index ( CBFi ) in the cortex microvasculature by monitoring the rapid fluctuations of near-infrared light diffusing through moving red blood cells. We tested the feasibility of monitoring CBFi with DCS in at-risk patients in the Neurosciences Intensive Care Unit. DCS data were acquired continuously for up to 20 h in six patients with aneurysmal subarachnoid hemorrhage, as permitted by clinical care. Mean arterial blood pressure was recorded synchronously, allowing us to derive autoregulation curves and to compute an autoregulation index. The autoregulation curves suggest disrupted cerebral autoregulation in most patients, with the severity of disruption and the limits of preserved autoregulation varying between subjects. Our findings suggest the potential of the DCS modality for noninvasive, long-term monitoring of cerebral perfusion, and autoregulation. PMID- 30450366 TI - Challenges When Translating and Culturally Adapting a Measurement Instrument: The Suitability and Comprehensibility of Materials (SAM+CAM). AB - There is evidence that low suitability and comprehensibility of printed education materials (PEMs) affects patients' and relatives' ability to read and comprehend information. However, few instruments measure the suitability of written information, and none exist in the Swedish language. The aim was to describe the translation and adaptation of the Suitability and Comprehensibility of Materials (SAM+CAM) instrument into the Swedish language and health care context and to explore challenges related to this process. The SAM+CAM instrument was translated and culturally adapted in five steps: forward translation, synthesis, back translation, expert review, and pretests. Differences were found when translating and culturally adapting the SAM+CAM instrument in the areas of semantic, idiomatic, and experiences. Participants revealed several clarity inconsistencies between items. They also identified linguistic differences and unfamiliar wording; they found that the instrument was perplexing to use and lacked knowledge regarding the specific health care areas in the examined PEMs. The cultural perspective is a significant factor that influences the usability of PEMs. Therefore, expert groups of participants are useful when adapting instruments to different cultures. The Swedish SAM+CAM instrument requires experienced and highly qualified raters. PMID- 30450367 TI - Mobility Programs for the Hospitalized Older Adult: A Scoping Review. AB - Objectives: This scoping review (a) describes programs to improve mobility in hospitalized adults and (b) determines the methods used to measure mobility. Method: The Joanna Briggs Institute Methodology for Scoping Reviews was used to conduct this review. Results: Our findings suggest that using a multidisciplinary approach may be the most effective way to promote mobility in hospitalized older adults. Most studies did not articulate how physical activity was measured, indicating that more research is needed. Discussion: The literature shows that implementation of protocols designed to improve the early and regular implementation of physical mobility activities improves the health outcomes of hospitalized older people. Costs associated with healthcare utilization are also reduced, including hospital length of stay. Mobility programs that quantified mobility through validated measurement tools or accelerometers are the most promising as they provide feedback that reinforces progress of the patient and the expected benefits of early mobility. PMID- 30450368 TI - Moderate Aerobic Training Decreases Blood Pressure but No Other Cardiovascular Risk Factors in Hypertensive Overweight/Obese Elderly Patients. AB - Hypertension and obesity are prevalent diseases in elderly people, and their combination can cause deleterious effects on physiological system. Moderate intensity aerobic training (MIAT) seems to be a beneficial approach to control and treat these diseases separately. However, few studies have investigated the impact of MIAT on cardiovascular risk factors associated with these conditions (i.e., elevated blood pressure values, blood markers, and body composition). Therefore, the present study was designed to investigate the effects of MIAT on blood pressure, blood markers, and body composition in hypertensive overweight/obese elderly patients. Twenty-four hypertensive overweight/obese elderly patients were randomized into control group (CG) and training group (TG), submitted to 12 weeks of MIAT of 50 min, 3 days per week, at 60% of maximal HR (heart rate). There was a decrease in diastolic blood pressure (-10.1 +/- 3.3; p = .01; effect size = 1.29) and mean arterial pressure (MAP; -8.2 +/- 3.7; p = .04; effect size = 0.94) following 12 weeks of training in the TG as compared with baseline. There was an increase in triacylglycerol levels in the TG (+0.1 +/ 0.0; p = .02). There were no significant changes in body composition for both groups. The present study revealed that 12 weeks of MIAT can decrease blood pressure in hypertensive obese elderly patients, with no significant modifications in blood markers and body composition. PMID- 30450369 TI - The Effect of Adherence to Screening Guidelines on the Risk of Alzheimer's Disease in Elderly Individuals Newly Diagnosed With Type 2 Diabetes Mellitus. AB - Objective: The aim of this study was to examine the possibility that type 2 diabetes and Alzheimer's disease may share common behavioral protective factors such as adherence to type 2 diabetes treatment guidelines given that these two diseases have both epidemiological and metabolic similarities. Method: The method used in this study is a retrospective cohort study of 3,797 U.S. Medicare fee-for service beneficiaries aged 66+ newly diagnosed with type 2 diabetes and without a prior record of Alzheimer's disease based on the Health and Retirement Study. Results: Results of a left-truncated Cox model showed that adherence reduces the risk of Alzheimer's disease by 20% to 24%. Other significant effects were college education (hazard ratio [HR]: 0.65; p value: .023), stroke (HR: 1.40; p value: .013), and 4+ limitations in physical functioning (HR: 1.33; p value: .008). Discussion: Risk of Alzheimer's disease can be reduced by behavioral factors. Possible mechanisms may include earlier start of interventions to reduce blood glucose levels and improve insulin sensitivity. PMID- 30450370 TI - Effect of Pain Severity on Executive Function Decline in Community-Dwelling Older Adults. AB - Objective: The purpose of this study was to explore the reciprocal relationship between pain severity and executive function in community-dwelling older adults. Method: In this prospective cohort study, 64 Japanese community-dwelling older adults aged 60 years or older (mean age 72.8 years; women, 68.8%) were analyzed. Pain severity was assessed by self-reported questionnaire while executive function was assessed by the Trail Making Test at baseline and at 1-year follow up assessment. A mixed effect model was conducted to analyze the effect of baseline executive function on change in pain severity and effect of baseline pain severity on change in executive function. Results: The effect of baseline Trail Making Test on change in pain severity was not significant. On the contrary, the effect of high baseline pain severity on the decline in set shifting (Trail Making Test Part B) was significant even after adjustment with age, sex, years of education, depressive symptoms, and analgesic drug use. Conclusion: Higher baseline pain severity was associated with greater executive function decline in community-dwelling older adults. Executive function decline due to severe pain should be considered as well as pain itself. PMID- 30450371 TI - Optimizing diffusion-weighted magnetic resonance imaging for evaluation of lung tumors: A comparison of respiratory triggered and free breathing techniques. AB - Purpose: The aim of this study was to compare respiratory-triggered (RT) and free breathing (FB) diffusion weighted imaging (DWI) techniques regarding apparent diffusion coefficient (ADC) measurements and repeatability in non-squamous non small cell lung cancer (NSCLC) measuring the total tumor volume. Material and Methods: A total of 57 magnetic resonance imaging (MRI) examinations were analyzed. DWI was obtained by a single-shot spin-echo echo-planar imaging sequence, and for each MRI examination 2 consecutive RT and 2 consecutive FB DWI sequences were performed. Two radiologists independently read the images and made measurements. For each tumor the mean ADC value of the whole tumor volume was calculated. The difference in mean ADCs between FB and RT DWI was evaluated using the paired-sample t-test. The repeatability of ADC measurements related to imaging method was evaluated by intra class correlations (ICC) for each of the FB and RT DWI pairs. Results: There were no significant differences in mean ADCs between FB and RT (Reader 1 p = 0.346, Reader 2 p = 0.583). The overall repeatability of ADC measurement was good for both acquisition methods, with ICCs > 0.9. Subgroup analysis showed somewhat poorer repeatability in small tumors (50 ml or less) and tumors in the lower lung zones for the RT acquisition, with ICC as low as 0.72. Conclusions: No difference in ADC measurement or repeatability between FB and RT DWI in whole lesion ADC measurements of adenocarcinomas in the lung was demonstrated. The results imply that in this setting the FB acquisition method is accurate and possibly more robust than the RT acquisition technique. PMID- 30450372 TI - Exercise, the diurnal cycle of cortisol and cognitive impairment in older adults. AB - Exercise has been shown to reduce the risk of developing Mild Cognitive Impairment and Alzheimer's disease as well as to improve cognition in healthy and cognitively impaired individuals. However, the mechanisms of these benefits are not well understood. The stress hypothesis suggests that the cognitive benefits attributed to exercise may partially be mediated by changes in the cortisol secretion pattern. Chronic stress may increase the risk of AD and exacerbate the cognitive deficits and brain pathology characteristic of the condition while physical activity has been shown to attenuate most of stress consequences and risk factors for AD. Initially, research on the effects of cortisol on cognition and physical activity focused on cortisol levels at one time point but the circadian pattern of cortisol secretion is complex and it is still unclear which aspects are most closely associated with cognitive function. Thus, the aim of this review was to analyze the exercise/stress/cognition hypothesis focusing on the effects of the diurnal cycle of cortisol on cognitive function and physical activity in older adults with and without cognitive impairment. PMID- 30450373 TI - Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter. AB - Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naive 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30 min/4 degrees C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress. PMID- 30450375 TI - Neuroendocrine and neuroimmune adaptation to Chronic Escalating Distress (CED): A novel model of chronic stress. AB - Acute and chronic stress challenges have a profound influence on the development and expression of subsequent affective disorders, alcohol use disorders, and natural aging processes. These experiments examined adaptation in neuroimmune and neuroendocrine responses that occurred as a result of exposure to a novel model of chronic stress, termed chronic escalating distress (CED). This model involves exposure to highly predictable daily stress challenges involving a systematic escalation in both the intensity and length of daily stress challenges, and has recently been shown to profoundly alter alcohol sensitivity. Male Sprague-Dawley rats were exposed to an 11 day procedure where days 1-5 consisted of 60 min of restraint, days 6-10 consisted of 60 min of restraint immediately followed by 30 min of forced swim, and on day 11 subjects were exposed to a 2 h session of intermittent footshock. Experiment 1 examined adaptation in the corticosterone (CORT) response at key points in the 11 day procedure, and found that the escalation in stressors disrupted habituation to restraint, whereas the CORT response to daily forced swim exposure increased across days. Experiment 2 investigated the impact of this stress paradigm on the expression of several cytokine (IL-1beta, IL-6, TNF-alpha) and cellular activation marker (c-Fos, CD14, CD200R) genes in key brain regions (PVN, HPC, & PFC) known to be influenced by stress. Interestingly, a history of CED had no effect on footshock-induced neuroimmune changes (increased IL-1 in the PVN; increased IL-6 in the HPC and PFC). In addition, acute footshock and CED produced similar c-fos induction within the PVN whereas CED led to enhanced c-fos induction in both the HPC and PFC. These findings support recent work indicating that neuroimmune responses to acute stress challenges persisted in rats with a recent history of repeated stress exposure, and that these effects occurred contemporaneously with ongoing changes in HPA axis reactivity. Overall, this CED model may serve as a highly tractable model for studying adaptation to chronic stress, and may have implications for understanding stress-induced alterations in alcohol sensitivity and natural aging processes. PMID- 30450377 TI - Contradictory effects of erythropoietin on inhibitory synaptic transmission in left and right prelimbic cortex of mice. AB - Erythropoietin (EPO) has been shown to improve cognitive function in mammals as well as in patients of psychiatric diseases by directly acting on the brain. In addition, EPO attenuates the synaptic transmission and enhances short- and long term synaptic plasticity in hippocampus of mice, although there are still many discrepancies between different studies. It has been suggested that the divergences of different studies take root in different in-vivo application schemata or in long-term trophic effects of EPO. In the current study, we investigated the direct effects of EPO in slices of prelimbic cortex (PrL) by acute ex-vivo application of EPO, so that the erythropoietic or other trophic effects could be entirely excluded. Our results showed that the EPO effects were contradictory between the left and the right PrL. It enhanced the inhibitory transmission in the left and depressed the inhibitory transmission in the right PrL. Strikingly, this lateralized effect of EPO could be consistently found in individual bi-lateral PrL of all tested mice. Thus, our data suggest that EPO differentially modulates the inhibitory synaptic transmission of neuronal networks in the left and the right PrL. We hypothesize that such lateralized effects of EPO contribute to the development of the lateralization of stress reaction in PFC and underlie the altered bilateral GAGAergic synaptic transmission and oscillation patterns under stress that impact the central emotional and cognitive control in physiology as well as in pathophysiology. PMID- 30450376 TI - Tauopathy and neurodegeneration: A role for stress. AB - Neurodegenerative diseases are characterized by an irreversible and progressive loss of neuronal structure and function. While many alterations to normal cellular processes occur during neurodegeneration, a pathological accumulation of aggregated proteins constitutes a hallmark of several neurodegenerative disorders. Alzheimer's disease, specifically, is pathologically defined by the formation of amyloid plaques and tangles of hyperphosphorylated tau protein. Stress has emerged as an important factor in the development and progression of neurodegenerative diseases, including Alzheimer's. Very little is known, however, regarding the effects of stress on the mechanisms controlling abnormal protein aggregation and clearance. Chronic stress activates the hypothalamic-pituitary adrenal (HPA) axis, causing an excessive secretion of glucocorticoids that are capable of impacting diverse physiological and cellular processes. The present review focuses on the influence of stress on a key feature of Alzheimer's disease pathology, emphasizing the relationship between tau phosphorylation and accumulation and its connection to HPA axis dysfunction. PMID- 30450374 TI - The potential of calibrated fMRI in the understanding of stress in eating disorders. AB - Eating disorders (ED), including Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED), are medically dangerous psychiatric disorders of unknown etiology. Accumulating evidence supports a biopsychosocial model that includes genetic heritability, neurobiological vulnerability, and psychosocial factors, such as stress, in the development and maintenance of ED. Notably, stress hormones influence appetite and eating, and dysfunction of the physiological stress response has been implicated in ED pathophysiology. Stress signals also appear associated with food reward neurocircuitry response in ED, providing a possible mechanism for the role of stress in appetite dysregulation. This paper provides a review of some of the interacting psychological, behavioral, physiological, and neurobiological mechanisms involved in the stress response among individuals with ED, and discusses novel neuroimaging techniques to address potential physiological confounds of studying neural correlates of stress in ED, such as calibrated fMRI. PMID- 30450379 TI - Stress reactivity and the developmental psychopathology of adolescent substance use. AB - Adolescence represents a period of risk for initiation of substance use and the development of substance use disorders (SUDs). In addition, during adolescence, there is rapid development of stress reactivity systems. This paper describes a conceptual model of the role of stress reactivity in the development of substance use in adolescence. It is proposed that some children develop maladaptive patterns of emotional, physiological, and neural reactivity to stressful situations that are either too high or too low and that their patterns of reactivity interact with increased stressful life events during adolescence to lead to potential for substance use and SUDs. In one pathway, youth develop a heightened reactivity to stress, which leads to high negative emotion and using substances to cope. In a second pathway, youth develop a blunted reactivity to stress, which leads to chronic under-arousal and using substances to increase sensation/arousal. We propose that girls may be more likely to take the high reactivity pathway to substance use and boys may be more likely to take the low reactivity pathway. We review existing studies of stress reactivity in adolescents, which support our theory that altered stress reactivity is correlated with and, in some cases, predictive of adolescent substance use, with some studies finding high stress reactivity and some finding low stress reactivity to be correlated with increased substance use and SUD risk. Some studies find that the blunted reactivity pathway to substance use occurs particularly for youth from high-risk contexts. Further, some evidence supports the proposed sex differences in stress reactivity pathways. We discuss future directions and implications of these findings for developing and refining developmentally-sensitive stress reactivity-focused SUD prevention programs. PMID- 30450378 TI - Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats. AB - The dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development. PMID- 30450380 TI - Neuroendocrine and immune pathways from pre- and perinatal stress to substance abuse. AB - Early life adversity is a documented risk factor for substance abuse and addiction. The pre- and perinatal period (i.e., from implantation, through pregnancy, to 6 months of age) is a critical period marked by high biological plasticity and vulnerability, making perinatal stress a particularly robust form of adversity. The neuroendocrine and immune systems are key mechanisms implicated in the transmission of addiction risk. We review animal and human studies that provide preliminary evidence for links between perinatal stress, neuroendocrine and immune dysregulation, and risk for substance abuse and addiction. A translational neuroscience perspective is employed to elucidate pre- and perinatally-induced biological mechanisms linked to addiction and discuss implications for prevention and intervention efforts. Significant evidence supports associations between pre- and perinatal stress and dysregulation of the hypothalamic-pituitary-adrenal axis and immune systems as well as links between neuroendocrine/immune functioning and addiction risk. More work is needed to explicitly examine the interplay between pre- and perinatal stress and neuroendocrine/immune disruptions that together heighten substance abuse risk. Future work is needed to fully understand how pre- and perinatal stress induces biological alterations to predispose individuals to higher risk for addiction. Such knowledge will strengthen theoretically-driven and empirically-supported prevention efforts for substance abuse and addiction. PMID- 30450382 TI - On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods. AB - In this review, we will discuss the safety of repeated treatments with ketamine for patients with treatment-resistant depression (TRD), a condition in which patients with major depression do not show any clinical improvements following treatments with at least two antidepressant drugs. We will discuss the effects of these treatments in both sexes at different developmental periods. Numerous small clinical studies have shown that a single, low-dose ketamine infusion can rapidly alleviate depressive symptoms and thoughts of suicidality in patients with TRD, and these effects can last for about one week. Interestingly, the antidepressant effects of ketamine can be prolonged with intermittent, repeated infusion regimens and produce more robust therapeutic effects when compared to a single infusion. The safety of such repeated treatments with ketamine has not been thoroughly investigated. Although more studies are needed, some clinical and preclinical reports indicated that repeated infusions of low doses of ketamine may have addictive properties, and suggested that adolescent and adult female subjects may be more sensitive to ketamine's addictive effects. Additionally, during ketamine infusions, many TRD patients report hallucinations and feelings of dissociation and depersonalization, and therefore the effects of repeated treatments of ketamine on cognition must be further examined. Some clinical reports indicated that, compared to women, men are more sensitive to the psychomimetic effects of ketamine. Preclinical studies extended these findings to both adolescent and adult male rodents and showed that male rodents at both developmental periods are more sensitive to ketamine's cognitive-altering effects. Accordingly, in this review we shall focus our discussion on the potential addictive and cognitive-impairing effects of repeated ketamine infusions in both sexes at two important developmental periods: adolescence and adulthood. Although more work about the safety of ketamine is warranted, we hope this review will bring some answers about the safety of treating TRD with repeated ketamine infusions. PMID- 30450383 TI - The social defeat/overcrowding murine psychosocial stress model results in a pharmacologically reversible body weight gain but not depression - related behaviours. AB - Depression is a highly prevalent psychiatric disorder, yet its etiology is not well understood. The validation of animal models is therefore a critical step towards advancing knowledge about the neurobiology of depression. Psychosocial stress has been promoted as a prospective animal model of depression, however, different protocols exist with variable responses, and further investigations are therefore required. We aimed to characterise the behavioural and body weight responses to the social defeat/overcrowding (SD/OC) model and to explore the effects of the antidepressant fluoxetine and the peroxynitrite scavenger, CuII(atsm), therein. Male C57BL/6JArc mice were exposed to a 19 day SD/OC protocol at two levels of aggression, determined by terminating SD bouts after one, or approximately five social defeat postures. This was followed by a battery of behavioural tests including social interaction test (SIT), locomotor activity (LMA), light-dark box test (LDB), saccharin preference test (SPT) and the forced swim test (FST). Mice were dosed daily with vehicle, fluoxetine (20 mg/kg) or CuII(atsm) (30 mg/kg) throughout the protocol. SD/OC increased body weight compared to controls, which was abolished by fluoxetine and attenuated by CuII(atsm). Weight gain specifically peaked during OC sessions but was not affected by either drug treatment. Fluoxetine reduced the number of defeat postures during fight bouts on some days. SD/OC otherwise failed to elicit depression- or anxiety-like behaviour in the tests measured. These data raise questions over the SD/OC model as an etiological model of depression-related behaviours but highlight the potential of this model for investigations into mechanisms regulating binge eating and weight gain under conditions of chronic social stress. PMID- 30450381 TI - Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF. AB - Both the ostensibly aversive effects of unpredictable episodes of social stress and the intensely rewarding effects of drugs of abuse activate the mesocorticolimbic dopamine systems. Significant neuroadaptations in interacting stress and reward neurocircuitry may underlie the striking connection between stress and substance use disorders. In rodent models, recurring intermittent exposure to social defeat stress appears to produce a distinct profile of neuroadaptations that translates most readily to the repercussions of social stress in humans. In the present review, preclinical rodent models of social defeat stress and subsequent alcohol, cocaine or opioid consumption are discussed with regard to: (1) the temporal pattern of social defeat stress, (2) male and female protocols of social stress-escalated drug consumption, and (3) the neuroplastic effects of social stress, which may contribute to escalated drug taking. Neuroadaptations in corticotropin-releasing factor (CRF) and CRF modulation of monoamines in the ventral tegmental area and the bed nucleus of the stria terminalis are highlighted as potential mechanisms underlying stress escalated drug consumption. However, the specific mechanisms that drive CRF mediated increases in dopamine require additional investigation as do the stress induced neuroadaptations that may contribute to the development of compulsive patterns of drug-taking. PMID- 30450385 TI - Elimination of vesicular zinc alters the behavioural and neuroanatomical effects of social defeat stress in mice. AB - Chronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc - zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice. PMID- 30450384 TI - A review of nonhuman primate models of early life stress and adolescent drug abuse. AB - Adolescence represents a developmental stage in which initiation of drug use typically occurs and is marked by dynamic neurobiological changes. These changes present a sensitive window during which perturbations to normative development lead to alterations in brain circuits critical for stress and emotional regulation as well as reward processing, potentially resulting in an increased susceptibility to psychopathologies. The occurrence of early life stress (ELS) is related to a greater risk for the development of substance use disorders (SUD) during adolescence. Studies using nonhuman primates (NHP) are ideally suited to examine how ELS may alter the development of neurobiological systems modulating the reinforcing effects of drugs, given their remarkable neurobiological, behavioral, and developmental homologies to humans. This review examines NHP models of ELS that have been used to characterize its effects on sensitivity to drug reinforcement, and proposes future directions using NHP models of ELS and drug abuse in an effort to develop more targeted intervention and prevention strategies for at risk clinical populations. PMID- 30450387 TI - Leveraging translational neuroscience to inform early intervention and addiction prevention for children exposed to early life stress. AB - Substance use and addiction are disproportionately experienced by individuals with a history of exposure to early life stress (ELS), such as maltreatment, domestic violence and parent psychopathology. Unfortunately, extant interventions have mixed effectiveness at improving outcome trajectories for ELS-exposed children, who are often underserved by evidenced-based programs. Here, we employ a translational neuroscience framework to delineate how neuroscience can deepen our understanding of ELS-linked alterations in children's function to inform the development of more targeted, effective early intervention and addiction prevention programs. Candidate neural pathways altered by ELS and linked to addiction are described across sensory, affective, motivational, and executive function domains. Next, we provide an example of the application of translational neuroscience principles in a family of early interventions (i.e. Multidimensional Treatment Foster Care - Preschool, Kids in Transition to School) focused on improving self-regulation in ELS-exposed children. Future directions and areas of unmet need in intervention research detail the significant potential of translational neuroscience to advance interventionists' ability to support positive adjustment in ELS-exposed children and prevent harmful addiction outcomes. PMID- 30450388 TI - Multimodal canonical correlation reveals converging neural circuitry across trauma-related disorders of affect and cognition. AB - Trauma-related disorders of affect and cognition (TRACs) are associated with a high degree of diagnostic comorbidity, which may suggest that these disorders share a set of underlying neural mechanisms. TRACs are characterized by aberrations in functional and structural circuits subserving verbal memory and affective anticipation. Yet, it remains unknown how the neural circuitry underlying these multiple mechanisms contribute to TRACs. Here, in a sample of 47 combat Veterans, we measured affective anticipation using functional magnetic resonance imaging (fMRI), verbal memory with fluorodeoxyglucose positron emission tomography (FDG-PET), and grey matter volume with structural magnetic resonance imaging (sMRI). Using a voxel-based multimodal canonical correlation analysis (mCCA), the set of neural measures were statistically integrated, or fused, with a set of TRAC symptom measures including mild traumatic brain injury (mTBI), posttraumatic stress, and depression severity. The first canonical correlation pair revealed neural convergence in clusters encompassing the middle frontal gyrus and supplemental motor area, regions implicated in top-down cognitive control and affect regulation. These results highlight the potential of leveraging multivariate neuroimaging analysis for linking neurobiological mechanisms associated with TRACs, paving the way for transdiagnostic biomarkers and targets for treatment. PMID- 30450386 TI - Diminished positive affect and traumatic stress: A biobehavioral review and commentary on trauma affective neuroscience. AB - Post-traumatic stress manifests in disturbed affect and emotion, including exaggerated severity and frequency of negative valence emotions, e.g., fear, anxiety, anger, shame, and guilt. However, another core feature of common post trauma psychopathologies, i.e. post-traumatic stress disorder (PTSD) and major depression, is diminished positive affect, or reduced frequency and intensity of positive emotions and affective states such as happiness, joy, love, interest, and desire/capacity for interpersonal affiliation. There remains a stark imbalance in the degree to which the neuroscience of each affective domain has been probed and characterized in PTSD, with our knowledge of post-trauma diminished positive affect remaining comparatively underdeveloped. This remains a prominent barrier to realizing the clinical breakthroughs likely to be afforded by the increasing availability of neuroscience assessment and intervention tools. In this review and commentary, the author summarizes the modest extant neuroimaging literature that has probed diminished positive affect in PTSD using reward processing behavioral paradigms, first briefly reviewing and outlining the neurocircuitry implicated in reward and positive emotion and its interrelationship with negative emotion and negative valence circuitry. Specific research guidelines are then offered to best and most efficiently develop the knowledge base in this area in a way that is clinically translatable and will exert a positive impact on routine clinical care. The author concludes with the prediction that the development of an integrated, bivalent theoretical and predictive model of how trauma impacts affective neurocircuitry to promote post trauma psychopathology will ultimately lead to breakthroughs in how trauma treatments are conceptualized mechanistically and developed pragmatically. PMID- 30450390 TI - Alternations in functional connectivity of amygdalar subregions under acute social stress. AB - The amygdala has long been considered a vital region involved in acute and chronic stress responses. Extensive evidences from animal and human studies suggest that the functional connectivity of amygdalar subnuclei (basolateral amygdala (BLA), centromedial amygdala (CMA) and superficial amygdala (SFA)) undergo specific alterations in stress-related psychopathology. However, whether and how intrinsic functional connectivity within the amygdalar subcomponents is differently altered in the aftermath of an acute stressor remains unknown. In the present study, using a within-subject design, we examined the impact of acute psychological social stress on the functional connectivity of amygdalar subregions at rest. Results showed that stress mainly affected the connectivity pattern of CMA. In particular, in the stress condition compared with the control, the connectivity of CMA to left posterior cingulate cortex and right thalamus was decreased under stress, while the connectivity of CMA to left caudate connectivity was increased at rest post-stressor. The findings suggest that healthy individuals may adapt to threatening surroundings by reducing threatening information input, and shifting to well-learned procedural behaviors. PMID- 30450392 TI - Data supporting the growth/no growth interface of Zygosaccharomyces bailii in simulated acid sauces. AB - This article contains experimental data, images and methods for the growth/no growth interface of Zygosaccharomyces bailii in simulated acid sauces. Mentioned data are related to the research article "Modeling growth/no growth interface of Zygosaccharomyces bailii in simulated acid sauces as a function of natamycin, xanthan gum and sodium chloride concentrations" (Zalazar et al., 2018) [1]. The growth was assessed colorimetrically by using 2-(4-iodophenyl)-3-(4-nitrophenyl) 5-phenyl-2H-tetrazolium chloride and 2-methoxy-1,4-naphthoquinone as detection reagents. Furthermore, yeast growth was confirmed by plate count. PMID- 30450389 TI - Mapping stress networks using functional magnetic resonance imaging in awake animals. AB - The neurobiology of stress is studied through behavioral neuroscience, endocrinology, neuronal morphology and neurophysiology. There is a shift in focus toward progressive changes throughout stress paradigms and individual susceptibility to stress that requires methods that allow for longitudinal study design and study of individual differences in stress response. Functional magnetic resonance imaging (fMRI), with the advantages of noninvasiveness and a large field of view, can be used for functionally mapping brain-wide regions and circuits critical to the stress response, making it suitable for longitudinal studies and understanding individual variability of short-term and long-term consequences of stress exposure. In addition, fMRI can be applied to both animals and humans, which is highly valuable in translating findings across species and examining whether the physiology and neural circuits involved in the stress response are conserved in mammals. However, compared to human fMRI studies, there are a number of factors that are essential for the success of fMRI studies in animals. This review discussed the use of fMRI in animal studies of stress. It reviewed advantages, challenges and technical considerations of the animal fMRI methodology as well as recent literature of stress studies using fMRI in animals. It also highlighted the development of combining fMRI with other methods and the future potential of fMRI in animal studies of stress. We conclude that animal fMRI studies, with their flexibility, low cost and short time frame compared to human studies, are crucial to advancing our understanding of the neurobiology of stress. PMID- 30450394 TI - Dataset concerning the hourly conversion factors for the cumulative energy demand and its non-renewable part, and hourly GHG emission factors of the Swiss mix during a one year period (2015-2016). AB - The data presented in this article are related to the research article entitled "Temporal variations in the primary energy use and greenhouse gas emissions of the electricity provided to the Swiss grid" Vuarnoz and Jusselme (2018). The provided data are the hourly CO2-eq emission factors, and the hourly conversion factors for the cumulative energy demand and its non-renewable part for the Swiss electricity mix over one year. These data have been assessed on the basis of an inventory of the technology used for electricity generation and an attributional life-cycle approach. The presented data are necessary for life-cycle assessment of all processes and products using electricity in Switzerland. They serve also as a sustainable benchmark when implementing renewable energy systems and energy storage. PMID- 30450393 TI - Data on SD-OCT image acquisition, ultrastructural features, and horizontal tissue shrinkage in the porcine retina. AB - The data presented in this article are related to the research paper entitled "Correlation of Spectral Domain Optical Coherence Tomography with Histology and Electron Microscopy in the Porcine Retina" (Xie et al., 2018) [2]. This research data highlights our technique for retinal fundus image acquisition during spectral domain optical coherence tomography (SD-OCT) in a large animal model. Low and high magnification electron micrographs are included to demonstrate the ultrastructural features of the porcine retina. Data on horizontal tissue shrinkage during processing of the porcine retina are presented. PMID- 30450395 TI - Metabarcoding data of bacterial diversity of the deep sea shark, Centroscyllium fabricii. AB - This data article describes the bacterial diversity of the deep sea shark, Centroscyllium fabricii. The data was acquired by metabarcoding using 16S rDNA. Centroscyllium fabricii, a deep sea shark found at depths below 275 m was sampled during Sagar Sampada cruise no 305 in the Indian Ocean and metagenomic DNA was isolated from the gut contents using QIAamp DNA stool minikit. V3 region of 16S rDNA region was amplified and the amplicons were sequenced on Illumina MiSeq system using 151 bp * 2 paired end reads. The data of this metagenome is available in the BioSample Submission Portal as Bio-Project PRJNA431407and Sequence Read Archive (SRA) accession number SRR6507004. PMID- 30450396 TI - Comparative cytotoxic activity between kaempferol and gallic acid against various cancer cell lines. AB - This data article indicates the in vitro cytotoxicity of kaempferol and gallic acid across different cancer cell lines including A2780 (ovarian), H460 (lung), A431 (skin), MIA PaCa-2 (pancreas), Du145 (prostate), HT29 (colon), MCF-7 (breast), BE2-C (neuroblastoma), SJ-G2, U87 and SMA (glioblastoma). The dataset showed that the inhibitory activity of kaempferol was comparatively stronger than gallic acid. Thereby, kaempferol is offered as a potent anticancer agent for further investigation and beneficial as a dietary supplement. The data within this article relates to the research article entitled "Screening phytochemical content, antioxidant, antimicrobial and cytotoxic activities of Catharanthus roseus (L.) G. Don stem extract and its fractions" (Pham et al., 2018). PMID- 30450397 TI - Data on cellular lipids of Yarrowia lipolytica grown on fatty substrates. AB - Yarrowia lipolytica, which is model oleaginous yeast with high industrial interest, was cultivated on fatty substrates. Data concerning fatty acid composition of both substrate and yeast lipids and comparisons of the experimental data with model predictions presented in "Biomodification of fats and oils and scenarios of adding value on renewable fatty materials through microbial fermentations: Modelling and trials with Yarrowia lipolytica" (Vasiliadou et al., 2018) were provided. Furthermore, the total yeast lipids were fractionated into their main fractions, that is, phospholipids, glucolipids plus sphingolipids and neutral lipids, and the fatty acid composition of each lipid fraction was reported. PMID- 30450398 TI - Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats. AB - The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the alpha-alkyl chain: methylone ( CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4 methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20 mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats. Briefly, plasma samples were collected via a jugular vein cannula, purified, and analyzed using a HPLC system. While we have previously reported on the consistent relationship between structure and pharmacokinetics of these synthetic cathinones in male, Sprague-Dawley rats (Grecco and Sprague, 2016), this data set suggests that there is no consistent relationship of chemical structure and pharmacokinetics of methylone, butylone and pentylone in female Sprague-Dawley rats. The findings from the present study further emphasize the need for the inclusion of female subjects in the pharmacokinetic studies of synthetic cathinones as it is very possible male-female differences may exist in rodent models. PMID- 30450391 TI - What does the Fos say? Using Fos-based approaches to understand the contribution of stress to substance use disorders. AB - Despite extensive research efforts, drug addiction persists as a largely unmet medical need. Perhaps the biggest challenge for treating addiction is the high rate of recidivism. While many factors can promote relapse in abstinent drug users, the contribution of stress is particularly problematic, as stress is uncontrollable and pervasive in the lives of those struggling with addiction. Thus, understanding the neurocircuitry that underlies the influence of stress on drug seeking is critical for guiding treatment. Preclinical research aimed at defining this neurocircuitry has, in part, relied upon the use of experimental approaches that allow visualization of cellular and circuit activity that corresponds to stressor-induced drug seeking in rodent relapse models. Much of what we have learned about the mechanisms that mediate stressor-induced relapse has been informed by studies that have used the expression of the immediate early gene, cfos, or its protein product, Fos, as post-mortem activity markers. In this review we provide an overview of the rodent models used to study stressor-induced relapse and briefly summarize what is known about the underlying neurocircuitry before describing the use of cfos/Fos-based approaches. In addition to reviewing findings obtained using this approach, its advantages and limitations are considered. Moreover, new techniques that leverage the expression profile of cfos to tag and manipulate cells based on their activity patterns are discussed. The intent of the review is to guide the interpretation of old and design of new studies that utilize cfos/Fos-based strategies to study the neurocircuitry that contributes to stress-related drug use. PMID- 30450399 TI - Data on safe hydrogen production from the solar photovoltaic solar panel through alkaline electrolyser under Algerian climate. AB - This data article is about hydrogen production from the solar photovoltaic solar panel through alkaline electrolyser under Algerian climate with the application of safe technology. Several pathways have been given different technologies for hydrogen production which were based on the experimental scale, where the catalysis of water by using alkaline electrolyser has taken the major part of the collecting data. However, in this data article, the photovoltaic solar system is integrated with a controller, an ammeter, a voltmeter, and an alkaline type water electrolyser (the electrolyte used is Na-OH). In fact, the alkaline electrolyser is the most common technology for the production of hydrogen through solar energy. Many technical problems have been involved to reduce the energy efficiency of the new design of the solar system, especially in photovoltaic panel solar system. One of the proposed solutions in this data is integrating of a numerical relay REF542 plus with a solar photovoltaic power station in the city of Adrar, which is located in the south of Algeria, to protect the electrical grid from over-current. This data is related to following references (Tributsch, 2008; Kai and Zhang, 2010; Chennouf et al., 2013). PMID- 30450400 TI - Saturated fatty acid regulated lncRNA dataset during in vitro human embryonic neurogenesis. AB - Human embryonic stem cells (hESCs) were used as a model of embryonic neurogenesis to identify the effect of excess fat uptake on neurodevelopment (Ardah et al., 2018). Herein, by directed differentiation of hESCs into neurons using established protocols, this data was generated for expression profiles of select lncRNAs during in vitro embryonic neurogenesis and their differential expression due to excess fat (palmitate) uptake. The undifferentiated hESCs were treated with 250 uM palmitate after identifying it as the highest concentration which is non-toxic to these cells. The palmitate treated hESCs were differentiated towards neurons keeping the levels of palmitate consistent throughout the differentiation process and fat uptake was confirmed by Oil Red O staining. The expression analysis of lncRNAs was performed by RT-qPCR on vehicle control and palmitate treated cells from 4 stages of differentiation, D0 (undifferentiated hESCs), D12 (neural stem cells), D44 (neural progenitors) and D70 (neurons) using lncRNAs array plates from Arraystar Inc. which contains 372 functionally identified lncRNAs found to be associated with lipid metabolism and other pathways (Cat# AS NR-004). PMID- 30450401 TI - Dataset on the distribution location and biological traits of freshwater fishes in the Yangtze River Basin. AB - In this data article, we provide the scientific and theoretical data on fish taxonomy including class, order, family, and genus in the Yangtze River. The Yangtze basin is divided into 56 units, and their geological information including latitude, longitude, latitude, and channel length is recorded. Fish presence/absence data at the unit scale are reported. Biological traits including morphological, physiological, and ecological characters of each fish species are also described, numeralized, and reported. These data are the foundation of the analyses and results in the article "Continental-scale analysis of taxonomic and functional fish diversity in the Yangtze River" (Kang et al., 2018). PMID- 30450402 TI - Dataset on the EEG time-frequency representation in children with different levels of mathematical achievement. AB - This article presents the data related to the research paper entitled "The analysis of EEG coherence reflects middle childhood differences in mathematical achievement" (Gonzalez-Garrido et al., 2018). The dataset is derived from the electroencephalographic (EEG) records registered from a total of 60 8-9-years-old children with different math skill levels (High: HA, Average: AA, and Low Achievement: LA) while performing a symbolic magnitude comparison task. The average brain patterns are shown through Time-Frequency Representations (TFR) for each group, and also grand-mean amplitudes within specific EEG epochs in a 19 electrode array are provided. Making this information publicly available for further analyses could significantly contribute to a better understanding on how math achievement in children associates with cognitive processing strategies. PMID- 30450404 TI - Identification of primary and secondary metabolites and transcriptome profile of soybean tissues during different stages of hypoxia. AB - NMR and chromatography methods combined with mass spectrometry are the most important analytical techniques employed for plant metabolomics screening. Metabolomic analysis integrated to transcriptome screening add an important extra dimension to the information flow from DNA to RNA to protein. The most useful NMR experiment in metabolomics analysis is the proton spectra due the high receptivity of 1H and important structural information, through proton-proton scalar coupling. Routinely, databases have been used in identification of primary metabolites, however, there is currently no comparable data for identification of secondary metabolites, mainly, due to signal overlap in normal 1H NMR spectra and natural variation of plant. Related to spectra overlap, alternatively, better resolution can be find using 1H pure shift and 2D NMR pulse sequence in complex samples due to spreading the resonances in a second dimension. Thus, in data brief we provide a catalogue of metabolites and expression levels of genes identified in soy leaves and roots under flooding stress. PMID- 30450403 TI - HPLC profiles and spectroscopic data of cassane-type furanoditerpenoids. AB - The data presented here are related to the research paper entitled "Hydroxylated furanoditerpenoids from the pupal case produced by the bruchid beetle Sulcobruchus sauteri inside the seed of Caesalpinia decapetala" (Akihara et al., 2018) [1]. In this data article, we provide high-performance liquid chromatography (HPLC) profiles of seven undescribed hydroxylated furanoditerpenoids, caesalsauteolide, 2-hydroxycaesaljapin, 2,7 dihydroxycaesaljapin, 2-hydroxycaesalacetal, caesalsauterol, 6 acetylcaesalsauterol, norcaesalsauterol isolated from the pupal cases produced by Sulcobruchus sauteri and four known compounds, caesaljaponin A (Kamikawa et al., 2015) [2], caesaljaponin B (Kamikawa et al., 2015) [2], caesalacetal (Kamikawa et al., 2016) [3], and caesaljapin (Kamikawa et al., 2016; Ogawa et al., 1992) [3], [4] isolated from the cotyledons of the intact seeds of Caesalpinia decapetala. Besides, 1D NMR, 2D NMR, and HRESIFTMS data of the seven undescribed furanoditerpenoids are also presented. PMID- 30450405 TI - Talimogene laherparepvec in combination with pembrolizumab leads to a complete response in a patient with refractory Merkel cell carcinoma. PMID- 30450406 TI - Fatal blastomycosis after exogenous immunosuppression in a healthy gardener. PMID- 30450407 TI - Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer's disease. AB - Introduction: The apolipoprotein E (APOE) e4 allele is a major genetic risk factor of late-onset Alzheimer's disease. However, its interaction with two other canonical risk factors, age and sex, is not clear. Previous studies have reported conflicting results on its differential effects in men and women, its association with young-onset AD before the age of 65 years, and its significance in genetic admixture populations. In these studies, the hazard of the e4 allele was assumed to be constant during aging. However, this hypothesis has not been tested and its violation may lead to significant biases and contribute to such discrepant findings. Methods: In a prospective cohort of 4727 subjects, we performed Cox regression analysis of the association of the e4 allele with AD age of onset. We then performed diagnostics on the resulting model and tested if the hazard of the e4 allele violated the assumption of proportionality during aging. We examined whether incorporating age stratifications and time-dependent coefficients could restore the proportionality. We then validated our findings in four independent cohorts. Results: Hazard of the e4 allele for AD was nonproportional. It took a stepwise decline around the age of 80 years for men and around the age of 75 years for women. By stratifying subjects into a younger group and an older group, we detected more consistent effects of the e4 allele across multiple independent cohorts. We also found that the e4 allele was a significant risk factor for young onset AD with age of onset before 65 years. Discussion: Age compositions of study cohorts can significantly bias the estimated effect of the APOE genotype. Studies of AD should consider hidden age structures among subjects and routinely employ appropriate age and sex stratification strategies or nonparametric modeling in experimental designs and data analysis. Finally, we argue that the e4 allele is a risk factor not only for late-onset AD but also for young-onset AD. PMID- 30450408 TI - Frailty is independently associated with 1-year mortality after hospitalization for acute heart failure. AB - Introduction: Frailty is a complex condition that results from the loss of physiological reserve across multiple systems. Its presence should be considered in the aging heart failure population, since it is an important predictor of death and institutionalization in the elderly. Methods and results: In a prospective, observational and analytical single-center study of 100 elderly patients hospitalized for acute heart failure, we assessed the characteristics associated with an increased hospital and 1-year mortality. Frailty was evaluated with the Clinical Frailty Scale, and there was a significant association between its presence and 1-year mortality (RR = 2.03; 95% CI = 1.18-3.48; p = 0.014), although not with in-hospital mortality. After adjusting for probable confounders, it remained independently associated with 1-year mortality. Conclusion: Frailty can be assessed with a simple bed-side scale and provides significant prognostic information in acute heart failure patients. PMID- 30450409 TI - Tobacco carcinogen research to aid understanding of cancer risk and influence policy. AB - : Education regarding the health effects associated with tobacco use has made important progress worldwide over the last few decades. Still, tobacco remains a significant cause of cancer and other diseases. As a result, significant worldwide morbidity and mortality is still attributable to tobacco use in modern times. Research into tobacco products, the carcinogens they contain, and how users metabolize them is an important benefit to the advancement of research aimed at reducing harm associated with tobacco use. This review summarizes the use of this type of research to study tobacco users' risk of developing cancer, especially head and neck cancer. In addition, we discuss the use of tobacco research to provide support for increasing levels of federal regulation of tobacco products. Level of Evidence: 4. PMID- 30450411 TI - We Respect Their Autonomy and Dignity, But How Do We Value Patient-Reported Experiences? PMID- 30450410 TI - Ultrafast Intraband Spectroscopy of Hot-Carrier Cooling in Lead-Halide Perovskites. AB - The rapid relaxation of above-band-gap "hot" carriers (HCs) imposes the key efficiency limit in lead-halide perovskite (LHP) solar cells. Recent studies have indicated that HC cooling in these systems may be sensitive to materials composition, as well as the energy and density of excited states. However, the key parameters underpinning the cooling mechanism are currently under debate. Here we use a sequence of ultrafast optical pulses (visible pump-infrared push infrared probe) to directly compare the intraband cooling dynamics in five common LHPs: FAPbI3, FAPbBr3, MAPbI3, MAPbBr3, and CsPbBr3. We observe ~100-900 fs cooling times, with slower cooling at higher HC densities. This effect is strongest in the all-inorganic Cs-based system, compared to the hybrid analogues with organic cations. These observations, together with band structure calculations, allow us to quantify the origin of the "hot-phonon bottleneck" in LHPs and assert the thermodynamic contribution of a symmetry-breaking organic cation toward rapid HC cooling. PMID- 30450412 TI - Advancing stem cells: New therapeutic strategies for treating central nervous system disorders. PMID- 30450414 TI - Healthy mitochondria for stroke cells. AB - Stroke is a debilitating disease that remains as a significant unmet need. Although our understanding of the disease pathology has advanced over the years, treatment options for stroke are limited. Recent studies have implicated the important role of healthy mitochondria in neuroprotection against stroke. Under the stroke pathological condition, transfer of healthy mitochondria is observed from astrocytes to ischemic neurons. However, without additional therapeutic intervention, such astrocyte-to-neuron transfer of mitochondria may not sufficiently afford a robust and stable therapeutic effect against the devastating primary insult and progressive neurodegeneration associated with stroke. We now explore the concept that transplantation of exogenous stem cells may serve as efficacious sources of healthy mitochondria for ischemic cells, not only neurons but also endothelial cells. This review captures the recent advances on the therapeutic potential of mitochondrial transfer as a novel stroke treatment. This paper is a review article. Referred literature in this article has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. PMID- 30450415 TI - Combination therapy for ischemic stroke: Novel approaches to lengthen therapeutic window of tissue plasminogen activator. AB - Tissue plasminogen activator (tPA) thrombolysis continues to be the gold standard therapy for ischemic stroke. Due to the time-limited treatment window, within 4.5 h of stroke onset, and a variety of potentially deadly complications related to delayed administration, particularly hemorrhagic transformation (HT), clinical use of tPA is limited. Combination therapies with other interventions, drug or nondrug, have been hypothesized as a logical approach to enhancing tPA effectiveness. Here, we discuss various potential pharmacological and nondrug treatments to minimize adverse effects, primarily HT, associated with delayed tPA administration. Pharmacological interventions include many that support the integrity of the blood-brain barrier (i.e., atorvastatin, batimastat, candesartan, cilostazol, fasudil, and minocycline), promote vascularization and preserve cerebrovasculature (i.e., coumarin derivative IMM-H004 and granulocyte colony stimulating factor), employing other mechanisms of action (i.e., oxygen transporters and ascorbic acid). Nondrug treatments are comprised of stem cell transplantation and gas therapies with multi-faceted approaches. Combination therapy with tPA and the aforementioned treatments demonstrated promise for mitigating the adverse complications associated with delayed tPA treatment and rescuing stroke-induced behavioral deficits. Therefore, the conjunctive therapy method is a novel therapeutic approach that can attempt to minimize the limitations of tPA treatment and possibly increase the therapeutic window for ischemic stroke treatment. PMID- 30450417 TI - Combination of cell transplantation and glial cell line-derived neurotrophic factor-secreting encapsulated cells in Parkinson's disease. AB - A major limitation of cell transplantation for Parkinson's disease (PD) is the mediocre survival of the grafted cells. Facilitating graft survival may improve the functional outcomes of the transplanted cells. Here, we discuss our observations that combination of rat fetal ventral mesencephalic (VM) tissue and encapsulated cells that secrete glial cell line-derived neurotrophic factor (GDNF) enhanced graft function in an animal model of PD. We described significant 2-fold increase in the number of tyrosine hydroxylase immunoreactive (TH-ir) cells per graft, as well as 1.7-fold and 9-fold increments in TH-ir fiber outgrowth into the host brain and toward the capsule with combined transplants and GDNF capsules as opposed to the VM transplants and mock-capsule group. These findings demonstrate that encapsulated GDNF-secreting cells improve graft survival that may optimize functional benefits for the treatment of PD. PMID- 30450416 TI - The final frontier: Transient microglia reduction after cosmic radiation exposure mitigates cognitive impairments and modulates phagocytic activity. AB - Microglia are the primary immune element within the brain, which are responsible for monitoring synapse function and neuron health. Exposure to cosmic radiation has the potential to cause long-term cognitive deficits in rodent models and therefore indicates a difficult challenge for future astronauts piloting interplanetary travel. Here, we discuss the potential of transient microglia depletion after the injury to ameliorate the harsh microenvironment of the brain and eliminate any potential long-term cognitive effects. Repopulation of microglia enables phagocytic phenotypes to be circumvented, via the reduction of Phagocytic and lysosomal markers, potentially being responsible for increased neuroprotection. Brief depletion of microglia after irradiation mitigated the development of any long-term memory deficits, comparable to healthy animals. Chronically, microglial levels were not affected by cosmic radiation followed by temporary microglia depletion. Following repopulation, improved recognition memory was paralleled by downregulated complement receptor C5aR. Preserved synapse function also demonstrated the therapeutic ability of microglia depletion as it corresponded with fewer phagocytic microglia phenotypes. The understanding of long-term radiation-induced cognitive impairments is vital for the protection of future astronauts and equally as important for current cancer patients. Temporary microglia depletion showed promise in preventing any deleterious cognitive impairments following exposure to elements of cosmic radiation, such as helium and high-charge nuclei. PMID- 30450413 TI - Mitochondrial targeting as a novel therapy for stroke. AB - Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit - a communication framework between neurons, their supply microvessels along with glial cells - underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. PMID- 30450418 TI - White-matter repair: Interaction between oligodendrocytes and the neurovascular unit. AB - There are currently no adequate treatments for white-matter injury, which often follows central nervous system maladies and their accompanying neurodegenerative processes. Indeed, the white matter is compromised by the deterioration of the blood-brain barrier and the demyelination of neuronal axons. Key repairs to the white matter are mediated by oligodendrocyte lineage cells after damaging events. Oligodendrocytes are supported by other cells in the neurovascular unit and these cells collaborate in processes such as angiogenesis, neurogenesis, and oligodendrogenesis. Understanding the various interactions between these cells and oligodendrocytes will be imperative for developing reparative therapies for impaired white matter. This minireview will discuss how oligodendrocytes and oligodendrocyte lineage cells mend damage to the white matter and restore brain function ensuing neural injury. PMID- 30450419 TI - Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury. AB - Increasing evidence have supported that Wharton's jelly mesenchymal stem cell (WJ MSCs) have immunomodulatory and protective effects against several diseases including kidney, liver pathologies, and heart injury. Few in vitro studies have reported that WJ-MSCs reduced inflammation in hippocampal slices after oxygen glucose deprivation. We recently reported the neuroprotective effects of human WJ MSCs (hWJ-MSCs) in rats exposed to a transient right middle cerebral artery occlusion. hWJ-MSCs transplantation significantly reduced brain infarction and microglia activation in the penumbra leading with a significant reduction of neurological deficits. Interestingly, the grafted hWJ-MSCs in the ischemic core were mostly incorporated into IBA1 (+) cells, suggesting that hWJ-MSCs were immunorejected by the host. The immune rejection of hWJ-MSCs was reduced in after cyclosporine A treatment. Moreover, the glia cell line-derived neurotrophic factor expression was significantly increased in the host brain after hWJ-MSCs transplantation. In conclusion, these results suggest that the protective effect of hWJ-MSCs may be due to the secretion of trophic factors rather than to the survival of grafted cells. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences. PMID- 30450420 TI - Encapsulated stem cells ameliorate depressive-like behavior via growth factor secretion. AB - As prevalence of depression continues to rise around the world, there remains a stagnation of available treatments as the affected population grows. The subset of treatment-resistant depression also is on the rise highlighting the need for innovative treatments to address this issue. Mesenchymal stem cells (MSCs) have been reported to attenuate depression-like behaviors, however, the effects of encapsulation of MSCs have yet to be investigated. Encapsulation of MSCs exhibited prolonged survival of exogenous cell injection accompanied with increased secretion of neurotrophic factors including vascular endothelial growth factor, ciliary neurotrophic factor, and others. The enhanced expression of these factors highlights the ability of encapsulated MSCs to upregulate the respective signaling pathways, which are associated with depression pathology and activation of neurogenesis. This treatment identifies a promising therapeutic option for depression, specifically treatment-resistant depression. Further, evaluation of long-term effects of the treatment is warranted. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases including PubMed. Some original themes in this article come from the laboratory practice in our research center and the authors' experiences. PMID- 30430140 TI - Importance of human demographic history knowledge in genetic studies involving multi-ethnic cohorts. AB - Paucity of data from African populations due to under-representation in human genetic studies has impeded detailed understanding of the heritable human genome variation. This is despite the fact that Africa has sizeable genetic, cultural and linguistic diversity. There are renewed efforts to understand health problems relevant to African populations using more comprehensive datasets, and by improving expertise in health-related genomics among African scientists. We emphasise that careful consideration of the sampled populations from national and within-continental cohorts in large multi-ethnic genetic research efforts is required to maximise the prospects of identifying and fine-mapping novel risk variants in indigenous populations. We caution that human demographic history should be taken into consideration in such prospective genetic-association studies. PMID- 30450421 TI - Effects of labeling human mesenchymal stem cells with superparamagnetic iron oxides on cellular functions and magnetic resonance contrast in hypoxic environments and long-term monitoring. AB - Ischemia, which involves decreased blood flow to a region and a corresponding deprivation of oxygen and nutrients, can be induced as a consequence of stroke or heart attack. A prevalent disease that affects many individuals worldwide, ischemic stroke results in functional and cognitive impairments, as neural cells in the brain receive inadequate nourishment and encounter inflammation and various other detrimental toxic factors that lead to their death. Given the scarce treatments for this disease in the clinic such as the administration of tissue plasminogen activator, which is only effective in a limited time window after the occurrence of stroke, it will be necessary to develop new strategies to ameliorate or prevent stroke-induced brain damage. Cell-based therapies appear to be a promising solution for treating ischemic stroke and many other ischemia associated and neurodegenerative maladies. Particularly, human mesenchymal stem cells (hMSCs) are of interest for cell transplantation in stroke, given their multipotency, accessibility, and reparative abilities. To determine the fate and survival of hMSC, which will be imperative for successful transplantation therapies, these cells may be monitored using magnetic resonance imaging and transfected with superparamagnetic iron oxide (SPIO), a contrast agent that facilitates the detection of these hMSCs. This review encompasses pertinent research and findings to reveal the effects of SPIO on hMSC functions in the context of transplantation in ischemic environments and over extended time periods. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences. PMID- 30450422 TI - Neurotrophic factor-based strategies to enhance survival and differentiation of neural progenitor cells toward the dopaminergic phenotype. AB - Parkinson's disease (PD) is a neurodegenerative disorder that presents with hallmark clinical symptoms of tremor at rest, bradykinesia, and muscle rigidity. Stem cell therapy has emerged as an experimental treatment for PD. However, optimizing the cell culture condition that allows enhanced survival and differentiation of cells toward the dopaminergic phenotype remains a logistical challenge. Here, we discuss the utility of a combination of neurotrophin-4/5 (NT 4/5) and glial cell line-derived neurotrophic factor (GDNF) in increasing the dopaminergic phenotypic expression of rat ventral mesencephalic (VM) tissue. Using organotypic explant cultures of fetal human ventral mesencephalon, we observed that NT-4/5 and GDNF as single factors, or in combination on DAergic neurons, increased survival and number of tyrosine hydroxylase immunoreactive neurons as well as the dopamine content in the culture medium. The application of specific neurotrophic factors, such as NT-4/5 and GDNF, as cell culture supplements or as adjunctive therapy to cell transplantation may achieve improved functional outcomes when contemplating cell-based regenerative medicine for PD. PMID- 30430140 TI - Importance of human demographic history knowledge in genetic studies involving multi-ethnic cohorts. AB - Paucity of data from African populations due to under-representation in human genetic studies has impeded detailed understanding of the heritable human genome variation. This is despite the fact that Africa has sizeable genetic, cultural and linguistic diversity. There are renewed efforts to understand health problems relevant to African populations using more comprehensive datasets, and by improving expertise in health-related genomics among African scientists. We emphasise that careful consideration of the sampled populations from national and within-continental cohorts in large multi-ethnic genetic research efforts is required to maximise the prospects of identifying and fine-mapping novel risk variants in indigenous populations. We caution that human demographic history should be taken into consideration in such prospective genetic-association studies. PMID- 30450425 TI - Molecular characterization and morphological description of cryptic haemoproteids in the laughingthrushes (Leiothrichidae) in the western and eastern Himalaya, India. AB - Background: Laughingthrushes (family: Leiothrichidae) consists of diverse and widespread species found in the Indian subcontinent but there is a lack of information on their avian haemosporidians. Methods: We sampled 231 laughingthrushes of 8 species in the western and eastern Himalaya in India. Using parasite morphology and cytochrome b sequences we describe 2 new Haemoproteus species harbored in 3 species of laughingthrushes and report a case of cryptic speciation. Results: First Haemoproteus lineage TROERY01 (GenBank: KY623720) found in Trochalopteron erythrocephalum (27.47%) and Trochalopteron variegatum (2.9%) in mid to high altitude tropical forests in the western and eastern Himalaya, was described as Haemoproteus (Parahaemoproteus) leiothrichus n. sp. (Haemosporida: Haemoproteidae). Second Haemoproteus lineage TROERY02 (GenBank: KY623721) described as Haemoproteus (Parahaemoproteus) homoleiothrichus n. sp. (Haemosporida: Haemoproteidae) was found in T. erythrocephalum (2.19%) and Trochalopteron lineatum (3.84%), albeit in low intensity, only in the western Himalaya. Both H. homoleiothrichus n. sp. and H. leiothrichus n. sp. showed no significant difference in morphological features in blood stages. A genetic divergence of 4.4% along with distinct phylogenetic position indicates that these 2 lineages represent cryptic species. Previously, T. erythrocephalum has been described as an additional host for a morphologically described Haemoproteus timalus in the oriental region. Our described species have several morphological features that are absent in H. timalus. These are, the presence of dumbbell-like shaped mature gametocytes, 'arm' like extensions of gametocytes and lateral displacement of nuclei of infected erythrocytes. Illustrations of blood stages of the new species are given, and phylogenetic analysis with morphologically described Haemoproteus species identifies parasites closely related to the 2 described parasites. Conclusions: The lineages described here have been recorded only in the laughingthrushes so far. These are the first parasites to be described with T. erythrocephalum as a type host from the western and eastern Himalaya in India. PMID- 30450427 TI - Evaluation and optimisation of unnatural amino acid incorporation and bioorthogonal bioconjugation for site-specific fluorescent labelling of proteins expressed in mammalian cells. AB - Many biophysical techniques that are available to study the structure, function and dynamics of cellular constituents require modification of the target molecules. Site-specific labelling of a protein is of particular interest for fluorescence-based single-molecule measurements including single-molecule FRET or super-resolution microscopy. The labelling procedure should be highly specific but minimally invasive to preserve sensitive biomolecules. The modern molecular engineering toolkit provides elegant solutions to achieve the site-specific modification of a protein of interest often necessitating the incorporation of an unnatural amino acid to introduce a unique reactive moiety. The Amber suppression strategy allows the site-specific incorporation of unnatural amino acids into a protein of interest. Recently, this approach has been transferred to the mammalian expression system. Here, we demonstrate how the combination of unnatural amino acid incorporation paired with current bioorthogonal labelling strategies allow the site-specific engineering of fluorescent dyes into proteins produced in the cellular environment of a human cell. We describe in detail which parameters are important to ensure efficient incorporation of unnatural amino acids into a target protein in human expression systems. We furthermore outline purification and bioorthogonal labelling strategies that allow fast protein preparation and labelling of the modified protein. This way, the complete eukaryotic proteome becomes available for single-molecule fluorescence assays. PMID- 30450428 TI - Recurrent thrombolysis of a stuttering lacunar infarction captured on serial MRIs. AB - Lacunar strokes account for about a fourth of all ischemic strokes. Pontine infarcts often present with stuttering symptoms, referred to as pontine warning syndrome (PWS). Patients presenting with fluctuating symptoms can appear to have rapidly improving symptoms and thus often go untreated despite the risk of recurrent deficits. MRI carries a higher sensitivity in detecting posterior circulation strokes compared to computed topagraphy, but does not always indicate irreversible injury. Here we present the first description of a stuttering lacune, captured radiographically on serial magnetic resonance imaging (MRI), that was initially averted with the administration of intravenous (IV) tissue plasminogen activator (tPA), only to return a month later and progress on imaging despite re-administration of tPA. During the first admission, our patient had spontaneous resolution of symptoms with complete reversal on restricted diffusion soon after IV tPA administration. On the second admission, the stuttering symptoms returned as did the same pontine lesion. Although his stuttering lesions lasted for several days, and the pontine lesion did ultimately progress to partial infarction on MRI, he was discharged home without neurologic deficits. Our case suggests that tPA may be of benefit in patients with lacunar pontine strokes even if symptoms rapidly improve or resolve. PMID- 30450426 TI - The environmental costs and benefits of high-yield farming. AB - How we manage farming and food systems to meet rising demand is pivotal to the future of biodiversity. Extensive field data suggest impacts on wild populations would be greatly reduced through boosting yields on existing farmland so as to spare remaining natural habitats. High-yield farming raises other concerns because expressed per unit area it can generate high levels of externalities such as greenhouse gas (GHG) emissions and nutrient losses. However, such metrics underestimate the overall impacts of lower-yield systems, so here we develop a framework that instead compares externality and land costs per unit production. Applying this to diverse datasets describing the externalities of four major farm sectors reveals that, rather than involving trade-offs, the externality and land costs of alternative production systems can co-vary positively: per unit production, land-efficient systems often produce lower externalities. For GHG emissions these associations become more strongly positive once forgone sequestration is included. Our conclusions are limited: remarkably few studies report externalities alongside yields; many important externalities and farming systems are inadequately measured; and realising the environmental benefits of high-yield systems typically requires additional measures to limit farmland expansion. Yet our results nevertheless suggest that trade-offs among key cost metrics are not as ubiquitous as sometimes perceived. PMID- 30450429 TI - Pseudotumor cerebri and lung cancer-associated jugular vein thrombosis: Role of anatomical variations of torcular herophili. AB - A 71-year-old male appeared at the facility complaining of disturbance of consciousness and bilateral papilledema. The laboratory test revealed anemia and coagulation abnormality. A physical examination and magnetic resonance imaging (MRI) of the brain with and without gadolinium showed no abnormalities. A lumbar puncture showed a high pressure, but a normal cerebrospinal fluid (CSF) cell count. Cerebral angiography showed no morphological abnormalities, but it revealed an asymmetric right dominant type of confluence of the sinuses with the partially-communicating left transverse sinus in the late phase. Furthermore, there was a delay in the cerebral circulation time (CCT). Subsequently, venography and ultrasonography revealed right internal jugular vein thrombosis associated with lung cancer. The patient recovered from the disturbance of consciousness immediately after an emergency ventriculoperitoneal shunt and anticoagulation therapy. This case was diagnosed as secondary pseudotumor cerebri (PTC). In order to facilitate the early detection of secondary PTC, it is important to take note of symptoms of intracranial hypertension with no remarkable intracranial lesions and to consider the possibility of PTC, especially in the patients with high risk factors for coagulopathy including lung cancer. PMID- 30450430 TI - Comparison of costs and outcomes of patients presenting with a rare brainstem syndrome. AB - In this case report we compare two patients presenting with similar symptoms of a brainstem syndrome including ataxia, dysarthria, and diplopia. Their MRIs showed hyperintense FLAIR signal changes with patchy areas of contrast enhancement within the brainstem particularly the pons and cerebellum. The broad differential diagnosis of this brainstem pathology included rhomboencephalitis, neurosarcoidosis, lymphoma, vasculitis, infection, and paraneoplastic or autoimmune process. Patient 1 had an extensive work up including CSF cytology, MRI brain spectroscopy, full body CT, cerebral angiogram, and ultimately brainstem biopsy. None of these studies were diagnostic of a specific etiology and total cost was $176,069. After months of declining medical condition without a clear diagnosis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was considered and the patient began steroid therapy resulting in clinical and radiographic improvement. Patient 2 had serum and CSF studies that were negative for infectious, paraneoplastic, and other inflammatory processes. The team diagnosed CLIPPERS and initiated steroid therapy within days resulting in dramatic clinical and radiographic resolution. The workup cost $12,905. Comparison of these cases shows how early awareness of CLIPPERS and a directed diagnostic work up can limit invasive diagnostic testing, expedite initiation of effective therapy, improve patient outcomes, and reduce cost. PMID- 30450431 TI - Surgical Treatment of a Patient With Nutcracker Syndrome via Transposition of the Left Renal Vein. AB - Introduction: Nutcracker syndrome (NCS) is caused by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery (SMA) where it passes in the fork formed at the bifurcation of these arteries. NCS leads to LRV hypertension, resulting in left flank and abdominal pain, with or without haematuria and pelvic ureteral varices. Report: The patient was a young female with diagnostic criteria of NCS, with severe clinical manifestations. The patient underwent transposition of the LRV approximately 3.0 cm below the original anatomic site and was anastomosed to the inferior vena cava (IVC) outside the meso-aortic compression zone. Conclusion: Although NCS is not as common as other clinical scenarios, it may be encountered by physicians in a variety of disciplines, and can cause substantial morbidity and mortality rates. This report addresses the surgical approach used in a particular case, as well as the possible complications and outcomes if not treated in due time. PMID- 30450432 TI - PVDF based ionogels: applications towards electrochemical devices and membrane separation processes. AB - Ionogels have emerged as one of the most interesting and captivating form of composites which credits to the outstanding characteristics. One of the most important constituent of ionogels is ionic liquid, which show many attractive properties notably non-volatility, in-flammability, negligible vapor pressure, tunability, thermal stability and solvating ability. A large variety of matrix materials have been under consideration for ionogels, presently, polymer/ionic liquid based ionogels have attracted much attention. Numerous polymeric materials such as have been utilized for these polymer/ionic liquids based ionogels. Polyvinylidene fluoride (PVDF) has been on top of the line as a matrix material for polymer based ionogels owing to its stability, aging and chemical resistance and mechanical strength. This review is primarily concerned with the properties of polyvinylidene fluoride based ionogels with an emphasis on their applications in various domains electrochemical devices, gas separation and liquid/liquid separations. PMID- 30450433 TI - Determinants of access and utilisation of seasonal climate information services among smallholder farmers in Makueni County, Kenya. AB - Climate change is a major development challenge in sub-Saharan Africa. This region is highly vulnerable to negative impacts of climate change due to low adaptive capacity and overreliance on rain-fed agriculture for food security and livelihood. Climate information services (CIS) have been developed in Kenya to help enhance farmers' adaptation to climatic shocks, but their access and utilisation remain low. The factors that influence farmers' access and use of CIS are not well-known. Using survey data from a sample of 250 households in Makueni County, this study estimated a two-step Heckprobit model to analyse the determinants of access and use of CIS. Results showed that the age of the household head reduced the likelihood of accessing CIS whereas household size, income, farm size, livelihood activity, television ownership and group membership increased it. Age, sex of the household head, and frequent exposure to drought reduced the likelihood of using CIS whereas access to improved seed, household income, radio ownership, and livelihood activity increased it. Efforts promoting access to and utilisation of CIS would benefit by building trust among farmers through provision of accurate information; promoting adoption of improved varieties of crops; and providing incentives for formation and participation in farmers' groups. PMID- 30450435 TI - Statistical analysis of environmental consequences of hazardous liquid pipeline accidents. AB - Although pipelines are the safest method to transport fuels, they are associated with risks due to failures, leading to significant negative consequences. This paper investigates pipeline accident data provided by PHMSA (Pipeline and Hazardous Material Safety Administration) between 2010 and 2017, with a focus on environmental consequences of hazardous liquid pipeline accidents. The average amount of released product, the average time elapsed between the accident, the emergency response from the oil company, and the average costs of environmental remediation are estimated. The impact on soil, water, and wildlife is investigated for frequency and magnitude, where possible. It was found that, on average, 85% of product released after an accident remained unrecovered, 53% of accidents led to soil contamination, 41% of accidents impacted environmentally sensitive areas, and 92% of water crossing pipelines involved in accidents were uncased. From an annual average total cost of USD 326 million, annual average environmental damage and remediation costs were USD 140 million. This analysis assists in the diagnosis of challenges that might be addressed with improved maintenance and inspection programs, especially for pipelines at higher risk of negative environmental consequences. Finally, the performance of safety management systems should be improved to efficiently respond to emergencies. PMID- 30450434 TI - MnO2 efficiently removes indigo carmine dyes from polluted water. AB - MnO2 is identified as a highly efficient sonocatalyst and sonophotocatalyst for the complete removal of even very small concentration of Indigo carmine (IC) dye pollutant from water. The effect of various reaction parameters, viz. dosage of the catalyst, concentration of pollutant, volume of reaction system, pH, dissolved gases, presence of anions/salts and oxidants etc. on the rate of degradation is evaluated and optimum parameters are identified. The degradation follows variable kinetics depending on the concentration of the substrate. The rate of degradation is facilitated by acidic pH. Classic oxidants H2O2 and S2O8 2 behave differently, with the former inhibiting and the latter enhancing the degradation. The effect of anions/salts on the degradation is complex and ranges from 'inhibition' (PO4 3-, CO3 2-, HCO3 -) and 'no effect' (SO4 2-, Cl-) to 'enhancement' (NO3 -, CH3COO-). The high affinity of MnO2 for O2 and its extremely efficient adsorption of H2O2 and the substrate play key roles in the efficiency of the process. Participation of lattice oxygen from MnO2 in the reaction, whenever the dissolved or adsorbed oxygen is deficient, is an important highlight of the process. Major transient intermediates formed during the process are identified by LC-MS. Combination of sonocatalysis with UV photolysis (sonophotocatalysis) enhances the efficiency of degradation and mineralization of IC. PMID- 30450436 TI - Nutrient enrichment in wadeable urban streams in the Piedmont Ecoregion of the Southeastern United States. AB - The U.S. Geological Survey (USGS) Southeastern Stream Quality Assessment (SESQA) collected weekly samples for nitrogen and phosphorus in 76 wadeable streams in the urbanized Piedmont Ecoregion of the Southeastern United States, during April June 2014. Total nitrogen (TN) concentrations in excess of U.S. Environmental Protection Agency (EPA) guidelines and statistically greater than at reference locations indicated nitrogen-nutrient enrichment in streams draining poultry confined animal feeding operations (CAFO) or urban centers. Nitrate plus nitrite (NO3 + NO2) dominated TN species in urban/CAFO-influenced streams. Streams that drained poultry CAFO and Washington DC had statistically higher NO3 + NO2 concentrations than streams draining Atlanta, Charlotte, Greenville, or Raleigh. In contrast, total phosphorus (TP) concentrations in Atlanta and Washington DC streams statistically were comparable to and lower than, respectively, reference stream concentrations. Over 50% of TP concentrations in Greenville, Charlotte, Raleigh and CAFO-influenced streams exceeded the EPA guideline and reference location mean concentrations, indicating phosphorus-nutrient enrichment. Urban land use, permitted point sources, and soil infiltration metrics best predicted TN exceedances. Elevated TN and NO3 + NO2 concentrations in urban streams during low flow were consistent with reduced in-stream dilution of point-source or groundwater contributions. Urban land use, permitted point sources, and surface runoff metrics best predicted TP exceedances. Elevated TP in CAFO and urban streams during high flow were consistent with non-point sources and particulate transport. PMID- 30450437 TI - Phosphorylation of extracellular signal-regulated kinase as a biomarker for cannabinoid receptor 2 activation. AB - Cannabinoid receptor 2 (CB2R) is a therapeutic target in inflammatory diseases; its activation by agonists provides important clinical information, but there are currently no methods to quantify CB2R activation in humans. Chinese hamster ovary (CHO)-K1 cells and mouse and human whole blood cells were used for experiments. CB2R was activated in cells by treatment with the agonist CP55,940. Cells were also pretreated with proprietary Compound A and B (experimental agonists). We developed our method based on the finding that CB2R ligand binding and activation stimulates acute-phase extracellular signal-regulated kinase (ERK) phosphorylation in human and rodent immune cells, after which CB2R becomes unresponsive to stimulation by a second CB2R agonist CP55940 for a certain time period. We detected ERK phosphorylation as a measure of target engagement in mouse and human whole blood cells by flow cytometry. In cells overexpressing human or mouse CB2R, pretreatment with Compound A dose-dependently inhibited ERK phosphorylation for 2 h, prolonging the time window for measuring ERK phosphorylation. Our method enables measurement of CB2R activation by its agonists in human blood cells based on detection of ERK phosphorylation, which is useful for therapeutic drug monitoring and other clinical applications. PMID- 30450438 TI - Electrical extraction of piezoelectric constants. AB - The piezoelectric materials are incorporated in smart structure to exhibit specific functionality. The activity of piezoelectric material dimension and electrical properties can be changed with an applied stress. These variations are translated to a change in the capacitance of the structure. This work takes a close outlook on the use of the capacitance-voltage measurements for the extraction of double piezoelectric thin film material deposited at the two faces of a flexible steel sheet. The piezoelectric thin film materials have been deposited using RF sputtering techniques. Gamry analyzer references 3000 was used to collect the capacitance-voltage measurements from both layers. The developed algorithm extracts directly the piezoelectric coefficients knowing the film thickness, the applied voltage, and the capacitance ratio. The capacitance ratio is the ratio between the capacitances of the film when the applied field in antiparallel and parallel to the polling field direction, respectively. The method has been calibrated using a piezoelectric bulk ceramic and validated by comparing the result with the reported values in the literature. The extracted values using the current approach match well the values extracted by other existing methods. PMID- 30450439 TI - A synoptic land change assessment of Ethiopia's Rainfed Agricultural Area for evidence-based agricultural ecosystem management. AB - This paper demonstrates synoptic ways of presenting and characterizing land change processes across Ethiopia's large, complex Rainfed Agricultural Area (RAA). We translated pixel-level detected changes into neighbourhood-level changes that are useful to decision-makers. First, we identified pixel-level changes without and with type/direction of change, based on land cover maps from the years 1986 and 2010. For type-/direction-based characterization, we sorted observed transitions into four categories of prominent land change processes ("forest degradation", "deforestation", "afforestation", and "no change"). Adopting appropriate window sizes for identified ecoregions in the study area, we ran a focal statistics summation operator separately on the two change rasters (with/without consideration of direction of change). The results obtained by applying the approach can be described in relative terms as well as qualitative terms, using ranges of change values that can be further classified using qualitative terms, i.e. ranging from "no change" to "high/substantial change". Our non-directional change assessment result showed that approximately 6% of the RAA is characterized by substantial change, whereas 40% appears stable ("no change"). Based on the directional-change assessment results, 3% of deforestation, 4% of forest degradation, and 3% of revegetation processes were found to constitute "high/substantial change". The types and intensity of landscape transformations display distinct spatial patterns linked to agro ecological belts and socio-economic dynamics. Minimal reverse changes were observed on some severely degraded lands in the highlands, but the overall per cent cover remains relatively small. Overall, vegetation degradation still exceeds regeneration by more than half a per cent. Relatively lower altitudes and middle altitudes exhibit higher transformation. The presented approach and resulting outputs can provide planners and decision-makers with a synoptic view of land change processes. It can support policy formulation of sustainable land management and rehabilitation activities of the agricultural ecosystem at national and regional scales. PMID- 30450440 TI - Conversion of adult human fibroblasts into neural precursor cells using chemically modified mRNA. AB - Direct reprogramming offers a unique approach by which to generate neural lineages for the study and treatment of neurological disorders. Our objective is to develop a clinically viable reprogramming strategy to generate neural precursor cells for the treatment of neurological disorders through cell replacement therapy. We initially developed a method for directly generating neural precursor cells (iNPs) from adult human fibroblasts by transient expression of the neural transcription factors, SOX2 and PAX6 using plasmid DNA. This study advances these findings by examining the use of chemically modified mRNA (cmRNA) for direct-to-iNP reprogramming. Chemically modified mRNA has the benefit of being extremely stable and non-immunogenic, offering a clinically suitable gene delivery system. The use of SOX2 and PAX6 cmRNA resulted in high co transfection efficiency and cell viability compared with plasmid transfection. Neural positioning and fate determinant genes were observed throughout reprogramming with ion channel and synaptic marker genes detected during differentiation. Differentiation of cmRNA-derived iNPs generated immature GABAergic or glutamatergic neuronal phenotypes in conjunction with astrocytes. This represents the first time a cmRNA approach has been used to directly reprogram adult human fibroblasts to iNPs, potentially providing an efficient system by which to generate human neurons for both research and clinical application. PMID- 30450441 TI - Dual Users and Electronic Cigarette Only Users: Consumption and Characteristics. AB - Background: E-cigarette use has grown in popularity, especially as the devices have been touted as smoking cessation tools. In an exploratory study, we sought to compare dual users (i.e., users of both combustible tobacco and e-cigarettes) to e-cigarette only users. Methods: The Electronic Cigarette Opinion Survey (ECOS) was employed to assess users' (n=78) perceptions and consumption of e cigarettes and combustible cigarettes. Quantity of e-juice and nicotine used and time of initial nicotine exposure were assessed. Multivariable logistic regression was used to evaluate the association between e-cigarette use behaviors and being an e-cigarette only user compared to a dual user. Results: Compared to dual users, e-cigarette only users consumed higher levels of nicotine in e-juice (p=0.0009) and more nicotine per month (p=0.03). For dual users, the time of first nicotine exposure after waking was significantly earlier than for e cigarette only users (mean= 9.6 minutes (SD= 8.0) and mean= 26.6 minutes (SD= 22.0), respectively; p=0.0056). Results from the regression models suggest the amount of e-juice consumed and time of first nicotine exposure after waking are significantly associated with being an e-cigarette only user. Conclusions: These findings shed light on the perceptions and use patterns of e-cigarette only users compared to dual users. As regulation of e-cigarettes is considered, understanding the impact of e-cigarettes and dual use is imperative. Despite frequent marketing claims that e-cigarettes are completely safe, health campaigns need to convey emerging and mixed findings on safety as well as current scientific uncertainty to the public. PMID- 30450443 TI - Cataract surgery in a patient with an angle gamma due to macular heterotopia. AB - Purpose: We report a case of cataract surgery in a patient with a detectable angle gamma due to macular heterotopia. Observation: A 48-year-old man had angle gamma due to macular heterotopia secondary to retinopathy of prematurity. The preoperative corrected distance visual acuity was 20/32 in the right eye and 20/200 in the left eye. Ocular deviation was esotropic at an angle of 70-80prism diopter. Only the right eye was capable of fixating due to the amblyopia in the left eye. The preoperative root mean square was measured (cornea: 1.32 MUm, total: 1.64 MUm in ordinary fixation position, cornea: 0.36 MUm, total: 3.40 MUm in pupil center position). The total aberration was lower in the ordinary fixation position than in the pupil center position. Corneal refractive power was 41.75 D in the ordinary fixation position and 43.05 D in the pupil center position. The axial lengths were 22.25 and 22.54 mm, respectively. We selected the VA60BBR intraocular lens (IOL) at +28.00 D based on the targeted fixation state. Target refraction was -1.32 D. The postoperative course was favorable, and the resulting visual acuity was 20/40. Conclusion: We report a case of cataract surgery on a patient with an angle gamma due to macular heterotopia. The postoperative course was favorable, and the patient's satisfaction was good considering that we selected the IOL's postoperative fixation state to meet the patient's occupational demands. PMID- 30450442 TI - A simplified morphological classification scheme for pyramidal cells in six layers of primary somatosensory cortex of juvenile rats. AB - The majority of neurons in the neocortex are excitatory pyramidal cells (PCs). Many systematic classification schemes have been proposed based the neuronal morphology, the chemical composition, and the synaptic connectivity, etc. Recently, a cortical column of primary somatosensory cortex (SSC) has been reconstruction and functionally simulated (Markram et al., 2015). Putting forward from this study, here we proposed a simplified classification scheme for PCs in all layers of the SSC by mainly identifying apical dendritic morphology based on a large data set of 3D neuron reconstructions. We used this scheme to classify three types in layer 2, two in layer 3, three in layer 4, four in layer 5, and six types in layer 6. These PC types were visually distinguished and confirmed by quantitative differences in their morphometric properties. The classes yielded using this scheme largely corresponded with PC classes that were defined previously based on other neuronal and synaptic properties such as long-range projects and synaptic innervations, further validating its applicability. Therefore, the morphology information of apical dendrites is sufficient for a simple scheme to classify a spectrum of anatomical types of PCs in the SSC. PMID- 30450445 TI - Should We Diagnose Autosomal Dominant Alport Syndrome When There Is a Pathogenic Heterozygous COL4A3 or COL4A4 Variant? PMID- 30450446 TI - Urinary Plasmin(ogen): New Predictor of Hypertension? PMID- 30450447 TI - Pitfalls and Challenges of Consenting to Genetic Research Studies. PMID- 30450444 TI - Exploring intermediate cell states through the lens of single cells. AB - As our catalog of cell states expands, appropriate characterization of these states and the transitions between them is crucial. Here we discuss the roles of intermediate cell states (ICSs) in this growing collection. We begin with definitions and discuss evidence for the existence of ICSs and their relevance in various tissues. We then provide a list of possible functions for ICSs with examples. Finally, we describe means by which ICSs and their functional roles can be identified from single-cell data or predicted from models. PMID- 30450448 TI - Balancing Immunosuppressive Efficacy and Prevention of Posttransplant Diabetes-A Question of Timing and Patient Selection. PMID- 30450449 TI - Moving Beyond Hip Fracture Risk Assessment for Patients on Dialysis. PMID- 30450450 TI - How to Evaluate Interventions for the Treatment and Care of Patients With Acute Kidney Injury. PMID- 30450451 TI - Critically Ill Definitions in Acute Kidney Injury Clinical Research. PMID- 30450452 TI - Paraffin Immunofluorescence: A Valuable Ancillary Technique in Renal Pathology. AB - Immunofluorescence on frozen tissue is the gold standard immunohistochemical technique for evaluation of immune deposits in the kidney. When frozen tissue is not available or lacks glomeruli, immunofluorescence can be performed on paraffin tissue after antigen retrieval (paraffin immunofluorescence). Excellent results can be obtained by paraffin immunofluorescence in most immune complex-mediated glomerulonephritides and dysproteinemia-associated kidney lesions, and thus this technique has become a valuable salvage technique in renal pathology. Furthermore, new data have emerged suggesting that paraffin immunofluorescence can be used as an unmasking technique, as it is more sensitive than frozen tissue immunofluorescence in some kidney lesions, such as crystalline light chain proximal tubulopathy and is needed to establish the diagnosis of certain unique lesions, such as membranous-like glomerulopathy with masked IgG kappa deposits and membranoproliferative glomerulonephritis with masked monotypic Ig deposits. However, it is important to recognize and be aware of the limitations and pitfalls associated with paraffin immunofluorescence. These include poor sensitivity for detection of C3 deposits and for the diagnosis of primary membranous nephropathy. Here, we summarize the available techniques of paraffin immunofluorescence, review its role and performance as a salvage and unmasking technique in renal pathology, address its limitations and pitfalls, and highlight unusual forms of glomerulopathy that require paraffin immunofluorescence for diagnosis. PMID- 30450453 TI - Consent for Genetic Biobanking in a Diverse Multisite CKD Cohort. AB - Introduction: The goal of this study was to examine patterns in the likelihood of consent to genetic research among participants in a prospective kidney disease cohort and biobank, and to determine demographic, clinical, and socioeconomic factors linked to consent for ongoing and future genetic research. Methods: The Clinical Phenotyping Resource and Biobank Core (C-PROBE) enrolled 1628 adult and pediatric patients with chronic kidney disease from 2009 to 2017 across 7 sites in the United States. Participants were asked at annual study visits for consent to provide DNA samples for future genetic studies. We compared characteristics of participants by initial consent outcome and consent status at their most recent study visit. Results: Of the C-PROBE participants, 96% consented to genetic studies at their initial study visit. Although African Americans were slightly less likely to consent at baseline (93% vs. 97%, odds ratio = 0.3, P < 0.02), there were no significant racial or ethnic differences with longitudinal participation. Also, pediatric and adult genetic consent rates were equivalent. The major persistent differences in the likelihood of consent were based on enrollment site, which ranged from 85% to 100% (P < 0.0001). Conclusion: Overall, genetic consent rates for kidney research within the C-PROBE cohort were high. However, differences in consent rates over time and by recruitment site highlight the complexity of genetic consent for biobanking, and potential limitations for generalizability of observations. PMID- 30450455 TI - A Prospective Micro-costing Pilot Study of the Health Economic Costs of Acute Kidney Injury. AB - Introduction: Acute kidney injury (AKI) prevalence in the UK is estimated to be approximately 20% of all emergency admissions. Complications of AKI have a huge impact on health care costs. Most studies that have researched the economic costs of AKI have used macro-level costing using national tariffs and applying this to hospital episode statistics. Methods: The Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) study was a pilot study that tested the provision of early specialist advice to improve outcomes for patients with AKI. As part of this prospective study, we undertook a health economics substudy that involved micro-costing to help more accurately define the total cost per patient. Results: We found that the total cost of providing an AKI alert system and an outreach service (intervention group) was lower than current practice (control group) for patients with AKI. Overall, an episode of AKI that required inpatient care costs approximately L5000 over 12 months, which is somewhat higher than previous UK estimates. Although it was feasible to collect the required complex dataset needed to conduct a health economics analysis of an outreach service, significant amounts of time and resources needed to be dedicated to this endeavor. Conclusion: We showed that it is possible to demonstrate a clearer, more detailed picture of the prolonged economic costs of AKI for a health care system, as part of a substudy of a larger trial. A larger scale, randomized controlled trial of AKI outreach is needed, with a prospective full economic evaluation conducted alongside the trial. PMID- 30450454 TI - Sleep-Disordered Breathing and Prevalent Albuminuria in Hispanics/Latinos. AB - Introduction: Although sleep-disordered breathing has been found to be associated with higher urine albumin excretion, this association has not been evaluated in Hispanic/Latino populations, which experience a high burden of end-stage renal disease compared with non-Hispanics. We evaluated the association of sleep disordered breathing with prevalent albuminuria among US Hispanics/Latinos. Methods: This was a cross-sectional study of baseline data from participants in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a population based study that enrolled 16,415 adults in 4 US communities. Sleep-disordered breathing was assessed using a home sleep apnea monitor for overnight recording and was defined using 3 thresholds of the apnea-hypopnea index (AHI; 3% desaturation): >=5, >=15, and >=30. Albuminuria was defined as a urine albumin-to creatinine ratio of >=30 mg/g. Results: There were 12,572 participants with complete data available for analysis. The age- and sex-adjusted prevalence of albuminuria was 9.1%. Mean age was 41 years, and 48% were men. Age- and sex adjusted prevalence of sleep-disordered breathing was higher among individuals with albuminuria compared with those without albuminuria (36% vs. 25% had AHI >=5, 18% vs. 9% had AHI >=15, and 9% vs. 4% had AHI >=30). In multivariable logistic regression analyses, AHIs >=5, >=15, and >=30 were associated with greater odds of albuminuria compared with those with AHIs <5, <15, and <30 (odds ratio [OR] 1.42, 95% confidence interval [CI]: 1.14-1.76; OR: 1.71, 95% CI: 1.33 2.20; and OR 1.93, 95% CI 1.34-2.79), respectively. This association varied by Hispanic/Latino background group. Conclusion: In US Hispanic/Latinos, sleep disordered breathing was independently associated with higher odds of prevalent albuminuria. PMID- 30450456 TI - Death and Postoperative Complications After Hip Fracture Repair: Dialysis Effect. AB - Introduction: It is unknown whether patients receiving dialysis have a higher morbidity and mortality risk after hip fracture repair conferred by their kidney failure or by the high comorbidity burden often present. Methods: We examined associations of dialysis dependency with postoperative complications, death, and readmission in a matched cohort study of U.S. patients undergoing hip fracture repair, from January 2010 to December 2013, in the American College of Surgeons National Surgical Quality Improvement Program. Matching included sex, age, race, diabetes mellitus, operation year, primary surgery type, and anesthesia technique. Results: Among 22,621 patients, 377 dialysis-dependent patients were matched to 1508 nondialysis patients. Median age was 78 years (interquartile range = 68-85) years, 56% were men, 70% were white, 43% had diabetes, and 47% underwent fracture fixation under mostly (80%) general anesthesia. Dialysis dependent patients had higher physical status classification, had more heart failure and hypoalbuminemia, and were less often smokers. After adjustment, a greater risk of prolonged postoperative stays beyond 7 days (odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.09-1.89), higher in-hospital mortality (OR = 3.13, CI = 1.72-5.7), and 30-day death (OR = 2.29, CI = 1.51-3.48) but not 30 day readmission (P = 0.09) was observed with dialysis dependency. Adjusted analyses in the original cohort (n = 22,621) were similar: the dialysis group had greater risk of prolonged postoperative stay (OR = 1.77, CI = 1.42-2.21), in hospital mortality (OR = 2.65, CI = 1.74-4.05), and 30-day death (OR = 2.03, CI = 1.48-2.80) and 30-day readmission (OR = 1.62, CI = 1.66-2.26). Conclusion: Dialysis dependency is associated with an increased risk of death and postoperative complications after hip fracture repair. These findings have implications for case-mix adjustment and quality metrics. PMID- 30450458 TI - Effect of PF-04634817, an Oral CCR2/5 Chemokine Receptor Antagonist, on Albuminuria in Adults with Overt Diabetic Nephropathy. AB - Introduction: Inflammatory cell recruitment, which is potentially mediated by the monocyte chemoattractant protein 1/C-C chemokine receptor type 2 (CCR2) system and by C-C chemokine receptor type 5 (CCR5) activity, may play a role in the development and progression of diabetic nephropathy. PF-04634817 is a dual chemokine CCR2/5 receptor antagonist that is being developed for the treatment of diabetic nephropathy. Methods: We evaluated the efficacy of PF-04634817 compared with matching placebo for reduction of albuminuria after 12 weeks of treatment in subjects with type 2 diabetes who received standard of care (SOC; angiotensin converting enzyme inhibitor or angiotensin receptor blocker therapy), in a randomized, double-blind, placebo-controlled, parallel-group phase 2 study. Results: A total of 226 subjects who received SOC with baseline estimated glomerular filtration rates between 20 and 75 ml/min per 1.73 m2 and a baseline urinary albumin-to-creatinine ratio (UACR) of >=300 mg/g were randomly assigned 3:1 to receive PF-04634817 (150 or 200 mg orally, once daily) or placebo. The primary analysis was Bayesian, with an informative prior for placebo response (equivalent to including an additional 80 subjects in the placebo arm). We observed a placebo-adjusted reduction in UACR of 8.2% (ratio 0.918; 95% credible interval: 0.75-1.09) at week 12 in the PF-04634817 arm. PF-04634817 appeared to be safe and well-tolerated. Conclusion: Despite the good safety profile shown by PF-04634817, clinical development for this indication was discontinued in light of the modest efficacy observed. PMID- 30450459 TI - Progression of Medial Arterial Calcification in CKD. AB - Introduction: Medial arterial calcification is common in chronic kidney disease (CKD) and portends poor clinical outcomes, but its progression relative to the severity of CKD and the role of other risk factors is unknown because of the lack of reliable quantification. Methods: Calcification of breast arteries detected by mammography, which is exclusively medial and correlates with medial calcification in peripheral arteries and with cardiovascular outcomes, was used to measure the progression of medial arterial calcification in women with CKD and end-stage renal disease (ESRD). Measurements showed intra- and interobserver correlations of 0.98, an interstudy variability of 8% to 11%, and a correlation with computed tomographic measurements of 0.92. Results: Progression of calcification was measured in 60 control subjects (estimated glomerular filtration rate (eGFR) >= 90 ml/min per 1.73 m2) and 137 subjects with CKD (eGFR < 90 ml/min per 1.73 m2). Progression in control subjects was linear over time and independent of age. The rate of progression was increased in CKD but only at eGFR < 40 ml/min per 1.73 m2 (median, 8.1 vs. 3.9 mm/breast/yr in controls; P = 0.006). Progression accelerated markedly in subjects with ESRD (median, 20 mm/breast/yr; n = 36), but did not differ from controls after kidney transplantation (n = 25). Diabetes significantly augmented progression in subjects with CKD and ESRD but not in controls. Conclusion: Mammography is a convenient and reliable method to measure the progression of medial arterial calcification. Progression does not increase until advanced stages of CKD, accelerates markedly in ESRD, and returns to control rates after kidney transplantation. Diabetes significantly increases progression in CKD and ESRD. PMID- 30450457 TI - Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus. AB - Introduction: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization. Methods: We conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein-cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months. Results: The study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2-12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8-8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms. Conclusion: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence. PMID- 30450460 TI - Chronic Kidney Disease, Queensland (CKD.QLD) Registry: Management of CKD With Telenephrology. AB - Introduction: Enabled by the Chronic Kidney Disease, Queensland (CKD.QLD) Registry, we aim to outline the structure, implementation, and outcomes of telenephrology clinics for the management of patients with chronic kidney disease (CKD) in rural, regional, and remote areas of the Darling Downs region in Queensland, Australia. Methods: This is an observational registry-based study involving adult patients with CKD, attending specialist clinics, and residing >=50 km away from Toowoomba Hospital. The telenephrology cohort (TC) included those who had their follow-up appointments via videoconference at local Queensland Health facilities, and the standard care cohort (SCC) included those who continue to have their follow-up in Toowoomba Hospital. Results: A total of 234 patients with CKD were seen via videoconference clinics between September 1, 2011 and December 31, 2016, representing 22.2% of the CKD registry cohort from Toowoomba Hospital. The baseline characteristics and comorbid profiles of both groups were similar. The Aboriginal population was overrepresented in the TC (22.2% vs. 5.9%). As a group for each visit, the TC traveled 100,000 km less (both ways) to see a specialist physically. During follow-up, 5.1% of patients in the TC were initiated on dialysis whereas 9.9% were initiated on dialysis in the SCC (P = 0.02). There was lower mortality in the TC (11.1% vs. 18.2%; P = 0.02). Conclusion: Telenephrology clinics were safe, economical, and efficient for the delivery of specialist care for patients with CKD living at a distance from the main referral hospital. Such care was comparable to standard care delivered at the main hospital but with clear benefits to the patients in terms of reduced travel distance, more independence, and similar outcomes. PMID- 30450461 TI - Impact of Acute Kidney Injury and CKD on Adverse Outcomes in Critically Ill Septic Patients. AB - Introduction: Chronic kidney disease (CKD) and acute kidney injury (AKI) are strongly associated with excess morbidity and mortality and frequently co-occur in critically ill septic patients, but how their interplay affects clinical outcomes is not well elucidated. Methods: We conducted a single-center, retrospective cohort study of 2632 adult patients admitted to the intensive care unit (ICU) with severe sepsis or septic shock. Subjects were classified into 6 groups according to baseline CKD (no-CKD: estimated glomerular filtration rate [eGFR] >=60; CKD: eGFR 15-59 ml/min per 1.73 m2) and incident AKI by the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (no-AKI, AKI stage 1, AKI stages >=2) during ICU stay. Study outcomes were 90-day mortality (in hospital or within 90 days of discharge) and incident/progressive CKD. Results: Prevalent CKD was 46% and incident AKI was 57%. Adjusted hazard ratios (95% confidence intervals) for 90-day mortality relative to the reference group of no-CKD/no-AKI were 1.5 (1.1-2.0) in no-CKD/AKI stage 1, 2.4 (1.9-3.1) in no CKD/AKI stages>=2, 1.1 (0.8-1.4) in CKD/no-AKI, 1.2 (0.9-1.6) in CKD/AKI stage 1, and 2.2 (1.7-2.9) in CKD/AKI stages >=2. A similar trend was observed for incident/progressive CKD during a median follow-up of 15.3 months. Conclusion: Stage 1 AKI on CKD was not associated with an independent increased risk of adverse outcomes in critically ill septic patients. AKI stages >=2 on CKD and any level of AKI in no-CKD patients were strongly and independently associated with adverse outcomes. Sepsis-associated stage 1 AKI on CKD may represent distinct underlying pathophysiology, with more prerenal cases and less severe de novo intrinsic damage, which needs further investigation. PMID- 30450462 TI - NPHS2 V260E Is a Frequent Cause of Steroid-Resistant Nephrotic Syndrome in Black South African Children. AB - Introduction: In South Africa (SA), steroid-resistant nephrotic syndrome (SRNS) is more frequent in black than in Indian children. Methods: Seeking a genetic basis for this disparity, we enrolled 33 Indian and 31 black children with steroid-sensitive nephrotic syndrome (SSNS) and SRNS from KwaZulu-Natal, SA; SRNS children underwent kidney biopsy. We sequenced NPHS2 and genotyped APOL1 in 15 SSNS and 64 SRNS unrelated patients and 104 controls and replicated results in 18 black patients with steroid-resistant focal segmental glomerulosclerosis (SR FSGS). Known FSGS genes (n = 21) were sequenced in a subset of patients. Results: Homozygosity for NPHS2 V260E was found in 8 of 30 black children with SRNS (27%); all 260E/E carriers had SR-FSGS. Combining SR-FSGS patients from the 2 groups, 14 of 42 (33%) were homozygous for V260E. One black control was heterozygous for V260E; no Indian patients or controls were carriers. Haplotype analysis indicated that homozygosity for V260E was not explained by cryptic consanguinity. Children with NPHS2 260E/E developed SRNS at earlier age than noncarriers (34 vs. 78 months, P = 0.01), and none achieved partial or complete remission (0% vs. 47%, P = 0.002). APOL1 variants did not associate with NS. Sequencing FSGS genes identified a CD2AP predicted pathogenic variant in the heterozygous state in 1 Indian case with SR-FSGS. Conclusion: NPHS2 260E/E was present in one-third of black FSGS patients, was absent in black controls and Indian patients, and affected patients were unresponsive to therapy. Genotyping V260E in black children from South Africa with NS will identify a substantial group with SR FSGS, potentially sparing these children biopsy and ineffective steroid treatment. PMID- 30450463 TI - Secondary Oxalate Nephropathy: A Systematic Review. AB - Introduction: Little is known of the clinical outcomes of secondary oxalate nephropathy. To inform clinical practice, we performed a systematic review of case reports and case series to examine the clinical characteristics and outcomes of patients with secondary oxalate nephropathy. Methods: Electronic databases were searched for case reports and case series of individual cases or cohorts of patients with biopsy-proven oxalate nephropathy in native or transplanted kidneys from 1950 until January 2018. Results: Fifty-seven case reports and 10 case series met the inclusion criteria, totaling 108 patients. The case series were meta-analyzed. Mean age was 56.4 years old, 59% were men, and 15% were kidney transplant recipients. Fat malabsorption (88%) was the most commonly attributed cause of oxalate nephropathy, followed by excessive dietary oxalate consumption (20%). The mean baseline serum creatinine was 1.3 mg/dl and peaked at 4.6 mg/dl. Proteinuria, hematuria, and urinary crystals was reported in 69%, 32%, and 26% of patients, respectively. Mean 24-hour urinary oxalate excretion was 85.4 mg/d. In addition to universal oxalate crystal deposition in tubules and/or interstitium, kidney biopsy findings included acute tubular injury (71%), tubular damage and atrophy (69%), and interstitial mononuclear cell infiltration (72%); 55% of patients required dialysis. None had complete recovery, 42% had partial recovery, and 58% remained dialysis-dependent. Thirty-three percent of patients died. Conclusion: Secondary oxalate nephropathy is a rare but potentially devastating condition. Renal replacement therapy is required in >50% of patients, and most patients remain dialysis-dependent. Studies are needed for effective preventive and treatment strategies in high-risk patients with hyperoxaluria-enabling conditions. PMID- 30450465 TI - Effect of Renin-Angiotensin-Aldosterone System Blockade on Outcomes in Patients With ESRD: A Prospective Cohort Study in Korea. AB - Introduction: Conflicting results still exist regarding the benefit of renin angiotensin-aldosterone system (RAAS) blockade on clinical outcomes in dialysis patients. The aim of this study was to evaluate the effects of RAAS blockade on survival in Korean patients with end-stage renal disease (ESRD). Methods: Our analysis was based on the data of 5223 patients enrolled from the Clinical Research Center for ESRD, a nationwide prospective observational cohort. Multivariate Cox regression was applied for risk factor analysis with the cumulative duration of RAAS blockade use as time-varying covariate. The risks for mortality from all causes and major cardiovascular event-free survival were estimated. Results: Compared to the control group, patients in the RAAS group were younger but had a higher proportion of diabetes mellitus, had higher systolic blood pressure, required a greater number of prescribed antihypertensive drugs, and had a longer dialysis duration. On multivariate time-varying Cox regression analysis, the RAAS group with cumulative duration of >90 days was significantly associated with a lower risk of mortality from all causes after adjustment for confounding (hazard ratio [HR] = 0.45, 95% confidence interval [CI] = 0.35-0.58, P < 0.0001). Major cardiovascular event-free survival was also better for the RAAS group than for the control group on multivariate analysis (HR = 0.27, 95% CI = 0.20-0.37, P < 0.0001), considering the cumulative duration of RAAS blockade use. Conclusion: In Korean patients with ESRD, we reported a specific benefit of RAAS blockade in improving overall survival after adjustment for confounding factors from real-world data. PMID- 30450466 TI - Augmented Cardiopulmonary Baroreflex Sensitivity in Intradialytic Hypertension. AB - Introduction: End-stage renal disease (ESRD) patients with a paradoxical increase in blood pressure (BP) during hemodialysis (HD), termed intradialytic hypertension (ID-HTN), are at significantly increased risk for mortality and adverse cardiovascular events. ID-HTN affects up to 15% of all HD patients, and the pathophysiologic mechanisms remain unknown. We hypothesized that ESRD patients prone to ID-HTN have heightened volume-sensitive cardiopulmonary baroreflex sensitivity (BRS) that leads to exaggerated increases in sympathetic nervous system (SNS) activation during HD. Methods: We studied ESRD patients on maintenance HD with ID-HTN (n = 10) and without ID-HTN (controls, n = 12) on an interdialytic day, 24 to 30 hours after their last HD session. We measured continuous muscle sympathetic nerve activity (MSNA), beat-to-beat arterial BP, and electrocardiography (ECG) at baseline, and during graded lower body negative pressure (LBNP). Low-dose LBNP isolates cardiopulmonary BRS, whereas higher doses allow assessment of physiologic responses to orthostatic stress. Results: The ID HTN patients had significantly higher pre- and post-HD BP, and greater interdialytic fluid weight gain compared to controls. There was a significantly greater increase in MSNA burst incidence (P = 0.044) during graded LBNP in the ID HTN group, suggesting heightened cardiopulmonary BRS. The ID-HTN group also had a trend toward increased diastolic BP response during LBNP, and had significantly greater increases in BP during the cold pressor test. Conclusion: Patients with ID-HTN have augmented cardiopulmonary BRS that may contribute to increased SNS activation and BP response during HD. PMID- 30450468 TI - Raising Awareness of Acute Kidney Injury: A Latin American Experience. AB - Introduction: Raising awareness of acute kidney injury (AKI) is an essential strategy for minimizing the burden of this lethal syndrome. The AKI Commission of the Latin American Society of Nephrology and Hypertension conducted an educational program based on networked learning. Methods: Two online courses with similar methodologies were developed, 1 course for nephrologists and the other for primary care physicians (PCP). The courses were developed as a distance education, asynchronous online modality with multiple educational strategies: written lessons, videos, e-rounds, and clinical simulation. Knowledge gain was explored through a 10-question test before and after course completion. Results: The course for nephrologists had 779 participants from 21 countries; 52% were male, and 46% were <35 years of age. Mean qualification increased from 5.87 to 8.01 (36% gain of knowledge). The course for PCPs had 2011 participants, 81% of whom were physicians. The time from graduation was <5 years in 52%. In both courses, clinical simulation was considered the best part and lack of time the main limitation for learning. Because 48% of the nephrologist course attendees were interested in AKI activities, a Latin American AKI Network site (RedIRA) composed of a brief review, a clinical forum, a self-assessment, and a bibliography on AKI was launched on a monthly basis in November 2016. To date there are 335 users from 18 countries. Conclusions: Distance education techniques were effective for learning about AKI and are a potential tool for the development of a sustainable structure for communication, exchange, and integration of physicians involved in the care of patients with AKI. PMID- 30450467 TI - Dysregulated Handling of Dietary Protein and Muscle Protein Synthesis After Mixed Meal Ingestion in Maintenance Hemodialysis Patients. AB - Introduction: Skeletal muscle loss is common in patients with renal failure who receive maintenance hemodialysis (MHD) therapy. Regular ingestion of protein-rich meals are recommended to help offset muscle protein loss in MHD patients, but little is known about the anabolic potential of this strategy. Methods: Eight MHD patients (age: 56 +/- 5 years; body mass index [BMI]: 32 +/- 2 kg/m2) and 8 nonuremic control subjects (age: 50 +/- 2 years: BMI: 31 +/- 1 kg/m2) received primed continuous L-[ring-2H5]phenylalanine and L-[1-13C]leucine infusions with blood and muscle biopsy sampling on a nondialysis day. Participants consumed a mixed meal (546 kcal; 20-g protein, 59-g carbohydrates, 26-g fat) with protein provided as L-[5,5,5-2H3]leucine-labeled eggs. Results: Circulating dietary amino acid availability was reduced in MHD patients (41 +/- 5%) versus control subjects (61 +/- 4%; P = 0.03). Basal muscle caspase-3 protein content was elevated (P = 0.03) and large neutral amino acid transporter 1 (LAT1) protein content was reduced (P = 0.02) in MHD patients versus control subjects. Basal muscle protein synthesis (MPS) was ~2-fold higher in MHD patients (0.030 +/- 0.005%/h) versus control subjects (0.014 +/- 0.003%/h) (P = 0.01). Meal ingestion failed to increase MPS in MHD patients (absolute change from basal: 0.0003 +/- 0.007%/h), but stimulated MPS in control subjects (0.009 +/- 0.002%/h; P = 0.004). Conclusions: MHD patients demonstrated muscle anabolic resistance to meal ingestion. This blunted postprandial MPS response in MHD patients might be related to high basal MPS, which results in a stimulatory ceiling effect and/or reduced plasma dietary amino acid availability after mixed-meal ingestion. PMID- 30450464 TI - Clinical Characteristics and Treatment Patterns of Children and Adults With IgA Nephropathy or IgA Vasculitis: Findings From the CureGN Study. AB - Introduction: The Cure Glomerulonephropathy Network (CureGN) is a 66-center longitudinal observational study of patients with biopsy-confirmed minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy (IgAN), including IgA vasculitis (IgAV). This study describes the clinical characteristics and treatment patterns in the IgA cohort, including comparisons between IgAN versus IgAV and adult versus pediatric patients. Methods: Patients with a diagnostic kidney biopsy within 5 years of screening were eligible to join CureGN. This is a descriptive analysis of clinical and treatment data collected at the time of enrollment. Results: A total of 667 patients (506 IgAN, 161 IgAV) constitute the IgAN/IgAV cohort (382 adults, 285 children). At biopsy, those with IgAV were younger (13.0 years vs. 29.6 years, P < 0.001), more frequently white (89.7% vs. 78.9%, P = 0.003), had a higher estimated glomerular filtration rate (103.5 vs. 70.6 ml/min per 1.73 m2, P < 0.001), and lower serum albumin (3.4 vs. 3.8 g/dl, P < 0.001) than those with IgAN. Adult and pediatric individuals with IgAV were more likely than those with IgAN to have been treated with immunosuppressive therapy at or prior to enrollment (79.5% vs. 54.0%, P < 0.001). Conclusion: This report highlights clinical differences between IgAV and IgAN and between children and adults with these diagnoses. We identified differences in treatment with immunosuppressive therapies by disease type. This description of baseline characteristics will serve as a foundation for future CureGN studies. PMID- 30450472 TI - Renal Hypertrophy in Liver Failure. PMID- 30450469 TI - Proenkephalin A 119-159 (Penkid) Is an Early Biomarker of Septic Acute Kidney Injury: The Kidney in Sepsis and Septic Shock (Kid-SSS) Study. AB - Introduction: Sepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock. Methods: The Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality. Results: Median age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median = 65 [IQR = 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P < 0.0001), also after adjustment for confounding factors (adjusted odds ratio = 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P < 0.0001). Penkid increase preceded elevation of serum creatinine with WRF and was low in renal recovery. Conclusion: Admission penkid concentration was associated with MAKEs, AKI, and WRF in a timely manner in septic patients. PMID- 30450471 TI - Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1 Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child. AB - Introduction: Monogenetic renal diseases, including recessively inherited nephrotic syndromes, represent a significant health burden despite being rare conditions. Precise diagnosis, including identification of the underlying molecular cause, is especially difficult in low-income countries and/or if affected individuals are unavailable for biochemical testing. Whole-exome sequencing (WES) has opened up novel diagnostic perspectives for these settings. However, sometimes the DNA of affected individuals is not suitable for WES due to low amounts or degradation. Methods: We report on the use of parental WES with implementation of specific stepwise variant filtering to identify the underlying molecular cause of the childhood-onset nephrotic syndrome as nephrosialidosis resulting from a mutation in NEU1. Results: Sequencing both parents enabled a nephrosialidosis diagnosis in the deceased child. To date, only 16 other cases of nephrosialidosis have been reported in the literature, with only 1 genetically confirmed case. After we reviewed the clinical information of all reported cases, we found that most patients presented with proteinuria, which started at between 2 and 3 years of age. Renal pathology showed mainly focal segmental glomerulosclerosis (FSGS)with vacuolated cells, and steroid treatment was always unsuccessful. Hepatomegaly was present in nearly all cases, whereas corneal clouding and a cherry red spot on the macula was observed in only approximately 50% of cases. Fourteen of 16 previously reported cases were no longer alive at the time of reporting. Conclusions: Our findings demonstrate the power of parental WES to diagnose rare genetic diseases, such as childhood-onset nephrotic syndrome. We further provide a comprehensive overview of the clinical course of nephrosialidosis and raise awareness of this ultra-rare condition as an underlying cause of FSGS. PMID- 30450470 TI - Urinary Plasmin(ogen) as a Prognostic Factor for Hypertension. AB - Introduction: Plasmin and its precursor, plasminogen, are detectable in urine from patients with glomerular disease. Urinary plasmin(ogen) levels correlate with blood pressure (BP) and may contribute to renal Na+ retention by activating the epithelial Na+ channel (ENaC). In a longitudinal nested-cohort study, we asked whether urinary plasmin(ogen) levels predict subsequent increase in BP, incident hypertension, or mortality in subjects with type I diabetes, who often develop proteinuria. Methods: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study followed up type I diabetic subjects for 25 years. Urine specimens from 70 subjects with a spectrum of baseline urinary albumin levels were examined. Outcomes included increased BP after 2 years (>=1 SD over baseline systolic or diastolic BP, examined via logistic regression), 25-year incident hypertension (>=140/90 mm Hg or initiating BP-lowering medications), and all-cause or cardiovascular mortality, examined using Cox regression. Results: Subjects experiencing a 2-year increase in BP had higher baseline urinary plasmin(ogen)/creatinine levels (uPl/Cr) than other subjects (P = 0.04); the difference in baseline urinary albumin/creatinine levels (uAlb/Cr) was similar (P = 0.07). Baseline uPl/Cr was associated with increased 25-year hypertension incidence (hazard ratio = 2.05, P = 0.001), all-cause mortality (HR = 2.05, P = 0.01) and cardiovascular mortality (HR = 3.30, P = 0.005), although not independent of uAlb/Cr. Conclusion: This is the first long-term prospective study addressing clinical outcomes associated with increased urinary plasmin(ogen). Findings are consistent with a role for plasmin(ogen) in promoting increased BP, but also demonstrate the difficulty in distinguishing effects due to plasmin(ogen) from those of albuminuria. PMID- 30450474 TI - N-methylamphetamine ("Crystal Meth")-Associated Acute Renal Cortical Necrosis. PMID- 30450473 TI - Multicenter Study Evaluating Intrarenal Oxygenation and Fibrosis Using Magnetic Resonance Imaging in Individuals With Advanced CKD. PMID- 30450475 TI - Case of Proteinuria, Worsening Hypertension, and Glomerular Endotheliosis With Erlotinib and Gefitinib. PMID- 30450476 TI - Hypokalemic Nephropathy. PMID- 30450477 TI - Autonomic Nervous System Dysregulation in Monozygous Twins With Nephropathic Cystinosis. PMID- 30450478 TI - Idiopathic Urinary Bladder Perforation in Early Childhood. PMID- 30450479 TI - Intravascular Large B-Cell Lymphoma of the Kidney. PMID- 30450482 TI - Preclinical common data elements (CDEs) for epilepsy: A joint ILAE/AES and NINDS translational initiative. PMID- 30450481 TI - Nontarget Biomolecules Alter Macromolecular Changes Induced by Bactericidal Low Temperature Plasma. AB - Low-temperature plasmas (LTPs) have a proven bactericidal activity governed by the generated reactive oxygen and nitrogen species (RONS) that target microbial cell components. However, RONS also interact with biomolecules in the environment. Here we assess the impact of these interactions upon exposure of liquid suspensions with variable organic content to an atmospheric-pressure dielectric barrier discharge plasma jet. Salmonella enterica serovar Typhimurium viability in the suspension was reduced in the absence [e.g., phosphate buffered saline (PBS)], but not in the presence of (high) organic content [Dulbecco's Modified Eagle's Medium (DMEM), DMEM supplemented with foetal calf serum, and Lysogeny Broth]. The reduced viability of LTP-treated bacteria in PBS correlated to a loss of membrane integrity, whereas double-strand DNA breaks could not be detected in treated single cells. The lack of bactericidal activity in solutions with high organic content correlated with a relative decrease of *OH and O3/O2(a1[Formula: see text])/O, and an increase of H2O2 and [Formula: see text] in the plasma-treated solutions. These results indicate that the redox reactions of LTP-generated RONS with nontarget biomolecules resulted in a RONS composition with reduced bactericidal activity. Therefore, the chemical composition of the bacterial environment should be considered in the development of LTP for antimicrobial treatment, and may affect other biomedical applications as well. PMID- 30450480 TI - Erratum: Evans M, Grams ME, Sang Y, et al., for the Chronic Kidney Disease Prognosis Consortium. Risk factors for prognosis in patients with severely decreased GFR. Kidney Int Rep. 2018;3:625-637. AB - [This corrects the article DOI: 10.1016/j.ekir.2018.01.002.]. PMID- 30450483 TI - Common data elements (CDEs) for preclinical epilepsy research: Introduction to CDEs and description of core CDEs. A TASK3 report of the ILAE/AES joint translational task force. AB - Common data elements (CDEs) are becoming more common as more areas of preclinical research have generated CDEs. Herein we provide an overview of the progress to date in generating CDEs for preclinical epilepsy research. Currently there are CDEs that have been developed for Physiology (in vivo), Behavior, Pharmacology, and Electroencephalography (EEG). Together the CDEs and methodologic considerations associated with these CDEs are laid out in consecutive manuscripts published in Epilepsia Open, each describing CDEs for their respective topic area. In addition to the overview of progress for the 4 subjects, core characteristics (Core CDEs) are described and explained. Data collection using a case report form (CRF) is described, and considerations that are involved in using the CDEs and CRFs are discussed. PMID- 30450484 TI - A companion to the preclinical common data elements on neurobehavioral comorbidities of epilepsy: a report of the TASK3 behavior working group of the ILAE/AES Joint Translational Task Force. AB - The provided companion has been developed by the Behavioral Working Group of the Joint Translational Task Force of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) with the purpose of assisting the implementation of Preclinical Common Data Elements (CDE) for studying and for reporting neurobehavioral comorbidities in rodent models of epilepsy. Case Report Forms (CRFs) are provided, which should be completed on a per animal/per test basis, whereas the CDEs are a compiled list of the elements that should be reported. This companion is not designed as a list of recommendations, or guidelines for how the tests should be run-rather, it describes the different types of assessments, and highlights the importance of rigorous data collection and transparency in this regard. The tests are divided into 7 categories for examining behavioral dysfunction on the syndrome level: deficits in learning and memory; depression; anxiety; autism; attention deficit/hyperactivity disorder; psychosis; and aggression. Correspondence and integration of these categories into the National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) is introduced. Developmental aspects are addressed through the introduction of developmental milestones. Discussion includes complexities, limitations, and biases associated with neurobehavioral testing, especially when performed in animals with epilepsy, as well as the importance of rigorous data collection and of transparent reporting. This represents, to our knowledge, the first such resource dedicated to preclinical CDEs for behavioral testing of rodents. PMID- 30450486 TI - A companion to the preclinical common data elements and case report forms for rodent EEG studies. A report of the TASK3 EEG Working Group of the ILAE/AES Joint Translational Task Force. AB - Electroencephalography (EEG) is commonly used in epilepsy and neuroscience research to study brain activity. The principles of EEG recording such as signal acquisition, digitization, and conditioning share similarities between animal and clinical EEG systems. In contrast, preclinical EEG studies demonstrate more variability and diversity than clinical studies in the types and locations of EEG electrodes, methods of data analysis, and scoring of EEG patterns and associated behaviors. The TASK3 EEG working group of the International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force has developed a set of preclinical common data elements (CDEs) and case report forms (CRFs) for recording, analysis, and scoring of animal EEG studies. This companion document accompanies the first set of proposed preclinical EEG CRFs and is intended to clarify the CDEs included in these worksheets. We provide 7 CRF and accompanying CDE modules for use by the research community, covering video acquisition, electrode information, experimental scheduling, and scoring of EEG activity. For ease of use, all data elements and input ranges are defined in supporting Excel charts (Appendix S1). PMID- 30450487 TI - Characterizing Concentration-Dependent Neural Dynamics of 4-Aminopyridine-Induced Epileptiform Activity. AB - Epilepsy remains one of the most common neurological disorders. In patients, it is characterized by unprovoked, spontaneous, and recurrent seizures or ictal events. Typically, inter-ictal events or large bouts of population level activity can be measured between seizures and are generally asymptomatic. Decades of research have focused on understanding the mechanisms leading to the development of seizure-like activity using various pro-convulsive pharmacological agents, including 4-aimnopyridine (4AP). However, the lack of consistency in the concentrations used for studying 4AP-induced epileptiform activity in animal models may give rise to differences in results and interpretation thereof. Indeed, the range of 4AP concentration in both in vivo and in vitro studies varies from 3 MUM to 40 mM. Here, we explored the effects of various 4AP concentrations on the development and characteristics of hippocampal epileptiform activity in acute mouse brain slices of either sex. Using multi-electrode array recordings, we show that 4AP induces hippocampal epileptiform activity for a broad range of concentrations. The frequency component and the spatiotemporal patterns of the epileptiform activity revealed a dose-dependent response. Finally, in the presence of 4AP, reduction of KCC2 co-transporter activity by KCC2 antagonist VU0240551 prevented the manifestation of the frequency component differences between different concentrations of 4AP. Overall, the study predicts that different concentrations of 4AP can result in the different mechanisms behind hippocampal epileptiform activity, of which some are dependent on the KCC2 co-transporter function. PMID- 30450488 TI - Innovative Approaches to Address Social Determinants of Health Among Adolescents and Young Adults. AB - Background: Social determinants are the leading causes of health disparities. Yet health care systems have not systemically addressed social determinants of health as it pertains to adolescents and young adults (AYAs), among other populations in need. This study identified promising innovative programs across the United States. Methods: Thirteen representatives from 10 programs completed a 45-min telephone interview. Transcripts were reviewed and analyzed to identify cross cutting themes. Results: Strategies included increasing access to quality, comprehensive and confidential health services, addressing the holistic needs of AYAs, collaborations across the health care delivery systems and other community services, and leveraging technology. Conclusion: This study showcased innovative approaches to inform future efforts. PMID- 30450485 TI - A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force. AB - Preclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab-to-lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated. PMID- 30450489 TI - TFEB, a master regulator of lysosome biogenesis and autophagy, is a new player in alcoholic liver disease. PMID- 30450490 TI - Active Deep Learning with Fisher Information for Patch-wise Semantic Segmentation. AB - Deep learning with convolutional neural networks (CNN) has achieved unprecedented success in segmentation, however it requires large training data, which is expensive to obtain. Active Learning (AL) frameworks can facilitate major improvements in CNN performance with intelligent selection of minimal data to be labeled. This paper proposes a novel diversified AL based on Fisher information (FI) for the first time for CNNs, where gradient computations from backpropagation are used for efficient computation of FI on the large CNN parameter space. We evaluated the proposed method in the context of newborn and adolescent brain extraction problem under two scenarios: (1) semi-automatic segmentation of a particular subject from a different age group or with a pathology not available in the original training data, where starting from an inaccurate pre-trained model, we iteratively label small number of voxels queried by AL until the model generates accurate segmentation for that subject, and (2) using AL to build a universal model generalizable to all images in a given data set. In both scenarios, FI-based AL improved performance after labeling a small percentage (less than 0.05%) of voxels. The results showed that FI-based AL significantly outperformed random sampling, and achieved accuracy higher than entropy-based querying in transfer learning, where the model learns to extract brains of newborn subjects given an initial model trained on adolescents. PMID- 30450491 TI - Semi-Automated Extraction of Crohns Disease MR Imaging Markers using a 3D Residual CNN with Distance Prior. AB - We propose a 3D residual convolutional neural network (CNN) algorithm with an integrated distance prior for segmenting the small bowel lumen and wall to enable extraction of pediatric Crohns disease (pCD) imaging markers from T1-weighted contrast-enhanced MR images. Our proposed segmentation framework enables, for the first time, to quantitatively assess luminal narrowing and dilation in CD aimed at optimizing surgical decisions as well as analyzing bowel wall thickness and tissue enhancement for assessment of response to therapy. Given seed points along the bowel lumen, the proposed algorithm automatically extracts 3D image patches centered on these points and a distance map from the interpolated centerline. These 3D patches and corresponding distance map are jointly used by the proposed residual CNN architecture to segment the lumen and the wall, and to extract imaging markers. Due to lack of available training data, we also propose a novel and efficient semi-automated segmentation algorithm based on graph-cuts technique as well as a software tool for quickly editing labeled data that was used to train our proposed CNN model. The method which is based on curved planar reformation of the small bowel is also useful for visualizing, manually refining, and measuring pCD imaging markers. In preliminary experiments, our CNN network obtained Dice coefficients of 75 +/- 18%, 81 +/- 8% and 97 +/- 2% for the lumen, wall and background, respectively. PMID- 30450492 TI - Four-Wire Interface ASIC for a Multi-Implant Link. AB - This paper describes an on-chip interface for recovering power and providing full duplex communication over an AC-coupled 4-wire lead between active implantable devices. The target application requires two modules to be implanted in the brain (cortex) and upper chest; connected via a subcutaneous lead. The brain implant consists of multiple identical "optrodes" that facilitate a bidirectional neural interface (electrical recording and optical stimulation), and the chest implant contains the power source (battery) and processor module. The proposed interface is integrated within each optrode ASIC allowing full-duplex and fully differential communication based on Manchester encoding. The system features a head-to-chest uplink data rate (up to 1.6 Mbps) that is higher than that of the chest-to-head downlink (100 kbps), which is superimposed on a power carrier. On chip power management provides an unregulated 5-V dc supply with up to 2.5-mA output current for stimulation, and two regulated voltages (3.3 and 3 V) with 60 dB power supply rejection ratio for recording and logic circuits. The 4-wire ASIC has been implemented in a 0.35-[Formula: see text] CMOS technology, occup-ying a 1.5-mm2 silicon area, and consumes a quiescent current of [Formula: see text]. The system allows power transmission with measured efficiency of up to 66% from the chest to the brain implant. The downlink and uplink communication are successfully tested in a system with two optrodes and through a 4-wire implantable lead. PMID- 30450493 TI - A Scalable Optoelectronic Neural Probe Architecture With Self-Diagnostic Capability. AB - There is a growing demand for the development of new types of implantable optoelectronics to support both basic neuroscience and optogenetic treatments for neurological disorders. Target specification requirements include multi-site optical stimulation, programmable radiance profile, safe operation, and miniaturization. It is also preferable to have a simple serial interface rather than large numbers of control lines. This paper demonstrates an optrode structure comprising of a standard complementary metal-oxide-semiconductor process with 18 optical stimulation drivers. Furthermore, diagnostic sensing circuitry is incorporated to determine the long-term functionality of the photonic elements. A digital control system is incorporated to allow independent multisite control and serial communication with external control units. PMID- 30450494 TI - Early Diagnosis of Autism Disease by Multi-channel CNNs. AB - Currently there are still no early biomarkers to detect infants with risk of autism spectrum disorder (ASD), which is mainly diagnosed based on behavior observations at three or four years old. Since intervention efforts may miss a critical developmental window after 2 years old, it is significant to identify imaging-based biomarkers for early diagnosis of ASD. Although some methods using magnetic resonance imaging (MRI) for brain disease prediction have been proposed in the last decade, few of them were developed for predicting ASD in early age. Inspired by deep multi-instance learning, in this paper, we propose a patch-level data-expanding strategy for multi-channel convolutional neural networks to automatically identify infants with risk of ASD in early age. Experiments were conducted on the National Database for Autism Research (NDAR), with results showing that our proposed method can significantly improve the performance of early diagnosis of ASD. PMID- 30450495 TI - Craniomaxillofacial Bony Structures Segmentation from MRI with Deep-Supervision Adversarial Learning. AB - Automatic segmentation of medical images finds abundant applications in clinical studies. Computed Tomography (CT) imaging plays a critical role in diagnostic and surgical planning of craniomaxillofacial (CMF) surgeries as it shows clear bony structures. However, CT imaging poses radiation risks for the subjects being scanned. Alternatively, Magnetic Resonance Imaging (MRI) is considered to be safe and provides good visualization of the soft tissues, but the bony structures appear invisible from MRI. Therefore, the segmentation of bony structures from MRI is quite challenging. In this paper, we propose a cascaded generative adversarial network with deep-supervision discriminator (Deep-supGAN) for automatic bony structures segmentation. The first block in this architecture is used to generate a high-quality CT image from an MRI, and the second block is used to segment bony structures from MRI and the generated CT image. Different from traditional discriminators, the deep-supervision discriminator distinguishes the generated CT from the ground-truth at different levels of feature maps. For segmentation, the loss is not only concentrated on the voxel level but also on the higher abstract perceptual levels. Experimental results show that the proposed method generates CT images with clearer structural details and also segments the bony structures more accurately compared with the state-of-the-art methods. PMID- 30450497 TI - In vitro and in vivo antiproliferative activity of organo-nickel SCS-pincer complexes on estrogen responsive MCF7 and MC4L2 breast cancer cells. Effects of amine fragment substitutions on BSA binding and cytotoxicity. AB - A family of organonickel complexes has been prepared, fully characterized, and tested for their antiproliferative activity against estrogen-responsive human breast cancer cells (MCF7). The three SCS-type pincer ligands HL1, HL2, and HL3 and their corresponding Ni(ii) complexes NiL1, NiL2, and NiL3 have been synthesized and fully characterized, including by single crystal diffraction studies for the complexes. The complexes possess square planar geometry with two symmetrical 5-membered nickellacycles. Fluorescence spectroscopy, circular dichroism measurements, molecular modeling, colorimetric based assay and tumor transplantation studies were used to evaluate the protein binding and antiproliferative activities of these organometallic complexes both in vitro and in vivo. Fluorescence quenching was used to investigate bovine serum albumin (BSA) interaction at different temperatures (293, 303 and 313 K), and the results were analyzed using the classical Stern-Volmer equation, allowing us to propose a dynamic quenching mechanism. Studies in vitro on the antiproliferative activity of the three organonickel complexes against estrogen-responsive human breast cancer cells (MCF7) showed promising antitumor activity for NiL1 containing pyrrolidine fragments. In vivo administration of this compound significantly inhibits tumor growth in estrogen-dependent MC4L2 cancer cells in female BALB/c mice. PMID- 30450498 TI - Algal oil rich in n-3 polyunsaturated fatty acids suppresses B16F10 melanoma lung metastasis by autophagy induction. AB - Melanoma is a malignant tumor that arises from epidermal melanocytes with high morbidity and mortality, and currently, there are no effective conventional genotoxic treatments or systematic treatment. Increasing evidence shows that n-3 polyunsaturated fatty acids (PUFAs) exhibit anti-melanoma activity, but their anti-melanoma mechanism remains elusive. Here, C57BL/6 mice were injected with B16F10 melanoma cells via a tail vein to establish a lung metastasis model. n-3 PUFAs were significantly increased in lung metastatic tissues from mice treated with algal oil, especially rich in docosahexaenoic acid (DHA). Algal oil treatment significantly suppressed pulmonary metastases and outgrowth of melanoma cells, which was associated with autophagy induction, as evidenced by an increase in LC3-II levels. In addition, algae oil-triggered autophagy was mediated by inactivation of the mammalian target of rapamycin (mTOR) and p38 mitogen activated protein (MAP) kinase, and activation of c-Jun N-terminal kinases (JNKs), which led to a decrease in p62 accumulation and decreased secretion of proinflammatory cytokine interleukin-1beta (IL-1beta). These results suggest that algal oil exerts its antitumourigenic activities via autophagy-mediated p62 elimination and anti-inflammatory properties. PMID- 30450500 TI - Methyl 5-MeO-N-aminoanthranilate, a minimalist fluorogenic probe for sensing cellular aldehydic load. AB - Methyl 5-MeO-N-aminoanthranilate, a fluorogenic probe comprising a single substituted benzene ring has been applied towards the fluorescence detection of endogenous carbonyls through rapid, catalyst-free complexation of these bio derived markers of cell stress under physiological conditions. The products formed during the reaction between the probe and aldehydic products of lipid peroxidation, including malondialdehyde and long-chain aliphatic aldehydes relevant to the oxidative decomposition of cell membranes, have been evaluated. Live cell imaging of diethyl maleate-induced oxidative stress with or without pretreatment with alpha-tocopherol was carried out, with the result suggesting that the presented molecule might serve as a minimalist molecular probe capable of cellular "Aldehydic Load" detection by fluorescence microscopy. This work also outlines functional constraints of the fluorogenic probe (i.e. intramolecular cyclization), providing a realistic evaluation of methyl 5-MeO-N aminoanthranilate for fluorescence-based aldehyde detection. PMID- 30450502 TI - Continuous-Flow Microreactors for Polymer Synthesis: Engineering Principles and Applications. AB - Polymerization is widely involved in the fabrication of high-performance materials. With its advantages, microreactors are typically applied to reaction processes which are limited by transport properties of conventional batch reactors. As demonstrated in this review, numerous polymerization processes are suitable to be conducted in microreactors with showing excellent polymerization performance (e.g., precisely controllable molecular weights and structures of polymer products). However, distinctive differences between polymerization processes and small-molecular reaction systems can be easily expected since fluid physical properties vary significantly during the polymerization. Herein, we firstly clearly describe the engineering principles such as mass transport phenomena and energy dissipation related to polymerization processes in microreactors, and then give a great deal of application examples (classified as homogeneous polymerization, heterogeneous polymerization, and photopolymerization) through which readers indeed can further understand these relevant principles. Finally, the remaining challenges associated with the application of microreactor technology for polymerization processes and remarking conclusions are presented. PMID- 30450503 TI - Correction to: Selective Forces Related to Spinocerebellar Ataxia Type 2. AB - The original version of this article unfortunately contained a mistake. The spelling of the surname of one co-author from the publication entitled "Selective Forces Related to Spinocerebellar Ataxia Type 2" that was recently published in the journal "The Cerebelum" was incorrect. PMID- 30450504 TI - Three-dimensional soft tissue analysis of the face following micro-implant supported maxillary skeletal expansion. AB - BACKGROUND: Skeletal maxillary expander (MSE) is one of the more recent expander designs being utilized for skeletal expansion by splitting the midpalatal sutures applying forces through palatal micro-implants. Its effects on the soft tissue remain a question asked by both patients and clinicians. The aim of this study was to analyze and quantify soft tissue facial changes induced by MSE. METHODS: 3D facial images (3dMD) were used to capture face scans of 25 patients generating 3D soft tissue meshes before expansion (T0), right after expansion (T1), and 1 year in retention (T2). MATLAB was then used, utilizing non-rigid iterative closest point algorithm, to align all samples in vertex correspondence and generate averages. Surface mapping of each average, along with its variance, allows for quantification of changes between the three pools of samples in 3D space. RESULTS: The generated 3D p-maps between T0 and T1 demonstrate that statistically significant changes (p < 0.05 and p < 0.01) are localized in the circummaxillary area (paranasal, lips, and both cheeks). Vector map shows a mean displacement of 1.5 mm in the paranasal area. The right cheek showing a mean displacement magnitude of 2.5 mm while the left cheek has a mean of 2.9 mm. Direction of vectors are latero-anterior with more dominant anterior direction. CONCLUSIONS: There are significant changes in paranasal, upper lip, and at both cheeks following expansion using MSE with greater magnitude at the cheeks area. Those changes do not relapse after 1 year (p < 0.05). PMID- 30450506 TI - Solar Photochemistry in Flow. AB - In recent years, photochemistry has been a highly active research field. This renaissance is linked to the upsurge of photoredox catalysis, a versatile platform for synthetic methodologies using visible light photons as a traceless reagent. In contrast with UV, visible light constitutes almost half of the ground solar irradiance, making the use of solar light in chemistry a sustainable and viable possibility. However, the direct use of sunlight to power chemical reactions is still little explored. This can be explained by both the hurdles associated with solar radiation (e.g., its variability, irreproducibility, high IR content, etc.) and the need for a specialized photoreactor. Most of these issues can be tackled with technological solutions, and especially with the recourse to flow chemistry. Flow chemistry goes hand in hand with photochemistry thanks to the uniform irradiation it provides to the reaction. Furthermore, a continuous-flow reactor can be easily integrated with different solar collectors (including compound parabolic concentrators and luminescent solar concentrators) and constitutes the most efficient approach to solar photochemistry. After a description of the characteristics of the solar radiation relevant to chemistry, this chapter critically describes the different type of solar photoreactors and their applications in synthetic organic chemistry. Finally, an outlook on the future of solar photochemistry in flow is included. PMID- 30450507 TI - Study of the enantioselectivity and recognition mechanism of sulfhydryl-compound functionalized gold nanochannel membranes. AB - Two new chiral membranes were prepared by modification of gold nanochannel membranes with D-penicillamine and N-acetyl-L-cysteine and were characterized by scanning electron microscopy and X-ray photoelectron spectroscopy. The effects of key factors such as the gold deposition time, the pH, and the concentration of sodium dihydrogen phosphate on the separation factor are discussed. Chiral resolution of amino acid enantiomers by the chiral membranes was investigated. The experimental results show that the D-penicillamine-modified membrane has good enantioselectivity toward tyrosine and phenylalanine enantiomers, whereas the N acetyl-L-cysteine-modified membrane has good enantioselectivity toward tyrosine and tryptophan enantiomers. Furthermore, the chiral recognition mechanism was studied by density functional theory. The calculation results indicate that the basic chiral recognition system of D-penicillamine complexes involves only one chiral selector and one selected enantiomer, whereas that of N-acetyl-L-cysteine complexes involves two chiral selectors and one selected enantiomer. Finally, the NH3+ group of D-penicillamine is proved to play an important role in enhancing interactions between complexes and improving enantioselectivity. Graphical abstract Enantioselective interactions between amino acid enantiomers and sulfhydryl-compound-functionalized gold nanochannel membranes. PMID- 30450508 TI - Single-layer graphene-coated gold chip for electrochemical surface plasmon resonance study. AB - Surface plasmon resonance (SPR) employs a gold (Au) thin film (ca. 50 nm in thickness) chip to generate a surface plasmonic wave (SPW) for in situ monitoring of the interface/surface, which makes it intrinsically compatible with electrochemistry for combined electrochemical surface plasmon resonance (EC-SPR) investigations. However, conventional SPR Au chips suffers from a high background signal, narrow electrochemical window, and limited electrochemical stability. Presented in this work is a novel SPR chip composed of the Au/long-chain alkane thiol self-assembled monolayer/single-layer graphene (Au/SAM/G) sandwich architecture to address these problems. On this chip, the single-layer graphene serves as a working electrode for electrochemical measurement, and the underlying Au film serves as the SPW support for SPR monitoring; the sandwiched thiol monolayer enables the electrical separation of the graphene and Au film to protect the Au film from electrochemical polarization. Our experiment indicates that the electrochemical window of such a chip extends beyond the hydrogen/oxygen evolution reaction potential on Au with significantly improved electrochemical stability and suppressed background signal. Moreover, its intrinsic SPR sensitivity is completely reserved even compared to that of the conventional SPR Au chip. This Au/SAM/G chip may offer a valuable solution to the EC-SPR investigations in harsh conditions. Graphical abstract ?. PMID- 30450509 TI - Molecular analysis of semen-like odor emitted by chestnut flowers using neutral desorption extractive atmospheric pressure chemical ionization mass spectrometry. AB - Knowledge about the chemical composition of floral volatile organic compounds (VOCs) is valuable in biological studies as well as for the flavor, cosmetic, and fragrance industries. The flowers of Chinese chestnut (Castanea mollissima) emit a distinctive semen-like odor; however, the chemical composition and biological role for the semen-like odor of chestnut flowers remain scarcely studied. Herein, we report the floral VOCs and the pollinators of chestnut flowers. A fast method based on a neutral desorption (ND) device coupled to extractive atmospheric pressure chemical ionization mass spectrometry (EAPCI-MS) was developed for the rapid identification of VOCs from freshly collected chestnut flowers without any chemical pretreatment. Chemical identification was performed using high resolution MS analysis in combination with tandem MS analysis and whenever possible was confirmed by the analysis of standard reference compounds. Twenty volatiles were identified, most of which are nitrogen-containing. Out of the identified volatiles, 1-pyrroline is known to have a semen-like odor and is probably also responsible for the semen-like odor of the chestnut flowers. Four nitrogenous VOCs of chestnut flowers, including 1-pyrroline, 1-piperideine, 2 pyrrolidone, and phenethylamine, were also common in other semen-like odor flowers such as Photinia serrulata, Castanopsis sclerophylla, and Stemona japonica, suggesting similar chemical origin. The main visitors of chestnut flowers were dipteran species, such as Eristalis tenax, Eristalis arvorum, Episyrphus balteatus, Lucilia sericata, Chrysomya megacephala, Chrysochus asclepiadeus, and Adalia bipunctata. Our results suggest that the chestnut flowers and other semen-like odor flowers may present a new type of sapromyophily. This study also indicates that ND-EAPCI-MS provides more sensitive and simpler detection of many VOCs (particularly nitrogen-containing VOCs) than GC-MS and therefore can be used to complement traditional approaches for the higher chemical coverage of VOCs analysis. Graphical abstract ?. PMID- 30450510 TI - Fast discrimination of bacteria using a filter paper-based SERS platform and PLS DA with uncertainty estimation. AB - Rapid and reliable identification of bacteria is an important issue in food, medical, forensic, and environmental sciences; however, conventional procedures are time-consuming and often require extensive financial and human resources. Herein, we present a label-free method for bacterial discrimination using surface enhanced Raman spectroscopy (SERS) and partial least squares discriminant analysis (PLS-DA). Filter paper decorated with gold nanoparticles was fabricated by the dip-coating method and it was utilized as a flexible and highly efficient SERS substrate. Suspensions of bacterial samples from three genera and six species were directly deposited on the filter paper-based SERS substrates before measurements. PLS-DA was successfully employed as a multivariate supervised model to classify and identify bacteria with efficiency, sensitivity, and specificity rates of 100% for all test samples. Variable importance in projection was associated with the presence/absence of some purine metabolites, whereas confidence intervals for each sample in the PLS-DA model were calculated using a resampling bootstrap procedure. Additionally, a potential new species of bacteria was analyzed by the proposed method and the result was in agreement with that obtained via 16S rRNA gene sequence analysis, thereby indicating that the SERS/PLS-DA approach has the potential to be a valuable tool for the discovery of novel bacteria. Graphical abstract This paper describes the discrimination of bacteria at the genus and species levels, after minimal sample preparation, using paper-based SERS substrates and PLS-DA with uncertainty estimation. PMID- 30450511 TI - Online extraction and cleanup-quadrupole time-of-flight tandem mass spectrometry for rapid analysis of bioactive components in natural products. AB - The challenges in direct analysis of a complex system (e.g., natural product, food, biological samples) by mass spectrometry (MS) are the sophisticated sample preparation methods and ionization suppression by matrix interferences. Consequently, a novel online extraction and cleanup-quadrupole time-of-flight tandem mass spectrometry (OLEC-QTOF-MS/MS) system was developed for rapid, efficient, and sensitive analysis of flavonoids in Citri Reticulatae Pericarpium (CRP). For the OLEC strategy, a guard column packed with solid CRP (0.5 mg) and C18 gel was positioned on a manual injection valve, in which interferences with large polarities were online removed by methanol-0.1% formic acid (25:75, v/v) for 3 min, while target flavonoids were online extracted by methanol-0.1% formic acid (70:30, v/v) for 10 min for the subsequent QTOF-MS/MS analysis. The method was validated using official marker, hesperidin, by external standard method. Excellent linear ranges from 0.02 to 52.0 MUg L-1 (R2, 0.9935) with a limit of detection (LOD) of 0.006 MUg were obtained. Acceptable reproducibility (RSD 8.1 and 9.6% for intra- and inter-day variations) and recoveries (from 99.5 to 112.0%) were also attained. In addition, 20 flavonoids in CRP were identified according to their exact mass and fragmentation ions in MS/MS spectra, and five of them were reported for the first time. Obviously, OLEC-QTOF-MS/MS presented several advantages, such as simple operation and high sensitivity, which provided new perspectives for rapid analysis of bioactive components in complex natural products. Graphical Abstract ?. PMID- 30450512 TI - Adieu a Tout Ca: The Editor-in-Chief Takes His Leave. PMID- 30450513 TI - Enhanced Therapeutic Potency of Nanoemulsified Garlic Oil Blend Towards Renal Abnormalities in Pre-diabetic Rats. AB - The therapeutic potency of ultrasonic nanoemulsified garlic oil blend using a non ionic surfactant (Tween 80) was assessed on pre-diabetic Wistar rats with microalbuminuria. The pre-diabetic condition was induced in male albino Wistar rats by supplementing high-fat diet. The prolonged period of the pre-diabetic state caused renal dysfunctioning, which was indicated by microalbuminuria. Treatment of pre-diabetic rats with nanoemulsified garlic oil blend significantly ameliorated the lipid profile (p < 0.001), urinary albumin (p < 0.01), microprotein (p < 0.001), urinary triglycerides (p < 0.01), serum triglycerides (p < 0.01), serum albumin (p < 0.05), and protein levels (p < 0.01) in comparison to treatment of pre-diabetic rats with garlic oil blend or atorvastatin. Similarly, histopathological investigations indicated a remarkable attenuation in the mesangial expansion and proliferation, glomerular and tubular basement membrane thickening, and the tubular lipid deposits on administering nanoemulsified garlic oil blend than garlic oil blend or atorvastatin. Moreover, nanoemulsified garlic oil blend significantly promoted renal podocin gene expression by 3.98-fold (p < 0.001) and attenuated increased urinary podocin level by 2.92-fold (p < 0.01). Thus, our study affirms that the efficacy of garlic oil blend was augmented upon nanoemulsification, which substantially ameliorated the renal abnormalities observed in the pre-diabetic condition than garlic oil blend or atorvastatin. PMID- 30450514 TI - Successful surgical repair for common arterial trunk with anterior crisscross pulmonary arteries and right aortic arch causing right bronchial compression. AB - A 1-month-old girl with common arterial trunk, anteriorly originated crisscross pulmonary arteries, unusual running right aortic arch and severe pulmonary hypertension was initially palliated by bilateral pulmonary artery banding. She developed sudden respiratory failure at 80 days old; and computed tomography revealed that the right main bronchus was severely compressed by the proximal aortic arch. When common arterial trunk repair was performed, the dominant aortic component of the common trunk incorporating both branch pulmonary arteries was cylindrically resected. End-to-end anastomosis of truncal root and distal ascending aorta was therefore performed to anteriorly retract the proximal arch, thereby relieving bronchial stenosis. The patient experienced an uneventful postoperative course, and postoperative computed tomography showed widely patent right main bronchus. PMID- 30450515 TI - Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology. AB - Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as "TDP-43 pathology" in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP 43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology. PMID- 30450516 TI - Postgenomic Properties of Natural Micronutrients. AB - Modern medical approaches to the therapy of various diseases, including cancer, are based on the use of toxic drugs. The unfavorable side effects of traditional medicine could be counterbalanced by addition of natural bioactive substances to conventional therapy due to their mild action on cells combined with the multitargeted effects. To elucidate the real mechanisms of their biological activity, versatile approaches including a number of "omics" such as genomics, transcriptomics, proteomics, and metabolomics are used. This review highlights inclusion of bioactive natural compounds into the therapy of chronic diseases from the viewpoint of modern omics-based nutritional biochemistry. The recently accumulated data argue for necessity to employ nutrigenetic and nutrimetabolomic analyses to prevent or diminish the risk of chronic diseases. PMID- 30450517 TI - Discoordination of Autonomic Support of Functions in the Pathogenesis Gastroesophageal Reflux Disease. AB - A cross-sectional study performed on a continuous sample of 32 patients (mean age 46.36+/-3.31 years) with gastroesophageal reflux disease and excess body weight showed that the disturbance of sympathetic/parasympathetic relationships, disruption of segmental and compensatory increase in the suprasegmental mechanisms of autonomic regulation determines the course of gastroesophageal reflux disease in these patients. PMID- 30450519 TI - Relationship between Cell Receptors and Tumor Cell Sensitivity to Oncolytic Enteroviruses. AB - Replicative ability of 5 oncolytic enterovirus strains was evaluated on a panel of 18 human normal and tumor cells. The capacity of each cell line to support replication of enterovirus strains varied. Cell lines weakly replicating one virus could be highly sensitive to another viral strain. Differences in the expression of CXADR cell receptor did not correlate with susceptibility to infection and replication of Coxsackie B virus, but complete inactivation of CXADR gene and poliovirus receptor gene (PVR) led to loss of the sensitivity to Coxsackie B5 and poliovirus, respectively. Detection of additional expression markers will contribute to understanding the causes of different sensitivity of tumor cells to viruses. PMID- 30450518 TI - New Experimental Facts on the Influence of Secondary Immunodeficiency on the Morphology and Biological Activity of Colorectal Tumor. AB - Colorectal tumors were studied 5 months after carcinogen injection to outbred albino rats with secondary immunodeficiency by common histological and immunobiochemical methods with the use of monoclonal and polyclonal antibodies to Ki-67, Bcl-2, p53, and VEGF. Injection of carcinogen to intact animals led to the formation of adenocarcinomas with high and moderate cell differentiation in the colon, while injection of carcinogen to animals with immunodeficiency was associated with a 1.5-fold higher incidence of GRADE 2 and GRADE 3 adenocarcinomas with more aggressive morphological phenotype and appearance of distant metastases. PMID- 30450520 TI - Effects of Neostigmine and Physostigmine on Activity of Na+,K+-ATPase in Various Subdivisions of Rat Brain. AB - The effects of intramuscular administration of neostigmine and physostigmine on Na+,K+-ATPase activity in various cerebral subdivisions were examined in rats. In CNS and peripheral tissues, both agents rapidly and significantly reduced activity of cholinesterases by 30-50%. The development of intoxication did not change the marker indices of stress reaction. In the cerebral cortex, physostigmine increased Na+,K+-ATPase activity, whereas neostigmine suppressed it. In addition, neostigmine decreased activity of this enzyme in the cerebellum. In contrast, both agents produced no effects on Na+,K+-ATPase activity in the striatum. The data corroborate the view on functional interaction between Na+,K+ ATPase and nicotinic cholinoreceptors in rat cerebral cortex. PMID- 30450521 TI - Effect of Vasopressin V1b Receptor Blockade on Activity of the Hypothalamic Pituitary-Adrenal Axis in Old Monkeys with Depression-Like and Anxious Behavior Subjected to Stress or Injected with Vasopressin. AB - The effect of selective antagonist of the arginine vasopressin (AVP) V1b receptors on the secretion of ACTH and corticosteroids in response to insulin induced hypoglycemia and injection of AVP is studied in old Macaca mulatta females with depression-like and anxious behavior. Intravenous antagonist in a dose of 1.1-1.7 MUg/kg inhibits the increase of ACTH concentration, induced by hypoglycemia or injection of AVP. The degree of increase in the concentrations of hydrocortisone and dehydroepiandrosterone sulfate has not changed or increased. The effects of AVP antagonist prove that previously detected disorders in the reaction of the hypothalamic-pituitary-adrenal system in old Macaca mulatta with depression-like and anxious behavior could be caused by excessive activation of vasopressin V1b receptors on the pituitary corticotrophs, while the use of V1b receptor antagonists seems to be a promising method for prevention of these disorders. PMID- 30450522 TI - Studying of the Mechanisms of Combined Effect of Dexamethasone, Doxorubicin, and Docetaxel on Breast Cancer Cells. AB - The sensitivity of MDA-MB231 breast cancer cells to the effects of pharmacological agents was evaluated by their motility and viability. Dexamethasone, doxorubicin, or docetaxel administered separately in their effective concentration suppressed cell motility (in 16 h) and caused cell death (in 48 h). The strength of the effects increased in the following order: dexa methasone 7.0% (79.3%), at least one documented symptomatic hypoglycemia (<= 3.9 mmol/l) event in the previous 3 months (63.8%), and two or more doses of insulin per day (53.1%). The mean individual HbA1c target was 6.8% in the NEED study cohort, with only 16% of participants reaching it. Most participants [281 (70.1%)] experienced symptomatic hypoglycemia. CONCLUSIONS: The NEED study showed that new insulin users of either basal or premix HM insulin have many unmet needs in the first 6-12 months of treatment. This confirms that in real-life settings novel insulins should be considered in the management of T2DM to reduce the number of symptomatic hypoglycemic events and reach a better HbA1c level. FUNDING: Sanofi, Serbia. PMID- 30450530 TI - GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, lacking effective targeted therapies, and whose underlying mechanisms are still unclear. The gene coding for Gametogenetin-binding protein (GGNBP2), also known as Zinc Finger Protein 403 (ZNF403), is located on chromosome 17q12-q23, a region known as a breast cancer susceptibility locus. We have previously reported that GGNBP2 functions as a tumor suppressor in estrogen receptor-positive breast cancer. The aim of this study was to evaluate the role and mechanisms of GGNBP2 in TNBC. METHODS: The effect of GGNBP2 on TNBC aggressiveness was investigated both in vitro and in vivo. The protein and mRNA expression levels were analyzed by western blotting and reverse transcription quantitative polymerase chain reaction, respectively. Fluorescence-activated cell sorting analysis was used to evaluate the cell cycle distribution and cell apoptosis. Immunohistochemistry was used to determine the expression of GGNBP2 in breast cancer tissues. RESULTS: We find that GGNBP2 expression decreases in TNBC tissues and is associated with the outcome of breast cancer patients. Furthermore, experimental overexpression of GGNBP2 in MDA-MB-231 and Cal51 cells suppresses cell proliferation, migration and invasion, reduces the cancer stem cell subpopulation, and promotes cell apoptosis in vitro as well as inhibits tumor growth in vivo. In these cell models, overexpression of GGNBP2 decreases the activation of IL-6/STAT3 signaling. CONCLUSION: Our data demonstrate that GGNBP2 suppresses cancer aggressiveness by inhibition of IL-6/STAT3 activation in TNBC. PMID- 30450532 TI - The role of adiponectin and leptin in the treatment of ovarian cancer patients. AB - INTRODUCTION: Ovarian cancer is most frequently detected in the advanced stage. Although its pathogenesis is not fully elucidated, it is assumed that body susceptibility and hormonal disorders are responsible. The role of some cytokines as predictors in the treatment process is still investigated. The aim of the study was to determine the relationship of adiponectin and leptin with the disease severity and response to chemotherapy. MATERIALS AND METHODS: 43 ovarian cancer patients were treated in the Department of Oncology of Specialist Hospital in Rybnik. Patients received 5-7 cycles of chemotherapy - the paclitaxel / carboplatin with or without bevacizumab. Using standard ELISA kits before and after chemotherapy, adiponectin and leptin concentrations were determined in the blood serum. RESULTS: The average adiponectin concentration before chemotherapy was found to be 8.83 +/- 3.19 MUg / ml, as compared to 10.37 +/- 4.18 MUg / ml (increase by 17.44%, p < 0.001) after treatment. Mean pre-treatment leptin concentration was 16.89 +/- 15.54 ng / ml, and 21.77 +/- 14.69 ng / ml after chemotherapy (increase by 28.89%, p < 0.01). A positive correlation was found between leptin concentration and age and BMI. There was no relationship of the disease severity with the response to treatment and the concentration of the adipokines. The leptin/adiponectin ratio (L/A) before treatment, correlate with the better the response to chemotherapy. CONCLUSIONS: Adiponectin and leptin do not correlate with the stage of ovarian cancer and response to chemotherapy. The L/A ratio may be considered a predictor of clinical response to treatment. PMID- 30450531 TI - Radical Trachelectomy for Early Stage Cervical Cancer. AB - OPINION STATEMENT: In patients with early-stage cervical cancer, radical hysterectomy and pelvic lymphadenectomy is the gold standard. However, this disease commonly affects women of childbearing age; thus an option to spare fertility is ideal. This option came to fruition in the early 90s when the Dargent procedure or radical trachelectomy was first reported. The procedure has subsequently been modified as technology has improved and now may be performed via minimally invasive techniques. Additionally, with the advent of the sentinel lymph node procedure, the morbidity in this usually young patient population has continued to improve. There is a multitude of data to show that oncologic outcomes, concerning recurrence and mortality, are comparable to radical hysterectomy, as well as obstetrical outcomes are favorable. Data to support its acceptance within the gynecologic oncology community has led to radical trachelectomy being implemented into governing body guidelines and should be offered to appropriate candidates with early-stage cervical cancer who wish to preserve fertility. PMID- 30450533 TI - RESISTANCE TO THYROID HORMONE WITH A MUTATION OF THE THYROID beta RECEPTOR GENE IN AN EIGHT-MONTH OLD INFANT: CASE REPORT. AB - INTRODUCTION: Resistance to thyroid hormone (RTHbeta) is a rare syndrome of impaired tissue responsiveness to thyroid hormones (THs). The disorder has autosomal dominant or recessive pattern of inheritance. Most of reported mutations have been detected in the thyroid hormone receptor beta gene (THRB). CASE REPORT: We present an 8-month-old infant with poor linear growth, decreased body weight, tachycardia, positive family history and suggestive neonatal features of RTHbeta. Both, our patient and his mother has elevated free thyroxine, free triiodothyronine and non-suppressed thyrotropin (TSH) concentration. The fluorescent sequencing analysis showed a heterozygous mutation c.728G>A in TRbeta gene. This pathogenic variant is known to be associated with THR. CONCLUSIONS: The clinical presentation of RTHbeta is variable ranging from isolated biochemical abnormalities to symptoms of thyrotoxicosis or hypothyroidism. The syndrome should be suspected in patients with increased serum TH level, accompanied by a normal or elevated TSH concentration. The affected patients require individualized management. Key words: resistance to thyroid hormone, thyroid hormone receptor beta, infant. PMID- 30450534 TI - [Tc]-99m thyroid scintigraphy in more than 210 cases of permanent congenital hypothyroidism and its correlation with the 1st diagnostic serum thyrotropin. AB - OBJECTIVE: A big part of cases of congenital hypothyroidism(CH) in Iran are transient. This study designed to investigate etiology of permanent CH(PCH) by thyroid scintigraphy(TS) and its relationship with the first diagnostic thyrotropin(TSH). METHODS: During twelve years (2005-2017) of CH screening in southwest Iran, all infants referred with the diagnosis of CH were followed until the 3rd birthday that they were reevaluated for serum T4,TSH after 3-4 weeks treatment discontinuation. If the last test indicated a PCH state (TSH>10mU/L with any levels of T4) TS was performed and based on the results patients were categorized as agenesis, dysgenesis (sublingual, thyroglossal cyst...) and, normal/diffuse goiter (indicating dyshormonogenesis). RESULTS: After exclusion of all transient CH subjects 224 permanent CH were enrolled (52.7%female). Seasonal distributions were as follow: Spring:25.7%, summer:27.9%, autumn:20.3%, and winter:26.1%. No significant differences were found between females and males and different mode of deliveries (55.4% were delivered by cesarean section) regarding T4,TSH(p>0.05). Of a total of 213 performed scan: 20.7% had agenesis, 36.2% had dysgenesis and 43.2% were normal or goiterous. Those with agenesis/dysgenetic thyroid had lower T4 and higher TSH than those with normal scan but they weren't significant. Compared to those who had TSH<40mU/L, patients with TSH>=40mU/L had 46% (95% CI; 1.06-2.02) more risk to have an agenesis or dysgenesis in TS. CONCLUSIONS: more than 40% of PCH subjects are caused by dyshormonogenesis in Iran. Having a TSH>=40mU/L after the first week of life significantly raises the probability of thyroid agenesis/dysgenesis as the cause. PMID- 30450535 TI - Pelvic lymph node metastasis in extramammary Paget disease of the scrotum without inguinal lymph node metastasis. PMID- 30450536 TI - Clinical and dermoscopic features associated with lichen planus-like keratoses that undergo skin biopsy: A single-center, observational study. AB - BACKGROUND/OBJECTIVES: Lichen planus-like keratoses (LPLK) are benign skin lesions that can mimic malignancy; the clinical and dermoscopic features distinguishing lichen planus-like keratoses from skin tumors have not been extensively studied. The objective of this study was to identify dermoscopic features that may prevent unnecessary biopsies of lichen planus-like keratoses. METHODS: Retrospective, observational study of biopsied skin lesions. We compared 355 lichen planus-like keratoses to 118 non-lichen planus-like keratoses lesions with lichen planus-like keratose in the differential diagnosis biopsied from August 1, 2015, to December 31, 2016. The investigators were blinded to the diagnosis of the lesions. A single-center, observational study in a tertiary center. RESULTS: Lichen planus-like keratoses were most frequently non-pigmented (61.7%), truncal (52.1%), and on sun-damaged skin (69.6%); the majority occurred in Whites (95.5%) and females (62.8%). Dermoscopically, lichen planus-like keratoses were more likely than non-lichen planus-like keratoses to have scale (42.5% vs 31.4%, P = 0.03) and orange colour (8.2% vs 0.9%, P = 0.01). Among lesions with peppering (n = 76; 63 lichen planus-like keratose and 13 non-lichen planus-like keratose), coarse +/- fine peppering (73% vs 38.5%, P = 0.02) and peppering as the only feature (34.9% vs 0%, P = 0.01) were associated with lichen planus-like keratoses. CONCLUSIONS: Lichen planus-like keratoses can be challenging to distinguish from benign and malignant skin tumors. The presence of dermoscopic scale and orange colour may aid in the recognition of lichen planus like keratose. Coarse peppering and the presence of peppering as the only dermoscopic feature may further aid the identification of pigmented lichen planus like keratoses. PMID- 30450537 TI - Acute stress responses after indirect exposure to the MH17 airplane crash. AB - People can experience disasters vicariously (indirectly) via conversation, social media, radio, and television, even when not directly involved in a disaster. This study examined whether vicarious exposure to the MH17-airplane crash in Ukraine, with 196 Dutch victims, elicited affective and somatic responses in Dutch adults about 2,600 km away, who happened to participate in an ongoing diary study. Participants (n = 141) filled out a diary three times a day for 30 days on their smartphones. Within-person changes in positive affect (PA) and negative affect (NA) and somatic symptoms after the crash were studied. Additionally, we tested whether between-person differences in response could be explained by age, baseline personality (NEO-FFI-3), and media exposure. The MH17 crash elicited a small within-person decrease in PA and an increase in NA and somatic symptoms. This response waned after 3 days and returned to baseline at day four. The decrease in PA was larger in more extraverted participants but smaller in those higher on neuroticism or conscientiousness. The NA response was smaller in elderly. Personality did not seem to moderate the NA and somatic response, and neither did media exposure. Dutch participants showed small acute somatic and affective responses up till 3 days to a disaster that they had not directly witnessed. Vicariously experienced disasters can thus elicit affective-visceral responses indicative of acute stress reactions. Personality and age explained some of the individual differences in this reaction. PMID- 30450538 TI - Structure of an Engineered Intein Reveals Thiazoline Ring and Provides Mechanistic Insight. AB - We have engineered an intein which spontaneously and reversibly forms a thiazoline ring at the native N-terminal Lys-Cys splice junction. We identified conditions to stablize the thiazoline ring and provide the first crystallographic evidence, at 1.54 A resolution, for its existence at an intein active site. The finding bolsters evidence for a tetrahedral oxythiazolidine splicing intermediate. Additionally, the pivotal mutation maps to a highly conserved B block threonine, which is now seen to play a causative role not only in ground state destabilization of the scissile N-terminal peptide bond, but also in steering the tetrahedral intermediate toward thioester formation, giving new insight into the splicing mechanism. We demonstrate the stability of the thiazoline ring at neutral pH as well as sensitivity to hydrolytic ring opening under acidic conditions. A pH cycling strategy to control N-terminal cleavage is proposed, which may be of interest for biotechnological applications requiring a splicing activity switch, such as for protein recovery in bioprocessing. This article is protected by copyright. All rights reserved. PMID- 30450539 TI - Circulating megakaryocyte and platelet microvesicles correlate with response to ruxolitinib and distinct disease severity in patients with myelofibrosis. PMID- 30450540 TI - A multi-site metastasis-on-a-chip microphysiological system for assessing metastatic preference of cancer cells. AB - Metastatic disease remains one of the primary reasons for cancer-related death, yet the majority of in vitro cancer models focus on the primary tumor sites. Here we describe a metastasis-on-a-chip device, that houses multiple bioengineered 3D organoids, established by a 3D photopatterning technique employing extracellular matrix-derived hydrogel biomaterials. Specifically, cancer cells begin in a colorectal cancer (CRC) organoid, which resides in a single microfluidic chamber connected to multiple downstream chambers in which liver, lung, and endothelial constructs are housed. Under recirculating fluid flow, tumor cells grow in the primary site, eventually enter circulation, and can be tracked via fluorescent imaging. Importantly, we describe that in the current version of this platform, HCT116 CRC cells preferentially home to the liver and lung constructs; the corresponding organs of which CRC metastases arise the most in human patients. We believe that in subsequent studies this platform can be implemented to better understand the mechanisms underlying metastasis, perhaps resulting in identification of targets for intervention. This article is protected by copyright. All rights reserved. PMID- 30450541 TI - Unusual dermoscopic feature of a melanocytic naevus on load bearing plantar skin never pressured because of cerebral palsy. PMID- 30450542 TI - Mechanisms of Unprimed and Dexamethasone-Primed Nonviral Gene Delivery to Human Mesenchymal Stem Cells. AB - Human mesenchymal stem cells (hMSCs) are under intense study for applications of cell and gene therapeutics because of their unique immunomodulatory and regenerative properties. Safe and efficient genetic modification of hMSCs could increase their clinical potential by allowing functional expression of therapeutic transgenes or control over behavior and differentiation. Viral gene delivery is efficient, but suffers from safety issues, while nonviral methods are safe, but highly inefficient, especially in hMSCs. Our lab previously demonstrated that priming cells prior to delivery of DNA complexes with dexamethasone (DEX), an anti-inflammatory glucocorticoid drug, significantly increases hMSC transfection success. This work systematically investigates the mechanisms of hMSC transfection and DEX-mediated enhancement of transfection. Our results show that hMSC transfection and its enhancement by DEX are decreased by inhibiting classical intracellular transport and nuclear import pathways, but DEX transfection priming does not increase cellular or nuclear internalization of plasmid DNA (pDNA). We also show that hMSC transgene expression is largely affected by pDNA promoter and enhancer sequence changes, but DEX-mediated enhancement of transfection is unaffected by any pDNA sequence changes. Furthermore, DEX-mediated transfection enhancement is not the result of increased transgene mRNA transcription or stability. However, DEX-priming increases total protein synthesis by preventing hMSC apoptosis induced by transfection, resulting in increased translation of transgenic protein. DEX may also promote further enhancement of transgenic reporter enzyme activity by other downstream mechanisms. Mechanistic studies of non-viral gene delivery will inform future rationally designed technologies for safe and efficient genetic modification of clinically relevant cell types. This article is protected by copyright. All rights reserved. PMID- 30450543 TI - Optimal designs for the generalized partial credit model. AB - Analysing ordinal data is becoming increasingly important in psychology, especially in the context of item response theory. The generalized partial credit model (GPCM) is probably the most widely used ordinal model and has found application in many large-scale educational assessment studies such as PISA. In the present paper, optimal test designs are investigated for estimating persons' abilities with the GPCM for calibrated tests when item parameters are known from previous studies. We find that local optimality may be achieved by assigning non zero probability only to the first and last categories independently of a person's ability. That is, when using such a design, the GPCM reduces to the dichotomous two-parameter logistic (2PL) model. Since locally optimal designs require the true ability to be known, we consider alternative Bayesian design criteria using weight distributions over the ability parameter space. For symmetric weight distributions, we derive necessary conditions for the optimal one-point design of two response categories to be Bayes optimal. Furthermore, we discuss examples of common symmetric weight distributions and investigate under what circumstances the necessary conditions are also sufficient. Since the 2PL model is a special case of the GPCM, all of these results hold for the 2PL model as well. PMID- 30450544 TI - Combinatorial impact of Sec signal peptides from Bacillus subtilis and bioprocess conditions on heterologous cutinase secretion by Corynebacterium glutamicum. AB - The impact of Sec signal peptides (SPs) from Bacillus subtilis in combination with IPTG concentration and feeding profile was investigated for heterologous protein secretion performance by Corynebacterium glutamicum using cutinase as model enzyme. Based on a comprehensive data set of about 150 bench-scale bioreactor cultivations in fed-batch mode and choosing the cutinase yield as objective, it was shown that relative secretion performance for bioprocesses remains very similar, irrespective of the applied SP enabling Sec mediated cutinase secretion. However, to achieve the maximal absolute cutinase yield, careful adjustment of bioprocess conditions was found to be necessary. A model based, two-step multiple regression approach resembled the collected data in a comprehensive way. Corresponding results suggest that the choice of the heterologous Sec SP and its interaction with the adjusted exponential feeding profile is highly relevant to maximize absolute cutinase yield in this study. For example, the impact of Sec SP is high at low growth rates and low at high growth rates. However, promising SecSPs could be inferred from less complex batch cultivations. The extensive data were also evaluated in terms of cutinase productivity, highlighting the well-known trade-off between yield and productivity in bioprocess development in detail. Conclusively, only the right combination of target protein, Sec SP, and bioprocess conditions is key to success. This article is protected by copyright. All rights reserved. PMID- 30450545 TI - The Effect of Beginning Treatment With Fremanezumab on Headache and Associated Symptoms in the Randomized Phase 2 Study of High Frequency Episodic Migraine: Post-Hoc Analyses on the First 3 Weeks of Treatment. AB - BACKGROUND: Migraine has a substantial impact on daily living, affecting productivity and quality of life for patients and their families. Patients frequently discontinue preventive medications in part because of a delay in headache and symptom relief due to the long dose titration procedures necessary for some migraine preventives. OBJECTIVE: To evaluate the efficacy of fremanezumab, a selective monoclonal CGRP ligand antibody, during the first 3 weeks of therapy in patients with high-frequency episodic migraine (HFEM) to relieve migraine headaches and associated symptoms and to reduce use of acute migraine medications. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, phase 2 study, patients with HFEM who met inclusion criteria and were 80% compliant with daily headache diary entry were randomized and treated once every 28 days for 3 months with either placebo or fremanezumab 225 or 675 mg. Compared to placebo, both doses of fremanezumab significantly reduced the primary endpoint of the HFEM study, change in the number of migraine days in month 3 relative to baseline. Herein, we performed post-hoc analyses to assess the efficacy of each dose during the first 3 weeks of treatment to reduce migraine headache parameters, associated migraine symptoms, and the consumption of acute migraine medications. RESULTS: The sample consisted of 297 study participants. Compared to placebo, decreases in migraine days were seen during the first week of therapy for both fremanezumab doses with least square mean (LSM) differences between fremanezumab 225 mg and placebo of -0.93 (95% CI: 1.36, -0.49) and between 675 mg dose and placebo of -1.02 (95% CI: -1.46, -0.58), both P < .0001. This benefit was maintained through the second week of therapy for the 225 and 675 mg doses, respectively, (-0.76 (95% CI: -1.11, -0.40) P < .0001, -.79 (95% CI: -1.15, -0.44) P < .0001) and the third week of therapy ( 0.64 (95% CI: -0.97, -0.30) P = .0003 and -0.64 (95% CI: -0.98, -0.30) P = .0003). Likewise in the first week, patients recorded reductions in associated migraine symptoms such as nausea, vomiting, photophobia, and phonophobia, which continued through weeks 2 and 3. There were also reductions in days with acute medication use to treat migraine for the 225 and 675 mg fremanezumab doses compared to placebo. In the first week, LSM differences between 225 mg and placebo were -1.02 (95% CI: -1.39, -0.64) and between 675 mg and placebo were 1.06 (95% CI: -1.39, -0.64) P < .0001); for the second and third weeks (-1.01 (95% CI: -1.14, -0.55) P < .0001; -.90 (95% CI: -1.04, -0.44) P < .0001; -.91 (95% CI: -0.92, -0.34) P < .0001; and -.83 (95% CI: -0.84, -0.26) P = .0002), respectively. CONCLUSION: Fremanezumab treatment resulted in a rapid preventive response in patients with HFEM, with reductions seen in several headache parameters and migraine symptoms within the first week after therapy initiation and continuing during the second and third weeks. Patients also were able to rapidly reduce their use of acute medications to treat migraine attacks. The trial is registered at Clinicaltrials.gov as NCT02025556. PMID- 30450546 TI - Periodontal condition in Japanese coronary heart disease patients: A comparison between coronary and non-coronary heart diseases. AB - OBJECTIVE: The aim of this clinical trial was to assess the relationship between periodontal bacterial burden and coronary heart disease (CHD) in Japanese population. BACKGROUND: Many epidemiological reports suggest that periodontitis is a risk factor for CHD; however, the influence of each periodontal bacterium and periodontal condition in Japanese CHD patients is unclear. METHODS: We studied 897 patients with cardiovascular diseases in Tokyo Medical and Dental University Hospital from May 2012 to August 2015. The subjects were divided into six groups according to age and the existence of CHD (46-60 years with CHD (n = 56): Group YC, 61-70 years with CHD (n = 106): Group MC, over 70 years with CHD (n = 177): Group EC, 46-60 years without CHD (n = 152): Group YN, 61-70 years without CHD (n = 216): Group MN, and over 70 years without CHD (n = 190): Group EN). RESULTS: We found that the patients in Groups MC and EC had deeper periodontal pocket compared to the patients in Group YN (P < 0.05), although there was no statistical difference of pocket depth between Group YC and Groups MC and EC. Many subjects in Group EC had high anti-Porphyromonas gingivalis and anti-Prevotella intermedia antibodies in comparison to Group EN (P < 0.05). The CHD patients generally had worse oral condition than the non-CHD patients. Elderly with CHD had a higher level of serum anti-Porphyromonas gingivalis antibody and anti-Prevotella intermedia antibody than those without CHD. CONCLUSION: Increased periodontal infection was found in Japanese CHD patients compared to non-CHD patients. PMID- 30450547 TI - Ultrasonographic assessment of costochondral cartilage for microtia reconstruction. PMID- 30450548 TI - Explicit modelling of radon-222 in HydroGeoSphere during steady state and dynamic transient storage. AB - Transient storage zones (TSZs) are located at the interface of rivers and their abutting aquifers and play an important role in hydrological and biogeochemical functioning of rivers. The natural radioactive tracer 222 Rn is a particularly well-suited tracer for studying TSZ water exchange and age. Although 222 Rn measurement techniques have developed rapidly, there has been less progress in modelling 222 Rn activities. Here we combine field measurements with the numerical model HydroGeoSphere (HGS) to simulate 222 Rn emanation, decay and transport during steady state (riffle-pool sequence) and transient (bank storage) conditions. Comparing the HGS mean water ages with the conventional 222 Rn apparent ages during steady state showed a systemic underestimation of apparent age with increasing dispersion and especially where large concentration gradients exist within the subsurface. A large underestimation of apparent water age was also observed at the advective front during bank storage where regional high 222 Rn groundwater mixes with newly infiltrated surface water. The explicit modelling of radiogenic tracers such as 222 Rn offers a physical interpretation of this data as well as a useful way to test simplified apparent age models. PMID- 30450549 TI - Regulating for a Reason: Emotion Regulation Goals are Linked to Spontaneous Strategy Use. AB - OBJECTIVE: We investigated how individual differences in emotion regulation goals predict emotion regulation strategy use in daily life. METHOD: Across three studies, we assessed two common types of emotion regulation goals (hedonic, social) and strategies spanning the entire process model of emotion regulation (Gross, 1998b). We conducted two studies using global measures with undergraduates (N = 394; 18-25 years; 69% female; 56% European-American) and community members (N = 302; 19-74 years; 50% female; 75% European-American), and a 9-day daily diary study with another community sample (N = 272; 23-85 years; 50% female; 84% European-American). RESULTS: Globally and in daily life, pro hedonic goals were positively associated with all antecedent-focused strategies (situation selection, situation modification, distraction, reappraisal), pro social goals were positively linked to reappraisal, and impression management goals positively predicted suppression. Contra-hedonic goals were negatively associated with reappraisal and positively associated with suppression in some studies. CONCLUSIONS: The reasons why people regulate their emotions are predictive of the strategies they use in daily life. These links may be functional, such that people typically use strategies that are suitable for their goals. These findings demonstrate the value of an individual difference approach and highlight the motivational component of emotion regulation. This article is protected by copyright. All rights reserved. PMID- 30450550 TI - Mesomelia-synostoses syndrome: Description of a patient presenting a monoallelic expression of SULF1 without alterations in the SLCOA1 gene. PMID- 30450551 TI - Healing differences in narrow diameter implants submitted to immediate and conventional loading in mandibular overdentures: A randomized clinical trial. AB - BACKGROUND: Biological responses to different loading protocols during the bone healing phase in subjects with long time since edentulism, rehabilitated with narrow diameter implants (NDIs) to retain mandibular overdentures (MOs), are still unavailable. OBJECTIVE: This randomized clinical trial compared the peri implant health, implant stability, and concentrations of pro- and anti inflammatory cytokines in the peri-implant crevicular fluid (PICF) in mandibular edentulous patients under conventional (CL) and immediate loading (IML) during healing. METHODOLOGY: Twenty totally edentulous patients received two NDIs (2.9 * 10 mm, Facility NeoPoros) placed in mandible anterior region and were randomly assigned to two loading protocols: CL (n = 10) and IML (n = 10). The following clinical outcomes were evaluated 1, 2, 4, 8, and 12 weeks after surgery: (a) peri implant tissue health (gingival index-GI, plaque index-PI, calculus-presence CP, probing depth-PD, and bleeding on probing-BOP); (b) implant stability quotient (ISQ); and (c) IL-1beta, IL-6, IL-10, and TNF-alpha levels in the PICF analyzed by ELISA. RESULTS: The CL group showed significantly higher CP scores at weeks 8 and 12. The IML group showed significantly higher GI from the first week onwards. The IML group presented significantly lower PD at all follow-up times, and higher BOP rates than CL at week 12. The ISQ values of the CL group were higher than those of the IML group, except at week 4. The IML group released significantly more TNF-alpha between weeks 1 and 4 and more IL-1beta during week 4-12, while releasing less IL-6 until week 8, mainly at week 2 (-47.6%). The release of IL-10 was similar for both groups and increased progressively over time. At week 12, the IML group released 45.74% more IL-10 than the CL group. The survival rates were 95% and 90% for CL and IML, respectively. CONCLUSION: The IML group presented more favorable PD at all evaluation times; the differences between the other clinical parameters were less systematic. The implant stability and the inflammatory marker concentrations were more stable in the CL group. PMID- 30450552 TI - Experimental animal model for assessment of tracheal epithelium regeneration. AB - OBJECTIVES/HYPOTHESIS: To develop an experimental model in rabbits for assessment of tracheal epithelium regeneration through application of either natural or artificial polymer scaffolds. STUDY DESIGN: First, we identified the size of full thickness mucosal defect, which does not allow self-healing (a "critical defect"), thus representing an adequate experimental model for regenerative therapy of tracheal epithelium damage. Then, two methods of polymer scaffold fixation at the site of the epithelium defect were compared: suturing and fixation with a stent. This was done through: 1) formation of a full-thickness anterolateral mucosal defect by tracheal mucosa excision; and 2) fixation of the scaffold at the site of the tracheal epithelium defect using sutures (through a tracheal wall "window") or a vascular stent (through a small tracheal incision). RESULTS: The dimension of a critical anterolateral mucosal defect of the trachea for rabbits was found to be 1.5 cm in length and more than 50% of the tracheal circumference. Fixation of the scaffold with a stent proved to be more efficient due to a uniform distribution of the pressure over the entire surface of the scaffold, whereas the suturing of the scaffold provided unsatisfactory results. In addition, fixation of the scaffold by suturing required formation of a large "window" in the tracheal wall. Thus, using the stent appeared to be technically less complicated and much less traumatic as compared to suturing. CONCLUSION: We present an experimental in vivo animal model of tracheal epithelium injury and recovery. It can be effectively used with certain further modifications as a basis for routine testing of bioengineered constructs. LEVEL OF EVIDENCE: NA. Laryngoscope, 2018. PMID- 30450553 TI - Ventricular global longitudinal strain is altered in children with sickle cell disease. AB - Cardiac disease is the primary cause of death in sickle cell disease (SCD). Right and left ventricular global longitudinal strain (RVGLS, LVGLS) are early markers of systolic dysfunction but are not well investigated among children with SCD. One hundred and forty-three patients with HbSS or HbSbeta0 -thalassaemia (median age 11 years, range 5-19 years) and 71 controls matched for age and sex were compared. RVGLS and LVGLS were measured and compared with conventional measures of echocardiography and markers of haemolysis and inflammation. RVGLS was higher in children with SCD than in controls (-25.72% +/- 3.45% vs. -24.54% +/- 2.41%, P = 0.005); LVGLS was not different. RVGLS decreased with older age in children with SCD (rho = 0.338, P < 0.001) but not among controls. Decreased RVGLS was associated with increased left atrial end diastolic volume (rho = 0.181, P = 0.04); RVGLS increased with cardiac output (r = -0.279, P = 0.01). RVGLS and LVGLS were not associated with disease-modifying therapies, degree of anaemia or haemolysis markers. Elevated RVGLS may indicate an early RV compensatory mechanism in response to upstream myocardial insults and elevated cardiac output. Global longitudinal strain may serve as an early marker of altered myocardial function in children with SCD. PMID- 30450554 TI - Characterizing and Enhancing Virus Removal by Protein A Chromatography. AB - Protein A chromatography is an effective capture step to separate Fc-containing biopharmaceuticals from cell culture impurities, but is generally not effective for virus removal, which tends to vary among different products. Previous findings have pointed to the differences in feedstocks to Protein A, composed of the products and other cell culture-related impurities. In order to separate the effect of the feedstock components on virus removal, and understand why certain monoclonal antibody (mAb) products have low virus log reduction values (LRVs) across Protein A chromatography, we investigated the partitioning of three types of viruses on Eshmuno(r) A columns. Using pure mAbs, we found that low LRVs were correlated with the presence of the particular mAb product itself, causing altered partitioning patterns. Three virus types were tested, and the trend in partitioning was the same for Retrovirus-like particles (RVLPs) expressed in the cell substrate, and its model virus Xenotropic Murine Leukemia Virus (XMuLV), while slightly different for Murine Minute Virus (MMV). These results were extended from previous observation described by Bach and Connell-Crowley (2015) studying XMuLV partitioning on MabSelect SuRe (MSS) columns, providing further evidence using additional types of viruses and resin. Other product-specific cell culture impurities in Harvested Cell Culture Fluid (HCCF) played a lesser role in causing low LRVs. In addition, using high throughput screening (HTS) methods and Eshmuno(r) A resin plates, we identified excipients with ionic and hydrophobic properties that could potentially alleviate the mAb-induced LRV reduction, indicating that both ionic and hydrophobic interactions were involved. More excipients of such nature or combinations, once optimized, can potentially be used as load and/or wash additives to improve virus removal by Protein A. We have demonstrated that HTS is a valuable tool for this type of screening, whether to gain deeper understanding of a mechanism, or to provide guidance during optimization of Protein A process with improved virus removal. This article is protected by copyright. All rights reserved. PMID- 30450555 TI - Endoscopic endonasal resection of adenoid cystic carcinoma of the sinonasal tract and skull base. AB - OBJECTIVES: Adenoid cystic carcinoma (ACC) is a locally aggressive salivary gland malignancy prone to perineural invasion and local recurrences. In the literature, few data exist to guide treatment when this tumor involves the paranasal sinuses and skull base. We report our experience in the management of sinonasal adenoid cystic carcinoma through an endoscopic endonasal approach. METHODS: Retrospective analysis of patients affected by sinonasal ACC treated through an endoscopic endonasal approach from 1997 to 2015, managed at the Universities of Varese and Brescia, Italy. RESULTS: Thirty-four patients were included in the analysis. The ethmoid sinus (55.9%), nasal septum (17.7%), maxillary sinus (11.7%), and sphenoid sinus (5.9%) were the primary tumor sites encountered. Twenty patients (58.8%) presented with T3 or T4, without any systemic spreading. Twenty-nine patients underwent endoscopic transnasal resection, whereas the involvement of the anterior skull base in five cases required a transnasal endoscopic craniectomy. Overall, 20 of 34 (58.8%) patients received some form of adjuvant radiotherapy. The follow-up ranged from 12 to 202 months (mean of 73.2 months). The 5-year overall, disease-specific, and recurrence-free survival rates were 86.5% +/- 7.39%, 86.5% +/- 7.39%, and 71.8% +/- 8.67%, respectively. CONCLUSIONS: The endoscopic approach is safe and effective for selected sinonasal ACC, reducing the comorbidities of the external approaches while producing similar oncological results. High T-stage, grade III histology, positive surgical margins, and perineural infiltration all have an important negative prognostic value. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30450556 TI - Skin tests in patients with delayed and immediate hypersensitivity to heparins: A case series. PMID- 30450557 TI - Ligamentous structures in human glans penis. AB - The corpus spongiosum reportedly occupies a larger proportion of the human glans penis than does the penile body, embedding the end of the corpus cavernosus (CC). However, anatomic descriptions about the fibrous structures of glans penis in the literature cause confusion during dissection and reconstructive surgery. Forty five penises of formalin-embalmed cadavers were dissected sagittally along the course of the distal urethra and observed macroscopically. Dense connective tissues adjacent to the fossa navicularis and spongiosum parts of the glans were cropped, and underwent Masson's trichrome and Verhoeff-Van-Gieson staining. Most (55.5%) of the specimens had distinct fibrous bands toward the distal tips of the glans penis, which elongated from the tunica albuginea of the CC. They comprised longitudinal collagen bundles continuous to the outer longitudinal layer of the tunica albuginea covering the CC and were intermingled with sparse elastic fibres. This architecture either did not reach the distal end of the glans penis (35.5% of cases), or was obscure or dispersed in all directions (9.0% of cases). The structural dimorphism and the variations in the ratio of dense connective tissue components of the fibrous skeleton are considered to contribute to the varying degrees of flexibility, distensibility and rigidity of the human glans penis. PMID- 30450559 TI - The 3D Isodose Structure based method for clinical dose distributions comparison in pretreatment patient-QA. AB - INTRODUCTION: Before the approval of any IMRT or VMAT treatment plan, QA tests are needed to reveal potential errors such as an inaccurate calculation of the dose distribution, the failure of the record-and-verify system or the delivery system of the linear accelerator. Currently the method adopted to compare the measured dose distribution with the TPS calculated dose distribution is gamma analysis. However gamma analysis has been shown to be ineffective for the clinical evaluation of treatment plans. We proposed and tested a new method (the Isodose Structures method) alternative to gamma analysis. METHOD: Different errors were introduced in thirty-three error-free Head and Neck plans. The modified plans were recalculated using TPS software and the dose distributions obtained were compared to those of the original (error-free) plans. The comparison was performed using gamma analysis and the new method. The target was to calculate overall and organ specific gamma passing rates as well as the Overlapping Ratio (OR) and Volume Ratio (VR) factors of the Isodose Structures method for each error-included plan. RESULTS: Eight of the thirty-three plans passed both the gamma analysis and the Isodose Structures (IS) analysis, ten plans did not pass either of them, while thirteen plans which did not pass the IS analysis, passed the gamma analysis. Two plans which did not pass gamma, passed IS analysis. Furthermore, DVH metrics could not detect the low agreement between the dose distributions of two error-free plans and the respective modified plans. In this case, the IS analysis also allowed us to detect clinically meaningful differences between measured and TPS dose distributions. CONCLUSIONS: The IS method analysis clearly showed a high efficiency in detecting clinically relevant differences between TPS and measured dose distributions not seen in gamma analysis and in DVH based metrics. Therefore IS analysis proved to be a valid tool, alternative to gamma analysis for dose comparison in patient-specific QA test. This article is protected by copyright. All rights reserved. PMID- 30450558 TI - Characterization and oxidative stability of oils and bioactive compounds of the fruits of Byrsonima cydoniifolia A. Juss. at different ripening stages. AB - BACKGROUND: Fruits present high concentrations of bioactive compounds that are beneficial to health due to their antioxidant properties. New alternatives to vegetable oils with such properties have been studied. We determined the chemical compounds of Byrsonima cydoniifolia A. Juss. fruits in three ripening stages as well as the optical behavior and quality level of the oils. RESULTS: The ripening stage affected the chemical composition of the fruits and oils. The fruits presented high values of bioactive compounds, as ascorbic acid (1.46-1.82g kg-1 ) and total phenols (3.54-15.91g GAE kg-1 ), as well as showed excellent antioxidant activity. The ripe fruits showed high content of carotenoids (45.90mg kg-1 ) were lutein is the major carotenoid, representing 55.56%. The oil of the ripe fruits showed high lipid content (252.6g kg-1 ) and contained oleic (521.83g kg-1 ), palmitic (209.13g kg-1 ) and linoleic (195.4g kg-1 ) fatty acids. The oil of ripe fruits showed the best oxidative stability, with longer induction period (22.29h) than the other oils. CONCLUSION: Fruits of Byrsonima cydoniifolia A. Juss. demonstrate to possess a promising potential for the use as functional ingredients. The oil of the ripe fruits was more stable and presents great potential to be used edible purposes. This article is protected by copyright. All rights reserved. PMID- 30450560 TI - Three novel mutations of the ATP2A2 gene in Chinese patients with Darier disease. PMID- 30450561 TI - Rapid quantification of quinine by multi-stacking in a portable microchip electrophoresis system. AB - A new multi-stacking pre-concentration procedure based on field-enhanced sample injection (FESI), field-amplified sample stacking, and transient isotachophoresis was developed and implemented in a compact microchip electrophoresis (MCE) with a double T-junction glass chip, coupled with an on-chip capacitively coupled contactless conductivity detection (C4 D) system. A mixture of the cationic target analyte and the terminating electrolyte (TE) from the two sample reservoirs was injected under FESI conditions within the two sample-loading channels. At the double T-junction, the stacked analyte zones were further concentrated under field-amplified stacking conditions and then subsequently focused by transient-isotachophoresis and separated along the separation channels. The proposed multi-stacking strategy was verified under a Universal Serial Bus (USB) fluorescence microscope employing Rhodamine 6G as the model analyte. This developed approach was subsequently used to monitor the target quinine present in human plasma samples. The total analysis time for quinine was approximately 200 s with a sensitivity enhancement factor of approximately 61 when compared to the typical gated injection. The detection and quantification limits of the developed approach for quinine were 3.0 MUg/mL and 10 MUg/mL, respectively, with intraday and interday repeatability (%RSDs, n = 5) of 3.6 and 4.4%. Recoveries in spiked human plasma were 98.1-99.8%. PMID- 30450562 TI - Death due to sepsis in patients diagnosed with prostate cancer. AB - BACKGROUND: To examine the prevalence and determinants of death due to sepsis in patients diagnosed with prostate cancer (Pca). PATIENTS AND METHODS: We performed a retrospective analysis of 910 986 patients diagnosed with Pca between 1992 and 2010 identified from the Surveillance, Epidemiology, and End Results (SEER) database. Prevalence of death due to sepsis after diagnosis was determined. Trends in incidence-based mortality rate (IBMR) due to sepsis were compared with those of patients diagnosed with other common cancers. Competing risk analysis was utilized to examine the determinants of the endpoint of sepsis-specific death (SSD) in Pca patients. RESULTS: Of the Pca patients examined, 2593 died because of sepsis. Sepsis-related IBMR in Pca patients increased by 19-folds from 0.62/1000 000 in 1992-12.26/1000 000 in 2010. Compared with other selected cancers, patients with Pca had the highest IBMR due to sepsis post-cancer diagnosis, and the highest annual percentage change in IBMR due to sepsis (average annual percentage change, 13.1%; 95%CI, 9.4-16.9%). Age, race, education, marital status, and definitive therapy were all significant predictors of death due to sepsis after Pca diagnosis (all P values < 0.05). CONCLUSION: Patients diagnosed with Pca are at increased risk of dying from sepsis, and the sepsis-related IBMR in these patients is increasing over time. There are significant disparities in the outcome of sepsis among Pca patients that require further research. PMID- 30450563 TI - Identification of a novel A allele with c.106del in the ABO*A1.02. PMID- 30450565 TI - Transcriptional control of natural killer cell differentiation. AB - Natural killer (NK) cells are highly specialized cytotoxic lymphocytes that provide protection against pathogens and malignant cells. They develop from common lymphoid progenitors via a multi-stage lineage commitment and differentiation process that gives rise to mature NK cells with potent cytotoxic functionality. Although generally considered cells of the innate immune system, recent studies have demonstrated that NK cells have the capacity to mount immune responses with features of adaptive immunity, including robust antigen-specific clonal-like expansion and the generation of long-lived memory cells that mediate enhanced recall responses. Here, we discuss specific transcription factors that have been shown to commonly and uniquely regulate NK cell development and effector and memory responses in experimental mouse models. PMID- 30450564 TI - A comparison of embalming fluids on the structures and properties of tissue in human cadavers. AB - Cadaveric material has long been used to teach anatomy and more recently to train students in clinical skills. The aim of this study was to develop a systematic approach to compare the impact of four embalming solutions on the tissues of human cadavers. To this end, a formalin-based solution, Thiel, Genelyn and Imperial College London soft-preservation (ICL-SP) solution were compared. The effect of these chemicals on the properties of the tissue was assessed by measuring the range of motion (ROM) of joints and measuring the dimensions of different structures on computed tomography (CT) images before and after embalming. The mean changes in the ratio (angle to ROM) differed statistically between embalming methods (Welch Statistic 3,1.672 = 67.213, p = 0.026). Thiel embalmed cadavers showed an increase in range of motion while ICL-SP cadavers remained relatively the same. Genelyn and formalin embalmed cadavers registered a notable decrease in range of motion. Furthermore, investigation into the impact of the embalming chemicals on the dimensions of internal organs and vessels revealed that Thiel embalming technique leads to a decrease in the dimension of the cardiovascular system alone while formalin-based solutions maintain the shape of the organs and vessels investigated. Our findings suggest that the joints of cadavers' embalmed using ICL-SP technique may faithfully mimic that of unembalmed cadavers and that formalin is necessary to retain shape and size of the organs and vessels investigated in this study. Despite this, a study with larger numbers of cadavers is required to confirm these findings. PMID- 30450566 TI - Measuring Thwarted Belongingness and Perceived Burdensomeness in Clinically Depressed and Suicidal Youth: Refinement and Reduction of the Interpersonal Needs Questionnaire. AB - OBJECTIVE: The Interpersonal-Psychological Theory of Suicide (IPTS) posits two constructs (thwarted belongingness (TB) and perceived burdensomeness (PB)) contribute to suicide ideation. These constructs are typically measured by the Interpersonal Needs Questionnaire (INQ); however, available INQ versions have demonstrated poor psychometric properties with youth. This study examined the INQ using Item Response Theory (IRT) to refine and reduce the scale for clinically depressed and suicidal youth. METHODS: Participants were 378 youth (Age M (SD) = 14.78 (1.41), 82.54% female) who completed the INQ. The INQ contains 25 items across two subscales (i.e., TB and PB) rated on a 7-point Likert-type scale. Rating scale performance, dimensionality, model fit, and instrument-level statistics were examined using IRT methodology. Post hoc analyses were performed to further reduce the scale. RESULTS: The INQ was reduced from 25 to 10 items (five per subscale), and response options were refined to four choices. Correlations between original and IRT-refined items were large (r = .97 for PB; r = .98 for TB). Additional item-level (e.g., fit, difficulty) and instrument-level (e.g., dimensionality) characteristics were examined. CONCLUSIONS: The newly refined INQ resulted in improved scale reliability and validity. The psychometrically improved INQ can assist clinicians and researchers identify adolescents at risk of experiencing suicide ideation. PMID- 30450567 TI - Expression of glial cells molecules in the optic nerve of adult dromedary camel (Camelus dromedarius): A histological and immunohistochemical analysis. AB - The optic nerve (ON) is an important organ in the visual system of animals, which transfers electrical impulses towards the brain from the retina. High enrichment of glial cells in ON is known to support neuron and regulate retinal homoeostasis. However, research on immunohistochemical of glial cells proteins in the camel is scanty in available literature. Hence, the current work is an attempt to investigate the histomorphology of camel ON with regard to the expression patterns of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and Iba1 for the three glial subtypes, namely astrocytes, oligodendrocytes and microglia, respectively. Optic nerves from fourteen dromedary camels were dissected and preserved in 10% formalin. Then, the paraffin embedding sections were subjected for histochemical and immunohistochemical analysis. Our results demonstrated that ON axons aggregate into fascicles that surrounded by light and densely stained glial cells. Then, we examined the myelin sheath using Heidenhain's and Mallory's phosphotungstic acid staining. Immunoassay results revealed that GFAP is enriched in the ON and distributed evenly, whereas MBP and Iba1 were present at scanty levels. Further analysis of mRNA level of GFAP, MBP and Iba1 in the ON confirmed an elevation of GFAP expression compared to MBP and Iba1. We further found partial co-localization of different types of glial cells that reflect their coordinated function in the ON. Although our data provide the first evidence for differential expression pattern of glial proteins, further molecular studies still required to reveal the specific function of these molecules in the camel ON. PMID- 30450568 TI - Definitive radiotherapy for Merkel cell carcinoma in the setting of epidermolysis bullosa simplex. PMID- 30450569 TI - Long noncoding RNA STXBP5-AS1 inhibits cell proliferation, migration, and invasion via preventing the PI3K/AKT against STXBP5 expression in non-small-cell lung carcinoma. AB - Long noncoding RNAs participate in carcinogenesis and tumor progression in non small-cell lung carcinoma (NSCLC), but the mechanisms underlying NSCLC tumorigenesis remain to be fully elucidated. Here, we reported the functional role and potential mechanism of long noncoding RNA syntaxin-binding protein 5 antisense RNA 1 (STXBP5-AS1) in NSCLC. First, our data revealed that the expression levels of STXBP5-AS1 in 31 NSCLC tissues were lower than in adjacent tissues using quantitative polymerase chain reaction (qPCR) and its expression was significantly associated with tumor metastasis of NSCLC patients. Moreover, CCK-8, scratch wound healing and transwell assay suggested that upregulation of STXBP5-AS1 repressed the proliferation, migration, and invasion in A549, NCI H292, and NCI-H460 cells. To explore the potential mechanism of STXBP5-AS1 in NSCLC, we first investigated the relationship among STXBP5-AS1, STXBP5, and AKT1 in A549 cells. Results indicated that STXBP5-AS1 was negatively related with STXBP5 and AKT1 at messenger RNA expression level using qPCR. In addition, we observed that STXBP5-AS1 had reverse effects on the protein levels of STXBP5 and phosphorylated AKT1 (p-AKT1) in A549 cells via Western blot assay, despite no significant effects on AKT1. Subsequently, LY294002, as the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway inhibitor, was used to further confirm the regulatory mechanism of STXBP5-AS1, which showed that knockdown of STXBP5-AS1 could rescue the expression of STXBP5 and p-AKT1 protein expression levels in A549 cells. Taken together, our results suggested that STXBP5-AS1, as a tumor suppressor, inhibits cell proliferation, migration, and invasion by preventing the PI3K/AKT against STXBP5 expression in NSCLC. PMID- 30450570 TI - In this Issue: Graphical Abstracts. PMID- 30450571 TI - Corrigendum. PMID- 30450572 TI - Bioimpedance vector analysis for the detection of extracellular volume overload and sarcopenia in systemic AL amyloidosis. PMID- 30450573 TI - Noninvasive quantification of oxygen saturation in the portal and hepatic veins in healthy mice and those with colorectal liver metastases using QSM MRI. AB - PURPOSE: This preclinical study investigated the use of QSM MRI to noninvasively measure venous oxygen saturation (SvO2) in the hepatic and portal veins. METHODS: QSM data were acquired from a cohort of healthy mice (n = 10) on a 9.4 Tesla MRI scanner under normoxic and hyperoxic conditions. Susceptibility was measured in the portal and hepatic veins and used to calculate SvO2 in each vessel under each condition. Blood was extracted from the inferior vena cava of 3 of the mice under each condition, and SvO2 was measured with a blood gas analyzer for comparison. QSM data were also acquired from a cohort of mice bearing liver tumors under normoxic conditions. Susceptibility was measured, and SvO2 calculated in the portal and hepatic veins and compared to the healthy mice. Statistical significance was assessed using a Wilcoxon matched-pairs signed rank test (normoxic vs. hyperoxic) or a Mann-Whitney test (healthy vs. tumor bearing). RESULTS: SvO2 calculated from QSM measurements in healthy mice under hyperoxia showed significant increases of 15% in the portal vein (P < 0.05) and 21% in the hepatic vein (P < 0.01) versus normoxia. These values agreed with inferior vena cava measurements from the blood gas analyzer (26% increase). SvO2 in the hepatic vein was significantly lower in the colorectal liver metastases cohort (30% +/- 11%) than the healthy mice (53% +/- 17%) (P < 0.05); differences in the portal vein were not significant. CONCLUSION: QSM is a feasible tool for noninvasively measuring SvO2 in the liver and can detect differences due to increased oxygen consumption in livers bearing colorectal metastases. PMID- 30450574 TI - Saposin C is a frequent target of paraproteins in Gaucher disease-associated MGUS/multiple myeloma. AB - Patients with Gaucher disease (GD) have an increased risk of monoclonal gammopathies for which antigenic targets might play a role in their pathogenesis. Here we report the identification of saposin C (sapC) as high-titre (1:1 000 000) target structure of 7/16 GD-associated paraproteins. Anti-sapC immunoglobulin (Ig) showed identity with the paraprotein Ig type and subclass in each patient that showed anti-sapC immunoreactivity. Absorption and depletion studies completely removed the paraprotein from the sera of GD patients. No immunoreactivity against sapC was detected in healthy donors and in other plasma cell dyscrasias, demonstrating that anti-sapC reactivity is highly restricted to GD. Several uncharacterized forms of post-translational modified sapC were detected but their role in the pathogenesis is not clear. We confirm the frequent presence of low-titre (1:250) anti-lysolipid reactivities in the sera of GD patients but we could show that this immunoreactivity is not mediated by the paraprotein and is not restricted to GD patients. PMID- 30450575 TI - Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008. AB - Asparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity >= 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13.8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4.68 * 10-8 ). We further identified two signals on chromosome 6 in relation to HLA-DQA1 (P = 9.37 * 10-6 ) and TAP2 (P = 1.59 * 10-5 ). This study associated variants in CNOT3 and in the human leucocyte antigen (HLA) region with PEG-asparaginase hypersensitivity, suggesting that not only genetic variations in the HLA region, but also regulation of these genes are of importance in the biology of this toxicity. Furthermore, our study emphasizes the importance of using asparaginase enzyme activity measurements to identify PEG-asparaginase hypersensitivity. PMID- 30450576 TI - Assessing Suicidal and NonSuicidal Self-Injury via In-Depth Interview or Self Report: Balancing Assessment Effort and Results. AB - OBJECTIVE: Both suicide and nonsuicidal self-injury (NSSI) represent major public health concerns, and effective assessment, management, and treatment requires assessment tools that can simultaneously be quick and accurate. This study compared the validity of a self-report measure of suicide attempts and NSSI acts with a gold standard in depth interview. METHOD: Ninety women answered questions about their suicidal behavior history using both a self-report assessment and in depth interview. RESULTS: The plurality of patients over estimated their suicidal acts using the self-report measure when compared to the gold standard interview. CONCLUSION: Self-report assessments may not be an accurate method of retrieving information about suicide. PMID- 30450577 TI - Putative tumor suppressor cytoglobin promotes aryl hydrocarbon receptor ligand mediated triple negative breast cancer cell death. AB - Nearly 40 000 women die annually from breast cancer in the United States. Clinically available targeted breast cancer therapy is largely ineffective in triple negative breast cancer (TNBC), characterized by tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2). TNBC is associated with a poor prognosis. Previous reports show that aryl hydrocarbon receptor (AhR) partial agonist 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) selectively inhibits the growth of breast cancer cells, including those of the TNBC subtype. We previously demonstrated that 5F 203 induced the expression of putative tumor suppressor gene cytoglobin (CYGB) in breast cancer cells. In the current study, we determined that 5F 203 induces apoptosis and caspase-3 activation in MDA-MB 468 TNBC cells and in T47D ER+ PR + Her2 - breast cancer cells. We also show that caspases and CYGB promote 5F 203-mediated apoptosis in MDA-MB-468 cells. 5F 203 induced lysosomal membrane permeabilization (LMP) and cathepsin B release in MDA MB-468 and T47D cells. In addition, silencing CYGB attenuated the ability of 5F 203 to induce caspase-3/-7 activation, proapoptotic gene expression, LMP, and cathepsin B release in MDA-MB-468 cells. Moreover, 5F 203 induced CYGB protein expression, proapoptotic protein expression, and caspase-3 cleavage in MDA-MB-468 cells and in MDA-MB-468 xenograft tumors grown orthotopically in athymic mice. These data provide a basis for the development of AhR ligands with the potential to restore CYGB expression as a novel strategy to treat TNBC. PMID- 30450578 TI - Response to treatment is more important than disease severity at diagnosis for prediction of early relapse in new-onset paediatric Crohn's disease. AB - BACKGROUND: Paediatric Crohn's disease is characteried by frequently relapsing disease which may lead to hospitalisations and complications. AIM: To develop predictive models for early relapse following first remission. METHODS: The GROWTH CD prospective inception cohort was designed to predict risk for early disease relapse and poor outcomes. Newly diagnosed children underwent endoscopies and imaging. They were phenotyped and followed at scheduled visits through 78 weeks for relapses. Twenty-eight dichotomous and continuous variables were assessed at baseline and week 12, including phenotype, inflammatory markers, disease activity (PCDAI) and other markers. Clinical relapses defined as PCDAI >10 after remission were recorded using a relapse form. Logistic regression & risk modelling was performed. RESULTS: We enrolled 282 eligible patients of whom 178 (63.6%) patients achieved steroid free remission by week 12. Disease complications developed in 22/76(29%) of patients with relapse compared to 20/206 (9.7%) without relapse (P = 0.01). Multivariable analysis demonstrated that while variables from age/gender at diagnosis were not predictive, week 12 variables including PCDAI >5 (P = 0.02), CRP >20 mg/L (P = 0.02), and faecal calprotectin >400 ug/g (P = 0.03) as optimal cut-offs were associated with increased risk of relapse. A prediction model for patients in remission including gender, age, week 12 PCDAI, calprotectin and CRP had sensitivity 43%, specificity 92%, PPV 78%, NPV 71% for relapse. CONCLUSIONS: Early relapses were associated with a higher risk for disease complications at followup. Relapse prediction based on week 12 disease activity or inflammation is superior to prediction using data from diagnosis. PMID- 30450579 TI - Simultaneous multi-slice cardiac cine with Fourier-encoded self-calibration at 7 Tesla. AB - PURPOSE: To accelerate cardiac cine at 7 tesla using simultaneous multi-slice (SMS) acquisition with self-calibration to resolve misalignment between calibration and imaging data due to breathing motion. METHODS: A spoiled-gradient echo cine sequence was modified with radiofrequency phase-cycled SMS excitations. A Fourier encoding strategy was applied along the cardiac phase dimension to allow for slice untangling and split-slice GRAPPA calibration. Split-slice GRAPPA was coupled with regular GRAPPA (SMS-GRAPPA) and L1-SPIRiT (SMS-L1SPIRiT) for image reconstruction. 3-slice SMS cine MRI was evaluated in ten subjects against single-slice cine MRI in terms of SNR and contrast-to-noise ratio and slice leakage. RESULTS: SNR decreased significantly from 10.1 +/- 7.1 for single-slice cine to 7.4 +/- 2.8 for SMS-GRAPPA (P = 0.02) and was recovered to 9.0 +/- 4.5 with SMS-L1SPIRiT (P = 0.02). Contrast to noise ratio decreased significantly from 14.5 +/- 8.1 for single-slice cine to 5.6 +/- 3.6 for SMS-GRAPPA (P < 0.0001) and increased slightly but significantly back to 6.7 +/- 4.4 for SMS L1SPIRiT (P = 0.03). Specific absorption rate restrictions imposed a reduced nominal flip angle (-37 +/- 7%, P = 0.02) for 3-slice SMS excitations compared to single-slice acquisitions. SMS slice leakage increased significantly from apex (8.6 +/- 6.5 %) to base (13.1 +/- 4.1 %, P = 0.03) in the left ventricle. CONCLUSION: Three-fold acceleration of cine at 7T was achieved using the proposed SMS technique. Fourier encoding self-calibration and regularized image reconstruction enabled simultaneous acquisition of three slices without significant SNR decrease but significant CNR decrease linked to the reduced nominal excitation flip angle. PMID- 30450580 TI - Role of miR-142 in the pathogenesis of osteosarcoma and its potential as therapeutic approach. AB - Osteosarcoma (OS) is the most common primary malignant tumor of the bone with a strong tendency to early metastasis, and occurs in growing bones more commonly in children and adolescents. Considering the limited therapeutic methods and lack of 100% success of these methods, developing innovative therapies with high efficacy and lower side effects is needed. Meanwhile, miRNAs and the studies indicating the involvement of miRNAs in OS development have attracted attentions as a result of the frequent abnormalities in expression of miRNAs in cancer. miRNAs are noncoding short sequences with lengths ranging from 18 to 25 nucleotides that play a very important role in cellular processes, such as proliferation, differentiation, migration, and apoptosis. MiRNAs can have either oncogenic or tumor suppressive role based on cellular function and targets. This review aimed to have overview on miR-142 as a tumor suppressor in OS. Moreover, the genes involved in the disease, such as RAC1, HMAG1, MMP9, MMP2, and E-cadherin, which have irregularities as a result of change in miR-142 expression, and, thereby, result in increasing the proliferation, invasion, and metastasis of the cells in the tissues and OS cells will be discussed. PMID- 30450581 TI - Mortality associated with tracheostomy complications in the United States: 2007 2016. AB - OBJECTIVES/HYPOTHESIS: To investigate patterns of tracheostomy-associated death in the United States. STUDY DESIGN: Retrospective database review. METHODS: We used Multiple Cause-of-Death data from the Centers for Disease Control and Prevention to determine cumulative national mortality associated with tracheostomy complications in the United States from 2007 to 2016. Using International Classification of Diseases, Tenth Revision data, we investigated how frequently tracheostomy-related complications were reported in cause of death data. We then compared the characteristics of patients with tracheostomy-related mortality to patients reported to have died of other causes. RESULTS: Over the 10 year period studied, we identified 623 tracheostomy-related deaths (537 adults and 86 children) out of 25,587,306 total deaths reported. Although absolute mortality was higher in adults, the reported base rate of tracheostomy complication-associated mortality was tenfold higher in children. Most tracheostomy-related deaths occurred in a hospital facility (74.5% in adults). Deaths associated with tracheostomy complications were significantly more common for African American children (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.26-3.24) and adults (OR: 1.59, 95% CI: 1.29-1.96) or in Hispanic adults (OR: 1.42, 95% CI: 1.06-1.89). Deaths related to a tracheostomy complication more commonly occurred on the weekend (OR: 1.24, 95% CI: 1.04-1.49) and in the most recent 2-year period (OR: 1.31, 95% CI: 1.03-1.68). Adults with a bachelor's, master's or doctorate degree were significantly less likely to have mortality associated with a tracheostomy-related complication (OR: 0.54, 95% CI: 0.39 0.75). CONCLUSIONS: Tracheostomy-related complications were implicated in the deaths of a significant number of individuals. Several demographic groups had increased likelihood of tracheostomy-related mortality. Future research is necessary to develop targeted interventions to decrease harm. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30450582 TI - Purification of a Conjugated Polysaccharide Vaccine using Tangential Flow Diafiltration. AB - Conjugated vaccines prepared from the capsular polysaccharide of Streptococcus pneumoniae can provide immunization against invasive pneumococcal disease, meningitis, and otitis media. One of the critical steps in the production of these vaccines is the removal of free (unreacted) polysaccharides from the protein-polysaccharide conjugate. Experimental studies were performed to evaluate the effects of membrane pore size, filtrate flux, and solution conditions on the transmission of both the conjugate and free polysaccharide through different ultrafiltration membranes. Conjugate purification was done using diafiltration performed in a linearly-scalable tangential flow filtration (TFF) cassette. More than 98% of the free polysaccharide was removed within a five diavolume diafiltration process, which is a significant improvement over previously reported results for purification of similar conjugated vaccines. These results clearly demonstrate the opportunities for using ultrafiltration / diafiltration for the final purification of conjugated vaccine products. This article is protected by copyright. All rights reserved. PMID- 30450583 TI - Cerebrospinal fluid-suppressed T2 -weighted MR imaging at 7 T for human brain. AB - PURPOSE: T2 -weighted lesional imaging is most commonly performed using inversion recovery turbo spin echoes. At 7 T, however, this acquisition is limited for specific absorption rate and resolution. This work describes and implements a method to generate CSF-suppressed T2 -weighted imaging. METHODS: The strategy uses a driven equilibrium spin-echo preparation within an inversion recovery with multiple 3D gradient-echo imaging blocks. Images are combined using the self normalization approach, which achieves CSF suppression through optimized timing of individual blocks and minimizes sources of variation due to coil receptivity, T2 * , and proton density. Simulations of the magnetization-prepared fluid attenuated inversion recovery gradient-echo (MPFLAGRE) method over T1 and T2 relaxation values are performed, and in vivo demonstrations using an 8 RESULTS: The specific absorption rate of the calculated MPFLAGRE sequence is 11.1 +/- 0.5 W (n = 5 volunteers), which is 74 +/- 2% of the US Food and Drug Administration guidelines. This method acquires both contrasts for CSF suppression with detection of long T2 components and T2 -weighted imaging in a single acquisition. In healthy controls, the former contrast generates increased signal in the cortical rim and ependyma. A comparison is shown with a conventional 3D SPACE fluid-attenuated inversion recovery acquisition, and sensitivity to pathology is demonstrated in an epilepsy patient. CONCLUSION: As applied with the 8 PMID- 30450584 TI - Molecular and cellular basis of mammary gland fibrosis and cancer risk. AB - Mammary gland luminal cells are maintained by the proliferation of ER- luminal progenitor (LP) cells. Human breast LP cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Telomeric repeat factor 2 (TRF2) protects telomeres from DNA damage response. TRF2 expression is reduced in human breast cancers. We deleted TRF2 expression in mammary gland epithelium. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. TRF2 deficient mammary tumors exhibited rapid onset and increased proliferation. Tumor derived LP cells failed to form tumors following transplantation. The MSC population was highly tumorigenic and maintained telomeres via the ALT mechanism. Telomere DNA damage response in mammary tumors resulted in p53 dependent ER+ cellular differentiation and sensitivity to anti-estrogen therapy. Our results provide a new in vivo model of mammographic density, stem cell differentiation, cancer risk, and therapeutic sensitivity. This article is protected by copyright. All rights reserved. PMID- 30450585 TI - Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing. AB - BACKGROUND: Genetic testing capability and guidelines are rapidly expanding to assess inherited prostate cancer (PCA). Clinical genetic data from multigene testing can provide insights into the germline pathogenic variant (PV) spectrum and correlates in men with PCA unselected for metastatic disease to optimize identification of men for genetic evaluation and management. METHODS: A retrospective cross-sectional analysis was conducted of de-identified clinical genetic testing data from a large commercial genetic testing laboratory in the US. ICD-10 claims codes were used to identify men with PCA, along with family history data. Gleason score was abstracted from test request forms. Overall PV rate among men with PCA was estimated, along with PVs in DNA repair genes. Family history and Gleason score association to germline DNA repair PVs was assessed using Fisher's exact test with correction for false-discovery. RESULTS: As of August 2017, genetic results were available on 1328 men with PCA. Overall PV rate was 15.6%, with 10.9% of PV in DNA repair genes. PVs were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). Breast cancer family history was significantly associated with germline DNA repair PVs (OR 1.89, [95%CI 1.33, 2.68], P = 0.003). Among men with Gleason score>= 6 (n = 706), Gleason> = 8 was significantly associated with DNA repair PVs (OR 1.85 [95%CI 1.22, 2.80], P = 0.004). CONCLUSIONS: A substantial proportion of men with PCA unselected for metastatic disease carry germline DNA repair PVs. Breast cancer family history and high Gleason score are important predictors to identify men with PCA who may carry germline DNA repair PVs. Our findings support current NCCN guidelines and have implications for genetic assessment, therapeutic management, and cascade testing for men with PCA and their families. PMID- 30450586 TI - Application of ultra-rapid qPCR and DNA chips for viral RNA detection and confirmation. AB - The rapid and accurate detection of the presence of microorganisms, such as viruses, has been an important issue in the fields of public health, as well as agriculture. A PCR-based detection method has been developed and applied in these fields to determine the presence of specific pathogens. Although the major advantage of real-time PCR is the monitoring of amplification and ability to quantify the template genes, the method described here should solve the problem of nonspecific product synthesis. We obtained viral RNA from infected samples by freezing and thawing; we rapidly synthesized cDNA from RNA, and then amplified the cDNA by rapid PCR in 10 Min. Finally, the PCR products were hybridized and quickly confirmed to be the target analyte on a DNA chip. Our newly proposed methods overcome the drawbacks of PCR-based detection and provide three additional advantages, namely, rapidly obtaining large amounts of RNA from samples, quickly detecting infective or pathogenic genes, and speedily confirming the detected exogenous genes. This application might be useful for detecting viral RNA and for the diagnosis of RNA virus-mediated diseases. PMID- 30450587 TI - Osteoradionecrosis of the sternoclavicular joint after laryngopharyngeal radiation. AB - OBJECTIVES: Adequate treatment of laryngopharyngeal malignancy often incorporates radiation therapy. Structures surrounding laryngopharynx exposed to traditional radiation doses are susceptible to posttreatment toxicity. Among poorly understood sequelae is the rare manifestation of sternoclavicular joint (SCJ) osteoradionecrosis (ORN). METHODS: Three institutional encounters prompted a comprehensive literature search, generating three published case reports. Systematic extraction and analysis (n = 6) of demographics, cancer history, comorbidities, ORN presentation, imaging, and management established the largest series to investigate this pathology. RESULTS: Patients were males (6), 54 to 70 years old, smokers (4), with Hypertension/dyslipidemia, myocardial infarction/coronary artery disease, second primary (2), diabetes mellitus (1), and myelofibrosis(1). Four underwent total laryngectomy, one primary, three as salvage. Five patients had concurrent chemoradiation (>=70 Gy). All patients presented with swollen, tender neck wounds concerning for persistent/recurrent malignancy. Computed tomography (CT) demonstrated bone erosion (5 of 5) and increased bone scan uptake (2 of 2). All responded to surgical exploration with drainage alone (1), sequestrectomy (2), or bone resection with synovectomy (3). Complete healing took 2 months to 3 years. One unrelated patient death occurred before control of ORN was achieved. DISCUSSION: Given varied patient characteristics, synergistic risk factors exist that alter bone radiation threshold, resulting in irreversible ischemic damage and osteoradionecrosis. Vascular susceptibility and inability to repair may regulate that threshold. Understanding this relationship will facilitate early detection and intervention. CONCLUSION: Integrating cases of sternoclavicular joint ORN promotes awareness of atypical laryngopharyngeal radiation complications, elucidates contributing factors, educates physicians on presentation and management, and provides a platform for prospective investigation. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 30450588 TI - Voice outcomes after endoscopic sinus surgery in patients with chronic rhinosinusitis with nasal polyposis. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to assess voice outcomes after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). STUDY DESIGN: Individual cohort study. METHODS: A study was performed of patients with CRSwNP who underwent ESS from July 2015 to May 2016 at a tertiary referral medical center. The main outcome measures were subjective improvement in patient-reported outcomes, using the 22-item Sino-Nasal Outcome Test (SNOT-22) and 10-item Voice Handicap Index (VHI-10). RESULTS: A total of 50 patients (age 47.9 years; 48% female), 66% revision and 34% primary, were available at a follow-up of 3 months. At the 3-month follow-up, both SNOT-22 and VHI-10 scores were improved from preoperative values (-41.8 and -14.7, respectively). CONCLUSIONS: Successful treatment of sinonasal disease can help to improve voice outcomes in patients with CRSwNP. There are inherent differences in the long-term outcomes of the results beyond 3 months based on practice patterns of ongoing medical management, but our results are interesting in that they show early improvement in voice outcomes. LEVEL OF EVIDENCE: 2b Laryngoscope, 2018. PMID- 30450589 TI - Mucocele formation following laryngeal cleft injection. AB - A 12-month-old male underwent injection laryngoplasty for dysphagia associated with a deep interarytenoid notch. He subsequently developed a large postcricoid mucocele requiring revision surgery and marsupialization of the cyst just 2 weeks following the initial surgery. Laryngoscope, 2018. PMID- 30450590 TI - Relationship Status and Suicidal Behavior in Gay Men: The Role of Thwarted Belongingness and Hope. AB - OBJECTIVE: Levels of suicidal behavior among gay men are a significant concern. The Interpersonal Theory of Suicide proposes that being unpartnered is a risk factor for suicidal behavior due to thwarted belongingness; however, this has yet to be tested empirically. Recent studies also indicate that the two components of hope, agency and pathways, may be protective against suicidal behavior. The first aim of the current study was to investigate whether thwarted belongingness mediates the relationship between relationship status and suicidal behavior in gay men. The study also examined whether agency and pathways weaken the association between relationship status and thwarted belongingness, and whether agency weakens the relation between thwarted belongingness and suicidal behavior. METHOD: A sample of 370 self-identified gay men aged from 18 to 66 years old (M = 26.13, SD = 8.02) completed the Suicidal Behaviors Questionnaire-Revised, the Interpersonal Needs Questionnaire-Revised, and the Adult Dispositional Hope Scale. RESULTS: Results showed that thwarted belongingness mediated the relationship between relationship status and suicidal behavior. The hypothesized moderated-mediation models were not supported. CONCLUSIONS: These findings have implications for the development of interventions that aim to reduce suicidal behaviors in gay men. PMID- 30450591 TI - A phase I trial investigating the Aurora B kinase inhibitor BI 811283 in combination with cytarabine in patients with acute myeloid leukaemia. PMID- 30450592 TI - Early ambulation versus bedrest after skin grafting in extramammary Paget's disease. PMID- 30450593 TI - Schneiderian Membrane Perforation via Transcrestal Sinus Floor Elevation: A Randomized Ex Vivo Study with Endoscopic Validation. AB - OBJECTIVE: To endoscopically determine the incidence of Schneiderian membrane perforation during transcrestal maxillary sinus floor elevation (SFE), in relation to the bone preparation technique, amount of bone graft, membrane elevation height and different surgical steps. MATERIALS AND METHODS: Seven cadaver heads corresponding to 12 maxillary sinuses were used to perform 3 SFE via transcrestal approach per sinus (36 elevations). Each sinus was randomly assigned to either the Sinus Crestal Approach (SCA) drill kit technique (experimental group) or the conventional osteotome technique (control group). During all phases of the surgery, the integrity of the sinus membrane was monitored through endoscopic examination. RESULTS: A significant difference was found in the incidence of perforation (P = 0.007) and vertical elevation height (P < 0.001) between the study groups, favoring the experimental group. A safety elevation threshold of 5 mm without bone graft and implant placement was estimated. A significant correlation was observed between residual ridge height and incidence of perforation (P < 0.001) (OR = 0.51). CONCLUSION: The SCA drill kit may demonstrate superior osteotomy preparation and membrane elevation capabilities to the osteotome technique, and significantly when 6 mm SFE is indicated. Residual ridge height and vertical elevation height are risk determinants factors. This article is protected by copyright. All rights reserved. PMID- 30450594 TI - Synergistic enantioseparation systems with either cyclodextrins or cyclofructans and L-alanine Tert butyl ester lactate. AB - The combined use of chiral ionic liquids (CILs) and conventional chiral selectors (CSs) in CE, to establish a synergistic system, has proven to be an effective approach for the separation of enantiomeric pairs. In this study, a new CE method was developed, employing a binary system of a CS, either a cyclodextrin (CD) or a cyclofructan (CF), and a chiral amino acid ester-based ionic liquid (AAIL), for the chiral separation of four basic, acidic and zwitterionic drug compounds. In particular, the enantioseparation of two anticoagulants, warfarin (WAR) and coumachlor (COU), a non-opioid analgesic, nefopam (NEF) and a third-generation antihistamine, fexofenadine (FXD), was examined, by supporting the BGE with a CS and the chiral AAIL L-alanine tert butyl ester lactate (L-AlaC4 Lac). Parameters, such as the type of the CS, the concentration of both the CS and L-AlaC4 Lac, and the BGE pH, were methodically examined in order to optimize the chiral separation of each analyte. It was observed that, in some cases, the addition of the AAIL into the BGE improved both resolution (Rs ) and efficiency (N) significantly. In other cases, the synergistic effect enabled baseline separation of analyte enantiomers, at a much lower concentration of the CS. Finally, after optimization of separation conditions, baseline separations (Rs >1.5) of all four analytes were achieved in less than 5 min. PMID- 30450595 TI - Potential biomarkers of the mature intervertebral disc identified at the single cell level. AB - Intervertebral disc (IVD) degeneration and trauma is a major socio-economic burden and the focus of cell-based regenerative medicine approaches. Despite numerous ongoing clinical trials attempting to replace ailing IVD cells with mesenchymal stem cells, a solid understanding of the identity and nature of cells in a healthy mature IVD is still in need of refinement. Although anatomically simple, the IVD is comprised of heterogeneous cell populations. Therefore, methods involving cell pooling for RNA profiling could be misleading. Here, by using RNA in situ hybridization and z proportion test, we have identified potential novel biomarkers through single cell assessment. We quantified the proportion of RNA transcribing cells for 50 genetic loci in the outer annulus fibrosus (AF) and nucleus pulposus (NP) in coccygeal bovine discs isolated from tails of four skeletally mature animals. Our data reconfirm existing data and suggest 10 novel markers such as Lam1 and Thy1 in the outer AF and Gli1, Gli3, Noto, Scx, Ptprc, Sox2, Zscan10 and LOC101904175 in the NP, including pluripotency markers, that indicate stemness potential of IVD cells. These markers could be added to existing biomarker panels for cell type characterization. Furthermore, our data once more demonstrate heterogeneity in cells of the AF and NP, indicating the need for single cell assessment by methods such as RNA in situ hybridization. Our work refines the molecular identity of outer AF and NP cells, which can benefit future regenerative medicine and tissue engineering strategies in humans. PMID- 30450596 TI - Association of sedentary time and physical activity during pregnancy with maternal and neonatal birth outcomes. AB - AIM: i) To analyse the association of objectively measured sedentary time (ST) and physical activity (PA) during early second trimester of pregnancy with maternal and neonatal birth outcomes; ii) to explore if ST and PA differ between women with vaginal or caesarean section deliveries. METHODS: Ninety-four Caucasian pregnant women (32.9+/-4.6 years old) participated in this prospective longitudinal study. Triaxial accelerometers were used to assess ST and PA intensity levels for seven consecutive days during second trimester of pregnancy. Birth data was collected from the obstetric medical records. Umbilical cord arterial and venous blood gas (pH, partial pressure of carbon dioxide and oxygen, and oxygen saturation) was analysed after birth. RESULTS: After adjusting for potential confounders, greater ST was associated with higher arterial and venous cord blood partial pressure of carbon dioxide and more acidic arterial and venous pH (all, p<0.01). Moderate PA, moderate-to-vigorous PA (MVPA), total PA and steps per day were positively associated with arterial cord blood oxygen saturation (all p<0.05). Steps per day were inversely associated with gestational age at birth (p<0.01), and duration of first stage of labour (p<0.05). Total and light PA were associated with a more alkaline pH in umbilical vein (all, p<0.01). Vigorous PA was inversely associated with the Apgar score (p<0.01). No significant differences were observed in ST and PA levels between women with vaginal and women with caesarean section deliveries (all, p>0.100). CONCLUSION: Increasing PA and decreasing ST during pregnancy might promote better maternal and neonatal birth markers. This article is protected by copyright. All rights reserved. PMID- 30450598 TI - Erratum to: Companions or patients? The impact of family presence in genetic consultations for inherited breast cancer: Relational autonomy in practice. PMID- 30450599 TI - Displacement and solidarity: An ethic of place-making. AB - Drawing on a conception of people as 'ecological subjects', creatures situated in specific social relations, locations, and material environments, I want to emphasize the importance of place and place-making for basing, demonstrating, and forging future solidarity. Solidarity, as I will define it here, involves reaching out through moral imagination and responsive action across social and/or geographic distance and asymmetry to assist other people who are vulnerable, and to advance justice. Contained in the practice of solidarity are two core 'enacted commitments', first, to engaging our moral imaginations and recognizing others in need and, second, to responsive action. Recognizing the suffering of displacement and responding through place-making should follow from even the most simplistic understanding of people as 'implaced'. Recognition, furthermore, that places are created and sustained, transformed, or neglected in ways that foster or perpetuate inequities, including health inequities, generates responsibilities concerning place-making. Place-based interventions, on either count, should be principal and, indeed, prioritized ways of showing solidarity for the vulnerable and promoting justice. Where solidaristic relations do not prevail, place-making can catalyze and nurture them, and over time advance justice. On the moral landscapes of bioethics, the terrain where care and health are or should be at the center of attention, an ethic of place and place-making for those who have been displaced - patients, the elderly, urban populations, and asylum-seekers, for instance - expresses and has rich potential for nurturing bonds of solidarity. PMID- 30450600 TI - Solidarity can make a difference: Addressing transformations in healthcare, demographics and technological replacement. PMID- 30450601 TI - Safety evaluation of a lyophilized platelet-derived hemostatic product. AB - BACKGROUND: Hemorrhage causes significant morbidity and mortality in people aged <65 years. A lyophilized platelet-derived hemostatic agent (Thrombosomes) demonstrated hemostatic efficacy in animal models. We report the results of the first safety trial of autologous Thrombosomes given to normal subjects. STUDY DESIGN AND METHODS: Ten subjects received autologous Thrombosomes prepared from their apheresis platelets, and five control subjects received a buffer solution. There were five cohorts, with three subjects per cohort (two in the Thrombosomes group and one in the control group). Doses escalated from 1/1,000 to 1/10 of a proposed efficacious dose. Cohorts 4 and 5 received the highest dose, but in Cohort 5, one-half the dose was infused 2 hours apart. Cohorts 1 through 3 were monitored for 42 days, Cohorts 4 and 5 were monitored for 60 days using hematology, coagulation, and chemistry assays and antibody testing. RESULTS: There were no serious adverse events (AEs) and no subject withdrawals. There were eight treatment-related AEs (TRAEs) in 5 of 15 subjects (33%) (four in the Thrombosomes group and one in the control group). Of four subjects receiving the highest doses, three had TRAEs. One had elevated D-dimer, prothrombin fragment 1 + 2, and white blood cell count (subject had concurrent upper respiratory tract infection); one had T-wave inversions in precordial leads V2 and V3 without elevated troponin or symptoms; and one had a platelet autoantibody without change in platelet count. All subjects' TRAEs resolved by Day 21. CONCLUSION: There were no serious AEs in this small study. Thrombosomes were considered safe at the doses assessed. Future, larger trials will be needed to further assess safety and efficacy. PMID- 30450602 TI - IGFBP7 regulates sepsis-induced acute kidney injury through ERK1/2 signaling. AB - IGFBP7 as an early biomarker has been used to identify patients at risk of developing acute kidney injury (AKI). Nevertheless, its role in AKI remains obscure. The aim of our study is to determine the role and mechanism of IGFBP7 in lipopolysaccharide (LPS)-induced HK-2 cells in vitro and on sepsis-induced AKI by cecal ligation and puncture (CLP) in vivo. Here, we identified that IGFBP7 expression was increased in patients with AKI and HK-2 cells with LPS (1, 2, and 5 MUg/mL) induction. HK-2 cells with LPS induction showed cell cycle arrest at G1 G0 phases and cell apoptosis and activated ERK1/2 parallel with the changes in the proteins belonging to the ERK1/2 pathway, including Cyclin D1, P21, Bax, and Bcl-2, which were inhibited by the IGFBP7 knockdown. Moreover, IGFBP7 overexpression significantly induced cell cycle arrest at G1-G0 phases and cell apoptosis of HK-2 cells, which were inhibited by PD98509, an ERK1/2 signaling inhibitor. IGFBP7 knockdown effectively alleviated the severity of the renal injury, evidenced by decreases in the urinary levels of creatinine, blood urea nitrogen, and albumin, cell apoptosis, and activation of ERK1/2 signaling in CLP mice. Taken together, our findings indicate that IGFBP7 regulates sepsis-induced AKI through ERK1/2 signaling. PMID- 30450603 TI - "He looks gorgeous" - iuMR images and the transforming of foetal and parental identities. AB - The MERIDIAN study examined whether in-utero MRI (iuMRI) improves the accuracy of diagnosis of foetal brain abnormalities, when used as an adjunct to ultrasound anomaly scanning. A diagnostic iuMRI differs from routine ultrasound screening because of its infrequent use and scanning procedure. Nested within this trial, this sociological study explored the acceptability of iuMRI as a technology and its contribution to parental decision-making. Our sociological interpretation of the role of iuMR images in prenatal diagnosis draws on narrative interviews with women (and some partners) who underwent MRI imaging at three different centres. Overall, participants found iuMRI helpful in decision-making because it either confirmed or disconfirmed previous results, or provided additional information. Expectant couples experienced the iuMR imaging process as informative, but also as having emotive and practical value. Our paper extends the existing sociological literature on antenatal testing and visualising the foetus, by using iuMR diagnostic imaging to further explore the concept of the unborn entity. Our data suggest that alongside the iuMR images, the 'parental gaze' and accompanying commentary are used by parents to construct and transform foetal and parental identities despite ongoing uncertainties about, and shifting social contexts to their pregnancy. PMID- 30450604 TI - Flash glucose monitoring-using technology to improve outcomes for patients with diabetes. PMID- 30450605 TI - Why do farm accidents persist? Normalising danger on the farm within the farm family. AB - In the western world, farming is the most dangerous occupation with the highest rates of accidents and fatalities. Farming remains largely a family business and most accidents happen to family members. Why do safety campaigns have such limited success and why do farm families bring this terrible grief on themselves? This article argues that farm accidents are a persistent social pattern requiring analysis of how families are socialised to interact with the farming space. Based on qualitative data gathered for a Scottish study, it is argued that within farm families there is a socialisation and normalisation of danger. Accidents are to be expected. Two key arguments are advanced. First, danger is normalised and children are socialised to undertake risky behaviour. Second, it is suggested that when women do take up farming, they consciously undertake dangerous farming activities to prove that they are 'authentic' farmers. No previous research has considered women's approach to danger, and the existing literature suggests women are more safety conscious. This is not supported by our findings. We argue that farm accidents and fatalities are a persistent social problem because family members socialise each other to accept danger as the norm. PMID- 30450606 TI - Is HIV prevention creating new biosocialities among gay men? Treatment as prevention and pre-exposure prophylaxis in Canada. AB - The advancements of "treatment as prevention" (TasP), "undetectable viral load" (UVL) and "pre-exposure prophylaxis" (PrEP) are redefining HIV prevention standards. Relying on the concept of biosociality, this article explores how gay men rally around, debate, and sometimes disagree about these emerging HIV prevention technologies. This article is based on data from the Resonance Project, a Canadian community-based research project. Twelve focus groups (totalling 86 gay and bisexual men) were held in three Canadian cities (Montreal, Toronto, Vancouver) in 2013-2014. Respondents view UVL and PrEP through the prism of their generational experience of HIV prevention. In this respect, biosocialities highlight an experiential dimension that is tied to the context of the HIV epidemic. The biosocialities of HIV prevention are also built around serological identities. However, our study shows the diversity of these positions. Analysis grounded in biosocialities is useful for better understanding how scientific information circulates, is made sense of, and generates debate among gay men. PMID- 30450607 TI - Programmable Construction of Peptide-Based Materials in Living Subjects: From Modular Design and Morphological Control to Theranostics. AB - Self-assembled nanomaterials show potential high efficiency as theranostics for high-performance bioimaging and disease treatment. However, the superstructures of pre-assembled nanomaterials may change in the complicated physiological conditions, resulting in compromised properties and/or biofunctions. Taking advantage of chemical self-assembly and biomedicine, a new strategy of "in vivo self-assembly" is proposed to in situ construct functional nanomaterials in living subjects to explore new biological effects. Herein, recent advances on peptide-based nanomaterials constructed by the in vivo self-assembly strategy are summarized. Modular peptide building blocks with various functions, such as targeting, self-assembly, tailoring, and biofunctional motifs, are employed for the construction of nanomaterials. Then, self-assembly of these building blocks in living systems to construct various morphologies of nanostructures and corresponding unique biological effects, such as assembly/aggregation-induced retention (AIR), are introduced, followed by their applications in high performance drug delivery and bioimaging. Finally, an outlook and perspective toward future developments of in vivo self-assembled peptide-based nanomaterials for translational medicine are concluded. PMID- 30450608 TI - Dealing with the sharp end of ingested foreign bodies. AB - Foreign bodies ingestion are common in children due to their the natural tendency to put things in mouth. Coins, batteries, small toys, safety pins and fish bones are some of the most common culprits. A retrospective study of 1,334 swallowing cases found that 80% of blunt, relatively small ingested foreign bodies pass through the gastrointestinal tract with no significant complications (1). However, the other 20% comprised of sharp, pointed, relatively larger objects and these became lodged in the gastrointestinal tract, causing an range of complications requiring emergency intervention (2). This article is protected by copyright. All rights reserved. PMID- 30450609 TI - CFD predicted pH gradients in lactic acid bacteria cultivations. AB - The formation of pH gradients in a 700 L batch fermentation of Streptococcus thermophilus was studied using multi-position pH measurements and computational fluid dynamic (CFD) modelling. To this end, a dynamic, kinetic model of S. thermophilus and a pH correlation were integrated into a validated one-phase CFD model, and a dynamic CFD simulation was performed. First, the fluid dynamics of the CFD model were validated with NaOH tracer pulse mixing experiments. Mixing experiments and simulations were performed while multiple pH sensors, which were placed vertically at different locations in the bioreactor, captured the response. A mixing time of about 46 s to reach 95 % homogeneity was measured and predicted at an impeller speed of 242 rpm. The CFD simulation of the S. thermophilus fermentation captured the experimentally observed pH gradients between a pH of 5.9 and 6.3, which occurred during the exponential growth phase. A pH higher than 7 was predicted in the vicinity of the base solution inlet. Biomass growth, lactic acid production, and substrate consumption matched the experimental observations. Moreover, the biokinetic results obtained from the CFD simulation were similar to a single-compartment simulation, for which a homogeneous distribution of the pH was assumed. This indicates no influence of pH gradients on growth in the studied bioreactor. This study verified that the pH gradients during a fermentation in the pilot-scale bioreactor could be accurately predicted using a coupled simulation of a biokinetic and a CFD model. In order to support the understanding and optimization of industrial-scale processes, future biokinetic CFD studies need to assess multiple types of environmental gradients, like pH, substrate, and dissolved oxygen, especially at industrial scale. This article is protected by copyright. All rights reserved. PMID- 30450610 TI - Model-based meta-analysis in ankylosing spondylitis: a quantitative comparison of biologics and small targeted molecules. AB - Information on the comparative efficacy is important for drug development as well as drug therapy. Up to now, the relative efficacy of approved biologics and many agents under investigation in ankylosing spondylitis (AS) are still unclear. The objective of this study was to quantify the relative efficacy and time-course of various treatments measured by Ankylosing Spondylitis Assessment Study group response criteria 20 (ASAS20) scores, change from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI). 34 double-blinded trials of 10 biologics and small molecules encompassing 5,339 patients with AS were included in this analysis. Three mathematical models with non-parametric placebo estimations were used to describe the longitudinal profile for the above three efficacy measures. The results detected significant differences among included treatments and infliximab and golimumab were found to have the highest efficacy in given dosage regimens across all measures. This article is protected by copyright. All rights reserved. PMID- 30450611 TI - In situ determination of trace elements in melt inclusions using laser ablation inductively coupled plasma-sector field-mass spectrometry. AB - RATIONALE: In situ trace element analysis of melt inclusions by laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) provides important geochemistry information. However, the precision and accuracy of this technique are affected by many factors, such as matrix effect, laser conditions, and calibration method. In addition, many previous LA-ICP-MS studies ablated entire melt inclusions along with their host minerals and obtained trace element composition by deconvoluting the mixed ablation signal, which may induce much uncertainty. METHODS: A 193 nm ArF laser ablation system combined with inductively coupled plasma-sector field-mass spectrometry (ICP-SF-MS) was used to investigate matrix effect, laser conditions, choice of external calibration standards, and data reduction strategy for in situ analysis of 36 major and trace elements in six common silicate reference glasses. The validity of the protocol present here was demonstrated by measuring trace elements in olivine-hosted melt inclusions. Instead of ablating entire melt inclusions along with their host minerals, melt inclusions were polished to the surface to avoid laser ablating the mineral host. RESULTS: The calibration lines calculated from the calibration standards should cross the coordinate origin, especially for low-concentration elements (<10 ppm). As the laser crater size increased from 17 to 33 MUm, the precision was improved from <20% to <8% (2RSD), and accuracy was improved from +/ 20% to better than +/-10%. Most measured trace elements in Dali melt inclusions are consistent with those in their host rocks. For mobile elements (Ba, Sr, Pb), melt inclusions display much smaller variations than their host rocks. CONCLUSIONS: A simple but accurate approach for in situ analysis of trace elements in melt inclusions by LA-ICP-SF-MS has been established, which should greatly facilitate the wider application of in situ trace element geochemistry to melt inclusion studies. PMID- 30450612 TI - A Smoothing-based Goodness-of-Fit Test of Covariance for Functional Data. AB - Functional data methods are often applied to longitudinal data as they provide a more flexible way to capture dependence across repeated observations. However, there is no formal testing procedure to determine if functional methods are actually necessary. We propose a goodness-of-fit test for comparing parametric covariance functions against general nonparametric alternatives for both irregularly observed longitudinal data and densely observed functional data. We consider a smoothing-based test statistic and approximate its null distribution using a bootstrap procedure. We focus on testing a quadratic polynomial covariance induced by a linear mixed effects model and the method can be used to test any smooth parametric covariance function. Performance and versatility of the proposed test is illustrated through a simulation study and three data applications. This article is protected by copyright. All rights reserved. PMID- 30450613 TI - Mood, Dimensional Personality, and Suicidality in a Longitudinal Sample of Patients with Bipolar Disorder and Controls. AB - OBJECTIVE: To evaluate the effects of mood and anxiety symptoms in relation to personality dimensions and clinical features such as trauma and substance use on suicidal behaviors in a longitudinal sample of individuals with bipolar illness (BP) and healthy controls (HC). METHODS: Mood, personality, and clinical features were assessed in 151 individuals with BP I and 119 HC. Clinical data were collected at baseline and at 2-year follow-up. Personality traits were measured using the NEO PI-R. RESULTS: In bivariate analyses, personality measures were significantly different between BP and HC, and between BP based on suicide attempt history. However, in regression analyses, baseline measures of depression, mania, anxiety, trauma, education, and age of BP onset correlated with personality domains, while a history of suicide attempts did not. Logistic regressions showed that prospective depression or mania, and a pattern of mixed mood features and chronicity of illness, along with two Neuroticism facet scores (N4-Self-Consciousness and N6-Vulnerability) were predictive of suicide ideation (SI) in the 2-year follow-up period. CONCLUSIONS: While dimensions of personality, trauma, and substance use clearly correlated with suicidal behaviors in BP, in multivariate models emerging mood symptoms were the most robust predictors of suicidality. These results reinforce the importance and attributable role of mood and anxiety symptoms in evaluating suicidal risk. PMID- 30450614 TI - Differential expression of Wilms' tumour 1 gene in porcine urogenital organs during development. AB - Wilms' tumour 1 gene (WT1) is essential for the development of mammalian urogenital system. However, the expression pattern of WT1 in the development of porcine urogenital organs is still unclear. Here, we examined the expression of WT1 mRNA and protein in porcine kidneys, ovaries and testes from embryonic days 35 and 60 (E35d, E60d, n = 3) to the newborn (0d, n = 4) and adult (210d, n = 3) stages, using real-time PCR and immunofluorescent staining. Real-time PCR analysis showed that porcine kidneys, ovaries and testes all expressed high level of WT1 mRNAs, especially in adult testes (p < 0.05 or 0.01 vs. kidney and ovary, respectively). Morphologically, characteristic microstructures of the kidneys, ovaries and testes were observed and discerned at all four stages. Immunofluorescently, WT1 expression was detected in a dynamic and context specific pattern during the development of these organs. Taken together, porcine urogenital organs express relatively high levels of WT1 mRNA. Dynamical and context-specific expression profile of WT1 in these organs occurs during their development, implying its close association with the development and function of porcine kidney, ovary and testis. PMID- 30450615 TI - Regional prevalence of health worker absenteeism in Tanzania. AB - Absenteeism of health workers in developing countries is common and can severely undermine the reliability of the health system. Therefore, it is important to understand where the prevalence of absenteeism is high. We develop a simple imputation method that combines a Service Delivery Indicators survey and a Service Provision Assessment survey to estimate the prevalence of absenteeism of health workers at the level of regions in Tanzania. The resulting estimates allow one to identify the regions in which the prevalence of absenteeism is significantly higher or lower than the national average and help policymakers determine priority areas for intervention. PMID- 30450616 TI - Low-cost Customizable Microscale Toolkit for Rapid Screening and Purification of Therapeutic Proteins. AB - Biopharmaceutical separations require tremendous amounts of optimization to achieve acceptable product purity. Typically, large volumes of reagents and biological materials are needed for testing different parameters, thus adding to the expense of biopharmaceutical process development. This study demonstrates a versatile and customizable microscale column (uCol) for biopharmaceutical separations using immobilized metal affinity chromatography (IMAC) as an example application to identify key parameters. uCols have excellent precision, efficiency, and reproducibility, can accommodate any affinity, ion-exchange or size-exclusion-based resin and are compatible with any HPLC system. uCols reduce reagent amounts, provide comparable purification performance and high-throughput, and are easy to automate compared to current conventional resin columns. We provide a detailed description of the fabrication methods, resin packing methods, and uCol validation experiments using a conventional HPLC system. Finite element modeling using COMSOL Multiphysics was employed to validate the experimental performance of the uCols. In this study, uCols were used for improving the purification achieved for granulocyte-colony stimulating factor (GCSF) expressed using a cell-free CHO in-vitro translation (IVT) system and were compared to a conventional 1 mL IMAC column. Experimental data revealed comparable purity with a 10-fold reduction in the amount of buffer, resin and purification time for the MUCols compared to conventional columns for similar protein yields. This article is protected by copyright. All rights reserved. PMID- 30450617 TI - Spray-dried plasma deficient in high-molecular-weight multimers of von Willebrand factor retains hemostatic properties. AB - BACKGROUND: Dried plasmas can overcome logistical barriers that prevent fresh frozen plasma (FFP) usage in acute resuscitation, but processing of these products can detrimentally alter the composition. Spray-dried plasma (SpDP) from single units is deficient in high-molecular-weight multimers of von Willebrand factor (vWF), a critical facilitator of platelet adhesion and thrombus formation. We hypothesized that converting high-molecular-weight multimers to smaller molecular-weight multimers would retain vWF's capacity to mediate platelet adhesion. STUDY DESIGN AND METHODS: SpDP obtained from untreated FFP was reconstituted with glycine-hydrochloric acid (HCl) and glycine (20 mM:50 mM) or pretreated with glycine-HCl (20 mM) or glycine-glycine-HCl (20 mM:50 mM) and reconstituted with water. In vitro hemostatic potential of SpDPs versus FFP or FFP spiked with 70 mM of glycine was evaluated, leading to a more detailed in vitro study of glycine-HCl-glycine (20 mM:50 mM) pretreated SpDP. Plasmas were combined with RBCs and platelets to observe global coagulation response. RESULTS: While vWF-ristocetin cofactor activity is significantly decreased (-41.13%; p < .0001) in SpDP, a model of vWF-mediated platelet adhesion to collagen under flow showed enhanced function (+13%; p < .01). Fewer microparticles, particularly of platelet origin, were observed in SpDP versus FFP (p < .0001). Small but significant differences in thromboelastography results were observed, although SpDP and FFP were within normal ranges. CONCLUSION: Comparable coagulability was observed in FFP and SpDP. The apparent paradox between vWF-ristocetin cofactor assay and vWF-mediated platelet adhesion may be explained by the increase in smaller multimers of vWF in SpDP, producing different outcomes in these assays. PMID- 30450618 TI - Key pathway and gene alterations in the gastric mucosa associated with obesity and obesity-related diabetes. AB - BACKGROUND AND OBJECTIVE: The stomach plays an important role in obesity and obesity-related diabetes; yet, little is known about key pathways in the gastric mucosa associated with obesity and diabetes. METHODS: We performed gene microarray and real time-polymerase chain reaction (RT-PCR) on gut mucosa samples from control subjects (CON), patients with simple obesity (OB), and patients with obesity and comorbid diabetes (OD) (n = 3 per group). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to predict the functional significance of differentially expressed genes. RESULTS: In total, 262 genes were upregulated and 265 genes were downregulated in the OB group whereas 1756 genes were upregulated and 1053 genes were downregulated in the OD group compared with the CON group. Of these, 23 were co-regulated in both comparisons. Seven differentially expressed genes were validated by RT-PCR (NRIP3, L1CAM, TPO, P2RY1, OR8A1, ADAMTS19, and ASIC3). A functional analysis revealed that genes differentially expressed between the OB or OD and CON groups played crucial roles in metabolic, T cell, and G-protein coupled receptor biological processes, and primarily participated in the PI3K-Akt and AGE-RAGE signaling pathways. CONCLUSIONS: Obesity and obesity-related diabetes are associated with important gene expression and pathway alterations in the stomach. PMID- 30450619 TI - Hunting for the high-affinity state of G-protein-coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging. AB - The concept of the high-affinity state postulates that a certain subset of G protein-coupled receptors is primarily responsible for receptor signaling in the living brain. Assessing the abundance of this subset is thus potentially highly relevant for studies concerning the responses of neurotransmission to pharmacological or physiological stimuli and the dysregulation of neurotransmission in neurological or psychiatric disorders. The high-affinity state is preferentially recognized by agonists in vitro. For this reason, agonist tracers have been developed as tools for the noninvasive imaging of the high affinity state with positron emission tomography (PET). This review provides an overview of agonist tracers that have been developed for PET imaging of the brain, and the experimental paradigms that have been developed for the estimation of the relative abundance of receptors configured in the high-affinity state. Agonist tracers appear to be more sensitive to endogenous neurotransmitter challenge than antagonists, as was originally expected. However, other expectations regarding agonist tracers have not been fulfilled. Potential reasons for difficulties in detecting the high-affinity state in vivo are discussed. PMID- 30450620 TI - Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma arising in patient with a history of EBV-positive mucocutaneous ulcer and EBV-positive nodal polymorphous B-lymphoproliferative disorder. AB - Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period. PMID- 30450621 TI - On the efficiency of adaptive sample size design. AB - Adaptive sample size designs, including group sequential designs, have been used as alternatives to fixed sample size designs to achieve more robust statistical power and better trial efficiency. This work investigates the efficiency of adaptive sample size designs as compared to group sequential designs. We show that given a group sequential design, a uniformly more efficient adaptive sample size design based on the same maximum sample size and rejection boundary can be constructed. While maintaining stable statistical power at the required level, the expected sample size of the obtained adaptive sample size design is uniformly smaller than that of the group sequential design with respect to a range of the true treatment difference. The finding provides further insights into the efficiency of adaptive sample size designs and challenges the popular belief of better efficiency associated with group sequential designs. Good adaptive performance plus easy implementation and other desirable operational features make adaptive sample size designs more attractive and applicable to modern clinical trials. PMID- 30450622 TI - Neuromodulation-dependent effect of gated high-frequency, LFMS-like electric field stimulation in mouse cortical slices. AB - Low-field magnetic stimulation (LFMS) is a gated high-frequency noninvasive brain stimulation method (500 Hz gated at 2 Hz) with a proposed antidepressant effect. However, it has remained unknown how such stimulation paradigms modulate neuronal network activity and how the induced changes depend on network state. Here we examined the immediate and outlasting effects of the gated high-frequency electric field associated with LFMS on the cortical activity as a function of neuromodulatory tone that defines network state. We used a sham-controlled study design to investigate effects of stimulation (20 minutes of 0.5s trains of 500 Hz charge-balanced pulse stimulation patterned at 0.5 Hz) on neural activity in mouse medial prefrontal cortex in vitro. Bath application of cholinergic and noradrenergic agents enabled us to examine the stimulation effects as function of neuromodulatory tone. The stimulation attenuated the increase in firing rate of layer V cortical neurons during post-stimulation period in presence of cholinergic activation. The same stimulation had no significant immediate or outlasting effect in absence of exogenous neuromodulators or in the presence of noradrenergic activation. These results provide electrophysiological insights into the neuromodulatory-dependent effects of gated high-frequency stimulation. More broadly, our results are the first to provide a mechanistic demonstration of how behavioral states and arousal levels may modify the effects of non-invasive brain stimulation. This article is protected by copyright. All rights reserved. PMID- 30450623 TI - How robust are reference pricing studies on outpatient medical procedures? Three different preprocessing techniques applied to difference-in differences. AB - The evaluation of policies that are not randomly assigned on outcomes generated by nonlinear data generating processes often requires modeling assumptions for which there is little theoretical guidance. This paper revisits previously published difference-in-differences results of an important example, the introduction of reference pricing to common outpatient procedures, to assess the robustness of the estimated impacts by using different matching, and reweighting techniques to preprocess the data. These techniques improve covariate balance and reduce model dependence. Specifically, we examine the robustness of the effect of reference pricing on patient site-of-care choice, total expenditures, and complication rates. We apply three preprocessing methods: propensity score reweighting, exact matching, and genetic matching. Propensity score reweighting is a technique for achieving covariate balance but does not balance higher-order moments and may lead to bias and inefficiency in estimating treatment effects in the context of nonlinear data generating processes. In contrast, exact matching and genetic matching are designed to balance higher-order moments. We find that although the use of the preprocessing techniques is a valuable robustness check showing that some results are sensitive to the method used, the three approaches generally yield results that do not statistically differ from the published results. PMID- 30450624 TI - The functions of FoxO transcription factors in epithelial wound healing. AB - Re-epithelialisation is a complex process that involves the migration and proliferation of keratinocytes, as well as the production of cytokines and growth factors that affect wound healing. The precise mechanisms that control the tissue repair process remain poorly understood. Recent evidence indicates that FoxO transcription factors play a crucial role in wound healing. In mammals, different isoforms of FoxO, namely, FoxO1, FoxO3, FoxO4 and FoxO6, are present; however, FoxO1 and FoxO3 primarily function in epithelial wound healing. The functions of FoxO proteins in normal wound healing are opposite of those in diabetic wound healing. On the one hand, FoxO transcription factors promote the migration of keratinocytes through up-regulating the expression of transforming growth factor beta and protecting keratinocytes from oxidative stress. On the other hand, FoxO transcription factors negatively regulate some genes that are needed for re epithelialisation and keratinocyte migration. This review provides a summary of the functions of FoxO proteins in re-epithelialisation. PMID- 30450625 TI - T11TS immunotherapy augments microglial and lymphocyte protective immune responses against Cryptococcus neoformans in the brain. AB - Cryptococcus neoformans, the encapsulated yeast acquired through inhalation remains localized in lungs, but harbours the CNS in immunocompromised individuals. Several treatment regimes have failed combating this disease totally, but long term usage of drugs lead to organ damage. As T11-target structure (T11TS) has documented profound immune potentiation, we aimed to investigate the role of microglia, pivotal immune cells of brain in ameliorating cryptococcosis, with T11TS immunotherapy. Murine model with C. neoformans infection were prepared by intraperitoneal injection and the brains of rats examined 7 days post infections for histopathology by PAS and Alcian blue staining corroborated with organ fungal burden evidencing restorative T11TS action on crytococcal meningitis. Immunotherapy with three doses of T11TS, a CD2 ligand, in C. neoformans infected rats, upregulate toll-like receptors 2, -4 and 9 of microglia, indicating increased phagocytosis of the fungus. Flowcytometric analysis revealed increased numbers of T11TS treated brain infiltrating CD4+ and CD8+ T-lymphocytes along with increased MHC-I and MHC-II on microglia, activating the infiltrating lymphocytes aiding the killing mechanism. Present study also indicated that T11TS increased production of Th1 inflammatory cytokines conducive to fungal elimination while the inhibitory Th2 cytokines were dampened. This preclinical study is first of its kind to show that T11TS effected profound immune stimulation of microglial activity of C. neoformans infected rats eradicating residual fungal burden from the brain and can be a useful therapeutic strategy in fighting against this deadly disease. This article is protected by copyright. All rights reserved. PMID- 30450626 TI - Pillar[5]-bis-thiacrown: An Adaptive Tricyclic Host Selectively Recognizing an Organic Guest by Dimetalation. AB - Some biological receptors change their shapes and rigidity by metalation to recognize substrates precisely via adaptive guest binding process. Herein we present a semi-flexible tricyclic host molecule whose conformation is rigidified by dimetalation to uptake organic guests selectively. Considering two metal binding sites and an empty space between them, pillar[5]-bis-thiacrown (L) was synthesized. The tricyclic host L forms a disilver(I) complex [Ag2 L(NO3 )2 ], with an Ag???Ag separation of 9.976 A. Binding studies based on 1 H NMR including 2D NOESY and DOSY experiments towards alpha,omega-dicyanoalkanes [CN(CH2 )n CN, n=2-6, shortly C2-C6] demonstrated that the dimetalated L, Ag2 L preferentially recognizes C2 over other guests than that of free L. Furthermore, the dimetalated the host only uptakes C2 in the presence of other guests. Crystal structures support the idea that the space between two silver(I) centers plays a decisive role on the selective guest binding forming an Ag-C2-Ag@L arrangement via the length-selective recognition. This work demonstrates the chemical example of the adaptive guest binding and presents a new perspective on the metallosupramolecules of pillararenes. PMID- 30450627 TI - Aloysia citriodora Palau (lemon verbena) for insomnia patients: A randomized, double-blind, placebo-controlled clinical trial of efficacy and safety. AB - Aloysia citriodora (A. citriodora) has a long history of traditional use for sedation and treatment of insomnia in different societies. This study was carried out to assess the efficacy of A. citriodora in patients with insomnia. One hundred patients were randomly divided into two groups of A. citriodora (total essential oil 1.66 mg/10 ml and total amount of flavonoid in terms of quercetin 3.22 mg/10 ml of the syrup) and placebo. They were advised to use 10 cc of the syrups; an hour before the bedtime for a period of 4 weeks. Participants were assessed using Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) questionnaires at the baseline and then 2 and 4 weeks after the enrollment. Mean scores of global PSQI and its four components including sleep latency, habitual sleep efficiency, daytime dysfunction, and subjective sleep quality and also ISI score in the A. citriodora group improved significantly after 4 weeks of treatment when compared with the placebo group (p < 0.001, for all of them). Also, improvement of global score of PSQI and ISI was observed in the intervention group as compared with the placebo group, 2 weeks after the enrollment (p < 0.001). The results of this study showed that oral intake of A. citriodora can be suggested as a complementary treatment for patients with insomnia. PMID- 30450628 TI - IL-28beta gene polymorphism determines virological response to PEGylated interferon therapy in hepatitis C virus genotype 4 Egyptian patients. AB - BACKGROUND: PEGylated interferon (PEG-IFN) in combination with ribavirin is the gold standard for chronic hepatitis C virus (HCV). The majority of patients received PEG-IFN/ribavirin achieve a sustained viral response (SVR), but few cases failed to respond. It was evident that host genetic factors determine the treatment-induced viral clearance as well as spontaneous response. In the current study, the rs12979860 polymorphism of IL28beta gene was analyzed and its association with the virological response to PEG-IFN treatment was determined. METHODS: One hundred and fifty Egyptian patients with HCV genotype 4 treated with PEG-IFN/ribavirin were assessed at 12 and 24 weeks of therapy, the rs12979860 genotype was determined using TaqMan-based quantitative polymerase chain reaction. RESULTS: Although the CC genotype was the most frequent (58%), the higher SVR was achieved for patients with favorable CC genotype (93%) in contrast to CT and TT genotypes. CONCLUSION: we conclude that IL28B polymorphism is highly associated with SVR to therapy in the Egyptian population infected with HCV genotype 4 and patients who carry CC genotype have a higher chance of SVR. PMID- 30450629 TI - Factors influencing blood pressure classification for adults: Gender differences. AB - AIM: Hypertension is a common condition contributing to many diseases. Factors influencing blood pressure (BP) classification for adults have changed over time. This study aimed to identify factors influencing BP classification according to gender. METHODS: Data from the Sixth Korean National Health and Nutrition Examination Survey (2014) were used in this descriptive, cross-sectional study. Participants were 1555 adults (589 men, 966 women). Measures included demographic, health-related, and lifestyle factors. RESULTS: Compared with the male normal BP group, in the male prehypertension group, body mass index, problem drinking, and reduced sleep duration were higher; and in the male hypertension group, age, poor subjective health status, body mass index, diabetes, problem drinking, smoking, and sodium intake were higher. Compared with the female normal BP group, age, and body mass index were higher in the female prehypertension group; and age, poor subjective health status, body mass index, menopause, and diabetes were higher in the female hypertension group. CONCLUSION: Hypertension and prehypertension prevention interventions for adults should be distinguished according to gender. PMID- 30450630 TI - Assessment of mold and yeast in some bakery products of Lahore, Pakistan based on LM and SEM. AB - The present investigation was designed to throw light on the microbial status of bakery products available in bakeries and supermarkets of Lahore. Different bakery samples such as biscuits, pizza, patties were collected from different localities such as Anar Kali, Chauburji, Faisal Town, Iqbal Town, Model Town, Muslim Town were investigated for mold and yeast using serial dilution technique inoculated over malt extract agar and potato dextrose agar under sterilized conditions. Isolated fungi were namely Alternaria alternata, Aspergillus niger, Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Curvularia americana, Fusarium solani, Penicillium digitatum, Saccharomyces cerevisiae, and Geotrichum candidum. Results depicted maximum fungal viable count in biscuits, collected from Model Town while minimum count was in the samples of Chauburji. In the case of pizza, the maximum fungal viable count was found in the sample of Muslim Town. In the case of patties, the maximum fungal viable count was found in the sample of Muslim Town while minimum count was found in the sample of Iqbal Town. Prevalence of microorganisms may be due to the use of contaminated raw material, use of polluted waters, human handling, and the use of contaminated containers. Contaminated food intake can lead to measurable signs of liver injury, inflammation, etc. Preventive measures like washing and drying of hands before preparing food, cleaning of food preparation areas, and the use of clean equipment can avoid microbes which cause hazards to human health. RESEARCH HIGHLIGHTS: Bakery products of Lahore, Pakistan is investigated for the first time on the basis of light microscopy (LM) and scanning electron microscopy (SEM) and found very significant to check the quality of bakery products or not. PMID- 30450631 TI - Changing trends in management of vestibular schwannoma: A National Cancer Database study. AB - OBJECTIVE: To describe changes in management trends of vestibular schwannoma (VS) and the effects of median income, education level, insurance status, and tumor size on receipt of treatment. METHODS: Cross-sectional analysis using the National Cancer Database from 2004 to 2014. All patients with a diagnosis of VS were identified between 2004 and 2014. Trends in treatment modality over time were analyzed. Correlation between demographics, institution type, median income, education level, and insurance status were assessed using univariate and multivariate logistic regressions. RESULTS: Of the 22,290 VS patients identified, 16,011 (71.8%) received treatment, whereas 6,279 (28.2%) received observation. Management trend analysis over the 11-year period revealed patients with tumor size < 1 cm are more frequently observed (34.6% of cases in 2004 vs. 60.8% of cases in 2014) and less frequently received surgery (34.6% vs. 16.8%). Multivariate analysis showed observation was more frequently used in patients >= 65 years; black patients; and those on Medicaid, Medicare, and noninsured (P < 0.0001). All tumors > 2 cm were more likely to be treated with surgery, specifically subtotal resections (P < 0.0001). Patients treated at nonacademic centers were more likely to receive linear accelerator, or LINAC (Accuray Incorporated, Sunnyvale, CA) therapy than Gamma Knife (Elekta, Stockholm, Sweden) (P < 0.0001). CONCLUSION: Management of VS is shifting toward increased observation, most significantly in tumors size < 1 cm. Insurance provider plays a significant role on receipt of treatment and modality, whereas income and education do not. LEVEL OF EVIDENCE: N/A Laryngoscope, 2018. PMID- 30450632 TI - CTCs-derived xenograft development in a Triple Negative breast cancer case. AB - Triple-negative breast cancer (TNBC) is characterized by high rates of metastasis and no available molecular targets. CTCs derived xenografts (CDX) have demonstrated to be a promising tool for understanding cancer biology. In this study a CDX from a TNBC patient was developed for the first time. After CDX characterization, WNT signalling was found as the main mechanism related with this tumor biology and potential CTCs markers were identified and subsequently validated in TNBC patients. In this cohort high levels of MELK expression were associated with poorer survival rates. Overall, this study demonstrates that CTCs from TNBC are tumorigenic and CDXs are a useful model to obtain valuable information about the tumor. This article is protected by copyright. All rights reserved. PMID- 30450633 TI - Reply to Letter to the Editor: "Nomenclature for real-time magnetic resonance imaging". PMID- 30450634 TI - Systematic review and meta-analysis: portal vein recanalisation and transjugular intrahepatic portosystemic shunt for portal vein thrombosis. AB - BACKGROUND: Transjugular intrahepatic portosystemic shunt has been increasingly used in patients with portal vein thrombosis to obtain patency, but evidenced based decisions are challenging. AIM: To evaluate published data on efficacy and safety of endovascular therapy in portal vein thrombosis. METHODS: Systematic search of PubMed, ISI, Scopus, and Embase for studies (in English, until October 2017) reporting feasibility, safety, 12-month portal vein recanalisation, transjugular intrahepatic portosystemic shunt patency, and survival in patients with benign portal vein thrombosis undergoing endovascular treatment. An independent extraction of articles using predefined data fields and quality indicators was used; pooled analyses based on random-effects models; heterogeneity assessment by Cochran's Q, I2 statistic, subgroup analyses, and meta-regression. RESULTS: Thirteen studies including 399 patients (92% cirrhosis; portal vein thrombosis: complete 46%, chronic 87%, cavernous transformation 17%, superior mesenteric vein involvement 55%) were included. Transjugular intrahepatic portosystemic shunt was technically feasible in 95% (95% CI: 89% 98%) with heterogeneity (I2 = 57%, P < 0.001) explained by cavernous transformation. Major complications occurred in 10% (95% CI: 6.0%-18.0%; I2 = 52%, P = 0.55). Additional catheter-directed thrombolysis was associated with more complications compared to transjugular intrahepatic portosystemic shunt alone or plus thrombectomy (17.6% vs 3.3%). Twelve-month portal vein recanalisation was 79% (95% CI: 67%-88%; I2 = 78%, P < 0.01). Shunt patency at 12 months was 84% (95% CI: 76%-90%; I2 = 62%, P < 0.01). Overall 12-month survival rate was 89%, with no heterogeneity. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt for portal vein thrombosis recanalisation was highly feasible, effective, and safe. Cavernous transformation was the main determinant of technical failure. Additional catheter-directed thrombolysis was associated with higher risk of severe complications. PMID- 30450635 TI - Assessment of microRNA-144-5p and its putative targets in inflamed gingiva from chronic periodontitis patients. AB - BACKGROUND AND OBJECTIVE: This study aimed to discover the distinctive MicroRNAs (miRNA) functioning in the pathogenesis of periodontal inflammation, which might be potential therapy targets of chronic periodontitis. MATERIAL AND METHODS: miRNA profiles of human inflamed gingival tissue from three previous microarrays were re-analysed. Gingival tissues were collected for the validation of overlapping miRNAs, and a network was constructed to show regulatory connection between overlapping miRNAs and periodontitis-associated target genes. Potential miRNAs were screened based on their expression levels and predicted target genes. Correlation analysis and binding site prediction were conducted to reveal the relationship between the potential miRNAs and their target genes. RESULTS: miR 144-5p, found to be upregulated in all three studies, showed the greatest upregulation (P < 0.0001). Another 16 miRNAs (10 upregulated and six downregulated) overlapped between any two of the three studies. All overlapping miRNAs had expected expression levels except for miR-203 during validation. Ten miRNAs (six upregulated and four downregulated) were found to have periodontal inflammation-associated targets. Cyclooxygenase 2 (COX2) and interleukin-17F (IL17F), predicted target genes of upregulated miR-144-5p, showed significant decreases and were negatively correlated with miR-144-5p in the periodontitis group (r = -0.742 for COX2, r = -0.615 for IL17F). CONCLUSION: This re-analysis of miRNA signatures has implied the potential regulatory mechanism of miR-144-5p and its potential for exploring alternative therapeutic approaches, especially those that use miRNA delivery systems to treat chronic periodontitis. Nevertheless, further study based on larger sample size and homogenous cells is needed to reveal the exact roles of miRNAs in chronic periodontitis. PMID- 30450636 TI - Health beliefs and behaviours in relation to sexually transmitted infections among South Korean juvenile offenders: A focused ethnography study. AB - AIM: This study explored health beliefs and behaviours related to sexually transmitted infections (STIs) from the perspective of juvenile offenders with STIs in three urban cities. METHODS: Data were collected using observations and in-depth interviews between July and November, 2014. Under the supervision of probation officers, 24 juvenile offenders with STIs were interviewed. Leininger's four-step method guided the data analysis. FINDINGS: From participants' perspectives, poor hygiene and a promiscuous lifestyle caused the STIs. The diseases were considered an adult disease with distinct symptoms and deformities, no cure, and therefore fatal. STIs were shameful for juveniles because their presence revealed sexually active behaviours. The juveniles' health-related behaviours included neglecting their STI symptoms because they did not know they were infected, mistaking STIs for other health conditions, choosing to suffer rather than revealing their diagnosis, and keeping their genitals clean. CONCLUSION: A large gap emerged between juveniles' beliefs and behaviours related to STIs. Policies and education are needed to provide accurate STI information for this population. PMID- 30450638 TI - Evaluation of magnetohydrodynamic effects in magnetic resonance electrical impedance tomography at ultra-high magnetic fields. AB - PURPOSE: Artifacts observed in experimental magnetic resonance electrical impedance tomography images were hypothesized to be because of magnetohydrodynamic (MHD) effects. THEORY AND METHODS: Simulations of MREIT acquisition in the presence of MHD and electrical current flow were performed to confirm findings. Laminar flow and (electrostatic) electrical conduction equations were bidirectionally coupled via Lorentz force equations, and finite element simulations were performed to predict flow velocity as a function of time. Gradient sequences used in spin-echo and gradient echo acquisitions were used to calculate overall effects on MR phase images for different electrical current application or phase-encoding directions. RESULTS: Calculated and experimental phase images agreed relatively well, both qualitatively and quantitatively, with some exceptions. Refocusing pulses in spin echo sequences did not appear to affect experimental phase images. CONCLUSION: MHD effects were confirmed as the cause of observed experimental phase changes in MREIT images obtained at high fields. These findings may have implications for quantitative measurement of viscosity using MRI techniques. Methods developed here may be also important in studies of safety and in vivo artifacts observed in high field MRI systems. PMID- 30450637 TI - Final Results of the RHAPSODY trial: A multi-center, Phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A APC, a Recombinant Variant of Human Activated Protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke. AB - OBJECTIVE: Agonism of the protease activated receptor (PAR) 1 by activated protein C (APC) provides neuroprotection and vasculoprotection in experimental neuro-injury models. The pleiotropic PAR1 agonist, 3K3A-APC, reduces neurologic injury and promotes vascular integrity; 3K3A-APC proved safe in human volunteers. We performed a randomized, controlled, blinded, trial to determine the maximally tolerated dose (MTD) of 3K3A-APC in ischemic stroke patients. METHODS: The NeuroNEXT trial RHAPSODY used a novel continual reassessment method to determine the MTD using tiers of 120, 240, 360 and 540MUg/kg 3K3A-APC. After intravenous tissue plasminogen activator, intraarterial mechanical thrombectomy, or both, patients were randomized to one of the four doses or placebo. Vasculoprotection was assessed as microbleed and intracranial hemorrhage (ICH) rates. RESULTS: Between January 2015 and July 2017 we treated 110 patients. Demographics resembled a typical stroke population. The MTD was the highest dose 3K3A-APC tested, 540MUg/kg, with an estimated toxicity rate of 7%. There was no difference in prespecified ICH rates. In exploratory analyses, 3K3A-APC reduced ICH rates compared to placebo from 86.5% to 67.4% in the combined treatment arms (p=0.046), and total hemorrhage volume from an average of 2.1+/-5.8 mL in placebo to 0.8+/ 2.1 mL in the combined treatment arms (p=0.066). INTERPRETATION: RHAPSODY is the first trial of a neuroprotectant for acute ischemic stroke in a trial design allowing thrombectomy, thrombolysis, or both. The MTD was 540MUg/kg for the PAR1 active cytoprotectant 3K3A-APC. A trend toward lower hemorrhage rate in an exploratory analysis requires confirmation. This article is protected by copyright. All rights reserved. PMID- 30450640 TI - C-H Functionalization of Commodity Polymers. AB - Synthetic manipulation of polymer substrates is one of the oldest and most reliable methods to increase the functional diversity of soft materials. Modifying the chemical structure of polymers that are already produced at a commodity scale leverages the current high-volume and low-cost production of commodity plastics for modern material discovery efforts. A myriad of polymer C-H functionalization methods have been developed, which enable the modification of material properties at both a lab and industrial scale. More recently, driven by advances in C!-H activation, photoredox catalysis, and radical chemistry, chemoselective approaches have emerged as a means to impart precise functionality onto commodity polymer substrates. This Review discusses the historical significance of and contemporary advances in the C-H functionalization of commodity polymers. The conceptual approach outlined herein presents exciting new directions for the field, including increasing the value of otherwise pervasive materials, uncovering entirely new material properties, and introducing a viable path to upcycle post-consumer plastic waste. PMID- 30450639 TI - Gene Expression in Hip Soft Tissues in Incipient Canine Hip Dysplasia and Osteoarthritis. AB - Canine hip dysplasia and developmental dysplasia of the human hip share demographic, phenotypic, and clinical features including the predisposition to develop osteoarthritis in affected joints. To support the results of genetic mapping studies for CHD and its concomitant osteoarthritis with functional information, we performed RNA-seq on hip capsule and teres ligament of affected and unaffected dogs. RNA seq showed that expressed genes segregated according age, capsule or ligament, and hip phenotype. Expression of HHIP, DACT2, and WIF1 was significantly higher in capsule from control hips than dysplastic hips indicating a disruption of the hedgehog signaling pathway. Expression of SPON 1, a key component of the WNT pathway, was increased significantly in both dysplastic capsule and ligament while FBN2 and EMILIN3 were significantly increased in dysplastic capsule. Of genes associated with human hip osteoarthritis, expression of ACAN, IGF1, CILP2, COL11A1, COL8A1, and HAPLN was increased significantly in dysplastic capsule. The significant increase in expression of PLA2F, TNFRSF, TMEM, and IGFBP in dysplastic capsule indicated an injury response. Gene set enrichment analysis revealed that genes involved in extracellular matrix structure, epithelial to mesenchymal transition, myogenesis, growth factor signaling, cancer and immune pathways were enriched in dysplastic capsule. For teres ligament from dysplastic joints, genes in retinoic signaling pathways and those encoding extracellular matrix synthesis, but not proteoglycans, were enriched. Hip tissues respond to abnormal mechanics early in dysplastic hip development and these pathways present targets for intervention in the early synovitis and capsulitis secondary to canine and human hip dysplasia. This article is protected by copyright. All rights reserved. PMID- 30450641 TI - The experience of hospital staff in applying the Gentle Persuasive Approaches to dementia care. AB - WHAT IS KNOWN ON THE SUBJECT?: Although the seminal work of McCormack et al. (International Practice Development Journal, 2015, 5, 1) and Nolan, Davies, Brown, Keady, and Nolan () provides useful conceptual frameworks in person centred care, research is needed to understand how theoretical concepts can be applied into practice to support dementia care. Also, evidence is needed to demonstrate the impacts of implementing person-centred care and staff experiences. WHAT DOES THIS PAPER ADD TO EXISTING KNOWLEDGE?: This paper adds to the emerging work that is providing a greater understanding of how team education in practice can make a difference in building capacity to improve dementia care. We offer timely evidence and useful insights into how an education programme, Gentle Persuasive Approaches (GPA), was implemented ("what worked" and "how") in a large Canadian hospital to improve knowledge and skills among staff in dementia care. The GPA education helped hospital staff enact person-centred care by cultivating shared values and a learning environment to change attitudes, practices and conditions for continuous practice development. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Mental health nurses in advance practice are well positioned to lead dementia education and advocate for person-centred care in hospitals. Hospital leaders are responsible for providing resources to cultivate a supportive environment for continuous learning to ensure the workforce gains the capacity to meet the changing demands and needs of the ageing population. System support is essential for creating conditions to enable person-centred care. ABSTRACT: Introduction Hospital staff lacks knowledge and skills in dementia care. There is a need to understand how person-centred care theory can be operationalized in staff's practices to improve dementia care. Aims To describe the staff's experiences of learning and applying the Gentle Persuasive Approaches (GPA) to enact person-centred care in a hospital. Methods Mixed methods, including posteducation survey and focus groups, were used. Thematic analysis was conducted to identify themes that describe participants' experiences. Results Three hundred and ten staff and leaders in a hospital participated in the GPA education and completed a posteducation survey (n = 297). After 1 year, two follow-up focus groups were conducted with interdisciplinary staff (n = 24) across medicine and mental health programmes. Our analysis identified three themes to enable person-centred care: (a) changing attitudes, (b) changing practices and (c) changing conditions. Discussion This study contributes to the literature by providing evidence of how an education programme was implemented in a large Canadian hospital to build capacity for dementia care. Joint education for interprofessional staff offers value in enabling person centred care. Implication Mental health nurses are in position to lead dementia education and advocate for person-centred care in hospitals. Staff need structural support to engage in team learning for practice improvement. PMID- 30450642 TI - Butanediol conversion to gamma-hydroxybutyrate markedly reduced by the alcohol dehydrogenase blocker fomepizole. AB - 1,4-Butanediol (BDO) - used as solvent, and abused for its euphoric effects - is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase (ADH). This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4MP) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP, followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (p=0.001) and AUC (p=0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (p=0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO. This article is protected by copyright. All rights reserved. PMID- 30450643 TI - Corrigendum. PMID- 30450644 TI - Evidence needed to understand gender identity: Commentary on Turban & Ehrensaft (2018). AB - Turban and Ehrensaft (2018) have provided a thoughtful review of transgender identity in children and adolescents, emphasizing the benefits of the affirmative approach in maintaining positive psychological health in transgender individuals. The review reveals significant gaps in our understanding of gender identity regarding its nature, development, plasticity, causes, and links with other aspects of gender, and of the long-term benefits and costs of childhood social transitions. A full understanding of transgender identity requires studying cisgender identity too, and recognition that gender identity is continuous, develops across time and is not synonymous with gender expression or variations in gender-typed characteristics. Considerable evidence is needed before we can be confident that we are providing optimal treatment for children who are gender variant. PMID- 30450645 TI - Editorial: Should child psychiatry be more like paediatric oncology? AB - Looked at from a public health perspective, psychiatric disorders are devastating and cost humanity a tremendous amount of suffering as well as resources. On the other hand, childhood cancer is relatively rare and on a large scale, causes much less mortality and morbidity. Yet, when it comes to anything from public perception, to funding or to hyperbolic tabloid headlines, oncology wins hands down. Children with cancer are also better off when it comes to the quality of services and respect patients get from the health care system, treaters, and their own families. Also the cure rates for come childhood cancers, such as leukaemia, have improved dramatically. What can possibly explain such puzzling differences? PMID- 30450646 TI - Dual benefit of supplementary oral 5-aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model. AB - BACKGROUND: Normal tissue damage caused by radiotherapy remains the largest dose limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate the supplementary oral 5-aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic prostate cancer (PCa) model. METHODS: To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC-CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC-CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki-67, gamma-H2AX, CD204, and uroplakin III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to "Stress & Toxicity PathwayFinder," "Mitochondria," and "Inflammasomes." RESULTS: The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin-1a (IL 1a), IL-1b, IL-12, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. CONCLUSIONS: Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa. PMID- 30450647 TI - The guanine nucleotide exchange factor Vav3 modulates oligodendrocyte precursor differentiation and supports remyelination in white matter lesions. AB - The tightly controlled processes of myelination and remyelination require the participation of the cytoskeleton. The reorganization of the cytoskeleton is controlled by small GTPases of the RhoA family. Here, we report that Vav3, a Rho GTPase regulating guanine nucleotide exchange factor (GEF) is involved in oligodendrocyte maturation, myelination and remyelination. When Vav3 was eliminated by genetic recombination, oligodendrocyte precursor cell (OPC) differentiation toward mature oligodendrocytes was accelerated. In contrast, Vav3 deficient oligodendrocytes displayed a reduced capacity to myelinate synthetic microfibers in vitro. Furthermore, remyelination was impaired in Vav3 knockout cerebellar slice cultures that were demyelinated by the addition of lysolecithin. In agreement with these observations, remyelination was compromised when the cuprizone model of myelin lesion was performed in Vav3-deficient mice. When Vav3 deficient oligodendrocytes were examined with Forster resonance energy transfer (FRET)-based biosensors, an altered activation profile of RhoA GTPases was revealed on the cellular level, which could be responsible for an impaired remyelination. Taken together, this study highlights Vav3 as a novel regulator of oligodendrocyte maturation and remyelination, suggesting that manipulation of the Vav3-dependent signaling pathway could help to improve myelin repair. PMID- 30450648 TI - The influence of body mass index on temperature management during general anaesthesia-A prospective observational study. AB - RATIONALE, AIMS, AND OBJECTIVES: During general anaesthesia, body core temperature is influenced by several factors that are either anaesthesia-related (type and duration of anaesthesia and fluid management), surgery-related (type of surgery and extent of the surgical procedure), or patient-related (age, gender, body weight, and preoperative body core temperature). Interestingly, data concerning body mass index (BMI) and its influence on patients' temperature are sparse. The aim of this study was to evaluate the impact of BMI on body core temperature under general anaesthesia. METHODS: A single centre, prospective, observational study was conducted at a university hospital. Two cohorts (lower limb surgery and abdominal surgery) were evaluated. Patients were treated according to actual German guidelines for the prevention of hypothermia. Temperature was measured sublingually prior to anaesthesia and during the first 60 minutes of anaesthesia. Each cohort was divided in three subgroups (BMI < 24 kg m-2 , BMI 25-34.9 kg m-2 , and BMI > 35 kg m-2 ) according to body weight. RESULTS: A total of 206 patients were evaluated. One hundred four underwent lower limb surgery; 102 underwent abdominal surgery. After induction of anaesthesia, temperature dropped in all subgroups, but this decline was more pronounced in patients with lower BMI. Significant differences concerning temperature changes were observed in abdominal surgery between low and high BMI groups. After 60 minutes of anaesthesia, group-dependent temperature differences had levelled out, and relevant differences compared with preoperative temperatures could no longer be observed in any of the groups. CONCLUSION: Current guidelines provide effective protection against perioperative hypothermia. In the current study, this was true for obese as well as normal weight patients. PMID- 30450649 TI - The association between early specialization and performance level with injury and illness risk in youth elite athletes. AB - A trend is observed towards more specialized training and selection into talent programs at an early age for youth athletes. Little is known how this might influence the risk of illness and injury. The aim of the study was to assess whether, in a group of youth elite athletes, those specializing early or performing best were at increased risk of incurring injury or illness after entering a specialized Sport Academy High School program. We enrolled 259 16-year old elite athletes. They completed a baseline web-based questionnaire covering their age at specialization, single- versus multi-sport involvement during the previous 2 years and current performance level (rated by themselves and their coach). Subsequently, the Oslo Sports Trauma Research Centre (OSTRC) questionnaire on health problems was used to self-report injuries and illnesses weekly for 26 weeks from October to May. In this specialized Sport Academy High School program, 39% of the athletes reported early specialization (at 12 years or younger). However, early specialization did not increase the risk of injury or illness during the 26 weeks, nor did being a single-sport athlete the previous two years increase this risk. The best performing athletes at the time of enrollment were not at greater risk of becoming injured or ill during the 26 weeks. In conclusion, in a group of youth elite athletes entering a specialized Sport Academy High School program neither early single-sport specialization nor performance level appears to represent risk factors for injury or illness after enrollment. PMID- 30450650 TI - Modularity is the mother of invention: a review of polymorphism in bryozoans. AB - Modularity is a fundamental concept in biology. Most taxa within the colonial invertebrate phylum Bryozoa have achieved division of labour through the development of specialized modules (polymorphs), and this group is perhaps the most outstanding exemplar of the phenomenon. We provide a comprehensive description of the diversity, morphology and function of these polymorphs and the significance of modularity to the evolutionary success of the phylum, which has >21000 described fossil and living species. Modular diversity likely arose from heterogeneous microenvironmental conditions, and cormidia (repeated clusters of associated modules) are an emergent property of the cue thresholds governing zooid plasticity. Polymorphs in a colony have, during phylogeny, transitioned into associated non-zooidal structures (appendages), increasing colonial integration. While the level of module compartmentalization is important for the evolution of bryozoan polymorphism, it may be less influential for other colonial invertebrates. PMID- 30450651 TI - ACT001 can prevent and reverse tamoxifen resistance in human breast cancer cell lines by inhibiting NF-kappaB activation. AB - Endocrine therapy is one of the main treatments for estrogen receptor-positive breast cancers. Tamoxifen is the most commonly used drug for endocrine therapy. However, primary or acquired tamoxifen resistance occurs in a large proportion of breast cancer patients, leading to therapeutic failure. We found that the combination of tamoxifen and ACT001, a nuclear factor-kappaB (NF-kappaB) signaling pathway inhibitor, effectively inhibited the proliferation of both tamoxifen-sensitive and tamoxifen-resistant cells. The tamoxifen-resistant cell line MCF7R/LCC9 showed active NF-kappaB signaling and high apoptosis-related gene transcription, especially for antiapoptotic genes, which could be diminished by treatment with ACT001. These results demonstrate that ACT001 can prevent and reverse tamoxifen resistance by inhibiting NF-kappaB activation. PMID- 30450652 TI - Comparison of filgrastim, pegfilgrastim, and lipegfilgrastim added to chemotherapy for mobilization of CD34+ cells in non-Hodgkin lymphoma patients. AB - BACKGROUND: Data are limited on the long-acting granulocyte-colony stimulating factors (G-CSFs) pegfilgrastim (PEG) and lipegfilgrastim (LIPEG) compared with filgrastim (FIL) regarding the mobilization efficiency of CD34+ cells, graft cellular composition, and engraftment. STUDY DESIGN AND METHODS: In this prospective nonrandomized study, 36 patients with non-Hodgkin lymphoma received FIL, 67 received PEG, and 16 patients received LIPEG as a cytokine after chemotherapy. We analyzed the mobilization and collection of CD34+ cells, cellular composition of blood grafts, and hematologic recovery after auto-SCT according to the type of G-CSF used. RESULTS: Patients in the LIPEG group had fewer apheresis sessions (1 vs. 2, p = 0.021 for FIL and p = 0.111 for PEG) as well as higher median blood CD34+ cell counts at the start of the first apheresis (LIPEG 74 * 106 /L vs. FIL 31 * 106 /L, p = 0.084 or PEG 27 * 106 /L, p = 0.021) and CD34+ yields of the first apheresis (FIL 5.1 * 106 /kg vs. FIL 2.3 * 106 /kg, p = 0.105 or PEG 1.8 * 106 /kg, p = 0.012). Also, the costs associated with G-CSF mobilization and apheresis were lower in the LIPEG group. The graft composition was comparable except for the higher infused CD34+ cell counts in the LIPEG group. The engraftment kinetics were significantly slower in the FIL group. CONCLUSION: LIPEG appears to be more efficient compared with PEG after chemotherapy to mobilize CD34+ cells for auto-SCT demonstrated as fewer sessions of aphereses needed as well as 2.8-fold CD34+ cell yields on the first apheresis day. Early hematologic recovery was more rapid in the LIPEG group. Thus further studies on LIPEG in the mobilization setting are warranted. PMID- 30450653 TI - A Germacalicene: Synthesis, Structure and Reactivity Zhaowen Dong, Lena Albers, Marc Schmidtmann and Thomas Muller*[a]. AB - The synthesis of germacalicene 7 from the reaction of dipotassium germole dianion K2[6] with 1,2-bis-diisopropylamino-3-chlorocyclopropenyl perchlorate is reported. Based on the crystal structure analysis and the results of DFT calculations, germacalicene 7 can be viewed as a cyclopropenium germacyclopentadienide ylid that is isoelectronic to alpha-cationic phosphanes. First reactivity studies revealed its nucleophilic character and resulted in the isolation of the air and moisture stable carbonyl iron 15 and the cationic silver complex 20. One electron oxidation of germacalicene 7 was achieved by its reaction with [Ph3C][B(C6F5)4] and the bis-cationic Ge-Ge bonded dimer 22 was isolated. PMID- 30450654 TI - Anti-inflammatory diet to reduce mortality: is it time for a precision medicine approach? PMID- 30450655 TI - Effect of different dry-polishing regimens on the intrapulpal temperature assessed with pulpal blood microcirculation model. AB - OBJECTIVE: The aim of the study was to evaluate the effect of different dry polishing regimens on the intrapulpal temperature assessed using a pulpal blood microcirculation model. MATERIALS AND METHODS: Eighty extracted human mandibular premolar teeth were used. Standardized class V cavity preparations were performed and were then restored. Teeth were divided into four main groups (n = 20): Fine polishing disc (SSF; 3M Sof-Lex, 3M ESPE, Minnesota); Super-fine polishing disc (SSS; 3M Sof-Lex); Spiral finishing wheel (SSW; 3M Sof-Lex); Enhance PoGo-One step diamond micro-polisher cup (EPO; Dentsply Sirona, Inc, Delaware). The main groups were divided: the low-load pressure (0.4N) and the high-load pressure (0.8N). The average change in intrachamber temperatures (Deltat), from initial to highest, were measured. RESULTS: The highest temperature increase was recorded in SSF08 (9.55 degrees C). The lowest value was recorded in EPO04 (1.9 degrees C). SSS08, SSW08, and EPO08 demonstrated significantly higher Deltat values than the low-load mode in SSS04, SSW04, and EPO04, respectively (P < .0001). CONCLUSIONS: Temperature was the least affected by the diamond cup in both pressure modes, and it was also less affected by the spiral finishing wheel in the low-load mode than in the high-load mode. Fine and super-fine discs had the greatest effect on intrachamber temperatures. CLINICAL SIGNIFICANCE: The present study suggests intrachamber temperature can rise among different dry-polishing regimes. Dental practitioners should pay attention to dry-polishing regimens and pressures for reducing heat-related dental problems. PMID- 30450656 TI - Venous thromboembolism in multiple myeloma - choice of prophylaxis, role of direct oral anticoagulants and special considerations. AB - Multiple myeloma is associated with a significant risk of venous thromboembolism (VTE), causing substantial levels of morbidity and mortality. The thrombogenicity of myeloma is multifactorial, with disease- and treatment-related factors playing important roles. Immunomodulatory drugs (IMiDs) and high-dose dexamethasone, in particular, are known to enhance the thrombotic potential of myeloma. For this reason, assessment of the VTE risk has long been advocated prior to treatment initiation in patients with myeloma requiring IMiD-based regimens. However, despite routine use of thromboprophylaxis, these patients can still develop VTE and its sequelae. The optimum choice and dose of thromboprophylactic drug is not entirely clear, and with this, there is growing interest regarding use of the direct oral anticoagulants in this setting. In this review we discuss the pathogenesis of thrombosis in multiple myeloma, its relation to some of the commonly used chemotherapeutic regimens, current risk stratification and the evidence supporting the different anticoagulants used as thromboprophylaxis. We propose an amended risk stratification, and consider management of challenging patients, including those with renal impairment and recurrent thrombosis. PMID- 30450658 TI - Insecticide dose and seasonal timing of trunk injection in apples influences efficacy and residues in nectar and plant parts. AB - BACKGROUND: Trunk injection is an established method for delivering pesticides in ornamental and shade trees, but further research is needed to determine efficacy and pollinator safety in tree fruit crops. Apple trees were injected in 2013 and 2014 with the insecticides emamectin benzoate, imidacloprid, dinotefuran, spinosad, chlorantraniliprole, or abamectin. Additional emamectin benzoate and imidacloprid injections were performed in the spring and fall of 2015. Nectar and pollen were sampled in the following spring to compare effects of application timings on insecticide loading into flowers. RESULTS: Neonicotinoids reduced Empoasca fabae density in the field. Emamectin benzoate, chlorantraniliprole, and abamectin resulted in moderate to high mortality and reduced Choristoneura rosaceana feeding in bioassays. Imidacloprid was not detected in nectar or pollen when injected in the spring and detected at 0.39 ng/g in pollen when injected the previous fall. Emamectin benzoate was not detected in nectar or pollen when injected the previous fall and detected at 7.36 ng/g (nectar) and 1.15 ng/g (pollen) when injected in the spring. CONCLUSIONS: This study identified a broader list of possible trunk injectable pesticides for apple trees. This study also shows that managing the seasonal timing of injection can reduce the risk of insecticide exposure to pollinators. This article is protected by copyright. All rights reserved. PMID- 30450657 TI - Quality of hypertension care: An improvement initiative in two outpatient health care centers. AB - RATIONALE, AIMS, AND OBJECTIVES: Hypertension control is an important public health goal; however, significant barriers remain in primary care practice. Our objective was to identify areas for improvement in hypertension care and implement changes in management to improve outcomes. We also aimed to evaluate whether quality improvement influences physician attitudes towards and adherence to current hypertension guidelines. METHOD: We conducted a non-experimental pre- vs post- design quality improvement study for ambulatory patients with a history of hypertension. Specific measures of hypertension care were assessed at baseline and 3 months post-implementation of the quality improvement initiative. De identified data were collected from 100 charts, randomly selected from the practice's electronic medical records, and compared with a national sample of peer data. The Intervention was based on the American Academy of Family Physicians METRIC Performance Improvement module. This consisted of creating a computerized registry, system improvements to the electronic medical records, and peer education workshops on best practices. A 7-item survey was completed by primary care physicians pre- and post-intervention. RESULTS: Improvement was demonstrated in several primary outcome measures: increased number of patients counselled on sodium intake (P = 0.005), physical activity (P = 0.001), alcohol consumption (P = 0.03), and weight reduction (P < 0.0001). Practice self assessment findings did not show a statistically significant change following the intervention. CONCLUSIONS: This quality improvement increased provider compliance with hypertension guidelines. However, more effort is required to modify physician practices for full compliance with the 2017 updated hypertension guidelines. PMID- 30450659 TI - Frequency and etiology of pulmonary hypertension in patients with myeloproliferative neoplasms. AB - OBJECTIVE: Pulmonary hypertension (PH) has been reported to be associated with myeloproliferative neoplasms (MPN), affecting 5-48% of MPN patients. With the aims to describe the prevalence of PH in Ph-MPN patients and explore the cause in identified subjects, we performed a prospective cohort study of Ph-MPN patients. METHOD: Transthoracic echocardiography (TTE) was performed on all patients. When the TTE was abnormal, further investigations were performed according to current guidelines from the European Society of Cardiology. The primary endpoint was the frequency of PH. The secondary endpoint was causes of PH. RESULTS: We included 158 patients, median age was 65 years. Fifty percent had polycythemia vera, 34% essential thrombocytosis, and 11% primary myelofibrosis, 3% post-ET myelofibrosis, and 2% post-PV-myelofibrosis. Only six patients (3.8%) were found to have a high probability of PH. They were all examined with right heart catheterization and all met the invasive criteria for PH. In all six patients other causes than MPN for PH were identified, although some contribution from the MPN could not be ruled out in three patients. CONCLUSION: In the largest study ever reported, we found a lower prevalence of PH (3.8%) than previously reported. Screening for PH in unselected MPN patients is not justified. This article is protected by copyright. All rights reserved. PMID- 30450660 TI - Localized primary malignant pericardial mesothelioma. AB - Primary malignant pericardial mesothelioma (PMPM) is an extremely rare tumor, which may appear as a localized or a diffuse mass encasing the heart. Diffuse PMPMs have a poor prognosis due to the difficulty of surgical excision, whereas localized PMPMs have clear margins, thus facilitating surgical excision. Timely diagnosis and proper treatment are crucial for a favorable prognosis. Eight cases of localized PMPMs have been reported so far, but their characteristics have not been fully described. Herein, we present a patient with localized PMPM and describe the diagnosis methods, treatment, and outcomes of these tumors. PMID- 30450661 TI - Pediatricians' proficiency in the care of the dysphonic child. AB - OBJECTIVES/HYPOTHESIS: Pediatricians are the first physicians to see a dysphonic child (DC), yet there are limited data on their proficiency in caring for them. The objective of this study was to understand how pediatricians' experience and their comfort in recognizing/diagnosing voice disorders affects their referral patterns and use of basic treatment options. STUDY DESIGN: Survey study. METHODS: A 13-question survey was sent to pediatricians in the Children's Hospital of Philadelphia's primary care network; 45/216 were returned. Statistical analyses were performed using the Student t test, linear/logistic regression model, Fisher exact test, Kruskal-Wallis test, and Spearman's correlation test. RESULTS: Pediatricians practicing longer are more comfortable recognizing dysphonia (P = .0022). They are significantly more likely to refer a DC, even without subjective complaints of hoarseness by the family/patient or compounding medical issues. For each year in practice, the probability of referring increases by 1.55% (P = .0017). Pediatricians with a higher percentage of dysphonic children in their practice are more likely to trust their own perceptual recognition when deciding to refer (P = .0496). Nearly all pediatricians (40/45) would refer to a pediatric otolaryngologist. None would refer to a laryngologist or a voice therapist. No factors significantly affected treatment options. CONCLUSIONS: Veteran pediatricians feel more comfortable diagnosing a voice disorder and are more likely to refer a DC, regardless of patient/parent complaints or compounding factors. Pediatricians are most likely to refer to a pediatric otolaryngologist versus a voice specialist. These findings suggest that education of younger, less experienced pediatricians about recognizing voice disorders and options for referral is needed. This may improve the overall care of the DC. LEVEL OF EVIDENCE: 4 Laryngoscope, 2018. PMID- 30450662 TI - Variants of hepatitis B virus surface antigen observed during therapy with nucleic acid polymer REP 2139-Ca have no influence on treatment outcome and its detection by diagnostic assays. AB - The treatment of patients suffering from HBeAg positive chronic hepatitis B with REP 2139-Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti-HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain lack of response to REP 2139-Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the "a" determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre-S/S open reading frame (ORF) was sequenced and pre-S1, pre-S2 and S amino acid sequences were analysed. We found no major differences between pre-S1, pre-S2 and S sequences in responders and non-responders correlated with low reduction of HBsAg. In addition, we found no mutations in the "a" determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre-S/S ORF has no direct influence on response to REP 2139-Ca therapy. This article is protected by copyright. All rights reserved. PMID- 30450663 TI - Activation of the mammalian target of rapamycin signaling pathway underlies a novel inhibitory role of ring finger protein 182 in ventricular remodeling after myocardial ischemia-reperfusion injury. AB - Myocardial ischemia-reperfusion injury (MIRI) is a major cause of cardiovascular disease, leading to mortality and disability associated with coronary occlusion worldwide. A correlation of mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-kappaB) signaling pathway has been observed with brain damage resulting from myocardial ischemia. Therefore, by establishing MIRI rat model, this study aimed to explore whether ring finger protein 182 (RNF182) regulates the mTOR signaling pathway affecting MIRI. Initially, MIRI rat model was successfully established, followed by either treatment of shRNF182 or phosphoesterase (PITE) (inhibitor of the mTOR signaling pathway). Then, the serum levels of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), and left ventricular end-diastolic pressure (LVEDP) were determined, followed by detection of myocardial infarct sizes and myocardial cell apoptosis. Moreover, the levels of related genes/proteins were determined to further determine the mechanisms of RNF182 in MIRI. First, RNF182 was upregulated in MIRI. Another key observation of this study was that rats with shRNF182 presented with downregulated SOD, GSH-Px, and MDA in serum, accompanied by decreased levels of LVEF, LVFS, LVSP, and LVEDP. In addition, both reduced myocardial infarct sizes and apoptosis of myocardial cells were observed after silencing RNF182. Furthermore, silencing of the RNF182 was observed to downregulate Bcl 2 associated X and cysteine proteinase 3 but upregulate mTOR, ribosome protein subunit 6 kinase 1, eukaryotic elongation factor 2, and B-cell lymphoma-2. Importantly, the effects of RNF182 silencing were reversed after PITE treatment. In conclusion, our study demonstrates that RNF182 silencing can prevent ventricular remodeling in rats after MIRI by activating the mTOR signaling pathway. PMID- 30450664 TI - Upper airway stimulation in obstructive sleep apnea improves glucose metabolism and reduces hedonic drive for food. AB - Upper airway stimulation is a new and effective second-line treatment for obstructive sleep apnea, but possible consequences on glucose metabolism and central regulation of food intake are unclear. Twenty patients were prospectively studied before and 12 months after obstructive sleep apnea treatment by upper airway stimulation. Respiratory parameters and daytime sleepiness were assessed to document effectiveness of treatment. Glucose metabolism was assessed by the oral glucose tolerance test, and hedonic versus homeostatic drive to eat was characterized. At 12 months, upper airway stimulation significantly improved measures of obstructive sleep apnea (all p < 0.01). Despite no change in body weight, fasting C-peptide insulin resistance index (p = 0.01) as well as insulin and C-peptide levels at 60 min during the oral glucose tolerance test (p < 0.02) were reduced. Hedonic drive to eat was strongly reduced (p < 0.05), while leptin and ghrelin remained unchanged (p > 0.15). Upper airway stimulation is effective in treatment of obstructive sleep apnea and improves glucose metabolism. Reduced hedonic drive to eat might contribute to these metabolic improvements. These promising findings are in need for long-term controlled evaluation of metabolic sequelae of upper airway stimulation and to mechanistically evaluate the metabolic benefits of upper airway stimulation in patients with obstructive sleep apnea. PMID- 30450665 TI - Optimizing aphid biocontrol with the predator Aphidoletes aphidimyza, based on biology and ecology. AB - Aphidoletes aphidimyza is one of the most important predators used in the augmentative biological control of aphids, key pests of many crops worldwide. Adult females are very efficient in locating aphid infestations over a relatively long range, up to 45 m, and deposit eggs near or within aphid colonies. The predatory larvae are aphid generalists preying on several agriculturally important aphid species. The successful use of this biocontrol agent in agricultural systems depends on several biotic and abiotic factors. Among biotic factors, aphid species, plant structure, interspecific competition and intraguild predation may significantly impact the predator's population dynamics. Key abiotic conditions include day lengths (above a critical threshold to prevent diapause), availability of mating sites in the crop, temperature (above 15 degrees C to enable egg laying), air relative humidity (above 70 %) and availability of pupation sites. Although several successes have been reported in open field crops with naturally occurring or released populations, commercial releases are primarily used in protected crops. Optimized emergence boxes combining provisioning of food sources for the adults, integration with the technological advances that occurred in the greenhouse environment lately, insights into the nutritional ecology in open field crops and exploration of the genetic variability are proposed as future directions to improve adoption and efficacy of A. aphidimyza in crop protection. This article is protected by copyright. All rights reserved. PMID- 30450666 TI - Recent clinical trends in Toll-like receptor targeting therapeutics. AB - Toll-like receptors (TLRs) are germline-encoded receptors that are central to innate and adaptive immune responses. Owing to their vital role in inflammation, TLRs are rational targets in clinics; thus, many ligands and biologics have been reported to overcome the progression of various inflammatory and malignant conditions and support the immune system. For each TLR, at least one, and often many, drug formulations are being evaluated. Ligands reported as stand-alone drugs may also be reported based on their use in combinatorial therapeutics as adjuvants. Despite their profound efficacy in TLR-modulation in preclinical studies, multiple drugs have been terminated at different stages of clinical trials. Here, TLR modulating drugs that have been evaluated in clinical trials are discussed, along with their mode of action, suggestive failure reasons, and ways to improve the clinical outcomes. This review presents recent advances in TLR-targeting drugs and provides directions for more successful immune system manipulation. PMID- 30450667 TI - Occipital Hairline: A forgotten area. AB - Hair restoration surgery is one of the fascinating fields of modern day cosmetic surgery. A good hair transplant is characterized by a naturalness in terms of strategic distribution of hair. A very important point which is very rarely taken care is the "posterior or occipital" hairline. It is formed by the posterior 1 cm of hair which are placed on the vertex or crown and constitute the part which is normally hidden by the long hair. Many surgeons while creating the slits in the recipient area forget this equally important point. And make the slits in the lines. As the care is taken while creating the slits in the anterior hairline, the same enthusiasm is required throughout the procedure especially the posterior part of the recipient area. The slits in the posterior hairline should also be created in a wavy, irregularly irregular fashion. The posterior hairline forms an important part of a hair restoration surgery. It contributes remarkably toward the overall naturalness of the results. A carefully executed posterior hairline reduces the chances of detection by the general public. PMID- 30450668 TI - Gastrointestinal: An oral clue to an unusual cause of pain abdomen: Burton's line. PMID- 30450669 TI - Symptom Science Research in the Era of Big Data: Leveraging Interdisciplinary Resources and Partners to Make It Happen. AB - PURPOSE: The purpose of this article is to review the concept of team science as well as its benefits and challenges, within the framework of how including new ways of knowing can advance nursing science. DESIGN: An exemplar highlights the experiences and strategies utilized by researchers at one school of nursing as they increasingly became involved in team science. METHODS: Presented are the steps and processes that occurred as team science became the norm, expanding to include a network of linked investigators. CONCLUSIONS: Although challenges to conducting team science exist, a reflection on how team science fits into the theoretical framework of Carper's Patterns of Knowing highlights its potential to drive nursing research forward. CLINICAL RELEVANCE: Leading or participating in team science can expand the lens by which nursing scientists conduct research that is meaningful to patients and families. PMID- 30450670 TI - Prevalence and heritability of benign prostatic hyperplasia and LUTS in men aged 40 years or older in Zhengzhou rural areas. AB - BACKGROUND: Benign prostate hyperplasia (BPH) is the most common disease among aging males, but no reports have addressed the prevalence of BPH in Zhengzhou. Therefore, we aimed to understand the prevalence of BPH in men aged 40 years or older in Zhengzhou's rural areas through a cross-sectional study and analyzed the correlation with epidemiologic factors and the heritability of the disease. MATERIALS AND METHODS: A multistage sampling method was used to randomly select male respondents in Zhengzhou's rural areas. Men who were 40 years of age or older and their first-degree relatives were subjected to the International Prostate Symptom Score (IPSS) and related examinations. Heritability was calculated according to the prevalence of the first-degree relatives in the case and control groups. RESULTS: The prevalence of BPH was 10.04%. Its prevalence increased with age, from 2.17% in men aged 40-44 years to 31.11% in men aged 80 years or older. The average volume of the prostate was 17.16 +/- 7.96 mL, and the average IPSS was 5.89 +/- 5.91. The analysis of the correlation between the associated risk factors and BPH revealed that prostatitis and a history of prostatic hyperplasia were significant factors. Obesity, smoking, drinking, diabetes, and hypertension were not correlated with BPH. Of the 94 first-degree relatives of the cases, 53 had BPH (56.38%); of the 106 first-degree relatives of the controls, five had BPH (4.72%). Heritability appeared to account for 40.48% of BPH cases. The heritability of incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia was 43.28, 71.37, 9.67, 5.67, 2.70, 53.36, and 19.12%, respectively. CONCLUSION: The total prevalence of BPH in men aged 40 years or older in Zhengzhou's rural areas was 10.04%, and the heritability of prostatic hyperplasia was 40.48%. PMID- 30450671 TI - Mature outcomes and prognostic indices in diffuse large B-cell lymphoma in Malawi: a prospective cohort. AB - Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged >=18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0.113 cells * 109 /l (interquartile range [IQR] 0.062-0.227) and 25 (49%) had HIV viral load <400 copies/MUl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) >=2 and lactate dehydrogenase (LDH) >2* upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2* ULN and PS >=2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation. PMID- 30450672 TI - Cu-Catalyzed Desulfonylative Amination of Benzhydryl Sulfones. AB - A new method for the synthesis of benzhydryl amines from the reaction of readily available sulfone derivatives with amines is described. The Cu-catalyzed desulfonylative amination not only provides structurally diverse benzhydryl amines in good yields, but is also applicable to iterative and intramolecular aminations. Control experiments suggest the formation of a Cu-carbene intermediate generated from the sulfone substrate, which represents a novel route for desulfonylative transformations. PMID- 30450673 TI - Insulin-like growth factor levels and chronic lymphocytic leukaemia: results from the MCC-Spain and EpiLymph-Spain studies. PMID- 30450674 TI - Intracellular reduction in ATP levels contributes to CYT997-induced suppression of metastasis of head and neck squamous carcinoma. AB - The incidence rate of head and neck squamous cell carcinoma (HNSCC) has steadily increased over the past decade. However, treatment options for metastatic HNSCC are often limited and the 5-year survival rate has remained static. Therefore, the development and assessment of more efficient but less toxic therapeutic strategies is an unmet need for treatment of more extensive HNSCC. Here, we report that CYT997, a novel microtubule-disrupting agent, exerts strong activity in inhibiting HNSCC cell invasion and metastasis. The loss of invasion capacity by CYT997 was accompanied by an associated increase in cell adhesion and the reversal of epithelial-mesenchymal transition (EMT). Increased expression of E cadherin protein and decreased expression of Vimentin protein became evident in HNSCC cells following CYT997 exposure, which were consistently observed in HNSCC xenografts from the mice receiving CYT997. Moreover, the capacity of invasive HNSCC cells to form pulmonary metastases was significantly blocked with CYT997 treatment, indicating that the diminishment of EMT traits contributes to CYT997 suppressed metastasis. Intriguingly, CYT997 impaired intracellular ATP levels in HNSCC cells, at least in part, through its inhibitory effect on the mitochondrial protein IF1. The addition of ATP attenuated CYT997-induced suppression of cell invasion, coupled with down-regulation of E-Cadherin and up-regulation of Vimentin. These findings support a critical role of ATP levels in cell invasion and metastasis under the influence of CYT997. Collectively, our data unveil the mechanism involved in mediating CYT997 action, and provide preclinical rationale for possible clinical application of CYT997 as a novel therapeutic strategy against aggressive HNSCC. PMID- 30450676 TI - What does Brexit mean for the UK social care workforce? Perspectives from the recruitment and retention frontline. AB - The UK's departure from the European Union (Brexit) is likely to result in greater immigration and employment restrictions on European Union/European Economic Area (EU/EEA) nationals within the United Kingdom. EU/EEA citizens constitute a significant proportion of the current social care workforce. Research evaluating the impact of Brexit on social care has highlighted potentially severe future workforce shortfalls, but has not engaged in detail with the experiences of social care personnel involved in day-to-day recruitment and retention activities. This article explores how social care managers evaluate Brexit's prospects for future workforce sustainability, through the prism of their organisation's workforce requirements. This qualitative study incorporated in-depth semi-structured interviews and questionnaire surveys with domiciliary and residential care managers. Data collection focused on an urban conurbation in south-west England, with demographic characteristics likely to make post-Brexit recruitment and retention in social care particularly challenging. A key finding is that, irrespective of whether they employ EU/EEA workers or not, research participants have deep concerns about Brexit's potential impact on the social care labour market. These include apprehensions about future restrictions on hiring EU/EEA nurses, as well as fears about increased competition for care staff and their organisation's future financial viability. This article amplifies the voices of managers as an under-researched group, bringing their perspectives on Brexit to bear on wider debates on social care workforce sustainability. PMID- 30450675 TI - Characterization of aged rat vocal fold fibroblasts. AB - OBJECTIVES/HYPOTHESIS: To elucidate the aging physiology of the vocal folds, we examined the characters of aged vocal fold fibroblasts (VFFs) in various conditions. STUDY DESIGN: In vitro study. METHODS: VFFs from young (12-week-old) and aged (19-month-old) Sprague-Dawley rats were compared. Proliferative capacity, ratio of myofibroblast to fibroblast, myofibroblast function, and extracellular matrix production were examined in the following conditions: naive, basic fibroblast growth factor (bFGF) supplemented, and hepatocyte growth factor (HGF) supplemented. RESULTS: Aged VFFs demonstrated reduced proliferation by cell counting, though the ratio of Ki-67-positive cells showed no difference. Aged VFFs exhibited an increased expression of alpha-smooth muscle actin (alpha-SMA); however, they demonstrated no enhanced contractile ability in a gel contraction assay. Type I collagen protein was increased age dependently, accompanied with decreased Mmp1 and unchanged Col1a1 transcription. Type I collagen protein and alpha-SMA represented quite similar reduction patterns to bFGF or HGF administration. CONCLUSIONS: The following possible characteristics of aged VFFs were implied: long duration of mitosis, increased myofibroblast population size with certain dysfunctions, reduced type I collagen turnover, and correlation between alpha-SMA expression and type I collagen metabolism. Further investigations of these features will help to clarify presbyphonia's pathology and establish treatment strategies. LEVEL OF EVIDENCE: NA Laryngoscope, 2018. PMID- 30450677 TI - Autologous platelet-rich gel for facial rejuvenation and wrinkle amelioration: A pilot study. AB - BACKGROUND: The demand for safe and minimally invasive soft tissue augmentation procedures has increased. Recently, a novel injectable gel based on the autologous platelet rich in growth factor (PRGF) technology has been developed to provide long-term shape and volume stability. It can be customized into low (LVG) or high viscosity (HVG) gel forms to meet different dermatological requirements. OBJECTIVES: The mechanical and biological properties of both gel forms have been evaluated. The clinical efficacy and safety of this autologous procedure were also evaluated. METHODS: Growth factor content and biomechanical properties of both gel forms were determined. The in vitro biological capacity on human dermal fibroblasts proliferation was assessed. Clinical performance analysis over ten patients was evaluated by standardized macrophotographs, 3D topographic images, and ultrasound analysis over periocular and nasolabial areas. RESULTS: Both gel types showed similar growth factor concentration. HVG showed a higher stiffness profile indicating its suitability for deeper tissue defect viscosupplementation while LVG showed optimal rheologic characteristics for superficial volumization. Both gels showed a noticeable biostability after catalytic enzyme degradation. Both forms significantly increased the mitogenic activity of dermal fibroblasts. All patients referred to be highly satisfied and presented optimal clinical results after one month. Overall clinical improvement was maintained for 16 weeks. At the end of the study, the ultrasound examination revealed a cutaneous regenerative effect. No adverse events occurred. CONCLUSIONS: This preliminary study suggests that autologous platelet gels have desirable mechanical and bioactive properties and allows moderate wrinkle reduction and efficient facial volume reposition with natural results. PMID- 30450678 TI - Coming to town: Reaching agreement on a thorny issue. AB - OBJECTIVE: To describe the process of gaining consensus across regional organisations in formulating measures to improve coordination of care for people from remote Far North Queensland communities coming to town (Cairns) to access health care. DESIGN: This is a descriptive study that includes survey data from workshop participants. SETTING: Coming to town for health care poses great challenges, especially for Indigenous Australians from remote communities. Numerous organisations are involved, communications are fragmented and there is no central coordinating body. The system frequently fails to deliver necessary services. This generates preventable cost burdens through missed flights, missed appointments, missed treatment opportunities and extra administration. Workshop organisers invited key service providers from across Far North Queensland. MAIN OUTCOME MEASURES: Using real-case scenarios, the task was to identify and prioritise the central issues and explore ways to address them. Participants jointly crafted the final recommendations and also posted suggestions on a 'wish list' board. A participant assessment survey was conducted at the end of the workshop, followed by an online survey 6 weeks later. RESULTS: There were 32 participants. The concluding survey indicated the workshop was well received and people valued the collaboration. There were six primary recommendations plus numerous wish-list suggestions. The best-supported recommendation was establishment of a coming to town Hub with a local coordinating team and community-based representatives. CONCLUSION: Implementation of the workshop recommendations and support of all key service providers should be culturally acceptable and resource-efficient with better health outcomes for travellers, their families and communities. PMID- 30450679 TI - Whole exome sequencing identified a novel DAG1 mutation in a patient with rare, mild and late age of onset muscular dystrophy-dystroglycanopathy. AB - Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 9 (MDDGC9) is the rarest type of autosomal recessive muscular dystrophies. MDDGC9 is manifested with an early onset in childhood. Patients with MDDGC9 usually identified with defective glycosylation of DAG1, hence it is known as "dystroglycanopathies". Here, we report a Chinese pedigree presented with mild MDDGC9. The proband is a 64 years old Chinese man. In this family, both the proband and proband's younger brother have been suffering from mild and late onset MDDGC9. Muscle biopsy showed that the left deltoid muscle with an advanced stage of dystrophic change. Immunohistochemistry staining of dystrophin, alpha-sarcoglycan, beta-sarcoglycan and dysferlin are normal. Molecular genetic analysis of the proband has been done with whole exome sequencing. A homozygous novel missense mutation (c.2326C>T; p.R776C) in the exon 3 of the DAG1 gene has been identified in the proband. Sanger sequencing revealed that this missense mutation is co-segregated well among the affected and unaffected (carrier) family members. This mutation is not detected in 200 normal healthy control individuals. This novel homozygous missense mutation (c.2326C>T) causes substitution of arginine by cystine at the position of 776 (p.R776C) which is evolutionarily highly conserved. Immunoblotting studies revealed that a significant reduction of alpha dystroglycan expression in the muscle tissue. The novelty of our study is that it is a first report of DAG1 associated muscular dystrophy-dystroglycanopathy (limb girdle), type C, 9 (MDDGC9) with mild and late age of onset. In Chinese population this is the first report of DAG1 associated MDDGC9. PMID- 30450680 TI - Body movements as pain indicators in older people with cognitive impairment - a systematic review. AB - BACKGROUND AND OBJECTIVE: Pain assessment tools for cognitively impaired older people, unable to self-report pain, are commonly founded upon observation of pain behavior, like facial expressions, vocalizations, and body movements. The scientific basis for claiming that body movements may indicate pain has not formerly been investigated in a systematic review. The objective was to explore research evidence for body movements being pain indicators in older people with cognitive impairment. DATA BASES AND DATA TREATMENT: MEDLINE, EMBASE, CINAHL, PsycINFO, and the Cochrane Library were searched systematically. Two researchers independently identified and consented on studies to be included. PRISMA statement for reporting systematic reviews was followed. Mixed Methods Appraisal Tool was used for critical evaluation of study quality. RESULTS: 2096 records from the literature searches were identified, and 17 quantitative and 8 qualitative studies were included in the review, the studies mainly related to older people with dementia. Quality scores ranged from 50 to 100%. We combined 62 items of body movements into 13 similar or synonymous items, and criteria for evidence were defined. Strong evidence was found for restlessness (agitation), rubbing, guarding, rigidity and physical aggression as the behaviors frequently responded (increased or decreased) to pain provoking activities, painful procedures, and/or pain medication. CONCLUSIONS: Among 13 categories of body movements, we found five with strong and five with moderate evidence of validity. As few items were typically included in many studies reflecting criterion validity, all should be included in future studies of patients with different characteristics, location, and duration of pain. This article is protected by copyright. All rights reserved. PMID- 30450681 TI - Combining hepatitis B core-related and surface antigens at end of nucleos(t)ide analogue treatment to predict off-therapy relapse risk. AB - BACKGROUND: There remains an unmet need for convenient biomarkers to assess the risks of discontinuing nucleos(t)ide analogues (NAs) in chronic hepatitis B (CHB). AIM: To investigate if hepatitis B core-related antigen (HBcrAg) is an independent of surface antigen (HBsAg) for risk prediction of NA cessation. METHODS: This prospective multicentre study enrolled 135 CHB patients who stopped entecavir or tenofovir after achieving viral remission for a median of 25.2 months. All patients stopped NA with negative HBeAg and undetectable viral DNA, and were then observed for clinical relapse and HBsAg loss. Predictors including HBsAg and HBcrAg levels were explored using Cox proportional hazard model and weighted to develop a risk score. RESULTS: During a median follow-up of 25.9 months, clinical relapse and HBsAg loss occurred in 66 and eight patients, respectively, with a 5-year cumulative incidence of 56.1% (95% CI 46.7-66.0%) and 8.8% (95% CI 4.3-17.4%), respectively. HBcrAg was an independent relapse predictor, as well as HBsAg, age, ALT and tenofovir use. A score (SCALE-B) was calculated by the equation of 35*HBsAg (log IU/mL) + 20*HBcrAg (log U/mL) + 2*age (year) + ALT (U/L) + 40 for tenofovir use. The concordance rates for clinical relapse were 0.87, 0.88, 0.87, 0.85 and 0.90 at 1, 2, 3, 4 and 5 years, respectively. Moreover, HBsAg loss occurred exclusively in low-risk patients predicted by the score. CONCLUSIONS: Serum HBcrAg and HBsAg levels were independent predictors of off-NA relapse and can be factored into a risk score to guide treatment cessation in patients with CHB. PMID- 30450682 TI - Perspectives on phronesis in professional nursing practice. AB - The concept of phronesis is venerable and is experiencing a resurgence in contemporary discourses on professional life. Aristotle's notion of phronesis involves reasoning and action based on ethical ideals oriented towards the human good. For Aristotle, humans possess the desire to do what is best for human flourishing, and to do so according to the application of virtues. Within health care, the pervasiveness of economic agendas, technological approaches and managerialism create conditions in which human relationships and moral reasoning are becoming increasingly de-valued. This creates a tension for nurses, and nursing leaders, as the desire to do what is morally right is often in conflict with contextual demands. In this paper, Aristotle's writing on phronesis is examined with a focus on his classic conceptions of eudaimonia, the virtues, deliberation, judgement, and praxis. Building on Aristotle's work, a number of contemporary views are explored with a focus on what various conceptualizations offer for the discipline of nursing. These expanded conceptions of phronesis include attention to: embodiment in practice; open-mindedness including the capacity to stay curious and open to recognizing what we do not know; perceptiveness as a disposition towards insight and aesthetic understanding; and reflexivity as an ongoing process of interrogation and inquiry into ourselves and our actions. Drawing on these concepts, we discuss the affordances of phronesis as a morally informed guiding force to attend to modern-day challenges in nursing practice and nursing leadership. PMID- 30450683 TI - Vitamin D and cardiometabolic disorders: a review of current evidence, genetic determinants and pathomechanisms. AB - Vitamin D deficiency has been implicated in the pathophysiology of cardiometabolic disorders including obesity, type 2 diabetes mellitus, cardiovascular diseases and polycystic ovary syndrome. Despite a large number of experimental and observational studies supporting a role for vitamin D in these pathologies, randomized controlled trials have reported little to no effect of vitamin D supplementation in the prevention or treatment of these disorders, although some results remain ambiguous. Polymorphisms in genes related to vitamin D metabolism, particularly in the vitamin D receptor and binding protein and the metabolizing enzyme 1-alpha-hydroxylase, have emerged as potential contributors to these divergent results. It is now becoming increasingly recognized that the effects and potential benefits of vitamin D supplementation may vary by several factors including vitamin D deficiency status, ethnicity and/or the presence of genetic variants, which affect individual responses to supplementation. However, these factors have seldom been explored in the available literature. Future trials should consider inter-individual differences and, in particular, should aim to clarify whether certain subgroups of individuals may benefit from vitamin D supplementation in the context of cardiometabolic health. PMID- 30450684 TI - Impact of appropriate use criteria for transesophageal echocardiograms on clinically meaningful care. AB - INTRODUCTION: The aim of this study was to evaluate appropriateness of transesophageal echocardiography (TEE) studies based on 2011 Appropriate Use Criteria (AUC) for Echocardiography and its impact on patient management. METHODS AND RESULTS: In a retrospective analysis of 100 inpatient TEEs, 85% of the TEEs ordered were determined to be appropriate, 9% were inappropriate, and 6% were uncertain. Inter-observer differences in the determination of AUC were seen in 24% of the studies, requiring a senior-level cardiologist to make the final determination of AUC score. The variance in interpretation by experts is concerning for how that might translate into differences in clinical practice. Of all TEEs, only 63% led to an active change in care, including changes in medications or procedures, while 37% did not. We found a statistically significant difference between cardiologists' and non-cardiologists' orders for TEE having an impact on patient's clinical care (41% vs 22%, respectively, P < 0.05) (Table ). While not statistically significant, a trend toward clinical change was observed in the appropriate vs inappropriate TEEs (70% vs 44%, respectively, P = 0.06). CONCLUSION: Ideally, the role of a diagnostic cardiovascular imaging test, such as a TEE, is to influence clinical care, if it is ordered appropriately on the right patient. While the AUC guides clinicians on the appropriate use of cardiovascular imaging, it is broadly written and offers room for interpretation to encompass variety of clinical scenarios. Clinical care paths that utilize AUC and standardize use of multidisciplinary institutional resources offer opportunity for optimal clinical impact and patient care. PMID- 30450685 TI - Alteration of T Cell Phenotypes in HIV-Neurotuberculosis Coinfection. AB - BACKGROUND: Neurotuberculosis is one of the commonest HIV associated opportunistic infections of the central nervous system in India. HIV-TB coinfection may lead to altered frequencies of T cells, thereby influencing the course and progression of the disease. METHODS: We examined the frequencies of T cell subsets in HIV infected individuals with neurotuberculosis (HIV+nTB+) as compared to individuals with HIV associated systemic TB (HIV+sTB+), asymptomatic HIV (HIV+TB-), non-HIV neuro TB (HIV-nTB+), non-HIV systemic TB (HIV-sTB+), and healthy controls (HIV-TB-). Activation and senescence profiles of CD4 and CD8 T cells and memory subsets in peripheral blood mononuclear cells were studied by flow cytometry. RESULTS: The significant observations among the T cell subsets in HIV+nTB+ were: (1) Naive T cells: decreased CD4 T cells compared to HIV-sTB+ (P = 0.005); decreased CD8 T cells compared to HIV-nTB+ and HIV-TB- (P <= 0.007), (2) Memory T cells: expanded CD4 TEMRA cells compared to HIV-nTB+, HIV-sTB+, and HIV TB- (P <= 0.003); expanded CD8 TEMRA cells compared to HIV-nTB+ and HIV-TB- (P <= 0.005), (3) Activated T cells: higher CD4 T cells compared to HIV-nTB+, HIV-sTB+, and HIV-TB- (P <= 0.004); higher CD8 T cells compared to HIV + TB-, HIV-nTB+, HIV sTB+, and HIV-TB- (P <= 0.001), and (4) Senescent T cells: increased CD8 T cells compared to HIV-nTB+ and HIV-TB- groups (P = 0.000). CONCLUSIONS: Increased activation compared to HIV+TB-, HIV-nTB+, HIV-sTB+, and HIV-TB- groups and increased senescence compared to HIV-nTB+ and HIV-TB- groups were observed in CD8 T cells in HIV+nTB+, suggesting that the frequencies of these T cell subsets are altered to a greater extent in these individuals. (c) 2018 International Clinical Cytometry Society. PMID- 30450687 TI - Two unrelated individuals carrying rare mosaic deletions in TCF4 gene. PMID- 30450686 TI - Polymorphism in the PBX1 gene is related to cystinuria in Brazilian families. AB - The aim of our study was to determine regions of loss of heterozygosity, copy number variation analysis, and single nucleotide polymorphisms (SNPs) in Brazilian patients with cystinuria. A linkage study was performed using DNA samples from six patients with cystinuria and six healthy individuals. Genotyping was done with the Genome-Wide Human SNP 6.0 arrays (Affymetrix, Inc., Santa Clara, CA, USA). For validation, SNPs were genotyped using a TaqMan(r) SNP Genotyping Assay Kit. The homozygote polymorphic genotype of SNP rs17383719 in the gene PBX1 was more frequent (P = 0.015) in cystinuric patients. The presence of the polymorphic allele for this SNP increased the chance of cystinuria by 3.0 fold (P = 0.036). Pre-B-cell leukaemia transcription factor 1 (PBX1) was overexpressed 3.3-fold in patients with cystinuria. However, when we compared the gene expression findings with the genotyping, patients with a polymorphic homozygote genotype had underexpression of PBX1, while patients with a heterozygote or wild-type homozygote genotype had overexpression of PBX1. There is a 3-fold increase in the risk of the development of cystinuria among individuals with this particular SNP in the PBX1 gene. We postulate that the presence of this SNP alters the expression of PBX1, thus affecting the renal absorption of cystine and other amino acids, predisposing to nephrolithiasis. PMID- 30450688 TI - Papuloerythroderma-like cutaneous involvement of a CD62L- subclone of T-cell prolymphocytic leukemia. AB - We report the case of an 88-year-old Japanese man with erythrodermic involvement of T-cell prolymphocytic leukemia (T-PLL). He had a history of pharyngeal diffuse large B-cell lymphoma successfully treated with polychemotherapy including cyclophosphamide and epirubicin, 6 years before the current illness. He presented with numerous reddish, coalescing, flat-topped papules on the trunk and extremities, sparing the skin folds of the abdomen, the features of which mimicked those of papuloerythroderma. Immunohistochemistry showed perivascular and epidermotropic infiltration of CD3+ CD4+ T cells in the cutaneous lesion. However, flow cytometric analysis revealed that the skin infiltrating T cells were negative for surface CD4, and that CD3+ CD4- CD8- cells made up 92% of the T cell fraction of peripheral blood. The circulating atypical T cells had a round or oval nucleus and prominent nucleoli, and the deletion of chromosomes 6q, 13 and 17. These cytological profiles were consistent with those of T-PLL and distinct from those of Sezary cells. The same T-cell clone was detected in the cutaneous lesion and peripheral blood, but the expression of CD62L was absent in the skin infiltrates and present in the circulating cells. No specific mutation was detected in STAT3 or STAT5B. Although low-dose oral etoposide had a beneficial effect on the skin rash, a fatal crisis of marked leukocytosis (169 * 103 /MUL) occurred 19 months after the illness onset. CD62L-leukemic cells of T PLL may infiltrate the skin to form papuloerythroderma-like cutaneous lesions. PMID- 30450689 TI - Regulation of faecal biomarkers in inflammatory bowel disease patients treated with oral mastiha (Pistacia lentiscus) supplement: A double-blind and placebo controlled randomised trial. AB - There is a keen research upon the effects of nutraceuticals on inflammatory bowel disease. The purpose of this study was to explore the effect of mastiha supplement, rich in bioactive nutraceuticals, in active inflammatory bowel disease. This is a randomised, double-blind, placebo-controlled clinical trial. Alpha total of 60 inflammatory bowel disease patients were enrolled and randomly allocated to mastiha (2.8 g/day) or placebo groups for 3 months adjunct to stable medical treatment. Medical and dietary history, Inflammatory Bowel Disease Questionnaire (IBDQ), Harvey-Bradshaw index, partial Mayo score, biochemical indices, faecal, and blood inflammatory markers were assessed. A clinically important difference between groups in IBDQ was defined as primary outcome. Inflammatory Bowel Disease Questionnaire score significantly improved in verum compared with baseline (p = 0.004). There was a significant decrease in faecal lysozyme in mastiha patients (p = 0.018) with the mean change being significant (p = 0.021), and significant increases of faecal lactoferrin (p = 0.001) and calprotectin (p = 0.029) in the placebo group. Fibrinogen reduced significantly (p = 0.006) with a significant mean change (p = 0.018), whereas iron increased (p = 0.032) in mastiha arm. Our results show regulation of faecal lysozyme by mastiha supplement adjunctive to pharmacological treatments in active inflammatory bowel disease. An effect secondary to a prebiotic potency is proposed. PMID- 30450691 TI - Nimodipine improves vocal fold and facial motion recovery after injury: A systematic review and meta-analysis. AB - INTRODUCTION: Nimodipine is a calcium channel blocker that has been used to treat hypertension and vasospasm. Emerging evidence in the literature suggests that it is neuroprotective by reducing cellular apoptosis after neuronal injury and promoting axonal sprouting at the nodes of Ranvier. OBJECTIVES: To conduct a systematic review of the usage of nimodipine in cranial nerve injury and to perform a meta-analysis to estimate the efficacy of nimodipine on functional recovery of the injured cranial nerves. METHODS: Literature search was performed in eight databases using preferred reporting items for systematic reviews and meta analyses (PRISMA) guidelines. Human studies that used nimodipine as a monotherapy for treating cranial nerve injury were included for review. Cranial nerve function recovery was the primary outcome measure. RESULTS: 672 records were screened and 58 full texts in English were assessed. Nine studies were included in the final review. 5 of these, including 110 participants who received nimodipine for either recurrent laryngeal nerve or facial nerve injury and 556 controls, were used for meta-analysis. Nimodipine significantly increased the odds of vocal fold motion recovery (odds ratio [OR] 13.73, 95% confidence interval [CI] 6.21, 30.38, P < .01), and the odds of facial motion recovery (OR 2.78, 95% CI 1.20, 6.44, P = .02). Overall, nimodipine-treated patients had significantly higher odds of recovering vocal fold or facial motion compared with controls (OR 6.09, 95% CI 3.41, 10.87, P < .01). CONCLUSION: Existing evidence supports the positive effect of nimodipine on vocal fold and facial motion recovery after injury. Future research should focus on randomized clinical trials comparing recovery rates between nimodipine- and placebo-treated groups. LEVEL OF EVIDENCE: 2a. Laryngoscope, 2018. PMID- 30450690 TI - First trimester physiological development of the fetal foot position using three dimensional ultrasound in virtual reality. AB - AIM: In anatomic studies of the embryo, it has been established that during the development of the lower limb, several changes in foot position can be observed defined as a temporary 'physiological clubfoot'. The aim of this study was to develop and test a measurement tool for objective documentation of the first trimester foot position in vivo and made an attempt to create a chart for first trimester foot position. METHODS: We developed a virtual orthopedic protractor for measuring foot positioning using three-dimensional virtual reality visualization. Three-dimensional ultrasound volumes of 112 pregnancies of women examined during the first trimester were studied in a BARCO I-Space. The frontal angle (plantar flexion) and the lateral angle (adduction) between the leg and foot were measured from 8 until 13 weeks gestational age. RESULTS: We observed that the frontal angle steadily decreases, whereas the lateral angle first increases, resulting in transient physiological clubfeet position at 10- to 11 week gestation, followed by a decrease to a normal foot position. CONCLUSION: A transient clubfoot position is present during the normal development of the lower limbs, and it has been measured in vivo for the first time. This study emphasizes that a diagnosis of congenital clubfoot should not be made in the first trimester of pregnancy. PMID- 30450692 TI - LncRNA CASC2 inhibits proliferation and migration of adenocarcinoma cells via miR 4735-3p and mTOR. AB - Lung adenocarcinoma is a major form of non-small-cell lung cancer that frequently strikes nonsmokers. The disease is often diagnosed at a late stage and the 5-year survival rate is very low. Although previous studies found many somatic alterations associated with lung adenocarcinoma, the molecular basis of the development and progression of the disease is not well understood. We found that long noncoding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2), a putative tumor suppressor, was downregulated in both patient adenocarcinoma tissues and cultured lung cancer cells. Its tumor suppression function seemed to be dependent on its binding to miR-4735-5p. Changing the levels of CASC2 and miR-4735-3p in the cultured adenocarcinoma cells could affect the malignant phenotypes as well as growth of tumors derived from the cells injected into nude mice. Furthermore, the lncRNA and miR-4735-3p interplay likely the suppressed tumor growth through the downstream mammalian target of rapamycin signaling pathway. The results have revealed molecular details that may be critical for the development of lung adenocarcinoma, opening opportunities for the development of novel, and therapeutic tools. PMID- 30450693 TI - High proportion of transient neonatal zinc deficiency causing alleles in the general population. AB - Loss of function (LoF) mutations in the zinc transporter SLC30A2/ZnT2 result in impaired zinc secretion into breast milk consequently causing transient neonatal zinc deficiency (TNZD) in exclusively breastfed infants. However, the frequency of TNZD causing alleles in the general population is yet unknown. Herein, we investigated 115 missense SLC30A2/ZnT2 mutations from the ExAC database, equally distributed in the entire coding region, harboured in 668 alleles in 60 706 healthy individuals of diverse ethnicity. To estimate the frequency of LoF SLC30A2/ZnT2 mutations in the general population, we used bioinformatics tools to predict the potential impact of these mutations on ZnT2 functionality, and corroborated these predictions by a zinc transport assay in human MCF-7 cells. We found 14 missense mutations that were markedly deleterious to zinc transport. Together with two conspicuous LoF mutations in the ExAC database, 26 SLC30A2/ZnT2 alleles harboured deleterious mutations, suggesting that at least 1 in 2334 newborn infants are at risk to develop TNZD. This high frequency of TNZD mutations combined with the World Health Organization-promoted increase in the rate of exclusive breastfeeding highlights the importance of genetic screening for inactivating SLC30A2/ZnT2 mutations in the general population for the early diagnosis and prevention of TNZD. PMID- 30450694 TI - Virus study for continuous low pH viral inactivation inside a coiled flow inverter (CFI). AB - Continuous processing for the production of monoclonal antibodies (mAb) gains more and more importance. Several solutions exist for all necessary production steps, leading to the possibility to build fully continuous processes. Low pH viral inactivation is part of the standard platform process for mAb production. Consequently, Klutz et al. introduced the coiled flow inverter (CFI) as a tool for continuous low pH viral inactivation. Besides theoretical calculations of viral reduction, no viral clearance study has been presented so far. Additionally, the validation of continuous viral clearance is often neglected in the already existing studies for continuous processing. This work shows in detail the development and execution of a virus study for continuous low pH viral inactivation inside a CFI. The concept presented is also valid for adaptation to other continuous viral clearance steps. The development of this concept includes the technical rationale for an experimental setup, a valid spiking procedure and finally a sampling method. The experimental results shown represent a viral study using xMuLV as a model virus. Two different Protein A (ProtA) chromatography setups with varying pH levels were tested. Additionally, one of these setups was tested against a batch experiment utilizing the same process material. The results show that sufficient low pH viral inactivation (LRV > 4) was achieved in all experiments. Complete viral inactivation took place within the first 14.5 min for both continuous studies and the batch study, hence showing similar results. This study therefore represents a successful virus study concept and experiment for a continuous viral inactivation step. Moreover, it was shown that the transfer from batch results to the continuous process is possible. This is accomplished by the narrow RTD of the CFI, showing how close the setup approaches ideal plug flow and with that batch operation. This article is protected by copyright. All rights reserved. PMID- 30450695 TI - Preparation and characterization of folic acid functionalized bioactive glass for targeted delivery and sustained release of methotrexate. AB - We have successfully prepared a novel targeted drug delivery system, composed of folic acid (FA) as targeting molecule, methotrexate (MTX) as anticancer drug, and bioactive glass (BG) as carrier. The BG nanoparticles were synthesized by sol-gel method with the dodecylamine as template. The surface of BG nanoparticles was grafted with amino groups by (3-aminopropyl) triethoxysilane, then, FA and MTX were covalently conjugated to the surface of modified BG through amidation reaction, so FA functionalized BG (BG-FA) and targeted drug delivery system (MTX BG-FA) were prepared. The physicochemical properties of BG, BG-NH2 , and BG-FA were characterized by various methods, such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, ultraviolet-visible, and so on. Moreover, the drug release results showed that the MTX-BG-FA had sustained release property because of the peptide bond between MTX and BG-FA. And the cytocompatibility evaluation demonstrated that the BG and BG-FA were biocompatible and BG-FA even could promote cell proliferation, while the MTX-BG-FA had high cytotoxicity owning to the sustained release of anticancer drug. From the above, it could be concluded that MTX-BG-FA could kill tumor cells targetedly and sustainedly, which made it a good cancer targeted therapy material. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2018. PMID- 30450696 TI - Advances in research and development of bioplastic for food packaging. AB - The paper reviews the recent developments in bioplastic food packaging. Several bioplastic materials (polylactide, polyhydroxyalkanoates, and starch) have been successfully converted into food packaging using conventional plastic conversion technologies including extrusion, injection molding, and compression molding. This review emphasizes the advances in bioplastic packaging with regard to active packaging applications and applications requiring gas and water barrier. Recently, bioplastic packaging has been developed into active packaging which can either control the release of active ingredients or scavenge undesirable substances. The review shows that antioxidant and antimicrobial functions are major developments for the control-release application in bioplastic packaging. Factors affecting the release of active ingredients have been reviewed. The sorption of low molecular weight substances such as humidity, aromas, and gases, also affects the properties of packaging materials. Some patents are available for oxygen-scavenging bioplastic packaging. Moreover, improved high-barrier packaging technologies (modified polymer, coating, and lamination) have been developed to increase the shelf-life of food products. This article is protected by copyright. All rights reserved. PMID- 30450697 TI - Craniofacial skeleton of Mexican tetra (Astyanax mexicanus): As a bone disease model. AB - A small fresh water fish, the Mexican tetra (Astyanax mexicanus) is a novel animal model in evolutionary developmental biology. The existence of morphologically distinct surface and cave morphs of this species allows simultaneous comparative analysis of phenotypic changes at different life stages. The cavefish harbours many favourable constructive traits (i.e. large jaws with an increased number of teeth, neuromast cells, enlarged olfactory pits and excess storage of adipose tissues) and regressive traits (i.e. reduced eye structures and pigmentation) which are essential for cave adaptation. A wide spectrum of natural craniofacial morphologies can be observed among the different cave populations. Recently, the Mexican tetra has been identified as a human disease model. The fully sequenced genome along with modern genome editing tools has allowed researchers to generate transgenic and targeted gene knockouts with phenotypes that resemble human pathological conditions. This review will discuss the anatomy of the craniofacial skeleton of A. mexicanus with a focus on morphologically variable facial bones, jaws that house continuously replacing teeth and pharyngeal skeleton. Further, the possible applications of this model animal in identifying human congenital and metabolic skeletal disorders is addressed. This article is protected by copyright. All rights reserved. PMID- 30450698 TI - Can Pharyngeal Packing Prevent Postoperative Nausea and Vomiting in Nasal Surgery? AB - OBJECTIVES: We aimed to perform a meta-analysis for the efficacy of pharyngeal packing during nasal surgery in the prevention of postoperative nausea and vomiting (PONV). DATA SOURCES: MEDLINE, SCOPUS, and the Cochrane database. METHODS: Two authors independently searched the databases for relevant studies from inception to October 2017. Included studies were randomized controlled studies published in English comparing pharyngeal packing during intubation (packing group) with no packing (control group) in patients who underwent nasal surgery. Outcomes of interest included the incidence of PONV and throat pain during the first 24 hours postsurgery. RESULTS: Ten studies were included in the meta-analysis. The incidence of moderate-to-severe PONV in the recovery room was significantly higher in the packing group than in the control group. However, the incidence of moderate-to-severe PONV significantly decreased and was lower in the packing group than in the control group at 2 hours postoperative. The incidence of throat pain was higher in the packing group than in the control group until 2 hours postoperative. CONCLUSIONS: Considering the occurrence of postoperative morbidity according to the time course, pharyngeal packing during nasal surgery does not alleviate PONV but instead could aggravate postoperative throat pain. Additionally, pharyngeal packing has the possibility of airway problem such as the foreign body aspiration. Based on our results, we suggest that there is no need to place a pharyngeal pack to prevent PONV in patients undergoing nasal surgery. LEVEL OF EVIDENCE: Ib. Laryngoscope, 2018. PMID- 30450699 TI - Retention in care among clinically stable antiretroviral therapy patients following a six-monthly clinical consultation schedule: findings from a cohort study in rural Malawi. AB - INTRODUCTION: Longer intervals between clinic consultations for clinically stable antiretroviral therapy (ART) patients may improve retention in care and reduce facility workload. We assessed long-term retention among clinically stable ART patients attending six-monthly clinical consultations (SMCC) with three-monthly fast-track drug refills, and estimated the number of consultations "saved" by this model of ART delivery in rural Malawi. METHODS: Stable patients (aged >=18 years, on first-line ART >=12 months, CD4 count >=300 cells/mL3 , without opportunistic infections, not pregnant/breastfeeding) were eligible for SMCC, with three-monthly drug refills from community health workers. Early enrollees were those starting SMCC within six months of eligibility, while late enrollees started at least 6 months after first eligibility. Kaplan-Meier methods were used to calculate cumulative probabilities of retention, stratified by timing of their enrolment and from first six-monthly clinical consultation. Cox regression was used to measure attrition hazards from the first six-monthly clinical consultation and risk factors for attrition, accounting for the time-varying nature of their eligibility and enrolment in this model of care. RESULTS: From 2008 to 2015, 22,633 clinically stable patients from 11 facilities were eligible for SMCC for at least three months, contributing 74,264 person-years of observation, and 18,363 persons (81%) initiated this model of care. The median time from eligibility to enrolment was 12 months and the median cumulative time on SMCC was 14.5 months. Five years after first SMCC eligibility, cumulative probabilities of retention were 85.5% (95% CI: 84.0% to 86.9%) among early enrollees and 93% (95% CI: 92.8% to 94.0%) among late enrollees. The cumulative probability of retention from first SMCC was 97.0% (95% CI: 96.7% to 97.3%) and 86% (95% CI: 85% to 87%) at one and five years respectively. Among eligible patients initiating SMCC, the adjusted hazards of attrition were 2.4 (95% CI: 2.0 to 2.8) times higher during periods of SMCC discontinuation compared to periods on SMCC. Male sex, younger age, more recent SMCC eligibility and WHO Stage 3/4 conditions in the past year were also independently associated with attrition from SMCC. Approximately 26,000 consultations were "saved" during 2014. CONCLUSION: After five years, retention among patients attending SMCC was high, especially among women and older patients, and its scale-up could facilitate universal access to ART. PMID- 30450700 TI - Perioperative management of tracheocutaneous fistula closure in children: A review of 96 cases. AB - BACKGROUND: A tracheocutaneous fistula is a known complication following tracheostomy decannulation. Although surgical techniques for its repair are well described, there is no consensus about perioperative management and this procedure may generate significant airway and respiratory complications intraoperatively, and in the early postoperative period. We aimed to describe variations in perioperative management in tracheocutaneous fistula closure, estimate the incidence of early airway and respiratory complications, and identify any predisposing factors. METHODS: The otorhinolaryngology surgical database identified 118 tracheocutaneous fistula closures from August 1994 to September 2015. Ninety-seven case notes were located generating 96 procedures for retrospective review. The data collected included demographics, comorbidities, anesthetic, and surgical technique, and complications up to 24 hours postoperatively. RESULTS: The median age at surgery was 5 years 10 months (range 1 year 8 months to 19 years 6 months). Preoperatively, 72% of patients had a "mini" sleep study (where the tracheocutaneous fistula is covered and saturations measured overnight). Ninety percent had an inhalational induction and 96% a tracheal intubation. Intraoperatively, laryngospasm occurred in 2% and there was difficulty ventilating in another 2%. A "leak test" to check fistula repair airtightness was recorded in 35%. Postoperatively 24% had one or more episodes of oxygen desaturation. Major complications occurred in five patients (incidence 5%, 95% CI 0.8-9.7); four patients had pneumothoraxes with two needing postoperative mechanical ventilation and one patient developed life-threatening subcutaneous emphysema. CONCLUSION: Perioperative care for children undergoing tracheocutaneous fistula closure was not standardized. Advocated tests such as preoperative "mini" sleep studies and "leak test" intraoperatively were not consistently performed. Intraoperative anesthetic complications were uncommon; however, major postoperative respiratory complications were 5%. PMID- 30450701 TI - CNKSR1 gene defect can cause syndromic autosomal recessive intellectual disability. AB - The advent of high-throughput sequencing technologies has led to an exponential increase in the identification of novel disease-causing genes in highly heterogeneous diseases. A novel frameshift mutation in CNKSR1 gene was detected by Next-Generation Sequencing (NGS) in an Iranian family with syndromic autosomal recessive intellectual disability (ARID). CNKSR1 encodes a connector enhancer of kinase suppressor of Ras 1, which acts as a scaffold component for receptor tyrosine kinase in mitogen-activated protein kinase (MAPK) cascades. CNKSR1 interacts with proteins which have already been shown to be associated with intellectual disability (ID) in the MAPK signaling pathway and promotes cell migration through RhoA-mediated c-Jun N-terminal kinase (JNK) activation. Lack of CNKSR1 transcripts and protein was observed in lymphoblastoid cells derived from affected patients using qRT-PCR and western blot analysis, respectively. Furthermore, RNAi-mediated knockdown of cnk, the CNKSR1 orthologue in Drosophila melanogaster brain, led to defects in eye and mushroom body (MB) structures. In conclusion, our findings support the possible role of CNKSR1 in brain development which can lead to cognitive impairment. PMID- 30450702 TI - National estimations of airway foreign bodies in children in the United States, 2000 to 2009. AB - OBJECTIVE: Identify risk factors associated with airway foreign bodies in children in the United States and report observed trends over time. DATA SOURCE: KID database (2000-2009). METHODS: ICD-9-CM codes for airway foreign bodies were used to identify patients. Risk factors were used for univariate analysis and a multivariate model to identify any increased risk of mortality. These factors were then also trended over time. RESULTS: Children with airway foreign bodies demonstrate similar risk factors as previously reported, such as male gender, age less than five years old, and lack of private insurance. The weighted mortality rate for pediatric inpatients with airway foreign bodies was about 2.75%. Fortunately, the rate remained relatively unchanged from 2000 to 2009. Geographically, urban hospital settings appeared to be more affected. Increased risks of mortality were noted for older age, urban hospital setting, and teaching hospital status. CONCLUSIONS: Our findings confirm previous findings and identified that the diagnosis of airway foreign bodies in children were associated with male gender, age less than five years old, lack of private insurance, and geographic location in an urban setting. Further investigation may be warranted to provide clarity on other factors found to have increased association with mortality for quality improvement. This article is protected by copyright. All rights reserved. PMID- 30450703 TI - Sedation effects of intranasal dexmedetomidine combined with ketamine and risk factors for sedation failure in young children during transthoracic echocardiography. AB - BACKGROUND: Sedation is often required for young children during transthoracic echocardiography. Dexmedetomidine and ketamine are two sedatives that are commonly used in children for procedural sedation, but they have some disadvantages when they are used alone. AIMS: The aim of this retrospective study was to analyze the effects and safety of intranasal sedation with a combination of dexmedetomidine and ketamine during transthoracic echocardiography in young children and to analyze risk factors for sedation failure. METHODS: After IRB approval, we retrospectively evaluated data on patients who underwent echocardiography between May 2016 and August 2017 utilizing a combination of dexmedetomidine 2 MUg/kg and ketamine 1 mg/kg. We collected information including heart rate, pulse oxygen saturation, sedation onset time, exam time, recovery time, and adverse reactions. Stepwise logistic regression analyses were performed to analyze the risk factors for sedation failure. RESULTS: Sedation was successful in 2212 patients (96%) and took effect in 15.7 (IQR: 10-23) min, while sedation failed in 92 patients. Cyanotic heart disease, history of sedation failure, history of congenital heart disease surgery, and fever were independent risk factors for sedation failure. Most of the patients in this study had an American Society of Anesthesiologists (ASA) grade of II to III, but no severe adverse reactions were observed. CONCLUSION: Intranasal sedation with a combination of dexmedetomidine and ketamine is effective and appears to have an acceptable safety profile for young children during transthoracic echocardiography. PMID- 30450704 TI - Stent "Hygiene". AB - Studies demonstrate ideal Stent expansion with prolonged inflations. Longer inflations, a mediator of greater stent expansion, lower immediate, subacute, and late stent failure. Research should focus on components of stent deployment that optimize early and late stent outcomes. PMID- 30450705 TI - Sheath size, radial occlusion, and ethnicity: Real or confounded? AB - Japanese participants experienced higher incidence of radial artery occlusion when compared to non-Japanese participants. The use of 6Fr Slender sheath was inferior for radial artery occlusion than 5Fr sheath in Japanese, but no different in non-Japanese participants. Is not clear if this apparent ethnical interaction is real versus confounded, warranting more research in the area. PMID- 30450706 TI - Residual damage in previously instrumented radial arteries. AB - Pre-procedural radial artery ultrasound may reduce both vascular access time and total procedure time in patients who previously had radial artery procedures. Many radial arteries that were previously instrumented appear to have chronic changes that may make them unfavorable for future use. Attention to best practice for radial artery catheterization and measurements of long-term radial artery damage may be important metrics for sustainable, long-term use of transradial access. PMID- 30450707 TI - Transfemoral PCI skill: Use it or lose it.....But #RadialFirst. AB - Despite, earlier concerns, is the article by Badri et al., there was no apparent increase in the rate of vascular complications with transfemoral percutaneous coronary intervention (PCI) associated with increasing levels of adoption of transradial PCI by individuals initially identified as primarily femoral operators (> 90% of PCI's via the femoral artery). Compared with the 2010-2011 period, patients undergoing PCI in the United States in 2014-2015 tended to be generally sicker. This fact, coupled with a liberalization in bleeding definition, likely led to an overall increase in the observed rate of vascular complications post-transfemoral PCI (from 1.3 to 1.64%) across the study time period. Despite the extensive body of evidence supporting the use of transradial over transfemoral PCI access, the vast majority (>80%) of primarily femoral operators in the United States have remained low radial adopters and the overall proportion of PCIs performed transradially across this time period by primarily transfemoral operators increased significantly, yet modestly (from 1.3 to 17.8%). PMID- 30450708 TI - Paravalvular leak after transcatheter aortic valve replacement: Avoid it or treat it if you can! AB - Paravalvular leaks (PVL) were more severe and frequent with medtronic core valves (MCV) when compared with Edward Sapien valves (ESV) immediately after transcatheter aortic valve replacement (TAVR). Severity and frequency of PVL improved in MCV overtime, but not in ESV. The decrease in frequency of PVL in MCV valves was earlier and more robust in the area surrounding the commissure between noncoronary cusp (NCC) to right coronary cusp (RCC) compared with other areas. Such preferential reduction of PVL was not seen in ESV. PMID- 30450709 TI - Plug vs. suture: Who wins in large bore access closure? AB - Large Bore Access in increasingly common and surgical closure used to be the gold standard for closure. Novel less invasive closure devices such as the suture based vascular devices offer a safe alternative to surgery. Recent developments provide us with MANTA (Essential Medical Inc., Malvern, Pennsylvania) a vascular closure device that seems to be as safe and associated with less bleeding. Certain genetic polymorphisms might account for HoTPR. PMID- 30450710 TI - A new simple tool to manage the no reflow phenomenon. AB - The management of no reflow post PCI remains a challenge. A novel modification of a standard balloon catheter allows the distal delivery of pharmacology. A variety of intracoronary drugs may be effective in restoring flow. PMID- 30450711 TI - Heparin for diagnostic trans-radial catheterization: Can we have some randomized data? AB - Marked heterogeneity exists regarding the dose, time and route of administration of unfractionated heparin for diagnostic trans-radial procedures. In an era of smaller caliber hydrophilic radial sheaths, patent hemostasis technique, and shorter compression times, the utility of heparin to prevent radial artery occlusion remains a question. A randomized clinical trial assessing the utility, timing, dose, and route of administration of unfractionated heparin for diagnostic radial catheterization with an aim to prevent radial artery occlusion is needed. PMID- 30450712 TI - A retrospective study on sleep-disordered breathing in Morquio-A syndrome. AB - Respiratory problems are common in Morquio-A syndrome (MPS IVA) but objective data on sleep-disordered breathing are scarce. The aim of our study was to review polygraphic (PG) findings and the need for noninvasive continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in children with MPS IVA. A retrospective review of the clinical charts and PG of 16 consecutive children (7 boys, mean age 10.5 +/- 4.2 years) with MPS IVA seen over a period of 3 years was performed. The prevalence of obstructive sleep apnea (OSA) was 69% with only five patients, all younger than 10 years old, having a normal PG. Four patients had mild OSA (apnea-hypopnea index [AHI] >=1.5 and <5 events/hr), three patients had moderate OSA (AHI >=5 and <10 events/hr), and three patients had severe OSA (AHI >= 10 events/hr). Among the 10 patients with OSA, 3 had prior adenoidectomy +/- tonsillectomy and 6 were on enzyme replacement therapy. Only one patient had a central apnea index >5 events/hr despite prior cervico-occipital decompression. Six patients, all older than 11 years old, were started on CPAP or NIV because of severe OSA (n = 4), nocturnal hypoventilation (n = 1), or impossibility to be weaned from NIV after an acute respiratory failure (n = 1). Prevalence of OSA is high in patients with MPS IVA, underlying the importance of a systematic screening for sleep-disordered breathing. CPAP and NIV are efficient and well accepted for treating sleep-disordered breathing. PMID- 30450713 TI - Silencing of ADAM33 restrains proliferation and induces apoptosis of airway smooth muscle cells in ovalbumin-induced asthma model. AB - A defibrinogen and metalloproteinase 33 (ADAM33) was reported to play an important role in asthma. Furthermore, ADAM33 may play a possible role in airway remodeling due to its high expression in myo-/fibroblasts, epithelium, as well as the airway smooth muscle cells (ASMCs). Thus, the study is supposed to investigate the effect of the downregulation of ADAM33 on the proliferation and apoptosis of ASMCs in allergic asthma. An ovalbumin-induced asthma model in rats was established for investigating the function of the silencing of ADAM33. ASMCs were cultured and divided into four groups after transfection. The messenger RNA and protein expressions of ADAM33 were measured by reverse transcription quantitative polymerase chain reaction and Western blot analysis. Cell proliferation was tested by cell counting kit-8 and cell apoptosis by TdT mediated dUTP nick-end labeling. The allergic asthma rats showed a large number of inflammatory cell infiltration, airway smooth muscle hypertrophy and hyperplasia, and increased WA t , WA m , and numbers of bronchial smooth muscle nucleus. Additionally, increased numbers of eosinophils and neutrophils, expressions of immunoglobulin E and interleukin-4, content of airway air pressure, and NO, although decreased in expression of interferon-gamma, were exhibited in rats with allergic asthma. In our study, upregulated ADAM33 was found, and after the silencing of ADAM33, decreased proliferation and increased apoptosis of ASMCs were observed. The study evidences that silencing of ADAM33 can decrease the proliferation and increase the apoptosis of ASMCs in a rat model of allergic asthma, suggesting ADAM33 represents a potential investigative focus target aiding allergic asthma. PMID- 30450714 TI - Tangled banks: a landscape genomic evaluation of wallace's riverine barrier hypothesis for three amazon plant species. AB - Wallace's Riverine Barrier hypotheses is one of the earliest biogeographic explanations for Amazon speciation, but it has rarely been tested in plants. In this study, we used three woody Amazonian plant species to evaluate Wallace's Hypothesis using tools of landscape genomics. We generated unlinked single nucleotide polymorphism (SNP) data from the nuclear genomes of 234 individuals (78 for each plant species) across 13 sampling sites along the Rio Branco, Brazil, for Amphirrhox longifolia (8,075 SNPs), Psychotria lupulina, (9,501 SNPs) and Passiflora spinosa (14,536 SNPs). Although significantly different migration rates were estimated between species, the population structure data do not support the hypothesis that the Rio Branco - an allopatric barrier for primates and birds - is a significant genetic barrier for Amphirrhox longifolia, Passiflora spinosa, or Psychotria lupulina. Overall, we demonstrated that medium sized rivers in the Amazon Basin, such as the Rio Branco, are permeable barriers to gene flow for animal dispersed and animal pollinated plant species. This article is protected by copyright. All rights reserved. PMID- 30450715 TI - Ablepharon and craniosynostosis in a patient with a localized TWIST1 basic domain substitution. AB - The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre-Chotzen syndrome and Sweeney-Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon. PMID- 30450716 TI - Lessons from the Ocean: Whale Baleen Fracture Resistance. AB - Whale baleen is a keratin-based biological material; it provides life-long (40 100 years) filter-feeding for baleen whales in place of teeth. This study reveals new aspects of the contribution of the baleen's hierarchical structure to its fracture toughness and connects it to the unique performance requirements, which require anisotropy of fracture resistance. Baleen plates are subjected to competing external effects of hydration and varying loading rates and demonstrate a high fracture toughness in transverse loading, which is the most important direction in the filtering function; in the longitudinal direction, the toughness is much lower since delamination and controlled flexure are expected and desirable. The compressive strength is also established and results support the fracture toughness measurements: it is also highly anisotropic, and exhibits a ductile-to-brittle transition with increasing strain rate in the dry condition, which is absent in the hydrated condition, conferring impact resistance to the baleen. Using 3D-printing prototypes that replicate the three principal structural features of the baleen plate (hollow medulla, mineralized tubules, and sandwich-tubular structure) are created, and the role of its structure in determining its mechanical behavior is demonstrated. These findings suggest new bioinspired engineering materials. PMID- 30450717 TI - Potential difficulty of distinguishing densely compacted thrombi from small calcific emboli. PMID- 30450718 TI - GW5-Like, a homolog of GW5, negatively regulates grain width, weight and salt resistance in rice. AB - Grain size is an important determinant of yield potential in crops. We previously demonstrated that natural mutations in the regulatory sequences of qSW5/GW5 confer grain width diversity in rice. However, the biological function of a GW5 homolog, named GW5-Like (GW5L), remains unknown. In this study, we report on GW5L knockout mutants in Kitaake, a japonica cultivar (cv.) considered to have a weak gw5 variant allele that confers shorter and wider grains. GW5L is evenly expressed in various tissues, and its protein product is localized to the plasma membrane. Biochemical assays verified that GW5L functions in a similar fashion to GW5. It positively regulates brassinosteroid (BR) signaling through repression of the phosphorylation activity of GSK2. Genetic data show that GW5L overexpression in either Kitaake or a GW5 knockout line, Kasaorf3 (indica cv. Kasalath background), causes more slender, longer grains relative to the wild-type. We also show that GW5L could confer salt stress resistance through an association with calmodulin protein OsCaM1-1. These findings identify GW5L as a negative regulator of both grain size and salt stress tolerance, and provide a potential target for breeders to improve grain yield and salt stress resistance in rice. PMID- 30450719 TI - Simultaneous quantification of N-butylthiophosphoric triamide and dicyandiamide in urea formulation by liquid chromatography with tandem mass spectrometry. AB - A new liquid chromatography with tandem mass spectrometry method employing a mixed-mode zwitterionic stationary phase was developed for simultaneous determination of urease inhibitor (N-butylthiophosphoric triamide) and nitrification inhibitor (dicyandiamide) in urea fertilizer. Molecular modeling based on density functional theory calculations was employed to provide an insight into the interaction mechanism of urea, dicyandiamide, and N butylthiophosphoric triamide with zwitterionic stationary phase in chromatographic separation system. The detection of analytes was performed on a triple quadrupole tandem mass spectrometer in multiple reaction monitoring mode using positive electrospray ionization. The ion transitions monitored were m/z 85 >68 for dicyandiamide and m/z 168.2->74 for N-butylthiophosphoric triamide, respectively. The standard calibration curves of dicyandiamide and N butylthiophosphoric triamide were linear over the range of 1.0 15 ppm (coefficient of determination = 0.9984), 0.05 1 ppm (coefficient of determination = 0.9995), with limit of detection of 25 and 5 ppb, respectively. The recoveries of low, middle, and high concentrations were from 96.7 to 105.8% for N-butylthiophosphoric triamide and 94.4 to 105.8% for dicyandiamide with accuracy (relative error %) of <=5.8% and <=5.8%, the precision (coefficients of variation) was <=2.0% and <=2.9%, respectively. The validated method was successfully applied on real urea samples to determine N-butylthiophosphoric triamide and dicyandiamide simultaneously. PMID- 30450720 TI - The importance of growing up: juvenile environment influences dispersal of individuals and their neighbours. AB - Dispersal is a key ecological process that is strongly influenced by both phenotype and environment. Here, we show that juvenile environment influences dispersal not only by shaping individual phenotypes, but also by changing the phenotypes of neighbouring conspecifics, which influence how individuals disperse. We used a model system (Tribolium castaneum, red flour beetles) to test how the past environment of dispersing individuals and their neighbours influences how they disperse in their current environment. We found that individuals dispersed especially far when exposed to a poor environment as adults if their phenotype, or even one-third of their neighbours' phenotypes, were shaped by a poor environment as juveniles. Juvenile environment therefore shapes dispersal both directly, by influencing phenotype, as well as indirectly, by influencing the external social environment. Thus, the juvenile environment of even a minority of individuals in a group can influence the dispersal of the entire group. PMID- 30450721 TI - Efficacy and safety of treatment of hyposecretory dry eye with platelet-rich plasma. AB - OBJECTIVE: To evaluate and compare the symptomatology and clinical findings in hyposecretory dry eye of the treatment with platelet-rich plasma (PRP) and artificial tears of sodium hyaluronate (SH). METHODS: Blind single-centre prospective comparative randomized study including 83 patients with hyposecretory dry eye and mean age of 64.0 years. Two groups were differentiated depending on the treatment applied: 44 patients treated with PRP (PRP group), and 39 patients treated with artificial tears of SH (SH group). Changes in Schimer test, tear osmolarity, corneal and conjunctival staining, tear film break-up time (TF-BUT), conjunctival hyperaemia, dry eye-related symptoms with the Ocular Surface Disease Index questionnaire, and caliciform cell density were evaluated during 30 days of treatment. RESULTS: Significantly larger reduction in symptomatology (p < 0.001), visual improvement (p < 0.001), reduction in hyperaemia (p < 0.001), and corneal and conjunctival staining (p < 0.001), increment of Schirmer test outcome (p <= 0.005), and reduction of osmolarity were found in the PRP group in both eyes compared to SH group at 15 and 30 days of treatment. Likewise, a significantly higher increment of caliciform cell density (p < 0.001) was found in the PRP group. Strong and statistically significant correlations were found in the PRP group of the change achieved in visual acuity, hyperaemia, osmolarity, and conjunctival and corneal staining with the baseline values of these variables (p < 0.001). CONCLUSION: PRP treatment in hyposecretory dry eye induces a more significant positive effect over symptomatology and different dry eye signs than SH, especially in moderate and severe cases. PMID- 30450722 TI - Long non-coding RNAs influence the transcriptome in pulmonary arterial hypertension: the role of PAXIP1-AS1. AB - In idiopathic pulmonary arterial hypertension (IPAH), global transcriptional changes induce a smooth muscle cell phenotype characterized by excessive proliferation, migration and apoptosis resistance. Long non-coding RNAs (lncRNAs) are key regulators of cellular function. Using a compartment-specific transcriptional profiling approach, we sought to investigate the link between transcriptional reprogramming by lncRNAs and the maladaptive smooth muscle cell phenotype in IPAH. Transcriptional profiling of small remodelled arteries from 18 IPAH patients and 17 controls revealed global perturbations in metabolic, neuronal, proliferative and immunological processes. We demonstrated an IPAH specific lncRNA expression profile and identified the lncRNA PAXIP1-AS1 as highly abundant. Comparative transcriptomic analysis and functional assays revealed an intrinsic role for PAXIP1-AS1 in orchestrating the hyperproliferative and migratory actions of IPAH smooth muscle cells. Further, we showed that PAXIP1-AS1 mechanistically interferes with the focal adhesion axis via regulation of expression and phosphorylation of its downstream target paxillin. Overall, we show that changes in the lncRNA transcriptome contribute to the disease-specific transcriptional landscape in IPAH. Our results suggest that lncRNAs, such as PAXIP1-AS1, can modulate smooth muscle cell function by affecting multiple IPAH specific transcriptional programs. PMID- 30450724 TI - Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. AB - Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realize in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e., "younger" cells), rather than dedifferentiation, which bears the risk of cancer? Here, we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follows different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimized risk of cancer. PMID- 30450723 TI - Evolutionary significance of the microbial assemblages of large benthic Foraminifera. AB - Large benthic Foraminifera (LBF) are major carbonate producers on coral reefs, and are hosts to a diverse symbiotic microbial community. During warm episodes in the geological past, these reef-building organisms expanded their geographical ranges as subtropical and tropical belts moved into higher latitudes. During these range-expansion periods, LBF were the most prolific carbonate producers on reefs, dominating shallow carbonate platforms over reef-building corals. Even though the fossil and modern distributions of groups of species that harbour different types of symbionts are known, the nature, mechanisms, and factors that influence their occurrence remain elusive. Furthermore, the presence of a diverse and persistent bacterial community has only recently gained attention. We examined recent advances in molecular identification of prokaryotic (i.e. bacteria) and eukaryotic (i.e. microalgae) associates, and palaeoecology, and place the partnership with bacteria and algae in the context of climate change. In critically reviewing the available fossil and modern data on symbiosis, we reveal a crucial role of microalgae in the response of LBF to ocean warming, and their capacity to colonise a variety of habitats, across both latitudes and broad depth ranges. Symbiont identity is a key factor enabling LBF to expand their geographic ranges when the sea-surface temperature increases. Our analyses showed that over the past 66 million years (My), diatom-bearing species were dominant in reef environments. The modern record shows that these species display a stable, persistent eukaryotic assemblage across their geographic distribution range, and are less dependent on symbiotic photosynthesis for survival. By contrast, dinoflagellate and chlorophytic species, which show a provincial distribution, tend to have a more flexible eukaryotic community throughout their range. This group is more dependent on their symbionts, and flexibility in their symbiosis is likely to be the driving force behind their evolutionary history, as they form a monophyletic group originating from a rhodophyte-bearing ancestor. The study of bacterial assemblages, while still in its infancy, is a promising field of study. Bacterial communities are likely to be shaped by the local environment, although a core bacterial microbiome is found in species with global distributions. Cryptic speciation is also an important factor that must be taken into consideration. As global warming intensifies, genetic divergence in hosts in addition to the range of flexibility/specificity within host-symbiont associations will be important elements in the continued evolutionary success of LBF species in a wide range of environments. Based on fossil and modern data, we conclude that the microbiome, which includes both algal and bacterial partners, is a key factor influencing the evolution of LBF. As a result, the microbiome assists LBF in colonising a wide range of habitats, and allowed them to become the most important calcifiers on shallow platforms worldwide during periods of ocean warming in the geologic past. Since LBF are crucial ecosystem engineers and prolific carbonate producers, the microbiome is a critical component that will play a central role in the responses of LBF to a changing ocean, and ultimately in shaping the future of coral reefs. PMID- 30450725 TI - Endogenous reduction of miR-185 accelerates cardiac function recovery in mice following myocardial infarction via targeting of cathepsin K. AB - Angiogenesis is critical for re-establishing the blood supply to the surviving myocardium after myocardial infarction (MI) in patients with acute coronary syndrome (ACS). MicroRNAs are recognised as important epigenetic regulators of endothelial function. The aim of this study was to determine the roles of microRNAs in angiogenesis. Eighteen circulating microRNAs including miR-185-5p were differently expressed in plasma from patients with ACS by high-throughput RNA sequencing. The expressional levels of miR-185-5p were dramatically reduced in hearts isolated from mice following MI and cultured human umbilical vein endothelial cells (HUVECs) under hypoxia, as determined by fluorescence in situ hybridisation and quantitative RT-PCR. Evidence from computational prediction and luciferase reporter gene activity indicated that cathepsin K (CatK) mRNA is a target of miR-185-5p. In HUVECs, miR-185-5p mimics inhibited cell proliferations, migrations and tube formations under hypoxia, while miR-185-5p inhibitors performed the opposites. Further, the inhibitory effects of miR-185-5p up regulation on cellular functions of HUVECs were abolished by CatK gene overexpression, and adenovirus-mediated CatK gene silencing ablated these enhancive effects in HUVECs under hypoxia. In vivo studies indicated that gain function of miR-185-5p by agomir infusion down-regulated CatK gene expression, impaired angiogenesis and delayed the recovery of cardiac functions in mice following MI. These actions of miR-185-5p agonists were mirrored by in vivo knockdown of CatK in mice with MI. Endogenous reductions of miR-185-5p in endothelial cells induced by hypoxia increase CatK gene expression to promote angiogenesis and to accelerate the recovery of cardiac function in mice following MI. PMID- 30450726 TI - Bioresorbable Silicon Nanomembranes and Iron Catalyst Nanoparticles for Flexible, Transient Electrochemical Dopamine Monitors. AB - A strategy of materials synthesis, characteristic evaluations, and manufacturing process for a mechanically elastic, biologically safe silicon-based dopamine detector that is designed to be completely transient, i.e., dissolved in water and/or biofluids, potentially in the brain after a desired period of operation, is introduced. Use of inexpensive, bioresorbable iron (Fe)-based nanoparticles (NPs) is one of the attractive choices for efficient catalytic oxidation of dopamine as an alternative for noble, nontransient platinum (Pt) nanoparticles, based on extensive studies of synthesized materials and catalytic reactions. Arrays of transient dopamine sensors validate electrochemical functionality to determine physiological levels of dopamine and to selectively sense dopamine in a variety of neurotransmitters, illuminating feasibilities for a higher level of soft, transient electronic implants integrated with other components of overall system. PMID- 30450727 TI - Involvement of sweet pepper CaLOX2 in jasmonate-dependent induced defence against Western flower thrips. AB - Insect herbivory can seriously hinder plant performance and reduce crop yield. Thrips are minute cell-content-feeding insects that are important vectors of viral plant pathogens, and are serious crop pests. We investigated the role of a sweet pepper (Capsicum annuum) lipoxygenase gene, CaLOX2, in the defense of pepper plants against Western flower thrips (Frankliniella occidentalis). This was done through a combination of in-silico, transcriptional, behavioral and chemical analyses. Our data show that CaLOX2 is involved in jasmonic acid (JA) biosynthesis and mediates plant resistance. Expression of the JA-related marker genes, CaLOX2 and CaPIN II, was induced by thrips feeding. Silencing of CaLOX2 in pepper plants through virus-induced gene silencing (VIGS) resulted in low levels of CaLOX2 transcripts, as well as significant reduction in the accumulation of JA, and its derivatives, upon thrips feeding compared to control plants. CaLOX2 silenced pepper plants exhibited enhanced susceptibility to thrips. This indicates that CaLOX2 mediates JA-dependent signalling, resulting in defense against thrips. Furthermore, exogenous application of JA to pepper plants increased plant resistance to thrips, constrained thrips population development and made plants less attractive to thrips. Thus, a multidisciplinary approach shows that an intact lipoxygenase pathway mediates various components of sweet pepper defense against F. occidentalis. PMID- 30450728 TI - Does Evaluation of Tumour Budding in Diagnostic Biopsies have a Clinical Relevance? A Systematic Review. AB - AIMS: Tumour budding has emerged as a promising prognostic marker in many cancers. We systematically reviewed all studies that evaluated tumour budding in diagnostic biopsies. METHODS AND RESULTS: We conducted a systematic review of PubMed, MEDLINE, Scopus, Web of Science and Cochrane library for all articles that have assessed tumour budding in diagnostic (i.e. pretreatment or preoperative) biopsies of any tumour type. Two independent researchers screened the retrieved studies, removed duplicates, excluded irrelevant studies and extracted data from the eligible studies. A total of 13 reports comprising 11 cohorts were found to have studied tumour budding in diagnostic biopsies. All these reports showed that evaluation of tumour budding in diagnostic biopsies was easily applicable. A strong association was observed between tumour budding score in diagnostic biopsies and corresponding surgical samples. Evaluation of tumour budding in diagnostic biopsies had a significant prognostic value for lymph node metastasis and patient survival. CONCLUSIONS: In all studies, tumour budding was a valuable marker of tumour aggressiveness and it can be evaluated in technically satisfactory diagnostic biopsies. Thus, the assessment of tumour budding seems to identify the behaviour of cancer, and therefore to facilitate treatment planning. This article is protected by copyright. All rights reserved. PMID- 30450729 TI - Living liver donation improves patient and graft survival in the pediatric population. AB - BACKGROUND: The utilization of living donor grafts resulted in an increased availability of liver for pediatric recipients, and accordingly, this was associated with a significantly decreased waiting time before liver transplantation as well as reduced pre-transplant mortality. We hypothesized that the use of living donors in pediatric LT may lead to improved graft and patient survival, when compared to LT using deceased donors. METHODS: Retrospective cohort analysis of pediatric recipients (aged <18 years) registered in the UNOS database who received a primary liver transplant between February 2002 and December 2016. Covariates predictive of survival by multivariable analyses were included in the Cox proportional hazards regression models to determine predictors of patient and graft survival. RESULTS: A total of 6312 children received a primary LT from a LD (n = 800) or a deceased donor (n = 5517; partial graft n = 1784 and whole graft n = 3733). Vascular and biliary complications were similar. Kaplan-Meier graft and patient survival rates were superior in LD recipients compared with recipients of deceased whole and reduced graft (Figures 1 and 2). In the multivariable analysis, LD were an independent predictor of improved patient and graft survival. CONCLUSION: The use of LD in children is associated with improved patient and graft survival. The option of LD should be introduced early on in the evaluation of every pediatric patient being evaluated for liver transplant. PMID- 30450730 TI - Second to fourth digit ratio and lung function (forced vital capacity): predictors of maximum urinary flow rate after holmium laser enucleation of the prostate. AB - BACKGROUND: Maximum urinary flow rate (Qmax) is usually increased after holmium laser enucleation of the prostate (HoLEP). However, improvements vary between patients and results regarding potential predictors of Qmax after HoLEP are inconsistent. Thus, we investigated pre-operative variables including second to fourth digit ratio (digit ratio) and pulmonary function test (PFT) findings as potential predictors of Qmax after HoLEP. METHODS: One hundred and ninety-five consecutive patients with benign prostatic hyperplasia (BPH) who underwent HoLEP were enrolled. Before HoLEP, PFTs were performed and lengths of second and fourth digits of right hands were measured by a single investigator using a digital vernier caliper. To identify independent predictors of Qmax after HoLEP, univariate and multivariate analyses were performed using linear regression models. RESULTS: Mean age and total prostate volume for all 195 study subjects were 69.4 years and 63.3 mL respectively. Mean pre-operative and post-operative Qmax values were 8.7 and 26.2 mL/sec respectively. Univariate analysis showed age (r = -0.181, p = 0.014), digit ratio (r = 0.213, p = 0.004), lung function (forced vital capacity (FVC): r = 0.218, p = 0.005; forced expiratory volume in 1 sec (FEV1): r = 0.166, p = 0.034), pre-operative Qmax (r = 0.264, p = 0.000), pre operative voided volume (VV) (r = 0.158, p = 0.033), and post-operative VV (r = 0.311, p = 0.000) were associated with post-operative Qmax, whereas multivariate analysis showed that digit ratio (beta = 0.285, p = 0.001), FVC (beta = 0.340, p = 0.039), and post-operative VV (beta = 0.301, p = 0.000) independently predicted post-operative Qmax. CONCLUSIONS: The independent predictors of Qmax after HoLEP were digit ratio and lung function (FVC) as well as post-operative VV. This means that the higher a man's digit ratio and lung function (FVC), the higher his Qmax after HoLEP. PMID- 30450731 TI - Peri-transplant Plasmapheresis in FSGS. PMID- 30450732 TI - Non-invasive measurement of reservoir pressure parameters from brachial-cuff blood pressure waveforms. AB - Reservoir pressure parameters [eg, reservoir pressure (RP) and excess pressure (XSP)] are biomarkers derived from blood pressure (BP) waveforms that have been shown to predict cardiovascular events independent of conventional cardiovascular risk markers. However, whether RP and XSP can be derived non-invasively from operator-independent cuff device measured brachial or central BP waveforms has never been examined. This study sought to achieve this by comparison of cuff reservoir pressure parameters with intra-aortic reservoir pressure parameters. 162 participants (aged 61 +/- 10 years, 72% male) undergoing coronary angiography had the simultaneous measurement of cuff BP waveforms (via SphygmoCor XCEL, AtCor Medical) and intra-aortic BP waveforms (via fluid-filled catheter). RP and XSP derived from cuff acquired brachial and central BP waveforms were compared with intra-aortic measures. Concordance between brachial-cuff and intra-aortic measurement was moderate-to-good for RP peak (36 +/- 11 vs 48 +/- 14 mm Hg, P < 0.001; ICC 0.77, 95% CI: 0.71-0.82), and poor-to-moderate for XSP peak (28 +/- 10 vs 24 +/- 9 mm Hg, P < 0.001; ICC 0.49, 95% CI: 0.35-0.60). Concordance between central-cuff and intra-aortic measurement was moderate-to-good for RP peak (35 +/ 9 vs 46 +/- 14 mm Hg, P < 0.001; ICC 0.77, 95% CI: 0.70-0.82), but poor for XSP peak (12 +/- 3 vs 24 +/- 9 mm Hg, P < 0.001; ICC 0.12, 95% CI: -0.13 to 0.31). In conclusion, both brachial-cuff and central-cuff methods can reasonably estimate intra-aortic RP, whereas XSP can only be acceptably derived from brachial-cuff BP waveforms. This should enable widespread application to determine the clinical significance, but there is significant room for refinement of the method. PMID- 30450733 TI - Free Radical Reactivity of a Phosphaalkene Explored Through Studies of Radical Isotopologues. AB - Muonium (Mu), an H atom analogue, is employed to probe the addition of free radicals to the P=C bond of a phosphaalkene. Specifically, two unprecedented muoniated free radicals, MesP. -CMu(Me)2 (1 a, minor product) and MesPMu-C. Me2 (1 b, major product), were detected by muon spin spectroscopy (MUSR) when a solution of MesP=CMe2 (1: Mes=2,4,6-trimethylphenyl) was exposed to a beam of positive muons (MU+ ). The MU+ serves as a source of Mu (that is, Mu=MU+ +e- ). To confirm the identity of the major product 1 b, its spectral features were compared to its isotopologue, MesPH-C. (Me)CH2 Mu (2 a). Conveniently, 2 a is the sole product of the reaction of MesPH(CMe=CH2 ) (2) with Mu. For all observed radicals, muon, proton, and phosphorus hyperfine coupling constants were determined by MUSR and compared to DFT-calculated values. PMID- 30450734 TI - A Novel Self-Assembled Mitochondria-Targeting Protein Nanoparticle Acting as Theranostic Platform for Cancer. AB - Self-assembled protein nanoparticles have attracted much attention in biomedicine because of their biocompatibility and biodegradability. Protein nanoparticles have become widely utilized as diagnostic or therapeutic agents for various cancers. However, there are no reports that protein nanoparticles can specifically target mitochondria. This targeting is desirable, since mitochondria are critical in the development of cancer cells. In this study, the discovery of a novel self-assembled metal protein nanoparticle, designated GST-MT-3, is reported, which targets the mitochondria of cancer cells within 30 min in vitro and rapidly accumulates in tumors within 1 h in vivo. The nanoparticles chelate cobalt ions [GST-MT-3(Co2+ )], which induces reactive oxygen species (ROS) production and reduces the mitochondrial membrane potential. These effects lead to antitumor activity in vivo. GST-MT-3(Co2+ ) with covalently conjugated paclitaxel synergistically suppress tumors and prolong survival. Importantly, the effective dosage of paclitaxel is 50-fold lower than that utilized in standard chemotherapy (0.2 vs 10 mg kg-1 ). To the best of the authors' knowledge, GST-MT 3 is the first reported protein nanoparticle that targets mitochondria. It has the potential to be an excellent platform for combination therapies. PMID- 30450735 TI - TSG101 promotes the proliferation, migration and invasion of hepatocellular carcinoma cells by regulating the PEG10. AB - The tumour susceptibility gene 101 (TSG101) is reported to play important roles in the development and progression of several human cancers. However, its potential roles and underlined mechanisms in human hepatocellular carcinoma (HCC) are still needed to be further clarified. In the present study, we reported that knock down of TSG101 suppressed the proliferation, migration and invasion of HCC cells, while overexpression of TSG101 facilitated them. Molecularly, the results revealed that knock down of TSG101 significantly decreased the cell cycle related regulatory factor p53 and p21. In another point, knock down of TSG101 also obviously decreased the level of metallopeptidase inhibitor TIMP1 (Tissue inhibitors of metalloproteinases 1), which results in inhibition of MMP2, MMP7 and MMP9. In contrast, overexpression of TSG101 had opposite effects. The iTRAQ proteomics analysis identified that oncogenic protein PEG10 (Paternally expressed gene 10) might be a potential downstream target of TSG101. Further investigation showed that TSG101 interacted with PEG10 and protected it from proteasomal degradation thereby regulating the expression of p53, p21 and MMPs. Finally, we found that both TSG101 and PEG10 proteins are up-regulated and presented a direct correlation in HCC patients. In conclusion, these results suggest that TSG101 is up-regulated in human HCC patients, which may accelerate the proliferation, migration and invasion of HCC cells through regulating PEG10. PMID- 30450736 TI - Engineering of TIMP-3 as a LAP-fusion protein for targeting to sites of inflammation. AB - Tissue inhibitor of metalloproteinase (TIMP)-3 is a natural inhibitor of a range of enzymes that degrade connective tissue and are involved in the pathogenesis of conditions such as arthritis and cancer. We describe here the engineering of TIMP 3 using a novel drug-delivery system known as the 'LAP technology'. This involves creating therapeutic proteins in fusion with the latency-associated peptide (LAP) from the cytokine TGF-? to generate proteins that are biologically inactive until cleavage of the LAP to release the therapy. LAP-TIMP-3 was successfully expressed in mammalian cells and the presence of the LAP resulted in a 14-fold increase in the quantity of recombinant TIMP-3 produced. LAP-TIMP-3 was latent until release from the LAP by treatment with matrix metalloproteinase when it could inhibit proteases of the adamalysins and adamalysins with thrombospondin motifs families, but not matrix metalloproteinases, indicating that this version of TIMP-3 is a more specific inhibitor than the native protein. There was sufficient protease activity in synovial fluid from human joints with osteoarthritis to release TIMP 3 from the LAP fusion. These results demonstrate the potential for development of TIMP-3 as a novel therapy for conditions where upregulation of catabolic enzymes are part of the pathology. PMID- 30450737 TI - Boosting Alkaline Hydrogen Evolution Activity with Ni-doped MoS2/Reduced Graphene Oxide Hybrid Aerogel. AB - Highly active, durable and cost-effective non-precious metal based electrocatalysts are urgently needed for the sluggish hydrogen evolution reaction (HER) in alkaline environment. Herein, a lyophilization-thermolysis method is successfully applied to prepare Ni-doped MoS2 (Ni-MoS2)/reduced graphene oxide (RGO) hybrid aerogel. MoS2 aerogel possesses higher density of exposed active sites than its corresponding bulk. Inheriting from GO with abundant functional groups during pyrolysis, RGO aerogel can uniformly disperse MoS2 and simultaneously maintain excellent conductivity. The incorporation of Ni atoms can accelerate the cleaving of HO-H bond and enhance the adsorption and desorption of intermediated OH-. Owing to the synergistic effect of the compositional and structural advantages in aerogel, Ni-MoS2/RGO hybrid aerogel delivers highly promoted HER kinetics in alkaline media. As a result, the optimal eta10 (overpotential at the current of 10 mA cm-2) of 168 mV in 1 M KOH is obtained, which is superior to MoS2/RGO hybrid aerogel (225 mV) and MoS2 aerogel (263 mV), letting alone bulk MoS2 (448 mV). Moreover, the eta60 (overpotential at the current of 60 mA cm-2) maintains at 262 mV after chronopotentiometry (CP) test at a constant current density of 10 mA cm-2 for 24 h, indicating an exceptionally stable HER process. PMID- 30450738 TI - The role of satellite glial cells in orofacial pain. AB - Some chronic pain conditions in the orofacial region are common, the mechanisms underlying which are unresolved. Satellite glial cells (SGCs) are the glial cells of the peripheral nervous system. In the sensory ganglia, each neuronal body is surrounded by SGCs forming distinct functional units. The unique structural organization enables SGCs to communicate with each other and with their enwrapped neurons via a variety of ways. There is a growing body of evidence that SGCs can influence the level of neuronal excitability and are involved in the development and/or maintenance of pain. The aim of this review was to summarize the latest advances made about the implication of SGCs in orofacial pain. It may offer new targets for the development of orofacial pain treatment. PMID- 30450740 TI - Priority Topics for Health Education to Support HIV Self-Management in Limited Resource Settings. AB - PURPOSE: The purpose of this study was to identify and prioritize the information that persons living with HIV (PLWH) in a limited-resource setting need to effectively manage their health. DESIGN AND METHODS: A data sources triangulation method was used to compare data from three separate sources: (a) 107 interviews with Spanish-speaking PLWH being seen at a healthcare clinic in the Dominican Republic (DR); (b) 40 interviews with Spanish-speaking healthcare providers from the same clinic in the DR; and (c) an integrative literature review of English- and Spanish-language articles that assessed the health information needs of PLWH in Latin America and the Caribbean. We compared information needs across sources and developed a prioritized list of the topics important to provide PLWH in a clinical setting. FINDINGS: Triangulation identified the most important topics for HIV-related health education for PLWH as medication and adherence, followed by transmission, including risks and prevention strategies, mental health management, and knowledge of HIV in general. CONCLUSIONS: The identification of evidence-based health education priorities establishes a guide that healthcare providers may use to help PLWH effectively manage their health and creates a foundation from which further studies on improving clinical interactions may be generated. CLINICAL RELEVANCE: Using the priorities identified, nurses and other health educators can improve patient education, and consequently self-management, by making evidence-based choices about what information to provide to their patients. PMID- 30450739 TI - Eye movements during path integration. AB - Self-motion induces spontaneous eye movements which serve the purpose of stabilizing the visual image on the retina. Previous studies have mainly focused on their reflexive nature and how the perceptual system disentangles visual flow components caused by eye movements and self-motion. Here, we investigated the role of eye movements in distance reproduction (path integration). We used bimodal (visual-auditory)-simulated self-motion: visual optic flow was paired with an auditory stimulus whose frequency was scaled with simulated speed. The task of the subjects in each trial was, first, to observe the simulated self motion over a certain distance (Encoding phase) and, second, to actively reproduce the observed distance using only visual, only auditory, or bimodal feedback (Reproduction phase). We found that eye positions and eye speeds were strongly correlated between the Encoding and the Reproduction phases. This was the case even when reproduction relied solely on auditory information and thus no visual stimulus was presented. We believe that these correlations are indicative of a contribution of eye movements to path integration. PMID- 30450741 TI - Caries severity declined besides persistent untreated deciduous teeth over a 22 years period: trends among children in Goiania, Brazil. AB - BACKGROUND: Evidence of time trends in early childhood caries in low and middle income countries in the second decade of the years 2000 is scarce AIM: To assess trends in early childhood caries prevalence and severity in 2- to 5 year-old children over a 22 years period (1993-2015) in Goiania, Midwest Brazil. Additionally, we aimed to investigate changes regarding affected dental arches and teeth DESIGN: A time-lag analysis of trends in caries was carried out using data from three cross-sectional studies based on the World Health Organization diagnostic criteria, in 1993 (N=1362), 2001 (N=1620) and 2015 (N=548) RESULTS: Caries prevalence declined from 45.1% in 1993 to 29.0% in 2015. Prevalence of severe caries (dmft>6) in 2015 was nearly one third of that found in 1993, and the SiC index (mean dmft of the highest tertile) decreased from 4.55 to 3.32. Decline was higher in the 1993-2001 than in the 2001-2015 time-lag. Posterior teeth and second molars had the greatest reductions. High proportions of untreated caries were found in all ages and survey years CONCLUSIONS: There were significant changes in caries prevalence and severity, marked by striking decline from 1993 to 2001, followed by less prominent decrease up to 2015, and high levels of untreated caries. This article is protected by copyright. All rights reserved. PMID- 30450742 TI - Next generation sequencing-based molecular diagnosis in familial congenital cataract expands the mutational spectrum in known congenital cataract genes. AB - Congenital cataract (CC) is a significant cause of childhood blindness worldwide. CC is a genetically heterogeneous disease because mutations in over 40 genes have been demonstrated to cause the disorder and up to 40% of cases arise from single gene mutations. Hence, next generation sequencing (NGS) of deoxyribonucleic acid is a suitable approach for CC molecular diagnosis. In this study, we used commercially available inherited disease NGS panels including 50 CC genes for the genetic diagnosis of 11 probands with hereditary CC. Causal variants were recognized in six families. A novel CRYGC variant, p.(Phe6Ser), was identified in two apparently unrelated families. Two additional novel variants in the crystallin genes CRYBB2 (p.[Gly149Asp]) and CRYGA (p.[Arg48Cys]) were also identified. One family carried the novel p.[Gly8_Leu11del] variant in GJA8, while another family exhibited the previously reported c.2826-9G>A pathogenic change in EPHA2. Our results illustrate the utility of NGS for diagnosing CC in our population, and our results contribute to expand the mutational spectrum with four novel pathogenic variants in known CC genes. PMID- 30450743 TI - Short contact with nickel is not harmless. PMID- 30450744 TI - CD123 expression levels in 846 acute leukemia patients based on standardized immunophenotyping. AB - BACKGROUND: While it is known that CD123 is normally strongly expressed on plasmacytoid dendritic cells and completely absent on nucleated red blood cells, detailed information regarding CD123 expression in acute leukemia is scarce and, if available, hard to compare due to different methodologies. METHODS: CD123 expression was evaluated using standardized EuroFlow immunophenotyping in 139 pediatric AML, 316 adult AML, 193 pediatric BCP-ALL, 69 adult BCP-ALL, 101 pediatric T-ALL, and 28 adult T-ALL patients. Paired diagnosis-relapse samples were available for 57 AML and 19 BCP-ALL patients. Leukemic stem cell (LSC) data was available for 32 pediatric AML patients. CD123 expression was evaluated based on mean fluorescence intensity, median fluorescence intensity, and percentage CD123 positive cells. RESULTS: EuroFlow panels were stable over time and between laboratories. CD123 was expressed in the majority of AML and BCP-ALL patients, but absent in most T-ALL patients. Within AML, CD123 expression was lower in erythroid/megakaryocytic leukemia, higher in NPM1 mutated and FLT3-ITD mutated leukemia, and comparable between LSC and leukemic blasts. Within BCP-ALL, CD123 expression was higher in patients with (high) hyperdiploid karyotypes and the BCR ABL fusion gene. Interestingly, CD123 expression was increased in BCP-ALL relapses while highly variable in AML relapses (compared to CD123 expression at diagnosis). CONCLUSIONS: Authors evaluated CD123 expression in a large cohort of acute leukemia patients, based on standardized and reproducible methodology. Our results may facilitate stratification of patients most likely to respond to CD123 targeted therapies and serve as reference for CD123 expression (in health and disease). (c) 2018 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society. PMID- 30450745 TI - Low-density lipoprotein net charge is a risk factor for atherosclerosis in lupus patients independent of lipid concentrations. AB - AIMS: Patients with systemic lupus erythematosus (SLE) suffer from accelerated atherosclerosis. Their most common cause of death is a cardiovascular disease (CVD), in spite of the presence of moderate lipid alterations and normal cardiovascular risk scores. However, cholesterol still accumulates in the arteries of SLE patients, so we aim to identify additional factors that may help explain the residual risk that exists in these patients. We focus on investigating whether the net charge contributes significantly to both the development and the progression of atherosclerosis in patients with SLE. METHODS: The lipoproteins from 78 patients with SLE and 32 controls were isolated via sequential ultracentrifugation. Lipoprotein subclasses distributions were analyzed via nuclear magnetic resonance spectroscopy and the net charges of very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low density lipoprotein (LDL) and high-density lipoprotein (HDL) were measured using a Zetasizer Nano-ZS. The degree of atherosclerosis (carotid intima-media thickness [cIMT]) was determined in all the participants. RESULTS: Each lipoprotein class exhibited a negative net charge. IDL and LDL net charge correlated negatively with cIMT (r = -0.274, P = 0.034; r = -0.288; P = 0.033, respectively) in patients with SLE. This effect was independent of age, body mass index (BMI), gender, tobacco consumption, high-sensitivity C-reactive protein (hsCRP), lipid concentration and lipoprotein particle number. LDL net charge explained 4% of the cIMT variability among these patients; this contribution was also independent of age, BMI, gender, tobacco consumption, lipids levels, apolipoproteins and hsCRP. CONCLUSIONS: Low-density lipoprotein net charge may be considered a new independent contributor to subclinical atherosclerosis in SLE patients. The observed relationship was independent of lipid concentrations and extends the prominent role that IDL and LDL play in cardiovascular risk. PMID- 30450746 TI - A note on compatibility for inference with missing data in the presence of auxiliary covariates. AB - Imputation and inference (or analysis) models that cannot be true simultaneously are frequently used in practice when missing outcomes are present. In these situations, the conclusions can be misleading depending on how "different" the implicit inference model, induced by the imputation model, is from the inference model actually used. We introduce model-based compatibility (MBC) and compare two MBC approaches to a non-MBC approach and explore the inferential validity of the latter in a simple case. In addition, we evaluate more complex cases through a series of simulation studies. Overall, we recommend caution when making inferences using a non-MBC analysis and point out when the inferential "cost" is the largest. PMID- 30450747 TI - Scleral asymmetry as a potential predictor for scleral lens compression. AB - PURPOSE: To identify the position and magnitude of lens compression due to short term miniscleral contact lens wear, as well as evaluating the usefulness of scleral asymmetry as a predictor for scleral lens decentered compression. METHODS: Fourteen healthy subjects (mean +/- S.D.: 29.2 +/- 6.0 years) wore a highly gas-permeable spherical haptic miniscleral contact lens during a 5-h period. Corneo-scleral height Fourier profilometry was captured using an Eye Surface Profiler (www.eaglet-eye.com) before and immediately after lens removal. Scleral asymmetry, lens compression location and magnitude were processed using custom-made algorithms, both globally and for scleral quadrants. RESULTS: Miniscleral contact lenses do not set uniformly on the ocular surface, with the largest decentration seen along the horizontal meridian. The greatest flexural stress exerted by the lens on the ocular surface occurs at the point coinciding with the inner diameter landing point of the lens and not with its overall diameter. Scleral asymmetry was significantly correlated with compression location (R = 0.71, p = 0.002) and compression magnitude (R = 0.81, p < 0.001), showing its potential as compression predictor. CONCLUSION: Larger amounts of scleral asymmetry will lead to more decentration of spherical haptic scleral lenses. Objective and accurate methods, like the one presented here, could help the practitioner prevent cases of scleral blanching or discomfort due to an excessive compression by the lens. PMID- 30450748 TI - Bearing witness in nursing practice: More than a moral obligation? AB - In this paper, we explore the concept of bearing witness in nursing practice. We examine the description of bearing witness in the nursing literature, particularly that offered by William Cody who suggests that bearing witness results in the limited moral obligation of "true presence." We then turn to Lorraine Code's work on testimony, drawing parallels between the concepts of testimony and bearing witness. Code suggests that receiving testimony results in a responsibility to respond, and that this is an ethico-political obligation. We discuss these ideas in relation to a Canadian exemplar of witnessing the Truth and Reconciliation Commission of Canada's work to understand and address the historical injustices done to Indigenous peoples in Canada. Here, we focus on the Commission's definition of witnessing and highlight the experience of Shelagh Rogers who served as an honorary witness. As an outcome of our analysis, we suggest that bearing witness in nursing practice is most usefully conceptualized as both a moral and a political obligation. Implications for nursing practice are suggested, including first, the need to critically examine our own understandings of power and privilege in order to authentically bear witness and avoid being complicit in injustice, and second, the concomitant responsibility to take action to challenge injustice once we have borne witness to it. PMID- 30450749 TI - Free-breathing, non-ECG, continuous myocardial T1 mapping with cardiovascular magnetic resonance Multitasking. AB - PURPOSE: To evaluate the accuracy and repeatability of a free-breathing, non electrocardiogram (ECG), continuous myocardial T1 and extracellular volume (ECV) mapping technique adapted from the Multitasking framework. METHODS: The Multitasking framework is adapted to quantify both myocardial native T1 and ECV with a free-breathing, non-ECG, continuous acquisition T1 mapping method. We acquire interleaved high-spatial resolution image data and high-temporal resolution auxiliary data following inversion-recovery pulses at set intervals and perform low-rank tensor imaging to reconstruct images at 344 inversion times, 20 cardiac phases, and 6 respiratory phases. The accuracy and repeatability of Multitasking T1 mapping in generating native T1 and ECV maps are compared with conventional techniques in a phantom, a simulation, 12 healthy subjects, and 10 acute myocardial infarction patients. RESULTS: In phantoms, Multitasking T1 mapping correlated strongly with the gold-standard spin-echo inversion recovery (R2 = 0.99). A simulation study demonstrated that Multitasking T1 mapping has similar myocardial sharpness to the fully sampled ground truth. In vivo native T1 and ECV values from Multitasking T1 mapping agree well with conventional MOLLI values and show good repeatability for native T1 and ECV mapping for 60 seconds, 30 seconds, or 15 seconds of data. Multitasking native T1 and ECV in myocardial infarction patients correlate positively with values from MOLLI. CONCLUSION: Multitasking T1 mapping can quantify native T1 and ECV in the myocardium with free-breathing, non-ECG, continuous scans with good image quality and good repeatability in vivo in healthy subjects, and correlation with MOLLI T1 and ECV in acute myocardial infarction patients. PMID- 30450750 TI - Efficient method for isolation of reticulocyte RNA from healthy individuals and hemolytic anaemia patients. AB - Despite enormous progress and development of high-throughput methods in genome wide mRNA analyses, data on the erythroid transcriptome are still limited, even though they could be useful in medical diagnostics and personalized therapy as well as in research on normal and pathological erythroid maturation. Although obtaining normal and pathological reticulocyte transcriptome profiles should contribute greatly to our understanding of the molecular bases of terminal erythroid differentiation as well as the mechanisms of the hematological diseases, a basic limitation of these studies is the difficulty of efficient reticulocyte RNA isolation from human peripheral blood. The restricted number of possible parallel experiments primarily concern healthy individuals with the lowest number of reticulocytes in the peripheral blood and a low RNA content. In the present study, an efficient method for reticulocyte RNA isolation from healthy individuals and hemolytic anaemia patients is presented. The procedure includes leukofiltration, Ficoll-Paque gradient centrifugation, Percoll gradient centrifugation, and negative (CD45 and CD61) immunomagnetic separation. This relatively fast and simple four-stage method was successfully applied to obtain a reticulocyte-rich population from healthy subjects, which was used to efficiently isolate the high-quality RNA essential for successful NGS-based transcriptome analysis. PMID- 30450751 TI - Integrated Weed Management (IWM): why are farmers reluctant to adopt non-chemical alternatives to herbicides? AB - Implementation of integrated weed management (IWM) has been poor, with little evidence of concomitant reductions in herbicide use. Non-chemical methods are often adopted as a means of compensating for reduced herbicide efficacy, due to increasing resistance, rather than as alternatives to herbicides. Reluctance to adopt non-chemical methods is not due to a lack of research or technology but to a lack of farmer motivation and action. Justifiably, herbicides are often seen as the easier option - their convenience outweighs the increased complexity, costs and management time associated with non-chemical alternatives. Greater use of non chemical alternatives to herbicides will only occur if the following seven aspects are addressed: 1. Better recognition of the reasons why farmers are reluctant to use non-chemical alternatives; 2. Encouraging farmers to adopt a longer-term approach to weed control; 3. Changing farmers' attitudes to pesticides; 4. Placing more attention to the individual farmer's perspective; 5. Greater involvement of economists, social scientists and marketing professionals; 6. Re-evaluating research and extension priorities; 7. Changing the mindset of funders of research and extension. If 'persuasion' fails to deliver greater implementation of IWM, authorities may resort to greater use of financial and other incentives combined with tougher regulations. This article is protected by copyright. All rights reserved. PMID- 30450752 TI - Electronic and Optical Properties of 2D Transition Metal Carbides and Nitrides (MXenes). AB - 2D transition metal carbides, carbonitrides, and nitrides, known as MXenes, are a rapidly growing family of 2D materials with close to 30 members experimentally synthesized, and dozens more studied theoretically. They exhibit outstanding electronic, optical, mechanical, and thermal properties with versatile transition metal and surface chemistries. They have shown promise in many applications, such as energy storage, electromagnetic interference shielding, transparent electrodes, sensors, catalysis, photothermal therapy, etc. The high electronic conductivity and wide range of optical absorption properties of MXenes are the key to their success in the aforementioned applications. However, relatively little is currently known about their fundamental electronic and optical properties, limiting their use to their full potential. Here, MXenes' electronic and optical properties from both theoretical and experimental perspectives, as well as applications related to those properties, are discussed, providing a guide for researchers who are exploring those properties of MXenes. PMID- 30450754 TI - The combined treatment of brassinin and imatinib synergistically downregulated the expression of MMP-9 in SW480 colon cancer cells. AB - In cancer treatment, which is a major cause of mortality today, combination studies with clinically used chemotherapeutics are becoming increasingly important as much as investigating the effects of novel natural compounds. In this context, phytoalexins constitute an important group due to their unique structure. Brassinin is an essential indole phytoalexin and is a biosynthetic precursor for other phytoalexins. The purpose of this study was to evaluate the anticancer effects of brassinin in combination with imatinib in SW480 cells. In the study, it was observed that brassinin-imatinib combination significantly increased cytotoxicity compared with the single treatment of both compounds and inhibited cell cycle at G0/G1 phase. Annexin V binding and fluorescence imaging assays showed that the combination of brasinin-imatinib induces apoptosis in a dose-dependent manner. Furthermore, the effect of brassinin on the activity of MMP-9 in SW480 cells was evaluated for the first time, and it was detected that MMP-9 activity was significantly reduced. The combination of brassinin-imatinib was found to inhibit MMP-9 activity as well as relative MMP-9 gene expression on a higher level compared with control and compounds alone. Our findings have revealed that the combination of brassinin-imatinib synergistically induces cytotoxicity and apoptosis in SW480 cells. The findings on MMP-9 downregulation have also revealed the anti-metastatic potential of treatment. PMID- 30450753 TI - Mental disorder comorbidity and suicidal thoughts and behaviors in the World Health Organization World Mental Health Surveys International College Student initiative. AB - OBJECTIVES: Comorbidity is a common feature of mental disorders. However, needs assessment surveys focus largely on individual disorders rather than on comorbidity even though the latter is more important for predicting suicidal thoughts and behaviors. In the current report, we take a step beyond this conventional approach by presenting data on the prevalence and correlates (sociodemographic factors, college-related factors, and suicidal thoughts and behaviors) of the main multivariate profiles of common comorbid Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV disorders among students participating in the first phase of the World Health Organization World Mental Health International College Student initiative. METHOD: A web-based mental health survey was administered to first year students in 19 colleges across eight countries (Australia, Belgium, Germany, Mexico, Northern Ireland, South Africa, Spain, United States; 45.5% pooled response rate) to screen for seven common DSM IV mental disorders: major depression, mania/hypomania, generalized anxiety disorder, panic disorder, attention-deficit/hyperactivity disorder, alcohol use disorder, and drug use disorder. We focus on the 14,348 respondents who provided complete data; 38.4% screened positive for at least one 12-month disorder. RESULTS: Multivariate disorder profiles were detected using latent class analysis (LCA). The least common class (C1; 1.9% of students) was made up of students with high comorbidity (four or more disorders, the majority including mania/hypomania). The remaining 12-month cases had profiles of internalizing externalizing comorbidity (C2; 5.8%), internalizing comorbidity (C3; 14.6%), and pure disorders (C4; 16.1%). The 1.9% of students in C1 had much higher prevalence of suicidal thoughts and behaviors than other students. Specifically, 15.4% of students in C1 made a suicide attempt in the 12 months before the survey compared with 1.3-2.6% of students with disorders in C2-4, 0.2% of students with lifetime disorders but no 12-month disorders (C5), and 0.1% of students with no lifetime disorders (C6). CONCLUSIONS: In line with prior research, comorbid mental disorders were common; however, sociodemographic correlates of LCA profiles were modest. The high level of comorbidity underscores the need to develop and test transdiagnostic approaches for treatment in college students. PMID- 30450755 TI - Reducing the number of samples in spatiotemporal dMRI acquisition design. AB - PURPOSE: Acquisition time is a major limitation in recovering brain white matter microstructure with diffusion magnetic resonance imaging. The aim of this paper is to bridge the gap between growing demands on spatiotemporal resolution of diffusion signal and the real-world time limitations. The authors introduce an acquisition scheme that reduces the number of samples under adjustable quality loss. METHODS: Finding a sampling scheme that maximizes signal quality and satisfies given time constraints is NP-hard. Therefore, a heuristic method based on genetic algorithm is proposed in order to find suboptimal solutions in acceptable time. The analyzed diffusion signal representation is defined in the qtau space, so that it captures both spacial and temporal phenomena. RESULTS: The experiments on synthetic data and in vivo diffusion images of the C57Bl6 wild type mouse corpus callosum reveal superiority of the proposed approach over random sampling and even distribution in the qtau space. CONCLUSIONS: The use of genetic algorithm allows to find acquisition parameters that guarantee high signal reconstruction accuracy under given time constraints. In practice, the proposed approach helps to accelerate the acquisition for the use of qtau-dMRI signal representation. PMID- 30450756 TI - Comprehensive analysis of the atenolol - DNA complex by viscometric, molecular docking and spectroscopic techniques. AB - This paper discusses multi-spectroscopic and molecular docking analysis of the interaction between atenolol (ATN) and deoxyribose nucleic acid (DNA) using alizarin (ALZ) as a spectroscopic probe. ATN is a beta1 -receptor antagonist belonging to the beta-blocker class of molecules. Experimental findings that were based on different spectroscopic analysis, melting studies, viscometric analysis, 1 H nuclear magnetic resonance and circular dichroism studies revealed the presence of a grove-binding mode. The effect of ionic strength was also studied, and observations suggested that electrostatic interaction also played a minor role during interaction. Molecular docking analysis suggested that the dominant force for the grove-binding phenomenon was hydrogen bonding between the 24-H residue of ATN and O of the 10-G residue, and the 40-H residue of ATN and N of the 17-A base residue. Competitive binding study of the ALZ-DNA complex with ATN showed that, despite an increase in the amount of ATN in the ALZ-DNA complex, the overall absorbance remained unchanged. The decrease in fluorescence in the ALZ DNA system may be due to new non-fluorescent ATN-DNA-ALZ complex formation. PMID- 30450757 TI - Clinical association of metabolic syndrome, C-reactive protein and testosterone levels with clinically significant prostate cancer. AB - Recently, the influence that metabolic syndrome (MetS), hormonal alterations and inflammation might have on prostate cancer (PCa) risk has been a subject of controversial debate. Herein, we aimed to investigate the association between MetS-components, C-reactive protein (CRP) and testosterone levels, and the risk of clinically significant PCa (Sig-PCa) at the time of prostate biopsy. For that, men scheduled for transrectal ultrasound guided biopsy of the prostate were studied. Clinical, laboratory parameters and criteria for MetS characterization just before the biopsy were collected. A total of 524 patients were analysed, being 195 (37.2%) subsequently diagnosed with PCa and 240 (45.8%) meet the diagnostic criteria for MetS. Among patients with PCa, MetS-diagnosis was present in 94 (48.2%). Remarkably, a higher risk of Sig-PCa was associated to MetS, greater number of MetS-components and higher CRP levels (odds-ratio: 1.83, 1.30 and 2.00, respectively; P < 0.05). Moreover, higher circulating CRP levels were also associated with a more aggressive Gleason score in PCa patients. Altogether, our data reveal a clear association between the presence of MetS, a greater number of MetS-components or CRP levels >2.5 mg/L with an increased Sig-PCa diagnosis and/or with aggressive features, suggesting that MetS and/or CRP levels might influence PCa pathophysiology. PMID- 30450758 TI - Mechanisms underlying Ucp1 dependent and independent adipocyte thermogenesis. AB - The growing focus on brown adipocytes has spurred an interest in their potential benefits for metabolic diseases. Brown and beige (or brite) adipocytes express high levels of uncoupling protein 1 (Ucp1) to dissipate heat instead of generating ATP. Ucp1 induction by stimuli including cold, exercise, and diet increases nonshivering thermogenesis, leading to increased energy expenditure and prevention of obesity. Recently, studies in adipocytes have indicated the existence of functional Ucp1-independent thermogenic regulators. Furthermore, substrate cycling involving creatine metabolites, cold-induced N-acyl amino acids, and oxidized lipids in white adipocytes can increase energy expenditure in the absence of Ucp1. These studies emphasize the need for a better understanding of the mechanisms governing energy expenditure in adipocytes and their potential applications in the prevention of human obesity and metabolic diseases. PMID- 30450759 TI - Two human MARs effectively increase transgene expression in transfected CHO cells. AB - Matrix attachment regions (MARs) can enhance the expression level of transgene in Chinese hamster ovaries (CHO) cell expression system. However, improvements in function and analyses of the mechanism remains unclear. In this study, we screened two new and more functional MAR elements from the human genome DNA. The human MAR-3 and MAR-7 element were cloned and inserted downstream of the polyA site in a eukaryotic vector. The constructs were transfected into CHO cells, and screened under G418 to produce the stably transfected cell pools. The expression levels and stability of enhanced green fluorescent protein (eGFP) were detected by flow cytometry. The transgene copy number and transgene expression at mRNA level were detected by quantitative real-time PCR. The results showed that the expression level of eGFP of cells transfected with MAR-containing vectors were all higher than those of the vectors without MARs under transient and stably transfection. The enhancing effect of MAR-7 was higher than that of MAR-3. Additionally, we found that MAR significantly increased eGFP copy numbers and eGFP gene mRNA expression level as compared with the vector without. In conclusion, MAR-3 and MAR-7 gene can promote the expression of transgene in transfected CHO cells, and its effect may be related to the increase of the number of copies. PMID- 30450760 TI - Comment on "Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service". PMID- 30450761 TI - Nanocarriers and Their Loading Strategies. AB - Nanocarriers are of paramount significance for drug delivery and nanomedicine technology. Given the imperfect systems and nonideal therapeutic effects, there are works to be done in synthesis as much as in biological studies, if not more so. Building the foundation of synthesis would offer more tools and deeper insights for exploring the biological systems with extreme complexity. This review aims at a broad-scope summary and classification of nanocarriers for drug delivery, with focus on the synthetic strategy and structural implications. The nanocarriers are divided into four categories according to the loading principle: molecular-level loading, surface loading, matrix loading, and cavity loading systems. Making comparisons across diverse nanocarrier systems would make it easier to see the fundamental characteristics, from where the weakness can be addressed and the strengths combined. The systematic comparisons may also inspire new ideas and methods. PMID- 30450762 TI - Basic-leucine zipper 17 and Hmg-CoA reductase degradation 3A are involved in salt acclimation memory in Arabidopsis. AB - Salt acclimation, which is induced by previous salt exposure, increases the resistance of plants to future exposure to salt stress. However, little is known about the underlying mechanism, particularly how plants store the "memory" of salt exposure. In this study, we established a system to study salt acclimation in Arabidopsis thaliana. Following treatment with a low concentration of salt, seedlings were allowed to recover to allow transitory salt responses to subside while maintaining the sustainable effects of salt acclimation. We performed transcriptome profiling analysis of these seedlings to identify genes related to salt acclimation memory. Notably, the expression of Basic-leucine zipper 17 (bZIP17) and Hmg-CoA reductase degradation 3A (HRD3A), which are important in the unfolded protein response (UPR) and endoplasmic reticulum-associated degradation (ERAD), respectively, increased following treatment with a low concentration of salt and remained at stably high levels after the stimulus was removed, a treatment which improved plant tolerance to future high-salinity challenge. Our findings suggest that the upregulated expression of important genes involved in the UPR and ERAD represents a "memory" of the history of salt exposure and enables more potent responses to future exposure to salt stress, providing new insights into the mechanisms underlying salt acclimation in plants. PMID- 30450763 TI - An additional case of Hennekam lymphangiectasia-lymphedema syndrome caused by loss-of-function mutation in ADAMTS3. AB - Hennekam lymphangiectasia-lymphedema syndrome (HKLLS) is a genetically heterogeneous lymphatic dysplasia with characteristic of facial dysmorphism, neurocognitive impairments, and abnormalities of the pericardium, intestinal tract, and extremities. It is an autosomal recessive condition caused by biallelic mutations in CCBE1 (collagen- and calcium-binding epidermal growth factor domain-containing protein 1) (HKLLS1; OMIM 235510) or FAT4 (HKLLS2; OMIM 616006). CCBE1 acts via ADAMTS3 (a disintegrin and metalloprotease with thrombospondin motifs-3 protease) to enhance vascular endothelial growth factor C signaling. There is report of one family supporting mutations in ADAMTS3 as causative for the phenotype labeled as HKLLS3. Here, we report an additional case of HKLLS that appears to be associated with homozygous nonsense mutation of ADAMTS3. PMID- 30450764 TI - Effect of autophagy on the resveratrol-induced apoptosis of ovarian cancer SKOV3 cells. AB - OBJECTIVE: This study aims to evaluate the relationship between apoptosis and autophagy induced by resveratrol (Res) in SKOV3 human ovarian cancer cell lines. METHODS: The experiment was divided into four groups: normal control group, Res group, Res combined with autophagy inhibitor 3-methyladenine (Res+3-MA) group, and Z-VAD-FMK group. SKOV3 cells were cultured and treated with Res and 3-MA for 24 hours. The processing concentration of Res was screened out by the Cell Counting Kit-8 (CCK8) assay. The cell survival rate was measured by the CCK8 assay. The expression of bule-associated protein light chain 3 beta 2 (LC3-II) and Beclin-1 was detected using Western blot analysis. The percentages of apoptotic and autophagic cells were analyzed using flow cytometry. RESULTS: The cell survival rate significantly decreased as Res concentration increased, and the differences were statistically significant (P < 0.05). The processing concentration of Res was 25 MUmol/L. After treatment with Res for 24 hours, the expression levels of autophagy-related protein LC3 and Beclin-l were significantly higher than in the other groups. Furthermore, the expression of LC3 and Beclin-l significantly declined in the Res+3-MA group compared with the Res group. However, the percentage of autophagic cells significantly decreased from 37.0% +/- 4.24% to 6.1% +/- 0.28%, and the percentage of apoptotic cells significantly increased from 24% +/- 4.55% to 67.0% +/- 4.3%; and the differences were statistically significant ( P < 0.05). CONCLUSION: Res can induce autophagy to inhibit apoptosis in tumor SKOV3 cells, and inhibition of Res+3-MA could not only enhance the effects of chemotherapy but also prevent normal cells from tumorigenesis. PMID- 30450765 TI - Sestrin2 regulates monocyte activation through AMPK-mTOR nexus under high-glucose and dyslipidemic conditions. AB - The vicious cycle between hyperinsulinemia and insulin resistance results in the progression of atherosclerosis in the vessel wall. The complex interaction between hyperglycemia and lipoprotein abnormalities promotes the development of atherogenesis. In the early phase of atherosclerosis, macrophage-derived foam cells play an important role in vascular remodeling. Mechanistic target of rapamycin (mTOR) signaling pathway has been identified to play an essential role in the initiation, progression, and complication of atherosclerosis. Recently sestrin2, an antioxidant, was shown to modulate TOR activity and thereby regulating glucose and lipid metabolism. But the role of sestrin2 in monocyte activation is still not clearly understood. Hence, this study is focussed on investigating the role of sestrin2 in monocyte activation under hyperglycemic and dyslipidemic conditions. High-glucose and oxidized low-density lipoprotein (LDL) treatments mediated proinflammatory cytokine production (M1) with a concomitant decrease in the anti-inflammatory cytokine (M2) levels in human monocytic THP1 cells. Both glucose and oxidized LDL (OxLDL) in a dose and time-dependent manner increased the mTOR activation with a marked reduction in the levels of pAMPK and sestrin2 expression. Both high-glucose and OxLDL treatment increased foam cell formation and adhesion of THP1 cells to endothelial cells. Experiments employing activator or inhibitor of adenosine monophosphate kinase (AMPK) as well as overexpression or silencing of sestrin2 indicated that high-glucose mediated monocyte polarization and adhesion of monocytes to the endothelial cells were appeared to be programmed via sestrin2-AMPK-mTOR nexus. Our results evidently suggest that sestrin2 plays a major role in regulating monocyte activation via the AMPK-mTOR-pathway under diabetic and dyslipidemic conditions and also AMPK regulates sestrin2 in a feedback mechanism. PMID- 30450766 TI - DLG5 suppresses breast cancer stem cell-like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression. AB - Tamoxifen (TAM) is a primary drug for treatment of estrogen receptor positive breast cancer. However, TAM resistance remains a serious threat to breast cancer patients and may be attributed to increased stemness of breast cancer. Here, we show that discs large homolog 5 (DLG5) expression is down-regulated in TAM resistant breast cancer and cells. DLG5 silencing decreased the sensitivity to TAM and increased the frequency and stemness of CD44+ /CD24- breast cancer stem cells (BCSCs) and TAZ, a transducer of the Hippo pathway, expression in MCF7 cells while DLG5 overexpression had opposite effects. TAZ silencing restored the sensitivity to TAM and reduced the frequency and stemness in TAM-resistant breast cancer cells. Taken together, our data indicate that down-regulated DLG5 expression increases the stemness of breast cancer cells by enhancing TAZ expression, contributing to TAM resistance in breast cancer. PMID- 30450768 TI - Immunometabolism features of metabolic deregulation and cancer. AB - Immunometabolism is a branch dealing at the interface of immune functionalities and metabolic regulations. Considered as a bidirectional trafficking, metabolic contents and their precursors bring a considerable change in immune cells signal transductions which as a result affect the metabolic organs and states as an implication. Lipid metabolic ingredients form a major chunk of daily diet and have a proven contribution in immune cells induction, which then undergo metabolic pathway shuffling inside their ownself. Lipid metabolic states activate relevant metabolic pathways inside immune cells that in turn prime appropriate responses to outside environment in various states including lipid metabolic disorders itself and cancers as an extension. Although data on Immunometabolism are still growing, but scientific community need to adjust and readjust according to recent data on given subject. This review attempts to provide current important data on Immunometabolism and consequently its metabolic ramifications. Incumbent data on various lipid metabolic deregulations like obesity, metabolic syndrome, obese asthma and atherosclerosis are analysed. Further, metabolic repercussions on cancers and its immune modalities are also analysed. PMID- 30450767 TI - TRPV4 regulates matrix stiffness and TGFbeta1-induced epithelial-mesenchymal transition. AB - Substrate stiffness (or rigidity) of the extracellular matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, matrix stiffness, and a biochemical signal, for example, transforming growth factor beta1 (TGFbeta1), in epithelial-mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFbeta1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFbeta1-induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E-cadherin, N-cadherin (NCAD) and alpha-smooth muscle actin (alpha-SMA), and (b) TRPV4 deficiency prevented matrix stiffness-induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and alpha-SMA, in a bleomycin-induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes-associated protein/transcriptional coactivator with PDZ-binding motif) in response to matrix stiffness and TGFbeta1, (b) TRPV4 deletion inhibited both matrix stiffness- and TGFbeta1-induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness- and TGFbeta1-induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT. PMID- 30450769 TI - The impact of financial incentives on health and health care: Evidence from a large wellness program. AB - Workplace wellness programs have become increasingly common in the United States, although there is not yet consensus regarding the ability of such programs to improve employees' health and reduce health care costs. In this paper, we study a program offered by a large U.S. employer that provides substantial financial incentives directly tied to employees' health. The program has a high participation rate among eligible employees, around 80%, and we analyze the data on the first 4 years of the program, linked to health care claims. We document robust improvements in employee health and a correlation between certain health improvements and reductions in health care cost. Despite the latter association, we cannot find direct evidence causally linking program participation to reduced health care costs, although it seems plausible that such a relationship will arise over longer horizons. PMID- 30450770 TI - Dysfunctional DNA repair pathway via defective FANCD2 gene engenders multifarious exomic and transcriptomic effects in Fanconi anemia. AB - BACKGROUND: Fanconi anemia (FA) affects only one in 130,000 births, but has severe and diverse clinical consequences. It has been theorized that defects in the FA DNA cross-link repair complex lead to a spectrum of variants that are responsible for those diverse clinical phenotypes. METHODS: Using NextGen sequencing, we show that a clinically derived FA cell line had accumulated numerous genetic variants, including high-impact mutations, such as deletion of start codons, introduction of premature stop codons, missense mutations, and INDELs. RESULTS: About 65% of SNPs and 55% of INDELs were found to be commonly present in both the FA dysfunctional and retrovirally corrected cell lines, showing their common origin. The number of INDELs, but not SNPs, is decreased in FANCD2-corrected samples, suggesting that FANCD2 deficiency preferentially promotes the origin of INDELs. These genetic modifications had a considerable effect on the transcriptome, with statistically significant changes in the expression of 270 genes. These genetic and transcriptomic variants significantly impacted pathways and molecular functions, spanning a diverse spectrum of disease phenotypes/symptoms, consistent with the disease diversity seen in FA patients. CONCLUSION: These results underscore the consequences of defects in the DNA cross link repair mechanism and indicate that accumulating diverse mutations from individual parent cells may make it difficult to anticipate the longitudinal clinical behavior of emerging disease states in an individual with FA. PMID- 30450771 TI - A Comparison of Common Hippopotamus (Artiodactyla) and Mysticete (Cetacea) Nostrils: An Open and Shut Case. AB - Hippos are considered the closest living relatives to cetaceans and they have some similar adaptations for aquatic living, such as a modified respiratory tract. Behavioral observations of male and female common hippos (Hippopotamus amphibius) at Disney's Animal Kingdom(r) and the Adventure Aquarium were conducted to describe and examine movements of the nostrils during respiration (inspiration, expiration, and inter-breath interval). The hippo nostril is a crescent shaped opening with lateral and medial aspects that are mobile and can be adducted and abducted to regulate the nostril opening. Notably, the default (resting) position of the nostrils is closed during the inter-breath interval, even when hippos are resting in water and their heads are not submerged. Similar to cetaceans, this aquatic adaptation protects the respiratory tract from an accidental incursion of water that can occur even when the nostrils are above water. Dissection of a deceased captive common hippo suggests there are separate muscles that pull the medial and lateral aspects for abduction. The internal nasal passage has a nasal plug that is similar in shape but less pronounced than the nasal plugs of two baleen whale species studied (minke whale Balaenoptera acutorostrata, fin whale B. physalus). Examination of the musculature suggests fibers attach from the premaxillae and extend caudally to retract the plug to open the nasal passage. We discuss similarities and differences of the nostrils/blowholes of fully aquatic, semi-aquatic, and terrestrial species to assess adaptations related to environmental conditions that may be convergent or derived from a common ancestor. This article is protected by copyright. All rights reserved. PMID- 30450772 TI - Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma. AB - SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation. PMID- 30450773 TI - Metformin attenuates the effect of Staphylococcus aureus on airway tight junctions by increasing PKCzeta-mediated phosphorylation of occludin. AB - Airway epithelial tight junction (TJ) proteins form a resistive barrier to the external environment, however, during respiratory bacterial infection TJs become disrupted compromising barrier function. This promotes glucose flux/accumulation into the lumen which acts as a nutrient source for bacterial growth. Metformin used for the treatment of diabetes increases transepithelial resistance (TEER) and partially prevents the effect of bacteria but the mechanisms of action are unclear. We investigated the effect of metformin and Staphylococcus aureus on TJ proteins, zonula occludins (ZO)-1 and occludin in human airway epithelial cells (H441). We also explored the role of AMP-activated protein kinase (AMPK) and PKCzeta in metformin-induced effects. Pretreatment with metformin prevented the S. aureus-induced changes in ZO-1 and occludin. Metformin also promoted increased abundance of full length over smaller cleaved occludin proteins. The nonspecific PKC inhibitor staurosporine reduced TEER but did not prevent the effect of metformin indicating that the pathway may involve atypical PKC isoforms. Investigation of TJ reassembly after calcium depletion showed that metformin increased TEER more rapidly and promoted the abundance and localization of occludin at the TJ. These effects were inhibited by the AMPK inhibitor, compound C and the PKCzeta pseudosubstrate inhibitor (PSI). Metformin increased phosphorylation of occludin and acetyl-coA-carboxylase but only the former was prevented by PSI. This study demonstrates that metformin improves TJ barrier function by promoting the abundance and assembly of full length occludin at the TJ and that this process involves phosphorylation of the protein via an AMPK PKCzeta pathway. PMID- 30450774 TI - Automatic detection of diabetic retinopathy and its progression in sequential fundus images of patients with diabetes. PMID- 30450775 TI - Wnt and BMP signaling pathways co-operatively induce the differentiation of multiple myeloma mesenchymal stem cells into osteoblasts by upregulating EMX2. AB - Osteoblast differentiation, defined as the process whereby a relatively unspecialized cell acquires the specialized features of an osteoblast, is directly linked to multiple myeloma (MM) bone disease. Wnt and bone morphogenetic protein (BMP) are proved to be implicated in the pathological or defective osteoblast differentiation process. This study aims to test the involvement of Wnt, bone morphogenetic proteins (BMP) pathways, and empty spiracles homeobox 2 (EMX2) in osteoblast differentiation and MM development. Initially, differentially expressed genes in bone marrow mesenchymal stem cells (MSCs) from MM patients and healthy donors were identified using microarray-based gene expression profiling. The functional role of Wnt and BMP in MM was determined. Next, we focused on the co-operative effects of Wnt and BMP on calcium deposition, alkaline phosphatase (ALP) activity, the number of mineralized nodules, and osteocalcin (OCN) content in MSCs. The expression patterns of Wnt and BMP pathway-related genes, EMX2 and osteoblast differentiation-related factors were determined to assess their effects on osteoblast differentiation. Furthermore, regulation of Wnt and BMP in ectopic osteogenesis was also investigated in vivo. An integrated genomic screen suggested that Wnt and BMP regularly co-operate to regulate EMX2 and affect MM. EMX2 was downregulated in MSCs. The activated Wnt and BMP resulted in more calcium salt deposits, mineralized nodules, and a noted increased in ALP activity and OCN content by upregulating EMX2, leading to induced differentiation of MSCs into osteoblasts. Collectively, this study demonstrated that Wnt and BMP pathways could co operatively stimulate differentiation of MSCs into osteoblasts and inhibit MM progression, representing potential targets for MM treatment. PMID- 30450776 TI - Growth patterns & overbite depth indicators of long & short faces in Korean adolescents: revisited through mixed effects analysis. AB - OBJECTIVE: The purpose was to evaluate skeletal factors related to the growth of subjects with skeletal open and deep bites based on lateral cephalographs from nine years of pure longitudinal data using mixed effect analysis. SETTING AND SAMPLE POPULATION: Fifty-one children with extreme lower anterior facial height to total anterior facial height (LAFH/TAFH) ratio values at the age of 14 were assigned to either skeletal open bite or skeletal deep bite groups from a total 223 subjects. MATERIAL & METHODS: The palatal plane angle (PPA), mandibular plane angle (MPA), gonial angle (GA), palatomandibular plane angle (PMA), upper gonial angle (UGA), lower gonial angle (LGA), occlusal plane angle (OPA), and overbite depth indicator (ODI) were measured and analyzed. Mixed-effects regression model analysis was used for the interpretation of data with random effects. RESULTS: MORPHOLOGICAL DIFFERENCES WERE EVIDENT FROM THE BEGINNING AND BECAME MORE: pronounced with age in MPA, GA, PMA, ODI, and LGA. The initial values of all variables were statistically significant. Annual increases with age were statistically significant in MPA, GA, OPA, ODI, and LGA. The morphological differences in the annual increases in MPA, GA, PMA, and LGA were also statistically significant. CONCLUSIONS: Morphologically different growth patterns were mainly contributed by lower anterior facial height dimensions. The extent of individual variations mandates judicious decision making in clinical situations. This article is protected by copyright. All rights reserved. PMID- 30450777 TI - In vivo neurochemical evidence that stimulation of accumbal GABAA and GABAB receptors each reduce acetylcholine efflux without affecting dopamine efflux in the nucleus accumbens of freely moving rats. AB - Cholinergic neurons in the nucleus accumbens contain GABAA and GABAB receptors that are thought to inhibit neural activity. We analyzed the roles of GABAA and GABAB receptors in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. The effects of GABA receptor ligands on the accumbal dopamine efflux were also analyzed because accumbal cholinergic and dopaminergic neurons could mutually interact. Drugs were applied intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 30-60 min infusions. To monitor basal acetylcholine, a low concentration of physostigmine (50 nM) was added to the perfusate. GABAA receptor agonist muscimol (3 and 30 pmol) induced a dose-related decrease in accumbal acetylcholine. GABAB receptor agonist baclofen (30 and 300 pmol) also produced a dose-related decrease in acetylcholine. GABAA receptor antagonist bicuculline (60 pmol) which failed to alter baseline acetylcholine counteracted the muscimol (30 pmol)-induced decrease in acetylcholine. GABAB receptor antagonist 2 hydroxysaclofen (12 nmol) which failed to change baseline acetylcholine, counteracted the baclofen (300 pmol)-induced decrease in acetylcholine. Neither muscimol (30 pmol) nor baclofen (300 pmol) which reduced accumbal acetylcholine altered baseline accumbal dopamine. Neither bicuculline (60 pmol) nor 2 hydroxysaclofen (12 nmol) also affected the baseline dopamine. These results show that GABAA and GABAB receptors each exert inhibitory roles in the regulation of accumbal cholinergic neural activity. The present results also provides in vivo neurochemical evidence that stimulation of GABAA and GABAB receptors each reduce acetylcholine efflux without affecting dopamine efflux in the nucleus accumbens of freely moving rats. PMID- 30450778 TI - Is there a female disadvantage in child undernutrition in South India?: Exploring gender differences in height in infancy, childhood, and adolescence in Andhra Pradesh and Telangana. AB - OBJECTIVE: The aim of this study was to investigate whether gender-based disparities in health and well-being extend to a female disadvantage in height in infancy, childhood, and adolescence in Andhra Pradesh and Telangana. METHODS: Using longitudinal data from the Young Lives study in Andhra Pradesh and Telangana, India, linear mixed effects and linear regression models examined associations between gender and height and the modifying influences of birth order and older siblings' gender composition. RESULTS: In the younger cohort, at 6-18 months, girls were 0.17-SDs of height for age z-scores (HAZ) taller than boys (P = .01). In the same cohort, the girls' advantage in HAZ was attenuated to 0.02 (P = .58) by 11-12 years. In the older cohort, the difference in HAZ between girls and boys was 0.04 (P = .61) at the beginning of the study when they were 7 8 years old; by 18-19 years of age, the difference had switched, with boys being 0.22-SD (P = .05) taller. There was no difference by birth order except in the younger cohort in which children with 2 or more siblings experienced height deficits compared with only children at 7-8 and 11-12 years. There was no differential effect of gender by birth order nor by the gender composition of siblings. CONCLUSION: A female disadvantage in undernutrition, as manifest in differences between girls and boys in HAZ, did not appear until later ages. Identifying how and why gendered disparities in standardized height emerge in late adolescence will help target more resources to improve conditions for girls and women in south India. PMID- 30450779 TI - Laparoscopic paraaortic lymph node dissection in a patient with nutcracker syndrome for rectal cancer - a video vignette. AB - The nutcracker syndrome is a rare anomaly. The left renal vein is compressed by the sharp angle (<25 degrees ) between the superior mesenteric artery (Iqbal, #5) and the aorta [1], which results in engorgement of the left renal vein and left ovarian vein [2]. This syndrome has been reported in a rectal cancer patient with cachexia [3]. This article is protected by copyright. All rights reserved. PMID- 30450780 TI - The temporal relationship of daily life stress, emotions, and bowel symptoms in irritable bowel syndrome-Diarrhea subtype: A smartphone-based experience sampling study. AB - BACKGROUND: The current study aimed to model the moment-to-moment relationship between daily life stress, emotions, and bowel symptoms among patients with irritable bowel syndrome-diarrhea subtype (IBS-D) in the flow of daily life using a smartphone-based experience sampling method (ESM). METHODS: Patients with IBS-D (N = 27) and healthy controls (HC; N = 30) completed ESM ratings of their real time daily life stress, which was defined as subjective stress related to daily activities, both positive and negative emotions, as well as bowel symptoms eight times a day for 14 consecutive days, following a baseline interview measuring bowel and mood symptoms. Moment-to-moment association between ESM variables was tested within and between groups using multilevel regression modeling. KEY RESULTS: Patients with IBS-D reported more severe bowel symptoms and lower positive affect than HCs, but levels of daily life stress and negative affect were comparable between groups. Time-lagged analysis of ESM data revealed that, among patients with IBS-D, daily life stress predicted a decrease in abdominal pain and urgency to defecation at a subsequent time point, whereas severity of bowel symptoms and occurrence of diarrhea predicted a subsequent increase in negative affect and daily life stress. The above associations were not found among HCs. CONCLUSIONS AND INFERENCES: ESM unveiled the dynamic relationship between bowel symptoms, stress, and emotionality. Patients with IBS-D responded to bowel symptoms with more stress and distress momentarily. Counter-intuitively, daily life activity stress appeared to ameliorate bowel symptoms, although a more rigorous study design is required to testify this claim. Psychological understanding of IBS-D is discussed. PMID- 30450781 TI - Dynamic Changes in Innate Immune Responses During Direct Acting Antiviral Therapy for HCV Infection. AB - The role of the endogenous interferon (IFN) system has been well characterized during IFN-based therapy for chronic hepatitis C virus (HCV) infection; less is known for direct-acting antivirals (DAAs). In this phase 3b open-label study, we assessed changes in IFN-stimulated genes (ISGs) in non-cirrhotic treatment-naive or pegIFN/RBV-experienced HCV-GT1a-infected patients receiving paritaprevir/ritonavir/ombitasvir+dasabuvir+ribavirin (PrOD+R) for 12 weeks. ISG expression was quantified from PBMCs at baseline, treatment weeks (TW)2, TW4, TW8, end-of-treatment (EOT) and at post-treatment week 12. Paired sera were used to assess IFN-alpha/IFN-related chemokines/cytokines. Twenty-five patients were enrolled. Overall SVR12 was 92% (no virologic failure [VF]) and 100% for those completing the study protocol. Two patients were excluded from the ISG analysis due to lack of post-treatment samples. The majority of ISGs were downregulated at TW2-TW4 (nadir TW4), however a relative increase was observed at TW8-EOT, although levels were lower than baseline. This downregulation was accompanied by increases in IFN-alpha/IFN-related chemokines, a finding not observed with TH 1/2 related cytokines. Following SVR, ISG expression returned to TW2 levels. In conclusion, PrOD+R for 12 weeks was well-tolerated with no VF. Our data demonstrate dynamic alterations in innate immune profiles during highly-potent IFN-free DAA therapy. The downregulation of ISG post-therapy suggests reversal of the "exhausted" ISG phenotype following SVR, and the rise in ISGs and IFNalpha/IFN-responsive chemokines late during therapy suggests resetting of IFN responsiveness that may be relevant in determining duration of or immunological sequelae from DAA therapy, including HBV reactivation. This article is protected by copyright. All rights reserved. PMID- 30450782 TI - Rapid tools to gain insights into the interaction dynamics of new 8 hydroxyquinolines with few fungal lines. AB - The combination of tools such as time-kill assay with subsequent application of mathematical modeling can clarify the potential of new antimicrobial compounds, since minimal inhibitory concentration (MIC) value does not provide a very detailed characterization of antimicrobial activity. Recently, our group has reported that the 8-hydroxy-5-quinolinesulfonic acid presents relevant antifungal activity. However, its intrinsic acidity could lead to an ionization process, decreasing fungal cell permeability. To overcome this potential problem and enhance activity, the purpose of this study was to synthesize and evaluate a novel series of hybrids between the 8-hydroxyquinoline core and sulfonamide and to prove their potential using broth microdilution method, obtaining the pharmacodynamic parameters of the most active derivatives combining time-kill studies and mathematical modeling and evaluating their toxicity. Compound 5a was the most potent, being active against all the fungal species tested, with low toxicity in normal cells. 5a and 5b have presented important antibacterial activity against Staphylococcus aureus strain. The EC50 values obtained by combination of time-kill studies with mathematical model were similar to those of MIC, which confirms the potential of compounds. In addition, these derivatives are non-irritant molecules with the absence of topical toxicity. Finally, 5a and 5b are promising candidates for treatment of dermatomycosis and candidiasis. PMID- 30450783 TI - Making a Material Difference: Materials Science Research at the National University of Singapore. PMID- 30450784 TI - Recent Advances in Stretchable Supercapacitors Enabled by Low-Dimensional Nanomaterials. AB - Supercapacitors (SCs) have shown great potential for mobile energy storage technology owing to their long-term durability, electrochemical stability, structural simplicity, as well as exceptional power density without much compromise in the energy density and cycle life parameters. As a result, stretchable SC devices have been incorporated in a variety of emerging electronics applications ranging from wearable electronic textiles to microrobots to integrated energy systems. In this review, the recent progress and achievements in the field of stretchable SCs enabled by low-dimensional nanomaterials such as polypyrrole, carbon nanotubes, and graphene are presented. First, the three major categories of stretchable supercapacitors are discussed: double-layer supercapacitors, pseudo-supercapacitors, and hybrid supercapacitors. Then, the representative progress in developing stretchable electrodes with low dimensional (0D, 1D, and 2D) nanomaterials is described. Next, the design strategies enabling the stretchability of the devices, including the wavy-shape design, wire-shape design, textile-shape design, kirigami-shape design, origami shape design, and serpentine bridge-island design are emphasized, with the aim of improving the electrochemical performance under the complex stretchability conditions that may be encountered in practical applications. Finally, the newest developments, major challenges, and outlook in the field of stretchable SC development and manufacturing are discussed. PMID- 30450785 TI - Compound heterozygous mutations in CFTR causing CBAVD in Chinese pedigrees. AB - BACKGROUND: Congenital bilateral absence of the vas deferens (CBAVD) is an important cause of obstructive azoospermia and male infertility. Mutations of CFTR caused the majority of CBAVD cases, and ADGRG2 was recently identified as a new pathogenic gene. Yet, most of the genetic evidence came from sporadic cases, and only one mutation in CFTR can be found in patients. METHODS: In present study, we collected two CBAVD pedigrees, each having two affected male siblings. We performed whole exome sequencing on all patients and validated all potential variants by Sanger sequencing. RESULTS: We excluded ADGRG2 variants but identified compound heterozygous variants of CFTR in both families (NM_000492.3:c.1210-33_1210-6GT[13]T[5] and c.4056G>C;p.Gln1352Cys in pedigree 1, c.592G>C;p.Ala198Pro and c.3717G>A;p.Arg1239= in pedigree 2), which were subsequently validated by direct sequencing. c.1210-33_1210-6GT[13]T[5] (also known as IVS8-T5-TG13) was a known disease-causing variant causing the skipping of exon 9 of CFTR and inherited from the proband's mother. p.Gln1352Cys and Ala198Pro were rare or novel in public databases and predicted to be deleterious. The p.Arg1239= was a synonymous variant but located at the end of an exon, which was predicted to alter the splicing pattern. CONCLUSION: Our study, in which compound heterozygous variants were identified in two pedigrees, provides more familial evidence that only recessive variants (homozygous or compound heterozygous) in CFTR cause CBAVD. Furthermore, whole exome sequencing may be utilized as a useful tool for mutation screening of genes causing CBAVD. PMID- 30450786 TI - Overexpression of IGF-IIRalpha regulates cardiac remodeling and aggravates high salt induced apoptosis and fibrosis in transgenic rats. AB - IGF-IIR activation regulates cardiac remodeling leading to apoptosis. Here, we identified the novel IGF-IIRalpha (150 KDa), a truncated IGF-IIR transcript enhances cardiac apoptosis under high-salt uptake in transgenic rat model. Echocardiographic analysis revealed decline in ejection fraction and fractional shortening percentage in IGF-IIRalpha (TG) rats. We found that IGF-IIRalpha TG rats developed severe apoptosis and fibrosis as identified through TUNEL assay and Masson's trichrome staining. Importantly, the heart functioning, apoptosis, and fibrosis were significantly affected under high-salt conditions in IGF IIRalpha (TG) rats. Significant upregulation of apoptosis was evident from decreased Bcl-2, p-AKT, and p-PI3K expressions with concomitant increase in Bad, cytochrome C, cleaved caspase 3 levels. We found that, IGF-IIRalpha highly induced tissue fibrosis through collagen accumulation (col I, col III) and up regulated various fibrotic markers such as tPA, uPA, TGF-beta, and vimentin expressions. The observed upregulation of fibrosis were significantly regulated under high-salt conditions and their over regulation under IGF-IIRalpha over expressions shows the key role of IGF-IIRalpha in promoting high-salt induced fibrosis. During IGF-IIRalpha over expression induced cardiotoxicity, under high salt condition, and it destroys the interaction between CHIP and HSF1, which promotes the degradation of HSF1 and results in upregulation of IGF-IIR/IGF IIRalpha expressions. Altogether, the study unveils novel IGF-IIRalpha in the regulation of cardiac apoptosis and fibrosis under high-salt diet. PMID- 30450788 TI - In memoriam: Prof. Dr. Guido Verhoeven 26/03/1945-19/08/2018. PMID- 30450787 TI - Dose-dependent effects of continuous positive airway pressure for sleep apnea on weight or metabolic function: Individual patient-level clinical trial meta analysis. AB - Therapeutic-continuous positive airway pressure seems to increase weight compared with placebo-continuous positive airway pressure. It is not known whether weight gain with therapeutic-continuous positive airway pressure dose is dependent or whether it causes metabolic dysfunction. Data synthesis of three randomised placebo-continuous positive airway pressure-controlled trials (2-3 months) was performed to test whether there is a dose-dependent effect of continuous positive airway pressure on weight. Fasting glucose, insulin, insulin resistance (homeostatic model assessment), lipids and visceral abdominal fat were also tested to determine any effect on metabolic function. Mixed-model analysis of variance was used to quantify these effects. One-hundred and twenty-eight patients were analysed. Overall there was a small increase in weight with therapeutic-continuous positive airway pressure use compared with placebo continuous positive airway pressure (difference: 1.17 kg; 0.37-1.97, p = 0.005), which was greater with high-use therapeutic-continuous positive airway pressure compared with high-use placebo-continuous positive airway pressure (1.45 kg; 0.10 2.80, p = 0.04). Continuous positive airway pressure use as a continuous variable was also significantly associated with weight change in continuous positive airway pressure users (0.30 kg hr-1 night-1 ; 0.04-0.56, p = 0.001), but not in placebo users (0.04 kg hr-1 night-1 ; -0.22 to 0.26, p = 0.76). Neither therapeutic-continuous positive airway pressure nor the dose of therapeutic continuous positive airway pressure caused any changes to metabolic outcomes. The weight gain effects of medium-term therapeutic-continuous positive airway pressure appear modest and are not accompanied by any adverse metabolic effects. PMID- 30450789 TI - Bad news: Families' experiences and feelings surrounding the diagnosis of Zika related microcephaly. AB - The rapidly increasing number of cases of Zika virus and limited understanding of its congenital sequelae (e.g., microcephaly) led to stories of fear and uncertainty across social media and other mass communication networks. In this study, we used techniques generic to netnography, a form of ethnography, using Internet-based computer-mediated communications as a source of data to understand the experience and perceptions of families with infants diagnosed with Zika related microcephaly. We screened 27 YouTubeTM videos published online between October 2015 and July 2016, during which the Zika epidemic started, peaked, and declined. We identified three themes: (a) experiencing the news of a diagnosis of Zika-associated microcephaly; (b) experiencing feelings and expectations of the 'imperfect' child; and (c) seeking to understand microcephaly to care for the child. We found that families experienced distressing feelings of shock, sadness, hopelessness, and pain, while dealing with emerging and sometimes conflicting information being transmitted by news outlets, uncertainty about the child's health, and healthcare providers' lack of clarity to guide the family members. The 'unknown' factor of ZIKA was an additional stressful factor in the experience of the families. PMID- 30450790 TI - Mesh migration into the large bowel following inguinal hernia repair. A new task for the colorectal surgeon? PMID- 30450791 TI - Systematic review of olfactory shifts related to obesity. AB - OBJECTIVE: The modern food environment is a key driver of rising levels of obesity. While olfaction is known to play a major role in food choice; however, its relationship to obesity is yet to be understood. This review assesses current knowledge of the interaction between obesity and olfaction. METHODS: This review is based on observational studies comparing olfactory abilities across weight groups (N = 10) and clinical studies evaluating olfactory changes following bariatric surgery (N = 9). Meta-analyses were performed on data collected by a standard olfactory assessment tool (Sniffin? Sticks), to test whether olfaction has any association with body weight or bariatric surgery. RESULTS: This review synthesizes findings derived from 38 datasets, with a total of 1432 individual olfactory assessments. The meta-analyses suggest that olfactory function is negatively correlated with body weight. In addition, Roux-en-Y gastric bypass patients frequently report olfactory changes, yet more pronounced and immediate shifts have been observed among sleeve gastrectomy recipients. CONCLUSIONS: Our review finds strong evidence for the link between olfaction and obesity and indicates that bariatric surgery (particularly the sleeve gastrectomy) is effective in reversing olfactory decline associated with obesity. In conclusion, we present mechanistic models to underpin the observed relationship between olfaction and obesity. PMID- 30450792 TI - Which patients with chronic pain are more likely to improve pain biology knowledge following education? AB - BACKGROUND: Pain education is an important part of multidisciplinary management of chronic pain. The characteristics of people likely to have the most improvement in pain biology knowledge following pain education are unknown. OBJECTIVE: To identify baseline factors predicting changes in pain biology knowledge in adults with chronic pain following a 2-hour multidisciplinary pain education session. METHODS: Fifty-five adults with chronic pain attended a 2-hour pain education session prior to a multidisciplinary assessment at a pain clinic. Patients completed the 12-item revised Neurophysiology of Pain Questionnaire (rNPQ, score /12) before and after the pain education session. The primary outcome was change in pain biology knowledge, evaluated with the change in rNPQ score. Ten preselected predictors were investigated using univariate models followed by multivariable models with a manual forwards-building process. RESULTS: Education level and age were significantly associated with change in rNPQ in the univariate models. Participants with higher levels of education had, on average, 1.96 (0.68 to 3.23) points more improvement in rNPQ score than those with lower levels of education. For every 10 years older a participant was, their rNPQ scores changed on average by 0.5 (0.1 to 0.8) points less. In the multivariable model, only education level remained significant, explaining 17% of the variance (R2 =0.17). Clinical variables assessed (pain severity, pain interference, pain self-efficacy, depression, anxiety, and pain catastrophizing) did not predict knowledge change. CONCLUSION: This study suggests that, of those patients with chronic pain who choose to attend pain education, more educated patients are more likely to improve their pain biology knowledge after a pain education session. This article is protected by copyright. All rights reserved. PMID- 30450793 TI - Investigation of Marine Mammal Lung Dynamics when Exposed to Underwater Explosion Impulse. AB - Very little is known about marine mammal susceptibility to primary blast injury (PBI) except in rare cases of opportunistic studies. As a result, traditional analysis techniques relied on methods developed more than 30 years ago using terrestrial mammals as surrogates. Modeling tools available today have the computing power to vastly improve calculation of safe ranges and injury zones from underwater explosions (UNDEX) employing morphologically accurate proxies with material properties similar to marine mammal tissues. The Dynamic System Mechanics Advanced Simulation (DYSMAS) fluid structure interaction (FSI) software is being used to simulate the complex phenomena of UNDEX, shock wave, and bubble pulse propagation through the water and transmission of energy to a cetacean focusing on the dynamic response of the thoracic cavity and air-filled lungs to a shock wave. The approach integrates fluid and structural analyses with the material properties of blubber, bone, and muscle using marine mammal morphometrics to eliminate unnecessary assumptions made during more traditional approaches to analysis developed before these types of data and computational power were available. DYSMAS analyses of a 1D gas bubble surrounded by water was found to closely match the classical bubble dynamics models. Further, DYSMAS models of a spherical gas bubble surrounded by tissue and rib structure demonstrate a global radial oscillation of the gas bubble, but also show significant local deflection and material strain in response to the UNDEX loading. The intended result of the investigation is an improved and scientifically defensible understanding of the effects of UNDEX on marine mammals. This article is protected by copyright. All rights reserved. PMID- 30450794 TI - The influence of high-intensity interval training on anthropometric variables of adults afflicted with overweight or obesity: a systematic review and network meta analysis. AB - OBJECTIVE: The goal of this study was to evaluate the influence of high-intensity interval training (HIIT) on anthropometric variables in adults afflicted with overweight or obesity and to compare the effects with those of moderate-intensity continuous training. METHODS: A computer literature search was performed for HIIT intervention studies that evaluated anthropometric variables in adults afflicted with overweight or obesity. RESULTS: Of the 857 articles retrieved in the electronic search, 48 met the inclusion criteria. The analyses demonstrated that HIIT was effective in decreasing body mass (-1.45 kg [95% CI: -1.85 to -1.05 kg]), body mass index (-0.44 kg m-2 [95% CI: -0.59 to -0.30 kg m-2 ]), waist circumference (-2.3 cm [95% CI: -3.1 to -1.4 cm]), waist/hip ratio (-0.01 [95% CI: -0.02 to -0.00]), body fat percentage (-1.29% [95% CI: -1.70% to -0.87%]) and abdominal visceral fat area (-6.83 cm2 [95% CI: -11.95 to -1.71 cm2 ]). When considering equalization between the two methods (energy expenditure or workload matched), no differences were found in any measure except body mass (for which HIIT was superior). CONCLUSIONS: High-intensity interval training and moderate intensity continuous training results were similar, particularly when equalization between the two methods was considered. Thus, HIIT can be used as a secondary method for the treatment of obesity in adults. PMID- 30450795 TI - Enhanced production of glutaric acid by NADH oxidase and GabD-reinforced bioconversion from L-lysine. AB - Glutaric acid is a promising alternative chemical to phthalate plasticizer, since it can be produced by the bioconversion of lysine. Though recent studies have enabled high-yield production of its precursor, 5-aminovaleric acid (AMV), glutaric acid production via the AMV pathway has been limited by need for cofactors. Introduction of NAD(P)H oxidase (Nox) with GabTD enzyme remarkably diminished the demand for NAD+ . Supply of oxygen through vigorous shaking had a significant effect on the conversion of AMV with a reduced requirement of NAD+ . A high conversion rate was achieved in Nox coupled GabTD reaction under optimized expression vector, TB medium, and pH 8.5 at high cell density. Supplementary expression of GabD resulted in the production of 353 +/- 35 mM glutaric acid with 88.3 +/- 8.7 % conversion from 400 mM AMV. Moreover, the reaction with a higher concentration of AMV could produce 528 +/- 21 mM glutaric acid with 66.0 +/- 2.7 % conversion. In addition, the co-biotransformation strategy of GabTD and DavBA whole cells could produce 282 mM glutaric acid with 70.8 % conversion from lysine, compared to the 111 mM glutaric acid yield from the combined GabTD-DavBA system. This article is protected by copyright. All rights reserved. PMID- 30450797 TI - Evolution of Reactions of a Fluoride Shuttle Battery at the Surfaces of BiF3 Microclusters Studied by In-Situ Raman Microscopy. AB - Fluoride shuttle batteries (FSBs), which utilize defluorination of metal fluorides and fluorination of resultant metals, are expected to have high energy densities. In situ Raman microscopy was conducted during FSB reactions of a nearly two-dimensional cluster of orthorhombic BiF3 microparticles partly embedded in a gold plating film (o-BiF3/gold). At a high overpotential, defluorination of the surface of an o-BiF3 particle (or cluster) was almost completed within about 120 seconds. At a low over potential, defluorination proceeded from the contours of the cluster that was in contact with the gold to the center of the cluster, suggesting that the rate-limiting process is electronic diffusion at the cluster surface. On the other hand, fluorination proceeded uniformly at the surface of the cluster to form BiF3 with a cubic structure (c-BiF3). The results will lead to the establishment of a strategy for efficient use of active materials with low electronic and ionic conductivities. PMID- 30450796 TI - Vagus nerve spiking activity associated with locomotion and cortical arousal states in a freely moving rat. AB - The vagus nerve serves as a central pathway for communication between the central and peripheral organs. Despite traditional knowledge of vagus nerve functions, detailed neurophysiological dynamics of the vagus nerve in naive behavior remain to be understood. In this study, we developed a new method to record spiking patterns from the cervical vagus nerve while simultaneously monitoring central and peripheral organ bioelectrical signals in a freely moving rat. When the rats transiently elevated locomotor activity, the frequency of vagus nerve spikes was correspondingly increased, and this activity was retained for several seconds after the increase in running speed terminated. Spike patterns of the vagus nerve were not robustly associated with which arms the animals entered on an elevated plus maze. During sniffing behavior, vagus nerve spikes were nearly absent. During stopping, the vagus nerve spike patterns differed considerably depending on external contexts and peripheral activity states associated with cortical arousal levels. Stimulation of the vagus nerve altered rat's running speed and cortical arousal states depending on running speed at the instant of stimulation. These observations are a new step for uncovering the physiological dynamics of the vagus nerve modulating the visceral organs such as cardio-vascular, respiratory and gastrointestinal systems. This article is protected by copyright. All rights reserved. PMID- 30450798 TI - Adult Bone Marrow Three-Dimensional Phenotypic Landscape of B-Cell Differentiation. AB - BACKGROUND: The different B-cell subsets in human bone marrow result from a dynamic equilibrium between endogenous production, B-cell bone marrow reentry and terminal plasma cell differentiation. Our aim was to define and quantify the different medullary B-cell subsets. METHODS: A series of 32 normal adult bone marrows plus 15 normal adult blood samples was studied by nine color flow cytometry (CD10, CD19, CD24, CD27, CD34, CD38, CD45, IgM, and IgD). With the Kaluza software radar plots, two 2D triple parametric histograms (CD10/CD34/CD45 and CD27/IgM/IgD) were set-up to identify six progenitor and five mature B-cell subsets. RESULTS: Very early B-cell progenitors were CD19neg/CD10pos/CD34pos. B cell progenitors were split into five subsets on the CD10/CD34/CD45 triple parametric histogram, sequentially ordered according to the loss of CD34 and CD10 and acquisition of surface IgM and IgD. CD19pos/CD38low mature B-cells were divided into four subsets on the CD27/IgM/IgD triple parametric histogram, with two stages of naive B-cells and two CD27hi marginal zone and switched memory B cell compartments. CD19pos/CD34neg/CD10low immature B-cells were the main bone marrow B-cell subset, accounting for one third of bone marrow B-cells. Transitional B-cells were the only immature bone marrow stage found in the blood. Compared to blood, the bone marrow was enriched in both marginal zone and switched B-cells. CONCLUSION: We provide the first analysis of 3D B-cell differentiation by multicolor flow cytometry leading to propose reference values for each bone marrow and blood B-cell compartment. This warrants further exploration of normal and pathological human B-cell maturation. (c) 2018 International Clinical Cytometry Society. PMID- 30450799 TI - DMD Open-access Variant Explorer (DOVE): A scalable, open-access, web-based tool to aid in clinical interpretation of genetic variants in the DMD gene. AB - BACKGROUND: Duchenne muscular dystrophy (Duchenne) is caused by pathogenic variants in the DMD gene. Antisense oligonucleotides (AONs) are one emerging precision medicine treatment for Duchenne. DMD molecular genetic testing results guide precision-therapy molecular eligibility, requiring healthcare providers to perform analyses currently uncommon in clinical laboratory and medical practices. Clear DMD variant notation and interpretation are key components of clinical care with the availability of precision medicine. METHODS: The DMD Open-access Variant Explorer (DOVE) is a web-based aid for DMD variant interpretation which additionally reports variant-specific predicted molecular eligibility for therapy. DOVE was developed in Python and adapted to the Django Web framework, integrates existing open-access tools, and does not rely on previous variant report/classification. RESULTS: DOVE [www.dmd.nl/DOVE] interprets colloquial and HGMD inputs of DMD variants to output HGMD variant nomenclature, theoretical molecular eligibility for therapy, and any predicted deleterious molecular consequences of therapy. DOVE relies on holistic in silico prediction of molecular eligibility for therapy in lieu of reference to an empirically defined, "variant-eligible" list. Examples illustrate the advantage and necessity for holistic variant interpretation. CONCLUSION: DOVE may prove useful for variant interpretation both at patient-level and in large-scale programs such as newborn screening and has broad application in concept to molecular genetic test result interpretation. PMID- 30450800 TI - Rhodium(III)-Catalyzed Enantioselective Coupling of Indoles and 7 Azabenzonorbornadienes by C-H Activation/Desymmetrization. AB - Chiral rhodium(III) cyclopentadienyl catalysts (CpX RhIII ) play significant roles in asymmetric arene C-H activation. Rh/Ir-catalyzed couplings of arenes and strained rings have been well-studied, but they have been limited to racemic systems. Reported in this work is the Cpx RhIII /AgSbF6 -catalyzed enantioselective desymmetrizative C-C coupling of N-pyrimidylindoles and 7 azabenzonorbornadienes with high efficiency and enantioselectivity. The role of AgSbF6 has been established by mechanistic studies. AgSbF6 enhances the catalytic activity by suppressing the C3-H activation of the indoles, activation which would otherwise lead to catalytically inactive species. PMID- 30450801 TI - Self-injurious behaviours in rhesus macaques: Potential glial mechanisms. AB - BACKGROUND: Self-injurious behaviour (SIB) can be classified as intentional, direct injuring of body tissue usually without suicidal intent. In its non suicidal form it is commonly seen as a clinical sign of borderline personality disorder, autism, PTSD, depression, and anxiety affecting a wide range of ages and conditions. In rhesus macaques SIB is most commonly manifested through hair plucking, self-biting, self-hitting, and head banging. SIB in the form of self biting is observed in approximately 5-15% of individually housed monkeys. Recently, glial cells are becoming recognised as key players in regulating behaviours. METHOD: The goal of this study was to determine the role of glial activation, including astrocytes, in macaques that had displayed SIB. To this end, we performed immunohistochemistry and next generation sequence of brain tissues from rhesus macaques with SIB. RESULTS: Our studies showed increased vimentin, but not nestin, expression on astrocytes of macaques displaying SIB. Initial RNA Seq analyses indicate activation of pathways involved in tissue remodelling, neuroinflammation and cAMP signalling. CONCLUSIONS: Glia are most probably activated in primates with self-injury, and are therefore potential novel targets for therapeutics. PMID- 30450802 TI - Self-injurious behaviour in people with intellectual disabilities. PMID- 30450803 TI - Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors. AB - BACKGROUND: Direct oral anticoagulants (DOACs) are efficacious in the treatment of cancer-associated thrombosis but are associated with an increased risk of hemorrhage compared with low molecular weight heparin in certain malignancies. Whether the DOACs increase the incidence of ICH in patients with brain tumors is not established. OBJECTIVES: To determine the cumulative incidence of ICH in DOACs compared to LMWH in patients with brain tumors and venous thromboembolism. PATIENTS AND METHODS: A retrospective comparative cohort study was performed. Radiographic images for all ICH events were reviewed and the primary endpoint was cumulative incidence of ICH at 12 months following initiation of anticoagulation. RESULTS AND CONCLUSIONS: A total of 172 patients with brain tumors were evaluated (42 DOAC and 131 LMWH). In the primary brain tumor cohort (N=67), the cumulative incidence of any ICH was 0% in patients receiving DOACs versus 36.8% (95% CI, 22.3-51.3%) in those treated with LMWH with a major ICH incidence of 18.2% (95% CI, 8.4-31.0). In the brain metastases cohort (N=105), DOACs did not increase the risk of any ICH relative to enoxaparin with an incidence of 27.8% (95% CI, 5.5 56.7%) compared with 52.9% (95% CI, 37.4-66.2%). Similarly, DOAC did not increase the incidence of major ICH in brain metastases with a cumulative incidence 11.1% (95% CI 0.5-40.6%) versus 17.8% (95% CI 10.2-27.2%). We conclude that DOACs are not associated with an increased incidence of ICH relative to LMWH in patients with brain metastases or primary brain tumors. This article is protected by copyright. All rights reserved. PMID- 30450804 TI - Infant male with TARP syndrome: Review of clinical features, prognosis, and commonalities with previously reported patients. AB - TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava) is a rare X-linked condition. As more patients are identified through genetic testing, it is increasingly clear that the original TARP acronym does not fully describe the complete phenotypic spectrum of this syndrome. The presented patient had genetically confirmed TARP syndrome and demonstrated new findings of hydronephrosis and hemodynamically significant hypertrophic obstructive cardiomyopathy. The patient also had physical findings common with previously reported individuals with TARP syndrome in the literature but not described by the TARP acronym. These features include central nervous system dysfunction, renal abnormalities, cardiac lesions other than atrial septal defect or persistent left superior vena cava, and distal limb defects other than talipes equinovarus. By adding to the known spectrum of the TARP phenotype, this report will aid clinicians as they care for patients with this rare condition. PMID- 30450805 TI - Autotaxin/lysophosphatidic acid signaling mediates obesity-related cardiomyopathy in mice and human subjects. AB - Obesity is associated with increased cardiovascular morbidity and mortality, but the direct signals to initiate or exaggerate cardiomyopathy remain largely unknown. Present study aims to explore the pathophysiological role of autotaxin/lysophosphatidic acid (LPA) in the process of cardiomyopathy during obesity. Through utilizing mouse model and clinical samples, present study investigates the therapeutic benefits of autotaxin inhibitor and clinical correlation to obesity-related cardiomyopathy. The elevated circulating levels of autotaxin are closely associated with cardiac parameters in mice. Administration with autotaxin inhibitor, PF-8380 effectively attenuates high fat diet-induced cardiac hypertrophy, dysfunction and inflammatory response. Consistently, autotaxin inhibition also decreases circulating LPA levels in obese mice. In in vitro study, LPA directly initiates cell size enlargement and inflammation in neonatal cardiomyocytes. More importantly, circulating levels of autotaxin are positively correlated with cardiac dysfunction and hypertrophy in 55 patients. In conclusion, present study uncovers the correlation between circulating autotaxin and cardiac parameters in mice and human patient, and provided solid evidence of the therapeutic application of autotaxin inhibitor in combating obesity-related cardiomyopathy. PMID- 30450806 TI - Microphthalmia is not a mandatory finding in X-linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu. AB - Mutations in BCOR cause X-linked dominant and X-linked recessive forms of syndromic microphthalmia. By exome sequencing, we identified the recurrent BCOR mutation p.Pro85Leu in two brothers and their unaffected mother. While the older brother's phenotype completely fits the described phenotypic spectrum of X-linked recessive BCOR-associated Lenz microphthalmia syndrome, the younger brother showed developmental delay, microcephaly, and skeletal anomalies, but not the key feature of microphthalmia. In contrast to the previously published families, our findings demonstrate a large variability of BCOR-associated, syndromic phenotypes, indicating incomplete penetrance of p.Pro85Leu with regards to microphthalmia in males. PMID- 30450807 TI - Cryo-EM is uncovering the mechanism of eukaryotic protein N-glycosylation. AB - N-glycosylation is one of the predominant modifications of eukaryotic proteins. It is catalyzed by oligosaccharyl transferase (OST), an eight-subunit protein complex in the endoplasmic reticulum membrane. OST transfers the oligosaccharide from a lipid-linked donor (LLO) to the Asn-Xaa-Ser/Thr sequon of nascent polypeptide, usually cotranslationally by partnering with the ribosome and the translocon. We and two other groups have recently determined high-resolution cryo EM structures of the yeast and mammalian OST complexes. In this Structural Snapshot, we describe the molecular mechanism of eukaryotic OST and its interaction with the translocon. PMID- 30450808 TI - Cyantraniliprole seed treatment efficiency against Agrotis ipsilon (Lepidoptera: Noctuidae) and residue concentrations in corn plants and soil. AB - BACKGROUND: The black cutworm Agrotis ipsilon is the most destructive early season insect pest of corn. In this study, the control efficiency of cyantraniliprole seed treatment against A. ipsilon was evaluated, and the residual concentrations of cyantraniliprole and its metabolite J9Z38 in the stalks of corn seedlings and soil were investigated. RESULTS: Plant pot experiments showed that A. ipsilon larval mortality was greater than 92% and that the percentage of corn seedlings damaged by A. ipsilon was less than 24% when corn seeds were treated with cyantraniliprole at 2 and 4 g AI kg-1 seed. Cyantraniliprole seed treatment at a dosage of 2 g AI kg-1 seed significantly reduced A. ipsilon infestation compared to chlorantraniliprole and clothianidin seed treatments in corn fields. Cyantraniliprole seed treatment resulted in more persistent control efficiency of A. ipsilon in spring than in summer. Cyantraniliprole and J9Z38 residues in corn stalks and soil degraded more slowly in the spring than in the summer. CONCLUSION: Cyantraniliprole used as a seed treatment can protect corn plants from A. ipsilon infestations throughout the seedling stage. The high biological activity of cyantraniliprole was consistent with the residue levels of cyantraniliprole in the corn stalks and soil. This article is protected by copyright. All rights reserved. PMID- 30450809 TI - Osterix promotes the migration and angiogenesis of breast cancer by upregulation of S100A4 expression. AB - As a key transcription factor required for bone formation, osterix (OSX) has been reported to be overexpressed in various cancers, however, its roles in breast cancer progression remain poorly understood. In this study, we demonstrated that OSX was highly expressed in metastatic breast cancer cells. Moreover, it could upregulate the expression of S100 calcium binding protein A4 (S100A4) and potentiate breast cancer cell migration and tumor angiogenesis in vitro and in vivo. Importantly, inhibition of S100A4 impaired OSX-induced cell migration and capillary-like tube formation. Restored S100A4 expression rescued OSX-short hairpin RNA-suppressed cell migration and capillary-like tube formation. Moreover, the expression levels of OSX and S100A4 correlated significantly in human breast tumors. Our study suggested that OSX acts as an oncogenic driver in cell migration and tumor angiogenesis, and may serve as a potential therapeutic target for human breast cancer treatment. PMID- 30450811 TI - Internet- and mobile-based interventions for anxiety disorders: A meta-analytic review of intervention components. AB - BACKGROUND: Although the efficacy of Internet- and mobile-based interventions (IMIs) for anxiety is established, little is known about the intervention components responsible for therapeutic change. We conducted the first comprehensive meta-analytic review of intervention components of IMIs for adult anxiety disorders. METHODS: Randomized controlled trials (RCTs) comparing IMIs for anxiety disorders to active online control groups, or IMIs to dismantled variations of the same intervention (+/- specific components) were identified by a systematic literature search in six databases. Outcomes were validated observer rated or self-report measures for anxiety symptom severity and treatment adherence (number of completed modules and completer rate). This meta-analytic review is registered with PROSPERO (CRD42017068268). RESULTS: We extracted the data of 34 RCTs (with 3,724 participants) and rated the risk of bias independently by two reviewers. Random-effects meta-analyses were performed on 19 comparisons of intervention components (i.a., different psychotherapeutic orientations, disorder-specific vs. transdiagnostic approaches, guidance factors). IMIs had a large effect when compared to active online controls on symptom severity (standardized mean difference [SMD] of -1.67 [95% CI: -2.93, 0.42]; P = 0.009). Thereby, guided IMIs were superior to unguided interventions on symptom severity (SMD of -0.39 [95% CI: -0.59, -0.18]; P = 0.0002) and adherence (SMD of 0.38 [95% CI: 0.10, 0.66]; P = 0.007). CONCLUSIONS: Overall, the results of this meta-analysis lend further support to the efficacy of IMIs for anxiety, pointing to their potential to augment service supplies. Still, future research is needed to determine which ingredients are essential, as this meta-analytic review found no evidence for incremental effects of several single intervention components apart from guidance. PMID- 30450810 TI - Modification of Carbon Nanotubes via Birch Reaction for Enhanced HER Catalyst by Constructing Pearl Necklace-Like NiCo2 P2 -CNT Composite. AB - Combining transition metal phosphides (TMPs) with carbon nanotubes (CNTs) is a promising and proven approach to enhance their performance in the electrochemical hydrogen evolution reaction (HER), due to the excellent conductivity and stability of CNTs. Generally, the deep oxidation of CNTs to form oxygen containing groups on their surface is indispensable before combining them with TMPs. However, such approaches inevitably introduce a large number of defects to CNTs and apparently decrease their stability and electrical conductivity. Hence, fabricating TMP-CNT composites which does not come at the expense of CNTs' high electrical conductivity is quite desirable. In this work, alkylated CNTs (named as ACNT) functionalized via the Birch reaction are used to prepare the pearl necklace-like NiCo2 P2 -ACNT composites for electrocatalysts toward HER in acidic and alkaline conditions, respectively. The X-ray photoelectron spectroscopy, transmission electron microscope, and Fourier transform infrared spectroscopy characterizations indicate that the ACNTs are well modified with functional groups and keep their structural integrity, thereby maximizing their excellent conductivity. Compared to bare NiCo2 P2 and the NiCo2 P2 -CNT composites prepared with mildly oxidized CNTs and deeply oxidized CNTs, the NiCo2 P2 -ACNTs show far better HER performance and much faster kinetics. PMID- 30450812 TI - An evaluation of the Virtual Monitoring Clinic, a novel nurse-led service for monitoring patients with stable rheumatoid arthritis. AB - OBJECTIVES: To study clinical and patient reported outcomes for the Virtual Monitoring Clinic (VMC), a remote nurse-led telemonitoring service for monitoring Rheumatoid Arthritis (RA) patients treated with disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients with stable RA enrolled in the VMC were followed up prospectively. The primary outcomes evaluated at 1-year follow-up were: Disease Activity Score-28 (DAS28), Routine Assessment of Patient Index Data 3 (RAPID3), and patient satisfaction assessed using an 11-point Likert scale. RESULTS: Of the 251 patients enrolled, 186 completed 1-year of follow-up. There was a 2.3% (n = 450) reduction in the annual workload from the rheumatology specialist outpatient clinic as a result of the VMC. Statistically significant improvement was seen in the mean patient satisfaction score (7.70-8.16, P <= 0.001), with 61.5% of patients opting for the VMC alternating with rheumatology outpatient clinic visits as their preferred mode of follow-up vis-a-vis standard care. There was a marginal increase in mean DAS28 and RAPID3 scores from 2.56 to 2.78 (P < 0.05) and 5.28 to 6.03 (P < 0.05), respectively. However, given that at 1-year follow-up more than half (72.0% and 63.4% based on DAS28 and RAPID3) of the patients' disease activity had improved or remained stable, and was in remission or low activity (73.1% and 53.2% based on DAS28 and RAPID3), the VMC seemed to maintain a stable RA disease activity for the majority of patients. CONCLUSIONS: The VMC is an effective and well-accepted novel approach for the management of patients with stable RA. PMID- 30450813 TI - Aromatic plants from Plateau des Cataractes : Occurrence of the citronella chemotype of Cymbopogon flexuosus (Nees ex Steud.) Wats. acclimatized in Congo Brazzaville. AB - Cymbopogon flexuosus var. flexuosus (citral chemotype) was introduced in a local plantation in 2006 at "Plateau des Cataractes", Congo-Brazzaville, to remedy the difficult adaptation and low production of essential oil of C. citratus, a source of citral. After some 10 years of acclimatization, C. flexuosus had adapted perfectly, with a very high biomass and essential oil production. In addition, a citronella chemotype (Cymbopogon flexuosus var. albescens) was unexpectedly identified among lemongrass in the field and grown in a local experimental citronella plot covering 0.25 ha. The essential oil was extracted by hydrodistillation and analyzed by GC and GC/MS to determine its chemotype. The citronella chemotype indicated by the chemical profile found was confirmed by descriptive statistics (radar plot) and by principal component analysis (PCA) and Ascending Hierarchical Clustering (AHC). PMID- 30450814 TI - Translation, cultural adaptation, validation, and reliability study of the Quick EBP-VIK instrument: Chinese version. AB - RATIONALE, AIMS, AND OBJECTIVES: Valid and reliable instruments for measuring are needed. To add knowledge to the subject of tools of evidence-based practice (EBP) evaluation in mainland China, the present study aims to translate the Quick-EBP VIK into Chinese, which is an instrument for the assessment of nurses' value, knowledge, and implementation of EBP, and to evaluate the metric characteristics of the Chinese version. METHODS: In this methodological study, a total sample of 402 nurses from mainland China was applied. Construct validity was evaluated by using factor analysis and further supported through known-group validity. A panel of experts examined the content validity. Internal consistency was determined using composite reliability and Cronbach alpha. The intraclass correlation coefficient (ICC) was calculated to assess test-retest reliability. RESULTS: The exploratory factor analysis revealed a three-factor structure model same to the original instrument. The confirmatory factor analysis showed a good fit model with a comparative fit index of 0.957 and a root mean square error of approximation of 0.065. Significant differences were found in the item means of the tool between nurses who received EBP training and those who had not, which supported the known-group validity. The Cronbach alpha and composite reliability for the three subscales were all higher than 0.70. The ICC ranged from 0.569 to 0.928 for the three subscales and from 0.494 to 0.903 for the items included in the instrument. CONCLUSION: The Chinese version of the Quick-EBP-VIK has evidence of acceptable reliability and validity and can be used to measure value, knowledge, and implementation of EBP for Chinese nurses. PMID- 30450816 TI - The Role of Lanthanum On A Nickel Oxide-Based Inverted Perovskite Solar Cell For Efficiency and Stability Improvement. AB - A high performing inverted perovskite solar cell (PSC) always relies on the hole transporting layer (HTL) quality and its interfaces. This work is the first to investigate the impact of lanthanum (La) incorporation within the NiOx matrix for high conductivity, charge extraction ability, and stability without compromising its power conversion efficiency. In the presence of La dopant, the La-NiOx quality is obviously improved; without the formation of pinholes. In addition, the inclusion of La alters the energy band alignment; consequently, enhances the hole transportation and widens the Voc (> 1V), as compared to the undoped-NiOx. The beneficial effect of La dopant is further revealed through the PL measurement and density of states (DOS) analysis, where trap states are passivated by La. More importantly, the perovskite solar cell, with La-doped NiOx as the HTL, exhibits 21% enhancement in efficiency and a remarkable stability than that of undoped-NiOx. This also unlocks another opportunity for commercialization. PMID- 30450817 TI - Development of a micelle-enhanced high-throughput fluorometric method for determination of niclosamide using a microplate reader. AB - The present paper describes the development and validation of a simple and sensitive micelle-enhanced high-throughput fluorometric method for the determination of niclosamide (NIC) in 96-microwell plates. The proposed method is based on the reduction of the nitro group of niclosamide to an amino group using Zn/HCl to give a highly fluorescent derivative that was developed simultaneously and measured at lambdaem 444 nm after excitation at lambdaex 275 nm. Tween-80 and carboxymethylcellulose (CMC) have been used as fluorescence enhancers and greatly enhanced the fluorescence by factors of 100-150%. The different experimental conditions affecting the fluorescence reaction were carefully investigated and optimized. The proposed method showed good linearity (r2 >= 0.9997) over the concentration ranges of 1-5 and 0.5-5 MUg/ml with lower detection limits of 0.01 and 0.008 MUg/ml and lower quantification limits of 0.04 and 0.03 MUg/ml on using Tween-80 and or CMC, respectively. The developed high-throughput method was successfully applied for the determination of niclosamide in both tablets and spiked plasma. The capability of the method for measuring microvolume samples made it convenient for handling a very large number of samples simultaneously. In addition, it is considered an environmentally friendly method with lower consumption of chemicals and solvents. PMID- 30450815 TI - Age-related ultrastructural changes of the basement membrane in the mouse blood brain barrier. AB - The blood-brain barrier (BBB) is essential for a functional neurovascular unit. Most studies focused on the cells forming the BBB, but very few studied the basement membrane (BM) of brain capillaries in ageing. We used transmission electron microscopy and electron tomography to investigate the BM of the BBB in ageing C57BL/6J mice. The thickness of the BM of the BBB from 24-month-old mice was double as compared with that of 6-month-old mice (107 nm vs 56 nm). The aged BBB showed lipid droplets gathering within the BM which further increased its thickness (up to 572 nm) and altered its structure. The lipids appeared to accumulate toward the glial side of the BM. Electron tomography showed that the lipid-rich BM regions are located in small pockets formed by the end-feet of astrocytes. These findings suggest an imbalance of the lipid metabolism and that may precede the structural alteration of the BM. These alterations may favour the accretion of abnormal proteins that lead to neurodegeneration in ageing. These findings warrant further investigation of the BM of brain capillaries and of adjoining cells as potential targets for future therapies. PMID- 30450818 TI - Reliability of scores obtained from standardized patient and instructor assessments. AB - INTRODUCTION: To obtain more reliable results from observation-based assessments, high-quality raters are key. Although this quality can be obtained by using instructors, extra workload can be a burden on them. To overcome this problem, one alternative to instructor raters can be standardized patients (SPs). METHOD: In this study, the students carried out an SP interview related to communication with an applicant/patient in the context of clinical skills training course. SPs rated student interviews just after interview and after watching a recording. Instructors rated students just by watching the recordings. To determine the appropriateness of use of SPs as raters, ratings of SPs and instructors were compared by using mean scores given to the interview performances of students' communication skills. Moreover, G theory was used to determine the reliability of scores. RESULTS: Standardized patients' ratings immediately after the interviews showed the highest scores, and these ratings were statistically different from the SPs' and instructors' ratings done while watching recordings. Besides, the G coefficient for the 4 instructors was 0.71, while that for the 12 SPs was estimated as 0.73. However, even when using 12 SPs, the obtained reliability coefficient of 0.73 brings into question the reliability of their ratings. Moreover, it was found that the one who contributed the most to reliability among instructors was the most experienced person in subject area. CONCLUSIONS: If SPs are to be used as raters, they will need more comprehensive training. More importantly, regardless of who the rater is, rater training is one of the most important factors in achieving more reliable and valid results. Moreover, having experience and knowledge about assessed topic is another crucial point of performance assessment by means of obtaining reliable results. PMID- 30450819 TI - Prevalence of minimal disease activity in Australian patients with Psoriatic Arthritis: Assessing the outcome of national funding criteria for biologic disease-modifying antirheumatic drug prescribing. AB - AIM: Discrepancies exist between international treatment guidelines and current Australian Pharmaceutical Benefits Scheme (PBS) criteria for funding biologic disease-modifying antirheumatic drug (bDMARD) prescribing in psoriatic arthritis (PsA). We aimed to determine the prevalence of minimal disease activity (MDA) achievement and differences in inflammatory marker levels between PsA patients who have and have not met the Australian PBS criteria for bDMARDs. METHOD: Consecutive participants diagnosed with PsA were assessed for MDA components and serum inflammatory markers. For those on bDMARDs, joint counts and inflammatory markers at the time of bDMARD qualification were compared with matched rheumatoid arthritis (RA) controls. RESULTS: Minimal disease activity was achieved by 56/105 participants overall. There were no differences in inflammatory marker levels or involved joint count patterns between the PsA and RA groups at the time of bDMARD qualification. Seventy-three percent of the 53 PsA patients on bDMARD achieved MDA, vs 33% in the non-bDMARD group (P < 0.001). More bDMARD than non-bDMARD patients achieved four out of seven MDA components. Of those with any enthesitis, its prevalence was higher in the non-bDMARD group (22 vs 10, P = 0.009). Regardless of treatment, there was no difference in inflammatory marker levels between those who did and did not achieve MDA. CONCLUSION: The Australian PBS criteria, funding bDMARD prescribing for PsA, select well for MDA achievers. A high prevalence of MDA non-achievement remains in patients ineligible for bDMARD funding, and enthesitis in this population is more common. Inflammatory markers were not discriminators between treatment or MDA achievement groups. PMID- 30450820 TI - Multiplexed In Vivo Imaging Using Size-Controlled Quantum Dots in the Second Near Infrared Window. AB - PbS/CdS core/shell quantum dots (QDs) that emit at the second near-infrared (NIR II, 1000-1700 nm) window are synthesized. The PbS seed size and CdS shell thicknesses are carefully controlled to produce bright and narrow fluorescence that are suitable for multiplexing. A polymer encapsulation yields polymer encapsulated NIR-II QDs (PQDs), which provides the QDs with long-term fluorescence stability over a week in biological media. Exploiting the simple bioconjugation capability of PQDs, folic acids are conjugated to PQDs that can efficiently label folate receptor overexpressing cell lines. The PQDs afford multiplexed and nearly real-time longitudinal whole-body in vivo imaging. Two NIR II QD probes are prepared: folic acid-conjugated PQDs (FA-PQDs) emitting at 1280 nm and unconjugated PQDs emitting at 1080 nm. The two PQDs are engineered to have compact and similar hydrodynamic sizes. A mixture of the folic acid-conjugated PQD and unconjugated PQDs is injected intravenously into a tumor-xenografted mouse, and the signals from them are monitored. This NIR-II whole-body imaging with the two PQDs provides precise evaluation of the active ligand-assisted tumor targeting capability of the FA-PQD probe because the hydrodynamic size control of the two PQDs effectively eliminates effects from the size-dependent accumulations by permeations and retentions in tumors. PMID- 30450821 TI - Senescent cells: A new Achilles' heel to exploit for cancer medicine? AB - Cellular senescence is a typical tumor-suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging related disorders principally via the senescence-associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti-aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications. PMID- 30450822 TI - Guidelines of prevention and treatment for alcoholic liver disease (2018, China). AB - Alcoholic liver disease (ALD), induced by long-term heavy alcohol consumption, encompasses a progressive clinical-histological spectrum of liver injuries from simple fatty liver to alcoholic hepatitis, hepatic fibrosis and cirrhosis. Excessive alcohol consumption may lead to extensive hepatocellular necrosis, and in severe cases to liver failure. PMID- 30450823 TI - Pharmacological effects of berberine on mood disorders. AB - Berberine, a natural isoquinoline alkaloid, is used in herbal medicine and has recently been shown to have efficacy in the treatment of mood disorders. Furthermore, berberine modulates neurotransmitters and their receptor systems within the central nervous system. However, the detailed mechanisms of its action remain unclear. This review summarizes the pharmacological effects of berberine on mood disorders. Therefore, it may be helpful for potential application in the treatment of mood disorders. PMID- 30450824 TI - Gels without Vapor Pressure: Soft, Nonaqueous, and Solvent-Free Supramolecular Biomaterials for Prospective Parenteral Drug Delivery Applications. AB - The engineering advantages of soft, nonaqueous, solvent-free supramolecular materials have resulted in their emerging transition and adoption from a predominantly food, cosmetics, and paint industry-driven technology to biocompatible matrices for parenteral drug delivery. Factors that have contributed to this trend are the drastic increase of hydrophobic and combination drugs in the pharmaceutical pipeline and the limitations of hydrated drug delivery materials with regard to poorly soluble drugs and biologics. This review highlights examples of nonaqueous, soft supramolecular materials, illustrates molecular engineering principles that may give rise to novel structures and unique properties, and explores emerging opportunities of application of these materials in parenteral drug delivery. PMID- 30450825 TI - More accurate and efficient segmentation of organs-at-risk in radiotherapy with Convolutional Neural Networks Cascades. AB - PURPOSE: Manual delineation of organs-at-risk (OARs) in radiotherapy is both time consuming and subjective. Automated and more accurate segmentation is of the utmost importance in clinical application. The purpose of this study is to further improve the segmentation accuracy and efficiency with a novel network named Convolutional Neural Networks (CNN) Cascades. METHODS: CNN Cascades was a two-step, coarse-to-fine approach that consisted of a Simple Region Detector (SRD) and a Fine Segmentation Unit (FSU). The SRD first used a relative shallow network to define the region of interest (ROI) where the organ was located, and then the FSU took the smaller ROI as input and adopted a deep network for fine segmentation. The imaging data (14,651 slices) of 100 head-and-neck patients with segmentations were used for this study. The performance was compared with the state-of-the-art single CNN in terms of accuracy with metrics of Dice similarity coefficient (DSC) and Hausdorff distance (HD) values. RESULTS: The proposed CNN Cascades outperformed the single CNN on accuracy for each OAR. Similarly, for the average of all OARs, it was also the best with mean DSC of 0.90 (SRD: 0.86, FSU: 0.87, and U-Net: 0.85) and the mean HD of 3.0 mm (SRD: 4.0, FSU: 3.6, and U-Net: 4.4). Meanwhile, the CNN Cascades reduced the mean segmentation time per patient by 48% (FSU) and 5% (U-Net), respectively. CONCLUSIONS: The proposed two-step network demonstrated superior performance by reducing the input region. This potentially can be an effective segmentation method that provides accurate and consistent delineation with reduced clinician interventions for clinical applications as well as for quality assurance of a multi-center clinical trial. This article is protected by copyright. All rights reserved. PMID- 30450827 TI - Fast and Quantitative Evaluation of Human Leukocyte Interaction with Aspergillus fumigatus Conidia by Flow Cytometry. AB - Systemic infections with the opportunistic mold Aspergillus fumigatus are a great threat to immunocompromised patients such as transplant recipients. Immunological research on A. fumigatus involves the measurement of phagocytosis of fungal conidia (spores) by human phagocytes. Here, we present a fast and flexible way to analyze phagocytosis by flow cytometry using fluorescein isothiocyanate (FITC) labeling of conidia prior to co-incubation with human leukocytes and an anti-FITC counterstaining step postincubation to allow the discrimination of internalized and adherent conidia. In contrast to many other protocols, this method can be combined with further surface marker analyses. We sought to determine phagocytosis rates of A. fumigatus conidia in different stages and after several incubation times using this method. Moreover, we provide an example of application by comparing phagocytosis of A. fumigatus mutants to the wild type. (c) 2018 International Society for Advancement of Cytometry. PMID- 30450826 TI - Exercise and GLUT4 in human subcutaneous adipose tissue. AB - To examine the effect of acute and chronic exercise on adipose tissue GLUT4 expression, a total of 20 healthy, male subjects performed one of two studies. Ten subjects performed cycle ergometer exercise for 60 min at 73 +/- 2% VO2 peak and abdominal adipose tissue samples were obtained immediately before and after exercise and after 3 h of recovery. Another 10 subjects completed 10 days of exercise training, comprising a combination of six sessions of 60 min at 75% VO2 peak and four sessions of 6 * 5 min at 90% VO2 peak, separated by 3 min at 40% VO2 peak. Abdominal adipose tissue and vastus lateralis muscle samples were obtained before training and 24 h after the last training session. A single bout of exercise did not change adipose tissue GLUT4 mRNA; however, there was a small, but significant, reduction in adipose tissue GLUT4 protein expression 3 h after exercise. There were no changes in adipose tissue GLUT4 or COX-IV expression following exercise training. In contrast, skeletal muscle GLUT4 and COX-IV were increased by 47% and 44%, respectively following exercise training. The exercise training-induced increase in GLUT4 expression was similar in both type I and type IIa single muscle fibers. Our results indicate that neither a single exercise bout, nor 10 days of exercise training, increased adipose tissue GLUT4, in contrast with the increases observed in skeletal muscle GLUT4 expression. PMID- 30450828 TI - Fibroblast growth factor 21 facilitates peripheral nerve regeneration through suppressing oxidative damage and autophagic cell death. AB - Seeking for effective drugs which are beneficial to facilitating axonal regrowth and elongation after peripheral nerve injury (PNI) has gained extensive attention. Fibroblast growth factor 21 (FGF21) is a metabolic factor that regulates blood glucose and lipid homeostasis. However, there is little concern for the potential protective effect of FGF21 on nerve regeneration after PNI and revealing related molecular mechanisms. Here, we firstly found that exogenous FGF21 administration remarkably promoted functional and morphologic recovery in a rat model of sciatic crush injury, manifesting as persistently improved motor and sensory function, enhanced axonal remyelination and regrowth and accelerated Schwann cells (SCs) proliferation. Furthermore, local FGF21 application attenuated the excessive activation of oxidative stress, which was accompanied with the activation of nuclear factor erythroid-2-related factor 2 (Nrf-2) transcription and extracellular regulated protein kinases (ERK) phosphorylation. We detected FGF21 also suppressed autophagic cell death in SCs. Additionally, treatment with the ERK inhibitor U0126 or autophagy inhibitor 3-MA partially abolishes anti-oxidant effect and reduces SCs death. Taken together, these results indicated that the role of FGF21 in remyelination and nerve regeneration after PNI was probably related to inhibit the excessive activation of ERK/Nrf-2 signalling-regulated oxidative stress and autophagy-induced cell death. Overall, our work suggests that FGF21 administration may provide a new therapy for PNI. PMID- 30450830 TI - A subunit of the HOPS endocytic tethering complex, FgVps41, is important for fungal development and plant infection in Fusarium graminearum. PMID- 30450831 TI - Diverse final electron acceptors: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 30450829 TI - Functional analysis of Salmonella Typhi adaptation to survival in water. AB - Contaminated water is a major risk factor associated with the transmission of Salmonella enterica serovar Typhi (S. Typhi), the aetiological agent of human typhoid. However, little is known about how this pathogen adapts to living in the aqueous environment. We used transcriptome analysis (RNA-seq) and transposon mutagenesis (TraDIS) to characterize these adaptive changes and identify multiple genes that contribute to survival. Over half of the genes in the S. Typhi genome altered expression level within the first 24 h following transfer from broth culture to water, although relatively few did so in the first 30 min. Genes linked to central metabolism, stress associated with arrested proton motive force and respiratory chain factors changed expression levels. Additionally, motility and chemotaxis genes increased expression, consistent with a scavenging lifestyle. The viaB-associated gene tviC encoding a glcNAc epimerase that is required for Vi polysaccharide biosynthesis was, along with several other genes, shown to contribute to survival in water. Thus, we define regulatory adaptation operating in S. Typhi that facilitates survival in water. PMID- 30450832 TI - Longitudinal monitoring of anti-saliva antibodies as markers of repellent efficacy against Phlebotomus perniciosus and Phlebotomus papatasi in dogs. AB - A 2-year longitudinal study of enzyme-linked immunosorbent assay (ELISA) antibodies against Phlebotomus perniciosus and Phlebotomus papatasi (Diptera: Psychodidae) sandfly saliva was performed in 32 Beagle dogs treated preventively with an imidacloprid-permethrin topical insecticide in an endemic area in Spain. Dogs were grouped into three sandfly exposure groups according to the time of inclusion in the study. Assays analysed immunoglobulin G (IgG) against salivary gland homogenates (SGH) of both species and recombinant P. papatasi rSP32 and P. perniciosus rSP03B proteins in serum. The dogs were participating in a Leishmania infantum (Kinetoplastida: Trypanosomatidae) vaccine trial and were experimentally infected with the parasite in the second year. No dog acquired natural L. infantum infections during the first year, but most developed anti-saliva antibodies, and median log-transformed optical densities (LODs) were seasonal, mimicking those of local sandflies. This indicates that the repellent efficacy of the insecticide used is below 100%. Multi-level modelling of LODs revealed variability among dogs, autocorrelation and differences according to the salivary antigen and the dog's age. However, dog seroprevalence, estimated using pre exposure LODs as cut-offs, was relatively low. This, and the fact that dogs did not become naturally infected with L. infantum, would support the efficacy and usefulness of this imidacloprid-permethrin topical insecticide in canine leishmaniasis control. PMID- 30450833 TI - Common mycorrhizal networks activate salicylic acid defense responses of trifoliate orange (Poncirus trifoliata). AB - Citrus canker, caused by Xanthomonas axonopodis pv. citri ('Xac'), is an important disease in citrus crops. Arbuscular mycorrhizal fungi (AMF) form symbiotic interactions with host plants and further affect their disease resistance, possibly by modulating the activity of salicylic acid (SA), a key phytohormone in disease resistance. Common mycorrhizal networks (CMNs) can interconnect plants, but it is not yet clear whether CMNs promote resistance to citrus canker and, if so, whether SA signaling is involved in this process. To test this possibility, we used a two-chambered rootbox to establish CMNs between trifoliate orange (Poncirus trifoliata) seedlings in chambers inoculated (treated) or not (neighboring) with the AMF, Paraglomus occultum. A subset of the AMF-inoculated seedlings were also inoculated with Xac (+AMF + Xac). At 2 days post-inoculation (dpi), compared with the +AMF - Xac treatment, neighboring seedlings in +AMF + Xac treatment had lower expression levels of the SA biosynthetic genes, PtPAL, PtEPS1, and PtPBS3, but higher SA levels, which attributed to the up-regulation of PtPAL and PtPBS3 in treated seedlings and the transfer of SA, via CMNs, to the neighboring seedlings. At 4 dpi, the pathogenesis-related (PR) protein genes, PtPR1, PtPR4, and PtPR5, and the transcriptional regulatory factor gene, PtNPR1, were activated in neighboring seedlings of +AMF + Xac treatment. At 9 dpi, root phenylalanine ammonia-lyase activity and total soluble phenol and lignin concentrations increased in neighboring seedlings of +AMF + Xac treatment, likely due to their linkage and signal transfer, via CMNs. These findings support the hypothesis that CMNs transfer the SA signal from infected to neighboring healthy seedlings, to activate defense responses and affording protection to neighboring plants against citrus canker infection. PMID- 30450834 TI - Knockdown of long noncoding RNA GAS5 attenuates H2 O2 -induced damage in retinal ganglion cells through upregulating miR-124: Potential role in traumatic brain injury. AB - BACKGROUND: Optic nerve injury is one of the most common and serious complications in traumatic brain injury (TBI). Alleviating degree of optic nerve injury is important to cure of TBI. This study explored the role of long noncoding RNA (lncRNA) GAS5 in mice retinal ganglion cells (RGCs) suffered to H2 O 2 injury. METHODS: Primary RGC (PRGCs) were treated with H2 O 2 to simulate an in vitro oxidation stress model. LncRNA GAS5 and miR-124 expressions were knocked down by cell transfection with short-hairpin RNA against GAS5 and miR-124 inhibitor, and the transfection efficiency was determined by qRT-PCR. Cell viability, apoptotic cell rate, and production of reactive oxygen species (ROS) was analyzed by CCK-8 assay, PI/FITC-Annexin V method, and DCFH-DA fluorometric assay. Cell apoptosis-associated proteins as well as activations of JAK/STAT3 signaling and JNK signaling were analyzed by Western blot. RESULTS: H2 O 2 treatment-induced cell injury was inhibited by lncRNA GAS5 silence. Specifically, knockdown of GAS5 improved viability of primary PRGCs, inhibited apoptosis, decreased ROS expression, increased antiapoptosis proteins' expressions, and decreased proapoptosis proteins' expressions. It was also found that miR-124 inhibitor treatment impaired the cell protective effect of GAS5 silence, indicating low level of GAS5 protected PRGCs via upregulating miR-124. GAS5 silence might exert cytoprotection effect via activating JAK/STAT3 signaling pathway and inhibiting activation of JNK signaling pathway. CONCLUSION: Knocking down lncRNA GAS5 alleviated H2 O 2 -induced injury in PRGCs via upregulation of miR-124, which might dependent on activation of JAK/STAT3 signaling pathway and inhibition of JNK signaling pathway. PMID- 30450836 TI - Prognostic impact of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in nasopharyngeal carcinoma: A retrospective study of 180 Taiwanese patients. PMID- 30450837 TI - Genistein inhibits Abeta25-35 -induced SH-SY5Y cell damage by modulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors. AB - In this study, we investigated the protective effects of genistein against SH SY5Y cell damage induced by beta-amyloid 25-35 peptide (Abeta25-35 ) and the underlying mechanisms. Abeta-induced neuronal death, apoptosis, glutamate receptor subunit expression, Ca2+ ion concentration, amino acid transmitter concentration, and apoptosis-related factor expression were evaluated to determine the effects of genistein on Abeta-induced neuronal death and apoptosis. The results showed that genistein increased the survival of SH-SY5Y cells and decreased the level of apoptosis induced by Abeta25-35 . In addition, genistein reversed the Abeta25-35 -induced changes in amino acid transmitters, alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, and N-methyl-d aspartate (NMDA) receptor subunits in SH-SY5Y cells. Abeta25-35 -induced changes in Ca2+ and B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) protein and gene levels in cells were also reversed by genistein. Our data suggest that genistein protects against Abeta25-35 -induced damage in SH-SY5Y cells, possibly by regulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors. PMID- 30450838 TI - Mast cell tetrahydrobiopterin contributes to itch in mice. AB - GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron-specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non-neuronal source of BH4 that may contribute to BH4-dependent phenotypes, we studied here the contribution of myeloid-derived BH4 to pain and itch in lysozyme M Cre-mediated GCH1 knockout (LysM-GCH1-/- ) and overexpressing mice (LysM-GCH1-HA). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM driven GCH1 knockout reduced, and its overexpression increased the scratching response in Compound 48/80 and hydroxychloroquine-evoked itch models, which involve histamine and non-histamine dependent signalling pathways. Mechanistically, GCH1 overexpression increased BH4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM-driven GCH1 knockout had opposite effects, and pharmacologic inhibition of GCH1 provided even stronger itch suppression. Inversely, intradermal BH4 provoked scratching behaviour in vivo and BH4 evoked an influx of calcium in sensory neurons. Together, these loss and gain-of-function experiments suggest that itch in mice is contributed by BH4 release plus BH4-driven mediator release from myeloid immune cells, which leads to activation of itch-responsive sensory neurons. PMID- 30450840 TI - The relationship between retinal thickness and neurodegeneration in early diabetic patients. PMID- 30450839 TI - PI3K activation within ventromedial prefrontal cortex regulates the expression of drug-seeking in two rodent species. AB - Phosphatidylinositide 3-kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B (aka Akt) to the cell membrane, the subsequent activation of which regulates many cellular functions. PI3K/Akt activity is up-regulated within mesocorticolimbic structures in animal models of alcoholism, but less is known regarding PI3K/Akt activity in animal models of cocaine addiction. Given that prefrontal cortex (PFC) is grossly dysregulated in addiction, we studied how cocaine affects protein indices of PFC PI3K/Akt activity in rat and mouse models and examined the relevance of PI3K activity for cocaine-related learning. Immunoblotting of mouse medial PFC at 3 weeks withdrawal from a cocaine-sensitization regimen (seven injections of 30 mg/kg, intraperitoneal [IP]) revealed increased kinase activity, as did immunoblotting of tissue from the ventral PFC of rats with a history of long-access intravenous cocaine self-administration (0.25 mg/0.1 mL infusion; 10 days of 6 h/d cocaine access). Interestingly, increased Akt phosphorylation was observed in rat ventromedial PFC at both 3- and 30-day withdrawal only in animals re-exposed to cocaine-associated cues. A conditioned place-preference paradigm in mice and a cue-elicited drug-seeking test in rats were conducted to determine the functional relevance for elevated PI3K activity for addiction-related behavior. In both cases, an intra-PFC infusion of the PI3K inhibitor wortmannin (50MUM) reduced drug-seeking behavior. Taken together, this cross-species, interdisciplinary, study provides convincing evidence that cocaine history produces an enduring increase in PI3K/Akt-dependent signaling within the more ventral aspect of the PFC that is relevant to behavioral reactivity to drug-associated cues/contexts. As such, PI3K inhibitors may well serve as an effective strategy for reducing drug cue reactivity and craving in cocaine addiction. PMID- 30450841 TI - Microbially influenced formation of Neoarchean ooids. AB - Ooids are accretionary grains commonly reported from turbulent, shallow-water environments. They have long been associated with microbially dominated ecosystems and often occur in close proximity to, or embedded within, stromatolites, yet have historically been thought to form solely through physicochemical processes. Numerous studies have revealed both constructive and destructive roles for microbes colonizing the surfaces of modern calcitic and aragonitic ooids, but there has been little evidence for the operation of these processes during the Archean and Proterozoic, when both ooids and microbially dominated ecosystems were more widespread. Recently described carbonate ooids from the 2.9 Ga Pongola Supergroup, South Africa, include well-preserved examples composed of diagenetic dolomite interpreted to have formed from a high-Mg-calcite precursor. Spatial distributions of organic matter and elements associated with metabolic activity (N, S, and P) were interpreted as evidence for a biologically induced origin. Here, we describe exceptionally well-preserved ooids composed of calcite, collected from Earth's oldest known carbonate lake system, the ~2.72 Ga Meentheena Member (Tumbiana Formation), Fortescue Group, Western Australia. We used optical microscopy, Raman spectroscopy, XRD, SEM-EDS, LA-ICP-MS, EA-IRMS, and a novel micro-XRF instrument to investigate an oolite shoal deposited between stromatolites that preserve abundant evidence for microbial activity. We report an extremely fine, radial-concentric, calcitic microfabric that is similar to the primary and early diagenetic fabrics of calcitic ooids reported from modern temperate lakes. Early diagenetic silica has trapped isotopically light and thermally mature organic matter. The close association of organic matter with mineral phases and microfabrics related to primary and early diagenetic processes suggest incorporation of organic matter occurred during accretion, likely due to the presence of microbial biofilms. We conclude that the oldest known calcitic ooids were likely formed through processes similar to those that mediate the accretion of ooids in similar environments today, including formation within a microbial biosphere. PMID- 30450842 TI - Autosomal recessive Stickler syndrome resulting from a COL9A3 mutation. AB - Stickler syndrome is a connective tissue disorder characterized by hearing loss, ocular anomalies, palatal defects, and skeletal abnormalities. The autosomal dominant form is the most common, but autosomal recessive forms have also been described. We report the second case of autosomal recessive Stickler syndrome due to homozygosity for a loss of function mutation in COL9A3, which encodes the alpha3 chain of type IX procollagen. The clinical features were similar to the previously described COL9A3 Stickler syndrome family, including moderate to severe sensorineural hearing loss, high myopia, and both tibial and femoral bowing at birth. Radiographs demonstrated abnormal capital femoral epiphyses and mild irregularities of the vertebral endplates. This case further establishes the phenotype associated with mutations in this gene. We suggest that loss of the alpha3 chain of type IX collagen results in a Stickler syndrome phenotype similar to that of the other autosomal recessive forms caused by mutations in genes encoding the alpha1 and alpha2 chains of type IX collagen. PMID- 30450843 TI - Recent Progress on Design and Synthesis of Nitrides for Mesoscopic and Perovskite Solar Cells. AB - With growing concerns on global warming and energy crisis, a variety of photovoltaic devices have attracted worldwide attention as alternative energy sources. Among them, organic/inorganic hybrid photovoltaics, typically mesoscopic and perovskite solar cells, are conspicuously promising owing to their potential in low-cost energy production, which mainly comes from unlimited combinations of materials optimized for each step of solar energy conversion. However, commercialization of organic/inorganic hybrid solar cells is hampered by costly electrocatalysts or hole transport materials. Currently, state-of-the-art dye- or quantum dot-sensitized solar cells and perovskite solar cells necessitate noble metals and high-price polymeric materials. In an attempt to resolve this issue, various kinds of metal compounds have been investigated, and nitrides have been actively reported to possess a number of favorable properties for the aforementioned purpose, such as excellent electrical conductivity, and superb electrocatalytic performance. Herein, we thoroughly review the use of nitrides as cost-effective electrocatalysts or hole transport materials in organic/inorganic hybrid solar cells. Nitrides with a variety of morphologies and scales are discussed in this article, together with the synergistic effect in the case of diverse composites. In addition, prospects and challenges for applying nitride materials are briefly suggested. PMID- 30450844 TI - Once I get on a puzzle, I can't get off: Cachexia and wasting in 2018. PMID- 30450849 TI - PLCE1 Promotes the Invasion and Migration of Esophageal Cancer Cells by Up Regulating the PKCalpha/NF-kappaB Pathway. AB - PURPOSE: To investigate the effect and mechanism of phospholipase C epsilon gene 1 (PLCE1) expression on esophageal cancer cell lines. MATERIALS AND METHODS: The esophageal carcinoma cell lines Eca109 and EC9706 and normal esophageal epithelial cell line HEEC were cultured. The expression of PLCE1, protein kinase C alpha (PKCalpha), and nuclear factor kappa B (NF-kappaB) p50/p65 homodimer in cells were comparatively analyzed. The esophageal cancer cells were divided into si-PLCE1, control siRNA (scramble), and mock groups that were transfected with specific siRNA for PLCE1, control siRNA, and blank controls, respectively. Expression of PLCE1, PKCalpha, p50, and p65 was detected by Western blotting. Transwell assay was used to detect migration and invasion of Eca109 and EC9706 cells. RESULTS: Compared with HEEC, the expression of PLCE1, PKCalpha, p50, and p65 was increased in Eca109 and EC9706 cells. The expression of PLCE1 was positively correlated with the expression of PKCalpha and p50 (PKCalpha: r=0.6328, p=0.032; p50: r=0.6754, p=0.041). PKCalpha expression had a positive correlation with the expression of p50 and p65 (p50: r=0.9127, p=0.000; p65: r=0.9256, p=0.000). Down-regulation of PLCE1 significantly decreased the expression of PKCalpha and NF-kappaB-related proteins (p65: p=0.002, p=0.004; p50: p=0.005, p=0.009) and inhibited the migration and invasion of Eca109 and EC9706 cells. CONCLUSION: PLCE1 activated NF-kappaB signaling by up-regulating PKCalpha, which could promote invasion and migration of esophageal cancer cells. PMID- 30450847 TI - Cancer Metabolism as a Mechanism of Treatment Resistance and Potential Therapeutic Target in Hepatocellular Carcinoma. AB - Various molecular targeted therapies and diagnostic modalities have been developed for the treatment of hepatocellular carcinoma (HCC); however, HCC still remains a difficult malignancy to cure. Recently, the focus has shifted to cancer metabolism for the diagnosis and treatment of various cancers, including HCC. In addition to conventional diagnostics, the measurement of enhanced tumor cell metabolism using F-18 fluorodeoxyglucose (18F-FDG) for increased glycolysis or C 11 acetate for fatty acid synthesis by positron emission tomography/computed tomography (PET/CT) is well established for clinical management of HCC. Unlike tumors displaying the Warburg effect, HCCs vary substantially in terms of 18F-FDG uptake, which considerably reduces the sensitivity for tumor detection. Accordingly, C-11 acetate has been proposed as a complementary radiotracer for detecting tumors that are not identified by 18F-FDG. In addition to HCC diagnosis, since the degree of 18F-FDG uptake converted to standardized uptake value (SUV) correlates well with tumor aggressiveness, 18F-FDG PET/CT scans can predict patient outcomes such as treatment response and survival with an inverse relationship between SUV and survival. The loss of tumor suppressor genes or activation of oncogenes plays an important role in promoting HCC development, and might be involved in the "metabolic reprogramming" of cancer cells. Mutations in various genes such as TERT, CTNNB1, TP53, and Axin1 are responsible for the development of HCC. Some microRNAs (miRNAs) involved in cancer metabolism are deregulated in HCC, indicating that the modulation of genes/miRNAs might affect HCC growth or metastasis. In this review, we will discuss cancer metabolism as a mechanism for treatment resistance, as well as an attractive potential therapeutic target in HCC. PMID- 30450848 TI - Gastric Cancer Stem Cells: Mechanisms and Therapeutic Approaches. AB - Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC stem-like cells (GCSCs), with unlimited self-renewal, differentiation, and tumor-regenerating capacities, contribute significantly to the refractory features of GC and have gained increasing attention for their role in GC drug resistance, relapse, and metastasis. Therapies targeting GCSCs seem to be one of the most promising methods to improve the outcomes of GC patients. Extensive investigations have attempted to outline the regulatory mechanisms in GCSCs and to develop GCSCs-targeting therapies with which to diminish GC drug resistance, metastasis and relapse. To the best of our knowledge, there is a lack of reviews summarizing these studies. In this review, we systematically recapitulated findings regarding the regulatory mechanisms of GCSCs, as well as therapies that target GCSCs, hoping to support the development of prognostic biomarkers and GCSCs-targeting anticancer therapies in GC. PMID- 30450850 TI - RPS15a Silencing Suppresses Cell Proliferation and Migration of Gastric Cancer. AB - PURPOSE: Information on the possible role of the ribosomal protein S15a (RPS15a) in gastric cancer is scarce. The aim of this study was to evaluate the impact of RPS15a gene expression on the growth and cell cycle of gastric cancer cells in vitro and in vivo. MATERIALS AND METHODS: RPS15a mRNA expression was examined in cancer tissues and their corresponding adjacent normal tissues of 40 gastric adenocarcinoma patients. Next, RPS15a was knocked down using a lentivirus mediated RNA interference (short hairpin RNA) system in the gastric cancer cell line BGC823. The effect of RPS15a knockdown was examined using CCK-8 assay, cell scratch test, colony formation assay, and flow cytometry. Finally, in nude mice, a tumorigenicity test was performed, and the tumor volume and weight were measured. RESULTS: RPS15a expression in tumor tissue was significantly greater than that in the adjacent normal tissue of gastric cancer patients. After RPS15a silencing, the BGC823 cell proliferation rate decreased significantly; most cells were arrested in the G0/G1 phase, cell growth was inhibited, and the migration rate was decreased. Colony formation assay showed that the number and size of clones in the RPS15a-silenced cells were fewer and smaller, compared to control cells. The nude mouse tumorigenicity test showed that RPS15a silencing had an inhibitory effect on tumor volume and mice weight. CONCLUSION: The present study found RPS15a expression to be higher in gastric tumors and its silencing in gastric cancer cells to inhibit the proliferation, growth, and migration thereof. Accordingly, RPS15a may be considered as a potential therapeutic target in gastric cancer. PMID- 30450851 TI - Effect of the Orally Active Growth Hormone Secretagogue MK-677 on Somatic Growth in Rats. AB - PURPOSE: Growth hormone secretagogues (GHSs) possess the ability to release growth hormone (GH) in the body. This study aimed to investigate the effects of MK-677, an orally active GHS, on somatic growth in rats. MATERIALS AND METHODS: The serum levels of GH were measured after oral administration of MK-677 to confirm GH stimulatory effects. Body weight, body length, tibia length, epiphyseal plate width, and serum levels of insulin-like growth factor (IGF)-I were measured after oral administration of 4 mg/kg of MK-677 for 6 weeks to investigate growth-promoting effects. RESULTS: Oral administration of MK-677 at 4 mg/kg increased peak GH concentrations by 1.8-fold, compared to baseline. However, oral administration of MK-677 for 6 weeks did not increase body growth or serum levels of IGF-I. At 6 weeks after treatment, the GH response to MK-677 was abolished. Pituitary GH mRNA and hypothalamic GH-releasing hormone mRNA, and GH secretagogue receptor (GHSR) mRNA expression in the pituitary and hypothalamus did not differ between the control and treatment group. Somatostatin (SST) mRNA expression in the hypothalamus was markedly increased in the treatment group, whereas SST receptor (SSTR)-2 mRNA expression in the pituitary gland was decreased. Protein expression of hypothalamic GHSR, SST, and pituitary SSTR-2 showed patterns similar to those for mRNA expression. CONCLUSION: Our results suggest that prolonged administration of MK-677 in rats does not promote growth despite the GH stimulatory effect of MK-677, which may be related to increased expression of SST in the hypothalamus. Further studies are needed to overcome the observed desensitization to GHS. PMID- 30450852 TI - Depletion of MicroRNA-373 Represses the Replication of Hepatitis C Virus via Activation of Type 1 Interferon Response by Targeting IRF5. AB - PURPOSE: Hepatitis C virus (HCV) poses a risk of chronic liver disease and threatens a significant number of people worldwide. MicroRNAs (miRNAs) are linked to the regulation of hepatocarcinogenesis. Although miR-373 is required for HCV infection, the underlying mechanisms of miR-373 involvement in HCV replication remain elusive. MATERIALS AND METHODS: Quantitative reverse transcription PCR assays were performed to detect the abundances of miR-373 and HCV RNA either in Huh 7.5 cells or liver biopsy specimens with HCV infection. Luciferase assay was employed to probe the interactions between miR-373 and interferon regulatory factor 5 (IRF5). Western blot was conducted to investigate the effect of miR-373 and IRF5 on HCV replication and activation of type 1 interferon (IFN) response in JFH1-infected Huh 7.5 cells. RESULTS: HCV infection appeared to be caused by increased miR-373 expression. Addition of miR-373 promoted HCV RNA expression, while miR-373 depletion led to an inhibitive effect on HCV replication. Concordantly, IRF5, as a direct target, was limited by miR-373 in JFH1-infected Huh 7.5 cells. In addition, introduction of IRF5 protected HCV replication in the presence of abundant miR-373. Furthermore, the miR-373-mediated inhibitory effect on type 1 IFN response was ablated following IRF5 accumulation. CONCLUSION: miR 373 abrogation reduced HCV replication via activation of type 1 IFN responses by targeting IRF5 in JFH1-infected Huh 7.5 cells, suggesting a promising therapeutic for treating HCV infection. PMID- 30450853 TI - Ophthalmoplegia in Mitochondrial Disease. AB - PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS. PMID- 30450855 TI - miR-34a Inhibitor May Effectively Protect against Sevoflurane-Induced Hippocampal Apoptosis through the Wnt/beta-Catenin Pathway by Targeting Wnt1. AB - PURPOSE: Research has shown that sevoflurane-induced toxicity causes neurodegeneration in the developing brain. miR-34a has been found to negatively regulate ketamine-induced hippocampal apoptosis and memory impairment. However, the role of miR-34a in sevoflurane-induced hippocampal neurodegeneration remains largely unclear. MATERIALS AND METHODS: C57/BL6 mice (7-day-old) inhaled 2.3% sevoflurane for 2 h/day over 3 consecutive days. miR-34a expression was reduced through intracerebroventricular injection with miR-34a interference lentivirus vector (LV-anti-miR-34a) into mouse hippocampus after anesthesia on the first day of exposure. Hippocampal apoptosis was detected by TUNEL assay and flow cytometry analysis. Spatial memory ability was evaluated by the Morris water maze test. The interaction between miR-34a and Wnt1 was confirmed by luciferase reporter assay, RNA immunoprecipitation, Western blot, and immunofluorescence staining. The effects of miR-34a on protein levels of B-cell lymphoma 2 (Bcl-2), bcl-2-like protein 4 (Bax), and Wnt/beta-catenin pathway-related proteins were evaluated using Western blot analysis. RESULTS: Sevoflurane upregulated hippocampal miR 34a, and miR-34a inhibitor attenuated sevoflurane-induced hippocampal apoptosis and memory impairment. miR-34a negatively regulated Wnt1 expression by targeting miR-34a in hippocampal neurons. Moreover, forced expression of Wnt1 markedly undermined miR-34a-mediated enhancement of sevoflurane-induced apoptosis of hippocampal neurons, while Wnt1 silencing greatly restored anti-miR-34a-mediated repression of sevoflurane-induced apoptosis of hippocampal neurons. Increased expression of miR-34a inhibited the Wnt/beta-catenin pathway in hippocampal neurons exposed to sevoflurane, while anti-miR-34a exerted the opposite effects. CONCLUSION: miR-34a inhibitor may effectively protect against sevoflurane-induced hippocampal apoptosis via activation of the Wnt/beta-catenin pathway by targeting Wnt1. PMID- 30450854 TI - The Brain Donation Program in South Korea. AB - PURPOSE: Obtaining brain tissue is critical to definite diagnosis and to furthering understanding of neurodegenerative diseases. The present authors have maintained the National Neuropathology Reference and Diagnostic Laboratories for Dementia in South Korea since 2016. We have built a nationwide brain bank network and are collecting brain tissues from patients with neurodegenerative diseases. We are aiming to facilitate analyses of clinic-pathological and image pathological correlations of neurodegenerative disease and to broaden understanding thereof. MATERIALS AND METHODS: We recruited participants through two routes: from memory clinics and the community. As a baseline evaluation, clinical interviews, a neurological examination, laboratory tests, neuropsychological tests, and MRI were undertaken. Some patients also underwent amyloid PET. RESULTS: We recruited 105 participants, 70 from clinics and 35 from the community. Among them, 11 died and were autopsied. The clinical diagnoses of the autopsied patients included four with Alzheimer's disease (AD), two with subcortical vascular dementia, two with non-fluent variant primary progressive aphasia, one with leukoencephalopathy, one with frontotemporal dementia (FTD), and one with Creutzfeldt-Jakob disease (CJD). Five patients underwent amyloid PET: two with AD, one with mixed dementia, one with FTD, and one with CJD. CONCLUSION: The clinical and neuropathological information to be obtained from this cohort in the future will provide a deeper understanding of the neuropathological mechanisms of cognitive impairment in Asia, especially Korea. PMID- 30450856 TI - Serum Periostin Levels: A Potential Serologic Marker for Toluene Diisocyanate Induced Occupational Asthma. AB - PURPOSE: Toluene diisocyanate (TDI) is a leading cause of occupational asthma (OA). Periostin is a matricellular protein implicated in type 2 immunity-driven asthma. Its pathogenic role in TDI-OA has not been completely elucidated. The present study was performed to investigate the role of periostin in TDI-OA. MATERIALS AND METHODS: Serum periostin levels were measured in subjects with TDI OA, asymptomatic TDI-exposure controls (AECs), non-occupational asthmatics (NAs), and unexposed normal controls (NCs). To understand the mechanism by which TDI induces periostin production, primary small airway epithelial cells (SAECs) were cultured under stimulation of TDI and neutrophils from asthmatic patients. RESULTS: Fifty-three subjects with TDI-OA, 71 AECs, 67 NAs, and 83 NCs were enrolled. Serum periostin levels were significantly higher in TDI-OA subjects than in AECs (p=0.001), NAs (p<0.001), and NCs (p<0.001). In TDI-exposed subjects (TDI-OA and AEC), the PC20 methacholine levels were significantly lower in subjects with a higher periostin level than in those with a lower periostin level. TDI exposure did not increase periostin production directly by SAECs; however, periostin production increased significantly after co-culture with TDI and neutrophils, which was suppressed by an antioxidant. In addition, increased release of TGF-beta1 was noted from SAECs when exposed to TDI and neutrophils, which was also suppressed by an antioxidant. CONCLUSION: These results suggest that an increased periostin level may contribute to the progression of airway inflammation to remodeling in TDI-exposed workers. A high serum periostin level is a potential serologic marker of the phenotype of TDI-OA. PMID- 30450858 TI - Single Ventilation during Cardiopulmonary Resuscitation Results in Better Neurological Outcomes in a Porcine Model of Cardiac Arrest. AB - PURPOSE: Recent basic life support (BLS) guidelines recommend a 30:2 compression to-ventilation ratio (CV2) or chest compression-only cardiopulmonary resuscitation (CC); however, there are inevitable risks of interruption of high quality cardiopulmonary resuscitation (CPR) in CV2 and hypoxemia in CC. In this study, we compared the short-term outcomes among CC, CV2, and 30:1 CV ratio (CV1). MATERIALS AND METHODS: In total, 42 pigs were randomly assigned to CC, CV1, or CV2 groups. After induction of ventricular fibrillation (VF), we observed pigs for 2 minutes without any intervention. Thereafter, BLS was started according to the assigned method and performed for 8 minutes. Defibrillation was performed after BLS and repeated every 2 minutes, followed by rhythm analysis. Advanced cardiac life support, including continuous chest compression with ventilation every 6 seconds and intravenous injection of 1 mg epinephrine every 4 minutes, was performed until the return of spontaneous circulation (ROSC) or 22 minutes after VF induction. Hemodynamic parameters and arterial blood gas profiles were compared among groups. ROSC, 24-hour survival, and neurologic outcomes were evaluated at 24 hours. RESULTS: The hemodynamic parameters during CPR did not differ among the study groups. Partial pressure of oxygen in arterial blood and arterial oxygen saturation were lowest in the CC group, compared to those in the other groups, during the BLS period (p=0.002 and p<0.001, respectively). The CV1 groups showed a significantly higher rate of favorable neurologic outcome (swine CPC 1 or 2) than the other groups (p=0.044). CONCLUSION: CPR with CV1 could promote better neurologic outcome than CV2 and CC. PMID- 30450857 TI - German Cockroach Extract Induces Matrix Metalloproteinase-1 Expression, Leading to Tight Junction Disruption in Human Airway Epithelial Cells. AB - PURPOSE: Cockroach exposure is a pivotal cause of asthma. Tight junctions are intercellular structures required for maintenance of the barrier function of the airway epithelium, which is impaired in this disease. Matrix metalloproteinases (MMPs) digest extracellular matrix components and are involved in asthma pathogenesis: MMP1 is a collagenase with a direct influence on airway obstruction in asthmatics. This study aimed to investigate the mechanism by which German cockroach extract (GCE) induces MMP1 expression and whether MMP1 release alters cellular tight junctions in human airway epithelial cells (NCI-H292). MATERIALS AND METHODS: mRNA and protein levels were determined using real-time PCR and ELISA. Tight junction proteins were detected using immunofluorescence staining. Epithelial barrier function was measured by transepithelial electrical resistance (TEER). The binding of a transcription factor to DNA molecules was determined by electrophoretic mobility shift assay, while the levels of tight junction proteins and phosphorylation were determined using Western blotting. RESULTS: GCE was shown to increase MMP1 expression, TEER, and tight junction degradation. Both an inhibitor and small interfering RNA (siRNA) of MMP1 significantly decreased GCE induced tight junction disruption. Furthermore, transient transfection with ETS1 and SP1 siRNA, and anti-TLR2 antibody pretreatment prevented MMP1 expression and tight junction degradation. An extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) inhibitor also blocked MMP1 release, ETS1/SP1 DNA binding, and tight junction alteration. CONCLUSION: GCE treatment increases MMP1 expression, leading to tight junction disruption, which is transcriptionally regulated and influenced by the ERK/MAPK pathway in airway epithelial cells. These findings may contribute to developing novel therapeutic strategies for airway diseases. PMID- 30450859 TI - Concerns for Older Adult Patients with Acute Hip Fracture. AB - PURPOSE: The purpose of this study was to identify concerns among older adult patients with acute hip fracture. MATERIALS AND METHODS: This study was performed with 152 consecutive patients with hip fracture. Details were obtained on perioperative concerns about hip fracture using a questionnaire that was specifically designed for this study and was administered face to face upon admission. The study inclusion criteria were age older than 65 years and having experienced femur neck, intertrochanteric, or subtrochanteric fracture. The exclusion criteria were not understanding the study purpose, having difficulty communicating, or refusing to participate. RESULTS: Older adult patients with acute hip fracture expressed concerns regarding excessive pain, medical staff, postoperative recovery, rehabilitation, and hospital expenses. In addition, fear of falling from the bed and anxiety regarding re-fracture were the patients' most significant concerns. CONCLUSION: Older adult patients reported fear of falling from bed and re-fracture as primary concerns. To overcome these concerns, fracture liaison services to prevent re-fracture should be introduced and enforced. PMID- 30450860 TI - Hypertension Risk with Abacavir Use among HIV-Infected Individuals: A Nationwide Cohort Study. AB - PURPOSE: A high risk of cardiovascular disease (CVD) is reported for HIV-infected individuals. While a link between abacavir and CVD risk is suggested, an association between abacavir and hypertension remains unclear. This study evaluated hypertension risk with abacavir use in comparison to non-abacavir antiretroviral treatment (ART). MATERIALS AND METHODS: From a nationwide cohort of HIV-infected individuals on their initial ART, 6493 who were free of hypertension at baseline were analyzed. The use of ART was treated as a time varying covariate measured as a daily unit. Incidence rate of hypertension was calculated, and Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) with 95% confidence interval (CI) of incident hypertension overall and among subgroups. RESULTS: From the 6493 participants, 24072 person years (PY) of follow-up were contributed during 2008-2016. The incidence rates of hypertension were 4.6 and 3.6 per 100 PY for abacavir and non-abacavir ART users, respectively. The population attributable fraction of abacavir use on hypertension was 12%. Abacavir exposure did not elevate the risk of hypertension among overall study population [HR, 1.2 (95% CI, 1.0-1.4), p=0.061]. However, those with poor ART adherence, defined as a medication possession ratio <50% [HR, 1.9 (95% CI, 1.5-2.4), p<0.0001] or requiring prophylactic antibiotics [HR, 1.2 (95% CI, 1.0-1.3), p=0.023], were at risk of hypertension induced by abacavir, as were men, individuals aged >=40 years, and patients visiting tertiary hospitals in urban areas. CONCLUSION: When present, poor ART adherence, requiring prophylactic antibiotics, male sex, and older age may warrant additional concern for hypertension in patients treated with abacavir. PMID- 30450861 TI - Identification of Anti-Gerbich Antibody in an Emirati Marrow Hematopoietic Progenitor Cell Donor with Fy(a-b-) Phenotype. AB - In this study, we report a case of anti-Gerbich (Ge) alloantibody to a high prevalence Ge antigen in a donor with Fy(a-b-) phenotype. The alloantibody was detected in an Emirati boy who was admitted to a Korean tertiary hospital for marrow hematopoietic progenitor cell donation. He did not have a history of transfusion. His blood type was A, RhD+, and findings from the antibody screening and identification test showed 2+ reactivity in all panel cells except autologous cells. We concluded that it would be very difficult to find compatible blood components for the donor and requested further tests from external laboratories. Anti-Ge2 was identified by additional tests in a foreign reference laboratory, and the Duffy genotype of the donor was FY*02/FY*02N.01 based on the Korean Rare Blood Program. Although the donor was not a Korean, as the number of foreign patients visiting Korea increases annually, there is growing interest in patients with rare blood types in the Korean population. However, there has been very little research on rare or high prevalence blood type antigen and antibody in the Korean population. Therefore, additional research in Korea is needed on rare blood group antibodies and antigens, including Ge cases. PMID- 30450862 TI - Metabolic parameters in young turkeys fed diets with different inclusion levels of copper nanoparticles. AB - The aim of this study was to verify the hypothesis postulating that the supplementation of turkey diets with Cu nanoparticles can lower dietary inclusion levels of Cu without compromising the growth rate and antioxidant status of turkeys. The experiment was carried out on 648 one-day-old Hybrid Converter turkeys divided into 6 groups with 6 replicates per group, in a two-factorial design with 3 dietary inclusion levels of Cu (20, 10 and 2 mg/kg) and 2 dietary sources of Cu - copper sulfate (Cu-SUL) and Cu nanoparticles (Cu-NP). At 42 days of age, blood samples were collected from 2 birds per replicate (12 birds per group), after slaughter livers were collected for analyses. Blood and liver samples were assayed for: Cu, Zn, Ca, P, Mg, GLU, TP, ALB, UREA, TAG, TC, UA, ALT, AST, ALT, GGT, ALP, SOD, GPx, CAT, VIT C, FRAP, GSH+GSSG, LOOH, MDA. The results of this experiment demonstrate that a decrease in the dietary inclusion levels of Cu from 10 mg/kg to 2 mg/kg does not compromise the growth performance of turkeys, but weakens antioxidant defense mechanisms. A Cu dose of 20 mg/kg induces oxidation reactions and has a much more inhibitory effect on the antioxidant defense system than dietary Cu content of 2 mg/kg. In turkeys, dietary supplementation with Cu-NP has a more beneficial effect on carbohydrate metabolism and antioxidant status compared with Cu-SUL. The results of analyses examining the antioxidant and metabolic status of young turkeys indicate that 10 mg/kg is the optimal dietary inclusion level of Cu. PMID- 30450863 TI - Freezability and fertility of frozen-thawed boar semen supplemented with ostrich egg yolk lipoproteins. AB - Lipoproteins, isolated from ostrich egg yolk (LPFo), provide excellent protection for boar spermatozoa against cryo-induced damage. The present study was performed to investigate the effects of LPFo on the freezability and fertilizing capacity of frozen-thawed (FT) boar semen after post-cervical artificial inseminations (post-CAIs). Semen, collected from 7 Polish Large White (PLW) and 4 Polish Landrace (PLR), was frozen in an extender containing LPFo. Post-CAIs were performed in 38 multiparous sows, using a catheter-cannula kit. Sows were inseminated 2* within one oestrus, and fertility parameters were recorded after farrowing. Neither boar (within breed) nor breed affected the quality of the pre freeze (PF) semen, such as total motility (TMOT), mitochondria membrane potential (MMP), plasma membrane integrity (PMI), osmotic resistance test (ORT) and DNA fragmentation. Differences in the freezability of boar semen were observed among the boars, whereas there were no marked breed effects. Post-thaw TMOT markedly declined over storage time in most of the boars, particularly at 60 min after thawing. Inseminations of post-weaned oestrus sows resulted in pregnancy and farrowing rates of 84.2% and 81.6%, respectively. Neither the mean number of piglets born (NB) nor the mean number of piglets born alive (NBA) was affected by boar or breed. The total number of piglets born was 365, resulting in 11.8 NB piglets, whereas the total number of piglets born alive was 353, with 11.4 NBA piglets per litter. The findings of this study reaffirm the variations in the freezability of boar semen. In this study the supplementation of ostrich egg yolk lipoproteins to the freezing extender of boar semen produced high proportions of functionally viable FT spermatozoa that were capable of providing acceptable fertility results after post-CAIs in multiparous sows. PMID- 30450865 TI - Effect of combinations of intravenous small-volume hypertonic sodium chloride, acetate Ringer, sodium bicarbonate, and lactate Ringer solutions along with oral fluid on the treatment of calf diarrhea. AB - The aim of this study was to compare effect of combinations of intravenous isotonic sodium bicarbonate (NaHCO3), acetate Ringer, lactate Ringer and small volume hypertonic sodium chloride (NaCI) solutions along with oral electrolyte solutions (OES) on the treatment of neonatal calf diarrhea with moderate dehydration and metabolic acidosis. Thirty-two calves with diarrhea were used in the study. Calves were randomly assigned to receive acetate Ringer solution (n=8), lactate Ringer solution (n=8), isotonic NaHCO3 (n=8) and 7.2% saline solutions (n=8), and two liters of OES were administrated to all calves orally at the end of intravenous administration. Blood samples for blood gas and biochemical analyses were collected at 0 hours and at 0.5, 1, 2, 4, 6 and 24 hours intervals. All the calves had mild to moderate metabolic acidosis on admission. Increased plasma volume and sodium concentration, but decreased serum total protein were observed within 0.5 hours following administration of hypertonic 7.2% NaCI + OES, compared to other 3 groups. In conclusion, administration of intravenous hypertonic 7.2% NaCI solution in small volume along with OES provided fast and effective improvement of dehydration and acid-base abnormalities within short time in treatment of calf diarrhea with moderate dehydration and metabolic acidosis. PMID- 30450864 TI - Lipogranulomas and pigment granulomas in livers of dogs with portosystemic shunt. AB - Lipogranulomas are lesions found in histopathological liver examination in humans and in various animal species, including dogs, especially those with portosystemic shunts. They consist of macrophages and other inflammatory cells, and sometimes they contain iron salts (pigment granuloma). This study aimed at determining the number of granulomas and cellular composition of lipogranulomas in dogs with the congenital extrahepatic portosystemic shunt, and to identify factors associated with their development. 44 archival liver samples from dogs with portosystemic shunt were stained using HE, Perl's method and - in randomly selected cases - immunohistochemically against CD56, CD20 and CD3 (DAKO). A reduction in the size of the liver was observed in all dogs during laparotomy, and the diameter of the vessel circumventing the liver was also measured (in 24 dogs). Lipogranulomas were found in 52.3% of samples; iron salts were present in 47.8% of them; 72% of cells in lipogranulomas were macrophages. In lipogranulomas both types of lymphocytes - T and B - were seen. The presence of lipogranulomas in liver samples in dogs was connected with fatty degeneration of hepatocytes and was correlated with the age of animals and with the diameter of the abnormal vessel circumventing the liver. Their formation appears to be triggered by severe ischemia and shortage of nutrient supply. PMID- 30450866 TI - Pharmacokinetic profiles of 5 mg/kg ibudilast, a phosphodiesterase inhibitor, orally administered to dogs in fasted and non-fasted states. A preliminary study. AB - Ibudilast (AV-411) is a non-selective inhibitor of cyclic nucleotide phosphodiesterase (PDE). It is currently marketed for human use in Asian countries for the treatment of asthma, cerebrovascular disorders and ocular allergies. Ibudilast has also been found to have an analgesic action for neuropathic pain at doses 5-10 times higher than those used in asthma therapy. Six healthy Labrador dogs were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, cross-over design (2x2 Latin square). Dogs in group 1 (n=3) were fasted for at least 10 hours overnight before the beginning of the experiment and 4 h following dosing while dogs in group 2 (n=3) received food ad libitum. During the first phase, each dog in group 1 and 2 received a single dose of 5 mg/kg ibudilast administered orally. After 1-week washout period the groups were rotated and the experiment was repeated. The analytical method, validated for dog plasma, was shown to be linear in the range 0.10-20 MUg/mL. The limit of detection (LOD) and quantification (LOQ) were 0.03 and 0.1 MUg/mL, respectively. No behavioural or health alterations were observed in the animals during or after the study. Ibudilast was detectable in plasma for up to 24 h showing a wide variability between animals. Although no statistically significant differences were observed in the present study between the fed and fasted states, examination of the raw data suggests that an effect may be present. The wide degree of variation observed in area under the curve (AUC) suggests that the investigation of population pharmacokinetic modelling is warranted. PMID- 30450867 TI - Molecular identification of Babesia spp isolated from Polish cattle with asymptomatic protozoa infections. AB - The aim of the paper was to study the epizootic situation of babesiosis in the cattle population in eastern Poland and possibly to determine what species of protozoa infects Polish cattle. Blood samples for molecular analysis (real time PCR) were collected from 192 dairy cows from various farms located in eastern Poland. The infection was detected in 10.4% of the samples. All animals were infected with Babesia occultans which sequence of the 18S RNA gene fragment showed a 93.1%, homology with the sequence of B. occultans EU 376017. This is the first report about the detection of B. occultans DNA in asymptomatic cattle in eastern Poland. PMID- 30450868 TI - CD4- and CD8-expressing cells found in the bovine and porcine anterior chamber of the eye. AB - The aim of the present study was to investigate whether the anterior chamber constitutes part of the normal migratory pathway of CD4+ and CD8+ lymphocytes in cattle and swine. The cells obtained from aqueous humor of cows and pigs were stained for CD4 and CD8 receptors, and subsequently analyzed with flow cytometry. The mean percentage of CD4+CD8-, CD4-CD8+ and CD4+CD8+ cells within the total lymphocyte population of the bovine anterior chamber was, respectively, 17.88, 12.64 and 27.26%. In turn, the mean values of these parameters in pigs were 1.77, 38.48 and 17.45, respectively. Among bovine and porcine CD4+CD8+ cells prevalent were those displaying CD4lowCD8low and CD4lowCD8high phenotypes, respectively. The results suggest that the anterior chamber in cattle and swine is an element in the normal migratory pathway of CD4+, CD8+ and CD4+CD8+ cells. Furthermore, the contribution of these subsets in the anterior chamber lymphocyte population can differ considerably between animal species. PMID- 30450869 TI - Infrared thermography as a rapid and non-invasive diagnostic tool to detect inflammatory foot diseases in dairy cows. AB - In this study the potential usefulness of infrared thermography (IRT) as a non invasive tool to rapidly screen the most common non-infectious foot lesions in dairy cows was evaluated. Thirty-eight healthy cows and 38 cows affected by foot diseases were enrolled. Diseased cows showed the following disorders at lateral and medial claw in the hind foot: white line lesion, sole ulcer, sole haemorrhage, horizontal fissure, axial fissure. Thermography images of hind foot were collected for each animal using a digital infrared camera. Foot temperature was measured in four regions: central area of the hind foot (A1), interdigital area of the hind foot (A2), lateral (A3) and medial (A4) claw in the hind foot. Higher temperature values in the regions A1 and A2 compared to A3 and A4 were found in both healthy and diseased cows (p0.001). Cows affected by foot diseases showed higher foot temperature values compared to healthy cows (p0.05) in all considered regions. This study highlights the potential application of IRT as a reliable, practical tool for detection of hoof lesions in dairy cows. Multiple scanning images and comparisons between affected and healthy anatomical structures could be useful in defining the consistency of abnormality. PMID- 30450870 TI - Subchondral bone cyst surgical treatment using the application of stem progenitor cells combined with alginate hydrogel in small joints in horses. AB - One of the most common reasons for horse lameness is subchondral bone cysts (SBCs), which are especially evident in young horse athletes. It is believed that SBC development is strongly associated with an individual's bone growth and/or bone microstructure impairment. Current methods of SBC treatment include pharmacological treatment or surgical procedures which may allow the bone within the cyst to rebuild and be restored to properly developed bone tissue. Thus, we propose filling the SBCs with a 3D complex of alginate hydrogel and autologous adipose derived mesenchymal stem cells (ASCs). We have observed at the in vitro level, that this hydrogel complex induces osteogenic and chondrogenic differentiation potential through the upregulation of bone morphogenetic protein, osteopontin, collagen type I and aggrecan mRNA levels. Moreover, we detected the creation of a 3D extracellular matrix (EM). To investigate the complex in vivo, we chose 8 horses of varying age suffering from SBC, which resulted in lameness, to undergo experimental surgery. We documented the horses' clinical appearance, lameness and radiographic appearance, to determine that there was clinical improvement in 87.75% of the patients (n=7, out of 8 horses) 6 months postoperatively and 100% (n=8, out of 8 horses) a year after surgery. These results are promising for the potential of this procedure to become the standard in SBC treatment. PMID- 30450871 TI - Impact of milk yield on pharmacokinetics of six intramammary drugs - a population approach. AB - The aim of the research was an examination of potential impact of milk yield on the intercompartmental clearance - distribution clearance as well as determination of the variability of obtained pharmacokinetic parameters by the population approach using a two-compartmental structural model. Blood perfusion has a considerable impact on physiology of the udder and kinetics of drugs that are distributed in this organ. The research was performed on healthy Holstein- Friesian and Polish Black-White cows at the age of 4-10 years. Determination of antibiotics (ampicillin, amoxicillin, cefoperazone, penicillin G prokaine, cloxacillin, cefacetril) concentration was carried out after their every intramammary administration to one quarter of the udder. A population pharmacokinetic model was created to fit milk concentration data. General milk yield of a single cow was used as a variable. A population analysis was conducted using non-linear mixed-effect modeling. The impact of milk productivity was set solely by reference to intercompartmental clearance only in case of penicillin G, cloxacillin and ampicillin. It, has been found that milk yield, depending on a drug, influenced the distribution clearance of the drug to varying degrees. It means indirectly that increased perfusion of the udder has a different impact on drug distribution from the udder to the bloodstream. PMID- 30450872 TI - Association of metabolic and inflammatory markers with milk yield in postpartum dairy cows treated with ketoprofen. AB - Inflammation together with lipolysis and ketogenesis in early lactation can cause low productivity and may be harmful to the cow health. The objective of the study was to determine if ketoprofen treatment in the first days following parturition would positively affect the milk production and whether it was associated with the metabolic and inflammatory response. The study was conducted on 30 cows divided into two groups of 15 cows each. The experimental group was treated with 3 mg * kg. bw. -1 ketoprofen for three consecutive days after parturition. The blood samples were collected on the first day of treatment and in the first and second week postpartum and they were analyzed for non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHB), tumour necrosis factor-a(TNF-a) and haptoglobin. The results suggested that ketoprofen-treated cows with a higher milk production had a significantly lower concentration of NEFA, BHB, TNF-a and haptoglobin in the first and second week postpartum. No differences were found in the control group in metabolic status regardless of the achieved level of milk production. Ketoprofen administration in postpartum cows can enhance the milk yield. The higher milk yield in the experimental group might be associated with a lower degree of lipolysis, ketogenesis and reduced inflammatory response in the first two weeks postpartum. PMID- 30450873 TI - Occurrence of mycotoxins in talkan: a cereal-based food traditional for Turkic population. AB - The consumption of cereal contaminated with mycotoxins poses a serious health risk for humans and animals. The present work aims to evaluate the presence of mycotoxins in talkan, a cereal-based food commonly consumed by the Turkic population. The presence of mycotoxins was investigated in a total of 50 samples obtained from Kazakhstan. After a preliminary screening using various ELISA kits, mycotoxins were confirmed and quantified by HPLC-MS/MS method. More than 28% of the samples were positive for at least one mycotoxin. The calculated probably daily intake for adults and children was 20% above the tolerable daily intake for aflatoxin B1 and deoxynivalenol, while it was above 100% for zearalenone, indicating a high risk for the Kazakh population. A total of 12 samples exhibited concentrations above the European maximum level for ochratoxin A, zearalenone and deoxynivalenol, however, these values were within the limits established by the Russia-Kazakhstan-Belarus Customs Union (TR CU 015/2011). PMID- 30450874 TI - Expression analysis of multifunctional RNA-binding protein hnRNP K during development of mammalian testis. AB - Heterogeneous nuclear ribonucleoprotein K (hnRNP K), is a multifunctional protein that participates in a variety of regulatory processes of signal transduction and gene expression. To further characterize the significance of hnRNP K in different male germ cells, we investigated the expression profiles of hnRNP K at different developmental stages in pig and rat testes, and conducted a comparative analysis of expression patterns between these two species. In porcine testis development, both the mRNA and protein level of hnRNP K were down-regulated from 3 months to 8 months. However, the expression level of hnRNP K was abundant across the embryonic period in rats, and decreased gradually from 0 day post partum (dpp) to 14 dpp, then increased with the highest level presenting at 90 dpp. Immunolocalization analysis further confirmed the differential expression and localization of hnRNP K protein during testis development in pigs and rats. The results showed that hnRNP K was widely distributed in gonocytes, spermatogonia, sertoli cells and Leydig cells. The dynamic expression profile of hnRNP K may imply its crucial and potential roles in the development of the testis, which will provide a theoretical basis for the future study of molecular mechanism regulation of spermatogenesis. PMID- 30450875 TI - Effects of subcutaneous melatonin implants and short-term intravaginal progestagen treatments on estrus induction and fertility of Kivircik ewes on seasonal anestrus. AB - The aim of this study was to compare the efficacy of estrus induction and fertility by using subcutaneous melatonin (MEL, T1) and short-term intravaginal medroxyprogesteronacetate plus pregnant mare serum gonadotropin treatments (sMAP+eCG, T2) in ewes on seasonaly anestrus. In this study, 105 mature clinically healthy Kivircik ewes in anestrus season and 4 rams were used. After synchronization applications, ewes exhibiting estrus signs were hand-mated with rams known to be fertile. Blood samples were collected at different times in order to determine progesterone (P4) concentrations. Results showed that estrus manipulation protocols induced significant improvement in pregnancy rate. All the fertility results obtained with the sMAP+eCG or MEL groups were similar, in seasonal anestrus. The efficacy duration of P4 in the MEL group was longer than that in short-term progestagen group. Plasma P4 concentrations was significantly different between the first (I) and last (III) measurement days (p0.01). Increase in P4 concentration in T2 group was faster than that in T1 group, and blood P4 concentrations at higher levels could successfully be achieved by using any of the protocols in this study during the seasonal anestrus. In conclusion, according to the results obtained, the hormone application groups received very high estrus response. In addition, the twin ratio was found to be higher in T1 group compared to those determined in the other groups (T2 and Control group). Furthermore, plasma P4 concentrations and high birth rates were obtained in ewes in T1 and T2 groups. These procedures can be considered a good alternative to traditional procedures due to its flexibility under field conditions. PMID- 30450876 TI - Anticoccidial effect of apple cider vinegar on broiler chicken: an organic treatment to measure anti-oxidant effect. AB - The objective of this study was to investigate the anticoccidial effect of apple cider vinegar added to drinking water with the anticoccidial effect of amprolium to feed broiler chicken. The study has adopted an observational approach to evaluate the anticoccidial effect of apple cider vinegar on broiler chicken. The antioxidative changes were measured adding natural apple cider vinegar to drinking water. Four hundred and fifty broiler chickens were purchased from the local market and distributed into three groups (T+vc: positive control, T-vc: negative control Tv: apple cider vinegar) with 150 chickens in each group. The three groups were further replicated into 3 blocks each containing 50 chickens. The groups were fed balanced diet, amprolium was added to the feed of positive control group, and apple cider vinegar was added to the water of Tv group. Measurements of the different variables were started from week 3, at the end of each week 3 birds were chosen randomly, blood samples were collected via the wing vein, and fecal oocysts were counted from intestinal contents of each individual bird using the McMaster technique. Broiler in the control groups T+ve and T-ve showed clinical signs of coccidiosis (blood in feces) and the number of coccidial oocytes in feces increased with time. In the vinegar group, no clinical signs of coccidiosis were observed. Concentrations of total antioxidants and catalase enzyme activity significantly increased (p<=0.05); while malondialdehyde concentration significantly decreased (p<=0.05). PMID- 30450877 TI - Detection of self-biting behavior of mink by loop-mediated isothermal amplification (LAMP) and sequence-characterized amplified regions (SCAR). AB - Self-biting disease occurs in most farmed fur animals in the world. The mechanism and rapid detection method of this disease has not been reported. We applied bulked sergeant analysis (BSA) in combination with RAPD method to analyze a molecular genetic marker linked with self-biting trait in mink group. The molecular marker was converted into SCAR and loop-mediated isothermal amplification (LAMP) marker for rapid detection of this disease. A single RAPD marker A10 amplified a specific band of 1000bp in self-biting minks. The sequences of the bands exhibited 73% similarity to the Canis Brucella. SCAR and LAMP marker were designed for the specific fragment of RAPD marker A10 and validated in 30 self-biting minks and 30 healthy minks. c2 test showed difference (p0.05) with SCAR and significant difference (p0.01) with LAMP in the detection rate between the two groups, but LAMP method was more accurate than SCAR method. This indicated that LAMP can be used as a positive marker to detect self-biting disease in minks. PMID- 30450878 TI - Incidence of clinical form of anestrus after unsuccessful service in cows in eight dairy herds in north-east of Poland. AB - There is no information available about the incidence of anestrus and its clinical forms after service in dairy cows in Poland. Thus, the aim of this study was to investigate the incidence of clinical forms of anoestrus after unsuccessful artificial insemination in dairy cows based on ultrasound examination. The study was carried out on 1543 Polish Holstein-Friesian cows in 8 dairy herds in north-east Poland over a three-year period. Cows were examined for pregnancy on day 35 after AI using a Honda 1500 portable ultrasound scanner equipped with a 5 MHz linear-array transducer. Cows diagnosed as pregnant were re examined on day 45. Of the 1543 inseminated cows, 408 (26.4%) showed no estrus signs and were diagnosed not-pregnant by ultrasonography, 328 (21.3%) returned to estrus within 35 days, and 807 (52.3%) were pregnant via artificial insemination. The incidence of anestrus after service in non-pregnant cows varied among herds from 10.3% to 32.9% of cows (p0.05). Based on ultrasound examination silent heat was diagnosed in 324 (79.4%), corpus luteum pseudograviditatis in 36 (8.8%), ovarian cysts in 26 (6.4%), and ovarian afunction in 22 (5.4%) of 408 anestrous, non-pregnant cows. The results of this study showed that the incidence of anestrus after service in dairy herds in North-East Poland was high. The most prevalent clinical form of post-service anestrus was silent heat. PMID- 30450879 TI - Effect of single treatment with cloprostenol or dinoprost on estrus and reproductive performance in anestrous dairy cows after service. AB - Previous studies have compared the effectiveness of dinoprost and cloprostenol in cows yielding conflicting results. The aim of our study was to evaluate the efficacy of single treatment with cloprostenol or dinoprost on estrus and reproductive performance in cows with unobserved estrus after service. The study was conducted over four years in two dairy herds of Polish Holstein Frisian cows under a herd health program with an average milk yield per cow over 9000 L. Cows (n=523) diagnosed ultrasonographically as non-pregnant and with a corpus luteum were randomly assigned to be treated with either cloprostenol (n=261) or dinoprost (n=262). The estrus detection rates after administration of cloprostenol or dinoprost were 59.4%, and 57.6%, respectively. The difference between both groups was not statistically significant (p>0.05). Distribution of observed estrus did not differ between cloprostenol and dinoprost. There were no differences (p>0.05) between cloprostenol and dinoprost in conception rate (65.2% vs. 66.2%, respectively) and pregnancy rate (57.5% vs. 54.9%, respectively). Mean days open were similar in cows of both treatments (177.5 +/- 74.6 days vs. 175.8 +/- 62.6 days, respectively; p>0.05). In conclusion, data from this study showed no significant differences in estrus detection rates and fertility between cows with unobserved estrus after service treated with cloprostenol or dinoprost. Both products are equally useful for the treatment of non-pregnant dairy cows with anestrus after service within a reproductive herd health program. PMID- 30450880 TI - Effect of experimental infections of various Tembusu virus strains isolated from geese, ducks and chickens on ducklings. AB - In order to compare the pathogenicity of different Tembusu virus (TMUV) strains from geese, ducks and chickens, 56 5-day-old Cherry Valley ducklings which were divided into 7 groups and infected intramuscularly with 7'105 PFU/ml per duck of six challenge virus stocks. The clinical signs, weight gain, mortality, macroscopic and microscopic lesions, virus loads in sera of 1, 3, 5, 7, 11 and 14 dpi and serum antibody titers were examined. The results showed that these viruses could make the young ducks sick, but the clinical signs differed with the different species-original strains. All the experimental groups lose markedly in weight gain compared to the control, but there were no obvious distinctions in weight gains, as well as macroscopic and microscopic lesions of dead ducks between the infected groups. However, the groups of waterfowl-derived strains (from geese and ducks) showed more serious clinical signs and higher relative expressions of virus loads in sera than those from chicken-derived. The mortality of waterfowl groups was 37.5%, and the greatest mortality of chicken groups was 12.5%. The serum antibodies of the geese-species group JS804 appeared earlier and were higher in the titers than others. Taken toghter, the pathogenicity of waterfowl-derived TMUV was more serious than chicken-derived TMUV and JS804 could be chosen as one TMUV vaccine strain to protect from the infection. PMID- 30450881 TI - Sequence variants of Yersinia enterocolitica ystB gene detected in wild animals in Poland. AB - The purpose of the study was to analyze a part of the nucleotide sequences of ystB gene Y. enterocolitica strains isolated from wild animals. The material for the study consists of 30 Y. enterocolitica biotype 1A strains obtained from different wild animal species and belonging to different genotypes. Phylogenetic analysis of ystB nucleotide sequences belonging to four regular genotypes G1, G2, G3, G4 and to five groups of variations V1, V2, V3, V4, V5 revealed significant differences of Y. enterocolitica strains isolated from wild animals. The most phylogenetically distant were strains belonging to V5. PMID- 30450882 TI - Effect of a single-dose parenteral selenium supplement administered to pregnant dairy cows on selenium and iron concentrations and immune status of calves. AB - The study was performed on 21 H-F calves divided into 3 groups of 7 animals each. The first group was composed of calves whose mothers did not receive an injection of Se preparation. The second and third groups consisted of calves whose mothers were administered injections of Se and vitamin E in a single dose of 10 ml and 30 ml, 10 days before the expected parturition date. 24 hours after birth, blood samples were collected from all calves to determine Se, Fe and IgG concentrations and the activity of GSH-Px and GGT. The results of the study indicate that the administration of a single-dose Se supplement to cows in late pregnancy increases Se concentration in calves and promotes passive transfer of immunity from the mother to offspring. PMID- 30450883 TI - Hemorrhagic pneumonia in neonatal minks in Greece concomitant with Leismania infantum detection. AB - In the present study a severe outbreak of hemorrhagic pneumonia (HP) in neonatal minks concomitant with Leismania infantum (L. infantum) detection is reported. The outbreak took place on a Greek mink farm and affected 1,362 mink kits, with 524 dying. Macroscopic lesions of 14 necropsied affected kits were confined to the respiratory system with dark red, consolidated lung lobes and to the small intestine with severe, acute, hemorrhagic and necrotic enteritis. Microscopic examination of lung sections revealed severe hemorrhagic pyogranulomatous pneumonia. Bacteria were obtained in pure culture from the lungs of all necropsied animals and were confirmed as Pseudomonas aeruginosa (P. aeruginosa). Three out of 14 (21.4%) animals were positive for the presence of L. infantum DNA. The outbreak was attributed to the infection of minks with P. aeruginosa, possibly as a consequence of being immuno-suppressed by L. infantum. Further research is necessary, especially on the pathogenesis of P. aeruginosa/L. infantum co-infection and the implications of this interaction on HP disease outcome. PMID- 30450884 TI - Effect of matrine on reducing damage to bovine mammary epithelial cells induced by Staphylococcus aureus alpha-hemolysin. AB - Taking bacterial virulence factors as targets is a new therapy for treating host bacterial infection. The aim of this study was to investigate the effect of matrine on alpha-hemolysin production of Staphylococcus aureus (S. aureus) and reducing the damage to bovine mammary epithelial cells (BMECs) induced by S. aureus alpha-hemolysin. Subinhibitory concentrations of matrine decreased the production of alpha-hemolysin in none dose-dependent manner and matrine exhibited a protective effect on S. aureus-induced BMECs injury. The results indicated that the structure of matrine may potentially be used as a basic structure for development of drugs aimed at curing and preventing dairy bovine mastitis. PMID- 30450885 TI - Investigation of the tick-borne pathogens Rickettsia helvetica and Anaplasma phagocytophilum in the blood of the domestic goat (Capra hircus). AB - The bacterial species Anaplasma phagocytophilum and Rickettsia helvetica are pathogenic for humans and domestic animals and are transmitted by ticks, e.g., of the Ixodes genus. Most of the vertebrate species constituting reservoirs for anaplasmas are known, but the potential reservoirs of rickettsiae are still under discussion. This study presents an analysis of the DNA of tick-borne pathogens isolated from the whole blood of goats grazing on meadows in West Pomerania, Poland. No DNA of A. phagocytophilum was found in the blood of the goats, while the DNA of R. helvetica was detected in 5.5% of the animals. The potential role of ruminants in the circulation of R. helvetica remains unknown. PMID- 30450886 TI - Influence of splicing mutation within the lysophosphatidic acid receptor 1 gene (LPAR1) on semen quality in Holstein-Friesian bulls. AB - Effect of single nucleotide polymorphism (SNP) in splicing site of the LPAR1 (lysophosphatidic acid receptor 1) gene on selected quality traits was investigated in frozen-thawed semen of Holstein-Friesian bulls. Splicing mutation A/G in the LPAR1 gene (rs43581860) was identified in 120 Holstein-Friesian bulls using PCR-RFLP technique (Hph I). Heterozygotes AG were the most frequent (37.5%) compared with AA (30.8%) and GG (31.7%) homozygotes. Observed differences in total motility (TM), sperm membrane integrity (SYBR-14/PI) and ATP content were significant between homozygotes AA or GG and heterozygotes AG. For all three traits disadvantageous effect of heterozygotes AG was detected. This means that LPAR1 splicing mutation has significant effect on semen quality and should be considered as a new marker of semen quality in Holstein-Friesian bulls. PMID- 30450887 TI - Relation between nitric oxide (NO) level in semen and certain properties of boar spermatozoa stored at 17 degrees C. AB - The aim of this study was to measure the NO level in boar semen held in a liquid state and to determine its putative relation to spermatozoa motility, plasma membrane integrity, mitochondrial membrane potential and ATP content. Generally, the percentage of spermatozoa which generated nitric oxide gradually increased, while NO level in the surrounding medium declined during the liquid preservation. NO generation in semen preserved in BTS was higher as compared to those in Androhep(r)Plus. We demonstrated the positive correlation between the NO level in fresh spermatozoa and their quality. We also showed negative correlation between nitric oxide level in spermatozoa preserved in BTS and sperm cells motility as well as plasma membrane integrity. Results obtained in this study confirm that NO may affect sperm physiology in a dualistic manner. PMID- 30450888 TI - The Triangular Sign, a Useful Diagnostic Marker for Biliary Atresia: A Case Series of Three Irish Infants AB - BackgroundThe triangular cord (TC) sign is the appearance of a triangular shaped echogenic density visualised immediately cranial to the portal vein bifurcation on ultrasonographic examination. Several studies have reported that this ultrasonographic sign is a reliable and helpful marker in identifying Biliary Atresia (BA).AimsTo report the identification of the TC sign in three infants with BA in the Rotunda Hospital, Dublin.MethodsA retrospective chart review was performed to evaluate the clinical presentation and imaging of the three patients with positive TC sign and BA.DiscussionTimely, accurate diagnosis of BA is essential to minimise morbidity and optimise patient outcome. The TC is a valuable ultrasonographic sign to aid early diagnosis of BA. PMID- 30450889 TI - A Review of the Parenteral Nutrition Supply Service in an Irish Neonatal Unit AB - BackgroundNeonatal Intensive Care (NICU) patients have individual nutritional requirements often requiring Patient Specific Parenteral Nutrition (PSPN). From October 2015, the national PSPN compounding service availability changed from 7 days per week service to 5 days per week (i.e. no weekend and limited bank holiday ordering available). The aim of this study was to examine the introduction of a 5 day only PSPN supply on neonatal patient parenteral nutrition availability in a tertiary NICU.MethodsWe performed a prospective assessment of the provision of a 5 day rather than 7 day ordering of PSPN over a one month period (June 2017).ResultsFifteen neonatal patients received a cumulative 89 days of PN during June 2017. 10 (66%) patients received PSPN during this time period. There was same day availability of PSPN in 62 of 89 days of PN (69%).ConclusionThorough education and training will help prescribers to make appropriate PSPN ordering decisions. Improvements to available stock bags may reduce the amount of PSPN that is required but a 7 day PSPN ordering service would improve efficient provision of clinically indicated PSPN to premature infants in NICU in Ireland. PMID- 30450890 TI - Staff Attitudes towards Patient Safety Culture and Working Conditions in an Irish Tertiary Neonatal Unit AB - IntroductionThere is little published research evaluating attitudes towards patient safety culture and working conditions in neonatal units. This study aimed to explore this within a Level III Irish neonatal unit setting.MethodsThis was a quantitative, cross-sectional study performed in the Rotunda Hospital, Dublin. A 30-item safety attitudes questionnaire (SAQ) was utilized to analyze staff perceptions in areas including job satisfaction, working conditions and stress recognition.ResultsThe 'Stress Recognition' domain received the highest score (75.3) followed by 'Job Satisfaction' domain with a mean score of 74.4. The lowest mean scale score in the neonatal unit was for 'Perceptions of Management', with a mean score of 50.7. Collaboration and Communication scores were high across all disciplines.ConclusionThis SAQ has highlighted a number of important areas for quality improvement and staff satisfaction in our neonatal unit. PMID- 30450891 TI - Polyoxometalate Compound-Derived MoP-Based Electrocatalyst with N-Doped Mesoporous Carbon as Matrix, a Cathode Material for Zn-H+ Battery. AB - H2 is confirmed as a perfect substitute for traditional fossil energy, which can be obtained through hydrogen evolution reaction (HER) after electrocatalytic H2O decomposition. High-performance electrocatalysts play a significant role in HER. Here, with coordination complex-modified Standberg-type polyoxometalate and peach juice as precursors, MoP-based electrocatalysts with N-doped mesoporous carbon as a matrix (MoP@NMC) were obtained. Remarkably, during synthesis, the extremely poisonous PH3 and highly explosive H2 were avoided. MoP@NMC exhibits very excellent electrocatalytic activity in acidic electrolytes. To get 10 mA.cm-2 current, MoP@NMC only requires 92 mV overpotential with Tafel slope 56 mV.dec-1. It also possesses perfect long time stability and durability in HER. More importantly, with MoP@NMC as the cathode and the Zn plate serving as the anode, a new type of battery, Zn-H+ battery, is assembled. In this Zn-H+ battery, Zn provides electrons, which pass through an external circuit and reach the cathode. Under the catalysis of MoP@NMC, the H+ ions are reduced by these electrons and form H2. The open circuit voltage of the Zn-H+ battery is 1.19 V. Its peak power density is 89.7 mW.cm-2. The energy density of this Zn-H+ battery arrives at 809 W h.kg-1 at 10 mA.cm-2. This work establishes a new piece of research field for HER. PMID- 30450892 TI - V2Te2O: A Two-Dimensional van der Waals Correlated Metal. AB - A metastable vanadium oxytelluride V2Te2O is prepared via a topochemical deintercalation of interlayer Rb+ cations in Rb1-deltaV2Te2O. The new ternary mixed-anion compound crystallizes in a body-centered tetragonal lattice with a = 3.9282(1) A and c = 13.277(5) A, containing V2O square nets that are sandwiched by Te-atomic sheets. The charge-neutral [V2OTe2] block layers stack along the c axis with van der Waals forces, which shows a metallic behavior with a dominant T2 dependence for resistivity at low temperatures. The electronic specific-heat coefficient reaches 33.9 mJ K-2 mol-1, ~4 times that of the electronic structure calculations, suggesting a significant electron-mass renormalization. The electron correlation effect is concurrently demonstrated by the Wilson and Kadowaki-Woods ratios. Neither charge/spin-density wave nor superconductivity was observed down to 0.03 K. PMID- 30450893 TI - Substantial Enhancement toward the Photocatalytic Activity of CdS Quantum Dots by Photonic Crystal-Supporting Films. AB - The introduction of photonic crystals (PC) to semiconductors, which usually appear in the form of inverse opal materials, has been proved to be an effective way to enhance the photocatalytic activity, but their enhancement factor is merely two- to fourfold in most previous reports. In this work, a supported thin film photocatalyst (CdS/SiO2-ETPTA), as a new PC-based catalyst system, is prepared for hydrogen evolution under visible light, which presents an 6.4- to 8.8-fold activity compared to the same CdS quantum dots deposited on a non-PC film. This substantial enhancement originates from the high reflectivity of PCs and absorption of reflected light by CdS, whose absorption edge exactly matches the stopband of PCs. Compared to the traditional inverse opal photocatalysts, the PC-supported photocatalyst possesses many advantages including simplified procedures in synthesis, a substantial enhancement of activity, flexible modification with mature thin-film techniques, good stability, and easy regeneration in reaction. PMID- 30450894 TI - Tunable Membrane Potential Reconstituted in Giant Vesicles Promotes Permeation of Cationic Peptides at Nanomolar Concentrations. AB - We investigate the influence of membrane potential on the permeation of cationic peptides. Therefore, we employ a microfluidic chip capable of capturing giant unilamellar vesicles (GUVs) in physical traps and fast exchange of chemical compounds. Control experiments with calcein proved that the vesicle membranes' integrity is not affected by the physical traps and applied shear forces. Combined with fluorescence correlation spectroscopy (FCS), permeation of fluorescently labeled peptides across vesicle membranes can be measured down to the nanomolar level. With the addition of a lipophilic ruthenium(II) complex Ru(C17)22+, GUVs consisting of mixed acyl phospholipids are prepared with a negative membrane potential, resembling the membrane asymmetry in cells. It serves as a driving force for the permeation of cationic cell-penetrating peptides nonaarginine (Arg9) and the HIV trans-activator of transcription peptide (TAT). Upon photo-oxidation of Ru(C17)22+, leading to hyperpolarization of the membrane, the permeation is enhanced significantly from 55% to 78% for Arg9. This specific enhancement for Arg9 is ascribed to the higher affinity of extra arginines to phosphoserine head groups. On the other hand, permeation is decreased by introducing an additional negative charge in close proximity to the N-terminal arginine residue by changing the fluorophore. In short, with the capability to reconstitute membrane potential as well as shear stress, our system is a suitable platform for modeling the membrane permeability of pharmaceutics candidates. PMID- 30450895 TI - Design and Realization of White Quantum Dot Light-Emitting Electrochemical Cell Hybrid Devices. AB - The simple device architecture as well as the solution-based processing makes light-emitting electrochemical cells (LECs) a promising device concept for large area flexible lighting solutions. The lack of deep-blue emitters, which are, at the same time, efficient, bright, and long-term stable, complementary to the wide variety of yellow-orange-emitting LECs, hampers the creation of white LECs. We present a hybrid device concept for the realization of white light emission by combining blue colloidal quantum dots (QDs) and an Ir-based ionic transition metal complex (iTMC) LEC in a new type of white QD-LEC hybrid device (QLEC). By careful arrangement of the active layers, we yield light emission from both the blue QDs and the yellow iTMC emitter already at voltages below 3 V. The QLEC devices show homogeneous white light emission with high color rendering index (up to 80), luminance levels above 850 cd m-2, and a maximum external quantum efficiency greater than 0.2%. PMID- 30450896 TI - Transition Metal-free, Bronsted Acid Mediated Cascade Sequence in the Reaction of Propargyl Alcohols with Sulfonamido-indoles/-indolines: Highly Substituted delta- and alpha-Carbolines. AB - Bronsted acid mediated, transition metal free, reaction of propargyl alcohols with sulfonamido-indoles/-indolines under mild conditions affords highly substituted delta- or alpha-carbolines in good to excellent yields. This protocol involves cascade reaction sequences of Friedel-Crafts alkylation/ [1,5]-hydrogen shift/ electrocyclization/ elimination/ [1,2]-aryl migration followed by aromatization. An unexpected regioselective tosyl group migration from indole 2- to 6-position and arene elimination leading to alpha-carbolines has also been discovered. PMID- 30450898 TI - Pitfalls in the ABTS Peroxidase Activity Test: Interference of Photochemical Processes. AB - ABTS (2,2'-azinobis(3-ethylbenzothiazoline)-6-sulfonic acid) oxidation to form its radical cation in the presence of H2O2 is frequently used as a test for determining the peroxidase activity of enzyme mimics. Detailed studies using salen-type Mn(III) complexes show that photochemical processes involving H2O2, ABTS, and the complex itself can lead to erroneous results. The capability of the complexes to act as *OH scavengers can be also relevant when the mechanism of their biological activity is considered. PMID- 30450897 TI - Potential-Controlled Tensiometry - a Tool for Understanding Wetting and Surface Properties of Conductive Powders by Electroimbibition. AB - Potential-controlled tensiometry is a voltage-induced method which enables measuring the contact angle between a powder bed and a liquid medium through the capillary rise method. This analytical tool provides a fine-grained technique for understanding wetting behavior of powders as well as solid surfaces in connection with the application of an electrical potential. In this work, the powder bed was brought into contact with an aluminum rod connected to a portable light-weight DAC-module (digital to analogue converter) powered by a lithium-polymer battery (LiPo). The presented analytical device can be charged up to +/-1000 mV. Both the power source and the DAC-module are light-weight in order to be conveniently attached to a force tensiometer without incorporating complex wiring. In this set up, we tested multiwall carbon nanotubes (MWCNT) and glassy carbon particles. An influence of the potential on the wetting behavior of glassy carbon particles is observed which demonstrates the working principle of the device. Surprisingly, no significant effect of the potential on the wetting behavior of MWCNT is indicated in the range studied. This technique can be a valuable tool to analyze the effect of changing surface properties applying electrical gradients on materials. PMID- 30450899 TI - Nitrogen-Doped Carbon Materials as Metal-Free Catalyst for the Dechlorination of Trichloroethylene by Sulfide. AB - A new method for trichloroethylene (TCE) dechlorination is proposed using sulfide (HS- and S2-) as reductant under the mediation of nitrogen-doped carbon materials (NCMs). About 99% of the TCE was converted to acetylene after 200 h using this method. Dechlorination of TCE in the NCMs-sulfide system (NCSS) followed pseudo first-order kinetics. Pyridinic N (N6) on surface of the NCMs appeared to play a critical role in NCSS as shown by the good linear relationship between the surface content of N6 and kobs. Nucleophilic substitution was suggested as the first step in TCE dechlorination, and the nucleophilic reagent was identified as a sulfur intermediate with C-S-S-H as the functional group. The generation of C-S S-H could be ascribed to the interaction between positively charged carbon atoms in N6 and negative charged sulfide. This work is the first to demonstrate that sulfide combined with NCMs can produce active substances that are effective in TCE dechlorination and the findings will assist in the development of strategies that use natural sulfide as reductant for detoxicating organic chloroethene contaminants. PMID- 30450900 TI - Total Synthesis of epi-Trichosetin. AB - The natural 3-decalinoyltetramic acid epi-trichosetin was synthesized in ten steps starting from (R) (+)-citronellal using an intramolecular Diels-Alder reaction and a Lacey-Dieckmann cyclization as the key steps. The use of a 2 nitrobenzyl protecting group resulted in an efficient synthetic endgame. The natural product was obtained in 4.1% overall yield. PMID- 30450901 TI - Single-Crystal X-ray Diffraction Studies of Solvated Crystals of C60 Reveal the Intermolecular Interactions between the Component Molecules. AB - The solid state structures of seven solvates of C60 (C60*4tetrachloroethylene, C60*2tetrachloroethylene, C60*3benzene, C60*n-pentane, C60*diethyl ether, C60*chlorobenzene, and C60*benzene*dichloromethane) were determined by single crystal X-ray diffraction at low temperature. At 90 K the fullerene and solvate components are generally well ordered and do not show the orientational disorder that plagues similar structures determined at room temperature. Interactions between the solvate molecules and the fullerene and between adjacent C60 molecules have been examined and analyzed. Van der Waals and weak charge-transfer interactions are important to help to organize the individual components in these structures. The weak Lewis acid behavior of C60, such as when it cocrystallizes with diethyl ether or chlorinated solvents, is apparent. In addition, pi-stacking interactions are prevalent. The solvates of C60 reported here were frequently obtained from attempts to cocrystallize C60 with another chemical compound that never actually formed the desired cocrystal but influenced solvate formation. PMID- 30450902 TI - Prediction of Lignin Content in Ruminant Diets and Fecal Samples Using Rapid Analytical Techniques. AB - The measurement of lignin content in ruminant diet and fecal samples is important for digestibility studies, but it is typically time-consuming and costly. The work reported involves correlation of traditional wet chemistry data with those from three rapid instrumental techniques, Fourier transform infrared spectroscopy (FTIR), conventional thermogravimteric analysis (TGA), and high-resolution TGA (MaxRes TGA) to predict the lignin content of diets and feces from digestibility trials. Calibration and performance data indicate that the FTIR model is acceptable for screening, while the conventional and MaxRes TGA predictions are high accuracy for quantitative analysis. Cross validation and model performance data reveal that MaxRes TGA provides the best-performing predictive model. This work shows that MaxRes TGA can accurately predict lignin content in ruminant diet and fecal samples with distinct advantages over traditional wet chemistry: namely, the requirement of small sample size, ease of sample preparation, speed of analysis, and high sample throughput at considerably lower cost. PMID- 30450903 TI - High-Crystallinity pi-Conjugated Small Molecules Based on Thienylene-Vinylene Thienylene: Critical Role of Self-Organization in Photovoltaic, Charge-Transport, and Morphological Properties. AB - Narrow-band-gap small molecules with pi-extended backbones are promising donor materials for solution-processed bulk-heterojunction (BHJ) organic solar cells (OSCs). Herein, a series of acceptor-donor-acceptor (A-D-A) photovoltaic small molecules incorporating thienylene-vinylene-thienylene (TVT) as a central D unit and alkyl-substituted rhodanine or 2-(1,1-dicyanomethylene)rhodanine as terminal A units are designed and synthesized. Their physical properties including photoabsorption, electronic energy levels, hole mobility, and morphological characteristics are systematically investigated. Using solvent vapor annealing (SVA), the morphologies of the BHJ photoactive layers composed of these small molecule donors and a [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) acceptor can be properly modulated. As a result of increased crystallinity of the donors and desired phase segregation between the donors and PC71BM upon rapid SVA treatment, the photovoltaic performances of the resultant OSC devices undergo drastic enhancement. The results reported here indicate that high-efficiency small-molecule OSCs can be achieved through rational design of the TVT-based molecular framework and optimization of the nanoscale phase-segregated morphology via proper SVA treatment. PMID- 30450904 TI - Metal-Free Synthesis of N-(Pyridine-2-yl)amides from Ketones via Selective Oxidative Cleavage of C(O)-C(Alkyl) Bond in Water. AB - The TBHP/TBAI-mediated synthesis of N-(pyridine-2-yl)amides in water from ketones and 2-aminopyridine via direct oxidative C-C bond cleavage has been developed. A series of ketones, including more challenging inactive aromatic ketones substituted with diverse long-chain alkyl groups, were selectively converted to N (pyridine-2-yl)amides. Furthermore, the protocol can be applied to aryl alkyl carbinols to afford the corresponding amides in moderate to good yields. PMID- 30450905 TI - Fluorinated Alcohol Promoted Reaction of Chlorohydrocarbon with Diverse Nucleophiles for Synthesis of Triarylmethanes and Tetraarylmethanes. AB - This paper reported an efficient synthesis of triarylmethanes and tetraarylmethanes from chlorohydrocarbon with miscellaneous nucleophiles in fluorinated alcohols, featuring metal free, wide substrate scope, excellent functional group tolerance and mild reaction conditions. PMID- 30450906 TI - Molecular Engineering of Bacillus paralicheniformis Acid Urease To Degrade Urea and Ethyl Carbamate in Model Chinese Rice Wine. AB - Bacillus paralicheniformis urease (BpUrease) has been shown to be a promising biocatalyst for degrading the carcinogenic chemical ethyl carbamate (EC or urethane) in rice wine. However, low EC affinity and catalytic efficiency limit the practical application of BpUrease. In this study, we improved the EC degradation capability of BpUrease by site-saturation mutagenesis (SSM). The best variant L253P/L287N showed a 49% increase in EC affinity, 1027% increase in catalytic efficiency ( kcat/ Km), and 583% increase in half-life ( t1/2) at 70 degrees C. Homology modeling analysis suggest that mutation of Leu253 to Pro increased the BpUrease EC specificity by affecting the interaction between Arg339 with the catalytic residue His323, while Leu287Asn mutation benefits EC specificity and affinity by changing the interaction networks among the residues in the catalytic pocket. Our results show that the L253P/L287N variant efficiently degraded urea and EC in a model rice wine, making it a good candidate for practical application in the food industry. PMID- 30450907 TI - Stereoselective Intermolecular [2 + 2] Cycloadditions of Erlenmeyer-Plochl Azlactones Using Visible Light Photoredox Catalysis. AB - The first report of the preparation of symmetric and nonsymmetric diaminotruxinic derivatives through the photoredox [2 + 2] cycloadditions of Erlenmeyer azlactones is described, affording the desired compounds in high regio- and diastereocontrol (only head-to-head coupling). Mechanistic studies by DFT suggest that the reaction proceeds through a neutral photocatalytic pathway. PMID- 30450908 TI - Natural Biomaterial-Based Edible and pH-Sensitive Films Combined with Electrochemical Writing for Intelligent Food Packaging. AB - An edible and pH-sensitive film combined with electrochemical writing was developed by using gelatin, gellan gum, and red radish anthocyanins extract for intelligent food packaging. The composite film showed an orange red-to-yellow color change in the pH range of 2-12. The tensile strength, ductility, and barrier abilities to ultraviolet (UV) light and oxygen of the films were improved as the concentration of red radish anthocyanins increased. Multicolor patterns were successfully drawn on the films by using the electrochemical writing method. The composite films, which acted as gas sensors, presented visible color changes in the presence of milk and fish spoilage, while the written patterns were well preserved. Accordingly, this composite film with written patterns could be an easy-to-use indicator with great potential for monitoring food spoilage as a part of an intelligent packaging system. PMID- 30450909 TI - One-Pot Reaction of Carboxylic Acids and Ynol Ethers for The Synthesis of beta Keto Esters. AB - An one-pot reaction of carboxylic acids and ynol ethers for the synthesis of beta keto esters has been developed. Under promotion of Ag2O, various carboxylic acids and ynol ethers could transform to alpha-acyloxy enol esters, which undergo a following DMAP-catalyzed rearrangement to deliver beta-keto esters rapidly. This method provides a direct approach to beta-keto esters from carboxylic acids without any preactivation. The protocol features mild reaction conditions, broad substrate scope, and the products could be transformed to an array of compounds. PMID- 30450910 TI - Correlation of Coexistent Charge Transfer States in F4TCNQ-Doped P3HT with Microstructure. AB - Understanding the interaction between organic semiconductors (OSCs) and dopants in thin films is critical for device optimization. The proclivity of a doped OSC to form free charges is predicated on the chemical and electronic interactions that occur between dopant and host. To date, doping has been assumed to occur via one of two mechanistic pathways: an integer charge transfer (ICT) between the OSC and dopant or hybridization of the frontier orbitals of both molecules to form a partial charge transfer complex (CPX). Using a combination of spectroscopies, we demonstrate that CPX and ICT states are present simultaneously in F4TCNQ-doped P3HT films and that the nature of the charge transfer interaction is strongly dependent on the local energetic environment. Our results suggest a multiphase model, where the local charge transfer mechanism is defined by the electronic driving force, governed by local microstructure in regioregular and regiorandom P3HT. PMID- 30450911 TI - Cytoscape stringApp: Network analysis and visualization of proteomics data. AB - Protein networks have become a popular tool for analyzing and visualizing the often long lists of proteins or genes obtained from proteomics and other high throughput technologies. One of the most popular sources of such networks is the STRING database, which provides protein networks for more than 2000 organisms, including both physical interactions from experimental data and functional associations from curated pathways, automatic text mining, and prediction methods. However, its web interface is mainly intended for inspection of small networks and their underlying evidence. The Cytoscape software, on the other hand, is much better suited for working with large networks and offers greater flexibility in terms of network analysis, import and visualization of additional data. To include both resources in the same workflow, we created stringApp, a Cytoscape app that makes it easy to import STRING networks into Cytoscape, retains the appearance and many of the features of STRING, and integrates data from associated databases. Here, we introduce many of the stringApp features and show how they can be used to carry out complex network analysis and visualization tasks on a typical proteomics dataset, all through the Cytoscape user interface. stringApp is freely available from the Cytoscape app store: http://apps.cytoscape.org/apps/stringapp. PMID- 30450912 TI - 2,4,5,7,9,10-Hexaethynylpyrenes: Synthesis, Properties, and Self-Assembly. AB - A series of 2,4,5,7,9,10-hexaethynylpyrenes was synthesized using 2,7,9,10 tetrabromopyrene-4,5-dione as the key intermediate. The effects of the position and number of the ethynyl groups on the physicochemical properties of the corresponding pyrenes were clarified by comparison with 4,5,9,10 tetraethynylpyrene and 2,7-diethynylpyrene derivatives. The prepared hexaethynylpyrenes that bear benzene moieties self-assemble via pi-pi stacking in solution and/or the condensed phase. PMID- 30450913 TI - MSstatsQC 2.0: R/Bioconductor package for statistical quality control of mass spectrometry-based proteomic experiments. AB - MSstatsQC is an R/Bioconductor package for statistical monitoring of longitudinal system suitability and quality control in mass spectrometry-based proteomics. MSstatsQC was initially designed for targeted Selected Reaction Monitoring experiments. This manuscript presents an extension, MSstatsQC 2.0, that supports experiments with global Data-Dependent and Data-Independent acquisition. The extension implements data processing and analyses that are specific to these acquisition types. It relies on the state-of-the-art methods of statistical process control to detect deviations from optimal performance of various metrics (such as intensity and retention time of chromatographic peaks), and to summarize the results across multiple metrics and analytes. Additionally, the web-based graphical user interface MSstatsQCgui, implemented as a separate R/Bioconductor package, provides a user-friendly way to visualize and report the results from MSstatsQC 2.0. PMID- 30450914 TI - Hydrophobicity-Adaptive Nanogels for Programmed Anticancer Drug Delivery. AB - Reconciling the conflicting needs for a prolonged circulation time, enhanced cellular uptake by bulk tumor cells and cancer stem cells (CSCs), and extensive tumor tissue penetration remains a major challenge for current nano drug delivery systems. Here we describe smart poly( N-isopropylacrylamide)-based nanogels with a fast adaptive hydrophobicity to solve these contradictory requirements for enhanced cancer chemotherapy. The nanogels are hydrophilic in the blood to prolong their circulation time. Once they accumulate at tumor sites, they rapidly become hydrophobic in response to tumor extracellular acidity. The adaptive hydrophobicity of the nanogels facilitates tumor accumulation, deep tumor penetration, and efficient uptake by bulk tumor cells and CSCs, resulting in a greater in vivo enrichment in tumor cells and side population cells. Together with lysosomal pH-regulated charge reversal and redox-responsive intracellular drug release, the nanogels escape from lysosomes and release their cargo doxorubicin. Thus, the nanogels significantly improve the in vivo anticancer efficacy and decrease side effects of doxorubicin. Strikingly, the ratio of CSCs is greatly decreased after treatment with the nanogels loaded with doxorubicin. Our current study provides new insights into designing effective anticancer drug delivery systems. PMID- 30450915 TI - Interventions for reducing levels of burden amongst informal carers of persons with dementia in the community. A systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVES: Caregiver burden can lead to increased stress, depression and health difficulties for caregivers and care-recipients. This systematic review aimed to examine the published evidence, for interventions designed to reduce levels of carer burden, in those caring for a person with dementia. METHODS: Three databases were searched (Medline, PsycINFO and CINAHL) for studies reporting on randomised controlled trials of non-pharmacological interventions for dementia related caregiver burden. Data quality checks were completed for included papers and meta-analysis was performed to estimate the efficacy of individual interventions and different categories of non-pharmacological intervention. RESULTS: Thirty studies were included in the analysis. Seven studies found a significant reduction in carer burden and a pooled effect found that intervening was more effective than treatment as usual (SMD = -0.18, CI = -0.30, -0.05). This result was small, but significant (p = 0.005). Multi-component interventions are more effective than other categories. High heterogeneity means that results should be interpreted with caution. CONCLUSIONS: Interventions that significantly reduced levels of burden should be replicated on a larger scale. The relative effectiveness of interventions targeting cognitive appraisals and coping styles suggests that future interventions might be informed by models theorising the role of these processes in carer burden. PMID- 30450916 TI - Redox and ligand binding dependent conformational ensembles in the human apoptosis-inducing factor regulate its pro-life and cell death functions. AB - AIMS: The Human apoptosis-inducingfactor (hAIF) supports OXPHOS biogenesis and programmed cell death, with missense mutations producing neurodegenerative phenotypes. hAIF senses the redox environment of cellular compartments, stabilizing a charge-transfer complex (CTC) dimer that modulates the protein interaction network. In this context we aimed to evaluate the subcellular pH, CTC formation, and pathogenic mutations effects on hAIF stability, and a thermal denaturation high-throughput screening (HTS) assay to discover AIF binders. RESULTS: Apoptotic hAIF?1-101 is not stable at intermembrane space (IMS) pH, but the 77-101 residues confer stability to the mitochondrial isoform. hAIF and its CTC populate different conformational ensembles with redox switch to the CTC producing a less stable and compact protein. The pathogenic G308E, ?R201 and E493V mutations modulate hAIF stability; particularly, ?R201 causes a population shift to a less stable conformation that remodels the active site structure and dynamics. We have identified new molecules that modulate the hAIF NADH/NAD+ association/dissociation equilibrium and regulate its catalytic efficiency. INNOVATION: Biophysical methods allow evaluating the regulation of hAIF functional ensembles and to develop an HTS assay to discover small molecules that might modulate hAIF stability and activities. CONCLUSION: The mitochondrial soluble 54-77 portion stabilizes hAIF at the IMS pH. NADH-redox linked conformational changes course with strong NAD+ binding and protein dimerization, but they produce a negative impact in overall hAIF stability. Loss of functionality in the R201 deletion is due to distortion of the active site architecture. We report molecules that may serve as leads in the development of hAIF bioactive compound. PMID- 30450917 TI - Reactive Oxygen Species Are Necessary for Bleomycin A5-Induced Apoptosis and Extracellular Matrix Elimination of Nasal Polyp-Derived Fibroblasts. AB - BACKGROUND:: The pathology of chronic rhinosinusitis with nasal polyp (CRSwNP) is characterized by the infiltration of a large number of fibroblasts, resulting in extracellular matrix (ECM) deposition. Intralesional bleomycin A5 (BLE) injection has proved to be effective and safe, providing a novel treatment for CRSwNP. However, the mechanism is not clearly understood. OBJECTIVES:: The aim of this study is to explore the possible mechanism of BLE-induced apoptosis in nasal polyp-derived fibroblasts (NPDFs). MATERIAL AND METHODS:: Dichloro-dihydro fluorescein diacetate probe, cell migration assays, and cell cycle analysis were used to detect the growth characteristics and basal reactive oxygen species (ROS) traits of NPDFs. Annexin V/propidium iodide and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay was used to detect BLE-induced apoptosis. As a control, the antioxidant glutathione (GSH) was used to abrogate ROS induced by BLE. Western blot analysis was used to evaluate the effects of BLE on apoptosis and the ECM proteins of NPDFs. RESULTS:: The results showed that NPDFs had more active growth characteristics and higher basal ROS levels than normal nasal mucosa fibroblasts (NMFCs). NPDFs were more sensitive to BLE-induced apoptosis and ROS accumulation. GSH abrogation inhibits BLE-induced ECM degradation and apoptosis in NPDFs through a mitochondrial-mediated pathway. CONCLUSIONS:: BLE induced NPDF apoptosis and ECM degradation through a mitochondrial-mediated pathway and in a ROS-dependent manner. PMID- 30450918 TI - Demographic-based risk of reporting psychopathology and poor health among mistreated older adults in the national elder mistreatment study wave II. AB - OBJECTIVES: Past year elder mistreatment rate is about 11% of community residing older adults, with significant demographic-based variations in prevalence. However, very little research on demographic variable-based differences in correlates of elder abuse, such as mental health, exist. The National Elder Mistreatment Study 8-year follow-up (NEMS II) specifically investigated the relation between demographic factors and the presence of these correlates (i.e. diagnoses of depression, post-traumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and self-ratings of physical health). METHODS: The NEMS II used random digit dial telephone survey methodology to assess demographic variables and reports of depression PTSD, GAD, and poor health, in 774 older adults. RESULTS: a consistent association was observed between demographic factors related to financial status and poor mental and general health ratings. DISCUSSION: A subset of demographic factors associated with increased risk of reporting elder abuse, low income and financial distress, were also associated with increased risk of reporting correlates of elder abuse that included depression, PTSD GAD and poor health. PMID- 30450919 TI - Decision-Making Capacity Among Elderly People: A Mapping of Health Professionals' and Laypeople's Views. AB - The views of laypeople and professionals (nurses, occupational therapists, psychologists, and physicians) on the capacity to make informed decisions of elderly people with depression or dementia were examined. Participants were presented with vignettes created by varying the levels of three factors: (a) the type of decision (e.g., agreeing to surgery), (b) the health problem (e.g., slight depression), and (c) the availability of social support. Through cluster analysis, four different positions were found. Seventeen percent of the participants considered that even persons suffering from slight depression were already quite incapacitated. In contrast, 24% considered that only elderly people suffering from moderate or severe dementia were impaired. The majority of participants (59%) expressed positions that can be considered as pragmatic. Level of impairment was viewed as a function of severity of illness or type of illness. No significant differences were found between health professional and laypeople. PMID- 30450920 TI - Validation and clinical application of a novel LC-MS method for quantification of dolutegravir in breast milk. AB - AIM: A novel, sensitive and reproducible method for quantification of dolutegravir (DTG) in dried breast milk spots (DBMS) was developed and validated for use in clinical studies. Its application enabled measurement of DTG pharmacokinetics in breastfeeding mothers and their infants. Results/methodology: Sample extraction was by liquid-liquid extraction using Tert-butyl methy-ether, with DTG-d5 as an internal standard. DTG was eluted on a reverse phase C18 Waters XBridge (3.5 MUm: 2.1 * 50 mm) column using a gradient mobile phase consisting of 0.1% formic acid in deionised water or methanol. The assay was validated over a calibration range of 10-4000 ng/ml. CONCLUSION: Stability, inter and intra-assay variability were acceptable according to FDA and EMA bioanalytical method guidelines. The assay is robust, accurate, precise and can be reliably applied for analysis of clinical samples in trials from low resource settings. PMID- 30450921 TI - Outcome after prostatic artery embolization in patients with symptomatic benign prostatic hyperplasia. AB - BACKGROUND: Prostatic artery embolization (PAE) has recently been described as a promising alternative treatment for lower urinary tract symptoms (LUTS) due to an enlarged, benign prostate. PURPOSE: To evaluate the safety, morbidity, and functional outcomes after PAE. MATERIAL AND METHODS: Twenty-nine consecutive patients were included. All patients had computed tomography angiography before the procedure. Microcatheters were used for selective embolization of the PAs. Large side branches to non-target organs were embolized with coils. The PAs were embolized with calibrated 300-500 um tris-acryl gelatin microspheres. Complications were recorded before discharge. Clinical visit was performed after three months, magnetic resonance imaging (MRI) after 6-12 months, and any further intervention recorded in the chart. Mean follow-up was 23 months. Clinical success was defined as no longer needing urinary catheter, no long-term complications, and no need of further interventions. RESULTS: Sixteen patients (55%) had permanent or intermittent catheter before the procedure. Bilateral embolization was performed in 26 patients (90%). Five patients underwent two procedures. Twelve of 16 patients (75%) with permanent or intermittent catheter were able to remove the catheter. Five patients were operated with transurethral resection of the prostate (TURP). Except for one patient, all patients without catheter at baseline improved in the International Prostate Symptom Score (IPSS) and had no further treatment. Twelve patients experienced complications; all were grade 1 according to the Clavien-Dindo classification. CONCLUSION: PAE reduced LUTS symptoms in most patients without severe complications. The treatment did not exclude additional surgical treatment when needed. PMID- 30450922 TI - Detecting impaired function of renal allografts at the early stage after transplantation using intravoxel incoherent motion imaging. AB - BACKGROUND: Detecting renal allografts with impaired function early after renal transplantation and timely intervention are important to ensure a successful outcome. PURPOSE: To detect impaired function of renal allografts at the early stage after renal transplantation using intravoxel incoherent motion imaging (IVIM). MATERIAL AND METHODS: Forty-six recipients with good allograft function and 32 recipients with impaired function were included in this study. All participants were scanned with IVIM using 11 b-values on a 3-T magnetic resonance (MR) scanner; the apparent diffusion coefficient (ADC), ADC of slow diffusion (ADCslow), pseudo-diffusion (ADCfast), and perfusion fraction (f) values were calculated using a full bi-exponential model. Correlations between estimated glomerular filtration rate (eGFR) and the IVIM parameters were assessed by using Spearman correlation analysis. Receiver operating characteristics were used to assess the diagnostic utilities for detecting allografts with impaired function. RESULTS: The ADC, ADCslow, ADCfast, and f values of the renal cortex and the ADC and ADCslow values of the renal medulla were significantly higher in allografts with good function compared to those with impaired function (all P < 0.05). There was a significant corticomedullary difference in ADCslow, ADC, and f in all allografts. ADCfast values were higher in the cortex than in the medulla for allografts with good function but no differences were seen in allografts with impaired function ( P > 0.05). Combined use of all cortical IVIM parameters has higher efficacy in detecting renal allograft dysfunction than any single parameter (sensitivity = 90.62%; specificity = 78.26%). CONCLUSION: IVIM technique may be useful for detecting renal allograft dysfunction, especially combined use of cortical parameters. PMID- 30450923 TI - NADPH Oxidase 4 Regulates Inflammation in Ischemic Heart Failure: Role of Soluble Epoxide Hydrolase. AB - AIMS: Oxidative stress is implicated in cardiomyocyte cell death and cardiac remodeling in the failing heart. The role of NADPH oxidase 4 (NOX4) in cardiac adaptation to pressure overload is controversial, but its function in myocardial ischemic stress has not been thoroughly elucidated. The present study examined the function of NOX4 in the pathogenesis of ischemic heart failure, utilizing mouse models, cell culture, and human heart samples. RESULTS: Nox4-/- mice showed a protective phenotype in response to permanent left anterior descending (LAD) coronary artery ligation with smaller infarction area, lower cardiomyocyte cross sectional area, higher capillary density, and less cell death versus wild-type mice. Nox4-/- mice had lower activity of soluble epoxide hydrolase (sEH), a potent regulator of inflammation. Nox4-/- mice also showed a 50% reduction in the number of infiltrating CD68+ macrophages in the peri-infarct zone versus wild type mice. Adenoviral overexpression of NOX4 in cardiomyoblast cells increased sEH expression and activity and CCL4 and CCL5 levels; inhibiting sEH activity in NOX4 overexpressing cells attenuated the cytokine levels. Human hearts with ischemic cardiomyopathy showed adverse cardiac remodeling, increased NOX4 and sEH protein expression and CCL4 and CCL5 levels compared to control nonfailing hearts. Innovation and Conclusion: These data from Nox4-/- mouse model and human heart tissues show for the first time that oxidative stress from increased NOX4 expression has a functional role in ischemic heart failure. One mechanism by which NOX4 contributes to ischemic heart failure is by increasing inflammatory cytokine production via enhanced sEH activity. PMID- 30450924 TI - Using telepresence for social connection: views of older people with dementia, families, and health professionals from a mixed methods pilot study. AB - OBJECTIVES: To explore the acceptability of telepresence robots in dementia care from the perspectives of people with dementia, family carers, and health professionals/trainees, and investigate the utility of a social presence assessment tool, the Modified-Temple Presence Inventory (Modified-TPI), for people with dementia. METHOD: A mixed-methods pilot study conducted in a social robotics laboratory. Three participant groups (n = 22) - dyads of people with dementia and their carers (n = 5 respectively), and health professionals/trainees (n = 12) - participated in individual one-off intervention sessions with the telepresence robot, Giraff, with follow-up interviews. Sessions covered how to use Giraff, followed by interactive practice in making a video-call involving conversation and manoeuvring of Giraff. Participants with dementia experienced receiving a call made by their carer; healthcare professionals/trainees experienced making and receiving a call. Outcomes of interest were sense of presence [Modified-TPI], affective response (International Positive and Negative Affect Schedule [I-PANAS-S]; Observable Displays of Affect Scale [ODAS]), and attitudes and reactions to Giraff (semi-structured interviews). RESULTS: Participants reported a sense of authenticity and social connection through the experience. They indicated positive social presence through Giraff, and significantly higher positive (mean score 18.77; +/-4.00) than negative affect (mean score 8.05; +/-1.76) on the I-PANAS-SF, and on the facial display subscale of the ODAS (positive - mean score 15.50; +/-3.51 versus negative - mean score 4.00; +/-0.00). CONCLUSION: Telepresence has potential use in situations where people with dementia require social connection. Studies with larger sample sizes, varied characteristics, and cost-effectiveness analysis are needed to inform the application of telepresence in healthcare practice. PMID- 30450925 TI - The beta-blocker uptitration in elderly with heart failure regarding biomarker levels: CIBIS-ELD substudy. AB - AIM: We investigated if the baseline value of mid-regional pro-atrial natriuretic peptide (NP), N-terminal pro-B-type NP and copeptin may be helpful in optimizing beta-blocker uptitration in elderly patients with heart failure. PATIENTS & METHODS: According to the biomarkers' levels, 457 patients were divided into three subgroups and compared with each other at baseline and 3 months after. RESULTS: All mid-regional pro-atrial NP and N-terminal pro-B-type NP subgroups had significant amelioration of left ventricle ejection fraction and New York Heart Association (NYHA) class after 3 months of beta-blocker uptitration (p < 0.001). More prominent improvement of left ventricle ejection fraction and New York Heart Association class was observed in subgroups with lower versus higher NPs levels. CONCLUSION: NPs levels, unlike copeptin levels, might be useful tool for objective selection of elderly heart failure patients who could have the greatest benefit of forced uptitration. PMID- 30450926 TI - Mortality risk of loneliness in the oldest old over a 10-year follow-up. AB - OBJECTIVE: To investigate the impact of loneliness on all-cause mortality in the oldest old population over a 10-year follow-up. METHOD: Participants were from the third wave of the Cambridge City over-75s Cohort (CC75C) study, a population based longitudinal study of older people aged 75 or over. Loneliness was measured two further times. At each wave, participants were asked how often they felt lonely and the answers were divided into three levels: not lonely, slightly lonely and lonely. The relationship between loneliness and all-cause mortality was examined using Cox regression with loneliness as a time-varying predictor. The association was adjusted for socio-demographic factors, number of chronic diseases, functional ability and depression. RESULTS: Seven hundred thirteen participants were seen at wave 3 (out of 2166 at baseline), of whom 665 had data on loneliness. The prevalence of feeling slightly lonely and lonely was 16% and 25%, respectively. Vital status was followed for a further 10 years. A total of 562 participants died during the follow-up. After adjusting for age, sex and other socio-demographic factors, loneliness was associated with a 20% increased risk of mortality (HR: 1.2, 95% CI: 1.0-1.6). The association was disappeared after further adjusting for health conditions and depression (HR: 1.0, 95% CI: 0.8-1.4). Individuals who reported being slightly lonely were not at risk of mortality. CONCLUSIONS: The association between loneliness and mortality was fully explained by health conditions, suggesting that in the very old age, health problem is the proximal risk factor for mortality. PMID- 30450927 TI - [Diabetology and solid organ transplantation]. AB - Diabetes increases the risk of different kidney diseases. The most important is diabetic nephropathy, however, ischemic kidney disease, chronic pyleonephritis and papilla necrosis may also develop. The prognosis of diabetic nephropathy has improved recently, however, it is still the primary cause of dialysis and transplantation. Cardiovascular diseases predict mostly mortality in diabetic patients, however, cerebrovascular insults and peripheral obstructive arterial diseases necessitating lower limb amputations are also important. Diabetic retinopathy is almost always present with diabetic nephropathy. Diabetic neuropathy may also develop, furthermore vascular complications often combine. All these urge complex workup, follow-up and early treatment. If transplantation is indicated, preemptive operation should be preferred, and living donation shows the best outcomes. Different forms of carbohydrate disorder may occur after transplantation: new-onset diabetes or diabetes known before transplantation may progress. Renal transplantation with pancreas transplantation may be indicated in type 1 diabetes with end-stage diabetic nephropathy, most often simultaneously. This may result in normoglycemia and insulin-independence and the progression of other complications may also halt. Transplant associated hyperglycemia occurs in most of the patients early, however, it is often transitory. Despite stabilization of the patient and of the immunosuppressive therapy, about one third of the patients may develop posttransplant diabetes. Insulin secretion disorder is the primary cause, but insulin resistance is also needed. Insulin administration may help, however, other antidiabetics can also be useful. Carbohydrate metabolism should be checked in both cadaveric and living donors. The authors make an attempt to summarize the above conditions with Hungarian relevance as well. Orv Hetil. 2018; 159(46): 1930-1939. PMID- 30450928 TI - [Machine perfusion: new opportunities in abdominal organ transplantation]. AB - Machine perfusion of marginal grafts might be a possible solution to organ shortage and a promising tool for reducing waiting list morbidity and mortality. In recent years, optimizing the circumstances of organ preservation prior to implantation via machine perfusion has become a hot topic of research. Machine perfusion offers a platform for organ reconditioning, assessment of cell viability and function, pharmacological preconditioning, prolongation of preservation time (ischemia time) and finally reducing graft injury. The objective of the new technology is to increase the pool of transplantable organs safely. Multicentric prospective studies have been evaluating the short and long term outcomes of different methods, however, several questions still remain unanswered. This review summarizes the recent advances in the field of machine perfusion, focusing on preclinical and clinical results. Machine perfusion seems to be a new milestone in the modern era of solid organ transplantation. Orv Hetil. 2018; 159(46): 1882-1890. PMID- 30450929 TI - [Role of interventional radiology in the transplantation of abdominal solid organs]. AB - The transplantation of the abdominal organs has a major role in the treatment of several diseases. All subspecialities affected with the transplantation showed a rapid development in the last decades. The cooperation of the specialists of different segments of medicine provides the success of organ transplantation. Teamwork is necessary throughout the whole process starting from securing the technical background and proper human workforce, followed by the lifelong management of organs and recipients as well. One of the key players of organ transplantation is radiology and interventional radiology - the role of the latter one is discussed in this review, including the minimally invasive treatment of pre- and post-transplantation situations and diseases. Besides vascular and non-vascular interventions, the options of interventional oncology will be mentioned based on international literature and Hungarian experience. Orv Hetil. 2018; 159(46): 1940-1947. PMID- 30450930 TI - [Examination of attitudes towards transplantation among patients with chronic renal failure]. AB - The patients' attitudes towards kidney transplantation are significantly affected by the acceptance of the treatment to have a better quality of life. Exploration of the cognitive-emotional relation in patients with chronic renal failure. Our study included 285 kidney patients. We investigated three groups of patients: predialysis, dialysis and transplantation patients. In the framework of a pre examination we have created an attitudinal questionnaire (85 items) that can be used to describe the cognitive and emotional attitude of kidney patients towards their illness and to measure scales. Negative attitudes towards transplantation were reported in dialysis and predialysis patients. In contrast, patients who had already undergone surgery were particularly positive about kidney transplantation. Many patients refuse transplantation which correlates with attitudes towards illness and healing. Our results showed that the exploration of the patients' cognitive emotional relation along with the medical diagnosis would have a better adherence towards the kidney substitutional treatment which ensures a better quality of life. Orv Hetil. 2018; 159(46): 1898-1904. PMID- 30450931 TI - [Solid organ transplantation in childhood]. AB - Paediatric organ transplantation today is considered and accepted and widely available therapy in children with end-stage organ failure. It is important to know that in childhood, diseases leading to end-stage organ failure differ from those in adults. Beside this, in children there are different surgical and paediatric challenges before and after transplantation (size differences of the patient and donor organ, special and paediatric infections, different pharmacokinetics and pharmacodynamics of immunosuppressive drugs, noncompliance). However, paediatric organ transplantation in the last decades became a success story of the Hungarian health care owing to several working groups in Hungary and outside the country. Orv Hetil. 2018; 159(46): 1948-1956. PMID- 30450932 TI - [Antibody-mediated rejection: challenge of the treatment in kidney transplantated patients]. AB - Antibody-mediated rejection (ABMR) is one of the factors affecting the long-term graft survival after kidney transplantation (KT). Two kidney transplant centres (University of Debrecen and University of Pecs) followed up their data of cadaveric KTs that had been performed between 2013 and 2017, and reviewed the literature. There were 454 KTs in the mentioned period, 18 cases (4%) were recognised as ABMRs. Biopsy has been performed in all cases. 22% were primary, and 78% retransplanted patients. The average age was 51.2 +/- 6 years. ABMR occurred 15.4 +/- 22.1 months after KT. Histology showed C4d positivity in 39% of the cases. The treatment was steroid bolus + intravenous immunoglobulin (IVIG) + plasma exchange (PE) in 16 cases, rituximab was additionally given in 5 cases. 47.4% of the patients are alive with a functioning graft, four (21%) died, and 31% of the patients had a graft loss due to ABMR. ABMR is a dangerous complication after KT. Diagnostic criteria has been unclear for years. Gold standard is the histology, however, accelerated ABMR may occur even in C4d negative cases. The exposed group includes young, retransplanted patients, having a preformed donor-specific antibody (DSA), and receiving a graft from an EC donor. The occurrence of de novo DSA and the kinetics of mean fluorescence intensity (MFI) of existing ones can be a signal for the risk of an ABMR. The effectiveness of rituximab is not proven, there is a lack of long-term controlled trials for new drugs. Our results of over 40% recovery is an extensively good result. Orv Hetil. 2018; 159(46): 1913-1929. PMID- 30450934 TI - [Miscellaneous]. PMID- 30450933 TI - [Anesthetics and intensive therapeutic aspects of liver transplantation]. AB - One of the most prominent results of our age is organ transplantation, the single treatment option for patients with end-stage organ failure. The success of transplants depends on the donor care, the patient preoperative preassessment, the perioperative care of organ transplantation and aftercare. Successful transplantation therefore requires a prominent level of continuous collaboration between the surgeon, anaesthesiologist, radiologist, internal medicine and hepatologist, laboratory physician and almost all their associates. The complex interdisciplinary approach based on the research results can be used to improve the patient's condition through pharmacotherapy, physiotherapy and psychotherapy during the time spent on waiting lists. The emergence of more active, targeted therapeutic options in perioperative graft resuscitation may help the currently inferior quality transplantable grafts or resuscitation out (machine perfusion) or in the recipient, thereby increasing the number of liver transplants. Deeper knowledge of hemostatic processes, along with the development of surgical techniques, would increase the number of blood transplant free transplants, thus improving the long-term survival of grafts. The present study aims at presenting the anaesthesia and early intensive therapy aspects of liver transplantation from aptitude assessment, through anaesthesia to early intensive therapeutic treatment. Orv Hetil. 2018; 159(46): 1891-1897. PMID- 30450936 TI - [Kidney exchange programmes in Europe. What is the status of Hungary? A summary of the first results of the ENCKEP (European Network for Collaboration on Kidney Exchange Programmes) COST Action]. AB - Patients with end-stage renal disease may exchange their willing, but incompatible donors among each other in centrally coordinated kidney exchange programmes. The aim of this writing is to summarise the results of the ENCKEP COST Action, and describe the lessons learned with regard to the plans for the Hungarian kidney exchange programme. The ENCKEP COST Action had several workshops since 2016 September, and its first working group conducted two surveys that they summarised in two handbooks; our description is based on these resources. There are already 10 national kidney exchange programmes in Europe, the oldest is in the Netherlands (operating since 2004) and the largest in the United Kingdom, where already more than 700 patients received a kidney through this programme in the last ten years. There are a number of countries with plans to start a kidney exchange programme, and international collaborations are also getting established in several regions. Kidney exchange programmes can significantly increase the opportunities of the kidney patients for getting living donor transplants, but for the successful operation of a kidney exchange programme the organisers have to resolve several medical, logistic, optimisation, ethical and legal issues. Orv Hetil. 2018; 159(46): 1905-1912. PMID- 30450935 TI - [The start of the Hungarian lung transplantation program and the first results]. AB - The first lung transplantation in Hungary was performed on 12th of December, 2015. It was a joint effort of the National Institute of Oncology and the Semmelweis University. Hereby we summarise the results and experiences from the first three years. Until August, 2018, 55 lung transplantations were performed in Hungary. This was a retrospective analysis. All patients were listed according to the recommendation of the Lung Transplantation Committee. All implanted lungs have been procured from brain dead donors. Postoperative treatment and rehabilitation of the patients were continued at the Semmelweis University. Between 12. 12. 2015 and 31. 07. 2018, our team performed 76 organ retrievals: out of 45 Hungarian offers, 23 came from Eurotransplant countries and 8 outside of the Eurotransplant region. From these donations, 54 double and 1 single side transplantations were successfully performed. The surgical approach was single side thoracotomy (n = 1), bilateral thoracotomy (n = 1) and in the majority of the cases clamshell incision (n = 53). For the intraoperative veno-arterial extracorporeal membrane oxygenation support was used. The extracorporeal membrane oxygenation support had to be prolonged in 3 patients into the early postoperative period, two other recipients were bridged to transplant with extracorporeal membrane oxygenation. In the same time period, one combined lung kidney transplantation was also performed. The distribution of recipients according to the underlying disease was: chronic obstructive pulmonary disease (n = 28); idiopathic pulmonary fibrosis (n = 8); cystic fibrosis (n = 12); primary pulmonary hypertension (n = 2); hystiocytosis-X (n = 1); bronchiectasis (n = 2); lymphangioleiomyomatosis (n = 1); and re-transplantation following bronchiolitis obliterans syndrome (n = 1), respectively. The mean age of recipients was 47.5 +/ 15.18 years. The youngest recipient was 13 years old. We unfortunately lost 12 patients on our waiting list. The mean intensive care unit stay was 24.6 +/- 18.18 days. Two patients were lost in the early postoperative phase. Tracheostomy was necessary in 13 cases due to the need of prolonged ventilation. 1-year survival of the recipients was 82.96% (until 31. 07. 2018). When looking at the first three years of the program, the case numbers elevated quickly throughout the years which is rather unique when compared to other centres in their starting period. Perioperative mortality and morbidity is comparable with high-volume lung transplantation centres. In the future we would like to increase the number of patients on the waiting list, thus increasing the total number of transplantations performed, and we are also planning to implement the use of the ex vivo lung perfusion system (EVLP) in our program. Orv Hetil. 2018; 159(46): 1859-1868. PMID- 30450937 TI - [Editor's commentary. Current issues of organ transplantation]. PMID- 30450939 TI - [Evolution of the Hungarian adult heart transplantation program]. AB - The authors give a short introduction of the Hungarian and the international history of adult heart transplantation, and highlight the similarities in the evolution of the two programs. Their aim was to show how the Hungarian post transplant survival changed in the last five years. They wanted to investigate how all the changes they had made in the program affected the post-transplant results. They investigated 496 heart transplantation data and compared to international data. Orv Hetil. 2018; 159(46): 1869-1875. PMID- 30450940 TI - Contribution of oxidative stress and impaired biogenesis of pancreatic beta-cells to type 2 diabetes. AB - SIGNIFICANCE: Type 2 diabetes development involves multiple changes in?beta cells, related to the oxidative stress and impaired redox signaling, beginning frequently by sustained overfeeding due to the resulting lipotoxicity and glucotoxicity. Uncovering relations among the dysregulated metabolism, impaired beta-cell "well being", biogenesis, or crosstalk with peripheral insulin resistance is required for elucidation of type 2 diabetes etiology. Recent Advances: It has been recognized that the oxidative stress, lipotoxicity and glucotoxocity cannot be separated from numerous other cell pathology events, such as the attempted compensation of?beta-cell for the increased insulin demand and dynamics of?beta-cell biogenesis and its "reversal" at dedifferentiation, i.e. from the concomitantly decreasing islet?beta-cell mass (also due to transdifferentiation) and low-grade islet or systemic inflammation. CRITICAL ISSUES: At prediabetes, the compensation responses of?beta-cells, attempting to delay the pathology progression - when exaggerated - set a new state, in which a self-checking redox signaling related to the expression of Ins gene expression is impaired. The resulting altered redox signaling, diminished insulin secretion responses to various segretagogues including glucose, may lead to excretion of cytokines or chemokines by?beta-cells or excretion of endosomes. They could substantiate putative stress signals to the periphery. Subsequent changes and lasting glucolipotoxicity promote islet inflammatory responses and further pathology spiral. FUTURE DIRECTIONS: should bring an understanding of the?beta cell selfchecking and related redox signaling, including the putative stress signal to periphery. Strategies to cure/prevent type 2 diabetes could be based on the substitution of the "wrong" signal by the "correct" self-checking signal. PMID- 30450938 TI - [The Semmelweis University extracorporeal membrane oxygenation program - 5 years' results and perspectives]. AB - The mechanical circulatory support (MCS) program of the Semmelweis University Heart and Vascular Centre has become established over the last five years. The main requirements of our MCS program to be developed first were the Heart Transplantation and Heart Failure Intensive Care Unit and a well trained medical team. The wide range of mechanical circulatory support devices provides suitable background for the adequate treatment of our patients in all indications. In this review, we present our results related to extracorporeal membrane oxygenation (ECMO) supports performed in the last five years. Between 2012 and 2017, we applied MCS support in 140 cases, among them 111 patients received ECMO support. The leading indications of ECMO support were the following: primary graft failure after heart transplantation (33 cases), postcardiotomy cardiogenic shock (18 patients), acute decompensation of end-stage heart failure (14 patients), acute myocardial infarction complicated with refractory cardiogenic shock (37 patients), cardiogenic shock developed after transcatheter aortic valve implantation (3 patients), malignant arrhythmia due to drug intoxication (1 patient) and acute respiratory distress syndrome (4 cases). The mortality of patients receiving ECMO support was 46%. The analysis of the results of ECMO support needs to change our approach. The mortality results show that we lost the half of our patients. However, the mortality in the conventionally treated patients would have been 100% without ECMO. In fact, we could save the life of half of these patients. Orv Hetil. 2018; 159(46): 1876-1881. PMID- 30450941 TI - Medialization Laryngoplasty in Pediatric Patients With Unilateral Vocal Fold Immobility: A Case Series. AB - OBJECTIVES:: The aims of this study were to describe the impact of laryngoplasty in pediatric unilateral vocal fold immobility (UVFI) and to determine the impact of etiology and technique on voice and swallowing. METHODS:: A retrospective review was conducted of all children with UVFI undergoing medialization laryngoplasty at a pediatric hospital (2010-2017). Data including demographics, etiology, subjective voice quality, and swallowing function were collected. RESULTS:: The median age at first surgery among 25 patients with UVFI was 11 years (range, 1.2-25 years). The causes of UVFI were iatrogenic (76%), congenital (16%), and idiopathic (8%). A total of 38 laryngoplasties (24 injections, 11 Silastic implants, 3 Gore-Tex) were performed. Postoperatively, 78% of patients reported improvements in voice and 81% in swallowing. The median duration of voice improvement was 1.0 years (range, 0.1-10 years), with no significant difference by etiology or laryngoplasty technique. Patients who were ?10 years of age at surgery reported voice improvement significantly more often than patients <10 years of age at surgery (94% vs 61%, P = .04). CONCLUSIONS:: UVFI has a significant impact on health and quality of life. In this study we found that laryngoplasty is an effective way to address both voice and swallowing in pediatric UVFI. A greater proportion of children with improved voice quality were older at injection. Surprisingly, there was no difference in duration of voice improvement between permanent and absorbable materials. Although this duration would be considered acceptable for many injectable materials, the limited duration in permanent implantation techniques may represent the challenges of managing UVFI in the growing larynx of the pediatric population. Injection laryngoplasty with absorbable materials may serve as an adequate method of addressing UVFI in this population. PMID- 30450942 TI - Oral Vancomycin for Secondary Prophylaxis of Clostridium difficile Infection. AB - OBJECTIVE: To summarize and critically appraise the evidence regarding oral vancomycin prophylaxis (OVP) to prevent recurrent Clostridium difficile infections (RCDIs), identify potential consequences of this emerging practice, and highlight future directions of study. DATA SOURCES: A MEDLINE literature search of English-language publications from 1947 through September 2018 was performed using the search terms vancomycin and C difficile and prophylaxis. Clinical trials were identified on the National Library of Medicine clinical trials registry. STUDY SELECTION AND DATA EXTRACTION: All clinical studies (n = 3) assessing oral vancomycin for secondary prophylaxis of C difficile infection (CDI) were evaluated by all authors. Other search results and references in selected publications were used for background and discussion. DATA SYNTHESIS: OVP reduced the risk of RCDI in high-risk patients taking systemic antibiotics. Variable dosing regimens and lack of safety data are limitations. OVP may have an adverse impact on the gastrointestinal microbiome, but this was not examined in the clinical studies. Relevance to Patient Care and Clinical Practice: Although current studies are limited by methodological concerns, clinicians can consider vancomycin 125 mg orally once or twice daily in high-risk patients receiving broad-spectrum antibacterial agents. Results of ongoing trials will define the most appropriate regimen and its impact on outcomes, including collateral damage. CONCLUSIONS: OVP reduces the risk of RCDIs and should be considered on a case-by case basis. Caution is warranted before routine use is implemented because the impact on long-term outcomes has not been assessed and the optimal regimen has not been defined. PMID- 30450943 TI - ANNALS EXPRESS: Retrospective evaluation of a local protocol used to enhance laboratory savings through minimising the performance of alkaline phosphatase isoenzyme analysis. AB - BACKGROUND: Alkaline phosphatase (ALP) isoenzyme analysis is an expensive and time-consuming laboratory test. We evaluated the effect of a locally-derived screening algorithm for ALP isoenzyme requests on the number of ALP isoenzyme analyses performed, laboratory cost, and patient care. METHOD: 110 ALP isoenzyme analysis requests from the year 2015 were reviewed and subsequent ALP concentrations were monitored over a 2-year period, to determine if the decision of performing/not performing ALP isoenzyme analysis, based on the algorithm, had an impact on patient care and laboratory cost. All ALP isoenzyme analysis requests with 2 consecutive elevated ALP concentrations (>upper limit of reference interval) were screened and, subject to the gamma glutamyl transferase (GGT) being within the reference interval, either Bone ALP or 25 hydroxyvitamin D (25-OHD) was measured depending on the age of the patient. RESULTS: Compliance with this algorithm led to the normalisation of subsequent serum ALP in 97% of patients without requiring ALP isoenzyme analysis. The cost of performing Bone ALP and 25-OHD in-house was L778.50 whilst the cost of performing ALP isoenzyme analysis would have been L3040. This resulted in a laboratory saving of L2261.50. CONCLUSIONS: Implementation of this algorithm led to a significant reduction in ALP isoenzyme analysis, without compromising patient care. Total savings could be increased if 25-OHD was used as a first-line test, for all patients with an elevated ALP and a normal GGT regardless of age. This algorithm is cost-effective and can be implemented in laboratories with 25-OHD assay. Keywords Alkaline phosphatase isoenzyme, Bone-specific alkaline phosphatase (Bone ALP), 25 hydroxyvitamin D (25-OHD), gamma glutamyl transferase (GGT), cost benefit. PMID- 30450944 TI - Factors affecting the will to live among elderly jews living in israel. AB - OBJECTIVES: The aim of this qualitative study was to explore factors that influence older persons' will to live (WTL). METHODS: Twenty-five Israeli elders were interviewed about what weakens and/or strengthens their WTL. Elements of the grounded theory method guided the data collection and analysis. RESULTS: Our analysis revealed that the elements that pertain to WTL could potentially both increase and decrease the WTL in elders. These factors included social networks, financial security, religious faith, working and volunteering, and honor versus ageism. CONCLUSIONS: Five factors represent different aspects of older persons' lives that influence the WTL. The first four themes including Social Networks, Religious Faith, Honor versus Ageism, and Working and Volunteering are consistent with the findings of the study of Blue Zones. Blue Zones are areas characterized by high life expectancy. Israel shares cultural characteristics with the Blue Zones, being a society with traditional collective characteristics stemming from the Jewish tradition. The last theme of financial security is related to the characteristics of Israel as a society in which the social gaps are large and many elderly are pushed to the social margins, and lack financial security. This study points to the unique cultural characteristics of Israel that affect the WTL among elderly Jews and proposes a hypothesis linking Israeli culture to the high life expectancy in Israel. PMID- 30450945 TI - Environment patterns and mental health of older adults in long-term care facilities: the role of activity profiles. AB - OBJECTIVES: This study adopts the International Classification of Functioning, Disability and Health (ICF) model to determine extent to which the clustered patterns of long-term care (LTC) environment and activity participation are associated with older residents' mental health. METHOD: This study enrolled a stratified equal probability sample of 634 older residents in 155 LTC institutions in Taiwan. Latent profile analysis and latent class analysis were conducted to explore the profiles for environment and activity participation. Multilevel modeling was performed to elucidate the hypothesized relationships. RESULTS: Three environment profiles (Low-, Moderate-, and High-Support Environment) based on physical, social, and attitudinal environment domains and two activity profiles (Low- and High-Activity Participation) across seven activity domains were identified. Compared to the Low-Support class, older adults in the Moderate- and High-Support Environment classes had better mental health. Older residents in those two classes were more likely to be in the "High Activity Participation" class, which in turn, exhibited better mental health. CONCLUSION: Environment and activity participation directly relate to older residents' mental health. Activity participation also mediates the link between environment and mental health. A combination of enhanced physical, social, and attitudinal environments, and continual engagement in various activities may optimize older LTC residents' mental health. PMID- 30450946 TI - Frailty, multimorbidity and functional status as predictors for health outcomes of acute psychiatric hospitalisation in older adults. AB - OBJECTIVES: Frailty, multimorbidity and functional decline predict adverse health outcomes in community dwelling older people and older patients in general hospitals. This study investigates whether these characteristics separately are independent predictors of health outcomes of acute psychiatric hospitalization. METHODS: Observational study in a prospectively sampled cohort of older patients, consecutively admitted to a psychiatric hospital. On admission we assessed frailty (Frailty Index and walking speed); multimorbidity (Cumulative Index Rating Scale Geriatrics (CIRS-G)) and functional status (Barthel Index). We used the Clinical Global Impressions of Improvement scale (CGI-I) as the psychiatric outcome measure, and dichotomized discharge destination as overall outcome measure: favourable (able to return home or previous care level) or adverse (death, or move to higher level of residential care). RESULTS: We included 120 patients, 74.6 years (+/-7.8). 52.5% of the patients was frail (FI >=0.25). The mean level of the CIRS-G was 13.5 (5.4). Mean CGI-I at discharge was 2.8 (+/- 1.0), indicating moderate improvement in the psychiatric outcome. Neither FI, CIRS-G, nor Barthel scores were, independent of age, sex and diagnosis, associated with the CGI-I. FI was predictive for adverse discharge destination (OR 1.91, 95%CI 1.09-3.37 per 0.1), as were higher CIRS-G (OR 1.19 95%CI 1.06 1.34, per point) and lower walking speed (OR 1.35 95%CI 1.06-1.72 per 0.1 m/s). CONCLUSIONS: Half of our patients were frail and had a high level of multimorbidity. The FI, walking speed and multimorbidity did not predict improvement of psychiatric symptoms at discharge, but independently helped to predict adverse discharge destination. PMID- 30450947 TI - Characterizing functional alterations in instrumental activities of daily living using latent class analysis: a population-based study (NEDICES). AB - BACKGROUND AND OBJECTIVES: The existence of different patterns of functional impairment in older adults has scarcely been addressed. This research investigates major patterns of functional impairment based on Pfeffer's Functional Activity Questionnaire (FAQ). RESEARCH DESIGN AND METHODS: The participants come from NEDICES (Neurological Disorders in Central Spain), a prospective population-based cohort study. A total of 3837 individuals without dementia who completed the Spanish version of the FAQ was selected. Latent Class Analysis (LCA) was carried out to examine potential cluster subgroups based on FAQ responses. RESULTS: The FAQ showed good internal consistency (Cronbach's alpha: 0.86) and moderate correlation (r = -.40) with cognitive performance on the Mini-Mental State Examination (MMSE-37). The response patterns revealed the presence of three latent classes: absence of functional alteration (Class 1), established functional alteration (Class 2), and minimal functional alteration (Class 3). Moreover, the probability of resolving Items 2 ('shopping alone for...'), 3 ('heating water...'), 4 ('preparing a balanced meal'), and 9 ('travelling out of neighbourhood...') was close to 0% for Class 2 membership, while those with the lowest probability of resolution for Class 3 were Items 2 and 9. Items 3 and 4 were the best to discriminate between different grades of functional alterations (Class 2 vs. Class 3). Discussion and Implications: Our findings indicate that the combination of overall FAQ score and item response pattern may help to classify individuals with different subtypes of functional impairment. The Spanish version of the FAQ is a useful tool for detection of functional impairment in older adults. PMID- 30450948 TI - Reciprocal relationships between the will-to-live and successful aging. AB - OBJECTIVES: The search for concomitants and predictors of successful aging is of theoretical and practical importance. In this study, we assessed the reciprocal relationships between the will-to-live (WTL) and both objective and subjective successful aging (SA) among older adults. METHODS: Interviews were conducted with 1,216 randomly selected persons aged 75+ years (T1) and repeated with 1,019 of these participants one year later (T2). At each session, we collected data on WTL, subjective SA, and objective SA (medical conditions, disability, pain symptoms), and demographics. Using SEM techniques, we examined cross-lagged autoregressive relationships between WTL and both objective and subjective SA. RESULTS: Significant reciprocal relationships were found among WTL, objective SA, and subjective SA. Higher WTL at T1 predicted higher objective and subjective SA at T2 (i.e., fewer medical conditions, less disability, less pain symptoms and higher ratings of subjective SA). Higher objective and subjective SA at T1 predicted higher WTL at T2. Comparison of the bidirectional temporal relationship between WTL and SA showed that the effect of WTL on objective SA was as strong as the reverse effect, but the influence of WTL on subjective SA was stronger than the reverse effect. Finally, objective SA at T1 predicted subjective SA at T2, but the reverse effect was not significant. CONCLUSION: WTL is an important precursor for both objective and subjective SA. It may also be maintained and further strengthened by successful aging. Policy makers and practitioners should consider WTL in their efforts to help older adults enhance and preserve SA. PMID- 30450949 TI - Joining forces to improve psychosocial care for people with cognitive deficits across diagnoses: social health as a common framework. AB - Cognitive deficits such as memory problems have a major impact on independence in daily life and participation in society in several populations, such as people with dementia, brain injury (i.e. stroke) or a severe mental illness such as schizophrenia. Similarities in the impact on participation and well-being have resulted in the development of comparable psychosocial interventions across populations, aiming to support people to adapt to cognitive deficits or by adapting the environment. These interventions are developed separately, without using the expertise in other fields. We argue that each of the fields and the field of psychosocial care in general would benefit from closer collaboration on development and evaluation of innovative psychosocial interventions. Collaboration has been complicated by the use of different care models and theoretical frameworks, each with their own terminology. The concept of social health - the ability to participate in work or other meaningful activities and to feel healthy despite a condition - translates to the leading care models within the fields of dementia, brain injury and severe mental illness. The concept of social health provides a common language and framework. In this paper, we elaborate on strategies for collaboration using examples of interventions to improve social health. PMID- 30450950 TI - Depressive symptoms and time perspective in older adults: associations beyond personality and negative life events. AB - OBJECTIVES: To examine the extent to which time perspective, an individual's habitual way of relating to the past, the present, and the future time frames, accounts for variations in self-reported depressive symptoms among older adults. METHOD: Four hundred two participants (60-90 years) completed the Center for Epidemiological Studies Depression scale (CES-D) and the Swedish Zimbardo Time perspective Inventory (S-ZTPI). The influence of personality as reflected by the Temperament and Character Inventory (TCI) and self-reported negative life events (NLEs) were controlled for in hierarchic regression analyses. RESULTS: The six S ZTPI dimensions accounted for 24.5% of the variance in CES-D scores beyond age and gender. Half of the variance remained when the TCI factors and NLEs were controlled for. Past Negative, Future Negative, and Past Positive (inverse association) were the significant unique predictors. Significant age interactions were observed for two S-ZTPI dimensions, with a diminished association to depressive symptoms for Future Negative and a magnified association for Present Fatalistic with higher age. CONCLUSIONS: The results demonstrate a substantial relation between facets of time perspective and depressive symptoms in old age. They also indicate an age-related shift in the relative importance from concerns about of the future (Future Negative) to the present (Present Fatalistic) with increased age. In young old-age, when the future is more 'open', future worries (Future Negative) may be a more frequent source of distress. In late senescence, perceived threats to autonomy (e.g. physical health problems and cognitive deficits), as reflected by higher scores on Present Fatalistic, may instead have more bearing on mood state. PMID- 30450951 TI - Integrated Pediatric Health Care in Pennsylvania: A Survey of Primary Care and Behavioral Health Providers. AB - This study reports on a statewide survey of medical and behavioral health professionals to advance the knowledge base on the benefits and obstacles to delivering integrated pediatric health care. Surveys distributed in 3 statewide provider networks were completed by 110 behavioral health specialists (BHSs) and 111 primary care physicians (PCPs). Survey content documented their perceptions about key services, benefits, barriers, and needed opportunities related to integrated care. Factor analyses identified 8 factors, and other items were examined individually. We compared responses by specialty group (BHS vs PCP) and integrated care experience (no vs yes). The findings revealed differences across domains by specialty subgroup. In several cases, BHS (vs PCP) respondents, especially those with integrated care experience, reported lower benefits, higher barriers, and fewer resource requests. The implications of these results for enhancing care integration development, delivery, training, and research are discussed along with the study's limitations and empirical literature. PMID- 30450952 TI - Neuropsychological consequences of chronic stress: the case of informal caregivers. AB - INTRODUCTION: Caring for a family member with a long-term illness is a significant source of chronic stress that might significantly accelerate the cognitive ageing of informal caregivers. Nevertheless, the absence of a defined theoretical body of literature on the neuropsychology of this population makes it difficult to understand what the characteristic neuropsychological deficits of these caregivers are. AIMS: The main aim of this study is to carry out a systematic review of studies of cognitive deficits present in informal caregivers of people with several chronic pathologies, and analyse the effects of cognitive behavioural interventions on caregivers' cognition. METHODS: The scientific literature was reviewed following the PRISMA quality criteria for reviews using the following digital databases: PubMEd, PsycINFO, and Dialnet. RESULTS: Identification of 2046 abstracts and retrieval of 211 full texts led to the inclusion of 38 papers. The studies showed heterogeneous results, but most of the cross-sectional studies reviewed that employed neuropsychological assessments concluded that informal caregivers reported a generalized cognitive deterioration, especially memory dysfunctions (i.e. learning verbal, visuospatial, and digit information). Moreover, they also presented low selective attention and capacity for inhibition, along with slow processing speed. Longitudinal studies confirmed that caregivers whose care situation was more prolonged showed a marked deterioration in their overall cognitive state, memory, processing speed, and vocabulary richness. However, although the patient's death does not seem to reverse the neuropsychological alterations in caregivers, cognitive-behavioural interventions that employ techniques to reduce stress levels, cognitive biases, and inadequate adaptation schemas seem to improve some of the aforementioned cognitive abilities. CONCLUSIONS: Results from this synthesis and critical analysis of neuropsychological deficits in informal caregivers offer guidelines for diagnosing caregivers' cognitive status by including a test battery covering all the domains considered relevant. Finally, given the ability of cognitive behavioural interventions to improve cognition in caregivers, further studies on their long-term effects on caregivers are warranted. Chronic stress entails an acceleration of the cognitive ageing Cross sectional studies concluded that informal caregivers reported a generalized cognitive deterioration Cognitive-behavioural interventions seem to improve cognitive abilities of caregivers. PMID- 30450953 TI - Identification of airborne pollen allergens from two avenue trees of India. AB - An attempt has been made to detect airborne pollen of Lagerstroemia speciosa (LS) and Spathodea campanulata (SC) - two common avenue trees of India as potential sources of aeroallergens and also to identify the major IgE-reactive components present in them. The airborne pollen concentration was assessed using a Burkard sampler. A detailed questionnaire on clinical data of 1490 patients was recorded based on hospital data. We assessed the allergenicity of pollen by in vivo and in vitro tests. The correlation among meteorological factors, pollen seasons and allergenic potency of patients was assessed by multiple regression analysis. The sensitivity of patients to pollen antigens was highly correlated with pollen seasons. In SDS-PAGE, 15 protein bands were detected from LS pollen, while 14 bands from SC. The IgE-specific immunoblotting with patients' sera allergic to LS displayed five major allergens, while four major allergens were detected from SC. This would be the first report from India to prove the allergenic potentiality of airborne pollen of these two common avenue trees of India. PMID- 30450954 TI - Poor sleep quality of third trimester exacerbates the risk of experiencing postnatal depression. AB - This study sought to investigate the effects of subjectively-determined poor prenatal sleep quality on postnatal depression (PND), after adjusting for prenatal psychological distress and perceived stress. From March 2016 to December 2017, we conducted a prospective longitudinal study using a convenience sample of 228 perinatal women. The participants completed the Pittsburgh Sleep Quality Index (PSQI), the 10-item Kessler Psychological Distress Scale (K10) and the Perceived Stress Scale (PSS) during the third trimester (Time 1 or T1), and completed the Edinburgh Postnatal Depression Scale (EPDS) at 1 months postpartum (Time 2 or T2). Logistic regression analyses were used to analyze the associations between subjective prenatal sleep quality and postnatal depression. The results showed that prenatal psychological distress (OR = 2.551, 95% CI = 1.221 ~ 5.329, P = 0.013) and perceived stress (OR = 2.881, 95% CI = 1.398 ~ 5.938, P= 0.007) were the strongest predictors of PND. Independent of this, poor subjective sleep quality (OR = 2.391, 95% CI = 1.072 ~ 5.556, P = 0.044) during pregnancy also predicted postnatal depressive symptoms. Treatment of psychological distress and perceived stress appears important for reducing the incidence of PND. Nonetheless, future studies might explore treatments to improve prenatal sleep quality. PMID- 30450955 TI - Impact of a goal-directed fluid therapy on length of hospital stay and costs of hepatobiliarypancreatic surgery: a prospective observational study. AB - AIM: The effectiveness of goal-directed fluid therapy (GDFT) algorithms in improving postoperative outcomes has extensively been suggested. Nevertheless, there is a lack of strong evidence regarding both the clinical impact and the cost-effectiveness of the GDFT protocols. The aim of this study is to evaluate the costs of patients undergoing hepatobiliopancreatic surgery when a GDFT protocol is applied. Materials & methods: Consecutive ASA I-III patients undergoing hepatobiliopancreatic surgery were included in this prospective observational study. Depending on device availability, patients were handled either by fluid therapy guided by Vigileo monitor-derived hemodynamic variables (Vigileo-GDFT group) or by standard fluid treatment (standard group). Postoperative length of stay and economic costs were analyzed. RESULTS: In total, 147 patients were included (71 in the Vigileo-GDFT group and 76 in the standard group). The total hospital length of stay was 13 (median, 1st-3rd quartile, 9-20) days for the Vigileo-GDFT group and 14 (8-21) days for the standard group (p = 0.58); no statistically significant differences between the two groups emerged regarding costs and postoperative complications. In both groups, complications were the main contributor to total cost sustained. CONCLUSION: The application of a GDFT algorithm did not reduced the total length of hospital stay and the global costs, which were mainly influenced by the number of complications. PMID- 30450956 TI - Neonatal intensive care unit admission and maternal postpartum depression. AB - OBJECTIVE: This study aimed to examine the impact of newborns' Neonatal Intensive Care Unit (NICU) admittance on maternal postpartum depression. BACKGROUND: Prior research on the parental psychological impacts of a NICU admittance typically includes a hospital sample of parents following birth, so the causality of NICU admittance and maternal depressive symptomatology is unclear. METHODS: 127 women across 38 counties in a South Central US state participated in online surveys in their third trimester and approximately six weeks post-birth in 2016. Pre- and post-birth assessments of depression were measured with the Center for Epidemiologic Studies Depression Scale (CES-D). NICU admittance was asked in the post-birth survey. t-Tests and multivariable regression analyses were used to determine predictors of NICU admittance and postnatal depressive symptomatology. RESULTS: Findings indicate that prenatal depression does not differ significantly between mothers by NICU admission status, but NICU admission is a significant predictor of postpartum depressive symptomatology. CONCLUSIONS: Having a newborn admitted to the NICU is a risk factor for maternal postpartum depression. These findings have implications for practice; screening mothers in the NICU for depression as a target for intervention has the potential to improve maternal well-being, which in turn should enhance subsequent infant developmental outcomes. PMID- 30450957 TI - Image-based multi-scale mechanical analysis of strain amplification in neurons embedded in collagen gel. AB - A general multi-scale strategy is presented for modeling the mechanical environment of a group of neurons that were embedded within a collagenous matrix. The results of the multi-scale simulation are used to estimate the local strains that arise in neurons when the extracellular matrix is deformed. The distribution of local strains was found to depend strongly on the configuration of the embedded neurons relative to the loading direction, reflecting the anisotropic mechanical behavior of the neurons. More importantly, the applied strain on the surrounding extracellular matrix is amplified in the neurons for all loading configurations that are considered. In the most severe case, the applied strain is amplified by at least a factor of 2 in 10% of the neurons' volume. The approach presented in this paper provides an extension to the capability of past methods by enabling the realistic representation of complex cell geometry into a multi-scale framework. The simulation results for the embedded neurons provide local strain information that is not accessible by current experimental techniques. PMID- 30450958 TI - Antioxidant activity optimization and GC-MS profile of aqueous extracts of Vernonanthura patens (Kunth) H. Rob. leaves. AB - The temperature and extraction time of aqueous extracts of Vernonanthura patens (Kunth) H. Rob. (AEVP) leaves obtained by decoction were optimized for maximum recovery of DPPH radical scavenging activity, ABTS+ inhibition activity, total phenolic content (TPC) and total flavonoids content (TFC) using response surface methodology (RSM). A central composite design (CCD) of 13 experimental runs was applied and second order polynomial models were used to describe the responses of the assessed extraction parameters. The optimized conditions: 79.79 degrees C and 126.23 minutes were found using the composite desirability function. The scavenging activity of assessed extracts could be correlated mostly to the presence of malic acid, succinic acid, alpha-ketoglutaric acid, citric acid, m hydroxybenzoic acid, caffeic acid, inositol, and beta-amyrin detected by gas chromatography-mass spectrometry (GC-MS). These results have not been reported and support the potential application of AEVP as natural source of antioxidants. PMID- 30450959 TI - Two new sesquiterpenes produced by the endophytic fungus Aspergillus fumigatus from Ligusticum wallichii. AB - Two previously undescribed sesquiterpenes along with nine known compounds were isolated from the fermentation broth of Aspergillus fumigatus, an endophyte of Ligusticum wallichii. Their structures were elucidated through extensive spectroscopic analysis combined with quantum chemical ECD calculations. Two new compounds exhibited moderate growth inhibition against MV4-11 and MDA-MB-231 cell lines. [Formula: see text]. PMID- 30450960 TI - A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia. AB - AIM: To evaluate the comparative efficacy and safety of gemtuzumab ozogamicin + daunorubicin-cytarabine (GO + DA) versus common induction therapies for newly diagnosed acute myeloid leukemia. Materials & methods: A network meta-analysis following a systematic literature review. RESULTS: In base-case analyses, GO + DA was associated with significantly greater overall survival and relapse-free survival versus most comparators, and similar rates of complete remission versus all evaluated comparators. Similar findings were seen in the subgroup analyses. Grade 3+ bleeding and hepatic events were higher with GO + DA versus some comparators, consistent with GO's profile. No differences were found for other evaluated outcomes. CONCLUSION: GO + DA provides significant overall survival and relapse-free survival benefit versus evaluated induction regimens for newly diagnosed acute myeloid leukemia. PMID- 30450961 TI - Two new prenylated C6-C3 compounds from Illicium micranthum Dunn. AB - Phytochemical investigation of Illicium micranthum led to the isolation of two new prenylated C6-C3 compounds, 12-O-methyl-2,3-dehydroillifunone C (1) and illiciminone A (2), together with three known analogues (3-5) and one known sesquiterpene lactone (6). The structures were established by extensive spectroscopic characterization and the reported data. All the isolates were evaluated for their acetylcholinesterase (AChE) inhibition activity. Compound 5 showed weak inhibitory activity (46.0%) at 50 MUM concentration. PMID- 30450962 TI - Minor acetylated metabolites from Euphrasia rostkoviana. AB - The phenylethanoids rostkovianoside, 6'-O-acetylcrassifolioside and the flavonoid rutin 3'''-acetate, were isolated from the methanolic extract of the aerial parts of Euphrasia rostkoviana Hayne. The structures of these previously undescribed compounds were elucidated by interpretation of spectroscopic data. The acetylation of rutin was also carried out and four ester derivatives were spectroscopically characterized. Finally, a chromatographic method was established to easily identify the acetylated position. PMID- 30450963 TI - Crowd Sourced Assessment of Ureteroscopy with Laser Lithotripsy video feed does not correlate with Trainee Experience. AB - OBJECTIVES: We sought to validate the use of crowd sourced surgical video evaluation in the evaluation of flexible ureteroscopic laser lithotripsy videos using a modified global assessment scale previously validated for ureteroscopic skills. METHODS: We collected video feeds from 30 intra-renal ureteroscopic laser lithotripsy cases where residents post graduate year(PGY) 2 through 6 handled the ureteroscope. The video feeds were annotated to represent the overall performance and to contain the parts of the procedure being scored. The videos were submitted to a commercially available surgical video evaluation platform. We used a validated ureteroscopic laser lithotripsy global assessment tool that was modified to account for the fact that this scoring system looked at the video feed only. Videos were evaluated by crowd workers recruited using Amazon's Mechanical Turk as well as 5 Endourology trained experts. Mean scores were calculated and intraclass correlation coefficients(ICCs) were computed for the expert domain and total scores. The ICCs were estimated using a linear mixed effects model. Spearman rank correlation coefficients were calculated as a measure of the strength of the relationships between the crowd mean and the expert average scores. RESULTS: 30 videos were reviewed 2,488 times by 487 crowd workers and five expert endourologists. ICCs between expert raters were all below accepted levels of correlation(0.30) with the overall score having an ICC of .000. Overall the crowd scores did not correlate with expert scores except for the stone retrieval domain (0.60 p = 0.015). Crowd sourced scores had a negative correlation with PGY level(-0.44 p=0.019). CONCLUSIONS: Given the poor agreement between experts and poor correlation between expert and crowd scores when evaluating video feeds of ureteroscopic laser lithotripsy, assessment of skills using intraoperative video feeds may not be reliable. This is further supported by the inverse correlation between crowd scores and PGY level. PMID- 30450964 TI - A new indole alkaloid from Cimicifuga heracleifolia. AB - A new alkaloid, (E)-3-(3-methyl-1-oxo-2-butenyl)-6-methoxy-1H-indole (1), along with two known ones, was isolated from the aerial parts of Cimicifuga heracleifolia. The structure of 1 was elucidated on the basis of extensive spectroscopic data analysis. The structures of known compounds were determined by comparison with the literature data. PMID- 30450965 TI - A novel acylated quercetin glycoside and compounds of inhibitory effects on alpha glucosidase from Panax ginseng flower buds. AB - A novel acylated quercetin glycoside, floralpanasenoside A (1) and five known flavonoid glycosides, panasenoside (2), quercetin 3-O-(2''-beta-D-glucopyranosyl) beta-D- galactopyranoside (3), trifolin (4) kaempferol 7-O-alpha-L-rhamnoside (5), and afzelin (6) were isolated from the flower buds of Panax ginseng. Their structures were established by spectroscopic data and comparison with the literature values. Four of the six isolated compounds including 1 (IC50 = 62.4) exhibited alpha-glucosidase inhibitory activity with IC50 values lower than acarbose (385.2 MUM). The molecular docking study indicated that 1 bound to the active site of alpha-glucosidase with numerous hydrogen bond interactions. PMID- 30450966 TI - Determination of indole-type phytonutrients in cruciferous vegetables. AB - Consumption of cruciferous vegetables has been associated with a low risk of developing cancer. Indole-type phytonutrients, derived from enzymatic hydrolysis of glucobrassicin, exhibit cancer-preventive properties and occur in all vegetables of the Brassicaceae family. A LC-Q-TOF-MS methodology was developed and applied in extracts from seven cruciferous vegetables allowing the rapid determination of indole-3-carbinol, indole-3-carbaldehyde, ascorbigen, indole-3 acetic acid and indole-3-acetonitrile. The novel method described herein, was validated and is characterized by low detection limits and excellent linearity. The simultaneous determination of indole-type phytonutrients in turnip and radish was performed for the first time. PMID- 30450967 TI - Coprinus comatus filtrate extract, a novel neuroprotective agent of natural origin. AB - In vitro acetylholinesterase (AChE) inhibitory activity of an autochthonous sample of the mushroom Coprinus comatus (encompassing fruiting body FB, mycelia M and filtrate F from the submerged cultivation) was the subject of this study. C. comatus F extract exhibited rather potent anti-AChE activity (73.0 +/- 1.5%) at in liquid conditions, comparable to those of the conventional drug donepezil (80.6 +/- 1.4%). Also, the same extract exhibited high anti-AChE activity (1 ug) in solid. While its FTIR spectrum indicated the presence of phenolic compounds, quercetin (28.1 ug g-1 d.w.) was found to affect the observed bioactivity (59.8 +/- 0.9%). This is the first report of profound anti-AChE activity of any C. comatus extract, a medicinal mushroom that has been successfully cultivated in P.R. China, due to the demanding needs of food industry. PMID- 30450968 TI - Neocucurbitacin D, a novel lactone-type norcucurbitacin as xanthine oxidase inhibitor from Herpetospermum pedunculosum. AB - A novel lactone-type norcucurbitacin, designated as neocucurbitacin D (1), together with five known cucurbitane triterpenes were isolated from traditional Tibetan medicine "Se Ji Mei Duo", which is the seed of Herpetospermum pedunculosum (Ser.) C.B. Clarke. The structure of neocucurbitacin D was elucidated by spectroscopic analysis, including 2D NMR and X-ray techniques. Compounds 1-6 were screened for their xanthine oxidase (XOD) inhibitory activity. Compound 1, 2 and 4 exhibited significant XOD inhibition with IC50 values ranging from 10.16 to 18.41 MUM. The absolute stereochemistry and XOD inhibitiory activity of lactone-type norcucurbitacins was reported firstly. PMID- 30450969 TI - A Unique Case of Sudden Cardiac Death in an Infant. PMID- 30450971 TI - Two new dammarane triterpenes isolated from Cleome khorassanica Bunge & Bien with cytotoxicity against DU-145 and LNCaP prostate cancer cell lines. AB - From the aerial parts of Cleome khorassanica Bunge & Bien, a new 3-oxo-4-oxa-A homo-25,26,27-trinordammarano-24,20-lactone triterpene (1), a new natural product 20,25-dihydroxy-3-oxodammarane triterpene (2), together with known 5-hydroxy 3,6,7,8,3',4',5'-heptamethoxyflavone (3), have been isolated and characterized. The chemical structure of the new compounds was determined by 1D and 2D NMR and HR tandem MS measurements. All three compounds were subjected to biological tests for evaluation of their cytotoxicity against prostate (DU-145 and LNCaP) cancer cells. Compounds 1, 2, and 3 showed cell growth inhibition in a dose dependent manner against DU-145 and LNCaP cells. PMID- 30450970 TI - Hsp90beta inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy. AB - The loss of glutamate transporter-1 (GLT-1) is associated with temporal lobe epilepsy (TLE). A recent study reported that Hsp90beta interacted with GLT-1 and recruited it to 20S proteasome for degradation. Therefore, inhibiting Hsp90beta may be a new strategy for treating epilepsy. So far, no studies have shown whether the inhibition of Hsp90beta had therapeutic effects on absence epilepsy. Using a model of absence epilepsy, we demonstrated that 17-allylamino-17 demethoxygeldanamycin (17AAG) and Ganetespib (STA9090) had no therapeutic effect. Although this is a negative result, it also has a meaningful exploration value for whether Hsp90 inhibitors have therapeutic effects on other epilepsy types. PMID- 30450973 TI - A new dihydrophenanthrene from Cymbidium finlaysonianum and structure revision of cymbinodin-A. AB - 1-(4-Hydroxybenzyl)-4,6-dimethoxy-9,10-dihydrophenanthrene-2,7-diol (13), a new dihydrophenanthrene, was isolated along with ferulic acid esters (1), eight phenanthrene derivatives (2, 3, 6-11) and three bibenzyls (4, 5, 12) from an epiphytic orchid, Cymbidium finlaysonianum. The molecular structure of cymbinodin A (2) was revised based on spectroscopic data and comparison with the literature. Compounds 2, 3, and 6-13 were evaluated and shown to be cytotoxic against human small cell lung cancer (NCI-H187) cell line. Cymbinodin-A displayed the highest cytotoxicity with an IC50 value of 3.73 uM. PMID- 30450972 TI - Is dry heat treatment (fluidotherapy) effective in improving hand function in patients with rheumatoid arthritis? A randomized controlled trial. AB - OBJECTIVE:: To evaluate the efficacy of dry heat treatment (fluidotherapy) in improving hand function in patients with rheumatoid arthritis. DESIGN:: Prospective randomized controlled trial. SETTING:: Departments of Physical Medicine and Rehabilitation and Rheumatology in a university hospital. SUBJECTS:: Patients with rheumatoid arthritis. INTERVENTIONS:: All patients were randomly divided into two groups. Group 1 underwent dry heat treatment (fluidotherapy) and Group 2 was a control group. Patients in both groups participated in a joint protection and exercise program. MAIN MEASURES:: Primary outcome measures were Health Assessment Questionnaire and Duruoz Hand Index. Secondary outcome measures were pain and stiffness, Grip Ability Test, Disease Activity Score-28, and grip strength. These assessments were performed at the hospital at baseline, week 3, and week 12. RESULTS:: A total of 93 participants were allocated to Group 1 ( n = 47) and Group 2 ( n = 46). The mean age of these groups was 54.19 +/- 11.15 years and 53.00 +/- 10.15 years, respectively ( P = 0.592). At baseline, there were no significant differences between the groups in any parameter except significantly poorer Health Assessment Questionnaire score in Group 1 ( P = 0.007). At week 3, there were no significant differences between the groups in any of the parameters ( P > 0.005). At week 12, Duruoz Hand Index scores were significantly better in Group 2 ( P = 0.039). CONCLUSION:: Dry heat treatment (fluidotherapy) was not effective in improving hand function in patients with rheumatoid arthritis. Moreover, no positive effect on any other clinical parameters was observed. PMID- 30450974 TI - The surgical anxiety questionnaire (SAQ): development and validation. AB - OBJECTIVE: Preoperative anxiety is often assessed using general anxiety measures; existing specific measures might lack content coverage and/or are not psychometrically validated. This study aimed to develop a new self-report measure of surgery-specific anxiety and test its psychometric properties. DESIGN: The surgical anxiety questionnaire (SAQ) was developed from themes identified in qualitative research and reviewed by an interdisciplinary expert team. It was administered preoperatively to 135 patients (56% female, mean age 51) on the day of surgery alongside additional measures of preoperative anxiety, state anxiety, perceived stress, depression and social desirability. Follow-up assessment was conducted immediately post-surgery and two weeks post-surgery (n = 114) to examine recovery and predictive validity of the scale. RESULTS: Factor analysis revealed a three component structure, including: concerns about health (six items), concerns about recovery (four items) and concerns about procedures (four items). Three additional items of relatively high concern were retained in the total score (17 items). The SAQ displayed good reliability, validity (content, construct and predictive) and adequate overall psychometric properties. CONCLUSIONS: Preliminary results suggest that the SAQ is a promising tool for measuring preoperative anxiety and predicting recovery. Recommendations for future research include employing a confirmatory factor analysis and examining test-retest reliability. PMID- 30450975 TI - Is single-anaesthetic bilateral total hip replacement using cemented stems safe and appropriate? A review of four decades of practice. AB - BACKGROUND:: Symptomatic bilateral hip osteoarthritis can be treated surgically with either staged or single-anaesthetic bilateral total hip replacement (BTHR). Today the typical candidate for BTHR is more likely to receive cementless implants. We present the experience of BTHR at our institution using cemented stems combined with cemented and uncemented sockets and, to our knowledge, the largest prospective single-centre series. PATIENTS AND METHODS:: This cohort study reviews all patients (319 patients: 638 hips) having BTHR at our institution between December 1977 and December 2015. No case was lost to follow up. Data were collected prospectively but reviewed retrospectively. Length of stay and complication rates were included, and data were compared with Hospital Episode Statistics figures for operations carried out between March 2005 and June 2014 to confirm local database validity. Patient experience and Oxford Hip Scores were obtained for a subgroup of this cohort, comparing them with patients who underwent bilateral staged operations performed within 1 year. RESULTS:: The rates for mortality, deep vein thrombosis, non-fatal myocardial infarction within 6 months were each 0.3% (1 episode) and non-fatal pulmonary embolism 0.6% (2 episodes). There were no intraoperative periprosthetic fractures or readmissions within 30 days. CONCLUSIONS:: Our study shows a low risk of complications when using cemented and hybrid BTHRs for selected patients and the risk of complications compares favourably with published results. Available functional scores compared favourably to a comparison group of patients undergoing bilateral staged procedures, and a positive impression on treatment experience from a subgroup of interviewed BTHR patients was noticeable. PMID- 30450976 TI - Association Between Serum C-Reactive Protein Concentration and Nutritional Status of Malignant Tumor Patients. AB - BACKGROUND: The level of the systemic inflammatory marker C-reactive protein (CRP) is elevated in many patients with malignant disease and may be related to nutritional status. OBJECTIVE: To analyze the association between serum CRP levels in patients with malignant tumors and their nutritional status. METHOD: A total of 3,692 cases were analyzed and the serum CRP levels were determined using an immunometric assay. Nutritional status was assessed by using patient-generated subjective global assessment (PG-SGA). The biochemical evaluation of prealbumin (PA), albumin (ALB), cholesterol (CHOL), and triglycerides (TG) were assayed within 48 h admission to the hospital. The association between serum CRP concentration and the nutritional status, the stage of the tumor and other factors was analyzed by univariate and multivariate logistic regression analysis. RESULT: Elevated serum CRP was observed in 47.6% (1,548/3,269) of patients compared with the reference value, and the median CRP concentration was 18.29 mg/l. Patient serum CRP concentrations in the malnourished group (PG-SGA B + C) were higher than in the well-nourished (PG-SGA A) patients (P < 0.05). The serum CRP level was related to the patients' age, gender, tumor stage, and was affected by hepatitis, liver cirrhosis, diabetes, but it has no effect on hypertension. The CRP high patients had lower PA and ALB levels, lower Karnofsky performance status scores, and higher PG-SGA scores (P < 0.05), and there was no relationship with CHOL and TG levels. Weight loss in the previous 1 mo was seen with CRP positive patients (P < 0.05). CONCLUSION: Almost 50% of malignant tumor patients had elevated serum CRP levels indicating a systemic inflammatory state. The nutritional status was worse in cancer patients with higher concentrations of serum CRP. The level of CRP was associated with the tumor stage, and, as stage is a prognostic factor, so can CRP be used as a prognostic maker in malignant tumors patients. PMID- 30450977 TI - How does education lead to healthier behaviours? Testing the mediational roles of perceived control, health literacy and social support. AB - OBJECTIVES: Educational attainment is increasingly recognised as a unique dimension of socioeconomic status (SES) and a powerful determinant of health behaviour-and thus physical health and mortality. However, very little is known about the specific pathways through which education influences these health behaviours. DESIGN: The present study used a nationally representative US survey to test three potential psychosocial pathways (perceived control, health literacy and social support) through which education might influence intake of fruits and vegetables (FV), physical activity (PA) and sedentary behaviour (SB), controlling for other aspects of SES (income, health insurance status) and demographics (age, gender, race/ethnicity). RESULTS: Both aspects of perceived control (locus of control, cancer fatalism) mediated the impact of education on FV and PA while only locus of control mediated the impact of education on SB. Further, only one aspect of health literacy (ability to understand recommendations) mediated education's effect on any health behaviour (FV). Social support did not mediate any of the effects of education on health behaviors. CONCLUSION: Future work explicitly assessing and testing these mediational pathways is needed to better understand how education influences people's health behaviours throughout their lives. PMID- 30450978 TI - Antioxidative protection of haemoglobin microparticles (HbMPs) by PolyDopamine. AB - Clinically applicable haemoglobin-based oxygen carriers (HBOCs) should neither induce immunological nor toxic reactions. Additionally, Hb should be protected against oxidation. In the absence of protective enzymes (superoxide dismutase (SOD) and catalase (CAT)) Hb is oxidized to MetHb and thus losing its function of oxygen delivery. Alternatively, polydopamine (PD), a scavenger of free radicals, could be used for Hb protection against oxidation Therefore, we synthetized HbMPs modified with PD. The content of functional haemoglobin in these PD-HbMPs was twice higher than that in the control HbMPs due to the protective antioxidant effect of PD. In addition, the PD-HbMPs exhibited a high scavenging activity of free radicals including H2O2 and excellent biocompatibility. In contrast to monomeric dopamine, which has been shown to produce toxic effects on neurons due to formation of H2O2, hydroxyl radicals and superoxide during the process of auto oxidation, PD-HbMPs are not neurotoxic. Consequently, the results presented here suggest a great potential of PD-HbMPs as HBOCs. PMID- 30450979 TI - Targeted delivery of YSA-functionalized and non-functionalized polymeric nanoparticles to injured pulmonary vasculature. AB - Ephrin type-A receptor 2 (EphA2) is a transmembrane receptor which is upregulated in injured lungs, including those treated with bleomycin. YSA peptide (YSAYPDSVPMMS), a mimic of ephrin ligands, binds to EphA2 receptors on cell surface with high affinity. In this study, we assessed the ability of YSA functionalized and non-functionalized poly (dl-lactide-co-glycolide) (PLGA) nanoparticles to enhance delivery to bleomycin treated cultured vascular endothelial cells and, in a bleomycin induced lung injury mouse model. Nanoparticles were loaded with a lipophilic fluorescent dye. Human umbilical vein endothelial cells (HUVEC) with or without 2-day bleomycin pretreatment (25 ug/ml) and adult mice with or without intratracheal instillation of bleomycin (0.1 U) were dosed with nanoparticles. Mice received nanoparticles via tail vein injection 4 days after bleomycin treatment. Three days after nanoparticle injection, tissues (lung, heart, kidney, spleen, liver, brain, eyes and whole blood) were harvested and quantified for fluorescence using IVIS imaging. Mean particle uptake increased with time and concentration for both types of particles in HUVEC, with the uptake being higher for YSA-functionalized nanoparticles. Bleomycin treatment increased the 3-h uptake of both types of nanoparticles in HUVEC by about two-fold, with the YSA-functionalized nanoparticle uptake being 1.66-fold compared to non-functionalized nanoparticles (p < .05). In mice, bleomycin injury resulted in 2.3- and 4.7-fold increase in the lung levels of non functionalized and YSA-functionalized nanoparticles (p < .05), respectively, although the differences between the two particle types were not significant. In conclusion, PLGA nanoparticle delivery to cultured vascular endothelial cells and mouse lungs in vivo is higher following bleomycin treatment, with the delivery tending to be higher for YSA functionalized nanoparticles. PMID- 30450980 TI - Dietary Fatty Acids and Other Nutrients in Relation to Inflammation and Particularly to Oral Mucosa Inflammation. A Literature Review. AB - Oral mucosa is site of inflammatory process development. When they are chronic, they provide a microenvironment based on cytokines and inflammatory mediators that contribute to cancer initiation, progression, invasion, and metastasis. Certain dietary fatty acids (FAs) have immunomodulatory, inflammatory, and antiinflammatory effects. This review examined the literature on inflammation, mainly referred to the oral mucosa, and its association with dietary FAs and other nutrients. A Pubmed search of studies published in English until June 2018 was carried out. N-3 FAs have shown immunomodulatory and antiinflammatory activity in certain human diseases. These FAs and their mediators may inhibit inflammation, angiogenesis, and cancer via multiple mechanisms. Studies on cellular models of murine and human intestinal mucosa indicate association between dietary n-3 FA intake and the inflammatory state of mucosa membranes. Nevertheless scarce information on the association between dietary FAs and oral inflammation could be found. Based on the evidence, we hypothesize that n-3 FAs reduce the oral mucosa inflammation thus decreasing the risk of developing precancerous lesions and cancer. Molecular and clinical studies referred to this topic should be carried out as a contribution to the oral cancer prevention. PMID- 30450981 TI - Synergistic co-delivery of doxorubicin and melittin using functionalized magnetic nanoparticles for cancer treatment: loading and in vitro release study by LC MS/MS. AB - In this study, citric acid-functionalized Fe3O4 magnetic nanoparticles (CA-MNPs) were prepared via a coprecipitation method and were fully characterized. Doxorubicin (DOX) and melittin (MEL), as anticancer agents, were loaded onto CA MNPs surface through electrostatic interactions with the aim to achieve an effective co-delivery system for cancer therapy. The loading efficiency and in vitro release profiles of DOX and MEL were investigated by liquid chromatography tandem mass spectrometry (LC-MS/MS). The MS/MS step was performed in the selected reaction monitoring (SRM) mode which enabled simultaneous quantification of the analytes with high specificity and sensitivity. An excellent loading efficiency of about 100% was achieved for DOX and MEL in a drug to nanocarrier ratio of 1:10. The in vitro release of the drugs from CA-MNPs was evaluated for 8 h at pH 7.4, 5.5 and 4.5. The experimental results revealed that the release behaviour of both of the anticancer agents was strongly pH-dependent and significantly enhanced at pH 4.5. The in vitro MTT assay on MCF-7 breast cancer cell line exhibited a synergistic effect between DOX and MEL which led to substantially greater antitumor efficacy, compared to single administration of these anticancer agents at equivalent doses. The results indicated that the co-delivery system of (DOX/MEL)-loaded CA-MNPs is highly capable to be used in magnetically targeted cancer therapy. PMID- 30450982 TI - Pooling and patient satisfaction in non-instrumented lumbar decompressive surgery. AB - OBJECTIVES: To determine the effect of pooling of patients for elective non instrumented lumbar decompression on patient satisfaction and waiting times. MATERIALS AND METHODS: We performed a retrospective review of Spine Tango and Theatre Databases of our Neurosurgical unit for patients who underwent elective primary non-instrumented lumbar decompression between January 2012 and 2016. Patient satisfaction scores at 3 and 12 months post-surgery were collected from the Spine Tango Registry, and patients categorised as pooled/non-pooled by searching theatre databases to determine their named listing and operating consultants. Results were analysed numerically and by performing chi-squared testing to determine if pooling affected patient satisfaction. Theatre records were analysed between January 2004-2006, January 2009-2011 and 2014-2016 to determine what effect implementation of the 18-week wait target system (2009) and of our pooled system (2012) had on waiting times to operation for patients undergoing elective primary non-instrumented lumbar decompression. RESULTS: There is no significant difference in patient satisfaction levels between pooled and non-pooled patients at 3 (p = .052) and 12 months (p = .5) post primary elective lumbar decompression (significance p < .05). There was no difference in average waiting time between the pooled and non-pooled groups. Both setting of 18-week targets and pooling improved waiting times. Setting of 18-week targets affected average waiting times markedly while pooling most notably reduced the variability in waiting times between patients for the same procedure. CONCLUSIONS: Pooling of patients for elective non-instrumented lumbar decompression in our unit has improved waiting times, particularly the variability in them, with no detriment to patient satisfaction. We would recommend other units to consider developing a system of pooling such as ours, to help maximise use of their current resources and avoid highly variable waiting times for patients for the same procedure within the same department. PMID- 30450983 TI - Management of a rare case of intraventricular ruptured dermoid cyst and chemical meningitis. AB - INTRODUCTION: Intraventricular dermoid cyst are very rare benign tumour. Due to benign nature, it may go un-noticed for years and might present with sudden rupture. Ruptured cyst can cause chemical meningitis, hydrocephalus, seizures etc. Due to lack of data, there are no defined guidelines about its management. We are reporting an interesting case of ruptured intraventricular dermoid cyst and chemical meningitis, who was managed successfully and will review the literature. CASE REPORT: A 48 years male patient was brought with complaint of sudden mental deterioration, irritability, headache, vomiting for 3 days. He had history of seizures for 1 year. On examination, his higher mental functions were deteriorated, had neck rigidity and left lower limb weakness. CT/MRI brain confirmed diagnosis of right frontal horn ruptured dermoid cyst with scattered fat droplets, hydrocephalus and ventriculitis. Excision of cyst was done via right trans-sulcal (superior frontal sulcus) approach. Patient recovered well. DISCUSSION: Intraventricular dermoid cyst are a rare benign lesion. Due to potential of rupture, it must be surgically treated. Steroids should be used to treat chemical meningitis. Various individual case reports have shown good outcome after surgical management. CONCLUSION: We recommend early surgery, thorough ventricular wash with ringer lactate, post-operative extraventricular drain and steroid cover to manage ruptured cyst and chemical meningitis. PMID- 30450984 TI - Unusual presentation of epilepsy of germinoma located in the frontal-lobe: case report and literature review. AB - Germinoma is rare in peripheral lobar locations in the brain, with only 10 cases of primary frontal lobe germinoma having been reported in the previous literature. Epilepsy is a rare manifestation of germinomas. We describe an unusual case of a primary frontal germinoma in a 21-year-old man who presented with epilepsy. A presumptive diagnosis of abscess or cystic glioma was made, and then, we performed microsurgery under magnetic resonance imaging (MRI) neuronavigation guidance. Postoperative histopathologic examination identified the tumour as a rare germinoma. Subsequently, adjuvant radiotherapy and chemotherapy programmes were adopted in the present case, and there were no recurrence and postoperative seizure symptoms observed in the follow-up 6 months after operation. PMID- 30450985 TI - Self-releasing of a titanium clamp (CranioFix) in cranioplasty. AB - The CranioFix(r) titanium clamp was developed for fixing bone flaps after craniotomy. In this case, to prevent cosmetic problems, the bone flaps were trimmed with a beveled edge, and a CranioFix clamp was used for bone flap fixation. As the brain swelled, the CranioFix clamp became loosened. If brain swelling is anticipated and bone margins have been trimmed, it may be better to consider other fixation methods. PMID- 30450986 TI - Spontaneous preoperative pituitary adenoma resolution following apoplexy: a case presentation and literature review. AB - PURPOSE: We aim to more fully understand the incidence and natural history of spontaneously resolving non-functioning pituitary adenomas (NFPAs). METHODS: We report a case of spontaneous complete resolution of a NFPA revealed by preoperative magnetic resonance imaging. In addition, we searched all major databases and neurosurgery journals to perform a comprehensive literature review of all previously reported cases of spontaneously resolving NFPAs. We discuss how these cases may contribute to our understanding of the natural course for non functional pituitary adenomas. RESULTS: To date, only twelve cases of spontaneously resolving nonfunctional pituitary adenomas have previously been reported. The presented case is the first reported spontaneously resolved nonfunctioning pituitary adenoma to recur. In all cases, apoplexy resulted in resolution of mass effect, obviating the need for surgical decompression. CONCLUSIONS: In all NFPA cases, the preoperative MRI should always be studied closely before surgery is initiated. Additionally, because we have demonstrated that the adenoma may regrow after spontaneous regression following apoplexy, these patients should be followed with regular serial MRIs to monitor for recurrence. PMID- 30450987 TI - Glioblastoma multiforme metastatic to lung in the absence of intracranial recurrence: case report. AB - We present the case of a 65 year old gentleman who underwent craniotomy and debulking of a left temporal glioblastoma multiforme (GBM). Post-operatively he received chemotherapy and radiotherapy with good response demonstrated on interval MRI scans. At 17 months post-diagnosis and in the absence of clinical or radiological recurrence, he presented with respiratory distress. He was found to have an exudative right-sided pleural effusion, nodular pleural thickening, a hilar mass and associated lymphadenopathy. Percutaneous pleural biopsy revealed metastatic GBM. Systemic GBM metastasis despite good response to oncological treatments and in the absence of intracranial recurrence is exceedingly rare. We review the literature concerning extra-neuraxial GBM metastasis and speculate why this phenomenon is extremely rare. PMID- 30450989 TI - Current state of integration of neurosurgical and orthopaedic spine services in the UK. PMID- 30450990 TI - Surgical treatment of pineal cysts in non-hydrocephalic and neurologically intact patients: selection of surgical candidates and clinical outcome. AB - PURPOSE: Management of patients presenting for various nonspecific complaints without clear neurological abnormalities and with normal ventricular size remains highly controversial. We intended to share our rationale for surgical treatment of patients who show symptoms of transient increase of intracranial pressure owing to the presence of the cyst. MATERIALS AND METHODS: We have retrospectively analyzed 28 cases of patients who presented without Parinaud syndrome nor ventricular enlargement and underwent pineal cyst removal in our centre between 2007 and 2015. We analyzed patients' age, sex, symptoms, preoperative cyst size, perioperative course, treatment outcome and neurologic status at discharge and at follow-up visits 4 and 12 months afterwards. RESULTS: Main complaints included paroxysmal headaches, nausea, vomiting, visual disturbances, syncope and transient depression of consciousness. Mean age of patients was 31 years (17-55); there were 24 females and 4 males. Mean cyst diameter was 17 mm (10-26). Decision about surgical treament was based on signs of transient increases of intracranial pressure. All patients underwent complete cyst excision via midline suboccipital craniotomy and infratentorial supracerebellar route. Short-lasting perioperative neurological signs (notably upgaze palsy) were noted in 22 cases and uniformly resolved within the observation period of 12 months. CONCLUSION: Abnormal neurological findings and ventricular enlargement are not indispensable to justify surgical treatment of pineal cysts. Judicious selection of surgical candidates based predominantly on clinical grounds can lead to excellent operative results. PMID- 30450988 TI - Pretreatment of simvastatin on liver trace element levels during endotoxemia. AB - There are a number of studies investigating anti-inflammatory effects of simvastatin in patients with sepsis and animal models. There are a few studies which investigated effect of simvastatin on elements in sepsis. In the present study, the impact of pretreatment with simvastatin on element levels was evaluated in liver during endotoxemia. Rats were divided into control, LPS, simvastatin, and simvastatin + LPS. The histopathologic examination of the liver was performed using hematoxylin and eosin. Selenium, zinc, iron, manganese, magnesium, and copper were analyzed using inductively coupled plasma - optical emission spectroscopy. In the LPS, the hepatocyte cell structure was damaged. In the simvastatin + LPS, hepatocyte, and sinusoidal cord damage were partially smaller than LPS. Levels of selenium, and copper significantly decreased in both of LPS and simvastatin + LPS. In the LPS group, iron was found to increase. In the simvastatin + LPS, zinc was increased. Simvastatin partially smaller liver damage by increasing zinc levels during endotoxemia. PMID- 30450991 TI - An unusual case of a grade I meningioma with perineural spread. AB - A 39-year-old lady with worsening intermittent diplopia and headaches was diagnosed with a WHO Grade I Meningothelial Meningioma with highly unusual perineural spread on imaging, making this the first reported case of this behaviour. Complete surgical resection was deemed too great a risk and the patient remains under observation. The process of perineural spread is not restricted to more aggressive brain tumours. PMID- 30450992 TI - Sinonasal undifferentiated carcinoma with metastasis to the extradural spine. AB - Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive cancer of the sinonasal tract and is often characterized by intracranial invasion. However, SNUC rarely metastasizes to the spine. In this paper, we present a case of extradural metastasis and invasion of the adjacent spine by SNUC. A 42-year-old man presented to our hospital with two-month history of anosmia and nosebleeds. Imaging studies showed a neoplasm of the ethmoid sinus with extension into the anterior cranial fossa. The patient underwent resection of the carcinoma and began chemoradiotherapy. After completing chemoradiotherapy the patient complained of neck pain radiating down the right arm, and imaging showed an extradural mass at the C5 vertebral level. The patient underwent laminectomy for debulking of this tumor. One month later, the patient complained of recurrent weakness and pain in the right shoulder and arm. Imaging showed an extradural tumor wrapping around the C7 and C8 nerve roots, as well as a separate tumor at C2 adherent to the dura. The extradural tumor at C2 was surgically resected. Further imaging showed multiple new soft tissue masses at the thoracic level. We present a case of SNUC metastasis to the extradural spine representing the second case reported in the literature. Peri-dural metastasis and resulting symptoms should be included in the differential diagnosis and assessment of patients with SNUC. PMID- 30450993 TI - Insulin resistance and oxidative marker in women with PCOS. AB - : Polycystic Ovary Syndrome is a multifactorial reproductive problem and a leading cause of female infertility worldwide. Evidences have shown that Oxidative Stress and decreased antioxidant status are often linked with PCOS. Insulin Resistance in PCOS patients ranges from 50% to 70% and may encourage OS by production of reactive oxygen species. OBJECTIVE: Our study determines serum MDA levels along with plasma glucose, serum insulin, and insulin resistance in obese and nonobese PCOS subjects. MATERIALS AND METHODS: A case control study was conducted on diagnosed 100 PCOS patients and 100 controls. Fasting plasma glucose was measured by enzymatic method. Insulin was estimated by chemiluminescent microparticle immunoassay using Abott Architect i 2000 SR analyser. Insulin resistance was calculated by HOMA-IR. Malonaldehyde is determined as Thiobarbituric acid reactive substances. RESULTS: CRP and serum MDA levels were increased in women with PCOS irrespective of obesity compared to their respective controls with a p value of < .001. However, though fasting glucose, serum insulin, and IR were increased in both obese and nonobese women with PCOS compared to their BMI adjusted controls with p value of < .001, the values were within reference range in nonobese women. CONCLUSION: Our study suggests that women with PCOS have oxidative stress and elevated CRP irrespective of obesity. However, hyperinsulinemia and Insulin resistance are seen only in obese women with PCOS, indicating that these women are at high risk for developing low grade inflammation and cardiovascular diseases. PMID- 30450994 TI - Complete embolization of jugular paragangliomas by direct puncture. Technical note. AB - OBJECTIVE: Intra-arterial embolization of jugular paragangliomas is an established endovascular technique. Intratumoral embolization by direct puncture has been proposed, prior to surgical treatment or radiosurgery to reduce the risk of cranial nerve deficits. METHODS: We examined the technical aspects of two patients with jugular paragangliomas embolized with liquid embolic agent by direct puncture of the lesion, as sole treatment. RESULTS: Two patients with jugular paragangliomas presented with lower cranial nerve deficits. The first patient showed an extended lesion (55-mm) and was treated with partial intra arterial embolization plus direct puncture and injection of Squid 18 and a second staged embolization by direct puncture and filling of the remainder of the lesion. The second patient with a smaller jugular paraganglioma (33-mm) was treated by single embolization by direct puncture of the tumor and injection of Squid 12 and Squid 18 obtaining complete filling of the lesion. No procedural complications were observed. Both patients showed no residual and initial improvement of the neurological deficits. CONCLUSION: The intratumoral embolization by direct puncture of jugular paragangliomas, under accurate radiological control is a safe procedure, and complete exclusion of the lesion can be obtained in selected cases. A staged particle embolization of the lesion by direct puncture can be proposed for large lesions. Only further studies with larger series and long-term follow-up will be able to define, if this strategy can be curative avoiding additional surgical or radio-surgical treatment. PMID- 30450995 TI - Comparison of clinical outcomes in anterior cervical discectomy versus foraminotomy for brachialgia. AB - AIM: The choice between anterior cervical discectomy & fusion (ACD) or posterior cervical foraminotomy (PCF) for the treatment of cervical brachialgia is controversial. This study aimes to compare clinical outcomes between these two operative inteventions for brachialgia. METHODS: Retrospective review of prospectively collected data was performed. Patients receiving a primary ACD or PCF to treat brachialgia, in a single tertiary neurosurgical unit were included. Surgical details, and patient reported outcomes (COMI-Neck questionnaire) were extracted from a prospectively maintained spinal procedure database. Minimum clinically important difference (MCID) was defined as a change in COMI score of 2 at 12 months. The student t-test, Chi-square test, and linear regression were used to compare groups. RESULTS: Between June 2011 ad February 2016 there were 634 ACD procedures (Median age 49; 321 Male), and 54 PCF procedures (Median age 50; 37 Male) perfomed for brachialgia. Age, ASA and pre-operative COMI were similar between the groups (p > .05). Complete outcome data was recorded at twelve months in 312 ACD and 36 PCF patients. Both ACD and PCF were associated with an improvement in COMI at 3 and 12 months (all p < .01). Mean change in COMI at 3 months was -2.38 for ACD, versus -2.31 for PCF (p = .88); at twelve months it was -2.94 for ACD, versus -2.67 for PCF (p = .55). MCID was seen in 59% of ACD cases, versus 58% of PCF cases at twelve months (p = .91). CONCLUSION: There was no significant difference between outcomes in the ACD and PCF groups. This is supportive of published literature. The proposed multicenter RCTs may inform further. PMID- 30450996 TI - Xanthomatous hypophysitis causing hypogonadotropic hypogonadism resulting in delayed presentation of slipped capital femoral epiphysis. AB - An 18-year-old man who underwent bilateral pinning of his hip joints after a left unstable Slipped Capital Femoral Epiphysis (right pinned prophylactically) was noted to have delayed secondary sexual characteristics and post-operative diabetes insipidus. The patient also described a history of fatigue, headache and polydipsia for the past 4 years. Endocrine investigations revealed reduced androgen levels, hypocortisolism, a borderline normal Serum ACE and secondary hypothyroidism. Magnetic Resonance Imaging of the pituitary gland identified an enhancing mass and a thickened stalk which trans-nasal endoscopic biopsy found to be necrotic with pus. Histology confirmed a diagnosis of Xanthomatous Hypophysitis, an inflammatory condition likely related to a partial rupture of a Rathke cleft cyst. The patient was subsequently commenced on Androgen, Thyroxine, Desmopressin and Hydrocortisone therapy with on-going endocrine follow-up. Although endocrine dysfunction & hypogonadism has been recognised to be a risk factor for SCFE at an atypically older age, due to reduced androgen levels leading to a weakened physeal plate, this is the first known case of a Xanthomatous Hypophysitis resulting in pituitary dysfunction and eventual SCFE. This case highlights that an increased range of pituitary disorders should be considered in late presentations of SCFE; and vice versa the risk of SCFE should be considered in patients with prolonged hypogonadotropic hypogonadism. PMID- 30450998 TI - Recurrent delayed-onset cerebral vasospasm following ruptured ICA aneurysm: case report. AB - We report a unique case of late-onsetcerebral vasospasm at 21 and again at 30 days following aneurismal subarachnoid hemorrhage. PMID- 30450997 TI - Variations in Toll-like receptor and nuclear factor-kappa B genes and the risk of glioma. AB - PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumour in the adult nervous system and is associated with a poor prognosis. NF-KB activation is an important driver of the malignant phenotype that confers a negative prognosis in patients with GBM. NF-KB plays a role in Toll-like Receptors (TLR)-induced tumourigenesis. The aim of the present study was to investigate the association of a promoter region polymorphism of NFKB1 gene encoding the p50 subunit of NF KB, namely -94ins/del ATTG, the most widely discussed the TLR2 Arg753Gln, TLR4Asp299Gly and TLR4Thr399Ile polymorphisms, their combined effects, and the glioma risk. METHODS: A group of 120 Glioma patients and 225 control subjects were screened for these four polymorphisms using the PCR-RFLP method. RESULTS: Statistical analysis indicates that the ins/ins genotype of NFKB -94ins/delATTG (p=0.003), and the AA genotype of TLR4Asp299Gly (p < 0.001) are risk factors for glioma and people carrying the ins allele have an approximately 1.47 times susceptibility risk of glioma whereas GG genotype of TLR2Arg753Gln seems to be protective against glioma (p = 0.002). Combined genotype analysis showed that del/ins-GG genotype of TLR2Arg753Gln-NFKB1, del/ins + GG genotype of TLR4Asp299Gly-NFKB1, del/ins-CC genotype of TLR4Thr399Ile-NFKB1 were risk factors for glioma development. CONCLUSION: NFKB1 -94ins/delATTG and TLR4Asp299Gly polymorphisms are associated with increased glioma cancer risk in a Turkish population. PMID- 30451000 TI - Physiological role of adiponectin in different tissues: a review. AB - Adiponectin is the most important adipokine secreted by the adipose tissue. It carries out an important role in setting up the metabolism and improving the function of various organs. Adiponectin in the kidneys prevents degradation of the renal arteries, reduces protein excretion, and improves filtration. This role is accomplished by regulating anabolic pathways and reducing oxidative stress in the renal tissue. This hormone in the liver prevents the accumulation of fat and free radicals that cause damage to liver cells and tissue. This adipokine, by preventing inflammatory processes, oxidative stress, obesity and insulin resistance, improves vascular function and prevents the development of atherosclerosis. It seems that adiponectin can also be a therapeutic target for many metabolic diseases. This study aims to clarify the adipose tissue discharge. Here, the diverse physiological actions of adiponectin were reviewed to provide an overview of its therapeutic potential in different metabolic disorders. PMID- 30450999 TI - High frequency of lumbar fusion in patients denied surgical treatment of the sacroiliac joint. AB - PURPOSE: Effective treatment of medical conditions relies on proper diagnosis. Clinical trials show the safety and effectiveness of sacroiliac joint (SIJ) fusion in patients with chronic SI joint dysfunction. To what extent is the condition under recognised? OBJECTIVE: To determine whether under recognition of SIJ pain affects healthcare trajectories in Spanish patients with low back pain. METHODS: Retrospective study of characteristics and consequences of 189 patients with persistent SIJ pain seen in an outpatient neurosurgery clinic. RESULTS: Patients with SIJ pain who were denied surgical treatment had a longer pain duration, higher likelihood of prior lumbar fusion, and a high rate (63%) of lumbar fusion within 2 years prior to SIJ pain diagnosis, which, in most cases, provided little benefit. CONCLUSIONS: Lack of knowledge of the role of the SIJ in chronic low back pain probably results in diagnostic confusion and may lead to misdirected treatment. PMID- 30451002 TI - Undergraduate neurosurgical conferences - what role do they play? AB - INTRODUCTION: Undergraduate student conferences provide networking opportunities for students interested in exploring a speciality. The ability to meet with like minded students, engage with senior clinicians and experience the practical side of a speciality are valuable in shaping the career trajectory of undergraduates. We report our experience of developing a national undergraduate neurosurgery conference - a combined project between the medical students of King's College London School of Medicine and the neurosurgery department at King's College Hospital NHS Foundation Trust. DESIGN: Evaluation of conference design and student feedback. METHODS: The conference was organised by medical students with support from a neurosurgical unit. Senior clinicians and trainees helped design practical workshops and a focused programme. Questionnaires were distributed before and after the conference to assess the quality of content and impact of the conference on students. RESULTS: Prior to the conference, 80.7% of respondents stated they were interested in a career in neurosurgery. After the conference the figure rose to 88.9%. The percentage of students who felt they understood what a career in neurosurgery involves increased from 38.6% to 92.1% of respondents. 39.0% of participants had no neurosurgery exposure prior to the conference. 91.9% of participants agreed or strongly agreed they would be more confident engaging with a neurosurgical department following the conference. All participants agreed (29.0%) or strongly agreed (71.0%) that they would recommend this conference to a colleague. CONCLUSIONS: Student conferences are a valuable method of increasing exposure to a career in neurosurgery. They serve a great purpose in demystifying the specialty and guiding those with an interest through the steps required to enter and progress. PMID- 30451001 TI - Microsurgical treatment for unruptured intracranial aneurysms: a modern single surgeon series. AB - With the rise of endovascular treatments for the management of unruptured intracranial aneurysms (UIAs), advances in microsurgical techniques are underrepresented in modern surgical series, which largely consist of patients with aneurysms unfit for coiling. We report a modern series of microsurgical treatment for UIAs performed by a single surgeon as the preferred treatment modality. We retrospectively reviewed the charts of all patients with UIAs treated by the senior author with microsurgical clipping over an 11-year period. Procedure-related mortality, major neurologic morbidity (modified Rankin Score 3 5), complications, and persistent neurologic deficits were recorded. Risk factors for persistent neurologic deficits and major morbidity or mortality were analyzed using multivariate logistic regression analysis. We identified 329 patients with 400 UIAs treated in 353 surgeries. The average age was 52 years, 80% of patients were women, and 13% had a previous subarachnoid hemorrhage. The average aneurysm size was 7 mm and 92% were in the anterior circulation. The mean follow-up was 15 months (range 0.5-125). There was one procedure-related death (0.3%), and two patients suffered major morbidity (0.6%). Twenty procedures (5.6%) resulted in a persistent neurologic deficit. Risk factors for death and major morbidity were increasing age and posterior circulation, while risk factors for persistent neurologic deficits were increasing aneurysm size and posterior circulation. We conclude that microsurgical clipping is safe, effective, and should be given strong consideration as the primary treatment modality for younger patients with small to medium sized UIAs in the anterior circulation. PMID- 30451003 TI - Fast-developing fatal diffuse leptomeningeal dissemination of a pineal germinoma in a young child: a case report and literature review. AB - BACKGROUND: Intracranial germinomas are uncommon and constitute less than 1% of all intracranial tumors. They usually arise in the midline of the brain, most commonly in the pineal region. Pineal germinomas tend to spread through the cerebrospinal fluid (CSF). However, pineal germinomas with fast-developing diffuse subarachnoid/leptomeningeal dissemination are extremely rare, especially in young children. METHODS: The case of a 4-year-old boy with a pineal germinoma who died of diffuse subarachnoid/leptomeningeal dissemination 1 month after radiotherapy is reported. A PubMed search with specific key terms was used to review cases of pineal germinomas with metastasis. RESULTS: The patient presented with a two-week history of worsening headache, visual disturbances and nonprojectile vomiting. Parinaud's sign was positive on physical examination. Head computed tomography (CT)/magnetic resonance imaging (MRI) revealed a lesion in the pineal region with eccentric calcification and obvious supratentorial hydrocephalus. Pineal germinoma was suspected. A ventriculoperitoneal (VP) shunt followed by focal radiotherapy ameliorated the headaches and visual disturbances. The patient was discharged home without further treatment due to financial difficulties. One month after discharge, he was readmitted due to worsening headache, vomiting and lethargy. MRI showed a decrease in the size of the pineal lesion but revealed a diffuse leptomeningeal enhancement including the sulcus, basal cistern, prepontine cistern, and supravermian cistern. The patient's condition deteriorated rapidly, and he died 26 hours after readmission. The characteristics of pineal germinomas with metastasis are reported based on a review of the literature. CONCLUSIONS: Metastases in pineal germinomas predominately occur in adolescents or young adults, most commonly as spinal "drop metastases." Dissemination usually develops several years after the initial tumor diagnosis and has a relatively good clinical prognosis. However, fast widespread subarachnoid/leptomeningeal dissemination and sudden death may occur in a young child before salvage treatment, as in the presented case. PMID- 30451004 TI - Surgical options for meralgia paresthetica: long-term outcomes in 13 cases. AB - BACKGROUND: Meralgia paresthetica is an entrapment neuropathy of the lateral femoral cutaneous nerve that may cause paresthesias, pain, and sensory loss of the anterior and lateral thigh. Treatment is primarily medical. Surgery is an option for patients who do not respond to medical treatments. METHODS: Patients whose symptoms did not improve after medical and conservative treatment for at least 3 months were included in this study. These patients underwent neurolysis and decompression surgery and had a mean postoperative follow-up of 38 months. Their pain levels were assessed by the VAS scoring system. RESULTS: In 8 (61.5%) patients, the symptoms completely resolved within the first 3 months. In 5 (38.5%) patients, the complaints persisted partially and the recovery was observed after 12 months. In patients having a metabolic etiology, the duration of recovery was up to 12 months. CONCLUSION: The long term results of surgery are good though only partial improvemnts in reported pain were seen in the early postoperative period, especially in patients with a metabolic etiology. PMID- 30451005 TI - Lawsonella clevelandensis causing spinal subdural empyema. AB - Lawsonella clevelandensis is a recently described species and genus of bacterium in the Corynebacterineae suborder which is Gram-stain positive, partially acid fast and anaerobic. Very few cases of human infection due to this organism are described and here we seek to add to the limited medical literature. We report the case of a 2-year-old girl who presented with an infected spinal dermoid cyst secondary to Lawsonella clevelandensis which required surgical drainage and a long course of antibiotics. We encountered diagnostic and therapeutic difficulties because this is a fastidious organism which was difficult to culture and ultimately required molecular detection and identification. To the best of our knowledge, this is only the seventh reported case of Lawsonella clevelandensis causing human infection worldwide and the first in the UK. This is the first reported case of Lawsonella clevelandensis infection in a child and the second reported case of this organism causing spinal infection. PMID- 30451006 TI - Long-term pain relief at five years after medical, repeat surgical procedures or no management for recurrence of trigeminal neuralgia after microvascular decompression: analysis of a historical cohort. AB - BACKGROUND: Management strategies for the recurrence of trigeminal neuralgia after microvascular decompression include repeat procedures, medical management or no further therapy. No consensus exists as to which strategy is best for pain relief. The aim of this study was to determine the characteristics of patients with recurrences after microvascular decompression in the cohort, and to compare long-term pain relief between different management strategies. MATERIALS AND METHODS: A historical cohort of patients who underwent microvascular decompression at a neurosurgical institution between 1982-2002, followed up by postal survey at five years, was included. Characteristics of patients who experienced a recurrence were compared to those who were recurrence free, and pain relief was compared between each management strategy. RESULTS: From 169 responders who were included in the study, 28 (16.6%) experienced a recurrence after MVD. No characteristics were significantly different between patients who experienced a recurrence and those who did not. Repeat procedures, including repeat microvascular decompression, partial sensory rhizotomy or radiofrequency thermocoagulation, yielded the highest proportion of pain relief after recurrence (p = 0.031), with 63.6% of patients pain-free at five-years. There was no evidence to suggest that the choice of repeat procedure influenced the likelihood of pain relief after recurrence. No further treatment yielded 57.1% pain-free, whereas medical therapy had the lowest proportion of pain-free patients, at 10.0%. CONCLUSION: A variety of options are available to patients for recurrence of TN after microvascular decompression with repeat procedures yielding the greatest likelihood of long-term pain relief in this historical cohort. The choice of management should consider the mechanism of recurrence, the benefits and risks of each option and the severity of the pain. Regardless of the management strategy selected, careful phenotyping of patients before and after surgery is paramount. PMID- 30451007 TI - Challenges with take-home naloxone in reducing heroin mortality: a review of fatal heroin overdose cases in Victoria, Australia. AB - AIM: Take-home naloxone (THN) programs have been implemented in order to reduce the number of heroin-overdose deaths. Because of recent legislative changes in Australia, there is a provision for a greater distribution of naloxone in the community, however, the potential impact of these changes for reduced heroin mortality remains unclear. The aim of this study was to examine the characteristics of the entire cohort of fatal heroin overdose cases and assess whether there was an opportunity for bystander intervention had naloxone been available at the location and time of each of the fatal overdose events to potentially avert the fatal outcome in these cases. METHODS: The circumstances related to the fatal overdose event for the cohort of heroin-overdose deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated. Coronial data were investigated for all cases and data linkage was performed to additionally investigate the Emergency Medical Services information about the circumstances of the fatal heroin overdose event for each of the decedents. RESULTS AND DISCUSSION: There were 235 fatal heroin overdose cases identified over the study period. Data revealed that the majority of fatal heroin overdose cases occurred at a private residence (n = 186, 79%) and where the decedent was also alone at the time of the fatal overdose event (n = 192, 83%). There were only 38 cases (17%) where the decedent was with someone else or there was a witness to the overdose event, and in half of these cases the witness was significantly impaired, incapacitated or asleep at the time of the fatal heroin overdose. There were 19 fatal heroin overdose cases (8%) identified where there was the potential for appropriate and timely intervention by a bystander or witness. CONCLUSION: This study demonstrated that THN introduction alone could have led to a very modest reduction in the number of fatal heroin overdose cases over the study period. A lack of supervision or a witness to provide meaningful and timely intervention was evident in most of the fatal heroin overdose cases. PMID- 30451008 TI - Sleep patterns and nocturnal cardiac autonomic activity in female athletes are affected by the timing of exercise and match location. AB - The aim of the current study was to analyze the influence of the timing of training and matches, and match location, on sleep pattern and nocturnal cardiac autonomic activity in female soccer players. A total of 17 female soccer players (age: 21.6 +/- 2.3 years; mean +/- SD) wore wrist actigraph units and heart rate (HR) monitors during night-sleep throughout 18 night-training days (NTD), 18 resting days (RD), and 6 match-days (MD; 3 away-matches [AM] and 3 home-matches [HM]) of the competitive period. Training load was quantified by session rating of perceived exertion (sRPE), heart rate (HR), training impulse (TRIMP), and subjective well-being. In NTD, sleep onset time and total sleep time were significantly impaired compared to MD (+ 1:47 [0:48; 1:55] hours and -1:35 [ 1:42; -0:57] hours, respectively; p< 0.001; mean difference +/- 95% confidence interval [CI]) and RD (+ 1:31 [0:52; 1:49] hours and -1:26 [-1:28; -0:55] hours, respectively; p< 0.001). In AM, sleep onset time was delayed compared to HM (+ 0:36 [0:12; 0:44] hours; p< 0.001). Sleep latency was higher in NTD compared to RD (+ 4 [2; 5] min; p< 0.001), as well as after AM compared to HM (+ 5 [1; 7] min; p< 0.001). HR during sleep was significantly increased after NTD and MD compared to RD (+ 4 [1; 5] b.p.m and + 3 [1; 4] b.p.m, respectively; p< 0.001). Furthermore, HR variability decreased after NTD and MD compared to RD (e.g., lnRMSSD, -0.09 [-0.18; -0.08] ln[ms] and -0.17 [-0.27; -0.11] ln[ms], respectively; p< 0.001). Overall, the time of day for soccer practice (i.e., training at night) and match location (i.e., away matches) may cause disruption in sleep patterns and/or in autonomic cardiac activity in female soccer players. Additionally, playing official matches during the day and training at night may affect nocturnal cardiac autonomic activity by decreasing vagal-related modulation and increasing HR during sleep. PMID- 30451009 TI - Cerebellopontine angle epidermoid with ipsilateral external ear atresia: an embryological association or a coincidence? AB - The cerebellopontine angle (CPA) is the most common site for intracranial epidermoids. They may have varied presentations viz facial pain, hemifacial spasms, headache and uncommonly features of raised intracranial pressure. Their association with external ear atresia has not been reported in literature to date. We present a very rare case of CPA epidermoid with ipsilateral external ear atresia. PMID- 30451010 TI - An epidemiologic study of pelvic organ prolapse in postmenopausal women: a population-based sample in China. AB - OBJECTIVE: This study aimed to assess the prevalence and factors associated with symptomatic pelvic organ prolapse (POP) in a representative sample of postmenopausal Chinese women. METHODS: A total of 20,008 postmenopausal Chinese women were recruited to this cross-sectional study between February 2014 and March 2016. The prevalence of symptomatic POP, defined as any stage II or higher POP resulting in symptoms, was assessed using questionnaires and physical examinations. Multivariable logistic regression was used to assess factors associated with symptomatic POP. RESULTS: Among all women with natural menopause included in the study (mean age =61.98 +/- 10.62 years), 2962 of 20,008 women (14.80%, 95% confidence interval [CI] 14.3-15.3%) had symptomatic POP. In the multivariate analysis, women were more likely to have symptomatic POP if aged 50 59 years (adjusted odds ratio [AOR] 1.322, 95% CI 1.123-1.560), 60-69 years (AOR 1.603, 95% CI 1.352-1.907), or above 70 years (AOR 1.824, 95% CI 1.158-2.197), compared with women aged 40-49 years. Having delivered two times (AOR 1.145, 95% CI 1.105-1.292) or three or more times (AOR 1.384, 95% CI 1.214-1.578) was significantly associated with symptomatic POP. Compared with normal weight women, overweight women (AOR 1.365, 95% CI 1.247-1.494) and obese women (AOR 1.548, 95% CI 1.344-1.780) were more likely to have POP. Living in an urban area, smoking, alcohol consumption, cough, constipation, mental labor, physical disease, and gynecological diseases were also associated with symptomatic POP. CONCLUSIONS: Symptomatic POP affects nearly 15% of postmenopausal women in China. The prevalence of symptomatic POP increases significantly with age, body mass index, and parity. PMID- 30451011 TI - Mental health problem or workplace problem or something else: what contributes to work perception? AB - PURPOSE: Work perception is an important predictor for work ability and, therefore, of interest for rehabilitation. Until now it is unclear to which extent different psychological aspects explain work perception. This study investigates in which way workplace problems on the one hand, and mental health and coping on the other hand, contribute to work perception. METHODS: A heterogeneous sample of 384 persons in working age with and without mental health problems was recruited. Participants gave self-reports on workplace problems, mental health problems, work-coping, work-anxiety, and work perception. RESULTS: Persons with mental health problems and workplace problems (M + W) perceive the highest degree of work demands, followed by persons with workplace problems but without mental health problems (NM + W). Work-anxiety appeared as the strongest factor explaining perception of high work demands, whereas general mental health problems did not contribute significantly to variance explanation. CONCLUSIONS: Persons with specific mental health problems in terms of work-anxiety may be expected to perceive higher work demands. They may be detected when asking for work perception, e.g., within the frame of return-to-work interventions in rehabilitation, or in occupational health settings by mental hazard analysis. Implications for rehabilitation Work perception is an important predictor for work ability. Work-anxiety plays a key role for work perception. Thus, work perception and work anxiety should be explored in the diagnostic phase of rehabilitation treatments. Work-anxiety should be considered not only in rehabilitation diagnostics and interventions in clinical settings, but considered in preventive activities at work: Self-ratings on work-anxiety and work perception (instead of general wellbeing) may be included in assessments for workplace exploration, or mental hazard analysis. They give hints concerning concrete work-related health problems. PMID- 30451012 TI - Long-term low salt diet increases blood pressure by activation of the renin angiotensin and sympathetic nervous systems. AB - Background The aim of this study was to investigate the effect of long-term low salt diet on blood pressure and its underlying mechanisms. Methods Male Sprague Dawley (SD) rats were divided into normal salt diet group (0.4%) and low salt diet group (0.04%). Blood pressure was measured with the non-invasive tail-cuff method. The contractile response of isolated mesenteric arteries was measured using a small vessel myograph. The effects on renal function of the intrarenal arterial infusion of candesartan (10 MUg/kg/min), an angiotensin II receptor type 1 (AT1R) antagonist, were also measured. The expressions of renal AT1R and mesenteric arterial alpha1A, alpha1B, and alpha1D adrenergic receptors were quantified by immunoblotting. Plasma levels of angiotensin II were also measured. Results Systolic blood pressure was significantly increased after 8 weeks of low salt diet. There were no obvious differences in the renal structure between the low and normal salt diet groups. However, the plasma angiotensin II levels and renal AT1R expression were higher in low than normal salt diet group. The intrarenal arterial infusion of candesartan increased urine flow and sodium excretion to a greater extent in the low than normal salt diet group. The expressions of alpha1A and alpha1D, but not alpha1B, adrenergic receptors, and phenylephrine-induced contraction were increased in mesenteric arteries from the low salt, relative to the normal salt diet group. Conclusion Activation of the renin-angiotensin and sympathetic nervous systems may be involved in the pathogenesis of long-term low salt diet-induced hypertension. PMID- 30451013 TI - Efficacy and safety of naltrexone for amfetamine and methamfetamine use disorder: a systematic review of randomized controlled trials. AB - INTRODUCTION: Amfetamine and methamfetamine abuse remains a prevalent health problem, increasing the burden on healthcare. Naltrexone, a u-opioid receptor antagonist, has been suggested as a promising treatment for amfetamine and methamfetamine use disorder. OBJECTIVE: To review the current evidence for the efficacy and safety of naltrexone as a pharmacological treatment for amfetamine and methamfetamine use disorder. The primary outcome was defined as abstinence or reduction of use. Secondary outcomes were, attenuated "positive" subjective effects (e.g., "feel good," "craving," etc.) of amfetamine or methamfetamine after naltrexone treatment, adverse events and physiological changes (e.g., blood pressure, heart rate). METHODS: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A systematic literature search was conducted on 2 April 2017, and updated on 31 March 2018. Records were retrieved from databases including PubMed, EMBASE Classic plus EMBASE 1980 via Ovid, and the databases were searched using keywords and/or headings: (naltrexone AND amfetamine AND dependence) OR (naltrexone AND amfetamine AND craving) OR (vivitrol AND amfetamine) OR (revia AND amfetamine) OR (naltrexone AND amfetamine) OR (naltrexone AND methamfetamine dependence) OR (naltrexone AND methamfetamine AND craving) OR (vivitrol AND methamfetamine) OR (revia AND methamfetamine) OR (naltrexone AND ice) OR (naltrexone AND crystal meth) OR (naltrexone AND methamfetamine). Studies investigating the effects of naltrexone on amfetamine or methamfetamine use were eligible for inclusion. All studies were rated as low risk of bias using the Cochrane tool for risk of bias. RESULTS: Among 591 identified studies, there were four randomized controlled trials. Two studies investigated the effects of naltrexone on amfetamine use disorder and two on methamfetamine use. Compared to placebo, the abstinence rate was increased significantly (p < 0.05) by naltrexone in one of two amfetamine studies, whereas there was no statistical difference in the only study reporting methamfetamine use. In one out of two amfetamine studies, naltrexone significantly attenuated either craving levels or subjective effects (e.g., "want more," "like effect") relative to placebo (p < 0.05). Additionally, only in one of two methamfetamine studies did naltrexone produce a significant reduction (p < 0.05) in craving levels or attenuated subjective effects. Both amfetamine and methamfetamine studies showed good tolerability of naltrexone, with few adverse events seen. CONCLUSIONS: There is presently insufficient evidence to support the use of naltrexone in amfetamine and metamfetamine use disorders. There is a compelling need for high-quality studies to further evaluate the potential use of naltrexone. PMID- 30451014 TI - Repurposing existing drugs: identification of irreversible IMPDH inhibitors by high-throughput screening. AB - Inosine 5'-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with kon values of 0.7 * 104 to 9.3 * 104 M-1.s-1. Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors. PMID- 30451015 TI - Design, characterization and in vivo evaluation of nanostructured lipid carriers (NLC) as a new drug delivery system for hydrochlorothiazide oral administration in pediatric therapy. AB - The hydrochlorothiazide (HCT) low solubility and permeability give rise to limited and variable bioavailability; its low stability makes it difficult to develop stable aqueous liquid formulations; its low dose makes the achievement of a homogeneous drug distribution very difficult. Thus, the aim of this study was to investigate the effectiveness of a strategy based on the development of nanostructured lipid carriers (NLC) as an innovative oral pediatric formulation of HCT with improved therapeutic efficacy. The performance of various synthetic and natural liquid lipids was examined and two different preparation methods were employed, i.e. homogenization-ultrasonication (HU) and microemulsion (ME), in order to evaluate their influence on the NLC properties in terms of size, polydispersity index, zeta-potential, entrapment efficiency, gastric stability, and drug release properties. Precirol(r)ATO5 was used as solid lipid and Tween(r)80 and Pluronic(r)F68 as surfactants, formerly selected in a previous study focused on the development of HCT-solid lipid nanoparticles (SLNs). The presence of Pluronic(r)F68 did not allow ME formation. On the contrary, using Tween(r)80, the ME method enabled a higher entrapment efficiency than the HU. Regardless of the preparation method, NLCs exhibited great entrapment efficiency values clearly higher than previous SLNs. Moreover, NLC-ME formulations provided a prolonged release, which lasted for 6 h. In particular, NLC-ME containing Tween(r)20 as Co-Surfactant showed the best performances, giving rise to a complete drug release, never achieved with previous SLN formulations, despite their successful results. In vivo studies on rats confirmed these results, displaying their best diuretic profile. Moreover, all HCT-loaded NLC formulations showed higher stability than the corresponding SLNs. PMID- 30451016 TI - Outbreak of Haff disease caused by consumption of crayfish (Procambarus clarkii) in nanjing, China. AB - CONTEXT: This paper reports a detailed epidemiological investigation of a large Haff disease outbreak in Nanjing, China, including laboratory analysis of water, river sediment, and fish. METHODS: Structured questionnaires were administered to all case-patients. An unmatched case-control study was conducted to identify the factors affecting the incidence of Haff disease. Thirteen samples of crayfish, together with four samples of water and four samples of sediment were collected and sent for laboratory analysis. RESULTS: The disease onset of 494 patients occurred between 2 am on 30 June 2016 and 3 am on 29 August 2016. The median incubation time for onset of symptoms after crayfish ingestion was 7.1 hours (range: 1-20 hours). All patients presented with or developed local or diffuse myalgia. However, no kidney injury was observed. Serum creatinine kinase was elevated in all patients (mean: 4614 U/L, median: 2000 U/L, range: 81-55200 U/L). The average number of crayfish consumed by patients on the day of illness was 20 (2-80). The case-control study revealed that eating a large quantity of crayfish, drinking alcohol, and eating the crayfish head and/or intestines were associated with an increased risk of disease. Chemical analysis of crayfish, river water and sediment did not identify known or novel toxins including anticoccidiosis drugs, niclosamide, organophosphorus pesticides, and microcystins. CONCLUSION: An outbreak of Haff Disease was associated with consumption of crayfish from the Yangtze River and its surrounding water system. Eating a large quantity of crayfish, eating the head and/or intestines, and consuming alcohol with the crayfish were associated with the development of Haff Disease. PMID- 30451018 TI - Prostaglandin E1 overdose in a term neonate with congenital heart disease. PMID- 30451017 TI - A characterization and disproportionality analysis of medication error related adverse events reported to the FAERS database. AB - OBJECTIVES: To characterize adverse reactions associated with medication errors (ME) reported in US Food and Drug Administration Adverse Event Reporting System (US-FAERS), and to identify the potential signals of disproportionate reporting (SDR) for different drugs. METHODS: ME associated Individual Case Study Report (ICSRs) were identified. ICSRs were categorized by patient age groups, affected stages of medication process and Anatomical Therapeutic Chemical classification system. Disproportionality analyses were performed for different age groups. RESULTS: 46,8677 ICSRs were retrieved. An increasing trend in reporting of cases of ME was observed during the studied period. Immunosuppressants and psycholeptic drugs were most frequently involved. Administration errors were reported most frequently, followed by prescribing and dispensing errors. In neonates, SDR following wrong drug administration, wrong dose, and accidental overdose were associated with methylergonovine, zidovudine, and acetaminophen. In elderlies, SDR were found for dose omission and underdose error associated with etanercept and evolocumab. CONCLUSION: While a detailed root-cause analysis for ME characteristic can rarely be performed on such a dataset, data mining for signals in spontaneous reporting database may assist in identifying potential ME in a more standardized and objective manner. Continued use of spontaneous reporting system for identifying MEs is encouraged to prevent unnecessary patient harm. PMID- 30451019 TI - Validating the ICF core set for cerebral palsy using a national disability sample in Taiwan. AB - PURPOSE: To validate the activities and participation (d) codes of two age specific brief International Classification of Functioning, Disability, and Health (ICF) core sets for school-aged children with cerebral palsy (CP), using national dataset of the child version of the Functioning Scale of the Disability Evaluation System (FUNDES) in Taiwan. METHODS: Students with CP aged 6-17.9 years (n = 546) in the national dataset were analyzed. Items of the child version of the FUNDES were linked to the ICF d-codes and matched to two brief ICF core sets for CP. The restriction rate of the linked d-codes were calculated. Random Forest regression was applied to select the important linked d-codes for predicting school participation frequency. RESULTS: The vast majority of the content of the Taiwanese dataset was covered by two core sets. The matched d-codes represent high restriction rates (80%) and most were important for predicting school participation. One important code, d740 (formal relationships, such as relationship with teachers), identified in this study were not included in two ICF core sets. CONCLUSIONS: Two brief ICF core sets for CP capture the majority of relevant functional information collected by the child version of the FUNDES. Some additional codes not covered in the international ICF core sets should be considered for inclusion in the revised Taiwanese version. Implications for rehabilitation Cerebral palsy (CP) is the most common cause of severe physical disability in childhood. ICF core sets for CP promote a comprehensive assessment and service provision. To ensure applicability, ICF core sets for CP were validated in Taiwan using the child and youth national dataset of the child version of the Functioning Scale of the Disability Evaluation System. This study shows content validity and proposes new ICF codes additions for the Taiwanese version. Among top five ICF-based predictors for school participation frequency, four of them were consistent in both children and youth groups as d310-d350 (basic communication), d750 (informal social relationships), d820 (school education), and d710-d720, d880 and d920 (social play), which could be taken into consideration in clinical application. PMID- 30451020 TI - Clinical and genetic determinants of chronic visual pathway changes after methanol - induced optic neuropathy: four-year follow-up study. AB - CONTEXT: Methanol poisoning induces acute optic neuropathy with possible long term visual damage. OBJECTIVE: To study the dynamics and key determinants of visual pathway functional changes during 4 years after acute methanol poisoning. METHODS: A total of 42 patients with confirmed methanol poisoning (mean age 45.7 +/- 4.4 years) were examined 4.9 +/- 0.6, 25.0 +/- 0.6, and 49.9 +/- 0.5 months after discharge. The following tests were performed: visual evoked potential (VEP), retinal nerve fiber layer (RNFL) measurement, brain magnetic resonance imaging (MRI), complete ocular examination, biochemical tests, and apolipoprotein E (ApoE) genotyping. RESULTS: Abnormal VEP P1 latency was registered in 18/42 right eyes (OD) and 21/42 left eyes (OS), abnormal N1P1 amplitude in 10/42 OD and OS. Mean P1 latency shortening during the follow-up was 15.0 +/- 2.0 ms for 36/42 (86%) OD and 14.9 +/- 2.4 ms for 35/42 (83%) OS, with maximum shortening up to 35.0 ms. No significant change of mean N1P1 amplitude was registered during follow-up. A further decrease in N1P1 amplitude >=1.0 mcV in at least one eye was observed in 17 of 36 patients (47%) with measurable amplitude (mean decrease 1.11 +/- 0.83 (OD)/-2.37 +/- 0.66 (OS) mcV versus -0.06 +/- 0.56 (OD)/-0.83 +/- 0.64 (OS) mcV in the study population; both p < .001). ApoE4 allele carriers had lower global and temporal RNFL thickness and longer initial P1 latency compared to the non-carriers (all p < .05). The odds ratio for abnormal visual function was 8.92 (3.00-36.50; 95%CI) for ApoE4 allele carriers (p < .001). The presence of ApoE4 allele was further associated with brain necrotic lesions (r = 0.384; p = .013) and brain hemorrhages (r = 0.395; p = .011). CONCLUSIONS: Improvement of optic nerve conductivity occurred in more than 80% of patients, but evoked potential amplitude tended to decrease during the 4 years of observation. ApoE4 allele carriers demonstrated lower RNFL thickness, longer P1 latency, and more frequent methanol-induced brain damage compared to non-carriers. PMID- 30451021 TI - Reply to Letter to the editor: efficacy and safety of a combination of HER2 targeted agents as first-line treatment for metastatic HER2-positive breast cancer: a network meta-analysis. PMID- 30451022 TI - Development of an evidence-based practice framework to guide decision making support for people with cognitive impairment due to acquired brain injury or intellectual disability. AB - PURPOSE: At least 5% of people in Australia and the USA have cognitive impairment and require support for decision-making. This paper details a research program whereby an evidence-based Support for Decision Making Practice Framework has been developed for those who support people with cognitive disabilities to make their own decisions across life domains. METHODS: The La Trobe framework was derived from a research program modeled on the Medical Research Council four-phase approach to development and evaluation of complex interventions. We completed phase one (development) by: (1) systematically reviewing peer-reviewed literature; and (2) undertaking qualitative exploration of the experience of support for decision-making from the perspectives of people with cognitive disabilities and their supporters through seven grounded theory studies. Results of phase two (feasibility and piloting) involving direct support workers and health professionals supported phase three (evaluation) and four (implementation), currently underway. RESULTS: The framework outlines the steps, principles, and strategies involved in support for decision-making. It focuses on understanding the will and preferences of people with cognitive disabilities and guides those who provide support including families, support workers, guardians, and health professionals. CONCLUSIONS: This framework applies across diverse contemporary contexts and is the first evidence-based guide to support for decision-making. Implications for Rehabilitation Support for decision-making is essential to maximise the participation of people with cognitive disability in decisions about their lives. Research has shown that support for decision making is a complex multifaceted process comprising multiple overlapping steps, delivered through individually tailored strategies and informed by practice principles. The La Trobe practice framework provides an evidence-based guide for engaging in effective support for decision-making with people with cognitive disability. PMID- 30451024 TI - Evaluation of the accuracy of "ChE check mobile" in measurement of acetylcholinesterase in pesticide poisoning. AB - BACKGROUND: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are used in clinical management to confirm the diagnosis and indicate the severity of organophosphorus and carbamate poisoning. ChE check mobile is a new portable cholinesterase testing system developed in Germany. The study aims to evaluate the accuracy of ChE check mobile compared to the standard reference method and Test-mate ChE system. METHODS: Patients with organophosphorus and carbamate poisoning were recruited from two general hospitals in Sri Lanka between September 2013 and November 2014. The AChE was measured using the three methods. RESULTS: Blood samples were collected from 185 self-poisoned patients (170 organophosphorus and 15 carbamate) and 20 normal individuals. ChE check mobile correlated well with spectrophotometer readings (Pearson's correlation coefficient 0.87) but gave higher values (Mean bias for AChE: +6.55 (95% CI: -11 to 24) U/g Hb). A similar positive bias from Test-mate results was also observed. Applying a correction factor derived from the volunteer samples (dividing by 1.353) greatly improved agreement in pesticide poisoned patients. CONCLUSIONS: ChE check mobile system allowed for rapid determination of AChE activity but gave somewhat higher AChE compared to other methods. Applying a correction factor of 1.353 provide a good agreement to both reference and Test-mate ChE machine in this setting. PMID- 30451023 TI - Carbonic anhydrase 12 mutation modulates membrane stability and volume regulation of aquaporin 5. AB - Patients carrying the carbonic anhydrase12 E143K mutation showed the dry mouth phenotype. The mechanism underlying the modulation of aquaporin 5 and function in the salivary glands by carbonic anhydrase12 remains unknown. In this study, we identified the mislocalised aquaporin 5 in the salivary glands carrying the E143K. The intracellular pH of E143K cells was more acidic than that of the cells carrying wild type. To evaluate the role of carbonic anhydrase12 on the volume regulation of aquaporin 5, the submandibular gland cells were subjected to hypotonic stimuli. E143K enhanced the extent of swelling of cells on hypotonicity. Aquaporin 5 modulates water influx through ion transporters to prevent osmotic imbalance. These results suggest that the carbonic anhydrase12 E143K, including acidification or inflammation, mediates volume dysregulation by the loss of aquaporin 5. Thus, carbonic anhydrase12 may determine sensible effects on the cellular osmotic regulation by modulating aquaporin 5. PMID- 30451025 TI - Factor structure of the Behavioral Assessment Screening Tool (BAST) in traumatic brain injury. AB - OBJECTIVE: Establish the factor structure of the Behavioral Assessment Screening Tool (BAST), a self-reported emotional/behavioral symptom measure for adults with traumatic brain injury (TBI). SETTING: Community. PARTICIPANTS: Community dwelling adults with moderate-severe TBI (n = 162; n = 110). DESIGN: Assessment development (cohort study). MAIN MEASURES: Behavioral Assessment Screening Tool. RESULTS: The original BAST included 61 items (55 primary, six secondary), an Environmental Context checklist including recent major life events, and three open-ended questions about other relevant factors. Two rounds of pilot testing and exploratory factor analysis of the BAST (n = 162; n = 110) reduced the total items to 37 primary items and six secondary coping items. The final BAST had a five-factor solution with communalities ranging from 0.323 to 0.771. Internal consistency reliabilities ranged from acceptable to excellent for all factors (Cronbach's alpha = 0.76-0.90). The items related to coping, given only to those endorsing stress, had a two-factor solution with communalities ranging from 0.224 to 0.605, but demonstrated acceptable to poor internal consistency (Cronbach's alpha = 0.46-0.68). Participants rated ease of use and overall satisfaction with completing the scale as high, with mean scores of 6.42 and 6.22 out of 7, respectively. CONCLUSIONS: The BAST, a measure of behavioral and emotional symptoms after TBI, has a multidimensional factor structure with evidence of good internal consistency reliability. Future work will evaluate the convergent, discriminant, and discriminative validity of the BAST and employ item response theory analyses to further develop a short version for mobile health assessment. Implications for Rehabilitation Long-term monitoring of behavioral and emotional symptoms after traumatic brain injury could improve clinical management and reduce negative participation and quality of life outcomes. The Behavioral Assessment Screening Tool demonstrates reliability for use among adults with chronic traumatic brain injury, through its factor structure and internal consistency reliabilities, to measure chronic behavioral and emotional symptoms. The Behavioral Assessment Screening Tool is a screening tool to identify potential behavioral and emotional problems that individuals with chronic traumatic brain injury may be experiencing; it could be implemented in a proactive, rather than reactive, system for long-term monitoring of these symptoms to improve early identification of clinical disorders. PMID- 30451026 TI - Performance and visual arts-based programs for children with disabilities: a scoping review focusing on psychosocial outcomes. AB - PURPOSE: There is a growing movement in pediatric rehabilitation to understand how approaches addressing aspects beyond body function contribute to enhanced psychosocial well-being. Among such approaches is the use of creative arts. A scoping review was undertaken to synthesize the current literature on performance and visual arts-based programs and outcomes for children with disabilities. METHODS: Data sources included CINAHL, MEDLINE, and PsycINFO. Eligible articles described programs involving performing or visual art activities in community and ambulatory care settings, delivered to children between 6 and 18 years with physical or developmental disabilities, and reported on at least one psychosocial outcome. Domains of interest included emotional, social, behavioral, physical, cognitive, and/or communicative functioning, which are known to impact well-being and participation. No limits were applied to study design. RESULTS: Twelve articles using primarily case study and quasi-experimental designs were identified, encompassing an 11-year period. Most programs focused on theater as the central modality. A majority of papers addressed changes in physical, cognitive, and communicative function (n = 8), followed by social function (n = 6), emotional function (n = 5), and finally, behavioral function (n = 3). Across individual papers, diverse study designs, measures, and outcomes were examined with positive qualitative and/or quantitative findings noted across all domains. CONCLUSIONS: Within an emerging evidence base, arts-based programs show potential to positively impact psychosocial well-being and warrant further investigation with broader populations of children with physical and developmental disabilities. A greater emphasis on programmatic approaches and enhanced methodological rigor to establishing benefits is needed to advance understanding. Implications for rehabilitation Pediatric therapists may wish to consider recommending arts-based programs for children with ASD, TBI, and other developmental disabilities given their potential in achieving psychosocial outcomes Arts-based programs in rehabilitation provide creative ideas (e.g., drawing, painting) and techniques (e.g., modeling, role-play), which may be incorporated into individualized or group-based therapy to promote psychosocial well-being Program evaluators and researchers are encouraged to adopt a programmatic approach to further explore how art activities facilitate psychosocial outcomes. PMID- 30451027 TI - Review of the use of telepathology for intraoperative consultation. AB - INTRODUCTION: The use of telepathology in intraoperative consultations has been increasing due to limited time and availability of pathologists, and the demand for increased access to pathology subspecialists in difficult cases. The five main categories of telepathology are (1) static, (2) dynamic, (3) robotic, (4) whole slide imaging (WSI), and (5) hybrid methods. The majority of these methods have been found to offer diagnostic accuracy rates similar to conventional microscopy, at the cost of slightly prolonged time to evaluate slides. Areas covered: Herein we discuss the salient features of each telepathology method and provide examples of their performance reported in the literature. Expert commentary: Telepathology systems from any of the aforementioned categories can be employed to achieve timely and accurate diagnoses as long as they meet clinical needs and are validated for the intended use case. The decision to purchase a particular system depends on the clinical application, specific needs and budget of the laboratory, as well as the personal preference of the telepathologists involved. The adoption of telepathology practice is likely to expand in order to meet the increasing demand for subspecialist consultation and as technology advances to improve diagnostic accuracy and workflow. PMID- 30451028 TI - Identification of categories of the International Classification of Functioning, Disability and Health in functional assessment measures for stroke survivors: a systematic review. AB - OBJECTIVE: Perform a systematic review to identify the categories of the International Classification of Functioning, Disability and Health linked to the concepts measured by functional assessment tools validated for Brazilian Portuguese: Timed Up and Go test, Functional Independence Measure, Barthel Index, and Rivermead Mobility Index and Modified Rankin Scale. METHODS: The Medline, Embase and CINAHL databases were consulted using a standardized search strategy. The studies were summarized using a pre-established set of specific criteria for the adequate linkage between the concepts identified in the assessment measures and the International Classification of Functioning, Disability and Health categories. Two independent reviewers performed the selection of the studies, data extraction and evaluation of the results. RESULTS: The search of the databanks led to the retrieval of 99 studies. However, only six articles were included in the present review. The linkage results of the studies included in the review were divergent, likely due to the taxonomic complexity of the International Classification of Functioning, Disability and Health, the difficulty in clearly relating the concepts of the assessment measures to the classifications and the fact that not all linkage rules were followed. "Activities and participation" was the most evaluated component, with mobility the most frequently covered category in the measures, followed by self-care. Among the measures analyzed, the Functional Independence Measure addresses a greater number of categories and therefore has the most concepts related to the International Classification of Functioning, Disability and Health, followed by the Barthel Index, Modified Rankin Scale, Rivermead Mobility Index and Timed Up and Go test. The Modified Rankin Scale was the assessment tool that most evaluated categories related to environmental factors. CONCLUSION: The Functional Independence Measure has more concepts related to the International Classification of Functioning, Disability and Health, since it addresses a greater number of categories. These findings can help guide health professionals in the selection of assessment tools for the evaluation of post-stroke functioning, making viable the use of the International Classification of Functioning, Disability and Health categories in clinical practice and public health services. Implications for rehabilitation This study standardized identification of the International Classification of Functioning, Disability and Health categories in the main outcome measures used to assess post-stroke functional capacity. Functional Independence Measure has more concepts related to the International Classification of Functioning, Disability and Health compared to other functional assessment instruments. Findings can enable physiotherapists and researchers choose the most appropriate measure that best corresponds to their field of interest. These results facilitate the implementation of the International Classification of Functioning, Disability and Health in clinical practice. Use of International Classification of Functioning, Disability and Health categories can standardize information on functional health. PMID- 30451029 TI - Type B botulism in a Korean couple after eating homemade doenjang. PMID- 30451030 TI - To what extent does therapy of chronic stroke patients address participation? A content analysis of ambulatory physical and occupational therapy based on the International Classification of Functioning, Disability, and Health framework. AB - PURPOSE: The study aim was to analyze whether ambulatory therapy of chronic stroke patients contains elements that specifically address "Activity and participation", and to what extent participation as a major goal in rehabilitation is realized in ambulatory care. METHOD: Qualitative and quantitative content analysis of standard therapy of 71 chronic stroke patients with upper limb impairment. 469 statements on therapy of 34 therapists were analyzed using data-driven and concept-driven coding based on the International Classification of Functioning, Disability and Health framework. RESULTS: Almost half of therapy provided to stroke patients was related to "Upper extremity" (47.5%), as one out of seven identified main categories. Regarding International Classification of Functioning, Disability, and Health framework, 75.1% of therapeutic practices in ambulatory therapy covered "Body functions," but only 13.2% addressed "Activities and participation". Some statements contained specific therapeutic concepts (9.4%) or isolated notes (2.1%) and were not linkable to the International Classification of Functioning, Disability and Health framework. CONCLUSIONS: Ambulatory therapy of chronic stroke patients is related, in part, to participation. There is potential for an increase in participation by applying therapeutic approaches, which actively involve the patients in goal-setting and therapeutic exercises to specifically address activities and participation. Implications for rehabilitation To realize participation as a major goal in the rehabilitation process ambulatory therapy of chronic stroke patients, one should focus on therapeutic approaches and exercises that specifically address activities and participation. Structured goal-setting, which actively involve patients, can be used to identify goals relevant to individual activities and participation. PMID- 30451031 TI - Pediatric airway management devices: an update on recent advances and future directions. AB - INTRODUCTION: Structural and physiologic differences between pediatric and adult patients make management of the pediatric airway a challenge. Many initial airway device designs were modeled for adult patients and simply downsized for the pediatric population. This paper reviews the last decade's design improvements in video laryngoscopes and supraglottic airway devices (SGAs), as well as advances in noninvasive oxygenation/ventilation techniques for pediatric airway management. Areas covered: Topic areas reviewed include basic principles of common and newer devices for video laryngoscopy, supraglottic airway management, and alternate ventilation techniques. A literature search was conducted in PubMed using device-specific keywords and limited to neonatal, infant, and pediatric populations. Articles were reviewed for evidence deemed high yield by the authors. Device specifications were obtained from manufacturer correspondences. Features, comparisons, advantages, and disadvantages are provided for each device class. We give expert commentary regarding the current state of clinical application, research considerations, as well as a 5-year outlook on potential areas of device design and development. Expert commentary: Video laryngoscopes and SGAs are safe and effective for use in children and improvements continue to be made for neonates and infants. The most significant area of new research is in the area of noninvasive airway devices for oxygenation and ventilation in difficult airways. PMID- 30451032 TI - Glycomics of prostate cancer: updates. AB - INTRODUCTION: Prostate cancer (PCa) is a life-threatening disease affecting millions of men. The current best PCa biomarker (level of prostate-specific antigen in serum) lacks specificity for PCa diagnostics and this is why novel PCa biomarkers in addition to the conventional ones based on biomolecules such as DNA, RNA and proteins need to be identified. Areas covered: This review details the potential of glycans-based biomarkers to become diagnostic, prognostic, predictive and therapeutic PCa biomarkers with a brief description of the innovative approaches applied to glycan analysis to date. Finally, the review covers the possibility to use exosomes as a rich source of glycans for future innovative and advanced diagnostics of PCa. The review covers updates in the field since 2016. Expert commentary: The summary provided in this review paper suggests that glycan-based biomarkers can offer high-assay accuracy not only for diagnostic purposes but also for monitoring/surveillance of the PCa disease. PMID- 30451033 TI - Workplace accommodations following work-related mild traumatic brain injury: what works? AB - BACKGROUND: Individuals who have experienced a work-related mild traumatic brain injury face a variety of challenges when returning to work. Research has demonstrated that the implementation of workplace accommodations can reduce the incidence of workplace disability. Few studies investigate work-related mild traumatic brain injury from injured workers' perspectives, and none examine workplace accommodations in detail. PURPOSE: This study explores the types of accommodations that individuals receive, and the factors that influence how they are provided and to whom. MATERIALS AND METHODS: This study is a qualitative secondary data analysis of 12 telephone interviews. ATLAS.ti software was used to facilitate coding and thematic analysis was used to analyze the data. RESULTS: This study makes explicit various accommodations identified as being useful or required by individuals on return to work. Participants identified a gradual return to work, and modified duties, among other accommodations. Components of the workplace social and structural environment, and the occupational context influenced how accommodations were provided and to whom. CONCLUSIONS: Obtaining appropriate support is of great importance to injured employees, their employers, insurers, and healthcare providers. Stakeholders should be aware of how to successfully identify and access appropriate workplace accommodations to support injured workers on return to work. Implications for rehabilitation Return to Work Accommodations * Workplace accommodations reduce the incidence of workplace disability. * Workplace accommodations can be formal or informal. * Participants identified a gradual return to work, modified duties, self-directed compensatory strategies, and allowances for medical appointments, among other accommodations, as being useful or required. * Stakeholders, including healthcare providers involved in rehabilitation, should be aware of how to successfully identify and implement these accommodations to ensure injured workers are supported on return to work. PMID- 30451034 TI - Determining the best approach to reduce the impact of exercise-induced atrial fibrillation: prevention, screening, or symptom-based treatment? AB - INTRODUCTION: Regular endurance exercise over the course of many years appears to increase the risk of atrial fibrillation (AF). These data challenge the notion that the benefits of physical activity have no appreciable limits. The incidence of exercise-induced AF is expected to increase as a consequence of the popularity of extreme endurance sports. Actions to reduce its impact are warranted. Areas covered: This review focuses on exercise-induced AF and reviews the existing data regarding the prevention, screening, and treatment of this disease, with the aim of elucidating the best options for this group of patients. Expert commentary: To date, strategies to deal with exercise-induced AF are unsatisfactory. Improved knowledge of AF pathology and better classification schemes are needed to address current pitfalls. PMID- 30451035 TI - Drug and therapeutics committees in Nigeria: evaluation of scope and functionality. AB - INTRODUCTION: Inappropriate use of medicines remains a problem, with consequences including increasing adverse drug reactions (ADRs) and prolonged hospitalizations. The Essential Medicines List and Drug and Therapeutics Committees (DTCs) are accepted initiatives to promote the rational use of medicines. However, little is known about DTC activities in Nigeria, the most populous African country. Areas covered: A cross-sectional questionnaire-based study was conducted among senior pharmacists, consultant physicians, and clinical pharmacologists in 12 leading tertiary health-care facilities across Nigeria. Expert commentary: Six (50%, 6/12) health-care facilities had existing DTCs with three (50%) having a subcommittee on antimicrobials. Seventy-five percent had infection control committees, with presence even in centers without DTCs. Chairpersons and secretaries of the DTCs were predominantly physicians (83.3%) and pharmacists (100%), respectively. Hospital formularies were available in five facilities with DTCs, while one facility without a DTC had an Essential Medicines Committee responsible for developing and updating the hospital formulary. The evaluation of ADRs was undertaken by pharmacovigilance units in nine facilities. Overall, DTCs were present in only half of the surveyed facilities and most were performing their statutory functions sub-optimally. The functioning of DTCs can be improved through government directives and mechanisms for continuous evaluation of activities. PMID- 30451036 TI - Presence of cyclopropane fatty acids in foods and estimation of dietary intake in the Italian population. AB - Cyclopropane fatty acids (CPFAs) are the most abundant cyclic fatty acids in microorganisms with unknown role(s) regarding their dietary relevance and biological effects in humans. This work was aimed to draw up a list of CPFAs containing foods for estimating their dietary intake in the Italian population to provide a basis for evaluating their nutritional relevance and potential health related effects. The CPFAs content of more than 500 food items was investigated and a preliminary dietary intake was assessed (12.0 +/- 6.0 mg/day), based on the data reported by the Italian National Food Consumption Survey INRAN-SCAI 2005-06. CPFAs should be considered of dietary relevance in view of their potential physiological activity in humans and their presence in significant amounts in dairy products, as Grana Padano cheese (9.0-30.0 mg/100 g), and in bovine meat (0.7-4.0 mg/100 g). Future studies should elucidate whether this uncommon class of fatty acids has a biological role in human health. PMID- 30451037 TI - Vaccine hesitancy 'outbreaks': using epidemiological modeling of the spread of ideas to understand the effects of vaccine related events on vaccine hesitancy. AB - INTRODUCTION: Vaccine hesitancy, a growing global problem which is aggravated by vaccine related rumors and (mis)information, has the potential to reverse the gains from vaccination. Areas covered: We describe a selection of vaccine-related events that have made headlines and highlight the effects that these have had on vaccine acceptance. Drawing on these cases, and an adaptation of an epidemiological modeling of the spread of ideas, we propose that vaccine hesitancy can be grouped into two categories: 'baseline' and 'reactive' vaccine hesitancy. 'Baseline' vaccine hesitancy refers to the level of refusal or delay in acceptance of vaccinations that is constantly present in the population. Though it may vary, changes are unlikely to be sudden or dramatic. 'Reactive' hesitancy, which often occurs because of vaccine-related events, is characterized by a rapid spike in levels of hesitancy, usually subsiding at a slow rate. Expert commentary: Different kinds of interventions are needed to address different forms of vaccine hesitancy. Modeling the diffusion of (mis)information during vaccine hesitancy 'outbreaks' is essential for designing interventions that will ensure appropriate management of 'reactive' hesitancy, and control of 'baseline' levels of vaccine hesitancy. More empirical research is needed to test and better understand this hypothesis. PMID- 30451038 TI - Targeting MTHFR for the treatment of migraines. AB - INTRODUCTION: Migraine is a common neurovascular disorder classified by the World Health Organization as one of the most debilitating diseases. Migraine is a complex disease and is a consequence of an interaction between genetic, epigenetic and environmental factors. The MTHFR gene is one of the few replicated genetic risk factors for migraine and encodes an enzyme that is crucial for the folate and the methionine cycles. Individuals carrying the T allele of the MTHFR C677T polymorphism have increased plasma concentrations of homocysteine which leads to endothelial cell injury and alterations in coagulant properties of blood. Areas covered: This review focuses on the recent advances in genetics and the role of the MTHFR gene and homocysteine metabolism in migraine etiopathogenesis. The article summarizes the potential of targeting MTHFR and homocysteine for disease prevention. Expert opinion: Determination of MTHFR C677T polymorphisms as well as measurement of homocysteine concentrations may be useful to migraine patients, particularly those suffering from migraine with aura. Preliminary studies support the use of folate, vitamin B6 and vitamin B12 for the prevention of migraine. However, the results of these studies await replication in larger randomized controlled clinical trials. PMID- 30451039 TI - Preventing suicidal behavior in patients with multiple sclerosis: a scoping review. AB - INTRODUCTION: Suicidal behavior is a relatively rare occurrence among patients with multiple sclerosis (MS). Nonetheless, it is important to identify and be aware of the constituting risk factors to prevent suicidal behavior among vulnerable patients. Areas covered: This scoped review will shortly outline well known biological and psychosocial risk factors for suicidal behavior among MS patients and suggest preventive initiatives. The preventive strategies should include a close monitoring of MS pharmacotherapy to prevent progression, and awareness and early identification of psychosocial risk factors across a variety of heathcare and social instances the patient may encounter during their life with the disease. The staff in these instances should be educated in detecting the MS patients at increased risk and refer them to relevant healthcare instances, including the general practitioner, neurologists, psychiatrist, etc. In addition, referral to social instances to support educational, vocational, and home environment to the state of the disease is of utmost importance. Expert commentary: Enhancing quality of life for as long as possible by these means may be held to reduce the risk for psychosocial problems and hence suicidal behavior. PMID- 30451040 TI - Patients' perceptions of faecal calprotectin testing in inflammatory bowel disease: results from a prospective multicentre patient-based survey. AB - INTRODUCTION: Despite its success, there appears to be practical issues with Faecal Calprotectin (FC) testing in Inflammatory Bowel Diseases (IBD), including sample collection, delivery and processing delays. Patients' perception and barriers to FC testing are yet to be explored in clinical practice. METHOD: A prospective patient survey was undertaken at IBD units in UK, Europe and Australia. A 9-point patient-based questionnaire was completed in clinic and included demographics, previous FC testing and FC sample difficulty rating score. Predictors of testing difficulty were derived using multivariable logistic regression analysis. RESULTS: A total of 585 patients with IBD completed the survey; 306 males with a median age of 43 years (IQR: 31-54). There were 446 patients (76%) who had prior FC testing experience. Of these, 37% (n = 165) rated FC testing difficult; 'sample collection' (n = 106; 67%) being the most common reason reported. Multivariable regression analysis identified age <49 years (odds ratio (OR): 2.5, CI:1.6-4.0), disease duration <35 months (OR 1.4, CI:0.9-2.1) and testing location (UK centre: OR 1.9, CI:1.2-3.1) as predictors of a difficult FC rating score. CONCLUSIONS: A total of 37% of patients find FC testing challenging, in particular those aged <49 years, disease duration <35 months. Further studies understanding and addressing these practical issues may aid higher FC uptake in clinic. PMID- 30451041 TI - Dual mobility cups in primary total hip arthroplasties: trend over time in use, patient characteristics, and mid-term revision in 3,038 cases in the Dutch Arthroplasty Register (2007-2016). AB - Background and purpose - We noticed an increased use of dual mobility cups (DMC) in primary total hip arthroplasty (THA) despite limited knowledge of implant longevity. Therefore, we determined the trend over time and mid-term cup revision rates of DMC compared with unipolar cups (UC) in primary THA. Patients and methods - All primary THA registered in the Dutch Arthroplasty Register (LROI) during 2007-2016 were included (n = 215,953) and divided into 2 groups - DMC THA (n = 3,038) and UC THA (n = 212,915). Crude competing risk and multivariable Cox regression analyses were performed with cup revision for any reason as primary endpoint. Adjustments were made for sex, age, diagnosis at primary THA, previous operation, ASA score, type of fixation, surgical approach, and femoral head size. Results - The proportion of primary DMC THA increased from 0.8% (n = 184) in 2010 to 2.6% (n = 740) in 2016. Patients who underwent DMC THA more often had a previous operation on the affected hip, a higher ASA score, and the diagnosis acute fracture or late posttraumatic status compared with the UC THA group. Overall 5-year cup revision rate was 1.5% (95% CI 1.0-2.3) for DMC and 1.4% (CI 1.3-1.4) for UC THA. Stratified analyses for patient characteristics showed no differences in cup revision rates between the 2 groups. Multivariable regression analyses showed no statistically significantly increased risk for revision for DMC THA (HR 0.9 [0.6-1.2]). Interpretation - The use of primary DMC THA increased with differences in patient characteristics. The 5-year cup revision rates for DMC THA and UC THA were comparable. PMID- 30451042 TI - Treatment of Cutaneous Lichen Planus (Part 2): A Review of Systemic Therapies. AB - BACKGROUND: Although numerous medications are available for the treatment of cutaneous lichen planus (CLP), recurrence is common and there is a lack of evidence of efficacy of many treatment options. Part 1 reviewed consolidated evidence from topical therapies and phototherapy. In Part 2, all systemic treatments are assessed. METHODS: All English studies, regardless of design, investigating the outcome of systemic treatment for CLP, until January 2018, were included. While there were only a few well designed randomised control trials (RCTs), evidence was extrapolated and graded from open trials, case series as well as case reports. RESULTS: Mini pulse therapy with corticosteroids should be considered over moderate daily dosing with retinoids being an alternative option. Low dose methotrexate is considered effective and safe provided it is regularly monitored. Azathioprine, cyclosporine and mycophenolate mofetil require larger more defined RCTs in resistant CLP. Low-molecular-weight heparins may be considered in patients with no response to first-line treatment. Biologics are potentially promising but there is a need for RCTs with a considerable duration to determine their long-term safety profiles. Evidence with various other drugs were reported. CONCLUSION: Clinicians may have a broader perspective on the efficacy of treatments across all study profiles. PMID- 30451043 TI - The rectal remnant after total colectomy for colitis - intra-operative,post operative and longer-term considerations. AB - OBJECTIVES: Acute severe colitis requires surgery in around 30% of the cases. Total colectomy with ileostomy is the standard procedure with distinct advantages to a laparoscopic approach. Less agreement exists regarding the formation or configuration of the retained rectal stump and its short-term and long-term management. In this review, aspects of management of the rectal remnant, including perioperative considerations, potential complications, medical treatment, surveillance and implications for proctectomy and reconstructive surgery are explored. METHODS: A thorough literature review exploring the PubMed and EMBASE databases was undertaken to clarify the evidence base surrounding areas of controversy in the surgical approach to acute severe colitis. In particular, focus was given to evidence surrounding management of the rectal remnant. RESULTS: There is a paucity of high quality evidence for optimal management of the rectal stump following colectomy, and randomised trials are lacking. Establishment of laparoscopic colectomy has been associated with distinct advantages as well as the emergence of unique considerations, including those specific to rectal remnant management. CONCLUSIONS: Early surgical involvement and a multidisciplinary approach to the management of acute severe colitis are advocated. Laparoscopic subtotal colectomy and ileostomy should be the operation of choice, with division of the rectum at the pelvic brim leaving a closed intraperitoneal remnant. If the rectum is severely inflamed, a mucus fistula may be useful, and an indwelling rectal catheter is probably advantageous to reduce the complications associated with stump dehiscence. Patients electing not to proceed to proctectomy should undergo surveillance for dysplasia of the rectum. PMID- 30451044 TI - Long noncoding RNA (lncRNA): A target in neuropathic pain. AB - INTRODUCTION: Current treatments for neuropathic pain are limited at least in part due to the incomplete understanding of its underlying mechanisms. Recent evidence reveals the dysregulated expression of long non-coding RNAs (lncRNAs) in the damaged nerve, dorsal root ganglion (DRG), and spinal cord dorsal horn following peripheral nerve injury. However, the role of the majority of lncRNAs in neuropathic pain genesis is still elusive. Unveiling the mechanisms of how lncRNAs participate in neuropathic pain may develop new strategies to prevent and/or treat this disorder. Areas covered: This review focuses on the dysregulation of lncRNAs in the DRG, spinal cord dorsal horn, and the injured peripheral nerves from preclinical rodent models of neuropathic pain. We provide evidence of how peripheral nerve injury causes the dysregulation of lncRNAs in these pain-related regions. The potential mechanisms of how dysregulated lncRNAs contribute to the pathogenesis of neuropathic pain are discussed. Expert opinion: The investigation on the role of the dysregulated lncRNAs in neuropathic pain might open up a novel avenue for therapeutic treatment of this disorder. However, current investigation is at the infancy stage, which challenges the translation of preclinical findings. More intensive study on lncRNAs is required before the preclinical findings are translated into therapeutic management for neuropathic pain. PMID- 30451045 TI - Frequency of alpha-Globin Gene Triplications and Coinheritance with beta-Globin Gene Mutations in the Iranian Population. AB - Numerical variation in alpha-globin genes is very important due to their roles as an effective factor for phenotype presentation. An unequal crossover from misalignment of a homologous sequence of an alpha-globin gene during meiosis can produce a numerical alteration. A single alpha-globin gene deletion is the most frequent mutation in alpha-thalassemia (alpha-thal) worldwide, while the additional alpha-globin chain is relatively common. The excess alpha-globin gene plays a critical role in pathophysiology of thalassemia, especially when in coinherited with beta-thalassemia (beta-thal). alpha-Globin triplication leads to an imbalanced ratio between alpha- and beta-globin chains, thus, it can exacerbate the clinical and hematological features of beta-thal. Different studies have been performed in various countries to determine the frequency of alpha-globin triplication and its genotype-phenotype correlation with beta-thal. In this study, we focused on the frequency of alpha-globin gene triplication and its characterization, either solely or in coexistence with beta-globin gene mutations in Iranian populations. We have investigated the alpha-globin gene rearrangements in 4010 individuals from different provinces of Iran with normal to abnormal hematological parameters. In total, the frequency of the alphaalphaalphaanti 3.7 triplication was 1.7% and phenotype aggravation was observed in alpha-globin triplication patients who were carriers of beta-thal. Therefore, identification of genotype-phenotype correlation of alpha-globin triplication with beta-thal can be very useful for predicting the severity of clinical manifestations during genetic counseling. PMID- 30451046 TI - Predictors of return to desired activity 12 months following unicompartmental and total knee arthroplasty. AB - Background and purpose - 1 in 5 patients are dissatisfied following unicompartmental or total knee arthroplasty (UKA or TKA). This may be partly explained by failing to return to desired activity post-arthroplasty. To facilitate return to desired activity, a greater understanding of predictors of return to desired activity in UKA and TKA patients is needed. We compared rates of return to desired activity 12 months following UKA vs. TKA, and identified and compared predictors of return to desired activity 12 months following UKA vs. TKA. Patients and methods - Patients were prospectively recruited from 2 hospitals prior to undergoing UKA or primary TKA. Patients reported preoperatively the activity/activities that were limited due to their knee that they wished to return to after arthroplasty. At 12-months postoperatively, patients reported whether they had returned to these activities ('return to desired activity'). Preoperative predictors evaluated were age, sex, BMI, education, comorbidities, pain expectations, Oxford Knee Score (OKS), UCLA Activity Score, and EQ-5D. Generalized linear models assessed the relationship between potential predictors and return-to-desired-activity. Results - The response rate of all patients eligible for 12-month follow-up was 74%. TKA patients (n = 575) were older (mean (SD) 70 (9) vs. 67 (10)) with a greater BMI (31 (6) vs. 30 (5)) than patients undergoing UKA (n = 420). 75% of UKA and 59% of TKA patients returned to desired activity. TKA patients had a greater risk of non return to desired activity than patients undergoing UKA (risk ratio (95% CI) 1.5 (1.2-1.8)). Predictors of non-return to desired activity following UKA were worse OKS (0.96 (0.93-0.99)), higher BMI (1.04 (1.01-1.08)), and worse expectations (1.9 (1.2-2.8)). Predictors of non-return to desired activity following TKA were worse EQ-5D (0.53 (0.33-0.85)) and worse OKS (0.98 (0.96-1.0)). Interpretation - UKA patients were more likely to return to desired activity than TKA patients. Predictors of return to desired activity differed following UKA and TKA. Optimizing selection of arthroplasty procedure based on patient characteristics and targeting predictors of poor outcome may facilitate return to desired activity with potential to enhance postoperative satisfaction. PMID- 30451047 TI - Validated repeatability of patient-reported outcome measures following primary total hip replacement: a mode of delivery comparison study with randomized sequencing. AB - Background and purpose - Patient-reported outcome measures (PROMs) are used to understand better the outcomes after total hip replacement (THR). These are administered in different settings using a variety of methods. We investigated whether the mode of delivery of commonly used PROMs affects the reported scores, 1 year after THR. Patients and methods - A prospective test-retest mode comparison study with randomized sequence was done in 66 patients who had undergone primary THR. PROMs were administered by 4 modes: self-administration, face-to-face interview, telephone interview, and postal questionnaire. PROMs included: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oxford Hip Score (OHS), EQ5D-3L (EQ5D), and Self-Administered Patient Satisfaction Scale (SAPS). Linear regression was used to estimate relationships between the mean scores for PROMs by mode. Individual paired differences by mode were calculated, relationships between modes were identified, and results adjusted by time delay and participant age. Results - There was no statistically significant difference between the mean PROM scores recorded for each mode of delivery for each score. Statistically significant differences in the individual paired differences were detected between modes for the WOMAC stiffness subscale, OHS, EQ5D, and SAPS. OHS difference in individual paired means between face-to face and telephone interview exceeded the minimal clinically important difference. Interpretation - PROMs mode of administration can affect the recorded results. Modes should not be mixed and may not be comparable between studies. It should not be assumed that different modes will obtain the same results and where not already established this should be checked by researchers before use. PMID- 30451048 TI - Hydro-Ethanolic Fruit Extract of Capsicum frutescens Reversed Triton-X-100 Induced Hyperlipidaemia in Rats. AB - This study evaluates the anti-hyperlipidaemic and antioxidant activities of hydro ethanolic fruits extract of Capsicum frutescens in hyperlipidemia rats. The secondary volatile metabolite constituents of the extract were identified using Gas chromatography. In vitro antioxidant activity of the extract (0.2-1.0 mg/mL) was investigated using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydrogen peroxide (H2O2) and hydroxyl radical (OH.). In vivo antioxidant and anti hyperlipidaemic properties of the extract were evaluated in triton X-100-induced hyperlipidaemic rats. Gas chromatogram indicates the presence of 13 compounds with tans beta-ocimene being the major constituent. The extract scavenged DPPH, H2O2 and OH. radicals in concentrations dependent manner. C. frutescens reversed triton X-100-mediated increase in serum total cholesterol, triglycerides and low density lipoprotein, and reduction in high-density lipoprotein. Triton X-100 mediated decrease in superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose 6-phospahte dehydrogenase were significantly reversed by the extract. The results indicate that C. frutescens has antioxidant and anti-hyperlipidaemic properties. PMID- 30451049 TI - Measurement properties of the OARSI core set of performance-based measures for hip osteoarthritis: a prospective cohort study on reliability, construct validity and responsiveness in 90 hip osteo-arthritis patients. AB - Background and purpose - Improvement of physical function is one of the main treatment goals in severe hip osteoarthritis (OA) patients. The Osteoarthritis Research Society International (OARSI) has identified a core set of performance based tests to assess the construct physical function: 30-s chair stand test (30 s CST), 4x10-meter fast-paced walk test (40 m FPWT), and a stair-climb test. Despite this recommendation, available evidence on the measurement properties is limited. We evaluated the reliability, validity, and responsiveness of these performance-based measures in patients with hip OA scheduled for total hip arthroplasty (THA). Patients and methods - Baseline and 12-month follow-up measurements were prospectively obtained in 90 end-stage hip OA patients who underwent THA. As there is no gold standard for comparison, the hypothesis testing method was used for construct validity and responsiveness analysis. A test can be assumed valid if >=75% of predefined hypotheses are confirmed. A subgroup (n = 30) underwent test-retest measurements for reliability analysis. The Oxford Hip Score, Hip injury and Osteoarthritis Outcome Score-Physical Function Short Form, pain during activity score, and muscle strength were used as comparator instruments. Results - Test-retest reliability was appropriate; intraclass correlation coefficient values exceeded 0.70 for all 3 tests. None of the performance-based measures reached 75% hypothesis confirmation for the construct validity or responsiveness analysis. Interpretation - The performance based tests have good reliability in the assessment of physical function. Construct validity and responsiveness, using patient-reported measures and muscle strength as comparator instruments, could not be confirmed. Therefore, our findings do not justify their use for clinical practice. PMID- 30451050 TI - Bioactive metabolites from the leaves of Withania adpressa. AB - CONTEXT: Withania (Solanaceae) species are known to be a rich source of withanolides, which have shown several biological properties. OBJECTIVE: To identify the compounds responsible for Withania adpressa Coss. antioxidant activity and further test them for their NF-kappaB inhibition and antiproliferative activity in multiple myeloma cells. MATERIALS AND METHODS: Compounds were obtained from the EtOAc extract of W. adpressa leaves. Structure elucidation was carried out mainly by 1D- and 2D-NMR, and mass spectrometry. Isolated compounds were tested in a dose-response for their in vitro NF-kappaB inhibition and antiproliferative activity in multiple myeloma cells after 5 and 72 h treatment, respectively. RESULTS: The fractionation resulted in the isolation of a new glycowithanolide named wadpressine (5) together with withanolide F, withaferin A, coagulin L, and nicotiflorin. The latter showed a moderate ability to scavenge free radicals in DPPH (IC50 = 35.3 uM) and NO (IC50 = 41.3 uM) assays. Withanolide F and withaferin A exhibited low uM antiproliferative activity against both multiple myeloma cancer stem cells and RPMI 8226 cells. Furthermore, they inhibited NF-kappaB activity with IC50 values of 1.2 and 0.047 uM, respectively. The other compounds showed a moderate inhibition of cell proliferation in RPMI 8226 cells, but were inactive against cancer stem cells and did not inhibit NF-kappaB activity. DISCUSSION AND CONCLUSIONS: One new glycowithanolide and four known compounds were isolated. Biological evaluation data gave further insight on the antitumor potential of withanolides for refractory cancers. PMID- 30451051 TI - The journeys of three ASPIRE winning medical schools toward excellence in student assessment. AB - INTRODUCTION: ASPIRE Excellence Awards in Student Assessment are offered to medical schools with innovative and comprehensive assessment programmes adjudged by international experts, using evidence-based criteria. The journeys of three ASPIRE-winning medical schools toward "assessment excellence" are presented. These schools include Aga Khan University Medical College (AKU-MC), Pakistan, Southern Illinois University School of Medicine (SIUSOM), USA, and University of Leeds School of Medicine, UK. METHODS: The unfolding journeys highlighting achievements, innovations, and essential components of each assessment programme were compared to identify differences and commonalities. RESULTS: Cultural contextual differences included developed-versus-developing country, east-west, type of regulatory bodies, and institutional-versus-national certifying/licensing examinations, which influence curricula and assessments. In all, 12 essential commonalities were found: alignment with institutional vision; sustained assessment leadership; stakeholder engagement; communication between curriculum and assessment; assessment-for-learning and feedback; longitudinal student profiling of outcome achievement; assessment rigor and robustness; 360 degrees feedback from-and-to assessment; continuous enrichment through rigorous quality assurance; societal sensitivity; influencing others; and a "wow factor." CONCLUSIONS: Although the journeys of the three medical schools were undertaken in different cultural contexts, similar core components highlight strong foundations in student assessment. The journeys continue as assessment programmes remain dynamic and measurement science expands. This article may be helpful to other institutions pursuing excellence in assessment. PMID- 30451052 TI - Measurement of FeNO with a portable, electrochemical analyzer using a 6-second exhalation time in 7-10-year-old children with asthma: comparison to a 10-second exhalation. AB - OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is a valuable tool for assessing Th2 inflammation in children with asthma. Exhalation times of 6 and 10 s meet the current recommendations for assessing FeNO. The 6-s exhalation provides an alternative for 7-10 year olds not able to complete the 10-s exhalation. METHODS: We performed a sub-analysis on data from 7-10-year-old children who participated in a previous study which evaluated the agreement of the 6 and 10-s exhalation times in 6-10 year olds with asthma. Agreement between observed FeNO results obtained by both modes was assessed by weighted Deming regression analysis and Bland-Altman plots. Repeatability was also assessed. RESULTS: Repeatability and agreement of the 6 and 10-s exhalations was demonstrated in 7-10 year olds with two measurements in each mode. Mean observed FeNO measurements were 33.59 ppb (SD = 25.804) for 6 s and 32.46 ppb (SD = 25.302) for 10-s exhalation. Paired differences were centered close to 0 ppb (median = 0.50). CONCLUSIONS: Children aged 7-10 years can successfully perform FeNO measurements using a portable, electrochemical FeNO analyzer. Measurements from the 6 and 10-s exhalations were repeatable and consistent with a high degree of agreement between one another. Thus, in young children successful FeNO measurements can be obtained in either the 6-s or 10-s mode, providing physicians valuable information on airway inflammation to aid in the diagnosis and treatment of asthma. PMID- 30451053 TI - Adolescents' mental health and well-being in developing countries: a cross sectional survey from Pakistan. AB - BACKGROUND: Despite global recognition of the significance of adolescents' mental health it remains a neglected area in research and health policy in Pakistan. AIM: To examine the rates of depression and anxiety and to assess the level of well-being among Pakistani adolescents. METHODS: A cross-sectional sample of 1124 adolescents (age 11-18 years) was recruited from schools in Rawalpindi, Pakistan. RESULTS: 17.2% and 21.4% participants were identified to be probable cases of depression and anxiety, respectively. The mean well-being score of the participants was 65.79 (S.D = 12.84). Girls were more anxious than boys. Depressive symptoms and well-being were significantly associated with age. Poor economic status, lower level of education and more negative life events were significantly associated with higher levels of depression and anxiety symptoms and poor well-being. CONCLUSION: To our knowledge, this is the first school-based observational research exploring the rates of symptoms of depression and anxiety as well as well-being among 11-18 years old in Pakistan. This study concludes that mental health of Pakistani adolescents is an important area of public health concern and provides information for making policy level decisions regarding evaluation, prevention and intervention of mental health problems among adolescents in Pakistan. PMID- 30451054 TI - Extracorporeal shock wave lithotripsy under intravenous sedation for treatment of urolithiasis. AB - BACKGROUND: In contrast to treatment with oral or intramuscular analgesics, extracorporeal shock wave lithotripsy (E.S.W.L.) can be performed with patients under sedation too. Besides the advantage of increased shock energy, patients tend to have more constant breathing excursions and are more idle during treatment, potentially increasing the stone-free ratio (S.F.R.) after treatment. METHODS: This study presents the results of 310 patients who underwent 400 E.S.W.L. procedures under sedation, with a stationary lithotripter. RESULTS: After one procedure, the S.F.R. was 54.8% (170/310). A second treatment was successful in 42.1% (32/76), a third treatment in 21.4% (3/14). Therefore, 66.1% (205/310) of patients eventually became stone-free. Kidney stones were successfully treated in 65.4% (161/246), ureteral stones in 68.8% (44/64) of cases. Patients with stones <=15 mm were successfully treated in 67.4% (194/288), patients with stones >15 mm in 50% (11/22) of cases. Considering each procedure individually, 45.3% (181/400) of procedures were successful after 3 weeks. Extending follow-up to 3 months is important, since 26.7% of stones (24/90) eventually still disappeared, increasing S.F.R. to 51.3% after one procedure. Complications occurred after 5.5% E.S.W.L.-procedures. CONCLUSIONS: E.S.W.L. is a well-tolerated, non-invasive procedure that produces reasonable stone clearance of both upper and lower urinary tract calculi. Performing the procedure whilst patients are intravenously sedated results in an acceptable S.F.R. Strong selection based on unfavourable factors could increase the chance on successful treatment and spare patients a pointless procedure. However, considering E.S.W.L.'s elegant nature, sometimes a more tolerant approach seems justifiable. PMID- 30451055 TI - Factors Associated With Older Adults' Enrollment in Balance Classes to Prevent Falls: Case-Control Study. AB - Balance training decreases fall risk among older adults, but few participate in such training. We examined the association of exposure to social marketing to promote balance classes, personal characteristics and other factors, with older adults' balance class participation. Adults aged ?60 years were eligible for this case-control study if they attended any church enrolled in a trial testing the effect of social marketing on balance class participation. Cases attended balance classes during the study period; controls were randomly sampled congregants who did not join a class. Cases were more likely to attend churches that received the social marketing program, and were older, more often female, and more frequently experienced "near falls" than controls. Participation was also associated with increasing age of the church's leader and rural church attendance. Programs to promote balance classes may need to be tailored to target some risk groups, including men and urban and suburban congregants. PMID- 30451056 TI - The correlation between body mass index and prostatic-related parameters in men 40 years or older in Zhengzhou. AB - PURPOSE: To understand the relationship between body mass index (BMI), age, prostate volume (PV), prostate-specific antigen (PSA), International Prostate Symptom Score (IPSS) and quality of life (QoL) in Zhengzhou. MATERIALS AND METHODS: In the cross-sectional study, men living in Zhengzhou were invited to participate in this study. Men who were 40 years or older were subjected to the IPSS and related examination. A total of 1360 participants were included. Body mass index < 18.5 kg/m2 was determined as underweight, 18.5-24.99 kg/m2 normal, 25-29.99 kg/m2 overweight, and >= 30 kg/m2 obese. RESULTS: The mean BMI was 24.81 +/- 3.37 kg/m2. The mean PSA was 1.50 +/- 0.81 ng/mL. The mean PV was 19.79 +/- 5.84 mL. The mean age was 59.64 +/- 11.05 years. The mean IPSS was 5.15 +/- 3.58 scores. The mean QoL was 2.64 +/- 1.39 scores. PSA showed a significant tendency to decrease with increasing BMI (r = -0.201, p < .001; ptrend < 001). The same with age (r = -0.060, p < .001; ptrend = .049) and QoL (r = -0.083, p = .002; ptrend = .014). But the result suggested that IPSS was positively correlated with BMI (r = 0.187, p < .001; ptrend < .001). PV increased with increasing BMI (r = 0.123, p < .001; ptrend < .001). CONCLUSIONS: Age, PSA, IPSS, and QoL decreased with increasing BMI. But larger PV was associated with higher BMI. PMID- 30451057 TI - Screening of mitochondrial tRNA mutations in 300 infants with hearing loss. AB - Mitochondrial DNA (MtDNA) mutations are the important causes for hearing loss. To see the contribution of mtDNA to deafness, we screened for mutations in mt-tRNA genes from 300 deaf infants and 200 healthy subjects. Moreover, we analyzed the mtDNA copy number and ROS levels in patients carrying the mt-tRNA mutations. Consequently, 3 mt-tRNA mutations: tRNALeu(UUR) A3243G; tRNAAla T5655C and tRNAGlu A14692G were identified, however, these mutations were not detected in controls. Of these, the A3243G mutation created a novel base-pairing (13G-23A) in the D-stem of tRNALeu(UUR); while the T5655C mutation occurred at the very conserved acceptor arm of tRNAAla; in addition, the A14692G mutation was located at position 55 in the TPsiC loop of tRNAGlu. Molecular analysis showed that patients harbouring the A3243G, T5655C and A14692G mutations had a lower level of mtDNA copy number, while ROS level increased significantly when compared with controls. Through the application of the pathogenicity scoring system, we noticed that the A3243G, T5655C and A14692G should be regarded as 'definitely pathogenic' mutations associated with deafness. Thus, our study provided novel insight into the pathophysiology, early detection of mitochondrial deafness. PMID- 30451058 TI - Renal tumor biopsies are associated with a low complication rate. AB - BACKGROUND: Due to the high incidence of benign lesions in renal masses, numerous studies have been performed to clarify the value of core needle biopsies. The aim of the present study was to describe the complication rate after renal tumor biopsies (RTB), in order to make recommendations on observation after the procedure. MATERIALS AND METHODS: Data from all patients who underwent percutaneous ultrasound-guided RTB between February 2013 and October 2016 due to CT verified solid renal masses were prospectively collected and kept in a well maintained database. Complications were collected retrospectively and classified according to the Clavien-Dindo (CD) classification system. RESULTS: Data from 224 consecutive patients were retrieved. Thirteen patients underwent unilateral repeat biopsies and three patients underwent bilateral biopsies; thus, a total of 240 procedures were analyzed. A total of 124 patients (51.7%) were discharged within 4 hours after the RTB procedures and 110 patients (45.8%) were discharged within 24 hours. The remaining six patients (2.5%) were hospitalized for more than 1 day, all due to co-morbidities which were unrelated to the procedure. In total, five patients (2.1%) experienced post-biopsy complications: one case of iatrogenic pneumothorax, one case of spontaneously resolving hematuria and three cases of fever. All complications were CD <=2 and all patients with complications were discharged within 24 hours, except for one patient who was hospitalized for 3 days due to management of bone pain. No correlation was found between the number of biopsies and complication rate. CONCLUSION: The overall complication rate following ultrasound-guided biopsies of renal tumors was low and all complications were mild. Given the current evidence, it is believed that ultrasound-guided RTB can be done as an outpatient procedure without the need for hospitalization. PMID- 30451059 TI - Elemental distribution in the edible leaves of Celosia trigyna from the western and northern regions of Nigeria. AB - Celosia trigyna, which belongs to the plant family Amaranthaceae, is a plant used in traditional medicine to treat several conditions such as sores, chest pains, diarrhoea and menstrual cramps in many countries in Africa. It is also consumed by the local people in Nigeria as soups, sauces and stews. In this study, the distribution and bioaccumulation of the elements in C. trigyna species and growth soil from the western and northern regions of Nigeria was investigated to determine the effects of geographical location on the uptake of elements by the plant. Elemental concentrations in the leaves from the western region were found to be in decreasing order of Ca > Mg > Fe > Mn > Zn > Cu > Pb > As > Ni. Concentrations of elements in the leaves from the northern region were found to be in decreasing order of Ca > Mg > Fe > Mn > Zn > Cu > As > Pb > Ni > Co > Cd. Proximate analysis of leaves from both regions compared well with the recommended dietary allowance making the leaves safe for human consumption. Principal component analysis was used to group elements having the same sources irrespective of their geographical locations. Cd, Co and Cr were not detected in the leaves from the western region. Concentrations of As and Pb were above maximum permissible limits in both regions, while Ayegunle and Bida (in the northern region) had the highest concentrations of Cd. The high level of these toxic metals may be attributed to anthropogenic activities. It is therefore important that the Nigerian agricultural extension system emphasizes the dangers of heavy metal contamination in leafy vegetables to farmers. Activities of the manufacturing industries in the study area should be adequately monitored under standard environmental protection laws. PMID- 30451060 TI - Tracking the Rise of Geriatric Emergency Departments in the United States. AB - The traditional model of emergency care no longer fits the growing needs of the over 20 million older adults annually seeking emergency department care. In 2007 a tailored "geriatric emergency department" model was introduced and rapidly replicated among hospitals, rising steeply over the past 5 years. This survey examined all U.S. emergency departments self-identifying themselves as Geriatric Emergency Departments (GEDs) and providing enhanced geriatric emergency care services. It was guided by the recently adopted Geriatric Emergency Department Guidelines and examined domains including, GED identity, staffing, and administration; education, equipment, and supplies; policies, procedures, and protocols; follow-up and transitions of care; and quality improvement. Results reveal a heterogeneous mix of GED staffing, procedures, physical environments and that GEDs' familiarity with the GED Guidelines is low. Findings will inform emergency departments and gerontologists nationwide about key GED model elements and will help hospitals to improve ED services for their older adult patients. PMID- 30451061 TI - Family Member Death and Subjective Life Expectancy Among Black and White Older Adults. AB - OBJECTIVE: To examine whether exposure to family member deaths throughout the life course is associated with subjective life expectancy-a person's assessment of their own mortality risk-at age 65, with attention to differences by race. METHOD: We analyzed 11 waves of data from a study of men and women above age 50 (Health and Retirement Study; n = 13,973). RESULTS: Experiencing the deaths of multiple family members before the respondent is 50 years old is negatively associated with subjective life expectancy at age 65. DISCUSSION: Understanding the life-course predictors of older adults' subjective life expectancy is particularly important because survival expectations influence long-term planning, health, and longevity. Moreover, Black Americans are exposed to more family member deaths earlier in their life compared with White Americans, with implications for long-term health and well-being. PMID- 30451062 TI - Research of stroke combined hyperlipidemia-induced erectile dysfunction in rat model. AB - OBJECTIVE: The study was aimed to evaluate the influences of erectile dysfunction (ED) in a rat model of stroke combined with hyperlipidemia (HLP). METHODS: Male Sprague-Dawley rats were divided into control and hyperlipidemia (HLP) groups. HLP model was constructed by feeding with high-fat and cholesterol diets. Serum levels of total cholesterol (TC), low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride (TG), and non-HDL were identified to check the model was success. Stroke model was established by FeCl3. ICP/MAP value was detected to evaluate the erectile function of rats. Serum level of lipoproteins and the expressions of endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF) were detected by ELISA. Hematoxylin-eosin (HE) staining of corpus cavernosum and measurement of penis length were utilized to assessment erectile function. Western blot was used. RESULTS: TC, TG, LDL, and non-HDL-C in serum were up-regulated, while HDL level was attenuated. After treatment, the serum lipid level recovered. From the ICP/MAP values, the erectile function of both two treatment groups recovered. The expression of PDE5A was up regulated, while the levels of eNOS and cGMP were suppressed after surgery. The length of penis was decreased, and corpus cavernosum was damaged following HLP and stroke. However, the erectile function was recovered after treatment. CONCLUSION: Stroke combined HLP caused ED through NO-cGMP-PDE5 pathway. PMID- 30451063 TI - Data Analytics and Modeling for Appointment No-show in Community Health Centers. AB - OBJECTIVES: Using predictive modeling techniques, we developed and compared appointment no-show prediction models to better understand appointment adherence in underserved populations. METHODS AND MATERIALS: We collected electronic health record (EHR) data and appointment data including patient, provider and clinical visit characteristics over a 3-year period. All patient data came from an urban system of community health centers (CHCs) with 10 facilities. We sought to identify critical variables through logistic regression, artificial neural network, and naive Bayes classifier models to predict missed appointments. We used 10-fold cross-validation to assess the models' ability to identify patients missing their appointments. RESULTS: Following data preprocessing and cleaning, the final dataset included 73811 unique appointments with 12,392 missed appointments. Predictors of missed appointments versus attended appointments included lead time (time between scheduling and the appointment), patient prior missed appointments, cell phone ownership, tobacco use and the number of days since last appointment. Models had a relatively high area under the curve for all 3 models (e.g., 0.86 for naive Bayes classifier). DISCUSSION: Patient appointment adherence varies across clinics within a healthcare system. Data analytics results demonstrate the value of existing clinical and operational data to address important operational and management issues. CONCLUSION: EHR data including patient and scheduling information predicted the missed appointments of underserved populations in urban CHCs. Our application of predictive modeling techniques helped prioritize the design and implementation of interventions that may improve efficiency in community health centers for more timely access to care. CHCs would benefit from investing in the technical resources needed to make these data readily available as a means to inform important operational and policy questions. PMID- 30451064 TI - Physician and patient treatment decision-making in relapsing-remitting multiple sclerosis in Europe and the USA. AB - OBJECTIVE: To assess factors used in treatment decision-making for relapsing remitting multiple sclerosis in both the 5EU (UK/Germany/France/Italy/Spain) and the USA. METHODS: Data were abstracted from the Ipsos Healthcare Global Multiple Sclerosis Therapy Monitor (data abstracted September-December, 2015-2017) a bi annual online chart-review study of patients with multiple sclerosis. RESULTS: Treatment choices were primarily due to efficacy for relapses while convenience factors, other than oral administration, were uncommon. Predominantly, the choice of disease modifying therapy at first line was jointly made, with patient involvement decreasing at later lines of treatment. CONCLUSION: Relapsing remitting multiple sclerosis patients are highly engaged in their treatment decisions, particularly early in the pathway. The majority were made jointly between the physician and patient, driven by efficacy. PMID- 30451065 TI - Astrocytes: Heterogeneous and Dynamic Phenotypes in Neurodegeneration and Innate Immunity. AB - Astrocytes are the most numerous cell type in the brain and perform several essential functions in supporting neuronal metabolism and actively participating in neural circuit and behavioral function. They also have essential roles as innate immune cells in responding to local neuropathology, and the manner in which they respond to brain injury and degeneration is the subject of increasing attention in neuroscience. Although activated astrocytes have long been thought of as a relatively homogenous population, which alter their phenotype in a relatively stereotyped way upon central nervous system injury, the last decade has revealed substantial heterogeneity in the basal state and significant heterogeneity of phenotype during reactive astrocytosis. Thus, phenotypic diversity occurs at two distinct levels: that determined by regionality and development and that determined by temporally dynamic changes to the environment of astrocytes during pathology. These inflammatory and pathological states shape the phenotype of these cells, with different consequences for destruction or recovery of the local tissue, and thus elucidating these phenotypic changes has significant therapeutic implications. In this review, we will focus on the phenotypic heterogeneity of astrocytes in health and disease and their propensity to change that phenotype upon subsequent stimuli. PMID- 30451066 TI - Contextualizing Experiences of Diabetes-Related Stress in Rural Dominican Republic. AB - Type 2 diabetes (T2D) is changing the burden of disease across Latin America. In this formative, qualitative study, we explored experiences of T2D diagnosis and management among adults in rural Dominican Republic. We conducted 28 in-depth interviews (12 men, 16 women) and used inductive analysis to explore the emotional burden of T2D and identify coping strategies. We found that stress relating to T2D began at diagnosis and persisted throughout management. Stress was produced by concerns about healthy food and medication access, fears about illness-induced injury, and the cyclical process of experiencing stress. Participants identified diabetes care and free medication services as external stress-reducers. Internally, participants' mitigated stress by not thinking about diabetes (" no dar mente"). Our study highlights the importance of a contextualized understanding of diabetes-related stress and the need for individual, clinic, and community-level interventions to reduce stressors and improve health outcomes among adults with T2D. PMID- 30451067 TI - Osteoconductive 3D porous composite scaffold from regenerated cellulose and cuttlebone-derived hydroxyapatite. AB - Recently, usage of marine-derived materials in biomedical field has come into prominence due to their promising characteristics such as biocompatibility, low immunogenicity and wide accessibility. Among these marine sources, cuttlebone has been used as a valuable component with its trace elemental composition in traditional medicine. Recent studies have focused on the use of cuttlebone as a bioactive agent for tissue engineering applications. In this study, hydroxyapatite particles were obtained by hydrothermal synthesis of cuttlebone and incorporated to cellulose scaffolds to fabricate an osteoconductive composite scaffold for bone regeneration. Elemental analysis of raw cuttlebone material from different coastal zones and cuttlebone-derived HAp showed that various macro , micro- and trace elements - Ca, P, Na, Mg, Cu, Sr, Cl, K, S, Br, Fe and Zn were found in a very similar amount. Moreover, biologically unfavorable heavy metals, such as Ag, Cd, Pb or V, were not detected in any cuttlebone specimen. Carbonated hydroxyapatite particle was further synthesized from cuttlebone microparticles via hydrothermal treatment and used as a mineral filler for the preparation of cellulose-based composite scaffolds. Interconnected highly porous structure of the scaffolds was confirmed by micro-computed tomography. The mean pore size of the scaffolds was 510 um with a porosity of 85%. The scaffolds were mechanically characterized with a compression test and cuttlebone-derived HAp incorporation enhanced the mechanical properties of cellulose scaffolds. In vitro cell culture studies indicated that MG-63 cells proliferated well on scaffolds. In addition, cuttlebone-derived hydroxyapatite significantly induced the ALP activity and osteocalcin secretion. Besides, HAp incorporation increased the surface mineralization which is the major step for bone tissue regeneration. PMID- 30451068 TI - Improved adaptive randomization strategies for a seamless Phase I/II dose-finding design. AB - In this article, we propose and evaluate three alternative randomization strategies to the adaptive randomization (AR) stage used in a seamless Phase I/II dose-finding design. The original design was proposed by Wages and Tait in 2015 for trials of molecularly targeted agents in cancer treatments, where dose efficacy assumptions are not always monotonically increasing. Our goal is to improve the design's overall performance regarding the estimation of optimal dose as well as patient allocation to effective treatments. The proposed methods calculate randomization probabilities based on the likelihood of every candidate model as opposed to the original design which selects the best model and then randomizes doses based on estimations from the selected model. Unlike the original method, our proposed adaption does not require an arbitrarily specified sample size for the adaptive randomization stage. Simulations are used to compare the proposed strategies and a final strategy is recommended. Under most scenarios, our recommended method allocates more patients to the optimal dose while improving accuracy in selecting the final optimal dose without increasing the overall risk of toxicity. PMID- 30451069 TI - Evaluating cerebrovascular reactivity during the early symptomatic phase of sport concussion. AB - Cerebrovascular reactivity (CVR) indexes the ability of blood vessels to respond to vasoactive stimuli and may be a sensitive biomarker of concussion. However, alterations in whole-brain CVR remain poorly understood during the early symptomatic phase of injury. In this study, CVR was assessed using blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) combined with a respiratory challenge paradigm; resting cerebral blood flow (CBF) was also evaluated using arterial spin labelling (ASL). Imaging data were collected for 77 university-level athletes, including 56 athletic uninjured controls and 21 concussed athletes scanned in the early symptomatic phase of injury (<7 days post-injury). The normal response to respiratory challenge was assessed in the athletic control group, in which a robust whole-brain response was seen. The concussed athletes were then compared to a matched subset of controls. Concussion was associated with greater reductions in BOLD activity during the early phase of the respiratory task, localized primarily in frontal and prefrontal areas, whereas no significant effects on resting global CBF were observed. In addition, greater symptom severity was associated with greater reductions in BOLD response, with effects seen throughout the brain. The study establishes fMRI with respiratory challenge as a robust method for assessing acute concussion-related alterations in CVR. Moreover, it highlights the importance of examining neurovascular response to physiological stressors after a concussion. PMID- 30451070 TI - EXPRESS: Adverse Physiologic Effects of Western Diet on Right Ventricular Structure and Function: Role of Lipid Accumulation and Metabolic Therapy. PMID- 30451071 TI - Strategies to Promote the Inclusion of Young Adults With Developmental Disabilities in Community-Based Health Studies. AB - We discuss strategies to promote the inclusion of people with developmental disabilities (DDs) in qualitative community-based research studies. Strategies were applied in three projects conducted between 2012 and 2017 that addressed issues of socioeconomic challenges, discrimination, and exclusion of children and young adults with developmental disabilities (YADD). Strategies included partnership with community organizations; inclusion of YADD, family caregivers (FCs), and service providers in advisory committees (ACs); and strategies to accommodate YADD. As part of our contribution, we discuss issues of invisibility and exclusion of individuals with DDs who have "low" functioning capacities. There is a need to review studies sampling inclusion criteria as they may constitute a barrier for participation. Preference for sampling "high" functioning individuals may reinforce exclusion in research, and replicate broader patterns of socioeconomic exclusion of individuals with disabilities. Our discussion of inclusive research is informed by critical disability studies and the underlying principle "nothing about us without us." PMID- 30451072 TI - Glycolytic inhibitor 2-deoxy-D-glucose at chronic low dose mimics calorie restriction in rats through mitohormetic induction of ROS. AB - Caloric restriction mimetics (CRMs) provide an exciting anti-aging intervention strategy. 2-deoxy-D-glucose (2-DG), a glycolytic inhibitor is known to works as a CRM at high doses, however chronic high dose has been linked to increased mortality in rats. We have investigated chronic low dose dietary administration of 2-DG on age-related stress protection in young and old age male wistar rats by evaluating age-dependent biomarkers in plasma and erythrocytes. Significant increase was observed in ROS generation in 2-DG treated rats (both young and old), concomitant with increase in erythrocyte plasma membrane redox system (PMRS), catalase (CAT) and superoxide dismutase (SOD). 2-DG treatment also decreased plasma sialic acid and advanced glycation end products (AGEs). We propose that 2-DG induces a mitohormetic response resulting in augmentation of defence mechanism(s) manifested by higher activity of PMRS, CAT and SOD. Our findings provide evidence that at chronic low dose 2-DG could be a potential CRM. PMID- 30451073 TI - Difference Within and Without: Health Care Providers' Engagement With Disability Arts. AB - Re*Vision, an assemblage of multimedia storytelling and arts-based research projects, works creatively and collaboratively with misrepresented communities to advance social well-being, inclusion, and justice. Drawing from videos created by health care providers in disability artist-led workshops, this article investigates the potential of disability arts to disrupt dominant conceptions of disability and invulnerable embodiments, and proliferate new representations of bodymind difference in health care. In exploring, remembering, and developing ideas related to their experiences with and assumptions about embodied difference, providers describe processes of unsettling the mythical norm of human embodiment common in health discourse/practice, coming to know disability in nonmedical ways, and re/discovering embodied differences and vulnerabilities. We argue that art-making produces instances of critical reflection wherein attitudes can shift, and new affective responses to difference can be made. Through self reflective engagement with disability arts practices, providers come to recognize assumptions underlying health care practices and the vulnerability of their own embodied lives. PMID- 30451074 TI - YAP/TAZ mechano-transduction as the underlying mechanism of neuronal differentiation induced by reduced graphene oxide. AB - AIM: The aim of this work is the dissection of the molecular pathways underlying the differentiation effect of reduced graphene oxide (GO) materials in the absence of differentiation agents. MATERIALS & METHODS: Reduced GO is obtained either by drop casting method and heat-treated or biological reduction by the interaction between GO and wtPrxI. Cells were grown on both materials and the differentiation process studied by immunological and morphological detection. RESULTS & CONCLUSION: The results obtained indicate that both reduction methods of GO can determine the modulation of pathway involved in mechano-transduction and differentiation, by affecting YAP/TAZ localization outside the nuclei and increasing neuronal differentiation markers. This suggests that the mechano transduction pathways are responsible for the differentiation process. PMID- 30451076 TI - Nanopharmaceuticals and nanomedicines currently on the market: challenges and opportunities. AB - There has been a revolution in nanotechnology and nanomedicine. Since 1980, there has been a remarkable increase in approved nano-based pharmaceutical products. These novel nano-based systems can either be therapeutic agents themselves, or else act as vehicles to carry different active pharmaceutical agents into specific parts of the body. Currently marketed nanostructures include nanocrystals, liposomes and lipid nanoparticles, PEGylated polymeric nanodrugs, other polymers, protein-based nanoparticles and metal-based nanoparticles. A range of issues must be addressed in the development of these nanostructures. Ethics, market size, possibility of market failure, costs and commercial development, are some topics which are on the table to be discussed. After passing all the ethical and biological assessments, and satisfying the investors as to future profitability, only a handful of these nanoformulations, successfully obtained marketing approval. We survey the range of nanomedicines that have received regulatory approval and are marketed. We discuss ethics, costs, commercial development and possible market failure. We estimate the global nanomedicine market size and future growth. Our goal is to summarize the different approved nanoformulations on the market, and briefly cover the challenges and future outlook. PMID- 30451077 TI - Insinuation Anxiety: Concern That Advice Rejection Will Signal Distrust After Conflict of Interest Disclosures. AB - When expert advisors have conflicts of interest, disclosure is a common regulatory response. In four experiments (three scenario experiments involving medical contexts, and one field experiment involving financial consequences for both parties), we show that disclosure of a financial or nonfinancial conflict of interest can have a perverse effect on the advisor-advisee relationship. Disclosure, perhaps naturally, decreases an advisee's trust in the advice. But disclosure can also lead to concern that failure to follow advice will be interpreted as a signal of distrust. That is, rejecting the advice could suggest that the advisee is insinuating that the advisor could be biased by the conflict of interest. We show that this insinuation anxiety persists whether the disclosure is voluntary or required by law and whether the disclosed conflict is big or small, but it diminishes when the disclosure is made by an external source rather than directly by the advisor. PMID- 30451079 TI - Little evidence for Fast Mapping (FM) in adults: A review and discussion. AB - Conventional memory theory proposes that the hippocampus is initially responsible for encoding new information, before this responsibility is gradually transferred to the neocortex. Therefore, a report in 2011 by Sharon et al. of hippocampal independent learning in humans was notable. These authors reported normal learning of new object-name associations under a Fast Mapping (FM) procedure in adults with hippocampal damage, who were amnesic according to more conventional explicit memorisation procedures. FM is an incidental learning paradigm, inspired by vocabulary acquisition in children, which is hypothesised to allow rapid, cortical-based memory formation. In the years since the original report, there has been, understandably, a growing interest in adult FM, not only because of its theoretical importance, but also because of its potential to help rehabilitate individuals with memory problems. We review the FM literature in individuals with amnesia and in healthy adults, using both explicit and implicit memory measures. Contrary to other recent reviews, we conclude that the evidence for FM in adults is weak, and restraint is needed before assuming the phenomenon exists. PMID- 30451078 TI - [EXPRESS] RNA-seq of Spinal Cord in Nerve-injured Rats after Spinal Cord Stimulation. AB - Spinal cord stimulation (SCS) has become an important modality in pain treatment especially for neuropathic pain conditions refractory to pharmacotherapy. However, the molecular control of inhibitory and excitatory mechanisms observed after SCS are poorly understood. Here we used RNA-seq to identify differences in the expression of genes and gene networks in spinal cord tissue from nerve injured rats with and without repetitive conventional SCS treatment. Five weeks after chronic constrictive injury (CCI) to the left sciatic nerve, male and female rats were randomized to receive repetitive SCS or no treatment. Rats receiving SCS underwent epidural placement of a miniature stimulating electrode and received 7 sessions of SCS (50 Hz, 80% motor threshold, 0.2 ms, constant current bipolar stimulation, 120 min/session) over 4 consecutive days. At 1-2 hours after the last SCS treatment, the L4-L6 spinal segments ipsilateral to the side of nerve injury was harvested and used to generate libraries for RNA-seq. Our RNA-seq data suggest further increases of many existing upregulated immune responses in CCI rats after repetitive SCS, including transcription of cell surface receptors and activation of non-neuronal cells. We also demonstrate that repetitive SCS represses transcription of several key synaptic signaling genes that encode scaffold proteins in the post-synaptic density. Our transcriptional studies suggest a potential relationship between specific genes and the therapeutic effects observed in patients undergoing conventional SCS after nerve injury. Furthermore, our results may help identify new therapeutic targets for improving the efficacy of conventional SCS and other chronic pain treatments. PMID- 30451080 TI - The place of transcranial direct current stimulation in the management of multiple sclerosis-related symptoms. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by chronic inflammation, demyelination, synaptopathy and neurodegeneration. Patients may exhibit sensory, motor, cognitive, emotional and behavioral symptoms throughout their disease process. Nowadays, the challenge is to find optimal treatment for MS symptoms, especially that available pharmacological interventions are faced by modest therapeutic outcomes and numerous side effects. Thus, finding alternative strategies might be of help in this context. The aim of this report is to visit the effects of transcranial direct current stimulation - a noninvasive brain stimulation technique - in the context of MS symptoms, namely fatigue, cognitive deficits, psychiatric complaints, neuropathic pain and some sensorimotor manifestations. PMID- 30451082 TI - Quality indicators for Palliative Day Services: A modified Delphi study. AB - BACKGROUND:: The goal of Palliative Day Services is to provide holistic care that contributes to the quality of life of people with life-threatening illness and their families. Quality indicators provide a means by which to describe, monitor and evaluate the quality of Palliative Day Services provision and act as a starting point for quality improvement. However, currently, there are no published quality indicators for Palliative Day Services. AIM:: To develop and provide the first set of quality indicators that describe and evaluate the quality of Palliative Day Services. DESIGN AND SETTING:: A modified Delphi technique was used to combine best available research evidence derived from a systematic scoping review with multidisciplinary expert appraisal of the appropriateness and feasibility of candidate indicators. The resulting indicators were compiled into 'toolkit' and tested in five UK Palliative Day Service settings. RESULTS:: A panel of experts independently reviewed evidence summaries for 182 candidate indicators and provided ratings on appropriateness, followed by a panel discussion and further independent ratings of appropriateness, feasibility and necessity. This exercise resulted in the identification of 30 indicators which were used in practice testing. The final indicator set comprised 7 structural indicators, 21 process indicators and 2 outcome indicators. CONCLUSION:: The indicators fulfil a previously unmet need among Palliative Day Service providers by delivering an appropriate and feasible means to assess, review, and communicate the quality of care, and to identify areas for quality improvement. PMID- 30451083 TI - Rapid repeat exposure to sub-threshold trauma causes synergistic axonal damage and functional deficits in the visual pathway in a mouse model. AB - We examined the effect of repeat exposure to a non-damaging insult on CNS axons using the optic projection as a model. The optic projection is attractive because its axons are spatially separated from the cell bodies, it is easily accessible, it is composed of long axons, and its function can be measured. We performed closed-system ocular neurotrauma in C57Bl/6 mice using bursts of 15psi or 26psi over-pressure air that caused no gross damage. We quantified the visual evoked potential (VEP) and total and degenerative axons in the optic nerve. Repeat exposure to a 15psi air blast caused more axon damage and vision loss than a single exposure to a 26psi air blast. However an increased VEP latency was detected in both groups. Exposure to three 15psi air blasts separated by 0.5 seconds caused 15% axon degeneration at two weeks. In contrast, no axon degeneration above sham levels was detected when the inter-injury interval was increased to 10 minutes. Exposure to 15psi air blasts once a day for 6 consecutive days caused 3% axon degeneration. Therefore, repeat mild trauma within an inter-injury interval of 1min or less causes synergistic axon damage, whereas mild trauma repeated at a longer inter-injury interval causes additive, cumulative damage. The synergistic damage may underlie the high incidence of traumatic brain injury and traumatic optic neuropathy in blast-injured service members since explosive blasts are multiple injury events that occur in a very short time span. This study also supports the use of the VEP as a biomarker for traumatic optic neuropathy. PMID- 30451084 TI - Long-term outcome of conservative and invasive treatment in patients with hypertrophic obstructive cardiomyopathy. AB - BACKGROUND AND OBJECTIVE: Treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM) can be either conservative or invasive (alcohol septal ablation (ASA) and myectomy). As there is no clear consensus on the long-term effects of these different strategies, the aim was to compare the long-term outcome in a large tertiary referral university hospital. METHODS: We retrospectively included 106 HOCM patients. Twenty-nine (27.4%) patients were treated conservatively, 25 (23.6%) underwent ASA and 52 (49.0%) myectomy. Endpoints were all-cause mortality and sudden cardiac death (SCD)-related events (including SCD, aborted SCD and appropriate ICD shocks). Kaplan-Meier survival analysis and Cox proportional hazard regression models were used. RESULTS: The mean follow-up period was 7.7 +/- 4.9 years. Overall, there was no significant difference in survival between the three treatment strategies (p = 0.7). Annual rates of SCD-related events at 5 years and the complete follow-up period were significantly higher (p = 0.034) after conservative treatment (4.9%/year and 2.7%/year, respectively) compared to ASA (0.9%/year, 0.5%/year) and myectomy (1.0%/year, 0.6%/year). Independent predictors of SCD-related events were: conservative treatment (HR 10.66; 1.88-60.55), a known mutation (HR 9.36; 1.43 61.20), left ventricular wall thickness (LVWT) > 30 mm (HR 6.48; 1.05-39.92) and non-sustained VT (HR 16.82; 2.29-123.29). Invasive treatment resulted in a significant higher proportion of patients requiring pacing (p = 0.033). CONCLUSIONS: Long-term mortality rates for patients with HOCM are similarly low between treatment groups. However, conservative treatment was associated with SCD related events, as were known mutations, increased LVWT and non-sustained VT. Invasive treatment was associated with a higher need for implantation of a pacemaker. PMID- 30451085 TI - Computational design, structure refinement and molecular dynamics simulation of novel engineered serratiopeptidase analogs. AB - Communicated by Ramaswamy H. Sarma. PMID- 30451086 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from non-academic institutions June 1-June 30, 2018. PMID- 30451087 TI - Frontline Workers' Career Pathways: A Detailed Look at Washington State's Medical Assistant Workforce. AB - Medical assistants (MAs) are a rapidly growing and increasingly important workforce. High MA turnover, however, is common and employers report applicants frequently do not meet their needs. We collected survey responses from a representative sample of 3,355 of Washington's MAs with certified status (MA-Cs) to understand their demographic, education, and employment backgrounds; job satisfaction; and career plans. Descriptive analyses showed 93.0% were female with a $19.91 mean hourly wage, and while generally satisfied, 56.2% indicated they would seek training or employment in another health care occupation within 5 years, with higher percentages among MA-Cs who felt overwhelmed by their workload and/or not satisfied with promotion opportunities. Regression analyses showed Hispanic, Black, and Asian MA-Cs were more likely than White MA-Cs to express interest in other health care careers. Strategies that strengthen MA career pathways and retain qualified workers should reward both employers and MAs and contribute to a stable and diverse workforce. PMID- 30451088 TI - Aflatoxin B1 in peanut oil from Western Guangdong, China, during 2016-2017. AB - Aflatoxin B1 (AFB1) occurrence in peanut oil samples randomly collected from family workshops in western Guangdong during 2016-2017 (n = 427) was surveyed. AFB1 content was screened by enzyme-linked immunosorbent assay (ELISA) protocol and analytically confirmed with an UPLC-MS/MS method. The limit of detection of the ELISA method was 1.08 MUg kg-1. The recovery values ranged from 84.4 to 92.6% with relative standard deviations of 2.2 to 4.8%. AFB1 was quantified in 47 samples (22.5%) with a range of 15.4-49.9 MUg kg-1 in 2016 and in 33 samples (15.1%) with 8.8-22.2 MUg kg-1 in 2017, respectively. The AFB1 contamination in peanut oil was season-depended in western Guangdong with the worst case in spring (24.2-37.9%). Overall, a significant reduction of AFB1 occurrence was observed in western Guangdong after 2016. It is advisable to control AFB1 in bulk and self pressed oil from family workshops and regulate it mandatorily if necessary. PMID- 30451089 TI - Double-sides sticking mechanism of vinblastine interacting with alpha,beta tubulin to get activity against cancer cells. AB - Vinblastine (VLB) and its derivatives have been used for clinical first-line drugs to treat various cancers. Due to the resistance and serious side effects from using VLB and its derivatives, there is a need to discover and develop novel VLB derivatives with high activity against cancer cells. In order to better discover and develop new VLB derivatives, we need to study the structural basis of VLB's anti-cancer cytotoxicity and the mechanism of its interaction with alpha,beta-tubulins. Based on the crystal structure of alpha,beta-microtubule complex protein, the molecular dynamics method including the sampling PMF method was used to study the variation of dissociation free energy (DeltaG) of alpha,beta-tubulins under different system conditions, and then from which to study the mechanism of the interaction between VLB and alpha,beta-tubulins. The obtained results show that the dissociation of pure alpha,beta-tubulins requires 197.8 kJ.mol-1 for DeltaG. When the VLB molecule exists between the interface of alpha,beta-tubulins, the dissociation DeltaG of alpha,beta-tubulins reaches 220.5 kJ.mol-1, which is greater than that of pure alpha,beta-tubulin. The VLB molecule is formed by connecting a vindoline moiety (VM) molecule with a catharanthine moiety (CM) molecule through a carbon-carbon bond, which is a larger molecule. When the CM molecule exists in the middle of alpha,beta-tubulin interface, the dissociation DeltaG of alpha,beta-tubulins is 46.2 kJ.mol-1, during which the CM moves with beta-tubulin. When the VM molecule exists between the middle of alpha,beta-tubulin interface, the dissociation DeltaG of alpha,beta-tubulins is 86.7 kJ.mol-1, during which it moves with alpha-tubulin. Therefore, the VLB molecule is like a double-sides tape to stick alpha-tubulin and beta-tubulin together. The VLB molecule intervenes the dynamic equilibrium between dissociation and aggregation of alpha-tubulin and beta-tubulin by a double-sides sticking mechanism to exert high activity with toxicity against cancer cell. Besides, our results demonstrate that VLB has its structural basis for anticancer cytotoxicity due to its two compositions composed of a CM molecule and a VM molecule although they have little toxicity against cancer cell alone. Communicated by Ramaswamy H. Sarma. PMID- 30451090 TI - Mixed odontogenic tumors in four young dogs: ameloblastic fibroma and ameloblastic fibro-odontoma. AB - Ameloblastic fibroma (AF) and ameloblastic fibro-odontoma (AFO) are mixed odontogenic tumors (odontogenic tumors with induction) that are reported only rarely in dogs. These tumors are histologically complex and, to a degree, recapitulate the early stages of tooth development, comprising 2 types of tissue: neoplastic odontogenic epithelium, and induced ectomesenchyme (dental pulp). AFOs are distinguished from AFs by the additional presence of hard dental matrices such as dentin. Herein, we describe the key diagnostic features of AF and AFO in 4 young dogs. PMID- 30451091 TI - Characteristics and outcomes of traumatic spinal cord injury in a low-resource setting. AB - Spinal cord injury (SCI) is relatively rare and affects an estimated 15-40 per 1 million people globally. All patients admitted from October 2016 to June 2017 at Kamuzu Central Hospital, Malawi with a spinal column injury were retrospectively studied. Out of 1442 patients, 46 had vertebral column injury, and half of these had neurological deficit. The most common mechanism of injury was road traffic crash (45.7%), and cervical SCIs were the most common (41.3%). The overall mortality was 15.2%, thus demonstrating devastating morbidity and mortality. Owing to the latter, and the relative lack of operative facilities, primary prevention remains the most effective way to attenuate the tragedy of SCIs. PMID- 30451093 TI - Abuse and older lesbian, gay bisexual, and trans (LGBT) people: a commentary and research agenda. AB - With increasing visibility of older lesbian, gay, bisexual and trans (LGBT) people, there is an urgent need to understand abuse in their lives. This is an under-researched area, which this scoping study (based on a literature review and a small subset of data taken from a larger project) serves to demonstrate. The content of this article formed the basis of a paper presented at a workshop on 'LGBT Elder Abuse' held at Keele University(UK) in 2017, convened and chaired by the author. It considers LGBT elder abuse in terms of polyvictimisation, intersectionality and the abuse of power. The identifies knowledge gaps, proposes a research agenda, and explains why such an agenda matters. In particular, the need for researchers of elder abuse, LGBT domestic abuse and organisational abuse to cut across their traditional boundaries of inquiry in order to address how the abuse of older LGBT people intersects with each domain. PMID- 30451092 TI - Urgent need to clarify the definition of chronic critical limb ischemia - a position paper from the European Society for Vascular Medicine. AB - Chronic critical lower limb ischemia (CLI) has been defined as ischemia that endangers the leg. An attempt was made to give a precise definition of CLI, based on clinical and hemodynamic data (Second European Consensus). CLI may be easily defined from a clinical point of view as rest pain of the distal foot or gangrene or ulceration. It is probably useful to add leg ulcers of other origin which do not heal because of severe ischemia, and to consider the impact of frailty on adverse outcome. From a hemodynamic viewpoint there is no consensus and most of the existing classifications are not based upon evidence. We should thus propose a definition and then validate it in a prospective cohort in order to define the patients at major risk of amputation, and also to define the categories of patients whose prognosis is improved by revascularisation. From today's available data, it seems clear that the patients with a systolic toe pressure (STP) below 30 mmHg must be revascularised whenever possible. However other patients with clinically suspected CLI and STP above 30 mmHg must be evaluated and treated in specialised vascular units and revascularisation has to be discussed on a case by case basis, taking into account other data such as the WiFi classification for ulcers.In conclusion, many useful but at times contradictory definitions of CLI have been suggested. Only a few have taken into account evidence, and none have been validated prospectively. This paper aims to address this and to give notice that a CLI registry within Europe will be set up to prospectively validate, or not, the previous and suggested definitions of CLI. PMID- 30451094 TI - Instrumental variable analyses for causal inference: Application to multilevel analyses of the alliance-outcome relation. AB - OBJECTIVE: To introduce readers to instrumental variable analyses for causal inferences using as an example a test of the hypothesis that the quality of the therapeutic alliance has a causal role in relation to the outcome of psychotherapy. METHOD: We used data from a recent non-inferiority trial of cognitive and dynamic therapies for major depressive disorder in a community mental health setting. The data (N = 161) were analyzed using standard approaches as well as a multilevel 2-stage instrumental variables approach that allows for causal interpretations by removing the influence of unmeasured confounds. RESULTS: Instrumental variables were created at the patient and therapist level using baseline patient and therapist variables. These baseline variables predicted the alliance but were otherwise unrelated to treatment outcome other than through their effects on the alliance. Standard multilevel mixed effects analyses revealed statistically significant associations of the alliance with outcome at the therapist level of analysis. The therapist level effect remained statistically significant when using the instrumental variables approach. CONCLUSION: Our results support the hypothesis that, at least at the therapist level, the alliance plays a causal role in producing better outcomes. Instrumental variable analyses can be a useful tool to supplement standard analyses. PMID- 30451095 TI - Venovo venous stent in the treatment of non-thrombotic or post-thrombotic iliac vein lesions - short-term results from the Arnsberg venous registry. AB - BACKGROUND: We sought to determine the patency and clinical symptom relief of the Venovo venous stent in the endovascular treatment of non-thrombotic (NIVL) or post-thrombotic venous obstruction (PTO) of the iliofemoral track over a period of 6 months. PATIENTS AND METHODS: A total of 80 patients (45 female, mean age 57 years) treated in 2016 and 2017 were included in the Arnsberg venous registry. Clinical improvement was determined by the revised venous clinical severity score (rVCSS) as well as the clinical, etiologic, anatomic and pathophysiologic (CEAP) score. Primary and secondary stent patency was evaluated using duplex ultrasound. RESULTS: Overall 6-months patency rates were 98 % for primary and 100 % for secondary patency. For NIVL primary patency was 97 %, whereas for PTO primary patency was 96 %. Early stent re-occlusion occurred in 3 patients within 34, 59 and 156 days after intervention. Two of these patients were successfully treated by endovascular mechanical thrombectomy and stent in stent implantation. Clinical improvement with a gain of >= 2 rVCSS levels was observed in 51 %. CEAP scores decreased from 4.3 to 2.7. CONCLUSIONS: In this first time report the novel Venovo venous stent showed adequate patency rates associated with reasonable clinical improvement and low device-related complications throughout a 6-months follow-up in both NIVL and PTO. PMID- 30451096 TI - Validation of a spectrophotometric method for GGT measurement in canine urine and determination of the urine GGT-to-creatinine ratio reference interval and biological variation in 41 healthy dogs. AB - The urine gamma-glutamyl transferase (GGT)-to-creatinine ratio has been used to monitor patients at risk of acute renal injury. We validated the spectrophotometric quantification of GGT in urine in a commercial biochemistry analyzer. The assay was precise, accurate, and linear. Intra-assay precision was 3.59% in 4 samples, with GGT concentrations of 47-195 U/L. Inter-assay precision in 3 samples with activities of 11-51 U/L was 7.74%. Accuracy was 97.3%, with an absolute bias of 2.7 U/L. Urine GGT was unaffected by hematuria, hemoglobinuria, or bacteriuria. Urine GGT was stable at 20 degrees C and 4 degrees C for up to 3 d. Storage by freezing at -20 degrees C resulted in a significant reduction in enzyme activity. A pH outside the range of 6.5-8 resulted in reduced GGT activity. The biological variation of urine GGT-to-creatinine ratio provided an index of individuality of 1.6, indicating that a population-based reference interval (RI) can be used. The reference change value was calculated, and an increase in consecutive measurements >43% is required to be regarded as significant. The urine GGT-to-creatinine ratio RI obtained in a population of 41 healthy dogs was 8.5-28.5 U/g. PMID- 30451097 TI - An explanation for the narrow carbohydrate substrate specificity of adenine phosphoribosyltransferase from Thermus thermophilus from the model of the enzyme, substrate and magnesium cation co-factor complex. PMID- 30451098 TI - Unseen, unheard and unprotected: prevalence and correlates of violence among female sex workers in Mozambique. AB - Violence against women, including female sex workers, is a public health concern worldwide. This is the first study in Mozambique to estimate the prevalence of and factors associated with physical and sexual violence against female sex workers. We used data collected from 1,250 women recruited using respondent driven sampling in the cities of Maputo, Beira and Nampula in 2011-12. Participants were 15 years of age and reported having had sex for money in the preceding six months. Prevalence of physical or sexual violence (defined as being hit or battered or raped or forced to have sex within the last 6 months) ranged from 10.0% to 25.6%. Strangers (37.0%) and acquaintances (31.2%) were reported to be the most frequent perpetrators of sexual violence. Among participants who experienced sexual violence, 65.9% and 87.0% did not seek medical care and police assistance, respectively. Physical or sexual violence was associated with city (adjusted odds ratio [AOR] 2.6 and 2.0 Nampula and Beira vs Maputo), age (AOR 1.9, aged 15-24 years vs aged 25 and older), unprotected sex with last client (AOR 1.6) and self-reported sexually transmitted infections (AOR 2.1). The high prevalence of violence found confirms the need for interventions to mitigate this problem. PMID- 30451101 TI - Help-seeking Pathway among Working-Age Adults with Suicidal Ideation: Testing the Integrated Model of Suicide Help-seeking. AB - Despite a high suicide rate among working-age adults, there is a significant lack of empirical evidence on their help-seeking behavior. This study tested the integrated model of suicide help-seeking to examine help-seeking behavior as a continuous decision-making process. Data were drawn from the 2011 and 2012 National Survey on Drug Use and Health (N = 1,414). Results from structural equational modeling analyses demonstrated that the integrated model fit reasonably well among the sample. Suicide help-seeking behavior is characterized by an inequitable access, where enabling factors affect throughout the help seeking pathway. The results provide a foundation for future help-seeking interventions. PMID- 30451099 TI - What Keeps Older Adults With Hearing Impairment From Adopting Hearing Aids? AB - The aim of this study was to compare elderly individuals who are hearing impaired but inexperienced in using hearing aids (hearing aid non-users; HA-NU) with their aided counterparts (hearing aid users; HA-U) across various auditory and non auditory measures in order to identify differences that might be associated with the low hearing aid uptake rate. We have drawn data of 72 HA-NU and 139 HA-U with a mild-to-moderate hearing loss, and matched these two groups on the degree of hearing impairment, age, and sex. First, HA-NU and HA-U were compared across 65 auditory, cognitive, health-specific, and socioeconomic test measures as well as measures assessing technology commitment. Second, a logistic regression approach was performed to identify relevant predictors for using hearing aids. Finally, we conducted a sensitivity analysis for the matching approach. Group comparisons indicated that HA-NU perceive their hearing problem as less severe than their aided counterparts. Furthermore, HA-NU showed worse technology commitment and lower socioeconomic status than HA-U. The logistic regression revealed self reported hearing performance, technology commitment, and the socioeconomic and health status as the most important predictors for using hearing aids. PMID- 30451100 TI - Feasibility of high-flow nasal cannula implementation for children with acute lower respiratory tract disease in rural Kenya. AB - BACKGROUND: High-flow nasal cannula (HFNC) is a well-established respiratory support device in high-income countries, but to our knowledge, its use in sub Saharan Africa has not been reported. This feasability study describes the implementation process of HFNC in rural Kenya. METHODS: HFNC was implemented in intensive care and high dependency units at Kijabe Hospital, Kenya for children with acute lower respiratory disease. Rate of intubation was compared with historical controls and challenges of implementation described. RESULTS: Fifteen patients received HFNC between January and November 2016, and compared to 25 historical control patients. Both groups had many comorbidities, and control patients were significantly younger. There were no significant differences in clinical outcome between the groups: 5 (33%) HFNC vs 12 (48%) controls required intubation; 10 (67%) HFNC vs 22 (88%) controls survived to discharge; and the HFNC required 3 vs the controls' 4 days on respiratory support. The greatest technical issues encountered were large pressure differences between air from a wall outlet (wall air) and oxygen and an inability to automatically refill humidifier water chambers. CONCLUSION: HFNC in limited-resource settings is feasible but there were technical challenges and concern about the increased workload. The small sample size, heterogeneous population, availability of oxygen and blending of wall air at the study site limit inferences for other sites in low- and middle-income countries. ABBREVIATIONS: ALRI, acute lower respiratory infection; CPAP, continuous positive airway pressure; ETAT, emergency triage, assessment and treatment; HDU, high dependency unit; HFNC, high-flow nasal cannula; HIC, high-income country; HR, heart rate; ICU, intensive care unit; LMIC, low- and middle-income countries; PSI, pounds per square inch; RR, respiratory rate; mRISC, modified Respiratory Index of Severity in Children. PMID- 30451102 TI - Exploring the role of psychosocial care in value-based oncology: Results from a survey of 3000 cancer patients and survivors. AB - PURPOSE: To explore the psychosocial needs of cancer patients and survivors across the United States and their implications for value-based oncology. DESIGN: A secondary analysis of findings from a cross-sectional national online survey. SAMPLE: Respondents were sampled and stratified by cancer type and geographic region to approximate the cancer-affected population of the United States. Breast, prostate, and colorectal were the most common cancers reported. Across surveys, the majority of respondents were female (57%), over 55 (60%), and white (70%) and had at least some college (36%). METHODS: Six online surveys were administered to cohorts of approximately 500 unique cancer patients and survivors. Survey topics included: (1) diagnosis, (2) treatment planning, (3) communication with providers, (4) insurance and financial concerns, (5) quality of life, side effects, and symptoms, and (6) survivorship and end-of-life. Descriptive analyses were used to explore psychosocial needs and experiences across three domains of patient-centered value in oncology. FINDINGS: Each survey received 500-527 responses. Respondents most commonly reported needing more information regarding their insurance coverage and out-of-pocket costs (65%), access to clinical trials (89%), and support organizations (45%). Forty-one percent were very or extremely distressed about cancer's impact on their ability to work and over 25% reported high-levels of cancer-related financial hardship. CONCLUSIONS: Patients and survivors reported significant unmet informational needs, financial hardship, distress, and symptoms or treatment side effects that interfered with daily life. Implications for Psychosocial Providers or Policy: Providers and payment reform advocates can improve value in oncology by ensuring access to comprehensive psychosocial care and informational support. PMID- 30451103 TI - Paediatric deaths in a tertiary government hospital setting, Malawi. AB - BACKGROUND: Malawisuccessfully achieved Millennium Development Goal (MDG) four by decreasing the under-5 mortality rate by two-thirds in 2012. Despite this progress child mortality is still high and in 2013, the leading causes of death in under-5s were malaria, acute respiratory infections and HIV/AIDS. AIMS: To determine the causes of inpatient child death including microbiological aetiologies in Malawi. METHODS: A prospective, descriptive study was undertaken in Queen Elizabeth Central Hospital over 12 months in 2015/2016. Data was collected for every paediatric covering HIV and nutritional status, cause of death, and microbiology. Deaths of inborn neonates were excluded. RESULTS: Of 13,827 admissions, there were 488 deaths, giving a mortality rate of 3.5%. One third of deaths (168) occurred in the first 24 h of admission and 255 after 48 h Sixty-eight per cent of those who died (332) were under 5 years of age. The five leading causes of death were sepsis (102), lower respiratory tract infection (67), acute gastroenteritis with severe dehydration (51), malaria (37) and meningitis (34). The leading non-communicable cause of death was solid tumour (12). Of the 362 children with a known HIV status 134 (37.0%) were HIV-infected or HIV-exposed. Of the 429 children with a known nutrional status, 93 had evidence of severe acute malnutrition (SAM). Blood cultures were obtained from 252 children 51 (20.2%) grew pathogenic bacteria with Klebsiella pneumoniae, Escherichia coli and Staphylococcus aureus being the most common. CONCLUSION: Despite a significant reduction in paediatric inpatient mortality in Malawi, infectious diseases remain the predominant cause. ABBREVIATIONS: ART: anti retroviral therapy; Child PIP: Child Healthcare Problem Identification Programme; CCF: congestive cardiac failure; CNS: central nervous system; CoNS: coagulase negative staphylococci; CSF: cerebrospinal fluid; DNA pcr: deoxyribonucleic acid polymerase chain reaction; ETAT: emergency triage assessment and treatment; LMIC: low- and middle-income countries; MDG: Millennium Development Goals; MRI: magnetic resonance imaging; MRSA: methicillin-resistant Staphylococcus aureus; NAI: non-accidental injury; NTS: non-typhi salmonella; PJP: Pneumocystis jiroveci pneumonia; PSHD: presumed severe HIV disease; QECH: Queen Elizabeth Central Hospital; RHD: rheumatic heart disease; RTA: road traffic accident; TB: tuberculosis; TBM: tuberculous meningitis; WHO: World Health Organization; SAM: severe acute malnutrition. PMID- 30451104 TI - Are older adults' home exposures to secondhand smoking during earlier life stages associated with current health status and life satisfaction in China? A multilevel approach. AB - Secondhand smoking (SHS) has become a critical challenge in Chinese society, and progress on SHS prevention remains unknown. There is little knowledge targeting Chinese older adults generally to investigate the associations between SHS exposure experiences during earlier life stages and health-related measurements. Using cross-sectional data from a nationally representative data set, the 2014 wave of the Chinese Longitudinal Healthy Longevity Survey (n = 4,414), multilevel logistic regression models with random effects for Chinese provinces were used for analyses. Two health-related measurements included self-reported health status and life satisfaction. All regression models included the same set of predictors and covariates with socioeconomic factors and basic biological information. Approximately 40% and 47% of older adults reported SHS exposure in childhood and in younger adulthood at home, respectively. Older adults with SHS exposure in childhood had lower odds of reporting better health status, compared with those who did not have such exposure (adjusted odds ratio [AOR] = 0.69, 95% CI [0.55, 0.86], p < .01). However, life satisfaction was not associated with any SHS exposure experiences. Policy makers and public health practitioners should continue to investigate the long-term effect of SHS exposure on human health, including older adults. Policy regarding SHS prevention should be enhanced. PMID- 30451105 TI - Implicit Association Test as an Analogical Learning Task. AB - The Implicit Association Test (IAT) is a popular tool for measuring attitudes. We suggest that performing an IAT could, however, also change attitudes via analogical learning. For instance, when performing an IAT in which participants categorize (previously unknown) Chinese characters, flowers, positive words, and negative words, participants could infer that Chinese characters relate to flowers as negative words relate to positive words. This analogy would imply that Chinese characters are opposite to flowers in terms of valence and thus that they are negative. Results from three studies (N = 602) confirmed that evaluative learning can occur when completing an IAT, and suggest that this effect can be described as analogical. We discuss the implications of our findings for research on analogy and research on the IAT as a measure of attitudes. PMID- 30451106 TI - What Makes a Quality Journal? PMID- 30451107 TI - Reaction Time of Erroneous Responses in the Go/No-Go Paradigm. AB - Reaction time (RT) of erroneous responses in go/no-go tasks tends to be shorter than RT of correct responses. An opposite difference has been reported ( Halperin, Wolf, Greenblatt, & Young, 1991 ) which could be attributed to differences in go trial probability, or to high memory demand. Two experiments aimed here to test these two explanations, a simultaneous matching task with low memory load (Experiment 1), and a sequential matching task with high memory load (Experiment 2). Go trial probability was also manipulated. Short false positive RT was obtained only in the sequential matching task with high go trial probability, while long false positive RT was obtained in the other three conditions. Low go trial probability and high memory load were both found to be sufficient, by themselves, to create long false positives attributable to confusion. Short false positives in the high go trial probability/low memory load condition were attributed to failure of response inhibition. PMID- 30451108 TI - pLoc_bal-mPlant: predict subcellular localization of plant proteins by general PseAAC and balancing training dataset. AB - Knowledge of protein subcellular localization is vitally important for both basic research and drug development. With the avalanche of protein sequences emerging in the post-genomic age, it is highly desired to develop computational tools for timely and effectively identifying their subcellular localization based on the sequence information alone. Recently, a predictor called "pLoc-mPlant" was developed for identifying the subcellular localization of plant proteins. Its performance is overwhelmingly better than that of the other predictors for the same purpose, particularly in dealing with multi-label systems in which some proteins, called "multiplex proteins", may simultaneously occur in two or more subcellular locations. Although it is indeed a very powerful predictor, more efforts are definitely needed to further improve it. This is because pLoc-mPlant was trained by an extremely skewed dataset in which some subsets (i.e., the protein numbers for some subcellular locations) were more than 10 times larger than the others. Accordingly, it cannot avoid the biased consequence caused by such an uneven training dataset. To overcome such biased consequence, we have developed a new and bias-free predictor called pLoc_bal-mPlant by balancing the training dataset. Cross-validation tests on exactly the same experiment-confirmed dataset have indicated that the proposed new predictor is remarkably superior to pLoc-mPlant, the existing state-of-the-art predictor in identifying the subcellular localization of plant proteins. To maximize the convenience for the majority of experimental scientists, a user-friendly web-server for the new predictor has been established at http://www.jci-bioinfo.cn/pLoc_bal-mPlant/, by which users can easily get their desired results without the need to go through the detailed mathematics. PMID- 30451109 TI - Current trends in protein engineering: updates and progress. AB - Proteins are one of the most important and resourceful biomolecules that find applications in health, industry, medicine, research, and biotechnology. Given its tremendous relevance, protein engineering has emerged as significant biotechnological intervention in this area. Strategic utilization of protein engineering methods and approaches has enabled better enzymatic properties, better stability, increased catalytic activity and most importantly, interesting and wide range applicability of proteins. In fact, the commercialization of engineered proteins have manifested in economically beneficial and viable solutions for industry and healthcare sector. Protein engineering has also evolved to become a powerful tool contributing significantly to the developments in both synthetic biology and metabolic engineering. The present review revisits the current trends in protein engineering approaches such as rational design, directed evolution, de novo design, computational approaches etc. and encompasses the recent progresses made in this field over the last few years. The review also throws light on advanced or futuristic protein engineering aspects, which are being explored for design and development of novel proteins with improved properties or advanced applications. PMID- 30451110 TI - Label Free Ultrasmall Fluoromagnetic Ferrite-clusters for Targeted Cancer Imaging and Drug Delivery. AB - The label free ultrasmall fluorescent ferrite clusters have been engineered in a controlled fashion which was stabilized by serum protein and functionalized by folic acid for the application of targeted multimodal optical and magnetic resonance (MR) cancer imaging. The ultra-small manganese ferrite nanoclusters (PMNCs) with a diameter of 4 nm has commendable effect on the longitudinal (T1) and transverse (T2) relaxation in MR imaging that was evident from the phantom and animal MRI. The calculated longitudinal molar relaxivity of nanoclusters was found to be 6.9 +/- 0.10 mM-1 S-1 which was exactly 2.22 times better than the conventional Gd-DOTA and their 4.01 ratio of the transverse (r2) and longitudinal (r1) relaxivities made them a potential candidate for the both T1 and T2 contrast agent in MRI. In addition, the fluorescence based small animal imaging showed folic acid driven accumulated fluorescent signal at the tumour site to conclude the capacity of PMNCs for targeted fluorescence imaging of cancer diagnosis. The cytotoxicity assay and histopathology studies were the evidence for its safe biodistribution in animal systems. Furthermore, the protein encapsulated clusters have ability to deliver the anticancer drug methotrexate (MTX) to the cancer tissues with a sustained manner. Therefore, one can conclude the remarkable efficacy of architect nanoclusters for theragnosis. PMID- 30451111 TI - Sucrose acetate isobutyrate as an in situ-forming implant for sustained release of local anesthetics. AB - In this study, an injectable sucrose acetate isobutyrate (SAIB) drug delivery system (SADS) was designed and fabricated for the sustained release of ropivacaine (RP) to prolong the duration local anesthesia. By mixing SAIB, RP, and N-methyl-2-pyrrolidone, the SADS was prepared in a sol state with low viscosity before injection. After subcutaneous injection, the pre-gel solution underwent gelation in situ to form a drug-released depot. The in vitro release profiles and in vivo pharmacokinetic analysis indicated that RP-SADS had suitable controlled release properties. Particularly, the RP-SADS significantly reduced the initial burst release after subcutaneous injection in rats. In pharmacodynamic analysis of rats, the duration of nerve blockade was prolonged by over 3-fold for the RP-SADS formulation compared to RP solution. Additionally, RP SADS showed good biocompatibility in vitro and in vivo. Thus, the SADS-based depot technology is a safe drug delivery strategy for sustained release of local anesthetics with long-term analgesia effects. PMID- 30451113 TI - Tetramethoxyluteolin for the treatment of neurodegenerative diseases. AB - Background Most neurodegenerative and other brain disorders, especially Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and autism spectrum disorder (ASD) continue to elude objective biomarkers and effective treatments. Increasing evidence indicates that such diseases involve focal inflammation of the brain. Objective To review the role of cytokine-neuropeptide interactions in the pathogenesis of inflammation of the brain and the beneficial role of natural flavonoids. Method Medline search was conducted (2000-2017) for articles using the terms allergy, amygdala, atopy, autism, brain, chemokines, cytokines, hypothalamus, immunity, inflammation, mast cells, microglia, neurotensin, peptides, substance P, TNF. Results Neuropeptides and cytokine stimulation of mast cells and microglia can results in focal inflammation in the hypothalamus and amygdala, thus explaining most of the symptoms at leass in ME/CFS and ASD. Some of the triggers may be corticotropin-releasing hormone (CRH), neurotensin (NT), and substance P (SP), which has synergistic action with IL-33. The natural flavonoids luteolin and tetramethoxyluteolin inhibit these processes and have neuroprotective actions. Tetramethoxyluteolin is also more metabolically stable and has greater oral absorption. Conclusion Inhibition of inflammatory processes unique to the brain with intranasal formulations of tetramethoxyluteolin could provide new possibilities for the understanding and treatment of neurodegenerative diseases. PMID- 30451112 TI - Overexpression of Nemo-like kinase promotes the proliferation and invasion of lung cancer cells and indicates poor prognosis. AB - Nemo-like kinase (NLK) is an evolutionarily conserved MAP kinase-related kinase involved in the pathogenesis of several human cancers. We examined the expression of NLK in lung cancer tissues through western blot analysis. We enhanced or knocked down NLK expression by gene transfection or RNA interference, respectively, in lung cancer cells and examined expression alterations of key proteins in the Wnt signaling pathway and in epithelial-mesenchymal transition (EMT). We also examined the roles of NLK in the proliferation and invasiveness of lung cancer cells by cell proliferation, colony formation, and Matrigel invasion assays. NLK expression was found to be significantly higher in lung cancer tissue samples than in corresponding healthy lung tissue samples. Overexpression of NLK correlated with poor prognosis of patients with lung cancer. Overexpression of NLK upregulated beta-catenin, TCF4, and Wnt target genes such as cyclin D1, c Myc, and MMP7. N-cadherin and TWIST, the key proteins in EMT, were upregulated, while E-cadherin expression was reduced. Additionally, proliferation, colony formation, and invasion turned out to be enhanced in NLK-overexpressing cells. After NLK knockdown in lung cancer cells, we obtained the opposite results. In conclusion, NLK is overexpressed in lung cancers and indicates poor prognosis. Overexpression of NLK activates the Wnt signaling pathway and EMT and promotes the proliferation and invasiveness of lung cancer cells. PMID- 30451114 TI - On the mechanisms of action of the low molecular weight fraction of commercial human serum albumin in osteoarthritis. AB - The low molecular weight fraction of commercial human serum albumin (LMWF5A) has been shown to successfully relieve pain and inflammation in severe osteoarthritis of the knee (OAK). LMWF5A contains at least three active components that could account for these anti-inflammatory and analgesic effects. We summarize in vitro experiments in bone marrow-derived mesenchymal stem cells, monocytic cell lines, chondrocytes, peripheral blood mononuclear cells, fibroblast-like synoviocytes, and endothelial cells on the biochemistry of anti-inflammatory changes induced by LMWF5A. We then look at four of the major pathways that cut across cell-type considerations to examine which biochemical reactions are affected by mTOR, COX 2, CD36, and AhR pathways. All three components show anti-inflammatory activities in at least some of the cell types. The in vitro experiments show that the effects of LMWF5A in chondrocytes and bone marrow-derived stem cells in particular, coupled with recent data from previous clinical trials of single and multiple injections of LMWF5A into OAK patients demonstrated improvements in pain, function, and Patient Global Assessment (PGA), as well as high responder rates that could be attributed to the multiple mechanism of action (MOA) pathways summarized here. In vitro and in vivo data are highly suggestive of LMWF5A being a disease-modifying drug for OAK. PMID- 30451115 TI - The Metformin Paradox. AB - INTRODUCTION: The Diabetes Prevention Program study results indicated that metformin therapy was not as beneficial as a lifestyle modification for delaying the development of type 2 diabetes in individuals at high risk of the disease. A key feature in the etiology of type 2 diabetes mellitus, which appears in the prediabetic phase, is a significant deficiency, compared to healthy controls, in highly flexible poly-cis-unsaturated fatty acyl chains in membrane phospholipids. This deficiency lowers membrane flexibility, which in turn, reduces the amount of all functional Class I glucose transporters, and thereby reduces glucose-mediated ATP production. This leads to an increase in essentially saturated free fatty acid (FFA) levels for fatty-acid-mediated ATP production, which will set up a vicious cycle of raising the levels of essentially saturated FFAs and lowering the level of transmembrane glucose transport. Metformin suppresses hepatic gluconeogenesis, which reduces the plasma glucose concentration. We hypothesize that chronic metformin treatment leads to an additional increase in essentially saturated FFAs, which causes an additional rise in membrane stiffness and hypoxia. So we propose that all these metformin-mediated activities accelerated the onset of type 2 diabetes in the participants of the metformin group in the Diabetes Prevention Program study, compared to those of the lifestyle intervention group in this study. CONCLUSION: We propose that the biochemical reactions, involved in the fatty-acid-mediated ATP production, play an important part in the harmful to health increase in the observed essentially saturated FFA concentrations. These statements should also extent to the metformin therapy of individuals with type 2 diabetes. PMID- 30451116 TI - Cucurbitacins as Anticancer Agents: A Patent Review. AB - BACKGROUND: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its anticancer effects. OBJECTIVE: This review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and structure-activity relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products. METHODS: The date about the published patents was downloaded via online open access patent databases. RESULTS: Cucurbitacins display significant anticancer properties, in particular cucurbitacins B and D which possess very potent effects towards number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C2-OH and C25-OH groups. Most importantly, an acyl ester of the C25-OH and, iso-propyl, n-propyl and ethyl ether groups of the C2-OH demonstrated the most increased anticancer activity. CONCLUSION: The significant anticancer effects of natural and semi-synthetic cucurbitacins put them as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterdimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers. PMID- 30451118 TI - Integrins as A New Target for Cancer Treatment. AB - Despite the great progress in the development of targeted therapies for different types of cancer utilizing monoclonal antibodies (e.g., cetuximab for colorectal cancer and head and neck cancer therapy), kinase inhibitors (e.g., sorafenib for kidney cancer and gastrointestinal stromal tumours therapy), and immunomodulatory treatments (e.g., nivolumab and pembrolizumab for melanoma therapy and lung cancer therapy), there is still a need to search for new, more effective treatments. Integrins are responsible for intercellular adhesion and interacting with the cellular matrix. The function of integrins is related to the transduction of intracellular signals associated with adhesion, migration, cell proliferation, differentiation, and apoptosis. Molecules targeting integrins that lead to cancer cell death have been developed. The most advanced molecules studied in clinical trials are abituzumab, intetumumab and cilengitide. There are different groups of anti-integrin drugs: monoclonal antibodies (e.g., abituzumab) and other, such as cilengitide, E7820 and MK-0429. These drugs have been evaluated in various cancer types. However, they have shown modest efficacy, and none of them have yet been approved for cancer treatment. Studies have shown that patient selection using biomarkers might improve the efficacy of anti-integrin cancer treatment. Many preclinical models have demonstrated promising results using integrin visualization for cancer detection and treatment efficacy monitoring; however, these strategies require further evaluation in humans. PMID- 30451117 TI - Antitumor Potential of Berberine and Cinnamic Acid against Solid Ehrlich Carcinoma in Mice. AB - BACKGROUND: Berberine and cinnamic acid are natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. OBJECTIVE: In the present study, we aimed to investigate the proapoptotic potential of cinnamic acid and berberine in cancer cells by examining their effect on the expression of proapoptotic and antiapoptotic genes. Moreover, the effects of berberine and cinnamic acid on the antitumor activity of cisplatin were investigated in Ehrlich solid tumor-bearing mice. RESULT: The results showed that berberine and cinnamic acid significantly decreased tumor growth and tumor volume (-74.8 and -75.5%, respectively) both as single agents and in combination with cisplatin. Moreover, both berberine and cinnamic acid increased the ratio of tumor growth inhibition ( 91.5 and -92.6%, respectively), mean survival time (61.5 and 26 days, respectively), and percentage increase in lifespan (559 and 263%, respectively) of the treated mice. Our results also showed that both berberine and cinnamic acid induced apoptosis by increasing the Bax/Bcl-2 ratio (74.1 and 45.1, respectively) and caspase-3 expression (14.3- and 11.6-fold increase, respectively). Additionally, berberine and cinnamic acid decreased oxidative stress markers, as shown by the decrease in lipid peroxidation and nitric oxide levels and increase in reduced glutathione level. CONCLUSION: These results suggest that berberine and cinnamic acid have potential as antitumor and antioxidant agents derived from natural sources, which could be used alone or in combination with regular chemotherapeutic agents, such as cisplatin. These effects could be attributed to the proapoptotic activity of berberine and cinnamic acid. PMID- 30451119 TI - Synthesis and In Vitro Evaluation of Tetrahydroquinoline Derivatives as Antiproliferative Compounds of Breast Cancer via Targeting The GPER. AB - Reports have demonstrated the role of the G protein-coupled estrogen receptor (GPER) in growth and proliferation of breast cancer cells. In an effort to develop new therapeutic strategies against breast cancer, we employed an in silico study to explore the binding modes of tetrahydroquinoline 2 and 4 to be compared with the reported ligands G1 and G1PABA. This study aimed to design and filtered ligands by in silico studies determining their Lipinsky rule, toxicity and binding properties with GPER to achieve experimental assays as anti proliferative compounds of breast cancer cell lines. In silico studies suggest as promissory two tetrahydroquinoline 2 and 4 which contain a carboxyl group instead of the acetyl group (as is needed for G1 synthesis), which added low (2) and high hindrance (4) chemical moieties to explore the polar, hydrophobic and hindrance effects. Docking and molecular dynamics simulations of the target compounds were performed with GPER to explore their binding mode and free energy values. In addition, the target small molecules were synthesized and assayed in vitro using breast cancer cells (MCF-7 and MDA-MB-231). Experimental assays showed that compound 2 decreased cell proliferation, showing IC50 values of 50 μM and 25 μM after 72 h of treatment of MCF-7 and MDA-MB-231 cell lines, respectively. Importantly, compound 2 showed a similar inhibitory effect on proliferation as that of the G1 compound in MDA-MB-231 cells, suggesting that both ligands reach the GPER-binding site in a similar way, as was demonstrated through in silico studies. In conclusion, a concentration-dependent inhibition of cell proliferation occurred with compound 2 in the two cell lines regardless of GPER. PMID- 30451120 TI - Virtual screening of natural products to select compounds with potential anticancer activity. AB - Cancer is the main cause of death, so the search for active agents to be used in the therapy of this disease, is necessary. According to studies conducted, substances derived from natural products have shown promise in this endeavor. To these researches, one can associate the aid of computational chemistry, which is increasingly gaining in popularity, due to the possibility of developing alternative strategies that could help to choose an appropriate set of compounds, avoiding unnecessary expenses with resources that would generate unwanted substance. Thus, the objective of this study was to carry out an approach to several studies that apply different methods of virtual screening to select natural products with potential anticancer activity. This review presents reports of studies conducted with some natural products, such as coumarin, quinone, tannins, alkaloids, flavonoids and terpenes. PMID- 30451121 TI - Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones. AB - Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD). The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 uM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity. PMID- 30451122 TI - A new schizophrenia model: immune activation is associated with induction of different neurotoxic products which together determine memory impairments and schizophrenia symptom dimensions. AB - OBJECTIVE: Recently, we reported that stable-phase schizophrenia is characterized by two interrelated symptom dimensions: PHEMN (psychotic, hostility, excitation, mannerism and negative symptoms); and DAPS (depressive, anxiety and physio somatic symptoms) and that Major Neuro-Cognitive psychosis (MNP) is the full blown phenotype of schizophrenia (largely overlapping with deficit schizophrenia). Herein we examined the effects of immune activation in association with tryptophan catabolite (TRYCAT) patterning and memory disorders on PHEMN/DAPS dimensions and MNP. METHOD: Serum levels of macrophage inflammatory protein-1 (MIP-1), soluble interleukin (IL)-1 receptor antagonist (sIL-1RA), IL 10, eotaxin, IgA/IgM responses to TRYCATs, and Consortium to Establish a Registry for Alzheimer's disease (CERAD) tests were assessed in 40 controls and 80 schizophrenia patients. RESULTS: Schizophrenia and MNP were predicted by significantly increased levels of IL-10, eotaxin and TRYCATs. A large part of the variance in both PHEMN/DAPS symptom dimensions (42.8%) was explained by cytokine levels and TRYCATs combined. The MIP+sIL-1RA+IL-10 composite score and eotaxin explained each around 19% of the variance in symptom dimensions, and approximately 18% of memory deficits. Moreover, MIP+sIL-1RA+IL-10 was significantly associated with elevations in picolinic acid, xanthurenic acid and 3-OH-kynurenine. Partial Least Squares path modeling shows that the highly significant effects of MIP+sIL-1RA+IL-10 on symptomatology are mediated by the effects of noxious TRYCATs on memory deficits. CONCLUSIONS: Current findings indicate that in schizophrenia, immune activation may underpin activation of indoleamine-2,3-dioxygenase and kynurenine monooxygenase, while impairments in episodic and semantic memory may be caused by the neurotoxic effects of TRYCATs and eotaxin. The combined effects of immune activation, eotaxin and memory defects determine to a large extent PHEMN/DAPS symptoms and the MNP phenotype. These findings indicate that schizophrenia phenomenology is largely mediated by multiple neuro-immune pathways and that immune activation, increased production of eotaxin and neurotoxic TRYCATs (picolinic acid, xanthurenic acid and 3-HO kynurenine) are new drug targets in schizophrenia and MNP. PMID- 30451123 TI - Thiopurine Methyltransferase genetic polymorphisms and activity and metabolic products of azathioprine in patients with inflammatory bowel disease. AB - BACKGROUND: Thiopurine S-methyltransferase (TPMT) is a cytoplasmic enzyme that catalyzes thiopurine drugs, such as 6-mercaptopurine, 6-thioguanine, and azathioprine. There is a correlation between thiopurine drug metabolism, response, and toxicity and genetic polymorphism of TPMT. The aim of this study is to assess TPMT genetic polymorphisms activity and metabolic products of AZA in patients with IBD. METHODS: Blood samples were obtained from 50 IBD unrelated patients from a private laboratory. We used polymerase chain reaction- restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to determine the TPMT gene for the different variants. A high-performance liquid chromatography system (HPLC) was carried out to determine the whole blood 6-TGN concentration. Determination of serum TMPT activity was done by ELISA kit. RESULTS: In IBD patients, 46/50 (92%) subjects were homozygous for the wild-type allele (TPMT*1/*1). Mutant TPMT*1/*2 and TPMT*1/*3C alleles were found in 4/46 (8%) and 3/47 (6%) of IBD patients, respectively. TPMT*1/*3B variant was not detected in any of the IBD patients. TPMT enzyme activity was higher in wild-type than that mutant variants TPMT*1/*2 and TPMT*1/*3C, suggesting that there are statistically significant differences between 6-TG levels and polymorphisms of TMPT enzyme. 6-TG levels significantly increased in IBD patients mutant variants TPMT*1/*2 and TPMT*1/*3C. CONCLUSIONS: Our results showed that TPMT polymorphisms are associated with 6-TGN levels in patients using AZA. This study sug!gests that AZA dosage may be determined according to the high or low prevalence of a TPMT genotype. Moreover, the results present the determination of metabolite for assessing possible safe effective dosage of the drug. PMID- 30451124 TI - Use of cocktail probe drugs for indexing cytochrome P450 enzymes in clinical pharmacology studies - Review of case studies. AB - Background The cocktail approach of probing drug metabolizing enzymes, in particular cytochrome P450 (CYP) enzymes, is a corner stone in clinical pharmacology studies. The first report of the famous "Pittsburg cocktail" has led the way for the availability of numerous cocktail substrate mixtures that provide options for indexing of CYP enzymes and/or evaluating the perpetrator capacity of the drug. Objectives The key objectives were: 1) to collate, tabulate, and discuss the various cocktail substrates to determine specific CYP enzyme activity in clinical pharmacology studies with specific case studies; 2) to introspect on how the cocktail approach has withstood the test of time and evolved for enabling key decision(s); 3) to provide some futuristic views on the use of cocktail in drug discovery and development. Methods: Review was compiled after consultation with databases such as PubMed (NCBI database) and Google scholar to source various published literature on cocktail approaches in drug development. Results In the reviewed case studies, CYP indexing was achieved using a single time point (differing for specific CYP enzyme) plasma determination of the metabolite to parent ratio for all CYP enzymes with the exception of CYP3A4/5, where multiple time points were required for exposure measurement of midazolam and its metabolite. Likewise, a single void of urine, for specific time duration, has been utilized for the recovery measurements of parent and metabolite for CYP indexing purposes. Conclusion: The review provides a comprehensive list of various types of cocktail approaches and discusses some key considerations including evolution of the cocktail approaches over time, perspectives and futuristic views for the use of probe drugs to aid execution of clinical pharmacology studies and data interpretation. PMID- 30451125 TI - Genomic loci associated with antibody-mediated immune responses in an F2 chicken population. AB - Immunity-related traits are heritable in chicken, therefore, it is possible to improve the inherent immunity by breeding programs. In this study using the Illumina chicken 60K single nucleotide polymorphisms (SNPs) chip, we performed a set of genome-wide association studies to determine candidate genes and loci responsible for primary and secondary antibody-mediated responses against sheep red blood cell. A F2 population descended from a commercial meat-type breed and an Iranian indigenous chicken was used for this study. Statistical analysis was based on a mixed linear model utilizing genomic relationship matrix to prevent spurious associations. Correction for multiple testing was done by applying 5% and 10% chromosomal false discovery rates (FDRs) for significant and suggestive thresholds, respectively. Nine significant and 17 suggestive associated SNPs were identified. Most of the SNPs that were suggestively associated with the primary response of total plasma immunoglobulins were also significantly associated with this trait in secondary response. Three SNPs were located within a narrow region of 23 kb on chromosome 16. Pathway analysis for the genes surrounding the associated SNPs showed that they are involve in antigen processing and presentation, primary immunodeficiency, vitamin digestion and absorption, cell adhesion molecules, phagosome, influenza A, folding, assembly and peptide loading of class I major histocompatibility complex, lipid digestion, mobilization, and transport (FDR < 0.1). Interestingly, there were common regains associated with multiple immune-related traits. PMID- 30451126 TI - Mixed-methods analysis of glove use as a barrier to hand hygiene. AB - Examination gloves have been previously noted as a possible barrier to hand hygiene. We performed a prospective quantitative and qualitative study to investigate. Glove usage was found to be a potential barrier to hand hygiene; this was driven by desire for personal safety and potentially learned during professional training. PMID- 30451127 TI - Nutrition knowledge related to breakfast skipping among Japanese adults aged 18 64 years: a cross-sectional study. AB - OBJECTIVE: Breakfast skipping is regarded as a public health issue among adults worldwide. Nutrition knowledge has been reported to be one of predictors of dietary behaviour. Therefore, the aim of the present study was to examine the association between nutrition knowledge and breakfast skipping. DESIGN: Data regarding nutrition knowledge were obtained by using a validated, self administered general nutrition knowledge questionnaire for Japanese adults (JGNKQ). Participants were classified into three nutrition knowledge level groups according to total JGNKQ score: Low, Middle and High. In addition, participants reported the frequency of meal consumption per week and rated the difficulty in finding time to eat breakfast, lunch and dinner in the lifestyle questionnaire. The differences in frequency of breakfast, lunch and dinner consumption among Low, Middle and High nutrition knowledge groups were determined by using ANCOVA adjusted for potential confounding factors. SETTING: Kanto region, Japan.ParticipantsJapanese adults aged 18-64 years (n 1165, 57.3% women). RESULTS: Mean age of the participants was 43.8 (sd 8.9) years. There were no significant differences found in the proportion of respondents reporting difficulty in finding time to eat each meal among the three groups. However, the frequency of breakfast consumption was significantly different among Low, Middle and High groups, while lunch and dinner frequency did not differ among the three groups. CONCLUSIONS: The present study suggests that nutrition knowledge level is related to breakfast skipping among Japanese adults. PMID- 30451128 TI - Bronchoscope-associated clusters of multidrug-resistant Pseudomonas aeruginosa and carbapenem-resistant Klebsiella pneumoniae. AB - OBJECTIVE: Recovery of multidrug-resistant (MDR) Pseudomonas aeruginosa and Klebsiella pneumoniae from a cluster of patients in the medical intensive care unit (MICU) prompted an epidemiologic investigation for a common exposure. METHODS: Clinical and microbiologic data from MICU patients were retrospectively reviewed, MICU bronchoscopes underwent culturing and borescopy, and bronchoscope reprocessing procedures were reviewed. Bronchoscope and clinical MDR isolates epidemiologically linked to the cluster underwent molecular typing using pulsed field gel electrophoresis (PFGE) followed by whole-genome sequencing. RESULTS: Of the 33 case patients, 23 (70%) were exposed to a common bronchoscope (B1). Both MDR P. aeruginosa and K. pneumonia were recovered from the bronchoscope's lumen, and borescopy revealed a luminal defect. Molecular testing demonstrated genetic relatedness among case patient and B1 isolates, providing strong evidence for horizontal bacterial transmission. MDR organism (MDRO) recovery in 19 patients was ultimately linked to B1 exposure, and 10 of 19 patients were classified as belonging to an MDRO pseudo-outbreak. CONCLUSIONS: Surveillance of bronchoscope derived clinical culture data was important for early detection of this outbreak, and whole-genome sequencing was important for the confirmation of findings. Visualization of bronchoscope lumens to confirm integrity should be a critical component of device reprocessing. PMID- 30451129 TI - Progress in home-based treatment. AB - Home-based treatment has been promoted as an alternative to hospital admission over the last 30 years, with the system in England being particularly well developed. There is less stigma, patients and families appear to prefer treatment at home, and there has been a significant reduction in the number of acute beds. In more recent years, there have been criticisms of the lack of effect on reducing hospital admissions and concerns have also been raised about patient safety. Home-based treatment is being further developed on the island of Ireland, and this will hopefully be influenced by current and future local research. PMID- 30451130 TI - Meteorological factors and its association with hand, foot and mouth disease in Southeast and East Asia areas: a meta-analysis. AB - Since the late 1990s, hand, foot and mouth disease (HFMD) has become a common health problem that mostly affects children and infants in Southeast and East Asia. Global climate change is considered to be one of the major risk factors for HFMD. This study aimed to assess the correlation between meteorological factors and HFMD in the Asia-Pacific region. PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Data and Weipu Database were searched to identify relevant articles published before May 2018. Data were collected and analysed using R software. We searched 2397 articles and identified 51 eligible papers in this study. The present study included eight meteorological factors; mean temperature, mean highest temperature, mean lowest temperature, rainfall, relative humidity and hours of sunshine were positively correlated with HFMD, with correlation coefficients (CORs) of 0.52 (95% confidence interval (CI) 0.42 0.60), 0.43 (95% CI 0.23-0.59), 0.43 (95% CI 0.23-0.60), 0.27 (95% CI 0.19-0.35), 0.19 (95% CI 0.02-0.35) and 0.19 (95% CI 0.11-0.27), respectively. There were sufficient data to support a negative correlation between mean pressure and HFMD (COR = -0.51, 95% CI -0.63 to -0.36). There was no notable correlation with wind speed (COR = 0.10, 95% CI -0.03 to 0.23). Our findings suggest that meteorological factors affect the incidence of HFMD to a certain extent. PMID- 30451131 TI - Decision-making in crisis resolution and home treatment teams: The AWARE framework. AB - Aims and methodThe aim of the study is to improve patient safety by identifying factors influencing gatekeeping decisions by crisis resolution and home treatment teams. A theoretical sampling method was used to recruit clinicians. Semi structured interviews to elicit various aspects of clinical decision-making were carried out. The transcripts were thematically analysed using a grounded theory approach. RESULTS: Patient needs (safety and treatment) was the primary driver behind decisions. The research also revealed that information gathered was processed using heuristics. We identified five key themes (anxiety, weighting, agenda, resource and experience), which were constructed into an acronym 'AWARE'.Clinical implicationsAWARE provides a framework to make explicit drivers for decision-making that are often implicit. Incorporating these drivers into reflective practice will help staff be more mindful of undue influences and result in improved clinical decisions.Declaration of interestNone. PMID- 30451132 TI - A retrospective study comparing the length of admission of medium secure unit patients admitted in the three decades since 1985. AB - Aims and methodAdmissions of patients to secure forensic hospitals are often lengthy. Previous research has examined factors associated with prolonged admission, but studies analysing admission data at a single medium secure unit (MSU) over a prolonged time period are lacking. We compared admission data for all patients admitted to a MSU in England during the years 1985, 1995, 2005 and 2012. RESULTS: The median length of admission increased from 167 days in 1985 to 580 days in 2012, though not in the intervening cohorts. There have been changes in the discharge destination of patients, away from independent accommodation in the community towards further care or supported accommodation.Clinical implicationsThe results suggest a change in the delivery of care. Further studies should be performed to assess whether the same trends exist at other sites. If these trends are also found elsewhere, this should trigger a specialty-wide discussion about admission length and its effects on bed availability.Declaration of interestNone. PMID- 30451133 TI - Geospatial cluster analyses of pneumonia-associated hospitalisations among adults in New York City, 2010-2014. AB - Pneumonia is a leading cause of death in New York City (NYC). We identified spatial clusters of pneumonia-associated hospitalisation for persons residing in NYC, aged ?18 years during 2010-2014. We detected pneumonia-associated hospitalisations using an all-payer inpatient dataset. Using geostatistical semivariogram modelling, local Moran's I cluster analyses and chi2 tests, we characterised differences between 'hot spots' and 'cold spots' for pneumonia associated hospitalisations. During 2010-2014, there were 141 730 pneumonia associated hospitalisations across 188 NYC neighbourhoods, of which 43.5% (N = 61 712) were sub-classified as severe. Hot spots of pneumonia-associated hospitalisation spanned 26 neighbourhoods in the Bronx, Manhattan and Staten Island, whereas cold spots were found in lower Manhattan and northeastern Queens. We identified hot spots of severe pneumonia-associated hospitalisation in the northern Bronx and the northern tip of Staten Island. For severe pneumonia associated hospitalisations, hot-spot patients were of lower mean age and a greater proportion identified as non-Hispanic Black compared with cold spot patients; additionally, hot-spot patients had a longer hospital stay and a greater proportion experienced in-hospital death compared with cold-spot patients. Pneumonia prevention efforts within NYC should consider examining the reasons for higher rates in hot-spot neighbourhoods, and focus interventions towards the Bronx, northern Manhattan and Staten Island. PMID- 30451135 TI - Familism values across the transition to adolescent motherhood: Links to family functioning and Mexican-origin adolescent mothers' adjustment. AB - Familism values are conceptualized as a key source of resilience for Latino adolescents' psychosocial adjustment. The current study addressed the developmental progression and correlates of familism within the context of the transition to adolescent motherhood. Participants were 191 Mexican-origin pregnant adolescents (15 to 18 years of age at first pregnancy; Mage = 16.76 years; SD = 0.98) who were having their first child. Adolescents completed interviews during their third trimester of pregnancy and annually for 5 years after (Waves 1 through 6). We examined changes in familism values across the transition to adolescent motherhood and the moderating role of age at pregnancy. Moderation analyses revealed differences in familism trajectories for younger versus older adolescents. We also examined whether familism values were related to family relationship dynamics (i.e., adolescents' relationships with their own mother figures) and adolescents' psychosocial adjustment, respectively, using multilevel models to test both between-person and within-person associations. Adolescents' stronger familism values were related to adolescent-mother figure warmth and conflict, coparenting communication, and three dimensions of social support from mother figures, but no associations emerged for coparental conflict, adolescents' depressive symptoms, or self-esteem. Discussion addresses these findings in the context of culturally grounded models of ethnic-racial minority youth development and psychopathology. PMID- 30451134 TI - Epidemiological survey and sequence information analysis of swine hepatitis E virus in Sichuan, China. AB - Hepatitis E is an important zoonosis that is prevalent in China. Hepatitis E virus (HEV) is a pathogen that affects humans and animals and endangers public health in China. In this study, the detection of HEV epidemics in swine in Sichuan Province, China, was carried out by nested real-time PCR. A total of 174 stool samples and 160 bile samples from swine in Sichuan Province were examined. In addition, software was used to analyse the biological evolution of HEV. The results showed that within 2 years of swine HEV (SHEV) infection in China, SHEV was first detected in Sichuan Province. HEV was endemic in Sichuan; the positive rate for pig farms was 11.1%, and the total positive sample rate was 10.5%. The age of swine with the highest positive rate (17.9%) was 5-9 weeks. The examined swine species in order of highest to lowest HEV infection rates were Chenghua pig, Large White, Duroc, Pietrain, Landrace and Hampshire. Nucleotide and amino acid sequence analysis showed that the HEV epidemic in swine in Sichuan Province was related to genotype IV, which had the highest homology to HEV in Beijing. Sichuan strains have greater variation than Chinese representative strains, which may indicate the presence of new HEV strains. PMID- 30451136 TI - Ethnic-racial identity content and the development of depressive symptoms among Latino adolescents. AB - The current study examined the concurrent and prospective associations of ethnic racial identity content (i.e., centrality, private regard, and public regard) and depressive symptomatology among Latino adolescents. Data were drawn from a longitudinal study of Latino adolescents (N = 148, 53.4% girls) who were 13-14 years old at Wave 1. Results indicated that higher ethnic-racial centrality at Waves 1 and 2 predicted fewer depressive symptoms at Waves 2 and 3, respectively. In addition, more positive private regard at Wave 1 predicted fewer depressive symptoms at Wave 2, and more positive public regard at Wave 2 predicted fewer symptoms at Wave 3. Thus, ethnic-racial identity content may serve as a cultural protective factor that is linked to diminished depressive symptomatology among Latino youth. PMID- 30451137 TI - Active coping moderates associations among race-related stress, rumination, and depressive symptoms in emerging adult African American women. AB - Cross-sectional and longitudinal research has shown that race-related stress is associated with increased depressive symptoms among racial/ethnic minorities. Rumination has long been considered a maladaptive self-regulatory response to race-related stress, and growing evidence suggests that it may be an important link in the relation between race-related stress and depression. More adaptive forms of self-regulation, such as active coping, may counteract the negative impact of rumination. We examined the influence of rumination on the relation between race-related stress and depressive symptoms in a sample (N = 69) of young adult (mean age = 20 +/- 1.5 years) African American women. We also considered the possible moderating effects of John Henryism, a form of persistent and determined goal striving, and vagally mediated heart rate variability, a purported biomarker of coping. Anticipatory race-related stress was indirectly associated with depressive symptoms through rumination: estimate = 0.07, 95% confidence interval [0.01, 0.16]. Both John Henryism and vagally mediated heart rate variability moderated the relationship between race-related stress and rumination; however, only John Henryism reliably influenced the indirect association between race-related stress and depression through rumination. We discuss these findings in the context of growing research examining the interplay between cultural and biological factors in the risk for poorer mental health. PMID- 30451138 TI - Cultural development and psychopathology. AB - Culture plays a pivotal role in adaptive and maladaptive development. However, culture remains disconnected from theory, research, training, assessment, and interventions in developmental psychopathology, limiting our understanding of the genesis and epigenesis of mental health. Cultural development and psychopathology research can help overcome this limitation by focusing on the elucidation of cultural risk, protective, and promotive factors, at the individual and social levels, that initiate, derail, or maintain trajectories of normal and abnormal behavior. The goal of this Special Issue is to showcase research on the association between culture, development, and psychopathology that investigates equifinality and multifinality in cultural development, the interplay between culture and biology, cultural assessment and interventions, and cultural differences and similarities. PMID- 30451139 TI - Reports of perceived racial discrimination among African American children predict negative affect and smoking behavior in adulthood: A sensitive period hypothesis. AB - We examined the prospective relations between a cultural risk factor, perceived racial discrimination (PRD), and subsequent negative affect and health behavior (smoking) in a panel of 889 African American children (part of the Family and Community Health Study). Cultural moderators (protective factors) of these relations were also examined. PRD was assessed six times from ages 10.5 (Wave 1) to 24.5 (Wave 6), and negative affect (anger and depressive symptoms) was assessed at Wave 2 (age 12.5) and Wave 6 (age 24.5). Results indicated that Wave 1 PRD predicted Wave 6 smoking, controlling for multiple factors related to smoking and/or PRD, including smoking at age 15.5. Structural equation models indicated that these relations between Wave 1 PRD and smoking were mediated by both early and later negative affect. The models also indicated that Wave 1 PRD had a direct impact on Wave 6 anger (assessed 14 years later), controlling for the effects of PRD on early affect. Cultural socialization was associated with lower rates of adolescent smoking, and it buffered the relation between PRD and Wave 6 anger. The impact of early PRD experiences along with suggestions for culturally informed interventions and preventive interventions that might buffer against early PRD effects are discussed. PMID- 30451140 TI - Intergenerational gaps in Mexican American values trajectories: Associations with parent-adolescent conflict and adolescent psychopathology. AB - Growth mixture modeling with a sample of 749 Mexican heritage families identified parallel trajectories of adolescents' and their mothers' heritage cultural values and parallel trajectories of adolescents' and their fathers' heritage cultural values from Grades 5 to 10. Parallel trajectory profiles were then used to test cultural gap-distress theory that predicts increased parent-adolescent conflict and adolescent psychopathology over time when adolescents become less aligned with Mexican heritage values compared to their parents. Six similar parallel profiles were identified for the mother-youth and father-youth dyads, but only one of the six was consistent with the hypothesized problem gap pattern in which adolescents' values were declining over time to become more discrepant from their parents. When compared to families in the other trajectory groups as a whole, mothers in the mother-adolescent problem gap trajectory group reported higher levels of mother-adolescent conflict in the 10th grade that accounted for subsequent increases in internalizing and externalizing symptoms assessed in 12th grade. Although the findings provided some support for cultural gap-distress predictions, they were not replicated with adolescent report of conflict nor with the father-adolescent trajectory group analyses. Exploratory pairwise comparisons between all six mother-adolescent trajectory groups revealed additional differences that qualified and extended these findings. PMID- 30451141 TI - Genetic moderation of the effects of the Family Check-Up intervention on children's internalizing symptoms: A longitudinal study with a racially/ethnically diverse sample. AB - Development involves synergistic interplay among genotypes and the physical and cultural environments, and integrating genetics into experimental designs that manipulate the environment can improve understanding of developmental psychopathology and intervention efficacy. Consistent with differential susceptibility theory, individuals can vary in their sensitivity to environmental conditions including intervention for reasons including their genotype. As a consequence, understanding genetic influences on intervention response is critical. Empirically, we tested an interaction between a genetic index representing sensitivity to the environment and the Family Check-Up intervention. Participants were drawn from the Early Steps Multisite randomized prevention trial that included a low-income and racially/ethnically diverse sample of children and their families followed longitudinally (n = 515). As hypothesized, polygenic sensitivity to the environment moderated the effects of the intervention on 10-year-old children's symptoms of internalizing psychopathology, such that children who were genetically sensitive and were randomly assigned to the intervention had fewer symptoms of child psychopathology than genetically sensitive children assigned to the control condition. A significant difference in internalizing symptoms assessed with a clinical interview emerged between the intervention and control groups for those 0.493 SD above the mean on polygenic sensitivity, or 25% of the sample. Similar to personalized medicine, it is time to understand individual and sociocultural differences in treatment response and individualize psychosocial interventions to reduce the burden of child psychopathology and maximize well-being for children growing up in a wide range of physical environments and cultures. PMID- 30451142 TI - Physical and psychosocial development of Mapuche and nonindigenous Chilean toddlers: A modest role of ethnicity. AB - Mapuche represents the largest indigenous group in Chile amounting to nearly 10% of the total population. In a longitudinal cohort of 12,398 children, we analyzed the role of ethnicity in physical and psychosocial development of Mapuche and nonindigenous Chilean toddlers (age 2.5 years), taking into account sociodemographic and caregiver characteristics. As indicated by our univariate analysis, the Mapuche developmental niche was characterized by lower income, lower maternal education, poorer quality of the home environment, longer breastfeeding, and higher parental stress. Physical development showed higher body mass index. Mapuche children showed less externalizing problems. We then analyzed the incremental contribution of ethnicity in a series of hierarchical regressions with the second wave of developmental measurements (age 4.5 years) as outcome variables, showing a significant but modest incremental contribution of ethnicity to the prediction of children's development between 2.5 and 4.5 years of age. Controlling for environmental variables, Mapuche showed less externalizing and internalizing, behavior problems. Socioeconomic status, quality of the home environment, and parenting stress were stronger predictors of socioemotional development than ethnicity per se. PMID- 30451143 TI - Sedation or anaesthesia decrease the stress response to electroejaculation and improve the quality of the collected semen in goat bucks. AB - Electroejaculation (EE) is stressful and probably painful; thus the administration of anaesthesia is recommended to decrease those negative effects. However, anaesthesia has a direct risk of provoking death, but sedation is less risky than anaesthesia. At the same time, alpha2-adrenergic agonists may improve semen quality. Therefore, the aim of the present study was to compare the physiological and behavioural responses indicative of stress and possibly pain, and the semen quality in electroejaculated untreated, anaesthetised or sedated goat bucks. Semen was collected from eight bucks using three different procedures in all them (EE in untreated bucks, EE under sedation or EE under general anaesthesia). The number of vocalizations during EE and the behavioural pattern before and after procedures were recorded. Pain visual analogue scale (VAS) score was also determined during EE. Rectal temperature, heart rate, serum cortisol concentration, biochemical and haematological parameters were measured before and after each procedure, and sperm characteristics were determined. Bucks vocalised more often when untreated than sedated or anaesthetised (P<0.02). The pain VAS score was greater when bucks were untreated than sedated or anaesthetised (P<0.002). The rectal temperature, heart rate, total protein, albumin and haemoglobin concentrations were greater when bucks were untreated than anaesthetised or sedated (P<0.02). Serum cortisol increased after EE (P=0.0006), without differences between procedures. The frequency and duration of lying down after EE were greater when bucks were anaesthetised than sedated or untreated (P<0.05), and were also greater when bucks were sedated than untreated (P<0.05). The number of times that the animal tried to stand up after EE was greater when bucks were anaesthetised than sedated or untreated (P<0.02). The sperm mass motility was greater when bucks were anaesthetised or sedated than when they were untreated (P=0.048). When animals were sedated, the ejaculate contained more spermatozoa with functional plasma membrane (P=0.03) and morphologically normal (P=0.05) than when they were untreated. In conclusion, general anaesthesia and sedation decreased the stress and probably the pain response provoked by EE and especially sedation improved the quality of the semen collected. PMID- 30451144 TI - The effects of crossbreeding with Norwegian Red dairy cattle on common postpartum diseases, fertility and body condition score. AB - Norwegian Red bulls, selected in Norway, have been used for crossbreeding with Israeli Holstein on commercial farms. The aim of this project was to investigate Norwegian Red*Israeli Holstein (NRX) performance to see how the daughters perform in a different environment than the one their sires were selected in. This was done by comparing health and fertility of NRX with their Israeli Holstein (HO) counterparts. The data consisted of 71 911 HO records and 10 595 NRX records from 33 855 cows in 23 Israeli dairy herds. Calving events took place between 2006 and 2016. Five postpartum disorders (mean frequency in HO v. NRX, %) recorded by veterinarians were analyzed: anestrus (37.4 v. 41.2), metritis (40.1 v. 28.6), ketosis (11.9 v. 7.1), lameness (7.1 v. 3.1) and retained placenta (6.2 v. 4.0). The incidence of abortions was also analyzed; HO had a mean frequency of 9.9% and NRX 8.2%. These traits were defined as binary traits, with '1' indicating that the disorder was present and a treatment took place at least once, or '0' if the cow did not show signs of that disorder. Days open (i.e. the number of days from calving to conception), body condition score (BCS) recorded on a 1 to 5 scale and changes in BCS from calving to peak lactation were also analyzed. A logistic model was used for the health traits, while days open and BCS were analyzed with linear models. The model included breed group, herd-year of calving, birth year and parity as fixed effects. There was a significantly higher risk (odds ratio for HO v. NRX in parentheses) of ketosis (1.46), metritis (1.78), lameness (2.07), retained placenta (1.41) and abortion (1.13) in HO compared with NRX. Israeli Holstein heifers and cows in parity 3 to 6 had fewer cases of anestrus than NRX but no differences were found between the groups in parities 1 and 2. Body condition score was higher for NRX than HO and there was less change in BCS from calving to peak lactation in NRX compared with HO. Likewise, NRX had fewer days open than HO. Results indicate that crossbreeding can produce cows with better fertility that are less susceptible to postpartum disorders. PMID- 30451145 TI - Innate immunity and metabolomic responses in dairy cows challenged intramammarily with lipopolysaccharide after subacute ruminal acidosis. AB - Subacute ruminal acidosis (SARA) is a prevalent metabolic disorder in dairy cows known to elicit local and systemic immune responses. We recently showed that cows experiencing SARA and challenged intramammarily with lipopolysaccharide (LPS) experienced stronger metabolic disturbances compared with cows without SARA. Therefore, we hypothesized that cows experiencing SARA have a modulated innate immune response and impaired plasma metabolome compared with healthy cows when experiencing an acute mastitis challenge. A total of 18 Simmental cows were subjected either to a Control (CON, n=6) or SARA (n=12) feeding regimen, receiving either 40% or 60% concentrates for 30 days. Thereafter, six SARA (SARA LPS) and the CON (CON-LPS) cows were intramammarily challenged with 50 ug LPS from Escherichia coli (O26 : B6), while the remaining six SARA cows (SARA-PLA) received a placebo. Blood and milk samples were analyzed for acute phase proteins and a targeted ESI-LC-MS/MS-based metabolomics approach was performed in blood samples 24 h after the LPS challenge. The LPS infusion caused a strong increase in immune response variables, with a higher concentration of milk amyloid A 48 h after the LPS challenge in SARA-LPS compared with CON-LPS cows. Cows receiving the LPS infusion had a lower plasma concentration of several amino acids and lysophosphatidylcholines but without differences in SARA cows and healthy cows. In conclusion, our results revealed that an intramammary LPS infusion increased acute phase proteins and modulated the blood metabolome. While no systemic differences between SARA and healthy cows were observed, cows experiencing SARA showed a higher concentration of an acute phase protein at the local level of the mammary gland. Further research is required to elucidate the underlying mechanisms and to evaluate its clinical significance for udder health. PMID- 30451146 TI - Breastfeeding: a key modulator of gut microbiota characteristics in late infancy. AB - The objective of this study was to investigate the impact of the most commonly cited factors that may have influenced infants' gut microbiota profiles at one year of age: mode of delivery, breastfeeding duration and antibiotic exposure. Barcoded V3/V4 amplicons of bacterial 16S-rRNA gene were prepared from the stool samples of 52 healthy 1-year-old Australian children and sequenced using the Illumina MiSeq platform. Following the quality checks, the data were processed using the Quantitative Insights Into Microbial Ecology pipeline and analysed using the Calypso package for microbiome data analysis. The stool microbiota profiles of children still breastfed were significantly different from that of children weaned earlier (P<0.05), independent of the age of solid food introduction. Among children still breastfed, Veillonella spp. abundance was higher. Children no longer breastfed possessed a more 'mature' microbiota, with notable increases of Firmicutes. The microbiota profiles of the children could not be differentiated by delivery mode or antibiotic exposure. Further analysis based on children's feeding patterns found children who were breastfed alongside solid food had significantly different microbiota profiles compared to that of children who were receiving both breastmilk and formula milk alongside solid food. This study provided evidence that breastfeeding continues to influence gut microbial community even at late infancy when these children are also consuming table foods. At this age, any impacts from mode of delivery or antibiotic exposure did not appear to be discernible imprints on the microbial community profiles of these healthy children. PMID- 30451147 TI - Feasibility and acceptability of a beverage intervention for Hispanic adults: results from a pilot randomized controlled trial. AB - OBJECTIVE: To assess the feasibility and acceptability of a beverage intervention in Hispanic adults. DESIGN: Eligible individuals identified as Hispanic, were 18 64 years old and had BMI 30.0-50.0 kg/m2. Participants were randomized 2:2:1 to one of three beverages: Mediterranean lemonade (ML), green tea (GT) or flavoured water control (FW). After a 2-week washout period, participants were asked to consume 32 oz (946 ml) of study beverage daily for 6 weeks and avoid other sources of tea, citrus, juice and sweetened beverages; water was permissible. Fasting blood samples were collected at baseline and 8 weeks to assess primary and secondary efficacy outcomes. SETTING: Tucson, AZ, USA.ParticipantsFifty-two participants were recruited over 6 months; fifty were randomized (twenty-one ML, nineteen GT, ten FW). Study population mean (sd) age 44.6 (sd 10.2) years, BMI 35.9 (4.6) kg/m2; 78 % female. RESULTS: Forty-four (88 %) completed the 8-week assessment. Self-reported adherence was high. No significant change (95 % CI) in total cholesterol (mg/dl) from baseline was shown -1.7 (-14.2, 10.9), -3.9 ( 17.2, 9.4) and -13.2 (-30.2, 3.8) for ML, GT and FW, respectively. Mean change in HDL-cholesterol (mg/dl) -2.3 (-5.3, 0.7; ML), -1.0 (-4.2, 2.2; GT), -3.9 (-8.0, 0.2; FW) and LDL-cholesterol (mg/dl) 0.2 (-11.3, 11.8; ML), 0.5 (-11.4, 12.4; GT), -9.8 (-25.0, 5.4; FW) were also non-significant. Fasting glucose (mg/dl) increased significantly by 5.2 (2.6, 7.9; ML) and 3.3 (0.58, 6.4; GT). No significant change in HbA1c was demonstrated. Due to the small sample size, potential confounders and effect modifiers were not investigated. CONCLUSIONS: Recruitment and retention figures indicate that a larger-scale trial is feasible; however, favourable changes in cardiometabolic biomarkers were not demonstrated. PMID- 30451148 TI - Mechanism of Bidirectional Leading-Strand Synthesis Establishment at Eukaryotic DNA Replication Origins. AB - DNA replication commences at eukaryotic replication origins following assembly and activation of bidirectional CMG helicases. Once activated, CMG unwinds the parental DNA duplex and DNA polymerase alpha-primase initiates synthesis on both template strands. By utilizing an origin-dependent replication system using purified yeast proteins, we have mapped start sites for leading-strand replication. Synthesis is mostly initiated outside the origin sequence. Strikingly, rightward leading strands are primed left of the origin and vice versa. We show that each leading strand is established from a lagging-strand primer synthesized by the replisome on the opposite side of the origin. Preventing elongation of primers synthesized left of the origin blocked rightward leading strands, demonstrating that replisomes are interdependent for leading strand synthesis establishment. The mechanism we reveal negates the need for dedicated leading-strand priming and necessitates a crucial role for the lagging strand polymerase Pol delta in connecting the nascent leading strand with the advancing replisome. PMID- 30451149 TI - Expert opinion on managing chronic HCV in patients with non-Hodgkin lymphoma and other extrahepatic malignancies. AB - HCV is a carcinogen that is well established as a major risk factor for hepatocellular carcinoma. Evidence that HCV plays a role in the development of extrahepatic malignancies is less robust; however, epidemiological studies have consistently demonstrated an association between HCV infection and B-cell non Hodgkin lymphoma (NHL). The strongest evidence for a link between HCV and tumourigenesis is the clear association between viral eradication, as indicated by achievement of sustained virological response, and remission of B-cell NHL. All-oral direct-acting antiviral-based therapies are effective in patients with HCV-associated NHL and well tolerated. For this reason, it is important that clinicians assess HCV-infected patients for HCV-associated extrahepatic malignancies so patients can receive timely diagnosis and treatment. PMID- 30451150 TI - Expert opinion on managing chronic HCV in patients with neuropsychiatric manifestations. AB - Neurological manifestations of HCV infection appear to be under-recognized in clinical practice despite the majority of HCV-infected patients experiencing symptoms such as fatigue, depression and cognitive dysfunction. There is also growing evidence for a link between HCV infection and an increased risk of Parkinson's disease. The mechanism underpinning the association between HCV and these neuropsychiatric syndromes still requires further investigation. Here we review the pre-clinical and clinical evidence for a link between HCV and effects on the central nervous system leading to neuropsychiatric syndromes. Lastly, we describe how improvements in neuropsychiatric manifestations of HCV following treatment have been observed, which is subsequently reflected in an overall improvement in health-related quality of life. PMID- 30451151 TI - Expert opinion on managing chronic HCV in patients with mixed cryoglobulinaemia vasculitis. AB - Mixed cryoglobulinaemia vasculitis (CryoVas) is a small-vessel systemic vasculitis caused by deposition of mixed cryoglobulins and is characterized by a wide range of clinical symptoms. HCV is the primary cause of CryoVas, which is associated with significant morbidity and mortality. The mortality rate among patients with HCV-associated CryoVas is 3* that of the general population, with a 63% 10-year survival rate. First-line treatment for CryoVas is anti-HCV therapy because viral clearance is associated with clinical improvement. The introduction of highly effective, interferon-free, direct-acting antiviral regimens provides additional treatment options for these patients. Here, we review recent studies investigating the effect of antiviral therapy on HCV-associated CryoVas and provide expert opinion for health-care professionals managing these patients. PMID- 30451152 TI - Expert opinion on managing chronic HCV in patients with cardiovascular disease. AB - Extrahepatic manifestations of chronic HCV infection include cardiovascular diseases and an increase in cardiovascular mortality. The pathogenic mechanisms by which HCV contributes to cardiovascular disease are not well defined, however, it is likely that systemic inflammation, and the promotion of other metabolic diseases are involved. In this Review, the evidence for HCV infection as a non traditional risk factor for cardiovascular disease is evaluated. Furthermore, practical advice to evaluate cardiovascular disease risk and disease in chronic hepatitis C patients are included for help in daily clinical practice. Despite the advances in therapies for the treatment of HCV, there remains a need for increased awareness among specialists so that patients are more likely to obtain the treatment required to mitigate disease progression. PMID- 30451153 TI - Expert opinion on the management of renal manifestations of chronic HCV infection. AB - Chronic HCV infection is a non-traditional (but modifiable) risk factor for chronic kidney disease and has been implicated in glomerular injury and nephrosclerotic disease. Three HCV direct-acting antiviral regimens are available for patients with severe kidney impairment: ombitasvir, paritaprevir with the pharmacokinetic enhancer ritonavir, and dasabuvir; glecaprevir plus pibrentasvir; and elbasvir plus grazoprevir. In patients with severe kidney impairment, sofosbuvir-free regimens are preferred because sofosbuvir accumulation has been associated with a progressive worsening of renal function. In this Review, we provide our expert opinion on the current HCV treatment paradigm and highlight the remaining issues that need to be overcome to improve the treatment of HCV in this population. PMID- 30451154 TI - Expert opinion on managing chronic HCV infection in patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) has been identified as an extrahepatic manifestation of chronic HCV infection. Conversely, in the context of chronic HCV infection, T2DM can accelerate the course of HCV-induced liver disease leading to increased risk of fibrosis, cirrhosis and hepatocellular carcinoma. The presence of T2DM negatively impacts the efficacy of interferon-based antiviral therapy, but real-world data with high-efficacy direct-acting antiviral therapies suggest high viral clearance rates in T2DM patients. In HCV-infected individuals, viral eradication is associated with a reduced risk of de novo T2DM in non-diabetic patients and beneficial metabolic changes in patients with T2DM, highlighting the importance of antiviral treatment and physician awareness of this association. PMID- 30451155 TI - Two-photon photoemission spectroscopy of unoccupied electronic states at CuPc/PTCDA/Ag(1 1 1) interfaces. AB - The unoccupied electronic structure of stacked layers of copper(II)phthalocyanine (CuPc) and perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) on Ag(1 1 1) has been investigated by means of two-photon photoemission (2PPE). We find a rich electronic structure comprising at least five unoccupied electronic states which we identify based on their energetic position and their dispersion in momentum space. More specifically, we observe the first and the second image-potential states of the modified Ag(1 1 1) surface, as well as the metal-organic interface state (IS) inherent to the PTCDA/Ag(1 1 1) interface. Moreover, two additional molecular features are observed for the CuPc/PTCDA/Ag(1 1 1) system which we attribute to an unoccupied molecular orbital (LUMO + 2) of CuPc. The 2PPE intensity of the IS exhibits a pronounced dependence on the pump photon energy, which closely follows the optical absorption of the outer molecular layer. This strongly points to charge transfer from the optically excited molecules to the interface state. PMID- 30451156 TI - The driving mechanism of the d-wave orbital order in the iron-based superconductors. AB - We study the driving mechanism and the form of the orbital order in the electronic nematic phase of the iron-based superconductors (IBSs) within the random phase approximation of a 5-band model. We find the magnetic correlation energy of the system can be significantly improved when an orbital order of the d wave form is spontaneously generated. On the other hand, the magnetic correlation energy increases as one introduce either an on-site or an extended s-wave orbital order. More specifically, we find that the on-site orbital order is disfavored by the Hund's rule coupling and the extended s-wave orbital order is disfavored by the stripy magnetic correlation pattern in the IBSs. Our work indicates that the orbital order and the spin nematic order in the IBSs develop in a cooperative fashion in the electronic nematic phase of the IBSs and should be both understood as a component of a composite order. PMID- 30451157 TI - The stability of binary Al12X nanoclusters (X = Sc and Ti): superatom or Wade's polyhedron. AB - Binary nanoclusters (NCs) exhibit strong potential as building blocks for tailor made scientific materials based on the precise tuning of their electron countings and spin states along with the synergistic effects that originate from the constituent elements. Herein, we studied the electronic and geometric structures of transition metal (TM) doped aluminum (Al) Al12X NCs (X = Sc and Ti), which are binary systems that extend from representative superatom [Formula: see text] anions. On the basis of the photoelectron spectroscopy (PES) and density functional theory (DFT) calculations, Al12X anion and neutral structures are characterized as vertex-replaced icosahedron. The highly stable exohedral Al12X icosahedron is described based on an electron counting rule derived from the coupling of Wade-Mingos' rule and the jellium model. PMID- 30451158 TI - Coexistence of pressure-induced structural phases in bulk black phosphorus: a combined x-ray diffraction and Raman study up to 18 GPa. AB - We report a study of the structural phase transitions induced by pressure in bulk black phosphorus by using both synchrotron x-ray diffraction for pressures up to 12.2 GPa and Raman spectroscopy up to 18.2 GPa. Very recently black phosphorus attracted large attention because of the unique properties of few-layers samples (phosphorene), but some basic questions are still open in the case of the bulk system. As concerning the presence of a Raman spectrum above 10 GPa, which should not be observed in an elemental simple cubic system, we propose a new explanation by attributing a key role to the non-hydrostatic conditions occurring in Raman experiments. Finally, a combined analysis of Raman and XRD data allowed us to obtain quantitative information on presence and extent of coexistences between different structural phases from ~5 up to ~15 GPa. This information can have an important role in theoretical studies on pressure-induced structural and electronic phase transitions in black phosphorus. PMID- 30451160 TI - Revolution in evolution. PMID- 30451159 TI - Structural determination of neutral Co n clusters (n = 4-10,13) through IR-UV two-color vibrational spectroscopy and DFT calculations. AB - We recorded IR spectra for neutral cobalt clusters via two-color IR-UV ionization, using the Free Electron Laser for intracavity experiments (FELICE). Well-resolved IR spectra are presented for [Formula: see text] (n = 4-10, 13) and analyzed with the help of Density Functional Theory calculations using two different correlation exchange functionals: the revisited Tao-Perdew-Staroverov Scuseria (revTPSS) and the frequently used Perdew-Burke-Ernzerhof (PBE) approaches. Although we have not performed an extensive structure search, we tentatively assign the spectra for all cluster sizes except for n = 7, and n = 10. We find that neither of the two functionals chosen clearly outperforms the other in predicting IR spectra, and that relatively low scaling factors of 0.82 (PBE) and 0.8 (revTPSS) are required. In contrast to the magnetic moments, the calculated electric dipole moments fluctuate strongly as a function of cluster size and could therefore be used as an indirect probe to the cluster structure. PMID- 30451161 TI - A perspective on the evolving field of vitreoretinal diseases. PMID- 30451162 TI - Fellowship training in India: How to produce leaders? PMID- 30451163 TI - Living legend in ophthalmology - Prof. Sohan Singh Hayreh. PMID- 30451164 TI - My ophthalmic research journey and contribution. PMID- 30451165 TI - Adventure in three worlds. AB - The author relates an unlikely journey from his rural village in India, through medical school, a prestigious fellowship with Sir Stewart Duke-Elder, and a colorful career in the United Kingdom and the USA, as a clinician and researcher, particularly in the area of vascular disease of the eye and optic nerve. PMID- 30451167 TI - Bilateral mastectomy, choroidal mass: A curve ball. PMID- 30451166 TI - Central retinal artery occlusion. AB - The pathogeneses, clinical features, and management of central retinal artery occlusion (CRAO) are discussed. CRAO consists of the following four distinct clinical entities: non-arteritic CRAO (NA-CRAO), transient NA-CRAO, NA-CRAO with cilioretinal artery sparing, and arteritic CRAO. Clinical characteristics, visual outcome, and management very much depend upon the type of CRAO. Contrary to the prevalent belief, spontaneous improvement in both visual acuity and visual fields does occur, mainly during the first 7 days. The incidence of spontaneous visual acuity improvement during the first 7 days differs significantly (P < 0.001) among the four types of CRAO; among them, in eyes with initial visual acuity of counting finger or worse, visual acuity improved, remained stable, or deteriorated in NA-CRAO in 22%, 66%, and 12%, respectively; in NA-CRAO with cilioretinal artery sparing in 67%, 33%, and none, respectively; and in transient NA-CRAO in 82%, 18%, and none, respectively. Arteritic CRAO shows no change. Recent studies have shown that administration of local intra-arterial thrombolytic agent not only has no beneficial effect but also can be harmful. Investigations to find the cause and to prevent or reduce the risk of any further visual problems are discussed. Prevalent multiple misconceptions on CRAO are discussed. PMID- 30451168 TI - Current role of optical coherence tomography angiography: Expert panel discussion. AB - Optical coherence tomography (OCT) angiography is a promising technique that provides depth resolved images of blood flow in the retina and choroid with levels of detail far exceeding that obtained with older forms of imaging and offers several advantages over conventional angiography to visualize the chorioretinal vasculature in a rapid and noninvasive manner. However, as with any evolving imaging technique, there are ongoing challenges in terms of need for new equipment, limitations of imaging capability and software processing techniques, as well as in understanding the implications of the imaging and its correlation with pathophysiology of the retina and choroid. This expert panel discussion is structured to provide an insight into the current state of OCT angiography. PMID- 30451169 TI - Management of central serous chorioretinopathy: Expert panel discussion. AB - Central serous chorioretinopathy (CSCR), one of the most common diseases in retina clinics, needs a special attention by retina specialists. Considering the challenges in diagnosis, classification, and management of this enigmatic disease and lack of level 1 evidence, there is a need for consensus with regard to establishing management protocols. PMID- 30451171 TI - Commentary: Management of central serous chorioretinopathy: Looking beyond the eye. PMID- 30451170 TI - Management of chronic central serous chorioretinopathy. AB - New treatment modalities for the management of central serous chorioretinopathy (CSC) now exist. While acute CSC generally resolves without the requirement for intervention, chronic CSC has been associated with persistent disruption in visual function. Current treatment approaches include photodynamic therapy, oral aldosterone antagonism and subthreshold multifocal laser. There has also been further investigation into a number of new treatments including antivascular endothelial growth factor treatment. Further investigation using developing optical coherence tomography imaging is helping to determine biomarkers of CSC activity, potential indicators of treatment response and indications of chronicity of disease activity. Further comparative study is required to determine the effectiveness of different forms of treatment in a range of patients with varied demographics, aetiology and chronicity of disease. PMID- 30451172 TI - Choroidal biomarkers. AB - A structurally and functionally intact choroid tissue is vitally important for the retina function. Although central retinal artery is responsible to supply the inner retina, choroidal vein network is responsible for the remaining one-third of the external part. Abnormal choroidal blood flow leads to photoreceptor dysfunction and photoreceptor death in the retina, and the choroid has vital roles in the pathophysiology of many diseases such as central serous chorioretinopathy, age-related macular degeneration, pathologic myopia, Vogt Koyanagi-Harada disease. Biomarkers of choroidal diseases can be identified in various imaging modalities that visualize the choroid. Indocyanine green angiography enables the visualization of choroid veins under the retinal pigment epithelium and choroidal blood flow. New insights into a precise structural and functional analysis of the choroid have been possible, thanks to recent progress in retinal imaging based on enhanced depth imaging (EDI) and swept-source optical coherence tomography (SS-OCT) technologies. Long-wavelength SS-OCT enables the choroid and the choroid-sclera interface to be imaged at greater depth and to quantify choroidal thickness profiles throughout a volume scan, thus exposing the morphology of intermediate and large choroidal vessels. Finally, OCT angiography allows a dye-free evaluation of the blood flow in the choriocapillaris and in the choroid. We hereby review different imaging findings of choroidal diseases that can be used as biomarkers of activity and response to the treatment. PMID- 30451173 TI - Current management strategy of polypoidal choroidal vasculopathy. AB - Polypoidal choroidal vasculopathy (PCV) is a retinal disorder commonly found in Asians presenting as neovascular age-related macular degeneration and is characterized by serous macular detachment, serous or hemorrhagic pigment epithelial detachment, subretinal hemorrhage, and occasionally visible orange-red subretinal nodular lesions. PCV is diagnosed using indocyanine green angiography (ICGA), and the lesions appear as polypoidal aneurysmal vascular lesions with or without abnormal branching vascular network. Although ICGA remains the gold standard for the diagnosis of PCV, various imaging modalities have also facilitated the diagnosis and monitoring of PCV. Recent advances in imaging technology including the use of high resolution spectral domain optical coherence tomography (OCT) and OCT angiography have provided new insights on the pathogenesis of PCV, suggesting a link between PCV and pachychoroid spectrum of macular disorders. With the evolving understanding on the pathogenesis and clinical characteristics of PCV, different therapeutic options have been proposed. These include intravitreal anti-vascular endothelial growth factor (anti-VEGF) monotherapy, combination therapy with anti-VEGF and verteporfin photodynamic therapy, and thermal laser photocoagulation. In recent years, major multi-center randomized clinical trials such as EVEREST, EVEREST II, and PLANET studies have been conducted to compare the efficacy and safety of various treatment options for PCV. This review aims to summarize the results of recent literature, clinical trials and studies to provide an update on the management options of PCV. An overall management strategy for PCV will also be proposed. PMID- 30451174 TI - Diabetic macular edema: Evidence-based management. AB - Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy with an increasing prevalence tied to the global epidemic in type 2 diabetes mellitus. Its pathophysiology starts with decreased retinal oxygen tension that manifests as retinal capillary hyperpermeability and increased intravascular pressure mediated by vascular endothelial growth factor (VEGF) upregulation and retinal vascular autoregulation, respectively. Spectral domain optical coherence tomography (SD-OCT) is the cornerstone of clinical assessment of DME. The foundation of treatment is metabolic control of hyperglycemia and blood pressure. Specific ophthalmic treatments include intravitreal anti-VEGF drug injections, intravitreal corticosteroid injections, focal laser photocoagulation, and vitrectomy, but a substantial fraction of eyes respond incompletely to all of these modalities resulting in visual loss and disordered retinal structure and vasculature visible on SD-OCT and OCT angiography. Efforts to close the gap between the results of interventions within randomized clinical trials and in real-world contexts, and to reduce the cost of care increasingly occupy innovation in the social organization of ophthalmic care of DME. Pharmacologic research is exploring other biochemical pathways involved in retinal vascular homeostasis that may provide new points of intervention effective in those cases unresponsive to current treatments. PMID- 30451175 TI - Current management of diabetic tractional retinal detachments. AB - Twenty-five percent of diabetes-related vision loss stems from complications of proliferative diabetic retinopathy (PDR). Panretinal photocoagulation has been the preferred treatment of high-risk PDR for decades and more recently intravitreal injections of drugs that inhibit the actions of vascular endothelial growth factor have become popular. But despite these treatments PDR may progress uncontrollably to advanced pathologies such as traction retinal detachments (TRDs), combined traction/rhegmatogenous retinal detachments (TRD/RRDs), vitreous hemorrhages, rubeosis iridis, and traction maculopathies, which produce mild-to severe loss of vision. TDR have long been the most common indication for PDR related vitreoretinal surgery. Vitrectomy surgery is indicated for recent (<6 months duration) TRD involving the macula, progressive TRD that threatens the macula, and recent data suggest that chronic macula-involving TRDs (>6 months duration) may also benefit. Combined TRD/RRD represents a particularly challenging surgical condition but advances in surgical instrumentation, dissection techniques, and post-operative tamponade have produced excellent success rates. The recent development of small-gauge vitrectomy systems has persuaded most surgeons to switch platforms since these appear to produce shorter surgical times and quicker post-operative recoveries. Pre-operative injections of bevacizumab are frequently administered for persistent neovascularization to facilitate surgical dissection of pre-retinal fibrosis and reduce the incidence of post-operative hemorrhages. Recent trends toward earlier surgical intervention and expanded indications are likely to continue as surgical instrumentation and techniques are further developed. PMID- 30451176 TI - Management of recurrent rhegmatogenous retinal detachment. AB - Rhegmatogenous retinal detachment (RRD) repair is one of the most common vitreoretinal surgeries a surgeon performs. In an ideal scenario, RRD can be repaired with a single surgical intervention; however, despite excellent skill, flawless technique, and the introduction of high-end technology, up to 10% of cases require additional interventions to ultimately repair recurrent detachments. It is thus important to study the outcomes of multiple interventions to understand whether performing repeat vitrectomy on patients with a history of failed surgeries is worthwhile. Thus, recurrent retinal detachment (re-RD) remains a significant challenge for vitreoretinal surgeons as well as the patients considering the economic and the emotional burden of undergoing multiple interventions. The advent of microincision vitrectomy system, perfluorocarbon liquids, and effective intraocular tamponades has opened new doors for managing re-RDs. In this article, we have reviewed and summarized the various causes and approaches for management for optimal anatomical and functional outcomes. PMID- 30451177 TI - Current concepts of macular buckle in myopic traction maculopathy. AB - Since its introduction by Charles L. Schepens, macular buckle (MB) surgery has evolved over the past 60 years. Optical coherence tomography (OCT) has given a paradigm shift to the understanding of myopic macula, thereby helping in objective evaluation of the various manifestation of traction maculopathy. Staphyloma evaluation by ultrasound, wide-field fundus photography, and MRI scans along with OCT has led to the resurgence of MB surgery in the treatment of myopic traction maculopathy (MTM). Various surgical techniques with different buckle materials are being performed with encouraging anatomical and functional success rates. This article reviews the literature to explain the current concept of MB surgery based on its evolution, different kinds of buckle materials, rationale for planning MB surgery, and different surgical techniques for the management of MTM. PMID- 30451178 TI - Qualitative comparison of choroidal vascularity measurement algorithms. AB - Purpose: To compare the accuracy of manual and automated binarization technique for the analysis of choroidal vasculature. Methods: This retrospective study was performed on a total of 98 eyes of 60 healthy subjects. Fovea-centered swept source optical coherence tomography (SS-OCT) scans were obtained and choroidal area was binarized using manual and automated image binarization technique separately. Choroidal vessel visualization in the binarized scans were subjectively graded (grades 0-100) by comparing them with the original OCT scan images by two masked graders. The subjective variability and repeatability was compared between two binarization method groups. Intergrader and intragrader variability was estimated using paired t-test. The degree of agreement between the grades for each observer and between the observers was evaluated using Bland Altman plot. Results: The mean accuracy grades of the automatically binarized images were significantly (P < 0.001) higher (93.38% +/- 1.70%) than that of manually binarized images (78.06% +/- 2.92%). There was a statistically significant variability and poor agreement between the mean interobserver grades in the manual binarization arm. Conclusion: Automated image binarization technique is faster and appears to be more accurate in comparison to the manual method. PMID- 30451179 TI - Commentary: Qualitative comparison of choroidal vascularity measurement algorithms. PMID- 30451180 TI - Correlation of optical coherence tomography angiography and microperimetry (MP3) features in wet age-related macular degeneration. AB - Purpose: To evaluate and correlate the functional treatment response using microperimetry (MP3) with the morphological findings on optical coherence tomography angiography (OCTA) in wet AMD pre- and post-treatment with anti vascular endothelial growth factor (VEGF). This was a single-centre prospective, interventional study. Methods: Patients with wet AMD were treated with 3 injections of intravitreal anti-VEGF at monthly intervals for 3 months and followed at 1, 2, 3, and 6 months postinjection. Using "overlay" features, morphologic characteristics of OCTA at the site of choroidal neovascular membrane (CNVM) lesion were analyzed and correlated functionally with MP3. Data were collected including visual acuity at presentation and follow-up with multimodal imaging features, treatment details, complications (if any), and treatment given for that complication. Descriptive observational analysis and paired t-test was used to compare the appearance of the neovascular network on OCTA imaging with retinal sensitivity on MP3. Results: OCTA in the pretreatment phase revealed CNVM as an abnormal vascular network arising from the choroid and invading the subretinal space. On MP3, decreased retinal sensitivity was observed corresponding to the area of CNVM. Post-treatment, OCTA revealed reduction in abnormal vascular network in 51 (91.07%) eyes that correlated with increased retinal sensitivity at the corresponding area on MP3. Statistical analysis showed baseline mean retinal sensitivity at the site of CNVM as 320.07 dB, which improved to 521.53 and 730.20 dB at 1 and 3 months postinjection follow-up, respectively. Conclusion: Combining the findings of OCTA and MP3 using "overlay" features gives us precise information of structure-function correlation at presentation and also in response to treatment. It also helps to improve patient's compliance, confidence to treatment, and their understanding of the disease process as well. PMID- 30451181 TI - "Double-layer sign" on spectral domain optical coherence tomography in pachychoroid spectrum disease. AB - Purpose: The "double-layer sign (DLS)" describes the shallow and irregular elevation of the retinal pigment epithelium from the underlying intact Bruch's membrane visualized on the spectral domain optical coherence tomography. In this study, we evaluated the frequency, characteristics of the space within the double layer and other features in the pachychoroid spectrum to aid the clinical diagnosis of these variants. Methods: This retrospective study evaluated the features of the DLS on multimodal imaging in consecutive patients with a clinical diagnosis of one of the four variants of pachychoroid: pachychoroid pigment epitheliopathy (PPE), pachychoroid neovasculopathy (PCN), chronic central serous chorioretinopathy (CCSCR), and polypoidal choroidal vasculopathy (PCV). The features of the DLS were graded by two masked graders. Results: Overall, 102 eyes of 79 consecutive patients with pachychoroid spectrum were identified for grading. Sixteen eyes with PPE did not show any evidence of DLS. The DLS was identified in 15/16 (93.75%) eyes with PCN, 11/35 (31.43%) with CCSCR, and 32/35 (91.43%) with PCV (P < 0.001). The space within the DLS showed moderate hyperreflectivity in all eyes with PCV and PCN, while the space in the DLS in CCSCR showed uniform hyporeflectivity in 10/11 (%) eyes. Conclusion: The DLS sign was most frequent in polypoidal vasculopathy and PCN. A hyporeflective gap within the DLS favored the diagnosis of CCSCR. PMID- 30451183 TI - Commentary: Interfere with the interface? PMID- 30451182 TI - The role of posterior vitreous detachment on the efficacy of anti-vascular endothelial growth factor intravitreal injection for treatment of neovascular age related macular degeneration. AB - Purpose: A prospective cohort study investigating the effect of posterior vitreous detachment (PVD) on the efficacy of intravitreal bevacizumab for exudative age-related macular degeneration (AMD), in view of evidence that the vitreoretinal interface impacts the severity of the disease. Methods: Treatment naive AMD eyes with (+) complete PVD and without (-) PVD on ultrasonography received three monthly and then pro re nata bevacizumab injections. Best corrected visual acuity (BCVA) on Snellen charts and optical coherence tomography (OCT) findings were recorded for 12 months. Secondary analysis included PVD definition and group allocation according to OCT baseline scan. Results: Forty one eyes of 34 patients met the inclusion criteria. At 12 months, median BCVA improved by 0.12 logMAR in the PVD+ group [interquartile range (IQR) -0.52, 0.03, P = 0.140] and remained the same in the PVD- group (IQR -0.12, 0.15, P = 0.643). Median central retinal thickness improved by 43.5 MUm and 43 MUm in the PVD+ (IQR -143, 3, P = 0.016) and PVD- group (IQR -90, -14, P = 0.008), respectively. All parameters were similar in the two groups at final follow up (P > 0.05). The secondary analysis included 32 eyes of 26 patients and showed no significant differences between the groups at the 12 months endpoint (P > 0.05). Conclusion: Our findings show no significant impact of PVD as assessed by ultrasound or by OCT on visual and anatomical outcomes in exudative AMD treated with bevacizumab. PMID- 30451185 TI - Commentary: Influence of orientation of the external linear incision created by the 25-gauge trocar and related factors on sclerotomy closure: A clinical and optical coherence tomographic study. PMID- 30451184 TI - Influence of orientation of the external linear incision created by the 25-gauge trocar and related factors on sclerotomy closure: A clinical and optical coherence tomographic study. AB - Purpose: To assess the influence of orientation of the external linear incision created by the trocar and related factors on sclerotomy closure in 25-gauge (25G) transconjunctival vitreous surgery (TVS). Methods: A total of 46 eyes of 46 patients who underwent 25G TVS (23 circumferential incisions and 23 radial incisions) were studied. Clinical and anterior segment optical coherence tomography (AS-OCT)-based comparison of self-sealed and sutured sclerotomies was done. The influence of age, ocular surgeries and injections, axial length, cannula type, sclerotomy quadrant, surgery duration, vitreous base excision, and tamponade on suture rates was analyzed. Results: Of the 46 eyes, 23 eyes required suturing [circumferential: 17 (74%) and radial: 6 (26%); P = 0.003]. A significantly lesser proportion of superonasal quadrant and inferotemporal quadrant sclerotomies needed suturing [9 (24%) and 12 (27%)] when compared with superotemporal quadrant [17 (37%)]. Sclerotomies to the left of the surgeon and the infusion port required significantly lesser suturing [10 (25%) and 13 (28%), respectively] when compared with that of surgeon's right [15 (35%)]. Suturing was significantly lesser when gas or oil tamponade was used [5 (36%) and 2 (20%), respectively] when compared with no tamponade [16 (73%)]. In eyes without tamponade, suturing was lesser with radial sclerotomies (P = 0.003). The odds of having an open sclerotomy tract on AS-OCT were >=5 when circumferential sclerotomies were used. Conclusion: Self-sealing was more common with radial external incisions. Tamponade was associated with less suturing. Superotemporal sclerotomies and sclerotomies toward the surgeon's dominant hand were often sutured. In this cohort, other factors did not influence sclerotomy closure. PMID- 30451186 TI - Comparison of clinical outcomes between "heads-up" 3D viewing system and conventional microscope in macular hole surgeries: A pilot study. AB - Purpose: To compare clinical outcomes of patients undergoing macular hole surgery with heads-up three-dimensional (3D) viewing system and conventional microscope. Methods: In all, 50 eyes of 50 patients with stage 3 or 4 macular hole were randomized and macular hole surgery [inverted internal limiting membrane (ILM) flap technique] was performed in 25 eyes using 3D viewing system and 25 eyes using conventional microscope. All surgeries were performed by a single surgeon. Patients were followed up for a period of 3 months. Logarithm of the minimum angle of resolution (logMAR) visual acuity, macular hole index, intraoperative parameters such as total surgical time, total ILM peel time, number of flap initiations, duration of Brilliant Blue G dye exposure, illumination intensity, postoperative logMAR visual acuity, and macular hole closure rates were recorded and compared between the two groups. Results: The mean age was 67.92 +/- 7.95 and 67.96 +/- 4.78 years in both groups, respectively (P = 0.98). Gender (P = 0.38) and right versus left eye (P = 0.39) were also comparable. Preoperative and postoperative best-corrected visual acuity (P = 0.86, 0.92), macular hole index (P = 0.96), total surgical time (P = 0.56), total ILM peel time (P = 0.49), number of flap initiations (P = 0.11), and macular hole closure rates (P = 0.61) were not statistically significant when compared between the two groups. Illumination intensity of microscope (100% vs 45%) and endoillumination (40% vs 13%) were significantly less in the 3D viewing system. Conclusion: The clinical outcomes of macular hole surgery using 3D viewing system are not inferior to that of conventional microscopes, and it has the added advantages of better ergonomics, reduced phototoxicity, peripheral visualization, magnification, and less asthenopia, and it serves as a good educational tool. PMID- 30451187 TI - Outcomes of rhegmatogenous retinal detachment surgery in eyes with pre-existing glaucoma drainage devices. AB - Purpose: To evaluate the outcome of rhegmatogenous retinal detachment (RRD) surgery in eyes with preplaced glaucoma drainage device (GDD) with respect to intraocular pressure (IOP) control as well as success of retinal detachment (RD) surgery. Methods: It is a retrospective case series. The case records of patients who underwent RD surgery after GDD implantation from 2000 to 2014 were screened. The demographic data, ocular examination findings at all visits, details pertaining to retinal detachment and its repair, and the postoperative course was documented. Results: Twelve patients were included in study. The mean age of patients was 24.3 years (median 11 years; range 3-72 years). Male: Female ratio was 3:1. Mean duration between GDD and RD was 24 months (4 days-91 months). Of the ten eyes that underwent surgery, nine eyes underwent pars plana vitrectomy, and in one eye scleral buckling was done. GDD was removed only in one eye. At final follow-up, retina was attached with controlled IOP in 6 (60%) eyes, of which 5 (50%) had improvement in best corrected visual acuity. Conclusion: Pars plana vitrectomy was required in almost all cases for the management of RD in eyes with preplaced GDD. Retinal reattachment with good IOP control could be achieved in 60% of eyes. Removal of the drainage device was not essential for the effective management of the RRD in most cases. With multidisciplinary approach, close follow-up and timely intervention, vision can be preserved along with glaucoma control and successful retinal reattachment. PMID- 30451188 TI - Outcome of vitreoretinal surgery for rhegmatogenous retinal detachment in X linked juvenile retinoschisis. AB - Purpose: Rhegmatogenous retinal detachment (RRD) is a vision-threatening complication of X-linked juvenile retinoschisis (XLRS). The aim of this study is to report the anatomical and functional outcomes of vitreoretinal surgery for the treatment of RRD in X-linked juvenile retinoschisis (XLRS). Methods: This is a retrospective, interventional, consecutive case series in which case records of 34 eyes of 28 XLRS patients, who underwent surgery for RRD, were reviewed. Statistical analysis used is as follows: visual outcomes were categorized into three groups: improved, remained stable or deteriorated. Wilcoxon signed-rank test was used to determine the difference in visual acuity at baseline and at final visit. Univariate binary logistic regression analysis was used to determine the risk factors for retinal detachment. Any P value < 0.05 was considered as statistical significant. Results: Mean age of the boys at presentation was 9.2 +/ 3.5 years. Indication for surgery was RRD in all eyes. Concurrent vitreous haemorrhage was present in four eyes (11.8%). The primary surgical intervention was scleral buckle in 12 eyes and pars plana vitrectomy in 22 eyes. Persistence of subretinal fluid/redetachment was seen in 15 eyes of which 11 eyes underwent additional surgeries. At final follow up, 27 eyes (79.4%) were noted to have an attached retina. Of the total eyes, in 20, 6 and 8 eyes the visual acuity improved, stabilized and deteriorated, respectively. Conclusion: Favourable outcomes are seen in a majority of eyes after vitreoretinal surgery for RRD in XLRS; however, multiple surgical interventions may be necessary. PMID- 30451189 TI - Commentary: Nuances in management of rhegmatogenous retinal detachment in X linked juvenile retinoschisis. PMID- 30451190 TI - Periocular topotecan for vitreous seeds in retinoblastoma. AB - Purpose: Refractory or recurrent vitreous seeds account for a large proportion of failure of eye salvage in retinoblastoma. The purpose of this study is to evaluate the efficacy of periocular topotecan (POT) in the management of vitreous seeds in retinoblastoma. Methods: Retrospective, interventional study of patients with retinoblastoma with vitreous seeds who received POT concurrent with intravenous chemotherapy (IVC). Results: Thirty-eight eyes of 35 patients received POT. Five eyes (13%) belonged to International Classification of Retinoblastoma group C, 23 eyes (61%) belonged to group D, and 10 eyes (26%) belonged to group E. Primary treatment included IVC with a combination of carboplatin, etoposide, and vincristine for a mean of 6 cycles (median 6; range 6 9). Concurrent to IVC from the fourth cycle onward, all patients received POT. Focal vitreous seeds were present in 20 eyes (53%) which received a mean of 3 injections (median 3; range 1-7). Diffuse vitreous seeds were present in 18 eyes (47%) which received a mean of 4 injections (median 5; range 1-7). At a mean follow-up of 8.5 months (median 5 months; range 1-15 months), regression of focal and diffuse vitreous seeds was achieved in 16 eyes (80%) and 8 eyes (44%), respectively. In all, 24 eyes (63%) had complete remission of vitreous seeds with POT given concurrently with IVC. Eye salvage was possible in 19 eyes (95%) with focal vitreous seeds and 12 eyes (68%) with diffuse VS. Enucleation was necessary for persistent vitreous seeds and viable tumor in five eyes (13%), viable tumor alone in one eye (0.02%), and recurrent vitreous seeds in one eye (0.02%). None of the patients developed systemic metastasis. Conclusion: POT administered concurrent with IVC is safe and effective in the initial management of vitreous seeds. PMID- 30451191 TI - Commentary: Periocular topotecan for retinoblastoma. PMID- 30451193 TI - Commentary: Post fever retinitis and vasculitis: A morphological conundrum. PMID- 30451192 TI - Ocular manifestations of Rickettsia conorii in South India. AB - Purpose: Among the major groups of rickettsiosis, the commonly reported diseases in India are: (a) Typhus group induced-scrub typhus, murine flea-borne typhus; (b) Spotted fever group induced-Indian tick typhus; and (c) Q fever. Though many scrub typhus outbreaks have been reported from India, only one outbreak of spotted fever-serologically proven Indian tick typhus (Rickettsia conorii)-has been reported. We report for the first time ocular manifestations of serologically proven R. conorii infection in a cluster of patients. Methods: In this retrospective study, case records patients with serologically proven Indian tick typhus (Rickettsia conorii) were reviewed for clinical manifestations and treatment outcomes. Results: : In the months of February to April 2016, a cluster of 12 patients (23 eyes) visited us with defective vision. Examination showed multifocal retinitis; mostly bilateral; patients had a history of fever approximately 4 weeks prior to onset of symptoms. After excluding other causes of multifocal retinitis, a diagnosis of rickettsial retinitis was made after Weil Felix test (WFT) was significantly positive, and enzyme-linked immunosorbent assay was positive for R. conorii. Course of the disease, visual outcome, and investigations are discussed. Doxycycline along with oral corticosteroids was effective in treating the condition. Conclusion: : Systematic fundus examination should be part of the routine evaluation of any patient who presents with fever and/or skin rash living in or returning from a specific endemic area. Clinical clues to diagnosing ocular rickettsiosis could be multifocal retinitis predominantly involving the posterior pole and macular involvement in the form of serous macular detachment or macular hard exudates. A positive WFT still serves as a useful and cheap diagnostic tool for laboratory diagnosis of rickettsial disease. Doxycycline along with oral corticosteroids was effective in treating the condition. PMID- 30451194 TI - The claw: A novel intraocular foreign body removal forceps. AB - Removal of intraocular foreign body (IOFB) from the posterior segment of the eye is challenging. In addition to surgical skill, it requires specific instrumentation to grasp and remove the IOFB. Small metallic IOFB can be removed using intraocular rare earth magnets but metallic IOFB larger than 3 mm and nonmetallic IOFBs like shot gun pellets, stones, or large glass fragments require specialized IOFB grasping forceps for removal. We describe the design and case based clinical applications of a novel IOFB removal forceps, "the claw" that consists of a titanium handle and a 27-mm, 19-G metallic shaft that houses four retractable prongs made of nitinol wire. When completely extended, the prongs measure 14 mm in length and open up to 8-8.5 mm in the widest extent. The four prongs offer a very secure grip without crushing or splintering the IOFB leading to minimal chances of IOFB slippage and inadvertent retinal trauma. PMID- 30451195 TI - Bimanual 25-gauge chandelier technique for direct perfluorocarbon liquid-silicone oil exchange in retinal detachments associated with giant retinal tear. AB - Direct perfluorocarbon liquid (PFCL)-silicone oil exchange presents its own set of challenges in the micro incision vitreous surgery era. We propose a simple bimanual technique to circumvent this problem. Thirteen eyes of patients with retinal detachment associated with giant retinal tears underwent vitrectomy followed by self-retaining endo illuminator (Chandelier) assisted direct PFCL silicone exchange. No intra or postoperative complications related to the surgical technique were noted. All patients had attached retinas and satisfactory visual recovery at 6 months. Direct bimanual PFCL silicone oil exchange using a Chandelier seems to be a safe and effective technique. PMID- 30451196 TI - Multimodal imaging of multiple macular holes. PMID- 30451197 TI - Multicolor imaging features of dissociated optic nerve fiber layer after internal limiting membrane peeling. PMID- 30451198 TI - Post-laser regression of diabetic neovascularization: An optical coherence tomography angiography study. PMID- 30451199 TI - Panoramic optical coherence tomography angiography features in acute zonal occult outer retinopathy. PMID- 30451200 TI - Multimodal imaging of acute zonal occult outer retinopathy in a Indian male. PMID- 30451201 TI - Persistent fetal vasculature - Clinical spectrum. PMID- 30451202 TI - Congenital retinal macrovessel in a patient with rhegmatogenous retinal detachment. PMID- 30451203 TI - Hydroxychloroquine-induced retinal toxicity in systemic lupus erythematosus. PMID- 30451204 TI - Combined central retinal vein occlusion and branch retinal artery occlusion. PMID- 30451205 TI - Combined central retinal artery and vein occlusion as the presenting manifestation of systemic lupus erythematosus. PMID- 30451206 TI - Secondary paracentral retinal hole following internal limiting membrane peeling for a large macular hole. PMID- 30451207 TI - Choroidal neovascularization associated with combined hamartoma of retina and retinal pigment epithelium: Multimodal imaging. AB - Combined hamartoma of retina and retinal pigment epithelium (CHRRPE) has been considered as a congenital benign entity with evidence of choroidal neovascularization membranes (CNVM) being associated with it in literature. This case series gives insight into the pathogenesis and the predisposing factors leading to CNVM formation in peripapillary CHRRPE using swept-source optical coherence tomography. In addition, lack of typical markers of CNVM (subretinal fluid/pigment epithelial detachment) in CHRRPE highlights the utility of optical coherence tomography angiography and the subtle optical coherence tomography findings such as "Bridge Sign" that could be instrumental in early diagnosis of CNVM in CHRRPE. PMID- 30451208 TI - Wyburn-Mason syndrome presenting with bilateral retinal racemose hemangioma with unilateral serous retinal detachment. AB - Wyburn-Mason syndrome is associated with unilateral retinal racemose hemangioma. Rarely, it presents with bilateral and symmetrical grade of malformation. We describe a 37-year old male, who presented with Wyburn-Mason syndrome presenting with bilateral but asymmetrical retinal hemangioma. The eye with advanced grade of hemangioma was complicated with exudation, intraretinal fluid, neurosensory detachment, and reduced vision. He was treated with one intravitreal injection of bevacizumab, after which both the intraretinal fluid and neurosensory detachment resolved. His vision improved and was maintained till 1 year of follow-up. PMID- 30451209 TI - Leukostasis retinopathy: An uncommon visual threatening complication of chronic myeloid leukemia with severe hyperleukocytosis - A case report and review of the literature. AB - To describe a rare case of an unusual visual threatening complication of chronic myeloid leukemia (CML). A 21-year-old male visited the hospital complaining of 1 week painless binocular acute visual loss without any other symptoms. The patient was diagnosed with CML. He then received emergent leukapheresis with imatinib treatment, which achieved obvious hematological remission. However, the visual acuity did not recover along with the CML remission and ocular structure relief. CML-related leukostasis could induce severe leukostasis retinopathy. Hematologists and ophthalmologists should pay more attention to this relatively rare and severe complication of CML. PMID- 30451211 TI - Commentary: Posterior polarannular and hemispheric choroidal and retinal dystrophy: Optical coherence tomographic angiography description of a rare case. PMID- 30451212 TI - Progressive, subretinal fibrosis mimicking retinal necrosis with poor visual prognosis in sympathetic ophthalmia: A rare finding. AB - We report a rare finding of progressive subretinal fibrosis mimicking retinal necrosis in 2 cases of sympathetic ophthalmia. Histopathology of the inciting eye and vitreous biopsy of the sympathizing eye ruled out infections and masquerades. Progression of inflammation and rapid deterioration of vision inspite of maximum immunosuppression are key findings in this variant of sympathetic ophthalmia. PMID- 30451210 TI - Posterior polar annular and hemispheric choroidal and retinal dystrophy: Optical coherence tomographic angiography description of a rare case. AB - Posterior polar annual choroidal dystrophy is a rare disease which affects the retina and choroid in an annular pattern. Our patient was referred to us a case of atypical retinitis pigmentosa. Fundus examination showed a normal optic disc, normal arterioles, and no bone spicules. The right eye showed a hemispheric pattern and the left eye showed an annular pattern of retinal and choroidal dystrophy. We describe the retinal and choroidal angiographic features of this case by optical coherence angiography. PMID- 30451213 TI - Role of Natural Killer T (NKT) Cells in Type II Diabetes-Induced Vascular Injuries. AB - BACKGROUND This study investigated the distribution and features of natural killer T (NKT) cells in the peripheral blood of diabetic patients, and their regulatory roles on vascular endothelial cells. MATERIAL AND METHODS Peripheral lymphocytes were isolated from diabetic patients. NKT cell distribution, proportion, and surface and intracellular markers were detected with flow cytometry. Peripheral blood-derived NKT cells were isolated and co-cultured with human umbilical vein endothelial cells (HUVECs). Proliferation and migration of HUVECs were assessed with the CCK-8 assay and the Transwell chamber assay. RESULTS The ratios of CD3-CD56+ NK and CD3+CD56+ NKT cells in the peripheral blood of patients with type II diabetes were significantly elevated. The expression levels of NKp30, NKG2D, and NKp44 on the surface were increased in the CD3+CD56+ NKT cells, while the expression levels of NKG2A and 158b were significantly downregulated. The expression level of granzymes in the peripheral blood-derived NKT cells were not changed in patients with type II diabetes, but the expression levels of IFNg and IL-4 were significantly increased. However, after co-culture with NKT cells derived from the peripheral blood of diabetic patients, the proliferation and migration of HUVECs were significantly inhibited, and was restored by treatment with IL-4 antibody. In addition, the IL-4 stimulus inhibited the proliferation and migration of HUVECs. ls were not changed in patients with type II diabetes, while the expression levels of IFNgamma and IL-4 were significantly increased. However, after co-cultured with NKT cells derived from the peripheral blood of diabetic patients, the proliferation and migration of HUVECs were significantly inhibited, which could significantly restored by the treatment of IL-4 antibody. In addition, the IL-4 stimulus could down-regulate the proliferation and migration of HUVECs. CONCLUSIONS Peripheral blood NKT cells are increased and activated in diabetes. NKT cells inhibit the proliferation and migration of HUVECs by secreting IL-4, thereby inducing vascular injuries. PMID- 30451214 TI - [Pheochromocytoma in multiple endocrine neoplasia 2A associated with pulmonary tuberculosis presenting as abdominal pain: a case report and literature review]. AB - Pheochromocytoma is a catecholamine-producing neoplasm that may occur sporadically or associated with hereditary diseases, such as multiple endocrine neoplasia. The classic symptoms are headache, sweating, and palpitations and are attributed to the sympathetic nervous system activity, usually presenting as paroxysms. On the other hand, pulmonary tuberculosis is an infectious disease considered a public health problem in many countries, whose incidence depends on risk factors such as immunosuppression. It is well known that endocrine-tumor diseases such as multiple endocrine neoplasia can predispose to chronic inflammation and immunosuppression. We report the case of a 38-year-old male patient who had an episode of arterial hypertension and abdominal pain as the first symptoms of a pheochromocytoma associated with multiple endocrine neoplasia type 2A. The patient developed pulmonary tuberculosis simultaneously, but we managed to treat both entities and achieve a favorable clinical course. PMID- 30451215 TI - Current knowledge on Hashimoto's encephalopathy: a literature review. AB - Hashimoto's encephalopathy is a rare disease, with a reported prevalence of 2.1 per 100 000. Clinical manifestations include confusion, decreased state of consciousness, cognitive deficit, seizures, myoclonus, ataxia, and focal neurological deficits. Due to the wide variety of signs and symptoms, clinical diagnostic suspicion is essential. Diagnosis is based on three pillars: the presence of neurological clinical manifestations after ruling out other causes of encephalopathy. 2) Presence of increased antithyroid antibodies. 3) Significant clinical improvement after the administration of immunomodulation. The treatment of Hashimoto's encephalopathy pursues two objectives: to control the autoimmune process and to control the complications of the disease. Although in most cases recovery is complete with treatment, the risk of relapse can range from 12.5 to 40% in follow-ups to 2 years. PMID- 30451216 TI - Ultrahigh Resolution Mouse Optical Coherence Tomography to Aid Intraocular Injection in Retinal Gene Therapy Research. AB - HR-SD-OCT is utilized to monitor the progression of photoreceptor degeneration in live mouse models, assess the delivery of therapeutic agents into the subretinal space, and to evaluate toxicity and efficacy in vivo. HR-SD-OCT uses near infrared light (800-880 nm) and has optics specifically designed for the unique optics of the mouse eye with sub-2-micron axial resolution. Transgenic mouse models of outer retinal (photoreceptor) degeneration and controls were imaged to assess the disease progression. Pulled glass microneedles were used to deliver sub retinal injections of adeno-associated virus (AAV) or nanoparticles (NP) via a trans-scleral and trans-choroidal approach. Careful positioning of the needle into the subretinal space was required prior to a calibrated pressure injection, which delivers fluid into the sub retinal space. Real time subretinal surgery was conducted on our retinal imaging system (RIS). HR-SD-OCT demonstrated progressive uniform retinal degeneration due to expression of a toxic mutant human mutant rhodopsin (P347S) (RHOP347S) transgene in mice. HR-SD-OCT allows rigorous quantification of all the retinal layers. Outer nuclear layer (ONL) thickness and photoreceptor outer segment length (OSL) measurements correlate with photoreceptor vitality, degeneration, or rescue. The RIS delivery system allows real-time visualization of subretinal injections in neonatal (~P10-14) or adult mice, and HR-SD-OCT immediately determines success of delivery and maps areal extent. HR-SD-OCT is a powerful tool that can evaluate the success of subretinal surgery in mice, in addition to measuring vitality of photoreceptors in vivo. HR SD-OCT can also be used to identify uniform animal cohorts to evaluate the extent of retinal degeneration, toxicity, and therapeutic rescue in preclinical gene therapy research studies. PMID- 30451218 TI - A Guide to Production, Crystallization, and Structure Determination of Human IKK1/alpha. AB - A class of extracellular stimuli requires activation of IKK1/alpha to induce generation of an NF-kappaB subunit, p52, through processing of its precursor p100. p52 functions as a homodimer or heterodimer with another NF-kappaB subunit, RelB. These dimers in turn regulate the expression of hundreds of genes involved in inflammation, cell survival, and cell cycle. IKK1/alpha primarily remains associated with IKK2/beta and NEMO as a ternary complex. However, a small pool of it is also observed as a low molecular weight complex(es). It is unknown if the p100 processing activity is triggered by activation of IKK1/alpha within the larger or the smaller complex pool. Constitutive activity of IKK1/alpha has been detected in several cancers and inflammatory diseases. To understand the mechanism of activation of IKK1/alpha, and enable its use as a drug target, we expressed recombinant IKK1/alpha in different host systems, such as E. coli, insect, and mammalian cells. We succeeded in expressing soluble IKK1/alpha in baculovirus infected insect cells, obtaining mg quantities of highly pure protein, crystallizing it in the presence of inhibitors, and determining its X ray crystal structure. Here, we describe the detailed steps to produce the recombinant protein, its crystallization, and its X-ray crystal structure determination. PMID- 30451217 TI - Visualize Drosophila Leg Motor Neuron Axons Through the Adult Cuticle. AB - The majority of work on the neuronal specification has been carried out in genetically and physiologically tractable models such as C. elegans, Drosophila larvae, and fish, which all engage in undulatory movements (like crawling or swimming) as their primary mode of locomotion. However, a more sophisticated understanding of the individual motor neuron (MN) specification-at least in terms of informing disease therapies-demands an equally tractable system that better models the complex appendage-based locomotion schemes of vertebrates. The adult Drosophila locomotor system in charge of walking meets all of these criteria with ease, since in this model it is possible to study the specification of a small number of easily distinguished leg MNs (approximately 50 MNs per leg) both using a vast array of powerful genetic tools, and in the physiological context of an appendage-based locomotion scheme. Here we describe a protocol to visualize the leg muscle innervation in an adult fly. PMID- 30451219 TI - Choice and No-Choice Bioassays to Study the Pupation Preference and Emergence Success of Ectropis grisescens. AB - Many insects live above the ground as larvae and adults and as pupate below the ground. Compared to the above-ground stages of their life cycles, less attention has been paid on how environmental factors affect these insects when they pupate within the soil. The tea looper, Ectropis grisescens Warren (Lepidoptera: Geometridae), is a severe pest of tea plants and has caused huge economic losses in South China. The protocols described here aim to investigate, through multiple choice bioassays, whether mature last-instar E. grisescens larvae can discriminate soil variables such as the substrate type and moisture content, and determine, through no-choice bioassays, the impact of the substrate type and moisture content on pupation behaviors and the emergence success of E. grisescens. The results would enhance the understanding of the pupation ecology of E. grisescens and may bring insights into soil-management tactics for suppressing E. grisescens populations. In addition, these bioassays can be modified to study the influences of various factors on the pupation behaviors and survivorship of soil-pupating pests. PMID- 30451220 TI - Visualizing Axonal Growth Cone Collapse and Early Amyloid beta Effects in Cultured Mouse Neurons. AB - Amyloid-beta (Abeta) causes memory impairments in Alzheimer's disease (AD). Although therapeutics have been shown to reduce Abeta levels in the brains of AD patients, these do not improve memory functions. Since Abeta aggregates in the brain before the appearance of memory impairments, targeting Abeta may be inefficient for treating AD patients who already exhibit memory deficits. Therefore, downstream signaling due to Abeta deposition should be blocked before AD development. Abeta induces axonal degeneration, leading to the disruption of neuronal networks and memory impairments. Although there are many studies on the mechanisms of Abeta toxicity, the source of Abeta toxicity remains unknown. To help identify the source, we propose a novel protocol that uses microscopy, gene transfection, and live cell imaging to investigate early changes caused by Abeta in axonal growth cones of cultured neurons. This protocol revealed that Abeta induced clathrin-mediated endocytosis in axonal growth cones followed by growth cone collapse, demonstrating that inhibition of endocytosis prevents Abeta toxicity. This protocol will be useful in studying the early effects of Abeta and may lead to more efficient and preventative AD treatment. PMID- 30451221 TI - Dissipative Microgravimetry to Study the Binding Dynamics of the Phospholipid Binding Protein Annexin A2 to Solid-supported Lipid Bilayers Using a Quartz Resonator. AB - The dissipative quartz crystal microbalance technique is a simple and label-free approach to measure simultaneously the mass uptake and viscoelastic properties of the absorbed/immobilized mass on sensor surfaces, allowing the measurements of the interaction of proteins with solid-supported surfaces, such as lipid bilayers, in real-time and with a high sensitivity. Annexins are a highly conserved group of phospholipid-binding proteins that interact reversibly with the negatively charged headgroups via the coordination of calcium ions. Here, we describe a protocol that was employed to quantitatively analyze the binding of annexin A2 (AnxA2) to planar lipid bilayers prepared on the surface of a quartz sensor. This protocol is optimized to obtain robust and reproducible data and includes a detailed step-by-step description. The method can be applied to other membrane-binding proteins and bilayer compositions. PMID- 30451222 TI - Use of Pre-Assembled Plastic Microfluidic Chips for Compartmentalizing Primary Murine Neurons. AB - Microfabricated methods to compartmentalize neurons have become essential tools for many neuroscientists. This protocol describes the use of a commercially available pre-assembled plastic chip for compartmentalizing cultured primary rat hippocampal neurons. These plastic chips, contained within the footprint of a standard microscope slide, are compatible with high-resolution, live, and fluorescence imaging. This protocol demonstrates how to retrograde label neurons via isolated axons using a modified rabies virus encoding a fluorescent protein, create isolated microenvironments within one compartment, and perform axotomy and immunocytochemistry on-chip. Neurons are cultured for >3 weeks within the plastic chips, illustrating the compatibility of these chips for long-term neuronal cultures. PMID- 30451223 TI - Affinity Purification of Chloroplast Translocon Protein Complexes Using the TAP Tag. AB - Chloroplast biogenesis requires the import of thousands of nucleus-encoded proteins into the plastid. The import of these proteins depends on the translocon at the outer (TOC) and inner (TIC) chloroplast membranes. The TOC and TIC complexes are multimeric and probably contain yet unknown components. One of the main goals in the field is to establish the complete inventory of TOC and TIC components. For the isolation of TOC-TIC complexes and the identification of new components, the preprotein receptor TOC159 has been modified N-terminally by the addition of the tandem affinity purification (TAP) tag resulting in TAP-TOC159. The TAP-tag is designed for two sequential affinity purification steps (hence "tandem affinity"). The TAP-tag used in these studies consists of a N-terminal IgG-binding domain derived from Staphylococcus aureus Protein A (ProtA) followed by a calmodulin-binding peptide (CBP). Between these two affinity tags, a tobacco etch virus (TEV) protease cleavage site has been included. Therefore, TEV protease can be used for gentle elution of TOC159-containing complexes after binding to IgG beads. In the protocol presented here, the second Calmodulin affinity purification step was omitted. The purification protocol starts with the preparation and solubilization of total cellular membranes. After the detergent treatment, the solubilized membrane proteins are incubated with IgG beads for the immunoisolation of TAP-TOC159-containing complexes. Upon binding and extensive washing, TAP-TOC159 containing complexes are cleaved and released from the IgG beads using the TEV protease whereby the S. aureus IgG-binding domain is removed. Western blotting of the isolated TOC159-containing complexes can be used to confirm the presence of known or suspected TOC and TIC proteins. More importantly, the TOC159-containing complexes have been used successfully to identify new components of the TOC and TIC complexes by mass spectrometry. The protocol that we present potentially allows the efficient isolation of any membrane-bound protein complex to be used for the identification of yet unknown components by mass spectrometry. PMID- 30451224 TI - Laser-assisted Lentiviral Gene Delivery to Mouse Fertilized Eggs. AB - Lentiviruses are efficient vectors for gene delivery to mammalian cells. Following transduction, the lentiviral genome is stably incorporated into the host chromosome and is passed on to progeny. Thus, they are ideal vectors for creation of stable cell lines, in vivo delivery of indicators, and transduction of single cell fertilized eggs to create transgenic animals. However, mouse fertilized eggs and early stage embryos are protected by the zona pellucida, a glycoprotein matrix that forms a barrier against lentiviral gene delivery. Lentiviruses are too large to penetrate the zona and are typically delivered by microinjection of viral particles into the perivitelline cavity, the space between the zona and the embryonic cells. The requirement for highly skilled technologists and specialized equipment has minimized the use of lentiviruses for gene delivery to mouse embryos. This article describes a protocol for permeabilizing the mouse fertilized eggs by perforating the zona with a laser. Laser-perforation does not result in any damage to embryos and allows lentiviruses to gain access to embryonic cells for gene delivery. Transduced embryos can develop into blastocyst in vitro, and if implanted in pseudopregnant mice, develop into transgenic pups. The laser used in this protocol is effective and easy to use. Genes delivered by lentiviruses stably incorporate into mouse embryonic cells and are germline transmittable. This is an alternative method for creation of transgenic mice that requires no micromanipulation and microinjection of fertilized eggs. PMID- 30451225 TI - Measurement of Force-Sensitive Protein Dynamics in Living Cells Using a Combination of Fluorescent Techniques. AB - Cells sense and respond to physical cues in their environment by converting mechanical stimuli into biochemically-detectable signals in a process called mechanotransduction. A crucial step in mechanotransduction is the transmission of forces between the external and internal environments. To transmit forces, there must be a sustained, unbroken physical linkage created by a series of protein protein interactions. For a given protein-protein interaction, mechanical load can either have no effect on the interaction, lead to faster disassociation of the interaction, or even stabilize the interaction. Understanding how molecular load dictates protein turnover in living cells can provide valuable information about the mechanical state of a protein, in turn elucidating its role in mechanotransduction. Existing techniques for measuring force-sensitive protein dynamics either lack direct measurements of protein load or rely on the measurements performed outside of the cellular context. Here, we describe a protocol for the Forster resonance energy transfer-fluorescence recovery after photobleaching (FRET-FRAP) technique, which enables the measurement of force sensitive protein dynamics within living cells. This technique is potentially applicable to any FRET-based tension sensor, facilitating the study of force sensitive protein dynamics in variety of subcellular structures and in different cell types. PMID- 30451226 TI - Measuring Dengue Virus RNA in the Culture Supernatant of Infected Cells by Real time Quantitative Polymerase Chain Reaction. AB - At present, real-time polymerase chain reaction (PCR) technology is an indispensable tool for the detection and quantification of viral genomes in research laboratories, as well as for molecular diagnosis, because of its sensitivity, specificity, and convenience. However, in most cases, the quantitative PCR (qPCR) assay generally used to detect virus infection has relied on the purification of viral nucleic acid prior to the PCR step. In this study, the fluorescence-based reverse transcription qPCR (RT-qPCR) assay is developed through the combination of a processing buffer and a one-step RT-PCR reagent so that the whole process, from the harvest of the culture supernatant of virus infected cells until real-time detection, can be performed without viral RNA purification. The established protocol enables the quantification of a wide range of RNA concentrations of dengue virus (DENV) within 90 min. In addition, the adaptability of the direct RT-qPCR assay to the evaluation of an antiviral agent is demonstrated by an in vitro experiment using a previously reported DENV inhibitor, mycophenolic acid (MPA). Moreover, other RNA viruses, including yellow fever virus (YFV), Chikungunya virus (CHIKV), and measles virus (MeV), can be quantified by direct RT-qPCR with the same protocol. Therefore, the direct RT qPCR assay described in this report is useful for monitoring RNA virus replication in a simple and rapid manner, which will be further developed into a promising platform for a high-throughput screening study and clinical diagnosis. PMID- 30451228 TI - A Purification and In Vitro Activity Assay for a (p)ppGpp Synthetase from Clostridium difficile. AB - Kinase and pyrophosphokinase enzymes transfer the gamma phosphate or the beta gamma pyrophosphate moiety from nucleotide triphosphate precursors to substrates to create phosphorylated products. The use of gamma-32-P labeled NTP precursors allows simultaneous monitoring of substrate utilization and product formation by radiography. Thin layer chromatography (TLC) on cellulose plates allows rapid separation and sensitive quantification of substrate and product. We present a method for utilizing the thin-layer chromatography to assay the pyrophosphokinase activity of a purified (p)ppGpp synthetase. This method has previously been used to characterize the activity of cyclic nucleotide and dinucleotide synthetases and is broadly suitable for characterizing the activity of any enzyme that hydrolyzes a nucleotide triphosphate bond or transfers a terminal phosphate from a phosphate donor to another molecule. PMID- 30451227 TI - Probing Cell Mechanics with Bead-Free Optical Tweezers in the Drosophila Embryo. AB - Morphogenesis requires coordination between genetic patterning and mechanical forces to robustly shape the cells and tissues. Hence, a challenge to understand morphogenetic processes is to directly measure cellular forces and mechanical properties in vivo during embryogenesis. Here, we present a setup of optical tweezers coupled to a light sheet microscope, which allows to directly apply forces on cell-cell contacts of the early Drosophila embryo, while imaging at a speed of several frames per second. This technique has the advantage that it does not require the injection of beads into the embryo, usually used as intermediate probes on which optical forces are exerted. We detail step by step the implementation of the setup, and propose tools to extract mechanical information from the experiments. By monitoring the displacements of cell-cell contacts in real time, one can perform tension measurements and investigate cell contacts' rheology. PMID- 30451229 TI - Database-guided Flow-cytometry for Evaluation of Bone Marrow Myeloid Cell Maturation. AB - A working group initiated within the French Cytometry Association (AFC) was developed in order to harmonize the application of multiparameter flow cytometry (MFC) for myeloid disease diagnosis in France. The protocol presented here was agreed-upon and applied between September 2013 and November 2015 in six French diagnostic laboratories (University Hospitals of Saint-Etienne, Grenoble, Clermont-Ferrand, Nice, and Lille and Institut Paoli-Calmettes in Marseille) and allowed the standardization of bone marrow sample preparation and data acquisition. Three maturation databases were developed for neutrophil, monocytic, and erythroid lineages with bone marrow from "healthy" donor individuals (individuals without any evidence of a hematopoietic disease). A robust method of analysis for each myeloid lineage should be applicable for routine diagnostic use. New cases can be analyzed in the same manner and compared against the usual databases. Thus, quantitative and qualitative phenotypic abnormalities can be identified and those above 2SD compared with data of normal bone marrow samples should be considered indicative of pathology. The major limitation is the higher variability between the data achieved using the monoclonal antibodies obtained with the methods based on hybridoma technologies and currently used in clinical diagnosis. Setting criteria for technical validation of the data acquired may help improve the utility of MFC for MDS diagnostics. The establishment of these criteria requires analysis against a database. The reduction of investigator subjectivity in data analysis is an important advantage of this method. PMID- 30451230 TI - Applicability Analysis of Assessment Methods for Morphological Parameters of Corroded Steel Bars. AB - The irregular and uneven residual sections along the length of a corroded steel bar substantially change its mechanical properties and significantly dominate the safety and performance of an existing concrete structure. As a result, it is important to measure the geometry and amount of corrosion of a steel bar in a structure properly to assess the residual bearing capacity and service life of the structure. This paper introduces and compares five different methods for measuring the geometry and amount of corrosion of a steel bar. A single 500 mm long and 14 mm diameter steel bar is the specimen that is subjected to accelerated corrosion in this protocol. Its morphology and the amount of corrosion were carefully measured before and after using mass loss measurements, a Vernier caliper, drainage measurements, 3D scanning, and X-ray micro-computed tomography (XCT). The applicability and suitability of these different methods were then evaluated. The results show that the Vernier caliper is the best choice for measuring the morphology of a non-corroded bar, while 3D scanning is the most suitable for quantifying the morphology of a corroded bar. PMID- 30451231 TI - An Efficient Sieving Method to Isolate Intact Glomeruli from Adult Rat Kidney. AB - Preservation of glomerular structure and function is pivotal in the prevention of glomerulonephritis, a category of kidney disease characterized by proteinuria which can eventually lead to chronic and end-stage renal disease. The glomerulus is a complex apparatus responsible for the filtration of plasma from the body. In disease, structural integrity is lost and allows for the abnormal leakage of plasma contents into the urine. A method to isolate and examine glomeruli in culture is critical for the study of these diseases. In this protocol, an efficient method of retrieving intact glomeruli from adult rat kidneys while conserving structural and morphological characteristics is described. This process is capable of generating high yields of glomeruli per kidney with minimal contamination from other nephron segments. With these glomeruli, injury conditions can be mimicked by incubating them with a variety of chemical toxins, including protamine sulfate, which causes foot process effacement and proteinuria in animal models. Degree of injury can be assessed using transmission electron microscopy, immunofluorescence staining, and western blotting. Nephrin and Wilms Tumor 1 (WT1) levels can also be assessed from these cultures. Due to the ease and flexibility of this protocol, the isolated glomeruli can be utilized as described or in a way that best suits the needs of the researcher to help better study glomerular health and structure in diseased states. PMID- 30451232 TI - Immunization of Adult Zebrafish for the Preclinical Screening of DNA-based Vaccines. AB - The interest in DNA-based vaccination has increased during the past two decades. DNA vaccination is based on the cloning of a sequence of a selected antigen or a combination of antigens into a plasmid, which enables a tailor-made and safe design. The administration of DNA vaccines into host cells leads to the expression of antigens that stimulate both humoral and cell-mediated immune responses. This report describes a protocol for the cloning of antigen sequences into the pCMV-EGFP plasmid, the immunization of adult zebrafish with the vaccine candidates by intramuscular microinjection, and the subsequent electroporation to improve intake. The vaccine antigens are expressed as green fluorescent protein (GFP)-fusion proteins, which allows the confirmation of the antigen expression under UV light from live fish and the quantification of expression levels of the fusion protein with ELISA, as well as their detection with a western blot analysis. The protective effect of the vaccine candidates is tested by infecting the fish with Mycobacterium marinum five weeks postvaccination, followed by the quantification of the bacteria with qPCR four weeks later. Compared to mammalian preclinical screening models, this method provides a cost-effective method for the preliminary screening of novel DNA-based vaccine candidates against a mycobacterial infection. The method can be further applied to screening DNA-based vaccines against various bacterial and viral diseases. PMID- 30451233 TI - Synthesis of Esters Via a Greener Steglich Esterification in Acetonitrile. AB - The Steglich esterification is a widely-used reaction for the synthesis of esters from carboxylic acids and alcohols. While efficient and mild, the reaction is commonly performed using chlorinated or amide solvent systems, which are hazardous to human health and the environment. Our methodology utilizes acetonitrile as a greener and less hazardous solvent system. This protocol exhibits rates and yields that are comparable to traditional solvent systems and employs an extraction and wash sequence that eliminates the need for the purification of the ester product via column chromatography. This general method can be used to couple a variety of carboxylic acids with 1 degrees and 2 degrees aliphatic alcohols, benzylic and allylic alcohols, and phenols to obtain pure esters in high yields. The goal of the protocol detailed here is to provide a greener alternative to a common esterification reaction, which could serve useful for ester synthesis in both academic and industrial applications. PMID- 30451235 TI - Expression of Fluorescent Fusion Proteins in Murine Bone Marrow-derived Dendritic Cells and Macrophages. AB - Dendritic cells and macrophages are crucial cells that form the first line of defense against pathogens. They also play important roles in the initiation of an adaptive immune response. Experimental work with these cells is rather challenging. Their abundance in organs and tissues is relatively low. As a result, they cannot be isolated in large numbers. They are also difficult to transfect with cDNA constructs. In the murine model, these problems can be partially overcome by in vitro differentiation from bone marrow progenitors in the presence of M-CSF for macrophages or GM-CSF for dendritic cells. In this way, it is possible to obtain large amounts of these cells from very few animals. Moreover, bone marrow progenitors can be transduced with retroviral vectors carrying cDNA constructs during early stages of cultivation prior to their differentiation into bone marrow derived dendritic cells and macrophages. Thus, retroviral transduction followed by differentiation in vitro can be used to express various cDNA constructs in these cells. The ability to express ectopic proteins substantially extends the range of experiments that can be performed on these cells, including live cell imaging of fluorescent proteins, tandem purifications for interactome analyses, structure-function analyses, monitoring of cellular functions with biosensors and many others. In this article, we describe a detailed protocol for retroviral transduction of murine bone marrow derived dendritic cells and macrophages with vectors coding for fluorescently tagged proteins. On the example of two adaptor proteins, OPAL1 and PSTPIP2, we demonstrate its practical application in flow cytometry and microscopy. We also discuss the advantages and limitations of this approach. PMID- 30451234 TI - Analyzing Neural Activity and Connectivity Using Intracranial EEG Data with SPM Software. AB - Measuring neural activity and connectivity associated with cognitive functions at high spatial and temporal resolutions is an important goal in cognitive neuroscience. Intracranial electroencephalography (EEG) can directly record electrical neural activity and has the unique potential to accomplish this goal. Traditionally, averaging analysis has been applied to analyze intracranial EEG data; however, several new techniques are available for depicting neural activity and intra- and inter-regional connectivity. Here, we introduce two analytical protocols we recently applied to analyze intracranial EEG data using the Statistical Parametric Mapping (SPM) software: time-frequency SPM analysis for neural activity and dynamic causal modeling of induced responses for intra- and inter-regional connectivity. We report our analysis of intracranial EEG data during the observation of faces as representative results. The results revealed that the inferior occipital gyrus (IOG) showed gamma-band activity at very early stages (110 ms) in response to faces, and both the IOG and amygdala showed rapid intra- and inter-regional connectivity using various types of oscillations. These analytical protocols have the potential to identify the neural mechanisms underlying cognitive functions with high spatial and temporal profiles. PMID- 30451236 TI - Three-Dimensional Printing of a Complex Aortic Anomaly. AB - Complex congenital aortic anomalies include diverse types of malformations that may be clinically asymptomatic or present with respiratory or esophageal symptoms. These anomalies may be associated with other congenital heart diseases. It is hard to identify the accurate anatomic vessel location from two-dimensional imaging data, such as computed tomography. As an additive manufacturing method, three-dimensional (3-D) printing can covert the acquired imaging data into 3-D physical models. This protocol describes the procedure for modeling the volumetric DICOM imaging into 3-D data and printing it as an anatomically realistic 3-D model. Using this model, surgeons can identify the vessel location of complex aortic anomalies, which is helpful for pre-operative planning and intra-operative guidance. PMID- 30451237 TI - Temporal Analysis of the Nuclear-to-cytoplasmic Translocation of a Herpes Simplex Virus 1 Protein by Immunofluorescent Confocal Microscopy. AB - Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is an immediate early protein containing a RING-type E3 ubiquitin ligase. It is responsible for the proteasomal degradation of host restrictive factors and the subsequent viral gene activation. ICP0 contains a canonical nuclear localization sequence (NLS). It enters the nucleus immediately after de novo synthesis and executes its anti host defense functions mainly in the nucleus. However, later in infection, ICP0 is found solely in the cytoplasm, suggesting the occurrence of a nuclear-to cytoplasmic translocation during HSV-1 infection. Presumably ICP0 translocation enables ICP0 to modulate its functions according to its subcellular locations at different infection phases. In order to delineate the biological function and regulatory mechanism of ICP0 nuclear-to-cytoplasmic translocation, we modified an immunofluorescent microscopy method to monitor ICP0 trafficking during HSV-1 infection. This protocol involves immunofluorescent staining, confocal microscope imaging, and nuclear vs. cytoplasmic distribution analysis. The goal of this protocol is to adapt the steady state confocal images taken in a time course into a quantitative documentation of ICP0 movement throughout the lytic infection. We propose that this method can be generalized to quantitatively analyze nuclear vs. cytoplasmic localization of other viral or cellular proteins without involving live imaging technology. PMID- 30451238 TI - Lentiviral Vector-mediated Gene Therapy of Hepatocytes Ex Vivo for Autologous Transplantation in Swine. AB - Gene therapy is an ideal choice to cure many inborn errors of metabolism of the liver. Ex-vivo, lentiviral vectors have been used successfully in the treatment of many hematopoietic diseases in humans, as their use offers stable transgene expression due to the vector's ability to integrate into the host genome. This method demonstrates the application of ex vivo gene therapy of hepatocytes to a large animal model of hereditary tyrosinemia type I. This process consists of 1) isolation of primary hepatocytes from the autologous donor/recipient animal, 2) ex vivo gene delivery via hepatocyte transduction with a lentiviral vector, and 3) autologous transplant of corrected hepatocytes via portal vein injection. Success of the method generally relies upon efficient and sterile removal of the liver resection, careful handling of the excised specimen for isolation of viable hepatocytes sufficient for re-engrafting, high-percentage transduction of the isolated cells, and aseptic surgical procedures throughout to prevent infection. Technical failure at any of these steps will result in low yield of viable transduced hepatocytes for autologous transplant or infection of the donor/recipient animal. The pig model of human type 1 hereditary tyrosinemia (HT 1) chosen for this approach is uniquely amenable to such a method, as even a small percentage of engraftment of corrected cells will lead to repopulation of the liver with healthy cells based on a powerful selective advantage over native diseased hepatocytes. Although this growth selection will not be true for all indications, this approach is a foundation for expansion into other indications and allows for manipulation of this environment to address additional diseases, both within the liver and beyond, while controlling for exposure to viral vector and opportunity for off-target toxicity and tumorigenicity. PMID- 30451239 TI - Structural Studies of Macromolecules in Solution using Small Angle X-Ray Scattering. AB - Protein-protein interactions involving proteins with multiple globular domains present technical challenges for determining how such complexes form and how the domains are oriented/positioned. Here, a protocol with the potential for elucidating which specific domains mediate interactions in multicomponent system through ab initio modeling is described. A method for calculating solution structures of macromolecules and their assemblies is provided that involves integrating data from small angle X-ray scattering (SAXS), chromatography, and atomic resolution structures together in a hybrid approach. A specific example is that of the complex of full-length nidogen-1, which assembles extracellular matrix proteins and forms an extended, curved nanostructure. One of its globular domains attaches to laminin gamma-1, which structures the basement membrane. This provides a basis for determining accurate structures of flexible multidomain protein complexes and is enabled by synchrotron sources coupled with automation robotics and size exclusion chromatography systems. This combination allows rapid analysis in which multiple oligomeric states are separated just prior to SAXS data collection. The analysis yields information on the radius of gyration, particle dimension, molecular shape and interdomain pairing. The protocol for generating 3D models of complexes by fitting high-resolution structures of the component proteins is also given. PMID- 30451240 TI - Measuring Interactions of Globular and Filamentous Proteins by Nuclear Magnetic Resonance Spectroscopy (NMR) and Microscale Thermophoresis (MST). AB - Filamentous proteins such as vimentin provide organization within cells by providing a structural scaffold with sites that bind proteins containing plakin repeats. Here, a protocol for detecting and measuring such interactions is described using the globular plakin repeat domain of envoplakin and the helical coil of vimentin. This provides a basis for determining whether a protein binds vimentin (or similar filamentous proteins) and for measurement of the affinity of the interaction. The globular protein of interest is labeled with 15N and titrated with vimentin protein in solution. A two-dimensional NMR spectrum is acquired to detect interactions by observing changes in peak shape or chemical shifts, and to elucidate effects of solution conditions including salt levels, which influence vimentin quaternary structure. If the protein of interest binds the filamentous ligand, the binding interaction is quantified by MST using the purified proteins. The approach is a straightforward way for determining whether a protein of interest binds a filament, and for assessing how alterations, such as mutations or solution conditions, affect the interaction. PMID- 30451241 TI - Metal Corrosion and the Efficiency of Corrosion Inhibitors in Less Conductive Media. AB - Material corrosion can be a limiting factor for different materials in many applications. Thus, it is necessary to better understand corrosion processes, prevent them and minimize the damages associated with them. One of the most important characteristics of corrosion processes is the corrosion rate. The measurement of corrosion rates is often very difficult or even impossible especially in less conductive, non-aqueous environments such as biofuels. Here, we present five different methods for the determination of corrosion rates and the efficiency of anti-corrosion protection in biofuels: (i) a static test, (ii) a dynamic test, (iii) a static test with a reflux cooler and electrochemical measurements (iv) in a two-electrode arrangement and (v) in a three-electrode arrangement. The static test is advantageous due to its low demands on material and instrumental equipment. The dynamic test allows for the testing of corrosion rates of metallic materials at more severe conditions. The static test with a reflux cooler allows for the testing in environments with higher viscosity (e.g., engine oils) at higher temperatures in the presence of oxidation or an inert atmosphere. The electrochemical measurements provide a more comprehensive view on corrosion processes. The presented cell geometries and arrangements (the two electrode and three-electrode systems) make it possible to perform measurements in biofuel environments without base electrolytes that could have a negative impact on the results and load them with measurement errors. The presented methods make it possible to study the corrosion aggressiveness of an environment, the corrosion resistance of metallic materials, and the efficiency of corrosion inhibitors with representative and reproducible results. The results obtained using these methods can help to understand corrosion processes in more detail to minimize the damages caused by corrosion. PMID- 30451242 TI - Detection and Quantification of Plasmodium falciparum in Aqueous Red Blood Cells by Attenuated Total Reflection Infrared Spectroscopy and Multivariate Data Analysis. AB - We demonstrate a method of quantification and detection of parasites in aqueous red blood cells (RBCs) by using a simple benchtop Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectrometer in conjunction with Multivariate Data Analysis (MVDA). 3D7 P. falciparum were cultured to 10% parasitemia ring stage parasites and used to spike fresh donor isolated RBCs to create a dilution series between 0-1%. 10 uL of each sample were placed onto the center of the ATR diamond window to acquire the spectrum. The sample data was treated to improve the signal to noise ratio and to remove the contribution of water, and then the second derivative was applied to resolve spectral features. The data were then analyzed using two types of MVDA: first Principal Component Analysis (PCA) to determine any outliers and then Partial Least Squares Regression (PLS-R) to build the quantification model. PMID- 30451243 TI - Comparative efficacy of continuous infusion of bupivacaine/fentanyl and ropivacaine/fentanyl for paediatric pain control after the Ravitch procedure and thoracotomy. A prospective randomized study. AB - AIMS: (1) To compare the efficacy of bupivacaine/fentanyl and ropivacaine/fentanyl for postoperative pain control (2). To identify the predictors of acute post-operative pain at rest, during deep breathing and coughing. METHODS: The study was performed in patients aged 6-18 years after thoracic surgery. The subjects were randomized to the bupivacaine 0.125%/fentanyl 5.0 MUg/mL (n=46) or ropivacaine 0.2%/fentanyl 5.0 MUg/mL (n=48) group; analgesic mixtures were administered through epidural catheter. All the patients received paracetamol and non-steroidal anti-inflammatory drugs. The observation period after surgery lasted 72 h. Pain intensity was assessed at rest, during deep breathing and coughing and was based on the Numerical Rating Scale and the FLACC scale (range 0-10). If the pain was above 2/10, the analgesia was modified. RESULTS: Median pain scores at rest (0.4 vs. 0.5), during deep breathing (0.3 vs. 0.3) and coughing (0.6 vs. 0.6) were comparable in BF and RF group. The intensity of pain at rest was associated with the number of drains inserted into the thorax (beta=0.39), the number of pain intensity measurements (beta=0.36) and the number of nursing interventions undertaken to relieve pain (beta=0.16). Pain intensity at rest determined the intensity of pain during deep breathing (beta=0.60), which in turn decided on the severity of pain during coughing (beta=0.80). The intensity of pain was increased by age. CONCLUSIONS: Thoracic epidural bupivacaine/fentanyl provided adequate pain relief and similar analgesia to ropivacaine/fentanyl. The effectiveness of analgesia depended on the number of pain measurements and interventions by nurses to relieve the pain. TRIAL REGISTRATION: ClinicalTrials.gov; Multimodal Analgesia in Children and Adolescents After the Ravitch Procedure and Thoracotomy; NCT03444636; https://clinicaltrials.gov/ct2/show/NCT03444636. PMID- 30451244 TI - The role of eicosanoids in renal diseases - potential therapeutic possibilities. AB - Eicosanoids are biologically active molecules that are created in the process of oxidation of arachidonic acid (AA) which is a constituent of the cell membrane phospholipids. Throughout the years it was evidenced by experiments that the lipid and lipid-derived metabolites play an important role in physiological and pathological processes in the kidneys. They are being considered as biomarkers in detecting acute kidney injury, nephrotoxicity, glomerulonephritis and early stages of diabetic nephropathy because of their participation in inflammatory processes and in oxidative stress. They might be also considered as potential novel targets of therapy. However, the role of eicosanoids is still not fully clear and needs to be explored in future studies. In this brief review, studies on the role of eicosanoids in physiological and pathological conditions, e.g. acute kidney injury (AKI) and chronic kidney disease (CKD), and in different renal replacement therapies, including kidney transplantation, are being discussed. PMID- 30451245 TI - Usefulness of the Triglycerides to High-Density Lipoprotein Cholesterol ratio (TG/HDL-C) in prediction of metabolic syndrome in Polish obese children and adolescents. AB - The triglycerides to high-density lipoprotein cholesterol ratio (TG/HDL-C) is a useful surrogate marker of insulin resistance and cardiovascular risk factors. We aimed to assess the relationship between the TG/HDL-C ratio and insulin resistance (IR) and its usefulness in prediction of the metabolic syndrome (MS). This retrospective study involved 122 obese children with the mean age of 11.6+/ 3 years and their 58 healthy lean peers. Anthropometric measurements, blood pressure, the plasma lipid profile and oral glucose tolerance test (OGTT) were analyzed. Based on the obtained results, the TG/HDL-C ratio and surrogate insulin resistance indices (HOMA-IR, FGIR, QUICKI, OGIS, Matsuda index) were calculated. The TG/HDL-C ratio positively correlated with weight, waist circumference, waist to hip ratio (WHR), lipid profile, HOMA-IR, fasting insulin and insulin measurements during OGTT, and negatively correlated with FGIR, QUICKI, OGIS, and the Matsuda index. Obese children with the TG/HDL-C ratio>=3 (47.5%) had higher values of WHR and HOMA-IR, and lower ones of FGIR, QUICKI, OGIS, and the Matsuda index when compared to their obese peers with the TG/HDL-C<3. The area under the curve (AUC) calculated for each insulin resistance index in prediction of the metabolic syndrome was the largest for the TG/HDL-C ratio (0.8936, 95% Cl:0.809 0.977, p=0.000). For 1 unit increase in the TG/HDL-C ratio, the odds for having MS increased by 2.09 times. The TG/HDL-C ratio is a good surrogate marker of insulin resistance in obese children. When comparing the usefulness of some IR markers in prediction of the metabolic syndrome, the TG/HDL-C ratio seems to be the best one and should be used in clinical practice to identify children at risk of metabolic syndrome development. PMID- 30451246 TI - Lewis acid catalysis: regioselective hydroboration of alkynes and alkenes promoted by scandium triflate. AB - The first commercially available scandium-catalysed selective hydroboration of alkynes and alkenes with HBpin (pin = OC-Me2CMe2O) in the presence of a catalytic amount of NaHBEt3 has been developed. This protocol can be applicable to a wide range of substrates including aromatic, aliphatic with cyclic and acyclic side chains, and heteroaryl systems with broad functional-group compatibility. Mechanistic studies revealed that the reaction occurs in a syn fashion via the sigma-bond metathesis between the alkenyl scandium species and HBpin. PMID- 30451247 TI - Unexpected, photochemically induced activation of the tetrabutylammonium cation by hexachloroplatinate(iv). AB - A dinuclear, butadiene-bridged complex, trans-MU2:eta2,eta2-1,3-butadiene bis(trichloroplatinate(ii)) (1) was unexpectedly obtained on photolysis of acetone solutions of (NBu4)2[PtCl6]. PMID- 30451248 TI - A dual signal amplification-assisted DNAzyme biosensor for ultrasensitive detection of Argonaute 2 activity. AB - We develop a new DNAzyme biosensor for Argonaute 2 (Ago2) assay based on target initiated rolling circle amplification in combination with an 8-17 DNAzyme mediated dual signal amplification strategy. This biosensor can achieve ultrahigh sensitivity with a detection limit of 0.35 pM, and it can be further used for the screening of Ago2 inhibitors and the accurate measurement of endogenous Ago2 from HeLa cell extracts. PMID- 30451249 TI - A clickable caging group as a new platform for modular caged compounds with improved photochemical properties. AB - A 6-bromo-7-hydroxycoumarin-4-ylmethyl (Bhc) caged compound having a click modifiable chemical handle was designed and synthesized. This molecule was applied to the synthesis of modular caged paclitaxels (PTXs) in which additional functional units could be easily installed. This system was used to prepare water soluble caged PTXs with improved photolysis efficiencies. PMID- 30451250 TI - A theoretical study of the photodynamics of salicylidene-2-anthrylamine in acetonitrile solution. AB - The ultrafast photoinduced processes of salicylidene-2-anthrylamine (2-AntSA) in acetonitrile solution have been investigated using DFT/TD-DFT static electronic structure calculations and excited state ab initio molecular dynamics simulations. Two different isoenergetic enol ground-state structures with suitable geometry for excited state intramolecular proton transfer (ESIPT) where chosen for the excited-state dynamics. The S1 relaxed potential energy profiles for the excited state intramolecular proton transfer and the N[double bond, length as m-dash]C double bond isomerization reactions predict that both reactions occur over an energy barrier and that they are competitive processes in the deactivation of the Franck-Condon state. The photodynamic simulations show that the ESIPT occurs in the femtosecond time scale for both conformers (77 and 213 fs for IA and IIA, respectively) and that the speed is modulated by the ability of the conformers to evolve toward a planar conformation in the S1 state. The trajectories predict two conical intersections which provide nonradiative relaxation pathways to the S0 state. The first one is located in the twisted enol region, where the proton transfer process is unlikely, and only occurs for the conformer IIA in a time scale >=600 fs. The second conical intersection is located in the cis-keto region, and represents an effective depopulation channel toward the trans-keto form. All our results are in remarkably good agreement with experiments. PMID- 30451251 TI - Semiconducting polymer-based nanoparticles for photothermal therapy at the second near-infrared window. AB - We designed novel diketopyrrolopyrrole polymer based nanoparticles (DPP-IID-FA), which exhibited strong light absorption and excellent photothermal conversion in the NIR optical window, and displayed high biocompatibility and photostability. Furthermore, our nanoparticles could be efficiently uptaken by cancer cells and exhibited outstanding anticancer ability both in vitro and in vivo under NIR-II laser irradiation. PMID- 30451252 TI - Q-Graphene-loaded metal organic framework nanocomposites with water-triggered fluorescence turn-on: fluorimetric test strips for directly sensing trace water in organic solvents. AB - A solid-state fluorimetric strategy has been developed using test strips coated with Q-graphene-loaded metal-organic framework nanocomposites featuring water triggered fluorescence turn-on. It can facilitate the real-time evaluation of trace water in organic solvents, with the level down to about 0.015% in alcohol. PMID- 30451253 TI - Chiral [16]-ane P4N2 macrocycles: stereoselective synthesis and unexpected intermolecular exchange of endocyclic fragments. AB - Chiral 1,9-diaza-3,7,11,15-tetraphosphacyclohexadecanes were stereoselectively synthesized as pure RPSPSPRP isomers via a one-pot Mannich-type condensation reaction of 1,3-bis(arylphosphino)propane, formaldehyde and optically active, as well as racemic, primary amines. An unprecedented intermolecular exchange of endocyclic amino fragments of 1,9-diaza-3,7,11,15-tetraphosphacyclohexadecanes was observed. The lability of the P-CH2-N fragment in macrocyclic aminomethylphosphines is the reason of the stereoisomerization, formation of products with medium-sized cycles as well as the exchange of endocyclic amino fragments. The mechanism of these transformations involving the formation of a methylenephosphonium intermediate and further intra- and intermolecular nucleophilic substitution is discussed. PMID- 30451254 TI - Ionization dynamics of a phenylenediamine derivative in solutions as revealed by femtosecond simultaneous and stepwise two-photon excitation. AB - Femtosecond transient absorption spectroscopy with off-resonant simultaneous and resonant stepwise two-photon excitation methods were applied to the direct observation of photoionization dynamics of a phenylenediamine derivative in n hexane, ethanol and acetonitrile solutions. Upon the selective excitation of the solute via the off-resonant two-photon excitation to the energy level almost equivalent with the ionization potential in the gas phase, rapid appearance of the radical cation (within ca. 100-200 fs) was observed in polar and nonpolar solutions. On the other hand, in the case where the excited energy level from the ground state is 0.8 eV lower than the ionization potential in the gas phase, the radical cation appears only in polar solutions in sub-ps to ps time scales, indicating that the photoionization does not occur directly from the highly electronically excited state even in the polar solution. Comparison of the dynamics between ethanol and acetonitrile solutions strongly suggested that the solvation process of the precursor species leading to the ionization took a crucial role in the electron ejection process with lower energy in polar solutions. PMID- 30451255 TI - Assessment of DFT for endohedral complexes' dipole moment: PNO-LCCSD-F12 as a reference method. AB - We present a systematic evaluation of the performance of a wide range of exchange correlation functionals and related dispersion correction schemes for the computation of dipole moments of endohedral complexes, formed through the encapsulation of an AB molecule (AB = LiF, HCl) inside carbon nanotubes (CNTs) of different diameter. The consistency and accuracy of (i) generalized gradient approximation, (ii) meta GGA, (iii) global hybrid, and (iv) range-separated hybrid density functionals are assessed. In total, 37 density functionals are tested. The results obtained using the highly accurate pair natural orbitals based explicitly correlated local coupled cluster singles doubles (PNO-LCCSD-F12) method of Werner and co-workers [Schwilk et al., J. Chem. Theory Comput., 2017, 13, 3650; Ma et al., J. Chem. Theory Comput., 2017, 13, 4871] with the aug-cc pVTZ basis set serve as a reference. The static electric dipole moment is computed via the finite field response or, when possible, as the expectation value of the dipole operator. Among others, it is shown that functionals belonging to the class of range-separated hybrids, provide results closest to the coupled cluster reference data. In particular, the omegaB97X as well as the M11 functional may be considered as a promising choice for computing electric properties of noncovalent endohedral complexes. On the other hand, the worst performance was found for the functionals which do not include the Hartree-Fock exchange. The analysis of both the coupled cluster and the DFT results indicates a strong coupling of dispersion and polarization that may also explain why lower level DFT methods, as well as Hartree-Fock and MP2, cannot yield dipole moments beyond a qualitative agreement with the higher order reference data. Interestingly, the much smaller and less systematically constructed basis sets of Pople of moderate size provide results of accuracy at least comparable with the extended Dunning's aug-cc-pVTZ basis set. PMID- 30451256 TI - Spin-crossover compounds based on iron(ii) complexes of 2,6-bis(pyrazol-1 yl)pyridine (bpp) functionalized with carboxylic acid and ethyl carboxylic acid. AB - Four new salts of the iron(ii) complex of the 2,6-bis(pyrazol-1-yl)pyridine ligand functionalized with a carboxylic acid group (bppCOOH) of formulas [Fe(bppCOOH)2](BF4)2 (1(BF4)2), [Fe(bppCOOH)2](CF3SO3)2.yMe2CO (1(CF3SO3)2.yMe2CO), [Fe(bppCOOH)2](AsF6)2.yMe2CO (1(AsF6)2.yMe2CO) and [Fe(bppCOOH)2](SbF6)2.yMe2CO (1(SbF6)2.yMe2CO) have been prepared and characterized together with a more complete structural and photomagnetic characterization of the previously reported [Fe(bppCOOH)2](ClO4)2 (1(ClO4)2). Furthermore, the iron(ii) complex of the ethyl ester derivative of bppCOOH (bppCOOEt) has been prepared and characterized (compound [Fe(bppCOOEt)2](ClO4)2.yMe2CO, 2(ClO4)2.yMe2CO). Isostructural 1(BF4)2 and 1(ClO4)2 show an abrupt and reversible spin transition with a much lower T1/2 for the BF4- salt. CF3SO3-, SbF6- and AsF6- counteranions and the bppCOOEt ligand lead to the incorporation of solvent molecules in the structures, which play an important role in the spin-crossover properties of these compounds. In the case of 1(CF3SO3)2.yMe2CO, a reversible spin transition is obtained after desolvation. All these compounds show a LIESST effect. PMID- 30451257 TI - Counteraction of denaturant-induced protein unfolding is a general property of stabilizing agents. AB - DSC measurements on RNase A at neutral pH show that five stabilizing agents, namely trimethylamine N-oxide, glucose, sucrose, betaine and sodium sulfate, can counteract the destabilizing action of urea, sodium perchlorate, guanidinium chloride and guanidinium thiocyanate. This is an important finding inferring that counteraction has a common physical origin, regardless of the chemical differences among the stabilizing agents and among the destabilizing ones. A rationalization is provided grounded on the following line of reasoning: (a) the decrease in solvent-excluded volume effect is the main stabilizing contribution of the native state; (b) its magnitude increases on increasing the density of the aqueous solution; (c) the density increases significantly in the ternary solutions containing water, a stabilizing agent and a destabilizing one, as indicated by the present experimental data. PMID- 30451258 TI - The crucial role of electron transfer from interfacial molecules in the negative potential shift of Au electrode immersed in ionic liquids. AB - Potential of zero charge (PZC) is essential in electrochemistry to understand physical and chemical phenomena at the interface between an electrode and a solution. A negative potential shift from the work function to the PZC has been experimentally observed in a metal/ionic liquid (IL) system, but the mechanism remains unclear and controversial. In this paper we provide valuable insight into the mechanism on the potential shift in the Au/IL (1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)amide: [BMIM][TFSA]) system using a computational approach combining classical molecular dynamics simulations and first-principles calculations. By separately estimating some contributions to the potential shift, the shift is calculated in an easy-to-understand manner. The resultant PZC is shown to be in good agreement with the experimental one. Among the contributions, the electron redistribution at the Au/IL interface is found to provide the largest negative potential change. This indicates that the redistribution plays a crucial role in determining the potential shift of the Au electrode immersed in the IL. Detailed analyses suggest that the redistribution corresponds to the electron transfer not only from the anionic TFSA but also from the cationic BMIM molecules to the Au electrode surface. This unique observation is understood to originate from the interfacial structure where the IL molecules are in very close proximity to the electrode surface via dispersion interaction. PMID- 30451260 TI - Gravitational spreading of granular paste droplets induced by mechanical vibrations. AB - Spreading experiments of granular paste droplets over a smooth and hydrophilic plate under vertical vibrations were performed. We show that applying vibrations tunes the spreading by changing the apparent viscosity of the paste and makes a Newtonian regime appear where R(t) ? t1/8. In this regime, the influence of the intensity of the vibrations, the diameter of the particles and the interstitial viscosity is investigated, and all experiments are rationalized by a lubrication Peclet number, in agreement with previous results from the literature. PMID- 30451259 TI - Chiral isoxazolidine-mediated stereoselective umpolung alpha-phenylation of methyl ketones. AB - An effective asymmetric alpha-phenylation of methyl ketones with triphenylaluminium in the presence of (+)-benzopyranoisoxazolidine has been developed. The reaction proceeds via the in situ formation of a chiral N alkoxyenamine and the subsequent diastereoselective nucleophilic phenylation to provide alpha-phenylated products in moderate to good yields, with high enantioselectivities. PMID- 30451261 TI - Polyoxometalates in dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) are the third generation of photovoltaic cells developed by Gratzel and O'Regan. They have the characteristics of low cost, simple manufacturing process, tunable optical properties, and higher photoelectric conversion efficiency (PCE). With an ever increasing energy crisis, there is an urgent need to develop highly efficient, environmentally benign, and energy-saving cell materials. Polyoxometalates (POMs), a kind of molecular inorganic quasi-semiconductor, are promising candidates for use in different parts of DSSCs due to their excellent photosensitivity, redox, and catalytic properties, as well as their relative stability. Following a brief introduction to the development of DSSCs and the potential virtues of POMs in DSSCs, we attempt to make some generalizations about the energy level regulation of POMs that is the underlying theoretical basis for their application in DSSCs, and then we summarize the research progress of POMs in DSSCs in recent years. This is organized in terms of the properties of POMs, namely, electron acceptor, photosensitivity, redox and catalysis, based on the accumulation of our research into POMs over many years. Meanwhile, in view of the fact that the properties of POMs depend primarily on their electronic structural diversity, we keep this point in mind throughout the article with a view to revealing their structure property relationships. Finally we provide a short summary and remarks on the future outlook. This review may be of interest to synthetic chemists devoted to designing POMs with specific structures, and researchers engaged in the extension of POMs to photoelectric materials. PMID- 30451262 TI - Internal dynamics of cyclohexanol and the cyclohexanol-water adduct. AB - Two conformers of cyclohexanol and the cyclohexanol-water adduct have been characterized in a jet expansion using rotational spectroscopy. In the gas phase, cyclohexanol adopts an equatorial position for the hydroxyl group, with the two conformers differing in the orientation of the hydroxylic hydrogen, either gauche or trans with respect to the aliphatic hydrogen at C(1). Axial cyclohexanol was not detected in the jet. The transitions of the gauche conformer are split into two component lines due to the tunneling effect of the O-H internal rotation, which connects two equivalent gauche minima. The tunneling splitting in the vibrational ground state has been determined to be DeltaE0+0- = 52(2) GHz. From this splitting, the inversion barriers connecting the two equivalent gauche conformers have been determined using a flexible model to be B2 = 377 cm-1. A single isomer is detected for the cyclohexanol-water dimer, in which the water molecule acts as a proton donor to the equatorial gauche ring. The presence of torsional tunneling in the adduct suggests a concerted large-amplitude-motion in which the internal rotation in the ring is accompanied by a torsion of the water molecule, to produce an equivalent enantiomer. The torsional tunneling in the adduct is reduced to DeltaE0+0- = 32.7(4) GHz and the potential barrier in the complex increases to B2 = 494 cm-1. PMID- 30451263 TI - Advances in the design of cell-permeable fluorescent probes for applications in live cell imaging. AB - Small fluorescent molecules have been an important tool for fluorescence-based imaging, thanks to their technical simplicity, sensitivity and structural flexibility. However, probing specific intracellular systems with a small fluorescent molecule is not an easy task owing to the intricate nature of the cells. Ideal imaging probes should be highly permeable and be without background noise to allow undisrupted observations. These probes will unquestionably be more advantageous for interrogating intracellular architectures and dynamics without compromising the cellular integrity, and could therefore be applied for applications in the native cellular environment. This review will highlight the advances in design strategies for cell-permeable fluorescent probes through a diversity-oriented fluorescence library approach and rational design via computational-aided predictive models. Here, we discuss a series of cell permeable probe applications for imaging specific cell types and intracellular biomolecules, as well as the cellular environment. PMID- 30451264 TI - Palladium catalyzed selective arylation of o-carboranes via B(4)-H activation: amide induced regioselectivity reversal. AB - By changing the charge distribution of boron vertices via introducing an amide on cage B(9), the selective B(4) arylation of o-carboranes via Suzuki-Miyaura coupling has been developed. A series of o-carborane derivatives decorated with diverse active groups have been synthesized with moderate to good yields, which have been proved to be further transformed to a novel kind of tri-substituted nido-carborane fused oxazole with potential application in boron neutron capture therapy, organometallic as well as coordination chemistry. PMID- 30451265 TI - MIL-100Cr with open Cr sites for a record N2O capture. AB - Nitrous oxide (N2O) is considered as the third most important greenhouse gas after carbon dioxide and methane and needs to be removed from air. Herein, we reported the metal-organic framework MIL-100Cr with open Cr sites for record N2O capture capacities of 5.78 mmol g-1 at 298 K and 8.25 mmol g-1 at 273 K, respectively. DFT calculations showed that the static binding energy of N2O on the open-Cr site is notably higher than that of N2, 72.5 kJ mol-1 vs. 51.6 kJ mol 1, which enforces MIL-100Cr to exhibit extremely high N2O/N2 ideal adsorbed solution theory (IAST) gas separation selectivity up to 1000. PMID- 30451266 TI - A single but hydrogen-bonded water molecule confined in an anisotropic subnanospace. AB - We have synthesized an open-cage C60 derivative having three hydroxy groups arranged in close proximity on the opening, which realized a single but hydrogen bonded water molecule inside its cavity. The confined H2O molecule showed characteristic translational and rotational motions via the formation/cleavage of H-bonds. It is worth noting that the confined H2O molecule is less acidic and less basic than bulk water. PMID- 30451267 TI - Preparation of bimetallic Au/Pt nanotriangles with tunable plasmonic properties and improved photocatalytic activity. AB - Bimetallic nanoparticles are widely used in chemical catalysis and energy conversion. Their practical performance can be better exploited through morphological control by adjusting the synthetic strategy. Herein, an aqueous phase route is used to achieve the controlled preparation of bimetallic Au/Pt and hollow Au/Pt/Au nanotriangles with tunable plasmonic properties and superior photocatalytic activity. By continuously adjusting the concentration of surfactant solution, the gradual growth orientation of Pt nanoparticles on Au nanotriangles is observed, which occurs first on the tips, then on the edges, and then on the facets. Three types of Au/Pt nanotriangles (including Pt on the tips (Au/Pt (tips)), Pt on the edges (Au/Pt (edges)), and Pt covering Au (Au@Pt)) with tunable plasmon resonance are obtained. Then, Au/Pt/Au nanotriangles with a hollow structure are synthesized based on Au/Pt (edges). By evaluating the reduction rate of p-nitrophenol under visible light irradiation, hollow Au/Pt/Au nanotriangles exhibit the best photocatalytic activity compared with Au and Au/Pt (edges). The hollow structure, high visible light absorption and a strong tip- and center-focused local electric field of Au/Pt/Au are thought to be responsible for their superior photocatalytic activity. PMID- 30451268 TI - Synthesis and physicochemical characterization of room temperature ionic liquids and their application in sodium ion batteries. AB - Sodium ion batteries (SIBs) based on IL electrolytes have attracted great attention, particularly in large-scale energy storage systems for renewable energy due to the abundance of sodium and the excellent safety resulting from the use of non-flammable ionic liquid (IL) electrolytes. In this article, a series of 15 functionalized room temperature ionic liquids (RTILs) suitable as electrolytes is presented. Special emphasis was laid on the purity of the synthesized RTILs and a consistent and uniform characterization of their physicochemical properties. Evaluation of the viscosity, conductivity, and thermal and electrochemical stabilities resulted in clear structure-property relationships, rendering the ether functionalized RTILs most promising for application in SIBs. Electrochemical investigations of the ether functionalized IL electrolytes in SIB half cells (Na0.6Mn0.9Co0.1O2 as cathode material) proved their compatibility with a SIB system. Stable cycling performance was achieved with the piperidinium based RTIL IL 6 outperforming the organic electrolyte by far with a retention of 81% after 350 cycles. These results show the suitability of RTILs to enhance the performance of SIB systems and serve as a basis for the design of high performance IL electrolytes. PMID- 30451269 TI - Correction: Polymeric hole-transport materials with side-chain redox-active groups for perovskite solar cells with good reproducibility. AB - Correction for 'Polymeric hole-transport materials with side-chain redox-active groups for perovskite solar cells with good reproducibility' by Rosinda Fuentes Pineda et al., Phys. Chem. Chem. Phys., 2018, 20, 25738-25745. PMID- 30451270 TI - Orientation-dependent optical characterization of atomically thin transition metal ditellurides. AB - Molybdenum ditellurides (MoTe2) have recently attracted attention owing to their excellent structurally tunable nature between 1T'(metallic)- and 2H(semiconducting)-phases; thus, the controllable fabrication and critical identification of MoTe2 are highly desired. Here, we semi-controllably synthesized 1T'- and 2H-MoTe2 crystals using the atmospheric pressure chemical vapor deposition (APCVD) technique and studied their grain-orientation dependency using polarization-sensitive optical microscopy, Raman scattering, and second harmonic generation (SHG) microspectroscopy. The polycrystalline 1T'-MoTe2 phase with quasi-1D "Mo-Mo" zigzag chains showed anisotropic optical absorption, leading to a clear visualization of the lattice domains. On the other hand, 2H MoTe2 lattice grains did not exhibit any discernible difference under polarized light illumination. The combined aforementioned microscopy techniques could be used as an easy-to-access and non-destructive tool for a quick and solid identification of intended lattice orientation development in industry-scale MoTe2 crystal manufacturing. PMID- 30451271 TI - Characterization and biological removal of organic compounds from hydraulic fracturing produced water. AB - Hydraulic fracturing generates large volumes of produced water, and treatment of produced water may be necessary for disposal or reuse. Biological treatment of produced water is a potential approach to remove organic constituents and reduce fouling, in conjunction with other treatment processes. This study investigates the biological treatability of produced water samples from the Utica and Bakken Shales using engineered biofilms. Observed total dissolved organic carbon (DOC) removal varied between 1-87% at normalized total dissolved solids concentrations, suggesting that the composition of produced water, including organic constituents and trace elements such as nutrients and metals, is an important driver of biological treatment performance. Mass spectrometric analyses of the DOC composition revealed various alkanes in all samples, but differences in non-ionic surfactant, halogenated, and acidic compound content. Statistical data reduction approaches suggest that the latter two groups are correlated with reduced biodegradation kinetics. These results demonstrate that the combination of biodegradation performance and organic speciation can guide the assessment of the biological treatment of produced water. PMID- 30451272 TI - Catalytic activity for the hydrogen evolution reaction of edges in Janus monolayer MoXY (X/Y = S, Se, and Te). AB - Monolayer transition metal dichalcogenides (TMDs) have been regarded as the most promising low-cost alternatives to noble metals as catalysts for the hydrogen evolution reaction (HER). However, their limited catalytically active sites for the HER hinder their practical application. In this paper, the catalytic performances of the edge sites of Janus monolayer MoXY (X/Y = S, Se and Te) were investigated using density functional theory. The results show that both the Mo edge and chalcogen atomic edges of Janus monolayer MoXY are catalytically active for the HER; thus Janus monolayer MoXY exhibits better catalytic performance than monolayer MoS2. These results are useful for the improvement of the catalytic performance of TMDs by the formation of the Janus monolayer MoXY. PMID- 30451273 TI - Photochemical reactions of triplet phenylphosphinidene with carbon monoxide and nitric oxide. AB - Here we report the photochemical reactions of triplet phenylphosphinidene with carbon monoxide and nitric oxide. The photolysis of phenylphosphirane in carbon monoxide-doped matrices enabled the first spectroscopic identification of phenylphosphaketene, the hitherto unreported phosphorus analogue of phenyl isocyanate. The hitherto undisclosed phosphinimine-N-oxyl radical formed upon UV irradiation of the phenylphosphinidene with nitric oxide in argon matrices at 10 K. PMID- 30451274 TI - Is prison truly a good place to be cared for? AB - We read with great interest Dirkzwager and Nieuwbeerta's recent article, which showed that mental health improved during detention by analysing the data of a prospective cohort that included 1664 Dutch male prisoners (1). This is a timely topic, as in recent years, the high level of mental health problems among prisoners has often been highlighted and because the role of deinstitutionalisation is often discussed with prisons, which are sometimes presented as modern asylums (2). This article is protected by copyright. All rights reserved. PMID- 30451275 TI - Management of Acute Changes in Condition in Skilled Nursing Facilities. AB - OBJECTIVES: To describe the presentation and management of acute changes in condition in skilled nursing facilities (SNFs) during implementation of a program designed to reduce unnecessary emergency department visits and hospitalizations. DESIGN: Secondary analysis of data from a randomized controlled trial involving 264 SNFs. PARTICIPANTS: One hundred thirty-three of the 264 participating SNFs that provided data on acute changes in condition: 55 in the intervention group, 78 in the control group. INTERVENTIONS: During a 12-month period, intervention SNFs received training and support for implementation of the Interventions to Reduce Acute Care Transfers program. Control SNFs were offered training and implementation support after the end of the 12-month trial. MEASURES: Project champions used a structured online tool to describe acute changes in condition that did not result in a hospital transfer within 72 hours of the change. RESULTS: Most of the 7,689 episodes of acute change in condition reported involved multiple changes that were not disease specific. Ten percent resulted in hospital transfer between 72 hours and 7 days after the change. Five acute changes had odds ratios for transfer greater than 2 (mental status change, abnormal vital signs, bleeding, shortness of breath, and unresponsiveness). Most transfers were for reasons other than the initial change in condition. CONCLUSIONS: A wide variety of acute changes in condition can be managed in SNFs without hospital transfer. Most of these changes are nonspecific and multiple, and when they are associated with hospital transfer, the reasons for the transfer are most often different from the initial acute change in condition. These data highlight the multifactorial nature of acute changes in condition in the SNF population and suggest that disease-specific protocols and assessment tools may not be the most appropriate approach to managing acute changes in condition in the SNF setting. PMID- 30451276 TI - Predictors to quality-of-life improvements after subthalamic stimulation in Parkinson's disease. AB - INTRODUCTION: Subthalamic deep brain stimulation (STN-DBS) has been reported to improve the quality of life (QoL) related to Parkinson's disease (PD). However, not all subjects are satisfied with the postsurgical QoL outcome. We aimed to detect the related factors and possible predictors to QoL improvement for those PD patients one year after STN DBS. MATERIALS & METHODS: 45 PD patients with bilateral STN-DBS surgery were included and followed up for 1 year. The Reliable Change Index (RCI) was adapted to determine the individual postsurgical QoL outcome. The changes of QoL were correlated with baseline parameters and the changes of progression parameters using Pearson's correlation. The exploratory stepwise regressions were adopted to detect the extents of baseline variables and progression parameters. The predictors to QoL outcome were detected using the logistic regression analysis. RESULTS: 51.1% of the patients reported a better QoL, 40.0% of patients reported an unchanged QoL, while 8.9% of patients reported a worsening of QoL. The subdomains of mobility, activity of daily living, cognition, and bodily discomfort improved significantly after the surgery. The presurgical factors including QoL, dopaminergic medication burden, disease stages, depression scores and postsurgical reductions in depression and non-motor scores were found to correlate with QoL changes. Furthermore, the greater presurgical QoL burden, lesser dopaminergic medication exposure and earlier disease stages were predictors to QoL improvements. CONCLUSION: The clinicians should carefully evaluate the non-motor symptoms and life quality in those patients at relatively earlier stages and with lower medicine dosage to get more successful DBS outcomes. This article is protected by copyright. All rights reserved. PMID- 30451277 TI - A caveat on the Savage-Dickey density ratio: The case of computing Bayes factors for regression parameters. AB - The Savage-Dickey density ratio is a simple method for computing the Bayes factor for an equality constraint on one or more parameters of a statistical model. In regression analysis, this includes the important scenario of testing whether one or more of the covariates have an effect on the dependent variable. However, the Savage-Dickey ratio only provides the correct Bayes factor if the prior distribution of the nuisance parameters under the nested model is identical to the conditional prior under the full model given the equality constraint. This condition is violated for multiple regression models with a Jeffreys-Zellner-Siow prior, which is often used as a default prior in psychology. Besides linear regression models, the limitation of the Savage-Dickey ratio is especially relevant when analytical solutions for the Bayes factor are not available. This is the case for generalized linear models, non-linear models, or cognitive process models with regression extensions. As a remedy, the correct Bayes factor can be computed using a generalized version of the Savage-Dickey density ratio. PMID- 30451278 TI - Pericardial adipose tissue and cardiovascular diseases: new insights from basic research. AB - All basic research original articles published in the European Journal of Clinical Investigation from November 2017 to October 2018 have been evaluated by the Council of the European Society of Clinical Investigation (ESCI) in November 2018. Three articles of outstanding quality have been selected and further judged in the final selection round on the basis of their scientific impact, novelty and overall translational value. Among the finalists, the article by Chia-Yu Wang et al. entitled "The role of pericardial adipose tissue in the heart of obese minipigs" gained the highest consideration by the ESCI Committee and has been rewarded the 2019 ESCI Award for the Best Basic Research Article. This article is protected by copyright. All rights reserved. PMID- 30451279 TI - Painful punctate palmoplantar keratoderma due to heterozygous mutations in AAGAB. AB - Punctate palmoplantar keratoderma (PPPK) is a rare, autosomal dominant disorder of keratinization with three main variants. PPPK type 1 (MIM 148600), also known as Buschke-Fischer-Brauer disease, is characterized by the progressive development of multiple small hyperkeratotic papules with central indentations that are irregularly distributed on the palms and soles, often deteriorating to more extensive diffuse hyperkeratosis on the weight-bearing areas of plantar skin. The PPPK1 gene was recently identified as the alpha and gamma-adaptin binding protein p34 gene AAGAB, and in a single case, the COL14A1 gene. This article is protected by copyright. All rights reserved. PMID- 30451280 TI - To Tailor Solutions, You Must Understand the Problems: Nursing Facility Resident Changes of Condition. PMID- 30451281 TI - Patients' understandings about cellulitis and views about how best to prevent recurrent episodes: mixed methods study in primary and secondary care. AB - BACKGROUND: Cellulitis is a common painful infection of the skin and underlying tissues that recurs in approximately a third of cases. The only proven strategy to reduce the risk of recurrence is long-term, low-dose antibiotics. Given current concerns about antibiotic resistance and the pressure to reduce antibiotic prescribing, other prevention strategies are needed. OBJECTIVES: To explore patients' views about cellulitis and different ways of preventing recurrent episodes. METHODS: Adults aged 18 or over with a history of first episode or recurrent cellulitis were invited through primary care, hospitals and advertising to complete a survey, take part in an interview, or both. RESULTS: Thirty interviews were conducted between August 2016 and July 2017. Two hundred and forty surveys were completed (response rate 17%). Triangulation of quantitative and qualitative data showed that people who have had cellulitis have wide-ranging beliefs about what can cause cellulitis and are often unaware of risk of recurrence or potential strategies to prevent recurrence. Enhanced foot hygiene, applying emollients daily, exercise and losing weight were more popular potential strategies than use of compression stockings or long-term antibiotics. Participants expressed caution about long-term oral antibiotics, particularly those who had experienced only one episode of cellulitis. CONCLUSIONS: People who have had cellulitis are keen to know about possible ways to prevent further episodes. Enhanced foot hygiene, applying emollients daily, exercise and losing weight were generally viewed to be more acceptable, feasible strategies than compression or antibiotics, but further research is needed to explore uptake and effectiveness in practice. This article is protected by copyright. All rights reserved. PMID- 30451282 TI - Predictors of successful manual rotation for occiput posterior positions. AB - OBJECTIVE: To identify predictors of the success of manual rotation of fetuses in an occiput posterior position. METHODS: A prospective, observational, single center study included all women with a singleton pregnancy at term with a fetus in an occiput posterior position for whom manual rotation was attempted from December 1, 2013, to April 30, 2015 at a tertiary care maternity unit in Nancy, France. Occiput posterior position was confirmed by ultrasonography, and success of manual rotation was defined by the occiput anterior position of the fetus after the attempt. RESULTS: Occiput posterior position was diagnosed in 233 (9.2%) of the 2522 deliveries during the study period and the majority of cases were managed successfully by manual rotation (167 [71.7%]). Factors associated with successful rotation were fetal engagement (adjusted odds ratio [aOR] 2.20, 95% confidence interval [CI] 1.05-4.56), spontaneous labor (aOR 1.85, 95% CI 1.01 3.43), and no failure to progress (aOR 2.01, 95% CI 1.02-3.94). Successful manual rotation was associated with lower rates of cesarean (P<0.001) and instrumental (P<0.001) deliveries. CONCLUSION: Study findings suggested that manual rotation, especially after fetal engagement, succeeded more often when performed systematically than when it was attempted after failure to progress. PMID- 30451283 TI - Availability and prescription of misoprostol for medical abortion in community pharmacies and associated factors in Accra, Ghana. AB - OBJECTIVE: To assess misoprostol availability at community pharmacies and determine factors affecting misoprostol prescription for medical abortion. METHODS: A cross-sectional quantitative survey of randomly sampled community pharmacies and their corresponding pharmacists/pharmacy workers was conducted in the city of Accra, Ghana. Structured questionnaires were administered to collect data between May 1 and July 28, 2016. Descriptive statistics (frequencies and proportions) and bivariate and logistic regression analysis were used to analyze the data. RESULTS: Of the 165 community pharmacies surveyed, approximately half (83 [50.3%]) stocked misoprostol. Availability of misoprostol however decreased when moving from first class to third class residential areas. 44 (26.7%) of the respondents had prescribed the drug at some time for medical abortion, but 140 (84.6%) indicated they would not prescribe the drug for medical abortion in future. Factors that significantly predicted misoprostol prescription for medical abortion included sex of the pharmacist/pharmacy worker, demand, and availability of misoprostol. CONCLUSIONS: Demand for misoprostol for medical abortion was found to be high but only half of community pharmacies stocked it, and most pharmacy workers did not wish to prescribe the drug. If community pharmacies are to effectively contribute to expanding access to safe abortion services in Ghana, the disparity between misoprostol provision and demand needs to be addressed. PMID- 30451284 TI - Crystal structure and catalytic activity of the PPM1K N94K mutant. AB - Protein Phosphatase Mg2+ /Mn2+ Dependent 1K (PPM1K),also named as PP2Cm or branched-chain alpha-ketoacid dehydrogenase complex phosphatase (BDP), is a member of the metal-dependent phosphatase family and an important metabolic regulator. Single nucleotide polymorphisms (SNPs) in PPM1K contributing to protein functional defects have been found to be associated with numerous human diseases, such as cardiovascular disease, maple syrup urine disease, type 2 diabetes, and neurological disease. PPM1K N94K is an identified missense mutant produced by one of the SNPs in the human PPM1K coding sequence. However, the effects of the N94K mutant on its activity and structural property have not been defined. Here, we performed a detailed enzymological study using steady-state kinetics in the presence of pNPP or phosphopeptide substrates and crystallographic analyses of the wild-type and N94K PPM1K. The PPM1K-N94K significantly impaired its Mg2+ dependent catalytic activity and structural analysis demonstrated that the N94K mutation induced a conformational change of the key residue in coordinating the Mg2+ in the active site. Specifically, three Mg2+ were located in the active site of the PPM1K N94K instead of two Mg2+ in the PPM1K wild type. Therefore, our results provide a structure basis for the metal ion-dependent PPM1K-N94K phosphatase activity. This article is protected by copyright. All rights reserved. PMID- 30451285 TI - Consumers' Opinion on Dried Pomegranate Arils to Determine the Best Processing Conditions. AB - Consumers' preference is essential to improve processed food products quality, but small companies sometimes lacks knowledge or tools to develop consumer studies. The aim of the present study was to investigate consumers' insight to recommend the best drying methodology for pomegranate arils. With the aim of providing information that industry can correlate to the drivers of liking, descriptive sensory characteristics, and volatile compounds of the samples were determined and related with consumers' responses. A total of 19 volatiles of dehydrated pomegranate arils were determined using solid-phase microextraction and gas chromatography-mass spectrometry. Partial least square regression (PLS) results indicated that consumers overall liking was positively correlated with "pom ID", "sweet", and "fruity" attributes, and also volatile compounds of the esters family. Overall liking was negatively correlated with the "off-flavor" and "burnt" attributes, related to the furan compounds family. Penalty analysis indicated that the sample corresponding with the current commercial product needed improvement on the "pom ID", "fruity", and "sweetness" parameters. All the samples processed using the proposed new drying techniques were more liked than the commercial sample, highlighting a sample dried using pre-osmotic dehydration in Wonderful concentrate pomegranate juice. PRACTICAL APPLICATION: Consumers' preference is essential to improve processed food products quality, but small companies sometimes lack knowledge or tools to conduct consumer studies. The present study provides useful information to understand consumers' preferences of a healthy product such as pomegranate dehydrated arils. Also, the link of physico chemical and sensory tools is clearly described, providing information about possible sensory quality indicators. PMID- 30451286 TI - Gabapentin and Tricyclics in the Treatment of Post-Concussive Headache, a Retrospective Cohort Study. AB - OBJECTIVE: To examine the association of commonly prescribed post-concussive medications, namely gabapentin and tricyclic antidepressants (TCAs), with symptom reduction after concussion. BACKGROUND: Concussion is a common diagnosis in modern medicine. Many providers use medication to target the residual symptoms of a concussion, with little evidence supporting their efficacy. DESIGN: Retrospective study with longitudinal analysis using mixed-effects and piecewise regression analyses of 277 patients presenting to an academic sports medicine clinic, all of whom were clinically diagnosed with a concussion. Main outcomes were patient-reported headache score (quantitative variable; 0-6) and combined symptom score (quantitative variable; 0-132) from the Post-Concussion Symptom Scale (PCSS). METHODS: Patients self-reported their symptom scores on the PCSS at the time of each clinic visit. Gabapentin or TCAs were prescribed to some patients during their follow-ups for headache treatment, based on physician judgment. Patients were classified into 3 groups: (1) no medication; (2) gabapentin; or (3) TCAs. Follow-up data were evaluated over 1 year. A mixed effects and piecewise regression analysis were performed to assess long- and short-term effects of medication status. RESULTS: The mixed-effects analysis showed a significant decrease in both headache and symptom scores over time in each medication group and in those not receiving medication (P <= .014 for all scenarios, B = -0.005 and -0.08, respectively). Although patients in the 2 medication groups showed significantly higher headache and symptom scores (P < .001), neither medication had a significant effect on longitudinal improvements in the outcome scores. The piecewise regression, however, showed short-term improvements with gabapentin (1.3 points, P = .004) and more sustained improvements with TCAs (3.5 points, P = .006). CONCLUSIONS: Patients recover from a concussion with time, regardless of medication. Gabapentin and TCAs appear to have immediate effects on improving symptom burden, but long-term outcomes show similar improvement compared to those who are not prescribed medication. More rigorous prospective studies are required to better elucidate their efficacy. PMID- 30451287 TI - Mechanisms of plant-soil feedback: interactions among biotic and abiotic drivers. AB - Plant-soil feedback (PSF) occurs when plants alter soil properties that influence the performance of seedlings, with consequent effects on plant populations and communities. Many processes influence PSF, including changes in nutrient availability and the accumulation of natural enemies, mutualists, or secondary chemicals. Typically, these mechanisms are investigated in isolation, yet no single mechanism is likely completely responsible for PSF as these processes can interact. Further, the outcome depends on which resources are limiting and the other plants and soil biota in the surrounding environment. As such, understanding the mechanisms of PSF and their role within plant communities requires quantifying the interactions among the processes influencing PSF and the associated abiotic and biotic contexts. This article is protected by copyright. All rights reserved. PMID- 30451288 TI - Cautionary notes on the use of Agrobacterium-mediated transient gene expression upon SGT1 silencing in Nicotiana benthamiana. AB - The suppressor of the G2 allele of skp1 (SGT1) is an essential component of the plant immune system, required for the induction of disease resistance mediated by many intracellular immune receptors containing nucleotide-binding and leucine rich repeat domains (NLRs) (Azevedo et al., 2002; Kadota et al., 2010). Accordingly, virus-induced gene silencing (VIGS) of SGT1 in Nicotiana benthamiana is commonly used to test for immune- or SGT1-dependence of hypersensitive response (HR), or HR-like cell death induced by pathogen effectors, elicitors, or heterologous protein overexpression (Supporting table 1). A reduction or loss of macroscopic cell death can be easily detected when the cellular reactions leading to such cell death require SGT1 activity, making this a powerful and straightforward assay. This article is protected by copyright. All rights reserved. PMID- 30451289 TI - Chronic overexpression of ubiquitin impairs learning, reduces synaptic plasticity, and enhances GRIA receptor turnover in mice. AB - Ubiquitin is an essential signaling protein that controls many different cellular processes. While cellular ubiquitin levels normally cycle between pools of free and conjugated ubiquitin, the balance of these ubiquitin pools can be shifted by exposure to a variety of cellular stresses. Altered ubiquitin pools are also observed in several neurological disorders, suggesting that imbalances in ubiquitin homeostasis may contribute to neuronal dysfunction. To examine the effects of increased ubiquitin levels on the mammalian nervous system, we generated transgenic mice that express ubiquitin under the control of the Thy1.2 promoter. While we did not detect global changes in levels of ubiquitin conjugates in the hippocampus, we found that increasing ubiquitin levels reduced AMPA (GRIA1-4) receptor expression without affecting the levels of NMDA (GRIN) or GABAA receptors. Ubiquitin overexpression also negatively impacted hippocampus dependent learning and memory as well as baseline excitability and synaptic plasticity at hippocampal CA3-CA1 synapses. These changes occurred in a dose dependent manner in that mice with the highest levels of ubiquitin overexpression had the greatest deficits in synaptic function and were the most impaired in the learning and memory tasks. As chronic elevation of ubiquitin expression in neurons is sufficient to cause changes in synaptic function and cognition, altered ubiquitin homeostasis may be an important contributor to the stress induced changes observed in neurological disorders. This article is protected by copyright. All rights reserved. PMID- 30451290 TI - Transcranial direct current stimulation in children with autism spectrum disorder: a systematic scoping review. AB - AIM: Our aim was to review available studies which test transcranial direct current stimulation (tDCS) to reduce symptom severity in children with autism spectrum disorder (ASD). METHOD: We performed a systematic scoping review in PubMed and PsychINFO databases for studies employing tDCS in children and adolescents with ASD. RESULTS: We found five studies (two small randomized controlled studies, one experimental study, one quasi-experimental study, and one case study) reporting positive effects of tDCS in ASD symptom reduction. Study design varied greatly and sample size ranged from 1 to 20 patients. INTERPRETATION: Preliminary evidence is encouraging of the potential usefulness of tDCS for treatment of ASD in children and adolescents. It suggests tentative support for reductions in symptom severity and, according to parental reports and clinical observations, improvements in some aspects of language. However, the evidence is sparse and of low quality, so the true effect of tDCS is likely to be substantially different from the estimate of effect in this review. Therefore, future randomized controlled trials are needed to draw conclusions regarding tDCS efficacy in paediatric samples with ASD. WHAT THIS PAPER ADDS: There is low confidence in the estimate of effect, but tentatively encouraging results warrant further investigation. PMID- 30451292 TI - Role of breast vascular calcification in predicting cardiovascular risk. AB - Cardiovascular disease is the leading cause of death in women worldwide, resulting in 8.6 million deaths annually. Computed tomography (CT) has been used to evaluate coronary artery calcification by quantifying the coronary calcium score (CCS)-a validated marker of cardiovascular risk. Additionally, mammography is the only method for population screening of breast cancer, but could also identify atherosclerosis, known as breast vascular calcification (BVC) . This article is protected by copyright. All rights reserved. PMID- 30451294 TI - Commentary on Nobrega-Jr et al. "Mesial temporal lobe epilepsy with hippocampal sclerosis is infrequently associated with neuronal antibodies". PMID- 30451293 TI - POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families. AB - BACKGROUND: Germline mutations in telomere-related genes such as POT1 and the TERT promoter predispose to familial melanoma. OBJECTIVE: To evaluate the prevalence of germline mutations in the POT1 gene and in the TERT promoter in a large cohort of Spanish melanoma-prone families (at least two affected individuals in first- or second-degree relatives). METHODS: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected case of each family and TERT promoter was sequenced in one affected case from 202 families (26 families were excluded due to DNA exhaustion/degradation). Additionally, TERT promoter sequencing was extended to addition 30 CDKN2A mutated families and 70 sporadic multiple primary melanoma patients (MPM) with a family history of other cancers. RESULTS: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr), a nonsense variant c.1030G>T (p.Glu344*), and two variants c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a MPM patient, but no germline mutations were detected in the TERT promoter in familial melanoma cases. CONCLUSIONS: Overall, 1.75% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in melanoma families in our population is extremely rare. This article is protected by copyright. All rights reserved. PMID- 30451291 TI - Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study. AB - OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for >=2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems. PMID- 30451295 TI - Creation and Validation of a Reactor Engineering Model for Multi-phase Red Wine Fermentations. AB - Red wine fermentations are performed in the presence of grape skins and seeds to ensure extraction of color and other phenolics. The presence of these solids results in two distinct phases in the fermentor, as the solids float to the top to form a "cap." Modeling of red wine fermentations is, therefore, complex and must consider spatial heterogeneity to predict fermentation kinetics. We have developed a reactor-engineering model for red wine fermentations that includes the fundamentals of fermentation kinetics, heat transfer, diffusion, and compressible fluid flow. To develop the heat transfer component of the model, the heat transfer properties of grapes were experimentally determined as a function of fermentation progression. COMSOL was used to solve all components of the model simultaneously utilizing a Finite Elements Analysis (FEA) approach. Predictions from this model were validated using prior experimental work. Model prediction and experimental data showed excellent agreement. The model was then used to predict spatial profiles of active yeast cell concentration and ethanol productivity, as well as liquid velocity profiles. Finally, the model was used to predict how these gradients would change with differences in initial bioavailable nitrogen concentration, a key parameter in predicting fermentation outcome in nitrogen-limited wine fermentations. This article is protected by copyright. All rights reserved. PMID- 30451296 TI - The Role of Innate Immunity in Mucopolysaccharidoses. AB - Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of GAGs and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regards to inflammation in mucopolysaccharidosis with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the TLR4 pathway. Innate immunity appears to have a dominating role in MPS; however furthering understanding of innate immune signalling would have significant impact on highlighting novel anti-inflammatory therapeutics for use in MPS disease. This article is protected by copyright. All rights reserved. PMID- 30451298 TI - A Glimmer of Hope. PMID- 30451299 TI - High carbon storage in carbon limited trees. AB - The concentrations of nonstructural carbohydrates (NSC) in plant tissues are commonly used as an indicator of total plant carbon (C) supply; but some evidence suggests the possibility for high NSC concentrations during periods of C limitation. Despite this uncertainty, NSC dynamics have not been investigated experimentally under long-term C-limitation. We exposed saplings of 10 temperate tree species differing in shade tolerance to 6% of ambient sunlight for 3 yr to induce C-limitation, and also defoliated one species, Carpinus betulus, in the third season. Growth and NSC concentrations were monitored to determine C allocation. Shade strongly reduced growth, but after an initial two-fold decrease, NSC concentrations of shaded saplings recovered to the level of unshaded saplings by the third season. NSC concentrations were generally more depleted under shade after leaf flush, and following herbivore attacks. Only under shade, artificial defoliation led to mortality and depleted NSC concentrations in surviving individuals. We conclude that, irrespective of shade tolerance, C-storage is maintained under prolonged shading, and thus high NSC concentrations can occur during C-limitation. Yet, our results also suggest that decreased NSC concentrations are indicative of C-limitation, and that additional leaf loss can lead to lethal C-shortage in deep shade. This article is protected by copyright. All rights reserved. PMID- 30451297 TI - Glutamate triggers intracellular Ca2+ oscillations and nitric oxide release by inducing NAADP- and InsP3 -dependent Ca2+ release in mouse brain endothelial cells. AB - The neurotransmitter glutamate increases cerebral blood flow by activating postsynaptic neurons and presynaptic glial cells within the neurovascular unit. Glutamate does so by causing an increase in intracellular Ca2+ concentration ([Ca2+ ]i ) in the target cells, which activates the Ca2+ /Calmodulin-dependent nitric oxide (NO) synthase to release NO. It is unclear whether brain endothelial cells also sense glutamate through an elevation in [Ca2+ ]i and NO production. The current study assessed whether and how glutamate drives Ca2+ -dependent NO release in bEND5 cells, an established model of brain endothelial cells. We found that glutamate induced a dose-dependent oscillatory increase in [Ca2+ ]i , which was maximally activated at 200 MUM and inhibited by alpha-methyl-4 carboxyphenylglycine, a selective blocker of Group 1 metabotropic glutamate receptors. Glutamate-induced intracellular Ca2+ oscillations were triggered by rhythmic endogenous Ca2+ mobilization and maintained over time by extracellular Ca2+ entry. Pharmacological manipulation revealed that glutamate-induced endogenous Ca2+ release was mediated by InsP3 -sensitive receptors and nicotinic acid adenine dinucleotide phosphate (NAADP) gated two-pore channel 1. Constitutive store-operated Ca2+ entry mediated Ca2+ entry during ongoing Ca2+ oscillations. Finally, glutamate evoked a robust, although delayed increase in NO levels, which was blocked by pharmacologically inhibition of the accompanying intracellular Ca2+ signals. Of note, glutamate induced Ca2+ -dependent NO release also in hCMEC/D3 cells, an established model of human brain microvascular endothelial cells. This investigation demonstrates for the first time that metabotropic glutamate-induced intracellular Ca2+ oscillations and NO release have the potential to impact on neurovascular coupling in the brain. PMID- 30451300 TI - The Emperor's New Gepants: Are the Effects of the New Oral CGRP Antagonists Clinically Meaningful? PMID- 30451301 TI - Elevated urinary orosomucoid excretion as a novel biomarker in Crohn's disease. AB - BACKGROUND: Laboratory markers are essential tools in the follow-up of patients with Crohn's disease (CD). Our aim was to investigate urinary concentrations of orosomucoid in relation to the inflammatory activity of CD and to compare it with clinical indices and conventional laboratory parameters. MATERIALS AND METHODS: Blood and urine samples of 86 patients (55 adults and 31 children) with CD and 68 healthy individuals (38 adults and 30 children) as controls were analyzed. Patients were categorized according to their clinical scores (Harvey-Bradshaw Index (HBI) or Pediatric Crohn's Disease Activity Index (PCDAI)). Urinary orosomucoid (u-ORM) was determined by automated immune turbidimetric assay and values were referred to urinary creatinine (u-ORM/u-CREAT, mg/mmol). RESULTS: U ORM/u-CREAT values were 7 times higher in children with active CD (0.50 vs. 0.07 mg/mmol, p<0.001) and 2 times higher in adults (0.32 vs. 0.14 mg/mmol, p=0.01) compared with patients with inactive disease. U-ORM/u-CREAT showed good correlation with conventional inflammatory markers (hs-CRP, serum ORM; p<0.01) and activity indices (HBI, p=0.018; PCDAI, p<0.001). U-ORM/u-CREAT had similar discriminative performance to hs-CRP and serum ORM in the differentiation of active from inactive pediatric CD patients. CONCLUSIONS: Our findings suggest that u-ORM/u-CREAT might serve as a valuable additional marker in the follow-up of CD patients, especially in children for whom the non-invasive sampling is a further advantage. This article is protected by copyright. All rights reserved. PMID- 30451302 TI - FPwatch: Facility-based Survey Data for Family Planning Market Analysis in Five FP2020-focus Countries. AB - This article describes datasets for the FPwatch Project, a comprehensive facility based family planning survey conducted by Population Services International in five countries in Africa and Asia from 2015 to 2017. Contents cover research design and background, methodology, sample selection, data collection, an overview of FPwatch indicators, and quality assurance measures taken. These datasets from the Democratic Republic of Congo, Ethiopia, India, Myanmar, and Nigeria complement other facility-based family planning surveys and are unique in their large-scale, standardized methodology, and comprehensive sampling approach. In addition, all datasets but Myanmar (private only) include both private and public facilities, a feature that gives a more complete picture of the family planning supply environment. Because of these factors, the data is well suited to inform global family planning efforts. PMID- 30451304 TI - An ONIOM investigation of the effect of conformation on bond dissociation energies in peptides. AB - In the present study, we use the ONIOM strategy of Morokuma and coworkers to examine the various C?H bond dissociation energies (BDEs) of a small peptide (2ONW) and compare these with values obtained for its component individual amino acid residues. To evaluate suitable methods for ONIOM-based geometry optimizations, we test an "internal consistency" approach against full B3-LYP//B3 LYP results, and find B3-LYP/6-31G(d):AM1 to be appropriate. We find that the BDEs at the alpha-carbon in 2ONW are generally larger than the corresponding values for the individual residues on their own. This is attributed to the constraints of the peptide backbone leading to conformations that are not ideal for captodative stabilization of the resulting alpha-radicals. At the more flexible beta- and gamma-positions, the differences between the BDEs in 2ONW and the individual residues are smaller. Overall, the alpha-BDEs are smaller than the beta- and gamma-BDEs in most cases. Thus, to rationalize the inertness of peptide backbones with respect to alpha-hydrogen abstraction that is frequently found experimentally, it is necessary to consider alternative protection mechanisms such as the polar effect. (c) 2018 Wiley Periodicals, Inc. PMID- 30451303 TI - Selective Embolization with Magnetized Microbeads using Magnetic Resonance Navigation in a Controlled-flow Liver Model. AB - PURPOSE: To demonstrate the feasibility of using a custom gradient sequence on an unmodified 3T magnetic resonance imaging (MRI) scanner to perform magnetic resonance navigation (MRN) by investigating the blood flow control method in vivo, reproducing the obtained rheology in a phantom mimicking porcine hepatic arterial anatomy, injecting magnetized microbead aggregates through an implantable catheter, and steering the aggregates across arterial bifurcations for selective tumor embolization. MATERIALS AND METHODS: In the first phase, arterial hepatic velocity was measured using cine phase-contrast imaging in seven pigs under free-flow conditions and controlled-flow conditions, whereby a balloon catheter is used to occlude arterial flow and saline is injected at different rates. Four out of the seven pigs previously underwent selective lobe embolization to simulate a chemoembolization procedure. In the second phase, the measured in vivo controlled-flow velocities were approximately reproduced in a Y shaped vascular bifurcation phantom by injecting saline at an average rate of 0.6 mL/s with a pulsatile component. Aggregates of 200-MUm magnetized particles were steered toward the right or left hepatic branch using a 20-mT/m MRN gradient. The phantom was oriented at 0 degrees , 45 degrees and 90 degrees with respect to the B0 magnetic field. The steering differences between left-right gradient and baseline were calculated using Fischer's exact test. A theoretical model of the trajectory of the aggregate within the main phantom branch taking into account gravity, magnetic force and hydrodynamic drag was also designed, solved and validated against the experimental results to characterize the physical limitations of the method. RESULTS: At an injection rate of 0.5 mL/s, the average flow velocity decreased from 20 +/- 15 cm/s to 8.4 +/- 5.0 cm/s after occlusion in non-embolized pigs and from 13.6 +/- 2.0 cm/s to 5.4 +/- 3.0 cm/s in previously embolized pigs. The pulsatility index, measured to be 1.7 +/- 1.8 and 1.1 +/- 0.1 for non-embolized and embolized pigs respectively, decreased to 0.6 +/- 0.4 and 0.7 +/- 0.3 after occlusion. For MRN performed at each orientation, the left-right distribution of aggregates was 55%, 25% and 75% on baseline and 100%, 100% and 100% (P < 0.001, P = 0.003, P = 0.003) after the application of MRN, respectively. According to the theoretical model, the aggregate reaches a stable transverse position located toward the direction of the gradient at a distance equal to 5.8% of the radius away from the centerline within 0.11 s, at which point the aggregate will have transited through a longitudinal distance of 1.0 mm from its release position. CONCLUSION: In this study, we showed that the use of a balloon catheter reduces arterial hepatic flow magnitude and variation with the aim to reduce steering failures caused by fast blood flow rates and low magnetic steering forces. A mathematical model confirmed that the reduced flow rate is low enough to maximize steering ratio. After reproducing the flow rate in a vascular bifurcation phantom, we demonstrated the feasibility of MRN after injection of microparticle aggregates through a dedicated injector. This work is an important step leading to MRN-based selective embolization techniques in humans. This article is protected by copyright. All rights reserved. PMID- 30451305 TI - Modeling rare blood in Canada. AB - BACKGROUND: Many countries maintain rare blood programs to provide access to blood for patients with complex serologies. These include a process to screen donors and a registry to record information about rare donors; blood agencies may also freeze some units. However, frozen blood is much more expensive than liquid blood. STUDY DESIGN AND METHODS: A two-phase approach to analysis was used to evaluate how rare a blood type must be before a frozen inventory is necessary and what screening rates are required to support a rare blood program. A simulation model was employed to evaluate the impact of inventory on patient access. RESULTS: Results suggested that, for 27 of 29 phenotypes managed by Canadian Blood Services, insufficient donors had been identified to ensure a stable inventory. Analytic results showed the screening rate necessary to ensure a stable inventory and the time frame to build a rare donor base. Twenty-nine simulation scenarios were executed to evaluate patient access to rare blood against inventory levels. Results show that some amount of frozen inventory is necessary for phenotypes rarer than 1 in 3000. However, holding more than two units apiece of O-, O+, A-, and A+ did not improve patient access. CONCLUSION: While some level of frozen blood is needed for rare blood, large inventories do not improve access. Modest amounts of frozen inventory, combined with increased door screening, provides the greatest chance of maximizing patient access. PMID- 30451306 TI - Theoretical study of correlations between the coordination structures and catalytic activities in polymer-stabilized au nanocluster catalysts. AB - Au nanoclusters (Au NCs) stabilized by poly(N-vinyl-2-pyrrolidone) and poly(allylamine), abbreviated to Au:PVP and Au:PAA, catalyze the aerobic oxidation of p-hydroxybenzyl alcohols, but the catalytic activity of Au:PVP is much higher than that of Au:PAA. To elucidate the correlations between the catalytic activities and coordination structures of the stabilizing polymer, the substrate accessibility on Au NCs was estimated by density functional theory (DFT) and molecular dynamics (MD) calculations. For MD simulations, we applied a systematic method to optimize the temperature parameters in temperature replica exchange molecular dynamics (T-REMD), and the coordination structures were comprehensively classified by multivariate analysis. The results show that the number of open active sites on the Au NCs is a good index for predicting the catalytic activities. (c) 2018 Wiley Periodicals, Inc. PMID- 30451307 TI - Effect of CTLA4-Ig (abatacept) Treatment on T cells and B cells in Peripheral Blood of Patients with Polymyositis and Dermatomyositis. AB - We aimed to evaluate in vivo effects of abatacept on phenotypes of T and B cells in the circulation of myositis patients in a sub-study of the ARTEMIS trial. Twelve patients with paired frozen PBMCs before and after 6-month abatacept treatment were included in this sub-study where mass cytometry (CyTOF) was chosen as a technology to be tested for its utility in a real life clinical immune monitoring setting. Using CyTOF, the peripheral T cell phenotypes demonstrated considerable variation over time and between individuals precluding the identification of treatment-specific changes. We therefore conclude that studies of patient cohorts displaying wide clinical heterogeneity using mass cytometry must be relatively large in order to be suited for discovery research and immune monitoring. Still, we did find some correlations with functional muscle outcome, namely positive correlations between the ratio of CD4+ T cells and CD8+ T cells (CD4/CD8) in peripheral blood samples both at baseline and after treatment with muscle endurance improvement as assessed by the functional index (FI-2) test. Our data suggests that the CD4/CD8 ratio in circulation at time of active disease may be a predictor of treatment efficacy in myositis patients. This article is protected by copyright. All rights reserved. PMID- 30451308 TI - Total intravenous anaesthesia with ketamine, medetomidine and guaifenesin compared with ketamine, medetomidine and midazolam in young horses anaesthetised for computerised tomography. AB - BACKGROUND: There is no information directly comparing midazolam with guaifenesin when used in combination with an alpha-2 agonist and ketamine to maintain anaesthesia via intravenous (i.v.) infusion in horses. OBJECTIVES: To compare ketamine-medetomidine-guaifenesin with ketamine-medetomidine-midazolam for total intravenous anaesthesia in young horses anaesthetised for computerised tomography. STUDY DESIGN: Prospective, randomised, blinded, crossover trial. METHODS: Fourteen weanlings received medetomidine 7 MUg/kg bwt i.v. and anaesthesia was induced with ketamine 2.2 mg/kg bwt i.v. On two separate occasions horses each received infusions of ketamine 3 mg/kg bwt/h, medetomidine 5 MUg/kg bwt/h, guaifenesin 100 mg/kg bwt/h (KMG) or ketamine 3 mg/kg bwt/h, medetomidine 5 MUg/kg bwt/h, midazolam 0.1 mg/kg bwt/h (KMM) for 50 min. Cardiorespiratory variables and anaesthetic depth were assessed every 5-10 min. Recovery times after the infusions ceased were recorded and recovery quality was assessed using a composite score system (CSS), simple descriptive scale (SDS) and visual analogue scale (VAS). Multivariable models were used to generate mean recovery scores for each treatment and each recovery score system and provide P values comparing treatment groups. RESULTS: Anaesthesia was uneventful with no difference in additional anaesthetic requirements and little clinically relevant differences in cardiopulmonary variables between groups. All horses recovered without incident with no significant difference in recovery times. Quality of the anaesthetic recovery was significantly better for the KMM group compared with the KMG group using the CSS (P<0.001), SDS (P<0.001) and VAS (P<0.001). MAIN LIMITATIONS: No surgical stimulus was applied and study animals may not represent general horse population. CONCLUSION: Midazolam is a suitable alternative to guaifenesin when co-infused with ketamine and medetomidine for anaesthesia in young horses undergoing non-invasive procedures. Both infusions produce a clinically comparable quality of anaesthesia; however, recovery from anaesthesia is of a better quality following an infusion of ketamine-medetomidine-midazolam. This article is protected by copyright. All rights reserved. PMID- 30451309 TI - Dynamic relaying properties of a beta-turn peptide in long-range electron transfer. AB - The relay stations play a significant role in long-range charge hopping transfer in proteins. Although studies have clarified that many more protein structural motifs can function as relays in charge hopping transfers by acting as intermediate charge carriers, the relaying properties are still poorly understood. In this work, taking a beta-turn oligopeptide as an example, we report a dynamic character of a relay with tunable relaying properties using the density functional theory calculations. Our main finding is that a beta-turn peptide can serve as an effective electron relay in facilitating long-range electron migration and its relay properties is vibration-tunable. The vibration induced structural transient distortions remarkably affect the lowest occupied molecular orbital (LUMO) energy, vertical electron affinity and electron-binding mode of the beta-turn oligopeptide and the singly occupied molecular orbital (SOMO) energy of the corresponding electron adduct and thus the relaying properties. Different vibration modes lead to different structural distortions and thus have different effects on the relaying properties and ability of the beta-turn peptide. For the relaying properties, there approximately is a linear negative correlation of electron affinity with the LUMO energy of the beta-turn or the SOMO energy of its electron adduct. Besides, such relaying properties also vary in the vibration evolution process, and the electron-binding modes may be tunable. As an important addition to the known static charge relaying properties occurring in various protein structural motifs, this work reports the dynamic electron-relaying characteristics of a beta-turn oligopeptide with variable relaying properties governed by molecular vibrations which can be applied to different proteins in mediating long-range charge transfers. Clearly, this work reveals molecular vibration effects on the electron relaying properties of protein structural motifs and provides new insights into the dynamics of long range charge transfers in proteins. (c) 2018 Wiley Periodicals, Inc. PMID- 30451310 TI - Ab initio surface hopping excited-state molecular dynamics approach on the basis of spin-orbit coupled states: An application to the A-band photodissociation of CH3 I. AB - Ab initio molecular dynamics approach has been extended to multi-state dynamics on the basis of the spin-orbit coupled electronic states that are obtained through diagonalization of the spin-orbit coupling matrix with the multi-state second-order multireference perturbation theory energies in diagonal elements and the spin-orbit coupling terms at the state-averaged complete active space self consistent field level in off-diagonal elements. Nonadiabatic transitions over the spin-orbit coupled states were taken into account explicitly by a surface hopping scheme with utilizing the nonadiabatic coupling terms calculated by numerical differentiation of the spin-orbit coupled wavefunctions and analytical nonadiabatic coupling terms. The present method was applied to the A-band photodissociation of methyl iodide, CH3 I + hv -> CH3 + I (2 P3/2 )/I* (2 P1/2 ), for which a pioneering theoretical work was reported by Amatatsu, Yabushita, and Morokuma. The present results reproduced well the experimental branching ratio and energy distributions in the dissociative products. (c) 2018 Wiley Periodicals, Inc. PMID- 30451311 TI - Veteran Preferences for the Caring Contacts Suicide Prevention Intervention. AB - OBJECTIVE: The Caring Contacts intervention has been implemented with a variety of methodologies. The purpose of this study was to examine high-risk inpatient preferences for the Caring Contacts intervention. METHOD: Veteran psychiatric inpatients (N = 154) completed an anonymous patient preferences survey to obtain feedback on Caring Contact methods such as message wording, preferred correspondent, frequency of contact, duration of the intervention, imagery, and mailing modality. RESULTS: Eighty-five percent of veterans Agreed or Strongly Agreed that they would like to receive Caring Contacts from at least one of the correspondent options, with inpatient or outpatient mental health counselor, or primary care physician most preferred. Example messages based on prior studies were overwhelmingly rated as caring and helpful; 84% believed that Caring Contacts could help suicidal individuals. Letters or postcards sent through postal mail were preferred over e-mail or text messages. Participants most commonly thought Caring Contacts should be sent monthly for a period of a year. CONCLUSIONS: The results of this study suggest that most high-risk veterans would perceive Caring Contacts as helpful and caring. The results provide several practical, helpful tips for programs seeking to establish a Caring Contacts program. PMID- 30451312 TI - Accelerated long-range corrected exchange functional using a two-gaussian operator combined with one-parameter progressive correlation functional [LC BOP(2Gau)]. AB - Recently, we proposed a simple yet efficient method for the computation of a long range corrected (LC) hybrid scheme [LC-DFT(2Gau)], which uses a modified two Gaussian attenuating operator instead of the error function for the long-range HF exchange integral. This method dramatically reduced the computational time while maintaining the improved features of the LC density functional theory (DFT). Here, we combined an LC hybrid scheme using a two-Gaussian attenuating operator with one-parameter progressive correlation functional and Becke88 exchange functional with varying range-separation parameter values [LC-BOP(2Gau) with various MU values of 0.16, 0.2, 0.25, 0.3, 0.35, 0.4, and 0.42] and demonstrated that LC-BOP(2Gau) reproduces well the thermochemical and frontier orbital energies of LC-BOP. Additionally, we revised the scaling factors of the Gaussian multipole screening scheme for LC-DFT(2Gau) to correspond to the angular momentum of orbitals, which decreased the energy deviations from the energy with the no screening scheme. (c) 2018 Wiley Periodicals, Inc. PMID- 30451313 TI - Lateral knowledge: shifting expertise for disaster management in Chile. AB - Deemed as technocratic and exclusionary, disaster management has failed in its promise of knowing, let alone controlling, catastrophic events. Consequently, disaster managers are searching outside of science for sense-making analytics. This paper analyses the emergent narratives articulated by disaster managers in Chile to cope with the uncertain nature of their object of intervention. It explores how knowledge of disasters is modified and enriched by disaster managers in what is termed here as 'lateral knowledge': the epistemic adjustment by which practitioners revalidate their expert status by expanding key assumptions about disaster risk reduction. The study, which draws on in-depth interviews with disaster managers in Chile, suggests that lateral knowledge is established both through the increasing validation of community knowledge and the recognition of politics as a critical mediator in the practice of disaster management. The paper concludes by making the larger point that public understanding of science scholars should pay more attention to the adapting capacities of expertise. PMID- 30451314 TI - Pinning down social vulnerability in Sindh Province, Pakistan: from narratives to numbers, and back again. AB - This paper reflects critically on the results of a vulnerability assessment process at the household and community scale using a quantitative vulnerabilities and capacities index. It validates a methodology for a social vulnerability assessment at the local scale in 62 villages across four agro ecological/livelihood zones in Sindh Province, Pakistan. The study finds that the move from vulnerability narratives to numbers improves the comparability and communicational strength of the concept. The depth and nuance of vulnerability, however, can be realised only by a return to narrative. Caution is needed, therefore: the index can be used in conjunction with qualitative assessments, but not instead of them. More substantively, the results show that vulnerability is more a function of historico-political economic factors and cultural ethos than any biophysical changes wrought by climate. The emerging gendered vulnerability picture revealed extremes of poverty and a lack of capacity to cope with contemporary environmental and social stresses. PMID- 30451315 TI - The effectiveness of PEPFAR's funding for women and children with HIV/AIDS. AB - Has President's Emergency Plan for AIDS Relief's (PEPFAR) funding been effective in reducing the rate of HIV new infections and AIDS-related deaths among women and children? While previous studies have found HIV/AIDS aid to be ineffective and PEPFAR funding to produce negative externalities, there is lack of empirical examination of the impact of PEPFAR on women and children despite the emphasis on prevention of mother-to-child transmission of HIV during the Bush and Obama administrations. Using descriptive analysis and difference-in-differences (DID) regression, this study finds that PEPFAR's funding has reduced the HIV new infections and AIDS-related death rates of women and children for both focus countries and recipient countries, which are those that were added in a second phase. These findings show that PEPFAR's strategy for women and children has been effective and that it should be continued. However, while PEPFAR has contributed to the fight against HIV/AIDS, the effects of its work have been underestimated. PMID- 30451317 TI - Analytical Methodologies for Space Exploration. PMID- 30451318 TI - Glycopyrronium tosylate in pediatric primary axillary hyperhidrosis: Post hoc analysis of efficacy and safety findings by age from two phase three randomized controlled trials. AB - OBJECTIVES: Hyperhidrosis in pediatric patients has been understudied. Post hoc analyses of two phase 3 randomized, vehicle-controlled, 4-week trials (ATMOS-1 [NCT02530281] and ATMOS-2 [NCT02530294]) were performed to assess efficacy and safety of topical anticholinergic glycopyrronium tosylate (GT) in pediatric patients. METHODS: Patients had primary axillary hyperhidrosis >= 6 months, average Axillary Sweating Daily Diary (ASDD/ASDD-Children [ASDD-C]) Item 2 (sweating severity) score >= 4, sweat production >= 50 mg/5 min (each axilla), and Hyperhidrosis Disease Severity Scale (HDSS) >= 3. Coprimary end points were >= 4-point improvement on ASDD/ASDD-C Item 2 (a validated patient-reported outcome) and change in gravimetrically measured sweat production at Week 4. Efficacy and safety data are shown through Week 4 for the pediatric (>= 9 to <= 16 years) vs older (> 16 years) subgroups. RESULTS: Six hundred and ninety-seven patients were randomized in ATMOS-1/ATMOS-2 (GT, N = 463; vehicle, N = 234); 44 were >= 9 to <= 16 years (GT, n = 25; vehicle, n = 19). Baseline disease characteristics were generally similar across subgroups. GT-treated pediatric vs older patients had comparable improvements in ASDD/ASDD-C Item 2 (sweating severity) responder rate, HDSS responder rate (>= 2-grade improvement]), sweat production, and quality of life (mean change from Baseline in Dermatology Life Quality Index [DLQI]/children's DLQI), with greater improvement vs vehicle. Treatment-emergent adverse events were similar between subgroups, and most were mild, transient, and infrequently led to discontinuation. CONCLUSIONS: Topical, once-daily GT improved disease severity (ASDD/ASDD-C, HDSS), sweat production, and quality of life (DLQI), with similar findings in children, adults, and the pooled population. GT was well tolerated, and treatment-emergent adverse events were qualitatively similar between subgroups and consistent with other anticholinergics. PMID- 30451319 TI - Gender differences, UV exposure and risk of lentigo maligna in a nationwide healthcare population cohort study. AB - BACKGROUND: Our understanding of the relationship between ultraviolet (UV) radiation exposure and lentigo maligna (LM) has been largely derived from epidemiologic/clinical studies based on invasive melanoma. Recent studies have shown gender differences in melanocytic tumours incidence. OBJECTIVE: To examine the association of UV light with LM by gender remains unclear. METHODS: Two prospective cohort study [Nurses' Health Study (1980-2012)] and [Health Professionals Follow-up Study (1986-2010)] were analysed. All participants with LM or MIS, non-LM type were included in analysis. UV index at birth, age 15, and age 30 were calculated by gender. Lifetime UV flux was calculated. Hazard ratios (HRs) were calculated. RESULTS: A total of 110 485 women from NHS and 41 015 men from HPFS were examined. A total of 281 LM and 776 melanoma in situ (MIS), non-LM cases were reported. Risk of LM increased with increasing UV flux exposure in multivariate-adjusted models for men (P for trend = 0.04), but not for women (P for trend = 0.91). CONCLUSIONS: UV flux may be associated with LM in men but not in women. PMID- 30451320 TI - Evaluation of medical and surgical treatments for hidradenitis suppurativa using real-life data from the Scandinavian registry (HISREG). AB - BACKGROUND: Hidradenitis suppurativa (HS) substantially affects health-related quality-of-life outcomes. Most treatment options are supported by low quality of evidence without validated outcomes. OBJECTIVE: The aim of this study was to evaluate the efficacy of surgical and medical interventions using physician- and patient-reported outcomes registered in HISREG. METHODS: Data were extracted for all adult patients registered in HISREG between January 2013 and April 2016. Primary endpoints included Dermatology Life Quality Index (DLQI) scores, pain as measured using a numeric rating scale (NRS), Sartorius score, and Hurley classification. Minimum clinically important differences (MCIDs) for DLQI and NRS pain were analyzed. Secondary endpoints included comparisons among different treatment groups, safety, and complications of various treatments. RESULTS: Two hundred fifty-five patients were included in the study: 31, 188, and 36 patients had Hurley stages I, II, and III disease, respectively. Treatment with CO2 lasers was the most common treatment modality. One hundred forty-nine patients (58.4%) were treated with surgical intervention, 87 (34.1%) received antibiotics and/or anti-inflammatory treatments, and 19 (7.5%) were treated with both surgery and medical intervention. No patients received biologic treatment. In patients with surgical treatments, Sartorius scores were significantly improved compared with baseline (p=0.001), 83 patients (55%) achieved a DLQI MCID, and 75 patients (49.7%) achieved an NRS pain MCID. In patients with medical treatments, Sartorius scores were not significantly improved compared with baseline (p=0.582); 25 patients (28%) achieved a DLQI MCID and 28 patients (31%) achieved an NRS pain MCID. In patients treated with surgical and medical combination, 9 (48%) achieved DLQI and NRS pain MCIDs and Sartorius scores were significantly improved. CONCLUSIONS: CO2 laser treatment is more effective than the non-biologic medical treatments in this analysis based on physician- and patient-derived outcomes. The study provides limited evidence for the combination of medical and surgical therapies in patients with HS. This article is protected by copyright. All rights reserved. PMID- 30451321 TI - Syzygium cumini extract induced reactive oxygen species mediated apoptosis in human oral squamous carcinoma cells. AB - BACKGROUND: Syzygium cumini (L.) Skeels (jambolan) is commonly used in Indian traditional medicine to treat a variety of diseases such as obesity, diabetes etc. The cytotoxic potential of Syzygium cumini (SC) against oral cancer cell line is remains elusive. Therefore, in this study, we evaluated the cytotoxic effect of S. cumini in human oral squamous cell carcinoma (OSCC) cell line (SCC 25 cells). MATERIAL AND METHODS: OSCC cells are treated with different concentrations (10, 20 and 40 MUg/mL) of S. cumuni for 24 h and cytotoxicity was analyzed by MTT assay. The intracellular reactive oxygen species (ROS) was measured using the indicator dye, 2',7'-dichlorofluorescin diacetate staining. Apoptosis-related morphological changes were evaluated by dual acridine orange/ethidium bromide (AO/EB) fluorescent staining and phosphatidylserine externalization was measured by annexin V assays. The protein and gene expression of cadherin-1 was evaluated by western blotting and PCR analysis. RESULTS: SC treatments caused cytotoxicity of OSCC cell line and induced intracellular ROS accumulation. This treatment also caused apoptosis related morphological changes and externalization of phosphatidylserine in OSCC cells. Further, SC treatments increased protein and gene expression of cadherin-1. CONCLUSION: S. cumini extract inhibits the proliferation of OSCC cells and induces apoptosis through ROS accumulation and therefore, it could be used for the prevention of OSCC. This article is protected by copyright. All rights reserved. PMID- 30451322 TI - Algorithmic risk assessments and the double-edged sword of youth. AB - At sentencing, youth can be considered both a mitigating circumstance because of its association with diminished culpability, and an aggravating circumstance because of its association with crime risk. In theory, judges and parole boards can recognize this double-edged sword phenomenon and balance the mitigating and aggravating effects of youth. But when sentencing authorities rely on algorithmic risk assessments, a practice that is becoming increasingly common, this balancing process may never take place. Algorithmic risk assessments often place heavy weights on age in a manner that is not fully transparent - or, in the case of proprietary "black box" algorithms, not transparent at all. For instance, our analysis of one of the leading black-box tools, the COMPAS Violent Recidivism Risk Score, shows that roughly 60% of the risk score it produces is attributable to age. We argue that this type of fact must be disclosed to sentencing authorities in an easily interpretable manner so that they understand the role an offender's age plays in the risk calculation. Failing to reveal that a stigmatic label such as "high risk of violent crime" is due primarily to a defendant's young age could lead to improper condemnation of a youthful offender, especially given the close association between risk labels and perceptions of character and moral blameworthiness. PMID- 30451323 TI - Loss-of-function mutation in DSG1 underlies focal palmoplantar keratoderma. PMID- 30451324 TI - Enzymatic Late-Stage Oxidation of Lead Compounds with Solubilizing Biomimetic Docking/Protecting groups. AB - Late-stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity, biocatalytic transformations, enzymatic oxidations in particular, are potentially very powerful because they could allow the synthesis of less lipophilic derivatives of a lead compound. In the majority of cases, enzymatic oxidations have been used in an empirical way as their regioselectivity is difficult to predict. In this publication, the concept of using docking/protecting groups in a biomimetic fashion was investigated, which could help steer the regioselectivity of a P450BM3 -mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic, and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies. PMID- 30451325 TI - Predictors of response to omalizumab and relapse in chronic spontaneous urticaria: a study of 470 patients. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is defined as spontaneous occurrence of wheals and/or angioedema for >=6 weeks. Omalizumab is a monoclonal anti-IgE antibody effective in refractory CSU, but its mechanism of action and markers predictive of response remain not completely defined. OBJECTIVES: To correlate baseline levels of two proposed biomarkers, total IgE (bIgE) and d dimer (bd-dimer), and clinical parameters to omalizumab response and to relapses after drug withdrawal. METHODS: In this retrospective Italian multicentre study, clinical data were collected in 470 CSU patients, and bIgE and bd-dimer were measured in 340 and 342 patients, respectively. Disease activity was determined by Urticaria Activity Score 7 (UAS7) at week 1 and 12 after omalizumab starting. Relapses were evaluated during a 2- and 3-month interval after a first and a second course of treatment, respectively. RESULTS: bIgE correlated to a good response to omalizumab since levels were significantly higher in responders than non-responders (P = 0.0002). Conversely, bd-dimer did not correlate to response. There was no correlation between both bIgE and d-dimer and either first or second relapse. Disease duration was significantly longer in patients who experienced either first or second relapse (P < 0.0001 and P = 0.0105, respectively), while baseline UAS7 correlated only to first relapse (P = 0.0023). CONCLUSIONS: Our study confirms bIgE as a reliable biomarker predicting response to omalizumab in CSU, while it does not support the usefulness of bd-dimer unlike previous findings. CSU duration before omalizumab and baseline UAS7 may be clinical markers of relapse risk. PMID- 30451326 TI - Anti-PD1 in Merkel cell carcinoma and cutaneous squamous cell carcinoma, description of five cases and recent data from the literature. PMID- 30451328 TI - Heterogeneity and variation of innovator biologics. PMID- 30451327 TI - Glimepiride prevents paraquat-induced Parkinsonism in mice: involvement of oxidative stress and neuroinflammation. AB - There is a growing number of epidemiological and molecular studies which suggest that diabetes is associated with an increased risk of Parkinson's disease (PD). Hence, in this study, the effect of glimepiride (GPD), a sulphonylurea (antidiabetic) on paraquat (PQT)-induced Parkinsonism was evaluated in mice. Thirty-six mice were randomly divided into six groups (n = 6) and treated orally for 21 consecutive days as follows: Group 1: vehicle (10 mL/kg), Group 2: PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 3-5: GPD (1, 2 or 4 mg/kg) + PQT (10 mg/kg, i.p., twice per week for 3 weeks), Group 6: GPD (4 mg/kg, p.o.). The effects of the treatment on motor coordination were evaluated using the rotarod performance, bar and open field tests while working memory was assayed using Y maze test. Paraquat injection induced significant decrease in falling time, number of crosses and percentage alternation behaviour with a concomitant increase in the duration of cataleptic behaviour in the rotarod, open field, Y maze and bar tests, respectively, which was ameliorated by GPD treatment. PQT also increased lipid peroxidation, peroxynitrite and TNF-alpha generations as well as deficit in superoxide dismutase and GSH activities in the midbrain. PQT induced oxidative stress and neuroinflammation was attenuated by GPD treatment. Findings from this study showed that GPD prevents PQT-induced motor dysfunction, memory impairment, oxidative stress and neuroinflammation through enhancement of antioxidant defense system and inhibition of pro-inflammatory cytokine release. Thus, GPD could be a potential adjunct in the management of Parkinsonism. PMID- 30451329 TI - Apremilast for moderate hidradenitis suppurativa: no significant change in lesional skin inflammatory biomarkers. AB - BACKGROUND: Treatment with apremilast has recently demonstrated clinically meaningful improvement in moderate hidradenitis suppurativa (HS). OBJECTIVE: To evaluate the change in expression of inflammatory markers in lesional skin of HS patients receiving apremilast 30 mg twice daily (n=15) for 16 weeks compared with placebo (n=5). METHODS: At baseline 5-mm punch biopsies were obtained from an index lesion (HSL) and non-lesional (HSN) skin in the same anatomical area. Subsequent HSL samples were taken as close as possible to the previously biopsied site at week 4 and week 16. After sampling, biopsies were split; one half was processed for in vivo mRNA analysis using real-time quantitative PCR; the other half was cultured for ex vivo protein analysis using a proximity extension assay (Olink). Linear mixed effects models were calculated to compare the levels of inflammatory markers in HSL skin between apremilast and placebo over time. RESULTS: At baseline, 17 proteins with a fold change >2 in HSL versus HSN skin were identified in 20 patients. The top 5 were IL-17A (5), S100A12, CST5, IL 12/23p40, CD6 (1) with fold changes ranging from 6.6 to 1638, respectively (FDR<0.044). Linear mixed effects models for 75 assays were calculated. Protein levels of S100A12 decreased during treatment in the apremilast group compared with the placebo group (p=0.014, FDR=0.186). None of the 14 genes exhibited significant changes in expression over time. However, an evident downward trend in relative mRNA expression of IL-17A and IL-17F was demonstrated in patients receiving apremilast. CONCLUSION: We did not detect statistically significant changes in inflammatory markers in HSL skin of HS patients receiving apremilast compared with placebo, despite clinical improvement in the apremilast group. Nonetheless, S100A12 and IL-17A were significantly elevated in HSL skin and showed a decrease in response to apremilast. The translational model in clinical trials involving HS clearly needs further improvement. This article is protected by copyright. All rights reserved. PMID- 30451330 TI - A new human delayed-matching-to-place test in a virtual environment reverse translated from the rodent watermaze paradigm: Characterization of performance measures and sex differences. AB - Watermaze tests of place learning and memory in rodents and corresponding reverse translated human paradigms in real or virtual environments are key tools to study hippocampal function. In common variants, the animal or human participant has to find a hidden goal that remains in the same place over many trials, allowing for incremental learning of the place with reference to distal cues surrounding the circular, featureless maze. Although the hippocampus is involved in incremental place learning, rodent studies have shown that the delayed-matching-to-place (DMP) watermaze test is a more sensitive assay of hippocampal function. On the DMP test, the goal location changes every four trials, requiring the rapid updating of place memory. Here, we developed a virtual DMP test reverse translated from the rat watermaze DMP paradigm. In two replications, participants showed 1-trial place learning, evidenced by marked latency and path length savings between Trials 1 and 2 to the same goal location, and by search preference for the vicinity of the goal when Trial 2 was run as probe trial (during which the goal was removed). The performance was remarkably similar to rats' performance on the watermaze DMP test. In both replications, male participants showed greater savings and search preferences compared to female participants. Male participants also showed better mental rotation performance, although mental rotation scores did not consistently correlate with DMP performance measures, pointing to distinct neurocognitive mechanisms. The remarkable similarity between rodent and human DMP performance suggests similar underlying neuro-psychological mechanisms, including hippocampus dependence. The new virtual DMP test may, therefore, provide a sensitive tool to probe human hippocampal function. PMID- 30451331 TI - The osmoresponsiveness of oxytocin and vasopressin neurones: mechanisms, allostasis and evolution. AB - In the rat supraoptic nucleus, every oxytocin cell projects to the posterior pituitary, and is involved in both reflex milk ejection during lactation, and in regulating uterine contractions during parturition. All are also osmosensitive, regulating natriuresis. All are also regulated by signals that control appetite, including neural and hormonal signals that arise from the gut after food intake and from the sites of energy storage. All are also involved in sexual behaviour, anxiety-related behaviours, and social behaviours. The challenge is to understand how a single population of neurones can coherently regulate such a diverse set of functions, and adapt to changing physiological states. Their multiple functions arise from complex intrinsic properties which confer sensitivity to a wide range of internal and environmental signals. Many of these properties have a distant evolutionary origin, in multi-functional, multisensory neurones of Urbilateria, the hypothesised common ancestor of vertebrates, insects and worms. Their properties allow different patterns of oxytocin release into the circulation from their axon terminals in the posterior pituitary, into other brain areas from axonal projections, and independent release from their dendrites. This article is protected by copyright. All rights reserved. PMID- 30451332 TI - Prenatal exposures and infant brain: Review of magnetic resonance imaging studies and a population description analysis. AB - Brain development is most rapid during the fetal period and the first years of life. This process can be affected by many in utero factors, such as chemical exposures and maternal health characteristics. The goal of this review is twofold: to review the most recent findings on the effects of these prenatal factors on the developing brain and to qualitatively assess how those factors were generally reported in studies on infants up to 2 years of age. To capture the latest findings in the field, we searched articles from PubMed 2012 onward with search terms referring to magnetic resonance imaging (MRI), brain development, and infancy. We identified 19 MRI studies focusing on the effects of prenatal environment and summarized them to highlight the recent advances in the field. We assessed population descriptions in a representative sample of 67 studies and conclude that prenatal factors that have been shown to affect brain metrics are not generally reported comprehensively. Based on our findings, we propose some improvements for population descriptions to account for plausible confounders and in time enable reliable meta-analyses to be performed. This could help the pediatric neuroimaging field move toward more reliable identification of biomarkers for developmental outcomes and to better decipher the nuances of normal and abnormal brain development. PMID- 30451334 TI - Genome-Wide Identification of microRNAs Regulating the Human Prion Protein. AB - The cellular prion protein (PrPC ) is best known for its misfolded disease causing conformer, PrPS c . Because the availability of PrPC is often limiting for prion propagation, understanding its regulation may point to possible therapeutic targets. We sought to determine to what extent the human microRNAome is involved in modulating PrPC levels through direct or indirect pathways. We probed PrPC protein levels in cells subjected to a genome-wide library encompassing 2019 miRNA mimics using a robust time-resolved fluorescence resonance screening assay. Screening was performed in three human neuroectodermal cell lines: U-251 MG, CHP-212 and SH-SY5Y. The three screens yielded 17 overlapping high-confidence miRNA mimic hits, 13 of which were found to regulate PrPC biosynthesis directly via binding to the PRNP 3'UTR, thereby inducing transcript degradation. The four remaining hits (miR-124-3p, 192-3p, 299-5p and 376b-3p) did not bind either the 3'UTR or CDS of PRNP, and were therefore deemed indirect regulators of PrPC . Our results show that multiple miRNAs regulate PrPC levels both directly and indirectly. These findings may have profound implications for prion disease pathogenesis and potentially also for their therapy. Furthermore, the possible role of PrPC as a mediator of Abeta toxicity suggests that its regulation by miRNAs may also impinge on Alzheimer's disease. This article is protected by copyright. All rights reserved. PMID- 30451333 TI - Endometrial carcinoma: Evaluation using diffusion-tensor imaging and its correlation with histopathologic findings. AB - BACKGROUND: Although the prognosis of endometrial carcinoma (EMC) patients strictly depends on tumor invasion depth and its histologic grade, accurate preoperative assessment of these prognostic factors is often difficult. PURPOSE: To determine the usefulness of diffusion-tensor imaging (DTI) as a noninvasive method for evaluating tumor invasion depth and its histologic grade in patients with EMC. STUDY TYPE: Prospective. POPULATION: Twenty-five consecutive patients with histologically confirmed EMC who were surgically treated at our institution. FIELD STRENGTH/SEQUENCE: DTI was performed with a 1.5T MRI system using a single shot echo-planar imaging sequence with b values of 0 and 1000 s/mm2 and motion probing gradients in nine noncollinear directions. ASSESSMENT: Fractional anisotropy (FA), mean diffusivity (MD), and axial diffusivity (AD) maps were analyzed by three observers and compared with histopathologic findings. STATISTICAL TESTS: Dunnett's test, Spearman's rank correlation coefficient, and receiver operating characteristic (ROC) curve analyses. RESULTS: FA maps from all patients distinctly identified the junctional zone as a high-FA zone (0.864 +/- 0.037) that was significantly different from the endometrium and outer myometrium (0.251 +/- 0.030 and 0.471 +/- 0.091, respectively; P < 0.001). All EMCs were clearly depicted as hypointense areas on all DTI maps. AD maps provided the best tumor-to-uterus contrast, and EMCs (0.977 +/- 0.120 * 10-3 mm2 /s) had significantly lower AD values than all other layers of the normal uterine wall (2.166 +/- 0.408, 2.010 +/- 0.289, and 2.655 +/- 0.203 * 10-3 mm2 /s, respectively; P < 0.001). EMCs were clearly demarcated from the normal uterine wall, and DTI maps and histopathologic data yielded identical findings regarding tumor invasion depth. FA values showed a significant inverse correlation (r = 0.818; P < 0.001) with histologic grades 1, 2, and 3 of endometrioid adenocarcinomas. DATA CONCLUSION: In patients with EMC, DTI may be useful for evaluating tumor invasion depth and its histologic grade. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 30451335 TI - Gene flow, divergent selection and resistance to introgression in two species of morning glories (Ipomoea). AB - Gene flow is thought to impede genetic divergence and speciation by homogenizing genomes. Recent theory and research suggest that sufficiently strong divergent selection can overpower gene flow, leading to loci that are highly differentiated compared to others. However, there are also alternative explanations for this pattern. Independent evidence that loci in highly differentiated regions are under divergent selection would allow these explanations to be distinguished, but such evidence is scarce. Here we present multiple lines of evidence that many of the highly divergent SNPs in a pair of sister morning glory species, Ipomoea cordatotriloba and I. lacunosa, are the result of divergent selection in the face of gene flow. We analyzed a SNP dataset across the genome to assess the amount of gene flow, resistance to introgression, and patterns of selection on loci resistant to introgression. We show that differentiation between the two species is much lower in sympatry than in allopatry, consistent with interspecific gene flow in sympatry. Gene flow appears to be substantially greater from I. lacunosa to I. cordatotriloba than in the reverse direction, resulting in sympatric and allopatric I. cordatotriloba being substantially more different than sympatric and allopatric I. lacunosa. Many SNPs highly differentiated in allopatry have experienced divergent selection, and despite gene flow in sympatry, resist homogenization in sympatry. Finally, five out of eight floral and inflorescence characteristics measured exhibit asymmetric convergence in sympatry. Consistent with the pattern of gene flow, I. cordatotriloba traits become much more like those of I. lacunosa than the reverse. Our investigation reveals the complex interplay between selection and gene flow that can occur during the early stages of speciation. This article is protected by copyright. All rights reserved. PMID- 30451336 TI - Electrical Stimulation and Recovery of Gastrointestinal Function Following Surgery: A Systematic Review. AB - OBJECTIVES: Postoperative ileus occurs in approximately 5-15% of patients following major abdominal surgery, and poses a substantial clinical and economic burden. Electrical stimulation has been proposed as a means to aid postoperative gastrointestinal (GI) recovery, but no methods have entered routine clinical practice. A systematic review was undertaken to assess electrical stimulation techniques and to evaluate their clinical efficacy in order to identify promising areas for future research. MATERIALS AND METHODS: Literature was searched using MEDLINE, EMBASE, Google Scholar and by assessing relevant clinical trial databases. Studies investigating the use of electrical stimulation for postoperative GI recovery were included, regardless of methods used or outcomes measured. A critical review was constructed encompassing all included studies and evaluating and synthesizing stimulation techniques, protocols, and clinical outcomes. RESULTS: A broad range of neuromodulation strategies and protocols were identified and assessed. Improved postoperative GI recovery following electrical stimulation was reported by 55% of studies (10/18), most commonly those assessing transcutaneous electrical nerve stimulation and electroacupuncture therapy (7/10). Several studies reported shorter time to first flatus and stool, shorter duration of hospital stay, and reduced postoperative pain. However, inconsistent reporting and limitations in trial design were common, compromising a definitive determination of electrical stimulation efficacy. CONCLUSIONS: Electrical stimulation appears to be a promising methodology to aid postoperative GI recovery, but greater attention to mechanisms of action and clinical trial quality is necessary for progress. Future research should also aim to apply validated and standardized gut recovery outcomes and consistent neuromodulation methodologies. PMID- 30451337 TI - Encouraging children to mentalise about a perceived outgroup increases prosocial behaviour towards outgroup members. AB - We investigated whether encouraging young children to discuss the mental states of an immigrant group would elicit more prosocial behaviour towards them and impact on their perception of a group member's emotional experience. Five- and 6 year-old children were either prompted to talk about the thoughts and feelings of this social group or to talk about their actions. Across two studies, we found that this manipulation increased the extent to which children shared with a novel member of the immigrant group who was the victim of a minor transgression. The manipulation did not lead to greater sharing towards a victim from the children's own culture and did not influence their perception of a victim's negative emotions. These results may ultimately have implications for interventions aimed at fostering positive intergroup relations within the context of immigration. This article is protected by copyright. All rights reserved. PMID- 30451338 TI - Turn On of a Ruthenium(II) Photocatalyst by DNA-Templated Ligation. AB - Here, the synthesis of a RuII photocatalyst by light-directed oligonucleotide templated ligation reaction is described. The photocatalyst was found to have tremendous potential for signal amplification with >15000 turnovers measured in 9 hours. A templated reaction was used to turn on the activity of this ruthenium(II) photocatalyst in response to a specific DNA sequence. The photocatalysis of the ruthenium(II) complex was harnessed to uncage a new precipitating dye that is highly fluorescent and photostable in the solid state. This reaction was used to discriminate between different DNA analytes based on localization of the precipitate as well as for in cellulo miRNA detection. Finally, a bipyridine ligand functionalized with two different peptide nucleic acid (PNA) sequences was shown to enable template-mediated ligation (turn on of the ruthenium(II) photocatalysis) and recruitment of substrate for templated photocatalysis. PMID- 30451339 TI - A Highly Active Ylide-Functionalized Phosphine for Palladium-Catalyzed Aminations of Aryl Chlorides. AB - Ylide-functionalized phosphine ligands (YPhos) were rationally designed to fit the requirements of Buchwald-Hartwig aminations at room temperature. This ligand class combines a strong electron-donating ability comparable to NHC ligands with high steric demand similar to biaryl phosphines. The active Pd species are stabilized by agostic C-H???Pd rather than by Pd-arene interactions. The practical advantage of YPhos ligands arises from their easy and scalable synthesis from widely available, inexpensive starting materials. Benchmark studies showed that YPhos-Pd complexes are superior to the best known phosphine ligands in room-temperature aminations of aryl chlorides. The utility of the catalysts was demonstrated by the synthesis of various arylamines in high yields within short reaction times. PMID- 30451340 TI - Resting-state functional connectivity after concussion is associated with clinical recovery. AB - There has been a recent call for longitudinal imaging studies to better characterize the time course of physiological recovery following sport-related concussion (SRC) and its relationship with clinical recovery. To address this, we evaluated changes to resting-state functional connectivity (rs-FC) of the whole brain network following SRC and explored associations between rs-FC and measures of clinical outcome. High school and collegiate football athletes were enrolled during preseason. Athletes that suffered SRC (N = 62) were assessed across the acute (within 48 hr) and sub-acute (days 8, 15, and 45) phases. Matched football athletes without concussion served as controls (N = 60) and participated in similar visits. Multi-band resting-state fMRI was used to assess whole-brain rs FC at each visit using network-based statistic and average nodal strength from regions of interest defined using a common whole-brain parcellation. Concussed athletes had elevated symptoms, psychological distress, and oculomotor, balance, and memory deficits at 48 hr postconcussion relative to controls, with diminished yet significant elevations in symptoms and psychological distress at 8 days. Both rs-FC analyses showed that concussed athletes had a global increase in connectivity at 8 days postconcussion relative to controls, with no differences at the 48-hr, 15-day, or 45-day visits. Further analysis revealed the group effect at the 8-day visit was driven by the large minority of concussed athletes still symptomatic at their visit; asymptomatic concussed athletes did not differ from controls. Findings from this large-scale, prospective study suggest whole brain rs-FC alterations following SRC are delayed in onset but associated with the presence of self-reported symptoms. PMID- 30451341 TI - Transgenerational lipid-reducing activity of benzylisoquinoline alkaloids in Caenorhabditis elegans. AB - Epigenetic mechanisms allow for transgenerational memory of an ancestor's environment and can affect the gene expression, physiology and phenotype of that ancestor's descendants, independent of DNA sequence alteration. Among many model organisms, Caenorhabditis elegans has been instrumental in studies of transgenerational inheritance, most of which have focused on the effects of external stressors of the parent worm on the lifespan and stress resistance of future generations. In this work, we used Nile red staining of accumulated lipids in C. elegans to investigate the transgenerational effect of two benzylisoquinoline alkaloids, namely, berberine and sanguinarine. Our results showed that a reduction in Nile red fluorescence can be propagated to subsequent worm generations. Using mutant worms, we found that the transgenerational effect requires the ASH-2 component of the histone H3K4me3 complex and the HRDE-1 worm Argonaute protein. Ash-2 is also required for transgenerational inheritance of the xenobiotic response in the worm. Our study offers new insights into transmissible drug effects across multiple generations and suggests the importance of such analyses in the drug development process. This article is protected by copyright. All rights reserved. PMID- 30451342 TI - A randomized clinical trial comparing Nitrofurazone-coated and uncoated urinary catheters in kidney transplant recipients: Results from a pilot study. AB - BACKGROUND: Urinary tract infections are frequent complications early after kidney transplantation, and the use of antimicrobial coated catheters in settings other than transplantation has shown promising results for infection prevention. The purpose of this study was to compare the efficacy of Nitrofurazone-coated silicone urinary catheters with non-impregnated silicone urinary catheters in reducing bacteriuria and urinary tract infections in kidney transplant recipients. METHODS: This single-center study, randomized controlled trial at the Hospital do Rim, a tertiary referral center in kidney transplantation, located in Sao Paulo, Brazil. Subjects involved living donor kidney transplant recipients, and were randomized 1:1 ratio with a computer-generated system to a Nitrofurazone coated silicone urinary catheter and non-impregnated silicone urinary catheter from March 2013 to December 2014. Patients with asymptomatic bacteriuria or urinary tract infection at baseline, deceased kidney transplant donors, patients with known hypersensitivity to nitrofurantoin, pregnancy, and those refusing to sign the informed consent form were excluded from the study. RESULTS: Two hundred fourteen subjects were randomized and one hundred seventy-six completed the study. There were no differences in the rates of asymptomatic bacteriuria (12.5% in the Nitrofurazone group and 11.4% in the control group, P = 0.99) and urinary tract infection (8% and 6.8%, P = 0.99) and the incidence of side effects was more frequent in the Nitrofurazone-impregnated silicone urinary catheter group (46.6% and 26.1%, P = 0.007). CONCLUSION: The study suggests that there is no beneficial effect of the employment of Nitrofurazone-coated urinary catheter. TRIAL REGISTRATION NUMBER: ISRCTN57888785. PMID- 30451343 TI - Discriminating Alzheimer's disease progression using a new hippocampal marker from T1-weighted MRI: The local surface roughness. AB - Hippocampal atrophy is one of the main hallmarks of Alzheimer's disease (AD). However, there is still controversy about whether this sign is a robust finding during the early stages of the disease, such as in mild cognitive impairment (MCI) and subjective cognitive decline (SCD). Considering this background, we proposed a new marker for assessing hippocampal atrophy: the local surface roughness (LSR). We tested this marker in a sample of 307 subjects (normal control (NC) = 70, SCD = 87, MCI = 137, AD = 13). In addition, 97 patients with MCI were followed-up over a 3-year period and classified as stable MCI (sMCI) (n = 61) or progressive MCI (pMCI) (n = 36). We did not find significant differences using traditional markers, such as normalized hippocampal volumes (NHV), between the NC and SCD groups or between the sMCI and pMCI groups. However, with LSR we found significant differences between the sMCI and pMCI groups and a better ability to discriminate between NC and SCD. The classification accuracy of the LSR for NC and SCD was 68.2%, while NHV had a 57.2% accuracy. In addition, the classification accuracy of the LSR for sMCI and pMCI was 74.3%, and NHV had a 68.3% accuracy. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on hippocampal markers and conversion times. The LSR marker showed better prediction of conversion to AD than NHV. These results suggest the relevance of considering the LSR as a new hippocampal marker for the AD continuum. PMID- 30451344 TI - Liquid-based endometrial cytology using SurePathTM is not inferior to suction endometrial tissue biopsy for detecting endometrial malignancies-Midterm report of a multicenter study advocated by Japan Association of Obstetricians and Gynecologists. AB - OBJECTIVE: We conducted a prospective, multicenter study to compare the clinical performance of liquid-based endometrial cytology using SurePathTM with that of the suction endometrial tissue biopsy. This study is officially advocated and reported by the Japan Association of Obstetricians and Gynecologists. By publishing our midterm data, we intend to disseminate the benefits of liquid based endometrial cytology system, using the descriptive reporting format and algorithmic interpretational approach. METHODS: From April 2014 to December 2015, we consecutively assessed 1,116 liquid-based endometrial cytology specimens and 1,044 suction endometrial tissue biopsy specimens in our 5 outpatient clinics. RESULTS: The sensitivity of suction tissue biopsies was 85.2%, whereas the sensitivity of liquid-based endometrial cytology was 92.2%. The specificity of suction tissue biopsies was 98.9%, whereas the specificity of liquid-based endometrial cytology was 98.5%. The negative predictive value of liquid-based endometrial cytology (99.1%) was higher than the negative predictive value of suction endometrial tissue biopsy (98.1%). However, the difference between these values was not significant. CONCLUSIONS: The clinical performance of liquid-based endometrial cytology for detecting endometrial malignancies was almost identical to the performance of suction endometrial tissue biopsy. This indicates that liquid-based endometrial cytology was not inferior to suction endometrial tissue biopsy for the detection of endometrial cancer. The liquid-based endometrial cytology is appropriate for various clinical situations as the first-step detecting tool. In addition, it could be used for cancer surveillance for women with signs highly suggestive of endometrial malignancies and in Lynch syndrome patients, on a larger scale. This article is protected by copyright. All rights reserved. PMID- 30451346 TI - Close look at the Potts shunt flow hemodynamics in a patient with severe pulmonary hypertension: 4D-flow MRI evaluation. PMID- 30451345 TI - Quantitative imaging biomarkers alliance (QIBA) recommendations for improved precision of DWI and DCE-MRI derived biomarkers in multicenter oncology trials. AB - Physiological properties of tumors can be measured both in vivo and noninvasively by diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging. Although these techniques have been used for more than two decades to study tumor diffusion, perfusion, and/or permeability, the methods and studies on how to reduce measurement error and bias in the derived imaging metrics is still lacking in the literature. This is of paramount importance because the objective is to translate these quantitative imaging biomarkers (QIBs) into clinical trials, and ultimately in clinical practice. Standardization of the image acquisition using appropriate phantoms is the first step from a technical performance standpoint. The next step is to assess whether the imaging metrics have clinical value and meet the requirements for being a QIB as defined by the Radiological Society of North America's Quantitative Imaging Biomarkers Alliance (QIBA). The goal and mission of QIBA and the National Cancer Institute Quantitative Imaging Network (QIN) initiatives are to provide technical performance standards (QIBA profiles) and QIN tools for producing reliable QIBs for use in the clinical imaging community. Some of QIBA's development of quantitative diffusion-weighted imaging and dynamic contrast-enhanced QIB profiles has been hampered by the lack of literature for repeatability and reproducibility of the derived QIBs. The available research on this topic is scant and is not in sync with improvements or upgrades in MRI technology over the years. This review focuses on the need for QIBs in oncology applications and emphasizes the importance of the assessment of their reproducibility and repeatability. Level of Evidence: 5 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2018. PMID- 30451347 TI - An Exploration of the Experiences and Educational Needs of Patients With Failed Back Surgery Syndrome Receiving Spinal Cord Stimulation. AB - OBJECTIVE: To explore the experience of spinal cord stimulation (SCS) for patients with failed back surgery syndrome (FBSS). METHODS: Adults with FBSS referred for SCS underwent semistructured interviews at three time points: before their SCS trial, after the trial, and three months after receiving the SCS implant. The face-to-face interviews were audio recorded, transcribed verbatim and analyzed thematically. RESULTS: Twelve adults (8 male, 4 female, aged 38-80 years, pain duration 1-26 years) were recruited. Six themes were identified; 1) What should I expect? 2) Varied outcomes, 3) Understanding pain and this new treatment, 4) Experiences of the SCS journey, 5) Getting used to the device, and 6) Finding out what I need to know. Participants' expectations were varied and the procedures were broadly viewed as minor surgery. Participants' expectations about SCS were not limited to pain relief and included reductions in medication, better sleep, and increased physical activity. Participants' understanding of pain and how SCS purports to work was limited. Throughout the process, practical challenges were identified such as the surgical wound management and battery recharging. Participants received information from multiple sources and identified a range of key information needs including a quick-start guide on how to operate the device and a list of dos and don'ts. CONCLUSIONS: Overall, participants' understanding of SCS was limited. The value participants placed on understanding of the process varied markedly. A list of practical informational needs has been identified. Bespoke, user-friendly, informational tools should be developed from this list to enhance the patient experience of SCS. PMID- 30451348 TI - Screening of bacterial isolates related to olive orchard pests in Tunisia using 16S ribosomal RNA and evaluation of their biotechnological potential. AB - AIM: This study investigated the bacterial diversity of dead insects collected from olive tree orchards widely cultivated in Tunisia. We aimed to explore metabolic diversity, screen enzymatic activities for biotechnological applications and carry out preliminary bioassays for bio-insecticide development. METHODS AND RESULTS: A total of 50 bacteria strains were randomly isolated from 4 different biotopes situated in Sfax (Tunisia). 16S rRNA gene sequencing was used to identify 24 species, and isolates were evaluated for enzymatic activity and antimicrobial potential. Nineteen of the total number of Bacillus strains have enzymatic activity compared to strains from the other genera (14/50). Our bacterial collection was evaluated for antimicrobial potential against bacterial and fungal isolates. Isolates B8-2 (Bacillus subtilis) showed strong antibacterial activities and isolates B2-3 (Bacillus licheniformis) and B10-1 (Serratia marcescens) showed the highest antifungal activity. Seventeen of the total number of isolates caused greater than 50% mortality rate of second and fourth instar larvae of Ephestia kuehniella. CONCLUSION: The selected species from olive orchards represent a broad-spectrum of antimicrobial and insecticidal activities and can be considered promising resources in biological control. SIGNIFICANCE AND IMPACT OF STUDY: Bacteria isolated from olive pests in olive orchards were investigated for detecting their potential biotechnological applications. This article is protected by copyright. All rights reserved. PMID- 30451349 TI - Modelled net carbon gain responses to climate change in boreal trees: impacts of photosynthetic parameter selection and acclimation. AB - Boreal forests are crucial in regulating global vegetation-atmosphere feedbacks, but the impact of climate change on boreal tree carbon fluxes is still unclear. Given the sensitivity of global vegetation models to photosynthetic and respiration parameters, we determined how predictions of net carbon gain (C-gain) respond to variation in these parameters using a stand-level model (MAESTRA). We also modelled how thermal acclimation of photosynthetic and respiratory temperature sensitivity alters predicted net C-gain responses to climate change. We modelled net C-gain of seven common boreal tree species under eight climate scenarios across a latitudinal gradient to capture a range of seasonal temperature conditions. Physiological parameter values were taken from the literature together with different approaches for thermally acclimating photosynthesis and respiration. At high latitudes, net C-gain was stimulated up to 400% by elevated temperatures and CO2 in the autumn but suppressed at the lowest latitudes during mid-summer under climate scenarios that included warming. Modelled net C-gain was more sensitive to photosynthetic capacity parameters (Vcmax , Jmax , Arrhenius temperature response parameters, and the ratio of Jmax to Vcmax ) than stomatal conductance or respiration parameters. The effect of photosynthetic thermal acclimation depended on the temperatures where it was applied: acclimation reduced net C-gain by 10-15% within the temperature range where the equations were derived but decreased net C-gain by 175% at temperatures outside this range. Thermal acclimation of respiration had small, but positive, impacts on net C-gain. We show that model simulations are highly sensitive to variation in photosynthetic parameters and highlight the need to better understand the mechanisms and drivers underlying this variability (e.g. whether variability is environmentally and/or biologically driven) for further model improvement. This article is protected by copyright. All rights reserved. PMID- 30451350 TI - Taxonomic significance of macro and micro-morphology of Geranium L. species Using Scanning Electron Microscopy. AB - Macro and micromorphology of different parts that is, sepals, petals, flowers, indumentum, and leaf shape of 22 Geranium L. taxa from Iran were studied. These taxa representing the eight sections of the genus as sect. Dissecta, sect. Geranium, and sect. Tuberosa (of subgen. Geranium); sect. Batrachioidea, sect. Divaricata, sect. Lucida, sect. Ruberta and sect. Trilopha (of subgen. Robertium), that were collected from different geographical habitats of Iran. The biometric study involved 27 quantitative and 33 qualitative characters which were studied by use of stereomicroscopy and scanning electron microscopy (SEM). Statistical analyses were done by use of PAST software. Principal Component Analysis defined the most variable characters. Results showed that the diagnostic features were; length, width, apex of sepals, petals, trichomes type in pedicles and sepals along with their density, the shape length and width of leaves. In general, the present study revealed that the species could be differentiated by macro and micro-morphological characters. Taxa of two subgenera were clearly separated based on selected characters. These characters were found useful for the taxonomic identification and species delimitation in almost all taxa studied at the sub generic level, although some species of section Geranium and section Dissecta are mixed and nested in both subgenea. PMID- 30451351 TI - November 2018 at a glance: from prediction of heart failure in asymptomatic subjects to advanced chronic heart failure. PMID- 30451352 TI - Synthesis of (+)-Darwinolide, a Biofilm-Penetrating Anti-MRSA Agent. AB - Darwinolide, a recently identified marine natural product from the Antarctic sponge Dendrilla membranosa, was shown to exhibit promising activity against the biofilm phase of methicillin-resistant Staphylococcus aureus. Its challenging tetracyclic rearranged spongian diterpenoid structure links a trimethylcyclohexyl subunit to a seven-membered core with two fused tetrahydrofurans. Here we describe the first synthesis of (+)-darwinolide featuring a convergent aldol fragment coupling, an Ireland-Claisen rearrangement and an organocatalytic desymmetrization as the key steps. Our results provide a foundation for the development of novel antibiofilm-specific antibiotics. PMID- 30451353 TI - Analysis of axial scanning range and magnification variation in wide-field microscope for measurement using an electrically tunable lens. AB - Inserting an electrically tunable lens (ETL), such as liquid lens or tunable acoustic gradient lens, into a microscope can enable fast axial scanning, autofocusing, and extended depth of field. However, placing the ETL at different positions has different influences on image quality. Specially, in a wide-field microscope for measurement, the magnification has to be constant when introducing an ETL, otherwise it will affect measurement accuracy. To determine the best position of ETL, axial scanning range and magnification variation are quantitatively analyzed and discussed in finite and infinite microscopes through theoretical analysis, optical simulation, and experiment for four configurations: when ETL is placed at the back focal plane of objective, at the conjugate plane of objective's back focal plane between two relay lenses, or behind two relay lenses, and at imaging detector plane. The obtained results are as follows. When ETL is placed at the back focal plane, the system has a large scanning range, but the magnification varies because the back focal plane is inside the objective. When ETL is placed between two relay lenses, the magnification stays constant, but the scanning range is small. When ETL is placed behind two relay lenses, the magnification keeps invariant and the scanning range is large, but ETL and two relay lenses are inside the microscope and the system has to be customized. Finally, when ETL is placed at imaging detector plane, the magnification stays constant, but the scanning range is 0, which means the system has no axial scanning capability. RESEARCH HIGHLIGHTS: An electrically tunable lens (ETL) is introduced into a wide-field microscope for measurement. Axial scanning range and magnification variation are analyzed and discussed. Theoretical analysis, ZEMAX optical simulation and experiments are performed. PMID- 30451354 TI - Genome-wide signals of drift and local adaptation during rapid lineage divergence in a songbird. AB - The formation of independent evolutionary lineages involves neutral and selective factors, and understanding their relative roles in population divergence is a fundamental goal of speciation research. Correlations between allele frequencies and environmental variability can reveal the role of selection, yet the relative contribution of drift can be difficult to establish. Recently diversified taxa like the Oregon junco (Aves, Passerellidae, Junco hyemalis oreganus) of western North America provide ideal scenarios to apply genetic-environment association analyses (GEA) while controlling for population structure. Analysis of genome wide SNP loci revealed marked genetic structure consisting of differentiated populations in isolated, dry southern mountain ranges, and less divergent, recently expanded populations in humid northern latitudes. We used correlations between genomic and environmental variance to test for three specific modes of evolutionary divergence: (i) drift in geographic isolation, (ii) differentiation along continuous selective gradients, and (iii) isolation by adaptation. We found evidence of strong drift in southern mountains, but also signals of local adaptation driven by temperature, precipitation, elevation and vegetation, especially when controlling for population history. We identified numerous variants under selection scattered across the genome, suggesting that local adaptation can promote rapid differentiation when acting over multiple independent loci. This article is protected by copyright. All rights reserved. PMID- 30451355 TI - New archaeal viruses discovered by metagenomic analysis of viral communities in enrichment cultures. AB - Viruses infecting hyperthermophilic archaea of the phylum Crenarchaeota display enormous morphological and genetic diversity, and are classified into 12 families. Eight of these families include only one or two species, indicating sparse sampling of the crenarchaeal virus diversity. In an attempt to expand the crenarchaeal virome, we explored virus diversity in the acidic, hot spring Umi Jigoku in Beppu, Japan. Environmental samples were used to establish enrichment cultures under conditions favoring virus replication. The host diversity in the enrichment cultures was restricted to members of the order Sulfolobales. Metagenomic sequencing of the viral communities yielded 7 complete or near complete double-stranded DNA virus genomes. Six of these genomes could be attributed to polyhedral and filamentous viruses that were observed by electron microscopy in the enrichment cultures. Two icosahedral viruses represented species in the family Portogloboviridae. Among the filamentous viruses, two were identified as new species in the families Rudiviridae and Lipothrixviridae, whereas two other formed a group seemingly distinct from the known virus genera. No particle morphotype could be unequivocally assigned to the seventh viral genome, which apparently represents a new virus type. Our results suggest that filamentous viruses are globally distributed and are prevalent virus types in extreme geothermal environments. This article is protected by copyright. All rights reserved. PMID- 30451356 TI - Targeting Vacancies in Nitridosilicates: Aliovalent Substitution of M2+ (M = Ca,Sr) by Sc3+ and U3. AB - Based on the known linking options of their fundamental building unit, i.e. SiN4 tetrahedra, nitridosilicates belong to the inorganic compound classes with the greatest structural variability. Although facilitating the discovery of novel Si N networks, this variability represents a challenge when targeting non stoichometric compounds. Meeting this challenge, we report on a strategy for targeted creation of vacancies in highly condensed nitridosilicates by exchanging divalent M2+ by trivalent M3+ via the ion exchange approach. As proof of concept, the first Sc and U nitridosilicates were prepared from alpha-Ca2Si5N8 and Sr2Si5N8. Powder X-ray diffraction (XRD) and synchrotron single-crystal XRD showed random vacancy distribution in Sc0.2Ca1.7Si5N8 and partial vacancy ordering in U0.5xSr2-0.75xSi5N8 with x ~ 1.05. The high chemical stability of U nitridosilicates makes them interesting candidates for immobilization of actinides. PMID- 30451357 TI - Protein profiling of fine needle aspirates reveals subtype-associated immune signatures and involvement of chemokines in breast cancer. AB - There are increasing demands for informative cancer biomarkers, accessible via minimally invasive procedures, both for initial diagnostics and follow-up of personalized cancer therapy, including immunotherapy. Fine needle aspiration (FNA) biopsy provides ready access to relevant tissue samples; however, the minute amounts of sample require sensitive multiplex molecular analysis to be of clinical biomarker utility. We have applied proximity extension assays (PEA) to analyze 167 proteins in FNA samples from patients with breast cancer (BC; n=25) and benign lesions (n=32). We demonstrate that the FNA BC samples could be divided into two main clusters, characterized by differences in expression levels of the estrogen receptor (ER) and the proliferation marker Ki67. This clustering corresponded to some extent to established BC subtypes. Our analysis also revealed several proteins whose expression levels differed between BC and benign lesions (e.g. CA9, GZMB, IL6, VEGFA, CXCL11, PDL1 and PCD1), as well as several chemokines correlating with ER and Ki67 status (e.g. CCL4, CCL8, CCL20, CXCL8, CXCL9 and CXCL17). Finally, we also identified three signatures that could predict Ki67 status, ER status and tumor grade, respectively, based on a small subset of proteins, which was dominated by chemokines. To our knowledge, expression profiles of CCL13 in benign lesions and BC have not previously been described but were shown herein to correlate with proliferation (p=0.00095), suggesting a role in advanced BC. Given the broad functional range of the proteins analyzed, immune-related proteins were overrepresented among the observed alterations. Our pilot study supports the emerging role of chemokines in BC progression. Due to the minimally traumatic sampling and clinically important molecular information for therapeutic decisions, this methodology is promising for future immunoscoring and monitoring of treatment efficacy in BC. PMID- 30451359 TI - The signal pathway for the repressive effect of dipyridamole on myofibroblast transdifferentiation. PMID- 30451358 TI - Morphological dissection and cellular and transcriptome characterizations of bamboo pith cavity formation reveal a pivotal role of genes related to programmed cell death. AB - Pith cavity formation is critical for bamboo to overcome the bending force during its fast growth; however, the underlying molecular mechanisms remain largely unknown. Multiple approaches, including anatomical dissection, mathematical modelling and transcriptome profiling, were employed in this study to investigate the biology of pith cavity formation in bamboo Pseudosasa japonica. We found that the corruption of pith tissue occurred sequentially and asymmetrically from the top-center of the internode down to the bottom, which might be caused by the combined effects of asymmetrical radial and axial tensile forces during shoot wall cell elongation and spiral growth of bamboo internodes. Programmed cell death (PCD) in pitch manifested by TUNEL positive nuclei, DNA cleavage and degraded organelles, and potentially regulated by ethylene and calcium signaling pathway, ROS burst, cell wall modification, proteolysis and nutrient recycle genes, might be responsible for pith tissue corruption of Ps. japonica. Although similar physiological changes and transcriptome profiles were found in different bamboo species, different formation rates of pith cavity were observed, which might be caused by different pith cells across the internode that were negatively correlated with the culm diameter. These findings provided a systematical view on the formation of bamboo pith cavity and revealed that PCD plays an important role in the bamboo pith cavity formation. This article is protected by copyright. All rights reserved. PMID- 30451361 TI - Tracking conformational changes in phosvitin throughout a crowding agent based titration. AB - In this paper, the sensitivity of Raman optical activity (ROA) towards small conformational changes is explored by tracking the structural changes in an intrinsically disordered protein, phosvitin, caused by different concentrations of crowding agent. It is shown that ROA is capable of tracking small conformational changes towards beta-sheet and alpha-helical secondary structural properties of the protein. Furthermore, it is indicated that the influence of the crowding agents Ficoll 70 and dextran 70 used on the structural properties of phosvitin differs significantly, with the structural changes induced by the presence of Ficoll 70 being more pronounced and being already visible at a lower concentration. The data also suggests that some spectral changes do not arise from a change in the secondary structure of the protein, but are related to differences in interaction between the phosphorylated residues of the protein and the sugar-based crowding agent. PMID- 30451360 TI - Evodiamine inhibits RANKL-induced osteoclastogenesis and prevents ovariectomy induced bone loss in mice. AB - Postmenopausal osteoporosis (PMO) is a progressive bone disease characterized by the over-production and activation of osteoclasts in elderly women. In our study, we investigated the anti-osteoclastogenic effect of evodiamine (EVO) in vivo and in vitro, as well as the underlying mechanism. By using an in vitro bone marrow macrophage (BMM)-derived osteoclast culture system, we found that EVO inhibited osteoclast formation, hydroxyapatite resorption and receptor activator of NF kappaB ligand (RANKL)-induced osteoclast marker gene and protein expression. Mechanistically, we found that EVO inhibited the degradation and RANKL-induced transcriptional activity of IkappaBalpha. RANKL-induced Ca2+ oscillations were also abrogated by EVO. In vivo, an ovariectomized (OVX) mouse model was established to mimic PMO, and OVX mice received oral administration of either EVO (10 mg/kg) or saline every other day. We found that EVO can attenuate bone loss in OVX mice by inhibiting osteoclastogenesis. Taken together, our findings suggest that EVO suppresses RANKL-induced osteoclastogenesis through NF-kappaB and calcium signalling pathways and has potential value as a therapeutic agent for PMO. PMID- 30451362 TI - Dual Gold-Catalyzed Cycloaromatization of Unconjugated (E)-Enediynes. AB - A synthesis of novel unconjugated (E)-enediynes from allenyl amino alcohols is reported and their gold-catalyzed cascade cycloaromatization to a broad range of enantioenriched substituted isoindolinones developed. Experimental and computational studies support the reaction proceeding via a dual-gold sigma,pi activation mode involving a key gold-vinylidene and allenyl-gold containing intermediate. PMID- 30451363 TI - Unveiling Ga(III) phthalocyanine-a different photosensitizer in neuroblastoma cellular model. AB - Phthalocyanines (Pc) and their metallated derivatives are strongly considered for photodynamic therapy (PDT) possessing unique properties as possible new photosensitizers (PS). We have used toxicological assessments, real-time monitoring of cellular impedance, and imagistic measurements for assessing the in vitro dark toxicity and PDT efficacy of Ga(III)-Pc in SHSy5Y neuroblastoma cells. We have established the non-toxic concentration range of Ga(III)-Pc, a compound which shows a high intracellular accumulation, with perinuclear distribution in confocal microscopy. By choosing Ga(III)Pc non-toxic dose, we performed in vitro experimental PDT hampering cellular proliferation. Our proposed Ga(III)-Pc could complete a future PS panel for neuroblastoma alternate therapy. PMID- 30451364 TI - A Flow Cytometric Study of ER Stress and Autophagy. AB - The mechanistic link between ER stress, autophagy, and resultant cell death was investigated by the use of drugs Thapsigargin (Tg) and Chloroquine (CQ) with prior induction and or blockade of autophagy and apoptosis which modulated the ER stress response and resultant form of cell death. All these biological processes can be measured flow cytometrically allowing the determination of the type of cell death, G1 cell cycle arrest, cell cycle dependent measurement of ER stress transducer PERK, misfolded proteins, reticulophagy, and autophagy marker LC3B. Jurkat cells after Tg or CQ treatment became necrotic and apoptotic, showed G1 cell cycle arrest, autophagy, and ER stress. Prior induction of autophagy before ER stress increased levels of necrotic and apoptotic cell death. Autophagy was further up-regulated, while PERK was reduced or abrogated. CQ showed reduced levels of misfolded proteins and reticulophagy, while Tg showed no change in misfolded protein levels but increased reticulophagy and thus displayed more ER stress. Prior blockade of apoptosis before induction of ER stress resulted in cell survival except with high Tg levels which induced necrosis. Autophagy was up regulated with modulation of PERK and reticulophagy levels with an abrogation of the misfolded protein response. Blockade of apoptosis with induction of autophagy before ER stress showed death by necrosis with high dose drugs and cell survival with low doses of drugs. CQ induced reduced levels G1 cell cycle arrest while it was maintained with Tg. Autophagy was also maintained with reduced levels of ER stress. These data demonstrates a profound link between the processes of ER stress, autophagy, and the resultant form of cell death all of which can be modulated depending upon the sequence and concentration of drugs employed. (c) 2018 International Society for Advancement of Cytometry. PMID- 30451365 TI - Intricate crosstalk between MYC and non-coding RNAs regulates hallmarks of cancer. AB - Myelocytomatosis viral oncogene homolog (MYC) plays an important role in the regulation of many cellular processes, and its expression is tightly regulated at the level of transcription, translation, protein stability, and activity. Despite this tight regulation, MYC is overexpressed in many cancers and contributes to multiple hallmarks of cancer. In recent years, it has become clear that noncoding RNAs add a crucial additional layer to the regulation of MYC and its downstream effects. So far, twenty-five microRNAs and eighteen long noncoding RNAs that regulate MYC have been identified. Thirty-three miRNAs and nineteen lncRNAs are downstream effectors of MYC that contribute to the broad oncogenic role of MYC, including its effects on diverse hallmarks of cancer. In this review, we give an overview of this extensive, multilayered noncoding RNA network that exists around MYC. Current data clearly show explicit roles of crosstalk between MYC and ncRNAs to allow tumorigenesis. PMID- 30451366 TI - Is short root anomaly (SRA) a risk factor for increased external apical root resorption in orthodontic patients? A retrospective case control study using cone beam computerized tomography. AB - OBJECTIVES: To compare the amount of external apical root resorption (EARR) secondary to orthodontic treatment in patients with Short Root Anomaly (SRA) compared to patients with average root lengths using Cone Beam Computed Tomography (CBCT). SETTINGS AND SAMPLE POPULATION: CBCT scans of 23 SRA and 26 control patients selected from 232 pretreatment scans from a single private practice. MATERIALS AND METHODS: CBCT scans before (T1) and after orthodontic treatment (T2) were evaluated for differences in the change in tooth and root length of the maxillary incisors between both groups. Gender, treatment duration, and age were examined as covariates. RESULTS: The mean values for root and tooth length of the maxillary incisors decreased by a range of 0.6 to 1.3 mm after orthodontic treatment. There was no significant difference between the groups for the majority of the measurements although there was a trend for less EARR in the SRA group. The maxillary left central incisor had significantly less proportional and non-proportional loss in tooth length in the SRA group. Age, gender, and treatment duration were not associated with change in the proportional and non proportional lengths for both groups. CONCLUSION: Patients with SRA did not exhibit a significant difference in the proportional and non-proportional change of length after orthodontic treatment when compared to the controls for most measurements. Only tooth length for the maxillary left central incisor had significantly less reduction after orthodontic treatment for both the proportional and non-proportional measurements in the SRA group compared to the control group. This article is protected by copyright. All rights reserved. PMID- 30451367 TI - TaCIPK10 interacts with and phosphorylates TaNH2 to activate wheat defense responses to stripe rust. AB - Calcineurin B-like interacting protein kinase (CIPKs) has been shown to be required for biotic stress tolerance of plants in plant-pathogen interactions. However, the roles of CIPKs in immune signalling of cereal crops and an in-depth knowledge of substrates of CIPKs in response to biotic stress are under debate. In this study, we identified and cloned a CIPK homologue gene TaCIPK10 from wheat. TaCIPK10 was rapidly induced by Puccinia striiformis f. sp. tritici (Pst) inoculation and salicylic acid (SA) treatment. In vitro phosphorylation assay demonstrated that the kinase activity of TaCIPK10 is regulated by Ca2+ and TaCBL4. Knockdown TaCIPK10 significantly reduced wheat resistance to Pst, whereas TaCIPK10 overexpression resulted in enhanced wheat resistance to Pst by the induction of defense response in different aspects, including hypersensitive cell death, ROS accumulation and pathogenesis-relative genes expression. Moreover, TaCIPK10 physically interacted with and phosphorylated TaNH2, which was homologous to AtNPR3/4. Silencing of TaNH2 in wheat resulted in enhanced susceptibility to the avirulent Pst race, CYR23, indicating its positive role in wheat resistance. Our results demonstrate that TaCIPK10 positively regulate wheat resistance to Pst as molecular links between of Ca2+ and downstream components of defense response and TaCIPK10 interacts with and phosphorylates TaNH2 to regulate wheat resistance to Pst. PMID- 30451368 TI - Otx2 enhances transdifferentiation of Muller cells-derived retinal stem cells into photoreceptor-like cells. AB - Retinal Muller glial cells have the potential of neurogenic retinal progenitor cells, and could reprogram into retinal-specific cell types such as photoreceptor cells. How to promote the differentiation of Muller cells into photoreceptor cells represents a promising therapy strategy for retinal degeneration diseases. This study aimed to enhance the transdifferentiation of rat Muller cells-derived retinal stem cells (MC-RSCs) into photoreceptor-like cells and explore the signalling mechanism. We dedifferentiated rat Muller cells into MC-RSCs which were infected with Otx2 overexpression lentivirus or control. The positive rate of photoreceptor-like cells among MC-RSCs treated with Otx2 overexpression lentivirus was significantly higher compared to control. Furthermore, pre treatment with Crx siRNA, Nrl siRNA, or GSK-3 inhibitor SB-216763 reduced the positive rate of photoreceptor-like cells among MC-RSCs treated with Otx2 overexpression lentivirus. Finally, Otx2 induced photoreceptor precursor cells were injected into subretinal space of N-methyl-N-nitrosourea induced rat model of retinal degeneration and partially recovered retinal degeneration in the rats. In conclusion, Otx2 enhances transdifferentiation of MC-RSCs into photoreceptor like cells and this is associated with the inhibition of Wnt signalling. Otx2 is a potential target for gene therapy of retinal degenerative diseases. PMID- 30451369 TI - Isolation of amaranthin synthetase from Chenopodium quinoa and construction of an amaranthin production system using suspension-cultured tobacco BY-2 cells. AB - Betalains are plant pigments primarily produced by plants of the order Caryophyllales. Because betalain possesses anti-inflammatory and anticancer activities, it may be useful as a pharmaceutical agent and dietary supplement. Recent studies have identified the genes involved in the betalain biosynthesis of betanin. Amaranthin and celosianin II are abundant in the quinoa (Chenopodium quinoa Willd.) hypocotyl, and amaranthin comprises glucuronic acid bound to betanin; therefore, this suggests the existence of a glucuronyltransferase involved in the synthesis of amaranthin in the quinoa hypocotyl. To identify the gene involved in amaranthin biosynthesis, we performed a BLAST analysis and phylogenetic tree analysis based on sequences homologous to flavonoid glycosyltransferase, followed by expression analysis on the quinoa hypocotyl to obtain three candidate proteins. Production of amaranthin in a transient Nicotiana benthamiana expression system was evaluated for these candidates and one was identified as having the ability to produce amaranthin. The gene encoding this protein was quinoa amaranthin synthetase 1 (CqAmaSy1). We also created a transgenic tobacco bright yellow-2 (BY-2) cell line wherein four betalain biosynthesis genes were introduced to facilitate amaranthin production. This transgenic cell line produced 13.67 +/- 4.13 MUm (mean +/- SEM) amaranthin and 26.60 +/- 1.53 MUm betanin, whereas the production of isoamaranthin and isobetanin could not be detected. Tests confirmed the ability of amaranthin and betanin to slightly suppress cancer cell viability. Furthermore, amaranthin was shown to significantly inhibit HIV-1 protease activity, whereas betanin did not. PMID- 30451370 TI - Metformin relieves neuropathic pain after spinal nerve ligation via autophagy flux stimulation. AB - Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c-Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain. PMID- 30451371 TI - Extracellular Vesicles from Neurosurgical Aspirates Identifies Chaperonin Containing TCP1 Subunit 6A (CCT6A) as a Potential Glioblastoma Biomarker with Prognostic Significance. AB - Glioblastoma, WHO-grade IV glioma, carries a dismal prognosis owing to its infiltrative growth and limited treatment options. Glioblastoma-derived extracellular vesicles (EVs; 30-1000nm membranous particles) influence the microenvironment to mediate tumour aggressiveness and carry oncogenic cargo across the blood-brain-barrier into the circulation. As such, EVs are biomarker reservoirs with enormous potential for assessing glioblastoma tumours in situ. Neurosurgical aspirates are rich sources of EVs, isolated directly from glioma microenvironments. Quantitative LC-MS/MS compared EV proteomes enriched from glioblastoma (n = 15) and glioma grade II-III (n = 7) aspirates and identified 298 differentially-abundant proteins (p-value<0.00496). Along with previously reported glioblastoma-associated biomarkers, levels of all eight subunits of the key molecular chaperone, T-complex protein 1 Ring complex (TRiC), were higher in glioblastoma-EVs, including CCT2, CCT3, CCT5, CCT6A, CCT7 and TCP1 (p<0.00496). Analogous increases in TRiC transcript levels and DNA copy numbers were detected in silico; CCT6A had the greatest induction of expression and amplification in glioblastoma and showed a negative association with survival (p = 0.006). CCT6A is co-localised with EGFR at 7p11.2, with a strong tendency for co-amplification (p<0.001). Immunohistochemistry corroborated the CCT6A proteomics measurements and indicated a potential link between EGFR and CCT6A tissue expression. Putative EV-biomarkers described here should be further assessed in peripheral blood. This article is protected by copyright. All rights reserved. PMID- 30451372 TI - Increased urokinase and consumption of alpha2 -antiplasmin as an explanation for the loss of benefit of tranexamic acid after treatment delay. AB - BACKGROUND: Tranexamic acid (TXA) is an effective antifibrinolytic agent, with a proven safety record. However, large clinical trials show TXA becomes ineffective or harmful if treatment is delayed beyond 3 hours. The mechanism is unknown but urokinase plasminogen activator (uPA) has been implicated. METHODS: Inhibitory mechanisms of TXA were explored in a variety of clot lysis systems using plasma and whole blood. Lysis by tissue plasminogen activator (tPA), uPA and plasmin were investigated. Coagulopathy was investigated using ROTEM and activated partial thromboplastin time (APTT). RESULTS: IC50 values for antifibrinolytic activity of TXA varied from <10 MUM to >1000 MUM depending on the system, but good fibrin protection was observed in the presence of tPA, uPA and plasmin. However, in plasma or blood, active plasmin was generated by TXA+uPA (but not tPA) and coagulopathy developed leading to no, or poor clot formation. The extent of coagulopathy was sensitive to available alpha2 -antiplasmin. No clot formed with plasma containing 40% normal alpha2 -antiplasmin, after short incubation with TXA+uPA. Adding purified alpha2 -antiplasmin progressively restored clotting. Plasmin could be inhibited by aprotinin, IC50 =530 nM, in plasma. CONCLUSIONS: TXA protects fibrin but stimulates uPA activity and slows inhibition of plasmin by alpha2 -antiplasmin. Plasmin proteolytic activity digests fibrinogen and disrupts coagulation, exacerbated when alpha2 -antiplasmin is consumed by ongoing fibrinolysis. Additional direct inhibition of plasmin by aprotinin may prevent development of coagulopathy and extend the useful time window of TXA treatment. This article is protected by copyright. All rights reserved. PMID- 30451373 TI - In situ Study Unravels Bio-Nanomechanical Behavior in a Magnetic Bacterial Nano cellulose (MBNC) Hydrogel for Neuro-Endovascular Reconstruction. AB - Surgical clipping and endovascular coiling are well recognized as conventional treatments of Penetrating Brain Injury aneurysms. These clinical approaches show partial success, but often result in thrombus formation and the rupture of aneurysm near arterial walls. The authors address these challenging brain traumas with a unique combination of a highly biocompatible biopolymer hydrogel rendered magnetic in a flexible and resilient membrane coating integrated to a scaffold stent platform at the aneurysm neck orifice, which enhances the revascularization modality. This work focuses on the in situ diagnosis of nano-mechanical behavior of bacterial nanocellulose (BNC) membranes in an aqueous environment used as tissue reconstruction substrates for cerebral aneurysmal neck defects. Nano mechanical evaluation, performed using instrumented nano-indentation, shows with very low normal loads between 0.01 to 0.5 mN, in the presence of deionized water. Mechanical testing and characterization reveals that the nano-scale response of BNC behaves similar to blood vessel walls with a very low Young's modulus, E (0.0025 to 0.04 GPa), and an evident creep effect (26.01 +/- 3.85 nm s-1 ). These results confirm a novel multi-functional membrane using BNC and rendered magnetic with local adhesion of iron-oxide magnetic nanoparticles. PMID- 30451374 TI - Chronic administration of theobromine inhibits mTOR signal in rats. AB - Theobromine is a caffeine derivative and the primary methylxanthine in Theobroma cacao. We have shown previously that theobromine inhibits the Akt-mammalian target of rapamycin (mTOR) signal in vitro. In this study, we investigated whether orally administered theobromine could inhibit mTOR activity in rats. mTOR is phosphorylated by Akt. Thus, the level of phosphorylated mTOR was used as an index of mTOR activity. Male Wistar rats were divided into two groups. The control group (CN) was fed a normal diet, while the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 40 days. We measured body and tissue weights, food and water intake, blood count, concentrations of theobromine in the plasma, liver and brain, and the levels of phosphorylated mTOR in the liver and brain. Orally administered theobromine did not affect the body and tissue weights, food and water intake, and blood count as determined by comparison with levels in rats that were fed standard chow. Theobromine was detected in the plasma, liver and brain obtained from TB rats, but was not detected in tissues obtained from CN rats. The phosphorylated mTOR levels in the liver and brain were significantly lower in TB rats than in CN rats. The results suggest that oral theobromine inhibits mTOR signalling in vivo. This article is protected by copyright. All rights reserved. PMID- 30451375 TI - Predictors and rates of recurrence of atrial arrhythmias following catheter ablation in adults with congenital heart disease. AB - BACKGROUND: Catheter ablation is commonly performed to treat atrial arrhythmias in adult congenital heart disease (ACHD). Despite the frequency of ablations in the ACHD population, predictors of recurrence remain poorly defined. OBJECTIVE: We sought to determine predictors of arrhythmia recurrence in ACHD patients following catheter ablation for atrial arrhythmias. METHODS: We performed a retrospective study of all catheter ablations for atrial arrhythmias performed in ACHD patients between January 12, 2005 and February 11, 2015 at our institution. Prespecified exposures of interest and time from ablation to recurrence were determined via chart review. RESULTS: Among 124 patients (mean age: 45 years) who underwent catheter ablation, 96 (77%) were treated for macro-reentrant atrial tachycardia, 10 (7%) for focal atrial tachycardia, 9 (7%) for atrial fibrillation, 7 (6%) for atrioventricular nodal reentrant tachycardia, and 2 (2%) for atrioventricular reentrant tachycardia. 15 (12%) required transseptal/transbaffle puncture. Fifty-one percent of patients recurred with a median time to recurrence of 1639 days. By univariate and multivariable analysis, body mass index (BMI) and Fontan status were the only variables associated with recurrence. Dose-dependent effect was observed with overweight (HR = 2.37, P = .012), obese (HR = 2.67, P = .009), and morbidly obese (HR = 4.23, P = .003) patients demonstrating an increasing risk for arrhythmia recurrence postablation. There was no significant different in recurrence rates by gender, age, non-Fontan diagnosis, or need for transseptal puncture. CONCLUSIONS: In our cohort of ACHD patients, BMI was a significant risk factor for arrhythmia recurrence postablation, independent of Fontan status. These findings may help guide treatment decisions for persistent arrhythmias in the ACHD population. PMID- 30451376 TI - Suppressing Protein Z-Dependent Inhibition of Factor Xa Improves Coagulation in Hemophilia A. AB - BACKGROUND: Hemostasis requires a balance between pro- and anti-coagulant factors. Hemophiliacs bleed due to a procoagulant deficiency. The targeted reduction in the activity of endogenous anticoagulant pathways is currently being investigated as a means of improving hemostasis in hemophilia. Protein Z (PZ) is a co-factor that serves as a catalyst for PZ-dependent protease inhibitor (ZPI) inactivation of factor (F)Xa at phospholipid surfaces. OBJECTIVES: Evaluate the effects of 1) PZ or ZPI gene-deletion in hemophilia mice and 2) blocking PZ in human hemophilic plasma. METHODS: 1) A Tail Vein Re-Bleeding assay (TVRB) was developed based on the serial disruption of clots forming over 15 minutes following a tail vein laceration in an anesthetized mouse. Wild type (WT)/FVIIIKO, PZKO/FVIIIKO and ZPIKO/FVIIIKO mice were evaluated in this model and their plasmas tested in thrombin generation assays. 2) A monoclonal antibody (Mab) against PZ was evaluated in human hemophilic plasma thrombin generation assays. RESULTS: 1) Clot formations (mean + SEM) in the TVRB were: 4.0 + 0.9 for WT/FVIIIKO mice; 23.8 + 1.1 for WT/FVIIIKO mice replaced with 100% FVIII; 15.2 + 1.1 for PZKO/FVIIIKO mice; and 14.7 + 1.2 for ZPIKO/FVIIIKO mice. Thrombin generation in PZKO/FVIIIKO and ZPIKO/FVIIIKO mouse plasmas was similar to FVIIIKO plasma replaced with ~15% rFVIII, 2) A Mab against PZ added to human hemophilia plasma enhanced thrombin generation to an extent similar to the addition of ~15% FVIII. CONCLUSIONS: Blockade of the PZ/ZPI system may be sufficient to ameliorate the phenotype of severe hemophilia. This article is protected by copyright. All rights reserved. PMID- 30451377 TI - Terminal deoxynucleotidyl transferase in synthesis and modification of nucleic acids. AB - The terminal deoxynucleotidyl transferase (TdT) belongs to the X Family of DNA polymerases. This unusual polymerase catalyzes the template-independent addition of random nucleotides on 3'-overhangs during V(D)J recombination. The biological function and intrinsic biochemical properties of the TdT have spurred the development of numerous oligonucleotide-based tools and methods especially when combined with modified nucleoside triphosphates. Here, we summarize the different applications stemming from the incorporation of modified nucleotides by the TdT. We also discuss the structural, mechanistic, and biochemical properties of this polymerase. PMID- 30451379 TI - Increased oxidative stress and CaMKII activity contribute to electro-mechanical defects in cardiomyocytes from a murine model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative genetic disorder. Although described as a brain pathology, there is evidence suggesting that defects in other systems can contribute to disease progression. In line with this, cardiovascular defects are a major cause of death in HD. To date, relatively little is known about the peripheral abnormalities associated with the disease. Here, we applied a range of assays to evaluate cardiac electro-mechanical properties in vivo, using a previously characterized mouse model of HD (BACHD), and in vitro, using cardiomyocytes isolated from the same mice. We observed conduction disturbances including QT interval prolongation in BACHD mice, indicative of cardiac dysfunction. Cardiomyocytes from these mice demonstrated cellular electro-mechanical abnormalities, including a prolonged action potential, arrhythmic contractions, and relaxation disturbances. Cellular arrhythmia was accompanied by an increase in calcium waves and increased Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity, suggesting that disruption of calcium homeostasis plays a key part. We also describe structural abnormalities in the mitochondria of BACHD-derived cardiomyocytes, indicative of oxidative stress. Consistent with this, imbalances in superoxide dismutase and glutathione peroxidase activities were detected. Our data provide an in vivo demonstration of cardiac abnormalities in HD together with new insights into the cellular mechanistic basis, providing a possible explanation for the higher cardiovascular risk in HD. This article is protected by copyright. All rights reserved. PMID- 30451380 TI - First evidence of cytotoxic effects of human protozoan parasites on zebra mussel (Dreissena polymorpha) hemocytes. AB - The interaction between human protozoan parasites and the immune cells of bivalves, that can accumulate them, is poorly described. The purpose of this study is to consider the mechanisms of action of some of these protozoa on zebra mussel hemocytes, by evaluating their cytotoxic potential. Hemocytes were exposed to Toxoplasma gondii, Giardia duodenalis or Cryptosporidium parvum (oo)cysts. The results showed a cytotoxic potency of the two largest protozoa on hemocytes, and suggested the formation of hemocyte aggregates. Thus, this study reveals the first signs of a hemocyte:protozoan interaction. This article is protected by copyright. All rights reserved. PMID- 30451381 TI - Vasopressor magnitude predicts poor outcome in adults with congenital heart disease after cardiac surgery. AB - BACKGROUND: High levels of vasoactive inotrope support (VIS) after congenital heart surgery are predictive of morbidity in pediatric patients. We sought to discern if this relationship applies to adults with congenital heart disease (ACHD). METHODS: We retrospectively studied adult patients (>=18 years old) admitted to the intensive care unit after cardiac surgery for congenital heart disease from 2002 to 2013 at Mayo Clinic. Vasoactive medication dose values within 96 hours of admission were examined to determine the relationship between VIS score and poor outcome of early mortality, early morbidity, or complication related morbidity. RESULTS: Overall, 1040 ACHD patients had cardiac surgery during the study time frame; 243 (23.4%) met study inclusion criteria. Sixty-two patients (25%), experienced composite poor outcome [including eight deaths within 90 days of hospital discharge (3%)]. Thirty-eight patients (15%) endured complication related early morbidity. The maximum VIS (maxVIS) score area under the curve was 0.92 (95% CI: 0.86-0.98) for in-hospital mortality; and 0.82 (95% CI: 0.76-0.89) for combined poor clinical outcome. On univariate analysis, maxVIS score >=3 was predictive of composite adverse outcome (OR: 14.2, 95% CI: 7.2 28.2; P < 0.001), prolonged ICU LOS ICU LOS (OR: 19.2; 95% CI: 8.7-42.1; P < 0.0001), prolonged mechanical ventilation (OR: 13.6; 95% CI: 4.4-41.8; P < 0.0001) and complication related morbidity (OR: 7.3; 95% CI: 3.4-15.5; P < 0.0001). CONCLUSIONS: MaxVIS score strongly predicted adverse outcomes and can be used as a risk prediction tool to facilitate early intervention that may improve outcome and assist with clinical decision making for ACHD patients after cardiac surgery. PMID- 30451382 TI - Glucose-dependent insulinotropic polypeptide deficiency reduced fat accumulation and insulin resistance but deteriorated bone loss in ovariectomized mice. AB - Given the established roles of glucose-dependent insulinotropic polypeptide (GIP) in promoting fat storage and bone formation, we assessed the contribution of GIP to obesity and osteopenia in ovariectomized mice with a gene encoding green fluorescent protein (GFP) inserted into the GIP locus, in which GIP was either reduced (GIPgfp/+ ) or absent (GIPgfp/gfp ). In GIPgfp/gfp mice, weight gain, subcutaneous and visceral fat mass were reduced and glucose intolerance was improved compared to wild-type (WT) mice with the same magnitude of insulin responses. Cancellous bone mineral density and bone cortical thickness were reduced in GIPgfp/gfp mice compared to WT mice. In GIPgfp/+ mice, weight gain, glucose intolerance and cancellous bone mineral density were not different from that of WT mice. These results indicate that the total elimination of GIP ameliorates weight gain and adiposity in ovariectomized mice, but it enhances osteopenia, particularly in cancellous bone by partly suppressing bone formation. This article is protected by copyright. All rights reserved. PMID- 30451383 TI - Embryonic cell migratory capacity is impaired upon exposure to glucose in vivo and in vitro. AB - BACKGROUND: Impairments in cell migration during vertebrate gastrulation lead to structural birth defects, such as heart defects and neural tube defects. These defects are more frequent in progeny from diabetic pregnancies, and we have recently provided evidence that maternal diabetes leads to impaired migration of embryonic mesodermal cells in a mouse model of diabetic pregnancy. METHODS: We here report the isolation of primary cell lines from normal and diabetes-exposed embryos of the nonobese diabetic mouse strain, and characterization of their energy metabolism and expression of nutrient transporter genes by quantitative real-time PCR. RESULTS: Expression levels of several genes in the glucose transporter and fatty acid transporter gene families were altered in diabetes exposed cells. Notably, primary cells from embryos with prior in vivo exposure to maternal diabetes exhibited reduced capacity for cell migration in vitro. CONCLUSIONS: Primary cells isolated from diabetes-exposed embryos retained a "memory" of their in vivo exposure, manifesting in cell migration impairment. Thus, we have successfully established an in vitro experimental model for the mesoderm migration defects observed in diabetes-exposed mouse embryos. PMID- 30451385 TI - Standard abbreviations. PMID- 30451384 TI - The role of hippocampus in the retrieval of autobiographical memories in patients with amnestic Mild Cognitive Impairment due to Alzheimer's disease. AB - The role of the hippocampus and neocortical areas in the retrieval of past memories in pre-dementia Alzheimer's disease (AD) patients was investigated. The aim was to assess whether the hippocampus has a temporary role in memory trace formation, according to the Cortical Reallocation Theory (CRT), or whether it continuously updates and enriches memories, according to the Multiple Trace Theory. According to the former theory, hippocampal damage should affect more recent memories, whereas the association cortex is expected to affect memories of the entire lifespan. In the second case, damage to either the hippocampus or the association cortices should affect memories of the entire lifespan. Seventeen patients with amnestic Mild Cognitive Impairment due to AD were submitted to autobiographical (i.e., episodic and semantic personal) memory assessment. Patients underwent MRI for the acquisition of T1-weighted brain volumes. Voxel based morphometry was used to assess correlations between grey matter (GM) volumes and autobiographical memory. Correlation analyses revealed a strict association between GM volumes in the hippocampus and patients' ability to retrieve the most recent but not the oldest autobiographical memories in both aspects, episodic and semantic. Moreover, patients' GM volumes in the pre-frontal and temporal polar areas were associated with recollection of episodic and semantic events, respectively. Finally, GM volumes in the precuneus and occipital cortex were associated with retrieval of the most recent episodic events. These findings indicate that the hippocampus has a specific time-dependent role; thus, they support the CRT. PMID- 30451386 TI - Secular changes in clinical manifestations of kidney disease among Japanese adults with type 2 diabetes, 1996-2014. AB - AIMS/INTRODUCTION: Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes and identified factors associated with these changes. MATERIALS AND METHODS: Using the 1996, 2001, 2006, and 2014 cohort data from the Japanese serial cross-sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (DKD) (albuminuria and/or reduced eGFR), patient characteristics, and their associations were analyzed. RESULTS: The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30 to 60 ml/min/1.73 m2 ) and severely reduced eGFR (<30 ml/min/1.73 m2 ) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we revealed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age-dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. CONCLUSIONS: During the last 20 years in Japan, the prevalence of albuminuria declined whereas that of reduced eGFR increased. Additionally, obesity- and high age-related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively. This article is protected by copyright. All rights reserved. PMID- 30451387 TI - Historical investigation of medical treatment for adult congenital heart disease: A Canadian perspective. AB - OBJECTIVE: The number of adults with congenital heart disease (CHD) has increased substantially because of medical advances that are extending life expectancy beyond childhood. A historical investigation is timely not only because of this significant demographic shift, but also because stakeholder engagement is increasingly important in shaping research directions. The study questions were: From the perspective of stakeholders, what is known about the medical treatment for the adult CHD cohort in Canada and how has it changed over time? DESIGN/METHODS: We harnessed the use of historical research methods and conducted interviews with 21 key informants in order to articulate a contextualized understanding of the evolution of adult CHD treatment in Canada. The informants recruited were currently or previously located in and/or involved in treatment in seven provinces and two territories across Canada including patients, families, advocates, researchers, and practitioners located in disciplines that included cardiology, cardiovascular surgery, nursing, psychology, dietetics, and kinesiology. RESULTS: Alongside findings that highlighted the significant demographic shift, the findings highlight key themes related to temporal shifts in treatment, emergence of organizational structures and use of evidence, comprehensive approaches to care, and future directions. A critical finding that requires immediate attention is the significantly disproportionate resources to the number of adults living with CHD, and as a result, the real risk of premature death for this population. CONCLUSIONS: The insights provided behoove the community of stakeholders to think creatively on how to draw attention to the inadequacy of resources and the unique and diverse needs of this population. PMID- 30451389 TI - Alcohol synthesis from CO2, H2 and olefins over alkali-promoted Au catalysts - a catalytic and in situ FTIR spectroscopic study. AB - Au/TiO2 and Au/SiO2 catalysts containing 2 wt% Au and different amounts of K or Cs were tested in alcohol synthesis from CO2, H2 and C2H4/C3H6. 1-propanol or 1 butanol/iso-butanol were obtained in the presence of C2H4 or C3H6. Over TiO2 based catalysts higher yields of the corresponding alcohols were obtained in comparison with their SiO2-based counterparts. This is caused by an enhanced ability of the TiO2-based catalysts for CO2 activation as concluded from in situ FTIR spectroscopic and TAP studies. The formed carbonate and formate species adsorbed on the support do not hamper CO2 conversion into CO and the hydroformylation reaction. The transformation of Audelta+ to active Au0 sites proceeds during an activation procedure. As reflected by CO adsorption and STEM the accessible Au0 sites are influenced by the amount of alkali dopants and the support. IR data and TAP tests reveal a very weak interaction of C2H4 with the catalyst suggesting its quick reaction with CO and H2 after activation on Au0 sites forming propanol and propane. PMID- 30451388 TI - Role of interleukin-7 in fusion of rat bone marrow mesenchymal stem cells with cardiomyocytes in vitro and improvement of cardiac function in vivo. AB - AIMS: Mesenchymal stem cells (MSCs) hold significant promise as potential therapeutic candidates following cardiac injury. However, to ensure survival of transplanted cells in ischemic environment, it is beneficial to precondition them with growth factors that play important role in cell survival and proliferation. Aim of this study is to use interleukin-7 (IL-7), a cell survival growth factor, to enhance the potential of rat bone marrow MSCs in terms of cell fusion in vitro and cardiac function in vivo. METHODS: Mesenchymal stem cells were transfected with IL-7 gene through retroviral vector. Normal and transfected MSCs were co cultured with neonatal cardiomyocytes (CMs) and cell fusion was analyzed by flow cytometry and fluorescence microscopy. These MSCs were also transplanted in rat model of myocardial infarction (MI) and changes at tissue level and cardiac function were assessed by histological analysis and echocardiography, respectively. RESULTS: Co-culture of IL-7 transfected MSCs and CMs showed significantly higher (P < 0.01) number of fused cells as compared to normal MSCs. Histological analysis of hearts transplanted with IL-7 transfected MSCs showed significant reduction (P < 0.001) in infarct size and better preservation (P < 0.001) of left ventricular wall thickness as compared to normal MSCs. Presence of cardiac-specific proteins, alpha-actinin, and troponin-T showed that the transplanted MSCs were differentiated into cardiomyocytes. Echocardiographic recordings of the experimental group transplanted with transfected MSCs showed significant increase in the ejection fraction and fractional shortening (P < 0.01), and decrease in diastolic and systolic left ventricular internal diameters (P < 0.001) and end systolic and diastolic volumes (P < 0.01 and P < 0.001, respectively). CONCLUSION: Interleukin-7 is able to enhance the fusogenic properties of MSCs and improve cardiac function. This improvement may be attributed to the supportive action of IL-7 on cell proliferation and cell survival contributing to the regeneration of damaged myocardium. PMID- 30451390 TI - Red Blood cell IMPDH activity in adults and children with or without azathioprine: relationship between thiopurine metabolites, ITPA and TPMT activities. AB - Inosine MonoPhosphate DeHydrogenase (IMPDH) is considered as the limiting enzyme of thiopurine metabolism for the formation of 6-Thioguanine nucleotides (6-TGN). No data are available on the influence of RBCs IMPDH activity on the metabolism of thiopurine drugs in subjects with IBD. The aim of this study was 1/ To carry out a phenotypic study of RBCs IMPDH activity in adults and children treated or not with azathioprine (AZA) for autoimmune diseases. 2/ To investigate the relationship between the activity of IMPDH, thiopurine metabolites and Inosine Triphosphatase (ITPA) and Thiopurine Methyl Transferase (TPMT) activities. IMPDH activity was determined in 97 adults and 67 children treated or not by AZA. 6 thioguanine nucleotides (6-TGN), 6-methylmercaptopurine nucleotides (6-MeMPN) levels, and ITPA as well as TPMT activities were measured in RBCs by HPLC. Using the Gaussian mixture model, distribution of IMPDH activity was evaluated. Influence of age, sex and AZA treatment on IMPDH activity were also assessed. A bimodal distribution in IMPDH activity was found with 87% of patients exhibiting normal activity and 13% of patients with high activity. No influence of age, sex and AZA therapy was found. There is no relationship between TPMT, ITPA and IMPDH activities. A negative correlation between IMPDH activity and 6-MeMPN was shown in adults and children (rs = -0.335 p = 0.014 and rs = -0.383 p = 0.012, respectively). Our results suggest that AZA-treated patients exhibiting lower IMPDH activity could have higher Me-6MPN levels with higher risk of hepatotoxicity. We demonstrated that RBCs matrix could be an interesting alternative to lymphocyte matrix to monitor thiopurine metabolites and enzyme activity. This article is protected by copyright. All rights reserved. PMID- 30451391 TI - A response regulator of the OmpR family is part of the regulatory network controlling the oxidative stress response of Rhodobacter sphaeroides. AB - As a free-living bacterium Rhodobacter sphaeroides needs to respond to many environmental stresses. Oxidative stress, membrane stress or heat stress induce the ompR-1 gene encoding a protein of the OmpR family. Overexpression of OmpR-1 results in increased resistance to organic peroxides and diamide. Our data demonstrate that OmpR-1 positively affects expression of several sRNAs with an established role in R. sphaeroides stress defences and negatively affects the promoter of the rpoHI gene. The RpoHI sigma factor has a main role in the activation of many stress responses. Thus OmpR-1 has a balancing effect on the activation of the RpoHI regulon. We present a model with OmpR-1 as part of a regulatory network controlling stress defences in R. sphaeroides. PMID- 30451392 TI - Results of a RCT on a Transition Support Program for Adults with ASD: Effects on Self-Determination and Quality of Life. AB - Few evidence-based services exist for people with Autism Spectrum Disorder (ASD) as they transition into adulthood, particularly those that foster appreciation of one's own goals and strengths. We developed a transition service for adults with ASD (without Intellectual Disability), and conducted a randomized controlled trial (RCT) focusing on self-report of Quality of Life and Self-Determination outcomes. Thirty participants aged 18-29 were randomized to immediate or delayed intervention, with 26 participants analyzed after 4 were lost to follow-up. Curriculum was tailored to participants' self-expressed needs in three areas: social communication, self-determination, and working with others. Groups of four to-six participants with ASD and two facilitators met weekly for 10 weeks. Positive intervention effects were observed on self-report of Quality of Life; the intervention group scored on average 2 points higher than the control group, 95% CI [-0.2, 3.9]. Positive effects were also observed on the Self Determination Scale (Interpersonal Cognitive Problem-Solving subdomain), where the intervention group scored 2 points higher than control group 95% CI [0.082, 3.4]. In addition, participants rated skills targeted by the curriculum 6 points higher after versus before intervention, 95% CI [3.7, 8.6]. This was echoed by a subset of parents rating their child's skills as seven points higher after versus before intervention, 95% CI [1, 14]. Autism Research 2018, 11: 1712-1728. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: These findings indicate that it is possible to increase Self-Determination and subjective Quality of Life in adults with ASD through a brief group-format service, and provide a model for doing so. Self-Determination abilities are linked to improved adult outcomes in individuals with other disabilities. These often overlooked factors should be incorporated in programming for adults with ASD as they transition to adulthood. PMID- 30451393 TI - Predictive value of iron parameters in neurocritically ill patients. AB - BACKGROUND: Iron, an essential mineral for human body, has the potential to cause toxicity at high levels. Previous studies have shown inconsistent predictive value of iron parameters in critically ill patients. Thus, we aimed to evaluate the performance of iron parameters in outcome prediction of neurocritically ill patients. METHODS: Retrospective data were collected from patients admitted to the neurocritical care unit (NCU) of a tertiary teaching hospital between August 2016 and January 2017. The iron parameters were obtained at NCU admission. Primary endpoints were short-term (30-day) mortality and long-term (6-month) poor outcome, with the latter defined as modified Rankin Scale of 4-6. The predictive value of variables was determined with univariate and multivariate logistic analysis. A further subanalysis was conducted in patients stratified by the level of estimated glomerular filtration rate (eGFR). RESULTS: Of 103 eligible patients, the etiology included stroke (58.2%, N = 60), central nervous system infection (13.6%, N = 14), and other neurologic disorders (28.2%, N = 29). The correlation analysis showed that the increase in ferritin, as well as the reduction in transferrin and total iron-binding capacity, had strong correlation with C-reactive protein, procalcitonin, duration of NCU stay, Acute Physiology and Chronic Health Evaluation II score, and Sequential Organ Failure Assessment score. In a further subanalysis of 75 patients with eGFR >= 60 ml/min/1.73 m2 , twelve (16.0%) patients died within 30 days and 39 (52.0%) patients achieved good follow-up outcome data. In the multivariate logistic regression analysis, we identified baseline ferritin level as an independent predictor of short-term mortality (OR: 1.002; 95% CI: 1.000-1.003; p = 0.008) and long-term functional outcome (OR: 1.002; 95% CI: 1.000-1.004; p = 0.031). CONCLUSIONS: Serum ferritin level at admission could be used as an independent predictor of short-term mortality and long-term functional outcome in neurocritically ill patients with eGFR >= 60 ml/min/1.73 m2 . PMID- 30451394 TI - Urinary symptoms are correlated with quality of life after deep brain stimulation in Parkinson's disease. AB - AIMS: Deep brain stimulation (DBS) is known to dramatically improve motor complications in patients with Parkinson's disease (PD), but its effect on urinary symptoms and health-related quality of life (HRQOL) remains unknown. We aimed to examine the relationship between urinary symptoms and HRQOL in patients with PD who underwent DBS. METHODS: The International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS) were determined to evaluate urinary symptoms in patients with PD who underwent DBS. Postoperative evaluations were performed at 3 months, 1 year, and 3 years postoperatively. We also performed a urodynamic study (UDS) in 13 patients with PD preoperatively and postoperatively. A follow-up UDS was performed 2.0 +/- 0.5 years postoperatively. RESULTS: The preoperative urinary symptoms questionnaire was completed by 28 patients, of whom 14 completed the postoperative urinary symptoms questionnaire after 3 months, 18 after 1 year, and 10 after 3 years. The mean OABSS and IPSS did not change significantly at any follow-up periods postoperatively. When assessing the relationship between urinary symptoms and HRQOL and motor functions, the OABSS and IPSS showed significant positive correlations with HRQOL at 3 months postoperatively. The OABSS and IPSS showed significant positive correlations with activities of daily living (ADL) during the off-phase at 3 years postoperatively. All urodynamic parameters remained unchanged postoperatively. CONCLUSIONS: Deep brain stimulation did not significantly affect urinary dysfunctions in patients with PD. Urinary symptoms might partially contribute to HRQOL at 3 months postoperatively and ADL during the off-phase at 3 years postoperatively. PMID- 30451395 TI - Left-right asymmetry influenced the infarct volume and neurological dysfunction following focal middle cerebral artery occlusion in rats. AB - OBJECTIVE: To investigate the differential effects of left versus right cerebral hemisphere on the infarct volume and behavioral function following focal cerebral ischemia in rats. METHODS AND MATERIALS: Middle cerebral artery occlusion (MCAO) was induced in the right-handed rats by filament insertion for 1.5 hr, and then reperfusion was established according to Zea-Longa method. A total of 36 male Sprague Dawley rats were randomly divided into a left MCAO group or a right MCAO group. The modified neurological severity scores (mNSS), tapered beam-walking test, and Morris water maze experiment were all carried out to evaluate the sensorimotor and cognitive outcomes at the 1d, 3d, and 7d after MCAO, respectively. Infarct volume of the brains was measured by triphenyltetrazolium chloride (TTC) staining. RESULTS: The sensorimotor function was more worse in the left MCAO group than that in the right MCAO group at the 1d, 3d, and 7d after MCAO (p < 0.05). While the cognitive function was much better in the left MCAO group than that in the right MCAO group at the 1d and 3d after MCAO (p < 0.05). But no significant difference was achieved in cognitive function between the two groups at 7d after MCAO (p > 0.05). There was no significant difference in total infarct volume between the two groups at the 1d, 3d, and 7d after MCAO, respectively (p > 0.05). CONCLUSION: The infarct volume is not affected significantly by the left or right MCAO model in the early days. The lesions in the left hemisphere produce more severe sensorimotor impairments, while more severe cognitive impairments are produced by the right hemispherical lesions. These findings suggest that it is structural and functional asymmetry between the two hemispheres other than infarct volume that affects the outcomes of rat MCAO. PMID- 30451396 TI - The pathological outcome of ThinPrep Pap tests diagnosed as glandular cell abnormalities alone versus combined glandular and squamous abnormalities. AB - BACKGROUND: Although the incidence of glandular cell abnormalities (GCA) on cervical cytology is low, the clinical and histologic findings are often significant. A combined diagnosis of squamous intraepithelial lesion (SIL) and GCA indicates concern for either two distinct lesions or single entity. The goal of this study is to evaluate the outcome of the diagnosis of GCA alone or in combination with squamous abnormality (SqA). METHODS: From January 2012-June 2017, our laboratory processed 162 088 ThinPrep Pap tests. 998 (0.61%) cases were reported as GCA. Histologic follow-up was available in 569 cases after excluding adenocarcinoma, NOS and atypical endometrial cells. HPV results were available in 429 (67.2%) cases. RESULTS: The surgical follow-up on 271 cases with GCA alone diagnosis revealed negative/benign lesions in 183 (67.5%) cases, glandular lesions in 40 (14.8%) cases; SqA in 47 (17.3%) cases; combined in 1 (0.4%) case. Surgical follow-up on 298 cases with dual interpretation revealed negative/benign lesions in 108 (36.2%) cases, SqA in 159 (53.4%) cases, GCA in 21 (7.0%) cases and only 10 (3.4%) cases were combined lesions. The mean age was 44 +/-13.36 years. The overall hrHPV-positive rate was 36.2%. Endometrial carcinoma was most common abnormality in patients >65 years (71.4%) especially with hrHPV-negative results. CIN 1-3 was the most common finding in patients <30 years (50%). CONCLUSION: A cytological diagnosis of GCA has a higher risk of glandular abnormality on surgical follow-up especially in the older and hrHPV-negative group (P < .0001) while a combined diagnosis has a higher risk of a squamous lesion especially in <30 years (P < .0001). The combination of cytology, hrHPV status and patient age can significantly aid in the stratification of the patient into high risk for glandular/squamous lesions which results in appropriate management. PMID- 30451397 TI - Application of Bayesian network modeling to pathology informatics. AB - BACKGROUND: In the era of extensive data collection, there is a growing need for a large scale data analysis with tools that can handle many variables in one modeling framework. In this article, we present our recent applications of Bayesian network modeling to pathology informatics. METHODS: Bayesian networks (BNs) are probabilistic graphical models that represent domain knowledge and allow investigators to process this knowledge following sound rules of probability theory. BNs can be built based on expert opinion as well as learned from accumulating data sets. BN modeling is now recognized as a suitable approach for knowledge representation and reasoning under uncertainty. Over the last two decades BN have been successfully applied to many studies on medical prognosis and diagnosis. RESULTS: Based on data and expert knowledge, we have constructed several BN models to assess patient risk for subsequent specific histopathologic diagnoses and their related prognosis in gynecological cytopathology and breast pathology. These models include the Pittsburgh Cervical Cancer Screening Model assessing risk for histopathologic diagnoses of cervical precancer and cervical cancer, modeling of the significance of benign-appearing endometrial cells in Pap tests, diagnostic modeling to determine whether adenocarcinoma in tissue specimens is of endometrial or endocervical origin, and models to assess risk for recurrence of invasive breast carcinoma and ductal carcinoma in situ. CONCLUSIONS: Bayesian network models can be used as powerful and flexible risk assessment tools on large clinical datasets and can quantitatively identify variables that are of greatest significance in predicting specific histopathologic diagnoses and their related prognosis. Resulting BN models are able to provide individualized quantitative risk assessments and prognostication for specific abnormal findings commonly reported in gynecological cytopathology and breast pathology. PMID- 30451398 TI - Mesenchymal Stem Cell Administration Attenuates Colon Cancer Progression by Modulating the Immune Component within the Colorectal Tumor Microenvironment. AB - We here determine the influence of mesenchymal stem cell (MSC) therapy on the progression of solid tumors. The influence of MSCs was investigated in human colorectal cancer cells as well as in an immunocompetent rat model of colorectal carcinogenesis representative of the human pathology. Treatment with bone marrow (BM)-derived MSCs significantly reduced both cancer initiation and cancer progression by increasing the number of tumor-free animals as well as decreasing the number and the size of the tumors by half, thereby extending their lifespan. The attenuation of cancer progression was mediated by the capacity of the MSCs to modulate the immune component. Specifically, in the adenocarcinomas (ADKs) of MSC treated rats, the infiltration of CD68+ monocytes/macrophages was 50% less while the presence of CD3+ lymphocytes increased almost twofold. The MSCs reprogrammed the macrophages to become regulatory cells involved in phagocytosis thereby inhibiting the production of proinflammatory cytokines. Furthermore, the MSCs decreased NK (Natural Killer) and rTh17 cell activities, Treg recruitment, the presence of CD8+ lymphocytes and endothelial cells while restoring Th17 cell activity. The expression of miR-150 and miR-7 increased up to fivefold indicating a likely role for these miRNAs in the modulation of tumor growth. Importantly, MSC administration limited the damage of healthy tissues and attenuated tumor growth following radiotherapy. Taken together, we here show that that MSCs have durable action on colon cancer development by modulating the immune component of the tumor microenvironment. In addition, we identify two miRNAs associated with the capacity of MSCs to attenuate cancer growth. Stem Cells Translational Medicine 2018; 1-16. PMID- 30451400 TI - A rare case of pediatric pleural effusion: Pancreaticopleural fistula. PMID- 30451399 TI - Diastolic stress test echocardiography in patients with suspected heart failure with preserved ejection fraction: a pilot study. AB - AIMS: The purpose of this pilot study was to assess the potential usefulness of diastolic stress test (DST) echocardiography in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Patients with suspected HFpEF (left ventricular ejection fraction >= 50%, exertional dyspnoea, septal E/e' at rest 9-14, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at rest < 220 pg/mL; n = 13) and a control group constituted from asymptomatic patients with arterial hypertension (n = 19) and healthy subjects (n = 18) were included. All patients were analysed by two-dimensional and Doppler echocardiography at rest and during exercise (DST) and underwent cardiopulmonary exercise testing and NT-proBNP analysis during exercise. HFpEF during exercise was defined as exertional dyspnoea and peak VO2 <= 20.0 mL/min/kg. In patients with suspected HFpEF at rest, 84.6% of these patients developed HFpEF during exercise, whereas in the group of asymptomatic patients with hypertension and healthy subjects, the rate of developed HFpEF during exercise was 0%. Regarding the diagnostic performance of DST to detect HFpEF during exercise, an E/e' ratio >15 during exercise was the most accurate parameter to detect HFpEF (accuracy 86%), albeit a low sensitivity (45.5%). Nonetheless, combining E/e' with tricuspid regurgitation (TR) velocity > 2.8 m/s during exercise provided a significant increase in the sensitivity to detect patients with HFpEF during exercise (sensitivity 72.7%, specificity 79.5%, and accuracy 78%). Consistent with these findings, an increase of E/e' was significantly linked to worse peak VO2 , and the combination of an increase of both E/e' and TR velocity was associated with elevated NT-proBNP values during exercise. CONCLUSIONS: The findings of this pilot study suggest that DST using E/e' ratio and TR velocity could be of potential usefulness to diagnose HFpEF during exercise in patients with suspected HFpEF at rest. PMID- 30451401 TI - Upcoming events of interest. PMID- 30451402 TI - Polish recommendations for lung ultrasound in internal medicine (POLLUS-IM). AB - The aim of this study was to establish recommendations for the use of lung ultrasound in internal medicine, based on reliable data and expert opinions. Methods: The bibliography from the databases (Pubmed, Medline, OVID, Embase) has been fully reviewed up to August 2017. Members of the expert group assessed the credibility of the literature data. Then, in three rounds, a discussion was held on individual recommendations (in accordance with the Delphi procedure) followed by secret voting. Thirty-eight recommendations for the use of lung ultrasound in internal medicine were established as well as discussed and subjected to secret voting in three rounds. The first 31 recommendations concerned the use of ultrasound in the diagnosis of the following conditions: pneumothorax, pulmonary consolidation, pneumonia, atelectasis, pulmonary embolism, malignant neoplastic lesions, interstitial lung lesions, cardiogenic pulmonary edema, interstitial lung diseases with fibrosis, dyspnea, pleural pain and acute cough. Furthermore, seven additional statements were made regarding the technical conditions of lung ultrasound examination and the need for training in the basics of lung ultrasound in a group of doctors during their specialization programs and medical students. The panel of experts established a consensus on all 38 recommendations. PMID- 30451403 TI - Pitfalls in ultrasound imaging of the stomach and the intestines. AB - The gastrointestinal tract is an extraordinary human organ in terms of its morphology and function. Its complex structure and enormous length as well as frequent presence of gas discourage many doctors performing ultrasound examination from its exploration. Moreover, there are anatomical structures in multiple locations which can mimic certain abnormalities. It is difficult to present an exhaustive account of the problem of gastrointestinal tract ultrasound imaging errors in a single work; therefore, this study focuses mainly on false positive errors which usually result from a lack of knowledge of anatomical variants of the gastrointestinal tract structure. In the case of the stomach, rugae and muscle layer thickening towards the pylorus have been mentioned, which constitute variants of the structure of this organ examined when empty. Diagnostic pitfalls in the small intestine may include the dudenojejunal flexure (ligament of Treitz), the horizontal part of the duodenum and the ileocaecal valve. The status of the apparent lesions in all of the cases mentioned will be resolved following fluid intake by the patient. In the colon, the varied structure of semilunar folds should be taken note of. Their large thickness can warrant suspicion of wall invasion or a polyp. In addition, the study emphasises the importance of appropriate preparation of a patient for gastrointestinal tract examination since it determines the accuracy of the diagnosis. The authors also take note of common 'sins' of physicians such as hasty examination and failure to comply with the stomach and appendix examination protocol. PMID- 30451404 TI - Articular abnormalities that may mimic arthritis. AB - There are numerous abnormalities that present with similar signs and symptoms to arthritis. In this article some of these conditions that can masquerade as arthritis are discussed. Synovial osteochondromatosis is an uncommon benign disorder marked by the metaplastic proliferation of multiple cartilaginous nodules in the synovial membrane of the joints, bursae, or tendon sheaths. Pigmented villonodular synovitis, also known as diffuse-type tenosynovial giant cell tumor, is a locally destructive fibrohistiocytic proliferation, characterized by many villous and nodular synovial protrusions which affects the joints. Synovial hemangioma is a rare benign lesion whose pathogenesis is still unclear. It commonly affects the knee joint, although the other articulations, such as elbow, wrist, and ankle may also be involved. Lipoma arborescens, also known as villous lipomatous proliferation of the synovial membrane, is a rare intra-articular disorder characterized by a non-neoplastic lipomatous proliferation of the synovium. The term "arborescens" refers to the characteristic tree-like morphology of the lesion, which resembles a frond-like mass. PMID- 30451405 TI - Classifications and imaging of juvenile spondyloarthritis. AB - Juvenile spondyloarthritis may be present in at least 3 subtypes of juvenile idiopathic arthritis according to the classification of the International League of Associations for Rheumatology. By contrast with spondyloarthritis in adults, juvenile spondyloarthritis starts with inflammation of peripheral joints and entheses in the majority of children, whereas sacroiliitis and spondylitis may develop many years after the disease onset. Peripheral joint involvement makes it difficult to differentiate juvenile spondyloarthritis from other juvenile idiopathic arthritis subtypes. Sacroiliitis, and especially spondylitis, although infrequent in childhood, may manifest as low back pain. In clinical practice, radiographs of the sacroiliac joints or pelvis are performed in most of the cases even though magnetic resonance imaging offers more accurate diagnosis of sacroiliitis. Neither disease classification criteria nor imaging recommendations have taken this advantage into account in patients with juvenile spondyloarthritis. The use of magnetic resonance imaging in evaluation of children and adolescents with a clinical suspicion of sacroiliitis would improve early diagnosis, identification of inflammatory changes and treatment. In this paper, we present the imaging features of juvenile spondyloarthritis in juvenile ankylosing spondylitis, juvenile psoriatic arthritis, reactive arthritis with spondyloarthritis, and juvenile arthropathies associated with inflammatory bowel disease. PMID- 30451406 TI - The diagnosis and management of shoulder pain. AB - Diagnosis is crucial in decision-making when treating a patient with shoulder pain. Ultrasound is also very important in the diagnostic and therapeutic pathway, especially when surgery is being considered. This article outlines the diagnostic pathway using the patient's history, physical examination and ultrasound examination. It is important to correlate the clinical assessment with the imaging signs. It is also important to treat the patient and not the images as there may be abnormalities detected on imaging that are not symptomatic. The article covers the important diagnosis of subdeltoid subacromial bursitis, glenohumeral joint capsulitis, calcific tendinosis, acromioclavicular joint osteoarthritis and long head of biceps tendinosis. It will guide the reader in how to use the findings to treat, using ultrasound-guided injection and other techniques, including steroid injections, hydrodilatation, barbotage and extracorporeal shockwave treatment. These are discussed with the knowledge from over 30 years of experience with a literature review evidential support. I have included tips to make these procedures more effective in treatment and final outcome. There is discussion regarding the use of steroid injections in the presence of a rotator cuff tear and how to proceed if the patient has more than one disease process. The sensible use of steroids and local anesthetics are included, bearing in mind that lidocaine and high concentrations of long-acting local anesthetics are chondrotoxic and should not be injected into joints. PMID- 30451407 TI - Acrania-exencephaly-anencephaly sequence phenotypic characterization using two- and three-dimensional ultrasound between 11 and 13 weeks and 6 days of gestation. AB - The study presents a pictorial essay of acrania-exencephaly-anencephaly sequence using two-(2D) and three-dimensional (3D) ultrasonography, documenting the different phenotypic characterization of this rare disease. Normal and abnormal fetuses were evaluated during the first trimester scan. The International Society of Ultrasound in Obstetrics and Gynecology practice guidelines were adopted to standardize first trimester anatomical ultrasound screening. The guidelines outline the importance of systematic fetal head and brain examination including the formation of cranial bones, choroid-plexus and ventricles. Acrania exencephaly-anencephaly sequence and/or other neural tube defects, such as meningoencephalocele, may be identified during a routine 11-14 week scan. Early first trimester detection of acrania-exencephaly-anencephaly sequence with the characterization of different related phenotypes, 2D and 3D ultrasound imaging as well as differential diagnosis are also presented in this pictorial essay. The main diagnostic ultrasound features of the disease may be characterized by findings of acrania with increased amniotic fluid echogenicity; "Mickey-Mouse" bi lobular face, cystic, elongated, irregular and overhanging head morphology. Lightening techniques have also been added to 3D ultrasound to enhance anatomical details. Moreover, discordant amniotic fluid echotexture in the setting of twin pregnancies may be the first sign of acrania-exencephaly-anencephaly sequence. Extracranial malformations, aneuploidy and genetic syndromes associated with acrania-exencephaly-anencephaly sequence are also reported and described. First trimester neuroscan by an expert sonographer with appropriate training together with the application of standardized protocol are essential for a high detection rate of this rare type of neural tube defect malformation during a scan performed at 11 and 13 weeks and 6 days. PMID- 30451409 TI - Ultrasound screening for pyelectasis in pregnant women. Clinical necessity or "art for art's sake"? AB - Renal pelvicalyceal dilatation is caused by urine retention in the upper urinary tract. It is referred to as pyelectasis in medical literature. This term does not indicate the cause that leads to the dilatation of and urine retention in the renal pelvicalyceal system. Mild pelvicalyceal dilatation during pregnancy is usually considered to be physiological in nature - it can occur in up to 90% of pregnant women. Retention is more common in the right kidney, in primigravidae, in the second half of pregnancy and in multiple pregnancies. Pyelectasis during pregnancy rarely causes clinical symptoms and often does not require treatment. Nevertheless, urine retention in the renal pelvicalyceal system is conducive to the development of asymptomatic bacteriuria and may be a risk factor for recurrent urinary tract infections, pyelonephritis and acute kidney failure; it may also cause renal colic. In consequence, this condition can lead to intrauterine infection and premature labor in the pregnant woman and to prematurity, anemia, congenital pneumonia or sepsis in the child. In a study conducted at the 3 rd Department of Gynecology of the Medical University of Lublin it was concluded that unilateral pyelectasis of more than 20 cm 3 is associated with a significant increase in the risk of asymptomatic bacteriuria. This volume corresponds to grade 3 and/or 4 pelvicalyceal dilatation according to the Society for Fetal Urology/European Federation of Societies for Ultrasound in Medicine and Biology classification. The pyelectasis volume measuring method using three-dimensional ultrasound scanning included in the criteria for the assessment of asymptomatic bacteriuria was assessed as sensitive and specific. The ultrasound-based evaluation of the kidneys for the presence of pyelectasis and its grade in pregnant women has some clinical implications. It allows for identifying cases with an increased risk of asymptomatic bacteriuria, which requires treatment in pregnant women. Screening during pregnancy for pyelectasis seems to be important in preventing asymptomatic bacteriuria from progressing to symptomatic urinary tract infection. PMID- 30451408 TI - Visceral artery aneurysms - classification, diagnosis and treatment. AB - Although visceral artery aneurysms are rare, mortality due to their rupture is high, estimated at even 25-75%. That is why it is significant to detect each such lesion. Visceral artery aneurysms are usually asymptomatic and found incidentally during examinations performed for other indications. Autopsy results suggest that most asymptomatic aneurysms remain undiagnosed during lifetime. Their prevalence in the population is therefore higher. The manifestation of a ruptured aneurysm depends on its location and may involve intraperitoneal hemorrhage, gastrointestinal and portal system bleeding with concomitant portal hypertension and bleeding from esophageal varices. Wide access to diagnostic tests, for example ultrasound, computed tomography or magnetic resonance imaging, helps establish the correct diagnosis and a therapeutic plan as well as select appropriate treatment. After a procedure, the same diagnostic tools enable assessment of treatment efficacy, or are used for the monitoring of aneurysm size and detection of potential complications in cases that are ineligible for treatment. The type of treatment depends on the size of an aneurysm, the course of the disease, risk of rupture and risk associated with surgery or endovascular procedure. Endovascular treatment is preferred in most cases. Aneurysms are excluded from the circulation using embolization coils, ethylene vinyl alcohol, stents, multilayer stents, stent grafts and histoacryl glue (or a combination of these methods). PMID- 30451410 TI - The role of ultrasonography in methotrexate therapy for ectopic pregnancy. AB - Medical management of ectopic pregnancy with methotrexate, an antimetabolite of folic acid, is an important alternative to surgical treatment, as it ensures a similar outcome whilst being far less invasive. Ultrasound evaluation does not only facilitate an accurate diagnosis, but also helps to select patients most likely to benefit from methotrexate treatment, as opposed to those with a high likelihood of failure of medical management, who are thus eligible for primary surgical treatment. Ultrasound also allows to monitor the outcome of methotrexate therapy. This study is a review of literature regarding the management of ectopic pregnancy with methotrexate. Such ultrasound findings as the size of the ectopic mass, presence of fetal heart rate and free fluid have been confirmed as effective eligibility criteria for therapy with methotrexate. In the future, possibly also endometrial stripe thickness and the vascularity of the ectopic mass may be considered predictive of successful methotrexate therapy. The initial increase in size of the ectopic mass following methotrexate therapy confirms its effectiveness, and should not prompt concern. PMID- 30451411 TI - Ultrasonographic criteria of cesarean scar defect evaluation. AB - Cesarean sections account for approximately 20% of all deliveries worldwide. In Poland, the percentage of women delivering by cesarean section amounts to over 43%. According to studies, the prevalence of cesarean scar defects ranges from 24 70%. Due to the overall cesarean section rate, this is a medical problem affecting a large population of women. In such cases, ultrasonographic evaluation of a cesarean scar reveals a hypoechoic space filled with postmenstrual blood, representing a myometrial tear at the wound site. Such an ultrasound appearance is referred to as a niche, and it forms after a cesarean section at the site of the hysterotomy of the anterior uterine wall, most commonly within the uterine isthmus. Currently, the exact cause of niche formation remains unexplained, yet the risk factors for its development are universally acknowledged. They include the site of hysterotomy, multiple previous cesarean section deliveries, suturing technique and maternal diabetes or smoking. Ultrasound evaluation of the cesarean section scar is an important element of obstetric and gynecologic practice, especially in the case of further pregnancies. It facilitates an early diagnosis of a cesarean scar ectopic pregnancy, and the prediction of the risk for perinatal dehiscence in the case of a vaginal birth after a cesarean section. PMID- 30451412 TI - Terrestrial Non-Parasitic Nematode Assemblages associated With Glyphosate tolerant and Conventional Soybean-Based Cropping Systems. AB - Information about the effects of glyphosate on nematodes is limited and contradictory, while none existing for South African agricultural fields. The abundance and identity of non-parasitic nematodes in the rhizospheres of commercial glyphosate-tolerant and conventional (non-glyphosate-tolerant), soybean cultivars from cultivated fields, and adjacent natural vegetation (reference system) were obtained for two growing seasons. The impact of glyphosate was also investigated on non-parasitic nematodes in a 2-year soybean maize cropping system. Thirty-two non-parasitic nematode genera were identified from soils of the three field ecosystems, with most of the genera occurring in natural vegetation (28), and less in conventional (23) and glyphosate-tolerant soybean (21). Bacterivores had the greatest diversity in soils of all three ecosystems during both seasons, while fungivores tended to be more abundant in glyphosate-tolerant soybean fields especially during the second season. Soils from the three ecosystems were disturbed and degraded with low abundance and diversity of omnivores and predators. Of the 14 genera identified from the soybean-maize cropping experiment, bacterivores dominated in terms of diversity in non-treated, and fungivores in glyphosate-treated plots. Soils from glyphosate treated plots were degraded, less enriched and fungal-mediated, while those from non-treated plots were disturbed, enriched, and bacterial-mediated. PMID- 30451413 TI - Responses of Anastrepha suspensa, Diachasmimorpha longicaudata, and Sensitivity of Guava Production to Heterorhabditis bacteriophora in Fruit Fly Integrated Pest Management. AB - Caribbean fruit fly, also known as Caribfly or Anastrepha suspensa , is a major tephritid pest of guavas. A virulent entomopathogenic nematode (EPN) species was investigated to suppress the fruit-to-soil stages of Caribflies, which are also attacked by the koinobiont parasitoid Diachasmimorpha longicaudata in south Florida. The main objective was to develop a feasible and cost-effective EPN application method for integrated pest management (IPM) of Caribfly to improve guava production. Naturally infested guavas were treated with increasing Heterorhabditis bacteriophora infective juvenile (IJ) concentration or rate (0, 25, 50, ..., 1,600 IJs cm -2 ) in field trials to measure the optimum IJ rate and then examine sensitivity of producing guavas to inclusion of Heterorhabditis bacteriophora in Caribfly IPM plans. Relative survival of Caribfly in treatments significantly decreased with increasing IJ rate from 0 to 100 IJs cm -2 . Similarly, probability of observing large numbers of parasitoid wasps ( Diachasmimorpha longicaudata ) in EPN treatments significantly declined with increasing IJ rate (0-100 IJs cm -2 ), even though the non-target effects of Heterorhabditis bacteriophora on relative survival of Diachasmimorpha longicaudata could not be determined because of few emerging parasitoid wasps. Optimum suppression (? 60%) of Caribfly was consistently achieved at 100 IJs cm 2 or 17,500 IJs fruit -1 . Profitability analysis showed that Heterorhabditis bacteriophora can be included in Caribfly IPM tactics to produce guavas. Costs of EPNs in Caribfly IPM are minimized if Heterorhabditis bacteriophora is strategically applied by spot treatment of fruit. Repayment of costs of EPN augmentation by spot treatments appears achievable by recovering 5.71% of the annual yield losses (?1,963 kg ha -1 ~ US$ 8,650 ha -1 ), which are largely due to Caribfly infestation. Hectare-wide EPN-augmentation (or broadcasting) method requires more fruit recovery than the total annual yield losses to repay its high costs. Profitability of guava production in south Florida will not be very sensitive to marginal costs of the spot treatment method, when compared to the field-wide broadcasting of Heterorhabditis bacteriophora . PMID- 30451414 TI - Survival and Infectivity of Entomopathogenic Nematodes Formulated in Sodium Alginate Beads. AB - An alternative control method to the use of chemical insecticides against soil dwelling insect pests is the application of entomopathogenic nematodes formulated in alginate beads for enhanced shelf life. The aim was to compare the benefit on nematode survival and infectivity of: (i) pre-conditioning of juveniles, and (ii) coating of alginate beads. The nematodes Steinernema glaseri , Steinernema carpocapsae, and Heterorhabditis bacteriophora were reproduced in last instar larvae of the wax moth Galleria mellonella and the infective juveniles emerged were subjected to two capture treatments: white traps and plaster of Paris, the latter was utilized as a pre-conditioning treatment. A total of 1,000 infective juveniles were formulated in each sodium alginate bead with or without an alginate coating. The beads were stored at 23 +/- 3 degrees C and a bidistilled water suspension of nematodes was set as a control. The survivorship of these formulates and their infectivity on Galleria mellonella larvae were evaluated every 7 d post-formulation (dpf). In beads without pre-conditioning juveniles nor coating, Steinernema carpocapsae had the higher survival rate (58.8%), the longest survival time (28 dpf) and the higher infectivity (100%) as well. Pre conditioning improved the survival and infectivity of Steinernema glaseri by 22.5% at 21 dpf and 70.0% at 14 dpf, respectively. Alginate coating increased survival (21.7%) and infectivity (95%) of Heterorhabditis bacteriophora for up to 28 dpf. The combination of pre-conditioning and coating slightly favored the survival (10% for up to 14 dpf) of Steinernema glaseri and infectivity (100% for up to 35 dpf) of Steinernema carpocapsae . Non pre-conditioned Steinernema carpocapsae formulated in uncoated beads was the combination with better performance in survivorship (58.8%) and infectivity (100%) at 28 dpf. It was concluded that non pre-conditioned Steinernema carpocapsae formulated in uncoated beads was the combination with better survivorship and infectivity. PMID- 30451415 TI - High Mitochondrial Genome Diversity and Intricate Population Structure of Bursaphelenchus xylophilus in Kyushu, Japan. AB - Mitogenomic diversity and genetic population structure of the pinewood nematode (PWN) Bursaphelenchus xylophilus inhabiting Kyushu, Japan were analyzed. A method for performing long PCR using single nematodes and sequencing nematode mitochondrial genomes individually is presented here. About 8 kb (~55%) of the complete mitochondrial genome was successfully obtained from 285 individuals collected from 12 populations. The 158 single nucleotide polymorphisms detected corresponded to 30 haplotypes, clearly classified into two clades. Haplotype diversity was 0.83, evidencing a remarkable high diversity within Kyushu. The high genetic differentiation among the 12 populations (0.331) might be due to past invasion and expansion routes of PWN in northeastern and southeastern Kyushu. The distinct genetic composition of populations within the northwestern, central western, and southwestern Kyushu seems to be mostly related to the extinction of pine forests and long-range migration of PWN due to human activity. Overall, direct long PCR and sequencing of single nematode individuals are effective methods for investigating mitochondrial polymorphisms, and these are effective tools for PWN population genetics and other intraspecific studies. PMID- 30451416 TI - NMR Analysis Reveals a Wealth of Metabolites in Root-Knot Nematode Resistant Roots of Citrullus amarus Watermelon Plants. AB - Citrullus amarus ( CA ) (previously known as Citrullus lanatus var. citroides ) accessions collected in southern Africa are known to have resistance to root-knot nematodes (RKN) and are suitable rootstocks for grafted watermelon. The objective of this study was to conduct a comparative metabolomics analysis and identify unique metabolites in roots of CA accessions versus roots of watermelon cultivars ( Citrullus lanatus (Thunb.) Matsum. and Nakai var. lanatus; CL ). Nuclear magnetic resonance (NMR) technology and principal component analysis (PCA) were used to analyze and compare metabolic profiles of seven CA accessions resistant to RKN along with two RKN-susceptible watermelon cultivars (Charleston Gray and Crimson Sweet). Calculation of the Mahalanobis distance revealed that the CA United States Plant Introduction (PI) 189225 (Line number 1832) and PI 482324 (1849) have the most distinct metabolic profiles compared with the watermelon cultivars Charleston Gray and Crimson Sweet, respectively. Several amino acids identified in the CA accessions were reported in previous studies to have a nematicidal effect. The results in this study indicate that roots of watermelon accessions collected in the wild are rich in metabolic compounds. These metabolic compounds may have been diminished in watermelon cultivars as a consequence of many years of cultivation and selection for desirable fruit qualities. PMID- 30451417 TI - Nematicidal Weeds, Solanum nigrum and Datura stramonium. AB - We investigated Solanum nigrum (seeds) and Datura stramonium (shoots) against root-knot nematodes in terms of J2 paralysis and egg hatch inhibition (methanol extract), as well as inhibition of nematode development in host roots (soil amending with either S. nigrum seeds' or D . stramonium shoots' meal). Datura stramonium was found equally effective at inhibiting motility of Meloidogyne incognita and Meloidogyne javanica (both EC 50 = 427 MUg mL -1 at 3 day), but inhibition occurred more quickly for M. incognita (1 day). Solanum nigrum was faster and more effective at inhibiting motility of M. incognita than M. javanica (EC 50 = 481 and 954 MUg mL -1 at 3 day, respectively). Datura stramonium was slower, but eventually more potent in decreasing egg hatch and cell division in M. incognita eggs, than S. nigrum . Specifically, D. stramonium significantly inhibited cell division in eggs immersed in at least 100 and 1 MUg mL -1 at Day 6 and 10, respectively. Solanum nigrum impeded cell division in un-differentiated eggs immersed in not less than 10 and 100 MUg mL -1 after days 2 and 6, respectively. Both extracts were similar in suppressing J2 exclosure but D. stramonium was effective in smaller test concentrations. Specifically, D. stramonium suppressed J2 emerging from eggs immersed in 10 MUg mL -1 at day2, and in at least 1 MUg mL -1 at day 6. Solanum nigrum significantly reduced J2 hatch from eggs immersed in a minimum of 100 MUg mL -1 at day 2 and not less than 1,000 MUg mL -1 at day 6. In pots, powdered S. nigrum seeds meal was more active than D. stramonium and the respective EC 50 females/ g values for M. incognita were 1.13 and 11.4 mg g -1 of soil, respectively. The chemical composition of active extracts was determined after derivatization by GC-MS. Chemical analysis of active extracts showed the presence of fatty acids with known nematicidal activity. PMID- 30451418 TI - Short-term Impacts of Tillage and Fertilizer Treatments on Soil and Root Borne Nematodes and Maize Yield in a Fine Textured Cambisol. AB - Conservation agriculture (CA) based on the principles of minimum soil disturbance, crop residue retention, and crop rotation has been the focus of intensive research in recent years. A study was carried out to determine the effects of tillage and fertilizer on the population densities of plant-parasitic nematodes in maize. Three tillage regimes, (i) basin planting, (ii) rip line seeding, and (iii) conventional tillage, were combined with four fertilizer regimes: (i) no-fertilizer, (ii) low fertilizer rate, (iii) medium fertilizer rate, and (iv) high fertilizer rate. The experiment was arranged as a split plot in randomized complete block design, replicated three times with tillage as the main plot factor and fertilizer as the sub-plot factor. The study was conducted on fine-textured Cambisol soils at Chinhoyi University of Technology farm, Zimbabwe, over two cropping seasons between December 2014 and April 2016. Eight plant-parasitic nematode genera were observed belonging to five groups based on their feeding sites: (i) sedentary endoparasites ( Meloidogyne and Rotylenchulus ), (ii) migratory endoparasites ( Pratylenchus ), (iii) semi-endoparasites ( Scutelonema and Helicotylenchus ), (iv) ectoparasites ( Xiphinema and Trichodorus ), and (v) algal, lichen or moss feeders ( Tylenchus ). In both cropping seasons, semi-endoparasitic nematodes were double under rip line seeding and triple under basin planting compared to conventional tillage. Basin planting had higher plant parasitic nematode richness than rip line seeding. Nematode densities did not have a measurable effect on maize grain yield. Maize grain yield was higher in rip line seeding (37%) and planting basins (52%) than conventional tillage during 2014/15 cropping season. On the other hand, during 2015/16 cropping season, maize grain yield was 78% and 113% higher in rip line seeding and basin planting, respectively, compared to conventional tillage. The results show that under the environmental and edaphic conditions of this specific study site, semi endoparasitic nematodes were higher under rip line seeding and basin planting compared to conventional tillage. The authors conclude that (i) plant-parasitic nematode genera exhibited differential responses to different tillage systems but were not affected by fertilizer application, and (ii) in the present study, maize grain yield response under different tillage and fertilizer regimes was overall not related to nematode population density and composition. PMID- 30451419 TI - Morphological and Molecular Characterization of Labrys filiformis n. sp. (Rhabditida: Tylenchidae) from Iran. AB - Labrys filiformis n. sp., the second species of the rare genus Labrys , was recovered from natural forests of Gilan province and is described based upon morphological and molecular characters. The new species is characterized by its smooth cuticle under light microscopy, lateral field with two incisures forming a single plain band, lip region continuous with body contour, dorso-ventrally flattened and forming four poorly prominent lobes, having a dorso-ventrally narrower protuberant labial plate laterally extended to the amphidial margins, oral area (oral plate) dorso-ventrally elongated and embedded in the labial plate with six small labial sensilla surrounding the slightly prominent oral aperture, amphidial apertures as longitudinally lemniscatic slits bordered by the labial plate extensions which are overlapped at the middle length of amphids, stylet delicate, 6 to 7 um long, elongate weakly developed fusiform median bulb with weak valve, wide excretory pore with long and heavily sclerotized duct, offset spermatheca filled with small spheroid sperm cells, 106 to 127 um long elongate conoid tail with filiform distal region and finely rounded tip. Molecular phylogenetic analyses were performed using a near-full length fragment of the 18S rDNA and the D2-D3 expansion segments of the 28S rDNA using Bayesian inference and maximum likelihood methods. In the inferred phylogenetic tree with 18S rDNA, the new species has a close affinity with several isolates of the type species, Labrys chinensis . The reconstructed phylogenetic tree using partial 28S rDNA, revealed the new species is nested inside the putative monophyletic group of several populations of L. chinensis . PMID- 30451420 TI - Two New Species of Pristionchus (Nematoda: Diplogastridae) from Taiwan and the Definition of the pacificus Species-Complex Sensu Stricto. AB - Pristionchus pacificus Sommer, Carta, Kim, and Sternberg, 1996 is an important model organism in evolutionary biology that aims to integrate developmental biology and evo-devo with population genetics and ecology. Functional studies in P. pacificus are supported by a well-established phylogenetic framework of around 30 species of the genus Pristionchus that have been described in the last decade based on their entomophilic and necromenic association with scarab beetles. Biogeographically, East Asia has emerged as a hotspot of Pristionchus speciation and recent samplings have therefore focused on Islands and mainland settings in East Asia. Here, we describe in a series of three publications the results of our sampling efforts in Taiwan, Japan, and Hongkong in 2016 and 2017. We describe a total of nine new species that cover different phylogenetic species-complexes of the Pristionchus genus. In this first publication, we describe two new species, Pristionchus sikae sp. n. and Pristionchus kurosawai sp. n. that are closely related to P. pacificus . Together with five previously described species they form the " pacificus species-complex sensu stricto" that is characterized by all species forming viable, but sterile F1 hybrids indicating reproductive isolation. P. sikae sp. n. and P. kurosawai sp. n. have a gonochorist mode of reproduction and they are described using morphology, morphometrics, mating experiments, and genome-wide sequence analysis. We discuss the extreme diversification in the pacificus species-complex sensu stricto in East Asia and its potential power to study speciation processes. PMID- 30451421 TI - Description of Xiphinema parachambersi sp. n. (Nematoda: Longidoridae) from Imported Ornamental Plants in Japan with a Key to Xiphinema Species in Group 1. AB - Xiphinema parachambersi n. sp. recovered in Ningbo, China, from the rhizosphere of ornamental plants ( Gardenia jasminoides and Euonymus hamiltonianus ) imported from Japan is described. The new species is characterized by a long female body 1,830 to 2,109 MU m long, odontostyle 105 to 116 MU m long, reproductive system mono-opisthodelphic, vulva located anteriorly at 25.2 to 27.7% of total body, long ovary 119 to 292 MU m with simple uterus and Z-organ absent, female tail elongated conoid with a rounded terminus. Only two juvenile stages were available to study and no male was found. The polytomous identification codes for this new species are A1, B4, C2, D23, E1, F2, G2, H2, I2, J2, K?, L1 and it belongs to the morphospecies group 1. Phylogenetic analysis based on the 18S, ITS1 and 28S D2/D3 sequences of the new species showed close relationships with X. chambersi . Morphologically, the new species is similar to X. chambersi , X. hangzhouense , and X. winotoi but can be differentiated by morphological characters and DNA sequences. To help identify the species, a diagnostic key to the group 1 species is presented. PMID- 30451422 TI - Characterization of Meloidogyne indica (Nematoda: Meloidogynidae) Parasitizing Neem in India, with a Molecular Phylogeny of the Species. AB - Neem is a perennial plant of family Meliaceae grown very commonly in India. During a survey in Rajasthan, India; a population of root-knot nematode was found in association with tender neem plants causing yellowing, stunting, and heavy root galling. Inspection of the perineal pattern morphology of the adult females, extracted from the galled roots, primarily led to identification of the species as Meloidogyne indica . Further, detailed morphological and morphometric illustrations of second-stage juveniles, males and females were carried out by light compound and scanning electron microscopy. Gross morphology and measurements were found consistent with the original description of M. indica infecting citrus by Whitehead (1968). The neem population was found to infect and reproduce on citrus. Additionally, evolutionary relationship was deduced by Maximum likelihood method using ITS rRNA, D2D3 expansion segment of 28S rRNA and mitochondrial COI sequences. Phylogenetic analyses based on these sequences showed sufficient divergence of M. indica to be differentiated as a unique species under the genus Meloidogyne . PMID- 30451423 TI - Discovery and Identification of Meloidogyne Species Using COI DNA Barcoding. AB - DNA barcoding with a new cytochrome oxidase c subunit 1 primer set generated a 721 to 724 bp fragment used for the identification of 322 Meloidogyne specimens, including 205 new sequences combined with 117 from GenBank. A maximum likelihood analysis grouped the specimens into 19 well-supported clades and four single specimen lineages. The "major" tropical apomictic species ( Meloidogyne arenaria , Meloidogyne incognita , Meloidogyne javanica ) were not discriminated by this barcode although some closely related species such as Meloidogyne konaensis were characterized by fixed diagnostic nucleotides. Species that were collected from multiple localities and strongly characterized as discrete lineages or species include Meloidogyne enterolobii , Meloidogyne partityla , Meloidogyne hapla , Meloidogyne graminicola , Meloidogyne naasi , Meloidogyne chitwoodi , and Meloidogyne fallax . Seven unnamed groups illustrate the limitations of DNA barcoding without the benefit of a well-populated reference library. The addition of these DNA sequences to GenBank and the Barcode of Life Database (BOLD) should stimulate and facilitate root-knot nematode identification and provide a first step in new species discovery. PMID- 30451425 TI - Morphological and Molecular Characterization of Paralongidorus sali Siddiqi, Hooper, and Khan, 1963 with a Description of the First-Stage Juvenile and Male of Longidorus jonesi Siddiqi, 1962 from China. AB - Longidorids are economically important plant-parasitic nematodes because several species are virus vectors. Populations of Paralongidorus sali and Longidorus jonesi , isolated from woody perennials of Hangzhou, Zhejiang, China, were characterized molecularly and morphologically. The morphometric data of the Chinese populations of both species were compared with other populations. The present study provided a first record of the occurrence of Paralongidorus in China coupled with description of the first-stage Juvenile and male of L. jonesi . Phylogenetic analysis based on 18S and D2-D3 expansion segments of 28S gene indicated that L. jonesi clustered with L. jonesi reported from Japan and P. sali grouped with P. bikanerensis from Iran. Considering the pathological and economic importance of this group of nematodes, the study emphasized the need of updated descriptions from accurately identified specimens, isolation of sufficient material for examination, and molecular and phylogenetic analysis for a better understanding and diagnostics of Longidorid nematodes. PMID- 30451424 TI - First Report of Bitylenchus hispaniensis, Pratylenchoides alkani, and Helicotylenchus vulgaris in Association with Cultivated and Wild Olives in Crete, Greece and Molecular Identification of Helicotylenchus microlobus and Merlinius brevidens. AB - Nematode samplings in cultivated and wild olive in Crete, Greece, yielded the presence of Bitylenchus hispaniensis , Helicotylenchus microlobus , Helicotylenchus vulgaris , Merlinius brevidens , and Pratylenchoides alkani . With the exception of H. microlobus and M. brevidens , reports of these plant parasitic nematode species constitute new records for Greece. Bitylenchus hispaniensis is also reported for first time in a country outside of Spain, where it was originally described. Pratylenchoides alkani is herein reported for the second time in the Mediterranean area and for the first time in association with olive. Two further populations of H. microlobus and H. vulgaris , from walnut and goji berry from Greece, were identified. Molecular data for all of these nematode species are provided, resulting in the first integrative identification of these Greek populations. PMID- 30451427 TI - First Report of Stubby-Root Nematode, Paratrichodorus minor, on Onion in Georgia, U.S.A. AB - Onions ( Allium cepa L.) are the leading vegetable crop in Georgia accounting for 13.7% of total state vegetable production ( Wolfe and Stubbs, 2017 ). In November 2017, two samples each of onion (var. Candy Ann) seedlings and soil were received from the University of Georgia Cooperative Extension office in Tattnall County, GA. The samples were collected from a nursery fumigated with metam sodium and used for sweet onion transplant production. Symptoms of the damaged plants included stunted growth both in the root system and foliage, tip die-back of the leaves ( Fig. 1A,B ), and slight swelling at the tip of roots. Vermiform life stages from the soil samples were extracted using centrifugal-flotation technique ( Jenkins, 1964 ). On an average, 67 stubby-root nematodes per 100 cm 3 of soil were obtained. Additional two soil samples were collected from the nursery in December 2017 to confirm the presence of the nematode. On an average, 1 and 75 nematodes per 100 cm 3 of soil were recovered from areas with healthy and infested plants, respectively. Because the male individuals were not found in the soil samples, females were used for species identification. Morphological and molecular analyses of females ( Fig. 2A-C ) identified the species as Paratrichodorus minor (Colbran) Siddiqi; ( Decraemer, 1995 ). Nematode body shape was "cigar-shaped" with dorsally curved "onchiostyle" stylet Females had an oval shaped vagina, vulva a transverse slit, and lateral body pores were absent. The measurements of females ( n = 20) included: body length 671.1 (570.1-785.3) um; body width 32.5 (27.8-37.0) um; onchiostyle 32.5 (31.1-34.8) um; anterior end to esophagus-intestinal valve 117.6 (101.2-128.5) um; a 21.5 (15.3-28.1) um; b 5.2 (4.9-6.3) um; V 52.9% (48.1-55.4%) um; and vagina length 8.7 (7.8-10.7) um. To confirm the identity of P. minor, DNA was extracted from single females ( n = 3) using Extract-N-Amp TM Tissue PCR Kit (Sigma-Alredich Inc., St. Louis, MO). The partial 18S rRNA, the D2-D3 expansion segments of 28S rRNA, and ITS1 rDNA were amplified using primer pairs 360F (5' CTACCACATCCAAGGAAGGC 3')/932R (5' TATCTGATCGCTGTCGAACC 3'), D2A (5' ACAAGTACCGTGAGGGAAAGTTG 3')/D3B (5' TCGGAAGGAACCAGCTACTA 3'), and BL18 (5' CCCGTCGCTACTACCGATT 3')/5818 (5' ACGARCCGAGTGATCCAC 3'), respectively ( Riga et al., 2007 ; Duarte et al., 2010 ; Ye et al., 2015 ; Shaver et al., 2016 ). The obtained PCR fragments were purified using QIAquick Gel Extraction Kit (Qiagen Inc., Santa Clara, CA, USA), sequenced and deposited in the GenBank databases (18S rRNA: MG856931; 28S rRNA: MG856933; ITS1 rDNA: MH464152). The 18S rRNA, 28S D2-D3, and ITS1 rDNA sequences shared 99% similarity (100% coverage) with GenBank accessions of P. minor from California, Arkansas, and China (18S rRNA: JN123365; 28S D2-D3: JN123395; ITS1 rDNA: GU645811). In a pathogenicity test, five sweet onion seeds var. Pirate were planted (one per pot) in 11.5-cm-diameter polyethylene pots containing 1,000 cm 3 of equal parts of pasteurized field soil and sand, and then inoculated with 1,000 fresh P. minor . Plants were grown for 9 wk in a greenhouse at 25 +/- 2 degrees C prior to extraction of nematodes from soil. Plant roots were abbreviated and final population density of P. minor was 2,856 +/- 104 per pot (285 nematodes/100 cm 3 of soil) confirming the nematode parasitism on onion. To our knowledge, this is the first report of P. minor parasitizing onion in Georgia. Stubby-root nematode ( Paratrichodorus sp.) has already been reported on corn, St. Augustine grass, and switchgrass in Georgia ( Heald and Perry, 1969 ; Davis and Timper, 2000 ; Mekete et al., 2011 ). In the U.S.A, P. minor is known to occur on diverse crops in most of the states ( Decraemer, 1995 ; CABI/EPPO, 2002 ). A survey of vegetable-producing areas in Georgia is currently under investigation to determine the distribution of this economically important nematode species. Figure 1Damage symptoms caused by stubby-root nematode Paratrichodorus minor on sweet onion in Georgia. A large area of stunted and chlorotic plant foliage (A); Infested seedlings with abbreviated roots and necrotic leaf tips (B). Figure 2Light microscopy micrographs showing morphological characters of stubby-root nematode, Paratrichodorus minor. Entire body (A), anterior end (B), and posterior region (C) of female nematode. PMID- 30451426 TI - Description of Aphelenchoides giblindavisi n. sp. (Nematoda: Aphelenchoididae), and Proposal for a New Combination. AB - One new and one known species of the genus Aphelenchoides from Iran are studied. Aphelenchoides giblindavisi n. sp. is mainly characterized by having five lines in the lateral fields at mid-body, and a single mucro with several tiny nodular protuberances, giving a warty appearance to it, as revealed by detailed scanning electron microscopic (SEM) studies. The new species is further characterized by having a body length of 546 to 795 MUm in females and 523 to 679 MUm in males, rounded lip region separated from the rest body by a shallow depression, 10 to 11 MUm long stylet with small basal swellings, its conus shorter than the shaft ( m = 36-43), 52 to 69 um long postvulval uterine sac (PUS), males with 16 to 18 MUm long arcuate spicules, and three pairs of caudal papillae. The new species was morphologically compared with two species of the genus having five lines in the lateral fields namely A. paramonovi and A. shamimi and species having a warty surfaced mucro at tail end and similar morphometric data ranges. The morphological features and morphometrics of the second studied species, A. helicus , agreed well with the data given for the type population. However, detailed study of fresh females revealed it has three drop-shaped stylet knobs and long PUS, making it typologically similar to the genus Robustodorus , meriting its taxonomic revision, i.e., transferring to it. In molecular phylogenetic analyses using partial small and large subunit ribosomal RNA gene (SSU and LSU rDNA) sequences, the new species formed a clade with A. heidelbergi in both SSU and LSU D2-D3 trees. The species A. helicus , however, clustered inside a well-supported clade of the genus Robustodorus in both trees, corroborating its newly proposed taxonomic placement as Robustodorus helicus n. comb. PMID- 30451428 TI - First Report of the Yellow Nutsedge Cyst Nematode, Heterodera cyperi, in Georgia, U.S.A. AB - Soil samples collected during a survey for plant-parasitic nematodes in Tift County GA in summer 2017 were submitted for routine diagnosis of nematodes to the Extension Nematology Lab at the Department of Plant Pathology, University of Georgia, Athens, Georgia. Cyst nematodes recovered by centrifugal flotation technique were discovered in the samples from two research sites in a field with a history of tobacco and vegetable production. Cyst nematodes from tobacco (10 cysts/100 cm 3 of soil) and vegetable (2 cysts/100 cm 3 of soil) sites had similar morphological features. Morphology and morphometric measurements of the cysts and J2 ( Fig. 1A-C ) were in agreement with those of Heterodera cyperi ( Golden et al., 1962 ; Romero and Lopez-Llorca, 1996 ). Measurements of J2 ( n = 12) included the length (range = 443-494 MUm, mean = 467.4 MUm) and width (18.3 24.4 MUm, 20.6 MUm) of body, stylet (19.1-20.8 MUm, 20.3 MUm), tail (61.6.0-66.4 MUm, 64.2 MUm), body width at anus (11.9-14.1 MUm, 12.8 MUm), and hyaline tail terminus (22.7-29.2 MUm, 26.3 MUm). The lateral field of J2 had three lines. Cysts ( n = 10; Fig. 1C ) were lemon-shaped, light to dark brown in color with protruding neck and vulval cone. The cysts had ambifenestrated vulval cone and no bullae was present. Morphometrics included body length excluding neck (370.5 714.4 MUm, 555.7 MUm); body width (165.6-411.1 MUm, 310.9 MUm); neck length (36.5 66.3 MUm, 49.8 MUm); fenestra length (26.3-42.5 MUm, 35.8 MUm), and fenestra width (19.1-31.5 MUm, 23.8 MUm). DNA was extracted from single cysts ( n = 3) and internal transcribed spacer (ITS) of rRNA and partial cytochrome oxidase I ( COI ) genes were amplified with primers TW81/AB28 and Het-coxiF/Het-coxiR, respectively ( Subbotin et al., 2001 ; Subbotin, 2015 ) and sequenced. The resulting sequences were deposited into the GenBank database (Accession no. MG825344 and MG857126) and also subjected to BLAST searches in the database. ITS sequence of H. cyperi showed 100% similarity (100% coverage) with that of a H. cyperi population from Spain (AF274388). COI sequence of H. cyperi showed 89% similarity (98% coverage) with that of H. guangdongensis (MF425735), and 88% similarity (83% coverage) with that of H. elachista (KC618473). The pathogenicity of H. cyperi was examined under greenhouse conditions using tobacco cv. K340, tomato cv. Tribute, cucumber cv. Thunder, and yellow nutsedge ( Cyperus esculentus L.). 3-wk-old seedlings of the test plants were transferred into Deepot D25L cell containers (5-cm-diam. * 25.4-cm deep) filled with sterilized sand: sand: soil mixture (1:2) and then inoculated with 1,000 eggs and J2 of H. cyperi . The plants were grown for 90 d in a greenhouse before examination of roots and extraction of cysts from the soil. Results showed that the nematode failed to reproduce on tobacco, tomato, and cucumber whereas white females and mature cysts of H. cyperi were observed on yellow nutsedge roots ( Fig. 1E ). The results confirmed that yellow nutsedeg was a host for the nematode, and tobacco, tomato, or cucumber were non-hosts. In the United States, H. cyperi was reported from Florida, North Carolina, and Arkansas ( Subbotin et al., 2010 ) infecting Cyperus spp. Yellow nutsedge is considered a serious weed problem in many cropping systems including peanut, cotton, tobacco, and vegetable crops in the Southern United States. To our knowledge, this is the first report of H. cyperi infecting yellow nutsedge in Georgia. Figure 1Photomicrographs of Heterodera cyperi from yellow nutsedge in Georgia. Whole body (A), the anterior region (B), and the posterior region (C) of J2. Cysts (D) recovered from the soil and the vulval cone of cyst with the ambifenestrate fenestra (E). A mature cyst (F) on the surface of yellow nutsedge root infected with the nematode. PMID- 30451429 TI - An Agent-Based Metapopulation Model Simulating Virus-Based Biocontrol of Heterodera Glycines. AB - With recently discovered soybean cyst nematode (SCN) viruses, biological control of the nematodes is a theoretical possibility. This study explores the question of what kinds of viruses would make useful biocontrol agents, taking into account evolutionary and population dynamics. An agent-based model, Soybean Cyst Nematode Simulation (SCNSim), was developed to simulate within-host virulence evolution in a virus-nematode-soybean ecosystem. SCNSim was used to predict nematode suppression under a range of viral mutation rates, initial virulences, and release strategies. The simulation model suggested that virus-based biocontrol worked best when the nematodes were inundated with the viruses. Under lower infection prevalence, the viral burden thinned out rapidly due to the limited mobility and high reproductive rate of the SCN. In accordance with the generally accepted trade-off theory, SCNSim predicted the optimal initial virulence for the maximum nematode suppression. Higher initial virulence resulted in shorter lifetime transmission, whereas viruses with lower initial virulence values evolved toward avirulence. SCNSim also indicated that a greater viral mutation rate reinforced the virulence pathotype, suggesting the presence of a virulence threshold necessary to achieve biocontrol against SCN. PMID- 30451430 TI - Revisiting the Life-Cycle of Pasteuria penetrans Infecting Meloidogyne incognita under Soil-Less Medium, and Effect of Streptomycin Sulfate on its Development. AB - Pasteuria penetrans is a Gram-positive, endospore forming soil bacterium, infecting root-knot nematodes, Meloidogyne spp. Being obligate in nature, the bacterium is not easily grown in vitro, and the in vivo culturing technique is relied on the soil-based microcosm since long. Hence, culturing of P. penetrans using CYG germination pouches as a soil-less medium for plant growth, promises to provide a contamination free environment along with ease in isolation of infected females from the plant roots. Additionally, this method increases the percentage of P. penetrans infected nematode females as compared with the soil-based system. Schematic observation of all the life stages of P. penetrans was documented, which revealed chronological fragmentation of vegetative microcolony inside the nematode body demonstrating the formation of some stages not reported earlier. Further, germination of endospores attached to infective juveniles was found to be most likely asynchronous as single female nematode contained most of the developing stages of P. penetrans concurrently. Additionally, the effect of an antibiotic, streptomycin sulfate was evaluated for effects on the growth and development of the bacterium at different concentrations. Higher doses of antibiotic were found to exert a negative impact on the development of P. penetrans , which shows the incompatibility of Pasteuria and streptomycin sulfate. PMID- 30451431 TI - Molecular Identification of Entomopathogenic Nematode Isolates from the Philippines and their Biological Control Potential Against Lepidopteran Pests of Corn. AB - In search for local entomopathogenic nematode (EPN) species as a biological control agent of lepidopterous insect pests of corn, a survey for EPN in the major islands in the Philippines was conducted. Seven EPN populations from 279 soil samples were isolated using Ostrinia furnacalis, the key target insect pest of corn in the country, as bait. Analysis of the ITS1-5.8S-ITS2 ribosomal DNA sequence revealed the presence of Steinernema abbasi, Steinernema minutum , Steinernema tami , and Heterorhabditis indica . The pathogenicity of these EPN was tested in Ostrinia furnacalis , Spodoptera litura , and Helicoverpa armigera larvae under laboratory conditions. All the EPN isolates were pathogenic to the lepidopteran species with, H. indica PBCB and S. abbasi MBLB exhibiting the highest virulence (88%-99.33% and 90%-100% mortality, respectively) at 48 hr post infection (HPI) and thus, further studies were done on these two EPN. The highest penetration rate at 48 HPI was observed in H. armigera infected with S. abbasi MBLB (28.15%), while the lowest was in O. furnacalis infected with H. indica PBCB (14.25%). Nonetheless, based on LC 50 at 48 HPI, H. indica PBCB was most virulent to S. litura (8.89 IJ per larva), but not significantly different from O. furnacalis (10.52 IJ per larva). Steinernema abbasi MBLB was most virulent to O. furnacalis (10.98 IJ per larva), but not significantly different to S. litura (17.08 IJ per larva). LT 50 estimates showed that O. furnacalis was significantly the most susceptible to H. indica PBCB (21.90 hr) and S. abbasi (21.18 hr). Our results suggest that H. indica PBCB and S. abbasi MBLB are good candidates as biological control agents against these insect pests of corn. Moreover, O. furnacalis as alternative bait for EPN was discussed. To date, this is the most extensive research on Philippine EPN, comprised of wide sampling coverage, molecular identification and bioefficacy assays. PMID- 30451432 TI - Nematode Genome Announcement: A Draft Genome for Rice Root-Knot Nematode, Meloidogyne graminicola. AB - The rice root-knot nematode Meloidogyne graminicola has emerged as a devastating pest of rice in South-East Asian countries. Here we present a draft genome sequence for M. graminicola , assembled using data from short and long insert libraries sequenced on Illumina GAIIx sequencing platform. PMID- 30451433 TI - Morphological Re-Description and 18 S rDNA Sequence Confirmation of the Pinworm Aspiculuris tetraptera (Nematoda, Heteroxynematidae) Infecting the Laboratory Mice Mus musculus. AB - Aspiculuris tetraptera is a heteroxynematid nematoda infecting most of the laboratory animals, occasionally mice which represent the mostly used animal for biological, medical, and pharmacological studies. The present study aimed to investigate the prevalence of nematode parasites infection in the laboratory mice Mus musculus in Egypt. Morphologically, this oxyurid possessed four distinct cephalic papillae on a cephalic plate, with three small rudimental lips carrying two sessile poorly developed labial papillae and one pair of amphidial pores. Esophagus divided into cylindrical corpus and globular bulb. Distinct cervical alae interrupted at the level of esophago-intestinal junction forming an acute angle. At the caudal end, twelve caudal papillae in male worms while an ovijector apparatus opening and a vulva surrounded by protruded lips in females were observed. The general morphological criteria include this nematode with other Aspiculuris species which were compared in the present study. Molecular characterization based on 18SSU rDNA sequencing performed to confirm the taxonomic position of this species and to documents the morphological data. Sequence alignment detects a percent of identity up to 88.0% with other Heteroxynematidae species. Phylogenetic analysis showed that the present recorded is a putative sister taxon to A. tetraptera recorded in a previous study. The SSU rDNA sequence has been deposited in the GenBank under the accession no. MG019400. PMID- 30451434 TI - Stauratostoma shelleyi n. gen., n. sp. (Nematoda: Rhabditida: Thelastomatidae) from Appalachian Polydesmid Millipedes (Polydesmida: Xystodesmidae). AB - Stauratostoma shelleyi n. gen., n. sp. is described from the midgut and hindgut of nine species of the millipede family Xystodesmidae collected in the southern Appalachian regions of North Carolina, Tennessee and Alabama. Specimens of S. shelleyi were morphologically examined with differential interference contrast, phase contrast, and scanning electron microscopy. The head of S. shelleyi differs from other thelastomatid nematodes in having a head region mushroom-shaped in profile; cruciform stomatal opening formed from four flaps; greatly expanded labial disc; and eight-sectored annule-like column supporting the labial disc. Thirteen nematodes from various hosts were sequenced for 28S LSU rDNA and compared with other millipede-inhabiting nematodes. Stauratostoma shelleyi is the sister group to the few Thelastoma spp. that have been molecularly characterized using the D2-D3 expansion segments of the 28S LSU rDNA. PMID- 30451435 TI - Activity of Vetiver Extracts and Essential Oil against Meloidogyne incognita. AB - Vetiver, a nonhost grass for certain nematodes, was studied for the production of compounds active against the southern root-knot nematode, Meloidogyne incognita . In laboratory assays studying the effects on second-stage juvenile (J2) activity and viability, crude vetiver root and shoot extracts were nematotoxic, resulting in 40% to 70% J2 mortality, and were also repellent to J2. Vetiver oil did not exhibit activity against J2 in these assays. Gas chromatography-mass spectrometry analyses of three crude vetiver root ethanol extracts and a commercial vetiver oil determined that two of the major components in each sample were the sesquiterpene acid 3,3,8,8-tetramethyltricyclo[5.1.0.0(2,4)]oct-5-ene-5-propanoic acid and the sesquiterpene alcohol 6-isopropenyl-4,8a-dimethyl-1,2,3,5,6,7,8,8a octahydronaphthalen-2-ol. The acid was present in higher amounts in the extracts than in the oil. These studies demonstrating nematotoxicity and repellency of vetiver-derived compounds to M. incognita suggest that plant chemistry plays a role in the nonhost status of vetiver to root-knot nematodes, and that the chemical constituents of vetiver may be useful for suppressing nematode populations in the soil. PMID- 30451436 TI - Molecular Characterization and Phylogeny of Ditylenchus weischeri from Cirsium arvense in the Prairie Provinces of Canada. AB - Ditylenchus weischeri that parasitizes the weed Cirsium arvense (L.) Scop., 1772, (creeping thistle) was described in 2011 from Russia based on their morphology, ITS-RFLP analysis, and Hsp 90 gene sequence of a few individuals and one field collection of the plant. More recently, we found C. arvense parasitized by D. weischeri in the Prairie Provinces of Canada. Plant host preference for D. weischeri was also distinct from D. dipsaci (Kuhn) Filipjev, 1936. In the current study, a comprehensive molecular analysis of many D. weischeri specimens from Canada is presented. Individuals from 41 C. arvense or yellow pea grain samples with seeds of C. arvense from the Prairie Provinces were sequenced for the internal transcribed spacer (ITS rDNA), large subunit (LSU) D2D3 28S rDNA, partial segment of small subunit (SSU) 18S rDNA, and the heat shock protein Hsp 90 gene. The analysis also included D. weischeri individuals from C. arvense from Russia and garlic with D. dipsaci from the Provinces of Ontario and Quebec in Canada. Available sequence data of Ditylenchus species retrieved from GenBank were used to phylogenetically position this species within the genus Ditylenchus . In all studied genes, several single-nucleotide polymorphisms between the Canadian D. weischeri and both Russian haplotype and individuals of D. weischeri from C. arvense from Russia were found. The sequences of ITS rDNA, LSU D2D3 28S rDNA, and Hsp 90 were used to construct separate dendrograms. For each of the three genes examined, D. weischeri was grouped separately from the other Ditylenchus . Ditylenchus samples from C. arvense was positioned to a single clade such as D. weischeri and distinct from D. dipsaci . With past reports of plant host preference and morphology, the results of this study provide further evidence for the fact that D. weischeri is distinct to be separated from D. dipsaci . Furthermore, minor differences in molecular divergence and morphology to the Russian haplotype and limited symptoms of disease on C. arvense in Prairie Canada suggest the Canadian and Russian populations of D. weischeri may be diverging. PMID- 30451437 TI - Description and Distribution of Three Criconematid Nematodes from Hangzhou, Zhejiang Province, China. AB - Populations of Criconemoides parvus , Discocriconemella hengsungica , and Discocriconemella limitanea , isolated in Hangzhou, China from the rhizosphere soil of woody perennials were characterized morphologically and molecularly. The morphometric data of the Chinese populations were compared with populations from other regions of the world. DNA barcoding with the mitochondrial COI gene confirmed conspecificity of Chinese and Costa Rican populations of D. limitanea . Phylogenetic assessment using a near full-length 18S ribosomal DNA sequence provided weak support for a grouping of Criconemoides parvus from China and C. annulatus from western North America. The phylogenetic position of D. hengsungica from China and an unknown species of Discocriconemella from Thailand relative to D. limitanea suggests that the genus Discocriconemella is not monophyletic. The study provides the first record of D. hengsungica in China and confirms the presence of C. parvus previously reported from China. Biogeographic implications of these nematode distributions are discussed. PMID- 30451438 TI - Description of Longidorus azarbaijanensis n. sp. (Dorylaimida: Longidoridae) from Iran. AB - Longidorus azarbaijanensis n. sp. is described and illustrated using morphological and molecular data. It was recovered in West Azarbaijan province, northwestern Iran, from the rhizospheric soil of foxtail weed. The new species is characterized by having 5.4 to 6.8 mm long females, offset, anteriorly flat lip region and separated from the rest of the body by a shallow constriction, funnel shaped amphidial pouches, the guiding ring at 23 to 27 um from the anterior end, 73 to 81 and 44 to 50 um long odontostyle and odontophore, respectively, 95.0 to 113.5 um long pharyngeal bulb, didelphic-amphidelphic reproductive system with long tubular uteri lacking sperm cells, vulva located at 52.0% to 56.4%, conical tail dorsally convex, ventrally flat, with bluntly rounded wide tip, for juvenile developmental stages and absence of males. The general body shape of the new species is similar to that of five known species of the genus namely L. euonymus, L. perangustus, L. persicus, L. protae and L. sturhani . The morphological differences of the new species with the aforementioned species are discussed. For all the aforementioned species (except L. protae, currently lacking molecular data) the differences of the new species was also confirmed with differences in molecular sequences of D2-D3 expansion domains of 28S rDNA and the corresponding phylogenetic analyses. The partial sequence of the internal transcribed spacer 1 (ITS1) of the new species was also used in phylogenetic analyses. In partial 28S tree, the clade including the new species and six other species ( L. attenuatus, Longidorus sp. and four above-mentioned species having molecular data for this fragment) was well supported in Bayesian inference. In the ITS1 tree, the new species formed a clade with L. euonymus , L. perangustus and L. persicus , as in 28S tree. This is one of the cases from which the morphologically similar species are separated using molecular sequences. PMID- 30451439 TI - Nothotylenchus andrassy n. sp. (Nematoda: Anguinidae) from Northern Iran. AB - Nothotylenchus andrassy n. sp. is described and illustrated from moss ( Sphagnum sp.) based on morphology and molecular analyses. Morphologically, this new species is characterized by a medium body size, six incisures in the lateral fields, and a delicate stylet (8-9 um long) with clearly defined knobs. Pharynx with fusiform, valveless, non-muscular and sometimes indistinct median bulb. Basal pharyngeal bulb elongated and offset from the intestine; a long post-vulval uterine sac (55% of vulva to anus distance); and elongate, conical tail with pointed tip. Nothotylenchus andrassy n. sp. is morphologically similar to five known species of the genus, namely Nothotylenchus geraerti , Nothotylenchus medians , Nothotylenchus affinis , Nothotylenchus buckleyi , and Nothotylenchus persicus . The results of molecular analysis of rRNA gene sequences, including the D2-D3 expansion region of 28S rRNA, internal transcribed spacer (ITS) rRNA and partial 18S rRNA gene are provide for the new species. PMID- 30451440 TI - First Report of Carrot Cyst Nematode Heterodera carotae in Mexico: Morphological, Molecular Characterization, and Host Range Study. AB - During 2008 to 2016 in several nematological surveys in the Tepeaca Valley, Puebla, Mexico, carrot cyst nematode, Heterodera carotae was found parasitizing carrots, Daucus carota . The nematode was present in 61% of the sampled fields with high population densities, causing severe carrot yield losses in the Tepeaca Valley. The aim of this work was to study morphology, morphometrics, host range, and molecular characterization of the nematode. The morphological and morphometric characterization was made using light and scanning electron microscopy of the second stage juveniles, females, males and cysts, and the host range study, was performed with nine different plants from five families. The molecular identification was made by sequencing and analysing the ITS rRNA and partial COI genes. It was shown that using presently available molecular tools it is not possible to make an accurate differentiation of H. carotae from H. cruciferae . The host range test allowed to distinguish these species from each other. Our study showed that male stylet length is longer for H. carotae compared with that for H. cruciferae . This is an example of importance of combination of several methods for the correct identification of cyst nematodes. To our knowledge, this is the first report of H. carotae in Mexico. PMID- 30451441 TI - Are Probiotic Really Safe for Humans? AB - Probiotic bacteria have been used as a health-promoting factor for a very long time. Nowadays, products containing probiotic bacteria are becoming more and more popular on the market. The term probiotics refers to the products belonging to the following groups: probiotic drugs (medicinal products - live biotherapeutic products for human use), medical devices, probiotic foods (e.g. foods, food ingredients, dietary supplements or food for special medical purposes), directly fed microorganisms (for animal use) and designer probiotics (genetically modified probiotics). Safety assessment of bacterial strains used as probiotics should be carefully studied. Even though probiotic bacteria have the generally recognized as safe (GRAS status), there are several reports about side effects triggered by the presence of these organisms. Microorganisms used as probiotics may cause systemic infections, stimulate the immune system, disturb metabolism and participate in horizontal gene transfer. PMID- 30451442 TI - Secondary Metabolites of Actinomycetes and their Antibacterial, Antifungal and Antiviral Properties. AB - The growing resistance of microorganisms towards antibiotics has become a serious global problem. Therapeutics with novel chemical scaffolds and/or mechanisms of action are urgently needed to combat infections caused by multidrug resistant pathogens, including bacteria, fungi and viruses. Development of novel antimicrobial agents is still highly dependent on the discovery of new natural products. At present, most antimicrobial drugs used in medicine are of natural origin. Among the natural producers of bioactive substances, Actinobacteria continue to be an important source of novel secondary metabolites for drug application. In this review, the authors report on the bioactive antimicrobial secondary metabolites of Actinobacteria that were described between 2011 and April 2018. Special attention is paid to the chemical scaffolds, biological activities and origin of these novel antibacterial, antifungal and antiviral compounds. Arenimycin C, chromopeptide lactone RSP 01, kocurin, macrolactins A1 and B1, chaxamycin D as well as anthracimycin are regarded as the most effective compounds with antibacterial activity. In turn, the highest potency among selected antifungal compounds is exhibited by enduspeptide B, neomaclafungins A-I and kribelloside D, while ahmpatinin i Bu, antimycin A1a, and pentapeptide 4862F are recognized as the strongest antiviral agents. PMID- 30451443 TI - Exopolysaccharides Produced by Lactobacillus rhamnosus KL 53A and Lactobacillus casei Fyos Affect Their Adhesion to Enterocytes. AB - Probiotics promote and help to maintain beneficial microbiota composition of the gastrointestinal tract ecosystem and have a positive impact on the host's health. Production of exopolysaccharides is an important feature of probiotic lactobacilli. It increases the chance of their survival in the gastrointestinal tract and promotes adhesion to the epithelium; therefore, exopolysaccharides are important for the process of colonization. Two lactic acid bacteria strains were used in this study: Lactobacillus rhamnosus KL 53A and Lactobacillus casei Fyos. Exopolysaccharides were isolated from bacterial cells and their monosaccharide composition was examined using liquid chromatography. The influence of exopolysaccharides on lactobacilli adhesion to enterocytes was studied after deglycosylation of the bacterial cells and incubation with the selected intestinal microbiota strains that metabolize polysaccharides - Faecalibacterium prausnitzii DSM 17677 and Blautia luti DSM 14534. Both deglycosylation and incubation with polysaccharide metabolizing strains influenced the ability of probiotic strains to adhere to enterocytes. Enzymatic deglycosylation decreased adhesion efficiency of L. rhamnosus KL 53A; however, co-incubation of both lactobacillus strains with F. prausnitzii DSM 17677 resulted in an increase of their adhesion efficiency. Exopolysaccharides are important adhesins of Lactobacillus spp. that influence their ability to colonize gut epithelium. Other members of gut microbiota can modify the adhesion property in situ ; therefore the composition and metabolic state of commensal bacteria may influence their probiotic action. PMID- 30451444 TI - Biohydrogen Production by Antarctic Psychrotolerant Klebsiella sp. ABZ11. AB - Lower temperature biohydrogen production has always been attractive, due to the lower energy requirements. However, the slow metabolic rate of psychrotolerant biohydrogen-producing bacteria is a common problem that affects their biohydrogen yield. This study reports on the improved substrate synthesis and biohydrogen productivity by the psychrotolerant Klebsiella sp. strain ABZ11, isolated from Antarctic seawater sample. The isolate was screened for biohydrogen production at 30 degrees C, under facultative anaerobic condition. The isolate is able to ferment glucose, fructose and sucrose with biohydrogen production rate and yield of 0.8 mol/l/h and 3.8 mol/g, respectively at 10 g/l glucose concentration. It also showed 74% carbohydrate uptake and 95% oxygen uptake ability, and a wide growth temperature range with optimum at 37 degrees C. Klebsiella sp. ABZ11 has a short biohydrogen production lag phase, fast substrate uptake and is able to tolerate the presence of oxygen in the culture medium. Thus, the isolate has a potential to be used for lower temperature biohydrogen production process. PMID- 30451445 TI - Evaluation of Modified Hodge Test as a Non-molecular Assay for Accurate Detection of KPC-producing Klebsiella pneumoniae. AB - Klebsiella pneumoniae carbapenemase (KPC) have become a major therapeutic challenge because of its increasingly fast dissemination throughout the world. Accurate detection of KPC is essential for optimal treatment. The Clinical and Laboratory Standards Institutes (CLSI) for fast detection of KPC producers currently recommend Modified Hodge Test (MHT) and Carba NP test. MHT can directly detect carbapenemase production in Enterobacteriaceae isolates. The current study was conducted to evaluate the capacity of MHT with two carbapenem disks for accurate detection of KPC. MHT was performed according to guidelines of CLSI to identify isolates with carbapenem resistance. In doing so, two substrates of MHT were assigned into two groups for examination: meropenem and ertapenem groups. A total of 96 non-repetitive clinical isolates of Klebsiella pneumoniae were tested. The presence of the bla KPC gene in each MHT-positive isolate was examined by PCR. A total of 54 isolates exhibited reduced susceptibility or resistance to carbapenems. Sensitivity of MHT with two carbapenem disks was similar. Specificity of the MHT with meropenem disk was 64% and with ertapenem disk was 53%. Detection of KPC by MHT with meropenem disk was found to be more effective than with ertapenem disk. Based on our results, the presence of KPC does not in itself influence the categorization of resistance. Therefore, the use of MHT with ertapenem disk for the rapid detection of KPC among K. pneumoniae for infection control should not be recommended. PMID- 30451446 TI - Optimization of Mixed Solid-state Fermentation of Soybean Meal by Lactobacillus Species and Clostridium butyricum. AB - Soybean meal is the main vegetable protein source in animal feed. Soybean meal contains several anti-nutritional factors, which directly affect digestion and absorption of soy protein, thereby reducing growth performance and value in animals. Fermented soybean meal is rich in probiotics and functional metabolites, which facilitates soybean protein digestion, absorption and utilization in piglets. However, the mixed solid-state fermentation (SSF) conditions of soybean meal remain to be optimized. In this study, we investigated the optimal parameters for SSF of soybean meal by Lactobacillus species and Clostridium butyricum . The results showed that two days of fermentation was sufficient to increase the viable count of bacteria, lactic acid levels and degradation of soybean protein in fermented soybean meal at the initial moisture content of 50%. The pH value, lowering sugar content and oligosaccharides in fermented soybean meal, was significantly reduced at the initial moisture content of 50% after two days of fermentation. Furthermore, the exogenous proteases used in combination with probiotics supplementation were further able to enhance the viable count of bacteria, degradation of soybean protein and lactic acid level in the fermented soybean meal. In addition, the pH value and sugar content in fermented soybean meal were considerably reduced in the presence of both proteases and probiotics. Furthermore, the fermented soybean meal also showed antibacterial activity against Staphylococcus aureus and Escherichia coli . These results together suggest that supplementation of both proteases and probiotics in SSF improves the nutritional value of fermented soybean meal and this is suitable as a protein source in animal feed. PMID- 30451447 TI - Broad Prebiotic Potential of Non-starch Polysaccharides from Oats (Avena sativa L.): an in vitro Study. AB - Prebiotics inducing the growth or activity of beneficial intestinal bacteria - probiotics producing short-chain fatty acids (SCFA) have lately received wide recognition for their beneficial influence on host intestinal microbiota and metabolic health. Some non-starch polysaccharides (NSP) are defined as prebiotics and oats being one of richest sources of NSP in grains are considered as potentially having prebiotic effect. However, information on fermentation of specific NSP of oats is limited. Moreover, bacterial cross-feeding interactions in which fermentation of prebiotics is involved is poorly characterized. Here, we report the exploration of new candidates for the syntrophic bacterial interactions and fermentability of oat non-starch polysaccharides (NSP). The results obtained by differentiating composition, viscosity and concentration of oats NSP in fermentation medium showed that Bacillus licheniformis pre-digests oat NSP, degrades high viscosity of oat beta-glucan and makes hemicellulose easier to access for other bacteria. Because of fermentation, B. licheniformis produces lactic and succinic acids, which further can be used by other bacteria for cross-feeding and SCFA production. PMID- 30451448 TI - The Effect of Silver Nanoparticles on Listeria monocytogenes PCM2191 Peptidoglycan Metabolism and Cell Permeability. AB - Listeria monocytogenes is Gram-positive bacterial pathogen, a causative agent of food poisoning and systemic disease - listeriosis. This species is still susceptible to several conventionally used antibiotics but an increase in its resistance has been reported. For this reason the search for new, alternative therapies is an urgent task. Silver nanoparticles seem to be the promising antibacterial agent. Minimal inhibitory concentration of silver nanoparticles was determined. Sublethal concentrations were used in study of nanosilver effect on cells lysis by estimation of the number of cells surviving the treatment with 0.25 or 0.5 of minimal inhibitory concentrations of silver nanoparticles. Autolysis of isolated peptidoglycan was studied by measuring the absorbance of preparation subjected to nanosilver treatment. Silver nanoparticles effect on L. monocytogenes envelopes permeability was determined by measuring the efflux of cF, DNA and proteins. It was demonstrated that nanosilver enhanced the lysis of L. monocytogenes cells and, to the lesser extent, autolysis of isolated peptidoglycan. The increase in the efflux of carboxyfluoresceine, DNA and proteins was also noted. The obtained results allow to postulate that L. monocytogenes peptidoglycan, constituting the main component of cell wall, is the target of silver nanoparticles activity against this pathogen. PMID- 30451449 TI - Isolation of Bacterial Endophytes from Phalaris arundinacea and their Potential in Diclofenac and Sulfamethoxazole Degradation. AB - Diclofenac (DCF), a non-steroidal anti-inflammatory drug (NSAID) and sulfamethoxazole (SMX), an antimicrobial agent, are in common use and can be often detected in the environment. The constructed wetland systems (CWs) are one of the technologies to remove them from the aquatic environment. The final effect of the treatment processes depends on many factors, including the interaction between plants and the plant-associated microorganisms present in the system. Bacteria living inside the plant as endophytes are exposed to secondary metabolites in the tissues. Therefore, they can possess the potential to degrade aromatic structures, including residues of pharmaceuticals. The endophytic strain MG7 identified as Microbacterium sp., obtained from root tissues of Phalaris arundinacea exposed to DCF and SMX was tested for the ability to remove 2 mg/l of SMX and DCF in monosubstrate cultures and in the presence of phenol as an additional carbon source. The MG7 strain was able to remove approximately 15% of DCF and 9% of SMX after 20 days of monosubstrate culture. However, a decrease in the optical density of the MG7 strain cultures was observed, caused by an insufficient carbon source for bacterial growth and proliferation. The adsorption of pharmaceuticals onto autoclaved cells was negligible, which confirmed that the tested strain was directly involved in the removal of DCF and SMX. In the presence of phenol as the additional carbon source, the MG7 strain was able to remove approximately 35% of DCF and 61% of SMX, while an increase in the optical density of the cultures was noted. The higher removal efficiency can be explained by adaptive mechanisms in microorganisms exposed to phenol (i.e. changes in the composition of membrane lipids) and by a co-metabolic mechanism, where non-growth substrates can be transformed by non-specific enzymes. The presence of both DCF and SMX and the influence of the supply frequency of CWs with the contaminated wastewater on the diversity of whole endophytic bacterial communities were demonstrated. The results of this study suggest the capability of the MG7 strain to degrade DCF and SMX. This finding deserves further investigations to improve wastewater treatment in CWs with the possible use of pharmaceuticals-degrading endophytes. PMID- 30451450 TI - Carbapenem-resistant Acinetobacter baumannii from Air and Patients of Intensive Care Units. AB - To understand the molecular epidemiology and antibiotic resistance of air and clinical isolates of Acinetobacter baumannii , the intensive care unit settings of a hospital in Northern China were surveyed in 2014. Twenty non-duplicate A. baumannii isolates were obtained from patients and five isolates of airborne A. baumannii were obtained from the wards' corridors. Pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were used to analyze the homology relationships of isolates. Resistance and resistance genes were detected by drug susceptibility test and PCR. The results demonstrated that all isolates can be classified into eight PFGE types and four sequence types (ST208, ST195, ST369 and ST530). A pair of isolates from patients (TAaba004) and from the air (TAaba012) that share 100% similarity in PFGE was identified, indicating that air might be a potential and important transmission route for A. baumannii . More than 80% of the isolates were resistant to carbapenems and aminoglycoside antibiotics. Twenty-four isolates, which were resistant to carbapenems, carried the bla OXA-23-like gene. The data indicated that air might be an alternative way for the transmission of A. baumannii . Hospitals should pay more attention to this route, and design new measures accordingly. PMID- 30451451 TI - Bacterial Microbiota and Fatty Acids in the Faeces of Overweight and Obese Children. AB - The growing number of children with overweight and obesity constitutes a major health problem of the modern world and it has been suggested that intestinal microbiota may influence energy intake from food. The objectives of this study were to determine quantity and proportions of dominant genera of Bacteroides, Prevotella (phylum Bacteroidetes ); Clostridium , Lactobacillus (phylum Firmicutes ) and Bifidobacterium (phylum Actinobacteria ) in the intestines and to determine the content of short-chain fatty acids (SCFAs) and branched-chain fatty acids (BCFAs) in the stool of 20 obese children and 20 children with normal body weight. Strains classified as Firmicutes ( Clostridium and Lactobacillus ) predominated in stool microbiota of obese children, while those of Bacteroidetes ( Prevotella and Bacteroides ) were in minority ( p < 0.001). Concentration of SCFAs in the stool of obese children was lower in comparison to the stool of normal weight children ( p = 0.04). However, these differences were significant only in obese children, not in overweight children in comparison with the lean ones. Therefore, in our study obesity was associated with intestinal dysbiosis and a predominance of phylum Firmicutes . Secondly, stool of obese children contained lower amounts of SCFAs. PMID- 30451452 TI - RNA Quality Control Using External Standard RNA. AB - In this paper, we propose a new evaluation method using external standard RNA for quality control of the extracted RNA. RNA Integrity Number and UV absorption are generally used as a basis for RNA quality control; however, these methods do not always reflect the quality of mRNA. While standard RNA is supposedly designed on the basis of mRNA, it has the potential to be used to evaluate the quality of the mRNA. In this study, we took into consideration the three essential factors, viz., yield of mRNA, inhibition to DNA polymerase, and degradation of mRNA for determining the RNA quality using standard RNA. It would be possible to know yield of mRNA and inhibition of the enzyme reaction by adding standard RNA before RNA extraction and looking at standard RNA loss. Degradation was evaluated by comparing the differences in the 3' and 5' regions of the RNA. In our study, it was demonstrated that in the crude extract of Saccharomyces cerevisiae , degradation was comparatively higher at the 3' end of RNA than at the 5' end. Hence, the degree of RNA degradation can be evaluated by comparing the ratio of degradation from the 3' and 5' end. PMID- 30451453 TI - Improved Production of Recombinant Human beta-NGF in Escherichia coli - a Bioreactor Scale Study. AB - Human nerve growth factor beta (beta-NGF) is considered a major therapeutic agent for treatment of neurodegenerative diseases. We have previously reported the optimized conditions for beta-NGF overproduction in Escherichia coli in a shake flask culture. In this study the optimal %DO (dissolved oxygen) and post induction temperature values for improved production of beta-NGF were found in the bioreactor scale using response surface methodology (RSM) as the most common statistical method. Also, for further enhancement of the yield, different post induction periods of time were selected for testing. In all experiments, the productivity level and bacterial cell growth were evaluated by western blotting technique and monitoring of absorbance at 600 nm, respectively. Our results indicated that %DO, the post-induction time and temperature have significant effects on the production of beta-NGF. After 2 hours of induction, the low post induction temperature of 32 degrees C and 20% DO were used to increase the production of beta-NGF in a 5-l bioreactor. Another important result obtained in this study was that the improved beta-NGF production was not achieved at highest dry cell weigh or highest cell growth. These results are definitely of importance for industrial beta-NGF production. PMID- 30451454 TI - The Emergence of Different Functionally Equivalent PAH Degrading Microbial Communities from a Single Soil in Liquid PAH Enrichment Cultures and Soil Microcosms Receiving PAHs with and without Bioaugmentation. AB - Polycyclic aromatic hydrocarbon (PAHs) are common soil contaminants of concern due to their toxicity toward plants, animals and microorganisms. The use of indigenous or added microbes (bioaugmentation) is commonly used for bioremediation of PAHs. In this work, the biodegradation rates and changes in the bacterial community structure were evaluated. The enrichment culture was useful for unambiguously identifying members of the soil bacterial community associated with PAH degradation and yielded a low diversity community. No significant difference in the rate of PAH degradation was observed between the microcosm receiving only PAHs or PAHs and bioaugmentation. Moreover, identical matches to the bioaugmentation inoculum were only observed at the initial stages of PAH degradation on day 8. After 22 days of incubation, the substantial degradation of all PAHs had occurred in both microcosms and the PAH contaminated soil had statistically significant increases in Alphaproteobacteria. There were also increases in Betaproteobacteria. In contrast, the PAH contaminated and bioaugmented soil was not enriched in PAH degrading Proteobacteria genera and, instead, an increase from 1.6% to 8% of the population occurred in the phylum Bacteroidetes class Flavobacteria, with Flavobacterium being the only identified genus. In addition, the newly discovered genus Ohtaekwangia increased from 0% to 3.2% of the total clones. These results indicate that the same soil microbial community can give rise to different PAH degrading consortia that are equally effective in PAH degradation efficiency. Moreover, these results suggest that the lack of efficacy of bioaugmentation in soils can be attributed to a lack of persistence of the introduced microbes, yet nonetheless may alter the microbial community that arises in response to PAH contamination in unexpected ways. PMID- 30451455 TI - Biochemical and Molecular Characterization of a Native Haloalkalophilic Tolerant Strain from the Texcoco Lake. AB - In the last decade several new genera have been isolated in alkaline and halophile growth conditions. The studies conducted in the Texcoco Lake soils have shown a generalized microbial adaptation to the specific conditions. In this research work, morphological and phylogenetic characterization of the HN31(22) strain that was isolated from the cited soil is presented. The strain was identified as a Gram-positive halophile and alkaline tolerant bacteria from the Nesterenkonia genus, which uses different substrates in metabolic processes. PMID- 30451456 TI - Gut Microbial Compositions in Four Age Groups of Tibetan Minipigs. AB - In this study, the gut microbiota was characterized in four age strata of Tibetan minipigs. Results indicated that the fecal bacteria of 7-, 28-, 56-, and 180-day old minipigs did not significantly differ in terms of phylogenetic diversity (i.e., PD whole tree) or the Shannon index (both, p > 0.05). Findings of a principal coordinate analysis demonstrated that fecal bacteria of 180-day-old minipigs were discernable from those of the other three age groups. From ages seven to 56 days, the abundance of Bacteroidetes or Firmicutes appeared to vary. Regarding genera, the populations of Bacteroides and Akkermansia decreased with increasing age. PMID- 30451457 TI - [Primary multiple malignant lung tumors. References and a clinical observation]. AB - The problem of primary multiple tumors is relevant to current clinical oncology because of increasing of number of patients with multiple malignant tumors and unsolved issues of treatment. Primary multiple malignant lung tumors is a common oncological situation requires an individualized, differentiated approach to treatment. The results of treatment are associated with the prevalence of the process, stages of tumor development, spare capacity of patients. There is presented clinical example of a patient with metachronous primary multiple malignant tumors of one lung. PMID- 30451458 TI - Publish or perish: Need for bibliometric and access reform. AB - Not available. PMID- 30451459 TI - Mapping the potential distribution of the schistosomiasis intermediate host Biomphalaria straminea in China. AB - Biomphalaria straminea is native to Brazil but has established a population in Guangdong Province, China. Its potential of expanding and transmitting Schistosoma mansoni is of great concern. We seek to map S. mansoni transmission potential by predicting ecological dimensions and potential distributions of B. straminea using state-of-the-art ecological niche model approaches. Two environmental datasets were selected to fit individual and ensemble niche models, together with the evaluation of niche conservatism during B. straminea invasion in China. A small area is still occupied by the introduced population compared to that in Brazil. A vast space with suitable climate remains unfilled and might be available to B. straminea. Contrasting results of niche conservatism evaluation were attained based on the two environmental datasets. The coastal areas in southern China, together with south-western Yunnan and southern Hainan and Taiwan were consistent supported by multiple model approaches, showing high climate suitability for B. straminea. Attention should be paid to the possibility of S. mansoni epidemic in these identified areas, as high pressure due to propagation and future climate change may further complicate conditions. Our results call for rigorous monitoring and supervising along these areas in China. PMID- 30451460 TI - Development of a hexagonal, mesh-based distribution method for community health centres. AB - Community health centres (CHCs) are the health gatekeepers of the local population. Location and numbers of the CHCs affect fairness and effectiveness with regard to access to primary health care. In the past, the distribution of the CHCs was solely empiric-based. The goal of this study was to devise a method for CHC distribution based on the principle of improving equity as well as ensuring efficiency. We tested the effectiveness and operability of the method through a process of revision and simulation using Guangdong Province, China as sample district. A methodology based on literature review and expert consultation was repeatedly applied until an ideal result had been reached. A hexagonal, mesh based method was developed and used to find a solution where the CHCs could be distributed where their location would be the most needed and total number suitable. Testing the effectiveness of the proposed plan, we found the proportion of area covered to be 52.8% and the proportion of the population covered 80.7%, which is 15.4% and 14.7%, respectively, better than before. It was concluded that the hexagonal mesh-based, distribution method can effectively define the location as well as the number or required CHCs, not only improving the accessibility for residents to primary health care services but also maximizing cost-effectiveness. Management of the city by grid is a new idea in urban management, which improves rationality of planning and also may be applied for many different purposes in addition to CHC localization. PMID- 30451461 TI - Bayesian zero-inflated spatio-temporal modelling of scrub typhus data in Korea, 2010-2014. AB - Scrub typhus, a bacterial, febrile disease commonly occurring in the autumn, can easily be cured if diagnosed early. However, it can develop serious complications and even lead to death. For this reason, it is an important issue to find the risk factors and thus be able to prevent outbreaks. We analyzed the monthly scrub typhus data over the entire areas of South Korea from 2010 through 2014. A 2 stage hierarchical framework was considered since weather data are covariates and the scrub typhus data have different spatial resolutions. At the first stage, we obtained the administrative-level estimates for weather data using a spatial model; in the second, we applied a Bayesian zero-inflated spatio-temporal model since the scrub typhus data include excess zero counts. We found that the zero inflated model considering the spatio-temporal interaction terms improves fitting and prediction performance. This study found that low humidity and a high proportion of elderly people are significantly associated with scrub typhus incidence. PMID- 30451462 TI - Spatial modelling and mapping of teen birth rates in Taiwan in the period 1995 2010. AB - Geographical variations in teen birth rates (TBR) still persist despite controlling for contextual factors. The aim of this research was to identify spatial patterns of TBR in Taiwan and to examine spatial relationships among different contextual factors. Using townships as the unit of analysis (N=359), this research used social and demographic variables for the years 1995, 2000, 2005 and 2010 and conducted spatial modelling of TBR. Geographical maps of TBR were presented, and Local Indicator of Spatial Autocorrelations was used to identify TBR clustering. Comparisons were made between ordinary least-squares models and spatial lag models, in which township-level TBRs were regressed on other township-level contextual characteristics. Our study found that townships with a high TBR were mostly in eastern, central and some southern regions of Taiwan, while townships with a low TBR were in the vicinity of metropolitan areas. The significant spatial lag indicated that townships would have a higher expected prevalence rate if adjacent townships have had higher rates. Results also indicated that the percentage of aborigines and the percentage of college educated people were consistently associated with TBR over the years. Interventions aimed at reducing TBR in Taiwan should consider the presence of spatial correlations and should incorporate neighbouring townships. PMID- 30451463 TI - Spatial analysis of asbestos exposure and occupational health care in Poland during the period 2004-2013. AB - Asbestos is carcinogenic to humans and exposure to this substance can cause a wide range of diseases. In Poland 1997, a statutory ban was introduced on the production, use and marketing of products containing asbestos. The National Programme for Asbestos Abatement for 2009-2032 includes scheduled activities considering asbestos exposure assessment and health protection. As there are several data sources for asbestos exposure in Poland, which are not linked, the aim of this study was to gather and order them developing a PostgreSQL database, an open-source, objectrelational system. The data gathered combines the following information: the quantity of asbestos-cement products in use, details of asbestos manufacturing plants, the results of the measurements of asbestos fibre concentrations in the air and cases of asbestos-related diseases. The relational database was then used to develop a spatial analysis of asbestos monitoring and exposure in Poland to demonstrate the current state of realisation of the National Asbestos Abatement Programme in the country for 2009-2032 with the use of geoinformation techniques. The use of a database on health aspects of occupational and environmental asbestos exposure was also proposed in Asbestos, Asbestosis, and Cancer: Helsinki Criteria update 2014. PMID- 30451464 TI - Comparing potential spatial access with self-reported travel times and cost analysis to haemodialysis facilities in North-eastern Iran. AB - End-stage renal disease patients regularly need haemodialysis three times a week. Their poor access to haemodialysis facilities is significantly associated with a high mortality rate. The present cross-sectional study aimed to measure the potential spatial access to dialysis services at a small area level (census tract level) in North Khorasan Province, Iran. The patients were interviewed to obtain their travel information. The two-step floating catchment area (2SFCA) method was used to measure the spatial accessibility of patients to the dialysis centres. The capacity of the dialysis centre was defined as the number of active dialysis facilities in each centre and the haemodialysis patients in each area were considered as the users of dialysis services. The travel cost from each patient's residence to the haemodialysis facilities was visualized by the Kriging interpolation algorithm in the study area. Spatial accessibility to the dialysis centre was poor in the northern part of the study area. Fortunately, there were not many haemodialysis patients in that area. Patients' travel costs were high in the northern areas compared to the rest of study area. We observed a statistically significant reverse correlation between the self-reported travel time and computed spatial accessibility (-0.570, P value <0.01, two-tailed spearman test). This study supports the notion that the 2SFCA method could be associated with revealed access time to dialysis facilities, especially in low traffic and in flat areas such as northern Khorasan. The mapping of patients' distribution and interpolated travel cost to the haemodialysis facilities could help policymakers to allocate health resources to the areas where the need is greater. PMID- 30451465 TI - Operational satellite-based temporal modelling of Aedes population in Argentina. AB - Aedes aegypti is a vector for Chikungunya, Dengue and Zika viruses in Latin America and is therefore a large public health problem for the region. For this reason, several inter-institutional and multidisciplinary efforts have been made to support vector control actions through the use of geospatial technologies. This study presents the development of an operational system for the application of free access to remotely sensed products capable of assessing the oviposition activity of Ae. aegypti in all of Argentina's northern region with the specific aim to improve the current Argentine National Dengue risk system. Temporal modelling implemented includes remotely sensed variables like the normalized difference vegetation index, the normalized difference water index, day and night land surface temperature and precipitation data available from NASA's tropical rainfall measuring mission and global precipitation measurement. As a training data set, four years of weekly mosquito oviposition data from four different cities in Argentina were used. A series of satellite-generated variables was built, downloading and resampling the these products both spatially and temporally. From an initial set of 41 variables chosen based on the correlation between these products and the oviposition series, a subset of 11 variables were preserved to develop temporal forecasting models of oviposition using a lineal multivariate method in the four cities. Subsequently, a general model was generated using data from the cities. Finally, in order to obtain a model that could be broadly used, an extrapolation method using the concept of environmental distance was developed. Although the system was oriented towards the surveillance of dengue fever, the methodology could also be applied to other relevant vector borne diseases as well as other geographical regions in Latin America. PMID- 30451466 TI - Geographical information system analysis on road accidents involving wandering dogs in the urban area of Naples. AB - In this study, the spatial distribution of road accidents involving wandering dogs on urban roads of Naples was assessed using kernel density estimation (KDE). The study included 423 dogs victim of road collisions in the period 2012-2015 collected from the medical records of Interdepartmental Centre of Veterinary Radiology, of Pathological Anatomy Service, of Veterinary Teaching Hospital, "Federico II" University of Naples, and of Veterinary Hospital Attendance of the Local Public Health Unit Napoli1. There were a significant prevalence of young male dogs and the KDE demonstrated the presence of five hotspots in five city neighbourhoods. All areas with the highest KDE were found to be peripheral zones in which wide green areas, uncultivated or cultivated, merged with built areas and crossed by large straight roads with a lot of intersections. Wandering dogs as other animals represent a mounting problem on urban roads in Italy, despite of the effort to reduce these populations. Better knowledge of this phenomenon is important with reference to taking countermeasures and improve road safety. It is also important with reference to One Health and the Decade of Action for Road Safety 2011- 2020 of the United Nations. PMID- 30451467 TI - Spatial and temporal characteristics of cancer in the period from 2004 to 2013 in the Hashemite Kingdom of Jordan. AB - Cancer in Jordan is a major public health problem and the second leading cause of death after heart disease. This study aimed at studying the spatial and temporal characteristics of cancer in Jordan and its 12 governorates for the period 2004 2013 to establish a baseline for future research and identification of cancer risk factors paving the way for developing a cancer control plan in the country. Numerical and graphical summaries, time-series additive seasonal decomposition, the method of least squares, and spacetime scan statistics were applied in a geographic information systems environment. Although the results indicate that the cancer incidence in Jordan is comparatively low, it is increasing over time. In the 10-year study period, a total of 44,741 cases was reported with a mean annual crude incidence rate of 68.4 cases/100,000, mean annual age-adjusted incidence rate of 111.9 cases/100,000, and a monthly rate increase of 1.2 (cases/100,000)/month. This study also revealed that the spatial and temporal characteristics of cancer vary among the governorates. Amman, which includes the capital city and hosts more than one-third of the population of the country, reported 61.0% of the total number of cases. Amman also reported the highest annual crude incidence rate (105.3 cases/100,000), the highest annual age adjusted incidence rate (160.6 cases/100,000), and the highest rate of increase (0.7 (cases/100,000)/month) forming a high-rate cluster. Excluding the three governorates Amman, Balqa, and Ma'daba, low-rate clusters were found with regard to the remaining governorates. All governorates, except Irbid and Mafraq, showed significant rates of increase of cancer incidence. However, no clear seasonality pattern with respect to cancer incidence was discerned. PMID- 30451468 TI - Remotely identifying potential vector habitat in areas of refugee and displaced person populations due to the Syrian civil war. AB - Historically leishmaniasis is most prevalent in established urban centres but this research shows that refugees and, most significantly, internally displaced persons are now commonly in areas characterized by the presence of fly habitats potentially leading to higher prominence of Leishmania infection. Areas engulfed by the Syrian civil war has thus caused the dispersal of humans into previously unpopulated areas amid habitats of the sand fly Phlebotomus papatasi that hosts the parasite Leishmania. The addition of new places of exposure to this disease add to difficulties with respect to diagnosis as well as provision of care and treatment. We used geospatial methodology adapting it to remotely identifying and analyzing sand fly habitats with the aim of measuring how common it is. Our methodology helps avoid the issue of resolution in satellite imagery by measuring likelihood rather than strictly known locations. We followed up this information with spatial analysis identifying which civilian populations are most prone to sand fly exposure, and therefore leishmaniasis, due to their geographical situation. Our results suggest that those most likely to be exposed to Leishmania are internally displaced persons, those camps less likely to receive medical relief and typically having temporary residents migrating elsewhere. PMID- 30451469 TI - Examining the impact of the number of regions used in cluster detection methods: An application to childhood asthma visits to a hospital in Manitoba, Canada. AB - The level of spatial aggregation is a major concern in cluster investigations. Combining regions to protect privacy may result in a loss of power and thus, can limit the information researchers can obtain. The impact of spatial aggregation on the ability to detect clusters is examined in this study, which shows the importance of choosing the correct level of spatial aggregation in cluster investigations. We applied the circular spatial scan statistic (CSS), flexible spatial scan statistic (FSS) and Bayesian disease mapping (BYM) approaches to a dataset containing childhood asthma visits to a hospital in Manitoba, Canada, using three different levels of spatial aggregation. Specifically, we used 56, 67 and 220 regions in the analysis, respectively. It is expected that the three scenarios will yield different results and will highlight the importance of using the right level of spatial aggregation. The three methods (CSS, FSS, BYM) examined in this study performed similarly when detecting potential clusters. However, for different levels of spatial aggregation, the potential clusters identified were different. As the number of regions used in the analysis increased, the total area identified in the cluster decreased. In general, potential clusters were identified in the central and northern parts of Manitoba. Overall, it is crucial to identify the appropriate number of regions to study spatial patterns of disease as it directly affects the results and consequently the conclusions. Additional investigation through future work is needed to determine which scenario of spatial aggregation is best. PMID- 30451470 TI - Effects of socio-economic and environmental factors on the spatial heterogeneity of dengue fever investigated at a fine scale. AB - The spatial pattern of dengue fever cases is the result of complex interactions between the virus, the host and the vector, which may be affected by environmental conditions. The largest outbreak of dengue fever in Guangzhou city, China occurred in 2014 with case numbers 2.7 times the number of cumulative cases since 1978 and a significantly non-random spatial distribution. Selecting Guangzhou City as the study area, we used scan statistics to analyze the spatial heterogeneity of dengue fever and a generalized additive model to evaluate and examine the effects of socio-economic and environmental factors on spatial heterogeneity at a fine scale. The study found that the spatial distribution of dengue fever is highly heterogeneous and various factors differ in relative importance. The junction of the central districts of Guangzhou is a high-risk area with the urban village and urban-rural fringe zone formed by urbanization as important regional factors. The low gross domestic product per capita, the high population density, the high road density were perceived as risk factors. The Asian subtropical coastal area together with the socioeconomic and environmental factors were found to be the key drivers at the fine scale explaining the high spatial heterogeneity of dengue fever in Guangzhou City. PMID- 30451471 TI - Assessments of residential and global positioning system activity space for food environments, body mass index and blood pressure among low-income housing residents in New York City. AB - Research has examined how the food environment affects the risk of cardiovascular disease (CVD). Many studies have focused on residential neighbourhoods, neglecting the activity spaces of individuals. The objective of this study was to investigate whether food environments in both residential and global positioning system (GPS)-defined activity space buffers are associated with body mass index (BMI) and blood pressure (BP) among low-income adults. Data came from the New York City Low Income Housing, Neighborhoods and Health Study, including BMI and BP data (n=102, age=39.3+/-14.1 years), and one week of GPS data. Five food environment variables around residential and GPS buffers included: fast-food restaurants, wait-service restaurants, corner stores, grocery stores, and supermarkets. We examined associations between food environments and BMI, systolic and diastolic BP, controlling for individual- and neighbourhood-level sociodemographics and population density. Within residential buffers, a higher grocery store density was associated with lower BMI (beta=- 0.20 kg/m2, P<0.05), and systolic and diastolic BP (beta =-1.16 mm Hg; and beta=-1.02 mm Hg, P<0.01, respectively). In contrast, a higher supermarket density was associated with higher systolic and diastolic BP (beta=1.74 mm Hg, P<0.05; and beta=1.68, P<0.01, respectively) within residential buffers. In GPS neighbourhoods, no associations were documented. Examining how food environments are associated with CVD risk and how differences in relationships vary by buffer types have the potential to shed light on determinants of CVD risk. Further research is needed to investigate these relationships, including refined measures of spatial accessibility/exposure, considering individual's mobility. PMID- 30451472 TI - A geographical information systems-based approach to health facilities and urban traffic system in Belgrade, Serbia. AB - We studied the geospatial distribution of health facilities in Belgrade, the capital of the Republic of Serbia, in relation to the public transport system. Analyses in this research were based on advanced geographical information systems using numerical methods. We calculated accessibility to health centres as based on public transport properties accounting for the movement of citizens, as well as patients, through the city. Based on results, the city of Belgrade has a moderate connectivity. Public health centres and a group of other health centres in the central-east part of the city have a better connectivity. Also, in this paper we estimated that the average time necessary to reach health facilities on foot is 100 minutes and by public transport vehicles such as buses, trams and trolleys is 42 minutes. PMID- 30451473 TI - Pleural mesothelioma in Poland: Spatial analysis of malignant mesothelioma prevalence in the period 1999-2013. AB - Malignant mesothelioma (MM), a rare and very deadly tumour, can be due to asbestos exposure. To better understand the cause of incidence of MM, spatial autocorrelation analysis with reference to the quantity of asbestos-cement products in use and the localisation of former asbestos manufacturing plants was applied. Geostatistical analysis shows that strong spatial clustering of MM incidence (referring to the general population as well as females and males separately) during the period 1999-2013 in the administrative units of Poland (provinces and counties). Incidence hotspots were found to be concentrated primarily in southern Poland but also seen in the county of Szczecin, which stands out in local autocorrelation analysis in north-western Poland. High incidence rates were discovered, in particular with reference to counties around former plants manufacturing asbestos-containing products, mainly asbestos-cement manufacturers. The highest frequency of MM incidence rate was found in within a 55 km radius of plants in or near the towns Trzebinia, Ogrodzieniec and Szczucin in the South, where asbestos-cement products had been manufactured for close to 40 years. Areas with significantly high incidence rates were also discovered in the provinces of Slaskie, Malopolskie and Swietokrzyskie in southern Poland. PMID- 30451474 TI - Planning and location of health care services in Jeddah City, Saudi Arabia: Discussion of the constructive use of geographical information systems. AB - Geographical information systems (GIS) is used for health care planning due to the increasing availability of geo-coded health data that is moving the field towards to health information systems. The aim of this paper is to present GIS applications for planning health services in Jeddah City. The discussion is focused on three major issues: i) identifying the location of health service facilities and their distribution; ii) modelling the level of density needed for health service facilities; and iii) identifying the required levels of accessibility to these health services. The issues covered include GIS, choropleth mapping, kernel density modelling, Euclidean (straight-line) distance and drive-time distance models. These approaches are essential and considered the major spatial decision models required to support health care for decision- makers and planners in Jeddah City, Saudi Arabia. PMID- 30451475 TI - Air versus water temperature of aquatic habitats in Delhi: Implications for transmission dynamics of Aedes aegypti. AB - The present study was planned to characterize the microclimate experienced by Aedes larvae in different breeding habitats by determining the temperature variations in water kept in containers during different months under natural conditions. The study was conducted in three municipal zones of Delhi. In each site, four types of container material (plastic, cement, iron and ceramic) were chosen for recording the water temperature in the containers. Daily air and water temperatures (mean, maximum and minimum values) recorded by HOBO and Tidbit data loggers, respectively, were compared using analysis of variance and Tukey's honest significant difference (HSD) tests. Mean monthly temperature of water varied from 16.9 to 33.0 degrees C in tin containers, 17.3 to 35.6 degrees C in plastic containers, 14.3 to 28.5 degrees C in ceramic pots, 23.3 to 30.4 degrees C in cemented underground tanks (UGT) and 15.8 to 35.1 degrees C in cemented overhead tanks (OHTs). Corresponding values for the air temperature ranged from 17.7 to 36.1 degrees C. The difference between temperature of water in the containers and air temperature was highest for ceramic pots. Daily mean, maximum and minimum temperatures recorded by different data loggers differed significantly (P<0.05). When Tukey HSD test was applied for data analysis, the daily mean air temperature differed significantly from the water temperature in tin and ceramic pots as well as cemented OHTs. The temperature of water in the different breeding habitats investigated was lower than the air temperature. Moreover, actual air temperature as recorded by HOBO was higher than the temperature recorded by local weather stations. Considering the ongoing climate change, cemented UGT and earthen pots may be more productive breeding habitats for the Aedes mosquito in the near future, while plastic and cemented OHTs might no longer be suitable for Aedes breeding. PMID- 30451477 TI - Analysis of the relationship between life expectancy and social determinants in a north-eastern region of Brazil, 2010-2017. AB - The process of population aging is a worldwide reality becoming a global public health challenge. Although population aging is especially noticeable in more developed regions, there has also been a significant advance in the quantity of elderly people in areas with unfavourable socioeconomic indicators, and a rapid growth in countries with a low level of economic development. This article presents an analysis based on spatial autocorrelation of the relationship between life expectancy and social determinants in a north-eastern region of Brazil. An ecological study was conducted using the secondary data of social, demographic, and health indicators of elderly people collected in the Brazilian Demographic Census of the 75 municipalities of the state of Sergipe. Spatial autocorrelation was evaluated using the Moran global index and the local indicators of space association. Multiple linear regression models were used to identify the relationship between life expectancy and social determinants. The South-eastern region of the state presented clusters with all indicators pointing to acceptable lifestyles, whereas the municipalities of the north-western and far-eastern regions were characterized by values demonstrating precarious living conditions. The high dependency ratio, illiteracy rate, and unemployment rate among elderly people had a negative impact on life expectancy. The evidence confirms that there is an autocorrelation between social determinants and life expectancy, indicating that the worse the social, economic, and health indicators are, the lower the life expectancy. This finding indicates the need to redirect public policies and formulate strategies aimed at reducing social and health inequalities. PMID- 30451476 TI - Spatiotemporal mapping and detection of mortality cluster due to cardiovascular disease with Bayesian hierarchical framework using integrated nested Laplace approximation: A discussion of suitable statistic applications in Kersa, Oromia, Ethiopia. AB - Cardiovascular diseases (CVDs) are the leading cause of death globally and the number one cause of death globally. Over 75% of CVD deaths take place in low- and middle-income countries. Hence, comprehensive information about the spatio temporal distribution of mortality due to cardio vascular disease is of interest. We fitted different spatio-temporal models within Bayesian hierarchical framework allowing different space-time interaction for mortality mapping with integrated nested Laplace approximations to analyze mortality data extracted from the health and demographic surveillance system in Kersa District in Hararege, Oromia Region, Ethiopia. The result indicates that non-parametric time trends models perform better than linear models. Among proposed models, one with non-parametric trend, type II interaction and second order random walk but without unstructured time effect was found to perform best according to our experience and. simulation study. An application based on real data revealed that, mortality due to CVD increased during the study period, while administrative regions in northern and south-eastern part of the study area showed a significantly elevated risk. The study highlighted distinct spatiotemporal clusters of mortality due to CVD within the study area. The study is a preliminary assessment step in prioritizing areas for further and more comprehensive research raising questions to be addressed by detailed investigation. Underlying contributing factors need to be identified and accurately quantified. PMID- 30451478 TI - Trend and spatial analysis of prostate cancer mortality in the state of Sergipe, Brazil. AB - This is an ecological study with exploratory analysis of spatial and temporal data based on mortality data with respect to prostate cancer obtained from the Mortality Information System concerning residents of the state of Sergipe, Brazil between 2000 and 2015. The analysis of temporal trends was performed using the Joinpoint Regression Program through Poisson regression. Spatial analysis was performed using the empirical Bayesian model, Kernel analysis, Global Moran and Local indices. There were 1,986 deaths due to prostate cancer, most of which occurring after 60 years of age. An increasing, non-constant but significant trend in mortality rates was noted. The kernel density estimator showed hotspot densities of the highest rates of prostate cancer mortality in the north-eastern and central regions of the state. High-risk clusters were identified for prostate cancer mortality (I = 0.55, P<0.01). There was an increase in prostate cancer mortality rates and a heterogeneous geographic distribution of risk areas, with high-risk priority areas identified in certain regions of the state. These priority areas include the municipalities located in the Northeast (Amparo do Sao Francisco, Aquidaba, Canhoba, Cedro de Sao Joao and Telha), the West (Frei Paulo and Pedra Mole) and the south-western region of the state (Poco Verde and Simao Dias). PMID- 30451479 TI - Implications from assessing environmental effects on spatio-temporal pattern of schistosomiasis in the Yangtze Basin, China. AB - Schistosomiasis remains a major public health problem in the South China, particularly in lake and marshland regions. Modelling the spatio-temporal pattern of schistosomiasis guides disease prevention and control programs and is a research area of growing interest. However, few attempts have been made to evaluate the changing (nonlinear) effects of environmental determinants on schistosomiasis. In this context, a hierarchical spatiotemporal model was applied to evaluate how environmental determinants affect the changing trend of schistosomiasis in Anhui Province, China, based on annual parasitological and environmental data for the period 1997-2010. Results showed that - compared to changing effect - environmental factors had a constant (linear) effect on schistosomiasis. The disease was also found to fluctuate over time, which was due to the two latest national schistosomiasis control programs. In addition to statistical benefits of this approach, our analysis implied that climate change might not contribute to variation of schistosomiasis; rather, prevention activities affect schistosomiasis when the disease prevalence remains at a low level. Finally, the analytical method proposed in our study provides a template for modelling the spatio-temporal pattern of a disease whose transmission is largely determined by environmental determinants. PMID- 30451480 TI - SeaGIS Abruzzo: A publicly available atlas of marine uses and natural resources in the Adriatic Sea Region. AB - In the Adriatic Sea, the European Union supported a cross-border cooperation research program, during which digital spatial data on shellfish production and relaying areas, regulated conditions on fishing activities, protected areas and restocking structures, administrative boundaries and sea bottom characteristics, were collated from digital repositories in various institutions and paper documents. A web-based geographical information system was developed to share data of the sea facing the Abruzzi region and to explore the spatial distribution of marine resources and maritime activities, thus focussing and facilitating fisheries management and providing a potential support to the regional planning of resource exploitation. PMID- 30451481 TI - Dispersal of harmful fruit fly pests by international trade and a loop-mediated isothermal amplification assay to prevent their introduction. AB - Global trade of plant products represents one of the major driving forces for the spread of invasive insect pests. This visualization illustrates the problem of unintended dispersal of economically harmful fruit fly pests using geospatial maps based on interception data from the Swiss import control process. Furthermore, it reports the development of a molecular diagnostic assay for rapid identification of these pests at points of entry such as sea- and airports as a prevention measure. The assay reliably differentiates between target and non target species within one hour and has been successfully evaluated for on-site use at a Swiss point of entry. PMID- 30451482 TI - Tracing Boron with Fluorescence and PET Imaging of Boronated Porphyrin Nanocomplex for Imaging Guided Boron Neutron Capture Therapy. AB - Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells that without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible Poly(lactide-co glycolide)-monomethoxy-poly(polyethylene-glycol) (PLGA-mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with previously reported boronated porphyrin drugs. Fluorescence imaging and PET imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17+/-13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumor to liver, muscle, fat and blood were 3.24+/-0.22, 61.46+/-20.26, 31.55+/-10.30 and 33.85+/-5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT. PMID- 30451483 TI - Bio-Based Electrospun Nanofiber of Polyhydroxyalkanoate Modified with Black Soldier Fly's Pupa Shell with Antibacterial and Cytocompatibility Properties. AB - We report on the antibacterial and cytocompatibility properties of a bio-based electrospun polyhydroxyalkanoate (PHA) nanofiber modified with Black Soldier Fly (BSF) pupa shell. A 5-50 MUm chitosan powder (CSP) was made by grinding BSF pupa shell in water, acid, alkali. CSP was combined with PHA in an electrospinning machine using a biaxial feed method and manufactured into a 50-500 nm antibacterial nanofiber. We studied the morphology, mechanical properties, water absorption, and antibacterial properties of the electrospun PHA/CSP nanofiber. To improve the fiber's compatibility and functionality, acrylic acid (AA) was grafted onto PHA. The resulting tensile properties and morphological characterizations indicated enhanced adhesion between CSP and PHA- g-AA nanofiber, as well as an improvement in its water resistance and tensile strength, compared with the PHA/CSP nanofiber. To study the cytocompatibility of the material, human foreskin fibroblasts were seeded onto the nanofiber specimens with 3.0 and 6.0 wt % CSP. Increasing the CSP content in PHA/CSP and PHA- g AA/CSP nanofibers enhanced cell proliferation; additionally, the nanofibers with CSP showed strong inhibition of bacteria. The enhanced antibacterial and biodegradable properties of PHA- g-AA/CSP and PHA/CSP nanofibers demonstrate their potential for biomedical material applications. PMID- 30451484 TI - Accelerating the Deployment of Anaerobic Digestion to Meet Zero Waste Goals. AB - The U.S. places approximately 53% of its total municipal solid waste (MSW) in landfills, but state and local governments across the country are now setting ambitious environmental and waste diversion policies requiring, among other things, diversion and utilization of organics. Municipalities across the U.S. are employing anaerobic digestion (AD) as part of their strategy to divert organic MSW from landfills, produce biogas, and yield other beneficial coproducts such as compost and fertilizer. However, AD faces many technical, regulatory, and economic barriers to greater deployment, including upstream waste contamination, local odor and air pollution concerns, lengthy siting and permitting processes, and requirements and sizable costs for interconnecting to the electric grid. We identify a combination of scientific, operational, and policy advancements that are needed to address these barriers. PMID- 30451485 TI - Recent structural insights into PRC2 regulation and substrate binding. AB - Polycomb group proteins are transcriptional repressors controlling gene expression patterns and maintaining cell type identity. The chemical modifications of histones and DNA by the regulated activity of chromatin modifying enzymes such as Polycomb help establish and maintain such expression patterns. Polycomb repressive complex 2 (PRC2) is the only known methyltransferase specific for histone H3 lysine 27 (H3K27) and catalyzes its tri methylation leading to the repressive H3K27me3 mark. Structural biology has made important contributions towards understanding the molecular mechanisms that ensure the spatiotemporal regulation of PRC2 activity and the establishment of inactive chromatin domains marked by H3K27me3. In this review, we discuss the recent structural studies that have advanced our understanding of PRC2 function, in particular the roles of inter-subunit interactions in complex assembly and the regulation of methyltransferase activity, as well as the mechanism of local H3K27me3 spreading leading to repressive domains. PMID- 30451486 TI - An immuno-biochip selectively captures tumor-derived exosomes and detects exosomal RNA for cancer diagnosis. AB - Tumor-derived exosomes (TEXs) play instrumental roles in tumor growth, angiogenesis, immune modulation, metastasis and drug resistance. TEX RNAs are a new class of non-invasive biomarkers for cancer. Neither current techniques such as qRT-PCR and next generation sequencing nor new ones such as electrochemical or surface plasmon resonance-based biosensors are able to selectively capture and separate TEXs from normal cell-derived exosomes, making TEX RNAs potentially less sensitive biomarkers. We developed an immuno-biochip that selectively captures TEXs using antibodies against tumor-associated proteins and quantifies in situ TEX RNAs using cationic lipoplexes containing molecular beacons. We used the immuno-biochip to measure the expression of miR-21 microRNA and TTF-1 mRNA in EGFR- or PD-L1-bearing exosomes from human sera, and achieved absolute sensitivity and specificity in distinguishing normal controls from non-small cell lung cancer patients. Our results demonstrated that the effective separation of TEXs from other exosomes greatly improved the detection sensitivity and specificity. Compared with traditional immunomagnetic separation-RNA isolation qRT-PCR workflow, the immuno-biochip showed superior lung cancer diagnostic performance, consumed less samples (~30 uL) and shortened assay time from ~24 h to 4 h. PMID- 30451487 TI - Hypoxia-activated small molecule-induced gene expression. AB - Hypoxia, conditions of reduced oxygen, occur in a wide variety of biological contexts, including solid tumours and bacterial biofilms, which are relevant to human health. Consequently, the development of chemical tools to study hypoxia is vital. Here we report a hypoxia-activated small molecule-mediated gene expression system using a bioreductive prodrug of the inducer isopropyl 1-thio-beta-D galactopyranoside (IPTG). As a proof-of-concept we have placed the production of a green fluorescent protein under the control of hypoxia. Our system has the potential to be extended to regulate the production of any given protein of choice. PMID- 30451488 TI - Potassium Dual-Ion Hybrid Batteries with Ultrahigh Rate Performance and Excellent Cycling Stability. AB - Potassium-ion batteries (KIBs) are regarded as a potential alternative battery technology to conventional lithium-ion batteries owing to their low potential, natural abundance, and the low cost of potassium. However, sluggish reaction kinetic of the much larger K+ ions leads to low rate capability and poor cycling performance of KIBs, restricting KIB's practical applications. Herein, we propose a novel full battery called a potassium dual-ion hybrid battery (KDHB) by employing an absorption-type hierarchical porous carbon as the anode material and an anion intercalation-type expanded graphite (EG) as the cathode material. Owing to the hybrid mechanism of the battery and capacitive reaction, the KDHB exhibits superior rate performance with a high capacity of 82 mA h g-1 even at a high current density of 3 A g-1 with negligible capacity decay. Moreover, the KDHB exhibits excellent cycling performance with 74.2% capacity retention after 2000 cycles at 1 A g-1, which is so far the best performance of the reported KDIBs. PMID- 30451489 TI - A Middle-Up Approach with Online Capillary Isoelectric Focusing-Mass Spectrometry for In-depth Characterization of Cetuximab Charge Heterogeneity. AB - Previously, we reported a new online capillary isoelectric focusing-mass spectrometry (CIEF-MS) method for intact monoclonal antibody (mAb) charge variant analysis using an electrokinetically pumped sheath-flow nanospray ion source on a time-of-flight (TOF) MS with a pressure-assisted chemical mobilization. The direct online CIEF-MS method exhibited excellent charge variants resolution conforming to those of imaged CIEF-UV (iCIEF-UV). However, for complex mAbs, CIEF MS spectra of the intact charge variant peaks may be overly convoluted to be effectively interpreted. In the current study, we implemented a middle-up approach to enhance the capability of the CIEF-MS method for characterizing complex mAbs charge variants by reducing sample complexity. To demonstrate such a strategy, we fragmented cetuximab through IdeS enzymatic cleavage and dithiothreitol (DTT) reduction. For the first time, online CIEF-MS resolved the complex charge variants of cetuximab at subunit level, corroborating the profiles obtained by iCIEF-UV. Furthermore, high resolution TOF mass spectra with high mass accuracy were obtained for the eight charge variants separated by CIEF-MS after IdeS cleavage, and for the eleven charge variants after IdeS digestion with subsequent DTT reduction. In-depth analyses revealed the identities of all charge variants, and pinpointed the causes of charge heterogeneity, which are in accord with those reported in the literature. The main sources of charge heterogeneity of cetuximab were identified as terminal lysine on the Fc domain (up to one on each single chain Fc), glycolyl neuraminic acid residues on the Fd' domain (up to two on each Fd'), and likely several deamidation species on the Fd' domain. No charge heterogeneity contribution was found from light chain. The in-depth characterization of complex charge variants for cetuximab demonstrates the remarkable capability of this middle-up CIEF-MS approach. This novel workflow holds great potential for detecting and elucidating charge variants to help understand protein with complex charge heterogeneity. PMID- 30451490 TI - Synthesis and Anisotropic Electrocatalytic Activity of Covellite Nanoplatelets with Fixed Thickness and Tunable Diameter. AB - Size- and shape-dependent electrochemical activity of nanostructures reveals relationships between nanostructure design and electrochemical performance. However, electrochemical performance of aspect-ratio-tunable quasi-two dimensional (2D) nanomaterials with anisotropic properties has not been fully investigated. We prepared monodispersed hexagonal covellite (CuS) nanoplatelets (NPls) of fixed thickness (~2 nm) but broadly tunable diameter (from 8 to >100 nm). These span a range of aspect ratios, from ~4 to >50, connecting quasi isotropic and quasi-2D regimes. Tests of electrochemical activity of the NPls for the oxygen reduction reaction in alkaline solution showed improved activity with increasing diameter. Combining experimental results with density functional theory calculations, we attribute size-dependent enhancement to anisotropy of conductivity and electrochemical activity. The lowest computed oxygen adsorption energy was on Cu sites exposed by cleaving covellite along (001) planes through tetrahedrally coordinated Cu atoms. The specific surface area of these planes, which are the top and bottom surfaces of the NPls, remains constant with changing diameter, for fixed NPl thickness. However, charge transport through the electrocatalyst film improves with increasing NPl diameter. These CuS NPl-carbon nanocatalysts provide inspiration for creating well-controlled layered nanomaterials for electrochemical applications and open up opportunities to design new electrocatalysts using transition-metal sulfides. PMID- 30451492 TI - Direct Quantitative Analysis of Multiple microRNAs (DQAMmiR) with Peptide Nucleic Acid Hybridization Probes. AB - Direct quantitative analysis of multiple miRNAs (DQAMmiR) is a hybridization based assay in which the excess of the DNA hybridization probes is separated from the miRNA-probe hybrids and the hybrids are separated from each other in gel-free capillary electrophoresis (CE) using two types of mobility shifters: single strand DNA binding protein (SSB) added to the CE run buffer and peptide drag tags conjugated with the probes. Here we introduce the second-generation DQAMmiR which utilizes peptide nucleic acid (PNA) rather than DNA hybridization probes and requires no SSB in the CE run buffer. PNA probes are electrically neutral while PNA-miRNA hybrids are negatively charged and this difference in charges can be a basis for separation of the hybrids from the probes. In this proof-of-principle work, we first experimentally confirmed that the PNA-RNA hybrid was separable from the excess of the PNA probe without SSB in the run buffer, resulting in a near 10-min time window, which would allow separation of up to 35 hybrids. Then, we adapted to PNA-RNA hybrids our previously developed physical model for predicting hybrid mobilities. The calculation performed with the new model indicated that PNA-RNA hybrids of slightly different lengths could be separated from each other without drag tags. Accordingly, we designed a simple experimental model capable of confirming: (i) separation of tag-free hybrids of different lengths and (ii) separation of same-length hybrids due to a drag tag on the PNA probe. The experimental model included three miRNAs: 20-nt miR-147a, 20-nt miR 378g, and 22-nt miR-21. The three complementary PNA probes had lengths matching those of the corresponding target miRNAs. The probe for miR-147a had a short 5 amino acid drag tag; the other two had no drag tags. We were able to achieve baseline separation of the three hybrids from each other. The LOQ of 14 pM along with the high accuracy (recovery > 90%) and precision (RSD ~ 10%) of the assay at pico-molar target concentrations suggest that PNA-facilitated DQAMmiR will be suitable for practical miRNA analysis. PMID- 30451491 TI - High-Conductivity Argyrodite Li6PS5Cl Solid Electrolytes Prepared via Optimized Sintering Processes for All-Solid-State Lithium-Sulfur Batteries. AB - Highly Li-ion conductive Li6PS5Cl solid-state electrolytes (SSEs) were prepared by solid-state sintering method. The influence of sintering temperature and duration on the phase, ionic conductivity, and activation energy of Li6PS5Cl was systematically investigated. The Li6PS5Cl electrolyte with a high ionic conductivity of 3.15 * 10-3 S cm-1 at room temperature (RT) was obtained by sintering at 550 degrees C for just 10 min, which was more efficient taking into account such a short preparation time in comparison with other reported methods to synthesize Li6PS5Cl SSEs. All-solid-state lithium sulfur batteries (ASSLSBs) based on the Li6PS5Cl SSE were assembled by using the nano-sulfur/multiwall carbon nanotube composite combined with Li6PS5Cl as the cathode and Li-In alloy as the anode. The cell delivered a high discharge capacity of 1850 mAh g-1 at RT for the first full cycle at 0.176 mA cm-2 (~0.1C). The discharge capacity was 1393 mAh g-1 after 50 cycles. In addition, the Coulombic efficiency remained nearly 100% during galvanostatic cycling. The experimental data showed that Li6PS5Cl was a good candidate for the SSE used in ASSLSBs. PMID- 30451493 TI - Correction to Negative Deviations from the Debye-Huckel Limiting Law for High Charge Polyvalent Electrolytes: Are They Real? PMID- 30451494 TI - Spectral Characterization of Eight Marine Phytoplankton Phyla and Assessing a Pigment-Based Taxonomic Discriminant Analysis for the in Situ Classification of Phytoplankton Blooms. AB - Early stage identification of harmful algal blooms (HABs) has gained significance for marine monitoring systems over the years. Various approaches for in situ classification have been developed. Among them, pigment-based taxonomic classification is one promising technique for in situ characterization of bloom compositions, although it is yet underutilized in marine monitoring programs. To demonstrate the applicability and importance of this powerful approach for monitoring programs, we combined an ultra low-cost and miniaturized multichannel fluorometer with Fisher's linear discriminant analysis (LDA). This enables the real-time characterization of algal blooms at order level based on their spectral properties. The classification capability of the algorithm was examined with a leave-one-out cross validation of 53 different unialgal cultures conducted in terms of standard statistical measures and independent figures of merit. The separation capability of the linear discriminant analysis was further successfully examined in mixed algal suspensions. Besides this, the impact of the growing status on the classification capability was assessed. Further, we provide a comprehensive study of spectral features of eight different phytoplankton phyla including an extensive study of fluorescence excitation spectra and marker pigments analyzed via HPLC. The analyzed phytoplankton species belong to the phyla of Cyanobacteria, Dinophyta (Dinoflagellates), Bacillariophyta (Diatoms), Haptophyta, Chlorophyta, Ochrophyta, Cryptophyta, and Euglenophyta. PMID- 30451495 TI - Synthesis of Difluoroalkyl Unsaturated beta-Amino Acid Derivatives Exclusively through Alkyne Difunctionalization. AB - Alkynes difunctionalization is a powerful strategy in organic synthesis that provides a convenient synthetic entry for internal alkenes. The main challenge in this field was considered to be the geometry control of the newly formed double bond (thermodynamically controlled or kinetically controlled). Herein, we report a novel procedure (through the cyclic compounds broken) to completely control the regioselectivity of olefins. The products, difluoroalkyl unsaturated beta-amino acid derivatives, have potential applications in some important pharmaceuticals on account of the special nature of fluorine atoms. PMID- 30451496 TI - Enantioselective Coupling of Dienes and Phosphine Oxides. AB - We report a Pd-catalyzed intermolecular hydrophosphinylation of 1,3-dienes to afford chiral allylic phosphine oxides. Commodity dienes and air stable phosphine oxides couple to generate organophosphorus building blocks with high enantio- and regiocontrol. This method constitutes the first asymmetric hydrophosphinylation of dienes. PMID- 30451497 TI - Size matters: ingestion of relatively large microplastics contaminated with environmental pollutants posed little risk for fish health and fillet quality. AB - In this study, we investigated biological effects associated with ingestion of polystyrene (PS) microplastic (MPs) in fish. We examined whether ingestion of contaminated PS MPs (100-400 um) results in chemical stress in rainbow trout (Oncorhynchus mykiss) liver and we explored whether this exposure can affect the oxidative stability of the fillet during ice storage. Juvenile rainbow trout were fed for 4 weeks with four different experimental diets: control (1) and feeds containing virgin PS MPs (2) or PS MPs exposed to sewage (3) or harbor (4) effluent. A suite of ecotoxicological biomarkers for oxidative stress and xenobiotic-related pathways was investigated in the hepatic tissue, and included gene expression analyses and enzymatic measurements. The potential impact of MPs exposure on fillet quality was investigated in a storage trial where lipid hydroperoxides, loss of redness and development of rancid odor were assessed as indications of lipid peroxidation. Although, chemical analysis of PS MPs revealed that particles sorb environmental contaminants (e.g. PAHs, nonylphenol and alcohol ethoxylates and others), the ingestion of relatively high doses of these PS MPs did not induce adverse hepatic stress in fish liver. Apart from a small effect on redness loss in fillets, PS MPs ingestion did not affect lipid peroxidation or rancid odor development, thus did not affecting fillet's quality. PMID- 30451498 TI - Exploration of CeO2-CuO Quantum Dots in Situ Grown on Graphene under Hypha Assistance for Highly Efficient Solar-Driven Hydrogen Production. AB - The development of an artificial model of photoinduced hydrogen production system requires efficient, long-term stability and cost-competitive photocatalysts to store solar energy in chemical bonds. However, the existing photocatalysts still suffer from the high cost, high recombination rate of photoexcited electron-hole pairs, and poor photostability. Herein, we demonstrate the synthesis of a p-type CuO/n-type CeO2 heterojunction in situ grown on graphene via a hypha assistance process. Amazingly, optical and photoelectrochemical measurements show the superiority of this hierarchically biomorphic structure. The observed H2 evolution rate of the CeO2-CuO quantum dots/graphene has reached 2481 MUmol.h-1.g 1 and remains unchanged in four hydrogen production cycles. Considering the convenience of microbial culture, this heterostructure system has great potential as a photocatalyst for solar-fuel conversion. PMID- 30451499 TI - Mn4+-Doped Heterodialkaline Fluorogermanate Red Phosphor with High Quantum Yield and Spectral Luminous Efficacy for Warm-White-Light-Emitting Device Application. AB - Narrow band red-emitting Mn4+-doped fluoride phosphor is an essential red component of modern white-light-emitting-diode (WLED) devices. Its luminescence has sensitivity to structure and influences the performance of WLED. In this paper, we report a high-performance Mn4+ phosphor based on a new heterodialkaline fluorogermanate, CsNaGeF6:Mn4+. As determined by the single-crystal X-ray diffraction analysis, the CsNaGeF6 compound crystallizes in the orthorhombic crystal system with space group Pbcm (No. 57). Under excitation by 360 and 470 nm photons, CsNaGeF6:Mn4+ emits intense red light near 630 nm with a high quantum yield of 95.6%. The electronic energy levels of the Mn4+ ion in Cs2GeF6, Na2GeF6, and CsNaGeF6 are calculated using the exchange charge model of crystal-field theory. The local Mn4+ environment inducing different zero-phonon-line emissions in the structures is probed by electron paramagnetic resonance. The Mn4+-doped heterodialkaline fluorogermanate CsNaGeF6:Mn4+ exhibits broader emission as a result of the lowest symmetry. It has higher quantum yield than Na2GeF6:Mn4+ and higher spectral luminous efficacy than Cs2GeF6:Mn4+. Given the good thermal stability and efficient luminescence, a prototype warm-WLED device with a color rendering index of 92.5, a correlated color temperature of 3783 K, and a luminous efficacy of 176.3 lm/W has been fabricated by employing the CsNaGeF6:Mn4+ phosphor as the red component. Our results not only reveal that a high performance Mn4+ red phosphor is achieved through cationic substitutions but also construct a relationship of performance-structure to guide the design of Mn4+ phosphors in the future. PMID- 30451500 TI - Sterol 14alpha-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae. AB - Sterol 14alpha-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity. PMID- 30451501 TI - Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations. AB - Computational methods to calculate ligand binding affinities are increasing in popularity, due to improvements in simulation algorithms, computational resources, and easy-to-use software. However, issues can arise in relative ligand binding free energy simulations if the ligands considered have different active site water networks, as simulations are typically performed with a predetermined number of water molecules (fixed N ensembles) in preassigned locations. If an alchemical perturbation is attempted where the change should result in a different active site water network, the water molecules may not be able to adapt appropriately within the time scales of the simulations-particularly if the active site is occluded. By combining the grand canonical ensemble (MUVT) to sample active site water molecules, with conventional alchemical free energy methods, the water network is able to dynamically adapt to the changing ligand. We refer to this approach as grand canonical alchemical perturbation (GCAP). In this work we demonstrate GCAP for two systems; Scytalone Dehydratase (SD) and Adenosine A2 A receptor. For both systems, GCAP is shown to perform well at reproducing experimental binding affinities. Calculating the relative binding affinities with a naive, conventional attempt to solvate the active site illustrates how poor results can be if proper consideration of water molecules in occluded pockets is neglected. GCAP results are shown to be consistent with time consuming double decoupling simulations. In addition, by obtaining the free energy surface for ligand perturbations, as a function of both the free energy coupling parameter and water chemical potential, it is possible to directly deconvolute the binding energetics in terms of protein-ligand direct interactions and protein binding site hydration. PMID- 30451502 TI - Total Synthesis of the Ortho-Hydroxylated Protoberberines (S)-Govaniadine, (S) Caseamine and (S)-Clarkeanidine via a Solvent-directed Pictet-Spengler reaction. AB - The common para-regioselectivity in Pictet-Spengler reactions with dopamine derivatives is redirected to the ortho-position by a simple change of solvents. In combination with a chiral auxiliary on nitrogen this ortho-selective Pictet Spengler produced the 1-benzyltetrahydro-isoquinoline alkaloids (S)-crassifoline, (S)-norcrassifoline and the bioactive, 1,2-dioxygenated tetrahydro-protoberberine alkaloids (S)-govaniadine, (S)-caseamine and (S)-clarkeanidine with high enantiopurity. Ortho/para ratios up to 89:19 and diastereomeric ratios up to 85:15 were obtained during formation of the B-ring. The general applicability of this solvent-directed regioselectivity was demonstrated with a second Pictet Spengler reaction as required for C-ring formation of caseamine (o/p = 14:86 in trifluoroethanol) and clarkeanidine (o/p = 86:14 in toluene). PMID- 30451503 TI - Rainbow trout maintain intestinal transport and barrier functions following exposure to polystyrene microplastics. AB - Ingestion has been proposed as a prominent exposure route for plastic debris in aquatic organisms, including fish. While the consequences of ingestion of large plastic litter are mostly understood, the impacts resulting from microplastics (MPs) are largely unknown. We designed a study aimed to assess impacts of MPs on fish intestinal physiology and examined integrity of extrinsic, physical and immunological barriers. Rainbow trout were exposed to polystyrene (PS) MPs (100 400 um) via feed for a period of 4 weeks. Fish were fed four types of diets: control, diets containing virgin PS particles, or particles exposed to two different environmental matrices (sewage or harbor effluent). Extrinsic barrier disturbance in intestinal tissue was evaluated via histology. The paracellular permeability towards ions and molecules was examined using Ussing chambers and mRNA expression analysis of tight junction proteins. Active transport was monitored as transepithelial potential difference, short-circuits current and uptake rate of amino acid 3H-lysine. Immune status parameters were measured through mRNA expression level of cytokines, lysozyme activity, and hematological analysis of immune cells. We could not show that PS MPs induced inflammatory responses or acted as physical and/or chemical hazards upon ingestion and exerted no measurable effects on intestinal permeability, active transport or electrophysiology. PMID- 30451504 TI - Gate Switching of Ultrafast Photoluminescence in Graphene. AB - The control of optical properties by electric means is the key to optoelectronic applications. For atomically thin two-dimensional (2D) materials, the natural advantage lies in that the carrier doping could be readily controlled through the electric gating effect, possibly affecting the optical properties. Exploiting this advantage, here we report the gate switching of the ultrafast upconverted photoluminescence from monolayer graphene. The luminescence can be completely switched off by the Pauli-blocking of one-photon interband transition in graphene with an on/off ratio exceeding 100, which is remarkable compared to other 2D semiconductors and 3D bulk counterparts. The chemical potential and pump fluence dependences of the luminescence are nicely described by a two-temperature model, including both the hot carrier dynamics and carrier-optical phonon interaction. This gate switchable and background-free photoluminescence can open up new opportunities for graphene-based ultrafast optoelectronic applications. PMID- 30451505 TI - Cypemycin Decarboxylase CypD Is Not Responsible for Aminovinyl-Cysteine (AviCys) Ring Formation. AB - The cypemycin decarboxylase CypD is investigated by using a synthetic oligopeptide, which contains the to-be-cyclized dehydroalanine (Dha) residue. It was shown that CypD efficiently catalyzes the decarboxylation of this Dha containing peptide, but the expected AviCys ring is not formed in the product, suggesting that CypD alone is not enough to form the AviCys ring. It was also shown that the Dha-containing peptide is a better substrate than two similar peptides with a Ser or a Cys residue, supporting that, in cypemycin biosynthesis, Dha formation is prior to decarboxylation of the C-terminal Cys. PMID- 30451506 TI - Redox fluctuations control the coupled cycling of iron and carbon in tropical forest soils. AB - Oscillating redox conditions are a common feature of humid tropical forest soils, driven by an ample supply and dynamics of reductants, high moisture, microbial oxygen consumption, and finely textured clays that limit diffusion. However, the net result of variable soil redox regimes on iron (Fe) mineral dynamics and associated carbon (C) forms and fluxes is poorly understood in tropical soils. Using a 44-day redox incubation experiment with humid tropical forest soils from Puerto Rico, we examined patterns in Fe and C transformations under four redox regimes: static anoxic, 'flux 4-day' (4d oxic, 4d anoxic), 'flux 8-day' (8d oxic, 4d anoxic) and static oxic. Prolonged anoxia promoted reductive dissolution of Fe oxides, and led to an increase in soluble Fe(II) and amorphous Fe oxide pools. Preferential dissolution of the less-crystalline Fe pool was evident immediately following a shift in bulk redox status (oxic to anoxic), and coincided with increased dissolved organic C, presumably due to acidification or direct release of organic matter (OM) from dissolving Fe(III) mineral phases. The average nominal oxidation state of water-soluble C was lowest under persistent anoxic conditions, suggesting that more reduced organic compounds were metabolically unavailable for microbial consumption under reducing conditions. Anoxic soil compounds had high H/C values (and were similar to lignin-like compounds) whereas oxic soil compounds had higher O/C values, akin to tannin- and cellulose-like components. Cumulative respiration derived from native soil organic C was highest in static oxic soils. These results show how Fe minerals and Fe-OM interactions in tropical soils are highly sensitive to variable redox effects. Shifting soil oxygen availability rapidly impacted exchanges between mineral-sorbed and aqueous C pools, increased the dissolved organic C pool under anoxic conditions implying that the periodicity of low-redox events may control the fate of C in wet tropical soils. PMID- 30451507 TI - Web-Based Search Tool for Visualizing Instrument Performance Using the Triple Knockout (TKO) Proteome Standard. AB - Multiplexing strategies are at the forefront of mass-spectrometry-based proteomics, with SPS-MS3 methods becoming increasingly commonplace. A known caveat of isobaric multiplexing is interference resulting from coisolated and cofragmented ions that do not originate from the selected precursor of interest. The triple knockout (TKO) standard was designed to benchmark data collection strategies to minimize interference. However, a limitation to its widespread use has been the lack of an automated analysis platform. We present a TKO Visualization Tool (TVT). The TVT viewer allows for automated, web-based, database searching of the TKO standard, returning traditional figures of merit, such as peptide and protein counts, scan-specific ion accumulation times, as well as the TKO-specific metric, the IFI (interference-free index). Moreover, the TVT viewer allows for plotting of two TKO standards to assess protocol optimizations, compare instruments, or measure degradation of instrument performance over time. We showcase the TVT viewer by probing the selection of (1) stationary phase resin, (2) MS2 isolation window width, and (3) number of synchronous precursor selection (SPS) ions for SPS-MS3 analysis. Using the TVT viewer will allow the proteomics community to search and compare TKO results to optimize user-specific data collection workflows. PMID- 30451508 TI - Electrostatically Driven Protein Adsorption: Charge Patches versus Charge Regulation. AB - The mechanisms of electrostatically driven adsorption of proteins on charged surfaces are studied with a new theoretical framework. The acid-base behavior, charge distribution and electrostatic contributions to the thermodynamic properties of the proteins are modeled in the presence of a charged surface. The method is validated against experimental titration curves and apparent pKas. The theory predicts that electrostatic interactions favor the adsorption of proteins at their isoelectric points on charged surfaces despite the fact that the protein has no net charge in solution. Two known mechanisms explain adsorption under these conditions: i. charge regulation (the charge of the protein changes due to the presence of the surface) and ii. charge patches (the protein orients to place charged amino acids near opposite surface charges). This work shows that both mechanisms contribute to adsorption at low ionic strengths, while only the charge patches mechanism operates at high ionic strength. Interestingly, the contribution of charge regulation is insensitive to protein orientation under all conditions, which validates the use of constant-charge simulations to determine the most stable orientation of adsorbed proteins. The present study also shows that the charged surface can induce large shifts in the apparent pKas of individual aminoacids in adsorbed proteins. Our conclusions are valid for all proteins studied in this work (lysozyme, alpha-amylase, RNAse and beta lactoglobuline), as well as for proteins that are not isoelectric, but have instead a net charge in solution of the same sign as the surface charge, i.e. the problem of protein adsorption on the 'wrong side' of the isoelectric point. PMID- 30451509 TI - Ethnic identity developmental trajectories during the transition to college. AB - The goal of this longitudinal study was to examine the trajectories of ethnic identity exploration and commitment in 538 ethnic-racial minority students during their first 2 years of college. Multilevel modeling analyses demonstrated ethnic identity development continued as students transitioned to college. Specifically, ethnic identity exploration increased in quadratic and linear slopes, whereas ethnic identity commitment increased in a linear slope only. These developmental trajectories were similar across ethnic-racial minority students, regardless of their race, gender, and nativity, with the exception of Asian American students who started college with a higher level of exploration compared to other minority students. In addition, the study found parental ethnic socialization to have a continued influence on ethnic identity development in college. These findings add to a growing number of longitudinal studies on ethnic identity development beyond adolescence. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451510 TI - Anhedonia as a phenotypic marker of familial transmission of polysubstance use trajectories across midadolescence. AB - Psychopathologic traits that arise in adolescence may increase proneness to substance use uptake as well as channel the familial transmission of substance use. Poly use is a common pattern of substance use in youth. To identify a parsimonious model of familial transmission of substance use, the current study tested whether anhedonia-a psychopathologic endophenotype manifested as the inability to experience pleasure-mediates the association of family history of substance use (FHS) with polysubstance use patterns across midadolescence. High school students (N = 3,392) in Los Angeles, CA, completed 4 semiannual surveys of mental health and substance use from ages 14- to 16-years-old. Use and co-use of cigarettes, alcohol, and marijuana across the 4 waves were reduced to 4 homogenous classes using parallel process growth mixture modeling: (a) abstainers (N = 1,629, 48.0%); (b) experimenters (N = 1,293, 38.1%); (c) polysubstance using marijuana escalators (N = 210, 6.2%); and (d) heavy polysubstance using cigarette escalators (N = 126, 3.7%). FHS was positively associated with membership in each of the three substance using trajectory groups (vs. the abstainers group). After adjusting for depressive symptoms and other covariates, associations of FHS with membership in the polysubstance using marijuana escalators group and with the heavy polysubstance using cigarette escalators group (in comparison with the abstainers or experimenters groups) were each significantly mediated by anhedonia in youth age 14 (the proportion mediated by anhedonia: 0.33-0.42). Etiology research and intervention addressing anhedonia may have value for understanding and preventing the familial transmission of adolescent polysubstance use patterns. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451511 TI - Problematic alcohol use and acute intoxication predict anger-related attentional biases: A test of the alcohol myopia theory. AB - Previous research has demonstrated a significant association between alcohol and aggression. However, the precise mechanisms underlying this relationship have yet to be fully elucidated. In the present study, we examined alcohol's effects on an attentional bias toward aggressogenic cues as the first step in a possible mediation model of alcohol-facilitated intimate partner aggression. More specifically, we tested an interactive effect of problematic alcohol use and acute alcohol intoxication on an attentional bias toward anger words. Participants in this study were 249 male and female heavy drinkers from the community with a history of past-year intimate partner aggression perpetration who participated in an alcohol-administration laboratory study assessing the effect of alcohol intoxication on cognitive biases. Multiple linear regression was used to test the proposed moderation model. Acute alcohol intoxication moderated the effect of problematic alcohol use on an attentional bias toward anger, with this effect being stronger for individuals in the alcohol compared to no-alcohol control condition. These findings suggest that problematic drinkers may be more likely to attend to aggressogenic stimuli while acutely intoxicated, relative to when they are sober. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451512 TI - Multimethod assessment of everyday functioning and memory abilities in Parkinson's disease. AB - OBJECTIVE: This study compared functional abilities in individuals with Parkinson's disease (PD) with normal cognition (PD-CN) and mild cognitive impairment (PD-MCI) using multiple assessment methods. Cognitive and physical correlates were also examined. METHOD: Participants were 42 nondemented individuals with PD (24 PD-CN, 18 PD-MCI) and 42 age-matched healthy controls. Functional abilities were assessed through direct observation and self- and informant-report questionnaires. Participants were administered an activity-based memory paradigm that assessed prospective, content, and temporal order memory as well as a test of mobility. RESULTS: Compared to the PD-CN and healthy control groups, participants with PD-MCI performed significantly worse on directly observed everyday activities, self- and informant-reports of instrumental activities of daily living (IADLs), and self-report of everyday activities requiring physical capacity. No significant differences were observed between PD CN and healthy controls. Among participants with PD, content memory correlated with all of the functional outcome measures, temporal order memory correlated with self-reported IADLs, and physical mobility correlated with self-reported physical capacity and content memory. CONCLUSIONS: The results indicated that PD MCI is associated with decreased ability to perform everyday activities. Reduced ability to correctly recall and sequence activities may contribute to lower functional abilities on IADLs, whereas noncognitive factors (i.e., mobility) may become more salient when the everyday task requires physical capacity. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451513 TI - Parents' and teachers' academic influences, behavioral engagement, and first- and fifth-grade achievement. AB - Parents and teachers-primary socializers across elementary grades-offer potentially differential support mechanisms for children's healthy functioning across developmental periods. Utilizing child, parent, teacher, and observational data from the National Institute of Child Health and Human Department Study of Early Child Care and Youth Development (n = 1,031), we employed a longitudinal path model to examine indirect associations between parents' and teachers' academic influences (i.e., direct parental involvement, the student-teacher relationship, instructional support) and achievement (reading and math) through behavioral engagement at 1st and 5th grades. Results indicated indirect associations linking direct parental involvement (positively, 1st grade only), student-teacher conflict (negatively, both grades), and instructional support (positively, both grades) to achievement via behavioral engagement, after accounting for the co-occurrence of parents' and teachers' academic influences and other child characteristics. School psychologists may opt for interventions focusing on parents' and teachers' academic influence to indirectly effect achievement by promoting elementary school behavioral engagement. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451514 TI - Post-deployment parenting in military couples: Associations with service members' PTSD symptoms. AB - Severity of posttraumatic stress disorder (PTSD) symptoms has been linked to parenting impairments in military service members (SMs), but little is known about how SMs' PTSD is related to their partners' parenting. This study evaluated associations of SMs' PTSD symptoms with parenting indices in SMs and their partners, with additional exploratory analyses of how intrapersonal and interpersonal distress might play a role in such associations. Online self-report measures were completed by 128 SMs who scored >27 on the PTSD Checklist (PCL-M) at baseline and their partners at four timepoints over 1.5 years. Data were analyzed using multilevel modeling, with timepoints nested within individuals within couples. SMs' PTSD symptoms were significantly associated with decreased parenting alliance and increased inconsistent discipline in SMs and partners, increased harsh parenting in SMs only, and increased supervision in partners only. Couple satisfaction and conflict accounted for PTSD symptoms' association with parenting alliance, and couple conflict accounted for the association with inconsistent discipline. Couple conflict, couple satisfaction, and individual depression accounted for SMs' increased harsh parenting. SM PTSD remained the only predictor of partners' supervision. Limitations include that data were collected from online self-report and from heterosexual Army couples only. Overall, SMs' PTSD symptoms showed associations with parenting in SMs and their partners, with some evidence of compensatory higher supervision by partners. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451515 TI - Psychology of addictive behaviors. AB - Having served as Associate Editor of Psychology of Addictive Behaviors (PAB) with three distinguished editors, Dr. Nancy Petry, Dr. Stephen Maisto, and Dr. Howard Shaffer, the author has learned from the very best how to work with other authors and reviewers to publish cutting-edge papers that will have a strong and sustained impact on the field. The author is grateful for their mentoring and the opportunity to apply what she has learned as Interim Editor of PAB, albeit under the untimely circumstances of Dr. Petry's death from cancer in July 2018. She aims to continue Dr. Petry's vision of PAB as one of the few journals to cover the full range of addictions, including behavioral addictions such as gambling, excessive Internet use, online gaming, and food addiction (Petry, 2015). High quality reviews remain a priority at PAB to ensure that the journal continues to be a top-choice outlet for exciting new findings driving the field. PAB also is increasing efforts to recognize reviewer contributions to the journal and the participation of early career investigators as reviewers (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451516 TI - Stressful life events influence transitions among latent classes of alcohol use. AB - Stressful life events (SLEs) have been associated with an increased risk of heavy drinking, suggesting individuals may use alcohol to cope with negative life events. However, little research has explored the extent to which SLEs have different effects on later alcohol use based on one's current alcohol use pattern. We replicated prototypical patterns of alcohol use via latent class analysis at Waves 2, 3, and 4 of the National Longitudinal Study of Adolescent to Adult Health (n = 4,569). Latent transition analysis was then used to examine the extent to which SLEs influenced the likelihood of stability or change in class membership from adolescence to early adulthood. Results suggested that adolescents were more likely to transition into different patterns of alcohol use as they entered early adulthood but were more likely to retain the same drinking pattern once in early adulthood. Among those who typically abstained, experiencing SLEs was associated with greater odds of transitioning to heavier drinking or problematic patterns of alcohol use. However, among those who had heavy or problematic alcohol use patterns, SLEs were associated with greater odds of decreasing alcohol use to either heavy or abstaining levels. Results suggest those who previously abstained may begin to use alcohol as a coping mechanism following stressful events, whereas those who drank heavily may decrease or abstain from alcohol use following life stress as a means of enacting positive life changes. The results encourage further study into factors that differentiate changes in alcohol use among light drinkers following SLEs. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451517 TI - Profiles of behavior change constructs for reducing alcohol use in women at risk of an alcohol-exposed pregnancy. AB - Using data from Project CHOICES, a randomized controlled trial to test an intervention to prevent alcohol-exposed pregnancies, this study examined process of change profiles composed of Transtheoretical Model of Change (TTM) constructs for alcohol. The primary purpose was to identify a profile of TTM variables associated with reduced drinking. Participants (n = 570) were women at risk of an alcohol-exposed pregnancy recruited from high risk settings. Profile analyses compared end-of-treatment (i.e., 3 months postintake) TTM construct mean profiles for women who reduced drinking to below NIAAA-defined risk levels1 (changers) with women who continued to drink at risk levels (nonchangers) at the 9-month follow-up. TTM construct profiles included experiential and behavioral processes of change, pros and cons for change, confidence to reduce drinking, and temptation to drink above risk levels. Results revealed a parallelism effect or interaction (p < .001) in the end-of-treatment TTM construct profiles for the changers versus the nonchangers at the 9-month follow-up. Changers reported greater pros (p < .001) and lower cons for change (p = .012), greater confidence (p = .030), lower temptation (p < .001) and greater use of the experiential (p < .001) and behavioral processes of change (p < .001). A larger percentage of the women from the CHOICES intervention were in the end-of-treatment profile of the changers (48%) compared with the control condition (39%; p = .042). Interventions can potentially be enhanced by clinicians' understanding what successful change "looks like" for specific clients in terms of their process use, decisional balance, and self-efficacy, allowing for tailored interventions targeted to each client's specific strengths and deficits. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451519 TI - "Not the same old thing: Establishing the unique contribution of drinking identity as a predictor of alcohol consumption and problems over time": Correction to Lindgren et al. (2016). AB - Reports an error in "Not the same old thing: Establishing the unique contribution of drinking identity as a predictor of alcohol consumption and problems over time" by Kristen P. Lindgren, Jason J. Ramirez, Cecilia C. Olin and Clayton Neighbors (Psychology of Addictive Behaviors, 2016[Sep], Vol 30[6], 659-671). In the article, in Table 2, the values reported for the Implicit ID Time interaction for the model predicting alcohol problems, when controlling for baseline consumption for the count portion of the model are incorrect. The correct values are present in the erratum. The online version of this article has been corrected (The following abstract of the original article appeared in record 2016-35226 001.) Drinking identity-how much individuals view themselves as drinkers-is a promising cognitive factor that predicts problem drinking. Implicit and explicit measures of drinking identity have been developed (the former assesses more reflexive/automatic cognitive processes; the latter more reflective/controlled cognitive processes): each predicts unique variance in alcohol consumption and problems. However, implicit and explicit identity's utility and uniqueness as predictors relative to cognitive factors important for problem drinking screening and intervention has not been evaluated. Thus, the current study evaluated implicit and explicit drinking identity as predictors of consumption and problems over time. Baseline measures of drinking identity, social norms, alcohol expectancies, and drinking motives were evaluated as predictors of consumption and problems (evaluated every 3 months over 2 academic years) in a sample of 506 students (57% female) in their first or second year of college. Results found that baseline identity measures predicted unique variance in consumption and problems over time. Further, when compared to each set of cognitive factors, the identity measures predicted unique variance in consumption and problems over time. Findings were more robust for explicit versus implicit identity and in models that did not control for baseline drinking. Drinking identity appears to be a unique predictor of problem drinking relative to social norms, alcohol expectancies, and drinking motives. Intervention and theory could benefit from including and considering drinking identity. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451518 TI - The effect of parental smoking on preadolescents' implicit and explicit perceptions of smoking-related cues. AB - Children of smokers are significantly more likely to experiment with cigarettes and become habitual smokers than children of nonsmokers. The current study examined the effect of parental smoking on children's implicit and explicit responses toward smoking behavior and smoking-related cues with the goal of identifying potential mechanisms for this relationship. A sample of 8-12-year-old children of smokers (n = 57) and children of nonsmokers (n = 86) completed a dot probe task to assess implicit attentional bias toward smoking cues and the Affect Misattribution Procedure (AMP) to assess implicit affective responses to smoking cues. In addition, children indicated their explicit perceptions of smokers and smoking behavior. Results demonstrated that children of smokers showed more sustained implicit attentional bias toward pictures of smoking stimuli presented alone than children of nonsmokers. Overall, participants showed negative implicit affective responses to smoking stimuli regardless of parental smoking. Children of smokers indicated that smokers would experience fewer negative consequences than children of nonsmokers; these relationships were moderated by age. Together, our findings suggest that parental smoking affects the ways that preadolescent children implicitly process smoking cues and their perceptions about smoking and its consequences. These findings help us understand the environmental mechanisms associated with smoking behavior in this vulnerable population. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451520 TI - The route of administration exacerbates prefrontal functional impairments in crack cocaine users. AB - Studies have evidenced more severe health consequences in individuals who smoked crack cocaine as compared to intranasal cocaine users. Differential neurocognitive deficits between the crack and intranasal cocaine-addicted patients, associated with prefrontal cortex functions, have never been tested using complex cognitive tasks in humans. In this study, we examined possible distinct neurocognitive deficits in 43 crack-addicted patients (CrD) compared with 36 intranasal cocaine-addicted patients (CD) and 32 controls. CrD and CD were evaluated after 2 weeks of supervised detoxification in two inpatient treatment programs. All the subjects were evaluated using an extensive battery of neurocognitive tasks, including the Trail Making Test, the Stroop Color-Word Test, the Digits Forward and Digits Backward tasks, the Controlled Oral Word Association Test, the Wechsler Adult Intelligence Scale, and the Frontal Assessment Battery. Differences in performance in the neurocognitive tests between the three groups were investigated controlling for age, IQ, psychiatric symptoms, and years of education. Both intranasal and crack users were impaired on a variety of cognitive measures relative to controls. Crack users performed worse than intranasal cocaine users in inhibitory control (p < .05) and general executive functioning (p < .01). Crack use seems to be more deleterious to neurocognitive functions associated with the prefrontal cortex. This may predispose crack-addicted patients to more severe negative clinical outcomes. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451522 TI - Populations and personalities. AB - The question of personality in nonhuman animals has loomed large in the study of animal behavior. This issue's featured article assessed the possibility that different environments generate different patterns of personality. Roy and Bhat (2018) studied common measures of personality in two populations of wild zebrafish, Danio rerio. Roy and Bhat's studies support the hypothesis that personality will depend in part on the populations being studied and the environmental variation experienced by individuals in those populations. Populations differing in their exposure to predation should be expected to differ in their propensity to engage in risky behavior (like foraging or courtship) in the context of cues and signals of predators. Beyond this important finding, though, Roy and Bhat (2018) found that higher, as opposed to lower, predation pressure seems to be associated with lower levels of intra- and interindividual variability in boldness-related behavior. Key next steps proposed by the authors include experimental studies aimed at determining the individual effects of variation in predation, water-flow, and food resources on boldness and aggression in these populations, including multiple generations and replicates of each sampled population. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451523 TI - Repeatability in boldness and aggression among wild zebrafish (Danio rerio) from two differing predation and flow regimes. AB - Although flexibility in behavior is adaptive, this flexibility is limited, and the extent of variation and consistency of a trait could depend on the environment. In this study, we investigated repeatability in risk-taking during feeding among individuals and agonistic interactions among dyads of wild zebrafish, Danio rerio, collected from two habitats that differed in predation and flow regimes. We measured boldness as the latency to emerge from a shelter and feed in the presence of predators. We tested this for each individual from the two populations repeatedly across seven trials. We assessed aggression by subjecting size- and sex-matched pairs of fish to dyadic contests repeatedly across seven trials. Individuals from the high-predation stream population were bolder than individuals from the low-predation stagnant water population. Males were bolder than females, and in the low-predation population, larger individuals took greater risks to feed than smaller individuals. The high-predation stream population showed lower inter- and intraindividual variation in boldness than the low-predation stagnant water population. Further, both populations showed significant repeatability in risk-taking during feeding. The high-predation stream habitat fish were more aggressive than low-predation stagnant-water fish. Male dyads from the low-predation stagnant-water population were significantly more aggressive than female dyads. Most fish from the low-predation stagnant water population did not show aggressive behavior, resulting in low between-dyad but high within-dyad variation in aggression. The difference in behavioral responses between the populations and consistency in these traits within individuals is discussed in the light of confounding role of ecological and state dependent factors. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451521 TI - Applying behavioral economic theory to problematic Internet use: An initial investigation. AB - The widespread availability of the Internet has had profound social, educational, and economic benefits. Yet, for some, Internet use can become compulsive and problematic. The current study seeks to apply a behavioral economic framework to Internet use, testing the hypothesis that, similar to other addictive behaviors, problematic Internet use is a reinforcer pathology, reflecting an overvaluation of an immediately acquirable reward relative to prosocial and delayed rewards. Data were collected through Amazon's Mechanical Turk data collection platform. A total of 256 adults (Mage = 27.87, SD = 4.79; 58.2% White, 23% Asian; 65.2% had an associate degree or greater) completed the survey. Measures of delay discounting, consideration of future consequences, Internet demand, and alternative reinforcement all contributed unique variance in predicting both problematic Internet use and Internet craving. In aggregate models controlling for all significant predictors, alternative reinforcement and future valuation variables contributed unique variance. Individuals with elevated demand and discounting were at greatest risk for problematic Internet use. Consistent with behavioral economic research among substance abusing samples, individuals engaging in heavy Internet use report elevated motivation for the target behavior coupled with diminished motivation for other potentially rewarding activities, especially those associated with delayed reward. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451524 TI - Wallace Craig's Appetites and aversions as constituents of instincts: A centennial appreciation. AB - Wallace Craig's "Appetites and Aversions as Constituents of Instincts," one of the seminal articles in animal behavior, comparative psychology, and ethology, appeared 100 years ago this year. The influence of this classic article is continuing and perhaps even expanding. Here we review the major ideas Craig offered in the article, provide a brief sketch of his scientific career and historical context, and examine the impact of the article on ethological and instinct theory. We also review some current applications of his work in diverse areas and discuss why it is cited more now than in earlier decades, especially in articles on causal mechanisms. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451526 TI - Machiavellian intelligence retrospective. AB - Thirty years on from the publication of Machiavellian Intelligence (Byrne & Whiten, 1988), it is time to consider how the ideas in it have influenced understanding of the evolution of intelligence, how they have been tested (and sometimes misunderstood), and whether they are still relevant today. This essay attempts to do so. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451525 TI - Celebrating the continued importance of "Machiavellian Intelligence" 30 years on. AB - The question of what has shaped primates' (and other species') cognitive capacities, whether technical or social demands, remains a hot topic of inquiry. Indeed, a key area of study within the field of comparative psychology in the last few decades has been the focus on social life as a driving force behind the evolution of cognition, studied from behavioral and neurological perspectives and from theoretical and empirical perspectives. Reflecting on contemporary studies of primate social cognition specifically, one cannot ignore the book, Machiavellian Intelligence, coedited by Richard Byrne and Andrew Whiten (Byrne & Whiten, 1988a). It is a keystone for the field: The volume as a whole has been cited over 3,000 times, without even including citations to individual chapters. This year, 2018, is the 30th anniversary of the first publication of Machiavellian Intelligence, and with this special issue of the Journal of Comparative Psychology, we mark that milestone. The key concept put forth in Machiavellian Intelligence was that primates' sociocognitive abilities were shaped by the complex social worlds that they inhabited, rather than the technical or foraging challenges that they faced, as had previously been posited. In this issue, we consider the strength of the Machiavellian intelligence hypothesis 30 years on to explain primate social cognition, and we consider its applicability to nonprimate species and to other cognitive domains. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451527 TI - Social, Machiavellian and cultural cognition: A golden age of discovery in comparative and evolutionary psychology. AB - The years since the publication of Machiavellian Intelligence have witnessed a golden age in discoveries concerning social cognition in human and nonhuman primates and many other animal taxa too. Here, I briefly dissect some of the variants of the social intelligence hypotheses that have evolved in this time and offer a selective overview of the scientific discoveries in this field, particularly in primates, over the last 30 years. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451528 TI - Communication as a fundamental part of machiavellian intelligence. AB - The Machiavellian intelligence hypothesis proposes that individuals in complex social groups require sophisticated social cognition. This hypothesis has advanced our understanding of the complex social lives of animals and how individuals interact with others in their groups. Machiavellian intelligence is the capacity of an individual to alter the behavior of others around it to the individual's own advantage. This capacity is typically facilitated by complex communicative systems, social systems, and cognitive abilities. Curiously, communication among group members has not traditionally been a focus of research related to the Machiavellian intelligence hypothesis. Here, we show how a focus on communicative and cognitive complexity together can elucidate nuanced manipulations for selfish gains in socially complex groups, under both competitive and cooperative scenarios. Finally, we argue more generally that a research emphasis on communication in complex social groups may accelerate our understanding of the social mechanisms underlying complex adaptive behavior. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451529 TI - Spontaneous social tool use in chimpanzees (Pan troglodytes). AB - Although there is good evidence that social animals show elaborate cognitive skills to deal with others, there are few reports of animals physically using social agents and their respective responses as means to an end-social tool use. In this case study, we investigated spontaneous and repeated social tool use behavior in chimpanzees (Pan troglodytes). We presented a group of chimpanzees with an apparatus, in which pushing two buttons would release juice from a distantly located fountain. Consequently, any one individual could only either push the buttons or drink from the fountain but never push and drink simultaneously. In this scenario, an adult male attempted to retrieve three other individuals and push them toward the buttons that, if pressed, released juice from the fountain. With this strategy, the social tool user increased his juice intake 10-fold. Interestingly, the strategy was stable over time, which was possibly enabled by playing with the social tools. With over 100 instances, we provide the biggest data set on social tool use recorded among nonhuman animals so far. The repeated use of other individuals as social tools may represent a complex social skill linked to Machiavellian intelligence. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451530 TI - Testing for anticipation of partners' reciprocity and other social parameters: An experimental approach in wild vervet monkeys (Chlorocebus pygerythrus). AB - It has been suggested that social challenges in group-living species in which individuals maintain long-term relationships select for advanced cognitive processes. A key challenge for testing this hypothesis is to design experiments that allow the assessment of animals' knowledge of conspecifics and how they use that information to their own advantage. Here, we present data on wild vervets using an experimental paradigm that induced a competitive context. After training females to obtain food from a personal box, we placed their box in proximity to another monkey's personal box to create potential conflict. We have previously shown that high-ranking female vervets exchange tolerance, though to a lesser extent when the audience contains an individual that outranks the subordinate partner, and coalitionary support for grooming. Our questions here were (a) whether subordinates adjust the likelihood of approaching their box when their recent dominant grooming partners are already present and (b) if dominants are more likely to threaten the box partner in the presence of their recent high ranking grooming partner. Although we found some effects of age and group on the subjects' behavior, no evidence emerged that subordinates incorporate the effects of recent grooming history. Dominants were more likely to threaten the box partner in the presence of a high-ranking individual within the audience, independent of their own grooming history. We suggest that our paradigm can be used to discern the degree to which individuals of different species take into account recent social history with others that affect these others' behavior toward themselves. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 30451531 TI - Adherence to instructions and fluctuation of force magnitude in cervical headgear therapy. AB - OBJECTIVES:: To investigate how patients adhere to instructions and how force magnitude fluctuates and influences the use of cervical headgear (CHG) therapy. MATERIALS AND METHODS:: In this controlled clinical trial, subjects (n = 40) were treated with CHG with light (L, 300 g) or heavy (H, 500 g) force. Patients were asked to wear CHG for 10 hours per day for 10 months (ie, during sleep), but the importance for treatment of wearing CHG also in the evening hours was emphasized. Adherence to instructions and force magnitude in CHG use were monitored by electronic module (Smartgear, Swissorthodontics, Switzerland). RESULTS:: Force magnitude can be set at a certain level, L or H, even if great individual variability is seen in all subjects (0-900 g). Children in the L group used CHG longer per day than those in the H group (9.3 hours +/-1.5 hours and 7.8 hours +/ 2.1 hours, respectively, P = .002). During evening hours, CHG was used more ( P = .02) in the L group than in the H group. In both groups, CHG was used less in the evening hours during school breaks than in the evening hours during school ( P < .001). CONCLUSIONS:: Children with lower force in CHG seem to adhere better to the instructions for CHG use. Daily rhythm also influences the time of appliance use regardless of force magnitude. The force can be set to a certain magnitude level, even though there is substantial individual variability. PMID- 30451532 TI - A Social Ecological Approach to Develop a Nutrition Education Program for Preventing Iron Deficiency Anemia in Young Children in Rural Pakistan. AB - Inappropriate feeding practices puts infants and young children at risk of iron deficiency anemia. Maternal complementary feeding (CF) behavior is determined by influences at various levels, including knowledge and attitude about feeding, inter-personal interaction with family/friends, community norms and support. The aim of this study is to understand the various influences on maternal CF behavior in order to develop a culturally appropriate nutrition education program to improve iron status of children aged 9-24 months. Using a social ecological approach, in-depth interviews with stakeholders revealed restraining factors that prevented behavior change. Culturally appropriate nutrition education messages were developed to address these constraints. PMID- 30451533 TI - What Have We Missed?: The Knowledge of and Access to the HPV Vaccine and Sex Education in China. AB - The author completed three doses of Gardasil vaccine, which helps to protect against diseases caused by HPV (genital human papillomavirus). The author, a woman born and raised in China, had no knowledge of HPV or the HPV vaccine until she came to the United States for graduate school. In this piece, she presents a personal intercultural medical story about her HPV vaccine process. She utilizes personal narratives to share with readers her experience with sex education and to convey people's attitudes toward sexuality and sex education in mainland China. PMID- 30451534 TI - Comparative effectiveness of uterine fibroids procedures using linked medical record and claims data. AB - AIMS: To compare durability of uterus-conserving procedures for symptomatic fibroids in terms of incidence and time to subsequent procedures. PATIENTS & METHODS: We conducted a retrospective database study of 2648 patients having a uterus-conserving procedure for uterine fibroids from 2005 to 2011 with a minimum of 2 years follow-up. RESULTS: Patients with myomectomy or uterine artery embolization as their index procedure had lower risk of a subsequent procedure during the study compared with patients who underwent endometrial ablation. CONCLUSION: While subject to known limitations of using electronic medical record and administrative claims data, this research provides additional evidence regarding expectations for time to subsequent procedures that may be helpful for women and their healthcare providers to consider when making treatment choices. PMID- 30451535 TI - Emotional exhaustion among anesthesia providers at a tertiary care center assessed using the MBI burnout survey. AB - Burnout is characterized by three components: emotional exhaustion, depersonalization, and low personal accomplishment. Burnout in health professionals results in reduced job satisfaction, decreased mental health and decreased quality of care, with rates ranging from 30-65% across medical specialties. The purpose of this study was to evaluate the prevalence of burnout components and identify factors associated with these components in physicians, residents, and certified nurse anesthetists (CRNAs) in a large academic anesthesiology department. A survey consisting of the Maslach Burnout Inventory Human Services Survey and additional demographic questions was distributed via email at 7-day intervals over 4 weeks to all anesthesia providers. Scores from individual questions on each of the three subscales were summed and sorted into low, medium, and high levels of each outcome variable. Fisher's exact chi-square tests were used for categorical data. Eighteen residents, 39 staff anesthesiologists, and 32 CRNAs comprised a total of 89 survey respondents. Rates of emotional exhaustion varied by provider types. Residents reported higher levels of emotional exhaustion than staff anesthesiologists and CRNAs. As a system, it is vital for leaders to identify those with or at risk for burnout, their risk factors, and strategies to mitigate risk. The goals of the healthcare system should aim to maintain both quality patient care and healthcare provider wellness. PMID- 30451537 TI - Perceived social support and mental health for college students in mainland China: the mediating effects of self-concept. AB - Previous studies revealed that both self-concept and social support were associated with mental health in college students. Very few studies have explored the ways these two variables work on mental health, particularly in mainland China. In the present study, 411 college students in northwest China were assessed using the School and Society Situations Scale (which includes a social support sub-scale and self-concept sub-scale) and Self-report Symptom Checklist 90. The results showed that a positive self-concept was positively correlated with individual perceived social support from parents, teachers, and peers, and that both self-concept and perceived social support were negatively associated with mental health problems. Moreover, structural equation modeling analyses showed that self-concept fully mediated the role of perceived social support in individuals' mental health. These results suggested that all kinds of perceived support from the social environment may help the college student form a positive self-concept, and the positive self-concept may help them resist and effectively cope with the risk factors related to mental health. These results also have implications in interventions to improve mental health in college students. PMID- 30451536 TI - A Comparison of High School Boys' and Girls' Lacrosse Injuries: Academic Years 2008-2009 Through 2015-2016. AB - CONTEXT: The sex-based differences in the structure and rules of boys' and girls' lacrosse result in very different styles of play, which may have significant implications for the rates and patterns of injuries. OBJECTIVE: To compare the epidemiology of injuries sustained by boys' and girls' lacrosse players. DESIGN: Injury surveillance study. SETTING: Web-based online surveillance system. PATIENTS OR OTHER PARTICIPANTS: The High School Reporting Injury Online (HS RIO) database was used to analyze injuries reported by certified athletic trainers from 2008-2009 through 2015-2016. MAIN OUTCOME MEASURE(S): Practice and competition injury rates, body site, diagnosis, and mechanism. RESULTS: Boys had a higher injury rate than girls (20.9 versus 15.7 per 10 000 athlete-exposures, respectively; rate ratio = 1.3, 95% confidence interval = 1.2, 1.4). The most commonly injured body sites for boys and girls overall were the lower extremities (38.0, 56.4%) and the head/neck (28.3, 29.8%). More specifically, the most frequently diagnosed injuries for both boys and girls in competitions were concussions (23.1, 25.6%), ankle ligament sp9rains (7.8, 15.3%), upper leg strains (4.8, 6.7%), and knee ligament sprains (4.2, 6.7%). The most cited mechanism of injury overall was contact with another player (22.0%); among boys, it was contact with a stick (14.8%) and among girls, the most frequent mechanisms were overuse (25.0%) and contact with a stick (14.7%). CONCLUSIONS: Injury rates and mechanisms of injuries differed between high school boys' and girls' lacrosse players. Boys had a higher rate of injury, with the most common mechanism of injury being contact with another player compared with overuse in girls. However, similarities were seen between sexes for the most frequently injured body sites and injury diagnoses. Future authors should continue to compare differences in injury rates, equipment upgrades, and rule changes in boys' and girls' lacrosse. PMID- 30451538 TI - A Pilot Study of Amino Acids in Unresectable Non-Small-Cell Lung Cancer Patients During Chemotherapy: A Randomized Serial N-of-1 Trials Design. AB - The aim of this study was to evaluate the effect of amino acids (AAs) on immune function and inflammation level in patients with NSCLC receiving chemotherapy. We conducted a series of randomized, multiple-crossover, double-blind, placebo controlled N-of-1 trials comparing AAs with isocaloric glucose in unresectable NSCLC patients and combined the individual results using Bayesian statistical modeling. 25 patients completed two cycles of chemotherapy. The baseline total blood albumin (ALB) level in all patients was 28 +/- 3.3 g/l, and the mean total ALB level in patients receiving AAs supplementation and isocaloric glucose was 29.2 +/- 2.2 and 28.1 +/- 3.7 g/l, respectively (P = 0.028). Patients' baseline C reactive protein (CRP) level was 4 +/- 1.2 mg/l, the mean total CRP level in patients receiving AAs supplementation and isocaloric glucose was 11 +/- 2.8 and 13 +/- 3.2 mg/l, respectively (P = 0.028). The baseline total blood CD4+ T cells level was 36 +/- 7.8%. The percentage of CD4+ T cells in patients receiving AAs supplementation and isocaloric glucose was 42 +/- 6.4 and 33.7 +/- 17.3, respectively (P = 0.034). Our preliminary results indicated that AAs improve immune status and suppress inflammation in unresectable NSCLC patients receiving chemotherapy. PMID- 30451539 TI - Efficacy of interventions aimed at improving physical activity in individuals with stroke: a systematic review. AB - PURPOSE: To identify interventions employed to increase post-stroke physical activity, evaluate their efficacy, and identify the gaps in literature. MATERIALS AND METHODS: Randomized controlled trials published until March 2018 were searched in MEDLINE, PEDro, EMBASE, LILACS, and SCIELO databases. The quality of each study and overall quality of evidence were assessed using the PEDro and the GRADE scales. RESULTS: Eighteen studies were included (good PEDro and very low GRADE-scores). In seven, the experimental groups showed significant increases in physical activity (aerobics, resistance, and home-based training; counseling, aerobics, resistance, and home-based training; electrical stimulation during walking; functional-task training; robot-assisted arm therapy; accelerometer based feedback, and physical activity encouragement). In seven, there were no significant between-group differences (physical activity plan; stretching, use of toe-spreaders, standard treatment; counseling; circuit video-game; functional task; counseling and cognitive training). The combined experimental and control groups showed significant declines in physical activity in one study (aerobic training or stretching) and increases in three others (aerobic, resistance or sham resistance training; stroke-with advice or only stroke-counseling; aerobic training, educational sessions, standard treatment, and coaching, or mobilization and standard treatment). A meta-analysis could not be performed, due to heterogeneity. CONCLUSIONS: Some interventions improved physical activity after stroke. However, the interpretability is limited. Implications for rehabilitation Individuals with stroke show low physical activity, which may compromise function and health. The use of interventions aimed at improving and maintaining physical activity of individuals with stroke are recommended. Some interventions, such as aerobic, resistance, and combined home-based training, electrical stimulation during walking, functional task training, and arm robot-assisted therapy, could improve the physical activity after stroke. PMID- 30451540 TI - Development of "My Wheelchair Guide" app: a qualitative study. AB - BACKGROUND: The smartphone app "My Wheelchair Guide" is designed to provide essential information about wheelchair use and service delivery for new wheelchair users. It aims to empower wheelchair users in taking ownership in acquiring appropriate wheelchairs, and guiding them to use their wheelchairs in a safe and effective manner. OBJECTIVE: This paper describes the development of the "My Wheelchair Guide" app and the usability evaluation of one of the app sections "Use a Wheelchair". METHOD: Ten manual wheelchair users and four seating/mobility professionals completed a survey on the ease of use and perceived usefulness of the app, and a semi-structured interview. Wheelchair users used checklists in the app to self-assess their wheelchairs' fit and set-up, and their wheelchair skills. Two investigators independently conducted content analysis of the interview transcripts and identified salient themes. RESULTS: All participants perceived the app to be easy to use. Both wheelchair users and wheelchair seating professionals recognized that the "Use a Wheelchair" section would be very beneficial for new wheelchair users. Self-assessment checklists facilitated participants to review their wheelchair set-up and skills. Participants also provided several suggestions and recommendations to revise and refine the app section. CONCLUSION: The app section was perceived to be a useful and easy-to-use educational tool by most of the study participants. Participants' feedback will be used to guide the app revision for a better user experience. Further studies could be conducted to assess the app effectiveness on improving wheelchair users' knowledge and facilitating self-advocacy for appropriate wheelchairs. Implications for rehabilitation Smartphone apps designed to support patient education and self-management regarding wheelchair use are perceived beneficial by both wheelchair users and clinical professionals. Smartphone apps support multimedia information presentation and user interaction, and can potentially create an effective learning environment for wheelchair users and their families to learn about their everyday devices. Users of educational apps prefer reduced text-based content and care about app aesthetics. PMID- 30451541 TI - Organizing stroke systems in the field for patients with suspected large vessel occlusion acute stroke. AB - INTRODUCTION: The dawn of endovascular stroke therapy has reshaped stroke care. Eligible patients need to be rushed to capable centers for intervention. This may entail bypassing closer hospitals that could confirm the diagnosis, administer thrombolytic therapy, then transfer patients for intervention. This has created a set of challenges: identifying endovascular candidates in the field, determining the best transport destination, and getting patients there quickly. Areas covered: This review provides a context for these emerging challenges. Current and emerging clinical prediction instruments for large vessel occlusion (LVO) are reviewed. The workflow in the thrombolysis-only primary stroke centers is reviewed, and interventions aimed at minimizing delays are highlighted. Innovations using mathematical modeling and devices for detection of LVO are reviewed. Expert commentary: More patients are expected to receive endovascular therapy as we push the boundaries for time and imaging criteria. Advances in detection and decision-making aids will improve the speed of treatment. Some patients will arrive at thrombolysis-only centers. This need to be triaged, diagnosed, treated, and transported promptly. Therefore, education of practitioners in these centers is paramount. Creating and facilitating infrastructure for imaging acquisition and sharing in such centers will reflect better care for stroke patients overall. PMID- 30451542 TI - Current knowledge about the impact of microgravity on the proteome. AB - INTRODUCTION: Microgravity (ug) is an extreme stressor for plants, animals, and humans and influences biological systems. Humans in space experience various health problems during and after a long-term stay in orbit. Various studies have demonstrated structural alterations and molecular biological changes within the cellular milieu of plants, bacteria, microorganisms, animals, and cells. These data were obtained by proteomics investigations applied in gravitational biology to elucidate changes in the proteome occurring when cells or organisms were exposed to real ug (r-ug) and simulated ug (s-ug). Areas covered: In this review, we summarize the current knowledge about the impact of ug on the proteome in plants, animals, and human cells. The literature suggests that ug impacts the proteome and thus various biological processes such as angiogenesis, apoptosis, cell adhesion, cytoskeleton, extracellular matrix proteins, migration, proliferation, stress response, and signal transduction. The changes in cellular function depend on the respective cell type. Expert commentary: This data is important for the topics of gravitational biology, tissue engineering, cancer research, and translational regenerative medicine. Moreover, it may provide new ideas for countermeasures to protect the health of future space travelers. PMID- 30451543 TI - What does the literature say about using electronic pillboxes for older adults? A systematic literature review. AB - PURPOSE: The purpose of this study is to answer two research questions: (1) What is the clinical evidence for the reported outcomes in studies on electronic pillboxes for older adults? and (2) What is the technology readiness level (TRL) of the electronic pillboxes used, or intended to be used, for older adults? METHODS: The scholarly literature was systematically searched and analyzed. Articles were included if they reported results about electronic pillboxes that were used or intended to be used for older adults' medication. RESULTS: Clinical studies used commercially well-established electronic pillboxes with a high TRL. New electronic pillboxes in development had a low TRL. The discovered outcome was mainly adherence to medication. The overall mean adherence to medication regimens for all the studies using an electronic pillbox was higher than the gold standard of a good adherence level cut-off point (mean adherence 88.8%>80%). However, we found a large variation in this variable (SD = 10.7). With regard to an older adult population's adherence to medication regimens, for the outcome variable of those who had undergone a kidney transplant, the clinical evidence that electronic pillboxes have a positive impact was strong (1b); for those with a chronic hepatitis C medical condition, the clinical evidence was medium (3), and for those with arterial hypertension and multiple chronic (diabetes and hypertension) medical conditions, the clinical evidence was weak (5). CONCLUSION: More research is needed in this area using designs that provide greater validity. Implications for Rehabilitation Electronic pillboxes with multiple reminders such as the "voice of a friend" or relative, which implies that electronic pillboxes which adopt "a social role" are advisable. An unequal level of clinical evidence that electronic pillboxes have a positive impact on the adherence outcome variable was found. For new electronic pillboxes still in development that specifically take into account older adults' needs, the TRL is still low; as a result, they could not be tested in real settings. PMID- 30451544 TI - Associations between ketone bodies and fasting plasma glucose in individuals with post-pancreatitis prediabetes. AB - CONTEXT: Levels of ketone bodies are altered in both acute pancreatitis and type 1 and type 2 diabetes. However, the role of ketone bodies in the pathogenesis of abnormal glucose metabolism after pancreatitis is largely unknown. OBJECTIVE: To investigate the associations between ketone bodies and glucose homeostasis in individuals with post-pancreatitis prediabetes (PPP) versus normoglycaemia after pancreatitis (NAP). METHODS: Fasting blood samples were analysed for acetoacetate, beta-hydroxybutyrate, and markers of glucose metabolism at a median of 26 months after acute pancreatitis. A series of linear regression analyses were conducted adjusting for patient- and pancreatitis-related characteristics. RESULTS: The study included 27 individuals with PPP and 52 with NAP. beta hydroxybutyrate was significantly associated with fasting plasma glucose (p = .002) and explained 26.2% of its variance in PPP, but not in NAP (p = .814; 0%). Acetoacetate was not significantly associated with fasting plasma glucose in both PPP (p = .681) or NAP (p = .661). CONCLUSIONS: An inverse association between beta-hydroxybutyrate and fasting plasma glucose characterises PPP and this may have translational implications. PMID- 30451545 TI - Impaired brain plasticity as a potential therapeutic target for treatment and prevention of dementia. AB - INTRODUCTION: In 2017, it was estimated that close to 50 million people were living with dementia worldwide and this number is expected to double every 20 years. No effective treatment exists yet probably because by the time Alzheimer's dementia (AD) has developed it is too late to intervene. Areas covered: Mild cognitive impairment (MCI) is a clinical state that typically precedes AD. In MCI, the prefrontal cortex supports compensatory mechanisms that depend on robust synaptic plasticity and that delay progression to AD. This review focuses on novel neurostimulation approaches that could enhance prefrontal cortical plasticity in vivo by enhancing prefrontal cortical plasticity and function in patients with MCI or AD. It also describes novel neurophysiological markers that could function as targets for such approaches. Expert commentary: Targeting synaptic plasticity in patients with early AD or at risk of developing AD could be a promising approach to slow progression or prevent AD. PMID- 30451546 TI - Biomarkers for bipolar disorder: current status and challenges ahead. AB - INTRODUCTION: Bipolar disorder (BD) is a chronic psychiatric disorder marked by clinical and pathophysiological heterogeneity. There is a high expectation that personalized approaches can improve the management of patients with BD. For that, identification and validation of potential biomarkers are fundamental. Areas covered: This manuscript will critically review the current status of different biomarkers for BD, including peripheral, genetic, neuroimaging, and neurophysiological candidates, discussing the challenges to move the field forward. Expert commentary: There are no lab or complementary tests currently recommended for the diagnosis or management of patients with BD. Panels composed by multiple biomarkers will probably contribute to stratifying patients according to their clinical stage, therapeutic response, and prognosis. PMID- 30451547 TI - Pharmacotherapy of postpartum obsessive-compulsive disorder: a systematic review. AB - INTRODUCTION: Despite the common occurrence of obsessive-compulsive disorder (OCD) after childbirth, the role of pharmacotherapy in its management is unclear. Areas covered: This systematic review aims to determine the role of drugs in the acute and preventative treatment of postpartum OCD. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four electronic databases including Medline/PubMed, PsycINFO, the Cochrane Database of Systematic Reviews, and Google Scholar were searched. A total of 10 articles - 1 randomized controlled trial, 2 open-label trials, 1 case series, and 6 case reports - were selected for review. Expert commentary: Currently there are no randomized, placebo-controlled drug trials in the acute or preventative treatment of postpartum OCD. The paucity of studies is surprising given that OCD commonly occurs in the postpartum period and untreated illness can be associated with persistence of OCD symptoms and a high degree of emotional distress. Studies are urgently needed to address the lack of controlled data especially in women with postpartum OCD alone, i.e. without comorbid psychiatric disorders. PMID- 30451548 TI - Risks associated with use of TNF inhibitors in children with rheumatic diseases. AB - INTRODUCTION: Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine involved in the pathogenesis of many inflammatory diseases. Several drugs blocking TNF-alpha are employed in clinical practice in pediatrics. Given their action on the immune system, TNF-alpha inhibitors have raised concerns on their safety profile since their introduction. A broad spectrum of side effects related to TNF inhibition has been reported: immunogenicity, infectious diseases, malignancies, and others. Areas covered: In order to assess the risk related to the use of anti-TNF-alpha agents in children with rheumatic diseases we analyzed data obtained from retrospective and prospective safety studies, case reports and case series, and controlled trials. Expert commentary: Anti-TNF-alpha agents have shown a remarkably good safety profile in the pediatric population so far. However, there are lots of questions to be answered and maintaining active surveillance on these drugs is necessary in order to not overlook any possible unexpected adverse effects. PMID- 30451549 TI - How can we best monitor 5-FU administration to maximize benefit to risk ratio? AB - INTRODUCTION: 5-Fluorouracil (5-FU) is currently used as a chemotherapy in several cancers such as head-and-neck (H&N) and colorectal cancers. 5-FU dosing is traditionally based on body surface area (BSA), but this strategy is usually associated with severe toxicities. 5-FU is mainly catabolized by dihydropyrimidine dehydrogenase (DPD), and 5-FU dosage adaptation according to DPD status at the first cycle of treatment is now recommended. To further optimize 5-FU-based chemotherapy, a body of evidences justifies therapeutic drug monitoring (TDM). Areas covered: 5-FU pharmacokinetics, relationships between pharmacokinetics and efficacy or toxicity of 5-FU, proofs of interest of 5-FU TDM and its practical considerations are discussed. Expert opinion: BSA-adjusted 5-FU administration is associated with a large inter-individual variability, and according to this strategy, many patients experience under- or overexposure. Moreover, relationships between 5-FU area under the curve (AUC) and its toxicity or efficacy have been demonstrated, at least in patients with colorectal or H&N cancers. 5-FU therapeutic index has been validated and algorithms of 5-FU dosage adaptation according to its AUC are now available. Advances in pre-analytical and analytical steps of 5-FU TDM make its use feasible in clinical practice. Thus, there are consistent evidences to recommend 5-FU TDM in patients with advanced colorectal or H&N cancers. PMID- 30451550 TI - An omentum-cultured 3D-printed artificial trachea: in vivo bioreactor. AB - The purpose of this study was to evaluate whether the prior implantation of a 3D printed polycaprolactone (PCL) artificial trachea in the omentum is beneficial for revascularization of the scaffold and reduces associated complications in the reconstruction of a circumferential tracheal defect. Ten New Zealand rabbits were divided into 2 groups: (1) PCL-OC group (PCL scaffold cultured in omentum for 2 weeks before transplantation) and (2) PCL group. In the PCL-OC group, newly formed connective tissue completely covered the luminal surface of the scaffold with mild inflammation at 2 weeks postoperatively; a minor degree of stenosis was noted at 8 weeks postoperatively. The PCL group showed scaffold exposure without any tissue regeneration at 2 weeks postoperatively, and a moderate degree of luminal stenosis 6 weeks after implantation. Histology revealed highly organized regenerated tissue composed of ciliated respiratory epithelium, and submucosal layer in the PCL-OC group. Neo-cartilage regeneration was noted in part of the regenerated tissue. The PCL group demonstrated severe inflammation and an unorganized structure compared to that of the PCL-OC group. In vivo omentum culture of the tracheal scaffold before transplantation is beneficial for rapid re-epithelialization and revascularization of the scaffold. It also prevents postoperative luminal stenosis. PMID- 30451551 TI - Balance and mobility in patients with newly diagnosed Parkinson's disease - a five-year follow-up of a cohort in northern Sweden. AB - BACKGROUND: The presence of early balance impairment in patients with Parkinson's disease has not been fully investigated. PURPOSE: The purpose of this study was to examine balance and mobility, self-perceived unsteadiness, self-reported falls, and effects of medication on balance among patients at their first visit to a neurological clinic and during the ensuing five years. MATERIALS AND METHODS: The participants were collected from a prospective longitudinal study. One hundred and forty-five patients with idiopathic Parkinson's disease and 31 healthy controls were included. The outcome measures were the Berg Balance Scale, the Timed Up and Go, the Postural Stability test and a questionnaire. RESULTS: At their first visit to the neurological clinic, the patients performed less well on the Berg Balance Scale (p < 0.001, r = 0.36), the Timed Up and Go (p < 0.001, r = 0.32), and the Postural Stability test (p < 0.001, r = 0.35) compared with the controls. In addition, a higher percentage of the patients reported self perceived unsteadiness (p < 0.001, phi = 0.47). During the ensuing five years, balance and mobility worsened both with and without medication (p < 0.01, r = 0.24-0.37), although with small median differences. CONCLUSIONS: Further studies are needed to confirm that minor balance impairments exist even at the time of diagnosis and worsen during the ensuing five years. IMPLICATIONS FOR REHABILITATION Impairments in balance and mobility may occur early in Parkinson's disease, especially in the elderly patients, and seem to worsen during the first five years. There is a need to use sensitive outcome measures and to ask the patients about unsteadiness and falls to detect balance impairment in this cohort. Parkinsonian medication has a limited effect on balance and may preferably be complemented with balance exercises to target balance impairment early in Parkinson's disease. PMID- 30451552 TI - Prediction of early mortality following stereotactic body radiotherapy for peripheral early-stage lung cancer. AB - BACKGROUND/PURPOSE: To investigate prognostic factors for death within 6 months of stereotactic body radiotherapy (SBRT) for patients with peripheral early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This analysis included 586 NSCLC patients with peripheral tumors treated with SBRT. Potential patient and tumor prognostic factors, including the Charlson Comorbidity Index (CCI) and Cumulative Illness Rating Scale (CIRS), were analyzed by logistic regression analysis for association with early mortality (death <6 months after SBRT). Additionally, CCI and CIRS were compared with respect to their predictive ability for early mortality by comparing multivariate models with each comorbidity index, and assessing their respective discriminatory abilities (C-index). RESULTS: A total of 36 patients (6.1%) died within 6 months of the start of SBRT. With a median follow-up of 25 months, 3-year overall survival was 54%. CIRS and tumor diameter were significant predictors of early mortality on multivariate analysis (p = .001). Patients with a CIRS score of 8 or higher and a tumor diameter over 3 cm had a 6-month survival of 70% versus 97% for those lacking these two features (p < .001). CCI was not predictive for early mortality on univariate nor multivariate analysis; the model containing CCI had a C-index of 0.65 versus 0.70 for the model containing CIRS. CONCLUSION: CIRS and tumor diameter predict for early-mortality in peripheral early-stage NSCLC treated with SBRT. CIRS may be a more useful comorbidity index than CCI in this population when assessing short term life expectancy. PMID- 30451554 TI - The use of Drosophila melanogaster as a model organism to study immune nanotoxicity. AB - Nanomaterials (NMs) are widely used in consumer and industrial products, as well as in the field of nanomedicine. Despite their wide array of applications, NMs are regarded as foreign entities by the body and thus induce various immune reactions. In mammals, NMs trigger differential recognition by immune cells such as macrophages, causing perturbation of the immune system. Studies on the pattern recognition of NMs have revealed that the Toll-like receptor signaling pathway plays an essential role in NM-induced innate immunity. However, effects caused by physicochemical properties of NMs on immune response and how NMs are recognized by immune cells are not fully understood. Furthermore, the complexity of the mammalian immune system and interspecies variation are still being debated, and the discordant results warrant the need to address these issues. Drosophila melanogaster has gained popularity as a model to study nanotoxicity. Drosophila innate immunity has extensively been studied, providing insights into our understanding of key signaling cascades involved, and importantly it has conserved immune-related genes and mechanogenetic pathways that represents a useful basis for studying its biological response at molecular level to environmental contaminants such as NMs. Moreover, various genetic tools and reagents enable to elucidate the molecular mechanisms underlying the internalization of NMs by immune cells. Furthermore, numerous forward and reverse genetic approaches can be employed to dissect complex biological processes, such as identifying signal transduction pathways and their core components involved in NM-induced immune responses. This review presents an overview of Drosophila innate immunity, as well as summarizes the impact of NM exposure on immune response in Drosophila. We also highlight the recent advancement of suitable methodologies and tools regarding the use of Drosophila as a model for studying the immune-related toxicity of NMs, taking into account the limitations associated with studying NM-induced toxicity in the mammalian system. PMID- 30451553 TI - Mental Health Researchers' Views About Service User Research: A Literature Review. AB - Services users are becoming actively involved in mental health research. How this is perceived by other researchers is not well known. The aim of this article is to review the international literature exploring other mental health researchers' views of service users conducting research, between 1996 and 2016. Searches of multiple databases (PubMed, PsycINFO, CINAHL, and Google Scholar) were undertaken. Combinations of terms related to service user research and mental health researcher perspectives, views, and attitudes were used. Manual inquiry of reference lists was also undertaken. Relevant papers were coded by topic, location, study design, and other dimensions. Five articles met inclusion criteria. Most referred to perceived benefits, such as greater validity of research findings, challenges of collaborating with service users, and the validity of research findings. There was some evidence of more openness to mental health service users providing suggestions, preferably in early stages of the research process. Reluctance to co-research with service users was reported. There is limited research directly addressing other mental health researchers' views about service user research; barriers to inclusion (whether involvement, co production or user-controlled) and creating incongruence with health policy statements. Further research to more fully understand these attitudes and how they might be influenced is warranted. PMID- 30451555 TI - Molecular identification and genetic diversity analysis of Chocolate mahseer (Neolissochilus hexagonolepis) populations of Northeast India, using mitochondrial DNA markers. AB - The population genetic structure and genetic diversity of Neolissochilus hexagonolepis were studied using three mitochondrial genes (CoxI, Cytb, ATPase 6/8). A total of 120 individuals representing nine populations from different drainages of Northeast India were used for the study. Thirty-three distinct haplotypes were identified from concatenated gene analysis. The total haplotype and nucleotide diversities are 0.8880 and 0.0280, respectively. The analysis of molecular variance (AMOVA) reveals that the main variation (89.33%) was among populations. Most of the populations showed high polymorphisms, parsimony and haplotype diversity which indicate genetically healthy stocks in the wild. The genetic differentiation patterns were consistent with geographical distributions. Pairwise FST comparison of populations showed significant genetic differentiation (0.9088, p < .05). The pattern of haplotype network and phylogenetic tree revealed six major groups. Results suggested that chocolate mahseer populations in Northeast India having high haplotype diversity and genetic differentiation can be utilized in breeding programs to maintain genetic diversity in the descendant populations. The present study would be beneficial for sustainable management, stock-specific strategies for breeding and conservation of the wild population of N. hexagonolepis in future. PMID- 30451556 TI - Phylogenetic analysis of sooty grunter and other major freshwater fishes in the suborder Percoidei based on mitochondrial DNA. AB - Perciformes is the largest order of fishes and vertebrates. Sooty grunter (Hephaestus fuliginosus) is an economic fish species in the Terapontidae family of Percoidei, a suborder within Perciformes. To conduct molecular-level analysis of the phylogenetic relationships between sooty grunter and major freshwater fishes in Percoidei, we analysed the entire sooty grunter mitochondrial genome sequence and obtained the mitochondrial genome information of 19 fishes from Terapontidae, Serranidae, and Centrarchidae families in Percoidei from GenBank. The complete length of the sooty grunter mitochondrial genome was 16,770 bp; it encoded 13 proteins, 2 rRNAs, 22 tRNAs, and a displacement loop (D-loop). Other than ND6 and eight tRNA genes that are encoded by the light strand, the majority of genes are encoded by the heavy strand. The sequence and distribution of sooty grunter mitochondrial-encoded genes and non-coding segment were similar to those of most vertebrates. The results of neighbour joining, maximum parsimony, and Bayesian inference analyses of the complete mitochondrial genome and six genes, including cytochrome oxidase I, cytochrome B, 12S rRNA, ND2, ND4, and ND5, were consistent. In the phylogenetic trees, fishes in Terapontidae and Centrarchidae formed monophyletic clades, whereas those in Serranidae were divided into two clades, each containing Lateolabrax and Siniperca species. Among the three freshwater fish species in Terapontidae, the freshwater Terapontidae were more closely related to jade perch than with silver perch, suggesting that freshwater Terapontidae fishes originate from marine fishes. In addition, the phylogenetic results indicated that Micropterus salmoides salmoides and Micropterus salmoides floridanus in Centrarchidae should be designated as two independent species, and Siniperca in Serranidae should be considered an independent family. The sooty grunter mitochondrial genome sequence obtained in this study could be used to conduct population genetic diversity and germplasm resource studies. Furthermore, the phylogenetic analysis results of freshwater fishes in Percoidei could provide a molecular basis for cross-breeding. PMID- 30451557 TI - Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration. AB - BACKGROUND: Age-related macular degeneration (AMD) is a common sight threatening condition. However, there are a number of monogenic macular dystrophies that are clinically similar to AMD, which can potentially provide pathogenetic insights. METHODS: Three siblings from a non-consanguineous Greek-Cypriot family reported central visual disturbance and nyctalopia. The patients had full ophthalmic examinations and color fundus photography, spectral-domain ocular coherence tomography and scanning laser ophthalmoscopy. Targeted polymerase chain reaction (PCR) was performed as a first step to attempt to identify suspected mutations in C1QTNF5 and TIMP3 followed by whole genome sequencing. RESULTS: The three patients were noted to have symptoms of nyctalopia, early paracentral visual field loss and, in older patients, central vision loss. Imaging identified pseudodrusen, retinal atrophy and RPE-Bruch's membrane separation. Whole genome sequencing of the proband revealed two novel heterozygous variants in C1QTNF5, c.556C>T, and c.569C>G. The mutation segregated with disease in this family, occurred in cis, and resulted in missense amino acid changes P186S and S190W in C1QTNF5. In silico modeling of the variants revealed that the S190W mutations was likely to have the greatest pathologic effect and that the combination of the mutations was likely to have an additive effect. CONCLUSIONS: The novel mutations in C1QTNF5 identified here expand the genotypic spectrum of mutations causing late-onset retinal dystrophy. PMID- 30451558 TI - Pharmacogenomics and Psychiatric Nursing. AB - The treatment of mental illness is often done on a trial-and-error basis and achieving therapeutic benefits from a medication is not always guaranteed. Pharmacogenomics explores the role of gene-gene interactions and interindividual responses to a drug and may be promising in the guidance of pharmacotherapeutic options. In the present study, the impact of pharmacogenomic testing in management of mental health medication was investigated. Participants were identified at a local outpatient mental health facility through convenience sampling. Retrospective chart review included medication history, adverse drug reactions, pharmacogenomic history, and demographic data including insurance coverage. Chart review focused on six months pre- and post-pharmacogenomic for a comparison with the patient serving as their own control. Results indicate a high incidence of alterations in two specific cytochrome enzymes, CYP2D6 and CYP2C19. In total, 82% of the sample had variations with CYP2D6, while 64% of individuals had variations with CYP2C19. In total, 91% of patients tested received Medicaid or Medicare. Post-pharmacogenomic testing, all patient drug regimens were modified, and all reported less adverse side effects. Moreover, advanced practice nurse providers educated patients about the availability of genetic testing, initiated testing and provided care based on findings. These results demonstrate the utility of genetic testing in the realm of mental health. Future directions involve further exploring the benefits of pharmacogenomic testing in this vulnerable population. PMID- 30451559 TI - Toxicity of copper oxide and basic copper carbonate nanoparticles after short term oral exposure in rats. AB - Copper oxide (CuO) nanoparticles (NPs) and copper carbonate nanoparticles (Cu2CO3(OH)2 NPs have applications as antimicrobial agents and wood preservatives: an application that may lead to oral ingestion via hand to mouth transfer. Rats were exposed by oral gavage to CuO NPs and Cu2CO3(OH)2 NPs for five consecutive days with doses from 1 to 512 mg/kg and 4 to 128 mg/kg per day, respectively, and toxicity was evaluated at days 6 and 26. Both CuO NPs and Cu2CO3(OH)2 NPs induced changes in hematology parameters, as well as clinical chemistry markers (e.g. increased alanine aminotransferase, ALT) indicative of liver damage For CuO NPs histopathological alterations were observed in bone marrow, stomach and liver mainly consisting of an inflammatory response, ulceration, and degeneration. Cu2CO3(OH)2 NPs induced morphological alterations in the stomach, liver, intestines, spleen, thymus, kidneys, and bone marrow. In spleen and thymus lymphoid, depletion was noted that warrants further immunotoxicological evaluation. The NPs showed partial dissolution in artificial simulated stomach fluids, while in intestinal conditions, the primary particles simultaneously shrank and agglomerated into large structures. This means that both copper ions and the particulate nanoforms should be considered as potential causal agents for the observed toxicity. For risk assessment, the lowest bench mark dose (BMD) was similar for both NPs for the serum liver enzyme AST (an indication of liver toxicity), being 26.2 mg/kg for CuO NPs and 30.8 mg/kg for Cu2CO3(OH)2 NPs. This was surprising since the histopathology evidence demonstrates more severe organ damage for Cu2CO3(OH)2 NPs than for CuO NPs. PMID- 30451560 TI - The Role of Peer Support Group in Subjective Well-Being of Wives of War Veterans with Post-Traumatic Stress Disorder. AB - This study aimed to investigate the effect of peer support group on subjective well-being (SWB) of wives of war veterans with post-traumatic stress disorder (PTSD). Selected participants were randomly assigned into intervention and control groups (n = 40 for each group). The intervention group was divided into four subgroups, with each participating in 8 weekly based 1.5 hr peer support group sessions. SWB and its dimensions in the intervention group increased significantly higher than those in the control group (p < 0.001). Peer support group can be a useful tool to enhance SWB in spouses of war veterans with PTSD. PMID- 30451561 TI - Validating the Use of Census Data on Education as a Measure of Socioeconomic Status in an Occupational Cohort. AB - PURPOSE: Adjusting for smoking status or a reliable surrogate (such as socioeconomic status (SES)) is critically important in occupational epidemiology studies when any smoking-related cancer or cardiovascular disease is an outcome of interest. Sometimes, however, data on smoking patterns or individual-level smoking surrogates such as job title, education, pay scale or other measures of SES are not readily available in occupational cohorts. METHODS AND MATERIALS: To obtain a surrogate measure for missing smoking or individual-level SES data, we demonstrate a method used to obtain and geocode residential address histories which were then linked to area-level SES measures from the United States Census in 3 test samples and then in a full cohort of workers from the Mound nuclear weapons facility in Dayton, Ohio, USA. The mean educational attainment of the Census Block Group was used to derive a categorical estimate of educational attainment which was compared to self-reported education available from Mound worker histories using Kappa statistics. Lung cancer mortality patterns between area-derived (AD) and self-reported (SR) education were investigated using Standardized Mortality Ratios (SMR) and Cox Proportional Hazards models with stratification or adjustment by either SR or AD education. RESULTS: Home address histories were obtained from linkages of individual worker data to online resources. In the test cohorts, mean educational attainment was the Census Block Group measure found to have the largest magnitude association with individual level SES measures. Among 7,251 Mound workers, 5,685 (78.4%) had at least one residential address match (mean 4.9 addresses) identified. The SR and AD educational attainment measures were highly correlated (weighted Kappa coefficient 0.10, p < 0.0001). SMR patterns by SR and AD educational attainment were similar, with steadily decreasing mortality with increased educational attainment by either measure. Cox models for lung cancer using AD education produced similar results as those using SR education as an adjustment factor. CONCLUSION: When individual-level SES indicators are not available for statistical adjustment, area-level SES measures can serve as a reliable surrogate when investigating outcomes that are affected by lifestyle factors such as smoking. PMID- 30451562 TI - Effects of irradiation conditions on the radiation sensitivity of microorganisms in the presence of OH-radical scavengers. AB - PURPOSE: The purpose of the paper was to investigate the protective effect of some scavengers of OH radicals (hydroxyl radicals) on the radiation sensitivity of bacteria (in some cases also yeast) under normoxic (in air) or hypoxic (suboxic) conditions and to compare the obtained results with those published earlier for the yeast, all in a wide interval of irradiation conditions. Another aim was to investigate a possible impact of the reaction order of the reaction between the scavengers and the OH radicals on the protection of the cells. MATERIALS AND METHODS: In order to study the protective effect of OH scavengers we used various concentrations of methanol and potassium formate (in some cases also ethanol) in isotonic salt solutions. These solutions containing living bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae) were irradiated with 60Co radiation using various doses and dose rates. Irradiation was performed in air, in some cases under the hypoxic conditions. The number of surviving cells was determined prior to and after irradiation in suspension with and without scavengers. The surviving fractions after irradiation with and without scavenger were evaluated. RESULTS: The surviving fraction of bacterial cells increases linearly with increasing concentration of both scavengers. The fraction of surviving cells does not increase with increasing concentration of the scavengers under suboxic conditions. The protective effect ? increases linearly with increasing scavenging efficiency and this dependence is much sharper under normoxic conditions than under suboxic ones. The specific protection k is much higher for the methanol than for the potassium formate. CONCLUSIONS: The basic characteristics of the impact of scavengers of OH radicals on radiation sensitivity of both bacteria and yeast are the same in a wide interval of doses and dose rates. The specific protection effect is much higher under the normoxic conditions. This protective effect is inversely proportional to the rate constant of the reaction between the scavenger and the OH radicals. It seems to be obvious that the presence of oxygen during irradiation is a necessary condition for the protective action of the scavengers which may be partially controlled by some transport processes and may be connected with the radiation sensitivity of the cells. On the other hand, the change of the reaction order of the reaction of the scavenger with the OH radicals has turned out to be unimportant. PMID- 30451563 TI - Impact of lithiated cobalt oxide and phosphate nanoparticles on rainbow trout gill epithelial cells. AB - Metal oxide and phosphate nanoparticles (NPs) are ubiquitous in emerging applications, ranging from energy storage to catalysis. Cobalt-containing NPs are particularly important, where their widespread use raises questions about the relationship between composition, structure, and potential for environmental impacts. To address this gap, we investigated the effects of lithiated metal oxide and phosphate NPs on rainbow trout gill epithelial cells, a model for environmental exposure. Lithium cobalt oxide (LCO) NPs significantly reduced cell viability at10 ug/mL, while a 10-fold higher concentration of lithiated cobalt hydroxyphosphate (LCP) NPs was required to significantly reduce viability. Exposure to Li+ and Co2+ alone, at concentrations relevant to ion released from the NPs, did not reduce cell viability and minimally impacted reactive oxygen species (ROS) levels. Both LCO- and LCP-NPs were found within membrane-bound organelles. However, only LCP-NPs underwent rapid and complete dissolution in artificial lysosomal fluid. Unlike LCP-NPs, LCO-NPs significantly increased intracellular ROS, could be found within abnormal multilamellar bodies, and induced formation of intracellular vacuoles. Increased p53 gene expression, measured in individual cells, was observed at sub-toxic concentrations of both LCO- and LCP-NPs, implicating both in inductions of cellular damage and stress at concentrations approaching predicted environmental levels. Our results implicate the intact NP, not the dissolved ions, in the observed adverse effects and show that LCO-NPs significantly impact cell viability accompanied by increase in intracellular ROS and formation of organelles indicative of cell stress, while LCP-NPs have minimal adverse effects, possibly due to their rapid dissolution in acidic organelles. PMID- 30451564 TI - An ecological perspective on implementing environmental control units for veterans with spinal cord injuries and disorders. AB - PURPOSE: Guided by an ecological perspective, the purpose of this study was to identify multilevel factors that influenced the implementation of environmental control units (ECUs) in Veterans Health Administration (VHA) Spinal Cord Injury/Disorders (SCI/D) Centres. MATERIALS AND METHODS: Mixed methods including an online survey and qualitative interviews of VHA healthcare employees. RESULTS: VHA healthcare employees participated in the online survey (n = 153, 21% participation rate) and semi-structured interview (n = 28; 54% participation rate). About 58.2% of survey respondents indicated that patients admitted to a VHA SCI/D Centre received ECU training. Interview participants reported that patients might benefit from educational materials on using ECUs. About 53.7% of survey respondents indicated that they did not receive ECU training. Interview participants emphasized that more healthcare employees needed to be trained to distribute ECU-related tasks including patient training and troubleshooting problems. The most common challenge was the coordination involved in moving patients out of rooms that were being outfitted with an ECU. CONCLUSIONS: Application of an ecological framework highlighted a range of factors at multiple levels that dynamically influence ECU implementation while accounting for the SCI/D care context. Integrating this technology with the care experiences of patients, the workflow of healthcare employees, and the structure of the organization may improve the implementation of ECUs. IMPLICATIONS FOR REHABILITATION An environmental control unit (ECU) is an assistive technology device that provides persons with a physical disability (e.g., spinal cord injuries and disorders) increased independence in a home, hospital, or rehabilitation facility setting. An ECU allows a person to access and control appliances like their hospital bed, lights, television, doors, nurse call button, telephone, and computer, thus, decreasing workload on attendants and family members while increasing independence for the user. Application of an ecological framework in this study highlighted a range of factors at multiple levels that dynamically influence ECU implementation while accounting for the SCI/D care context. Integrating this technology with the care experiences of patients, the workflow of healthcare employees, and the structure of the organization may improve the implementation of ECUs in an inpatient setting. PMID- 30451565 TI - Magnaporthe oryzae Abp1, a MoArk1 kinase-interacting actin binding protein, links actin cytoskeleton regulation to growth, endocytosis, and pathogenesis. AB - The actin cytoskeleton and actin-coupled endocytosis are conserved cellular processes required for the normal growth and pathogenesis of the rice blast fungus Magnaporthe oryzae. We have previously shown that both actin-regulating kinase MoArk1 and adenylyl cyclase-associated protein MoCap1 regulate actin dynamics and endocytosis to play a key role in virulence of the fungus. To understand the underlying mechanism, we have characterized the actin-binding protein MoAbp1 that interacts with MoArk1 from M. oryzae. The DeltaMoabp1 mutant exhibited delayed endocytosis and defects in the growth, host penetration, and invasive growth. Consistent with its putative function associated with actin binding, MoAbp1 regulates the localization of actin patches and plays a role in MoArk1 phosphorylation. In addition, MoAbp1 interacts with MoCap1 affecting its normal patch localization pattern and the actin protein MoAct1 through its conserved domains. Taken together, our results support a notion that MoAbp1 functions as a protein scaffold linking MoArk1, MoCap1 and MoAct1 to regulate actin cytoskeleton dynamics critical in growth and pathogenicity of the blast fungus. PMID- 30451566 TI - Dosimetry for the study of medical radiation workers with a focus on the mean absorbed dose to the lung, brain and other organs. AB - BACKGROUND: The reconstruction of lifetime radiation doses for medical workers presents special challenges not commonly encountered for the other worker cohorts comprising the Million Worker Study (MWS). METHODS: The selection of approximately 175,000 medical radiation workers relies on using estimates of lifetime and annual personal monitoring results collected since 1977. Approaches have been created to adjust the monitoring results so that mean organ absorbed doses can be estimated. RESULTS: Changes in medical technology and practices have altered the radiation exposure environments to which a worker may have been exposed during their career. Other temporal factors include shifts in regulatory requirements that influenced the conduct of radiation monitoring and the changes in the measured dose quantities. CONCLUSIONS: The use of leaded aprons during exposure to lower energy x rays encountered in fluoroscopically based radiology adds complexity to account for the shielding of the organs located in the torso when dosimeters were worn over leaded aprons. Estimating doses to unshielded tissues such as the brain and lens of the eye become less challenging when dosimeters are worn at the collar above the apron. The absence of leaded aprons in the higher energy photon settings lead to a more straightforward process of relating dosimeter results to mean organ doses. PMID- 30451567 TI - Metabolomics predicts the pharmacological profile of new psychoactive substances. AB - BACKGROUND:: The unprecedented proliferation of new psychoactive substances (NPS) threatens public health and challenges drug policy. Information on NPS pharmacology and toxicity is, in most cases, unavailable or very limited and, given the large number of new compounds released on the market each year, their timely evaluation by current standards is certainly challenging. AIMS:: We present here a metabolomics-targeted approach to predict the pharmacological profile of NPS. METHODS:: We have created a machine learning algorithm employing the quantification of monoamine neurotransmitters and steroid hormones in rats to predict the similarity of new drugs to classical ones of abuse (MDMA (3,4-methyl enedioxy methamphetamine), methamphetamine, cocaine, heroin and Delta9 tetrahydrocannabinol). RESULTS:: We have characterized each classical drug of abuse and two examples of NPS (mephedrone and JWH-018) following alterations observed in the targeted metabolome profile (monoamine neurotransmitters and steroid hormones) in different brain areas, plasma and urine at 1 h and 4 h post drug/vehicle administration. As proof of concept, our model successfully predicted the pharmacological profile of a synthetic cannabinoid (JWH-018) as a cannabinoid-like drug and synthetic cathinone (mephedrone) as a MDMA-like psychostimulant. CONCLUSION:: Our approach allows a fast NPS pharmacological classification which will benefit both drug risk evaluation policies and public health. PMID- 30451568 TI - Biological Outcomes of gamma-radiation Induced DNA Damages in Breast and Lung Cancer Cells Pretreated with Free Radical Scavengers. AB - PURPOSE: Investigation of effects on DNA of gamma-irradiated human cancer cells pretreated with free radical scavengers is aimed to create reference data which would enable assessment of the relative efficiency of high LET radiations used in hadron therapy, i.e., protons and carbon ions. MATERIALS AND METHODS: MCF-7 breast and HTB177 lung cancer cells are irradiated with gamma-rays. To minimize indirect effects of irradiation, dimethyl sulfoxide (DMSO) or glycerol are applied as free radical scavengers. Biological response to irradiation is evaluated through clonogenic cell survival, immunocytochemical and cell cycle analysis, as well as expression of proteins involved in DNA damage response. RESULTS: Examined cell lines reveal similar level of radioresistance. Application of scavengers leads to the rise of cell survival and decreases the number of DNA double strand breaks in irradiated cells. Differences in cell cycle and protein expression between the two cell lines are probably caused by different DNA damage repair mechanisms that are activated. CONCLUSION: The obtained results show that DMSO and glycerol have good scavenging capacity, and may be used to minimize DNA damage induced by free radicals. Therefore, they will be used as the reference for comparison with high LET irradiations, as well as good experimental data suitable for validation of numerical simulations. PMID- 30451569 TI - "Ag-Gag" Laws: Evolution, Resurgence, and Public Health Implications. AB - The term "ag-gag" refers to state laws that intentionally limit public access to information about agricultural production practices, particularly livestock production. Originally created in the 1990s, these laws have recently experienced a resurgence in state legislatures. We discuss the recent history of ag-gag laws in the United States and question whether such ag-gag laws create a "chilling effect" on reporting and investigation of occupational health, community health, and food safety concerns related to industrial food animal production. We conclude with a discussion of the role of environmental and occupational health professionals to encourage critical evaluation of how ag-gag laws might influence the health, safety, and interests of day-to-day agricultural laborers and the public living proximal to industrial food animal production. PMID- 30451570 TI - Central Nervous System Processing of Emotions in Children with Fecal Incontinence and Constipation. AB - OBJECTIVE: Fecal incontinence and constipation are common disorders in childhood. The enteric nervous system and the central nervous system are highly interactive along the brain-gut axis. The interaction is mainly afferent. These afferent pathways include centers that are involved in the central nervous processing of emotions as the mid/posterior insula and the anterior cingulate cortex. A previous study revealed altered processing of emotions in children with fecal incontinence. The present study replicates these results. METHODS: In order to analyze the processing of emotions, we compared the event-related potentials of 25 children with fecal incontinence and constipation to those of 15 control children during the presentation of positive, negative, and neutral pictures. RESULTS: Children with fecal incontinence and constipation showed altered processing of emotions, especially in the parietal and central cortical regions. CONCLUSIONS: The main study results of the previous study were replicated, increasing the certainty and validity of the findings. PMID- 30451572 TI - The UK significant polyp and early colorectal cancer (SPECC) program. PMID- 30451571 TI - [Psychopathology in adolescents from seven countries: What role does controlling identity development and family relationships play?] AB - Psychopathology in adolescents from seven countries: What role does controlling identity development and family relationships play? Abstract. This study analyzed the unique effects of gender and culture on psychopathology in adolescents from seven countries, after controlling for factors that might have contributed to variations in psychopathology. In a sample of 2259 adolescents (M = 15 years; 54 % female) from France, Germany, Turkey, Greece, Peru, Pakistan, and Poland, we assessed identity development, maternal parenting (support, psychological control, anxious rearing), and psychopathology (internalizing, externalizing). Using an analysis of covariance (ANCOVA), we analyzed country, sex, age, and the interaction country x sex as independent variables, while controlling for maternal rearing dimensions and identity development as covariates. This resulted in similar findings for internalizing and externalizing symptoms: Identity rumination and maternal rearing (support, psychological control, anxious rearing) proved to be significant covariates. Further, country, sex, age, and the interaction country x sex were significant. These analyses result in a clearer picture of culture- and gender-specific effects on psychopathology, which is helpful in designing interventions. PMID- 30451573 TI - Observational pilot study of patients with carpal tunnel syndrome treated with Nucleo CMP ForteTM. AB - AIM: Carpal tunnel syndrome (CTS) is a very common entrapment neuropathy characterized by pain and paresthesia in the territory of the median nerve. Although this syndrome has a considerable impact on the patient's quality of life, its medical treatment is far from optimal. MATERIAL & METHODS: We performed an observational study to evaluate Nucleo CMP ForteTM in patients with electromyography-confirmed, mild-moderate CTS. Pain was assessed using a visual analog scale, electromyogram and the SF-36. RESULTS: Pain decreased significantly after 6 months. Quality of life improved significantly in the pain dimensions. No significant differences were observed in electromyographic findings. No adverse events were reported. CONCLUSIONS: Nucleotides could prove useful for the nonsurgical treatment of CTS. Further studies are necessary to confirm this. PMID- 30451574 TI - Fetal Anthropometric Features: A Postmortem Study of Fetuses After the Termination of Pregnancy for Psychosocial Reasons Between 12 and 20 Gestational Weeks. AB - INTRODUCTION: Reference ranges in fetal postmortem anthropometric data derive from heterogeneous studies and rely on data obtained after intrauterine fetal death and abortion, which may introduce bias in the reported fetal growth parameters. We report anthropometric findings in fetuses with the least variation due to cause of death or developmental anomalies. METHODS: We analyzed fetuses after the termination of pregnancy for psychosocial reasons. The external measurements, X-ray dimensions, and body and organ weights were recorded as well as the placenta weight. A thorough and standardized postmortem analysis allowed the design of 2 different groups. Group 1 was composed of fetuses (1) born to mothers with no relevant obstetrical history, (2) no X-ray anomaly, (3) no abnormal autopsy findings, and (4) unremarkable placenta histology. An anomaly in any of these 4 entities moved the fetuses to Group 2. For reference ranges and graph construction, a well-designed statistical methodology was applied. RESULTS: A total of 335 fetuses were analyzed during an 11-year period. Group 1 comprised 232 fetuses aged 12 to 20 gestational weeks, whereas 103 fetuses were considered in Group 2. Comparison between the 2 groups showed almost no differences. Only the Group 1 results were submitted to statistical analysis, and reference ranges and graphs were constructed. CONCLUSIONS: To the best of our knowledge, we provide in this study the first anthropometric references established from almost normal fetuses, albeit for a limited fetal timeframe. PMID- 30451575 TI - Radiation-induced genomic instability, epigenetic mechanisms and the mitochondria: A dysfunctional menage a trois? AB - PURPOSE: This article presents a perspective examining the evidence for a link between radiation-induced genomic instability, epigenetic mechanisms and mitochondrial dysfunction. Significant evidence suggests that mitochondrial dysfunction accompanies radiation-induced genomic instability. Similarly, it is well recognized that mitochondria synthesize the methyl, acetyl and phosphate donors necessary for covalent DNA and histone modifications. Although we have long invoked epigentic mechanisms as drivers of persistent genomic instability, most studies arguably provide only correlative data to support this assertion. CONCLUSIONS: In many ways clarifying the precise mechanisms by which mitochondrial dysfunction contributes to an altered epigenetic landscape to perpeturate radiation-induced instability is still an emerging field despite the fact that we have posited exactly such for decades. This important concept has broad implications in the context of normal tissue and tumor radiation responses. A solid foundation has been laid, though, offering hints for future well-designed studies to cement the paradigm shift. PMID- 30451576 TI - In vitro immunotoxicological assessment of a potent microbicidal nanocomposite based on graphene oxide and silver nanoparticles. AB - Graphene oxide (GO) and silver nanoparticles (AgNPs) can be formed into a hybrid nanomaterial, known as GOAg nanocomposite, which presents high antibacterial activity. The successful translation of this nanomaterial into medical use depends on critical information about its toxicological profile. In keeping with a Safe-by-design approach, we evaluated the immunotoxicity of GOAg using J774 and primary murine macrophages. The interaction between GOAg and macrophages was investigated with a scanning electron microscope (SEM). High-throughput technologies were employed to evaluate cell viability, apoptosis/necrosis, mitochondrial depolarization and lipid peroxidation. The inflammogenicity of nanomaterials was predicted after quantification of the cytokines IL-1beta, TNF alpha and IL-10 before and after stimulation with interferon-gamma (IFN-gamma). The ratio between CD80 and CD206 macrophage populations were also estimated. In addition, the production of nitric oxide (NO) was investigated. SEM surveys revealed the potential of GOAg to induce frustrated phagocytosis. GOAg induced a dose-dependent mitochondrial depolarization, apoptosis and lipid peroxidation to J774 macrophages. GOAg toxicity was not modified in an inflammatory microenvironment, but its toxicity was within the range of concentrations used in bacterial inactivation. GOAg did not induce primary macrophages to significantly produce inflammatory cytokines, and previous macrophage stimulation did not enhance GOAg inflammogenicity. Additionally, the pristine nanomaterials and GOAg do not shift macrophages polarization towards M1. Sublethal concentrations of GOAg did not impair macrophages NO production. Finally, we suggest options for improvement of GOAg nanocomposite in ways that may help minimize its possible adverse outcomes to human health. PMID- 30451577 TI - Functional cognitive disorders: demographic and clinical features contribute to a positive diagnosis. AB - AIM: To examine features associated with functional cognitive disorders (FCDs) compared with neurological cognitive disorders (dementia, mild cognitive impairment, transient amnesias) in consecutive patients referred to a secondary care cognitive disorders clinic. METHODS: Patients diagnosed with either neurological cognitive disorder or FCD were compared by demographic (age, gender, handedness, referral source) and clinical features (family history of dementia, clinical signs, Likert screening measure of subjective memory complaint, mini Addenbrooke's Cognitive Examination). RESULTS: Patients diagnosed with FCD were younger than those with neurological cognitive disorders, and more likely to attend alone, have a family history of dementia and be categorized as positive for subjective memory complaint. CONCLUSION: These data suggest features which may be helpful in making a positive diagnosis of FCD and differentiating from neurological cognitive disorders. PMID- 30451578 TI - Radiolabeled ultra-small Fe3O4 nanoprobes for tumor-targeted multimodal imaging. AB - AIM: In the present study, we aimed to characterize the tumor-targeting properties of ultra-small iron oxide nanoparticles (IONPs) as multimodality imaging contrast agent. METHODS: The dimeric cRGD peptides [cyclic(Cys-Arg-Gly Asp-dSer-Cys)-Tyr-dSer-Lys-Tyr-cyclic(Cys-Arg-Gly-Asp-dSer-Cys)], which specifically targeted integrin-alphavbeta3 receptor highly overexpressed in tumor vasculature and tumor cells, were covalently conjugated onto the surface of ultra small IONPs followed by the labeling of nuclide 125I- through the chloramine-T method to afford the desired 125I-(cRGD)2-IONPs nanoprobe.125I-(cRGD)2-IONPs were injected into tumor-bearing mice for magnetic resonance (MR) and single photon emission computed tomography (SPECT) multi-modality imaging of tumors. RESULTS: The prepared IONPs demonstrated were very useful for T1/T2 and SPECT imaging of tumors in vivo, exhibiting a high tumor uptake of a clinically useful target-to background ratio in a short time. CONCLUSION: We successfully developed a novel integrin-alphavbeta3 receptor-targeted ultra-small IONPs, which could be successfully used as T1-T2-MRI/SPECT contrast agents for high-resolution and high sensitivity of tumor imaging in vivo. PMID- 30451579 TI - 5-HT2A receptors and Parkinson's disease psychosis: a pharmacological discussion. PMID- 30451580 TI - Persons with dementia and care partners' perspectives on memory clinics in primary care. AB - AIMS: To understand persons with dementia (PWD) and care partners' experiences with the Primary Care Collaborative Memory Clinic (PCCMC) care model. METHODS: Interviews were conducted with a purposeful sample of PWD (n = 12) and care partners (N = 16) to identify their perspectives of care received in the clinic and suggestions for improvement. RESULTS: PWD and care partners were satisfied with care received within the PCCMC, had positive interactions with and perceived a strong sense of support from team members and felt listened to; the necessity of cognitive testing was recognized but disliked. CONCLUSIONS: The PCCMC care model can address many existing gaps in dementia care as experienced by PWD and care partners. PMID- 30451581 TI - Multidimensional Assessment of Interoceptive Awareness: Psychometric Properties of the Portuguese Version. AB - Interoceptive awareness involves several mind-body dimensions and can be evaluated by self-report with the Multidimensional Assessment of Interoceptive Awareness (MAIA), which has been translated and validated in several countries and is being used in research and clinical contexts. This study systematically translated the MAIA with six additional items using a focus group and evaluated its psychometric properties in a respondent sample of 204 Portuguese university students (52% females; M = 21.3, SD = 3.9 years). Based on exploratory factor analysis, we refined the tool into a 33-item version and tested it in a separate sample ( n = 286; 63% females; M = 21.3, SD = 4.7 years). We then conducted confirmatory factor analysis and examined test-retest reliability and convergent and discriminant validity. We confirmed an acceptable model fit for this Portuguese version (MAIA-P) with 33 items and seven scales; it showed good construct validity and acceptable temporal reliability, The MAIA-P appears to be valuable for assessing self-reported interoceptive awareness in Portuguese healthy adults. PMID- 30451582 TI - Lipid profile change after bariatric surgeries: laparoscopic gastric plication versus mini gastric bypass. AB - INTRODUCTION: Bariatric surgeries are known to have profound effects on lipid profile. Laparoscopic gastric plication (LGP) has been shown to have a comparable effect on weight loss rather than Roux-en-Y gastric bypass (RYGB) and mini gastric bypass (MGB). But the post-operative effect on lipid profile is not well compared. We aimed to compare post-operative lipid profile change after LGP and MGB. METHODS: In a retrospective analysis, we reviewed 91 patients for at least 12 months. Patients were assigned to undergo either LGP (71 patients) or MGB (20 patients). Preoperative and postoperative visits were accomplished and weight, BMI, fasting blood glucose (FBG) and lipid profile including triglyceride (TG), and total cholesterol (TC) levels were repeatedly measured. Follow up rate for the first year was 100%. RESULTS: LGP significantly decreased both TG and TC levels in each follow up (all p values < .05). The same trends were observed in BMI reduction, total body weight loss percentage, and FBG. When comparing either TC or TG level between LGP and MGB, there was just one statistically significant result in TG reduction at 6 months (p value = .042) while MGB showed more reduction. All other variables in different follow up visits were not significantly different between two techniques. CONCLUSIONS: LGP would result in lipid profile improvement lasting at least for one year. Lipid-lowering effect seems to be similar between LGP and MGB. This lipid-lowering property and weight reduction might be indicative that LGP is an alternative for RYGB and MGB in selective patients. PMID- 30451583 TI - New insights into the binding interaction of food protein ovalbumin with malachite green dye by hybrid spectroscopic and molecular docking analysis. PMID- 30451584 TI - Occurrence, Distribution, and Characteristics of Boscalid-Resistant Corynespora cassiicola in China. AB - Corynespora blight, caused by Corynespora cassiicola (Berk. & M.A. Curtis) C.T. Wei, has become an important disease affecting cucumber in China. Its management mainly depends on fungicides; however, no research has been conducted to assess the sensitivity of C. cassiicola in China to boscalid, a succinate dehydrogenase inhibitor (SDHI). To facilitate boscalid resistance monitoring, baseline sensitivity was established. The EC50 value (i.e., the concentration that results in 50% mycelial growth inhibition) frequency distribution was unimodal with a right-hand tail; with the means 0.95 +/- 0.51 MUg/ml and the range 0.03 to 2.85 MUg/ml. We then assessed the sensitivity of C. cassiicola to boscalid using discriminatory doses and EC50 values. In total, 27.8% of the 798 isolates were resistant, distributed in five provinces and two municipalities. Thirty-seven isolates with different resistance levels to boscalid were also evaluated for their sensitivity to carboxin, fluopyram, and penthiopyrad. Seven SDHI resistance patterns were observed (i.e., I: BosMRFluoMRPenLRCarSS; II: BosVHRFluoSSPenMRCarR; III: BosLRFluoMRPenLRCarR; IV: BosMRFluoMRPenMRCarR; V: BosHRFluoMRPenHRCarR; VI: BosHRFluoHRPenHRCarR; and VII: BosHRFluoSSPenLR CarR, VHR: very highly resistant; HR: highly resistant; MR: moderately resistant; LR: low resistant; R: resistant; SS: supersensitive), corresponding to seven mutations in sdhB/C/D genes, respectively. PMID- 30451585 TI - The analysis of saturated and aromatic mineral oil hydrocarbons in dry foods and from recycled paperboard packages by online HPLC-GC-FID. AB - The purpose of this study was to determine the concentrations of mineral oil hydrocarbons in dry foodstuffs packed in recycled paperboard, which were imported from different foreign countries to Germany. After collection, mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH) in dry foodstuffs and recycled paperboard were analysed using online coupled high performance liquid chromatography-gas chromatography-flame ionisation detection (online HPLC-GC-FID) far before the end of the shelf life of the samples. Our results showed that recycled paperboard has MOAH content higher than that of dry foodstuffs. The proportion of MOAH within total mineral oil hydrocarbons was determined to be 7-45% in dry foodstuffs and 4-48% in paperboard. In addition, 29% of the products were found to contain over 1.00 mg/kg MOAH, with a maximum of 2.72 mg/kg in oatmeal. White colour recycled paperboard contained lower amounts of MOSH and MOAH than that of brown and grey colour recycled paperboard. The MOSH concentration in dry foodstuffs ranged from 0.11 to 21.92 mg/kg (?C25 hydrocarbons), which may be an indication of rapid migration. The lowest determined MOSH concentrations (?C25 hydrocarbons) were found in sea salt and soda samples, even when their paperboard contained high mineral oil hydrocarbons. Our three samples in packages containing internal bags (for complete barriers) were found to have low mineral oil concentration due to reduced migration through plastic (acrylate-coated polypropylene). However, one sample, a 'crispy' product with an internal bag, contained the extreme amount of 21.92 mg/kg. Differences in contaminants observed in both dry foodstuffs and recycled paperboard may have been due to the different packaging and production techniques of the different countries. In addition, 8 of 24 dry foodstuff samples contained MOSH concentrations frequently exceeding the 2.0 mg/kg limit for MOSH C20-C35. PMID- 30451586 TI - Suicide, mental, and physical health condition stigma in medical students. AB - The current study aimed to compare the personal stigma of suicide with the personal stigma for other mental and physical health conditions. 116 Australian medical students (58% women), aged between 20 and 41 years (M = 25.02, SD = 3.80), completed an online survey. Suicide was more highly stigmatized than most of the other mental and physical health conditions in both attitudes toward suicide and willingness to disclose. The current study highlights the need for further medical student education in suicide, as ongoing negative attitudes could negatively affect patient care and disclosure. PMID- 30451587 TI - Microplastic in bottled natural mineral water - literature review and considerations on exposure and risk assessment. AB - Microplastics have been ubiquitously found and identified in aquatic and terrestrial environments for several years. Due to their occurrence in the oceans, microplastics were also found and characterised in seafood products and in other foods and beverages such as beer, honey and table salt. Very recently, microplastic particles were also determined in bottled mineral water. The objective of this publication is to present and discuss a compilation of the currently available literature data on microplastics in bottled mineral water. The related oral exposure of the consumer from substances present in microplastics and from the plastics particles themselves is estimated and toxicological arguments for and considerations on risk assessment from the consumption of bottled mineral water containing microplastics are presented. Exposure estimations based on the reported microplastic amounts found in mineral water and the assumption of total mass transfer of small molecules like additives and oligomers present in the plastic would not raise a safety concern. Available toxicokinetic data suggests that marginal fraction of the ingested low amount of microplastics can be absorbed, if at all, the conclusion is very likely that the reported amounts present in bottled mineral water do not raise a safety concern for the consumer. Considering the use of plastic materials in our daily life, occurrence of microplastics in beverages is likely a minor exposure pathway for plastic particles. Due to recent progress in analytical methods and the public discussion on plastics marine litter, public concern about eating and drinking microplastics with food, and related safety issues was raised. However, a better data basis for exposure estimates and risk assessment would be very helpful to better accommodate consumer concerns. The intention of this paper is to deliver a contribution to this topic taking the bottled mineral water as a case example. PMID- 30451588 TI - Time-resolved fluorescent immunochromatographic assay-based on three antibody labels for the simultaneous detection of aflatoxin B1 and zearalenone in Chinese herbal medicines. AB - A time-resolved fluorescent immunochromatographic assay (TRFICA) was successfully developed for the sensitive, simultaneous, and quantitative detection of aflatoxin B1 (AFB1) and zearalenone (ZEN) in Chinese herbal medicines. Eu nanospheres (EuNPs) with unique optical properties increased the stability and sensitivity of the immunochromatographic assay. To obtain stable quantitative results, we applied a three-label system in which monoclonal antibodies for AFB1 and ZEN were conjugated to the EuNPs as detection probes on the test line (T line), and EuNP-labelled chicken IgY conjugates acted as the reference on the control line (C line). The fluorescence intensities of the T and C lines were recorded, and the T/C ratio was employed as the quantitative signal for the elimination of strip variation and matrix effects. The parameters that affected the TRFICA were optimised. Under optimal conditions, the established TRFICA gave good linear ranges from 0.60 MUg/kg to 3.92 MUg/kg for AFB1 and from 0.40 MUg/kg to 1.28 MUg/kg for ZEN. The limits of detection for AFB1 and ZEN were as low as 0.60 and 0.40 MUg/kg, respectively, in Chinese herbal medicines Semen coicis, Rhizoma dioscoreae, and Platycodon grandiflorus, respectively. The average recoveries of the spiked samples were 73%-95% for AFB1 and 75.83%-90% for ZEN, both with a relative standard deviation of < 9.08%. The results of 15 actual samples detected by the developed TRFICA showed a satisfactory correlation with those of ultra-performance liquid chromatography tandem mass spectrometry. Therefore, the TRFICA is a simple, rapid, and sensitive approach to quantitatively detect mycotoxins in Chinese herbal medicines. PMID- 30451589 TI - Grief and Post-traumatic Growth Following Miscarriage: The Role of Meaning Reconstruction and Partner Supportive Communication. AB - This study used the meaning reconstruction model of bereavement and the theory of conversationally induced reappraisals to investigate factors that influence the association between grief following a miscarriage and post-traumatic growth. Participants included 298 women who had experienced a miscarriage within the previous year. As predicted, a moderate level of grief corresponded with the most post-traumatic growth among bereaved mothers and meaning reconstruction and partner supportive communication moderated this association. The results clarify how grief is integral to post-traumatic growth in the aftermath of a miscarriage and how intrapersonal and interpersonal coping resources can foster post traumatic growth in the face of grief. PMID- 30451591 TI - Intrapsychic and Interpersonal Views of Transference: Let's Not Fight (So Much). PMID- 30451590 TI - Perceived Loss of Social Contact and Trauma Symptoms among Adolescents Who Have Experienced Sexual Abuse. AB - Child sexual abuse (CSA) is a robust predictor of trauma symptoms. Past research has identified many correlates of trauma symptoms following disclosure of CSA. Theory suggests that loss of social contact may be another important contributor to adolescents' trauma symptoms following CSA. A clinical sample of 166 adolescents (95% female) between 11 and 19 years (M = 13.80, SD = 1.87) reported on perceived loss of social contact, the extent to which the CSA was coercive, appraisals of self-blame for the abuse, supportiveness of a primary non-abusing caregiver, and trauma symptoms. The adolescent's relationship to the abuser, abuse severity and duration were coded from forensic interviews. Results indicated that greater perceived loss of social contact was associated with higher levels of trauma symptoms, even after controlling for other correlates of trauma symptoms and demographic variables. These findings suggest that perceived loss of social contact may be an important variable to consider in assessing and intervening with adolescents who have been sexually abused. PMID- 30451592 TI - The Relationship Between Narcissism and Taking Charge: The Role of Energy at Work and Hierarchical Level. AB - Drawing on the framework of human energy in organizations, this study proposed a moderated mediation model between narcissism and taking charge, as well as the role of energy at work and the employee's hierarchy within organizations. A sample of 312 employees at one Chinese manufacturing company suggested that employees with narcissistic personality are more apt to exhibit taking charge at work via their energy at work. In addition, the results also indicated that employees' hierarchical level within organization reinforced the indirect effect of energy at work between narcissism and taking charge. These findings have important implications for narcissism research and managerial practices. PMID- 30451593 TI - Racial and Linguistic Status Differences in the Effect of Interscholastic Sport Participation on School Engagement and Academic Performance Among High School Students. AB - The purpose of the study was to examine whether the effects of interscholastic sport participation on academic performance and school engagement vary by race and linguistic status of high school students. High school participants ( n = 16,200) were selected from the Education Longitudinal Study: 2002, a nationally representative database. Results of a structural equation model showed that Asian, black, and Hispanic students' interscholastic sport participation had a positive effect on grade point average, while the effect was not significant for white students. However, white students' interscholastic sport participation was likely to have a positive, indirect effect on grade point average through their engagement in school. The results showed no linguistic status variation in the effects of interscholastic sport participation on school engagement and grade point average. The findings suggest that supporting high school students in school-sponsored extracurricular sport programs should be continued, highlighting the important role of schools in shaping the proper educational environment for sport participation. PMID- 30451594 TI - Psychometric properties of the Chinese-version Stroke and Aphasia Quality of Life Scale 39-generic version (SAQOL-39g). AB - BACKGROUND AND PURPOSE: Aphasia is a common outcome of stroke affecting one-third of the post-stroke population in China. While the quality of life (QOL) may be affected, care is often inadequately guided due to lack of validated measure for Chinese population with stroke-induced aphasia. This study aimed to develop a Chinese-version of the Stroke and Aphasia Quality of Life-39 generic version (SAQOL-39g) and evaluate its feasibility, reliability, and validity in Chinese patients with stroke-induced aphasia. METHODS: The process of translation and adaptation suggested by WHO was used to develop the Chinese-version of SAQOL-39. We evaluated the feasibility, reliability, and validity of the scale in 84 aphasia patients and their proxies by assessing the internal consistency of the test items, test-retest consistency, and the structural validity of data. RESULTS: The self-report and the proxy-report form were completed within 21.4 and 13.3 min on average, respectively. Physical, communication, and psychological subdomains were extracted as three common factors. The Cronbach's alpha coefficients of overall domain and subdomains for both forms ranged from 0.879 to 0.950, indicating high internal consistency. The intraclass correlation coefficients ranged from 0.804 to 0.987 for overall domain and subdomains of the forms. No significant difference was found between two forms. CONCLUSIONS: The Chinese-version SAQOL-39g has excellent reliability, validity, and feasibility for measuring the QOL of Chinese post-stroke aphasia patients. The consistency between self-report and proxy-report forms was good, implying that the proxy report form can be used to assess the QOL of post-stroke aphasia patients. PMID- 30451595 TI - Sleep and neuropsychological performance in HIV+ subjects on efavirenz-based therapy and response to switch in therapy. AB - The antiretroviral drug efavirenz (EFV) has been linked to disordered sleep and cognitive abnormalities. We examined sleep and cognitive function and subsequent changes following switch to an alternative integrase inhibitor-based regimen. Thirty-two HIV-infected individuals on EFV, emtricitabine, and tenofovir (EFV/FTC/TDF) without traditional risk factors for obstructive sleep apnea (OSA) were randomized 2:1 to switch to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) or to continue EFV/FTC/TDF therapy for 12 weeks. Overnight polysomnography and standardized sleep and neuropsychological assessments were performed at baseline and at 12 weeks. No significant differences in change over 12 weeks were noted between the two arms in any sleep or neuropsychological test parameter. At entry, however, the rate of sleep disordered breathing (SDB) was substantially higher in study subjects compared to published age-matched norms and resulted in a high assessed OSA rate of 59.4%. Respiratory Disturbance Index (RDI), a measure of SDB, correlated with age- and education-adjusted global neuropsychological Z-score (NPZ) (r = -0.35, p = 0.05). Sleep Maintenance Efficiency, Wake after Sleep Onset, REM Sleep and RDI correlated with domain specific NPZ for learning and memory (all p-values <= 0.05). Among HIV-infected individuals on EFV-based therapy and without traditional risk factors for OSA, sleep and neuropsychological abnormalities do not readily reverse after discontinuation of EFV. High baseline rates of SDB and abnormalities in sleep architecture exist in this population correlating with neuropsychological impairment. The role of HIV immuno-virologic or lifestyle factors as contributing etiologies should be explored. OSA may be an under-recognized etiology for cognitive dysfunction during chronic HIV. PMID- 30451596 TI - Impact of agronomic factors on fusarium mycotoxins in harvested wheat. AB - The aim of this study was to model fusarium mycotoxins against agronomic factors in order to identify those that have the greatest impact on mycotoxin levels in harvested wheat. To achieve this, fusarium mycotoxins levels were monitored, and associated agronomic data collected, in approximately 150 English wheat fields/year between 2006 and 2013. Results showed large seasonal variation in fusarium mycotoxin levels, with high levels in 2008 (13% and 29% exceeding legal limit for unprocessed soft wheat intended for human consumption for deoxynivalenol (DON) and zearalenone (ZON), respectively) and 2012 (10% and 15% exceeding legal limit for unprocessed soft wheat intended for human consumption for DON and ZON, respectively) and low levels in 2006 and 2011 (no samples exceeding legal limits for unprocessed soft wheat intended for human consumption for DON or ZON). Analysis of agronomic factors identified previous crop, cultivation and variety as the greatest risk factors. The greatest risk of mycotoxin development in grain was following maize as a previous crop and minimum tillage. The combined effect of these factors gave respective average DON and ZON levels 20 and 14 times higher than other previous crop and cultivation combinations. A newly quantified risk factor was harvest date. A 1-month delay in harvest resulted in a 10 and 25 times greater mean DON and ZON concentration, respectively, when compared to crops harvested around the long-term regional average harvest date. These results highlight the highly seasonal variation in fusarium mycotoxins in wheat and the agronomic factors that should be avoided to minimise fusarium mycotoxin levels in harvested wheat. PMID- 30451597 TI - Preventive effects of oxytocin and oxytocin receptor in breast cancer pathogenesis. AB - AIM: Modifications of oxytocin (OT) concentration and OT receptor (OXTR) expression level have different effects on breast cancer-derived cells. This study was conducted to evaluate OT variation in breast cancer patients and to evaluate OXTR expression changes in breast cancer tissues. METHODS: The plasma concentrations of OT in both breast cancer patients and healthy individuals' samples were assessed. OXTR variations were then assessed in both cancerous and noncancerous breast tissues. RESULTS: OT had an increase in breast cancer patients and expression of OXTR in contralateral breast was more than cancerous tissues. CONCLUSION: Despite the high levels of OT concentration in breast cancer patients, it seems that a lower expression of OXTR in cancerous tissues can be effective in the breast cancer progression. PMID- 30451598 TI - Alcohol and Suicide Risk: Examining the Role of Meaning-Making. AB - OBJECTIVE: Conceptual understandings of meaning-making suggest that it may have protective value in regard to alcohol misuse and suicidal behavior. Accordingly, the aim of this study was to examine whether meaning-making attenuated the relationship between alcohol misuse and suicide risk severity in a population of active-duty service members. METHODS: The sample (N = 97) was recruited while presenting for emergency behavioral health services in circumstances indicative of high-risk suicidality: endorsing current suicidal ideation with intent to die. Those who reported ideation with a lifetime history of a past suicide attempt were conceptualized as being in a more severe category of suicide risk than ideation without a lifetime history of a past suicide attempt. Participants completed the Suicidal Behaviors Questionnaire-Revised, Meaning in Life Questionnaire, Alcohol Use Disorders Identification Test consumption questions, and items that assessed demographic variables. Data were analyzed using chi squared test of independence, Fisher's exact test, Kendall rank correlation coefficient, and logistic regression modeling. RESULTS: Regression analysis identified a statistically significant association between number of drinks consumed daily and reporting a lifetime history of a past suicide attempt, odds ratio (OR) = 1.60, 95% confidence interval (CI) [1.11, 2.32], p = .01. Number of drinks consumed remained significant even after adjusting for both the search for and presence of meaning, OR = 1.70, 95% CI [1.16, 2.51], p = .01. These results remained unchanged even when adjusting for gender, race, ethnicity, and relationship status. No statistically significant interaction effects were noted between meaning-making and alcohol consumption. CONCLUSIONS: Meaning-making did not appear to attenuate the effect of alcohol misuse on suicide risk severity in a sample of service members at high-risk of suicidality. Additional research is needed to better understand the relationship among meaning-making, alcohol misuse, and suicidal behavior. PMID- 30451599 TI - Telomerase-related monogenic lung fibrosis presenting with subacute onset: a case report and review of literature. AB - OBJECTIVES: Monogenic pulmonary fibrosis related to telomerase mutations is characterized by a large spectrum of clinical presentations. The disease may affect several organs including bone marrow, liver and skin. This case illustrates some of the most salient features of telomere-related Interstitial Lung Disease(ILD). METHODS: Single case study and review of the litterature. RESULTS: We report the case of a 44-year-old man admitted to our unit for subacute pulmonary fibrosis. No underlying cause could be identified. Personal and familial history was highly suggestive of monogenic telomere related lung fibrosis. Genetic investigation confirmed a mutation in the TERT gene, coding for one of the components of telomerase. Given the severe hypoxemia unresponsive to supportive treatment, he was referred for urgent lung transplantation, with a favourable outcome. Genetic counselling was proposed to his family. CONCLUSIONS: Telomerase-related monogenic lung fibrosis may present with a subacute onset, requiring urgent lung transplantation. Extra-thoracic clinical manifestations and familial history are key elements pointing towards the diagnosis. PMID- 30451600 TI - Prevalence and risk factors of musculoskeletal disorders among farmers involved in manual farm operations. AB - The aim of the current investigation is to determine the risk factors affecting the musculoskeletal system of 100 manual working farmers of India. The information regarding prevalence and risk factors of musculoskeletal disorders (MSDs) was collected using a semi-structured questionnaire. For evaluating the risk in operations, rapid entire body assessment (REBA) and rapid upper limb assessment (RULA) techniques were used. The existence of various risk factors and their influence on the MSDs were found significant during crop cutting/harvesting and weeding operations. Manual farm working postures may be exposing farmers to a substantial risk of developing MSDs in one or more body parts including lower back, fingers, hands/wrists, and shoulders. Postural analysis by RULA and REBA shows the high prevalence of MSDs which should be reduced by ergonomic interventions. PMID- 30451601 TI - Alcohol Use and Drinking Motives Among Suddenly Bereaved College Students. AB - OBJECTIVE: Thousands of Americans grieve the sudden death of a loved one each year. These sudden deaths may be the result of violent deaths, as in the cases of homicide, suicide, or fatal accidents, or may occur as the result of natural causes such as heart attacks or strokes. Sudden loss survivors often experience negative mental health outcomes such as depression, prolonged grief disorder, and posttraumatic stress disorder. Survivors may also misuse alcohol for varied reasons after these losses, which can put them at risk for alcohol-related consequences. Thus, the purpose of this study was to explore associations between psychological distress and alcohol-related outcomes among young adults with a history of sudden loss. METHODS: A sample of 659 young adults completed a series of self-report measures assessing loss history, psychosocial distress, perceived alcohol-related problems, and drinking motives. RESULTS: Results showed that survivors of sudden, violent losses reported higher rates of past 30-day alcohol use than those who had lost a loved one to a sudden, natural loss or those who reported no loss history. Although there were no statistically significant differences in drinking motives between violent or natural loss survivors, more severe depression symptoms among bereaved individuals were associated with drinking to cope and to conform. Participants experiencing prolonged grief symptoms were also more likely to report drinking to conform. CONCLUSIONS: Bereavement-related distress may influence drinking motives among young adults with a history of sudden loss. PMID- 30451602 TI - Vitamin K status and inflammation are associated with cognition in older Irish adults. AB - Studies have shown associations between reduced vitamin K status and poor cognitive function. However, despite this apparent link, direct studies measuring cognitive function, vitamin K status and inflammation are lacking. In the current study, The ELDERMET cohort was investigated to identify associations between cognition, vitamin K status and inflammation. The primary aim of the ELDERMET study was to investigate the relationship between gut bacteria, diet, lifestyle and health in 500 older Irish adults. Significant differences in serum phylloquinone, dietary phylloquinone and inflammatory markers were found across varying levels of cognitive function, after controlling for sex, age, body mass index (BMI), triglycerides and blood pressure. In addition, significantly higher levels of dietary phylloquinone were found in those with better cognition compared to those with the poorest function. Higher levels of inflammatory were also associated with poor cognition. Furthermore, both dietary and serum phylloquinone were significant independent predictors of good cognitive function, after controlling for confounders. This study highlights the importance of dietary vitamin K as a potentially protective cognitive factor; it also provides evidence for the correlation between cognition and inflammation. Strategies should be devised by which elderly populations can access rich dietary sources of phylloquinone to maintain cognition. PMID- 30451603 TI - Two cases of glutaric aciduria type II: how to differentiate from inflammatory myopathies? AB - Muscle weakness is a nonspecific finding of myopathy of any etiology that include iatrogenic, toxic, endocrinological, infectious, immunologic, and metabolic disorders. Among the metabolic myopathies glutaric aciduria type II (GAII) is an autosomal recessively inherited rare disorder of fatty acid and amino acid metabolisms. The late onset form is heterogeneous in terms of symptomatology and severity and for the cases that chronic manifestations of lipid storage myopathy are the only clues for the disease, differential diagnosis can be challenging. Here we report two cases of GAII: the first one was 18-year old boy who presented with proximal muscle weakness and in another center, he was diagnosed as polymyositis and treated with immunosuppressive therapies. He admitted to our clinic with ongoing muscle weakness and symptoms that were related to the side effects of immunosuppressive therapies. The second case was also presented with muscle weakness. For both cases, muscle biopsies and urinary organic acid analyses were consistent with the diagnosis of GAII. To differentiate inflammatory myositis from non-inflammatory myopathies; rheumatic symptoms, accompanying complaints of the patient and autoantibody positivity can be helpful. To our knowledge this is the first report to underline the differential diagnosis of inflammatory myopathies from metabolic myopathies. PMID- 30451605 TI - Meeting report GV-SOLAS annual conference 2018. PMID- 30451604 TI - Protocol for Psychosocial Interventions Based on Integrative Body-Mind-Spirit (IBMS) Model for Children with Eczema and Their Parent Caregivers. AB - PURPOSE: Eczema is a pediatric skin disease that affects the psychosocial well being of both children and their parent caregivers. This paper outlines a protocol for an experimental study that evaluates the effectiveness of a psychosocial empowerment program for children with eczema and their parent caregivers. METHOD: A multi-center randomized controlled trial is proposed, where parent-child dyads are randomized into two arms: an intervention group and wait list control group. The intervention is delivered to participants in a parallel group format based on the Integrative Body-Mind-Spirit model which focuses on holistic well-being. Quality of life is measured before and after the intervention is provided, and five weeks after the intervention has been completed. DISCUSSION: The suggested model fills a research gap in existing interventions, and provides new knowledge by evaluating the effectiveness of a tailored psychosocial intervention, delivered in group settings, for parent-child dyads affected by eczema. PMID- 30451606 TI - Registration is opened for the 14th FELASA Congress! PMID- 30451607 TI - Newly created title of the Diplomate Specialized Veterinarian in Laboratory Animal Science (Dipl. SVLAS) awarded by the Swiss Association of Veterinarians in Industry and Research (SAVIR). PMID- 30451608 TI - What does the GV-SOLAS actually do? PMID- 30451609 TI - En Espana se presenta el primer informe anual del Acuerdo de Transparencia en Experimentacion Animal. PMID- 30451610 TI - Fulfilling our responsibility to animals during the final stages of life. PMID- 30451611 TI - Letters to the Editor. PMID- 30451612 TI - Use of a locking compression plate for equine proximal interphalangeal joint arthrodesis: 29 cases (2008-2014). AB - OBJECTIVE To describe clinical use of a locking compression plate (LCP) for proximal interphalangeal joint (PIPJ) arthrodesis in horses and compare outcomes for horses that underwent the procedure as treatment for fracture of the middle phalanx (P2) versus other causes. DESIGN Retrospective case series. ANIMALS 29 client-owned horses. PROCEDURES Medical records of 2 veterinary teaching hospitals from 2008 through 2014 were reviewed to identify horses that underwent PIPJ arthrodesis of 1 limb. Signalment, surgical, and outcome-related variables were recorded. Owners were contacted from 1 to 6 years after surgery to determine rehabilitation time, current use of the horse, and overall owner satisfaction with the procedure. Success was determined on the basis of owner satisfaction and outcome for intended use. Variables of interest were compared statistically between horses that underwent surgery for P2 fracture versus other reasons. RESULTS 14 horses underwent surgery for treatment of P2 fracture, and 15 had surgery because of osteoarthritis, subluxation, or osteochondrosis. Median convalescent time after surgery (with no riding or unrestricted exercise) was 7 months. Four horses were euthanized; of 23 known alive at follow-up, 22 were not lame, and 18 had returned to their intended use (8 and 10 at higher and lower owner-reported levels of work, respectively). Horses undergoing arthrodesis for reasons other than fracture were significantly more likely to return to their previous level of work. Twenty-two of 24 owners contacted indicated satisfaction with the procedure. CONCLUSIONS AND CLINICAL RELEVANCE Surgical arthrodesis of the PIPJ was successful in most horses of the study population. Various nuances of the system for fracture repair need to be understood prior to its use. PMID- 30451613 TI - Diet-associated dilated cardiomyopathy in dogs: what do we know? PMID- 30451614 TI - Outcomes of surgical repair of congenital palatal defects in dogs. AB - OBJECTIVE To determine and identify variables associated with outcomes of surgical repair of congenital palatal defects in dogs. DESIGN Retrospective case series with nested observational study. ANIMALS 26 dogs that underwent surgical repair of congenital palatal defects at 2 veterinary teaching hospitals from 2007 to 2016. PROCEDURES Data were collected from medical records regarding dog age and body weight at the time of surgical defect repair, prior surgical history, skull type (brachycephalic, mesocephalic, or dolichocephalic), surgical technique used for defect repair, and defect severity. Functional outcome as well as frequency and location of oronasal fistula (ONF) formation were recorded. These outcomes were compared among various groups. RESULTS Surgical defect repair achieved functional success in 22 of the 26 (85%) dogs. An ONF formed after initial repair in 13 (50%) dogs, and the most common location was the hard palate. Hard palate ONF formation was more common in dogs > 8 months of age at the time of initial repair; ONF at the junction between the hard and soft palates was more common in dogs > 8 months of age at the time of initial repair and in dogs with a history of failed surgical repair. An unsuccessful functional outcome was more common in dogs weighing < 1 kg (2.2 lb) at the time of initial repair. CONCLUSIONS AND CLINICAL RELEVANCE Patient age, patient size, and defect characteristics should be taken into consideration when planning and assessing prognoses for surgical repair of congenital palatal defects in dogs. PMID- 30451615 TI - A minimally invasive surgical technique for ureteral ostioplasty in two fillies with ureteral ectopia. AB - CASE DESCRIPTION 2 fillies, aged 3 months and 1 month, were examined because of urinary incontinence and urine scalding. CLINICAL FINDINGS In horse 1, ultrasonography did not reveal any structural abnormalities of the kidneys; however, unilateral ureteral ectopia was diagnosed cystoscopically. In horse 2, CT revealed bilateral nephropathy, bilateral distended ureters (up to 3.6 cm in diameter), and bilateral ureteral ectopia. Cystoscopy revealed intramural ureteral ectopia with abnormally caudally positioned ureteral ostia in both horses. TREATMENT AND OUTCOME Ureteral ostioplasty was performed under cystoscopic guidance. Laparoscopic scissors (horse 1) or a vessel-sealing device (horse 2) was introduced, and the tissue separating the intramural portion of the ureter from the urethra and bladder was cut longitudinally in a cranial direction toward the trigone. After surgery, both horses were continent and voided normal streams of urine for the duration of the follow-up periods of 20 and 9 months for horse 1 and horse 2, respectively. CLINICAL RELEVANCE Cystoscopically guided ureteral ostioplasty provided an effective and minimally invasive surgical treatment option for correction of ureteral ectopia in 2 fillies. PMID- 30451616 TI - Bias, sensitivity, and specificity of Doppler ultrasonic flow detector measurement of blood pressure for detecting and monitoring hypotension in anesthetized dogs. AB - OBJECTIVE To determine the bias, sensitivity, and specificity of Doppler ultrasonic flow detector measurement of blood pressure (DBPM) to detect hypotension in dogs with various disease states and to determine whether patient characteristics could affect accuracy of DBPM in dogs. DESIGN Prospective cross sectional study. ANIMALS 146 client-owned dogs undergoing general anesthesia at a veterinary teaching hospital between April 2007 and August 2010. PROCEDURES Data collected for each dog were breed, limb conformation, sex, American Society of Anesthesiologists physical status classification, anesthetic protocol, surgical procedure, arterial catheter size and location, and DBPM location. Doppler and invasive blood pressure measurements (IBPMs; criterion standard) were simultaneously recorded every 5 minutes throughout anesthesia. Hypotension was defined as mean arterial blood pressure < 60 mm Hg or DBPM < 90 mm Hg. Repeated measures Bland-Altman analysis was performed to determine bias between DBPMs and IBPMs. Overall sensitivity and specificity of DBPM to detect hypotension were calculated with 2 methods, and values were recalculated for specific patient groups and compared. RESULTS Bias of DBPM was 2.8 mm Hg with wide 95% limits of agreement (-46.4 to 51.9 mm Hg). For the 2 calculation methods, sensitivity of DBPM to detect hypotension was 69.2% and 66.7% and specificity was 82.2% and 86.8%. No significant differences in sensitivity or specificity were identified regarding limb conformation, gauge of catheter (20 vs 22) used for IBPM, or side (ipsilateral or contralateral) of paired measurements. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that in dogs of the present study, DBPM was unreliable for detecting hypotension. PMID- 30451617 TI - Plant-based diets for dogs. PMID- 30451618 TI - ECG of the Month. PMID- 30451619 TI - Myocardial hypertrophy associated with long-term phenylpropanolamine use in a dog. AB - CASE DESCRIPTION A 9-year-old spayed female Dalmatian was examined because of progressive pelvic limb paraparesis. CLINICAL FINDINGS The dog had a history of chronic urinary incontinence and had been treated with phenylpropanolamine (PPA) for almost 8.5 years. Intervertebral disk disease at T12-13 was diagnosed, and a hemilaminectomy was performed. Three days after surgery, the dog developed a ventricular tachyarrhythmia. Severe left and mild right ventricular hypertrophy were detected by echocardiography. TREATMENT AND OUTCOME The arrhythmia was controlled with sotalol. Phenylpropanolamine administration was discontinued immediately before surgery and was not resumed. Heart rate and rhythm and blood pressure were within reference limits, and the ventricular hypertrophy had almost completely resolved 5 months later. Sotalol administration was discontinued. Shortly after the 5-month recheck evaluation, PPA administration was resumed, albeit at a lower dosage than that before surgery, for control of urinary incontinence. At the 10-month recheck evaluation, the dog was hypertensive and ventricular hypertrophy had recurred. Discontinuation of PPA administration was recommended but not heeded. The dog developed marked azotemia 1.5 years after surgery, which was managed by the referring veterinarian, and was subsequently lost to follow-up. CLINICAL RELEVANCE The fact that the ventricular hypertrophy almost completely resolved when PPA administration was discontinued and then recurred after it was resumed strongly suggested the drug was an important contributing factor to the cardiac disease of this patient. Patients receiving PPA on a long-term basis should be frequently monitored for cardiac disease, and use of other adrenergic receptor agonists should be avoided in such patients. PMID- 30451620 TI - Barriers and next steps to providing a spectrum of effective health care to companion animals. PMID- 30451621 TI - The role of companion animal veterinarians in one-health efforts to combat antimicrobial resistance. PMID- 30451622 TI - Pathology in Practice. PMID- 30451625 TI - What Is Your Diagnosis? PMID- 30451624 TI - What Is Your Neurologic Diagnosis? PMID- 30451626 TI - Rate of return to agility competition for dogs with cranial cruciate ligament tears treated with tibial plateau leveling osteotomy. AB - OBJECTIVE To determine rate of and factors associated with return to agility competition for dogs with cranial cruciate ligament (CrCL) rupture treated with tibial plateau leveling osteotomy (TPLO). DESIGN Retrospective case series with nested case-control study. ANIMALS 31 dogs involved in agility competition with CrCL tears treated by TPLO at a private veterinary clinic from 2007 through 2013. PROCEDURES Medical records were reviewed to collect information on dog signalment, lesion characteristics, and surgical data. Owners completed a survey regarding whether and when their dog returned to agility competition after TPLO and, if so, how the dog performed. Performance data before and after TPLO were compared. RESULTS 20 of 31 (65%) dogs returned to agility competition after TPLO, 16 (80%) of which returned within 9 months after TPLO. The mean convalescent period for returning dogs was 7.5 months (range, 3 to 12 months). No dog that returned to competition sustained an injury to the affected limb during the follow-up period. No significant difference was identified between dogs that returned or did not return to agility competition regarding severity of osteoarthritis or proportions with meniscal injury or partial (vs complete) CrCL tears. CONCLUSIONS AND CLINICAL RELEVANCE These data suggested that the prognosis for returning to agility competition was good for dogs undergoing TPLO. None of the evaluated lesion characteristics were associated with return to competition. Rate of return to competition and duration of the convalescent period may be useful outcome variables for future investigations involving orthopedic procedures in dogs. PMID- 30451627 TI - Pathology in Practice. PMID- 30451628 TI - Hand surgery in Greece. PMID- 30451629 TI - Repair of soft tissue defects in finger, thumb and forearm: less invasive methods with similar outcomes. AB - We review recent developments in using occlusive dressings, dermal templates, and venous flaps for less invasive approaches to treat soft tissue defects of the forearm and fingers. Occlusive dressings can be used for thumb tip or fingertip trauma with soft tissue defects of small or moderate sizes. They permit skin regeneration without use of skin graft or a flap transfer. This is currently a popular way to treat tip soft tissue defects in European countries. Extensive soft tissue defects in the thumb, fingers, hand and forearm require flap transfers traditionally, but in recent years, surgeons use dermal templates to cover the defect site to allow regeneration of subcutaneous tissues, over which a skin graft is used in lieu of a flap. Transfer of a venous flap is currently a reliable procedure and is less invasive compared with conventional flaps, which usually damage a named artery in the donor. We advocate that less invasive methods should be considered for soft tissue defects in the hand and forearm. PMID- 30451631 TI - Reply. PMID- 30451630 TI - Letter about a Published Paper. PMID- 30451632 TI - The IFSSH Ezine for the free flow of information of hand surgeons and therapists worldwide. PMID- 30451633 TI - Understanding how an invasive vector drives Pierce's disease epidemics: seasonality and vine-to-vine spread. AB - For vector-borne plant pathogens, disease epidemics may be attributable to multiple mechanisms, including introduction of a novel vector whose epidemiological role differs from that of native vectors. In such cases, understanding an exotic vector's ability to drive an epidemic is central to mitigating its impact. We studied how the invasive glassy-winged sharpshooter (Homalodisca vitripennis Germar) can drive Pierce's disease (PD) outbreaks in vineyards, focusing on its potential to promote vine-to-vine (i.e. secondary) spread of Xylella fastidiosa, relative to potential constraints stemming from seasonality in the pathosystem. First, we developed a general vector-borne disease model to understand the consequences for disease dynamics of 1) seasonal acquisition efficiency and 2) seasonal host recovery from infection. Results of the modeling indicate that these two sources of seasonality could constrain disease incidence, particularly when working in concert. Next, we established a field cage experiment to determine whether H. vitripennis promotes vine-to-vine spread, and look for evidence of seasonality in spread. Broadly, results from the experiment support assumptions of the model; there was modest to significant increase in the frequency of pathogen spread over the first season, and those new infections that occurred later in the season were more likely to recover during winter. Ultimately, by the end of the second season there was not evidence of significant secondary spread, likely due to a combination of seasonal constraints and low transmission efficiency by H. vitripennis. Collectively, these results suggest that although H. vitripennis may be able to promote vine-to-vine spread in certain contexts, it may not be the key factor explaining its impact. Rather, the ability of H. vitripennis to drive epidemics is likely to be more directly related to its potential to reach higher population densities than native vectors. PMID- 30451634 TI - Fusarium graminearum Chemotype by Spring Wheat Genotype Interaction Effects in Type I and II Resistance Response Assays. AB - Fusarium Head Blight (FHB), caused by several Fusarium species, is a worldwide problem that severely impacts cereal grain yield and poses major risks to human and animal health due to production of the mycotoxin deoxynivalenol (DON), its acetylated forms, 3-acetyl deoxynivalenol (3-ADON) and 15-acetyl deoxynivalenol (15-ADON). Recent studies suggest an inconsistent effect of F. graminearum chemotypes and resistance of wheat (Triticum aestivum L.) genotypes. To gain insight into the interaction effects of F. graminearum chemotypes and spring wheat genotypes on FHB resistance response, ten spring wheat genotypes with varying levels of FHB resistance were inoculated with ten F. graminearum isolates, consisting of five 3-ADON- and five 15-ADON-producing isolates and evaluated in Type I (spray inoculation) and Type II (point inoculation) resistance assays. Wheat genotypes carrying the resistance allele of the Fhb-1 QTL on chromosome 3BS had lower disease in Type II evaluations, regardless of F. graminearum isolate or chemotype. Isolates of F. graminearum were also significantly different for disease aggressiveness. In addition, the 3-ADON producing isolates were 18% more aggressive than the 15-ADON isolates in Type I resistance assays. No difference in aggressiveness of the two chemotypes was observed, when tested in Type II resistance assays. There was no interaction effect between F. graminearum chemotypes and spring wheat genotypes, suggesting that screening of germplasm for resistance can be performed with limited number of aggressive isolates. PMID- 30451635 TI - Transmission Efficiency of Xylella fastidiosa subsp. pauca Sequence Types by Sharpshooter Vectors After in vitro Acquisition. AB - Xylella fastidiosa subsp. pauca is genetically diverse and has many vector species. But there is limited information on vector specificity and efficiency for different sequence types (STs) within the pathogen subspecies. Both STs of X. fastidiosa and vectors differ in their associations with plants, so assessment of vector competence should include standardized vector acquisition ability of bacteria from artificial diets. This work aimed to adapt and validate an in vitro acquisition system for strains of X. fastidiosa that cause citrus variegated chlorosis, and to compare the transmission efficiency of STs of subspecies pauca by different species of sharpshooter vector. First, acquisition and transmission of ST13 by Bucephalogonia xanthophis and Macugonalia leucomelas was tested using an artificial diet with bacteria grown on minimum defined medium (Xfm) with or without 1% galacturonic acid (GA). Subsequently, four sharpshooter species (B. xanthophis, M. leucomelas, M. cavifrons and Sibovia sagata) were compared as vectors of ST13 acquired from artificial diets, and four STs of pauca (11, 13, 65 and 70) were tested for acquisition and transmission by M. leucomelas. The artificial system allowed efficient acquisition and transmission of ST13 to plants, with no differences between the media tested. ST13 was transmitted more efficiently by B. xanthophis and M. leucomelas when compared to M. cavifrons and Sibovia sagata. Different STs influenced acquisition and transmission rates by M. leucomelas. The differences in vector competence, despite the standardized acquisition system, suggest that ST-vector foregut and/or vector-plant interactions may influence bacterial acquisition, retention and inoculation by the insect. PMID- 30451636 TI - Necrotrophic exploitation and subversion of plant defense: a lifestyle or just a phase, and implications in breeding resistance. AB - Breeding disease resistant plants is a critical, environmentally friendly component of any strategy to sustainably feed and cloth the 9.8 billion people expected to live on Earth by 2050. Here I review current literature detailing plant defense responses as they relate to diverse biological outcomes; disease resistance, susceptibility, and establishment of mutualistic plant-microbial relationships. Of particular interest is the degree to which these outcomes are a function of plant-associated microorganisms' lifestyles; biotrophic, hemibiotrophic, necrotrophic, or mutualistic. For the sake of brevity, necrotrophic pathogens and the necrotrophic phase of pathogenicity are emphasized in this review, with special attention given to the host-specific pathogens that exploit defense. Defense responses related to generalist necrotrophs and mutualists are discussed in the context of excellent reviews by others. In addition, host evolutionary trade-offs of disease resistance with other desirable traits are considered in the context of breeding for durable disease resistance. PMID- 30451637 TI - Multiple introductions without admixture of Colletotrichum truncatum associated with soybean anthracnose in Brazil. AB - Knowledge of the population structure, genetic diversity and reproductive mode of plant pathogens can help to implement effective disease management strategies. Anthracnose is one of the most prominent diseases in soybean and is mainly associated with the species Colletotrichum truncatum. However, the genetic structure of C. truncatum populations associated with soybean remains unknown. We collected C. truncatum isolates from 10 sites representing two Brazilian states (Mato Grosso and Goias) and used 13 highly polymorphic microsatellite markers to investigate the population genetic structure of the pathogen. Analyses revealed high gene and haplotypic diversity within populations, as well low genetic differentiation and sharing of multilocus haplotypes among populations and regions. Bayesian and multivariate analysis revealed the presence of three distinct genetic clusters with at least two groups coexisting in all locations, and all of them coexisting in 8 locations. We found limited evidence for admixture between clusters, with only two isolates showing non-zero membership with a second cluster. Analyses of linkage disequilibrium rejected the hypothesis of random mating in all clusters, but values of the index of association were low and not consistent with long-term lack of sexual reproduction. Our findings suggest that Brazilian C. truncatum populations resulted from at least three founder events that led to three genetic clusters that spread throughout the country, raising questions with respect to the factors allowing their maintenance in syntopy without evidence of admixture between them. PMID- 30451638 TI - Fluctuation, invisibility, fatigue - the barriers to maintaining employment with systemic lupus erythematosus: results of an online survey. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with high levels of workplace disability and unemployment. The objective of this study was to understand the reasons for this and to describe the barriers and facilitators of employment identified by people with SLE to develop appropriate solutions. Unemployment, as well as unsuitable work, has adverse health outcomes. METHODS: Adults with SLE completed a UK-specific online survey, through the LUPUS UK website, designed to find out more about the difficulties and successes that people with SLE have in maintaining employment. The survey was predominantly qualitative, to understand participants' employment experiences to generate possible solutions. RESULTS: Three hundred and ninety-three people gave detailed responses to the survey within eight weeks. Every respondent reported a detrimental effect of SLE on their ability to work: 40.45% had left employment because of it. The themes of concern to respondents were unambiguous: (i) the difficulties of working (and career damage) with SLE, (ii) fear and anxiety overshadowing work/family life, (iii) the greater potential to remain in some employment or stay in full employment when modifications of work pattern and support from management and colleagues were available. SLE-related fatigue, its invisibility and fluctuating nature were felt to be the main barriers to maintaining employment. Numerous respondents could work only part-time and anxiety was high regarding their future ability to continue working. Many had taken substantial pay reductions and refused offered promotions to preserve their health. Distress due to loss of work and the benefits it brings were reported by every respondent who had left work. CONCLUSION: SLE presents specific difficulties for maintaining employment - fatigue, fluctuation and invisibility - not addressed by current anti-discrimination legislation or currently available 'reasonable adjustments'. This study demonstrates that (i) employment is an important area of concern for people with SLE, (ii) SLE has significant detrimental effects on individuals' ability to participate and progress in employment, (iii) legislators and employers need information about SLE as invisibility and fluctuation cause hidden problems, and (iv) more data is needed to inform workplace adjustments if individual distress and societal loss of skills are to be addressed. PMID- 30451639 TI - Risk of systemic lupus erythematosus in patients with human papillomavirus infection: a population-based retrospective cohort study. AB - BACKGROUND: Viral infection contributing to systemic lupus erythematosus (SLE) development has been largely reported. However, the SLE risk in patients with human papillomavirus (HPV) infection is unknown. METHODS: Data were retrieved from the Longitudinal Health Insurance Database (2000) in Taiwan. We identified 43,567 patients with HPV infection and 174,268 age- and sex-matched uninfected controls from 2002 to 2012. Individuals were followed up from index date (first date of diagnosis with HPV) until the occurrence of SLE, at the end of the study (December 2013), or when they were withdrawn from the insurance program. The incidence rate ratio (IRR) was calculated using the univariate Poisson regression. The adjusted hazard ratios (aHRs) were calculated, and sensitive and subgroups analyses were also conducted. RESULTS: Compared with the non-HPV controls, the IRR of SLE in HPV patients was 1.52 (95% confidence interval (CI): 1.09-2.12). The risk of SLE in HPV-infected individuals was significantly high (aHR: 1.48, 95% CI: 1.06-2.06) after adjusting for age, sex, and comorbidities. Men aged between 16 and 45 years were more susceptible to developing SLE (aHR: 21.57, 95% CI: 2.52-184.60, p = 0.0051). CONCLUSION: Our study showed a significantly higher risk of SLE among HPV-infected patients, especially in men aged between 16 and 45 years. PMID- 30451640 TI - Pulmonary thromboendarterectomy is a curative resolution for chronic thromboembolic pulmonary hypertension associated with antiphospholipid syndrome: a retrospective cohort study. AB - BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening condition with poor prognosis in patients with antiphospholipid syndrome (APS). Pulmonary thromboendarterectomy (PTE) is the optimal surgical option for CTEPH. OBJECTIVES: This retrospective cohort study aimed to evaluate the efficacy and risk of PTE in patients with APS-associated CTEPH. METHODS: Consecutive patients with APS-associated CTEPH diagnosed between January 2012 and September 2017 at Peking Union Medical College Hospital were retrospectively evaluated. Demographics, clinical manifestations, antiphospholipid antibody (aPL) profiles, and pulmonary arterial hypertension-targeted medications were collected. Deterioration of cardiac function and death were chosen as the endpoints, in order to assess the effect of PTE on short-term and long-term prognoses (evaluated by the change of cardiac function after treatment and cardiac deterioration or death in the follow-up, respectively). RESULTS: A total of 20 patients with APS-associated CTEPH were enrolled, and eight patients underwent PTE. Chi-square test ( p = 0.01) and Kaplan-Meier curves (log rank test, p = 0.04) showed that there were statistically significant differences in both short-term and long-term prognoses between patients with and without PTE. CONCLUSION: These results provide strong evidence that PTE is a curative resolution in patients with APS-associated CTEPH. Following a full specialized and multidisciplinary risk-benefit evaluation to limit the risk of thrombosis or bleeding and to manage possible thrombocytopenia, PTE is at least a temporal curative resolution for CTEPH complicated with APS. PMID- 30451641 TI - Infections in newly diagnosed Spanish patients with systemic lupus erythematosus: data from the RELES cohort. AB - OBJECTIVES: Using data of patients from the inception cohort Registro Espanol de Lupus Eritematoso Sistemico (RELES), we aimed to analyse the incidence of severe infection in the first two years of follow-up and how predictors of infection change during the course of systemic lupus erythematosus (SLE). MATERIAL AND METHODS: The study included 282 patients. Markers of lupus activity, prednisone doses and immunosuppressive therapy were compared between patients with and without infections in the first and second year of the disease. Drug therapy administered during the first month of follow-up has been considered as a potential predictor of infections during the first year and medications administered during the first year have been considered potential predictors of infections during the second. RESULTS: Nineteen patients (6.4%) had a documented episode of major infection during the first year of follow-up and 16 patients (5.67%) during the second. The following variables were associated with infections during the first year: hypocomplementaemia at diagnosis ( p < 0.01), nephritis at diagnosis ( p = 0.03), SLEDAI score ( p < 0.01), prednisone >30 mg/day ( p = 0.01), methylprednisolone pulses ( p = 0.05) and mycophenolate use ( p = 0.02). The independent variables in the final model were hypocomplementaemia (odds ratio (OR) 4.41, 95% confidence interval (CI) 0.96-20.20, p = 0.05) and a dose of prednisone >30 mg/day (OR 6.60, 95% CI 1.34-32.42, p = 0.02). The following variables were associated with infections during the second year: dose of prednisone > 7.5 mg/day ( p = 0.05), methylprednisolone pulses ( p = 0.07), duration of therapy with antimalarials ( p = 0.09), therapy with mycophenolate ( p = 0.01), therapy with cyclophosphamide ( p = 0.05). The independent variables in the final model were a dose of prednisone >7.5 mg/day (OR 4.52, 95% CI 0.99 21, p = 0.054) and duration of therapy with antimalarials as a protective factor (OR 0.99, 95% CI 0.99-1.00, p = 0.053). CONCLUSIONS: The low incidence of early infections in the RELES cohort is partially explained by the extended use of antimalarials and by the general avoidance of prolonged high doses of prednisone. Patients with high baseline activity are at a higher risk of infection during the first months but therapy with medium-high doses of prednisone is the main predictor of infectious events. Thus, every effort should be made to limit oral glucocorticoid use from the very beginning of the SLE course. PMID- 30451642 TI - The Person of the Therapist and the Liberation of the Patient. PMID- 30451643 TI - Calls made to the Poisons Information Centre reveal need for improved risk management of cleaning agents in the workplace. AB - PURPOSE: To investigate chemical injuries caused by cleaning agents and disinfectants by reviewing poison control data. METHODS: We performed a five year retrospective analysis of calls to the Swedish Poisons Information Centre (PIC) concerning occupational use of cleaning agents and disinfectants. In addition, callers for 17 new cases were interviewed. RESULTS: Out of 8240 occupationally related cases handled by the PIC during 2010 through 2014, 24% concerned cleaning agents and disinfectants (N = 1983). Of these, one-third were classified as major risk cases, generally due to potential for corrosive eye- and skin injuries. The most frequent type of workplaces were restaurants and caterers. However, information about occupation was only identifiable for 30% of the cases. Follow up interviews exemplify how limited awareness of safety data sheets and disregard of protective equipment may contribute to health related outcomes such as absence at work. CONCLUSIONS: Management and prevention strategies for cleaning agents should be improved. PIC records hold relevant information both for designing interventions and future research on occupational health and safety management. We suggest that systematic collection by PIC of information on occupation and age would further improve the usefulness for occupational injury surveillance purposes. PMID- 30451644 TI - Conversation on the Ebola outbreak in Sierra Leone with Sinead Walsh and Oliver Johnson. PMID- 30451645 TI - Perceived suicide stigma, secrecy about suicide loss and mental health outcomes. AB - Perceived suicide stigma and consequent secrecy about suicide loss could contribute to impaired mental health among suicide loss survivors. Using online survey data from 195 suicide loss survivors, higher perceived suicide stigma was associated with more grief difficulties, higher suicidality, and less personal growth. Secrecy partly mediated the association between perceived suicide stigma and grief difficulties as well as suicidality and completely mediated the association between perceived suicide stigma and personal growth. Our findings suggest that supporting suicide loss survivors in coping with perceived suicide stigma could reduce secrecy about suicide loss and by this improve their mental health outcomes. PMID- 30451646 TI - Attitudes toward euthanasia among hospice nurses: Political ideology or religious commitment? AB - Attitudes toward euthanasia have been linked with political ideology among hospice nurses; however, a larger body of research has linked attitudes toward euthanasia with religiosity. The purpose of this study was to explore relationships between political ideology, religious commitment, and attitudes toward active and passive euthanasia among hospice nurses. Hospice nurses (N = 90) volunteered to take an online survey. Religious commitment fully mediated the relationship between social political ideology and disapproval of active euthanasia. The results suggest that, among hospice nurses, religious commitment accounts for links between social political ideology and disapproval of active euthanasia. PMID- 30451647 TI - Exposure to airborne nano-titanium dioxide during airless spray painting and sanding. AB - Objectives of the study were to measure and characterize exposure to airborne nanoscale titanium dioxide during airless spraying and sanding of a nano-enabled paint, and to evaluate the effectiveness of dust capture methods in reducing airborne nanoparticle concentrations. A tradesperson performed the work activities in an environmentally-controlled chamber. Samples were collected in the tradesperson's breathing zone and in surrounding areas to assess bystander exposure. Filter-based samples were analyzed using gravimetric methods, scanning electron microscopy, and energy dispersive spectroscopy. Differential particle count data were obtained by means of a scanning mobility particle sizer. Local exhaust ventilation provided statistically significant reductions of airborne nanoparticle concentrations during sanding. Sanding the paint after drying with a handheld power sander generated relatively low levels of airborne titanium dioxide. In contrast, task-based exposure measurements collected during the initial airless spray application of the nano-enabled paint suggested a potential for occupational exposures to exceed the time-weighted average exposure limit for ultrafine titanium dioxide recommended by the National Institute for Occupational Safety and Health. Painters applying nano-enabled coatings may have little recourse but to rely, in some instances, on lower tiers of the hierarchy of controls, such as personal protective equipment. In light of these findings, employers and industrial hygienists should characterize exposures and implement the hierarchy of controls to ensure painters are sufficiently protected. PMID- 30451648 TI - A novel cognitive-behavioral stress management method for multiple sclerosis. A brief report of an observational study. AB - OBJECTIVES: Psychological stress is an important risk factor for multiple sclerosis (MS) onset, relapse, neurological symptoms and psychosocial adjustment to the disease. Mounting evidence suggests that stress management could halt the disease progression and improve patients' wellbeing. The aim of this study was to investigate the effectiveness of a novel cognitive-behavioral stress management technique (called Pythagorean Self-Awareness Intervention - PSAI) routinely used in our clinics in patients with MS. METHODS: In this observational study, 148 MS patients receiving PSAI for 8-weeks were compared patients who followed only usual care. Measurements included cognitive function, psychological distress and physical fatigue. Propensity score (PS) methods (given the observational design) and linear mixed models were employed to address study's endpoints. RESULTS: A total of 128 (86.5%) of MS patients fulfilled the PS criteria for analyses (72 in the PSAI group and 56 in the control group). Patients of tertiary education, longer disease duration, higher cognitive score and psychological distress were more likely to choose to participate in the PSAI group. PSAI patients were found with statistical significant beneficial changes in cognitive speed processing, verbal memory, stress, anxiety, depression and fatigue. Based on the numbers needed-to-treat of the weighted data, PSAI was particularly effective in improving cognitive speed processing (NNT = 10) and stress (NNT = 12). DISCUSSION: PSAI can benefit cognitive function and psychological distress in MS patients. Future studies should expand these results in randomized trials and by using longer follow-up and MS activity-related endpoints. ABBREVIATIONS: BICAMS: Brief International Cognitive Assessment for Multiple Sclerosis BVMT-R: Brief Visuospatial Memory Test Revised CVLT: California Verbal Learning Test DASS: Depression Anxiety Stress Scale EDSS: Expanded Disability Status Scale MS: Multiple Sclerosis NNT: Numbers Needed to Treat PS: Propensity Score PSAI: Pythagorean Self-Awareness Intervention RR: Relapsing Remitting SDMT: Symbol Digits Modalities Test VAS-PF: Visual Analogue Scale Physical Fatigue. PMID- 30451649 TI - Hepatitis C virus intrinsic molecular determinants may contribute to the development of cholestatic hepatitis after liver transplantation. AB - Cholestatic hepatitis C (CHC) is a severe form of hepatitis C virus (HCV) infection recurrence that leads to high graft loss rates early after liver transplantation (LT). To investigate the pathogenic mechanisms of CHC, we analysed HCV quasispecies in CHC patients compared to a control group (mild hepatitis C recurrence) by deep pyrosequencing. At the time of LT, NS5B quasispecies complexity was similar between the two groups but, after LT, it decreased more sharply in CHC patients than in the control group. Interestingly, the major variant before LT propagated efficiently and remained as the dominant sequence after LT in 62 % of CHC patients versus 11 % of controls (P=0.031). Sequence analysis of the complete non-structural region in a limited number of patients revealed a potential 12 aa signature specific to the CHC group. These data suggest that intrinsic molecular determinants in the circulating HCV quasispecies may provide a fitness advantage, contributing to the development of CHC. PMID- 30451650 TI - The impact of the absence of Toll-like receptor-2 during Sporothrix brasiliensis infection. AB - PURPOSE: Sporothrix brasiliensis, a member of the Sporothrix schenckii complex, is a major cause of epidemic outbreaks of sporotrichosis due to its greater virulence and ability to evade the immune system. The absence of studies about this species led to this study, with the aim to evaluate the importance of Toll like receptor-2 (TLR-2) during S. brasiliensis infection. METHODOLOGY: In vitro assays were performed using bone marrow-derived macrophages from both wild-type (C57BL/6) and TLR-2 knockout (-/-) mice. In vivo assays were also performed, on which the mice (C57BL/6 and TLR-2-/-) were intraperitoneally infected with S. brasiliensis yeast American Type Culture Collection MYA-4831 and euthanized on days 7, 14 and 28 post infection. The following parameters were then evaluated: fungal burden in spleen, liver, kidney and brain; the production of cytokines TNF alpha, IFN-gamma, IL-4, IL-2, IL-6 and IL-10. RESULTS: The in vitro results showed that the absence of TLR-2 resulted in impaired phagocytosis, microbicide mechanisms utilizing the production of nitric oxide, and the cytokine production (TNF-alpha, IL-6 and IL-10). The in vivo results demonstrated that the absence of TLR-2 during experimental S. brasiliensis infection promoted increased dissemination after 14 and 28 days and suggests a polarized Th17 response in an attempt to control the infection. CONCLUSIONS: TLR-2 signalling appears to be important in the innate immune response against S. brasiliensis. PMID- 30451651 TI - Interferon regulatory factors 3 and 7 have distinct roles in the pathogenesis of alphavirus encephalomyelitis. AB - Interferon (IFN) regulatory factors (IRFs) are important determinants of the innate response to infection. We evaluated the role(s) of combined and individual IRF deficiencies in the outcome of infection of C57BL/6 mice with Sindbis virus, an alphavirus that infects neurons and causes encephalomyelitis. The brain and spinal cord levels of Irf7, but not Irf3 mRNAs, were increased after infection. IRF3/5/7-/- and IRF3/7-/- mice died within 3-4 days with uncontrolled virus replication, similar to IFNalpha receptor-deficient mice, while all wild-type (WT) mice recovered. IRF3-/- and IRF7-/- mice had brain levels of IFNalpha that were lower, but brain and spinal cord levels of IFNbeta and IFN-stimulated gene mRNAs that were similar to or higher than WT mice without detectable serum IFN or increases in Ifna or Ifnb mRNAs in the lymph nodes, indicating that the differences in outcome were not due to deficiencies in the central nervous system (CNS) type I IFN response. IRF3-/- mice developed persistent neurological deficits and had more spinal cord inflammation and higher CNS levels of Il1b and Ifngamma mRNAs than WT mice, but all mice survived. IRF7-/- mice died 5-8 days after infection with rapidly progressive paralysis and differed from both WT and IRF3-/- mice in the induction of higher CNS levels of IFNbeta, tumour necrosis factor (TNF) alpha and Cxcl13 mRNA, delayed virus clearance and more extensive cell death. Therefore, fatal disease in IRF7-/- mice is likely due to immune mediated neurotoxicity associated with failure to regulate the production of inflammatory cytokines such as TNFalpha in the CNS. PMID- 30451652 TI - A pharmacokinetic and pharmacodynamic evaluation of iclaprim activity against wild-type and corresponding thymidine kinase-deficient Staphylococcus aureus in a mouse abscess model. AB - The efficacy of iclaprim against Staphylococcus aureus ATCC 25923 and its corresponding isogenic TK-deficient mutant S. aureus strain AH 1246 mixed with cytodex beads was studied in a mouse abscess infection model. Iclaprim (2-80 mg kg-1) administered as a single dose via the subcutaneous route (2 h post infection) was efficacious against the TK-deficient mutant with 1 and 2 log10 c.f.u. reductions at the 24 h post initiation of treatment time point, at doses of 14.4 and 30 mg kg-1, respectively. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK-competent) S. aureus strain, ATCC 25923, at all doses tested. The PK/PD parameter which appeared to correlate best with efficacy was AUC/MIC (R2=0.91). This study showed that TK-deficient mutants may be used to evaluate DHFRi activity and PK/PD relationship in a mouse abscess model. PMID- 30451653 TI - Musculoskeletal manifestations of alkaptonuria: A case report and literature review. AB - Alkaptonuria (AKU) is a rare autosomal recessive disorder that results from the deficient activity of homogentisate 1,2-dioxygenase and leads to increased levels of homogentisic acid (HGA) and its oxidized product benzoquinone acetic acid (BQA). Both HGA and BQA form polymerized deposits that lead to a bluish-black discoloration of the cartilage as well as degeneration, inflammation, and calcification of the tendons, ligaments, intervertebral discs, and large joints and increased bone resorption. A brittle and fragmented cartilage forms and leads to aberrant loading of the subchondral bone. These fragments then adhere to the synovial membrane and cause fibrosis or chondromatosis, leading to ochronotic arthropathy. Ochronotic tendinopathy most commonly affects the patellar or Achilles tendon and can lead to enthesopathy or spontaneous tendon ruptures. Ochronotic pigments deposited in the bone impair the bone mineralization process and lead to osteopenia or osteoporosis. Here, we report a case of a patient with several musculoskeletal manifestations of AKU and reviewed the literature to summarize the pathophysiology, clinical characteristics, and radiologic findings of the rheumatic features of AKU. Though medical treatment options are limited, early identification of AKU can facilitate prompt surgical intervention. PMID- 30451654 TI - Imaging in rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis: An international viewpoint on the current knowledge and future research priorities. AB - Imaging is increasingly used in the routine management of rheumatic diseases as well as in the clinical trials of these disorders. This viewpoint, authored by a group of international imaging experts following two meetings dedicated to imaging in rheumatology, reports a consensus about the current knowledge and addresses where further research should be focused based on the views of the international imaging experts and discussion of the evidence with attending imaging practitioners. The goal was to maximize the potential of imaging to improve the clinical management of four rheumatic diseases. These rheumatic diseases include rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and osteoarthritis. PMID- 30451655 TI - A single-arm, open-label study to assess the immunogenicity, safety, and efficacy of etanercept manufactured using the serum-free, high-capacity manufacturing process administered to patients with rheumatoid arthritis. AB - OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of etanercept (ETN) manufactured using the serum-free, high-capacity manufacturing (SFHCM) process in patients with rheumatoid arthritis (RA). METHODS: In this global, multicenter, open-label, single-arm study (NCT02378506), 187 adult patients with moderate to severe RA received ETN 50 mg once weekly for 24 weeks manufactured using the SFHCM process. Immunogenicity (presence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs)) was assessed at 12 and 24 weeks. Safety and efficacy were evaluated at 4, 12, and 24 weeks. RESULTS: Eight (4.5%) patients tested positive for ADA, and there were no NAbs detected at any time throughout the study. Ninety (48.1%) patients reported treatment-emergent adverse events (AEs), of which 27 (14.4%) reported injection-site reactions, and 43 (23.0%) reported infections. The majority of AEs were mild or moderate in severity, and the drug was well tolerated. Throughout the duration of the study (week 4 to week 24), there was a progressive increase in the American College of Rheumatology (ACR)-defined responses (ACR20: 55.9%-82.0%, ACR50: 16.1%-57.8%, and ACR70: 3.2% 26.7%) from baseline and the proportion of patients achieving low disease activity and remission, with a corresponding decrease in measures of disease activity. CONCLUSION: The immunogenicity, safety, and efficacy of ETN manufactured using the SFHCM process were similar to the current approved ETN formulation. ClinicalTrials.gov registration: NCT02378506. PMID- 30451656 TI - [P2X4, Ca2+ and CXCL5, a new pro-inflammatory trio]. PMID- 30451657 TI - [Immunotherapy and targeted therapy, a promising combination to fight cancer]. PMID- 30451658 TI - [Hepatic Hippo signaling inhibits protumoral microenvironment allowing to suppress hepatocellular carcinoma]. PMID- 30451659 TI - [Contribution of B lymphocytes in acquired resistance to targeted therapies in metastatic melanoma]. PMID- 30451660 TI - [Next generation biobanking: the challenge of data]. AB - Human biological samples are key resources in unravelling physiopathological factors underlying diseases and influencing their outcome. By making use of these resources, genomics, proteomics and molecular imaging techniques have achieved unprecedented progress in the past decade. The development of genomics platforms, molecular imaging as well as bioinformatics allowed a significant development of the biomarkers field thus realizing significant advances towards personalized medicine. The exponential increase of data, their complexity, the necessity of their integration for analysis require the development of appropriate infrastructures. These latter should integrate experts from different fields as well as an optimal organisation of biobanks including novel access and exchange rules for biological material and data. PMID- 30451661 TI - [Opportunities and challenges of blockchain technology in the healthcare industry]. AB - Often described as a tool to build trust among stakeholders with divergent interests, blockchain technology has been of interest to many sectors since it was first used in 2008. Initially designed to record financial transactions between individuals, its applications have largely evolved with technological advances and the growing interest of international companies. In the healthcare sector, blockchain is interesting for many of its features: its immutability which makes it an excellent support for authenticating sensitive data such as clinical trials consents, the possibility of publishing smart contracts that automate and facilitate many processes or the constitution of a network that agrees on the state of the information. Much acclaimed, blockchain technology is still to be tested in real-life conditions and adapted to a particularly complex regulatory and economic context in the healthcare sector. PMID- 30451662 TI - [Public-private partnerships to address innovation stakes of both industrialized and limited income countries]. PMID- 30451663 TI - [Anti-TNFalpha antibodies in melanoma immunotherapy]. PMID- 30451664 TI - [DNA lesion proximity favors mutagenesis]. PMID- 30451665 TI - [Upside-down topology in metastatic colorectal carcinomas]. PMID- 30451666 TI - [Chromatin mobility upon DNA damage: a multi-scale story]. PMID- 30451667 TI - [The most ancestral mycobacterial ESX-4 secretion system is essential for intracellular growth of Mycobacterium abscessus within environmental and human phagocytes]. PMID- 30451668 TI - [Streptococcus gallolyticus: an opportunistic pathogen associated with colorectal cancer]. PMID- 30451669 TI - [A novel class of polycationic macromolecules against multiresistant pathogens]. PMID- 30451670 TI - [A gammaherpesvirus infection protects against the development of allergic asthma]. PMID- 30451671 TI - [A restless REM sleep may be sign of emerging neurodegenerative diseases]. PMID- 30451672 TI - [IL6R is the key therapeutical target in pulmonary arterial hypertension]. PMID- 30451673 TI - [Spontaneous preterm birth and the maternal microbiome]. AB - Preterm birth is the leading cause of perinatal mortality and morbidity. Despite the efforts spent over the past 40 years to solve the physiopathological processes involved in the triggering of prematurity, efficient therapeutics are still lacking. Recently, growing body of evidence suggests that the maternal microbiome is a major player for a normal pregnancy and that dysbiosis is associated with preterm birth. The vaginal microbiome and its commensal Lactobacillus species may protect the uterus of ascending dissemination of pathogens. The uterus can also be contaminated with oral bacteria by the blood stream. Thus, the maternal microbiome can play both a protective role or a causal role in the triggering of preterm birth. PMID- 30451674 TI - [Gel-forming mucins structure governs mucus gels viscoelasticity]. AB - Mucus is the first line of innate mucosal defense in all mammals. Gel-forming mucins control the rheological properties of mucus hydrogels by forming a network in which hydrophilic and hydrophobic regions coexist, and it has been revealed that the network is formed through both covalent links and reversible links such as hydrophobic interactions in order to modulate the structure as a function of the physiological necessities. Here, we review the structure and functions of the mucus in terms of the gel-forming mucins protein-protein interactions, also called interactome. Since it is difficult to characterize the low energy reversible interactions due to their dependence on physico-chemical environment, their role is not well understood. Still, they constitute a promising target to counteract mucus abnormalities observed in mucus-associated diseases. PMID- 30451675 TI - [The CRISPR-Cas system: beyond genome editing]. AB - CRISPR-Cas is an adaptive immune system used by many microbes to defend against nucleic acids invasion such as viral genomes. The microbial system uses its CRISPR locus to store genetic information that will generate short CRISPR RNAs. The latter with endonucleases (Cas) prevent future viral infections. Parts of this system were exploited to develop a powerful genome editing tool that was adapted for a variety of organisms. The ability of the CRISPR-Cas9 technology to effectively and precisely cut a targeted genomic DNA region has the potential to may be one day cure genetic diseases. The malleability of this editing tool also offers a wide range of possibilities from modulations of gene expression to epigenetic modifications. The natural CRISPR loci found in bacteria can be used to differentiate microbial strains or to study the interactions between bacteria and its habitat. Addressing CRISPR-Cas fundamentals in microbes and its popular use in eukaryotes, this review presents an update on a system that has revolutionized biological sciences. PMID- 30451676 TI - [Heart rate: when macrophages hit the note]. AB - Macrophages regulate cardiac homeostasis under pathological and physiological conditions. Recent studies have elegantly substantiated the presence of specific subset of macrophages residing within the distal atrioventricular node in mice and humans. These macrophages directly couple with cardiomyocytes via connexin-43 containing gap junctions and increase atrioventricular conduction by accelerating cardiomyocyte repolarization. Conditional deletion of connexin-43 in macrophages or congenital lack of macrophages delay nodal conduction and foster progressive atrioventricular block. Exhaustive understanding of the role of tissue-resident macrophages in normal and aberrant cardiac conduction could initiate the development of therapeutic strategies focused on the modulation of macrophage functions in heart arrhythmia. PMID- 30451677 TI - [Liquid biopsy: a possible approach for cancer screening]. AB - Liquid biopsy has emerged as a promising avenue for cancer screening. Several circulating biomarkers such as circulating DNA, circulating tumor cells, circulating microRNAs and others have shown promise for theragnostics and patient's monitoring. Early detection may help reduce cancer-related mortality and increase overall patient survival. Most cancer types lack specific biomarkers and despite intensive efforts in this area, the development of effective clinical screening techniques has been limited. The noninvasive nature of liquid biopsy represents an advantage over other approaches to define cancer biomarkers, particularly for the development of cancer screening tests. This review presents the various studies based on the analysis of liquid biopsy aiming to develop tests for cancer screening and early detection. So far, no test developed from liquid biopsy proves to be both specific and sensitive enough to be used as a universal screening test. However, the potential of this new approach appears more and more credible, given the recent developments of sophisticated multi parametric methods. PMID- 30451678 TI - [Hepatitis delta virus replication and the role of the small hepatitis delta protein S-HDAg]. AB - Hepatitis delta virus (HDV) is a mammalian defective virus. Its genome is a small single-stranded circular RNA of approximately 1,680 nucleotides. To spread, HDV relies on hepatitis B virus envelope proteins that are needed for viral particle assembly and egress. Severe clinical features of HBV-HDV infection include acute fulminant hepatitis and chronic liver fibrosis leading to cirrhosis and hepatocellular carcinoma. One uniqueness of HDV relies on its genome similarity to viroids, small plant infectious uncoated RNAs. Devoid of viral replicase activity, HDV has to use host DNA-dependant RNA Pol II to replicate its genomic RNA. Thus, one can ask how does this replication occur? We describe first here the major steps of the viral RNA transcription and replication and then we detail the role of the Small HD protein in these processes, especially with regard to the Pol II recruitment. PMID- 30451679 TI - [Gene therapy progress: hopes for Usher syndrome]. AB - Hearing and balance impairment are major concerns and a serious public health burden, as it affects millions of people worldwide, but still lacks an effective curative therapy. Recent breakthroughs in preclinical and clinical studies using viral gene therapy suggest that such an approach might succeed in curing many genetic diseases. Our actual understanding and the comprehensive analysis of the molecular bases of genetic deafness forms have provided the multiple bridges toward gene therapy to correct, replace, or modify the expression of defective endogenous genes involved in deafness. The aim of this review article is to summarize the recent advances in the restoration of cochlear and vestibular functions by local gene therapy in mouse models of Usher syndrome, the leading genetic cause of deafness associated with blindness in the world. We focus herein on therapeutic approaches with the highest potential for clinical application. PMID- 30451680 TI - [Revisiting the origins of life: from atoms to molecules, reproduction, then replication]. PMID- 30451681 TI - [Contribution of C.S. Peirce thought to the representation knowledge and medical reasoning]. AB - Modelling knowledge and medical reasoning can be an epistemological project especially now, as medicine seems to reach a scientific status. Through his work on semiotics, abductive reasoning and pragmatism, CS Peirce (1839-1914) offers a series of original solutions. These solutions can give an account of (be considered as a theorical ground for) most of the medical activity in various fields such as the evaluation of the students, the knowledge bases and expert systems, the formal descriptions languages (ontologies), and the evidence-based medicine. By mean of this article, we aim at introducing the medical doctors to this complex but lighting thought on a profession which now uses all the most modern resources of knowledge engineering. PMID- 30451682 TI - [Towards success against senescence?] AB - Senescent cells are involved in many age-related diseases, and the effects of their elimination by "senolytic" drugs is an active research field. A recent paper describes a convenient murine model of induced senescence and uses it to convincingly demonstrate the positive effects of senolytics on performance and lifespan. Clinical studies have already been initiated; this approach hold promise to eventually improve human "healthspan". PMID- 30451683 TI - The Toll pathway inhibits tissue growth and regulates cell fitness in an infection-dependent manner. AB - The Toll pathway regulates the cellular response to infection via the transcriptional upregulation of antimicrobial peptides. In Drosophila, apart from its role in innate immunity, this pathway has also been reported to be important for the elimination of loser cells in a process referred to as cell competition, which can be locally triggered by secreted factors released from winner cells. In this work, we provide evidence that the inhibition of Toll signaling not only increases the fitness of loser cells, but also bestows a clonal growth advantage on wild-type cells. We further demonstrate that this growth advantage depends on basal infection levels since it is no longer present under axenic conditions but exacerbated upon intense pathogen exposure. Thus, the Toll pathway functions as a fine-tuned pro-apoptotic and anti-proliferative regulator, underlining the existence of a trade-off between innate immunity and growth during development. PMID- 30451684 TI - Unique morphogenetic signatures define mammalian neck muscles and associated connective tissues. AB - In vertebrates, head and trunk muscles develop from different mesodermal populations and are regulated by distinct genetic networks. Neck muscles at the head-trunk interface remain poorly defined due to their complex morphogenesis and dual mesodermal origins. Here, we use genetically modified mice to establish a 3D model that integrates regulatory genes, cell populations and morphogenetic events that define this transition zone. We show that the evolutionary conserved cucullaris-derived muscles originate from posterior cardiopharyngeal mesoderm, not lateral plate mesoderm, and we define new boundaries for neural crest and mesodermal contributions to neck connective tissue. Furthermore, lineage studies and functional analysis of Tbx1- and Pax3-null mice reveal a unique developmental program for somitic neck muscles that is distinct from that of somitic trunk muscles. Our findings unveil the embryological and developmental requirements underlying tetrapod neck myogenesis and provide a blueprint to investigate how muscle subsets are selectively affected in some human myopathies. PMID- 30451686 TI - Sucrose intensity coding and decision-making in rat gustatory cortices. AB - Sucrose's sweet intensity is one attribute contributing to the overconsumption of high-energy palatable foods. However, it is not known how sucrose intensity is encoded and used to make perceptual decisions by neurons in taste-sensitive cortices. We trained rats in a sucrose intensity discrimination task and found that sucrose evoked a widespread response in neurons recorded in posterior-Insula (pIC), anterior-Insula (aIC), and Orbitofrontal cortex (OFC). Remarkably, only a few Intensity-selective neurons conveyed the most information about sucrose's intensity, indicating that for sweetness the gustatory system used a compact and distributed code. Sucrose intensity was encoded in both firing-rates and spike timing. The pIC, aIC, and OFC neurons tracked movement direction, with OFC neurons yielding the most robust response. aIC and OFC neurons encoded the subject's choices, whereas all three regions tracked reward omission. Overall, these multimodal areas provide a neural representation of perceived sucrose intensity, and of task-related information underlying perceptual decision-making. PMID- 30451685 TI - Lipidation-independent vacuolar functions of Atg8 rely on its noncanonical interaction with a vacuole membrane protein. AB - The ubiquitin-like protein Atg8, in its lipidated form, plays central roles in autophagy. Yet, remarkably, Atg8 also carries out lipidation-independent functions in non-autophagic processes. How Atg8 performs its moonlighting roles is unclear. Here we report that in the fission yeast Schizosaccharomyces pombe and the budding yeast Saccharomyces cerevisiae, the lipidation-independent roles of Atg8 in maintaining normal morphology and functions of the vacuole require its interaction with a vacuole membrane protein Hfl1 (homolog of human TMEM184 proteins). Crystal structures revealed that the Atg8-Hfl1 interaction is not mediated by the typical Atg8-family-interacting motif (AIM) that forms an intermolecular beta-sheet with Atg8. Instead, the Atg8-binding regions in Hfl1 proteins adopt a helical conformation, thus representing a new type of AIMs (termed helical AIMs here). These results deepen our understanding of both the functional versatility of Atg8 and the mechanistic diversity of Atg8 binding. PMID- 30451687 TI - Intravascular assessment of coronary arteries in patients with cyanotic congenital heart disease. AB - AIMS: Patients with cyanotic congenital heart disease (CCHD) have been suggested to develop less atherosclerosis than the general population. This study aimed to evaluate the extent of coronary atherosclerosis in patients with CCHD using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS). METHODS AND RESULTS: Fifteen patients with CCHD (women, 9; median age, 53 years) and 14 acyanotic controls (women, 6; median age, 53 years) were examined with IVUS-NIRS of the right coronary artery (RCA). The patients with CCHD presented with a larger RCA diameter than the controls (external-elastic-membrane diameter, 6.1 [4.8-6.7] vs. 4.7 [4.1-5.1] mm, respectively; p=0.01). No difference in area stenosis was found between the patients and the controls (15.8% [12.3-19.7%] vs. 15.2% [9.5-18.8%]; p=0.87). The presence of lipid by NIRS was noted in 43% of patients with CCHD and in 92% of the controls; however, no differences in total or max-4-mm lipid-core-burden-index (LCBI) or in plasma lipid-profile were found. CONCLUSIONS: Patients with CCHD presented with larger coronary arteries than acyanotic controls. No difference in the degree of area-stenosis in the coronary arteries was found between the cyanotic and acyanotic patients; however, a lower proportion of patients with CCHD showed a positive LCBI. PMID- 30451689 TI - The ESC Congress 2018 and the legacy of Eugene Braunwald. PMID- 30451688 TI - First-in-human experience of a new generation transfemoral transcatheter aortic valve for the treatment of severe aortic regurgitation: the J-Valve transfemoral system. PMID- 30451690 TI - Drug-coated balloons versus drug-eluting stents for in-stent restenosis: the saga continues. PMID- 30451691 TI - Transradial left main PCI is safe and effective. PMID- 30451692 TI - The evolution of PCI registries: implementing a sustainable future for health systems and clinicians. PMID- 30451693 TI - Optical coherence tomography revisited: imaging and imagination. PMID- 30451694 TI - Women and ischaemic heart disease: treat her like a lady! PMID- 30451695 TI - Patient Focus in Interventional Cardiology: the EAPCI Initiative. PMID- 30451696 TI - Prognosis of geriatric patients with severe kidney disease. AB - : Over three million French people present a severe chronic kidney disease, among which there is a high prevalence of elder subjects. We conducted a prospective monocentric study in a geriatric acute care ward. The aims were to determine the short-term prognosis of patients with severe chronic kidney disease and to determine the factors associated with mortality at six-months. METHODS: Patients 75 years of age and older, with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (chronic kidney disease epidemiology CKD-EPI) were recruited. A comprehensive geriatric assessment was performed at hospital discharge. Comprehensive geriatric assessment was performed: Activities of daily livings and Instrumental activities of daily livings scores, of the risk of pressure sore with Exton-Smith scale, the cognitive status with MMSE score, nutritional status according to Mini-nutritional assessment short form and albuminemia, comorbidities with Cumulative illness rating scale, number of drugs in presciption and living status. Six months follow-up was performed to assess vital status and evolution of the eGFR. RESULTS: Sixty-seven patients were included, mean age 88.6+/-4.82 years with a mean eGFR of 21.3+/-6 mL/min. Mortality rate at six months was 36%. Multivariate analysis showed that a high CIRS score (RR=1.52; IC 95% 1.05-2.19) and a decline of creatinine clearance>= 2 mL/min (4.72; 1.27 17.52) were predictive of mortality. On the opposite, a high MNA-SF score was protective (0.76; 0.62-0.94). CONCLUSION: Prognosis of geriatric patients with severe chronic kidney disease is poor. Comprehensive geriatric assessment helps to assess short-term prognosis, in a focus of person-centered care. PMID- 30451697 TI - Clinical and paraclinical patterns of presentation, and sensitivity of diagnostic scores for pulmonary embolism at the emergencies: retrospective study on the impact of age at the University hospitals of Strasbourg (France). AB - : The diagnosis of pulmonary embolism remains difficult. The objective of this study was to analyze the effect of age on the clinical presentation mode and the sensitivity of the diagnostic scores. METHODS: In retrospect, all patients discharged with a documented diagnosis of pulmonary embolism from the adult emergency service of the Regional university hospital of Strasbourg (France) over a year were considered. According to 4 age categories (<70, 70-74, 75-80 and >80 years) the data from the medical records were analyzed and compared. Diagnostic scores of Wells and modified Geneva were calculated. RESULTS: 117 patients met the inclusion criteria (mean age 71.8+/-13.8 years, women 54%). Chest pain was less common after 80 years; no difference was observed for syncope or dyspnea although the oxygen saturation is lower in old age. For diagnosis, 25% of patients had a lung scintigraphy with an increased recourse with age (<70 years: 10%, >80 years: 41%). Thoracic computed tomography angiography concerned 79% of patients with a significant decrease of his use in older. The sensitivity of the diagnostic scores was low but increased with age when the strong and intermediate probabilities of pulmonary embolism were combined. CONCLUSION: This study confirms the low specificity of the clinical signs of pulmonary embolism, whatever the age. It also shows the low sensitivity of the diagnostic scores in the 70 years or older. PMID- 30451698 TI - Community and activists demand for tenofovir/emtricitabine or lamivudine/dolutegravir and routine viral load testing. AB - PURPOSE OF REVIEW: Since the beginning of the HIV epidemic, informed communities have demanded and fought for access to life-saving treatment. The last several years have seen interesting developments in this area - particularly with respect to the switch to dolutegravir (DTG)-based regimens and scale-up of routine viral load testing (RVLT), and how these directly and indirectly impact issues of treatment optimization, HIV drug resistance, and sexual and reproductive health. In this review, we present recent advances in antiretroviral treatment and monitoring in the context of how treatment education and community demand for them. RECENT FINDINGS: The latest developments with DTG and RVLT highlight underlying issues for global health systems that need to be addressed - including drug surveillance, supply chain management, and comprehensive care linkages - and the importance of community engagement in such issues. SUMMARY: Decisions about treatment must be grounded in informed community demand, and should exist in the context of optimal care and treatment across the entire HIV cascade. Informed advocacy is essential for people living with HIV and their communities, so that they benefit from existing and future therapeutic advances. Research is needed on the importance of community demand across the HIV treatment cascade. PMID- 30451699 TI - Demand creation for primary biomedical prevention: identifying lessons across interventions to inform daily oral preexposure prophylaxis programs. AB - PURPOSE OF REVIEW: At a moment when UNAIDS (Joint United Nations Programme on HIV/AIDS) has acknowledged a 'prevention crisis,' and multiple countries and implementers are emphasizing 'user-centered' and/or differentiated models of delivering HIV treatment and prevention, it is essential to understand and act on best practices from all relevant interventions to create effective oral preexposure prophylaxis (PrEP) programs. RECENT FINDINGS: It is possible to adapt private sector approaches to understanding and segmenting the preferences and mindsets of potential consumers to primary HIV prevention programs, as demonstrated by a voluntary medical male circumcision (VMMC)-focused intervention that successfully trained and supported counselors to identify and deliver tailored messages to men potentially undergoing VMMC. Literature on PrEP and demand creation is less extensive and suggests uneven application of user centered design and demand-side thinking; a recent analysis of condom programing demonstrates that failure to maintain resources for social marketing can drive a collapse in use and an increase in HIV incidence. SUMMARY: Approaches to demand creation for primary prevention are dynamic and evolving. However, the lag between implementation and publication means that there is a paucity of PrEP specific information. Insights from VMMC and other strategies can and must be considered as part of a more holistic approach to increasing demand for primary prevention interventions. PMID- 30451700 TI - Epidemiology of Concussions in High School Boys' Ice Hockey, 2008/09 to 2016/17 School Years. AB - OBJECTIVE: This study examined the epidemiology of concussions in high school boys' ice hockey during the 2008/09 to 2016/17 school years. DESIGN: Prospective cohort study. Athletic trainers from an average 33 high schools annually reported boys' ice hockey concussion and athlete-exposure (AE) data for the High School Reporting Information Online system. SETTING: Convenience sample of high school boys' ice hockey programs during the 2008/09 to 2016/17 school years. PATIENTS OR OTHER PARTICIPANTS: High school boys' ice hockey players (aged ~14-18 years). INDEPENDENT VARIABLES: Concussion data on event type, injury mechanism, symptom resolution time, and time loss were obtained. MAIN OUTCOME MEASURES: Concussion rates with 95% confidence intervals (CIs) and distributions were calculated. RESULTS: Overall, 348 concussions were reported in boys' ice hockey during the 2008/09 to 2016/17 academic years, leading to a concussion rate of 0.68/1000 AEs (95% CI, 0.61-0.75). Most occurred in competitions (85.6%), particularly after the first period (72.1% of all competition concussions). Among practice concussions, most occurred after the first hour of practice (60.0%). Most concussions were due to player contact (47.7%) and boards/glass contact (31.9%). Although 69.0% of concussed athletes had symptoms resolve in less than 7 days, only 14.1% returned to activity within a week. CONCLUSIONS: Most concussions occurred within the second and third periods. Preventive strategies that counter an increased risk of concussion due to a greater intensity of gameplay coupled with increased fatigue may be warranted. Moreover, athletes may further benefit from prevention efforts that focus on anticipating impacts during gameplay. PMID- 30451701 TI - Mycotic coronary aneurysm after percutaneous treatment of chronic total occlusion. PMID- 30451702 TI - Ambulatory blood pressure monitoring tolerability and blood pressure status in adolescents: the SHIP AHOY study. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) provides a more precise assessment of blood pressure (BP) status than clinic BP and is currently recommended in the evaluation of elevated BP in children and adolescents. Yet, ABPM can be uncomfortable for patients and cumbersome to perform. OBJECTIVE: Evaluation of the tolerability to ABPM in 232 adolescent participants (median age: 15.7 years, 64% white, 16% Hispanic, 53% male) in the Study of Hypertension In Pediatrics Adult Hypertension Onset in Youth and its potential effects on ABPM results. PARTICIPANTS AND METHODS: Ambulatory BP status (normal vs. hypertension) was determined by sex and height-specific pediatric cut-points. Participants were asked to rank their wake and sleep tolerability to ABPM from 1 (most tolerant) to 10 (least tolerant); those with tolerability score of at least 8 were considered ABPM intolerant. RESULTS: Forty-three (19%) participants had wake ambulatory hypertension (HTN), 42 (18%) had sleep ambulatory HTN, and 64 (28%) had overall (wake and/or sleep) ambulatory HTN. Forty (17%) participants were intolerant to ABPM during wake hours and 58 (25%) were intolerant during sleep. ABPM intolerance during wake (but not sleep) hours was independently associated with wake (odds ratio: 2.34, 95% confidence interval: 1.01-5.39) and overall (odds ratio: 2.94, 95% confidence interval: 1.21-7.18) ambulatory HTN. CONCLUSION: Poor tolerability to ABPM is associated with a higher prevalence of ambulatory HTN in adolescents, and should be taken into consideration at time of ABPM interpretation. PMID- 30451703 TI - Expanding the phenotype in autosomal dominant mental retardation-24: a novel variation in DEAF1 gene. PMID- 30451704 TI - Meier-Gorlin syndrome: an additional case report in an adult woman. PMID- 30451705 TI - Epidemiology of atrial fibrillation in patients with cirrhosis and clinical significance: a meta-analysis. AB - OBJECTIVE: The epidemiology of atrial fibrillation (AF) in patients with cirrhosis and its clinical significance remain unclear. This study aimed (i) to investigate the pooled prevalence and/or incidence of AF in patients with cirrhosis and (ii) to assess the mortality risk of AF in patients with cirrhosis. PATIENTS AND METHODS: A literature search for studies that reported incidence of AF in patients with cirrhosis was carried out using Medline, Embase, and Cochrane Database from inception through July 2018. Pooled incidence with 95% confidence interval (CI) was calculated using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42018102664). RESULTS: Seven cohort studies including 385 866 patients with cirrhosis were identified. The pooled estimated prevalence of AF in patients with cirrhosis was 5.0% (95% CI: 2.8-8.6%). When studies that solely assessed patients undergoing transplant evaluation or on transplant waiting list were excluded, the pooled estimated prevalence of AF in patients with cirrhosis was 7.4% (95% CI: 3.5-15.2%). There was a significant association between AF and increased mortality risk in cirrhotic patients with a pooled odds ratio of 1.44 (95% CI: 1.36-1.53). CONCLUSION: The overall estimated prevalence of AF among patients with cirrhosis is 5.0%. Our study demonstrates a statistically significant increased mortality risk in cirrhotic patients with AF. PMID- 30451706 TI - Effectiveness of psychological interventions for women with type 2 diabetes who are overweight or obese: a systematic review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objectives of this review are to. PMID- 30451707 TI - Experiences of older adults accessing specialized health care services in rural or remote areas: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what are the experiences of older adults accessing specialized health care services in rural or remote areas? PMID- 30451708 TI - Quadriceps architecture in individuals with patellofemoral pain: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: are there differences in quadriceps architectural parameters between healthy individuals and those with patellofemoral pain? PMID- 30451709 TI - Fatigue and the measurement of fatigue: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objectives of this review are to identify and present definitions of fatigue and theoretical, conceptual and mechanistic models of fatigue, and to identify the commonly used instruments that measure fatigue in humans and the settings in which they are used.Specifically, the review questions are. PMID- 30451711 TI - Experiences of adults participating in infertility support groups: a qualitative systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what are the experiences of adults participating in infertility treatment support groups? PMID- 30451710 TI - Development, prescription and adherence to exercise programs in the management of people with hand osteoarthritis: a scoping review protocol. AB - REVIEW QUESTIONS: The review questions for this scoping review are. PMID- 30451712 TI - Frameworks for evaluation of community health centers' services and outcomes: a scoping review protocol. AB - REVIEW OBJECTIVES/QUESTION: The objective of this scoping review is to identify and map the frameworks used to evaluate services and outcomes of community health centers within the broader context of primary health care.The primary question for this scoping review is: what are the frameworks used to evaluate services and outcomes of community health centers?Secondary questions for this review are. PMID- 30451713 TI - Update in the use and evaluation of poly (ADP-ribose) polymerase inhibitors in epithelial ovarian cancer: current and pending clinical research. AB - PURPOSE OF REVIEW: This review will provide an update of recently presented clinical data as well as discuss ongoing trials focused on the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into the treatment paradigm for ovarian cancer. RECENT FINDINGS: As of this publication, PARPi have indications in many parts of the globe as maintenance therapy following response to platinum based chemotherapy in the setting of platinum-sensitive recurrence. In addition, in the United States, two PARPi have indications as monotherapy treatment for recurrent ovarian cancer in patients with a BRCA mutation and at least two prior lines of therapy. Exciting data was published in October 2018, demonstrating an unprecedented benefit to utilization of olaparib following response to front-line platinum-based chemotherapy among patients with a BRCA mutation and this data is expected to expand the indication for olaparib globally. SUMMARY: Ongoing studies will seek to expand the benefit of PARPi beyond the BRCA population in front-line therapy as well as to overcome inherent and acquired resistance to PARPi with studies of novel combinations with antiangiogenesis agents, immune-oncology agents and chemotherapy. These efforts may identify more settings and populations in which PARPi provide clinical benefit. PMID- 30451714 TI - Epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer: what is the preferred first-line therapy? AB - PURPOSE OF REVIEW: Epidermal growth factor receptor (EGFR) mt+ nonsmall cell lung cancer (NSCLC) were the first molecularly described NSCLC with an established 'targeted' therapy inhibiting mutated EGFR [EGFR tyrosine kinase inhibitor (TKI)]. EGFR TKI of first and second generation have led to an unprecedented improvement in objective response rate, progression-free survival (PFS) and overall survival (OS) compared with chemotherapy with a significantly reduced toxicity and improved quality of life. Fast elucidation of the most frequent resistance mechanism against first and second-generation TKI, T790M, led to the approval of the third-generation TKI osimertinib in second line. RECENT FINDINGS: Recently, the FLAURA study showed an impressive PFS benefit and immature OS data for osimertinib against solely first-generation TKI's. Also, the ARCHER study comparing dacomitinib against first-generation TKI showed a PFS and also OS benefit. Two studies combining EGFR TKI and antiangiogenesis showed PFS but no OS benefit. Lately, the combination of TKI and chemotherapy has seen a revival with the NEJ009 study, resulting in an impressive median OS of 55 months. SUMMARY: Therefore, potentially four different therapeutic options are available in first line therapy of EGFR mt+ NSCLC, first, second, third generation, TKI + antiangiogenic agent and TKI + chemotherapy. The purpose of the review is to help to guide physicians to decide in their treatment choice and discuss potential directions of research. PMID- 30451715 TI - Suicide Decapitation by a Detonating Cord: A Case Report. AB - In the field of forensic pathology, suicides consist of a considerable portion of the workload. Among the many methods used to commit suicide, using a detonation cord explosive is quite unique. We report the case of a man who committed suicide by detonation cord resulting in decapitation. This case report highlights the fact that the injury patterns observed in explosion-related deaths can be highly variable and that in cases with isolated injuries postmortem imaging and histology are an important adjunct to the standard death investigation. The ultimate goal of explosion-related investigations should be geared toward a well documented and complete postmortem examination with the appropriate use of ancillary studies that provide a clear interpretation of the mechanism, cause, and manner of death. PMID- 30451716 TI - Transitioning to E-Prescribing: Preformatted Prescription Forms Improve Safety, Formulary Compliance, Prescribing Satisfaction, and Perceived Efficiency. AB - OBJECTIVES: Compared with blank prescriptions, electronic prescribing (e prescribing) is safer and more formulary-compliant, satisfying, and efficient. Owing to cost, fewer publicly funded organizations use e-prescribing but may afford preformatted prescription forms. We investigated whether preformatted prescription forms confer similar benefits as e-prescribing. METHODS: Two preformatted prescription forms containing medications' name, strength, dose, route, frequency, number of refills, and restrictions were released in an adult medicine clinic, which previously used blank forms. Pharmacy data were evaluated for changes in prescribing safety and formulary compliance. Surveys assessed changes in prescribing satisfaction and perceived efficiency. RESULTS: Preformatted prescription forms yielded safer, more formulary-compliant prescribing than blank forms. Among medications preformatted on forms, a smaller percentage of pharmacy interventions were for prescribing errors compared with the same medications prescribed previously using blank forms (54% vs. 31%, P = 0.014). Among medications preformatted on forms, a smaller percentage of pharmacy interventions were for formulary noncompliance compared with the same medications prescribed previously using blank forms (21% vs. 4%, P = 0.002).Nearly all respondents felt preformatted forms helped with legibility and choosing the correct dose and proper strength. Fifty percent of respondents indicated the forms improved medication selection.Preformatted forms were perceived as more satisfying and efficient. Ninety-three percent of respondents stated they would use the forms on their next patient. CONCLUSIONS: Preformatted prescription forms achieved the major objectives of e-prescribing: safer, more formulary-compliant, satisfying, and efficient prescribing. They can serve as a transitional phase to e-prescribing for resource-constrained organizations such as publicly funded clinics. PMID- 30451717 TI - Patient Safety: An Important yet Neglected Issue in Nursing Education: Erratum. PMID- 30451718 TI - Patient Experiences With Handling of Analgesic Transdermal Patches and Challenges in Correct Drug Administration: A Pilot Study on Patient Education. AB - BACKGROUND: Although problems during transdermal patch administration are primarily caused by insufficient knowledge, patient education programs are lacking. We compared patient education by a clinical pharmacist on knowledge on correct patch administration with routine counseling during patient-physician consultation in a pilot study. METHODS: After baseline assessment of knowledge and difficulties with patch administration, patients in the outpatient pain clinic of Heidelberg University Hospital were allocated to intervention (n = 12) or control group (n = 11). In both groups, identical information leaflets on transdermal patch use were dispensed. Intervention patients additionally received verbal counseling on correct patch administration by a clinical pharmacist. After 4 weeks, patients were called for a follow-up assessment on knowledge and perspective on administration difficulties. RESULTS: Patients reported several difficulties with transdermal patch administration, such as local skin reaction, difficulties with opening the packaging, and poor adhesion. Although patient education increased the ratio of correct answers in the intervention group twice as much than in the control group, overall knowledge was comparable between groups after education (P = 0.602). CONCLUSIONS: Patients encountered numerous problems with transdermal patch administration although on long-term use. Patient education can improve knowledge on correct patch administration. However, the pilot study demonstrated the need for further efforts to improve ease of use of transdermal patch, such as patch adhesion. PMID- 30451719 TI - Neutropenia in Barth syndrome: characteristics, risks, and management. AB - PURPOSE OF REVIEW: Barth syndrome (BTHS) is an X-linked disease characterized by defective remodeling of phospholipid side chains in mitochondrial membranes. Major features include neutropenia, dilated cardiomyopathy, motor delay and proximal myopathy, feeding problems, and constitutional growth delay. We conducted this review of neutropenia in BTHS to aid in the diagnosis of this disease, and to improve understanding of both the consequences of neutropenia and the benefits of treatment with granulocyte colony-stimulating factor (G-CSF). RECENT FINDINGS: In 88 patients with BTHS, neutropenia, that is, at least one count below 1.5 * 10/l, was detected in 74 (84%) and 44% had severe chronic neutropenia, with multiple counts below 0.5 * 10/l. The pattern of neutropenia varied between intermittent and unpredictable, chronic and severe, or cyclical with mathematically regular oscillations. Monocytosis, that is, monocytes more than 1.0 * 10/l, was observed at least once in 64 of 85 (75%) patients. G-CSF was administered to 39 of 88 patients (44%). Weekly average G-CSF doses ranged from 0.12 to 10.92 MUg/kg/day (mean 1.16 MUg/kg/day, median 1.16 MUg/kg/day). Antibiotic prophylaxis was additionally employed in 21 of 26 neutropenic patients. Pretreatment bone marrow evaluations predominantly showed reduced myeloid maturation which normalized on G-CSF therapy in seven of 13 examined. Consistent clinical improvement, with reduced signs and symptoms of infections, was observed in response to prophylactic G-CSF +/- prophylactic antibiotics. However, despite G-CSF and antibiotics, one adult patient died with multiple infections related to indwelling medical devices and gastrostomy site infection after 15.5 years on G-CSF and a pediatric patient required gastrostomy removal for recurrent abdominal wall cellulitis. SUMMARY: BTHS should be considered in any men with neutropenia accompanied by any of the characteristic features of this syndrome. Prophylaxis with G-CSF +/- antibiotics prevents serious bacterial infections in the more severe neutropenic patients although infections remain a threat even in patients who are very compliant with therapy, especially in those with indwelling devices. PMID- 30451720 TI - Neutropenia in glycogen storage disease Ib: outcomes for patients treated with granulocyte colony-stimulating factor. AB - PURPOSE OF REVIEW: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6 phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. RECENT FINDINGS: The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0 mcg/kg/day (range 0.01-93.1 mcg/kg/day) for a median of 10.3 years (range 0.01 29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 * 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. SUMMARY: GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain. PMID- 30451722 TI - Editorial: Update in myeloid biology. PMID- 30451721 TI - Cell biology of activated protein C. AB - PURPOSE OF REVIEW: The serine protease activated protein C (aPC) was initially characterized as an endogenous anticoagulant, but in addition conveys anti inflammatory, barrier-protective, and pro cell-survival functions. Its endogenous anticoagulant function hampered the successful and continuous implantation of aPC as a therapeutic agent in septic patients. However, it became increasingly apparent that aPC controls cellular function largely independent of its anticoagulant effects through cell-specific and context-specific receptor complexes and intracellular signaling pathways. The purpose of this review is to outline the mechanisms of aPC-dependent cell signaling and its intracellular molecular targets. RECENT FINDINGS: With the advent of new therapeutic agents either modulating directly and specifically the activity of coagulation proteases or interfering with protease-activated receptor signaling a better understanding not only of the receptor mechanisms but also of the intracellular signaling mechanisms controlled by aPC in a disease-specific and context-specific fashion, is required to tailor new therapeutic approaches based on aPC's anti inflammatory, barrier-protective, and pro cell-survival functions. SUMMARY: This review summarizes recent insights into the intracellular signaling pathways controlled by aPC in a cell-specific and context-specific fashion. We focus on aPC-mediated barrier protection, inhibition of inflammation, and cytoprotecting within this review. PMID- 30451723 TI - Intraluminal Pulmonary Vein Stenosis in Children: A "New" Lesion. AB - Pulmonary vein stenosis (PVS) is a rare disorder that leads to progressive narrowing of the extrapulmonary veins. PVS has been reported in both children and adults and in its worse iteration leads to pulmonary hypertension, right ventricular failure, and death. Multiple etiologies of PVS have been described in children and adults. This review will focus on intraluminal PVS in children. Intraluminal PVS has an estimated incidence ranging from 0.0017% to 0.03%. It is associated with conditions such as prematurity, bronchopulmonary dysplasia, necrotizing enterocolitis, Smith-Lemli-Opitz syndrome, and Down syndrome. Cardiac catheterization and pulmonary vein angiography are the gold standard for diagnosis and anatomic delineation. Other imaging modalities including magnetic resonance imaging, chest tomography, and transesophageal echocardiography are increasingly being used. Mortality of PVS in children is approximately 50%. Predictors of mortality include involvement of >=3 pulmonary veins, bilateral pulmonary vein involvement, onset of PVS in infancy, elevated pulmonary artery pressure or systolic pulmonary artery-to-aortic pressure ratio, right ventricular dysfunction, restenosis after surgery, distal/upstream disease, and disease progression to previously uninvolved pulmonary veins. Treatment includes catheter based pulmonary vein dilations with or without stenting, surgical interventions, medical therapy, and in some instances, lung transplantation. Cardiac catheterization for PVS involves a comprehensive hemodynamic and anatomic assessment of the pulmonary veins as well as therapeutic transcatheter interventions. Several surgical strategies have been used. Sutureless repair is currently most commonly used, but patch venoplasty, endarterectomy, ostial resection, and reimplantation are used in select circumstances as well. Medical therapies such as imatinib mesylate and bevacizumab are increasingly being used in an effort to suppress the myofibroblastic proliferation seen in PVS patients. Lung transplantation has been used as an alternative treatment strategy for end stage, refractory PVS. Nonetheless, despite the different innovative approaches used, morbidity and mortality remain high. At present, the preferred treatment strategy is frequent reassessment of disease progression to guide use of catheter based and surgical interventions in conjunction with medical therapy. PMID- 30451724 TI - Comment on "Race/Ethnicity and Sex Both Affect Opioid Administration in the Emergency Room". PMID- 30451725 TI - Systematic Review of the Efficacy and Safety of Gabapentin and Pregabalin for Pain in Children and Adolescents. AB - The barriers to opioid use in some countries necessitate the need to identify suitable alternatives or adjuncts for pain relief. The gabapentinoids (gabapentin and pregabalin) are approved for the management of persistent pain in adults, but not in children. Searches were conducted in Embase, Medline, Scopus, and Web of Science up until November 2017, for randomized controlled trials that investigated the analgesic effects of gabapentin or pregabalin in children and adolescents <18 years of age. A total of 7 publications were identified, 5 regarding gabapentin as prophylactic postsurgical pain relief for either adenotonsillectomy (n = 3) or scoliosis surgery (n = 2), and 1 for gabapentin treatment of chronic regional pain syndrome/neuropathic pain. One study investigated the efficacy of pregabalin as a treatment for fibromyalgia. Based on the studies' primary outcomes alone, neither of the chronic pain studies involving gabapentin and pregabalin showed significant efficacy compared with amitriptyline or placebo, respectively. Two of the prophylactic gabapentin studies for adenotonsillectomy and idiopathic scoliosis surgery reported significantly fewer children requiring analgesia and lower opioid requirement, respectively, compared with placebo. Two of the identified clinical trials (conducted by the same first author) on the efficacy of gabapentin for prophylactic postadenotonsillectomy pain relief were omitted from narrative synthesis due to clear evidence of fabricated data. Overall, this review identified a paucity of evidence for the analgesic effect and safety of gabapentinoids in children. We also suggest audit of any current evidence-based practice and clinical guidelines that have cited the research studies with fabricated data. PMID- 30451726 TI - Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats. AB - BACKGROUND: Glycocalyx shedding after traumatic hemorrhagic or septic shock, as well as different resuscitation fluids, has been causally linked to increased vascular barrier permeability (VBP) resulting in tissue edema. In nontraumatic hemorrhagic shock (NTHS), it remains questionable whether glycocalyx degradation in itself results in an alteration of VBP. The composition of fluids can also have a modulatory effect on glycocalyx shedding and VBP. We hypothesized that the shedding of the glycocalyx during NTHS has little effect on VBP and that the composition of fluids can modulate these effects. METHODS: Fully instrumented Wistar-albino rats were subjected to a pressure-controlled NTHS (mean arterial pressure of 30 mm Hg) for 60 minutes. Animals were fluid resuscitated with Ringer's acetate, balanced hydroxyethyl starch (HES) solution, or 0.9% normal saline to a mean arterial pressure of 80 mm Hg and compared with shams or nonresuscitated NTHS. Glycocalyx shed products were determined at baseline and 60 minutes after fluid resuscitation. Skeletal muscle microcirculation was visualized using handheld vital microscopy. VBP changes were assessed using plasma decay of 3 fluorescent dyes (40- and 500-kDa dextran and 70-kDa albumin), Evans blue dye exclusion, intravital fluorescence microscopy, and determination of tissue edema (wet/dry weight ratio). RESULTS: All glycocalyx shedding products were upgraded as a result of NTHS. Syndecan-1 significantly increased in NTHS (mean difference, -1668; 95% confidence interval [CI], -2336 to -1001; P < .0001), balanced crystalloid (mean difference, -964.2; 95% CI, -1492 to -436.4; P = .0001), and HES (mean difference, -1030; 95% CI, -1594 to -465.8; P = .0001) groups at the end of the experiment compared to baseline. Hyaluronan levels were higher at the end of the experiment in nonresuscitated NTHS (-923.1; 95% CI, 1216 to -630; P = .0001) and balanced crystalloid (-1039; 95% CI, -1332 to 745.5; P = .0001) or HES (-394.2; 95% CI, -670.1 to -118.3; P = .0027) groups compared to controls. Glycocalyx shedding resulted in microcirculation alterations as observed by handheld video microscopy. Total vessel density was altered in the normal saline (mean difference, 4.092; 95% CI, 0.6195-7.564; P = .016) and hemorrhagic shock (mean difference, 5.022; 95% CI, 1.55-8.495; P = .0024) groups compared to the control group, as well as the perfused vessel density and mean flow index. Despite degradation of endothelial glycocalyx, VBP as determined by 4 independent assays remained intact and continued to be so following fluid resuscitation. CONCLUSIONS: NTHS induced glycocalyx shedding and microcirculation alterations, without altering VBP. Fluid resuscitation partially restored the microcirculation without altering VBP. These results challenge the concept that the glycocalyx barrier is a significant contributor to VBP. PMID- 30451727 TI - In Response. PMID- 30451728 TI - Progressive Increase in Scholarly Productivity of New American Board of Anesthesiology Diplomates From 2006 to 2016: A Bibliometric Analysis. AB - BACKGROUND: Improving research productivity is a common goal in academic anesthesiology. Initiatives to enhance scholarly productivity in anesthesiology were proposed more than a decade ago as a result of emphasis on clinical work. We hypothesized that American Board of Anesthesiology diplomates certified from 2006 to 2016 would be progressively more likely to have published at least once during this time period. METHODS: A complete list of 17,332 new diplomates was obtained from the American Board of Anesthesiology for the years 2006 to 2016. These names were queried using PubMed, and the number of publications up to and including the diplomate's year of primary certification was recorded. Descriptive statistics and logistic regression analysis were used to analyze the association of the year of primary certification and whether a diplomate had published at least once. RESULTS: The percentage of American Board of Anesthesiology diplomates with >=1 publication at the time of primary certification increased from 14.9% to 29.3% from 2006 to 2016. The mean number of publications per diplomate more than doubled from 0.31 to 0.79. Logistic regression analysis revealed the year of primary certification as significantly associated with having >=1 publication (P < .001). Using 2006 as the reference year, odds of having published at least once were higher in the years 2010 to 2016, with the highest odds ratio of having a article published occurring in 2016: 2.359 (confidence interval, 1.978-2.812; P < .001). CONCLUSIONS: Publications by new diplomates of the American Board of Anesthesiology have increased between 2006 and 2016. Whether the observed increase in publications could reflect efforts to stimulate interest in academic objectives during training remains to be proven. PMID- 30451729 TI - Editorial: Improvements in cataract surgery planning, technique, and outcomes. PMID- 30451730 TI - Accelerated Hypofractionated Radiation Therapy for Elderly Frail Bladder Cancer Patients Unfit for Surgery or Chemotherapy. AB - PURPOSE/OBJECTIVES: The main purpose of this study was to report treatment outcomes of definitive image-guided accelerated hypofractionated radiation therapy for elderly patients with muscle-invasive bladder cancer unsuitable for surgery or trimodality therapy. MATERIALS AND METHODS: Patients with confirmed muscle-invasive or high-risk T1 transitional cell carcinoma of the bladder, stage T1-T4aN0M0, who underwent transurethral resection of bladder tumor were irradiated with 45 Gy in 15 fractions. Comorbidity was assessed by Charlson Comorbidity Index. Cystoscopy, cytology, and computerised tomography imaging were used to evaluate treatment outcomes. RESULTS: Seventeen patients with a median age of 87 (range, 81 to 95) years and age-adjusted Charlson Comorbidity Index >=3 were included. Transurethral resection of bladder tumor was incomplete in 65%. Radiation technique evolved from 3-dimensional conformal radiotherapy (3D CRT, 47%) to volumetric modulated arc therapy (VMAT, 53%). Ninety-four percent completed radiotherapy, with a median time of 20 days. The median follow-up was 65.3 months. Complete local response at 3-month cystoscopy was 69%. Six patients developed a local recurrence (35%), and 2 patients developed distant metastases (11.7%). Overall survival at 1 year was 47% and 23% at 2 years. Cancer-specific survival at 1 and 2 years were 85% and 63%, respectively. Acute grade 3 gastrointestinal or genitourinary toxicities were 6% and 24%, respectively. No grade 4 toxicity was documented. Diarrhea of any grade occurred in 35% of patients treated with 3D CRT, but in none of the patients treated with VMAT (P=0.002). CONCLUSIONS: Accelerated hypofractionated radiotherapy alone provides good local control in elderly patients unfit for chemoradiotherapy. Contemporary radiation techniques such as VMAT were associated with reduced bowel toxicity compared with 3D CRT. PMID- 30451731 TI - SMARCA4-deficient Thoracic Sarcomas: Clinicopathologic Study of 30 Cases With an Emphasis on Their Nosology and Differential Diagnoses. AB - SMARCA4-deficient thoracic sarcoma (SMARCA4-DTS) is a recently described entity with an aggressive clinical course and specific genetic alterations of the BAF chromatin remodeling complex. In the present study, we reviewed the clinical and pathologic features of 30 cases of SMARCA4-DTS, discussed its main differential diagnoses and the challenging diagnostic scenarios that the average pathologist may face. In addition, we tested the specificity of the "SMARCA4-DTS immunohistochemical signature" (co-loss of SMARCA4 and SMARCA2 with overexpression of SOX2) in a large cohort of intrathoracic malignancies. Patients ranged from 28 to 90 years of age (median: 48 y), with a marked male predominance (male:female=9:1) and they were usually smokers. Tumors were generally large compressive masses located in the mediastinum (n=13), pleura (n=5), lung (n=2) or in 2 or more of these topographies (n=10). Treatment strategies were varied, including 1 case treated with EZH2 inhibitors. Median overall survival was 6 months. Histologically, tumors were poorly differentiated frequently showing rhabdoid features. A subset of cases showed a focal myxoid stroma (7%, n=2/30) and rare cases displayed a previously unreported pattern simulating desmoplastic small round cell tumors (7%, n=2/30). Making a diagnosis was challenging when dealing with biopsy material from massively necrotic tumors and in this setting the expression of SOX2, CD34, and SALL4 proved useful. All tested cases displayed concomitant loss of SMARCA4 and SMARCA2 and most tumors expressed epithelial markers (Pan-keratin or EMA) (n=29/30), SOX2 (n=26/27), and CD34 (n=17/27). SMARCB1 expression was retained in all cases (23/23). SALL4 and Claudin-4 were expressed in a subset of cases (n=7/21 and 2/19, respectively). TTF-1 and P63 were focally expressed in 1 case each. P40 and NUT were not expressed (0/23 and 0/20, respectively) The SMARCA4-DTS immunohistochemical signature was both sensitive and specific, with only a subset of small cell carcinoma of the ovary hypercalcemic type showing overlapping phenotypes. Our study confirms and expands the specific features of SMARCA4-DTS, emphasizing the fact that they can be straightforwardly identified by pathologists. PMID- 30451732 TI - Molecular Profiling of Pheochromocytoma and Abdominal Paraganglioma Stratified by the PASS Algorithm Reveals Chromogranin B as Associated With Histologic Prediction of Malignant Behavior. AB - Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGL, are believed to exhibit malignant potential-but only subsets of cases will display full-blown malignant properties. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) algorithm is a proposed histologic system to detect potential for aggressive behavior, but little is known regarding the coupling to underlying molecular genetics. In this study, a total of 92 PPGLs, previously characterized for susceptibility gene status and mRNA expressional profiles, were histologically assessed using the PASS criteria. A total of 32/92 PPGLs (35%) exhibited a PASS score >=4, including all 8 cases with malignant behavior (7 with known metastases and 1 with extensively infiltrative local recurrence). Statistical analyzes between expressional data and clinical parameters as well as individual PASS criteria yielded significant associations to Chromogranin B (CHGB), BRCA2, HIST1H3B, BUB1B, and RET to name a few, and CHGB had the strongest correlation to both PASS and metastasis/local recurrence of all analyzed genes. Evident CHGB downregulation was observed in PPGLs with high PASS and overtly malignant behavior, and was also associated with shorter disease related survival. This finding was validated using quantitative real-time polymerase chain reaction, in which CHGB expression correlated with both PASS and metastasis/local recurrence with consistent findings obtained in the TCGA cohort. Moreover, immunohistochemical analyses of subsets of tumors showed a correlation between high PASS scores and negative or weak CHGB protein expression. Patients with PPGLs obtaining high PASS scores postoperatively, also exhibited low preoperative plasma levels of CHGB. These data collectively point out CHGB as a possible preoperative and postoperative marker for PPGLs with potential for aggressive behavior. PMID- 30451733 TI - Morphologic Overlap Between Inflammatory Myofibroblastic Tumor and IgG4-related Disease: Lessons From Next-generation Sequencing. AB - Inflammatory myofibroblastic tumor (IMT), a locally aggressive neoplasm capable of metastasis, may show an immunoglobulin (Ig)G4-rich lymphoplasmacytic infiltrate. Prior reports suggest that storiform-fibrosis and obliterative phlebitis aid in the distinction of IMT from IgG4-related diseases. Herein, we highlight the morphologic overlap between the 2 diseases, and emphasize the importance of a multiplex fusion assay in the distinction of IgG4-related disease (IgG4-RD) from IMT. We identified 7 IMTs with morphologic and immunohistochemical features of IgG4-RD; 3 patients were originally diagnosed with IgG4-RD. Demographic, clinical and morphologic data was recorded. We also reevaluated 56 patients with IgG4-RD. We performed immunohistochemistry for IgG4, IgG, ALK, and ROS1. In situ hybridization for IgG4 and IgG was performed in selected cases. A multiplex next-generation sequencing-based RNA assay for gene fusions was performed to detect all known IMT-related gene fusions. All 7 IMTs showed a dense lymphoplasmacytic infiltrate and storiform-type fibrosis, with obliterative phlebitis noted in 3 cases. The neoplastic stromal cells constituted <5% of overall cellularity and stromal atypia was either absent or focal and mild. Elevated numbers of IgG4 positive cells and increased IgG4 to IgG ratio was identified in all cases. Four cases showed ALK related abnormalities: 3 fusions and one alternative transcription initiation; while 2 patients showed ROS1 and NTRK3 fusions. One tumor was negative for known IMT-related gene fusions. All 56 IgG4-RD cases were negative for ALK and ROS1 on immunohistochemistry; 6 cases were negative on the fusion assay. Highly inflamed IMTs are indistinguishable from IgG4-RD both histologically and on immunohistochemistry for IgG4. We advocate scrutinizing patients with presumptive single organ IgG4-RD for IMT and the diagnostic algorithm should include ALK and ROS1 immunohistochemistry and, in selected cases, a next-generation sequencing-based fusion assay that covers known IMT-associated gene fusions. PMID- 30451734 TI - Fluid management and bioimpedance study in peritoneal dialysis. AB - PURPOSE OF REVIEW: Maintaining euvolaemia is an essential yet challenging objective in management of patients on peritoneal dialysis. Optimal method to assess volume status remains to be determined. In this review, we will discuss the risk factors and clinical outcomes of fluid overload in PD patients, and examine the role of bioimpedance study in fluid management. RECENT FINDINGS: Applying bioimpedance study to measure body composition has attracted increasing attention because it is noninvasive and provides point-of-care assessment of fluid status. Observational studies suggested that presence of residual renal function did not necessarily protect peritoneal dialysis patients from developing fluid overload. This reinforces the importance of fluid restriction in peritoneal dialysis patients, in whom the thirst sensation could be exacerbated by hyperglycaemia. Notably, fluid overload is present in significant portion of asymptomatic patients. Moreover, bioimpedance-defined fluid overload is associated with increase in all-cause mortality, technique failure and possibly excess peritonitis rate. SUMMARY: Although future studies should investigate the clinical benefit of bioimpedance-guided fluid management in high-risk subgroup, raising awareness among clinicians, together with structured clinical assessment and dietary counselling are the cornerstone to maintain stable fluid status. PMID- 30451735 TI - Unmet challenges in membranous nephropathy. AB - PURPOSE OF REVIEW: Despite major advances in since the discovery of the phospholipase A2 receptor (PLA2R) as the major autoantigen on podocytes in primary membranous nephropathy, there are still several unanswered questions as highlighted here. RECENT FINDINGS: A substantial body of literature, included in more than 680 articles since 2009, has documented genetic susceptibility to primary membranous nephropathy involving PLA2R1 and class II MHC alleles, the clinical value of anti-PLA2R assays, the significance of epitope spreading of the anti-PLA2R response, discovery of thrombospondin type I domain-containing 7A (THSD7A) as a minor antigen in primary membranous nephropathy, and the ability to transfer disease into mice by infusion of anti-THSD7A sera. However, the normal physiology and pathophysiology of PLA2R and THSD7A in podocytes is still unknown and the genetic influence on disease susceptibility is unexplained. We still do not know what causes loss of self-tolerance to PLA2R and THSD7A or how the autoantibodies, which are predominantly of the IgG4 subclass, cause podocyte injury and proteinuria. Complement deposits are prominent in membranous nephropathy but we are still uncertain how the complement system is activated and whether or not it plays a role in podocyte damage. Notwithstanding the advances over the past decade, our treatments have not changed substantially. SUMMARY: This review identifies opportunities to extend the advances that have been made to better understand the immunopathogenesis and genetic basis of primary membranous nephropathy and apply the knowledge to design more specific therapies. PMID- 30451737 TI - Genes and environment in chronic kidney disease hotspots. AB - PURPOSE OF REVIEW: Chronic kidney disease (CKD) can cluster in geographic locations or in people of particular genetic ancestries. We explore APOL1 nephropathy and Balkan nephropathy as examples of CKD clustering that illustrate genetics and environment conspiring to cause high rates of kidney disease. Unexplained hotspots of kidney disease in Asia and Central America are then considered from the perspective of potential gene * environment interactions. RECENT FINDINGS: We report on evidence supporting both genes and environment in these CKD hotspots. Differing genetic susceptibility between populations and within populations may explain why causal environmental risk factors have been so hard to identify conclusively. Similarly, one cannot explain why these epidemics of kidney disease are happening now without invoking environmental changes. SUMMARY: Approaches to these CKD hotspots are of necessity becoming more holistic. Genetic studies may help us identify the environmental triggers by teaching us about disease biology and may empower environmental risk factor studies by allowing for stratification of study participants by genetic susceptibility. PMID- 30451738 TI - Donor Urinary C5a Levels Independently Correlate With Posttransplant Delayed Graft Function. AB - BACKGROUND: Accumulating evidence implicates the complement cascade as pathogenically contributing to ischemia-reperfusion injury and delayed graft function (DGF) in human kidney transplant recipients. Building upon observations that kidney injury can initiate in the donor before nephrectomy, we tested the hypothesis that anaphylatoxins C3a and C5a in donor urine prior to transplantation associate with risk of post-transplant injury. METHODS: We evaluated the effects of C3a and C5a in donor urine on outcomes of 469 deceased donors and their corresponding 902 kidney recipients in a subset of a prospective cohort study. RESULTS: We found a 3-fold increase of urinary C5a concentrations in donors with stage 2 and 3 AKI compared donors without AKI (p<0.001). Donor C5a was higher for the recipients with DGF (defined as dialysis in the first week post-transplant) compared to non-DGF (p=0.002). In adjusted analyses, C5a remained independently associated with recipient DGF for donors without AKI (RR 1.31; 95% CI, 1.13-1.54). For donors with AKI, however, urinary C5a was not associated with DGF. We observed a trend toward better 12-month allograft function for kidneys from donors with C5a concentrations in the lowest tertile (p=0.09). Urinary C3a was not associated with donor AKI, recipient DGF, or 12 month allograft function. CONCLUSIONS: Urinary C5a correlates with the degree of donor AKI. In the absence of clinical donor AKI, donor urinary C5a concentrations associate with recipient DGF, providing a foundation for testing interventions aimed at preventing DGF within this high-risk patient subgroup. PMID- 30451736 TI - Fibroblast growth factor 23 and alpha-Klotho co-dependent and independent functions. AB - PURPOSE OF REVIEW: The current review examines what is known about the FGF 23/alpha-Klotho co-dependent and independent pathophysiological effects, and whether FGF-23 and/or alpha-Klotho are potential therapeutic targets. RECENT FINDINGS: FGF-23 is a hormone derived mainly from bone, and alpha-Klotho is a transmembrane protein. Together they form a trimeric signaling complex with FGFRs in target tissues to mediate the physiological functions of FGF-23. Local and systemic factors control FGF-23 release from osteoblast/osteocytes in bone, and circulating FGF-23 activates FGFR/alpha-Klotho complexes in kidney proximal and distal renal tubules to regulate renal phosphate excretion, 1,25 (OH)2D metabolism, sodium and calcium reabsorption, and ACE2 and alpha-Klotho expression. The resulting bone-renal-cardiac-immune networks provide a new understanding of bone and mineral homeostasis, as well as identify other biological effects FGF-23. Direct FGF-23 activation of FGFRs in the absence of alpha-Klotho is proposed to mediate cardiotoxic and adverse innate immune effects of excess FGF-23, particularly in chronic kidney disease, but this FGF-23, alpha Klotho-independent signaling is controversial. In addition, circulating soluble Klotho (sKl) released from the distal tubule by ectodomain shedding is proposed to have beneficial health effects independent of FGF-23. SUMMARY: Separation of FGF-23 and alpha-Klotho independent functions has been difficult in mammalian systems and understanding FGF-23/alpha-Klotho co-dependent and independent effects are incomplete. Antagonism of FGF-23 is important in treatment of hypophosphatemic disorders caused by excess FGF-23, but its role in chronic kidney disease is uncertain. Administration of recombinant sKl is an unproven therapeutic strategy that theoretically could improve the healt span and lifespan of patients with alpha-Klotho deficiency. PMID- 30451740 TI - Societal and Professional Obligation in the Care of the Living Organ Donor. PMID- 30451739 TI - Future Trends in Demand for Liver Transplant: Birth-Cohort Effects among Patients with NASH and HCC. AB - BACKGROUND: With increasing U.S. adiposity, NASH is now a leading liver transplant (LT) indication. Given its association with hepatocellular carcinoma (HCC), the burden of NASH is substantial. We analyzed birth-cohort effects among NASH LT registrants, with and without HCC. METHODS: All new LT registrants in UNOS (1995-2015) were identified. Birth-cohorts were: 1936-1940, 1941-1945, 1946 1950, 1951-1955, 1956-1960, 1961-1965, 1966-1970, 1971-2015. Poisson regression examined trends in LT registration, by disease etiology (NASH, HCV, OTHER), and HCC. RESULTS: We identified 182,368 LT registrants with median age 52 years (range 0-86). Nine-percent (n=16,160) had NASH, 38% (n=69,004) HCV, 53% (n=97,204) OTHER. HCC was present in: 13% (n=2,181), 27% (n=18,295), and 11% (n=10,902), of NASH, HCV, and OTHER, respectively. LT registration for HCC increased significantly from 2002-2015 across all etiologies (NASH 6%?18%; HCV 19%?51%; OTHER 9%?16%, p<0.0001 for all). NASH LT registrations, with and without HCC, increased sharply in patients born from 1945-2015. This upward NASH trend is in stark contrast to HCV LT registrations, which showed a general decline. Notably, a sharp rise in LT registrations is among younger NASH patients (35-55 years), mirroring the increasing adiposity across all age groups in the U.S. POPULATION: CONCLUSIONS: NASH LT registrants, with and without HCC, increased over time, and are projected to increase unabated in the future, notably among younger birth-cohorts ("Adipose Wave Effect"). HCC LT registration patterns demonstrate that, compared to HCV, NASH patients encompass younger birth-cohorts. These data illustrate that the full impact of NASH on demand for LT is yet to be realized. PMID- 30451741 TI - mTOR Inhibitor Everolimus in Regulatory T cell Expansion for Clinical Application in Transplantation. AB - BACKGROUND: Experimental and pre-clinical evidence suggest that adoptive transfer of regulatory T cells (Tregs) could be an appropriate therapeutic strategy to induce tolerance and improve graft survival in transplanted patients. The University of Kentucky Transplant Service Line is developing a novel Phase I/II clinical trial with ex vivo expanded autologous Tregs as an adoptive cellular therapy in renal transplant recipients who are using everolimus (EVR)-based immunosuppressive regimen. METHODS: The aim of this study was to determine the mechanisms of action and efficacy of EVR for the development of functionally competent Treg cell-based adoptive immunotherapy in transplantation to integrate a common EVR-based regimen in vivo (in the patient) and ex vivo (in the expansion of autologous Treg cells). CD25 Treg cells were selected from leukapheresis product with a GMP-compliant cell separation system and placed in 5-day (short) or 21-day (long) culture with EVR or rapamycin (RAPA). Multi-parametric flow cytometry analyses were used to monitor the expansion rates, phenotype, autophagic flux and suppressor function of the cells. PI3K/AKT/mTOR signaling pathway profiles of treated cells were analyzed by western blot and cell bioenergetic parameters by extracellular flux analysis. RESULTS: EVR-treated cells showed temporary slower growth, lower metabolic rates, and reduced phosphorylation of AKT compared to RAPA-treated cells. In spite of these differences, the expansion rates, phenotype, and suppressor function of long-term Treg cells in culture with EVR were similar to those with RAPA. CONCLUSIONS: Our results support the feasibility of EVR to expand functionally competent Treg cells for their clinical use. PMID- 30451742 TI - Reevaluation of the Kidney Donor Risk Index (KDRI). AB - BACKGROUND: The Kidney Donor Risk Index (KDRI) is a score applicable to deceased kidney donors which reflects relative graft failure risk associated with deceased donor characteristics. The KDRI is widely used in kidney transplant outcomes research. Moreover, an abbreviated version of KDRI is the basis, for allocation purposes, of the "top 20%" designation for deceased donor kidneys. Data upon which the KDRI model was based used kidney transplants performed between 1995 and 2005. Our purpose in this report was to evaluate the need to update the coefficients in the KDRI formula, with the objective of either (a) proposing new coefficients or (b) endorsing continued used of the existing formula. METHODS: Using data obtained from the Scientific Registry of Transplant Recipients (SRTR), we analyzed n=156,069 deceased donor adult kidney transplants occurring from 2000 to 2016. Cox regression was used to model the risk of graft failure. We then tested for differences between the original and updated regression coefficients, and compared the performance of the original and updated KDRI formulas with respect to discrimination and predictive accuracy. RESULTS: In testing for equality between the original and updated KDRIs, few coefficients were significantly different. Moreover, the original and updated KDRI yielded very similar risk discrimination and predictive accuracy. CONCLUSIONS: Overall, our results indicate that the original KDRI is robust and is not meaningfully improved by an update derived through modeling analogous to that originally employed. PMID- 30451743 TI - Female Representation and Implicit Gender Bias at the 2017 American Society of Colon and Rectal Surgeons Annual Scientific and Tripartite Meeting. AB - BACKGROUND: Women surgeons are underrepresented in academic surgery and may be subject to implicit gender bias. In colorectal surgery, women comprise 42% of new graduates, but only 19% of Diplomates in the United States. OBJECTIVE: We evaluated the representation of women at the 2017 American Society of Colon and Rectal Surgeons Scientific and Tripartite Meeting and assessed for implicit gender bias. DESIGN: This was a prospective observational study. SETTING: The study occurred at the 2017 Tripartite Meeting. MAIN OUTCOME MEASURES: The primary outcome measured was the percentage of women in the formal program relative to conference attendees and forms of address. METHODS: Female program representation was quantified by role (moderator or speaker), session type, and topic. Introductions of speakers by moderators were classified as formal (using a professional title) or informal (using name only), and further stratified by gender. RESULTS: Of physicians and medical students, 32% (n = 484) of the 1532 attendees were women. Women comprised 28% of moderators (n = 26) and 28% of speakers (n = 80). The highest percentage of women moderators and speakers was in education (48%) and the lowest was in techniques and technology (17%). In the 41 of 47 sessions evaluated, female moderators were more likely than male moderators to use formal introductions (68.7% vs 54.0%, p = 0.02). There was no difference when female moderators formally introduced female versus male speakers (73.9% vs 66.7%, p = 0.52); however, male moderators were significantly less likely to formally introduce a female versus male speaker (36.4% vs 59.2%, p = 0.003). LIMITATIONS: Yearly program gender composition may fluctuate. Low numbers in certain areas limit interpretability. Other factors potentially influenced speaker introductions. CONCLUSIONS: Overall, program representation of women was similar to meeting demographics, although with low numbers in some topics. An imbalance in the formality of speaker introductions between genders was observed. Awareness of implicit gender bias may improve gender equity and inclusiveness in our specialty. See Video Abstract at http://links.lww.com/DCR/A802. PMID- 30451744 TI - Robotic Transanal Minimally Invasive Surgery for the Excision of Rectal Neoplasia: Clinical Experience With 58 Consecutive Patients. AB - BACKGROUND: Given the significant perioperative risks and costs of total mesorectal excision, minimally invasive transanal surgical approaches have grown in popularity for early rectal cancer and rectal polyps. This article discusses a transanal robotic surgery technique to perform full-thickness resections of benign and malignant rectal neoplasms. OBJECTIVE: The purpose of this study was to describe an initial experience with robotic transanal minimally invasive surgery. DESIGN: This was a retrospective cohort study of consecutive patients who underwent robotic transanal minimally invasive surgery. SETTINGS: The study was conducted at a high-volume colorectal surgery practice with a large health maintenance organization. PATIENTS: Patients at Southern California Kaiser Permanente with early rectal cancer and rectal polyps amenable to transanal excision were included. INTERVENTIONS: Transanal resection of rectal tumors were removed using robotic transanal minimally invasive surgery. MAIN OUTCOME MEASURES: Local recurrence of rectal pathology was measured. RESULTS: A total of 58 patients underwent robotic transanal minimally invasive surgery with full thickness rectal resection by 4 surgeons for the following indications: rectal cancer (n = 28), rectal polyp (n = 18), rectal carcinoid (n = 11), and rectal GI stromal tumor (n = 1). Mean operative time was 66.2 minutes (range, 17-180 min). The mean tumor height from the anal verge was 8.8 cm (range, 4-14 cm), and the mean specimen size was 3.3 cm (range, 1.3-8.2 cm). A total of 57 (98.3%) of 58 specimens were intact, and 55 (94.8%) of 58 specimens had negative surgical margins. At a mean follow-up of 11.5 months (range, 0.3-33.3 mo), 3 patients (5.5%) developed local recurrences, and all underwent successful salvage surgery. LIMITATIONS: The study was limited by being a retrospective, nonrandomized trial with short follow-up. CONCLUSIONS: Robotic transanal minimally invasive surgery is a safe, oncologically effective surgical approach for rectal polyps and early rectal cancers. It offers the oncologic benefits and perioperative complication profile of other transanal minimally invasive surgical approaches but also enhances surgeon ergonomics and provides an efficient transanal rectal platform. See Video Abstract at http://links.lww.com/DCR/A759. PMID- 30451745 TI - Impact of American Society of Colorectal Surgeons' Research Foundation Grants on Academic Colorectal Surgeons' Career Trajectory. PMID- 30451746 TI - Short- and Long-term Outcomes of Minimally Invasive Versus Open Multivisceral Resection for Locally Advanced Colorectal Cancer. AB - BACKGROUND: Colorectal cancer invading the adjacent organs/structures is detected in 5% to 20% of all surgical interventions performed for the management of colorectal cancer. OBJECTIVE: Our purpose is to verify the safety and feasibility of laparoscopic surgery for the treatment of locally advanced colorectal cancer invading the adjacent organs. DESIGN: This is a retrospective study. SETTINGS: The study was conducted at a single institution in Japan. PATIENTS: We compared the morbidity, appropriate oncological resection, and disease-free survival of laparoscopic and open multivisceral resection in patients with colorectal carcinoma in the period between 2007 and 2015. MAIN OUTCOME MEASURES: The primary outcome measures were curative resection rate, morbidity rate, and recurrence of laparoscopic and open multivisceral resection in patients with colorectal cancer. RESULTS: Thirty-one patients received laparoscopic surgery, and 50 received open surgery. The amount of blood loss was smaller in the laparoscopic group than in the open group (60 vs 595 mL, p < 0.01). Curative surgery was performed in 46 patients of the open group (92.0%) and in 30 patients of the laparoscopic group (96.8%). Days until oral intake (5 vs 7 days, p < 0.01) and postoperative hospital stay (14 vs 19 days, p < 0.01) were shorter in the laparoscopic group. Overall morbidity was not different between the groups (22.5% vs 40.0%). Three year disease-free survival rates were 62.7% in the open group and 56.7% in the laparoscopic group (p = 0.5776). LIMITATION: This study was a retrospective small study conducted at a single institute. CONCLUSION: Laparoscopic multivisceral resection may be a safe, less invasive alternative to open surgery, with less blood loss and shorter hospital stay, and was not inferior to open surgery based on long-term oncological end points. See Video Abstract at http://links.lww.com/DCR/A785. PMID- 30451747 TI - Accuracy of Anal Cytology for Diagnostic of Precursor Lesions of Anal Cancer: Systematic Review and Meta-analysis. AB - BACKGROUND: Anal canal carcinoma is relevant because it commonly occurs in high risk groups, and its incidence has been increasing. OBJECTIVE: This study evaluated the accuracy of anal cytology in the screening of precursor lesions of anal cancer, compared with histopathologic examination as the reference, in all subjects and in men who have sex with men, HIV-infected men and women, and men who have sex with men and HIV-infected subgroups. DATA SOURCES: The data included studies identified in the MEDLINE, Latin American and Caribbean Health Sciences, Cochrane Library, and Embase electronic databases, as well as in the grey literature. The search terms included anal cancer, anal dysplasia, anal intraepithelial neoplasia, screening, and anal cytology. STUDY SELECTION: After excluding studies with no histopathological data and those with duplicate and missing data, 34 primary studies were included. INTERVENTION: Cytology of anal smears was studied. MAIN OUTCOME MEASURES: Sensitivity, specificity, diagnostic OR, and area under the curve were measured. RESULTS: A total of 5093 patients were included. The pooled sensitivity of anal cytology was 85.0% (95% CI, 82.0% 87.0%) and pooled specificity was 43.2% (95% CI, 41.4%-45.1%) for the detection of anal intraepithelial neoplasia grade 2 or worse versus anal intraepithelial neoplasia grade 1 and normal when measuring all subjects. The accuracy of anal cytology was higher in the men who have sex with men and HIV-infected and men who have sex with men only subgroups. LIMITATIONS: This study was limited by its specificity. CONCLUSIONS: The study results support the hypothesis that cytology is a good test for the screening of anal cancer. PMID- 30451748 TI - C-Reactive Protein Values After Colorectal Resection: Can We Discharge a Patient With a C-Reactive Protein Value >100? A Retrospective Cohort Study. AB - BACKGROUND: C-reactive protein is a useful negative predictive test for the development of anastomotic leakage following colorectal surgery. Evolution of procedures (laparoscopy, enhanced recovery program, early discharge, complex redo surgery) may influence C-reactive protein values; however, this is poorly studied to date. OBJECTIVE: The aim of this study is to evaluate C-reactive protein as an indicator of postoperative complication and as a predictor for discharge. DESIGN: This is retrospective study of a consecutive monocentric cohort. SETTINGS: All patients undergoing a colorectal resection with anastomosis (2014-2015) were included. MAIN OUTCOMES MEASURES: C-reactive protein, leukocytosis, type of resection, and postoperative course were the primary outcomes measured. RESULTS: A total of 522 patients were included. The majority had either a colorectal (n = 159, 31%) or coloanal anastomosis (n = 150, 29%). Overall morbidity was 29.3%. C reactive protein was significantly higher among patient having intra-abdominal complications at an early stage (day 1-2) (164.6 vs 136.2; p = 0.0028) and late stage (day 3-4) (209.4 vs 132.1; p < 0.0001). In multivariate analysis, early C reactive protein was associated with BMI (coefficient, 4.9; 95% CI, 3.2-6.5; p < 0.0001) and open surgical procedures (coefficient, 43.1; 95% CI, 27-59.1; p < 0.0001), while late C-reactive protein value was influenced by BMI (coefficient, 4.8; 95% CI, 2.5-7.0; p = 0.0024) and associated extracolonic procedures (coefficient, 34.2; 95% CI, 2.7-65.6; p = 0.033). Sensitivity, specificity, negative predictive values, and positive predictive values for intra-abdominal complication were 85.9%, 33.6%, 89.3%, and 27.1% for an early C-reactive protein <100 mg/L and 72.7%, 75.4%, 89.4%, and 49.2% for a late C-reactive protein <100 mg/L. Four hundred seven patients with an uneventful postoperative course were discharged at day 8 +/- 6.4 with a mean discharge C-reactive protein of 83.5 +/- 67.4. Thirty-eight patients (9.3%) were readmitted and had a significantly higher discharge C-reactive protein (138.6 +/- 94.1 vs 77.8 +/- 61.2, p = 0.0004). Readmission rate was 16.5% for patients with a discharge C-reactive protein >100 mg/L vs 6% with C-reactive protein <100 mg/L (p = 0.0008). For patients included in an enhanced recovery program (discharge at day 4 +/- 2.4), the threshold should be higher because discharge is around day 3 or 4. With a C-reactive protein <140, readmission rate was 2% vs 19%, (p = 0.056). LIMITATIONS: This study includes retrospective data. CONCLUSION: C-reactive protein <100 mg/L is associated with a lower risk of intra-abdominal complication and readmission rates. See Video Abstract at http://links.lww.com/DCR/A749. PMID- 30451749 TI - A Quality-of-Life Comparison of Two Fecal Incontinence Phenotypes: Isolated Fecal Incontinence Versus Concurrent Fecal Incontinence With Constipation. AB - BACKGROUND: Many patients with fecal incontinence report coexisting constipation. This subset of patients has not been well characterized or understood. OBJECTIVE: The purpose of this study was to report the frequency of fecal incontinence with concurrent constipation and to compare quality-of-life outcomes of patients with fecal incontinence with and without constipation. DESIGN: This was a prospective cohort study. Survey data, including Fecal Incontinence Severity Index, Constipation Severity Instrument, Fecal Incontinence Quality of Life survey (categorized as lifestyle, coping, depression, and embarrassment), Pelvic Organ Prolapse Inventory and Urinary Distress Inventory surveys, and anorectal physiology testing were obtained. SETTINGS: The study was conducted as a single institution study from January 2007 to January 2017. PATIENTS: Study patients had fecal incontinence presented to a tertiary pelvic floor center. MAIN OUTCOME MEASURES: Quality-of-life survey findings were measured. RESULTS: A total of 946 patients with fecal incontinence were identified, and 656 (69.3%) had coexisting constipation. Patients with fecal incontinence with constipation were less likely to report a history of pregnancy (89.2% vs 91.4%; p = 0.001) or complicated delivery, such as requiring instrumentation (9.1% vs 18.1%; p = 0.005), when compared with patients with isolated fecal incontinence. Patients with fecal incontinence with constipation had higher rates of coexisting pelvic organ prolapse (Pelvic Organ Prolapse Inventory: 18.4 vs 8.2; p < 0.01), higher rates of urinary incontinence (Urinary Distress Inventory: 30.2 vs 23.4; p = 0.01), and higher pressure findings on manometry; intussusception on defecography was common. Patients with fecal incontinence with concurrent constipation had less severe incontinence scores at presentation (21.0 vs 23.8; p < 0.001) and yet lower overall health satisfaction (28.9% vs 42.5%; p < 0.001). Quality-of-life scores declined as constipation severity increased for lifestyle, coping, depression, and embarrassment. LIMITATIONS: This was a single-institution study, and surgeon preference could bias population and anorectal physiology testing. CONCLUSIONS: Patients with fecal incontinence with concurrent constipation represent a different disease phenotype and have different clinical and anorectal physiology test findings and worse overall quality of life. Treatment of these patients requires careful consideration of prolapse pathology with coordinated treatment of coexisting disorders. See Video Abstract at http://links.lww.com/DCR/A783. PMID- 30451750 TI - Clinical Implications of Pretreatment: Lymphocyte-to-Monocyte Ratio in Patients With Rectal Cancer Receiving Preoperative Chemoradiotherapy. AB - BACKGROUND: Despite advances in local control of rectal cancer, recurrence in distant organs is still one of the main causes of mortality. Prognostic biomarkers would be valuable for the treatment of patients who have rectal cancer. OBJECTIVE: The aim of our study was to investigate the prognostic impact of lymphocyte-to-monocyte ratio in patients with rectal cancer receiving preoperative chemoradiotherapy, and to clarify the clinical significance of lymphocyte-to-monocyte ratio. DESIGN: Prospectively maintained data of patients with rectal cancer were retrospectively evaluated to clarify the clinical relevance of the lymphocyte-to-monocyte ratio. SETTING: This study was conducted at a single expert center. PATIENTS: A total of 119 consecutive patients with rectal cancer through chemoradiotherapy followed by total mesorectal excision at our institute were enrolled in this study. Eight patients were excluded because of a lack of laboratory data, and finally 111 patients were assessed in this study. MAIN OUTCOME MEASURES: The primary outcome measured was the clinical relevance of the lymphocyte-to-monocyte ratio in patients with rectal cancer receiving chemoradiotherapy. RESULTS: Patients with a low pretreatment lymphocyte to-monocyte ratio showed poor prognosis significantly both in overall survival and disease-free survival of those with rectal cancer receiving chemoradiotherapy. Multivariate analyses showed that low pretreatment lymphocyte to-monocyte ratio level, presence of pathological lymph node metastasis (ypN(+)), and high pretreatment serum C-reactive protein level were independent prognostic factors of overall survival and disease-free survival. In addition, time-to-event analysis divided into 2 groups by ypN status showed that low pretreatment lymphocyte-to-monocyte ratio was correlated with poor overall survival and disease-free survival not only in group ypN(-) but also in group ypN(+). LIMITATIONS: The present study had several limitations, including that it was a retrospective observational and single institutional study with Japanese patients. CONCLUSIONS: The combination of lymphocyte-to-monocyte ratio and ypN status can be a predictive marker of poor prognosis and recurrence among patients with rectal cancer undergoing preoperative chemoradiotherapy. See Video Abstract at http://links.lww.com/DCR/A780. PMID- 30451751 TI - Hemorrhoidal Disease Symptom Score and Short Health ScaleHD: New Tools to Evaluate Symptoms and Health-Related Quality of Life in Hemorrhoidal Disease. AB - BACKGROUND: There are no adequately validated tools to evaluate symptoms or disease-specific health-related quality of life in hemorrhoidal disease. OBJECTIVE: The purpose of this study was to assess validity, reliability, and responsiveness of a symptom score of patient-reported pain, itching, bleeding, soiling, and prolapse (Hemorrhoidal Disease Symptom Score). In addition, the study set out to assess reliability and responsiveness of an instrument to measure health-related quality of life in patients with hemorrhoids (Short Health ScaleHD), with 1 item in its 4 dimensions: symptom load, functional status, disease-specific worries, and general well-being. DESIGN: This was a cross sectional (validity and reliability) and longitudinal (responsiveness) study. SETTINGS: The study was conducted at a single center. PATIENTS: Cohort 1 included 295 patients with hemorrhoids to study validity and 60 patients with test-retest scores to study reliability. Cohort 2 included 128 and 121 patients operated for hemorrhoids to study responsiveness of the Hemorrhoidal Disease Symptom Score and the Short Health ScaleHD. MAIN OUTCOME MEASURES: The study evaluated validity, reliability, and responsiveness. Patient-reported symptom load on a 7-point Likert scale was used as comparator, and receiver operating characteristics curve assessed discriminative validity. Interclass correlation assessed reliability. Receiver operating characteristics curve assessed responsiveness, meaning the ability to discriminate between patients with and without improvement after surgery. RESULTS: The Hemorrhoidal Disease Symptom Score demonstrated the ability to discriminate between patients reporting high or low symptom load (area under the curve = 0.786 (95% CI, 0.725-0.848)). The Hemorrhoidal Disease Symptom Score and the Short Health ScaleHD demonstrated adequate reliability and responsiveness, with interclass correlation of 0.822 (95% CI, 0.715-0.891) and 0.763 (95% CI, 0.634-0.851) and area under the curve of 0.843 (95% CI, 0.756 0.929) and 0.840 (95% CI, 0.752-0.929). LIMITATIONS: We had no gold standard comparator to assess validity and responsiveness. CONCLUSIONS: The findings suggest that the Hemorrhoidal Disease Symptom Score is valid, reliable, and responsive and that the Short Health ScaleHD is reliable and responsive. Used together, these tools provide a good overview of symptoms and their impact on patient well-being. See Video Abstract at http://links.lww.com/DCR/A770. PMID- 30451752 TI - The Contributions of Internal Intussusception, Irritable Bowel Syndrome, and Pelvic Floor Dyssynergia to Obstructed Defecation Syndrome. AB - BACKGROUND: Recently, there has been a trend toward surgical management of internal intussusception despite an unclear correlation with constipation symptoms. OBJECTIVE: This study characterizes constipation in patients with obstructed defecation syndrome and identifies whether internal intussusception or other diagnoses such as irritable bowel syndrome may be contributing to symptoms. DESIGN: Patients evaluated for obstructed defecation at a pelvic floor disorder center were studied from a prospectively maintained database. With the use of defecography, patients were classified by Oxford Rectal Prolapse Grade. Coexisting disorders such as enterocele, rectocele, and dyssynergia were also identified. The presence of irritable bowel syndrome was defined using Rome IV criteria, and constipation severity was quantified with the Varma constipation severity instrument. SETTINGS: This study was conducted at a tertiary care university medical center (Massachusetts General Hospital). PATIENTS: The study included 317 consecutive patients with defecography imaging and a completed constipation severity instrument survey from May 2007 to July 2016. MAIN OUTCOME MEASURES: The primary outcome measures were the Varma Constipation Severity Instrument overall score and obstructed defecation subscale score. RESULTS: Of 317 patients evaluated, 95 (30.0%) had no internal intussusception, 126 (39.7%) had intra-rectal intussusception, and 96 (30.3%) had intra-anal intussusception. There was no association between rising grade of internal intussusception and either overall constipation score or obstructed defecation subscale score. Irritable bowel syndrome was associated with an increase in overall constipation score and obstructed defecation subscale score (40.5 +/- 13.6 vs 36.0 +/- 15.1, p = 0.007, and 22.3 +/- 5.8 vs 20.0 +/- 6.6, p < 0.001). Multivariate regression found irritable bowel syndrome and dyssynergia to be associated with a significant increase in obstructed defecation subscale scores. LIMITATIONS: The study was limited because it was an observational study from a single center. CONCLUSIONS: Patients referred for surgical management of obstructive defecation syndrome should be screened and treated for irritable bowel syndrome and dyssynergia before considering surgical intervention. See Video Abstract at http://links.lww.com/DCR/A782. PMID- 30451753 TI - Is Conversion of a Failed IPAA to a Continent Ileostomy a Risk Factor for Long Term Failure? AB - BACKGROUND: A continent ileostomy may be offered to patients in hopes of avoiding permanent ileostomy. Data on the outcomes of continent ileostomy patients with a history of a failed IPAA are limited. OBJECTIVE: This study aimed to assess whether a history of previous failed IPAA had an effect on continent ileostomy survival and the long-term outcomes. DESIGN: This was a retrospective cohort study. SETTINGS: This investigation took place in a high-volume, specialized colorectal surgery department. PATIENTS: Patients who underwent continent ileostomy construction after IPAA failure between 1982 and 2013 were evaluated and compared with patients who have no history of IPAA surgery. MAIN OUTCOME MEASURES: Functional outcomes and long-term complications were compared. RESULTS: A total of 67 patients fulfilled the case-matching criteria and were included in the analysis. Requirement of major (52% vs 61%; p = 0.756) and minor (15% vs 19%; p = 0.492) revisions were comparable between patients who had continent ileostomy after a failed IPAA and those who had continent ileostomy without having a previous restorative procedure. Intubations per day (5 vs 5; p = 0.804) and per night (1 vs 1; p = 0.700) were similar in both groups. Our data show no clear relationship between failure of continent ileostomy and history of failed IPAA (p = 0.638). The most common cause of continent ileostomy failure was enterocutaneous/enteroenteric fistula (n = 14). Six patients died during the study period because of other causes unrelated to continent ileostomy. LIMITATIONS: This study was limited by its retrospective and nonrandomized nature. CONCLUSIONS: Converting a failed IPAA to a continent ileostomy did not worsen continent ileostomy outcomes in this selected group of patients. When a redo IPAA is not feasible, continent ileostomy can be offered as an alternative to conventional end ileostomy in highly motivated patients. See Video Abstract at http://links.lww.com/DCR/A803. PMID- 30451754 TI - Outcomes for Ulcerative Colitis With Delayed Emergency Colectomy Are Worse When Controlling for Preoperative Risk Factors. AB - BACKGROUND: Increasing evidence supports immediate colectomy in acute fulminant ulcerative colitis in comparison with ongoing medical management. Prior studies have been limited to inpatient-only administrative data sets or single institution experiences. OBJECTIVE: The purpose of this study was to compare outcomes of early versus delayed emergency colectomy in patients admitted with ulcerative colitis flares while controlling for known preoperative risks and acuity. DESIGN: This is a cohort study of patients undergoing emergent total abdominal colectomies for ulcerative colitis compared by the timing of surgery. SETTING: Adult patients undergoing a total abdominal colectomy for ulcerative colitis, 2005 to 2015, were identified in the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: Patients undergoing total abdominal colectomy with an operative indication of ulcerative colitis admitted on a nonelective basis were selected. MAIN OUTCOME MEASURE: The primary outcomes measured were 30-day National Surgical Quality Improvement Program-reported mortality and postoperative complications, and early operation within 2 days of admission. RESULTS: We identified 572 total abdominal colectomies after propensity score matching. Median time to surgery was 1 hospital day in the early group versus 6 hospital days in the delayed group (p < 0.001). Early operation was associated with a lower mortality rate (4.9% versus 20.3% in matched groups, p < 0.001) and lower complication rate (64.5% versus 72.0%, p = 0.052). Multivariable logistic regression with propensity weighting of mortality on preoperative risk factors demonstrated that early surgery is associated with an 82% decrease in the odds of death compared with delayed surgery (p < 0.001). Regression of morbidity on preoperative risk factors demonstrated that early surgery is associated with a 35% decrease in the odds of a complication with delayed surgery (p = 0.034). LIMITATIONS: Quality improvement data were used for clinical research questions. CONCLUSIONS: Patients undergoing immediate surgical intervention for acute ulcerative colitis have decreased postoperative complications and mortality rates. Rapid and early transitioning from medical to surgical management may benefit those expected to require surgery on the same admission. See Video Abstract at http://links.lww.com/DCR/A800. PMID- 30451755 TI - Impact of the "Weekend Effect" for Hospital Discharges on Readmissions After Elective Colectomy. AB - BACKGROUND: Hospital readmissions after elective colectomy are costly and potentially preventable. It is unknown whether hospital discharge on a weekend impacts readmission risk. OBJECTIVE: This study aimed to use a national database to determine whether discharge on a weekend versus weekday impacts the risk of readmission, and to determine what discharge-related factors impact this risk. DESIGN: This investigation is a retrospective cohort study. SETTINGS: Data were derived from the University HealthSystem Consortium, PATIENTS:: Adults who underwent elective colectomy from 2011 to 2015 were included. MAIN OUTCOME MEASURES: The primary outcome measured was the 30-day hospital readmission rate. RESULTS: Of the 76,031 patients who survived the index hospitalization, the mean age of the study population was 58 years; half were men and more than 75% were white. Overall, 20,829 (27%) were discharged on the weekend, and the remaining 55,202 (73%) were discharged on weekdays. The overall 30-day readmission rate was 10.5%; 8.9% for those discharged on the weekend vs 11.1% for those discharged during the weekday (unadjusted OR, 0.78; 95% CI, 0.74-0.83). The adjusted readmission risk was lower for patients discharged home without services (routine, without organized home health service) on a weekend compared with on a weekday (adjusted OR, 0.87; 95% CI, 0.81-0.93; readmission rates, 7.4% vs 8.9%, p < 0.001); however, the combination of weekend discharge and the need for home services increased readmission risk (adjusted OR, 1.39; 95% CI, 1.25-1.55; readmission rate, 16.2% vs 8.9%, p < 0.001). Although patients discharged to rehabilitation and skilled nursing facilities were at an increased risk of readmission compared with those discharged to home, there was no additive increase in risk of readmission for weekend discharge. LIMITATIONS: Data did not capture readmission beyond 30 days or to nonindex hospitals. CONCLUSIONS: Patients discharged on a weekend following elective colectomy were at increased risk of readmission compared with patients discharged on a weekday if they required organized home health services. Further prospective studies are needed to identify areas of intervention to improve the discharge infrastructure. See Video Abstract at http://links.lww.com/DCR/A799. PMID- 30451756 TI - Profile of Consecutive Fecal Calprotectin Levels in the Perioperative Period and Its Predictive Capacity for Early Endoscopic Recurrence in Crohn's Disease. AB - BACKGROUND: The perioperative behavior of fecal calprotectin and whether it predicts early postoperative endoscopic recurrence of Crohn's disease are unknown. OBJECTIVE: We aimed to compare the perioperative profiles of fecal calprotectin between patients with Crohn's disease and patients without Crohn's disease undergoing intestinal resection and to identify the association between consecutive fecal calprotectin levels and endoscopic recurrence 3 months after surgery in patients with Crohn's disease. DESIGN: This was a prospective observational study. SETTINGS: This study was conducted in a tertiary referral hospital. PATIENTS: One hundred fourteen consecutive patients (90 Crohn's disease, 24 non-Crohn's disease) who underwent resection were recruited. MAIN OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify variations and risk factors. The predictive accuracy of the possible predictors was assessed by using receiver operating characteristic curves. RESULTS: The fecal calprotectin levels on preoperative day 14 and postoperative days 14, 21, 28, 60, and 90 were higher in the Crohn's disease group than they were in non Crohn's disease group (p < 0.05). Twenty patients (22.2%) developed endoscopic recurrence 3 months after resection. The trend for fecal calprotectin change (Deltafecal calprotectin) from preoperative day 14 to postoperative day 14 was opposite in the recurrence and nonrecurrence groups. Multivariate analysis showed that this change was a predictive factor of early endoscopic recurrence (p < 0.05). DeltaFecal calprotectin was more accurate at predicting early endoscopic recurrence than was fecal calprotectin at single time points with a cutoff value of 240 MUg/g. LIMITATIONS: This is a single-center trial with a limited cohort of patients. CONCLUSIONS: The perioperative fecal calprotectin levels were higher in patients with Crohn's disease than they were in the control group. The change in fecal calprotectin levels from preoperative day 14 to postoperative day 14 could serve as a practical predictive index for early postoperative endoscopic recurrence. See Video Abstract at http://links.lww.com/DCR/A796. PMID- 30451757 TI - Topical Oxymetazoline for Fecal Incontinence in Patients with Spinal Cord Injury: A Double-Blind Randomized Controlled Crossover Study. AB - BACKGROUND: Topical alpha-agonists contract the internal anal sphincter muscle; therefore, they may serve as treatment for fecal incontinence. OBJECTIVES: The aim of this study was to investigate the effect of the alpha-agonist oxymetazoline 1.0% on fecal incontinence in patients with spinal cord injury. DESIGN: This was a double-blind, crossover study. Before randomization, all patients underwent a 1-day, open-label anal manometry and pharmacokinetic study. SETTINGS: The study was conducted at the Department of Internal Medicine, Semmelweis University, Hungary. PATIENTS: Nineteen patients were enrolled into a randomized double-blind, placebo-controlled clinical trial with 2 arms: placebo for 4 weeks followed by oxymetazoline for 4 weeks, or vice versa, with an interval 2-week washout period, in a crossover trial design. Treatment order was randomly assigned, and fecal incontinence was captured with daily diaries. MAIN OUTCOME MEASURES: The primary outcome measured was the number of fecal incontinence episodes in the 8 and 12 hours after drug administration. RESULTS: Resting anal pressure increased in response to oxymetzoline (25.2%). The change in the mean fecal incontinence episodes per month (12 hours post drug application) favored oxymetazoline over placebo: 26.3 (SD +/-28.4) versus 36 (SD +/-39.8) (p = 0.021). When only nongas episodes were included, the mean number of episodes decreased from 10.1 (+4.3) to 6.3 (+/-2.1) fecal incontinence episodes per month (p = 0.022). No difference was observed in adverse events between treatment and placebo periods. All pharmacokinetic samples were below the detection limit. LIMITATIONS: The study was limited by the small number of participants. CONCLUSIONS: In this study, oxymetazoline gel presented a clear clinical beneficial effect accompanied by a favorable safety and tolerability profile. Results of the pharmacokinetic analysis indicate that the clinical benefit was mainly due to a local effect of oxymetazoline. Future studies are planned to investigate higher doses of oxymetazoline for this indication. See Video Abstract at http://links.lww.com/DCR/A797. PMID- 30451758 TI - Selection of Patients With Rectal Cancer for Preoperative Chemoradiotherapy Are T Category and Nodal Status All That Matters? AB - BACKGROUND: Although the accuracy of preoperative MRI staging has been established on follow-up histopathologic examination, the reproducibility of MRI staging has been evaluated in studies with expert radiologists reading a large sample of MRI images and therefore is not generalizable to the real-world setting. OBJECTIVE: The purpose of this study was to evaluate the interrater reliability of MRI for distance to the mesorectal fascia, T category, mesorectal lymph node status, and extramural depth of invasion for preoperative staging of primary rectal cancer. DESIGN: This was a prospective, cross-sectional survey. SETTINGS: The study was conducted in Ontario, Canada. PARTICIPANTS: Participants included GI radiologists. INTERVENTIONS: Participants read 5 preselected staging MRIs using a synoptic report and participated in an educational Webinar. MAIN OUTCOME MEASURES: Distance to the mesorectal fascia, T category, extramural depth of invasion, and mesorectal lymph node status for each MRI were abstracted. Data were analyzed in aggregate using percentage of agreement, Fleiss kappa, and interclass correlation coefficients to assess interrater reliability. RESULTS: Reliability was highest for distance to the mesorectal fascia with an intraclass correlation of 0.58 (95% CI, 0.27-0.80). Kappa scores for T category, mesorectal lymph node status, and extramural depth of invasion were 0.38 (95% CI, 0.23 0.46), 0.41 (95% CI, 0.32-0.49), and 0.37 (95% CI, 0.16-0.82). There was no difference when radiologists were stratified by experience or volume. LIMITATIONS: Scores may have been affected by MRI selection, because they were chosen to demonstrate diagnostic challenges for the Webinar and did not reflect a representative sample. CONCLUSIONS: Interrater reliability was highest for distance to mesorectal fascia and therefore it may be a more reliable criterion than T category, extramural depth of invasion, or mesorectal lymph node status. Combined with the fact that an uninvolved mesorectal fascia is more consistent with the overall goal of rectal cancer surgery, it should be considered as an important MRI criterion for preoperative treatment decision making in the real world setting. See Video Abstract at http://links.lww.com/DCR/A763. PMID- 30451759 TI - Ileal Pouch Excision: A Contemporary Observational Cohort. AB - BACKGROUND: Pouch excision is required for many of those patients experiencing pouch failure in whom ileostomy alone is inadequate and revision surgery is not appropriate. The published rate of pouch failure is approximately 10% at 10 years, resulting in a growing cohort of patients requiring excision. OBJECTIVE: In this article, we aim to describe the indications for excision and postoperative outcomes at our center since 2004. DESIGN: This is a retrospective observational study. SETTINGS: This study was conducted at a tertiary referral center for ileal pouch dysfunction. Cases were documented from 2004 to 2017. PATIENTS: The cohort comprised 92 patients; 83% were diagnosed with ulcerative colitis, 15% with familial adenomatous polyposis, and 2% with indeterminate colitis. INTERVENTIONS: Patients underwent excision of pelvic ileal pouches. MAIN OUTCOME MEASURES: The primary outcomes measured were the time to perineal wound healing and healing at 6 months. Thirty- and 90-day morbidity and mortality were evaluated. RESULTS: Postoperative histology was consistent with Crohn's disease in 1 patient. The median time from pouch creation to excision was 7 years. The rate of perineal wound healing at 6 months was 78%, and regression analysis demonstrated significantly improved chances of healing for noninfective indications for excision (p = 0.023; OR, 15.22; 95% CI, 1.45-160.27) and for more recent procedures (p = 0.032; OR, 12.00; 95% CI, 1.87-76.87). LIMITATIONS: This study was limited because it was retrospective in nature, and it was a single center experience. CONCLUSIONS: This study represents the most contemporary cohort of patients undergoing pouch excision surgery. The procedure retains a relatively high postoperative morbidity, but this study demonstrates a learning curve with improving perineal healing over time associated with a high institutional volume. Defunctioning ileostomy may improve perineal wound healing in patients with infective indications for excision. Further investigation is required to establish the quality-of-life benefits of pouch excision in this modern cohort. See Video Abstract at http://links.lww.com/DCR/A804. PMID- 30451760 TI - Laparoscopic Ventral Rectopexy Versus Stapled Trans-Anal Rectal Resection for Treatment of Obstructed Defecation in the Elderly: Long-Term Results of a Prospective Randomized Study. AB - BACKGROUND: Obstructed defecation is a common complaint in coloproctology. Many anal, abdominal, and laparoscopic procedures are adopted to correct the underlying condition. OBJECTIVE: The purpose of this study was to compare long term functional outcome, recurrence rate, and quality of life between laparoscopic ventral rectopexy and stapled transanal rectal resection in the treatment of obstructed defecation. DESIGN: This was a prospective randomized study. SETTING: This study was performed at academic medical centers. PATIENTS: Patients were included if they had obstructed defecation attributed to pelvic structural abnormalities that did not to respond to conservative measures. Exclusion criteria included nonrelaxing puborectalis, previous abdominal surgery, other anal pathology, and pudendal neuropathy. INTERVENTION: Patients were randomly allocated to either laparoscopic ventral rectopexy (group 1) or stapled transanal rectal resection (group 2). MAIN OUTCOME MEASURES: The primary outcome measures were improvement of modified obstructed defecation score and recurrences after >=3 years of follow-up. Secondary outcomes were postoperative complications, continence status using Wexner incontinence score, and quality of life using Patient Assessment of Constipation-Quality of Life Questionnaire. RESULTS: The study included 112 patients (56 in each arm). ASA score II was reported in 32 patients (18 in group 1 and 14 in group 2; p = 0.12), whereas 3 patients in each group had ASA score III. Minor postoperative complications were seen in 11 patients (20%) of group 1 and 14 patients of group 2 (25%; p = 0.65). During follow-up, 3 patients had fecal urgency after stapled transanal rectal resection but no sexual dysfunction in either procedure. After 6 months, modified obstructed defecation score improvement >50% was reported in 73% versus 82% in groups 1 and 2 (p = 0.36). After a mean follow-up of 41 months, recurrences of symptoms were reported in 7% in group 1 versus 24% in group 2 (p = 0.04). Six months postoperation, perineal descent improved >50% in defecogram in 80% of group 1 versus no improvement in group 2. Quality of life significantly improved in both groups after 6 months; however a significant long-term drop (>36 months) was seen only in group 2. LIMITATIONS: Possible limitations of this study are the presence of a single operator and the absence of blindness of the technique for both patient and assessor. CONCLUSIONS: In elderly patients even with comorbidities, both laparoscopic ventral rectopexy and stapled transanal rectal resection are safe and can improve function of the anorectum in patients with obstructed defecation attributed to structural abnormalities. Laparoscopic ventral rectopexy has better long-term functional outcome, less complications, and less recurrences compared with stapled transanal rectal resection. Perineal descent only improves after laparoscopic ventral rectopexy. Stapled transanal rectal resection was shown not to be the first choice in elderly patients with obstructed defecation unless they had a medical contraindication to laparoscopic procedures. See Video Abstract at http://links.lww.com/DCR/A788. PMID- 30451761 TI - Conditional Probability of Survival After Neoadjuvant Chemoradiation and Proctectomy for Rectal Cancer: What Matters and When. AB - BACKGROUND: Disease-free survival estimated from the time of surgery does not account for the changing likelihood of survival based on time already accrued. Conditional disease-free survival is defined as the probability of remaining disease free after reaching a specific time point without recurrence. OBJECTIVE: The purpose of this study was to evaluate conditional disease-free survival for patients with rectal cancer who were treated by proctectomy after neoadjuvant chemoradiation. DESIGN: Demographics, tumor characteristics, and tumor regression scores were assessed. Three-year conditional disease-free survival was estimated at x year after surgery based on the formula cDFS3 = DFS(x+3)/DFS(x), where DFS is disease-free survival and cDFS is conditional disease-free survival. Analyses were performed using Cox proportional hazards models. SETTING: The study was conducted at a single tertiary referral center. PATIENTS: A total of 545 patients with rectal cancer who were treated by neoadjuvant chemoradiation and curative intent surgery between 1992 and 2012 were included. MAIN OUTCOME MEASURES: Disease-free survival and conditional disease-free survival were measured. RESULTS: The median patient age was 57.5 years, and 28.4% were women. Median follow-up was 5.9 years. Disease-free survival at 1, 3, and 5 years was 89%, 71%, and 63%. The probability of remaining disease free for an additional 3 years for patients disease free at 1, 3, and 5 years was 75%, 83%, and 82%. Tumor regression, pathologic stage, margin status, differentiation, and procedure (low anterior versus abdominoperineal resection) were associated with disease-free survival on multivariable analysis (p < 0.05), but their relevance varied over time. R1 resection and differentiation were initially significant but not at 5 years. In contrast, tumor regression after neoadjuvant chemoradiation had a long lasting impact on survival (at 5 y, conditional disease-free survival for an additional 3 y: 91%, 85%, 76%, and 71% for regression scores 0, 1, 2, and 3; p = 0.002). LIMITATIONS: This was a retrospective study over 20 years, with evolution in adjuvant therapies during this time. CONCLUSIONS: Conditional disease-free survival estimates improved over time, confirming that most patients will see a recurrence within the first few years. The impact of specific prognostic factors evolves variably over time. This information is useful to patients and providers and can help guide counseling and surveillance. See Video Abstract at http://links.lww.com/DCR/A771. PMID- 30451762 TI - The Effect of Surgical Training and Operative Approach on Outcomes in Acute Diverticulitis: Should Guidelines Be Revised? AB - BACKGROUND: Current guidelines accept partial colectomy and primary anastomosis with proximal diversion for select patients with perforated diverticulitis based on low-quality evidence. OBJECTIVE: This study aimed to compare the effect of operative approach and surgeon training on outcomes following urgent/emergent colectomy for diverticulitis. DESIGN: This is a statewide retrospective cohort study. SETTING: Data were obtained from the New York State all-payer sample from 2000 to 2014. PATIENTS: All patients who underwent an urgent/emergent sigmoid colectomy for diverticulitis with creation of an end colostomy or primary anastomosis with proximal diversion were included. We excluded all patients age <18 years, with IBD, colorectal cancer, ischemic colitis, or elective operations. MAIN OUTCOME MEASURES: The main outcomes measured were postoperative in-hospital mortality and complications, RESULTS:: A total of 10,780 patients underwent urgent/emergent colectomy for diverticulitis: 10,600 (98.3%) received a Hartmann procedure and 180 (1.7%) received primary anastomosis with proximal diversion. Colorectal surgeons performed 6.0% of all operations. Utilization of primary anastomosis with proximal diversion was greater among colorectal surgeons but remained low overall (4.2% vs 1.5%; p < 0.001). Postoperative mortality was 2 fold greater when noncolorectal surgeons performed primary anastomosis vs Hartmann procedure (15% vs 7.4%; p < 0.001) and 1.4 times greater among noncolorectal surgeons than among colorectal surgeons (7.5% vs 5.3%; p = 0.04). On multivariable logistic regression (adjusting for patient demographics/characteristics, year, hospital academic status, and surgeon training) primary anastomosis with proximal diversion remained associated with increased mortality (OR, 2.7; 95% CI,1.7-4.4; p < 0.001), complications (OR, 1.8; 95% CI, 1.3-2.5; p < 0.001), and reoperation (OR, 3.4; 95% CI, 1.8-6.3; p < 0.001), whereas colorectal board certification was associated with decreased mortality (OR, 0.66; 95% CI, 0.46-0.95; p = 0.03). LIMITATIONS: Selection bias secondary to retrospective nature and absence of disease severity were limitations of this study. CONCLUSIONS: Despite current recommendations for primary anastomosis with proximal diversion for perforated diverticulitis, this operation in New York State was associated with increased postoperative morbidity and mortality when performed by general surgeons. Given that the majority of urgent/emergent colectomies for diverticulitis are not performed by colorectal surgeons, guidelines for operative management of perforated diverticulitis should be reevaluated. See Video Abstract at http://links.lww.com/DCR/A772. PMID- 30451763 TI - Persistent Fistula After Anorectal Abscess Drainage: Local Experience of 11 Years. AB - BACKGROUND: The characteristics of patients who develop a fistula-in-ano after an anorectal abscess are unclear. OBJECTIVE: Our study explored this relationship and patient factors associated with fistula development. DESIGN: International Classification of Diseases, 10 Revision, and Classification of Interventions and Procedures, version 4, codes were used to identify all of the patients with a primary anorectal abscess. Multivariable analysis was used to identify factors predictive of fistula formation. SETTINGS: The study was conducted in a district general hospital. PATIENTS: Patients with anorectal abscess who were admitted to our institution (2004-2015) were included. MAIN OUTCOMES MEASURES: The rate of subsequent fistula formation was measured. RESULTS: A total of 1970 abscess patients were identified; 70.0% (n = 1379) were men, and 7.3% (n = 144) had Crohn's disease. Fistulas occurred in 16.2% (n = 319) at a median of 7 months (interquartile range, 3-7 mo). Patients with Crohn's disease were more than twice as likely to develop a fistula than patients without Crohn's disease (32.6% vs 14.9%; OR = 2.5 (95% CI, 1.7-3.7); p < 0.001). Patients with Crohn's disease with a fistula were more likely to be women (55.3% vs 34.6%; p = 0.007) and aged <30 years (51.1% vs 24.3%; p < 0.001) versus patients without Crohn's disease with a fistula. At multivariable analysis of the entire cohort, male sex (OR = 0.7 (95% CI, 0.5-0.9); p = 0.005) and diabetes mellitus (OR = 0.5 (95% CI, 0.3-0.9); p = 0.027) were associated with a reduced likelihood of developing a fistula after abscess formation. LIMITATIONS: The study was limited by its single-center scope, retrospective analysis, and lack of an established definition for Crohn's disease. CONCLUSIONS: Abscesses are more common in men, but progression to fistula is more likely in women. The rate of fistula progression in Crohn's disease is twice that in patients without Crohn's disease. Identification of patients at risk may help delineate those who will benefit from a more conservative surgical approach, enhanced follow-up, or investigation after abscess drainage. See Video Abstract at http://links.lww.com/DCR/A798. PMID- 30451764 TI - Magnetic Resonance Texture Analysis in Identifying Complete Pathological Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer. AB - BACKGROUND: A certain proportion of patients with locally advanced rectal cancer experience complete response after undergoing neoadjuvant chemoradiotherapy. These patients might be suitable for a conservative "watch and wait" approach, avoiding high-morbidity surgery. Texture analysis is a new modality that can assess heterogeneity in medical images by statistically analyzing gray-level intensities on a pixel-by-pixel basis. This study hypothesizes that texture analysis of magnetic resonance images can identify patients with a complete response. OBJECTIVE: This study aims to determine whether texture analysis of magnetic resonance images as a quantitative imaging biomarker can accurately identify patients with complete response. DESIGN: This is a retrospective diagnostic accuracy study. SETTINGS: This study was conducted at Colchester General Hospital, January 2003 to 2014. PATIENTS: All patients diagnosed with locally advanced rectal cancer who underwent long-course chemoradiotherapy, had a posttreatment magnetic resonance scan, and underwent surgery are included. INTERVENTION: Texture analysis was extracted from T2-weighted magnetic resonance images of the rectal cancer. MAIN OUTCOME MEASURES: Textural features that are able to identify complete responders were identified by a Mann-Whitney U test. Their diagnostic accuracy in identifying complete responders was determined by the area under the receiver operator characteristics curve. Cutoff values were determined by the Youden index. Pathology was the standard of reference. RESULTS: One hundred fourteen patients with first posttreatment MRI scans (6.2 weeks after completion of neoadjuvant treatment) were included. Sixty-eight patients had a second posttreatment scan (10.4 weeks). With no filtration, mean (p = 0.033), SD (p = 0.048), entropy (p = 0.007), and skewness (p = 0.000) from first posttreatment scans, and SD (p = 0.042), entropy (p = 0.014), mean of positive pixels (p = 0.032), and skewness (p = 0.000) from second posttreatment scans were all able to identify complete response. Area under the curve ranged from 0.750 to 0.88. LIMITATIONS: Texture analysis of MRI is a new modality; therefore, further studies are necessary to standardize the methodology of extraction of texture features, timing of scans, and acquisition parameters. CONCLUSIONS: Texture analysis of MRI is a potentially significant imaging biomarker that can accurately identify patients who have experienced complete response and might be suitable for a nonsurgical approach. (Cinicaltrials.gov:NCT02439086). See Video Abstract at http://links.lww.com/DCR/A760. PMID- 30451765 TI - Nursing and the Attitude of Gratitude: Keep the Spark Burning. PMID- 30451766 TI - Orthopaedic Nurse Certification: certus facere. PMID- 30451767 TI - Keep It Moving and Remember to P.A.C. (Pharmacology, Ambulation, and Compression) for Venous Thromboembolism Prevention. AB - The purpose of this article is to describe in detail how an academic hospital system took on the challenge of deep vein thrombosis (DVT) prevention. A VTE Prevention Task Force was formed in response to an increased incidence of hospital acquired DVTs. The interdisciplinary team reviewed the literature and examined the current state of organizational venous thromboembolism (VTE) prevention to identify gaps in process, determine opportunity and approaches for practice and process improvements, and develop standardized VTE prevention protocols. The article discusses the process taken in developing a highly motivated interdisciplinary team, the implementation of a care bundle, and the highly effective educational and surveillance tools used that helped improve patient outcomes by driving down the VTE rate. PMID- 30451768 TI - Keep It Moving and Remember to P.A.C. (Pharmacology, Ambulation, and Compression) for Venous Thromboembolism Prevention. PMID- 30451770 TI - Surgical Complications Associated With Cervical Spine Surgery. PMID- 30451769 TI - Surgical Complications Associated With Cervical Spine Surgery. AB - Cervical spine complaints are routinely evaluated in the office and urgent care facilities. Many of these complaints will resolve with conservative modalities. However, when operative intervention is necessary for nontraumatic pathology, recognition of pre-, intra-, and postoperative complications is imperative. This article reviews basic anatomy and surgical anatomy of the cervical spine. The common surgical approaches to the cervical spine as well complications that can occur from an anterior and posterior perspective are discussed. Cervical spine surgery when used in the appropriate clinical scenarios can be very successful. It is important to remember that risk reduction begins prior to the surgery with appropriate planning, identification of any anatomical anomalies, and adequate preparation. PMID- 30451772 TI - Snapping Hip Syndrome. PMID- 30451771 TI - Snapping Hip Syndrome. AB - Coxa saltans, or snapping hip syndrome, is a common orthopaedic problem that can easily be diagnosed and treated when the proper evaluation and management are utilized. It is often seen in growing adolescents, athletes, and people with sudden increase in physical activity. A thorough physical examination will help decipher whether the snapping hip is intra-articular or extra-articular and will help guide treatment options. This article reviews how to perform a physical assessment and treatment options such as medications, stretching, physical therapy, articular injections, and possible surgical interventions. Complications from conservative treatments are rare, but weakness, infection, nerve damage, and atrophy may occur following surgical procedures. PMID- 30451773 TI - Does Information Become Actual Knowledge in Surgical Spine Patients? A Qualitative Study. AB - BACKGROUND: It is seldom questioned, if information delivered (to a patient) actually produces knowledge. There is a lack of understanding of how patients in general, surgical patients in particular, perceive, process, and translate clinical information in their everyday lives. The objective of this study was to elucidate how patients undergoing spinal fusion surgery manage and assimilate information provided by clinicians and how they adapt and embrace this information pre- and postsurgery. METHODS: The study employed qualitative methods of ethnographic observation and semistructured interview with a total of 14 individuals, that is, spinal fusion patients (n = 6) and clinicians (n = 8) over a 4-month period in 2014. RESULTS: The results highlight that in the course of treatment, patients embrace or reject information on the basis of their previous experience, expectations, and confidence in their own ability. Overall, patients adjusting to everyday life after spinal fusion surgery used 4 strategies of information processing about their individual life situation. Patients do not use just one of these strategies but may use a number of strategies depending on the situation. Such production of knowledge is pivotal to the behavior of patients through their treatment trajectory. CONCLUSIONS: This study points to the challenges of supporting patients to assimilate information and affect health related behaviors, recognizing that knowledge and behavior change are emergent processes in patients and not a linear outcome of information. PMID- 30451774 TI - The Impact of a Phone Assistance Nursing Program on Adherence to Home Exercises and Final Outcomes in Patients Who Underwent Shoulder Instability Surgery: A Randomized Controlled Study. AB - PURPOSE: The purpose of this study was to assess the impact of a phone assistance nursing program as an adjunct to conventional physiotherapy to increase adherence to a home exercise program on functional outcomes of patients who underwent shoulder instability surgery. METHODS: A randomized controlled study of 70 patients allocated to a phone assistance program (study group, n = 36 patients) or conventional postoperative management (control group, n = 34 patients) was conducted. All patients in both groups received conventional rehabilitation at the outpatient clinic after surgery. In addition, patients in the study group received phone calls from a nurse (who had access to a physiotherapist) 3 days per week. During the calls these patients received a coaching session about self care and support with the home exercise program. Evaluations were performed during a follow-up of 12 months for range of motion (ROM), pain (visual analog scale [VAS] score), Disability of the Arm, Shoulder, and Hand (DASH) score, Oxford Shoulder Instability Score (OSIS), and Rowe score. RESULTS: All scores significantly improved from preoperative to the final follow-up in both groups (p = .001). At the final follow-up, there were no significant differences between groups in VAS, DASH, or Rowe scores. However, those in the study group had significantly better OSIS (p = .013) and ROM (p = .001), particularly for anterior forward motion (p = .001). Likewise, the study group achieved full motion and function significantly faster than the control group (p = .002). The amount of rehabilitation sessions at the outpatient clinic was 1.7 times higher in the control group (p = .004) than in the study group. CONCLUSION: The phone assistance nursing program was an effective procedure to significantly improve the outcomes of conventional physiotherapy in patients who have undergone an operation for shoulder instability. PMID- 30451777 TI - Tibial Stress Fracture in a Runner. PMID- 30451775 TI - Bone Marrow Aspirate Concentrate for Orthopaedic Use. AB - Biological-based therapies are rapidly expanding for different musculoskeletal conditions because of their potential benefits including their minimal invasiveness, capacity for unprecedented healing, and potential for rapid recovery. In this regard, although several approaches have been reported in the literature, most of the body of the literature is increasingly based on platelet rich plasma, bone marrow aspirate concentrate, and cell-based therapy studies. Although further basic science and clinical research is needed to elucidate the long-term outcome of these therapies in the treatment of several injuries, there is compelling evidence for their use for certain indications. The purpose of this article was to review the main aspects of bone marrow aspirate concentrate, which is one of the few forms of stem cell delivery approved by the Food and Drug Administration, and, furthermore, to critically assess the current evidence-based recommendations and identify potential avenues for development. PMID- 30451778 TI - Tibial Stress Fracture in a Runner. PMID- 30451780 TI - New Certificants April 1-June 30, 2018. PMID- 30451779 TI - Two Books: One on Clinical Orientation and Onboarding and the Second About Everyday Bias. PMID- 30451781 TI - Sacral Dysmorphism and its Implication on the Size of the Sacroiliac Joint Surface. AB - STUDY DESIGN: This is a retrospective data analysis. OBJECTIVE: The aim of this study was to analyze the prevalence of sacral dysmorphism and its correlation to the size of the sacroiliac joint (SIJ) surface based on computed tomography (CT) scans. SUMMARY OF BACKGROUND DATA: Sacroiliac screw fixation is a widely accepted technique for stabilization of posterior pelvic ring injuries. Safe sacral screw placement may be impaired by sacral dysmorphism. The prevalence and impact of sacral dysmorphism on the size of the SIJ surface is unknown. MATERIALS AND METHODS: In total, 269 CT scans were evaluated for the presence of the 5 signs of sacral dysmorphism (mammillary bodies, tongue-in-groove, residual upper sacral disk space, colinearity, and dysmorphic sacral neural foramina). The size of the SIJ surface was calculated by measuring the sacral joint line of the SIJ on each axial CT slice. Logistic regression analyses were conducted to reveal sex-related or age-related differences and correlations between the presence of the dysmorphic signs and the size of the SIJ surface. RESULTS: Prevalence rates of the dysmorphic signs ranged from 5% (colinearity) to 70% (residual sacral disk space). Only 15% did not show any sign of sacral dysmorphism. The average size of the SIJ surface was 7.36 cm; it was significantly larger in male (8.46 cm) than in female (6.11 cm) patients (P<0.001). The presence of tongue-in-groove morphology was associated with a significantly larger SIJ surface (P<0.001), the presence of a residual upper sacral disk space with a significantly smaller joint surface (P=0.006). CONCLUSIONS: The prevalence of sacral dysmorphism is remarkably high in a normal population and it is questionable if the respective signs should be called dysmorphic after all. The possibility of a smaller joint surface in female patients and patients with a residual upper sacral disk space should be considered in the planning of iliosacral screw placement. PMID- 30451782 TI - Radiological Evaluation Does Not Reflect the Clinical Outcome After Surgery in Unstable Thoracolumbar and Lumbar Type A Fractures Without Neurological Symptoms: A Comparative Study of 2 Cohorts Treated by Open or Percutaneous Surgery. AB - STUDY DESIGN: This is a prospective study of 2 cohorts. OBJECTIVE: Compare the clinical and radiologic outcome of 2 cohorts of unstable thoracolumbar and lumbar fractures treated by open posterior fixation (OPF) with bone graft or by percutaneous fixation (PCF) without grafting. SUMMARY OF BACKGROUND DATA: In recent years, PCF is the most common treatment of thoracolumbar fractures. To date, no studies have analyzed clinical outcomes in terms of return to work. MATERIAL AND METHODS: Two cohorts of patients with unstable thoracolumbar and lumbar fractures fractures (type A2, A3, and A4) without neurological symptoms underwent OPF (n=91) or PCF (n=54) between 2010 and 2015. A conventional radiologic study was performed in the preoperative, immediate postoperative period, 1-year, and 2-year follow-up. Clinical outcomes were evaluated by Visual Analog Scale and Oswestry Disability Index scores at 1-year and 2-year follow-up. The period to return to work and the type of work were also recorded. RESULTS: The percentages of correction were significantly higher in cases operated by OPF: fracture angle (P<0.001), kyphotic deformity (P<0.001), vertebral compression (P<0.001), and displacement (P<0.001). Cases operated by PCF experienced greater loss of correction at 2-year follow-up, especially in fracture displacement (P<0.001), deformity angle (P<0.001), kyphotic deformity (P<0.001), and in the sagittal index (P<0.001). Besides this greater loss of correction, PCF cases showed better Visual Analog Scale (P<0.001) and Oswestry Disability Index scores (P<0.001) at final follow-up. The percentage of patients returning to the same heavy work position was higher in the PCF group (P<0.001) and in a shorter period of time (P<0.001). CONCLUSIONS: The greater loss of correction of patients undergoing PCF does not reflect the clinical outcomes that were significantly better as compared to patients undergoing open fixation with grafting. It would be useful to further evaluate if the radiological changes could have a long-term clinical significance. PMID- 30451783 TI - A Classification System for Spinal Cord Compression and its Association With Neurological Deficit in Spinal Epidural Abscess. AB - STUDY DESIGN: This was a retrospective case-control study. OBJECTIVE: We aim to describe a novel 5-point grading system to determine the degree and severity of spinal cord compression secondary to a spinal epidural abscess (SEA). Secondarily, we aim to correlate the degree of compression with clinical presentation and outcomes. SUMMARY OF BACKGROUND DATA: Mechanical compression plays an important role in the pathophysiology of neurological dysfunction in SEA. Unfortunately, no standardized classification system for describing the degree of spinal cord compression exists. The lack of a validated grading system makes it challenging to study and consistently report the relationship between cord compression and clinical presentation/outcomes in SEA. MATERIALS AND METHODS: Patients 18 years and older admitted to our hospital system with a diagnosis of SEA located above the conus medullaris between 1993 and 2016 were included. Using pretreatment axial magnetic resonance images, we developed a 5 point classification scale to determine the degree of spinal cord compression. After assigning a compression grade to each abscess, we investigated the relationship between the degree of compression and presenting neurological symptoms. Furthermore, we assessed the association between compression grade and clinical outcomes. RESULTS: Three hundred thirty-nine patients were included in the study. Patients with high-grade cord compression (grades 4 and 5) were significantly more likely to present with pretreatment motor deficit, sensory changes, and bowel/bladder incontinence. With respect to clinical outcomes, increasing degree of compression was not associated with failure of nonoperative management, residual motor deficit, or 90-day mortality. CONCLUSIONS: We report a novel grading system for spinal cord compression in SEA with 5 progressively increasing grades of compression. High-grade abscesses with cord compression were significantly associated with neurological deficit at presentation but not with poor outcomes. We hope that this classification system will allow for greater consistency in reporting the association between cord compression and neurological deficit in SEA. PMID- 30451784 TI - Is the Use of Intraoperative Corticosteroids Harmful in Lumbar Decompression Surgery? PMID- 30451785 TI - Grading of Complications After Cervical Deformity-corrective Surgery: Are Existing Classification Systems Applicable? AB - STUDY DESIGN: This is a retrospective review of prospective multicenter cervical deformity (CD) database. OBJECTIVE: Assess the impact of complication type and Clavien complication (Cc) grade on clinical outcomes of surgical CD patients BACKGROUND:: Validated for general surgery, the Clavien-Dindo complication classification system allows for broad comparison of postoperative complications; however, the applicability of this system is unclear in CD-specific populations. METHODS: Surgical CD patients above 18 years with baseline and postoperative clinical data were included. Primary outcomes were complication type (renal, infection, cardiac, pulmonary, gastrointestinal, neurological, musculoskeletal, implant-related, radiographic, operative, wound) and Cc grade (I, II, III, IV, V). Secondary outcomes were estimated blood loss (EBL), length of stay (LOS), reoperation, and health-related quality of life (HRQL) score. The univariate analysis assessed the impact of complication type and Cc grade on improvement markers and 1-year postoperative HRQL outcomes. RESULTS: In total, 153 patients (61+/-10 y, 61% female) underwent surgery for CD (8.1+/-4.6 levels fused; surgical approach included 48% posterior, 18% anterior, 34% combined). Overall, 63% of patients suffered at least 1 complication. Complication breakdown by type: renal (2.0%), infection (5.2%), cardiac (7.2%), pulmonary (3.9%), gastrointestinal (2.0%), neurological (26.1%), musculoskeletal (0.0%), implant related (3.9%), radiographic (16.3%), operative (7.8%), and wound (5.2%). Of complication types, only operative complications were associated with increased EBL (P=0.004), whereas renal, cardiac, pulmonary, gastrointestinal, neurological, radiographic, and wound infections were associated with increased LOS (P<0.050). Patients were also assessed by Cc grade: I (28%), II (14.3%), III (16.3%), IV (6.5%), and V (0.7%). Grades I and V were associated with increased EBL (both P<0.050); Cc grade V was the only complication not associated with increased LOS (P=0.610). Increasing complication severity was correlated with increased risk of reoperation (r=0.512; P<0.001), but not inferior 1-year HRQL outcomes (all P>0.05). CONCLUSIONS: Increasing complication severity, assessed by the Clavien Dindo classification system, was not associated with increased EBL, inpatient LOS, or inferior 1-year postoperative HRQL outcomes. Only operative complications were associated with increased EBL. These results suggest a need for modification of the Clavien system to increase applicability and utility in CD-specific populations. PMID- 30451786 TI - Natural killer cell-based immunotherapy: a new fighter against melanoma? AB - Changes in the expression of proteins on cancer cell surface are a typical outcome of malignant transformation. Natural killers (NKs) utilize a set of activating and inhibitory receptors that enable them to recognize altered protein expression and then destroy 'stressed' cells such as cancer or virus-infected cells. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA and MICB, respectively) are expressed by various human tumors and can be recognized by activating NK cell receptor NKG2D. However, cancer frequently escapes recognition by NK cells by proteolytic shedding of MICA and MICB proteins. A study carried out by Ferrari de Andrade and colleagues showed that monoclonal antibody targeting the site of proteolytic shedding of MICA and MICB reduced the progression of melanoma in immunocompromised and immune competent mice models by activation of NKG2D. This approach prevented the reduction of essential immunostimulatory ligands (MICA/MICB) and restored NK cell-driven anticancer immunity. PMID- 30451787 TI - TRAF2 and FKBP51 as possible markers for identification of suitable melanoma tumors for tumor necrosis factor-alpha inhibition. AB - Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine, whose role in melanoma is controversial. Although high-dose TNF-alpha is approved for the treatment of patients with in transit-metastatic melanoma confined to the limb, diverse preclinical models of melanoma have shown that TNF-alpha can induce cell invasion. Biomarkers that can differentiate between the dual role of TNF-alpha are needed. TRAF2 is critical to TNF receptor-induced activation of nuclear factor-kappaB (NF-kappaB), allowing shifting from death to survival-signaling cascades. The large immunophilin FKBP51 acts as a scaffold and catalyst in the IkappaB kinase complex assembly and activation. Here, using microscopy and an electrophoretic mobility-shift assay, we provide further evidence in support of the essential role of FKBP51 in sustaining the TNF-alpha NF-kappaB signaling in melanoma. Through the cross-linking reaction with the chemical linker disuccinimidyl glutarate, we show that a direct interaction occurs between FKBP51 and TRAF2 in melanoma cells. Immunohistochemistry of tumor samples from 24 patients with cutaneous melanomas showed a correlation between the expressions of the two proteins. Given the association of FKBP51 and TRAF2 with TNF-alpha induced NF-kappaB signaling and their correlation in tumor samples, we propose that the two proteins can be exploited as useful markers for the identification of those melanoma tumors that can benefit from TNF-alpha inhibition. Future studies will address this hypothesis. PMID- 30451788 TI - Integration of protein interaction and gene co-expression information for identification of melanoma candidate genes. AB - Cutaneous melanoma is an aggressive form of skin cancer that causes death worldwide. Although much has been learned about the molecular basis of melanoma genesis and progression, there is also increasing appreciation for the continuing discovery of melanoma genes to improve the genetic understanding of this malignancy. In the present study, melanoma candidate genes were identified by analysis of the common network from cancer type-specific RNA-Seq co-expression data and protein-protein interaction profiles. Then, an integrated network containing the known melanoma-related genes represented as seed genes and the putative genes represented as linker genes was generated using the subnetwork extraction algorithm. According to the network topology property of the putative genes, we selected seven key genes (CREB1, XPO1, SP3, TNFRSF1B, CD40LG, UBR1, and ZNF484) as candidate genes of melanoma. Subsequent analysis showed that six of these genes are melanoma-associated genes and one (ZNF484) is a cancer-associated gene on the basis of the existing literature. A signature comprising these seven key genes was developed and an overall survival analysis of 461 cutaneous melanoma cases was carried out. This seven-gene signature can accurately determine the risk profile for cutaneous melanoma tumors (log-rank P=3.27E-05) and be validated on an independent clinical cohort (log-rank P=0.028). The presented seven genes might serve as candidates for studying the molecular mechanisms and help improve the prognostic risk assessment, which have clinical implications for melanoma patients. PMID- 30451790 TI - The Impact of Endoscopic Retrograde Cholangiopancreatography on Islet Cell Yield During Total Pancreatectomy With Islet Autotransplantation. AB - OBJECTIVES: Many patients with recurrent acute and chronic pancreatitis who are candidates for total pancreatectomy and islet cell autotransplantation (TPIAT) undergo endoscopic retrograde cholangiopancreatography (ERCP). However, little is known on the impact of ERCP on TPIAT outcomes. We aimed to explore the effect of antecedent ERCP on islet yield and postoperative insulin requirement after TPIAT. METHODS: Through a prospectively maintained database, we identified patients who underwent TPIAT at our institution between 2009 and 2016. After adjusting for confounders, islet cell yield and postoperative insulin requirement were compared between subjects who did and did not undergo ERCP within 2 years prior to TPIAT. RESULTS: Data were available on 167 TPIAT patients during the study period; 105 (62.9%) had undergone ERCP within 2 years prior. Prior ERCP was not associated with a reduction in islet equivalents per patient kilogram (odds ratio, 1.37; 95% confidence interval, 0.75-2.5; P = 0.31). Antecedent ERCP was not associated with increased postoperative insulin requirement among patients with no diabetes undergoing TPIAT (odds ratio, 0.85; 95% confidence interval, 0.39-1.83; P = 0.67). CONCLUSIONS: Antecedent ERCP does not appear to have a deleterious impact on islet cell yield during TPIAT. Additional multicenter data are needed to more clearly determine the impact of ERCP in this context. PMID- 30451789 TI - Hypertension and childhood migration: a nationwide study of 2.7 million adolescents. AB - OBJECTIVES: Immigration studies can shed light on hypertension development and reveal high-risk populations. To this end, we investigated the association between age at immigration and hypertension occurrence at adolescence among immigrants to Israel. METHODS: We analyzed cross-sectional data on 2 681 294 adolescents assessed for mandatory military service at approximately 17 years of age between 1967 and 2016. The study population constituted of 410 488 immigrants with origins in Ethiopia, Middle East and North Africa, Former USSR and Western Countries. Age at immigration was categorized into 0-5, 6-11 and 12-19 years. Odds ratios (ORs) for hypertension were calculated according to age at immigration with Israel-born participants as controls. Models were made to account for possible confounders. Additionally, the study population was stratified by country of origin and each immigrant group referenced to Israel born participants of the same origin. RESULTS: In the fully-adjusted model, immigrants arriving until age 11 years had comparable ORs for hypertension to the Israeli-born reference group, whereas recent immigrants, arriving at age 12-19 years had a marked lower OR of 0.30 (95% CI 0.27-0.33; P < 0.001). The lower hypertension odds among recent immigrants persisted in all models and when the study sample was stratified by sex and origin, with all but those of Western origin showing a graded decrease with increasing age at migration categories. CONCLUSION: Immigrants arriving earlier in childhood lose their protection against hypertension at adolescence relative to the Israeli-born, likely because of lifestyle acculturation. Prevention programs are needed, beginning upon arrival and placing emphasis on nutritional and physical activity habits. PMID- 30451792 TI - Transient Expression of Interleukin-21 in the Second Hit of Acute Pancreatitis May Potentiate Immune Paresis in Severe Acute Pancreatitis. AB - OBJECTIVES: Interleukin-21 (IL-21) is a cytokine associated with tissue inflammation, autoimmune and infectious diseases. Organ dysfunction and death can occur in patients with acute pancreatitis (AP) in two distinct clinical phases. Initially, a systemic inflammatory response syndrome may be followed by systemic sepsis from infected pancreatic necrosis, known as the "second hit." The expression and possible role of IL-21 in AP has not been established. METHODS: Thirty-six patients with mild, moderate, and severe AP (SAP) were enrolled. Peripheral blood samples of patients were drawn on days 7, 9, 11, and 13. Reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine the expression and concentration of IL-21. RESULTS: Interleukin-21 mRNA levels increased significantly at day 9 in severe (P = 0.002) pancreatitis compared with both the mild and control patient groups. At the protein level, IL-21 was elevated in SAP patients compared with those with mild pancreatitis, although this was not significant. Furthermore, day 9 IL-21 was elevated in septic SAP patients and patients with pancreatic necrosis. CONCLUSIONS: Interleukin-21 is transiently elevated in SAP compared with the mild/moderate group, and hence IL-21 may contribute to the immune imbalance that occurs in AP. PMID- 30451791 TI - Performance of a Multidisciplinary Pancreas Cancer Conference in Predicting and Managing Resectable Pancreatic Cancer. AB - OBJECTIVES: Surgery is the curative treatment for pancreatic ductal adenocarcinoma (PDA). Guidelines recommend utilizing a multidisciplinary pancreatic cancer conference (MDPC) in treatment; however, data are limited. The objective of this study was to assess the accuracy of an MDPC. METHODS: Patients with PDA presented at an MDPC were prospectively collected from April 2013 to August 2016. Patients were included if the MDPC predicted them to have resectable PDA and underwent upfront surgery. Secondary aims were to compare differences in tumor characteristics, time to surgery, and resection rates with patients prior to MDPC implementation (pre-MDPC). RESULTS: A total of 278 patients were presented at the MDPC. After excluding borderline and nonresectable cases, 91 patients were predicted as resectable on evaluation, and 70 were fit for surgery. The MDPC predicted resection in 91.4%. The MDPC had larger tumor size (32.6 vs 24.0 mm), greater proportion of stage II tumor, and a shorter time from diagnosis to resection (27.3 vs 35.5 days) compared with the pre-MDPC. Microscopically negative resections were similar between MDPC and pre-MDPC (85.9% vs 88.0%) despite advanced tumor size and stage. CONCLUSIONS: The MDPC demonstrates a high resection rate. Compared with a pre-MDPC, MDPC provides shorter time to surgery and selects for advanced tumors. PMID- 30451793 TI - Prevalence of Asymptomatic Intraductal Papillary Mucinous Neoplasms in Healthy and Ill Populations Detected by Ultrasonography: A Single-Center Study of 6353 Outpatients. AB - OBJECTIVES: The aim of this study was to establish the prevalence of intraductal papillary mucinous neoplasms (IPMNs) without and with high-risk stigmata (HRS)/worrisome features (WF) and the epidemiologic association between IPMNs and other diseases. METHODS: Ultrasound examinations of outpatients were evaluated. The IPMN was confirmed by magnetic resonance imaging. The prevalence of IPMNs and HRS/WF IPMNs was calculated. The association between IPMNs and other diseases was studied. RESULTS: The prevalence rate of IPMNs was 3.4%. A total of 1,531,264 IPMNs were expected in Italian population (2.5%), whereas 2257 per 100,000 citizens (2.3%) were expected in the European standard population (ESP2013). The prevalence rates of HRS/WF IPMNs were 0.5%, 0.7%, and 0.6%, in our, the Italian, and the ESP2013 populations, respectively. A total of 432,881 and 620 HRS/WF IPMNs per 100,000 residents were expected in the Italian and the ESP2013 populations, respectively. The IPMN prevalence increased over 50 years of age (odds ratio [OR], 3.2; P < 0.001) and over 70 years of age (OR, 1.9; P < 0.001). Female sex was related to the presence of IPMNs (OR, 1.9; P < 0.001). CONCLUSIONS: Intraductal papillary mucinous neoplasms had a high prevalence in asymptomatic nonhospitalized populations. Age older than 50 years identified a possible risk category. PMID- 30451795 TI - Endoscopic Ultrasound Assessment of Pancreatic Duct Diameter Predicts Neuroendocrine Tumors and Other Pancreas Masses. AB - OBJECTIVES: Distinguishing neuroendocrine tumors (NETs) and other pancreas lesions from adenocarcinomas via endoscopic ultrasound (EUS) requires additional tissue for special staining and processing. Our aim was to determine if main pancreatic duct (PD) diameter on EUS helps to differentiate NET and other unusual tumors from adenocarcinoma. METHODS: We evaluated 30 consecutive patients diagnosed with NET or other pancreas lesions by EUS with 90 matched patients who were found to have adenocarcinoma. Dilated PD was defined as greater than 3 mm. Multivariate logistic regression was used to evaluate associations between lesion type and PD diameter. RESULTS: Among the 30 patients with NET/other pancreas lesions, 21 had NETs, 7 had metastases, and 2 had lymphomas. A dilated PD was demonstrated in only 3.3% of pancreatic NET/other lesions but present in 88.9% of cases of primary adenocarcinoma (P < 0.01). In multivariate analysis, a normal PD diameter and absence of clinical symptoms strongly predicted the presence of pancreatic NET/other versus adenocarcinoma (P < 0.01). CONCLUSIONS: The absence of PD dilation upstream of the lesion suggests NET or other lesions rather than adenocarcinoma. This finding should prompt endosonographers to obtain additional tissue at the time of EUS to send for special studies. PMID- 30451794 TI - Magnetic Resonance Imaging as a Valid Noninvasive Tool for the Assessment of Pancreatic Fibrosis. AB - OBJECTIVES: The aim of this study was to evaluate the utility of magnetic resonance imaging (MRI) for the noninvasive assessment of pancreatic fibrosis (PF). METHODS: Fifty-two patients who underwent surgical resection of the pancreas, histological examination of resection margins, preoperative abdominal MRI, and fecal elastase-1 test were enrolled in the study. Pancreatic tissue was identified on the MRI T1-, T2-, and diffusion-weighted imaging sequences. Apparent diffusion coefficient (ADC) was measured at the expected resection margin of the pancreas. RESULTS: There was a significant negative correlation between the ADC mean and histologically determined PF (r = -0.752, P = 0.001). For equal to or greater than 25% of PF, the ADC cutoff value was 1.331 or less, with a sensitivity of 77% and specificity of 88%. The unenhanced T1-weighted signal intensity ratio (T1SI) cutoff value was 172.1 or less. For equal to or greater than 50% of PF, the ADC cutoff value was 1.316 or less with a sensitivity of 85% and specificity of 88%. The highest sensitivity was obtained by combining ADC and T1SI values. CONCLUSIONS: Combining both the ADC and T1SI measurement allows the detection of early PF with good sensitivity and specificity. Magnetic resonance imaging has the advantage of being noninvasive and widely used in the clinical setting, thus making our results easily transferable to routine clinical practice. PMID- 30451796 TI - Expression of Epithelial-Mesenchymal Transition Proteins in Pancreatic Anaplastic (Undifferentiated) Carcinoma. AB - OBJECTIVES: The aim of this study was to identify an association of pancreatic anaplastic carcinoma (APC) with the epithelial-mesenchymal transition (EMT). METHODS: Resected APCs (n = 24) were examined to assess components of APCs, including carcinomatous, transitional, and sarcomatous regions. Analysis was performed based on the immunoreactivity of E-cadherin and 3 EMT-related proteins: Slug (zinc finger protein SNAI2), Twist (Twist-related protein 1), and Zeb1 (zinc finger E-box-binding homeobox 1). Expression score was determined based on staining intensity and stained area of the target cells. Finally, we performed a hierarchical clustering based on the expression pattern of E-cadherin and EMT related proteins of the sarcomatous component. RESULTS: The expression score of E cadherin decreased in the order of sarcomatous > transitional > carcinomatous components (P < 0.01). Although there were significant differences in the immunohistochemical scores of Slug, Twist, and Zeb1 between carcinomatous and transitional components (P < 0.01), the significant difference in immunohistochemical score of Zeb1 between transitional and sarcomatous components was found (P < 0.05). Furthermore, APCs were divided into 2 subgroups based on the expression patterns of E-cadherin and EMT-related proteins (hierarchical clustering analysis). Consequently, these subgroups were distinguished by Twist expression. CONCLUSIONS: Epithelial-mesenchymal transition plays an essential role in the pathogenesis of APC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30451797 TI - Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis. AB - OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta analysis on this topic. RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality of more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality of more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence of more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior. PMID- 30451798 TI - Tenascin C, Fibronectin, and Tumor-Stroma Ratio in Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma with increased expression of tenascin C and fibronectin. Their role and tumor-stroma ratio in PDAC are not well known. The aim of this study was to evaluate tenascin C and fibronectin expression and tumor-stroma ratio and their prognostic relevance in PDAC. METHODS: Ninety-five resected PDACs were immunohistochemically stained for tenascin C and fibronectin, and the expression was separately assessed in tumor bulk and front. Tumor-stroma ratio was determined with sections stained with hematoxylin-eosin. RESULTS: Tenascin C and fibronectin were abundantly expressed in the stroma of PDAC, but absent in adjacent normal pancreatic tissue. Fibronectin expression of the bulk was associated with high T class (P = 0.045). In the main analysis, tenascin C and fibronectin expression and tumor-stroma ratio were not associated with patient survival. In a subgroup analysis of early-stage PDAC (T1-T2 tumors), high tenascin C expression in the tumor bulk was associated with poor prognosis (hazard ratio, 8.23; 95% confidence interval, 2.71-24.96). CONCLUSIONS: Tenascin C and fibronectin are abundantly expressed in PDAC, but they seem to have no major association with patient survival. However, in early-stage PDAC, tenascin C expression of the tumor bulk may have prognostic impact. Tumor-stroma ratio has no prognostic value in PDAC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 30451799 TI - Endoscopic Resection of Duodenal Carcinoid Tumors: A Single-Center Comparison Between Simple Polypectomy and Endoscopic Mucosal Resection. AB - OBJECTIVES: Endoscopic resection is preferred for duodenal carcinoids less than 20 mm; however, the efficacy of simple polypectomy has not been compared with advanced endoscopic resection techniques. METHODS: We performed a retrospective review of 33 patients who underwent endoscopic duodenal carcinoid resection (10 simple, 23 endoscopic mucosal resection) at the Hospital of the University of Pennsylvania between January 1, 2006, and June 15, 2017. The primary outcomes were resection margin positivity and local tumor recurrence. RESULTS: There were no significant differences in demographics or tumor functionality. Lesions managed with simple polypectomy had smaller median gross specimen size (6.0 mm vs 8.0 mm, P = 0.043). There was no significant difference in pathology resection margins between simple polypectomy and endoscopic mucosal resection (86% vs 68% positive, P = 0.64). Local recurrence on surveillance endoscopy was also similar (14.3% vs 17.7%, respectively; P = 1.000), with median time to recurrence 2.3 months (interquartile range, 1.2-5.4 months). The median follow-up time in patients without local recurrence was 21.4 months (interquartile range, 7.1-39.6 months). CONCLUSIONS: Simple polypectomy may be adequate treatment of small duodenal carcinoids, although further studies are needed for validation and to define the upper limits of tumor size that can be managed with this technique. PMID- 30451800 TI - Proinsulin Expressing Neuroendocrine Tumors of the Pancreas: An Underrecognized Entity. AB - OBJECTIVES: Rare cases of pancreatic neuroendocrine tumors (PNETs) that produce only proinsulin (PI) and manifest with hypoglycemia have been reported. Proinsulin expression in PNET has not been systematically studied, and the clinicopathologic features of such tumors remain unknown. METHODS: We studied expression of PI by immunohistochemistry (IHC) in 136 PNETs from 2 high-volume surgical oncology centers and assessed all available clinicopathologic data. RESULTS: Thirty-six (26%) of PNETs were positive for PI by IHC, most (89%) of which coexpressed insulin IHC. Nine PI-positive tumors represented functional insulinomas. Patients with PI IHC-positive tumors demonstrated significantly lower mean preoperative serum glucose compared with PI-negative PNET patients, even when insulinomas were excluded. No differences in survival between PI IHC positive and PI IHC-negative tumors were observed. We identified 2 PI-positive PNETs from hypoglycemic patients, which were not insulinomas or other functional variants and in which serum PI was never tested. These may have been undetected proinsulinomas. CONCLUSIONS: Proinsulin-expressing PNETs (functional or non) are not uncommon. Patients who present with hypoglycemia and normal insulin levels should be screened for proinsulinoma. Proinsulin IHC could also be used to screen for proinsulinoma. To further elucidate the clinical significance of PI expressing PNETs, prospective studies are required. PMID- 30451801 TI - Repeatability of Anterior Curvature Metrics in Healthy and Keratoconic Eyes with a Portable Handheld Topographer. AB - SIGNIFICANCE: This is a prospective observational investigation that studies the repeatability of several outcomes obtained with the Keratron Scout in healthy and keratoconic corneas. In addition, we have been able to determine the "noise" values of the instrument, which can be very useful when evaluating possible progression in keratoconus (KCN). PURPOSE: The purpose of this study was to evaluate the repeatability of several anterior curvature metrics provided by a portable and handheld Placido disk-based topographer in healthy and keratoconic eyes. METHODS: One eye from 50 keratoconic patients and 50 eyes from healthy patients were included in this prospective observational study. Two consecutive sessions (with three scans per session) were performed, and the following parameters were analyzed with a Keratron Scout topographer: flat keratometry, steep keratometry, flat corneal axis, corneal astigmatism, and flat and steep asphericities. In addition, in the KCN cohort, indices derived from the Cone Location and Magnitude Index were also recorded. Intrasession (first session, all three measurements) and intersession (one measurement from each session, selected randomly) statistics were calculated. The following variables were calculated: within-subject standard deviation, coefficient of repeatability (R), coefficient of variation, and intraclass correlation coefficient (ICC). RESULTS: In healthy eyes, the intrasession and intersession ICCs were high (0.947 to 0.999), and for both flat keratometry and steep keratometry, the within-subject standard deviation was 0.08 and R was 0.24 diopters. Repeatability was slightly lower in the KCN group, but the ICC was greater than 0.95, whereas the R for flat keratometry was 0.41 diopters. CONCLUSIONS: The Keratron Scout provides repeatable measures for the studied metrics in healthy and keratoconic eyes. PMID- 30451802 TI - Ranibizumab versus Dexamethasone Implant in Macular Edema Secondary to Branch Retinal Vein Occlusion: Two-year Outcomes. AB - SIGNIFICANCE: We compared the 24-month outcomes of ranibizumab and dexamethasone implants in treatment-naive branch retinal vein occlusion patients. Ranibizumab was effective in improving visual outcomes, whereas the dexamethasone implant was not. PURPOSE: The aim of this study was to compare the 2-year real-world outcomes of intravitreal ranibizumab with dexamethasone implants in patients with macular edema secondary to branch retinal vein occlusion. METHODS: The treatment-naive branch retinal vein occlusion patients with macular edema who were treated with intravitreal ranibizumab or dexamethasone implant were included retrospectively. Primary outcome measures were the change in best-corrected visual acuity and central retinal thickness. RESULTS: Eighty-seven eyes of 87 patients were included. Mean +/- SD best-corrected visual acuity in the intravitreal ranibizumab group at baseline and 24 months was 0.64 +/- 0.48 and 0.49 +/- 0.44 logMAR (P < .05). Mean +/- SD best-corrected visual acuity in the intravitreal dexamethasone implant group at baseline and 24 months was 0.98 +/- 0.56 and 0.92 +/- 0.61 logMAR (P > .05). Mean +/- SD central retinal thickness in the intravitreal ranibizumab group at baseline and 24 months was 530 +/- 150 and 337 +/- 103 MUm (P < .05). Mean +/- SD central retinal thickness in the intravitreal dexamethasone implant group at baseline and 24 months was 591 +/- 113 and 335 +/- 99 MUm (P < .05). Mean +/- SD number of injections at 24 months was 5.6 +/- 1.8 in the intravitreal ranibizumab group and 2.7 +/- 1.1 in the dexamethasone implant group (P < .0001). Progression in lens opacity was detected in 5.7% of the phakic patients in the intravitreal ranibizumab group and 46.1% of them in the dexamethasone implant group (P < .0001). None of the patients in the intravitreal ranibizumab group and 9 (22.0%) of 41 patients in the dexamethasone implant group showed an increase of more than 10 mmHg in intraocular pressure. CONCLUSIONS: Ranibizumab was effective in the treatment of macular edema secondary to branch retinal vein occlusion in both visual and anatomical outcomes; however, dexamethasone implant was effective only in anatomical outcomes. PMID- 30451803 TI - Measuring Daily Disposable Contact Lenses against Nonwearer Benchmarks. AB - SIGNIFICANCE: Since becoming a popular form of refractive error correction, contact lenses have aspired to replicate the nonwearer experience. This study assessed how well currently available daily disposable soft lenses have achieved that goal, using a graphical representation to show individual lens behavior relative to benchmarks. PURPOSE: The purpose of this study was to assess comfort, vision, and adverse events during daily disposable contact lens wear, relative to emmetropes and spectacle wearers. METHOD: Three-month clinical studies, where participants either wore one of five daily disposable contact lenses (n = 201), were full-time spectacle wearers with no history of contact lens wear (n = 34), or emmetropic non-contact lens wearers (n = 40). Vision quality and comfort were assessed at the beginning and end of the day (1 to 10). Corneal infiltrative events were recorded. Between-group comparisons were made using a linear mixed model and literature estimates of clinical significance. RESULTS: Initial comfort among emmetropes (mean +/- 95% confidence interval, 8.0 +/- 0.5) was not significantly different from any of the lens types (range, 7.2 +/- 0.4 to 8.0 +/- 0.4, all P > .06) or spectacle wearers (7.3 +/- 0.5, P = .45). Comfort deteriorated during the day in all groups (P < .05). End-of-day comfort for emmetropes (7.3 +/- 0.6) was significantly better, only than lenses B (5.7 +/- 0.6, P < .001) and D (6.2 +/- 0.5, P = .01). Vision quality for emmetropes (8.6 +/- 0.5) was better than spectacle wearers (7.8 +/- 0.5, P = .04) and lenses A (7.6 +/- 0.4, P = .003) and B (7.5 +/- 0.4, P < .001). Corneal infiltrative events occurred in 0% of emmetropes and 2.9% of spectacle wearers and ranged from 2.4 to 7.5% in lens wearers. CONCLUSIONS: Under the conditions of this study, comfort and vision with some contemporary daily disposable contact lenses were indistinguishable from nonwearing emmetropes. Although the contact lens-wearing groups had rates of corneal infiltrative events that were not statistically different from the nonwearers, the study had insufficient power to permit robust conclusions in this respect. PMID- 30451804 TI - Accuracy of a Smartphone-based Autorefractor Compared with Criterion-standard Refraction. AB - SIGNIFICANCE: Uncorrected refractive error is a prevalent problem throughout the world especially among the low-income population who have limited access to professional eye care and cannot afford eyeglasses. PURPOSE: The purpose of this study was to evaluate the accuracy and usability of a low-cost, portable, smartphone-based autorefractor (Netra, EyeNetra Inc., Somerville, MA) in adults. METHODS: A cross-sectional study was conducted to compare the portable refractor with subjective (manifest and cycloplegic) refraction for sequential adult participants with best-corrected visual acuity of 20/40 or greater. For each method of refraction, the spherical equivalent was calculated. Differences between methods were tested with linear mixed regression models. A validated usability questionnaire was administered regarding ease of use (100-point scale, higher scores better) for the portable autorefractor. RESULTS: Eighty-seven subjects (152 eyes) were studied (age range, 20 to 90 years; mean +/- standard deviation, 51.9 +/- 18.3 years). Mean spherical equivalent by the portable device was -2.76 D (range, -14.75 to 3.63 D) compared with -2.49 D (range, -15.25 to 4.25 D) by manifest refraction. The mean relative difference in spherical equivalent between methods was -0.27 D (P = .001, significantly different than 0 D). The mean absolute difference between methods was 0.69 D (P < .001, significantly different than 0.5-D absolute difference). Similar results were found when comparing spherical equivalent between Netra and cycloplegic refraction methods. Subjects reported average ease of use for the Netra of 75.4 +/- 19.8. CONCLUSIONS: The portable autorefractor had small but clinically significant differences from subjective refraction. The device's scores on the usability scale indicate good overall patient acceptance. The device may be valuable for use where there is limited access to a trained refractionist. PMID- 30451805 TI - Identification of a CNGB1 Frameshift Mutation in a Han Chinese Family with Retinitis Pigmentosa. AB - SIGNIFICANCE: Retinitis pigmentosa (RP) is a severe hereditary retinal disorder characterized by progressive degeneration of rod and cone photoreceptors. This study identified a novel frameshift mutation, c.385delC, p.(L129WfsTer148), in the cyclic nucleotide-gated channel beta 1 (CNGB1) gene of a consanguineous Han Chinese family with autosomal recessive RP (arRP). This expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling. PURPOSE: The present study sought to identify potential pathogenetic gene mutations in a five-generation consanguineous Han Chinese family with RP. METHODS: Two members of a five-generation consanguineous Han Chinese pedigree with arRP and 100 normal individuals were enrolled in this study. Exome sequencing was performed on the 70-year-old male proband from a consanguineous family to screen potential pathogenic mutations according to the American College of Medical Genetics and Genomics for the interpretation of sequence variants. Sanger sequencing was performed on the proband, the proband's unaffected son, and 100 normal individuals to verify the disease-causing mutation. RESULTS: A novel frameshift mutation, c.385delC, p.(L129WfsTer148), with homozygous status in the CNGB1 gene was identified in the proband of the family with arRP, and the mutation with heterozygous status was carried by the asymptomatic son. CONCLUSIONS: The c.385delC (p.(L129WfsTer148)) mutation in the CNGB1 gene screened by exome sequencing is probably responsible for the RP phenotype in this family. The result expands the spectrum of CNGB1 gene variants in RP cases and possibly refines future genetic counseling. PMID- 30451806 TI - Visual Performance of Daily-disposable Multifocal Soft Contact Lenses: A Randomized, Double-blind Clinical Trial. AB - SIGNIFICANCE: The present study highlights the differences between modern daily disposable multifocal soft contact lenses to assist eye care practitioners in fitting presbyopic contact lens wearers. PURPOSE: The purpose of this study was to compare visual performance of three daily-disposable multifocal contact lenses. METHODS: Presbyopes (n = 72) wore 1-Day Acuvue Moist Multifocal, BioTrue ONEday for Presbyopia, and Dailies AquaComfort Plus Multifocal for 1 week in a prospective, randomized, double-blind, crossover clinical trial. After 1 week, high- and low-contrast visual acuities (HCVA, LCVA) were measured between 6 m and 40 cm and stereopsis at 40 cm. Subjective performance was assessed with 1- to 10 point rating scales for clarity, ghosting, driving vision, vision stability, ease of focusing, overall vision satisfaction, and ocular comfort. Willingness to purchase was reported with categorical responses. Linear mixed models and chi tests were used for analysis, and level of significance was set at 5%. RESULTS: BioTrue provided better HCVA and LCVA at distance than did Acuvue Moist (P <= .03). Subjectively, Acuvue Moist was rated lowest for distance clarity, distance ghosting, and driving vision (P <= .05). Acuvue Moist provided better HCVA at 70 to 40 cm and LCVA at 1 m to 40 cm than did BioTrue (P <= .01) and better LCVA at 1 m to 50 cm than did AquaComfort Plus (P <= .02). AquaComfort Plus also provided better HCVA and LCVA at 50 and 40 cm than did BioTrue (P <= .03). Acuvue Moist provided better stereopsis than did BioTrue (P = .02). Subjectively, BioTrue was rated lowest for near clarity (P <= .007) and lower than Acuvue Moist for intermediate clarity and near ghosting (P <= .04). No other differences were found between lenses (P > .05). CONCLUSIONS: BioTrue had better distance performance compared with near, whereas Acuvue Moist performed conversely. AquaComfort Plus performed reasonably overall. PMID- 30451807 TI - Comparison of the Ultraviolet Light Filtering across Different Intraocular Lenses. AB - SIGNIFICANCE: We have analyzed the ultraviolet transmittance of some commercial intraocular lenses (IOLs). The results show differences of wavelength cutoff among them. PURPOSE: The purpose of this study was to measure and compare the ultraviolet light transmittance of different IOLs made out of acrylic hydrophobic, hydrophilic, and hydrophilic with hydrophobic surface materials from different manufacturers. METHODS: The spectral transmission curves of eight monofocal IOLs with the same dioptric power of +20.0 diopters were measured using a PerkinElmer Lambda 35 ultraviolet/visible spectrometer. Two IOLs of each type were tested three times. The ultraviolet cutoff wavelength at 10% transmission and the mean values were calculated. RESULTS: All lenses prevented transmission of ultraviolet C (200 to 280 nm) and B radiation (280 to 315 nm). However, not all IOLs provided the same filtering properties in ultraviolet A (315 to 380 nm). Within the ultraviolet A range, the ultraviolet radiation cutoff wavelength of 10% ranges from approximately 360 to 400 nm. HOYA iSert 250 provided a cutoff wavelength of 398.4 nm; AcrySof SA60AT, 396.2 nm; AcrySof SA60WF, 395.7 nm; CT Asphina 404, 378.34 nm; Tecnis ZCB00, 377.70 nm; CT Lucia 607P, 379 nm; C-Flex 570C, 377 nm; and enVista MX60, 360 nm. CONCLUSIONS: Intraocular lenses of different materials and manufacturers have different ultraviolet transmission characteristics. AcrySof (SA60AT and SA60WF) and HOYA iSert 250 provided the highest ultraviolet radiation transmission; the cutoff wavelength of 10% is close to 400 nm. In contrast, enVista IOL showed the lowest ultraviolet radiation cutoff. PMID- 30451808 TI - Scotoma Simulation in Healthy Subjects. AB - SIGNIFICANCE: This article shows a successful concept for simulating central scotoma, which is associated with age-related macular degeneration (AMD), in healthy subjects by an induced dark spot at the retina using occlusive contact lenses. The new concept includes a control mechanism to adjust the scotoma size through controlling pupil size without medication. Therefore, a miniaturized full field adaptation device was used. PURPOSE: The aim of this study was to design a novel concept to simulate AMD scotoma in healthy subjects using occlusive contact lenses. METHODS: To define an optimal set of lens parameters, we constructed an optical model and considered both the anatomical pupil diameter and the opaque central zone diameter of the contact lens. To adjust the scotoma size, we built a miniaturized full-field adaptation device. We demonstrate the validity of this novel concept by functional measurements of visual fields using automated threshold perimetry. Finally, we conducted a perception study including two tasks, consisting of pictograms and letters. The stimuli were presented at different eccentricities and magnifications. RESULTS: The visual fields of all 10 volunteers exhibited absolute scotomas. The loss of contrast sensitivity ranged within 27 and 36 dB (P < .05), and the scotoma localizations were nearly centered to the macula (mean variation, 2.0 +/- 4.8 degrees horizontally; 3.5 +/- 4.7 degrees vertically). The eccentric perception of letters showed the largest numbers of correctly identified stimuli. The perception of pictograms showed significantly reduced numbers (P < .0001) and revealed a dependency on magnification. The results suggest that best perception is possible for magnified stimuli near the scotoma. CONCLUSIONS: We demonstrated that the creation of an absolute simulated AMD scotoma is possible using occlusive contact lenses combined with a miniaturized full-field adaptation device. PMID- 30451809 TI - Ophthalmic Conditions Associated with Inpatient Falls among Veterans. AB - SIGNIFICANCE: Efforts to describe the relationship between pathological visual impairment and fall risk are typically confined to community dwellers. Among admitted patients, however, the associations are less understood. Fall risk assessment tools are used in some clinical settings, but most do not capture the suspected importance of ophthalmic pathologies in predicting the likelihood of an inpatient fall. PURPOSE: The purpose of this study was to determine the association between ophthalmic conditions and inpatient falls at the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC), where vision and ophthalmic conditions are not considered when assessing fall risk. METHODS: This is a population-based, retrospective case-control study of 805 patients admitted to the MEDVAMC in January 2014 who had also visited the MEDVAMC Eye Clinic within 1 year of admission. The patients' eye examinations, ophthalmic diagnoses, and other indicators of constitutive health were compared between 60 patients who experienced an inpatient fall ("cases") and 749 patients who did not ("controls"). Significant differences between the cases and the controls were determined using logistic regression models. RESULTS: Baseline demographics were similar among the two groups. Ophthalmic conditions associated with an increased incidence of inpatient falls included age-related macular degeneration (odds ratio, 3.9; 95% confidence interval, 1.5 to 9.9; P = .008) and a presenting visual acuity of worse than 20/40 in the better-seeing eye (odds ratio, 2.0; 95% confidence interval, 1.0 to 4.1; P = .04). Those without falls demonstrated a better mean presenting visual acuity in the better-seeing eye compared with those who fell (logMAR, 0.12 +/- 0.23 vs. 0.28 +/- 0.49, P < .001). CONCLUSIONS: In this population, age-related macular degeneration and poor presenting visual acuity in the better-seeing eye are associated with increased incidence of inpatient falls. An assessment of visual function and ophthalmic diagnoses may be warranted upon admission to the hospital for increased prevention of inpatient falls. PMID- 30451810 TI - Recovery of Bone Mineral Mass After Upper Limb Fractures in Children and Teenagers. AB - BACKGROUND: Loss of bone mineral mass and muscle atrophy are predictable consequences of cast-mediated immobilization following wrist and forearm fractures. This study aimed to prospectively determine whether previously reported lower bone mineral mass following immobilization for wrist and forearm fractures in children and teenagers had recovered at 6- and 18-month follow-up. METHODS: We recruited 50 children and teenagers who underwent a cast-mediated immobilization for a forearm or wrist fracture. Dual-energy x-ray absorptiometry scans of different skeletal sites were performed at the time of fracture, at cast removal, at 6 and at 18-month follow-up. Injured patients were paired with healthy controls according to sex and age. Dual-energy x-ray absorptiometry values were compared between groups and the injured and uninjured forearms of the patients. RESULTS: At the time of fracture, injured and healthy subjects showed no differences between their bone mineral density (BMD) and bone mineral content (BMC) z-scores at the lumbar spine, or between their BMDs at the peripheral wrist. At cast removal, upper limb bone mineral variables were significantly lower in the injured group (except for the ultradistal radius) than in the uninjured group, with differences ranging from 3.8% to 10.2%. No residual decrease in bone mineral variables was observed at any upper limb site at 6- and 18-month follow-up (28 injured patients). Significant residual increases in the BMDs and BMCs were observed for the injured group's ultradistal radius and whole wrists (+4.8% to +5.2%). CONCLUSIONS: A rapid bone mass reversal occurs by resumption of mobilization, with full bone recovery 6 months after a forearm or wrist fracture. Finally, healing bone callus could introduce a bias into the interpretation of BMD and BMC data at the fracture site, not only at cast removal but also 18 months after the fracture. PMID- 30451811 TI - Operative Reduction for Developmental Dysplasia of the Hip: Epidemiology Over 16 Years. AB - BACKGROUND: The burden of surgical treatment for infantile developmental dysplasia of the hip (DDH) is unknown. We aimed to investigate the epidemiology of operative DDH reductions in the United States and identify potential at-risk populations. METHODS: The Healthcare Utilization Project Kids' Inpatient Database (1997 to 2012) were analyzed. International Classification of Diseases (ICD-9) codes identified inpatient hospitalizations for DDH reductions excluding neuromuscular cases. Hospital variables and patient demographics were captured. Weighted population-level counts were calculated to allow for national estimates. RESULTS: An estimated 5525 (95% confidence interval, 4907.8-6142.2) operative reductions were performed. In total, 73.3% were open with a mean age at the reduction of 2.3 years (95% confidence interval, 2.1-2.5). In total, 70.0% were female and 42.3% were white. Regional distribution varied: 36.4% of reductions occurred in the West, 22.8% in the South, 21.9% in the Midwest, and 18.9% in the Northeast. Operative reductions decreased over time; open reductions decreased by 5.6% and closed by 53.4%. Mean age at treatment increased from 1.6 to 3.7 years (P<0.001). On multivariate analysis, age (P<0.001) and geographic location (P<0.05) were associated with open reduction. Patients in the West had increased odds of being Hispanic or Asian/Pacific Islander [odds ratio (OR), 4.9, P<0.001 and OR, 2.8; P=0.008]. In the South and Midwest, the highest income quartile was protective (OR, 0.4; P=0.001 and OR, 0.5; P=0.018). CONCLUSIONS: The frequency of closed reductions decreased more over time compared with open reductions. However, the mean age of children undergoing reductions increased suggesting a possible delay in diagnosis. The data suggests that there is room for improvement in screening. Targeted research in identified populations may reduce the burden of surgical disease in infantile DDH. LEVEL OF EVIDENCE: Level III. PMID- 30451812 TI - Retrograde Stainless Steel Flexible Nails Have Superior Resistance to Bending in Distal Third Femoral Shaft Fractures. AB - BACKGROUND: It has been shown that retrograde titanium flexible intramedullary nails (Ti FIN) provide superior resistance to bending compared to antegrade Ti FIN in distal femur fractures. The purpose of this study was to compare resistance to torsional and bending forces of stainless steel (SS) FIN, with or without a locking screw, and Ti FIN in distal third femoral shaft fractures. We hypothesize that locked retrograde SS FIN will demonstrate greater resistance to both bending and torsional forces. METHODS: Thirty adolescent synthetic femur models were used to simulate transverse distal femoral fractures at either 60 mm or 90 mm proximal to the distal femoral physis. The femurs were instrumented with antegrade Ti FIN, antegrade SS FIN, retrograde Ti FIN, retrograde SS FIN, or retrograde locked SS FIN. Three models for each construct at both osteotomy levels were tested. Models were analyzed to determine maximum resistance to bending and torsion. RESULTS: In fractures 60 mm from the physis, retrograde SS FIN demonstrated statistically superior resistance to bending when compared with both antegrade and retrograde Ti FIN (P=0.001 and 0.008, respectively) and antegrade SS FIN (P=0.0001). Locked SS constructs showed a trend towards greater resistance to bending forces when compared with unlocked constructs (P>0.05). No significant difference was seen in resistance to bending when fractures were 90 mm proximal to the distal femoral physis between the five groups. No significant differences were observed in resistance to torsion in either the proximal or distal fracture models, regardless of construct type. CONCLUSIONS: Retrograde SS FIN confer significantly greater resistance to bending forces for fractures 60 mm proximal to the distal femoral physis compared with Ti FIN or antegrade entry SS FIN. In fractures 90 mm from the physis, no differences were noted in our model. Our results support the use of retrograde SS nails in the pediatric patient with distal femoral shaft fractures. LEVEL OF EVIDENCE: Level II-comparative biomechanical study. PMID- 30451813 TI - The Spatial Order of Physeal Maturation in the Normal Human Knee Using Magnetic Resonance Imaging. AB - BACKGROUND: The spatial order of physeal maturation around the distal tibia has been shown to place adolescent patients at risk for certain transitional injuries, such as Tillaux or triplane fractures. Less is known about physeal maturation around the knee. The purpose of this study was to establish the spatial order of physeal maturation in the normal human knee using magnetic resonance imaging (MRI). METHODS: We retrospectively collected all knee MRI scans from patients presenting to our institution from January 2004 to January 2014. Patients who were suspected on the basis of clinical or radiographic findings of having abnormal knee physeal development or injury were excluded. We then applied a previously described MRI staging system of knee physeal maturation to the MRI scans of the remaining patients at 8 defined knee locations. Associations between the stage of maturation and mean chronological age were then evaluated across the 8 knee locations. Interrater and intrarater reliabilities were assessed. RESULTS: A total of 165 knee MRI scans (from 98 boys, 67 girls) met the inclusion criteria. Significant differences were found between each stage of physeal maturation and the mean chronological ages at all 8 knee locations for both boys and girls (each, P<0.001). Interestingly, within each stage of physeal maturation, no significant difference was found in the mean chronological ages at any of the 8 knee locations, suggesting that physeal development occurs uniformly in the normal human knee for both boys and girls. Interrater and intrarater reliability were nearly perfect at all locations. CONCLUSIONS: The spatial order of physeal maturation in the normal human knee was uniform across 8 knee locations for both boys and girls. This uniformity may help to explain why transitional injuries do not follow a recognizable pattern in the knee. Furthermore, the uniformity aids with surgical decision making, because minimal growth modulation or disturbance is likely when early physeal closure is present in a portion of the physis. LEVEL OF EVIDENCE: Level III. PMID- 30451814 TI - Use of Combined Botulinum Toxin and Physical Therapy for Treatment Resistant Congenital Muscular Torticollis. AB - BACKGROUND: Physical therapy (PT) alone is not always effective for treatment of congenital muscular torticollis (CMT). The adjunctive use of botulinum toxin (BTX) injection into the sternocleidomastoid, followed by PT, could provide correction and avoid more invasive surgery. Aims of the study were to review clinical and caregiver-reported outcomes of children with resistant CMT treated by BTX injection combined with a guided-PT program. METHODS: Medical records of consecutive children with resistant CMT treated by our protocol between 2010 and 2015 were reviewed. A minimum 2-year follow-up was required. Demographic parameters, numbers of BTX required and pre-BTX and post-BTX head tilt and range of neck rotation were recorded. A univariate analysis test was conducted to identify variables related to the need of repeated BTX injections. A phone interview with the caregivers was done regarding their satisfaction. RESULTS: A cohort of 39 patients with treatment resistant CMT were identified that had an average age of 14 (range, 6.5 to 27.6) months at initiation of BTX treatment. Multiple BTX injections were utilized in 21/39 (54%) of patients. No patient required tendon lengthening surgery. At the final evaluation, there was improvement in both head tilt (18.7+/-6.8 degrees vs. 1.7+/-2.4 degrees, mean difference (95% CI) 16.9 (14.6-19.3); P<0.001) and range of neck motion (56.0 degrees +/-11.7 degrees vs. 86.0+/-3.8 degrees, mean difference (95% CI) 30.0 (26.1-33.9), P<0.001). Pre-BTX parameters were not associated with the requirement of repeated BTX injections (P>0.05). Caregivers were satisfied with the treatment protocol. No untoward effect was observed during the study period. CONCLUSIONS: The proposed minimally invasive protocol provided correction of resistant CMT and obviated the need for more invasive surgical procedures. LEVEL OF EVIDENCE: Level IV. PMID- 30451815 TI - High Correlation Between Achieved and Expected Distraction Using Magnetically Controlled Growth Rods (MCGR) With Rib to Pelvis Fixation in Pediatric Spine Deformity. AB - PURPOSE: Magnetically controlled implant systems have been established to treat severe progressive spinal deformity in children. The purpose of this study was to evaluate (1) the ratio between achieved and expected distraction length, (2) the complication rate and its risk factors as well as (3) the correlation of the distraction length and the length of the spine. METHODS: A total of 40 patients with an average follow-up of 34 (14 to 57) months were prospectively included in the study. Children underwent lengthening procedures every three months. The ratio between the distraction lengths was determined by comparing the measured distraction length of the rod on radiographs with the distraction length displayed on the external remote controller for the magnetically controlled growing rod (MCGR). Age, weight, height, and complications were repeatedly recorded. RESULTS: The analysis of 746 procedures showed the actual distraction to be 94.4% of the expected one. No difference between implants on the concave and convex spinal side was observed. The overall complication rate was 4.6% mainly because of failure of the implant or lack of implant extension, which was directly related to an increased BMI. There was also a strong correlation between achieved implant distraction length and gain in spinal length. CONCLUSIONS: Our study demonstrates a high ratio (0.94) between achieved and expected distraction length of magnetically controlled spinal rods. The complication rate was low (4.6%) and correlated to a high BMI. The correlation between the achieved implant distraction length and spinal length indicates the efficiency of the MCGR therapy. LEVEL OF EVIDENCE: Therapeutic Level IV. PMID- 30451816 TI - Ranolazine as an additional antianginal therapy in patients with stable symptomatic coronary artery disease. AB - INTRODUCTION: There are several effective therapeutic alternatives for stable coronary artery, in terms of prevention of cardiovascular morbidity and mortality. However, the best way to achieve symptomatic control is a matter of debate, particularly in those who do not respond to first-line therapy. This summary aims to evaluate the role of ranolazine as an additional therapy to standard antianginal treatment in patients with persistent symptoms. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified four systematic reviews including 16 studies overall, all of which were randomized trials. We concluded additional treatment with ranolazine might decrease the frequency of anginal episodes but increase adverse effects. It probably has no effect on the risk of death or acute myocardial infarction. PMID- 30451817 TI - Non-contrast computed tomography for the diagnosis of non-traumatic subarachnoid hemorrhage. AB - INTRODUCTION: Subarachnoid hemorrhage is a neurosurgical emergency that requires timely diagnosis due to its severity and the existence of therapeutic measures that are effective when carried out in time. The most used diagnostic sequence to rule it out is computed tomography without contrast which, if negative, is followed by lumbar puncture. However, it has been suggested that a negative non contrast computed tomography (without blood) may rule out the diagnosis. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including nine studies. We concluded the diagnostic accuracy of non-contrast computed tomography is probably very high, but the clinical impact of relying only on this test has not yet been evaluated. PMID- 30451818 TI - Correction to: Ginkgo biloba for the treatment of tinnitus. PMID- 30451819 TI - Locomotion modulates specific functional cell types in the mouse visual thalamus. AB - The visual system is composed of diverse cell types that encode distinct aspects of the visual scene and may form separate processing channels. Here we present further evidence for that hypothesis whereby functional cell groups in the dorsal lateral geniculate nucleus (dLGN) are differentially modulated during behavior. Using simultaneous multi-electrode recordings in dLGN and primary visual cortex (V1) of behaving mice, we characterized the impact of locomotor activity on response amplitude, variability, correlation and spatiotemporal tuning. Locomotion strongly impacts the amplitudes of dLGN and V1 responses but the effects on variability and correlations are relatively minor. With regards to tunings, locomotion enhances dLGN responses to high temporal frequencies, preferentially affecting ON transient cells and neurons with nonlinear responses to high spatial frequencies. Channel specific modulations may serve to highlight particular visual inputs during active behaviors. PMID- 30451820 TI - Long non-coding RNA H19 confers 5-Fu resistance in colorectal cancer by promoting SIRT1-mediated autophagy. AB - Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. The role of the differentially expressed lncRNAs in 5-Fluorouracil chemoresistance has not fully explained. Here, we observed lncRNA H19 was associated with the 5-Fu resistance in CRC. Quantitative analysis indicated that H19 was significantly increased in recurrent CRC patient samples. Kaplan-Meier survival analysis indicated that high H19 expression in CRC tissues was significantly associated with poor recurrent free survival. Our functional studies demonstrated that H19 promoted colorectal cells 5-Fu resistance. Mechanistically, H19 triggered autophagy via SIRT1 to induce cancer chemoresistance. Furthermore, bioinformatics analysis showed that miR-194-5p could directly bind to H19, suggesting H19 might work as a ceRNA to sponge miR 194-5p, which was confirmed by Dual-luciferase reporter assay and Immunoprecipitation assay. Extensively, our study also showed that SIRT1 is the novel direct target of miR-194-5p in CRC cells. Taken together, our study suggests that H19 mediates 5-Fu resistance in CRC via SIRT1 mediated autophagy. Our finding provides a novel mechanistic role of H19 in CRC chemoresistance, suggesting that H19 may function as a marker for prediction of chemotherapeutic response to 5-Fu. PMID- 30451821 TI - Sumoylation of RORgammat regulates TH17 differentiation and thymocyte development. AB - RORgammat controls the differentiation of TH17 cells, which are mediators of autoimmune conditions such as experimental autoimmune encephalomyelitis (EAE). RORgammat also regulates thymocyte development and lymph node genesis. Here we show that the function of RORgammat is regulated by its sumoylation. Loss of Sumo3, but not Sumo1, dampens TH17 differentiation and delays the progression of thymic CD8+ immature single-positive cells (ISPs). RORgammat is SUMO3-modified by E3 ligase PIAS4 at lysine 31 (K31), and the mutation of K31 to arginine in mice prevents RORgammat sumoylation, leading to impaired TH17 differentiation, resistance to TH17-mediated EAE, accumulation of thymic ISPs, and a lack of Peyer's patches. Mechanistically, sumoylation of RORgammat-K31 recruits histone acetyltransferase KAT2A, which stabilizes the binding of SRC1 to enhance RORgammat transcription factor activity. This study thus demonstrates that sumoylation is a critical mechanism for regulating RORgammat function, and reveals new drug targets for preventing TH17-mediated autoimmunity. PMID- 30451822 TI - Cell metabolism regulates integrin mechanosensing via an SLC3A2-dependent sphingolipid biosynthesis pathway. AB - Mechanical and metabolic cues independently contribute to the regulation of cell and tissue homeostasis. However, how they cross-regulate each other during this process remains largely unknown. Here, we show that cellular metabolism can regulate integrin rigidity-sensing via the sphingolipid metabolic pathway controlled by the amino acid transporter and integrin coreceptor CD98hc (SLC3A2). Genetic invalidation of CD98hc in dermal cells and tissue impairs rigidity sensing and mechanical signaling downstream of integrins, including RhoA activation, resulting in aberrant tissue mechanical homeostasis. Unexpectedly, we found that this regulation does not occur directly through regulation of integrins by CD98hc but indirectly, via the regulation of sphingolipid synthesis and the delta-4-desaturase DES2. Loss of CD98hc decreases sphingolipid availability preventing proper membrane recruitment, shuttling and activation of upstream regulators of RhoA including Src kinases and GEF-H1. Altogether, our results unravel a novel cross-talk regulation between integrin mechanosensing and cellular metabolism which may constitute an important new regulatory framework contributing to mechanical homeostasis. PMID- 30451823 TI - Continuous negative-to-positive tuning of thermal expansion achieved by controlled gas sorption in porous coordination frameworks. AB - Control of the thermomechanical properties of functional materials is of great fundamental and technological significance, with the achievement of zero or negative thermal expansion behavior being a key goal for various applications. A dynamic, reversible mode of control is demonstrated for the first time in two Prussian blue derivative frameworks whose coefficients of thermal expansion are tuned continuously from negative to positive values by varying the concentration of adsorbed CO2. A simple empirical model that captures site-specific guest contributions to the framework expansion is derived, and displays excellent agreement with the observed lattice behaviour. PMID- 30451824 TI - Palladium concave nanocrystals with high-index facets accelerate ascorbate oxidation in cancer treatment. AB - Intravenous pharmacological dose of ascorbate has been proposed as a potential antitumor therapy; however, its therapeutic efficacy is limited due to the slow autoxidation. Here, we report that palladium (Pd) nanocrystals, which possess intrinsic oxidase-like activity, accelerate the autoxidation of ascorbate, leading to the enhancement of its antitumor efficacy. The oxidase-like activity of Pd nanocrystals was facet-dependent, with the concave nanostructure enclosed by high-index facets catalyzing ascorbate autoxidation more efficiently than the planar nanostructure enclosed by low-index facets. Our first-principles calculations provide the underlying molecular mechanisms for the facet-dependent activation of O2 molecule and subsequent ascorbate oxidation. Further in vitro and in vivo assays demonstrate the enhancement of the antitumor efficacy of ascorbate with these Pd concave nanocubes. Our animal experiments also indicate the combined approach with both ascorbate and Pd concave nanocubes displays an even better efficacy than currently available clinical medicines, with no obvious cytotoxicity to normal cells. PMID- 30451825 TI - Loss of oocyte Rps26 in mice arrests oocyte growth and causes premature ovarian failure. AB - Global transcriptional activity increases as oocytes grow and is silenced in fully grown oocytes. Thus, the chromatin configuration varies during oocyte growth, but the molecular mechanisms regulating these changes remain to be clarified. Here, we studied a susceptibility gene of polycystic ovary syndrome (PCOS), RPS26, which is a ribosomal protein-encoding gene that is highly expressed in the ovary, but the functions of which remain unknown. Specific knockout of Rps26 in mouse oocytes resulted in retarded follicle development from pre-antral follicles to antral follicles, while the chromatin configurations of the oocytes were arrested at the transition from the non-surrounded nucleolus (NSN) to surrounded nucleolus (SN)-type. As a consequence, all oocytes died by postnatal day 84 resulting in premature ovarian failure (POF). Loss of Rps26 in oocytes led to decreased mRNA transcription and low levels of histone trimethylation on H3K4/H3K9 and DNA methylation at 5-cytosine, high levels of which are required for oocytes to transform from NSN to SN-type. Low protein levels of oocyte-derived growth differentiation factor 9, bone morphogenetic protein 15, and the oocyte-granulosa cell gap junction protein connexin 37 inhibited oocyte growth and retarded follicle development. The disruption of the phosphoinositide 3-kinase/protein kinase B/Forkhead box O-3a pathway contributed to oocyte death and follicle atresia. These results provide genetic clues for the clinical diagnosis of POF, especially in PCOS patients without treatment. PMID- 30451826 TI - Molecular basis of maintaining an oxidizing environment under anaerobiosis by soluble fumarate reductase. AB - Osm1 and Frd1 are soluble fumarate reductases from yeast that are critical for allowing survival under anaerobic conditions. Although they maintain redox balance during anaerobiosis, the underlying mechanism is not understood. Here, we report the crystal structure of a eukaryotic soluble fumarate reductase, which is unique among soluble fumarate reductases as it lacks a heme domain. Structural and enzymatic analyses indicate that Osm1 has a specific binding pocket for flavin molecules, including FAD, FMN, and riboflavin, catalyzing their oxidation while reducing fumarate to succinate. Moreover, ER-resident Osm1 can transfer electrons from the Ero1 FAD cofactor to fumarate either by free FAD or by a direct interaction, allowing de novo disulfide bond formation in the absence of oxygen. We conclude that soluble eukaryotic fumarate reductases can maintain an oxidizing environment under anaerobic conditions, either by oxidizing cellular flavin cofactors or by a direct interaction with flavoenzymes such as Ero1. PMID- 30451827 TI - Effective removal of mercury from aqueous streams via electrochemical alloy formation on platinum. AB - Retrieval of mercury from aqueous streams has significant environmental and societal importance due to its very high toxicity and mobility. We present here a method to retrieve mercury from aqueous feeds via electrochemical alloy formation on thin platinum films. This application is a green and effective alternative to traditional chemical decontamination techniques. Under applied potential, mercury ions in solution form a stable PtHg4 alloy with platinum on the cathode. A 100 nanometres platinum film was fully converted to a 750 nanometres thick layer of PtHg4. The overall removal capacity is very high, > 88 g mercury per cm3. The electrodes can easily be regenerated after use. Efficient and selective decontamination is possible in a wide pH range, allowing processing of industrial, municipal, and natural waters. The method is suited for both high and low concentrations of mercury and can reduce mercury levels far below the limits allowed in drinking water. PMID- 30451828 TI - Single cell RNA-seq and ATAC-seq analysis of cardiac progenitor cell transition states and lineage settlement. AB - Formation and segregation of cell lineages forming the heart have been studied extensively but the underlying gene regulatory networks and epigenetic changes driving cell fate transitions during early cardiogenesis are still only partially understood. Here, we comprehensively characterize mouse cardiac progenitor cells (CPCs) marked by Nkx2-5 and Isl1 expression from E7.5 to E9.5 using single-cell RNA sequencing and transposase-accessible chromatin profiling (ATAC-seq). By leveraging on cell-to-cell transcriptome and chromatin accessibility heterogeneity, we identify different previously unknown cardiac subpopulations. Reconstruction of developmental trajectories reveal that multipotent Isl1+ CPC pass through an attractor state before separating into different developmental branches, whereas extended expression of Nkx2-5 commits CPC to an unidirectional cardiomyocyte fate. Furthermore, we show that CPC fate transitions are associated with distinct open chromatin states critically depending on Isl1 and Nkx2-5. Our data provide a model of transcriptional and epigenetic regulations during cardiac progenitor cell fate decisions at single-cell resolution. PMID- 30451829 TI - Ecology and evolution of facilitation among symbionts. AB - Facilitation occurs when one species positively impacts the fitness of another, and has predominantly been studied in free-living species like plants. Facilitation can also occur among symbiont (mutualistic or parasitic) species or strains, but equivalent studies are scarce. To advance an integrated view of the effect of facilitation on symbiont ecology and evolution, we review empirical evidence and their underlying mechanisms, explore the factors favouring its emergence, and discuss its consequences for virulence and transmission. We argue that the facilitation concept can improve understanding of the evolutionary forces shaping symbiont communities and their effects on hosts. PMID- 30451830 TI - Wnt/beta-catenin signaling regulates VE-cadherin-mediated anastomosis of brain capillaries by counteracting S1pr1 signaling. AB - Canonical Wnt signaling is crucial for vascularization of the central nervous system and blood-brain barrier (BBB) formation. BBB formation and modulation are not only important for development, but also relevant for vascular and neurodegenerative diseases. However, there is little understanding of how Wnt signaling contributes to brain angiogenesis and BBB formation. Here we show, using high resolution in vivo imaging and temporal and spatial manipulation of Wnt signaling, different requirements for Wnt signaling during brain angiogenesis and BBB formation. In the absence of Wnt signaling, premature Sphingosine-1 phosphate receptor (S1pr) signaling reduces VE-cadherin and Esama at cell-cell junctions. We suggest that Wnt signaling suppresses S1pr signaling during angiogenesis to enable the dynamic junction formation during anastomosis, whereas later S1pr signaling regulates BBB maturation and VE-cadherin stabilization. Our data provides a link between brain angiogenesis and BBB formation and identifies Wnt signaling as coordinator of the timing and as regulator of anastomosis. PMID- 30451832 TI - RACK1 promotes tumorigenicity of colon cancer by inducing cell autophagy. AB - RACK1 is upregulated in the various types of human cancers, and considered to play a role in the development and progression of human cancer. However, the role and mechanism of RACK in the colon cancer are poorly understood. In this study, we detected RACK1 expression in 63 normal colonic mucosa, 60 colonic inflammatory polyps, 60 colonic adenomas, 180 colon adenocarcinomas, and 40 lymph node metastases by immunohistochemistry, and observed that RACK1 expression was progressively elevated in the carcinogenic process of human colonic epithelium, and RACK1 expressional levels were positively correlated with the malignant degree and lymph node metastasis of colon cancers, and negatively correlated with the patient survival. With a combination of loss-of-function and gain-of-function approaches, we observed that RACK1 promoted colon cancer cell proliferation, inhibited colon cancer cell apoptosis, and enhanced the anchorage-independent and xenograft growth of colon cancer cells. Moreover, we found that RACK1-induced autophagy of colon cancer cells; RACK1-induced autophagy promoted colon cancer cell proliferation and inhibited colon cancer cell apoptosis. Our data suggest that RACK1 acts as an oncogene in colon cancer, and RACK1-induced autophagy promotes proliferation and survival of colon cancer, highlighting the therapeutic potential of autophagy inhibitor in the colon cancer with high RACK1 expression. PMID- 30451831 TI - TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. AB - Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors. PMID- 30451833 TI - Contribution of p62/SQSTM1 to PDGF-BB-induced myofibroblast-like phenotypic transition in vascular smooth muscle cells lacking Smpd1 gene. AB - Accumulating evidence indicates a critical role of autophagy in regulating vascular smooth muscle cell (SMC) homeostasis in atherogenesis. However, little is known about the modulatory role of autophagy in PDGF-BB-induced SMC transition towards the synthetic phenotype and extracellular matrix remodeling. We recently demonstrated that acid sphingomyelinase (ASM, encoded by Smpd1 gene) controls autophagy maturation in coronary arterial SMCs. Here, we demonstrate that PDGF-BB stimulation causes a myofibroblast-like non-canonical synthetic phenotype transition in Smpd1-/- SMCs. These non-canonical phenotypic changes induced by PDGF-BB in Smpd1-/- SMCs were characterized by increased expression of fibroblast specific protein (FSP-1), massive deposition of collagen type I, decreased cell size, elevated inflammatory status with enhanced cytokine release and adhesion molecule expression. Mechanistically, PDGF-BB induces prolonged Akt activation that causes decreased autophagosome biogenesis and thereby exaggerates p62/SQSTM1 accumulation in Smpd1-/- SMCs. More importantly, Akt inhibition or p62/SQSTM1 gene silencing attenuates PDGF-BB-induced phenotypic changes in Smpd1-/- SMCs. This first demonstration of a p62/SQSTM1-dependent myofibroblast-like phenotypic transition in Smpd1-/- SMCs suggests that ASM-mediated autophagy pathway contributes to maintaining the arterial smooth muscle homeostasis in situation of vascular remodeling during atherosclerosis. PMID- 30451834 TI - Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells. AB - Trefoil factor 3 (TFF3) expression is positively associated with advanced clinicopathological features of mammary carcinoma (MC). Herein, we provide evidence for a functional role of TFF3 in oncogenic transformation of immortalized, but otherwise normal human mammary epithelial cells (HMECs), namely, HMEC-hTERT, MCF10A, and MCF12A. Forced expression of TFF3 in immortalized HMECs enhanced cell proliferation, cell survival, anchorage-independent growth, produced highly disorganised three-dimensional (3D) acinar structures and generated tumours in immunocompromised mice. Forced expression of TFF3 in immortalized-HMECs stimulated STAT3 activity that was required for TFF3 stimulated cell proliferation, survival, and anchorage-independent growth. TFF3 specifically utilised STAT3 activity to govern a transcriptional program, which was required for TFF3-stimulated oncogenic transformation of immortalized-HMECs, including transcriptional upregulation of CCND1 and BCL2. siRNA-mediated depletion or functional inhibition of STAT3 significantly inhibited the TFF3 stimulated transcription of CCND1 and BCL2 and oncogenicity in immortalized HMECs. Furthermore, DOX-inducible expression of TFF3 in HMEC-hTERT cells also permitted anchorage-independent growth and produced disorganized acinar structures in 3D Matrigel culture. Removal of DOX-induced expression of TFF3 in HMEC-hTERT cells, previously grown with DOX, resulted in efficient normalisation of the disorganized acinar architecture and attenuated cell viability in Matrigel culture. Cumulatively, these findings suggest that TFF3 is a potent oncogene and its increased expression along with hTERT in HMECs is sufficient to produce oncogenic transformation. PMID- 30451835 TI - Engulfing cells promote neuronal regeneration and remove neuronal debris through distinct biochemical functions of CED-1. AB - Two important biological events happen coincidently soon after nerve injury in the peripheral nervous system in C. elegans: removal of axon debris and initiation of axon regeneration. But, it is not known how these two events are co regulated. Mutants of ced-1, a homolog of Draper and MEGF10, display defects in both events. One model is that those events could be related. But our data suggest that they are actually separable. CED-1 functions in the muscle-type engulfing cells in both events and is enriched in muscle protrusions in close contact with axon debris and regenerating axons. Its two functions occur through distinct biochemical mechanisms; extracellular domain-mediated adhesion for regeneration and extracellular domain binding-induced intracellular domain signaling for debris removal. These studies identify CED-1 in engulfing cells as a receptor in debris removal but as an adhesion molecule in neuronal regeneration, and have important implications for understanding neural circuit repair after injury. PMID- 30451836 TI - Fungal spores as a source of sodium salt particles in the Amazon basin. AB - In the Amazon basin, particles containing mixed sodium salts are routinely observed and are attributed to marine aerosols transported from the Atlantic Ocean. Using chemical imaging analysis, we show that, during the wet season, fungal spores emitted by the forest biosphere contribute at least 30% (by number) to sodium salt particles in the central Amazon basin. Hydration experiments indicate that sodium content in fungal spores governs their growth factors. Modeling results suggest that fungal spores account for ~69% (31-95%) of the total sodium mass during the wet season and that their fractional contribution increases during nighttime. Contrary to common assumptions that sodium-containing aerosols originate primarily from marine sources, our results suggest that locally-emitted fungal spores contribute substantially to the number and mass of coarse particles containing sodium. Hence, their role in cloud formation and contribution to salt cycles and the terrestrial ecosystem in the Amazon basin warrant further consideration. PMID- 30451837 TI - EPH receptor A2 governs a feedback loop that activates Wnt/beta-catenin signaling in gastric cancer. AB - The erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases. EphA2 is highly correlated with the formation of many solid tumors and has been linked to the dysregulation of signaling pathways that promote tumor cell proliferation, migration, and invasion as well as angiogenesis. Deregulation of Wnt signaling is implicated in many forms of human disease including gastric cancer. We previously reported that EphA2 promotes the epithelial-mesenchymal transition through Wnt/beta-catenin signaling in gastric cancer. Herein, we present a novel mechanism by which EphA2 regulates Wnt/beta-catenin signaling. EphA2 acts as a receptor for Wnt ligands and recruits Axin1 to the plasma membrane by directly binding Dvl2. The EphA2 Dvl2/Axin1 interaction was enhanced by Wnt3a treatment, suggesting that EphA2 acts as a functional receptor for the Wnt/beta-catenin pathway and plays a vital role in downstream signaling. We showed that Dvl2 mediates the EphA2-Axin1 interaction by binding to the tyrosine kinase domain of EphA2. We propose that EphA2/Dvl2/Axin1 forms a complex that destabilizes the beta-catenin destruction complex and allows beta-catenin to translocate to the nucleus and initiate the transcription of c-MYC, the primary Wnt signaling target gene. Intriguingly, c MYC could bind directly to the EphA2 and Wnt1 promoter to enhance their transcription. The entire process formed an EphA2-mediated feed-forward loop. A small molecular inhibitor of EphA2 potently inhibited the proliferation of gastric cancer in vitro and in vivo, including gastric cancer patient-derived xenografts. Thus, our data identify EphA2 as an excellent candidate for gastric cancer therapy. PMID- 30451838 TI - Crosstalks between mTORC1 and mTORC2 variagate cytokine signaling to control NK maturation and effector function. AB - The metabolic checkpoint kinase mechanistic/mammalian target of rapamycin (mTOR) regulates natural killer (NK) cell development and function, but the exact underlying mechanisms remain unclear. Here, we show, via conditional deletion of Raptor (mTORC1) or Rictor (mTORC2), that mTORC1 and mTORC2 promote NK cell maturation in a cooperative and non-redundant manner, mainly by controlling the expression of Tbx21 and Eomes. Intriguingly, mTORC1 and mTORC2 regulate cytolytic function in an opposing way, exhibiting promoting and inhibitory effects on the anti-tumor ability and metabolism, respectively. mTORC1 sustains mTORC2 activity by maintaining CD122-mediated IL-15 signaling, whereas mTORC2 represses mTORC1 modulated NK cell effector functions by restraining STAT5-mediated SLC7A5 expression. These positive and negative crosstalks between mTORC1 and mTORC2 signaling thus variegate the magnitudes and kinetics of NK cell activation, and help define a paradigm for the modulation of NK maturation and effector functions. PMID- 30451839 TI - Orthogonal Cas9-Cas9 chimeras provide a versatile platform for genome editing. AB - The development of robust, versatile and accurate toolsets is critical to facilitate therapeutic genome editing applications. Here we establish RNA programmable Cas9-Cas9 chimeras, in single- and dual-nuclease formats, as versatile genome engineering systems. In both of these formats, Cas9-Cas9 fusions display an expanded targeting repertoire and achieve highly specific genome editing. Dual-nuclease Cas9-Cas9 chimeras have distinct advantages over monomeric Cas9s including higher target site activity and the generation of predictable precise deletion products between their target sites. At a therapeutically relevant site within the BCL11A erythroid enhancer, Cas9-Cas9 nucleases produced precise deletions that comprised up to 97% of all sequence alterations. Thus Cas9 Cas9 chimeras represent an important tool that could be particularly valuable for therapeutic genome editing applications where a precise cleavage position and defined sequence end products are desirable. PMID- 30451840 TI - A chromosome-scale assembly of the sorghum genome using nanopore sequencing and optical mapping. AB - Long-read sequencing technologies have greatly facilitated assemblies of large eukaryotic genomes. In this paper, Oxford Nanopore sequences generated on a MinION sequencer are combined with Bionano Genomics Direct Label and Stain (DLS) optical maps to generate a chromosome-scale de novo assembly of the repeat-rich Sorghum bicolor Tx430 genome. The final assembly consists of 29 scaffolds, encompassing in most cases entire chromosome arms. It has a scaffold N50 of 33.28 Mbps and covers 90% of the expected genome length. A sequence accuracy of 99.85% is obtained after aligning the assembly against Illumina Tx430 data and 99.6% of the 34,211 public gene models align to the assembly. Comparisons of Tx430 and BTx623 DLS maps against the public BTx623 v3.0.1 genome assembly suggest substantial discrepancies whose origin remains to be determined. In summary, this study demonstrates that informative assemblies of complex plant genomes can be generated by combining nanopore sequencing with DLS optical maps. PMID- 30451841 TI - Tamoxifen therapy in a murine model of myotubular myopathy. AB - Myotubular myopathy (MTM) is a severe X-linked disease without existing therapies. Here, we show that tamoxifen ameliorates MTM-related histopathological and functional abnormalities in mice, and nearly doubles survival. The beneficial effects of tamoxifen are mediated primarily via estrogen receptor signaling, as demonstrated through in vitro studies and in vivo phenotypic rescue with estradiol. RNA sequencing and protein expression analyses revealed that rescue is mediated in part through post-transcriptional reduction of dynamin-2, a known MTM modifier. These findings demonstrate an unexpected ability of tamoxifen to improve the murine MTM phenotype, providing preclinical evidence to support clinical translation. PMID- 30451842 TI - Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes. AB - Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials. PMID- 30451843 TI - Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy. AB - X-linked myotubular myopathy (XLMTM, also known as XLCNM) is a severe congenital muscular disorder due to mutations in the myotubularin gene, MTM1. It is characterized by generalized hypotonia, leading to neonatal death of most patients. No specific treatment exists. Here, we show that tamoxifen, a well known drug used against breast cancer, rescues the phenotype of Mtm1-deficient mice. Tamoxifen increases lifespan several-fold while improving overall motor function and preventing disease progression including lower limb paralysis. Tamoxifen corrects functional, histological and molecular hallmarks of XLMTM, with improved force output, myonuclei positioning, myofibrillar structure, triad number, and excitation-contraction coupling. Tamoxifen normalizes the expression level of the XLMTM disease modifiers DNM2 and PI3KC2B, likely contributing to the phenotypic rescue. Our findings demonstrate that tamoxifen is a promising candidate for clinical evaluation in XLMTM patients. PMID- 30451845 TI - Control of spin-wave transmission by a programmable domain wall. AB - Active manipulation of spin waves is essential for the development of magnon based technologies. Here, we demonstrate programmable spin-wave filtering by resetting the spin structure of pinned 90 degrees Neel domain walls in a continuous CoFeB film with abrupt rotations of uniaxial magnetic anisotropy. Using micro-focused Brillouin light scattering and micromagnetic simulations, we show that broad 90 degrees head-to-head or tail-to-tail magnetic domain walls are transparent to spin waves over a broad frequency range. In contrast, magnetic switching to a 90 degrees head-to-tail configuration produces much narrower and strongly reflecting domain walls at the same pinning locations. Based on these results, we propose a magnetic spin-wave valve with two parallel domain walls. Switching the spin-wave valve from an open to a closed state changes the transmission of spin waves from nearly 100 to 0%. Active control over spin-wave transport through programmable domain walls could be utilized in magnonic logic devices or non-volatile memory elements. PMID- 30451844 TI - Age-related declines in alpha-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. AB - While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the "anti-aging" protein, alpha-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of alpha-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for alpha-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with alpha-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for alpha-Klotho in the regulation of MPC mitochondrial function and implicate alpha-Klotho declines as a driver of impaired muscle regeneration with age. PMID- 30451846 TI - Nutrient supply controls particulate elemental concentrations and ratios in the low latitude eastern Indian Ocean. AB - Variation in ocean C:N:P of particulate organic matter (POM) has led to competing hypotheses for the underlying drivers. Each hypothesis predicts C:N:P equally well due to regional co-variance in environmental conditions and biodiversity. The Indian Ocean offers a unique positive temperature and nutrient supply relationship to test these hypotheses. Here we show how elemental concentrations and ratios vary over daily and regional scales. POM concentrations were lowest in the southern gyre, elevated across the equator, and peaked in the Bay of Bengal. Elemental ratios were highest in the gyre, but approached Redfield proportions northwards. As Prochlorococcus dominated the phytoplankton community, biodiversity changes could not explain the elemental variation. Instead, our data supports the nutrient supply hypothesis. Finally, gyre dissolved iron concentrations suggest extensive iron stress, leading to depressed ratios compared to other gyres. We propose a model whereby differences in iron supply and N2-fixation influence C:N:P levels across ocean gyres. PMID- 30451847 TI - Author Correction: Substantiating freedom from parasitic infection by combining transmission model predictions with disease surveys. AB - The original version of this Article contained an error in the spelling of Emily Griswold, which was incorrectly given as Emily Grisworld. This error has now been corrected in both the PDF and HTML versions of the Article. PMID- 30451848 TI - Growth factor gene IGF1 is associated with bill size in the black-bellied seedcracker Pyrenestes ostrinus. AB - Pyrenestes finches are unique among birds in showing a non-sex-determined polymorphism in bill size and are considered a textbook example of disruptive selection. Morphs breed randomly with respect to bill size, and differ in diet and feeding performance relative to seed hardness. Previous breeding experiments are consistent with the polymorphism being controlled by a single genetic factor. Here, we use genome-wide pooled sequencing to explore the underlying genetic basis of bill morphology and identify a single candidate region. Targeted resequencing reveals extensive linkage disequilibrium across a 300 Kb region containing the insulin-like growth factor 1 (IGF1) gene, with a single 5-million year-old haplotype associating with phenotypic dominance of the large-billed morph. We find no genetic similarities controlling bill size in the well-studied Darwin's finches (Geospiza). Our results show how a single genetic factor may control bill size and provide a foundation for future studies to examine this phenomenon within and among avian species. PMID- 30451849 TI - A continuous-time MaxSAT solver with high analog performance. AB - Many real-life optimization problems can be formulated in Boolean logic as MaxSAT, a class of problems where the task is finding Boolean assignments to variables satisfying the maximum number of logical constraints. Since MaxSAT is NP-hard, no algorithm is known to efficiently solve these problems. Here we present a continuous-time analog solver for MaxSAT and show that the scaling of the escape rate, an invariant of the solver's dynamics, can predict the maximum number of satisfiable constraints, often well before finding the optimal assignment. Simulating the solver, we illustrate its performance on MaxSAT competition problems, then apply it to two-color Ramsey number R(m, m) problems. Although it finds colorings without monochromatic 5-cliques of complete graphs on N <= 42 vertices, the best coloring for N = 43 has two monochromatic 5-cliques, supporting the conjecture that R(5, 5) = 43. This approach shows the potential of continuous-time analog dynamical systems as algorithms for discrete optimization. PMID- 30451851 TI - Publisher Correction: Engineering bacterial vortex lattice via direct laser lithography. AB - The original version of this Article contained errors in Fig. 2. In Fig. 2d, the label below the blue circle incorrectly read "Si,a(t) < 0" and should have read "Si,a(t) > 0". Furthermore, the sequence of labels on the side of the bottom three figures panels in Fig. 2d from top to bottom incorrectly read "S9,70 > 0, S9,70 > 0, S9,70 < 0", and should have read "S9,70 < 0, S9,70 > 0, S9,70 < 0". Finally, in the legend to Fig. 2, the scale bar size description "Scale bar: 100MUm" was incorrectly placed in the description of panel c, and should have been placed in the description of panel d. These errors have been corrected in both the PDF and HTML versions of the Article. PMID- 30451850 TI - Studying and modulating schizophrenia-associated dysfunctions of oligodendrocytes with patient-specific cell systems. AB - Postmortem studies in patients with schizophrenia (SCZ) have revealed deficits in myelination, abnormalities in myelin gene expression and altered numbers of oligodendrocytes in the brain. However, gaining mechanistic insight into oligodendrocyte (OL) dysfunction and its contribution to SCZ has been challenging because of technical hurdles. The advent of individual patient-derived human induced pluripotent stem cells (hiPSCs), combined with the generation of in principle any neuronal and glial cell type, including OLs and oligodendrocyte precursor cells (OPCs), holds great potential for understanding the molecular basis of the aetiopathogenesis of genetically complex psychiatric diseases such as SCZ and could pave the way towards personalized medicine. The development of neuronal and glial co-culture systems now appears to enable the in vitro study of SCZ-relevant neurobiological endophenotypes, including OL dysfunction and myelination, with unprecedented construct validity. Nonetheless, the meaningful stratification of patients before the subsequent functional analyses of patient derived cell systems still represents an important bottleneck. Here, to improve the predictive power of ex vivo disease modelling we propose using hiPSC technology to focus on representatives of patient subgroups stratified for genomic and/or phenomic features and neurobiological cell systems. Therefore, this review will outline the evidence for the involvement of OPCs/OLs in SCZ in the context of their proposed functions, including myelination and axon support, the implications for hiPSC-based cellular disease modelling and potential strategies for patient selection. PMID- 30451852 TI - The 27 kDa Trypanosoma brucei Pentatricopeptide Repeat Protein is a G-tract Specific RNA Binding Protein. AB - Pentatricopeptide repeat (PPR) proteins, a helical repeat family of organellar RNA binding proteins, play essential roles in post-transcriptional RNA processing. In Trypanosoma brucei, an expanded family of PPR proteins localize to the parasite's single mitochondrion, where they are believed to perform important roles in both RNA processing and translation. We studied the RNA binding specificity of the simplest T. brucei PPR protein (KRIPP11) using electrophoretic mobility shift assays, fluorescence anisotropy, circular dichroism spectroscopy, and in vitro selection. We found KRIPP11 to be an RNA binding protein with specificity for sequences of four or more consecutive guanosine residues (G tracts). Such G-tracts are dramatically enriched in T. brucei mitochondrial transcripts that are destined for extensive uridine insertion/deletion editing but are not present in mRNAs following editing. We further found that the quadruplex oligoguanosine RNA conformation is preferentially recognized by KRIPP11 over other conformational forms, and is bound without disruption of the quadruplex structure. In combination with prior data demonstrating association of KRIPP11 with the small ribosomal subunit, these results suggest possible roles for KRIPP11 in bridging mRNA maturation and translation or in facilitating translation of unusual dual-coded open reading frames. PMID- 30451853 TI - Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. AB - Flow of cerebrospinal fluid (CSF) through perivascular spaces (PVSs) in the brain is important for clearance of metabolic waste. Arterial pulsations are thought to drive flow, but this has never been quantitatively shown. We used particle tracking to quantify CSF flow velocities in PVSs of live mice. CSF flow is pulsatile and driven primarily by the cardiac cycle. The speed of the arterial wall matches that of the CSF, suggesting arterial wall motion is the principal driving mechanism, via a process known as perivascular pumping. Increasing blood pressure leaves the artery diameter unchanged but changes the pulsations of the arterial wall, increasing backflow and thereby reducing net flow in the PVS. Perfusion-fixation alters the normal flow direction and causes a 10-fold reduction in PVS size. We conclude that particle tracking velocimetry enables the study of CSF flow in unprecedented detail and that studying the PVS in vivo avoids fixation artifacts. PMID- 30451855 TI - Three-dimensional kinematics of canine hind limbs: in vivo, biplanar, high frequency fluoroscopic analysis of four breeds during walking and trotting. AB - The first high-precision 3D in vivo hindlimb kinematic data to be recorded in normal dogs of four different breeds (Beagle, French bulldog, Malinois, Whippet) using biplanar, high-frequency fluoroscopy combined with a 3D optoelectric system followed by a markerless XROMM analysis (Scientific Rotoscoping, SR or 3D-2D registration process) reveal a) 3D hindlimb kinematics to an unprecedented degree of precision and b) substantial limitations to the use of skin marker-based data. We expected hindlimb kinematics to differ in relation to body shape. But, a comparison of the four breeds sets the French bulldog aside from the others in terms of trajectories in the frontal plane (abduction/adduction) and long axis rotation of the femur. French bulldogs translate extensive femoral long axis rotation (>30 degrees ) into a strong lateral displacement and rotations about the craniocaudal (roll) and the distal-proximal (yaw) axes of the pelvis in order to compensate for a highly abducted hindlimb position from the beginning of stance. We assume that breeds which exhibit unusual kinematics, especially high femoral abduction, might be susceptible to a higher long-term loading of the cruciate ligaments. PMID- 30451854 TI - Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets. AB - Non-typhoidal Salmonella (NTS) are highly prevalent food-borne pathogens. Recently, a highly invasive, multi-drug resistant S. Typhimurium, ST313, emerged as a major cause of bacteraemia in children and immunosuppressed adults, however the pathogenic mechanisms remain unclear. Here, we utilize invasive and non invasive Salmonella strains combined with single-cell RNA-sequencing to study the transcriptome of individual infected and bystander monocyte-derived dendritic cells (MoDCs) implicated in disseminating invasive ST313. Compared with non invasive Salmonella, ST313 directs a highly heterogeneous innate immune response. Bystander MoDCs exhibit a hyper-activated profile potentially diverting adaptive immunity away from infected cells. MoDCs harbouring invasive Salmonella display higher expression of IL10 and MARCH1 concomitant with lower expression of CD83 to evade adaptive immune detection. Finally, we demonstrate how these mechanisms conjointly restrain MoDC-mediated activation of Salmonella-specific CD4+ T cell clones. Here, we show how invasive ST313 exploits discrete evasion strategies within infected and bystander MoDCs to mediate its dissemination in vivo. PMID- 30451856 TI - Downregulation of macrophage Irs2 by hyperinsulinemia impairs IL-4-indeuced M2a subtype macrophage activation in obesity. AB - M2a-subtype macrophage activation is known to be impaired in obesity, although the underlying mechanisms remain poorly understood. Herein, we demonstrate that, the IL-4/Irs2/Akt pathway is selectively impaired, along with decreased macrophage Irs2 expression, although IL-4/STAT6 pathway is maintained. Indeed, myeloid cell-specific Irs2-deficient mice show impairment of IL-4-induced M2a subtype macrophage activation, as a result of stabilization of the FoxO1/HDAC3/NCoR1 corepressor complex, resulting in insulin resistance under the HF diet condition. Moreover, the reduction of macrophage Irs2 expression is mediated by hyperinsulinemia via the insulin receptor (IR). In myeloid cell specific IR-deficient mice, the IL-4/Irs2 pathway is preserved in the macrophages, which results in a reduced degree of insulin resistance, because of the lack of IR-mediated downregulation of Irs2. We conclude that downregulation of Irs2 in macrophages caused by hyperinsulinemia is responsible for systemic insulin resistance via impairment of M2a-subtype macrophage activation in obesity. PMID- 30451857 TI - Hidden diversity of soil giant viruses. AB - Known giant virus diversity is currently skewed towards viruses isolated from aquatic environments and cultivated in the laboratory. Here, we employ cultivation-independent metagenomics and mini-metagenomics on soils from the Harvard Forest, leading to the discovery of 16 novel giant viruses, chiefly recovered by mini-metagenomics. The candidate viruses greatly expand phylogenetic diversity of known giant viruses and either represented novel lineages or are affiliated with klosneuviruses, Cafeteria roenbergensis virus or tupanviruses. One assembled genome with a size of 2.4 Mb represents the largest currently known viral genome in the Mimiviridae, and others encode up to 80% orphan genes. In addition, we find more than 240 major capsid proteins encoded on unbinned metagenome fragments, further indicating that giant viruses are underexplored in soil ecosystems. The fact that most of these novel viruses evaded detection in bulk metagenomes suggests that mini-metagenomics could be a valuable approach to unearth viral giants. PMID- 30451858 TI - Signal peptide represses GluK1 surface and synaptic trafficking through binding to amino-terminal domain. AB - Kainate-type glutamate receptors play critical roles in excitatory synaptic transmission and synaptic plasticity in the brain. GluK1 and GluK2 possess fundamentally different capabilities in surface trafficking as well as synaptic targeting in hippocampal CA1 neurons. Here we find that the excitatory postsynaptic currents (EPSCs) are significantly increased by the chimeric GluK1(SPGluK2) receptor, in which the signal peptide of GluK1 is replaced with that of GluK2. Coexpression of GluK1 signal peptide completely suppresses the gain in trafficking ability of GluK1(SPGluK2), indicating that the signal peptide represses receptor trafficking in a trans manner. Furthermore, we demonstrate that the signal peptide directly interacts with the amino-terminal domain (ATD) to inhibit the synaptic and surface expression of GluK1. Thus, we have uncovered a trafficking mechanism for kainate receptors and propose that the cleaved signal peptide behaves as a ligand of GluK1, through binding with the ATD, to repress forward trafficking of the receptor. PMID- 30451859 TI - Author Correction: Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia. AB - The original version of this Article contained an error in Figure 4. In panel i, the lower CYA and alpha-SMA images were inadvertently inverted. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30451860 TI - Memory formation and long-term maintenance of IL-7Ralpha+ ILC1s via a lymph node liver axis. AB - Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Ralpha, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Ralpha+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Ralpha+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Ralpha+ ILC1 population and reveal a LN liver axis that is essential for ILC1 memory generation and long-term maintenance. PMID- 30451861 TI - Translation of non-standard codon nucleotides reveals minimal requirements for codon-anticodon interactions. AB - The precise interplay between the mRNA codon and the tRNA anticodon is crucial for ensuring efficient and accurate translation by the ribosome. The insertion of RNA nucleobase derivatives in the mRNA allowed us to modulate the stability of the codon-anticodon interaction in the decoding site of bacterial and eukaryotic ribosomes, allowing an in-depth analysis of codon recognition. We found the hydrogen bond between the N1 of purines and the N3 of pyrimidines to be sufficient for decoding of the first two codon nucleotides, whereas adequate stacking between the RNA bases is critical at the wobble position. Inosine, found in eukaryotic mRNAs, is an important example of destabilization of the codon anticodon interaction. Whereas single inosines are efficiently translated, multiple inosines, e.g., in the serotonin receptor 5-HT2C mRNA, inhibit translation. Thus, our results indicate that despite the robustness of the decoding process, its tolerance toward the weakening of codon-anticodon interactions is limited. PMID- 30451862 TI - Two-dimensional tessellation by molecular tiles constructed from halogen-halogen and halogen-metal networks. AB - Molecular tessellations are often discovered serendipitously, and the mechanisms by which specific molecules can be tiled seamlessly to form periodic tessellation remain unclear. Fabrication of molecular tessellation with higher symmetry compared with traditional Bravais lattices promises potential applications as photonic crystals. Here, we demonstrate that highly complex tessellation can be constructed on Au(111) from a single molecular building block, hexakis(4 iodophenyl)benzene (HPBI). HPBI gives rise to two self-assembly phases on Au(111) that possess the same geometric symmetry but different packing densities, on account of the presence of halogen-bonded and halogen-metal coordinated networks. Sub-domains of these phases with self-similarity serve as tiles in the periodic tessellations to express polygons consisting of parallelograms and two types of triangles. Our work highlights the important principle of constructing multiple phases with self-similarity from a single building block, which may constitute a new route to construct complex tessellations. PMID- 30451863 TI - RIG-I like receptor sensing of host RNAs facilitates the cell-intrinsic immune response to KSHV infection. AB - The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. However, evidence suggests RLRs participate in innate immune recognition of other pathogens, including DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi's sarcoma and primary effusion lymphoma (PEL). Here, we demonstrate that RLRs restrict KSHV lytic reactivation and we demonstrate that restriction is facilitated by the recognition of host-derived RNAs. Misprocessed noncoding RNAs represent an abundant class of RIG-I substrates, and biochemical characterizations reveal that an infection-dependent reduction in the cellular triphosphatase DUSP11 results in an accumulation of select triphosphorylated noncoding RNAs, enabling their recognition by RIG-I. These findings reveal an intricate relationship between RNA processing and innate immunity, and demonstrate that an antiviral innate immune response can be elicited by the sensing of misprocessed cellular RNAs. PMID- 30451864 TI - Effective connectivity of the anterior hippocampus predicts recollection confidence during natural memory retrieval. AB - Human interactions with the world are influenced by memories of recent events. This effect, often triggered by perceptual cues, occurs naturally and without conscious effort. However, the neuroscience of involuntary memory in a dynamic milieu has received much less attention than the mechanisms of voluntary retrieval with deliberate purpose. Here, we investigate the neural processes driven by naturalistic cues that relate to, and presumably trigger the retrieval of recent experiences. Viewing the continuation of recently viewed clips evokes greater bilateral activation in anterior hippocampus, precuneus and angular gyrus than naive clips. While these regions manifest reciprocal connectivity, continued viewing specifically modulates the effective connectivity from the anterior hippocampus to the precuneus. The strength of this modulation predicts participants' confidence in later voluntary recall of news details. Our study reveals network mechanisms of dynamic, involuntary memory retrieval and its relevance to metacognition in a rich context resembling everyday life. PMID- 30451865 TI - Hydrostatic pressure-generated reactive oxygen species induce osteoarthritic conditions in cartilage pellet cultures. AB - Osteoarthritis (OA) is one of the most common causes of disability and represents a major socio-economic burden. Despite intensive research, the molecular mechanisms responsible for the initiation and progression of OA remain inconclusive. In recent years experimental findings revealed elevated levels of reactive oxygen species (ROS) as a major factor contributing to the onset and progression of OA. Hence, we designed a hydrostatic pressure bioreactor system that is capable of stimulating cartilage cell cultures with elevated ROS levels. Increased ROS levels in the media did not only lead to an inhibition of glycosaminoglycans and collagen II formation but also to a reduction of already formed glycosaminoglycans and collagen II in chondrogenic mesenchymal stem cell pellet cultures. These effects were associated with the elevated activity of matrix metalloproteinases as well as the increased expression of several inflammatory cytokines. ROS activated different signaling pathways including PI3K/Akt and MAPK/ERK which are known to be involved in OA initiation and progression. Utilizing the presented bioreactor system, an OA in vitro model based on the generation of ROS was developed that enables the further investigation of ROS effects on cartilage degradation but can also be used as a versatile tool for anti-oxidative drug testing. PMID- 30451866 TI - Manipulation of the dephasing time by strong coupling between localized and propagating surface plasmon modes. AB - Strong coupling between two resonance modes leads to the formation of new hybrid modes exhibiting disparate characteristics owing to the reversible exchange of information between different uncoupled modes. Here, we realize the strong coupling between the localized surface plasmon resonance and surface plasmon polariton Bloch wave using multilayer nanostructures. An anticrossing behavior with a splitting energy of 144 meV can be observed from the far-field spectra. More importantly, we investigate the near-field properties in both the frequency and time domains using photoemission electron microscopy. In the frequency domain, the near-field spectra visually demonstrate normal-mode splitting and display the extent of coupling. Importantly, the variation of the dephasing time of the hybrid modes against the detuning is observed directly in the time domain. These findings signify the evolution of the dissipation and the exchange of information in plasmonic strong coupling systems and pave the way to manipulate the dephasing time of plasmon modes, which can benefit many applications of plasmonics. PMID- 30451867 TI - Publisher Correction: All-inorganic cesium lead iodide perovskite solar cells with stabilized efficiency beyond 15. AB - In the original version of this Article, the author name 'Shengzhong Liu' was incorrectly given as 'Liu Shengzhong'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30451868 TI - Synthetic RNA-based logic computation in mammalian cells. AB - Synthetic biological circuits are designed to regulate gene expressions to control cell function. To date, these circuits often use DNA-delivery methods, which may lead to random genomic integration. To lower this risk, an all RNA system, in which the circuit and delivery method are constituted of RNA components, is preferred. However, the construction of complexed circuits using RNA-delivered devices in living cells has remained a challenge. Here we show synthetic mRNA-delivered circuits with RNA-binding proteins for logic computation in mammalian cells. We create a set of logic circuits (AND, OR, NAND, NOR, and XOR gates) using microRNA (miRNA)- and protein-responsive mRNAs as decision making controllers that are used to express transgenes in response to intracellular inputs. Importantly, we demonstrate that an apoptosis-regulatory AND gate that senses two miRNAs can selectively eliminate target cells. Thus, our synthetic RNA circuits with logic operation could provide a powerful tool for future therapeutic applications. PMID- 30451869 TI - Competitive repopulation of an empty microglial niche yields functionally distinct subsets of microglia-like cells. AB - Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a- microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct. PMID- 30451871 TI - Personality Traits in Patients with Neuroepithelial Tumors - A Prospective Study. AB - Aim of this study was to analyze personality traits in patients with neuroepithelial brain tumors. Personality alteration is a common feature in brain tumor patients, but not much is known about associations between specific personality changes and brain tumors. We assessed potential factors influencing personality such as tumor location, tumor grade and tumor volume. Mini-mental state examination (MMSE), Beck's Depression Inventory II (BDI-II), and the NEO Five-Factor Inventory (NEO-FFI) for the five factors of personality were acquired. Patients had lower scores regarding the factor openness and higher scores regarding the BDI-II compared to the norm population. No significant influencing factors (tumor entity, location) were found regarding personality traits. Neuroticism was associated with depression, whereas extraversion showed an opposed association. Patients with intrinsic brain tumors have differences in personality traits compared to the control population, with an emphasis on the factor openness. No significant confounding factors like tumor grade, entity, or location were found for personality traits. PMID- 30451870 TI - Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. AB - Clostridium difficile is the leading cause of pseudomembranous colitis in hospitalized patients. C. difficile enterotoxins TcdA and TcdB promote this inflammatory condition via a cytotoxic response on intestinal epithelial cells (IECs), but the underlying mechanisms are incompletely understood. Additionally, TcdA and TcdB engage the Pyrin inflammasome in macrophages, but whether Pyrin modulates CDI pathophysiology is unknown. Here we show that the Pyrin inflammasome is not functional in IECs and that Pyrin signaling is dispensable for CDI-associated IEC death and for in vivo pathogenesis. Instead, our studies establish that C. difficile enterotoxins induce activation of executioner caspases 3/7 via the intrinsic apoptosis pathway, and demonstrate that caspase 3/7-mediated IEC apoptosis is critical for in vivo host defense during early stages of CDI. In conclusion, our findings dismiss a critical role for inflammasomes in CDI pathogenesis, and identify IEC apoptosis as a host defense mechanism that restricts C. difficile infection in vivo. PMID- 30451872 TI - Comparative genome-wide analysis of WRKY transcription factors in two Asian legume crops: Adzuki bean and Mung bean. AB - The seminal participation of WRKY transcription factors in plant development, metabolism and in the governance of defense mechanism implicated their gaining importance for genomic and functional studies. The recent release of draft genome sequences of two legume crops, Adzuki bean (Vigna angularis) and Mung bean (Vigna radiata) has paved the way for characterization of WRKY gene family in these crops. We found 84 WRKY genes in Adzuki bean (VaWRKY) and 85 WRKY genes in Mung bean (VrWRKY). Based on the phylogenetic analysis, VaWRKY genes were classified into three groups with 15 members in Group I, 56 members in Group II, and 13 members in Group III, which was comparable to VrWRKY distribution in Mung bean, 16, 56 and 13 members in Group I, II and III, respectively. The few tandem and segmental duplication events suggested that recent duplication plays no prominent role in the expansion VaWRKY and VrWRKY genes. The illustration of gene-structure and their encoded protein-domains further revealed the nature of WRKY proteins. Moreover, the identification of abiotic or biotic stress-responsive cis regulatory elements in the promoter regions of some WRKY genes provides fundamental insights for their further implementation in stress-tolerance and genetic improvement of agronomic traits. PMID- 30451873 TI - Toenail manganese as a potential biomarker for in utero and early childhood exposure studies. AB - Elevated in utero and early childhood exposure to manganese may have adverse effects on neurodevelopment. We conducted preliminary analyses to evaluate toenails as a matrix for investigating manganese exposure in infants. Infant and maternal toenail and hair samples were collected from 25 infants (7 months old) and their mothers. A subset of mothers was recruited in the third trimester of pregnancy and some also provided pre-natal toenail, hair, and blood samples, cord blood, and additional post-natal samples. Collected samples were analyzed by inductively coupled plasma mass-spectrometry. Toenail manganese levels in infants ranged from below the limit of detection (LOD) to 2.80 ug/g. Only 1 toenail sample and 4 hair samples contained levels of manganese below LOD. Associations between infant and maternal biomarkers were not statistically significant. Analysis of multiple post-natal toenail samples from a single infant-mother pair showed an increase in the infant's toenail manganese and a decrease in maternal toenail manganese over the first year of the infant's life. Overall, our findings suggest that toenails may serve as a valuable biological matrix for measuring manganese exposure in newborns and infants; however, additional studies are needed to determine the impact of the timing of toenail sample collection on its utility in assessing early life exposure and health outcomes. PMID- 30451874 TI - A Novel Targeted Analysis of Peripheral Steroids by Ultra-Performance Supercritical Fluid Chromatography Hyphenated to Tandem Mass Spectrometry. AB - Ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS) is an alternative method for steroid analysis. Continuous development of analytical methodologies for steroid profiling is of major importance in the clinical environment to provide useful and more comprehensive data. The aim of this study was to identify and quantify a large number of endogenous steroids from the four major classes (estrogens, androgens, progestogens and corticosteroids) simultaneously within a short analytical time. This novel UPSFC-MS/MS method with electrospray in positive ionisation (ESI+) mode is robust, selective and present sufficiently high sensitivity to profile nineteen steroids in 50 uL human plasma. Under optimised conditions, nineteen different steroids were separated with high efficiency in the multiple reaction monitoring (MRM) mode. The linearity of the method was good with correlation coefficients (R2) in the range of 0.9983-0.9999 and with calibration range from 0.05-500 ng/mL in human plasma. The intraday and interday precision of the method, as RSD, was less than 15%. The accuracy of the nineteen analytes varied between 80 to 116%. Finally, the novel method was successfully applied for the determination of nineteen steroids within 5 minutes providing the possibility to use it for research as well as routine healthcare practice. PMID- 30451875 TI - Human chemosignals of disgust facilitate food judgment. AB - Choosing food is not a trivial decision that people need to make daily, which is often subject to social influences. Here, we studied a human homolog of social transmission of food preference (STFP) as observed in rodents and other animals via chemosignals of body secretions. Human social chemosignals (sweat) produced during a disgust or neutral state among a group of donors were presented to participants undergoing a 2-alternative-forced-choice food healthiness judgment task during functional magnetic resonance imaging (fMRI). Response speed and two key signal detection indices-d' (discrimination sensitivity) and beta (response bias)-converged to indicate that social chemosignals of disgust facilitated food healthiness decisions, in contrast to primary disgust elicitors (disgust odors) that impaired the judgment. fMRI analyses (disgust vs. neutral sweat) revealed that the fusiform face area (FFA), amygdala, and orbitofrontal cortex (OFC) were engaged in processing social chemosignals of disgust during food judgment. Importantly, a double contrast of social signaling across modalities (olfactory vs. visual-facial expressions) indicated that the FFA and OFC exhibited preferential response to social chemosignals of disgust. Together, our findings provide initial evidence for human STFP, where social chemosignals are incorporated into food decisions by engaging social and emotional areas of the brain. PMID- 30451876 TI - Genetic and pharmacological validation of TAK1 inhibition in macrophages as a therapeutic strategy to effectively inhibit TNF secretion. AB - Immune challenge of invading macrophages at sites of infection is associated with release of TNF, which triggers a local cytokine storm as part of the normal inflammatory response. Whereas this response maybe beneficial in fighting off infections, similar responses triggered in autoimmune diseases contribute significantly to the underlying damaging pathology associated with these diseases. Here we show that Takinib, a highly discriminatory inhibitor of transforming growth factor Beta- activated kinase 1 (TAK1), selectively and potently reduces TNF production in pro-inflammatory THP-1 macrophages. A complete survey of 110 cytokines, showed robust loss of proinflammatory cytokine responsiveness to lipopolysaccharide (LPS) and interferon gamma (IFNgamma) challenge in response to Takinib. The mechanisms of action of Takinib was recapitulated in TAK1 KO macrophages. TAK1 KO cells showed significant loss of TNF production as well as release of IL-6 in response to LPS challenge. Furthermore, Takinib blocked the ability of exogenously added LPS to promote phosphorylation of, c-Jun, p38 protein kinases as well as downstream transcription factors regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB). In a mouse LPS challenge model, Takinib significantly reduced TNF serum levels. Our findings demonstrate that Takinib has utility in the treatment inflammatory disease by locally suppressing TNF production from invading macrophages. PMID- 30451877 TI - An altered gene expression profile in tyramine-exposed intestinal cell cultures supports the genotoxicity of this biogenic amine at dietary concentrations. AB - Tyramine, histamine and putrescine are the most commonly detected and most abundant biogenic amines (BA) in food. The consumption of food with high concentrations of these BA is discouraged by the main food safety agencies, but legal limits have only been set for histamine. The present work reports a transcriptomic investigation of the oncogenic potential of the above-mentioned BA, as assessed in the HT29 human intestinal epithelial cell line. Tyramine had a greater effect on the expression of genes involved in tumorigenesis than did histamine or putrescine. Since some of the genes that showed altered expression in tyramine-exposed cells are involved in DNA damage and repair, the effect of this BA on the expression of other genes involved in the DNA damage response was investigated. The results suggest that tyramine might be genotoxic for intestinal cells at concentrations easily found in BA-rich food. Moreover, a role in promoting intestinal cancer cannot be excluded. PMID- 30451879 TI - Properties of cell signaling pathways and gene expression systems operating far from steady-state. AB - Ligand-receptor systems, covalent modification cycles, and transcriptional networks are basic units of signaling systems and their steady-state properties are well understood. However, the behavior of such systems before steady-state is poorly characterized. Here, we analyzed the properties of input-output curves for each of these systems as they approach steady-state. In ligand-receptor systems, the EC50 (concentration of the ligand that occupies 50% of the receptors) is higher before the system reaches steady-state. Based on this behavior, we have previously defined PRESS (for pre-equilibrium sensing and signaling), a general "systems level" mechanism cells may use to overcome input saturation. Originally, we showed that, given a step stimulation, PRESS operates when the kinetics of ligand-receptor binding are slower than the downstream signaling steps. Now, we show that, provided the input increases slowly, it is not essential for the ligand binding reaction itself to be slow. In addition, we demonstrate that covalent modification cycles and gene expression systems may also operate in PRESS mode. Thus, nearly all biochemical processes may operate in PRESS mode, suggesting that this mechanism may be ubiquitous in cell signaling systems. PMID- 30451878 TI - Awareness, treatment and control of hypertension among hypertensive patients aged 18 to 59 years old in the northeast of China. AB - Hypertension not only has a high prevalence, but also brings disease burden to the affected patients. To assess the level of awareness, treatment and control of hypertension in the northeast of China, we investigated the rates of awareness, treatment and control of hypertension and identified its related factors among hypertensive patients aged 18 to 59 years old in Jilin, China. The data (n = 4632) for the present study were extracted from a cross-sectional study in Jilin. Among individuals with hypertension, the standardized rates of awareness, treatment and control of hypertension were 44.9%, 36.5%, 24.3%, respectively. The rates of awareness and treatment of hypertension among middle aged patients were higher than those among young patients. Compared to patients with normal Body Mass index (BMI), obese hypertensive patients had a higher rate of treatment (43.7% vs. 25.9%) and a lower rate of control (18.9% vs. 29.6%). Compared to patients with normal BMI, patients who were obese were more likely to take measures to treat hypertension (OR = 2.50, 95%CI: 2.05-3.05); but were less likely to have well-controlled blood pressure (OR = 0.55, 95%CI: 0.40-0.78). BMI is one of the influencing factors of hypertension awareness, treatment and control among patients 18 to 59 years old with hypertension. PMID- 30451880 TI - Taxon-specific responses to different forestry treatments in a temperate forest. AB - There are only few studies that explore the ecological consequences of forest management on several organism groups. We studied the short-term effects of four forestry treatments including preparation cutting, clear-cutting, retention tree group and gap-cutting in a temperate managed forest on the assemblage structure of understory plants, enchytraeid worms, spiders and ground beetles. Here we show, that the effect of treatments on the different facets of assemblage structure was taxon-specific. Clear-cutting and retention tree group strongly impoverished enchytraeids assemblages. Even if the species richness and cover of plants increased in clear-cutting and gap-cutting, their species composition moderately changed after treatments. For spiders only their species composition was influenced by the treatments, while the response of ground beetles was slightly affected. Short-term effect of forest management interventions on biodiversity might be compensated by the dispersal (spiders, ground beetles) and resilience (plants) of organism groups, however sedentary soil organism showed high sensitivity. PMID- 30451881 TI - Chronic intake of 4-Methylimidazole induces Hyperinsulinemia and Hypoglycaemia via Pancreatic Beta Cell Hyperplasia and Glucose Dyshomeostasis. AB - Caramel colours are the preferential food colouring agent globally, reaches wide age groups through eatables. Colas, a sweetened carbonated drink are most common caramel coloured beverage and its consumption is linked with diabetes, obesity, pancreatic cancer and other endocrine disorders. A major by-product produced during caramelization is 4-methylimidazole (4-MEI) that is detected in noteworthy concentrations in colas and other beverages. Previous studies revealed the neurotoxic and carcinogenic potential of 4-MEI in animals at higher doses but the effect of 4-MEI at theoretical maximum daily intake dose on glucose homeostasis is unexplored. Here, mice treated with 4-MEI (32 ug/kg bodyweight/day) for seven weeks exhibited severe hypoglycaemia and hyperinsulinemia mediated by hyperplasia of pancreatic beta cells and induces metabolic alterations. On combinatorial treatment, 4-MEI suppressed the glucogenic potential of non-artificial sweeteners and promotes lipogenesis. Furthermore, increased levels of C-peptide, LDL cholesterol and triglycerides were observed in the humans with regular intake of 4-MEI containing beverages. In summary, 4-MEI induced pancreatic beta cell hyperplasia and leads to disruption of glucose and lipid homeostasis. This study suggests the need for further assessment and reconsideration of the wide usage of 4-MEI containing caramels as food additives. PMID- 30451882 TI - Microfluidic Assay Measures Increased Neutrophil Extracellular Traps Circulating in Blood after Burn Injuries. AB - Cell-free DNA (cf-DNA) concentration in human plasma is often increased after burn and trauma injuries. Two major sources of cf-DNA are the parenchymal cells damaged by the injury and various circulating cells indirectly altered by the response to injury. The cf-DNA originating from neutrophils, also known as circulating neutrophil extracellular traps (cNETs), is of notable interest because cNETs have been associated with pathological processes in other conditions, including cancer, autoimmunity, etc. Both intact chromatin and oligonucleotides, which are the by-product of cf-DNA degradation, are assumed to contribute to the cf-DNA in patients. However, traditional assays for cf-DNA quantification do not distinguish between cNETs and cf-DNA of other origins and do not differentiate between intact chromatin and oligonucleotides. Here we measure the amount of intact cNETs in the circulation, using a microfluidic device that mechanically traps chromatin fibers directly from blood and an immunofluorescence protocol that detects neutrophil-specific proteins associated with chromatin. In a rat model of burn injury, we determined that the chromatin fibers in the circulation after injury originate exclusively from neutrophils and are cNETs. We found that the concentration of cNETs surges the first day after injury and then decreases slowly over several days. In a secondary sepsis model, which involved a burn injury followed by cecal-ligation-puncture, we measured additional increases in cNETs in the days after sepsis was induced. These results validate a microfluidic assay for the quantification of cNETs and will facilitate fruther studies probing the contribution of cNETs to complications after burns and sepsis. PMID- 30451883 TI - Author Correction: Non-collinear spin states in bottom-up fabricated atomic chains. AB - The original version of this Article contained an error in Fig. 3 in which Fig. 3b and Fig. 3e incorrectly duplicated Fig. 2a and Fig.2d, respectively. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 30451884 TI - Convective forces increase CXCR4-dependent glioblastoma cell invasion in GL261 murine model. AB - Glioblastoma is the most common and malignant form of brain cancer. Its invasive nature limits treatment efficacy and promotes inevitable recurrence. Previous in vitro studies showed that interstitial fluid flow, a factor characteristically increased in cancer, increases glioma cell invasion through CXCR4-CXCL12 signaling. It is currently unknown if these effects translate in vivo. We used the therapeutic technique of convection enhanced delivery (CED) to test if convective flow alters glioma invasion in a syngeneic GL261 mouse model of glioblastoma. The GL261 cell line was flow responsive in vitro, dependent upon CXCR4 and CXCL12. Additionally, transplanting GL261 intracranially increased the populations of CXCR4+ and double positive cells versus 3D culture. We showed that inducing convective flow within implanted tumors indeed increased invasion over untreated controls, and administering the CXCR4 antagonist AMD3100 (5 mg/kg) effectively eliminated this response. These data confirm that glioma invasion is stimulated by convective flow in vivo and depends on CXCR4 signaling. We also showed that expression of CXCR4 and CXCL12 is increased in patients having received standard therapy, when CED might be elected. Hence, targeting flow stimulated invasion may prove beneficial as a second line of therapy, particularly in patients chosen to receive treatment by convection enhanced delivery. PMID- 30451885 TI - Systematic Study of Ferromagnetism in CrxSb2-xTe3 Topological Insulator Thin Films using Electrical and Optical Techniques. AB - Ferromagnetic ordering in a topological insulator can break time-reversal symmetry, realizing dissipationless electronic states in the absence of a magnetic field. The control of the magnetic state is of great importance for future device applications. We provide a detailed systematic study of the magnetic state in highly doped CrxSb2-xTe3 thin films using electrical transport, magneto-optic Kerr effect measurements and terahertz time domain spectroscopy, and also report an efficient electric gating of ferromagnetic order using the electrolyte ionic liquid [DEME][TFSI]. Upon increasing the Cr concentration from x = 0.15 to 0.76, the Curie temperature (Tc) was observed to increase by ~5 times to 176 K. In addition, it was possible to modify the magnetic moment by up to 50% with a gate bias variation of just +/-3 V, which corresponds to an increase in carrier density by 50%. Further analysis on a sample with x = 0.76 exhibits a clear insulator-metal transition at Tc, indicating the consistency between the electrical and optical measurements. The direct correlation obtained between the carrier density and ferromagnetism - in both electrostatic and chemical doping - using optical and electrical means strongly suggests a carrier-mediated Ruderman Kittel-Kasuya-Yoshida (RKKY) coupling scenario. Our low-voltage means of manipulating ferromagnetism, and consistency in optical and electrical measurements provides a way to realize exotic quantum states for spintronic and low energy magneto-electronic device applications. PMID- 30451886 TI - Atypical postural control can be detected via computer vision analysis in toddlers with autism spectrum disorder. AB - Evidence suggests that differences in motor function are an early feature of autism spectrum disorder (ASD). One aspect of motor ability that develops during childhood is postural control, reflected in the ability to maintain a steady head and body position without excessive sway. Observational studies have documented differences in postural control in older children with ASD. The present study used computer vision analysis to assess midline head postural control, as reflected in the rate of spontaneous head movements during states of active attention, in 104 toddlers between 16-31 months of age (Mean = 22 months), 22 of whom were diagnosed with ASD. Time-series data revealed robust group differences in the rate of head movements while the toddlers watched movies depicting social and nonsocial stimuli. Toddlers with ASD exhibited a significantly higher rate of head movement as compared to non-ASD toddlers, suggesting difficulties in maintaining midline position of the head while engaging attentional systems. The use of digital phenotyping approaches, such as computer vision analysis, to quantify variation in early motor behaviors will allow for more precise, objective, and quantitative characterization of early motor signatures and potentially provide new automated methods for early autism risk identification. PMID- 30451887 TI - High Pressure Metamorphism Caused by Fluid Induced Weakening of Deep Continental Crust. AB - Studies of mineral equilibria in metamorphic rocks have given valuable insights into the tectonic processes operating at convergent plate margins during an orogeny. Geodynamic models simulating orogenesis and crustal thickening have been constrained by temperature and pressure estimates inferred from the mineral assemblages of the various lithologies involved along with age constrains from increasingly precise geochronological techniques. During such studies it is assumed that the pressure experienced by a given rock is uniquely related to its depth of burial. This assumption has been challenged by recent studies of high pressure (HP) and ultrahigh pressure (UHP) rocks. Here, we describe an example of Caledonian HP metamorphism from the Bergen Arcs in western Norway, and show that the associated formation of Caledonian eclogites at the expense of Proterozoic granulites was related to local pressure perturbations rather than burial, and that the HP metamorphism resulted from fluid-induced weakening of an initially dry and highly stressed lower crust when thrust upon the hyperextended margin of the Baltic shield. PMID- 30451888 TI - Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents. AB - Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-CFX scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans. PMID- 30451889 TI - Sequences encoding C2H2 zinc fingers inhibit polyadenylation and mRNA export in human cells. AB - The large C2H2-Zinc Finger (C2H2-ZNF) gene family has rapidly expanded in primates through gene duplication. There is consequently considerable sequence homology between family members at both the nucleotide and amino acid level, allowing for coordinated regulation and shared functions. Here we show that multiple C2H2-ZNF mRNAs experience differential polyadenylation resulting in populations with short and long poly(A) tails. Furthermore, a significant proportion of C2H2-ZNF mRNAs are retained in the nucleus. Intriguingly, both short poly(A) tails and nuclear retention can be specified by the repeated elements that encode zinc finger motifs. These Zinc finger Coding Regions (ZCRs) appear to restrict polyadenylation of nascent RNAs and at the same time impede their export. However, the polyadenylation process is not necessary for nuclear retention of ZNF mRNAs. We propose that inefficient polyadenylation and export may allow C2H2-ZNF mRNAs to moonlight as non-coding RNAs or to be stored for later use. PMID- 30451890 TI - Silibinin, A Natural Blend In Polytherapy Formulation For Targeting Cd44v6 Expressing Colon Cancer Stem Cells. AB - Colon cancer stem cells have been attributed to poor prognosis, therapeutic resistance and aggressive nature of the malignancy. Recent reports associated CD44v6 expression with relapse, metastasis and reduced 5-year survival of colon cancer patients, thereby making it a potential therapeutic target. Thus, in this study, comprehensive prediction and screening of CD44v6 against 1674 lead compounds was conducted. Silibinin was identified as a potential compound targeting CD44v6. Inorder to substantiate these findings, the cytotoxic effect of 5FU, Silibinin and 5FU+ Silibinin was assessed on human colon carcinoma cell line HCT116 derived CD44+ subpopulation. 5FU+ Silibinin inhibited cell proliferation of CD44+ subpopulation at lower concentration than Silibinin standalone. Further, corresponding to CD44v6 knockdown cells, 5FU+ Silibinin treatment significantly decreased CD44v6, Nanog, CTNNB1 and CDKN2A expression whereas increased E cadherin expression in HCT116 derived CD44+ cells. Moreover, synergistic effect of these drugs suppressed sphere formation, inhibited cell migration, triggered PARP cleavage and perturbation in mitochondrial membrane potential, thereby activating intrinsic apoptotic pathways and induced autophagic cell death. Importantly, 5FU+ Silibinin could inhibit PI3K/MAPK dual activation and arrest the cell cycle at G0/G1 phase. Thus, our study suggests that inhibition of CD44v6 attenuates stemness of colon cancer stem cells and holds a prospect of potent therapeutic target. PMID- 30451891 TI - Clinical management and prevention of dental caries in athletes: A four-year randomized controlled clinical trial. AB - The aims of this four-year randomized controlled clinical trial were to gain insights into management and prevention of dental caries and the effect of stannous fluoride products in athletes. Fifty-four participants were randomized into test and control groups. The test group used special stannous fluoride products. The primary endpoint dental caries was assessed by the ICDAS-II-System and analyzed both by a linear mixed model for repeated measures and a generalized linear mixed model. During the observation period an increase in caries-free surfaces from 64.91 +/- 6.42 at baseline to 73.22 +/- 4.43 was observed. In surfaces with caries superficialis and caries media, a decrease from 13.94 +/- 5.70 and 2.96 +/- 2.55 surfaces at baseline to 7.89 +/- 3.18 and 0.46 +/- 0.78 after 2.5 years was noted, respectively. The analysis showed no effect of stannous fluoride products, but a significant difference for the time of examination (p < 0.0001). In addition, it could be shown that at any time of examination, the odds of developing caries media on a new surface was significantly lower than at baseline (up to 25-times). Due to biannual dental examinations, professional tooth cleaning and restorative treatment the number of caries-free surfaces increased and the odds of a new surface to be afflicted with caries media decreased 25-fold. PMID- 30451892 TI - Decreased BDNF Release in Cortical Neurons of a Knock-in Mouse Model of Huntington's Disease. AB - Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an increase in CAG repeats in the Huntingtin gene (HTT). The striatum is one of the most vulnerable brain regions in HD, and altered delivery of BDNF to the striatum is believed to underlie this high vulnerability. However, the delivery of BDNF to the striatum in HD remains poorly understood. Here, we used real-time imaging to visualize release of BDNF from cortical neurons cultured alone or co-cultured with striatal neurons. BDNF release was significantly decreased in the cortical neurons of zQ175 mice (a knock-in model of HD), and total internal reflection fluorescence microscopy revealed several release patterns of single BDNF-containing vesicles, with distinct kinetics and prevalence, in co-cultured cortical HD neurons. Notably, a smaller proportion of single BDNF-containing vesicles underwent full release in HD neurons than in wild type neurons. This decreased release of BDNF in cortical neurons might lead to decreased BDNF levels in the striatum because the striatum receives BDNF mainly from the cortex. In addition, we observed a decrease in the total travel length and speed of BDNF-containing vesicles in HD neurons, indicating altered transport of these vesicles in HD. Our findings suggest a potential mechanism for the vulnerability of striatal neurons in HD and offer new insights into the pathogenic mechanisms underlying the degeneration of neurons in HD. PMID- 30451893 TI - Electrophysiological properties of human beta-cell lines EndoC-betaH1 and -betaH2 conform with human beta-cells. AB - Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-betaH1 and EndoC-betaH2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca2+]i, membrane depolarisation and increased action potential firing. Similar to human primary beta cells, KATP channel activity is low at 1 mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the KATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large conductance Ca2+-activated K+ channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electron-dense core surrounded by a thin clear halo. We conclude that the EndoC-betaH1 and -betaH2 cells share many features of primary human beta-cells and thus represent a useful experimental model. PMID- 30451896 TI - Trends and regional variations in the administrative prevalence of attention deficit/hyperactivity disorder among children and adolescents in Germany. AB - There is a controversy regarding temporal trends in prevalence of attention deficit/hyperactivity disorder (ADHD). Using nationwide claims data containing data for approximately six million statutory health insured children we aimed to examine a) trends of ADHD administrative prevalence during 2009-2016; b) regional variations in prevalence, and c) factors associated with an increased chance of ADHD diagnosis. The ICD-10 code 'F90-hyperkinetic disorder' was used to define an ADHD case. Global and Local Moran's I tests were used to examine the spatial autocorrelation and k-means-cluster analysis to examine the course of ADHD prevalence in administrative districts over years. Two-level logistic regression was applied to examine individual- and district-level factors associated with ADHD diagnosis. The administrative prevalence of ADHD was 4.33% (95% CI: 4.31 4.34%). We observed pronounced small-area differences on the district level with prevalences ranging between 1.6% and 9.7%. There was evidence of strong spatial autocorrelation (Global Moran's I: 0.46, p < 0.0001). The k-means-method identified six clusters of different size; all with a stagnating trend in the prevalence over the observation period of eight years. On the district level, a lower proportion of foreign citizens, and a higher density of paediatric psychiatrists and paediatricians were positively associated with ADHD with a more pronounced effect in urban districts. PMID- 30451895 TI - Automatic detection of major depressive disorder using electrodermal activity. AB - Major depressive disorder (MDD) is a common psychiatric disorder and the leading cause of disability worldwide. However, current methods used to diagnose depression mainly rely on clinical interviews and self-reported scales of depressive symptoms, which lack objectivity and efficiency. To address this challenge, we present a machine learning approach to screen for MDD using electrodermal activity (EDA). Participants included 30 patients with MDD and 37 healthy controls. Their EDA was measured during five experimental phases consisted of baseline, mental arithmetic task, recovery from the stress task, relaxation task, and recovery from the relaxation task, which elicited multiple alterations in autonomic activity. Selected EDA features were extracted from each phase, and differential EDA features between two distinct phases were evaluated. By using these features as input data and performing feature selection with SVM RFE, 74% accuracy, 74% sensitivity, and 71% specificity could be achieved by our decision tree classifier. The most relevant features selected by SVM-RFE included differential EDA features and features from the stress and relaxation tasks. These findings suggest that automatic detection of depression based on EDA features is feasible and that monitoring changes in physiological signal when a subject is experiencing autonomic arousal and recovery may enhance discrimination power. PMID- 30451894 TI - Spatio-temporal cluster and distribution of human brucellosis in Shanxi Province of China between 2011 and 2016. AB - In recent years, the incidence of human brucellosis (HB) in the Shanxi province has ranked to be the top five among the 31 China provinces. HB data in Shanxi province between 2011 and 2016 were collected from the Centers for Disease Control and Prevention. Spatial and temporal distribution of HB was evaluated using spatial autocorrelation analysis and space-time scan analysis. The global Moran's I index ranged from 0.37 to 0.50 between 2011 and 2016 (all P < 0.05), and the "high-high" clusters of HB were located at the northern Shanxi, while the "low-low" clusters in the central and southeastern Shanxi. The high-incidence time interval was between March and July with a 2-fold higher risk of HB compared to the other months in the same year. One most likely cluster and three secondary clusters were identified. The radius of the most likely cluster region was 158.03 km containing 10,051 HB cases. Compared to the remaining regions, people dwelling in the most likely region were reported 4.50-fold ascended risk of incident HB. HB cases during the high-risk time interval of each year were more likely to be younger, to be males or to be farmers or herdsman than that during the low-risk time interval. The HB incidence had a significantly high correlation with the number of the cattle or sheep especially in the northern Shanxi. HB in Shanxi showed unique spatio-temporal clustering. Public health concern for HB in Shanxi should give priority to the northern region especially between the late spring and early summer. PMID- 30451897 TI - The evolutionary dynamics of microRNAs in domestic mammals. AB - MiRNAs are crucial regulators of gene expression found across both the plant and animal kingdoms. While the number of annotated miRNAs deposited in miRBase has greatly increased in recent years, few studies provided comparative analyses across sets of related species, or investigated the role of miRNAs in the evolution of gene regulation. We generated small RNA libraries across 5 mammalian species (cow, dog, horse, pig and rabbit) from 4 different tissues (brain, heart, kidney and testis). We identified 1676 miRBase and 413 novel miRNAs by manually curating the set of computational predictions obtained from miRCat and miRDeep2. Our dataset spanning five species has enabled us to investigate the molecular mechanisms and selective pressures driving the evolution of miRNAs in mammals. We highlight the important contributions of intronic sequences (366 orthogroups), duplication events (135 orthogroups) and repetitive elements (37 orthogroups) in the emergence of new miRNA loci. We use this framework to estimate the patterns of gains and losses across the phylogeny, and observe high levels of miRNA turnover. Additionally, the identification of lineage-specific losses enables the characterisation of the selective constraints acting on the associated target sites. Compared to the miRBase subset, novel miRNAs tend to be more tissue specific. 20 percent of novel orthogroups are restricted to the brain, and their target repertoires appear to be enriched for neuron activity and differentiation processes. These findings may reflect an important role for young miRNAs in the evolution of brain expression plasticity. Many seed sequences appear to be specific to either the cow or the dog. Analyses on the associated targets highlight the presence of several genes under artificial positive selection, suggesting an involvement of these miRNAs in the domestication process. Altogether, we provide an overview on the evolutionary mechanisms responsible for miRNA turnover in 5 domestic species, and their possible contribution to the evolution of gene regulation. PMID- 30451898 TI - Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis. AB - It was already described that genetic inhibition of NUPR1 induces tumor growth arrest. In this paper we studied the metabolism changes after NUPR1 downregulation in pancreatic cancer cells, which results in a significant decrease of OXPHOS activity with a concomitant lower ATP production which precedes the necrotic cell death. We demonstrated that NUPR1 downregulation induces a mitochondrial failure with a loss of the mitochondrial membrane potential, a strong increase in ROS production and a concomitant relocalization of mitochondria to the vicinity of the endoplasmic reticulum (ER). In addition, the transcriptomic analysis of NUPR1-deficient cells shows a decrease in the expression of some ER stress response-associated genes. Indeed, in ER stressors treated cells with thapsigargin, brefeldin A or tunicamycin, a greater increase in necrosis and decrease of ATP content was observed in NUPR1-defficent cells. Finally, in vivo experiments, using acute pancreatitis which induces ER stress as well as NUPR1 activation, we observed that NUPR1 expression protects acinar cells from necrosis in mice. Importantly, we also report that the cell death observed after knocking-down NUPR1 expression is completely reversed by incubation with Necrostatin-1, but not by inhibiting caspase activity with Z-VAD-FMK. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death mediated by a programmed necrosis. PMID- 30451899 TI - Bioavailability of a novel form of silicon supplement. AB - In this study, we assessed uptake and potential efficacy of a novel, pH neutral form of silicon supplement in vitro and using broiler chickens as a model species. In vitro bioavailability of this supplement was significantly higher than other commercial supplements tested, all of which claim available silica content. To confirm bioavailability of the new supplement in vivo, a broiler chick feeding trial reported blood uptake that was significantly higher than a Bamboo-derived silicon supplement. We assessed dose response of the novel supplement in a further study with increased dose related levels of silicon being detected in the blood and tibia. We found tibia and foot ash residue as a percentage of dry mass was higher with inclusion of the novel supplement in the diet, particularly in young birds and that this was followed by significant increase in tibia breaking strength. This novel supplement may therefore have applications in the improvement of bone integrity, with implications for the reduction of lameness in broilers. These results indicate the novel silica supplement is readily absorbed in chicks, and transported in the blood supply to sites such as the skeleton due to it being present in a non-condensed, monomeric form. There is potential for wider application of this silica supplement in other species where bone breakages are a problem, including high performance sport. PMID- 30451900 TI - Author Correction: Expression-based drug screening of neural progenitor cells from individuals with schizophrenia. AB - In the originally published version of this Article, the affiliation details for Eric E. Schadt and Radoslav Savic incorrectly omitted 'Sema4, a Mount Sinai venture, Stamford, Connecticut, USA'. This has been corrected in both the PDF and HTML versions of the Article. PMID- 30451901 TI - Fluoride-doped amorphous calcium phosphate nanoparticles as a promising biomimetic material for dental remineralization. AB - Demineralization of dental hard tissue is a widespread problem and the main responsible for dental caries and dentin hypersensitivity. The most promising strategies to induce the precipitation of new mineral phase are the application of materials releasing gradually Ca2+ and PO43- ions or mimicking the mineral phase of the host tissue. However, the design of formulations covering both processes is so far a challenge in preventive dentistry. In this work, we have synthesized innovative biomimetic amorphous calcium phosphate (ACP), which has been, for the first time, doped with fluoride ions (FACP) to obtain materials with enhanced anti-caries and remineralizing properties. Significantly, the doping with fluoride (F) did not vary the physico-chemical features of ACP but resulted in a faster conversion to the crystalline apatite phase in water, as observed by in-situ time-dependent Raman experiments. The efficacy of the as synthesized ACP and FACP samples to occlude dentinal tubules and induce enamel remineralization has been tested in vitro in human molar teeth. The samples showed good ability to partially occlude the tubules of acid-etched dentin and to restore demineralized enamel into its native structure. Results demonstrate that ACP and FACP are promising biomimetic materials in preventive dentistry to hinder demineralization of dental hard tissues. PMID- 30451902 TI - Hydrogen production by Sulfurospirillum species enables syntrophic interactions of Epsilonproteobacteria. AB - Hydrogen-producing bacteria are of environmental importance, since hydrogen is a major electron donor for prokaryotes in anoxic ecosystems. Epsilonproteobacteria are currently considered to be hydrogen-oxidizing bacteria exclusively. Here, we report hydrogen production upon pyruvate fermentation for free-living Epsilonproteobacteria, Sulfurospirillum spp. The amount of hydrogen produced is different in two subgroups of Sulfurospirillum spp., represented by S. cavolei and S. multivorans. The former produces more hydrogen and excretes acetate as sole organic acid, while the latter additionally produces lactate and succinate. Hydrogen production can be assigned by differential proteomics to a hydrogenase (similar to hydrogenase 4 from E. coli) that is more abundant during fermentation. A syntrophic interaction is established between Sulfurospirillum multivorans and Methanococcus voltae when cocultured with lactate as sole substrate, as the former cannot grow fermentatively on lactate alone and the latter relies on hydrogen for growth. This might hint to a yet unrecognized role of Epsilonproteobacteria as hydrogen producers in anoxic microbial communities. PMID- 30451903 TI - Robustness of elastic properties in polymer nanocomposite films examined over the full volume fraction range. AB - Polymers with nanoparticle inclusions are attractive materials because physical properties can be tuned by varying size and volume fraction range. However, elastic behavior can degrade at higher inclusion fractions when particle-particle contacts become important, and sophisticated measurement techniques are required to study this crossover. Here, we report on the mechanical properties of materials with BaTiO3 nanoparticles (diameters < 10 nm) in a polymer (poly(methyl methacrylate)) matrix, deposited as films in different thickness ranges. Two well known techniques, time and frequency domain Brillouin light scattering, were employed to probe the composition dependence of their elastic modulus. The time domain experiment revealed the biphasic state of the system at the highest particle volume fraction, whereas frequency domain Brillouin scattering provided comprehensive information on ancillary variables such as refractive index and directionality. Both techniques prove complementary, and can in particular be used to probe the susceptibility of elastic properties in polymer nanocomposites to aging. PMID- 30451904 TI - The characterization of flavored hookahs aroma profile and in response to heating as analyzed via headspace solid-phase microextraction (SPME) and chemometrics. AB - Flavors profiling in flavored hookah tobacco is an issue of increasing scrutiny for the health sector owing to its adverse effects on humans, especially being heated to produce smoke. This study aims at tackling the components involved in the flavored hookah tobacco from a chemical and biological point of view. Detecting individual flavor compounds, within a complex hookah tobacco matrix was accomplished using headspace solid phase microextraction (SPME). A total of 114 volatiles were identified in 13 flavored hookah tobacco products, with esters amounting for the major component up to 40%. Whereas oxygenated monoterpenes presented another major volatile class, contributing up to 23%, including (E) anethole. Superheating flavored hookah tobacco at 190 degrees C resulted in the release of a mixture of phenol derivatives and polycyclic aromatic compounds that are indicative of coal tar, a major component produced during hookah tobacco usage with potential health hazards. This study provides the first comprehensive volatile profile of hookah tobacco products from different origins identifying chemical components involved in flavors. It is expected to serve as informative grounds for the better understanding of hookah tobacco production and usage. The information presented is also expected to raise awareness on the health risks of hookah tobacco smoking. PMID- 30451905 TI - An anti-clogging method for improving the performance and lifespan of blood plasma separation devices in real-time and continuous microfluidic systems. AB - On-chip blood plasma separators using microfluidic channels are typically developed as disposable devices for short-term use only because blood cells tend to clog the microchannels, limiting their application in real-time and continuous systems. In this study, we propose an anti-clogging method. We applied dielectrophoresis to prevent microchannel clogging in a plasma separator that can be used over long periods for real-time and continuous monitoring. Prior to applying the anti-clogging method, the blood plasma separator stopped working after 4 h. In contrast, by manipulating the separator with the new anti-clogging method at a voltage of 20 V, it continued working in a long-term experiment for 12 h without performance deterioration or an increase in cell loss. Two critical performance parameters of the manipulated separator, the purity efficiency and the plasma yield, were 97.23 +/- 5.43% and 38.95 +/- 9.34%, respectively, at 20 V after 15 min. Interestingly, the two performance parameters did not decrease during the long-term experiment. Hence, the blood plasma separator with the anti clogging method is an interesting device for use in real-time and continuous blood plasma separation systems because of its consistent performance and improved lifespan. PMID- 30451906 TI - Individual variability in diving, movement and activity patterns of adult bearded seals in Svalbard, Norway. AB - Bearded seals are one of the least studied Arctic marine mammals, despite their circumpolar distribution and importance as a resource to Inuit communities. In this study, adult bearded seals (Erignathus barbatus) were equipped with GPS Argos-CTD-SRDLs in Svalbard, Norway (2011-2012, n = 7) to document their diving, activity and movement patterns in a region where their habitat is changing rapidly. Five seals transmitted for > 8 months, sending 21,738 GPS-positions and 17,866 dives between July and April. The seals spent little time hauled out (<= 5%). Diving, which occupied 74 +/- 3% of their time, was generally shallow (24 +/ 7 m, max: 391 m) and of short duration (6.6 +/- 1.5 min, max: 24 min) with deeper, longer dives in winter/spring compared to summer. All seals occupied shallow, coastal areas and relatively small 50% home ranges (10-32 km2). However, individuals exhibited high degrees of specialization in their habitat use and diving behaviour, differing markedly with respect to proportions of benthic vs pelagic dives (range: 51-95% benthic dives), distance to glacier fronts (range: 3 22 km) and in the time spent at the bottom of dives (range: 43-77%). Having specialized strategies within a generalist population may help bearded seals adapt in a rapidly changing Arctic ecosystem. PMID- 30451908 TI - Phosphorescent Energy Downshifting for Diminishing Surface Recombination in Silicon Nanowire Solar Cells. AB - Molecularly engineered Ir(III) complexes can transfer energy from short wavelength photons (lambda < 450 nm) to photons of longer wavelength (lambda > 500 nm), which can enhance the otherwise low internal quantum efficiency (IQE) of crystalline Si (c-Si) nanowire solar cells (NWSCs) in the short-wavelength region. Herein, we demonstrate a phosphorescent energy downshifting system using Ir(III) complexes at short wavelengths (300-450 nm) to diminish the severe surface recombination that occurs in c-Si NWSCs. The developed Ir(III) complexes can be considered promising energy converters because they exhibit superior intrinsic properties such as a high quantum yield, a large Stokes shift, a long exciton diffusion length in crystalline film, and a reproducible synthetic procedure. Using the developed Ir(III) complexes, highly crystalline energy downshifting layers were fabricated by ultrasonic spray deposition to enhance the photoluminescence efficiency by increasing the radiative decay. With the optimized energy downshifting layer, our 1 cm2 c-Si NWSCs with Ir(III) complexes exhibited a higher IQE value for short-wavelength light (300-450 nm) compared with that of bare Si NWSCs without Ir(III) complexes, resulting in a notable increase in the short-circuit current density (from 34.4 mA.cm-2 to 36.5 mA.cm 2). PMID- 30451907 TI - Integrated PTR-ToF-MS, GWAS and biological pathway analyses reveal the contribution of cow's genome to cheese volatilome. AB - Volatile organic compounds (VOCs) are small molecules that contribute to the distinctive flavour of cheese which is an important attribute for consumer acceptability. To investigate whether cow's genetic background might contribute to cheese volatilome, we carried out genome-wide association studies (GWAS) and pathway-based analyses for 173 spectrometric peaks tentatively associated with several VOCs obtained from proton-transfer-reaction mass spectrometry (PTR-ToF MS) analyses of 1,075 model cheeses produced using raw whole-milk from Brown Swiss cows. Overall, we detected 186 SNPs associated with 120 traits, several of which mapped close to genes involved in protein (e.g. CSN3, GNRHR and FAM169A), fat (e.g. AGPAT3, SCD5, and GPAM) and carbohydrate (e.g. B3GNT2, B4GALT1, and PHKB) metabolism. Gene set enrichment analysis showed that pathways connected with proteolysis/amino acid metabolism (purine and nitrogen metabolism) as well as fat metabolism (long-term potentiation) and mammary gland function (tight junction) were overrepresented. Our results provide the first evidence of a putative link between cow's genes and cheese flavour and offer new insights into the role of potential candidate loci and the biological functions contributing to the cheese volatilome. PMID- 30451909 TI - Obesity shows preserved plasma proteome in large independent clinical cohorts. AB - Holistic human proteome maps are expected to complement comprehensive profile assessment of health and disease phenotypes. However, methodologies to analyze proteomes in human tissue or body fluid samples at relevant scale and performance are still limited in clinical research. Their deployment and demonstration in large enough human populations are even sparser. In the present study, we have characterized and compared the plasma proteomes of two large independent cohorts of obese and overweight individuals using shotgun mass spectrometry (MS)-based proteomics. Herein, we showed, in both populations from different continents of about 500 individuals each, the concordance of plasma protein MS measurements in terms of variability, gender-specificity, and age-relationship. Additionally, we replicated several known and new associations between proteins, clinical and molecular variables, such as insulin and glucose concentrations. In conclusion, our MS-based analyses of plasma samples from independent human cohorts proved the practical feasibility and efficiency of a large and unified discovery/replication approach in proteomics, which was also recently coined "rectangular" design. PMID- 30451910 TI - Effects of spatial consistency and individual difference on touch-induced visual suppression effect. AB - Crossmodal studies have reported not only facilitatory but also inhibitory perceptual interactions. For instance, tactile stimulation to the index finger of a hand leads to the degradation of visual discrimination performance (touch induced visual suppression, TIVS). It has been suggested that the magnitude of TIVS depends on the spatial congruency of visuo-tactile stimuli and on individual differences in task performance. We performed a detailed investigation of the effects of spatial consistency and individual differences on the occurrence of TIVS. The visual target and tactile stimulus were presented at co-localized, ipsilateral but not co-localized, or contralateral positions. The degree of autistic traits has been reported to be well variable among the general population and to reflect differences in sensory processing. Therefore, we assessed the magnitude of autistic traits using the autism-spectrum quotient (AQ) as an index of individual differences. TIVS occurred particularly at the ipsilateral but not co-localized position. In contrast, the magnitude of the TIVS was positively correlated with the AQ score when the stimuli were presented at the co-localized position. These findings suggest that the occurrence of TIVS can be modulated both by the spatial relationship between the visual and tactile stimuli and by individual differences in autistic traits. PMID- 30451911 TI - Low loss photonic nanocavity via dark magnetic dipole resonant mode near metal. AB - The dielectric-semiconductor-dielectric-metal 4 layered structure is a well established configuration to support TM hybrid plasmonic modes, which have demonstrated significant advantages over pure photonic modes in structures without metal to achieve low loss resonant cavities at sub-diffraction limited volumes. The photonic modes with TE characteristics supported by the same 4 layered structure, on the other hand, are less studied. Here we show that a low loss photonic mode with TE01 characteristics exists in the dielectric semiconductor-dielectric-metal 4 layered structure if a truncated cylindrical disk is chosen as the semiconductor core. This mode exhibits the lowest cavity loss among all resonant modes, including both pure photonic and hybrid plasmonic modes, at cavity radius <150 nm and within the wavelength range 620 nm to 685 nm, with a footprint ~0.83 (lambda/2neff)2, physical size ~0.47 (lambda/2neff)3 and a mode volume down to 0.3 (lambda/2neff)3. The low cavity loss of this TE01 mode is attributed to its substantially reduced radiation loss to the far field by the creation of image charges through the metal response. Because of the low mode penetration in the metal, this photonic mode show equally low cavity loss near industry relevant metals such as Cu. Our study demonstrates an alternative to hybrid plamonic modes and metallo-dielectric modes to achieve low loss cavities with extremely small footprints. PMID- 30451912 TI - Endogenous calcitonin regulates lipid and glucose metabolism in diet-induced obesity mice. AB - Calcitonin (CT) plays an important role in calcium homeostasis, and its precursor, proCT, is positively associated with the body mass index in the general human population. However, the physiological role of endogenous CT in the regulation of metabolism remains unclear. Knockout mice with gene-targeted deletion of exon 4 of Calca (CT KO) were generated by targeted modification in embryonic stem cells. Male mice were used in all experiments and were fed a slightly higher fat diet than the standard diet. The CT KO mice did not exhibit any abnormal findings in appearance, but exhibited weight loss from 15 months old, i.e., significantly decreased liver, adipose tissue, and kidney weights, compared with wild-type control mice. Furthermore, CT KO mice exhibited significantly decreased fat contents in the liver, lipid droplets in adipose tissues, serum glucose, and lipid levels, and significantly increased insulin sensitivity and serum adiponectin levels. CT significantly promoted 3T3-L1 adipocyte differentiation and suppressed adiponectin release. These results suggested that CT gene deletion prevents obesity, hyperglycemia, and hyperlipidemia in aged male mice. This is the first definitive evidence that CT may contribute to glucose and lipid metabolism in aged male mice, possibly via decreased adiponectin secretion from adipocytes. PMID- 30451914 TI - Observing the devastating coffee berry borer (Hypothenemus hampei) inside the coffee berry using micro-computed tomography. AB - The coffee berry borer is the most devastating insect pest of coffee throughout the world. The insect spends most of its life cycle inside the coffee berry, which makes it quite difficult to observe its behaviour. Micro-computed tomography (micro-CT) was used to observe all developmental stages of the coffee berry borer inside coffee berries (Coffea canephora). An interesting oviposition pattern involving a sequential placement of eggs starting in the periphery of the seed and moving inwards was observed. Micro-CT should be useful in elucidating unknown life history aspects of other seed-feeding bark beetles as well as of bark and ambrosia beetles in general. PMID- 30451913 TI - Inverse Relationship between Metabolic Syndrome and 25-Hydroxyvitamin D Concentration in Elderly People without Vitamin D deficiency. AB - Vitamin D status is inversely associated with the prevalence of metabolic syndrome (MetS). Whether this is true in the elderly without vitamin D deficiency is rarely investigated. Our data source is a cross-sectional survey of 1,966 community-dwelling elderly Taiwanese in 2012. An overnight fasting blood were obtained for biochemistry variables. Vitamin D deficiency was defined as serum 25 hydroxyvitamin D3 [25(OH)D] concentration <20 ng/mL. MetS is defined using modified ATP-III criteria. Of 523 participants without vitamin D deficiency (Men/Women = 269/254, age = 76.0 +/- 6.2 years old [65-102 years old]), mean 25(OH)D was 44.0 +/- 11.1 ng/mL, and the MetS prevalence of MS was 46.5%. Serum 25(OH)D was negatively associated with osteocalcin, the homeostatic model assessment insulin resistance (HOMA-IR) index, body mass index (BMI), and glycated hemoglobin A1c. Participants with more MetS features have lower serum 25(OH)D and osteocalcin. Binary logistic regression models showed that 25(OH)D, physical activity, and osteocalcin were negatively independent MetS factors, but that the HOMA-IR index, BMI, and being female were positively independent factors. The risk of MetS was progressively lower along with the increased 25(OH)D concentration, even above 60 ng/mL. In conclusion, a low 25(OH)D concentration is an independent risk factor for MetS in elderly people without vitamin D deficiency. PMID- 30451915 TI - Spent embryo culture medium metabolites are related to the in vitro attachment ability of blastocysts. AB - The metabolomic profile of an embryo culture medium can aid in the advanced prediction of embryonic developmental potential and genetic integrity. But it is not known if this technology can be used to determine the in vitro potential of inner cell mass (ICM) in adherence and proliferation. Here, we investigated the developmental potential of mouse 2-cell embryos carrying cisplatin-induced DNA lesions (IDL), beyond blastocyst stage using ICM outgrowth assay. The genetic integrity of ICM cells was determined by comet assay. The metabolic signatures of spent medium were recorded 84 hours post injection of hCG (hpi-hCG), and after 96 hours of extended in vitro culture (Ex 96) by NMR spectroscopy. We observed that blastocysts that lack the ability to adhere in vitro had an increased requirement of pyruvate (p < 0.01), lactate (p < 0.01), and were accompanied by a significant reduction of pyruvate-alanine ratio in the culture medium. We propose that the aforementioned metabolites from 84 hpi-hCG spent medium be further explored using appropriate experimental models, to prove their potential as biomarkers in the prediction of implantation ability of in vitro derived human embryos in clinical settings. PMID- 30451916 TI - Systematic Analysis of SIN3 Histone Modifying Complex Components During Development. AB - Establishment and maintenance of histone acetylation levels are critical for metazoan development and viability. Disruption of the balance between acetylation and deacetylation by treatment with chemical histone deacetylase (HDAC) inhibitors results in loss of cell proliferation, differentiation and/or apoptosis. Histone deacetylation by the SIN3 complex is essential in Drosophila and mice, as loss of the scaffolding factor SIN3 or the associated HDAC results in lethality. The objective of this study is to elucidate contributions of SIN3 complex components to these essential processes. We used the Drosophila model organism to carry out a systematic functional analysis of the SIN3 complex. We find that SIN3 associated proteins are essential for viability and cell proliferation during development. Additionally, tissue specific reduction of SIN3 complex components results in abnormal wing development. Interestingly, while knockdown of each factor resulted in similar phenotypes, their individual effects on recruitment of SIN3 to polytene chromosomes are distinct. Reduction of some factors leads to large changes in the morphology of the chromosome and/or greatly reduced SIN3 binding. These findings suggest that while individual SIN3 complex components work through distinct molecular mechanisms, they each make a substantial contribution to the overall function of this highly conserved histone deacetylase complex. PMID- 30451917 TI - Vimentin deficiency in macrophages induces increased oxidative stress and vascular inflammation but attenuates atherosclerosis in mice. AB - The aim was to clarify the role of vimentin, an intermediate filament protein abundantly expressed in activated macrophages and foam cells, in macrophages during atherogenesis. Global gene expression, lipid uptake, ROS, and inflammation were analyzed in bone-marrow derived macrophages from vimentin-deficient (Vim-/-) and wild-type (Vim+/+) mice. Atherosclerosis was induced in Ldlr-/- mice transplanted with Vim-/- and Vim+/+ bone marrow, and in Vim-/- and Vim+/+ mice injected with a PCSK9 gain-of-function virus. The mice were fed an atherogenic diet for 12-15 weeks. We observed impaired uptake of native LDL but increased uptake of oxLDL in Vim-/- macrophages. FACS analysis revealed increased surface expression of the scavenger receptor CD36 on Vim-/- macrophages. Vim-/- macrophages also displayed increased markers of oxidative stress, activity of the transcription factor NF-kappaB, secretion of proinflammatory cytokines and GLUT1 mediated glucose uptake. Vim-/- mice displayed decreased atherogenesis despite increased vascular inflammation and increased CD36 expression on macrophages in two mouse models of atherosclerosis. We demonstrate that vimentin has a strong suppressive effect on oxidative stress and that Vim-/- mice display increased vascular inflammation with increased CD36 expression on macrophages despite decreased subendothelial lipid accumulation. Thus, vimentin has a key role in regulating inflammation in macrophages during atherogenesis. PMID- 30451918 TI - Conversion from environmental filtering to randomness as assembly rule of ground beetle assemblages along an urbanization gradient. AB - Urbanization fragments, isolates or eliminates natural habitats, and changes the structure and composition of assemblages living in the remaining natural fragments. Knowing assembly rules is necessary to support and/or maintain biodiversity in urban habitats. We hypothesized that forest communities in rural sites are organized by environmental filtering, but this may be changed by urbanization, and in the suburban and urban forest fragments replaced by randomly organized assemblages, influenced by the colonization of species from the surrounding matrix. Evaluating simultaneously the functional and phylogenetic relationships of co-existing species, we showed that at the rural sites, co existing ground beetle species were functionally and phylogenetically more similar than expected by chance, indicating that environmental filtering was the likely process structuring these communities. Contrary to this, in urban and suburban sites, the co-occurring species were functionally and phylogenetically not different from the null model, indicating randomly structured assemblages. According to our findings, changes in environmental and habitat characteristics accompanied by urbanization lead to assemblages of randomly colonized species from the surrounding matrix, threatening proper ecosystem functioning. To reassemble stochastically assembled species of urban and suburban fragments to structured, properly functioning communities, appropriate management strategies are needed which simultaneously consider recreational, economic and conservation criteria. PMID- 30451919 TI - Selective eye fixations on diagnostic face regions of dynamic emotional expressions: KDEF-dyn database. AB - Prior research using static facial stimuli (photographs) has identified diagnostic face regions (i.e., functional for recognition) of emotional expressions. In the current study, we aimed to determine attentional orienting, engagement, and time course of fixation on diagnostic regions. To this end, we assessed the eye movements of observers inspecting dynamic expressions that changed from a neutral to an emotional face. A new stimulus set (KDEF-dyn) was developed, which comprises 240 video-clips of 40 human models portraying six basic emotions (happy, sad, angry, fearful, disgusted, and surprised). For validation purposes, 72 observers categorized the expressions while gaze behavior was measured (probability of first fixation, entry time, gaze duration, and number of fixations). Specific visual scanpath profiles characterized each emotional expression: The eye region was looked at earlier and longer for angry and sad faces; the mouth region, for happy faces; and the nose/cheek region, for disgusted faces; the eye and the mouth regions attracted attention in a more balanced manner for surprise and fear. These profiles reflected enhanced selective attention to expression-specific diagnostic face regions. The KDEF-dyn stimuli and the validation data will be available to the scientific community as a useful tool for research on emotional facial expression processing. PMID- 30451920 TI - Characterization of a new N-terminally acetylated extra-mitochondrial isoform of frataxin in human erythrocytes. AB - Frataxin is a highly conserved protein encoded by the frataxin (FXN) gene. The full-length 210-amino acid form of protein frataxin (1-210; isoform A) expressed in the cytosol of cells rapidly translocates to the mitochondria, where it is converted to the mature form (81-210) by mitochondrial processing peptidase. Mature frataxin (81-210) is a critically important protein because it facilitates the assembly of mitochondrial iron-sulfur cluster protein complexes such as aconitase, lipoate synthase, and succinate dehydrogenases. Decreased expression of frataxin protein is responsible for the devastating rare genetic disease of Friedreich's ataxia. The mitochondrial form of frataxin has long been thought to be present in erythrocytes even though paradoxically, erythrocytes lack mitochondria. We have discovered that erythrocyte frataxin is in fact a novel isoform of frataxin (isoform E) with 135-amino acids and an N-terminally acetylated methionine residue. There is three times as much isoform E in erythrocytes (20.9 +/- 6.4 ng/mL) from the whole blood of healthy volunteers (n = 10) when compared with the mature mitochondrial frataxin present in other blood cells (7.1 +/- 1.0 ng/mL). Isoform E lacks a mitochondrial targeting sequence and so is distributed to both cytosol and the nucleus when expressed in cultured cells. When extra-mitochondrial frataxin isoform E is expressed in HEK 293 cells, it is converted to a shorter isoform identical to the mature frataxin found in mitochondria, which raises the possibility that it is involved in disease etiology. The ability to specifically quantify extra-mitochondrial and mitochondrial isoforms of frataxin in whole blood will make it possible to readily follow the natural history of diseases such as Friedreich's ataxia and monitor the efficacy of therapeutic interventions. PMID- 30451922 TI - Study on Nature-inspired Fractal Design-based Flexible Counter Electrodes for Dye Sensitized Solar Cells Fabricated using Additive Manufacturing. AB - Dye-Sensitized Solar Cells (DSSC) are third generation solar cells used as an alternative to traditional silicon solar cells. DSSCs are characterized by their durability, easy handling and ability to perform better under diverse lighting conditions which makes them an ideal choice for indoor applications. However, DSSCs suffer from several limitations including low efficiencies, susceptibility to electrolyte leakage under extreme weather conditions, and the need for expensive materials and fabrication techniques which limits their large-scale industrial applications. Addressing these limitations through efficient design and manufacturing techniques are critical in ensuring that the DSSCs transform from the current small-scale laboratory levels to sizeable industrial production. This research attempts to address some of these significant limitations by introducing the concepts of nature-inspired fractal-based design followed by the additive manufacturing process to fabricate cost-effective, flexible counter electrodes for DSSCs. The new conceptual fractal-based design counter electrodes overcome the limitations of conventional planar designs by significantly increasing the number of active reaction sites which enhances the catalytic activity thereby improving the performance. The fabrication of these innovative fractal designs is realized through cost-effective manufacturing techniques including additive manufacturing and selective electrochemical co-deposition processes. The results of the study suggest that the fractal-based counter electrodes perform better than conventional designs. Additionally, the fractal designs and additive manufacturing technology help in addressing the problems of electrolyte leakage, cost of fabrication, and scalability of DSSCs. PMID- 30451921 TI - Temperature Sensing of Deep Abdominal Region in Mice by Using Over-1000 nm Near Infrared Luminescence of Rare-Earth-Doped NaYF4 Nanothermometer. AB - Luminescence nanothermometry has attracted much attention as a non-contact thermal sensing technique. However, it is not widely explored for in vivo applications owing to the low transparency of tissues for the light to be used. In this study, we performed biological temperature sensing in deep tissues using beta-NaYF4 nanoparticles co-doped with Yb3+, Ho3+, and Er3+ (NaYF4: Yb3+, Ho3+, Er3+ NPs), which displayed two emission peaks at 1150 nm (Ho3+) and 1550 nm (Er3+) in the >1000 nm near-infrared wavelength region, where the scattering and absorption of light by biological tissues are at the minimum. The change in the luminescence intensity ratio of the emission peaks of Ho3+ and Er3+ (IHo/IEr) in the NaYF4: Yb3+, Ho3+, Er3+ nanothermometer differs corresponding to the thickness of the tissue. Therefore, the relationship between IHo/IEr ratio and temperature needs to be calibrated by the depth of the nanothermometer. The temperature-dependent change in the IHo/IEr was evident at the peritoneal cavity level, which is deeper than the subcutaneous tissue level. The designed experimental system for temperature imaging will open the window to novel luminescent nanothermometers for in vivo deep tissue temperature sensing. PMID- 30451923 TI - Lipoprotein markers associated with disability from multiple sclerosis. AB - Altered lipid metabolism is a feature of chronic inflammatory disorders. Increased plasma lipids and lipoproteins have been associated with multiple sclerosis (MS) disease activity. Our objective was to characterise the specific lipids and associated plasma lipoproteins increased in MS and to test for an association with disability. Plasma samples were collected from 27 RRMS patients (median EDSS, 1.5, range 1-7) and 31 healthy controls. Concentrations of lipids within lipoprotein sub-classes were determined from NMR spectra. Plasma cytokines were measured using the MesoScale Discovery V-PLEX kit. Associations were tested using multivariate linear regression. Differences between the patient and volunteer groups were found for lipids within VLDL and HDL lipoprotein sub fractions (p < 0.05). Multivariate regression demonstrated a high correlation between lipids within VLDL sub-classes and the Expanded Disability Status Scale (EDSS) (p < 0.05). An optimal model for EDSS included free cholesterol carried by VLDL-2, gender and age (R2 = 0.38, p < 0.05). Free cholesterol carried by VLDL-2 was highly correlated with plasma cytokines CCL-17 and IL-7 (R2 = 0.78, p < 0.0001). These results highlight relationships between disability, inflammatory responses and systemic lipid metabolism in RRMS. Altered lipid metabolism with systemic inflammation may contribute to immune activation. PMID- 30451925 TI - Physical mechanisms of oceanic mantle earthquakes: Comparison of natural and experimental events. AB - Because they provide information about the spatial distribution of brittle deformation, both seismologists and experimentalists use b-values to study earthquake populations. Here, we present the b-values for intermediate-depth intraslab earthquakes in the Pacific slab beneath the Tohoku and Hokkaido regions, northeastern Japan and find a difference in the lower-plane event b values in the double seismic zone. Lower-plane events reveal significantly larger b-values beneath Tohoku (0.96) than Hokkaido (0.86), implying that the brittle deformation beneath Hokkaido is more localized and leads to higher ratio of relatively large lower-plane events than occur beneath Tohoku. We also estimated the b-values for experimental earthquakes, and found they increase with increasing antigorite content in serpentinized peridotite. These experimental earthquakes already led to the "dehydration driven stress transfer" (DDST) model, which suggests that a highly hydrated peridotite is not required when oceanic mantle events occur. A comparison of experimental and natural earthquake b-values implies that lower-plane peridotite is more hydrated beneath the Tohoku region, which could also explain the difference in oceanic-plate velocity structures near the trench identified in Ocean Bottom Seismometer studies off Tohoku and Hokkaido. These results suggest that lower-plane events occur in fresh peridotite near serpentinized faults. PMID- 30451924 TI - Molecular and isotopic evidence for the processing of starchy plants in Early Neolithic pottery from China. AB - Organic residue analysis of ancient ceramic vessels enables the investigation of natural resources that were used in daily cooking practices in different part of the world. Despite many methodological advances, the utilization of plants in pottery has been difficult to demonstrate chemically, hindering the study of their role in ancient society, a topic that is especially important to understanding early agricultural practices at the start of the Neolithic period. Here, we present the first lipid residue study on the Chinese Neolithic pottery dated to 5.0 k - 4.7 k cal BC from the Tianluoshan site, Zhejiang province, a key site with early evidence for rice domestication. Through the identification of novel molecular biomarkers and extensive stable isotope analysis, we suggest that the pottery in Tianluoshan were largely used for processing starchy plant foods. These results not only highlight the significance of starchy plants in Neolithic southern China but also show a clear difference with other contemporary sites in northern Eurasia, where pottery is clearly orientated to aquatic resource exploitation. These differences may be linked with the early development of rice agriculture in China compared to its much later adoption in adjacent northerly regions. PMID- 30451926 TI - Controlled compensation via non-equilibrium electrons in ZnO. AB - Doping wide-band-gap semiconductor with impurities always accompanied spontaneous compensation of opposite charged intrinsic defects, which lead to invalid control of the type of free carriers. We demonstrate an effectual route to overcoming such detrimental defects formation during doping by suppressing Fermi level shifting using non-equilibrium carriers gathering on the polar epitaxial surfaces. Non-equilibrium carriers are generated by ultraviolet light excited interband transitions (photon energy greater than bandgap). Because the p-type dopants are compensated by non-equilibrium electrons at metal-polar surfaces, donor-type native defects are inhibited. This new doping strategy provides an attractive solution to self-compensation problems in wide-band-gap semiconductors with spontaneous polarization of the future. PMID- 30451927 TI - Comparative genomic and functional analyses of four sequenced Bacillus cereus genomes reveal conservation of genes relevant to plant-growth-promoting traits. AB - Some Bacillus strains function as predominant plant-growth-promoting rhizobacteria. Bacillus cereus 905 is a rod-shaped Gram-positive bacterium isolated from wheat rhizosphere and is a rhizobacterium that exhibits significant plant-growth-promoting effects. Species belonging to the genus Bacillus are observed in numerous different habitats. Several papers on B. cereus are related to pathogens that causes food-borne illness and industrial applications. However, genomic analysis of plant-associated B. cereus has yet to be reported. Here, we conducted a genomic analysis comparing strain 905 with three other B. cereus strains and investigate the genomic characteristics and evolution traits of the species in different niches. The genome sizes of four B. cereus strains range from 5.38 M to 6.40 M, and the number of protein-coding genes varies in the four strains. Comparisons of the four B. cereus strains reveal 3,998 core genes. The function of strain-specific genes are related to carbohydrate, amino acid and coenzyme metabolism and transcription. Analysis of single nucleotide polymorphisms (SNPs) indicates local diversification of the four strains. SNPs are unevenly distributed throughout the four genomes, and function interpretation of regions with high SNP density coincides with the function of strain-specific genes. Detailed analysis indicates that certain SNPs contribute to the formation of strain-specific genes. By contrast, genes related to plant-growth-promoting traits are highly conserved. This study shows the genomic differences between four strains from different niches and provides an in-depth understanding of the genome architecture of these species, thus facilitating genetic engineering and agricultural applications in the future. PMID- 30451928 TI - Electrical activation of degenerated photoreceptors in blind mouse retina elicited network-mediated responses in different types of ganglion cells. AB - Electrical (e-) stimulation is explored in schemes to rescue the vision of blind people, e.g. those affected by Retinitis Pigmentosa (RP). We e-activated subretinally the surviving degenerated photoreceptors (d-Phrs) of the rd1 mouse (RP model) and evoked visual responses in the blind retina. The e-stimulation was applied with a single platinum/iridium electrode. The d-Phrs (calcium-imaging) and ganglion cells (GC) activity (MEA-recording) were recorded in simultaneous multilayer recordings. The findings of this study confirm that the d-Phrs responded to e-stimulation and modulated the retinal network-activity. The application of blockers revealed that the synaptic interactions were dependent on voltage-gated calcium channels and mediated by the transmitters glutamate and GABA. Moreover, the gap junctions coupled networks promoted the lateral-spread of the e-evoked activity in the outer (~60 um) and inner (~120 um) retina. The activated GCs were identified as subtypes of the ON, OFF and ON-OFF classes. In conclusion, d-Phrs are the ideal interface partners for implants to elicit enhanced visual responses at higher temporal and spatial resolution. Furthermore, the retina's intact circuity at the onset of complete blindness makes it a tempting target when considering the implantation of implants into young patients to provide a seamless transition from blinding to chip-aided vision. PMID- 30451929 TI - Three-dimensional structure of the orbicularis retaining ligament: an anatomical study using micro-computed tomography. AB - The orbicularis retaining ligament (ORL) is an important structure for maintaining the eyelid and cheek skin and contouring the characteristic facial appearance. However, the ORL is a delicate structure that is easily damaged in manual dissection. This study aimed to comprehensively investigate the ORL using a micro-computed tomography (mCT) with phosphotungstic acid (PTA) preparation for the acquisition of its three-dimensional information non-destructively. Twenty two specimens were obtained from non-embalmed human cadaver (mean age 73.7 years). Multidirectional images of the mCT showed that the ORL consisted of continuous tiny plates with a multilayered plexiform shape. The modified Verhoeff Van Gieson staining and immunofluorescence revealed a ligamentous tissue consisting of multiple fibroelastic bundles. The preorbicularis fibres of the ORL had more layers and a more intricate arrangement than its retro-orbicularis fibres. The number, complexity and ambiguity of the ORL fibres increased in the lateral area and their density and extent increased near the dermis. Its dermal anchorage was shown as a confluence of its fibroelastic tissue into the dermis. The ORL comprises a multilayered meshwork of very thin continuous fibroelastic plates and its related cutaneous deformities might be a complicated outcome of subcutaneous tissue shrinkage, lipid accumulation and ORL retention. PMID- 30451930 TI - Floating photonic crystals utilizing magnetically aligned biogenic guanine platelets. AB - Recently, structural colour formation and light control by accumulated guanine crystals were reported. However, the relationship between light interference by guanine platelets and light intensity in an individual platelet must be examined further. This study presents experimental evidence that the guanine crystal platelets of fishes aid in efficiently controlling the enhancement of light intensity based on light interference between platelets floating in a micro space. In addition, a magnetic orientation technique enabled us to dynamically modulate the arrangement of platelets floating in water. A group orientation of the platelets under magnetic fields exhibited a distinct enhancement of the light interference between platelets present in the micro-space, and a two-fold enhancement of the reflected light intensity was achieved by comparing two arrangements of magnetically oriented platelets. The developed micro-optic light control method employing tiny platelets floating under aqueous liquid conditions is expected to facilitate the creation of tuneable optical micro-devices, e.g., a micro-'search-light' for individual cell analysis. PMID- 30451931 TI - Campylobacter jejuni bile exposure influences outer membrane vesicles protein content and bacterial interaction with epithelial cells. AB - Campylobacter jejuni is a prevalent human pathogen and a major cause of bacterial gastroenteritis in the world. In humans, C. jejuni colonizes the intestinal tract and its tolerance to bile is crucial for bacteria to survive and establish infection. C. jejuni produces outer membrane vesicles (OMVs) which have been suggested to be involved in virulence. In this study, the proteome composition of C. jejuni OMVs in response to low concentration of bile was investigated. We showed that exposure of C. jejuni to low concentrations of bile, similar to the concentration in cecum, induced significant changes in the protein profile of OMVs released during growth without affecting the protein profile of the bacteria. This suggests that bile influences a selective packing of the OMVs after bacterial exposure to low bile. A low concentration of bile was found to increase bacterial adhesion to intestinal epithelial cells, likely by an enhanced hydrophobicity of the cell membrane following exposure to bile. The increased bacterial adhesiveness was not associated with increased invasion, instead bile exposure decreased C. jejuni invasion. OMVs released from bacteria upon exposure to low bile showed to increase both adhesion and invasion of non-bile-exposed bacteria into intestinal epithelial cells. These findings suggest that C. jejuni in environments with low concentrations of bile produce OMVs that facilitates colonization of the bacteria, and this could potentially contribute to virulence of C. jejuni in the gut. PMID- 30451932 TI - Access to high-impact mutations constrains the evolution of antibiotic resistance in soft agar. AB - Despite widespread resistance to many important antibiotics, the factors that govern the emergence and prevalence of antibiotic-resistant bacteria are still unclear. When exposed to antibiotic gradients in soft agar plates measuring as little as 1.25 * 11 cm we found that Escherichia coli rapidly became resistant to representatives from every class of antibiotics active against Gram-negative bacteria. Evolution kinetics were independent of the frequency of spontaneous mutations that confer antibiotic resistance or antibiotic dose-response curves, and were only loosely correlated to maximal antibiotic concentrations. Instead, rapid evolution required unrealized mutations that could markedly decrease antibiotic susceptibility. When bacteria could not evolve through these "high impact" mutations, populations frequently bottlenecked, reducing the number of cells from which mutants could arise and prolonging evolution times. This effect was independent of the antibiotic's mechanism of action, and may affect the evolution of antibiotic resistance in clinical settings. PMID- 30451934 TI - Application of geostatistical approaches to predict the spatio-temporal distribution of summer ozone in Houston, Texas. AB - Mitigation of adverse effects of air pollution requires understanding underlying exposures, such as ambient ozone concentrations. Geostatistical approaches were employed to analyze temporal trends and estimate spatial patterns of summertime ozone concentrations for Houston, Texas, based on hourly ozone observations obtained from the Texas Commission on Environmental Quality. We systematically assess the accuracy of several spatial interpolation methods, comparing inverse distance weighting, simple kriging, ordinary kriging, and universal kriging methods utilizing the hourly ozone observations and meteorological measurements from monitoring sites. Model uncertainty was assessed by leave-one-out cross validation. Kriging methods performed better, showing greater consistency in the generated surfaces, fewer interpolation errors, and lower biases. Universal kriging did not significantly improve the interpolation results compared to ordinary kriging, and thus ordinary kriging was determined to be the optimal method, striking a balance between accuracy and simplicity. The resulting spatial patterns indicate that the more industrialized areas east and northeast of Houston exhibit the highest summertime ozone concentrations. Estimated daily maximum 8 h ozone concentration fields generated will be used to inform research on population health risks from exposure to surface ozone in Houston. PMID- 30451933 TI - Large-scale in-silico statistical mutagenesis analysis sheds light on the deleteriousness landscape of the human proteome. AB - Next generation sequencing technologies are providing increasing amounts of sequencing data, paving the way for improvements in clinical genetics and precision medicine. The interpretation of the observed genomic variants in the light of their phenotypic effects is thus emerging as a crucial task to solve in order to advance our understanding of how exomic variants affect proteins and how the proteins' functional changes affect human health. Since the experimental evaluation of the effects of every observed variant is unfeasible, Bioinformatics methods are being developed to address this challenge in-silico, by predicting the impact of millions of variants, thus providing insight into the deleteriousness landscape of entire proteomes. Here we show the feasibility of this approach by using the recently developed DEOGEN2 variant-effect predictor to perform the largest in-silico mutagenesis scan to date. We computed the deleteriousness score of 170 million variants over 15000 human proteins and we analysed the results, investigating how the predicted deleteriousness landscape of the proteins relates to known functionally and structurally relevant protein regions and biophysical properties. Moreover, we qualitatively validated our results by comparing them with two mutagenesis studies targeting two specific proteins, showing the consistency of DEOGEN2 predictions with respect to experimental data. PMID- 30451935 TI - Author Correction: Regulatory role of G9a and LSD1 in the Transcription of Olfactory Receptors during Leukaemia Cell Differentiation. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30451936 TI - Recent trends in mucopolysaccharidosis research. AB - Mucopolysaccharidosis (MPS) is a group of inherited conditions involving metabolic dysfunction. Lysosomal enzyme deficiency leads to the accumulation of glycosaminoglycan (GAG) resulting in systemic symptoms, and is categorized into seven types caused by deficiency in one of eleven different enzymes. The pathophysiological mechanism of these diseases has been investigated, indicating impaired autophagy in neuronal damage initiation, association of activated microglia and astrocytes with the neuroinflammatory processes, and involvement of tauopathy. A new inherited error of metabolism resulting in a multisystem disorder with features of the MPS was also identified. Additionally, new therapeutic methods are being developed that could improve conventional therapies, such as new recombinant enzymes that can penetrate the blood brain barrier, hematopoietic stem cell transplantation with reduced intensity conditioning, gene therapy using a viral vector system or gene editing, and substrate reduction therapy. In this review, we discuss the recent developments in MPS research and provide a framework for developing strategies. PMID- 30451937 TI - Contributions of precipitation and temperature to the large scale geographic distribution of fleshy-fruited plant species: Growth form matters. AB - Fruit type, an important reproductive trait, is closely related to reproduction strategy, community dynamics and biotic interactions. However, limited research has explored the geographic distribution of fruit type and the underlying abiotic factors influencing this on a large scale. Here we aim to study large-scale distribution patterns of fleshy-fruited plant species and the most important environmental drivers for different growth forms in utilizing the fruit type and distribution data for over 27000 plant species in China. Results indicated that the proportion of fleshy-fruited species was higher in southeast China, and this pattern was consistent between different growth forms. Overall, the proportion of fleshy-fruited species was higher in wet, warm, and stable environments. Notably, mean annual precipitation had the greatest predictive contribution to woody fleshy-fruited species distributions, but mean annual temperature best predicted the herbaceous fleshy-fruited species distributions. We provide the first map of a large-scale distribution of fleshy-fruited plant species for different growth forms in the northern hemisphere and show that these geographic patterns are mainly determined by contrasting climatic gradients. Recognizing that climate factors have different relationships with different growth forms of fleshy fruited species advances our knowledge about fruit type and environment. This work contributes to predictions of the global distribution of fleshy-fruited species under future climate change scenarios and provides a reference for continued research on the complex interactions between plants, frugivores and the environment. PMID- 30451938 TI - Publisher Correction: The diagnostic accuracy of circulating tumor DNA for the detection of EGFR-T790M mutation in NSCLC: a systematic review and meta-analysis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30451939 TI - Author Correction: Agricultural landscapes and the Loire River influence the genetic structure of the marbled newt in Western France. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30451940 TI - Crystalline structure, electronic and lattice-dynamics properties of NbTe2. AB - Layered-structure materials are currently relevant given their quasi-2D nature. Knowledge of their physical properties is currently of major interest. Niobium ditelluride possesses a monoclinic layered-structure with a distortion in the tellurium planes. This structural complexity has hindered the determination of its fundamental physical properties. In this work, NbTe2 crystals were used to elucidate its structural, compositional, electronic and vibrational properties. These findings have been compared with calculations based on density functional theory. The chemical composition and elemental distribution at the nanoscale were obtained through atom probe tomography. Ultraviolet photoelectron spectroscopy allowed the first determination of the work function of NbTe2. Its high value, 5.32 eV, and chemical stability allow foreseeing applications such as contact in optoelectronics. Raman spectra were obtained using different excitation laser lines: 488, 633, and 785 nm. The vibrational frequencies were in agreement with those determined through density functional theory. It was possible to detect a theoretically-predicted, low-frequency, low-intensity Raman active mode not previously observed. The dispersion curves and electronic band structure were calculated, along with their corresponding density of states. The electrical properties, as well as a pseudo-gap in the density of states around the Fermi energy are characteristics proper of a semi metal. PMID- 30451942 TI - Correlation between sleep duration and hypertension: a dose-response meta analysis. AB - To deeply investigate the correlation between sleep duration and hypertension. The electronic databases Cochrane Library, Pubmed and Embase updated to December 2017 were retrieved, and manual searching for paper-based documents was also performed. After studies were selected according to the predefined screening criteria, their qualities were assessed using Newcastle-Ottawa Scale. Based on R 3.43 software, the association between sleep duration and hypertension was analyzed by dose-response meta-analysis, using relative risk (RR) and 95% confidence interval (95% CI) as effect indexes. Furthermore, publication bias of the eligible studies was evaluated using Egger's test. In addition, sensitivity analysis was conducted through ignoring one study per time and then observing its influences on the pooled results. A total of 9 studies (involving 48525 objects) were included in this dose-response meta-analysis, which had high qualities. The differences in <=5 h vs. 7 h, 6 h vs. 7 h, and 9 h vs. 7 h groups had statistical significances, suggesting that hypertension risk was higher for shorter sleep duration (P < 0.05). There was no significant difference in >9 h vs. 7 h group. No publication bias was found for the eligible studies, indicating that our results were highly credible (t = 0.030, P = 0.9766). However, the pooled results were reversed after ignoring each included study per time. Dose-response meta analysis showed that the hypertension risk reduced for 0.3207% when the sleep duration increased by 1 h. Shorter sleep duration contributes to the increase of hypertension risk. PMID- 30451943 TI - Author Correction: Tuneable poration: host defense peptides as sequence probes for antimicrobial mechanisms. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30451941 TI - Differential toxicities of fine particulate matters from various sources. AB - Fine particulate matters less than 2.5 um (PM2.5) in the ambient atmosphere are strongly associated with adverse health effects. However, it is unlikely that all fine particles are equally toxic in view of their different sizes and chemical components. Toxicity of fine particles produced from various combustion sources (diesel engine, gasoline engine, biomass burning (rice straw and pine stem burning), and coal combustion) and non-combustion sources (road dust including sea spray aerosols, ammonium sulfate, ammonium nitrate, and secondary organic aerosols (SOA)), which are known major sources of PM2.5, was determined. Multiple biological and chemical endpoints were integrated for various source-specific aerosols to derive toxicity scores for particles originating from different sources. The highest toxicity score was obtained for diesel engine exhaust particles, followed by gasoline engine exhaust particles, biomass burning particles, coal combustion particles, and road dust, suggesting that traffic plays the most critical role in enhancing the toxic effects of fine particles. The toxicity ranking of fine particles produced from various sources can be used to better understand the adverse health effects caused by different fine particle types in the ambient atmosphere, and to provide practical management of fine particles beyond what can be achieved only using PM mass which is the current regulation standard. PMID- 30451944 TI - Black carbon yields highest nutrient and lowest arsenic release when using rice residuals in paddy soils. AB - Rice straw increasingly remains on the fields for nutrient supply to the next generation of crop plants. It can be applied either fresh or after burning to black carbon or ash. A central concern during rice cultivation is accumulation of carcinogenic arsenic and the question arises how much rice straw application contributes to nutrient versus arsenic supply in paddy fields. Laboratory incubation experiments were performed to assess the effect of rice straw, black carbon and ash on element mobilization. Our experiments showed initially higher silicon and phosphorus release from black carbon compared to fresh straw amendments. However, more re-sorption to soil lead to finally slightly lower pore water concentrations for black carbon versus fresh straw amendments. Highest arsenic, iron, manganese and dissolved organic carbon concentrations were observed after fresh rice straw application. Black carbon and ash application lead to only minor increases of arsenic compared to controls without amendments. Overall, for silicon and phosphorus the soil acts as sink while for iron and arsenic it was the main source. In summary, burning of rice straw to black carbon prior to application seems to yield a high increase in desired nutrient and a decrease in undesired arsenic mobilization in paddy soils. PMID- 30451945 TI - Similarity-based future common neighbors model for link prediction in complex networks. AB - Link prediction aims to predict the existence of unknown links via the network information. However, most similarity-based algorithms only utilize the current common neighbor information and cannot get high enough prediction accuracy in evolving networks. So this paper firstly defines the future common neighbors that can turn into the common neighbors in the future. To analyse whether the future common neighbors contribute to the current link prediction, we propose the similarity-based future common neighbors (SFCN) model for link prediction, which accurately locate all the future common neighbors besides the current common neighbors in networks and effectively measure their contributions. We also design and observe three MATLAB simulation experiments. The first experiment, which adjusts two parameter weights in the SFCN model, reveals that the future common neighbors make more contributions than the current common neighbors in complex networks. And two more experiments, which compares the SFCN model with eight algorithms in five networks, demonstrate that the SFCN model has higher accuracy and better performance robustness. PMID- 30451946 TI - Midday meals do not impair mouse memory. AB - Nocturnal mice fed in the middle of the light period exhibit food anticipatory rhythms of behavior and physiology under control of food-entrainable circadian clocks in the brain and body. This is presumed to be adaptive by aligning behavior and physiology with predictable mealtimes. This assumption is challenged by a report that daytime feeding schedules impair cognitive processes important for survival, including object memory and contextual fear conditioning assessed at two times of day. To further evaluate these effects, mice were restricted to a 6 h daily meal in the middle of the light or dark period and object memory was tested at four times of day. Object memory was not impaired by daytime feeding, and did not exhibit circadian variation in either group. To determine whether impairment might depend on methodology, experimental procedures used previously to detect impairment were followed. Daytime feeding induced food anticipatory rhythms and shifted hippocampal clock genes, but again did not impair object memory. Spontaneous alternation and contextual fear conditioning were also not impaired. Hippocampal memory function appears more robust to time of day and daytime feeding schedules than previously reported; day-fed mice can remember what they have seen, where they have been, and where it is dangerous. PMID- 30451947 TI - Amplification of Mitochondrial Activity in the Healing Response Following Rotator Cuff Tendon Injury. AB - Mitochondrial function following rotator cuff tendon injury (RCI) influences the tendon healing. We examined the mitochondrial morphology and function under hypoxia in the shoulder tendon tissue from surgically-induced tenotomy-RCI rat model and cultured swine tenocytes. The tendon tissue was collected post-injury on 3-5 (Group-A), 10-12 (Group-B), and 22-24 (Group-C), days and the corresponding contralateral tendons were used as control for each group. There was higher protein expression of citrate synthase (P < 0.0001) [10.22 MFI (mean fluorescent intensity)] and complex-1 (P = 0.0008) (7.86 MFI) in Group-A and Group-B that decreased in Group-C [(P = 0.0201) (5.78 MFI and (P = 0.7915) (2.32 MFI), respectively] compared to control tendons. The ratio of BAX:Bcl2 (Bcl2 associated x protein:B cell lymphoma 2) in RCI tendons increased by 50.5% (Group A) and 68.4% (Group-B) and decreased by 25.8% (Group-C) compared to normoxic controls. Hypoxia increased beta-tubulin expression (P = 0067) and reduced PGC1 alpha (P = 0412) expression in the isolated swine tenocytes with no effect on the protein expression of Complex-1 (P = 7409) and citrate synthase (P = 0.3290). Also, the hypoxic tenocytes exhibited about 4-fold increase in mitochondrial superoxide (P < 0.0001), altered morphology and mitochondrial pore integrity, and increase in mitochondrial density compared to normoxic controls. These findings suggest the critical role of mitochondria in the RCI healing response. PMID- 30451948 TI - Perioperative aspirin and long-term survival in patients undergoing coronary artery bypass graft. AB - This study aimed to examine association between perioperative uses of aspirin and long-term survival in patients undergoing CABG. A retrospective cohort study was performed in 9,584 consecutive patients receiving cardiac surgery from three tertiary hospitals. Of all the patients, 4,132 patients undergoing CABG met inclusion criteria and were divided into four groups: with or without preoperative or postoperative aspirin respectively. 30-day postoperative and long term mortality were compared with the use of propensity scores and inverse probability weighting adjustment to reduce the treatment-selection bias. The patients taking preoperative aspirin presented significantly more with comorbidities. However, the results of this study showed that preoperative aspirin (vs. no preoperative aspirin) was associated with significantly reduced the risk of 30-day mortality in the patients undergoing CABG. Further, the results of long-term mortality showed that the patients taking preoperative aspirin and postoperative aspirin (vs. not taking) were associated with significantly reduced the risk of 4-year mortality (14.8% vs. 18.1%, RR: 0.82, 95% CI: 0.75-0.89, P = 0.005; 10.7% vs. 16.2%, RR: 0.66, 95% CI: 0.50-0.82, P = 0.003). In conclusion, this cohort study showed that perioperative (before and after surgery) use of aspirin was associated with significant reduction in 30-day mortality without significant bleeding complications, also improved long-term survival in patients undergoing CABG. PMID- 30451949 TI - Author Correction: Discovery of small molecule inhibitors of MyD88-dependent signaling pathways using a computational screen. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30451950 TI - Coexistence of turbulence-like and glassy behaviours in a photonic system. AB - Coexistence of physical phenomena can occur in quite unexpected ways. Here we demonstrate the first evidence in any physical system of the coexistence in the same set of measurements of two of the most challenging phenomena in complex systems: turbulence and spin glasses. We employ a quasi-one-dimensional random fibre laser, which displays all essential ingredients underlying both behaviours, namely disorder, frustration and nonlinearity, as well as turbulent energy cascades and intermittent energy flux between fluctuation scales. Our extensive experimental results are theoretically supported by a newly defined photonic Pearson correlation coefficient that unveils the role of the intermittency and describes remarkably well both the spin-glass Parisi overlap parameter and the distribution of turbulent-like intensity increments. Our findings open the way to unravel subtle connections with other complex phenomena, such as disordered nonlinear wave propagation, Levy statistics of intensity fluctuations, and rogue waves. PMID- 30451951 TI - Publisher Correction: An improved method of crafting a multi-electrode spiral cuff for the selective stimulation of peripheral nerves. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 30451952 TI - Author Correction: Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30451953 TI - Deep transfer learning-based hologram classification for molecular diagnostics. AB - Lens-free digital in-line holography (LDIH) is a promising microscopic tool that overcomes several drawbacks (e.g., limited field of view) of traditional lens based microcopy. However, extensive computation is required to reconstruct object images from the complex diffraction patterns produced by LDIH. This limits LDIH utility for point-of-care applications, particularly in resource limited settings. We describe a deep transfer learning (DTL) based approach to process LDIH images in the context of cellular analyses. Specifically, we captured holograms of cells labeled with molecular-specific microbeads and trained neural networks to classify these holograms without reconstruction. Using raw holograms as input, the trained networks were able to classify individual cells according to the number of cell-bound microbeads. The DTL-based approach including a VGG19 pretrained network showed robust performance with experimental data. Combined with the developed DTL approach, LDIH could be realized as a low-cost, portable tool for point-of-care diagnostics. PMID- 30451955 TI - Translational target for checkpoint inhibitors. PMID- 30451954 TI - Detection of correlated hidden factors from single cell transcriptomes using Iteratively Adjusted-SVA (IA-SVA). AB - Single cell RNA-sequencing (scRNA-seq) precisely characterizes gene expression levels and dissects variation in expression associated with the state (technical or biological) and the type of the cell, which is averaged out in bulk measurements. Multiple and correlated sources contribute to gene expression variation in single cells, which makes their estimation difficult with the existing methods developed for batch correction (e.g., surrogate variable analysis (SVA)) that estimate orthogonal transformations of these sources. We developed iteratively adjusted surrogate variable analysis (IA-SVA) that can estimate hidden factors even when they are correlated with other sources of variation by identifying a set of genes associated with each hidden factor in an iterative manner. Analysis of scRNA-seq data from human cells showed that IA-SVA could accurately capture hidden variation arising from technical (e.g., stacked doublet cells) or biological sources (e.g., cell type or cell-cycle stage). Furthermore, IA-SVA delivers a set of genes associated with the detected hidden source to be used in downstream data analyses. As a proof of concept, IA-SVA recapitulated known marker genes for islet cell subsets (e.g., alpha, beta), which improved the grouping of subsets into distinct clusters. Taken together, IA SVA is an effective and novel method to dissect multiple and correlated sources of variation in scRNA-seq data. PMID- 30451956 TI - Common solar wind drivers behind magnetic storm-magnetospheric substorm dependency. AB - The dynamical relationship between magnetic storms and magnetospheric substorms is one of the most controversial issues of contemporary space research. Here, we address this issue through a causal inference approach to two corresponding indices in conjunction with several relevant solar wind variables. We find that the vertical component of the interplanetary magnetic field is the strongest and common driver of both storms and substorms. Further, our results suggest, at least based on the analyzed indices, that there is no statistical evidence for a direct or indirect dependency between substorms and storms and their statistical association can be explained by the common solar drivers. Given the powerful statistical tests we performed (by simultaneously taking into account time series of indices and solar wind variables), a physical mechanism through which substorms directly or indirectly drive storms or vice versa is, therefore, unlikely. PMID- 30451957 TI - Spontaneous activity emerging from an inferred network model captures complex spatio-temporal dynamics of spike data. AB - Inference methods are widely used to recover effective models from observed data. However, few studies attempted to investigate the dynamics of inferred models in neuroscience, and none, to our knowledge, at the network level. We introduce a principled modification of a widely used generalized linear model (GLM), and learn its structural and dynamic parameters from in-vitro spike data. The spontaneous activity of the new model captures prominent features of the non stationary and non-linear dynamics displayed by the biological network, where the reference GLM largely fails, and also reflects fine-grained spatio-temporal dynamical features. Two ingredients were key for success. The first is a saturating transfer function: beyond its biological plausibility, it limits the neuron's information transfer, improving robustness against endogenous and external noise. The second is a super-Poisson spikes generative mechanism; it accounts for the undersampling of the network, and allows the model neuron to flexibly incorporate the observed activity fluctuations. PMID- 30451958 TI - Zika virus infection perturbs osteoblast function. AB - Zika virus (ZIKV) infection is typically characterized by a mild self-limiting disease presenting with fever, rash, myalgia and arthralgia and severe fetal complications during pregnancy such as microcephaly, subcortical calcifications and arthrogyropsis. Virus-induced arthralgia due to perturbed osteoblast function has been described for other arboviruses. In case of ZIKV infection, the role of osteoblasts in ZIKV pathogenesis and bone related pathology remains unknown. Here, we study the effect of ZIKV infection on osteoblast differentiation, maturation and function by quantifying activity and gene expression of key biomarkers, using human bone marrow-derived mesenchymal stromal cells (MSCs, osteoblast precursors). MSCs were induced to differentiate into osteoblasts and we found that osteoblasts were highly susceptible to ZIKV infection. While infection did not cause a cytopathic effect, a significant reduction of key osteogenic markers such as ALP, RUNX2, calcium contents and increased expression of IL6 in ZIKV-infected MSCs implicated a delay in osteoblast development and maturation, as compared to uninfected controls. In conclusion, we have developed and characterized a new in vitro model to study the role of bone development in ZIKV pathogenesis, which will help to identify possible new targets for developing therapeutic and preventive measures. PMID- 30451960 TI - Quantitative Gadolinium-Free Cardiac Fibrosis Imaging in End Stage Renal Disease Patients Reveals A Longitudinal Correlation with Structural and Functional Decline. AB - Patients with end stage renal disease (ESRD) suffer high mortality from arrhythmias linked to fibrosis, but are contraindicated to late gadolinium enhancement magnetic resonance imaging (MRI). We present a quantitative method for gadolinium-free cardiac fibrosis imaging using magnetization transfer (MT) weighted MRI, and probe correlations with widely used surrogate markers including cardiac structure and contractile function in patients with ESRD. In a sub-group of patients who returned for follow-up imaging after one year, we examine the correlation between changes in fibrosis and ventricular structure/function. Quantification of changes in MT revealed significantly greater fibrotic burden in patients with ESRD compared to a healthy age matched control cohort. Ventricular mechanics, including circumferential strain and diastolic strain rate were unchanged in patients with ESRD. No correlation was observed between fibrotic burden and concomitant measures of either circumferential or longitudinal strains or strain rates. However, among patients who returned for follow up examination a strong correlation existed between initial fibrotic burden and subsequent loss of contractile function. Gadolinium-free myocardial fibrosis imaging in patients with ESRD revealed a complex and longitudinal, not contemporary, association between fibrosis and ventricular contractile function. PMID- 30451961 TI - Thidiazuron-induced somatic embryogenesis and changes of antioxidant properties in tissue cultures of half-high blueberry plants. AB - An efficient protocol of somatic embryogenesis (SE) has been developed for the first time in four half-high blueberry (Vaccinium corymbosum L. * V. angustifolium Ait.) cultivars. Thidiazuron (TDZ), a plant growth regulator with potential activities for shoot regeneration and shoot proliferation, was found most effective for somatic embryo formation when added to a nutrient medium at high concentration (9 uM). Although TDZ was also best for embryo germination at low concentration (2.3 uM), it was followed by zeatin at 4.6 uM for the same. Plantlets developed from SE were removed from the nutrient medium and transferred on a peat: perlite medium where 100% survival rate was acquired following the acclimatization process in a greenhouse. The concentrations of total phenolic and flavonoid contents were higher in greenhouse-grown conventionally cutting propagated donor mother plants than those of respective SE plants for 'St. Cloud', 'Patriot' and 'Northblue' but not for 'Chippewa'. The effect of propagation method and/or the older age of donor mother plants were clearly visible exclusively as the 15-year-old donor plants showed higher level of 2,2 diphenyl-1-picrylhydrazyl scavenging activity than the eight-weeks-old SE plants in all four cultivars. PMID- 30451959 TI - Peculiar features of the plastids of the colourless alga Euglena longa and photosynthetic euglenophytes unveiled by transcriptome analyses. AB - Euglenophytes are a familiar algal group with green alga-derived secondary plastids, but the knowledge of euglenophyte plastid function and evolution is still highly incomplete. With this in mind we sequenced and analysed the transcriptome of the non-photosynthetic species Euglena longa. The transcriptomic data confirmed the absence of genes for the photosynthetic machinery, but provided candidate plastid-localised proteins bearing N-terminal bipartite topogenic signals (BTSs) of the characteristic euglenophyte type. Further comparative analyses including transcriptome assemblies available for photosynthetic euglenophytes enabled us to unveil salient aspects of the basic euglenophyte plastid infrastructure, such as plastidial targeting of several proteins as C-terminal translational fusions with other BTS-bearing proteins or replacement of the conventional eubacteria-derived plastidial ribosomal protein L24 by homologs of archaeo-eukaryotic origin. Strikingly, no homologs of any key component of the TOC/TIC system and the plastid division apparatus are discernible in euglenophytes, and the machinery for intraplastidial protein targeting has been simplified by the loss of the cpSRP/cpFtsY system and the SEC2 translocon. Lastly, euglenophytes proved to encode a plastid-targeted homolog of the termination factor Rho horizontally acquired from a Lambdaproteobacteria related donor. Our study thus further documents a substantial remodelling of the euglenophyte plastid compared to its green algal progenitor. PMID- 30451962 TI - The efficacy of serum cell death biomarkers for diagnosing biliary tract cancer. AB - In this study, we determined the efficacy of the cell death biomarker cytokeratin 18 for diagnosing biliary tract cancer (BTC). We recruited 36 patients with BTC (Malignant group) and 45 patients with benign biliary tract disease (Benign group) for this study. We used M30 and M65 as cell death biomarkers. M30 levels indicate apoptosis, and M65 levels indicate both apoptosis and necrosis. M30 and M65 levels were significantly higher in the Malignant group than in the Benign group (142.4 +/- 117.0 vs 48.9 +/- 71.2 U/l, P < 0.001; 1513.3 +/- 837.4 vs 882.2 +/- 831.2 U/l, P = 0.001). The diagnosability of M30 was the highest of the four markers (CEA, CA19-9, M30, M65) (cut-off value: 74.429 U/l, sensitivity: 72.2%, specificity: 77.1%, AUC: 0.771). The sensitivity of M30 (cut-off value: 74.429 U/l) was significantly higher than that of biliary cytology (76% (19/25) vs 12% (3/25), P < 0.001), and the accuracy of M30 was significantly higher than that of biliary cytology (78.3% (36/46) vs 52.2% (24/46), P = 0.015). The sensitivity of M30 (cut-off value: 74.429 U/l) was significantly higher than that of biliary cytology and brush cytology (72.4% (21/29) vs 24.1% (7/29), P < 0.001). In conclusion, cell death biomarkers were increased in patients with BTC, and M30 could efficiently diagnose BTC. PMID- 30451964 TI - Author Correction: Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis. AB - This corrects the article DOI: 10.1038/ncomms15857. PMID- 30451965 TI - The 44th Annual Meeting of the European Society for Blood and Marrow Transplantation: Physicians Poster Sessions. PMID- 30451963 TI - IL-1beta- and IL-4-polarized macrophages have opposite effects on adipogenesis of intramuscular fibro-adipogenic progenitors in humans. AB - Intramuscular fat deposition represents a negative prognostic factor for several myopathies, metabolic diseases and aging. Fibro-adipogenic progenitors (FAPs) are considered as the main source of intramuscular adipocytes, but the mechanisms controlling their adipogenic potential are still not elucidated in humans. The aim of this study was to explore the regulation of human FAP adipogenesis by macrophages. We found that CD140a-expressing FAPs were located close to CD68 positive macrophages in muscles from patients with Duchenne muscular dystrophy (DMD). This strongly suggests a potential interaction between FAPs and macrophages in vivo. Isolated human primary FAPs were then differentiated in the presence of conditioned media obtained from primary blood monocyte-polarized macrophages. Molecules released by IL-1beta-polarized macrophages (M(IL-1beta)) drastically reduced FAP adipogenic potential as assessed by decreased cellular lipid accumulation and reduced gene expression of adipogenic markers. This was associated with an increased gene expression of pro-inflammatory cytokines in FAPs. Conversely, factors secreted by IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis. Finally, the inhibition of FAP adipocyte differentiation by M(IL-1beta) macrophages requires the stimulation of Smad2 phosphorylation of FAPs. Our findings identify a novel potential crosstalk between FAPs and M(IL-1beta) and M(IL-4) macrophages in the development of adipocyte accumulation in human skeletal muscles. PMID- 30451966 TI - Author Correction: Antimicrobial Peptide Potency is Facilitated by Greater Conformational Flexibility when Binding to Gram-negative Bacterial Inner Membranes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30451967 TI - Author Correction: Sequential formation and resolution of multiple rosettes drive embryo remodelling after implantation. AB - In the version of this Article originally published, the first name of author Guangdun Peng was spelled incorrectly as Guangdum. This has now been amended in all versions of the Article. PMID- 30451968 TI - Publisher Correction: Multiple phosphorylations control recruitment of the KMN network onto kinetochores. AB - In the version of this Article originally published, the 'ON' and 'OFF' labels in panel c of Fig. 6 were incorrect. For the Tet treated cells (+Tet) in both image panels, CENP-T should have been 'OFF' and CENP-T Delta90 should have been 'ON'. For the cells untreated with Tet (-Tet) in both graph panels, CENP-T Delta90 should have been 'ON'. This has now been amended. PMID- 30451970 TI - The role of thymic tolerance in CNS autoimmune disease. AB - The contributions of the peripheral adaptive and innate immune systems to CNS autoimmunity have been extensively studied. However, the role of thymic selection in these conditions is much less well understood. The thymus is the primary lymphoid organ for the generation of T cells; thymic mechanisms ensure that cells with an overt autoreactive specificity are eliminated before they emigrate to the periphery and control the generation of thymic regulatory T cells. Evidence from animal studies demonstrates that thymic T cell selection is important for establishing tolerance to autoantigens. However, there is a considerable knowledge gap regarding the role of thymic selection in autoimmune conditions of the human CNS. In this Review, we critically examine the current body of experimental evidence for the contribution of thymic tolerance to CNS autoimmune diseases. An understanding of why dysfunction of either thymic or peripheral tolerance mechanisms rarely leads to CNS inflammation is currently lacking. We examine the potential of de novo T cell formation and thymic selection as novel therapeutic avenues and highlight areas for future study that are likely to make these targets the focus of future treatments. PMID- 30451971 TI - POLG-related disorders and their neurological manifestations. AB - The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions. PMID- 30451969 TI - Extracellular microRNAs profile in human follicular fluid and IVF outcomes. AB - Encapsulated microRNAs (i.e., miRNAs within the extracellular vesicles, i.e., EV miRNAs) have been detected in follicular fluid in both animal and human studies and different profiles have been associated with IVF cycle characteristics. However, limited studies to date have investigated other IVF outcomes, including fertilization status and embryo quality on day three". In this cohort, we performed a cross-sectional analysis on 126 women who contributed follicular fluid from a single follicle during a single IVF cycle. One hundred and ninety two EV-miRNAs were assessed by univariable fold-change and multivariable logistic regression analyses. Hsa-miR-92a and hsa-miR-130b, were over-expressed in follicular fluid samples from oocytes that failed to fertilize compared to those that were normally fertilized. Additionally, hsa-miR-888 was over-expressed and hsa-miR-214 and hsa-miR-454 were under-expressed in samples that resulted in impaired day-3 embryo quality compared to top-quality day-3 embryos. After adjusting for confounders as BMI, smoking and total motile sperm, associations of these EV-miRNAs remained significant. In-silico KEGG pathway analyses assigned the identified EV-miRNAs to pathways of follicular growth and development, cellular signaling, oocyte meiosis, and ovarian function. Our findings suggest that EV-miRNAs may play a role in pathways of ovarian function and follicle development, which could be essential for understanding the molecular mechanisms that could lead to a successful pregnancy and birth. PMID- 30451972 TI - Wnt-beta-catenin signalling in liver development, health and disease. AB - The canonical Wnt-beta-catenin pathway is a complex, evolutionarily conserved signalling mechanism that regulates fundamental physiological and pathological processes. Wnt-beta-catenin signalling tightly controls embryogenesis, including hepatobiliary development, maturation and zonation. In the mature healthy liver, the Wnt-beta-catenin pathway is mostly inactive but can become re-activated during cell renewal and/or regenerative processes, as well as in certain pathological conditions, diseases, pre-malignant conditions and cancer. In hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumours in adults, Wnt-beta-catenin signalling is frequently hyperactivated and promotes tumour growth and dissemination. A substantial proportion of liver tumours (mainly HCC and, to a lesser extent, CCA) have mutations in genes encoding key components of the Wnt-beta-catenin signalling pathway. Likewise, hepatoblastoma, the most common paediatric liver cancer, is characterized by Wnt-beta-catenin activation, mostly as a result of beta-catenin mutations. In this Review, we discuss the most relevant molecular mechanisms of action and regulation of Wnt-beta-catenin signalling in liver development and pathophysiology. Moreover, we highlight important preclinical and clinical studies and future directions in basic and clinical research. PMID- 30451973 TI - Biallelic GALM pathogenic variants cause a novel type of galactosemia. AB - PURPOSE: Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. METHODS: Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. RESULTS: The highest blood galactose levels observed in each patient were 17.3-41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between beta- and alpha-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients' peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. CONCLUSION: Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia. PMID- 30451974 TI - Graphene platelets from shungite rock modulate electropolymerization and charge storage mechanisms of soft-template synthetized polypyrrole-based nanocomposites. AB - We report here on soft-template electropolymerizations of polypyrrole (Ppy)-based nanocomposites triggered by graphene platelets (GP) from shungite (SH) rocks. A properly designed procedure for an efficient extraction of graphene platelets from SH powders is established to produce remarkable graphene materials in a low oxidation state and with a high electrical conductivity (1490 S cm-1). By using positively and negatively charged templating surfactants the role played by the graphene units on the electropolymerization reactions is pointed out by SEM, EDX, TEM, SAED, XPS and Raman spectroscopy. The morphological/structural characterizations highlight that GP from SH have a surface chemistry suitable for selective and mutual interactions with the growing Ppy chains. CV and galvanostatic charge/discharge measurements evidence that GP improve the transport of both electrons and ions within the bulk material by means of a synergistic action with the polymer phase. This cooperative behavior induces an enhancement of the specific capacitance up to 250 F g-1 at 2 A g-1. The Ppy-GP materials produced following the settled protocols result to be appropriate for fabricating multifunctional charge transport and storage electroactive systems. PMID- 30451975 TI - Periodontitis affects glucoregulatory hormones in severely obese individuals. AB - OBJECTIVE: To evaluate the effect of periodontitis (PD) on glucoregulatory hormones in obesity, never explored so far, a cross-sectional study was conducted in 110 severely obese, non-diabetic individuals. METHODS: We collected clinical periodontal parameters, including probing pocket depth (PPD), bleeding on probing (BOP), clinical attachment level (CAL). Insulin, glucagon, GLP-1 and GIP were measured after 3 days of standardized diet. RESULTS: Forty-seven subjects had periodontitis (PD+) and 63 did not (PD-). PD+ showed 30.3% of gingival sites with PPD > 4 mm, 55.2% of BOP sites and a mean CAL loss of 4.1 mm. Compared with PD-, PD+ had higher glucagon (26.60 [25.22] vs 3.93 [7.50] ng/l, p < 0.0001) and GIP levels (10.56 [13.30] vs 6.43 [8.43] pmol/l, p < 0.001), while GLP-1 was reduced (11.78 [10.07] vs 23.34 [16.80] pmol/l, p < 0.0001). Insulin did not differ. In PD+, after adjustment for confounders, PPD was positively related to glucagon (beta = 0.424, p = 0.002) and inversely to GLP-1 (beta = -0.159, p = 0.044). CONCLUSIONS: We describe for the first time an impaired incretin axis coupled with a relative hyperglucagonemia in obese non-diabetic individuals with PD, that might contribute to deteriorate their glucose tolerance and partially explain the higher risk of diabetes observed in these patients. PMID- 30451976 TI - Employing fingerprinting of medicinal plants by means of LC-MS and machine learning for species identification task. AB - A dataset of liquid chromatography-mass spectrometry measurements of medicinal plant extracts from 74 species was generated and used for training and validating plant species identification algorithms. Various strategies for data handling and feature space extraction were tested. Constrained Tucker decomposition, large scale (more than 1500 variables) discrete Bayesian Networks and autoencoder based dimensionality reduction coupled with continuous Bayes classifier and logistic regression were optimized to achieve the best accuracy. Even with elimination of all retention time values accuracies of up to 96% and 92% were achieved on validation set for plant species and plant organ identification respectively. Benefits and drawbacks of used algortihms were discussed. Preliminary test showed that developed approaches exhibit tolerance to changes in data created by using different extraction methods and/or equipment. Dataset with more than 2200 chromatograms was published in an open repository. PMID- 30451977 TI - A Frechet tree distance measure to compare phylogeographic spread paths across trees. AB - Phylogeographic methods reconstruct the origin and spread of taxa by inferring locations for internal nodes of the phylogenetic tree from sampling locations of genetic sequences. This is commonly applied to study pathogen outbreaks and spread. To evaluate such reconstructions, the inferred spread paths from root to leaf nodes should be compared to other methods or references. Usually, ancestral state reconstructions are evaluated by node-wise comparisons, therefore requiring the same tree topology, which is usually unknown. Here, we present a method for comparing phylogeographies across different trees inferred from the same taxa. We compare paths of locations by calculating discrete Frechet distances. By correcting the distances by the number of paths going through a node, we define the Frechet tree distance as a distance measure between phylogeographies. As an application, we compare phylogeographic spread patterns on trees inferred with different methods from hemagglutinin sequences of H5N1 influenza viruses, finding that both tree inference and ancestral reconstruction cause variation in phylogeographic spread that is not directly reflected by topological differences. The method is suitable for comparing phylogeographies inferred with different tree or phylogeographic inference methods to each other or to a known ground truth, thus enabling a quality assessment of such techniques. PMID- 30451979 TI - Reduced MHCII levels in relapsed AML. PMID- 30451978 TI - Similar recovery time of microbial functions from fungicide stress across biogeographical regions. AB - Determining whether the structural and functional stress responses of communities are similar across space and time is paramount for forecasting and extrapolating the consequences of anthropogenic pressures on ecosystems and their services. Stream ecosystems are under high anthropogenic pressure; however, studies have only examined the response of stream communities across large scales over multiple generations. We studied the responses of leaf-associated microbial communities in streams within three European biogeographical regions to chemical stress in a microcosm experiment with multiple cycles of fungicide pollution and resource colonisation. Fungal community composition and the ecosystem function leaf decomposition were measured as response variables. Microbial leaf decomposition showed similar recovery times under environmental levels of fungicide exposure across regions. Initially, the decomposition declined (between 19 and 53%) under fungicide stress and recovered to control levels during the third cycle of pollution and colonisation. Although community composition and its stress response varied between regions, this suggests similar functional community adaptation towards fungicide stress over time. Genetic, epigenetic and physiological adaptations, as well as species turnover, may have contributed to community adaptation but further studies are required to determine if and to which extent these mechanisms are operating. Overall, our findings provide the first evidence of a similar functional response of microbial leaf decomposition to chemical stress across space and time. PMID- 30451980 TI - The environment: what's in a word? PMID- 30451981 TI - Quantum computers put blockchain security at risk. PMID- 30451983 TI - Stress management in T cells. PMID- 30451982 TI - Heparin-binding epidermal growth factor (HB-EGF) drives EMT in patients with COPD: implications for disease pathogenesis and novel therapies. AB - Chronic obstructive pulmonary disease (COPD) is a progressive and devastating chronic lung condition that has a significant global burden, both medically and financially. Currently there are no medications that can alter the course of disease. At best, the drugs in clinical practice provide symptomatic relief to suffering patients by alleviating acute exacerbations. Most of current clinical research activities are in late severe disease with lesser attention given to early disease manifestations. There is as yet, a lack of understanding of the underlying mechanisms of disease progression and the molecular switches that are involved in their manifestation. Small airway fibrosis and obliteration are known to cause fixed airflow obstruction in COPD, and the consequential damage to the lung has an early onset. So far, there is little evidence of the mechanisms that underlie this aspect of pathology. However, emerging research confirms that airway epithelial reprogramming or epithelial to mesenchymal transition (EMT) is a key mechanism that drives fibrotic remodelling changes in smokers and patients with COPD. A recent study by Lai et al. further highlights the importance of EMT in smoking-related COPD pathology. The authors identify HB-EGF, an EGFR ligand, as a key driver of EMT and a potential new therapeutic target for the amelioration of EMT and airway remodelling. There are also wider implications in lung cancer prophylaxis, which is another major comorbidity associated with COPD. We consider that improved molecular understanding of the intricate pathways associated with epithelial cell plasticity in smokers and patients with COPD will have major therapeutic implications. PMID- 30451984 TI - N6-mA marks the spot. PMID- 30451985 TI - Dividing paths in fatty liver disease. PMID- 30451986 TI - Longitudinal interaction between APOA5 -1131T>C and overweight in the acceleration of age-related increase in arterial stiffness through the regulation of circulating triglycerides. AB - We aimed to evaluate whether the longitudinal interaction between APOA5-1131C variants and overweight could accelerate age-related increases in arterial stiffness and circulating triglycerides in healthy subjects. This 3-year prospective cohort study included 503 healthy subjects. Brachial-ankle pulse wave velocity (baPWV), triglycerides, APOA5 -1131T > C, apolipoprotein (apo) A-V level, and low-density lipoprotein (LDL) particle size were measured at baseline and within a mean follow-up period of 3 years. At the 3-year follow-up, in the overweight group, subjects with the C allele showed increases in triglycerides and baPWV relative to baseline. Additionally, in the overweight group, there was a genotype effect on changes in triglycerides: subjects with the C allele had greater increases in triglyceride concentrations than subjects with the TT genotype. Furthermore, overweight subjects with the C allele had greater increases in triglyceride concentrations than normal-weight subjects with the C allele (P-interaction = 0.013). Overweight subjects with the C allele had greater increases in baPWV than normal-weight subjects with the C allele (P-interaction = 0.047). Changes in baPWV were affected by age, baseline baPWV, and changes in systolic blood pressure (BP) and triglycerides. Changes in triglycerides were affected by APOA5 -1131T > C genotype, age, baseline triglyceride level, and changes in BMI and apo A-V. In the overweight group, changes in baPWV were affected by changes in systolic BP, LDL particle size, and triglycerides. This prospective study shows that the interactive effect between APOA5 -1131C variants and overweight can accelerate age-related increase in arterial stiffness via the regulation of circulating triglycerides in healthy subjects. PMID- 30451987 TI - Diet with greater inflammatory potential is associated with higher prevalence of fatty liver among US adults. AB - The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising-caused, at least in part, by unhealthy lifestyles including poor dietary choices. We examined the link between the inflammatory potential of diet as measured by the Dietary Inflammatory Index (DII(r)) and liver function tests [summarised by the fatty liver index (FLI)]. Of 20,643 US NHANES participants, 48.7% were men and the mean age was 47.3 years. Significant associations were apparent between increasing DII score and prevalent fatty liver. Individuals in the fourth DII quartile had nearly a six-fold higher likelihood of fatty liver [odds ratio (OR) = 5.97, 95% confidence interval: 4.44-8.02] compared with those in the first quartile. Moderation analysis indicated a significant impact of adiposity on the link between FLI and DII score (p < 0.001). This study provides further evidence of an association between the inflammatory potential of diet and fatty liver. PMID- 30451988 TI - A scaffold for signaling of Tim-4-mediated efferocytosis is formed by fibronectin. AB - An essential step during clearance of apoptotic cells is the recognition of phosphatidylserine (PS) exposed on apoptotic cells by its receptors on phagocytes. Tim-4 directly binding to PS and functioning as a tethering receptor for phagocytosis of apoptotic cells has been extensively studied over the past decade. However, the molecular mechanisms by which Tim-4 collaborates with other engulfment receptors during efferocytosis remain elusive. By comparing efferocytosis induced by Tim-4 with that by Anxa5-GPI, an artificial tethering receptor, we found that Tim-4 possesses auxiliary machinery to induce a higher level of efferocytosis than Anxa5-GPI. To search for that, we performed a yeast two-hybrid screen and identified Fibronectin (Fn1) as a novel Tim-4-associating protein. Tim-4 directly associated with Fn1 and formed a complex with integrins via the association of Fn1. Through Tim-4-/- mice and cell-based assays, we found that modulation of the Fn1 level affected efferocytosis induced by Tim-4 and disruption of the interaction between Tim-4 and Fn1 abrogated Tim-4-mediated efferocytosis. In addition, Tim-4 depletion attenuated integrin signaling activation and perturbation of integrin signaling suppressed Tim-4-promoted efferocytosis. Taken together, the data suggest that Fn1 locates Tim-4 and integrins in close proximity by acting as a scaffold, resulting in synergistic cooperation of Tim-4 with integrins for efficient efferocytosis. PMID- 30451989 TI - Targeting CDK7 increases the stability of Snail to promote the dissemination of colorectal cancer. AB - Targeted inhibition of cyclin-dependent kinase 7 (CDK7) via its covalent inhibitor THZ1 can suppress the growth of various cancers, while its roles on colorectal cancer (CRC) remain obscure. Here we report that the expression of CDK7 is upregulated in CRC cells and tissues. THZ1 exhibits high potency and selectivity against CRC cells both in vitro and in vivo via induction of cell apoptosis rather than cell cycle disruption. Intriguingly, THZ1 treatment increases the ability of epithelial mesenchymal transition (EMT) and in vivo metastasis to liver of CRC cells. Mechanistical studies reveal that THZ1 increases the expression of Snail, while not other EMT-transcription factors, via enhancing its protein stability rather than mRNA expression or translation. By screening Snail stability related factors via qRT-PCR, results indicate THZ1 and si-CDK7 decrease the expression of protein kinase D1 (PKD1) in CRC cells. Down regulation of PKD1 mediates THZ1 up regulated Snail via dephosphorylation of Snail Ser 11 and prevention of proteasome mediated degradation. Clinical analysis confirms that CDK7 is significantly (p < 0.05) negatively correlated with the expression of mesenchymal markers including FN1, VIM, and MMP2. CRC patients whose tumors expressing less CDK7/SNAI1 or PKD1/SNAI1 showed significant (p < 0.05) poorer overall survival (OS) rate as compared with those with greater levels. Collectively, our data suggest that targeted inhibition of CDK7 can trigger the metastasis of CRC during cancer development via PKD1/Snail axis, which imposes great challenge that inhibition of CDK7 is a potential approach for cancer treatment. PMID- 30451991 TI - A massively parallel reporter assay dissects the influence of chromatin structure on cis-regulatory activity. AB - A gene's position in the genome can profoundly affect its expression because regional differences in chromatin modulate the activity of locally acting cis regulatory sequences (CRSs). Here we study how CRSs and regional chromatin act in concert on a genome-wide scale. We present a massively parallel reporter gene assay that measures the activities of hundreds of different CRSs, each integrated at many specific genomic locations. Although genome location strongly affected CRS activity, the relative strengths of CRSs were maintained at all chromosomal locations. The intrinsic activities of CRSs also correlated with their activities in plasmid-based assays. We explain our data with a quantitative model in which expression levels are set by independent contributions from local CRSs and the regional chromatin environment, rather than by more complex sequence- or protein specific interactions between these two factors. The methods we present will help investigators determine when regulatory information is integrated in a modular fashion and when regulatory sequences interact in more complex ways. PMID- 30451990 TI - RNAi modulation of placental sFLT1 for the treatment of preeclampsia. AB - Preeclampsia is a placentally induced hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality to mothers and fetuses. Clinical manifestations of preterm preeclampsia result from excess circulating soluble vascular endothelial growth factor receptor FLT1 (sFLT1 or sVEGFR1) of placental origin. Here we identify short interfering RNAs (siRNAs) that selectively silence the three sFLT1 mRNA isoforms primarily responsible for placental overexpression of sFLT1 without reducing levels of full-length FLT1 mRNA. Full chemical stabilization in the context of hydrophobic modifications enabled productive siRNA accumulation in the placenta (up to 7% of injected dose) and reduced circulating sFLT1 in pregnant mice (up to 50%). In a baboon preeclampsia model, a single dose of siRNAs suppressed sFLT1 overexpression and clinical signs of preeclampsia. Our results demonstrate RNAi-based extrahepatic modulation of gene expression with nonformulated siRNAs in nonhuman primates and establish a path toward a new treatment paradigm for patients with preterm preeclampsia. PMID- 30451992 TI - T cell receptor fingerprinting enables in-depth characterization of the interactions governing recognition of peptide-MHC complexes. AB - The promiscuous nature of T-cell receptors (TCRs) allows T cells to recognize a large variety of pathogens, but makes it challenging to understand and control T cell recognition. Existing technologies provide limited information about the key requirements for T-cell recognition and the ability of TCRs to cross-recognize structurally related elements. Here we present a 'one-pot' strategy for determining the interactions that govern TCR recognition of peptide-major histocompatibility complex (pMHC). We measured the relative affinities of TCRs to libraries of barcoded peptide-MHC variants and applied this knowledge to understand the recognition motif, here termed the TCR fingerprint. The TCR fingerprints of 16 different TCRs were identified and used to predict and validate cross-recognized peptides from the human proteome. The identified fingerprints differed among TCRs recognizing the same epitope, demonstrating the value of this strategy for understanding T-cell interactions and assessing potential cross-recognition before selection of TCRs for clinical development. PMID- 30451993 TI - Lung Cancer Screening: Implementation of and Barriers to a Nurse Practitioner-Led Program. AB - Lung cancer accounts for more American deaths annually than any other cancer, and the survival rate is low among those diagnosed with advanced-stage disease. Screening with low-dose computed tomography (CT) can help to reduce mortality. CT screening for lung cancer should be performed in the context of a comprehensive screening program, rather than as a single isolated test. The addition of the nurse practitioner role is instrumental in creating a lung cancer screening program that may increase patient satisfaction and that meets regulatory criteria. PMID- 30451994 TI - Celiac Plexus Block: Management of Abdominal Pain in Patients With Late-Stage Cancer. AB - BACKGROUND: A majority of patients with abdominal cancer report intractable abdominal pain as their disease progresses. For intractable abdominal pain related to malignancy, celiac plexus block can provide relief and reduce the use of oral opioids, helping to improve quality of life. OBJECTIVES: The aim of this article is to explore the feasibility and effectiveness of celiac plexus block as a pain management option for patients with late-stage abdominal cancer. METHODS: A literature review of articles about pain in late-stage patients with cancer, with a focus on abdominal pain, pain management techniques, and quality of life, was undertaken. FINDINGS: Celiac plexus block is an effective nontraditional pain management strategy that treats intractable abdominal pain and improves patients' quality of life. PMID- 30451995 TI - Pain Assessment: Use of the Defense and Veterans Pain Rating Scale in Patients With Cancer. AB - BACKGROUND: Thorough, consistent pain assessment and reassessment are critical to guide and evaluate interventions designed to improve pain. OBJECTIVES: Based on a literature review about functional pain assessment, clinicians selected and then implemented the Defense and Veterans Pain Rating Scale (DVPRS) as a pain assessment instrument option in a comprehensive cancer center. METHODS: The DVPRS was added as a pain assessment instrument in clinical oncology practice. From postimplementation chart review and clinician satisfaction surveys, the DVPRS was evaluated for the following. FINDINGS: Seventy-eight percent of nurses surveyed (N = 64) preferred the DVPRS over any other pain assessment tool. Inpatient and ambulatory patients surveyed (N = 144) agreed that a Likert-type scale in the DVPRS was easier to understand, easier to use, and better in describing their pain than the numeric rating scale. PMID- 30451996 TI - Hemorrhagic Cystitis: Treatment With Hyperbaric Oxygen Therapy in Patients With Acute Lymphoblastic Leukemia. AB - BACKGROUND: Hyperbaric oxygen therapy is a rare treatment modality for hemorrhagic cystitis (HC) following BK virus reactivation in the immunosuppressed population. Clinicians need to be aware of the etiology, preventive measures, complications, and various management techniques in HC while treating patients undergoing bone marrow transplantation. OBJECTIVES: This study details the pathologic progression of HC in a patient with acute lymphoblastic leukemia harboring BK virus after cytotoxic induction chemotherapy and haploidentical marrow transplantation. METHODS: A search of PubMed for literature published from 1973-2018 was conducted using keywords. FINDINGS: Hyperbaric oxygen therapy in chemotherapy-induced and BK virus-associated HC is a viable management option in parallel with tapering of immunosuppressives, bladder irrigation, and IV resuscitation within the post-transplantation acute lymphoblastic leukemia population. PMID- 30451997 TI - 5-Fluorouracil and Capecitabine: Assessment and Treatment of Uncommon Early-Onset Severe Toxicities Associated With Administration. AB - BACKGROUND: Uncommon early-onset severe toxicities from 5-fluorouracil (5-FU) and capecitabine can be fatal if early warning signs are not recognized and treated promptly. OBJECTIVES: This article delineates the differences between expected side effects and uncommon early-onset severe toxicities from 5-FU and capecitabine. It also provides background for understanding the reasons patients may develop these toxicities and reviews the efficacy of standard supportive care against a novel therapy (uridine triacetate). METHODS: A panel of nurses convened to review the literature about toxicities associated with 5-FU and capecitabine administration and determined methods to educate nurses about toxicities and treatment. FINDINGS: Standard supportive care for 5-FU and capecitabine toxicities is associated with high fatality rates. Uridine triacetate treatment within 96 hours of administration is associated with survival. PMID- 30451998 TI - What Do You Do When Oncology Chooses You? AB - My journey through nursing school at the University of Hawaii Maui College has been the most challenging but, by far, the most memorable adventure of my life. During this short-lived period, I lost my mom, who was also my best friend, to stage IV non-small cell lung cancer. Almost three years have passed, but the memories and the emotions are still quite vivid. PMID- 30451999 TI - Foundations of Practice. AB - A highly disproportionate burden of cancer is manifested in the world's poorest societies. Since 2016, I have volunteered with the Washington, DC-based organization Health Volunteers Overseas and have provided oncology and palliative nursing education and consultation in Vietnam, Honduras, and Bhutan. In addition, I have volunteered with Living Room International in Kenya, focusing on hospice nursing resource enhancement. I have traveled more than 50,000 miles to those four resource-impoverished nations and witnessed hardships beyond description. PMID- 30452000 TI - Homeless With Cancer: An Unrecognized Problem in the United States. AB - Homelessness is a national problem that is worsening. Some challenges the homeless face-lack of shelter, food, health care, support, and opportunities-are well known. Cancer, an unrecognized problem among the homeless, is a leading cause of their deaths. PMID- 30452001 TI - Vincristine Minibag Administration: A Quality Improvement Project to Minimize Medical Errors. AB - Vincristine is a cytotoxic chemotherapy agent classified as an antitumor alkaloid and is part of the vinca alkaloid family. Vincristine's mechanism of action is to primarily inhibit mitosis of the cancer cell and is given by IV route only for treatment. Accidental intrathecal administration of vincristine has lethal consequences for patients. To minimize the risk of accidental intrathecal administration of vincristine, 14 infusion centers participated in a quality improvement project to change the practice of vincristine administration from IV push to IV piggyback via minibag and gravity. After three months, all infusion centers successfully implemented the practice. PMID- 30452002 TI - Temperature Measurements: Comparison of Different Thermometer Types for Patients With Cancer. AB - BACKGROUND: Accurate temperature measurement in patients with cancer is critical. Many patients are neutropenic; therefore, fever represents an oncologic emergency, and, in many cases, it can be the only indication of a life threatening infection. Although oral thermometers most closely represent true core temperature, patients may have barriers to oral thermometry. OBJECTIVES: The purpose of this study was to assess the accuracy of two alternative, noninvasive thermometers (tympanic and temporal artery) by comparing them to an oral thermometer. METHODS: A method-comparison study design was used. Each participant received three temperature measurements. The dependent variable was the difference in temperature between the test thermometers and the oral thermometer. FINDINGS: The results suggest that neither of the test thermometers accurately represented core temperature, particularly in febrile patients. Both the tympanic and temporal artery thermometers became less accurate as oral temperature increased. PMID- 30452003 TI - Cancer-Related Pain: Understanding Genetic Influences and Determining Implications for Practice. AB - Pain can be highly variable and unpredictable. Genetics may be key to identifying pain mechanisms that control the intensity, duration, and physiologic response in individuals with chronic pain. Pharmaco-genomics and precision medicine are permitting advances in pain control with analgesic drugs that have increased effectiveness and lead to decreased side effects. Knowledge of genetic variations related to how and why patients experience pain will aid in identifying those at risk, provide a better understanding of the phenomenon of pain, and possibly lead to innovative therapies to control pain. PMID- 30452004 TI - Monitoring Temperature: Knowledge and Skills of Outpatients With Cancer. AB - BACKGROUND: Elevated temperature can be the first sign of infection; obtaining an accurate temperature in patients undergoing chemotherapy is critical. OBJECTIVES: This study sought to determine outpatients' temperature-monitoring knowledge and skills; whether an educational DVD could increase knowledge; and the level of agreement between a home thermometer and a calibrated hospital thermometer. METHODS: The intervention was an educational DVD. Patients completed a survey and were observed taking their temperature. Investigators rated whether the correct steps were taken and then obtained the temperature. The bias and precision of the patient's thermometer were determined. FINDINGS: Knowledge scores averaged 68%. Most participants correctly identified elevated temperatures for fever (91%); less than 50% correctly identified other signs of infection, and less than 25% correctly identified activities that could falsely elevate or depress temperature readings. PMID- 30452005 TI - Fall Risk Perceptions: A Study of Hospitalized Patients With Hematologic Malignancies. AB - BACKGROUND: Inpatient falls cause harm, increased length of stay, and high costs. Patients with hematologic malignancies have a unique set of fall risk factors, and studies indicate that patients lack accurate perception of fall risk. OBJECTIVES: This study describes patient perceptions of fall risk in people with hematologic malignancies and compares patient and nurse perceptions of fall risk. METHODS: This mixed-methods study used descriptive statistical and narrative analyses. A convenience sample of patients was interviewed about perception of fall risk. Descriptive analysis of patient data and analysis around correlation between patient and nurse assessment of fall risk were completed. FINDINGS: Themes emerged about participants' prior experience with falls and perceptions of fall education. Participants who reported feeling weak prior to hospitalization perceived being at high fall risk, consistent with nurse assessment. Several patients reported feeling at low risk. Data showed discrepancies in patients' perceptions of nursing education. PMID- 30452006 TI - Interprofessional Lung Cancer Tumor Board: The Role of the Oncology Nurse Navigator in Improving Adherence to National Guidelines and Streamlining Patient Care. AB - BACKGROUND: Lung cancer traditionally has a high morbidity and mortality rate because of late diagnosis. Use of a tumor board has been noted as one way to improve patient care and quality of life. OBJECTIVES: This article aimed to determine the contributions of an oncology nurse navigator (ONN) related to physician adherence to guidelines and streamlined patient care in an interprofessional lung cancer tumor board. METHODS: Retrospective chart review was performed for 18 months prior to and following implementation of the lung cancer tumor board. FINDINGS: After implementation of the lung cancer tumor board and the creation of clinical pathways by the ONN, diagnosis of early-stage non small cell lung cancer and the use of diagnostic workups increased. PMID- 30452007 TI - Meeting of the Minds: A Lifelong Personal and Professional Relationship. AB - The old adage "meeting of the minds" is always an exciting and motivating experience. I only wish that every healthcare provider could share this type of encounter in his or her professional career. Fortunately, I was lucky enough to meet Renee almost 20 years ago when we were both assigned to facilitate a metastatic breast cancer support group. Her role was the clinical social worker, and mine was to provide knowledge and education as the oncology educator. We were a fabulous team. PMID- 30452008 TI - Blood and Marrow Transplantation RN Fellowship: Design, Outcomes, and Facilitating Transition to Practice. AB - Recruiting and retaining blood and marrow transplantation (BMT) nurses remains challenging. In accordance with the Institute of Medicine recommendation to establish programs to prepare nurses for transition to specialty practice areas, a BMT fellowship program was designed and implemented at a large academic medical center. The yearlong fellowship program consists of monthly class sessions, observation experiences, case study presentations, and evidence-based project development. Outcomes related to retention, certification, and scholarship are presented. PMID- 30452009 TI - NO SToPS: Assessment of a Supportive Care Program to Reduce Treatment Breaks in Patients With Head and Neck Cancer. AB - NO SToPS is an interprofessional supportive care program implemented in 2008 for patients with head and neck cancer undergoing chemoradiation. The goals of the program are to reduce radiation treatment breaks and hospitalizations related to toxicity from this difficult treatment. Breaks lead to lower locoregional control and survival rates in this population. This article describes the effect of the NO SToPS program. PMID- 30452010 TI - Clinical Trials Informed Consent: An Educational Intervention to Improve Nurses' Knowledge and Communications Skills. AB - BACKGROUND: Teach-back is an evidence-based tool recommended for use during informed consent (IC) discussions. The nurses' role in the IC process is important, particularly for patient education and advocacy. OBJECTIVES: The aim was to initiate and evaluate an educational program for nurses to improve knowledge and communication skills used in IC for cancer clinical trials. METHODS: An educational program was presented to nurses. Anonymous pre-, post-, and one-month postprogram surveys measured nurses' knowledge of research and the importance of and confidence using teach-back during IC discussions. FINDINGS: Nurses had high research knowledge scores and statistically significant improvement in pre- and post-test scores of conviction and confidence using teach back. Nurses employed essential elements of teach-back before the program but had greater recognition of elements after the program. PMID- 30452011 TI - Partial Breast Irradiation: A Longitudinal Study of Symptoms and Quality of Life. AB - BACKGROUND: In many women with early-stage breast cancer, breast-conserving surgery (BCS) with partial breast irradiation (PBI) has similar overall survival and local recurrence rates compared to BCS with whole-breast irradiation (WBI). A better understanding of the quality of life (QOL) outcomes during and following BCS with PBI versus BCS with WBI is needed. OBJECTIVES: This study was conducted to examine symptoms, symptom distress, cosmesis, QOL, and perceived body image in women during and after BCS with PBI. METHODS: A convenience sample of 31 women completed self-reports pre- and post-PBI over six months. Descriptive statistics and repeated- measures analysis were performed at baseline and three times post PBI. FINDINGS: Most women reported satisfaction with body image and good QOL, despite a small decline in social well-being. Fatigue and mild to moderate symptom distress persisted over time. PMID- 30452012 TI - Venous Flare Reactions: A Case Report of Reactions Following Etoposide Infusion. AB - Venous flare reaction, a localized allergic response associated with the administration of an irritant, is one of the most common chemotherapy infusion related reactions. Etoposide, a drug commonly used in patients with lung cancer, has been reported to be an irritant with vesicant properties depending on the volume administered. This article presents the case of a patient who has a venous flare reaction immediately following the administration of etoposide for the treatment of diffuse large B-cell lymphoma. Managing such complications is crucial to maintaining patient safety. Proper training and education should be incorporated into nursing practice when identifying, preventing, and managing such reactions. PMID- 30452013 TI - HPV and Oral Cancer: The Need to Integrate Oral Health Practices Into Nursing Education. AB - BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer has increased in recent decades. With a shortage of dental professionals, nurses may be key in detecting oral cancer and educating patients. OBJECTIVES: The aim of this study is to assess students in nursing and dental programs for their oral and oropharyngeal cancer knowledge and perceptions of responsibility and capability of performing oral screenings and HPV counseling. METHODS: 158 surveys were completed by students attending nursing and dental programs at a midwestern university. The chi-squared test and analysis of variance were used to calculate differences in frequencies of categorical and interval data. FINDINGS: Many students across programs were unaware of the potential effectiveness of the HPV vaccination in reducing oropharyngeal cancer. Nursing and nurse practitioner students were less likely to believe they could perform an examination or that it was within their perceived scope of practice. PMID- 30452014 TI - Immunotherapy in Pediatric Oncology: An Overview of Therapy Types and Nursing Implications. AB - BACKGROUND: By using the body's own protective system to fight cancer, immunotherapy is not only effective but also is associated with fewer side effects than chemotherapy. OBJECTIVES: This article provides an overview of four types of immunotherapy (monoclonal antibodies, chimeric antigen receptors, immune checkpoint inhibitors, and cancer vaccines) and discusses the critical role assumed by nurses in the care of patients receiving immunotherapy. METHODS: A review of the literature was undertaken to identify, describe, and compare the types of immunotherapy used and studied for use in pediatric oncology. FINDINGS: Nurses caring for pediatric patients with cancer may have little experience with immunotherapy. However, they should become knowledgeable about it, particularly as it becomes further integrated into pediatric cancer treatments. PMID- 30452015 TI - Response to "Male Patients With Breast Cancer: Addressing Needs Using an Educational Task Force". AB - Male breast cancer is associated with hereditary risk for developing breast and other cancers. An estimated 4% of men with breast cancer have BRCA1 mutations, and 4%-16% have BRCA2 mutations. Men with a diagnosis of breast cancer have unique needs that need to be addressed in a caring and comprehensive manner. PMID- 30452016 TI - Interprofessional Approach in Gero-Oncology. AB - This supplement provides case studies to highlight the importance of using an interprofessional approach to care for older adults. The Oncology Nursing Society (ONS) has been instrumental in disseminating important work and findings in the care of older adults with cancer. PMID- 30452017 TI - Older Adults With Lung Cancer: Assessment, Treatment Options, Survivorship Issues, and Palliative Care Strategies. AB - BACKGROUND: Treatment advances offer options for cancer treatment in older adults that are less invasive and have fewer side effects. Geriatric assessment is a key component of treatment planning to identify functional and physiologic status and is the basis of decision making. OBJECTIVES: This article discusses the role of geriatric assessment, treatment options (e.g., surgical, chemotherapy, radiation therapy), survivorship issues, and palliative care strategies for older adults with cancer. METHODS: Literature was reviewed to identify geriatric assessment implications, current treatment strategies, and survivorship and palliative care interventions for older adults with cancer based on a case study approach. FINDINGS: Geriatric assessment is key to identifying deficits and disabilities in older adults with cancer and is a critical component in oncology treatment planning. Evidence-based, less invasive treatment options are available and offer older adults more tolerable oncologic therapies. PMID- 30452018 TI - Financial Toxicity: Limitations and Challenges When Caring for Older Adult Patients With Cancer. AB - BACKGROUND: Financial toxicity refers to the unintended financial consequences and distress that patients and families can incur during treatment of cancer. Financial issues can add further stress to an already stressful situation. OBJECTIVES: This article aims to increase awareness of the financial burden of cancer treatment in older adults with cancer and its effect on health-related quality of life for patients and their families and to increase knowledge of institutional and community resources to help patients manage financial concerns. METHODS: A literature search was performed to investigate the burden of financial toxicity on older adults with cancer. FINDINGS: High levels of financial burden have been linked to lower adherence to cancer treatments, shorter survival, poorer prognosis, and greater risk of recurrence. Older adults are particularly vulnerable and more likely to experience financial toxicity. Incorporating discussions about financial burden and exploring options to defray costs are key components of quality and patient-centered care. PMID- 30452019 TI - Nursing Education: Review of Assessment, Clinical Care, and Implications for Practice Regarding Older Adult Patients With Cancer. AB - BACKGROUND: As the population of older adults continues to increase, the healthcare system must adapt to respond to their unique and complicated health needs. More than half of all patients diagnosed with cancer in America are aged 65 years or older. The appropriate care for older adult patients with cancer requires a holistic approach with careful coordination of interprofessional providers. OBJECTIVES: This article aims to describe the components of the comprehensive geriatric assessment, summarize the importance of exercise in older adults, discuss the harms of polypharmacy, and evaluate the initiatives to improve geriatric nursing education. METHODS: The literature was reviewed and summarized to provide information on comprehensive geriatric assessment, exercise, polypharmacy, and geriatric nursing education. FINDINGS: Numerous assessment tools can help guide the care of older adult patients with cancer. Because many nurses have little formal geriatric-specific training, there is a growing need for targeted education to ensure best practices. PMID- 30452020 TI - Transitional Care: Methods and Processes for Transitioning Older Adults With Cancer in a Postacute Setting. AB - BACKGROUND: The concept of transitional care and the methods and processes to efficiently and effectively transition patients between a variety of care settings remains a continuous healthcare goal. Despite the numerous transitional care models that have been developed and implemented in a myriad of healthcare settings, increasing healthcare costs and substandard patient outcomes persist. OBJECTIVES: This article will examine the topic of older adults with cancer when transitioned to a skilled nursing setting and the challenges they may face along the care continuum. In addition, it will look at the continuity of care between the hospital and skilled nursing facility, as well as explore some of the clinical difficulties experienced by older adult patients with cancer in the postacute care setting. METHODS: Keyword searches were conducted in a selected literature review of CINAHL(r), Ovid, PubMed, and Google Scholar databases. FINDINGS: Successful transitional care models are built around effective communication and often include an interprofessional team approach and/or a nurse navigator to aid in the effective execution of medical treatment and patient care plans. PMID- 30452021 TI - Frailty in Older Adults: Assessment, Support, and Treatment Implications in Patients With Cancer. AB - BACKGROUND: Frailty is defined as a disability in those of advanced age, often with comorbidities, poor nutritional status, cognitive decline, and reduced functional status. OBJECTIVES: The purpose of this article is to discuss the concept of frailty, assess the use of a comprehensive geriatric assessment (CGA), and understand the implications for treatment to maintain or enhance physical, functional, and cognitive health of older adult patients with cancer. METHODS: Literature about frailty in older adult patients diagnosed with cancer was reviewed to determine evidence-based assessment and treatment options. FINDINGS: About half of all older adult patients with cancer experience some degree of frailty. CGA is a useful way to evaluate frailty and the extent of limitations. Many frailty-specific tools have been developed. Evidence-based strategies are available to address limitations associated with frailty in older adult patients with cancer. PMID- 30452022 TI - Native mass spectrometry goes more native: investigation of membrane protein complexes directly from SMALPs. AB - Other than more widely used methods, the use of styrene maleic acid allows the direct extraction of membrane proteins from the lipid bilayer into SMALPs keeping it in its native lipid surrounding. Here we present the combined use of SMALPs and LILBID-MS, allowing determination of oligomeric states of membrane proteins of different functionality directly from the native nanodiscs. PMID- 30452023 TI - The other side of the superoxide radical anion: its ability to chemically repair DNA oxidized sites. AB - The superoxide radical anion can repair oxidative damage. In particular, it was demonstrated that O2- can repair oxidized DNA by electron transfer, restoring the original structure of this important molecule. Acid-base equilibria have been considered, and the influence of the pH on the main reaction mechanism has been explored. PMID- 30452024 TI - Fluorescent Wittig reagent as a novel ratiometric probe for the quantification of 5-formyluracil and its application in cell imaging. AB - The chemically selective detection of natural nucleobase modifications has been regarded as the key step in understanding their important roles in epigenetics. Herein, for the first time, we introduce a Wittig reaction into the design of reaction-based fluorescent probes for ratiometrically detecting 5fU, selectively labelling 5fU-modified DNA and imaging intracellular 5fU produced by gamma irradiation. PMID- 30452025 TI - Raman spectroscopic features of primary cardiac microvascular endothelial cells (CMECs) isolated from the murine heart. AB - Gaining knowledge on the biochemical profile of primary endothelial cells on a subcellular level can contribute to better understanding of cardiovascular disease. In this work, primary cardiac microvascular endothelial cells (CMECs) isolated from the mouse heart and murine H5V endothelial cell line were characterized with the use of a Raman imaging technique. Primary CMECs displayed a distinct Raman-based biochemical phenotype as compared with other cells isolated from the heart and were characterized by a low lipid content. In contrast to the murine H5V endothelial cell line, CMECs did not display lipid droplets (LDs) in the cytoplasm, while the former have many low-unsaturated LDs. In conclusion, Raman imaging is a fast and efficient tool to analyse single coronary endothelial cells in a non-invasive manner that can prove useful to characterize biochemical changes in a single isolated primary endothelial cell from a diseased heart. PMID- 30452026 TI - A simple lateral flow biosensor for rapid detection of lead(ii) ions based on G quadruplex structure-switching. AB - A novel lateral flow biosensor for rapid detection of Pb2+ was established for the first time based on Pb2+-induced G-quadruplex structure-switching. Semi quantitative results could be read by reference to a colorimetric card. The whole process only took 15 minutes with a visual detection limit of 25 nM. PMID- 30452027 TI - Improving the light harvesting and colour range of methyl ammonium lead tri bromide (MAPbBr3) perovskite solar cells through co-sensitisation with organic dyes. AB - Co-sensitisation of methylammonium lead tri-bromide perovskite solar cells with red (D205) and blue (SQ2) organic dyes improves device efficiencies and allows device colour tuning. Sensitising the film after perovskite crystallisation produces higher device efficiencies (2.6% SQ2, 3.1% D205) than perovskite-only devices (2%) and devices sensitised before the perovskite layer deposition (1.5% SQ2, 2.0% D205). PMID- 30452028 TI - Controlled release of agrochemicals and heavy metal ion capture dual-functional redox-responsive hydrogel for soil remediation. AB - Novel redox-responsive hydrogels were prepared based on disulfide-crosslinked carboxymethyl cellulose for the controlled-release of agrochemicals. After release, the reduced hydrogels could capture heavy metal ions in soil via strong complexation between the ions and thiol groups generated by disconnected disulfide bonds, thus benefiting plant growth and soil remediation synchronously. PMID- 30452029 TI - Tacticity effects in side-chain photoluminescent polymers. AB - Stereoregular side-chain photoluminescent (PL) polymers were synthesized via the stereospecific polymerization of 9,9-dibutyl-2-(4-vinylphenyl)-9H-fluorene. The resulting isotactic, syndiotactic and atactic poly(9,9-dibutyl-2-(4-vinylphenyl) 9H-fluorene) polymers were used as stereoregular polymer samples for examining the configurational tacticity effect on their PL properties. Our results revealed a unique tacticity-dependent effect as observed by an obvious red-shifting of the PL emission by increasing the degree of isotacticity of these stereoregular polymers; despite the ultraviolet spectra of these polymers exhibited similar absorption patterns. This study provides a new structural design for the syntheses of PL polymers. PMID- 30452030 TI - Diverse supramolecular structures self-assembled by a simple aryl chloride on Ag(111) and Cu(111). AB - Diverse self-assembled structures were obtained on Cu(111) and Ag(111) surfaces by using a simple and small 4,4''-dichloro-1,1':4',1''-terphenyl molecule. Surprisingly, a complicated supramolecular self-assembled vortex structure, composed of 15 molecules in a large unit, was realized through the collaboration of hydrogen bonding and halogen bonding. PMID- 30452031 TI - Fe-Doped ZnO nanoparticle toxicity: assessment by a new generation of nanodescriptors. AB - In the search for novel tools to combat cancer, nanoparticles (NPs) have attracted a lot of attention. Recently, the controlled release of cancer-cell killing metal ions from doped NPs has shown promise, but fine tuning of dissolution kinetics is required to ensure specificity and minimize undesirable toxic side-effects. Theoretical tools to help in reaching a proper understanding and finally be able to control the dissolution kinetics by NP design have not been available until now. Here, we present a novel set of true nanodescriptors to analyze the charge distribution, the effect of doping and surface coating of whole metal oxide NP structures. The polarizable model of oxygen atoms enables light to be shed on the charge distribution on the NP surface, allowing the in detail study of the factors influencing the release of metal ions from NPs. The descriptors and their capabilities are demonstrated on a Fe-doped ZnO nanoparticle system, a system with practical outlook and available experimental data. PMID- 30452032 TI - Predicting archetypal nanoparticle shapes using a combination of thermodynamic theory and machine learning. AB - Machine learning is a useful way of identifying representative or pure nanoparticle shapes as part of a larger ensemble, but its predictive capabilities can be limited when a large dataset of candidate structures must already exist. Ideally one would like to use machine learning to define the ideal dataset for future, more computationally intensive, studies before a significant amount of resources are consumed. In this work we combine an established analytical phenomenological model and statistical machine learning to predict the archetypes and prototypes of a diverse ensemble of 2380 platinum nanoparticle morphologies developed with less than twenty input electronic structure simulations. By parameterising a size- and shape-dependent thermodynamic model, probabilities are assigned to seventeen different shapes between three and thirty nanometres, which together with structural features such as nanoparticle diameter, surface area, sphericity and facet configuration form the basis for archetypal analysis and K means clustering. Using this approach we rapidly identify six "pure" archetypes and twelve "representative" prototypes that can be used in future computational studies of properties such as catalysis. PMID- 30452033 TI - Remarkable negative differential resistance and perfect spin-filtering effects of the indium triphosphide (InP3) monolayer tuned by electric and optical ways. AB - Fully spin-polarized current and negative differential resistance (NDR) are two important electronic transport properties for spintronic nanodevices based on two dimensional materials. Here, we describe both the electric and optical tuning of the spin-polarized electronic transport properties of the indium triphosphide (InP3) monolayer, which is doped with Ge atoms, by using quantum transport calculations. The spin degeneration of the InP3 monolayer is lifted due to the doping of Ge atoms. By applying a small bias voltage, a fully spin-polarized current can be obtained along both the armchair and zigzag directions. Moreover, a remarkable NDR is observed for the current along the zigzag direction, which shows a huge peak-to-valley ratio of 3.1 * 103, while in the armchair direction, a lower peak-to-valley ratio of 5.5 is obtained. Alternatively, a fully spin polarized photocurrent can also be generated under the illumination of linearly polarized light by tuning either the photon energy or the polarization angle. PMID- 30452034 TI - Phosphane tuning in heteroleptic [Cu(N^N)(P^P)]+ complexes for light-emitting electrochemical cells. AB - The synthesis and characterization of five [Cu(P^P)(N^N)][PF6] complexes in which P^P = 2,7-bis(tert-butyl)-4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (tBu2xantphos) or the chiral 4,5-bis(mesitylphenylphosphino)-9,9-dimethylxanthene (xantphosMes2) and N^N = 2,2'-bipyridine (bpy), 6-methyl-2,2'-bipyridine (6 Mebpy) or 6,6'-dimethyl-2,2'-bipyridine (6,6'-Me2bpy) are reported. Single crystal structures of four of the compounds confirm that the copper(i) centre is in a distorted tetrahedral environment. In [Cu(xantphosMes2)(6-Mebpy)][PF6], the 6-Mebpy unit is disordered over two equally populated orientations and this disorder parallels a combination of two dynamic processes which we propose for [Cu(xantphosMes2)(N^N)]+ cations in solution. Density functional theory (DFT) calculations reveal that the energy difference between the two conformers observed in the solid-state structure of [Cu(xantphosMes2)(6-Mebpy)][PF6] differ in energy by only 0.28 kcal mol-1. Upon excitation into the MLCT region (lambdaexc = 365 nm), the [Cu(P^P)(N^N)][PF6] compounds are yellow to orange emitters. Increasing the number of Me groups in the bpy unit shifts the emission to higher energies, and moves the Cu+/Cu2+ oxidation to higher potentials. Photoluminescence quantum yields (PLQYs) of the compounds are low in solution, but in the solid state PLQYs of up to 59% (for [Cu(tBu2xantphos)(6,6'-Me2bpy)]+) are observed. Increased excited-state lifetimes at low temperature are consistent with the complexes exhibiting thermally activated delayed fluorescence (TADF). This is supported by the small energy difference calculated between the lowest energy singlet and triplet excited states (0.17-0.25 eV). The compounds were tested in simple bilayer light-emitting electrochemical cells (LECs). The optoelectronic performances of complexes containing xantphosMes2 were generally lower with respect to those with tBu2xantphos, which led to bright and efficient devices. The best performing LECs were obtained for the complex [Cu(tBu2xantphos)(6,6'-Me2bpy)][PF6] due to the increased steric hindrance at the N^N ligand, resulting in higher PLQY. PMID- 30452035 TI - The adverse role of excess negative ions in reducing the photoluminescence from water soluble MAA-CdSe/ZnS quantum dots in various phosphate buffers. AB - The use of CdSe/ZnS quantum dots in making biosensors or biomarkers requires them to be water soluble, which can be achieved by conjugating with MAA. We report observation of modulation in the photoluminescence intensities of MAA conjugated CdSe/ZnS QDs (MAA-QDs) that depended strongly on the types and quantity of negative ions present in various kinds of phosphate buffers. The deterioration of PL was attributed to the presence of excess ions in the media that altered the energy and occupation of HOMO and LUMO levels of MAA. Instantaneously, strong reduction in the PL intensity with pH was observed. MAA-QDs incubated for more than 24 hours in the phosphate buffer at pH ~ 7.0-8.0 showed recovery and enhanced PL intensity, which was attributed to the presence of excess positive ions and a small amount of OH-. Saline buffers showed no significant recovery due to the presence of additional Cl- ions. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) measurements were successfully employed to determine the band edges of the MAA-QD system in the presence of excess positive or negative ions (Na+, H+, Cl-, and OH-) in the media. Thus, it is very important to have complete knowledge of the ions present in the buffer when using MAA-QDs for biomarking or biosensing applications. PMID- 30452036 TI - Ultra-strong nanotwinned Al-Ni solid solution alloys with significant plasticity. AB - Twin boundaries have been proven effective for strengthening metallic materials while maintaining plasticity. Al, however, has low twinning propensity due to its high stacking fault energy. Here we show, by using a small amount of Ni solutes, high-density twin boundaries and stacking faults in sputtered Al-Ni solid solution alloys. Density function theory calculations show that the Ni solute facilitates the formation of stacking faults and stabilizes nanotwins in Al-Ni solid solution alloys. In situ micropillar compression studies reveal a high flow stress (exceeding 1.7 GPa), comparable to high strength martensitic steels and Ni alloys. Furthermore, significant plasticity was observed in these nanotwinned Al Ni alloy films due to the existence of high density twin boundaries and 9R phase. PMID- 30452037 TI - Small-molecules that covalently react with a human prolyl hydroxylase - towards activity modulation and substrate capture. AB - We describe covalently binding modulators of the activity of human prolyl hydroxylase domain 2 (PHD2) and studies towards a strategy for photocapture of PHD2 substrates. Reversible active site binding of electrophile bearing compounds enables susbsequent covalent reaction with a lysine residue (K408) in the flexible C-terminal region of PHD2 to give a modified protein that retains catalytic activity. PMID- 30452038 TI - Detection of lymph node metastasis with near-infrared upconversion luminescent nanoprobes. AB - The detection of lymph node metastasis is of great importance for therapy planning and prognosis of cancers, but remains challenging in the clinic. In the current study, we report a tumor-specific imaging probe constructed with NaGdF4:Yb,Tm,Ca@NaLuF4 core@shell upconversion nanoparticles showing distinctive near infrared emission. The following studies revealed that the characteristic Tm dopant emission at 804 nm showed a penetration depth up to 7.7 mm through multi layered mice skin tissues, substantially greater than emissions at 655 nm and 541 nm typically from the widely used Er dopant, which is apparently favorable for sensitive tumor diagnosis. The cell binding assay further revealed that the anti HER2 antibodies covalently attached on the particle surface endowed the nanoprobe with excellent binding specificity in targeting HER2-positive cancer cells in vitro, which further enabled the detection of lymph node metastasis of breast cancer in vivo in mice. In addition, the pharmacokinetics of the resulting nanoprobes were intensively studied through both upconversion luminescence imaging and SPECT imaging for comparing with that of the mother particles. The results obtained through both approaches were well consistent and revealed that the surface conjugation of antibodies largely altered the pharmacokinetic behaviors and substantially prolonged the blood half-life of the underlying nanoparticles, which was never reported before. PMID- 30452039 TI - Metabolic functions of the human gut microbiota: the role of metalloenzymes. AB - Covering: up to the end of 2017The human body is composed of an equal number of human and microbial cells. While the microbial community inhabiting the human gastrointestinal tract plays an essential role in host health, these organisms have also been connected to various diseases. Yet, the gut microbial functions that modulate host biology are not well established. In this review, we describe metabolic functions of the human gut microbiota that involve metalloenzymes. These activities enable gut microbial colonization, mediate interactions with the host, and impact human health and disease. We highlight cases in which enzyme characterization has advanced our understanding of the gut microbiota and examples that illustrate the diverse ways in which metalloenzymes facilitate both essential and unique functions of this community. Finally, we analyze Human Microbiome Project sequencing datasets to assess the distribution of a prominent family of metalloenzymes in human-associated microbial communities, guiding future enzyme characterization efforts. PMID- 30452040 TI - Entropy in multiple equilibria, compounds with different sites. AB - The influence of entropy in multiple chemical equilibria is investigated for systems with different types of sites for the condition that the binding enthalpy of the species is the same within each type of sites and independent of those species that are already bonded. This allows splitting of the free reaction enthalpy into the particle distribution term and all other contributions for each type of sites separately and, hence, to evaluate this entropy contribution to the free reaction enthalpy. The situations for which this applies can be chemically very different, e.g. acid base, ligand exchange, isomerisation, conformational change, rearrangement of a ligand, ion exchange, adsorption of a species on the surface of a particle or a dendrimer, insertion of charged or neutral species into the cavities of a microporous or mesoporous host. We provide physical insight by discussing Xrc1{n1ABn2}Xrc2 systems. The number of coordination sites A and B are n1 and n2, respectively. The indices rc1 = 1, 2,...,n1 and rc2 = 1, 2,...,n2 count the number of X bonded to sites A and sites B, respectively. An important result is that the large number of equilibrium constants needed to describe those situations can be expressed as a function of two constants only. This allows studying systems quantitatively by experimental and theoretical means which otherwise might be difficult to handle. It has also implication for theoretical studies in the sense that it is sufficient to model only two reactions instead of many in order to describe a system. The results remain valid for systems with more than two types of different sites. The description of the entropy driven development of the fractional equilibrium coverage of the sites provides a new tool for understanding adsorption and ion exchange isotherms. The fractional equilibrium coverage of the sites can be described as a linear combination of individual Langmuir isotherms despite of the fact that such a linear combination has never the shape of the original Langmuir isotherm. This is remarkable and very useful. It provides us with new tools for describing and testing isotherms based on well defined, transparent physical ideas. Explicit solution for systems with 2, 3, 4, 5, 6, and 12 coordination sites are reported. Applications to a system with 12 coordination sites serve to illustrate information that can be obtained for complex situations. PMID- 30452041 TI - Controlling the phase transition in nanocrystalline ferroelectric thin films via cation ratio. AB - Traditionally, the ferroelectric Curie temperature can be manipulated by chemical substitution, e.g., in Ba1-xSrxTiO3 as one of the archetypical representatives. Here, we show a novel approach to tune the ferroelectric phase transition applicable for nanostructured thin films. We demonstrate this effect in nano grained BaTiO3 films. Based on an enhanced metastable cation solubility with Ba/Ti-ratios of 0.8 to 1.06, a significant shift of the phase transition temperature is discovered. The transition temperature increases linearly from 212 K to 350 K with increasing Ba/Ti ratio. For all Ba/Ti ratios, a completely diffused phase transition is present resulting in a negligible temperature sensitivity of the dielectric constant. Schottky defects are identified as the driving force behind the off-stoichiometry and the shift of the phase transition temperature as they locally induce lattice strain. Complementary temperature dependent Raman experiments reveal the presence of the hexagonal polymorph in addition to the perovskite phase in all cases. Interestingly, the hexagonal BaTiO3 influences the structural transformation on the Ba-rich side, while on the Ti-rich side no changes for the hexagonal polymorph at the ferroelectric transition temperature are observed. This concerted structural change of both polymorphs on the Ba-rich side causes a broad phase transition region spanning over a wide range up to 420 K including the transition temperature of 350 K obtained from dielectric measurements. These findings are promising for fine adjustment of the phase transition temperature and low temperature coefficient of permittivity. PMID- 30452042 TI - A ruthenium(ii) complex-cyanine energy transfer scaffold based luminescence probe for ratiometric detection and imaging of mitochondrial peroxynitrite. AB - A novel ruthenium(ii) complex-cyanine energy transfer scaffold has been established for the development of a ratiometric luminescence probe for ONOO- detection. The probe, Ru-Cy5, is localized in mitochondria of live cells, allowing ratiometric sensing and imaging of ONOO- therein. PMID- 30452043 TI - Antiferromagnetic ordering based on intermolecular London dispersion interactions in amphiphilic TEMPO ammonium salts. AB - Antiferromagnetic coupling in TEMPO-based radicals can be enhanced via self assembly through London dispersion interactions in amphiphilic solids. The synthesis, magnetic characterization, and three crystal structures of the solid radical ion salts (R-DMAT-n)X with various counterions X and alkyl chain lengths n are reported. Magnetic susceptibility and absolute EPR signal intensity measurements show singlet-triplet transitions in a number of cases, which is discussed in relation to the crystal structures. Antiferromagnetic ordering effects are sensitive to both the length of the alkyl chain and the counter anion. PMID- 30452044 TI - Correction: Oxygen diffusion in single crystal barium titanate. AB - Correction for 'Oxygen diffusion in single crystal barium titanate' by Markus Kessel et al., Phys. Chem. Chem. Phys., 2015, 17, 12587-12597. PMID- 30452045 TI - Size-selected silver nanoparticles for MALDI-TOF mass spectrometry of amyloid beta peptides. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is one of the most efficient mass spectrometric techniques for the analysis of high molecular-weight compounds with superior selectivity and sensitivity. Common MALDI matrices are low molecular weight (LMW) organics and will therefore produce a large amount of matrix-related ion peaks, which limits the use of MALDI-MS for the detection of LMW molecules. A major breakthrough of this limitation was made by the introduction of surface assisted desorption/ionization techniques, with graphite particles firstly as the matrix, followed by expansion into other types of nanoparticles or nanostructures. However, previous studies failed to address well the optimum size and concentration of Ag NPs to be used as the MALDI matrix. In this study, to explore and compare the efficiency of different sized silver nanoparticles (Ag NPs) as the MALDI matrix for the detection of LMW molecules, three different sized Ag NPs (2.8 +/- 1.0, 12.8 +/- 3.2 and 44.2 +/- 5.0 nm) have been successfully developed as the MALDI time-of-flight MS (MALDI-TOF MS) matrix and amyloid-beta (Abeta) peptides, crucially involved in Alzheimer's disease and a variety of cancers, were chosen as an example of LMW molecules in our MALDI-TOF MS analysis with Ag NPs as matrices. The results showed size-selected MS signals with the smallest (2.8 +/- 1.0 nm) Ag NP matrix producing the highest spectral intensities, when compared with other larger sized Ag NP matrices and conventional matrices such as SA and DHB. Furthermore, the optimal concentrations for different sized Ag NPs as matrices were determined as follows: 0.125 nM (2.8 +/- 1.0 nm Ag NPs), 0.0625 nM (12.8 +/- 3.2 nm Ag NPs), and 0.03125 nM (44.2 +/- 5.0 nm Ag NPs), respectively. These results not only corroborated that Ag NPs could act as a very suitable matrix to assist in the desorption/ionization of LMW molecules but also revealed size-selected mass spectrometry signals with smaller Ag NPs as the MALDI matrix bearing more advantages than their larger counterparts. These novel findings paved the way for wider applications of MALDI MS using Ag NPs as matrices for the analysis of LMW molecules. PMID- 30452046 TI - Functional protein nanostructures: a chemical toolbox. AB - Nature has evolved an optimal synthetic factory in the form of translational and posttranslational processes by which millions of proteins with defined primary sequences and 3D structures can be built. Nature's toolkit gives rise to protein building blocks, which dictates their spatial arrangement to form functional protein nanostructures that serve a myriad of functions in cells, ranging from biocatalysis, formation of structural networks, and regulation of biochemical processes, to sensing. With the advent of chemical tools for site-selective protein modifications and recombinant engineering, there is a rapid development to develop and apply synthetic methods for creating structurally defined, functional protein nanostructures for a broad range of applications in the fields of catalysis, materials and biomedical sciences. In this review, design principles and structural features for achieving and characterizing functional protein nanostructures by synthetic approaches are summarized. The synthetic customization of protein building blocks, the design and introduction of recognition units and linkers and subsequent assembly into structurally defined protein architectures are discussed herein. Key examples of these supramolecular protein nanostructures, their unique functions and resultant impact for biomedical applications are highlighted. PMID- 30452048 TI - Charge transfer at the nanoscale and the role of the out-of-plane vibrations in the selection rules of surface-enhanced Raman scattering. AB - Surface-enhanced Raman scattering (SERS) spectroscopy of pyridazine shows the selective enhancement of the bands recorded at about 1570, 1450 and 380 cm-1, which are assigned to two different types of vibrations. The first two correspond to in-plane 8a;nuring and 19b;delta(CH) totally symmetric A1 modes, respectively, while the last band is assigned to the out-of-plane 16b;tauring,B1 vibration. The selective enhancement has been analyzed on the basis of a resonant Raman process involving photoexcited metal (M)-to-molecule (A) charge transfer (CT: M-A + hnu > M+-A-) states of the metal-adsorbate surface complex, which have also been related to the doublet electronic states of the corresponding radical anion of the adsorbate (A-). According to the selection rules of the electromagnetic/plasmonic SERS enhancement mechanism, the simultaneous enhancement of in-plane and out-of-plane modes could be attributed to different orientations of the adsorbate (perpendicular and parallel, respectively, or tilted) with respect to the metallic surface. The calculated resonance Raman-CT spectra (SERS-CT) and the vibrational wavenumbers of isolated pyridazine and of the pyridazine-Ag2 complex obtained from electronic structure calculations suggest a single type of molecule adsorbed with perpendicular orientation. The relative SERS enhancements of both in-plane and out-of-plane modes are due to Franck-Condon factors related to differences between the equilibrium geometries (A1 vibrations, DeltaQ ? 0) and gradients (B1 vibrations, Deltanu ? 0 and DeltaQ ? 0), respectively, of the potential energy surfaces of the involved ground and photoinduced CT electronic states. Therefore, the selective enhancement of the SERS bands of pyridazine is controlled by a general metal-to-molecule resonant CT mechanism. This conclusion supports the usefulness of SERS in studying the subtle electronic structure of charged interfaces as well as key processes such as electron transfer at the nanoscale. PMID- 30452047 TI - Accuracy of methods for reporting inorganic element concentrations and radioactivity in oil and gas wastewaters from the Appalachian Basin, U.S. based on an inter-laboratory comparison. AB - Accurate and precise analyses of oil and gas (O&G) wastewaters and solids (e.g., sediments and sludge) are important for the regulatory monitoring of O&G development and tracing potential O&G contamination in the environment. In this study, 15 laboratories participated in an inter-laboratory comparison on the chemical characterization of three O&G wastewaters from the Appalachian Basin and four solids impacted by O&G development, with the goal of evaluating the quality of data and the accuracy of measurements for various analytes of concern. Using a variety of different methods, analytes in the wastewaters with high concentrations (i.e., >5 mg L-1) were easily detectable with relatively high accuracy, often within +/-10% of the most probable value (MPV). In contrast, often less than 7 of the 15 labs were able to report detectable trace metal(loid) concentrations (i.e., Cr, Ni, Cu, Zn, As, and Pb) with accuracies of approximately +/-40%. Despite most labs using inductively coupled plasma mass spectrometry (ICP-MS) with low instrument detection capabilities for trace metal analyses, large dilution factors during sample preparation and low trace metal concentrations in the wastewaters limited the number of quantifiable determinations and likely influenced analytical accuracy. In contrast, all the labs measuring Ra in the wastewaters were able to report detectable concentrations using a variety of methods including gamma spectroscopy and wet chemical approaches following Environmental Protection Agency (EPA) standard methods. However, the reported radium activities were often greater than +/-30% different to the MPV possibly due to calibration inconsistencies among labs, radon leakage, or failing to correct for self-attenuation. Reported radium activities in solid materials had less variability (+/-20% from MPV) but accuracy could likely be improved by using certified radium standards and accounting for self-attenuation that results from matrix interferences or a density difference between the calibration standard and the unknown sample. This inter-laboratory comparison illustrates that numerous methods can be used to measure major cation, minor cation, and anion concentrations in O&G wastewaters with relatively high accuracy while trace metal(loid) and radioactivity analyses in liquids may often be over +/-20% different from the MPV. PMID- 30452049 TI - Engineered fluorescent carbon dots as promising immune adjuvants to efficiently enhance cancer immunotherapy. AB - Currently, cancer immunotherapy appears to be an effective strategy for cancer therapy, but the state of unresponsiveness to tumor antigenic stimulation in immune systems is one of the stumbling blocks to the clinical applications of cancer immunotherapy. Nanomaterials have been increasingly applied in cancer immunotherapy by virtue of their irreplaceable superiority to carry antigens to specific sites and stimulate immune responses. Among the many excellent fluorescent nanomaterials, carbon dots (CDs) stand out from the others as a result of their extraordinary performance. Therefore, photoluminescent CDs were used as vaccine adjuvants to be combined with tumor protein antigen model ovalbumin (OVA), with red, yellow and green colored luminescence under different excitation wavelengths. These CDs could positively contribute to antigen uptake and efficiently accelerate the maturation of dendritic cells (DCs). The obtained nanocomposite of CDs and OVA (CDs-OVA) could efficiently enhance the expression of costimulatory molecules CD80 and CD86, and the production of tumor necrosis factor alpha (TNF-alpha) from DCs. In addition, CDs-OVA could also strongly stimulate splenocyte proliferation and the production of interferon gamma (IFN gamma). In addition, this CDs-OVA vaccine could effectively be endocytosed and processed by immune cells in vivo, then it could induce strong antigen-specific cellular immune responses to inhibit the growth of B16-OVA melanoma cancer in C57BL/6 mice. This work represents not only the first report of CDs as vaccine adjuvants for tumor inhibition, but also opens up many possibilities for more biomedical applications of CDs in cancer immunotherapy and in other potential clinical applications. PMID- 30452050 TI - Synergic effects of upconversion nanoparticles NaYbF4:Ho3+ and ZrO2 enhanced the efficiency in hole-conductor-free perovskite solar cells. AB - Extending the spectral absorption of organic-inorganic mixed-cation perovskite solar cells (PSCs) from visible light to the near-infrared (NIR) range minimizes the nonabsorption loss of solar photons. Few studies have focused on the application of high-fluorescence NaYbF4:Ho3+ upconversion nanoparticles (UCNPs) in solar cells. In this study, NaYbF4:Ho3+ UCNPs were successfully prepared using a solvothermal method. We incorporated the NaYbF4:Ho3+ UCNPs into ZrO2 as the scaffold layer for FA0.4MA0.6PbI3 perovskite solar cells. This design enabled the dual-functional effects, that is, the harvesting of NIR light and its conversion to visible light and the reduction of the electron-hole recombination rate. The effect of different amounts of NaYbF4:Ho3+ UCNPs on the device performance was investigated in detail. The best-performance devices based on optimized addition of UCNPs (40 wt%) could achieve a power conversion efficiency as high as 14.32%, an increase of 28.8% compared with conventional ZrO2 nanoparticle-based PSCs (11.12%). The design of the synergetic operation of UCNPs and ZrO2 in the mesoporous structure of PSCs enhanced the photocurrent and photovoltage. The results offered the flexibility for the device architecture and broaden the solar spectral use of UCNP-based devices. PMID- 30452051 TI - Nanomodel visualization of fluid injections in tight formations. AB - The transport and phase change of a complex fluid mixture under nanoconfinement is of fundamental importance in nanoscience, and limits the recovery efficiency from tight oil reservoirs (<10%). Herein, through experiments and supporting theory we characterize the transport and phase change of a nanoconfined complex fluid mixture. Our nanofluidic platform, nanomodel, replicates shale reservoirs in terms of mean pore size (~100 nm), permeability (~MUD) and porosity (~10%). We screen conditions for the most promising shale EOR strategies, directly quantifying their pore-scale efficiency and underlying mechanisms. We find that immiscible gas (N2) flooding presents a prohibitively large capillary pressure threshold (~2 MPa). Miscible (CO2) gas flooding eliminates this threshold leading to film-wise stable oil displacement with high recovery efficiency. Strong capillary forces present barriers as well as opportunities for recovery strategies unique to nanoporous reservoirs by transitioning from a miscible to an immiscible condition locally within the reservoir. These results quantify the fundamental transport and phase change mechanisms applicable to nanoconfined complex fluids, with direct implications in unconventional oil as well as nanoporous media more broadly. PMID- 30452052 TI - Evaluation of the neuroprotective effect of EGCG: a potential mechanism of mitochondrial dysfunction and mitochondrial dynamics after subarachnoid hemorrhage. AB - (-)-Epigallocatechin-3-gallate (EGCG), the main bioactive component of tea catechins, exhibits broad-spectrum health efficacy against mitochondrial damage after subarachnoid hemorrhage (SAH). The mechanisms, however, are largely unknown. Here, the ability of EGCG to rescue mitochondrial dysfunction and mitochondrial dynamics following the inhibition of cell death was investigated by using in vitro and in vivo SAH models. EGCG blocked the cytosolic channel ([Ca2+])i influx via voltage-gated calcium channels (VGCCs), which induced mitochondrial dysfunction, including mitochondrial membrane potential depolarization and reactive oxygen species (ROS) release. As expected, EGCG ameliorated oxyhemoglobin (OxyHb)-induced impairment of mitochondrial dynamics by regulating the expression of Drp1, Fis1, OPA1, Mfn1, and Mfn2. As a result, EGCG restored the increases in fragmented mitochondria and the mtDNA copy number in the OxyHb group to almost the normal level after SAH. In addition, the normal autophagic flux induced by EGCG at both the initiation and formation stages regulated Atg5 and Beclin-1 after SAH for the timely elimination of damaged mitochondria. In the end, EGCG increased the neurological score by decreasing cell death through the cyt c-mediated intrinsic apoptotic pathway. The results revealed the mechanisms behind the neuroprotective effects of EGCG via inhibition of the overloaded [Ca2+]i-induced mitochondrial dysfunction and the imbalanced mitochondrial fusion and fission cycle. Therefore, the simultaneous inhibition and timely elimination of damaged mitochondria could determine the therapeutic effect of EGCG. PMID- 30452053 TI - One-step solvothermal fabrication of Cu@PANI core-shell nanospheres for hydrogen evolution. AB - Polyaniline(PANI)-decorated Cu nanoparticles were prepared by a facile solvothermal method. Different reaction temperatures resulted in different morphologies of the Cu/PANI composites, which exhibited good photocatalytic activities. When the mass ratio of PANI increased to 2.5 wt%, the H2 evolution rate reached 1.97 mmol g-1 h-1 in lactic acid solution under solar light irradiation, which is about 2 times higher than that of pure Cu nanoparticles (1.06 mmol g-1 h-1). The introduction of PANI can improve the separation efficiency of the photo-generated electron-hole pairs, where PANI acts as a hole reservoir for trapping holes generated by the Cu NPs and hindering the recombination of the electron-hole pairs. A possible mechanism is presented to explain the photocatalytic process using Cu@PANI core-shell nanospheres as the photocatalyst. PMID- 30452054 TI - Surface relief of magnetoactive elastomeric films in a homogeneous magnetic field: molecular dynamics simulations. AB - The structure of a thin magnetoactive elastomeric (MAE) film adsorbed on a solid substrate is studied by molecular dynamics simulations. Within the adopted coarse grained approach, a MAE film consists of magnetic particles modeled as soft-core spheres, carrying point dipoles, connected by elastic springs representing a polymer matrix. MAE films containing 20, 25 and 30 vol% of randomly distributed magnetic particles are simulated. Once a magnetic field is applied, the competition between dipolar, elastic and Zeeman forces leads to the restructuring of the layer. The distribution of the magnetic particles as well as elastic strains within the MAE films are calculated for various magnetic fields applied perpendicular to the film surface. It is shown that the surface roughness increases strongly with growing magnetic field. For a given magnetic field, the roughness is larger for the softer polymeric matrix and exhibits a nonmonotonic dependence on the magnetic particle concentration. The obtained results provide a better understanding of the MAE surface structuring as well as possible guidelines for fabrication of MAE films with a tunable surface topology. PMID- 30452055 TI - Aza-tricycles containing a perfluoroalkyl group: synthesis, structure and fluorescence. AB - Perfluoroalkyl-containing aza-tricycles have been prepared in one synthetic operation via an ambient light-promoted three-component reaction of beta-oxo esters, perfluoroalkyl iodide and DBU. Intramolecular C-FO and double C-HF weak interactions and intermolecular C-HO and C-Hpi hydrogen bondings were observed partly due to the incorporation of the perfluoroalkyl group. The perfluoroalkylated non-planar aza-tricycles exhibit interesting room-temperature AIE fluorescence and acid-induced fluorescence enhancement characters. PMID- 30452056 TI - One-step synthesis of N,N'-substituted 4-imidazolidinones by an isocyanide-based pseudo-five-multicomponent reaction. AB - A pseudo-five-multicomponent reaction involving an isocyanide, a primary amine, two molecules of formaldehyde and water is reported, which gives N,N'-substituted 4-imidazolidinones when trifluoroethanol is used as the solvent. The reaction proceeds with good yields and with a wide variety of amines and isocyanides, providing an efficient new entry to these heterocycles. A preliminary study of the reaction mechanism suggests that trifluoroethanol, although acting as the solvent, is directly involved as a reagent in the reaction pathway. PMID- 30452057 TI - Laser assisted tattoo removal - state of the art and new developments. AB - Decorative tattoos including permanent make-up are very popular world-wide. However, some people regret tattooing and seek tattoo removal. Tattooed skin contains numerous solid particles of tattoo pigments. A major mechanism of tattoo removal is laser assisted fragmentation of these particles, which are then transported away from the skin. For many years, Q-switched lasers with nanosecond pulse durations at high light intensities have been applied to cause such fragmentation via rapid heating up while sparing the adjacent tissue. Despite the long-lasting use of such laser treatment, the exact mechanisms of laser assisted fragmentation are hardly investigated. Due to short and intense laser pulses applied, non-linear effects of light (e.g. photoacoustic and optical breakdown) and nonlinear thermal properties in tattoo particles may play a crucial role. In the past few years, lasers with even shorter pulse duration in the sub-nanosecond range were launched for tattoo removal. Theoretical considerations assumed that pulse durations shorter than nanoseconds allow even more effective fragmentation of tattoo particles. A couple of initial studies affirm the effectiveness of picosecond pulses in tattoo treatment, especially in clearing black tattoos. Furthermore, treatment with picosecond lasers seems to be less painful. Consequently, picosecond technology may be a new strategy for more effective removal of tattoo pigments at a lower rate of side effects. But there is an urgent need for more well-designed and randomized controlled trials to compare this treatment modality to the traditional nanosecond technology regarding efficacy and adverse reactions. PMID- 30452058 TI - Wall friction and Janssen effect in the solidification of suspensions. AB - We address the mechanical effect of rigid boundaries on freezing suspensions. For this we perform the directional solidification of monodispersed suspensions in thin samples and we document the thickness h of the dense particle layer that builds up at the solidification front. We evidence a change of regime in the evolution of h with the solidification velocity V with, at large velocity, an inverse proportionality and, at low velocity, a much weaker trend. By modelling the force balance in the critical state for particle trapping and the dissipation phenomena in the whole layer, we link the former evolution to viscous dissipation and the latter evolution to solid friction at the rigid sample plates. Solid friction is shown to induce an analog of the Janssen effect on the whole layer. We determine its dependence on the friction coefficient between particles and plates, on the Janssen's redirection coefficient in the particle layer, and on the sample depth. Fits of the resulting relationship to data confirm its relevance at all sample depths and provide quantitative determinations of the main parameters, especially the Janssen's characteristic length and the transition thickness h between the above regimes. Altogether, this study thus clarifies the mechanical implication of boundaries on freezing suspensions and, on a general viewpoint, provides a bridge between the issues of freezing suspensions and of granular materials. PMID- 30452060 TI - Buyer Beware: Avoiding the Minefield of Predatory Conferences. PMID- 30452059 TI - Intermolecular alkene difunctionalizations for the synthesis of saturated heterocycles. AB - Saturated heterocycles are important structural motifs in a range of pharmaceuticals and agrochemicals. As a result of their importance, syntheses of these molecules have been extensively investigated. Despite the progress in this area, the most adopted strategies are still often characterized with inefficiency or relying on functionalizations with specialized precursors and pre-existing cores. This review highlights a dynamic synthetic strategy for the direct synthesis of saturated heterocycles from intermolecular alkene difunctionalizations. These coupling processes are highly modular, and therefore, offer perhaps the most convenient means to prepare diverse heterocyclic structures in compound libraries for bioactivity evoluations. PMID- 30452061 TI - Sleep-Disordered Breathing and Cerebral Oxygenation During Sleep in Adults With Mild Cognitive Impairment. AB - The current study examined relationships between laterality in cerebral oxygenation (L-COX), sleep-disordered breathing (SDB), and daytime function in 16 adults with mild cognitive impairment (MCI). All participants underwent two nights of diagnostic polysomnography. Using dual-cerebral oximetry, L-COX was defined by differences >=4% in right- versus left-sided percent cerebral oxyhemoglobin saturation. Eight patients had SDB. L-COX was found in five patients, but only on nights with SDB. Greater L-COX was associated more severe SDB: higher frequency of apneas + hypopneas per hour (r = 0.66, p < 0.01), desaturations per hour (r = 0.73, p < 0.01), and percent time with oxygen saturation <88% (r = 0.65, p < 0.01). Greater laterality, but not severity of SDB, was associated with poorer functional ability (Lawton Instrumental Activities of Daily Living Scale: r = -0.83, p = 0.02), lower cognitive function (Mini-Mental State Examination: r = -0.76, p = 0.03), and greater daytime sleepiness (Epworth Sleepiness Scale: r = 0.85, p < 0.001). L-COX associated with SDB suggests disruptions in cerebral autoregulation and need for aggressive treatment of SDB in individuals with MCI. [Res Gerontol Nurs. 2018; 11(6):282 292.]. PMID- 30452062 TI - Community Engagement Model to Match Psychosocial Health Needs. AB - The purpose of the current study was to develop a model from community engagement (CE) process data to guide future CE for a focused health problem. Community based participatory research was used to engage older adults affected by cancer and their family caregivers in eight cancer clusters in one northeastern U.S. state. CE was focused on informing participants about a national telephone helpline offering psychosocial cancer services. A purposeful sample by settings in the cancer clusters yielded an estimated 200,500 individuals who participated in information sessions, health fairs, sporting events, and the media (i.e., print, radio, or television). A general inductive approach was used to analyze CE data and resulted in a four-phase model that health professionals consider in initiating CE. Strategies are discussed for resolving two roadblocks that were identified. This model serves as a guide to standardize CE that informs a community about available services to address a focused health problem. [Res Gerontol Nurs. 2018; 11(6):293-305.]. PMID- 30452063 TI - Prosociality as a Form of Productive Aging: Predictors and Their Relationship With Subjective Well-Being. AB - The current study emphasizes the importance of active and productive aging to promote health and autonomy among older adults, highlighting effects on social and familial levels. A questionnaire was administered to a sample of 198 individuals older than 65 living in Palafrugell, Spain with the objective of determining which factors influence informal helping behavior among older adults and the relationship between these factors and well-being and variables such as perception of health and economic status. Satisfaction with free time and participation in various activities, as well as education level in individuals younger than 80, were identified as predictors of helping behavior. A statistically significant and positive relationship was observed between helping others and satisfaction with free time and feeling happy. This study contributes to understanding prosocial behavior among older adults by examining the relationship between prosocial behavior and subjective well-being and contribution to productive aging. [Res Gerontol Nurs. 2018; 11(6):306-315.]. PMID- 30452065 TI - Congratulations to the 2018 Blue Ribbon Article Award Winners. PMID- 30452064 TI - The Role of Evidence-Based Medicine in Current Practice. PMID- 30452066 TI - A Review of Novel Antibiotic Regimens for the Treatment of Orthopedic Infections. AB - As a result of the increasing numbers of joint replacement surgeries and other implant-associated procedures performed, the incidences of periprosthetic joint infections and osteomyelitis are on the rise. Antibiotic resistance to gram positive species, which are mostly isolated from such infections, is a significant obstacle in clinical practice. Promising clinical outcomes have been reported with the use of novel antibiotics for patients with periprosthetic joint infections and osteomyelitis. Further research is necessary for the establishment of these novel antibiotic therapies in routine clinical practice. [Orthopedics. 2018; 41(6):323-328.]. PMID- 30452067 TI - Association of Trunk Rotational Velocity with Spine Mobility and Curvatures in Para Table Tennis Players. AB - This study investigates the relationship of trunk rotational velocity with mobility and curvature of the spine in wheelchair table tennis players. Eleven para table tennis players and 13 able-bodied athletes performed 5 seated trunk rotations to each side with 1 kg barbell placed on the shoulders. Trunk rotational velocity and respective angular displacement were significantly lower in para table tennis players compared to able-bodied athletes. Both groups showed similar values of thoracic kyphosis. However, para table tennis players exhibited lower lumbar inversion and pelvic retroversion compared to able-bodied athletes. Peak and mean velocity in the acceleration phase of trunk rotation correlated with angular displacement in both para table tennis players (r=0.912, p=0.001; r=0.819, p=0.013) and able-bodied athletes (r=0.790, p=0.026; r=0.673, p=0.032). These velocity values were also associated with lumbar curvature (r=-0.787, p=0.003; r=- 0.713, p=0.009) and pelvic tilt angle (r=0.694, p=0.014; r=0.746, p=0.007) in para table tennis players. Findings indicate that slower velocity of trunk rotations in para table tennis players might be due to their limited range of trunk rotational motion. Decreased posterior concavity could also contribute to these lower values. However, other biomechanical factors may have an impact on the association between these variables and have yet to be documented. PMID- 30452068 TI - Infertility Treatments and Long-Term Neurologic Morbidity of the Offspring. AB - OBJECTIVE: To determine the risk of long-term neurologic morbidity among children (up to 18 years) born following in vitro fertilization (IVF) or ovulation induction (OI) treatments as compared with spontaneously conceived. STUDY DESIGN: A population-based cohort analysis was performed, including data from the perinatal computerized database on all singleton infants born at the Soroka University Medical Center (SUMC) between the years 1991 and 2014. This perinatal database was linked and cross-matched with the SUMC computerized dataset of all pediatric hospitalizations. RESULTS: Neurologic morbidity was significantly more common in IVF (3.7%) and OI (4.1%) offspring as compared with those following spontaneous pregnancies (3.1%; p = 0.017). In particular, attention deficit/hyperactivity disorders and headaches were more common in the OI group and sleep disorders in the IVF group, whereas autism and cerebral palsy were comparable between the groups. In the Weibull multivariable analysis, while controlling for maternal age, preterm delivery, birthweight centile, maternal diabetes, and hypertensive disorders, IVF (adjusted hazard ratio [HR]: 1.40; 95% confidence interval [CI]: 1.14-1.71; p = 0.001), but not OI (adjusted HR: 1.17' 95% CI: 0.92-1.48; p = 0.196), was noted as an independent risk factor for long term pediatric neurologic morbidity. CONCLUSION: IVF offspring appear to be at an increased risk of long-term neurologic morbidity up to 18 years of age. PMID- 30452069 TI - The Effect of Intrapartum Vancomycin on Vaginal Group B Streptococcus Colony Counts. AB - OBJECTIVE: To define the temporal relationship between intrapartum intravenous vancomycin administration and vaginal group B streptococcus (GBS) colony counts. STUDY DESIGN: Prospective cohort study conducted from October 2014 to February 2017. Women with antenatal cultures demonstrating GBS colonization and a plan for vancomycin administration were eligible. Intrapartum vaginal cultures were collected prior to the first vancomycin infusion and every 2 hours up to five collections or delivery. Results were analyzed in two groups: participants with at least one positive intrapartum culture and those without any positive intrapartum cultures. RESULTS: A total of 63 women were enrolled. Among consented women, a total of 8 were excluded and 3 participants' cultures were never plated, thus leaving a total of 52 women for analysis. The degree of vaginal GBS colonization varied between subjects and was not normally distributed. Colony counts dropped rapidly from hour 0 to hour 2 (median: 6.0 * 108 vs. 1.0 * 108, p < 0.01). Standardizing hour 0 colony counts to 100%, the percent decline in colony counts from hour 0 to hour 2 was significant (p = 0.03), and at each subsequent time point fell further. CONCLUSION: GBS vaginal colony counts fall rapidly after intrapartum vancomycin administration. PMID- 30452070 TI - Correction: The Effects of Melatonin Supplementation on Glycemic Control: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - In the article, the name of the co-author was given incorrectly. The correct name of the author is Mohammad Ali Mansournia.In the abstract section the correct abbreviation of "mean difference" is MD. PMID- 30452071 TI - [Folic Acid Intake Among Women in Berlin According to Their Socio-Economic Status]. AB - INTRODUCTION: The intake of folic acid before and during pregnancy is known to reduce the risk of neural tube defects. Many pregnant women do take folic acid at some point during their pregnancy. Very few of them start taking supplements before conception as recommended. The aim of this study was to find out more about the supplementation behavior among pregnant women and postpartum women in Berlin. METHODS: Pregnant women and postpartum women were asked to anonymously fill in a questionnaire about potential folic acid intake. We conducted a logistic regression analysis to identify independent predictors of folic acid intake during pregnancy. RESULTS: 90.7% (n=1069) of women did take folic acid at some point during their pregnancy, 37.8% (n=445) before conception as advised. Women are more likely to take folic acid before conception when they have planned their pregnancy, when they are better educated, earn more money and are older. Non-German(-speaking) women took significantly less folic acid than German women. Education, income and planning of the pregnancy were identified as independent predictors of folic acid intake prior to conception. CONCLUSION: Almost two thirds of pregnant women do not take folic acid when they need it most, especially those women who do not make much money, are not well educated, are young, and/or have not planned their pregnancy. Additionally, the supplementation rate is lower among non-German women and/or women who do not speak any German. PMID- 30452072 TI - Comparative Pharmacokinetics of Mitragynine after Oral Administration of Mitragyna speciosa (Kratom) Leaf Extracts in Rats. AB - Kratom (Mitragyna speciosa) has been examined for its opioid activity, especially for the treatment of opioid withdrawal and pain. Mitragynine, the most abundant alkaloid in kratom, is thought to be the major psychoactive alkaloid. An HPLC method was developed for the quantification of mitragynine in kratom leaf extracts. In addition, a multiple reaction mode based UPLC-MS/MS method was developed and validated for the quantification of mitragynine in rat plasma. Pharmacokinetic studies were performed by comparing a single intravenous dose of mitragynine (5 mg/kg, mitragynine hydrochloride) to a single oral dose of mitragynine (20 mg/kg, mitragynine hydrochloride), lyophilized kratom tea, and the organic fraction of the lyophilized kratom tea at an equivalent mitragynine dose of 20 mg/kg in rats. After intravenous administration, mitragynine exhibited a biexponential decrease in the concentration-time profile, indicating the fast distribution of mitragynine from the systemic circulation or central compartment to the peripheral compartments. Mitragynine hydrochloride, lyophilized kratom tea, and the lyophilized kratom tea organic fraction were dosed orally and the absolute oral bioavailability of mitragynine in rats was found to be 1.5- and 1.8 fold higher than that of mitragynine dosed alone. The results provide evidence that an equivalent oral dose of the traditional preparation (lyophilized kratom tea) and formulated/manufactured products (organic fraction) of kratom leaves provide better systemic exposure of mitragynine than that of mitragynine dosed alone. PMID- 30452073 TI - Anti-Inflammatory Activity of Lobaric Acid via Suppressing NF-kappaB/MAPK Pathways or NLRP3 Inflammasome Activation. AB - Lobaric acid (LA) is a constituent of the lichen Stereocaulon alpinum. LA has multiple biological activities, including antibacterial and antioxidant ones. The purpose of this study was to investigate the effect of LA and its mechanism on lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. Macrophages were pretreated with different concentrations of LA (0.2 - 20 uM), followed by LPS stimulation. LA treatment of LPS stimulated macrophages decreased their nitric oxide production and the expression of cyclooxygenase-2 and prostaglandin E2. LA also significantly reduced the production of tumor necrosis factor-alpha and interleukin (IL)-6 by inhibiting the activation of mitogen activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB). Additionally, LA inhibited the production of IL-1beta and IL-18, as well as caspase-1 maturation, by inhibition of NLRP3 inflammasome activation in LPS/ATP stimulated cells. These results strongly suggest that LA could inhibit inflammation by downregulating NF-kappaB/MAPK pathways and NLRP3 inflammasome activation in activated macrophages. These results reveal a new therapeutic approach to modulate inflammatory diseases linked to deregulated inflammasome activities. PMID- 30452074 TI - Regulation of Animal Research in Science: How to Harm Both Science and Animal Protection. PMID- 30452075 TI - Influence of Medication-Induced Preconditioning or Remote Ischemic Preconditioning on the Intrinsic Vascular Extracellular RNA/Ribonuclease System in Cardioprotection. AB - BACKGROUND: It has been demonstrated that remote ischemic preconditioning (RIPC) increases ribonuclease (RNase) levels and protects the heart by reducing extracellular ribonucleic acid (eRNA). As medication-induced preconditioning (MIPC) is also a powerful tool for cardioprotection, we examined the influence of both types of preconditioning on the eRNA/RNase system. METHODS: In 17 male rats, RIPC (3 * 5 minute hind-leg ischemia) or MIPC (isoflurane and buprenorphine anesthesia) was performed. Five rats served as control and did not undergo preconditioning (non-MIPC). After preconditioning, eRNA levels and RNase activity were determined in plasma, and the hearts were mounted on a blood-perfused Langendorff ischemia/reperfusion apparatus. Hemodynamic, metabolic, and electron microscopic parameters were determined. Furthermore, MIPC with one anesthetic drug only (isoflurane, buprenorphine, or etomidate) was induced in another five rats. After 30 minutes, eRNA levels and RNase activity were determined and compared with an RIPC group (n = 5). RESULTS: The plasma of RIPC-treated rats had higher RNase activity and lower eRNA levels than that of MIPC-treated rats. In addition, RIPC increased RNase activity more than MIPC with one drug alone. The RNase activity and eRNA levels in these MIPC groups differed considerably. Hemodynamic parameters of RIPC- and MIPC-treated hearts were better preserved after 90-minute ischemia than those of non-MIPC hearts. No obvious differences were noted between MIPC and RIPC regarding hemodynamics, metabolism, or structural parameters. CONCLUSIONS: Our results suggest that RIPC does not have any additional cardioprotective benefit in this experimental system. However, the influence of RIPC on the eRNA/RNase system was greater than that of MIPC. PMID- 30452076 TI - Six-Month Performance of a 3-Dimensional Annuloplasty Ring for Repair of Functional Tricuspid Regurgitation. AB - BACKGROUND: Functional tricuspid regurgitation (FTR) secondary to left-sided heart disease may lead to poor quality of life and reduced long-term survival. This study evaluated clinical and functional outcomes of patients undergoing tricuspid valve (TV) repair using a rigid three-dimensional ring (Contour 3D, Medtronic) concomitant with another procedure. METHODS: From September 2011 to July 2015, 112 patients (mean age 70.9 +/- 9.0 years) were enrolled at 10 centers in Europe, Israel, and the United States. Inclusion criteria were FTR >= moderate and/or tricuspid annular diameter (TAD) >= 40 mm. Echocardiography was planned before surgery and at discharge with echocardiographic and clinical follow-ups performed 6 months postoperatively. RESULTS: Three fourths (74.4%) of patients had higher than moderate TR. Mean TAD was 41.0 +/- 7.3 mm; 61.7% of patients were in the New York Heart Association (NYHA) class III/IV. The most common concomitant procedure was mitral valve repair (57 patients, 53.3%). The 30-day mortality rate was 0.9% (n = 1). The mean EuroSCORE II was 8.9 +/- 8.4% (median: 5.9%; interquartile range: 3.5-11.5%). The observed to expected ratio (O/E) based on the median was 0.1. Six deaths occurred during follow-up (three cardiac related). Mean implanted ring size was 30.3 +/- 2.7. At 6 months, 94.4% of patients showed <= mild TR, and 92.0% were in NYHA class I/II (p < 0.001 vs baseline for both). Mean pressure gradient across the TV was 2.0 +/- 1.1 mm Hg; leaflet coaptation length was 7.5 +/- 3.3 mm. CONCLUSION: The Contour 3D annuloplasty ring used for treatment of FTR substantially reduced TR for up to 6 postoperative months with low mean pressure gradients across the TV and significant improvement in NYHA class. REGISTRATION: www.ClinicalTrials.gov, NCT01532921. PMID- 30452077 TI - In vitro Anti-Trypanosomal Activities of Indanone-Based Chalcones. AB - Human African trypanosomiasis is a neglected infectious disease that affects mostly people living in the rural areas of Africa. Current treatment options are limited to just four drugs that have been in use of four to nine decades. The life-threatening toxic side-effects associated with the use of these drugs are disconcerting. Poor efficacy, low oral bioavailability, and high cost are other shortcomings of current HAT treatments. Evaluating the potentials of known hits for other therapeutic areas may be a fast and convenient method to discover new hit compounds against alternative targets. A library of 34 known indanone based chalcones was screened against T.b. brucei and nine potent hits, having IC50 values between 0.5-8.9 uM, were found. The SAR studies of this series could provide useful information in guiding future exploration of this class of compounds in search of more potent, safe, and low cost anti-trypanosomal agents. Graphical Abstract. PMID- 30452078 TI - Investigating Intestinal Permeability of Bortezomib Using a Validated HPLC-UV Method. AB - Bortezomib (BTZ), as a proteasome inhibitor, has been used for treatment of patients with relapsed/refractory multiple myeloma and mantle cell lymphoma. BTZ is available for intravenous injection or subcutaneous administration. In this study, for evaluating the potential of BTZ oral delivery, intestinal permeability of BTZ was determined using in situ single-pass intestinal perfusion (SPIP) technique and the perfused solutions were analyzed using a validated HPLC-UV method. The chromatographic separation was performed using a C18 column via isocratic mode at a flow rate of 0.5 mL/min at 270 nm. The mobile phase was a mixture of methanol/deionized water (50:50% v/v) with 0.1% glacial acetic acid. The results indicated that calibration curves were linear (r2 ?0.99) in a concentration range of 1.65-5 ug/mL for BTZ and 8.33-25 ug/mL for phenol red. A limit of quantitation of 1.03 and 6.67 ug/mL was obtained for BTZ and phenol red, respectively. The recovery values were in the range of 96.5-105.4% for BTZ, and 88-99.2% for phenol red. The relative standard deviations (RSD) were <=4.9% for BTZ and <=7% for phenol red. Stability studies indicated that the working standard solution is stable over a period of 48 h at room temperature. Finally, an effective permeability (Peff) value of (3.36+/-0.5)*10-5 cm/sec (mean+/-SEM) was achieved for BTZ. Moreover, it was predicted that BTZ belongs to the biopharmaceutical class III. PMID- 30452079 TI - Epstein - Barr virus association with plasma cell neoplasms. AB - AIMS: Epstein-Barr virus (EBV) expression has been reported in several hematopoietic and non-hematopoietic disorders but its expression in plasma cell neoplasms has been largely limited to immunodeficiency-related cases such as in the setting of post-organ transplantation or human immunodeficiency virus (HIV) infection. The aim of this study is to evaluate the association of EBV with plasma cell neoplasms, mainly in immunocompetent patients. METHODS AND RESULTS: We retrospectively studied 147 cases of patients with different plasma cell neoplasms (109 plasma cell myelomas, 22 plasmacytomas, and 16 monoclonal gammopathy cases). Six patients were immunocompromised. EBV was positive in 6 cases; 3 immunocompromised (2 patients with HIV infection and 1 patient was post renal transplant) and 3 immunocompetent patients with plasmacytoma and variable plasmablastic features. CONCLUSIONS: Our data shows that EBV was negative in all plasma cell myeloma cases in immunocompetent patients and has an overall low association with the different plasma cell neoplasms in the immunocompetent setting. When expressed, it is usually associated with variable plasmablastic features. PMID- 30452080 TI - Osmosensing, osmosignalling and inflammation: how intervertebral disc cells respond to altered osmolarity. AB - Intervertebral disc (IVD) cells are naturally exposed to high osmolarity and complex mechanical loading, which drive microenvironmental osmotic changes. Age- and degeneration-induced degradation of the IVD's extracellular matrix causes osmotic imbalance, which, together with an altered function of cellular receptors and signalling pathways, instigates local osmotic stress. Cellular responses to osmotic stress include osmoadaptation and activation of pro-inflammatory pathways. This review summarises the current knowledge on how IVD cells sense local osmotic changes and translate these signals into physiological or pathophysiological responses, with a focus on inflammation. Furthermore, it discusses the expression and function of putative membrane osmosensors (e.g. solute carrier transporters, transient receptor potential channels, aquaporins and acid-sensing ion channels) and osmosignalling mediators [e.g. tonicity response-element-binding protein/nuclear factor of activated T-cells 5 (TonEBP/NFAT5), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)] in healthy and degenerated IVDs. Finally, an overview of the potential therapeutic targets for modifying osmosensing and osmosignalling in degenerated IVDs is provided. PMID- 30452081 TI - Reply to: Comments on the Aging Tsunami and Senior Healthcare Development in China. PMID- 30452082 TI - Development and implementation of a group based mental health intervention for unaccompanied minors. AB - Unaccompanied refugee minors (UMs) are at significant risk to experience severe mental health symptoms (Derluyn, Broekaert & Schuyten). Trauma-focused treatments have been found to be effective for traumatized refugees (Slobodin & de Jong). However, trauma-focused mental health services are seldom available, and treatment fails when UMs lack trust in service providers (Majumder, O'Reilly, Karim & Vostanis). In order to address this gap, a 10-session group based mental health intervention for UMs was developed and then pilot tested in 3 accommodation units for UMs in Finland. The implementation and effectiveness of the intervention was studied by qualitative and quantitative methods. The process was completed by 18 UMs. Symptom measures showed no statistically significant changes on the mental health variables studied. However, staff members and UMs reported increased trust and communication, and participating staff members felt empowered to facilitate groups independently. The group model promoted social interaction and built trust in the accommodation units. Further studies are required to UMs. PMID- 30452083 TI - Incremental clinical utility of continuous performance tests in childhood ADHD - an evidence-based assessment approach. AB - Despite extensive research on attention deficit hyperactivity disorder (ADHD), there are still uncertainties regarding the clinical utility of different ADHD assessment methods. This study aimed to examine the incremental clinical utility of Conners' continuous performance test (CPT) II and QbTest in diagnostic assessments and treatment monitoring of attention deficit hyperactivity disorder (ADHD). Retrospective data from child and adolescent psychiatric records of two populations were studied. The diagnostic clinical utility of Conners' CPT II and QbTest was analysed using receiver operator characteristics (ROC) and post-test probability in 80 children with and 38 without ADHD. Dose titrations of central stimulants in 56 children with ADHD were evaluated using QbTest and the Swanson, Nolan, Pelham, version IV (SNAP-IV) scale. Conners' CPT II, but not QbTest, had incremental clinical utility in diagnostic assessment of children with ADHD when teacher and parent ratings were inconclusive. QbTest proved useful in titration of central stimulant treatment when parent ratings were inconclusive. Continuous performance tests were found to be clinically useful when rating scales were inconclusive. PMID- 30452085 TI - Strategies for Managing the Aging Tsunami in China: Weifang Model. PMID- 30452084 TI - Effect of Hospitalizations on Physical Activity Patterns in Mobility-Limited Older Adults. AB - OBJECTIVES: To evaluate the effect of hospitalizations on patterns of sedentary and physical activity time in mobility-limited older adults randomized to structured physical activity or health education. DESIGN: Secondary analysis of investigator-blinded, parallel-group, randomized trial conducted at 8 U.S. centers between February 2010 and December 2013. PARTICIPANTS: Sedentary men and women aged 70 to 89 at baseline who wore a hip-fitted accelerometer 7 consecutive days at baseline and 6, 12, and 24 months after randomization (N=1,341). MEASUREMENTS: Participants were randomized to a physical activity (PA; n = 669) intervention that included aerobic, resistance, and flexibility training or to a health education (HE; n = 672) intervention that consisted of workshops on older adult health and light upper-extremity stretching. Accelerometer patterns were characterized as bouts of sedentary (<100 counts/min; >=1, >=10, >=30, >=60 minute lengths) and activity (>=100 counts/min; >=1, >=2, >=5, >=10 minute lengths) time. Each participant was categorized as having 0, 1 to 3, or 4 or more cumulative hospital days before each accelerometer assessment. RESULTS: Hospitalization increased sedentary time similarly in both intervention groups (8 min/d for 1-3 cumulative hospital days and 16 min/d for >=4 cumulative hospital days). Hospitalization was also associated with less physical activity time across all bouts of less than 10 minutes (>=1: -7 min/d for 1-3 cumulative hospital days, -16 min/d for >=4 cumulative hospital days; >=2: -5 min/d for 1-3 cumulative hospital days, -11 min/d for >=4 cumulative hospital days; >=5: -3 min/d for 1-3 cumulative hospital days, -4 min/d for >=4 cumulative hospital days). There was no evidence of recovery to prehospitalization levels (time effect p >.41). PA participants had less sedentary time in bouts of less than 30 minutes than HE participants (-8 to -10 min/d) and more total activity (+3 to +6 min/d), although hospital-related changes were similar between the intervention groups (interaction effect p >.26). CONCLUSION: Participating in a PA intervention before hospitalization had expected benefits, but participants remained susceptible to hospitalization's detrimental effects on their daily activity levels. There was no evidence of better activity recovery after hospitalization. PMID- 30452086 TI - A blueprint for cancer screening and early detection: Advancing screening's contribution to cancer control. AB - From the mid-20th century, accumulating evidence has supported the introduction of screening for cancers of the cervix, breast, colon and rectum, prostate (via shared decisions), and lung. The opportunity to detect and treat precursor lesions and invasive disease at a more favorable stage has contributed substantially to reduced incidence, morbidity, and mortality. However, as new discoveries portend advancements in technology and risk-based screening, we fail to fulfill the greatest potential of the existing technology, in terms of both full access among the target population and the delivery of state-of-the art care at each crucial step in the cascade of events that characterize successful cancer screening. There also is insufficient commitment to invest in the development of new technologies, incentivize the development of new ideas, and rapidly evaluate promising new technology. In this report, the authors summarize the status of cancer screening and propose a blueprint for the nation to further advance the contribution of screening to cancer control. PMID- 30452087 TI - Outcomes of secondary solid tumor malignancies among patients with myeloma: A population-based study. AB - BACKGROUND: Therapeutic advances have extended survival for patients with myeloma, who may develop secondary cancers. METHODS: Using the population-based Surveillance, Epidemiology, and End Results registry (2004-2015), the authors examined the characteristics, overall and cause-specific survival, and cumulative incidence function of cancer-related death among patients with myeloma with secondary cancers of the breast, prostate, lung, colon/rectum, or bladder or melanoma. Each patient was matched based on age, sex, race, and year of diagnosis to 50 controls from a general population who were diagnosed with the index cancer. RESULTS: Patients with myeloma with breast, prostate, or lung cancer were more commonly diagnosed at an early stage, whereas the stage distribution did not differ significantly among patients with melanoma, colorectal cancer, or bladder cancer. For all studied cancers except those of the lung, overall mortality was significantly higher among patients with myeloma compared with controls (hazard ratios, 1.84-2.81). However, the cumulative incidence function of cancer-related death did not differ (subhazard ratios, 0.84-0.99) and was surpassed by myeloma related deaths (23% to 35% at 5 years). In patients with lung cancer, cancer related mortality was uniquely lower among patients with myeloma (subhazard ratio, 0.59; 95% confidence interval, 0.52-0.68), even after adjustment for stage of disease. There was no significant difference noted with regard to noncancer deaths for any studied solid tumor. Use of surgery (evaluated in patients with nonmetastatic tumors, and in addition matched by disease stage) did not differ between cases and controls, except for fewer prostatectomies being noted among patients with myeloma (odds ratio, 0.56; 95% confidence interval, 0.42-0.74). CONCLUSIONS: The results of the current study support curative treatment approaches to secondary cancers among patients with myeloma while highlighting the need for ongoing active myeloma management. PMID- 30452088 TI - Multifactorial Examination of Caregiver Burden in a National Sample of Family and Unpaid Caregivers. AB - OBJECTIVES: To examine factors associated with caregiver burden from a multifactorial perspective by examining caregiver and care recipient characteristics and a full range of caregiving tasks. DESIGN: Nationally representative surveys of community-dwelling older adults and their family caregivers residing in the United States. SETTING: 2011 National Health and Aging Trends Study and National Study of Caregiving. PARTICIPANTS: Community-dwelling older adults and their family caregivers. MEASUREMENTS: Caregiver burden, comprising emotional, physical, and financial difficulties associated with caregiving. RESULTS: An estimated 14.9 million caregivers assisted 7.6 million care recipients. More than half of caregivers reported burden related to caregiving. In a multivariable regression model, caregivers who assisted with more activities of daily living and instrumental activities of daily living, health management tasks, and health system logistics were more likely to experience burden, as were female caregivers, adult child caregivers, caregivers in poor health, caregivers with anxiety symptoms, and those using respite care. Dementia was the only care recipient characteristic associated with burden. CONCLUSION: Caregiver characteristics and provision of caregiving tasks determine caregiver burden more than care recipient characteristics. Absence of an association between type of a care recipient's chronic conditions and burden, except for dementia, suggests that the tasks that caregivers who assist older adults with a variety of health conditions undertake shape the experience of caregiving. PMID- 30452089 TI - The Disaster of Wording. PMID- 30452090 TI - Frequency and immunophenotype of IL10 producing regulatory B cells in Optic Neuritis. AB - : Mouse models of Multiple Sclerosis (MS) have shown the importance of interleukin-10 (IL10) producing regulatory B-cells (Bregs) in dampening disease activity and inhibiting disease initiation and progression. In MS and other autoimmune diseases decreased frequency and functionality of Bregs correlate with disease activity and the percentage of IL10 producing Bregs decrease during relapse and normalizes in remission. Optic Neuritis (ON) is a common first clinical manifestation of MS and IL10 producing Bregs may be crucial in the transition from ON to MS, we therefore investigate the frequency and function of Bregs in ON as a clinical model of early demyelinating disease. METHODS: B-cells were purified from 27 patients with ON sampled close to symptom onset 23 days [7 41] (median [range]) and 13 healthy controls. The B-cells were stimulated and cultured for 48 hours with CD40ligand and CpG before measurement of intracellular IL10 and the surface markers CD19, CD1d, CD5, CD24, CD38 and CD27 by flow cytometry. The frequency of B-cell subsets was analysed in peripheral blood and cerebral spinal fluid (CSF) of patients. RESULTS: 65% of the IL10 producing Bregs co-expressed CD24 and CD38, and only 14% were CD24highCD27+, suggesting that the naive B-cells are the primary source of IL10 in the B-cell culture followed by memory cells in both healthy controls and patients. The frequency of naive CD19+CD24+CD38+ Bregs are higher in ON compared with controls. The ability of Bregs to produce IL10 are at normal levels in both ON patients with high and low risk of progression to MS. We found no correlation between Bregs function and the presence of brain white matter lesions by Magnetic Resonance Imaging or CSF oligoclonal bands indicative of ON patients carrying a higher risk of conversion to MS. The frequencies of IL10 producing B-cells did also not correlate with the conversion to MS at two years follow up. CONCLUSION: IL10 were primarily produced by naive and memory B-cells. The frequency of IL10 secreting B-cells did not correlate with risk factors of MS. Bregs function at clinical onset of ON is not a determining factor for conversion to MS. This article is protected by copyright. All rights reserved. PMID- 30452091 TI - Vitamin C Supplementation in the Critically Ill: A Systematic Review and Meta Analysis. AB - Vitamin C, an enzyme cofactor and antioxidant, could hasten the resolution of inflammation, oxidative stress, and microvascular dysfunction. While observational studies have demonstrated that critical illness is associated with low levels of vitamin C, randomized controlled trials (RCTs) of vitamin C, alone or in combination with other antioxidants, have yielded contradicting results. We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials (inception to December 2017) for RCTs comparing vitamin C, by enteral or parenteral routes, with placebo or none, in intensive care unit (ICU) patients. Two independent reviewers assessed study eligibility without language restrictions and abstracted data. Overall mortality was the primary outcome; secondary outcomes were incident infections, ICU length of stay (LOS), hospital LOS, and duration of mechanical ventilation (MV). We prespecified 5 subgroups hypothesized to benefit more from vitamin C. Eleven randomized trials were included. When 9 RCTs (n = 1322) reporting mortality were pooled, vitamin C was not associated with reduced risk of mortality (risk ratio [RR] 0.72, 95% confidence interval [CI]: 0.43-1.20, P = .21). No effect was found on infections, ICU or hospital LOS, or duration of MV. In multiple subgroup comparison, no statistically significant subgroup effects were observed. However, we did observe a tendency towards a mortality reduction (RR 0.21; 95% CI: 0.04-1.05; P = .06) when intravenous high-dose vitamin C monotherapy was administered. Current evidence does not support supplementing critically ill patients with vitamin C. A moderately large treatment effect may exist, but further studies, particularly of monotherapy administration, are warranted. PMID- 30452092 TI - Effects of Nutrition Supplementation on Osmolality of Expressed Human Milk. AB - BACKGROUND: Provision of human milk to premature infants optimizes outcomes, but it must be supplemented to meet their nutrient and caloric requirements for growth. Our objective was to quantify the osmolality of human milk mixed with commercially available human milk fortifiers (HMF) and powdered infant formula, as currently fed to premature infants, simulating standard neonatal intensive care unit feeding practices for mixing and refrigerator storage. METHODS: Expressed human milk (EHM) samples obtained from mothers of premature infants (<=32 weeks gestation) were mixed with standard commercial products, and osmolalities were quantified. RESULTS: HMF significantly increased the micronutrient content and osmolality of EHM. Osmolalities were 291 +/- 6 mOsm/kg (mean +/- SD) for unsupplemented milk, and 505 +/- 5 and 315 +/- 19 mOsm/kg after supplementation to 24 kcal/oz using 2 current U.S. Liquid EHM fortifiers. When using powdered infant formulas to further increase the caloric content of fortified EHM >24 kcal/oz, osmolalities increased by 10.5-23.0 mOsm/kg for each additional kcal/oz. The use of powdered formulas alone (without HMF) increased osmolality without comparable increases in nutrient content. Refrigeration for 24 hours did not affect osmolalites. CONCLUSION: Our finding that several common feeding formulations exceed 450 mOsm/kg, and the lack of evidence of adverse effect, raise the question of whether current maximum osmolality guidelines should be reevaluated to enable optimal nutrition for infants in neonatal intensive care. PMID- 30452093 TI - Investigation of Structure and Dynamics in a Photochromic Molecular Crystal by NMR Crystallography. AB - A photochromic anil, N-(3,5-di-t-butylsalicylidene)-4-amino-pyridine, has been studied by single-crystal X-ray diffraction, multinuclear magic-angle spinning NMR and first-principles density functional theory (DFT) calculations. Interpretation of the solid-state NMR data on the basis of calculated chemical shifts confirms the structure is primarily composed of molecules in the ground state enol tautomer, while thermally-activated cis-keto and photoisomerised trans keto states exist as low-level defects with populations that are too low to detect experimentally. Variable temperature 13 C NMR data reveals evidence for solid-state dynamics which is found to be associated with fast rotational motion of t-butyl groups and 180 degrees flips of the pyridine ring, contrasting the time-averaged structure obtained by X-ray diffraction. Comparison of calculated chemical shifts for the full crystal structure and an isolated molecule also reveals evidence for an intermolecular hydrogen-bond involving the pyridine ring and an adjacent imine carbon which facilitates the flipping motion. The DFT calculations also reveal that the molecular conformation in the crystal structure is very close to the energetic minimum for an isolated molecule, indicating that the ring dynamics arise as a result of considerable steric freedom of the pyridine ring and which also allows the molecule to adopt a favourable conformation for photochromism. PMID- 30452094 TI - Protein Provision in Critically Ill Adults Requiring Enteral Nutrition: Are Guidelines Being Met? AB - BACKGROUND: In a previous audit, 81% of enteral protein prescriptions failed to meet protein guidelines. To address this, a very high-protein enteral formula and protein supplements were introduced, and protein prescriptions were adjusted to account for nonnutrition energy sources displacing enteral formula. This follow up audit compared protein provision in critically ill adults requiring exclusive enteral nutrition (EN), first, with local and international guidelines, and second, after changes to practice, with the previous audit in the same intensive care unit (ICU). METHODS: Data were collected from 106 adults consecutively admitted to the ICU of a U.K. tertiary hospital and requiring exclusive EN >=3 days. Protein targets based on local guidelines (1.25, 1.5, or 2.0 g/kg/d), nutrition prescription, and delivery were recorded for 24 hours between days 1-3, 5-7, 8-10, and 18-20 post-ICU admission. RESULTS: The proportion of day 1-3 protein prescriptions meeting protein targets increased from 19% in 2015 to 69% in 2017 (P < .0005, phi = 0.50). The median percentage of protein target delivered was lower than prescribed (79% vs 103%; (P < .0005; r = 0.53) and EN delivery only met the target of 22% of patients. The proportion of protein prescriptions meeting protein targets was similar for days 1-3 (69%), 5-7 (71%), and 8-10 (68%), but increased slightly by days 18-20 (74%). The proportion of patients for which EN delivery met protein targets increased with the number of days post-ICU admission (22%, 26%, 37%, and 53% for days 1-3, 5-7, 8-10, and 18 20, respectively). CONCLUSION: The proportion of protein prescriptions meeting guideline targets was higher after changes to practice. PMID- 30452095 TI - Methyl sulfates as methoxy isotopic reference materials for delta13 C and delta 2 H measurements. AB - RATIONALE: Stable hydrogen and carbon isotope ratios of methoxy groups (OCH3 ) of plant organic matter have many potential applications in biogeochemical, atmospheric and food research. So far, most of the analyses of plant methoxy groups by isotope ratio mass spectrometry have employed liquid iodomethane (CH3 I) as the reference material to normalise stable isotope measurements of these moieties to isotope-delta scales. However, comparisons of measurements of stable hydrogen and carbon isotopes of plant methoxy groups are still hindered by the lack of suitable reference materials. METHODS: We have investigated two methyl sulfate salts (HUBG1 and HUBG2), which exclusively contain carbon and hydrogen from one methoxy group, for their suitability as methoxy reference materials. Firstl, the stable hydrogen and carbon isotope values of the bulk compounds were calibrated against international reference substances by high temperature conversion- and elemental analyser isotope ratio mass spectrometry (HTC- and EA IRMS). In a second step these values were compared with values obtained by measurements using gas chromatography isotope ratio mass spectrometry (GC-IRMS) where prior to analysis the methoxy groups were converted to gaseous iodomethane. RESULTS: The 2 H- and 13 C isotopic abundances of HUBG1 measured by HTC- and EA IRMS and expressed as delta-values on the usual international scales are -144.5+/ 1.2 mUr (n=30) and -50.31+/-0.16 mUr (n=14), respectively. For HUBG2 we obtained 102.0+/-1.3 mUr (n=32) and +1.60+/-0.12 mUr (n=16). Furthermore, the values obtained by GC/IRMS were in good agreement with the HTC- and EA-IRMS values CONCLUSIONS: We suggest that both methyl sulfates are suitable reference materials for normalization of isotope measurements of carbon of plant methoxy groups to isotope-delta scales and for inter-laboratory calibration. For stable hydrogen isotope measurements we suggest that next to HUBG1 and HUBG2 additional reference materials are required to cover the full range of plant methoxy groups reported so far. PMID- 30452096 TI - Employing a Nutrition Nurse in Neonatal Intensive Care Unit Improved Nutrition and Growth Outcomes in Preterm Neonates. AB - BACKGROUND: Nutrition nurses are clinical nurse specialists with knowledge and experience in nutrition support. We aimed to investigate the nutrition and growth outcomes after employment of a nutrition nurse in our level III neonatal intensive care unit (NICU). METHODS: A retrospective cohort study including preterm neonates < 34 weeks and < 2000 g were conducted. Nutrition and growth outcomes of infants in pre-nutrition-nurse and post-nutrition-nurse periods were compared. Primary outcome was presence of postnatal growth retardation (PGR) at term-equivalent age (body weight < 10 percentile at 40 weeks postmenstrual age). RESULTS: Infants in pre-nutrition-nurse (n = 38) and post-nutrition-nurse (n = 40) periods were similar with regard to gestational age, birth weight, gender, and perinatal characteristics. The initiation of parenteral nutrition after admission to NICU (30.8 +/- 24.1 vs 6.7 +/- 7.6 hours, P < 0,001) and attainment of full enteral feedings (27.3 +/-18.1 vs 18.7 +/- 11.3 days, P = 0.034) were earlier in post-nutrition-nurse period. First feeds were more commonly started with breast milk (29% vs 75%, P < 0.001); breastfeeding was more common at discharge (79% vs 95%, P = 0.045) and longer in duration (6.1 +/- 7.3 vs 8.4 +/- 6.3 months, P = 0.008) in post-nutrition-nurse period. Primary outcome PGR at term-equivalent age was lower in post-nutrition-nurse period (57.9% vs 27.5%, P = 0.007). CONCLUSION: Employing a nutrition nurse improved quality of nutrition support, increased breastfeeding, and decreased PGR in preterm neonates. Further prospective evaluation of outcomes in the presence of a nutrition nurse is needed to generalize these findings to other NICUs. PMID- 30452097 TI - Inhibition of the Oxygen Sensor PHD2 Enhances Tissue-Engineered Endochondral Bone Formation. AB - Tissue engineering holds great promise for bone regenerative medicine, but clinical translation remains challenging. An important factor is the low cell survival after implantation, primarily caused by the lack of functional vasculature at the bone defect. Interestingly, bone development and repair initiate predominantly via an avascular cartilage template, indicating that chondrocytes are adapted to limited vascularization. Given these advantageous properties of chondrocytes, we questioned whether tissue-engineered cartilage intermediates implanted ectopically in mice are able to form bone, even when the volume size increases. Here, we show that endochondral ossification proceeds efficiently when implant size is limited (<=30 mm3 ), but chondrogenesis and matrix synthesis are impaired in the center of larger implants, leading to a fibrotic core. Increasing the level of angiogenic growth factors does not improve this outcome, because this strategy enhances peripheral bone formation, but disrupts the conversion of cartilage into bone in the center, resulting in a fibrotic core, even in small implants. On the other hand, activation of hypoxia signaling in cells before implantation stimulates chondrogenesis and matrix production, which culminates in enhanced bone formation throughout the entire implant. Together, our results show that induction of angiogenesis alone may lead to adverse effects during endochondral bone repair, whereas activation of hypoxia signaling represents a superior therapeutic strategy to improve endochondral bone regeneration in large tissue-engineered implants. (c) 2018 American Society for Bone and Mineral Research. PMID- 30452098 TI - Effect of glycerol on reconstructed human oral mucosa. AB - The majority of severely ill patients experience dry mouth. For institutionalized patients, this condition is commonly treated using glycerol as a lubricant. However, because of its possibly desiccating effect, some countries do not advocate the use of glycerol. This study aimed to investigate dose-dependent effects of glycerol on homeostasis and tissue integrity of in vitro-reconstructed normal human buccal mucosa (RNHBM). Primary keratinocytes and fibroblasts were isolated and expanded from biopsies of mucosa from eight healthy volunteers. Ninety-six samples of RNHBM were prepared and exposed for 24 h to 17%, 42.5%, or 85% glycerol, or to distilled H2 O (control). Sections were stained with haematoxylin and eosin (H&E) to evaluate epithelial thickness or used for immunohistochemistry to measure expression of Ki67 (proliferation), cleaved caspase-3 (apoptosis), and E-cadherin (tissue-integrity). Positive cells and cell layers, as detected by immunohistochemistry, were counted. Epithelial thickness, proliferation, and apoptosis were significantly increased by exposure to 42.5% and 85% glycerol. No significant differences in apoptosis or proliferation were found between controls and RNHBM exposed to 17% glycerol. E-cadherin expression was not significantly affected by exposure to any of the concentrations of glycerol tested. This study shows that glycerol affects tissue homeostasis, but not tissue integrity, of RNHBM at glycerol concentrations above 42.5%. PMID- 30452099 TI - Prevalence, Characteristics, and Outcome of Cow's Milk Protein Allergy in Chinese Infants: A Population-Based Survey. AB - BACKGROUND: Cow's milk protein allergy (CMPA) is commonly seen in children. There have been no reports of the true prevalence of CMPA in Chinese infants. The aim of this population-based study is to determine the prevalence, clinical characteristics, and outcome of CMPA in Chinese infants. METHODS: We carried out a prospective survey in 7 participating hospitals throughout southern China. We included infants <=12 months of age during the survey. For those suspected of CMPA, oral food challenge with cow's milk protein (CMP) was performed. A follow up telephone interview was conducted at 12 months after the diagnosis to assess the clinical outcome of CMPA. RESULTS: A total of 9910 questionnaire surveys were distributed and 7364 (74.3%) were returned. The eligible survey number of surveys was 6768 (91.9%). A total of 182 infants was confirmed with CMPA, including 13 with anaphylactic reactions, 28 with clinical symptoms and serum immunoglobulin E (sIgE) >3.5 IU/mL, and 141 with positive CMP challenge test. The prevalence of CMPA was 2.69%. Infants with confirmed CMPA had significantly stronger family history of either 1 or both parents with food allergy, higher Cesarean section rate, and lower rate of breastfeeding, compared with those without CMPA. At 12 month telephone follow-up of 176 CMPA infants, 136 infants (77.3%) had become tolerant to CMP. CONCLUSIONS: The prevalence of CMPA was 2.69%. CMPA infants had a strong family history of food allergy and atopy. Both Cesarean delivery and formula feeding were risk factors for CMPA. At 12-month follow-up, the majority of CMPA infants had become tolerant to CMP. PMID- 30452100 TI - Remarkable Aggregation Behavior of a Six-membered Cyclic Frustrated Phosphane/Borane Lewis Pair: Formation of a Supramolecular Cyclooctameric Macrocyclic Ring System. AB - The six-membered cyclic frustrated phosphane/borane Lewis pair 7 was liberated from its HB(C6F5)2 adduct 6 by treatment with vinylcyclohexane. The system 7 is an active FLP that undergoes cycloaddition reactions with suitable pi-reagents and it splits dihydrogen. At r.t. in solution compound 7 is a monomer, however, in the crystal and in solution at low temperature it aggregates to a thermodynamically favored supramolecular macrocyclic cyclooctamer. PMID- 30452101 TI - Diazotrophic community and associated dinitrogen fixation within the temperate coral Oculina patagonica. AB - Dinitrogen (N2 ) fixing bacteria (diazotrophs) are an important source of new nitrogen in oligotrophic environments and represent stable members of the microbiome in tropical corals, while information on corals from temperate oligotrophic regions is lacking. Therefore, this study provides new insights into the diversity and activity of diazotrophs associated with the temperate coral Oculina patagonica from the Mediterranean Sea by combining metabarcoding sequencing of amplicons of both the 16S rRNA and nifH genes and 15 N2 stable isotope tracer analysis to assess diazotroph-derived nitrogen (DDN) assimilation by the coral. Results show that the diazotrophic community of O. patagonica is dominated by autotrophic bacteria (i.e. Cyanobacteria and Chlorobia). The majority of DDN was assimilated into the tissue and skeletal matrix, and DDN assimilation significantly increased in bleached corals. Thus, diazotrophs may constitute an additional nitrogen source for the coral host, when nutrient exchange with Symbiodinium is disrupted (e.g. bleaching) and external food supply is limited (e.g. oligotrophic summer season). Furthermore, we hypothesize that DDN can facilitate the fast proliferation of endolithic algae, which provide an alternative carbon source for bleached O. patagonica. Overall, O. patagonica could serve as a good model for investigating the importance of diazotrophs in coral recovery from bleaching. This article is protected by copyright. All rights reserved. PMID- 30452102 TI - Genomic analysis of the mesophilic Thermotogae genus Mesotoga reveals phylogeographic structure and genomic determinants of its distinct metabolism. AB - The genus Mesotoga, the only described mesophilic Thermotogae lineage, is common in mesothermic anaerobic hydrocarbon-rich environments. Besides mesophily, Mesotoga displays lineage-specific phenotypes, such as no or little H2 production and dependence on sulfur-compound reduction, which may influence its ecological role. We used comparative genomics of 18 Mesotoga strains (pairwise 16S rRNA identity > 99%) and a transcriptome of M. prima to investigate how life at moderate temperatures affects phylogeography and to interrogate the genomic features of its lineage-specific metabolism. We propose that Mesotoga accomplish H2 oxidation and thiosulfate reduction using a sulfide dehydrogenase and a hydrogenase-complex and that a pyruvate:ferredoxin oxidoreductase acquired from Clostridia is responsible for oxidizing acetate. Phylogenetic analysis revealed three distinct Mesotoga lineages (89.6-99.9% average nucleotide identity [ANI] within lineages, 79.3-87.6% ANI between lineages) having different geographic distribution patterns and high levels of intra-lineage recombination but little geneflow between lineages. Including data from metagenomes, phylogeographic patterns suggest that geographical separation historically has been more important for Mesotoga than hyperthermophilic Thermotoga and we hypothesize that distribution of Mesotoga is constrained by their anaerobic lifestyle. Our data also suggest that recent anthropogenic activities and environments (e.g., wastewater treatment, oil exploration) have expanded Mesotoga habitats and dispersal capabilities. This article is protected by copyright. All rights reserved. PMID- 30452103 TI - Digging into the Sequential Space of Thiolactone Precision Polymers: A Combinatorial Strategy to Identify Functional Domains. AB - Functional sequences of precision polymers based on thiolactone/Michael chemistry are identified from a large one-bead one-compound library. Single bead readout by MALDI-TOF MS/MS identifies sequences that preferentially host m-THPC as second generation photosensitizer drug. The corresponding Tla/Michael-PEG conjugates render m-THPC available in solution and drug payload as well as drug release kinetics can be fine-tuned by the precision segment. PMID- 30452104 TI - A Z-scheme inspired photobioelectrochemical H2O/O2 cell with 1V open-circuit voltage combining photosystem II and PbS quantum dots. AB - A biohybrid photobioanode mimicking the Z-Scheme has been developed by functional integration of photosystem II (PSII) and PbS quantum dots (QDs) within an inverse opal TiO2 architecture giving rise to a rather negative water oxidation potential of about -0.55 V vs. Ag/AgCl, 1M KCl at neutral pH. The electrical linkage between both light-sensitive entities has been established via an Os-complex modified redox polymer (POs) allowing the formation of a multi-step electron transfer chain under illumination starting with the photo-activated water oxidation at PSII followed by an electron transfer from PSII via POs to the photo excited QDs and finally to the TiO2 electrode. The photobioanode has been coupled to a novel transparent, inverse opal ATO cathode modified with an O2 reducing bilirubin oxidase for the construction of a H2O/O2 photobioelectrochemical cell reaching a high open-circuit voltage of about 1 V. PMID- 30452105 TI - A report of affective switching associated with ketamine: The case of ketamine induced mania is not closed. AB - Sub-anesthetic doses of ketamine (0.3 mg/kg/hr or less) are increasingly being used for depression and chronic pain, but carry a risk of manic induction. Patients who may receive ketamine should be screened for a bipolar diathesis prior to treatment. Olanzapine and lorazepam appear to be effective in treating mania associated with ketamine. This article is protected by copyright. All rights reserved. PMID- 30452106 TI - Efficient Cytoplasmic Delivery of Antisense Probes Assisted by Cyclized Peptide mediated Photo-induced Endosomal Escape. AB - Intracellular delivery and endosomal release of antisense oligonucleotides remain a significant challenge in the development of gene-targeted therapeutics. Previously, non-covalently cyclized TAT peptide (Cyc-TAT), in which the final ring-closing step is accomplished by hybridization of two short complementary gammaPNA segments, has been proven more efficient than its linear analogues to enter cells. Since Cyc-TAT also readily accommodates a binding site, i.e., an overhanging gammaPNA sequence, for co-delivery of functional nucleic acid probes into cells, herein we demonstrated that the overhang-Cyc-TAT penetrated into A549 cells, carrying an anti-telomerase gammaPNA, which specifically reduced telomerase activity over 97%. In addition, we firstly reported that the cyclized TAT(FAM) can much more efficiently escape endosomes than the linear TAT(FAM) by LED illumination (490 nm). Based on this observation, the endosomal release of overhang-Cyc-TAT(FAM)/anti-telomerase gammaPNA complex can be greatly enhanced by photo-activation, shortening the cell treatment time from 60 h to 3 h with the same high efficiency in inhibiting telomerase activity inside A549 cells. PMID- 30452107 TI - Metal-Ligand Cooperative Synthesis of Benzonitrile via Electrochemical Reduction and Photolytic Splitting of Dinitrogen. AB - Thermal nitrogen fixation relies on strong reductants to overcome the extraordinarily large N-N bond energy. Photochemical strategies that drive N2 fixation are scarcely developed. Here, the synthesis of a dinuclear N2-bridged complex is presented upon reduction of a rhenium(III) pincer platform. Photochemical splitting into terminal nitride complexes is triggered by visible light. Clean N-transfer with benzoyl chloride to free benzamide and benzonitrile is enabled by cooperative 2H+/2e- transfer of the pincer ligand. A three-step cycle is demonstrated for N2 to nitrile fixation that relies on electrochemical reduction, photochemical N2-splitting and thermal N-transfer. PMID- 30452108 TI - Controlled Construction of Cyclic d / l Peptide Nanorods. AB - Cyclic d / l peptides (CPs) assemble spontaneously via backbone H-bonding to form extended nanostructures. These modular materials have great potential as versatile bionanomaterials. However, the useful development of CP nanomaterials requires practical methods to direct and control their assembly. In this work, we present novel, heterogeneous, covalently linked CP tetramers that achieve local control over the CP subunit order and composition through coupling of amino acid side-chains using copper-activated azide-alkyne cycloaddition and disulfide bond formation. Cryo-transmission electron microscopy revealed the formation of highly ordered, fibrous nanostructures, while NMR studies showed that these systems have strong intramolecular H-bonding in solution. The introduction of inter-CP tethers is expected to enable the development of complex nanomaterials with controllable chemical properties, facilitating the development of precisely functionalized or "decorated" peptide nanostructures. PMID- 30452109 TI - Building from Ga-Porphyrins: Synthesis of Ga-Acetylide Complexes Using Acetylenes and Polyynes. AB - Multidimensional, conjugated building blocks have been formed through the axial coordination of polyynes to the central Ga atom of tetraarylporphyrins. Electron deficient pentafluorophenyl substituents in the meso-positions provide more stable sigma-acetylide complexes to Ga than analogous structures with tert butylphenyl groups. Mono-, di-, and triynes have been used, including a pyridyl endcapped diyne that allows for formation of porphyrin triads through coordination of the pyridyl ligand to a Ru porphyrin. PMID- 30452111 TI - Orthologous peramine and pyrrolopyrazine-producing biosynthetic gene clusters in Metarhizium rileyi, Metarhizium majus and Cladonia grayi. AB - Peramine is a non-ribosomal peptide-derived pyrrolopyrazine (PPZ)-containing molecule with anti-insect properties. Peramine is known to be produced by fungi from genus Epichloe, which form mutualistic endophytic associations with cool season grass hosts. Peramine biosynthesis has been proposed to require only the two-module non-ribosomal peptide synthetase (NRPS) peramine synthetase (PerA), which is encoded by the 8.3 kb gene perA, though this has not been conclusively proven. Until recently, both peramine and perA were thought to be exclusive to fungi of genus Epichloe; however, a putative perA homolog was recently identified in the genome of the insect-pathogenic fungus Metarhizium rileyi. We use a heterologous expression system and a hydrophilic interaction chromatography-based analysis method to confirm that PerA is the only pathway-specific protein required for peramine biosynthesis. The perA homolog from M. rileyi (MR_perA) is shown to encode a functional peramine synthetase, establishing a precedent for distribution of perA orthologs beyond genus Epichloe, with perA being part of a larger seven-gene PPZ cluster in M. rileyi, Metarhizium majus and the stalked-cup lichen fungus Cladonia grayi. These PPZ genes encode proteins predicted to derivatise peramine into more complex PPZ metabolites, with the orphaned perA gene of Epichloe spp. representing an example of reductive evolution. This article is protected by copyright. All rights reserved. PMID- 30452110 TI - Probing membrane protein insertion into lipid bilayers by solid-state NMR. AB - Determination of the environment surrounding a protein is often key to understanding function, and can also be used to infer structural properties of the protein itself. Using proton-detected solid-state NMR, we show that reduced spin diffusion within the protein under conditions of fast magic-angle spinning, high magnetic field, and sample deuteration allows the efficient measurement of site-specific exposure to mobile water and lipids. We demonstrate this site specificity on two membrane proteins, the human voltage dependent anion channel, and the alkane transporter AlkL from Pseudomonas putida. Transfer from lipids is observed selectively in the membrane spanning region, and an average lipid protein transfer rate of 6 s-1 was determined for residues protected from exchange. Transfer within the protein, as tracked in the 15N-1H 2D plane, was estimated from initial rates and found to be in a similar range of about 8 to 15 s-1 for several resolved residues, explaining the site specificity. PMID- 30452112 TI - Computational prediction of the 1H and 13C NMR chemical shifts for protonated alkylpyrroles - electron correlation and not solvation is the salvation. AB - Prediction of chemical shifts in organic cations is known to be a challenge. In this article we meet this challenge for alpha-protonated alkylpyrroles, a class of compounds not yet studied in this context, and present a combined experimental and theoretical study of the 13C and 1H chemical shifts in three selected pyrroles. We have investigated the importance of the solvation model, basis set and quantum chemical method with the goal of developing a simple computational protocol, which allows prediction of 13C and 1H chemical shifts with a sufficient accuracy for identification of such compounds in mixtures. We find that density functional theory with the B3LYP functional is not sufficient for reproducing all 13C chemical shifts, while already the simplest correlated wave function model, Moller-Plesset perturbation theory (MP2), leads to almost perfect agreement with the experimental data. Treatment of solvent effects generally improves somewhat the agreement with experiment and can in most cases be accomplished by a simple polarizable continuum model. The only exception is the N-H proton, which requires inclusion of explicit solvent molecules in the calculation. PMID- 30452113 TI - In vivo evolution of viral virulence: switching of deformed wing virus between hosts results in virulence changes and sequence shifts. AB - The health of the Western honey bee is threatened by a global epidemic of deformed wing virus (DWV) infections driven by the ectoparasitic mite Varroa destructor acting as mechanical and biological virus vector. Three different variants of DWV, DWV-A, -B and -C exist. Virulence differences between these variants and their relation to V. destructor are still controversially discussed. We performed laboratory experiments to analyze the virulence of DWV directly isolated from crippled bees (DWVP0 ) or after one additional passage in bee pupae (DWVP1 ). We demonstrated that DWVP0 was more virulent than DWVP1 for pupae, when pupal mortality was taken as virulence marker, and for adult bees, when neurotropism and cognitive impairment were taken as virulence markers. Phylogenetic analysis supported that DWV exists as quasispecies and showed that DWVP0 clustered with DWV-B and DWVP1 with DWV-A when the phylogeny was based on the master sequences of the RNA-dependent RNA polymerase but not so when it was based on the VP3 region master sequences. We propose that switching of DWV between the bee and the mite host is accompanied by changes in viral sequence, tissue tropism and virulence and that the RNA-dependent RNA polymerase is involved in determining host range and virulence. PMID- 30452114 TI - Synthesis and Derivatization of 1,1-[18 F]Difluorinated Alkenes. AB - A general method for the synthesis of 1,1-[18 F]difluorinated alkenes from [18 F]fluoride is reported. This transformation is highly regioselective giving the desired 18 F-fluoroalkenes with radiochemical purities of up to 77 % within 20 minutes and a molar activity (Am ) of 1 GBq MUmol-1 . The transformations are operationally simple to perform and were readily translated onto a commercial automated synthesis unit. The resultant 1,1-[18 F]difluorinated alkene motif is prevalent in numerous drug molecules, and this is the first general method to synthesize this motif with fluorine-18. 18 F-fluorinated alkenes are excellent building blocks and participate in a number of post-labeling transformations to access a range of 18 F-perfluorinated functional groups that have never before been radiolabeled with non-carrier-added [18 F]fluoride. This method considerably expands the range of 18 F-motifs accessible to radiochemists. PMID- 30452115 TI - Community structural differences shape microbial responses to high molecular weight organic matter. AB - The extent to which differences in microbial community structure result in variations in organic matter (OM) degradation is not well understood. Here, we tested the hypothesis that distinct marine microbial communities from North Atlantic surface and bottom waters would exhibit varying compositional succession and functional shifts in response to the same pool of complex high molecular weight (HMW-OM). We also hypothesized that microbial communities would produce a broader spectrum of enzymes upon exposure to HMW-OM, indicating a greater potential to degrade these compounds than reflected by initial enzymatic activities. Our results show that community succession in amended mesocosms was congruent with cell growth, increased bacterial production, and most notably, with substantial shifts in enzymatic activities. In all amended mesocosms, closely-related taxa that were initially rare became dominant at time frames during which a broader spectrum of active enzymes were detected compared to initial timepoints, indicating a similar response among different communities. However, succession on the whole-community level, and the rates, spectra, and progression of enzymatic activities, reveal robust differences among distinct communities from discrete water masses. These results underscore the crucial role of rare bacterial taxa in ocean carbon cycling and the importance of bacterial community structure for HMW-OM degradation. This article is protected by copyright. All rights reserved. PMID- 30452116 TI - Comparative metabolomics reveals defense-related modification of citrinin by Penicillium citrinum within a synthetic Penicillium-Pseudomonas community. AB - Co-occurring microorganisms have been proved to influence the performance of each other by metabolic means in nature. Here we generated a synthetic fungal bacterial community comprising Penicillium citrinum and Pseudomonas aeruginosa employing the previously described membrane-separated co-culture device. By applying a newly-designed molecular networking routine, new citrinin-related metabolites induced by the fungal-bacterial cross-talk were unveiled in trace amounts. A mechanically-cycled co-culture setup with external pumping forces accelerating the chemically interspecies communication was then developed to boost the production of cross-talk-induced metabolites. Multivariate data analysis combined with molecular networking revealed the accumulation of a pair of co-culture-induced molecules whose productions were positively correlated to the exchange rate in the new co-cultures, facilitating the discovery of the previously undescribed antibiotic citrinolide with a novel skeleton. This highly oxidized citrinin adduct showed significantly enhanced antibiotic property against the partner strain P. aeruginosa than its precursor citrinin, suggesting a role in the microbial competition. Thus we propose competitive-advantage oriented structural modification driven by microbial defense response mechanism in the interspecies cross-talk might be a promising approach in the search for novel antibiotics. Besides, this study highlights the utility of MS-based metabolomics as an effective tool in the direct biochemical analysis of the community metabolism. This article is protected by copyright. All rights reserved. PMID- 30452118 TI - Investigations on the mechanism of progesterone in inhibiting endometrial cancer cell cycle and viability via regulation of long noncoding RNA NEAT1/microRNA-146b 5p mediated Wnt/beta-catenin signaling. AB - Progesterone is often used to protect the endometrium and prevent endometrial cancer. An intensive study on its molecular mechanism in endometrial cancer would contribute to the development of more promising therapies. Relevant lncRNAs and mRNAs expression data in endometrial cancer cell line Ishikawa pretreated and post-treated with progesterone were derived from Gene Expression Omnibus (accession no. GSE29435), and then we analyzed long noncoding RNAs and mRNAs with differential expressions in two different conditions. The Cytoscape software, TargetScan, miRanda, and Human microRNA Disease Database (HMDD) websites were employed. Gene set enrichment analysis (GSEA) was used to determine related Kyoto Encyclopedia of Genes and Genomes pathways alteration in Ishikawa cells treated with progesterone. In addition to bioinformatics analysis, Reverse Transcription Polymerase Chain Reaction (RT-PCR), Western blot, and dual-luciferase reporter assays were performed. The impact of progesterone on cell propagation and cell cycle was testified by colony formation and flow cytometry analysis. LncRNA nuclear enriched abundant transcript 1 (NEAT1) was the most significantly downregulated lncRNA in endometrial cancer cells treated with progesterone. Lymphoid enhancing factor 1 (LEF1) was positively associated with NEAT1, and eventually hsa_miR-146b-5p was validated to target both LEF1 and NEAT1. Wnt/beta catenin signaling pathway was identified to involve in endometrial cancer. NEAT1 or LEF1 was overexpressed in endometrial cancer cells while downregulated following post-treatment with progesterone. Conversely, miR-146b-5p was notably decreased in Ishikawa cells while upregulated after treatment with progesterone. Downstream gene c-myc or MMP9 regulated by upstream gene LEF1 in Wnt/beta-catenin signaling pathway was remarkably increased in Ishikawa cells and positively related with NEAT1. Progesterone inhibited cell cycle and viability through regulating NEAT1/miR-146b-5p axis via Wnt/beta-catenin signaling pathway. Progesterone exerted suppressive influence on endometrial cancer progression via regulation of lncRNA NEAT1/miR-146b-5p-mediated Wnt/beta-catenin signaling pathway, which might reveal new strategies for developing more effective therapeutics. (c) 2018 IUBMB Life, :1-12, 2018. PMID- 30452119 TI - Authors' Reply to Diagnostic Pitfalls and Treatment Challenges in Interstitial Pneumonia with Autoimmune Features. AB - We thank Dr. Novikov and colleagues for their thoughtful comments on our recent review. We agree that the ATS/ERS classification criteria for IPAF will most certainly need to be reviewed, revised, and validated moving forward. We also agree whole-heartedly with the critical collaboration between rheumatologists and pulmonologists in the management of these patients. In our ongoing prospective longitudinal cohort, >93% of patients are co-managed by rheumatology and pulmonology. We strongly advocate this approach worldwide both to provide accurate classification/diagnosis at the time of presentation and to monitor for the emergence of a clearly defined connective tissue disease (CTD). This article is protected by copyright. All rights reserved. PMID- 30452117 TI - Angiotensin II confers resistance to apoptosis in cardiac myofibroblasts through the AT1/ERK1/2/RSK1 pathway. AB - Myofibroblast apoptosis is essential for normal resolution of wound repair, including cardiac infarction repair. Impaired cardiac myofibroblast (CMF) apoptosis is associated with excessive extracellular matrix (ECM) deposition, which could be responsible for pathological cardiac fibrosis. Conventionally, angiotensin II (Ang II), a soluble peptide, is implicated in fibrogenesis because it induces cardiac fibroblast (CFb) proliferation, differentiation, and collagen synthesis. However, the role of Ang II in regulation of CMF survival and apoptosis has not been fully clarified. In this report, we cultured neonatal rat CFbs, which transform into CMFs after passage 3 (6-8 days), and investigated the effects of Ang II on CMFs challenged by TNF-alpha combined with cycloheximide and the underlying mechanisms. Here, we show that Ang II rapidly activates MAPKs but not AKT in CMFs and confers apoptosis resistance, as evidenced by the inhibition of caspase-3 cleavage, early apoptotic cells and late apoptotic cells. This inhibitory effect of Ang II was reversed by blockade of AT1 or inactivation of ERK1/2 or RSK1 but not AT2, indicating that activation of the prosurvival AT1/ERK1/2/RSK1 signaling pathway mediates apoptosis resistance. TGF-beta, a latent fibrotic factor, was found to have no relation to Ang II-induced apoptosis resistance in our study. Furthermore, Ang II-mediated apoptosis resistance, which was conferred by activation of the AT1/ERK1/2/RSK1 signaling pathway, was also confirmed in human adult ventricular cardiac myofibroblasts. Collectively, our findings suggest a novel profibrotic mechanism of Ang II in which it promotes myofibroblast resistance to apoptosis in addition to classical mechanisms, providing a potential novel therapeutic approach by targeting prosurvival signaling pathways. (c) 2018 IUBMB Life, 2018. PMID- 30452120 TI - Antineoplastic constituents from the chemical diversified extract of Radix puerariae. AB - To enhance the structural diversity of isoflavonoids and provide more derivatives for the biological screening, a semisynthetic mixture was generated by diversification of the crude extract of Radix puerariae through the chemical reaction with hydrazine hydrate. Thirteen derivatives (1-13) were isolated from the semisynthetic mixture, and all those structures were identified by spectroscopic methods in combination with X-ray crystallographic analysis, including eleven 3,4-diarylpyrazoles (1-11) and two 5-phenyl-6-benzyldihy dropyridazinones (12 and 13). Among them, nine compounds (5-13) were new derivatives. All the new compounds were evaluated on the inhibitory activities against the prostate cancer cell lines LNCaP and PC3. Compounds 12 and 13 were found to exhibit much more potent inhibitory activities against the androgen dependent LNCaP cells than the androgen independent PC3 cells. Rapid synthesis of new 3,4-diarylpyrazoles and two 5-phenyl-6-benzyldihydropyridazinones with significant biological activity highlights the great potential of one-pot combinatorial modification for the diversification of natural products. PMID- 30452121 TI - High-affinity L-malate transporter DcuE of Actinobacillus succinogenes catalyses reversible exchange of C4 -dicarboxylates. AB - Actinobacillus succinogenes is a natural succinate producer, which is the result of fumarate respiration. Succinate production from anaerobic growth with C4 dicarboxylates requires transporters catalysing uptake and efflux of C4 dicarboxylates. Transporter Asuc_1999 (DcuE) found in A. succinogenes belongs to the Dcu family and was considered the main transporter for fumarate respiration. However, deletion of dcuE affected L-malate uptake of A. succinogenes rather than fumarate uptake. DcuE complemented anaerobic growth of Escherichia coli on L malate or fumarate; thus, the transporter was characterised in E. coli heterologously. Time-dependent uptake and competitive inhibition assays demonstrated that L-malate is the most preferred substrate for uptake by DcuE. The Vmax of DcuE for L-malate was 20.04 MUmol/gDW?min with Km of 57 MUM. The Vmax for L-malate was comparable to that for fumarate, whereas the Km for L-malate was 8 times lower than that for fumarate. The catalytic efficiency of DcuE for L malate was 7.3-fold higher than that for fumarate, showing high efficiency and high affinity for L-malate. Furthermore, DcuE catalysed the reversible exchange of three C4 -dicarboxylates-L-malate, fumarate, and succinate-but the preferred substrate for uptake was L-malate. Under physiological conditions, the C4 dicarboxylates were reduced to succinate. Therefore, DcuE is proposed as the L malate/succinate antiporter in A. succinogenes. This article is protected by copyright. All rights reserved. PMID- 30452122 TI - Inhibition of arachidonate 15-lipoxygenase reduces the epithelial-mesenchymal transition in eosinophilic chronic rhinosinusitis with nasal polyps. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) is a distinguishing characteristic of chronic rhinosinusitis with nasal polyps (CRSwNP). The underlying mechanism remains largely unknown. Arachidonate 15-lipoxygenase (ALOX15), an enzyme involved in arachidonic acid metabolism, has been reported to cause airway epithelial injury and thus may further promote the EMT. The aim of this study was to evaluate the role of ALOX15 during the EMT process in CRSwNP. METHODS: A total of 54 samples were obtained, including 10 from healthy control, 16 from non-eosinophilic CRSwNP, and 28 from eosinophilic CRSwNP. Hematoxylin and eosin staining was performed to determine the basement membrane (BM) thickness. The concentration of molecules mediating remodeling was assayed by Luminex. The messenger RNA (mRNA) and protein levels of target genes were measured by quantitative real-time polymerase chain reaction (PCR) and Western blotting. RESULTS: EMT was enhanced in eosinophilic CRSwNP compared with the healthy controls and non-eosinophilic CRSwNP infiltrated with lymphocytes and/or plasma cells. The expression pattern of molecules related to remodeling, including matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and transforming growth factor beta (TGF-beta) family members, differed between the subtypes of CRSwNP. The mRNA level of ALOX15 was correlated with the BM thickness and MMP-1 and TGF-beta3 expression. The inhibition of ALOX15 by PD146176 could induce claudin-1, claudin-4, claudin-7, zonula occludens (ZO)-1, ZO-2, E-Cadherin, TIMP-1, and TIMP-3 expressions and reduce the levels of MMP-1 and N-Cadherin in epithelial cells acquired from eosinophilic CRSwNP patients. CONCLUSION: The specific inhibition of ALOX15 could attenuate the EMT, which may provide an alternative method for the treatment of CRSwNP. PMID- 30452123 TI - Improved biocompatibility of profiled sutures through lower macrophages adhesion. AB - The biocompatibility of a textile implant is determined by various parameters, such as material composition and surface chemistry. However, little is known about the influence of geometry of sutures on biocompatibility. To elucidate this factor we focused on geometry-modification resulting in ultrafine polyethylene terephthalate (UFPET) suture and a snowflake like shaped polyvenylidenfluorid (PVDF) suture. Forty-eight rats were divided into two observation periods. In each rat 3 out of 4 sutures (profiled UFPET, snowflake-like profiled PVDF, reference Prolene and Mersilene suture) were randomly placed into the subcutaneous tissue. Rats were euthanized after 7 and 21 days and samples were explanted. Foreign body granuloma was measured and expression of CD68, TUNEL, Ki 67 and Collagen I/III ratio were determined. The profiled (snowflake) suture showed a significantly smaller FBG in comparison to standard sutures (p < 0.001). Both modified sutures showed a significant lower tissue remodeling by Ki-67 and TUNEL expression (p < 0.03). Furthermore, profiled sutures caused a lower inflammatory reaction expressed in a significant lower amount of CD68 positive macrophages after 21 days (p < 0.001). Modifications of suture geometry alter the foreign body granuloma and the inflammatory reaction. Therefore, profiled sutures might be a promising approach to improve biocompatibility of textile mesh prosthesis. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 30452124 TI - A 31 year old man with periostitis deformans. AB - A case of a 31-year-old male was noted to have marked joint swelling and tenderness accompanied by elevated alkaline phosphatase, and florid periostitis on radiographs. The patient was under treatment for fungal infection with voriconazole. Discontinuation of voriconazole resulted in resolution of his symptoms and radiographic findings. Mechanisms for how voriconazole causes periostitis, including information relating to its pharmacologic characteristics and its effects on bone metabolism, are discussed. Increasing our knowledge on voriconazole-related periostitis have the potential to further our understanding of common disorders such as osteoporosis and tap into other therapeutic options for it. This article is protected by copyright. All rights reserved. PMID- 30452125 TI - Quality of recovery in patients undergoing endoscopic sinus surgery after general anesthesia: total intravenous anesthesia vs desflurane anesthesia. AB - BACKGROUND: For sinus surgery, some centers favor total intravenous anesthesia (TIVA) over inhalation anesthesia. However, whether TIVA affects the patient's perceived quality of recovery remains unclear. This study used the Quality of Recovery-40 questionnaire (QoR-40) to compare patient recovery between surgical patients who received TIVA and those who received desflurane (DES) anesthesia. METHODS: Eighty patients (20 to 65 years old) undergoing endoscopic sinus surgery were prospectively enrolled and randomized to either the TIVA (propofol and remifentanil infusion) or DES (desflurane inhalation and remifentanil infusion) group. The QoR-40 was administered before surgery, at 6 hours after surgery, and on postoperative day 1 (POD1). Incidence of nausea and vomiting, remifentanil consumption, blood loss, and pain treatment were recorded. The influence of lesion extent (indexed as Lund-Mackay [LM] score) on recovery quality was also assessed. RESULTS: Forty patients were randomized into the TIVA group, and 40 patients were randomized into the DES group. The QoR-40 score at 6 hours after surgery was significantly higher in the TIVA group compared with the DES group (188.2 vs 182.6, respectively; p = 0.049), indicating a better quality of recovery in the TIVA group. TIVA resulted in less blood loss (p < 0.0001). A high LM score (>=12) was associated with lower QoR-40 scores at 6 hours after surgery (180.2 vs 187.2, p = 0.028) and on POD1 (181.5 vs 190.3, p = 0.003). CONCLUSION: This study shows that the quality of recovery for endoscopic sinus surgery patients was better with TIVA than with desflurane anesthesia. A high LM score was related to poorer recovery quality. PMID- 30452126 TI - Accuracy of diagnosing mantle cell lymphoma and identifying its variants on fine needle aspiration biopsy. AB - BACKGROUND: Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma portending an aggressive clinical course; the blastoid and pleomorphic morphological variants have an even worse prognosis. In addition, patients with classic morphology and a high proliferation index (HPI), also have reduced survival. Although variants have been defined, to the authors' knowledge the ability to detect these subtypes by fine-needle aspiration biopsy (FNAB) has not been described. METHODS: MCL cases diagnosed by lymph node FNAB with concurrent core needle biopsy were reviewed from 146 patients, accounting for 172 specimen pairs. FNAB and core needle biopsy diagnoses were compared to determine concordance rates. Flow cytometric immunophenotype and Ki-67 rates were evaluated. RESULTS: The classic subtype was diagnosed in 58% of cases (99 of 172 pairs) and variant morphology was diagnosed in 42% of cases (73 of 172 pairs) by histology. Twenty nine patients presented with variant morphology whereas 28 underwent transformation. A nontraditional immunophenotype including loss of CD5 or FMC-7 and expression of CD23 and CD10 was found in 44% of variants (29 of 66 variants) and 19% of classic subtypes (18 of 94 classic subtypes) (P = .0008). Ki-67 rates averaged from 56% to 76% for blastoid and pleomorphic cases, 53% to 55% for MCL HPI cases, and 17% to 19% for classic cases. The sensitivity and specificity to detect MCL variants by FNAB were 74% and 93%, respectively. CONCLUSIONS: The accuracy of diagnosing MCL is high when adequate samples for cytomorphology and flow cytometry are obtained. Subtyping variants by cytomorphology alone has challenges, but overall demonstrates high sensitivity and specificity. The performance of Ki-67 on cytology specimens is useful for detecting MCL with HPI. PMID- 30452127 TI - In-office balloon sinus dilation versus medical therapy for recurrent acute rhinosinusitis: a randomized, placebo-controlled study. AB - BACKGROUND: A limited number of studies have demonstrated symptomatic improvement for recurrent acute rhinosinusitis (RARS) patients after endoscopic sinus surgery. In this randomized, controlled study we evaluated 24-week outcomes for balloon sinus dilation (BSD) performed in-office (IO) with medical management (MM) as compared with MM only for RARS patients. METHODS: Adults diagnosed with RARS were randomized to groups with BSD plus MM (n = 29) or MM alone (n = 30). Patients who received MM alone also received a sham BSD-IO procedure to blind them to group assignment. Patients were followed to 48 weeks posttreatment. The primary outcome was the difference between arms in change in Chronic Sinusitis Survey (CSS) score from baseline to 24 weeks. Secondary endpoints included comparisons of Rhinosinusitis Disability Index (RSDI) score, medication usage, medical care visits, and sinus infections. RESULTS: Change in patient-reported quality of life (QOL), as measured by the CSS total score from baseline to 24 weeks, was significantly greater in the BSD plus MM group compared with the MM only group (37.3 +/- 24.4 [n = 26] vs 21.8 +/- 29.0 [n = 27]; p = 0.0424). CONCLUSION: BSD plus MM proved superior to MM alone in enhancing QOL for RARS patients. BSD plus MM should be considered as a viable treatment option for properly diagnosed RARS patients. PMID- 30452128 TI - Apples and oranges Our drug pricing system does not compute. PMID- 30452129 TI - Precise prescriptions Mayo uses pharmacogenomics to help match medications to patients' genetic makeup. AB - Mayo uses pharmacogenomics to help match medications to patients' genetic makeup. PMID- 30452130 TI - Wing Man. AB - On a gray March day, Stephen Wagner, MD, putters in the large hanger where he keeps his Beechcraft King Air E90. PMID- 30452131 TI - Expensive Medicine: Drug prices are increasingly hard to swallow. Effective remedies prove elusive. AB - Two lawsuits filed this year in federal court claim that three drugmakers have colluded in order to simultaneously raise the price of insulin. PMID- 30452132 TI - Epinephrine entrepreneur. AB - A Minnesota allergist continues his quest to build a better--and cheaper--drug injection device for people with severe food allergies. PMID- 30452134 TI - The session so far. AB - Only a few weeks remain n what has been a frustrating legislative session for physicians (it must conclude by May 22). Here's a rundown of the MMA's priorities. PMID- 30452133 TI - The merits of MIIC. AB - Minnesota's immunization information system excels at population health surveillance. PMID- 30452135 TI - Viewpoint: A concerted effort. AB - When physicians sit down with their elected officials to talk health care, you can believe it has a significant impact. PMID- 30452137 TI - Tackling addiction in primary care. AB - In the exam room, providers can identify--and often treat--patients who need help with a substance use disorder. PMID- 30452138 TI - Addressing the opioid epidemic in general medical settings. AB - As awareness of the opioid epidemic in this country has grown, so has the number of efforts to respond to it. This article reviews national and state efforts involving the medical community. It also reports on new funding coming to Minnesota with passage of the 21 st Century Cures Act, and it calls for increased involvement at the health system level. The hope is that with greater awareness of these efforts, health care providers will be better equipped to address the full spectrum of the epidemic. PMID- 30452136 TI - The changing landscape of drug abuse What's new? What can we do? AB - Every corner of the country is touched by drug abuse and addiction--Minnesota is no exception. Drug-induced deaths have tripled since 1990 and now outnumber fatalities from motor vehicle accidents. Deaths from opioid overdoes in particular have skyrocketed; they now outnumber cocaine and methamphetamine overdoes deaths, combined. PMID- 30452139 TI - Substance abuse and insomnia. AB - Insomnia is a common complaint among people with substance use disorders. The relationship between sleep problems and substance abuse is bidirectional: People who have trouble sleeping may medicate with alcohol or illicit drugs or misuse prescription medications. And taking certain substances can interfere with sleep. This article reviews that relationship and presents information about the two evidence-based treatments for insomnia: prescription sleep medications and cognitive behavioral therapy for insomnia. Clinicians treating people with a substance use disorder or insomnia should be aware of the risks of comorbidity, and they should understand the risks and benefits of treatment for the insomnia. PMID- 30452140 TI - Tularemia in Minnesota: an emerging and underappreciated infection. AB - Tularemia is a rare but often serious infectious disease caused by Francisella tularensis, a bacterium with an extremely low infectious dose and the ability to cause illness through several routes including arthropod bites, contact with infected animals and exposure to contaminated water, food or soil. Tularemia is found throughout the northern hemisphere, and cases have occurred in all U.S. states except Hawaii. Thirteen cases have been reported to the Minnesota Department of Health since 1994, including 3 in 2016. This article presents the 2016 cases as well as data on all the reported cases. Clinicians should consider tularemia in patients with a compatible clinical illness and exposure history, particularly those who present with acute fever and regional lymphadenopathy. Treatment should be initiated early in highly suspect cases, without waiting for laboratory results. PMID- 30452141 TI - AN ATTEMPT TO HALT THE EVER-INCREASING PREVALENCE OF MORBIDITIES RESULTING FROM EXCESS DIETARY SODIUM INTAKE. The Lebanese Experience. PMID- 30452143 TI - 25 (OH) VITAMIN D DEFICIENCY IN HEMODIALYSIS (HD) PATIENTS AND A MATCHING SAMPLE OF THE GENERAL POPULATION: EXPERIENCE OF ONE CENTER. A Pilot Study. AB - INTRODUCTION: 25 (OH) vitamin D plays an important role in many places through the body. Its deficien- cy can cause rickets or osteomalacia. This is particularly im- portant in hemodialysis (HD) patients who are at icreased risk due to decreased sunlight exposure and deterioration of their mineral homeostasis. OBJECTIVES: To determine the prevalence of 25 (OH) vitamin D deficiency in HD patients at Rafic Hariri University Hospital (RHUH), compared to a sample of the general population matched for gender and age, and to evaluate the effectiveness of 25 (OH) vitamin D supplementation in HD deficient group. METHODS: This is a cross sectional study conducted since December 2012, comparing the prevalence of 25 (OH) vitamin D deficiency in HD patients in the dialysis center at RHUH, with patients from the general population who sought medical attention at RHUH for purposes other than HD, matched for age and gender. 25 (OH) vitamin D levels were measured with radio- immunoassay method (LOINC) at CIC European Lab, Bar- celona, Spain. A pilot study was conducted with the 34 HD patients who turned out to be deficient or insufficient in 25 (OH) vitamin D. We supplemented them with cholecalciferol over 6 months. We then assessed their vitamin D levels, and biochemistry parameters. RESULTS: The prevalence of 25 (OH) vitamin D deficiency in the sample of HD patients at baseline was 32% while that of insufficiency was 36%. The prevalence of 25 (OH) vitamin D deficiency in the sample of general population was 67%. No correlation was found be- tween 25 (OH) vitamin D levels and the studied parameters. In the pilot study, after six months of cholecalciferol supple- mentation, there was a significant improvement in 25 (OH) vitamin D levels in the deficient and insufficient groups. CONCLUSION: The sample studied in the general population showed high prevalence of 25 (OH) vitamin D deficiency (67%). The sample studied in HD patients showed a preva- lence of 25 (OH) vitamin D deficiency of 32% and insuffi- ciency of 36%. The pilot study showed that 25 (OH) vitamin D supplementation in the form of cholecalciferol is beneficial in HD patients. PMID- 30452142 TI - WHAT IS THE HEALTH STATUS OF INSTITUTIONALIZED ELDERLY IN LEBANON? A Preliminary Cross-Sectional National Survey. AB - BACKGROUND: Medical conditions and depen- dency levels of the elderly in the Lebanese long-term care institutions have not been described. This may undermine care commissioning and development to institutionalized elderly. Data to inform policy and practice are needed. OBJECTIVE: To identify clinical diagnoses and dependency levels among elderly residents in long-term care institutions in Lebanon. METHODS: Cross-sectional survey of long-term care institutions throughout Lebanon as identified by the Mihistry of Social Affairs. RESULTS: Thirty-one out of 42 long- term care institutions have been included in this survey. Among them, 1371 elderly subjects were included in the analysis; 75.6% were over the age of 75, and female repre- sented 67%. Medical morbidities and associated disabilities have driven admission in 70.5% of residents; 45.6% of resi- dents reported dernentia, stroke or other neurodegenerativb disease. Overall, 60% of residents required locomotor assis- tance. CONCLUSIONS: Elderly residents in long-term carb institutions are predominantly females, with mental and/or locomotor disabilities resulting fror neurological and ar- thritic conditions. Targeting healthcare for such health condi- tions remains a challenge for the institutions. PMID- 30452144 TI - SYNDROME DES ANTIPHOSPHOLIPIES. A PROPOS DE 30 CAS. AB - OBJECTIVES: To analyze clinical and immuno- logic manifestations of Lebanese patients with the antiphos- pholipid syndrome (APS). PATIENTS AND METHODS: Our study was retrospective and was done on hospitalized patients be- tween 2001 and 2013. All these patients fulfilled the interna- tional criteria for diagnosis (Sydney criteria). RESULTS: Of the 30 patients selected, we noticed a female predominance (sex ratio: 2.75). The age at diagnosis ranged between 9 and 72 years with a mean age of 43 - 17 years. "Primary" APS was present in 70% of patients; APS was associated with systemic lupus erythematosus (SLE) in 23% of patients, with a mixed connective tissue disease in 3% and systemic vasculitis in 3%. A catastrophic APS occurred in 3 cases (10%). The most com- mon presenting manifestations were deep venous thrombosis (53%), pulmonary embolism (33%) and stroke (13%). Eleven patients (37%) had venous thrombosis, 7 (23%) had arterial thrombosis alone and 7 (23%) both arterial and venous throm- bosis. Deep venous thrombosis occurred mostly in the lower limbs (70%) whereas arterial thrombosis occurred in cerebral arteries in 50% of cases. The most common fetal complica- tions were early fetal loss (62.5%). Anticardiolipin antibodies were the most frequently identified antibodies (83%), followed by anti-p2GPI (70%) and anticoagulant lupus (11%). An effec- tive anticoagulation by anti-vitamin K was performed in 29 pa- tients. Corticosteroids were prescribed in 13 cases and were associated to immunosuppressant drugs in 6 cases of second- ary APS and the 3 catastrophic APS. The patients with cat- astrophic APS received also intravenous immunoglobulin. Response to treatment was favorable in 86% of patients with a mean follow up of 6 4 years. We deplored 4 deaths, 2 with- in the catastrophic APS. CONCLUSION: The APS does not seem to have particular features in Lebanon. The primary form seems to be the most common. It is important to diagnose this syn- drome earlier before the onset of serious complications. PMID- 30452146 TI - [Not Available]. AB - OBJECTIVES: Musculoskeletal ultrasound has evolved throughout the last decade. This procedure allows accurate corticosteroid injections guidance. Precision is much higher than the infiltration performed blindly or under fluoro- scopy. The purpose of our approach is to describe our tech- nique in ultrasound-guided infiltration of the shoulder with an overview of the results. MATERIAL AND METHOD: 123 cases of ultrasound-guided infiltration of the shoulder were selected in our institution from July 2011 to June 2012. They are divided into sub acromial sub-deltoid bursitis, biceps tenosynovitis, acromioclavicular osteoarthritis, adhesive capsulitis and cal- cific tendinosis lavage and aspiration. RESULTS: The infiltra- tion technique and the sonographic appearance in each con- dition are described. The rate of improvement is estimated between 70 and 80%. CONCLUSION: The ultrasound-guided infiltration provides an accurate and minimally invasive thera- peutic option before any surgery. Recovery and socio-profes- sional integration prove to be optimal and fast. PMID- 30452145 TI - EVALUATION OF MULTIDISCIPLINARY TEAM MEETINGS IN URO-ONCOLOGY. AB - OBJECTIVES: The objective of this study was to examine the impact of multidisciplinary team meetings on the management decisions for urological cancers. A pro- spective study was conducted. METHODS: The study popu- lation is cases presented to multidisciplinary teams at Notre- Dame de Secours University Medical Center between July 2012 and July 2014. Data was collected by a standard pro forma. RESULTS: 189 cases were presented in multidisci- plinary meetings during the study period. Results of this study showed that multidisciplinary team meetings change management decisions in 40.7% of cases. Change in man- agement decisions was mainly significant in testicular can- cer (57.1%), prostate cancer (42.7%) and bladder cancer (38.2%), with less important changes in renal cancer (33.3%). Prostate cancer cases with Gleason score 7 (51.7%) and bladder tumors with TNM ;t T2 (85.7%) were the most mod- ified in their respective groups. CONCLUSION: Multidiscipli- nary team meetings have a major impact in therapeutic de- cisions taken by urologists for newly diagnosed urological cancers. PMID- 30452147 TI - EARLY INCREASE of CA 19-9 in ADVANCED PANCREATIC CANCER RECEIVING FOLFIRINOX. Is it a sign of efficacy?. AB - INTRODUCTION: Advanced pancreatic cancer (APC), one of the most aggressive tunors, was considered to be resistant to chemotherapy for decades. FOLFIRINOX (5 FU, leucovorin, iNinotecah and oxaliplatin) regimen showed an improvement of quality of life and overall sUrvival.ir APb patients with good performance status (ECOG < 2). MATERIAL AND METHODS: Seven patients diagnosed with APO, during a six month period, received FOLFIRINOX as first line treat- ment. Tumor measurement Was assesed every two months and CA 19-9, tHe specific tumor marker of pahcteatid can6er, was assessed every two wedks at every cycle. RESULTS: Three patients ouf of seven receiving FOLFiRINOX dtpe- riented an early And transitory increase of CA 19-9 after th6 first two cybles resulting ih a considerable response with a median survival of 15 mnths and suggesting a fhdel of fdmor release syndrome. CONCLUSION: This phenoMenon of early and transitory increase of CA 19-9 in APC could reflect the high efficacy of FOLFIRINOX and could predict better out- come in these patients. PMID- 30452148 TI - RELATIONSHIP OF PERSONALITY TRAITS WITH ANXIETY, DEPRESSIVE AND PTSD SYMPTOMATOLOGY AND ACADEMIC PERFORMANCE. Experience with an Arab college student sample. AB - BACKGROUND: The objective was to highlight the profile of Eysenck Personality Questionnaire traits of a sample of Arab college students, and assess the relationship of trait scores with gender, age and symptoms of anxiety, depression, PTSD and grade point average (GPA) score. Similar reports from the Arab world were restricted to neuroticism/extraversion and rarely involved traumatic experience and psychosocial performance. METHODS: Participants (N = 624) were Kuwaiti national college students who completed, in class, the EPQ- 90, Hopkins Symptoms Checklist, and the PTSD Checklist. RESULTS: Men had higher psychoticism (p < 0.004) and extra- version (p <0.03) scores, while women had higher neuroticism (p < 0.001) and lie scale scores (p < 0.001). Students with the lowest GPA had the highest scores for psychoticism (p< 0.01). Psychoticism and neuroticism were significantly correlated with each other, but negatively with extraversion and lie scale. The correlations of psychopathology were strongest with neu- roticism and psychoticism; and negative with extraversion and the lie scale. In regression analyses, the dominant predictor of psychopathology was neuroticism. With neuroticism as covari- ate, the sex difference in depression scores was no longer sig- nificant. CONCLUSIONS: Our findings support the usefulness of neuroticism as reflecting characteristic level of distress; and a combination of high neuroticism and low extraversion as vul- nerability marker for psychopathology. Psychoticism needs further study as a marker of psychosocial underachievement. PMID- 30452149 TI - [Not Available]. PMID- 30452150 TI - AUTISM IN REVIEW. AB - Autism spectrum disorders are a group of neurodevelopmental disorders characterized by impaired verbal and/or nonverbal communication in addition to repeti- tive stereotypical behaviors. We present a review article on this topic. Criteria for diagnosis are defined by the Diagnos- tic and Statistical Manual of Mental Disorders Fifth Edition (DSM 5). Abnormalities at the level of synapses, including newly described genetic perturbations, have been implicated in the pathogenesis of autism. Non-invasive modalities like Diffusion Tensor Magnetic Resonance Imaging have identi- fied white matter tract involvemeht in the brains of autistic in- dividuals. Early and intensive intervention impact prognosis. Risperidone and aripiprazole are FDA approved for irritability in autism although no known medication relieves core symp- toms of social and communication impairment. Fluoxetine is used to decrease anxiety in autistic patients. PMID- 30452151 TI - CIRCULATING microRNAs: POTENTIAL BIOMARKERS IN CANCER DETECTION, DIAGNOSIS AND PROGNOSIS. AB - A large family of small 18-25 nucleotide long non coding RNA molecules now known as microRNA (miRNA) was described two decades ago, and has been recently es- tablished as post-transcriptional gene regulators. miRNAs were shown to be involved in the regulation of diverse phys- iological and developmental processes. Moreover, dysregula- tion of specific miRNAs has been implicated later in several pathologies including cancer. Owing to their presence and stability in body fluids, miRNAs have been investigated as novel circulating non-invasive biomarkers. Accordingly, their role as potential diagnostic, prognostic or predictive biomark- ers for many cancer types has recently emerged. This review tackles the use of circulating miRNAs in cancer detection, diagnosis and prognosis, giving examples using common solid tumors and discussing the advantages of their use, the challenges facing this novel circulating biomarker and recorn- mendatidns to overcome them. PMID- 30452152 TI - SMOKING . WE DO NOT WANT TO QUIT!. PMID- 30452153 TI - Improved Syntheses of (+)-Iridomyrmecin and (-)-Isoiridomyrmecin, Major Components of Matatabilactone. AB - Improved syntheses'of iridomyrmecin and isoiridomyrmecin, major components of matatabilactone, are described. The synthesis features a direct transformation of nepetalactol into key intermediates by DIBAL-H reduction and provides an expeditious and straightforward production of iridoid lactones for biological investigations of the Matatabi phenomenon. PMID- 30452154 TI - New Secoiridoid Glucoside, and a Metabolite Profile of Scabiosa lucida. AB - ourteen secondary metabolites, including a new secoiridoid glucoside (1), were isolated from the aerial parts of Scabiosa licida by a combination of column hromatography, preparative and semi-preparative HPLC. They were identified by extensive NMR, and ESI-MS experiments, and by comparison with iterature data. PMID- 30452155 TI - Dipasperoside B, a New Trisiridoid Glucoside from Dipsacus asper. AB - Dipasperoside B (1), isolated from the root of Dipsacus asper, was determined to be a first example of naturally occurring iridoid glucoside trimer with an unusual skeleton featuring oxaloacetic acid derived moiety coupled with a secoiridoid nucleus in the central part, on the basis of spectroscopic data. Dipasperoside B (1) revealed the inhibitory activity against nitric oxide (NO) production in a lipopolysaccharide (LPS)-activated murine macrophage RAW264.7 cell line, with an IC50 value of 21.3 MUM, identical to a positive control, N(G) monomethyl-L-arginine (L-NMMA, IC50 22.6 MUM), without any significant cytotoxicity. PMID- 30452156 TI - First Isolation of Bicyclic Ditellurides from the Reaction of Camphor Hydrazone with Tellurium Tetrachloride. AB - Reaction of camphor hydrazone with TeCI4 under basic conditions gave an isomeric mixture of vinyl ditelluride and Wagner-Meerwein rearranged ditelluride. Initially formed tellurocamphor enolized and oxidized to give vinyl telluride, whereas tellurocamphor complexed with TeC4 to afford carbocation, which rearranged in a Wagner-Meerwein manner to afford the rearranged ditelluride. Photolysis of ditelluride in methyl methacrylate solution gave the radical polymerization product, PMMA, in which ditelluride acted as a radical initiator. PMID- 30452157 TI - Two New Lobane Diterpenes from a Bornean Soft Coral Sinularia sp. AB - Two new lobane diterpenoids, prenyl-alpha-elemenone (1) and ent-prenyl-beta elemene (2), along with ,a known compound, alpha-murrolene (3) were isolated from a population of Bomean soft coral Sinularia sp. The structures of these compounds were elucidated on the basis of spectroscopic, including 2D NMR, and HR-MS data. These compounds were tested for their cytotoxicity and antibacterial activities against antibiotic resistant clinical strains. PMID- 30452158 TI - Three New Eremophilanes from a Ligularia Hybrid Collected in China. AB - Three new eremophilanes were isolated from a sample of Ligularia collected in Yunnan province of China and their structures were determined. The chemical - constituents including eleven eremophilanes (major constituents: 6 acyloxyfuranoeremophilan-IObeta-ols) were similar to those of a hybrid of L. cyathiceps and L. subspicata, however, the base sequence of the ITS 1-5.8S-ITS2 region was typical of L. cyathiceps, indicating backcrossing. PMID- 30452159 TI - Eudesmane Sesquiterpenoids from the Wood of Platycarya strobilacea. AB - The wood of Platycarya strobilacea Sieb. et Zucc. (Juglandaceae) was used as incense. In this study, three new sesquiterpenes (2, 4, 5) and one nor- sesquiterpene (3) were isolated and their structures determined as 7-hydroperoxy 11-hydroxy-2,4-cycloeudesman-8-one (2), 8-hydroxy-13-nor-2,4- cycloeudesman-7-en I 1-one (3), 2,4-cycloeudesma-7(11), 8-dien-(12,8)-olide (4), and 8-hydroxy-8,12 peroxy-2,4-cycloeudesm-7(l I)-ene (5). In addition, the absolute configuration of a previously reported sesquiterpene was revised based on the calculation of its ECD spectrum. PMID- 30452160 TI - Rickicaryophyllane A, a Caryophyllane from the Ascomyceteous Fungus Hypoxylon rickii and a 10-Norbotryane Congener. AB - Herein we report the isolation from Hypoxylon rickii of a new sesquiterpenoid (1) with a caryophyllane skeleton. The planar structure of 1 was elucidat ed by NMR and HRMS data as the 1,12-dihydro-l-hydroxyl derivative of caryophyllenol-I, for which we propose the name rickicaryophyllane A. Its relative stereochemistry was assigned with a series of ID NOESY experiments, while the IR,2S,5R,9R absolute configuration was demonstrated by Mosher's analysis. Besides, we isolated 3 (hydroxymethyl)-1,1,3,5-tetramethyl-1,2,3,5,6,7-hexahydro-4H-inden-4-one (2) as a new 10-norbotryane derivative and the known metabolite orcacetophenone (3). PMID- 30452161 TI - Guaiane Sesquiterpenoids from the Gorgonian Menella woodin. AB - Two new guaiane derivatives (1 and 2) along with six known sesquiterpenoids (3-8) were isolated from the gorgonian Menella woodin. Their structures -were elucidated by ID and 2D NMR and HRESIMS data as well as by comparison of their spectra with those in the literature. Relative configurations of asymmetric centers in 1 and 2 were suggested on the basis of NOESY and ID NOE correlations, absolute stereochemistry of these compounds was proposed in result of comparison of calculated (for both enatiomers) and experimental ECD. Some suggestions were made regarding a biosynthesis of guaiane sesquiterpenoids in this species. All the compounds were firstly isolated from M woodin. PMID- 30452162 TI - A New Pimarane-type Diterpenoid from the Seeds of Bowdichia virgilioides. AB - A new pimarane-type diterpenoid, sucupiol (1), and nine known -furanocassane-type diterpenoids, vouacapane (2), 7beta-hydroxyvouacapane (3) 7beta-acetox yvouacapane (4), 6alpha-hydroxyvouacapane (5), 6alpha-acetoxyvouacapane (6), sucutinirane F (7), sucutinirane E (8), 6alpha, 7beta-diacetoxyvouacapane (9), and 6alpha, 7beta-diacetoxyvouacapane-14beta-al (10), were isolated from the seeds of Bowdichia virgilioides and their structures were elucidated by using 2D NMR data. The isolation of I provides evidence to support the presence of intermediate A in the course of biosynthesis of furanocassane-type diterpenoids. PMID- 30452163 TI - Oxygenated Diterpenes from the Indo-Pacific Nudibranchs Goniobranchus splendidus and Ardeadoris egretta. AB - Five new diterpenes (1-5), each with a highly oxygenated spongian framework, were characterized from an organic extract of a specimen of the nudibranch Goniobranchus splendidus collected from Eastern Australia. The new diterpene 7alpha-hydroxydendrillol-3 (6) was identified from specimens of Ardeodoris egretta. The structures and relative configurations of the six new metabolites have been elucidated by analysis of their spectroscopic data. PMID- 30452164 TI - Triterpenoids from Schisandra propinqua var. propinqua. AB - Four new triterpenoids, propindilactone T (1), propindilactone U (2), changnanic acid 3-methyl ester (3) and schipropinic. acid (4), together with five known ones (5-9), were isolated and identified from the stems and leaves of Schisandra propinqua var. propinqua; their structures were determined based on spectroscopic and mass spectrometric analyses. The absolute configuration of 1 was confirmed by X-ray analysis. Compounds 1, 2, and 4-9 were tested for their cytotoxic activities against five human tumor cell lines; all were inactive except for 8, which showed weak activity against some of the cell lines. PMID- 30452165 TI - 7alpha-Hydroxyfriedelan-3-one-26-ol-29-oic acid and other Constituents from Pileostegia viburnoides var. glabrescens. AB - Phytochemical investigation of the roots and rhizomes of Pileostegia viburnoides var. glabrescens led to the isolation and identification of 31 compounds (1-31), 25 of which (1-2, 4-7, 9-12, 15-18, 21-31) were isolated from the Pileostegia genus for the first time. 7alpha-Hydroxyfriedelan-3-one-26-ol-29-oic acid (1) is a new friedelane-type triterpene. The structure of n-butyl-beta-D fructopyranoside (2) was determined by single-crystal X-ray diffraction. Compounds 4 and 12 displayed marginal cytotoxicity against the P388 murine leukemia cell line with IC50 values of 13.4 MUM and 25.0 MUM, respectively. Compound 23 exhibited marginal anti-inflammatory activity by the inhibition of lipopolysaccharide induced nitric oxide production in RAW 264.7 macrophage cells, with an IC50 value of 32.0 MUM. Compounds 3, 8-10, 25, and 27 were phytotoxic to the dicot Lactuca sativa (lettuce) and/or the monocot Agrostis stolonifera (bentgrass). PMID- 30452166 TI - Tirucallane Glycoside from the Leaves of Antidesma bunius and Inhibitory NO Production in BV2 Cells and RAW264.7 Macrophages. AB - One new tirucallane-type triterpene glycoside, antidesoside (1), along with two biflavones, podocarpusflavone A (2) and amentoflavone (3) and two megastigmane glycosides, byzantionoside B (4), and (6S,9R)-roseoside (5) were isolated from the methanol extract of Antidesma bunius leaves. Their structures were determined by spectroscopic methods and in comparison with the published data. Compounds 1 - 3 were found to show strong inhibitory effect of NO production in BV2.cells and RAW264.7 macrophages LPS-stimulated, with IC50 values ranging from 8.5 to 26.9 MUM. PMID- 30452168 TI - Structure Revision of (22E)-24-Methylcholesta-8(14),22-diene- 3beta,5alpha,6beta,7alpha-tetraol from the Marine-Derived Fungus Penicillium sp. AB - Careful reexamination of the published 1H- and 13C-NMR spectral data of (22E)-24 methylcholesta-8(14),22-diene-3beta,5alpha,6beta,7alpha-tetraol (1), isolated from the marine-derived fungus Penicillium sp., indicates that, in reality, the compound is 5alpha,6alpha-epoxy-(22E,24R)-24-methylcholesta-8(14),22-diene 3beta,7alpha-diol (5). PMID- 30452167 TI - Fallaxosides C1, C2, D1 and D2, Unusual Oligosulfated Triterpene Glycosides from the Sea Cucumber Cucumariafallax (Cucumariidae, Dendrochirotida, Holothurioidea) and Taxonomic Status of this Animal. AB - Four hew triterpene glycosides, fallaxosides C, (1), C2 (2), D, (3) and D2 (4) along with the known cucumarioside A3-2 (5) and koreoside A (6) have-been isolated from the sea cucumber Cucumaria fallax (Cucumariidae, Dendrochirotida). Structures of the glycosides have been elucidated by 2D NMR spectroscopy and mass spectrometry. All of the glycosides are rare non-holostane derivatives having shortened side chains and contain pentasaccharide carbohydrate moieties with two or three sulfate groups. Structures of these triterpene glycosides and their comparison with those earlier isolated from Cucuniaria spp. and Pseudocnus dubiosus leoninus allow us to suggest that the present assignment of C. fallax to the genus Pseudocnus is not correct, and this species.should be assigned to the genus Cucumaria. Cytotoxic activity of glycosides 1-5 against the ascite form of mouse Ehrlich carcinoma cells and mouse spleen lymphocytes and hemolytic activity against mouse erythrocytes have been studied. The glycosides were expectedly not active in all the tests due to the absence of an 18(20)-lactone in their aglycones and the presence of several sulfate groups. There was one exception, cucumarioside A3-2 (5), which. demonstrated a weak cytotoxicity against lymphocytes and moderate hemolytic activity. PMID- 30452169 TI - Alkaloids from the Tuber of Stephania cf. rotunda. AB - Chemical investigation of the tuber of Stephania cf. rotunda collected in Vietnam led to the isolation of a new stephaoxocane-type alkaloid, stepharotudine (1), twenty -eight known alkaloids, and two known amides. The chemical structures of the isolated compounds were determined by spectroscopic and chemical methods. The absolute configuration of the new compound was determined from its CD spectrum and by 1H NMR analyses of its MPA esters. For the known alkaloids ()crebanme-beta N-oxide (2), uthongine (3), and palmatrubine (4), fully assigned NMR data are also reported for the first time. PMID- 30452170 TI - Quantitative Determination of Principal Alkaloid and Flavonoid Constituents in Wintersweet, the Flower Buds of Chimonanthuspraecox. AB - A quantitative analytical method has been-developed for four alkaloids (1-4), identified as constituents responsible for the melanogenesis inhibitory activity of the.extracts of wintersweet, the flower buds of Chimonanthus praecox (L.) Link (Calycanthaceae). Concurrently, a quantitative analytical protocol has been developed for five flavonoids (5-9), which also exhibited inhibitory activity. To approve the validity of the developed protocols, five extracts of the flower buds collected in Chinese market were evaluated. The optimum conditions of separation and detection of these alkaloids (1-4) and flavonoids (5-9) were achieved on a common ODS column using a MeOH-H20 mobile phase with different additives [Et2NH for alkaloids (1-4); acetic acid for flavonoids (5-9)]. The results. indicated that these assays were reproducible and precise, and could be readily utilized for evaluation of the melanogenesis inhibitory activity of -wintersweet on the basis of the content of the functional species. The principal flavonoid constituents (5-9) also exhibited lipid accumulation inhibitory activity. PMID- 30452171 TI - Efficient Preparation of Various O-Methylquercetins by Selective Demethylation. AB - penia-O-Methylquercetin (2) was prepared by permethylation of quercetin (1). Selective demethylation of 2 using either BBr or BCl3/TBAI (tetrabutylammonium iodide) gave five O-methylquercetins (3-6), with satisfactory yields. The reaction can be easily scaled-up. We established an efficient and large-scale preparation of O-methylquercetins. PMID- 30452172 TI - A New Flavonol Triglycoside from Eustoma grandiflorum. AB - A new flavonol triglycoside, kaempferol 3-0-alpha-L-rhamnopyranosyl (1>6)-(3-0-E p-coumaroyl)- beta-D-galactopyranoside-7-0-alpha-L-rhamnopyranoside (1: Eustograndifloside A) was isolated from the flower of Eustoma grandiflonm in addition to eight known flavonols (2: kaempferol 3-0-a-L-rhamnopyranosyl (1->6) (4-0-E-p-coumdarhyl)-m-D-galactopyraoside-7-0-alpha-L-rhamnopyranoside, ,3: kaempferol 3-0-beta-robinobioside-7-0-alpha-L-rhamnopyranoside, 4: isorhamne-tin 3-0-alpha-L-rhamnopyranosyl (1->2). [alpha-L-rhamnopyranosyl (1->6)]-(4-O-E-p couinaroyl)-beta-D-galactopyrAnoside-7-0-alpha-L-rhamnopyranoside, 5: kaempferol 3-0-alpha-L-rhamnopyranosyl (1->2) [(X-L-rhamnopyranosyl (1-6)] (4-0-E-p coumaroyl)-beta-D-galactopyranoside-7-0-alpha-L-rhamnopyranoside, 6: kaempferol 3 0-beta-robinobioside, 7: quercetin 3-0-beta-robinobioside, 8: isorhamnetin 3-0 beta-robinobioside, and 9: kaempferol 7-0-alpha-L-rhamnopyranoside) and two known secoiridoid glycosides (10: swertiamarin and 11: sweroside). The structure elucidation of these compounds was accomplished through analyses of spectroscopic, including 1D and 2D NMR, and ESIMS data. PMID- 30452173 TI - Crataegusins A and B, New Flavanocoumarins from the Dried Fruits of Crataegus pinnatifida var. major (Rosaceae). AB - Crataegusins A (1) and B (2), new flavanocoumarins, were isolated from the crude drug Crataegus Frictus, i.e., the dried fruits of Crataegus pinnatifida var. major..Their structures were determined by spectroscopic methods. They were unique in terms of carrying a 3-(or 4-)substituted coumarin substructure while a flavanocoumarin generally does not carry any substituents in the 2-pyron ring. They showed a significant DPPH reducing activity compared with epicatechin Their production would be biosynthetically regulated considering the results of an LC MS analysis of the dried and fresh fruits, fruit skin, hypanthia, and leaves. Their structures led the authors to consider a hypothetical general biosynthetic pathway of the flavanocoumarins, to which a flavan-3-ol is converted through a Michael addition and successive oxidative decarboxylation or dehydration pathway. PMID- 30452174 TI - Ancistrotectoquinones A and B, the First Quinoid Naphthylisoquinoline Alkaloids, from the Chinese Liana Ancistrocladus tectorius. AB - From the leaves and stems of Ancistrocladus tectorius (Ancistrocladaceae) from the Chinese island Hainan, two novel-type 7,3'-coupled naphthylisoquinolines, named ancistrotectoquinones A (4) and B (5), were isolated. They are the first alkaloids with a 1,4-naphthoquinone portion coupled to an isoquinoline moiety. Due to the lowered degree of steric hindrance next to the biaryl axis and for electronic reasons, 4 and 5 occur as pairs of configurationally semi-stable, and, thus slowly interconverting atropo-diastereomers. The Gibbs free energies of activation between the two atropisomers of ancistrotectoquinone A (4a/b) were determined by measuring the time-dependent decrease of diastereomeric purity of freshly separated samples enriched with the M- or P-atropisomer and, computationally, by DFT calculations. The absolute configurations at the biaryl axes of the atropo-diastereomers of 4a/b and 5a/b were assigned by online LC-CD analysis. The stereostructure of 4a/b was further confirmed by its semi-synthesis from the likewise 7,3'-coupled 'normal' naphthylisoquinoline alkaloid ancistrotectorine (6), by biomimetic oxidation with Fremy's salt. PMID- 30452175 TI - Anticandidal Effects of Thymoquinone: Mode of Action Determined by Transmission Electron Microscopy (TEM). AB - Thymoquin6ne (TQ) is one of the bioactive constituents of black cumin seed (Nigella sativa L.) oil. It is well known that this natural volatile quinone has remarkable antimicrobial effects, especially against Candida species. Consequently, in this present study TQ was evaluated for its anticandidal effects against. 14 differet.pathogenic Candida strains by using the in vitro, partly modified, microdilution CLSI M27-A2 method. After TQ treatment at the minimum inhibitory concentration (MIC), ultra-thin sections of C. albicans cells were thoroughly evaluated by transmission electron microscopy (TEM). The mode of action of TQ on different Candida cells was elaborated, where their disintegration and disorganization with amorphous nucleus were observed microscopically. PMID- 30452176 TI - Effective Production of Aromatic Polyketides in Streptomyces using a Combined Culture Method. AB - Combinedculture is a fermentation method which efficiently induces secondary metabolite production in Streptomyces by co-culturing them with mycolic acid containing bacteria. As a result of combined-culture screening -of our terrestrial Streptomyces collection using UV-HPLC, one of the tested strains, Streptoinyces. sp. TAKO-2, produced two known aromatic polyketides, julichrome Q6 (1) and julichrome Q8.8 (2), when co-cultured with the mycolic acid- containing bacterium Tsukamurella pulmonis TP-B0596. The structures of 1 and 2 were confirmed by spectroscopic analysis and literature data. PMID- 30452177 TI - A New Neolignan Glycoside from Vetiveria zizanioides Roots. AB - A new neolignan glycoside (1) and four known aromatic compounds (2-5) were isolated. from the roots of Vetiveria zizanioides. The structure of compound 1 was determined based on spectroscopic analysis and hydrolysis. The structure of known flavonoid glycoside 3 was confirmed by X-ray crystallography. Compound 5 showed weak cytotoxic activity against HL-60 cells with an IC50 value of 13.1 +/- 0.04 MUM. PMID- 30452178 TI - A New Neolignan from Panicum turgidum. AB - A new neolignan, paniculignan (1), and a known lignan, tetracentronside B (2), were isolated from Panicum turgidum. The structure of 1 was elucidated by extensive spectroscopic methods including ID and 2D NMR and HR-ESI-MS. The relative configuration of 1 was determined on the basis of circular dichroism spetroscopy, optical rotation, and NOESY correlations. PMID- 30452179 TI - Chemical Composition and Antimicrobial Activity of Populus nigra Shoot Resin. AB - The chemical composition of Populus nigra shoot resin has been investigated by chromatographic and spectroscopic methods. The analyses resulted in identification of 19 known compounds. The resin exhibited low activity against selected microorganisms. PMID- 30452180 TI - Constituents from Entada scandens with TRAIL-resistance Overcoming Activity. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent because of its ability to selectively kill tumor cells. But TRAIL-resistance is a major problem of its therapy. A search for compounds for abrogating TRAIL-resistance has, thus, become an important strategy for anticancer drug discovery. In search of bioactive natural products for overcoming TRAIL-resistance, we previously reported some compounds with TRAIL resistance overcoming activity. Bioassay guided fractionation of Entada scandens led to the isolation of four compounds (1-4). Of the isolates, compounds 1 and 3 showed moderate TRAIL-resistance overcoming activity in TRAIL-resistant human gastric adenocarcinoma (AGS) cells. PMID- 30452181 TI - Synthesis of Piceatannol, an Oxygenated Analog of Resveratrol. AB - Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene, 2), an oxygenated analog of resveratrol (1), was synthesized. It is one of the naturally occurring polyphenolic stilbenoids contained in red wine, and possesses many kinds of beneficial effects such as anticancer activity. The trans-stilbene skeleton of 2 was constructed by Pd-catalyzed Suzuki-Miyaura cross coupling reaction of triflate 8 with (E)-alkenylboronoate 13. The key intermediate 13 was prepared diastereoselectively by acid-catalyzed hydroboration of pinacolborane 12 to alkyne 11. PMID- 30452182 TI - Helvafuranone Produced by the Fungus Aspergillus nidulans BF0142 Isolated from Hot Spring-derived Soil. AB - The fungus, Aspergillus nidulans BFO 142, was isolated from hot spring-derived soil collected at Hell Valley in Noboribetsu, Hokkaido, Japan. A new furanone compound designated helvafuranone (1) was isolated along with microperfuranone (2), 9-hydroxymicroperfuranone (3), diorcinol (4), emestrin (5), and sterigmatocystin (6), from a culture broth of A. nidulans BF0142. The structure of 1 was elucidated as 5-hydroxy-4-(4-hydroxybenzyl)-3-(4- hydroxybenzyl)furanone based on various NMR experiments and chemical modifications. PMID- 30452183 TI - A New Polycyclic Polyprenylated Acylphloroglucinol Derivative from Garcinia verrucosa. AB - In our continuing phytochemical screening program aimed at finding major constituents. of endemic Madagascar plants as potential templates for semisynthesis, we investigated the ethyl acetate extract of stem bark of Garcinia verrucosa. Fractionation of the extract led to the isolation of the major compound named garcicosin. -Its structure was elucidated by spectroscopic methods including ID and 2D homo- and heteronuclear NMR techniques (COSY, HSQC, HMBC and NOESY), and HR-mass spectromnetry. PMID- 30452184 TI - Chemotypic Variation of Conocephalum salebrosum in the Southeastern Appalachian Range: A Search for Cryptic Plant Biodiversity Around the Tennessee River Valley. AB - The chemotaxonomy of the Conocephalum spp. complex, based on GC-MS analysis of the volatile compositions, has helped to reveal cryptic biodiversity and delineate actual distribution patterns of chemotypes. In the Appalachian Mountains, two samples from eastern central part of the range were previously shown to.be C. salebrosum. Additionally, it has recently come to light that stress can alter the volatile composition of C. conicun. This study address a previously unsampled region of the southeastern Appalachians, a region that is a biodiversity epicenter, to determine if more chemotypic diversity remains to be seen for the Conocephalun spp. complex. A common garden experiment was performed, but yielded more of a common stress experiment, and significantly altered the volatile compositions. Wild-collected controls and a meta-analysis of these data and those from previous works suggest that the common garden experiment caused stress and that the liverworts sampled belong to the C. salebrosin clade of of the Conocephalum spp. complex. PMID- 30452185 TI - Essential Oils of some Mentha Species and Cultivars, their Chemistry and Bacteriostatic Activity. AB - The major purpose of this study was to determine the chemical relationships between the essential oils (EO) obtained form 18 mint samples of different species and its cultivrs. GC/MS analysis of all essential oils showed that oxygenated monoterpenoids are the major components of these oils, with the exception of Mentha arvensis 'Banana'. Based on the. chemical composition of the essential oils, the analyzed mints can be divided into five groups. Group I was characterized by the-presence of menthol and menthone, piperitenone oxide is the major constituent of group II, linalool of group III, carvone characterizes group IV, while 3-octanone is the most characteristic compound for group V. A reference strain of biofilm forming Staphylococcus epidermidis ATTC 35984 was tested against the obtained essential oils. Two of them, M suaveolens 'Variegata' and M x piperita 'Almira' exhibited significant bacteriostatic activity. The MIC values of these EOs were 0.25% and 0.5% respectively in comparison with an average MIC of 4% of the other tested mint EOs. Both active EOs are characterized by the presence of piperitenone oxide as the major component. PMID- 30452186 TI - Chemical Composition and Antimicrobial Activity of the Essential Oil from Flowers of Eryngium triquetrum (Apiaceae) Collected Wild in Sicily. AB - The chemical composition of the essential oil from flowers of Eringiun triquetrum Vahl. collected in Sicily was evaluated by GC and GC-MS. The main components were pulegone (50.6%), piperitenone (30.5%) and menthone (7.0%). Comparison of this oil with other studied oils of Eringium species is dis6ussed. The oil showed good antibacterial and antifungal activities against some microorganisms that infest historical art works. PMID- 30452187 TI - Antioxidant, Antimicrobial, and Cytotoxic Properties of Aniba parviflora Essential Oils from the Amazon. AB - Essential oils (EOs) from leaves and branches of Aniba parviflora (Meisn.) Mez were obtained by hydrodistillation and their chemical compositions determined by gas chromatography - mass spectrometry. Oxygenated sesquiterpenoids were the most representative compound class in both EOs (~ 40%). However, the leaf EO was rich in beta-phellandrene (15.1%), linalool (14.1%), and y-eudesmol (12.9%). The EO from the branches showed high concentrations of gamma-eudesmol (16.8%), beta caryophyllene (15.7%), linalool (12.4%), beta-phellandrene (6.7%), and bicyclogermacrene (6.0%). The EOs were screened for radical-scavenging activity using the DPPH assay. In the DPPH assay, the EOs showed an antioxidant activity with TEAC values of 296.8 +/- 20.2 and 357.3 +/- 43.8 mg.TE.mL-1, about one-third that of the Trolox standard. The EOs were subjected to antibacterial screening and displayed promising activity against Escherichia coli (MIC < 19.5 MUg.mL-1). In addition, the EOs were tested for cytotoxic activity against MCF-7 breast tumor cells and the leaf EO (IC50 = 67.9 +/- 3.0 MUg.mL-1.) was more active than that from the branches (IC50 = 102.2 +/- 3.0 MUg.mL-1). PMID- 30452188 TI - Antioxidant, Anti-inflammatory and Anti-hyperglycaemic Activities of Essential Oils from Thymbra capitata, Thymus albicans, Thymus caespititius, Thymus carnosus, Thymus lotocephalus and Thymus mastichina from Portugal. AB - The in viro antioxidant, anti-inflammatory, anti-hyperglycaemic, and anti acetylcholinesterase activities of the essential oils (EOs) isolated from six Lamiaceae species (Thymbra capitata,. Thymus albicans, Th. caespititius, Th. carnosus, Th. lotocephalus and Th. mastichina) grown in Portugal, were evaluated. Th. caespititius and T. capitata carvacrol/thymol-rich EOs showed the best capacity for preventing lipid peroxidation, and scavenging the 2,2'-azino- bis(3 ethylbenzothiazoline-6-sulphonid acid) (ABTS) and peroxyl free radicals, as well as for inhibiting lipoxygenase and a-amylase. However, Th. caespititius and Th. lotocephalus 1,8-cineole and linalool rich EOs were the best inhibitors of a glucosidase. T capitata, Th. lotocephalus and Th. albicans EOs were the: most active for inhibiting acetyleholinesterase. Th. caespititius and Th. mastichina EOs were the main scavengers of nitric oxide (NO) radicals. The comparison between the present data with a survey of the existing literature on the in vitro biological activities of the essential oils isolated from the same species from Portuguese origin, using other.methodologies, showed some differences. For instance the use of two oxidizable substrates (egg yolk andlecithin liposomes) led to distinct results mainly for those samples with relatively low activity. In addition, the EOs capacity for scavenging peroxyl radicals-was also influenced by the presence of cyclodextrins, as a synergism seemed to occur between EOs and those carbohydrates. PMID- 30452189 TI - Icacina trichantha, A Tropical Medicinal Plant. AB - This is a review on the pharmacological properties and chemical composition of Icacina trichantha (Icacinaceac), a food and medicinal plant native to West Africa. The tuber is a good source of nutrients such as starch; it also exhibits a variety of pharmacological activities in animal models. Chemical analysis has revealed the presence of a series of unusual pimarane-type diterpenes. PMID- 30452191 TI - Biosynthetic Pathways of Purine and Pyridine Alkaloids in Coffee Plants. AB - Caffeine (1,3,7-N-trimethylxanthine) and trigonelline (IN-methylnicotinic acid) are major alkaloids in coffee plants. The key enzymes involved-in the biosyntliesis of these compounds are very closely related N-methyltransferases belonging to the motif B' family of methyltransferases. The major biosynthetic pathways of caffeine and trigonelline are summarized in this review, including new evidence obtained from recombinant enzymes. In addition, precursor supply pathways are discussed with newly obtained results. Transgenic plants produced by the modification of the expression of N-methyltransferase genes are also introduced. PMID- 30452190 TI - Phellinus igniarius: A Pharmacologically Active Polypore Mushroom. AB - Mushrooms have been widely used in traditional medicine for the treatment of various diseases. Today, their therapeutic value is scientifically studied and appreciated. Research indicates that polypores - a large group of fungi of the phylum Basdioinycota - exhibit antiviral, antimicrobial, anticancer, anti allergic, anti-atherogenic, hypoglycemic, hepatoprotective and anti-inflammatory activities. Phellinus igniarius, a polypore mushroom, is one of the most used in traditional Asian medicine. Its potent anticancer activity has been repeatedly reported. In the past two decades, numerous pharmacologically active metabolites have been isolated and identified from P. igniarius. Among the large number of compounds, the most active group are polysaccharides. They modulate immune responses and inhibit tumor growth. PMID- 30452192 TI - [The founder of Russian oncology - N.N.Petrov]. AB - In December, 2016 it will be 140 years since the birth of N. N. Petrov - the outstanding figure of native oncology who laid the foundation of the new practical and scientific direction of works in the USSR in the XX century executed. PMID- 30452193 TI - [Modern trends in surgery of gastrointestinal tract tumors]. AB - Development of cancer surgery in recent decades occurs on a background of continuing scientific and technical progress. New technologies after the completion of clinical trials maximally quickly are included in the routine practice of specialized medical centers. At present an escalation of indications for extensive advanced and combined operations in locally advanced and even metastatic tumors goes in parallel with the introduction of minimally invasive interventions, search categories of patients, for whom the radicalism of treatment can be achieved without significant surgical aggression. The study of modern trends of this process will allow seeing the promising areas of scientific research, assuming the image of the future of surgery for cancer. PMID- 30452194 TI - [Endovideosurgery (minimally invasive surgery) in treatment for malignant tumors of female genital organs: a 5-year experience of the clinic of the N.N.Petrov Research Institute of Oncology]. AB - During the period of 2010-2015 laparoscopic surgery was performed in 1263 patients: 1113 with endometrial cancer (588 hysterectomies, 509 hysterectomies with pelvic lymphadenectomy, among them 16 with sentinel lymph node (SLN) mapping with Indocyanine green (ICG)); 86 with cervical cancer (80 nerve-sparing radical hysterectomies (NSRH), among them 15 with SLN mapping, 6 radical vaginal trachelectomies with endovideoassisted lymphadenectomy); 64 with ovarian malignancies. The average operating time in the group of hysterectomies was 101 minutes, in the group of hysterectomies with pelvic lymphadenectomy - 184 minutes, in the group of NSRH - 230 minutes. Average blood loss was less than 50 ml. No intraoperative complications were registered. Asymptomatic lymph cysts were observed in 122 cases. Symptomatic lymph cysts requiring surgical treatment were registered in 9 cases. Inconsistencies of vaginal sutures after radical hysterectomy were in two cases, ureterovaginal fistulas - in two cases. During a 3-year follow-up period twelve recurrences were observed in endometrial cancer patients (12/443; 2,7%), four patients (0,9%) died from disease. After NSRH two local recurrences (2,5%) were registered in patients with cervical cancer, after radical trachelectomy -two local recurrences (33%). One patient became pregnant in the group of vaginal trachelectomies. Therefore laparoscopic approach in treatment of female genital malignacies allows performing an adequate volume of surgery with minimal risk of intra- and postoperative complications, favorable course of the rehabilitation period, and oncological safety. PMID- 30452195 TI - [Breast cancer: clinical and experimental research]. AB - This manuscript includes an update on the latest developments in the biology of breast cancer as well as the most recent advances in prevention and multidisciplinary management of this disease: surgery after neoadjuvant chemotherapy and anti-HER2 therapy of HER2 positive breast cancer, neoadjuvant and adjuvant endocrine treatment of ER+ (Luminal A) breast cancer. Our task (as in the St. Gallen and ESMO consensus recommendations) is to assist physicians to improve both therapy impact in patients and their results. PMID- 30452196 TI - [New approaches to treatment for malignant tumors using perfusion technologies]. AB - The paper summarizes and analyzes the results of complex treatment of patients with malignant tumors performed in the N.N.Petrov Research Institute of Oncology using perfusion technologies. Safety and efficacy data on various chemoperfusion is presented: intraperitoneal chemoperfusion combined with cytoreductive surgery in patients with locally advanced and disseminated gastric cancer, recurrent ovarian cancer and pseudomyxoma peritonei; isolated lung perfusion combined with metastasectomy in patients with lung metastases; isolated limb perfusion with/without cytoreduction in patients with locally advanced skin melanoma and locally advanced soft-tissue sarcoma. The conclusion is made that both intraperitoneal and isolated chemoperfusions are not associated with higher incidence of intra- and postoperative morbidity. However safety of the procedures could be increased through optimizing tactics of surgical procedures prior to chemoperfusions. The use of perfusion technologies provides significant survival advantage in patients who can't benefit from conservative treatment. PMID- 30452198 TI - Venous thromboembolism in acute medically ill patients: identifying unmet needs and weighing the value of prophylaxis. PMID- 30452199 TI - The use of betrixaban for extended prophylaxis of venous thromboembolism events in hospitalized, high-risk patients. PMID- 30452200 TI - Best practices for implementing venous thromboembolism prophylaxis across the continuum of care. PMID- 30452201 TI - Hospital cancer pain management by electronic health record-based automatic screening. AB - OBJECTIVES: A cancer pain clinic (CPC) service is a thorough, comprehensive consultation service for patients with uncontrolled cancer pain. The aim of this study was to determine the success of a new CPC service with enrollment via electronic health record-based automatic screening at 1 cancer center in Korea. STUDY DESIGN: A case-control study and a satisfaction survey. METHODS: The intervention group (n = 158) was enrolled in the CPC service, whereas the control group (n = 158), which was matched using propensity scores, did not participate in the service. The pain scores of participants were compared using an independent t test. Thirty-nine patients and 20 physicians completed a self administered survey on instructions for pain-relief medications, effective usage of long-acting and short-acting opioids, perceptions of or barriers to CPC services, knowledge of opioid use, and overall satisfaction. RESULTS: Although the baseline pain score of the intervention group was significantly higher than that of the control group (P = .013), the difference in the decrease of pain between the groups was significant at days 1 (P = .001) and 2 (P = .039). Although the difference in pain scores disappeared on day 3, total pain score was significantly lower in the intervention group than in the control group (P = .012). When comparing pain relief events (<4 points on a 0-10 numeric rating scale that measured pain daily), the intervention group experienced more relief events than did controls (P = .017). Patients were satisfied with their physicians giving clear instructions and considering their opinions about pain relief medications. The oncology residents expressed satisfaction with the management of patients with opioid-naive or intractable pain. CONCLUSIONS: The new CPC service seems to provide effective pain relief and users seem to be highly satisfied with it. These results support the importance of an integrated and specialized approach to cancer-related pain management. PMID- 30452202 TI - Impact of dementia on costs of modifiable comorbid conditions. AB - OBJECTIVES: To use the CMS 5% data sample to explore the impact of Alzheimer disease and other dementias (ADOD) on individual and population costs of certain potentially modifiable comorbid conditions, in order to assist in the design of population health management (PHM) programs for individuals with ADOD. STUDY DESIGN: A cross-sectional retrospective analysis was performed on parts A and B claims data of 1,056,741 Medicare beneficiaries 65 years and older with service dates in 2010. METHODS: The primary analysis compared the prevalence and costs of 15 comorbid conditions among those with and without ADOD in the entire sample of 1,056,741; in addition, a subset of beneficiaries without ADOD were matched by age, sex, and race on a 1:1 basis to beneficiaries with ADOD. Prevalence and cost ratios were calculated to examine the impact of potentially modifiable study comorbid conditions in both populations. RESULTS: The prevalence of ADOD in the entire sample was 9.4%, and their costs represented 22.8% of the total. In the matched sample, all 15 comorbid conditions chosen for the study were more prevalent and showed higher mean individual costs in beneficiaries with ADOD compared with those without. The ADOD population also had higher costs and prevalence than the non-ADOD population when single comorbid conditions were examined separately. Study conditions with the highest individual cost ratios were urinary tract infections (UTIs), diabetes with complications, and fractures. Study conditions with the highest population cost ratios were fractures, UTIs, and diabetes without complications. CONCLUSIONS: Prevalence and costs of all study comorbidities were higher in beneficiaries with ADOD compared with those without. Individual cost ratios and population cost ratios may be useful for PHM programs trying to cost-effectively manage individuals with ADOD and comorbid chronic conditions. PMID- 30452203 TI - Patients' adoption of and feature access within electronic patient portals. AB - OBJECTIVES: We describe online portal account adoption and feature access among subgroups of patients who traditionally have been disadvantaged or represent those with high healthcare needs. STUDY DESIGN: Retrospective cohort study of insured primary care patients 18 years and older (N = 20,282) receiving care from an integrated health system. METHODS: Using data from an electronic health record repository, portal adoption was defined by 1 or more online sessions. Feature access (ie, messaging, appointment management, visit/admission summaries, and medical record access and management) was defined by user-initiated "clicks." Multivariable regression methods were used to identify patient factors associated with portal adoption and feature access among adopters. RESULTS: One-third of patients were portal adopters, with African Americans (odds ratio [OR], 0.50; 95% CI, 0.46-0.56), Hispanics (OR, 0.63; 95% CI, 0.47-0.84), those 70 years and older (OR, 0.48; 95% CI, 0.44-0.52), and those preferring a language other than English (OR, 0.43; 95% CI, 0.31-0.59) less likely to be adopters. On the other hand, the likelihood of portal adoption increased with a higher number of comorbidities (OR, 1.04; 95% CI, 1.02-1.07). Among adopters, record access and management features (95.9%) were accessed most commonly. The majority of adopters also accessed appointment management (76.6%) and messaging (59.1%) features. Similar race and age disparities were found in feature access among adopters. CONCLUSIONS: The diversity of portal features accessed may bode well for the ability of portals to engage some patients, but without purposeful intervention, reliance on portals alone for patient engagement may exacerbate known social disparities-even among those with an activated portal account. PMID- 30452204 TI - Predicting 30-day emergency department revisits. AB - OBJECTIVES: To develop a predictive model that hospitals or healthcare systems can use to identify patients at high risk of revisiting the emergency department (ED) within 30 days and thus reduce unnecessary ED use through proactive interventions. STUDY DESIGN: A retrospective analysis of fiscal years (FYs) 2013 and 2014 data from 4 Veterans Affairs hospitals in upstate New York. METHODS: This study developed a predictive model based on administrative data, a publicly available patient classification system, and logistic regression. The study data were from 4 Veterans Affairs hospitals in upstate New York; FY 2013 data were used to predict 30-day revisits in FY 2014. All 22,734 patients with ED visits were included in the analysis. The predictive variables were patient demographics, prior-year utilization, and comorbidities. To prevent overfitting, we validated the model by the split-sample method. The predictive power of the model is measured by C statistics. RESULTS: In the first model using only patient demographics, the C statistics were 0.568 (95% CI, 0.555-0.580) and 0.556 (95% CI, 0.543-0.568) for the development and validation samples, respectively. In the second model with prior-year utilization added, the C statistics were 0.748 (95% CI, 0.737-0.759) for both samples. In the final model with comorbidities added, the C statistics reached 0.773 (95% CI, 0.762-0.784) and 0.763 (95% CI, 0.753 0.774) for the development and validation samples, respectively. CONCLUSIONS: The predictive model we developed in this study is straightforward to implement and offers significantly higher predictive power than other models reported in the literature. Hospitals and healthcare systems can use it to identify high-risk "frequent flyers" for early interventions to reduce ED revisits. PMID- 30452205 TI - Effects of a community-based care management model for super-utilizers. AB - OBJECTIVES: Medicare, Medicaid, and commercial plans have all explored ways to improve outcomes for patients with high costs and complex medical and social needs. The purpose of this study was to test the effectiveness of a high intensity care management program that the Rutgers University Center for State Health Policy (CSHP) implemented as an adaptation of a promising model developed by the Camden Coalition of Healthcare Providers. STUDY DESIGN: We estimated the impact of the program on 6 utilization and spending outcomes for a subgroup of beneficiaries enrolled in Medicare fee-for-service (n = 149) and a matched comparison group (n = 1130). METHODS: We used Medicare claims for all analyses. We used propensity score matching to construct a comparison group of beneficiaries with baseline characteristics similar to those of program participants. We employed regression models to test the relationship between program enrollment and outcomes over a 12-month period while controlling for baseline characteristics. RESULTS: A test of joint significance across all outcomes showed that the CSHP program reduced service use and spending in aggregate (P = .012), although estimates for most of the individual measures were not statistically significant. Participants had 37% fewer unplanned readmissions (P = .086) than did comparison beneficiaries. Although we did not find statistically significant results for the other 5 outcomes, the CIs for these outcomes spanned substantively large effects. CONCLUSIONS: Although these findings are mixed, they suggest that adaptations of the Camden model hold promise for reducing short-term service use and spending for Medicare super utilizers. PMID- 30452206 TI - A narrow view of Choosing Wisely. AB - This letter argues that an editorial published in the August 2018 issue provides an unduly limited perspective of the impact of Choosing Wisely. PMID- 30452207 TI - Understanding and improving value frameworks with real-world patient outcomes. AB - OBJECTIVES: To provide recommendations that will improve approaches to measuring the value of new medical technologies to patients. STUDY DESIGN: Informed discussion by experts after literature review. METHODS: A working group was formed, and participants discussed how value frameworks should incorporate key features important to patients in evaluating new medical technologies, particularly for chronic diseases. RESULTS: The working group suggests that new value frameworks should integrate real-world evidence to complement randomized controlled trials, incorporate the ways in which real-world behavior mediates outcomes, and explicitly discuss how therapies affect real-world equity and disparities in care. CONCLUSIONS: Collective stakeholders that include key decision makers within our healthcare system need to recognize the importance of implementing real-world evidence and devote resources to further research into the chronic disease areas in which the impact of human behavior is amplified by the duration of disease and treatment. PMID- 30452208 TI - A randomized, pragmatic, pharmacist-led intervention reduced opioids following orthopedic surgery. AB - OBJECTIVES: To determine whether a pharmacist-led, patient-directed intervention can reduce opioid use following total hip arthroplasty (THA) or total knee arthroplasty (TKA). STUDY DESIGN: Randomized trial. METHODS: Patients scheduled to undergo THA or TKA (during 2015 and 2016) were randomized to usual care or intervention. We ranked patients according to predicted risk of persistent opioid use and selected the top 60% for inclusion (n = 561); all contributed to the analysis. Intervention patients were mailed materials 2 weeks before and after surgery, plus they received telephone intervention from specially trained pharmacists if they filled opioid prescriptions in the 28 to 90 days following surgery. Our primary outcome was the dispensed morphine equivalents (DME) in the 90 days following surgery, modeled using a natural log transformation. RESULTS: A total of 561 patients were randomized (286 usual care, 118 THA and 168 TKA; 275 intervention, 107 THA and 168 TKA); the mean age was 66 years, and 60% were female. Overall, we found no meaningful reduction in DME for intervention versus usual care (geometric mean ratio, 0.92 [95% CI, 0.69-1.21]). However, there was effect modification by whether the patient had TKA or THA (interaction P <.01). Those undergoing THA in the intervention group used significantly less DME than did those undergoing THA in the usual care group (geometric mean ratio, 0.52 [95% CI, 0.33-0.82]). CONCLUSIONS: Our pharmacist-led, patient-directed intervention to reduce opioid use demonstrated a reduction in opioid dispensings in the 90 days following THA but not TKA. PMID- 30452209 TI - Cost of pharmacotherapy for opioid use disorders following inpatient detoxification. AB - OBJECTIVES: To estimate the costs of providing extended-release injectable naltrexone (XR-NTX) and buprenorphine-naloxone (BUP-NX) following inpatient detoxification using data derived from a multisite randomized controlled trial at 8 US community-based treatment programs. STUDY DESIGN: Cost data were collected for 3 intervention phases: program start-up, inpatient detoxification, and up to 24 weeks of medication induction and management visits (post detoxification). Cost analyses were from the healthcare sector perspective (2015 US$); patient costs are also reported. METHODS: We conducted site visits, administered a cost survey to treatment programs, and analyzed study data on medication and services utilization. Nationally representative sources were used to estimate unit costs. Uncertainty was evaluated in sensitivity analyses. RESULTS: Mean start-up costs were $1071 per program for XR-NTX and $828 per program for BUP-NX. Mean costs per participant were $5416 for XR-NTX (57% detoxification, 37% medication, 3% provider, 3% patient) and $4148 for BUP-NX (64% detoxification, 12% medication, 10% provider, 14% patient). Total cost per participant ranged by site from $2979 to $8963 for XR-NTX and from $2521 to $6486 for BUP-NX. CONCLUSIONS: For treatment providers, offering XR-NTX and/or BUP-NX as part of existing detoxification treatment modalities generates modest costs in addition to the costs of detoxification, which vary substantially among the 8 sites. From the patient's perspective, the costs associated with medication management visits may be a barrier for some individuals considering these treatments. PMID- 30452210 TI - Overdose risk for veterans receiving opioids from multiple sources. AB - OBJECTIVES: The aim of this study was to evaluate whether veterans in Massachusetts receiving opioids and/or benzodiazepines from both Veterans Health Administration (VHA) and non-VHA pharmacies are at higher risk of adverse events compared with those receiving opioids at VHA pharmacies only. STUDY DESIGN: A cohort study of veterans who filled a prescription for any Schedule II through V substance at a Massachusetts VHA pharmacy. Prescriptions were recorded in the Massachusetts Department of Public Health Chapter 55 data set. METHODS: The study sample included 16,866 veterans residing in Massachusetts, of whom 9238 (54.8%) received controlled substances from VHA pharmacies only and 7628 (45.2%) had filled prescriptions at both VHA and non-VHA pharmacies ("dual care users") between October 1, 2013, and December 31, 2015. Our primary outcomes were nonfatal opioid overdose, fatal opioid overdose, and all-cause mortality. RESULTS: Compared with VHA-only users, more dual care users resided in rural areas (12.6% vs 10.6%), received high-dose opioid therapy (26.3% vs 7.3%), had concurrent prescriptions of opioids and benzodiazepines (34.8% vs 8.2%), and had opioid use disorder (6.8% vs 1.6%) (P <.0001 for all). In adjusted models, dual care users had higher odds of nonfatal opioid overdose (odds ratio [OR], 1.29; 95% CI, 0.98-1.71) and all-cause mortality (OR, 1.66; 95% CI, 1.43-1.93) compared with VHA-only users. Dual care use was not associated with fatal opioid overdoses. CONCLUSIONS: Among veterans in Massachusetts, receipt of opioids from multiple sources was associated with worse outcomes, specifically nonfatal opioid overdose and mortality. Better information sharing between VHA and non-VHA pharmacies and prescribers has the potential to improve patient safety. PMID- 30452211 TI - [Specific features of drug sensitivity of hereditary cancers]. AB - Until recently the detection of carriers of mutations in hereditary cancer genes was aimed almost exclusively to the detection of subjects-at-risk, and consequently, personalized monitoring and preventive actions. However, it was revealed several years ago that some hereditary cancers are characterized by unique biological features and, therefore, unusual spectrum of drug sensitivity. For example, BRCA1/2-associated cancers usually demonstrate somatic loss of the remaining gene allele, and, hence, tumor-specific defects of DNA repair of double strand breaks. This mechanism determines increased sensitivity of BRCA1/2-related cancers to cisplatin, mitomycin C and PARP inhibitors. Cancers arising as a part of Lynch syndrome can be effectively treated by the modulators of immune response. Tumors in patients with tuberous sclerosis often regress after administration of mTOR inhibitors. For the time being, there is already about a dozen of drugs demonstrating specific activity towards certain categories of hereditary cancers. PMID- 30452212 TI - [Oncoendocrinology: interim results and new challenges]. AB - Over the few past years there have been passed many significant and positive changes in various fields of oncology due to both the use of achievements, stimulated by previous generations, and the progress of modern technology. This largely concerns endocrinology of malignant tumors, which is reflected in this article on the basis of the experience of the N.N.Petrov Research Institute of Oncology gained during recent times. Above all it is about the features of tumors of hormone-dependent tissues, hormonal and metabolic shifts, associated with them, and the ways of their correction based on the principles of personalized medicine. PMID- 30452213 TI - Current market and regulatory landscape of biosimilars. AB - The introduction of biologic therapies has improved the treatment landscape for multiple diseases, particularly in the areas of oncology, rheumatology, and endocrinology. Although they are effective, biologics are associated with increased costs that result in economic burden for healthcare professionals and patients. Biosimilars are biologic medical products that are almost an identical copy of the original product. There are differences in the regulatory requirements for the original biologic product and a biosimilar, as biosimilars gain FDA approval through an abbreviated approval pathway. The incorporation of these products into the US market will potentially result in improved patient access and decreased healthcare costs. There are barriers, such as lack of familiarity, that affect the use of biosimilars. Strategies to overcome these barriers are essential to improve the uptake of these products in the United States. PMID- 30452214 TI - Optimizing use and addressing challenges to uptake of biosimilars. AB - With the passing and implementation of the Biologics Price Competition and Innovation Act in 2010, biosimilars became a new classification of FDA-approved drugs. The biosimilar classification, created with a streamlined drug approval process, was intended to spur competition and reduce the cost of biological product therapies. Since the first FDA-approved biosimilar in 2015, the impact of biosimilars on the US biological product market remains to be seen. As more biosimilar products are approved and marketed, cost-savings are expected with predictions ranging from $54 billion to $250 billion by the mid-2020s. However, a multitude of factors may diminish the cost-saving potential of biosimilars. For biosimilars to gain market share, patients, physicians, and other healthcare professionals will need to accept biosimilars as safe and effective alternatives to reference-biologic products. A key factor in gaining this acceptance is educating the public, physicians, and healthcare professionals on the rigorous approval standards required of biosimilars by the FDA. Other factors that will affect market share of biosimilars include litigation actions by biopharmaceutical manufacturers; positions stated by physician organizations; and the influences of insurers and managed care. The clinical and basic science required for biosimilar approvals will be major underlying elements driving biosimilar acceptance and increased market presence. PMID- 30452215 TI - [Prospects of use of antidiabetic biguanides for cancer prevention and treatment: results of preclinical studies]. AB - The critical analysis of preclinical testing of anticarcinogenic and antitumor activity of biguanides presented in this paper. Experiments have been conducted using in total more than 20 models of carcinogenesis including models of spontaneous , chemically- , radiation- and virus-induced carcinogenesis, as well as carcinoigenesis induced by special fat diets and by genetic modification in rodents. Cancer preventive effect of buiguanides has been studied in relation to total tumor incidence and to 17 target organs in animals of 3 species, including 25 various strains of mice, 4 strains of rats and 1 strain of hamsters using various routs of administration and doses. In the majority of cases (86%) the exposure to biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed, however there was no any case of stimulation of carcinogenesis by antidiabetic biguanides., Metformin suppressed tumor growth in the majority of in vitro studies conducted in 46 different cell lines originated from malignant tumors of 15 localization as well as in athymic mice with xenografts of 31 tumor lines. It was concluded that there are sufficient experimental evidences of anticarcinogenic and antitumor effects of antidiabetic biguanides revealed in a number of models of induced and spontaneous carcinogenesis. PMID- 30452216 TI - 3D-Printed Surface Architecture Enhancing Superhydrophobicity and Viscous Droplet Repellency. AB - Macro-textured superhydrophobic surfaces can reduce droplet-substrate contact times of impacting water droplets; however, surface designs with similar performance for significantly more viscous liquids are missing, despite their importance in nature and technology such as for chemical shielding, food staining repellency, and supercooled (viscous) water droplet removal in anti-icing applications. Here, we introduce a deterministic, controllable and up-scalable method to fabricate superhydrophobic surfaces with a 3D-printed architecture, combining arrays of alternating surface protrusions and indentations. We show a more than threefold contact time reduction of impacting viscous droplets up to a fluid viscosity of 3.7 mPa.s, which equals 3.7 times the viscosity of water at room temperature, covering the viscosity of many chemicals and supercooled water. Based on the combined consideration of the fluid flow within and the simultaneous droplet dynamics above the texture, we recommend future pathways to rationally architecture such surfaces, all realizable with the methodology presented here. PMID- 30452217 TI - From Alloy to Oxide: Capturing the Early Stages of Oxidation on Ni-Cr(100) Alloys. AB - The interaction of oxygen with Ni-Cr(100) alloy surfaces is studied using Scanning Tunneling Microscopy (STM) and Spectroscopy (STS) to observe the initial steps of oxidation and formation of the alloy-oxide interface. The progression of oxidation was observed for Ni(100) and Ni-Cr(100) thin films including Ni 8wt.%Cr(100) and Ni-12wt.%Cr(100), which were grown on MgO(100) in-situ. These surfaces were exposed to between one and 150 L O2 at 500 oC, and additional annealing steps were performed at 500 oC and 600 oC. Each oxidation and annealing step was studied with STM and STS, and differential conductance maps delivered spatially resolved information on doping and bandgap distributions. Initial NiO nucleation and growth begins along the step edges of the Ni-Cr alloy accompanied by the formation of small oxide particles on the terraces. The incubation period known in oxidation of Ni(100) is absent on Ni-Cr alloy surfaces illustrating the significant changes in surface chemistry triggered by Cr alloying. Step edge faceting is initiated by step edge decoration of a NiO-Ni (7?8) coincidence lattice, which is expressed in moire patterns in the STM images. Small patches of NiO are susceptible to reduction during annealing, but additional oxidation steps stabilize the NiO, which has a cube-on-cube epitaxial interface and a NiO-Ni (6?7) coincidence lattice grows into the terrace. NiO regions are interspersed with areas covered predominantly with a novel cross-type reconstruction, which is interpreted tentatively as a Cr-rich, phase-separated region. Statistical analysis of the geometric features of the surface oxide including step edge heights, and NiO wedge angles illustrate the layer-by-layer growth mode of NiO in this pre-Cabrera Mott regime, and the restructuring of the alloy-oxide interface during the oxidation process. This experimental approach has offered greater insight into the progression of oxide growth in Ni-Cr thin films and underscores the dramatic impact of alloying on oxidation process in the pre Cabrera-Mott regime. PMID- 30452218 TI - Tailoring Hollow Nanostructures by catalytic strategy for Superior Lithium and Sodium Storage. AB - Nowadays, a novel catalyzed strategy for designing 3D carbon nanosheet frameworks is widely concerned in the field of energy storage. Herein, 3D hollow structure with nickel and nanographitic domains is presented to fabrication of functionalized with hollow microporous carbon embedded with expanded defective nanographitic domains or hollow nickel oxide composites followingly. The hollow microporous carbon coupling nanographitic domains exhibits excellent long-term cyclicity (4000 cycles for lithium storage, 2000 cycles for sodium storage), which is mainly due to the formation of defects in the nano-graphite for catalytic strategy. The hollow nickel oxide composites show the capacities of 1093 mA*hg-1 after 400 cycles with the high coulombic efficiency at a current density of 200 mA*g-1 for lithium storage and superior rate performance at different current densities for sodium storage. Stable and great energy storage features stem from the fact that the hollow structure can provide more active sites for ionic diffusion/storage and a free shuttle space for electrons. PMID- 30452219 TI - DNA-encoded library-derived DDR1 inhibitor prevents fibrosis and renal function loss in a genetic mouse model of Alport syndrome. AB - The importance of DDR1 in renal fibrosis has been shown via gene knockout and use of antisense oligonucleotides; however, these techniques act via a reduction of DDR1 protein while we prove the therapeutic potential of inhibiting DDR1 phosphorylation with a small molecule. To date, efforts to generate a selective small-molecule to specifically modulate the activity of DDR1 in an in vivo model have been unsuccessful. We performed parallel DNA encoded library screens against DDR1 and DDR2, and discovered a chemical series that is highly selective for DDR1 over DDR2. Structure-guided optimization efforts yielded the potent DDR1 inhibitor 2.45, which possesses excellent kinome selectivity (including 64-fold selectivity over DDR2 in a biochemical assay), a clean in vitro safety profile, and favorable pharmacokinetic and physicochemical properties. As desired, compound 2.45 modulates DDR1 phosphorylation in vitro as well as prevents collagen-induced activation of renal epithelial cells expressing DDR1. Compound 2.45 preserves renal function and reduces tissue damage in Col4a3-/- mice (the preclinical mouse model of Alport syndrome) when employing a therapeutic dosing regime, indicating the real therapeutic value of selectively inhibiting DDR1 phosphorylation in vivo. Our results may have wider significance as Col4a3-/- mice also represent a model for chronic kidney disease, a disease which affects 10% of the global population. PMID- 30452220 TI - Facilitating CO2 transport across mixed matrix membranes containing multifunctional nanocapsules. AB - Mixed matrix membranes (MMMs) have exhibited advantages in overcoming the trade off effect, although it is still intensively demanded in the design of multifunctional fillers to improve CO2 separation performance. At present, MMMs with transport channels present an effective strategy to obtain ultrahigh CO2 permselectivity. In this work, Pebax-based MMMs was fabricated by incorporating nanocapsules (NCs), whose exterior, interior and transverse shell surfaces contained abundant carboxylic acid groups. NCs, similar to vesicles in cells, provide favourable physical and chemical microenvironments to the constructed CO2 transport channels, enhancing the CO2 permselectivity via both a facilitated transport mechanism and a solution-diffusion mechanism. CO2 permselectivity of MMMs doped with 20 wt% NCs surpassed the 2008 Robeson limit; an increase in CO2 permeability was up to 1431 +/- 35 Barrer for pure gas, which was a 362% enhancement from the pure membrane, and an increase of the CO2/CH4 and CO2/N2 ideal selectivities to 46 +/- 1.4 and 69 +/- 2.7, corresponding to 44% and 23% enhancements from the pure membrane, respectively. This study provides an ingenious strategy to enhance the gas permselectivity of MMMs. PMID- 30452221 TI - Binding of lignin nanoparticles at oil-water interfaces: An ecofriendly alternative to oil spill recovery. AB - Synthetic amphiphiles used for managing large-scale oil spills have toxic impact on the environment and marine life. Developing new oil spill recovery technologies is critical to minimize the environmental and ecological impact of such disasters. Here we show that a mixture of lignin nanoparticles and 1 pentanol form a biocompatible alternative to non-degradable, synthetic amphiphiles used for oil spill recovery. The pentanol in the mixture generates initial Marangoni flow and confines spilled oil into thick slick on the surface of water. While the alcohol solubilizes, lignin nanoparticles irreversibly adsorb onto the oil-water interface. We find that the lignin nanoparticles adsorption to the oil-water interface is governed by a combination of electrostatic, van der Waals and hydrophobic interactions between the particles and the interface. These interactions, combined with interparticle electrostatic repulsion between nanoparticles adsorbed at the oil-water interface, drive the formation of a sub monolayer. The sub-monolayer transforms into a film of jammed nanoparticles due a compressive stress acting on the interface upon the solubilization of the pentanol. This interfacial layer of lignin nanoparticles restricts oil from re spreading and locks the oil in its confined state. The herded state of the oil with the interfacial layer of nanoparticles facilitates safe removal of the spilled oil using mechanical methods. The study presents a new principle of using a mixture of a heavy alcohol and biocompatible nanoparticles for oil herding application, thus providing an ecofriendly alternative to oil spill recovery. PMID- 30452222 TI - Construction of MoS2/C Hierarchical Tubular Heterostructures for High-Performance Sodium Ion Batteries. AB - Molybdenum disulfide (MoS2) has been considered to be a promising anode material for sodium ion batteries (SIBs), because of its high capacity and graphene-like layered structure. However, irreversible conversion reaction during the sodiation/desodiation process is a major problem that must be overcome before its practical applications. In this work, MoS2/amorphous carbon (C) microtubes (MTs) composed of heterostructured MoS2/C nanosheets have been developed via a simple template method. The existence of MoS2/C heterointerface plays a key role in achieving high and stable performance by stabilizing the reaction products Mo and sulfide phases, providing fast electronic and Na+ ions diffusion mobility, and alleviating the volume change. MoS2/C MTs exhibit a high reversible specific capacity of 563.5 mA h g-1 at 0.2 A g-1, good rate performance (520.5, 489.4, 452.9, 425.1, and 401.3 mA h g-1 at 0.5, 1.0, 2.0, 5.0, and 10.0 A g-1, respectively), and excellent cycling stability (484.9 mA h g-1 at 2.0 A g-1 after 1500 cycles). PMID- 30452223 TI - Tension-Induced Translocation of an Ultrashort Carbon Nanotube through a Phospholipid Bilayer. AB - Increasing awareness of bioeffects and toxicity of nanomaterials interacting with cells puts in focus the mechanisms by which nanomaterials can cross lipid membranes. Apart from well-discussed energy-dependent endocytosis for large objects and passive diffusion through membranes by solute molecules, other translocation mechanisms based on physical principles can exist. We show the importance of membrane tension on the translocation through lipid bilayers of ultrashort carbon nanotubes (USCNTs). By using a combination of a microfluidic setup and single chain mean field (SCMF) theory, we observed that, under membrane tension, USCNT inserted into a lipid bilayer may spontaneously nucleate an unstable local pore, allowing it to escape from the bilayer. We demonstrated that stretching of the membrane is essential for triggering this mechanism of translocation, and no translocation is observed at low membrane tension. For this purpose, a quantitative analysis of the kinetic pathway associated with USCNT translocation induced by tension was performed in a specially designed microfluidic device, simultaneously combining optical fluorescence microscopy and electrophysiological measurements. An important outcome of these findings is the identification of the way to control the nanomaterial translocation through the lipid bilayer by membrane tension that can be useful in many practical applications. PMID- 30452224 TI - Correction to Copper Silicate Hollow Microspheres-Incorporated Scaffolds for Chemo-Photothermal Therapy of Melanoma and Tissue Healing. PMID- 30452225 TI - Sea Urchin Embryo Model As a Reliable in Vivo Phenotypic Screen to Characterize Selective Antimitotic Molecules. Comparative evaluation of Combretapyrazoles, isoxazoles, -1,2,3-triazoles, and -pyrroles as Tubulin-Binding Agents. AB - A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3 hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3 triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4 diarylisoxazoles was increased. PMID- 30452226 TI - Layered-Structure SbPO4/Reduced Graphene Oxide: An Advanced Anode Material for Sodium Ion Batteries. AB - Sodium ion batteries are one of most promising alternatives to lithium ion batteries for large-scale energy storage, due to the high abundance and low cost of sodium in the earth. However, the lack of advanced electrode materials greatly affects their applications. Here, layered-structure SbPO4 is explored as an anode material for sodium ion batteries in terms of SbPO4 nanorods on reduced graphene oxide (SbPO4/rGO). In situ transmission electron microscopy images reveal the preferential expansion along the transverse direction of the nanorods upon the first discharging, which arises from the reduction of SbPO4 to Sb and the subsequent alloying of Sb as supported by in situ X-ray diffraction and selected area electron diffraction patterns. SbPO4/rGO exhibits a capacity retention of 99% after 100 cycles at 0.5 A g-1 both in half cells and in full cells. Its specific capacity at 5 A g-1 is 214 mA h g-1 in half cells or 134 mA h g-1 in full cells. Moreover, the energy density of the full cells at 1.2 kW kg-1total is still 99.8 W h kg-1total, very promising as an advanced electrode material. PMID- 30452227 TI - Biodegradable nanoparticles containing mechanism based peptide inhibitors reduce polyglutamine aggregation in cell models and alleviate motor symptoms in Drosophila model of Huntington's disease. AB - Detailed study of the molecular mechanism behind the pathogenesis of Huntington's disease (HD) suggests that the polyglutamine aggregation is one of the fundamental reasons. Despite of discovery of many potential molecules, HD therapy is yet limited to symptomatic relief. Among these molecules, few mechanism based peptide inhibitors of polyglutamine aggregation (QBP1, NT17 and PGQ9P2) have shown promising activity; however, poor blood-brain barrier (BBB) penetration, low bioavailability and low half-life may hinder their therapeutic potential. Hence, to deliver them to brain for assessing their efficacy, we have designed and synthesized peptide loaded poly-D, L-lactide-co-glycolide (PLGA) nanoparticles of size less than 200 nm by carbodiimide chemistry and nanoprecipitation protocols. For brain delivery, PLGA nanoparticles were coated with polysorbate 80 which aids receptor mediated internalization. Using in vitro BBB model of Madin-Darby Canine Kidney cells and healthy mice, the translocation of polysorbate 80 coated fluorescent nanoparticles was confirmed. Moreover, QBP1, NT17 and PGQ9P2 loaded PLGA nanoparticles showed dose dependent inhibition of polyglutamine aggregation in cell models of HD (Neuro 2A and PC12 cells) and improved motor performance in Drosophila model of HD. Additionally, no toxicity in cells and animals confirmed biocompatibility of the nanoparticulate formulations. Based on this work, future studies can be designed in higher animal models to test peptide loaded nanoparticles in HD and other polyglutamine expansion related diseases. PMID- 30452228 TI - Ultrahigh Conductivity and Superior Interfacial Adhesion of a Nanostructured, Photonic Sintered Copper Membrane for Printed Flexible Hybrid Electronics. AB - Inkjet-printed electronics using metal particles typically lack electrical conductivity and interfacial adhesion with an underlying substrate. To address the inherent issues of printed materials, this paper introduces advanced materials and processing methodologies. Enhanced adhesion of the inkjet-printed copper (Cu) on a flexible polyimide film is achieved by using a new surface modification technique, a nanostructured self-assembled monolayer (SAM) of (3 mercaptopropyl)trimethoxysilane. A standardized adhesion test reveals the superior adhesion strength (1192.27 N/m) of printed Cu on the polymer film, while maintaining extreme mechanical flexibility proven by 100,000 bending cycles. In addition to the increased adhesion, the nanostructured SAM treatment on printed Cu prevents formation of native oxide layers. Combined with newly synthesized Cu ink and associated sintering technique with an intense pulsed ultraviolet and visible light absorption, it enables ultrahigh conductivity of printed Cu (2.3 x 10-6 Omega?cm), which is the highest electrical conductivity reported to date. The comprehensive materials engineering technologies offer highly reliable printing of Cu patterns for immediate use in wearable flexible hybrid electronics. In vivo demonstration of printed, skin-conformal Cu electrodes indicates a very low skin-electrode impedance (< 50 kOmega) without a conductive gel and successfully measures three types of biopotentials, including electrocardiograms, electromyograms, and electrooculograms. PMID- 30452230 TI - All-2D Material Inkjet-Printed Capacitors: Toward Fully Printed Integrated Circuits. AB - A well-defined insulating layer is of primary importance in the fabrication of passive ( e.g., capacitors) and active ( e.g., transistors) components in integrated circuits. One of the most widely known two-dimensional (2D) dielectric materials is hexagonal boron nitride (hBN). Solution-based techniques are cost effective and allow simple methods to be used for device fabrication. In particular, inkjet printing is a low-cost, noncontact approach, which also allows for device design flexibility, produces no material wastage, and offers compatibility with almost any surface of interest, including flexible substrates. In this work, we use water-based and biocompatible graphene and hBN inks to fabricate all-2D material and inkjet-printed capacitors. We demonstrate an areal capacitance of 2.0 +/- 0.3 nF cm-2 for a dielectric thickness of ~3 MUm and negligible leakage currents, averaged across more than 100 devices. This gives rise to a derived dielectric constant of 6.1 +/- 1.7. The inkjet printed hBN dielectric has a breakdown field of 1.9 +/- 0.3 MV cm-1. Fully printed capacitors with sub-micrometer hBN layer thicknesses have also been demonstrated. The capacitors are then exploited in two fully printed demonstrators: a resistor capacitor (RC) low-pass filter and a graphene-based field effect transistor. PMID- 30452229 TI - Atomic-Level Doping of Metal Clusters. AB - Atomically precise noble metal (mainly silver and gold) nanoclusters are an emerging category of promising functional materials for future applications in energy, sensing, catalysis, and nanoelectronics. These nanoclusters are protected by ligands such as thiols, phosphines, and hydride and have sizes between those of atoms and plasmonic nanoparticles. In metallurgy, the properties of a pure metal are modified by the addition of other metals, which often offers augmented characteristics, making them more utilizable for real-life applications. In this Account, we discuss how the incorporation of various metal atoms into existing protected nanoclusters tunes their structure and properties. The process of incorporating metals into an existing cluster is known as doping; the product is known as a doped cluster, and the incorporated metal atom is called a dopant/foreign atom. We first present a brief historical overview of protected clusters and the need for doping and explain (with examples) the difference between an "alloy" and a "doped" cluster, which are two frequently confused terms. We then discuss several commonly observed challenges in the synthesis of doped clusters: (i) doping produces a mixture of compositions that prevents the growth of single crystals; (ii) doping with foreign atoms sometimes changes the overall composition and structure of the parent cluster; and (iii) doping beyond a certain number of foreign atoms decomposes the doped cluster. After delineating the challenges, we review a few potential synthetic methods for doped clusters: (i) the co-reduction method, (ii) the galvanic exchange method, (iii) ligand induced conversion of bimetallic clusters to doped clusters, and (iv) intercluster reactions. As a foreign atom is able to occupy different positions within the structure of the parent cluster, we examine the structural relationship between the parent clusters and their different foreign-atom-doped clusters. We then show how doping enhances the stability, luminescence, and catalytic properties of clusters. The enhancement factor highly depends on the number and nature of the foreign atoms, which can also alter the charge state of the parent cluster. Atomic-level doping of foreign atoms in the parent cluster is confirmed by high-resolution electrospray ionization and matrix-assisted laser desorption ionization mass spectrometry techniques and single-crystal X-ray diffraction methods. The photophysical properties of the doped clusters are investigated using both time-dependent and steady-state luminescence and optical absorption spectroscopies. After presenting an overview of atomic-level doping in metal clusters and demonstrating its importance for enriching the chemistry and photophysics of clusters and extending their applications, we conclude this Account with a brief perspective on the field's future. PMID- 30452231 TI - Internalization of Methotrexate Conjugates by Folate Receptor-alpha. AB - The folate antagonist methotrexate is a cytotoxic drug used in the treatment of several cancer types. The entry of methotrexate into the cell is mediated by two main transport systems: the reduced folate carrier and membrane-associated folate receptors. These transporters differ considerably in their mechanism of (anti)folate uptake, substrate specificity, and tissue specificity. Although the mechanism of action of the reduced folate carrier is fairly well-established, that of the folate receptor has remained unknown. The development of specific folate receptor-targeted antifolates would be accelerated if additional mechanistic data were to become available. In this work, we used two fluorescently labeled conjugates of methotrexate, differently linked at the terminal groups, to clarify the uptake mechanism by folate receptor-alpha. The results demonstrate the importance of methotrexate amino groups in the interaction with folate receptor-alpha. PMID- 30452232 TI - Tellurium Precursor for Nanocrystal Synthesis: Tris(dimethylamino)phosphine Telluride. AB - Preparations of CdTe quantum platelets, magic-size (CdTe)13 nanoclusters, and CdTe quantum wires are described using (Me2N)3PTe (with (Me2N)3P) as a Te precursor. The (Me2N)3PTe/(Me2N)3P precursor mixture is shown to be more reactive than mixtures of trialkylphosphine tellurides and the corresponding trialkylphosphines, R3PTe/R3P, which are commonly employed in nanocrystal syntheses. For syntheses conducted in primary amine solvents, (Me2N)3PTe and (Me2N)3P undergo a transamination reaction, affording (Me2N) x(RHN)3- xPTe and (Me2N) x(RHN)3- xP (R = n-octyl or oleyl). The transaminated (Me2N) x(RHN)3- xPTe derivatives are shown to be the likely Te precursors under those conditions. The enhanced reactivities of the tris(amino)phosphine tellurides are ascribed to increased nucleophilicity due to the amino-N lone pairs. PMID- 30452233 TI - The Endosomal Escape of Nanoparticles: Towards More Efficient Cellular Delivery. AB - Many emerging therapies rely on the delivery of biological cargo into the cytosol. Nanoparticle delivery systems hold great potential to deliver these therapeutics but are hindered by entrapment and subsequent degradation in acidic compartments of the endo/lysosomal pathway. Engineering polymeric delivery systems that are able to escape the endosome has significant potential to address this issue. However, the development of safe and effective delivery systems that can reliably deliver cargo to the cytosol is still a challenge. Greater understanding of the properties that govern endosomal escape and how it can be quantified is important for the development of more efficient systems. This review highlights the current understanding of the mechanisms by which nanoparticles escape the endosome, and the emerging techniques to improve the quantification of endosomal escape. PMID- 30452234 TI - On-Resin Macrocyclization of Peptides Using Vinyl Sulfonamides as a Thiol-Michael "Click" Acceptor. AB - Macrocyclization of linear peptides imparts improved stability to enzymatic degradation and increases potency of function. Many successful macrocyclization of peptides both in solution and on-resin have been achieved but are limited in scope as they lack selectivity, require long reaction times, or necessitate heat. To overcome these drawbacks a robust and facile strategy was developed employing thiol-Michael click chemistry via an N-methyl vinyl sulfonamide. We demonstrate its balance of reactivity and high stability through FTIR model kinetic studies, reaching 88% conversion over 30 min, and NMR stability studies, revealing no apparent degradation over an 8 day period in basic conditions. Using a commercially available reagent, 2-chloroethane sulfonyl chloride, the cell adhesion peptide, RGDS, was functionalized and macrocyclized on-resin with a relative efficiency of over 95%. The simplistic nature of this process demonstrates the effectiveness of vinyl sulfonamides as a thiol-Michael click acceptor and its applicability to many other bioconjugation applications. PMID- 30452235 TI - N-prenylation of tryptophan by an aromatic prenyltransferase from the cyanobactin biosynthetic pathway. AB - Aromatic prenylation is an important step in the biosynthesis of many natural products and leads to an astonishing diversity of chemical structures. Cyanobactin pathways frequently encode aromatic prenyltransferases that catalyze the prenylation of these macrocyclic and linear peptides. Here we characterized the anacyclamide (acy) biosynthetic gene cluster from Anabaena sp. UHCC-0232. Partial reconstitution of the anacyclamide pathway, heterologous expression and in vitro biochemical characterization of the enzyme demonstrate that the AcyF enzyme encoded in this biosynthetic gene cluster is a Trp N-prenyltransferase. Phylogenetic analysis suggests the monophyletic origin and rapid diversification of the cyanobactin prenyltransferase enzymes and the multiple origins of N-1 Trp prenylation in prenylated natural products. The AcyF enzyme displayed high flexibility towards a range of Trp-containing substrates and represents an interesting new tool for biocatalytic applications. PMID- 30452236 TI - Combined Numerical and Experimental Investigation of Localized Electroporation Based Cell Transfection and Sampling. AB - Localized electroporation has evolved as an effective technology for the delivery of foreign molecules into cells while preserving their viability. Consequently, this technique has potential applications in sampling the contents of live cells and the temporal assessment of cellular states at the single-cell level. Although there have been numerous experimental reports on localized electroporation-based delivery, a lack of a mechanistic understanding of the process hinders its implementation in sampling. In this work, we develop a multiphysics model that predicts the transport of molecules into and out of the cell during localized electroporation. Based on the model predictions, we optimize experimental parameters such as buffer conditions, electric field strength, cell confluency, and density of nanochannels in the substrate for successful delivery and sampling via localized electroporation. We also identify that cell membrane tension plays a crucial role in enhancing both the amount and the uniformity of molecular transport, particularly for macromolecules. We qualitatively validate the model predictions on a localized electroporation platform by delivering large molecules (bovine serum albumin and mCherry-encoding plasmid) and by sampling an exogeneous protein (tdTomato) in an engineered cell line. PMID- 30452237 TI - Phosphonate-Substituted Ruthenium(II) Bipyridyl Derivative as a Photoelectrochemical Probe for Sensitive and Selective Detection of Mercury(II) in Biofluids. AB - A ruthenium(II) bipyridyl derivative photoelectrochemical probe, Ru-1, is synthesized and coupled with TiO2 nanoparticles (Ru-1/TiO2) for the specific recognition and highly sensitive photoelectrochemical (PEC) detection of Hg2+ in a series of biofluids. The probe is designed with a chromophore, a thiocyanate recognition unit, a pi-conjugated photoelectron-transfer pathway, and a phosphonate anchor. TiO2 nanoparticles with strong affinity to phosphonate and suitable conduction band energy are used as intermediate layers to increase the Ru-1 adsorption amount and amplify the photocurrent response. Under irradiation, the Ru-1/TiO2/fluorine-doped tin oxide (FTO), with strong visible light harvesting capacity, aqueous stability, and efficient photoelectron transfer, shows a high and stable photocurrent response. In the presence of Hg2+, however, the specific Hg2+ and NCS coordination changes the photophysical properties of Ru 1, imposing the probe with a wider band gap, a weaker absorbance, and a poorer photoelectron and hole separation efficiency, thus resulting in a significant photocurrent decrease. On the basis of the Hg2+-induced photocurrent change, the Ru-1/TiO2/FTO shows good selectivity and high sensitivity toward the PEC detection of Hg2+, with wide linear ranges from 10-12 to 10-7 and 10-7 to 10-3 g/mL, and a low limit of detection of 0.63 pg/mL. The PEC probe is recyclable and accurate for selective detection of Hg2+ in urine, serum, and cell extracts. The whole analysis can be completed within 15 min. These good analytical performances indicate that the PEC method might have great potential for the onsite detection of small molecules in biosystems. PMID- 30452238 TI - Reprogramming Exosomes as Nanoscale Controllers of Cellular Immunity. AB - Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting synthetic multivalent antibodies retargeted exosomes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy. PMID- 30452239 TI - Lewis-Acid-Catalyzed BODIPY Boron Functionalization Using Trimethylsilyl Nucleophiles. AB - A novel and straightforward strategy for boron functionalization in boron dipyrromethenes (BODIPYs) is developed. In particular, this synthetic strategy provides new possibilities for the synthesis of sp2 N-substituted (B-NCS and NCO), benzotriazole- and trifluoroacetamide-substituted BODIPYs that were hitherto unknown. These new BODIPYs display an array of highly desirable photophysical properties (0.04 < Phif < 0.86), paving the road for further investigations in material applications. PMID- 30452240 TI - Reinventing (Bio)chemical Analysis with Paper. AB - This paper focuses on one of the most commonly encountered materials in our society, namely paper. Paper is an inherently complex material, yet its use provides for chemical analysis approaches that are elegant in their simplicity of execution. In the first half of the previous century, paper in scientific research was used mainly for filtration and chromatographic separation. While its use decreased with the rise of modern elution chromatography, paper remains a versatile substrate for low-cost analytical tests. Recently, we have seen renewed interest to work with paper in (bio)analytical science, a result of the growing demand for inexpensive, portable analysis. Dried blood spotting, paper microfluidics, and paper spray ionization are areas in which paper is (re)establishing itself as an important material. These research areas all exploit several properties of paper, including stable sample storage, passive fluid movement and manipulation, chromatographic separation/extraction, modifiable surface and/or volume, easily altered shape, easy transport, and low cost. We propose that the real, and to date underexploited, potential of paper lies in utilizing its combined characteristics to add new dimensions to paper based (bio)chemical analysis, expanding its applicability. This article provides the reader with a short historical perspective on the scientific use of paper and the developments that led to the establishment of the aforementioned research areas. We review important characteristics of paper and place them in a scientific context in this descriptive, yet critical, assessment of the achieved and the achievable in paper-based analysis. The ultimate goal is the exploration of integrative approaches at the interface between the different fields in which paper is or can be used. PMID- 30452241 TI - Phosphorus Removal and Recovery from Wastewater using Fe-Dosing Bioreactor and Cofermentation: Investigation by X-ray Absorption Near-Edge Structure Spectroscopy. AB - A new phosphorus (P) removal and recovery process that integrates an FeCl3 dosing, membrane bioreactor (MBR), and side-stream cofermentation was developed for wastewater treatment. The Fe and P species and their transformation mechanisms via aerobic and anaerobic conditions were investigated with X-ray absorption near edge structure (XANES) spectroscopy. In the new treatment system, 98.4% of the total P in domestic wastewater was removed and retained in activated sludge in the MBR. During the subsequent acidogenic cofermentation with food waste, P in the MBR sludge was released and eventually recovered as vivianite, achieving an overall P recovery efficiency of 61.9% from wastewater. The main pathways for P removal and recovery with iron dosing and acidogenic fermentation were determined by XANES analysis. The results showed that Fe-enhanced P removal with the MBR was mainly achieved by precipitation as ferric phosphate (24.2%) and adsorption onto hydrous iron oxides (60.3%). During anaerobic fermentation, transition from Fe(III)-P to Fe(II)-P complex occurred in the sludge, leading to Fe(II) dissolution and P release. The pH decrease and microbial Fe reduction were crucial conditions for effective P extraction from the MBR sludge. The efficiency of P recovery increased with an increase in the fermentation time and organic load and a decrease of pH in the solution. PMID- 30452242 TI - RNA recognition-like motifs activate a MAPK. AB - Smk1 is a MAPK in the yeast Saccharomyces cerevisiae that controls the post meiotic program of spore formation. Ssp2 is a meiosis-specific protein that activates Smk1 and triggers the autophosphorylation of its activation loop. A fragment of Ssp2 that is sufficient to activate Smk1 contains two segments that resemble RNA Recognition Motifs (RRMs). Mutations in either of these motifs eliminated Ssp2's ability to activate Smk1. In contrast, deletions and insertions within the segment linking the RRM-like motifs only partially reduced the activity of Ssp2. Moreover, the two RRM-like motifs expressed as separate proteins in bacteria activated Smk1. We also find that both motifs can be cross linked to Smk1 and that at least one of the motifs binds near the ATP-binding pocket of the MAPK. These findings demonstrate that motifs related to RRMs can directly activate protein kinases. PMID- 30452243 TI - Electrocatalytic Water Reduction Beginning with a {Fe(NO)2}10-Reduced Dinitrosyliron Complex: Identification of Nitrogen-Doped FeO x(OH) y as a Real Heterogeneous Catalyst. AB - Electron paramagnetic resonance, IR, single-crystal X-ray diffraction, and density functional theory computation reveal that the electronic structure of alpha-diimine-coordinated {Fe(NO)2}10-reduced dinitrosyliron complexes (DNICs) may best be described as [{Fe(NO)2}10-L*], with the added electron residing mainly on the alpha-diimine ligand framework. The combination of electrochemistry, gas chromatography, Fourier transform infrared, X-ray photoelectron spectroscopy, and scanning electron microscopy-energy-dispersive X ray studies demonstrates that the cathodic potential promotes/triggers the transformation of an alpha-diimine-coordinated {Fe(NO)2}10-reduced DNIC into a particulate deposit on the electrode, and electrodeposited-film electrodes, CFeO and CFeNO, are kinetically dominant electrocatalysts responsible for hydrogen evolution reaction (HER) from water with quantitative Faradaic efficiency. In comparison with the CFeO electrode reaching a current density of 10 mA/cm2 with an overpotential of 333 mV for HER, the nitrogen-doped iron oxide electrode, CFeNO, requires 147 mV of overpotential to achieve a current density of 10 mA/cm2 in a 1 M NaOH aqueous solution. The CFeNO electrode exhibits higher kinetic efficiency (Tafel slope of 59 mV/dec) than the CFeO electrode (Tafel slope of 122 mV/dec) in alkaline conditions. As opposed to high Rct (74.3 Omega) displayed by the CFeO electrode, the smaller charge-transfer resistance ( Rct) of the CFeNO electrode (34.0 Omega) demonstrated that the better HER catalytic activity may be ascribed to the incorporation of nitrogen into iron oxide architecture, which increases the surface roughness and electroconductivity of the CFeNO electrode (56.9% iron content and nitrogen electron-donating effect) and improves HER catalysis by polarizing the incoming water molecule (acting as a proton tray). This result implicates that a (NH4)2SO4-assisted nitrogen-doping strategy is a direct and effective method to realize synergistic regulation of the reaction dynamics, catalytically active sites and electronic conductivity, endowing this nitrogen-doped material CFeNO electrode as a promising HER electrocatalyst under alkaline conditions. PMID- 30452244 TI - Interaction Analysis between Gravity-Driven Ceramic Membrane and Smaller Organic Matter: Implications for Retention and Fouling Mechanism in Ultralow Pressure Driven Filtration System. AB - Gravity-driven membranes (GDM) generally achieve high retention performance in filtration of organic matter with a smaller size than the membrane pore, yet the in-depth mechanism remains unclear. Thorough analysis of the retention mechanism is crucial for optimizing GDM properties and improving GDM filtration performance. The performance and interaction mechanism of gravity-driven ceramic membrane (GDCM) filtrating smaller organic matter (SOM) were systematically studied. Rejection rate grew noticeably for like-charged foulant, whereas it only grew slightly for opposite-charged foulant as operation height decreased. Flux declined more seriously at lower operation height, probably due to heavier cake fouling caused by the rejected foulant. Interactions of ceramic membrane-SOM were analyzed through extended Derjaguin-Landau-Verwey-Overbeek theory (XDLVO) and hydrodynamic permeation drag (PD). Among van der Waals (LW), acid-base (AB), and electrostatic (EL) forces in XDLVO, EL played a significant role on GDCM filtrating SOM, and altering membrane electrostatic property could greatly influence SOM filtration. Furthermore, the rising PD force largely weakened the EL dominant zone with operation height increasing, while barely influencing the LW and AB dominant zones. Therefore, the weakened EL-dominant repulsive zone caused less rejection of like-charged foulant with operation height increasing. Fe2O3- and MnO2-modified membranes further validated the comprehensive influence of LW, AB, EL, and PD interactions on GDCM filtration. The possible "trade-off" of pore blocking-cake fouling with operation height decreasing demonstrated potential enhancement for both rejection and antifouling performance by electrically modified membrane under ultralow pressure. This study provides insight on membrane selection/preparation/modification and performance control of ultralow pressure-driven filtration. PMID- 30452245 TI - Semisynthesis of Matrinic Acid/Alcohol/Ester Derivatives, Their Pesticidal Activities and Investigation of Mechanisms of Action against Tetranychus cinnabarinus. AB - To discover new natural-product-based potential pesticides, 85 matrinic acid/alcohol/ester derivatives were synthesized by structural modifications of a quinolizidine alkaloid matrine. N-(4-Methyl)benzylmatrinyl n-decylate (76) and N (2-chloro)benzylmatrinyl n-undecylate (86) exhibited greater than 7-fold more pronounced acaricidal activity than matrine against Tetranychus cinnabarinus; N (2-chloro)benzylmatrinyl benzoate (80) showed the most promising insecticidal activity against Mythimna separata. The carboxyl group of matrinic acids, and introduction of n-decyl/n-undecylcarbonyl into matrinic alcohols were important for the acaricidal activity; introduction of alkyloxy into the carboxyl of matrinic acids, and introduction of the electron-withdrawing groups on the N benzyl of matrinic esters were necessary for the insecticidal activity. Through RT-PCR and qRT-PCR analysis, it showed that the lactam ring of matrine was vital for action on VGSC; opening the lactam ring of matrine and the alkylcarbonyl of side-chain were two important factors for acting with alpha1, alpha2 and alpha4 nAChR subunits; alpha1, alpha2, alpha4 and beta3 subunits may be the target of action of compound 86 against T. cinnabarinus. PMID- 30452246 TI - Instructed Assembly of Peptides for Intracellular Enzyme Sequestration. AB - Liquid-like droplets of biomacromolecules are emerging as a fundamental mechanism of cellular signaling, but designing synthetic mimics to form such membraneless organelles remains unexplored. Here we report the use of supramolecular assemblies of small peptides, as a mimic of biomacromolecular condensates, for intracellular sequestration of enzymes on endoplasmic reticulum (ER). Specifically, integrating a short peptide with naproxen (a nonsteroidal anti inflammatory drug (NSAID) and a ligand of cyclooxygenase-2 (COX-2)) generates an enzymatic substrate that acts as a precursor for instructed assembly. Slowly dephosphorylating the precursors by phosphatases forms the corresponding hydrogelators in a cellular environment, which results in the supramolecular assemblies on ER. Consisting of the precursor and the hydrogelator molecules, the assemblies enable the sequestration of COX-2 and protein-tyrosine phosphatase 1B (PTP1B) on ER. Further structure-activity investigation reveals that the colocalization of COX-2 and PTP1B relies on the NSAID motif, the phosphotyrosine, and the enzymatic dephosphorylation of the precursor. This work, for the first time, illustrates the use of supramolecular processes for associating enzymes in cells and may provide insights for understanding intracellular liquid condensates and a new strategy for modulating protein-protein interactions. PMID- 30452247 TI - Linear scaling pseudo Fermi-operator expansion for fractional occupation. AB - Recursive Fermi-operator expansion methods for the calculation of the idempotent density ma- trix are valid only at zero electronic temperature with integer occupation numbers. We show how such methods can be modified to include fractional occupation numbers of an approximate or pseudo Fermi-Dirac distribution and how the corresponding entropy term of the free energy is calculated. The proposed methodology is demonstrated and evaluated for different electronic structure methods including density functional tight-binding theory, Kohn-Sham density functional theory using numerical orbitals, and quantum chemistry Hartree-Fock theory using Gaussian basis functions. PMID- 30452248 TI - Site-Selective Nucleation and Size Control of Gold Nanoparticle Photothermal Antennae on the Pore Structures of a Virus. AB - In this Article, we show that the surface of the bacteriophage Qbeta is equipped with natural ligands for the synthesis of small gold nanoparticles (AuNPs). By exploiting disulfides in the protein secondary structure and the geometry formed from the capsid quaternary structure, we find that we can produce regularly arrayed patterns of ~6 nm AuNPs across the surface of the virus-like particle. Experimental and computational analyses provide insight into the formation and stability of this composite. We further show that the entrapped genetic material can hold upward of 500 molecules of the anticancer drug Doxorubicin without leaking and without interfering with the synthesis of the AuNPs. This direct nucleation of nanoparticles on the capsid allows for exceptional conduction of photothermal energy upon nanosecond laser irradiation. As a proof of principle, we demonstrate that this energy is capable of rapidly releasing the drug from the capsid without heating the bulk solution, allowing for highly targeted cell killing in vitro. PMID- 30452249 TI - Structure-Activity Relationships of Photoswitchable Diarylethene-Based beta Hairpin Peptides as Membranolytic Antimicrobial and Anticancer Agents. AB - Five series (28 structures) of photoswitchable beta-hairpin peptides were synthesized, based on the cyclic scaffold of the natural antibiotic gramicidin S. Cell-type selectivity was compared for all activated (diarylethene ring-open) and deactivated (closed) forms in terms of antibacterial activity (MIC against E. coli and B. subtilis), anticancer activity (IC50 against HeLa cell line), and hemolytic cytotoxicity (HC50 against human erythrocytes). Correlations between the conformational plasticity of the peptides, their hydrophobicity and their bioactivity were also analyzed. Considerable improvements in selectivity were achieved compared to the reference compound. We found a dissociation of the anticancer activity from hemolysis. Phototherapeutic indices (PTI) - HC50(closed)/MIC(open) and HC50(closed)/IC50(open) - were introduced for the peptides as safety criteria. The highest PTI for HeLa-selective toxicity were observed among analogues containing hydroxyleucine on the hydrophobic face. For one compound, high PTIs were demonstrated across a range of different cancer cell lines, including a doxorubicin-resistant one. PMID- 30452250 TI - Lead-Free Direct Bandgap Double Perovskite Nanocrystals with Bright Dual-Color Emission. AB - Lead-free double perovskite nanocrystals (NCs), i.e. Cs2AgInxBi1?xCl6 (x = 0, 0.25, 0.5 0.75 and 0.9), that can be tuned from the indirect bandgap (x = 0, 0.25 and 0.5) to the direct bandgap (x = 0.75 and 0.9) are designed. Direct-bandgap NCs exhibit 3 times greater absorption cross-section, lower sub-bandgap trap states, and >5 times photoluminescence quantum efficiency (PLQE) compared with those observed for indirect bandgap NCs (Cs2AgBiCl6). A PLQE of 36.6% for direct bandgap NCs is comparable to those observed for lead-perovskite NCs in the violet region. Besides the band edge violet emission, the direct bandgap NCs exhibit bright orange (570 nm) emission. Density functional theory calculations suggesting forbidden transition is responsible for the orange emission, which is supported by time resolved PL and PL excitation spectra. The successful design of lead-free direct bandgap perovskite NCs with superior optical properties opens the door for high performance lead-free perovskite optoelectronic devices. PMID- 30452251 TI - Self-Assembly of Goldberg Polyhedra from a Concave [WV5O11(RCO2)5(SO4)]3- Building Block with 5-Fold Symmetry. AB - Nanoscale regular polyhedra with icosahedral symmetry exist naturally as exemplified by virus capsids and fullerenes. Nevertheless, their generation by supramolecular chemistry through the linking of 5-fold symmetry vertices remains unmet because of the absence of 5-fold symmetry building blocks with the requisite geometric features. This situation contrasts with that of tetrahedral and octahedral symmetry metal-organic polyhedra (MOPs), for which appropriate triangular and square molecular building blocks (MBBs) that can serve as vertices or faces are readily available. Herein, we report isolation of a pentagonal [WV5O11(SO4)6]8- cluster and reveal its utility to afford the first four examples of nanoscale Goldberg MOPs, based upon 5-fold MBBs. Two 32-faced G v(1,1) MOPs and two 42-faced G v(2,0) MOPs were formed using linear or triangular organic ligands, respectively. The largest Goldberg MOP-4, exhibits a diameter of 4.3 nm, can trap fullerene C60 molecules in its interstitial cavities. PMID- 30452252 TI - Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives. AB - The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. Structure-activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116. PMID- 30452253 TI - 4,6- O-Pyruvyl Ketal Modified N-Acetylmannosamine of the Secondary Cell Wall Polysaccharide of Bacillus anthracis Is the Anchoring Residue for Its Surface Layer Proteins. AB - The secondary cell wall polysaccharide (SCWP) of Bacillus anthracis plays a key role in the organization of the cell envelope of vegetative cells and is intimately involved in host-guest interactions. Genetic studies have indicated that it anchors S-layer and S-layer-associated proteins, which are involved in multiple vital biological functions, to the cell surface of B. anthracis. Phenotypic observations indicate that specific functional groups of the terminal unit of SCWP, including 4,6- O-pyruvyl ketal and acetyl esters, are important for binding of these proteins. These observations are based on genetic manipulations and have not been corroborated by direct binding studies. To address this issue, a synthetic strategy was developed that could provide a range of pyruvylated oligosaccharides derived from B. anthracis SCWP bearing base-labile acetyl esters and free amino groups. The resulting oligosaccharides were used in binding studies with a panel of S-layer and S-layer-associated proteins, which identified structural features of SCWP important for binding. A single pyruvylated ManNAc monosaccharide exhibited strong binding to all proteins, making it a promising structure for S-layer protein manipulation. The acetyl esters and free amine of SCWP did not significantly impact binding, and this observation is contrary to a proposed model in which SCWP acetylation is a prerequisite for association of some but not all S-layer and S-layer-associated proteins. PMID- 30452254 TI - Scalable Fiber-Like Micelles and Block Co-micelles by Polymerization-Induced Crystallization-Driven Self-Assembly. AB - Self-assembled 1D block copolymer nanoparticles (micelles) are of interest for a range of applications. However, mor-phologically pure samples are often challenging to access, and precise dimensional control is not possible. Moreover, the development of synthetic protocols that operate on a commercially viable scale has been a major challenge. Herein, we describe the preparation 1D fiber like micelles with crystalline cores at high concentrations by a one-pot process termed polymerization-induced crystallization-driven self-assembly (PI-CDSA). We also demonstrate the formation of uniform fibers by living PI-CDSA, a process in which block copolymer synthesis, self-assembly, and seeded growth are combined. We have demonstrated that the method is successful for block copolymers that possess the same composi-tion as that of the seed (homoepitaxial growth) and also where the coronal chemistries differ to give segmented 1D fibers known as block co-micelles. We have also shown that heteroepitaxial growth allows the formation of scaled up block co-micelles where the composition of both the core and corona was varied. These proof of concept experiments indicate that PI-CDSA is a promising, scalable route to a variety of polydisperse or uniform 1D nanoparticles based on block copolymers with different crystalline core chemistries and, therefore, functions. PMID- 30452255 TI - Ultrafast Excited-State Dynamics of Hydrogen-Bonded Cytosine Microsolvated Clusters with Protic and Aprotic Polar Solvents. AB - Microsolvation effects on the ultrafast excited-state deactivation dynamics of cytosine (Cy) were studied in hydrogen-bonded Cy clusters with protic and aprotic solvents using mass-resolved femtosecond pump-probe ionization spectroscopy. Two protic solvents, water (H2O) and methanol (MeOH), and one aprotic solvent, tetrahydrofuran (THF), were investigated, and transients of Cy.(H2O)1-6, Cy.(MeOH)1-3, and Cy.THF microsolvated clusters produced in supersonic expansions were measured. With the aid of electronic structure calculations, we assigned the observed dynamics to the low-energy isomers of various Cy clusters and discussed the microsolvation effect on the excited-state deactivation dynamics. With the protic solvents only the microsolvated clusters of Cy keto tautomer were observed. The observed decay time constants of Cy.(H2O) n are 0.5 ps for n = 1 and ~0.2-0.25 ps for n = 2-6. For Cy.(MeOH) n clusters, the decay time constant for n = 1 cluster is similar to that of the Cy monohydrate, but for n = 2 and 3 the decays are about a factor of 2 slower than the corresponding microhydrates. With the aprotic solvent, THF, hydrogen-bonded complexes of both keto and enol tautomers are present in the beam. The keto-Cy.THF shows a decay similar to that of the keto-Cy monomer, whereas the enol-Cy.THF exhibits a 2-fold slower decay than the enol-Cy monomer, suggesting an increase in the barrier to excited-state deactivation upon binding of one THF molecule to the enol form of Cy. PMID- 30452256 TI - Multi-Triggered Supramolecular DNA/Bipyridinium Dithienylethene Hydrogels Driven by Light, Redox and Chemical Stimuli for Shape-Memory and Self-Healing Applications. AB - Multi-triggered DNA/bipyridinium-dithienylethene (DTE) hybrid carboxymethyl cellulose (CMC) based hydrogels are introduced. DTE exhibits cyclic and reversible photoisomerization properties, switching between the closed state (DTEc), the electron acceptor, and the open isomer (DTEo) that lacks electron acceptor properties. One system includes the syn-thesis of CMC chains modified with electron donor dopamine sites and self-complementary nucleic acid tethers. In the presence of DTEc and the CMC scaffold, a stiff hydrogel, cooperatively stabilized by dopamine/DTEc donor-acceptor in-teractions and by the duplex nucleic acids is formed. The cyclic and reversible formation and dissociation of the supra-molecular donor-acceptor interactions, through light-induced photoisomerization of DTE, or via the oxidation and sub-sequent reduction of the dopamine sites, leads to hydrogels of switchable stiffness. Another system introduces a stimuli-responsive hydrogel triggered by one of the three alternative signals. The stiff multi-triggered hydrogel consists of CMC chains crosslinked by the dopamine/DTEc donor-acceptor interactions, and by supramolecular K+-stabilized G-quadruplexes. The G-quadruplexes are reversibly separated in the presence of 18-crown-6 ether, and reformed upon the addition of K+. The stiff hydrogel undergoes reversible transitions between high-stiffness and low-stiffness states triggered by light, redox agents or K+/crown ether. The hybrid donor-acceptor/G-quadruplex crosslinked hydrogels show shape-memory and self-healing features. By using three different triggers and two alternative memory-codes, e.g. the dopamine/DTEc or the K+-stabilized G-quadruplexes, the guided shape-memory formation of the hydrogel matrices are demonstrated. PMID- 30452257 TI - Ionic Hydrogen and Halogen Bonding in the Gas Phase Association of Acetonitrile and Acetone with Halogenated Benzene Cations. AB - Herein, we report on the gas phase association of the small polar and aprotic solvent molecules acetonitrile (CH3CN) and acetone (CH3COCH3) with the halogenated benzene radical cations (C6H5X+*, X=F, Cl, Br, and I) using the mass selected ion mobility technique and density functional theory calculations. The association energies (-DeltaH degrees ) of CH3CN (CH3COCH3) with C6H5F+* and C6H5I+* are similar [13.0 (13.3) and 13.2 (14.1) kcal/mol, respectively] but higher than those of CH3CN (CH3COCH3) with C6H5Cl+* and C6H5Br+* [10.5 (11.5) and 10.9 (10.6) kcal/mol, respectively]. However, the electrostatic potentials of the lowest energy structures of C6H5Br+*(CH3CN) and C6H5Br+*(CH3COCH3) or C6H5I+*(CH3CN) and C6H5I+*(CH3COCH3) complexes clearly show the formation of the ionic halogen bonds (IXBs) C-Brdelta+- - NCCH3 and C-Brdelta+- - OC(CH3)2 or C Idelta+- - NCCH3 and C-Idelta+- - OC(CH3)2 driven by positively charged sigma holes on the external sides of the C-Br and C-I bond axes of the bromobenzene and iodobenzene radical cations, respectively. For the C6H5F+*(CH3CN) complex, the dominant interaction involves a T-shaped structure between the N atom of CH3CN and the C atom of the C-F bond of C6H5F+*. The structure of the C6H5Cl+*(CH3CN) complex shows the formation of unconventional ionic hydrogen bonds (uIHBs) between the N atom of CH3CN and the C-H bonds of the C6H5Cl+* cation. Similar results are obtained for the association of acetone with the halogenated benzene radical cations. Again, the C6H5Br+*(CH3COCH3) and C6H5I+*(CH3COCH3) complexes show the formation of IXBs while the C6H5F+*(CH3COCH3) and C6H5Cl+*(CH3COCH3) complexes form mainly T-shaped and IHB structures. The formation of IXBs of the iodobenzene cation with acetonitrile or acetone involves a significant entropy loss (-DeltaS degrees = 25-27 cal mol-1 K-1) resulting from the formation of more ordered and highly directional structures between the nitrogen or oxygen lone pair of electrons of acetonitrile or acetone, respectively and the electropositive region around the iodine atom of the iodobenzene cation. In comparison, for the association of acetonitrile or acetone with the fluorobenzene, chlorobenzene and bromobenzene cations, -DeltaS degrees = 16-23 cal/mol K consistent with the formation of less ordered structures and loose interactions. The lowest energy structures of the C6H5Br+*(CH3COCH3)2 and C6H5I+*(CH3COCH3)2 clusters show a novel combination of ionic halogen bonding and hydrogen bonding where the oxygen atom of one acetone molecule forms the halogen bond while the oxygen atom of the second acetone molecule becomes the hydrogen acceptor from the methyl group of the first acetone molecule. PMID- 30452258 TI - Effects of Mild Oxidative and Structural Modifications Induced by Argon-Plasma on Physicochemical Properties of Actomyosin from King Prawn (Litopenaeus Vannamei). AB - Application of cold plasma, a minimal processing technology, has gained significant popularity particularly in the area of shelf-life extension or modification of food ingredients in the food industry. In this study, the effects of an atmospheric pressure plasma jet (APPJ) generated in argon gas as a function of treatment time on natural actomyosin (NAM) extracted from king prawn (Litopenaeus vannamei) was examined. Both changes in structure and physicochemical properties were also characterized in terms of solubility, turbidity, and foaming and emulsifying properties, and various spectroscopic responses. Results revealed that prawn NAM exhibited a correlating decrease in pH and slight increase (P > 0.05) in solubility in the first 3 min of plasma exposure due to the formation of soluble aggregates. A rise in turbidity was also noted. In addition, an enhancement of both foaming and emulsifying capacities was apparent. A red shift in the maximum wavelength of intrinsic fluorescence indicated the unfolding of tertiary structure. Additionally, plasma treatment led to slight decrease in total sulfhydryl content and enhancement of protein-protein interaction at longer treatment duration. Overall, mild oxidation from argon plasma could modulate the functional properties of seafood proteins. These findings provide peculiar insights and emphasize the need for optimal selection of plasma processing conditions, in order to achieve safe and high-quality crustacean seafood products. PMID- 30452259 TI - Three-Dimensional Fully Conjugated Carbaporphyrin Cage. AB - A fully conjugated three-dimensional (3D) expanded carbaporphyrin (2) was prepared in a one-pot procedure that involves a [2+4] condensation reaction between a dibenzo[ g, p]chrysene-bearing tetrapyrrole precursor (1) and pentafluorobenzaldehyde, followed by oxidation. Single crystal X-ray diffraction analysis revealed that 2 possesses a cage-like structure consisting of four dipyrromethenes and two bridging dibenzo[ g, p]chrysene units. As prepared, 2 is nonaromatic as inferred from UV-vis-NIR and 1H NMR spectroscopy and a near-zero ( 1.75) nucleus-independent chemical shift (NICS) value. In contrast, after protonation with trifluoroacetic acid (TFA), the cage gains global aromatic character as inferred from the large negative NICS value (-11.63) and diatropic ring current observed in the anisotropy of the induced current density (ACID) plot, as well as the ca. 8-fold increase in the excited state lifetime. In addition, the size of the cavity increases to ca. 143 A3 upon protonation as deduced from a single crystal X-ray diffraction analysis. To our knowledge, this is the largest carbaporphyrin prepared to date and the first with a fully conjugated 3D cage structure whose size and electronic features may be tuned through protonation. PMID- 30452260 TI - Grayanane Diterpenoid Glucosides from the Leaves of Rhododendron micranthum and Their Bioactivities Evaluation. AB - Thirteen new grayanane diterpenoid glucosides, 3- epi-grayanoside B (1), micranthanosides A-E (2-6), 7alpha-hydroxygrayanoside C (7), micranthanoside F (8), 14beta-acetyoxymicranthanoside F (9), micranthanoside G (10), 14- O acetylmicranthanoside G (11), 14beta-hydroxypieroside A (12), and micranthanoside H (13), and six known analogues (14-19) were isolated from the leaves of Rhododendron micranthum. The structures of 1-19 were elucidated based on spectroscopic analysis, comparison with literature, and chemical methods. The absolute configurations of 3- epi-grayanoside B (1) and micranthanosides A (2) and C (4) were defined by single-crystal X-ray diffraction analysis. This is the first report of the crystal structures of grayanane diterpenoid glucosides. 3- epi-Grayanoside B (1) represents the first example of a 3alpha-oxygrayanane diterpenoid glucoside, and micranthanosides A-D (2-5) are the first examples of 5alpha-hydroxy-1-beta H-grayanane diterpenoids. In addition, micranthanosides C-F (4-6 and 8) and 14beta-acetyoxymicranthanoside F (9) represent the first examples of grayanane glucosides with the glucosylation at C-16. All the grayanane diterpenoid glucosides 1-19 were assayed for their anti-inflammatory, antitumor, and PTP1B inhibitory activities, but did not show significant activities at 40 MUM. Grayanane diterpenoid glucosides 1-18 were evaluated for their antinociceptive activity, and compounds 2, 3, 7-10, 12, 13, and 16 showed significant antinociceptive effects with percentage inhibitions in excess of 50%. PMID- 30452261 TI - Physicochemical basis and comparison of two Type II Sex Pheromone Components binding with Pheromone-Binding Protein 2 from Tea Geometrid, Ectropis obliqua. AB - Lepidopteran geometrid moth can produce complex Type II sex pheromone components to attract males and trigger mating behavior. Although several sex pheromone components have been identified, it remains unclear whether their physicochemical roles in sex pheromone sensing are the same. Therefore, we utilized tea geometrid (Ectropis obliqua) as an example model, to investigate and compare the physicochemical basis of two key Type II sex pheromone components, cis-6,7-epoxy (3Z,9Z)-3,9-octadecadiene (Z3Z9-6,7-epo-18:Hy) and (Z,Z,Z)-3,6,9-octadecatriene (Z3Z6Z9-18:Hy) interacting with pheromone-binding protein 2 (EoblPBP2) from E. obliqua. Multispectral, thermodynamic, docking, and site-directed mutagenesis indicated that the major sex pheromone component Z3Z9-6,7-epo-18:Hy is more susceptible to pH-tuned than the minor component Z3Z6Z9-18:Hy, whereas Z3Z6Z9 18:Hy seems to be more susceptible to temperature and amino acid mutations than Z3Z9-6,7-epo-18:Hy. Our study suggests that different components of Type II sex pheromone play different binding characters under specific conditions in the physicochemical behavior. This deeply supplements the theoretical knowledge of Type II pheromones involved in the recognition and discrimination in Lepidopteran sex pheromones family. PMID- 30452262 TI - Proline- and arginine-rich peptides as flexible allosteric modulators of human proteasome activity. AB - Proline- and arginine-rich peptide PR11 is an allosteric inhibitor of 20S proteasome. We modified its sequence inter alia by introducing HbYX, RYX or RHbX C-terminal extensions (Hb-hydrophobic moiety, R-arginine, Y-tyrosine, X-any residue). We found that an aromatic penultimate Hb residue improved the inhibitory capacity. Remarkably, the HbYX motif converted the inhibitor into a very good activator, able to stimulate 20S to efficiently degrade protein substrates, such as alpha-synuclein and enolase. Moreover, the HbYX containing peptide activated proteasome in cultured fibroblasts. The positive and negative PR modulators differently influenced the proteasome conformational dynamics and affected opening of the substrate entry pore. The resolved crystal structure showed PR inhibitor bound far from the active sites, at the proteasome outer face. Our studies indicated moieties crucial for constructing positive and negative modulators of 20S and showed the opportunity to tune proteasome activity by allosteric regulators based on PR peptide scaffold. PMID- 30452263 TI - Low-Temperature Effect on the Electronic Structure and Spectral-Fluorescent Properties of Highly Dipolar Merocyanines. AB - Absorption and fluorescence spectra of a vinylogous series of reversely solvatochromic merocyanines based on benzimidazole and malononitrile have been studied in frozen ethanol solutions at 77 K. It is found that they possess negative thermochromism - in contrast to both positively solvatochromic merocyanines and negatively solvatochromic symmetrical ionic polymethines - and even stronger negative thermofluorochromism. It has been deduced from the spectral data, that at low temperature their electronic structure becomes more dipolar, deviating substantially from the virtual ideal polymethine in both the ground and excited states. At that, owing probably to high polarity and ordering of frozen ethanol, the dipolarity of the studied merocyanines increases with the polymethine chain lengthening - the tendency not observed for them in common solvents. The conclusions, based on the spectra data analysis, have been verified by the (TD)DFT-PCM simulations of the dyes within the four-level scheme of electronic transitions. PMID- 30452264 TI - Use of Density Functional Based Tight Binding Methods in Vibrational Circular Dichroism. AB - Vibrational circular dichroism (VCD) is a spectroscopic technique used to resolve the absolute configuration of chiral systems. Obtaining a theoretical VCD spectrum requires computing atomic polar and axial tensors on top of the computationally demanding construction of the force constant matrix. In this study we evaluated a VCD model in which all necessary quantities are obtained with density functional based tight binding (DFTB) theory. The analyzed DFTB parametrizations fail at providing accurate vibrational frequencies and electric dipole gradients but yield reasonable normal modes at a fraction of the computational cost of density functional theory (DFT). Thus, by applying DFTB in composite methods along with DFT, we show that it is possible to obtain accurate VCD spectra at a much lower computational demand. PMID- 30452265 TI - Shedding Light on the Dark Corners of MOF Thin Films: Growth and Structural Stability of ZIF-8 Layers Probed by Optical Waveguide Spectroscopy. AB - Due to its many features and possible applications, metal-organic frameworks have attracted increasing attention in recent years. Within this type of materials, hydrophobic zeolitic imidazolate framework constituted of Zn2+ metal centers, coordinated by 2-methylimidazolate organic linkers (ZIF-8); has proved to be a highly versatile porous support compatible with diverse applications ranging from sensing platforms to electronics or energy-related devices. However, the study of a crucial parameter such as their structural stability towards exposure to different aqueous environments (relevant for a wide range of applications), remains only partially addressed and constitutes one of the main goals of the present work. By synthesizing mono- and multimode ZIF-8 optical waveguides for both optical waveguide and surface plasmon resonance spectroscopy, it was possible to characterize the ZIF-8 film growth, and its stability in different sensor-relevant liquid environments. Additionally, characterization of polyelectrolyte-modified films was explored, as it constitutes a relevant strategy in order to confer differential properties and enhanced stability to the films. PMID- 30452266 TI - Encapsulation of the Sulfur Compounds by Cucurbit[7]uril: A Quantum Chemistry Study. AB - Benzothiophene (BT) and dibenzothiophene (DT) are the most important contaminants in the petroleum derivatives responsible for serious environmental and health problems. Therefore, we have investigated the absorption of these compounds for the first time by considering cucurbit[7]uril (CB[7]) as the host molecule and using the theoretical levels of density functional theory//B3LYP-D3/6-31G(d). BT and DT absorbed into CB[7] do not undergo a significant structural change in the CB[7] structure. The energy gap of the S-compounds@CB[7] in water and hexane solvents was approximately 5 eV, and this large value implies that the complexes have high chemical stability. Moreover, the absorption of the BT and DT into CB[7] in the water and hexane solvents is a favorable process, whereas the lowest binding energy was observed between the dibenzothiophene and CB[7] in the DT@CB[7] complex. The solvation enthalpy shows a preferential solvation of the complexes in water than in hexane solvent. This trend is confirmed by the AIM analysis that shows the highest stability for the DT@CB[7] system with the contribution of cooperative hydrogen bonding. The transfer free energy of S compounds@CB[7] complexes from hexane to water are -66.12 and -59.56 kcal/mol for BT@CB[7] and DT@CB[7], respectively, implying the spontaneous transference of these complexes from hexane to water solvent. Overall, our results show that the cucurbiturils can be a new class of host molecules to be used in the removal of S compounds from petroleum derivatives. Finally, a schematic flow diagram of the desulfurization process by cucurbiturils was proposed. PMID- 30452267 TI - Stepwise Two-Photon-Induced Electron Transfer from Higher Excited States of Noncovalently Bound Porphyrin-CdS/ZnS Core/Shell Nanocrystals. AB - There has been an increasing amount of interest in stepwise two-photon absorption (2PA)-induced photochemical reactions because of their extremely lower power thresholds compared to that of the simultaneous process and drastic reaction enhancements in some cases. However, stepwise 2PA-induced photochemical reactions were reported only in single chromophores and covalently bound bi-chromophores and there are few reports on these reactions in noncovalently bound systems because of weak electronic interactions among chromophores. This study demonstrated the stepwise 2PA-induced electron transfer from higher excited states in noncovalently bound protoporphyrin IX.CdS/ZnS core/shell nanocrystals (NCs). The electron transfer from higher excited states of porphyrin to CdS NCs successfully overcomes the activation barrier associated with the wide bandgap ZnS shell, indicating that a high reduction potential can be obtained with the stepwise 2PA process. The concept presented in this study can be applied to various noncovalently bound multi-chromophore systems to explore nonlinear photoresponses. PMID- 30452268 TI - Co-delivery of miR-4638-5p and docetaxel based on redox-sensitive polypeptide micelles as an improved strategy for the treatment of castration-resistant prostate cancer. AB - In this work, we have developed a reducible, self-assembling disulfide cross linked and peptide-based micelle system for co-delivery of miR-4638-5p and DTX to improve the efficacy of castration-resistant prostate cancer (CRPC) therapy. The result showed that DTX in micelles (DTX-VPs) inhibited cell growth and induced apoptosis more effectively than free DTX both in vitro and in vivo. In addition, the DTX and miR-4638-5p loaded micelles (Co-VPs) achieved the most pronounced anticancer effect of all groups. Immunohistochemical analysis indicated that miR 4638-5p in micelle system could effectively downregulate the expression of Kidins220 and further improve the anticancer effect by enhancing tumor cell apoptosis and suppressing tumor cell proliferation. Finally, the bio-imaging analysis demonstrated that DIR in micelles (DIR-VPs) showed a higher concentration and a longer retention time in tumor tissue than free DIR did, indicating an excellent tumor-targeting ability of the micelle system. All these results suggest that co-delivery of miR-4638-5p and DTX via polypeptide micelle system has a potential for CRPC treatment. PMID- 30452269 TI - Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276 Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature. AB - Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of the tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of a PD-1/PD-L1 blockade. A CD276-targeting agent (IRD alphaCD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting efficacy and therapeutic effects of IRD-alphaCD276/Fab with or without an anti-PD-1/PD-L1 blockade were tested in subcutaneous and lung metastatic tumor models. PDT using IRD-alphaCD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD L1 levels were also markedly increased after PDT using IRD-alphaCD276/Fab, as evidenced by noninvasive PD-L1-targeted small-animal PET imaging. In combination with an anti-PD-1/PD-L1 blockade, IRD-alphaCD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8+ T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD 1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses. PMID- 30452270 TI - A One-Pot Reaction toward the Diastereoselective Synthesis of Substituted Morpholines. AB - The diastereoselective synthesis of various substituted morpholines has been achieved from vinyloxiranes and amino-alcohols under sequential Pd(0)-catalyzed Tsuji-Trost/Fe(III)-catalyzed heterocyclization. Using the same strategy, 2,6-, 2,5-, and 2,3-disubstituted as well as 2,5,6- and 2,3,5-trisubstituted morpholines were obtained in good to excellent yields and diastereoselectivities. PMID- 30452271 TI - Tunable Spin-Superconductor Coupling of Spin 1/2 Vanadyl Phthalocyanine Molecules. AB - Atomic-scale magnetic moments in contact with superconductors host rich physics based on the emergence of Yu-Shiba-Rusinov (YSR) magnetic bound states within the superconducting condensate. Here, we focus on a magnetic bound state induced into Pb nanoislands by individual vanadyl phthalocyanine (VOPc) molecules deposited on the Pb surface. The VOPc molecule is characterized by a spin magnitude of 1/2 arising from a well-isolated singly occupied d xy-orbital and is a promising candidate for a molecular spin qubit with long coherence times. X-ray magnetic circular dichroism (XMCD) measurements show that the molecular spin remains unperturbed even for molecules directly deposited on the Pb surface. Scanning tunneling spectroscopy and density functional theory (DFT) calculations identify two adsorption geometries for this "asymmetric" molecule (i.e., absence of a horizontal symmetry plane): (a) oxygen pointing toward the vacuum with the Pc laying on the Pb, showing negligible spin-superconductor interaction, and (b) oxygen pointing toward the Pb, presenting an efficient interaction with the Pb and promoting a Yu-Shiba-Rusinov bound state. Additionally, we find that in the first case a YSR state can be induced smoothly by exerting mechanical force on the molecules with the scanning tunneling microscope (STM) tip. This allows the interaction strength to be tuned continuously from an isolated molecular spin case, through the quantum critical point (where the bound state energy is zero) and beyond. DFT indicates that a gradual bending of the VO bond relative to the Pc ligand plane promoted by the STM tip can modify the interaction in a continuously tunable manner. The ability to induce a tunable YSR state in the superconductor suggests the possibility of introducing coupled spins on superconductors with switchable interaction. PMID- 30452272 TI - Convergent Synthesis of Taxol Skeleton via Decarbonylative Radical Coupling Reaction. AB - The highly oxygenated 6/8/6-membered ABC-ring 2 of taxol was assembled in a convergent fashion. A decarbonylative radical reaction between alpha-alkoxyacyl telluride 4 and cyanocyclohexenone 5 linked the A- and C-rings and stereoselectively installed the C2- and C3-tertiary carbon centers of 3. After the C8-quaternary stereocenter was constructed, the C9-methyl ketone and the C11 vinyl triflate of 30 participated in Pd(0)-promoted cyclization of the eight membered B-ring, giving rise to the taxol skeleton 2. PMID- 30452273 TI - Cluster of Differentiation 46 is the Major Receptor in Human Blood-Brain Barrier Endothelial Cells for Uptake of Exosomes Derived from Brain-Metastatic Melanoma Cells (SK-Mel-28). AB - Brain metastasis is a frequent complication of cancer, and may be mediated at least in part by the internalization of cancer-cell-derived exosomes into brain capillary endothelial cells. Clarifying the mechanism(s) of this internalization is of interest because it could help us to develop ways to block brain metastasis, as well as affording a potential new route for drug delivery into the brain. Therefore, the purpose of the present study was to address this issue by identifying the receptors involved in the internalization of exosomes derived from a brain-metastatic cancer cell line (SK-Mel-28) into human blood-brain barrier endothelial cells (hCMEC/D3 cells). The combination of sulfo-SBED-based cross-linking and comprehensive proteomics yielded 20 proteins as exosome receptor candidates in hCMEC/D3 cells. Uptake of PKH67-labeled exosomes by hCMEC/D3 cells measured at 37 degrees C was significantly reduced by 95.6% at 4 degrees C and by 15.3% in the presence of 1 mM RGD peptide, an integrin ligand. Therefore, we focused on the identified RGD receptors; integrin alpha5 and integrin alphaV, and CD46, which is reported to act as an adenovirus receptor, together with integrin alphaV. A mixture of neutralizing antibodies against integrin alpha5 and integrin alphaV significantly decreased the exosome uptake by 11.8%, while application of CD46 siRNA reduced it by 39.0%. Immunohistochemical analysis confirmed the presence of CD46 in human brain capillary endothelial cells. These results suggest that CD46 is a major receptor for uptake of SK-Mel 28-derived exosomes by human blood-brain barrier endothelial cells (hCMEC/D3 cells). PMID- 30452274 TI - Organocatalytic Asymmetric Atroposelective Construction of Axially Chiral 1,4 Distyrene 2,3-Naphthalene Diols. AB - An efficient organocatalytic construction of enantioenriched axially chiral 1,4 distyrene 2,3-naphthalene diols through the nucleophilic addition of alpha-amido sulfone to in situ generated vinylidene o-quinone methide is described. The reaction pathway was investigated by isolating reaction intermediates and performing a kinetic resolution process. Axially chiral 1,4-distyrene 2,3 naphthalene diol was used as the chiral ligand for the enantioselective addition of diethylzinc to naphthalene formaldehyde. The preliminary results revealed that these adducts could be potentially used as ligands in asymmetric synthesis. PMID- 30452275 TI - Surface with Reversible Green-light-switched Wettability by Donor-Acceptor Stenhouse Adducts. AB - In this report, we designed surfaces with reversible green-light-switched wettability by Donor-Acceptor Stenhouse adducts (DASAs). Photoresponsive micro/nanoparticles were prepared by coating polydopamine on the surface of silica micro/nanoparticles and then post-modifying with DASA molecules. Then, the particles were immobilized on glass substrates surface either by double-sided adhesive tapes or crosslinking polydimethylsiloxane. Silica micro/nanoparticles with various diameters (0.2, 2.5 and 85 MUm) were used to fabricate the photoresponsive surface. Green light irradiation switches the hydrophobic linear DASA to hydrophilic cyclic isomer, which further increases the wettability and contact angle hysteresis on surface. On the other hand, heating (100 oC) induces the cyclic-to-linear isomerization of DASA molecules, and switches the surface back to hydrophobic. The wettability of the DASAs modified surface is reversible under alternately green light irradiating and heating. PMID- 30452276 TI - Patterning Bubbles by the Stick-slip Motion of the Advancing Triple Phase Line on Nano-structures. AB - The stick-slip motion of the triple phase contact line (TCL) has wide applications in inkjet printing, surface coatings, functional material assembly and device fabrication. Here, for the first time, we report that on an alumina substrate with nano-structures, the stick-slip motion of the advancing TCL during spreading of an emulsion droplet can serve as an effective nano-patterning process. Air, enclosed in the substrate nano-structures, can be exchanged with liquid during the 'stick' phase, resulting in the formation of bubbles arranged in a ring pattern. The process takes place in two stages: rings of air form first, and then, as the volume of air increases they separate into air bubbles as a result of the Plateau Rayleigh instability. During the first stage, the rings form due to the stick-slip of the advancing TCL, and is ascribed to hydrogen bonding interactions. Ultimate bubble size is dependent upon substrate pore dimensions. The process was simulated using finite element analysis to elucidate the mechanism asso-ciated with subsequent bubble formation. The simulations corroborate well with the experimental results. This stick-slip motion of the advancing TCL provides new in-sights into phenomena associated with droplet spreading and wetting, and the ability to control the formation of patterned bubbles will be promising in applications ranging from microfluidics to printing of functional materials and devices based on bubble templates and applications requiring submerged hydrophobic surface. PMID- 30452277 TI - Swelling Dynamics of Surface-Attached Hydrogel Thin Films in Vapor Flows. AB - Hydrogel coatings absorb water vapor, or other solvents, and, as such, are good candidates for antifog applications. In the present study, the transfer of vapor from the atmosphere to hydrogel thin films is measured in a situation where water vapor flows alongside the coating which is set to a temperature lower than the ambient temperature. The effect of the physico-chemistry of the hydrogel film on the swelling kinetics is particularly investigated. By using model thin films of surface-grafted polymer networks with controlled thickness, varied cross-links density, and varied affinity for water, we were able to determine the effect of the film hygroscopy on the dynamics of swelling of the film. These experimental results are accounted for by a diffusion-advection model that is supplemented with a boundary condition at the hydrogel surface: we show that the latter can be determined from the equilibrium sorption isotherms of the polymer films. Altogether, this paper offers a predictive tool for the swelling kinetics of any hydrophilic hydrogel thin film. PMID- 30452278 TI - Polymer-Mediated Drug Supersaturation Controlled by Drug-Polymer Interactions Persisting in an Aqueous Environment. AB - We investigated the drug-polymer interactions in nonaqueous and aqueous environments between a poorly water-soluble drug, BAY1161909 (909), and two commonly used polymers in amorphous solid dispersions, i.e., PVP and HPMC-AS. In an nonaqueous state, with a drug-polymer Flory-Huggins interaction parameter, solution NMR and FT-IR results revealed that strong specific interactions existed between 909 and PVP, while not between 909 and HPMC-AS. After prolonged moisture exposure under 95% RH, 909/PVP intermolecular interaction no longer existed, while hydrophobic interaction between 909 and HPMC-AS occurred and persisted. In an aqueous supersaturation study of 909, codissolved PVP significantly outperformed predissolved PVP in maintaining 909 supersaturation. We hypothesized that the codissolved PVP formed a specific interaction with 909, and thus, it was able to prolong 909 supersaturation before disruption of the interaction in aqueous medium, while predissolved PVP formed hydrogen bonds with water, and thus, it was no longer able to form specific interactions with 909 to prolong its supersaturation. In contrast, HPMC-AS effectively mediated 909 supersaturation through hydrophobic interaction, which became pronounced in an aqueous environment and was independent of how HPMC-AS was added. This hypothesis was supported by dynamic light scattering analysis, wherein the formation of nanosized drug/polymer aggregations was found to be correlating with the supersaturation of 909. In summary, we concluded that polymer-mediated drug supersaturation was controlled by drug-polymer interactions persisting in an aqueous environment. Therefore, the physical nature of the drug-polymer interaction as well as the dissolution kinetic of the drug and polymer are all critically important to achieve an optimal ASD formulation design. PMID- 30452279 TI - Use of Nutritional Supplements in Youth with Medicated and Unmedicated Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: To find out whether use of nutritional supplements (NUS) differs between children and adolescents with attention-deficit/hyperactivity disorder (ADHD; medicated or unmedicated), compared with those without the disorder. METHODS: We used cross-sectional data from the population-based I.Family study conducted between 2013 and 2014 in eight European countries. Parents completed questionnaires and participated in interviews, for example, on health and medical history of their child. Data from 5067 children and adolescents aged 5-17 years were included. Exposures were medicated (with ADHD-approved medication) and unmedicated ADHD. The outcome was the use of NUS, measured by use of any or multiple different NUS. Multivariable logistic regression adjusted for sociodemographics and health determinants was used to find ADHD-depending differences. RESULTS: The study sample comprised 4490 children and adolescents without ADHD and 51 medicated and 76 unmedicated subjects with ADHD. Regarding the use of any NUS, no statistically significant differences were found between children and adolescents without ADHD (18%) and those with medicated (18%) or unmedicated ADHD (22%). However, discrepancies appear when considering multiple use of NUS, not reported for any medicated ADHD subject but remarkably often for unmedicated ADHD subjects (13%), resulting in an adjusted odds ratio of 2.6 (95% confidence interval, 1.2-5.6) when compared with those without ADHD (5%). CONCLUSION: Children and adolescents who were not using medication for treating ADHD potentially took NUS as oral remedies. Given the potential for a delay of indicated treatments and for use of those NUS which have no proven effectiveness, pediatricians should actively explore whether NUS have been used to treat ADHD core symptoms, and families should be informed that the average effect size has to be considered small. PMID- 30452280 TI - Lateral Meniscal Posterior Root Repair With Anterior Cruciate Ligament Reconstruction Better Restores Knee Stability. AB - BACKGROUND:: The effect of lateral meniscal posterior root tear and repair commonly seen in clinical practice in the setting of anterior cruciate ligament (ACL) reconstruction-is not known. PURPOSE/HYPOTHESIS:: This study evaluated the effect of tear and repair of the lateral meniscal posterior root on the biomechanics of the ACL-reconstructed knee. It was hypothesized that anterior tibial translation would increase under anterior loading and simulated pivot shift loading with the root tear of the posterior lateral meniscus, while repair of the root tear would reduce it close to the noninjured state. STUDY DESIGN:: Controlled laboratory study. METHODS:: Thirteen fresh-frozen adult human knees were tested with a robotic testing system under 2 loading conditions: (1) an 89.0 N anterior tibial load applied at full extension and 15 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion and (2) a combined 7.0-N.m valgus and 5.0-N.m internal tibial torque (simulated pivot-shift test) applied at full extension and 15 degrees and 30 degrees of knee flexion. The following knee states were tested: intact knee, ACL reconstruction and intact lateral meniscus, ACL reconstruction and lateral meniscal posterior root tear, and ACL reconstruction and lateral meniscal posterior root repair. RESULTS:: In the ACL reconstructed knee, a tear of the lateral meniscal posterior root significantly increased knee laxity under anterior loading by as much as 1 mm. The transosseous pullout suture root repair improved knee stability under anterior tibial and simulated pivot-shift loading. Root repair improved the ACL graft force closer to that of the native ACL under anterior tibial loading. CONCLUSION:: Lateral meniscal posterior root injury further destabilizes the ACL-reconstructed knee, and root repair improves knee stability. CLINICAL RELEVANCE:: This study suggests a rationale for surgical repair of the lateral meniscus, which can restore stability close to that of the premeniscal injury state. PMID- 30452282 TI - Academy of Breastfeeding Medicine Experience. PMID- 30452281 TI - Weight-Change Trajectories of Pediatric Outpatients Treated with Risperidone or Aripiprazole in a Naturalistic Setting. AB - OBJECTIVES: Second-generation antipsychotics (SGAs) increase appetite and weight, leading toward a metabolic syndrome. Risperidone and aripiprazole, the most widely used pediatric SGAs, have been studied predominantly in short-term clinical trials, where risperidone leads to a rapid weight increase and aripiprazole to a slower one, while long-term effects are not yet elucidated. Factors that may influence weight gain are likewise not clarified, although baseline weight, previous SGA exposure, pubertal status, and type of SGA have been suggested as moderators. We analyzed weight gain induced by risperidone and aripiprazole in a sample of pediatric outpatients enrolled into a 2-year observational study. METHODS: We assessed at several time points their body mass index (BMI)-Z scores (age and sex-corrected and referred to national norms). We used hierarchical mixed-effects modeling to design BMI-Z trajectories and observed the effects of several variables on determining them. RESULTS: The study group comprised of 127 patients, predominantly males (79%), of 12.6 years on average, treated with risperidone (81%) and aripiprazole (19%) for disruptive behavioral symptoms in patients with and without neurodevelopmental disorders. Overall, BMI-Z was 1.2 at first and 1.4 at last visit (no significant change). We could design four weight-change trajectories, determined by the factors: drug (risperidone/aripiprazole) and age status (children/adolescent). Additional factors not retained in the model but possibly explanatory include the previous duration of SGA treatment and a progressive patient-selection effect due to dropouts in this observational study. Risperidone treatment was associated with trends of BMI-Z increase in children and decrease in adolescents. Aripiprazole treatment was associated with significant BMI-Z increase, higher in children than in adolescents. Results are probably due to longer previous drug exposure in adolescents. CONCLUSIONS: Children were at risk of weight gain more than adolescents, for both risperidone and, of note, aripiprazole. Adolescents and patients with long previous drug exposure tend to reach stable BMI-Z, although in the range between excessive weight and obesity. PMID- 30452283 TI - A Retrospective Chart Review of Buspirone for the Treatment of Anxiety in Psychiatrically Referred Youth with High-Functioning Autism Spectrum Disorder. AB - OBJECTIVES: Anxiety disorders (ADs) are commonly associated with high-functioning Autism Spectrum Disorder (HF-ASD) and often worsen with age. Buspirone is a commonly prescribed anxiolytic drug with a favorable tolerability profile that may offer potential benefits in anxiety management for patients with HF-ASD. This study examines inadequately explored tolerability and effectiveness of buspirone in treating ADs comorbid with high-functioning ASD. METHODS: A retrospective chart review of a 1-year period was conducted in psychiatrically referred population of HF-ASD youth with AD (age 8-17 years) who were treated with buspirone (N = 31). Information on the demographics and treatment history was recorded. Effectiveness was assessed through the Clinical Global Impressions Scale (CGI) severity (CGI-S) and improvement (CGI-I) scores noted by the treating clinician. RESULTS: A total of 31 patients were prescribed buspirone during the determined period, at a mean dose of 41.61 +/- 24.10 mg for an average duration of 272 +/- 125 days. Change in the CGI-S mean scores with treatment suggests an overall improvement in the severity of anxiety symptoms (MT1 = 4.9 +/- 0.7; MT2 = 2.8 +/- 0.87; p < 0.001). Significant improvement in anxiety symptoms (CGI-I <= 2) was observed in 58% and mild improvement (CGI-I = 3) in 29% of the HF-ASD patients who received buspirone treatment. Buspirone was well tolerated with no adverse events reported by the majority of participants, with the exception of two subjects who developed treatment emergent adverse events (activation and mood lability). CONCLUSIONS: Findings from this retrospective chart review suggest a promising role of buspirone in managing anxiety among youth with HF-ASD. Further research with prospective and randomized-controlled trials is necessary. PMID- 30452284 TI - Comparison of energy-matched high-intensity interval and moderate-intensity continuous exercise sessions on latency to eat, energy intake, and appetite. AB - High-intensity interval exercises (HIIex) have gained popularity but their effects on eating behavior are poorly known. The aim of this study was to evaluate whether the effects of HIIex on the three main components of eating behavior (appetite, intake, and latency to eat) differ from those of moderate intensity continuous exercises (MICex) matched for energy expenditure. Fifteen young normal-weight males completed three sessions in a counterbalanced order: HIIex (30-s bouts at 90% of VO2max interceded with 60-s bouts at 35% of VO2max for 20 min), MICex (42% of VO2max for 40 min), and a resting session (REST). Trials were scheduled 80 and 100 min after a standard breakfast for MICex and HIIex, respectively. At 120 min, participants were isolated until they asked for lunch. Appetite was rated on four visual analog scales (hunger, desire to eat, fullness, and prospective consumption) every 15 min until meal request. Results showed that the mean latency of requesting lunch was significantly longer after HIIex than after REST (+17.3 +/- 4.3 min, P = 0.004), but not after MICex (P = 0.686). Energy intake was not different between conditions, leading to a negative energy balance in the two exercise sessions. Thus, the effects of HIIex on eating behavior are likely primarily mediated through the latency of meal initiation. However, inter-individual variability was large and further studies are needed to identify the predictive factors of this response. PMID- 30452285 TI - Teratozoospermia with amorphous sperm head associate with abnormal chromatin condensation in a Chinese family. AB - Male infertility affects approximately 7% of the male population. In about 40% of affected patients, the etiology remains unknown. Here, we report the cases of two infertile brothers who have a uniquely prevalent sperm phenotype with completely amorphous sperm heads. To investigate the mechanisms of familial teratozoospermia with amorphous sperm heads, chromatin condensation was assessed by aniline blue staining, western blot, sperm chromatin structure assay and atomic force microscopy in both the two brothers and 40 control fertile donors. Our results showed an abnormal condensation of chromatin with amorphous headed sperm. We suggest that abnormal chromatin condensation which was induced by disturbances in the process of histone-protamine replacement may be a possible cause of familial teratozoospermia with amorphous head, and the elasticity of sperm nuclei could be a new index to assess sperm quality. Additionally, for the first time, the current study provided a new biomechanics strategy for evaluating pathological sperm contributes to our understanding of teratozoospermia.Abbreviations: SCSA: sperm chromatin structure assay; AFM: atomic force microscopy; ICSI: intracytoplasmic sperm injection; HDS: high DNA stainability; DFI: DNA fragmentation index; PBS: phosphate-buffered saline; DTT: dithiothreitol; FITC: fluorescein isothiocyanate; DAPI: 4',6-diamidino-2-pheneylindole; SSC: standard saline citrate. PMID- 30452286 TI - Epidermal Growth Factor Receptor Mutation Detection in Cerebrospinal Fluid of Lung Adenocarcinoma Patients with Leptomeningeal Metastasis. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative. OBJECTIVE: To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM. METHODS: Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded. RESULTS: Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion. CONCLUSIONS: EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments. PMID- 30452287 TI - Glucose-induced changes in the bacterial communities of mine tailings at different acidification stages. AB - Ecological restoration technologies applied to tailings can influence the associated bacterial communities. However, whether the shifts in these bacterial communities are caused by increased organic carbon, is unknown. Glucose-induced respiration and high-throughput sequencing were used to assess the microbial activity and bacterial communities, respectively. Glucose addition increased the microbial activity, and glucose-ammonium nitrate addition resulted in slightly higher CO2 emission than did glucose addition alone, suggesting that carbon and nitrogen limited microbial community growth. In neutral pH tailings, the bacterial taxa that increased by glucose addition were assigned to the phyla Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes, Firmicutes and Planctomycetes. However, the bacterial taxa that increased by glucose addition in acidic tailings only belonged to the phylum Actinobacteria (maximum increase of 43.78%). In addition, the abundances of the total nitrogen-fixing genera and that of the genus Arthrobacter (representing approximately 97.89% of the total nitrogen-fixing genera) increased by glucose addition in acidic tailings (maximum increase of 46.98%). In contrast, the relative abundances of the total iron- and/or sulfur-oxidizing bacteria decreased (maximum decrease of 10.41%) in response to the addition of glucose. These findings indicate that the addition of organic carbon is beneficial to the development of bacterial communities in mine tailings. PMID- 30452288 TI - Central and Peripheral Cues to Difficulty in a Dynamic Task. AB - OBJECTIVE:: We used this experiment to determine the degree to which cues to difficulty are used to make judgments of difficulty (JODs). BACKGROUND:: Traditional approaches involve seeking to standardize the information people used to evaluate subjective workload; however, it is likely that conscious and unconscious cues underlie peoples' JODs. METHOD:: We designed a video game task that tested the degree to which time-on-task, performance-based feedback, and central cues to difficulty informed JODs. These relationships were modeled along five continuous dimensions of difficulty. RESULTS:: Central cues most strongly contributed to JODs; judgments were supplemented by peripheral cues (performance based feedback and time-on-task) even though these cues were not always valid. In addition, participants became more likely to rate the task as "easier" over time. CONCLUSION:: Although central cues are strong predictors of task difficulty, people confuse task difficulty (central cues), effort allocation and skill (performance-based feedback), and proxy cues to difficulty (time) when making JODs. APPLICATION:: Identifying the functional relationships between cues to difficulty and JODs will provide valuable insight regarding the information that people use to evaluate tasks and to make decisions. PMID- 30452289 TI - Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree. AB - AIMS: To identify potential causative gene mutations in a large Han Chinese pedigree with diffuse nonepidermolytic palmoplantar keratoderma (NEPPK). METHODS: We enrolled 11 patients and 8 healthy individuals from a pedigree with NEPPK and 100 randomly selected healthy controls. Biopsy samples were obtained from the proband. Genomic DNA was extracted from a peripheral blood sample from each participant. Mutation detection via polymerase chain reaction and Sanger sequencing of relevant potential causative genes, including KRT1, KRT6C, KRT10, KRT16, AQP5, and SERPINB7, was performed. Comparisons were made between sequencing outcomes and currently available reference genome databases, including HGMD Pro, Pubmed, 1000 Genomics, and dbSNP. RESULTS: Histological findings, clinical features, and medical history were in accordance with the diagnosis of diffuse NEPPK. We identified a novel splice-site mutation c.1255-1G > C in intron 6 of KRT1 in all individuals with NEPPK in the pedigree. CONCLUSIONS: Diffuse NEPPK is a relatively rare subtype of palmoplantar keratoderma. The results of this study expand the spectrum of KRT1 mutations in diffuse NEPPK and provide insights into the understanding of its underlying pathological mechanisms and phenotype-genotype correlations. PMID- 30452290 TI - The EluNIRTM Ridaforolimus Eluting Coronary Stent System. AB - INTRODUCTION: First generation drug-eluting stents (DES) were developed and indeed proved their superiority compared to bare-metal stent in minimizing neo intimal hyperplasia and in-stent restenosis (ISR), overall, reducing target vessel revascularization (TVR). Newer-generation DES are characterized by thinner struts, more biocompatible and either durable, biodegradable or polymer-free surfaces, better device profile and refined drug elution. Area covered: The EluNIRTM (Medinol, Tel Aviv, Israel) Ridaforolimus Eluting Coronary Stent System is a new DES with unique properties. In this review, we highlight the special characteristics of the stent and summarize relevant clinical data. The EluNIRTM was studied in two clinical trials, the NIREUS trial and the larger, pivotal, BIONICS trial. These trials collectively provide data on the safety, performance and efficacy of the device. Expert commentary: The newly FDA approved EluNIRTM stent features an elastomeric durable polymer which elutes a novel drug, Ridaforolimus. The stent has thin struts with variable widths and a delivery catheter with a spring tip. These characteristics may explain the good angiographic and clinical results of this stent, which were non-inferior to the FDA approved Medtronic ResoluteTM stent DES. PMID- 30452291 TI - Depression, antidepressants, and the risk of non-valvular atrial fibrillation: A nationwide Danish matched cohort study. AB - BACKGROUND: Depression is associated with an increased risk of a series of cardiovascular diseases and with increased symptom burden in patients with atrial fibrillation. The aim of this study was to determine the association between depression as well as antidepressant treatment and the risk of incident atrial fibrillation. DESIGN: A nationwide register-based study comparing the atrial fibrillation risk in all Danes initiating antidepressant treatment from 2000 to 2013 ( N = 785,254) with that in a 1:5-matched sample from the general population. METHODS: Cox regression was used to estimate adjusted hazard ratios (aHRs) and associated 95% confidence intervals (95% CIs), both after initiation of treatment and in the month before when patients were assumed to have medically untreated depression. RESULTS: Antidepressant treatment was associated with a three-fold higher risk of atrial fibrillation during the first month (aHR = 3.18 (95% CI: 2.98-3.39)). This association gradually attenuated over the following year (aHR = 1.37 (95% CI: 1.31-1.44) 2-6 months after antidepressant therapy initiation, and aHR = 1.11 (95% CI: 1.06-1.16) 6-12 months after). However, the associated atrial fibrillation risk was even higher in the month before starting antidepressant treatment (aHR = 7.65 (95% CI: 7.05-8.30) from 30 to 15 days before, and aHR = 4.29 (95% CI: 3.94-4.67) the last 15 days before). Overall, 0.4% of patients were diagnosed with atrial fibrillation from 30 days before to 30 days after antidepressant treatment. CONCLUSIONS: Antidepressant users had a substantially increased atrial fibrillation risk, particularly before treatment initiation. Whether this mirrors a causal relation between depression and atrial fibrillation may have large consequences for public health and should be discussed. PMID- 30452292 TI - Carbohydrate Ligands on Magnetic Nanoparticles for Centrifuge-Free Extraction of Pathogenic Contaminants in Pasteurized Milk. AB - Rapid detection of bacterial contamination in the food supply chain is critically important for food safety monitoring. Reliable extraction and concentration of bacteria from complex matrices is required to achieve high detection sensitivity, especially in situations of low contamination and infective dose. Carbohydrate ligands that attach to microbial cell-surface epitopes are promising economical and biocompatible substitutes for cell-targeting ligands and antibodies. Two different carbohydrate ligands immobilized onto magnetic nanoparticles (MNPs) were easily suspended in liquid food (milk) and allowed expedient extraction of microbes within minutes, without the need for centrifugation or loss in capture capacity. In this pilot study, 25-mL samples of undiluted milk were spiked with 5 mg of MNPs and artificially contaminated with bacteria at 3 to 5 log CFU/mL. MNPs and bacteria formed MNP-cell complexes, which were rapidly separated from the milk matrix with a simple magnet to allow supernatant removal. MNP-cell complexes were then concentrated by resuspension in 1 mL of fresh milk and plated per Bacteriological Analytical Manual procedures. Capture was carried out in vitamin D, 2% reduced fat, and fat-free milk spiked with Salmonella Enteritidis, Escherichia coli O157:H7, and Bacillus cereus for a combined total of 18 experiments (three replicates each). An additional eight experiments were conducted to investigate the effect of competitive bacteria on capture. All experiments were carried out over several months to account for environmental variations. Capture efficiency, on a log basis, for all combinations of milk and bacteria was 73 to 90%. Long-term exposure of the MNPs to milk did not markedly affect capture efficiency. These carbohydrate-functionalized MNPs have potential as nonspecific receptors for rapid extraction of bacteria from complex liquids, opening the door to discovery of biocompatible ligands that can reliably target pathogens in our food. PMID- 30452293 TI - Exposure to Metals from Artisanal Cheeses Made with Goat's Milk. AB - Cheeses are an important source of essential elements. Nevertheless, the level of some metals could pose a health risk. Therefore, the concentration of trace elements and toxic metals (Cr, Cu, Li, Ni, Sr, Pb, Cd, and Al) has been determined in artisanal cheeses from different geographical locations, and the intake of these metals from cheese consumption has been evaluated. The metal concentration was determined in a total of 90 cheese samples from different locations by using inductively coupled plasma atomic emission spectroscopy. The highest concentration of Al (35.1 +/- 4.42 mg/kg, wet weight) was found in artisanal cheeses from Zamora (Spain), followed by Sr (6.85 +/- 0.35 mg/kg, wet weight) in artisanal cheeses from Cadiz (Spain). A daily consumption of 23.2 g of cheese provides a significant dietary contribution for Al of 0.82% of its tolerable weekly intake of 1 mg/kg of body weight per week. Canary Islands cheeses have a higher metal content than the non-Canary cheese, which could be because of the volcanic characteristics of the island soils. The intake of toxic metals and trace elements poses no risk to the health of adults. PMID- 30452294 TI - What should guide our patient management of vulvovaginal atrophy? AB - Genitourinary syndrome of menopause including vulvovaginal atrophy is commonly experienced by postmenopausal women, reducing their quality of life. The aim of this review is to assess current treatment options within the framework of recent management guidelines. Recommendations include use of treatments addressing both symptoms and the underlying pathophysiology, and proactive patient discussion. Both prescription and non-prescription options are recognized, including non hormone-based approaches. Local therapy is preferable in the primary treatment of genitourinary syndrome of menopause symptoms as risk of adverse events is reduced, although long-term safety data are limited. Management of patients with a history of breast cancer requires careful consideration, although estrogen therapy has not been associated with increased risk of breast cancer or of recurrence. Treatment should consider ongoing cancer therapy. As multiple, comparable options exist, treatment choice may be due to experience and patient preference. Best management requires effective patient-physician communication and shared decision-making. PMID- 30452295 TI - Effects of texting on accident risk during a sudden hazardous event: Analysis of predetection and postdetection phases. AB - OBJECTIVE: The present study aims to quantify the effects of texting and driver behavior on the accident risk associated with a sudden event. Further, the study attempts to compare the effects of driving behavior of inexperienced young and professional drivers on risk during predetection and postdetection phases of the event. METHODS: Forty-nine drivers from 2 categories-inexperienced young drivers and experienced professional drivers-took part in simulated experiments. The participants drove in a free-flow road environment under 3 driving conditions: no distraction (baseline) and writing short and long texts while driving. The participants were exposed to a sudden hazardous event during each drive. Accident probability during the sudden event was modeled with a generalized linear mixed model (with a logit link function). RESULTS: As expected, both texting tasks increased accident risk, and the risk was much higher for inexperienced young drivers than for professional drivers. Time lapsed in reducing speed increased the odds for accident risk significantly. A comparative analysis of the driver categories showed that impairment in driving behavior due to the texting tasks was similar for both groups during the predetection phase. However, the risk associated with the texting tasks was higher for young drivers during the postdetection phase. A possible reason could be that young drivers had 65% and 75% higher approach speeds (than the professional drivers) during the short and long text tasks, respectively. CONCLUSIONS: The results provide statistical evidence that increased speed is expressed as increased risk-taking behavior among young drivers, which subsequently is the main reason for their higher accident risk during texting tasks. Moreover, the results confirm that professional drivers are not able to mitigate the increased accident risk associated with texting tasks due to late detection of the event during the tasks. PMID- 30452296 TI - Sex differences in the vascular function and related mechanisms: role of 17beta estradiol. AB - The incidence of cardiovascular disease (CVD) is lower in premenopausal women but increases with age and menopause compared with similarly aged men. Based on the prevalence of CVD in postmenopausal women, sex hormone-dependent mechanisms have been postulated to be the primary factors responsible for the protection from CVD in premenopausal women. Recent Women's Health Initiative studies, Cochrane Review studies, the Early Versus Late Intervention Trial with Estradiol Study, and the Kronos Early Estrogen Prevention Study have suggested that beneficial effects of hormone replacement therapy (HRT) are seen in women of <60 yr of age and if initiated within <10 yr of menopause. In contrast, the beneficial effects of HRT are not seen in women of >60 yr of age and if commenced after 10 yr of menopause. The higher incidence of CVD and the failure of HRT in postmenopausal aged women could be partly associated with fundamental differences in the vascular structure and function between men and women and in between pre- and postmenopausal women, respectively. In this regard, previous studies from human and animal studies have identified several sex differences in vascular function and associated mechanisms. The female sex hormone 17beta-estradiol regulates the majority of these mechanisms. In this review, we summarize the sex differences in vascular structure, myogenic properties, endothelium-dependent and -independent mechanisms, and the role of 17beta-estradiol in the regulation of vascular function. PMID- 30452297 TI - The Anthropology of Epidemic Control: Technologies and Materialities. PMID- 30452298 TI - CRISPR-Cas9: New Heights, New Hesitations. PMID- 30452299 TI - Long Noncoding RNA MRPL39 Inhibits Gastric Cancer Proliferation and Progression by Directly Targeting miR-130. AB - BACKGROUND: Gastric cancer (GC) is one of the most prevalent malignant tumors displaying both high incidence and mortality throughout much of the world. Recently, long noncoding RNAs (lncRNAs) have been implicated in the development and progression of GC. MATERIALS AND METHODS: In the present study, we investigated the biological function and molecular mechanisms of lncRNA MRPL39 in GC. RESULTS: We found that MRPL39 was significantly downregulated in GC tissues and cell lines and that its expression level was negatively associated with carcinoma size, tumor, lymph node, metastasis (TNM) stage, and lymphatic metastasis. Patients with low MRPL39 expression levels revealed a short overall and disease-free survival period. Over-expression of MRPL39 in the GC cell lines BGC823 and SGC-7901 inhibited cell growth, proliferation, migration, and invasion. MiR-130, a putative target gene of MRPL39, displayed an inverse association with the expression of MRPL39 in GC tissues and cell lines. Moreover, a luciferase assay demonstrated a direct binding between the miR-130 and MRPL39, and the reintroduction of miR-130 abrogated the anti-tumor effect of MRPL39 on GC cells. CONCLUSION: Taken together, these findings indicate that MRPL39 serves as a tumor suppressor by directly targeting miR-130 in GC, which suggests that it might be a novel biomarker in the diagnosis and prognosis of GC. PMID- 30452300 TI - What Factors Contribute to Falls-Related Distal Radius Fracture? AB - METHODS:: A sample of 1453 patients (430 men; 1023 women; age range: 18 to 89 years) supplemented by new interview data from 29 patients (19 women) were examined. Chi-square and descriptive analysis of quantitative data, descriptive thematic analysis of qualitative data were compared to determine data convergence and divergence. RESULTS:: A higher number of DRF were observed in the 45 to 64 year-old group (44%), employed people (48%), in winter months (41%) and in low energy fractures (75%). Themes emerged from qualitative data on the cause of the fracture included: environmental factors, behavioural factors, physical factors and sports activities. CONCLUSION:: Reasons for DRF are multifactorial. Preventive strategies with an emphasis on environmental and behavioural factor modifications are likely to decrease the number of DRF. PMID- 30452301 TI - Reproductive Outcomes After a Childhood and Adolescent Young Adult Cancer Diagnosis in Female Cancer Survivors: A Systematic Review and Meta-analysis. AB - Improvements in cancer therapy for childhood and adolescent and young adult (AYA) survivors have increased in excess of 80% among pediatric patients and in excess of 85% among AYA cancer patients. Our research group explored the late effects consequences of cancer treatment on pregnancy and birth outcomes subsequent to a childhood (0-14 years) or AYA (15-25 years) diagnosis of cancer in female cancer survivors. Embase and Medline databases were searched. There were 17 review (n = 10 matched and n = 7 unmatched) studies that met the inclusion criteria. Subanalyses were conducted on 10 matched studies. The median age for all studies for patients at diagnosis and birth was 11 and 27 years, respectively. In matched cohort studies, female childhood and AYA cancer patients, who received chemotherapy alone, had a pooled estimated rate of 18% of experiencing a live birth compared with 10% of females who received radiotherapy alone and subsequently had a live birth. Females who received surgery alone reported higher pooled estimated rates of 44% for a live birth. For matched retrospective review studies, 79% (n = 973) of women experienced a live birth, of which 22% of these babies were born preterm. This meta-analysis found lower birth rates for survivors. Access to fertility-related information and discussions around fertility preservation options and oncofertility psychosocial support should be offered to all cancer patients and their families before starting cancer treatment. PMID- 30452302 TI - CYCS gene variants associated with thrombocytopenia. PMID- 30452303 TI - Dosimetry and uncertainty approaches for the million person study of low-dose radiation health effects: overview of the recommendations in NCRP Report No. 178. AB - PURPOSE: Scientific Committee 6-9 was established by the National Council on Radiation Protection and Measurements (NCRP), charged to provide guidance in the derivation of organ doses and their uncertainty, and produced a report, NCRP Report No. 178, Deriving Organ Doses and their Uncertainty for Epidemiologic Studies with a focus on the Million Person Study of Low-Dose Radiation Health Effects (MPS). This review summarizes the conclusions and recommendations of NCRP Report No. 178, with a concentration on and overview of the dosimetry and uncertainty approaches for the cohorts in the MPS, along with guidelines regarding the essential approaches used to estimate organ doses and their uncertainties (from external and internal sources) within the framework of an epidemiologic study. CONCLUSIONS: The success of the MPS is tied to the validity of the dose reconstruction approaches to provide realistic estimates of organ specific radiation absorbed doses that are as accurate and precise as possible and to properly evaluate their accompanying uncertainties. The dosimetry aspects for the MPS are challenging in that they address diverse exposure scenarios for diverse occupational groups being studied over a period of up to 70 y. Specific dosimetric reconstruction issues differ among the varied exposed populations that are considered: atomic veterans, U.S. Department of Energy workers exposed to both penetrating radiation and intakes of radionuclides, nuclear power plant workers, medical radiation workers, and industrial radiographers. While a major source of radiation exposure to the study population comes from external gamma- or x-ray sources, for some of the study groups, there is also a meaningful component of radionuclide intakes that requires internal radiation dosimetry assessments. PMID- 30452304 TI - Use of Face Information Varies Systematically From Developmental Prosopagnosics to Super-Recognizers. AB - Face-recognition abilities differ largely in the neurologically typical population. We examined how the use of information varies with face-recognition ability from developmental prosopagnosics to super-recognizers. Specifically, we investigated the use of facial features at different spatial scales in 112 individuals, including 5 developmental prosopagnosics and 8 super-recognizers, during an online famous-face-identification task using the bubbles method. We discovered that viewing of the eyes and mouth to identify faces at relatively high spatial frequencies is strongly correlated with face-recognition ability, evaluated from two independent measures. We also showed that the abilities of developmental prosopagnosics and super-recognizers are explained by a model that predicts face-recognition ability from the use of information built solely from participants with intermediate face-recognition abilities ( n = 99). This supports the hypothesis that the use of information varies quantitatively from developmental prosopagnosics to super-recognizers as a function of face recognition ability. PMID- 30452305 TI - Upper urinary tract urothelial carcinoma and its variants: transition from morphology to personalized molecular characterization in diagnosis, prognosis, and therapy. AB - INTRODUCTION: Upper tract urothelial carcinoma (UTUC) accounts for 5% of urothelial carcinomas (UCs), the estimated annual incidence being 1-2 cases per 100,000 inhabitants. The aim of this review was to summarize the main morphologic features of UTUC as well as the current status and future role of its molecular characterization in diagnosis, prognosis, and therapy. Areas covered: Several studies on the UTUCs have shown the diagnostic, prognostic, and therapeutic significance of standard pathological features, such as tumor stage, grade, and lymph node metastasis. Investigations have also identified novel factors, in particular, variant histologies, and molecular biomarkers. Based on these, predictive tools have been developed. Expert commentary: The morphology of the UTUC has been considered to be the same as that of Bladder Urothelial carcinoma (BUC). Molecular characterization studies, including genomics, have shown changes in UTUC occurring at differing frequencies in comparison with BUC, the former with unique molecular subtypes and different responses to treatment. PMID- 30452306 TI - Augmentation of DTH reaction of mycobacterial antigenic cocktail using synthetic mycobacterial 19-kDa lipoprotein as a TLR-stimulant. AB - The current study proposed that previously characterized individual antigenic proteins could represent potential replacement for conventional purified protein derivative (PPD) in tuberculosis skin testing when used in cocktails triggered by suitable TLR-stimulants that would provide the missing pro-inflammatory stimulus. Three different cocktails of previously selected antigens, including C1 (ESAT 6/CPF-10/MPB-83); C2 (ESAT-6/MPB-64/MPB-83); and C3 (CPF-10/MPB-64/MPB-83), were evaluated in vitro using lymphocytic proliferation and IFN-gamma production assays, as well as mRNA and protein expression levels of TNF-alpha, IL-12p40, and IL-2 as pro-inflammatory molecules. C1 showed the highest significant induction of pro-inflammatory molecules as compared to other cocktails, yet still significantly lower than that induced by conventional PPD. Interestingly, inclusion of the synthetic Mycobacterium tuberculosis 19-kDa lipoprotein (Pam3Cys SSNKSTTGSGETTTA) as a TLR-stimulant resulted in obvious augmentation of C1 induced pro-inflammatory molecules to levels comparable to that of PPD. In addition, skin testing using sensitized guinea pig model revealed comparable significant reaction to that of conventional PPD. ESAT-6/CPF-10/MPB-83 cocktail is suggested as a potential alternative skin-testing reagent when used in combination with the M. tuberculosis 19-kDa lipoprotein as a TLR-stimulant. PMID- 30452307 TI - Definition of Episodic Dyspnea in Cancer Patients: A Delphi-Based Consensus among Spanish Experts: The INSPIRA Study. AB - BACKGROUND: Episodic dyspnea is an increasingly recognized phenomenon that occurs frequently in patients with cancer. Although numerous definitions have been proposed to describe episodic dyspnea, to date, no common widely accepted definition in Spanish has yet emerged. Without a clear well-accepted definition, it is difficult to design rigorous clinical trials to evaluate candidate treatments for this emerging entity and to compare outcomes among studies. OBJECTIVE: The aim of the study was to reach a consensus definition of episodic dyspnea in the Spanish language based on professional criteria in cancer patients. DESIGN: A two-round Delphi study. SETTING/SUBJECTS: Sixty-one Spanish specialists in medical oncology, radiation oncology, pneumology, palliative care, and pain management participated in the study. MEASUREMENTS: Sixteen different questions on dyspnea-related terminology, including the definition of episodic dyspnea, were assessed. RESULTS: The panel of experts reached a consensus on 75% of the 16 assessments proposed: 56.25% in agreement and 18.75% in disagreement. The term that most panelists considered most appropriate to define dyspnea exacerbation was dyspnea crisis. The panelists disagreed that dyspnea exacerbation is equivalent to dyspnea at effort and that the presence of dyspnea at rest is required for exacerbation to occur. However, there was wide agreement that exacerbation may or may not be predictable and can be triggered by comorbidities as well as emotional, environmental, or effort factors. CONCLUSIONS: The broad consensus reached in this study is a necessary first step to design high-quality methodological studies to better understand episodic dyspnea and improve treatment. PMID- 30452308 TI - Accuracy of casts fabricated by digital and conventional implant impressions. AB - The purpose of this study was to compare the accuracy of stereolithographic casts with those obtained using conventional implant impressions. An epoxy resin model containing dental implants was used as master model. Dental casts (n=10) were fabricated through both conventional and digital implant impressions. The conventional casts (CC), stereolithographic casts (SC) and the master model (MM) were digitized and the accuracy was determined through a deviation analysis and linear measure-ments. Data were analyzed using paired Student's t-test with p < 0.05. Stereolithographic casts showed higher deviation at vestibular area (CIC: 41 +/- 28.87; SC: 117 +/- 36.83 um) and lingual cusps (CC: 40.70 +/- 19.79; SC: 80 +/- 42.95 um) in comparison to conventional casts. No statistically significant difference was found for linear measurements of conventional and digital casts. The entire-arch accuracy was comparable between casts. However, stereolithographic casts were less accurate at the cusp level in comparison with conventional casts. PMID- 30452309 TI - Severe case of Osteonecrosis following implant placement in a patient in therapy with bisphosphonates: A case report. AB - Osteonecrosis of the jaw is a rare complication that have been associated with the use of bisphosphonates (BP). A 77 years old patient presented in April 2013 asking for a consultation. She reported that in May 2009, she underwent an implant rehabilitation with 8 implants and an immediately loaded fixed prosthesis in the maxilla. After few months the patient started to report pain and purulent secretions, that were neglected by the clinician for several years. She decided to refer to the Dental Clinic after another acute pain episode. Once the fixed prosthesis was removed exposition of necrotic bone were found in correspondence of the implants. The patient reported to had taken oral Alendronic Acid to treat osteoporosis since before 2006. The patient underwent a functional endoscopic sinus surgery and a removal of necrotic bone blocks. Three years of follow up showed healed tissues with no recurrence, although the alveolar crest appear irregular on radiographs. PMID- 30452310 TI - 3-min all-out effort on cycle ergometer is valid to estimate the anaerobic capacity by measurement of blood lactate and excess post-exercise oxygen consumption. AB - The purpose of this study was to investigate the use of a single 3-min all-out maximal effort to estimate anaerobic capacity (AC) through the lactate and excess post-exercise oxygen consumption (EPOC) response methods (AC[La-]+EPOCfast) on a cycle ergometer. Eleven physically active men (age = 28.1 +/- 4.0 yrs, height = 175.1 +/- 4.2 cm, body mass = 74.8 +/- 11.9 kg and ?O2max = 40.7 +/- 7.3 mL kg-1 min-1), participated in the study and performed: i) five submaximal efforts, ii) a supramaximal effort at 115% of intensity of ?O2max, and iii) a 3-min all-out maximal effort. Anaerobic capacity was estimated using the supramaximal effort through conventional maximal accumulated oxygen deficit (MAOD) and also through the sum of oxygen equivalents from the glycolytic (fast component of excess post exercise oxygen consumption) and phosphagen pathways (blood lactate accumulation) (AC[La-]+EPOCfast), while during the 3-min all-out maximal effort the anaerobic capacity was estimated using the AC[La-]+EPOCfast procedure. There were no significant differences between the three methods (p > 0.05). Additionally, the anaerobic capacity estimated during the 3-min all-out effort was significantly correlated with the MAOD (r = 0.74; p = 0.009) and AC[La-]+EPOCfast methods (r = 0.65; p = 0.029). Therefore, it is possible to conclude that the 3-min all-out effort is valid to estimate anaerobic capacity in physically active men during a single cycle ergometer effort. PMID- 30452311 TI - The voyage of thought: navigating knowledge across the sixteenth-century world. PMID- 30452312 TI - Propionibacterium acnes related anti-inflammation and skin hydration activities of madecassoside, a pentacyclic triterpene saponin from Centella asiatica. AB - Madecassoside is a major pentacyclic triterpene saponin from Centella asiatica with multiple pharmaceutical activities. In this study, we focused on its Propionibacterium acnes related anti-inflammation and skin hydration activities, both of which play important roles in skin homeostasis and barrier function. Madecassoside significantly inhibited the pro-inflammatory cytokine IL-1beta, TLR2 and nuclear translocation of NF-kappaB in P. acnes stimulated THP-1 human monocytic cells. In addition, madecasssoside exhibited significant effects on enhancement of skin hydration through increasing the key moisturizing contributors of aquaporin-3, loricrin and involucrin in HaCaT keratinocytes as well as hyaluronan (HA) secretion in human dermal fibroblasts. The upregulation of HA synthases (HAS1, HAS2, HAS3) and inhibition to ROS formation accounted for the increment of HA content. Together, the in vitro study implied the potential medical and cosmetic application of madecassoside in skin protection. PMID- 30452314 TI - Outcomes of Laparoscopic Cholecystectomy in Patients Supported with a Left Ventricular Assist Device. AB - BACKGROUND: An increasing number of end-stage heart failure patients are supported with left ventricular assist device (LVAD) implantation and must be maintained on consistent anticoagulation. These patients are experiencing prolonged survival and, in some, there is development of new biliary disease. However, safety and outcomes of this procedure in this unique patient group is not well reported. METHODS: This was a retrospective single-center review. All adult patients supported on an implanted, continuous flow LVAD from 2007 to 2016 were screened. Baseline characteristics, laboratory values, and operative details were collected through retrospective chart review and an institutional LVAD registry. RESULTS: Of the 798 patients screened, 5 (0.63%) underwent laparoscopic cholecystectomy after LVAD implantation. In 4 patients (80%), the indication for surgery was symptomatic cholelithiasis and 1 patient (20%) had symptomatic acalculous cholecystitis. The average time from LVAD implantation to laparoscopic cholecystectomy was 254 +/- 158 days. Average (corrected) preoperative international normalized ratio (INR) was 1.34 +/- 0.30. Average preoperative hemoglobin was 11.28 +/- 2.41 g/dL. All patients were on warfarin preoperatively and admitted before their operations for bridging with a heparin drip. Average postoperative change in hemoglobin was -1.16 +/- 1.97 g/dL. The only major postoperative complication in this cohort was the development of an abdominal wall hematoma in 1 patient requiring operative evacuation. The average length of stay was 13.2 +/- 4.6 days. Three patients (60%) took an average of 12 days to reach therapeutic INR. CONCLUSIONS: Laparoscopic cholecystectomies can be performed safely in LVAD patients. Prolonged hospital stay is mainly owing to time required to reach a therapeutic INR postoperatively. LEVEL OF EVIDENCE: II, prognostic. PMID- 30452316 TI - Systemic Lupus Erythematosus and the Eye. PMID- 30452317 TI - Interleukin-33, a Potential Cytokine Expressed in Tumor Microenvironment Involves in Antitumor Immunotherapy Through Facilitates CD8+ T Cells. AB - Interleukin-33 (IL-33) is a cytokine with pleiotropic functions in various diseases; however, its role in the antitumor immune response is still unclear. We found the expression of IL-33/ST2 in nonsmall cell lung tumor microenvironment. Furthermore, we found that IL-33 promoted effector functions of CD8+ T cells that play a critical role in antitumor immune response. In addition, we found that IL 33 enhanced tumor vaccine effector functions in mice. Altogether, these findings suggest that IL-33, through facilitates CD8+ T cells in microenvironment to provide a profound effect in antitumor immunotherapy. PMID- 30452319 TI - The Big 3. PMID- 30452318 TI - Obese Patients with Type 2 Diabetes: Outcomes After Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Bariatric surgery is superior to medical treatment for type 2 diabetes mellitus (T2DM) control in obese patients. Reports in the literature have been mainly based on Roux-en-Y gastric bypass (RYGB) or adjustable gastric band. The aim of this study was to analyze mid- and long-term metabolic results after laparoscopic sleeve gastrectomy (LSG). METHODS: Obese patients with T2DM undergoing LSG were included in this study. Selection criteria for T2DM remission were: post-operatory fasting glucose (FG) level <100 mg/dL, and hemoglobin A1c (HbA1c) <6% without medication. RESULTS: Between January 2009 and July 2016, 166 T2DM obese patients underwent LSG and completed >=1 year follow-up. There were 101 women (60.8%; mean age 49.07 +/- 12.8 years). Initial body mass index (BMI) was 46.44 +/- 7.68 kg/m2. Mean time since T2DM diagnosis was 5.95 years (1-28). Preoperative HbA1c was 7.53% +/- 0.97%. Before LSG, 75.3% (n = 125) were receiving oral hypoglycemic agents, and 13.25% (n = 22) insulin. Mean follow-up was 65 +/- 10 months. Complete T2DM remission was achieved in 78.3%, 76.2%, and 71.4% at 1, 3, and >=5 years respectively; in the long term, 7.2% attained partial remission, 10% improved, and 11.4% experienced recurrence of the disease. Remission rate was significantly lower in patients under insulin therapy preoperatively, and in patients with T2DM diagnosed >=5 years before consultation (P = .0004 and .0001, respectively). CONCLUSIONS: At mid- and long-term follow up, T2DM control was satisfactory after LSG. Preoperative insulin therapy and T2DM duration >=5 years were predictors of less favorable outcomes. PMID- 30452320 TI - Commonly used medication for Lupus. PMID- 30452321 TI - Management of pregnancy in systemic lupus erythematosus: What a GP should know. PMID- 30452322 TI - Introduction. PMID- 30452323 TI - Update on Lupus Nephritis for GPs. PMID- 30452324 TI - Vaccination in SLE patients. PMID- 30452325 TI - Thrombotic antiphospholipid syndrome. PMID- 30452326 TI - Antiphospholipid syndrome in obstetrics. AB - Antiphospholipid syndrome (APS) covers a spectrum of clinical manifestations ranging from recurrent pregnancy loss and obstetric complications from placental dysfunction through to thrombotic disease. This article will focus on the common manifestations of the pregnancy-related complications of APS. This includes clinical manifestations, diagnosis and management, as general practitioners will need to be able to recognize the disorder and will also have patients under their care receiving treatment for APS. PMID- 30452327 TI - Neuropsychiatric symptoms in lupus. AB - Patients with lupus experience a high burden of neuropsychiatric symptoms. While some patients have frank neurological complications, this represents a minority. Most neuropsychiatric symptoms are chronic and not associated with brain imaging abnormalities, for example, fatigue, 'brain fog' and altered mood. Factors which contribute to these symptoms may include medications, infections, the psychological burden of chronic unpredictable disease, and the direct effects of inflammation on the brain. This article summarizes our current understanding of psychological symptoms in lupus, and how this informs our approach to management. PMID- 30452328 TI - Hughes syndrome (antiphospholipid syndrome) and the nervous system. PMID- 30452329 TI - Primary Sjogren's syndrome. AB - Primary Sjogren's syndrome (pSS) is a systemic autoimmune disorder characterized by focal lymphocytic infiltration of the exocrine glands causing dry eyes and dry mouth. Similar glandular features can also occur as a late complication in patients with other rheumatic disorders, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and scleroderma ('secondary' Sjogren's syndrome).1 Anti-Ro and/or anti-La (ENA) antibodies are found in approximately 70% of pSS patients, generally with ANA positivity. Hypergammaglobulinaemia is also common. Systemic features also occur in some patients with pSS. A positive rheumatoid factor (RF) is often seen and so if patients present with arthritis, dryness and a positive RF a diagnosis of pSS should be considered as a possible alternative to RA. Anti-CCP antibodies are more specific for RA. PMID- 30452330 TI - A British pathologist and child neurologist who described familial dementing disease and the neuropathology of subacute combined degeneration. PMID- 30452331 TI - Characteristics of Local Delivery Agents for Treating Peri-implantitis on Dental Implant Surfaces: A Preclinical Study. AB - Local delivery agents are widely used in peri-implantitis treatments. The aim of this study was to identify local delivery agents remaining on the dental implant surfaces and to analyze the components of these residues after applying various cleaning methods. Implants were prepared with a sand-blasted, large-grit, acid etched surface. Four kinds of local delivery agents were applied on the implant surfaces: chlorhexidine gel (group 2), tetracycline solution (group 3), and two kinds of minocycline hydrochloride agents (groups 4 and 5). Group 1 comprised normal saline as a control. Two cleaning methods were applied for different durations as follows: (1) running distilled water for 10 s (subgroup A), 5 min (subgroup B), and 15 min (subgroup C); and (2) the water spray of a dental-unit chair for 10 s (subgroup D) and 5 min (subgroup E). Scanning electron microscopy and energy-dispersive x-ray spectroscopy were used to analyze the surface morphology and residue components for all implants. The amount of local delivery agents removed from the implant surfaces in groups 1, 2, 3, and 5 increased with the cleaning duration and pressure. However, Minocline (DongKook Pharmaceutical, Seoul, Korea) remained coated on the implant surfaces in group 4 under all cleaning conditions. Minocline could not be cleaned off well by water due to its hydrophobicity. Therefore, directly using this agent on implant surfaces with peri-implantitis should be carefully considered. The presence of local delivery agent residues without drug efficacies on implant surfaces might interfere with re-osseointegration and act as a reservoir of microorganisms. PMID- 30452332 TI - Seasonality of Immunological and Health-State Parameters of Wild Broadnose Sevengill Shark, Notorynchus cepedianus. AB - Seasonal fluctuation in environmental parameters can influence immune responses of vertebrates and consequently influence their health and disease resistance. Although seasonality of immune function is well documented in a broad range of vertebrate taxa, this information remains virtually unexplored in cartilaginous fish. Here we examine seasonal variation in immune and general-health parameters of free-living adult broadnose sevengill sharks, Notorynchus cepedianus, along an annual cycle. We sampled sharks during autumn/winter (i.e., coolest temperatures and nonreproductive period) and spring/summer (i.e., warmest temperatures and active reproductive period) and assessed aspects of immunity, general condition, and reproductive hormone levels. A seasonal influence was observed in some, but not all, parameters evaluated. Lower lymphocyte counts and higher heterophil counts and granulocyte to lymphocyte (G?L) ratios were observed in sharks sampled during autumn/winter than in those sampled during spring/summer. On the other hand, total leukocyte counts, eosinophil counts, bacterial agglutination mediated by natural antibodies, and hematocrit did not vary seasonally. The observed seasonal patterns could be explained as (1) greater levels of stress based on the G?L ratio, (2) a sign of immunosuppression or depressed immune investment based on the low lymphocyte counts, and/or (3) a sign of ongoing infection based on the higher heterophil counts in the colder seasons with respect to the warmer ones. In addition, the pattern is in line with the notion that while acquired components are usually depressed by lower temperatures, some innate components might increase to offset that reduction. Immune and health-state parameters were mostly independent of reproductive hormone levels, providing little support for a trade-off with reproduction. Overall, the observed seasonal pattern in immunity of broadnose sevengill sharks could be related to changes in abiotic environmental condition, such as water temperature and photoperiod, although other factors such as availability of high-quality food may play a part. PMID- 30452333 TI - Patient Acceptance of e-Health Services in Saudi Arabia: An Integrative Perspective. AB - BACKGROUND: e-Health has been expansively considered as a technological intervention for fundamental enhancement in the healthcare sector to mitigate the enormous demand and supply of healthcare in both developed and developing nations. In 2000, the Saudi government established a committee for health reform to develop an information technology strategic plan for healthcare and for deploying e-health applications within the country. The objective of e-health systems was to provide better healthcare to patients and to increase the efficiency of healthcare organizations. Despite numerous e-health interventions to provide healthcare services, very little is studied about the adoption process of e-health from users' viewpoints in Saudi Arabia. This study minimizes this knowledge gap by studying the factors affecting the adoption and acceptance of e health in the context of Saudi Arabia. MATERIALS AND METHODS: This study has combined the Technology Acceptance Model and Theory of Planned Behavior frameworks to evaluate the factors influencing the patient acceptance of e-health services in Saudi Arabia. Data were collected from patients at various private and public hospitals in Saudi Arabia. The partial least square technique based on structural equation modeling was applied to analyze the survey data. RESULTS: The study shows the significant influence of perceived usefulness and perceived ease of use on the attitude. Furthermore, attitude and subjective norm (p < 0.05) significantly influence patient behavioral intention (BI) to use e-health services. However, perceived behavioral control (p > 0.05) had no significant influence on patient BI to use e-health services. CONCLUSIONS: The findings of this study might be useful to policymakers, the government, and healthcare service providers in Saudi Arabia and other developing countries. PMID- 30452334 TI - Case 264. AB - History A 28-year-old woman presented to the emergency department with painful swelling of the third finger on her right hand, which developed quickly. She had no relevant medical or surgical history. Her pain was worse at night, with stiffness decreasing during the morning. Clinical examination revealed generalized swelling of the third finger, cyanotic skin, and fingernail splitting on the second finger of the left hand ( Fig 1 ). Laboratory test results were normal, with no evidence of inflammatory disease. Radiographs of both hands were obtained ( Fig 2 ). CT scanning ( Fig 3 ) and MRI ( Fig 4 ) were also performed. [Figure: see text] [Figure: see text] [Figure: see text] [Figure: see text] [Figure: see text] [Figure: see text] [Figure: see text] [Figure: see text]. PMID- 30452335 TI - Case 260: Endobronchial Posttransplantation Lymphoproliferative Disease. AB - History A 31-year-old woman with a history of bilateral orthotopic lung transplantation performed 10 months earlier for cystic fibrosis presented for a routine follow-up appointment, with her chief symptom being a cough. The cough started approximately 1 month prior to this appointment and was minimally productive of clear to yellow phlegm. In addition to her cough, she reported increased sinus congestion and a sensation of "something in her upper chest." She denied shortness of breath, wheezing, hemoptysis, or cigarette smoking. Review of systems was negative for fever, chills, or night sweats. At physical examination, the patient was afebrile, borderline tachycardic (heart rate, 99 beats per minute), and mildly hypertensive (blood pressure, 138/99 mm Hg). Oxygen saturation was 96% on room air. Laboratory evaluation revealed a white blood cell count of 3.5 * 109/L (normal range, [3.2-9.8] * 109/L). Pulmonary function testing was notable for a newly decreased ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) of 64% (2.0 and 3.4 L, respectively) (normal FEV1-to-FVC ratio, 80%), suggesting an obstructive lung process. One month prior to presentation, the patient's sputum cultures grew Pseudomonas and methicillin-resistant Staphylococcus aureus. The patient showed no evidence of active infection at the time of bronchoscopy. Thus, the bacteria were favored to reflect colonization, and antibiotic therapy was not administered at that time. The patient was taking an immunosuppression regimen of mycophenolate mofetil (CellCept; Genentech, San Francisco, Calif) (1 g twice daily), prednisone (10 mg daily), and tacrolimus (Prograf; Astellas Pharma US, Northbrook, Ill) (goal therapeutic range, 12-14 ng/mL). The patient was sent for posteroanterior and lateral chest radiography followed by chest CT ( Figs 1 - 3 ) and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT ( Fig 4 ). PMID- 30452336 TI - Phase II Trial of Trastuzumab and Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Salivary Duct Carcinoma. AB - PURPOSE: Clinical evidence demonstrating the effectiveness of systemic therapy for advanced salivary duct carcinoma (SDC) is lacking because of the disease's rarity. We assessed the efficacy and toxicity of trastuzumab plus docetaxel in patients with locally advanced and/or recurrent or metastatic human epidermal growth factor receptor 2-positive SDC. PATIENTS AND METHODS: This was a single center, single-arm, open-label, phase II study in Japan. The patients received trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Docetaxel 70 mg/m2 was administrated every 3 weeks. The primary end point was the overall response rate; the secondary end points included the clinical benefit rate, progression-free survival, overall survival, and toxicity. This study is registered with the University Hospital Medical Information Network Clinical Trials Registry (Identification No. UMIN000009437). RESULTS: Fifty-seven eligible patients with SDC were enrolled. The overall response rate was 70.2% (95% CI, 56.6% to 81.6%), and the clinical benefit rate was 84.2% (95% CI, 72.1% to 92.5%). Median progression-free and overall survival times were 8.9 months (95% CI, 7.8 to 9.9 months) and 39.7 months (95% CI, not reached), respectively. The most frequent adverse event was anemia (52 patients [91%]), followed by a decreased WBC count (51 patients [89%]) and neutropenia (50 patients [88%]). The most frequently observed grade 4 adverse event was a decreased neutrophil count (34 patients [60%]). Grade 3 febrile neutropenia was reported in eight patients (14%). No grade 2 or greater adverse events of heart failure or left ventricular ejection fraction decline to less than 50% occurred. CONCLUSION: Our data show encouraging efficacy of trastuzumab plus docetaxel therapy in patients with human epidermal growth factor receptor 2-positive SDC, with a manageable toxicity profile. PMID- 30452337 TI - Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. AB - PURPOSE: To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment. METHODS: ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel's review of the evidence from six trials. RESULTS: The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment. RECOMMENDATIONS: The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines . PMID- 30452338 TI - Shining light inside the tunnel: using photovoice as a strategy to define the needs for health promotion among families of low socioeconomic status. AB - PURPOSE: This study aimed to identify opportunities to improve the current health and social situation of low socioeconomic status (SES) families and to gain a better understanding of the main needs regarding health promotion. Low-SES families were approached to participate in a photovoice study. METHOD: The study took place in the municipality of Vaals, which is located in the southernmost part of the Netherlands. A diverse group of ten people from eight different families took about 150 photographs within their community on topics they considered important for their health and quality of life. This was followed by individual interviews and a focus group interview. RESULTS: Four main needs were identified: meeting each other, helping each other, feeling safe and being mobile. The photographs showed that health-related themes had low priority for these families. CONCLUSION: The low-SES families focused on upstream factors relating to independence, self-resilience and a sense of belonging, to help them cope with their current situation. This study represents a first step towards the development of a community approach to health promotion in low-SES families. PMID- 30452339 TI - AI Tackles Hospital Infections: Machine Learning Is Helping Clinicians. AB - For Ashley Zappia (Figure 1), getting her hands dirty was part of her job. Even though she always tried to remain as clean as possible, her work as a nursing aide at a Southern California hospital required a lot of diapering, changing, and other hands-on tasks. She was mostly in the ER, where physical contact with bodily fluids from sick patients was normal. She was careful to wash her hands frequently, even though she almost always wore gowns and gloves with all patients. Every time she left or entered a room, she lathered her hands in hand sanitizer gel. Just 27 years old, she was young and healthy. On paper, she was at low risk for infection. That?s why, at first, she thought little of a urinary tract infection (UTI) that seemed to appear out of nowhere. PMID- 30452340 TI - Discovering Cancer Earlier: A New US$100 Million X Prize Aims to Shift the Odds in Cancer Survival. AB - According to the National Cancer Institute, 4 million people die of cancer worldwide every year-almost 500 every hour. But the most shocking thing about that statistic is this: more than a third and possibly even the vast majority of those deaths could have been prevented through sufficiently early detection. Now, a new competition aims to turn that situation around. PMID- 30452341 TI - Direct-To-Consumer Genetic Testing: Is the Public Ready for Simple, At-Home DNA Tests to Detect Disease Risk? AB - Most genetic testing requires a doctor's prescription. In April 2017, however, the U.S. Food and Drug Administration (FDA) gave genetics company 23andMe the go ahead to sell DNA tests assessing the user's level of risk for ten health conditions, including Parkinson's disease and late-onset Alzheimer's disease. This was followed nearly a year later by approval to sell tests for three mutations in the genes BRCA1 and BRCA2 linked to increased breast cancer risk. These remain the only FDA-approved direct-to-consumer (DTC) tests for genetic risk of disease. PMID- 30452342 TI - Opening Act: New Multidisciplinary Approaches Yield Thinner, Stronger, Better Stents. AB - When an artery is blocked, stents are often the best way to open up the vessel. A mesh stent is tightly crimped over a tiny balloon and guided to the troubled spot; the balloon is inflated, expanding the stent, which forces the vessel open. Blood flow is restored. PMID- 30452343 TI - The Eye as a Window to Health: Albeit Slow, Research is Progressing on Contact Lenses for Medical Diagnostics. AB - The idea is a compelling one: a device that looks and feels like an ordinary contact lens but that can continuously monitor a variety of health indicators. For a diabetic, such a lens might update blood glucose levels and, using a built in flashing LED indicator light, signal when a condition needs attention. Diabetic patients might be saved from the need for repeated finger prick tests and could be monitored for longer periods of time and for a greater variety of parameters at once. PMID- 30452344 TI - Healthcare in the Age of Interoperability: The Promise of Fast Healthcare Interoperability Resources. AB - The first article of this series (see "About This Series") mentioned that, after the success of its new messaging standard for electronic health record (EHR) systems, Health Level 7 (HL7) found it difficult to develop and widely deploy a standard for the rich representation of clinical data for use in patient care. This was due, in large part, to the complexity of medicine and the resulting complexity of the clinical terminologies developed to represent it. PMID- 30452345 TI - A New Vision for Preventing Pressure Ulcers: Wearable Wireless Devices Could Help Solve a Common-and Serious-Problem. AB - With an aging population, the incidence and prevalence of wound problems is on the rise. Bedsores (also known as pressure ulcers or decubitus ulcers) are painful, take months to heal, and, for many patients, never do, leading to other health problems. The condition has become so acute that treating bedsores is now a significant burden on the healthcare system. An estimated 2.5 million pressure ulcers are treated in U.S. hospitals each year, adding US$11 billion annually to health care costs. PMID- 30452346 TI - Eco-friendly highly sensitive transducers based on a new KNN-NTK-FM lead-free piezoelectric ceramic for high-frequency biomedical ultrasonic imaging applications. AB - High-frequency ultrasonic imaging with improved spatial resolution has gained increasing attention in the field of biomedical imaging. Sensitivity of transducers plays a pivotal role in determining ultrasonic image quality. Conventional ultrasonic transducers are mostly made from lead-based piezoelectric materials that may be harmful to the human body and the environment. In this study, a new (K,Na)NbO -KTiNbO -BaZrO -Fe O -MgO (KNN-NTK-FM) lead-free piezoelectric ceramic was utilized in developing eco-friendly transducers for high-frequency biomedical ultrasonic imaging applications. A needle transducer with a small active aperture size of 0.45 * 0.55 mm was designed and evaluated. The fabricated transducer exhibits great performance with a high center frequency (52.6 MHz), a good electromechanical coupling ( ~ 0.45), a large bandwidth (64.4% at -6 dB), and a very low two-way insertion loss (10.1 dB). Such high sensitivity is superior to those transducers based on other lead-free piezoelectric materials and can even be comparable to the lead-based ones. Imaging performance of the KNN NTK-FM needle transducer was analyzed by imaging a wire phantom and an agar tissue-mimicking phantom. Imaging capabilities of the transducer were further demonstrated by ex vivo imaging studies on a porcine eyeball and a rabbit aorta. The results suggest that the KNN-NTK-FM piezoceramic has many attractive properties over other lead-free piezoelectric materials in developing eco friendly highly sensitive transducers for high-frequency biomedical ultrasonic imaging applications. PMID- 30452347 TI - Development and In Silico Evaluation of a Model-Based Closed-Loop Fluid Resuscitation Control Algorithm. AB - OBJECTIVE: To develop and evaluate in silico a model-based closed-loop fluid resuscitation control algorithm via blood volume feedback. METHODS: Model-based adaptive control algorithm for fluid resuscitation was developed by leveraging a low-order lumped-parameter blood volume dynamics model, and then in silico evaluated based on a detailed mechanistic model of circulatory physiology. The algorithm operates in two steps: (1) the blood volume dynamics model is individualized based on the patient's fractional blood volume response to an initial fluid bolus via system identification; and (2) an adaptive control law built on the individualized blood volume dynamics model regulates the blood volume of the patient. RESULTS: The algorithm was able to track the blood volume set point as well as accurately estimate and monitor the patient's absolute blood volume level. The algorithm significantly outperformed a population-based proportional-integral-derivative control. CONCLUSION: Model-based development of closed-loop fluid resuscitation control algorithm may enable regulation of blood volume and monitoring of absolute blood volume level. SIGNIFICANCE: Model-based closed-loop fluid resuscitation algorithm may offer opportunities for standardized and patient-tailored therapy and reduction of clinician workload. PMID- 30452348 TI - Dual-Continuum Design Approach for Intuitive and Low-Cost Upper Gastrointestinal Endoscopy. AB - OBJECTIVE: This paper introduces a methodology to design intuitive, low-cost, and portable devices for visual inspection of the upper gastrointestinal tract. METHODS: The proposed approach mechanically couples a multi-backbone continuum structure, as the user interface, and a parallel bellows actuator, as the endoscopic tip. Analytical modeling techniques derived from continuum robotics were adopted to describe the endoscopic tip motion from user input, accounting for variations in component size and pneumatic compressibility. The modeling framework was used to improve intuitiveness of user-to-task mapping. This was assessed against a 1:1 target, while ease-of-use was validated using landmark identification tasks performed in a stomach simulator by one expert and ten non expert users; benchmarked against conventional flexible endoscopy. Pre-clinical validation consisted of comparative trials in in-vivo porcine and human cadaver models. RESULTS: Target mapping was achieved with an average error of 5 degrees in bending angle. Simulated endoscopies were performed by an expert user successfully, within a time comparable to conventional endoscopy (<1 minute difference). Non-experts using the proposed device achieved visualization of the stomach in a shorter time (9s faster on average) than with a conventional endoscope. The estimated cost is <10 USD and <30 USD for disposable and reusable parts, respectively. Significance and Conclusions: Flexible endoscopes are complex and expensive devices, actuated via non-intuitive cable-driven mechanisms. They frequently break, requiring costly repair, and necessitate a dedicated reprocessing facility to prevent cross contamination. The proposed solution is portable, inexpensive, and easy to use, thus lending itself to disposable use by personnel without formal training in flexible endoscopy. PMID- 30452349 TI - Tactile Stimulation Improves Sensorimotor Rhythm-based BCI Performance in Stroke Patients. AB - OBJECTIVE: BCI decoding accuracy plays a crucial role in practical applications. With accurate feedback, BCI-based therapy determines beneficial neural plasticity in stroke patients. In this study, we aimed at improving sensorimotor rhythm (SMR)-based BCI performance by integrating motor tasks with tactile stimulation. METHODS: Eleven stroke patients were recruited for three experimental conditions, i.e., motor attempt (MA) condition, tactile stimulation (TS) condition, and tactile stimulation-assisted motor attempt (TS-MA) condition. Tactile stimulation was delivered to the paretic hand wrist during both task and idle states using a DC vibrator. RESULTS: We observed that the TS-MA condition achieved greater motor related cortical activation (MRCA) in alpha-beta band when compared with both TS and MA conditions. Consequently, online BCI decoding accuracies between task and idle states were significantly improved from 74.5% in the MA condition to 85.1% in the TS-MA condition (p < 0.001), whereas the accuracy in the TS condition was 54.6% (approaching to the chance level of 50%). CONCLUSION: This finding demonstrates that sensory afferent from peripheral nerves benefits the neural process of sensorimotor cortex in stroke patients. With appropriate sensory stimulation, MRCA is enhanced and corresponding brain patterns are more discriminative. SIGNIFICANCE: This novel SMR-BCI paradigm shows great promise to facilitate the practical application of BCI-based stroke rehabilitation. PMID- 30452350 TI - A Wireless Head-mountable Device with Tapered Optical Fiber-coupled Laser Diode for Light Delivery in Deep Brain Regions. AB - Optogenetics sets new experimental paradigms that can reveal cell type-specific contributions on the neural basis of behavior. Since most of the available systems for this purpose are based on approaches that tether animals to a set of cables, recent research activities have been focused on minimizing external factors that can alter animal movements. Current wireless optogenetic systems are based on waveguide-coupled LED and implanted LEDs. However, each configuration separately suffers from significant limitations, such as low coupling efficiency, penetration depth and invasiveness of waveguide-coupled LED, and local heat generated by implanted MULEDs. This work presents a novel wireless head-mountable stimulating system for a wide-volume light delivery. The device couples the output of a semiconductor laser diode (LD) to a tapered optical fiber (TF) on a wireless platform. The LD-TF coupling was engineered by setting up far-field analysis, which allows the full exploitation of the mode division demultiplexing properties of TFs. The output delivered light along the tapered segment is capable of stimulating structures of depths up to ~2mm. TFs are tapered to a gradual taper angle (2 degrees to 10 degrees ) that ends with a sharp tip (~500 nm) for smooth insertion and less invasiveness. Thus, the proposed system extends the capabilities of wireless optogenetic by offering a novel solution for wide volume light delivery in deep brain regions. PMID- 30452351 TI - Bioimpedance Analysis of Epithelial Monolayers after Exposure to Nanosecond Pulsed Electric Fields. AB - Exposures to pulsed electric fields (PEFs) are known to affect cell membranes and consequently also cell-cell interactions as well as associated characteristics. Bioimpedance analysis offers direct and non-invasive insights into structural and functional changes of cell membranes and extracellular matrices through a rigorous evaluation of electrical parameters. Accordingly, the multi-frequency impedance of confluent monolayers of rat liver epithelial WB-F344 cells was monitored in situ before and after exposure to nanosecond PEFs (nsPEFs). The results were fitted by two Cole models in series to obtain the Cole parameters for the monolayer. For an interpretation of the results, dielectric parameters, were correlated with changes of the TJ protein zonula occludens (ZO-1) and the paracellular permeability of the monolayer Cole parameters in general change as a function of pulse number and time. The findings demonstrate that impedance analysis is an effective method to monitor changes of TJs cell-cell contacts and paracellular permeability and relate them to exposure parameters. PMID- 30452353 TI - Assessing reliability of myocardial blood flow after motion correction with dynamic PET using a Bayesian framework. AB - The estimation of myocardial blood flow (MBF) in dynamic PET can be biased by many different processes. A major source of error, particularly in clinical applications, is patient motion. Patient motion, or gross motion, creates displacements between different PET frames as well as between the PET frames and the CT-derived attenuation map, leading to errors in MBF calculation from voxel time series. Motion correction techniques are challenging to evaluate quantitatively and the impact on MBF reliability is not fully understood. Most metrics, such as Signal to Noise Ratio (SNR), are characteristic of static images, and are not specific to motion correction in dynamic data. This study presents a new approach of estimating motion correction quality in dynamic cardiac PET imaging. It relies on calculating a MBF surrogate, K1, along with the uncertainty on the parameter. This technique exploits a Bayesian framework, representing the kinetic parameters as a probability distribution, from which uncertainty measures can be extracted. If the uncertainty extracted is high the parameter studied is considered to have high variability - or low confidence - and vice versa. The robustness of the framework is evaluated on simulated time activity curves to ensure that uncertainties are consistently estimated at multiple levels of noise. Our framework is applied on 40 patient datasets, divided in 4 motion magnitude categories. Experienced observers manually realigned clinical datasets with 3D translations to correct for motion. K1 uncertainties were compared before and after correction. A reduction of uncertainty after motion correction of up to 60% demonstrates the benefit of motion correction in dynamic PET and as well as provides evidence of the usefulness of the new method presented. PMID- 30452352 TI - Deep Sequential Segmentation of Organs in Volumetric Medical Scans. AB - Segmentation in 3D scans is playing an increasingly important role in current clinical practice supporting diagnosis, tissue quantification, or treatment planning. The current 3D approaches based on Convolutional Neural Networks (CNN) usually suffer from at least three main issues caused predominantly by implementation constraints - first, they require resizing the volume to the lower resolutional reference dimensions, second, the capacity of such approaches is very limited due to memory restrictions, and third, all slices of volumes have to be available at any given training or testing time. We address these problems by a U-Net-like [1] architecture consisting of bidirectional Convolutional Long Short-Term Memory (C-LSTM) [2] and convolutional, pooling, upsampling and concatenation layers enclosed into timedistributed wrappers. Our network can either process the full volumes in a sequential manner, or segment slabs of slices on demand. We demonstrate performance of our architecture on vertebrae and liver segmentation tasks in 3D CT scans. PMID- 30452354 TI - Acoustic Characterization of the CLINIcell for Ultrasound Contrast Agent Studies. AB - Ultrasound contrast agents consist of gas-filled coated microbubbles that oscillate upon ultrasound insonification. Their characteristic oscillatory response provides contrast enhancement for imaging and has the potential to locally enhance drug delivery. Since microbubble response depends on the local acoustic pressure, an ultrasound compatible chamber is needed to study their behavior and the underlying drug delivery pathways. In this study, we determined the amplitude of the acoustic pressure in the CLINIcell, an optically transparent chamber suitable for cell culture. The pressure field was characterized based on microbubble response recorded using the Brandaris 128 ultra-high speed camera and an iterative processing method. The results were compared to a control experiment performed in an OptiCell, which is conventionally used in microbubble studies. Microbubbles in the CLINIcell responded in a controlled manner, comparable to those in the OptiCell. For frequencies from 1 to 4 MHz, the mean pressure amplitude was -5.4 dB with respect to the externally applied field. The predictable ultrasound pressure demonstrates the potential of the CLINIcell as an optical, ultrasound, and cell culture compatible device to study microbubble oscillation behavior and ultrasound-mediated drug delivery. PMID- 30452355 TI - Efficient Frequency-Domain Synthetic Aperture Focusing Techniques for Imaging with a High-Frequency Single-Element Focused Transducer. AB - Synthetic aperture focusing techniques (SAFT) make the spatial resolution of the conventional ultrasound imaging from a single-element focused transducer more uniform in the lateral direction. In this work, two new frequency-domain (FD SAFT) algorithms are proposed, which are based on the synthetic aperture radar's wavenumber algorithm, and 2D matched filtering technique for the image reconstruction. The first algorithm is the FD-SAFT virtual source (FD-SAFT-VS) that treats the focus of a focused transducer as a virtual source having a finite size and the diffraction effect in the far-field is taken into consideration in the image reconstruction. The second algorithm is the FD-SAFT deconvolution (FD SAFT-DE) that uses the simulated point spread function of the imaging system as a matched filter kernel in the image reconstruction. The performance of the proposed algorithms was studied using a series of simulations and experiments, and it was compared with the conventional B-mode and time-domain SAFT imaging techniques. The image quality was analyzed in terms of spatial resolution, side lobe level, signal-to-noise ratio (SNR), contrast resolution, contrast-to-speckle ratio (CSR), and ex vivo image quality. The results showed that the FD-SAFT-VS had the smallest spatial resolution and FD-SAFT-DE had the second smallest spatial resolution. In addition, FD-SAFT-DE had generally the largest SNR. The computation run time of FD-SAFT-VS and FD-SAFT-DE, depending on the image size, was lower by 4 to 174 times and 4 to 189 times, respectively, compared to the TD SAFT-VPS. PMID- 30452356 TI - RF Channel-Select Micromechanical Disk Filters, Part I: Design. AB - This part one of two papers introduces a design flow for micromechanical RF channel-select filters with tiny fractional bandwidths capable of eliminating strong adjacent channel block-ers directly after the antenna, hence reducing the dynamic range requirement of subsequent stages in an RF front-end. Much like VLSI transistor circuit design, the mechanical circuit design flow described herein is hierarchical with a design stack built upon vi-brating micromechanical disk building blocks capable of Q's ex-ceeding 10,000 that enable low filter passband loss for tiny frac-tional bandwidths. Array-composites of half-wavelength coupled identical vibrating disks constitute a second level of hierarchy that reduces the filter termination impedance. A next level of hierarchy couples array-composites with full-wavelength beams to affect fully-balanced differential operation. Finally, identical differential blocks coupled with quarter-wavelength beams generate the de-sired passband. Part II of this study corroborates the efficacy of this design hierarchy via experimental results that introduce a 39nm-gap capacitive transducer, voltage-controlled frequency tuning, and differential operation towards demonstration of a 0.1% bandwidth, 223.4-MHz channel-select filter with only 2.7dB of in-band insertion loss and 50dB of stopband rejection. PMID- 30452357 TI - Cross-correlation Signal Processing for Axion and WISP Dark Matter Searches. AB - The search for dark matter is of fundamental importance to our understanding of the universe. Weakly-Interacting Slim Particles (WISPs) such as axions and hidden sector photons (HSPs) are well motivated candidates for the dark matter. Some of the most sensitive and mature experiments to detect WISPs rely on microwave cavities, and the detection of weak photon signals. It is often suggested to power combine multiple cavities, which creates a host of technical concerns. We outline a scheme based on cross-correlation for power combining cavities and increasing the signal-to-noise ratio of a candidate WISP signal. PMID- 30452358 TI - Al0.83Sc0.17N Contour Mode Resonators with electromechanical coupling in excess of 4.5. AB - In this paper we demonstrate the fabrication of contour mode resonators (CMRs) with Al0.83Sc0.17N as piezoelectric layer. Moreover, we assess the electromechanical coupling and the maximum achieved quality factor from 150 MHz to 500 MHz. In comparison to pure aluminum nitride (AlN) CMRs, our results show electromechanical coupling coefficients of more than a 2* factor higher at around 200 MHz. The highest quality factor is measured on a CMR operating at 388 MHz and is in excess of 1600. From the characterization of devices operating at different frequencies material parameters of the Al0.83Sc0.17N are extracted such as the stiffness constant, the relative permittivity and the piezoelectric constant. In particular, the reported d31 piezoelectric constant is equal to -3.9 pm/V. This represents a 2.25* improvement when compared to pure AlN. Finally, we report the first temperature compensation experimental results for Al0.83Sc0.17N CMRs. Our results show that about 1.5 MUm of sputtered oxide, deposited on top of released resonator, allows near zero TCF for CMRs operating up to 500 MHz. PMID- 30452359 TI - A Numerical Optimization Method for Transducer Transfer Functions by the Linearity of the Phase Spectrum. AB - New ultrasound imaging and therapeutic modalities may require transducer designs that are not readily facilitated by conventional design guidelines and analytical expressions. This motivates the investigation of numerical methods for complex transducer structures. Based on a mathematical theorem, we propose a new numerical design and optimization method for ultrasound transducers by linearizing the phase spectrum of transducer transfer functions. A gradient-based algorithm obtains the optimal transducer by varying a selected set of transducer parameters. To demonstrate the linear phase method, a simulated air-backed 4 MHz single element imaging transducer with two matching layers, bondlines, and electrodes is optimized by varying the impedances and thicknesses of the matching layers. The magnitude spectrum resembles that of a Gaussian and, compared to a conventional transducer, the time-sidelobe level is reduced by more than 15 dB. Moreover, we apply the linear phase method to analyze and compensate for bondlines that resonate within the passband. Lastly, we address the challenge of obtaining materials for the matching layers with the optimized impedance values by calculating alternative material pairs. PMID- 30452360 TI - Unified No-Reference Quality Assessment of Singly and Multiply Distorted Stereoscopic Images. AB - A challenging problem in no-reference quality assessment of multiply distorted stereoscopic images (MDSIs) is to simulate the monocular and binocular visual properties under a mixed type of distortions. Due to the joint effects of multiple distortions in MDSIs, the underlying monocular and binocular visual mechanisms have different manifestations with those of singly distorted stereoscopic images (SDSIs). This paper presents a unified no-reference quality evaluator for SDSIs and MDSIs by learning monocular and binocular local visual primitives (MBLVPs). The main idea is to learn MB-LVPs to characterize the local receptive field properties of the visual cortex in response to SDSIs and MDSIs. Furthermore, we also consider that the learning of primitives should be performed in a task-driven manner. For this, two penalty terms including reconstruction error and quality inconsistency are jointly minimized within a supervised dictionary learning framework, generating a set of quality-oriented MB-LVPs for each single and multiple distortion modality. Given an input stereoscopic image, feature encoding is performed using the learned MB-LVPs as codebooks, resulting in the corresponding monocular and binocular responses. Finally, responses across all the modalities are fused with probabilistic weights which are determined by the modality-specific sparse reconstruction errors, yielding the final monocular and binocular features for quality regression. The superiority of our method has been verified on several SDSI and MDSI databases. PMID- 30452361 TI - On-Device Scalable Image-Based Localization via Prioritized Cascade Search and Fast One-Many RANSAC. AB - We present the design of an entire on-device system for large-scale urban localization using images. The proposed design integrates compact image retrieval and 2D-3D correspondence search to estimate the location in extensive city regions. Our design is GPS agnostic and does not require network connection. In order to overcome the resource constraints of mobile devices, we propose a system design that leverages the scalability advantage of image retrieval and accuracy of 3D model-based localization. Furthermore, we propose a new hashing-based cascade search for fast computation of 2D-3D correspondences. In addition, we propose a new one-many RANSAC for accurate pose estimation. The new one-many RANSAC addresses the challenge of repetitive building structures (e.g. windows and balconies) in urban localization. Extensive experiments demonstrate that our 2D-3D correspondence search achieves the state-of-the-art localization accuracy on multiple benchmark datasets. Furthermore, our experiments on a large Google street view image dataset show the potential of large-scale localization entirely on a typical mobile device. PMID- 30452362 TI - A Local Metric for Defocus Blur Detection Based on CNN Feature Learning. AB - Defocus blur detection is an important and challenging task in computer vision and digital imaging fields. Previous work on defocus blur detection has put a lot of effort into designing local sharpness metric maps. This paper presents a simple yet effective method to automatically obtain the local metric map for defocus blur detection, which based on the feature learning of multiple convolutional neural networks (ConvNets). The ConvNets automatically learn the most locally relevant features at the super-pixel level of the image in a supervised manner. By extracting convolution kernels from the trained neural network structures and processing it with principal component analysis, we can automatically obtain the local sharpness metric by reshaping the principal component vector. Meanwhile, an effective iterative updating mechanism is proposed to refine the defocus blur detection result from coarse to fine by exploiting the intrinsic peculiarity of the hyperbolic tangent function. The experimental results demonstrate that our proposed method consistently performed better than previous state-of-the-art methods. PMID- 30452363 TI - Local geometric deformations in the DHT domain with applications. AB - Local rotation, translation and scaling of the image domain represent a basic toolkit in adaptive image processing such as image registration, template matching, local invariant feature detection, super-resolution imaging, among others. In this article, it is shown how the local rotation, scaling and translations can be performed in the discrete Hermite transform (DHT) domain. As the DHT satisfies the generalized steerability property, basic geometric operations are expressed as linear mappings in the DHT domain and hence can facilitate the solution of many image processing problems. The local rotation and scaling were previously shown in the continuous domain using the Hermite Transform, the former is used here as a good approximation for discrete images, whereas the latter is extended to a discrete domain. In addition, the local translation operation is fully developed in the discrete domain. The application of these three operations is illustrated with three exemplar applications including 1) mathematical morphology, 2) template matching and 3) depth from defocus. The simple yet effective methods presented in the paper indicate that local image decompositions satisfying the steerability property, such as the DHT, are desirable for solving a number of interesting image processing problems. PMID- 30452364 TI - Image enhancement with PDEs and nonconservative advection flow fields. PMID- 30452365 TI - A Non-Local Dual-Domain Approach to Cartoon and Texture Decomposition. AB - This paper addresses the problem of cartoon and texture decomposition. Microtextures being characterized by their power spectrum, we propose to extract cartoon and texture components from the information provided by the power spectrum of image patches. The contribution of texture to the spectrum of a patch is detected as statistically significant spectral components with respect to a null hypothesis modeling the power spectrum of a non-textured patch. The null hypothesis model is built upon a coarse cartoon representation obtained by a basic yet fast filtering algorithm of the literature. Hence the term "dual domain": the coarse decomposition is obtained in the spatial domain and is an input of the proposed spectral approach. The statistical model is also built upon the power spectrum of patches with similar textures across the image. The proposed approach therefore falls within the family of non-local methods. Experimental results are shown in various application areas, including canvas pattern removal in fine arts painting, or periodic noise removal in remote sensing imaging. PMID- 30452366 TI - A Continuous Random Walk Model With Explicit Coherence Regularization for Image Segmentation. AB - Random walk is a popular and efficient algorithm for image segmentation, especially for extracting regions of interest (ROIs). One difficulty with the random walk algorithm is the requirement for solving a huge sparse linear system when applied to large images. Another limitation is its sensitivity to seeds distribution, i.e., the segmentation result depends on the number of seeds as well as their placement, which puts a burden on users. In this paper, we first propose a continuous random walk model with explicit coherence regularization (CRWCR) for the extracted ROI, which helps to reduce the seeds sensitivity, so as to reduce the user interactions. Then, a very efficient algorithm to solve the CRWCR model will be developed, which helps to remove the difficulty of solving huge linear systems. Our algorithm consists of two stages: initialization by performing one-dimensional random walk sweeping based on user-provided seeds, followed by the alternating direction scheme, i.e., Peaceman-Rachford scheme for further correction. The first stage aims to provide a good initial guess for the ROI, and it is very fast since we just solve a limited number of one-dimensional random walk problems. Then, this initial guess is evolved to the ideal solution by applying the second stage, which should also be very efficient since it fits well for GPU computing, and 10 iterations are usually sufficient for convergence. Numerical experiments are provided to validate the proposed model as well as the efficiency of the two-stage algorithm. PMID- 30452367 TI - CNN Fixations: An unraveling approach to visualize the discriminative image regions. AB - Deep convolutional neural networks (CNN) have revolutionized various fields of vision research and have seen unprecedented adoption for multiple tasks such as classification, detection, captioning, etc. However, they offer little transparency into their inner workings and are often treated as black boxes that deliver excellent performance. In this work, we aim at alleviating this opaqueness of CNNs by providing visual explanations for the network's predictions. Our approach can analyze a variety of CNN based models trained for vision applications such as object recognition and caption generation. Unlike existing methods, we achieve this via unraveling the forward pass operation. The proposed method exploits feature dependencies across the layer hierarchy and uncovers the discriminative image locations that guide the network's predictions. We name these locations CNNFixations, loosely analogous to human eye fixations. Our approach is a generic method that requires no architectural changes, additional training or gradient computation and computes the important image locations (CNN Fixations). We demonstrate through a variety of applications that our approach is able to localize the discriminative image locations across different network architectures, diverse vision tasks and data modalities. PMID- 30452368 TI - Zero-Shot Learning via Robust Latent Representation and Manifold Regularization. AB - Zero-shot learning (ZSL) for visual recognition aims to accurately recognize objects of unseen classes through mapping the visual feature to an embedding space spanned by class semantic information. However, the semantic gap across visual features and their underlying semantics is still a big obstacle in zero shot learning. Conventional ZSL methods construct the mapping typically focus on the original visual features which are independent of the zero-shot learning tasks, thus degrade the prediction performance. In this paper, we propose an effective method to uncover an appropriate latent representation of data for the purpose of zero-shot classification. Specifically, we formulate a novel framework to jointly learn the latent subspace and cross-modal embedding to link visual features with their semantic representations. The proposed framework combines feature learning and semantics prediction such that the learned data representation is more discriminative to predict the semantic vectors, hence improves the overall classification performance. To learn a robust latent subspace, we explicitly avoid the information loss by ensuring the reconstruction ability of the obtained data representation. An efficient algorithm is designed to solve the proposed optimization problem. To fully exploit the intrinsic geometric structure of data, we develop a manifold regularization strategy to refine the learned semantic representations, leading to further improvements of the classification performance. To validate the effectiveness of the proposed approach, extensive experiments are conducted on three ZSL benchmarks and encouraging results are achieved compared to the state-of-theart ZSL methods. PMID- 30452369 TI - Multi-Modal Multi-Scale Deep Learning for Large-Scale Image Annotation. AB - Image annotation aims to annotate a given image with a variable number of class labels corresponding to diverse visual concepts. In this paper, we address two main issues in large-scale image annotation: 1) how to learn a rich feature representation suitable for predicting a diverse set of visual concepts ranging from object, scene to abstract concept and 2) how to annotate an image with the optimal number of class labels. To address the first issue, we propose a novel multi-scale deep model for extracting rich and discriminative features capable of representing a wide range of visual concepts. Specifically, a novel two-branch deep neural network architecture is proposed, which comprises a very deep main network branch and a companion feature fusion network branch designed for fusing the multi-scale features computed from the main branch. The deep model is also made multi-modal by taking noisy user-provided tags as model input to complement the image input. For tackling the second issue, we introduce a label quantity prediction auxiliary task to the main label prediction task to explicitly estimate the optimal label number for a given image. Extensive experiments are carried out on two large-scale image annotation benchmark datasets, and the results show that our method significantly outperforms the state of the art. PMID- 30452370 TI - Unsupervised Deep Video Hashing via Balanced Code for Large-Scale Video Retrieval. AB - This paper proposes a deep hashing framework, namely Unsupervised Deep Video Hashing (UDVH), for largescale video similarity search with the aim to learn compact yet effective binary codes. Our UDVH produces the hash codes in a self taught manner by jointly integrating discriminative video representation with optimal code learning, where an efficient alternating approach is adopted to optimize the objective function. The key differences from most existing video hashing methods lie in 1) UDVH is an unsupervised hashing method that generates hash codes by cooperatively utilizing feature clustering and a specifically designed binarization with the original neighborhood structure preserved in the binary space; 2) a specific rotation is developed and applied onto video features such that the variance of each dimension can be balanced, thus facilitating the subsequent quantization step. Extensive experiments performed on three popular video datasets show that UDVH is overwhelmingly better than the state-of-the-arts in terms of various evaluation metrics, which makes it practical in real-world applications. PMID- 30452371 TI - RGB-'D' Saliency Detection With Pseudo Depth. AB - Recent studies have shown the effectiveness of using depth information in salient object detection. However, the most commonly seen images so far are still RGB images that do not contain the depth data. Meanwhile, the human brain can extract the geometric model of a scene from an RGB-only image and hence provides a 3D perception of the scene. Inspired by this observation, we propose a new concept named RGB-'D' saliency detection, which derives pseudo depth from the RGB images and then performs 3D saliency detection. The pseudo depth can be utilized as image features, prior knowledge, an additional image channel, or independent depth-induced models to boost the performance of traditional RGB saliency models. As an illustration, we develop a new salient object detection algorithm that uses the pseudo depth to derive a depth-driven background prior and a depth contrast feature. Extensive experiments on several standard databases validate the promising performance of the proposed algorithm. In addition, we also adapt two supervised RGB saliency models to our RGB-'D' saliency framework for performance enhancement. The results further demonstrate the generalization ability of the proposed RGB-'D' saliency framework. PMID- 30452372 TI - Bi-directional Spatial-Semantic Attention Networks for Image-Text Matching. AB - Image-text matching by deep models has recently made remarkable achievements in many tasks, such as image caption and image search. A major challenge of matching the image and text lies in that they usually have complicated underlying relations between them and simply modeling the relations may lead to suboptimal performance. In this paper, we develop a novel approach Bi-directional Spatial Semantic Attention Networks (BSSAN), which leverages both the word to regions (W2R) relation and image object to words (O2W) relation in a holistic deep framework for more effectively matching. Specifically, to effectively encode the W2R relation, we adopt LSTM with bilinear attention function to infer the image regions which are more related to the particular words, which is referred as the W2R attention network. On the other side, the O2W attention network is proposed to discover the semanticallyclose words for each visual object in the image, i.e., the visual object to words (O2W) relation. Then a deep model unifying both of the two directional attention networks into a holistic learning framework is proposed to learn the matching scores of image and text pairs. Compared to existing image-text matching methods, our approach achieves state-of-the-art performance on the datasets of Flickr30K and MSCOCO. PMID- 30452373 TI - Spectral Mesh Segmentation via Gradient Minimization. AB - Mesh segmentation is a process of partitioning a mesh model into meaningful parts --- a fundamental problem in various disciplines. This paper introduces a novel mesh segmentation method inspired by sparsity pursuit. Based on the local geometric and topological information of a given mesh, we build a Laplacian matrix whose Fiedler vector is used to characterize the uniformity among elements of the same segment. By analyzing the Fiedler vector, we reformulate the mesh segmentation problem as a $?ell_0$ gradient minimization problem. To solve this problem efficiently, we adopt a coarse-to-fine strategy. A fast heuristic algorithm is firstly devised to find a rational coarse segmentation, and then an optimization algorithm based on the alternating direction method of multiplier (ADMM) is proposed to refine the segment boundaries within their local regions. To extract the inherent hierarchical structure of the given mesh, our method performs segmentation in a recursive way. Experimental results demonstrate that the presented method outperforms the state-of-the-art segmentation methods when evaluated on the Princeton Segmentation Benchmark, the LIFL/LIRIS Segmentation Benchmark and a number of other complex meshes. PMID- 30452374 TI - Noise-Assisted Multivariate EMD-Based Mean-Phase Coherence Analysis to Evaluate Phase-Synchrony Dynamics in Epilepsy Patients. AB - Spatiotemporal evolution of synchrony dynamics among neuronal populations plays an important role in decoding complicated brain function in normal cognitive processing as well as during pathological conditions such as epileptic seizures. In this paper, a non-linear analytical methodology is proposed to quantitatively evaluate the phase-synchrony dynamics in epilepsy patients. A set of finite neuronal oscillators was adaptively extracted from a multi-channel electrocorticographic (ECoG) dataset utilizing noise-assisted multivariate empirical mode de-composition (NA-MEMD). Next, the instantaneous phases of the oscillatory functions were extracted using the Hilbert transform in order to be utilized in the mean-phase coherence analysis. The phase-synchrony dynamics were then assessed using eigenvalue decomposition. The extracted neuronal oscillators were grouped with respect to their frequency range into wideband (1-600 Hz), ripple (80-250 Hz), and fast-ripple (250-600 Hz) bands in order to investigate the dynamics of ECoG activity in these frequency ranges as seizures evolve. Drug refractory patients with frontal and temporal lobe epilepsy demonstrated a reduction in phase-synchrony around seizure onset. However, the network phase synchrony started to increase towards seizure end and achieved its maximum level at seizure offset for both types of epilepsy. This result suggests that hyper synchronization of the epileptic network may be an essential self-regulatory mechanism by which the brain terminates seizures. PMID- 30452375 TI - Modulation Mode Detection & Classification for in-Vivo Nano-Scale Communication Systems Operating in Terahertz Band. AB - This work initiates the efforts to design an intelligent/ cognitive nano receiver operating in Terahertz (THz) band. Specifically, we investigate two essential ingredients of an intelligent nano receiver-modulation mode detection (to differentiate between pulse based modulation and carrier based modulation), and modulation classification (to identify the exact modulation scheme in use). To implement modulation mode detection, we construct a binary hypothesis test in nano-receiver's passband, and provide closed-form expressions for the two error probabilities. As for modulation classification, we aim to represent the received signal of interest by a Gaussian mixture model (GMM). This necessitates the explicit estimation of the THz channel impulse response, and its subsequent compensation (via deconvolution). We then learn the GMM parameters via Expectation-Maximization algorithm. We then do Gaussian approximation of each mixture density to compute symmetric Kullback-Leibler divergence in order to differentiate between various modulation schemes (i.e., M-ary phase shift keying, M-ary quadrature amplitude modulation). The simulation results on mode detection indicate that there exists a unique Pareto-optimal point (for both SNR and the decision threshold) where both error probabilities are minimized. The main takeaway message by the simulation results on modulation classification is that for a pre-specified probability of correct classification, higher SNR is required to correctly identify a higher order modulation scheme. On a broader note, this work should trigger the interest of the community in the design of intelligent/cognitive nano receivers (capable of performing various intelligent tasks, e.g., modulation prediction etc.). PMID- 30452376 TI - Stability Analysis of Biological Networks' Diffusion State. AB - Computational knowledge acquired from noisy networks is not reliable and the network topology determines the reliability. Protein-protein interaction networks have uncertain topologies and noise that contain false positive and false negative edges at high rates. In this study, we analyze effects of the existing mutations in a network topology to the diffusion state of that network. To evaluate the sensitivity of the diffusion state, we derive the fitness measures based on the mathematically defined stability of a network. Searching for an influential set of edges in a network is a difficult problem. We handle the computational challenge by developing a novel metaheuristic optimization method and we find influential mutations time-efficiently. Our experiments, conducted on both synthetic and real networks from public databases, demonstrated that our method obtained better results than competitors for all types of network topologies. This is the first-time that the diffusion has been evaluated under topological mutations. Our analysis identifies significant biological results about the stability of biological - synthetic networks and diffusion state. In this manner, mutations in protein-protein interaction network topologies have a significant influence on the diffusion state of the network. Network stability is more affected by the network model than the network size. PMID- 30452377 TI - Cache Friendly Optimisation of de Bruijn Graph based Local Re-assembly in Variant Calling. AB - A variant caller is used to identify variations in an individual genome (compared to the reference genome) in a genome processing pipeline. For the sake of accuracy, modern variant callers perform many local re-assemblies on small regions of the genome using a graph based algorithm. However, such graph-based data structures are inefficiently stored in the linear memory of modern computers, which in turn reduces computing efficiency. Therefore, variant calling can take several CPU hours for a typical human genome. We have sped up the local re-assembly algorithm with no impact on its accuracy, by the effective use of the memory hierarchy. The proposed algorithm maximises data locality so that the fast internal processor memory (cache) is efficiently used. By the increased use of caches, accesses to main memory are minimised. The resulting algorithm is up to twice as fast as the original one when executed on a commodity computer and could gain even more speed up on computers with less complex memory subsystems. PMID- 30452378 TI - A Fully Integrated RF-powered Energy-replenishing Current-controlled Stimulator. AB - This paper presents a fully-integrated current-controlled stimulator that is powered directly from on-chip coil antenna and achieves adiabatic energy replenishing operation without any bulky external components. Adiabatic supply voltages, which can reach a differential range of up to 7.2 V, are directly generated from an on-chip 190-MHz resonant LC tank via a self-cascading/folding rectifier network, bypassing the losses that would otherwise be introduced by the 0.8 V system supply-generating rectifier and regulator. The stimulator occupies 0.22 mm in a 180 nm silicon-on-insulator (SOI) process, and produces differential currents up to 145 MUA. Using a charge replenishing scheme, the stimulator redirects the charges accumulated across the electrodes to the system power supplies for 63.1% of stimulation energy recycling. To benchmark the efficiency of stimulation, a figure of merit termed the Stimulator Efficiency Factor (SEF) is introduced. The adiabatic power rails and energy replenishment scheme enabled our stimulator to achieve an SEF of 6.0. PMID- 30452379 TI - A Reduced-Wire ICE Catheter ASIC with Tx Beamforming and Rx Time-Division Multiplexing. AB - This paper presents a single chip reduced-wire active catheter application specific integrated circuit (ASIC), equipped with programmable transmit (Tx) beamforming and receive (Rx) time-division multiplexing (TDM). The proposed front end ASIC is designed for driving a 64-channel 1D transducer array in intracardiac echocardiography (ICE) ultrasound catheters. The ASIC is implemented in 60 V 0.18 MUm HV-BCD technology, integrating Tx beamformers with high voltage (HV) pulsers and Rx front-end in the same chip, which occupies 2.6*11 mm that can fit in the catheter size of 9 F (<3 mm). The proposed system reduces the number of wires from >64 to only 22 by integrating Tx beamformer which is programmable using a single low-voltage differential signaling (LVDS) data line. In Rx mode, the system uses 8:1 TDM with direct digital demultiplexing (DDD) providing raw channel data which enables dynamic Rx beamforming using individual array elements. This system has been successfully used for B-mode imaging on standard ultrasound phantom with 401 mW of average power consumption. The ASIC has a compact element pitch-matched layout, which is also compatible with capacitive micromachined ultrasound transducer (CMUT)-on-CMOS application. This system addresses cable number and dimensional restrictions in catheters to enable ICE imaging under magnetic resonance imaging (MRI) by reducing radio frequency (RF) induced heating. PMID- 30452380 TI - Toward Whole-hand Kinesthetic Feedback: A Survey of Force Feedback Gloves. AB - Force feedback gloves have found many applications in fields such as teleoperation and virtual reality. In order to enhance the immersive feeling of interaction with remote or virtual environments, glove-like haptic devices are used, which enable users to touch and manipulate virtual objects in a more intuitive and direct way via the dexterous manipulation and sensitive perception capabilities of human hands. In this survey, we aim to identify the gaps between existing force feedback gloves and the desired ones that can provide robust and realistic sensation of the interaction with diverse virtual environments. By examining existing force feedback gloves, the pros and cons of existing design solutions to the major sub-systems including sensing, actuation, control, transmission and structure are discussed. Future research topics are put forward with design challenges being elaborated. Innovative design solutions are needed to enable the utility of wearable haptic gloves in the upcoming virtual reality era. PMID- 30452381 TI - Employing Domain Indexes to Efficiently Query Medical Data from Multiple Repositories. AB - Content-based retrieval still remains one of the main problems with respect to controversies and challenges in digital healthcare over big data. To properly address this problem, there is a need for efficient computational techniques, especially in scenarios involving queries across multiple data repositories. In such scenarios, the common computational approach searches the repositories separately and combines the results into one final response, which slows down the process altogether. In order to improve the performance of queries in that kind of scenario, we present the Domain Index, a new category of index structures intended to efficiently query a data domain across multiple repositories, regardless of the repository to which the data belong. To evaluate our method, we carried out experiments involving content-based queries, namely Range and kNN (k Nearest Neighbor) queries, (i) over real-world data from a public dataset of mammograms, as well as (ii) over synthetic data to perform scalability evaluations. The results show that images from any repository are seamlessly retrieved, sustaining performance gains of up to 53% in Range queries and up to 81% in kNN queries. Regarding scalability, our proposal scaled well as we increased (i) the cardinality of data (up to 59% of gain) and (ii) the number of queried repositories (up to 71% of gain). Hence, our method enables significant performance improvements, and should be of most importance for medical data repository maintainers and for physicians' IT support. PMID- 30452382 TI - Photoplethysmographic Waveform Versus Heart Rate Variability to Identify Low Stress States. Attention Test. AB - Our long-term goal is the development of an automatic identifier of attentional states. In order to accomplish it, we should firstly be able to identify different states based on physiological signals. So, the first aim of this work is to identify the most appropriate features, to detect a subject high performance state. For that, a database of electrocardiographic (ECG) and photopletysmographic (PPG) signals is recorded in two unequivocally defined states (rest and attention task) from up to 50 subjects as a sample of the population. Time and frequency parameters of heart/pulse rate variability have been computed from the ECG/PPG signals respectively. Additionally, the respiratory rate has been estimated from both signals and also six morphological parameters from PPG. In total, twenty six features are obtained for each subject. They provide information about the autonomic nervous system and the physiological response of the subject to an attention demand task. Results show an increase of sympathetic activation when the subjects perform the attention test. The amplitude and width of the PPG pulse were more sensitive that the classical sympathetic markers (normalised power in LF and LF/HF ratio) for identifying this attentional state. State classification accuracy reaches a mean of 892%, a maximum of 93% and a minimum of 85%, in the hundred classifications made by only selecting four parameters extracted from the PPG signal (pulse amplitude, pulse width, pulse downward slope and mean pulse rate). These results suggest that attentional states could be identified by PPG. PMID- 30452383 TI - On the Parzen Kernel-Based Probability Density Function Learning Procedures Over Time-Varying Streaming Data With Applications to Pattern Classification. AB - In this paper, we propose a recursive variant of the Parzen kernel density estimator (KDE) to track changes of dynamic density over data streams in a nonstationary environment. In stationary environments, well-established traditional KDE techniques have nice asymptotic properties. Their existing extensions to deal with stream data are mostly based on various heuristic concepts (losing convergence properties). In this paper, we study recursive KDEs, called recursive concept drift tracking KDEs, and prove their weak (in probability) and strong (with probability one) convergence, resulting in perfect tracking properties as the sample size approaches infinity. In three theorems and subsequent examples, we show how to choose the bandwidth and learning rate of a recursive KDE in order to ensure weak and strong convergence. The simulation results illustrate the effectiveness of our algorithm both for density estimation and classification over time-varying stream data. PMID- 30452384 TI - Mobile Robot Networks for Environmental Monitoring: A Cooperative Receding Horizon Temporal Logic Control Approach. AB - This paper deals with the problem of environmental monitoring by designing and analyzing a cooperative receding horizon temporal logic (CRH-TL) control approach for mobile robot networks. First, a radial basis function network is used to model the distribution of environmental attributes in the monitored environment. On the basis of the established environment model, the problem of environmental monitoring can be formulated as a dynamical optimization problem. Second, an acceptable node set is obtained by enforcing appropriate constraints from linear temporal logic (LTL) specifications on the task of environmental monitoring. Third, by designing a cooperative energy function and using the acceptable node set, the CRH-TL control approach is proposed to generate the movement trajectory of each robot, which satisfies the given LTL specifications while guiding mobile robot networks to trace the peaks of environmental attributes. Finally, the effectiveness of the proposed CRH-TL control approach is illustrated for the problem of environmental monitoring. PMID- 30452385 TI - Automated Identification of Hookahs (Waterpipes) on Instagram: An Application in Feature Extraction Using Convolutional Neural Network and Support Vector Machine Classification. AB - BACKGROUND: Instagram, with millions of posts per day, can be used to inform public health surveillance targets and policies. However, current research relying on image-based data often relies on hand coding of images, which is time consuming and costly, ultimately limiting the scope of the study. Current best practices in automated image classification (eg, support vector machine (SVM), backpropagation neural network, and artificial neural network) are limited in their capacity to accurately distinguish between objects within images. OBJECTIVE: This study aimed to demonstrate how a convolutional neural network (CNN) can be used to extract unique features within an image and how SVM can then be used to classify the image. METHODS: Images of waterpipes or hookah (an emerging tobacco product possessing similar harms to that of cigarettes) were collected from Instagram and used in the analyses (N=840). A CNN was used to extract unique features from images identified to contain waterpipes. An SVM classifier was built to distinguish between images with and without waterpipes. Methods for image classification were then compared to show how a CNN+SVM classifier could improve accuracy. RESULTS: As the number of validated training images increased, the total number of extracted features increased. In addition, as the number of features learned by the SVM classifier increased, the average level of accuracy increased. Overall, 99.5% (418/420) of images classified were correctly identified as either hookah or nonhookah images. This level of accuracy was an improvement over earlier methods that used SVM, CNN, or bag-of-features alone. CONCLUSIONS: A CNN extracts more features of images, allowing an SVM classifier to be better informed, resulting in higher accuracy compared with methods that extract fewer features. Future research can use this method to grow the scope of image-based studies. The methods presented here might help detect increases in the popularity of certain tobacco products over time on social media. By taking images of waterpipes from Instagram, we place our methods in a context that can be utilized to inform health researchers analyzing social media to understand user experience with emerging tobacco products and inform public health surveillance targets and policies. PMID- 30452386 TI - Neutrophil elastase-cleaved corticosteroid-binding globulin is absent in human plasma. AB - Corticosteroid-binding globulin (CBG) transports glucocorticoids in blood and is a serine protease inhibitor family member. Human CBG has a reactive center loop (RCL) which, when cleaved by neutrophil elastase (NE), disrupts its steroid binding activity. Measurements of CBG levels are typically based on steroid binding capacity or immunoassays. Discrepancies in ELISAs using monoclonal antibodies that discriminate between intact vs RCL-cleaved CBG have been interpreted as evidence that CBG with a cleaved RCL and low affinity for cortisol exists in the circulation. We examined the biochemical properties of plasma CBG in samples with discordant ELISA measurements and sought to identify RCL-cleaved CBG in human blood samples. Plasma CBG-binding capacity and ELISA values were consistent in arterial and venous blood draining skeletal muscle, liver and brain, as well as from a tissue (adipose) expected to contain activated neutrophils in obese individuals. Moreover, RCL-cleaved CBG was undetectable in plasma from critically ill patients, irrespective of whether their ELISA measurements were concordant or discordant. We found no evidence of RCL-cleaved CBG in plasma using a heat-dependent polymerization assay, and CBG that resists immunoprecipitation with a monoclonal antibody designed to specifically recognize an intact RCL, bound steroids with a high affinity. In addition, mass spectrometry confirmed the absence of NE-cleaved CBG in plasma in which ELISA values were highly discordant. Human CBG with a NE-cleaved RCL and low affinity for steroids is absent in blood samples, and CBG ELISA discrepancies likely reflect structural differences that alter epitopes recognized by specific monoclonal antibodies. PMID- 30452387 TI - Advanced synthesis of highly crystallized hexagonal boron nitride by coupling polymer-derived ceramics and spark plasma sintering processes-influence of the crystallization promoter and sintering temperature. AB - Hexagonal boron nitride nanosheets (BNNSs) are promising 2D materials due to their exceptional chemical and thermal stabilities together with their electrical insulation properties. A combined synthesis method involving the polymer-derived ceramics (PDCs) route and the spark plasma sintering (SPS) process is proposed, leading to well-crystallized and pure layered h-BN crystals, prone to be exfoliated into large BNNSs. Here we focus more specifically on the influence of two key parameters of the process to be optimized: the Li3N concentration (0-10 wt%) and the SPS temperature (1200 degrees C-1950 degrees C). The presence of Li3N, added as crystal promoter in the pre-ceramic powder, significantly improves the crystallinity level of the product, as evidenced by XRD, SEM and Raman spectrometry. SPS temperature strongly modifies the size of the resulting h-BN flakes. The influence of SPS temperature on both purity and crystallinity is studied using cathodoluminescence. h-BN flakes larger than 200 MUm2 (average flake area) are obtained. Few-layered BNNSs are successfully isolated, through exfoliation process. PMID- 30452388 TI - Bottom-up fabrication of InAs-on-nothing MOSFET using selective area molecular beam epitaxy. AB - In this paper we report on the fabrication and electrical characterization of InAs-on-nothing metal-oxide-semiconductor field-effect transistor composed of a suspended InAs channel and raised InAs n+ contacts. This architecture is obtained using 3D selective and localized molecular beam epitaxy on a lattice mismatched InP substrate. The suspended InAs channel and InAs n+ contacts feature a reproducible and uniform shape with well-defined 3D sidewalls. Devices with 1 MUm gate length present a saturation drain current (I Dsat) of 300 mA mm-1 at V DS = 0.8 V and a trans-conductance (GM ) of 120 mS mm-1 at V DS = 0.5 V. In terms of electrostatic control, the devices display a minimal subthreshold swing of 110 mV dec-1 at V DS = 0.5 V and a small drain induced barrier lowering of 50 mV V-1. PMID- 30452389 TI - Few layered MoS2 grown on pencil graphite: a unique single-step approach to fabricate economical, binder-free electrode for supercapacitor applications. AB - While all reports on supercapacitors are based on electrodes that are fabricated either using expensive, complex fabrication techniques or multiple steps based synthesis routes, the current work is the first report of one-step hydrothermally grown MoS2 on pencil graphite electrode (PGE) for ultra-high performance supercapacitor application. Field emission scanning electron microscope images revealed MoS2 micro-flower like structure containing interwoven nanosheets whereas chemical characterizations data confirmed the successful growth of few layered (>4 layers) MoS2 on PGE. The performance of the electrode was optimized using various grades of pencil, and it was found that the areal capacitance of the MoS2 grown on 1H PGE(7178.8 mF cm-2) was about 3.4 and 4.1 folds greater than those of the MoS2 grown on 2B, 6H PGE at the same current density respectively. This low cost, binder-free MoS2 based PGE paves a novel way towards the advancement of affordable electrodes for energy storage-conversion and bioanalytical applications. PMID- 30452390 TI - Electron transport phenomena at the interface of Al electrode and heavily doped degenerate ZnO nanoparticles in quantum dot light emitting diode. AB - ZnO nanoparticles (NPs) of 4-5 nm, widely adopted as an electron transport layer (ETL) in quantum dot light emitting diodes (QD-LEDs), were synthesized using the solution-precipitation process. It is notable that synthesized ZnO NPs are highly degenerate intrinsic semiconductors and their donor concentration can be increased up to N D = 6.9 * 1021 cm-3 by annealing at 140 degrees C in air. An optical bandgap increase of as large as 0.16-0.33 eV by degeneracy is explained well by the Burstein-Moss shift. In order to investigate the influence of intrinsic defects of ZnO NP ETLs on the performance of QD-LED devices without a combined annealing temperature between ZnO NP ETLs and the emissive QD layer, pre annealed ZnO NPs at 60 degrees C, 90 degrees C, 140 degrees C, and 180 degrees C were spin-coated on the annealed QD layer without further post annealing. As the annealing temperature increases from 60 degrees C to 180 degrees C, the defect density related to oxygen vacancy (V O) in ZnO NPs is reduced from 34.4% to 17.8%, whereas the defect density of interstitial Zn (Zni) is increased. Increased Zni reduces the width (W) of the depletion region from 0.21 to 0.12 nm and lowers the Schottky barrier (FB) between ZnO NPs and the Al electrode from 1.19 to 0.98 eV. We reveal for the first time that carrier conduction between ZnO NP ETLs and the Al electrode is largely affected by the concentration of Zni above the conduction band minimum, and effectively described by space charge limited current and trap charge limited current models. PMID- 30452391 TI - Soft hydrogen plasma induced phase transition in monolayer and few-layer MoTe2. AB - Phase transition from the semiconducting hexagonal (2H) phase to the metallic monoclinic (1T') phase in two-dimensional (2D) transition metal dichalcogenides like MoTe2 is not only of great importance in fundamental study but also of technological significance for broad device applications. Here we report a universal, facile, scalable and reversible phase engineering technique (between 2H and 1T' phases) for both monolayer and few-layer MoTe2 based on a soft hydrogen plasma treatment. The 2H -> 1T' transition was confirmed by a series of characterizations including Raman spectra and mapping studies, XPS analysis and FET device measurements at varying temperatures. We attribute the phase transition to the warping of Te-Mo bonds and the lateral sliding of the top Te layer induced by the soft hydrogen ion bombardment according to both the structural and electronic characterizations as well as the horizontal comparison with the cases of Ar or O2 plasma treatment. We have also prepared a 2D heterostructure containing periodical 2H and 1T' MoTe2 and showed that such phase transition can be readily reversed by post annealing. These results thus provide a robust and efficient approach for the phase engineering of monolayer and few layer MoTe2 and could aid the development of 2D optoelectronic, memory and reconfigurable devices. PMID- 30452392 TI - Clustering of MnFe2O4 nanoparticles and the effect of field intensity in the generation of heat for hyperthermia application. AB - MnFe2O4 nanoparticles thinly coated with oleic acid were successfully synthesized via a co-precipitation technique. Morphological analysis shows the co-existence of different nanoparticle assemblies such as dense agglomeration, chain clustering, and random clustering, the effect of which was then reflected in the FTIR spectrum and magnetization behavior of the MnFe2O4 nanoparticles. Induction heating study collectively discusses the association of dipolar energy and magnetic anisotropy energy with the applied field intensity in various nanoparticle clustering systems. The highest applied field intensity (H250: 14.98 kAm-1) at a nanoparticle concentration of 2 mg ml-1 shows a maximum specific absorption rate of 98.37 W g-1, which is attributed to the effect of threshold field amplitude surpassing the dipolar field energy. The nanoparticle clustering due to an interdigitated effect and chain clustering can effectively contribute to heat generation via Neelian and hysteresis loss mechanism at a suitable high field intensity. PMID- 30452393 TI - Outcomes of the lower trapezius muscle activities during various narrow-base push up exercises. AB - BACKGROUND: In clinics, training of the lower trapezius muscle for the rehabilitation of the shoulder is often applied. The narrow-base push-up exercise is considered suitable training of the proximal shoulder complex, but the effect on the lower trapezius muscle has not yet been investigated. OBJECTIVE: The purpose of this study was to investigate the effect of push-up, push-up plus, and support surfaces on the lower trapezius muscle during the narrow-base push-up exercise. METHODS: A total of 11 males participated in this study. Surface electromyographic response of the lower trapezius muscle was examined during the narrow-base push-up exercise. RESULTS: The lower trapezius muscle activity increased significantly in both the stable and the unstable conditions during the narrow-base push-up phase compared with both conditions during the narrow-base push-up plus phase. CONCLUSIONS: The narrow-base push-up is considered a suitable exercise for strengthening the lower trapezius muscle regardless of support surfaces. PMID- 30452394 TI - Long-term effects of diagonal active stretching versus static stretching for cervical neuromuscular dysfunction, disability and pain: An 8 weeks follow-up study. AB - BACKGROUND: A high prevalence and incidence of neck and shoulder pain are common problems that require more attention from health service providers and researchers. Recent findings have indicated that the neck stretching is the one of the most effective physical therapy interventions. Although the recovery of the pain through the stretching exercise has been described in a previous study, functional advantages and changes of the neuromuscular control has not been suggested. Additionally, there was a lack of studies that considered methods of stretching. OBJECTIVE: The purpose of the present study was to examine the long term effects of stretching methods for cervical neuromuscular dysfunction, disability and pain in a sample of sedentary workers with neck pain. METHODS: Twenty-four sedentary workers with neck pain participated in this study and were assigned to the following two groups: static stretching (SS), and diagonal active stretching (DS). Active cervical range of motion (ROM), pressure pain threshold (PPT), self reported questionnaire (Neck Disability Index, NDI), and the flexion relaxation ratio (FRR) from the cervical erector spinae muscles were measured at pre-treatment, post-treatment (after 4 weeks) and follow-up (after 6 and 8 weeks). RESULTS: In both groups, the values obtained for the cervical ROM as flexion, extension, lateral flexion, were significantly increased in comparison to pre-treatment (p< 0.05). Significant increases of the left and right neck rotation, left and right FRR were only observed in the DS group (p<0.05). The NDI score of the SS group was significantly lower than that of the DS group (p< 0.05). CONCLUSIONS: Our findings suggest that both static and diagonal stretching exercises were effective for reducing disability of the neck and increasing cervical range of motion. Compared to the SS, in addition, present results suggest that changes of the activation patterns as FRR, and cervical rotational movement could be accomplished with the DS. PMID- 30452395 TI - Trunk peak torque, muscle activation pattern and sudden loading compensation in adolescent athletes with back pain. AB - OBJECTIVE: To evaluate trunk peak torque and muscle activation pattern during isokinetic and sudden trunk loading (STL) between adolescent athletes with/without back pain. METHODS: Nine adolescent athletes with back pain (BP) (m/f 2/7; 15.6 +/- 1.2 y; 177 +/- 9 cm; 67 +/- 13 kg; 22.5 +/- 9.8 h/week) and nine matched controls (m/f 2/7; 15.7 +/- 1.4 y; 177 +/- 12 cm; 65 +/- 9 kg; 16.5 +/- 8.0 h/week training) were included. Trunk strength in rotation and flexion/extension was assessed. Sudden trunk loading was measured during eccentric extension and rotation (30?/s) with additional perturbation. Trunk muscle activity was measured using a 12 lead-EMG (electromyography). Main outcome measures were peak torque [Nm] and MVC normalized EMG-amplitudes (RMS [%]) for each muscle. Additionally, the mean EMG-RMS for four areas of the trunk was calculated (right/left ventral, right/left dorsal). RESULTS: Back pain showed lower trunk peak torque for all conditions in extension/flexion, but not for rotation. EMG amplitudes were increased for BP athletes with statistical significant differences for dorsal muscles in rotation and extension (p< 0.0042), not for ventral muscles in flexion. CONCLUSIONS: The evaluation of strength and muscle activity in isokinetic and sudden trunk loading presents altered trunk function in adolescent back pain athletes. Training interventions focusing on trunk strength and muscular activation pattern appears reasonable. PMID- 30452396 TI - Efficacy of combined ozone and platelet-rich-plasma treatment versus platelet rich-plasma treatment alone in early stage knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a chronic disease most often occurring in knee joints, leading to pain of varying severity and deterioration in daily living activities. OBJECTIVE: To compare efficacy of platelet-rich-plasma (PRP) versus PRP in combination with ozone gas injection in patients with early stage knee OA. METHODS: Retrospective data of patients who received PRP alone (n= 45) or combined treatment (PRP + ozone, n= 35) injection was analyzed. Patients were evaluated using the visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores. RESULTS: In both PRP alone and combined treatment groups, post-treatment VAS and WOMAC scores at month 1, month 3, and month 6 showed a significant reduction compared to pre-treatment scores (p< 0.001). Physical function and total WOMAC scores as well as VAS scores at post-treatment month 3 were significantly lower in the combined treatment group compared to the PRP alone group. Moreover, in the combined treatment group, VAS scores on Day 10 and hyper-inflammation at the injection site was significantly lower than the PRP alone group. CONCLUSION: In general, similar efficacy was observed between treatment with PRP alone and treatment with PRP in combination with ozone. However, patients receiving ozone treatment are less likely to experience post-injection pain and are more likely to recover faster when compared to patients receiving PRP treatment alone. PMID- 30452397 TI - Analysis of clinical characteristics of bone marrow proliferative tumor progression to acute myeloid leukemia. AB - OBJECTIVE: This study aims to analyze Chinese patients who developed acute leukemia after being diagnosed and treated for Philadelphia chromosome (Ph) negative chronic myeloproliferative neoplasms (MPNs), and compare the findings of this series with similar studies from literature. METHODS: Nine patients who progressed to leukemia after being diagnosed with MPN were included into the present study. Clinical data including age, treatment modalities and duration of use in the myeloproliferative phase, latency to leukemic transformation (LT), characteristics of leukemia, chemotherapy administration, and survival after LT were examined. Furthermore, factors associated with leukemia transformation were analyzed. RESULTS: Over a 13-year period, nine patients had LT in 192 Ph-negative MPNs. Among these patients, two patients had polycythemia vera (PV), three patients had essential thrombocythemia (ET), and four patients had myelofibrosis (MF). The median age at MPN diagnosis was 51 years old (range: 42-69 years old), and the median age upon reaching LT was 57 years old (range: 46-72 years old). Furthermore, the median latency to LT was 72.8 months (range: 7-144 months). Five patients had cytogenetic abnormalities (62.5%), with abnormalities in chromosomes -5, +8 and -7 being common. Eight patients underwent the JAK2 V617F gene test when diagnosed with MPN. The prognosis of patients with LT was poor, and the average survival time was 6.7 months. This was not correlated with the treatment. CONCLUSION: LT in Ph-negative MPNs is rare, and has poor prognosis, which has been consistently reported in a number of studies, However, this needs to be further confirmed through larger studies. PMID- 30452398 TI - Correlation of circulating pro-angiogenic miRNAs with cardiotoxicity induced by epirubicin/cyclophosphamide followed by docetaxel in patients with breast cancer. AB - OBJECTIVE: This study aimed to evaluate predictive value of 14 pro-angiogenic miRNAs for cardiotoxicity induced by epirubicin/cyclophosphamide follow by docetaxel (EC-D) in breast cancer (BC) patients. METHODS: Three hundred and sixty three BC patients receiving EC-D neoadjuvant chemotherapy were consecutively enrolled in this prospective cohort study. Peripheral blood sample was obtained from each patient, and plasma was separated. The expressions of 14 pro-angiogenic miRNAs, cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) were evaluated. Left ventricular ejection fraction (LVEF) level at C0, the end of 4 cycles of EC chemotherapy (C4), the end of 4 cycles of docetaxel treatment (C8), 3rd months (M3), 6th months (M6), 9th months (M9) and 12th months (M12) after surgery were assessed. RESULTS: LVEF decreased at C4, C8, M3, M6, M9 and M12 compared with C0, and the total cardiotoxicity incidence was 5.2%. Additionally, the levels of let-7f, miR-17-5p, miR-20a, miR-126, miR-210 and miR 378 were reduced in cardiotoxicity patients. Multivariate logistic regression revealed that miR-17-5p and miR-20a were independently predictive factors for less cardiotoxicity. Receiver operating characteristics (ROC) curve displayed a satisfactory predictive value for lower cardiotoxicity risk with area under curve (AUC) of 0.842 of the combination of the miR-17-5p and miR-20a expressions. In addition, let-7f,miR-126, miR-210 and miR-378 levels negatively correlated with cTnI expression, and let-7f and miR-130a expressions reversely correlated with NT proBNP level.CONLUSIONS: miR-17-5p and miR-20a could be served as biomarkers for lower cardiotoxicity induced by EC-D neoadjuvant chemotherapy in BC patients. PMID- 30452399 TI - MiR-337-3p suppresses the proliferation and metastasis of clear cell renal cell carcinoma cells via modulating Capn4. AB - OBJECTIVE: Renal cancer accounts for about 3% of human cancer, and clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Recently, microRNAs (miRNAs) are found to be the biomarkers for cancer diagnosis, prognosis and the targets for tumor management. This study aimed to examine the expression of miR-337-3p in ccRCC and to elucidate the molecular mechanisms underlying miR-337-3p-mediated ccRCC progression. METHODS: The miRNA and mRNA expression levels in ccRCC cells and tissues were measured by qRT-PCR. Cell proliferation, cell adhesion, colony growth and cell invasion were examined by CCK-8 assay, cell adhesion assay, colony formation assay and Transwell invasion assay, respectively. The protein levels were detected by western blot assay. The effects of miR-337-3p on tumor growth in vivo was assessed in a nude mice xenograft model. RESULTS: MiR-337-3p was down-regulated in ccRCC cell lines, and miR-337-3p overexpression suppressed cell proliferation, colony growth and invasion, but enhanced cell adhesion in ccRCC; while knockdown of miR-337-3p exerted the opposite effects on ccRCC. Bioinformatics analysis and luciferase reporter assay showed that Calpain small subunit 1 (Capn4) was negatively regulated by miR-337-3p, and overexpression of miR-337-3p attenuated the miR-337 3p-mediated effects on ccRCC cellular functions. In addition, miR-337-3p also suppressed epithelial-mesenchymal transition in ccRCC. The in vivo tumor growth was markedly suppressed after miR-337-3p overexpression. Data from clinical data showed that down-regulation of miR-337-3p and up-regulation of Capn4 mRNA and protein were identified in the ccRCC tissues, and miR-337-3p expression level was inversely correlated with Capn4 mRNA expression level in ccRCC tissues. CONCLUSIONS: Collectively, these data suggested the tumor suppressive role of miR 337-3p in ccRCC. MiR-337-3p suppressed cell proliferation and metastasis in ccRCC partially via targeting Capn4. PMID- 30452400 TI - High serum Hsp70 level predicts poor survival in colorectal cancer: Results obtained in an independent validation cohort. AB - BACKGROUND: Hsp70 plays important role in the development and progression of cancer. Previously we described the association between serum Hsp70 levels and mortality of colorectal cancer. OBJECTIVE: In this new prospective study we aimed to confirm and extend our previous findings in a larger cohort of patients, based on a longer follow-up period. METHODS: Two hundred and thirty-two patients diagnosed with colorectal cancer were enrolled in the study. Baseline serum Hsp70 level and classical biomarker levels were measured. Patients were treated according to stage of the tumor and follow-up lasted for a median 46.4 months. RESULTS: We found that serum Hsp70 concentrations increase significantly with stage of the disease (1.79; 2.23 and 3.21 ng/ml in stage I+II, III and IV respectively, p= 0.012 and 0.002, Mann-Whitney test) and with other known biomarkers of the disease. We managed to confirm our previous findings that high baseline serum Hsp70 level (> 1.64 ng/ml) predicted poor 5-year survival (risk of death HR: 1.94 CI: 1.294-2.909; univariate; HR: 2.418 CI: 1.373-4.258; multivariate Cox regression analysis) in the whole patient population and also in subgroups of stage IV and stage III disease. The strongest association was observed in women under age of 70 (HR: 8.12, CI: 2.02-35.84; p= 0.004; multivariate Cox regression). The power of this colorectal cancer prognostic model could be amplified by combining Hsp70 levels and inflammatory markers. Patients with high Hsp70, CRP and high baseline WBC or platelet count had 5-times higher risk of death (HR: 5.07 CI: 2.74-9.39, p< 0.0001; and HR: 4.98 CI: 3.08 8.06, p< 0.0001 respectively). CONCLUSIONS: These results confirm and validate our previous findings that serum Hsp70 is a useful biomarker of colorectal cancer. PMID- 30452401 TI - Comprehensive analysis of aberrantly expressed profiles of lncRNAs, miRNAs and mRNAs with associated ceRNA network in Cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is a highly malignant and poorly differentiated bile duct cancer with an extremely poor prognosis, but the pathogenesis of CCA remains not well-known. Attention has been increasingly focused on long noncoding RNAs, which plays an important role in tumorigenesis. However, the roles of cancer specific lncRNA and its related competitive endogenous RNAs (ceRNA) network in CCA remain elusive. In this study, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 36 CCA tissues and 9 normal tissues in The Cancer Genome Atlas. 1434 cancer specific lncRNAs, 68 miRNAs and 3538 mRNAs (|logFC|> 1, p< 0.05) were identified. Based on bioinformatics generated from miRcode, starBase, miRTarBase, TargetScan and miRDB, we constructed an lncRNA-miRNA-mRNA network (ceRNA network) in CCA. We constructed the lncRNA-miRNA-mRNA ceRNA network consisting of 206 molecules and 454 interactions. In addition, we used Cytoscape software to visualize the ceRNA network in WGCNA, 22 mRNA network modules were identified, five of which were significantly related to tumor grade and survival time. Moreover, three lncRNAs COL18A1-AS1, SLC6A1-AS1 and HULC were found to be significantly associated with overall survival. The present study provides novel insight for better understanding of lncRNA-related ceRNA network in CCA and useful resource for identifcation of novel biomarkers of CCA. PMID- 30452402 TI - Long noncoding RNA HOTTIP is a significant indicator of ovarian cancer prognosis and enhances cell proliferation and invasion. AB - Long noncoding RNAs (LncRNAs) are involved in the occurrence and progression of human tumors including ovarian cancer (OC). Long noncoding RNA HOTTIP has been found to be involved in several human tumors development. However, the role of HOTTIP in OC remains large unknown. In the present study, our results observed that lncRNA HOTTIP expression levels were notably higher in ovarian cancer tissue samples compared to adjacent normal tissue samples. Increased lncRNA HOTTIP expression levels were significantly associated with advanced FIGO stage and lymph node metastasis of ovarian cancer patients. Survival plots analysis results showed high lncRNA HOTTIP expression levels in ovarian cancer patients showed a poor prognosis compared to patients with low lncRNA HOTTIP expression levels. Function assays showed that lncRNA HOTTIP knockdown in ovarian cancer cells decreased cell proliferation and cell invasion capacities. Furthermore, we demonstrated that inhibition of lncRNA HOTTIP suppressed Wnt/beta-catenin signaling by downregulating beta-catenin expression. Thus, these results suggest that aberrant HOTTIP expression level could serve as a promising biomarker for monitoring ovarian cancer and potential target of ovarian cancer treatment. PMID- 30452403 TI - Correlation of long non-coding RNA taurine-upregulated gene 1 with disease conditions and prognosis, as well as its effect on cell activities in acute myeloid leukemia. AB - OBJECTIVE: This study aimed to investigate the correlation of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) with clinicopathological characteristics and prognosis in acute myeloid leukemia (AML) patients, as well as its function in cell proliferation and apoptosis. METHODS: Two hundred and thirty six de novo AML patients were consecutively enrolled and then underwent conventional induction chemotherapy. Bone marrow samples were obtained from all AML patients and controls. Quantitative polymerase chain reaction assay was performed to detect lncRNA TUG1 expression. KG-1 cells were transfected by TUG1 inhibitor (TUG1 (-)) and blank inhibitor (NC (-)) plasmids. Cell proliferation and apoptosis were evaluated by CCK8 and AV/PI assays, and apoptotic markers expressions were detected by Western blot assay. RESULTS: LncRNA TUG1 expression was higher in AML patients compared to controls, and it was positively correlated with white blood cell counts as well as poor risk stratification. Additionally, elevated lncRNA TUG1 expression was observed in non-complete remission (non-CR) patients compared to CR patients, and it was correlated with shorter event-free survival and overall survival in AML patients. In the in vitro experiments, lncRNA TUG1 expression was upregulated in AML cell lines compared to control cells, and cell proliferation ability was reduced, but cell apoptosis rate was promoted in TUG1 (-) group compared to NC (-) group at 72 hours after transfection in KG-1 cells. CONCLUSIONS: LncRNA TUG1 predicts advanced disease conditions and poor prognosis in AML patients, and its knockout decreases proliferation and increases apoptosis of AML cells. PMID- 30452404 TI - Increased expression of lncRNA SNHG12 predicts a poor prognosis of nasopharyngeal carcinoma and regulates cell proliferation and metastasis by modulating Notch signal pathway. AB - BACKGROUND: Small nucleolar RNA host gene 12 (SNHG12) has been shown to be a long noncoding RNA (lncRNA) that facilitates the progression of a number of malignancies. However, the expression pattern and biological function of SNHG12 in nasopharyngeal carcinoma (NPC) have not been investigated. OBJECTIVE: The aim of our study is to investigate the expression, clinical significance and function of SNHG12 in NPC. METHODS: RT-PCR was used to detect the expression of SNHG12 in NPC cell lines and primary tumor tissues. The correlation of SNHG12 with clinicopathological features and patient prognosis was analyzed. The biologic functions of SNHG12 in NPC were explored by MTT assay, colony formation assay, wound healing assays, transwell assay and flow cytometric analysis in vitro. The expression of EMT markers and Notch signal pathway markers were determined by western blotting. RESULTS: The expression levels of SNHG12 were up-regulated in both NPC tissues and cell lines. High SNHG12 expression was significantly associated with clinical stage, grade and poor prognosis. Multivariate analysis demonstrated that high lncRNA SNHG12 expression was an independent poor prognostic factor for NPC patients. Functionally, knockdown of SNHG12 suppressed NPC cells proliferation, migration and invasion. Mechanistic investigations showed that knockdown of SNHG12 suppressed the activation of EMT and Notch-1 signal pathway. CONCLUSIONS: Our data suggest that SNHG12 promotes the progression of NPC and is a potential therapeutic target for NPC intervention. PMID- 30452405 TI - Prolonged systemic inflammation and damage to the vascular endothelium following intratracheal instillation of air pollution nanoparticles in rats. AB - BACKGROUND: Exposure to air pollution is associated with cardiovascular disease, including increased morbidity and mortality rates. OBJECTIVE: The aim of this investigation was to assess the effect, in rats, of intratracheal instillation of particulate air pollution on biomarkers of leucocyte activation and vascular endothelial damage. METHODS: Air pollution particles (PM10) were instilled into rats, and blood samples were taken three days and six weeks post instillation. Plasma neutrophil elastase and VonWillebrand factor were measured by ELISA. RESULTS: Plasma neutrophil elastase increased from 175+/-44 ng/ml at baseline to 288+/-26 ng/ml 3 days post instillation (p = 0.038). vWF increased from 0.160+/ 0.015 IU/ml at baseline to 0.224+/-0.015 IU/ml at 3 days post and 0.208+/-0.01 IU/ml at 6 weeks post (p = 0.006, ANOVA). sICAM-1 increased from 17.75+/-0.70 ng/ml at baseline to 19.03+/-0.33 ng/ml at 3 days post and 21.72+/-1.16 ng/ml at 6 weeks post (p = 0.009, ANOVA). CONCLUSION: Instillation caused prolonged systemic inflammation, activation of blood leucocytes and damage to the vascular endothelium. PMID- 30452406 TI - Use of RBC deformability index as an early marker of diabetic nephropathy. AB - BACKGROUND AND OBJECTIVE: Hemorheologic alterations have been suggested to play a role in the pathogenesis of diabetic microvascular complications. We measured various hemorheologic parameters and assessed their possible role as a diagnostic tool for diabetic nephropathy (DN). METHODS: 248 subjects with type 2 diabetes and 222 subjects with prediabetes were included in this study. Hemorheologic parameters, including erythrocyte sedimentation rate (ESR), elongation index at 3 Pa (EI) were measured using microfluidic hemorheometer. Various metabolic parameters were measured from fasting blood samples. The subjects were stratified into three groups according to classification of DN by urinary albumin to creatinine ratio (ACR) and four groups by estimated glomerular filtration rate (GFR), than analyzed. RESULTS: Significant differences were observed in metabolic and hemorheologic parameters according to progression of DN. Among them, (Fibrinogen*ESR)/ EI differed in all three groups of urinary ACR. In multiple regression analysis, (Fibrinogen*ESR)/ EI was an independent predictor of urine ACR after adjusted with confounding factors (beta = 0.010, p < 0.001). (Fibrinogen*ESR)/ EI also showed significant difference no or minimal CKD stage, moderate CKD and severe CKD classified by GFR. This parameter showed area under curve (AUC) of the receiver operating characteristic (ROC) curve of 0.762, and moderate sensitivity and specificity to predict prevalence of microalbuminuria. CONCLUSIONS: (Fibrinogen*ESR)/ EI is a sensitive parameter for screening diabetic nephropathy. PMID- 30452407 TI - Predicting cervical lymph node metastasis in patients with papillary thyroid cancer (PTC) - Why contrast-enhanced ultrasound (CEUS) was performed before thyroidectomy. AB - The objective of this research was to investigate the clinical value of contrast enhanced ultrasound (CEUS) for prediction of cervical lymph node metastasis (CLNM) in papillary thyroid cancer (PTC).One hundred and eighty-six patients with PTC confirmed by fine needle aspiration (FNA) were preoperatively performed CEUS.A multivariate analysis was performed to predict CLNM by 15 independent variables. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance.There were totally 37 patients with CLNM confirmed by pathology. Multivariate analysis demonstrated that intensity at peak time, capsule contact and size on CEUS were the three strongest independent predictors for CLNM. ROC analyses of these characteristics showed the areas under the curve (Az), sensitivity, and specificity were 0.650, 48.6 %, 79.8 %; 0.586, 67.6%, 49.7%; and 0.612, 56.8%, 64.4% for intensity at peak time, capsule contact, and size, respectively.The CEUS patterns of PTC are relative to not only the size of PTC but also the possibility of CLNM after thyroidectomy. CEUS seem to be a tool to predict CLNM in PTC patients. PMID- 30452408 TI - Terminologies regarding sickle cell retinopathy. PMID- 30452409 TI - TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study. AB - Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57 34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10-38.00) and Alzheimer's disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15-2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11-4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22-3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58-3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort specific features. PMID- 30452410 TI - The Association between Social Engagement, Loneliness, and Risk of Dementia: A Systematic Review and Meta-Analysis. AB - It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 - May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31-1.96; I2 = 0.00%) and poor social support (RR = 1.28, 95% CI 1.01-1.62; I2 = 55.51%). In long-term studies (>=10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80-0.96; I2 = 0.00%). Loneliness was associated with non-significantly increased risk (RR = 1.38, 95% CI 0.98-1.94; I2 = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention. PMID- 30452411 TI - Impact of Olfactory Priming on Food Intake in an Alzheimer's Disease Unit. AB - Alzheimer's disease (AD) is often associated with feeding difficulties and changes in eating behavior with may lead to malnutrition. In French nursing homes, AD patients may live in special care units that better meet dementia residents' needs. However, meals are often delivered to AD patients by using meal trays coming from central kitchens. This led to the disappearance of cues that could help residents to foresee mealtime, such as the smell of food odors. The aim of the present study was to assess the impact of odorizing the dining room of AD Units with a meat odor before lunch on subsequent food intake and eating behavior. Thirty-two residents (>75 years old) from three AD Units were included in the study. They participated in two control lunches and two primed lunches, for which a meat odor was diffused in the dining room 15 minutes before the arrival of the meal tray (olfactory priming). Results of the first replication showed a significant effect of olfactory priming, with a 25% increase in meat and vegetable consumption compared to the control condition. Behavioral measurements also showed a significant increase of resident's interest toward the meal in the primed lunch. However, this effect was no longer observed when the priming session was replicated two weeks later with the same priming odor and the same menu. Although further research is needed to understand why this priming effect cannot be replicated, our experiment is one of the very first to investigate the effect of food odor priming on subsequent food intake in AD patients in a real life setting. PMID- 30452412 TI - Long-Term Severe Mental Disorders Preceding Behavioral Variant Frontotemporal Dementia: Frequency and Clinical Correlates in an Outpatient Sample. AB - BACKGROUND: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. OBJECTIVES: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. METHODS: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD-) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. RESULTS: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p = 0.01), use of antipsychotics (p = 0.01), family history of psychosis (p = 0.01), presence of primitive reflexes (p = 0.04), Frontal Assessment Battery performance (p = 0.01), Ekman's facial emotion recognition test (p = 0.03), frequency of apathy (p = 0.03), and stereotyped behavior (p = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. CONCLUSIONS: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features. PMID- 30452413 TI - Observational Study of Clinical and Functional Progression Based on Initial Brain MRI Characteristics in Patients with Alzheimer's Disease. AB - BACKGROUND: Magnetic resonance imaging (MRI) is a useful tool to predict the diagnosis and progression of Alzheimer's disease (AD), especially for primary physicians. However, the correlation between baseline MRI findings and AD progression has not been fully established. OBJECTIVE: To investigate the correlation between hippocampal atrophy (HA) and white matter hyperintensities (WMH) on initial brain MRI images and the degree of cognitive decline and functional changes over 1 year. METHODS: In this prospective, 12-month observational study, dementia outpatients were recruited from 29 centers across South Korea. Baseline assessments of HA and WMH on baseline brain MRI were derived as well as cognitive function, dementia severity, activities of daily living, and acetylcholinesterase inhibitor (AChEI) use. Follow-up assessments were conducted at 6 and 12 months. RESULTS: Among 899 enrolled dementia patients, 748 were diagnosed with AD of whom 654 (87%) were taking AChEIs. Baseline WMH showed significant correlations with age, current alcohol consumption, and Clinical Dementia Rating score; baseline HA was correlated with age, family history, physical exercise, and the results of cognitive assessments. Among the AChEI group, changes in the Korean version of the Instrumental Activities of Daily Living (K-IADL) were correlated with the severity of HA on baseline brain MRI, but not with the baseline severity of WMH. In the no AChEI group, changes in K-IADL were correlated with the severity of WMH and HA at baseline. CONCLUSION: Baseline MRI findings could be a useful tool for predicting future clinical outcomes by primary physicians, especially in relation to patients' functional status. PMID- 30452414 TI - Microbleeds and Cerebral Amyloid Angiopathy in the Brains of People with Down Syndrome with Alzheimer's Disease. AB - Cerebrovascular pathology is a significant mediator in Alzheimer's disease (AD) in the general population. In people with Down syndrome (DS), the contribution of vascular pathology to dementia may play a similar role in age of onset and/or the rate of progression of AD. In the current study, we explored the extent of microbleeds (MBs) and the link between cerebral amyloid angiopathy (CAA) and MBs in the frontal cortex (FCTX) and occipital cortex (OCTX) in an autopsy series from individuals with DS (<40 years), DS with AD pathology (DSAD), sporadic AD, and control cases (2-83 years). Sections were immunostained against Abeta1 - 40 and an adjacent section stained using Prussian blue for MBs. MBs were both counted and averaged in each case and CAA was scored based on previously published methods. MBs were more frequent in DS cases relative to controls but present to a similar extent as sporadic AD. This aligned with CAA scores, with more extensive CAA in DS relative to controls in both brain regions. CAA was also more frequent in DSAD cases relative to sporadic AD. We found CAA to be associated with MBs and that MBs increased with age in DS after 30 years of age in the OCTX and after 40 years of age in the FCTX. MB and CAA appear to be a significant contributors to the development of dementia in people with DS and are important targets for future clinical trials. PMID- 30452415 TI - Brains for Dementia Research: Evolution in a Longitudinal Brain Donation Cohort to Maximize Current and Future Value. AB - Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that 'big data', readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia. PMID- 30452416 TI - Ceftriaxone Improves Cognitive Function and Upregulates GLT-1-Related Glutamate Glutamine Cycle in APP/PS1 Mice. AB - Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle. PMID- 30452417 TI - Glucagon-Like Peptide-2 Receptor is Involved in Spatial Cognitive Dysfunction in Rats After Chronic Cerebral Hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH. PMID- 30452418 TI - Aberrant Neuronal Cell Cycle Re-Entry: The Pathological Confluence of Alzheimer's Disease and Brain Insulin Resistance, and Its Relation to Cancer. AB - Aberrant neuronal cell cycle re-entry (CCR) is a phenomenon that precedes and may mechanistically lead to a majority of the neuronal loss observed in Alzheimer's disease (AD). Recent developments concerning the regulation of aberrant neuronal CCR in AD suggest that there are potential intracellular signaling "hotspots" in AD, cancer, and brain insulin resistance, the latter of which is characteristically associated with AD. Critically, these common signaling nodes across different human diseases may represent currently untapped therapeutic opportunities for AD. Specifically, repurposing of existing US Food and Drug Administration-approved pharmacological agents, including experimental therapeutics that target the cell cycle in cancer, may be an innovative avenue for future AD-directed drug discovery and development. In this review we discuss overlapping aspects of AD, cancer, and brain insulin resistance from the perspective of neuronal CCR, and consider strategies to exploit them for prevention or therapeutic intervention of AD. PMID- 30452419 TI - Efficacy, Acceptability, and Safety of Intravenous Immunoglobulin Administration for Mild-To-Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis. AB - A systematic review and meta-analysis of the efficacy/safety of intravenous immunoglobulin (IVIG) administration in mild-to-moderate Alzheimer's disease (AD) patients was performed. Six randomized double-blind, placebo-controlled trials (n = 801) were included in this study. No significant difference in cognitive function was observed between the groups. Moreover, IVIG was inferior to placebo in behavioral disturbances (mean difference = 2.19). Further, IVIG administration was associated with a higher incidence of rash than placebo. Our results do not support IVIG administration for mild-to-moderate AD, suggesting that IVIG is not effective to treat mild-to-moderate AD and that it deteriorates behavioral and psychological symptoms of dementia in mild-to-moderate AD. PMID- 30452420 TI - Longitudinal Biochemical Assay Analysis of Mutant Huntingtin Exon 1 Protein in R6/2 Mice. AB - BACKGROUND: Biochemical analysis of mutant huntingtin (mHTT) aggregation species in HD mice is a common measure to track disease. A longitudinal and systematic study of how tissue processing affects detection of conformers has not yet been reported. Understanding the homeostatic flux of mHTT over time and under different processing conditions would aid in interpretation of pre-clinical assessments of disease interventions. OBJECTIVE: Provide a systematic evaluation of tissue lysis methods and molecular and biochemical assays in parallel with behavioral readouts in R6/2 mice to establish a baseline for HTT exon1 protein accumulation. METHODS: Established biochemical methods were used to process tissue from R6/2 mice of specific ages following behavior tasks. Aggregation states and accumulation of mHTT exon 1 protein were evaluated using multiple break and assay methods to determine potential conformational flux assay specificity in detection of mHTT species, and tissue specificity of conformers. RESULTS: Detection of mHTT exon 1 protein species varied based on biochemical processing and analysis providing a baseline for subsequent studies in R6/2 mice. Insoluble, high molecular weight species of mHTT exon 1 protein increased and tracked with onset of behavioral impairments in R6/2 mice using multiple assay methods. CONCLUSIONS: Conformational flux from soluble monomer to high molecular weight, insoluble species of mHTT exon 1 protein was generally consistent for multiple assay methods throughout R6/2 disease progression; however, the results support the use of multiple biochemical techniques to detect mHTT exon 1 protein species for preclinical assessments in HD mouse models expressing mHTT exon 1 protein. PMID- 30452421 TI - Transcriptional Regulation of the Huntingtin Gene. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide expansion in the HTT gene, which encodes for an abnormal polyglutamine tract in the huntingtin protein (HTT). This review examines the known mechanisms of HTT gene regulation. We discuss HTT expression patterns, features of the HTT promoter, regulatory regions of the HTT promoter with functional significance, and HTT regulators located outside of the proximal promoter region. The factors that influence HTT expression in the brain and the mechanisms of HTT transcriptional regulation are currently poorly understood, despite continuing research. Expanding knowledge of HTT regulation will inform future studies investigating HTT function. Improving understanding of HTT expression and control may also uncover novel therapeutic approaches for HD through the development of methods to modulate mHTT levels. PMID- 30452422 TI - Phase 1 Study of Edasalonexent (CAT-1004), an Oral NF-kappaB Inhibitor, in Pediatric Patients with Duchenne Muscular Dystrophy. AB - BACKGROUND: Edasalonexent is an orally administered small molecule designed to inhibit NF-kappaB, which is activated from infancy in Duchenne muscular dystrophy and is central to causing muscle damage and preventing muscle regeneration. OBJECTIVE: Evaluate the safety, tolerability, pharmacokinetics and exploratory pharmacodynamics of three doses of edasalonexent in ambulatory males >=4 to <8 years of age with genetically confirmed Duchenne muscular dystrophy. METHODS: This was a 1-week, open-label, multiple-dose study with 3 sequential ascending doses (33, 67 and 100 mg/kg/day) of edasalonexent administered under different dietary conditions to 17 males with a mean age of 5.5 years. RESULTS: All doses of edasalonexent were well tolerated, with no serious adverse events, no drug discontinuations and no dose reductions. The majority of adverse events were mild, and the most common adverse events were gastrointestinal (primarily diarrhea). Edasalonexent was rapidly absorbed with peak levels observed 2-6 hours after dosing and exposures appeared to increase nearly proportionally to dose for the 2 lower and all 3 doses under low-fat and high-fat meal conditions, respectively. Only minor plasma accumulation of edasalonexent was observed with 7 days of dosing. After treatment with edasalonexent for 7 days, levels of NF kappaB-regulated genes and serum proteins were decreased. CONCLUSIONS: This first report of edasalonexent oral administration for one week in male pediatric patients with Duchenne muscular dystrophy showed that treatment was well tolerated and inhibited NF-kB pathways. PMID- 30452423 TI - Pattern of Habitual Physical Exercise in Myasthenia Gravis Patients. AB - BACKGROUND: Notwithstanding the amount of deliberate exercise, the daily patterns of active versus sedentary behavior have a major influence on health outcomes [1]. Patterns of habitual active and sedentary behavior in Myasthenia Gravis (MG) patients, as well as their possible relations to disease activity, are not known. OBJECTIVE: To evaluate baseline patterns of physical and sedentary behavior in MG patients. METHODS: Activity patterns of twenty-seven MG patients were assessed by a Dynaport MoveMonitor (McRoberts) accelerometer, worn for seven consecutive days. The amount of time spent in moderate and vigorous intensity activities, physical activity level (PAL), number of steps/day and sedentary time were assessed and correlations to disease severity were analyzed. The results were compared to general recommendations and published data of healthy individuals and to data of patients with the chronic disorders chronic obstructive pulmonary disease (COPD) and mitochondrial myopathy. RESULTS: MG patients had sedentary behavior during 78+/-7% of the day. There was neither a correlation between disease severity and number of steps/day (R = - 0.15; p = 0.56) nor between disease severity and PAL (R = 0.33; p = 0.26). Nevertheless, the MG patients met the recommendations of daily deliberate exercise (181+/-158 MET min/day). PAL was lower in MG patients (1.5+/-0.138) than in healthy individuals (1.67+/-0.145, p < 0.00001). CONCLUSION: Although a majority of MG patients meet the recommendations of deliberate exercise, their baseline physical activity levels are dominated by sedentary behavior. In comparison with a healthy population, MG patients are less physically active, but the reason for this remains unclear with no correlations between disease severity and physical activity patterns. PMID- 30452424 TI - Single Inflammatory Trigger Leads to Neuroinflammation in LRRK2 Rodent Model without Degeneration of Dopaminergic Neurons. AB - BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic risk factor for Parkinson's disease (PD). While the corresponding pathogenic mechanisms remain largely unknown, LRRK2 has been implicated in the immune system. OBJECTIVE: To assess whether LRRK2 mutations alter the sensitivity to a single peripheral inflammatory trigger, with ultimate impact on dopaminergic integrity, using a longitudinal imaging-based study design. METHODS: Rats carrying LRRK2 p.G2019S and non-transgenic (NT) littermates were treated peripherally with lipopolysaccharide (LPS). They were monitored over 10 months with PET markers for neuroinflammation and dopaminergic integrity, and with behavioral testing. Tyrosine hydroxylase and CD68 expression were assessed postmortem, 12 months after LPS treatment, in the striatum and substantia nigra. RESULTS: Longitudinal [11C]PBR28 PET imaging revealed that LPS treatment caused inflammation in the brain, increasing over time, as compared to saline (corrected p = 0.008). LPS treated LRRK2 animals exhibited significantly increased neuroinflammation in the cortex and ventral-regions compared to saline treated animals (LRRK2 and NT) at 10 months post treatment, with the increase in [11C]PBR28 binding from baseline averaging 0.128+/-0.045 g/mL. For LPS treated NT animals, the increase was not significant. CD68 immunohistochemistry data supported the imaging results, but without reaching statistical significance. No dopaminergic degeneration was observed. CONCLUSION: A single peripheral inflammatory trigger elicited long lasting, progressive neuroinflammation. A trend for an exacerbated inflammatory response in LRRK2 animals compared to NT controls was observed. Translationally, this implies that repeated exposure to inflammatory triggers may be needed for LRRK2 mutation carriers to develop active PD. PMID- 30452425 TI - Stepping over an obstacle in patients with lumbar spinal stenosis: Trunk and lower extremities of kinematic and muscle activation normalized by double limb support. A preliminary study. AB - BACKGROUND: Patients with LSS tend to adopt a flexed lumbar posture and trunk position, particularly when stepping over an obstacle, as this activity alters the biomechanical demands placed on the trunk and lower extremities. OBJECTIVE: To investigate the effects of lumbar spinal stenosis (LSS) on patients' trunk and lower-extremity kinematics, and on activities involving the gluteus medius (GMed) and vastus lateralis (VL). METHODS: All participants (9 older adult patients with LSS and 11 control subjects) were required to negotiate an obstacle while walking. Trunk and lower-extremity kinematic data and GMed and VL activities were recorded using a synchronized 3D motion capture system and surface electromyography. RESULTS: The thoracic (12.01?+/- 8.82? and 16.45?+/- 10.80?) and spinal (9.92?+/- 14.03? and 5.99?+/- 15.94?) flexion angles of the leading and trailing swing limbs were higher, and the pelvic anterior tilting angle (2.37?+/- 7.76? and 10.38?+/- 8.07?) was lower in the LSS group than in the control group (p< 0.05). With the exception of toe-off and normalized GMed activities in the contralateral leading limb (p> 0.05), all GMed (256.73 +/- 112.22%, 174.00 +/- 75.79%, and 270.57 +/- 114.45%, respectively) and VL (208.98 +/- 124.81%, 182.97 +/- 93.23%, 283.91 +/- 154.71%, and 394.42 +/- 108.94%, respectively) activities of the contralateral leading and trailing swing limb (heel-strike and toe-off normalized activities) were significantly higher in the LSS group than in the control group (p< 0.05). CONCLUSIONS: Patients with LSS exhibited trunk-flexed postures when stepping over an obstacle, and these trunk alignments placed higher demands on the GMed and VL activities normalized by double-limb support during joint loading in the single-leg stance. These findings support clinical recommendations for regulating the physical activity of obstacle negotiation that may be beneficial in the management of patients with LSS. PMID- 30452426 TI - Investigating the effect of daily sleep on memory capacity in college students. AB - BACKGROUND: Sleep is a natural periodic state of rest for body and mind and daily sleep affects physical and mental health. However, it is essential to address intensity of sleep characteristics affecting the memory capacity of humans positively or negatively. OBJECTIVE: Using wearable devices to observe and assess the effect of daily sleep on memory capacity of college students. METHODS: This study assessed the daily sleep characteristics and memory capacity of 39 college students who used wrist-worn devices. The spatial span test (SST) was used to evaluate the memory capacity. RESULTS: The study indicated a negative correlation between memory capacity and awake count on the test date and during the week before the test date (r=-0.153 (95% CI: -0.032, -0.282), r=-0.391 (95% CI: 0.520, -0.235), respectively). However, the minutes asleep on the test date and during the week before the test date positively affected memory capacity (r= 0.127 (95% CI: 0.220, 0.025), r= 0.370 (95% CI: 0.208, 0.500), respectively). In addition, spending ? 6 hours and 42 minutes asleep on the test date or ? 6 hours and 37 minutes asleep per day on average during the week before the test date resulted in a better memory capacity. CONCLUSIONS: A lower awake count led to a higher memory capacity in college students, as did more minutes asleep. PMID- 30452427 TI - Effects of different education methods in peritoneal dialysis application training on psychomotor skills and self-efficacy of nursing students. AB - BACKGROUND: Applying the proper technique for connections in Peritoneal Dialysis (PD) is crucial in preventing potential infectious complications. OBJECTIVES: The aim of this study is to investigate the effects of different education methods in peritoneal dialysis (PD) application training on the psychomotor skills and self efficacy of nursing students. METHODS: The randomized controlled and experimental study was conducted with a total of 28 nursing student participants. The PD training was provided theoretically and by using a PD simulator for the experimental group and by using videos for the control group. At the end of the training, each student who was included in the experimental and control group were asked to perform PD on the PD simulator one by one. Psychomotor skills were evaluated according to the PD application skill evaluation criteria. Self efficacy of the students before and after the application was also measured. RESULTS: Psychomotor skill scores of the students were found to be significantly higher in the experimental group, and there was no significant difference between the experimental and control groups in terms of self-efficacy scores. No statistically significant difference was detected between the self-efficacy scores of the experimental group regarding pre- and post-test results. CONCLUSION: This technique can be used to improve the development of psychomotor skills, since the demonstration of the PD application with the simulation technique is effective in the development of psychomotor skills. PMID- 30452428 TI - Analyzing the effect of an arch support functional insole on walking and jogging in young, healthy females. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to explore the effectiveness of arch support functional insoles to prevent metatarsalgia. METHOD: Twenty-five healthy females participated in the study. A Vicon motion capture system was used to collect kinematics data of the lower limb. An AMTI force plate was used to record the vertical ground reaction force (GRF), and the Novel Pedar-X System was used to measure foot pressure while subjects wore normal insoles or functional insoles with an arch support during walking and jogging. RESULTS: With the arch support functional insoles, the first metatarsal (FM) region's contact area was increased and the peak pressure and time-pressure integral of the FM and second and third metatarsal (SATM) were areas decreased. This suggests a lower risk of longitude stress injuries in these areas. The ankle dorsiflexion angle of jogging with the 'arch support functional insoles' (RF) and walking with the 'arch support functional insoles' (WF) were significantly increased at initial contact and the knee and hip flexion angle of RF and WF were reduced. The peak hip extension angle of WF and RF also declined. The vertical loading rate of RF was lower, which would be beneficial in reducing the risk of lower limb injuries during jogging. CONCLUSIONS: The results demonstrate that arch support functional insoles can be used effectively to prevent and decrease pain and promote a suitable weight-bearing pattern in the foot for promoting the health of young females. PMID- 30452429 TI - Increased health information technology investment decreases uncompensated care cost: A study of Texas hospitals. AB - BACKGROUND: Many previous research studies have demonstrated that investing in health information technology (IT) in a hospital setting has potential benefits, including eliminating duplicate or unnecessary tests and adverse drug events, conserving healthcare provider time and effort by making information more readily available, and reducing cost by increasing efficiency or productivity metrics. However, the effect of health IT on uncompensated care has not been reported yet. OBJECTIVE: The objective of this study was to examine the effect of health IT investment on uncompensated care provided by hospitals. METHODS: The general linear model (GLM) with log link and normal distribution was used to estimate the association between health IT spending and the provision of uncompensated care using Texas American Hospital Association (AHA) data from 2004 to 2010. RESULTS: The total health IT investment was significantly and negatively associated with the provision of uncompensated care. When health IT investment was increased by 10%, the provision of uncompensated care was reduced by 2.7%. Health IT investment was also significantly and negatively associated with bad debt. When health IT investment was increased by 10%, bad debt was decreased by 3.2%. CONCLUSION: Health IT investment was negatively associated with the provision of uncompensated care. This means that health IT could reduce administrative burden and improve efficiency of tracking patient insurance status and billings. PMID- 30452430 TI - Identification of the self-confidence and self-efficacy levels of student nurses when performing blood drawing for the first time on their peers. AB - BACKGROUND: Blood sampling is frequently used in health to evaluate diagnosis and treatments. The first blood drawing is most important skill for nursing students. Nursing students gain these skills during their first years of education. OBJECTIVE: To identify the self-confidence and self-efficacy levels of first year nursing students when performing taking blood on their peers for the first time. METHODS: The sample (n= 70) of this descriptive and cross-sectional research comprised first year nursing students. The research was conducted in two stages; theoretical training and laboratory work and students' first taking blood on their peers. A Student Information Form, Blood drawing Skill Practice Evaluation Control Form, Self-Confidence Scale, and General Self-Efficacy Scale were used for data collection. Percentage calculations and the Mann-Whitney U test were used for data analysis. RESULTS: The total mean score of the students' self confidence was 130.09 +/- 15.94 (Min = 91, Max = 157), and total mean score of self-efficacy was identified as 31.71 +/- 3.92 (Min = 20, Max = 39). No statistically significant difference was detected between the students' sex and high school type regarding self-confidence and self-efficacy total mean scores (p> 0.05). CONCLUSIONS: It was observed that students' self-confidence and self efficacy levels were high when performing taking blood on their peers for the first time. PMID- 30452431 TI - Relative radiographic bone density measurement in revision hip arthroplasty and its correlation with qualitative subjective assessment by experienced surgeons. AB - BACKGROUND: Conventional radiography (CR) is the imaging method of choice in monitoring bone remodelling and other stability parameters after total hip arthroplasty (THA). Quantitative roentgen- or computed-tomography-based methods to determine bone density are prone to metal artifacts and often very costly, which is why they are not used as standard in a clinical setting. Since subjective assessment of bone remodelling in CR also has a certain susceptibility to errors, semi-quantitative methods have been developed to help approximate periprosthetic bone density development via CR to open up an additional tool for documentation of radiographic THA follow-up. OBJECTIVE: Proof-of-principle of a newly designed imaging-software-aided method to measure relative bone density around the femoral stem in a series of conventional radiographs following THA. METHODS: Eighty-six patients with hip modular tapered, fluted titanium stems were selected from the clinical database and series of baseline and postoperative follow-up radiographs were obtained after 24 and 48 weeks. Relative bone densities were measured per Gruen zones G1-7 with the use of an open-source image analysis package (ImageJ) by means of greyscale histograms. In addition, subjective evaluation of selected cases was performed by three independent, blinded orthopedic surgeons. Besides descriptive and nonparametric analyses, intra-class correlation (ICC) was performed and objective and subjective results were compared by linear regression analysis. RESULTS: Two individual cases are presented as a proof-of-principle. Increase or decrease of bone density could be measured correctly over time in each case. In a collective analysis there were no significant differences in mean relative bone densities between groups after 24 and 48 weeks, although a positive tendency was visible towards increased bone formation over time. Individual analyses by Gruen zones revealed that some zones, namely the proximal ones (e.g. G6), exhibit a broader scattering than others over time. This could be explained by the design of the evaluated tapered revision stem that achieves distal fixation and allows for proximal micromotion. Correlation analysis with subjective ratings (inter-rater reliability ICC = 0.71) showed a positive correlation with objective results, suggesting a feasibility of the method for clinical use. CONCLUSIONS: In conclusion the presented method is an easy and accessible tool to quantify relative bone density changes during THA follow-up. It shows a positive correlation to established subjective assessment of bone remodelling and may therefore serve as a quantitative supplement in clinical documentation. PMID- 30452432 TI - Expert knowledge-infused deep learning for automatic lung nodule detection. AB - BACKGROUND: Computer aided detection (CADe) of pulmonary nodules from computed tomography (CT) is crucial for early diagnosis of lung cancer. Self-learned features obtained by training datasets via deep learning have facilitated CADe of the nodules. However, the complexity of CT lung images renders a challenge of extracting effective features by self-learning only. This condition is exacerbated for limited size of datasets. On the other hand, the engineered features have been widely studied. OBJECTIVE: We proposed a novel nodule CADe which aims to relieve the challenge by the use of available engineered features to prevent convolution neural networks (CNN) from overfitting under dataset limitation and reduce the running-time complexity of self-learning. METHODS: The CADe methodology infuses adequately the engineered features, particularly texture features, into the deep learning process. RESULTS: The methodology was validated on 208 patients with at least one juxta-pleural nodule from the public LIDC-IDRI database. Results demonstrated that the methodology achieves a sensitivity of 88% with 1.9 false positives per scan and a sensitivity of 94.01% with 4.01 false positives per scan. CONCLUSIONS: The methodology shows high performance compared with the state-of-the-art results, in terms of accuracy and efficiency, from both existing CNN-based approaches and engineered feature-based classifications. PMID- 30452433 TI - Systematic Review and Meta-Analysis of Diagnostic Accuracy of Endoscopic Ultrasound (EUS)-Guided Fine-Needle Aspiration (FNA) Using 22-gauge and 25-gauge Needles for Pancreatic Masses. AB - BACKGROUND Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been used for detecting pancreatic cancer. We aimed to compare the diagnostic yield of both 22-gauge and 25-gauge EUS-FNA for the detection of pancreatic cancer. MATERIAL AND METHODS We searched the electronic databases including PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library up to June 13, 2017. Two reviewers independently screened studies and extracted data. RESULTS We analyzed data from 1824 patients from 16 included studies. The estimated pooled data for the 22-gauge needles reported sensitivity was 0.89 (0.83-0.93), specificity was 1.00 (0.74-1.00), positive LR was 485.28 (2.55-92 000) and negative LR was 0.11 (0.07-0.17). Results for the 25-gauge needles showed the pooled sensitivity, specificity, positive and negative LR was 0.90 (0.86-0.93), 0.99 (0.89-1.00), 59.53 (7.99-443.66), and 0.10 (0.07-0.14), respectively. The 25-gauge needle had significantly higher pooled sensitivity than the 22-gauge needle (0.90 vs. 0.87, chi2=5.26, P=0.02) while there was no difference in the pooled specificity (0.96 vs. 0.98, chi2=2.12, P=0.15). The quality of most studies was assessed favorable using QUADAS-2 (quality assessment of diagnostic accuracy studies-2). CONCLUSIONS Our findings revealed that the 25-gauge EUS-FNA used for pancreatic lesions could have a higher diagnostic yield than using 22-gauge EUS-FNA. Nevertheless, well designed prospective studies recruiting more patients are needed. PMID- 30452434 TI - Rosetta FunFolDes - A general framework for the computational design of functional proteins. AB - The robust computational design of functional proteins has the potential to deeply impact translational research and broaden our understanding of the determinants of protein function and stability. The low success rates of computational design protocols and the extensive in vitro optimization often required, highlight the challenge of designing proteins that perform essential biochemical functions, such as binding or catalysis. One of the most simplistic approaches for the design of function is to adopt functional motifs in naturally occurring proteins and transplant them to computationally designed proteins. The structural complexity of the functional motif largely determines how readily one can find host protein structures that are "designable", meaning that are likely to present the functional motif in the desired conformation. One promising route to enhance the "designability" of protein structures is to allow backbone flexibility. Here, we present a computational approach that couples conformational folding with sequence design to embed functional motifs into heterologous proteins-Rosetta Functional Folding and Design (FunFolDes). We performed extensive computational benchmarks, where we observed that the enforcement of functional requirements resulted in designs distant from the global energetic minimum of the protein. An observation consistent with several experimental studies that have revealed function-stability tradeoffs. To test the design capabilities of FunFolDes we transplanted two viral epitopes into distant structural templates including one de novo "functionless" fold, which represent two typical challenges where the designability problem arises. The designed proteins were experimentally characterized showing high binding affinities to monoclonal antibodies, making them valuable candidates for vaccine design endeavors. Overall, we present an accessible strategy to repurpose old protein folds for new functions. This may lead to important improvements on the computational design of proteins, with structurally complex functional sites, that can perform elaborate biochemical functions related to binding and catalysis. PMID- 30452436 TI - CYP-mediated permethrin resistance in Aedes aegypti and evidence for trans regulation. AB - Aedes aegypti poses a serious risk to human health due to its wide global distribution, high vector competence for several arboviruses, frequent human biting, and ability to thrive in urban environments. Pyrethroid insecticides remain the primary means of controlling adult A. aegypti populations during disease outbreaks. As a result of decades of use, pyrethroid resistance is a global problem. Cytochrome P450 monooxygenase (CYP)-mediated detoxification is one of the primary mechanisms of pyrethroid resistance. However, the specific CYP(s) responsible for resistance have not been unequivocally determined. We introgressed the resistance alleles from the resistant A. aegypti strain, Singapore (SP), into the genetic background of the susceptible ROCK strain. The resulting strain (CKR) was congenic to ROCK. Our primary goal was to determine which CYPs in SP are linked to resistance. To do this, we first determined which CYPs overexpressed in SP are also overexpressed in CKR, with the assumption that only the CYPs linked to resistance will be overexpressed in CKR relative to ROCK. Next, we determined whether any of the overexpressed CYPs were genetically linked to resistance (cis-regulated) or not (trans-regulated). We found that CYP6BB2, CYP6Z8, CYP9M5 and CYP9M6 were overexpressed in SP as well as in CKR. Based on the genomic sequences and polymorphisms of five single copy CYPs (CYP4C50, 6BB2, 6F2, 6F3 and 6Z8) in each strain, none of these genes were linked to resistance, except for CYP6BB2, which was partially linked to the resistance locus. Hence, overexpression of these four CYPs is due to a trans-regulatory factor(s). Knowledge on the specific CYPs and their regulators involved in resistance is critical for resistance management strategies because it aids in the development of new control chemicals, provides information on potential environmental modulators of resistance, and allows for the detection of resistance markers before resistance becomes fixed in the population. PMID- 30452435 TI - Spread of GES-5 carbapenemase-producing Pseudomonas aeruginosa clinical isolates in Japan due to clonal expansion of ST235. AB - The first outbreak in Japan of GES-5 carbapenemase-producing Pseudomonas aeruginosa occurred in a long-term care facility in 2014. To assess the spread of GES-5 producing P. aeruginosa clinical isolates in medical settings in Japan, 1,476 carbapenem-resistant P. aeruginosa isolates obtained from 2012 to 2016 were characterized. Of these 1,476 isolates, 104 (7.0%) harbored blaGES-5. Southern blotting revealed that the blaGES-5 was located on the chromosome. The isolation rates of these GES-5 producers increased significantly every year, from 2.0% (6 of 295) in 2012 to 2.8% (8 of 283) in 2013 to 5.3% (16 of 303) in 2014 to 9.7% (29 of 300) in 2015 to 15.3% (45 of 295) in 2016. Of the 104 GES-5 producers, 102 belonged to clonal complex (CC) 235, including 99 belonging to ST235 and three belonging to ST2233). Whole genome sequence analysis revealed that CC235 P. aeruginosa harboring blaGES-5 spread in a clonal manner. These results indicate that these GES-5 producing CC235 P. aeruginosa clinical isolates have spread in medical settings throughout Japan. PMID- 30452437 TI - Klf5 suppresses ERK signaling in mouse pluripotent stem cells. AB - Mouse embryonic stem cells (ESCs) are pluripotent stem cells, which have the ability to differentiate into all three germ layers: mesoderm, endoderm, and ectoderm. Proper levels of phosphorylated extracellular signal-regulated kinase (pERK) are critical for maintaining pluripotency, as elevated pERK evoked by fibroblast growth factor (FGF) receptor activation results in differentiation of ESCs, while, conversely, reduction of pERK by a MEK inhibitor maintains a pluripotent ground state. However, mechanisms underlying proper control of pERK levels in mouse ESCs are not fully understood. Here, we find that Klf5, a Kruppel like transcription factor family member, is a component of pERK regulation in mouse ESCs. We show that ERK signaling is overactivated in Klf5-KO ESCs and the overactivated ERK in Klf5-KO ESCs is suppressed by the introduction of Klf5, but not Klf2 or Klf4, indicating a unique role for Klf5 in ERK suppression. Moreover, Klf5 regulates Spred1, a negative regulator of the FGF-ERK pathway. Klf5 also facilitates reprogramming of EpiSCs into a naive state in combination with a glycogen synthase kinase 3 inhibitor and LIF, and in place of a MEK inhibitor. Taken together, these results show for the first time that Klf5 has a unique role suppressing ERK activity in mouse ESCs. PMID- 30452438 TI - Co-expression of IL-15 enhances anti-neuroblastoma effectivity of a tyrosine hydroxylase-directed DNA vaccination in mice. AB - Long-term survival of high-risk neuroblastoma (NB) patients still remains under 50%. Here, we report the generation, in vitro characterization and anti-tumor effectivity of a new bicistronic xenogenic DNA vaccine encoding tyrosine hydroxylase (TH) that is highly expressed in NB tumors, and the immune stimulating cytokine interleukin 15 (IL-15) that induces cytotoxic but not regulatory T cells. The DNA sequences of TH linked to ubiquitin and of IL-15 were integrated into the bicistronic expression vector pIRES. Successful production and bioactivity of the vaccine-derived IL-15- and TH protein were shown by ELISA, bioactivity assay and western blot analysis. Further, DNA vaccine-driven gene transfer to the antigen presenting cells of Peyer's patches using attenuated Salmonella typhimurium that served as oral delivery system was shown by immunofluorescence analysis. The anti-tumor effect of the generated vaccine was evaluated in a syngeneic mouse model (A/J mice, n = 12) after immunization with S. typhimurium (3* prior and 3* after tumor implantation). Importantly, TH-/IL-15 based DNA vaccination resulted in an enhanced tumor remission in 45.5% of mice compared to controls (TH (16.7%), IL-15 (0%)) and reduced spontaneous metastasis (30.0%) compared to controls (TH (63.6%), IL-15 (70.0%)). Interestingly, similar levels of tumor infiltrating CD8+ T cells were observed among all experimental groups. Finally, co-expression of IL-15 did not result in elevated regulatory T cell levels in tumor environment measured by flow cytometry. In conclusion, co expression of the stimulatory cytokine IL-15 enhanced the NB-specific anti-tumor effectivity of a TH-directed vaccination in mice and may provide a novel immunological approach for NB patients. PMID- 30452439 TI - Antivirus effectiveness of ivermectin on dengue virus type 2 in Aedes albopictus. AB - BACKGROUND: Dengue fever is the most rapidly spreading mosquito-borne viral disease over the past 50 years, with a 30-fold increase in global incidence. Dengue vector control is a key component for the dengue control strategy, since no absolutely effective vaccine or drug is available yet. However, the rapid rise and spread of mosquito insecticide resistance have become major threats to the efficiency of insecticide-based vector control activities. Thus, innovative vector control tools are badly needed. This study aims to confirm the antivirus effectiveness of ivermectin on dengue virus type 2 (DENV-2) in Aedes albopictus (Skuse, 1894), then to explore its potential use in the combating to the dengue epidemics. METHODS: Aedes albopictus were first infected with DENV-2 in human whole blood, and at the fourth day after infectious blood feeding, they were divided into eight groups. Seven of them were held for six days with access to 0, 2, 4, 8, 16, 32 and 64 ng/ml ivermectin, respectively, and the last one was set as a historical control group, which was stored at -80 degrees C until being detected at the same time with the other groups. Each mosquito was detected using real-time fluorescent RT-PCR kit. DENV-2 RNA concentration (copies/ml) and infection rate in each group were compared. RESULTS: Both of quantitatively and qualitatively inhibiting effects of ivermectin have been detected in this study. Generally, DENV-2 replicated well in Aedes albopictus without ivermectin intervention, whose virus loads exhibited significantly higher when the mosquitoes were holding from 4 days to 10 days after infectious blood feeding. In contrast, with the treatment of ivermectin, the infection rate was reduced by as much as 49.63%. The regression equation between infection rates (Y2) and ivermectin concentration log2 values (X2) was obtained as Y2 = 91.41-7.21*X2 with R2 = 0.89. CONCLUSION: Ivermectin can directly or indirectly inhibit DENV-2 multiplication in Aedes albopictus. Moreover, the actual concentration for application in zooprophylaxis needs to be confirmed in the further field trials. PMID- 30452440 TI - Simulations of blood as a suspension predicts a depth dependent hematocrit in the circulation throughout the cerebral cortex. AB - Recent advances in modeling oxygen supply to cortical brain tissue have begun to elucidate the functional mechanisms of neurovascular coupling. While the principal mechanisms of blood flow regulation after neuronal firing are generally known, mechanistic hemodynamic simulations cannot yet pinpoint the exact spatial and temporal coordination between the network of arteries, arterioles, capillaries and veins for the entire brain. Because of the potential significance of blood flow and oxygen supply simulations for illuminating spatiotemporal regulation inside the cortical microanatomy, there is a need to create mathematical models of the entire cerebral circulation with realistic anatomical detail. Our hypothesis is that an anatomically accurate reconstruction of the cerebrocirculatory architecture will inform about possible regulatory mechanisms of the neurovascular interface. In this article, we introduce large-scale networks of the murine cerebral circulation spanning the Circle of Willis, main cerebral arteries connected to the pial network down to the microcirculation in the capillary bed. Several multiscale models were generated from state-of-the-art neuroimaging data. Using a vascular network construction algorithm, the entire circulation of the middle cerebral artery was synthesized. Blood flow simulations indicate a consistent trend of higher hematocrit in deeper cortical layers, while surface layers with shorter vascular path lengths seem to carry comparatively lower red blood cell (RBC) concentrations. Moreover, the variability of RBC flux decreases with cortical depth. These results support the notion that plasma skimming serves a self-regulating function for maintaining uniform oxygen perfusion to neurons irrespective of their location in the blood supply hierarchy. Our computations also demonstrate the practicality of simulating blood flow for large portions of the mouse brain with existing computer resources. The efficient simulation of blood flow throughout the entire middle cerebral artery (MCA) territory is a promising milestone towards the final aim of predicting blood flow patterns for the entire brain. PMID- 30452441 TI - Prediction of stillbirth in women with overweight or obesity-A register-based cohort study. AB - OBJECTIVE: To develop a model for prediction of stillbirth after the 28th gestational week in singleton pregnancies of women with overweight or obesity. METHOD: This is a register-based cohort study. The first trimester screening database including data from 2006 until 2015 was cross-linked with the Swedish Medical Birth Register and the Swedish Register of Total Population. The final study cohort comprised 145,319 pregnancies, out of which 45,859 pregnancies were complicated by overweight or obesity and without pre-gestational diabetes. There were in total 282 stillbirths. Prediction models for stillbirth in pregnancies with overweight or obesity were constructed based on maternal characteristics, pregnancy complications and biochemical markers. Receiver Operating Characteristic (ROC) and area under curve (AUC) were calculated, based on logistic regression analyses. RESULTS: The prevalence of stillbirth was 1.6/1000 births and 2.6/1000 births in normal weight and overweight/obese women, respectively. The final predictive model had an AUC of 0.69 (95% CI: 0.64-0.74) with a sensitivity of 28% at a 90% fixed specificity. CONCLUSIONS: It is possible to predict 28% of stillbirths in overweight or obese women, at a false positive rate of 10%. In particular, growth-restricted fetuses are at increased risk of stillbirth. PMID- 30452442 TI - Recruitment of the motor system during music listening: An ALE meta-analysis of fMRI data. AB - Several neuroimaging studies have shown that listening to music activates brain regions that reside in the motor system, even when there is no overt movement. However, many of these studies report the activation of varying motor system areas that include the primary motor cortex, supplementary motor area, dorsal and ventral pre-motor areas and parietal regions. In order to examine what specific roles are played by various motor regions during music perception, we used activation likelihood estimation (ALE) to conduct a meta-analysis of neuroimaging literature on passive music listening. After extensive search of the literature, 42 studies were analyzed resulting in a total of 386 unique subjects contributing 694 activation foci in total. As suspected, auditory activations were found in the bilateral superior temporal gyrus, transverse temporal gyrus, insula, pyramis, bilateral precentral gyrus, and bilateral medial frontal gyrus. We also saw the widespread activation of motor networks including left and right lateral premotor cortex, right primary motor cortex, and the left cerebellum. These results suggest a central role of the motor system in music and rhythm perception. We discuss these findings in the context of the Action Simulation for Auditory Prediction (ASAP) model and other predictive coding accounts of brain function. PMID- 30452443 TI - Vertical transmission of naturally occurring Bunyamwera and insect-specific flavivirus infections in mosquitoes from islands and mainland shores of Lakes Victoria and Baringo in Kenya. AB - BACKGROUND: Many arboviruses transmitted by mosquitoes have been implicated as causative agents of both human and animal illnesses in East Africa. Although epidemics of arboviral emerging infectious diseases have risen in frequency in recent years, the extent to which mosquitoes maintain pathogens in circulation during inter-epidemic periods is still poorly understood. This study aimed to investigate whether arboviruses may be maintained by vertical transmission via immature life stages of different mosquito vector species. METHODOLOGY: We collected immature mosquitoes (egg, larva, pupa) on the shores and islands of Lake Baringo and Lake Victoria in western Kenya and reared them to adults. Mosquito pools (<=25 specimens/pool) of each species were screened for mosquito borne viruses by high-resolution melting analysis and sequencing of multiplex PCR products of genus-specific primers (alphaviruses, flaviviruses, phleboviruses and Bunyamwera-group orthobunyaviruses). We further confirmed positive samples by culturing in baby hamster kidney and Aedes mosquito cell lines and re-sequencing. PRINCIPAL FINDINGS: Culex univittatus (2/31pools) and Anopheles gambiae (1/77 pools) from the Lake Victoria region were positive for Bunyamwera virus, a pathogenic virus that is of public health concern. In addition, Aedes aegypti (3/50), Aedes luteocephalus (3/13), Aedes spp. (2/15), and Culex pipiens (1/140) pools were positive for Aedes flaviviruses at Lake Victoria, whereas at Lake Baringo, three pools of An. gambiae mosquitoes were positive for Anopheles flavivirus. These insect-specific flaviviruses (ISFVs), which are presumably non pathogenic to vertebrates, were found in known medically important arbovirus and malaria vectors. CONCLUSIONS: Our results suggest that not only ISFVs, but also a pathogenic arbovirus, are naturally maintained within mosquito populations by vertical transmission, even in the absence of vertebrate hosts. Therefore, virus and vector surveillance, even during inter-epidemics, and the study of vector arbovirus-ISFV interactions, may aid in identifying arbovirus transmission risks, with the potential to inform control strategies that lead to disease prevention. PMID- 30452444 TI - Antenatal care in rural Bangladesh: Gaps in adequate coverage and content. AB - INTRODUCTION: Antenatal care (ANC) has long been considered a critical component of the continuum of care during pregnancy, with the potential to contribute to the survival and thriving of women and newborns. Although ANC utilization has increased in over the past decades, adequate coverage and content of ANC contacts have fallen under increased scrutiny. The objectives of this article are to describe the coverage and content of ANC contacts in the context of rural Bangladesh. METHODS: A community-based, cross-sectional household survey was conducted in two sub-districts of Netrokona district, Bangladesh in 2016. A total of 737 women with a recent birth outcome were interviewed. Respondents reported on the ANC contacts and the content of these contacts. Descriptive statistics were used to report coverage and content of ANC contacts stratified by covariates. Chi-square tests were performed to explore whether the estimates are different among different categories and significant differences were reported at p<0.05. RESULTS: Around 25% of women attended at least four ANC contacts, with only 11% initiating ANC in the first trimester of pregnancy. Blood pressure was measured in almost all of the ANC contacts (92%), and abdominal examination performed in 80% and weight measured in 85% of ANC contacts. Urine tests were conducted in less than half of the ANC contacts, whereas blood screening tests and ultrasound were conducted in 45% contacts. Health care providers counselled women on danger signs in only 66% of the ANC contacts. Overall, the content of facility-based ANC contacts were better than home-based ANC contacts across all components. CONCLUSIONS: Adequate coverage of ANC remains poor in Netrokona, Bangladesh and important gaps remain in the content of ANC contacts when women attend these services. PMID- 30452445 TI - Modelling the cost-effectiveness of a rapid diagnostic test (IgMFA) for uncomplicated typhoid fever in Cambodia. AB - Typhoid fever is a common cause of fever in Cambodian children but diagnosis and treatment are usually presumptive owing to the lack of quick and accurate tests at an initial consultation. This study aimed to evaluate the cost-effectiveness of using a rapid diagnostic test (RDT) for typhoid fever diagnosis, an immunoglobulin M lateral flow assay (IgMFA), in a remote health centre setting in Cambodia from a healthcare provider perspective. A cost-effectiveness analysis (CEA) with decision analytic modelling was conducted. We constructed a decision tree model comparing the IgMFA versus clinical diagnosis in a hypothetical cohort with 1000 children in each arm. The costs included direct medical costs only. The eligibility was children (<=14 years old) with fever. Time horizon was day seven from the initial consultation. The number of treatment success in typhoid fever cases was the primary health outcome. The number of correctly diagnosed typhoid fever cases (true-positives) was the intermediate health outcome. We obtained the incremental cost effectiveness ratio (ICER), expressed as the difference in costs divided by the difference in the number of treatment success between the two arms. Sensitivity analyses were conducted. The IgMFA detected 5.87 more true positives than the clinical diagnosis (38.45 versus 32.59) per 1000 children and there were 3.61 more treatment successes (46.78 versus 43.17). The incremental cost of the IgMFA was estimated at $5700; therefore, the ICER to have one additional treatment success was estimated to be $1579. The key drivers for the ICER were the relative sensitivity of IgMFA versus clinical diagnosis, the cost of IgMFA, and the prevalence of typhoid fever or multi-drug resistant strains. The IgMFA was more costly but more effective than the clinical diagnosis in the base-case analysis. An IgMFA could be more cost-effective than the base-case if the sensitivity of IgMFA was higher or cost lower. Decision makers may use a willingness-to-pay threshold that considers the additional cost of hospitalisation for treatment failures. PMID- 30452446 TI - A geographical location prediction method based on continuous time series Markov model. AB - Trajectory data uploaded by mobile devices is growing quickly. It represents the movement of an individual or a device based on the longitude and latitude coordinates collected by GPS. The location based service has a broad application prospect in the real world. As the traditional location prediction models which are based on the discrete state sequence cannot predict the locations in real time, we propose a Continuous Time Series Markov Model (CTS-MM) to solve this problem. The method takes the Gaussian Mixed Model (GMM) to simulate the posterior probability of a location in the continuous time series. The probability calculation method and state transition model of the Hidden Markov Model (HMM) are improved to get the precise location prediction. The experimental results on GeoLife data show that CTS-MM performs better for location prediction in exact minute than traditional location prediction models. PMID- 30452447 TI - Flow cytometric analysis of lymphocyte profiles in mediastinal lymphadenopathy of sarcoidosis. AB - Lymphocyte profiles in mediastinal lymph nodes may reflect the immune status of patients with sarcoidosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is useful for the diagnosis of diseases with mediastinal lymphadenopathy including sarcoidosis. The purpose of this study was to determine lymphocyte profiles of lymph nodes in sarcoidosis by analyzing EBUS-TBNA samples. We prepared single cell suspensions from EBUS-TBNA samples of mediastinal lymph nodes from patients with sarcoidosis or lung cancer and analyzed surface markers (CD3, CD4, CD8, CD19, CD25) and FoxP3 expression in the resultant lymphocytes using flow cytometry. We studied 26 patients with sarcoidosis and 16 with lung cancer with mediastinal lymph node metastases. In sarcoidosis, the CD4/CD8 ratio was significantly more elevated in lymph nodes than in bronchoalveolar lavage fluid (P<0.001), although both were strongly correlated. The CD4/CD8 ratio was significantly higher in stage I than in stage II both in the BAL fluid and lymph nodes. When compared with lung cancer lymph node metastasis, the CD4/CD8 ratio was significantly higher in sarcoidosis, whereas the CD3/CD19 ratio was significantly higher in lung cancer. The proportion of regulatory T cells (CD4+, CD25+, FoxP3 high) did not differ between sarcoidosis and lung cancer samples. Lymphocyte profiles in mediastinal lymphadenopathy can be analyzed by flow cytometry of EBUS-TBNA samples. These findings might help elucidate the immunopathology of sarcoidosis. PMID- 30452448 TI - Examining mineral-associated soil organic matter pools through depth in harvested forest soil profiles. AB - Mineral-associated organic matter is associated with a suite of soil minerals that can confer stability, resulting in the potential for long-term storage of carbon (C). Not all interactions impart the same level of protection, however; evidence is suggesting that C in certain mineral pools is dynamic and vulnerable to disturbance in the decades following harvesting. The objective of this research was to describe and characterize organic matter-mineral interactions through depth in horizons of soils of contrasting stand age. Sequential selective dissolutions representing increasingly stable mineral-associated organic matter pools from water soluble minerals (deionized water), organo-metal complexes (Na pyrophosphate), poorly-crystalline minerals (HCl hydroxylamine), and crystalline secondary minerals (Na-dithionite HCl)) were carried out for Ae, Bf and BC horizons sampled from a Young and Mature forest site (35 and 110 years post harvest) in Mooseland, Nova Scotia, Canada. Sequential selective dissolution extracts were analyzed for C, delta13C, iron (Fe) and aluminum (Al). Organo-metal complexes (OMC) were the largest mineral-associated OM pool in all horizons. This pool dominated the C distribution in B horizons (~60-70% of Bf bulk C), with a minor contribution from poorly-crystalline (PCrys), crystalline (Crys) minerals and water soluble (WS) associations. C in OMC and PCrys pools explained the variation in bulk C in horizons through depth at both sites. Twice as much C in OMC pools was measured at the Mature site compared to the Young site in the Bf horizons, supported by higher C:(Fe+Al) ratios. Isotopic analysis indicated that this extraction procedure isolated distinct mineral-associated OM pools. delta13C signatures of pyrophosphate-extracted OMC pools ranged from -270/00 to -280/00, similar to delta13C of bulk C and to plant-derived humic acids and associated biomass. The water soluble phase (mean delta13C = -29 0/00) was up to 2 0/00 more depleted, whereas the delta13C of Crys pools were more enriched in 13C (-130/00 to -16 0/00) compared to bulk soil. The results from this study suggest that association with minerals does not necessarily confer stability: organo-metal pools dominate in podzol horizons through depth, and contribute most to C storage, but are potentially susceptible to destabilization following the physical changes resulting from forest harvesting disturbance. PMID- 30452449 TI - Spen limits intestinal stem cell self-renewal. AB - Precise regulation of stem cell self-renewal and differentiation properties is essential for tissue homeostasis. Using the adult Drosophila intestine to study molecular mechanisms controlling stem cell properties, we identify the gene split ends (spen) in a genetic screen as a novel regulator of intestinal stem cell fate (ISC). Spen family genes encode conserved RNA recognition motif-containing proteins that are reported to have roles in RNA splicing and transcriptional regulation. We demonstrate that spen acts at multiple points in the ISC lineage with an ISC-intrinsic function in controlling early commitment events of the stem cells and functions in terminally differentiated cells to further limit the proliferation of ISCs. Using two-color cell sorting of stem cells and their daughters, we characterize spen-dependent changes in RNA abundance and exon usage and find potential key regulators downstream of spen. Our work identifies spen as an important regulator of adult stem cells in the Drosophila intestine, provides new insight to Spen-family protein functions, and may also shed light on Spen's mode of action in other developmental contexts. PMID- 30452450 TI - Genetic variants influence on the placenta regulatory landscape. AB - From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications. By producing and analyzing DNA sequence variation (n = 303), DNA methylation (n = 303) and mRNA expression data (n = 80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations. These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions. PMID- 30452452 TI - Genetic architecture and selective sweeps after polygenic adaptation to distant trait optima. AB - Understanding the genetic basis of phenotypic adaptation to changing environments is an essential goal of population and quantitative genetics. While technological advances now allow interrogation of genome-wide genotyping data in large panels, our understanding of the process of polygenic adaptation is still limited. To address this limitation, we use extensive forward-time simulation to explore the impacts of variation in demography, trait genetics, and selection on the rate and mode of adaptation and the resulting genetic architecture. We simulate a population adapting to an optimum shift, modeling sequence variation for 20 QTL for each of 12 different demographies for 100 different traits varying in the effect size distribution of new mutations, the strength of stabilizing selection, and the contribution of the genomic background. We then use random forest regression approaches to learn the relative importance of input parameters in determining a number of aspects of the process of adaptation, including the speed of adaptation, the relative frequency of hard sweeps and sweeps from standing variation, or the final genetic architecture of the trait. We find that selective sweeps occur even for traits under relatively weak selection and where the genetic background explains most of the variation. Though most sweeps occur from variation segregating in the ancestral population, new mutations can be important for traits under strong stabilizing selection that undergo a large optimum shift. We also show that population bottlenecks and expansion impact overall genetic variation as well as the relative importance of sweeps from standing variation and the speed with which adaptation can occur. We then compare our results to two traits under selection during maize domestication, showing that our simulations qualitatively recapitulate differences between them. Overall, our results underscore the complex population genetics of individual loci in even relatively simple quantitative trait models, but provide a glimpse into the factors that drive this complexity and the potential of these approaches for understanding polygenic adaptation. PMID- 30452451 TI - Selective inhibition of carbonic anhydrase IX over carbonic anhydrase XII in breast cancer cells using benzene sulfonamides: Disconnect between activity and growth inhibition. AB - Carbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Ki values for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation. PMID- 30452453 TI - Parameters associated with therapeutic response using peritoneal dialysis for therapy refractory heart failure and congestive right ventricular dysfunction. AB - BACKGROUND: In patients with refractory heart failure (HF) peritoneal dialysis (PD) is associated with improved functional status and decrease in hospitalization. However, previous studies did not focus on right ventricular dysfunction as an important pathophysiologic component of cardiorenal syndrome. METHODS: In a prospective cohort study PD was started in 40 patients with refractory right HF (with/without left HF). Refractoriness to conservative therapy was defined as persistent right heart congestion/ascites with intensified diuretic treatment and/or >=2 hospitalizations within 6 months because of cardiac decompensation despite optimal medical treatment, and/or acute renal failure during intensified conservative treatment of cardiac decompensations. RESULTS: Patient survival was 55.0% at 1 year, 35.0% at 2 years and 27.5% at 3 years. The number of hospitalization days declined after initiation of PD for both cardiac [13 (IQR 1-53) days before vs. 1 (IQR 0-12) days after start of PD, p<0.001] and unplanned reasons [12 (IQR 3-44) days before vs. 1 (IQR 0-33) days after start of PD, p = 0.007]. Using a combined endpoint including survival time of >=1 year and either improvement in quality of life or decline in hospitalizations we found that patients with extended ascites, higher systolic pulmonary artery pressure, more marked impairment of right ventricular function and tricuspid valve insufficiency, higher residual renal function as well as those who could perform PD without assistance have benefited most from this therapy. CONCLUSIONS: Patients with more pronounced backward failure, less marked residual renal functional impairment and those not depending on assistance for therapy are likely to profit most from PD. PMID- 30452454 TI - Community networks of services for pregnant and parenting women with problematic substance use. AB - Integrated treatment programs for pregnant and parenting women who use substances operate at the intersection of multiple service systems, including specialized substance use services, the broader health system, child protection, and social services. Our objectives were to describe the composition and structure of community care networks surrounding integrated treatment programs in selected communities in Ontario, Canada. We used a two-stage snowball method to collect network data from 5 purposively selected integrated treatment programs in communities in Ontario. Front-line staff with integrated treatment programs identified their top 5 service partners, who were then contacted and asked to provide the same information (n = 30). We used social network analysis to measure the cohesiveness, reciprocity, and betweenness centrality in the integrated treatment program's ego network. We described network composition in terms of representation of different service types. Across communities, common service partners were child protection, substance use or mental health services, parenting and child support, and other social services. Primary and pre-natal care, opioid agonist therapy, and legal services were rarely named as partners. Networks varied in network cohesiveness, as indicated by connectivity between the service partners and reciprocal ties to the integrated treatment programs. Integrated treatment programs commonly brokered the connections between other service partners. Findings suggest that these integrated treatment programs have achieved a level of success in developing cross-sectoral partnerships, with child protection services, parenting and child support, and social services featuring prominently in the networks. In contrast, there was a lack of close connections with physician-based services, highlighting a potential target for future quality improvement initiatives in this sector. PMID- 30452455 TI - A novel image encryption scheme based on quantum dynamical spinning and rotations. AB - Quantum information processing made a tremendous and remarkable impact on number of classical mechanic's problems. The impact does not only stop at classical mechanics but also the cyber security paradigm. Quantum information and cryptography are two classes of quantum information processing which use the idea of qubits instead of bits as in classical information security. The idea of fast computations with multiple complexity level is becoming more realistic in the age of quantum information due to quantum parallelism where a single quantum computer does allow to compute hundreds of classical computers with less efforts and more accuracy. The evolution of quantum information processing replaces a number of classical mechanic's aspects in computational and cyber security sciences. Our aim here is to introduce concepts of applied quantum dynamics in cryptography, which leads to an evolution of quantum cryptography. Quantum cryptography is one of the most astonishing solicitations of quantum information theory. To measure the quantum state of any system is not possible without disturbing that system. The facts of quantum mechanics on traditional cryptosystems lead to a new protocol and achieving maximum remarkable security for systems. The scope of this paper is to design an innovative encryption scheme for digital data based on quantum spinning and rotation operators. PMID- 30452456 TI - FOXO1 regulates uterine epithelial integrity and progesterone receptor expression critical for embryo implantation. AB - Successful embryo implantation requires a receptive endometrium. Poor uterine receptivity can account for implantation failure in women who experience recurrent pregnancy loss or multiple rounds of unsuccessful in vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivity in vivo. Uterine ablation of Foxo1 using the progesterone receptor Cre (PgrCre) mouse model resulted in infertility due to altered epithelial cell polarity and apoptosis, preventing the embryo from penetrating the luminal epithelium. Analysis of the uterine transcriptome after Foxo1 ablation identified alterations in gene expression for transcripts involved in the activation of cell invasion, molecular transport, apoptosis, beta-catenin (CTNNB1) signaling pathway, and an increase in PGR signaling. The increase of PGR signaling was due to PGR expression being retained in the uterine epithelium during the window of receptivity. Constitutive expression of epithelial PGR during this receptive period inhibited expression of FOXO1 in the nucleus of the uterine epithelium. The reciprocal expression of PGR and FOXO1 was conserved in human endometrial samples during the proliferative and secretory phase. This demonstrates that expression of FOXO1 and the loss of PGR during the window of receptivity are interrelated and critical for embryo implantation. PMID- 30452457 TI - Comparative organizational research starts with sound measurement: Validity and invariance of Turker's corporate social responsibility scale in five cross cultural samples. AB - As organizational research turned its focus to Corporate Social Responsibility (CSR), interest also grew in the individual's perspective on CSR. When looking for cross-cultural comparisons of the effects of CSR, measurement invariance is of utter importance as a questionnaire might not be equivalent in all investigated samples and thus bias results. We examined a previously published questionnaire assessing different aspects of personal CSR ratings. Factorial validity and measurement invariance was tested by means of confirmatory factor analysis and Bayesian structural equation modeling in five samples (total N = 1120): 2 US-American, 2 German, and 1 English-speaking Indian sample. In an exploratory-confirmatory approach, the originally proposed factor structure was altered to finally comprise four facets of CSR: employee-related CSR, environmental CSR, philanthropy and customer-related CSR. Measurement invariance tests showed evidence for small differences of the English and German version as well as significant divergences of the measurement model in the Indian sample. In conclusion, we show the validity of the questionnaire for a circumscribed Western context but are hesitant about further transfers. Future research on perception of CSR in non-western contexts might depend on new and tailored questionnaires. PMID- 30452458 TI - Deleterious mitochondrial DNA point mutations are overrepresented in Drosophila expressing a proofreading-defective DNA polymerase gamma. AB - Mitochondrial DNA (mtDNA) mutations cause severe maternally inherited syndromes and the accumulation of somatic mtDNA mutations is implicated in aging and common diseases. However, the mechanisms that influence the frequency and pathogenicity of mtDNA mutations are poorly understood. To address this matter, we created a Drosophila mtDNA mutator strain expressing a proofreading-deficient form of the mitochondrial DNA polymerase. Mutator flies have a dramatically increased somatic mtDNA mutation frequency that correlates with the dosage of the proofreading deficient polymerase. Mutator flies also exhibit mitochondrial dysfunction, shortened lifespan, a progressive locomotor deficit, and loss of dopaminergic neurons. Surprisingly, the frequency of nonsynonymous, pathogenic, and conserved site mutations in mutator flies exceeded predictions of a neutral mutational model, indicating the existence of a positive selection mechanism that favors deleterious mtDNA variants. We propose from these findings that deleterious mtDNA mutations are overrepresented because they selectively evade quality control surveillance or because they are amplified through compensatory mitochondrial biogenesis. PMID- 30452459 TI - Alkaline water improves exercise-induced metabolic acidosis and enhances anaerobic exercise performance in combat sport athletes. AB - Hydration is one of the most significant issues for combat sports as athletes often use water restriction for quick weight loss before competition. It appears that alkaline water can be an effective alternative to sodium bicarbonate in preventing the effects of exercise-induced metabolic acidosis. Therefore, the main aim of the present study was to investigate, in a double blind, placebo controlled randomized study, the impact of mineral-based highly alkaline water on acid-base balance, hydration status, and anaerobic capacity. Sixteen well trained combat sport athletes (n = 16), were randomly divided into two groups; the experimental group (EG; n = 8), which ingested highly alkaline water for three weeks, and the control group (CG; n = 8), which received regular table water. Anaerobic performance was evaluated by two double 30 s Wingate tests for lower and upper limbs, respectively, with a passive rest interval of 3 minutes between the bouts of exercise. Fingertip capillary blood samples for the assessment of lactate concentration were drawn at rest and during the 3rd min of recovery. In addition, acid-base equilibrium and electrolyte status were evaluated. Urine samples were evaluated for specific gravity and pH. The results indicate that drinking alkalized water enhances hydration, improves acid-base balance and anaerobic exercise performance. PMID- 30452460 TI - Evaluating gentrification's relation to neighborhood and city health. AB - Gentrification has been argued to contribute to urban inequalities, including those of health disparities. Extant research has yet to conduct a systematic study of gentrification's relation with neighborhood health outcomes nationally. This gap is addressed in the current study through the utilization of census tract data from the Center for Disease Control's 500 Cities project, the 2000 Census and the 2010-2014 American Community Survey to examine how gentrification relates to local self-rated physical health in select cities across the United States. We examine gentrification's association with neighborhood rates of poor self-rated physical health. We contextualize this relationship by evaluating gentrification's relation with city-level self-rated health inequalities. We find gentrification was significantly and positively related with self-rated physical neighborhood health outcomes. However, the presence and magnitude of gentrification within a city was not associated with health outcomes for cities overall. Based on these findings, we argue that gentrification's health benefits for cities are limited at best, though gentrification does not appear to be associated with deepening city-level health inequalities, either. PMID- 30452461 TI - Correction: Are two internal thoracic grafts better than one in patients with chronic obstructive lung disease? Analysis of 387 cases between 1996-2011. AB - [This corrects the article DOI: 10.1371/journal.pone.0201227.]. PMID- 30452462 TI - Enzymatic synthesis of alpha-flavone glucoside via regioselective transglucosylation by amylosucrase from Deinococcus geothermalis. AB - alpha-Flavone glycosides have beneficial properties for applications in the pharmaceutical, cosmetic, and food industries. However, their chemical syntheses are often limited by a low efficiency or scarcity of substrates. In this study, alpha-flavone glucosides were enzymatically synthesized by amylosucrase from Deinococcus geothermalis (DGAS) using sucrose and various flavones as a donor for glucosyl units and acceptors, respectively. Luteolin was the most effective acceptor in the transglucosylation reaction using DGAS among nine flavone materials (apigenin, chrysin, 6,7-dihydroxyflavone, homoorientin, 7 hydroxyflavone, isorhoifolin, luteolin, luteolin-3',7-diglucoside, and orientin). The highest production yield of luteolin glucoside was 86%, with a 7:1 molar ratio of donor to acceptor molecules, in 50 mM Tris-HCl buffer (pH 7) at 37 degrees C for 24 h using 2 U of DGAS. The synthesized luteolin glucoside was identified as luteolin-4'-O-alpha-D-glucopyranoside with a glucose molecule linked to the C-4' position on the B-ring of luteolin via an alpha-glucosidic bond, as determined by 1H and 13C nuclear magnetic resonance. This result clearly confirmed that the glucosylated luteolin was successfully synthesized by DGAS and it can be applied as a functional ingredient. Furthermore, this approach using DGAS has the potential to be utilized for the synthesis of various glucosylated products using different types of polyphenols to enhance their functionalities. PMID- 30452463 TI - RNA virus evasion of nonsense-mediated decay. AB - Nonsense-mediated decay (NMD) is a host RNA control pathway that removes aberrant transcripts with long 3' untranslated regions (UTRs) due to premature termination codons (PTCs) that arise through mutation or defective splicing. To maximize coding potential, RNA viruses often contain internally located stop codons that should also be prime targets for NMD. Using an agroinfiltration-based NMD assay in Nicotiana benthamiana, we identified two segments conferring NMD-resistance in the carmovirus Turnip crinkle virus (TCV) genome. The ribosome readthrough structure just downstream of the TCV p28 termination codon stabilized an NMD sensitive reporter as did a frameshifting element from umbravirus Pea enation mosaic virus. In addition, a 51-nt unstructured region (USR) at the beginning of the TCV 3' UTR increased NMD-resistance 3-fold when inserted into an unrelated NMD-sensitive 3' UTR. Several additional carmovirus 3' UTRs also conferred varying levels of NMD resistance depending on the construct despite no sequence similarity in the analogous region. Instead, these regions displayed a marked lack of RNA structure immediately following the NMD-targeted stop codon. NMD resistance was only slightly reduced by conversion of 19 pyrimidines in the USR to purines, but resistance was abolished when a 2-nt mutation was introduced downstream of the USR that substantially increased the secondary structure in the USR through formation of a stable hairpin. The same 2-nt mutation also enhanced the NMD susceptibility of a subgenomic RNA expressed independently of the genomic RNA. The conserved lack of RNA structure among most carmoviruses at the 5' end of their 3' UTR could serve to enhance subgenomic RNA stability, which would increase expression of the encoded capsid protein that also functions as the RNA silencing suppressor. These results demonstrate that the TCV genome has features that are inherently NMD-resistant and these strategies could be widespread among RNA viruses and NMD-resistant host mRNAs with long 3' UTRs. PMID- 30452464 TI - Community dynamics can modify the direction of simulated warming effects on crop yield. AB - Climate change affects agriculture through a range of direct and indirect pathways. These include direct changes to impacts of pests and diseases on crops and indirect effects produced by interactions between organisms. It remains unclear whether the net effects of these biotic influences will be beneficial or detrimental to crop yield because few studies consider multiple interactions within communities and the net effects of these on community structure and yield. In this study, we created two experimental grapevine communities in field cages, and quantified direct and indirect effects of key pest and disease species under simulated climate change conditions (elevated temperature and reduced humidity). We found that the net impact of simulated climate change on total yield differed for the two communities, with increased yield in one community and no effect in the other. These effects, and the interactions between pests and pathogens, may also have been affected by the prevailing abiotic conditions, and we discuss how these may contribute to our findings. These results demonstrate that future research should consider more of the interactions between key organisms affecting crops under varying abiotic conditions to help generate future recommendations for adapting to the effects of climate change. PMID- 30452465 TI - Association between continuity of care and subsequent hospitalization and mortality in patients with mood disorders: Results from the Korea National Health Insurance cohort. AB - Concerns have been raised about the loss of treatment continuity in unipolar and bipolar depressive disorder patients as continuity of care (COC) may be associated with patient outcomes. This study aimed to examine the relationship between COC and subsequent hospitalization, all-cause mortality, and suicide mortality in individuals with unipolar and bipolar disorder. Data were from the National Health Insurance (NHI) cohort, 2002 to 2013. Study participants included individuals first diagnosed with unipolar depressive disorder or bipolar affective disorder. The independent variable was COC for the first year of outpatient visits after diagnosis, measured using the usual provider of care (UPC) index. The dependent variables were hospitalization in the year after COC measurement, all-cause mortality, and suicide mortality. Analysis was conducted using logistic regression and Cox proportional hazards survival regression. A total of 48,558 individuals were analyzed for hospitalization and 48,947 for all cause and suicide mortality. Compared to the low COC group, the medium [odds ratio (OR) 0.30, 95 percent confidence interval (95% CI) 0.19-0.47] and the high COC group (OR 0.14, 95% CI 0.09-0.21) showed statistically significant decreased odds of hospitalization. Additionally, lower likelihoods of suicide death were found in the high (HR 0.35, 95% CI 0.16-0.74) compared to the low COC group. The results infer an association between COC after first diagnosis of unipolar or bipolar depressive disorder and hospitalization and suicide mortality, suggesting the potential importance of treatment continuity in improving patient outcomes. PMID- 30452466 TI - Characterization of ADME genes variation in Roma and 20 populations worldwide. AB - The products of the polymorphic ADME genes are involved in Absorption, Distribution, Metabolism, and Excretion of drugs. The pharmacogenetic data have been studied extensively due to their clinical importance in the appropriate drug prescription, but such data from the isolated populations are rather scarce. We analyzed the distribution of 95 polymorphisms in 31 core ADME genes in 20 populations worldwide and in newly genotyped samples from the Roma (Gypsy) population living in Croatia. Global distribution of ADME core gene loci differentiated three major clusters; (1) African, (2) East Asian, and (3) joint European, South Asian and South American cluster. The SLCO1B3 (rs4149117) and CYP3A4 (rs2242480) genes differentiated at the highest level the African group of populations, while NAT2 gene loci (rs1208, rs1801280, and rs1799929) and VKORC1 (rs9923231) differentiated East Asian populations. The VKORC1 rs9923231 was among the investigated loci the one with the largest global minor allele frequency (MAF) range; its MAF ranged from 0.027 in Nigeria to 0.924 in Han Chinese. The distribution of the investigated gene loci positions Roma population within the joined European and South Asian clusters, suggesting that their ADME gene pool is a combination of ancestral (Indian) and more recent (European) surrounding, as it was already implied by other genetic markers. However, when compared to the populations worldwide, the Croatian Roma have extreme MAF values in 10 out of the 95 investigated ADME core gene loci. Among loci which have extraordinary MAFs in Roma population two have strong proof of clinical importance: rs1799853 (CYP2C9) for warfarin dosage, and rs12248560 (CYP2C19) for clopidogrel dosage, efficacy and toxicity. This finding confirms the importance of taking the Roma as well as the other isolated populations'genetic profiles into account in pharmaco therapeutic practice. PMID- 30452467 TI - Efficient and reproducible experimental infections of rats with Blastocystis spp. AB - Although Blastocystis spp. infect probably more than 1 billion people worldwide, their clinical significance is still controversial and their pathophysiology remains poorly understood. In this study, we describe a protocol for an efficient and reproducible model of chronic infection in rats, laying the groundwork for future work to evaluate the pathogenic potential of this parasite. In our experimental conditions, we were unable to infect rats using vacuolar forms of an axenically cultivated ST4 isolate, but we successfully established chronic infections of 4 week-old rats after oral administration of both ST3 and ST4 purified cysts isolated from human stool samples. The infection protocol was also applied to 4 week-old C57BL/9, BALB/C and C3H mice, but any mouse was found to be infected by Blastocystis. Minimal cyst inoculum required for rat infection was higher with ST3 (105) than with ST4 (102). These results were confirmed by co housing experiments highlighting a higher contagious potential of ST4 in rats compared to ST3. Finally, experiments mimicking fecal microbiota transfer from infected to healthy animals showed that Blastocystis spp. could easily infect a new host, even though its intestinal microbiota is not disturbed. In conclusion, our results provide a well-documented and robust rat model of Blastocystis chronic infection, reproducing "natural" infection. This model will be of great interest to study host parasite interactions and to better evaluate clinical significance of Blastocystis. PMID- 30452468 TI - Salmonella escapes adaptive immune response via SIRT2 mediated modulation of innate immune response in dendritic cells. AB - Salmonella being a successful pathogen, employs a plethora of immune evasion mechanisms. This contributes to pathogenesis, persistence and also limits the efficacy of available treatment. All these contributing factors call upon for new drug targets against Salmonella. For the first time, we have demonstrated that Salmonella upregulates sirtuin 2 (SIRT2), an NAD+ dependent deacetylase in dendritic cells (DC). SIRT2 upregulation results in translocation of NFkappaB p65 to the nucleus. This further upregulates NOS2 transcription and nitric oxide (NO) production. NO subsequently shows antibacterial activity and suppresses T cell proliferation. NOS2 mediated effect of SIRT2 is further validated by the absence of effect of SIRT2 inhibition in NOS2-/- mice. Inhibition of SIRT2 increases intracellular survival of the pathogen and enhances antigen presentation in vitro. However, in vivo SIRT2 inhibition shows lower bacterial organ burden and reduced tissue damage. SIRT2 knockout mice also demonstrate reduced bacterial organ burden compared to wild-type mice. Collectively, our results prove the role of SIRT2 in Salmonella pathogenesis and the mechanism of action. This can aid in designing of host-targeted therapeutics directed towards inhibition of SIRT2. PMID- 30452469 TI - Fetal age assessment for Holstein cattle. AB - Although transport and slaughter of cattle during the last 10% of the gestation period is prohibited in the European Union, such cattle are sometimes sent for slaughter. The late term pregnancy is usually not recognized by the authorities until the uterus is inspected after slaughter and a near term fetus is observed. Accurate post mortem determination of age of bovine fetuses is therefore of major importance as evidence for the subsequent prosecution of the owner. Fetometric measurements such as crown-rump length (CRL) have been used, but these existing estimators have often been established based on insufficiently described study populations or phenotypes that may have changed in the past decades. Morphological characteristics are also used, but few data are available on the correlation between fetal age and the development of these characteristics. The objectives of this study were to investigate the correlation between fetal age and morphological features of bovine Holstein fetuses and to evaluate the use of these features alone and in combination with fetometric measurements to predict fetal age. We collected fetuses from 274 pregnant Holstein cows with recorded insemination dates slaughtered at a Danish abattoir. Gender, teeth development, occurrence of pigmentation, coat, tactile hair and other morphological features were recorded along with CRL, head width, head length and body weight (BW). The gestational length was calculated based on recorded insemination and slaughter dates, and coefficients of variation (R2) were determined for all recorded variables. Notably, the highest R2 was recorded for head length (0.985) followed by CRL (0.979) and head width (0.974). The categorical (morphological) variables were less informative. When used in multivariable models, they did offer statistically significance, but for practical purposes, limited additional information. A multivariable model including the fetometric variables head length and width in combination with CRL resulted in R2 = 0.99 with predictions that were roughly within +/- 11-12 days in 95% of cases. We conclude that the model based on the fetometric variables only provided the most precise predictions, while combination with morphological features such as eruption of teeth, pigmentation and coat mostly increased the width of the prediction intervals. PMID- 30452470 TI - Automated phenotyping for early vigour of field pea seedlings in controlled environment by colour imaging technology. AB - Early vigour of seedlings is a beneficial trait of field pea (Pisum sativum L.) that contributes to weed control, water use efficiency and is likely to contribute to yield under certain environments. Although breeding is considered the most effective approach to improve early vigour of field pea, the absence of a robust and high-throughput phenotyping tool to dissect this complex trait is currently a major obstacle of genetic improvement programs to address this issue. To develop this tool, separate trials on 44 genetically diverse field pea genotypes were conducted in the automated plant phenotyping platform of Plant Phenomics Victoria, Horsham and in the field, respectively. High correlation between estimated plant parameters derived from the automated phenotyping platform and important early vigour traits such as shoot biomass, leaf area and plant height indicated that the derived plant parameters can be used to predict vigour traits in field pea seedlings. Plant growth analysis demonstrated that the "broken-stick" model fitted well with the growth pattern of all field pea genotypes and can be used to determine the linear growth phase. Further analysis suggested that the estimated plant parameters collected at the linear growth phase can effectively differentiate early vigour across field pea genotypes. High correlation between normalised difference vegetation indices captured from the field trial and estimated shoot biomass and top-view area confirmed the consistent performance of early vigour field pea genotypes under controlled and field environments. Overall, our results demonstrated that this robust screening tool is highly applicable and will enable breeding programs to rapidly identify early vigour traits and utilise germplasm to contribute to the genetic improvement of field peas. PMID- 30452472 TI - The equivalence of measures on the Connectedness to Nature Scale: A comparison between ordinal methods of DIF detection. AB - The Connectedness to Nature Scale has been used in many different countries and settings. However, no one has yet tested the equivalence of these measures. Equivalence of measures has been the subject of much research in recent years, due to the importance of measuring in the same way when comparing between different groups. The present work studied the differential item functioning (DIF) of the CNS in a Spanish group and a North American group of respondents, using two different methods of detecting DIF. It also evaluated the overall equivalence of the scale. The results reveal differential functioning in most items, and only configural invariance is given. Thus, we suggest a reappraisal of the scale when comparing results from different countries since otherwise the conclusions drawn might be incorrect. PMID- 30452471 TI - Protective effects of a traditional herbal extract from Stellaria dichotoma var. lanceolata against Mycobacterium abscessus infections. AB - Stellaria dichotoma var. lanceolata (SdLv), a member of the Caryophyllaceae, is a traditional herbal medicine that has been used to treat fever, night sweats, and malaria in East Asia. Inflammation plays an essential role in both host defense and pathogenesis during infection by diverse intracellular pathogens. Herein, we showed that an herbal extract from SdLv effectively attenuated inflammatory responses from infection of Mycobacterium abscessus (Mab), but not Toxoplasma gondii (T. gondii). In primary murine macrophages, Mab infection resulted in the rapid activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK), as well as in the generation of proinflammatory cytokines, such as tumor necrosis factor alpha and interleukin-6, which were all significantly inhibited by pretreatment with SdLv. However, herbal extracts from Bupleurum chinense DC. (Buch) or Bupleurum falcatum L. (Bufa) did not affect M. abs-induced activation of proinflammatory responses. Importantly, we demonstrated that generation of intracellular reactive oxygen species, which are important signaling intermediaries in the activation of NF-kappaB and the MAPK signaling pathway, was rapidly increased in Mab-infected macrophages, and this was effectively suppressed by pretreatment with SdLv, but not Buch and Bufa. We further found that the treatment of Buch and Bufa, but not SdLv, led to the activation of NF-kappaB and the MAPK signaling pathway and the generation of intracellular reactive oxygen species. Moreover, oral administration of SdLv significantly reduced lethality in Mab-infected mice. Collectively, these results suggest the possible use of SdLv as an effective treatment for Mab infection. PMID- 30452473 TI - Features of interactions responsible for antifungal activity against resistant type cytochrome bc1: A data-driven analysis based on the binding free energy at the atomic level. AB - Quinone outside inhibitors (QoIs), which inhibit the mitochondrial respiratory system by binding to the Qo site of Complex III in fungi, are widely used as pesticides with broad spectrum antifungal activity. However, excessive use of QoIs leads to pesticide resistance through mutation of amino acid residues in the Qo site. Recently, metyltetraprole, a novel QoI that is effective against wild type and resistant mutant fungi, was developed. Interestingly, metyltetraprole has a very similar structure to other QoIs, azoxystrobin and pyraclostrobin, which do not act on resistant mutants. However, it is unknown how slight structural differences in these inhibitors alter their effectiveness towards fungi with amino acid mutations in the Qo site of Complex III. Therefore, we studied the features of interactions of inhibitors effective towards resistant mutants by quantitatively comparing the interaction profiles of three QoIs at the atomic level. First, we reproduced the binding affinity by the thermodynamic integration (TI) method, which treated explicitly environmental molecules and considered the pseudo-binding pathway. As such, a good correlation (R2 = 0.74) was observed between the binding free energy calculated using the TI method and experimentally observed pIC50 value in 12 inhibitor-target pairs, including wild type and mutant Complex III in two fungal species, Zymoseptoria tritici and Pyrenophora teres. Trajectory analysis of this TI calculation revealed that the effectiveness against resistant mutant fungi strongly depended on the interaction of constituent parts of the inhibitor disposed near the active center of the target protein. Specifically, the key in the effectiveness against resistant mutant fungi is that the corresponding component part, tetrazolinone moiety of metyltetraprole, traded off Coulomb and van der Waals interactions in response to subtle changes in the binding pose. PMID- 30452474 TI - Effect of dietary phosphorus intake and age on intestinal phosphorus absorption efficiency and phosphorus balance in male rats. AB - Intestinal phosphorus absorption is an important component of whole-body phosphorus metabolism, and limiting dietary phosphorus absorption is particularly of interest as a therapeutic target in patients with chronic kidney disease to manage mineral bone disorders. Yet, mechanisms and regulation of intestinal phosphorus absorption have not been adequately studied and discrepancies in findings exist based on the absorption assessment technique used. In vitro techniques show rather consistent effects of dietary phosphorus intake level and age on intestinal sodium-dependent phosphate transport. But, the few studies that have used in vivo techniques conflict with these in vitro studies. Therefore, we aimed to investigate the effects of dietary phosphorus intake level on phosphorus absorption using the in situ ligated loop technique in three different aged rats. Male Sprague-Dawley rats (n = 72), were studied at 10-, 20-, and 30-weeks-of-age on a low (0.1%), normal (0.6%), or high (1.2%) phosphorus diet in a 3x3 factorial design (n = 8/group). Rats were fed their assigned diet for 2-weeks prior to absorption testing by jejunal ligated loop as a non-survival procedure, utilizing 33P radioisotope. Metabolic cages were used for determination of calcium and phosphorus balance over the final four days prior to sacrifice, and blood was collected at the time of sacrifice for biochemistries. Our results show that phosphorus absorption was higher in 10-week-old rats compared with 20- and 30 week-olds and this corresponded to higher gene expression of the major phosphate transporter, NaPi-2b, as well as higher whole-body phosphorus balance and net phosphorus absorption. Dietary phosphorus intake level did not affect jejunal phosphorus absorption or NaPi-2b gene expression. Our results contrast with studies utilizing in vitro techniques, but corroborate results of other rodent studies utilizing in situ or in vivo methods. Thus, there is need for additional studies that employ more physiological methods of phosphorus absorption assessment. PMID- 30452475 TI - Correction: The Allometry of Bee Proboscis Length and Its Uses in Ecology. AB - [This corrects the article DOI: 10.1371/journal.pone.0151482.]. PMID- 30452476 TI - Measuring executive dysfunction in Parkinson's disease: Reliability and validity of the Spanish version of Frontal Assessment Battery (FAB-E). AB - BACKGROUND: Deficits in executive functions (EFs) are frequently detected in patients with Parkinson's disease (PD). The Frontal Assessment Battery (FAB) is a screening test for assessing EFs although it has not been so far adapted and validated in Spain. We evaluated the reliability and validity of the Spanish version of the FAB (FAB-E) in PD patients. MATERIALS AND METHODS: Our study included 54 healthy subjects and 67 PD patients. Cognitive assessment of participants was conducted using the FAB-E, Mini-Mental State Examination (MMSE), Trail Making Test (TMT), Revised-Barcelona Test (RBT) and Executive Interview (EXIT-25). Internal consistency, intra- and test-retest reliabilities, concurrent and discriminant validity of the FAB-E were examined. To evaluate the influence of cognitive dysfunction in PD on the performance of the FAB-E, we also classified the PD patients into groups according to their cognitive status as measured by the MMSE using published criteria to identify cognitive deficits in PD. RESULTS: The FAB-E showed good internal consistency (alpha = 0.751). The intraclass correlation coefficients (ranging from 0.559 to 0.891) and Spearman correlations (from 0.494 to 0.864) of the FAB-E subtests indicated a good-strong reliability. The total and subtest scores generally showed a good concurrent validity, except for the prehension behaviour item of the FAB-E and the Interference and Go/no-go tasks of the EXIT-25 that presented low estimates. Excluding the prehension behaviour subtest, the performance of the FAB-E was higher in the control group than in PD patients. Cognitive dysfunction in PD patients also indicated significant poorer FAB-E scores excepting the motor and prehension behaviour subtests. Discriminant analysis determined a cut-off of 14.5 was optimal to differentiate healthy subjects from PD patients. Moreover, a cut off <12.5 allocated satisfactorily those PD patients with cognitive impairment (MMSE<26) and scores <11.5 classified suitably those PD patients with dementia (MMSE<24). CONCLUSION: The FAB-E is an accurate tool for evaluating EFs in patients with PD and can provide useful information for distinguishing PD patients with and without cognitive dysfunction at a bedside assessment. PMID- 30452477 TI - Radiation exposure dose and influencing factors during endoscopic retrograde cholangiopancreatography. AB - INTRODUCTION: Various endoscopic procedures under fluoroscopic guidance are being rapidly adopted, and radiation exposure is considered to be increasing. However, there is little concern about this issue in gastroenterology practice. This study aims to evaluate the actual radiation exposure dose (RD) during endoscopic retrograde cholangiopancreatography (ERCP) and the factors affecting the RD. METHODS: In this retrospective, single-center cohort study of 1157 consecutive patients who underwent ERCP between October 2012 and February 2017, we analyzed the influences of patient characteristics, procedure time (min), total fluoroscopy time (min), type of processing engine, experience of the endoscopist, and type of disease on the total RD (mGy). RESULTS: The median procedure times were 28 min for common bile duct stones (CBDS), 25 min for distal malignant biliary obstruction (MBO), and 30 min for proximal MBO. Similarly, the median fluoroscopy times were 10.3, 8.8, and 13.4 min, and the median RDs were 167, 123, and 242 mGy, respectively. Proximal MBO required significantly longer procedure time and fluoroscopy time and resulted in greater RD than distal MBO (P = 0.0006, <0.0001, <0.0001) and CBDS (P = 0.015, <0.0001, <0.0001). Multiple linear regression showed that distal MBO and a novel processing engine negatively correlate with RD (P = 0.04, <0.0001) and that proximal MBO positively correlates with RD (P = 0.0001). DISCUSSION: Procedure time and fluoroscopy time were significantly longer for proximal MBO than for CBDS and distal MBO. The type of disease and processing engine significantly influenced the RD during ERCP. PMID- 30452478 TI - Density Functional Theory based study on structural, vibrational and NMR properties of cis - trans fulleropyrrolidine mono-adducts. AB - Since the early nineties, countless publications have been devoted to the study of possible uses of [60] fullerene (C60) and its derivatives in the fields of materials and nano-biomedical sciences. However, in spite of the importance of conformers notably from the pharmacological point of view, the cis/trans isomerization of C60 mono-adducts has been rarely seldom investigated. Here we present the results of DFT calculations of the structural, vibrational and NMR properties of both cis and trans isomers of fulleropyrrolidine mono-adduct obtained by photo-addition of glycine methyl ester to C60. Taken together, our results have shown that the cis isomer is more stable than the trans one. For the cis conformation, the simulated vibrational spectrum shows a more intense peak at 1298 cm-1. While 13C spectra revealed no significant differences between the two isomers as compared to experimental results, the calculated 1H chemical shifts show a significant difference between the two conformers in both the gas phase and in solution. The trans isomer presents a proton at 5.86 ppm, which is more deshielded than the proton of the cis conformer (5.24 ppm). PMID- 30452479 TI - Ruminative minds, wandering minds: Effects of rumination and mind wandering on lexical associations, pitch imitation and eye behaviour. AB - This study demonstrates that rumination is reflected in two behavioural signals that both play an important role in face-to-face interactions and provides evidence for the negative impact of rumination on social cognition. Sixty-one students were randomly assigned either to a condition in which rumination was induced or to a control condition. Their task was to play a speech-based word association game with an Embodied Conversational Agent during which their word associations, pitch imitation and eye movements were measured. Two questionnaires assessed their ruminative tendencies and mind wandering thoughts, respectively. Rumination predicted differences in task-related mind wandering, polarity of lexical associations, pitch imitation, and blinks while mind wandering predicted differences in saccades. This outcome may show that rumination has a negative impact on certain aspects of social interactions. PMID- 30452480 TI - Problem-based learning for anesthesia resident operating room crisis management training. AB - BACKGROUND: Senior anesthesia residents must acquire competency in crisis management for operating room (OR) emergencies. We conducted problem based learning (PBL) OR emergency scenarios for anesthesia residents, focused on emergencies in 'Airway', 'Circulation', 'Central venous catheter', and 'Pain management complications'. Non-technical skills are an integral component of team based OR emergency management. METHODS: Prior to integrated OR emergency clinical and non-technical skills PBL training, participating 35 anesthesia residents completed two 5-point scale surveys regarding frequency of emergency experiences in the operating room, and self-confidence for anesthesia-related crisis management. Repeat administration of the self-confidence survey was completed immediately following PBL training. RESULTS: Post-PBL resident clinical management self- confidence improved (P<0.05) in all scenarios on Circulation, Central venous catheter, and Pain treatment related complication topics. Impossible intubation, impossible oxygenation, and awake intubation did not show significant difference following PBL. CONCLUSION: Our findings suggest that PBL for OR emergency management can improve resident self- confidence in anesthesia residents. PMID- 30452481 TI - Using machine learning to investigate self-medication purchasing in England via high street retailer loyalty card data. AB - The availability alongside growing awareness of medicine has led to increased self-treatment of minor ailments. Self-medication is where one 'self' diagnoses and prescribes over the counter medicines for treatment. The self-care movement has important policy implications, perceived to relieve the National Health Service (NHS) burden, increasing patient subsistence and freeing resources for more serious ailments. However, there has been little research exploring how self medication behaviours vary between population groups due to a lack of available data. The aim of our study is to evaluate how high street retailer loyalty card data can help inform our understanding of how individuals self-medicate in England. Transaction level loyalty card data was acquired from a national high street retailer for England for 2012-2014. We calculated the proportion of loyalty card customers (n ~ 10 million) within Lower Super Output Areas who purchased the following medicines: 'coughs and colds', 'Hayfever', 'pain relief' and 'sun preps'. Machine learning was used to explore how 50 sociodemographic and health accessibility features were associated towards explaining purchasing of each product group. Random Forests are used as a baseline and Gradient Boosting as our final model. Our results showed that pain relief was the most common medicine purchased. There was little difference in purchasing behaviours by sex other than for sun preps. The gradient boosting models demonstrated that socioeconomic status of areas, as well as air pollution, were important predictors of each medicine. Our study adds to the self-medication literature through demonstrating the usefulness of loyalty card records for producing insights about how self-medication varies at the national level. Big data offer novel insights that add to and address issues that traditional studies are unable to consider. New forms of data through data linkage may offer opportunities to improve current public health decision making surrounding at risk population groups within self-medication behaviours. PMID- 30452482 TI - Farm-level and community aggregate economic impacts of adopting climate smart agricultural practices in three mega environments. AB - Recent studies highlight a growing concern over the limited adoption of climate smart agricultural (CSA) practices despite their potential benefits on adaptation, mitigation and productivity. Literature indicates several factors behind the lack of adoption including socio-demographic and economic conditions, agro-ecological scales and the nature of the practices. This paper examines to what extent and under which conditions such factors influence the adoption of CSA practices at farm, household and community level across three study sites in different continents: Vietnam, Nicaragua and Uganda. While cost benefit analysis (CBA) is employed to assess the farm-level profitability of CSA practices, the aggregate community impact disaggregated by different groups of farmer typologies with specific socio-economic features is derived from the adoption rate estimated by the relative advantage of practices and the income level of each group. Our main findings show great variation of farm-profitability of CSA practices across scales. Similar practices could generate different profitability depending on crop typologies, input access and prices, household types and local context. Regarding the aggregate profitability of CSA practices at regional scale, we found that under particular conditions, relevant factors of adoption matter to the adoption pattern and thereby affects the ranking. Such conditions include (i) high income inequality, (ii) large profitability gap of prioritized CSA practices, and (iii) large proportion of cost and benefit of the practices in the level of income. This study contributes to enhancing the prioritization process of CSA practices and provides practical guidance for research and policy to tailor the investment to appropriate end-users to assure the greatest impact for the community. PMID- 30452483 TI - Preoperative grading of intracranial meningioma by magnetic resonance spectroscopy (1H-MRS). AB - Although proton magnetic resonance spectroscopy (1H-MRS) is a common method for the evaluation of intracranial meningiomas, controversy exists regarding which parameter of 1H-MRS best predicts the histopathological grade of an intracranial meningioma. In this study, we evaluated the results of pre-operative 1H-MRS to identify predictive factors for high-grade intracranial meningioma. Thirteen patients with World Health Organization (WHO) grade II-III meningioma (confirmed by pathology) were defined as high-grade; twenty-two patients with WHO grade I meningioma were defined as low-grade. All patients were evaluated by 1H-MRS before surgery. The relationships between the ratios of metabolites (N acetylaspartate [NAA], creatine [Cr], and choline [Cho]) and the diagnosis of high-grade meningioma were analyzed. According to Mann-Whitney U test analysis, the Cho/NAA ratio in cases of high-grade meningioma was significantly higher than in cases of low-grade meningioma (6.34 +/- 7.90 vs. 1.58 +/- 0.77, p<0.05); however, there were no differences in age, Cho/Cr, or NAA/Cr. According to conditional inference tree analysis, the optimal cut-off point for the Cho/NAA ration between high-grade and low-grade meningioma was 2.409 (sensitivity = 61.54%; specificity = 86.36%). This analysis of pre-operative 1H-MRS metabolite ratio demonstrated that the Cho/NAA ratio may provide a simple and practical predictive value for high-grade intracranial meningiomas, and may aid neurosurgeons in efforts to design an appropriate surgical plan and treatment strategy before surgery. PMID- 30452484 TI - Macrophage activation by IFN-gamma triggers restriction of phagosomal copper from intracellular pathogens. AB - Copper toxicity and copper limitation can both be effective host defense mechanisms against pathogens. Tolerance of high copper by fungi makes toxicity as a defense mechanism largely ineffective against fungal pathogens. A forward genetic screen for Histoplasma capsulatum mutant yeasts unable to replicate within macrophages showed the Ctr3 copper transporter is required for intramacrophage proliferation. Ctr3 mediates copper uptake and is required for growth in low copper. Transcription of the CTR3 gene is induced by differentiation of H. capsulatum into pathogenic yeasts and by low available copper, but not decreased iron. Low expression of a CTR3 transcriptional reporter by intracellular yeasts implies that phagosomes of non-activated macrophages have moderate copper levels. This is further supported by the replication of Ctr3 deficient yeasts within the phagosome of non-activated macrophages. However, IFN gamma activation of phagocytes causes restriction of phagosomal copper as shown by upregulation of the CTR3 transcriptional reporter and by the failure of Ctr3 deficient yeasts, but not Ctr3 expressing yeasts, to proliferate within these macrophages. Accordingly, in a respiratory model of histoplasmosis, Ctr3 deficient yeasts are fully virulent during phases of the innate immune response but are attenuated after the onset of adaptive immunity. Thus, while technical limitations prevent direct measurement of phagosomal copper concentrations and copper-independent factors can influence gene expression, both the CTR3 promoter induction and the attenuation of Ctr3-deficient yeasts indicate activation of macrophages switches the phagosome from a copper-replete to a copper-depleted environment, forcing H. capsulatum reliance on Ctr3 for copper acquisition. PMID- 30452485 TI - Performance and variability of QuantiFERON Gold Plus assay associated with phlebotomy type. AB - BACKGROUND: QuantiFERON Gold Plus (Plus) assay has two approved methods for blood collection: direct in-tube (Plus direct) or the transfer of blood from a lithium heparin tube (Plus transfer). Currently, there is little data comparing the results of Plus and the QuantiFERON Gold In-Tube (Gold) based on blood collection. METHODS: In 2017, high risk healthcare workers undergoing annual tuberculosis infection screening at Houston Methodist Hospital, a private hospital in the Texas Medical Center (Houston, TX, U.S.A.) were consented and enrolled in a study comparing the Gold-in-tube (Gold), Plus direct in-tube, and Plus transfer assays. Blood was drawn concurrently for all 3 assays. RESULTS: Phlebotomy occurred on 300 consecutive, consented and enrolled participants in the study. The proportion of positive test results for the Gold, Plus direct and Plus transfer assays were 10% (29/300), 12% (35/299) and 17% (51/299), respectively. The agreement in the results of Gold versus Plus direct, Gold versus Plus transfer, and Plus direct versus Plus transfer was 91%, kappa (kappa) = 0.56; 91%, kappa = 0.59; and 85%, kappa = 0.37, respectively. CONCLUSIONS: Among high risk healthcare workers in a low prevalence tuberculosis setting, the Gold Plus assay had a higher proportion of positive results than the Gold in-tube assay. The agreement between the Gold, Plus direct and Plus transfer assays was unexpectedly low for simultaneously obtained samples. Blood transfer using lithium heparin offers individual clinics and public health programs greater ability to customize protocols, but variability of results still exists. PMID- 30452486 TI - Crop diversity and stability of revenue on farms in Central Europe: An analysis of big data from a comprehensive agricultural census in Bavaria. AB - Diversity of agricultural landscapes is important to maintain the provision of ecosystem services. In face of decreasing support measures for agricultural markets in the European Union, diversified crop portfolios could also offer a possibility to stabilize revenue at farm level (portfolio effect). We hypothesize that (i) diversity of crop portfolios changes along spatial gradients in the study area (Bavaria, Germany), (ii) the composition of portfolios depends on farm parameters, and (iii) more diverse portfolios on arable land provide higher revenue stability. We analysed agricultural census data comprising all farms (N = 105 314) in the study area and identified 26 typical crop portfolios. We show that portfolio composition is related to farm characteristics (whole farm revenue, farm type, farm size) and location. Currently, diversification of crop portfolios fails to promote stability of portfolio revenue in the study area, where policy still indirectly influences market prices of energy crops. We conclude that the portfolio effect as a natural insurance was less important in recent years due to high market prices for specific crops. This low need for natural insurances probably favoured simplified portfolios leading to decreased agricultural diversity. PMID- 30452487 TI - Selective targeting of histone modification fails to prevent graft versus host disease after hematopoietic cell transplantation. AB - Allogeneic hematopoietic cell transplantation is often complicated by graft versus host disease (GvHD), primarily mediated through allo-reactive donor T cells in the donor stem cell graft. Enhancer of Zeste Homolog 2 (EZH2), a histone lysine N-methyltransferase and a component of the Polycomb Repressive Complex 2, has been shown to play a role in GvHD pathology. Although not yet clear, one proposed mechanism is through selective tri-methylation of lysine 27 in histone 3 (H3K27me3) that marks the promoter region of multiple pro-apoptotic genes, leading to repression of these genes in allo-reactive T cells. We found that selective pharmacologic inhibition of H3K27me3 with EPZ6438 or GSK126 did not prevent murine GvHD. This suggests the GvHD mitigating properties of DZNep are independent from H3K27me3 inhibition. Furthermore, while pharmacologic inhibition of EZH2 by DZNep has been shown to be effective in abrogating mouse GvHD, we found that DZNep was not effective in preventing GvHD in a human T cell xenograft mouse model. Although EZH2 is an attractive target to harness donor allo-reactive T cells in the post-transplant setting to modulate GvHD and the anti-leukemia effect, our results suggest that more selective and effective ways to inhibit EZH2 in human T cells are required. PMID- 30452488 TI - SignalDetDDI: An SAS macro for detecting adverse drug-drug interactions in spontaneous reporting systems. AB - Statistical methods for detecting adverse drug reactions (ADRs) resulting from drug-drug interactions (DDIs) have been used in recent years to analyze the datasets in spontaneous reporting systems. We provide the SignalDetDDI macro in SAS to calculate the criteria for detecting ADRs resulting from the concomitant use of two drugs. We outline two criteria for detecting DDIs with the combination of two drugs and illustrate the implementation of the macro by way of an example. To implement the macro, a user specifies the target ADR and the two drugs to be evaluated. The SignalDetDDI macro outputs a table showing the number of reports on ADRs, the values of the two criteria for detecting ADRs, and the presence of DDIs. This macro enables users to easily and automatically assess the clinical DDIs that result from ADRs. The SignalDetDDI macro is freely available in the Supporting Information. PMID- 30452489 TI - The Hsp70 co-chaperone Ydj1/HDJ2 regulates ribonucleotide reductase activity. AB - Hsp70 is a well-conserved molecular chaperone involved in the folding, stabilization, and eventual degradation of many "client" proteins. Hsp70 is regulated by a suite of co-chaperone molecules that assist in Hsp70-client interaction and stimulate the intrinsic ATPase activity of Hsp70. While previous studies have shown the anticancer target ribonucleotide reductase (RNR) is a client of Hsp70, the regulatory co-chaperones involved remain to be determined. To identify co-chaperone(s) involved in RNR activity, 28 yeast co-chaperone knockout mutants were screened for sensitivity to the RNR-perturbing agent Hydroxyurea. Ydj1, an important cytoplasmic Hsp70 co-chaperone was identified to be required for growth on HU. Ydj1 bound the RNR subunit Rnr2 and cells lacking Ydj1 showed a destabilized RNR complex. Suggesting broad conservation from yeast to human, HDJ2 binds R2B and regulates RNR stability in human cells. Perturbation of the Ssa1-Ydj1 interaction through mutation or Hsp70-HDJ2 via the small molecule 116-9e compromised RNR function, suggesting chaperone dependence of this novel role. Mammalian cells lacking HDJ2 were significantly more sensitive to RNR inhibiting drugs such as hydroxyurea, gemcitabine and triapine. Taken together, this work suggests a novel anticancer strategy-inhibition of RNR by targeting Hsp70 co-chaperone function. PMID- 30452491 TI - Hemifacial Hyperhidrosis in a Patient With an Apical Non-Small Cell Lung Cancer. PMID- 30452492 TI - Detecting a Survival Benefit to Dose Escalation. PMID- 30452490 TI - Hyper-phosphorylation of Rb S249 together with CDK5R2/p39 overexpression are associated with impaired cell adhesion and epithelial-to-mesenchymal transition: Implications as a potential lung cancer grading and staging biomarker. AB - Prediction of lung cancer metastasis relies on post-resection assessment of tumor histology, which is a severe limitation since only a minority of lung cancer patients are diagnosed with resectable disease. Therefore, characterization of metastasis-predicting biomarkers in pre-resection small biopsy specimens is urgently needed. Here we report a biomarker consisting of the phosphorylation of the retinoblastoma protein (Rb) on serine 249 combined with elevated p39 expression. This biomarker correlates with epithelial-to-mesenchymal transition traits in non-small cell lung carcinoma (NSCLC) cells. Immunohistochemistry staining of NSCLC tumor microarrays showed that strong phospho-Rb S249 staining positively correlated with tumor grade specifically in the squamous cell carcinoma (SCC) subtype. Strong immunoreactivity for p39 positively correlated with tumor stage, lymph node invasion, and distant metastases, also in SCC. Linear regression analyses showed that the combined scoring for phospho-Rb S249, p39 and E-cadherin in SCC is even more accurate at predicting tumor staging, relative to each score individually. We propose that combined immunohistochemistry staining of NSCLC samples for Rb phosphorylation on S249, p39, and E-cadherin protein expression could aid in the assessment of tumor staging and metastatic potential when tested in small primary tumor biopsies. The intense staining for phospho-Rb S249 that we observed in high grade SCC could also aid in the precise sub-classification of poorly differentiated SCCs. PMID- 30452493 TI - Childhood Self-Perceptions in Children With Amblyopia: Is the Problem the Disease or the Treatment? PMID- 30452494 TI - Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status. AB - Importance: Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR). Objective: To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR. Design, Setting, and Participants: This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat. Main Outcomes and Measures: The primary outcome was positive predictive value. Results: Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable). Conclusions and Relevance: Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors. PMID- 30452495 TI - Antihunger Groups Are Blocking Nutrition Progress in the Supplemental Nutrition Assistance Program. PMID- 30452496 TI - Detecting a Survival Benefit to Dose Escalation-Reply. PMID- 30452497 TI - Prevalence and Severity of Alzheimer Disease in Individuals With Down Syndrome. PMID- 30452498 TI - Completion Rate and Reporting of Mandatory Pediatric Postmarketing Studies Under the US Pediatric Research Equity Act. AB - Importance: Many medicines prescribed to children have not been studied or formally approved for pediatric use. The Pediatric Research Equity Act of 2003 authorized the US Food and Drug Administration (FDA) to require pediatric clinical studies. Objective: To evaluate the characteristics, completion rate, and transparency of study design and results for mandatory pediatric postmarketing studies required under the Pediatric Research Equity Act. Design and Setting: A retrospective cohort study was conducted of pediatric postmarketing studies required for new drugs and new indications approved by the FDA between January 1, 2007, and December 31, 2014, with follow-up through December 1, 2017. Information on the status, design, and results of pediatric studies was obtained from publicly available FDA databases and ClinicalTrials.gov, direct communication with the FDA, and searches of MEDLINE, EMBASE, and Web of Science for peer-reviewed publications. Main Outcomes and Measures: Characteristics and transparency of pediatric studies, results reporting (in ClinicalTrials.gov, peer-reviewed literature, or FDA documents), and availability of pediatric information in drug labels. Rates and times to study completion were evaluated using Cox proportional hazards regression models. Results: Between 2007 and 2014, the FDA approved 114 new drugs and new indications for already approved drugs that were subject to Pediatric Research Equity Act requirements. These drugs were associated with 222 required pediatric postmarketing clinical studies. Overall, 75 pediatric studies (33.8%) were completed as of December 1, 2017. The rates of completion were significantly lower for efficacy studies (38 of 132 [28.8%]) compared with pharmacokinetic studies (19 of 34 [55.9%]; adjusted hazard ratio, 0.31; 95% CI, 0.12-0.82). Information on randomization, blinding, comparator, end point, and study size could not be identified for 74 studies (33.3%), and no reason for discontinuation was provided for 29 of the 42 discontinued studies (69.0%). Among the completed studies, the results were reported for 57 (76.0%). At the time of approval, 18 of 114 drug approvals (15.8%) had any pediatric efficacy, safety, or dosing information in their labels. After a median duration of follow-up of 6.8 years (interquartile range, 4.7-9.1 years), 47 of 114 of drug labels (41.2%) had any pediatric information. Conclusions and Relevance: Only 33.8% of mandatory pediatric postmarketing studies have been completed after a median follow-up of 6.8 years, and most drug labels do not include information important for pediatric use. To improve evidence-based prescribing of medicines to children, more timely completion of pediatric drug studies is needed. PMID- 30452499 TI - Association Between Lymph Node Ratio and Recurrence and Survival Outcomes in Patients With Oral Cavity Cancer. AB - Importance: Oral cavity squamous cell carcinoma (OCSCC) is associated with often delayed clinical diagnosis, poor prognosis, and expensive therapeutic approaches. Prognostic accuracy is important in improving treatment outcomes of patients with this disease. Objectives: To assess lymph node ratio (LNR) and other factors in estimating response to treatment and provide prognostic information helpful for clinical decision making. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 2000, to December 31, 2015, at an academic hospital in Denver, Colorado. Participants included 149 patients with primary OCSCC who received curative-intent surgery and/or postoperative adjuvant therapies. Analysis was performed from December 8, 2017, to August 15, 2018. Main Outcomes and Measures: Overall survival (OS), disease-free survival (DFS), locoregional disease-free survival (LRDFS), and distant metastasis-free survival (DMDFS) adjusted for known prognostic risk factors, as well as correlation of LNR with other histopathologic prognostic factors. Results: Of the 149 patients included in analysis, 105 were men (70.5%); the median age at diagnosis was 59 years (range, 28-88 years). Using the Kaplan-Meier method, the 5-year survival estimates for OS rate was 40.4% (95% CI, 31.3%-49.3%); DFS, 48.6% (95% CI, 38.6% 58.0%); LRDFS, 57.7% (95% CI, 46.6%-67.2%); and DMDFS, 74.7% (95% CI, 65.1% 82.0%). The median follow-up was 20 months for all patients and 34.5 months (range, 0-137 months) for surviving patients. Nonwhite race (hazard ratio [HR], 2.15; 95% CI, 1.22-3.81), T3-T4 category (HR, 1.99; 95% CI, 1.18-3.35), and LNR greater than 10% (HR, 2.71; 95% CI, 1.39-5.27) were associated with poorer OS. Nonwhite patients also had higher risk of locoregional failures (HR, 2.47; 95% CI, 1.28-4.79), whereas women were more likely to have distant metastasis (HR, 2.55; 95% CI, 1.14-5.71). Floor-of-mouth subsite had fewer locoregional recurrences than did other subsites (HR, 0.45, 95% CI, 0.21-0.99). An LNR greater than 10% independently was associated with worse OS (HR, 2.71; 95% CI, 1.39 5.27), DFS (HR, 2.48; 95% CI, 1.18-5.22), and DMDFS (HR, 6.05; 95% CI, 1.54 23.71). The LNR was associated with N-stage (Cramer V, 0.69; 95% CI, 0.58-0.78), extracapsular extension (Cramer V, 0.55; 95% CI, 0.44-0.66), lymphovascular invasion (Cramer V, 0.46; 95% CI, 0.27-0.61); number of excised lymph nodes (Cramer V, 0.24; 95% CI, 0.06-0.37), margin (Cramer V, 0.22; 95% CI, 0.05-0.38), and tumor thickness combined with depth of invasion (Cramer V, 0.25; 95% CI, 0.05 0.38). Conclusions and Relevance: Locoregional treatment failure remained the predominant pattern of failure. An advanced pathologic stage and nonwhite race were found to be associated with worse outcomes. The findings from this study suggest that LNR is the most robust prognostic factor and appears to have implications for risk stratification in this disease. PMID- 30452500 TI - Factors in Premature Infants Associated With Low Risk of Developing Retinopathy of Prematurity. AB - Importance: Most premature infants will not develop retinopathy of prematurity (ROP) of clinical relevance, yet screening evaluations often continue beyond hospital discharge, even for those infants without ROP. Objectives: To identify the characteristics of infants at low risk for ROP, for whom further postdischarge screening may be of limited value. Design, Setting, and Participants: This study took place in North American neonatal intensive care units where clinicians had expertise in ROP. Infants with birth weight less than 1251 g who were born at or transferred into an Telemedicine Approaches to Evaluating Acute-Phase ROP (e-ROP) study center were enrolled. The study included post hoc analysis of prospectively collected in-hospital ROP examination results among infants enrolled in the e-ROP study. We characterized infants without ROP and performed logistic regression on the subset of infants who were 27 to 33 weeks' gestational age to determine characteristics associated with the absence of ROP during all in-hospital examinations. Main Outcomes and Measures: The main measure was the absence of ROP prior to hospital discharge; the main outcome was treatment for ROP. Results: A total of 1257 infants born at 22 to 35 weeks' gestation (median [interquartile range (IQR)], 26 [25-28] weeks) with birth weights less than 1251 g (median [IQR], 860 [690-1040] g) underwent 4113 ROP examinations between 31 and 47 weeks' postmenstrual age. Overall, 1153 examinations (38%) showed no ROP, and 456 infants (36%) did not have ROP prior to study center discharge or study end point. Among infants without ROP during examinations at 32 and 33 weeks' postmenstrual age, 16 (9.4%) and 14 (5.3%) subsequently underwent ROP treatment, respectively. At hospital discharge, there was no ROP in 59% of infants of 27 to 33 weeks' gestational age, compared with 15% of those who were less than 27 weeks' gestational age (difference, 44% [95% CI, 38.5%-48.1%]; P <= .001). With more than 85% follow-up among infants without ROP by 37 weeks' postmenstrual age, none (95% CI, 0%-0.98%) were treated for ROP. In multivariate analysis of infants born at 27 to 33 weeks' gestation, larger birth weight (OR, 4.1 [95% CI, 1.6-10.3]) and higher gestational age (OR, 4.0 [95% CI, 1.5-10.8]) were significantly associated with absence of ROP. Conclusions and Relevance: These findings suggest that, for infants of 27 weeks' gestational age or greater and birth weights larger than 750 g, if no ROP has been detected by discharge at near-term postmenstrual age, then further ROP surveillance has limited value. Studies of all infants at risk are needed to develop more specific, objective criteria for termination of ROP surveillance and focus resources on infants at higher risk of ROP. Trial Registration: ClinicalTrials.gov Identifier: NCT01264276. PMID- 30452501 TI - Development of Therapeutics for Children-A Tricky Balancing Act. PMID- 30452502 TI - Firearm Storage and Adult Alcohol Misuse Among Washington State Households With Children. AB - Importance: Firearm injuries and fatalities among children are an important public health problem. Children living with an adult misusing alcohol may be at a heightened risk for self-harm or unintentional injury, highlighting the need to investigate the association between household firearm storage and adult alcohol misuse. Objectives: To characterize household firearm presence among children by various sociodemographic characteristics, and to assess the association between children living in a home with an unsafely stored firearm and an adult reporting alcohol misuse. Design, Setting, and Participants: This cross-sectional investigation uses data from the 2013 and 2016 Behavioral Risk Factor Surveillance System in the state of Washington, a program that administers a telephone survey statewide to randomly selected noninstitutionalized adults at least 18 years of age about their health-related risk behaviors, chronic health conditions, and use of preventive services. The 2013 and 2016 data included 5241 responses to the firearm ownership and storage module and the Random Child Selection module (intended for a randomly selected child younger than age 18 years and reported by an adult living in the same household). Data for this study were collected from January 1 through December 31, 2013, and January 1 through December 31, 2016. Data were analyzed from March through May 2018. Main Outcomes and Measures: The primary outcomes were a child's residence in a firearm-owning home, the manner in which household firearms were stored, and the adult respondent's alcohol consumption. Results: Among the 3443 children living in a non-firearm-owning household, 50.7% were male (all values given as a percentage only are weighted); among those reporting specific age, the weighted mean age was 9.3 years (unweighted mean [SD], 10.1 [5.2] years). In the 1756 children living in a firearm-owning household, 52.5% were male; among those reporting specific age, the weighted mean age was 9.1 years (unweighted mean [SD], 9.8 [5.4] years). An estimated 470 000 children (29.4%; 95% CI, 27.3%-31.7%) in the state resided in a firearm-owning household. Among them, 258 000 children (54.6%; 95% CI, 51.5% 57.6%) lived with at least 1 firearm that was not stored safely (ie, not locked and unloaded). Firearms were more likely to be stored unsafely in homes in which an adult reported alcohol misuse (prevalence ratio: 1.20; 95% CI, 1.07-1.35). Conclusions and Relevance: Children living in a household with an adult who misuses alcohol may be more likely to live with an unsafely stored firearm, which is concerning given the association between adult alcohol misuse and children's risk for sustaining injury. PMID- 30452503 TI - Association of Prenatal Exposures of Polybrominated Diphenyl Ethers With Hypospadias. PMID- 30452504 TI - Duration of Pediatric Clinical Trials Submitted to the US Food and Drug Administration. AB - Importance: The increasing prevalence of pediatric chronic disease has resulted in increased exposure to long-term drug therapy in children. The duration of recently completed drug trials that support approval for drug therapy in children with chronic diseases has not been systematically evaluated. Such information is a vital first step in forming safety pharmacovigilance strategies for drugs used for long-term therapy in children. Objective: To characterize the duration of clinical trials submitted to the US Food and Drug Administration (FDA) for pediatric drug approvals, with a focus on drugs used for long-term therapy. Design and Setting: A review was performed of all safety and efficacy clinical trials conducted under the Best Pharmaceuticals for Children Act or the Pediatric Review Equity Act and submitted to the FDA from September 1, 2007, to December 31, 2014, to support the approval of drugs frequently used for long-term therapy in children. Statistical analysis was performed from July 1, 2015, to December 31, 2017. Main Outcomes and Measures: Maximum duration of trials submitted to support FDA approval of drugs for children. Results: A total of 306 trials supporting 86 drugs intended for long-term use in children were eligible for the primary analysis. The drugs most commonly evaluated were for treatment of neurologic (25 [29%]), pulmonary (16 [19%]), and anti-infective (14 [16%]) indications. The median maximum trial duration by drug was 44 weeks (minimum, 1.1 week; maximum, 364 weeks). For nearly two-thirds of the drugs (52 [61%]), the maximum trial duration was less than 52 weeks. For 10 of the drugs (12%), the maximum trial duration was 3 years or more. Maximum duration of trials did not vary by therapeutic category, minimum age of enrollment, calendar year, or legislative mandate. Conclusions and Relevance: Pediatric clinical trials designed to sufficiently investigate drug safety and efficacy to support FDA approval are of relatively limited duration. Given the potential long-term exposure of patients to these drugs, the clinical community should consider whether new approaches are needed to better understand the safety associated with long-term use of these drugs. PMID- 30452505 TI - Association of Prenatal Exposures of Polybrominated Diphenyl Ethers With Hypospadias. PMID- 30452506 TI - The Tonsillectomy Tweet. PMID- 30452507 TI - Risk of Intimate Partner Homicide Among Caregivers in an Urban Children's Hospital. PMID- 30452508 TI - Central Scotoma After Liver Transplant. PMID- 30452509 TI - Association of Prenatal Exposures of Polybrominated Diphenyl Ethers With Hypospadias-Reply. PMID- 30452510 TI - Evaluation of Parental Perspectives and Concerns About Pediatric Tonsillectomy in Social Media. AB - Importance: Tonsillectomy is common in children, but little is known about parental preferences and values concerning this surgical procedure. Twitter offers an opportunity to evaluate parental understanding and experience of tonsillectomy care. Objective: To identify parental perspectives about tonsillectomy in children that may not be apparent in a routine clinical encounter. Design, Setting, and Participants: In this qualitative study, social media platform Twitter was searched for posts (tweets) published between January 1, 2008, and December 31, 2017, by US-based parents about their child's tonsillectomy. Modified grounded theory was applied to develop a coding taxonomy to classify the tweets. Tweets were assessed for thematic synthesis and classification, and descriptive statistics were obtained for each theme. Main Outcomes and Measures: Themes of parental experiences and perspectives about their child's tonsillectomy. Results: Of the 5801 total tweets retrieved, 782 (13.5%) satisfied the inclusion criteria. Tweets were categorized under 2 overarching themes: procedural concerns (549 tweets [70.2%]) and attitudes or experiences (498 [63.7%]). Common tweets under procedural concerns mentioned surgical indication for tonsillectomy (55 tweets [7.0%]); eg, "strep-I think it's tonsil removing time...") and recovery (227 tweets [29.0%]), including child's attitude (89 tweets [11.4%]; eg, "so hard to get my daughter to eat") and parental experience (87 tweets [11.1%]; eg, "tonsillectomy recovery sucks for the parent as much as the kid!"). Common tweets regarding attitudes or experiences included the tenor of overall care (225 tweets [28.6%]; eg, "Tonsillectomy is a bear") and fears or apprehensions (209 tweets [26.6%]). Conclusions and Relevance: These social media findings may be used to guide clinicians in educating and counseling parents as well as further engaging parents and children in shared decision making for tonsillectomy. PMID- 30452511 TI - Topical Tazarotene Gel, 0.1%, as a Novel Treatment Approach for Atrophic Postacne Scars: A Randomized Active-Controlled Clinical Trial. AB - Importance: Evidence is robust for the effectiveness of microneedle therapy in the management of postacne atrophic scarring. A home-based topical treatment with an efficacy comparable to microneedling would be a useful addition in the armamentarium of acne scar management. Objective: To compare the efficacy of topical tazarotene gel, 0.1%, with microneedling therapy in the management of moderate to severe atrophic acne scars. Design, Setting, and Participants: Prospective, observer-blinded, active-controlled, randomized clinical trial with 6 months of follow-up conducted between June 2, 2017, and February 28, 2018, at a tertiary care hospital in India. Thirty-six patients with grade 2 to 4 facial atrophic postacne scars and without a history of procedural treatment of acne scars within the previous year were recruited. Analyses were conducted using data from the evaluable population. Interventions: Both halves of each participant's face were randomized to receive either microneedling or topical tazarotene therapy. Microneedling was conducted on 1 side of the face with a dermaroller having a needle length of 1.5 mm for a total of 4 sessions during the course of 3 months. Participants were instructed to apply topical tazarotene gel, 0.1%, to the other side of the face once every night during this same period. Main Outcomes and Measures: Patients were followed up at 3 and 6 months by a blinded observer, and improvements in acne scar severity based on Goodman and Baron quantitative and qualitative scores and a subjective independent dermatologist score (range, 0-10, with higher scores indicating better improvement) were assessed. Patient satisfaction was assessed using a patient global assessment score (ranging from 0 for no response to 10 for maximum improvement) at these follow-up visits. Results: There were 36 participants (13 men and 23 women; mean [range] age, 23.4 [18-30] years), and the median (interquartile range [IQR]) duration of acne was 6 (4-8) years. For the 34 participants included in the complete data analyses, the median (IQR) quantitative score for acne scar severity at the 6-month follow-up visit following treatment with either tazarotene (from a baseline of 8.0 [6.0-9.8] to 5.0 [3.0-6.0]) or microneedling (from a baseline of 7.0 [6.0-10.8] to 4.5 [3.0-6.0]) indicated significant improvement (P < .001) that was comparable for both treatments (median [IQR] change in severity score from baseline, 2.5 [2.0-4.0] vs 3.0 [2.0-4.0]; P = .42). By contrast, median qualitative acne scar scores were the same for both treatment groups at baseline and did not significantly change following either treatment. Conclusions and Relevance: The present clinical trial showed comparable outcomes of both treatments for the overall improvement of quantitative facial acne scar severity. Level of Evidence: 1. Trial Registration: ClinicalTrials.gov Identifier: NCT03170596. PMID- 30452512 TI - Health Impairment From Nasal Airway Obstruction and Changes in Health Utility Values From Septorhinoplasty. AB - Importance: The association of nasal airway obstruction with health is significant, and the health care resources utilized in open septorhinoplasty need to be included in health economic analyses. Objectives: To describe the association of nasal airway obstruction and subsequent open septorhinoplasty with patient health. Design, Setting, and Participants: A prospective case series study was conducted from September 30, 2009, to October 29, 2015, at 2 tertiary rhinologic centers in Sydney, Australia, among 144 consecutive adult patients (age, >=18 years) with nasal airway obstruction from septal and nasal valve disorders. Interventions: Open septorhinoplasty. Main Outcomes and Measures: Patients were assessed before undergoing open septorhinoplasty and then 6 months after the procedure. Health utility values (HUVs) were derived from the 36-Item Short Form Health Survey. Nasal obstruction severity was also measured using the Nasal Obstruction Symptom Evaluation (NOSE) questionnaire and the Sino-Nasal Outcome Test 22 questionnaires. Results: A total of 144 patients (85 women and 59 men; mean [SD] age, 38 [13] years) were assessed. The baseline mean (SD) HUV for patients in this study was 0.72 (0.09), which was below the weighted mean (SD) Australian norm of 0.81 (0.22). After open septorhinoplasty, the mean (SD) HUV improved to 0.78 (0.12) (P < .001). Improvements in HUV were associated with changes in disease-specific patient-reported outcome measures, including Nasal Obstruction Symptom Evaluation scores (r = -0.48; P = .01) and Sino-Nasal Outcome Test 22 scores (r = -0.68; P = .01). Conclusions and Relevance: Patients with nasal airway obstruction reported baseline HUVs that were lower than the Australian norm and similar to those in individuals with chronic diseases with significant health expenditure. There was a clinically and statistically significant improvement in HUVs after open septorhinoplasty that was associated with a reduction in Nasal Obstruction Symptom Evaluation and Sino-Nasal Outcome Test 22 scores. Outcomes from this study may be used for health economic analyses of the benefit associated with open septorhinoplasty. Level of Evidence: 4. PMID- 30452513 TI - Retained Nasal Trumpet for 20 Months: An Unusual Foreign Body. PMID- 30452514 TI - Association of Prenatal Exposure to Air Pollution With Autism Spectrum Disorder. AB - Importance: The etiology of autism spectrum disorder (ASD) is poorly understood, but prior studies suggest associations with airborne pollutants. Objective: To evaluate the association between prenatal exposures to airborne pollutants and ASD in a large population-based cohort. Design, Setting, and Participants: This population-based cohort encompassed nearly all births in Metro Vancouver, British Columbia, Canada, from 2004 through 2009, with follow-up through 2014. Children were diagnosed with ASD using a standardized assessment with the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. Monthly mean exposures to particulate matter with a diameter less than 2.5 um (PM2.5), nitric oxide (NO), and nitrogen dioxide (NO2) at the maternal residence during pregnancy were estimated with temporally adjusted, high-resolution land use regression models. The association between prenatal air pollution exposures and the odds of developing ASD was evaluated using logistic regression adjusted for child sex, birth month, birth year, maternal age, maternal birthplace, and neighborhood-level urbanicity and income band. Data analysis occurred from June 2016 to May 2018. Exposures: Mean monthly concentrations of ambient PM2.5, NO, and NO2 at the maternal residence during pregnancy, calculated retrospectively using temporally adjusted, high-resolution land use regression models. Main Outcomes and Measures: Autism spectrum disorder diagnoses based on standardized assessment of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule. The hypothesis being tested was formulated during data collection. Results: In a cohort of 132 256 births, 1307 children (1.0%) were diagnosed with ASD by the age of 5 years. The final sample size for the PM2.5 adjusted model was 129 439 children, and for NO and NO2, it was 129 436 children; of these, 1276 (1.0%) were diagnosed with ASD. Adjusted odds ratios for ASD per interquartile range (IQR) were not significant for exposure to PM2.5 during pregnancy (1.04 [95% CI, 0.98-1.10] per 1.5 MUg/m3 increase [IQR] in PM2.5) or NO2 (1.06 [95% CI, 0.99-1.12] per 4.8 ppb [IQR] increase in NO2) but the odds ratio was significant for NO (1.07 [95% CI, 1.01-1.13] per 10.7 ppb [IQR] increase in NO). Odds ratios for male children were 1.04 (95% CI, 0.98-1.10) for PM2.5; 1.09 (95% CI, 1.02-1.15) for NO; and 1.07 (95% CI, 1.00-1.13) for NO2. For female children, they were for 1.03 (95% CI, 0.90-1.18) for PM2.5; 0.98 (95% CI, 0.83-1.13) for NO; and 1.00 (95% CI, 0.86-1.16) for NO2. Conclusions and Relevance: In a population-based birth cohort, we detected an association between exposure to NO and ASD but no significant association with PM2.5 and NO2. PMID- 30452515 TI - Cancer Care Chronicles-Social Media and Gender Equity in Oncology. PMID- 30452516 TI - A Posterior Triangle Neck Mass in a Pediatric Patient. PMID- 30452517 TI - Night Blindness, Ring Scotoma, and a Nonrecordable Electroretinogram in an Elderly Woman. PMID- 30452518 TI - Self-perception of School-Aged Children With Amblyopia and Its Association With Reading Speed and Motor Skills. AB - Importance: Reading and eye-hand coordination deficits in children with amblyopia may impede their ability to demonstrate their knowledge and skills, compete in sports and physical activities, and interact with peers. Because perceived scholastic, social, and athletic competence are key determinants of self-esteem in school-aged children, these deficits may influence a child's self-perception. Objective: To determine whether amblyopia is associated with lowered self perception of competence, appearance, conduct, and global self-worth and whether the self-perception of children with amblyopia is associated with their performance of reading and eye-hand tasks. Design, Setting, and Participants: This cross-sectional study was conducted from January 2016 to June 2017 at the Pediatric Vision Laboratory of the Retina Foundation of the Southwest and included healthy children in grades 3 to 8, including 50 children with amblyopia; 13 children without amblyopia with strabismus, anisometropia, or both; and 18 control children. Main Outcomes and Measures: Self-perception was assessed using the Self-perception Profile for Children, which includes 5 domains: scholastic, social, and athletic competence; physical appearance; behavioral conduct; and a separate scale for global self-worth. Reading speed and eye-hand task performance were evaluated with the Readalyzer (Bernell) and Movement Assessment Battery for Children, 2nd Edition. Visual acuity and stereoacuity also were assessed. Results: Of 50 participants, 31 (62%) were girls, 31 (62%) were non-Hispanic white, 6 (12%) were Hispanic white, 3 (6%) were African American, 4 (8%) were Asian/Pacific Islander, and 3 (6%) were more than 1 race/ethnicity, and the mean [SD] age was 10.6 [1.3] years. Children with amblyopia had significantly lower scores than control children for scholastic (mean [SD], 2.93 [0.74] vs 3.58 [0.24]; mean [SD] difference, 0.65 [0.36]; 95% CI, 0.29-1.01; P = .004), social (mean [SD], 2.95 [0.64] vs 3.62 [0.35]; mean [SD] difference, 0.67 [0.32]; 95% CI, 0.35-0.99] P < .001), and athletic (mean [SD], 2.61 [0.65] vs 3.43 [0.52]; mean [SD] difference, 0.82 [0.34]; 95% CI, 0.48-1.16; P = .001) competence domains. Among children with amblyopia, a lower self-perception of scholastic competence was associated with a slower reading speed (r = 0.49, 95% CI, 0.17 0.72; P = .002) and a lower self-perception of scholastic, social, and athletic competence was associated with worse performance of aiming and catching (scholastic r = 0.48; 95% CI, 0.16-0.71; P = .007; social r = 0.63; 95% CI, 0.35 0.81; P < .001; athletic r = 0.53; 95% CI, 0.21-0.75; P = .003). No differences in the self-perception of physical appearance (mean [SD], 3.32 [0.63] vs 3.64 [0.40]), conduct (mean [SD], 3.09 [0.56] vs 3.34 [0.66]), or global self-worth (mean [SD], 3.42 [0.42] vs 3.69 [0.36]) were found between the amblyopic and control groups. Conclusions and Relevance: These findings suggest that lower self perception is associated with slower reading speed and worse motor skills and may highlight the wide-ranging effects of altered visual development for children with amblyopia in their everyday lives. PMID- 30452519 TI - Use of Corticosteroid-Eluting Sinus Stents Between 2012 and 2017. PMID- 30452520 TI - Competing Risks for a Diagnosis of Invasive Breast Cancer. PMID- 30452521 TI - Surgery vs Radiotherapy in the Management of Biopsy Gleason Score 9-10 Prostate Cancer and the Risk of Mortality. AB - Importance: It is unknown how treatment with radical prostatectomy (RP) and adjuvant external beam radiotherapy (EBRT), androgen deprivation therapy (ADT), or both (termed MaxRP) compares with treatment with EBRT, brachytherapy, and ADT (termed MaxRT). Objective: To investigate whether treatment of Gleason score 9-10 prostate cancer with MaxRP vs MaxRT was associated with prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) risk. Design, Setting, and Participants: The study cohort comprised 639 men with clinical T1-4,N0M0 biopsy Gleason score 9-10 prostate cancer. Between February 6, 1992, and April 26, 2013, a total of 80 men were consecutively treated with MaxRT at the Chicago Prostate Cancer Center, and 559 men were consecutively treated with RP and pelvic lymph node dissection at the Martini-Klinik Prostate Cancer Center. Follow-up started on the day of prostate EBRT or RP and concluded on October 27, 2017. Exposures: Of the 559 men managed with RP and pelvic lymph node dissection, 88 (15.7%) received adjuvant EBRT, 49 (8.8%) received ADT, and 50 (8.9%) received both. Main Outcomes and Measures: Treatment propensity score-adjusted risk of PCSM and ACM and the likelihood of equivalence of these risks between treatments using a plausibility index. Results: The cohort included 639 men, with a mean (SD) age of 65.83 (6.52) years. After median follow-ups of 5.51 years (interquartile range, 2.19-6.95 years) among 80 men treated with MaxRT and 4.78 years (interquartile range, 4.01-6.05 years) among 559 men treated with RP-containing treatments, 161 men had died, 106 (65.8%) from prostate cancer. There was no significant difference in the risk of PCSM (adjusted hazard ratio, 1.33; 95% CI, 0.49-3.64; P = .58) and ACM (adjusted hazard ratio, 0.80; 95% CI, 0.36-1.81; P = .60) when comparing men who underwent MaxRP vs MaxRT, with plausibility indexes for equivalence of 76.75% for the end point of the risk of PCSM and 77.97% for the end point of the risk of ACM. Plausibility indexes for all other treatment comparisons were less than 63%. Conclusions and Relevance: Results of this study suggest that it is plausible that treatment with MaxRP or MaxRT for men with biopsy Gleason score 9-10 prostate cancer can lead to equivalent risk of PCSM and ACM. PMID- 30452522 TI - Association of Dementia With Mortality Among Adults With Down Syndrome Older Than 35 Years. AB - Importance: This work quantifies the fatal burden of dementia associated with Alzheimer disease in individuals with Down syndrome (DS). Objective: To explore the association of dementia associated with Alzheimer disease with mortality and examine factors associated with dementia in adults with DS. Design, Settings and Participants: Prospective longitudinal study in a community setting in England. Data collection began March 29, 2012. Cases were censored on December 13, 2017. The potential sample consisted of all adults 36 years and older from the London Down Syndrome Consortium cohort with 2 data times and dementia status recorded (N = 300); 6 withdrew from study, 28 were lost to follow-up, and 55 had a single data collection point at time of analysis. The final sample consisted of 211 participants, with 503.92 person-years' follow-up. Exposures: Dementia status, age, sex, APOE genotype, level of intellectual disability, health variables, and living situation. Main Outcomes and Measures: Crude mortality rates, time to death, and time to dementia diagnosis with proportional hazards of predictors. Results: Of the 211 participants, 96 were women (45.5%) and 66 (31.3%) had a clinical dementia diagnosis. Twenty-seven participants (11 female; mean age at death, 56.74 years) died during the study period. Seventy percent had dementia. Crude mortality rates for individuals with dementia (1191.85 deaths per 10 000 person-years; 95% CI, 1168.49-1215.21) were 5 times higher than for those without (232.22 deaths per 10 000 person-years; 95% CI, 227.67-236.77). For those with dementia, APOE epsilon4 carriers had a 7-fold increased risk of death (hazard ratio [HR], 6.91; 95% CI, 1.756-27.195). For those without dementia, epilepsy with onset after age 36 years was associated with mortality (HR, 9.66; 95% CI, 1.59-58.56). APOE epsilon4 carriers (HR, 4.91; 95% CI, 2.53-9.56), adults with early-onset epilepsy (HR, 3.61; 95% CI, 1.12-11.60), multiple health comorbidities (HR, 1.956; 95% CI, 1.087-3.519), and those living with family (HR, 2.14; 95% CI, 1.08-4.20) received significantly earlier dementia diagnoses. Conclusions and Relevance: Dementia was associated with mortality in 70% of older adults with DS. APOE epsilon4 carriers and/or people with multiple comorbid health conditions were at increased risk of dementia and death, highlighting the need for good health care. For those who died without a dementia diagnosis, late onset epilepsy was the only significant factor associated with death, raising questions about potentially undiagnosed dementia cases in this group. PMID- 30452523 TI - Genetic Neural Networks: An artificial neural network architecture for capturing gene expression relationships. AB - Motivation: Gene expression prediction is one of the grand challenges in computational biology. The availability of transcriptomics data combined with recent advances in artificial neural networks provide an unprecedented opportunity to create predictive models of gene expression with far reaching applications. Results: We present the Genetic Neural Network (GNN), an artificial neural network for predicting genome-wide gene expression given gene knockouts and master regulator perturbations. In its core, the GNN maps existing gene regulatory information in its architecture and it uses cell nodes that have been specifically designed to capture the dependencies and non-linear dynamics that exist in gene networks. These two key features make the GNN architecture capable to capture complex relationships without the need of large training datasets. As a result, GNNs were 40% more accurate on average than competing architectures (MLP, RNN, BiRNN) when compared on hundreds of curated and inferred transcription modules. Our results argue that GNNs can become the architecture of choice when building predictors of gene expression from exponentially growing corpus of genome-wide transcriptomics data. Availability and implementation: https://github.com/IBPA/GNN. Supplementary Information: Supplementary data are available at Bioinformatics online. PMID- 30452524 TI - Seminal vesicle secretory protein 7, PATE4, is not required for sperm function but for copulatory plug formation to ensure fecundity. AB - Seminal vesicle secretions (SVSs), together with spermatozoa, are ejaculated into the female reproductive tract. SVS7, also known as PATE4, is one of the major SVS proteins found in the seminal vesicle, copulatory plug, and uterine fluid after copulation. Here, we generated Pate4 knockout (-/-) mice and examined the detailed function of PATE4 on male fecundity. The morphology and weight of Pate4 /- seminal vesicles were comparable to the control. Although Pate4-/- cauda epididymal spermatozoa have no overt defects during in vitro fertilization, Pate4 /- males were subfertile. We found that the copulatory plugs were smaller in the vagina of females mated with Pate4-/- males, leading to semen leakage and a decreased sperm count in the uterus. When the females mated with Pate4-/- males were immediately re-caged with Pate4 + / + males, the females had subsequent productive matings. When the cauda epididymal spermatozoa were injected into the uterus and plugged artificially [artificial insemination (AI)], Pate4-/- spermatozoa could efficiently fertilize eggs as compared to wild-type spermatozoa. We finally examined the effect of SVSs on AI, and observed no difference in fertilization rates between Pate4 + / + and Pate4-/- SVSs. In conclusion, PATE4 is a novel factor in forming the copulatory plug that inhibits sequential matings and maintains spermatozoa in the uterus to ensure male fecundity. PMID- 30452525 TI - The US Food and Drug Administration's Authorization of the First Cannabis-Derived Pharmaceutical: Are We Out of the Haze? PMID- 30452526 TI - Association of Severe Hydrocephalus With Congenital Zika Syndrome. AB - Importance: Hydrocephalus is a treatable but potentially fatal complication that has not been previously described in congenial Zika syndrome (CZS). Objective: To describe the clinical features and imaging findings in 24 patients with congenital Zika syndrome (CZS) who developed hydrocephalus. Design, Setting, and Participants: This case series included patients with hydrocephalus who were born in October and November 2015 and followed up until mid-2017 in the 2 largest national referral centers for CZS in Brazil. The participants included consecutively enrolled children with a clinical and laboratorial diagnosis of CZS who developed clinical and/or image findings suggestive of hydrocephalus and who were confirmed to experience increased intracranial hypertension during ventriculoperitoneal shunt procedures. Main Outcomes and Measures: To retrospectively describe clinical and image findings in these 24 patients. Results: This multicenter cohort included 308 patients with CZS; 24 consecutive children were enrolled in this study. These children were aged between 3 to 18 months, and 13 of 24 (54%) were female. All patients presented with at least 1 positive test result for anti-Zika antibodies in cerebrospinal fluid or serum and had classic signs of CZS. At the time of hydrocephalus diagnosis, only 14 of 24 patients (58%) had symptoms and signs suggestive of hydrocephalus (mainly worsening seizures, vomiting, irritability, and/or sudden increase of head circumference percentile). Two of 24 patients (8%) had no symptoms suggestive of hydrocephalus but were found to have reduced brain volume on repeated imaging. Cerebellar or brainstem hypoplasia on baseline imaging were found in 18 of 23 patients (78%). At the second computed tomographic scan, all patients showed a marked increase of ventricular volume, compatible with communicating hydrocephalus, and reduction of brain tissue that was visibly worse than on baseline imaging for the 23 patients with repeated scans. Conclusions and Relevance: We present evidence that hydrocephalus is a complication of CZS in at least a proportion of patients. The clinical spectrum of this condition continues to evolve, but given that presenting signs and symptoms of hydrocephalus can be challenging to recognize in CZS, we provisionally recommend that high suspicion and appropriate monitoring for hydrocephalus should be part of the standard care of patients with CZS. PMID- 30452527 TI - The landscape of miRNA-related ceRNA networks for marking different renal cell carcinoma subtypes. AB - We know that different types of cancers usually have different responses to the same treatment. Therefore, it is important to understand the similarities and differences across subtypes of cancers, so as to provide a basis for the individualized treatments. Until now, no comprehensive investigation on competing endogenous RNAs (ceRNAs) has been reported for the three main subtypes of renal cell carcinoma (RCC), so the regulation characteristics of ceRNAs in three subtypes are not well revealed. This paper firstly describes a comparative analysis of ceRNA-ceRNA interaction networks for all the three subtypes of RCC based on differential microRNAs (miRNAs). We comprehensively summarized all miRNA and messenger RNAdata of RCC from 126 matched tumor-normal tissues in The Cancer Genome Atlas, systematically analyzed a total of more than 80 000 ceRNA interactions and highlighted the common and specific properties among them, aiming to identify critical genes to classify them for providing supplementary help in the precise diagnosis of RCC. From three aspects, including common or specific ceRNAs, upregulated or downregulated and classifications across the three subtypes, we highlighted the common and specific properties for the three subtypes and also explored the classification of RCC by combining the specific ceRNAs with differential regulations. Moreover, for the most major subtype of clear cell renal cell carcinoma (KIRC), three critical genes were screened out from KIRC ceRNA network and further demonstrated to be the potential biomarkers of KIRC by performing biological experiments at the transcriptional level. PMID- 30452528 TI - Ambient volatile organic compounds and racial/ethnic disparities in gestational diabetes mellitus: Are Asian/Pacific Islander women at greater risk? AB - U.S. Asian/Pacific Islander communities experience high air pollution levels. Asian/Pacific Islanders may be predisposed to pancreatic beta-cell dysfunction and have the highest prevalence of gestational diabetes mellitus (GDM) compared to other racial/ethnic groups. Exposure to high levels of volatile organic compounds (VOCs) impairs pancreatic beta-cell function, leading to insulin resistance, but racial/ethnic differences in this association are unexamined. We analyzed singleton deliveries (n=220,065) from the Consortium on Safe Labor (2002 2008). Exposure to 14 VOCs in each hospital referral region was based on modified Community Multiscale Air Quality models. Logistic regression estimated odds ratios for GDM associated with high (>=75th percentile) compared to low (<75th percentile) VOC exposure three-months preconception and first trimester of pregnancy. Preconception and first trimester exposure to high VOC levels were associated with increased odds of GDM among Whites and Asian/Pacific Islanders. GDM risk was significantly higher for Asian/Pacific Islanders compared to Whites for most VOCs. Preconception benzene exposure was associated with 29% (95% confidence interval [CI]: 12-47%) increased odds of GDM among Whites compared to 45% (95% CI: 16-81%) increased odds among Asian/Pacific Islanders. These novel findings highlight environmental health disparities impacting pregnant women. Increased focus on GDM risk in U.S. Asian/Pacific Islander communities is warranted. PMID- 30452531 TI - Tolerance to seed predation mediated by seed size increases at lower latitudes in a Mediterranean oak. AB - Background and Aims: The ability of plants to allocate energy to resistance against herbivores changes with abiotic conditions and thus may vary along geographical clines, with important consequences for plant communities. Seed size is a plant trait potentially influencing plant tolerance to endoparasites, and seed size often varies across latitude. Consequently, plant tolerance to endoparasites may change across geographical clines. Methods: The interaction between Quercus ilex (holm oak) and seed-predating Curculio spp. (weevils) was explored along most of the latitudinal range of Q. ilex. This included quantification of variation in seed size, survival likelihood of infested seeds, multi-infestation of acorns and community composition of Curculio weevils in acorns. Key Results: Larger seeds had a higher probability of surviving weevil attack (i.e. embryo not predated). Southern populations of oak produced on average four times larger seeds than those of northern populations. Consequently, the probability of survival of infested acorns decreased with latitude. The community composition of Curculio varied, with large weevils (C. elephas) dominating in southern populations and small weevils (C. glandium) dominating in northern populations. However, damage tolerance was robust against this turnover in predator functional traits. Furthermore, we did not detect any change in multi infestation of acorns along the geographical gradient. Conclusions: Quercus ilex tolerance to seed predation by Curculio weevils increases toward the southern end of its distribution. Generally, studies on geographical variation in plant defence against enemies largely ignore seed attributes or they focus on seed physical barriers. Thus, this research suggests another dimension in which geographical trends in plant defences should be considered, i.e. geographical variation in tolerance to seed predators mediated by seed size. PMID- 30452532 TI - Infertility in a cohort of male Danish firefighters - a register based study. AB - The aim of this study was to examine infertility among male firefighters in Denmark. We therefore established a cohort of 4,710 past and present male Danish firefighters through personnel and membership records from employers and trade unions. Information on vital status and infertility was linked to cohort members from 1984-2017 from the Danish Civil Registration System, the In Vitro Fertilisation Register and the National Patient Register using their Danish personal identification numbers. Hazard ratios (HRs) with corresponding confidence intervals (CIs) were estimated for male factor and overall infertility through cox regression analyses comparing the firefighters to two reference groups; a sample of employees and military men. Among the full time firefighters, male factor infertility was increased compared to the sample of employees (In Vitro Fertilisation model HR 1.46, 95% CI 1.10-1.94 and National Patient Register model HR 1.53, 95% CI 1.18-1.98). Results were less consistent using the military as reference. Further, the increase in infertility seemed restricted to time employed as firefighter. No increase in risk of either male factor or overall infertility was seen among the part time/volunteer firefighters. Thus, full time firefighting was associated with an increased risk of being diagnosed with male factor infertility in our cohort. PMID- 30452533 TI - Systolic Blood Pressure Trajectories in the Acute Phase and Clinical Outcomes in Two-year Follow-up among Patients with Ischemic Stroke. AB - Background: Optimal blood pressure (BP) levels during acute ischemic stroke have not been established. We studied associations between systolic BP trajectories during acute phase and subsequent clinical outcomes among patients with ischemic stroke. Methods: 4,036 patients with acute ischemic stroke and elevated BP from the CATIS trial were included in this analysis. Three BPs were measured every 2 hours in day 1, every 4 hours during days 2 and 3, and every 8 hours thereafter until hospital discharge or death. Clinical outcomes were assessed at 3, 12 and 24 months. Latent variable mixture modeling was used to identify subgroups that share a similar underlying trajectory of systolic BP during the first seven days after stroke onset. Logistic regression and Cox proportional hazards models were used to examine the associations between systolic BP trajectories and clinical outcomes during follow-up. Results: We identified five systolic BP trajectories of high, high-to-moderate-low, moderate-high, moderate-low, and low. Compared to participants in high trajectory, multiple-adjusted odds ratios (95% confidence interval) of all-cause mortality at 3 months for individuals in high-to-moderate low, moderate-high, moderate-low, and low were 0.34 (0.15-0.77), 0.58 (0.32 1.04), 0.29 (0.15-0.56), and 0.56 (0.26-1.19), respectively. Likewise, the corresponding hazard ratios for all-cause mortality in 24 months were 0.66 (0.44 1.00), 0.74 (0.53-1.05), 0.45 (0.32-0.66), and 0.61 (0.40-0.93), respectively. Similar associations were observed for recurrent stroke and cardiovascular disease, and in both the intervention and control groups. Conclusion: Patients with moderate-low systolic BP during acute ischemic stroke had a lower risk of adverse clinical outcomes. PMID- 30452534 TI - Clustering of samples with a tree-shaped dependence structure, with an application to microscopic time lapse imaging. AB - Motivation: Recent imaging technologies allow for high-throughput tracking of cells as they migrate, divide, express fluorescent markers, and change their morphology. The interpretation of these data requires unbiased, efficient statistical methods that model the dynamics of cell phenotypes. Results: We introduce treeHFM, a probabilistic model which generalizes the theory of hidden Markov models to tree structured data. While accounting for the entire genealogy of a cell, treeHFM categorizes cells according to their primary phenotypic features. It models all relevant events in a cell's life, including cell division, and thereby enables the analysis of event order and cell fate heterogeneity. Simulations show higher accuracy in predicting correct state labels when modeling the more complex, tree-shaped dependency of samples over standard HMM modeling. Applying treeHFM to time lapse images of hematopoietic progenitor cell differentiation, we demonstrate that progenitor cells undergo a well-ordered sequence of differentiation events. Availability: The treeHFM is implemented in C++. We provide wrapper functions for the programming languages R (CRAN package, https://CRAN.R-project.org/package=treeHFM and Matlab (available at Mathworks Central, http://se.mathworks.com/matlabcentral/fileexchange/57575 treehfml). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30452535 TI - Links Between Behavior Change Techniques and Mechanisms of Action: An Expert Consensus Study. AB - Background: Understanding the mechanisms through which behavior change techniques (BCTs) can modify behavior is important for the development and evaluation of effective behavioral interventions. To advance the field, we require a shared knowledge of the mechanisms of action (MoAs) through which BCTs may operate when influencing behavior. Purpose: To elicit expert consensus on links between BCTs and MoAs. Methods: In a modified Nominal Group Technique study, 105 international behavior change experts rated, discussed, and rerated links between 61 frequently used BCTs and 26 MoAs. The criterion for consensus was that at least 80 per cent of experts reached agreement about a link. Heat maps were used to present the data relating to all possible links. Results: Of 1,586 possible links (61 BCTs * 26 MoAs), 51 of 61 (83.6 per cent) BCTs had a definite link to one or more MoAs (mean [SD] = 1.44 [0.96], range = 1-4), and 20 of 26 (76.9 per cent) MoAs had a definite link to one or more BCTs (mean [SD] = 3.27 [2.91], range = 9). Ninety (5.7 per cent) were identified as "definite" links, 464 (29.2 per cent) as "definitely not" links, and 1,032 (65.1 per cent) as "possible" or "unsure" links. No "definite" links were identified for 10 BCTs (e.g., "Action Planning" and "Behavioural Substitution") and for six MoAs (e.g., "Needs" and "Optimism"). Conclusions: The matrix of links between BCTs and MoAs provides a basis for those developing and synthesizing behavioral interventions. These links also provide a framework for specifying empirical tests in future studies. PMID- 30452536 TI - Root system size response of bzh semi-dwarf oilseed rape hybrids to different nitrogen levels in the field. AB - Background and Aims: In oilseed rape (Brassica napus) semi-dwarf hybrid varieties from crosses between bzh dwarf and normal-type lines are of increasing interest. They have improved nitrogen (N) uptake, N-utilization and N-use efficiency compared to normal types. This study aimed to elucidate whether these N-related effects can be explained by the bzh shoot growth-type alone or also by differences in root traits. Methods: Root system size was measured using root electrical capacitance (EC) in field trials with two N levels in two sets of genotypes segregating for the bzh-locus: (1) 108 doubled haploid (DH) test hybrids in two seasons, 2010-2012, and (2) 16 near-isogenic hybrids in the 2016 17 season. Quantitative trait loci (QTL) for root EC were estimated in DH test hybrids. Seedling root architecture parameters were monitored in vitro. Key Results: In vitro root growth showed a higher root: shoot ratio in bzh semi-dwarf hybrids. Root EC in field trials was higher at high N supply than at zero N fertilization. In most trials semi-dwarf hybrids had higher EC than normal-type hybrids, but they reduced root EC in response to N limitation more than normal types. Root EC was more heritable at the end of flowering (h2 = 0.73) than at the beginning of flowering (h2 = 0.36) in near-isogenic hybrids and had a lower heritability in trials of DH test hybrids (h2 = 0.27). A QTL for root EC in the genomic region of the bzh-locus on linkage group A06 was significant at zero N fertilization. Conclusions: Root EC proved to be a meaningful method in oilseed rape breeding programmes targeting root system size. The greater reduction of semi-dwarf root EC compared to the normal type under low N supply with simultaneous increase in N efficiency implies that in roots it is not a question of 'the more the merrier' and that the bzh root system reacts highly economically when N is scarce. PMID- 30452537 TI - Can Suicide Attempt be Related to Problem Drinking: Cohort Study. AB - Aims: Alcohol consumption is a well-established risk factor in suicidal behaviour, but there is still discussion about which factor might imply greater suicide risk-acute alcohol intoxication or being a problems drinkers. The aim of this study was to analyse the association between a suicide attempt and the drinking pattern and to evaluate the risk factors for suicide attempt among problem drinkers versus non-problem drinkers. Short summary: We found that problem drinking (CAGE >=2) is an important issue in suicide attempts. Factors predicting suicide attempt among problem drinkers were male gender, younger age, being married or in a partnership status, low education and acute alcohol intoxication prior a suicide attempt. Methods: A cohort study was performed including all cases of patients (n = 425) hospitalized in the Lithuanian University of Health Sciences after a suicide attempt. Participants completed a self-administered questionnaire that included questions on sociodemographic characteristics, the nature of the suicide attempt, the question of alcohol consumption prior to the suicide attempt and a CAGE questionnaire screening for problem drinking (CAGE >= 2). Results: Two-thirds (70.9%) of male and 43.2% of female suicide attempters were problem drinkers. Problem drinking versus non problem drinking increased the risk of suicide attempt especially according to gender (3.2 times for male), age (1.08 times for younger age), marital status (among married or in a partnership-1.58 times), education level (among < 12 years 2.04 times) and acute alcohol intoxication prior a suicide attempt (8.15 times among intoxicated). Conclusions: Our results highlight that being a problem drinker as well as the use of alcohol at the time of the event is an important issue in suicide attempt,. PMID- 30452538 TI - Some desirable properties of the Bonferroni correction: is the Bonferroni correction really so bad? PMID- 30452539 TI - CAARS: comparative assembly and annotation of RNA-Seq data. AB - Motivation: RNA sequencing is a widely used approach to obtain transcript sequences in non-model organisms, notably for performing comparative analyses. However, current bioinformatic pipelines do not take full advantage of pre existing reference data in related species for improving RNA-seq assembly, annotation, and gene family reconstruction. Results: We built an automated pipeline named CAARS to combine novel data from RNA-Seq experiments with existing multi-species gene family alignments. RNA-Seq reads are assembled into transcripts by both de novo and assisted assemblies. Then, CAARS incorporates transcripts into gene families, builds gene alignments and trees, and uses phylogenetic information to classify the genes as orthologs and paralogs of existing genes. We used CAARS to assemble and annotate RNA-Seq data in rodents and fishes using distantly related genomes as reference, a difficult case for this kind of analysis. We showed CAARS assemblies are more complete and accurate than those assembled by a standard pipeline consisting of de novo assembly coupled with annotation by sequence similarity on a guide species. In addition to annotated transcripts, CAARS provides gene family alignments and trees, annotated with orthology relationships, directly usable for downstream comparative analyses. Availability and implementation: CAARS is implemented in Python and Ocaml and is freely available at https://github.com/carinerey/caars. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 30452540 TI - Time to First Cigarette and the Risk of Hypertension: A Nationwide Representative Study in Korea. AB - BACKGROUND: While previous studies have explored the effect of smoking on blood pressure, little is still known about the role of time to first cigarette (TTFC) an indicator of nicotine dependence-on hypertension. Therefore, we evaluated this association using representative nationwide data. METHODS: Current daily smokers (N = 941; aged 19-79 years) who participated in the 7th version of the Korea National Health and Nutrition Examination Survey I (2016) were included. We categorized participants into four groups according to their TTFC. Furthermore, we categorized participants into hypertensive and non-hypertensive groups based on whether they were taking antihypertensive medications or had high blood pressure (>=140/90 mmHg). The association of daily TTFC and hypertension was examined without adjusting for any covariates; after adjusting for smoking behaviors; and after adjusting for demographic characteristics, socioeconomic status, health-related behaviors, and comorbidities. RESULTS: In the fully adjusted weighted regression analysis, participants reporting TTFC <= 5 minutes (vs. >60 minutes) had roughly twice the odds of having hypertension (confidence interval (CI) = 1.07-4.16) and the adjusted odds ratios compared with TTFC of greater than 60 minutes were 1.53 (CI = 0.81-2.86) for 6-30 minutes and 1.31 (0.68-2.50) for 31-60 minutes (Ptrend = .03). CONCLUSIONS: Hypertension risk increases with shorter TTFC. Especially, TTFC <= 5 minutes, may prove valuable in assessing the risk of hypertension. Screening smokers based on their TTFC might be useful in assessing their risk of hypertension and smoking cessation programs. PMID- 30452541 TI - Associations Between Features of Placental Morphology and Birthweight in Dichorionic Twins. AB - Low birthweight is associated with both perinatal and long-term morbidity and mortality and may be a result of abnormal placental development and function. Studies in singletons have reported associations between features of placental morphology and birthweight. Evaluating similar associations within twin pairs offers a unique opportunity to control for key confounders shared within a twin pair, including gestational age, parental characteristics, and intrauterine environment, which may otherwise be unfeasible. This analysis utilized 208 sets of dichorionic twins with unfused placentas from three studies in the US, completed from 2012-2013, 2006-2008, and 1959-1966. We used linear regression to model difference in birthweight within a twin pair as a function of differences in placental characteristics (thickness, two-dimensional surface area, intraplacental difference in diameters). After controlling for sex discordance, a 75.3cm2 difference in placental surface area, which reflects the interquartile range, was associated with a difference in birthweight of 142.1 grams (95% confidence interval [CI]: 62.9, 221.3). The magnitude of the association may also be larger for same-sex male pairs than same-sex female pairs (males: 265.8 grams, 95% CI: 60.8, 470.8; females: 133.0 grams, 95% CI: 15.7, 250.3). Strong associations between surface area and birthweight are consistent with reported results for singleton pregnancies. PMID- 30452542 TI - Maternal Iodine Intake in Pregnancy and Childhood Neurodevelopment At 18 months. AB - There are limited and inconsistent data suggesting that mild iodine deficiency in pregnancy may be associated with poorer developmental outcomes in children. Between 2011and 2015, we conducted a prospective cohort study in Australia examining the relationship between maternal iodine intake in pregnancy and childhood neurodevelopment, assessed using Bayley Scales of Infant and Toddler Development (Bayley-III) in 699 children at 18 months. Maternal iodine intake and urinary iodine concentration (UIC) were assessed at study entry (<20 weeks' gestation) and at 28 weeks' gestation. Maternal iodine intake in the lowest (< 220 MUg/day) or highest (>=391 MUg/day) quartiles was associated with lower cognitive, language and motor scores [mean difference (95% CI) ranged from 2.4 (0.01, 4.8) to 7.0 (2.8, 11.1) points lower] and a higher odds [Odds Ratio (95% CI) ranged from 2.7 (1.3, 5.6) to 2.8 (1.3, 5.7)] of cognitive developmental delay (Bayley score < 85), compared with mothers with an iodine intake in the middle quartiles. There was no association between UIC in pregnancy and Bayley III outcomes regardless of whether UIC and the outcomes were analyzed as continuous or category variables. Both low and high iodine intakes in pregnancy were associated with poorer childhood neurodevelopment in this iodine sufficient population. PMID- 30452543 TI - Bioinformatics methodologies for coeliac disease and its comorbidities. AB - Coeliac disease (CD) is a complex, multifactorial pathology caused by different factors, such as nutrition, immunological response and genetic factors. Many autoimmune diseases are comorbidities for CD, and a comprehensive and integrated analysis with bioinformatics approaches can help in evaluating the interconnections among all the selected pathologies. We first performed a detailed survey of gene expression data available in public repositories on CD and less commonly considered comorbidities. Then we developed an innovative pipeline that integrates gene expression, cell-type data and online resources (e.g. a list of comorbidities from the literature), using bioinformatics methods such as gene set enrichment analysis and semantic similarity. Our pipeline is written in R language, available at the following link: http://bioinformatica.isa.cnr.it/COELIAC_DISEASE/SCRIPTS/. We found a list of common differential expressed genes, gene ontology terms and pathways among CD and comorbidities and the closeness among the selected pathologies by means of disease ontology terms. Physicians and other researchers, such as molecular biologists, systems biologists and pharmacologists can use it to analyze pathology in detail, from differential expressed genes to ontologies, performing a comparison with the pathology comorbidities or with other diseases. PMID- 30452544 TI - Evolutionary dynamics of residual disease in human glioblastoma. AB - Glioblastoma is the most common and aggressive adult brain malignancy against which conventional surgery and chemoradiation provide limited benefit. Even when a good treatment response is obtained, recurrence inevitably occurs either locally (c.80%) or distally (c.20%), driven by cancer clones that are often genomically distinct from those in the primary tumour. Glioblastoma cells display a characteristic infiltrative phenotype, invading the surrounding tissue and often spreading across the whole brain. Cancer cells responsible for relapse can reside in two compartments of residual disease that are left behind after treatment: the infiltrated normal brain parenchyma, and the sub-ventricular zone (SVZ). However, these two sources of residual disease in glioblastoma are understudied because of the difficulty in sampling these regions during surgery. Here we present the results of whole-exome sequencing of 69 multi-region samples collected using fluorescence-guided resection from 11 patients, including the infiltrating tumour margin (M) and the SVZ for each patient, as well as matched blood. We used a phylogenomic approach to dissect the spatio-temporal evolution of each tumour and unveil the relation between residual disease and the main tumour mass. We also analysed two patients with paired primary-recurrence samples with matched residual disease. Our results suggest that infiltrative subclones can arise early during tumour growth in a subset of patients. After treatment, the infiltrative subclones may seed the growth of a recurrent tumour, thus representing the 'missing link' between the primary tumour and recurrent disease. These results are consistent with recognised clinical phenotypic behaviour and suggest that more specific therapeutic targeting of cells in the infiltrated brain parenchyma may improve patient's outcome. PMID- 30452545 TI - iCatch: a new strategy for capturing large DNA fragments using homing endonucleases. AB - Natural genetic materials contain many biosynthetic gene clusters encoding potentially valuable natural products, many of which can be used directly without codon optimization or other manipulations. With the development of synthetic biology, several DNA assembly standards have been proposed, conveniently facilitating the reuse of natural materials. Among these standards, the iBrick assembly standard was developed by our laboratory to manipulate large DNA fragments, employing two homing endonucleases. Considering the difficulty of cloning large iBrick parts using conventional endonuclease-mediated restriction and ligation methods, we herein present a new method, known as iCatch, which readily captures biosynthetic gene clusters. As the clusters cloned by iCatch have the prefix and suffix of the iBrick standard, they serve as new iBrick parts and are therefore conducive to further editing and assembly with the iBrick standard. iCatch employs the natural homologous recombination system to flank the region of interest with I-SceI and PI-PspI recognition sites, after which the genome is digested with I-SceI or PI-PspI and the fragments are then self-ligated to clone the target DNA fragments. We used this method to successfully capture the actinorhodin biosynthetic cluster from Streptomyces coelicolor and then heterologously expressed this cluster in a thermophilic Streptomyces strain. We propose that iCatch can be used for the cloning of DNA sequences that are dozens of kilobases in length, facilitating the heterologous expression of microbial natural products. Moreover, this cloning methodology can be a complementary tool for the iBrick standard, especially in applications requiring the manipulation of large DNA fragments. PMID- 30452546 TI - Loss-of-function mutations with circadian rhythm regulator Per1/Per2 lead to premature ovarian insufficiency. AB - Mechanism underlying premature ovarian insufficiency remains incompletely understood. Here we report that mice with Per1m/m; Per2m/m double mutations display a decrease in female fertility starting approximately at 20-week-old, with significantly less pups born from 32-week-old onwards. Histological analysis revealed that a significant reduction of ovarian follicles was observed in the Per1/Per2 mutants compared with the littermate controls examined at 26- and 52 week-old while the difference was not statistically significant between the two groups at 3- and 8-week-old. We further showed that vascular development including the ovarian follicle associated vascular growth appeared normal in the Per1/Per2 mutant mice, although clock genes were reported to regulate angiogenesis in zebrafish. The findings imply that loss-of-function mutations with Per1/Per2 result in a premature depletion of ovarian follicle reserve leading to the decline of reproductive capacity. PMID- 30452547 TI - DiPhiSeq: Robust comparison of expression levels on RNA-Seq data with large sample sizes. AB - Motivation: In the analysis of RNA-Seq data, detecting differentially expressed (DE) genes has been a hot research area in recent years and many methods have been proposed. DE genes show different average expression levels in different sample groups, and thus can be important biological markers. While generally very successful, these methods need to be further tailored and improved for cancerous data, which often features quite diverse expression in the samples from the cancer group, and this diversity is much larger than that in the control group. Results: We propose a statistical method that can detect not only genes that show different average expressions, but also genes that show different diversities of expressions in different groups. These "differentially dispersed" genes can be important clinical markers. Our method uses a redescending penalty on the quasi likelihood function, and thus has superior robustness against outliers and other noise. Simulations and real data analysis demonstrate that DiPhiSeq outperforms existing methods in the presence of outliers, and identifies unique sets of genes. Availability: DiPhiSeq is publicly available as an R package on CRAN: https://cran.r-project.org/package=DiPhiSeq. Supplementary Information: Supplementary data supplemental_materials.pdf are available at Bioinformatics online. PMID- 30452548 TI - An Investigation of Selection Bias in Estimating Racial Disparity in Stroke Risk Factors: The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. AB - Selection due to survival or attrition may bias estimates of racial disparities in health, but few studies quantify the likely magnitude of such bias. In a large national cohort with moderate loss to follow-up, we contrast racial differences in two stroke risk factors, incident hypertension and incident left ventricular hypertrophy estimated by complete case analyses, inverse probability of attrition weighting, and the Survivor Average Causal Effect. We utilized data on 12,497 black and 17,660 white participants enrolled from 2003 through 2007 and collected incident risk factor data approximately 10 years after baseline. At follow-up, 21.0% of whites and 23.0% of blacks had died; additionally 22.0% of whites and 28.4% of blacks had withdrawn. Individual probabilities of completing the follow up visit were estimated using baseline demographic and health characteristics. Adjusted risk ratio estimates of racial disparities from complete case analyses in both incident hypertension (1.11 [95% CI: 1.02, 1.21]) and incident left ventricular hypertrophy (1.02 [95% CI: 0.84, 1.24]) were virtually identical to estimates from inverse probability of attrition weighting and Survivor Average Causal Effect. Despite racial differences in mortality and attrition, we found little evidence of selection bias in the estimation of racial differences for these incident risk factors. PMID- 30452551 TI - Multiple sensory impairment is associated with increased risk of dementia among black and white older adults. AB - Background: Few studies have examined impairment in multiple senses (multisensory impairment) and risk of dementia in comparison to having a single or no sensory impairment. Methods: We studied 1,810 black and white non-demented participants from Health, Aging, and Body Composition (Health ABC) Study aged 70-79 at enrollment. Sensory impairment was determined at our study baseline (Year 3-5 of Health ABC) using established cut-points for vision (Bailey-Lovie visual acuity and Pelli-Robson contrast sensitivity test), hearing (audiometric testing), smell (12-item Cross-Cultural Smell Identification Test), and touch (peripheral nerve function tests). Incident dementia over 10 years of follow-up was based on hospitalization records, dementia medications, or >=1.5 Standard Deviation decline in Modified Mini-Mental State Exam score (race-specific). Cox proportional hazard models with adjustment for demographics, health behaviors, and health conditions evaluated the relationship between risk of dementia and increasing number of sensory impairments. Results: Sensory impairments were common: 28% had visual impairment, 35% had hearing loss, 22% had poor smell, 12% had touch insensitivity; 26% had 2+ impairments, and 5.6% had 3+ sensory impairments. Number of impairments was associated with risk of dementia in a graded fashion (p<0.001). Compared to no sensory impairments, the adjusted Hazard Ratio (HR) was 1.5 (95%CI:1.1,2.0) for 1 sensory impairment, 1.9 (95%CI:1.4,2.6) for 2 sensory impairments, and 2.8 (95%CI:1.9,4.3) for 3+ sensory impairments. Conclusions: Multisensory impairment was strongly associated with increased risk of dementia. Although, the nature of this relationship needs further investigation, sensory function assessment in multiple domains may help identify patients at high risk of dementia. PMID- 30452552 TI - Leadless pacing using the transcatheter pacing system (Micra TPS) in the real world: initial Swiss experience from the Romandie region. PMID- 30452553 TI - Association of Interpersonal Violence With Women's Health. PMID- 30452554 TI - Focused ultrasound thalamotomy location determines clinical benefits in patients with essential tremor. AB - Magnetic resonance guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive ablative treatment for essential tremor. The size and location of therapeutic lesions producing the optimal clinical benefits while minimizing adverse effects are not known. We examined these relationships in patients with essential tremor undergoing MRgFUS. We studied 66 patients with essential tremor who underwent MRgFUS between 2012 and 2017. We assessed the Clinical Rating Scale for Tremor (CRST) scores at 3 months after the procedure and tracked the adverse effects (sensory, motor, speech, gait, and dysmetria) 1 day (acute) and 3 months after the procedure. Clinical data associated with the postoperative Day 1 lesions were used to correlate the size and location of lesions with tremor benefit and acute adverse effects. Diffusion-weighted imaging was used to assess whether acute adverse effects were related to lesions encroaching on nearby major white matter tracts (medial lemniscus, pyramidal, and dentato-rubro-thalamic). The area of optimal tremor response at 3 months after the procedure was identified at the posterior portion of the ventral intermediate nucleus. Lesions extending beyond the posterior region of the ventral intermediate nucleus and lateral to the lateral thalamic border were associated with increased risk of acute adverse sensory and motor effects, respectively. Acute adverse effects on gait and dysmetria occurred with lesions inferolateral to the thalamus. Lesions inferolateral to the thalamus or medial to the ventral intermediate nucleus were also associated with acute adverse speech effects. Diffusion-weighted imaging revealed that lesions associated with adverse sensory and gait/dysmetria effects compromised the medial lemniscus and dentato-rubro-thalamic tracts, respectively. Lesions associated with adverse motor and speech effects encroached on the pyramidal tract. Lesions larger than 170 mm3 were associated with an increased risk of acute adverse effects. Tremor improvement and acute adverse effects of MRgFUS for essential tremor are highly dependent on the location and size of lesions. These novel findings could refine current MRgFUS treatment planning and targeting, thereby improving clinical outcomes in patients. PMID- 30452555 TI - Klotho deficiency accelerates stem cells aging by impairing telomerase activity. AB - Understanding the effect of molecular pathways involved in the age-dependent deterioration of stem cell function is critical for developing new therapies. The overexpression of Klotho (KL), an anti-aging protein, causes treated animal models to enjoy extended lifespans. Now, the question stands: Does KL-deficiency accelerate stem cell aging and telomere shortening? If so, what are the specific mechanisms by which it does this, and is cycloastragenol (CAG) treatment enough to restore telomerase activity in aged stem cells? We found that KL-deficiency diminished telomerase activity by altering the expression of TERF1 and TERT, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. Telomerase activity decreased with KL-siRNA knockdown. This suggests that both KL and telomeres regulate the stem cell aging process through telomerase subunits TERF1, POT1 and TERT using the TGFbeta, Insulin, and Wnt signaling. These pathways can rejuvenate stem cell populations in a CD90-dependent mechanism. Stem cell dysfunctions were largely provoked by KL deficiency and telomere shortening, owing to altered expression of TERF1, TGFbeta1, CD90, POT1, TERT, and bFGF. The CAG treatment partially rescued telomerase deterioration, suggesting that KL plays a critical role in life extension by regulating telomere length and telomerase activity. PMID- 30452556 TI - Deficiency of the T cell regulator Casitas B-cell lymphoma-B aggravates atherosclerosis by inducing CD8+ T cell-mediated macrophage death. AB - Aims: The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results: The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb-/-Apoe-/- mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8+ T cells. Cblb-/-Apoe-/- macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8+ T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFNgamma and granzyme B production was enhanced in Cblb-/-Apoe-/- CD8+ T cells, which provoked macrophage killing. Depletion of CD8+ T cells in Cblb-/-Apoe-/- bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8+ T cells. Conclusion: Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8+ T cell activation and CD8+ T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques. PMID- 30452557 TI - Review: Long-chain omega-3 fatty acids have no effect on mortality or overall cardiovascular events. PMID- 30452558 TI - Review: In adults, increasing omega-6 fatty acid intake does not reduce mortality or overall cardiovascular events. PMID- 30452559 TI - Review: In VTE, reduced- and full-dose extended DOAC therapies do not differ and are better than no extended therapy. PMID- 30452560 TI - Pooled RCTs: Adding LABAs to ICSs do not increase serious asthma events and reduce exacerbations. PMID- 30452561 TI - In Barrett esophagus, high- vs low-dose esomeprazole improved clinical outcomes; aspirin vs no aspirin did not. PMID- 30452562 TI - Review: In coronary artery disease, PCI reduces 30-day and 5-year risk for stroke compared with CABG. PMID- 30452563 TI - In persistent hypertension, low-dose triple-pill therapy increased the likelihood of achieving target BP at 6 mo. PMID- 30452565 TI - Some invasive inpatient and outpatient procedures were linked to infective endocarditis. PMID- 30452564 TI - Pooled RCTs: Low-dose ASA reduced CV events in persons < 70 kg; higher-dose ASA was effective at higher body weights. PMID- 30452566 TI - Risk scores overestimated risk for CVD in newly diagnosed type 2 diabetes. PMID- 30452567 TI - Heart Failure. PMID- 30452568 TI - Heart Failure. PMID- 30452569 TI - Defining, Estimating, and Communicating Overdiagnosis in Cancer Screening. PMID- 30452570 TI - Defining, Estimating, and Communicating Overdiagnosis in Cancer Screening. PMID- 30452571 TI - Firearms and Dementia. PMID- 30452573 TI - Correction: Harms of Breast Cancer Screening. PMID- 30452572 TI - Firearms and Dementia. PMID- 30452574 TI - Dust Bath. PMID- 30452575 TI - the doctor told him. PMID- 30452576 TI - Keep at Bay. PMID- 30452577 TI - The Privilege of Grief. PMID- 30452578 TI - Web Exclusive. Annals for Hospitalists Inpatient Notes - How I Changed My Practice-Perioperative Bridging Anticoagulation. PMID- 30452579 TI - Web Exclusive. Annals Consult Guys - The Art of Medicine-or Medicine in Art? PMID- 30452580 TI - Web Exclusive. Annals On Call - Primary Aldosteronism: How Often Are We Missing It? PMID- 30452581 TI - Annals for Hospitalists - 20 November 2018. PMID- 30452582 TI - Annals for Educators - 20 November 2018. PMID- 30452583 TI - A Novel Pollen Transfer Mechanism by Honey Bee Foragers on Highbush Blueberry (Ericales: Ericaceae). AB - Honey bees (Apis mellifera L. (Hymenoptera: Apidae)) are effective pollinators of many crops but are thought to be inefficient in pollinating blueberries (Vaccinium corymbosum L.) due to their inability to buzz pollinate. Nonetheless, commercial growers rent honey bee hives for pollination, resulting in the dominance of honey bee workers visiting flowers during bloom. The objective of this study was to examine where on the honey bee pollen is carried and how it is transferred from flower to bee to the stigma of other flowers. Examination of 90 honey bee workers foraging on blueberry flowers documented that blueberry pollen tetrads were present on all body parts. Relative amounts were as follows: head 12%, body 6%, legs 19%, and tarsi 63%. Quantities on the body subregions ranged from an average of 400 tetrads on the basitarsi to 16 on the fore tarsal claws. Thus, a single contact between many of the pollen-carrying body parts and a stigma has the potential to transfer significant amounts of pollen. The study also revealed that bee behaviors unrelated to the intentional collection of nectar and pollen, such as the frequent touching of stigmas by the claws, tarsi, or legs, while foraging, grooming, and walking across flower clusters, could result in pollen transfer. These contacts occurred 65.9% of the time a honey bee landed on a flower cluster. These findings have broad implications for future assessments of the efficiencies of various bee species in pollinating diverse crops and plants. PMID- 30452584 TI - Geographical access to GPs and modes of cancer diagnosis in England: a cross sectional study. AB - Background: Poor geographical access to health services and routes to a cancer diagnosis such as emergency presentations have previously been associated with worse cancer outcomes. However, the extent to which access to GPs determines the route that patients take to obtain a cancer diagnosis is unknown. Methods: We used a linked dataset of cancer registry and hospital records of patients with a cancer diagnosis between 2006 and 2010 across eight different cancer sites. Primary outcomes were defined as 'desirable routes to diagnosis' [screen-detected and 2-week wait (TWW) referrals] and 'less desirable routes' [emergency presentations and death certificate only (DCO)]. All other routes (GP referral, inpatient elective and other outpatient) were specified as the reference category. Geographical access was measured as travel time in minutes from patients to their GP, and multinomial logistic regression was used to estimate relative risk ratios (RRR). Results: Longer travel was associated with increased risk of diagnosis via emergency and DCO, but decreased risk of diagnosis via screening and TWW. Patients travelling over 30 minutes had the highest risk of a DCO diagnosis, which was statistically significant for breast, colorectal, lung, prostate, stomach and ovarian cancers (compared with patients with travel times <=10 minutes: RRR 5.89, 7.02, 2.30, 4.75, 10.41; P < 0.01 and 3.51, P < 0.05). Discussion: Poor access to GPs may discourage early engagement with health services, decreasing the likelihood of screening uptake and increasing the likelihood of emergency presentations. Extra effort is needed to promote early diagnosis in more distant patients. PMID- 30452585 TI - Curveball: A tool for rapid measurement of contrast sensitivity based on smooth eye movements. AB - The contrast sensitivity function (CSF) is an informative measure of visual function, but current tools for assessing it are limited by the attentional, motor, and communicative abilities of the participant. Impairments in these abilities can prevent participants from engaging with tasks or following an experimenter's instructions. Here, we describe an efficient new tool for measuring contrast sensitivity, Curveball, and empirically validate it with a sample of healthy adults. The Curveball algorithm continuously infers stimulus visibility through smooth eye tracking instead of perceptual report, and rapidly lowers stimulus contrast in real time until a threshold is found. The procedure requires minimal instruction to administer and takes only five minutes to estimate a full CSF, which is comparable to the best existing methods available for healthy adults. Task repeatability was high: the coefficients of repeatability were 0.275 (in log10 units of RMS contrast) within the same session and 0.227 across different days. We also present evidence that the task is robust across illumination changes, well correlated with results from conventional psychophysical methods, and highly sensitive to improvements in visual acuity from refractive correction. Our findings indicate that Curveball is a promising means of accurately assessing contrast sensitivity in previously neglected populations. PMID- 30452586 TI - The development of Bayesian integration in sensorimotor estimation. AB - Examining development is important in addressing questions about whether Bayesian principles are hard coded in the brain. If the brain is inherently Bayesian, then behavior should show the signatures of Bayesian computation from an early stage in life. Children should integrate probabilistic information from prior and likelihood distributions to reach decisions and should be as statistically efficient as adults, when individual reliabilities are taken into account. To test this idea, we examined the integration of prior and likelihood information in a simple position-estimation task comparing children ages 6-11 years and adults. Some combination of prior and likelihood was present in the youngest sample tested (6-8 years old), and in most participants a Bayesian model fit the data better than simple baseline models. However, younger subjects tended to have parameters further from the optimal values, and all groups showed considerable biases. Our findings support some level of Bayesian integration in all age groups, with evidence that children use probabilistic quantities less efficiently than adults do during sensorimotor estimation. PMID- 30452587 TI - Visual perceptual learning modulates decision network in the human brain: The evidence from psychophysics, modeling, and functional magnetic resonance imaging. AB - Perceptual learning refers to improved perceptual performance after intensive training and was initially suggested to reflect long-term plasticity in early visual cortex. Recent behavioral and neurophysiological evidence further suggested that the plasticity in brain regions related to decision making could also contribute to the observed training effects. However, how perceptual learning modulates the responses of decision-related regions in the human brain remains largely unknown. In the present study, we combined psychophysics and functional magnetic resonance imaging (fMRI), and adopted a model-based approach to investigate this issue. We trained participants on a motion direction discrimination task and fitted their behavioral data using the linear ballistic accumulator model. The results from model fitting showed that behavioral improvement could be well explained by a specific improvement in sensory information accumulation. A critical model parameter, the drift rate of the information accumulation, was correlated with the fMRI responses derived from three spatial independent components: ventral premotor cortex (PMv), supplementary eye field (SEF), and the fronto-parietal network, including intraparietal sulcus (IPS) and frontal eye field (FEF). In this decision network, we found that the behavioral training effects were accompanied by signal enhancement specific to trained direction in PMv and FEF. Further, we also found direction-specific signal reduction in sensory areas (V3A and MT+), as well as the strengthened effective connectivity from V3A to PMv and from IPS to FEF. These findings provide evidence for the learning-induced decision refinement after perceptual learning and the brain regions that are involved in this process. PMID- 30452588 TI - Hyperreflective Intraretinal Foci as an OCT Biomarker of Retinal Inflammation in Diabetic Macular Edema. PMID- 30452589 TI - Author Response: Hyperreflective Intraretinal Foci as an OCT Biomarker of Retinal Inflammation in Diabetic Macular Edema. PMID- 30452590 TI - Spectrum of Variants in 389 Chinese Probands With Familial Exudative Vitreoretinopathy. AB - Purpose: To identify potentially pathogenic variants (PPVs) in Chinese familial exudative vitreoretinopathy (FEVR) patients in FZD4, LRP5, NDP, TSPAN12, ZNF408, and KIF11 genes. Methods: Blood samples were collected from probands and their parent(s). Genomic DNA was analyzed by next-generation sequencing, and the sequence of selected variants were validated by Sanger sequencing. The potential pathogenicity of a variant was evaluated by in silico analysis and by cosegregation of the variant with disease. Each proband was subjected to comprehensive retinal examinations, and the severity of FEVR was individually graded for each eye. Whenever possible, fundus fluorescein angiography was obtained and analyzed for parent(s) of each proband. Variation in mutation expressivity was analyzed. Results: Three hundred eighty-nine consecutive FEVR patients from 389 families participated in this study. About 74% of the probands were children younger than 7 years old. One hundred one PPVs, 49 variants with unknown significance (VUS), were identified, including 73 novel PPVs and 38 novel VUS. One hundred ten probands carried PPV (28.3%), and 51 probands carried VUS (13.1%). PPVs in FZD4, LRP5, TSPAN12, NDP, ZNF408, and KIF11 were found in 8.48%, 9.00%, 5.91%, 4.63%, 0.77%, and 0.77% of the cohort, respectively. Probands carrying PPVs in NDP and KIF11 had more severe FEVR in general than those carrying PPVs in other genes. Overall, variants in LRP5 and FZD4 showed more significant variation in phenotype than variants in TSPAN12 and NDP genes. Conclusions: Our study expanded the spectrum of PPVs associated with FEVR. PMID- 30452591 TI - The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema. AB - Purpose: To evaluate the effect of intravitreal ranibizumab injections on aqueous concentrations of angiogenic or inflammatory cytokines in patients with diabetic macular edema (DME). Methods: Thirty eyes of 25 patients with center-involved DME were recruited to the study. All had a central macular thickness (CMT) of >300 MUm and best-corrected visual acuity (BCVA) between 28 and 70 logMAR letters (Snellen equivalent 20/320-20/40). At baseline, all eyes had 0.1 mL of aqueous collected before ranibizumab treatment. At week 4, a second ranibizumab injection was administered and at week 8, aqueous sampling was repeated before a third ranibizumab injection. From week 12, all eyes were followed at 4-weekly intervals and the need for ranibizumab treatment was determined by BCVA and CMT measurements. Levels of 32 cytokines were assessed at baseline and at week 8 using a multiplex array assay. Results: Following two consecutive ranibizumab injections, there was a statistically significant reduction in VEGF (P < 0.00001), as well as IL-1beta (P = 0.00006), IL-7 (P = 0.00002), IL-8 (P = 0.00023), IL-10 (P < 0.00001), IL-12 (P < 0.00001), IL-17 (P = 0.00024), MCP-1 (P = 0.00023), and TNF-alpha (P < 0.00001). There was also an upregulation of soluble VEGF receptor-2 (P = 0.00004). A P < 0.0015 was considered significant in this study. Conclusions: Ranibizumab treatment influences various inflammatory cytokine concentrations in addition to reducing aqueous VEGF concentrations in patients with DME. This may contribute to its therapeutic effect in patients with DME. PMID- 30452592 TI - CD40 Enhances Sphingolipids in Orbital Fibroblasts: Potential Role of Sphingosine 1-Phosphate in Inflammatory T-Cell Migration in Graves' Orbitopathy. AB - Purpose: Graves' orbitopathy (GO) is an autoimmune orbital disorder associated with Graves' disease caused by thyrotropin receptor autoantibodies. Orbital fibroblasts (OFs) and CD40 play a key role in disease pathogenesis. The bioactive lipid sphingosine-1-phosphate (S1P) has been implicated in promoting adipogenesis, fibrosis, and inflammation in OFs. We investigated the role of CD40 signaling in inducing S1P activity in orbital inflammation. Methods: OFs and T cells were derived from GO patients and healthy control (Ctl) persons. S1P abundance in orbital tissues was evaluated by immunofluorescence. OFs were stimulated with CD40 ligand and S1P levels were determined by ELISA. Further, activities of acid sphingomyelinase (ASM), acid ceramidase, and sphingosine kinase were measured by ultraperformance liquid chromatography. Sphingosine and ceramide contents were analyzed by mass spectrometry. Finally, the role for S1P in T-cell attraction was investigated by T-cell migration assays. Results: GO orbital tissue showed elevated amounts of S1P as compared to control samples. Stimulation of CD40 induced S1P expression in GO-derived OFs, while Ctl-OFs remained unaffected. A significant increase of ASM and sphingosine kinase activities, as well as lipid formation, was observed in GO-derived OFs. Migration assay of T cells in the presence of SphK inhibitor revealed that S1P released by GO-OFs attracted T cells for migration. Conclusions: The results demonstrated that CD40 ligand stimulates GO fibroblast to produce S1P, which is a driving force for T-cell migration. The results support the use of S1P receptor signaling modulators in GO management. PMID- 30452593 TI - Intravitreal Injection of AAV Expressing Soluble VEGF Receptor-1 Variant Induces Anti-VEGF Activity and Suppresses Choroidal Neovascularization. AB - Purpose: With anti-VEGF-based treatments for wet AMD requiring frequent injections, it is often burdensome to both patients and healthcare providers. To explore its possibility as a desirable alternative, we investigated the therapeutic potential of a recombinant adeno-associated virus 2 expressing a soluble variant of VEGF receptor-1 (rAAV2-sVEGFRv-1) in a laser-induced choroidal neovascularization (CNV) model, as CNV is a defining feature of AMD progression. Methods: C57/B6 mice were intravitreally administered with rAAV2-sVEGFRv-1, rAAV2 GFP, or clinically used bevacizumab after CNV lesions were induced via laser photocoagulation. Immunostaining was performed with phalloidin and CD31 to measure CNV extensiveness, F4/80 and CD11b for inflammatory cell infiltration, and pan-cytokeratin to visualize fibrotic progression. Results: rAAV2-sVEGFRv-1 (5.0 * 107 viral genomes) possesses antiangiogenic, anti-inflammatory, and antifibrotic properties. rAAV2-sVEGFRv-1 was demonstrated to significantly decrease retinal CNV lesion size (1336 +/- 186) when compared to rAAV2-GFP treated (2949 +/- 437, P = 0.0043), mock-treated (3075 +/- 265, P = 0.0013), and bevacizumab-treated models (995 +/- 234). Infiltration by inflammatory cells significantly decreased with rAAV2-sVEGFRv-1 administration, while groups treated with rAAV2-GFP did not. Additionally, antiapoptotic activity was observed via TUNEL assay in rAAV2-sVEGFRv-1 (16.0 +/- 3.6) and rAAV2-GFP (46.0 +/- 7.5, P = 0.003). Overall, the rAAV2-sVEGFRv-1 viral vector was positively comparable to bevacizumab, indicating it as effective as approved therapeutics. Conclusions: The ability of a low dose of rAAV2-sVEGFRv-1 to exert a therapeutically relevant anti-VEGF effect in a CNV model is demonstrated, and strongly suggests gene therapy as an effective and convenient treatment for sustained VEGF suppression. PMID- 30452594 TI - Estimation of Contrast Sensitivity From Fixational Eye Movements. AB - Purpose: Even during steady fixation, people make small eye movements such as microsaccades, whose rate is altered by presentation of salient stimuli. Our goal was to develop a practical method for objectively and robustly estimating contrast sensitivity from microsaccade rates in a diverse population. Methods: Participants, recruited to cover a range of contrast sensitivities, were visually normal (n = 19), amblyopic (n = 10), or had cataract (n = 9). Monocular contrast sensitivity was estimated behaviorally while binocular eye movements were recorded during interleaved passive trials. A probabilistic inference approach was used to establish the likelihood of observed microsaccade rates given the presence or absence of a salient stimulus. Contrast sensitivity was estimated from a function fitted to the scaled log-likelihood ratio of the observed microsaccades in the presence or absence of a salient stimulus across a range of contrasts. Results: Microsaccade rate signature shapes were heterogeneous; nevertheless, estimates of contrast sensitivity could be obtained in all participants. Microsaccade-estimated contrast sensitivity was unbiased compared to behavioral estimates (1.2% mean), with which they were strongly correlated (Spearman's rho 0.74, P < 0.001, median absolute difference 7.6%). Measurement precision of microsaccade-based contrast sensitivity estimates was worse than that of behavioral estimates, requiring more than 20 times as many presentations to equate precision. Conclusions: Microsaccade rate signatures are heterogeneous in shape when measured across populations with a broad range of contrast sensitivities. Contrast sensitivity can be robustly estimated from rate signatures by probabilistic inference, but more stimulus presentations are currently required to achieve similarly precise estimates to behavioral techniques. PMID- 30452595 TI - Clinically Relevant Outcome Measures for the I307N Rhodopsin Mouse: A Model of Inducible Autosomal Dominant Retinitis Pigmentosa. AB - Purpose: The I307N rhodopsin (Rho) mouse is a light-inducible model of autosomal dominant retinitis pigmentosa (adRP) that may be useful in testing therapies. We investigated the time-course of retinal changes of the I307N Rho mouse with spectral-domain optical coherence tomography (SD-OCT). Methods: SD-OCT was performed up to day 30 after light damage; electroretinography (ERG) was employed to evaluate photoreceptor function. We utilized ImageJ to analyze reflectivity of the retina. We used light and electron microscopy to assess retinal organization. We stained synaptophysin and zonula occludins-1 with immunohistochemistry to determine injury to the plexiform layers and retinal pigment epithelium (RPE). We performed lectin staining to evaluate retinal blood vessels. Results: Retinal degeneration increased with longer exposures to light. An increase in retinal thickness was detected by SD-OCT on day 1 after light challenge followed by loss of the outer nuclear layer (ONL) by day 8. Degeneration was most severe in the nasal and inferior retina. Hyper-reflectivity on SD-OCT developed as early as 1 day after light exposure. Disorganization of the ONL, condensation of photoreceptor chromatin, disruption of the outer limiting membrane, and disarray of outer segments were associated with the hyper-reflectivity. Retraction of the outer plexiform synapses and resorption of the subretinal detachment contributed to retinal thinning. The RPE remained intact, whereas atrophied major retinal vessels were evident after light damage. Conclusions: Our time-course analysis of retinal degeneration in the I307N Rho mouse with SD-OCT and other outcome measures should enable the use of the mouse model in preclinical efficacy studies and mechanistic studies. PMID- 30452596 TI - SIRT1 Deletion Impairs Retinal Endothelial Cell Migration Through Downregulation of VEGF-A/VEGFR-2 and MMP14. AB - Purpose: Silent information regulator protein 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase that is abundantly expressed in vascular endothelial cells (VECs), and it has an essential role in angiogenesis. However, its contribution to retinal vascular development remains unclear. Here we characterize its involvement in regulating this process under both physiological and pathologic conditions. Methods: Endothelium-specific Sirt1 knockout mice were established using the Cre-lox system. VECs were isolated using magnetic beads and identified by immunostaining. Retinal whole-mount staining analyzed the retinal vascular patterns. SIRT1 was knocked down or overexpressed in human retinal microvascular endothelial cells (HRMECs) using small interfering RNA (siRNA) or lentivirus infection, respectively. Scratch assay, Transwell, and Matrigel angiogenesis assay evaluated cell migration and tube formation, respectively. Quantitative RT-PCR analyzed genes regulating VEC migration. Western blotting determined protein expression. Coimmunoprecipitation detected the interaction of hypoxia-inducible factor 1alpha (HIF-1alpha) and SIRT1 as well as acetylation status of HIF-1alpha. Results: Specific deletion of Sirt1 in VECs dramatically delayed retinal vessel expansion and reduced vessel density. In the oxygen induced retinopathy (OIR) mouse model, Sirt1 ablation markedly suppressed retinal revascularization and consequently increased retinal avascularity. SIRT1 downregulation in HRMECs inhibited cell migration and tube formation, while overexpression of SIRT1 had the opposite effects. Vascular endothelial growth factor-A (VEGF-A)/VEGF receptor-2 (VEGFR-2), and matrix metalloproteinases 14 (MMP14) expression significantly declined in Sirt1-null VECs, as well as SIRT1 siRNA-transfected HRMECs. SIRT1 downregulation upregulated the HIF-1alpha acetylation status. Conversely, SIRT1 overexpression decreased this response. Conclusions: SIRT1 contributes to both physiological and pathologic retinal angiogenesis through promoting retinal VEC migration. Its underlying molecular mechanism involves SIRT1-mediated deacetylation of HIF-1alpha and subsequent upregulation of VEGF-A/VEGFR-2 and MMP14 expression. PMID- 30452597 TI - Blood Flow in Monocular Retinoblastoma Assessed by Color Doppler and Correlations With High-Risk Pathologic Features. AB - Purpose: To use color Doppler to analyze blood flow in the retrobulbar central retinal artery (CRA) and central retinal vein (CRV) in monocular retinoblastoma. Methods: This prospective study included patients with group D and E retinoblastomas managed with only enucleation. Peak blood velocities were assessed in the CRA and CRV of tumor-containing eyes (CRAv and CRVv, respectively). The resistivity index in the CRA (RIa) and pulse index in the CRV (PIv) were calculated and related to optic nerve invasion (ONi), choroid invasion (mCHi), and tumor volume. RIa and PIv were also calculated for healthy eyes. Results: In total, 25 patients with a mean age of 30.8-months old were included. The means (SD) for CRAv, CRVv, RIa, and PIv were 26.94 (12.32) cm/s, 16.2 (9.56) cm/s, 0.88 (0.12) and 0.79 (0.29), respectively. Tumor volume was significantly correlated with CRAv (P = 0.025) and RIa (P = 0.032). ONi was present in 19 eyes and correlated with a smaller PIv (P < 0.001). A PIv less than 0.935 had a sensitivity of 89.5% and specificity of 83.3% for predicting ONi. mCHi was not correlated with flow values. Healthy eyes had a significantly lower RIa (P < 0.001) and lower PIv than eyes with (P = 0.009) and without (P < 0.001) ONi. Conclusions: In advanced-stage monocular retinoblastoma, tumor volume was directly correlated with CRAv and RIa, and lower PIv was correlated with optic nerve invasion when a predictive cut-off value of less than 0.935 was applied. Comparisons with healthy eyes showed that tumor-containing eyes were associated with higher RIa and PIv values. PMID- 30452598 TI - The Relationship Between the Sighting Eye and Functional and Structural Asymmetries in Glaucoma. AB - Purpose: To determine the relationship between the sighting eye choice and functional and structural asymmetries in open-angle glaucoma (OAG). Methods: Two hundred patients with bilateral OAG underwent dominant eye testing using a hole in-a-card test. The paired eyes were divided into worse and better eyes according to the mean deviation (MD) of visual field (VF) results. Based on the results, patients whose sighting eyes corresponded to eyes with a better VF were designated as group 1, and those whose sighting eyes corresponded to eyes with a worse VF as group 2. Results: The sighting eye corresponded predominantly to eyes with better VFs (P < 0.001). The MD of the worse eye was significantly lower (P = 0.008), and the intereye difference in MD was significantly larger in group 1 than in group 2 (P < 0.001). In a comparison of regional VF threshold values and corresponding retinal nerve fiber layer thickness (RNFLT), the superior and inferior VF threshold values were consistently more deteriorated in the nonsighting worse eyes in group 1 (P = 0.009 and 0.003), compared with the sighting worse eyes in group 2, whereas the corresponding RNFLT was not significantly different between the groups. Multiple linear regression analysis showed that the sighting eye choice (P = 0.047), higher vertical cup-to disc ratio (P = 0.042), older age (P = 0.044), thinner average RNFLT (P = 0.007), and average ganglion cell-inner plexiform layer thickness of worse eyes (P < 0.001) were significantly associated with the MD of the worse eyes. Conclusions: The sighting eye choice was associated with functional asymmetry between eyes with glaucoma. The functional deterioration was evident in nonsighting eyes with worse VFs. PMID- 30452599 TI - Time-Course Change in Eye Shape and Development of Staphyloma in Highly Myopic Eyes. AB - Purpose: To quantitatively assess the posterior pole shape change in highly myopic eyes and to investigate the factors determining the speed of shape change. Methods: Local curvature of the Bruch's membrane on the optical coherence tomography image was measured at intervals of 1 MUm, and the mean curvature and curvature variance were calculated for 1094 eyes with an axial length of >=26 mm. Speed of shape change was calculated using two points of mean curvature and curvature variance, and compared according to age, sex, axial length, and baseline eye shape. Results: The posterior pole shape of females changed significantly greater than males (P < 0.01). Protruding change through the mean curvature was the greatest in the eyes with an axial length of >=28 mm and <29 mm, while undulating change through the curvature variance became greater with axial length elongation in the eyes with an axial length of <29 mm and showed similar change in the eyes with an axial length of >=29 mm. The eyes with a flatter shape at baseline tended to show a slow shape change, whereas those with moderate shape deformation at baseline showed faster shape change. Conclusions: Quantitative evaluation of posterior pole eye shape clearly demonstrated significant time-dependent protruding and undulating changes in highly myopic eyes. Sex, axial length, and baseline posterior pole eye shape significantly affected speed of the posterior pole shape change. Our findings will facilitate risk assessment of staphyloma-associated complications in highly myopic eyes through measurement of speed of the posterior pole shape change. PMID- 30452600 TI - Orientation Tuning and Contrast Dependence of Continuous Flash Suppression in Amblyopia and Normal Vision. AB - Purpose: Suppression in amblyopia may be an unequal form of normal interocular suppression or a distinct pathophysiology. To explore this issue, we examined the orientation tuning and contrast dependence of continuous flash suppression (CFS) in adults with amblyopia and visually normal controls. Methods: Nine patients (mean age, 26.9 +/- SD 4.7 years) and 11 controls (mean age, 24.8 +/- SD 5.3 years) participated. In the CFS paradigm, spatially one-dimensional noise refreshing at 10 Hz was displayed in one eye to induce suppression of the other eye, and suppression strength was measured by using a grating contrast increment detection task. In experiment 1, noise contrast was fixed and the orientation difference between the noise and the grating was varied. In experiment 2, noise and grating orientations were identical and noise contrast was varied. Results: Suppression patterns varied in both groups. In experiment 1, controls showed consistently orientation-tuned CFS (mean half-height bandwidth, 35.8 degrees +/- SD 21.5 degrees ) with near-equal strength between eyes. Five of nine patients with amblyopia exhibited orientation-independent CFS. Eight patients had markedly unequal suppression between eyes. Experiment 2 found that increasing the noise contrast to the amblyopic eye may produce suppression of the fellow eye, but suppression remained unequal between eyes. Conclusions: Our data revealed that orientation specificity in CFS was very broad or absent in some patients with amblyopia, which could not be predicted by clinical measures. Suppression was unbalanced across the entire contrast range for most patients. This suggests that abnormal early visual experience disrupts the development of interocular suppression mechanisms. PMID- 30452601 TI - Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Promote Neuroprotection in a Genetic DBA/2J Mouse Model of Glaucoma. AB - Purpose: To determine if bone marrow-derived stem cell (BMSC) small extracellular vesicles (sEV) promote retinal ganglion cell (RGC) neuroprotection in the genetic DBA/2J mouse model of glaucoma for 12 months. Methods: BMSC sEV and control fibroblast-derived sEV were intravitreally injected into 3-month-old DBA/2J mice once a month for 9 months. IOP and positive scotopic threshold responses were measured from 3 months: IOP was measured monthly and positive scotopic threshold responses were measured every 3 months. RGC neuroprotection was determined in wholemounts stained with RNA binding protein with multiple splicing (RBPMS), whereas axonal damage was assessed using paraphenylenediamine staining. Results: As expected, DBA/2J mice developed chronic ocular hypertension beginning at 6 months. The delivery of BMSC sEV, but not fibroblast sEV, provided significant neuroprotective effects for RBPMS+ RGC while significantly reducing the number of degenerating axons seen in the optic nerve. BMSC sEV significantly preserved RGC function in 6-month-old mice, but provided no benefit at 9 and 12 months. Conclusions: BMSC sEV are an effective neuroprotective treatment in a chronic model of ocular hypertension for 1 year, preserving RGC numbers and protecting against axonal degeneration. PMID- 30452602 TI - Disorganization of Retinal Inner Layers (DRIL) and Neuroretinal Dysfunction in Early Diabetic Retinopathy. AB - Purpose: To elucidate the relationship between disorganization of retinal inner layers (DRILs) and retinal function in diabetic patients without diabetic retinopathy (DR) and with nonproliferative DR, but without diabetic macular edema (DME). Methods: Fifty-seven participants with diabetes mellitus (DM) and 18 healthy controls underwent comprehensive ophthalmic examination, fundus photography, and spectral-domain optical coherence tomography. Scans of the fovea were evaluated for the presence of DRIL. Retinal function was evaluated using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity, the quick contrast sensitivity function (qCSF) on the AST Sentio Platform, short-wavelength automated perimetry (SWAP), standard automated perimetry (SAP), and frequency doubling perimetry (FDP). ANOVA and Kruskal-Wallis were used to compare retinal function in subjects with and without DRIL. Tukey-Kramer test and Wilcoxon were used for post hoc analysis. Results: DRIL was identified in 9 of 57 diabetic subjects. DRIL subjects had higher body mass index and longer diabetes duration compared to diabetic subjects without DRIL (P = 0.03 and P = 0.009, respectively). Subjects with DRIL had reduced ETDRS visual acuity (P = 0.003), contrast sensitivity function (P = 0.0003), and SAP performance (PSD, P < 0.0001) compared to controls and diabetic subjects without DRIL. Structural analysis revealed inner retinal thinning, and some outer retinal thinning, associated with DRIL. Conclusions: Diabetic subjects with DRIL have reduced retinal function compared to those without DRIL, and defective retinal lamination may be an early cellular consequence of diabetes responsible for this in some patients. Following further longitudinal studies, DRIL may be a readily available and reliable structural biomarker for reduced retinal function in early diabetic neuroretinal disease. PMID- 30452603 TI - Macular Inner Retinal Layer Thickness in Relation to Photopic and Mesopic Contrast Sensitivity in Healthy Young and Older Subjects. AB - Purpose: To examine relationships between the thicknesses of ganglion cell (GC) related macular layers and central photopic or mesopic contrast sensitivity (CS) in healthy eyes. Methods: Measurements were made in 38 young and 38 older healthy individuals. Total, inner, and outer retinal layer (IRL) thicknesses were measured in the macula region through spectral-domain optical coherence tomography (SD-OCT) across three subfields, or rings, centered at the fovea: central foveal, pericentral, and peripheral. Ganglion cell complex and circumpapillary retinal nerve fiber layer thicknesses were also measured. Low spatial-frequency CS for gratings presented at the central 10 degrees visual field were measured through computerized psychophysical tests under photopic and mesopic conditions. Relationships were examined by uni- and multivariate regression analysis. Results: Peripheral IRL thickness emerged as the only independent predictor of photopic CS (P = 0.001) in the young group and of photopic (P = 0.026) and mesopic CS (P = 0.001) in the older group. The slopes of regression lines used to predict CS from peripheral IRL thickness were significantly different for pair-wise comparisons of both photopic CS and age group (P = 0.0001) and mesopic CS (P = 0.0001) and age group. These models explained 37% of the variability in photopic CS and 36% of the variability in mesopic CS. Conclusions: Macular IRL thinning likely due to GC loss was related to reduced photopic and mesopic CS in older healthy eyes. In contrast, in the young eyes, a thicker macular IRL, possibly indicating transient gliosis, was associated with reduced CS. PMID- 30452604 TI - Outbreak of Tattoo-Associated Nontuberculous Mycobacterial Skin Infections. AB - BACKGROUND: On April 29, 2015, the Florida Department of Health in Miami-Dade County (DOH-Miami-Dade) was notified by a local dermatologist of three patients with suspect nontuberculous mycobacterial (NTM) infection after receiving tattoos at a local tattoo studio. METHODS: DOH-Miami-Dade conducted interviews and offered testing, described below, to tattoo studio clients reporting rashes. Culture of clinical isolates and identification were performed at the Florida Bureau of Public Health Laboratories (BPHL). Characterization of NTM was performed by the Centers for Disease Control and Prevention (CDC) and the United States Food and Drug Administration (FDA), respectively. Whole-genome sequencing (WGS) and single-nucleotide polymorphism (SNP) analyses were used to construct a phylogeny among 21 Mycobacterium isolates at FDA. RESULTS: Thirty-eight of 226 interviewed clients were identified as outbreak-associated cases. Multivariate logistic regression revealed individuals who reported grey tattoo ink in their tattoos were 8.2 times as likely to report a rash [95% CI: 3.07-22.13]. Multiple NTM species were identified in clinical and environmental specimens. Phylogenetic results from environmental samples and skin biopsies indicated that two M. fortuitum isolates (greywash ink and a skin biopsy) and 11 M. abscessus isolates (five from the implicated bottle of greywash tattoo ink, two from tap water, and four from skin biopsies) were indistinguishable. In addition, M. chelonae was isolated from five unopened bottles of greywash ink provided by two other tattoo studios in Miami-Dade County. CONCLUSIONS: WGS and SNP analyses identified the tap water and the bottle of greywash tattoo ink as the sources of the NTM infections. PMID- 30452606 TI - Drug-eluting stents are not alike - does it matter? PMID- 30452605 TI - Victimization in the workplace: a new target for cardiovascular prevention? PMID- 30452607 TI - Is the amount of glow predicting the fire? Residual inflammatory risk after percutaneous coronary intervention. PMID- 30452608 TI - Severe Morbidity and Mortality Associated With Respiratory Syncytial Virus Versus Influenza Infection in Hospitalized Older Adults. AB - Background: Respiratory syncytial virus (RSV) is an important but under recognized cause of serious respiratory illness in adults. Recent comparative data on RSV and influenza infection in hospitalized adults may increase awareness of RSV disease burden in adults. Methods: Hospitalized adults >=60 years old testing positive for RSV or influenza by multiplex RT-PCR or viral culture between 01/01/2011 and 06/30/2015 were identified from Kaiser Permanente Southern California electronic medical records. Baseline characteristics, comorbidities, utilization, and outcomes were compared between patients with RSV and influenza infection. Results: The study included 645 RSV- and 1878 influenza-infected hospitalized adults with most infections detected by multiplex PCR (RSV=92%, influenza=83%). Patients with RSV were slightly older than those with influenza (mean: 78.5 versus 77.4 years; p=0.035), and more likely to have congestive heart failure (35.3% versus 24.5%; p<0.001) and chronic obstructive pulmonary disease (COPD), chronic bronchitis, or emphysema (29.8% versus 24.3%; p=0.006) at baseline. In adjusted analyses, RSV infection was associated with greater odds of length of stay >=7 days (odds ratio [OR]=1.5; 95% confidence interval [CI]: 1.2 1.8, p<0.001), pneumonia (OR=2.7; 95%CI: 2.2-3.2, p<0.001), intensive care unit admission (OR=1.3; 95%CI: 1.0-1.7, p=0.023), exacerbation of COPD, chronic bronchitis, or emphysema (OR=1.7; 95%CI: 1.3-2.4, p=0.001), and greater mortality within one year of admission (OR=1.3; 95%CI: 1.0-1.6, p=0.019). Conclusion: RSV infection may result in greater morbidity and mortality among older hospitalized adults than influenza. Increased recognition of RSV disease burden in adults will be important to the evaluation and use of RSV vaccines and antivirals after their introduction. PMID- 30452609 TI - Fractional flow reserve, instantaneous wave-free ratio, and resting Pd/Pa compared with [15O]H2O positron emission tomography myocardial perfusion imaging: a PACIFIC trial sub-study. AB - Aims: Guidelines recommend the use of fractional flow reserve (FFR) to guide percutaneous coronary intervention. For this purpose, physiological lesion assessment without adenosine may have a similar diagnostic accuracy as FFR. We aimed to investigate the performances of FFR, resting instantaneous wave-free ratio (iFR), and resting Pd/Pa compared with [15O]H2O positron emission tomography (PET) perfusion imaging. Methods and results: [15O]H2O PET and intracoronary pressure measurements were evaluated in 320 coronary arteries (of which 136 coronary stenoses) in 129 stable patients. The primary analysis consisting of the area-under-the-receiver-operating-characteristic curve for impaired PET hyperaemic myocardial blood flow (MBF) <2.3 mL?min-1?g-1 in coronary stenoses was 0.78 [95% confidence interval (CI): 0.70-0.85] for FFR, 0.74 (95% CI: 0.66-0.81) for iFR, and 0.75 (95% CI: 0.67-0.82) for Pd/Pa. No significant differences between area-under-the-receiver-operating-characteristic curve were observed for any two indices compared. In a secondary analysis, the diagnostic accuracy compared with impaired PET hyperaemic MBF in coronary stenoses was 72% (95% CI: 64-79%, kappa: 0.44) for FFR <=0.80, 72% (95% CI: 64-80%, kappa: 0.44) for iFR <=0.89, and 70% (95% CI: 62-78%, kappa: 0.40) for Pd/Pa <=0.92. Other secondary analyses included a comparison of physiological indices with PET hyperaemic MBF in all vessels and all of the aforementioned analyses using PET myocardial perfusion reserve as comparator. Statistical testing for the secondary analyses showed results that were consistent with the results of the primary analysis. Conclusion: Fractional flow reserve, iFR, and Pd/Pa showed a similar performance when compared with PET imaging. Our results support the validity of invasive physiological lesion assessment under resting conditions by iFR or Pd/Pa. Trial registration: Sub-study of the PACIFIC trial with clinicaltrials.gov identifier: NCT01521468. PMID- 30452610 TI - Leadless pacemakers: learning from experience. PMID- 30452612 TI - Has the time finally come to measure hsCRP universally in primary and secondary cardiovascular prevention? PMID- 30452611 TI - Prospective evaluation and long term follow up of patients referred to secondary care based upon natriuretic peptide levels in primary care. AB - Objectives: The UK National Institute for Health and Care Excellence (UK-NICE) and European Society of Cardiology (ESC) guidelines advise natriuretic peptide (NP) assessment in patients presenting to primary care with symptoms possibly due to chronic heart failure (HF), to determine need for specialist involvement. This prospective service evaluation aimed to describe the diagnostic and prognostic utility of these guidelines. Methods: We prospectively collected clinical, echocardiography and outcomes data (minimum 5yrs) from all patients referred to the Leeds HF Service for 12m following the initiation of the NP-guideline directed pathway. Results: Between May 1st 2012 and August 1st 2013, 1020 people with symptoms possibly due to HF attended either with a raised NT-pro-BNP or a previous myocardial infarction (MI) with an overall rate of LVSD of 33%. Of these, 991 satisfied the ESC criteria (NT-pro-BNP >=125pg/mL) in whom the rate of LVSD was 32%, and 821 the UK-NICE criteria in whom the rate of LVSD was 49% in those with a previous MI, 25% in those with NT-pro-BNP concentration 400 2000pg/mL and 54% in those with NT-pro-BNP concentration of > 2000pg/mL. An NT pro-BNP concentration 125-400pg/mL had a 12% risk of LVSD. Specificity was poor in women >70yrs, who made up the largest proportion of attendees. Elevated NT-pro BNP levels were associated with lower survival even in the absence of LVSD. Conclusion: In people referred through the ESC and UK-NICE guidelines, elevated NT-pro-BNP is a marker of increased mortality risk, but there is wide variation in specificity for LVSD. Age- and sex-adjusted criteria might improve performance. PMID- 30452613 TI - Post-stroke memory deficits and barriers to seeking help: views of patients and carers. AB - Background: Memory and cognitive deficits post stroke are common and associated with increased risk of future dementia. Rehabilitation tends to focus on physical recovery; however, once in the community, it is unclear what happens in the longer term to the stroke-survivor with new memory difficulties. Objective: The aim of this qualitative study was to examine in stroke-survivors what factors influence contact with health professionals. Method: Semi-structured interviews were conducted with stroke-survivors and their family carers where memory difficulties were reported at 6 months post stroke. A topic guide was used which sought to critically examine participants care experience following their stroke diagnosis. All participants were interviewed at baseline (around 6 months post stroke) and offered an interview at around 12 months post stroke. All interviews were conducted in the North East of England. All transcripts were coded and thematically analysed. Results: Ten stroke-survivors (age range 72-84 years) were interviewed alongside five carers at baseline; eight stroke-survivors and four carers agreed to a follow-up interview. Three main barriers were identified: (i) fear of a dementia diagnosis; (ii) denial or minimization of symptoms leading to adaptation and (iii) obstacles to seeking help in the community. Conclusions: With an ageing population and increase in stroke-survival, the burden of post stroke cognitive impairment and dementia will only increase. Stroke-survivors and their family carers in this study have identified issues that may hinder their presentation to health care professionals at a personal and organizational level. Health professionals need to be aware of these potential issues when planning services for stroke-survivors. PMID- 30452615 TI - Leadless pacemakers: learning from experience-Authors' reply. PMID- 30452614 TI - Workplace bullying and workplace violence as risk factors for cardiovascular disease: a multi-cohort study. AB - Aims: To assess the associations between bullying and violence at work and cardiovascular disease (CVD). Methods and results: Participants were 79 201 working men and women, aged 18-65 years and free of CVD and were sourced from three cohort studies from Sweden and Denmark. Exposure to workplace bullying and violence was measured at baseline using self-reports. Participants were linked to nationwide health and death registers to ascertain incident CVD, including coronary heart disease and cerebrovascular disease. Study-specific results were estimated by marginal structural Cox regression and were combined using fixed effect meta-analysis. Nine percent reported being bullied at work and 13% recorded exposure to workplace violence during the past year. We recorded 3229 incident CVD cases with a mean follow-up of 12.4 years (765 in the first 4 years). After adjustment for age, sex, country of birth, marital status, and educational level, being bullied at work vs. not was associated with a hazard ratio (HR) of 1.59 [95% confidence interval (CI) 1.28-1.98] for CVD. Experiencing workplace violence vs. not was associated with a HR of 1.25 (95% CI 1.12-1.40) for CVD. The population attributable risk was 5.0% for workplace bullying and 3.1% for workplace violence. The excess risk remained similar in analyses with different follow-up lengths, cardiovascular risk stratifications, and after additional adjustments. Dose-response relations were observed for both workplace bullying and violence (Ptrend < 0.001). There was only negligible heterogeneity in study-specific estimates. Conclusion: Bullying and violence are common at workplaces and those exposed to these stressors are at higher risk of CVD. PMID- 30452616 TI - Infliximab Trough Levels Are Associated With Mucosal Healing During Maintenance Treatment With Infliximab in Paediatric Crohn's Disease. AB - Background and Aims: Mucosal healing is an important treatment goal in Crohn's disease. We investigated the association between serum infliximab trough levels and mucosal healing, and the infliximab cut-off levels required for mucosal healing in paediatric patients. Methods: In this multicentre, retrospective, cross-sectional study, medical records and electronic data of paediatric patients with luminal Crohn's disease, who had received infliximab for >=1 year, were examined. Ileocolonoscopy was performed on the same day as the infliximab infusion, and serum samples for trough levels were collected immediately before infusion. Mucosal healing was defined as a Simple Endoscopic Score for Crohn's Disease of 0. Univariate, multivariate logistic regression, and receiver operating characteristic curve analyses were performed. Results: Overall, 105 patients [median age 14.8 years] were included, with mucosal healing observed in 48.6%. Median serum infliximab trough levels were higher in patients with mucosal healing [4.5 ug/mL] than without [3.3 ug/mL, p = 0.002]. In the final multivariate model, infliximab trough level >=4.2 ug/mL [p = 0.002] and >=1-year duration from diagnosis to infliximab treatment [p = 0.003] were positively and negatively associated with mucosal healing, respectively. The infliximab trough level for achieving mucosal healing with a specificity of 80% was >=5 ug/mL. Conclusions: Associations between serum infliximab trough concentrations and mucosal healing were observed in paediatric patients. Identification of the infliximab trough level that positively associates with mucosal healing in most paediatric patients with Crohn's disease [>=5 ug/mL] may guide treatment decisions to optimise therapeutic response in the era of treat-to-target. PMID- 30452617 TI - Increased risk of late-onset Streptococcus pneumoniae meningitis in adults with prior head or spine surgeries. AB - In a case-control study within the Kaiser Permanente Northern California adult population, prior head or spine surgery (H/SS) was associated with increased Streptococcus pneumoniae meningitis outside of the postoperative period (no prior H/SS, odds ratio 6.0, 95% CI 1.9-18.6). Among the cases, only 33.3% had received any prior pneumococcal vaccinations. PMID- 30452618 TI - Faecal calprotectin and MRI Enterography in ileal Crohn's disease: correlations between disease activity and long term follow up. AB - Background and Aims: Magnetic resonance enterography (MRE) is the gold standard for assessing ileal inflammation in Crohn's disease. The aim of the present study was to correlate faecal calprotectin (FC) to MRE via a simple score in an exclusive ileal cohort with long term follow up for association with time to surgery or biologic therapy. Methods: 150 MRE studies with matched FC (+/-30 days) were identified from the Edinburgh FC Register (2008-12; n=18,138). Scans were re-read blinded to clinical data, independently by 2 expert GI radiologists to generate a simple MRE score (range 0-10) from assessment of the worst segment plus total disease extent. Results: 119 MRE scans were evaluated from 104 patients with ileal CD (L1 or L3 with panproctocolectomy). ROC analysis showed an AUC of 0.77(0.67-0.87, p<0.0001) for FC and MRE score>1 with an optimal cut-off of 145MUg/g for severe inflammation on MRE with 69.3% (57.6-79.5) sensitivity and 71.4% (53.7-85.4) specificity. Long-term follow up over median (IQR) 2086 days (1786-2353) revealed FC145MUg/g was associated with reduced biologic-free survival until 3years post-MRE, whereas MRE score (severe versus absent) was associated with reduced surgery- and biologic-free survival throughout follow-up. Backwards stepwise logistic regression revealed length of ileal disease (OR3.8, 1.1-13.2, p=0.034) and increased bowel wall thickness at MRE (OR4.2, 1.6-10.7, p<0.0001) or female sex (OR5.2, 1.5-18.7, p=0.011) at MRE increased risk of biologic use or surgery respectively. Conclusions: FC correlates well to MRE assessment of ileal CD with MRE parameters associated with long term biologic and surgery free remission. PMID- 30452619 TI - Ciprofloxacin penetration into infected hepatic cysts in autosomal dominant polycystic kidney disease: a case report. PMID- 30452620 TI - Diverting Stoma for Refractory Ano-perineal Crohn's Disease, Is It Really Useful in the Anti-TNF Era? A multivariate analysis in 74 consecutive patients. AB - Background & Aims: Faecal diversion (FD) can be proposed in patients with refractory anoperineal Crohn's disease (APCD). This study aimed to assess long term results of this strategy, following the advent of the anti-TNF era. Methods: All patients who underwent FD for refractory APCD between 2005 and 2017 were included, excluding patients with a history of ileal pouch-anal anastomosis. A multivariate analysis regarding absence of stoma reversal (SR) was performed. Results: A total of 65 consecutive patients who underwent FD for APCD (comprising anoperineal fistula (n=40, 62%), rectovaginal fistula (n=21, 32%), fissures and/or ulceration (n=9, 14%), and/or anal stricture (n=5, 8%)) were included. At the time of FD, 34 patients (52%) presented with small bowel Crohn's disease (CD) involvement, 29 (45%) with colonic involvement, and 19 (29%) with rectal involvement. Following FD, 54 patients (83%) were treated with anti-TNF therapy, prescribed for isolated APCD (n=10, 15%) or luminal CD with APCD (n=44, 68%). After a mean follow-up of 49 +/- 29 (7-120) months, SR was not possible in 32 patients (49%), including 17 patients (26%) requiring a subsequent proctectomy with abdominoperineal excision. In multivariate analysis, rectal CD involvement was the only independent factor associated with a reduced rate of SR (Odds-ratio: 4.0 [1.153-14.000]; p=0.029), whereas anti-TNF therapy had no impact on SR rate. Conclusions: FD can be performed in selected patients with refractory APCD, to avoid abdominoperineal resection. However, this strategy should be proposed with caution in patients presenting with rectal CD involvement. Anti-TNF therapy has no impact on SR rate. PMID- 30452621 TI - Measles Seroprevalence and Vaccine Responses in HIV-Infected Adolescents and Adults: A Systematic Review. AB - Background: The World Health Organization recommends an additional dose of measles-containing vaccine (MCV) for HIV-infected children receiving highly active antiretroviral therapy (HAART) following immune reconstitution. We conducted a systematic review to synthesize available evidence regarding measles seroprevalence and measles vaccine immunogenicity, efficacy, and safety in HIV infected adolescents and adults to provide the evidence base for recommendations on the need for measles vaccination. Methods: We conducted searches of Medline (Ovid), Embase, Cohrane Library, PubMed, LILACS, INDMED, AIM, and WHO Global Index Medicus databases. Identified studies were screened independently by two reviewers. Results: The search identified 30 studies meeting inclusion criteria. Across studies, measles seroprevalence was high (median: 92%, 27 studies), with no significant difference compared to HIV-uninfected participants (10 studies). In six studies that evaluated the immunogenicity of MCV among seronegative HIV infected adults, measles seropositivity at end of follow-up ranged from 0% to 56% (median: 39%). No severe adverse events were reported following measles vaccination in HIV-infected patients. Conclusions: Based on similar measles seroprevalence between HIV-infected and HIV-uninfected adolescents and adults, and the low response to vaccination, these studies do not support the need for an additional dose of MCV in HIV-infected adolescents and adults. These findings support WHO guidelines that measles vaccine be administered to potentially susceptible, asymptomatic HIV-infected adults, and may be considered for those with symptomatic HIV infection if not severely immunosuppressed. Measles susceptible adolescents and adults, regardless of HIV-status, may require targeted vaccination efforts to reach critical vaccination thresholds and achieve regional elimination goals. PMID- 30452622 TI - ErbB4 acts as a suppressor in colitis and its associated carcinoma by negatively regulating cholesterol metabolism. AB - Previously we reported that ErbB4 played a protective role in chronic liver injury and hepatocellular carcinoma. Herein, we examined the role of ErbB4 in the development of colitis-associated cancer (CAC) in ErbB4 knockout mice models, in vitro cell lines and clinical samples. We found that ErbB4 deficiency may lead to more severe inflammation, slower recovery, and the development of CAC. Further, loss of ErbB4 could activate KRAS by up regulating rate-limiting enzymes in cholesterol metabolism pathway through interacting with the transcription factor SREBF1. In clinic samples, ErbB4 is down-regulated in colonic tissues from Crohn's disease patients. And data from The Cancer Genome Atlas also showed significant negative correlation between ErbB4 and several cholesterol metabolic enzymes. In conclusion, our study uncovers ErbB4 as a protector in the development of colitis-associated cancer, for its loss could activate KRAS by up regulating cholesterol metabolism through interaction with SREBF1. PMID- 30452623 TI - Metabarcoding successfully tracks temporal changes in eukaryotic communities in coastal sediments. AB - Metabarcoding is a method that combines high-throughput DNA sequencing and DNA based identification. Previously, this method has been successfully used to target spatial variation of eukaryote communities in marine sediments, however, the temporal changes in these communities remain understudied. Here, we follow the temporal changes of the eukaryote communities in Baltic Sea surface sediments collected from two coastal localities during three seasons of two consecutive years. Our study reveals that the structure of the sediment eukaryotic ecosystem was primarily driven by annual and seasonal changes in prevailing environmental conditions, whereas spatial variation was a less significant factor in explaining the variance in eukaryotic communities over time. Therefore, our data suggests that shifts in regional climate regime or large-scale changes in the environment are the overdriving factors in shaping the coastal eukaryotic sediment ecosystems rather than small-scale changes in local environmental conditions or heterogeneity in ecosystem structure. More studies targeting temporal changes are needed to further understand the long-term trends in ecosystem stability and response to climate change. Furthermore, this work contributes to the recent efforts in developing metabarcoding applications for environmental biomonitoring, proving a comprehensive option for traditional monitoring approaches. PMID- 30452624 TI - Injury among the immigrant population in Canada: exploring the research landscape through a systematic scoping review. AB - Background: Injuries are the leading cause of death among younger Canadians and represent a large economic burden on the Canadian population. Although immigrants comprise more than 20% of the Canadian population, the research landscape on injury in this group is unclear. We conducted a scoping review to summarize existing research regarding injuries among Canadian immigrants to identify research gaps and future research opportunities. Methods: Relevant electronic databases of peer-reviewed articles and grey literature were systematically searched. Original articles were selected based on predefined criteria. Relevant information from the articles was extracted and reported in the review. Results: After a comprehensive search, screening and full-text evaluation, 28 articles were selected for the synthesis. Of the injuries that have been studied among Canadian immigrants, the majority focused on occupational injuries, followed by road traffic accidents. Of the 28 studies, 16 were quantitative and 12 were qualitative. The research themes among occupational injury papers centred on factors leading to injury, factors leading to delayed reporting and compensation of injury and post-occupational injury experiences. Language barriers, informal training and the mismatch between education and occupation among immigrants were found to be the most frequent determinants of injury risk. Conclusions: The synthesized knowledge in this scoping review offers an understanding of the current research landscape on injury among immigrants that can be used to assist policymakers, service providers, employers and researchers regarding injuries in this population. PMID- 30452625 TI - Circulating microRNAs combined with PSA for accurate and non-invasive prostate cancer detection. AB - The dosage of prostate specific antigen (PSA), an easily evaluable and non invasive biomarker, has made early detection of prostate cancer (PCa) possible. However, it leads to high percentages of unnecessary biopsies and may miss aggressive tumors in men with PSA levels below 4 ng/ml. Therefore, we propose to combine circulating microRNAs with PSA, to improve the diagnostic route for PCa.Plasma microRNA profiling identified candidate diagnostic microRNAs in a discovery cohort of 60 tumors and 60 controls (men with benign prostatic hyperplasia or healthy donors). Linear models with an empirical Bayesian approach and multivariate penalized logistic regression were applied to select tumor associated microRNAs and/or clinical variables. A classifier was developed and tested on a validation cohort of 68 tumors and 174 controls consecutively collected, where microRNAs were evaluated by quantitative real-time polymerase chain reaction.A classifier based on miR-103a-3p, let-7a-5p and PSA could detect both overall and clinically significant tumors better than PSA alone, even in 50 69 aged men with PSA <= 4ng/ml. Even in the validation cohort, the classifier performed better than PSA alone in terms of specificity and positive-predictive value, allowing to correctly identify 8 out of 9 tumors undetected by PSA, including three high-risk and three tumors in 50-69 years old men. 34% of carriers of non-malignant lesions with PSA in the 4-16 ng/ml interval, who may avoid unnecessary biopsies, were correctly identified.Coupling two circulating microRNAs with PSA could be a useful strategy to diagnose clinically significant PCa and avoid an important fraction of unnecessary biopsies. PMID- 30452626 TI - Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity. PMID- 30452627 TI - The Voyage Out: Endocrine Discoveries. PMID- 30452628 TI - The neglect of migrant oral health: setting a research agenda for Europe. PMID- 30452629 TI - Primary health care 40 years after Alma Ata 1978: addressing new challenges in a changing society. PMID- 30452630 TI - European Public Health News. PMID- 30452631 TI - A decade of catheter ablation of cardiac arrhythmias in Sweden: ablation practices and outcomes. AB - Aims: Catheter ablation is considered the treatment of choice for many tachyarrhythmias, but convincing 'real-world' data on efficacy and safety are lacking. Using Swedish national registry data, the ablation spectrum, procedural characteristics, as well as ablation efficacy and reported adverse events are reported. Methods and Results: Consecutive patients (>=18 years of age) undergoing catheter ablation in Sweden between 01 January 2006 and 31 December 2015 were included in the study. Follow-up (repeat ablation and vital status) was collected through 31 December 2016. A total of 26 642 patients (57 +/- 15 years, 62% men), undergoing a total of 34 428 ablation procedures were included in the study. In total, 4034 accessory pathway/Wolff-Parkinson-White syndrome (12%), 7358 AV-nodal re-entrant tachycardia (21%), 1813 atrial tachycardia (5.2%), 5481 typical atrial flutter (16%), 11 916 atrial fibrillation (AF, 35%), 2415 AV-nodal (7.0%), 581 premature ventricular contraction (PVC, 1.7%), and 964 ventricular tachycardia (VT) ablations (2.8%) were performed. Median follow-up time was 4.7 years (interquartile range 2.7-7.0). The spectrum of treated arrhythmias changed over time, with a gradual increase in AF, VT, and PVC ablation (P < 0.001). Decreasing procedural times and utilization of fluoroscopy with time, were seen for all arrhythmia types. The rates of repeat ablation differed between ablation types, with the highest repeat ablation seen in AF (41% within 3 years). The rate of reported adverse events was low (n = 595, 1.7%). Death in the immediate period following ablation was rare (n = 116, 0.34%). Conclusion: Catheter ablations have shifted towards more complex procedures over the past decade. Fluoroscopy time has markedly decreased and the efficacy of catheter ablation seems to improve for AF. PMID- 30452632 TI - Applying definitions for multidrug resistance, extensive drug resistance and pandrug resistance to clinically significant livestock and companion animal bacterial pathogens-authors' response. PMID- 30452633 TI - Prevalent misconceptions about opioid use disorders in the United States produce failed policy and public health responses. AB - The current opioid crisis in the United States has emerged from higher demand for and prescribing of opioids as chronic pain medication. This led to massive diversion of prescription opioids into illicit markets. A peculiar tragedy is that many health professionals prescribed opioids in a misguided response to legitimate concerns that pain was under-recognized and undertreated. The crisis grew not only from over-prescribing, but also from other sources, including a lack of research into non-opioid pain management, ethical lapses in corporate marketing, historical stigmas directed against people who use drugs, and failures to deploy evidence-based therapies for opioid addiction and to comprehend the limitations of supply side regulatory approaches. Regulations that restricted opioid prescribing perversely accelerated narco-trafficking of heroin and fentanyl with consequent increases in opioid overdose mortality As injection replaced oral consumption, outbreaks of hepatitis B and C virus and HIV infections have resulted. This viewpoint explores the origins of the crisis and directions needed for effective mitigation. PMID- 30452634 TI - High Cancer Burden Among Antiretroviral Therapy Users in Malawi: a Record Linkage Study of Observational HIV Cohorts and Cancer Registry Data. AB - Background: With antiretroviral therapy (ART), AIDS-defining cancer incidence has declined and non-AIDS defining cancers are now more frequent among HIV-infected populations in high-income countries. In sub-Saharan Africa, limited epidemiological data describe cancer burden among ART users. Methods: We used probabilistic algorithms to link cases from the population-based cancer registry with electronic medical records supporting ART delivery in the Malawi's two largest HIV cohorts, Lighthouse Trust (LT; 2007-2010) and Queen Elizabeth Central Hospital (QECH; 2000-2010). Age-adjusted cancer incidence rates (IR) and 95% confidence intervals were estimated by cancer site, early versus late incidence periods (4 -24 and >24 months after ART start), and WHO stage among naive ART initiators enrolled for at least 90 days. Results: We identified 4,346 cancers among 28,576 persons. Most people initiated ART at advanced WHO stage (LT stage 3/4: 55%; QECH stage 3/4: 66%); 12% of patients had prevalent malignancies at ART initiation, which were predominantly AIDS-defining eligibility criteria for initiating ART. Kaposi sarcoma (KS) had the highest IR (634.7 per 100,000 person years), followed by cervical cancer (36.6). KS incidence was highest during the early period 4-24 months after ART initiation. Non-AIDS defining cancers (NADC) accounted for 6% of new cancers. Conclusions: Under historical ART guidelines, NADC were observed at low rates, and were eclipsed by high KS and cervical cancer burden. Cancer burden among Malawian ART users does not yet mirror high-income countries. Integrated cancer screening and management in HIV clinics, especially for KS and cervical cancer, remain important priorities in the current Malawi context. PMID- 30452635 TI - Experiences of People With Dementia in Pakistan: Help-Seeking, Understanding, Stigma, and Religion. AB - Background and Objectives: The prevalence of dementia will increase in low- and middle-income countries like Pakistan. Specialist dementia services are rare in Pakistan. Public awareness of dementia is low, and norms about family care can lead to stigma. Religion plays a role in caregiving, but the interaction between dementia and Islam is less clear. Research Design and Methods: Qualitative interviews were carried out with 20 people with dementia in Karachi and Lahore. Interviews were conducted in Urdu, translated to English, and respondents' views on help-seeking experiences, understanding of diagnosis, stigma, and religion were analyzed thematically. Results: Although some people with dementia understood what dementia is, others did not. This finding shows a more positive perspective on diagnosis in Pakistan than previously thought. Help-seeking was facilitated by social and financial capital, and clinical practice. Stigma was more common within the family than in the community. Dementia symptoms had a serious impact on religious obligations such as daily prayers. Participants were unaware that dementia exempts them from certain religious obligations. Discussion and Implications: Understanding of dementia was incomplete despite all participants having a formal diagnosis. Pathways to help-seeking need to be more widely accessible. Clarification is needed about exemption from religious obligations due to cognitive impairment, and policy makers would benefit from engaging with community and religious leaders on this topic. The study is novel in identifying the interaction between dementia symptoms and Islamic obligatory daily prayers, and how this causes distress among people living with dementia and family caregivers. PMID- 30452636 TI - Health in the Anthropocene Epoch-implications for epidemiology. PMID- 30452637 TI - Comment on: Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. PMID- 30452638 TI - Gut-Directed Pelvic Floor Behavioral Treatment for Fecal Incontinence and Constipation in Patients with Inflammatory Bowel Disease. AB - Background: Patients with inflammatory bowel disease (IBD) often experience functional bowel symptoms despite achieving disease remission. Although behavioral treatment (bowel and pelvic floor muscle retraining) is effective for managing constipation or fecal incontinence in non-IBD patients, there is limited evidence for its efficacy in patients with quiescent inflammatory bowel disease. The aim of this study was to evaluate the outcome of gut-directed behavioral treatment, including pelvic floor muscle training, for symptoms of constipation or fecal incontinence in patients with IBD in disease remission. Methods: The outcome of consecutive patients with IBD in remission and symptoms of constipation or fecal incontinence was evaluated. Patients referred to a multidisciplinary gastroenterology clinic underwent gut-directed behavioral treatment, including pelvic floor muscle training. The primary outcome was patient-reported rating of change in symptoms on a 7-point Likert scale at the completion of treatment. Results: Forty IBD patients (median age, 35 years; 80% female; 24 Crohn's disease [CD], 12 ulcerative colitis [UC], 4 UC with ileoanal pouch) with ongoing symptoms of constipation (55%) or fecal incontinence (45%), despite drug therapy, were included. The median symptom duration at referral was 2 years. Thirty-five (87%) completed treatment with a median of 2 sessions. Improvement of "6 = much better" or "7 = very much better" was reported by 77% (17/22) with fecal incontinence and 83% (15/18) with constipation. Improvement occurred irrespective of IBD diagnosis, previous perianal fistulae, colorectal surgery, presence of an ileoanal pouch, or past obstetric trauma. Conclusions: Behavioral treatment effectively improves functional gut symptoms in a large majority of patients who are in IBD disease remission and who have not responded to drug therapy. 10.1093/ibd/izy344_video1izy344.video15968879349001. PMID- 30452640 TI - Comparison of regional with general anesthesia on mortality and perioperative length of stay in older patients after hip fracture surgery. AB - Objective: The aim of this study was to examine whether anesthetic technique is associated with 30- or 90-day mortality and perioperative length of stay (LOS). Design: We used a retrospective cohort design using a healthcare insurance claims database. Setting: The Fukuoka Prefecture's claims database of older patients who underwent hip fracture surgery under general or regional (spinal or epidural) anesthesia from April 2012 to March 2016 was used for analyses. Participants: The database under analyses contained 16 125 participants of hip fracture surgery under general or regional anesthesia. Main Outcome Measure: We measured 30- and 90-day mortalities and perioperative LOS. Results: In a propensity score-matched cohort, we found no significant differences in 30- and 90-day mortalities after adjusting for confounding factors. The reconverted perioperative LOS for the general and regional anesthesia groups was, respectively, 29.7 (29.1-30.4) and 28.0 (27.4-28.6) days in the matched cohort. Therefore, the perioperative LOS in the regional anesthesia group was significantly shorter by 1.7 days than in the general anesthesia group (P < 0.001). Conclusions: This study demonstrated that the use of regional anesthesia was not associated with 30- or 90-day mortality, but it was associated with slightly shorter perioperative LOS. Since Japan has much longer LOS than other countries, our findings have implications for more efficient healthcare resource utilization and quality assurance in geriatric care. PMID- 30452641 TI - Med4way: a Stata command to investigate mediating and interactive mechanisms using the four-way effect decomposition. AB - The overall effect of an exposure on an outcome, in the presence of a mediator with which the exposure may interact, can be decomposed into four components that correspond to the portion of the effect that is due: (i) to neither mediation nor interaction; (ii) to just interaction (but not mediation); (iii) to both mediation and interaction; and (iv) to just mediation (but not interaction). This four-way decomposition unifies methods to attribute effects to interactions and methods that assess mediation. We introduce the Stata command med4way to estimate the causal contrasts that arise in this decomposition. Med4way is implemented as a Stata stand-alone command requiring Stata version 10 or higher (StataCorp, College Station, TX, USA), and allows estimating the four-way decomposition using parametric regression models. Med4way can be used when the outcome is continuous, dichotomous, count or survival time, and the mediator is continuous or binary. The command accommodates cohort and case-control designs. We present two examples of application of the command to gain insight on important public health problems. In the first application, we employ med4way to investigate the role of birth outcomes in explaining the effect of maternal exposure to manganese on child neurodevelopment. In the second application, we investigate the role of stage at diagnosis in explaining income disparities in colorectal cancer survival. The command is freely available on GitHub [https://github.com/anddis/med4way] and has been published under General Public License (GPL) version 3. PMID- 30452639 TI - Genomic analyses in african populations identify novel risk loci for cleft palate. AB - Orofacial clefts are common developmental disorders that pose significant clinical, economic and psychological problems. We conducted genome-wide association analyses for isolated cleft palate (CPO) and cleft lip with or without palate (CL/P) with ~17 million markers in sub- Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice shows expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously-reported 8q24 locus was the most significant for CL/P in our study and we replicated several previously reported loci including PAX7 and VAX1. PMID- 30452642 TI - AbGRI1-5, a novel AbGRI1 variant in an Acinetobacter baumannii GC2 isolate from Adelaide, Australia. PMID- 30452643 TI - Being With Objects of Meaning: Cherished Possessions and Opportunities to Maintain Aging in Place. AB - Background and Objectives: Research regarding the role that cherished possessions play in experiences of aging and daily life has tended to focus on how possessions assist individuals in "looking back" and remembering important experiences, relationships, and identities. Here, we consider how the possessions that older adults keep at home inform their present experiences of aging and also facilitate the ongoing maintenance of aging in place. Research Design and Methods: We employed an interpretive phenomenologically inspired research strategy that enabled an in-depth examination of older adult's experiences of cherished possessions. This approach emphasized participants' own situated meanings. In-depth interviews were followed by participatory photo-elicitation interviews and journaling. Results: The majority of study participants interacted with cherished possessions to connect with their past selves, but also to cope with times of challenge and change in the present, and in some cases, to cultivate a sense of being able to maintain aging in place. For some older adults, however, possessions disrupted sense of self, place attachment, and daily life. Cherished possessions, therefore, play a significant role in opportunities to maintain aging in place. Discussion and Implications: The material culture of home and its relationship to experiences of aging may provide or disrupt opportunities to maintain aging in place. Interventions based on possessions that are easy to access and employ to provide comfort and affirm peoples' preferred relationships to self, others, and the living environment could make a difference to the quality of life for older adults. PMID- 30452644 TI - Traditional and complementary medicine as health promotion technology in Brazil. AB - Conventional medicine-understood as a medicalized and commodified model based on biomedical and natural hard sciences that provide legitimization and institutionalism to its practices-is hegemonic in health systems. This article examines interfaces between health promotion (HP) and traditional and complementary medicine (T&CM), especially as found in the Brazilian Health System (SUS). In order to analyze the tensions between paradigms that strive for scientific authority in public policies and practices, especially those related to SUS, we rely on Bourdieu's concept of scientific field. Our guidelines to identify the principles and values that mark the HP and T&CM movements were official documents (policies) and scientific publications on the subject. Analysis showed that the underlying values and principles of HP and T&CM converge and add complexity to the health model and its praxis-HP with its theoretical advances and T&CM with its conceptually coherent practices. Both movements recognize the multidimensional and indivisible nature of 'being' and its social and environmental determination. Together, they strengthen the possibilities of offering practices based on HP principles, such as holism, integrality, sustainability, empowerment, autonomy, social participation and others. This encounter offers a promising path for strengthening resistance against the individualized and monetized 'out-of-pocket' medicine model, and favors the reorientation of primary health care toward a more democratic and health promoting model for SUS. PMID- 30452646 TI - The history in epidemiology. PMID- 30452645 TI - Adherence to components of Health Promoting Schools in schools of Bengaluru, India. AB - Schools provide a crucial platform for health promotion as the school years are a vital stage in one's life, where lifelong general and oral health-related behaviours are developed and established. The components of Health Promoting Schools (HPSs) suggested by World Health Organization provide guidance for facilitating health promotion within this setting. This study aimed to assess the adherence to the components of HPSs amongst schools in Bengaluru, India utilizing a comprehensive tool developed for the purpose. A cross-sectional survey was conducted among randomly selected 61 schools. Data were collected through structured interviews with the head of the schools, direct observation of school premises and verification of records. The significant findings of the study were that 80.3% of the schools had proper ventilation and separate washrooms for boys and girls, 83.6 and 88.5% of the schools had natural light and adequate water supply correspondingly. Only 39.3% of the schools had washrooms that were cleaned daily, and 55.7% of the schools were in proximity to business that sold tobacco products. Oral health education was not integrated into the curriculum in 39.3% of the schools, and 29.5% of the schools had no playgrounds. The study tool appeared to be sensitive in identifying the finer components of HPSs, indicating the lack of strict adherence to the components of HPSs in Bengaluru. This information can be utilized to design appropriate interventions at micro, meso and macro level to strengthen the capacity of schools for the attainment of health promotion. PMID- 30452647 TI - Elevation in Cell Cycle and Protein Metabolism Gene Transcription in Inactive Colonic Tissue From Icelandic Patients With Ulcerative Colitis. AB - Background: A combination of genetic and environmental factors is thought to be involved in the pathogenesis of ulcerative colitis (UC). In Iceland, the incidence of UC is one of the highest in the world. The aim of this study was to characterize patients with UC and identify potential germline mutations and pathways that could be associated with UC in this population. Methods: Exome sequencing and genome-wide microarray analysis on macroscopically noninflamed colonic mucosa from patients and controls were performed. Exome sequence data were examined for very rare or novel mutations that were over-represented in the UC cohort. Combined matching of variant analysis and downstream influence on transcriptomic expression in the rectum were analyzed. Results: One thousand eight hundred thirty-eight genes were differentially expressed in rectal tissue from UC patients and identified an upregulation in genes associated with cell cycle control and protein processing in the endoplasmic reticulum (ER). Two missense mutations in thiopurine S-methyltransferase (TPMT) with a minor allele frequency of 0.22 in the UC patients compared with a reported 0.062 in the Icelandic population were identified. A predicted damaging mutation in the gene SLC26A3 is potentially associated with increased expression of DUOX2 and DUOXA2 in rectal tissue. Conclusions: Colonic mucosa of UC patients demonstrates evidence of an elevation in genes involving cell proliferation and processing of proteins within the ER. Exome sequencing identified a possible increased prevalence of 2 damaging TPMT variants within the UC population, suggesting screening the UC population before initiation of thiopurine analogue therapy to avoid toxicity associated with these mutations. PMID- 30452648 TI - Effects of Sodium and Chloride source and concentration on nursery pig growth performance. AB - Three studies were conducted to determine the effects of source and concentration of Na and Cl on pig growth performance from 7 to 12 kg. In all 3 experiments, pigs were fed a common diet (0.33% Na and 0.77% Cl) for 7 or 8 days after weaning then randomly assigned to dietary treatments. In experiment 1, 360 mixed-sex pigs were used in a 14-d study with 15 replications per treatment and 6 pigs per pen. Treatments included a 10% dried whey diet with 0.60% added salt (0.37% Na and 0.75% Cl); or 3 diets with 7.2% crystalline lactose with either: 0.35% added salt (0.18% Na and 0.47% Cl); 0.78% added salt (0.35% Na and 0.72% Cl); or 1.15% NaHCO3 and 0.40% KCl (0.35% Na and 0.45% Cl). Pigs fed the 0.78% added salt lactose diet had greater (P < 0.05) average daily gain (ADG) than pigs fed the 0.35% added salt-lactose diet, with others intermediate. In experiment 2, 360 barrows were used in a 14-d study with 12 replications per treatment and 5 pigs per pen. Treatments included 2 added salt diets (providing 0.13% Na and 0.35% Cl or 0.35% Na and 0.68% Cl), 3 diets with Na and Cl provided by KCl and NaHCO3 (0.13, 0.35, or 0.57% Na and 0.50% Cl), or a diet with NaHCO3 and CaCl2 (0.35% Na and 0.50% Cl). Regardless of Na source, ADG and average daily feed intake (ADFI) increased (quadratic, P< 0.05) as dietary Na increased from 0.13 to 0.35%, with no further benefits observed thereafter. There was no evidence for differences among pigs fed NaCl or NaHCO3 nor evidence for differences among pigs fed the different Na and Cl sources at similar concentrations. In experiment 3, 300 pigs were used in a 21-d trial with 10 replications per treatment and 5 pigs per pen. Treatments included a control diet with added salt to provide 0.33% Na and 0.55% Cl or 5 diets with 0.33 % Na and added KCl to provide 0.09, 0.21, 0.32, 0.45, or 0.55% Cl. Average daily gain and gain to feed ratio (G:F) increased (quadratic, P< 0.035) as Cl increased from 0.09 to 0.32%. Pigs fed the control diet (added salt) and the 0.55% Cl diet had similar ADG. For ADG and ADFI, the broken line linear model indicated a breakpoint of 0.23% Cl. For G:F, the quadratic polynomial model suggested the maximum at 0.38% Cl. In conclusion, 7- to 12- kg pigs fed diets that contained at least 0.35% Na and 0.38% Cl had greater ADG and G:F compared to pigs fed diets with lower concentrations and minimal effects were observed among the sources of Na or Cl used in these studies. PMID- 30452649 TI - Perceptions of an online 'train-the-champion' approach to increase workplace movement. AB - Prolonged sitting is now recognized as an emergent work health and safety issue. To address the need for a scalable sitting-reduction intervention for workplaces, the BeUpstandingTM Champion Toolkit was developed. This free, online toolkit uses a 'train-the-champion' approach, providing a step-by-step guide and resources to workplace champions to assist them in raising awareness and building a supportive culture to reduce sitting time in their team. This qualitative study explored champion and staff perceptions of the beta (test) version of the toolkit. Seven work teams, from a range of workplace sectors (blue-/white-collar), sizes (small/medium/large) and locations (urban/regional) participated; all team members were exposed to the program (n = 603). Approximately 4 months after program initiation, semi-structured interviews were conducted with all champions (n = 7); focus groups were conducted with a random sample of staff (n = 40). Champions were followed-up again at 12 months (n = 5). Transcripts were coded by two researchers, with codes organized into overarching themes. All champions found the 'train-the-champion' approach, and the toolkit acceptable. Common enablers for intervention delivery included: champion passion for staff health and wellbeing; perceived fit of the program within existing practice; and, management support. Champions and staff reported improvements in knowledge/awareness about sitting, cultural norms, perceived stress, productivity and resilience. Facilitators for sustained change over time included a stable organizational climate and ongoing management support; barriers included workload intensification. The beta version of the BeUpstandingTM Champion Toolkit was highly acceptable to workplace champions and staff, and was perceived to have benefits for team culture and staff knowledge and wellbeing. PMID- 30452650 TI - Identification of dropout predictors to a community-based physical activity programme that uses motivational interviewing. AB - Background: Participant dropout reduces intervention effectiveness. Predicting dropout has been investigated for Exercise Referral Schemes, but not physical activity (PA) interventions with Motivational Interviewing (MI). Methods: Data from attendees (n = 619) to a community-based PA programme utilizing MI techniques were analysed using a chi-squared test to determine dropout and attendance group differences. Binary logistic regression investigated the likelihood of dropout before 12 weeks. Results: A total of 44.7% of participants dropped out, with statistical (P < 0.05) differences between groups for age, PA and disability. Regression for each variable showed participants aged 61-70 years (OR = 0.28, CI = 0.09-0.79; P = 0.018), >70 years (OR = 0.30, CI = 0.09-0.90; P = 0.036), and high PA (OR = 0.40, CI = 0.20-0.75; P = 0.006) reduced dropout likelihood. Endocrine system disorders (OR = 4.24, CI = 1.19-19.43; P = 0.036) and musculoskeletal disorders (OR = 3.14, CI = 1.84-5.45; P < 0.001) increased dropout likelihood. Significant variables were combined in a single regression model. Dropout significantly reduced for 61-70 years old (OR = 0.31, CI = 0.10 0.90; P = 0.035), and high PA (OR = 0.39, CI = 0.19-0.76; P = 0.008). Musculoskeletal disorders increased dropout (OR = 2.67, CI = 1.53-4.75; P < 0.001). Conclusions: Age, PA and disability type significantly influence dropout at 12 weeks. These are the first results specific to MI based programmes indicating the inclusion of MI and highlighting the need for further research. PMID- 30452651 TI - Translocation and calmodulin-activation of the adenylate cyclase toxin (CyaA) of Bordetella pertussis. AB - The adenylate cyclase toxin (CyaA) is a multi-domain protein secreted by Bordetella pertussis, the causative agent of whooping cough. CyaA is involved in the early stages of respiratory tract colonization by Bordetella pertussis. CyaA is produced and acylated in the bacteria, and secreted via a dedicated secretion system. The cell intoxication process involves a unique mechanism of transport of the CyaA toxin catalytic domain (ACD) across the plasma membrane of eukaryotic cells. Once translocated, ACD binds to and is activated by calmodulin and produces high amounts of cAMP, subverting the physiology of eukaryotic cells. Here, we review our work on the identification and characterization of a critical region of CyaA, the translocation region, required to deliver ACD into the cytosol of target cells. The translocation region contains a segment that exhibits membrane-active properties, i.e. is able to fold upon membrane interaction and permeabilize lipid bilayers. We proposed that this region is required to locally destabilize the membrane, decreasing the energy required for ACD translocation. To further study the translocation process we developed a tethered bilayer lipid membrane (tBLM) design that recapitulate the ACD transport across a membrane separating two hermetic compartments. We showed that ACD translocation is critically dependent on calcium, membrane potential, CyaA acylation, and on the presence of calmodulin in the trans compartment. Finally, we describe how calmodulin-binding triggers key conformational changes in ACD, leading to its activation and production of supraphysiological concentrations of cAMP. PMID- 30452652 TI - Psychosocial Outcomes of Children and Adolescents With Severe Congenital Heart Defect: A Systematic Review and Meta-Analysis. AB - Objective: Over the past 20 years, there has been a growing interest in the psychosocial outcomes of children and adolescents born with a congenital heart defect (CHD). This systematic review and meta-analysis aims to appraise and synthesize current literature on the psychosocial outcomes of children and adolescents with severe CHD. Methods: A search of studies examining psychosocial outcomes in children and adolescents with severe CHD was performed. Meta-analyses were used to calculate the prevalence of psychosocial impairments and the standardized mean differences between cases and controls. Results that were not included in the meta-analysis were collated using descriptive statistics. Results: A total of 16 studies were included in this review, and results were summarized according to three domains: behavior, social cognition, and self esteem. Results from a meta-analysis identified that 25% of children and adolescents with CHD presented behavioral problems. Children and adolescents with CHD had more problematic behavior than healthy peers (standardized mean difference; g = 0.71). Young people with CHD had significantly more difficulties inferring on the mental states of others (standardized mean difference; g = 0.72). In contrast, identifying the emotions of others and self-esteem was not statistically different from healthy controls. Conclusion: This review and meta analysis provides evidence to support the presence of psychosocial difficulties in children and adolescents born with a severe CHD giving grounds for the systematic assessment of behavior and social cognition during their clinical follow-up. PMID- 30452653 TI - Evaluation of marbling and enhancement's abilities to compensate for reduced beef palatability at elevated degrees of doneness. AB - The objectives of this study were to evaluate the extent marbling compensates for reduced beef palatability at elevated degrees of doneness and to determine the relationship of residual moisture and fat in cooked steaks to beef palatability, specifically beef juiciness. Paired strip loins (IMPS # 180) were collected to equally represent five quality treatments [Prime, Top Choice (modest and moderate marbling), Low Choice, Select, and Select Enhanced (110% of raw weight)]. Steaks were grouped into sets of three consecutively cut steaks and randomly assigned a degree of doneness (DOD): very-rare (VR; 55 degrees C), rare (R; 60 degrees C), medium-rare (MR; 63 degrees C), medium (M; 71 degrees C), well-done (WD; 77 degrees C), or very well-done (VWD; 82 degrees C). Samples were subjected to consumer and trained sensory evaluation, Warner-Braztler shear force (WBSF), slice shear force (SSF), pressed juice percentage (PJP) evaluation, and raw and cooked proximate analysis. There were no (P > 0.05) quality treatment * DOD interactions for consumer sensory ratings, indicating increased DOD had the same negative impact regardless of marbling level. There was a quality treatment * DOD interaction (P < 0.05) for the percentage of steaks rated acceptable by consumers for juiciness. Increased marbling modified the point in which steaks became unacceptable for juiciness. Similarly, there was a quality treatment * DOD interaction (P < 0.05) for trained juiciness ratings. When cooked to MR and lower, Prime was rated only 8 to 18% higher (P < 0.05) than Select for trained juiciness ratings, but was rated 38 to 123% higher (P < 0.05) than Select when cooked to M and higher. Besides cooking loss, combined cooked moisture and fat percentage was more highly associated (P < 0.01) to consumer juiciness (r = 0.69) and trained initial (r = 0.84) and sustained (r = 0.85) juiciness ratings than all other objective evaluations. Using regression analyses, cooked moisture and fat percentages, alone, were poor indicators of consumer and trained juiciness ratings. However, when combined, the regression equations explained 45, 74, and 69% of the variation in consumer, trained initial, and trained sustained juiciness ratings, respectively. These results indicate that increased marbling levels only offer "insurance" for juiciness of steaks that are cooked to high degrees of doneness, but not for other palatability traits. Additionally, cooked residual moisture and fat percentages, when combined, are a good indicator of sensory juiciness ratings. PMID- 30452654 TI - Klebsiella pneumoniae infection biology: living to counteract host defences. AB - Klebsiella species cause a wide range of diseases including pneumonia, UTIs, bloodstream infections, and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals. Klebsiella is also responsible for a significant number of community-acquired infections. A defining feature of these infections is their morbidity and mortality, and the Klebsiella strains associated with them are considered hypervirulent. The increasing isolation of multidrug resistant strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Not surprisingly, this pathogen has then been singled out as an 'urgent threat to human health' by several organizations. This review summarizes the tremendous progress has been made to uncover the sophisticated immune evasion strategies of K. pneumoniae. The co-evolution of Klebsiella in response to the challenge of an activated immune has made Klebsiella a formidable pathogen exploiting stealth strategies and actively suppressing innate immune defences to overcome host responses to survive in the tissues. A better understanding of Klebsiella immune evasion strategies in the context of the host pathogen interactions is pivotal to develop new therapeutics, which can be based on antagonizing the anti-immune strategies of this pathogen. PMID- 30452655 TI - The injectable contraceptive medroxyprogesterone acetate attenuates Mycobacterium tuberculosis-specific host immunity through the glucocorticoid receptor. AB - Background: The effects of the widely used progestin-only injectable contraceptives, medroxyprogesterone acetate (MPA) and norethisterone acetate (NET A), on host susceptibility to Mycobacterium tuberculosis (M.tb) are unknown. Methods: We recruited HIV uninfected females, not taking any contraceptives, from Cape Town, South Africa, to evaluate the effect of MPA, NET-A, dexamethasone on M.tb containment in monocyte-derived macrophages (MDMs) co-incubated with purified protein derivative (PPD)-driven peripheral blood-derived effector cells. Results: MPA (p<0.005) and dexamethasone (p<0.01), but not NET-A, significantly attenuated M.tb containment in M.tb-infected macrophages co-cultured with PPD driven effector cells at physiologically relevant concentrations and in a dose dependent manner. Antagonising the glucocorticoid receptor with RU486 abrogated the reduction in M.tb containment. In PPD-stimulated PBMCs MPA and dexamethasone, but not NET, upregulated (median; interquartile range [p value]) regulatory T cells (5.3%;3.1-18.2%[p<0.05]), reduced CD4+ T-cell IFN-? (21%;0.5-28%[p<0.05]) and granzyme B production (12.6%;7-13.5%[p<0.05]), and reduced CD8+ perforin activity (2.2%;0.1-7%;p<0.05). RU486 reversed regulatory T cell up-regulation, and the inhibitory effect on Th1 and granzyme/perforin-related pathways. Conclusions: MPA, but not NET-A, subverts mycobacterial containment in vitro, and downregulates pathways associated with protective CD8+ and CD4+-related host immunity via the glucocorticoid receptor. These data potentially inform the selection and use of injectable contraceptives in TB endemic countries. PMID- 30452656 TI - Erratum to Malignancy and Mortality in Pediatric-onset Inflammatory Bowel Disease: A Systematic Review. PMID- 30452657 TI - Effects of microbial phytase on mucin synthesis, gastric protein hydrolysis, and degradation of phytate along the gastrointestinal tract of growing pigs. AB - An experiment was conducted to test the hypothesis that pigs fed diets supplemented with exogenous phytase reduce mucin synthesis in the small intestine, increase protein hydrolysis in the stomach, increase breakdown of phytate along the gastrointestinal tract, and increase mineral and AA digestibility. A diet based on corn, soybean meal, and canola meal was formulated to meet requirements for growing pigs except for Ca and P, which were lower than requirements. Three additional diets were formulated by adding 750, 1,500, or 3,000 units of phytase (FTU) per kg to the basal diet. Eight growing barrows (38.45 +/- 3.06 kg) were prepared with a T-cannula in the duodenum and another T cannula in the distal ileum. Pigs were housed individually and allotted to a replicated 4 * 4 Latin square design with 4 pigs and 4 periods in each square. Each period lasted 14 days with the initial 7 days being the adaptation period to the diets. Pigs were fed twice daily in combined amounts equal to 3.2 times the estimated requirement for maintenance energy. Results indicated that the apparent ileal digestibility (AID) and the apparent total tract digestibility (ATTD) of Ca and P increased (linear and quadratic, P <= 0.05) as phytase inclusion increased. However, values for AID of Ca and P were not different from values for ATTD of Ca and P, indicating that there is no net absorption of Ca and P in the hindgut. The apparent duodenal digestibility (ADD) of Ca and P were approximately 30% and 10 to 20%, respectively, indicating some digestion in the stomach of both Ca and P. A quadratic increase (P < 0.05) of the AID of gross energy (GE) was observed with the breakpoint around 1,500 FTU, but there was a negative linear (P <= 0.001) effect of dietary phytase on the ATTD of GE. Phytase did not affect mucin synthesis in the small intestine, protein hydrolysis in the stomach, or ileal digestibility of dispensable and indispensable amino acids. However, degradation of higher phytate esters (IP6 and IP5) into lower phytate esters (IP4 and IP3) and inositol increased as dietary phytase increased, indicating that it is possible to completely degrade dietary phytate if microbial phytase is included by at least 3,000 FTU in the diet. In conclusion, supplementing diets with phytase resulted in increased degradation of phytate and phytate esters and improved digestibility of Ca and P, but phytase did not change intestinal mucin synthesis, gastric protein hydrolysis, or the AID of AA. PMID- 30452658 TI - Dosimetric research into target regions and organs at risk in three-dimensional intracavitary brachytherapy techniques for Chinese patients with cervical carcinoma. AB - The present study aimed to compare the dosages of target regions and organs at risk (OARs) in 3D intracavitary brachytherapy (ICBT) and conventional 2D ICBT for Chinese patients with cervical carcinoma. ICBT was performed in a total of 66 patients with Stage IB to IVA cervical carcinoma who had not received surgery but who had received whole-pelvic external-beam radiotherapy (EBRT). Plans for the 3D ICBT and the conventional 2D-ICBT were individually designed for every patient. The dosages differences between the target regions and the OARs in patients with each of the various stages of cervical carcinoma were compared between the two ICBT plans. There was no significant difference in the dose at Point A between the two ICBT plans. However, the CTVhr-D90, CTVhr-D100 and CTVir-D90 in 3D-ICBT were much higher than in 2D-ICBT, especially in Stage IIB (P < 0.05). As compared with conventional 2D-ICBT, the dosages of DICRU and D2.0cm3 in the rectum/bladder, and D2.0cm3 in the sigmoid/small bowel were decreased significantly in 3D-ICBT (P < 0.05). For patients with Stage IIA, IIB and IIIB, the D2.0cm3 in the rectum/bladder was significantly reduced in 3D-ICBT (P < 0.05). It was demonstrated that, in Chinese patients, 3D-ICBT for cervical carcinoma could optimize the target coverage and reduce the dosages to the OARs compared with conventional 2D-ICBT. PMID- 30452659 TI - Anogenital distance is associated with semen quality but not reproductive hormones in 1106 young men from the general population. AB - STUDY QUESTION: Is anogenital distance (AGD) associated with semen quality and reproductive hormones in men from the general population? SUMMARY ANSWER: Short AGD measured from the anus to the base of scrotum (AGDAS) was associated with reduced sperm counts and morphology but not with sperm motility or reproductive hormones. WHAT IS KNOWN ALREADY: AGD is longer in males than in females. In rodents, AGD is a well-established and sensitive marker of disruption during the masculinization programming window in utero and it has been suggested to be so in humans as well. Therefore, the average AGD would be expected to be shorter in men with poor semen quality, which some studies have confirmed while others have not. STUDY DESIGN, SIZE, DURATION: This cross-sectional population-based study was of 1106 men included between 2012 and 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men from the general Danish population (median age 19 years), unselected with regard to fertility status and semen quality, delivered a semen sample, had a blood sample drawn, which was analyzed for concentrations of reproductive hormones, and answered a comprehensive questionnaire. They also had a physical examination performed including determination of AGD measured as the distance between anus and scrotum (AGDAS) and penis (AGDAP). Odds ratios (OR) and 95% CI were estimated for a man having abnormal semen parameters according to the World Health Organization's reference values or a low/high concentration of reproductive hormones (defined as the lowest or highest 10%) depending on AGD. AGD was categorized in four strata: <=10th percentile, 10th-30th percentile, 30th 50th percentile and >50th percentile. MAIN RESULTS AND THE ROLE OF CHANCE: Men with the 10% shortest AGDAS had a more than doubled risk (OR: 2.19, 95% CI: 1.40 3.42) of being in the subfertile range for either sperm concentration (<15 million/mL) or sperm morphology (<4%) compared to men with AGDAS above the median (reference). Men in the 10th-30th percentile also had an increased OR of 1.48 (95% CI: 1.06-2.08) but not men in the 30th-50th percentile (OR: 1.14, 95% CI: 0.81-1.62). AGDAP was only weakly related to semen quality. AGD was not associated with testicular volume or any of the reproductive hormones. LIMITATIONS, REASONS FOR CAUTION: Limitations include the potential non differential misclassification of reproductive outcomes based on a single semen and blood sample and some between-examiner differences in AGD measurements which introduces noise and may result in an underestimation of observed associations. WIDER IMPLICATIONS OF THE FINDINGS: Our study of men from the general population confirmed associations between AGD and semen quality, supporting the hypothesis that AGD in humans could be a marker of fetal testicular development. This suggests that the low semen quality in Danish men may partly be explained by prenatal factors. STUDY FUNDING/COMPETING INTEREST(S): The study has received financial support from the ReproUnion (L.P.); the Research fund of Rigshospitalet, Copenhagen University Hospital (N.J.); Grants R01ES016863-04 and R01ES016863-02S4; National Institute of Environmental Health Sciences (NIEHS) and National Institute of Environmental Health Sciences grant (P30ES023515) (S.S.); the European Union (Contract numbers BMH4-CT96-0314, QLK4-CT-1999-01422, QLK4-CT 2002-00603, FP7/2007-2013, DEER Grant agreement no. 212844); the Danish Ministry of Health; the Danish Environmental Protection Agency; A.P. Moller and wife Chastine McKinney Mollers foundation; and Svend Andersens Foundation. None of the funders had any role in the study design, collection, analysis or interpretation of data, writing of the paper or publication decisions. The authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A. PMID- 30452660 TI - The Digital Divide in Health-Related Technology Use: The Significance of Race/Ethnicity. AB - Background and Objectives: Technology can enhance the health and quality of life of diverse populations and may play an important role in reducing health disparities. Although a "digital divide" between the young and the old has been noted, it is unclear whether the use of technology for managing health differs by race/ethnicity among older adults. This study uses nationally representative data from community-dwelling older Americans to characterize racial/ethnic differences in health-related technology use. Design and Methods: Data came from 1,336 white, black, and Hispanic adults aged 54 and older who completed the 2014 technology module of the Health and Retirement Study. Racial/ethnic differences in overall health-related technology use were assessed using Poisson regression. Then, F tests were used to assess differences in the use of phone calls, text messages, E mails, social media, health management sites, health-related mobile applications, web searches, and brain games for health purposes. Results: Compared to whites, older blacks and Hispanics were less likely to use technology for health-related purposes after accounting for demographic characteristics, education, and health conditions. They were also less likely to make or receive phone calls, use health management sites, search the web for health information, and use brain games for their health. Discussion and Implications: Older racial and ethnic minorities are less likely than whites to use certain technologies when managing their health. These findings highlight the importance of understanding the patterns of health related technology use across racially and ethnically diverse populations to appropriately tailor interventions aimed at improving minority health and eliminating health disparities. PMID- 30452661 TI - Population pharmacokinetics of ribavirin in lung transplant recipients and examination of current and alternative dosing regimens. AB - Background: Ribavirin is used in the treatment of respiratory paramyxovirus infection in lung transplant recipients; however, its pharmacokinetic profile in the transplant population is unknown despite the potential for alterations due to underlying pathology. Furthermore, the ability of current regimens to meet exposure targets has not been established. Objectives: This study examined the pharmacokinetics of ribavirin in a lung transplant population for which current and alternative dosing regimens were assessed. Methods: Population pharmacokinetic modelling was conducted in NONMEM using concentration-time data from 24 lung transplant recipients and 6 healthy volunteers. Monte Carlo simulation was used to assess the ability of dosing regimens to achieve pre specified target concentrations. Results and conclusions: A three-compartment model with first-order elimination most adequately described ribavirin concentration-time data, with CLCR and patient type (i.e. lung transplant) identified as significant covariates in the model. Simulations indicate that current regimens achieve efficacious concentrations within 24 h of treatment initiation that increase to supra-therapeutic levels over the treatment period. A regimen of 8 mg/kg q6h orally for 48 h followed by 8 mg/kg q24h orally for the remainder of the treatment period was predicted to result in >90% of patients exhibiting concentrations within the defined target range throughout the entire treatment course. Additional work to formally establish target therapeutic concentrations is required; however, this study provides a valuable first step in determining optimal ribavirin treatment regimens for paramyxovirus infections in the lung transplant population. PMID- 30452662 TI - Loss of psoas major muscle volume during systemic chemotherapy is related to worse prognosis in testicular cancer. AB - Objective: In several cancers, the loss of skeletal muscle is well associated with oncological outcome. However, its effect is unknown in testicular cancer. This study evaluated the prognostic impact of psoas major muscle volume loss during systemic chemotherapy. Methods: This was a retrospective study of patients who underwent chemotherapy from 2008 to 2017. Psoas major muscle volume was calculated by volume analyzer software, and its loss was calculated during systemic chemotherapy. The patients were divided according to muscle volume loss: Group 1 (<20%) and Group 2 (>=20%). The losses were compared with Kaplan-Meier curves, and a Cox proportional hazard model was applied to test predictors of poor prognosis. Results: Fifty patients were included. Seventeen were classified into Group 1, and 33 into Group 2. The Kaplan-Meier curves revealed that the progression-free and the overall survival of Group 1 were significantly better than those of Group 2 (P = 0.002, P = 0.03, respectively). A multivariate analysis identified psoas major muscle volume loss as a significant and independent predictor of poor prognosis. Conclusions: Patients with psoas major muscle volume loss during chemotherapy had a significantly worse prognosis than those without loss. PMID- 30452663 TI - Potential lethal damage repair in glioblastoma cells irradiated with ion beams of various types and levels of linear energy transfer. AB - Glioblastoma (GBM), a Grade IV brain tumour, is a well-known radioresistant cancer. To investigate one of the causes of radioresistance, we studied the capacity for potential lethal damage repair (PLDR) of three altered strains of GBM: T98G, U87 and LN18, irradiated with various ions and various levels of linear energy transfer (LET). The GBM cells were exposed to 12C and 28Si ion beams with LETs of 55, 100 and 200 keV/MUm, and with X-ray beams of 1.7 keV/MUm. Mono-energetic 12C ions and 28Si ions were generated by the Heavy Ion Medical Accelerator at the National Institute of Radiological Science, Chiba, Japan. Clonogenic assays were used to determine cell inactivation. The ability of the cells to repair potential lethal damage was demonstrated by allowing one identical set of irradiated cells to repair for 24 h before subplating. The results show there is definite PLDR with X-rays, some evidence of PLDR at 55 keV/MUm, and minimal PLDR at 100 keV/MUm. There is no observable PLDR at 200 keV/MUm. This is the first study, to the authors' knowledge, demonstrating the capability of GBM cells to repair potential lethal damage following charged ion irradiations. It is concluded that a GBM's PLDR is dependent on LET, dose and GBM strain; and the more radioresistant the cell strain, the greater the PLDR. PMID- 30452664 TI - Toxicity and clinical outcomes with definitive three-dimensional conformal radiotherapy (3DCRT) and concurrent cisplatin chemotherapy in locally advanced cervical carcinoma. AB - Objective(s): This study aimed to retrospectively evaluate the toxicity and clinical outcomes in patients of locally advanced cervical cancer treated with three-dimensional conformal radiotherapy (3DCRT) and concurrent chemotherapy. Material and methods: Two hundred and ten newly diagnosed patients of locally advanced cervical cancer of FIGO 2009 Stage II-III treated with 3DCRT (46 Gy/23 fractions/41/2 weeks) and weekly concurrent Cisplatin (40 mg/m2), from January 2013 to 2015 were analyzed. A planning computed tomography was performed and contouring was done according to published guidelines. External radiotherapy was followed by Intracavitary brachytherapy delivered to a dose of 9 Gy HDR in 2 fractions, given one week apart. The endpoints were treatment related toxicities and clinical outcomes. Local control (LC), overall survival (OS) and disease free survival (DFS) were evaluated and toxicities were documented using the common terminology criteria for adverse events (v3.0) (CTCAE). Results: The median follow up time was 37 (range, 19-54) months. The 3 year OS, DFS and LC were 84.2%, 80.6% and 81% respectively. Grade >=3 acute skin, upper and lower gastrointestinal (GI) and genitourinary (GU) toxicity was observed in 3 (1.4%), 11 (5.2%), 12 (5.7%) and 0 (0%) patients, respectively. Grade <=2 hematological toxicity was observed in 154 (73.3%) patients. Grade >=3 late GI and GU toxicity was seen in 9 (4.2%) patients and 2 (0.9%) patients, respectively. Conclusion: 3DCRT with concurrent chemotherapy results in good loco-regional control with acceptable normal tissue toxicity. In the background of indeterminate evidence regarding routine practice of intensity modulated radiotherapy in carcinoma of the cervix, 3DCRT may be considered as the treatment of choice. PMID- 30452665 TI - The Relationship of Adolescent and Parent Preferences for Treatment Modality With Satisfaction, Attrition, Adherence, and Efficacy: The Coping With Head Injury Through Problem-Solving (CHIPS) Study. AB - Objective: To characterize treatment preferences for delivery of family problem solving treatment (F-PST) to adolescents with behavioral challenges following traumatic brain injury (TBI) and to examine associations with attrition, adherence, satisfaction, and efficacy. Method: Adolescents who had been hospitalized for moderate to severe TBI were randomized to face-to-face F-PST (n = 34), therapist-guided online F-PST (n = 56), and self-guided online F-PST (n = 60). Adolescents and parents rated treatment convenience and anticipated benefit before group assignment. Sessions completed served as an index of adherence. Satisfaction was rated posttreatment. The Behavior Rating Inventory of Executive Function and Strengths and Difficulties Questionnaire were used to assess parent reported behavioral concerns. Results: Both parents and adolescents were more likely to agree or strongly agree that they anticipated self-guided online F-PST to be the most convenient relative to either of the therapist-involved approaches. Parents were also less likely to anticipate face-to-face treatment as most beneficial, relative to the two online treatments. Adolescent preferences were significantly related to attrition with 27% versus 13% dropout rates for those assigned to nonpreferred and preferred treatments, respectively. Parent and adolescent preferences before treatment were unrelated to post-intervention satisfaction, adherence, or improvements in parent-reported child behavior problems. Conclusions: Online treatments are perceived favorably among adolescents with TBI and their parents. For adolescents, these pretreatment preferences influenced treatment completion. Poor correspondence between initial preferences and posttreatment satisfaction and benefit suggests that therapeutic experience more strongly influences ultimate satisfaction. PMID- 30452666 TI - Detectable Vesicular Stomatitis Virus (VSV)-Specific Humoral and Cellular Immune Responses Following VSV-Ebola Virus Vaccination in Humans. AB - In response to the Ebola virus (EBOV) crisis of 2013-2016, a recombinant vesicular stomatitis virus (VSV)-based EBOV vaccine was clinically tested (NCT02283099). A single-dose regimen of VSV-EBOV revealed a safe and immunogenic profile and demonstrated clinical efficacy. While EBOV-specific immune responses to this candidate vaccine have previously been investigated, limited human data on immunity to the VSV vector are available. Within the scope of a phase 1 study, we performed a comprehensive longitudinal analysis of adaptive immune responses to internal VSV proteins following VSV-EBOV immunization. While no preexisting immunity to the vector was observed, more than one-third of subjects developed VSV-specific cytotoxic T-lymphocyte responses and antibodies. PMID- 30452667 TI - Accurate measurement of electric potentials in biased GaAs compound semiconductors by phase-shifting electron holography. AB - The innate electric potentials in biased p- and n-type GaAs compound semiconductors and the built-in potential were successfully measured with high accuracy and precision by applying in situ phase-shifting electron holography to a wedge-shaped GaAs specimen. A cryo-focused-ion-beam system was used to prepare the 35 degrees -wedge-shaped specimen with smooth surfaces for a precise measurement. The specimen was biased in a transmission electron microscope, and holograms with high-contrast interference fringes were recorded for the phase shifting method. A clear phase image around the p-n junction was reconstructed even in a thick region (thickness of ~700 nm) at a spatial resolution of 1 nm and precision of 0.01 rad. The innate electric potentials of the unbiased p- and n type layers were measured to be 12.96 +/- 0.17 V and 14.43 +/- 0.19 V, respectively. The built-in potential was determined to be 1.48 +/- 0.02 V. In addition, the in situ biasing measurement revealed that the measured electric potential difference between the p and n regions changed by an amount equal to the voltage applied to the specimen, which indicates that all of the external voltage was applied to the p-n junction and that no voltage loss occurred at the other regions. PMID- 30452668 TI - Electron tomography in plant cell biology. AB - Electron tomography (ET) approaches are based on the imaging of a biological specimen at different tilt angles by transmission electron microscopy (TEM). ET can be applied to both plastic-embedded and frozen samples. Technological advancements in TEM, direct electron detection, automated image collection, and imaging processing algorithms allow for 2-7-nm scale axial resolution in tomographic reconstructions of cells and organelles. In this review, we discussed the application of ET in plant cell biology and new opportunities for imaging plant cells by cryo-ET and other 3D electron microscopy approaches. PMID- 30452669 TI - Reaching rural veterans: a new mechanism to connect rural, low-income US Veterans with resources and improve food security. AB - Background: Rural, low-income US veterans face additional barriers to accessing food and resources compared to urban veterans. Based on both social-ecological and cultural competence approaches, the Reaching Rural Veterans (RRV) pilot intervention built on the existing infrastructure of food pantries to improve food security and connect rural, low-income veterans with resources. This article describes the process of implementing and evaluating RRV. Methods: Five rural food pantries within each of two states, Indiana and Kentucky, received training in cultural competence and held monthly outreach events where food and services were offered to veterans. Veteran adult participants completed an assessment at baseline and 3-month follow-up that measured food security using the US Household Food Security Survey Module and self-reported resource enrollment. Repeated measures logistic regression models evaluated the odds of improving food security and resource enrollment from baseline to follow-up (significance P < 0.05). Results: RRV recruited 234 participants; 53% completed the follow-up assessment. At follow-up, the odds of household (P = 0.009) and adult (P = 0.01) food security increased, as did enrollment in one or more of the following resources: Temporary Assistance for Needy Families, Supplemental Security Income, General Assistance or Assistance from the Township Trustee (P = 0.005). Conclusions: RRV yielded promising preliminary results of improved food security and resource use. PMID- 30452670 TI - Circulating neutrophil extracellular traps and neutrophil activation are increased in proportion to disease severity in human malaria. AB - Background: Neutrophil activation results in Plasmodium parasite killing in vitro, but neutrophil products including neutrophil extracellular traps (NETs) mediate host organ damage and may contribute to severe malaria. The role of NETs in the pathogenesis of severe malaria has not been examined. Methods: In Papua, Indonesia, we enrolled adults with symptomatic Plasmodium falciparum (n=47 uncomplicated, n=8 severe), P. vivax (n=37) or P. malariae (n=14) malaria; asymptomatic P. falciparum (n=19) or P. vivax (n=21) parasitemia; and healthy adults (n=23) without parasitemia. Neutrophil activation and NETs were quantified by immunoassays and microscopy, and correlated with parasite biomass and disease severity. Results: In patients with symptomatic malaria, neutrophil activation and NET counts were increased in all three Plasmodium species. In falciparum malaria, neutrophil activation and NET counts positively correlated with parasite biomass (Spearman rho=0.41, p=0.005 and r 2=0.26, p=0.002, respectively) and were significantly increased in severe disease. Conversely, NETs were inversely associated with parasitemia in adults with asymptomatic P. falciparum infection (r 2=0.24, p=0.031), but not asymptomatic P. vivax infection. Conclusion: Whilst NETs may inhibit parasite growth in asymptomatic P. falciparum infection, neutrophil activation and NET release may contribute to pathogenesis in severe falciparum malaria. Agents with potential to attenuate these processes should be evaluated. PMID- 30452672 TI - Erratum. PMID- 30452671 TI - Pretreatment Hepatitis B Viral Load Predicts Long-term Hepatitis B Response after Anti-hepatitis C Therapy in Hepatitis B/C Dual-infected Patients. AB - Background: We aimed to investigate the long-term outcomes in hepatitis B (HBV)/hepatitis C (HCV) dual-infected patients after anti-HCV therapy. Methods: A total of 192 HBV/HCV dual-infected patients who had received pegylated interferon treatment were recruited. The investigation outcomes included HBV DNA >=2000 IU/mL, with or without alanine aminotransferase (ALT) >=2-fold the upper limit of normal, and hepatitis B surface antigen (HBsAg) seroclearance. Results: Four (2.1%) patients developed early HBV reactivation before the end of treatment. Fifty (26.6%) of the remained patients had an episode of HBV DNA >=2000 IU/mL in a mean follow-up of 68.8 months. The risk was 4.6 per 100-person-year. Only 19 (10.1%) patients developed concomitant ALT flare with oral HBV antiviral therapy; the risk was 1.7 per 100-person-year. Despite HBV flare, 67 (34.9%) patients had a favorable outcome of HBsAg seroclearance. The probability was 5.7 per 100 person-year. A pretreatment HBV DNA level of 300 IU/mL served as an independent predictor for all the outcomes. The combined pretreatment HBV DNA level and HCV response further enhanced the prediction of HBV flare and HBsAg seroclearance. Conclusions: A pretreatment HBV DNA level of 300 IU/mL predicts HBV flare and HBsAg seroclearance after anti-HCV therapy. PMID- 30452673 TI - Grounding Moral Authority in Spirit. PMID- 30452674 TI - The Future of Roman Catholic Bioethics. PMID- 30452675 TI - Engelhardt's Diagnosis and Prescription: Persuasive or Problematic? AB - In a spirit of critical appreciation, this essay challenges several core aspects of the critique of secular morality and the defense of Orthodox Christianity offered by H. Tristram Engelhardt in After God. First, I argue that his procedurally driven approach to a binding morality based solely on a principle of permission leaves morality without any substantive definition in general terms, in ways that are both conceptually problematic and also at odds with Engelhardt's long-standing distinction between non-malevolence and beneficence. Second, I question the accuracy or adequacy of Engelhardt's critique of the Enlightenment project for his unwarranted privileging of a particular version of Enlightenment thinking at the expense of other Enlightenment perspectives less amenable to Engelhardt's working generalizations. Third, I challenge the theoretical cogency of Engelhardt's insistence on the ubiquity and intractability of moral controversies and his depiction of moral strangers and moral friends as, in effect, mutually exclusive terms. Finally, I question Engelhardt's embrace of a divine command model of ethics as the appropriate resolution of Euthyphro's dilemma and suggest that there may be intermediate approaches to the usual starkly drawn contrasts between divine command and naturalist accounts. PMID- 30452676 TI - The Journal of Medicine and Philosophy would like to Thank the following Guest Reviewers for their help during the past year. PMID- 30452677 TI - Committing to Priorities: Incompleteness in Macro-Level Health Care Allocation and Its Implications. AB - This article argues that values that apply to health care allocation entail the possibility of "spectrum arguments," and that it is plausible that they often fail to determine a best alternative. In order to deal with this problem, a two step process is suggested. First, we should identify the Strongly Uncovered Set that excludes all alternatives that are worse than some alternatives and not better in any relevant dimension from the set of eligible alternatives. Because the remaining set of alternatives often contain more than one element, we need some complementary method of selecting a unique alternative. In order to address this issue, I suggest that we must invoke caps on the values that are used to evaluate alternatives, and that these caps must be grounded in collective commitments. PMID- 30452678 TI - Brief Remarks on Engelhardt's After God. AB - >Engelhardt's After God gives a comprehensive perspective on the deepest and hardest issues in both moral philosophy and bioethics of our time. Although the book is an intelligent critique of contemporary moral philosophy in favor of a kind of traditionalism rooted in the perspective of the Orthodox Church, containing numerous forceful arguments, I ultimately disagree with Engelhardt on several main points stemming from his pessimistic view of our current culture and society. I have neither the pretense to open new perspectives, nor to put forward new arguments, and I am aware that I might be wrong. I simply want to present a different position on the quest for meaning. PMID- 30452679 TI - God as the Good: A Critique of H. Tristram Engelhardt, Jr.'s After God. AB - Despite its many strengths, Engelhardt's After God displays two surprising features: an affinity for voluntaristic ethics and a tendency to oppose Eastern Orthodoxy (as a purely revealed religion) to philosophy. Neither of these is in keeping with the mainstream of Eastern Orthodox tradition. Here, I offer a modest corrective. I begin with the figure of Socrates as presented in the Apology and Phaedo, highlighting the role that faith plays for Socrates and the reasons why he was widely admired by the early Church. I then describe more broadly the attitude of the Greek Church Fathers to philosophy, showing that, although they were cautious of its potential errors, they nonetheless embraced the ideal of philosophy as a way of life dedicated to the pursuit of wisdom. For many, in fact, Christianity is itself simply the true philosophy, an attitude that led many of the most eminent patristic and Byzantine theologians to draw extensively on philosophical sources. Finally, I discuss the Euthyphro dilemma, contrasting the voluntaristic approach favored by Engelhardt with the Platonic approach adopted by the mainstream of Orthodox tradition. PMID- 30452680 TI - Erratum to: Taxonomic structure and functional association of foxtail millet root microbiome. PMID- 30452681 TI - Similar Immunological Profiles Between African Endemic and HIV1-associated Epidemic Kaposi's Sarcoma Patients Reveal the Primary Role of KSHV in KS Pathogenesis. AB - Background: Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is etiologically linked to all KS forms but mechanisms underlying KS development are unclear. The high incidence of KS in HIV-1 + individuals, implicates immune dysregulation in co-infection; however, the lack of in-depth characterization of KSHV immune responses in African endemic-KS makes the pathogenetic role of HIV-1 unclear. The study objective was to investigate the HIV-1 and KSHV roles in viral-nucleic-acid detection, antibody and cytokine responses in PCR confirmed epidemic-KS and endemic-KS patients, and non-cancer controls from sub-Saharan Africa. Methods: KSHV viral-DNA (vDNA), total anti-KSHV antibody, KSHV-neutralizing antibody (nAb) and cytokines were quantified. Mann-Whitney U-test was used to assess differences between groups where P-value <0.05 was considered significant. Results: Consistently, KSHV-vDNA was detectable in tumors but variably in plasma and PBMCs of KS patients. Consistent with elevated antibody-associated cytokines (IL-6, IL 5 and IL-10), total and nAb titers were higher in epidemic-KS and endemic-KS patients than in controls (P<0.05). Despite HIV-1 co-infection in epidemic-KS, total and nAb titers were similar between epidemic-KS and endemic-KS patients (P=0.3). Conclusions: Detection of similar antibody and cytokine responses in epidemic-KS and endemic-KS patients suggest that KSHV drives KS pathogenesis, whereas HIV-1 co-infection exacerbates and accelerates KSHV pathogenesis and KS development. PMID- 30452682 TI - Assembly of a Parts List of the Human Mitotic Cell Cycle Machinery. AB - The set of proteins required for mitotic division remains poorly characterised. Here, an extensive series of correlation analyses of human and mouse transcriptomics data was performed to identify genes strongly and reproducibly associated with cells undergoing S/G2-M phases of the cell cycle. In so doing, a list of 701 cell cycle-associated genes were defined and whilst it was shown that many are only expressed during these phases, the expression of others is also driven by alternative promoters. Of this list, 496 genes have known cell cycle functions, whereas 205 were assigned as putative cell cycle genes, 53 of which are functionally uncharacterised. Among these, 27 were screened for subcellular localisation revealing many to be nuclear localised and at least four to be novel centrosomal proteins. Furthermore, 10 others inhibited cell proliferation upon siRNA knockdown. This study presents the first comprehensive list of human cell cycle proteins, identifying many new candidate proteins. PMID- 30452683 TI - Mechanism suppressing H3K9 trimethylation in pluripotent stem cells and its demise by polyQ-expanded huntingtin mutations. AB - Pluripotent stem cells are invaluable resources to study development and disease, holding a great promise for regenerative medicine. Here we use human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) from patients with Huntington's disease (HD-iPSCs) to shed light into the normal function of huntingtin (HTT) and its demise in disease. We find that HTT binds ATF7IP, a regulator of the histone H3 methyltransferase SETDB1. HTT inhibits the interaction of the ATF7IP-SETDB1 complex with other heterochromatin regulators and transcriptional repressors, maintaining low levels of H3K9 trimethylation (H3K9me3) in hESCs. Loss of HTT promotes global increased H3K9me3 levels and enrichment of H3K9me3 marks at distinct genes, including transcriptional regulators of neuronal differentiation. Although these genes are normally expressed at low amounts in hESCs, HTT knockdown (KD) reduces their induction during neural differentiation. Notably, mutant expanded polyglutamine repeats in HTT diminish its interaction with ATF7IP-SETDB1 complex and trigger H3K9me3 in HD iPSCs. Conversely, KD of ATF7IP in HD-iPSCs reduces H3K9me3 alterations and ameliorates gene expression changes in their neural counterparts. Taken together, our results indicate ATF7IP as a potential target to correct aberrant H3K9me3 levels induced by mutant HTT. PMID- 30452684 TI - Mutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy. AB - Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange. PMID- 30452685 TI - Emergency Care of The Burn Patient Before The Burn Center: A Systematic Review and Meta-analysis. AB - Background: Good burn care starts with correct management of the burn patient prior to transfer to a burn center. The purpose of this study was to perform a systematic review of the medical literature describing pre-burn center care. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for this review. Studies were included if they were published from a burn center and they measured or evaluated any aspect of pre-burn center care of adult or pediatric acute burn patients referred to that burn center. A comprehensive search of MEDLINE, EMBASE, and Cochrane databases was performed from their inception to May 28, 2018. Outcomes of interest included errors in burn size estimation, airway management, fluid resuscitation, dressings and wound care, use of systemic antibiotics, core temperature monitoring and preservation, and analgesia provision. Meta-analysis of the discrepancy between pre-burn center and burn center burn size estimation was conducted. Results: From 3768 initially identified titles, 37 studies were included in this systematic review. Burn size estimation was frequently inaccurate. The ratio of overestimation to underestimation in burn size ranged between 2.2:1 to 19:1. The pooled mean absolute error in % total body surface area burn was 6.28 (95% CI: 4.72, 7.85). The average relative percent error in burn size estimation by referring providers ranged between 75% and 3500%. Unnecessary endotracheal intubation was performed in 28% to 53% of transfers. Over-estimation and over delivery of fluid resuscitation volumes was prevalent, but other problems pertaining to resuscitation included administration of the wrong fluid, and failure to titrate fluids. Wounds were not consistently covered with simple dry dressings or sheets. Core temperature was not consistently monitored or preserved. Analgesics were often not given or were of insufficient dose. Conclusion: Many elements of pre-burn center care need improvement. These findings should be used to form the foundation of future initiatives between burn professionals and emergency providers to improve care of the burn patient before transfer to a burn center. PMID- 30452686 TI - THERMOLUMINESCENCE OF NEWLY DEVELOPED HIGHLY SENSITIVE alpha-Al2O3:C BY THE VERTICAL GRADIENT FREEZING METHOD. AB - A highly sensitive alpha-Al2O3:C crystal was directly grown by the vertical gradient freezing (VGF) method using Al2O3 and graphite powder as the raw materials. The main thermoluminescence (TL) characteristics of alpha-Al2O3:C detectors grown by the VGF method and TLD-500K detectors were compared. The alpha Al2O3:C grown by the VGF method shows good dosimetric properties, such as high TL sensitivity (152 times higher than that of the TLD-100 at heating rate of 1 degrees C/s), an extremely low residual signal of 0.03%, a minimum measurable dose of 0.12 MUGy and an excellent linear response within the dose range studied from 1 MUGy to 10 Gy. The alpha-Al2O3:C detectors grown by the VGF method have a higher sensitivity and a better linear response compared to the TLD-500K detectors. Both kinds of alpha-Al2O3:C can be used in an unannealed form and to measure the very low dose in environmental monitoring and personnel dosimetry. PMID- 30452687 TI - Nivolumab and stereotactic radiation therapy for the treatment of patients with Stage IV non-small-cell lung cancer. AB - Background: Radiation therapy might modify the cancer immune environment to enhance the antitumor effect of immune checkpoint inhibitors. We performed a feasibility study of nivolumab following stereotactic radiation therapy for chemotherapy pretreated advanced non-small-cell lung cancer. Patients and methods: Pretreated advanced/recurrent non-small-cell lung cancer patients received stereotactic radiation therapy to one of the disease sites. Nivolumab at a dose of 3 mg/kg was given within 2 weeks after the completion of stereotactic radiation therapy and continued every 2 weeks thereafter until disease progression or unacceptable toxicities. The primary endpoint was the occurrence rate of Grade 3 pneumonitis (within 12 weeks) or other non-hematological toxicity (within 8 weeks). Results: From September 2016 to September 2017, six patients were enrolled. Five received stereotactic radiation therapy to their primary lesions. All patients received nivolumab on the following day after stereotactic radiation therapy completion. Grade 3 pneumonitis occurred in one patient, but no other serious adverse events were reported for the other patients. One complete response and two partial responses were achieved. Four patients had measurable lesions outside the irradiated area, of whom three patients responded to the treatment. The initial progression sites were mainly outside the irradiated field, including one brain metastasis. Conclusions: Nivolumab therapy immediately following stereotactic radiation therapy was well tolerated. This sequential combination warrants further study. PMID- 30452688 TI - Knock-downs for drought-induced cysteine-protease genes alter barley leaf structure and the response to abiotic and biotic stresses. AB - To survive under water deprivation, plants alter gene expression patterns, make structural and physiological adjustments and optimize the efficient use of water. Protein turn-over is required for a rapid degradation of proteins and an effective nutrient recycling. In barley, the transcriptional responses of the C1A cysteine protease family to drought revealed the up-regulation of four genes in stressed leaves. Knock-down lines for HvPap-1 and HvPap-19 protease-encoding genes showed unexpected changes in leaf cuticle thickness and stomata pore area. Photosystem II efficiency and total amount of proteins was almost unaltered in stressed transgenic leaves while both parameters diminished in stressed WT plants. Although the proteolytic pattern activities in knock-down lines did not change, the amino acid accumulation increased in response to drought concomitant to a higher ABA content. JA and JA-Ile concentration increased in stressed leaves of WT and HvPap-1 knock-down leaves, but their levels were lower in HvPap-19 knock-down lines, indicating a specific hormonal crosstalk of the process. This work demonstrates that structural and physiological alterations due to the low expression of some cysteine proteases have important effects in response to drought and also in defense against fungal infection and mite feeding mediated by Magnaporthe oryzae and Tetranychus urticae, respectively. PMID- 30452689 TI - Rapid Communication: Maternal melatonin implants improve fetal oxygen supply and body weight at term in sheep pregnancies. AB - Fetal hypoxia, resulting in oxidative stress in pregnancies contributes to reduced fetal growth. Melatonin, a potent antioxidant has been associated with improved oxidative status. Maternal oral melatonin supplementation in sheep from day 50 of gestation ameliorates the consequences of fetal growth restriction in sheep. In rats, melatonin supplementation increases fetal weight via improved placental efficiency and reduction of oxidative stress. The objective of this study was to evaluate whether melatonin supplementation of single (S)- or twin bearing (T) ewes using either 0 (0MEL), 1 (18 mg MEL) or 2 (36 mg MEL) slow release 18-mg melatonin implants (Regulin(r)) from 100 to 140 days of pregnancy (n=8 per group) influenced fetal oxygen supply and fetal weight. Fetal umbilical vein blood samples were collected at P140 and partial pressure of oxygen (PO2) and hemoglobin saturation by oxygen (SatHb) measured. The placenta from each fetus was excised and placentomes individually weighed and typed (A-D). Pregnancy rank, sex of the fetus, number of implants and their interaction on fetal weight, blood gases and placentome weight were analyzed using ANOVA. A 22% and 14% increase (P < 0.05) in body weight was obtained in 36 and 18 mg MEL compared to 0 MEL twin male fetuses, respectively but no treatment effects were observed in singletons or females from twin pregnancies. Fetuses from ewes receiving 36 mg MEL had an 18-20% increase in cord PO2 (P < 0.05) compared to 18 mg MEL and 0MEL fetuses, which in turn did not differ. Fetal weight was positively correlated with PO2 (r = 0.37; P = 0.02), SatHb (r = 0.26; P = 0.03) and O2 content (r = 0.236; P = 0.048). No treatment effect on placentome average weight, total placentome weight per fetus or per ewe nor total number of placentomes per fetus was observed. However, placentae from 36 mg MEL fetuses had a greater proportion of Type C (P < 0.05) than 0MEL and 18 mg MEL ewes, and tended to have lower proportion of Type A (P = 0.1), and greater proportion of Type D (P = 0.06) placentomes, compared to 0MEL ewes. These results indicate that maternal melatonin implants, independently of sex, improve oxygen supply to the fetus, which could potentially improve lamb vigour at birth. In addition, melatonin can increase fetal weight of twin males, by improving placental adaptation and fetal blood oxygenation. PMID- 30452690 TI - Associations Between Control Beliefs and Response Time Inconsistency in Older Adults Vary as a Function of Attentional Task Demands. AB - Objective: Control beliefs are established correlates of cognitive aging. Despite recent demonstrations that response time inconsistency (RTI) represents a proxy for cognitive processing efficiency, few investigations have explored links between RTI and psychosocial correlates. We examined associations among RTI and control beliefs (perceived competence and locus of control) for two choice response time (RT) tasks varying in their attentional demands. Method: Control beliefs and RTI were measured weekly for 5 weeks in a sample of 304 community dwelling older adults (Mage = 74.11 years, SD = 6.05, range = 64-92, 68.58% female). Results: Multilevel models revealed that for the attentionally demanding task, reporting higher perceived competence than usual was associated with lower RTI for relatively younger participants and greater RTI for relatively older participants. For the less attentionally demanding task, reporting higher perceived competence than usual was associated with lower RTI for relatively older participants. Links between locus of control and RTI were comparatively scant. Discussion: Our findings suggest that control beliefs may have adaptive and maladaptive influences on RTI, depending on dimension of control beliefs, individual differences in level of control beliefs and age, as well as attentional task demands. Both for whom and when control beliefs can be leveraged to optimize cognitive aging are discussed. PMID- 30452691 TI - Starch granule initiation and morphogenesis - progress in Arabidopsis and cereals. AB - Starch, the major storage carbohydrate in plants, is synthesised in plastids as semi-crystalline, insoluble granules. Many organs and cell types accumulate starch at some point during their development and maturation. The biosynthesis of the starch polymers, amylopectin and amylose, is relatively well understood and mostly conserved between organs and species. However, we are only beginning to understand the mechanism by which starch granules are initiated, and the factors that control the number of granules per plastid and the size/shape of granules. Here, we review recent progress in understanding starch granule initiation and morphogenesis. In Arabidopsis, granule initiation requires several newly discovered proteins with specific locations within the chloroplast, and also on the availability of maltooligosaccharides which act as primers for initiation. We also describe progress in understanding granule biogenesis in the endosperm of cereal grains - within which there is large inter-species variation in granule initiation patterns and morphology. Investigating whether this diversity results from differences between species in the functions of known proteins, and/or from the presence of novel, unidentified proteins, is a promising area of future research. Expanding our knowledge in these areas will lead to new strategies for improving the quality of cereal crops by modifying starch granule size and shape in vivo. PMID- 30452692 TI - Radiation-induced dermatitis after administration of mogamulizumab for adult T cell leukaemia/lymphoma: a multi-institutional retrospective study. AB - Background: Cutaneous adverse reactions are frequently induced by mogamulizumab. Cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and severe photosensitivity related to mogamulizumab have been reported. This study investigated whether severe radiation-induced dermatitis occurred in patients undergoing radiotherapy after the administration of mogamulizumab for adult T cell leukaemia/lymphoma. Methods: We retrospectively reviewed 46 courses of radiotherapy administered to 15 consecutive patients with adult T-cell leukaemia/lymphoma (acute, n = 7; lymphoma, n = 7; smouldering, n = 1) who received mogamulizumab before or during radiotherapy at three institutions between 2012 and 2017. Results: During 43 of the 46 radiotherapy courses, patients developed Grade <=1 radiation-induced dermatitis. No patient developed Grade >=3 radiation-induced dermatitis. No patient was prescribed ointments as prophylactic treatment for radiation-induced dermatitis. Development of radiation induced dermatitis was not significantly associated with the number of days since the administration of mogamulizumab prior to radiotherapy (P = 0.85), frequency of administration of mogamulizumab before/during radiotherapy (P = 0.33), administration of mogamulizumab during radiotherapy (P = 0.41) or types of lesions in adult T-cell leukaemia/lymphoma cases (cutaneous vs. non-cutaneous, P = 0.74). Development of radiation-induced dermatitis was significantly related to the total cutaneous dose (mean, 31.9 Gy [95% confidence interval: 26.6-37.1 Gy] vs. 19.7 Gy [95% confidence interval: 16.2-23.2 Gy], P = 0.0004) and total prescribed dose (mean, 31.5 Gy [95% confidence interval: 26.2-36.8 Gy] vs. 18.5 Gy [95% confidence interval: 15.0-22.0 Gy], P = 0.0002). Conclusion: None of the 15 patients who received moderate-dose radiotherapy developed severe radiation induced dermatitis during the 46 courses of radiotherapy after mogamulizumab administration. PMID- 30452693 TI - Carbon and blue water footprints of California sheep production. AB - While the environmental impacts of livestock production, such as greenhouse gas emissions and water usage, have been studied for a variety of U.S. livestock production systems, the environmental impact of U.S. sheep production is still unknown. A cradle-to-farm gate life cycle assessment (LCA) was conducted according to international standards (ISO 14040/44), analyzing the impacts of case studies representing five different meat sheep production systems in California, and focusing on carbon footprint (carbon dioxide equivalents, CO2e) and irrigated water usage (MT). This study is the first to look specifically at the carbon footprint of the California sheep industry and consider both wool and meat production across the diverse sheep production systems within California. This study also explicitly examined the carbon footprint of hair sheep as compared with wooled sheep production. Data were derived from producer interviews and literature values, and California-specific emission factors were used wherever possible. Flock outputs studied included market lamb meat, breeding stock, two-day-old lambs, cull adult meat, and wool. Four different methane prediction models were examined, including the current IPCC Tier 1 and 2 equations, and an additional sensitivity analysis was conducted to examine the effect of a fixed versus flexible coefficient of gain (kg) in mature ewes on carbon footprint per ewe. Mass, economic, and protein mass allocation were used to examine the impact of allocation method on carbon footprint and water usage, while sensitivity analyses were used to examine the impact of ewe replacement rate (% of ewe flock/year) and lamb crop (lambs born/ewe bred) on carbon footprint per kg market lamb. The carbon footprint of market lamb production ranged from 13.9 to 30.6 kg CO2e/kg market lamb production on a mass basis, 10.4 to 18.1 kg CO2e/kg market lamb on an economic basis, and 6.6 to 10.1 kg CO2e/kg market lamb on a protein mass basis. Enteric methane (CH4) production was the largest single source of emissions for all case studies, averaging 72% of total emissions. Emissions from feed production averaged 22% in total, primarily from manure emissions credited to feed. Whole-ranch water usage ranged from 2.1 to 44.8 MT/kg market lamb, almost entirely from feed production. Overall results were in agreement with those from meat-focused sheep systems in the UK as well as beef raised under similar conditions in California. PMID- 30452694 TI - THE COMPARISON OF THE EXTERNAL DOSE RATE MEASUREMENT OF CHILDREN AND ADOLESCENT PATIENTS WITH ADULT PATIENTS TREATED WITH RADIOIODINE THERAPY. AB - The aim of this study is to evaluate the radiation safety of caregiving people contacting the child and adolescent patients with thyroid cancer who received radioactive iodine-131 (RIT) treatment by comparison with external dose rate measurements of adult patients according to their administered activities and days of hospitalization. We retrospectively evaluated external dose rate measurement of 158 children and adolescent patients and 158 adult patients. During the RIT, the hospitalization time were grouped as 2, 3 and 4 d, and the administered activities as <3700, 3700 and >3700 MBq. The values of external dose rate measurements of children and adolescents were statistically significantly higher than the adult group. Different approaches in radiation safety rules are required for children and adolescents. In terms of radiation safety, we suggest that more specific regulations for family members and caregivers should be established and informed. PMID- 30452695 TI - VIGS - empowering genetics in non-model organisms. AB - Virus-induced gene silencing (VIGS) is an RNA interference-based technology used to transiently knock-down target gene expression, utilizing modified plant viral genomes. VIGS can be adapted to many angiosperm species that cover large phylogenetic distances, allowing the analysis of gene functions in species recalcitrant to stable genetic transformation. With a vast amount of sequence information already available and even more so in the future, VIGS provides a means to analyze functions of candidate genes identified in large genomic or transcriptomic screens. Here, we provide a comprehensive overview of target species and VIGS vector systems, with recent key publications in the field, and we explain how plant viruses are modified to serve as VIGS vectors. And, as many publications on the VIGS technique are being published, we introduce minimal reporting guidelines for carrying out these experiments with the aim of increasing comparability between experiments. Finally, we propose means for statistical evaluation of phenotypic results obtained by VIGS treated plants, as the analysis is challenging due to the predominantly transient nature of the silencing effect. PMID- 30452696 TI - Introduction to the Fifth Global Summit on the Health Effects of Yogurt. PMID- 30452697 TI - Novel perspectives on fermented milks and cardiometabolic health with a focus on type 2 diabetes. AB - This review will explore the observational and mechanistic evidence supporting the hypothesis that fermented milk consumption has beneficial effects on metabolism. Live cultures in fermented dairy are thought to contribute to gut microbial balance, which is likely an instrumental mechanism that protects the host against gut dysbiosis and systemic inflammation associated with cardiometabolic diseases. Lactic acid bacteria (LAB) release bioactive metabolites, such as exopolysaccharides and peptides, that have the potential to exert a wide range of metabolic and regulatory functions. In particular, peptides derived from fermented dairy products are likely to exert greater cardiometabolic and anti-inflammatory effects than nonfermented dairy. It is hypothesized that LAB-derived bioactive peptides have the potential to protect the host against cardiometabolic diseases through antimicrobial actions and to effect changes in gene expression of glucose regulatory and anti-inflammatory signaling pathways. The peptides released through fermentation may explain some of the health effects of fermented dairy products on cardiometabolic disease risk observed in epidemiological studies, particularly type 2 diabetes; however, mechanisms have yet to be explored in detail. PMID- 30452698 TI - The role of yogurt in food-based dietary guidelines. AB - In the modern food technology era, one of the aims of food safety and quality is to eliminate or reduce the number of microorganisms in food. This may now be changing. In particular, the importance of live microorganisms as beneficial food constituents is now being recognized. Microorganisms present in food that contribute to the human diet include not only viable bacteria but also metabolites and bioactive components. Yogurt is one of the most biologically active foods consumed by humans. It is an excellent source of proteins, vitamins, and minerals. Additionally, the nutritional value is especially high relative to cost. Potential nutritional benefits are also associated with the ingestion of the bacteria that are ordinarily present at the time of consumption. Thus, yogurt serves as a major source of live bacteria in the human diet, as well as a delivery vehicle for added probiotic bacteria. Yogurt may provide a simple and affordable solution for enhancing the nutritional value of the diet, including the intake of live bacteria and their metabolites. A further benefit may be obtained when yogurt is used as a carrier for specific probiotic bacteria and/or prebiotic compounds. These factors suggest that yogurt could have a more visible role in food-based dietary guidelines. PMID- 30452699 TI - Yogurt and other fermented foods as sources of health-promoting bacteria. AB - Increased consumption of yogurt, kefir, and other fermented foods has been driven, in part, by the health benefits these products may confer. Epidemiological studies have shown that the consumption of fermented foods is associated with reduced risks of type 2 diabetes, metabolic syndrome, and heart disease, along with improved weight management. The microorganisms present in these foods are suggested to contribute to these health benefits. Among these are the yogurt starter culture organisms Streptococcus thermophilus and Lactobacillus delbrueckii subsp bulgaricus as well as Bifidobacterium and Lactobacillus strains that are added for their probiotic properties. In contrast, for other fermented foods, such as sauerkraut, kimchi, and miso, fermentation is initiated by autochthonous microbes present in the raw material. In both cases, for these fermentation-associated microbes to influence the gut microbiome and contribute to host health, they must overcome, at least transiently, colonization resistance and other host defense factors. Culture and culture-independent methods have now clearly established that many of these microbes present in fermented dairy and nondairy foods do reach the gastrointestinal tract. Several studies have shown that consumption of yogurt and other fermented foods may improve intestinal and extraintestinal health and might be useful in improving lactose malabsorption, treating infectious diarrhea, reducing the duration and incidence of respiratory infections, and enhancing immune and anti-inflammatory responses. PMID- 30452700 TI - Hybrid sterility with meiotic metaphase arrest in intersubspecific mouse crosses. AB - Although organisms belonging to different species and subspecies sometimes produce fertile offspring, a hallmark of the speciation process is reproductive isolation, characterized by hybrid sterility (HS) due to failure in gametogenesis. In mammals, HS is usually exhibited by males, the heterogametic sex. The phenotypic manifestations of HS are complex. The most frequently observed are abnormalities in both autosomal and sex chromosome interactions that are linked to meiotic prophase arrest or post-meiotic spermiogenesis aberrations and lead to defective or absent gametes. The aim of this study was to determine the HS phenotypes in intersubspecific F1 mice produced by matings between Mus musculus molossinus-derived strains and diverse Mus musculus domesticus-inbred laboratory mouse strains. Most of these crosses produced fertile F1 offspring. However, when female BALB/cJ (domesticus) mice were mated to male JF1/MsJ (molossinus) mice, the (BALBdomxJF1mol)F1 males were sterile, whereas the (JF1molxBALBdom)F1 males produced by the reciprocal crossings were fertile; thus the sterility phenotype was asymmetric. The sterile (BALBdomxJF1mol) F1 males exhibited a high rate of meiotic metaphase arrest with misaligned chromosomes, probably related to a high frequency of XY dissociation. Intriguingly, in the sterile (BALBdomxJF1mol)F1 males we observed aberrant allele-specific expression of several meiotic genes, that play critical roles in important meiotic events including chromosome pairing. Together, these observations of an asymmetrical HS phenotype in intersubspecific F1 males, probably owing to meiotic defects in the meiotic behavior of the XY chromosomes pair and possibly also transcriptional misregulation of meiotic genes, provide new models and directions for understanding speciation mechanisms in mammals. PMID- 30452702 TI - IMPUTOR: Phylogenetically Aware Software for Imputation of Errors in Next Generation Sequencing. PMID- 30452701 TI - The top six risky behaviors among Iranian university students: a national survey. AB - Background: Multiple risk-taking behaviors are associated with increased risk of poor educational attainment, morbidity and premature mortality. This study involved a large representative sample of Iranian university students addressing multiple risk behaviors and associated factors. Methods: This cross-sectional study included 4261 participants, involving 13 medical universities throughout the country in 2017. The following six risky behaviors were addressed: (a) smoking cigarettes during the past month, (b) using some kinds of illicit drugs during the past month, (c) drinking alcohol during the past month, (d) engaging unprotected sex during the past year, (e) having suicidal ideation during the past month or attempting suicide in the past year, (f) and Internet addiction. The 20-item internet addiction test and the 28-item general health questionnaire were used. Results: Almost 37.3% of the participants engaged in at least one out of six risky behaviors. The prevalence of Internet addiction was 24.5%, cigarette smoking 13.5%, alcohol use 7.8%, illicit drug abuse 4.9%, unprotected sex 7.8%, suicidal ideation 7.4%, attempting suicide 1.7% and general health problems 38.9%. Conclusion: A majority of the Iranian university students studied engaged in at least one risky behavior. Engaging in one risky behavior increases the risk of engaging in other risk-taking behaviors. PMID- 30452703 TI - Combined Transpetrosal Approach With Preservation of Superior Petrosal Vein Drainage for a Cerebellopontine Angle Epidermoid Cyst Extending Into Meckel's Cave: 3-Dimensional Operative Video. AB - The combined transpetrosal approach enables wide exposure around the petroclival region by cutting the tentorium and superior petrosal sinus. We often choose this approach for removal of tumors ventral to the facial and vestibulocochlear nerves, such as petroclival meningioma and epidermoid cyst, because complete removal of the tumor under direct visualization is required to prevent its later recurrence, especially in young patients. Recent reports revealed anatomical variations of the drainage of the superior petrosal sinus, and dural incision considering preservation of the superior petrosal vein was proposed.1-3 This 3 dimensional video shows a patient with an epidermoid cyst, which was surgically treated using the combined transpetrosal approach, with consideration of the variation of the superior petrosal sinus and preservation of the drainage route of the superior petrosal vein. The video was reproduced after informed consent of the patient. The patient is a 31-yr-old woman who presented with a left cerebellopontine angle epidermoid cyst extending into Meckel's cave. The superior petrosal sinus was of the lateral type, draining only laterally into the transverse-sigmoid junction without medial connection with the cavernous sinus.1 The combined transpetrosal approach was performed with cutting of the superior petrosal sinus medial to the entry point of the superior petrosal vein, in order to preserve its drainage into the transverse-sigmoid junction. Meckel' cave was opened along its lateral margin, and tumor removal was accomplished, leaving only a minute part of the capsule strongly adhering to the neurovascular structures. The patient had no new permanent neurological deficits during follow-up.The figures in the video were modified from Matsushima et al1 by permission of the Congress of Neurological Surgeons. PMID- 30452704 TI - ESTIMATION OF PATIENT LENS DOSE ASSOCIATED WITH C-ARM CONE-BEAM COMPUTED TOMOGRAPHY USAGE DURING INTERVENTIONAL NEURORADIOLOGY. AB - The purpose of this study was to investigate the dose distribution and lens doses associated with C-arm cone-beam computed tomography (CBCT), using a head phantom, and to estimate the contribution ratio of C-arm CBCT to each patient's lens dose during interventional neuroradiology ('lens dose ratio') in 109 clinical cases. In the phantom study, the peak skin doses and respective right and left lens doses of C-arm CBCT were as follows: 63.0 +/- 1.9 mGy, 19.7 +/- 1.4 mGy and 21.9 +/- 0.8 mGy in whole brain C-arm CBCT and 39.2 +/- 1.4 mGy, 4.7 +/- 0.9 mGy and 3.6 +/- 0.3 mGy in high-resolution C-arm CBCT. In the clinical study, the lens dose ratios were 25.4 +/- 8.7% in the right lens and 19.1 +/- 9.8% in the left lens. This study shows that, on average, ~25% of patients' total lens dose was contributed by C-arm CBCT. PMID- 30452705 TI - Web-Based Contingency Management for Adolescent Tobacco Smokers: A Clinical Trial. AB - Introduction: Adolescence is a critical time when the majority of tobacco users initiate smoking. Contingency management for adolescent smoking cessation has shown promise in previous studies, but efficacy following removal of contingencies is not well understood. The current study examined a remote form of contingency management among non-treatment seeking adolescent smokers. Methods: Participants (N=127) submitted breath carbon monoxide (CO) thrice daily throughout a 42-day program. For this randomized trial, participants in the active condition (n = 63) were reinforced for providing CO measurements on schedule and below a set criterion, while those in the control condition (n = 64) were reinforced for providing CO measurements on schedule. Self-reported smoking and urinary cotinine levels were collected at several time points. Results: Active condition showed greater within-group reductions in CO levels relative to control condition, but not at 3- or 6-month follow-up. Active condition reported significantly less smoking during treatment compared to control condition, but not at follow-up. There were no significant differences for urinary cotinine. Overall treatment adherence was low, with only 37% and 51% of possible CO samples being submitted among active and control, respectively. Poor treatment adherence may explain the disparity between CO and cotinine results, and poor follow-up treatment efficacy. Conclusions: This study replicates feasibility of a remote form of contingency management for adolescent smoking. CO results suggest active condition reduced smoking within group, but treatment adherence and post treatment efficacy was poor. Future research should focus on increasing adherence for this type of program among adolescent smokers. Implications: This study demonstrates feasibility of a remote form of contingency management therapy for smoking cessation among adolescents, while providing post-treatment efficacy data. Within group efficacy of this form of treatment is suggested, but treatment adherence and follow-up efficacy were poor. This study underscores the need for further development of contingency management therapy for adolescent smoking cessation, which emphasizes better treatment adherence and post-treatment efficacy. PMID- 30452706 TI - Effects of supplementation with different rapeseed oil sources and levels on production performance, egg quality, and serum parameters in laying hens. AB - This study was to determine the effects of rapeseed oil on production performance, egg quality, and serum parameters in laying hens. A total of 1,080 hens (33-wk-old) were randomly divided into a 1 plus 4 * 2 factorial design including four different rapeseed oil sources [high erucic acid of Mianyang city (MH); high erucic acid of Deyang city (DH); low erucic acid of Mianyang (ML); low erucic acid of Deyang (DL)] at two levels (2% and 4%) for 12 wk. The egg production and egg weight were decreased (P < 0.05) during 9 to 12 wk and 1 to 12 wk, while the average daily feed intake (ADFI) and feed conversion ratio were decreased (P < 0.01) in all phases compared to the control group. Adding ML as oil source had higher (P < 0.05) egg weight compared to DH in all periods in spite of levels. Meanwhile, layers fed 4% rapeseed oil decreased (P < 0.01) egg production compared with 2% in all phases except 1 to 4 wk. Regardless of rapeseed oil sources, hens fed 4% oil decreased (P < 0.05) egg weight in contrast to 2% during the whole experiment except 5 to 8 wk. The ADFI was lower (P < 0.01) in 4% oil inclusion groups compared with 2% during overall phase. Rapeseed oil decreased the yolk color (P < 0.01) and yolk ratio (P = 0.02) and increased (P < 0.01) the albumen height and Haugh unit at 12 wk. Dietary rapeseed oil supplementation resulted in a decreased total triglyceride (TG; P < 0.01) and increased high-density lipoprotein cholesterol (P = 0.02). Regardless of rapeseed oil levels, layers fed MH had higher TG (P < 0.01), TC (P < 0.05), low-density lipoprotein cholesterol (P < 0.05), alanine transaminase (P < 0.01) than those fed other sources. Taken together, the addition of rapeseed oil decreased laying performance, reduced TC and TG in the serum, and increased Haugh unit, with low erucic acid or 2% group showed more pronounced results among all treatments. PMID- 30452707 TI - Differential proteomic analysis to identify proteins associated with beak deformity in chickens1. AB - The beak is the dominant avian facial feature, and beak deformity occurs in 0.5 to 2.5% of some indigenous chicken breeds, resulting in difficulties when eating, drinking, and performing natural behaviors. Previous studies on beak deformity focused largely on candidate molecules associated with skeletogenic development, providing insight into the molecular and genetic underpinnings of beak deformity. The present study was performed to identify candidate proteins related to this malformation in chickens. Three 12-day-old Beijing-You roosters with deformed beaks (D1, D2, and D3) and 3 with normal beaks (N1, N2, and N3) were used, and total beak proteins were isolated and subjected to standard iTRAQ labeling, strong cation-exchange chromatography, and liquid chromatography-tandem mass spectrometry. Mascot 2.3.02 was used to identify and quantitatively analyze proteins. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were used to identify functions and metabolic pathways of differentially expressed proteins, and key proteins were further validated using western blot. A total of 2,370, 2,401, and 2,378 proteins were reliably quantified in 3 biological replicates, among which, 2,345 were common to all, and 92 were differentially expressed between the 2 groups. These included 37 upregulated and 55 downregulated proteins in deformed beaks. Pentraxin-related protein 3, hemopexin, lipoprotein lipase, retinoid-binding protein 7, and biliverdin reductase A were downregulated in all 3 sets, while parvalbumin, peptidyl-prolyl cis-trans isomerase, and ubiquitin-fold modifier 1 were upregulated. Pathway analysis returned no enriched pathways, and western blot validated the iTRAQ results. Parvalbumin and lipoprotein lipase could be firstly selected as key proteins in view of their known functions in regulating the buffering of intracellular free Ca2+ in both cartilage and bone cells and bone mass, respectively. Their potential roles in beak deformity, however, deserve further studies. In summary, the onset of beak deformity could be very complex, and this study will be helpful for future investigation of mechanistic explanation for beak deformity. PMID- 30452708 TI - L-Arginine supplementation enhances growth performance, lean muscle, and bone density but not fat in broiler chickens. AB - This study evaluated the effects of crystalline arginine (Arg) on performance and body composition in male broilers. A total of 600 1-day-old Ross 308 broilers were distributed in a completely randomized design, with 5 treatments and 6 replicates of 20 birds. The treatments were given as a percentage of the Ross 308 requirement, and defined as 70, 80, 90, 100 (Ross 308 requirement), and 110% of Arg. Body weight gain (BWG), feed intake (FI), and feed conversion ratio (FCR) were evaluated at 10, 24, and 42 d. Bone growth was measured from 7 to 11 d using mineral apposition rate (MAR) technique. At 42 d, 2 birds per pen were euthanized for bone mineral density (BMD) and body composition measurement using dual-energy X-ray absorptiometry, and liver gene expression and muscle diameter size analysis. The means were subjected to ANOVA and, when significant (P <= 0.05), were compared by Dunnett's test. Regression analyses were performed to evaluate trends of Arg dose response. Birds fed 70 and 80% of Arg had lower BWG than the ones fed 100% of Arg (P < 0.001), with quadratic effects for all phases (P < 0.001, R2 = 0.94). The 70% of Arg group showed lower FI compared to 100% from 11 to 24 d and 1 to 42 d (P < 0.009), with quadratic and linear effects (P < 0.049, R2 > 0.72), respectively. The 70% of Arg group showed higher FCR compared to 100% (P < 0.0001) with quadratic effects (P < 0.002, R2 > 0.94) for all periods. At 42 d, the 70% of Arg group showed lower BMD, tissue, and lean muscle percentage than 100% of Arg. There was a quadratic effect of Arg levels on lean muscle (P = 0.046, R2 = 0.89). Therefore, the dietary supplementation with Arg is necessary as it leads to an overall body growth with increased lean deposition and BMD, without increasing fat accretion in Ross 308 broiler chickens. PMID- 30452709 TI - An important cause of chest pain in granulomatosis with polyangiitis. PMID- 30452710 TI - Rewarding effects of nicotine in adolescent and adult male and female rats as measured using intracranial self-stimulation. AB - Introduction: Tobacco is highly addictive and after the development of dependence it is difficult to quit smoking. Therefore, it is important to understand the factors that play a role in the initiation of smoking. The rewarding effects of nicotine play a role in the initiation of smoking and the goal of the present study was to determine the rewarding effects of nicotine in adolescent and adult male and female rats. Methods: Male and female Wistar rats were prepared with intracranial self-stimulation (ICSS) electrodes between postnatal day (P) 23 and 33. They were then trained on the ICSS procedure and the effect of nicotine (0, 0.03, 0.1, 0.3 mg/kg) on the reward thresholds and response latencies was investigated during adolescence (P40-59) or adulthood (>P75). Results: Nicotine lowered the brain reward thresholds of the adult and adolescent male and female rats. The nicotine-induced decrease in the reward thresholds was the same in the adult male and adult female rats. However, nicotine induced a greater decrease in the reward thresholds of the adolescent female rats than the adolescent male rats. Nicotine decreased the response latencies of all groups and there was no effect of age or sex. Conclusions: Nicotine enhances reward function and psychomotor performance in adolescent and adult male and female rats. Adolescent female rats are more sensitive to the acute rewarding effects of nicotine than adolescent male rats. Therefore, the rewarding effects of nicotine might play a greater role in the initiation of smoking in adolescent females than in adolescent males. Implications : he great majority of people start smoking during adolescence. The present studies suggest that during this period female rats are more sensitive to the acute rewarding effects of low and intermediate doses of nicotine than male rats. The rewarding properties of nicotine play a role in the initiation of smoking and establishing habitual smoking. Therefore, the present findings might explain why adolescent females are at a higher risk for becoming nicotine dependent than adolescent males. PMID- 30452711 TI - The influence of Farmatan(r) and Flimabend(r) on the mucosal immunity of broiler chicken1. AB - The aim of the present study was to monitor selected parameters of mucosal immunity in jejunum and ileum (immunoglobulin A [IgA], mucin 2 [MUC-2], and pro inflammatory cytokines) in commercial broiler farm chicken after treatment with flubendazole (Flimabend(r)) and natural extract from chestnut wood (Farmatan(r)). A total of 24 forty-day-old Kalimero-Super Master hybrid chickens were divided into 4 groups (n = 6): the Fli group received Flimabend(r) per os, 100 mg/g suspension in 1.43 mg of active substance/kg body weight during 7 d of experiment; the Far group received Farmatan(r)per os at 0.2% concentration for 6 h/d during 5 d (experimental d 3 to 7); the Far + Fli group received a combination of doses administered in the same way as for the first two groups; and the C group represented control with no active substance administration. The concentrations of secretory IgA (sIgA) and MUC-2 and relative expression of selected immune parameters were evaluated. Our results show strong suppressive effect of the Farmatan(r) and Flimabend(r) combination on relative expression of IL-1beta and IL-18 in selected parts of the intestine. On the other hand, administration of natural extract from selected chestnut wood (Farmatan(r)) increased expression of total IgA as well as concentration of sIgA in the studied parts of the chicken intestine. Moreover, expression and concentration of MUC-2 was positively affected by addition of Farmatan(r). In contrast, 7-d administration of Flimabend(r) resulted in upregulation of pro-inflammatory cytokines and decrease in IgA and MUC-2 gene expression. In conclusion, for maintenance of mucosal immunity via activation of IgA and mucin production, the long-term preventive use of Farmatan(r) is a suitable choice. PMID- 30452712 TI - Neighborhood differences in alternative tobacco product availability and advertising in New York City: Implications for health disparities. AB - Introduction: Alternative tobacco products (ATPs), such as cigars, smokeless tobacco, and electronic nicotine delivery systems (ENDS), have a strong presence in the U.S. retail environment amid declining cigarette consumption. This study documented the promotion of ATPs in tobacco retailers in New York City and examined associations with neighborhood demographics. Methods: Data on product availability and advertising were collected from a stratified, random sample of tobacco retailers in 2017 (n=796). Multilevel models estimated adjusted prevalence ratios (aPRs) for each outcome by neighborhood racial/ethnic composition and median household income. Results: Nearly half (49.8%) of retailers carried 99-cent cigarillos, but availability was significantly greater in neighborhoods in the highest (vs. lowest) quartile for the percentage of Black residents [68.2%, aPR: 1.59 (1.19, 2.11)] and in the lowest (vs. highest) income quartile [67.3%, aPR: 1.56 (1.04, 2.35)]. Conversely, retailers in neighborhoods with the highest percentage of White residents were significantly more likely to carry ENDS [66.4%, aPR: 1.71 (1.11, 2.62)]. Advertisements for ENDS were less common in neighborhoods in the highest (vs. lowest) quartiles for the percentage of Black and Hispanic residents [20.3%, aPR: 0.64 (0.41, 0.99); 22.9%, aPR: 0.62 (0.40, 0.98)]. Conclusions: The marketing of inexpensive, combusted tobacco products disproportionately saturates low-income, minority communities, while potentially lower risk, non-combusted products are more accessible in largely White and higher income neighborhoods. This pattern may exacerbate tobacco related inequities. Public health policies should prioritize reducing the appeal and affordability of the most harmful tobacco products to help reduce health disparities. Implications: While cigarette promotion at the point-of-sale is well documented in the literature, questions remain about the ways in which alternative tobacco products (ATPs) are marketed in communities. Importantly, these products fall on a continuum of harm, with combusted tobacco overwhelmingly responsible for tobacco-related death and disease. We found that retailers in minority and low-income communities were more likely to carry and advertise inexpensive ATPs such as cigarillos, while potentially less risky, non-combusted products such as smokeless tobacco and e-cigarettes were more accessible in higher income and predominantly White neighborhoods. Policies aligned with product risk may help reduce health disparities. PMID- 30452713 TI - The effect of helminths on granulocyte activation: a cluster-randomized placebo controlled trial in Indonesia. AB - Background: Eosinophils are a prominent cell type in the host response to helminths, and some evidence suggests that neutrophils might also play a role. However, little is known about the activation status of these granulocytes during helminth infection. Methods: We analysed the expression of eosinophil and neutrophil activation markers in peripheral blood by flow cytometry, and measured serum levels of eosinophil granule proteins in 300 subjects residing in an area endemic for soil-transmitted helminths (STH). The data generated are on samples before and after 1 year of 3-monthly albendazole treatment. Results: Anthelmintic treatment significantly reduced the prevalence of STH. While eosinophil numbers were significantly higher in STH-infected compared to uninfected subjects and significantly decreased following albendazole treatment, there was no effect exerted by the helminths on either eosinophil nor neutrophil activation. Although at baseline, eosinophil granule protein levels were not different between STH infected and uninfected subjects, treatment significantly reduced the levels of eosinophil-derived neurotoxin (EDN) in those infected at baseline. Conclusions: These results show that besides decreasing eosinophil numbers, anthelmintic treatment does not significantly change the activation status of eosinophils, nor of neutrophils, and the only effect seen was a reduction on circulating levels of EDN. PMID- 30452714 TI - E-Cigarette Use is Associated with Intentions to Lose Weight among High School Students. AB - Introduction: Recent literature has demonstrated individuals may be using e cigarettes as a method of weight loss/management. Furthermore, e-cigarette companies are developing and patenting technologies related to e-cigarettes and weight loss. This study aims to determine the association between intentions to lose weight and e-cigarette use behaviors among a nationally representative sample of high school students. Methods: Data were obtained from the 2015 Youth Risk Behavior Survey. Participants were 12,847 students in grades 9-12 in the United States. Multivariate multinomial logistic regression models assessed the association between past 30-day e-cigarette use and weight loss intentions among 9-12 grade students. Subsample analyses were conducted, stratified by sex. Covariates included perceived weight, sex, race/ethnicity, grade, and past 30-day tobacco use. Results: Overall, 23.7% of the sample used e-cigarettes in the past 30-days. E-cigarette use was associated with 1.38 (1.07 - 1.78) greater risk of intentions to lose weight among the full sample, controlling for covariates. Among girls, e-cigarette use was associated with 1.44 (1.05 - 1.97) greater risk of intentions to lose weight, controlling for covariates. Among boys, e-cigarette use was associated with 1.40 (1.04 - 1.88) greater odds of intentions to gain weight, controlling for covariates. Conclusion: Findings show a significant association between e-cigarette use and intentions to lose weight among high school students, among the full sample. Interestingly, e-cigarette use was statistically associated with intentions to gain weight among boys. Longitudinal study is needed to further examine this relationship. Implications and Contribution: This is the one of the first studies reporting on e-cigarette use and weight loss intentions among adolescents; both highly prevalent among this population. These findings are an important development in the study of e cigarette use given the established link between conventional cigarette smoking and weight loss/management. PMID- 30452715 TI - Craniospinal irradiation as part of re-irradiation for children with recurrent intracranial ependymoma. AB - Background: The goal of this study was to evaluate outcomes in children with relapsed, molecularly-characterized intracranial ependymoma treated with or without craniospinal irradiation (CSI) as part of a course of repeat radiation therapy (re-RT). Methods: This was a retrospective cohort study of 31 children. Patients with distant relapse received CSI as part of re-RT. For patients with locally recurrent ependymoma, those treated before 2012 were re-irradiated with focal re-RT. In 2012, institutional practice changed to offer CSI, followed by boost re-RT to the site of resected or gross disease. Results: Median follow-up was 5.5 years. Of 9 patients with distant relapse after initial RT, 2-year freedom-from-progression (FFP) and overall survival (OS) were 12.5% and 62.5%, respectively. There were 22 patients with local failure after initial RT. In these patients, use of CSI during re-RT was associated with improvement in 5-year FFP (83.3% with CSI vs. 15.2% with focal re-RT only, p = 0.030). In the subgroup of patients with infratentorial primary disease, CSI during re-RT also improved 5 year FFP (100% with CSI, 10.0% with focal re-RT only, p = 0.036). 23 patients had known molecular status; all had posterior fossa group A tumours (n = 17) or RELA fused tumours (n = 6). No patient developed radiation necrosis after fractionated re-RT, though almost all survivors required assistance throughout formal schooling. Five out of ten long-term survivors have not developed neuroendocrine deficits. Conclusions: Re-irradiation with CSI is a safe and effective treatment for children with locally recurrent ependymoma and improves disease control as compared with focal re-irradiation, with the benefit most apparent for those with infratentorial primary tumours. PMID- 30452716 TI - ASSESSMENT OF INDOOR GAMMA RADIATION AND DETERMINATION OF EXCESS LIFETIME CANCER RISK IN TEHRAN IN WINTER AND SPRING 2017. AB - Natural radiation is a feature of the environment in which we live. One of the contributions of human exposure to ionizing radiation due to natural sources arises from gamma radiation. Therefore, present study was aimed to evaluate and map indoor gamma dose rate in Tehran. The corresponding annual effective dose (AED) and excess lifetime cancer risk (ELCR) were also calculated. All measurements were performed by a Geiger Muller detector in 43 dwellings in Tehran. The average indoor gamma dose rate in Tehran was appointed as 343.2 nGy/h. AED and ELCR were calculated as 2.4 mSv and 10.3 * 10-3, respectively. The evaluated indoor gamma dose rate and calculated AEDs and lifetime cancer risk were found higher than the world average value. PMID- 30452717 TI - The impact of Bacillus subtilis DSM 32315 on the pathology, performance, and intestinal microbiome of broiler chickens in a necrotic enteritis challenge. AB - It was hypothesized that dietary inclusion of Bacillus subtilis DSM 32315 could inhibit Clostridium perfringens induced necrotic enteritis (NE), thereby improving broiler performance. Male, d 0 chicks were randomly assigned 14 birds/pen, 11 pens/treatment in 3 treatments: a basal diet (control), a coccidiostat fed control (Narasin), and a direct fed microbial (DFM) B. subtilis DSM 32315 treatment. Necrotic enteritis was induced in all birds by oral inoculation of Eimeria maxima oocysts on d 12 and a virulent C. perfringens on d 16. Mortality was reduced (P < 0.001) in DFM and Narasin compared to control. DFM reduced (P < 0.001) feed conversion ratio (FCR) compared to control. Furthermore, DFM and Narasin reduced (P < 0.001) footpad lesions. The DFM was shown to increase (P < 0.05) Bacillus spp. and decrease (P < 0.05) C. perfringens in the ileum and cecum at several time points. To investigate microbiome changes in the cecum, digesta samples were analyzed with % guanine and cytosine (%G+C) microbial profiling which fractionates bacterial chromosomes based on the %G+C in DNA. The method revealed treatment profile peaks in low (27.0 to 34.5%), mid (40.5 to 54.0%), and high (59.0 to 68.0%) G+C fractions. 16S rRNA gene amplification and high throughput sequencing was conducted on each of these fractions in order to elucidate specific bacterial population differences. In the low and mid %G+C fractions, DFM had greater abundance of Lactobacillaceae family members (P = 0.03 and P = 0.01, respectively) and Lactobacillus salivarius (P = 0.04 and P = 0.01, respectively) than control or Narasin. Lactobacillus johnsonii was also greater in the low %G+C fraction compared to control and Narasin (P = 0.01). Lachnospiraceae (P = 0.04) and Ruminococcaceae (P < 0.01) in the mid %G+C fraction were reduced in the DFM compared to control. Positive alterations to the microbial populations in the gut of broilers may at least be a partial mechanism by which B. subtilis DSM 32315 reduced pathology and improved performance of broilers in the NE challenge. PMID- 30452718 TI - CDB-a database for protein heterodimeric complexes. AB - Crystallographic structures of protein complexes are essential to develop proteomic and structural biology methods, as prediction of protein-protein interaction (PPI) sites and protein-protein docking. Such structures can aid the development of protein complexation inhibitors. Complex DataBase (CDB), accessible at www.jct-bioinfo.com/cdb/search, is a database web application for heterodimeric protein crystallographic complexes along with the crystallographic structures of each individual unbound protein. Direct access to crystallographic structures of protein complexes, along with provided annotations, can serve as starting point for constructing new experimental protein complexes sets of any type, for protein binding studies, and the development and evaluation of PPIs prediction methods. PMID- 30452719 TI - Pattern of care in adjuvant therapy for resected Stage I non-small cell lung cancer: real-world data from Japan. AB - Background: Adjuvant tegafur/uracil (UFT) chemotherapy is recommended for patients with completely resected Stage I non-small cell lung cancer (NSCLC) in Japan. A Phase III trial, the Japan Clinical Oncology Group (JCOG) 0707, comparing the survival benefit of UFT and S-1 (tegafur/gimeracil/oteracil) for this population is being conducted. However, the selection of patients in the randomized clinical trial (RCT) may not represent the real-world population. The present study aimed to investigate the pattern of care for patients receiving adjuvant chemotherapy for completely resected NSCLC. Methods: Patients with completely resected pathological Stage I (T1 > 2 cm and T2 in 6th TNM edition) NSCLC eligible for the JCOG0707 trial but excluded from it during the enrollment period (2008-13) were eligible for this study. Physicians from institutions that participated in the JCOG0707 retrospectively assessed the medical records of each patient. Results: This study enrolled 5006 patients, 85% of those initially considered for participation in the JCOG0707 trial (5006 of 5923 patients). Among them, 2389 were ineligible for the trial and 2617 had not been enrolled despite being eligible. The most frequent reason for non-enrollment despite eligibility was the decline in patients' participation, and the major reasons for trial ineligibility were concomitant malignancy and comorbidities. Of all the patients enrolled in our study, 1659 received adjuvant chemotherapy, mainly UFT. Conclusions: Our study indicates that only 15% of the real-world patients with completely resected NSCLC were enrolled into the adjuvant chemotherapy RCT, and among those not participating in the trial, one-third received adjuvant chemotherapy. PMID- 30452720 TI - The European Certificate in Nephrology: what is involved and how to prepare. PMID- 30452721 TI - A Framework and Resources for Shared Decision Making: Opportunities for Improved Physical Therapy Outcomes. AB - Shared decision making (SDM) is a collaborative approach between clinicians and patients, where the best available evidence is integrated with patients' values and preferences for managing their health problems. Shared decision making may enhance patient-centered care and increase patients' satisfaction, engagement, adherence, and ability to self-manage their conditions. Despite its potential benefits, SDM is underutilized by physical therapists, and frequent mismatches between patients' and therapists' rehabilitation goals have been reported. Physical therapists can use evidence-based strategies, tools, and techniques to address these problems. This paper presents a model for SDM and explains its association with improved patient outcomes and relevance to situations commonly encountered in physical therapy. It describes freely available resources, including health literacy universal precautions, teach-back, motivational interviewing, decision aids, and patient-reported outcome measures that can help physical therapists integrate SDM into their clinical practices. This paper also explains SDM facilitators and barriers, suggests a theoretical framework to address them, and highlights the need for SDM promotion within physical therapy practice, education, administration, and research. PMID- 30452722 TI - Canaries in the Health Care Coal Mines. PMID- 30452723 TI - News From the Foundation for Physical Therapy. PMID- 30452724 TI - Genome-wide regulatory adaptation shapes population-level genomic landscapes in Heliconius. AB - cis-regulatory evolution is an important engine of organismal diversification. While recent studies have looked at genomic patterns of regulatory evolution between species, we still have a poor understanding of the magnitude and nature of regulatory variation within species. Here we examine the evolution of regulatory element activity over wing development in three Heliconius erato butterfly populations to determine how regulatory variation is associated with population structure. We show that intraspecific divergence in chromatin accessibility and regulatory activity is abundant, and that regulatory variants are spatially clustered in the genome. Regions with strong population structure are highly enriched for regulatory variants, and enrichment patterns are associated with developmental stage and gene expression. We also found that variable regulatory elements are particularly enriched in species-specific genomic regions and LINE elements. Our findings suggest that genome-wide selection on chromatin accessibility and regulatory activity is an important force driving patterns of genomic divergence within Heliconius species. This work also provides a resource for study of gene regulatory evolution in Heliconius erato and other heliconiine butterflies. PMID- 30452725 TI - Are U.S. Adults Reporting Less Sleep?: Findings from Sleep Duration Trends in the National Health Interview Survey, 2004-2017. AB - Study Objectives: To document trends in self-reported sleep duration for the non institutionalized U.S. civilian population from 2004-2017 and examine how sleep trends vary by race/ethnicity. Methods: We use data from the National Health Interview Survey (NHIS) for U.S. non-institutionalized adults aged 18-84 from 2004 to 2017 (N=398,382). NHIS respondents were asked how much they slept in a 24 hour period on average, which we categorized as: <=6 hours (short-sleep), 7-8 hours (adequate-sleep), and >=9 hours (long-sleep). We used multinomial logistic regression models to examine trends in self-reported sleep duration and assess race/ethnic differences in these trends. Our models statistically adjusted for demographic, socioeconomic, familial, behavioral, and health covariates. Results: The prevalence of short sleep duration was relatively stable from 2004-2012. However, results from multinomial logistic regression models indicated there was an increasing trend toward short sleep beginning in 2013 (b: 0.09, 95% CI: 0.05 0.14) that continued through 2017 (b: 0.18, 95% CI: 0.13-0.23). This trend was significantly more pronounced among Hispanics and non-Hispanic blacks, which resulted in widening racial/ethnic differences in reports of short sleep. Conclusions: Recent increases in reports of short sleep are concerning as short sleep has been linked with a number of adverse health outcomes in the population. Moreover, growing race/ethnic disparities in short sleep may have consequences for racial and ethnic health disparities. PMID- 30452726 TI - Relevance of the intestinal health-related pathways to broiler residual feed intake revealed by duodenal transcriptome profiling. AB - In broiler production, there is a continuous effort to breed feed efficient chickens. Residual feed intake (RFI) is an accurate indicator that has been accepted as an alternative measure of the conventional feed conversion ratio. This study conducted a duodenal transcriptome survey to explore the molecular basis of broiler RFI. Results showed that there are 599 genes that were differentially expressed (DE) in the duodenum between high RFI and low RFI (LRFI) broilers. Functional analysis showed that RFI can be explained by differences in the regulation of the immune system process, complement activation, nutrient digestion, and absorption pathways. Among those processes, the glutathione S transferase family and serpin family are involved in glutathione metabolism and TGF-beta signaling. These genes are involved in complement and coagulation cascade pathways that constitute a new regulatory network to reduce oxidative stress and inflammatory reaction, as well as to improve the defense capability in LRFI broilers. Ten DE genes related to the digestive tract health and digestive function, CCK, MPEG1, EPHB2, SERPINH1, VANGL2, CYFIP2, PCDH19, TGFBI, SCUBE3 and CATHL1, were identified as candidate genes related to RFI. In conclusion, the results indicate that there is less oxidative stress, less inflammatory reactions, and better digestion and absorption in the duodenum of the LRFI broilers, which might result in improved intestinal health and contribute to an increase in the efficiency of feed conversion. PMID- 30452727 TI - Is Schizophrenia a Risk Factor for Breast Cancer?-Evidence From Genetic Data. AB - Observational epidemiological studies have found an association between schizophrenia and breast cancer, but it is not known if the relationship is a causal one. We used summary statistics from very large genome-wide association studies of schizophrenia (n = 40675 cases and 64643 controls) and breast cancer (n = 122977 cases and 105974 controls) to investigate whether there is evidence that the association is partly due to shared genetic risk factors and whether there is evidence of a causal relationship. Using LD-score regression, we found that there is a small but significant genetic correlation (rG) between the 2 disorders (rG = 0.14, SE = 0.03, P = 4.75 * 10-8), indicating shared genetic risk factors. Using 142 genetic variants associated with schizophrenia as instrumental variables that are a proxy for having schizophrenia, we estimated a causal effect of schizophrenia on breast cancer on the observed scale as bxy = 0.032 (SE = 0.009, P = 2.3 * 10-4). A 1 SD increase in liability to schizophrenia increases risk of breast cancer 1.09-fold. In contrast, the estimated causal effect of breast cancer on schizophrenia from 191 instruments was not significantly different from zero (bxy = -0.005, SE = 0.012, P = .67). No evidence for pleiotropy was found and adjusting for the effects of smoking or parity did not alter the results. These results provide evidence that the previously observed association is due to schizophrenia causally increasing risk for breast cancer. Genetic variants may provide an avenue to elucidating the mechanism underpinning this relationship. PMID- 30452728 TI - Are the Same Health Warnings Effective Across Different Countries? An Experimental Study in Seven Countries. AB - Introduction: More than 100 countries have implemented pictorial health warnings on cigarette packages. However, few studies have compared how consumers from different geographic and cultural contexts respond to health warning content. The current study compares perceptions of warnings among adult smokers and youth in seven countries, to examine the efficacy of different health warning themes and images. Methods: Between 2010 and 2012, online and face-to-face surveys were conducted with ~500 adult smokers and ~500 youth (age 16-18) smokers and non smokers in each of Mexico, United States, China, Germany, India, Bangladesh, and Republic of Korea (total N=8,182). Respondents were randomized to view and rate sets of 5-7 health warnings (each set for a different health effect); each set included a text-only warning and various types (i.e., themes) of pictorial warnings, including graphic health effects, "lived experience", symbolic images, and personal testimonials. Mixed-effects models were utilized to examine perceived effectiveness of warning themes, and between-country differences in responses. Results: Overall, pictorial warnings were rated as more effective than text-only warnings (p<.001). Among pictorial themes, 'graphic' health effects were rated as more effective than warnings depicting 'lived experience' (p<.001) or 'symbolic' images (p<.001). Pictorial warnings with personal testimonials were rated as more effective than the same images with didactic text (p<.001). While the magnitude of differences between warning themes varied across countries, the pattern of findings was generally consistent. Conclusions: The findings support the efficacy of graphic pictorial warnings across diverse geographic and cultural contexts, and support sharing health warning images across jurisdictions. Implications: Although over 100 countries have implemented pictorial health warnings on cigarette packages, there is little research on the most effective types of message content across geographic and cultural contexts. The current study examined perceived effectiveness of text and pictorial health warnings featuring different message content-graphic health effects, "lived experience", personal testimonials, and symbolic imagery-among more than 8,000 adults and youth in Mexico, US, China, Germany, India, Bangladesh, and Korea. Across countries, "graphic" pictorial messages were rated as most effective. Consistencies across countries in rating message content suggests there may be 'globally effective' themes and styles for designing effective health warnings. PMID- 30452729 TI - PATIENT DOSE IN DIGITAL RADIOGRAPHY UTILISING BMI CLASSIFICATION. AB - Dose audit is important towards optimisation of patients' radiation protection in diagnostic radiography. In this study, the effect of the body mass index (BMI) on radiation dose received by 1869 adult patients undergoing chest, abdomen, lumbar spine, kidneys and urinary bladder (KUB) and pelvis radiography in an X-ray room with a digital radiography system was investigated. Patients were categorised into three groups (normal, overweight and obese) based on the BMI values. The patients' entrance surface air kerma (ESAK) and the effective dose (ED) were calculated based on the X-ray tube output, exposure parameters and technical data, as well as utilising appropriate conversion coefficients of the recorded kerma area product (KAP) values. The local diagnostic reference levels (LDRLs) were established at the 75th percentile of the distribution of ESAK and KAP values. Statistically, a significant increase was found in ESAK, KAP and ED values, for all examinations, both for overweight and obese patients compared to normal patients (Mann-Whitney test, p < 0.0001). Regarding the gender of the patients, a statistically significant increase was found in the dose values for male patients compared to female patients, except for the chest LAT examinations (Mann-Whitney test, p = 0.06). The percentage increase for chest PA, chest LAT, abdomen AP, lumbar spine AP, lumbar spine LAT, pelvis AP and KUB AP in overweight patients was 75%, 100%, 136%, 130%, 70%, 66% and 174% for median ESAK, 67%, 81%, 135%, 134%, 85%, 63% and 172% for median KAP, as well as 89%, 54%, 146%, 138%, 82%, 57% and 183% for median ED values, respectively. For obese patients, the corresponding increases were 200%, 186%, 459%, 345%, 203%, 150% and 785% for median ESAK, 200%, 185%, 423%, 357%, 227%, 142% and 597% for median KAP, as well as 222%, 156%, 446%, 363%, 218%, 136% and 625% for median ED. The corresponding LDRLs for overweight patients were 0.17 mGy, 1.21 mGy, 3.74 mGy, 7.70 mGy, 7.99 mGy, 4.07mGy, 5.03 mGy and 0.13 Gy cm2, 0.69 Gy cm2, 2.35 Gy cm2, 2.10 Gy cm2, 2.59 Gy cm2, 2.13 Gy cm2, 2.49 Gy cm2 in terms of ESAK and KAP values, respectively, while in the case of obese patients were 0.28 mGy, 1.82 mGy, 7.26 mGy, 15.10 mGy, 13.86 mGy, 6.89 mGy, 13.40 mGy and 0.21 Gy cm2, 1.10 Gy cm2, 4.68 Gy cm2, 4.01 Gy cm2, 4.80 Gy cm2, 3.27 Gy cm2, 6.02 Gy cm2, respectively. It can be concluded that overweight and obese patients received a significantly increased radiation dose. Careful adjustment of imaging protocols is needed for these patients to reduce patient dose, while keeping the image quality at an acceptable level. Additional studies need to be conducted for these patient groups, that could further contribute to the development of radiation protection culture in diagnostic radiography. PMID- 30452730 TI - Hepatitis B assessment without hepatitis B virus DNA quantification: a prospective cohort study in Uganda. AB - Background: Chronic hepatitis B infection affects 240 million people, with the highest prevalence in Africa and Asia, and results in 700 000 deaths annually. Access to diagnostics, particularly for hepatitis B virus viral load quantification (HBV DNA), is a major barrier to treatment. We aimed to test World Health Organization guidelines for hepatitis B management in resource-limited settings. Methods: We compared treatment allocation with and without the use of HBV DNA in a cohort in Uganda. Hepatitis B surface antigen test-positive, human immunodeficiency virus-negative, treatment-naive adults were recruited prospectively. Following liver ultrasound and routine haematological and biochemical tests, preliminary allocations into treatment and observation groups were made. HBV DNA was performed for each participant and final treatment decisions were made and compared with preliminary allocations. Results: Full assessment was completed for 100 participants; treatment was indicated in 20. Assessment without HBV DNA identified patients for treatment with a positive predictive value of 88.2% and a negative predictive value of 94% compared with assessment using HBV DNA. Conclusions: Where HBV DNA is unavailable, patients with hepatitis B can be assessed by liver ultrasound and routine laboratory tests. These findings will enable physicians in resource-limited settings to initiate treatment more readily and inform policy with regards to viral hepatitis elimination. PMID- 30452731 TI - Trypanosoma cruzi diversity in naturally infected nonhuman primates in Louisiana assessed by deep sequencing of the mini-exon gene. AB - Background: Trypanosoma cruzi is a zoonotic pathogen of increasing relevance in the USA, with a growing number of autochthonous cases identified in recent years. The identification of parasite genotypes is key to understanding transmission cycles and their dynamics and consequently human infection. Natural T. cruzi infection is present in captive nonhuman primate colonies in the southern USA. Methods: We investigated T. cruzi genetic diversity through a metabarcoding and next-generation sequencing approach of the mini-exon gene to characterize the parasite genotypes circulating in nonhuman primates in southern Louisiana. Results: We confirmed the presence of T. cruzi in multiple tissues of 12 seropositive animals, including heart, liver, spleen and gut. The TcI discrete typing unit (DTU) predominated in these hosts, and specifically TcIa, but we also detected two cases of coinfections with TcVI and TcIV parasites, unambiguously confirming the circulation of TcVI in the USA. Multiple mini-exon haplotypes were identified in each host, ranging from 6 to 11. Conclusions: The observation of multiple T. cruzi sequence haplotypes in each nonhuman primate indicates possible multiclonal infections. These data suggest the participation of these nonhuman primates in local parasite transmission cycles and highlight the value of these naturally infected animals for the study of human Chagas disease. PMID- 30452732 TI - Efficacy and safety of a nicotine mouth spray for smoking cessation; a randomized, multicenter, controlled study in a naturalistic setting. AB - Background: Nicotine replacement therapy (NRT) has been demonstrated to be an effective pharmacological treatment for smoking cessation, and most types of NRT have been approved as over-the-counter (OTC) medications. In an effort to create a fast-acting, flexible and discreet NRT, a nicotine mouth spray (NMS) has been developed. This study was designed to assess the efficacy and safety of NMS in a naturalistic setting in the United States. Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel group, 26-week study in 1198 smokers motivated to quit. The study was designed to resemble an OTC environment, and thus included limited intervention, limited motivational screening, and no behavioral support. The primary efficacy endpoint was carbon monoxide (CO) verified, self-reported continuous abstinence from smoking from Week 2 until Week 6. The safety of NMS was assessed by measuring vital signs, visual mouth inspection, and collection of subject-reported adverse events (AEs). Results: The percentage of subjects with CO verified continuous abstinence from Week 2 to Week 6 was statistically significantly greater in the NMS group compared with the placebo group (5.0% vs 2.5%, P=0.021). Statistically significant treatment effects for the NMS were maintained throughout the 26-week period. The study medications were generally well tolerated. The severity of AEs was similar for both treatment groups, and most AEs were of mild or moderate severity. Conclusions: These study results demonstrate that the NMS is an effective and safe smoking cessation option for smokers motivated to quit, even in a naturalistic setting and without behavioral support. Implications: This study demonstrated the safety, efficacy, and acceptability of a nicotine mouth spray in an OTC environment with no behavioral counseling or support. It provides an additional option for smokers motivated to quit. PMID- 30452733 TI - A 'Mixture of Britannia and Boadicea': Dorothy Crisp's Conservatism and the Limits of Right-Wing Women's Political Activism, 1927-48. AB - Dorothy Crisp is known for being the militant Chairman of the British Housewives League (BHL) after the Second World War, but historians have failed to recognize that her views and actions were the culmination of over twenty years of right wing journalism and political activism through which she tried to influence the Conservative Party. This article re-evaluates Crisp's Conservatism and her political career. It asks why such a powerful pro-Conservative female activist failed to secure a place within Conservative politics during the 1930s and the 1940s. In doing so, it shows that Crisp was not willing to conform to traditional gender roles inside the Party or the broader Conservative movement and that she was a vocal advocate for gender equality. It was the combination of her attitude towards women's issues and her older brand of imperialist, ultra-patriotic, anti statist Conservatism that was unusual for a right-wing woman in this period. Crisp's views on women's issues did not fit the domesticity agenda of the BHL or that of the 'Tory women's tradition', which could not provide her with an opportunity to achieve her career goals. The article also explores how the Party handled challenges from independent right-wing activists, especially women, in a period when 'one-nation' Conservatism was dominant. It engages with recent debates about 'Conservative feminism' and argues that Crisp was also an important figure because she kept alive the model of the independent radical female Conservative, which would become the hallmark of Margaret Thatcher's politics a generation later. PMID- 30452734 TI - Differences in Sleep Between Concussed and Non-Concussed College Students: A Matched Case-Control Study. AB - Study Objectives: To describe sleep 2-3 days post-concussion through symptom recovery and make comparison to well-matched non-concussed controls. Methods: Twenty college students were physician diagnosed with a concussion and compared to 20 non-concussed controls matched on age, sex, physical activity, and sleep quality. A wrist-worn ActiGraph GT9X Link was provided during initial evaluation (within 72 hours post-injury for concussed) and worn continuously until symptom resolution (duration matched for non-concussed). All participants completed a sleep symptom severity checklist, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). Separate 2(group) x 3(time-points) mixed model ANOVAs were conducted to compare actigraphy sleep outcomes (sleep onset latency (SOL), normalized wake after sleep onset (WASOnorm), total sleep time (TST), sleep efficiency, and number of awakenings) across recovery stages (2-3 days post-injury, mid-point, and end of recovery). Intraindividual coefficient of variation was calculated for each sleep outcome. Mann Whitney U tests compared PSQI global score, ESS total score, and sleep symptom severity between groups (alpha=0.05). Results: At 2-3 days post-injury, concussed individuals took longer to fall asleep compared to controls (p=0.002). Greater intraindividual variability in WASOnorm(p=0.017) and TST (p=0.044) existed in concussed individuals across recovery. Poorer sleep quality (p<0.001), excessive daytime sleepiness (p=0.014), and worse sleep symptoms (p<0.001) existed in concussed compared to controls. Conclusion: Concussed individuals took longer to fall asleep 2-3 days post-concussion, experienced greater variation in sleep fragmentation and sleep time until symptom resolution and reported worse sleep quality. Our preliminary findings may guide researchers interested in better understanding sleep post-concussion. PMID- 30452735 TI - Individuals with insomnia misrecognize angry faces as fearful faces while missing the eyes: An eye-tracking study. AB - Individuals with insomnia have been found to have disturbed perception of facial expressions. Through eye movement examinations, here we test the hypothesis that this effect is due to impaired visual attention functions for retrieving diagnostic features in facial expression judgments. 23 individuals with insomnia symptoms and 23 controls without insomnia completed a task to categorize happy, sad, fearful, and angry facial expressions. The participants with insomnia were less accurate in recognizing angry faces and misidentified them as fearful faces more often than the controls. A hidden Markov modeling approach for eye movement data analysis revealed that when viewing facial expressions, more individuals with insomnia adopted a nose-mouth eye movement pattern focusing on the vertical face midline while more controls adopted an eyes-mouth pattern preferentially attending to lateral features, particularly the two eyes. As previous studies found that the primary diagnostic feature for recognizing angry faces is the eyes while the diagnostic features for other facial expressions involve the mouth region, missing the eye region may contribute to specific difficulties in recognizing angry facial expressions, consistent with our behavioral finding in participants with insomnia symptoms. Taken together, the findings suggest that impaired information selection through visual attention control may be related to the compromised emotion perception in individuals with insomnia. PMID- 30452736 TI - A moso bamboo drought-induced 19 protein, PeDi19-4, enhanced drought and salt tolerance in plants via the ABA-dependent signaling pathway. AB - Here, ten drought-induced 19 proteins (Di19) from Phyllostachys edulis were analyzed and an important stress-related candidate gene (PeDi19-4) was isolated based on analysis of phylogenetic relationships and expression profiles. PeDi19-4 is a nuclear localization protein that can bind the conserved TACA(A/G)T sequence, as determined using EMSA. PeDi19-4 has no transcriptional activity in yeast but functions as a transcription activator in plants. Overexpression of PeDi19-4 in rice and Arabidopsis thaliana enhanced drought and salt tolerance as determined through phenotypic analysis and the use of stress-associated physiological indicators. PeDi19-4 transgenic plants showed increased sensitivity to ABA (abscisic acid) during seed germination and early seedling growth. Additionally, transgenic rice accumulated more ABA than wild-type plants under drought and salt stress conditions. Moreover, the stomata of PeDi19-4 overexpressing plants changed significantly with ABA treatment. RNA-sequencing revealed that PeDi19-4 regulated the expression of a wide spectrum of stress/ABA responsive DEGs. The stress-responsive genes (OsZFP252 and OsNAC6) and ABA responsive genes (OsBZ8 and OsbZIP23) were direct targets of PeDi19-4. Our research indicated that PeDi19-4 enhanced drought and salt tolerance in plants via the ABA-dependent signaling pathway. PMID- 30452737 TI - Image analysis procedure for the optical scanning of fine-root dynamics: errors depending on the observer and root-viewing window size. AB - Clarifying the dynamics of fine roots is critical to understanding carbon and nutrient cycling in forest ecosystems. An optical scanner can potentially be used in studying fine-root dynamics in forest ecosystems. The present study examined image analysis procedures suitable for an optical scanner having a large (210 mm * 297 mm) root-viewing window. We proposed a protocol for analyzing whole soil images obtained by an optical scanner that cover depths of 0-210 mm. We tested our protocol using six observers with different experience in studying roots. The observers obtained data from the manual digitization of sequential soil images recorded for a Bornean tropical forest according to the protocol. Additionally, the study examined the potential tradeoff between the soil image size and accuracy of estimates of fine-root dynamics in a simple exercise. The six observers learned the protocol and obtained similar temporal patterns of fine root growth and biomass with error of 10-20% regardless of their experience. However, there were large errors in decomposition owing to the low visibility of decomposed fine roots. The simple exercise revealed that a smaller root-viewing window (smaller than 60% of the original window) produces patterns of fine-root dynamics that are different from those for the original window size. The study showed the high applicability of our image analysis approach for whole soil images taken by optical scanners in estimating the fine-root dynamics of forest ecosystems. PMID- 30452738 TI - Competing Risks for a Diagnosis of Invasive Breast Cancer-Reply. PMID- 30452739 TI - The Network Structure of Tobacco Withdrawal in a Community Sample of Smokers Treated with Nicotine Patch and Behavioral Counseling. AB - Introduction: Network theories of psychopathology highlight that, rather than being indicators of a latent disorder, symptoms of disorders can causally interact with one another in a network. The present study examined tobacco withdrawal from a network perspective. Methods: Participants (n = 525, 50.67% female) completed the Minnesota Tobacco Withdrawal Scale (MTWS) four times (2 weeks prior to a target quit day, on the target quit day, and 4 and 8 weeks after the target quit day) over the course of 8 weeks of treatment with nicotine patch and behavioral counseling within a randomized clinical trial testing long-term nicotine patch therapy in treatment-seeking smokers. The conditional dependence among 7 withdrawal symptoms was estimated at each of the four measurement occasions. Influential symptoms of withdrawal were identified using centrality indices. Changes in network structure were examined using the network comparison test. Results: Findings indicated many associations among the individual symptoms of withdrawal. The strongest associations that emerged were between sleep problems and restlessness, and associations among affective symptoms. Restlessness and affective symptoms emerged as the most central symptoms in the withdrawal networks. Minimal differences in the structure of the withdrawal networks emerged across time. Conclusions: The co-occurrence of withdrawal symptoms may result from interactions among symptoms of withdrawal rather than simply reflecting passive indicators of a latent disorder. Findings encourage greater consideration of individual withdrawal symptoms and their potential interactions and may be used to generate hypotheses that may be tested in future intensive longitudinal studies. PMID- 30452740 TI - Exposure to 1,2-dichloropropane upregulates the expression of activation-induced cytidine deaminase (AID) in human cholangiocytes co-cultured with macrophages. AB - Background: 1,2-dichloropropane (1,2-DCP) was reclassified recently by IARC as a Group 1 carcinogen based on epidemiological studies on an outbreak of cholangiocarcinoma in offset-printing workers exposed to 1,2-DCP in Japan. However, the underlying mechanism of 1,2-DCP-induced cholangiocarcinoma remains obscure. A previous whole-genome mutation analysis of cholangiocarcinoma of four cases exposed to 1,2-DCP suggested the involvement of activation-induced cytidine deaminase (AID), based on specific signatures of mutation patterns. Objectives: To determine whether exposure to 1,2-DCP induces expression of AID in human cholangiocytes. Methods: Human MMNK-1 cholangiocytes, differentiated THP-1 macrophages, and co-cultures of MMNK-1/THP-1 cells were exposed to 1,2-DCP at different concentrations and time-intervals. The mRNA expression levels of AID and related genes were quantified by real-time PCR. Protein expression was measured by immunostaining. Alkaline Comet assay was performed to examine DNA damage. Results: 1,2-DCP alone did not change AID expression in MMNK-1 cholangiocytes. 1,2-DCP significantly increased pro-inflammatory cytokine TNF alpha expression in THP-1 macrophages. TNF-alpha treatment upregulated expression of AID, NF-kappaB and IkappaB in MMNK-1 cholangiocytes. SN50, a NF-kappaB inhibitor, significantly downregulated TNF-alpha-induced AID expression, suggesting the involvement of NF-kappaB pathway in TNF-alpha-induced AID expression. Exposure to 1,2-DCP significantly increased AID expression in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages. Comet assay showed that 1,2 DCP-induced DNA damage in MMNK-1 cholangiocytes, as indicated by increased tail DNA% and tail moment, was enhanced when co-cultured with macrophages. Conclusions: The results suggest that inflammatory response of macrophages and consequent aberrant AID expression or DNA damage in the cholangiocytes underlie the mechanism of 1,2-DCP-induced cholangiocarcinoma in humans. PMID- 30452741 TI - Internet and Audiology: A Review of the Third International Meeting. AB - Purpose: In this introduction, the four members of the scientific committee for the Third International Meeting on Internet and Audiology describe the meeting that took place at the University of Louisville on July 27-28, 2017. Method: This special issue, with a decidedly clinical focus, includes 14 articles that arose from presentations given at the Third International Meeting on Internet and Audiology. All touch upon the theme of innovation as it pertains to teleaudiology and mobile health (mHealth), application of Big Data to audiology, and ethics of internet and telemedicine. Conclusion: Innovations in teleaudiology, mHealth, and Internet-based audiology are developing at a rapid pace and thus research in the field must continue. We invite readers to the next International Meeting on Internet and Audiology that will take place in Southampton, England, June 17-18, 2019. PMID- 30452742 TI - Innovation in the Context of Audiology and in the Context of the Internet. AB - Purpose: This article explores different meanings of innovation within the context of audiology and the Internet. Case studies are used to illustrate and elaborate on the new types of innovation and their levels of impact. Method: The article defines innovation, providing case studies illustrating a taxonomy of innovation types. Results: Innovation ranges from minor changes in technology implemented on existing platforms to radical or disruptive changes that provide exceptional benefits and transform markets. Innovations within the context of audiology and the Internet can be found across that range. The case studies presented demonstrate that innovations in hearing care can span across a number of innovation types and levels of impact. Considering the global need for improved access and efficiency in hearing care, innovations that demonstrate a sustainable impact on a large scale, with the potential to rapidly upscale this impact, should be prioritized. Conclusions: It is unclear presently what types of innovations are likely to have the most profound impacts on audiology in the coming years. In the best case, they will lead to more efficient, effective, and widespread availability of hearing health on a global scale. PMID- 30452743 TI - Techniques for Remotely Programming Children With Cochlear Implants Using Pediatric Audiological Methods via Telepractice. AB - Purpose: The purpose of this report is to describe the equipment setup and techniques for successfully testing behavioral thresholds in young children with cochlear implants (CIs) using telepractice. We will also discuss challenges associated with pediatric CI programming that are unique to the use of distance technology, and we will describe ways to overcome those challenges. Last, we will review the results from 2 recent studies specifically targeted toward testing behavioral thresholds in young children with CIs. Method: Conditioned play audiometry or visual reinforcement audiometry was used to measure behavioral thresholds (T levels) for 35 young children with CIs (n = 19 for conditioned play audiometry and n = 16 for visual reinforcement audiometry). Participants were tested in the traditional in-person condition and in the remote condition using an AB-BA study design over 2 visits. Results: There was no significant difference in T levels between the in-person and remote conditions, indicating that it is feasible to test young children using conventional pediatric testing procedures via remote technology. The primary challenges encountered were in regard to proper camera and video monitor placement at the remote site and the timing of communication between the audiologist and test assistant. Conclusions: The results from studies to date suggest that distance technology can be used successfully to program CI sound processors for young children using standard, age-appropriate testing techniques. The alternative of remote testing has substantial implications for reducing time and travel burdens for families, potentially leading to the construction of appropriate maps for young children with CIs in a timelier manner. PMID- 30452744 TI - Stories From the Webcams: Cincinnati Children's Hospital Medical Center Audiology Telehealth and Pediatric Auditory Device Services. AB - Purpose: The purpose of this manuscript is to describe the regulatory, technological, and training considerations for audiologists investigating telehealth and to offer some examples of audiology services provided through telehealth. Method: The authors presented the regulatory components, the technology required for audiology staff and patients, and staff training for the audiology telehealth program at Cincinnati Children's Hospital Medical Center. Four case studies highlighting the successful use of telehealth in providing auditory device services to patients were also presented. Results and Conclusion: The described regulatory, technological, and training hierarchy provides a framework for audiologists interested in starting a telehealth program. The cases presented illustrate that telehealth can be used to provide some auditory device services, such as troubleshooting, mapping, and parent consulting. PMID- 30452745 TI - User-Innovated eHealth Solutions for Service Delivery to Older Persons With Hearing Impairment. AB - Purpose: The successful design and innovation of eHealth solutions directly involve end users in the process to seek a better understanding of their needs. This article presents user-innovated eHealth solutions targeting older persons with hearing impairment. Our research question was: What are the key users' needs, expectations, and visions within future hearing rehabilitation service delivery? Method: We applied a participatory design approach to facilitate the design of future eHealth solutions via focus groups. We involved older persons with hearing impairment (n = 36), significant others (n = 10), and audiologists (n = 8) following 2 methods: (a) human-centered design for interactive systems and (b) user innovation management. Through 3 rounds of focus groups, we facilitated a process progressing from insights and visions for requirements (Phase 1), to app such as paper version wireframes (Phase 2), and to digital prototypes envisioning future eHealth solutions (Phase 3). Each focus group was video-recorded and photographed, resulting in a rich data set that was analyzed through inductive thematic analysis. Results: The results are presented via (a) a storyboard envisioning future client journeys, (b) 3 key themes for future eHealth solutions, (c) 4 levels of interest and willingness to invest time and effort in digital solutions, and (d) 2 technical savviness types and their different preferences for rehabilitation strategies. Conclusions: Future eHealth solutions must offer personalized rehabilitation strategies that are appropriate for every person with hearing impairment and their level of technical savviness. Thus, a central requirement is anchoring of digital support in the clients' everyday life situations by facilitating easy access to personalized information, communication, and learning milieus. Moreover, the participants' visions for eHealth solutions call for providing both traditional analogue and digital services. Supplemental Material: https://doi.org/10.23641/asha.7310729. PMID- 30452746 TI - Empowering Senior Cochlear Implant Users at Home via a Tablet Computer Application. AB - Purpose: The introduction of connectivity technologies in hearing implants allows new ways to support cochlear implant (CI) users remotely. Some functionalities and services that are traditionally only available in an in-clinic care model can now also be accessed at home. This study explores the feasibility of a prototype of a tablet computer application (MyHearingApp [MHA]) in a group of senior experienced CI users at home, evaluating usability and user motivation. Method: Based on user feedback, a tablet computer application (MHA) for the Cochlear Nucleus 6 CP910 sound processor was designed implementing six different functionalities: (a) My Hearing Tests, (b) My Environment, (c) My Hearing Journey, (d) Tip of the Day, (e) Recipient Portal, and (f) Program Use and Events. The clinical evaluation design was a prospective study of the MHA in 16 senior experienced CI users. During 4 weeks, participants could freely explore the functionalities. At the end, the usability and their motivation for uptake and adherence were measured using a baseline and follow-up questionnaire. Results: Based on the System Usability Score (as part of the follow-up questionnaire), a good level of usability was indicated (M = 75.6, range: 62.5 92.5, SD = 8.6). The ability to perform hearing tests at home is ranked as the most relevant functionality within the MHA. According to the Intrinsic Motivation Inventory (Deci, Eghrari, Patrick, & Leone, 1994) questionnaire (as part of the follow-up questionnaire), participants reported high levels of interest and enjoyment, found themselves competent, and did not experience pressure while working with the app. Conclusions: This study evaluated a tablet computer application (MHA) for experienced senior CI users by means of a prospective design, which provided novel insights into delivering CI care into the home of the CI user. The user feedback from this small-scale study suggests that the participants are open to take more responsibility for and to become a more active actor in their own hearing care, if only this is facilitated with the right tools. This may foster the evolution from a clinic-led to a more patient-centered care model, where CI users feel more empowered in the self-management of their hearing implant device. PMID- 30452747 TI - Long-Term Efficacy of Audiologist-Guided Internet-Based Cognitive Behavior Therapy for Tinnitus. AB - Purpose: The purpose of this study was to investigate the long-term outcomes 1 year after undertaking an audiologist-guided Internet-based cognitive behavioral therapy (iCBT) intervention for tinnitus. Secondary aims were to identify any predictors of outcome and whether there were any unwanted events related to undertaking iCBT for tinnitus. Method: Participants who had previously undertaken a randomized iCBT efficacy trial for tinnitus were invited to participate. Of the 146 who were initially randomized for the efficacy trial, 104 participants completed the 1-year postintervention assessment measures. The primary outcome was a change in tinnitus distress as assessed by the Tinnitus Functional Index. Secondary assessment measures were included for insomnia, anxiety, depression, hearing handicap, hyperacusis, cognitive failures, and satisfaction with life. An intention-to-treat analysis using repeated-measures analysis of variance and hierarchical multiple regression was used for statistical analysis. Unwanted effects were categorized according to the unwanted events checklist. Results: Undertaking iCBT for tinnitus led to significant improvements 1 year postintervention for tinnitus and related difficulties, for example, insomnia, anxiety, depression, hearing handicap, hyperacusis, and life satisfaction. The best predictors of improving tinnitus severity at 1-year postintervention were greater baseline tinnitus severity scores, reading more of the modules, and higher satisfaction with the intervention. Unwanted events were reported by 11% of the participants and were more likely to be reported by women than men. These events were related to worsening of symptoms, the emergence of new symptoms, negative well-being, and prolongation of treatment. Conclusions: The clinical benefits of audiologist-guided iCBT for tinnitus and tinnitus-related difficulties were sustained 1 year postintervention. Predictors of outcome indicated that the intervention is applicable to a wide range of participants regardless of their demographic backgrounds. Attempts should be made to minimize unwanted events in subsequent trials. PMID- 30452748 TI - A Smartphone National Hearing Test: Performance and Characteristics of Users. AB - Purpose: The smartphone digits-in-noise hearing test, called hearZA, was made available as a self-test in South Africa in March 2016. This study determined characteristics and test performance of the listeners who took the test. Method: A retrospective analysis of 24,072 persons who completed a test between March 2016 and August 2017 was conducted. User characteristics, including age, English speaking competence, and self-reported hearing difficulty, were analyzed. Regression analyses were conducted to determine predictors of the speech reception threshold. Results: Overall referral rate of the hearZA test was 22.4%, and 37% of these reported a known hearing difficulty. Age distributions showed that 33.2% of listeners were ages 30 years and younger, 40.5% were between ages 31 and 50 years, and 26.4% were older than 50 years. Age, self-reported English speaking competence, and self-reported hearing difficulty were significant predictors of the speech reception threshold. Conclusions: High test uptake, particularly among younger users, and high overall referral rate indicates that the hearZA app addresses a public health need. The test also reaches target audiences, including those with self-reported hearing difficulty and those with normal hearing who should monitor their hearing ability. PMID- 30452749 TI - Identification and Management of Middle Ear Disorders in a Rural Cleft Care Program: A Telemedicine Approach. AB - Purpose: The aim of this study was to devise a grassroots-level strategy for identification and management of middle ear disorders in a community-based program for individuals with cleft lip and palate in 2 rural districts in the state of Tamil Nadu in South India. Method: Community workers underwent training to conduct video otoscopy using the ENTraview device. Community workers conducted video otoscopy on 160 individuals with cleft lip and palate between 3 and 35 years old in the community. Middle ear conditions were identified using store-and forward telepractice. Diagnostic telehearing evaluation was conducted using synchronous pure tone audiometry and tympanometry for those who were identified with tympanic membrane (TM) and/or middle ear diseases (MEDs). A review of data collected over a 13-month period was carried out to assess coverage and follow-up intervention rates. Results: The program was successful in achieving 80% coverage for identification of TM and MEDs within 13 months of program implementation. TM and/or MEDs were identified in 26% (82/320 ears) of those who underwent video otoscopy. Telehearing evaluations were completed on 42 ears of individuals with TM and/or MEDs; 52% (22/42 ears) of these individuals had a minimal, mild, or moderate degree of hearing loss. Regarding follow-up for intervention, 78% qualified for surgical intervention, and 31% qualified for medication. Conclusions: This grassroots-level telemedicine approach was successful in achieving better coverage, and store-and-forward telepractice helped in providing remote diagnosis and recommendation by otolaryngologists to all individuals with TM/MEDs in the rural community. The follow-up for otological intervention significantly improved from that achieved in the previous years. PMID- 30452750 TI - Geographic Distribution of the Hearing Aid Dispensing Workforce: A Teleaudiology Planning Assessment for Arizona. AB - Purpose: Teleaudiology helps connect patients in rural and underresourced areas to hearing health care providers, minimizing the barrier of geography (Swanepoel et al., 2010). In the United States, teleaudiology is at the initial stages of implementation (Bush, Thompson, Irungu, & Ayugi, 2016). Telehealth researchers recommend conducting a comprehensive planning assessment to optimize implementation and adoption (AlDossary, Martin-Khan, Bradford, Armfield, & Smith, 2017; Alverson et al., 2008; Krupinski, 2015). A geographic analysis of the hearing aid dispensing workforce served as the initial stage of a teleaudiology planning assessment in Arizona. Method: The analysis used publically available data sets from the U.S. Census, Arizona Department of Health Services, and the U.S. Veterans Administration. Geographic information system tools were used to analyze and visually represent population, potential teleaudiology site data, and hearing aid dispensing workforce (defined as audiologists and hearing instrument specialists licensed to dispense hearing aids in Arizona). ArcGIS was used to generate road networks and travel distance estimations. Results: The number of audiologists per county ranged from 0 to 216 (average 22.1). Six out of Arizona's 15 counties lacked a single audiologist, and 2 counties lacked a hearing instrument specialist. Potential expansion sites for teleaudiology were located in areas of the state that lacked practice locations for hearing aid services. Conclusions: There are geographic areas of Arizona that lack licensed hearing aid locations yet are populated by individuals who may need services. Resource availability data inform teleaudiology program expansion. Future research will include data from providers and community members on their perceived needs for services. PMID- 30452751 TI - An Application of the Medical Research Council's Guidelines for Evaluating Complex Interventions: A Usability Study Assessing Smartphone-Connected Listening Devices in Adults With Hearing Loss. AB - Purpose: The purpose of this study is to provide an example of the Medical Research Council's guidelines for evaluating complex health care interventions in the context of smartphone-connected listening devices in adults with hearing loss. Method: Twenty existing hearing aid users trialed 1 of the following smartphone-connected listening devices: made-for-smartphone hearing aids, a personal sound amplification product, and a smartphone "hearing aid" application used with either wireless or wired earphones. Following 2 weeks of use in their everyday lives, participants completed self-report outcome measures. Results: Relative to conventional hearing aids, self-reported use, benefit, and satisfaction were higher, and residual disability was lower for made-for smartphone hearing aids. The converse was found for the other smartphone connected listening devices trialed. Similarly, overall usability was judged to be "above average" for the made-for-smartphone hearing aids, but "below average" for the remaining devices. Conclusions: This developmental work, guided by the Medical Research Council's framework, lays the foundation for feasibility and pilot studies, leading to high-quality research assessing the effectiveness of smartphone-connected listening devices. This future evidence is necessary to guide health care commissioners and policymakers when considering new service delivery models for adults living with hearing loss. PMID- 30452752 TI - Automated Characterization of Mobile Health Apps' Features by Extracting Information From the Web: An Exploratory Study. AB - Purpose: The aim of this study was to test the viability of a novel method for automated characterization of mobile health apps. Method: In this exploratory study, we developed the basic modules of an automated method, based on text analytics, able to characterize the apps' medical specialties by extracting information from the web. We analyzed apps in the Medical and Health & Fitness categories on the U.S. iTunes store. Results: We automatically crawled 42,007 Medical and 79,557 Health & Fitness apps' webpages. After removing duplicates and non-English apps, the database included 80,490 apps. We tested the accuracy of the automated method on a subset of 400 apps. We observed 91% accuracy for the identification of apps related to health or medicine, 95% accuracy for sensory systems apps, and an average of 82% accuracy for classification into medical specialties. Conclusions: These preliminary results suggested the viability of automated characterization of apps based on text analytics and highlighted directions for improvement in terms of classification rules and vocabularies, analysis of semantic types, and extraction of key features (promoters, services, and users). The availability of automated tools for app characterization is important as it may support health care professionals in informed, aware selection of health apps to recommend to their patients. PMID- 30452753 TI - Big Data for Sound Policies: Toward Evidence-Informed Hearing Health Policies. AB - Purpose: The scarcity of health care resources calls for their rational allocation, including within hearing health care. Policies define the course of action to reach specific goals such as optimal hearing health. The process of policy making can be divided into 4 steps: (a) problem identification and issue recognition, (b) policy formulation, (c) policy implementation, and (d) policy evaluation. Data and evidence, especially Big Data, can inform each of the steps of this process. Big Data can inform the macrolevel (policies that determine the general goals and actions), mesolevel (specific services and guidelines in organizations), and microlevel (clinical care) of hearing health care services. The research project EVOTION applies Big Data collection and analysis to form an evidence base for future hearing health care policies. Method: The EVOTION research project collects heterogeneous data both from retrospective and prospective cohorts (clinical validation) of people with hearing impairment. Retrospective data from clinical repositories in the United Kingdom and Denmark will be combined. As part of a clinical validation, over 1,000 people with hearing impairment will receive smart EVOTION hearing aids and a mobile phone application from clinics located in the United Kingdom and Greece. These clients will also complete a battery of assessments, and a subsample will also receive a smartwatch including biosensors. Big Data analytics will identify associations between client characteristics, context, and hearing aid outcomes. Results: The evidence EVOTION will generate is relevant especially for the first 2 steps of the policy-making process, namely, problem identification and issue recognition, as well as policy formulation. EVOTION will inform microlevel, mesolevel, and macrolevel of hearing health care services through evidence-informed policies, clinical guidelines, and clinical care. Conclusion: In the future, Big Data can inform all steps of the hearing health policy-making process and all levels of hearing health care services. PMID- 30452754 TI - Findings and Ethical Considerations From a Thematic Analysis of Threads Within Tinnitus Online Support Groups. AB - Purpose: Tinnitus is the perception of noise without a corresponding external stimulus. Current management typically aims to moderate associated psychosocial stressors and allow sufferers to retain an adequate quality of life. With the increasing recognition of the Internet as a repository for health advice, information, and support, the online support group has become a popular coping strategy for those living with chronic conditions such as tinnitus. Patients find that communicating with each other, providing encouragement, and sharing information in the absence of physical and temporal boundaries are invaluable ways of managing their condition. The purpose of this study was to explore the potential positive and negative consequences of participating in online support groups for tinnitus. Method: Discussion forum threads were collated from across 4 public online support group websites. All threads were initiated between February and April 2016. Texts from these threads were coded by 3 separate analysts using both inductive and deductive thematic analysis, until data saturation was reached. Results: Analysis of 75 threads (641 individual posts) found 9 independent themes pertaining to aspects of participation in tinnitus online support groups. The results revealed that using the forums allowed users to exchange knowledge and experiences, express complex emotions, profit from a network of support, and engage in everyday conversation away from the burden of their tinnitus. However, some experiences appeared to be compromised by negative messages, limited communication, and informational issues such as conflicting advice or information overload. Conclusions: This study represents the 1st research into discussion forums in tinnitus online support groups. A nonintrusive (passive) analysis method was used, whereby messages comprising the dataset were retrieved without direct interaction with the discussion forum. Individuals and the community of tinnitus online support groups are deemed to be at low risk from potential harm in this study. Most tinnitus patients likely benefit from accessing online support groups, for example, they discover they are not alone, and they find new coping strategies. However, for those who are particularly vulnerable or prone to psychological stress, accessing these groups could be detrimental. PMID- 30452755 TI - Toward Better Outcomes in Audiology Distance Education: An Educational Data Mining Approach. AB - Purpose: This article introduces concepts and a general taxonomy used by the educational data mining (EDM) community, as well as examples of their applications, with the aims of providing audiology educators with a referential basis for developing this area. Method: A narrative review was carried out to present an overview of EDM and its main methods. Some of these methods were exemplified with analysis of real data from an Internet-based specialization course on pediatric auditory rehabilitation. Results: The review introduced EDM main concepts and applications and described methods from its area. Real data examples illustrated EDM use to predict interpersonal help-seeking, model interpersonal interaction, analyze students' trajectories within a course's module, and understand how students approached group assignments. Some of the insights provided by EDM to support teaching and learning processes were also described. Conclusions: EDM methods offer new tools to discover knowledge from digital traces (i.e., logs) and support key stakeholders (students, instructors, or course administrators) to raise awareness about course dynamics. This approach has the potential to foster a better understanding and management of educational processes in audiology distance education. PMID- 30452757 TI - Identification of Master Regulator Genes of UV Response and Their Implications for Skin Carcinogenesis. AB - Solar UV radiation is a major environmental risk factor for skin cancer. Despite decades of robust and meritorious investigation, our understanding of the mechanisms underlying UV-induced skin carcinogenesis remain incomplete. We previously performed comprehensive transcriptomic profiling in human keratinocytes following exposure to different UV radiation conditions to generate UV-specific gene expression signatures. In this study, we utilized VIPER, a robust systems biology tool, on UV-specific skin cell gene signatures to identify master regulators (MRs) of UV-induced transcriptomic changes. We identified multiple prominent candidate UV MRs, including forkhead box M1 (FOXM1), thyroid hormone receptor interactor 13, and DNA isomerase II alpha, which play important roles in cell cycle regulation and genome stability. MR protein activity was either activated or suppressed by UV in normal keratinocytes. Intriguingly, many of the UV-suppressed MRs were activated in human skin squamous cell carcinomas (SCCs), highlighting their importance in skin cancer development. We further demonstrated that selective inhibition of FOXM1, whose activity was elevated in SCC cells, was detrimental to SCC cell survival. Taken together, our study uncovered novel UV master regulators that can be explored as new therapeutic targets for future skin cancer treatment. PMID- 30452758 TI - Genetic engineering of Ehrlich pathway modulate production of higher alcohols in engineered Yarrowia lipolytica. AB - Microbial cells can produce a vast spectrum of chemical compounds, including those most desired by the global chemical market, as for example higher alcohols, which are promising alternative fuels and chemical feedstock. In the current research, we investigated the effects of the Ehrlich pathway genetic engineering on higher alcohols production in Y. lipolytica, which directly follows our previous findings concerning elucidation of putative molecular identities involved in this pathway. To this end, we constructed two alternative expression cassettes composed of previously identified genes, putatively involved in the Ehrlich pathway in Y. lipolytica, and cloned them under the control of constitutive pTEF promoter, and by this-released them from extensive native regulation. The effects of the pathway engineering were investigated upon provision of different, Ehrlich pathway-inducing amino acids (L-Phe, L-Leu, L-Ile and L-Val). In general, amplification of the Ehrlich pathway in many cases led to increased formation of a respective higher alcohol from its precursor. We observed interesting effects of aminotransferase BAT2 deletion on synthesis of 2 phenylethanol and its acetate ester, significant relationship between L-Val and L Phe catabolic pathways, and extensive 'cross-induction' of the derivative compounds synthesis by non-direct precursors. PMID- 30452760 TI - Corrigendum. PMID- 30452759 TI - Genome analyses for the Tohoku Medical Megabank Project toward establishment of personalized healthcare. AB - Personalized healthcare (PHC) based on an individual's genetic make-up is one of the most advanced, yet feasible, forms of medical care. The Tohoku Medical Megabank (TMM) Project aims to combine population genomics, medical genetics, and prospective cohort studies to develop a critical infrastructure for the establishment of PHC. To date, a TMM-CommCohort (adult general population) and a TMM-BirThree Cohort (birth+three-generation families) have conducted recruitments and baseline surveys. Genome analyses as part of the TMM Project will aid in the development of a high-fidelity whole-genome Japanese reference panel, in designing custom single-nucleotide polymorphism (SNP) arrays specific to Japanese, and in estimation of the biological significance of genetic variations through linked investigations of the cohorts. Whole-genome sequencing from >3,500 unrelated Japanese and establishment of a Japanese reference genome sequence from long-read data have been done. We next aim to obtain genotype data for all TMM cohort participants (>150,000) using our custom SNP arrays. These data will help identify disease-associated genomic signatures in the Japanese population, while genomic data from TMM-BirThree Cohort participants will be used to improve the reference genome panel. Follow-up of the cohort participants will allow us to test the genetic markers and, consequently, contribute to the realization of PHC. PMID- 30452761 TI - Parental Relationship Dissolution and Child Development: The Role of Child Sleep Quality. AB - We utilized the Fragile Families and Child Wellbeing longitudinal dataset to evaluate associations among a maternal relationship dissolution, childhood sleep, and child development, specifically externalizing and internalizing symptoms, attention and social difficulties, as well as cognitive ability, when children were ages 5 (n=3590) and 9 (n=3062). A maternal relationship dissolution was related to poorer child sleep quality at ages 5 and 9. There was evidence of an indirect relation from a maternal relationship dissolution to child development through poor sleep quality when the child was 5 and 9 years old. The implications of this work are discussed. PMID- 30452762 TI - Instructing Residents in Strabismus Surgery. PMID- 30452763 TI - I Went in for a Routine Eye Examination. PMID- 30452764 TI - Not Focusing on Myopia Is Shortsighted. PMID- 30452765 TI - Diagnosing and Treating Thyroid Ophthalmopathy. PMID- 30452766 TI - Systemic Associations of Childhood Glaucoma: A Review. AB - PURPOSE: To review systemic associations of childhood glaucoma. METHODS: Patients younger than 15 years and diagnosed as having glaucoma were divided into four groups: isolated primary congenital glaucoma, glaucoma with other congenital ocular anomalies, congenital glaucoma with known systemic diseases, and secondary glaucoma. Prevalence and type of systemic associations in each group were studied. RESULTS: A retrospective analysis of 371 patients diagnosed as having glaucoma was done. In the primary congenital glaucoma group, 13 of 218 (5.9%) patients had an associated systemic illness: congenital heart disease and global developmental delay were the most common systemic manifestations. In the congenital ocular anomalies group, 10 of 63 (15.8%) patients had an associated systemic illness. Axenfeld-Reiger syndrome, aniridia, and Peters' anomaly frequently had systemic comorbidities with congenital heart disease. In the known systemic diseases group, all 18 (100%) patients had systemic manifestations of an associated syndrome: Sturge-Weber and Down syndrome were the most frequent. In the secondary glaucoma group, 9 of 72 (12.5%) patients had systemic involvement, which was often seen as the most common cause after congenital cataract surgery. These children had congenital heart disease and global developmental delay as a consequence of congenital rubella and congenital cytomegalovirus infection. CONCLUSIONS: The study found that 12.9% of patients with childhood glaucoma had an associated systemic abnormality. Patients with congenital glaucoma and other ocular anomalies have a three times higher risk of an underlying systemic anomaly than patients with isolated primary congenital glaucoma. A team comprising an ophthalmologist, pediatrician, and anesthesiologist is recommended to treat these cases. [J Pediatr Ophthalmol Strabismus. 2018;55(6):397-402.]. PMID- 30452767 TI - Refractive Trend of Stage 3 Retinopathy of Prematurity. AB - PURPOSE: To analyze the yearly refractive trend in patients with stage 3 retinopathy of prematurity (ROP) over a 7-year time period. METHODS: This was a retrospective review of 70 eyes of 35 patients with stage 3 ROP. RESULTS: Of the 70 eyes, 46 received laser ablation and 24 did not. There was a similar distribution between zone II and zone III disease in both groups (P = .87). The average final refraction in the laser group was -0.83 diopters (D) in comparison to +1.61 D in the no laser group. The final refractive change was -3.55 D in the laser group and -0.25 D in the no laser group. A greater myopic shift was observed in the first 2 years of life than between years 2 and 7 in both groups. CONCLUSIONS: Infants who underwent laser treatment for stage 3 ROP tended to have higher myopia than those with stage 3 ROP who did not require treatment. [J Pediatr Ophthalmol Strabismus. 2018;55(6):403-406.]. PMID- 30452769 TI - Choroidal Ganglioneuronal Hamartoma in Neurofibromatosis Type-1. PMID- 30452768 TI - Postoperative Stereopsis in Adult Patients With Horizontal Comitant Strabismus With Normal Vision Who Are Stereoblind. AB - PURPOSE: To examine stereopsis in patients with comitant horizontal strabismus who had normal vision and were stereoblind following the strabismus surgery. METHODS: Twenty patients with primary comitant horizontal strabismus and normal corrected visual acuity were included in this study. The stereoacuity was quantitatively measured by the random dot butterfly stereotest, the Randot Preschool Stereoacuity Test (Stereo Optical, Inc., Chicago, IL), and synoptophore. RESULTS: Twenty patients with comitant strabismus (14 exotropia and 6 esotropia) with normal corrected visual acuity but without stereopsis were included. The average prism deviation was 63.55 +/- 18.52 prism diopters (PD) (range: 30 to 90 PD). The mean duration of strabismus was 17.93 +/- 7.0 years (range: 5 to 30 years). At 3 days postoperatively, 22.2% (4 of 18) of the patients had improved stereopsis and the mean stereoacuity was 60 +/- 28.28 seconds of arc by random dot butterfly stereotest and 150 +/- 57.74 seconds of arc by Randot Preschool Stereoacuity Test (P < .05). For the fusion and stereopsis at far measured by the synoptophore, 11.1% (2 of 18) of the patients demonstrated recovery of fusion and substantial recovery of stereopsis. The mean stereoacuity (at far) was 200 seconds of arc. At the last follow-up visit (3 to 12 months, average 6.55 +/- 3.46 months), 45% (9 of 20) of the patients demonstrated substantial near stereopsis recovery and the median stereoacuity was 53.33 +/- 33.17 seconds of arc by random dot butterfly stereotest and 95.56 +/- 63.07 seconds of arc by the Randot Preschool Stereoacuity Test (P < .01). A total of 25% (5 of 20) of the patients demonstrated recovery of fusion and 15% (3 of 20) of the patients showed substantial recovery of stereopsis at far. The median stereoacuity (at far) was 193.33 +/- 179.26 seconds of arc. CONCLUSIONS: The results demonstrated that adult patients with comitant strabismus who had good vision and were stereoblind benefited from strabismus surgery and the stereopsis improved. Near stereopsis was easier to regain than far stereopsis. [J Pediatr Ophthalmol Strabismus. 2018;55(6):407-411.]. PMID- 30452770 TI - HCN4 Gene Variations in Sudden Unexplained Nocturnal Death Syndrome in the Southern Han Chinese Population. AB - Sudden unexplained nocturnal death syndrome (SUNDS) is widely considered to be related to hereditary fatal arrhythmias. Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) channels are widely distributed in sinus myocytes and play a profound role in generating pacemaker electro-activity in cardiomyocytes. In the present study, the potential correlation between HCN4 gene variations and the occurrence of SUNDS was investigated. Genomic DNA was extracted from blood samples of both 119 unrelated SUNDS patients and 184 healthy individuals and screened for candidate HCN4 gene variants. One missense heterozygous variant c.1578C>T (Ala195Val) and four synonymous heterozygous variants c.1552C>T, c.2833C>T, c.3823C>T, and c.4189C>A were discovered in the SUNDS cases. The missense variant c.1578C>T (Ala195Val) was absent in 163 recruited controls and 105 persons of the Southern Han Chinese population, had in silico prediction indications as damaging, and was reported prevalent in sudden infant death, and is thus likely to be involved in SUNDS. PMID- 30452771 TI - Homicidal Paraquat Poisoning. AB - Paraquat poisoning usually results from suicide, occupational, or accidental exposure. Herein, we report a rare fatal case of homicidal paraquat poisoning. A 58-year-old man was poisoned by taking paraquat-mixed medicine and wearing paraquat-soaked underwear. In the absence of a history of paraquat exposure, the patient was misdiagnosed with pulmonary infection and scrotal dermatitis and died of respiratory failure 24 days after the initial exposure to paraquat. Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to detect and quantify paraquat in postmortem specimens. The concentration of paraquat in postmortem specimens from high to low is lung (0.49 MUg/g), brain (0.32 MUg/g), kidney (0.24 MUg/g), liver (0.20 MUg/g), cardiac blood (0.11 MUg/mL), and stomach wall ( 13 months, <=5 metastatic nodes in the lungs, the size of the largest metastasis in the lungs <=20 mm, intralobular location of metastases in the lungs as well as the time of doubling the volume of metastases >64 days for chest computed tomography. PMID- 30452858 TI - [The use of SPECT-CT for visualization of sentinel lymph nodes and lymph drainage pathways in prostate cancer patients]. AB - There was studied the use of SPECT-CT for visualization of sentinel lymph nodes and lymph drainage pathways in 35 patients with localized prostate cancer (cT1-T2 N0 M0). Sentinel lymph nodes were imaged in 31 (89%) patients. There were advantageously detected drainage pathways to exterior (77%) and internal iliac (58%) lymph nodes. Visceral (29%) lymph nodes (paraprostatic, paravesical and mesorectal) were less determined. There was established high informative value of SPECT-CT for imaging sentinel lymph nodes, determining their location as well as identification of lymph drainage pathways in patients with prostate cancer. PMID- 30452859 TI - [The role of laparoscopic salvage lymphadenectomy in patients after initial extended lymphadenectomy for prostate cancer]. AB - This work presents results of the analysis of safety and efficacy of laparoscopic superextended lymphadenectomy, which was performed in patients with clinical progression (the presence of lesions in the lymph nodes of the pelvis and beyond) after undergoing prostatectomy. A feature of the work is that these patients initially extended lymphadenectomy was performed. Clinical detection of foci was carried out by 11C-PET/ CT. Laparoscopic salvage lymphadenectomy appears to be the safe method of performing surgery. When monitoring patients there was evaluated the effectiveness of the operation - the percentage of patients with marked regression and stabilization of markers (PSA), duration of remission. The analysis of the data attempted to determine the predictors of non-response patients after salvage lymphadenectomy. PMID- 30452860 TI - [Creation of a statistical model for prediction of Hodgkin's lymphoma in young adults]. AB - The aim of this study was to create a multi-dimensional correlation matrix of determinants giving information on the degree of influence on survival of young adults with Hodgkin's lymphoma each variable as well as the effect of the interaction of these variables with each other. 87 patients with Hodgkin's lymphoma at the age of 19 to 29 years (mean age 24 +/- 4 years) were included in the study. Multiple matrix containing the coefficients of correlation of survival and correlation coefficients of 35 analyzed factors was of 5 significant determinants (volume of tumor lesion, stage IV of disease, E-damage, accelerated erythrocyte sedimentation rate, leukocytosis). Construction of the correlation matrix in order to select factors to be included in the equation, which contained the pair correlation coefficients of overall survival and each of factors, showed that only the volume of tumor lesion (correlation coefficient 0.2570, p = 0.026) influences on sign-result. Multiple regression equation is represented as follows y=0,166667-0,227273x[volume]; R2=0,0643674507. This equation allows for given values of the factor "volume of tumor lesion" to have theoretical values of resultant sign (survival), substituting the actual values of the factor in it. PMID- 30452861 TI - Gold Nanoparticles in Cancer Treatment. AB - Colloidal gold has been studied for its potential application in medicine for centuries. However, synthesis and evaluation of various gold nanoparticles have only recently been met with a wide interest of scientists. Current studies confirm numerous advantages of nanogold over different nanomaterials, primarily due to highly optimized protocols for the production of gold nanoparticles of countless sizes and shapes, featured with unique properties. The possibility to modify the surface of nanogold particles with different targeting and functional compounds significantly broadens the range of their potential biomedical applications, with particular emphasis on cancer treatment. Functionalized gold nanoparticles exhibit good biocompatibility and controllable biodistribution patterns, which make them particularly fine candidates for the basis of innovative therapies. Considering the high amount of scientific data on nanogold, this review summarizes recent advances in the field of medical application of gold nanoparticles for the therapy of cancer. PMID- 30452862 TI - Optically Active Inverse Opal Photonic Crystals. AB - Chiral photonic crystals have been a widely investigated topic in chemistry, physics and biology. Till now, the research about chiral photonic crystals has been conducted on the objects of helical structures, while the chiral photonic crystals made of periodic chiral media remain unexplored experimentally. In this work, we have successfully constructed three-dimensional chiral polymer inverse opal photonic crystals (3D CPIOPCs) by a template-based method. Impressively, the 3D CPIOPCs exhibit emerging circular dichroism responses near the photonic band gaps. The experiments and calculations clearly elucidate the contribution of photonic structures and chiral media to this characteristic optical activity. PMID- 30452863 TI - Photoreduction of CO2 with a Formate Dehydrogenase Driven by Photosystem II Using a Semi-artificial Z-Scheme Architecture. AB - Solar-driven coupling of water oxidation with CO2 reduction sustains life on our planet and is of high priority in contemporary energy research. Here, we report a photoelectrochemical tandem device that performs photocatalytic reduction of CO2 to formate. We employ a semi-artificial design, which wires a W-dependent formate dehydrogenase (FDH) cathode to a photoanode containing the photosynthetic water oxidation enzyme, Photosystem II, via a synthetic dye with complementary light absorption. From a biological perspective, the system achieves a metabolically inaccessible pathway of light-driven CO2 fixation to formate. From a synthetic point of view, it represents a proof-of-principle system utilizing precious-metal free catalysts for selective CO2-to-formate conversion using water as an electron donor. This hybrid platform demonstrates the translatability and versatility of coupling abiotic and biotic components to create challenging models for solar fuel and chemical synthesis. PMID- 30452864 TI - Mix-and-Match Proteomics: Using advanced iodoTMT multiplexing to investigate cysteine oxidation changes with respect to protein expression. AB - Cysteine redox state has been identified as one of the key biological influences behind protein structure and/or function. Altered protein redox state has been shown to cause significant physiological changes and can leave proteins with changed sensitivity to oxidative stress. Protein redox state changes are recognized as an important mediator of disease, cellular abnormalities or environmental changes and therefore their characterization is of interest. Isotopic or isobaric labeling followed by sample multiplexing and analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS) allows relative comparison of protein expression levels or of protein redox state between several samples. Combining analysis of protein expression level and redox state into one analysis would add an extra dimension and permit the normalization of protein redox changes with protein abundance. To achieve this, we have developed a quantitation workflow that uses commercially available cysteine-reactive tandem mass tags (iodoTMT) to differentially label cysteine residues, and applied it to two Leishmania mexicana cell-lines that have previously shown different responses to oxidative stress. The individually labeled samples have been pooled in different combinations to create multiple sixplex samples in order to study the relationship between cysteine oxidation and overall protein expression, as well as providing information about protein oxidation levels in each cell-line. The results highlight eleven proteins that are differentially expressed between the two cell-lines and/or have significant redox changes. This advanced multiplexing method effectively demonstrates the flexibility of tandem mass tags and how they can be used to maximize the amount of information that can be acquired. PMID- 30452865 TI - Aromatic Motifs Dictate Nanohelix Handedness of Tripeptides. AB - Self-assembly of peptides and amyloid fibrils offers an appealing approach for creating chiral nanostructures, which has promising applications in the fields of biology and materials science. Although numerous self-assembled chiral materials have been designed, the precise control of their twisting tendency and their handedness is still a challenge. Herein, we report the self-assembly of chiral nanostructures with precisely tailored architectures by changing the amino acid sequences of the peptides. We designed a series of self-assembling tripeptides bearing different l-amino acid sequences. The peptide with l-Phe-l-Phe sequence preferred to self-assemble into left-handed nanohelices, while with l-Phe-l-Trp right-handed nanohelices would be formed. Moreover, the diameter of the self assembled nanohelices could be tailored by changing the terminal amino acids (His, Arg, Ser, Glu, and Asp). Circular dichroism (CD) and molecular dynamics simulations (MDSs) revealed that both of the right- and left-handed nanohelices formed by the tripeptides showed negative Cotton effects in the peptide adsorption region but exhibited nearly opposite CD Cotton effects in the aromatic regions. These results indicated that the handedness of the self-assembled helical nanofibers was not only determined by the chirality of the peptide backbone but also closely related to the aromatic stacking, hydrogen bonding and steric interactions induced by the side chains. The findings deepen our understanding on the chiral self-assembly of peptide and offer opportunities for the creation of highly functional chiral nanomaterials. PMID- 30452866 TI - Predictive Modeling of Energy and Emissions from Shale Gas Development. AB - Contributions of individual preproduction activities to overall energy use and greenhouse gas (GHG) emissions during shale gas development are not well understood nor quantified. This paper uses predictive modeling combining the physics of reservoir development operations with depositional attributes of shale gas basins to account for energy requirements and GHG emissions during shale gas well development. We focus on shale gas development from the Montney basin in Canada and account for the energy use during drilling and fluid pumping for reservoir stimulation, in addition to preproduction emissions arising from energy use and potential gas releases during operations. Detailed modeling of activities and events that take place during each stage of development is described. Relative to the hydraulic fracturing activity, we observe significantly higher energy intensity for the well drilling and mud circulation activities. Well completion flowback gas is found to be the predominant potential source of GHG emission. When these results are expressed on an annual basis, consistent with the convention of most climate policy goals and directives, environmental impacts of our growing natural gas economy are better appreciated. Estimated likely GHG emission from new development wells in 2017 in the Montney Formation, alone, is 2.68 million metric ton CO2e. However, on a preproduction requirements basis and dependent on mean estimated ultimate recovery (EUR), energy return on invested energy for shale gas from the Montney Formation in Canada is estimated to be about 3,400. The approach described here can be reliably extended to areas, globally, where natural gas development is becoming prominent. PMID- 30452867 TI - Seasonal and annual source appointment of carbonaceous ultrafine particulate matter (PM0.1) in polluted California cities. AB - Samples of ultrafine particle matter mass (PM0.1) were collected over twelve months at three cities in California: Los Angeles, East Oakland, San Pablo, and over six months at Fresno. Molecular markers adjusted for volatility and reactivity were used to calculate PM0.1 source contributions. Wood burning was a significant source of PM0.1 organic carbon (OC) during the winter months in northern California (17-47%) but made smaller contributions in other months (0 8%) and was minor in all seasons in Los Angeles (0-5%), expect December (17%) during holiday celebrations. Meat cooking was the largest source of PM0.1 OC across all sites (13-29%), followed by gasoline combustion (7-21%). Motor oil and diesel fuel combustion made smaller contributions to PM0.1 OC (3-10% and 3-7%, respectively). Unresolved sources accounted for 22-56% of the PM0.1 OC. The lack of a clear seasonal profile for this unresolved OC suggests that it may be a primary source rather than secondary organic aerosol (SOA). PM0.1 elemental carbon (EC) was dominated by diesel fuel combustion with less than 15% contribution from other sources. All sources besides wood smoke exhibited relatively constant seasonal source contributions to PM0.1 OC reflecting approximately constant emissions over the annual cycle. Annual-average source contributions to PM0.1 OC calculated with traditional molecular markers were similar to the source contributions calculated with the modified molecular markers that account for volatility and reactivity. PMID- 30452868 TI - Novel Hydrogel-Forming Microneedle Array for Intradermal Vaccination in Mice Using Ovalbumin as a Model Protein Antigen. AB - Global vaccination strategies have traditionally relied on the hypodermic needle and syringe model. However, to facilitate increased immunization coverage and reduce costs, novel methods of vaccine delivery are warranted. Dissolving microneedle arrays (MNs) have been proposed as an alternative approach to the hypodermic needle, offering the prospect for self-vaccination and increased immunogenicity via direct targeting of skin dendritic cells. This study, for the first time, compares the use of novel hydrogel-forming MNs and dissolving MNs for the delivery of a model protein antigen ovalbumin (OVA). We provide comparative data on both MN types in terms of in vitro characteristics and in vivo immunogenicity. Herein, both MN platforms were tested and characterized in terms of mechanical integrity and insertion properties using a validated skin insertion model. A comparative in vivo vaccination study in BALB/c mice was conducted, whereby anti-OVA specific IgG was used as a measure of delivery efficacy and subsequent immune response. While vaccination of mice with both MN platforms resulted in IgG responses, those vaccinated with dissolving MNs had significantly higher IgG titers ( p < 0.0149), despite the quantity of OVA delivered being significantly less. This study highlights the importance of MN design and the potential impact of dissolving MN polymers on the immune response to vaccine antigens. Furthermore, detailed studies are therefore required to elucidate the effects of polymer-vaccine interactions and their subsequent effect on immune responses. PMID- 30452869 TI - Indicators of Physical Activity Among Children and Youth in 9 Countries With Low to Medium Human Development Indices: A Global Matrix 3.0 Paper. AB - BACKGROUND: This study compares results of physical activity report cards from 9 countries with low to medium human development indices, participating in the Global Matrix 3.0 initiative. METHODS: Country-specific report cards were informed by relevant data and government policy documents, reporting on 10 core indicators of physical activity for children and youth. Data were synthesized by report card working groups following a harmonized process. Grade assignments for each indicator utilized a standard grading rubric. Indicators were grouped into one of 2 categories: daily behaviors and settings and sources of influence. Descriptive statistics (average grades) were computed after letter grades were converted into interval variables. Spearman's rank correlation coefficients were calculated for all correlation analyses. RESULTS: Mean grades for daily behaviors were higher (C) than those for settings and sources of influence (D+). Twenty nine out of the possible 90 grades were assigned an incomplete. There were moderate to strong positive and negative relationships between different global indices and overall physical activity, organized sport and physical activity, active play, family, community and environment, and government. CONCLUSIONS: Findings demonstrate an urgent need for high-quality data at the country level in order to better characterize the physical activity levels of children and youth in countries with low to medium human development indices. PMID- 30452870 TI - An Automated Algorithm to Quantify Collagen Distribution in Aortic Wall. AB - Arterial diseases including abdominal aortic aneurysm and atherosclerosis are biomechanical diseases characterized by significant changes in the structure and strength of the vessel wall. It is now established that local variations in fibrillar collagen and elastin matrix turnover is critical to arterial stiffening and progression of the disease. The collagen content in the aortic wall has nominally been quantified by biochemical assays and immunohistochemical analysis as the total amount because of the difficulty in separating the media and adventitia. In this work, we have developed an algorithm for automatic quantification of layer-specific collagen content from bright-field and polarized microscopic images of histological sections of mouse aorta stained with Picrosirius red (PSR) stain. The images were processed sequentially including separation of layers, erosion, segregation of regions, binarization, and quantification of pixel intensities to obtain collagen content in the media and adventitia separately. We observed that the automated algorithm rapidly and accurately quantified collagen content from a wide range of image quality compared with manual measurements particularly when the medial and adventitial layers overlap. Together, our algorithm will be of significant impact in the rapid, reliable, and accurate analyses of collagen distribution in histological sections of connective tissues. PMID- 30452871 TI - The Arterial Anatomy of the Lateral Ligament Complex of the Ankle: A Cadaveric Study. AB - BACKGROUND:: Ankle sprains are the most common musculoskeletal injury in the United States. Chronic lateral ankle instability can ultimately require operative intervention to decrease pain and restore stability to the ankle joint. There are no anatomic studies investigating the vascular supply to the lateral ankle ligamentous complex. PURPOSE:: To define the vascular anatomy of the lateral ligament complex of the ankle. STUDY DESIGN:: Descriptive laboratory study. METHODS:: Thirty pairs of cadaveric specimens (60 total legs) were amputated below the knee. India ink, followed by Ward blue latex, was injected into the peroneal, anterior tibial, and posterior tibial arteries to identify the vascular supply of the lateral ligaments of the ankle. Chemical debridement was performed with 8.0% sodium hypochlorite to remove the soft tissues, leaving casts of the vascular anatomy intact. The vascular supply to the lateral ligament complex was then evaluated and recorded. RESULTS:: The vascular supply to the lateral ankle ligaments was characterized in 56 specimens: 52 (92.9%) had arterial supply with an origin from the perforating anterior branch of the peroneal artery; 51 (91.1%), from the posterior branch of the peroneal artery; 29 (51.8%), from the lateral tarsal branch of the dorsalis pedis; and 12 (21.4%), from the posterior tibial artery. The anterior branch of the peroneal artery was the dominant vascular supply in 39 specimens (69.6%). CONCLUSION:: There are 4 separate sources of extraosseous blood supply to the lateral ligaments of the ankle. In all specimens, the anterior talofibular ligament was supplied by the anterior branch of the peroneal artery and/or the lateral tarsal artery of the dorsalis pedis, while the posterior talofibular ligament was supplied by the posterior branch of the peroneal artery and/or the posterior tibial artery. The calcaneofibular ligament received variable contributions from the anterior and posterior branches of the peroneal artery, with few specimens receiving a contribution from the lateral tarsal or posterior tibial arteries. CLINICAL RELEVANCE:: Understanding the vascular anatomy of the lateral ligament complex is beneficial when considering surgical management and may provide insight into factors that lead to chronic instability. PMID- 30452872 TI - Impaired Junctions and Invaded Macrophages in Oral Epithelia With Oral Pain. AB - Recurrent or chronic oral pain is a great burden for patients. Recently, the links between epithelial barrier loss and disease were extended to include initiation and propagation. To explore the effects of pathohistological changes in oral epithelia on pain, we utilized labial mucosa samples in diagnostic labial gland biopsies from patients with suspected Sjogren's syndrome (SS), because they frequently experience pain and discomfort. In most labial mucosa samples from patients diagnosed with SS, disseminated epithelial cellular edema was prevalent as ballooning degeneration. The disrupted epithelia contained larger numbers of infiltrating macrophages in patients with oral pain than in patients without pain. Immunohistochemistry revealed that edematous areas were distinct from normal areas, with disarranged cell-cell adhesion molecules (filamentous actin, E cadherin, beta-catenin). Furthermore, edematous areas were devoid of immunostaining for transient receptor potential channel vanilloid 4 (TRPV4), a key molecule in adherens junctions. In an investigation on whether impaired TRPV4 affect cell-cell adhesion, calcium stimulation induced intimate cell-cell contacts among oral epithelial cells from wild-type mice, while intercellular spaces were apparent in cells from TRPV4-knockout mice. The present findings highlight the relationship between macrophages and epithelia in oral pain processing, and identify TRPV4-mediated cell-cell contacts as a possible target for pain treatment. PMID- 30452873 TI - Higher Rates of Lower Extremity Injury on Synthetic Turf Compared With Natural Turf Among National Football League Athletes: Epidemiologic Confirmation of a Biomechanical Hypothesis. AB - BACKGROUND:: Biomechanical studies have shown that synthetic turf surfaces do not release cleats as readily as natural turf, and it has been hypothesized that concomitant increased loading on the foot contributes to the incidence of lower body injuries. This study evaluates this hypothesis from an epidemiologic perspective, examining whether the lower extremity injury rate in National Football League (NFL) games is greater on contemporary synthetic turfs as compared with natural surfaces. HYPOTHESIS:: Incidence of lower body injury is higher on synthetic turf than on natural turf among elite NFL athletes playing on modern-generation surfaces. STUDY DESIGN:: Cohort study; Level of evidence, 3. METHODS:: Lower extremity injuries reported during 2012-2016 regular season games were included, with all 32 NFL teams reporting injuries under mandated, consistent data collection guidelines. Poisson models were used to construct crude and adjusted incidence rate ratios (IRRs) to estimate the influence of surface type on lower body injury groupings (all lower extremity, knee, ankle/foot) for any injury reported as causing a player to miss football participation as well as injuries resulting in >=8 days missed. A secondary analysis was performed on noncontact/surface contact injuries. RESULTS:: Play on synthetic turf resulted in a 16% increase in lower extremity injuries per play than that on natural turf (IRR, 1.16; 95% CI, 1.10-1.23). This association between synthetic turf and injury remained when injuries were restricted to those that resulted in >=8 days missed, as well as when categorizations were narrowed to focus on distal injuries anatomically closer to the playing surface (knee, ankle/foot). The higher rate of injury on synthetic turf was notably stronger when injuries were restricted to noncontact/surface contact injuries (IRRs, 1.20 2.03; all statistically significant). CONCLUSION:: These results support the biomechanical mechanism hypothesized and add confidence to the conclusion that synthetic turf surfaces have a causal impact on lower extremity injury. PMID- 30452874 TI - A deficit in post-graphemic writing processes: Evidence for a graphomotor buffer. AB - Post-graphemic writing processes transform abstract letter representations into representations of writing movements. We describe an individual with an acquired post-graphemic writing deficit. NGN is normal in spelling words aloud, but impaired in writing words to dictation, with most errors involving letter substitutions (e.g., RUMOR written as BUMOR). NGN's deficit affects graphic motor plans, which specify the writing strokes for producing letters. Analyses of writing speed, fluency, and stroke patterns suggest that NGN's errors result from incomplete motor-plan activation. NGN's error rate is high for the first letter in a word, and declines across subsequent positions. On the basis of this serial position effect and other results, we propose that post-graphemic writing mechanisms include a graphomotor buffer, a writing-specific working memory that holds activated graphic motor plans bound to specific serial positions. We suggest that NGN's graphomotor buffer is damaged such that early serial positions are affected most severely. Finally, we present results speaking to the roles and capabilities of the graphomotor buffer, and the structure of graphic motor plans. PMID- 30452875 TI - Leukocyte Nucleus Reveals a Linear Order of Chromosomes Separated in Two Parental Genomes That Favors the Process of Gene Activation. AB - Analysis of trisomy 8 cells and the chromosome-specific fluorescence in situ hybridization (FISH) signals on the ring-shaped nucleus of a neutrophil reveal that homologue chromosomes orient in diametrical opposition to each other. This positioning results in a separation of the two haploid sets of parental chromosomes organized as two exclusive groups. These two groups impart the nucleus a symmetry that fortifies immune protection by accelerating chemotaxis. The ring form of the nucleus is a legacy of the orientation of chromosomes as a rosette during metaphase and telophase stages. A dual control maintains this spatial order: (1) chromosomes are tethered to the centriole all through the cell cycle, and (2) during their circular orientation in telophase the chromosomes bind to each other with lamins, which reorganize the nuclear membrane of the daughter nuclei, generating an additional anchorage. Here, chromosomes serve as temporary packets to assure proper distribution of the nuclear DNA during mitosis. The remainder time of the cell cycle the chromosomes are chained together across the telomeres, allowing a continuous sequence of genes of the two genomes, maternal and paternal, thus facilitating easy reading of the gene sequence. Exceptions to these orders are either physiological and temporary, or pathological and disease causing. PMID- 30452876 TI - Closing the Evidence Gap in Interstitial Lung Disease: The Promise of Real World Data. AB - The complexity of modern medicine generates an enormous number of clinical questions, resulting in an expanding evidence gap that cannot be addressed by traditional clinical trials alone. Simultaneously, today's health systems generate an unprecedented amount of routine health information, known as "real world data". Advances in computing power and analytical capabilities have recently made it possible to transform real world data into evidence. In turn, real world evidence can inform medical decision making, improve individual and population health, and transform the relationship between clinical medicine and research. The potential to leverage real world data to generate knowledge is well illustrated in the study of interstitial lung disease, a group of rare lung diseases that are challenging and expensive to evaluate in the context of traditional trials. Harnessing the power of large, heterogenous, real world data cohorts enables investigators to improve our understanding of disease and disease management by addressing questions related to longitudinal outcomes, treatment risks and effectiveness. In this Perspective we review 1) sources of real world data and the process for converting data into evidence for use in clinical research; 2) prior and current applications of real world data to advance clinical research, using the field of interstitial lung disease as an example and 3) the challenges and opportunities for future, widespread use of real world data in clinical research - specifically technical, operational and cultural issues. PMID- 30452877 TI - Proinflammatory Effects of Calprotectin in Graves' Orbitopathy. AB - PURPOSE: Early detection and control of inflammation are important to manage Graves' orbitopathy (GO). We investigated the effects of calprotectin (S100A8/A9) on orbital fibroblast inflammation and GO pathogenesis. METHODS: We measured serum calprotectin, S100A8 and S100A9 mRNA expression in orbital fat/connective tissue from GO patients and healthy controls, and proinflammatory cytokines in primary cultured orbital fibroblasts. RESULTS: The serum levels of S100A8/A9 and the expression of S100A8/A9 mRNA in orbital tissue were higher in the GO patients than in the healthy controls. The serum calprotectin levels positively correlated with the clinical activity score and serum thyroid-stimulating immunoglobulin levels. In cultured GO orbital fibroblasts, S100A8/A9 increased the expression of interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1, as well as the phosphorylation of extracellular signal-regulated kinase and nuclear factor kappaB. CONCLUSION: We demonstrated the potential of calprotectin as a biomarker of GO severity and proinflammatory responses to S100A8/A9 in GO orbital fibroblasts. PMID- 30452878 TI - Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the progression of diabetes. AB - Loss of functional beta-cell mass caused by lipotoxicity is a key pathogenic factor in the development of type 2 diabetes mellitus (T2DM). We have previously reported that sphingosine kinase (SK)1 is an endogenous protector of beta-cells against lipotoxicity. The current study reports that SK2, another isoform of SK, is a crucial mediator of lipotoxicity in beta-cells. Exposure of beta-cells to palmitatic acid (PA), a saturated free fatty acid, resulted in a nearly 2-fold increase in SK2 expression, which paralleled the induction of cell death in a similar dose- and time-dependent fashion. Silencing SK2 expression by its specific small interfering RNAs significantly inhibited PA-induced cell death and caspase-3 activation, whereas overexpression of SK2 promoted lipotoxicity in beta cells. Mechanistically, upon exposure to PA, endogenous SK2 was shuttled from the nucleus to the cytoplasm, where it interacted with B-cell lymphoma-extra-large (Bcl-xL), leading to mitochondrial apoptotic pathway activation and cell death. By blocking SK2 translocation and its interaction with Bcl-xL, either the nuclear export signal mutant (L423A/L425A) or the BH3 domain mutant (L219A) of SK2 significantly attenuated beta-cell lipotoxicity. Furthermore, SK2 deficiency in mice significantly prevented the loss of beta-cell mass, preserved insulin production, and ameliorated the diabetic phenotype in an established T2DM model induced by feeding a high-fat diet accompanied by administration of streptozotocin. These findings provide the first evidence, in vitro and in vivo, of a critical role for SK2 in mediating beta-cell lipotoxicity and the progression of diabetes.-Song, Z., Wang, W., Li, N., Yan, S., Rong, K., Lan, T., Xia, P. Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the progression of diabetes. PMID- 30452879 TI - Two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. AB - Colonization of the gut by certain probiotic Lactobacillus reuteri strains has been associated with reduced risk of inflammatory diseases and colorectal cancer. Previous studies pointed to a functional link between immunomodulation, histamine production, and folate metabolism, the central 1-carbon pathway for the transfer of methyl groups. Using mass spectrometry and NMR spectroscopy, we analyzed folate metabolites of L. reuteri strain 6475 and discovered that the bacterium produces a 2-carbon-transporting folate in the form of 5,10-ethenyl tetrahydrofolyl polyglutamate. Isotopic labeling permitted us to trace the source of the 2-carbon unit back to acetate of the culture medium. We show that the 2C folate cycle of L. reuteri is capable of transferring 2 carbon atoms to homocysteine to generate the unconventional amino acid ethionine, a known immunomodulator. When we treated monocytic THP-1 cells with ethionine, their transcription of TNF-alpha was inhibited and cell proliferation reduced. Mass spectrometry of THP-1 histones revealed incorporation of ethionine instead of methionine into proteins, a reduction of histone-methylation, and ethylation of histone lysine residues. Our findings suggest that the microbiome can expose the host to ethionine through a novel 2-carbon transporting variant of the folate cycle and modify human chromatin via ethylation.-Roth, D., Chiang, A. J., Hu, W., Gugiu, G. B., Morra, C. N., Versalovic, J., Kalkum, M. The two-carbon folate cycle of commensal Lactobacillus reuteri 6475 gives rise to immunomodulatory ethionine, a source for histone ethylation. PMID- 30452880 TI - Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca2+ signaling. AB - Reactive oxygen species (ROS) derived from NADPH oxidase (Nox) has been shown to activate ADP-ribosyl cyclase (ARC), which produces the Ca2+ mobilizing second messenger, cyclic ADP-ribose (cADPR). In the present study, we examined how ROS activates cluster of differentiation (CD)38, a mammalian prototype of ARC. CD38 exists in type II and III forms with opposing membrane orientation. This study showed the coexpression of type II and III CD38 in lymphokine-activated killer (LAK) cells. The catalytic site of the constitutively active type II CD38 faces the outside of the cell or the inside of early endosomes (EEs), whereas the basally inactive type III CD38 faces the cytosol. Type III CD38 interacted with Nox4/phosphorylated-p22phox (p-p22phox) in EEs of LAK cells upon IL-8 treatment. H2O2 derived from Nox4 activated type III CD38 by forming a disulfide bond between Cys164 and Cys177, resulting in increased cADPR formation. Our study identified the mechanism by which type III CD38 is activated in an immune cell (LAK), in which H2O2 generated by Nox4 oxidizes and activates type III CD38 to generate cADPR. These findings provide a novel model of cross-talk between ROS and Ca2+ signaling.-Park, D.-R., Nam, T.-S., Kim, Y.-W., Bae, Y. S., Kim, U.-H. Oxidative activation of type III CD38 by NADPH oxidase-derived hydrogen peroxide in Ca2+ signaling. PMID- 30452881 TI - Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1. AB - The unfolded protein response (UPR) is an adaptive signaling pathway activated in response to endoplasmic reticulum (ER) stress. The effectors of the UPR are potent transcription activators; however, some genes are suppressed by ER stress at the mRNA level. The mechanisms underlying UPR-mediated gene suppression are less known. Exploration of the effect of UPR on NK cells ligand expression found that the transcription of NK group 2 member D (NKG2D) ligand major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) is suppressed by the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway of the UPR. Deletion of IRE1 or XBP1 was sufficient to promote mRNA and surface levels of MICA. Accordingly, NKG2D played a greater role in the killing of IRE1/XBP1 knockout target cells. Analysis of effectors downstream to XBP1s identified E2F transcription factor 1 (E2F1) as linking UPR and MICA transcription. The inverse correlation between XBP1 and E2F1 or MICA expression was corroborated in RNA-Seq analysis of 470 primary melanoma tumors. While mechanisms that connect XBP1 to E2F1 are not fully understood, we implicate a few microRNA molecules that are modulated by ER stress and possess dual suppression of E2F1 and MICA. Because of the importance of E2F1 and MICA in cancer progression and recognition, these observations could be exploited for cancer therapy by manipulating the UPR in tumor cells.-Obiedat, A., Seidel, E., Mahameed, M., Berhani, O., Tsukerman, P., Voutetakis, K., Chatziioannou, A., McMahon, M., Avril, T., Chevet, E., Mandelboim, O., Tirosh, B. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1. PMID- 30452882 TI - JNK and ATF4 as two important platforms for tumor necrosis factor-alpha stimulated shedding of receptor for advanced glycation end products. AB - Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological regulation and underlying mechanisms are scarcely understood. In endothelium-specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF-alpha level. Treatment with TNF-alpha also significantly increased serum sRAGE. In human microvascular endothelial cells or human umbilical vein endothelial cells with RAGE overexpression, TNF-alpha markedly induced RAGE shedding, which was dependent on MMP9 and ADAM10. TNF-alpha-stimulated MMP9 expression was completely dependent on JNK activation, with its inhibition partially effective in suppressing TNF-alpha-induced RAGE shedding. In contrast, TNF-alpha transiently induced activation transcription factor (ATF)4, a major component in unfolded protein response (UPR), whereas knockdown of ATF4 abrogated TNF-alpha-stimulated RAGE shedding. Protein levels of the pro and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other components of UPR, including XBP1 and ATF6, failed to block TNF-alpha-stimulated RAGE shedding. Although the endoplasmic reticulum stressors thapsigargin and tunicamycin induced markedly and sustained expression of ATF4 and XBP-1, they did not induce RAGE shedding to the same level as TNF-alpha, suggesting that ATF4 is necessary but not sufficient alone for TNF-alpha-mediated RAGE shedding. ATF4 inhibition did not affect TNF-alpha-stimulated MMP9 expression, whereas inhibition of JNK activity did not influence ADAM10 activation. Thus, inflammatory cascades including TNF-alpha induced RAGE shedding in endothelial cells in vivo and in vitro. JNK and ATF4 may be 2 platforms for regulation of TNF-alpha-stimulated RAGE shedding.-Miyoshi, A., Koyama, S., Sasagawa-Monden, M., Kadoya, M., Konishi, K., Shoji, T., Inaba, M., Yamamoto, Y., Koyama, H. JNK and ATF4 as two important platforms for tumor necrosis factor-alpha-stimulated shedding of receptor for advanced glycation end products. PMID- 30452883 TI - Clozapine and shared care: the consumer experience. AB - Clozapine is a high-risk medication with restrictions that may increase consumer treatment burden. Shared care may improve access, reduce burden and promote primary care management. However, knowledge about the consumer experience of clozapine treatment within a shared-care setting has not been previously reported to the authors' knowledge. The aim of this study was to explore the consumer experience within the shared-care setting. This mixed-methods study examined consumers' experiences with a clozapine shared-care program in an urban setting in Queensland, Australia. Eligible consumers (n=35) participated in a semi structured interview, including a survey. Analysis was descriptive and thematic. Ten (28.6%) consumers participated. Survey results found a strong belief in the necessity for clozapine, with a low level of reported treatment burden and minimal adverse effects. Four themes were identified from the interviews: (i) understanding of illness and recovery; (ii) positive outcomes of treatment; (iii) acceptance of treatment burden; and (iv) communication pathways. Participants reported positive experiences in the clozapine shared-care program, citing clozapine's efficacy and the GP relationship as key benefits, however communication between clinicians and consumers must be enhanced to reduce risk of suboptimal treatment and adverse drug events. PMID- 30452884 TI - Calcium-mediated Protein Folding and Stabilization of Salmonella Biofilm associated Protein A. AB - Biofilm-associated proteins (BAPs) are important for early biofilm formation (adhesion) by bacteria and are also found in mature biofilms. BapA from Salmonella is a ~386-kDa surface protein, comprising 27 tandem repeats predicted to be bacterial Ig-like (BIg) domains. Such tandem repeats are conserved for BAPs across different bacterial species, but the function of these domains is not completely understood. In this work, we report the first study of the mechanical stability of the BapA protein. Using magnetic tweezers, we show that the folding of BapA BIg domains requires calcium binding and the folded domains have differential mechanical stabilities. Importantly, we identify that >100 nM concentration of calcium is needed for folding of the BIg domains, and the stability of the folded BIg domains is regulated by calcium over a wide concentration range from sub-micromolar (MUM) to millimolar (mM). Only at mM calcium concentrations, as found in the extracellular environment, do the BIg domains have the saturated mechanical stability. BapA has been suggested to be involved in Salmonella invasion, and it is likely a crucial mechanical component of biofilms. Therefore, our results provide new insights into the potential roles of BapA as a structural maintenance component of Salmonella biofilm and also Salmonella invasion. PMID- 30452885 TI - Smoking and Solid Organ Transplantation: A review article highlighting the effects of smoking on solid organ transplantation outcomes. AB - Tobacco smoking is the leading preventable cause of death worldwide. Both donor and recipient smoking have been shown to increase graft loss and mortality in solid organ transplant recipients in many studies. Only in lung transplants is smoking a universal contraindication to transplantation. Transplant centers implement different policies regarding smoking recipients and allografts from smoking donors. Due to scarcity of available allografts the risks of smoking have to be weighed against the risks of a longer transplant wait list period. Although transplant centers implement different strategies to encourage smoking cessation pre and post-transplant, not many studies have been published that validate the efficacy of smoking cessation interventions in this vulnerable population. This article summarizes the results of studies investigating the prevalence, impact on outcomes and cessation interventions of smoking in the transplant population. We report herein a review of the elevated risks of infection, malignancy, graft loss, cardiovascular events and mortality in solid organ transplant populations. PMID- 30452886 TI - The Rise of Documentation and the Destruction of Modern Medicine. PMID- 30452887 TI - Top-cited articles in The American Journal of Obstetrics & Gynecology: a bibliometric analysis. AB - BACKGROUND: The American Journal of Obstetrics and Gynecology (AJOG) has had a profound influence in nearly 150 years of publishing. A bibliometric analysis, which uses citation analysis to evaluate the impact of articles, can be used to identify the most impactful papers in AJOG's history. OBJECTIVE: The objective was to identify and characterize the top-cited articles published in AJOG since 1920. STUDY DESIGN: We used the Web of Science and Scopus databases to identify the most frequently cited AJOG articles from 1920-2018. The top 100 articles from each database were included in our analysis. Articles were evaluated for several characteristics including year of publication, article type, topic, open access, and country of origin. Using the Scopus data, we performed an unadjusted categorical analysis to characterize the articles and a two time point analysis to compare articles before and after 1995, the median year of publication from each database list. RESULTS: The top 100 articles from each database were included in the analysis. This includes 120 total articles; 80 articles listed in both and 20 unique in each database. Over half (52%) were observational studies, 9% were RCTs, and 75% were from US authors. When the post-1995 studies were compared to the articles published before 1995, articles were more frequently cited (median 27 versus 13 citations per year, P <0.001), more likely to be randomized (14.0% versus 4.8%, P=0.009) and more likely to originate from international authors (33.3% versus 17.5%, P=0.045). CONCLUSIONS: Slightly more than half of the top-cited papers in AJOG since 1920 were observational studies and three-quarters of all papers were from US authors. Compared to top-cited papers before 1995, the Journal's top-cited papers after 1995 were more likely to be randomized and to originate from international authors. PMID- 30452888 TI - Small molecule inhibition of dipeptidyl peptidase-4 enhances bone marrow progenitor cell function and angiogenesis in diabetic wounds. AB - In diabetes, stromal cell-derived factor-1 (SDF-1) expression and progenitor cell recruitment are reduced. Dipeptidyl peptidase-4 (DPP-4) inhibits SDF-1 expression and progenitor cell recruitment. Here we examined the impact of the DPP-4 inhibitor, MK0626, on progenitor cell kinetics in the context of wound healing. Wildtype (WT) murine fibroblasts cultured under high-glucose to reproduce a diabetic microenvironment were exposed to MK0626, glipizide, or no treatment, and SDF-1 expression was measured with ELISA. Diabetic mice received MK0626, glipizide, or no treatment for 6 weeks and then were wounded. Immunohistochemistry was used to quantify neovascularization and SDF-1 expression. Gene expression was measured at the RNA and protein level using quantitative polymerase chain reaction and ELISA, respectively. Flow cytometry was used to characterize bone marrow-derived mesenchymal progenitor cell (BM-MPC) population recruitment to wounds. BM-MPC gene expression was assayed using microfluidic single cell analysis. WT murine fibroblasts exposed to MK0626 demonstrated increased SDF-1 expression. MK0626 treatment significantly accelerated wound healing and increased wound vascularity, SDF-1 expression, and dermal thickness in diabetic wounds. MK0626 treatment increased the number of BM MPCs present in bone marrow and in diabetic wounds. MK0626 had no effect on BM MPC population dynamics. BM-MPCs harvested from MK0626-treated mice exhibited increased chemotaxis in response to SDF-1 when compared to diabetic controls. Treatment with a DPP-4 inhibitor significantly improved wound healing, angiogenesis, and endogenous progenitor cell recruitment in the setting of diabetes. PMID- 30452889 TI - Association of polymorphisms in serotonin and nitric oxide genes with clinical outcome of dengue in Brazilian northeast population. AB - Serotonin and nitric oxide seem to be involved in Dengue virus infection. The aim of this study was to investigate if SNPs in serotonin and nitric oxide are associated with dengue severity. A retrospective case-control study was conducted, with groups of dengue fever (DF; n = 78) and dengue hemorrhagic fever patients (DHF; n = 49). Genotyping was performed using qPCR and PCR. The power of the sample size was calculated by G*power software. The heterozygous SL for 5 HTTLPR SNP was significantly correlated with protection against progression to DHF in the codominant SS/SL/LL (OR = 0.22, 95% CI = 0.06-0.81, p = 0.011) and overdominant models SL vs SS + LL (OR = 0.19, 95% CI = 0.06-0.65, p = 0.003). For the ENOS (rs1799983) SNP, the genotype GT was positively associated with protection for development of the clinical form in DHF compared to dengue fever (OR = 0.39, 95% CI = (0.13-1.14), p = 0.0058) in codominant GG/GT/TT and overdominant model GT vs GG + TT (OR = 0.35, 95% CI = (0.12-1.02), p = 0.04). To our knowledge, this is the first study to identify the association of the serotonin and nitric oxide SNPs with dengue severity. PMID- 30452890 TI - Tuberculosis evolution and climate change: How much work is ahead? PMID- 30452891 TI - Do ratings of swallowing function differ by videofluoroscopic rate? An exploratory analysis in patients after acute stroke. AB - OBJECTIVE: To determine differences between continuous videofluoroscopic swallow studies (VFSS) with a pulse rate and frame rate of 30 and the same swallows reduced to 15 frames per second (fps) on measures of swallowing function in patients after acute ischemic stroke. DESIGN: Blinded comparison. SETTING: Acute hospital. PARTICIPANTS: 20 patients after ischemic stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Single and sequential sips of thin liquids, single sips of nectar liquids, pudding, and cookie boluses were rated on measures of timing of swallowing events, Modified Barium Swallowing Impairment Profile component scores, and Penetration-Aspiration Scale scores. The ratings for videos at 15 fps and 30 fps were compared by Wilcoxon signed rank tests. RESULTS: Pharyngeal transit time was longer and bolus entry into the hypopharynx was later for 30 fps than for 15 fps. Components of Oral Residue and Pharyngoesophageal Segment Opening ratings were more severe for 15fps than 30 fps, whereas Bolus Transport and Initiation of Pharyngeal Swallow were rated as more severe for 30 fps than for 15 fps. There was no difference between 30 fps and 15 fps on the remaining measures, including Penetration-Aspiration Scale scores. CONCLUSION: Continuous VFSS recorded at 30fps and their down-sampled 15 fps duplicates yielded contrasting results on certain durational and functional measures of swallowing, though not on others. VFSS should be administered continuously or at 30 pulses per second for valid assessment of swallowing while using other methods to reduce radiation exposure. PMID- 30452892 TI - Effect of Transcutaneous Electrical Nerve Stimulation (TENS) on spasticity in adults with stroke: A systematic review and meta-analysis. AB - OBJECTIVES: 1. To determine the effect of transcutaneous electrical nerve stimulation (TENS) on post-stroke spasticity. 2a. To determine the effect of different parameters (intensity, frequency, and duration) of TENS on spasticity reduction in adults with stroke; 2b. To determine the influence of time since stroke on the effectiveness of TENS on spasticity. DATA SOURCES: PubMed, PEDro, CINAHL, Web of Science, CENTRAL and EMBASE databases were searched from inception to March 2017. STUDY SELECTION: Randomized controlled trial (RCT), quasi RCT and non-RCT were included if: (a) they evaluated the effects of TENS for the management of spasticity in participants with acute/sub-acute/chronic stroke using clinical and neurophysiological tools; and (b) TENS was delivered either alone or as an adjunct to other treatments. DATA EXTRACTION: Two authors independently screened and extracted data from 15 of the 829 studies retrieved through the search using a pilot tested pro-forma. Disagreements were resolved through discussion with other authors. Quality of studies was assessed using Cochrane risk of bias criteria. DATA SYNTHESIS: Meta-analysis was performed using a random-effects model which showed (a) TENS along with other physical therapy treatments was more effective in reducing spasticity in the lower limbs compared to placebo TENS (SMD -0.64, 95% CI -0.98 to -0.31; p = 0.0001; I2 =17%); and (b) TENS, when administered along with other physical therapy treatments, was effective in reducing spasticity when compared to other physical therapy interventions alone (SMD -0.83, 95% CI -1.51 to -0.15; p =0.02; I2 = 27%). There were limited studies to evaluate the effectiveness of TENS for upper limb spasticity. CONCLUSION: There is strong evidence that TENS as an adjunct is effective in reducing lower limb spasticity when applied for more than 30 minutes over nerve or muscle belly in chronic stroke survivors. (Review protocol registered at PROSPERO: CRD42015020151). PMID- 30452893 TI - Label-free drug screening assay multiplexed with an orthogonal time-resolved fluorescence labeled assay. AB - Cell-based assays against cell surface receptor targets are essential in vitro models of target-based drug discovery. At the lead generation phase large-scale functional screening assays monitoring individual cellular readouts detect interactions between the compounds and the predefined pathways but might lack sufficient sensitivity owing to the complexity of downstream signaling pathways. Cellular label-free assays offer advantages over labeled detection approaches as they reflect whole-cell responses without the prerequisite of detecting only a single cellular analyte and introducing additional genetic manipulations in favor of the chosen detection method. The combination of a label-free assay and labeled assays might integrate the advantageous characteristics of both approaches with regards to added pharmacological information and a bigger pool of chemical starting material. Here we report multiplexing of dynamic mass redistribution label-free technology with HTRF-based cAMP detection on an alpha2c adrenergic receptor expressing cell line. Besides describing the challenging assay development work associated with the set goal, a pilot screening campaign on ca. 1600 compounds is also presented. The combined assay demonstrated the ability to detect relevant activities in both readouts. Interpretation of the results as well as an outlook for further possible opportunities and applications are also discussed. PMID- 30452894 TI - Bm-iAANAT3: Expression and characterization of a novel arylalkylamine N acyltransferase from Bombyx mori. AB - The arylalkylamine N-acyltransferases (AANATs) are enzymes that catalyze the acyl CoA-dependent formation of N-acylarylalkylamides: acyl-CoA + arylalkylamine -> N acylarylalkylamides + CoA-SH. Herein, we describe our study of a previously uncharacterized AANAT from Bombyx mori: Bm-iAANAT3. Bm-iAANAT3 catalyzes the direct formation of N-acylarylalkylamides and accepts a broad range of short chain acyl-CoA thioesters and amines as substrates. Acyl-CoA thioesters possessing an acyl chain length >10 carbon atoms are not substrates for Bm iAANAT3. We report that Bm-iAANAT3 is a "versatile generalist", most likely, functioning in amine acetylation - a reaction in amine inactivation/excretion, cuticle sclerotization, and melanism. We propose a kinetic and chemical mechanism for Bm-iAANAT3 that is consistent with our steady-state kinetic analysis, dead end inhibition studies, determination of the pH-rate profiles, and site-directed mutagenesis of a catalytically important amino acid in Bm-iAANAT3. These mechanistic studies of Bm-iAANAT3 will foster the development of novel compounds targeted against this enzyme and other insect AANATs for the control of insect pests. PMID- 30452895 TI - Mitochondrial dysfunction induces muscle atrophy during prolonged inactivity: A review of the causes and effects. AB - Prolonged skeletal muscle inactivity (e.g. limb immobilization, bed rest, mechanical ventilation, spinal cord injury, etc.) results in muscle atrophy that manifests into a decreased quality of life and in select patient populations, a higher risk of morbidity and mortality. Thus, understanding the processes that contribute to muscle atrophy during prolonged periods of muscle disuse is an important area of research. In this regard, mitochondrial dysfunction has been directly linked to the muscle wasting that occurs during extended periods of skeletal muscle inactivity. While the concept that mitochondrial dysfunction contributes to disuse muscle atrophy has been contemplated for nearly 50 years, the mechanisms connecting mitochondrial signaling events to skeletal muscle atrophy remained largely unexplained until recently. Indeed, emerging evidence reveals that mitochondrial dysfunction and the associated mitochondrial signaling events are a requirement for several forms of inactivity-induced skeletal muscle atrophy. Specifically, inactivity-induced alterations in skeletal muscle mitochondria phenotype and increased ROS emission, impaired Ca2+ handling, and release of mitochondria-specific proteolytic activators are established occurrences that promote fiber atrophy during prolonged periods of muscle inactivity. This review highlights the evidence that directly connects mitochondrial dysfunction and aberrant mitochondrial signaling with skeletal muscle atrophy and discusses the mechanisms linking these interconnected phenomena. PMID- 30452896 TI - Characterization of a new member of kunitz-type protein family from the venom of Persian false-horned viper, Pseudocerastes persicus. AB - A new member of kunitz-type protein family, PPTI (PseudocerastesPersicusTrypsin Inhibitor), was isolated from the venom of Persian false horned viper Pseudocerastes persicus and characterized. Mass spectrometry and amino acid sequencing revealed that PPTI is a 68 amino acid protein with molecular weight of about 7.6 kDa. The first amino acid residue of PPTI is N-terminally blocked via a post translational modification to pyroglutamyl. Sequence comparison against UniProtKB shows a high sequence similarity of PPTI with kunitz-type proteins, especially serine protease inhibitors and dendrotoxins (DTXs). The number of cysteines and disulfide bonding pattern of PPTI are the same as kunitz-type proteins. Based on sequence derive information, anti-protease activity of PPTI against trypsin was experimentally examined. The constructed homology models of PPTI confirmed the ability of PPTI to fold similarly to kunitz domain. The presence of characteristic basic-hydrophobic functional dyad of DTXs in PPTI supports its inhibitory potential against potassium channels. In summary, this study hypothesized the dual functionality of PPTI according to its inhibitory effect on trypsin and its potential ability in blocking potassium channel. PMID- 30452897 TI - Dkk1 involvement and its potential as a biomarker in pancreatic ductal adenocarcinoma. AB - Dickkopf-1 (Dkk1)'s dysregulation has been implicated in the pathogenesis of a variety of cancers. It is part of the Dkk family of proteins that includes Dkk2, Dkk3 and Dkk4. This family of secreted proteins shares similar conserved cysteine domains and inhibits the Wnt/b-catenin pathway by causing proteasomal B-catenin degradation, inducing apoptosis, and preventing cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer mortality in the United States due to the late stage of diagnosis and the limited effectiveness of current therapy. Dkk1 is found increased in PADC patients' specimens and serum. Dkk1 can be a promising biomarker specific to PDAC, which has the potential to increase PDAC survival rates through improving early stage detection and monitoring progression compared to current biomarker gold standards. In addition, recent studies suggest that Dkk1 could be an excellent target for cancer immunotherapy. Interestingly, Dkk1-CKAP4-PI3K/AKT signal pathway also plays role in pancreatic cancer cell proliferation. In this review, we present the multiple mechanisms of Dkk1 in PDAC studied thus far and explore its function, regulation, and clinical applications in gynecological cancers including pancreatic ductal adenocarcinoma (PDAC), breast, ovarian, cervical, and endometrial cancer. Further research into Dkk1's mechanism and use as a diagnostic tool, alone or in combination with other biomarkers, could prove clinically useful for better understanding the pathology of PDAC and improving its early detection and treatment. PMID- 30452898 TI - Omeprazole protects against cisplatin-induced nephrotoxicity by alleviating oxidative stress, inflammation, and transporter-mediated cisplatin accumulation in rats and HK-2 cells. AB - The present study assessed the therapeutic potential of omeprazole (OME), the most commonly prescribed proton pump inhibitor (PPI) used to treat gastroesophageal hyperacidity, against cisplatin (CP)-induced toxicity in human renal tubular HK-2 cells and rat kidneys. Herein, we observed that exposure of HK 2 cells to OME reversed the injury caused by CP, including enhancing cell viability and alleviating intracellular reactive oxygen species (ROS) generation and membrane damage. Concomitantly, acute exposure of male SD rats to CP induced histopathological changes, which were prevented by co-administration with OME. Inflammation and oxidative stress were inhibited by OME during CP-induced renal injury by increasing the activity of superoxide dismutase, and reducing the levels of malondialdehyde, both in vivo and in vitro. The expression levels of major inflammatory response markers were significantly decreased in HK-2 cells and rat kidneys in response to OME. OME reduced CP cellular uptake through organic cation transporters 2 (OCT2) and the prompt efflux of CP by P glycoprotein (P-gp), thereby reducing the accumulation of CP in kidney tissue and increasing its serum levels. These data demonstrate that CP-induced kidney damage is positively correlated with its cellular accumulation. Concurrently, OME showed renoprotective effect against CP-induced toxicity in HK-2 cells and rat kidneys, by suppressing oxidative stress and mediating NF-kappaB-dependent inflammation, apoptosis, and transporter function. As OME is commonly used in combination with CP during chemotherapy treatment, this study highlights the clinical significance of OME in alleviating CP-induced nephrotoxicity. PMID- 30452899 TI - Oenothein B inhibits human non-small cell lung cancer A549 cell proliferation by ROS-mediated PI3K/Akt/NF-kappaB signaling pathway. AB - Oenothein B has a wide range of biological activities. The present study probed into the underlying mechanism on how Oenothein B inhibits the proliferation of a lung cancer line A549. Our results showed that Oenothein B effectively inhibited the proliferation of A549 cells by inducing apoptosis and arresting cells at G1 stage. Furthermore, Oenothein B not only increased the level of intracellular reactive oxygen species (ROS), but also induced the upregulation of intracellular apoptotic triggers (cleavage caspase-3, PARP, cytochrome c level in the cytosol, Bax). Moreover, ROS inhibitor (N-acetyl-L-cystein, NAC) and PI3K agonist (Insulin like growth factor 1, IGF-1) could resist cell proliferation inhibition induced by Oenothein B, respectively. ROS inhibitor significantly abrogated the activation of caspase 3/7 and 9 in the presence of Oenothein B. Additionally, suppression of p-PI3K and p-Akt, p-NF-kappaB by Oenothein B could be compensated by treatment with ROS inhibitor. To summarize, these results demonstrated that Oenothein B was able to prevent cell proliferation probably via ROS-mediated PI3K/Akt/NF-kappaB signaling pathway. PMID- 30452900 TI - Antidepressant agomelatine attenuates behavioral deficits and concomitant pathology observed in streptozotocin-induced model of Alzheimer's disease in male rats. AB - Experimental findings suggest that the melatonin system has a beneficial role in models of Alzheimer's disease (ADs). The aim of the present study was to explore whether the atypical antidepressant agomelatine (Ago), which is a melatonin MT1 and MT2 agonist and 5-HT2C antagonist, is effective against behavioral, biochemical and histological impairments in streptozotocin (STZ)-induced model of ADs in male rats. Male Sprague Dawley rats were treated intraperitoneally (i.p.) with Ago (40 mg/kg) for 30 days starting three months following the intracerebroventricular (icv) injection of STZ. Chronic Ago treatment reduced anxiety-like behavior of STZ-treated rats in the elevated plus maze, increased the preference to saccharine and corrected the spatial memory impairment in the eight-arm radial arm maze test. This melatonin analogue restored STZ-induced biochemical changes, including an increase of beta amyloid (Abeta) protein, and signal markers of inflammation (TNF-alpha and IL-1 beta). Ago exerted partial neuroprotection, specifically in the temporal CA3b subfield of the dorsal hippocampus and temporal piriform cortex. The ability of Ago to alleviate behavioral symptoms and concomitant neuropathological events observed in a model of sporadic ADs suggests that this melatonin alternative can be considered a promising adjuvant in this disease. PMID- 30452901 TI - Updates in diagnostic and clinical laboratory immunology from the 30th annual meeting of the Association of Medical Laboratory Immunologists (AMLI). PMID- 30452902 TI - Developmental stress reduces body condition across avian life-history stages: A comparison of quantitative magnetic resonance data and condition indices. AB - Animals exposed to stressful developmental conditions can experience sustained physiological, behavioral, and fitness effects. While extensive research shows how developmental stress affects development, few studies have examined the effects on body composition. To test the effects of developmental stress on nestling and adult body composition, we dosed nestling zebra finches (Taeniopygia guttata) with either a corticosterone (CORT) or control treatment. We calculated condition indices (scaled mass, residual mass, and ratio indices) from morphometric measurements and used quantitative magnetic resonance (QMR) to assess body composition during early development and adulthood. We compared these three traditionally-used condition indices to QMR-derived body composition measurements, to test how well they predict relative fat mass. Our results show that developmental stress decreases body mass, and has a dose-dependent effect on tarsus length in nestling birds. Furthermore, stress treatment during the nestling period had long-lasting effects on adult body mass, lean mass and tarsus length. None of the three condition indices were good indicators of relative fat mass in nestlings, but all indices were closely associated with relative fat mass in adults. The scaled mass index was more closely associated with relative fat mass than the other condition indices, when calculated from wing chord length in nestlings. In adults however, the residual mass index and the ratio index were better indicators of relative body fat than the scaled mass index, when calculated from tarsus length. Our data demonstrate the short and long-term impact of developmental stress on birds, and highlight important age-related factors to consider when using condition indices. PMID- 30452903 TI - The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. AB - Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by the prolyl 3- (C-P3H) and prolyl 4- (C-P4H) hydroxylases is essential for normal cell function. Here we have investigated the expression, transcriptional regulation and function of the C-P3H and C-P4H families in melanoma. We show that the CP3H family exemplified by Leprel1 and Leprel2 are subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumour suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a sub-set of melanomas, the CP4H family members P4HA1, P4HA2 and P4HA3 are often over expressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumour suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation and particularly invasiveness of melanoma cells. Pharmacological inhibition with multiple selective C-P4H inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the C-P3H and C-P4H families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of C-P4H is an attractive strategy to reduce the invasive properties of melanoma cells. PMID- 30452904 TI - Impact of training level on Postplacental Levonorgestrel 52mg intrauterine device expulsion. AB - OBJECTIVE: To determine the association between provider training level and postplacental intrauterine device (IUD) outcomes following insertion instruction by email only. STUDY DESIGN: We conducted a single-center chart review of demographics, insertion, and clinical outcomes within six months of delivery for 116 patients who underwent postplacental levonorgestrel 52mg IUD placement from October 1, 2016 to March 31, 2017. RESULTS: We confirmed IUD retention, removal, or expulsion in 87 of 116 (75.0%) patients by six months after delivery. Complete expulsion or removal for malposition occurred in 20 (23.0%) patients and more frequently after vaginal than cesarean delivery (30.2% vs. 4.2%, OR 9.93 [95% CI 1.25-78.96]) and when a Postgraduate Year (PGY) 1 physician placed the IUD compared to a PGY 2-4 or attending physician (37.5% vs. 14.5%, OR 3.52 [95% CI 1.25-9.94)). CONCLUSION: Postplacental levonorgestrel 52mg IUD expulsion rates are associated with provider training level as well as delivery route, though the individual association of each of these factors is difficult to ascertain given the high degree of collinearity between these two variables in our study. PMID- 30452905 TI - Genetic ablation of Gpr37l1 delays tumor occurrence in Ptch1+/- mouse models of medulloblastoma. AB - The G-protein coupled receptor 37-like 1 (Gpr37l1) is specifically expressed in most astrocytic glial cells, including cerebellar Bergmann astrocytes and interacts with patched 1 (Ptch1), a co-receptor of the sonic hedgehog (Shh) smoothened (Smo) signaling complex. Gpr37l1 null mutant mice exhibit precocious post-natal cerebellar development, with altered Shh-Smo mitogenic cascade and premature down-regulation of granule cell precursor (GCP) proliferation. Gpr37l1 expression is downregulated in medulloblastoma (MB) and upregulated in glioma and glioblastoma tumors. Shh-associated MBs originate postnatally, from dysregulated hyperproliferation of GCPs in developing cerebellum's external granular layer (EGL), as shown in heterozygous Ptch1+/- knock-out mouse strains that model human MB occurrence and progression. This study investigates cerebellar MB phenotypes in newly produced Gpr37l1, Ptch1 double mutant mice. Natural history analysis shows that Gpr37l1 genetic ablation, in Ptch1+/- model animals, results in marked deferment of post-natal tumor occurrence and decreased incidence of more aggressive tumor types. It is also associated with the delayed and diminished presence of more severe types of hyperplastic lesions in Ptch1+/- mice. Consistently, during early post-natal development Gpr37l1-/-;Ptch1+/- pups exhibit reduction in cerebellar GCP proliferation and EGL thickness and a precocious, sustained expression of wingless-type MMTV integration site member 3 (Wnt3), a specific inhibitor of Shh-induced neuronal mitogenesis, in comparison with Ptch1+/- heterozygous single mutants. These findings highlight the specific involvement of Gpr37l1 in modulating postnatal cerebellar Shh-Ptch1-Smo mitogenic signaling in both normal and pathological conditions. The novel Gpr37l1-/ ;Ptch1+/- mouse models may thus be instrumental in the detailed characterization of the initial phases of Shh-associated MB insurgence and development. PMID- 30452906 TI - Flotillins in the intercalated disc are potential modulators of cardiac excitability. AB - BACKGROUND: The intercalated disc (ID) is important for cardiac remodeling and has become a subject of intensive research efforts. However, as yet the composition of the ID has still not been conclusively resolved and the role of many proteins identified in the ID, like Flotillin-2, is often unknown. The Flotillin proteins are known to be involved in the stabilization of cadherins and desmosomes in the epidermis and upon cancer development. However, their role in the heart has so far not been investigated. Therefore, in this study, we aimed at identifying the role of Flotillin-1 and Flotillin-2 in the cardiac ID. METHODS: Location of Flotillins in human and murine cardiac tissue was evaluated by fluorescent immunolabeling and co-immunoprecipitation. In addition, the effect of Flotillin knockout (KO) on proteins of the ID and in electrical excitation and conduction was investigated in cardiac samples of wildtype (WT), Flotillin-1 KO, Flotilin-2 KO and Flotilin-1/2 double KO mice. Consequences of Flotillin knockdown (KD) on cardiac function were studied (patch clamp and Multi Electrode Array (MEA)) in neonatal rat cardiomyocytes (NRCMs) transfected with siRNAs against Flotillin-1 and/or Flotillin-2. RESULTS: First, we confirmed presence in the ID and mutual binding of Flotillin-1 and Flotillin-2 in murine and human cardiac tissue. Flotillin KO mice did not show cardiac fibrosis, nor hypertrophy or changes in expression of the desmosomal ID proteins. However, protein expression of the cardiac sodium channel NaV1.5 was significantly decreased in Flotillin-1 and Flotillin-1/2 KO mice compared to WT mice. In addition, sodium current density showed a significant decrease upon Flotillin-1/2 KD in NRCMs as compared to scrambled siRNA-transfected NRCMs. MEA recordings of Flotillin-2 KD NRCM cultures showed a significantly decreased spike amplitude and a tendency of a reduced spike slope when compared to control and scrambled siRNA-transfected cultures. CONCLUSIONS: In this study, we demonstrate the presence of Flotillin-1, in addition to Flotillin-2 in the cardiac ID. Our findings indicate a modulatory role of Flotillins on NaV1.5 expression at the ID, with potential consequences for cardiac excitation. PMID- 30452907 TI - Comparison of different chemically modified inhibitors of miR-199b in vivo. AB - MicroRNAs (miRNAs) have recently received great attention for their regulatory roles in diverse cellular processes and for their contribution to several human pathologies. Modulation of miRNAs in vivo provides beneficial therapeutic strategies for the treatment of many diseases, as evidenced by various preclinical studies. However, specific issues regarding the in vivo use of miRNA inhibitors (antimiRs) such as organ-specific delivery, optimal dosing and formulation of the best chemistry to obtain efficient miRNA inhibition remain to be addressed. Here, we aimed at comparing the in vivo efficacy of different chemistry-based antimiR oligonucleotides to inhibit cardiac expression of miR 199b, a highly promising therapeutic target for the treatment of pressure overload-induced cardiac dysfunction. For this purpose, four different designs of oligonucleotides to inhibit miR-199b were initially developed. Systemic administration to wildtype mice on three consecutive days was followed by organ harvesting, seven days after the first injection, in order to quantify the dose dependent changes in miR-199b expression levels. When comparing the efficiency of each inhibitor at the highest applied dose we observed that the antagomir was the only inhibitor inducing complete inhibition of miR-199b in the heart. LNA reduced expression in the heart by 50 percent while the Zen-AMO and F/MOE chemistries failed to repress miR-199b expression in the heart at any given dose, in vivo. Further optimization was achieved by subjecting the antagomir and LNA nucleotides to additional chemical modifications. Interestingly, antagomir modification by replacing the cholesterol moiety from the 3' to the 5' end of the molecule significantly improved the inhibitory capacity, as reflected by a 75 percent downregulation of miR-199b expression already at a concentration of 5 mg/kg/day. Similar results could be obtained with a LNA-RNA molecule but upon administration of 80 mg/kg/day. These findings show that, from all the chemistries tested by us, an antagomir carrying the cholesterol group at the 5' end was the most efficient inhibitor of miR-199b in the heart, in vivo. Moreover, our data also emphasize the importance of chemistry optimization and best dose range finding to achieve the greatest efficacy in miRNA inhibition in vivo. PMID- 30452908 TI - The roles of ubiquitination in extrinsic cell death pathways and its implications for therapeutics. AB - Regulation of cell survival and death, including apoptosis and necroptosis, is important for normal development and tissue homeostasis, and disruption of these processes can cause cancer, inflammatory diseases, and degenerative diseases. Ubiquitination is a cellular process that induces proteasomal degradation by covalently attaching ubiquitin to the substrate protein. In addition to proteolytic ubiquitination, nonproteolytic ubiquitination, such as M1-linked and K63-linked ubiquitination, has been shown to be important in recent studies, which have demonstrated its function in cell signaling pathways that regulate inflammation and cell death pathways. In this review, we summarize the TRAIL- and TNF-induced death receptor signaling pathways along with recent advances in this field and illustrate how different types of ubiquitination control cell death and survival. In particular, we provide an overview of the different types of ubiquitination, target residues, and modifying enzymes, including E3 ligases and deubiquitinating enzymes. Given the relevance of these regulatory pathways in human disease, we hope that a better understanding of the regulatory mechanisms of cell death pathways will provide insights into and therapeutic strategies for related diseases. PMID- 30452909 TI - Vildagliptin reduced extracellular matrix degradation in human primary chondrocytes. AB - In the present study, we investigated the effects of the specific DPP-4 inhibitor vildagliptin on degradation of type II collagen and aggrecan, the main components of the articular extracellular matrix, in primary human chondrocytes. The results of our study reveal that vildagliptin reduced degradation of the articular extracellular matrix (ECM) by downregulating IL-1beta-induced expression of matrix metalloproteinases-3 (MMP-3), matrix metalloproteinases-13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). We also found that vildagliptin ameliorated IL-1beta-induced activation of the JNK/AP-1 and nuclear factor-kappaB (NF-kappaB) pro-inflammatory signaling pathways by downregulating phosphorylation of JNK and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaBalpha), activation of c-Fos/c-Jun, and nuclear translocation of p65. Our findings suggest that vildagliptin may serve as a novel treatment for excessive degradation of the articular ECM in osteoarthritis (OA). PMID- 30452910 TI - Galectins as potential emerging key targets in different types of leukemia. AB - Galectins are carbohydrate-binding proteins and these have very high affinity for beta-galactoside containing glycoproteins and glycolipids. Amongst sixteen types of galectin, the role of galectin 1, 3, 9 and 12 is defined in the development and progression of different types of leukemia including acute myeloid leukemia, acute promyelocytic leukemia, B-cell precursor acute lymphoblastic leukemia, adult T cell leukemia and chronic lymphocytic leukemia. There are multiple mechanisms through which these galectins may affect tumor proliferation. These may include increased production of tumor resistance conferring proteins such as multidrug resistance (MDR-1) and myeloid cell leukemia (MCL-1). Moreover, galectin-9 may act on Tim-3 receptors present on the circulating CD8+ T cells to impair immune system function and the latter provide an ideal environment for the proliferation of leukemic cells. The present review describes the role and mechanisms involved in galectin-mediated development and progression of different types of leukemia. PMID- 30452911 TI - Differences among muscarinic agonists in M1 receptor-mediated nonselective cation channel activation and TASK1 channel inhibition in adrenal medullary cells. AB - Muscarinic receptor stimulation induces depolarizing inward currents and catecholamine secretion in adrenal medullary (AM) cells from various mammals. In guinea-pig AM cells muscarine and oxotremorine at concentrations <= 1 MUM produce activation of nonselective cation channels with a similar potency and efficacy, whereas muscarine at higher concentrations produces not only nonselective cation channel activation, but also TASK1 channel inhibition. In rat AM cells, the muscarinic M1 receptor is involved in TASK1 channel inhibition in response to muscarinic agonists, and the efficacy of oxotremorine is half that of muscarine. These pharmacological findings might indicate that different muscarinic receptor subtypes are responsible for the regulation of nonselective cation and TASK1 channel activities. The present study aimed to determine the muscarinic receptor subtypes involved in nonselective cation channel activation in guinea-pig and mouse AM cells. The inward current evoked by 1 MUM muscarine was completely suppressed by 100 MUM quinine, whereas 30 MUM muscarine-induced inward currents were comprised of quinine-sensitive and -insensitive components. The electrophysiological and pharmacological properties of the muscarine-induced currents indicated that the quinine-sensitive and insensitive components are due to nonselective cation channel activation and TASK1 channel inhibition, respectively. Muscarine at 30 MUM failed to induce any current in AM cells treated with muscarinic toxin 7 or genetically deleted of the M1 receptor. The KD value of VU0255035 against the muscarinic receptor mediating nonselective cation channel activation was 17.5 nM. These results indicate that the M1 receptor mediates nonselective cation channel activation as well as TASK1 channel inhibition. PMID- 30452912 TI - Elevated lipolysis in adipose tissue by doxorubicin via PPARalpha activation associated with hepatic steatosis and insulin resistance. AB - Adipose dysfunction is tightly associated with hepatic insulin resistance and steatosis condition. Doxorubicin would disturb the lipid metabolism both in adipose and liver. Here we projected that doxorubicin would impede lipogenesis and elevated lipolysis in adipose tissue would elevate the circulatory lipid profile and leads to insulin resistance. Further exacerbated lipid profile in circulation would impair the lipid metabolism in hepatic tissue which leads to fatty liver condition and consequently related disease during doxorubicin treatment. Doxorubicin impairs the lipogenesis through PPARgamma and augments lipolysis and fatty acid oxidation through ATGL and PPARalpha in adipose tissue. Increased fatty acid level by adipose tissue in circulation would translocate into the liver and dysregulates AHR, PXR, PPARgamma, ATGL and Apo B,which further develop insulin resistance and hepatic steatosis condition. The findings add to the mechanistic role of association between adipose tissue dysfunction and hepatic dysfunction. PMID- 30452913 TI - Application of convolutional neural network in the diagnosis of the invasion depth of gastric cancer based on conventional endoscopy. AB - BACKGROUND AND AIMS: According to guidelines, endoscopic resection should only be performed for patients whose early gastric cancer invasion depth is within the mucosa or submucosa of the stomach regardless of lymph node involvement. The accurate prediction of invasion depth based on endoscopic images is crucial for screening patients for endoscopic resection. We constructed a convolutional neural network computer-aided detection (CNN-CAD) system based on endoscopic images to determine invasion depth and screen patients for endoscopic resection. METHODS: Endoscopic images of gastric cancer tumors were obtained from the Endoscopy Center of Zhongshan Hospital. An artificial intelligence-based CNN-CAD system was developed through transfer learning leveraging a state-of-the-art pretrained CNN architecture, ResNet50. A total of 790 images served as a development dataset, and another 203 images served as a test dataset. We used the CNN-CAD system to determine the invasion depth of gastric cancer and evaluated the system's classification accuracy by calculating its sensitivity, specificity, and area under the receiver operating characteristic curve. RESULTS: The area under the receiver operating characteristic curve for the CNN-CAD system was 0.94 (95% confidence interval (CI), 0.90-0.97). At a threshold value of 0.5, sensitivity was 76.47%, and specificity was 95.56%. Overall accuracy was 89.16%. Positive and negative predictive values were 89.66% and 88.97%, respectively. The CNN-CAD system achieved significantly higher accuracy (by 17.25%; 95% CI, 11.63 22.59) and specificity (by 32.21%; 95% CI, 26.78-37.44) than human endoscopists. CONCLUSIONS: We constructed a CNN-CAD system to determine the invasion depth of gastric cancer with high accuracy and specificity. This system distinguished early gastric cancer from deeper submucosal invasion and minimized overestimation of invasion depth, which could reduce unnecessary gastrectomy. PMID- 30452914 TI - Efficacy of autofluorescence imaging for flat neoplasm detection: a multicenter randomized controlled trial (A-FLAT trial). AB - BACKGROUND & AIMS: Colorectal flat (nonpolypoid) lesions can be overlooked during colonoscopy. This study evaluated the efficacy of updated autofluorescence imaging (AFI) for detecting colorectal flat neoplasms. METHODS: This was a prospective, multicenter, randomized controlled trial in 9 Japanese tertiary institutions. Patients undergoing colonoscopy due to positive fecal immunochemical tests (FIT), surveillance after polypectomy, or investigation of minor symptoms were enrolled and randomly assigned to either the white-light imaging (WLI) or the AFI group. Primary outcome measurement was number of flat neoplasms per patient. RESULTS: From November 2015 to June 2017, 817 patients were enrolled. After excluding 15 patients, 802 were finally analyzed (404, WLI; 398, AFI). Patients' background (sex, age, indication of colonoscopy, experience of endoscopists) and quality of colonoscopy (bowel preparation, sedative use, cecal insertion rate, insertion and withdrawal time) were not different between groups. Number of flat neoplasms in each patient (95% confidence interval) was significantly higher in AFI than in the WLI group (0.87 [0.78-0.97] vs 0.53 [0.46 0.61]), whereas overall and polypoid neoplasm detection were not significantly different between the groups (1.33 [1.22-1.45] vs 1.14 [1.03-1.24], 0.46 [0.40 0.53] vs. 0.60 [0.53-0.68]). Flat neoplasms were more frequently detected in the right-sided colon with AFI (0.61 [0.54-0.70] vs 0.30 [0.25-0.36]), but not in the left-sided colon and rectum (0.26 [0.21-0.32] vs 0.23 [0.19-0.28]). CONCLUSION: Updated AFI improves the detection of flat colorectal neoplasms in the right sided colon compared with WLI (UMIN Clinical Trials Registry number, UMIN000019355). PMID- 30452915 TI - Adenoma detection rates in colonoscopies for positive fecal immunochemical tests versus direct screening colonoscopies. AB - BACKGROUND AND AIM: Recent guidelines propose higher adenoma detection rate (ADR) benchmarks for colonoscopies performed for positive fecal immunochemical tests (FIT), but this is based on low quality evidence. We aimed to compare ADR, advanced ADR (AADR), and number of adenoma per colonoscopy (APC) in direct screening colonoscopy (DSC) versus FIT positive colonoscopy (FITC) in a multicenter Asia Pacific cohort to justify differential targets. METHODS: Asymptomatic average-risk subjects at or above 50 years of age who underwent screening colonoscopy directly or as follow-up for positive OC-Sensor FIT were identified from eight sites across the Asia Pacific region. Overall, sex-specific ADR, overall AADR, and overall APC were compared between the 2 screening methods. Multivariable logistic regression was performed to adjust for confounding by differences in patient characteristics. Linear regression was used to correlate ADR with APC, and to propose APC benchmarks. RESULTS: A total of 2,901 (mean age 60.1years, 57% men) individuals had DSC, whereas 2,485 (mean age 62.8 years, 57% men) subjects underwent FITC. Overall ADR (53.6% vs 37.5%; OR, 1.93; p<0.001), male-specific ADR (61.6% vs 44.6%; OR, 2; p<0.001), female-specific ADR (43.2% vs 28.2%; OR, 1.94; p<0.001) and overall advanced ADR (29.9% vs 4.9%; OR, 8.2; p<0.001) in FITC were significantly higher than the corresponding values for DSC. Differences remained significant after adjustment for patient characteristics. ADR was strongly and positively correlated to APC, with an ADR of 45% and 35% correlating to an APC of ~1 and ~0.65. CONCLUSIONS: Results from this international multicenter cohort study provide early evidence that newly proposed higher ADR targets are justified as quality indicators for FIT-positive colonoscopy. PMID- 30452916 TI - Cytomegalovirus-associated colonic pseudotumor. PMID- 30452917 TI - Diversity Within U.S. Gastroenterology Physician Practices: The Pipeline, Cultural Competencies, and GI Societies Approaches. PMID- 30452918 TI - An Endoscopic Transluminal Approach, Compared to Minimally Invasive Surgery, Reduces Complications and Costs for Patients With Necrotizing Pancreatitis. AB - BACKGROUND & AIMS: Infected necrotizing pancreatitis is a highly morbid disease with poor outcomes. Intervention strategies have progressed from open necrosectomy to minimally invasive approaches. We compared outcomes of minimally invasive surgery vs endoscopic approaches for patients with infected necrotizing pancreatitis. METHODS: We performed a single-center, randomized trial of 66 patients with confirmed or suspected infected necrotizing pancreatitis who required intervention from May 12, 2014 through March 24, 2017. Patients were randomly assigned to groups that received minimally invasive surgery (laparoscopic or video-assisted retroperitoneal debridement, depending on location of collection, n=32) or an endoscopic step-up approach (transluminal drainage with or without necrosectomy, n=34). The primary endpoint was a composite of major complications (new-onset multiple organ failure, new-onset systemic dysfunction, enteral or pancreatic-cutaneous fistula, bleeding and perforation of a visceral organ) or death during 6 months of follow up. RESULTS: The primary endpoint occurred in 11.8% of patients who received the endoscopic procedure and 40.6% of patients who received the minimally invasive surgery (risk ratio, 0.29; 95% CI, 0.11-0.80; P=.007). Although there was no significant difference in mortality (endoscopy 8.8% vs surgery 6.3%; P=.999), none of the patients assigned to the endoscopic approach developed enteral or pancreatic cutaneous fistulae compared to 28.1% of the patients who underwent surgery (P=.001). The mean number of major complications per patient was significantly higher in the surgery group (0.69+/-1.03) compared to the endoscopy group (0.15+/ 0.44) (P=.007). The physical health scores for quality of life at 3 months was better with the endoscopic approach (P=.039) and mean total cost was lower ($75,830) compared to $117,492 for surgery (P=.039). CONCLUSIONS: In a randomized trial of 66 patients, an endoscopic transluminal approach for infected necrotizing pancreatitis, compared to minimally invasive surgery, significantly reduced major complications, lowered costs, and increased quality of life. Clinicaltrials.gov no: NCT02084537. PMID- 30452919 TI - Acceptance and Commitment Therapy Reduces Psychological Stress in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: Patients with Crohn's disease or ulcerative colitis patients have relatively high levels of stress and psychological dysfunction. Acceptance and commitment therapy (ACT) is a psychological intervention that comprises acceptance and mindfulness procedures along with commitment and behavior change strategies to increase psychological flexibility and reduce stress. We performed a randomized controlled trial to investigate the effect of ACT on stress in subjects with inflammatory bowel diseases (IBD). METHODS: One hundred twenty-two subjects with quiescent or stable mildly active IBD were randomly assigned to an 8-week ACT program or treatment as usual (control group). Clinical, demographic, disease activity and psychological data, blood and feces were collected at baseline and at 8 weeks and 3 months after the intervention (week 20). Scalp hair was collected at baseline and week 20 for measurement of steroid concentrations. The primary endpoint was change in stress symptoms, assessed with the DASS-21. Secondary endpoints included changes in perceived stress, anxiety, depression, quality of life domains, disease activity, and cortisol concentration in hair. RESULTS: Seventy-nine subjects were included in the complete case intention to treat analysis. There was a 39% and 45% reduction in stress in the treatment group from baseline to 8 and 20 weeks, respectively, compared with 8% and 11% in the control group (group x time interaction, P=.001). ACT was associated with reduced perceived stress (P=.036) and depression (P=.010), but not anxiety (P=.388) compared with controls. In the intention to treat analysis, changes in all 4 quality of life domains over time were similar in ACT and control groups. In the per-protocol analysis, the overall wellbeing quality of life domain improved in the ACT group compared with controls (P=.009). Subjective and objective disease activity measurements were similar between groups over the study period (all P values >.05). Hair cortisol concentrations correlated with stress (rs 0.205; P=.050) and anxiety (rs 0.208; P=.046) at baseline, but did not change significantly in the ACT group over the study period compared with controls (P=.831). CONCLUSION: In a randomized controlled trial of patients with IBD, an 8-week ACT therapy course improved stress and other indices of psychological health. ClinicalTrials.gov Identifier: NCT02350920. PMID- 30452920 TI - ATF4 Deficiency Promotes Intestinal Inflammation in Mice by Reducing Uptake of Glutamine and Expression of Antimicrobial Peptides. AB - BACKGROUND & AIMS: Activating transcription factor 4 (ATF4) regulates genes involved in the inflammatory response, amino acid metabolism, autophagy, and endoplasmic reticulum stress. We investigated whether its activity is altered in patients with inflammatory bowel diseases (IBD) and mice with enterocolitis. METHODS: We obtained biopsy samples during endoscopy from inflamed and/or uninflamed regions of colon from 21 patients with active CD, 22 patients with active UC, and 38 individuals without IBD (controls), and of ileum from 19 patients with active CD and 8 individuals without IBD in China. Mice with disruption of Atf4 specifically in intestinal epithelial cells (Atf4DeltaIEC mice) and Atf4-floxed mice (controls) were given dextran sodium sulfate (DSS) to induce colitis. Some mice were given injections of recombinant defensin alpha 1 (DEFA1) and supplementation of L-alanyl-glutamine or glutamine in drinking water. Human and mouse ileal and colon tissues were analyzed by quantitative real-time PCR, immunoblots, and immunohistochemistry. Serum and IEC amino acids were measured by high-performance liquid chromatography-tandem mass spectrometry. Levels of ATF4 were knocked down in IEC-18 cells with small interfering RNAs. Microbiomes were analyzed in ileal feces from mice using 16S ribosomal DNA sequencing. RESULTS: Levels of ATF4 were significantly decreased in inflamed intestinal mucosa from patients with active CD or active UC, compared with uninflamed regions or intestinal mucosa from controls. ATF4 was also decreased in colonic epithelia from mice with colitis to mice without colitis. Atf4DeltaIEC mice developed spontaneous enterocolitis, and colitis of greater severity than control mice following administration of DSS. Atf4DeltaIEC mice had decreased serum levels of glutamine and reduced levels of antimicrobial peptides, such as Defa1, Defa4, Defa5, Camp and Lyz1 in ileal Paneth cells. Atf4DeltaIEC mice had alterations in ileal microbiomes, compared to control mice; these changes were reversed by administration of glutamine. Injections of DEFA1 reduced the severity of spontaneous enteritis and DSS-induced colitis in Atf4DeltaIEC mice. We found that expression of solute carrier family 1 member 5 (SLC1A5), a glutamine transporter, was directly regulated by ATF4 in cell lines. Overexpression of SLC1A5 in IEC-18 or primary IEC cells increased glutamine uptake and expression of antimicrobial peptides. Knockdown of ATF4 in IEC-18 cells increased expression of inflammatory cytokines, whereas overexpression of SLC1A5 in the knockdown cells reduced cytokine expression. Levels of SLC1A5 were decreased in inflamed intestinal mucosa of patients with CD and UC and correlated with levels of ATF4. CONCLUSIONS: Levels of ATF4 are decreased in inflamed intestinal mucosa from patients with active CD or UC. In mice, ATF4 deficiency reduces glutamine uptake by intestinal epithelial cells and expression of antimicrobial peptides by decreasing transcription of Slc1a5. ATF4 might therefore be a target for the treatment of IBD. PMID- 30452921 TI - Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice with Chronic Intestinal Inflammation. AB - BACKGROUND & AIMS: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) frequently resulting in functional damage, bowel obstruction, and surgery. Interleukin 36 (IL36) is a group of cytokines in the IL1 family with inflammatory effects. We studied expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in development of intestinal fibrosis in human tissues and mice. METHODS: We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis (UC), and 26 patients without inflammatory bowel diseases (controls). Tissues were analyzed by histology to detect fibrosis and immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R and we studied intestinal tissues from Il1rl2-/- mice; colitis and fibrosis was induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2-/- to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied. RESULTS: Mucosal and submucosal tissues from patients with CD or UC had higher levels of collagens including type VI collagen compared to tissues from controls. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed alpha smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2-/- mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis following administration of DSS or TNBS, but bone marrow cells from Il1rl2-/- mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation. CONCLUSION: We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD, compared with controls. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD. PMID- 30452922 TI - Activation of autophagy, observed in liver tissues from patients with Wilson disease and from Atp7b-deficient animals, protects hepatocytes from copper induced apoptosis. AB - BACKGROUND AND AIMS: Wilson disease is an inherited disorder of copper metabolism that leads to copper accumulation and toxicity in liver and brain. It is caused by mutations in the ATPase copper transporting beta gene (ATP7B), which encodes a protein that transports copper out of heaptocytes into the bile. We studied ATP7B deficient cells and animals to identify strategies to reduce copper toxicity in patients with Wilson disease. METHODS: We used RNA-seq to compare gene expression patterns between wild-type and ATP7B-knockout HepG2 cells exposed to copper. We collected blood and liver tissues from Atp7b-/- and Atp7b+/- (control) rats (LPP) and mice; some mice were given 5 daily injections of an autophagy inhibitor (spautin-1) or vehicle. We obtained liver biopsies from 2 patients with Wilson disease in Italy and liver tissues from patients without Wilson disease (control). Liver tissues were analyzed by immunohistochemistry, immunofluorescence, cell viability, and apoptosis assays, as well as by electron and confocal microscopy. Proteins were knocked down in cell lines using small interfering RNAs. Levels of copper were measured in cell lysates, blood samples, liver homogenates, and subcellular fractions by spectroscopy. RESULTS: Following exposure to copper, ATP7B-knockout cells had significant increases in expression of 103 genes that regulate autophagy (including MAP1LC3A, known as LC3), compared with wild-type cells. Electron and confocal microscopy revealed more autophagic structures in the cytoplasm of ATP7B-knockout cells than wild-type cells following copper exposure. Hepatocytes in liver tissues from patients with Wilson disease, as well as Atp7b-/- mice and rats (but not controls), had multiple autophagosomes. In ATP7B-knockout cells, mTOR had reduced activity and was dissociated from lysosomes; this resulted in translocation of the mTOR substrate transcription factor EB (TFEB) to the nucleus, and activation of autophagy related genes. In wild-type HepG2 cells (but not ATP7B-knockout cells), exposure to copper and amino acids induced recruitment of mTOR to lysosomes. Pharmacologic inhibitors of autophagy or knockdown of autophagy proteins ATG7 and ATG13 induced and accelerated death of ATP7B-knockout HepG2 cells, compared to wild-type cells. Autophagy protected ATP7B-knockout cells from copper-induced death. CONCLUSION: ATP7B-deficient hepatocytes, such as in those in patients with Wilson disease, activate autophagy in response to copper overload to prevent copper-induced apoptosis. Agents designed to activate this autophagic pathway might reduce copper toxicity in patients with Wilson disease. PMID- 30452923 TI - Consortium for Eosinophilic Researchers (CEGIR): Advancing the Field of Eosinophilic GI Disorders Through Collaboration. PMID- 30452924 TI - Analysis of effectiveness of Iranian snake antivenom on Viper venom induced effects including analysis of immunologic biomarkers in the Echis carinatus sochureki envenomed victims. AB - Snakebite is an important toxicologic emergency with the potential of triggering local and systemic inflammation. Antivenom has remained the mainstay of treatment for snakebite envenomation. In this study we sought to investigate the effectiveness of Iranian antivenom in a series of 44 viper envenomed patients through analysis of changes in clinical severity and the levels of inflammatory markers. Clinical envenomation severity assessed by snakebite severity score (SSS) and laboratory exams of the patients were recorded before (baseline visit) and after antivenom therapy. During 12-h antivenom therapy, the median (range) score of SSS significantly decreased from 3.5 (2-10) on admission to 1 (0-5) in the last visit (P < 0.001). Moreover, a significant decrease in prothrombin time and international normalized ratio was found (P = 0.006 and 0.008; respectively). Plasma concentrations of interleukin (IL) 1-beta, IL-6, IL-8, tumor necrosis factor alpha (TNF-alpha), complement hemolytic activity (CH50) were also measured in 10 severely Echis carinatus sochureki envenomed victims and 10 age and gender matched healthy controls. Except IL-8, the baseline levels of IL-1beta, IL-6 and TNF-alpha in victims were significantly higher than healthy controls (P = 0.005, <0.001 and < 0.001, respectively). Moreover, the baseline level of CH50 was significantly lower in the patients compared to healthy controls (P < 0.001). After 12-h antivenom therapy, the plasma levels of IL-1beta, IL-6 and TNF-alpha significantly decreased (P = 0.032, 0.006 and 0.003, respectively), the levels of IL-8 remained relatively unchanged and the CH50 significantly increased (P = 0.011). Iranian snake antivenom was effective in treating viper bite envenomation as it reversed clinical venom effects and restored near normal underlying inflammatory status. This study is the first to ascertain and report the effectiveness of this antivenom in human subjects. PMID- 30452925 TI - Role of P2X3 receptors in scratching behavior in mouse models. AB - We identified P2X3 purinoceptors (P2X3Rs) as ligand-gated channels whose activation stimulates a subpopulation of sensory neurons expressing Mas-related G protein-coupled receptor A3 (MrgprA3), linked to itch. P2X3Rs may be targets for treatment of chronic itch. PMID- 30452926 TI - Tipping the balance: a biased nanobody antagonist of CCR3 with potential for the treatment of eosinophilic inflammation. PMID- 30452927 TI - Paradoxical gastrointestinal reactions in patients taking tumor necrosis factor inhibitors: a rare event that broadens the histologic Spectrum of medication associated injury. AB - Tumor necrosis factor (TNF) inhibitors are widely used in the therapy of certain autoimmune disorders. Paradoxical immunologic reactions manifesting as new-onset autoimmune disease or exacerbation of the underlying condition have been reported in association with these drugs. In this study, we reviewed gastrointestinal biopsies and clinical findings in patients with rheumatologic disease on TNF inhibitor therapy and compared to patients with rheumatologic disease not on TNF inhibitors. Eighteen biopsies from nine patients treated with TNF inhibitor therapy and 249 biopsies from 120 control patients not treated with TNF inhibitors were included. Among patients taking a TNF inhibitor, 55.6% were female and the median age was 47 (range, 30-67years). Four (44.4%) patients were taking etanercept, four (44.4%) adalimumab, and one (11.1%) certolizumab pegol. Of the 120 control patients, 75 (62.5%) were female and the median age was 62 (range, 26-85years). Paradoxical reactions were observed in three (33.3%) of nine patients on TNF inhibitors, including two (22.2%) with inflammatory bowel disease like changes and one (11.1%) with sarcoid-like granulomas. All three patients showed symptomatic and histologic improvement or resolution after discontinuation of therapy. These reactions were not observed in any of the control patients (P=.0002). Our results indicate that among patients with rheumatologic disease, paradoxical reactions of the gastrointestinal tract are associated with TNF inhibitor therapy. Knowledge of this association is important as symptoms and histologic features may improve following medication switch. PMID- 30452928 TI - High plasma FGF21 levels predicts major cardiovascular events in patients treated with atorvastatin (from the Treating to New Targets [TNT] Study). AB - BACKGROUND: Higher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants. METHODS: After 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization. RESULTS: Higher ln transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1 year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction. CONCLUSIONS: Higher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin treated patients. PMID- 30452929 TI - In vivo proof-of-concept for two experimental antiviral drugs, both directed to cellular targets, using a murine cytomegalovirus model. AB - Infections with the human cytomegalovirus (HCMV) cause serious medical problems including organ rejection and congenital infection. Treatment of HCMV infections with currently available medication targeting viral enzymes is often accompanied with severe side effects and the occurrence of drug-resistant viruses. This demands novel therapeutical approaches like targeting genetically stable host cell proteins that are crucial for virus replication. Although numerous experimental drugs with promising in vitro efficacy have been identified, the lack of available data in animal models limits their potential for further clinical development. Recently, we described the very strong in vitro antiherpesviral activity of the NF-kappaB inhibitor TF27 and the CDK7 inhibitor LDC4297 at low nanomolar concentrations. In the present study, we present first data for the in vivo efficacy of both experimental drugs using an established cytomegalovirus animal model (murine CMV replication in immunodefective Rag -/- mice). The main findings of this study are (i) a strong inhibitory potency against beta- and gamma-herpesviruses of both compounds in vitro, (ii) even more important, a pronounced anticytomegaloviral activity also exerted in vivo, that resulted from (iii) a restriction of viral replication to the site of infection, thus preventing organ dissemination, (iv) in the absence of major compound associated adverse events. Thus, we provide evidence for a strong antiviral potency in vivo and proof-of-concept for both drugs, which may encourage their further drug development, possibly including pharmacologically optimized derivatives, for a potential use in future antiherpesviral treatment. PMID- 30452930 TI - Intrahippocampal administration of 5-HT6 receptor drugs on memory consolidation and amnesia protocols. AB - To our knowledge the intrahippocampal serotonergic 5-HT6 receptor tone on memory and amnesia models remains unexplored. Hence, in the present work we tested intrahippocampal administration of serotonin or 5-hydroxytryptamine (5-HT)6 receptor experimental molecules with differential intrinsic activity. Methods: In the present study, Automatized Autoshaping memory task was used, useful measuring memory, neural markers, and pharmacological effects. We are hypothesizing that experimental molecules with differential intrinsic activity might reveal serotonergic tone. Particularly, intrahippocampal administration of 5-HT6 receptor compounds with differential intrinsic activity (i.e., agonistic and antagonistic) might evidencing a serotonergic tone via this receptor. Bilateral intrahippocampal dose-response curves show that administration of EMD386088 (10 and 100 MUg) had no effect or (50 MUg) decreased conditioned responses (CR) in short- and long-term memory (STM and LTM, respectively); while SB-399885 (10 or 100 MUg) significantly decreased CR in STM and LTM (24 and 48-h) or (50 MUg) had no effect; thus suggesting that there is a 5-HT6 receptor tone regulating both STM and LTM. Moreover, intrahippocampal inactive doses of EMD386088 (5 MUg) plus SB-399885 (0.5 MUg) did not affect STM and LTM; however, partially or completely prevented the scopolamine or dizocilpine-induced amnesia. Thus confirming that both drugs exerted their effects through 5-HT6 receptor and that there is a hippocampal serotonergic tone under amnesic states, similar to that striatal. PMID- 30452931 TI - Human papillomavirus detection in urine: Effect of a first-void urine collection device and timing of collection. AB - Great interest has been directed towards the use of first-void (FV) urine as a liquid biopsy for high-risk HPV DNA testing. The aim of this study was to investigate the potential effect of a first generation FV urine collection device on the detection of HPV DNA and to assess if the concentration of HPV DNA varies between FV urine collected in the morning and those collected later during the day. In this prospective cohort study, 33 self-reported HPV-positive women participated. An FV urine sample was collected by these women in the morning (first urine of the day) and another sample was collected later that day for four consecutive days using two different collection methods; i.e., the Colli-Pee(r) and a standard urine cup. Samples were collected at home and returned at ambient temperature to the laboratory by postal mail. HPV DNA testing was conducted with the Riatol qPCR HPV genotyping assay. Based on the combined generalized linear mixed model used, there was no significant impact of the timing of collection (morning versus later during the day) on copies of HPV DNA, whereas Colli-Pee(r) collected samples show higher HPV concentrations than cup collected samples. However, at high concentrations of hDNA, the benefit of the Colli-Pee(r) disappeared. PMID- 30452932 TI - Class A scavenger receptors mediate extracellular dsRNA sensing, leading to downstream antiviral gene expression in a novel American toad cell line, BufoTad. AB - Viral double-stranded (ds)RNA is a potent pathogen-associated molecular pattern (PAMP), capable of inducing a strong antiviral state within the cell, protecting the cell from virus infection. In mammals and fish, sensing extracellular dsRNA is mediated by cell-surface class A scavenger receptors (SR-As). Currently, very little is known about SR-As in amphibians, including: sequence, expression patterns and function. To this end, SR-A expression and function was studied in a novel American toad (Anaxyrus americanus) tadpole cell line called BufoTad. BufoTad was derived from a whole tadpole. The cell line exhibits a cobblestone morphology and expresses abundant levels of transcripts for cytokeratin 19, vimentin, claudin 3, chemokine receptor CXCR4, and SR-AI, one of the five members of the SR-A family, collectively suggesting that BufoTad could be endothelial like. BufoTad cells bound acetylated LDL, whereas the Xenopus laevis kidney epithelial A6 cell line did not, suggesting functional SR-A activity in BufoTad cells. Additionally, three SR-A competitive ligands (DxSO4, fucoidan, poly inosine (pI)) completely blocked AcLDL binding in BufoTad cells, whereas their three corresponding non-competitive ligands (ChSO4, fetuin, poly cytosine (pC)) did not. A commercial dsRNA, poly IC, induced robust expression of an Mx-like gene transcript, a possible antiviral protein in BufoTad cells. Employing the same SR-A ligand blocking assay used for AcLDL blocked dsRNA-induced ISG expression. This study is the first demonstration that amphibian SR-As have functional ligand binding activities in a live biological cellular model and that sensing extracellular dsRNA in amphibian cells leads to antiviral gene expression that is mediated by class A scavenger receptors. PMID- 30452933 TI - Roles of polymorphic cathelicidins in innate immunity of soft-shell turtle, Pelodiscus sinensis. AB - Cathelicidins are a class of gene-encoded immune effectors in vertebrate innate immune system. Though being extensively studied in mammals, little is known about the roles of cathelicidins in turtles, the water-dwelling vertebrates in the order Testudines. In the present study, six novel cathelicidins (Ps-CATH1-6) with different tissue and inducible expression patterns were characterized from the turtle of economic importance, Chinese soft-shell turtle (Pelodiscus sinensis). Although the structures of Ps-CATH1-6 precursors were identical with most of the other known cathelicidins, the mature peptides of Ps-CATH1-6 showed low sequence similarity with the other cathelicidins. Functional studies indicated that some of them either directly kill pathogens via inducing the permeabilization in bacterial membrane (Ps-CATH4, 6), or boost infection-resolving immunity by selectively inhibiting pro-inflammatory responses (Ps-CATH2, 4, 6) through MAPKs and NF-kappaB pathways. Ps-CATH2, 4, and 6, which assume the hallmark amphipathic alpha-helical conformations as most of the other host defense peptides, exhibit evident in vivo protection by significantly reducing the bacterial loads in bacterial infected turtles. Collectively, the discovery of novel Ps-CATHs with pleiotropic structures and functions helps elucidating the roles of cathelicidins in the Chinese softshell turtle innate immunity, and better understanding the survival strategy of Chinese softshell turtle in harsh habitat. PMID- 30452934 TI - Anxious brain networks: A coordinate-based activation likelihood estimation meta analysis of resting-state functional connectivity studies in anxiety. AB - Anxiety and anxiety disorders are associated with specific alterations to functional brain networks, including intra-networks and inter-networks. Given the heterogeneity within anxiety disorders and inconsistencies in functional network differences across studies, identifying common patterns of altered brain networks in anxiety is imperative. Here, we conducted an activation likelihood estimation meta-analysis of resting-state functional connectivity studies in anxiety and anxiety disorders (including 835 individuals with different levels of anxiety or anxiety disorders and 508 controls). Results show that anxiety can be characterized by hypo-connectivity of the affective network with executive control network (ECN) and default mode network (DMN), as well as decoupling of the ECN with the DMN. The connectivity within the salience network and its connectivity with sensorimotor network are also attenuated. These results reveal consistent dysregulations of affective and cognitive control related networks over networks related to emotion processing in anxiety and anxiety disorders. The current findings provide an empirical foundation for an integrated model of brain network alterations that are common across anxiety and anxiety disorders. PMID- 30452935 TI - Low and medium frequency auditory steady-state responses decrease during NREM sleep. AB - Previous research on auditory steady-state responses (ASSRs) demonstrated sensitivity of 40 Hz ASSR to changes in the level of arousal, both in sleep and in general anaesthesia. In this study we extended the range of stimulation frequencies, using also low and medium stimulation frequencies (4, 6, 8, 12, 20, 40 Hz) and studied their susceptibility to the loss of consciousness in NREM sleep (N2 and N3 stages). Effects of NREM sleep were examined in power domain with relative power (RP), and in phase domain using inter-trial phase coherence (PC) parameter. The activity in power domain was also compared to no-stimulation data. Regions displaying significant waking-NREM sleep differences were selected using non-parametric suprathreshold cluster test. For 4, 6, 20 and 40 Hz stimulation relative power of ASSRs was lower in NREM sleep, with maximal change for 40 Hz stimulation. This decrease was not seen in no-stimulation condition. For all stimulation frequencies (except 12 Hz) we observed decrease of phase coherence of ASSR during NREM sleep. Our results demonstrate that low and medium frequency ASSRs are state-sensitive, thus susceptible to loss of consciousness during NREM sleep. Diminishing of power and phase coherence may result from cortical down states and/or thalamic inhibition. Our results support possible use of low- and medium-frequency ASSRs for discrimination between states of altered consciousness and emphasize the role of the auditory system in determining these variations. PMID- 30452936 TI - Store-operated Ca2+ entry and Ca2+ responses to hypothalamic releasing hormones in anterior pituitary cells from Orai1-/- and heptaTRPC knockout mice. AB - Store operated Ca2+ entry (SOCE) is the most important Ca2+ entry pathway in non excitable cells. However, SOCE can also play a pivotal role in excitable cells such as anterior pituitary (AP) cells. The AP gland contains five different cell types that release six major AP hormones controlling most of the entire endocrine system. AP hormone release is modulated by Ca2+ signals induced by different hypothalamic releasing hormones (HRHs) acting on specific receptors in AP cells. TRH and LHRH both induce Ca2+ release and Ca2+ entry in responsive cells while GHRH and CRH only induce Ca2+ entry. SOCE has been shown to contribute to Ca2+ responses induced by TRH and LHRH but no molecular evidence has been provided. Accordingly, we used AP cells isolated from mice devoid of Orai1 channels (noted as Orai1-/- or Orai1 KO mice) and mice lacking expression of all seven canonical TRP channels (TRPC) from TRPC1 to TRPC7 (noted as heptaTRPC KO mice) to investigate contribution of these putative channel proteins to SOCE and intracellular Ca2+ responses induced by HRHs. We found that thapsigargin-evoked SOCE is lost in AP cells from Orai1-/- mice but unaffected in cells from heptaTRPC KO mice. Conversely, while spontaneous intracellular Ca2+-oscillations related to electrical activity were not affected in the Orai1-/- mice, these responses were significantly reduced in heptaTRPC KO mice. We also found that Ca2+ entry induced by TRH and LHRH is decreased in AP cells isolated from Orai1-/ . In addition, Ca2+ responses to several HRHs, particularly TRH and GHRH, are decreased in the heptaTRPC KO mice. These results indicate that expression of Orai1, and not TRPC channel proteins, is necessary for thapsigargin-evoked SOCE and is required to support Ca2+ entry induced by TRH and LHRH in mouse AP cells. In contrast, TRPC channel proteins appear to contribute to spontaneous Ca2+ oscillations and Ca2+ responses induced by TRH and GHRH. We conclude that expression of Orai1 and TRPC channels proteins may play differential and significant roles in AP physiology and endocrine control. PMID- 30452937 TI - Alternative fast analysis method for cellulose sponge surface sampling wipes with low concentrations of Bacillus Spores. AB - Environmental sampling is a critical component of the post decontamination verification process following a bioterrorism event. The current work was performed to produce a less labor-intensive method for processing cellulose sponge-wipes used for sampling areas potentially contaminated with low concentrations (i.e., post-decontamination) of Bacillus anthracis spores. An alternative fast-analysis processing method was compared to the processing protocol validated by the Centers for Disease Control and Prevention (CDC) for the Laboratory Response Network (LRN). Glazed tile coupons (1102 cm2) were inoculated with 50, 500, or 5000 spores of Bacillus thuringiensis subsp. kurstaki (Btk), then sampled with cellulose sponges. Sampling was limited to a 25- by 25 cm area and performed in the same manner as the CDC sampling method. Samples were then processed using either the alternative "Fast Analysis" method or the "CDC method". Three different analysts repeated the tests at each concentration utilizing each method. Mean recoveries, labor time, and potentially hazardous waste produced were compared for the two methods. The mean percent recoveries and standard errors for the samples processed using the "CDC method" were 39.9 +/- 6.7, 43 +/- 7.6, and 36.8 +/- 10.1 for the 5000, 500, and 50 spore loading levels, respectively; compared to 54.2 +/- 12.9, 64.2 +/- 21.7, and 45.2 +/- 8.6 for the "Fast Analysis" method. At each titer tested the "Fast Analysis" method resulted in a statistically significant higher percent recovery. Furthermore, analysts processed samples utilizing the "Fast Analysis" method in less than half the time and generated half as much potentially hazardous waste compared to the "CDC method". PMID- 30452938 TI - Metagenomic analysis of uncultured microorganisms and their enzymatic attributes. AB - Although second generation biofuel technology is a sustainable route for bioethanol production it is not currently a robust technology because of certain hindrances viz., unavailability of potential enzyme resources, low efficiency of enzymes and restricted availability of potent enzymes that work under harsh conditions in industrial processes. Therefore, bioprospecting of extremophilic microorganisms using metagenomics is a promising alternative to discover novel microbes and enzymes with efficient tolerance to unfavourable conditions and thus could revolutionize the energy sector. Metagenomics a recent field in "omics" technology enables the genomic study of uncultured microorganisms with the goal of better understanding microbial dynamics. Metagenomics in conjunction with NextGen Sequencing technology facilitates the sequencing of microbial DNA directly from environmental samples and has expanded, and transformed our knowledge of the microbial world. However, filtering the meaningful information from the millions of genomic sequences offers a serious challenge to bioinformaticians. The current review holds the opinion tool 'know- how' to unravel the secrets of nature while expediting the bio-industrial world. We also discuss the novel biocatalytic agents discovered through metagenomics and how bioengineering plays a pivotal role to enhance their efficiency. PMID- 30452939 TI - Partial pressure of arterial carbon dioxide after resuscitation from cardiac arrest and neurological outcome: A prospective multi-center protocol-directed cohort study. AB - AIMS: Partial pressure of arterial carbon dioxide (PaCO2) is a regulator of cerebral blood flow after brain injury. We sought to test the association between PaCO2 after resuscitation from cardiac arrest and neurological outcome. METHODS: A prospective protocol-directed cohort study across six hospitals. INCLUSION CRITERIA: age >= 18, non-traumatic cardiac arrest, mechanically ventilated after return of spontaneous circulation (ROSC), and receipt of targeted temperature management. Per protocol, PaCO2 was measured by arterial blood gas analyses at one and six hours after ROSC. We determined the mean PaCO2 over this initial six hours after ROSC. The primary outcome was good neurological function at hospital discharge, defined a priori as a modified Rankin Scale <= 3. Multivariable Poisson regression analysis was used to test the association between PaCO2 and neurological outcome. RESULTS: Of the 280 patients included, the median (interquartile range) PaCO2 was 44 (37-52) mmHg and 30% had good neurological function. We found mean PaCO2 had a quadratic (inverted "U" shaped) association with good neurological outcome, with a mean PaCO2 of 68 mmHg having the highest predictive probability of good neurological outcome, and worse neurological outcome at higher and lower PaCO2. Presence of metabolic acidosis attenuated the association between PaCO2 and good neurological outcome, with a PaCO2 of 51 mmHg having the highest predictive probability of good neurological outcome among patients with metabolic acidosis. CONCLUSION: PaCO2 has a "U" shaped association with neurological outcome, with mild to moderate hypercapnia having the highest probability of good neurological outcome. PMID- 30452940 TI - The molecular basis of the anti-diabetic properties of camel milk. AB - Over the years, strong evidence have been accumulated in favor of the beneficial effects of camel milk on glucose homeostasis with significant anti-diabetic properties in both human and animal diabetic models. However, the cellular and molecular mechanisms involved in such effects remain not understood. In this review, we speculated about the potential mechanisms and summarized few mechanistic-based studies that investigated the biological activity of camel milk and its protein components on the different aspects that may be involved in the anti-diabetic effects. A special emphasis is given to the molecular events engaged by camel milk proteins/peptides on two key aspects: insulin secretion and insulin receptor activity. Thus, the review gives a molecular rationale to the anti-diabetic effects of camel milk. This will help to identify the anti-diabetic agent(s) contained in camel milk and to understand better its mechanism of action in order to use it for the management of diabetes mellitus. PMID- 30452941 TI - Genomic updates in understanding PTSD. AB - Twin studies as well as more recent genetics-based heritability analyses demonstrate that up to 40 to 50% of the variance in predicting PTSD following trauma is heritable. However, most of the specific gene pathways and mechanism that mediate risk vs. resilience for PTSD following trauma exposure have yet to be elucidated. This review will examine the latest results from large scale Genome-wide association studies as well as other approaches aimed at understanding mechanisms of development of and recovery from PTSD. PMID- 30452942 TI - Alterations in white matter microstructure and regional volume are related to motor functions in boys with autism spectrum disorder. AB - BACKGROUND: Altered inter-regional structural connectivity related to higher cognitive functions has been commonly reported in individuals with autism spectrum disorder (ASD). However, whether these alterations similarly involve cortico-cerebellar motor circuitries remains largely elusive. METHODS: Using a cross-modality approach accounting for in-scanner motion levels, we investigated white matter (WM) properties in motor circuits of 55 boys with ASD (aged 8-18 years) and 68 age-matched typically developing boys. Regional WM volumes in the primary motor, supplementary motor, somatosensory, and cerebellar areas were investigated using voxel-based morphometry. Diffusion spectrum imaging tractography was used to estimate WM integrity of the corticospinal, cortico ponto-cerebellar (including fronto-ponto-cerebellar and parieto-ponto cerebellar), and dentato-rubro-thalamo-cortical tracts. The reaction time test in the Cambridge Neuropsychological Test Automated Battery was used to assess motor performances. RESULTS: Boys with ASD had shorter movement time, increased WM volumes in the left somatosensory area, but decreased generalized fractional anisotropy value in the left parieto-ponto-cerebellar tract, compared to controls. A positive correlation between movement time and microstructural properties of the left parieto-ponto-cerebellar tract was found in boys with ASD. CONCLUSIONS: As the first study to demonstrate altered WM properties in the left somatosensory area, and its descending pathway connecting to the cerebellum in ASD, current results may highlight a potential new target of interventions for motor performance in ASD. PMID- 30452943 TI - Complete genome sequence and phylogenetic analysis of a novel dicistrovirus associated with the whitefly Bemisia tabaci. AB - A novel single-stranded RNA virus was detected in a whitefly (Bemisia tabaci) sample subjected to high-throughput sequencing. The 8293 nt-long genome presents a polyadenylated 3' end, and contains two ORFs encoding putative 1596 and 849 aa long proteins. These putative proteins display significant similarity to replicase and capsid polyproteins, respectively, of discitroviruses. Its complete genome sequence shared the highest nucleotide identity (59.8%) with cricket paralysis virus (family Dicistroviridae, genus Cripavirus). Phylogenetic analyses showed that this new virus putative protein sequences clustered with those from members of Dicistroviridae. However, the replicase and capsid polyprotein sequences clustered with those of members of different genera, respectively to Aparavirus and Cripavirus. RT-PCR using newly collected adult and nymph whitefly samples confirmed the presence of this virus in field populations of B. tabaci. Genome sequence and organization, and polyproteins comparison indicate that this virus is a new species of the family Dicistroviridae. The name Bemisia-associated dicistrovirus 1 is proposed for this virus. PMID- 30452944 TI - Discovery of highly divergent lineages of plant-associated astro-like viruses sheds light on the emergence of potyviruses. AB - RNA viruses are believed to have originated from a common ancestor, but how this ancestral genome evolved into the large variety of genomic architectures and viral proteomes we see today remains largely unknown. Tackling this question is hindered by the lack of universally conserved proteins other than the RNA dependent RNA polymerase (RdRp) as well as a limited RNA virus sampling. The latter is still heavily biased towards relatively few viral lineages from a non representative collection of hosts, which complicates studies aiming to reveal possible trajectories during the evolution of RNA virus genomes that are favored over others. We report the discovery of 11 highly divergent lineages of viruses with genomic architectures that resemble those of the astroviruses. These genomes were initially identified through a sequence homology search in more than 6600 plant transcriptome projects from the Sequence Read Archive (SRA) using astrovirus representatives as query. Seed-based viral genome assembly of unprocessed SRA data for several dozens of the most promising hits resulted in two viral genome sequences with full-length coding regions, nine partial genomes and a much larger number of short sequence fragments. Genomic and phylogenetic characterization of the 11 discovered viruses, which we coined plastroviruses (plant-associated astro-like viruses), showed that they are related to both astro and potyviruses and allowed us to identify divergent Serine protease, RdRp and viral capsid domains encoded in the plastrovirus genome. Interestingly, some of the plastroviruses shared different features with potyviruses including the replacement of the catalytic Ser by a Cys residue in the protease active site. These results suggest that plastroviruses may have reached different points on an evolutionary trajectory from astro-like to poty-like genomes. A model how potyviruses might have emerged from (pl)astro-like ancestors in a multi-step process is discussed. PMID- 30452945 TI - Associations between premenstrual syndrome and postpartum depression: A systematic literature review. AB - Overlapping symptoms between premenstrual syndrome (PMS) and postpartum depression (PPD) suggest that these disorders may share a common etiology and pathology. Moreover, PMS is a risk factor for the development of PPD. This review aims to synthesize the evidence regarding associations between PMS and PPD. Studies were systematically reviewed through identification in PubMed, ISI web of knowledge, PsycINFO and JSTOR databases. A total of 16 studies met inclusion criteria. Three studies revealed an initial significant association between both variables, but it did not remain significant after the inclusion of confounders (e.g. personality, socio-demographic factors) into the analyses. Eleven papers found a positive association between PMS and PPD beyond the effects of biopsychosocial confounders (p < .05). Finally, two studies did not find any significant association between both variables. This review demonstrated that there is a positive association - potentially a mechanism - between PMS and PPD, which may depend on specific confounders. PMID- 30452946 TI - Shifts in frontal asymmetry underlying impulsive and controlled decision-making. AB - The frontal cortices are asymmetrically activated in impulsive and inhibitory action. However, no past work has examined shifts in frontal asymmetric activation during active impulse control or risk-taking behavior. The current study examined impulsive and controlled behavior in a behavioral risk-taking task (Balloon Analogue Risk Task) under alcohol or neutral cue exposure while EEG was recorded. Results revealed activity shifted towards greater relative left frontal activation on alcohol trials with impulsive behavior (balloon explosion) driven by reduced activation of the right inferior frontal gyrus. In contrast, activity from the first half to the second half of alcohol trials with successful impulse control (cash out) localized to reduced activation of the left inferior frontal gyrus. These findings suggest that shifting of right or left frontal asymmetry in inhibitory or impulsive behaviors stem from activation of the inferior frontal gyrus and reveal the importance of examining shifts in neural activity during behavioral processes. PMID- 30452947 TI - Apoptosis versus Axon Pruning: Molecular Intersection of Two Distinct Pathways for Axon Degeneration. AB - Neurons are capable of degenerating their axons for the physiological clearance and refinement of unnecessary connections via the programmed degenerative pathways of apoptosis and axon pruning. While both pathways mediate axon degeneration they are however distinct. Whereas in apoptosis the entire neuron, both axons and cell body, degenerates, in the context of axon pruning only the targeted axon segments are selectively degenerated. Interestingly, the molecular pathways mediating axon degeneration in these two contexts have significant mechanistic overlap but also retain distinct differences. In this review, we describe the peripheral neuronal cell culture models used to study the molecular pathways of apoptosis and pruning. We outline what is known about the molecular mechanisms of apoptosis and axon pruning and focus on highlighting the similarities and differences of these two pathways. PMID- 30452948 TI - Gestational stress induced differential expression of HDAC2 in male rat offspring hippocampus during development. AB - Accumulating evidence from preclinical and clinical studies indicates prenatal exposure to stress or excess glucocorticoids can affect offspring brain. HDAC2 is an important target of glucocorticoid. Here we detected HDAC2 expression in male offspring hippocampus from gestational restraint stressed rat during development and the relationship between HDAC2 expression and behaviors and neurogenesis in male offspring. Pregnant rats received restrained stress during the last week of pregnancy. Expressions of HDAC2 in offspring hippocampus were detected on postnatal 0 day (P0) and 60 days (P60). Neurogenesis was evaluated by Doublecortin (DCX) staining on P60. Anxiety-like behavior and cognition were detected in open field, elevated plus maze, novel object recognition test, and Barnes maze. We found that HDAC2 expression in the hippocampus of male prenatally stressed offspring (MPSO) was similar to the male control offspring on P0, but significantly lower on P60. Corresponding to the decreased expression of HDAC2 in MPSO hippocampus at P60, neurogenesis in the dentate gyrus of MPSO was significantly lower than the control male offspring. And MPSO also showed greater anxiety and poorer learning and memories abilities than control male offspring. These showed that HDAC2 could partly explain the effects of gestational stress on male offspring behaviors. PMID- 30452949 TI - Bacteriophage-based biomaterials for tissue regeneration. AB - Bacteriophage, also called phage, is a human-safe bacteria-specific virus. It is a monodisperse biological nanostructure made of proteins (forming the outside surface) and nucleic acids (encased in the protein capsid). Among different types of phages, filamentous phages have received great attention in tissue regeneration research due to their unique nanofiber-like morphology. They can be produced in an error-free format, self-assemble into ordered scaffolds, display multiple signaling peptides site-specifically, and serve as a platform for identifying novel signaling or homing peptides. They can direct stem cell differentiation into specific cell types when they are organized into proper patterns or display suitable peptides. These unusual features have allowed scientists to employ them to regenerate a variety of tissues, including bone, nerves, cartilage, skin, and heart. This review will summarize the progress in the field of phage-based tissue regeneration and the future directions in this field. PMID- 30452950 TI - Hospital-by-Hospital Carbapenem Use in Japan: A Nationwide Ecological Study. AB - OBJECTIVES: To determine the nationwide distribution of carbapenem use on a hospital-by-hospital basis and to build predictive models using available hospital data from Japan. METHODS: We conducted an ecological study using open data released from the Government of Japan. We analysed the distribution of days of therapy with carbapenem (per 1000 patient-days) and built predictive models. We listed and compared the top 1% heavy users by crude distribution and observed per-predicted ratio distribution. Our analysis was conducted in three subcategories stratified by hospital characteristics (tertiary hospitals, secondary acute care hospitals, and fee-for-service hospitals) and among patients in two age groups (16-65 years and >65 years). RESULTS: The median days of therapy in the 16-65-year-old group were 7.24 for tertiary hospitals, 3.28 for secondary acute care hospitals, and 1.42 for fee-for-service hospitals. The median days of therapy of the >65-year-old group were 17.28 for tertiary hospitals, 14.43 for secondary acute care hospitals, and 8.21 for fee-for-service hospitals. For multivariable linear regression analyses, each model selected a different combination of covariates from the potential predictors based on hospital characteristics. CONCLUSIONS: This study determined hospital-by-hospital patterns of carbapenem use in Japan. Because a single predictive model was not appropriate for all hospitals, tailored models are needed to identify hospitals that are heavy users of carbapenem. These findings may serve as a reference to support further research on antibiotic use in healthcare and aid future policies. PMID- 30452951 TI - Activation of the alpha7 nicotinic acetylcholine receptor upregulates blood-brain barrier function through increased claudin-5 and occludin expression in rat brain endothelial cells. AB - The blood-brain barrier (BBB) is formed by brain endothelial cells (BECs) and regulates brain homeostasis by restricting the entry of blood-borne substances into the brain. Recent in vivo studies have shown that administration of nicotinic acetylcholine receptor (nAChR) agonists protects against BBB disruption and neuroinflammation induced by stroke and traumatic brain injury through the systemic cholinergic anti-inflammatory pathway. In the present study, we focused on the nAChRs expressed on BECs rather than those widely expressed in the central nervous system and peripheral tissues, and examined whether activation of the nAChRs on BECs facilitates BBB function. We used primary cultures of rat brain endothelial cells to evaluate brain endothelial permeability and tight junction (TJ)-related protein expression after a 24-h exposure to PHA543613 (a selective alpha7 nAChR agonist) or 5-iodo-A-85380 (a selective alpha4beta2 nAChR agonist). We found that PHA543613 decreased sodium fluorescein permeability and increased the expression levels of claudin-5 and occludin, key TJ components. In contrast, 5-iodo-A-85380 had no effect on brain endothelial permeability or TJ protein expression. These findings suggest that the selective activation of alpha7 nAChRs on BECs has a specific role in upregulating BBB properties through increased claudin-5 and occludin expression. PMID- 30452952 TI - A simple technique to increase field of view (FOV) of a USB dematoscope. PMID- 30452953 TI - Skin Diseases of the Breast and Nipple Part 2: Inflammatory and Infectious Diseases. AB - Certain dermatologic conditions are unique to the breast and nipple, whereas others may incidentally involve these structures. All require a nuanced approach to diagnosis and treatment due to the functional, sexual and aesthetic importance of this area. The lactating patient requires special management since certain treatment options are contraindicated. All dermatologic conditions involving the breast and nipple require careful evaluation since breast malignancy can be mistaken for a benign condition or may trigger the development of certain dermatologic conditions. This article reviews common and uncommon inflammatory and infectious conditions of the breast and nipple and provides insight into diagnosis and treatment of this heterogeneous group of diseases. For the purposes of this article, these conditions are divided into 4 distinct categories: 1) Dermatitis; 2) Radiation-induced Changes; 3) Mastitis; and 4) miscellaneous dermatologic conditions of the breast and nipple. PMID- 30452954 TI - Skin Diseases of the Breast and Nipple Part I: Benign and Malignant Tumors. AB - Evaluation and management of dermatologic diseases of the breast and nipple requires an understanding of the unique anatomy of the breast and nipple as well as an awareness of the significant emotional, cultural, and sexual considerations that may come into play when treating this anatomic area. Part I of this 2 Part CME Series reviews breast anatomy, congenital breast anomalies, and benign and malignant breast tumors. Specifically, an emphasis is placed on inflammatory breast cancer and breast cancer with non-inflammatory skin involvement as well as on cutaneous metastases to the breast and from breast cancer. Familiarity of the dermatologist with the cutaneous manifestations of breast cancer will facilitate the diagnosis of breast malignancy and assist with staging, prognostication, and evaluation for recurrence. This article also discusses genodermatoses that predispose to breast pathology and provides imaging recommendations for evaluating a palpable breast mass. PMID- 30452955 TI - Amyloid-beta promotes neurotoxicity by Cdk5-induced p53 stabilization. AB - Neurodegeneration in selective brain areas underlies the pathology of Alzheimer's disease (AD). Although oligomeric amyloid-beta (Abeta) plays a central role in the AD pathogenesis, the mechanism of neuronal loss in response to Abeta remains elusive. The p53 tumor suppressor protein, a key regulator of cell apoptosis, has been described to accumulate in affected brain areas from AD patients. However, whether p53 plays any role in AD pathogenesis remains unknown. To address this issue, here we investigated the involvement of p53 on Abeta-induced neuronal apoptosis. We found that exposure of neurons to oligomers of the amyloidogenic fragment 25-35 of the Abeta peptide (Abeta25-35) promoted p53 protein phosphorylation and stabilization, leading to mitochondrial dysfunction and neuronal apoptosis. To address the underlying mechanism, we focused on cyclin dependent kinase-5 (Cdk5), a known p53-phosphorylating kinase. The results revealed that Abeta25-35 treatment activated Cdk5, and that inhibiting Cdk5 activity prevented p53 protein stabilization. Furthermore, Abeta25-35-mediated mitochondrial dysfunction and neuronal apoptosis were prevented by both genetic and pharmacological inhibition of either p53 or Cdk5 activities. This effect was mimicked with the full-length peptide Abeta1-42. To confirm the mechanism in vivo, Abeta25-35 was stereotaxically injected in the cerebral right ventricle of mice, a treatment that caused p53 protein accumulation, dendrite disruption and neuronal death. Furthermore, these effects were prevented in p53 knockout mice or by pharmacologically inhibiting p53. Thus, Abeta25-35 triggers Cdk5 activation to induce p53 phosphorylation and stabilization, which leads to neuronal damage. Inhibition of the Cdk5-p53 pathway may therefore represent a novel therapeutic strategy against Abeta-induced neurodegeneration. PMID- 30452956 TI - Neuroprotective effect of l-serine against white matter demyelination by harnessing and modulating inflammation in mice. AB - Demyelination in white matter is the end product of numerous pathological processes. This study was designed to evaluate the neuroprotective effect of l serine and the underlying mechanisms against the demyelinating injury of white matter. A model of focal demyelinating lesions (FDL) was established using the two-point stereotactic injection of 0.25% lysophosphatidylcholine (LPC, 10 MUg per point) into the corpus callosum of mice. Mice were then intraperitoneally injected with one of three doses of l-serine (114, 342, or 1026 mg/kg) 2 h after FDL, and then twice daily for the next five days. Behavior tests and histological analysis were assessed for up to twenty-eight days post-FDL induction. Electron microscopy was used for ultrastructural investigation. In vitro, we applied primary co-cultures of microglia and oligodendrocytes for oxygen glucose deprivation (OGD). After establishing FDL, l-serine treatment: 1) improved spatial learning, memory and cognitive ability in mice, and relieved anxiety for 4 weeks post-FDL induction; 2) reduced abnormally dephosphorylated neurofilament proteins, increased myelin basic protein, and preserved anatomic myelinated axons; 3) inhibited microglia activation and reduced the release of inflammatory factors; 4) promoted recruitment and proliferation of oligodendrocyte progenitor cells, and the efficiency of subsequent remyelination on day twenty-eight post FDL induction. In vitro experiments, showed that l-serine not only directly protected against oligodendrocytes from OGD damage, but also provided an indirect protective effect by regulating microglia. In our study, l-serine offered long lasting behavioral and oligodendrocyte protection and promoted remyelination. Therefore, l-serine may be an effective clinical treatment aganist white matter injury. PMID- 30452957 TI - Comparing forest governance models against invasive biological threats. AB - In order to take account of the negative effects of invasive species and pathogens on networked forest areas, we study the dynamics of stochastic closed loop input-output systems faced with the risk of external random perturbations. The extension of previous works on robustness is carried out by introducing a negative feedback mechanism, such that the output from an element contained in the system behaves as a negative input toward elements to which it is connected. Through the study of an overall network divided into compartments barely connected to one another, we first consider the pathway pertaining to monofunctional zoning. By looking at a single aggregated structure, we then move our focus to the pathway proper to multifunctionality. Our results show that, at significant time scales, the monofunctional-zoning mode of forest governance, generally applied in Australasia, performs robustly against invasive biological threats at all levels of outbreak probability. The multifunctional mode of forest governance, further practiced in Western Europe, is mainly sturdy when the probability of invasion verges into certainty. Should this not be the case, robustness is ensured would disturbers and perturbations be uncorrelated. Accordingly, the monofunctional pathway can afford adopting control strategies for outbreak avoidance, which is only acceptable in case the expected invasion can be halted. For the sake of maintaining low likelihood of invasion, the multifunctional pathway is compelled to applying preventive strategies. PMID- 30452958 TI - Identification of protein subcellular localization via integrating evolutionary and physicochemical information into Chou's general PseAAC. AB - Identifying the location of proteins in a cell plays an important role in understanding their functions, such as drug design, therapeutic target discovery and biological research. However, the traditional subcellular localization experiments are time-consuming, laborious and small scale. With the development of next-generation sequencing technology, the number of proteins has grown exponentially, which lays the foundation of the computational method for identifying protein subcellular localization. Although many methods for predicting subcellular localization of proteins have been proposed, most of them are limited to single-location. In this paper, we propose a multi-kernel SVM to predict subcellular localization of both multi-location and single-location proteins. First, we make use of the evolutionary information extracted from position specific scoring matrix (PSSM) and physicochemical properties of proteins, by Chou's general PseAAC and other efficient functions. Then, we propose a multi-kernel support vector machine (SVM) model to identify multi-label protein subcellular localization. As a result, our method has a good performance on predicting subcellular localization of proteins. It achieves an average precision of 0.7065 and 0.6889 on two human datasets, respectively. All results are higher than those achieved by other existing methods. Therefore, we provide an efficient system via a novel perspective to study the protein subcellular localization. PMID- 30452959 TI - Mathematical modeling of hepatitis c virus (HCV) prevention among people who inject drugs: A review of the literature and insights for elimination strategies. AB - In 2016, the World Health Organization issued global elimination targets for hepatitis C virus (HCV), including an 80% reduction in HCV incidence by 2030. The vast majority of new HCV infections occur among people who inject drugs (PWID), and as such elimination strategies require particular focus on this population. As governments urgently require guidance on how to achieve elimination among PWID, mathematical modeling can provide critical information on the level and targeting of intervention are required. In this paper we review the epidemic modeling literature on HCV transmission and prevention among PWID, highlight main differences in mathematical formulation, and discuss key insights provided by these models in terms of achieving WHO elimination targets among PWID. Overall, the vast majority of modeling studies utilized a deterministic compartmental susceptible-infected-susceptible structure, with select studies utilizing individual-based network transmission models. In general, these studies found that harm reduction alone is unlikely to achieve elimination targets among PWID. However, modeling indicates elimination is achievable in a wide variety of epidemic settings with harm reduction scale-up combined with modest levels of HCV treatment for PWID. Unfortunately, current levels of testing and treatment are generally insufficient to achieve elimination in most settings, and require further scale-up. Additionally, network-based treatment strategies as well as prison-based treatment and harm reduction provision could provide important additional population benefits. Overall, epidemic modeling has and continues to play a critical role in informing HCV elimination strategies worldwide. PMID- 30452960 TI - Predicting protein-protein interactions by fusing various Chou's pseudo components and using wavelet denoising approach. AB - Research on protein-protein interactions (PPIs) not only helps to reveal the nature of life activities but also plays a driving role in understanding the mechanisms of disease activity and the development of effective drugs. The rapid development of machine learning provides new opportunities and challenges for understanding the mechanism of PPIs. It plays an important role in the field of proteomics research. In recent years, an increasing number of computational methods for predicting PPIs have been developed. This paper proposes a new method for predicting PPIs based on multi-information fusion. First, the pseudo-amino acid composition (PseAAC), auto-covariance (AC) and encoding based on grouped weight (EBGW) methods are used to extract the features of protein sequences, and the extracted three groups of feature vectors were fused. Secondly, the fused feature vectors are denoised by two-dimensional (2-D) wavelet denoising. Finally, the denoised feature vectors are input to the support vector machine (SVM) classifier to predict the PPIs. The ACC of PPIs of Helicobacter pylori (H. pylori) and Saccharomyces cerevisiae (S. cerevisiae) datasets were 95.97% and 95.55% by 5-fold cross-validation test and compared with other prediction methods. The experimental results show that the proposed multi-information fusion prediction method can effectively improve the prediction performance of PPIs. The source code and all datasets are available at https://github.com/QUST AIBBDRC/PPIs-WDSVM/. PMID- 30452961 TI - Analysis and prediction of animal toxins by various Chou's pseudo components and reduced amino acid compositions. AB - The animal toxin proteins are one of the disulfide rich small peptides that detected in venomous species. They are used as pharmacological tools and therapeutic agents in medicine for the high specificity of their targets. The successful analysis and prediction of toxin proteins may have important signification for the pharmacological and therapeutic researches of toxins. In this study, significant differences were found between the toxins and the non toxins in amino acid compositions and several important biological properties. The random forest was firstly proposed to predict the animal toxin proteins by selecting 400 pseudo amino acid compositions and the dipeptide compositions of reduced amino acid alphabet as the input parameters. Based on dipeptide composition of reduced amino acid alphabet with 13 reduced amino acids, the best overall accuracy of 85.71% was obtained. These results indicated that our algorithm was an efficient tool for the animal toxin prediction. PMID- 30452962 TI - Robotic Assisted Proximal Perineal Urethroplasty: Improving Visualization and Ergonomics. AB - OBJECTIVES: To describe the use of the robotic platform for proximal suture placement during perineal urethroplasty in the posterior and proximal anterior urethra. Repair of posterior urethral and proximal bulbar strictures requires deep perineal dissection, making visualization and accurate placement of sutures challenging. The robotic platform has demonstrated benefits in these characteristics in deep pelvic surgery. METHODS: We report a retrospective review of ten patients who underwent robotic-assisted urethroplasty at a single institution by a single surgeon in a one year period. All patients underwent a standard perineal dissection with robotic-assisted placement of proximal sutures. Post-operative outcomes include urethroplasty leak rate as determined by voiding cystourethrograms (VCUG), urethroplasty success rate, and perioperative complications. RESULTS: The mean age of this cohort was 43 years old (14-68). Average stricture length was 2.2cm (1.5-3.0cm) and most frequently in the bulbar urethra (5/10). Seven patients underwent non-transecting urethroplasties while three underwent transecting anastomotic repair. At post-operative VCUG, no patient had urinary extravasation. Average set-up time for the robotic portion of the surgery was 15 minutes with 30-45 minutes needed for suture placement. CONCLUSIONS: Robotic-assisted urethroplasty provides excellent visualization and ergonomics for posterior and proximal bulbar urethral reconstruction. This is particularly helpful in patients with narrow pelvic anatomy and long distances from the perineal skin to the proximal urethral edge. Operative and post operative outcomes are comparable to the standard approach with improved surgeon comfort and visualization. Additional follow up is required to assess long term outcomes in comparison to a standard approach. PMID- 30452963 TI - SYMPTOM DURATION IN PATIENTS WITH UROLOGIC CHRONIC PELVIC PAIN SYNDROME (UCPPS) IS NOT ASSOCIATED WITH PAIN SEVERITY, NON-UROLOGIC SYNDROMES AND MENTAL HEALTH SYMPTOMS: A MULTIDISCIPLINARY APPROACH TO THE STUDY OF CHRONIC PELVIC PAIN (MAPP) NETWORK STUDY. AB - OBJECTIVE: To evaluate if patients with urologic chronic pelvic pain syndromes (UCPPS) with longer duration of symptoms experience more severe pain and urologic symptoms, higher rates of chronic overlapping pain conditions (COPC) and psychosocial comorbidities than those with a more recent onset of the condition. We evaluated cross-sectional associations between UCPPS symptom duration and 1) symptom severity, 2) presence of COPC, and 3) mental health comorbidities. METHODS: We analyzed baseline data from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP). Symptom severity, COPC and mental health comorbidities were compared between patients with symptom duration of < 2 versus >= 2 years. Symptom severity was assessed by the Genitourinary Pain Index (GUPI), the Interstitial Cystitis Symptom and Problem Index (ICSI and ICPI), and Likert scales for pelvic pain, urgency and frequency. Depression and anxiety were evaluated with the Hospital Anxiety and Depression Scale (HADS) and stress with the Perceived Stress Scale (PSS). RESULTS: Males (but not females) with UCPPS symptom duration >= 2 years had more severe symptoms than those with < 2 years. Participants with short (< 2 years) and longer (>= 2 years) symptom duration were as likely to experience COPC. CONCLUSION: Longer UCPPS symptom duration was associated with more severe symptoms only in limited patient subpopulations. Symptom duration was not associated with risk for COPC or mental health comorbidities. Females with longer UCPPS duration had decreased distress, but the association was largely attributable to age. PMID- 30452964 TI - CDC73 germline mutation in a family with mixed epithelial and stromal tumors. AB - OBJECTIVE: To describe a family in which three members presented with mixed epithelial tumor of the kidney (MEST) and were found to possess a germline mutation in CDC73, a gene which is associated with hyperparathyroidism-jaw tumor syndrome (HPT-JT). MATERIALS AND METHODS: Blood and tumor DNA from three family members who presented with a primary diagnosis of MEST was subjected to targeted gene sequencing to identify potential genetic components. RESULTS: A germline start codon mutation (p.M1I) in CDC73 was identified in all three family members who presented with MEST and two tumors from one patient demonstrated somatic copy neutral loss of heterozygosity. Patients presented with no evidence of hyperparathyroidism or jaw tumors, but both female patients had hysterectomies at an early age due to excessive bleeding and numerous fibroids, which is common in HPT-JT. A germline p.M1I mutation has been previously reported in a family with clinical features of HPT-JT. CONCLUSION: Patients with MEST may be at risk for HPT-JT and CDC73 germline mutation testing of MEST patients should be considered. PMID- 30452965 TI - Methylene blue injection via percutaneous renal cyst puncture used in flexible ureteroscope for treatment of parapelvic cysts: A modified method for easily locating cystic wall. AB - OBJECTIVE: To describe a modified technique for easily locating cystic wall during flexible ureteroscopic surgery for treatment of parapelvic renal cysts. METHODS: Nineteen patients with symptomatic/asymptomatic parapelvic renal cyst were treated with modified or conventional flexible ureteroscopic surgery between Feb. 2015 to Mar. 2017, and the differences of the two techniques were compared. The detailed surgical procedures and results, postoperative complications, and patients' follow-ups were evaluated. RESULTS: All the patients received endoscopic management by flexible ureteroscope successfully, without requiring another complicated surgery. The cysts were seen clearly in 9 patients with modified method. 2/10 patients who underwent conventional ureteroscopic surgery changed to the modified surgery intra-operatively since it was difficult to identify the cyst. The total time of search and incision of cysts was 24.2+/-6.2 minutes and 17.7+/-2.5 minutes for conventional and modified technique respectively (p=0.01), of which 11.4+/-4.8 minutes and 5.1+/-1.1 minutes to search the cysts, respectively (p=0.002), and the mean time of the procedure of puncture was 8+/-2.3 minutes. Duration of pure incising the cystic wall was 12.8+/-3.3 minutes and 12.6+/-2.5 minutes for patients who underwent conventional and modified technique, respectively (p=0.859). All patients acquired relief from the presentation of flank discomfort after surgery. All of the patients were followed-up over 12 months and no serious complications and recurrence was observed. CONCLUSION: The modified technique can decrease time of searching the renal cyst and decrease the total time in flexible ureteroscopic treatment of parapelvic cysts. The limitations of our study were also observed and further studies are needed. PMID- 30452966 TI - Can the Penile Cuff Test Predict the Outcome of Holmium Laser Enucleation of the Prostate for Benign Prostatic Obstruction? AB - OBJECTIVE: To determine whether the penile cuff test can predict surgical outcomes prior to Holmium laser enucleation of the prostate for benign prostatic obstruction. METHODS: Men scheduled to undergo Holmium laser enucleation of the prostate were enrolled in this study, and all patients underwent the penile cuff test prior to and 3 months after surgery. Patients were categorized as obstructed, nonobstructed, or uncertain by nomogram. Surgical outcomes were assessed by evaluating changes in their international prostate symptom score, quality of life index, and maximum flow rate preoperatively and 3 months postoperatively. The proportion of patients with good outcomes was compared among nomogram-classified groups, and postoperative changes in position on the nomogram were assessed. RESULTS: A total of 125 patients were analyzed. After surgery, the overall treatment efficacy and symptomatic treatment efficacy were not different between obstructed and nonobstructed patients. However, the maximum flow rate and quality of life score were significantly higher after surgery in obstructed patients compared to nonobstructed patients. After surgery, 75.7% of patients with obstruction and 63.6% of patients categorized as uncertain for obstruction transitioned to the nonobstructed group, while 77.3% of nonobstructed patients remained in the nonobstructed group. CONCLUSION: The penile cuff test can be used in patients with bladder outlet obstruction to predict good functional outcome and improved quality of life following treatment with Holmium laser enucleation. After Holmium laser enucleation of the prostate, the majority of patients were classified as nonobstructed. PMID- 30452967 TI - Reply: Letter-to-the-editor: Direct Vision Internal Urethrotomy for short anterior urethral strictures and Beyond: Success Rates, Predictors of Treatment Failure and Recurrence Management. PMID- 30452968 TI - En Bloc Thulium Laser Enucleation of the Prostate: a step-by-step guide to improve enucleation time and efficiency for endoscopic enucleation of prostatic adenoma. AB - OBJECTIVE: To present a reproducible step by step approach to En-Bloc Thulium Laser Enucleation of the Prostate (ThuLEP) for benign prostatic hyperplasia surgical treatment. Laser adenoma enucleation is nowadays a recognized surgical treatment for benign prostatic enlargement. Some variants to the classical 3 lobes laser techique have been proposed, in order to overcome the main concerns regarding the original procedure1,2,3,4. After a vast experience with the 3-lobes ThuLEP, we developed our own en-bloc enucleation technique. METHODS: The capsular plane is identified only once, at the level of the prostatic apex, at 5 o'clock; this plane is followed ascending towards the bladder neck, separating the left lobe from the prostatic capsule from 5 to 11 o'clock. The right and median lobes are then enucleated following the same plane clockwise and the two planes are joined anteriorly at 11 o'clock. Finally, enucleation is completed by incising the remaining mucosal flap from 10 to 2 o'clock. We have already proved the clear advantages provided by this technique compared to the "three-lobes" enucleation5. RESULTS: Our single-center experience with this technique includes 140 procedures performed up to June 2018. Mean prostatic adenoma volume was 66.7 mL (range 20 220 +/- 32.85 standard deviation (SD)). Mean total surgical time was 60.93 min (25-133 +/- 23.6 SD); mean enucleation time was 18.3 minutes (8.2-36.53 +/- 5.62 SD), mean enucleation time normalized per adenoma gram was 0.32 min/g (0.12-0.8 +/- 0.15 SD) and mean energy needed for the enucleation normalized per adenoma gram was 1852.13 J/g (689-6129 +/-862.4 SD). Only one case of reintervention for clot evacuation (Clavien grade IIIb) was necessary. CONCLUSION: En Bloc ThuLEP provides an anatomical approach for endoscopic enucleation of prostatic adenoma. We believe that this sequence optimizes efficiency and efficacy in a reproducible way. PMID- 30452969 TI - "Re:Direct Vision Internal Urethrotomy for Short Anterior Urethral Strictures and Beyond: Success Rates, Predictors of Treatment Failure and Recurrence Management". PMID- 30452970 TI - Modulation of inducible nitric oxide synthase pathway by eugenol and telmisartan in carbon tetrachloride-induced liver injury in rats. AB - AIMS: Inducible nitric oxide synthase (iNOS) pathway has been in the limelight since its discovery as a key mediator in the process of liver fibrogenesis. Therefore, the objective of the current study was to elucidate the in vivo molecular mechanism underlying the hepatic preventive relevance of eugenol (EUG) and telmisartan (TEL) through iNOS pathway modulation against carbon tetrachloride (CCl4)-induced hepatic injury. METHODS: Sixty healthy male albino rats were used in this study. Serum aminotransferases activities and NO levels were assessed. Hepatic malondialdehyde (MDA), total nitrite/nitrate content and reduced glutathione (GSH) concentration were estimated. Liver NF-kB, TNF-alpha, IL-6 and iNOS proteins expressions were investigated by western blot assay. Histopathological examination was done. KEY FINDINGS: CCl4 resulted in damage to centrilobular regions of the liver, elevation of serum aminotransferases, rise in oxidative parameters level, and up-regulation of NF-kB, TNF-alpha, IL-6 as well as iNOS proteins expressions. Treatment of fibrotic rats with either EUG or TEL significantly alleviated CCl4-induced biochemical, inflammatory and histopathological changes. Moreover, the combined administration of EUG with TEL has an ameliorative effect which is greater than either of them alone. SIGNIFICANCE: In conclusion, the combination therapy between EUG and TEL is more effective than either drug alone which is attributed to suppression of NO production and iNOS protein expression. The results support that use of EUG and TEL exerts beneficial effects in the attenuation of CCl4-induced liver fibrosis in rats. PMID- 30452971 TI - Genistein inhibits Ang II-induced CRP and MMP-9 generations via the ER-p38/ERK1/2 PPARgamma-NF-kappaB signaling pathway in rat vascular smooth muscle cells. AB - AIMS: C-reactive protein (CRP) and matrix metalloproteinase (MMP)-9 are involved in the inflammation of atherosclerosis lesions. Genistein (Gen) has been demonstrated to exert beneficial effect on the cardiovascular system. However, it remains unclear whether Gen produces anti-inflammatory effect in vascular smooth muscle cells (VSMCs). Therefore, we investigated the effects of Gen on CRP and MMP-9 expressions induced by angiotensin (Ang) II in VSMCs and the related molecular mechanism. MAIN METHODS: Rat VSMCs were cultured, and Ang II was used as a stimulant for CRP and MMP-9 expressions. CRP level was measured by ELISA. The mRNA and protein expressions of related indexes were identified by reverse transcription-polymerase chain reaction and western blot, respectively. KEY FINDINGS: Gen inhibited Ang II-stimulated CRP and MMP-9 mRNA and protein expressions in concentration- and time-dependent manners. Additionally, Gen ameliorated Ang II-induced p-ERK1/2, p-p38 and NF-kappaB expressions, antagonized Ang II-downregulated peroxisome proliferation-activated receptor (PPAR) gamma and estrogen receptor (ER) beta expressions. After treating the VSMCs with GW9662 or ICI182780 in Gen treated groups, inhibitory effect of Gen on CRP and MMP-9 expressions were antagonized in Ang II-stimulated VSMCs. The treatment of VSMCs with ICI182780 abolished downregulations of p-p38/p-ERK1/2, and antagonized upregulation of PPARgamma by Gen in Ang II-stimulated VSMCs. Moreover, the inhibitory effect of Gen on Ang II-stimulated NF-kappaB expression was abolished after preincubation of VSMCs with GW9662 in Gen treated groups. SIGNIFICANCE: Gen exerts anti-inflammatory property via the ER-p38/ERK1/2-PPARgamma-NF-kappaB CRP/MMP-9 signal pathway in Ang II-stimulated VSMCs. PMID- 30452972 TI - Silibinin inhibits endometrial carcinoma via blocking pathways of STAT3 activation and SREBP1-mediated lipid accumulation. AB - AIMS: To seek new conservative treatments for young women with early-stage endometrial carcinoma (EC) who desire to retain fertility, we investigated the effects and the underlying mechanism of silibinin in EC, which exhibits promising anti-cancer and tumour-suppressing properties in many malignant tumours. MAIN METHODS: Through relevant experiments such as MTT assay, cell colony formation assay and subcutaneous xenograft experiment, we showed that silibinin inhibited the proliferation of EC cells and tumours. Silibinin significantly induced cell cycle arrest and promoted apoptosis in vitro. In vivo TUNEL assay confirmed the apoptotic effect caused by silibinin. STAT3 is activated in the development of tumours. Silibinin notably inhibited the expression of STAT3 phosphorylation and regulated the expression of downstream genes involved in cell cycle and apoptosis at protein and mRNA levels in EC cells. Furthermore, silibinin decreased the expression of intranuclear SREBP1, which is a key regulator of lipid metabolism in the nucleus, and reduced the lipid accumulation in EC cells. Downregulation of the expression levels of SREBP1 and its downstream genes associated with lipid metabolism was also observed in silibinin-treated EC cells. KEY FINDINGS: The results revealed that a novel anticancer drug, silibinin, markedly suppressed cell proliferation, cell cycle progression, apoptosis inhibition and lipid accumulation by blocking STAT3 and SERBP1 signalling pathways in EC cells. SIGNIFICANCE: Silibinin has anti-tumour characteristics and inhibits abnormal lipid metabolism in EC. This compound is expected to contribute to the conservative and adjuvant treatment of EC and should therefore be investigated further. PMID- 30452973 TI - Exploring the Dendritic Spine Pathology in a Schizophrenia-related Neurodevelopmental Animal Model. AB - Schizophrenia is a neurodevelopmental disorder identified by psychotic episodes, as well as cognitive deficits. There are reports of multiple alterations in the brain in schizophrenia, such as fewer dendritic spines with shape abnormalities in cortical and subcortical areas. A correlation has been established between shape and function in dendritic spines; and as the main site of excitatory synapses, the dendritic spine pathology represents a potential target for novel therapeutic tools in schizophrenia. Neonatal ventral hippocampus lesion (nVHL) in the rat has been extensively used to examine some of the pathophysiological mechanisms of schizophrenia since it mimics several behaviors, as well as abnormalities in morphological corticolimbic neurons. Thus, in this report, we determined the effects of the nVHL on locomotor behavior and memory in postpubertal rats. Also, we explored the density and the dynamics of the dendritic spines in the pyramidal neurons of layers 3 and 5 of the prefrontal cortex (PFC) and basolateral amygdala (BLA), and also in the nucleus accumbens (NAcc) medium spiny neurons (MSN). We found that nVHL rats have exhibited both hyperlocomotion and memory deficits. nVHL also reduced the number of dendritic spines and decreased the proportion of mature spines in these neurons. In conclusion, nVHL triggers behavioral abnormalities in postpubertal rats that can be associated not only with the lack of dendritic spines but also with distortion of these structures in corticolimbic neurons. Hence, the nVHL can be useful to explore the mechanisms of the dendritic spine pathology and its implications for schizophrenia. PMID- 30452974 TI - Poly (lactide-co-glycolide) (PLGA) Scaffold Induces Short-term Nerve Regeneration and Functional Recovery Following Sciatic Nerve Transection in Rats. AB - Peripheral nerve injury is an important cause of incapability and has limited available treatment. Autologous donor nerve implant is the golden standard treatment, however, may cause secondary deficits. Stem cells show positive results in preclinical settings, preserving tissue and function. We tested the efficacy of stem cells derived from human exfoliated deciduous teeth seeded in poly (lactide-co-glycolide) scaffolds in sciatic nerve transection model. Seventy two adult male Wistar rats had 7-mm nerve gap bridge using scaffolds with (or without) stem cells. Animals were randomly divided into: sham-operated; sham operated without scaffold; sham-operated + scaffold + stem cells; sciatic transection + no treatment; sciatic transection + acellular scaffolds; sciatic transection + scaffold + stem cells. Sciatic Functional Index and Ladder Rung Walking tests were performed before (-1), 14 and 28 days after surgery. Morphometric nerve measurement and muscle weights were assessed. Scaffolds with stem cells improved function in Sciatic Functional Index. Acellular scaffold was effective, promoting functional recovery and nerve regeneration following nerve injury. Scaffolds provide better nerve regeneration and functional recovery after sciatic transection. Despite cell therapy promoting faster recovery after sciatic transection in the Sciatic Index Score, stem cells did not improve functional and morphological recovery after nerve injury. This is the first study testing the potential use of scaffolds combined with stem cells in the early stages after injury. Scaffolds with stem cells could accelerate nerve recovery and favor adjuvant therapies, evidencing the need for further studies to increase the knowledge about stem cells' mechanisms. PMID- 30452975 TI - Gene Expression Profiling of Two Epilepsy Models Reveals the ECM/Integrin signaling Pathway is Involved in Epiletogenesis. AB - The molecular mechanisms underlying the development of epilepsy, i.e., epileptogenesis, are due to altered expression of a series of genes. Global expression profiling of temporal lobe epilepsy is confounded by a number of factors, including the variability among animal species, animal models, and tissue sampling time-points. In this study, we pooled two microarray datasets of the most used pilocarpine and kainic acid epilepsy models from the Gene Expression Omnibus database. A total of 567 known and novel genes were commonly differentially expressed across the two models. Pathway analyses demonstrated that the dysregulated genes were involved in 46 pathways. Real-time PCR and western blot analysis confirmed the activation of extracellular matrix (ECM)/integrin signaling pathways. Moreover, targeting ECM/integrin signaling inhibits astrocyte activation and promotes neuron injury in the hippocampus of epileptic mice. This study may provide a "gene/pathway database" that with further investigation can determine the mechanisms underlining epileptogenesis and the possible targets for neuron protection in the hippocampus after status epilepticus. PMID- 30452976 TI - An EEG-EMG correlation-based brain-computer interface for hand orthosis supported neuro-rehabilitation. AB - BACKGROUND: Corticomuscular coupling has been investigated for long, to find out the underlying mechanisms behind cortical drives to produce different motor tasks. Although important in rehabilitation perspective, the use of corticomuscular coupling for driving brain-computer interface (BCI)-based neurorehabilitation is much ignored. This is primarily due to the fact that the EEG-EMG coherence popularly used to compute corticomuscular coupling, fails to produce sufficient accuracy in single-trial based prediction of motor tasks in a BCI system. NEW METHOD: In this study, we have introduced a new corticomuscular feature extraction method based on the correlation between band-limited power time-courses (CBPT) associated with EEG and EMG. 16 healthy individuals and 8 hemiplegic patients participated in a BCI-based hand orthosis triggering task, to test the performance of the CBPT method. The healthy population was equally divided into two groups; one experimental group for CBPT-based BCI experiment and another control group for EEG-EMG coherence based BCI experiment. RESULTS: The classification accuracy of the CBPT-based BCI system was found to be 92.81 +/- 2.09% for the healthy experimental group and 84.53 +/- 4.58% for the patients' group. COMPARISON WITH EXISTING METHOD: The CBPT method significantly (p-value < 0.05) outperformed the conventional EEG-EMG coherence method in terms of classification accuracy. CONCLUSIONS: The experimental results clearly indicate that the EEG-EMG CBPT is a better alternative as a corticomuscular feature to drive a BCI system. Additionally, it is also feasible to use the proposed method to design BCI-based robotic neurorehabilitation paradigms. PMID- 30452977 TI - Stimulating the sleeping brain: Current approaches to modulating memory-related sleep physiology. AB - BACKGROUND: One of the most audacious proposals throughout the history of psychology was the potential ability to learn while we sleep. The idea penetrated culture via sci-fi movies and inspired the invention of devices that claimed to teach foreign languages, facts, and even quit smoking by simply listening to audiocassettes or other devices during sleep. However, the promises from this endeavor didn't stand up to experimental scrutiny, and the dream was shunned from the scientific community. Despite the historic evidence that the sleeping brain cannot learn new complex information (i.e., words, images, facts), a new wave of current interventions are demonstrating that sleep can be manipulated to strengthen recent memories. NEW METHOD: Several recent approaches have been developed that play with the sleeping brain in order to modify ongoing memory processing. Here, we provide an overview of the available techniques to non invasively modulate memory-related sleep physiology, including sensory, vestibular and electrical stimulation, as well as pharmacological approaches. RESULTS: N/A. COMPARISON WITH EXISTING METHODS: N/A. CONCLUSIONS: Although the results are encouraging, suggesting that in general the sleeping brain may be optimized for better memory performance, the road to bring these techniques in free-living conditions is paved with unanswered questions and technical challenges that need to be carefully addressed. PMID- 30452978 TI - Bayesian multi-dipole modelling in the frequency domain. AB - BACKGROUND: Magneto- and Electro-encephalography record the electromagnetic field generated by neural currents with high temporal frequency and good spatial resolution, and are therefore well suited for source localization in the time and in the frequency domain. In particular, localization of the generators of neural oscillations is very important in the study of cognitive processes in the healthy and in the pathological brain. NEW METHOD: We introduce the use of a Bayesian multi-dipole localization method in the frequency domain. Given the Fourier Transform of the data at one or multiple frequencies and/or trials, the algorithm approximates numerically the posterior distribution with Monte Carlo techniques. RESULTS: We use synthetic data to show that the proposed method behaves well under a wide range of experimental conditions, including low signal-to-noise ratios and correlated sources. We use dipole clusters to mimic the effect of extended sources. In addition, we test the algorithm on real MEG data to confirm its feasibility. COMPARISON WITH EXISTING METHOD(S): Throughout the whole study, DICS (Dynamic Imaging of Coherent Sources) is used systematically as a benchmark. The two methods provide similar general pictures; the posterior distributions of the Bayesian approach contain much richer information at the price of a higher computational cost. CONCLUSIONS: The Bayesian method described in this paper represents a reliable approach for localization of multiple dipoles in the frequency domain. PMID- 30452979 TI - Multifractal detrended fluctuation analysis of continuous neural time series in primate visual cortex. AB - BACKGROUND: Local field potential (LFP) recordings have become an important tool to study the activity of populations of neurons. The functional activity of LFPs is usually compared with the activity of neighboring single spike neurons with sampling rates much higher than those of the continuous field potential channel (5 kHz). However, comparison of these signals generated with the lower sampling rate technique is important. NEW METHOD: In this study, we provide an analysis of extracellular field potential time series using the sophisticated nonlinear multifractal detrended fluctuation analysis (MF-DFA). Using the MF-DFA, we demonstrate that the integral of the singularity spectrum is a powerful new method to measure the response tuning of spikes in the continuous field potential channel. RESULTS: Results show that the spikes in the continuous channel at frequency ranges above the LFP component signals were consistently tuned similar to those in the spike channel. Our results also show that using a low-pass filter (<250 Hz), which is commonly applied as a preprocessing step to insulate LFPs from spikes, significantly influences the nonlinearity of the multifractal time series. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Our approach for inferring the tuning curve of spiking activity from the continuous channel has some advantages compared to conventional methods such as spike trains. The MF-DFA does not require any preprocessing of the raw signal data and makes no assumptions about the time series characteristics. This method is robust and can be applied to short time series of continuous raw signals. PMID- 30452980 TI - Effect of immobilization on the activity of catalase carried by poly(HEMA-GMA) cryogels. AB - Hydrogen peroxide is converted by catalase to molecular oxygen and water to remove oxidative stress. In this study, catalase immobilization was performed using poly(2-hydroxyethyl methacrylate-glycidyl methacrylate) (poly(HEMA-GMA)) cryogels with different amounts of GMA. Catalase adsorption capacity of 298.7 +/- 9.9 mg/g was achieved at the end of 9 h using the poly(HEMA-GMA)-250 cryogel. Kinetic parameters and the inhibitory effects of pesticides such as 4,4'-DDE and 4,4'-DDT on the activity of free and immobilized catalase enzyme were investigated. While the Vmax value of the immobilized enzyme was reduced 4-fold compared to the free enzyme, in the case of the comparison of the KM values, the affinity of the immobilized enzyme was increased by 1.94 times against the substrate. The inhibitory effect of 4,4'-DDT pesticide was found to be higher for the immobilized and free enzyme. NaCl (1 M, pH: 7.0) solution was used for desorption of the adsorbed catalase enzyme. A desorption ratio of 96.45% was achieved. The technique used in this study is promising regarding for the immobilization of catalase enzyme to increase the operational activity. Therefore, poly(HEMA-GMA) cryogels have the potential to be used for immobilization of catalase enzyme in the fields of biology and biochemistry. PMID- 30452981 TI - Long non-coding RNA LINC00978 promotes cell proliferation and tumorigenesis via regulating microRNA-497/NTRK3 axis in gastric cancer. AB - Gastric cancer (GC) is the most common gastrointestinal malignancy in the digestive system. Recent studies have proven that long non-coding RNAs (lncRNAs) are closely related to tumor growth and metastasis. The study aimed to explore the effect of LINC00978 on GC cells proliferation and tumorigenesis. LINC00978 was up-regulated in GC tissues and cell lines. Up-regulation of LINC00978 was positively correlated with low survival rate. LINC00978 silence inhibited proliferation, metastasis, and promoted apoptosis in BGC-823 cells. Additionally, LINC00978 functioned as competing endogenous RNA to inhibit miR-497 expression. Further, NTRK3 was confirmed as a target gene of miR-497. Up-regulation of NTRK3 was found in GC tissues, and the positive correlation was presented between LINC00978 and NTRK3. Further, LINC00978 promoted cell proliferation and tumor weight by regulation of NTRK3. These findings demonstrated that LINC00978 promoted cell proliferation and tumorigenesis by regulating miR-497/NTRK3 axis in GC. PMID- 30452982 TI - Decolorization of crystal violet from aqueous solutions by a novel adsorbent chitosan/nanodiopside using response surface methodology and artificial neural network-genetic algorithm. AB - A novel adsorbent of chitosan/nanodiopside nanocomposite (CS-NDIO) was synthesized as a green composite for the removal of crystal violet (CV) and characterized by techniques like XRD, FT-IR, BET, and FESEM analysis. The influence of parameters like molar ratios of CS to NDIO, initial pH of the solution, dosage of adsorbent, initial concentration of CV and contact time was investigated and evaluated by central composite design (CCD; 5 levels and 4 factors). Also, Hybrid model of (ANN) model with genetic algorithm (GA) optimization was applied to the experimental data get through CCD. The optimized molar ratio of CS-NDIO was found: 20/80. Optimal parameter choice for maximum CV adsorption process using CCD and ANN-GA were as follows: pH = 7.50 and 7.499, adsorbent mass: 0.0077 and 0.0077 g, CV concentration: 20.000 and 20.002 mg/L, and contact time: 25.00 and 25.00 min, respectively. The evaluation adsorption equilibrium and kinetic data were fitted with the Langmuir monolayer isotherm model (qmax: 104.66 mg g-1 and R2: 0.9937) and pseudo-second order kinetics mechanism (R2: 0.9978). Thermodynamic parameters (R2: 0.9180, DeltaH degrees : 74.93 kJ mol-1, DeltaG degrees : -12.89 kJ mol-1, and DeltaS degrees : 0.93 kJ mol-1 K-1) were calculated and indicating adsorption to be an exothermic and spontaneous process. PMID- 30452983 TI - DNA polymerase beta of Leishmania donovani is important for infectivity and it protects the parasite against oxidative damage. AB - The visceral leishmaniasis is caused by L. donovani, a neglected tropical disease with an estimated number of 500,000 cases worldwide. Apart from the absence of effective vaccine, the available drugs have limitations like toxic side effects and emergence of drug resistance. The genome of Leishmania is remarkably challenged by the oxidative stress present inside the human macrophage. To maintain genomic integrity, a number of specialized DNA repair pathways assist in the recognition and repair of damaged DNA. In general, Base Excision Repair (BER) plays an essential role in the maintenance of genomic stability. We demonstrate here that the treatment of L. donovani with oxidative agents causes DNA damage and upregulation of Polbeta. On the other hand, parasite overexpressing Polbeta shows more resistance against Amp B, H2O2 and menadione as compared to wild type cells. We also observed a higher infectivity in the parasites that overexpress Polbeta. The upregulation of Polbeta was also found in stationary phase and axenic amastigote of L. donovani. Overall, we propose that Polbeta is crucial for infectivity and survival of the parasite. Discovery of specific inhibitors against Polbeta could offer an attractive strategy against leishmaniasis. PMID- 30452984 TI - Relationship between structural properties and antitumor activity of Astragalus polysaccharides extracted with different temperatures. AB - This study investigated the effects of different temperatures on structural characterization and antitumor activity of polysaccharides from Astragalus membranaceus. APS4 and APS90 were extracted at 4 degrees C and 90 degrees C, respectively, and purified by Sephadex G-200 column. APS4-90 were obtained from APS4 after treatment at 90 degrees C for 6h. MTT results showed that APS4 possessed the highest inhibitory effects on MGC-803, A549 and HepG2 cells. HPGPC analysis showed that the average molecular weights of these polysaccharides were approximately 1.5*106Da, while the asymmetrical peak of APS4-90 suggested heat degradation and configuration changes of APS4. GC, NMR and methylation results showed that these three polysaccharides had similar monosaccharide components (mainly contain glucose), and their backbones were composed of (1->2)-alpha-d Glcp. However, APS4 showed higher content of (1->2,6)-alpha-d-Glcp compared to APS4-90 and APS90, which indicated that higher branched degree would be responsible for the stronger in vitro antitumor activity in APS4. These results were also confirmed by specific rotation and SEM analysis. Our study suggested that APS4 had the potential application for cancer treatment. PMID- 30452985 TI - Biological macromolecules and mesenchymal stem cells: Basic research for regenerative therapies in veterinary medicine. PMID- 30452986 TI - Properties of potato starch treated with microwave radiation and enriched with mineral additives. AB - The paper discusses how microwave radiation and mineral additives affect selected physical and chemical properties of potato starch. Potato starch was irradiated with microwaves of 440 W or 800 W and then enriched with ions of potassium, magnesium, copper, or iron. Atomic absorption spectroscopy showed an effective incorporation of ions, while mineral saturation depended on both the microwave radiation density and the element being introduced. The data obtained prove that the microwave radiation and saturation with minerals affect the rheology and thermal characteristics of the samples under examination. Both the degree and the vector of the transformation depend on the microwave output and the mineral component introduced. Generation of radicals depends on starch degradation at high temperature while microwaves affect the number of the radicals formed. Amounts of the heat-generated radicals depend on the microwave output and the type of metal ions introduced into the starch structure. PMID- 30452987 TI - Green route for the fabrication of self-healable hydrogels based on tricarboxy cellulose and poly(vinyl alcohol). AB - A new approach for the preparation of poly (vinyl alcohol) (PVA) - cellulose based composite hydrogels by freezing/thawing method was conceived. We synthesized firstly the tricarboxy cellulose (OxC) (bearing three carboxyl groups in one anhydroglucose unit) using a one shot oxidation procedure and subsequently, the aqueous solutions of OxC were mixed with PVA solutions in different ratios, in the absence of any supplementary cross-linking agent. The spectral methods, FTIR, 1H, 13C NMR, as well as rheology measurements were used to assess the degree of interaction between the two components. The morphology studies of the resulted hydrogels, performed by SEM shows an excellent distribution of the tricarboxy cellulose inside the PVA matrix, the addition of tricarboxy cellulose contributing to an increase of the pore size. The rheological investigation reveals the synergistic network when an optimum amount of tricarboxy cellulose was introduced. In addition, the self-healing behavior reveals by the viscoelastic behavior, strongly recommend these hydrogels as potential candidates in tissue engineering applications. PMID- 30452988 TI - Detection of CD9 and CD81 tetraspanins in bovine and porcine oocytes and embryos. AB - Tetraspanins are multifunctional molecules located in specific microdomains on the plasma membrane. Thanks to their ability to form networks with other proteins they can participate in many cellular functions. Tetraspanins are part of the interactive network in gametes; however, their precise role in fertilization is not yet clear. The aim of this study was to compare the localization of CD9 and CD81 tetraspanins during oocyte maturation and early development of the embryos in bovine and porcine model. CD9 was detected on the oocyte plasma membrane and vesicles in the perivitelline space of bovine oocytes and embryos. We suggest that CD9 could be a component involved in transzonal projections. Based on the results of in vitro fertilization assay, CD9 and CD81 seem to be part of a more complex fusion network on the plasma membrane of bovine oocytes. On the other hand, both tetraspanins showed a clustered expression pattern on the plasma membrane and inner margin of zona pellucida (ZP) in porcine oocytes and embryos. We found a new species-specific pattern of CD9 and CD81 distribution in ZP which could reflect their specialized role in processes associated with cell adhesion and intercellular communication upon fertilization. PMID- 30452989 TI - Acidic polysaccharides isolated from marine algae inhibit the early step of viral infection. AB - We examined the effects of various acidic polysaccharides isolated from marine algae on the infection and replication of human immunodeficiency virus type-1 (HIV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), and human T-cell leukemia virus type-1 (HTLV-1). It was found that sulfated fucan polysaccharides, ascophyllan, and two fucoidans derived from different sources significantly inhibited the early step of HIV-1 (R9 and JR-FL) infection, while they did not affect the late step. The alginate oligomer consisted of uronic acids and sulfated-galactan porphyran showed no significant inhibitory effects. In addition, ascophyllan and two fucoidans inhibited the early step of HBV infection in a dose-dependent manner. Furthermore, these polysaccharides inhibited the early step of HCV infection but had no inhibitory effects on HTLV-1 replication. To further examine the specificity of these polysaccharides in viral infections, we used vesicular stomatitis virus (VSV)-G-pseudotyped HIV-1 infection. Ascophyllan, the two fucoidans, and alginate oligomer also potently inhibited VSV G-pseudotyped HIV-1 infection in HeLa cells. Taken together, these results suggest that the acidic polysaccharides used in this study are capable of inhibiting the early step of viral infections depending on the polysaccharides but not in a strict species-specific manner. PMID- 30452990 TI - Preparation and characterization of chitosan/polyacrylic acid/copper nanocomposites and their impact on onion production. AB - Chitosan nanoparticles (CS-NPs) and chitosan/polyacrylic acid hydrogel nanoparticles (CS/PAA-HNPs) were obtained by ionic gelation with tripolyphosphate anions and copolymerization of CS with acrylic acid (AA), respectively. The prepared NPs were loaded by different concentrations of copper (1, 2 and 3% with respect to CS) to obtain chitosan/copper nanocomposites (CS/Cu-NCs) and chitosan/polyacrylic acid/copper hydrogel nanocomposites (CS/PAA/Cu-HNCs). The prepared NPs and their NCs were characterized by different techniques. The swelling properties and copper release from CS/Cu-NCs and CS/PAA/Cu-HNCs were evaluated. The antibacterial activity of the prepared samples against bacteria (e.g., Staphylococcus aureus and Pseudomonas aeruginosa), fungi, and yeast were investigated. The results displayed that the copper release, as well as the swelling percentage of CS/PAA/Cu-HNCs, were higher than that of CS/Cu-NCs. Furthermore, the impact of using CuSO4, CS/Cu-NCs, and CS/PAA/Cu-HNCs as a different source of copper on chlorophyll content, vegetative growth, minerals content, and the yield of onion plants during two seasons 2016 and 2017 were studied. It was found that the yield, plant growth, and nutrient content of onion bulbs were improved using CS/PAA-HNPs, which was loaded with 75 ppm copper, as foliar spray for onion plants. PMID- 30452991 TI - Composition characterization of oyster polysaccharides from Crassostrea hongkongensis and their protective effect against H2O2-induced oxidative damage in IEC-6 cells. AB - The proliferative activity of oyster polysaccharides in intestine epithelial cells (IEC-6) alleviated 5-fluorouracil-induced intestinal inflammation. In this study, we aimed to measure the ability of oyster polysaccharides to promote IEC-6 cell migration and antioxidant activity and further describe their cytoprotective effect on H2O2-challenged IEC-6 cells. The C30-60% fraction of polysaccharides (CHP2) showed rapid stimulation of IEC-6 cell migration after wounding. Then, CHP2 was fractionated into four fractions, namely, CHP2-1, CHP2-2, CHP2-3 and CHP2-4. The CHP2-3 fraction possessed high scavenging activities against 2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and oxygen radical absorbance capacity (ORAC), in comparison with other fractions. And CHP2-3 was heteropolysaccharide with sulfuric esters, and it was mainly composed of glucose, galactose and arabinose and had an average molecular weight of 41.81 kDa. Pretreatment with CHP2 and CHP2-3 significantly improved the survival rate of H2O2-treated IEC-6 cells, and reduced intracellular reactive oxygen species (ROS) levels. Moreover, CHP2-3 also significantly decreased H2O2-mediated increases in the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6), and attenuated nuclear factor-kappaB (NF-kappaB) p65 activation. These results indicate that CHP2-3 may play a vital role in reducing oxidative damage in IEC-6 cells via radical scavenging, decreasing proinflammatory factors secretion, inhibiting the NF-kappaB pathway, and thus, reducing cell apoptosis. PMID- 30452992 TI - Effect of TiO2 on highly elastic, stretchable UV protective nanocomposite films formed by using a combination of k-Carrageenan, xanthan gum and gellan gum. AB - The hydrogel based composite film was prepared from k-Carrageenan (k-C), xanthan gum (X) and gellan gum (G) by solvent casting method. The transparent films made from these gellable materials with synergistic hydrogel composition have soft texture, good elasticity and excellent break strength. The k-C/X/G based nanocomposite films prepared from different weight ratio of TiO2 nanoparticles were characterized for new packaging materials. The morphology, structure and microstructure properties of the k-C/X/G and TiO2 nanocomposite films were characterized by FT-IR, XRD and SEM analysis. By the incorporation of TiO2 in the k-C/X/G nanocomposite films, the tensile strength, tensile modulus, Tg and thermal stability of the films were greatly enhanced. Due to the hydrophobic nature of the TiO2 nanoparticles there is an increase in contact angle whereas moisture content of the films decreased. The water vapor permeability (WVP) and ultra violet lights transmittance decrease upon increasing the TiO2 content. The k-C/X/G and TiO2 nanocomposites effectively shield the UV light, exhibited partial microbial activity against Staphylococcus aureus and have a high potential for the application in food and non-food industries as UV shielding packaging materials. PMID- 30452993 TI - Inulinase immobilized gold-magnetic nanoparticles as a magnetically recyclable biocatalyst for facial and efficient inulin biotransformation to high fructose syrup. AB - To date, the high cost of enzyme production, lack of enzyme reusability and operational stability are the main limitations of the enzyme's application in industry. In this work, inulinase was covalently immobilized on the surface of glutathione-coated gold magnetic nanoparticles (GSH-AuMNPs). The synthesized NPs were fully characterized. The effects of different restriction factors such as substrate concentration, temperature, and pH on the performance and stability of the enzyme were examined. The maximum activity and immobilization yield were estimated 83% and 93%, respectively. The immobilized inulinase showed maximum activity at pH 4.5 and 60 degrees C. The kinetic parameters of the immobilized enzyme were not changed significantly after the immobilization process. The reusability assessment indicated that approximately 78% of the initial activity of immobilized inulinase remained after ten times recycling. The storage stability of inulinase was improved by the immobilization process. The inulin hydrolysates were checked by HPLC and the end products only contained two components, 98% of fructose and up to 2% of glucose in both free enzyme and immobilized enzyme systems. This study introduced a simple, effective and inexpensive immobilization process, which is applicable in different biomedical, biotechnological and food industries. PMID- 30452994 TI - Removal of phosphate and nitrate ions from aqueous solution using La3+ incorporated chitosan biopolymeric matrix membrane. AB - The present investigation was carried out for the removal of phosphate and nitrate ions from aqueous solution using lanthanum incorporated chitosan membrane (La@CS) prepared by casting method. Systematic adsorption studies were performed by varying the influencing parameters like contact time, dosage, pH, interfering anions and temperature were optimized for the maximum phosphate and nitrate adsorption capacities. The adsorption equilibrium process was examined by Freundlich, Langmuir and Dubinin-Radushkevich isotherm models. The La@CS membrane showed an adsorption capacity of 76.6 and 62.6 mg/g for phosphate and nitrate ions respectively. Thermodynamic parameters such as ?G degrees , ?H degrees and ?S degrees were calculated to understand the nature of adsorption. The synthesized La@CS membrane was characterized by FTIR, SEM, EDAX with mapping analysis, XRD, AFM, TGA-DSC and zero point charge analysis. The possible adsorption mechanism was found to be electrostatic attraction as well as by ion exchange between La@CS membrane and both anions like phosphate and nitrate. The experimental results clearly indicated that the prepared La@CS membrane could be utilized for the removal of phosphate and nitrate ions from aqueous solution. PMID- 30452995 TI - Studies on the properties and biodegradability of PVA/Trapa natans starch (N-st) composite films and PVA/N-st-g-poly (EMA) composite films. AB - The morphological modification of Trapa natans starch was done by grafting the methylmethacrylate (EMA) using ferrous ammonium sulphate-potassium persulphate as a redox initiator. Different reaction parameters such as reaction temperature, time, monomer concentration, pH and solvent were optimized to get maximum graft yield (56%). The graft copolymers thus formed were characterized by Fourier transform infrared, scanning electron microscopy, X-ray diffraction and TGA/DTA/DTG techniques. PVA/starch (N-st) composite films and PVA/N-Starch grafted-poly (EMA) composite films were prepared separately by using glycerol as a plasticizer. The effect and content of grafted starch on the mechanical properties, water uptake (%), and biodegradability of the composite films were observed. Elongation at break % of PVA/starch-grafted-poly (EMA) (1:1) increased up to 38.9% of pure PVA/N-starch composites (1:1). With further increase in the ratio of grafted starch from (50% to 70%) Elongation at break, % increased to a great extent. There was 223.14% increased in PVA/starch-grafted-poly (EMA) (3:7) as compared to pure PVA/N-starch (3:7) composite films. The Max stress increased up to 100% in PVA/N-starch-grafted-poly (EMA) (3:7) composite film of pure PVA/N starch composite films (3:7). There were 41.63% decreases in water uptake in PVA/N-starch-grafted-poly (EMA) (3:7) composite films as compared to PVA/N-starch composite films. PMID- 30452996 TI - Chitosan-gold collapse gel/poly (bromophenol blue) redox-active film. A perspective for selective electrochemical sensing of flutamide. AB - Chitosan-gold collapse gel (CS-Au CG) was prepared by reducing chloroauric acid (HAuCl4) with a polysaccharide, chitosan (CS), in the absence of chemical and physical agents. CS-Au CG was used for the first time as a suitable nano biocomposite sensing film for efficient one-step electrochemical deposition of poly (bromophenol blue) (PBPB) redox mediator through amino-hydroxyl reaction to prepare a novel anti-androgen drug flutamide (FLU) sensor using glassy carbon electrode (GCE). The effect of electropolymerization cycle, scan rate, pH, and concentration of CS-Au CG/PBPB film on electrochemical behavior of FLU molecules was investigated. The excellent synergetic effect of CS-Au CG/PBPB film showed substantially enhanced electrocatalytic activity for FLU due to the halogen-nitro synthon molecular recognition processes. The selectivity of CS-Au CG/PBPB film sensor for FLU was discussed in detail. The fabricated electrochemical sensor exhibited good linearity in the ranges of 0.01-1245 MUM. And also superior sensitivity (0.63 MUAMUM-1 cm-2) along with low limit of detection (4.8 nM) was obtained for FLU determination. The CS-Au CG/PBPB film showed an excellent selectivity, good reproducibility, and stability. In addition, the proposed sensor was successfully used to analysis of FLU drug in human urine and human blood serum samples with satisfactory results. PMID- 30452997 TI - RIFM fragrance ingredient safety assessment, citronellyl phenylacetate, CAS Registry Number 139-70-8. PMID- 30452998 TI - RIFM fragrance ingredient safety assessment, pentyl phenylacetate, CAS Registry Number 5137-52-0. PMID- 30452999 TI - RIFM fragrance ingredient safety assessment, methyl isovalerate, CAS Registry Number 556-24-1. PMID- 30453000 TI - RIFM fragrance ingredient safety assessment, ethyl trans-2-butenoate, CAS Registry Number 623-70-1. PMID- 30453001 TI - Citronellol, a monoterpene alcohol with promising pharmacological activities - A systematic review. AB - Many diseases, such as inflammatory and central nervous system disorders, currently have a limited number of effective side-effect free treatments. Citronellol (CT) is a monoterpene alcohol present in the essential oil of several plants used in cooking and traditional medicine, such as those of the genus Cymbopogon and Citrus, with pharmacological activities already described in the literature. The aim of this review was to summarize the pharmacological activities already attributed to CT that could be used in treatments for humans. The databases PubMed, MedLine, Scopus, Lilacs and Scielo were searched using the terms "Citronellol" and "Drug effect". 32 articles were identified and used in the study. Twenty-one articles demonstrated CT activities, including antibiotic and antifungal effects in vitro, and 11 properties including analgesic and anticonvulsant effects in vivo, besides presenting low toxicity. In view of the need to discover new drugs and the activities reported for CT, it can be stated that CT is a promising molecule to target in future pharmacological studies. PMID- 30453002 TI - RIFM fragrance ingredient safety assessment, isononyl acetate (isomer unspecified), CAS Registry Number 40379-24-6. PMID- 30453003 TI - 3-Monochloropropane-1, 2-diol causes irreversible damage to reproductive ability independent of hormone changes in adult male rats. AB - 3-MCPD, a contaminant frequently detected in foodstuffs, has been reported to damage human kidneys and testes. Previous studies can be used to evaluate the risk to humans of exposure to excessive 3-MCPD for a short period. However, the effects of withdrawal after 3-MCPD exposure have rarely been studied. Adult male SD rats were orally administered 0, 36 and 72 mg 3-MCPD/kg b.w./day for 4 weeks, followed by a 7-week recovery period. 3-MCPD significantly reduced RBC, HGB and HCT levels, indicating a phenotype of anemia, which returned to normal after the recovery period. 3-MCPD induced dysfunction in the liver and kidneys, which were characterized by hepatomegaly and elevated serum ALT, TBIL levels, and nephromegaly and elevated serum urea, UA contents. These effects were also restored to normal after the recovery period. Although the abnormal levels of testosterone and progesterone returned to normal, 3-MCPD-induced atrophy in testes, decreased sperm concentration and motility, and an increased rate of teratosperm still existed after the recovery period. 3-MCPD can induce restorable anemia and dysfunction in liver and kidney but irreversibly damage the reproductive system with normal sex hormone levels. This study may provide a novel perspective for characterizing the ongoing risk of exposure to 3-MCPD. PMID- 30453004 TI - RIFM fragrance ingredient safety assessment, butyl benzoate, CAS registry number 136-60-7. PMID- 30453005 TI - Intracellular emetic signaling cascades by which the selective neurokinin type 1 receptor (NK1R) agonist GR73632 evokes vomiting in the least shrew (Cryptotis parva). AB - To characterize mechanisms involved in neurokinin type 1 receptor (NK1R)-mediated emesis, we investigated the brainstem emetic signaling pathways following treating least shrews with the selective NK1R agonist GR73632. In addition to episodes of vomiting over a 30-min observation period, a significant increase in substance P-immunoreactivity in the emetic brainstem dorsal motor nucleus of the vagus (DMNX) occurred at 15 min post an intraperitoneal (i.p.) injection GR73632 (5 mg/kg). In addition, time-dependent upregulation of phosphorylation of several emesis -associated protein kinases occurred in the brainstem. In fact, Western blots demonstrated significant phosphorylations of Ca2+/calmodulin kinase IIalpha (CaMKIIalpha), extracellular signal-regulated protein kinase1/2 (ERK1/2), protein kinase B (Akt) as well as alpha and betaII isoforms of protein kinase C (PKCalpha/betaII). Moreover, enhanced phospho-ERK1/2 immunoreactivity was also observed in both brainstem slices containing the dorsal vagal complex emetic nuclei as well as in jejunal sections from the shrew small intestine. Furthermore, our behavioral findings demonstrated that the following agents suppressed vomiting evoked by GR73632 in a dose-dependent manner: i) the NK1R antagonist netupitant (i.p.); ii) the L-type Ca2+ channel (LTCC) antagonist nifedipine (subcutaneous, s.c.); iii) the inositol trisphosphate receptor (IP3R) antagonist 2-APB (i.p.); iv) store-operated Ca2+ entry inhibitors YM-58483 and MRS-1845, (i.p.); v) the ERK1/2 pathway inhibitor U0126 (i.p.); vi) the PKC inhibitor GF109203X (i.p.); and vii) the inhibitor of phosphatidylinositol 3 kinase (PI3K)-Akt pathway LY294002 (i.p.). Moreover, NK1R, LTCC, and IP3R are required for GR73632-evoked CaMKIIalpha, ERK1/2, Akt and PKCalpha/betaII phosphorylation. In addition, evoked ERK1/2 phosphorylation was sensitive to inhibitors of PKC and PI3K. These findings indicate that the LTCC/IP3R-dependent PI3K/PKCalpha/betaII-ERK1/2 signaling pathways are involved in NK1R-mediated vomiting. PMID- 30453006 TI - Bromelain with peroxidase from pineapple are more potent to target leukemia growth inhibition - A comparison with only bromelain. AB - The natural anti-cancer agent bromelain is found to be beneficial for either single or multi-targeted therapy in gastric and skin carcinoma, by inhibiting cancer cell growth. Importantly, the presence of peroxidase enhances its biological efficiency. We have now evaluated a panel of cancer cell lines with bromelain in presence or absence of peroxidase to identify that the combination has higher apoptosis inducing potential in all those cell lines. Bromelain plus peroxidase (BM-PR) inhibited acute myeloid (K562) cell proliferation and altered the morphological features. Incidence of apoptosis was established by using annexin V exposure and this was confirmed that the cell cycle was arrested at G0/G1 phase in a concentration-dependent manner. BM-PR increased the intracellular ROS level and altered the mitochondrial membrane potential, as detected using dichlorofluores cin diacetate (DCFDA). It also regulated the expression of apoptosis-related proteins like Bax, Bcl2, caspase-3 and cytochrome besides causing up-regulation of p53 as determined by western blot analysis. These results suggest that BM-PR from pineapple induces apoptosis better than only bromelain in acute myeloid leukemia cells possibly via mitochondria dependent pathway. PMID- 30453007 TI - Legal aspects of zebrafish neuropharmacology and neurotoxicology research. AB - Despite the growing emphasis on translational neuropharmacology and drug discovery research, the legality underlying these fields are seldom considered. The zebrafish (Danio rerio) is an increasingly utilized model organism in neuropharmacology and neurotoxicology. As the acceptance of zebrafish in biomedicine continues to grow, the legal aspects of their applications remain outpaced by this exponential growth. Therefore, there is a need to evaluate the legal aspects of zebrafish applications to CNS drug research. Here, we discuss a wide range of regulatory topics relevant to zebrafish research, such as the bioethics of experimentation (including studies of stress and pain), welfare protection laws, the recent advances in CNS drug discovery, and specific legal aspects of controlled substance research in this aquatic species. The conceptualization and understanding of the zebrafish welfare and its promise as a model in toxicology can also potentially shape environmental protection practices and inform policy making. PMID- 30453008 TI - Safety evaluation of 3'-siallylactose sodium salt supplementation on growth and clinical parameters in neonatal piglets. AB - Sialyllactose (SL) is an abundant oligosaccharide in human milk with health benefits that include intestinal maturation, gut microbiota modulation, and cognitive development. Recent technological advances support large scale production of different forms of sialyllactose, which will enable their use as a food ingredient. The objective of the study was to investigate the dose-dependent effects of novel enzymatically-synthesized 3'-sialyllactose (3'SL) sodium salt supplemented to swine milk replacer on growth, hematological parameters and tissue histology in a pre-clinical neonatal pig model. Forty-five two-day-old male and female pigs were provided one of four experimental diets for 21 days. Diets were formulated to contain 0 (CON), 140 (LOW), 200 (MOD) or 500 (HIGH) mg/L of 3'SL sodium salt. Samples were collected on days 8 and 22 of the study for hematological and histological analyses. The addition of 3'SL sodium salt to formula at all doses was well-tolerated by neonatal piglets and supported growth and development comparable to those observed in the CON group. In addition, serum chemistries as well as hematology and organ microscopic structure were unaffected by 3'SL (p > 0.05). These data provide supportive evidence for the safety of supplementation of this enzymatically-synthesized 3'SL sodium salt to human infant formula. PMID- 30453009 TI - Safety evaluation of beta-agarase preparations from Streptomyces coelicolor A3(2). AB - Recent studies on neoagarooligosaccharides prepared by hydrolyzing agar with beta agarase DagA produced from Streptomyces coelicolor A3(2) have enhanced our knowledge about the enzymatic utility of S. coelicolor. For safety evaluation, a crude extracellular protein containing DagA (crDagA) was prepared from the culture broth of S. coelicolor A3(2) M22-2C43, a highly productive strain of DagA. All genotoxicity tests, such as bacterial reverse mutation assay, eukaryotic chromosomal aberration assay, and in vivo micronucleus assay in mice showed no mutagenic activity of crDagA. No abnormalities were found in the appearance or behavior upon single oral administration up to 20,000 mg/kg body weight (BW) [318 mg TOS (Total Organic Solids)/kg BW] and long-term repeated oral administration toxicity tests up to 10,000 mg/kg BW/day (159 mg TOS/kg BW/day) in Sprague Dawley(r)TM rats. In addition, there were no statistically significant differences in the body weight change, food intake, hematology, blood biochemistry, organ weight, and clinical signs between the crDagA-administered and non-administered groups during the experimental period. This result showed that crDagA produced from S. coelicolor A3(2) is a safe, non-toxic substance, and therefore, can be used safely for manufacturing neoagarooligosaccharide, a functional substance effective in improving metabolic syndrome. PMID- 30453010 TI - Can 24 weeks strength training reduce feelings of depression and increase neurotransmitter in elderly females? AB - BACKGROUND: Geriatric depression is common due to the high rate of chronic diseases suffered by the older population. There is a well-established effect of exercise on one's wellbeing, however, for the elderly females there is dearth in research addressing exercise and its effect on their neurotransmitters and depression score. Therefore, this study aimed to investigate the effects of 24 weeks of the Growing Stronger program on neurotransmitter and depression of older women. METHODS: Twenty-one older women, aged between 67 and 81, participated in this study. The participants were randomly assigned into a strength exercise (n = 11) and control group (n = 10) (age 76.40 +/- 3.27, height 152.77 +/- 5.63 kg, Weight 52.35 +/- 2.86Kg, BMI 22.50 +/- 1.88). The strength exercise group (age 76.10 +/- 3.85, height 151.14 +/- 5.42 kg, Weight 54.74 +/- 6.73Kg, BMI 23.96 +/- 2.70) participated for 50-80 min a day three times per week for a total of 24 weeks. All participants had their height, weight, blood testing and depression score tested before and after the training program. Two-way ANOVA with effect sizes was used to identify differences between times in each group and the statistical significance was set at 0.05. RESULTS: In neurotransmitter factor, serotonin, dopamine, epinephrine, and norepinephrine significantly decreased in the strength exercise group but not for the control group. Notably, one participant whose serotonin level was lower than normal range before the exercise program showed normal level in serotonin after the program. In depression factor, there were no significant differences for both the strength exercise group and control group. CONCLUSION: The results suggest that the effect of strength exercise on neurotransmitter and depression score remain unclear, but highlight the need for future studies investigating the relationship between strength training and depression. PMID- 30453011 TI - Challenging the dose-response-time data approach: Analysis of a complex system. AB - This study presents an extensive dose-response-time (DRT) meta-analysis of the nicotinic acid-induced inhibition of free fatty acids and insulin release. The purpose was to quantify the implications of lacking exposure data when analysing complex pharmacodynamic systems. The DRT model successfully characterised various response behaviours-including time-delays, rebound, feedback mechanisms, and adaptation-on both the individual and the population level. Comparing the fitted DRT model to an exposure-driven reference analysis showed that bias and uncertainty were introduced in the parameter estimates. However, most estimates were within one standard error from the reference. In both approaches, a few parameters suffered from practical identifiability issues, likely due to large differences in half-lives of the different rate processes. Moreover, the optimal dosing strategies predicted by the DRT model differed slightly from those of the exposure-driven analysis, having a lower optimal steady-state reduction of free fatty acids exposure. PMID- 30453012 TI - Neuronal ceroid lipofuscinosis related ER membrane protein CLN8 regulates PP2A activity and ceramide levels. AB - The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders. CLN8 deficiency causes a subtype of NCL, referred to as CLN8 disease. CLN8 is an ER resident protein with unknown function; however, a role in ceramide metabolism has been suggested. In this report, we identified PP2A and its biological inhibitor I2PP2A as interacting proteins of CLN8. PP2A is one of the major serine/threonine phosphatases in cells and governs a wide range of signaling pathways by dephosphorylating critical signaling molecules. We showed that the phosphorylation levels of several substrates of PP2A, namely Akt, S6 kinase, and GSK3beta, were decreased in CLN8 disease patient fibroblasts. This reduction can be reversed by inhibiting PP2A phosphatase activity with cantharidin, suggesting a higher PP2A activity in CLN8 deficient cells. Since ceramides are known to bind and influence the activity of PP2A and I2PP2A, we further examined whether ceramide levels in the CLN8 deficient cells were changed. Interestingly, the ceramide levels were reduced by 60% in CLN8 disease patient cells compared to controls. Furthermore, we observed that the conversion of ER-localized NBD-C6-ceramide to glucosylceramide and sphingomyelin in the Golgi apparatus was not affected in CLN8-deficient cells, indicating transport of ceramides from ER to the Golgi apparatus was normal. A model of how CLN8 along with ceramides affects I2PP2A and PP2A binding and activities is proposed. PMID- 30453013 TI - Anhydrobiosis: Inside yeast cells. AB - Under natural conditions yeast cells as well as other microorganisms are regularly subjected to the influence of severe drought, which leads to their serious dehydration. The dry seasons are then changed by rains and there is a restoration of normal water potential inside the cells. To survive such seasonal changes a lot of vegetative microbial cells, which belong to various genera and species, may be able to enter into a state of anhydrobiosis, in which their metabolism is temporarily and reversibly suspended or delayed. This evolutionarily developed adaptation to extreme conditions of the environment is widely used for practical goals - for conservation of microorganisms in collections, for maintenance and long storage of different important strain producers and for other various biotechnological purposes. This current review presents the most important data obtained mainly in the studies of the structural and functional changes in yeast cells during dehydration. It describes the changes of the main organelles of eukaryotic cells and their role in cell survival in a dry state. The review provides information regarding the role of water in the structure and functions of biological macromolecules and membranes. Some important intracellular protective reactions of eukaryotic organisms, which were revealed in these studies and may have more general importance, are also discussed. The results of the studies of yeast anhydrobiosis summarized in the review show the possibilities of improving the conservation and long-term storage of various microorganisms and of increasing the quality of industrially produced dry microbial preparations. PMID- 30453014 TI - Signal interaction between the tumour and inflammatory cells in patients with gastrointestinal cancer: Implications for treatment. AB - Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention. PMID- 30453015 TI - miR-382-5p modulates the ATRA-induced differentiation of acute promyelocytic leukemia by targeting tumor suppressor PTEN. AB - In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic differentiation and maturation. MicroRNAs play pivotal roles in formation of the leukemic phenotype. Previously, microRNA-382-5p (miR-382-5p) was upregulated in acute myeloid leukemia (AML) with t(15;17). In the present study, we found that miR-382-5p expression was elevated with ATRA-induced differentiation of APL. To investigate the potential functional role of miR-382 5p in APL differentiation, an APL cell line was transfected with miR-382-5p mimics, inhibitors, or negative control (NC). The results showed in APL cell line NB4 that miR-382-5p downregulation upon ATRA treatment was a key event in the drug response. Mechanistic investigations revealed that miR-382-5p targeted the ATRA-regulated tumor suppressor gene PTEN through direct binding to its 3' UTR. Enforced expression of miR-382-5p or specific PTEN inhibitors inhibited ATRA induced granulocytic differentiation via regulation of the cell cycle regulator cyclinD1. Conversely, PTEN overexpression promoted differentiation and enhanced sensitivity of NB4 cell line to physiological levels of ATRA. Finally, we found that PTEN overexpression restored PML nuclear bodies (NBs). Taken together, these results demonstrated that up-regulated miR-382-5p in NB4 cell line inhibited granulocytic differentiation through the miR-382-5p/PTEN axis, uncovering PTEN as a critical element in the granulocytic differentiation program induced by ATRA in APL. PMID- 30453016 TI - Transvenous pacing in complex post-operative congenital heart disease guided by angiography: A case report. AB - Transvenous pacing in patients with postoperative complex congenital heart disease (CHD) can be challenging and pose technical challenges to lead placement because of the complex anatomy, distortions produced by the surgical procedures, and the altered relationship of cardiac chambers. We describe the utility of angiography for transvenous dual chamber pacemaker implantation in a post operative complex congenital heart disease. PMID- 30453017 TI - The mechanistic links between insulin and human organic anion transporter 4. AB - Human organic anion transporter 4 (hOAT4) belongs to a class of organic anion transporters that exert critical function in the secretion, absorption, and distribution of numerous drugs in the body, such as anti-viral drugs, anti-cancer therapeutics, antibiotics, antihypertensive medicine, and anti-inflammatory drugs. hOAT4 is richly existent in the kidney and placenta. We previously established that serum- and glucocorticoid-inducible kinases (sgk) stimulate hOAT4 expression and transport activity by abrogating the inhibitory effect of a ubiquitin ligase Nedd4-2. Insulin is one of the upstream signaling molecules for sgk. We therefore investigated the effect of insulin on hOAT4 function. We showed that insulin stimulated hOAT4 expression and transport activity, and the action of insulin was abolished in cells overexpressing Nedd4-2-specific siRNA to knockdown the endogenous Nedd4-2. We further showed that insulin phosphorylated serine 327 on Nedd4-2 and weakened the interaction between hOAT4 and Nedd4-2. Interestingly, in cells overexpressing sgk2, the stimulatory effect of insulin on hOAT4 was diminished. In addition, the stimulatory effect of insulin on hOAT4 was blocked by wortmannin and buparlisib, two PI3K inhibitors. In conclusion, our study demonstrated that insulin stimulates hOAT4 expression and transport activity by abrogating the inhibition effect of Nedd4-2 on the transporter. Moreover, insulin regulates hOAT4 by competing with sgk2 rather than through sgk2. PMID- 30453018 TI - Antimicrobial magnetic nanoparticles based-therapies for controlling infectious diseases. AB - In the last years, the antimicrobial resistance against antibiotics has become a serious health issue, arise as global threat. This has generated a search for new strategies in the progress of new antimicrobial therapies. In this context, different nanosystems with antimicrobial properties have been studied. Specifically, magnetic nanoparticles seem to be very attractive due to their relatively simple synthesis, intrinsic antimicrobial activity, low toxicity and high versatility. Iron oxide NPs (IONPs) was authorized by the World Health Organization for human used in biomedical applications such as in vivo drug delivery systems, magnetic guided therapy and contrast agent for magnetic resonance imaging have been widely documented. Furthermore, the antimicrobial activity of different magnetic nanoparticles has recently been demonstrated. This review elucidates the recent progress of IONPs in drug delivery systems and focuses on the treatment of infectious diseases and target the possible detrimental biological effects and associated safety issues. PMID- 30453019 TI - Development of mechanistic models to identify critical formulation and process variables of pastes for 3D printing of modified release tablets. AB - The future of pharmaceutical manufacturing may be significantly transformed by 3 dimensional (3D) printing. As an emerging technology, the indicators of quality for materials and processes used in 3D printing have not been fully established. The objective of this study was to identify the critical material attributes of semisolid paste formulations filled into cartridges for 3D printing of personalized medicine. Nineteen semisolid formulations were prepared per a fractional factorial design with three replicates of the center point. The variables investigated included percent loading of API and various soluble and insoluble excipients. Pastes were characterized for viscoelastic characteristics during the 3D printing process including creep recovery, cross-modulus and extrudability models. Packing efficiency of pastes into 3D printing cartridges was also evaluated by X-ray tomography. Changes in composition of 3D printing pastes resulted in significant variations in their viscoelastic parameters, namely their elastic deformation, flow and relaxation behaviors. The percent of soluble excipients incorporated was the most significant factor affecting the creep behavior of pastes. Cross-over stresses were assessed to indicate the minimum pressure needed for the pastes to initiate flow. Increasing solid and swellable contents of the pastes from 7% to 63% w/w increased significantly (p < 0.05) the cross-over stress from 0.93 * 10-3 Pa to 9.47 * 10-3 Pa. Increasing soluble ingredients of paste from 30% to 80% w/w was found to increase flow of the paste from 0.41 * 10-3 to 3.85 * 10-3 %/s. X-ray tomography images revealed inclusion of air bubbles during packing of pastes into cartridges. These bubbles may affect the relaxation behavior of the pastes; hence bubbles should be eliminated. This study unveiled the critical material attributes that could be controlled for consistent 3D printing by microextrusion. PMID- 30453020 TI - Interleukin-1 mediates ischaemic brain injury via distinct actions on endothelial cells and cholinergic neurons. AB - The cytokine interleukin-1 (IL-1) is a key contributor to neuroinflammation and brain injury, yet mechanisms by which IL-1 triggers neuronal injury remain unknown. Here we induced conditional deletion of IL-1R1 in brain endothelial cells, neurons and blood cells to assess site-specific IL-1 actions in a model of cerebral ischaemia in mice. Tamoxifen treatment of IL-1R1 floxed (fl/fl) mice crossed with mice expressing tamoxifen-inducible Cre-recombinase under the Slco1c1 promoter resulted in brain endothelium-specific deletion of IL-1R1 and a significant decrease in infarct size (29%), blood-brain barrier (BBB) breakdown (53%) and neurological deficit (40%) compared to vehicle-treated or control (IL 1R1fl/fl) mice. Absence of brain endothelial IL-1 signalling improved cerebral blood flow, followed by reduced neutrophil infiltration and vascular activation 24 h after brain injury. Conditional IL-1R1 deletion in neurons using tamoxifen inducible nestin-Cre mice resulted in reduced neuronal injury (25%) and altered microglia-neuron interactions, without affecting cerebral perfusion or vascular activation. Deletion of IL-1R1 specifically in cholinergic neurons reduced infarct size, brain oedema and improved functional outcome. Ubiquitous deletion of IL-1R1 had no effect on brain injury, suggesting beneficial compensatory mechanisms on other cells against the detrimental effects of IL-1 on endothelial cells and neurons. We also show that IL-1R1 signalling deletion in platelets or myeloid cells does not contribute to brain injury after experimental stroke. Thus, brain endothelial and neuronal (cholinergic) IL-1R1 mediate detrimental actions of IL-1 in the brain in ischaemic stroke. Cell-specific targeting of IL 1R1 in the brain could therefore have therapeutic benefits in stroke and other cerebrovascular diseases. PMID- 30453021 TI - A single peri-sciatic nerve administration of the adenosine 2A receptor agonist ATL313 produces long-lasting anti-allodynia and anti-inflammatory effects in male rats. AB - Neuropathic pain is a widespread problem which remains poorly managed by currently available therapeutics. Peripheral nerve injury and inflammation leads to changes at the nerve injury site, including activation of resident and recruited peripheral immune cells, that lead to neuronal central sensitization and pain amplification. The present series of studies tested the effects of peri sciatic nerve delivery of single doses of adenosine 2A receptor (A2aR) agonists on pain and neuroinflammation. The data provide converging lines of evidence supportive that A2aR agonism at the site of peripheral nerve injury and inflammation is effective in suppressing ongoing neuropathic pain. After A2aR agonism resolved neuropathic pain, a return of pain enhancement (allodynia) was observed in response to peri-sciatic injection of H-89, which can inhibit protein kinase A, and by peri-sciatic injection of neutralizing antibody against the potent anti-inflammatory cytokine interleukin-10. A2aR agonist actions at the nerve injury site suppress neuroinflammation, as reflected by decreased release of interleukin-1beta and nitric oxide, as well as decreased sciatic expression of markers of monocytes/macrophages and inducible nitric oxide synthase. Taken together, the data are supportive that A2aR agonists, acting at the level of peripheral nerve injury, may be of therapeutic value in treating chronic pain of neuroinflammatory origin. PMID- 30453022 TI - Reducing age-dependent monocyte-derived macrophage activation contributes to the therapeutic efficacy of NADPH oxidase inhibition in spinal cord injury. AB - OBJECTIVE: The average age at the time of spinal cord injury (SCI) has increased to 43 years old. Middle-aged mice (14 months old, MO) exhibit impaired recovery after SCI with age-dependent increases in reactive oxygen species (ROS) production through NADPH oxidase (NOX) along with pro-inflammatory macrophage activation. Despite these aging differences, clinical therapies are being examined in individuals regardless of age based upon preclinical data generated primarily using young animals (~4 MO). Our objective is to test the extent to which age affects SCI treatment efficacy. Specifically, we hypothesize that the effectiveness of apocynin, a NOX inhibitor, is age-dependent in SCI. METHODS: Apocynin treatment (5 mg/kg) or vehicle was administered 1 and 6 h after moderate T9 contusion SCI (50kdyn IH) and then daily for 1 week to 4 and 14 MO mice. Locomotor and anatomical recovery was evaluated for 28 days. Monocyte-derived macrophage (MDM) and microglial activation and ROS production were evaluated at 3 and 28 days post-injury. RESULTS: Apocynin improved functional and anatomical recovery in 14 but not 4 MO SCI mice. Apocynin-mediated recovery was coincident with significant reductions in MDM infiltration and MDM-ROS production in 14 MO SCI mice. Importantly, microglial activation was unaffected by treatment. CONCLUSION: These results indicate that apocynin exhibits age-dependent neuroprotective effects by blocking excessive neuroinflammation through NOX mediated ROS production in MDMs. Further, these data identify age as a critical regulator for SCI treatment efficacy and indicate that pharmacologically reduced macrophage, but not microglia, activation and ROS production reverses age associated neurological impairments. PMID- 30453023 TI - Intellectual functioning in clinically confirmed fetal valproate syndrome. AB - BACKGROUND: An increased risk of impaired intelligence (IQ) has been documented in valproate-exposed children, but investigations have not previously focused on those with a clinical diagnosis of Fetal Valproate Syndrome (FVS). METHODS: This cross sectional observational study recruited individuals with a diagnosis of FVS and completed standardized assessments of intellectual abilities making comparisons to a normative comparison group. Both mean difference (MD) and prevalence of scores below the lower average range were analyzed. RESULTS: The mean full-scale IQ in 31 individuals with FVS (mean age 14.97; range 6-27 years) was 19 points lower (19.55, 95% CI -24.94 to 14.15), and IQ scores <70 were present in 26%. The mean differences for verbal comprehension (21.07, 95% CI 25.84 to -16.29), working memory (19.77, 95% CI -25.00 to -14.55) and processing speed (16.87, 95% CI -22.24 to -11.50) performances were poorer than expected with the mean differences over one standard deviation from the comparison group. Sixty one percent of cases demonstrated disproportionately lower verbal comprehension ability. There were no significant group differences for IQ in high vs. moderate dose valproate or mono vs. polytherapy. There were no differences in IQ between those with and those without a major congenital malformation. The requirement for educational intervention was high at 74%. CONCLUSION: Intellectual difficulties are a central feature of FVS and are more severe in their presentation in individuals with a diagnosis of valproate embryopathy. Individuals with FVS who present with the characteristic facial presentation should be considered at high risk of cognitive difficulties regardless of the dose of valproate exposure or the presence of a major congenital malformation. PMID- 30453024 TI - Predictive PBPK modeling as a tool in the formulation of the drug candidate TMP 001. AB - Since many drugs in the therapy scheme of multiple sclerosis (MS) are applied parenterally with significant side effects, oral treatment is the most accepted therapy option for chronic diseases like MS. The drug candidate TMP-001, which has disease-modifying properties, can be applied orally. Beside other symptoms, swallowing disorders have a major impact not only on the health status and quality of life of MS patients, but also impede reliable drug therapy. Consequently, the development of an easy-to-swallow liquid oral dosage form supported by a combined PBPK-IVIVC model was approached. In this context, the impact of formulation parameters was studied. Biorelevant in vitro drug release studies resulted in an almost complete release of 96.91% +/- 1.00% in the intestine which was translated to rapidly increasing in silico plasma profiles. The predictions were compared to the outcome of a phase I clinical trial. A partial parameter sensitivity analysis of the in silico model deepened our understanding of the physiological processes underlying human pharmacokinetics. PMID- 30453025 TI - Hyaluronan-based dissolving microneedles with high antigen content for intradermal vaccination: formulation, physicochemical characterization and immunogenicity assessment. AB - The purpose of this study was to optimize the manufacturing of dissolving microneedles (dMNs) and to increase the antigen loading in dMNs to investigate the effect on their physicochemical properties. To achieve this, a novel single array wells polydimethylsiloxane mold was designed, minimizing antigen wastage during fabrication and achieving homogeneous antigen distribution among the dMN arrays. Using this mold, hyaluronan (HA)-based dMNs were fabricated and tested for maximal ovalbumin (OVA) content. dMNs could be fabricated with an OVA:HA ratio as high as 1:1 (w/w), without compromising their properties such as shape and penetration into the ex vivo human skin, even after storage at high humidity and temperature. High antigen loading did not induce protein aggregation during dMN fabrication as demonstrated by complementary analytical methods. However, the dissolution rate in ex vivo human skin decreased with increasing antigen loading. About 2.7 ug OVA could be delivered in mice by using a single array with an OVA:HA ratio of 1:3 (w/w). Intradermal vaccination with dMNs induced an immune response similar as subcutaneous injection and faster than after hollow microneedle injection. In conclusion, results suggest that i) the polydimethylsiloxane mold design has an impact on the manufacturing of dMNs, ii) the increase in antigen loading in dMNs affects the microneedle dissolution and iii) dMNs are a valid alternative for vaccine administration over conventional injection. PMID- 30453026 TI - Clustered miR-2, miR-13a, miR-13b and miR-71 coordinately target Notch gene to regulate oogenesis of the migratory locust Locusta migratoria. AB - MicroRNAs (miRNAs), ~22-nt small noncoding RNAs with a crucial role in various biological processes of organisms, are usually clustered in the genome. However, little is known about the miRNA clusters involved in insect reproduction. By small RNA sequencing and quantification followed by qRT-PCR, we found that the expression of invertebrate-specific miR-2/13/71 cluster including miR-2, miR-13a, miR-13b and miR-71 significantly decreased after adult ecdysis of the migratory locust, Locusta migratoria. Luciferase reporter assay and RNA immunoprecipitation demonstrated that miR-2/13/71 bound to the protein coding sequence of Notch and downregulated its expression. Injection of miR-2/13/71 agomiRs led to significant decrease of Notch expression as well as markedly reduced levels of Vitellogenin mRNA, suppressed oocyte maturation and impaired ovarian growth. Moreover, the expression of miR-2/13/71 was repressed by juvenile hormone (JH). Our results thus point to a previously unidentified mechanism by which JH-repressed miR 2/13/71 coordinately downregulates Notch to modulate insect reproduction. The increase of JH and decrease of miR-2/13/71 expression in both previtellogenic and vitellogenic stages of adult females ensure a high level of Notch expression, critically contributing to JH-dependent vitellogenesis and oogenesis. PMID- 30453027 TI - Silicone oil migration into periorbital space surrounding an extraocular muscle after sutureless 23-gauge vitrectomy in a child. PMID- 30453028 TI - Engineering therapeutic bispecific antibodies using CrossMab technology. AB - Bispecific antibodies have recently gained major interest as they allow novel mechanisms-of-action and/or therapeutic applications that cannot be achieved using conventional IgG-based antibodies. A major issue in engineering IgG-based bispecific antibodies has been to enable the correct association of heavy and light chains resulting in correct assembly of the desired bispecific antibody in sufficient yield. Various approaches have been described during recent years to tackle this challenge. We have developed the so-called CrossMab technology that enforces correct light chain association based on the domain crossover of immunoglobulin domains in the Fab region of the bispecific antibody. This versatile technology allows the generation of different bispecific antibody formats including asymmetric heterodimeric monovalent 1 + 1 bispecific antibodies and asymmetric heterodimeric bispecific antibodies with 2 + 1 valency in combination with approaches enabling Fc-hetermodimerization like knob-into-hole technology as well as the generation of tetravalent symmetric bispecific antibodies with 2 + 2 valency, also known as Tandem-Fab based IgG antibodies, using processes suitable for the large scale production of therapeutic bispecific antibodies. Notably, as of now, at least eight different bispecific antibodies using CrossMab technology entered clinical development, and additional CrossMabs are in late preclinical development. This review provides a summary of the status and progress with the engineering and generation of CrossMab technology based bispecific antibodies as well as their therapeutic application. PMID- 30453029 TI - Improving the Evaluation and Management of Abnormal Uterine Bleeding in Adolescent Females Presenting for Emergency Care. AB - OBJECTIVE: We sought to improve emergency care for adolescents with abnormal uterine bleeding (AUB) by developing a clinical effectiveness guideline (CEG) and assessing its impact on quality of care. STUDY DESIGN: A stakeholder engagement group designed a CEG algorithm for emergency AUB management. Pediatric residents received CEG training and their knowledge and attitudes were assessed using pre- and post-intervention surveys. ICD-9 and 10 codes identified electronic health record data (EHR) for patients presenting to the pediatric emergency department (ED) for AUB 6 months before and after CEG implementation. A weighted, 20-point scoring system consisting of prioritized aspects of history, laboratory studies and management was developed to quantify the quality of care provided. MAIN OUTCOME MEASURES: Descriptive statistics, Chi Square Test, Wilcoxon Rank Sum Test, and a run chart were used for analysis. RESULTS: Pediatric residents reported higher confidence and knowledge scores post-CEG implementation. Of the 91 patients identified, 62 met inclusion criteria. Median score was 14 +/-7 before CEG implementation and 15.5 +/- 6 after. Wilcoxon Rank Sum Test showed a difference in AUB evaluation and management scores (p=0.09) following implementation of the CEG. Run chart data showed no shifts or trends (overall median score, 14-points). Both pre- and post-implementation, points were deducted most frequently for not assessing personal/family clotting disorder history. The largest improvements in care were with appropriate medication dosing and disposition. CONCLUSIONS: We designed a CEG and educational intervention for AUB management in a pediatric ED. These findings suggest our CEG may be an effective tool to improve emergency AUB care for adolescents and could increase trainees' confidence in managing this condition, though additional cycles are needed. PMID- 30453030 TI - Adverse neonatal outcomes in overweight and obese adolescents compared with normal weight adolescents and low risk adults. AB - STUDY OBJECTIVE: To evaluate the association between maternal body mass index and neonatal outcomes in adolescents and to compare neonatal outcomes between overweight and obese adolescents and obstetric low-risk adult women. DESIGN: Retrospective cohort study using data from the Swedish Medical Birth Register. SETTING: Sweden PARTICIPANTS: All 31,386 primiparous adolescents <20 years and 178,844 standard women, defined as normal weight, obstetric low-risk adult women delivered between 1992-2013. The adolescents were categorized according to weight and height in early pregnancy into body mass index groups according to the WHO classification. Logistic regression models were used. MAIN OUTCOME MEASURES: Neonatal outcomes in relation to maternal body mass index groups. RESULTS: In the adolescents, 19.5% and 7.3% were overweight and obese, respectively. Compared with normal weight adolescents, overweight adolescents had lower risk of having small for gestational age neonates, and higher risks having neonates with macrosomia, being large for gestational age and with Apgar score <7 at 5 minutes. The obese adolescents had increased risks for having neonates being large for gestational age (3.8% versus 1.3%, aOR 2.97, 95%CI 2.30-3.84), with macrosomia (>4500 g) (4.6% versus 1.4%, aOR 2.95, 95%CI 2.33-3.73), and with Apgar score <7 at 5 minutes (2.2% versus 1.1%, aOR 1.98, 95%CI 1.43-2.76) than normal weight adolescents. Compared with the standard women, overweight and obese adolescents had overall more adverse neonatal outcomes. CONCLUSIONS: Overweight and obese adolescents had predominantly increased risks for adverse neonatal outcomes compared with both normal weight adolescents and standard women. PMID- 30453031 TI - Bundle-specific tractography with incorporated anatomical and orientational priors. AB - Anatomical white matter bundles vary in shape, size, length, and complexity, making diffusion MRI tractography reconstruction of some bundles more difficult than others. As a result, bundles reconstruction often suffers from a poor spatial extent recovery. To fill-up the white matter volume as much and as best as possible, millions of streamlines can be generated and filtering techniques applied to address this issue. However, well-known problems and biases are introduced such as the creation of a large number of false positives and over representation of easy-to-track parts of bundles and under-representation of hard to-track. To address these challenges, we developed a Bundle-Specific Tractography (BST) algorithm. It incorporates anatomical and orientational prior knowledge during the process of streamline tracing to increase reproducibility, sensitivity, specificity and efficiency when reconstructing certain bundles of interest. BST outperforms classical deterministic, probabilistic, and global tractography methods. The increase in anatomically plausible streamlines, with larger spatial coverage, helps to accurately represent the full shape of bundles, which could greatly enhance and robustify tract-based and connectivity-based neuroimaging studies. PMID- 30453032 TI - Brain dynamics and temporal trajectories during task and naturalistic processing. AB - Human functional Magnetic Resonance Imaging (fMRI) data are acquired while participants engage in diverse perceptual, motor, cognitive, and emotional tasks. Although data are acquired temporally, they are most often treated in a quasi static manner. Yet, a fuller understanding of the mechanisms that support mental functions necessitates the characterization of dynamic properties. Here, we describe an approach employing a class of recurrent neural networks called reservoir computing, and show the feasibility and potential of using it for the analysis of temporal properties of brain data. We show that reservoirs can be used effectively both for condition classification and for characterizing lower dimensional "trajectories" of temporal data. Classification accuracy was approximately 90% for short clips of "social interactions" and around 70% for clips extracted from movie segments. Data representations with 12 or fewer dimensions (from an original space with over 300) attained classification accuracy within 5% of the full data. We hypothesize that such low-dimensional trajectories may provide "signatures" that can be associated with tasks and/or mental states. The approach was applied across participants (that is, training in one set of participants, and testing in a separate group), showing that representations generalized well to unseen participants. Taken together, we believe the present approach provides a promising framework to characterize dynamic fMRI information during both tasks and naturalistic conditions. PMID- 30453033 TI - Pharmacological targeting of mitochondria in cancer stem cells: An ancient organelle at the crossroad of novel anti-cancer therapies. AB - Mitochondria play vital roles in various cellular processes, ranging from cellular metabolism to signal transduction and cell death regulation. As these properties are critical for cancer growth, the mitochondrion has recently become an attractive target for anti-cancer therapies. In addition, it has come to light that mitochondria are crucially involved in the regulation of stem cell identity, differentiation and fate. A similar role for mitochondria has been also demonstrated in malignant stem-like cells termed cancer stem cells (CSCs), which are implicated in progression and resistance of many tumors. In this review, we summarize different mitochondrial functions reported to promote acquisition and maintenance of CSC phenotype and discuss the rationale for their therapeutic targeting. Particular emphasis is given to therapeutics that act directly through modulation of these mitochondrial functions and have recently emerged as promising anti-CSC drugs in pre-clinical studies. This review highlights the intriguing aspects of mitochondrial biology that may have a crucial role in cancer initiation, progression, and resistance and which might facilitate pharmacological targeting. Indeed, understanding of mitochondrial function in the regulation of CSCs will promote the development of novel CSC-targeted therapeutic strategies, which could significantly improve the long-term survival of cancer patients. PMID- 30453034 TI - Can 14-3-3 proteins serve as therapeutic targets for the treatment of metabolic diseases? AB - Since their initial characterization as abundant brain proteins more than 5 decades ago, a resurgence into understanding the cellular functions of 14-3-3 proteins has emerged. While one of the earliest functions attributed to this eukaryotic scaffold protein family was the activation of enzymes involved in catecholamine and serotonin biosynthesis, 14-3-3 proteins have since been implicated in the regulation of several cellular processes including cell-cycle control, apoptosis, and metabolism. Moreover, increasing lines of evidence demonstrate links between changes in 14-3-3 protein function and the pathogenesis of chronic diseases. As a result, this has raised the question of whether 14-3-3 proteins represent viable targets for pharmacological intervention against diseases such as obesity, diabetes and cancer. In addition to providing an overview of the 14-3-3 protein family, we will discuss their connections to metabolism and metabolic diseases. We will also elaborate on the potential of targeting 14-3-3 proteins, as well as components of their interactomes, for developing novel therapies for treating metabolic diseases, including diabetes and obesity. PMID- 30453035 TI - Diversification of shrub frogs (Rhacophoridae, Pseudophilautus) in Sri Lanka - timing and geographic context. AB - Pseudophilautus comprises an endemic diversification predominantly associated with the wet tropical regions of Sri Lanka that provides an opportunity to examine the effects of geography and historical climate change on diversification. Using a time-calibrated multi-gene phylogeny, we analyze the tempo of diversification in the context of past climate and geography to identify historical drivers of current patterns of diversity and distribution. Molecular dating suggests that the diversification was seeded by migration across a land bridge connection from India during a period of climatic cooling and drying, the Oi-1 glacial maximum around the Eocene-Oligocene boundary. Lineage-through-time plots suggest a gradual and constant rate of diversification, beginning in the Oligocene and extending through the late Miocene and early Pliocene with a slight burst in the Pleistocene. There is no indication of an early-burst phase of diversification characteristic of many adaptive radiations, nor were there bursts of diversification associated with favorable climate shifts such as the intensification of monsoons. However, a late Miocene (8.8 MYA) back-migration to India occurred following the establishment of the monsoon. The back migration, however, did not trigger a diversification in India similar to that manifest in Sri Lanka, likely due to occupation of available habitat, and consequent lack of ecological opportunity, by the earlier radiation of a sister lineage of frogs (Raorchestes) with similar ecology. Phylogenetic area reconstructions show a pattern of sister species distributed across adjacent mountain ranges or from different parts of large montane regions, highlighting the importance of isolation and allopatric speciation. Hence, local species communities are composed of species from disparate clades that, in most cases, have been assembled through migration rather than in situ speciation. Lowland lineages are derived from montane lineages. Thus, the hills of Sri Lanka acted as species pumps as well as refuges throughout the 31 million years of evolution, highlighting the importance of tropical montane regions for both the generation and maintenance of biodiversity. PMID- 30453036 TI - Cloning and effects of fasting on the brain expression levels of appetite regulators and reproductive hormones in glass catfish (Kryptopterus vitreolus). AB - The regulation of feeding is a complex process that involves coordination between various signals. Feeding hormones can be described as orexigenic (stimulate food intake, e.g. orexin and neuropeptide Y - NPY) or anorexigenic (inhibit food intake, e.g. cocaine and amphetamine regulated transcript - CART). Reproduction and energy homeostasis are closely linked, as factors that affect appetite have also been shown to influence reproductive hormones and behaviors. Gonadotropin releasing hormone (GnRH) is one of the most influential factors controlling reproduction. Although our understanding of the endocrine regulation of feeding and reproduction in fish is progressing, many gaps still remain, particularly in catfish. Glass catfish (Kryptopterus vitreolus) are freshwater fish known for their natural transparency. In this study, we isolated cDNA encoding reproductive hormones (GnRH1, GnRH2) and appetite regulators (orexin, NPY, and CART) from glass catfish and examined their distribution in various tissues. All peptides had wide distributions across various brain and peripheral tissues, except CART, which was only present in brain. In order to assess whether limited energy supply affects these peptides, we examined the effects of fasting on their brain mRNA expression levels. Fasting increased the expression of both the orexigenic (i.e. orexin and NPY) and anorexigenic (i.e. CART) hormones, and decreased expression levels of GnRH1, but did not affect GnRH2. Overall, our results suggest that fasting affects the expression of peptides involved in both feeding and reproduction, and provides new insights on the endocrine mechanisms that regulate feeding and reproduction in catfish. PMID- 30453037 TI - Environmental enrichment restores oxidative balance in animals chronically exposed to toluene: Comparison with melatonin. AB - Inhalants are widely used as recreational drugs, and toluene is the main chemical compound present in most inhalants used for these purposes. Previous studies have shown that repeated toluene exposure produces cellular death and memory impairment, while environmental enrichment (EE) rescues from those effects. However, the mechanisms involved in those responses are unclear. Previous studies have shown that toluene induces a redox imbalance at the neuronal level; although, details on the mechanism of action of environmental enrichment enhancing antioxidant capacity remain to be explored. It is also unexplored whether this putative antioxidant capacity is similar to that produced by pharmacological antioxidants. To study this hypothesis, Swiss-Webster male mice were chronically exposed to toluene (0 or 4000 ppm, 30 min/day/4 weeks). Subsequently, neurochemical tests were conducted to measure biomarkers of oxidative stress (ROS, NO, GSH/GSSG ratio and SOD activity) in the hippocampus and the prefrontal cortex. In the second part of the study, we evaluated the putative antioxidant capacity of environmental enrichment and compared it to that of melatonin, a known free radical scavenger and inductor of antioxidant defences. The results showed that chronic toluene exposure increased the levels of pro-oxidative molecules and decreased the antioxidant markers. Conversely, environmental enrichment restored oxidative balance in animals previously exposed to toluene. Furthermore, the effects of EE were similar to those obtained with melatonin. Altogether, alterations in oxidative balance could represent an intermediate signalling pathway in the cascade of effects induced by toluene, while EE and melatonin appear to have the ability to rescue those effects. PMID- 30453038 TI - Systematically engineering the biosynthesis of a green biosurfactant surfactin by Bacillus subtilis 168. AB - The biosynthesis of surfactin has attracted broad interest; however, there is a bottleneck in its low yield in wild strains and the ability to engineer Bacillus producers. Because the key metabolic mechanisms in the surfactin synthesis pathway remain unclear, genetic engineering approaches are all ending up with a single or a few gene modifications. The aim of this study is to develop a systematic engineering approach to improve the biosynthesis of surfactin. First, we restored surfactin biosynthetic activity by integrating a complete sfp gene into the nonproducing Bacillus subtilis 168 strain and obtained a surfactin titer of 0.4 g/l. Second, we reduced competition by deleting biofilm formation-related genes and nonribosomal peptide synthetases/polyketide synthase pathways (3.8% of the total genome), which increased the surfactin titer by 3.3-fold. Third, we improved cellular tolerance to surfactin by overexpressing potential self resistance-associated proteins, which further increased the surfactin titer by 8.5-fold. Fourth, we increased the supply of precursor branched-chain fatty acids by engineering the branched-chain fatty acid biosynthesis pathway, resulting in an increase of the surfactin titer to 8.5 g/l (a 20.3-fold increase). Finally, due to the preference of the glycolytic pathway for cell growth, we diverted precursor acetyl-CoA away from cell growth to surfactin biosynthesis by enhancing the transcription of srfA. The final surfactin titer increased to 12.8 g/l, with a yield of 65.0 mmol/mol sucrose (42% of the theoretical yield) in the metabolically engineered strain. To the best of our knowledge, this is the highest titer and yield that has been reported. This study may pave the way for the commercial production of green surfactin. More broadly, our work presents another successful example of the modularization of metabolic pathways for improving titer and yield in biotechnological production. PMID- 30453039 TI - Analyzing Excess Risk from Matched Designs with Double Controls: Author response. PMID- 30453040 TI - The roles of sirtuins family in cell metabolism during tumor development. AB - Altering energy metabolism to meet the uncontrolled proliferation and metastasis has emerged as one of the most significant hallmarks in tumors. However, the detailed molecular mechanisms and regulatory actions underlying have not been fully elucidated. As a family of NAD+ dependent protein modifying enzymes, sirtuins (SIRT1-SIRT7) have multiple catalytic functions such as deacetylase, desuccinylase, demalonylase, demyristoylase, depalmitoylase, and/or mono-ADP ribosyltransferase. They play important roles in regulating cell metabolism, especially in glucose and lipid metabolism, thereby exerting complex functions in either increasing or decreasing malignant characteristics in tumors. This review highlights the major function and its mechanisms of sirtuins in cellular metabolic reprogramming, such as glucose metabolism including aerobic glycolysis (the Warburg effect), oxidative phosphorylation (OXPHOS)/tricarboxylic acid (TCA) cycle and glutamine metabolism; lipometabolism including fatty acid metabolism, cholesterol metabolism, ketone body metabolism and acetate metabolism; as well as leucine metabolism and the urea cycle in tumorigenesis and cancer development. PMID- 30453041 TI - The multiverse nature of epithelial to mesenchymal transition. AB - The epithelial mesenchymal transition (EMT) program is defined as a cellular transition from an epithelial to a mesenchymal state. This process occurs to provide the cell with new phenotypic assets and new skills to perform complex processes. EMT is regulated at multilayer levels, including transcriptional control of gene expression, regulation of RNA splicing, and translational/post translational control. Although transcriptional regulation by EMT-inducing transcription factors (EMT-TFs), including Zeb, Snail and Slug members, is generally considered the master step in this process, emerging data indicate that all these regulatory networks may have a role in the control of EMT. There is a sort of parallelism between the biological and still unrevealed EMT complexity and the cosmological hypothesis that sustains the universe may exist as a multiverse. The presence of different EMT transition states together with the occurrence of multiple layers of regulation support the idea that EMT is just one on many out there. Is the activation of a single layer of regulation sufficient to initiate the whole EMT program? Can we postulate the activation of different EMT "dimensions"? If we think about these layers as multiple separate "universes", various scenarios can be revealed. PMID- 30453042 TI - Establishing a role for environmental toxicant exposure induced epigenetic remodeling in malignant transformation. AB - Humans are exposed to a wide variety of environmental exposures throughout their lifespan. These include both naturally occurring toxins and chemical toxicants like pesticides, herbicides, and industrial chemicals, many of which have been implicated as possible contributors to human disease susceptibility [1-3]. We, and others, have hypothesized that environmental exposures may cause adaptive epigenetic changes in regenerative cell populations and developing organisms, leading to abnormal gene expression and increased disease susceptibility later in life [3]. Common epigenetic changes include changes in miRNA expression, covalent histone modifications, and methylation of DNA. Importantly, due to their heritable nature, abnormal epigenetic modifications which occur within stem cells may be particularly deleterious. Abnormal epigenetic changes in regenerative cell linages can be passed onto a large population of daughter cells and can persist for long periods of time. It is well established that an accumulation of epigenetic changes can lead to many human diseases including cancer [4-6]. Subsequently, it is imperative that we increase our understanding of how common environmental toxins and toxicants can induce epigenetic changes, particularly in stem cell populations. In this review, we will discuss how common environmental exposures in the United States and around the world may lead to epigenetic changes and discuss potential links to human disease, including cancer. PMID- 30453043 TI - Interruption of immune responses in primary macrophages exposed to nonylphenol provides insights into the role of ER and NF-KB in immunotoxicity of Persian sturgeon. AB - The severe decline in population of sturgeons due to pollution highlighted poor understanding about the immunotoxicological responses of sturgeons. This study was designed in three experiments to find out how nonylphenol (NP) interrupts some pro-inflammatory immune parameters in macrophages from Persian sturgeon (Acipencer persicous) as the oldest vertebrate model conserving intact innate immune system. After determination of IC50 values of NP (200 MUM), some pro inflammatory immune parameters and induced apoptosis in macrophages at low dose (10 nM) and high dose (100 nM) of NP and of 17beta estradiol (E2) (positive control) were determined after 6, 24 and 48 h of the exposure (as the first experiment). The two doses of NP induced pro-inflammatory reaction and apoptosis with strong correlations, whereas this result was observed more obviously in high dose of E2. In the second experiments, the macrophages were exposed to the two doses of NP along with estrogen receptor alpha (ERalpha) antagonist, which consequently decreased the induction of pro-inflammatory reactions. Similarly, in the third experiment, NF-KB and ERalpha antagonists were used and pro inflammatory reactions decreased compared to the control group (P < 0.05). Decreasing correlation between immune parameters following the second and third experiments verified interaction between ERalpha and NF-KB pathways. Thus, NP could be immune disrupter and apoptosis inducer in sturgeon macrophages in vitro, even in low dose. For the first time, this study revealed that NP can induce pro inflammatory reactions in macrophages derived from sturgeons. PMID- 30453044 TI - Analysis of agglutinants elicited by antiserum of channel catfish immunized with extracellular proteins of virulent Aeromonas hydrophila. AB - Motile Aeromonas septicemia (MAS), caused by new virulent Aeromonas hydrophila (vAh) strains, has been one of the major diseases in channel catfish in recent years. Previous studies showed that channel catfish developed immunity against vAh infection after immunization with the pathogen's extracellular proteins (ECP). To understand the mechanisms associated with the immunity, anti-ECP fish serum (antiserum) was analyzed in this study. Our results revealed that the antiserum elicited agglutination of both ECP and cells of vAh. Five fish proteins were identified in ECP agglutinants, including two innate immunity associated proteins (serotransferrin and rhamnose-binding lectin), two immunoglobulin M (IgM) molecules (IgM heavy chain and light chain) and a constitutively-produced protein (warm temperature acclimation protein). More than 68 vAh proteins in ECP were recognized and caused to aggregate by IgM in the antiserum. IgM was isolated from vAh cell agglutinants and the native IgM was shown to form a tetramer that was responsible for bacterial agglutination. Immunoblotting analysis indicated that the isolated native IgM was able to recognize some proteins in ECP, such as aerolysin and hemolysin (in the form of a high molecular weight heterologous polymer). Gene expression analysis by quantitative PCR showed that fish immunized with vAh ECP had more transcripts of genes coding for IgM, serotransferrin and rhamnose binding lectin than mock-immunized fish. Both innate and antibody mediated immune responses in serum and expressed genes contributed to fish immunity upon immunization with ECP. Results of this study shed light on the versatility of vAh antigens and catfish IgM, which would help identify specific antigens for vaccine development and antigen specific antibodies in catfish. PMID- 30453045 TI - Antibiotics and chemical disease-control agents reduce innate disease resistance in crayfish. AB - The aquaculture industry has developed rapidly in recent years, and in China Crayfish Procambarus clarkii represent an important aquaculture fishery. However, bacterial and viral diseases are becoming an increasingly serious threat, causing considerable economic losses. Farmers use a large number of drugs and chemicals to destroy pathogenic microorganisms and to purify aquaculture water. The purpose of this study was to assess the effects of such drugs on crayfish immune systems. Five of the most commonly used fishery drugs and water treatment chemicals were analyzed: norfloxacin, calcium hypochlorite, quick lime, povidone iodine and copper sulfate. Crayfish immune activity tests revealed that total hemocytes counts, as well as the activities of phenoloxidase and superoxide dismutase, decreased following exposure to all five treatments. These treatments, especially calcium hypochlorite and norfloxacin, significantly enhanced hemocyte apoptosis in crayfish, regardless of disease status. Calcium hypochlorite, in particular, led to a significant decrease in the survival rates of crayfish infected with white spot syndrome virus or Vibrio alginolyticus. Our results indicate that water treatment and disease control compounds commonly used in aquaculture can reduce the innate immunity and therefore disease resistance of crayfish. PMID- 30453046 TI - Identification of outer membrane protein TolC as the major adhesin and potential vaccine candidate for Vibrio harveyi in hybrid grouper, Epinephelus fuscoguttatus (?) * E. lanceolatus (?). AB - Vibrio harveyi is a serious pathogen of scale drop and muscle necrosis disease in marine commercial fishes. Adhesion to and colonization of the host cells surfaces is the first and crucial step for pathogenic bacterial infection, which is usually mediated by outer membrane proteins (Omps). The objectives of this study were to identify the major adhesin in Omps that plays the essential role in adhesion of V. harveyi to the host cells, and to assess the potential of this adhesin as a vaccine candidate for V. harveyi infection. We observed that pathogenic V. harveyi adhered to the surface of grouper embryonic cells (GEM cells) and induced apoptosis of them. Native Omps were extracted from nine different V. harveyi strains, and five common Omp bands were isolated by SDS-PAGE analysis. Western blot analysis and an anti-native Omp antibodies blocking assay indicated that one strong and several weak immunoreactivity Omps bands presence. Next, a total of five Omps, including TolC, Agg (Agglutination protein), Omp47, Fla (Flagellin), and OmpW, were identified and their encoding genes were cloned, characterized, and expressed in E. coli. The purified recombinant TolC could competitively inhibit the invasion of V. harveyi to GEM cells in vitro, and anti TolC antibody also could significantly block the adhesion of V. harveyi to GEM cells. When used to immunize hybrid groupers, the recombinant TolC could confer significant protection to fish against experimental V. harveyi challenge. These data suggested that outer membrane protein TolC functions as a major adhesin in V. harveyi and could be a potential vaccine candidate for V. harveyi infection. PMID- 30453047 TI - The gelatinase MMP-9like is involved in regulation of LPS inflammatory response in Ciona robusta. AB - Matrix metalloproteinases (MMPs) are a family of endopeptidases collectively able to degrade the components of the extracellular matrix (ECM), with important roles in many biological processes, such as embryogenesis, normal tissue remodelling, angiogenesis and wound healing. New views on the function of MMPs reveal that they regulate inflammatory response and therefore might represent an early step in the evolution of the immune system. MMPs can affect the activity of cytokines involved in inflammation including TGF-beta and TNF-alpha. MMPs are widely distributed in all kingdoms of life and have likely evolved from a single-domain protein which underwent successive rounds of duplications. In this study, we focused on the Ciona robusta (formerly known as Ciona intestinalis) MMP gelatinase homologue. Gene organization, phylogenetic analysis and 3D modeling supported the closest correlation of C. robusta gelatinase with the human MMP-9. Real-time PCR analysis and zymographic assay showed a prompt expression induced by LPS inoculation and an upregulation of enzymatic activity. Furthermore, we showed that before of the well-known increase of TGF-beta and TNF-alpha levels, a MMP-9like boost occurred, suggesting a possible involvement of MMP-9like in regulating inflammatory response in C. robusta. PMID- 30453048 TI - Identification of thioredoxin domain-containing protein 17 from big-belly seahorse Hippocampus abdominalis: Molecular insights, immune responses, and functional characterization. AB - Thioredoxin domain-containing protein 17 (TXNDC17) is a small protein (~14 kDa) involved in maintaining cellular redox homeostasis via a thiol-disulfide reductase activity. In this study, TXNDC17 was identified and characterized from Hippocampus abdominalis. The open reading frame (ORF) consisted of 369 bp and 123 amino acids. Similar to the other thioredoxins, TXNDC17 contained a conserved WCXXC functional motif. The highest spatial mRNA expressions of HaTXNDC17 were observed in the muscle, brain, and intestine. Interestingly, the mRNA expression of HaTXNDC17 in blood showed significant upregulation at 48 h against all the pathogen associated molecular patterns (PAMPs) and bacteria. Further, HaTXNDC17 transcripts in the trunk kidney were significantly upregulated at 24-48 h by bacterial endotoxin lipopolysaccharides (LPS), viral mimic polyinosinic: polycytidylic acid (poly I:C), and gram-negative bacteria (Edwardsiella tarda). The DPPH assay showed that the radical scavenging activity varies in a concentration-dependent manner. The insulin reduction assay demonstrated a significant logarithmic relationship with the concentration of rHaTXNDC17. Moreover, FHM cells treated with recombinant HaTXNDC17 significantly enhanced cellular viability under oxidative stress. Together, these results show that HaTXNDC17 function is important for maintaining cellular redox homeostasis and that it is also involved in the immune mechanism in seahorses. PMID- 30453049 TI - Inhibition of JNK and activation of the AMPK-Nrf2 axis by corosolic acid suppress osteolysis and oxidative stress. AB - The intracellular reactive oxygen species contribute to RANKL-induced osteoclastogenesis and osteolysis. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a redox-sensitive transcription factor, is critical in the cellular defense against oxidative stress by induction of antioxidants and cytoprotective enzymes. In the current study, it was first demonstrated that RANKL-induced osteoclastogenesis and hydroxylapatite resorption were suppressed by Corosolic acid (CA) via inhibiting p-JNK and activating p-AMPK. Meanwhile, p-65, p-38, Akt, and GSK-3beta were partly inhibited during the treatment of CA. Osteoclastogenesis related genes, including NFATc1, c-fos, cathepsin K, and CTR were down-regulated by CA as well. Furthermore, the intracellular oxidative stress of CA-treated osteoclasts was dramatically decreased and Nrf2 was translocated into the nucleus to activate antioxidants including HO-1, NQO-1, and GCLC by CA. The LPS-induced mice calvarial osteolysis model was established for the in vivo investigation. Micro-CT morphometric analysis revealed that the treatment of CA restored LPS-induced bone loss and formation of osteoclasts. Besides, p-p65 and p-JNK were activated in the LPS group but inhibited by CA in vivo. The treatment of CA also activated p-AMPK during its attenuating LPS induced osteolysis. Conclusively, CA effectively protects against LPS-induced osteolysis by suppressing osteoclastogenesis and oxidative stress through the inhibition of the JNK and activation of the AMPK-Nrf2 axis. PMID- 30453050 TI - Toxicological safety evaluation in acute and 28-day studies of aqueous extract from Serjania marginata Casar. (Sapindaceae) leaves in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Serjania marginata Casar. (Sapindaceae) is a species traditionally known to be used for the treatment of gastric pain and inflammatory symptoms. AIM OF THIS STUDY: Due to the therapeutic importance of this species, this study investigated the toxicological effects of S. marginata leaves (AESM), after a single and a repeated exposure in rats. MATERIALS AND METHODS: For the acute toxicity test, 2000 mg/kg of AESM was administered to male and female rats by gavage, whereas for subacute toxicity test, 30, 150, or 750 mg/kg of AESM were used. RESULTS: No evidence of toxicity was observed in the animals acutely exposed to the extract, indicating that the LD50 is higher than 2000 mg/kg. After the repeated administration of AESM the hematological and biochemical parameters were unaltered, except the erythrocytes number and albumin levels in the exposed animals. Moreover, daily administration of this extract caused alteration on kidney histology. AESM also induced an increase of abnormal sperm, however the other reproductive parameters analyzed, in both sexes, were not altered by the treatment. CONCLUSION: Although AESM was not toxic after a single exposure, its use after prolonged periods affected some analyzed parameters, indicating that precautions should be taken when it is given over longer periods. PMID- 30453051 TI - Ethnopharmacological uses, phytochemistry, biological activities of Debregeasia salicifolia: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Debregeasia salicifolia Rendle (DS) is used traditionally for the treatment of several diseases including; urinary system diseases, bone fractures, boils, diarrhea accompanied with blood, carbuncles, pimples, dermatitis, skin rash, eczema, and tumors. Additionally, it is used as an antiseptic and antifungal agent. AIM OF THE STUDY: To document up to date information regarding D. salicifolia and link the traditional uses with its reported pharmacological evidences. The review covers taxonomy, distribution, traditional uses, active phytochemical constituents and pharmacological activities for DS. MATERIALS AND METHODS: The electronic databases such as Google Scholar, E-Resource Portal of Imam Abdulrahman bin Faisal University, Scopus, PubMed, Springer Link, etc. as well as textbooks were used to gather all relevant information about DS. RESULTS: Ethnomedicinal studies revealed a wide use of DS for various traditional purposes in the south Asian community. The uses for diarrhea, cancer, urinary complaints and skin diseases were supported by pharmacological studies. In-vitro pharmacological studies confirmed its therapeutic activities e.g. antimicrobial, anticancer, and antioxidant. Moreover, analgesic and anti-diarrheal activities were also established in animal's in-vivo activities. Despite enormous literature regarding DS, the main focus of research and interest was antimicrobial and cytotoxic activities. Quantitative and qualitative phytochemical analysis proved the presence of various classes of phytochemicals in DS extract; triterpenes, phytosterols, tannins, flavonoids and anthraquinone. CONCLUSION: Though most of the traditional uses for the plant were supported by in-vitro and in-vivo pharmacological studies, however lack of clinical trials and shortage of in-depth mechanistic in-vivo studies was noted in the review. Hence, more elaborative in-vivo studies with quality clinical trials may be focused in order to confirm the safety and efficacy of reported activities in humans which will help explore the plant's therapeutic potentials. PMID- 30453052 TI - Symptom Trajectories Are Associated With Co-Occurring Symptoms During Chemotherapy For Breast Cancer. AB - CONTEXT: Symptoms are reported to co-occur during treatment for breast cancer. We previously identified 3 patterns of fatigue and 2 patterns of disturbed sleep, depressed mood, and anxiety in women undergoing chemotherapy for breast cancer using a Latent Growth Mixture Model. OBJECTIVES: The purpose of this study was to explore whether membership in symptom classes of fatigue, disturbed sleep, depressed mood and anxiety is associated with other symptoms at moderate-to severe levels. METHODS: Using data from 3 longitudinal studies, Wilcoxin rank sum tests and Jonckheere-Terpstra tests for trend were used to distinguish between classes of women on co-occurring symptoms. Summative scores were calculated, including the number of days subjects reported moderate-to-severe levels (4 or higher on a 0-10 scale) of 7 symptoms during 2 cycles of chemotherapy and compared to class membership. RESULTS: Participants (n = 166) in the higher fatigue severity class reported more days with moderate to severe disturbed sleep, depressed mood, anxiety, nausea, and trouble thinking. Women in the higher severity disturbed sleep class reported more days with moderate to severe fatigue, depressed mood, anxiety, and trouble thinking. Women in the higher depressed mood severity class reported more days with moderate to severe fatigue, disturbed sleep, anxiety, and nausea. Women in the higher anxiety severity class reported more days with moderate to severe fatigue, disturbed sleep, and depressed mood. CONCLUSION: Moderate to severe symptoms co-occur during cancer treatment for breast cancer. The dynamic process of multiple symptoms may be altered by future identification of a shared etiology. PMID- 30453053 TI - Edema of advanced cancer: prevalence, etiology and conservative management - a single hospice cross sectional study. PMID- 30453054 TI - Does Caregiving Strain Increase as Patients with and without Dementia Approach the End of Life? AB - CONTEXT: Family caregivers play critical and demanding roles in the care of persons with dementia through the end of life. OBJECTIVES: To determine whether caregiving strain increases for dementia caregivers as older adults approach the end of life, and secondarily, whether this association differs for non-dementia caregivers. METHODS: Participants included a nationally representative sample of community-living older adults receiving help with self-care or indoor mobility and their primary caregivers (3,422 dyads). Older adults' death within 12-months of survey was assessed from linked Medicare enrollment files. Multivariable logistic regression was used to assess the association between dementia and end of-life status and a composite measure of caregiving strain (range: 0-9, using a cut point of 5 to define "high" strain) after comprehensively adjusting for other older adult and caregiver factors. RESULTS: The prevalence of dementia in our sample was 30.1%; 13.2% of the sample died within 12-months. The proportion of caregivers who experienced high strain ranged from a low of 13.5% among non dementia, non-end-of-life caregivers to a high of 35.0% among dementia caregivers of older adults who died within 12-months. Among dementia caregivers, the odds of high caregiving strain was nearly twice as high (aOR = 1.94, 95% CI: 1.10-3.45) for those who were assisting older adults nearing end of life. Among non-dementia caregivers, providing care near the end of life was not associated with high strain. CONCLUSION: Increased strain toward the end of life is particularly notable for dementia caregivers. Interventions are needed to address the needs of this population. PMID- 30453055 TI - Osteoarthritis year in review 2018: clinical. AB - Osteoarthritis (OA) is the most common joint disease in the world, with an age associated increase in both incidence and prevalence. Clinical and epidemiologic research is crucial to better understand risk factors for disease, find the best treatments for symptoms, and identify therapies to slow down or even prevent disease progression. This paper is based on a systematic review of the osteoarthritis literature published in English between 2017/05/01 and 2018/04/25, with a focus on papers which have the potential to improve patient care, or which suggest novel areas for future research. PMID- 30453056 TI - Association of Bariatric Surgery and National Medication Utilization. AB - BACKGROUND: Bariatric surgery is an effective and enduring treatment for severe obesity. In addition to improvements in health status, bariatric surgery has been noted to potentially decrease post-operative health care costs particularly medication utilization. STUDY DESIGN: Longitudinal analysis of 2007-2012 claims data comparing a bariatric surgery cohort with a propensity matched non-surgical control group over a total five-year time period. Truven Health Analytics MarketScan Commercial Claims and Encounters Database with a total enrollment of 56 million covered lives from all insurers and representing all 50 states was employed. An initial sample of 384,343 obese patients were identified with a total of 5,978 matched 1:1 pairs of obese bariatric surgery cases and controls without bariatric surgery being designated following matching and propensity score matching procedure. 2,700 of those matched pairs had at least 4 years of follow-up following index date. RESULTS: The matched cohorts included 2,700 patients (77.2% female; mean age 47.1 years). During the 4-year follow-up period, bariatric surgery patients had 22.6% lower pharmacy costs compared to non surgical controls (p<0.001). Mean total pharmacy costs showed a sustained decrease in the surgery group compared to the matched controls ($8,411 vs. $9,900; p<0.001). Medication utilization in the surgery group declined significantly from 1-year pre-operative to 4-years post-operative in contrast to the control group. In the 4-year post-surgery period, the number of anti diabetic, antihypertensive and cardiac prescriptions in the surgical cases reduced by 73.7%, 48.3%, and 48.9%, respectively compared to the controls. CONCLUSIONS: Total pharmacy utilization and costs showed a significant and sustained reduction over 4-year follow-up period among patients undergoing gastric bypass or band surgery in comparison to a propensity-matched control group. PMID- 30453057 TI - Evaluation for Genetic Disorders in the Absence of a Clinical Indication for Testing: Elective Genomic Testing. AB - The increasing quality and diminishing cost of next-generation sequencing has transformed our ability to interrogate large quantities of genetic information. This has led to a dramatic increase in the number of elective genomic tests performed. In this article, elective test denotes a test that a patient chooses to undertake without a clinical indication. The variety of elective genomic testing options is considerable. Because these offerings provide differing levels of sensitivity and specificity, it can be difficult to choose among them. A simple rubric to compare offerings is not readily available. We propose a framework designated completeness that evaluates both analytical and interpretative components of genomic tests. We then illustrate how this framework can be used to evaluate the expanding landscape of elective genomic testing. PMID- 30453058 TI - Pharmacophore-based models for therapeutic drugs against phosphorylated tau in Alzheimer's disease. AB - Phosphorylated tau (P-tau) has received much attention in the field of Alzheimer's disease (AD), as a potential therapeutic target owing to its involvement with synaptic damage and neuronal dysfunction. The continuous failure of amyloid beta (Abeta)-targeted therapeutics highlights the urgency to consider alternative therapeutic strategies for AD. The present review describes the latest developments in tau biology and function. It also explains abnormal interactions between P-tau with Abeta and the mitochondrial fission protein Drp1, leading to excessive mitochondrial fragmentation and synaptic damage in AD neurons. This article also addresses 3D pharmacophore-based drug models designed to treat patients with AD and other tauopathies. PMID- 30453059 TI - Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption. AB - It was in 400 BC that Hippocrates reportedly stated that "death sits in the colon". The growth in our knowledge of the intestinal microbiome, the gut-brain axis and their function and imbalance has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance. PMID- 30453060 TI - Comparative transcriptome analysis of diploid and triploid hybrid groupers (Epinephelus coioides? * E. lanceolatus?) reveals the mechanism of abnormal gonadal development in triploid hybrids. AB - In our previous studies, diploid and triploid hybrids have been detected from the hybridization of Epinephelus coioides? * E. lanceolatus?. The triploid groupers have been found to be delayed in gonadal development, but the mechanism remains poorly understood. In this study, we examined the gonadal development, assayed the serum steroid hormone levels, and compared the BP (brain and pituitary) and G (gonad) transcriptomes of 18-month-old diploid and triploid hybrids. The results showed that levels of serum estradiol-17beta and testosterone were significantly higher in triploid groupers. The RNA-seq data revealed that 1518 and 14,963 differentially expressed genes were identified in the BP and G transcriptome, respectively. Further analysis revealed that the expression levels of genes involved in the sexual differentiation pathway and sex steroid synthesis pathway are significantly higher in triploid hybrids. Our findings provided a comprehensive insight into a better understanding of the regulatory mechanisms of sterility in triploid hybrid fish. PMID- 30453061 TI - Comparative genomics inferred two distinct populations of piscine pathogenic Streptococcus agalactiae, serotype Ia ST7 and serotype III ST283, in Thailand and Vietnam. AB - The genomes of Streptococcus agalactiae (group B streptococcus; GBS) collected from diseased fish in Thailand and Vietnam over a nine-year period (2008-2016) were sequenced and compared (n = 21). Based on capsular serotype and multilocus sequence typing (MLST), GBS isolates are divided into 2 groups comprised of i) serotype Ia; sequence type (ST)7 and ii) serotype III; ST283. Population structure inferred by core genome (cg)MLST and Bayesian clustering analysis also strongly indicated distribution of two GBS populations in both Thailand and Vietnam. Deep phylogenetic analysis implied by CRISPR array's spacer diversity was able to cluster GBS isolates according to their temporal and geographic origins, though ST7 has varying CRISPR1-spacer profiles when compared to ST283 strains. Based on overall genotypic features, Thai ST283 strains were closely related to the Singaporean ST283 strain causing foodborne illness in humans in 2015, thus, signifying zoonotic potential of this GBS population in the country. PMID- 30453062 TI - A study of the impact of DNA helical rise on protein-DNA interaction. AB - Nucleosomes are not uniformly distributed along DNA and their positioning (termed "nucleosomal landscape") can be derived using data available for several genomes. In this study we analyzed DNA helical rise profiles through a tetranucleotide code, and we defined the nucleosomal landscape of several sequences forming dinucleosomes and of the sequences of huntingtin, myotonic dystrophy type 1 and fragile mental retardation 2 genes, which contained several repeated sequences. We also analyzed the profiles of some sequences interacting with transcription factors or with RNA polymerase II. In the genomes of Cenorhabditis elegans, Mus musculus and Homo sapiens we found profiles with extremely low helical rise values, characteristic of nucleosome free regions. We defined these regions as "holes" and found that their presence correlates with lamina associated domains sequences. Altogether, this study shows that DNA helical rise profile may have a role in gene expression modulation and in shaping chromosomal structure. PMID- 30453063 TI - The long noncoding RNA NORAD promotes the growth of gastric cancer cells by sponging miR-608. AB - Dysfunction of long non-coding RNAs (lncRNAs) has been suggested to play pivotal roles in the initiation and progression of human cancers. The noncoding RNA activated by DNA damage (NORAD) is a recently identified, highly conserved lncRNA that is essential for the mitotic cell division. Recent studies demonstrated the potential oncogenic function of NORAD in bladder cancer and colon cancer, however, the role and clinical value of NORAD have not been illustrated in gastric cancer. Here, we found that NORAD was highly expressed in gastric cancer tissues and cell lines. Overexpression of NORAD was significantly correlated with the worse prognosis of the gastric cancer patients. Down-regulation of NORAD suppressed the proliferation and migration of gastric cancer cells. Mechanistically, NORAD acted as a competitive endogenous RNA (ceRNA), which sponged miR-608 and suppressed the expression of miR-608 in gastric cancer cells. Further experiments demonstrated that miR-608 targeted the forkhead box O6 (FOXO6) and negatively regulated the expression of FOXO6. Consistent with the inhibitory effect of NORAD on miR-608, overexpression of NORAD enhanced the level of FOXO6 in gastric cancer cells. Overexpression of FOXO6 attenuated the inhibitory effect of miR-608 on the gastric cancer cell growth. Collectively, our results demonstrated that NORAD promoted the growth of gastric cancer cells via modulating the miR-608/FOXO6 pathway. PMID- 30453064 TI - Toll-like receptor 9 polymorphisms and Hepatitis B virus clearance in Moroccan chronic carriers. AB - OBJECTIVES: Toll-like receptor 9 (TLR9) plays a crucial role in the innate immune response against viral infections. The failure of this system may result, in an attenuated immune response against HBV. Recent research has focused on the possibility of targeting the defects in TLR9 pathway as a novel approach for anti HBV treatment. Our study aimed to assess the impact of both TLR9 rs5743836 and rs187084 polymorphisms on spontaneous HBV clearance in Moroccan chronic HBV carriers. METHODS: In this study, 239 individuals chronically infected with HBV (CHB) and 133 subjects who spontaneously resolved the infection (SRB) were genotyped using a Taqman allelic discrimination assay. RESULTS/CONCLUSION: Remarkably, we observed a dosage effect of both SNPs on viral loads; with a significant increase of circulating HBV DNA within AA, AG to GG rs5743836 genotypes, whereas the inverse phenomenon was noticed within rs187084 genotypes. There were no consistent association between TLR9 polymorphisms and spontaneous clearance of HBV, however, a significant association was observed between rs187084 AA genotype and HBV progression to advanced liver disease. Further studies on larger populations might be necessary to understand the modulating effect of TLR9 polymorphisms on HBV loads that remain a viral factor of paramount importance to predict HCC development. PMID- 30453065 TI - Independent association of whole blood miR-328 expression and polymorphism at 3'UTR of the PAX6 gene with myopia. AB - PURPOSE: This study aimed to find associations between miR-328 expression in whole blood, polymorphism at 3'UTR of the PAX6 gene (paired box homeotic gene 6) and myopia. METHODS: We evaluated 451 individuals (142 individuals with low, 49 with moderate and 13 with high-degree myopia, and 247 healthy individuals). DNA and RNA were extracted from peripheral blood samples. Expression of miR-328 was assessed and genotyping of single-nucleotide polymorphisms (SNPs) of the PAX6 (rs662702) performed using the Applied Biosystems 7900HT Real-Time Polymerase Chain Reaction System. RESULTS: Moderate and high degree myopia showed significant differences between TT and CT genotypes of the PAX6 gene (p < 0.001). In the myopia group, 71.4% of the subjects had the TT genotype and 28.6% had the CT genotype; meanwhile in the control group, 97.1% had the TT genotype and 2.9% had the CT genotype. The odds ratio of having moderate and/or high degree myopia for individuals with the CT genotype was 13.6 (2.865-64.55) 95% CI versus TT genotype (p = 0.001). MiR-328 results showed that ?Ct values differed statistically significantly between the myopia and control groups. Patients with myopia in the peripheral blood cells had a higher expression of miR-328 than controls (p < 0.05). CONCLUSIONS: Significant differences were detected between the PAX6 gene (rs662702) TT and CT genotypes in moderate and high degree myopia; the risk C allele increased the risk for myopia. The expression level of miR-328 in peripheral blood cells was higher in patients with myopia than controls. We did not find the association between expression of mir-328 in the peripheral blood cells and PAX6 gene (rs662702) polymorphism comparing myopia and control groups. PMID- 30453066 TI - Genome-wide identification and expression analysis of glycine-rich RNA-binding protein family in sweet potato wild relative Ipomoea trifida. AB - Glycine-rich RNA-binding proteins (GRPs) contain RNA recognition motif (RRM) and glycine-rich domains at the N- or C-terminus, respectively, and they participate in varied physiological and biochemical processes, as well as environmental stresses. Sweet potato from the genus Ipomoea is one of the most important crops. However, the role of the GRP gene family in Ipomoea plant species has not been reported yet. At the same time, the genome of sweet potato remains to be elucidated, but the genome of I. trifida which is most probably the progenitor of the sweet potato was released recently. In this regard, we carried out genome wide analysis of GRP family members in I. trifida. Here, we identified nine GRP genes in I. trifida and investigated their motif distribution, promoters and gene structure. Subsequently, we performed phylogenetic analysis with the GRP genes from I. trifida, Arabidopsis thaliana, Zea mays L. and Oryza sativa to investigate their phylogenetic relationship. Moreover, we studied the expression patterns of ItGRPs in the roots, stems, young and mature leaves and flowers and found that ItGRP genes were tissue-specific. Meanwhile, the expression profiles under four abiotic stress conditions, including heat, cold, salt and drought stress treatments, revealed that some genes were markedly up-regulated or down regulated. Taken together, our findings will provide reference to studies on the function of GRP genes in the development and stress response of I. trifida. PMID- 30453067 TI - Association of genetic polymorphisms with age at menarche in Russian women. AB - OBJECTIVES: Examine the association of genetic polymorphisms with age at menarche (AAM) in Russian women. STUDY DESIGN: A total of 1613 Russian females were recruited for the study. Fifty two polymorphisms were analyzed for their association with AAM, height, and BMI. The associations were analyzed assuming the additive, dominant, and recessive models and using the log-linear regression as implemented in PLINK v. 2.050. The 2-, 3-, and 4-loci models of gene-gene interactions were analyzed using the MB-MDR method and validated by the permutation test. MAIN OUTCOME MEASURES: Genetic polymorphism rs6438424 3q13.32 was independently associated with AAM in Russian women. In addition, 14 SNPs were determined as possible contributors to this trait through gene-gene interactions. RESULTS: The obtained results suggest that 14 out of 52 studied polymorphisms may contribute to AAM in Russian women. The rs6438424 3q13.32 polymorphism was associated with AAM according to both additive and dominant models (rperm = 0.005). In total 12 two-, three-, and four-locus models of gene-gene interactions were determined as contributing to AAM (pperm <= 0.006). Nine of the 14 AAM associated SNPs are also associated with height and BMI (pperm <= 0.003). Among 14 AAM-associated SNPs (a priori all having regulatory significance), the highest regulatory potential was determined for rs4633 COMT, rs2164808 POMC, rs2252673INSR, rs6438424 3q13.32, and rs10769908 STK33. Eleven loci are cis-eQTL and affect expression of 14 genes in various tissues and organs (FDR < 0.05). The neuropeptide-encoding genes were overrepresented among the AAM-associated genes (pbonf = 0.039). CONCLUSIONS: The rs6438424 polymorphism is independently associated with AAM in Russian females in this study. The other 14 SNPs manifest this association through gene-gene interactions. PMID- 30453068 TI - The human oncogene SCL/TAL1 interrupting locus (STIL) promotes tumor growth through MAPK/ERK, PI3K/Akt and AMPK pathways in prostate cancer. AB - The morbidity and mortality of prostate cancer (PCa) in China have increased obviously, which became the second leading cause of death in men with cancer. Hedgehog (Hh) signaling pathway is a key signaling pathway involved in the prostate cancer progression. The human oncogene SCL/TAL1 interrupting locus (STIL) can modulate the Hh signaling pathway, but its function in PCa has not been reported. Here, we showed that STIL was increased in high grade prostate cancer tissue. Knockdown of STIL in prostate cancer cells PC-3 and DU 145 significantly decreased the proliferation of cells and induced cellular apoptosis through casepase3/7 mediated pathway. Moreover, the colony formation ability was also inhibited when knockdown of STIL by lentivirus-mediated shRNA. Furthermore, the cellular signaling antibody array analysis revealed which signaling pathway was affected when silencing STIL. Altogether, we found that STIL could affect MAPK/ERK, PI3K/Akt and AMPK signaling pathways, thus promoting cellular proliferation, colony formation and suppressing cellular apoptosis in prostate cancer. PMID- 30453069 TI - Identification of microRNAs in granulosa cells from patients with different levels of ovarian reserve function and the potential regulatory function of miR 23a in granulosa cell apoptosis. AB - This study aimed to determine the microRNA (miRNA) profiles in granulosa cells (GCs) from the follicular fluid (FF) of patients with varying levels of ovarian reserve function. We included 45 women undergoing in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment. After collecting GCs from each patient, total RNA was extracted from 12 samples. Using Illumina/deep sequencing technology, we analyzed the small RNAs in each group. Using the R package, we identified the differentially expressed (DE) miRNAs among patients with varying levels of ovarian reserve function. We identified 20 conserved and 3 novel miRNAs that were upregulated in the poor ovarian response (POR) group and 30 conserved miRNAs and 1 novel miRNA that were upregulated in the polycystic ovary syndrome (PCOS) group. Bioinformatics analysis revealed complementary pairing between miR-23a and the 3'-untranslated region (UTR) of the Sirt1 mRNA. miR-23a can regulate SIRT1 protein expression at the posttranscriptional level in GCs. Overexpressing miR-23a can inhibit the expression of SIRT1, decrease the stimulatory effect of SIRT1 on the ERK1/2 pathway, inhibit the expression of p ERK1/2, and increase apoptosis in GCs. Previous studies confirmed that miR-23a targets SIRT1 and promotes apoptosis in GCs by inhibiting the ERK1/2 signaling pathway. This study provides a novel perspective regarding the role of miRNAs in the regulation of human GC apoptosis in vitro. PMID- 30453070 TI - Identification and expression analysis of a novel miRNA derived from ERV-E1 LTR in Equus caballus. AB - Horses (Equus caballus) have been domesticated and bred to enhance speed, strength, and agility. Members of the Equus caballus Endogenous Retrovirus (EqERV) family affect several of these abilities in horses. EqERV elements have been integrated in the horse genome during evolution and generate repeat elements such as long terminal repeats (LTRs). LTR sequences are involved in retrovirus replication and play an essential function in post-transcriptional control mechanisms, such as by providing binding sites for microRNAs (miRNAs) or generating miRNA precursors. In this study, we identified a novel miRNA derived from EqERV-E1 LTR using various bioinformatics tools. To examine the relationship between EqERV-E1 LTR and similar elements, we used BLAST2seq and phylogenetic analysis. LTR sequences were located in the untranslated region (UTR) of mRNAs and also formed the stem-loop secondary structure. The sequence was registered in the DDBJ database as LTR derived miRNA under the accession number corresponding to LC383797 (referred to eca-miR-1804). Quantitative polymerase chain reaction (qPCR) to confirm the expression of eca-miR-1804 and the similar miR-1255a, showed an almost identical expression pattern in eight different equine tissues. Therefore, these data imply that the LTR could function as an miRNA, which is expressed in the examined equine tissues. In addition, the current study provides inputs for additional functional studies concerning the LTR of other EqERV families. PMID- 30453071 TI - Mitogenomics of Central American weakly-electric fishes. AB - Electric fishes are a diverse group of freshwater organisms with the ability to generate electric organ discharges (EODs) that are used for communication and electrolocation. This group (ca. 200 species) has originated in South America, and six species colonized the Central American Isthmus. Here, we assembled the complete mitochondrial genomes (mitogenomes) for three Central American electric fishes (i.e. Sternopygus dariensis, Brachyhypopomus occidentalis, and Apteronotus rostratus), and, based on these data, explored their phylogenetic position among Gymnotiformes. The three mitogenomes show the same gene order, as reported for other fishes, with a size ranging from 16,631 to 17,093 bp. We uncovered a novel 60 bp intergenic spacer (IGS) located between the COII and tRNALys genes, which appears to be unique to the Apteronotidae. Furthermore, phylogenetic relationships supported the traditional monophyly of Gymnotiformes, with the three species positioned within their respective family. In addition, the genus Apteronotus belongs to the early diverging lineage of the order. Finally, we found high sequence divergence (13%) between our B. occidentalis specimen and a sequence previously reported in GenBank, suggesting that the prior mitogenome of B. occidentalis represents a different South American species. Indeed, phylogenetic analyses using Cytochrome b gene across the genus placed the previously reported individual within B. bennetti. Our study provides novel mitogenome resources that will advance our understanding of the diversity and phylogenetic history of Neotropical fishes. PMID- 30453072 TI - Multiple transcription factors mediating the expressional regulation of myosin heavy chain gene involved in the indeterminate muscle growth of fish. AB - Torafugu myosin heavy chain gene, MYHM2528-1, is specifically expressed in neonatal slow and fast muscle fibers, suggesting its functional role in indeterminate muscle growth in fish. However, the transcriptional regulatory mechanisms of MYHM2528-1 involved in indeterminate muscle growth in fish remained unknown. We previously isolated a 2100 bp 5'- flanking sequence of torafugu MYHM2528-1 that showed sufficient promoter activity to allow specific gene expression in neonatal muscle fibers of zebrafish. Here, we examined the cis regulatory mechanism of 2100 bp 5'-flanking region of torafugu MYHM2528-1 using deletion-mutation analysis in zebrafish embryo. We discovered that myoblast determining factor (MyoD) binding elements play a key role and participate in the transcriptional regulation of MYHM2528-1 expression in zebrafish embryos. We further discovered that paired box protein (Pax3) are required for promoting MYHM2528-1 expression and myocyte enhancer factor-2 (MEF2) binding sites participate in the transcriptional regulation of MYHM2528-1 expression in slow/fast skeletal muscles. Our study also confirmed that the nuclear factor of activated T-cell (NFAT) binding sites take part in the transcriptional regulation of MYHM2528-1 expression in slow and fast muscles fiber in relation to indeterminate muscle growth. These results obviously confirmed that multiple cis elements in the 5'-flanking region of MYHM2528-1 function in the transcriptional regulation of its expression. PMID- 30453073 TI - Genome-wide characterization of the cellulose synthase gene superfamily in Solanum lycopersicum. AB - The cellulose synthase gene superfamily, which includes the cellulose synthase (CesA) and cellulose synthase-like (Csl) gene families, plays a vital role in the biosynthesis of cellulose and hemicellulose in plants. However, these genes have not been extensively studied in tomato (Solanum lycopersicum), a model for Solanaceae plants and for fleshy fruit development. Here, we identified and systematically analyzed 38 CesA/Csl family members that contained cellulose synthase domain regions, and categorized their encoded proteins into 6 subfamilies (CesA, CslA, CslB, CslD, CslE, and CslG) based on phylogenetic analysis. Most CesA/Csl genes from tomato are closely related to those from Arabidopsis, but the families have distinct features regarding gene structure, chromosome distribution and localization, phylogeny, and deduced protein sequence, indicating that they arose via different evolutionary process. Furthermore, expression analysis of CesA/Csl genes in different tissues at various developmental stages showed that most CesAs were constitutively expressed with differential expression levels in various organs; three CslD genes were expressed specifically in flowers, and four CesA and five Csl putative genes were preferentially expressed in fruits. Our results provide insight into the general characteristics of the CesA/Csl genes in tomato, and lay the foundation for further functional studies of CesA/Csl genes in tomato and other Solanaceae species. PMID- 30453074 TI - Investigation of the synergistic effects of paclitaxel and herbal substances and endemic plant extracts on cell cycle and apoptosis signal pathways in prostate cancer cell lines. AB - Paclitaxel, which isolated from Taxus brevifolia, is recently started to be used against prostate cancer treatment and it is a very effective compound against cancer. In this study, we aimed to test the synergistic effect of two plant active compounds (sulphoraphane (SFN) and silymarin (SILY)) and several endemic plant species from Turkey (such as Phlomis leucophracta, Rubia davisiana, Alkanna tinctoria), which are known to have anticarcinogenic effect on androgen independent PC3 and DU145, and androgen-dependent VCaP prostate cancer cell lines, with paclitaxel on the expression of cell cycle signaling and apoptosis regulator genes. Herbal substances and endemic herbal extracts were combined with Paclitaxel drug. IC50 doses were identified as real-time online. The most effective synergistic doses were determined according to isobologram analysis. The apoptotic effects of effective combined doses were evaluated by TUNEL, Annexin V, and JC-1 methods. Apoptotic and/or cell cycle arrest effects of confirmed combined doses on the expression of genes in these pathways were assessed by real-time online. Endemic plant extracts (Alkanna tinctoria, Phlomis leucophracta and Rubia davisiana, IC50 < 220 MUg/ml) and herbal substances (SILY, and SFN IC50 < 130 MUM) indicated antiproliferative and apoptotic effects in prostate cancer cell lines. They testified to the synergistic effect of paclitaxel with endemic plant extracts (Combination Index CI, ED50 < 0.41). The combinations, which indicate the synergistic effect was increased to the Bax/Bcl 2 ratio by suppressing Bcl-2 gene expression into the prostate cancer cell lines. Besides, they increased the expression of TNFRSF10A, TNFRSF1A, CHEK1, CDKN1A, CDKN2B, CDK8, CDKN3 and CASP14 and decreased BAD, CDK5RAP1, CDC20, cyclin H, CDK5RAP1, CDC20. The effective doses of paclitaxel were reduced and G2/M arrest was induced by the endemic plant extracts and herbal substances that indicate a synergistic effect with paclitaxel. By using different combination of herbal extracts or active substances with paclitaxel, more economical and efficient treatment strategies can be developed. PMID- 30453075 TI - Litigations involving ureteral injury related to minimally invasive gynecologic surgery - Lessons learned from a legal literature review. AB - Ureteral injury is a known complication of minimally invasive gynecologic surgery (MIGS). Despite being discussed preoperatively and included in consent forms, litigations that involve such injury continue to be prevalent. Our aim was to review all major litigations involving ureteral injuries related to minimally invasive gynecologic surgery to determine the most common allegations from plaintiffs and highlight factors that aided defendants. We utilized Lexis Nexis, a comprehensive legal database, to search all publicly available federal and state level cases on ureteral injury related to gynecologic surgeries. 59 cases resulted from our search. Out of these cases, 19 were deemed pertinent to our question. These 19 case occurred between 1993 and 2018. The most common allegations included medical negligence, lack of informed consent, and medical battery. 8 out of 19 cases (42%) were decided in favor of the defendants, 3 out of 19 cases (16%) in favor of the plaintiffs, and the remaining cases proceeded to further trial or are ongoing. The monetary compensation to a plaintiff was as high as $426,079.50. Meticulous documentation, comprehensive consent procedure, timely post-operative evaluation, and the use of immediate post-operative cystoscopy were the critical factors that aided the defendants. Meticulous documentation, comprehensive consent procedure, timely post-operative evaluation, and the use of immediate post-operative cystoscopy can aid minimally invasive gynecologic surgeons involved in litigations involving ureteral injury. PMID- 30453076 TI - Rationale and design for eHealth Familias Unidas Primary Care: A drug use, sexual risk behavior, and STI preventive intervention for hispanic youth in pediatric primary care clinics. AB - Family-based behavioral interventions are efficacious and effective in preventing drug use and sexual risk behaviors; unfortunately, they have not been evaluated and disseminated in pediatric primary care practice, where they can have a significant impact. There is an increased focus on integrating parenting interventions into primary care to reduce health disparities among ethnic minorities such as Hispanics. Although Hispanic youth demonstrate higher levels of drug use and sexual risk behaviors than their non-Hispanic counterparts, few parenting interventions are available for Hispanic youth, and none have been delivered specifically to Hispanic adolescents in primary care. Therefore, this manuscript describes the rationale and design of an Internet-based, family centered, Hispanic-specific, evidence-based prevention intervention, eHealth Familias Unidas Primary Care. Hispanic adolescents (n = 456) and their care givers will be recruited from pediatric primary care clinics in South Florida and randomized to: eHealth Familias Unidas Primary Care or prevention as usual. The intervention will be delivered by trained interns, clinic volunteers, social workers, mental health counselors, students, and nurses. Outcomes will be measured at baseline and 6, 12, 24, and 36 months post-baseline. This study will determine whether the intervention, compared to prevention as usual, is effective in reducing drug use, unprotected sex, and STI incidence in Hispanic youth through the improvement of family functioning. Additionally, we will determine the cost effectiveness of delivering eHealth Familias Unidas within primary care settings. The effectiveness of eHealth Familias Unidas Primary Care will further inform the need to integrate effective behavioral health interventions into primary care settings. PMID- 30453077 TI - Preventing tick bites - Educational resources. PMID- 30453078 TI - A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in TP63 gene in Arrhythmogenic Cardiomyopathy patients. AB - BACKGROUND: Arrhythmogenic Cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for about 60% of ACM cases, but the remaining 40% is still genetically elusive. OBJECTIVE: The purpose of this study was to identify the underlying genetic cause in ACM probands. METHODS: DNA samples from 40 ACM probands, negative for mutations in the 3 major ACM genes (DSP, PKP2 and DSG2), were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. RESULTS: About half of patients resulted to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed one or more variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Amongst the latter, we focused on two novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and iASPP are known to be interacting partners. iASPP is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the TP63 variant has been scored as likely pathogenic and the PPP1R13L variant as of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated-mRNA decay, causing haploinsufficiency. CONCLUSIONS: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined. PMID- 30453079 TI - Corneal pain and experimental model development. AB - The cornea is a valuable tissue for studying peripheral sensory nerve structure and regeneration due to its avascularity, transparency, and dense innervation. Somatosensory innervation of the cornea serves to identify changes in environmental stimuli at the ocular surface, thereby promoting barrier function to protect the eye against injury or infection. Due to regulatory demands to screen ocular safety of potential chemical exposure, a need remains to develop functional human tissue models to predict ocular damage and pain using in vitro based systems to increase throughput and minimize animal use. In this review, we summarize the anatomical and functional roles of corneal innervation in propagation of sensory input, corneal neuropathies associated with pain, and the status of current in vivo and in vitro models. Emphasis is placed on tissue engineering approaches to study the human corneal pain response in vitro with integration of proper cell types, controlled microenvironment, and high throughput readouts to predict pain induction. Further developments in this field will aid in defining molecular signatures to distinguish acute and chronic pain triggers based on the immune response and epithelial, stromal, and neuronal interactions that occur at the ocular surface that lead to functional outcomes in the brain depending on severity and persistence of the stimulus. PMID- 30453080 TI - Deep learning-based preoperative predictive analytics for patient-reported outcomes following lumbar diskectomy: Feasibility of center-specific modelling. AB - BACKGROUND CONTEXT: There is considerable variability in patient-reported outcome measures (PROM) following surgery for lumbar disk herniation (LDH). Individualized prediction tools that are derived from center- or even surgeon specific data could provide valuable insights for shared decision-making. PURPOSE: To evaluate the feasibility of deriving robust deep learning-based predictive analytics from single-center, single-surgeon data. STUDY DESIGN: Derivation of predictive models from a prospective registry. PATIENT SAMPLE: Patients who underwent single-level tubular microdiskectomy for LDH. OUTCOME MEASURES: Numeric rating scales (NRS) for leg and back pain severity and Oswestry Disability Index (ODI) scores at 12 months postoperatively. METHODS: Data were derived from a prospective registry. We trained deep neural network-based and logistic regression-based prediction models for PROM. The primary endpoint was achievement of the minimum clinically important difference (MCID) in NRS and ODI, defined as a 30% or greater improvement from baseline. Univariate predictors of MCID were also identified using conventional statistics. RESULTS: A total of 422 patients were included (mean [SD] age: 48.5 [11.5] years; 207 [49%] female). After 1 year, 337 (80%), 219 (52%), and 337 (80%) patients reported a clinically relevant improvement in leg pain, back pain, and functional disability, respectively. The deep learning models predicted MCID with high area-under-the curve (AUC) of 0.87, 0.90, and 0.84, as well as accuracy of 85%, 87%, and 75%. The regression models provided inferior performance measures for each of the outcomes. CONCLUSIONS: Our study demonstrates that generating personalized and robust deep learning-based analytics for outcome prediction is feasible even with limited amounts of center-specific data. With prospective validation, the ability to preoperatively and reliably inform patients about the likelihood of symptom improvement could prove useful in patient counselling and shared decision-making. PMID- 30453081 TI - Seasonal environmental parameters influence biochemical responses of the fiddler crab Minuca rapax to contamination in situ. AB - The mudflat fiddler crab Minuca rapax, typical of mangroves and intertidal zones in the Western Atlantic Ocean, responds to fluctuations in environmental parameters by biochemical and physiological adjustments. Such biochemical effects are commonly employed in environmental studies as biomarkers of estuarine contamination. This study evaluates biochemical responses in the gills and hepatopancreas of M. rapax in situ from localities exhibiting different types and levels of contamination, against a backdrop of fluctuations in environmental parameters like salinity and temperature common to estuarine regions. The biochemical biomarkers metallothionein (MT)-like protein titers and glutathione S transferase (GST), glutathione peroxidase (GPx) and acetylcholinesterase (AChE) activities were used to evaluate responses to environmental contamination and seasonal changes in environmental parameters. Crabs were collected during two seasons, the austral winter and summer, at three sites along the coast of the state of Sao Paulo, Brazil that present decreasing degrees of environmental contamination: Ilha Diana, Santos (ID) > Rio Itapanhau, Bertioga (RI) > Picinguaba, Ubatuba (P), a pristine control site. Our findings show that MT were induced in crabs from the contaminated sites (ID and RI) mainly during winter, revealing the activation of detoxification mechanisms; however MT were also induced in P crabs during the summer rainy season. GPX, GST and AChE activities were altered in P crabs during summer and in ID and RI crabs in winter. While enzyme activities in summer crabs may reflect seasonal changes in precipitation and salinity, in winter these altered activities appear to reflect contamination, although an effect of environmental parameters cannot be excluded. These findings reveal a strong seasonal influence on biochemical biomarker responses in Minuca rapax, a relevant factor to consider when interpreting the impact of environmental contamination in estuaries. PMID- 30453082 TI - Disparities in the diagnosis and treatment of lung cancer among people with disabilities. AB - INTRODUCTION: Potential disparities in the diagnosis, treatment, and survival of lung cancer patients with and without disabilities were rarely investigated. METHODS: We conducted a retrospective cohort study with a dataset linking the KNHS database, disability registration data, and Korean Central Cancer Registry data. A total of 13,591 people with disabilities who were diagnosed with lung cancer and 43,809 age- and sex-matched control subjects with diagnosed lung cancer were included. RESULTS: Unknown stage was more common in people with severe disabilities (13.1% vs. 10.3%), especially those with communication (14.2%) or mental/cognitive disability (15.7%). People with disabilities were less likely to undergo surgery (adjusted odds ratio [aOR] 0.82, 95% confidence interval [95% CI] 0.77-0.86), chemotherapy (aOR=0.80, 95% CI 0.77-0.84), or radiotherapy (aOR=0.92, 95% CI 0.88-0.96). This was more evident for people with severe communication impairment (aORs 0.46 for surgery; 0.64 for chemotherapy) and severe brain/mental impairment (aORs 0.39 for surgery; 0.47 for chemotherapy; 0.49 for radiotherapy). Patients with disabilities had a slightly higher overall mortality compared to people with no disability (adjusted hazard ratio [aHR] 1.08; 95% CI, 1.06-1.11), especially in the severe disability group (aHR, 1.20; 95% CI 1.16-1.24). CONCLUSIONS: Lung cancer patients with disabilities, especially severe ones, underwent less staging work-up and treatment even though their treatment outcomes were only slightly worse than those of people without a disability. While some degree of disparity might be attributed to reasonable clinical judgement, unequal clinical care for people with communication and brain/mental disabilities suggests unjustifiable disability-related barriers which need to be addressed. PMID- 30453083 TI - Prediction of HIV integrase resistance mutation using in silico approaches. AB - The Antiretroviral Therapy (ART) has been providing better treatment for the Human Immunodeficiency Virus 1 (HIV) infection, by reducing its viral load to undetectable levels and recovering the immune system. However, new HIV mutations could induce drug resistance to ART, increasing the viral load and disruption of immune system. One of these drugs is Dolutegravir (DTG), which inhibits HIV integrase (INT) activity. Our objective was to predict novel HIV mutations related to DTG resistance using in silico approaches in order to stablish a framework of searching for new HIV drug-resistant mutations. To this end, we modelled the INT structure and produced a mutational profile to investigate hotspots that may affect INT. Being the Y226K mutation the most frequent (0.3) and with a higher DeltaDeltaG (+2.07), we selected to test the framework. To ratify the impact of Y226K, we docked the mutant INT with the DTG and compared the results with the Wild Type (WT) with known drug-resistant mutations. Moreover, we performed molecular dynamics simulations and calculated the binding energy along the time-course. When we compared the energies of the systems, the Y226K complex showed less binding affinity (DeltaDeltaG = 104.88) than the other mutated complexes compared with the WT, the Y226K complex showed even less binding affinity (DeltaDeltaG = 104.88). This variant somehow impedes the attachment of DTG to INT, indicating this mutant as possible resistance mutation. PMID- 30453084 TI - Factors predictive of the development of surgical site infection in thyroidectomy - An analysis of NSQIP database. AB - BACKGROUND: Surgical Site Infection (SSI) is an uncommon but serious complication of thyroidectomy when encountered. STUDY DESIGN: NSQIP Participant Use File (PUF) from 2012 to 2015 were queried. Thyroidectomy was identified with CPT 60210, 12, 20, 25, 40, 52, 54, 60 in patients >=18 years and clean (Wound Classification 1) wounds. Uni- and multivariate logistic regression testing were performed. A subgroup analysis for patients that underwent thyroidectomy for cancer was performed. RESULTS: 57,371 patients were included in the study. SSI incidence was 0.4%. On univariate analysis age 18-29, age>70, male gender, BMI 19 to <25, BMI 40 to <50, ASA classes other than class 4, diabetes, White race, COPD, current smoker, CHF, hypertension disseminated cancer and ventilator dependent within 48 h prior to surgery were pre-operative variables with P-value <0.2 between the two groups. On multivariate regression analysis age >=80, gender male, BMI 40 to <50, current smoker and ventilation within 48 h preceding surgery remained statistically significant. After ventilation, age>=80 was associated with the greatest odds (OR) ratio (2.382). In the subgroup analysis age >=80, White race, and CHF were predictive of SSI. CONCLUSION: SSI following thyroidectomy with a clean wound is rare. Routine use of antibiotics should not be undertaken in patients undergoing thyroidectomy and should only be considered for high risk patients or for those patients with contaminated wounds. PMID- 30453085 TI - A meta-analysis of transfemoral endovascular treatment of common carotid artery lesions. AB - OBJECTIVE: High grade stenoses of the common carotid artery (CCA) are rare and represent a therapeutic dilemma for the treating physician. Endovascular treatment through antegrade access has been proposed as a less invasive treatment option. The aim of this study is to review the existing literature on such procedure. METHODS: A meta-analysis of all studies reporting on endovascular treatment for the treatment of CCA was performed. RESULT: Six studies, including 227 patients were identified. Forty-nine percent of the patients were male, 55% symptomatic. Lesions were located in CCA in 237 cases, in innominate artery (IA) in 4 cases, combined with carotid artery (ICA) in 28 and subclavian artery in 5 cases. Reported technical success of the procedure was 97.9%. In of the 234 successful endovascular treatment, a stent was implanted. Thirty-day mortality and stroke rate were 0.4% and 3.1%, respectively. During a mean follow-up of 8.4 to 31.7 months, four patients presented symptoms of cerebral ischemia and 18 died (none related to the procedure). Thirty-one patients developed restenosis of the CCA lesion, successful re-percutaneous transluminal angioplasty was done in 9 cases. CONCLUSION: This meta-analysis reported the largest collection of patients having undergone endovascular treatment of CCA stenosis or occlusion. Results from this study showed that thirty-day mortality and stroke rate were 0.4% and 3.1%. Procedure is absolutely effective and no significant change of stroke was found with or without embolic protection device. In sum, balloon angioplasty with stenting of the component of this disease should be pursued to decrease risk of stroke. PMID- 30453086 TI - Respiratory muscle oxygenation is not impacted by hypoxia during repeated-sprint exercise. AB - This study aimed to investigate whether exercise hyperpnoea contributes to an impairment of locomotor muscle oxygenation and performance during repeated-sprint exercise in normoxia and hypoxia. Subjects performed ten 10-s sprints, separated by 30 s of passive rest while breathing either a normoxic (21% O2) or hypoxic (15% O2) gas mixture. Muscle oxygenation of the vastus lateralis and intercostal muscles was examined with near-infrared spectroscopy. Sprint and recovery vastus lateralis deoxyhaemoglobin was elevated in hypoxia by 9.2% (90% confidence interval 0.2 to 18.0) and 14.1% (90% CL 4.9 to 23.3%) compared to normoxia, respectively. There were no clear differences in respiratory muscle deoxyhaemoglobin (-0.1%, 90% CL -2.9 to 0.9%) or oxyhaemoglobin (0.9%, 90% CL 0.8 to 2.6%) between conditions. Maintenance of respiratory muscle oxygenation may contribute to the rise of vastus lateralis deoxyhaemoglobin in hypoxia during intermittent sprint cycling. This manuscript presents data which extends the fact that oxygen competition could be a limiting factor of exercise capacity. PMID- 30453087 TI - Structural insights into substrate selectivity, catalytic mechanism and redox regulation of rice photosystem II core phosphatase. AB - Photosystem II (PSII) core phosphatase (PBCP) selectively dephosphorylates PSII core proteins including D1, D2, CP43 and PsbH. The function of PBCP is required for efficient degradation of D1 protein in the repair cycle of PSII, a supramolecular machinery highly susceptible to photodamage during oxygenic photosynthesis. Here we present structural and functional studies of PBCP from Oryza sativa (OsPBCP). In a symmetrical homodimer of OsPBCP, each monomer contains a PP2C-type phosphatase core domain, a large characteristic motif of PBCPs and two small motifs around the active site. The large motif contributes to the formation of a substrate-binding surface groove and is crucial for the selectivity of PBCP toward PSII core proteins against the light-harvesting proteins. Remarkably, the phosphatase activity of OsPBCP is strongly inhibited by glutathione and H2O2. S-glutathionylation of cysteine residues may introduce steric hindrance and allosteric effects to the active site. The results provide detailed mechanistic insights into the substrate selectivity, redox regulation and catalytic mechanism of PBCP. PMID- 30453088 TI - Bone remodeling following MR-guided focused ultrasound: Evaluation with HR-pQCT and FTIR. AB - Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel non-invasive ablation technique that uses focused sound energy to destroy focal tumors, primarily via heat deposition. It is widely used for palliation of pain from bone metastases and has also recently gained popularity as a technique for ablation of benign bone tumors and facet degenerative joint disease (rhizotomy). Clinically, in a subset of patients who have undergone MRgFUS of bone, a variety of treatment responses have been noted on follow-up imaging, including focal sclerosis within the target lesion or more exuberant proliferative changes associated with the periosteum. In this study, high resolution peripheral quantitative CT (HR-pQCT) was used to evaluate remodeling of bone following ablation in a swine model of MRgFUS and compared to samples from a control, non-treated femur. Within each treated femur, two lesions were created: a higher energy focused ultrasound dose was used for one lesion compared to a lower energy dose for the second lesion. Exuberant, extra-cortical bone formation was detected at the higher energy ablation zones, with volumes ranging from 340 mm3 to 1040 mm3. More subtle endosteal and cortical changes were detected in the lower energy ablation zones, however cortical thickness was significantly increased at these sites compared to control bone. For both high and low energy lesions, lower bone mineral density and tissue mineral density was noted in treated regions compared to control regions, consistent with the formation of newly mineralized tissue. Following HR pQCT analysis, Fourier transform infrared (FTIR) spectroscopy was subsequently used to detect biochemical changes associated with remodeling of bone following MRgFUS, and compared to samples from the control, non-treated femur. Findings were compared with histopathologic examination following hematoxylin-eosin staining. FTIR analysis demonstrated lower mineral/phosphate ratio and increased crystallinity compared to the control samples (p = 0.013). Histopathologic review demonstrated associated areas of endosteal inflammation, scarring, fat necrosis, and new extra-cortical bone formation associated with the ablations. Overall, these findings provide novel characterization of new bone formation following MRgFUS ablation. PMID- 30453089 TI - Detoxification and activating blood circulation decoction reduces restenosis involving the TLR4/NF-kappaB pathway after balloon injury. AB - Restenosis is a major problem after percutaneous coronary intervention (PCI) treatment. Inflammation is one of the major core mechanisms involved in the occurrence of restenosis, and plays an important role in intimal hyperplasia. Detoxification and activating blood circulation decoction (DABCD) is a traditional Chinese medicine that is used in the treatment and prevention of atherosclerotic and inflammatory diseases. Our previous studies demonstrated that DABCD-mediated cardioprotection involves anti-inflammatory mechanisms and could be developed as a novel drug for the treatment of vascular smooth muscle cell (VSMC) proliferation and aortic restenosis. A rat model of postoperative restenosis after PCI was generated by balloon injury to determine the protective effects and potential mechanisms of DABCD. The injured segments of aortae were collected on days 14 and 28 after the operation to observe the morphological changes in the vascular structure and measure the proportion of inflammatory factors in plasma and vascular tissues, as well as test the proliferative activity of VSMCs. The expression of related proteins, namely, Toll-like receptor (TLR) 4 and nuclear factor (NF)-kappaB, in the mechanistic study was clarified by western blot analysis. We tested the hypothesis that the cardioprotective effects of DABCD on aortic restenosis are associated with the inhibition of aortic intimal hyperplasia in this model. Our results showed that DABCD has protective effect on rat aortic restenosis and the anti-inflammatory mechanism of DABCD on balloon-induced restenosis in rat may be due to its ability to inhibit TLR4 mediated NF-kappaB signaling pathways. DABCD may be a potential therapeutic agent against restenosis. PMID- 30453090 TI - Rare and fatal case of upper gastrointestinal bleeding. PMID- 30453091 TI - Incarcerated Spigelian Hernia. PMID- 30453092 TI - Direct conversion of mouse embryonic fibroblast to osteoblast cells using hLMP-3 with Yamanaka factors. AB - Large bone defects and bone loss after fractures remain significant challenges for orthopedic surgeons. Our study aims to find an available, applicable and biological treatment for bone regeneration overcoming the limitations in ESC/iPSC technology. We directly reprogrammed the mouse embryonic fibroblast (MEF) into osteoblast cells using different combinations of Yamanaka factors with human lim mineralization protein-3 (hLMP-3). LMP is an intracellular LIM-domain protein acting as an effective positive regulator of the osteoblast differentiation. After transduction, cells were cultured in osteogenic medium, and then examined for osteoblast formation. The expression of osteogenic markers (BMP2, Runx2 and Osterix) during reprogramming and in vitro mineralization assay revealed that the best reprogramming cocktail was (c-Myc - Oct4) with hLMP-3. In addition, both immunofluorescent staining and western blot analysis confirmed that osteocalcin (OCN) expression increased in the cells treated with the c-Myc/Oct4/hLMP3 cocktail than using hLMP-3 alone. Furthermore, this reprogramming cocktail showed efficient healing in an induced femoral bone defect in rat animal model one month after transplantation. In the present study, we reported for the first time the effect of combining Yamanaka factors with hLMP-3 to induce osteoblast cells from MEF both in vitro and in vivo. PMID- 30453093 TI - Development of a brief screening tool for Early Literacy Skills in Preschool Children. AB - BACKGROUND: Preschool children develop early literacy skills (ELS) needed for reading acquisition. Screening for delayed ELS could trigger interventions to prevent reading problems. OBJECTIVE: To develop a brief screening test for ELS delays, the Early Literacy Skills Assessment Tool (ELSAT). METHODS: This study included 4-year-old typically-developing, English language predominant children attending preschool. The ELSAT comprised 63 items relating to three main ELS domains and was piloted with 21 children. After excluding items that were non discriminatory, 57 items remained and were administered to 96 children. Items were compared with reference measures of ELS (Get Ready to Read - Revised), and language (Peabody Picture Vocabulary Test-4 and Phonological Awareness from the Comprehensive Test of Phonological Processing-2). Within-domain reliability was calculated for each of the three ELS domains and item correlations between all ELSAT items and the reference measures were calculated. RESULTS: A final set of 10 items was retained that represented all three ELS domains and that maximized correlations with reference measures. Cronbach's alpha for the refined 10-item ELSAT was 0.868; correlations between individual items and a composite of the reference measures ranged from 0.409 to 0.617 (all ps < .01). In a receiver operating characteristic (ROC) curve analysis, a cut-off score of <=5 predicted a below average score for any of the reference measures with sensitivity of 90%, specificity of 71.4%, and area under the curve of 0.872. CONCLUSION: The 10-item ELSAT shows strong psychometric properties, and with further validation may prove valuable in screening preschool children for ELS delays. PMID- 30453094 TI - Treg/Th17 imbalance is associated with poor autoimmune hepatitis prognosis. PMID- 30453095 TI - Synthesis of novel triazole-derived glycopeptides as analogs of alpha dystroglycan mucins. AB - alpha-Dystroglycan (alpha-DG) mucins are essential for maintenance of the structural and functional stability of the muscle fiber and, when hypoglycosylated, they are directly involved in pathological processes such as dystroglycanopathies. Thus, this work reports the synthesis of the novel 1,2,3 triazole-derived glycosyl amino acids alphaGlcNAc-1-O-triazol-2Manalpha-ThrOH (1) and Gal-beta1,4-alphaGlcNAc-1-O-triazol-2Manalpha-ThrOH (2), followed by solid phase assembly to get the corresponding glycopeptides NHAcThrVal[alphaGlcNAc-1 triazol-2Manalpha]ThrIleArgGlyOH (3) and NHAcThrVal[Gal-beta1,4-alphaGlcNAc-1 triazol-2Manalpha]ThrIleArgGlyOH (4) as analogs of alpha-DG mucins. The glycosyl amino acids 1 (72%) and 2 (35%) were synthesized by Cu(I)-assisted 1,3-dipolar azide-alkyne cycloaddition reactions (CuAAC) between the azide-glycosyl amino acid alphaManN3-FmocThrOBn (5) and the corresponding alkyne-functionalyzed sugars 2'-propynyl-alphaGlcNAc (6) and 2'-propynyl-Gal-beta1,4-alphaGlcNAc (7), followed by hydrogenation reactions. Subsequently, glycopeptides 3 (23%) and 4 (12%) were obtained by solid phase synthesis, involving sequential couplings of Fmoc protected amino acids or the glycosyl amino acids 1 and 2, followed by cleavage from resin, N-acetylation and O-deacetylation (NaOMe) reactions. Lastly, enzymatic galactosylation of glycopeptide 3 with bovine beta-1,4-GalT showed that it was not a substrate for this enzyme, which could be better elucidated by docking simulations with beta-1,4-GalT. PMID- 30453096 TI - Synthesis of C-beta-d-glucopyranosyl derivatives of some fused azoles for the inhibition of glycogen phosphorylase. AB - Annulated C-beta-d-glucopyranosyl heterocycles were synthesized and tested as inhibitors of glycogen phosphorylase. 2-(beta-d-Glucopyranosyl)-1H-imidazo[4,5 b]pyridine was formed by ring-closure of O-perbenzoylated C-beta-d-glucopyranosyl formic acid with 2,3-diaminopyridine in the presence of triphenylphosphite. Cyclisations of bromomethyl 2,3,4,6-tetra-O-benzoyl-beta-d-glucopyranosyl ketone with a set of 2-aminoheterocycles resulted in constitutionally reversed C-beta-d glucopyranosyl imidazoles fused by pyridine, pyrimidine, thiazole, 1,3,4 thiadiazole, benzothiazole and benzimidazole. O-Debenzoylation of the above compounds was effected by standard transesterification to get the test compounds. The 1H-imidazo[4,5-b]pyridine proved to be a low micromolar inhibitor (Ki = 21.1 MUM) of rabbit muscle glycogen phosphorylase b, while the other heterocycles displayed weak or no inhibition against the same enzyme. PMID- 30453097 TI - Monkeypox - Enhancing public health preparedness for an emerging lethal human zoonotic epidemic threat in the wake of the smallpox post-eradication era. AB - The identification of monkeypox in 3 separate patients in the United Kingdom in September raised media and political attention on an emerging public health threat. Nigeria, whose last confirmed case of monkeypox was in 1978, is currently experiencing an unusually large and outbreak of human monkeypox cases, a 'One Human-Environmental-Animal Health' approach is being effectively used to define and tackle the outbreak. As of 13th October 2018, there have been one hundred and sixteen confirmed cases the majority of whom are under 40 years. Over the past 20 years ten Central and West African countries have reported monkeypox cases which have risen exponentially. We review the history and evolution of monkeypox outbreaks in Africa and USA, the changing clinical presentations, and discuss possible factors underlying the increasing numbers being detected including the cessation of smallpox vaccination programs. Major knowledge gaps remain on the epidemiology, host reservoir, and emergence, transmission, pathogenesis and prevention of monkeypoz. PMID- 30453099 TI - How language and event recall can shape memory for time. AB - How do we represent the duration of past events that we have conceptualized through language? Prior research suggests that memory for duration depends on the segmental structure perceived at encoding. However, it remains unclear why duration memory displays characteristic distortions and whether language-mediated encoding can further distort duration memory. Here we examine these questions and specifically ask whether the amount of event information recalled relative to the stimulus duration explains temporal distortions. In several studies, participants first studied animated stimuli described by phrases implying either fast or slow motion (e.g., a mule vs car going up a road). They then mentally reproduced the stimuli from memory (as if replaying them in their minds) and verbally recalled them. We manipulated the amount of stimulus study and the type of recall cue (visual vs linguistic) to assess the role of language and information recalled on the length of mental reproductions. Results indicated that the density of the information recalled (number of details recalled per second) explained temporal distortions: higher density events were lengthened and lower density events were shortened. Moreover, language additionally lengthened or shortened duration reproductions when phrases cued the task, suggesting that episodic details and verbal conceptual features were combined during recollection rather than encoding. These results suggest that the density of the details recalled and language-mediated recollection shape memory for event duration. We argue that temporal memory distortions stem from event encoding and retrieval mechanisms. Implications of these findings for theories of time, memory and language are discussed. PMID- 30453098 TI - Optimizing memory strategy use in young and older adults: The role of metamemory and internal strategy use. AB - We explored whether experiencing differential efficacy of reading and generation for memory in an initial learning trial led younger and older adults to improve recall of read items in a subsequent learning trial, leading to a reduction of the generation effect. In the first trial, generation improved the memory performance of both young and older adults. However, in Trial 2, the generation effect remained significant for older adults only, confirming that they did not change the way they processed read items, unlike the young adults. The older adults were also less spontaneously aware that generation led to better memory performance in the first trial, and, in contrast to the young adults, awareness did not result in a reduction of the generation effect. Moreover, the age-related differences in generation effect reduction were mediated by an independent measure of self-reported internal strategy use. However, when an appropriate environmental support was provided between both trials, older adults improved read items recall at the second trial as well as younger ones, leading to an elimination of the generation advantage for both groups. Environmental support reduced the implication of internal strategy use in the generation effect reduction, suggesting that age-related differences in the implementation of effective encoding processes in Trial 2 would be the consequence of a metamemory deficit, and reduced capacity to self-initiate internal strategies. PMID- 30453100 TI - Chemosensitivity is differentially regulated by the SDF-1/CXCR4 and SDF-1/CXCR7 axes in acute lymphoblastic leukemia with MLL gene rearrangements. AB - Although recent advances in chemotherapy have markedly improved outcome of acute lymphoblastic leukemia (ALL), infantile ALL with MLL gene rearrangements (MLL+ALL) is refractory to chemotherapy. We have shown that specific cytokines FLT3 ligand and TGFbeta1 both of which are produced from bone marrow stromal cells synergistically induced MLL+ALL cells into chemo-resistant quiescence, and that treatment of MLL+ALL cells with inhibitors against FLT3 and/or TGFbeta1 receptor partially but significantly converts them toward chemo-sensitive. In the present study, we showed that MLL+ALL cells expressed CXCR4 and CXCR7, both receptors for the same chemokine stromal cell derived factor-1 (SDF-1), but their biological events were differentially regulated by the SDF-1/CXCR4 and SDF 1/CXCR7 axes and particularly exerted an opposite effect for determining chemo sensitivity of MLL+ALL cells; enhancement via the SDF-1/CXCR4 axis vs. suppression via the SDF-1/CXCR7 axis. Because cytosine-arabinoside-induced apoptosis of MLL+ALL cells was inhibited by pretreatment with the CXCR4 inhibitor but rather accelerated by pretreatment with the CXCR7 inhibitor, an application of the CXCR7 inhibitor may become a good treatment option in future for MLL+ALL patients. MLL+ALL has a unique gene profile distinguishable from other types of ALL and AML, and should be investigated separately in responses to biological active agents including chemokine inhibitors. PMID- 30453101 TI - Short implants as an alternative to sinus lift for the rehabilitation of posterior maxillary atrophies: Systematic review and meta-analysis. AB - INTRODUCTION: The choice of treatment for implant rehabilitation for maxillary atrophy is crucial. It involves either between the use of short implants or performing sinus lift and the establishment of standard implants: what would be the best choice in term of survival rate and complications? We conducted a systematic review to try to answer this question. MATERIALS AND METHODS: An electronic and manual search of clinical studies (between 2007 and 2017) comparing short implants to standard implants associated with sinus lift was performed. All the articles are read and analyzed then selected according to previously defined inclusion criteria. Eighteen articles were selected from the 358 articles: 15 randomized controlled trials, 1 cohort study and 2 systematic reviews. RESULTS: The studies were divided according to their follow-up periods: short (< 1 year), medium (1 year) and long (> 1 year). The results of the study showed a survival rate for short implants ranging from 91.8% to 100%, and from 87.8% to 100% for standard implants associated with sinus lift. Biological complications predominate with the perforation of Schneider's membrane, which is by far the most common complication. The results of the meta-analysis did not show a statistically significant difference in the survival rate of the two procedures over the short, medium and long term. However but the study of complications shows that in the short and medium term, the results are in favor of short implants. DISCUSSIONS: Compared to standard implants associated with sinus lift, short implants have the advantage of being a solution with a high survival rate, it is less expensive, requiring less surgical time, presenting fewer complications compared to advanced surgery of sinus lift and thus obtaining more patient satisfaction. CONCLUSION: Short implants are a reliable alternative compared to standard implants associated with sinus lift. They present an alternative with the same survival rate and fewer complications. PMID- 30453102 TI - MR-guided navigation for botulinum toxin injection in the lateral pterygoid muscle. First results in the treatment of temporomandibular joint disorders. AB - INTRODUCTION: Hyperactivity of the lateral pterygoid muscle (LPM) is one of the presumed mechanisms of the onset of temporomandibular disorders (TMD) and explains why intramuscular injection of botulinum toxin (BT) may be indicated for treatment. Intramuscular injection without guidance is difficult because of its deep location. The objectives of this study were to determine the feasibility of MR-guided navigation for BT injection in the LPM in TMD and to report about our first results. PATIENTS AND METHODS: Six patients suffering from persistent myogenic TMD were enrolled in a prospective study and treated with intramuscular injection of BT A: 20 UI in each LPM with MR-guided navigation using the Brainlab plateform (Kolibri(r), Brainlab(r), Munich, Germany) the target being the center of the upper head, 30 UI in each masseter and 20 UI in each temporal with clinical guidance. The investigated outcomes were: pain intensity, maximum interincisal opening and joint sounds. RESULTS: MR-guided navigation could be used in all patients and the target could constantly be reached. Pain improvement [mean reduction of 4.4 on a numeric scale (p = 0.0579)] was observed in 66.7% of the patients. Significant improvement of maximum interincisal opening was found (p = 0.0360) and joint sounds tend to disappear (p = 0.5594). DISCUSSION: MR guided navigation is an effective method for tracking the upper head of the LPM and allows for a precise injection of BT. Injection of BT in the upper head of the LPM, the masseter and the temporal muscles is effective in refractory TMD. A combination of this morphologic guidance with electromyographic tracking would allow to select more carefully the muscles to be injected. PMID- 30453103 TI - Finite element analysis of the human orbit. behavior of titanium mesh for orbital floor reconstruction in case of trauma recurrence. AB - INTRODUCTION: The Authors' main purpose was to simulate the behavior of a titanium mesh implant (TMI) used to reconstruct the orbital floor under the stress of a blunt trauma. MATERIALS AND METHODS: The orbital floor of a previously validated finite element model (FEM) of the human orbit was numerically fractured and reconstructed by a simplified TMI. Data from a CT scan of the head were computed with MICMICS (Materialise, Louvain, Belgium) software to re-create the skull's geometry. The meshing production, the model's properties management and the simulations of blunt traumas of the orbit were conducted on HYPERWORKS(r) software (Altair Engineering, Detroit, MI, USA). Some of the elements of the orbital floor were selected and removed to model the fracture; these elements were duplicated, their characteristics being changed by those of titanium to create a TMI covering this fracture. A 3D FEM composed of 640 000 elements was used to perform 21 blunt trauma simulations on the reconstructed orbit. RESULTS: In 90,4% (19/21) of the tests conducted, the TMI, whether free from any bony attachment or screwed to the orbital rim, has tended to move in the orbit and / or to deform. DISCUSSION: In the event of traumatic recurrence, which is not rare, TMIs may deform in a "blow-in" motion and threaten intra-orbital structures. PMID- 30453104 TI - Orthodontic - Surgical management in a Class II case with idiopathic root resorption. AB - Patients with root resorption and malocclusion can benefit from orthodontic treatment with or without surgery. However, orthodontics has a risk of inducing or aggravating root resorption, therefore the duration of the treatment is of utmost importance. In this paper, a surgery-first protocol with lower jaw advancement and precise interdental alveolar osteotomies was conducted to accelerate the treatment of a 14-year-old female patient who presented with a Class II division 2 malocclusion, anterior dental crowding and idiopathic root resorption. One week after the surgery, the patient received postoperative orthodontic treatment for 6 months with weekly activation the first month. The clinical outcome was satisfactory with complete clinical resolution and no tooth loss. This surgery approach allowed an 'en bloc' tooth movement and induced an increased bone remodelling, which resulted in an accelerated tooth movement. The reduction of treatment time was beneficial and no aggravation of the root resorption was seen. PMID- 30453105 TI - Effect of menstrual cycle on ethanol drinking in rhesus monkeys. AB - BACKGROUND: Sex differences in the abuse-related effects of alcohol have been demonstrated in the clinic and in preclinical animal models. Less is known about the influence of menstrual cycle phase on drinking. METHODS: In this study, we examined the relationship between menstrual cycle phase and intake of ethanol (EtOH) in five adult female rhesus monkeys. Subjects consumed a 4% EtOH solution in their home cage 6 h per day, 5 days per week and pressed a lever to receive food pellets during the drinking session. Menstrual cycle was determined with vaginal swabs 5-7 days per week. To facilitate comparison with previous studies, the cycle was divided three different ways for analysis. RESULTS: First, no significant difference was observed when EtOH intake was compared between phases defined as "follicular" (days 5-10) and "luteal" (19-24). Second, when the cycle was further divided into four phases [early follicular (days 1-7), late follicular (8-14), early luteal (15-21) and late luteal (22-next cycle)], significant differences were detected, with intake highest in phases that bracket menses and lowest in the late follicular phase. Finally, EtOH intake during "mid cycle" (days 12-16) was significantly lower than during "menses" (days 1-5) and "late luteal" (last 5 days). Effect sizes were small to moderate, although absolute differences in EtOH intake (g/kg) were <15%. Food-maintained responding was not different across phases. CONCLUSIONS: Menstrual cycle has modest but statistically significant and selective effects on EtOH drinking, with higher EtOH intake observed in the peri-menstrual period compared to the middle of the cycle. PMID- 30453106 TI - Application of vested interest theory to prevention of non-medical prescription stimulant and marijuana use: Unforeseen benefits of attitude-behavior inconsistency. AB - BACKGROUND: Vested interest (VI) has been found to enhance attitude-behavior consistency in several contexts. With an eye toward a potentially novel method of prevention (i.e., reducing perceived VI to minimize attitude-behavior consistency among those positively inclined toward psychotropic substance use), the current investigation explores whether VI moderates attitude-intention consistency regarding nonmedical use of prescription stimulants (NUPS) and marijuana. METHODS: Emphasizing prevention, the study focused exclusively on non-users. Study 1a assessed college students (N = 310) attitudes, VI, and intentions regarding NUPS among those with no prior NUPS experience. Respondents were sampled using Amazon's Mechanical Turk. Study 1b investigated marijuana-abstinent college students (N = 93), recruited from college classrooms. RESULTS: The pattern of results was similar in both studies. In addition to an association between attitudes and VI, analysis revealed main effects for attitudes and VI on substance use intentions. Moreover, VI moderated the attitude-intention relationship (p < .01). Attitudes were most weakly associated with usage intentions when perceptions of VI were low (vs. moderate or strong). CONCLUSION: Results of these studies replicate and expand prior findings relating VI to drug use, and suggest a potential path for future prevention efforts. The current study was cross-sectional, however if the causal pathways are as theorized, an intervention that reduces subjective VI has the potential to reduce positive attitudes while simultaneously reducing the influence of favorable attitudes on intentions. PMID- 30453107 TI - Testing the biosocial cognitive model of substance use in cannabis users referred to treatment. AB - BACKGROUND: The bioSocial Cognitive Theory (bSCT) hypothesizes two pathways linking dimensions of impulsivity to substance use. The first predicts that the association between reward sensitivity and substance use is mediated by positive outcome expectancies. The second predicts that the relationship between rash impulsiveness and substance use is mediated by refusal self-efficacy. This model has received empirical support in studies of alcohol use. The present research provides the first application of bSCT to a cannabis treatment population and aims to extend its utility to understanding cannabis use and severity of dependence. DESIGN: 273 patients referred for cannabis treatment completed a clinical assessment that contained measures of interest. SETTING: A public hospital alcohol and drug clinic. MEASUREMENTS: The Sensitivity to Reward Scale, Dysfunctional Impulsivity Scale, Cannabis Expectancy Questionnaire, Cannabis Refusal Self-Efficacy Questionnaire and Severity of Dependence Scale-Cannabis were completed, along with measures of cannabis consumption. FINDINGS: The bSCT model provided a good fit to the data for cannabis use and severity of dependence outcomes. The association between reward sensitivity and each cannabis outcome was fully mediated by positive cannabis expectancies and cannabis refusal self efficacy. The relationship between rash impulsiveness and each cannabis outcome was fully mediated by cannabis refusal self-efficacy. CONCLUSIONS: Findings support the application of the bSCT model to cannabis use and dependence severity and highlight the important role of social cognitive mechanisms in understanding the association between impulsivity traits and these outcomes. The differential association of impulsivity traits to social cognition may assist targeted treatment efforts. PMID- 30453108 TI - Influence of Abuse History on Concurrent Benzodiazepine and Opioid Use in Chronic Pain Patients. AB - An important predictor of opioid overdose is co-use of benzodiazepines, which are often prescribed for anxiety. Coping with anxiety may be particularly difficult among individuals with a history of abuse as it is often linked to higher pain severity and poorer coping skills. We explored whether abuse history moderated the association between anxiety and benzodiazepine use among current opioids users. New patients at a tertiary-care, outpatient pain clinic completed self report measures of medication use, anxiety, and physical and sexual abuse history (child abuse only, adult abuse only, or cumulative abuse). The present study included adult patients reporting current opioid use (n = 1,785). Approximately 16% reported co-use of benzodiazepines and 17% reported a history of abuse. Patients reporting child abuse only and cumulative abuse reported co-use of benzodiazepines and opioids more often than those denying abuse and patients reporting adult abuse only (p < 0.001). Multivariate logistic regression analyses showed that the probability of benzodiazepine use among patients reporting cumulative abuse increased sharply at high levels of anxiety (p = 0.003). Cumulative abuse may increase sensitivity to psychological distress and put patients at risk for co-use. Providers should be aware of life history factors, including abuse, that may drive the need for medication. Perspective: This article examines the association between history of abuse victimization and co-use of benzodiazepines among chronic pain patients reporting current opioid use. The findings suggest that cumulative victimization across the lifespan may contribute to co-use by increasing sensitivity to psychological or physical distress or by negatively impacting coping skills. PMID- 30453109 TI - AAPT Diagnostic Criteria for Fibromyalgia. AB - Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks, (ACTTION) public-private partnership with the United States (U.S.) Food and Drug Administration (FDA) and the American Pain Society (APS), initiated the ACTTION APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population based studies conducted in the United Kingdom (U.K.). The FM working group established a revised diagnosis of FM, and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice. PMID- 30453110 TI - Online comments about psychiatric neurosurgery and psychopharmacological interventions: Public perceptions and concerns. AB - The field of biological psychiatry is controversial, with both academics and members of the public questioning the validity and the responsible use of psychiatric technological interventions. The field of neuroethics provides insight into these controversies by examining key themes that characterize specific topics, attitudes, and reasoning tools that people use to evaluate interventions in the brain and mind. This study offers new empirical neuroethical insights into how the public responds to the use and development of psychiatric technological interventions by comparing how the public evaluates pharmacological and neurosurgical psychiatric interventions, in the context of online comments on news media articles about these topics. We analyzed 1142 comments from 108 articles dealing with psychopharmacological and psychiatric neurosurgery interventions on websites of major circulation USA newspapers and magazines published between 2005 and 2015. Personal anecdote, medical professional issues, medicalization, social issues, disadvantages, scientific issues and cautionary realism were among the main themes raised by commenters. The insights derived from the comments can contribute to improving communication between professionals and the public as well as to incorporating the public's views in policy decisions about psychiatric interventions. PMID- 30453111 TI - Self-reported versus GPS-derived indicators of daily mobility in a sample of healthy older adults. AB - In light of novel opportunities to use sensor data to observe individuals' day-to day mobility in the context of healthy aging research, it is important to understand how meaningful mobility indicators can be extracted from such data and to which degree these sensor-derived indicators are comparable to corresponding self-reports. We used sensor (GPS and accelerometer) and self-reported data from 27 healthy older adults (>=67 years) who participated in the MOASIS project over a 30-day period. Based on sensor data we computed three commonly used daily mobility indicators: life space (LS), travel duration using passive (i.e., motorized) modes of transportation (pMOT) and travel duration using active (i.e., non-motorized) modes of transportation (aMOT). We assessed the degree to which these sensor-derived indicators compare to corresponding self-reports at a within person level, computing intraindividual correlations (iCorrs), subsequently assessing whether iCorrs can be associated with participants' socio-demographic characteristics on a between-person level. Moderate to large positive mean iCorrs between the respective self-reported and sensor-derived indicators were found (r = 0.75 for LS, 0.51 for pMOT and 0.36 for aMOT). In comparison to sensor-derived indicators, self-reported LS slightly underestimates, while self-reported aMOT as well as pMOT considerably overestimate the amount of daily mobility. Participants with access to a car have higher probabilities of agreement in the pMOT indicator. Sensor-based assessments are promising as they are "objective", involve less participant burden and observations can be extended over long periods. The findings of this paper help researchers on mobility and aging to estimate the magnitude and direction of potential differences in the assessed variable due to the assessment methods. PMID- 30453112 TI - SNAP benefits and childhood asthma. AB - Anecdotal and descriptive evidence has led to the claim that some low-income households may face a "eat or breathe" tradeoff, but quantitative evidence is scarce. We link Medicaid claims data to monthly Supplemental Nutritional Assistance Program (SNAP) participation data from the state of Missouri from 2010 to 2013 to explore monthly patterns in children's emergency room (ER) claims for asthma and to examine whether these patterns are sensitive to the timing and amount of SNAP benefits. This allows us to empirically test whether SNAP households with Medicaid insurance face trade-offs between food and medicine that increases the likelihood that a child in a SNAP and Medicaid household will go to the ER for asthma at the end of the month. While we do not find overwhelming evidence that the timing of SNAP benefits receipt are associated with the timing of asthma-related ER visits, we do find clear evidence that increased SNAP benefits are associated with a reduction in the overall probability of an asthma related ER visit. PMID- 30453113 TI - 4-HNE carbonylation induces local conformational changes on bovine serum albumin and thioredoxin. A molecular dynamics study. AB - 4-hydroxy-2-nonenal (4-HNE) is the main end product of peroxidation in lipids, capable of introduce carbonyl groups to nucleophilic amino acids via Michael additions and alter protein function. It has been reported that 4-HNE protein carbonylation is associated with intracellular protein aggregation, the pathogenesis of neurodegenerative and metabolic diseases and yet it is unclear how the carbonylation affects the protein structure and dynamics at the atomic level. Here, we analysis the structural effects of 4-HNE modification through formation of Michael adducts of Cys-4HNE, His-4HNE and Lys-4HNE on Serum Albumin (BSA) and Thioredoxin (TRX). Since both proteins have experimental evidence to possess 4-HNE-modifications on cysteine, histidine and lysine residues, extended molecular dynamics simulations were performed with AMBER to study the carbonylation effects in the structure of these proteins. BSA is the main protein of plasma while TRX is an important antioxidant enzyme. Results showed local changes and alteration in the conformational stability, folding and flexibility after including the 4-HNE modification. DSSP analysis showed important structural modifications as a consequence of the inclusion of the modified residues. Analysis of the computed trajectories suggests that 4-HNE decreases stability, increases local flexibility and produced modest unfolding on both tested proteins. Finally, all the systems evaluated shown an increase in the lipophilic potential and a modest decrease in the electrostatic potential in BSA but an increase in TRX. PMID- 30453114 TI - Gating and inactivation of mechanosensitive channels of small conductance: A continuum mechanics study. AB - Mechanosensitive channels of small conductance (MscS) in Escherichia coli (E. coli) serve as a paradigm for understanding the gating behaviors of the MscS family of ion channels. In this work, we develop a continuum mechanics framework to explore the conformational states of MscS during the gating transition. A complete gating transition trajectory from the closed to the open state along with partially open intermediates is obtained, and the open structure is close to the available structural model from crystallographic studies. The computational efficiency of the modeling framework makes it possible to explore the roles of various structural elements (e.g., loops that connect transmembrane helices) and specific interactions in the gating transition. It is observed that removing either the Asp62-Arg131 salt bridge or the Phe68-Leu111 non-polar interaction leads to essentially non-conducting structures even with a membrane tension close to the lysis limit. The loop connecting TM2 (the second transmembrane helix) and TM3 is found to be essential for force transmission during gating, while the loop connecting TM1 and TM2 does not make any major contribution. Based on the different structural evolutions observed when the TM3 kink is treated as a loop or a helical segment, we propose that the helical propensity of the kink plays a central role in inactivation; i.e., under prolonged sub-threshold membrane tension, transition of the initially flexible loop to a helical segment in TM3 may lead to MscS inactivation. Finally, the gating transition of MscS under different transmembrane voltages is explored and found to be essentially voltage independent. Collectively, results from the current continuum mechanics analysis provide further insights into the gating transition of MscS at structural and physical levels, and specific predictions are proposed for further experimental investigations. PMID- 30453115 TI - The performance of sol-gel silica coated Y-TZP for veneered and monolithic dental restorations. AB - OBJECTIVES: The purpose of the study was to characterize the microstructure, constituents, and mechanical properties of mono and bilayered zirconia specimens infiltrated with silica by the sol gel method. METHODS: 180 zirconia discs (14-mm diameter) were divided in 3 groups (n = 60) according to thickness (1.2, 0.5 mm) and further divided in two groups (n = 30) according to treatment (infiltrated or not). Disk thickness was 1.2 mm for the control samples. Veneering feldspathic porcelain had two thicknesses (0.5 mm and 1 mm) at the tops of the zirconia discs. All groups were subjected to the biaxial flexural test in an aqueous medium. Weibull analysis was performed for determination of the Weibull modulus (m) and characteristic strength (sigma0). The specimens were characterized by SEM and EDS and XRD. Hardness and elastic modulus were measured by nano-indentation and pulse-echo methods, respectively. Fracture toughness was determined by the nano-indentation technique. A scratch test was used for evaluation of the adhesion between the zirconia and porcelain. RESULTS: There was less variability (higher Weibull modulus) in the infiltrated monolithic specimens; biaxial flexural strength was not statistically higher in the veneered infiltrated specimens and was decreased for the 1-mm veneered infiltrated group. The diffractograms showed formation of ZrSiO4 crystal phase. Hardness also increased in the infiltrated monolithic zirconia, whereas fracture toughness decreased. Adhesion between zirconia and porcelain was superior in the non-infiltrated monolithic specimens. CONCLUSIONS: Infiltration increased the structural homogeneity and hardness of the monolithic zirconia, but it reduced fracture toughness, and the adhesion to porcelain. CLINICAL SIGNIFICANCE: Within the limitations of the present study, it is possible to recommend the infiltration of silica gel in zirconia only for monolithic restorations. PMID- 30453116 TI - Association between proprotein convertase subtilisin/kexin 9 (PCSK9) and lipoprotein subclasses in children with type 1 diabetes mellitus: Effects of glycemic control. AB - BACKGROUND AND AIMS: Dyslipidemia in type 1 diabetes mellitus (T1DM) is characterised by altered distributions of low-density lipoprotein (LDL) and high density lipoprotein (HDL) subclasses. Recent studies suggested that proprotein convertase subtilisin/kexin 9 (PCSK9) may contribute to the development of dyslipidemia in T1DM. In this cross-sectional study, we investigated the association between PCSK9 and lipoprotein subclasses in young T1DM patients, with respect to glycemic control. METHODS: Plasma PCSK9 and lipoprotein subclasses were determined in 207 patients with T1DM (106 boys and 101 girls), aged 13.9 +/- 3.0 years and treated by intensive insulin therapy. RESULTS: Plasma PCSK9 levels significantly increased with worsening of glycemic control (p < 0.001). T1DM patients with poor glucoregulation had the highest proportion of small, dense LDL (sdLDL) and smaller HDL particles, as well. PCSK9 was positively associated with markers of glucose homeostasis and serum lipid parameters only in patients with suboptimal/poor glucoregulation. In well-controlled T1DM, plasma PCSK9 level was inversely associated with a relative proportion of sdLDL particles (p < 0.01) and this association remained significant in multivariate analysis. In T1DM patients with suboptimal/poor glycemic control, PCSK9 was positively associated with the proportion of the smallest HDL3c particles (p < 0.001), but negatively with HDL size (p < 0.05). CONCLUSIONS: The extent of achieved metabolic control modifies the association between PCSK9 and lipoprotein subclasses in T1DM. Further investigations are needed to reveal whether the observed effects of glycemic control on PCSK9 and sdLDL levels have causal consequences on CVD risk in young patients with T1DM. PMID- 30453117 TI - Life course trajectories of cardiovascular risk: Impact on atherosclerotic and metabolic indicators. AB - BACKGROUND AND AIMS: In this analysis, we estimated population-level trajectory groups of life course cardiovascular risk to explore their impact on mid-life atherosclerotic and metabolic outcomes. METHODS: This prospective study followed n = 1269 Bogalusa Heart participants, each with at least 4 study visits from childhood in 1973 through adulthood in 2016. We used discrete mixture modeling to determine trajectories of cardiovascular risk percentiles from childhood to adulthood. Outcomes included mid-life subclinical atherosclerotic measures [(carotid intima-media thickness (cIMT), pulse wave velocity (PWV)], metabolic indicators [(diabetes and body mass index (BMI)], and short physical performance battery (SPPB). RESULTS: Between the mean ages of 9.6-48.3 years, we estimated five distinct trajectory groups of life course cardiovascular risk (High-Low, High-High, Mid-Low, Low-Low, and Low-High). Adult metabolic and vascular outcomes were significantly determined by life course cardiovascular risk trajectory groups (all p < 0.01). Those in the High-Low group had lower risks of diabetes (20% vs. 28%, respectively; p = .12) and lower BMIs (32.4 kg/m2vs. 34.6 kg/m2; p = .06) than those who remained at high risk (High-High) throughout life. However, the High-Low group had better cIMT (0.89 mm vs. 1.05 mm; p < .0001) and PWV (7.8 m/s vs. 8.2 m/s; p = .03) than the High-High group. For all outcomes, those in the Low-Low group fared best. CONCLUSIONS: We found considerable movement between low- and high-relative cardiovascular risk strata over the life course. Children who improved their relative cardiovascular risk over the life course achieved better mid-life atherosclerotic health despite maintaining relatively poor metabolic health through adulthood. PMID- 30453118 TI - MicroRNA-142-3p improves vascular relaxation in uremia. AB - BACKGROUND AND AIMS: Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. Therefore, we aimed to characterize the putative role of microRNAs (miR)s in uremic vascular remodelling and endothelial dysfunction. METHODS: We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by mass spectrometry and wire myography. RESULTS: The expression pattern of miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulse-wave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation. CONCLUSIONS: Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD. PMID- 30453119 TI - Effect of toe dorsiflexion on the regional distribution of plantar fascia shear wave velocity. AB - BACKGROUND: The plantar fascia is exposed to repetitive tensile stress induced by cyclic loads associated with daily activities, such as walking and running. Due to overuse or abnormal foot alignment, insertional and distal (i.e., mid substance) regions within the plantar fascia may exhibit microtears, which leads to plantar fasciopathy. Ultrasound shear wave elastography is an imaging technique to measure shear wave velocity propagating through biological tissues, considered herein as an index of tensile stress. This study aimed to quantify the effect of toe dorsiflexion on the regional distribution of plantar fascia shear wave velocity. METHODS: Shear wave velocity of the plantar fascia was measured in the insertional and distal regions using ultrasound shear wave elastography in sixteen healthy participants (7 males and 9 females). The measurements were performed while the toes were maintained in neutral or dorsiflexed positions. FINDINGS: When considering the insertional region, there was no significant difference in shear wave velocity between neutral toe position [mean (SEM): 5.4 (0.6) m/s] and dorsiflexed toe position [5.5 (0.5) m/s] (P = 0.88; effect size = 0.05). When considering the distal region, there was a significant difference in shear wave velocity between the neutral position [7.8 (0.4) m/s] and dorsiflexed position [9.9 (0.3) m/s] (P = 0.002; effect size = 0.88). The difference in shear wave velocity between the insertional and distal regions showed a large effect size for either neutral (P = 0.010; effect size = 0.75) or dorsiflexed toe position (P = 0.003; effect size = 0.86). INTERPRETATION: In contrast to clinical beliefs, these findings suggest that toe dorsiflexion induces non-homogeneous changes in tensile stress within the plantar fascia. PMID- 30453120 TI - Immediate effects of kinesiotaping on acromiohumeral distance and shoulder proprioception in individuals with symptomatic rotator cuff tendinopathy. AB - BACKGROUND: Kinesiotaping is widely used for the rehabilitation of rotator cuff tendinopathy. It has been argued to reduce symptoms and functional limitations through improvement of proprioceptive feedback. In addition, kinesiotaping has been reported to increase the subacromial space in healthy subjects. However, its effects on the acromiohumeral distance and shoulder proprioception of individuals with rotator cuff tendinopathy have not been ascertained. This study investigated the immediate effects of kinesiotaping on the acromiohumeral distance and shoulder proprioception in individuals with rotator cuff tendinopathy. METHODS: Twenty-two individuals with chronic rotator cuff tendinopathy were included. The acromiohumeral distance was measured using an ultrasound scanner at rest and 60 degrees shoulder abduction. Proprioception was measured through active joint repositioning in low- (45 degrees -65 degrees ) and mid-amplitude (80 degrees 100 degrees ) of shoulder flexion and abduction. A wireless inertial measurement unit system was used to quantify shoulder angles. First, measurements were taken without kinesiotaping. Thereafter, kinesiotaping was applied on the symptomatic shoulder, and the same measurements were retaken. Repeated measures ANOVAs were used for statistical analyses. FINDINGS: Kinesiotaping induced a significant increase in acromiohumeral distance at 60 degrees abduction (?AHD = 0.94 mm; 95%CI: 0.50-1.38, p < 0.001), exceeding the minimal detectable change (0.70 mm). No significant difference was observed in acromiohumeral distance at rest or in proprioception during active joint repositioning in both low- and mid-amplitude (p > 0.05). INTERPRETATION: Kinesiotaping led to an immediate increase in acromiohumeral distance at 60 degrees of abduction that, although it seems a minor change (?10.5%), it may be significant for symptomatic patients, whereas it had no immediate effect on active joint repositioning. PMID- 30453121 TI - "His tummy's only tiny" - Scientific feeding advice versus women's knowledge. Women's experiences of feeding their late preterm babies. AB - OBJECTIVE: This paper reports on one element of a study exploring the experiences of women who are caring for late preterm baby/babies (LPBs) and focuses on their experiences of breastfeeding. DESIGN: As this study aimed to privilege women's experiences, a feminist approach was utilised, with individual qualitative interviews in two phases conducted with a purposefully selected sample of women who were caring for a late preterm baby or babies. Template Analysis linked to Birth Territory Theory (BTT) was used to identify key issues and experiences of women. SETTING AND PARTICIPANTS: Women (N = 24 to N = 14) were recruited from an NHS Trust Hospital in the South West region of England. FINDINGS: Infant feeding was planned with alarm clock precision. Babies, whether breast or formula fed, were subject to strict feeding guidelines/supplementation/volumes dictated by doctors and enforced by nurses and midwives and greatly impacted on women's experiences of caring. Women were powerless at times to influence feeding and regimes did not facilitate instinctive mother-care or enable babies to demonstrate innate feeding behaviours (such as rooting and early feeding cues). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The current approach to caring for women and their late PTBs tends to result in feeding becoming a source of stress and anxiety for women, rather than a positive experience. To resolve this, staff caring for women who have LPBs should focus on supporting women to trust their instincts, and to guide them in developing confidence in their ability to read their babies' cues, rather than in focusing on strict regimes of feeding. This should include individualised consideration of whether supplementation is required in the early days. PMID- 30453122 TI - Client and provider factors associated with companionship during labor and birth in Kigoma Region, Tanzania. AB - BACKGROUND: Labor and birth companionship is a key aspect of respectful maternity care. Lack of companionship deters women from accessing facility-based delivery care, though formal and informal policies against companionship are common in sub Saharan African countries. AIM: To identify client and provider factors associated with labor and birth companionship DESIGN: Cross-sectional evaluation among delivery clients and providers in 61 health facilities in Kigoma Region, Tanzania, April-July 2016. METHODS: Multilevel, mixed effects logistic regression analyses were conducted on linked data from providers (n = 249) and delivery clients (n = 935). Outcome variables were Companion in labor and Companion at the time of birth. FINDINGS: Less than half of women reported having a labor companion (44.7%) and 12% reported having a birth companion. Among providers, 26.1% and 10.0% reported allowing a labor and birth companion, respectively. Clients had significantly greater odds of having a labor companion if their provider reported the following traits: working more than 55 hours/week (aOR 2.46, 95% CI 1.23-4.97), feeling very satisfied with their job (aOR 3.66, 95% CI 1.36-9.85), and allowing women to have a labor companion (aOR 3.73, 95% CI 1.58 8.81). Clients had significantly lower odds of having a labor companion if their provider reported having an on-site supervisor (aOR 0.48, 95% CI 0.24-0.95). Clients had significantly greater odds of having a birth companion if they self reported labor complications (aOR 2.82, 95% CI 1.02-7.81) and had a labor companion (aOR 44.74, 95% CI 11.99-166.91). Clients had significantly greater odds of having a birth companion if their provider attended more than 10 deliveries in the last month (aOR 3.43, 95% CI 1.08-10.96) compared to fewer deliveries. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These results suggest that health providers are the gatekeepers of companionship, and the work environment influences providers' allowance of companionship. Facilities where providers experience staff shortages and high workload may be particularly responsive to programmatic interventions that aim to increase staff acceptance of birth companionship. PMID- 30453123 TI - Cortisol relates to regional limbic system structure in older but not younger adults. AB - We investigated if the relationship between age and regional limbic system brain structure would be moderated by diurnal cortisol output and diurnal cortisol slope. Participants aged 23-83 years collected seven salivary cortisol samples each day for 10 consecutive days and underwent magnetic resonance imaging. Age, sex, cortisol, and an age x cortisol interaction were tested as predictors of hippocampal and amygdalar volume and caudal and rostral anterior cingulate cortex (ACC) thickness. We found significant interactions between age and cortisol on left and right amygdalar volumes and right caudal ACC thickness. Older adults with higher cortisol output had smaller left and right amygdalar volumes than older adults with lower cortisol output and younger adults with higher cortisol output. Older and younger adults with lower cortisol output had similar amygdalar volumes. Older adults with a steeper decline in diurnal cortisol had a thicker right caudal ACC than younger adults with a similarly shaped cortisol slope. Hippocampal volume was not related to either cortisol slope or output, nor was pallidum volume which was assessed as an extra-limbic control region. Results suggest that subtle differences in cortisol output are related to differences in limbic system structure in older but not younger adults. PMID- 30453124 TI - Increased frequency of mind wandering in healthy women using oral contraceptives. AB - Oral contraceptive (OC) is the most common type of contraceptive method used in industrialized countries. A recent epidemiological study showed that OC use was associated with the onset of depression in young women. Mind wandering, a cognitive process associated with spontaneous thoughts unrelated to the task at hand, has previously been associated with depressive thinking. Consequently, mind wandering might be a precursor for cognitive vulnerability in individuals who are at-risk for mood disorders. The purpose of this study was to examine the frequency and nature of mind wandering in women using OC in comparison to two control groups: naturally cycling women and men. We recruited 71 participants (28 women currently using OC, 14 naturally cycling women in the luteal phase of their menstrual cycle and 29 men) aged between 18 and 35 years, and measured the frequency and nature (guilt/fear oriented and positive) of mind wandering using the short version of the Imaginal Process Inventory. In all analyses, we controlled for depressive symptoms to delineate the unique association between OC use and mind wandering. We also measured estradiol, progesterone and testosterone to confirm expected group differences in sex hormones concentrations. Results show that women using OC presented increased frequency of mind wandering when compared to naturally cycling women and men who did not differ between each other. The three groups did not differ in terms of the nature of mind wandering. These results show that OC use is associated with increased frequency of mind wandering and suggest that the association between OC use and dysphoric mood described in previous studies may be partially explained by the impact of OC use on cognitive processes underlying mind wandering. PMID- 30453125 TI - The role of education on the association between disability and depressive symptoms among community-dwelling older adults: Evidence from Frailty in Brazilian Older People (Fibra) study. AB - OBJECTIVES: To explore whether higher socioeconomic status attenuates the effects of depressive symptoms on disability among older adults. METHODS: We conducted a cross-sectional study based on 596 older adults, aged 65 and over, from a large city (Belo Horizonte) in Brazil. Disability was defined as limitation in activities such as Basic Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). Covariates were age, comorbidities, Body Mass Index (BMI) and grip strength. Statistical analyses were based on Ordinal Logistic Regression and calculated separately for men and women. RESULTS: Elderly women with disability and higher education levels have similar prevalence of depressive symptoms compared to those without disability (17.9% and 16.1%, respectively), but lower compared to those disabled with lower education (37.2%). A positive gradient trend was observed for depressive symptoms across disability categories among women (OR = 2.61; 95% CI 1.52, 4.48). However, these patterns were not observed among men. CONCLUSION: A higher level of education attenuates odds of depressive symptoms in elderly women with disability but does not eliminate it. Therefore, screening for depressive symptoms in low-educated elderly women is important in order to identify them and start early prevention care for target risk population and decrease the disability expenses for health services. PMID- 30453126 TI - The carboxyl-terminal region of human coagulation factor X as a natural linker for fusion strategies. AB - Fusion with human serum albumin (HSA), which represents a well-established technique to extend half-life of therapeutic proteins, commonly exploits intervening peptide linkers as key components. Here, we explored the human coagulation factor X (FX) carboxyl-terminal region, previously demonstrated by us to be dispensable for secretion and coagulant activity, as a natural linker for fusion purposes. To test our hypothesis, we compared direct FX-HSA fusion with the designed FX-HSA fusion proteins mimicking the recombinant activated factor VII (rFVIIa)-HSA or factor IX (FIX)-HSA chimeras, both strongly dependent from artificial linkers. Three constructs were produced by direct tandem fusion (FX HSA) and through flexible (glycine/serine; FX-GS-HSA, mimicking rFVIIa-HSA) or cleavable (incorporating the FX activation site; FX-CL-HSA, mimicking FIX-HSA) linkers. The FX-HSA was efficiently secreted and displayed prolonged plasma persistence in mice. All chimeras possessed remarkable pro-coagulant activity, comparable to FX for FX-HSA (88.7 +/- 6.0%) and FX-CL-HSA (98.0 +/- 16.4%) or reduced for FX-GS-HSA (55.8 +/- 5.4%). Upon incubation with activators, FX-HSA and FX-CL-HSA displayed a correct activation profile while the FX-GS-HSA activation was slightly defective. In fluorogenic-based assays, FX-HSA showed normal activity over time and a specific amidolytic activity (1.0 +/- 0.12) comparable to that of FX. Overall, the FX-HSA features indicate that the FX carboxyl-terminal region represents an intrinsic sequence allowing direct tandem fusion. Our results provide the first experimental evidence for i) a coagulation factor fusion protein with biological properties independent from artificial linkers, ii) the suitability of FX carboxyl-terminal region as a natural linker for fusion purposes. PMID- 30453127 TI - Gulf War illness associated with abnormal auditory P1 event-related potential: Evidence of impaired cholinergic processing replicated in a national sample. AB - Our team previously reported event-related potential (ERP) and hyperarousal patterns from a study of one construction battalion of the U.S. Naval Reserve who served during the 1991 Persian Gulf War. We sought to replicate these findings in a sample that was more representative of the entire Gulf War-era veteran population, including male and female participants from four branches of the military. We collected ERP data from 40 veterans meeting Haley criteria for Gulf War syndromes 1-3 and from 22 matched Gulf War veteran controls while they performed an auditory oddball task. Reports of hyperarousal from the ill veterans were significantly greater than those from the control veterans, and P1 amplitudes in Syndromes 2 and 3 were significantly higher than P1 amplitudes in Syndrome 1, replicating our previous findings. Many of the contributors to the generation of the P1 potential are also involved in the regulation of arousal and are modulated by cholinergic and dopaminergic systems-two systems whose dysfunction has been implicated in Gulf War illness. These differences among the three syndrome groups where their means were on either side of controls is a replication of our previous ERP study and is consistent with previous imaging studies of this population. PMID- 30453128 TI - Unrecorded alcohol in East Africa: A case study of Kenya. AB - Alcohol misuse contributes substantially to the global morbidity and mortality burden. Unrecorded alcohol, alcohol that is purchased by means which precludes regulation, represents a substantial proportion of the alcohol consumed in East Africa. In Kenya, homebrew also known as traditional brew, has been linked to several fatalities and hospitalizations. Previously banned, the Kenyan government recently legalized homebrew in an effort to regulate and reduce its harm. Despite legalization, however, homebrew continues to be endemic. In this paper, we examine the scope and harm associated with unrecorded alcohol in Kenya, and discuss current policies and interventions aimed at reducing production and consumption of unrecorded alcohol in the Kenyan context that reflect its culture, politics, environment and resources. PMID- 30453129 TI - Quantification of trans-resveratrol and its metabolites in human plasma using ultra-high performance liquid chromatography tandem quadrupole-orbitrap mass spectrometry. AB - Trans-resveratrol is a stilbene polyphenol with a large spectrum of biological activities. This is why it is widely studied in terms of activities, bioavailability and quantitation in different foods, beverages and biological matrices. Different analytical methods are employed for its quantitation. In this study a quadrupole-orbitrap tandem mass spectrometer coupled to a reverse phase ultra-high performance liquid chromatography is applied to a quantitation of trans-resveratrol and its metabolites trans-resveratrol-3-O-beta-d-glucuronide, trans-resveratrol-4'-O-beta-d-glucuronide, trans-resveratrol-3-O-sulfate, a,b dihydroresveratrol, a,b-dihydroresveratrol-glucuronide, a,b-dihydroresveratrol glucuronide-sulfate, a,b-dihydroresveratrol-sulfate, trans-resveratrol-3,5-O-beta d-diglucuronide, trans-resveratrol-3,4'-O-d-beta-diglucuronide, trans-resveratrol 3-O-beta-d-glucuronide-sulfate and trans-resveratrol-4'-O-beta-d-glucuronide sulfate in human plasma. MS/MS experiments coupled to a high resolving power and accurate mass measurements as well as the use of labeled internal standards enabled the achievement of linear calibration curves across the four orders of magnitude concentration ranges. The method was validated in terms of specificity and selectivity, accuracy and precision, sensitivity and matrix effect and can be now applied to pharmacokinetic studies or routine analysis. In addition, the application of quadrupole-orbitrap mass spectrometer to the quantitation of trans resveratrol and its metabolites provides acquisition of full collision induced dissociation spectra of analyzed compounds giving place to the structural characterization and sensitivity and linear concentration ranges respecting the accuracy and precision, specificity and selectivity requirements. PMID- 30453130 TI - 238Pu/(239+240)Pu activity ratio as an indicator of Pu originating from the FDNPP accident in the terrestrial environment of Fukushima Prefecture. AB - The Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident has caused significant radionuclide contamination. Pu isotopes at the level of GBq were released from the damaged reactors to terrestrial and marine ecosystems. In this work, 35 samples were collected at different locations of Fukushima. Samples consisted of three types, soil, forest litter and alluvial dust (road dust, sludges from drainage systems and below gutter pipe outflows). The obtained activity ratios of 238Pu/(239+240)Pu ranged from 0.030 to 1.86. 14 of our samples contained trace amounts of Pu originating from the damaged reactors (2SM verification). Our study identified a few previously unknown "hot spots" of 238Pu/(239+240)Pu activity ratio localized in an area between 15 and 30 km in the northwest direction from the FDNPP. Additionally, results obtained in this study combined with previously published data allowed us to prepare a map of spatial distribution of the Pu isotope fingerprints (238Pu/(239+240)Pu) in Fukushima Prefecture. PMID- 30453131 TI - Impacts of cold weather on emergency hospital admission in Texas, 2004-2013. AB - Cold weather has been identified as a major cause of weather-related deaths in the U.S. Although the effects of cold weather on mortality has been investigated extensively, studies on how cold weather affects hospital admissions are limited particularly in the Southern United States. This study aimed to examine impacts of cold weather on emergency hospital admissions (EHA) in 12 major Texas metropolitan statistical areas (MSAs) for the 10-year period, 2004-2013. A two stage approach was employed to examine the associations between cold weather and EHA. First, the cold effects on each MSA were estimated using distributed lag non linear models (DLNM). Then a random effects meta-analysis was applied to estimate pooled effects across all 12 MSAs. Percent increase in risk and corresponding 95% confidence intervals (CIs) were estimated as with a 1 degrees C ( degrees C) decrease in temperature below a MSA-specific threshold for cold effects. Age stratified and cause-specific EHA were modeled separately. The majority of the 12 Texas MSAs were associated with an increased risk in EHA ranging from 0.1% to 3.8% with a 1 0C decrease below cold thresholds. The pooled effect estimate was 1.6% (95% CI: 0.9%, 2.2%) increase in all-cause EHA risk with 1 0C decrease in temperature. Cold wave effects were also observed in most eastern and southern Texas MSAs. Effects of cold on all-cause EHA were highest in the very elderly (2.4%, 95% CI: 1.2%, 3.6%). Pooled estimates for cause-specific EHA association were strongest in pneumonia (3.3%, 95% CI: 2.8%, 3.9%), followed by chronic obstructive pulmonary disease (3.3%, 95% CI: 2.1%, 4.5%) and respiratory diseases (2.8%, 95% CI: 1.9%, 3.7%). Cold weather generally increases EHA risk significantly in Texas, especially in respiratory diseases, and cold effects estimates increased by elderly population (aged over 75 years). Our findings provide insight into better intervention strategy to reduce adverse health effects of cold weather among targeted vulnerable populations. PMID- 30453132 TI - Plasmonic enhancement in lateral flow sensors for improved sensing of E. coli O157:H7. AB - We propose a plasmonic enhanced lateral flow sensor (pLFS) concept with an enhanced colorimetric signal by utilizing liposome encapsulating reagent to trigger the aggregation of gold nanoparticles (GNPs). Our signal enhancement strategy incorporates the simplicity of lateral flow immunoassays (LFIA) utilizing plasmonic enhancement. The conceptualized hybrid pLFS for onsite rapid detection of pathogens in low numbers in a user friendly format requiring simple steps is the first step in the translation of plasmonic enhancement sensing to a practical regime. The pLFS was carried out with a biotinylated liposome label ruptured to release branched polyethylenimine (BPEI) to trigger the aggregation of GNPs for colorimetric signal generation. BPEI has multiple amino groups and more positive charges in PBS buffer, therefore few of the BPEI groups could induce the aggregation of GNPs, resulting in an enhanced colorimetric signal to detect E. coli O157:H7. Compared with the reported conventional LFIA, the proposed pLFS demonstrated more than 1000-fold improvement in sensitivity. The pLFS could detect as low as 100 CFU/ml of E. coli O157:H7 in buffer and 600 CFU/ml E. coli O157:H7 in liquid food systems. PMID- 30453133 TI - Red light-driven photoelectrochemical biosensing for ultrasensitive and scatheless assay of tumor cells based on hypotoxic AgInS2 nanoparticles. AB - A novel red light-driven photoelectrochemical (PEC) biosensing platform based on hypotoxic ternary mercaptopropionic acid (MPA)-capped AgInS2 nanoparticles (NPs) with excellent hydrophily and biocompatibility was proposed. AgInS2 NPs as a PEC sensing substrate exhibited high photon-to-current conversion efficiency under red light excitation, generating an intensive photocurrent for enhancing the sensitivity of PEC determination. After the introduction of the amino-terminated sgc8c aptamer onto the interface of AgInS2 NPs, the overexpressed protein tyrosine kinase-7 on the surface of lymphoblast CCRF-CEM cells could be efficiently captured. Using CCRF-CEM cell as a model analyte, an ultrasensitive PEC biosensor for scatheless assay of cells at the applied potential of 0.15 V under a red light excitation of 630 nm was designed based on the significant decline of photocurrent intensity after capturing CCRF-CEM cells. The developed PEC cytosensor demonstrated an excellent cell-capture ability, as well as a wide linear range from 1.5 * 102 to 3.0 * 105 cells/mL and a low detection limit of 16 cells/mL for CCRF-CEM cells. In addition, the resulting assay method verified high selectivity and negligible cytotoxicity for cells assay. This work provided an alternative method for scatheless assay of tumor cells, which would have promising prospect in clinical diagnoses of cancer. PMID- 30453135 TI - Red blood cell adhesion can be reduced by non-reactive macromolecules. AB - To date, the mechanisms behind red blood cell (RBC) adhesion remain unclear. However, polymer depletion at the red cell surface has been shown to play a significant role. Interestingly, most previous studies have focused on the adhesion-promoting effects of one type of large polymer or plasma protein. However, the situation in vivo is more complex in that one needs to consider a mixture of various bio-macromolecules. To explore this complexity, Interference Reflection Microscopy was used to investigate how mixtures of various polymers affect RBC adhesion. RBC adhesion to albumin-coated glass coverslips was studied in the presence of two pro-adhesion polymers [dextran70 kDa and 35 kDa poly(ethylene glycol) (PEG 35)] with and without three types of smaller polymers: dextran 10 kDa, PEG 10 kDa and Poloxamer 188. Our findings show that the presence of small polymers can inhibit the adhesion-promoting effects of dextran 70 and PEG 35, with a more pronounced reduction for heterogeneous mixtures. Interpretation of our results in terms of the depletion model appears appropriate, in that our findings are consistent with the assumption that this reduction occurs because of an increase of small molecules in the depletion region. This study thus suggests that depletion interaction can control cell-cell interactions in complex environments (e.g., in vivo), and indicates that considering the interplay of all plasma constituents is important in order to understand the pathophysiology of diseases associated with cell adhesion and vascular complications. PMID- 30453134 TI - Updated European Consensus Statement on diagnosis and treatment of adult ADHD. AB - Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD. PMID- 30453136 TI - Laser writing of nanostructured silicon arrays for the SERS detection of biomolecules with inhibited oxidation. AB - The present work reports the processing of laser irradiated Si arrays (LISi) and underlines their surface enhanced Raman scattering (SERS) functionality. A nanostructured Si/SiOx surface forms providing additional fluidic and photoprotective properties. Because of their optical and surface characteristics, the arrays exhibit a SERS analytical enhancing factor of 500, without any noble metals such as gold or silver. Micro-Raman maps allowed studying LISi properties, identifying maximum amplification in nanostructured areas characterized by the presence of 7 nm Si nanocrystals. These structures are confined by a SiOx layer as illustrated by XPS valence band measurements. The highly hydrophilic LISi areas allow a pre-concentration of target molecules prior to SERS analysis. A relevant application of LISi was found in the detection of apomorphine (APO), a drug used for the treatment of Parkinson's disease. In contrast with what is obtained by using gold SERS substrates, LISi allows the detection of APO with no sign of oxidation. This invites for the use of the Si/SiOx SERS detection in future systems for the personalized delivery of APO. PMID- 30453137 TI - Cigarette smoke induces ROS mediated autophagy impairment in human corneal epithelial cells. AB - Cigarette smoke is an important indoor air pollutant which has deleterious effects on human health. Continued daily exposure to cigarette smoke has been attributed to the risk factor of ocular surface diseases. However, the mechanisms underlying the ocular surface damage are not fully elucidated. In this study, exposure to cigarette smoke extract (CSE) induced a dose- and time-dependent cytotoxicity in human corneal epithelial (HCE) cells, supported by the observation of reduced cell viability, increased apoptotic cells, elevated intracellular oxidative stress and loss of mitochondrial transmembrane potential. In addition, CSE exposure led to the impairment of proteostasis and autophagy, which resulted in the accumulation of ubiquitinated proteins as aggregates in peri-nuclear spaces. Furthermore, the autophagy inducer, cysteamine was shown to attenuate the CSE induced cell damage, oxidative stress and mitochondrial dysfunction in HCE cells. Moreover, cysteamine inhibited the formation of ubiquitin-positive aggregates around the peri-nuclear region, through regulating the autophagic activity of HCE cells. Similar to in vitro experiments, cigarette smoke induced proteostasis and autophagy impairment in corneal epithelial cells could be rescued by cysteamine in a cigarette smoke-exposed murine model. Therefore, this study may provide first evidence that dysfunction of autophagy contributes to the pathogenesis of ocular surface diseases associated with cigarette smoke exposure. Besides, it also suggests the potential therapeutic value of cysteamine in the prevention and treatment of cigarette smoke induced ocular surface injury. CSE induces cytotoxicity and accumulation of ubiquitinated proteins in HCE cells due to impairment of proteostasis and autophagy, which can be rescued by cysteamine. PMID- 30453138 TI - A metagenomic analysis framework for characterization of antibiotic resistomes in river environment: Application to an urban river in Beijing. AB - River is considered generally as a natural reservoir of antibiotic resistance genes (ARGs) in environments. For the prevention and control of ARG risks, it is critical to comprehensively characterize the antibiotic resistomes and their associations in riverine systems. In this study, we proposed a metagenomic framework for identifying antibiotic resistomes in river sediments from multiple categories, including ARG potential, ARG hosts, pathogenicity potential, co selection potential and gene transfer potential, and applied it to understand the presence, hosts, and co-occurrence of ARGs in the sediments of an urban river in Beijing. Results showed that a total of 203 ARG subtypes belonging to 21 ARG types were detected in the river sediments with an abundance range of 107.7 1004.1*/Gb, dominated by multidrug, macrolide-lincosamide-streptogramin, bacitracin, quinolone and sulfonamide resistance genes. Host-tracking analysis identified Dechloromonas, Pseudoxanthomonas, Arenimonas, Lysobacter and Pseudomonas as the major hosts of ARGs. A number of ARG-carrying contigs (ACCs) were annotated as fragments of pathogenic bacteria and carried multiple multidrug ARGs. In addition, various biocide/metal resistance genes (B/MRGs) and mobile genetic elements (MGEs), including prophages, plasmids, integrons and transposons, were detected in the river sediments. More importantly, the co occurrence analysis via ACCs showed a strong association of ARGs with B/MRGs and MGEs, indicating high potential of co-selection and active horizontal transmission for ARGs in the river environment, likely driven by the frequent impact of anthropogenic activities in that area. PMID- 30453139 TI - Cyanobacterial blooms act as sink and source of endocrine disruptors in the third largest freshwater lake in China. AB - Cyanobacterial blooms are of global concern due to the multiple harmful risks they pose towards aquatic ecosystem and human health. However, information on the fate of organic pollutants mediated by cyanobacterial blooms in eutrophic water remains elusive. In the present study, endocrine disruptive potentials of phytoplankton samples were evaluated throughout a year-long surveillance in a large and eutrophic freshwater lake. Severe cyanobacterial blooms persisted during our sampling campaigns. Estrogenic agonistic, anti-estrogenic, anti androgenic, and anti-glucocorticogenic effects were observed in the phytoplankton samples using in vitro reporter gene bioassays. 27 endocrine disrupting chemicals (EDCs) of different modes of action were detected in the samples via UPLC-MS/MS system. Results from mass balance analysis indicated that the measured estrogenic activities were greater than the predicted estrogenic potencies from chemical analysis, demonstrating that chemical analysis of targeted EDCs is unable to fully explain the compounds responsible for the observed estrogenicities. Results from Spearman's correlation analysis concluded that the concentrations of ten EDCs in phytoplankton samples were negatively correlated with cyanobacterial biomass, suggesting the potential occurrence of biomass bio-dilution effects of EDCs due to the huge biomass of cyanobacteria during bloom seasons. The present study provided complementary information about the potential endocrine disruptive risks of cyanobacterial blooms, which is important for understanding and regulating EDCs in eutrophic lakes. PMID- 30453140 TI - Short-term effect of relatively low level air pollution on outpatient visit in Shennongjia, China. AB - BACKGROUND: Many cities in China are currently experiencing severe air pollution due to modernization. Previous studies investigating the effects of air pollutants exposure were particularly conducted in severe air polluted area and studies in low pollution areas were sparse. METHODS: To quantitatively assess the short-term effects of ambient air pollutants (PM2.5, PM10, SO2, NO2, CO and O3) on outpatient visits in low pollution area, we conducted a time-series analysis from Jan 1, 2015 to Dec 31, 2016 in Shennongjia, China. Generalized additive model (GAM) was used to evaluate the influence of PM2.5 on daily hospital outpatient visits with different lag structures. We also conducted stratified analysis to explore the association between PM2.5 concentration and outpatient visits in different seasons. RESULTS: In the present study, per IQR increment of PM2.5, PM10, NO2, CO and O3 were related with 1.92% (0.76%-3.09%), 1.92% (0.77% 3.07%), 2.74% (95% CI: 1.65%-3.83%), 1.89% (95% CI: 0.68%-3.10%) and 2.30% (95% CI: 0.65%-3.95%) increase on respiratory outpatient visits. Significant associations were found between PM2.5, PM10, NO2 and respiratory outpatient visits at lag0:1, lag0:2 days. The effects of PM2.5 were more evident in the cool season than in the warm season. CONCLUSIONS: Our study showed that short-term exposures to PM2.5, PM10, NO2, CO and O3 were related with increased risk of outpatient visits of respiratory diseases, and highlighted the adverse effect of air pollutants exposure, especially PM2.5 exposure in cool season on health in low pollution area. PMID- 30453141 TI - Proliferation inhibition of novel diphenylamine derivatives. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the world but some NSAIDs such as diclofenac and tolfenamic acid display levels of cytotoxicity, an effect which has been attributed to the presence of diphenylamine contained in their structures. A novel series of diphenylamine derivatives were synthetised and evaluated for their cytotoxic activities and proliferation inhibition. The most active compounds in the cytotoxicity tests were derivative 6g with an IC50 value of 2.5 +/- 1.1 * 10-6 M and derivative 6f with an IC50 value of 6.0 +/- 3.0 * 10-6 M (L1210 cell line) after 48 h incubation. The results demonstrate that leukemic L1210 cells were much more sensitive to compounds 6f and 6g than the HEK293T cells (IC50 = 35 * 10-6 M for 6f and IC50 > 50 * 10-6 M for 6g) and NIH-3T3 (IC50 > 50 * 10-6 M for both derivatives). The IC50 values show that these substances may selectively kill leukemic cells over non-cancer cells. Cell cycle analysis revealed that a primary trend of the diphenylamine derivatives was to arrest the cells in the G1-phase of the cell cycle within the first 24 h. UV-visible, fluorescence spectroscopy and circular dichroism were used in order to study the binding mode of the novel compounds with DNA. The binding constants determined by UV-visible spectroscopy were found to be in the range of 2.1-8.7 * 104 M-1. We suggest that the observed trend for binding constant K is likely to be a result of different binding thermodynamics accompanying the formation of the complexes. PMID- 30453142 TI - Potential bioisosteres of beta-uracilalanines derived from 1H-1,2,3-triazole-C carboxylic acids. AB - The 1H-1,2,3-triazole-originated derivatives of willardiine were obtained by: (i) construction of the 1H-1,2,3-triazole ring in 1,3-dipolar cycloaddition of the uracil-derived azides and the carboxylate-bearing alkynes or alpha-acylphosphorus ylide, or (ii) N-alkylation of the uracil derivative with the 1H-1,2,3-triazole-4 carboxylate-derived mesylate. The latter method offered: (i) reproducible results, (ii) a significant reduction of amounts of auxiliary materials, (iii) reduction in wastes and (iv) reduction in a number of manual operations required for obtaining the reaction product. Compound 6a exhibited significant binding affinity to hHS1S2I ligand-binding domain of GluR2 receptor (EC50 = 2.90 uM) and decreased viability of human astrocytoma MOG-G-CCM cells in higher extent than known AMPA antagonist GYKI 52466. PMID- 30453143 TI - Dynamic knee joint stiffness and contralateral knee joint loading during prolonged walking in patients with unilateral knee osteoarthritis. AB - BACKGROUND: Long duration walking, a commonly recommended treatment option for knee osteoarthritis (OA), may lead to increased knee joint loading. RESEARCH QUESTION: To evaluate the effects of prolonged walking on dynamic knee joint stiffness and contralateral knee joint contact forces (KCFs) in individuals with unilateral symptomatic knee OA. METHODS: Twenty-six older adults with knee OA completed a 45-minute bout of walking on a treadmill. Dynamic knee joint stiffness, estimated KCFs, measured ground reaction forces (GRFs), and simulated muscle forces were evaluated for both the symptomatic and asymptomatic limbs at 15-minute intervals using repeated measures, analysis of variance (ANOVA). RESULTS: Dynamic knee joint stiffness during the early weight-acceptance phase of gait was significantly higher for the symptomatic limb throughout the 45-minute bout of walking. A significant increase in peak KCFs and simulated muscle forces were also observed during the weight-acceptance phase of gait for both limbs after 30 and 45 min of walking. Additionally, significantly elevated peak KCFs and muscle forces were observed during the late-stance phase of gait for the contralateral asymptomatic limb throughout the 45-minute bout of walking. SIGNIFICANCE: Walking durations of 30 min or greater lead to increased knee joint loading. Additionally, the elevated dynamic knee joint stiffness observed for the symptomatic knee during the weight acceptance phase of gait appears to be unrelated to the knee joint loading profile. Finally, the greater KCFs during the late-stance phase of gait observed for the asymptomatic limb are consistent with previously demonstrated risk factors for OA development and progression. PMID- 30453144 TI - Evaluation of PCR-based methods for the identification of enteroaggregative hemorrhagic Escherichia coli in sprouts. AB - In this study real-time PCR assays were evaluated for the detection of enteroaggregative hemorrhagic Escherichia coli (EAHEC) O104:H4 in artificially contaminated mung bean and/alfalfa sprouts inoculated with 1, 10, and 100 CFU of EAHEC O104:H4 per 25 g sample (20, 10, and 2 replicates respectively). After selective culture enrichment the samples were tested using commercial real-time PCR kits detecting aggR/aaiC, stx/eae, and wzxO104. Using the commercial real time PCR kits, the artificially contaminated samples were detected in the range of 75-80% positive results when contaminated with approximately 1 CFU, and 100% at 10 and 100 CFU. Microbiological detection employing O104-specific immunomagnetic capture and plating onto chromogenic media (modified Rainbow Agar and CHROMagar STEC) and confirmation by latex agglutination and PCR gave similar results (Cohen's kappa value between 0.61 and 1). In addition, the real-time PCR assay targeting the aggR and aaiC genes, indicative of enteroaggregative Escherichia coli (EAggEC), was tested against a panel of 60 bacterial strains and demonstrated 100% exclusivity (54 strains) and 100% inclusivity (6 strains). This study demonstrates the efficacy of the real-time PCR assays for the specific and sensitive detection of EAHEC from spouts. PMID- 30453145 TI - GPCR homo-oligomerization. AB - G protein-coupled receptors (GPCRs) are an extensive class of trans-plasma membrane proteins that function to regulate a wide range of physiological functions. Despite a general perception that GPCRs exist as monomers an extensive literature has examined whether GPCRs can also form dimers and even higher-order oligomers, and if such organization influences various aspects of GPCR function, including cellular trafficking, ligand binding, G protein coupling and signalling. Here we focus on recent studies that employ approaches ranging from computational methods to single molecule tracking and both quantal brightness and fluorescence fluctuation measurements to assess the organization, stability and potential functional significance of dimers and oligomers within the class A, rhodopsin-like GPCR family. PMID- 30453146 TI - Determinants of antenatal care utilization in India: a spatial evaluation of evidence for public health reforms. AB - OBJECTIVE: The objective is to examine the spatial variations and to identify the determinants of antenatal care (ANC) utilization while controlling for the spatial dependence in the data. STUDY DESIGN: This is an ecological study on ANC utilization data from District Level Household Survey-4 (2012-2013) in India. METHODS: A secondary data analysis was performed on the derived data. The unit of analysis in this ecological study was 275 districts from 20 states of India. The study comprises ever married women of reproductive age. Determinants of ANC utilization were obtained using ordinary least square (OLS), spatial lag, and spatial error models. Model adequacy check was performed using the Akaike information criterion, R-squared, log likelihood, and Schwarz criterion. The software used is GeoDa and Quantum Geographic Information System. RESULTS: The presence of spatial autocorrelation (Moron's I = 0.6210) enforces the usage of geographic properties while modeling. The geographic clustering of low-rate districts was observed in states in Northeast India. In the present study, the model adequacy check reveals that the spatial error model performs better than the spatial lag and OLS models. The spatial pattern of the percentage of pregnant women with full ANC was observed to be associated with literacy (P = 0.04), birth order (P < 0.001), Janani Suraksha Yojana beneficiaries (P = 0.048), and availability of health infrastructure, staff, and services (P = 0.023). CONCLUSIONS: The present study findings provide valuable insights into factors affecting ANC utilization. In addition to available ANC services, customized safe motherhood interventions and region-specific awareness programs would enhance the utilization, ensuring better maternal and child health. PMID- 30453147 TI - NecroX-5 ameliorates inflammation by skewing macrophages to the M2 phenotype. AB - This study aimed to evaluate the role of NecroX-5, a powerful anti-inflammatory agent, on the functional plasticity of macrophages and the possible underlying mechanism using RAW264.7 cells, thioglycollate-elicited peritoneal macrophages from C57BL/6 mice, and a murine model of dextran sodium sulfate (DSS)-induced colitis. The change in cell morphology was examined by scanning electron microscopy. The expression of CD206, arginase (Arg)-1, and inducible nitric oxide synthase (iNOS) were examined by western blotting. The production of inflammatory cytokines was detected by enzyme-linked immunosorbent assays and statistical comparisons were made. The results showed that treatment of RAW264.7 cells with NecroX-5 caused an elongated shape in comparison to non-treated cells. The expression levels of macrophage mannose receptor CD206 and Arg-1, specific markers of M2 cells, were significantly upregulated by NecroX-5 treatment, while those of iNOS (M1 macrophages) was decreased. In addition, NecroX-5 significantly reduced the secretion of inflammatory cytokines, while interleukin (IL)-4 and IL 13 secretion in the supernatant was significantly enhanced. Treatment with NecroX 5 considerably ameliorated the progression of DSS-induced colitis and significantly inhibited the mRNA expression of pro-inflammatory cytokines, including tumor necrosis factor-alpha and IL-1beta. Taken together, our findings demonstrated that NecroX-5 might dampen inflammation by switching the M1 phenotype to the M2 phenotype due to IL-4 and IL-13 induction. PMID- 30453148 TI - Epicatechin alleviates inflammation in lipopolysaccharide-induced acute lung injury in mice by inhibiting the p38 MAPK signaling pathway. AB - The p38 MAPK signaling pathway plays a key role in lung inflammation and the development of acute lung injury (ALI). We previously reported that the phenolic compound procyanidin B1 inhibits inflammation by suppressing the p38 MAPK signaling pathway. Here, we asked whether the monomer of procyanidin B1, epicatechin (EC), can alleviate LPS-induced ALI in mice, and if so, whether EC acts by inhibiting p38 MAPK. C57BL/6 mice were randomly divided into four groups (n = 8) and received EC alone, vehicle (sham group), LPS alone, or LPS and EC. LPS was administered via intraperitoneal injection and EC via nasogastric feeding. Lung histopathology, alveolocapillary membrane permeability, inflammation, and p38 MAPK pathway activation were assessed by immunohistochemistry, tissue wet/dry weight analysis, quantitative PCR, protein assays, ELISA, and western blot analysis using lung tissue and/or bronchoalveolar fluid. We also performed molecular modeling and in vitro enzymatic assays to examine the potential interaction between EC and p38 MAPK at the molecular level. We found that LPS caused an increase in ALI-associated lung pathology accompanied by activation of p-p38 pathway components and the transcription factor AP1. All of these effects were substantially reduced by treatment with EC. Furthermore, molecular modeling suggested that EC suppressed p38 MAPK signaling by hydrogen bonding with Glu71, Ala 111, Asp112, and Leu171 in the active site of p38alpha. In vitro kinase assays confirmed the ability of EC to directly inhibit purified p38 MAPK. Collectively, our data suggest that the naturally occurring compound EC could be a new therapeutic option for ALI. PMID- 30453150 TI - Toxicological findings in 1000 cases of suspected drug facilitated sexual assault in the United States. AB - The purpose of this study was to identify the extent and types of drugs found in alleged drug facilitated sexual assaults (DFSA) in 37 states and 1 territory of the United States. In total, 1000 cases were reviewed. Between the cases that gender was provided (613), most of the victims (91.68%) were woman, mean age of 26.8 years old. Blood and/or urine samples were tested. Twenty-one point six percent of the cases were negative for intoxicating substances. A hundred and one different substances were detected. Overall, ethanol was the most prevalent substance, detected in 30.9% of the cases (309 cases), followed by cannabinoids (THC/THCCOOH/11-OH-THC) (28.8% of cases), amphetamine/methamphetamine (16.5% of cases), cocaine/metabolites (10.4% of cases), and clonazepam/metabolite (7.6% of cases). The mean, median and range concentrations of ethanol in blood (n = 309) were 98.6 mg/dL, 82.0 mg/dL and 9.2-366 mg/dL, respectively. Ethanol and cannabinoids were the most frequent combination found. The absence of alcohol and drugs in some cases may represent delay in collecting samples. PMID- 30453149 TI - Genetic polymorphisms in tumor necrosis factor alpha and interleukin-10 are associated with an increased risk of cervical cancer. AB - Most cases of cervical cancer are the result of infection with specific high-risk types of human papillomavirus (HPV). Investigating the genetic basis of the host immune response, particularly cytokine function, could help further characterize the progression of cervical HPV infection into neoplasia. Prior studies have demonstrated a correlation between genetic variants of tumor necrosis factor alpha (TNF-alpha, TNF gene) and/or interleukin-10 (IL-10, IL10 gene) and cervical cancer susceptibility. However, some of the results have been contradictory. We sought to resolve these discrepancies by carrying out our study in a large cohort of Chinese women. In order to assess the association of TNF and IL10 genotypes with cervical cancer susceptibility, the polymorphisms in TNF (-238 G/A, -308 G/A) and IL10 (-592 C/A, -819 C/T, -1082 A/G) were genotyped and odds ratios for the genotype and allele frequencies between cervical cancer patients and healthy controls were calculated. Also, the functional relevance of these polymorphisms was evaluated using enzyme-linked immunosorbent assays (ELISAs) and in vitro lymphocyte proliferation assays. The TNF-238 AA genotype frequency was lower in patients than in controls (p < 0.05). TNF-308 AA, IL10-592 CA/AA, and IL10-819 CC/CT genotype frequencies were higher in cervical cancer patients than in controls (p < 0.05). The frequency of the TNF-238 A allele was significantly lower in patients, while the frequency of the -308 A allele was significantly higher (p < 0.05). No significant differences between patients and controls were found in the genotype or allele frequencies of IL10-1082 A/G (p > 0.05). Furthermore, the combinations of TNF-238 GA or GG and IL10-592 CC; TNF-238 GA or GG and IL10-592 CA or AA; TNF-308 AA and IL10-592 CC; and TNF-308 AA and IL10-592 CA or AA in cervical cancer patients were statistically significant (p < 0.0167). Upon stimulation with PHA, peripheral blood mononuclear cells (PBMCs) with the TNF-308AA genotype exhibited significantly higher proliferation rates, elevated IL-4, TGF-beta levels, and lower IL-2 levels (p < 0.05). For IL10-592C/A, the AA and CA genotypes were significantly associated with higher proliferation rates, elevated IL-4 and IL-10 levels (p < 0.05). We also found that for TNF-308 G/A or IL10-592 C/A variants, the combination of TNF-308 GG or GA with IL10 CA or AA had an association with the severity of cervical cancer. Taken together, these results suggest that TNF-308 AA and IL10-592 CA/AA genotypes may increase susceptibility to cervical cancer by altering the immune response of an individual. PMID- 30453151 TI - Serum prolactin level and its correlation with psychopathology in drug free/drug naive schizophrenia a case control study. AB - BACKGROUND: There is a discrepancy in literature regarding level of prolactin in drug free/ drug naive patients with non-affective psychosis. Few earlier studies have found low levels of prolactin whereas recent studies have found high levels of prolactin when compared to controls. Most of these studies have not considered the possible confounding factors. Also ours is the first study that evaluated the correlation between psychopathology & prolactin levels after considering the confounding agents. METHOD: It was a cross sectional, hospital based case control study. Purposive sampling was done to identify the cases of schizophrenia. 59 cases and 59 controls fulfilling inclusion and exclusion criteria were taken for the study after taking consent. Socio-demographic and other relevant clinical data were collected. Scores of PANSS AND BPRS were collected on the day of admission. Blood samples were collected from 8 to 10 am in the morning. Samples were centrifuged and the serum was stored in sterile vials at minus 80 degrees centigrade. Serum Prolactin, free T3, freeT4, Thyroid Stimulating Hormone & Cortisol levels were evaluated for both cases and controls and correlation between them and with psychopathology of cases was seen. RESULTS: Our study showed that prolactin level was increased in drug free/naive cases of schizophrenia. Significant difference was found between T4 levels of cases and controls. No correlation was found between prolactin and psychopathology. CONCLUSION: Prolactin is increased in drug free/ drug naive patients of schizophrenia and this is not related to confounding factors. There was no significant correlation between prolactin and psychopathology. PMID- 30453152 TI - Induction of rod versus cone photoreceptor-specific progenitors from retinal precursor cells. AB - During development, multipotent progenitors undergo temporally-restricted differentiation into post-mitotic retinal cells; however, the mechanisms of progenitor division that occurs during retinogenesis remain controversial. Using clonal analyses (lineage tracing and single cell cultures), we identify rod versus cone lineage-specific progenitors derived from both adult retinal stem cells and embryonic neural retinal precursors. Taurine and retinoic acid are shown to act in an instructive and lineage-restricted manner early in the progenitor lineage hierarchy to produce rod-restricted progenitors from stem cell progeny. We also identify an instructive, but lineage-independent, mechanism for the specification of cone-restricted progenitors through the suppression of multiple differentiation signaling pathways. These data indicate that exogenous signals play critical roles in directing lineage decisions and resulting in fate restricted rod or cone photoreceptor progenitors in culture. Additional factors may be involved in governing photoreceptor fates in vivo. PMID- 30453153 TI - Generation of an iPSC line, INMi001-A, carrying the two most common USH2A mutations from a compound heterozygote with non-syndromic retinitis pigmentosa. AB - We generated an induced pluripotent stem cell (iPSC) line from a patient with non syndromic retinitis pigmentosa who is a compound heterozygote for the two most frequent USH2A variants, c.2276G > T and c.2299delG localized in exon 13. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail. The generated cells were pluripotent and genetically stable. This iPSC line will be an important tool for studying the pathogenesis of these USH2A mutations and for developing treatments that, due their high prevalence, will target a large patient population. PMID- 30453154 TI - In vitro expression of genetically encoded non-standard peptides consisting of exotic amino acid building blocks. AB - Ribosomal incorporation of non-proteinogenic amino acids (NPaa) into peptides have made significant progress in recent years. These non-standard peptides have been utilized for a plethora of applications in the fields of chemical biology and therapeutics. Here we comprehensively review recent advances for the incorporation of exotic NPaa into peptide chain using custom-made in vitro translation system under reprogrammed genetic code. Such approaches allow us to express non-standard peptides containing various amino acid building blocks in the mRNA-encoding manner, leading to the discovery of therapeutically useful macrocyclic molecules with molecular weight of less than 2500 Da. PMID- 30453155 TI - Psychiatric disorders and autism in young children with 22q11.2 deletion syndrome compared to children with idiopathic autism. AB - BACKGROUND: The 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition characterized by high rates of psychiatric disorders. To our knowledge, this is the first study to assess psychiatric disorders in young children with 22q11DS using a structured psychiatric diagnostic interview, and one of few studies to use the complete gold standard diagnostic evaluation to examine the prevalence of autism spectrum disorder (ASD) in young children with 22q11DS and compare it to a matched control group with iASD. METHODS: We identified the psychiatric disorders and autistic phenotype of young children with 22q11DS (age 3-8 years) and compared them with those of age and sex-matched children with idiopathic autism (iASD). We used the gold standard psychiatric and ASD assessments including the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observation Schedule (ADOS) and a clinical examination by a child psychiatrist. RESULTS: Eighty-four percent of the children with 22q11DS had at least one psychiatric disorder, including anxiety disorders and ADHD, and 16% met strict criteria for ASD. Children with 22q11DS and ASD symptoms had less severe overall ASD symptoms than those with iASD. Children with 22q11DS, regardless of ASD diagnosis, were characterized by repetitive restricted behaviors. CONCLUSIONS: Our results highlight the need to screen for psychiatric disorders in 22q11DS and treat them already in preschool years. PMID- 30453156 TI - LC-MS/MS-based quantification of efflux transporter proteins at the BBB. AB - Targeted protein quantification using tandem mass spectrometry coupled to high performance chromatography (LC-MS/MS) has been used to quantify proteins involved in the absorption, distribution, metabolism and excretion (ADME) of xenobiotics to better understand these processes. At the blood-brain barrier (BBB), these proteins are particularly important for the maintenance of brain homeostasis, but also regulate the distribution of therapeutic drugs. Absolute quantification (AQUA) is achieved by using stable isotope labeled surrogate peptides specific to the target protein and analyzing the digested proteins in a triple-quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode to achieve a high specificity, sensitivity, accuracy and reproducibility. The main objective in this work was to develop and validate an UHPLC-MS/MS method for quantification of the ATP-binding cassette (ABC) transporter proteins Bcrp and P-gp and Na+/K + ATPase pump at the BBB. Three isoforms of the alpha-subunit from this pump (Atp1a 1, 2 and 3) were quantified to evaluate the presence of non-endothelial cells in the BBB using one common and three isoform-specific peptides; while Bcrp ad P-gp were quantified using 2 and 3 peptides, respectively, to improve the confidence on their quantification. The protein digestion was optimized, and the analytical method was comprehensively validated according to the American Food and Drug Administration Bioanalytical Method Validation Guidance published in 2018. Linearity across four magnitude orders (0.125 to 510 pmol.mL-1) sub-pmol.mL-1 LOD and LOQ, accuracy and precision (deviation < 15% and CV < 15%) were proven for most of the peptides by analyzing calibration curves and four levels of quality controls in both a pure solution and a complex matrix of digested yeast proteins, to mimic the matrix effect. In addition, digestion performance and stability of the peptides was shown using standard peptides spiked in a yeast digest or mouse kidney plasma membrane proteins as a study case. The validated method was used to characterize mouse kidney plasma membrane proteins, mouse brain cortical vessels and rat brain cortical microvessels. Most of the results agree with previously reported values, although some differences are seen due to different sample treatment, heterogeneity of the sample or peptide used. Importantly, the use of three peptides allowed the quantification of P-gp in mouse kidney plasma membrane proteins which was below the limit of quantification of the previously NTTGALTTR peptide. The different levels obtained for each peptide highlight the importance and difficulty of choosing surrogate peptides for protein quantification. In addition, using isoform-specific peptides for the quantification of the Na+/K + ATPase pump, we evaluated the presence of neuronal and glial cells on rat and mouse brain cortical vessels in addition to endothelial cells. In mouse liver and kidney, only the alpha-1 isoform was detected. PMID- 30453157 TI - Novel Bruton tyrosine kinase inhibitor acalabrutinib quantification by validated LC-MS/MS method: An application to pharmacokinetic study in Sprague Dawley rats. AB - USFDA has approved a novel Bruton tyrosine kinase (BTK) inhibitor acalabrutinib (ACA) for the treatment of mantle cell lymphoma in adults. ACA is more potent and selective with fewer side effects compared to other Bruton tyrosine kinase inhibitors. In the current work a highly sensitive, selective and specific LC MS/MS method for the estimation of acalabrutinib (ACA) in rat plasma was developed. Agilent Eclipse Plus C 8 column (50 mm * 4.6 mm, MUm), with gradient elution using 10 mM ammonium formate and acetonitrile as mobile phase at a flow rate of 0.6 mL/min was used for the chromatographic separation. The ion transitions were quantified in positive mode with MRM transition of 466.1->372.3 for ACA and 236.8->194.0 for internal standard (IS). Solid phase extraction process was used as sample preparation approach. The method was validated according to USFDA bioanalytical guidelines. The method provided good linearity over the range of 0.2-199.14 ng/mL for ACA with short run time of 4 min. The method offers very high sensitivity (0.2 ng/mL) and was free from matrix interferences. The validated LC-MS/MS method was successfully applied for in vivo pharmacokinetic study in Sprague Dawley rats. The Cmax of ACA was found to be 25.56 ng/mL reaching at time of 0.5 h. The developed analytical method can also be utilized for bioequivalence studies and/or for pharmacokinetic studies in clinics. PMID- 30453158 TI - Ginkgo leaf-based synthesis of nitrogen-doped carbon quantum dots for highly sensitive detection of salazosulfapyridine in mouse plasma. AB - A simple, economical hydrothermal strategy for synthesizing nitrogen-doped carbon quantum dots (N-CQDs) was developed using Ginko leaves as a carbon source. These N-CQDs have strong blue fluorescence, excitation-relevant emissions, high monodispersity, good stability, good water solubility, and a 22.8% fluorescence quantum yield. They average 3 nm in size, and have maximum excitation and emission wavelengths of 350 and 436 nm, respectively. They are used as an effective fluorescent sensing platform for the label-free sensitive detection of salazosulfapyridine (SASP) due to the strong quenching effect of SASP. When SASP concentration is 0.1-80 MUmol/L, there is a good linear relationship with a detection limit of 40 nmol/L. This method was successfully applied to detect SASP in mouse plasma. The results show that the SASP recovery range was 96%-101%. RSDs ranged from 2.6% to 3.1%. PMID- 30453159 TI - Estimation of neuronal dynamics based on sparse modeling. AB - Elucidating neural dynamics is one of the important subjects in neuroscience. To elucidate nonlinear dynamics of single neurons, it is important to extract nonlinear membrane currents from many types of membrane current candidates. In this study, we propose a sparse modeling method for estimating a conductance based neuron model from observed data, by extracting necessary membrane currents from multiple candidates. We show using simulated data that our proposed sparse modeling approach with different sparsity levels for distinct membrane currents extracts only necessary membrane currents from candidates more accurately, compared with least-squares method and sparse method with uniform sparsity level. PMID- 30453160 TI - A biotin receptor-targeted silicon(IV) phthalocyanine for in vivo tumor imaging and photodynamic therapy. AB - Phthalocyanines (Pcs) are a kind of potential photosensitizers for fluorescence imaging and photodynamic therapy (PDT). However, the clinical application of Pcs is suffered from their poor solubility, high aggregation tendency and low tumor specificity. To address these problems, two biotin moieties were linked to the axial positions of silicon(IV) phthalocyanine (SiPc) through hydrophilic polyethylene glycol (PEG) linkers to synthesize a new water-soluble and tumor targeting photosensitizer (compound 1). The introduction of PEG linkers on SiPc markedly reduced the aggregation tendency of the conjugate. In vitro assays also proved that compound 1 could specifically accumulate in biotin receptor (BR) positive Hela cells through the BR-mediated internalization. Owing to the good characteristics of water-solubility and low aggregation, the bioactivity of compound 1 was examined in the xenograft tumor model. In vivo imaging and tissue distribution studies showed that compound 1 selectively accumulated in the tumor tissue, with tolerable signals found in other organs of the tumor-bearing mice. Furthermore, compound 1 could significantly depress tumor progression in vivo under irradiation. After 14 days of the treatment, the tumor volumes were even smaller than the beginning size. All these results reveal that compound 1 is a promising candidate, with low aggregation tendency, high tumor-specificity and water-solubility, for in vivo tumor diagnosis and PDT treatment. PMID- 30453161 TI - Comparative study of the chemiluminescence of coelenterazine, coelenterazine-e and Cypridina luciferin with an experimental and theoretical approach. AB - Imidazopyrazinone is a typical scaffold present in marine bioluminescence, in which thermal energy is converted into excitation energy in an enzyme-catalyzed reaction. In fact, the imidazopyrazinone scaffold is a common link among organisms of eight phyla. The characterization of the light emission mechanism is essential for the development of future applications in bioimaging, bioanalysis and biomedicine. Herein, we have studied the chemiluminescent reaction of three commercially-available imidazopyrazinones (Cypridina luciferin, Coelenterazine and Coelenterazine-e) in several aprotic solvents at different pH. We have found that at acidic pH only DMF and DMSO consistently present high light emission, while chemiluminescence in other solvents is negligible. We have attributed this to the inability of most solvents to allow for the deprotonation of the imidazopyrazinone core, thereby preventing the oxygenation step. We have also observed that increasing the pH of the solution leads to the inhibition of chemiluminescence, which we attributed to the deprotonation of the dioxetanone intermediate, as the neutral species is the one associated with efficient chemiexcitation. We have also observed that the pKa of dioxetanone increases with the dielectric constant of the medium. Finally, our work indicated that the chemiexcitation yield increases with increasing polarity of the medium, due to a reduced transition dipole moment associated with S0 -> S1 transition. PMID- 30453162 TI - Fabrication of MgO nanostructures and its efficient photocatalytic, antibacterial and anticancer performance. AB - Magnesium oxide (MgO) nanostructures were prepared using microwave-assisted (M 1) and hydrothermal (M 2) methods and characterized by XRD, SEM and FT-IR. It exhibits cubic structure with an average crystallite size of 20 nm (M 1) and 14 nm (M 2) and the lattice strain (WH plot) is 0.0017 (M 1), 0.0037 (M 2). It's spherical and rods like structures are confirmed through SEM and TEM. The vibrational stretching mode of MgO is 439 (M 1) and 449 cm-1 (M 2). The optical bandgap is estimated as 5.93 eV (M 1) and 5.85 eV (M 2) through UV-Vis spectra. The fluorescence spectrum shows emission peaks at 414 and 437 (M 1) and 367 and 385 nm (M 2). The photodegradation studies of MgO nanostructures were assessed by monitoring the decolorization of methylene blue and Congo red dyes in aqueous solution under sunlight irradiation. The antibacterial activities of M 1 and M 2 are investigated against the gram-negative (Escherichia coli, Shigella flexneri, Salmonella typhi, Proteus mirabilis, Aeromonas hydrophila and Vibrio cholera) and gram-positive (Bacillus subtilis and Rhodococcus rhodochrous) bacteria. The zone of inhibition of 24 (M 1) and 25 mm (M 2) indicates high antibacterial activity towards the gram negative bacterium A. hydrophila. Confocal laser scanning microscopic (CLSM) analysis was utilized for understanding the variation in antibacterial activity between different orientations of MgO nanostructures. The cytotoxicity assay confirmed that the prepared nanostructures are non - toxic to normal healthy RBC's. In-vitro anticancer efficiency (IC50) of MgO nanostructures against human lung cancer cell line (A549) was investigated. PMID- 30453163 TI - Stable Sn/Pb-Based Perovskite Solar Cells with a Coherent 2D/3D Interface. AB - Low-band-gap metal halide perovskite semiconductor based on mixed Sn/Pb is a key component to realize high-efficiency tandem perovskite solar cells. However, the mixed perovskites are unstable in air due to the oxidation of Sn2+. To overcome the stability problem, we introduced N-(3-aminopropyl)-2-pyrrolidinone into the CH3NH3Sn0.5Pb0.5IxCl3-x thin film. The carbonyl group on the molecule interacts with Sn2+/Pb2+ by Lewis acid coordination, forming vertically oriented 2D layered perovskite. The 2D phase is seamlessly connected to the bulk perovskite crystal, with a lattice coherently extending across the two phases. Based on this 2D/3D hybrid structure, we assembled low-band-gap Sn-based perovskite solar cells with power conversion efficiency greater than 12%. The best device was among the most stable Sn-based organic-inorganic hybrid perovskite solar cells to date, keeping 90% of its initial performance at ambient condition without encapsulation, and more than 70% under continuous illumination in an N2-filled glovebox for over 1 month. PMID- 30453164 TI - Biomechanics of Endothelial Tubule Formation Differentially Modulated by Cerebral Cavernous Malformation Proteins. AB - At early stages of organismal development, endothelial cells self-organize into complex networks subsequently giving rise to mature blood vessels. The compromised collective behavior of endothelial cells leads to the development of a number of vascular diseases, many of which can be life-threatening. Cerebral cavernous malformation is an example of vascular diseases caused by abnormal development of blood vessels in the brain. Despite numerous efforts to date, enlarged blood vessels (cavernomas) can be effectively treated only by risky and complex brain surgery. In this work, we use a comprehensive simulation model to dissect the mechanisms contributing to an emergent behavior of the multicellular system. By tightly integrating computational and experimental approaches we gain a systems-level understanding of the basic mechanisms of vascular tubule formation, its destabilization, and pharmacological rescue, which may facilitate the development of new strategies for manipulating collective endothelial cell behavior in the disease context. PMID- 30453165 TI - Disease quantification on PET/CT images without explicit object delineation. AB - PURPOSE: The derivation of quantitative information from images in a clinically practical way continues to face a major hurdle because of image segmentation challenges. This paper presents a novel approach, called automatic anatomy recognition-disease quantification (AAR-DQ), for disease quantification (DQ) on positron emission tomography/computed tomography (PET/CT) images. This approach explores how to decouple DQ methods from explicit dependence on object (e.g., organ) delineation through the use of only object recognition results from our recently developed automatic anatomy recognition (AAR) method to quantify disease burden. METHOD: The AAR-DQ process starts off with the AAR approach for modeling anatomy and automatically recognizing objects on low-dose CT images of PET/CT acquisitions. It incorporates novel aspects of model building that relate to finding an optimal disease map for each organ. The parameters of the disease map are estimated from a set of training image data sets including normal subjects and patients with metastatic cancer. The result of recognition for an object on a patient image is the location of a fuzzy model for the object which is optimally adjusted for the image. The model is used as a fuzzy mask on the PET image for estimating a fuzzy disease map for the specific patient and subsequently for quantifying disease based on this map. This process handles blur arising in PET images from partial volume effect entirely through accurate fuzzy mapping to account for heterogeneity and gradation of disease content at the voxel level without explicitly performing correction for the partial volume effect. Disease quantification is performed from the fuzzy disease map in terms of total lesion glycolysis (TLG) and standardized uptake value (SUV) statistics. We also demonstrate that the method of disease quantification is applicable even when the "object" of interest is recognized manually with a simple and quick action such as interactively specifying a 3D box ROI. Depending on the degree of automaticity for object and lesion recognition on PET/CT, DQ can be performed at the object level either semi-automatically (DQ-MO) or automatically (DQ-AO), or at the lesion level either semi-automatically (DQ-ML) or automatically. RESULTS: We utilized 67 data sets in total: 16 normal data sets used for model building, and 20 phantom data sets plus 31 patient data sets (with various types of metastatic cancer) used for testing the three methods DQ-AO, DQ-MO, and DQ-ML. The parameters of the disease map were estimated using the leave-one-out strategy. The organs of focus were left and right lungs and liver, and the disease quantities measured were TLG, SUVMean, and SUVMax. On phantom data sets, overall error for the three parameters were approximately 6%, 3%, and 0%, respectively, with TLG error varying from 2% for large "lesions" (37 mm diameter) to 37% for small "lesions" (10 mm diameter). On patient data sets, for non-conspicuous lesions, those overall errors were approximately 19%, 14% and 0%; for conspicuous lesions, these overall errors were approximately 9%, 7%, 0%, respectively, with errors in estimation being generally smaller for liver than for lungs, although without statistical significance. CONCLUSIONS: Accurate disease quantification on PET/CT images without performing explicit delineation of lesions is feasible following object recognition. Method DQ-MO generally yields more accurate results than DQ-AO although the difference is statistically not significant. Compared to current methods from the literature, almost all of which focus only on lesion level DQ and not organ-level DQ, our results were comparable for large lesions and were superior for smaller lesions, with less demand on training data and computational resources. DQ-AO and even DQ-MO seem to have the potential for quantifying disease burden body-wide routinely via the AAR-DQ approach. PMID- 30453166 TI - MRI-based pelvimetric measurements as predictors for a successful vaginal breech delivery in the Frankfurt Breech at term cohort (FRABAT). AB - OBJECTIVES: The purpose of this study was to investigate the role of the maternal pelvis, assessed by MRI pelvimetry in nulliparous women expecting a term fetus in breech presentation, to predict a successful and safe vaginal birth. STUDY DESIGN: In this monocentric and anonymized cohort study, we enrolled 367 nulliparous women with breech presentation at 39+0 to 41+0 weeks of gestation during a period of 8 years at the University Women's Hospital in Frankfurt/Main. Pelvic measurements were obtained by standard MRI imaging. We correlated the obstetric conjugate, the pubic angle and the distance between the ischial tuberosities (intertuberous distance) with the maternal and fetal outcomes of vaginally intended breech births. The data was evaluated using logistic regression analysis. RESULTS: 241 of 367 participants (65.7%) experienced a successful vaginal delivery whereas 126 patients (34.3%) were subjected to secondary cesarean section. An increasing obstetric conjugate was significantly associated with an increasing rate of successful vaginal deliveries. No significant correlation of the intertuberous distance and the pubic angle with the mode of delivery could be shown. Although statistically not significant, we were able to define cut-off values of 10.9 cm in the intertuberous distance and 70 degrees in the pubic angle; below these values, no successful vaginal delivery was recorded. No significant differences in the short-term outcomes were seen between the neonates of the vaginal delivery and the cesarean section groups. Inter- and intraobserver variability showed excellent reproducibility for all MRI parameters. CONCLUSION: The obstetric conjugate correlates with the rate of vaginal deliveries in nulliparous women at term and can be used as a useful criterion for pre-selection and counseling of women with breech presentation and the desire for a vaginal delivery. PMID- 30453167 TI - Pregnancy outcome after first trimester exposure to ionizing radiations. AB - OBJECTIVE: To evaluate the effects of ionizing radiation exposure during the first trimester of pregnancy in usual clinical situations. STUDY DESIGN: We conducted a prospective observational cohort study using data collected between 1987 and 2014. This database was authorized by the French "Commission Nationale de l'Informatique et des Libertes". The exposed group consisted of 319 pregnant women exposed to sub diaphragmatic ionizing radiations for diagnostic purposes, during the first trimester of pregnancy, and the control group consisted of 319 pregnant women without any exposure or exposed to non-teratogenic agents. Data on maternal history and radiations exposure were collected on first contact, and pregnancy outcomes were documented at follow-up. An univariate analysis was performed to compare both groups for the main outcomes. RESULTS: Exposure to sub diaphragmatic ionizing radiation for diagnosis purpose (median fetal dose of 3.1 mGy [0.2-130.0]) during the first trimester of pregnancy was not significantly associated with an increased risk of malformations (1.5% vs 1.8%, p = 1.00), miscarriage (7.8% vs 7.2%, p = 0.88), in utero fetal death (0.3% vs 0%, p = 1.00) or fetal growth restriction (5.4% vs 3.5%, p = 0.62). CONCLUSION: Pregnant women exposed to irradiant diagnostic procedures do not present a higher risk of malformations, miscarriage, in utero fetal death or fetal growth restriction and should be reassured, even if the examination focused on the pelvis. PMID- 30453168 TI - Long-chain polyunsaturated fatty acid biosynthesis and its response to cadmium exposure in silver pomfret. AB - Despite a close interaction between cadmium (Cd) and long-chain polyunsaturated fatty acid (LC-PUFA) metabolism, the influence of Cd exposure on the endogenous synthesis of LC-PUFA has received little attention. In the present study, we hypothesized that Cd exposure would affect the synthesis of LC-PUFA in the marine fish silver pomfret (Pampus argenteus). Therefore, the molecular basis of LC-PUFA biosynthesis and regulation was investigated as the first step to understanding the mechanisms underpinning the effects of Cd exposure. Thereafter, transcriptional regulation of the genes that participate in LC-PUFA biosynthesis and regulation by Cd exposure were also explored. Our results showed that fatty acyl desaturase 2 (Fads2) and elongases of very long-chain fatty acids 5 (Elovl5), two key enzymes involved in LC-PUFA biosynthesis, enabled silver pomfret to biosynthesize 20:3n-6 and 20:4n-3 from 18:2n-6 and 18:3n-3. The results also raise the possibility that silver pomfret may have the ability to produce docosahexaenoic acid (DHA, 22:6n-3) from endogenous eicosapentaenoic acid (EPA, 20:5n-3). The expression of silver pomfret fads2 and elovl5 was transcriptionally regulated by the peroxisome proliferator activated receptor alpha (Pparalpha). The expression of fads2, elovl5 and pparalpha in the brain was significantly increased in response to Cd exposure. In addition, Cd exposure significantly reduced the DHA concentration and significantly increased the malondialdehyde concentration in the brain of silver pomfret. Cd exposure likely increases brain-specific DHA synthesis from EPA by transcriptionally activating fads2 and elovl5 via Pparalpha in silver pomfret. This regulation may be a coping mechanism for the reduction of DHA caused by Cd-oxidative stress in the brains of silver pomfret. PMID- 30453169 TI - Evaluation of objective response, disease control and progression-free survival as surrogate end-points for overall survival in anti-programmed death-1 and anti programmed death ligand 1 trials. AB - BACKGROUND: We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST) criteria-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could be valid surrogate end points for overall survival (OS) in anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) trials. METHODS: We systematically reviewed phase 2 and phase 3 trials of anti-PD-1/PD-L1 drug trials of advanced or recurrent solid tumours that reported OS and at least one of the RECIST criteria-based end points. We used Spearman rank correlation to evaluate the strength of the association between these end-points and OS and a linear regression model, weighted by the sample size, to assess the association between the treatment effect on these end-points and OS. We also performed sensitivity analyses and a leave-one-out cross-validation approach to evaluate the robustness of our findings. RESULTS: Forty-three qualifying trails comprising 15,088 patients were eligible. PFS showed good correlation with OS (squared Spearman rank correlation coefficient [rs2] = 0.54; P < 0.001), while ORR and DCR illustrated moderate association with OS (rs2 = 0.29 and 0.28, respectively; both P < 0.001). The correlation was moderate between the treatment effects on PFS and OS (coefficient of determination [R2] = 0.37, P < 0.001) and poor among ORR, DCR and OS (R2 = 0.10 and 0.08, respectively); these were confirmed by sensitivity analyses (all R2 < 0.75) and the leave-one-out cross-validation approach. CONCLUSIONS: No RECIST criteria-based end-points could be a valid surrogate for OS. At present, we proposed to set OS as the primary end-point in anti-PD-1/PD-L1 drug trials of advanced or recurrent solid tumours. PMID- 30453170 TI - Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors. AB - AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side effects of checkpoint therapy. METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised. RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases. CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase. PMID- 30453171 TI - Alleviation of cadmium toxicity to tobacco (Nicotiana tabacum) by biofertilizers involves the changes of soil aggregates and bacterial communities. AB - Tobacco leaves usually accumulate and concentrate high levels of cadmium (Cd) when growing in contaminated soil, and the transfer of Cd through tobacco smoke to human body could cause serious health risks. In this study, we explored the impact of biofertilizers on alleviating Cd-induced growth inhibition of tobacco leaves. Tobacco (Nicotiana tabacum L.) was planted in three naturally Cd-polluted soils from Chinese main tobacco-planting areas. Adding biofertilizer alleviated Cd-induced degradation of tobacco leaves quality, represented by the balanced K, Cl, N, nicotine or sugar contents and their ratios; Cd reduction rate of tobacco leaves was increased and soil extractable Cd was decreased, when compared with CK (no extra biofertilizer addition). The following changing tendencies were believed to be responsible for immobilizing soil Cd and alleviating its toxicity to tobacco leaves: the re-distribution of Cd from the fraction of smaller soil aggregates to the fraction of larger soil aggregates; and the shift of major soil microbes by increasing the abundance of beneficial taxa such as those from the phyla Actinobacteria, Proteobacteria or Chloroflexi. In all biofertilizer treatments, the effectiveness in mitigating Cd toxicity to tobacco leaves was dependent on the type of biofertilizer and soil applied. This study provides a feasible way to control or reduce Cd toxicity for sustainable tobacco production. PMID- 30453172 TI - Impact of ambient PM2.5 on adverse birth outcome and potential molecular mechanism. AB - PM2.5 (particulate matter <=2.5 um in aerodynamic diameter) refers to atmospheric particulate matter (PM) with an aerodynamic diameter of equal and less than 2.5 um that tends to be suspended for long periods of time and travel over long distances in both outdoor and indoor atmospheres. PM2.5, along with the toxic compounds attached on it, may cause a wide range of disorders. The fetus is considered to be highly susceptible to a variety of toxicants including atmospheric pollutants such as PM2.5 through prenatal exposure. To better understand the relationship between maternal exposure to PM2.5 and adverse birth outcomes for reproduction and fetus development, we studied the published data on this issue including case-control studies, cohort studies and meta-analyses studies, and summarized the basic impact of ambient particulate matter on adverse birth outcomes. Research evidence indicates that PM2.5 has a potential to induce low birth weight (LBW), preterm birth (PTB), and stillbirth. A further in-depth analysis shows that oxidative stress, DNA methylation, mitochondrial DNA (mtDNA) content alteration, and endocrine disruptions may all play an important role in PM2.5 induced adverse effects to pregnant women and fetuses. In addition, PM2.5 exposure can cause male reproductive toxicity, leading to associated adverse pregnancy outcomes. PMID- 30453173 TI - Xenobiotic biotransformation, oxidative stress and obesogenic molecular biomarker responses in Tilapia guineensis from Eleyele Lake, Nigeria. AB - Despite the important ecosystem and hydrological roles of coastal and inland waters, there are no established biomonitoring protocols for evaluating environmental, wildlife and human health for these coastlines in Nigeria. In the present study, contaminants tissue burden and effects at molecular and physiological levels, were investigated in Tilapia guineensis from a man-made lake (Eleyele Lake) that is used for municipal domestic water supply and compared to a reference site (Igboho Lake). Gene expression of phase I and II biotransformation systems, oxidative stress and obesogen responses were analyzed using real-time PCR, and these results were related to general health index (condition factor: CF) and muscle burden of trace metals, aliphatic and polycyclic aromatic hydrocarbons (PAHs). We observed a significant increase in phase I and II biotransformation systems, oxidative stress and obesogen responses in male and female fish from Eleyele lake compared with the reference site. Overall, our data showed significant relationships between biological responses and tissue concentrations of metals and PAHs for the Eleyele lake compared with the reference site. Given that a positive influence on genes and pathways associated with metabolic status has been previously associated with peroxisome proliferator activated receptors (PPARs), xenobiotic compounds that activate PPARs may produce changes in energy and metabolic processes, leading to obesity. The high CF (>1 = good health condition) observed, coupled with the high muscle burden of inorganic and organic contaminants in fish from Eleyele lake, suggest a potential obesogenic effect in these fishes. These findings represent co relational evidence that the Eleyele lake is contaminated and consequently affecting biological and physiological integrity of organisms inhabiting the lake. These findings also suggest potential health risks for humans, since the lake is extensively used for domestic water supply and fisheries. PMID- 30453174 TI - Maternal exposure to di-n-butyl phthalate promotes Snail1-mediated epithelial mesenchymal transition of renal tubular epithelial cells via upregulation of TGF beta1 during renal fibrosis in rat offspring. AB - We previously demonstrated that maternal exposure to di-n-butyl phthalate (DBP) resulted in renal fibrosis in male offspring; however, the underlying mechanism governing this effect has not been thoroughly elucidated to date. We hypothesized that DBP exposure induces TGF-beta expression and abnormal activation of epithelial-mesenchymal transition (EMT) in fibrotic kidneys. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. In the DBP-exposed group, immunohistochemistry (IHC) staining showed increased expression of TGF-beta1 and EMT markers. In rat kidney tubular epithelial cells (NRK52E), ROS production increased expression levels of TGF-beta1 and subsequently contributed to the induction of Snail1-mediated EMT. Notably, DBP exposure also promoted autophagy that downregulated TGF-beta1. Taken together, our findings suggest that maternal exposure to DBP promotes EMT in tubular epithelial cells via upregulation of TGF-beta1. PMID- 30453175 TI - Ecotoxicity of Caenorhabditis elegans following a step and repeated chronic exposure to tetrabromobisphenol A. AB - To better understand the toxicity of tetrabromobisphenol A (TBBPA), its effects on the model nematode Caenorhabditis elegans were investigated. Following a step and repeated chronic exposure from L4-larvae to day-10 adult, physiology endpoints (growth and locomotion behaviors including head thrashes, body bends and pumping rate), biochemical endpoints (reactive oxygen species, superoxide dismutase activity, catalase activity), and molecular stress-related gene expression were tested at environmentally relevant concentrations of TBBPA (0.01 100 ug/L). The results showed that concentrations of TBBPA greater than 10 ug/L, clearly influenced the physiology behaviors (growth and locomotion endpoints). Under repeated exposure, C. elegans exhibited adaptive responses in head thrashes and pumping rate. Compared to toxicity evaluation following repeated chronic exposure, a significantly greater response was induced at the same concentration following a step chronic exposure. Reactive oxygen species production was significantly enhanced following a step and repeated TBBPA exposure at the concentrations of 1 and 10 ug/L, respectively. qRT-PCR showed that ctl-1, ctl-2, ctl-3 and sod-3 expression significantly increased, which was obviously correlated with physiological and biochemical behaviors under both treatment conditions according to Pearson correlation test analysis. sod-3 and ctl-2 mutations were more sensitive than the wild-type N2 under a step chronic TBBPA exposure at a level of 10 ug/L. Thus, chronic exposure to TBBPA induces an oxidative stress response in C. elegans, with ctl-2 and sod-3 playing a vital role in TBBPA-induced toxicity in nematodes. PMID- 30453176 TI - Barnacle colonization of shoes: Evaluation of a novel approach to estimate the time spent in water of human remains. AB - Estimating the time since death (minimum Post Mortem Interval, minPMI) is a necessary part of a forensic investigation. Besides considering the typical signs of death, minPMI can be estimated using the insects and other arthropods that colonize the remains (forensic entomology). In an aquatic environment, both insects and crustaceans may provide information regarding the time spent in water of the remains (minimum Floating Interval, minFI and minimum Post Mortem Submersion Interval, minPMSI), and this can also assist in determining the minPMI. Barnacles (Crustacea: Cirripedia) are common crustaceans that colonize solid substrates in marine environments and they can be found in association with organic and inorganic remains recovered from the sea. Barnacles colonize both floating and submerged remains and their growth rate is temperature dependent. Despite their potential to be indicative of the minFI and/or minPMSI, only a few case studies have considered it for this purpose, and scant research has been conducted in this field. Assuming that the vast majority of the bodies found in the sea are clothed, this research is focused on the barnacle colonization of two different types of shoes placed in the sea, in order to (1) identify the colonizing species in the chosen environment; (2) identify the settlement preferences of the barnacles associated with the shoes; and (3) determine the factors affecting the growth rate of the barnacles associated with the shoes. In April 2016 64 sport shoes (SS) and 64 patent leather shoes (PLS) were placed in the Boston Harbor (MA-USA) at 8/10m below sea level. Four of each shoe type were collected every two weeks for seven months. Individual barnacles from each shoe were sampled and measured to determine species and age. The overall colonization density and settlement preference was statistically analyzed. Results show that (a) Amphibalanus improvisus (Darwin) (Crustacea: Cirripedia: Sessilia) colonized the vast majority of shoes; (b) colonization occurred in less than 30 days and continued throughout the research period; (c) a significant difference in colonization densities was found between the SS and PLS, with PLS seeing higher densities; (d) barnacles showed preferential colonization of specific sections on both shoe types; (e) barnacle growth was found to be significantly affected by water temperature and shoe type but not by the time spent in water; (f) time spent in water and shoe type had a highly significant effect on the total number of barnacles per shoe, whereas water temperature did not. PMID- 30453177 TI - Geometric morphometrics on juvenile crania: Exploring age and sex variation in an Australian population. AB - For medico-legal forensic practitioners the identification of unknown remains is an important part of any investigation, often predicated on having accurate estimations of age and sex. In considering the specific skeletal elements available to facilitate such biological information, the cranium is frequently targeted for analysis, as it exhibits marked traits of sexual dimorphism, and also has a predictable pattern of growth. There are, however, instances where it may not be possible to estimate skeletal sex, especially in the juvenile skeleton. There is still considerable uncertainty surrounding the age at which the human cranium is quantifiably dimorphic. The aim of the present study is to explore age and sex variation in three-dimensionally reconstructed MDCT scans of the juvenile cranium. The study sample comprises 152 juvenile crania from a Western Australian population; a total of 52 three-dimensional landmarks are acquired and analyzed using Procrustean geometric morphometrics. Group discrimination is assessed between sexes and across age classes. Results demonstrate that sexual dimorphism and age variation is discernible through geometric morphometric analysis of form, size and shape. Relative to sex and age, size is found to be generally equivalent to, or even more accurate than, shape data. There is little quantifiable sexual dimorphism in individuals younger than 12years of age with most variation related to age; discrimination improves with increasing age, with average hit rate (HR) values increasing from just over 50% (52-58%) to more than 90% (93-94%) accuracy at 18years. In contrast, differences between contiguous age classes follow the opposite trend and tend to be larger in prepubertal groups, while becoming progressively smaller in older age classes. This study demonstrates that simple linear interlandmark distances describing overall cranial size may provide a simple option for preliminary classifications of age and sex in skeletal remains of forensic interest. However, although recombining size and shape to perform analyses using form generally does not appreciably improve predictive accuracy, it potentially contributes to increased confidence in group assessment (especially for sex) and thus offers a promising, albeit complex, type of information to discriminate groups based on cranial size and/or shape. PMID- 30453178 TI - Pharmacokinetics of difloxacin in Japanese quails (Coturnix japonica) after single intravenous and oral administration. AB - Pharmacokinetics of difloxacin (DF), a fluoroquinolone antibiotic, were investigated in Japanese quails (Coturnix japonica) after a single intravenous (IV) and oral (PO) administration of 10 mg/kg bodyweight. Plasma concentration profiles of DF were analyzed by a compartmental pharmacokinetic method. Following IV injection, the plasma concentration vs time profile was best described by a two-compartment open model. Elimination half-life (t1/2beta), total body clearance (Cltot), volume of distribution at steady state (Vdss) and mean residence time (MRT) of DF were 5.45 +/- 0.14 h, 0.22 +/- 0.01 L/kg/h, 1.54 +/- 0.06 L/kg and 6.92 +/- 0.19 h, respectively. Following PO administration, DF was rapidly absorbed, with peak plasma concentration (Cmax) of 3.67 MUg/mL attained at 1.90 h (Tmax) after administration. Absorption half-life (t1/2ab), elimination half-life (t1/2el), mean absorption time (MAT) were 0.5 h, 5.26 h and 1.11 h, respectively. The bioavailability (F) following PO administration of DF was high (84.40%). For a successful clinical effect of DF in quails, a multiple dosage regimen of 10 mg/kg bodyweight, administered orally every 24 h is recommended to maintain effective plasma concentrations with bacterial infections, in which MIC90 is <0.2 MUg/mL. PMID- 30453179 TI - A combination of electrochemotherapy, gene electrotransfer of plasmid encoding canine IL-12 and cytoreductive surgery in the treatment of canine oral malignant melanoma. AB - The aim of this study was to evaluate the safety and efficacy of the combination of electrochemotherapy (ECT) with bleomycin and gene electrotransfer (GET) of plasmid encoding canine interleukin 12 (IL-12) for the treatment of canine oral malignant melanoma (OMM). Our focus was to determine the effect of the treatment on achieving local tumor control and stimulation of an antitumor immune response. Nine dogs with histologically confirmed OMM stage I to III were included in a prospective, non-randomized study. The dogs were treated with a combination of cytoreductive surgery, ECT and IL-12 GET, which was repeated up to five times, depending on the clinical response to the treatment, evaluated according to the follow-up protocol (7, 14 and 28 days after, the last treatment). One month after treatment, the objective response (OR) rate was 67% (6/9). Median survival time (MST) was 6 months and, even though the disease progressed in 8/9 patients at the end of the observation period (2 to 22 months), four animals were euthanized due to tumor-unrelated reasons. In addition, we observed a decline in the percentage of regulatory T cells (Treg) in the peripheral blood in the course of the treatment, which could be attributed to a systemic antitumor response to IL-12 GET. The results of this study suggest that a combination of ECT and IL-12 GET may be beneficial for dogs with OMM, especially when other treatment approaches are not acceptable due to their invasiveness or cost. PMID- 30453180 TI - Vaccination at different anatomic sites induces different levels of the immune responses. AB - This study was to evaluate the effects of anatomical sites for vaccination on the immune responses. In experiment A, rats were subcutaneously (s.c.) immunized with a quintuplet vaccine twice at houhai acupoint, underjaw, popliteal fossa or back with a two weeks interval. The serum specific antibody levels were determined 2, 4 and 6 weeks after second immunization. Splenocytes were separated for detection of lymphocyte proliferation and cytokine mRNA expression. In experiment B, 10 female Rottweiler puppies at their age of 34 +/- 2 days were subcutaneously injected with a bivalent vaccine Nobivac(r) Puppy DP containing live attenuated canine distemper virus (CDV) and parvovirus (CPV) for primary vaccination, and a quadrivalent vaccine Nobivac(r) DHPPI containing live attenuated canine distemper virus (CDV), adenovirus type 2 (CAV-2), parvovirus (CPV) and parainfluenza virus (CPIV) for subsequent vaccination at houhai acupoint (4 dogs), the shoulder (3 dogs) or the nape (3 dogs) region. Blood samples were collected at 0, 2, 4 and 6 weeks after vaccination for determination of serum specific antibody responses by ELISA. The results showed that injection of a vaccine in houhai acupoint induced the highest antibody responses in both rats and dogs. When a vaccine was injected in houhai acupoint, significantly increased proliferative responses to Con A and LPS as well as mRNA expression of IL-4, IL-10, IL-12 and IFN-gamma of splenocytes were detected in rats. Therefore, houhai acupoint is recommended for injection of a vaccine to improve the immune response in dogs. PMID- 30453181 TI - A bi-factor model of the Montgomery Asberg depression rating scale and future cognitive impairments in older adults: A 6-year follow-up study. AB - Depression has been found to be associated with cognitive decline. This study evaluated the association of general depressive symptoms and motivational-related symptoms with cognitive impairment 6 years later and to explore the role of potential underlying mechanisms. In 2690 cognitively healthy persons aged >=60 from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) depressive symptoms were derived from the Montgomery Asberg Depression Rating Scale (MADRS). Cognitive performance was assessed at baseline and 6 years later in 1810 persons with the Mini Mental State Examination (global cognition), Digit Span Forward (short-term memory), Digit Span Backward (working memory), Clock test (visuospatial construction), and the 5-item test (immediate and delayed recall). Bi-factor analysis on the MADRS yielded a General Depression factor and an unrelated Motivational factor. After adjusting for demographics, the General Depression factor was only associated with 6-year impairment in delayed recall (OR (95% CI): 1.18 (1.04-1.34)). This association was no longer significant after adjusting for demographics, cardiovascular risk, lifestyle factors and medication use. The Motivational factor was not significantly associated with future cognitive impairments after adjusting for demographics. Concluding, almost all associations of general depressive symptoms and motivational-related symptoms with future cognitive impairments appeared to be confounded by demographics. Only the association of general depressive symptoms with future memory impairments appeared to be explained by a combination of demographics, cardiovascular risk, lifestyle and medication use. PMID- 30453182 TI - Monitoring and evaluation design of Malawi's Right Foods at the Right Time nutrition program. AB - Child stunting is a public health problem in Malawi. In 2014, the Government of Malawi launched the Right Foods at the Right Time (RFRT) program in Ntchisi district delivering nutrition social and behavior change communication, a small quantity lipid-based nutrient supplement to children 6-23 months, and nutrition sensitive activities. Monitoring and evaluation (M&E) systems are key aspects of successful program implementation. We describe these and the methodology for an impact evaluation that was conducted for this program. Two monitoring systems using traditional and electronic platforms were established to register and track program delivery and processes including number of eligible beneficiaries, worker performance, program participation, and to monitor input, output, and outcome indicators. The impact evaluation used comparative cross-sectional and longitudinal designs to assess impact on anthropometric and infant and young child feeding outcomes. Three cross-sectional surveys (base-, mid-, and end-line) and two longitudinal cohorts of children followed in 6-month intervals from 6 to 24 months of age, were conducted in sampled households in the program and a neighboring comparison district. Additional M&E included qualitative studies, a process evaluation, and a cost-effectiveness study. The current paper describes lessons from this program's M&E, and demonstrates how multiple implementation research activities can inform course-correction and program scale-up. PMID- 30453183 TI - The characteristics and reporting quality of research impact case studies: A systematic review. AB - Despite the growing expectation that researchers report the impact of their research using a case study approach, systematic reviews of research impact have focused on frameworks, indicators, methods of data collection and assessment rather than impact case studies. Our aim is to provide an overview of the characteristics of published research impact case studies, including translation activities, and their reporting quality. We searched for peer-reviewed impact studies published between 2000 and 2018 using a case study approach and selected 25 suitable papers. We applied descriptive statistics to study characteristics, conducted thematic analysis of research translation activities and assessed reporting quality using the 10-point ISRIA statement. 24 papers reported intermediate impacts, such as advocacy, or the development of statements, tools, or technology. 4 reported on longer-term societal impacts, such as health outcomes and economic return on investment. 7 reported on translation activities. Papers scored well against the ISRIA statement on 5 domains of reporting quality. Weakest scores centred around identification of stakeholder needs and stakeholder involvement, and ethics and conflict of interest. We identified the need for more consistency in reporting through a case study approach, more systematic reporting of translation pathways and greater transparency concerning estimated costs and benefits of the research and its translation and impact assessment. PMID- 30453184 TI - Rescuing microtubules from the brink of catastrophe: CLASPs lead the way. AB - Microtubules are cytoskeletal polymers that dynamically remodel to perform essential cellular functions. Individual microtubules alternate between phases of growth and shrinkage via sudden transitions called catastrophe and rescue, driven by losing and regaining a stabilizing cap at the dynamic microtubule end. New in vitro studies now show that a conserved family of CLASP proteins specifically modulate microtubule catastrophe and rescue transitions. Further, recent cryo electron microscopy approaches have elucidated new structural features of the stabilizing cap. Together, these new advances provide a clearer view on the complexity of the microtubule end and its regulation. PMID- 30453185 TI - A novel coumarin-based fluorescence chemosensor for Al3+ and its application in cell imaging. AB - As an efficient turn-on fluorescent chemosensor for Al3+, a new coumarin derivative (CND) has been designed and synthesized by the condensation of 8 formyl-7-hydroxycoumarin with niacin hydrazide. The spectroscopic studies revealed that the sensor CND exhibited a remarkable fluorescence enhancement towards Al3+ with high selectivity and sensitivity in EtOH-HEPES (95:5, v/v, pH = 7.40), which was attributed to the photoinduced electron transfer (PET) and CN isomerization mechanism. Fluorescence titration calculations data showed that the detection limit and the association constants of CND for Al3+ were found to be 2.51 * 10-7 M and 9.64 * 104 M-1, respectively. The results of experiments, including Job's plot, 1H NMR titration and ESI-MS, revealed that the stoichiometric binding between CND and Al3+ was 1:1. The investigations of the pH dependency of CND for Al3+ detection, and the cell imaging suggested the sensor CND could be promisingly applied for the recognition of Al3+ in biological cells. PMID- 30453186 TI - Nitrogen-doped fluorescent carbon dots for highly sensitive and selective detection of tannic acid. AB - Herein, a facile approach for highly sensitive and selective detection of tannic acid (TA) was proposed with the nitrogen-doped fluorescent carbon dots (NCDs) as a novel fluorescent probe, using sodium citrate and aminopyrazine as precursors. The as-synthesized NCDs exhibited multiple advantages including high quantum yield (11.8%), good water solubility and satisfactory stability. In addition, the NCDs displayed excitation-independent emission behavior with fluorescence emission peak remaining at 389 nm under excitation of 270-350 nm. Significantly, the fluorescence quenching of as-fabricated NCDs was observed with the increasing TA concentration, and the calibration curve displayed a wide linear region ranging from 0.40 to 9.0 MUmol L-1 with a detection limit of 0.12 MUmol L-1. This fluorescent probe also performed well in determining TA in beer samples with average recoveries of TA ranging from 96.1% to 104.4% and the relative standard deviation less than 5%, which provided a reliable, rapid and simple method to determine TA in real samples. Thus, this method offered a valuable insight for its practical applications. PMID- 30453187 TI - Optical H2S and SO2 sensor based on chemical conversion and partition differential optical absorption spectroscopy. AB - An optical sensor based on chemical conversion and partition differential optical absorption spectroscopy is developed to detect hydrogen sulfide (H2S) and sulfur dioxide (SO2) gas in sulfur hexafluoride (SF6) decomposition products. Given that the absorption cross sections of SO2 and H2S overlap in 170-230 nm band, the differential lines of H2S are very few, meanwhile the corresponding absorption cross sections are small in comparison to that of SO2, thus H2S can be detected by reacting with oxygen to convert to SO2 in the presence of UV light. Through the concentration variation of SO2 before and after chemical reaction, the concentration of H2S can be obtained. Meanwhile the partition differential optical absorption spectroscopy method deduced from Beer-Lambert's law is introduced to weaken the influence of electronic noise on the measuring result, especially in low concentration. The SO2 detection limit of 12 ppb per meter can be achieved. The optical sensor can measure the concentrations of H2S and SO2, so it is suitable for the fault diagnosis of gas insulated switchgear (GIS). PMID- 30453188 TI - Zeolite fillers for resin-based composites with remineralizing potential. AB - The objective of the study is to obtain the modified zeolite powders and to apply these materials as active fillers in the dental composites with the remineralizing potential. Three different synthesis pathways were applied to receive LTA-type (Linde A-type) zeolites. All zeolites were subjected to the ion exchange process and mineralization of surface with hydroxyapatite (HA) layer. As a result a calcium form and surface modified form of these materials were prepared. The effectiveness of each modification process was confirmed by X-ray Diffractometry, Infrared and Raman Spectroscopy. Materials were also characterized by Scanning Electron Microscopy, Energy Dispersive Spectroscopy and nitrogen adsorption/desorption measurements. The remineralizing potential was specified as an ability to release calcium ions during the incubation in saline with the use of Inductively Coupled Plasma-Mass Spectrometry. The obtained zeolite fillers were placed in the organic matrix to create photopolymerizable composites with potential dental applications. The homogeneity of the filler distribution in polymeric matrix was checked by the Raman spectra mapping. Composites containing calcium form of zeolites as well as zeolites with the HA layer proved to have the ability to release calcium ions during incubation in saline in the amount comparable to calcium phosphates-filled composites or even higher than dental glass-filled composites. The ability to release calcium ions, together with good mechanical properties and mass stability testify the suitability of prepared composites in potential dental applications. PMID- 30453189 TI - Thermal, spectroscopic, electrochemical, and electroluminescent characterization of malononitrile derivatives with triphenylamine structure. AB - Three push-pull molecules with linear, quadrupolar and tripodal arrangements, consisting of triphenylamine (electro-donor) substituted with malononitrile groups (electro-acceptor), were synthesized with high yield by a simple procedure. Impact of the number of malononitrile substituents on optoelectronic properties was investigated with cyclic voltammetry, absorption and emission spectroscopy, as well as density functional theory calculation. The derivatives formed amorphous materials and exhibited low energy band gaps ranging from 2.06 to 2.49 eV. UV-Vis absorption and photoluminescence emission spectra were investigated in solutions (CHCl3, NMP) and in solid-state as thin films and two kinds of blends (with PMMA and PVK:PBD). Quantum yield of photoluminescence was dependent on the molecule structure, solvent, and solid-state layer formulation. The compounds exhibited high photoluminescence quantum yield in the range of 15 42% and 12-59% in solid-state as film and blend with PMMA (1 wt%), respectively, being promising for applications in light emitting diodes. The diodes with active layer consisting of neat derivatives and compounds molecularly dispersed in PVK:PBD (50:50 wt%) matrix showed orange and green electroluminescence. PMID- 30453190 TI - Study on the pathological and biomedical characteristics of spinal cord injury by confocal Raman microspectral imaging. AB - Confocal Raman microspectral imaging (CRMI) in combination with multivariate analysis was used to study pathological progression after spinal cord injury (SCI). By establishing moderate contusion in rat models, ex vivo longitudinal spinal cord tissue sections were prepared for microspectroscopic analysis. Comparative studies were then performed to determine the pathological distinctions among before injury (BI), one day post-injury (1 DPI), seven days post-injury (7 DPI), and 14days post-injury (14 DPI) groups. Multivariate analysis algorithms, including K-mean cluster analysis (KCA) and principal component analysis (PCA), were conducted to highlight biochemical and structural variations after tissue damage. It is confirmed that typical spectral features and profiles can illustrate some fundamental and significant pathological processes post-injury, such as neuron apoptosis, hemorrhage, demyelination, and chondroitin sulfate proteoglycans (CSPGs) upregulation. Further, by establishing spectra-structure correlations, the reconstructed spectral images revealed some minute and important morphological characteristics following tissue injury, such as glial scar formation surrounding the cavity structure. The observed spectral phenomena also provide a detailed view on relevant pathobiological factors, which are involved in the spread of secondary damage after traumatic spinal cord injury. Our findings not only provide a spectral perspective to the well-known cellular mechanisms underlying SCI, but further provide a sound basis for developing real-time Raman methodologies to evaluate the prognostic factors and therapeutic results of SCI. PMID- 30453191 TI - Excited state hydrogen bond and proton transfer mechanism for (2-hydroxy-4 methoxyphenyl)(phenyl)-methanone azine: A theoretical investigation. AB - A novel fluorescence molecule (2-hydroxy-4-methoxyphenyl)(phenyl)-methanone azine (HMPM) has been explored theoretically in this present work. Based on density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods, we investigate the excited state hydrogen bonding behaviors and excite state intramolecular proton transfer (ESIPT) process for HMPM molecule. Via simulating the reduced density gradient (RDG) versus sign(lambda2)rho, we firstly verify the double intramolecular hydrogen bonds (O1H2?N3 and O4H5?N6) for HMPM system. Comparing with the changes about these two hydrogen bonds (i.e., bond distances, bond angles and infrared (IR) vibrational spectra), we find that they should be enhanced in the first excited state upon the photo-excitation. The shortened hydrogen bonding distance of H2?N3 and H5?N6 provide the possibility for ESIPT reaction. Given the photo-excitation process, we confirm the charge redistribution around the hydrogen bonding moieties plays an important role as a driving force for the ESIPT process. Further, via constructing S0-state and S1 state potential energy surfaces (PESs), we confirm the excited state double proton transfer (ESDPT) is excludable since the high optimized energy and high potential energy barrier. While the low potential barrier for excited state single proton transfer path results in the ultrafast ESIPT reaction, which explains why the initial HMPM fluorescence peak cannot be detected in previous experimental phenomenon. This work not only clarifies the excited state dynamical behavior for HMPM system, but also explains previous experimental phenomenon and attributions about steady state spectra. We hope this work can facilitate novel applications based on the novel HMPM system in future. PMID- 30453192 TI - Probing the reverse micelle environment with a cationic dye by varying oil and water content of micelles. AB - In the present work, spectroscopic properties of crystal violet (CV) within water in-hexane sodium base (2-ethyl hexyl) sulfosuccinate (AOT) reverse micellar environment was investigated as a function of water contents (W = [H2O]/[AOT] = 6,10) in AOT and also function of mass fraction of nanodroplet (MFD = 0.01, 0.04, 0.07, and 0.1) by using UV/visible, and fluorescence techniques. A deviation in the absorption spectra of crystal violet at the high CV concentration (0.002 M) was observed in the AOT reversed micelles. The Quenching in the emission intensity of crystal violet at high CV concentration and blue shift in lambdamax of fluorescence of dye was observed as a function of MFD in AOT RMs. At high concentration of dye, molecules of CV can be reside interfacial region but near core of AOT. At low dye concentration, the CV molecules also can be in interfacial region but far from core. The Stokes shift of CV at high concentration decreased with mass fraction of nano-droplet (MFD), whereas at the low CV concentration, its variation often increased. The ratio of ground state to the excited state dipole moment of crystal violet dye also affected by the change in W values and MFD values. The change in dipole moment and stokes shift indicates the different environment around CV for different W and MFD values. PMID- 30453193 TI - Synthesis and photophysical studies on 2-styryl phenanthro[9,10-d]oxazole derivatives. AB - A new series of 2-styryl phenanthro[9,10-d]oxazoles was readily accessible from the condensation reaction of 9,10-phenanthroquinone with cinnamaldehydes in the presence of lactic acid. All these styryl dyes were isolated in good yields and characterized by various analytical and spectroscopic techniques. One of the dyes containing NO2 group (3d) was structurally characterized by single crystal X-ray analysis. These dyes displayed emission in blue to green region with larger Stokes shift values characteristic to the nature of substituents. In addition, positive solvatochromic trend was observed by increasing the solvent polarity suggestive of a more stabilized polar excited state. Moreover, the addition of trifluoroacetic acid leads to a prominent blue-shift in visible and emission color changes owing to the protonation of the nitrogen atom of oxazole moiety. Among the all, the oxazole derivative having NMe2 group (3b) exhibits good response to acidic pH in the range of 3.0 to 5.6 with a good linearity upon decreasing the pH from 8.0 to 2.16. The absorption studies were further supported by density functional theory calculations. PMID- 30453194 TI - Computational study of halogen-free Boron based dicationic ionic liquids of [bis Mim][BMB]2 and [bis-Mim][BScB]2. AB - In this paper, the structures and energetics of 1,3-bis[3-methylimidazolium-yl] pentane ([bis-Mim]2+) dication and bis(mandelato) borate [BMB]- and bis(salicylato) borate [BScB]-anions in isolated forms, ion pairs (IPs) and dicationic ionic liquids (DILs) were studied by Density Functional Theory (DFT) at the M06-2X/6-31G(d,p) level of theory. According to the IUPAC criteria, the hydrogen bonds between anion and cation were characterized and classified in the optimized geometries of the isolated ions, IPs and DILs. Inspection of the optimized structures revealed that the interionic hydrogen binding has important effect on the ions structures. The interaction energies between a dication and anions have been described in terms of NBO charge distribution, the stabilization energy E(2) values, changes of vibrational frequencies and the reduced density gradient (RDG) analysis. Also, the reactivity and interactions between chemical species were interpreted in terms of global electronic properties. Electrostatic potential surfaces (ESP) have been applied for visualizing the charge related properties and characterization of the most energetic sites of isolated ions and ion complexes. PMID- 30453195 TI - Characterization of gastric cells infection by diverse Helicobacter pylori strains through Fourier-transform infrared spectroscopy. AB - The infection of Helicobacter pylori, covering 50% of the world-population, leads to diverse gastric diseases as ulcers and cancer along the life-time of the human host. To promote the discovery of biomarkers of bacterial infection, in the present work, Fourier-transform infrared spectra were acquired from adenocarcinoma gastric cells, incubated with H. pylori strains presenting different genotypes concerning the virulent factors cytotoxin associated gene A and vacuolating cytotoxin A. Defined absorbance ratios were evaluated by diverse methods of statistical inference, according to the fulfillment of the tests assumptions. It was possible to define from the gastric cells, diverse absorbance ratios enabling to discriminate: i) The infection; ii) the bacteria genotype; and iii) the gastric disease of the patients from which the bacteria were isolated. These biomarkers could fasten the knowledge of the complex infection process while promoting a platform for a new diagnostic method, rapid but also specific and sensitive towards the diagnosis of both infection and bacterial virulence. PMID- 30453196 TI - Determination of amlodipine and atorvastatin mixture by different spectrophotometric methods with or without regression equations. AB - Four new, simple, and reproducible spectrophotometric methods were developed and validated for the simultaneous determination of Amlodipine (AML) and Atorvastatin (AT) in bulk powder and pharmaceutical dosage form. The four methods include two progressive and two successive resolution techniques. The two progressive methods are Absorbance Subtraction (AS) and Amplitude Modulation (AM), while the two successive methods are Constant Value (CV) and Concentration Value. In the Concentration Value method, the concentration of the drugs is determined from the graphical representation without the use of regression equations. Linearity range for the two progressive methods was from 5 MUg/mL-35 MUg/mL while for the two successive methods was from 5 MUg/mL-55 MUg/mL. The four methods were validated according to the ICH guidelines and were found to be accurate, precise, and selective. The methods were also applied for determination of the mixture in the marketed pharmaceutical dosage form. Results obtained were compared with reported methods. Also, One-way ANOVA statistical test was done between all the proposed spectrophotometric methods where no significant differences were found. PMID- 30453197 TI - Designer macrophages: Pitfalls and opportunities for modelling macrophage phenotypes from pluripotent stem cells. AB - Macrophages are phagocytic immune cells resident in every tissue that are not only important for host defence, but are also involved in tissue homeostasis, injury, and disease. Despite increasingly sophisticated methods for in vitro macrophage isolation, expansion and activation over the past three decades, these have largely been restricted to modelling bone-marrow or blood-derived cells. The in vitro derivation of macrophages from human pluripotent stem cells provides new opportunities to study macrophage biology, including the factors that impact human myeloid development and those that induce macrophage activation. While sharing many of the functional characteristics of monocyte-derived macrophages, stem cell-derived macrophages may offer new opportunities to understand the role of development or tissue context in innate immune cell function. Immune responsiveness to pathogenic challenge is known to be impacted by a macrophage's history of prior exposure, as well as ontogeny and tissue context. Therefore, we explore the factors of in vitro derivation likely to influence macrophage phenotype and function. PMID- 30453198 TI - Lower self-report fatigue in multiple sclerosis is associated with localized white matter tract disruption between amygdala, temporal pole, insula, and other connected structures. AB - BACKGROUND: Fatigue, a frequent and disabling symptom for people with multiple sclerosis (PwMS), inconsistently correlates with white matter (WM) pathology. Network-based analysis, accounting for the manner in which lesions disrupt networks of structurally connected gray matter (GM) regions, may provide additional insight. OBJECTIVE: To identify patterns of WM tract disruption which explain self-reported fatigue severity in PwMS. METHODS: 137 PwMS and 50 age- and sex-matched healthy controls (HC) underwent fatigue assessment and brain MRI. Lesion maps were applied to determine the severity of WM tract disruption between pairs of GM regions. Then, the Network-Based-Statistics tool was applied to identify structural networks whose disruption explained fatigue severity. To determine whether these networks explain unique variance above conventional MRI measures and depression, regressions were applied controlling for age, sex, brain volume, T2-lesion volume, and depression. RESULTS: Patient-perceived fatigue in PwMS was positively associated with overall lesion burden (beta = 0.563, p-value < 0.001). In contrast, localized disruptions in WM tracts between regions including the amygdala, insula, hippocampus, putamen, temporal pole, caudal middle-frontal gyrus, rostral-middle-frontal gyrus, inferior-parietal gyrus, and banks of the superior temporal sulcus were significantly negatively correlated with fatigue in PwMS (beta = -0.586, p-value < 0.001). Average disruption within this specific, localized network explained significant additional variance in fatigue above what was otherwise explained by depression and conventional MRI measures of neuropathology (DeltaR2 = 0.078, p-value < 0.001). CONCLUSION: Although overall lesion burden correlates positively with fatigue in PwMS, localized WM damage between the amygdala, temporal pole, and other connected structures is associated with lower severity of patient-perceived fatigue. PMID- 30453199 TI - Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis. AB - INTRODUCTION: In this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. METHODS: We studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. RESULTS: The mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 +/- 1.0 vs 1.7 +/- 1.0, p < 0.05) and at T2 (1.4 +/- 1.3 vs 2.9 +/- 1.8, p < 0.001). Volume loss of thalamus (-0.5% +/- 0.2% vs. -1.1% +/- 0.4%; p < 0.001), globus pallidus (-4.4% +/- 3.1% vs. -8.2% +/- 4.5%; p < 0.001), hippocampus (-0.7% +/- 0.3% vs. -1.5% +/- 0.5%; p < 0.001) and cerebellum (-0.5% +/- 0.3% vs. -0.9% +/- 0.4%; p < 0.001) was also lower in the GA group. A more pronounced cortical thinning was observed in cingulate (p = 0.04), cuneus and frontomarginal gyrus (p = 0.01 for both comparisons) of the untreated patients. CONCLUSION: Our findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage. PMID- 30453200 TI - Self-reflection during first clinical practice: The experiences of nursing students. AB - BACKGROUND: Self-reflection can be used as a tool for describing student experiences and have a significant impact on their learning. It enables nursing students to develop the ability to identify and analyse their problems and find possible solutions. OBJECTIVE: To present students' self- reflection in their first clinical practice as their first stage of our nursing study program. METHODOLOGY: The research was based on a naturalistic philosophical paradigm using a qualitative methodological approach. The research took place at one of the Slovenian universities with an undergraduate nursing education program. Purposive sampling was chosen. The data were obtained through written self reflection diary entries collected between March and June 2016. A thematic analysis was selected for data analysis. Ensuring that all ethical considerations were covered, seventeen students in the first clinical practice were included. FINDINGS: Three main thematic themes were identified that define the experience of students in their first clinical practice: (1) emotional experience, (2) interpersonal relationships, (3) learning. CONCLUSIONS: The research has found that the experiences and the perceptions of students in the first clinical practice are mainly expressed emotionally. Self-reflection helps students to express emotions and feelings to reliving and to identifying problems and also, to understanding themselves better. Further research should be focused on the importance of the students' self-reflections in their professional and personal growth. PMID- 30453201 TI - The mediating effects on the relationship between campus life adaptation and clinical competence. AB - BACKGROUND: The solution to the shortage of nursing staff is to improve the quality of nursing education and training rather than to increase the admission capacity. It is necessary for the university to establish the current level of nursing education and find ways to improve it. The clinical competence of nursing college students is an ability to perform the desired nursing role to solve the nursing needs of the subjects in the clinical field, which is an important aspect of nursing students' practical training. Therefore, to improve the quality of practical training, it is necessary to improve the clinical competence of nursing students. OBJECTIVES: The purpose of this study was to investigate the mediating effect of social support and resilience on the relationships of campus life adaptation and clinical competence. DESIGN: This study is of a cross-sectional, descriptive correlation design. METHODS: Characteristics of the respondents, campus life adaptation, social support, resilience, and clinical competence were collected, using self-reported questionnaires, from July 1 to September 10, 2017. Data were analyzed by frequency, percentage, mean, standard deviation, t-test and ANOVA with Scheffe post hoc, Pearson correlation coefficients, the 3-steps multiple regression statistics of Baron and Kenny. RESULTS: Social support and resilience had a partial mediating effect on the relationships of campus life adaptation and clinical competence. In addition, clinical competence increased as more male nursing students enrolled and more students adapted well to the nursing department. CONCLUSIONS: The result of this study is expected to be used as evidence data for the development of a program to improve the clinical competence of nursing students. PMID- 30453202 TI - The impact on nursing students' opinions and motivation of using a "Nursing Escape Room" as a teaching game: A descriptive study. AB - BACKGROUND: According to previous studies on nursing education, although the use of games can produce positive results, the vast majority are based on questions and answers or on clinical situations. As an alternative, the 'Escape Room' teaching game is a much more dynamic option to asses theoretical and practical knowledge, and it may also promote teamwork and the ability to perform under pressure. OBJECTIVES: To analyse nursing students' opinions and study motivations after using the nursing 'Escape Room' teaching game. DESIGN: Cross-sectional descriptive study. PARTICIPANTS: Second-year nursing students enrolled in the 'Adult Nursing 1' subject. METHOD: After completing the teaching game, the students who had taken part in it were asked to fill in an ad-hoc questionnaire on the matter. In this game, students have 30 min in which they must solve the riddles and puzzles presented, and thus escape. In doing so, they must demonstrate both theoretical and practical knowledge, and a teacher will remain in the classroom to assess whether the nursing techniques in question are correctly performed. RESULTS: The nursing students who took part in the game strongly believed that this 'helped them learn the subject' (4.8 points) and that 'more games of this type should be included in their nursing studies' (4.8 points). Overall, they considered that 'the game was enjoyable' (4.6 points), 'helped them in the exam' (4.6 points), and 'motivated them to study' (4.5 points). CONCLUSIONS: The 'Escape Room' is a useful game; it stimulates learning, is fun to play, and motivates studying. PMID- 30453203 TI - Incorporating medication administration safety in undergraduate nursing education: A literature review. AB - OBJECTIVE: The purpose of this review was to identify methods for incorporating medication administration safety in undergraduate nursing education. DESIGN: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines directed this review. DATA SOURCES: A search of four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Education Resources Information Center, Google Scholar, and MedLine/PubMed MedLine/PubMed) as well as hand searches were conducted to identify original research published between 2005 and 2018. REVIEW METHODS: Original empirical research describing a method for incorporating medication administration safety concepts in nursing education and examining its effectiveness on undergraduate nursing students' outcomes were selected for review. Articles describing medication safety education for graduate students, students other than those in nursing, and practicing nurses were excluded. RESULTS: Twelve original research articles were included for review. Three methods for incorporating medication administration safety in undergraduate nursing education were identified: simulation experiences, technology aids, and online learning modules. Most studies were conducted in North America. The use of different interventions as well as different outcome measures was noted as a limitation to the collective body of research in this area. Also, there was a lack of information regarding psychometric properties of instruments used among the studies reviewed. CONCLUSION: Simulation experiences, use of technology aids, and online learning modules helped increase medication safety competence of nursing students. However, simulation equipment, select technology aids, and online learning may not be available for all nursing programs; therefore, educators should consider developing and testing classroom-based educational interventions. Moreover, future researchers should use or develop psychometrically sound instruments to measure nursing students' outcomes including competencies about medication administration safety. PMID- 30453204 TI - Updates on autoinflammatory diseases. AB - Autoinflammatory diseases are hyperinflammatory, immune dysregulatory diseases caused by innate immune cells dysregulation that present typically in the perinatal period with systemic and organ-targeted inflammation, but with improved genetic testing and the development of diagnostic criteria, milder and later onset forms are being detected in adulthood. While the discovery of gain-of function mutations in innate sensors linked to the production of proinflammatory cytokines provided the bases for anti-cytokine therapies that changed disease and patient outcomes, the field is expanding with the increasing discovery of disease causing loss-of-function mutations in genes with cellular house-keeping functions that affect cell homeostasis and when dysregulated trigger innate inflammatory pathways. This review focuses on updates on molecular pathways and diseases that cause predominantly IL-1beta and Type-I IFN-mediated autoinflammatory diseases. PMID- 30453205 TI - Dracula teeth-like image on MRI of a patient with non alcoholic Wernicke encephalopathy. PMID- 30453206 TI - Response to Letter to the Editor: "Plasma beta-amyloid1-42 reference values". PMID- 30453207 TI - Association of office-based provider visits with emergency department utilization among publicly insured stroke survivors. AB - OBJECTIVE: To evaluate the association between visits to office-based providers and Emergency Department (ED) utilization among stroke survivors. METHODS: We analyzed 12-years of data representing a weighted sample of 3,317,794 publicly insured US adults aged >=18 years with stroke, using the Medical Expenditure Panel Survey Household Component (MEPS-HC), 2003-2014 dataset. We used a negative binomial regression model that accounts for dispersion to estimate the association between office-based and ED visits controlling for covariates. We used a multivariate logistic regression model to identify independent predictors of ED visits. RESULTS: Annual mean (SD) ED visits and office based visits for publicly insured stroke survivors were 0.60 (1.10) and 12.2 (19.9) respectively. Each unit increase in office based visits was associated with a 1% increase in ED visit (p = 0.008). Being unmarried (adjusted OR = 1.26; 95% CI: 1.015-1.564) and having several comorbidities (adjusted OR = 1.93; 95% CI: 1.553-2.412) were associated with a higher likelihood of at least one ED visit. The odds for an ED visit for individuals aged 45-64, those aged 65 years and above, and those with a college or higher level of education were respectively 34% (OR = 0.66; 95% CI: 0.454-0.965), 52% (OR = 0.48; 95% CI: 0.330-0.701), and 36% (OR = 0.64; 95% CI: 0.497-0.834) lower than their counterparts. CONCLUSIONS: Contrary to our expectations, there was a direct relationship between ED visits and office base visits among U.S. stroke survivors. This finding may reflect the difficulties associated with managing stroke survivors with multiple co-morbidities or complex psycho-socio-economic issues. PMID- 30453208 TI - AQP4 antibody-positive NMO spectrum disorder associated with Takayasu arteritis. PMID- 30453209 TI - Historical and clinical aspects of the 1918 H1N1 pandemic in the United States. AB - One hundred years have passed since the 1918 influenza pandemic caused substantial illness globally, with an estimated 50 million deaths. A number of factors, including World War I, contributed to the spread of the pandemic virus, which often caused high symptomatic attack rates and severe illness. Major achievements over the last 100 years have been made in influenza prevention, diagnosis, and treatment; however, the potential for a severe pandemic to emerge remains unchanged. We provide a review of the historical context and clinical aspects of illness due to the influenza A(H1N1) virus as it emerged and spread in 1918, with a focus on the experience in the United States. Understanding the significant social disruption and burden of illness from the 1918 pandemic can help us imagine the possible impacts of a high severity pandemic if it were to emerge now. PMID- 30453210 TI - Role of Tobacco vein banding mosaic virus 3'-UTR on virus systemic infection in tobacco. AB - To investigate the role of Tobacco vein banding mosaic virus (TVBMV) 3'-UTR in virus systemic infection, three types of deletions were introduced into TVBMV infectious clone pCaTVBMV-GFP. Mutants with deletions at the nucleotide position 8-42, 43-141, or 163-174 in the 3'-UTR failed to cause systemic infection in N. benthamiana plants. Other deletion mutants caused delayed systemic infection and milder vein clearing and mosaic symptoms. Most progeny mutant virus had acquired nucleotides, similar to or different from the deleted nucleotide sequences, after a single passage in the host plant. Nucleotides at the position 8-42 near the 5' terminus of TVBMV 3'-UTR could form a stem-loop (SL) like structure which was crucial for TVBMV systemic movement in tobacco. We proposed that this SL like structure, and thus 3'-UTR, has an essential role in TVBMV systemic infection. PMID- 30453211 TI - Localization of the kinase Ataxia Telangiectasia Mutated to Adenovirus E4 mutant DNA replication centers is important for its inhibitory effect on viral DNA accumulation. AB - Adenovirus (Ad) type 5 (Ad5) E4 deletion mutants including H5dl1007 (E4-) induce a DNA damage response (DDR) that activates the kinase ataxia-telangiectasia mutated (ATM), which can interfere with efficient viral DNA replication. We find that localization of active phosphorylated ATM (pATM) to E4- viral replication centers (VRCs) is important for its inhibitory effect. ATM is necessary for localization of RNF8 and 53BP1 to E4 mutant VRCs, while recruitment of DDR factors Mre11, Mdc1 and gammaH2AX is ATM-independent, raising the possibility that ATM may affect viral chromatin at VRCs. We assessed E4- and Ad5 chromatin organization by micrococcal nuclease (MN) digestion. A significant fraction of Ad5 DNA is somewhat resistant to MN digestion, whereas E4- DNA is more susceptible. ATM inhibition increases the fraction of E4- DNA that is resistant to MN digestion. Our results address possible mechanisms through which ATM inhibits E4- DNA replication. PMID- 30453212 TI - Pre-vascularized dermis model for fast and functional anastomosis with host vasculature. AB - Skin engineering for clinical applications has gained numerous advances, however, most of the available dermis substitutes are exogenous matrices acting for a limited time. Indeed, after implantation these matrices need to be colonized by host cells such as fibroblast and endothelial cells which respectively produce their own extracellular matrix and set a vascular network within the construct. These steps are essential to guarantee implant efficacy, but they may require a long time depending on tissue dimension and lesion severity. Here we show the pre vascularization process of a dermis equivalent featured by an endogenous matrix produced by human dermal fibroblasts. In this environment, endothelial cells were able to develop mature capillary-like-structures (CLS) as demonstrated by both the inner lumen and the positivity for alpha-SMA, laminin and collagen. The pre vascularized dermis model (PVD) so obtained had a human matrix populated by fibroblasts as well as a complex capillary network making the construct ready to be implanted. These features make the graft very easy to handle during the surgery. In vivo results showed that 7 days after implantation CLS effectively anastomosed with host vessels. Therefore we argue that the proposed PVD may represent a new class of dermis substitute of strong clinical interest. PMID- 30453213 TI - NTA-Co3+-His6 versus NTA-Ni2+-His6 mediated E-Cadherin surface immobilization enhances cellular traction. AB - Understanding the biological impact of strategies for protein immobilization onto bioactive surfaces is crucial for the design of biomimetic materials. A common strategy used to immobilize or label recombinant proteins is to exploit the Ni2+ mediated interaction of nitrilotriacetic acid (NTA) with the hexahistidine tag (His6-tag) present on recombinant proteins. While this method ensures a controlled orientation and functionality of the protein, the kinetically labile nature of the bond ensures only its weak immobilization onto the surface. Recently, it has been shown that the oxidation of Co2+ to Co3+ greatly stabilizes the bond between NTA and the His6-tagged proteins, making it inert to ligand exchange and resistant to chelators. This approach not only has the potential to improve the quality of biomimetic material functionalization and molecule labeling but could also affect cellular mechanical responses for which the mechanical strength of the protein-surface bond is crucial. Here, we compared gold (Au) nanopatterned polyacrylamide (PAA) hydrogels functionalized with E cadherin via Co3+ with those functionalized via Ni2+ for studying adhesion mediated responses in keratinocytes. We show that keratinocytes develop higher and a broader range of adhesion forces, leading to extended cell spreading and colony organization on Co3+ vs. Ni2+. This work uniquely shows that stabilizing the NTA/His6-tag bond via Co3+ for protein immobilization significantly impacts cellular phenotype on biomimetic materials by impacting cell signaling. PMID- 30453214 TI - A black phosphorus/manganese dioxide nanoplatform: Oxygen self-supply monitoring, photodynamic therapy enhancement and feedback. AB - Selecting the timing of laser treatment is an important task for improving O2 dependent photodynamic therapy (PDT) efficiency. Here, a black phosphorus-based strategy was developed for dual-mode monitoring oxygen self-supply, enhancing photodynamic therapy, and feeding back therapeutic effect. The hybridized nanoplatform (R-MnO2-FBP) was prepared by assembly of Rhodamine B (RhB) encapsulated manganese dioxide (R-MnO2) as O2 supplier and indicator, and fluorescein isothiocyanate (FITC)-labelled peptide-functionalized black phosphorus as the theranostic agent. The time-dependent assays suggested that the O2 release was proportional to the liberation of Mn2+ and RhB in the R-MnO2-FBP system. After specific delivery into cancer cells, R-MnO2-FBP was dissociated in the acidic and H2O2-rich environment and generated oxygen to overcome hypoxia associated PDT resistance. In the meantime, it released both Mn2+and RhB dye, leading to dual-mode (magnetic resonance imaging/fluorescence imaging) monitoring of the oxygen self-supply process. More significantly, the imaging-guided PDT in hypoxic cells displayed 51.6% of cell apoptosis at optimizing timing of laser application, which could also be confirmed by the FITC fluorescence recovery induced by the activated caspase-3 in apoptotic cells. In vivo photonic therapy by R-MnO2-FBP further demonstrated the ability of R-MnO2-FBP to choose the timing of laser application, providing an efficient approach for the enhancement of PDT process. PMID- 30453215 TI - Engineered tendon-fibrocartilage-bone composite and bone marrow-derived mesenchymal stem cell sheet augmentation promotes rotator cuff healing in a non weight-bearing canine model. AB - Reducing rotator cuff failure after repair remains a challenge due to suboptimal tendon-to-bone healing. In this study we report a novel biomaterial with engineered tendon-fibrocartilage-bone composite (TFBC) and bone marrow-derived mesenchymal stem cell sheet (BMSCS); this construct was tested for augmentation of rotator cuff repair using a canine non-weight-bearing (NWB) model. A total of 42 mixed-breed dogs were randomly allocated to 3 groups (n = 14 each). Unilateral infraspinatus tendon underwent suture repair only (control); augmentation with engineered TFBC alone (TFBC), or augmentation with engineered TFBC and BMSCS (TFBC + BMSCS). Histomorphometric analysis and biomechanical testing were performed at 6 weeks after surgery. The TFBC + BMSCS augmented repairs demonstrated superior histological scores, greater new fibrocartilage formation and collagen fiber organization at the tendon-bone interface compared with the controls. The ultimate failure load and ultimate stress were 286.80 +/- 45.02 N and 4.50 +/- 1.11 MPa for TFBC + BMSCS group, 163.20 +/- 61.21 N and 2.60 +/- 0.97 MPa for control group (TFBC + BMSCS vs control, P = 1.12E-04 and 0.003, respectively), 206.10 +/- 60.99 N and 3.20 +/- 1.31 MPa for TFBC group (TFBC + BMSCS vs TFBC, P = 0.009 and 0.045, respectively). In conclusion, application of an engineered TFBC and BMSCS can enhance rotator cuff healing in terms of anatomic structure, collagen organization and biomechanical strength in a canine NWB model. Combined TFBC and BMSCS augmentation is a promising strategy for rotator cuff tears and has a high potential impact on clinical practice. PMID- 30453216 TI - Chasing Chimeras - The elusive stable chondrogenic phenotype. AB - The choice of the best-suited cell population for the regeneration of damaged or diseased cartilage depends on the effectiveness of culture conditions (e.g. media supplements, three-dimensional scaffolds, mechanical stimulation, oxygen tension, co-culture systems) to induce stable chondrogenic phenotype. Herein, advances and shortfalls in in vitro, preclinical and clinical setting of various in vitro microenvironment modulators on maintaining chondrocyte phenotype or directing stem cells towards chondrogenic lineage are critically discussed. Chondrocytes possess low isolation efficiency, limited proliferative potential and rapid phenotypic drift in culture. Mesenchymal stem cells are relatively readily available, possess high proliferation potential, exhibit great chondrogenic differentiation capacity, but they tend to acquire a hypertrophic phenotype when exposed to chondrogenic stimuli. Embryonic and induced pluripotent stem cells, despite their promising in vitro and preclinical data, are still under investigated. Although a stable chondrogenic phenotype remains elusive, recent advances in in vitro microenvironment modulators are likely to develop clinically and commercially-relevant therapies in the years to come. PMID- 30453217 TI - What specifically contributes to disturbed non-verbal fluency in patients with bipolar disorder: Ineffective performance initiation, slowed processing or lack of the execution strategy? AB - The study aimed at identifying the cognitive and clinical determinants of impaired design fluency in bipolar patients, with special reference to processing speed and performance strategy. A sample of bipolar disorder patients (BD, n = 45) and matched healthy controls (HC, n = 42) underwent the assessment of figural fluency, cognitive and manual speed, cognitive effort and affective state. An electronic version of design fluency test was applied, enabling assessment of performance speed, execution strategy and spontaneous fluctuations in production efficiency. Additional clinical variables were also controlled. BD patients produced significantly less unique designs, performed slower, utilized less effective strategy, their ability to concentrate designs production in the initial phase of performance was significantly reduced compared with HC. Regression analysis revealed that in BD patients design fluency main outcome was significantly predicted by slowed creation of designs and the number of hospitalizations, while in the HC group, the main fluency result was predicted only by the executive strategy indicators. Our study showed that non-verbal fluency in BD group was determined by essentially different neuropsychological functions than in healthy controls. Obtained findings confirm that cognitive slowdown should be an important goal of cognitive remediation and pharmacological interventions in bipolar disorder. PMID- 30453218 TI - Serum albumin concentration of donor cows as an indicator of developmental competence of oocytes. AB - Adequate nutrition is required for maintenance of normal reproduction in cattle. Albumin, the best marker and fundamental part of nutrition, most abundant plasma protein and major component of fetal bovine serum, is the best predictor of malnourishment in South African cattle. The aim of this study was to determine if serum albumin concentrations of donor cows predict the developmental competence of oocytes, and if additional protein supplementation of the in vitro culture media improves embryo outcomes in oocytes from cows with inadequate serum albumin concentrations. Oocytes (n = 1024) were recovered from donors with inadequate (<=35.9 g/L), or adequate serum albumin concentrations (>=36.0 g/L). Four hundred and sixty oocytes originated from cows with inadequate serum albumin and 564 from cows with adequate serum albumin. Oocytes of these cohorts were randomly allocated to a control and supplemented fetal bovine serum in vitro embryo culture protocol. Multiple linear, logistic and Poisson regression analyses were performed to estimate the effects of different covariates on linear, binary and count data respectively. Mixed effects Poisson regression was performed for the number of oocytes that developed into blastocysts by the seventh day of culture. Adequate serum albumin concentration of donor cows independently resulted in 46% increased blastocyst formation in the control protocol (P = 0.02). Although fetal bovine serum supplementation of the culture protocol did not affect blastocyst formation in oocytes originating from cows with inadequate serum albumin, it independently reduced blastocyst formation by 30% in oocytes originating from cows with adequate serum albumin (P = 0.02). Other independent predictors of blastocyst outcome included higher serum urea nitrogen, lower beta (beta) hydroxybutyric acid concentrations and lower fat classification of donor cows. It is concluded that adequate serum albumin of donor cows is a significant predictor of developmental competence of oocytes, and that in vitro supplementation of fetal bovine serum does not improve developmental competence of oocytes and can lead to negative blastocyst outcomes. Further research is required to determine optimal protein supplementation for oocytes originating from inadequately nourished cows. PMID- 30453219 TI - LC-MS-guided isolation of anti-inflammatory 2-(2-phenylethyl)chromone dimers from Chinese agarwood (Aquilaria sinensis). AB - Fifteen previously undescribed 2-(2-phenylethyl)chromone dimers, along with two known analogues were isolated from Chinese agarwood (Aquilaria sinensis) by a LC MS-guided fractionation procedure. Their structures were elucidated on the basis of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The isolated compounds exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with IC50 values in the range 0.6 37.1 MUM. PMID- 30453220 TI - Recruitment manoeuvres for adults with acute respiratory distress syndrome receiving mechanical ventilation: a systematic review and meta-analysis. AB - PURPOSE: To determine if recruitment manoeuvres (RMs) would decrease 28-day mortality of patients with acute respiratory distress syndrome (ARDS) compared with standard care. MATERIALS AND METHODS: Relevant randomized controlled trials (RCTs) published prior to April 26, 2018 were systematically searched. The primary outcome was mortality. The secondary outcomes were oxygenation, barotrauma or pneumothorax, the need for rescue therapies. Data were pooled using the random effects model. And the quality of evidence was assessed by the GRADE system. RESULTS: Of 3180 identified studies, 15 were eligibly included in our analysis (N = 2755 participants). In the primary outcome, RMs were not associated with reducing 28-day mortality (RR 0.90; 95% CI 0.74-1.09), ICU mortality (RR 0.92; 95% CI 0.74-1.1), and the in-hospital mortaliy (RR 1.02; 95% CI 0.93-1.12). In the secondary outcomes, RMs could improve oxygenation (MD 37.85; 95% CI 11.08 64.61), the rates of barotrauma (RR 1.42; 95% CI 0.83-2.42) and the need for rescue therapies (RR 0.69; 95% CI 0.42-1.12) did not show any difference in the ARDS patients with RMs. CONCLUSIONS: Earlier meta-analyses found decreased mortality with RMs, in the contrary, our results indicate that RMs could improve oxygenation without detrimental effects, but it does not appear to reduce mortality. PMID- 30453221 TI - Periodically kicked network of RLC oscillators to produce ECG signals. AB - We propose a simple model of the electrical activity of the heart that reproduces realistic healthy electrocardiogram (ECG) signals. The model consists of two RLC linear oscillators periodically kicked by impulses of the main pacemaker with the frequency rate of a real heart. In the proposed model, one oscillator represents the atria, another represents the ventricles, and an electrical cardiac conduction system is included using a coupling capacitor, which can be either unidirectional or bidirectional. The network of the two capacitively coupled oscillators is periodically kicked by the main pacemaker to introduce the periodic forcing of limit cycles into the system; a time delay is introduced to represent the electrical transport delay from atria to ventricles. In this manner, healthy synthetic ECG signals are obtained by combining the signals of the currents of the oscillators. We show that an analytical solution of the model can be obtained when a single impulse is applied. From this, by the superposition principle, a solution with an impulse train is obtained. Note that analytical treatment is a feature not available in current cardiac oscillator models. PMID- 30453222 TI - Degradation of fluorene and phenanthrene in PAHs-contaminated soil using Pseudomonas and Bacillus strains isolated from oil spill sites. AB - Biodegradation of 3-ring and 4-ring polycyclic aromatic hydrocarbons (PAHs) model (fluorene, phenanthrene, fluoranthene and pyrene) were investigated. Twenty-seven bacterial strains were isolated from contaminated-site by oil spills. PAHs degrading bacteria were screened to select high tolerant species for ensuring an efficient bioremediation. Each of the isolated bacterial strains was grown under different PAHs concentrations (250, 500, 1000 and 1500 mg/L). Among the 27 strains, 8 resulted to be resistant to high concentration level of PAHs (1500 mg/L) and thereof can use PAHs as sole source of carbon and energy. The most tolerant strains were molecularly identified using mass spectrometer MALDI-TOF VITEK MS and 16S rDNA sequencing approaches. The identified bacterial strains Pseudomonas stutzeri (P. stutzeri), Bacillus simplex (B. simplex) and Bacillus pumilus (B. pumilus) were used for the bioremediation experiment of soils contaminated by PAHs. The studies were conducted under controlled conditions using soil spiked with a mixture of the target PAHs and the three microcosm strains. The results revealed that only fluorene and phenanthrene, which are low molecular weight PAHs, were degraded efficiently within 72 days of test organism incubation. These degradations were about 65-86% and 86-95% for fluorene and phenanthrene, respectively. At the same time and conversely to fluorene and phenanthrene, the high molecular weight PAHs, pyrene and fluoranthene were recalcitrant to these selected microbial strains. The biodegradation kinetics of both fluorene and phenanthrene were fit a first order rate with R2 values ranging from 0.88 to 0.92. The half-lives of phenanthrene (2.4-2.7 days) and those of fluorene (3.5-4.6 days) were all less than 10 days, delineating therefore acclimatization with the strains. PMID- 30453223 TI - Arithmetic learning modifies the functional connectivity of the fronto-parietal network. AB - How Resting-State Functional Connectivity (RSFC) is modified by learning is an important but rarely asked question. Here we used functional near-infrared spectroscopy (fNIRS) to measure changes in RSFC after learning novel subtraction and multiplication facts by forty-one young adult volunteers. We also measured changes in regional hemoglobin concentration. Fronto-parietal RSFC was modified by arithmetic learning and the fronto-parietal RSFC configuration before learning predicted the effectiveness of arithmetic learning. We also found a significant learning effect indicated by a monotonic decrease in reaction time and an increase in accuracy. Regional task-dependent oxy-hemoglobin concentration differentiated subtraction from multiplication learning supporting previous fMRI findings. These results suggest the sensitivity and importance of fronto-parietal connectivity to arithmetic learning. PMID- 30453224 TI - Unemployment insurance and cigarette smoking. AB - We provide evidence for the causal relationship between unemployment insurance (UI) and individuals' smoking behavior using the 1995-2011 Current Population Survey-Tobacco Use Supplement data. Our identification relies on the exploitation of the exogenous variations of the maximum UI weekly benefits across states and over years. Instead of focusing on all unemployed people, we concentrate on those who are eligible for UI benefits. We find that when the maximum UI weekly benefit level increases by $100, smoking cessation increases by approximately 2.9 percentage points among the UI-eligible unemployed. The results are robust to various model specifications. We also explore the mechanism and find suggestive evidence that the increase in the maximum UI weekly benefit leads to a decrease in the probability of over-work of the respective spouse. Moreover, the unemployed who are less educated are more responsive to the increasing UI benefits. PMID- 30453225 TI - Are some neighborhoods bad for your waistline? A test of neighborhood exposure effects on BMI. AB - I study the causal impact of neighborhoods on body mass index (BMI). Through exploiting variation in the number of years individuals have lived in their neighborhood, using a data set from California, I examine if there exist causal effects of exposure to neighborhoods with high potential effects on one's BMI. The identifying assumption is that there are no unobserved individual level characteristics correlated with both BMI and moving, after controlling for observables. I find evidence that suggests that neighborhoods do not have a causal impact on BMI. PMID- 30453226 TI - Self-assembly of intramolecularly hydrogen-bonded amphiphilic diboronic acid for saccharide recognition. AB - HYPOTHESIS: The designed organic boronic acid molecule featuring both hydrophilic and hydrophobic moieties, makes a potential functional surfactant. Selective recognition of saccharides through morphological changes of phenylboronic acid based self-assembly system by saccharide stimulation is a key concept in boronic acid design. EXPERIMENTS: In the present study, we designed a tuning-fork-shaped amphiphilic diboronic acid (OPAB-C8) which formed vesicular aggregates through self-assembly in aqueous solution and evaluated its saccharide recognition function. The formation of the vesicular aggregates was determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS) measurements. The response of OPAB-C8 to saccharide was measured through ultraviolet-visible (UV-vis) titration experiments. FINDINGS: The stoichiometric ratio of OPAB-C8 and glucose complex was 1:2, while that of fructose or galactose was 1:1, and OPAB-C8 showed excellent binding affinity to glucose with binding constant was up to 4.6 * 106 M-2. When dealing with glucose, the vesicular aggregates transformed to larger aggregates, whereas the vesicular aggregates disassembled in the presence of fructose. The results revealed that the selective recognition of saccharides through morphological changes was feasible by diboronic acid self-assembled in aqueous solution. PMID- 30453227 TI - Vascular endothelial growth factor immobilized on mussel-inspired three dimensional bilayered scaffold for artificial vascular graft application: In vitro and in vivo evaluations. AB - Currently, there is a great clinical demand for biocompatible and robust tissue engineered tubular scaffolds for use as artificial vascular graft materials. Despite considerable research on vascular scaffolds, there has still been only limited development of scaffold materials possessing both sufficient mechanical strengths and biological effects for vascular application. In this work, we designed a mechanically robust, bilayered scaffold and manufactured it by combining electrospinning (ELSP) and three-dimensional (3D) printing techniques. This material was coated with polydopamine (PDA) and vascular endothelial growth factor (VEGF) was grafted directly on the scaffold surface to induce potent angiogenic activity. We confirmed that the coated-PDA layer was evenly deposited on the bare polycaprolactone (PCL) scaffold and could enable abundant VEGF immobilization with enhanced hydrophilicity. The VEGF immobilized porous tubular scaffold was well prepared without mechanical weakness induced by surface modification steps. During in vitro and in vivo testing, VEGF immobilized scaffolds elicited markedly enhanced vascular cell proliferation and angiogenic differentiation, as compared to non-treated groups. These results demonstrate that the developed scaffolds may represent an innovative paradigm in vascular tissue engineering by inducing angiogenesis as a means of remodeling and healing vascular defects for use in restorative procedures. PMID- 30453228 TI - Hexagonal SnS nanoplates assembled onto hierarchical Bi2WO6 with enhanced photocatalytic activity in detoxification and disinfection. AB - A novel Z-scheme heterostructure, SnS nanoplates deposited Bi2WO6, was successfully fabricated via a simple bath sonication method. The positive synergetic effect between SnS and Bi2WO6 greatly improved the photocatalytic activity of SnS-Bi2WO6 composites in dye degradation and bacterial inactivation. Under visible light irradiation, the photocatalytic degradation activity of SnS Bi2WO6 composites (0.50 wt% SnS) was about 5.8 times higher than that of pure Bi2WO6. As for the disinfection experiment, the survival ratio for 60 min in the presence of Bi2WO6 and SnS-Bi2WO6 composites was 50% and 32%, respectively. This result was consistent with the photocatalytic degradation reaction. The mechanism of photocatalytic reactions was also explored by the quenching experiment and electrochemical analysis. It indicated that the main oxidative species in the photocatalytic degradation process were holes and hydro oxygen radicals (e.g. HO2 and H2O2). In addition, the formation of the heterostructure could greatly suppress the recombination of photogenerated charge carriers. All these results suggested that the as-prepared SnS-Bi2WO6 composites could be served as efficient photocatalysts for wastewater treatment. PMID- 30453229 TI - Ion transport in a pH-regulated conical nanopore filled with a power-law fluid. AB - Extending previous electrokinetic analyses based on a Newtonian fluid to power law fluids, we investigate the behaviors of the ion current rectification (ICR) and the ion selectivity S of a conical nanopore having a pH-regulated surface. The bulk salt concentration Cbulk, the solution pH, and the power-law index n are examined in detail for their influences on these behaviors. We show that the ICR ratio for the case where pH is lower than the isoelectric point (IEP) of the nanopore surface is different both quantitatively and qualitatively from that for the case where pH > IEP. The relative magnitude of the ICR ratio as n varies depends largely on the level of Cbulk. In contrast, S (pH < IEP) is qualitatively similar to that for S(pH > IEP), where |S| decreases with increasing Cbulk and/or decreasing n. In addition, S is very sensitive to n, for example, a decrease of n from 1.0 (Newtonian fluid) to 0.9 (pseudoplastic fluid) can yield a 245% increase in S at Cbulk = 100 mM. Implying that the performance of ion separation can be improved by tuning the fluid viscosity. Mechanisms are proposed for explaining the observed behaviors in the ICR ratio. PMID- 30453230 TI - Twisted palladium-copper nanochains toward efficient electrocatalytic oxidation of formic acid. AB - Twisted PdCu nanochains are synthesized successfully via a staged thermal treatment route, offering rich twin boundaries as catalytic "active sites" and modified electronic effects. Toward formic acid oxidation, the twisted PdCu nanochains hold the highest catalytic peak current density (1108.2 mA mg-1Pd) over previous reported PdCu alloy catalysts, and also much higher catalytic activity and durability comparing with Pd nanochains and commercial Pd/C. The catalytic enhancement mechanism to PdCu nanochains is proposed and discussed. Additionally, we found that the formation of PdCu nanochains follows a typical anisotropic growth approach, and the multiple steps of staged thermal treatment route displays a vital role in fabricating the unique PdCu nanochains while the introduced Cu precursors might affect the reduction rate of Pd species and act as deposition or nucleation sites for twisted structure in terms of rich twin boundaries. This work describes an efficient, low-Pd loading catalyst for electrooxidation of formic acid, and also demonstrates a universal method to fabricate other defect-rich catalysts for broad applications in energy conversion and storage systems and sensing devices. PMID- 30453231 TI - Patch-based classification of thyroid nodules in ultrasound images using direction independent features extracted by two-threshold binary decomposition. AB - Ultrasound imaging of the thyroid gland is considered to be the best diagnostic choice for evaluating thyroid nodules in early stages, since it has been marked as cost-effective, non-invasive and risk-free. Computer aided diagnosis (CAD) systems can offer a second opinion to radiologists, thereby increasing the overall diagnostic accuracy of ultrasound imaging. Although current CAD systems exhibit promising results, their use in clinical practice is limited. Some of the main limitations are that the majority use direction dependent features so, they are only compatible with static images in just one plane (axial or longitudinal), requiring precise segmentation of a nodule. Our intention has been to design a CAD system which will use only direction independent features i.e., not dependent upon the orientation or inclination angle of the ultrasound probe when acquiring the image. In this study, 60 thyroid nodules (20 malignant, 40 benign) were divided into small patches of 17 * 17 pixels, which were then used to extract several direction independent features by employing Two-Threshold Binary Decomposition, a method that decomposes an image into the set of binary images. The features were then used in Random Forests (RF) and Support Vector Machine (SVM) classifiers to categorize nodules into malignant and benign classes. Classification was evaluated using group 10-fold cross-validation method. Performance on individual patches was then averaged to classify whole nodules with the following results: overall accuracy, sensitivity, specificity and area under receiver operating characteristics (ROC) curve: 95%, 95%, 95%, 0.971 for RF and; 91.6%, 95%, 90%, 0.965 for SVM respectively. The patch-based CAD system we present can provide support to radiologists in their current diagnosis of thyroid nodules, whereby it can increase the overall accuracy of ultrasound imaging. PMID- 30453232 TI - Morphology and phylogeny of two Phialina species (Ciliophora, Haptoria) from northern China. AB - The morphology and infraciliature of two haptorian ciliates, Phialina clampi nov. spec. and P. caudata (Kahl, 1933) nov. comb. (original combination: Lacrymaria caudataKahl, 1933), isolated from sandy sediments of an estuary in Yantai, northern China, were investigated using live observations and protargol preparations. Phialina clampi nov. spec. is distinguished from its congeners by the following traits: extended cells about 80-300 * 18-50 MUm in vivo; a single oval-shaped macronucleus; caudally located contractile vacuole; two types of extrusomes: type I about 20-35 * 1-4 MUm in size, type II 1.5-3.0 * 0.7-1.0 MUm in size and attached to somatic cortex; 27-31 somatic kineties. Phialina caudata is characterized as follows: extended cells about 80-170 * 20-45 MUm in vivo; body radish-shaped, with a sharp posterior end; a single globular to oval macronucleus and micronucleus; subterminal contractile vacuole; 20-24 somatic kineties. Phylogenetic analyses based on SSU rRNA gene sequences indicate that P. caudata clusters with an unidentified Phialina before grouping with Phialina clampi, which form a basal clade of the family Lacrymariidae. PMID- 30453233 TI - Importance of ciliates as food for fish larvae in a shallow sea bay and a large shallow lake. AB - We estimated the consumption of planktonic ciliates by fish larvae in the Vainameri Sea (a shallow semi-enclosed bay of the Baltic Sea) and Lake Vortsjarv (a shallow and eutrophic lake). Our primary hypothesis was that planktonic ciliates constitute a substantial component of the diet of fish larvae in both environments. We also assumed that the contribution of ciliates to larval nutrition is bigger in lacustrine than in marine environment because ciliates are usually more abundant in lakes. The nutrition of field collected larval fish was determined by gut content analysis using epifluorescence microscopy. Our study revealed that ciliates occurred in the alimentary tracts of all fish species examined. We discovered that the consumption of ciliates by first-feeding fish larvae contributed approximately 40 and 60% of their total consumed carbon in the Vainameri and in Vortsjarv, respectively. Ciliates represent essentially important food for fish larvae and sufficient protozoan food may enhance larval growth in the beginning of the exogenous feeding and shorten the most vulnerable period in larval stage before shifting to larger prey. PMID- 30453234 TI - In vivo hippocampal subfield shape related to TDP-43, amyloid beta, and tau pathologies. AB - Despite advances in the development of biomarkers for Alzheimer's disease (AD), accurate ante-mortem diagnosis remains challenging because a variety of neuropathologic disease states can coexist and contribute to the AD dementia syndrome. Here, we report a neuroimaging study correlating hippocampal deformity with regional AD and transactive response DNA-binding protein of 43 kDA pathology burden. We used hippocampal shape analysis of ante-mortem T1-weighted structural magnetic resonance imaging images of 42 participants from two longitudinal cohort studies conducted by the Rush Alzheimer's Disease Center. Surfaces were generated for the whole hippocampus and zones approximating the underlying subfields using a previously developed automated image-segmentation pipeline. Multiple linear regression models were constructed to correlate the shape with pathology measures while accounting for covariates, with relationships mapped out onto hippocampal surface locations. A significant relationship existed between higher paired helical filaments-tau burden and inward hippocampal shape deformity in zones approximating CA1 and subiculum which persisted after accounting for coexisting pathologies. No significant patterns of inward surface deformity were associated with amyloid-beta or transactive response DNA-binding protein of 43 kDA after including covariates. Our findings indicate that hippocampal shape deformity measures in surface zones approximating CA1 may represent a biomarker for postmortem AD pathology. PMID- 30453235 TI - Efficient phloem transport significantly remobilizes cadmium from old to young organs in a hyperaccumulator Sedum alfredii. AB - Our knowledge of cadmium (Cd) in hyperaccumulators mainly concerns root uptake, xylem translocation and foliar detoxification, while little attention has been paid to the role of phloem remobilization. We investigated Cd distribution in different organs of the hyperaccumulating ecotype (HE) of Sedum alfredii and compared its Cd phloem transport with that of the non-hyperaccumulating ecotype (NHE). In HE, results of micro X-ray fluorescence revealed that Cd preferentially accumulated in younger organs compared to the older, and its primary distribution sites changed from parenchyma to vascular/epidermal cells with increased organ age. Strong Cd signals in phloem cells were observed in HE old stems. Pre-stored Cd was readily exported from older to growing leaves, which could be accelerated by leaf senescence. Short-term feeding experiments showed that phloem-mediated Cd transport is rapid and efficient in HE. HE relocated 44% of the total leaf labelled Cd to other organs, while over 90% Cd was retained in labelled leaves of NHE. High Cd was detected in HE phloem exudates but not in those from NHE leaves. In conclusion, Cd phloem transport is efficient and important for dominating the age-dependent Cd allocation in plants of HE S. alfredii. PMID- 30453236 TI - In vitro and in vivo studies of oxidative stress responses against acrylamide toxicity in zebrafish. AB - Acrylamide (AA) is widely used in soil stabilization, water treatment, and industrial products and found in certain foods; however, its toxicity is an expanding global concern. Thus, to reveal the mechanisms involved in the development of, or protection from AA-induced toxicity has important significance. For this purpose, here we explored the intracellular stress response signaling pathways activated by AA exposure in zebrafish model. BRF41 cells derived from zebrafish were exposed to AA, and changes in the expression levels of 31 genes, including endoplasmic reticulum stress response-, oxidative stress response-, osmotic stress response-, and DNA damage and repair-related genes, were analyzed by PCR array. 12 genes upregulated in AA-exposed BRF41 cells were analyzed in zebrafish larvae by quantitative real time PCR, and the expression of all tested oxidative stress response-related genes was upregulated. Spatial expression patterns of these genes were visualized and found that their expression was upregulated and ectopically induced. In addition, AA-induced toxicity in BRF41 cells and the expression of glutathione S-transferase pi 1 (gstp1) in zebrafish larvae were reduced by N-acetylcysteine. Furthermore, inhibition of Gst activity enhanced AA toxicity. From these results, we concluded that the elicited oxidative stress response critically contributes to the protection from AA-induced toxicity. PMID- 30453237 TI - Non-uniform filtration velocity of process gas passing through a long bag filter. AB - Filtration velocity is one of the dominant parameters that determine the pressure drop through a bag filter. Experimental investigation of the air flow pattern around a bag filter inside a bag house is very difficult because of the complexity of the 3-D air flow. For this reason, we numerically investigated flow characteristics along a bag filter in detail. We newly found that the filtration velocity is non-uniform along the axial direction of a long bag filter when the height of the filter is greater than 10 m. The filtration velocity is very small at the bottom of the bag filter but very large at the top. For bag filter lengths of over 10 m, 70% of total inlet flow is filtered in just the top 30% of the long bag filter. This indicates that the top section of the long bag filter could deteriorate faster than the bottom section, making it necessary to develop a new method to avoid the problem. We developed an equation that can help predict the initial pressure drop across long bag filters with different heights, but identical filtration characteristics. PMID- 30453238 TI - Degradation of nitrobenzene by synchronistic oxidation and reduction in an internal circulation microelectrolysis reactor. AB - The degradation of nitrobenzene by synchronistic oxidation and reduction was investigated using an internal circulation microelectrolysis (ICE) reactor with an active volume of 0.018 m3. Compared with a conventional fixed bed reactor with and without aeration, the ICE reactor exhibited a markedly higher nitrobenzene degradation efficiency. The effects of various operational parameters such as reaction time, aeration rate, initial nitrobenzene concentration, initial pH, and a volume ratio of iron and carbon (Fe/C) were also investigated. The optimal operating conditions (reaction time = 60 min, aeration rate = 5 * 10-4 m3/s, initial concentration of nitrobenzene = 300 mg/L, pH = 3.0, Fe/C = 1:1) gave removal efficiencies of nitrobenzene and chemical oxygen demand of 98.2% and 58%, respectively. The biodegradability index of the treated nitrobenzene solution was 0.45, which is 22 times that of the original solution. The reaction intermediates were identified through high-performance liquid chromatography, ultraviolet visible spectroscopy, Fourier transform infrared spectroscopy, gas chromatography mass spectrometry, and ion chromatography. The primary intermediates were determined to be aniline, phenol, and carboxylic acids, indicating that nitrobenzene was synchronously oxidized and reduced in the ICE reactor. Based on the identified intermediates, a possible pathway for nitrobenzene degradation in the ICE reactor is proposed. PMID- 30453239 TI - The binding properties of copper and lead onto compost-derived DOM using Fourier transform infrared, UV-vis and fluorescence spectra combined with two-dimensional correlation analysis. AB - Three dissolved organic matter (DOM) samples were obtained from municipal solid wastes at the initial (C0), high-temperature (C7) and mature (C51) period during composting. Two-dimensional correlation spectroscopy (2D-COS) analysis on Fourier transform infrared (FTIR), ultraviolet visible (UV-vis), and synchronous fluorescence spectra (SFS) were used to investigate the metal binding properties of compost-derived DOM. Synchronous and asynchronous maps of 2D-FTIR-COS of DOM Cu(II) and DOM-Pb(II) were similar, however, the susceptibility and binding sequence of the corresponding spectral region was different. The N-H (amide I), phenolic OH, and C-O of alcohols, ethers, and esters were the most susceptive in the C0, C7, and C51 samples, respectively. 2D absorption COS indicated that the preferential binding with Cu(II) was shown to be at 305 nm for C0, at 236 nm for C7 and C51, and with Pb(II) at 247 nm for C0, at 233 nm for C7 and C51. 2D-SFS COS indicated that protein-like matter showed a higher susceptibility and preferential binding with Cu(II) than humic-like substances. DOM showed a higher complexing affinity with Cu(II) than Pb(II) on the basis of the log K values. Spectral techniques combined with 2D-COS are useful to understand the binding heterogeneities of ligand sites within DOM-Cu(II) or Pb(II) during the composting. PMID- 30453240 TI - State of the art and future challenges for polycyclic aromatic hydrocarbons is sediments: sources, fate, bioavailability and remediation techniques. AB - Polycyclic aromatic hydrocarbons (PAHs) are amongst the most abundant contaminants found in the aquatic environment. Due to their toxicity and carcinogenicity, their sources, fate, behaviour, and cleanup techniques have been widely investigated in the last several decades. When entering the sediment-water system, PAH fate is determined by particular PAH and sediment physico-chemical properties. Most of the PAHs will be associated with fine-grained, organic-rich, sediment material. This makes sediment an ultimate sink for these pollutants. This association results in sediment contamination, and in this manner, sediments represent a permanent source of water pollution from which benthic organisms may accumulate toxic compounds, predominantly in lipid-rich tissues. A tendency for biomagnification can result in critical body burdens in higher trophic species. In recent years, researchers have developed numerous methods for measuring bioavailable fractions (chemical methods, non-exhaustive extraction, and biomimetic methods), as valuable tools in a risk-based approach for remediation or management of contaminated sites. Contaminated sediments pose challenging cleanup and management problems, as conventional environmental dredging techniques are invasive, expensive, and sometimes ineffective or hard to apply to large and diverse sediment sites. Recent studies have shown that a combination of strategies including in situ approaches is likely to provide the most effective long-term solution for dealing with contaminated sediments. Such in situ approaches include, but are not limited to: bioaugmentation, biostimulation, phytoremediation, electrokinetic remediation, surfactant addition and application of different sorbent amendments (carbon-rich such as activated carbon and biochar) that can reduce exposure and limit the redistribution of contaminants in the environment. PMID- 30453241 TI - Perivascular epithelioid cell tumor outgrowth from the liver. AB - INTRODUCTION: Perivascular epithelioid celltumor (PEComa) is a rare mesenchymal neoplasia and can be found in various body sites. On the other hand, hepatic PEComa is very rare, with only a few studies having reported hepatic malignant PEComa. There is no gold standard regarding the use of diagnostic imaging studies. The diagnosis of hepatic PEComa is made by a positive immunohistochemical staining for HMB45 and Melan A. Herein, we discussed the therapeutic and follow-up process of a symptomatic hepatic PEComa case. PRESENTATION OF CASE: A 22-year-old woman presented with a palpable mass in abdomen. A computerized tomographic examination showed a giant hepatic mass of left lobe origin, which was excised surgically. The pathology result was reported as a PEComa. DISCUSSION: The diagnostic approach, treatment modalities, and follow-up procedures are not standard. The main treatment modality for PEComa is surgical excision with adequate surgical margin. CONCLUSION: A longer follow-up is required for patients with hepatic PEComa because the nature of the disease is not entirely clear. PMID- 30453242 TI - Computer assisted total knee arthroplasty for osteoarthritis to secondary to congenital dislocation of the patella: A case report. AB - INTRODUCTION: Late presentation of congenital patella dislocation (CPD) with advanced osteoarthritis is very rare. Total knee arthroplasty (TKA) provides a valid treatment option for adults with CPD who have absence of the femoral sulcus and associated osteoarthritis. TKA for knee with CPD demand more precise technique because TKA correct the unusual pathologies for primary osteoarthritis, eg, tibial external rotation, absence of femoral groove, patella hypoplasia, and realignment of extensor mechanism. CASE PRESENTATION: This case is a CPD with advanced osteoarthritis of left knee in a seventy-two-year old woman. We used a computer assisted navigation for a restoration of alignment, extension and flexion gap balancing, and mediolateral symmetry in the TKA, and operated it successfully. CONCLUSION: TKA is a useful procedure for osteoarthritis of the knee in association with CPD. In hard case of osteoarthritis with CPD, computer assisted navigation is a useful tool for the TKA. PMID- 30453243 TI - Rare documented case report of a retroperitoneal hernia as a complication to an anterior retroperitoneal spinal exposure. AB - INTRODUCTION: Anterior retroperitoneal spinal exposures are widely used today for spinal surgeries. Incisional hernias are a documented complication of anterior spine exposures; however, there are no documented cases of hernias into the dissected retroperitoneal space. We presented this exceptionally rare patient's complication to underscores the critical importance of preserving the peritoneum as a biologic barrier during retroperitoneal spine exposures. PRESENTATION OF CASE: An obese 54 year-old female with a history of two recurrent small bowel obstructions treated conservatively after a retroperitoneal spinal exposure presented with another small bowel obstruction. The patient was taken to the operating room for exploratory laparotomy. Intraoperatively, the patient was found to have multiple loops of small bowel herniated through a small defect in the peritoneum. The small bowel was severely adherent to the retroperitoneum, resulting in torsion and obstruction. DISCUSSION: Based on intraoperative findings, we feel that the retroperitoneal hernia was directly related to the anterior lumbar spine exposure, in which peritoneal disruption is a well-reported phenomenon. There was mention of a peritoneal defect noted during the spine exposure procedure, with attempts to primarily close the defect. CONCLUSION: While disruption of the peritoneum occurs not infrequently during these primarily retroperitoneal procedures, this case should serve as a cautionary tale and reinforce the need for identification and immediate repair of any peritoneal defects that may be created during this type of procedure. PMID- 30453244 TI - Targeting PUMA/Bcl-xL interaction by new specific compounds to unleash apoptotic process in cancer cells. AB - We describe the first examples of small molecules able to disrupt the nanomolar interaction between the pro-apoptotic protein PUMA and its anti-apoptotic counterpart BcL-xL in malignant cells. Based on molecular modelling studies, we propose a rationale to this result, through a new "bottle-opener"-type strategy which could be of general use in the area of protein-protein interaction studies. PMID- 30453245 TI - Discovery of novel arylethenesulfonyl fluorides as potential candidates against methicillin-resistant of Staphylococcus aureus (MRSA) for overcoming multidrug resistance of bacterial infections. AB - The multidrug-resistant Staphylococcus aureus (MRSA) is one of the most prevalent human pathogens involved in many minor to major disease burdens throughout the world. Inhibition of biofilm formation is an attractive strategy to treat diseases associated with MRSA infection. In the present investigation, a series of functional group diverse (hetero)aryl fluorosulfonyl analogs were designed, synthesized and tested as antibacterial agents against Staphylococcal spp., and as anti-biofilm candidates. Compounds 8, 15, and 67 were found to possess potent in vitro antibacterial activity among this class of sulfonyl fluorides (MIC = 0.818 +/- 0.42, 0.840 +/- 0.37 and 0.811 +/- 0.37 MUg/mL respectively). The analogs 8, 15, 36, and 67 exhibited outstanding anti-biofilm properties compared to other available synthetic antibiotics. The efficacy of synthetic analogs displayed membrane-damaging effect and they are also validated by cellular content release assay. The insight physiological changes were explored by studying the intracellular redox activities through changing cyclic voltammetric (CV) method. The compounds 8, 15, 22, 32, 36, 51, and 67 were found to participate in the interfering in the electron transport chain (ETC) of MRSA. The analogs 8, 15, and 67 possess great potentiality for discovery and development of anti-staphylococcal drugs to treat the MRSA infections. PMID- 30453246 TI - Thiazole, thio and semicarbazone derivatives against tropical infective diseases: Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria. AB - Thiazole, thiosemicarbazone and semicarbazone moieties are privileged scaffolds (acting as primary pharmacophores) in many compounds that are useful to treat several diseases, mainly tropical infectious diseases. In this review article, we critically analyzed the contribution of these scaffolds to medicinal chemistry in the last five years, focusing on tropical infectious diseases, such as Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria. We also present perspectives for their use in drug design in order to contribute to the development of new drugs. PMID- 30453247 TI - Fluoroquinolone-isatin hybrids and their biological activities. AB - Hybridization of different pharmacophores from various bioactive substances into a single molecule is the potential weapon to prevent the drug resistance since this strategy can provide new leads with complimentary activities and/or multiple pharmacological targets. Fluoroquinolone and isatin are common pharmacophores, and their derivatives possess various biological activities. Obviously, hybridization of these two pharmacophores into one molecule may result in novel candidates with broader spectrum, higher efficiency, lower toxicity as well as multiple mechanisms of action. Therefore, fluoroquinolone-isatin hybrids have the potential for clinical deployment in the control and eradication of various diseases. This review covers the recent advances of fluoroquinolone-isatin hybrids as potential anti-bacterial, anti-tubercular, anti-viral and anti-cancer agents. The structure-activity relationship is also discussed to pave the way for the further rational development of this kind of hybrids. PMID- 30453248 TI - Design, synthesis and biological evaluation of novel 1-phenyl phenanthridin-6(5H) one derivatives as anti-tumor agents targeting TOPK. AB - T-lymphokine-activated killer cell-originated protein kinase (TOPK) is a serine threonine mitogen-activated protein kinase that is highly expressed in many types of human cancer. Due to its important role in cancer progression, TOPK is becoming an attractive target in chemotherapeutic drug design. In this study, a series of 1-phenyl phenanthridin-6(5H)-one derivatives have been identified as a novel chemical class of TOPK inhibitors. Some of them displayed very potent anti cancer activity with IC50s less than 100 nM, superior than reference compound OTS964. The most potent compound, 9g suppressed the growth of cancer cells by apoptosis and specifically inhibited the activities of TOPK. Oral administration of 9g effectively suppressed tumor growth with TGI >79.7% in colorectal cancer xenograft models, demonstrating superior efficacy compared to OTS964. Pharmacokinetic studies reveal its good oral bioavailability. Our findings therefore show that 9g is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic agent against colorectal cancer. PMID- 30453249 TI - The use of proteomic technologies to study molecular mechanisms of multidrug resistance in cancer. AB - Multidrug resistance (MDR), defined as the cross-resistance of cancer cells toward a broad range of chemotherapeutic agents, is a universal and intractable problem in chemotherapy. The understanding of MDR mechanisms is essential to discover the potential biomarkers for predicting multidrug resistance and more importantly, tackling and preventing multidrug resistance. Multiple technologies have been used to study MDR mechanisms including comparative genomic hybridization, DNA array, differential display RT-PCR and various immunoassays. Compared with these approaches, proteomic technologies allow a high through-put analysis of protein detection, protein quantification and protein interaction with high accuracy. With the rapid development of proteomic studies in recent years, proteomic technologies have made substantial contributions to the characterization of MDR mechanisms including MDR-related protein detection and quantification, as well as the characterization of drug-transporter binding sites. This review offers a comprehensive illustration of MDR, proteomic technologies and the discoveries made in understanding MDR mechanisms using proteomic approaches. PMID- 30453250 TI - Biomass production and biochemical profiles of a freshwater microalga Chlorella kessleri in mixotrophic culture: Effects of light intensity and photoperiodicity. AB - In this work, different light conditions (light intensity and photoperiodicity) were set up to investigate the impact of light on growth, chemical compositions and fatty acid profiles of Chlorella kessleri in mixotrophic cultures. Results indicated that C. kessleri could absorb and utilize glucose rapidly when light intensity was <= 90 uE m-2 s-1, and a maximum algal biomass of 1.17 g L-1 was obtained in the cultures with 2 g L-1 glucose at a light intensity and light/dark (L/D) cycle of 90 uE m-2 s-1 and 20L:4D, respectively. Additionally, this alga would accumulate a large amount of chlorophyll a (about 30 mg g-1) in the mixotrophic cultures under a low light intensity (<=90 uE m-2 s-1), and the algal chemical compositions changed with light intensity and photoperiodicity. Results of fatty acid profiles suggested that the algal biomass could be used as animal feeds or a good-quality biodiesel feedstock. PMID- 30453251 TI - Effect of ammonium nitrogen on microalgal growth, biochemical composition and photosynthetic performance in mixotrophic cultivation. AB - To enhance microalgal growth and optimize ammonium utilization, the effect of ammonium on microalgal growth, biochemical composition and photosynthetic performance were investigated by mixotrophic cultivation of microalga Spirulina platensis comparing with autotrophic cultivation. The results indicated that elevated ammonium significantly affected the microalgal growth, but the microalga in mixotrophic cultivation showed better growth and stronger tolerance to higher ammonium. The microalgal proteins were increased by increasing nitrogen concentration. The synthesis of microalgal carbohydrates was inhibited by higher ammonium, especially in mixotrophic cultivation. The addition of ammonium decreased the microalgal lipids in autotrophic cultivation but increased microalgal lipids in mixotrophic cultivation. Ammonium negatively affected the microalgal photosynthetic performance. The inhibition was intensified by elevated ammonium, inducing stronger photosystem protection mechanism, particularly in mixotrophic cultivation. The rate of ammonium inhibition to the microalgal photosystem was quick in the early stage by decreasing electron transport rate of PS II. PMID- 30453252 TI - Production of natamycin by Streptomyces gilvosporeus Z28 through solid-state fermentation using agro-industrial residues. AB - At present, submerged fermentation (SmF) is the unique approach for natamycin production. This study aims to propose a strategy for natamycin production through solid-state fermentation (SSF). The maximum natamycin concentration (9.62 mg.gds-1) was obtained with a substrate mixture containing wheat bran, rapeseed cake, rice hull and crude glycerol in a 5 L flask at 28 degrees C, and the initial moisture content and inoculum size was set as 70% and 15%, individually. A 30 L scale-up fermentation showed similar parameters and produced 9.27 mg.gds-1 natamycin at the 8th day. Besides, natamycin could be continuously produced by repeated-batch fermentation for 5 cycles through SSF. Compared to SmF, SSF led to a 50.05% cost reduction of raw materials, less energy consumption and waste water discharge, which was of great significance in industrial fermentation. To our best knowledge, this is the first report on natamycin production through SSF process. PMID- 30453253 TI - Plasmatic and chamber-specific modulation of cardiac microRNAs in an acute model of DOX-induced cardiotoxicity. AB - BACKGROUND: Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo. METHODS: Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 MUM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs. RESULTS: Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug. CONCLUSIONS: This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset. PMID- 30453254 TI - Lavender oil (Lavandula angustifolia) attenuates renal ischemia/reperfusion injury in rats through suppression of inflammation, oxidative stress and apoptosis. AB - Renal ischemia/reperfusion (I/R) injury following kidney transplantation has been found to be a great clinical problem owing to initiation of acute inflammatory responses and subsequently rapid loss of kidney function. It is well known that lavender oil exhibits an extensive spectrum of pharmacological and biochemical activities. The purpose of this study was to clarify molecular targets of lavender in treatment of this disease. Male Wistar rats weighing 200-250 g were divided into three major groups: sham, I/R, and I/R + different doses of lavender oil (L1:50 mg/kg, L2: 100 mg/kg, and L3: 200 mg/kg). A rat model of renal I/R (45 min ischemia and 24 h reperfusion) was created and lavender was administrated at 1 h after the beginning of reperfusion (i.p). Activities of antioxidant enzymes such as SOD, GPX, and CAT, and lipid peroxidation were evaluated. The expression of inflammatory cytokines such as TNFalpha, IL1beta, and IL10 was determined by IHC and ELISA assay. Apoptosis activity and tissue damage were evaluated by TUNEL and H & E staining, respectively. Our results showed that lavender oil markedly restored activities of antioxidant enzymes and reduced lipid peroxidation (P < 0.05). Lavender significantly decreased levels of TNFalpha and IL1beta and increased level of IL10 in a dose-dependent manner (P < 0.05). Lavender reduced TUNEL positive cells in a dose-dependent manner. However, lavender reduced damage to peritubular capillaries and contributed to preservation of normal morphology of renal cells. In sum, our findings establish a fundamental foundation for future drug industry to decrease the rates of rejection in kidney transplant patients. PMID- 30453255 TI - Virtual water quality monitoring at inactive monitoring sites using Monte Carlo optimized artificial neural networks: A case study of Danube River (Serbia). AB - Rationalization of water quality monitoring stations nowadays is applied in many countries. In some cases, missing data from abandoned/inactive stations, spatial and temporal, could be very important, hence the use of artificial neural networks (ANNs) for virtual water quality monitoring at inactive monitoring sites was investigated. The aim was to develop single-output and simultaneous ANNs for the spatial interpolation of 18 water quality parameters at single- and multi inactive monitoring sites on Danube River course through Serbia. Those different modeling approaches were considered in order to determine the most suitable combination of models. The variable selection and sensitivity analysis in the case of simultaneous models were performed using a modified procedure based on Monte Carlo Simulations (MCS). In general, the multi-target models tend to be more accurate than single target ones, while single output models outperform the simultaneous ones. Hence, for particular monitoring network and set of water quality parameters the optimal combination of models must be defined based on model's accuracy and computational effort needed. The MCS selection procedure has proved to be efficient only in the case of simultaneous multi-target model. MCS based analysis of input-output interactions has shown all significant interactions in the case of simultaneous single-target are grouped as a complex cluster of interactions, where majority of inputs influence on several outputs. In the case multi-target model those interactions were portioned in five separate clusters, there majority of them mimic the input-output interactions that are present in single output models. The modeling strategy for study area was proposed on the basis of the performance of created models (mean average percentage error < 10%): simultaneous multi-target model for pH, alkalinity, conductivity, hardness, dissolved oxygen, HCO3-, SO42- and Ca, single-output multi-target models for temperature and Cl-, simultaneous single-target models for Mg and CO2, single output single target models for NO3-. PMID- 30453256 TI - Current ambient and elevated ozone effects on poplar: A global meta-analysis and response relationships. AB - The effects of current and future elevated O3 concentrations (e[O3]) were investigated by a meta-analysis for poplar, a widely distributed genus in the Northern Hemisphere with global economic importance. Current [O3] has significantly reduced CO2 assimilation rate (Pn) by 33% and total biomass by 4% in comparison with low O3 level (charcoal-filtered air, CF). Relative to CF, an increase in future [O3] would further enhance the reduction in total biomass by 24%, plant height by 17% and plant leaf area by 19%. Isoprene emissions could decline by 34% under e[O3], with feedback implications in reducing the formation of secondary air pollutants including O3. Reduced stomatal conductance and lower foliar area might increase runoff and freshwater availability in O3 polluted areas. Higher cumulated O3 exposure over a threshold of 40 ppb (AOT40) induced larger reductions in Pn, total biomass and isoprene emission. Relationships of light-saturated photosynthesis rates (Asat), total biomass and chlorophyll content with AOT40 using a global dataset are provided. These relationships are expected to improve O3 risk assessment and also to support the inclusion of the effect of O3 in models addressing plantation productivity and carbon sink capacity. PMID- 30453257 TI - Sunlight induced aggregation of dissolved organic matter: Role of proteins in linking organic carbon and nitrogen cycling in seawater. AB - Organic matter export from the euphotic zone is a key component of oceanic carbon (C) and nitrogen (N) cycles. Although interactions between these two cycles are important, studies on geochemical processes to directly connect them are limited. Here we show that sunlight can induce chemical aggregation of dissolved organic matter (DOM) into high N containing photo-aggregates. The size of microgels in natural coastal seawaters increased by18~25% compared to corresponding dark controls. Within a relatively short time (1 h), the C and N sequestered into the photo-aggregates accounted for 10% and 13% of the bulk particulate C and N, respectively. The N/C ratio of the photo-aggregates was two times higher after sunlight irradiation. Furthermore, we show that the aggregation process was dependent on reactive oxygen species (ROS). To accommodate for the different organic material in the marine environment, we monitored the particle size in various extracellular polymeric substances (EPS) and model biopolymers using flow cytometry, dynamic laser scattering, and scanning electron microscopy. We found that proteins play important roles in light-induced aggregation, which is in contrast to previous views that sunlight can break down DOM and interrupt aggregation. The photo-flocculation process involving organic N provides new insights into DOM assembly, bioavailability, and sedimentation, and thus potentially link the C and N cycles. PMID- 30453258 TI - Persistent impact of human activities on trace metals in the Yangtze River Estuary and the East China Sea: Evidence from sedimentary records of the last 60 years. AB - Three sediment cores taken from the Yangtze River Estuary (YRE) and the East China Sea (ECS) in 2016 were analyzed for trace metals (Pb, Zn, Cu, Cr and As), major elements (Al, Fe and Mn), sediment composition, chemical properties (Eh and pH), and natural/artificial radionuclides (210Pb/137Cs) to decipher the high resolution historical variation in anthropogenic metals over the past 60 years. The results showed that anthropogenic Pb was primarily derived from atmospheric deposition, while anthropogenic Zn, Cu and As were carried out by fluvial discharge. In the YRE, the recent decrease in sedimentary metals could be largely a result of intensified erosion, which was triggered by the construction of dams in particular the Three Gorges Dam (TGD) in 2003 and soil-conservation projects. In comparison, sedimentary records in the deposition-dominated environment of the ECS showed that anthropogenic Pb and Cr began to gradually increase following 1970, but a remarkable increase in anthropogenic Zn and Cu occurred in 1990, probably reflect the different origins and dispersion pathways of these elements. Anthropogenic Pb and Cr exhibited a sharp decrease near early 2000s due to increasing investment in treating pollution. Being sensitive to the substantial reduction in riverine particulate flux of Zn and Cu from the Yangtze River, the concentrations of anthropogenic Zn and Cu in the cores decreased by 5-27% in 2005 2016. Furthermore, a prominent increase trend of As record after 1990, probably due to the excessive pesticides used in agricultural activity. PMID- 30453259 TI - Footprints from the past: The influence of past human activities on vegetation and soil across five archaeological sites in Greenland. AB - Climate change has irrevocable consequences for the otherwise well-preserved archaeological deposits in the Arctic. Vegetation changes are expected to impact archaeological sites, but currently the effects are poorly understood. In this article we investigate five archaeological sites and the surrounding natural areas along a climate gradient in Southwest Greenland in terms of vegetation types, above- and below-ground biomass, soil geochemistry and spectral properties. The investigations are based on data from site-sampling and optical remote sensing from an unmanned aerial vehicle (UAV) and satellites. Results show that the archaeological sites are dominated by graminoids with approximately two times more above- and below-ground biomass than the surrounding areas, where the vegetation is more heterogeneous. This difference is associated with a 2-6 times higher content of plant available phosphorus and water extractable nitrate and ammonium in the archaeological deposits compared to the surrounding soil. Furthermore, the vegetation at archaeological sites is less affected by the regional climate variations than the surrounding natural areas. This suggests that soil-vegetation interactions at archaeological sites are markedly different from the natural environment. Thus, the long-term vulnerability of buried archaeological remains cannot be assessed based on existing projections of Arctic vegetation change. Finally, the study demonstrates that vegetation within archaeological sites has distinct spectral properties, and there is a great potential for using satellite imagery for large scale vegetation monitoring of archaeological sites and for archaeological prospection in the Arctic. PMID- 30453260 TI - Field-based evidence for enrichment of antibiotic resistance genes and mobile genetic elements in manure-amended vegetable soils. AB - The increasing prevalence of antibiotic resistance genes (ARGs) and antibiotic resistant bacteria (ARB) in the soil environment represents a serious threat to public health. In this study, the diversity and abundance of ARGs and mobile genetic elements (MGEs) in different years of manure-amended vegetable soils were investigated. A total of eight genes, including four tetracycline resistance genes: tetW, tetM, tetO and tetT; two sulfonamide resistance genes: sul1 and sul2; and two MGEs: intI1 and intI2; were quantified in ten vegetable soils. The relative abundance of ARGs in soils amended with manure was significantly higher than that in soils without manure application. The relative abundance of the intI1 and intI2 genes had significantly positive correlations with the relative abundance of the tetW, tetO, sul1 and sul2 genes. Under different concentrations of antibiotics, the resistant bacteria rates of manure-amended soil were much higher than the control soil. Bacillus and Chryseobacterium, more likely to be multi-drug-resistant bacteria, were detected in both two antibiotics. Moreover, the significant correlation was found between the concentrations of Cu and Zn and the ARGs. Our findings provide empirical evidence that the dissemination risk of ARGs and ARB in long-term manure-amended vegetable soils, which might promote to the development of effective strategies to reduce the spread of ARGs in agro ecosystems. PMID- 30453261 TI - Factors governing variations of provincial consumption-based water footprints in China: An analysis based on comparison with national average. AB - Although several studies have revealed that the consumption-based water footprint (WF) is unequal in space, the contributing factors to this spatial inequality have rarely been quantified. This study addresses this need by quantifying the effects that determine the difference of one region's WF per capita and a benchmark average value. A decomposition framework is developed. Using provincial water uses in China as a case study, this framework breaks down the deviation of one province's per capita WF from the national average value into effects of five key factors, namely, the actual-requisite WF difference, direct water use intensity, economic production structure, consumption level and consumption structure. The structural decomposition analysis is adapted to investigate differences between the provincial WFs and national average value, in contrast to its conventional use for examining changes of an environmental variable over time. The results indicate that the drivers of a high or low WF level in different provinces are diverse. The dominant factors are most often the direct water use intensity and consumption level, which may contribute over 1000 and 400m3 of per capita WFs per year, respectively. The results assist in the diagnosis of per capita WF for each province. Policy suggestions highlighting feasible institutional or technological arrangements are made for each province, which have the potential to reduce consumption-based WF inequality without compromising living standards of inhabitants. PMID- 30453262 TI - The human health risk estimation of inhaled oil spill emissions with and without adding dispersant. AB - Airborne toxic compounds emitted from polluted seawater polluted after an oil spill raise health concerns when inhaled by humans or other species. Inhalation of these toxic compounds as volatile organic compounds (VOCs) or airborne fine particulate matter (PM) may cause serious pulmonary diseases, including lung cancer. Spraying chemical dispersants to enhance distribution of the crude oil into the water was employed extensively during the Deepwater Horizon spill. There is some evidence that dispersion of the crude oil decreased the emission rate of the VOCs but increased the emission rates of fine PM that may carry toxic compounds. In this study, the cancer risks and non-cancer hazards of the detected VOCs and particulates for spill-response workers were estimated with and without use of dispersant under action of breaking waves. A subchronic exposure scenario was modeled to address the inhalation health threat during initial phases of an oil spill response. A dosimetry model was used to estimate regional deposition of PM. Use of dispersant reduced benzene cancer risks from 57 to 37 excess lifetime cancer cases per million for 1 h of daily exposure that continues for 3 months. Adding dispersant resulted in emissions reductions of the lighter VOCs (up to 30% lower). However, hazard quotients (HQs) of the non-carcinogenic VOCs even after dispersant addition were above 1 meaning there are serious concerns about exposure to these VOCs. Inhalation of airborne particles emitted from the slick containing dispersant increased the total mass of deposited particles in upper respiratory regions compared to the slick of crude oil only. This study showed the application of dispersant onto the pollution slick increased the total mass burden to the human respiratory system about 10 times, an exploratory HQ analysis is presented to evaluate the potential health risk. PMID- 30453263 TI - Quick start-up and stable operation of a one-stage deammonification reactor with a low quantity of AOB and ANAMMOX biomass. AB - In this study, a quick start-up of one-stage deammonification in an immobilized aerobic ammonium oxidizing bacteria (AOB) and anoxic ammonium oxidizing (ANAMMOX) bacteria up-flow reactor (IAAR) was successfully achieved. With the aid of gel layers, AOB and ANAMMOX bacteria had excellent spatial distribution, theoretically meeting dissolved oxygen requirements for the simultaneous processes of aerobic and anaerobic ammonium oxidizing. The results indicated that an IAAR containing 0.4 g-VSS L-1 immobilized biomass achieved a nitrogen removal rate (NRR) of 0.53 kg-N m-3 d-1 after only 10 days of operation and subsequently reached a maximum nitrogen removal rate (NRRmax) of 3.73 kg-N m-3 d-1. The micro profiles of DO and pH were measured using microelectrodes to help understand the stratification of the microbial processes inside the gel layers. The distribution of AOB and ANAMMOX bacteria within the gel layers was verified using fluorescence in situ hybridization (FISH) analysis. The community distribution in the FISH three-dimensional images closely corresponded to the micro-profiles of DO concentration and pH, enabling rapid adaptation and stable operation of the reactor seeded with a quite low quantity of biomass. PMID- 30453264 TI - Heterogeneous fenton-like degradation of ofloxacin over sludge derived carbon as catalysts: Mechanism and performance. AB - In this study, heterogeneous Fenton-like degradation of ofloxacin (OFX) was investigated by sludge derived carbon (SC). The effects of SC catalyst, temperature and pH on the efficiency of ofloxacin degradation were investigated. SC treated with sulfuric acid (SC-H2SO4) performed high catalytic activity, indicating that sulfate group produced low pH of the surface and was beneficial for heterogeneous Fenton-like degradation. The removal of ofloxacin and TOC was 91.5% and 62.3%, respectively, after 180 min adsorption and 540 min oxidation, at pH 6 and a dosage of 138 mg L-1 H2O2. It was found that OFX conversion increased with the decrease of pH and OFX was degraded under the wide range of pH (3-6) by SC-H2SO4. These promising results clearly demonstrate the potential of the heterogeneous Fenton-like process for the effective degradation of ofloxacin by SC-H2SO4. Based on intermediated products identified by gas chromatography-mass spectrometry, a possible OFX oxidation pathway in Fenton-like reaction was proposed. PMID- 30453265 TI - Environmental and spatial variables determine the taxonomic but not functional structure patterns of microbial communities in alpine grasslands. AB - There is considerable debate regarding how the taxonomic diversity of microbial communities relates to the functional diversity across space while similar questions have been explored in macro-organism communities. Here, we investigated the taxonomic and functional diversity patterns of soil microbial communities by coupling the data obtained from marker genes sequencing and functional gene surveys. Meanwhile, we evaluated the relative effects of environment and geographic distance on shaping these patterns in alpine grasslands of northern China. Although the taxonomic diversity and composition of microbial communities varied across sites, we found no consistent changes in the functional structure. Both the environmental factors and geographic distance concurrently affected the taxonomic diversity patterns but they had no effects on the spatial variations in functional genes. The functional alpha diversity was weakly correlated to the taxonomic alpha diversity across sites. Moreover, we found no significant relationship between the taxonomic and functional composition similarity among microbial communities. Together, our results provide evidence that spatial variation in microbial functions could be independent of their variations in taxonomic diversity. Even the drivers of spatial variations in the functional structure could be totally different from those of taxonomic variations such as environmental differences and dispersal limitation. Our findings suggest that spatial variations of microbial function structure within a community would not follow the variations of taxonomic structures due to different drivers between both of them over space. PMID- 30453266 TI - Effect of phthalates on development, reproduction, fat metabolism and lifespan in Daphnia magna. AB - Phthalates are used as plasticizers to increase durability, resistivity and flexibility of plastic materials. The commonly used phthalate, diethylhexyl phthalate (DEHP) is used in different plastic materials like food packaging, toys and medical devices. DEHP has been linked to different toxicities in humans as well as in animals, and as a consequence other phthalates, including dibutyl phthalate (DBP) and diethyl phthalate (DEP) are being introduced. The increased use of phthalates has resulted in contamination of aquatic ecosystem and it directly threatens the aquatic life. In this study, we analyzed the effects of three phthalates DEHP, DEP and DBP using freshwater organism Daphnia magna. Although, exposure of the three phthalates at 1 and 10 MUM did not result any lethality and hatching delay, the chronic exposure for 14 days resulted in reduction of body length. There was enhanced fat accumulation on exposure to all the phthalates, as indicated by oil red O staining. qRT-PCR analysis of genes involved in fat metabolism suggests that the increase in fat content could be due to inhibition of absorption and catabolism of fatty acids. Reproduction analysis showed that DBP and DEP did not alter fecundity but surprisingly, DEHP at 1 MUM increased reproduction by 1.5 fold compared to control group. Phthalates also showed negative effect on lifespan as DEP at 10 MUM and DBP at both 1 and 10 MUM significantly reduced the lifespan. Our data indicates that along with the banned phthalate DEHP, the other substitute phthalates DEP and DBP could also have detrimental effect on aquatic organisms. PMID- 30453267 TI - A prolonged dry season and nitrogen deposition interactively affect CO2 fluxes in an annual Mediterranean grassland. AB - Mediterranean annual grasslands are species-diverse ecosystems of high economic and ecological value. CO2 and water fluxes in these grasslands are triggered by the first rains in autumn, after a long hot and dry summer. Climate change scenarios project altered rainfall patterns, such as prolonged dry season into the autumn, while simultaneously nitrogen (N) deposition is increasing globally. However, how these global change drivers will interact to affect Mediterranean grassland CO2, water fluxes and productivity is still unclear. In a greenhouse experiment, we subjected the seedbank of an annual Mediterranean grassland to a factorial treatment, by prolonging the dry season by 0 days (i.e. no autumn drought), 50 days and 100 days and crossing these drought treatments with two levels of N deposition: no N and N addition. A delayed onset of the rain season, i.e., a prolonged dry season, induced lower CO2 and water fluxes throughout the growing season and a lower aboveground biomass by the end of the study period. However, N addition attenuated the effects on NEE, Reco and GPP, but did not affect aboveground biomass or functional group composition. A prolonged dry season also lowered the productivity of forbs, the dominant functional group in our grassland. Our results anticipate important effects of interacting global change drivers on Mediterranean grassland functioning. PMID- 30453268 TI - Mapping and evaluating cultivated land fallow in Southwest China using multisource data. AB - Accurately and effectively mapping and evaluating cultivated land fallow has already become an important issue that has received much attention in China. However, systematically analysing regional cultivated land fallow remains inadequate because current studies have mainly focused on quantifying cultivated land fallow using statistical data based on administrative units or a single aspect of cultivated land fallow using high or medium spatial resolution images at the local or regional scales. Against the existing shortcomings, this study first developed an integrated index of cultivated land fallow (ILF) for mapping and evaluating cultivated land fallow in Southwest China using multisource spatial data. The performance of the ILF was validated by comparing its results with Google Earth images and ecological carrying capacity of cultivated land (TEC). And the spatial distribution of cultivated land fallow in Southwest China was evaluated at the regional, provincial and metropolitan scales. The results revealed that the ILF provided a reliable evaluation of cultivated land fallow in Southwest China. Compared to the Google earth images, the pixel with the high ILF value was the cultivated land that was found to prioritize fallow. There was also a significant correlation between ILF and TEC at the prefectural level in Sichuan, with an R2 value >0.65. In Southwest China, the cultivated land related to highly appropriate fallow (HAF) accounted for 5.73% of the total cultivated land in 2010. The cultivated land related to inappropriate fallow (IF) accounted for 53.26% and 37.36% in Sichuan and Chongqing but only comprised 22.90% and 19.72% in Yunnan and Guizhou, respectively. Special attention needs to be paid to Guiyang and Kunming, where the HAF made up 25.38% and 17.48% of their total cultivated land, respectively. Human activities have been found to already become the most important impact factors for cultivated land fallow in Southwest China. This study is especially valuable for providing a scientific basis for policy making on viable cultivated land fallow policy in Southwest China. PMID- 30453270 TI - Comparison of visual analysis, non-overlap methods, and effect sizes in the evaluation of parent implemented functional assessment based interventions. AB - We used an existing body of research (i.e., parent implemented functional assessment based interventions) to examine visual analysis features and processes and evaluate the reliability of two frequently used non-overlap indices (NAP & Tau-U) and a novel effect size index-the between-case standardized mean difference (BC-SMD). Results indicated that visual analysis terms and procedures were inconsistently used across studies. Further, there was limited agreement between the non-overlap indices and independent visual analysis. Results regarding the BC-SMD were inconclusive given only 5 of the 15 studies were eligible for analyses for different dependent variables. Our results suggest that visual analysis standards are needed by which single case researchers analyze and report their results. Further, additional research is needed refining SCR effect sizes, which can be used to describe the magnitude of change within and across SCR studies with functional relations. PMID- 30453269 TI - Phosphoproteome Profiling Reveals Multifunctional Protein NPM1 as part of the Irradiation Response of Tumor Cells. AB - To fight resistances to radiotherapy, the understanding of escape mechanisms of tumor cells is crucial. The aim of this study was to identify phosphoproteins that are regulated upon irradiation. The comparative analysis of the phosphoproteome before and after irradiation brought nucleophosmin (NPM1) into focus as a versatile phosphoprotein that has already been associated with tumorigenesis. We could show that knockdown of NPM1 significantly reduces tumor cell survival after irradiation. NPM1 is dephosphorylated stepwise within 1 hour after irradiation at two of its major phosphorylation sites: threonine-199 and threonine-234/237. This dephosphorylation is not the result of a fast cell cycle arrest, and we found a heterogenous intracellular distribution of NPM1 between the nucleoli, the nucleoplasm, and the cytoplasm after irradiation. We hypothesize that the dephosphorylation of NPM1 at threonine-199 and threonine 234/237 is part of the immediate response to irradiation and of importance for tumor cell survival. These findings could make NPM1 an attractive pharmaceutical target to radiosensitize tumor cells and improve the outcome of radiotherapy by inhibiting the pathways that help tumor cells to escape cell death after gamma irradiation. PMID- 30453271 TI - Cushing response-based warning system for intensive care of brain-injured patients. AB - OBJECTIVE: Cushing response (CR) is categorized. Wavelet transform (WT) and decision tree (DT) are utilized to analyze physiological signals from neurocritical patients. A warning model is built for recognition of CR, real-time evaluation of intracranial condition and prediction of neurological outcome. METHODS: Physiological signals of neurocritical patients are preprocessed by WT and compressed by linear regression. An algorithm labels each segment as pathological, physiological, negative or uncertain CR. The DT identifies CR. Continuous data input to the established DT predicts condition at that moment and following outcome. RESULTS: From 33 neurocritical patients, 422,524 sets of physiological signals were collected. The cross-validation scores of DT ranged from 0.562 to 0.579 with averaged accuracy rate 60.6% (3.5-98.1%). The model correctly predicted the outcome of the training group, 87.9% in accuracy. The ratios of pathological CR were 9.3 +/- 16.6%, 74.2 +/- 29.7% and 99.7 +/- 0.3% in patients of good, coma and death groups, respectively. The prediction accuracy for a test set of 103 patients reached 81.6%. CONCLUSIONS: Cushing response categorization helps in identifying critical conditions and predicting outcome. SIGNIFICANCE: A novel concept of four categories of Cushing response is proposed to represent broader ranges of intracranial change. PMID- 30453273 TI - Xenophyophores (Rhizaria, Foraminifera) from the Eastern Clarion-Clipperton Zone (equatorial Pacific): the Genus Psammina. AB - Xenophyophores are important megafaunal organisms in the abyssal Clarion Clipperton Zone (CCZ; equatorial Pacific), a region hosting commercially significant deposits of polymetallic nodules. Previous studies assigned those with attached, fan-like tests to Psammina limbata, a species described from the central CCZ based on morphology. Here, we redescribe the holotype of P. limbata and then show that limbata-like morphotypes collected in the eastern CCZ include three genetically distinct species. Psammina aff. limbata is closest morphologically to P. limbata. The others are described as P. microgranulata sp. nov. and P. rotunda sp. nov. These fan-shaped species form a well-supported clade with P. tortilis sp. nov., a morphologically variable species exhibiting features typical of both Psammina and Semipsammina. A second clade containing Psammina sp. 3, and two species questionably assigned to Galatheammina branches at the base of this group. The genus Psammina includes another 9 described species for which there are no genetic data, leaving open the question of whether Psammina as a whole is monophyletic. Our study increases the number of xenophyophore species described from the eastern CCZ from 8 to 11, with a further 25 morphotypes currently undescribed. Many additional species of these giant foraminifera undoubtedly await discovery in abyssal settings. PMID- 30453272 TI - Fine structure and Molecular Phylogenetic Position of Two Marine Gregarines, Selenidium pygospionis sp. n. and S. pherusae sp. n., with Notes on the Phylogeny of Archigregarinida (Apicomplexa). AB - Archigregarines are a key group for understanding the early evolution of Apicomplexa. Here we report morphological, ultrastructural, and molecular phylogenetic evidence from two archigregarine species: Selenidium pygospionis sp. n. and S. pherusae sp. n. They exhibited typical features of archigregarines. Additionally, an axial row of vacuoles of a presumably nutrient distribution system was revealed in S. pygospionis. Intracellular stages of S. pygospionis found in the host intestinal epithelium may point to the initial intracellular localization in the course of parasite development. Available archigregarine SSU (18S) rDNA sequences formed four major lineages fitting the taxonomical affiliations of their hosts, but not the morphological or biological features used for the taxonomical revision by Levine (1971). Consequently, the genus Selenidioides Levine, 1971 should be abolished. The branching order of these lineages was unresolved; topology tests rejected neither para- nor monophyly of archigregarines. We provided phylogenies based on LSU (28S) rDNA and near complete ribosomal operon (concatenated SSU, 5.8S, LSU rDNAs) sequences including S. pygospionis sequences. Although being preliminary, they nevertheless revealed the monophyly of gregarines previously challenged by many molecular phylogenetic studies. Despite their molecular-phylogenetic heterogeneity, archigregarines exhibit an extremely conservative plesiomorphic structure; their ultrastructural key features appear to be symplesiomorphies rather than synapomorphies. PMID- 30453274 TI - The Response of Three Southern Ocean Phytoplankton Species to Ocean Acidification and Light Availability: A Transcriptomic Study. AB - Ocean acidification (OA) and high light was found to negatively affect the Antarctic key species Phaeocystis antarctica, Fragilariopsis kerguelensis and Chaetoceros debilis. To unravel the underlying physiological response at the transcriptomic level, these species were grown under ambient and elevated pCO2 combined with low or high light. RNA sequencing revealed that the haptophyte was much more tolerant towards OA than the two diatoms as only these showed distinct OA-dependent gene regulation patterns. Under ambient pCO2, high light resulted in decreased glycolysis in P. antarctica. Contrastingly, upregulation of genes related to cell division and transcription as well as reduced expression of both cata- and anabolic carbon related pathways were seen in C. debilis. OA in combination with low light led to reduced respiration, but also surprisingly to higher expression of genes involved in light protection, transcription and translation in C. debilis. Though not affecting P. antarctica, OA combined with high light caused also photosensitivity in both diatoms. As additional response reallocation of carbon to lipids was found in C. debilis under these conditions. Overall, we conclude that P. antarctica is better adapted than the two diatoms to OA and high light. PMID- 30453275 TI - Electrochemical oxidation of gaseous benzene on a Sb-SnO2/foam Ti nano-coating electrode in all-solid cell. AB - An all-solid cell with a solid polymer electrolyte was applied to electrochemical oxidation of low-concentration indoor gaseous aromatic pollution. Antimony-doped tin dioxide nanocoatings deposited on a titanium foam substrate (Ti/Sb-SnO2) with different Sb/Sn ratios (4.8-14.0 mol%) and loading weight of Sb-SnO2 (4.4-7.7 mg cm-2) were used as dimensionally stable anodes. Sn and Sb were homogeneously dispersed on the substrate, and a crack-free nanocoating was built when the loading of nanocoating was increased to 6.3 mg cm-2. The activity tests for oxidation of benzene showed that 40 ppm gaseous benzene was converted to CO2 with high selectivity (85%) at the low cell voltage of 2.0 V in this all-solid cell. The conversion of benzene was greatly increased from 30% to 100% upon increasing the Sb/Sn ratio of the nanocoating from 4.7 mol% to 14.0 mol%. With the increase of nanocoating loading (Sb/Sn = 14.0 mol%) from 6.3 to 7.7 mg cm-2, the conversion of 100 ppm benzene was increased from 70% to 100%. Cyclic voltammetry revealed that high Sb content in the oxide nanocoating increased the overpotential and current intensity of the oxygen evolution reaction. The large outer charge qo* related to the electroactive surface of the SS-7.7/Ti3 electrode was up to 305.3 mC cm-2, which were responsible for its excellent electrochemical performance in the benzene oxidation process. Our studies provide a potential method for removal of indoor VOCs at ambient temperature. PMID- 30453276 TI - Acid mine drainage affects the diversity and metal resistance gene profile of sediment bacterial community along a river. AB - Acid mine drainage (AMD) is one of the most hazardous byproducts of some types of mining. However, research on how AMD affects the bacterial community structure of downstream riverine ecosystems and the distribution of metal resistance genes (MRGs) along pollution gradient is limited. Comprehensive geochemical and high throughput next-generation sequencing analyses can be integrated to characterize spatial distributions and MRG profiles of sediment bacteria communities along the AMD-contaminated Hengshi River. We found that (1) diversities of bacterial communities significantly and gradually increased along the river with decreasing contamination, suggesting community composition reflected changes in geochemical conditions; (2) relative abundances of phyla Proteobacteria and genus Halomonas and Planococcaceae that function in metal reduction decreased along the AMD gradient; (3) low levels of sediment salinity, sulfate, aquatic lead (Pb), and cadmium (Cd) were negatively correlated with bacterial diversity despite pH was in a positive manner with diversity; and (4) arsenic (As) and copper (Cu) resistance genes corresponded to sediment concentrations of As and Cu, respectively. Altogether, our findings offer initial insight into the distribution patterns of sediment bacterial community structure, diversity and MRGs along a lotic ecosystem contaminated by AMD, and the factors that affect them. PMID- 30453277 TI - Peroxymonosulfate improved photocatalytic degradation of atrazine by activated carbon/graphitic carbon nitride composite under visible light irradiation. AB - The photocatalytic degradation of atrazine by activated carbon/graphitic carbon nitride composites with peroxymonosulfate (PMS) was investigated under visible light irradiation. The photocatalysts were prepared at different activated carbon (AC) loaded percentages and characterized by XRD, FT-IR, BET surface area, SEM, UV-Vis absorbance, photocurrent response and EIS. Several parameters which might influence the degradation efficiency were studied including PMS concentration, solution pH, catalyst dosage, initial atrazine concentration as well as water matrix effect. The results indicated that incorporation of AC contributes effectively in suppressing the recombination of electron-holes pairs and enhancing the photocatalytic performance of graphitic carbon nitride. More significantly, the degradation efficiency of atrazine showed remarkable improvement with PMS addition under visible light irradiation. The reaction rate constant of the 10% AC/g-C3N4/Vis/PMS system (0.0376 min-1) was approximately 2.9 times higher than that of g-C3N4/Vis/PMS system (0.0128 min-1). Results from quenching tests revealed that both sulfate and hydroxyl radicals were involved in the degradation of atrazine, while the latter is the main contributor. This paper constitutes an insight for the metal-free catalyst activation of PMS by photocatalysis for environmental remediation. PMID- 30453278 TI - Effects of feeding endophyte-infected tall fescue seeds to stocker Angus steers on retail quality attributes of beef strip steaks. AB - The objective of this study was to determine the effects of feeding endophyte infected tall fescue seeds to Angus steers during the stocker phase on the quality attributes of beef strip steaks during retail display. Endophyte-infected tall fescue seeds had no effect on steak surface lean color, myoglobin forms, proximate composition, thiobarbituric acid reactive substances, aerobic plate count, pH, activity of superoxide dismutase and metmyoglobin reductase, shear force, and sensory attributes (P >= 0.087). However, lightness, redness, oxymyoglobin percentage, and MRA decreased from 45.01, 32.60, 67.61%, and 9.54 MUM/min/g, respectively, on d 0 to 40.11, 21.83, 48.95%, and 2.30 MUM/min/g, respectively, on d 7 (P <= 0.001). Thiobarbituric acid reactive substances were increased by 30% by d 5 (P = 0.015) and APC was increased by 0.5 log CFU/g by d 7 (P <= 0.012). PMID- 30453279 TI - Efficacy of multi-stage sous-vide cooking on tenderness of low value beef muscles. AB - The efficacy of thermal activation of residual proteolytic enzymes on shear force and deformation of 72 beef supraspinatus (SS) and rectus femoris (RF) muscles was tested using multi-stage sous-vide cooking (M-SV; 1 h at 39 degrees C, 1 h at 49 degrees C, 4 h at 59 degrees C), single-stage sous-vide cooking (S-SV; 4 h at 59 degrees C), and waterbath cooking (22 min at 70 degrees C, to 59 degrees C). Two storage conditions (1 week at 2 degrees C; 2 weeks at -1.5 degrees C) followed, then meat was reheated to and tested at 55 degrees C. Shear force decreased by 17-21% with S-SV (P < 0.001) and appeared to affect both myofibrillar and collagen components, likely through heat activation of cathepsin B & L and 20S proteasome. A further 5-6% increase was realized with M-SV (P: SS = 0.006, RF = 0.12) affecting primarily the myofibrillar component, likely from calpain-2 activation. The degree of deformation increased with sous-vide cooking in general (P < 0.001). No meaningful effects of post-cooking storage were found (P > 0.05). PMID- 30453280 TI - Effect of new generation medium voltage electrical stimulation on the meat quality of beef slaughtered in a Chinese abattoir. AB - In this study, a medium voltage electrical stimulation (ES) system with three parameter combinations (A: 1A, 1.55 ms pulse width, 27 s; B: 0.55A, 1 ms pulse width, 34 s; C: 0.55A, 2 ms pulse width, 20s) were applied to beef carcases (n = 24; 319 +/- 26.4 kg), in the context of a very slow pH decline rate in the abattoir. All the ES combinations significantly accelerated the rate of pH decline (reflected by temp@pH 6.0, i.e. temperature when pH drops to 6.0), resulting in a tenderness improvement even after 14 days ageing compared to the controls. Sarcomere length was not different between treatments and controls, and it was not a contributor to the tenderness improvement, instead, physical disruption revealed by transmission electron microscopic images may have led to the improvement. Retail colour was significantly improved by either combination B or C after 7 days of ageing. Combination B shows the most promise for commercial application, however, verification on more animals is required before commercial adoption. PMID- 30453281 TI - Cancer-Associated Fibroblasts Accelerate Malignant Progression of Non-Small Cell Lung Cancer via Connexin 43-Formed Unidirectional Gap Junctional Intercellular Communication. AB - BACKGROUND/AIMS: Gap junctions, which are assembled by connexins, can directly connect the cytoplasm of adjacent cells and enable gap junctional intercellular communication (GJIC) as well as metabolic coupling between neighboring cells. Here, we investigated the role of connexin 43 (Cx43) and its derived GJIC in the interplay between non-small cell lung cancer (NSCLC) cells and cancer-associated fibroblasts (CAFs). METHODS: CAFs and NSCLC cells were co-cultured with direct contact and separated using flow cytometry. Glucose uptake, lactate production, and the expression and activity of PKM-2 and LDH-A in sorted CAFs were measured by a colorimetric assay, western blotting, and enzyme-linked immunosorbent assay (ELISA). Meanwhile, E-cadherin and N-cadherin expression and the migration and invasion of sorted NSCLC cells were detected by western blotting, wound width, and Transwell assays. Pyruvate, acetyl-CoA, and citric acid levels, ATP levels, and LDH-B and alpha-KG activity in sorted NSCLC cells were determined by a colorimetric or fluorometric assay and ELISA, respectively. Functional GJIC between cells and the subcellular location of connexins were detected by a "Parachute" assay and immunofluorescence. Levels of alpha-SMA, Cx43, and LDH-B in tissue from patients with NSCLC were determined by immunohistochemistry. RESULTS: Cx43 accumulated in the plasma membrane, which favored the assembly of asymmetric unidirectional GJIC from CAFs to NSCLC cells. CAFs underwent increased aerobic glycolysis and promoted the epithelial-mesenchymal transition, migration, and invasion of NSCLC cells. In contrast, NSCLC cells experienced enhanced oxidative phosphorylation upon CAF stimulation, with an increase in ATP generation and thereby activation of the PI3K/Akt and MAPK/ERK pathways. Metabolic coupling between CAFs and NSCLC cells was under the strict control of Cx43-formed unidirectional GJIC. Patients with high tri-expression of alpha-SMA, Cx43, and LDH-B had the shortest overall survival and relapse-free survival compared with those with individual overexpression or high bi-expression. CONCLUSION: Cx43 formed unidirectional GJIC plays a critical role in mediating close metabolic cooperation between CAFs and NSCLC cells to support the malignant progression of NSCLC. PMID- 30453282 TI - Leukocyte Cell-Derived Chemotaxin 2 Retards Non-Small Cell Lung Cancer Progression Through Antagonizing MET and EGFR Activities. AB - BACKGROUND/AIMS: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy is a clinical option for non-small cell lung cancer (NSCLC) harboring activating EGFR mutations or for cancer with wild-type (WT) EGFR when chemotherapy has failed. MET receptor activation or MET gene amplification was reported to be a major mechanism of acquired resistance to EGFR TKI therapy in NSCLC cells. Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that was shown to suppress metastasis of hepatocellular carcinoma via inhibiting MET activity. Until now, the biological function responsible for LECT2's action in human NSCLC remains unclear. METHODS: LECT2 knockout (KO) mice and NOD/SCID/IL2rgnull (NSG) mice were respectively used to investigate the effects of LECT2 on the tumorigenicity and metastasis of murine (Lewis lung carcinoma, LLC) and human (HCC827) lung cancer cells. The effect of LECT2 on in vitro cell proliferation was evaluated, using MTS and colony formation assays. The effect of LECT2 on cell motility was evaluated using transwell migration and invasion assays. An enzyme-linked immunosorbent assay was performed to detect secreted LECT2 in plasma and media. Co-immunoprecipitation and Western blot assays were used to investigate the underlying mechanisms of LECT2 in NSCLC cells. RESULTS: Compared to WT mice, mice with LECT2 deletion exhibited enhanced growth and metastasis of LLC cells, and survival times decreased in LLC-implanted mice. Overexpression of LECT2 in orthotopic human HCC827 xenografts in NSG mice resulted in significant inhibition of tumor growth and metastasis. In vitro, overexpression of LECT2 or treatment with a recombinant LECT2 protein impaired the colony-forming ability and motility of NSCLC cells (HCC827 and PC9) harboring high levels of activated EGFR and MET. Mechanistic investigations found that LECT2 bound to MET and EGFR to antagonize their activation and further suppress their common downstream pathways: phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase. CONCLUSION: EGFR-MET signaling is critical for aggressive behaviors of NSCLC and is recognized as a therapeutic target for NSCLC especially for patients with acquired resistance to EGFR-TKI therapy. Our findings demonstrate, for the first time, that LECT2 functions as a suppressor of the progression of NSCLC by targeting EGFR-MET signaling. PMID- 30453283 TI - Inhibition of Lithium Sensitive Orai1/ STIM1 Expression and Store Operated Ca2+ Entry in Chorea-Acanthocytosis Neurons by NF-kappaB Inhibitor Wogonin. AB - BACKGROUND/AIMS: The neurodegenerative disease Chorea-Acanthocytosis (ChAc) is caused by loss-of-function-mutations of the chorein-encoding gene VPS13A. In ChAc neurons transcript levels and protein abundance of Ca2+ release activated channel moiety (CRAC) Orai1 as well as its regulator STIM1/2 are decreased, resulting in blunted store operated Ca2+-entry (SOCE) and enhanced suicidal cell death. SOCE is up-regulated and cell death decreased by lithium. The effects of lithium are paralleled by upregulation of serum & glucocorticoid inducible kinase SGK1 and abrogated by pharmacological SGK1 inhibition. In other cell types SGK1 has been shown to be partially effective by upregulation of NFkappaB, a transcription factor stimulating the expression of Orai1 and STIM. The present study explored whether pharmacological inhibition of NFkappaB interferes with Orai1/STIM1/2 expression and SOCE and their upregulation by lithium in ChAc neurons. METHODS: Cortical neurons were differentiated from induced pluripotent stem cells generated from fibroblasts of ChAc patients and healthy volunteers. Orai1 and STIM1 transcript levels and protein abundance were estimated from qRT-PCR and Western blotting, respectively, cytosolic Ca2+-activity ([Ca2+]i) from Fura-2 fluorescence, SOCE from increase of [Ca2+]i following Ca2+ re-addition after Ca2+ store depletion with sarco-endoplasmatic Ca2+-ATPase inhibitor thapsigargin (1uM), as well as CRAC current utilizing whole cell patch clamp recording. RESULTS: Orai1 and STIM1 transcript levels and protein abundance as well as SOCE and CRAC current were significantly enhanced by lithium treatment (2 mM, 24 hours). These effects were reversed by NFkappaB inhibitor wogonin (50 uM). CONCLUSION: The stimulation of expression and function of Orai1/STIM1/2 by lithium in ChAc neurons are disrupted by pharmacological NFkappaB inhibition. PMID- 30453284 TI - Galectin-1 Promotes Metastasis in Gastric Cancer Through a Sphingosine-1 Phosphate Receptor 1-Dependent Mechanism. AB - BACKGROUND/AIMS: Increased expression of galectin-1 (Gal-1) in gastric cancer (GC) promotes metastasis and correlates with poor prognosis. The mechanisms by which Gal-1 promotes GC metastasis remain unknown. METHODS: Gal-1and Sphingosine 1-phosphate receptor 1 (S1PR1) were determined by immunohistochemistry(IHC) and quantitative real time polymerase chain reaction (qRT-PCR) in GC specimens. Stably transfected Gal-1 or S1PR1 into SGC7901 and MGC-803 cells, western blot and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. RESULTS: Overexpression of Gal-1 enhanced expression of S1PR1 in SGC 7901 cells, and increased cell invasion, while knockdown Gal-1 in MGC-803 cells reduced S1PR1 expression and diminished invasion. Simultaneous knockdown of Gal-1 and overexpression of S1PR1 in MGC803 cells rescued invasive ability of MGC803 cells. S1PR1 was associated with expression of epithelial-to-mesenchymal transition (EMT) markers in vitro and in clinical samples. EMT induced in MGC-803 cells by TGF-beta1 was accompanied by S1PR1 activation, while knockdown of S1PR1 reduced response to TGF-beta1, suggest that Gal-1 promotes GC invasion by activating EMT through a S1PR1-dependent mechanism. Overexpression of S1PR1 promoted subcutaneous xenograft growth and pulmonary metastases, and enhanced expression of EMT markers. CONCLUSION: Galectin-1 promotes metastasis in gastric cancer through a S1PR1- dependent mechanism, our results indicate that targeting S1PR1 may be a novel strategy to treat GC metastasis. PMID- 30453285 TI - Doublecortin-Like Kinase 1 (DCLK1) Regulates B Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (Bmi-1) and is Associated with Metastasis and Prognosis in Pancreatic Cancer. AB - BACKGROUND/AIMS: Cancer stem cells (CSCs) are largely responsible for tumor relapse and metastatic behavior. Doublecortin-like kinase 1 (DCLK1) was recently reported to be a biomarker for gastrointestinal CSCs and involved in the epithelial-mesenchymal transition (EMT) and tumor progression. B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1) is a crucial regulator of CSC self-renewal, malignant transformation and EMT, and a previous study from our group showed that Bmi-1 is upregulated in pancreatic cancer progression and participates in EMT. However, it remains unclear whether DCLK1 is involved in pancreatic cancer or whether DCLK1 is associated with the altered level of Bmi-1 expression. METHODS: The correlation of DCLK1 expression and clinical features of pancreatic cancer was analyzed in 210 paraffin-embedded archived pancreatic cancer specimens by immunohistochemical analysis. The biological effects of DCLK1 siRNA on cells were investigated by examining cell proliferation using a cell counting kit and cell colony assays, cell migration by wound healing assay and cell invasion by Transwell invasion assay. We further investigated the effect of therapeutic siRNA targeting DCLK1 on pancreatic cancer cell growth in vivo. Moreover, the molecular mechanism by which DCLK1 upregulates Bmi-1 expression was explored using real-time PCR, western blotting and Co-immunoprecipitation assay. RESULTS: DCLK1 is overexpressed in pancreatic cancer and is related to metastasis and prognosis. Knockdown of DCLK1 markedly suppressed cell growth in vitro and in vivo and also inhibited the migration and invasion of pancreatic cancer cells. Furthermore, we found that DCLK1 silencing could inhibit EMT in cancer cells via downregulation of Bmi-1 and the mesenchymal markers Snail and Vimentin and upregulation of the epithelial marker E-cadherin. Moreover, high DCLK1 expression in human pancreatic cancer samples was associated with a mesenchymal phenotype and increased cell proliferation. Further co-immunoprecipitation indicated that DCLK1 did not interact with Bmi-1 directly. CONCLUSION: Our data suggest that upregulation of DCLK1 may contribute to pancreatic cancer metastasis and poor prognosis by increasing Bmi-1 expression indirectly. The findings indicate that inhibiting DCLK1 expression might be a novel strategy for pancreatic cancer therapy. PMID- 30453286 TI - Antifibrotics: Shrinking the Box of Therapeutic Uncertainty. PMID- 30453287 TI - Confined Thalamic Deep Brain Stimulation in Refractory Essential Tremor. AB - BACKGROUND: Thalamic ventral intermediate nucleus (VIM) deep brain stimulation (DBS) is an effective therapy for medication-refractory essential tremor (ET). However, 13-40% of patients with an initially robust tremor efficacy lose this benefit over time despite reprogramming attempts. At our institution, a cohort of ET patients with VIM DBS underwent implantation of a second anterior (ventralis oralis anterior; VOA) DBS lead to permit "confined stimulation." We sought to assess whether confined stimulation conferred additional tremor capture compared to VIM or VOA stimulation alone. METHODS: Seven patients participated in a protocol-based programming session during which a video-recorded Fahn-Tolosa Marin Part A (FTM-A) tremor rating scale was used in the following 4 DBS states: off stimulation, VIM stimulation alone, VOA stimulation alone, and dual lead (confined) stimulation. RESULTS: The average (SD) baseline FTM-A off score was 17.6 (4.0). VIM stimulation alone lowered the average FTM-A total score to 6.9 (4.0). Confined stimulation further attenuated the tremor, reducing the total score to 5.7 (2.8). CONCLUSIONS: Confined thalamic DBS can provide additional symptomatic benefits in patients with unsatisfactory tremor control from VIM or VOA stimulation alone. PMID- 30453288 TI - Predictive Early Recurrence Factors of Preoperative Clinicophysiological Findings in Pancreatic Cancer. AB - BACKGROUND: We aimed to evaluate the use of preoperative clinicophysiological parameters as predictive risk factors for early recurrence of pancreatic ductal adenocarcinoma (PDAC) after curative resection. METHODS: A total of 260 patients who underwent pancreatic resection for PDAC between 2007 and 2015 were examined retrospectively. We divided the patients into those with early recurrence (within 6 months; group A, n = 52) and those with relapse within >=6 months or without recurrence (group B, n = 208). Data regarding clinicophysiological parameters were analyzed as predictors of disease-free survival (DFS). These factors were analyzed by chi2 tests on univariate analysis and Cox proportional hazard models on multivariate analyses. Kaplan-Meier survival curves were generated using log rank tests. RESULTS: Groups A and B had significantly different preoperative carbohydrate antigen 19-9 (CA19-9) levels, carcinoembryonic antigen (CEA) levels, and curability. Univariate and multivariate analysis showed that CA19-9 and CEA were independent prognostic factors for early recurrence. Patients with CA19-9 levels > 124.65 U/mL had significantly shorter DFS than those with lower levels, as did patients with CEA levels > 4.45 ng/mL. CONCLUSIONS: Our results show that elevated CA19-9 (> 124.65 U/mL) and CEA (> 4.45 ng/mL) were independent predictors of early recurrence after pancreatic resection in PDAC patients. PMID- 30453289 TI - MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/beta-Catenin Signaling. AB - BACKGROUND/AIMS: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/beta-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/beta-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/beta-catenin pathway in hepatocellular carcinoma (HCC). METHODS: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR 197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. RESULTS: Using a miRNA microarray analysis of HCC specimens and compared with non metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/beta-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/beta-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. CONCLUSION: miR 197 promotes HCC invasion and metastasis by activating Wnt/beta-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC. PMID- 30453290 TI - Interrelationship of Opioid Dependence, Impaired Impulse Control, and Depressive Symptoms: An Open-Label Cross-Sectional Study of Patients in Maintenance Therapy. AB - OBJECTIVE: A growing number of studies indicate increased impulsivity in patients with opioid dependence (OD). However, few studies exclude concomitant drug use and consider depression as a comorbidity, both of which can bias results. AIM: We aimed to compare impulsivity in patients with OD enrolled in maintenance therapy (ICD code F11.22) and well-matched healthy controls taking psychopathological impairments into account. Furthermore, we compared the result to risky behavioral patterns in patients. METHODS: This cross-sectional study included 50 patients with OD enrolled in either methadone or buprenorphine maintenance therapy and 50 healthy controls matched for gender, age, education, marital status, and premorbid intelligence. Abstinence from benzodiazepines, amphetamines, and cocaine was verified by urine analysis. We used the Barratt Impulsiveness Scale 11 (BIS-11), Beck's Depression Inventory (BDI), the Symptom Checklist 90 Revised (SCL-90R), and the European version of the Addiction Severity Index (EuropASI). RESULTS: Patients exhibited significantly worse impulse control than healthy individuals. We found no correlation between impulsiveness and reported risky behavior patterns but found a significant correlation between depressive symptoms and psychopathological impairment. CONCLUSIONS: Patients with OD showed a higher impulsivity than healthy individuals. Impulsivity could be a cause or a consequence of a substance use disorder; further research is warranted to explain this relationship. Impulsivity was associated with depression, an important confounder; future research needs to take this into account. PMID- 30453291 TI - Preliminaries. PMID- 30453292 TI - [Clinical value of transperineal saturation biopsy in patients with suspicious for prostate cancer]. AB - The aim of the study was to evaluate clinical value of transperineal saturation biopsy (TPSB) in 52 patients with suspicious for prostate cancer (PCa): 31 - primary patients and 17 - men with non-effective transrectal biopsy. PCa was diagnosed in 31 of 52 (59,6%) patients. Focal lesions revealed in 6 (19,4%), multifocal - in another 25 (80,6%) cases. TPSB is very helpful in primary diagnosis and for therapy planning. PMID- 30453293 TI - Association of Dopamine Beta-Hydroxylase Polymorphisms with Alzheimer's Disease, Parkinson's Disease and Schizophrenia: Evidence Based on Currently Available Loci. AB - BACKGROUND/AIMS: The neuropathies Alzheimer's disease (AD), Parkinson's disease (PD), and schizophrenia (SCZ) have different pathological mechanisms but share some common neurodegenerative features, such as gradual loss of neuronal structure and function. Dopamine beta-hydroxylase (DBH), a gene located in the chromosomal region 9q34, plays a crucial role in the process of converting dopamine into norepinephrine (NE). Several case-control studies have reported this pathway in the pathogenesis of AD, PD and SCZ. However, the results are controversial. METHODS: We conducted a meta-analysis to estimate the associations between polymorphisms in this gene and AD, PD and SCZ. Seven databases (PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, SZ Gene and AD Gene) were searched to identify eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the associations of DBH variants with AD, PD and SCZ susceptibility. RESULTS: A total of 41 studies involving 10506 cases and 15083 controls were included in our meta analysis. The analysis results indicated that a lack of association (P > 0.05) was observed between most of the currently available DBH polymorphisms and the neurological diseases AD, PD and SCZ; however, the DBH rs1611131 (allelic model: OR = 0.889, 95% CI: 0.815 - 0.969; dominant model: OR = 0.868, 95% CI: 0.778 - 0.968), rs2283123 (allelic model: OR = 0.285, 95% CI: 0.095 - 0.862; dominant model: OR = 0.290, 95% CI: 0.094 -0.897) and rs2007153 (allelic model: OR = 2.196, 95% CI: 1.506 - 3.200; dominant model: OR = 2.985, 95% CI: 1.465 - 6.084; recessive model: OR = 2.729, 95% CI: 1.548 - 4.812) variants were shown to be significantly associated with the risk of AD (the former variant) and SCZ (the latter two variants). CONCLUSION: On the one hand, most DBH polymorphisms from the currently available loci showed no linkage to AD, PD or SCZ, indicating the lower possibility of these loci serving as genetic markers of the risks of diseases with neurodegenerative characteristics. On the other hand, the DBH rs2283123 and rs2007153 polymorphisms could have opposite effects on SCZ development in Caucasians and be more specific in Croatians, while the DBH rs1611131 minor variant might have a protective effect on AD risk in Caucasians; however, these results require further study. PMID- 30453294 TI - Retinal Anlage Tumor of Epididymis: A Diagnostic Challenge on Cytology. PMID- 30453295 TI - Modesty, Objectification, and Disordered Eating Patterns - A Comparative Study Between Veiled and Non-Veiled Muslim Women Residing in Kuwait. AB - BACKGROUND: The common thread running through all forms of sexual objectification is the experience of being treated as a body (or collection of body parts) valued predominantly for its use to (or consumption by) others. Girls and women who adopt a peculiar view of self, an effect called self-objectification may contribute to women's depression, sexual dysfunction, and eating disorders. The objectives of the study are to investigate the impact of modesty (in terms of veiling, i.e. hijab) on objectification, by others and by the self, body image and behaviors indicative of eating disturbance of veiled and unveiled Muslim women in Kuwait. METHODS: It is a community-based, cross-sectional study conducted through online survey. The respondents were females living in Kuwait. RESULTS: Unveiled women experienced more objectification by others than veiled women. There were no significant differences found between veiled and unveiled women in self-objectification and eating disorder symptomatology. There is a negative significant relationship between modesty of clothing and objectification by others. No significant relationship was found between modesty of clothing and self-objectification and eating disorders scales. For the objectification by others scale, data shows that there is a positive relationship between this scale and eating disorders. Eating disorders were found to have a negative relationship with self-objectification. CONCLUSION: The results of the study are significant as they clearly demonstrate a weak negative relationship between clothing preferences/affiliations and eating disorders. PMID- 30453296 TI - Vitamin K Supplementation Modulates Bone Metabolism and Ultra-Structure of Ovariectomized Mice. AB - BACKGROUND/AIMS: Osteoporosis is a bone metabolic disease that affects mostly post-menopausal women. There has been shown that vitamin K (VK) supplementation during menopause may decrease bone loss as well as risk of bone breaking. Aiming to clarify the beneficial role of VK in bone metabolism during menopause, we investigated mineral metabolism and bone ultrastructure of ovariectomized (OVX) mice. METHODS: To determine the effects chronic use of VK in bone structure and mineral metabolism in OVX mice, we used several methods, such as DXA, uCTScan, and SEM as well as biomolecular techniques, such as ELISA and qRT-PCR. In addition, complete analysis of serum hormonal and other molecules associated to bone and lipid metabolism were evaluated overview the effects of VK in menopause murine model. RESULTS: VK treatment significantly affects Pi metabolism independently of OVX, changing Pi plasma, urinary output, balance, and Pi bone mass. Interestingly, VK also increased VLDL in mice independently of castration. In addition, VK increased compact bone mass in OVX mice when we evaluated it by DXA, histomorphometry, uCTScanning. VK increased bone formation markers, osteocalcin, HYP- osteocalcin, and AP whereas it decreased bone resorption markers, such as urinary DPD/creatinine ratio and plasmatic TRAP. Surprisingly, SEM images revealed that VK treatment led to amelioration of microfractures observed in OVX untreated controls. In addition, SHAM operated VK treated mice exhibited higher number of migrating osteoblasts and in situ secretion of AP. OVX led to decreased to in situ secretion of AP that was restored by VK treatment. Moreover, VK treatment increased mRNA expression of bone Calbindin 28KDa independently of OVX. CONCLUSION: VK treatment in OVX mice exhibited beneficial effects on bone ultrastructure, mostly by altering osteoblastic function and secretion of organic bone matrix. Therefore, VK could be useful to treat osteopenic/osteoporotic patients. PMID- 30453297 TI - Effects of IRW and IQW on Oxidative Stress and Gut Microbiota in Dextran Sodium Sulfate-Induced Colitis. AB - BACKGROUND/AIMS: There are known links between inflammatory bowel disease (IBD) and changes in the microbiota of the gut and inflammation and oxidative stress. In this study, a colitis model induced by dextran sodium sulfate (DSS) in mice is used to evaluate whether the presence of bioactive peptides IRW (Ile-Arg-Trp) and IQW (Ile-Gln-Trp) peptides is advantageous. METHODS: The mice were arbitrarily assigned to the following four groups: (i) control (untreated), (ii) dextran sodium sulfate (DSS) treated, (iii) IRW-DSS treated, and (iv) IQW-DSS treated. For 7 days, the control group subjects had unrestricted access to untreated drinking water, whereas the drinking water supplied to the subjects in the DSS, IRW-DSS, and IQW-DSS groups during this period consisted of 5% DSS solution. The colonic lesions were scored after hematoxylin and eosin staining. Serum antioxidant capacity was analyzed by 2,2'-azino-bis(3-ethylbenz-thiazoline-6 sulfonic acid) (ABTS) radical cation decolorization test and the microbiota in the colonic contents were sequenced by HiSeq2500 PE250. RESULTS: The presence of DSS reduced daily weight gain, enhanced histopathology scores, and inhibited antioxidant enzyme expression. Superoxide dismutase, catalase, and glutathione peroxidase activities in the DSS-induced colitis model were significantly enhanced (P < 0.05) in the presence of dietary IRW and IQW. Furthermore, the Simpson index was significantly increased (P < 0.05) in the presence of dietary IRW and IQW compared to the control group. IRW and IQW increased the abundance of Coprococcus_1, Ruminococcaceae_UCG-014, and Desulfovibrio compared to the control group and DSS group. Furthermore, IQW decreased the abundance of Bacteroides in relation to the control group, but increased Parabacteroides. In addition, IRW increased the level of Anaerotruncus, Oscillibacter, and Ruminiclostridium_9 compared to the control group. CONCLUSION: This study concludes that the presence of IRW or IQW can mitigate DSS-induced oxidative stress by improving the activities of antioxidant enzymes, increasing intestinal microbial diversity and enhancing the abundance of gut microbiota, which may help maintain the homeostasis of host health and microenvironment in a DSS-induced mouse model, thus providing a potential further treatment for IBD patients. PMID- 30453298 TI - Factors Associated with the Caregivers' Desire to Institutionalize Persons with Dementia: A Cross-Sectional Study. AB - BACKGROUND/AIMS: Dementia is one of the main reasons for institutionalization among the elderly. Few studies have explored factors associated with the caregivers' (CG) desire to institutionalize (DTI) a person with dementia (PWD). The objective of this study is to identify modifiable and non-modifiable psychosocial and sociodemographic factors associated with a caregiver's DTI. METHODS: Cross-sectional data of 355 informal CG of community-dwelling PWD were analyzed. Several characteristics were identified in CG and PWD to be included in a multivariable regression model based on the purposeful selection method. RESULTS: Positively modifiable associated factors were: higher CG burden, being affected by behavioral problems, and respite care use. Positively associated non modifiable factors were: CG older age, being professionally active, and CG higher educational level. Cohabitation and change of professional situation were negatively associated. CONCLUSION: Although no causality can be assumed, several practical recommendations can be suggested. First of all, these results reconfirm the importance of multicomponent strategies, especially support aimed at decreasing burden and in learning coping strategies. Also, CG might benefit from information about support options, such as respite care services. Finally, special attention should be given to older and working CG. In the latter, flexible and adaptive working conditions might alleviate burden and therefore reduce the DTI of the PWD. PMID- 30453299 TI - Diabetes Mellitus: Is It Protective against Aneurysm? A Narrative Review. AB - OBJECTIVES: In the course of extensive clinical aortic surgery, we noticed that the aorta was quite thick and fibrotic in diabetic patients. We thought the diabetic aortic aorta might be inimitable to aortic dissection. On this basis, we set out to review information in the literature regarding aortic growth and dissection in diabetic patients. METHODS: We used a 2-step search approach to the available literature on diabetes and aneurysm. Firstly, databases including PubMed, Cochrane, Embase and TRIP were searched. Secondly, relevant studies were identified through secondary sources including references of initially selected articles. We address the relationship between diabetes and the incidence, prevalence, growth, mortality and rupture of an aneurysm. RESULTS: Diabetes is thought to exert a protective role in both thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). Diabetics were shown to have a slower aneurysm growth rate, lower rupture rate, delayed (> 65 years) age of rupture, decreased rate of mortality from an aneurysm and a decreased length of hospital stay. There was also noted a decreased rate of incidence and prevalence of TAA and AAA in diabetics, smaller aneurysm diameter, reduction in matrix metalloproteinases and an increased aortic wall stress in diabetics. Antidiabetic agents like metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors may protect against an aneurysm. CONCLUSION: Our literature review provides strong (but often circumstantial) evidence that diabetic patients exhibit slower growth of aortic aneurysms and a lower rate of aortic dissection. Furthermore, clinical and experimental studies indicate that common antidiabetic medications on their own inhibit growth of aortic aneurysms. These findings indicate a paradoxically beneficial effect of the otherwise highly detrimental diabetic state. PMID- 30453300 TI - Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes. AB - BACKGROUND/AIMS: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4+ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. METHODS: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4+ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53-/-) mice or the specific inhibitor pifithrin-alpha (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real time PCR, and cytokine levels in culture supernatants were determined by enzyme linked immunosorbent assay. RESULTS: Splenic CD4+ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53-/ ) maintained CD4+ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4+ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. CONCLUSION: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells. PMID- 30453301 TI - The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes. AB - BACKGROUND/AIMS: Podocytes are dynamic polarized cells on the surface of glomerular capillaries that are an essential part of the glomerular filtration barrier. AMP-activated protein kinase (AMPK), a key regulator of glucose and fatty acid metabolism, plays a major role in obesity and type 2 diabetes. Accumulating evidence suggests that TRPC6 channels are crucial mediators of calcium transport in podocytes and are involved in regulating glomerular filtration. Here we investigated whether the AMPK-TRPC6 pathway is involved in insulin-dependent cytoskeleton reorganization and glucose uptake in cultured rat podocytes. METHODS: Western blot and immunofluorescence analysis confirmed AMPKalpha and TRPC6 expression, the phosphorylation of proteins associated with actin cytoskeleton reorganization (PAK, rac1, and cofilin), and the expression of insulin signaling proteins (Akt, Insulin receptor). Coimmunoprecipitation and immunofluorescence results demonstrated AMPKalpha/TRPC6 interaction. To ask whether TRPC6 is involved in the insulin regulation of glucose transport, we measured insulin-dependent (1, 2-3H)-deoxy-D-glucose uptake into podocytes after reducing TRPC6 activity pharmacologically and biochemically (TRPC6 siRNA). RESULTS: The results suggested a key role for the TRPC6 channel in the mediation of insulin-dependent activation of AMPKalpha2 and glucose uptake. Moreover, AMPK and TRPC6 activation were required to stimulate the Rac1 signaling pathway. CONCLUSION: These results suggest a potentially important new mechanism that regulates glucose transport in podocytes and that could be injurious during diabetes. PMID- 30453302 TI - Long Noncoding RNA HOST2 Promotes Epithelial-Mesenchymal Transition, Proliferation, Invasion and Migration of Hepatocellular Carcinoma Cells by Activating the JAK2-STAT3 Signaling Pathway. AB - BACKGROUND/AIMS: This study aims to examine the effect of long noncoding RNA HOST2 (LncRNA HOST2) on epithelial-mesenchymal transition (EMT), proliferation, invasion and migration of hepatocellular carcinoma (HCC) cells via activation of the JAK2-STAT3 signaling pathway. METHODS: HCC and para-cancerous tissues were collected from 136 HCC patients. Immunohistochemistry was used to detect the expression of JAK2 and STAT3. HCC SMMC7721 cells were grouped into blank, negative control (NC), HOST2 mimic and HOST2 inhibitor groups. The mRNA and protein expression levels of HOST2, JAK2, STAT3, E-cadherin, vimentin, Snail, Slug, Twist and Zeb1 in tissues and cells were determined by reverse transcription -quantitative polymerase chain reaction (RT-qPCR) and Western blotting, respectively. An MTT assay, scratch test and Transwell assay were applied to measure cell proliferation, migration and invasion, respectively. RESULTS: The levels of JAK2, STAT3 and vimentin were higher in HCC tissues, while the expression of E-cadherin was lower in HCC tissues compared with para cancerous tissues. The silencing of HOST2 significantly decreased cell proliferation, migration and invasion, reduced the levels of HOST2, JAK2, STAT3 and vimentin, and elevated the expression of E-cadherin. HOST2 silencing also decreased the levels of Snail, Slug and Twist but increased the level of Zeb1 protein, while the opposite findings were observed in the HOST2 mimic group. CONCLUSION: These results reveal a possible mechanism in HCC in which LncRNA HOST2 may increase EMT and enhance proliferation, invasion and metastasis of HCC cells via activation of the JAK2-STAT3 signaling pathway. PMID- 30453303 TI - Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson's Disease following Oral Administration. AB - BACKGROUND: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist. OBJECTIVE: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson's disease. METHODS: Following overnight levodopa (L-dopa, Sinemet(r)) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated. RESULTS: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF 06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of -10.59 with a one-sided 90% upper CI of PF 06412562 versus placebo model-based contrast of (-inf, -7.44) at 1.5-2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate. CONCLUSIONS: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists. PMID- 30453304 TI - SphK1/S1P Mediates PDGF-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation via miR-21/BMPRII/Id1 Signaling Pathway. AB - BACKGROUND/AIMS: The underlying molecular mechanisms involved in sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate (S1P) mediation of platelet-derived growth factor (PDGF)-induced pulmonary arterial smooth muscle cell (PASMC) proliferation are still unclear, and the present study aims to address this issue. METHODS: Small interfering RNA (siRNA) and microRNA inhibitor transfection was performed to block the expression of SphK1, bone morphogenetic protein receptor II (BMPRII) and microRNA-21 (miR-21). Gene expression levels of SphK1, BMPRII and inhibitor of DNA binding 1 (Id1) were detected by immunoblotting, miR 21 expression level was examined with qRT-PCR, and S1P production was measured by ELISA. Additionally, PASMC proliferation was determined by BrdU incorporation assay. RESULTS: Our results indicated that PDGF increased the expression of SphK1 protein and S1P production, up-regulated miR-21 expression, reduced BMPRII and Id1 expression, and promoted PASMCs proliferation. Pre-silencing of SphK1 with siRNA reversed PDGF-induced S1P production, miR-21 up-regulation, BMPRII and Id1 down-regulation, as well as PASMC proliferation. Pre-inhibition of miR-21 also blocked BMPRII and Id1 down-regulation as well as PASMC proliferation caused by PDGF. Knockdown of BMPRII down-regulated Id1 expression in PASMCs. We further found that inhibition of PI3K/Akt and ERK signaling pathways, particularly ERK cascade, suppressed PDGF-induced above changes. CONCLUSION: Our study indicates that SphK1/S1P pathway plays an important role in PDGF-induced PASMC proliferation via miR-21/BMPRII/Id1 axis and targeting against SphK1/S1P axis might be a novel strategy in the prevention and treatment of pulmonary arterial hypertension (PAH). PMID- 30453305 TI - Cytoskeleton Structure in Mouse Sperm and Testes After 30 Days of Hindlimb Unloading and 12 Hours of Recovery. AB - BACKGROUND/AIMS: Changes in the external mechanical field result in cytoskeleton reorganization and the formation of adaptive patterns in different types of cells, including somatic cells and sex cells. The aim of this research was to study the protein and mRNA content of cytoskeletal and sperm-specific genes in the sperm and testis cells of mice. METHODS: Mice were subjected to 30 days of antiorthostatic suspension to simulate weightlessness, followed by 12 h of recovery, while receiving essential phospholipids at a dosage of 500 mg/kg/day (30HSE and 30HSE+12h groups) or a similar dosage of a placebo (30HS and 30HS+12h groups). Accordingly, reference groups (CE group and C group) were formed. The total number and the percentage of motile spermatozoa were calculated using a Makler chamber. To analyze the number of viable spermatozoa and the permeability of their membranes, eosin staining was used as well as Diff-Quick for a morphological evaluation. Relative protein and mRNA content was estimated in a western blot and quantitative PCR assay, respectively. RESULTS: The relative protein expression levels of actin (beta and gamma) and two alpha-actinin isoforms (1 and 4) remained constant in the sperm of all study groups, except for the 30HS+12h group, where the alpha-actinin-4 level was 13% higher than in the reference group (p < 0.1). In the testis cells, the relative actin isoform content was equivalent to that in the spermatozoa. However, in the testis cells, the ACTN1 mRNA content was 17% higher in the 30HS group than in the C group (p < 0.05), and decreased after 12 h of recovery. In contrast, the ACTN4 mRNA content was 20% lower in the 30HS group than in the reference group (p < 0.05) and increased after the 12-h recovery period. At the same time, in the group administered the essential phospholipids, the relative ACTN1 and ACTN4 mRNA content did not differ from those of the reference group. The relative beta tubulin content was similar in the reference C group and the reference CE group, which was administered the essential phospholipids. In the 30HS and 30HS+12h groups, the beta-tubulin content decreased by 19% and 22% (p < 0.05), respectively, and they also decreased in the groups administered the essential phospholipids (30HSE and 30HSE+12h groups, by 27% and 33%, respectively, p < 0.05). In the testis tissue, the relative tubulin content did not change in any of the experimental groups. At the same time, the relative mRNA content of the genes encoding the studied cytoskeletal proteins increased, which may indicate the protein content was regulated mainly at the translational level. CONCLUSION: The spermogram parameters and the content of the sperm-specific proteins and the associated mRNAs revealed a decrease in the number of mature spermatozoa in mice suspended under conditions of weightlessness. Moreover, the decrease was prevented by the administration of essential phospholipids. PMID- 30453306 TI - Disulphide Bridges in Surfactant Protein B Analogues Affect Their Activity in Synthetic Surfactant Preparations. AB - BACKGROUND: Limited supply and complicated manufacturing procedure of animal derived surfactants make the development of synthetic surfactants warranted. The synthesis of surfactant protein (SP)-B and SP-C is complicated and several analogues have been developed. Mini-BLeu is an analogue that corresponds to the first and last helix of SP-B joined by a loop and linked by 2 disulphide bridges. SP-C33Leu is an SP-C analogue that can be cost-efficiently produced, but no such analogue has yet been described for SP-B. OBJECTIVE: To design short SP-B analogues which lack disulphide bridges, are easy to produce and are efficacious in a preterm rabbit fetus model of neonatal RDS. METHODS: Synthetic surfactants were prepared by adding 2 or 8% (w/w) of synthetic variants of Mini-B27, similar to Mini-BLeu but with a short loop, or different peptides covering helix 1 of SP B to 2% (w/w) of SP-C33Leu in 80 mg/mL of 1,2-dipalmitoyl-sn-glycero-3 phosphocholine/egg yolk phosphatidylcholine/1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoglycerol, 50: 40: 10 (by weight). Premature newborn rabbit fetuses were treated with 200 mg/kg of the surfactant preparations and ventilated with defined pressures for 30 min without positive end-expiratory pressure. Tidal volumes were registered during the experiments and lung gas volumes were measured at the end of the ventilation period. RESULTS: Synthetic surfactant containing the Mini-B27 analogue with 2 disulphides gives similar lung gas volumes as treatment with an animal-derived surfactant preparation, but all other SP-B analogues gave lower lung gas volumes. All synthetic surfactants studied gave no significant differences in compliances except the surfactant containing the Mini-B27 analogue without cysteines that performed somewhat better at 30 min. CONCLUSION: The helix loop-helix SP-B analogues tested in this study require the presence of 2 disulphide bridges for optimal activity in a rabbit RDS model. PMID- 30453307 TI - Circular RNA Hsa_Circ_0091579 Serves as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: An increasing number of studies have suggested that circular RNAs (circRNAs) have vital roles in carcinogenesis and tumor progression. However, the function of circRNAs in hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: We investigated the levels of circRNAs in patients with HCC to identify potential diagnostic biomarkers. We examined circRNA expression profiles in liver tumors and paired non-cancerous liver tissues from three HCC patients with cancer thrombus using a circRNA microarray. Bioinformatics analysis was performed to find circRNAs with significantly altered expression levels between tumors and their paired non-tumor tissues. We confirmed our initial findings by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curves were also applied to identify a candidate circRNA with the optimal specificity and sensitivity. Finally, X-tile software was adopted to calculate the most efficient cut-off value for hsa_circ_0091579 expression. RESULTS: Microarray analysis identified 20 unique circRNAs that were differentially expressed between tumor and non-tumor tissues (P < 0.05). The expression of these 20 circRNAs was verified by qRT-PCR. The expression of hsa_circ_16245-1 and hsa_circ_0091579 mRNA was consistent with their levels as tested by the microarray. The ROC curves showed that both hsa_circ_16245-1 and hsa_circ_0091579 had favorable specificity and sensitivity. We further confirmed that hsa_circ_0091579 was significantly upregulated in HCC and its high expression was intimately associated with a worse overall survival in patients with HCC. CONCLUSION: Hsa_circ_0091579 may play a critical role in HCC progression and serve as a potential biomarker for the prognosis of patients with HCC. PMID- 30453308 TI - Long Noncoding RNA SNHG16 Promotes Cell Proliferation by Sponging MicroRNA-205 and Upregulating ZEB1 Expression in Osteosarcoma. AB - BACKGROUND/AIMS: Long noncoding RNAs (lncRNAs) have been a research hotspot, as they play important roles in tumor development. However, their expression pattern and biological function in osteosarcoma have not yet been clarified. METHODS: Differentially expressed lncRNAs in osteosarcoma and paracarcinoma tissues were identified by screening an lncRNA microarray, and candidate lncRNAs were verified by quantitative real-time PCR (qRT-PCR). A series of bioinformatics and molecular biological methods were adopted to investigate the interaction among lncRNA, microRNA (miRNA), and miRNA target genes during the development and occurrence of osteosarcoma. Cell viability was measured using a Cell Counting Kit-8 assay. RESULTS: Chip microarray screening combined with the validation of differentially expressed candidate lncRNAs showed that the lncRNA small nucleolar RNA host gene 16 (SNHG16) had the largest fold change. SNHG16 was highly expressed in osteosarcoma tissues and cell lines, and its downregulation led to the suppressed proliferation of osteosarcoma cells. Further investigations revealed that SNHG16 could upregulate zinc finger E-box-binding homeobox 1 (ZEB1) expression by acting as an endogenous sponge of miR-205. Moreover, rescue assays proved that the effects of SNHG16 on the proliferation of osteosarcoma cells were dependent on miR-205. CONCLUSION: SNHG16 can significantly enhance the proliferation of osteosarcoma cells. In addition, SNHG16, miR-205, and ZEB1 interact in a common pathway during the development and occurrence of osteosarcoma, providing novel targets for intervention in the treatment of osteosarcoma. PMID- 30453309 TI - Association Between Gestational Weight Gain and Pregnancy Complications or Adverse Delivery Outcomes in Chinese Han Dichorionic Twin Pregnancies: Validation of the Institute of Medicine (IOM) 2009 Guidelines. AB - BACKGROUND Excessive or insufficient gestational weight gain (GWG) is associated with increased risks of pregnancy complications and adverse delivery outcomes in dichorionic twin pregnancies. The provisional Institute of Medicine (IOM) 2009 guidelines suggested the optimal GWG based on limited epidemiological data collected from Western populations. However, such a recommendation has not yet been validated in a Chinese Han population, the world's largest ethnic group. The objective of this study was to assess the effect of IOM guidelines by determining the neonatal and maternal outcomes associated with gaining weight below, within, and above the IOM provisional guidelines on GWG in Chinese Han twin pregnancies. MATERIAL AND METHODS A historical cohort study of 350 twin-conceiving Han women in Chongqing Women and Children's Health Center delivering liveborn twin infants between January 2015 and November 2016 was conducted. The participants were divided into 3 groups according to the 2009 Institute of Medicine recommendations of GWG: a low GWG group, an adequate GWG group, and a high GWG group. The incidence of pregnancy complications and the delivery outcomes were compared between the groups, and the correlation of GWG and pregnancy complications or delivery outcome was investigated by logistic regression analysis. RESULTS In Han Chinese people, the gestational age (GA) at delivery was significantly different among various GWG groups, and low maternal GWG is associated with shorter GA. Although low GWG increased the incidence of VPTD, it did not impact PTD in twin pregnancies. Moreover, GWG was negatively correlated with the incidence of PPROM and was positively correlated with GHP development in twin pregnancies. CONCLUSIONS The recommendations of the 2009 IOM guidelines about GWG is beneficial in reducing the incidence of VPTD and PPROM in Han Chinese dichorionic twin pregnancies, but failed to eliminate the development of PTD, PROM, GDM, PE, ICP, and SGA. PMID- 30453310 TI - Inconsistent Reporting of Potential Conflicts of Interest in JAMA Cardiology. PMID- 30453311 TI - Inconsistent Reporting of Potential Conflicts of Interest Disclosure. PMID- 30453312 TI - Inconsistent Reporting of Potential Conflicts of Interest in JAMA. PMID- 30453313 TI - Magic Mouthwash for Oral Mucositis: A Teachable Moment. PMID- 30453314 TI - Inconsistent Conflict of Interest Disclosure. PMID- 30453315 TI - Protecting the Value of Medical Science in the Age of Social Media and "Fake News". PMID- 30453316 TI - Sketch and Speak: An Expository Intervention Using Note-Taking and Oral Practice for Children With Language-Related Learning Disabilities. AB - Purpose: This preliminary study investigated an intervention procedure employing 2 types of note-taking and oral practice to improve expository reporting skills. Procedure: Forty-four 4th to 6th graders with language-related learning disabilities from 9 schools were assigned to treatment or control conditions that were balanced for grade, oral language, and other features. The treatment condition received 6 30-min individual or pair sessions from the school of speech language pathologists (SLPs). Treatment involved reducing statements from grade level science articles into concise ideas, recording the ideas as pictographic and conventional notes, and expanding from the notes into full oral sentences that are then combined into oral reports. Participants were pretested and posttested on taking notes from grade-level history articles and using the notes to give oral reports. Posttesting also included written reports 1 to 3 days following the oral reports. Results: The treatment group showed significantly greater improvement than the control group on multiple quality features of the notes and oral reports. Quantity, holistic oral quality, and delayed written reports were not significantly better. The SLPs reported high levels of student engagement and learning of skills and content within treatment. They attributed the perceived benefits to the elements of simplicity, visuals, oral practice, repeated opportunities, and visible progress. Conclusion: This study indicates potential for Sketch and Speak to improve student performance in expository reporting and gives direction for strengthening and further investigating this novel SLP treatment. Supplemental Material: https://doi.org/10.23641/asha.7268651. PMID- 30453317 TI - Effects of elastase digestion on the murine vaginal wall biaxial mechanical response. AB - Although the underlying mechanisms of pelvic organ prolapse (POP) remain unknown, disruption of elastic fiber metabolism within the vaginal wall extracellular matrix has been highly implicated. It has been hypothesized that elastic fiber fragmentation correlates to decreased structural integrity and increased risk of prolapse; however, the mechanisms by which elastic fiber damage may contribute to prolapse are poorly understood. Further, the role of elastic fibers in normal vaginal wall mechanics has not been fully ascertained. Therefore, the objective of this study is to investigate the contribution of elastic fibers to murine vaginal wall mechanics. Vaginal tissue from C57BL/6 female mice were mechanically tested using biaxial extension-inflation protocols before and after intraluminal exposure to elastase. Elastase digestion induced marked changes in the vaginal geometry, and biaxial mechanical properties, suggesting that elastic fibers may play an important role in vaginal wall mechanical function. Additionally, a constitutive model that considered two diagonal families of collagen fibers with a slight preference towards the circumferential direction described the data reasonably well before and after digestion. The present findings may be important to determine the underlying structural and mechanical mechanisms of POP, and aid in the development of growth and remodeling models for improved assessment and prediction of changes in structure-function relationships with prolapse development. Keywords: vaginal wall, women's health, mechanical testing, pelvic floor disorders, elastic fibers Disclosures: none. PMID- 30453318 TI - Softening Our Approach to Discussing Prognosis. PMID- 30453320 TI - Inconsistent Reporting of Potential Conflicts of Interest in JAMA Pediatrics. PMID- 30453319 TI - Associations of Intimate Partner Violence, Sexual Assault, and Posttraumatic Stress Disorder With Menopause Symptoms Among Midlife and Older Women. AB - Importance: Little is known about the prevalence of traumatic exposures among midlife and older women and the association of these traumatic exposures with health issues. Objective: To examine the associations of intimate partner violence (IPV), sexual assault, and posttraumatic stress with menopause symptoms among midlife and older women. Design, Setting, and Participants: A cross sectional analysis of data from a multiethnic cohort of 2016 women 40 to 80 years of age in the Kaiser Permanente Northern California health care system was conducted from November 15, 2008, to March 30, 2012. Statistical analysis was conducted from June 8, 2016, to September 6, 2017. Exposures: Lifetime physical or emotional IPV, sexual assault, and current symptoms of posttraumatic stress disorder, assessed with standardized questionnaires. Main Outcomes and Measures: Difficulty sleeping, vasomotor symptoms, and vaginal symptoms, assessed with standardized questionnaires. Results: Among the 2016 women enrolled, the mean (SD) age was 60.5 (9.5) years, and 792 of 2011 with race/ethnicity data (39.4)% were non-Latina white (403 [20.0%] Latina, 429 [21.3%] black, and 387 [19.2%] Asian). Lifetime emotional IPV was reported by 423 women (21.0%), lifetime physical IPV was reported by 316 women (15.7%), sexual assault was reported by 382 women (18.9%), and 450 of 2000 women (22.5%) had current clinically significant symptoms of posttraumatic stress disorder. In multivariable analyses adjusted for age, race/ethnicity, educational level, body mass index, menopause status, hormone therapy, and parity, symptoms of posttraumatic stress disorder were associated with difficulty sleeping (odds ratio [OR], 3.02; 95% CI, 2.22 4.09), vasomotor symptoms (hot flashes: OR, 1.69; 95% CI, 1.34-2.12; night sweats: OR, 1.72; 95% CI, 1.37-2.15), and vaginal symptoms (vaginal dryness: OR, 1.73; 95% CI, 1.37-2.18; vaginal irritation: OR, 2.20; 95% CI, 1.66-2.93; pain with intercourse: OR, 2.16; 95% CI, 1.57-2.98). Emotional IPV was associated with difficulty sleeping (OR, 1.36; 95% CI, 1.09-1.71), night sweats (OR, 1.50; 95% CI, 1.19-1.89), and pain with intercourse (OR, 1.60; 95% CI, 1.14-2.25). Physical IPV was associated with night sweats (OR, 1.33; 95% CI, 1.03-1.72). Sexual assault was associated with vaginal symptoms (vaginal dryness: OR, 1.41; 95% CI, 1.10-1.82; vaginal irritation: OR, 1.42; 95% CI, 1.04-1.95; pain with intercourse: OR 1.44; 95% CI, 1.00-2.06). Conclusions and Relevance: Lifetime history of IPV or sexual assault and current clinically significant symptoms of posttraumatic stress disorder are common and are associated with menopause symptoms. These findings highlight the need for greater recognition of these exposures by clinicians caring for midlife and older women. PMID- 30453321 TI - A Young Woman With Chest Pain. PMID- 30453322 TI - Serum Creatinine in the Critically Ill Patient With Sepsis. PMID- 30453323 TI - Enriching Communicative Environments: Leveraging Advances in Neuroplasticity for Improving Outcomes in Neurogenic Communication Disorders. AB - Purpose: Research manipulating the complexity of housing environments for healthy and brain-damaged animals has offered strong, well-replicated evidence for the positive impacts in animal models of enriched environments on neuroplasticity and behavioral outcomes across the lifespan. This article reviews foundational work on environmental enrichment from the animal literature and considers how it relates to a line of research examining rich communicative environments among adults with aphasia, amnesia, and related cognitive-communication disorders. Method: Drawing on the authors' own research and the broader literature, this article first presents a critical review of environmental complexity from the animal literature. Building on that animal research, the second section begins by defining rich communicative environments for humans (highlighting the combined effects of complexity, voluntariness, and experiential quality). It then introduces key frameworks for analyzing and designing rich communicative environments: distributed communication and functional systems along with sociocultural theories of learning and development in humans that support them. The final section provides an overview of Hengst's and Duff's basic and translational research, which has been designed to exploit the insights of sociocultural theories and research on environmental complexity. In particular, this research has aimed to enrich communicative interactions in clinical settings, to trace specific communicative resources that characterize such interactions, and to marshal rich communicative environments for therapeutic goals for individuals with aphasia and amnesia. Conclusions: This article concludes by arguing that enriching and optimizing environments and experiences offers a very promising approach to rehabilitation efforts designed to enhance the reorganization of cognitive-communicative abilities after brain injury. Such interventions would require clinicians to use the principles outlined here to enrich communicative environments and to target distributed communication in functional systems (not the isolated language of individuals). PMID- 30453324 TI - Expansion of the Medicare 340B Payment Program: Hospital Participation, Prescribing Patterns and Reimbursement, and Legal Challenges. PMID- 30453325 TI - Inconsistent Reporting of Potential Conflicts of Interest Disclosure. PMID- 30453326 TI - IMPACT OF CALCIUM QUANTIFICATIONS ON STENT EXPANSIONS. AB - Severely calcified plaque is of great concern when planning and implementing a stenting intervention. In this work, computational models were developed to investigate the influence of calcium characteristics on stenting outcomes. The commonly used clinical measurements of calcium (i.e., the arc angle, maximum thickness, length, and volume) were varied to estimate stenting outcomes in terms of lumen gain, stent underexpansion, strut malapposition, and stress or strain distributions of the stenotic lesion. Results have shown that stenting outcomes were most sensitive to the arc angle of the calcium. A thick calcium with a large arc angle resulted in poor stenting outcomes, such as severe stent underexpansion, D-shaped lumen, increased strut malapposition, and large stresses or strains in the plaque. This was attributed to the circumferential stretch of the tissue. Specifically, the non-calcium component was stretched significantly more than the calcium. The circumferential stretch ratios of calcium and non calcium component were approximately 2.35 and 1.44, respectively, regardless of calcium characteristics. In addition, the peak stress or strain within the artery and non-calcium component of the plaque occurred at the area adjacent to calcium edges (i.e., the interface between the calcium and the non-calcium component) coincident with the location of peak malapposition. It is worth noting that the calcium played a protective role for the artery underneath, which was at the expense of the overstretch and stress concentrations in the other portion of the artery. PMID- 30453327 TI - Evaluation of Causes of Protected Health Information Breaches. PMID- 30453328 TI - An Injury Risk Function for the Leg, Foot, and Ankle Exposed to Axial Impact Loading using Force and Impulse. AB - Most injury risk functions for dynamic axial loading of the leg have been targeted toward automotive applications such as predicting injury caused by intrusion into the occupant compartment from frontal collisions. Recent focus on leg injuries in the military has led to questions about the applicability of these injury risk functions shorter duration, higher amplitude loading associated with underbody blast. To investigate these questions, data was collected from seven separate test series that subjected post-mortem human legs to axial impact. A force and impulse based Weibull survival model was developed from these studies to estimate fracture risk. Specimen age was included as a covariate to reduce variance and improve survival model fit. The injury criterion estimated 50 percent risk of injury for a 50th-percentile male leg exposed to 13 N s of impulse at peak force and 8.07 kN of force for force durations less than and greater than half the natural period of the leg, respectively. A supplemental statistical analysis estimated that the proposed injury risk function improves injury prediction accuracy by more than 9% compared to the predictions from automobile-based risk functions developed for automotive intrusion. The proposed leg injury risk function not only improves injury prediction for higher-rate conditions, but also provides a single injury prediction tool for an expanded range of load durations ranging from 5 to 90 ms, which spans both automotive and military loading environments. PMID- 30453329 TI - The Intensive Cognitive-Communication Rehabilitation Program for Young Adults With Acquired Brain Injury. AB - Purpose: This study investigated the effects of an intensive cognitive communication rehabilitation (ICCR) program for young individuals with chronic acquired brain injury. Method: ICCR included classroom lectures; metacognitive instruction, modeling, and application; technology skills training; and individual cognitive-linguistic therapy. Four individuals participated in the intensive program (6 hr with 1-hr lunch break * 4 days * 12 weeks of treatment): 3 participants completed 3 consecutive semesters, and 1 participant completed 1 semester. Two controls did not receive treatment and completed assessments before and after the 12-week treatment interval only. Results: All 4 experimental participants demonstrated significant improvements on at least 1 standardized cognitive-linguistic measure, whereas controls did not. Furthermore, time point significantly predicted participants' scores on 2 of the 4 standardized outcome measures, indicating that as duration in ICCR increased, scores also increased. Participants who completed multiple semesters of ICCR also improved in their therapy and personal goals, classroom behavior, life participation, and quality of life. Conclusion: After ICCR, participants showed gains in their cognitive linguistic functioning, classroom participation, and individual therapy. They also demonstrated improvements outside the classroom and in their overall well being. There is a gap between the large population of young adults with acquired brain injury who wish to return to higher education and a lack of rehabilitation programs supporting reentry into academic environments; ICCR is a first step in reducing that gap. PMID- 30453330 TI - Monitoring Jet Engines and the Health of People. PMID- 30453331 TI - Speech Intervention Outcomes Associated With Word Lexicality and Intervention Intensity. AB - Purpose: This study examined how lexical representations and intervention intensity affect phonological acquisition and generalization in children with speech sound disorders. Method: Using a single-subject multiple baseline design, 24 children with speech sound disorders (3;6 to 6;10 [years;months]) were split into 3 word lexicality types targeting word-initial complex singleton phonemes: /r l ? theta/. Specifically, academic vocabulary words, nonwords (NWs), and high frequency (HF) words were contrasted. Intervention intensity was examined by comparing the performance of 12 children who completed eleven 50-min sessions (4 children/word type) to the performance of 12 who completed 19 sessions (4 children/word type). Children's production accuracy of their treated phonemes and overall percent consonants correct values were used to measure phonological generalization via percentage accuracy scores and d scores. Results: All word lexicality conditions elicited phonological change, suggesting that academic vocabulary words, NWs, and HF words are viable intervention targets. Group mean averages were similarly high for the NWs and HF words, although children in the NW condition demonstrated more consistent phonological gains. Children who received 19 intervention sessions achieved 6 times more gains in treated sound accuracy than did children who received 11 sessions. Conclusions: Word lexicality did not significantly influence children's intervention outcomes. More intensive intervention, as characterized by the number sessions, resulted in greater phonological change than did a shorter intervention program. Intervention intensity outcomes should be considered when establishing best practices for speech intervention scheduling. Supplemental Material: https://doi.org/10.23641/asha.7336055. PMID- 30453332 TI - Short-Term Intensive Therapy and Outcomes for Athletes With Paradoxical Vocal Fold Motion Disorder. AB - Purpose: The aim of the study was to develop a treatment for athletes with paradoxical vocal fold motion disorder (PVFMD) based on exercise physiology and learning theory principles and administer it over a preestablished time frame. Method: A prospective, repeated-measures, within-subject group design was used. Eleven adolescent/teen athletes diagnosed with PVFMD via laryngoscopy received short-term intensive (STI) therapy. Eight of the athletes returned for extended follow-up. Changes in postexercise inspiratory (Ri) and expiratory (Re) resistances and Modified Borg Dyspnea Scale (MBDS) ratings collected at baseline were compared immediately posttreatment and at extended follow-up. Dyspnea Index scores were collected at baseline and at extended follow-up. Two no-treatment control athletes with PVFMD participated in two exercise challenges-baseline and 6 weeks later. Results: Immediately after STI therapy, athletes attained significant improvement in Ri, Re, and MBDS ratings. These changes were maintained at extended follow-up as well as a significant change in Dyspnea Index scores. The 2 control athletes who were reassessed 6 weeks after baseline experienced negative changes in postexercise Ri and MBDS ratings. Conclusion: STI therapy that incorporated individuality, specificity, and variable practice effectively changed outcome measures posttreatment with further improvement observed at extended follow-up. These results provide preliminary evidence for STI therapy for PVFMD. PMID- 30453333 TI - Sensitivity to Morphosyntactic Information in Preschool Children With and Without Developmental Language Disorder: A Follow-Up Study. AB - Purpose: This study tested children's sensitivity to tense/agreement information in fronted auxiliaries during online comprehension of questions (e.g., Are the nice little dogs running?). Data from children with developmental language disorder (DLD) were compared to previously published data from typically developing (TD) children matched according to sentence comprehension test scores. Method: Fifteen 5-year-old children with DLD and fifteen 3-year-old TD children participated in a looking-while-listening task. Children viewed pairs of pictures, 1 with a single agent and 1 with multiple agents, accompanied by a sentence with a fronted auxiliary (is + single agent or are + two agents) or a control sentence. Proportion looking to the target was measured. Results: Children with DLD did not show anticipatory looking based on the number information contained in the auxiliary (is or are) as the younger TD children had. Both groups showed significant increases in looking to the target upon hearing the subject noun (e.g., dogs). Conclusions: Despite the groups' similar sentence comprehension abilities and ability to accurately respond to the information provided by the subject noun, children with DLD did not show sensitivity to number information on the fronted auxiliary. This insensitivity is considered in light of these children's weaker command of tense/agreement forms in their speech. Specifically, we consider the possibility that failure to grasp the relation between the subject-verb sequence (e.g., dogs running) and preceding information (e.g., are) in questions in the input contributes to the protracted inconsistency in producing auxiliary forms in obligatory contexts by children with DLD. Supplemental Material: https://doi.org/10.23641/asha.7283459. PMID- 30453334 TI - Association Between Supplemental Nutrition Assistance Program Participation and Cost-Related Medication Nonadherence Among Older Adults With Diabetes. AB - Importance: Understanding if the association of social programs with health care access and utilization, especially among older adults with costly chronic medical conditions, can help in improving strategies for self-management of disease. Objective: To examine whether participation in the Supplemental Nutrition Assistance Program (SNAP) is associated with a reduced likelihood of low-income older adults with diabetes (aged >=65 years) needing to forgo medications because of cost. Design, Setting, and Participants: This repeated cross-sectional, population-based study included 1302 seniors who participated in the National Health Interview Survey from 2013 through 2016. Individuals in the study were diagnosed with diabetes or borderline diabetes, were eligible to receive SNAP benefits, were prescribed medications, and incurred more than zero US dollars in out-of-pocket medical expenses in the past year. The data analysis was performed from October 2017 to April 2018. Exposures: Self-reported participation in SNAP. Main Outcomes and Measures: Cost-related medication nonadherence derived from responses to whether in the past year, older adults with diabetes delayed refilling a prescription, took less medication, and skipped medication doses because of cost. To estimate the association between participation in SNAP and cost-related medication nonadherence, we used 2-stage, regression-adjusted propensity score matching, conditional on sociodemographic and health and health care-related characteristics of individuals. Estimated propensity scores were used to create matched groups of participants in SNAP and eligible nonparticipants. After matching, a fully adjusted weighted model that included all covariates plus food security status was used to estimate the association between SNAP and cost-related medication nonadherence in the matched sample. Results: The final analytic sample before matching included 1385 older adults (448 [32.3%] men, 769 [55.5%] non-Hispanic white, and 628 [45.3%] aged >=75 years), with 503 of them participating in SNAP (36.3%) and 178 reporting cost related medication nonadherence (12.9%) in the past year. After matching, 1302 older adults were retained (434 [33.3%] men, 716 [55.0%] non-Hispanic white, and 581 [44.6%] aged >=75 years); treatment and comparison groups were similar for all characteristics. Participants in SNAP had a moderate decrease in cost-related medication nonadherence compared with eligible nonparticipants (5.3 percentage point reduction; 95% CI, 0.5-10.0 percentage point reduction; P = .03). Similar reductions were observed for subgroups that had prescription drug coverage (5.8 percentage point reduction; 95% CI, 0.6-11.0) and less than $500 in out-of-pocket medical costs in the previous year (6.4 percentage point reduction; 95% CI, 0.8 11.9), but not for older adults lacking prescription coverage or those with higher medical costs. Results remained robust to several sensitivity analyses. Conclusions and Relevance: The findings suggest that participation in SNAP may help improve adherence to treatment regimens among older adults with diabetes. Connecting these individuals with SNAP may be a feasible strategy for improving health outcomes. PMID- 30453335 TI - [The relationship between intake of lithium and neuroradiological alterations in bipolar disorder. Are there predictors of clinical remission?] AB - For avoiding affective episodes, patients with bipolar disorders are treated with mood stabilizers. Under that term, the substances lithium, valproic acid, lamotrigine and carbamazepine are included. In the light of upcoming new psychiatric concepts, the use of second generation antipsychotics is also taken into consideration in pharmacological treatment. In this review, the relation between brain structure and the use of lithium in bipolar disorders is examined. Therefore, results from MRI-, DTI-, SPECT-studies assessing this relation, were included.Most of the studies are cross-sectional and examined the effects of lithium. The latter is associated with increased cortical and sub-cortical gray matter volume and ameliorative white matter microstructure. 7-lithium spectroscopy showed a significant difference in brain-lithium concentrations between remitted and non-remitted patients.There are preclinical studies reporting induction of promitotic and antiapoptotic effects by lithium. This literature underpins the hypothesis of lithium-induced neurogenesis. However, osmotic and physical effects of lithium could also explain the demonstrated volume gain in bipolar human brain.Cross-sectional design and small patient groups are typical limitations of numerous studies included in this review.Notably, with the 7-lithium spectroscopy of the central nervous system, new perspectives in clinical research to clarify pharmacokinetic differences between remitted and non-remitted bipolar patients can be established in future. PMID- 30453336 TI - Correction: Intervention Strategies into Glycoprotein Hormone Receptors for Modulating (Mal-)function, with Special Emphasis on the TSH Receptor. PMID- 30453337 TI - Linking Electronic Health Record and Trauma Registry Data: Assessing the Value of Probabilistic Linkage. AB - BACKGROUND: Electronic health record (EHR) systems contain large volumes of novel heterogeneous data that can be linked to trauma registry data to enable innovative research not possible with either data source alone. OBJECTIVE: This article describes an approach for linking electronically extracted EHR data to trauma registry data at the institutional level and assesses the value of probabilistic linkage. METHODS: Encounter data were independently obtained from the EHR data warehouse (n = 1,632) and the pediatric trauma registry (n = 1,829) at a Level I pediatric trauma center. Deterministic linkage was attempted using nine different combinations of medical record number (MRN), encounter identity (ID) (visit ID), age, gender, and emergency department (ED) arrival date. True matches from the best performing variable combination were used to create a gold standard, which was used to evaluate the performance of each variable combination, and to train a probabilistic algorithm that was separately used to link records unmatched by deterministic linkage and the entire cohort. Additional records that matched probabilistically were investigated via chart review and compared against records that matched deterministically. RESULTS: Deterministic linkage with exact matching on any three of MRN, encounter ID, age, gender, and ED arrival date gave the best yield of 1,276 true matches while an additional probabilistic linkage step following deterministic linkage yielded 110 true matches. These records contained a significantly higher number of boys compared to records that matched deterministically and etiology was attributable to mismatch between MRNs in the two data sets. Probabilistic linkage of the entire cohort yielded 1,363 true matches. CONCLUSION: The combination of deterministic and an additional probabilistic method represents a robust approach for linking EHR data to trauma registry data. This approach may be generalizable to studies involving other registries and databases. PMID- 30453338 TI - Leveraging Electronic Dental Record Data to Classify Patients Based on Their Smoking Intensity. AB - BACKGROUND: Smoking is an established risk factor for oral diseases and, therefore, dental clinicians routinely assess and record their patients' detailed smoking status. Researchers have successfully extracted smoking history from electronic health records (EHRs) using text mining methods. However, they could not retrieve patients' smoking intensity due to its limited availability in the EHR. The presence of detailed smoking information in the electronic dental record (EDR) often under a separate section allows retrieving this information with less preprocessing. OBJECTIVE: To determine patients' detailed smoking status based on smoking intensity from the EDR. METHODS: First, the authors created a reference standard of 3,296 unique patients' smoking histories from the EDR that classified patients based on their smoking intensity. Next, they trained three machine learning classifiers (support vector machine, random forest, and naive Bayes) using the training set (2,176) and evaluated performances on test set (1,120) using precision (P), recall (R), and F-measure (F). Finally, they applied the best classifier to classify smoking status from an additional 3,114 patients' smoking histories. RESULTS: Support vector machine performed best to classify patients into smokers, nonsmokers, and unknowns (P, R, F: 98%); intermittent smoker (P: 95%, R: 98%, F: 96%); past smoker (P, R, F: 89%); light smoker (P, R, F: 87%); smokers with unknown intensity (P: 76%, R: 86%, F: 81%), and intermediate smoker (P: 90%, R: 88%, F: 89%). It performed moderately to differentiate heavy smokers (P: 90%, R: 44%, F: 60%). EDR could be a valuable source for obtaining patients' detailed smoking information. CONCLUSION: EDR data could serve as a valuable source for obtaining patients' detailed smoking information based on their smoking intensity that may not be readily available in the EHR. PMID- 30453339 TI - Electronic Collection of Multilingual Patient-Reported Outcomes across Europe. AB - BACKGROUND: Patient-reported outcomes (PROs) are information provided directly by patients that helps in improving patient diagnosis and treatment. Validated translations of PROs can be used to treat international patients. Electronic systems and especially mobile devices provide a great opportunity for their collection; however, these systems are normally study-oriented and therefore single language, not scalable, and not interoperable. OBJECTIVES: This article reports the development of a multicenter, multilingual, and interoperable electronic PRO (ePRO) system and evaluates its user satisfaction in an international clinical study. METHODS: The ePRO named "MoPat2" was developed using Java 8 and jQuery Mobile 1.4.5. The system was evaluated in the context of the European dermatology project "European Network on Assessment of Severity and Burden of Pruritus"(PruNet), which aimed to unify the assessment of itch in routine dermatological care in Europe. Twenty-six clinicians and 468 patients from 8 European clinical centers were asked to complete a user satisfaction questionnaire regarding the use of MoPat2 with a tablet personal computer. The results were then analyzed and correlated with the age, gender, and language of the respondents. RESULTS: MoPat2 was enhanced with multilingual capabilities and is now able to conduct surveys in several languages, as well as store and display the results in the local language. The interviewed clinicians rated the system with an average score of 2.0 ("good") in a 1 to 5 Likert scale. Note that 93.9% of the patients (439 of 468) reported having got on well using the system and 88.9% (416 of 456) would be willing to further use it. The age of the patients not willing to further use MoPat2 was, in average, considerably higher than the age of patients willing to use the system. CONCLUSIONS: This study represents the first use of an ePRO system for the collection of multilingual PROs in an international, multicenter setting. MoPat2 has been evaluated by both clinicians and patients in the context of a European dermatological study, resulting in a high user satisfaction. The system will be further developed to include new features such as patient follow-ups outside of the clinical setting. PMID- 30453340 TI - Apixaban for the Treatment of Chronic Disseminated Intravascular Coagulation: A Report of Two Cases. AB - Characteristic features of disseminated intravascular coagulation (DIC) are the opposing risks of bleeding (due to consumptive coagulopathy and hyperfibrinolysis) and organ failure (due to widespread microvascular thromboses). The purpose of anticoagulation in DIC is to attenuate excessive thrombin generation and fibrin deposition. While heparins have been shown to be beneficial in this context, the safety and efficacy of direct oral anticoagulants have not yet been sufficiently addressed. Here, we report two patients in whom chronic DIC was stabilized upon administration of apixaban: an elderly male with aortic dissection presenting with significant mucocutaneous bleeding and a younger female with Klippel-Trenaunay-Weber syndrome presenting with multiple superficial vein thromboses (SVTs). In addition to an improvement in DIC parameters, both patients benefited clinically with resolution of bleeding symptoms and prevention of further SVTs, respectively. Oral apixaban thus showed promising safety and efficacy in the management of DIC caused by vascular abnormalities; still further investigations are needed to support these findings. PMID- 30453341 TI - New Insights into Platelet Signalling Pathways by Functional and Proteomic Approaches. AB - As circulating sentinels of vascular integrity, platelets act as crucial haemostatic cells as well as important inflammatory and immune cells, whereas under pathological conditions platelets drive thrombotic as well as non thrombotic diseases related to chronic inflammation. In addition, platelets serve as an important cellular model to study the biology and pharmacology of signal transduction pathways. Platelet inhibition and activation responses are mediated by multiple signalling networks, which are tightly regulated by balanced catalysis of protein phosphorylation and dephosphorylation through protein kinases and protein phosphatases, respectively. However, we are only at the beginning of understanding the complexity of interacting signalling pathways and their impact on platelet function. Here, we review current functional and proteomic approaches that lead to novel concepts of understanding the proteome, kinome and phosphatome of human platelets. A more in-depth understanding of both protein kinases and protein phosphatases using human platelets will contribute to evaluate their further diagnostic and therapeutic potential in inflammation- and immune-mediated diseases. PMID- 30453342 TI - Comparison of the Effects of Prophylactic and Therapeutic Administrations on Peripheral Neuropathy in Streptozotocin-Diabetic Rats with Gliclazide or Methylcobalamin. AB - OBJECTIVE: To observe the differences in curative effects between prophylactic and therapeutic administrations of Gliclazide (GLZ) or Methylcobalamin (MCA) on diabetic peripheral neuropathy in rats. METHODS: GLZ (25 mg/kg/day) or MCA (175 MUg/kg/day) was orally administrated prophylactically to streptozotocin-induced diabetic rats for 8 weeks before diabetic peripheral neuropathy developed or administrated therapeutically after diabetic peripheral neuropathy developed, respectively. The motor nerve conduction velocities (MNCV), aldose reductase (AR) activities, the polyol contents and antioxidative enzyme activities in the sciatic never tissues were determined. The morphology of sciatic never tissues was observed. RESULTS: In comparison to vehicle, most of the changes in the sciatic nerves of the diabetic rats (e. g., delayed MNCV, altered/damaged nerve structure, enhanced AR activity, increased polyol contents, altered Cu, Zn superoxide dismutase, glutathione-peroxidase activities, and elevated malondialdehyde level) were significantly ameliorated by prophylactic administration with either GLZ or MCA. In contrast, only few of above-mentioned parameters were alleviated in DPN rats by therapeutic administration with GLZ or MCA as compared to vehicle. The curative effects of GLZ or MCA prophylactic administration on MNCV, AR activity, polyol contents and antioxidative enzyme activities were markedly stronger than therapeutic administration. CONCLUSION: prophylactic administration of GLZ or MCA was superior to the therapeutic administration in alleviation of diabetic neuropathy in STZ-rats, suggesting that pharmacotherapy should be initiated at a much earlier stage before diabetic neuropathy developed, but not at a later stage after never damage reached. PMID- 30453343 TI - alpha1-Antichymotrypsin Present in Therapeutic C1-Inhibitor Products Competes with Selectin-Sialyl LewisX Interaction. AB - BACKGROUND: C1-inhibitor (C1-inh) therapeutics can reduce neutrophil activity in various inflammatory conditions. This 'novel' anti-inflammatory effect of C1-inh is attributed to the tetrasaccharide sialyl LewisX (SLeX) present on its N glycans. Via SLeX, C1-inh is suggested to interact with selectins on inflamed endothelium and prevent neutrophil rolling. However, C1-inh products contain plasma glycoprotein alpha1-antichymotrypsin (ACT) as a co-purified protein impurity. OBJECTIVE: This article investigates the contribution of ACT to the effects observed with C1-inh. MATERIALS AND METHODS: We have separated C1-inh and ACT from a therapeutic C1-inh preparation and investigated the influence of these proteins on SLeX-selectin interactions in a specific in vitro model, which makes use of rolling of SLeX-coated beads on immobilized E-selectin. RESULTS: We find that ACT and not C1-inh, shows a clear sialic acid-dependent interference in SLeX-selectin interactions, at concentrations present in C1-inh therapeutics. Furthermore, we do not find any evidence of SLeX on C1-inh using either Western blotting with anti-SLeX antibodies (CSLEX1 and KM93) or by mass spectrometric analysis of N-glycans. C1-inh reacts weakly to antibody HECA-452, which detects a broad range of selectin ligands, but ACT gives a much stronger signal, suggesting the presence of a selectin ligand on ACT. CONCLUSION: The 'novel' anti inflammatory effects of C1-inh are unlikely due to SLeX on C1-inh and can in fact be due to SLeX-like glycans on ACT, present in C1-inh products. In view of our results, it is important to assess the role of ACT in vivo and revisit past studies performed with commercial C1-inh. PMID- 30453344 TI - METoclopramide Administration as a Strategy to Overcome MORPHine-ticagrelOr Interaction in PatientS with Unstable Angina PectorIS-The METAMORPHOSIS Trial. AB - Extensive search for methods of overcoming morphine-related delay of the absorption and onset of action of oral P2Y12 inhibitors in patients presenting with acute coronary syndrome is on-going. The aim of the trial was to investigate whether metoclopramide co-administration could reduce this delay and improve the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ticagrelor and its active metabolite AR-C124900XX. Plasma concentration of both compounds and platelet reactivity were evaluated in nine pre-defined time points within 6 hours after administration of ticagrelor loading dose. The results of our study show that mean platelet activity within the first hour was noticeably higher in metoclopramide-naive patients. Moreover, ticagrelor mean plasma concentration was significantly higher within the initial four time points (15, 30, 45, 60 minutes) in patients receiving metoclopramide (p = 0.039; p = 0.009; p = 0.005; p = 0.008, respectively). To conclude, the co-administration of metoclopramide in patients presenting with unstable angina and treated with morphine, has a beneficial effect on the PK/PD profile of ticagrelor and its metabolite; however, its impact on ST-elevation myocardial infarction patients requires further investigation. PMID- 30453345 TI - The Actin Regulator Coronin-1A Modulates Platelet Shape Change and Consolidates Arterial Thrombosis. AB - Coronin-1A (Coro1A) belongs to a family of highly conserved actin-binding proteins that regulate cytoskeletal re-arrangement. In mammalians, Coro1A expression is most abundant in the haematopoietic lineage, where it regulates various cellular processes. The role of Coro1A in platelets has been previously unknown. Here, we identified Coro1A in human and mouse platelets. Genetic absence of Coro1A in mouse platelets inhibited agonist-induced actin polymerization and altered cofilin phosphoregulation, leading to a reduction in spreading and low dose collagen induced aggregation. Furthermore, Coro1A-deficient mice displayed a defect in ferric chloride-induced arterial thrombosis with prolonged thrombus formation and reduced thrombus size. Immunofluorescence analysis revealed a less compact thrombus structure with reduced density of platelets and fibrinogen. In summary, Coro1A has a role in platelet biology with impact on spreading, aggregation and thrombosis. PMID- 30453346 TI - The Inter-Relationship of Platelets with Interleukin-1beta-Mediated Inflammation in Humans. AB - BACKGROUND: Inflammation and coagulation are key processes in cardiovascular diseases (CVDs). The Canakinumab Anti-inflammatory Thrombosis Outcome Study trial affirmed the importance of inflammation in CVD by showing that inhibition of the interleukin (IL)-1beta pathway prevents recurrent CVD. A bi-directional relationship exists between inflammation and coagulation, but the precise interaction of platelets and IL-1beta-mediated inflammation is incompletely understood. We aimed to determine the inter-relationship between platelets and inflammation-and especially IL-1beta-in a cohort of healthy volunteers. METHODS: We used data from the 500-Human Functional Genomics cohort, which consists of approximately 500 Caucasian, healthy individuals. We determined associations of plasma levels of IL-1beta and other inflammatory proteins with platelet number and reactivity, the association of platelet reactivity with ex vivo cytokine production as well as the impact of genetic variations through a genome-wide association study (GWAS). RESULTS: Platelets were associated with IL-1beta on different levels. First, platelet number was positively associated with plasma IL 1beta concentrations (p = 8.9 * 10-9) and inversely with concentrations of alpha 1-anti-trypsin (p = 1.04 * 10-18), which is a known antagonist of IL-1beta. Second, platelet degranulation capacity, as determined by agonist-induced P selectin expression, was associated with ex vivo IL-1beta and IL-6 production. Third, several platelet single-nucleotide polymorphisms (SNPs) were associated with cytokine production and there was a significant platelet SNP enrichment in specific biological important pathways. Finally, platelet SNPs were enriched among SNPs earlier identified in GWAS studies in blood-related diseases and immune-mediated diseases. CONCLUSION: This comprehensive assessment of factors associated with platelet number and reactivity reinforces the important inter relationship of platelets and IL-1beta-mediated inflammation. PMID- 30453347 TI - Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre Eclampsia. AB - Pre-eclampsia (PE) is a chronic inflammatory disease in pregnancy, which is associated with enhanced blood coagulation and high thrombotic risk. To date, the mechanisms underlying such an association are not fully understood. Previous studies reported high levels of plasma deoxyribonucleic acid (DNA) in PE women, but the cellular source of the circulation DNA remains unknown. In this study, we tested the hypothesis that activated neutrophils undergoing cell death, also called NETosis, may be responsible for the elevated plasma DNA levels in PE women. We analysed plasma samples from non-pregnant, normal pregnant and PE women and found high levels of double-stranded DNA, myeloperoxidase (an abundant neutrophil granular enzyme) and histones (the major nucleosome proteins) in PE derived samples, indicating increased NETosis in the maternal circulation. The high plasma DNA levels positively correlated with enhanced blood coagulation in PE women. When isolated neutrophils from normal individuals were incubated with PE-derived plasma, an elevated NETosis-stimulating activity was detected. Further experiments showed that endothelial micro-particles, but not soluble proteins, in the plasma were primarily responsible for the NETosis-stimulating activity in PE women. These results indicate that circulating micro-particles from damaged maternal endothelium are a potent stimulator for neutrophil activation and NETosis in PE women. Given the pro-coagulant and pro-thrombotic nature of granular and nuclear contents from neutrophils, enhanced systemic NETosis may represent an important mechanism underlying the hyper-coagulability and increased thrombotic risk in PE. PMID- 30453348 TI - Fusion of Factor IX to Factor XIII-B Sub-Unit Improves the Pharmacokinetic Profile of Factor IX. AB - Prophylaxis is currently considered the optimal care for severe haemophilia. For patients and their families one of the major difficulties with prophylaxis is the need for frequent venipunctures. The half-life of standard factor IX (FIX) concentrates is approximately 18 hours, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention in patients with severe haemophilia B. Prolonging the half-life of FIX can therefore reduce the frequency of infusions. Recently, extended half-life recombinant FIX (rFIX) concentrates have been developed. We designed a new rFIX molecule fused to coagulation FXIII-B sub-unit. This sub-unit is responsible for the long half-life of the FXIII molecule (10-12 days). The rFIX-LXa-FXIIIB fusion protein contains a short linker sequence cleavable by activated FX (FXa), to separate rFIX from the carrier protein as soon as traces of FXa are generated, leaving rFIX free to perform its enzymatic role in the tenase complex. The rFIX-LXa-FXIIIB fusion protein was expressed in human hepatic Huh-7 cells and Chinese hamster ovary cells, and both wild-type rFIX (rFIX-WT) and rFIX-LXa-FXIIIB showed similar clotting activity and thrombin generation capacity in vivo after injection in haemophilia B mice compared with rFIX-WT. The half-life of the rFIX-LXa-FXIIIB molecule in WT mice and rats was 3.9- and 2.2-fold longer, respectively, compared with rFIX-WT. A potential advantage of this new molecule is its capacity to bind to fibrinogen via FXIII-B, which might accelerate fibrin clot formation and thus improve haemostatic capacity of the molecule. PMID- 30453349 TI - Treatment Persistence in Atrial Fibrillation: The Next Major Hurdle. PMID- 30453350 TI - Oh Heavy Burden: Recognizing the Risk of Venous Thromboembolism in Women Undergoing Assisted Reproduction. PMID- 30453351 TI - Stroke Severity in Patients on Non-Vitamin K Antagonist Oral Anticoagulants with a Standard or Insufficient Dose. AB - BACKGROUND: The stroke severity or functional outcomes could differ because the efficacy of non-vitamin K antagonist oral anticoagulants (NOACs) could be different according to the dose. We investigated whether there was any difference in the stroke outcomes in patients with non-valvular atrial fibrillation (NVAF) by their prior medication status, including standard-dosed versus under-dosed NOACs. MATERIALS AND METHODS: We enrolled 858 patients with acute ischaemic stroke with chronic NVAF admitted at six hospitals in Korea. We categorized their prior medication status as follows: (1) no anti-thrombotics (n = 219), (2) only anti-platelet (n = 347), (3) warfarin with a sub-therapeutic intensity (n = 185), (4) warfarin with a therapeutic intensity (n = 37), (5) under-dosed NOAC (n = 27) and (6) standard-dosed NOAC (n = 43). We compared the initial stroke severity between groups. RESULTS: Among the 858 patients, the patients on standard-dosed NOACs had the lowest initial National Institute of Health Stroke Scale (NIHSS) score, followed by those on warfarin with a therapeutic intensity and those on only anti-platelet (p < 0.05). Multivariate analysis demonstrated that the NIHSS score was significantly low in the patients on warfarin with a therapeutic intensity (B, -5.602; 95% confidence interval [CI], -8.636 to -2.568; p < 0.001) or those on standard-dosed NOACs (B, -3.588; 95% CI, -6.405 to -0.771; p = 0.013), while there was no difference in the NIHSS score between the patients not taking any anti-thrombotics and those on warfarin with a sub-therapeutic intensity or under-dosed NOACs. CONCLUSION: Use of warfarin with a therapeutic intensity or standard-dosed NOACs was associated with a relatively mild stroke in the patients with NVAF. PMID- 30453352 TI - Safety of In-Hospital Only Thromboprophylaxis after Fast-Track Total Hip and Knee Arthroplasty: A Prospective Follow-Up Study in 17,582 Procedures. AB - Most international guidelines recommend pharmacological thromboprophylaxis after total hip and knee arthroplasty (THA/TKA) for 10 to 35 days. However, a recent cohort study on fast-track THA and TKA questioned the need for prolonged thromboprophylaxis when length of stay (LOS) is <= 5 days. We aimed at re investigating the incidence of venous thromboembolism (VTE) in fast-track THA and TKA with in-hospital only thromboprophylaxis when LOS was <= 5 days. Prospective cohort study from 1 December 2011 to 30 October 2015 on elective unilateral THA/TKA with in-hospital only thromboprophylaxis if LOS was <= 5 days. Prospective information on co-morbidity and complete 90-day follow-up through the Danish National Patient Registry and medical records. Patients with pre-operative use of anticoagulants were excluded. In per protocol analysis, 17,582 (95.5%) had LOS of <= 5 days (median, 2 [interquartile range, 2-3]) and in-hospital thromboprophylaxis only. Incidence of symptomatic VTE was 0.40%, consisting of 28 (0.16%) pulmonary embolisms (PEs), 38 (0.22%) deep vein thrombosis (DVT) and 4 (0.02%) combined DVT and PE. Two PEs (0.01%) were fatal. VTE-associated risk factors with in-hospital only thromboprophylaxis were age > 85 years, odds ratio (OR) of 3.74 (95% confidence interval: 1.15-12.14, p = 0.028), body mass index (BMI) of 35 to 40, OR of 2.55 (1.02-6.35, p = 0.045) and BMI > 40, OR of 3.28 (1.02-10.56, p = 0.046). In conclusion, 90-day incidence of VTE after fast-track THA and TKA with in-hospital thromboprophylaxis only was 0.40%. Prolonged thromboprophylaxis may be reserved for LOS > 5 days or specific high-risk patients, but requires further studies regarding optimal type and duration of thromboprophylaxis. PMID- 30453353 TI - Outcome and Associated Findings in Individuals with Pre- and Postnatal Diagnosis of Tetralogy of Fallot (TOF) and Prediction of Early Postnatal Intervention. AB - PURPOSE: The aim of our retrospective evaluation was to compare the outcome of patients with prenatal and postnatal diagnosis of Tetralogy of Fallot (TOF) and to analyze prenatal echocardiographic parameters predicting intervention within 30 days postnatal. MATERIALS AND METHODS: We evaluated 142 patients in our pediatric heart center and prenatal diagnosis center and prenatal practice Praenatal plus in Cologne between 01/08 - 06/16. RESULTS: Within the prenatal diagnosis group, 6/74 fetuses (8.1 %) had TOF with pulmonary atresia (TOF-PA), and 6 (8.1 %) had absent pulmonary valve syndrome (TOF-APVS). 14 (18.9 %) had an abnormal karyotype including 9/14 (64.3 %) with microdeletion 22q11.2. 25 (33.8 %) had extracardiac malformation. 4 (5.4 %) had agenesis of ductus arteriosus (DA), 22 (29.7 %) had right aortic arch (RAA) and 9 (12.2 %) had major aortopulmonary collateral arteries (MAPCAs). Within the postnatal diagnosis group, no patient had TOF-PA, 4/68 (5.9 %) had TOF-APVS. 12 (17.6 %) had extracardiac malformations, 9 (13.2 %) had an abnormal karyotype including 2/9 with microdeletion 22q11.2. 10 (14.7 %) had RAA, 9 (13.2 %) had MAPCAs. There were no cases with agenesis of DA. Increasing z-score values of the left/right pulmonary artery (LPA/RPA) prenatally were associated with a lower probability for early postnatal intervention (RPA: p = 0.017; LPA: p = 0.013). Within the prenatal diagnosis group, 12 of 41 (29.3 %) live-born patients with follow-up and intention to treat needed early intervention versus 7 (10.3 %) in the postnatal diagnosis group (p = 0.02). Within the postnatal diagnosis group, there were no deaths, while 2 (4.9 %) post-intervention deaths occurred in the prenatal diagnosis group. CONCLUSION: There are no significant differences concerning post-intervention survival in the prenatal diagnosis group versus the postnatal diagnosis group. Complex cases may be underrepresented in the postnatal diagnosis group. Smaller RPA/LPA values prenatally seem to be associated with early postnatal intervention. PMID- 30453354 TI - Diffuse White Matter Involvement in Subacute Sclerosing Panencephalitis. PMID- 30453355 TI - Owl's Eye Sign in a Reversible Etiology of Spastic Quadriparesis. PMID- 30453356 TI - Bilateral Posterior Circulation Stroke in a Child with Type 1 Diabetes Mellitus. PMID- 30453357 TI - Diagnostic Pathway to Nonsense Mutation Dystrophinopathy: A Tertiary-Center, Retrospective Experience. AB - Up to 15% of Duchenne's muscular dystrophy (DMD) is caused by nonsense mutations (nm-DMD). In this study, we aimed to evaluate the age at diagnosis, presentations, and diagnostic approach in 43 nm-DMD boys. The mean age at presentation and diagnosis was 3 years and 4 years, respectively. Presenting signs or symptoms were asymptomatic creatine kinase (CK) elevation (40%), muscle weakness (30%), motor delay (18%), and walking difficulties (12%). Multiplex polymerase chain reaction (PCR) of the most commonly deleted exons were negative (n = 17), and muscle biopsy was consistent with dystrophinopathy (n = 24). In all patients, multiplex ligation-dependent probe amplification (MLPA) followed by direct sequencing of all exons, revealed nm-DMD. Mean age at genetic diagnosis was 6 years 8 months. Patients were evaluated in two-time periods, between 2006 and 2011 (Group I: n = 10) and 2011 and 2017 (Group II: n = 33). The mean age at diagnosis/genetic confirmation in Group I and in Group II was 3 years 9 months/10 years, and 4 years 1 month/5 years 9 months, respectively. Most frequently performed first step diagnostic tests in Group I and Group II were muscle biopsy and MLPA.Our study reflects the change in the age at genetic diagnosis and diagnostic approach to nm-DMD depending on the advances and availability of genetic testing. PMID- 30453358 TI - Adverse Effects of Treatment with Valproic Acid during the Neonatal Period. AB - INTRODUCTION: Valproic acid (VPA) is rarely used in neonatal period. In children under 2 years old, serious adverse effects are appear to be more frequent. AIM: The aim of our study is to report the adverse effects observed in a population of full-term newborns treated with VPA. METHOD: Full-term newborns, hospitalized at the Toulouse CHU, who presented with neonatal seizures and who received long-term treatment with VPA between 2004 and 2014 were included. RESULTS: For 5 of the 123 newborns treated with VPA, treatment had to be discontinued due to adverse effects. Three patients presented with disturbances in consciousness within 48 hours of treatment initiation, one case with a moderate overdose and two with hyperammoniemia (157 and 327 MUmol/L) without any drug overdose or underlying liver or metabolic disease (VPA-induced hyperammonemic encephalopathy). Two patients presented with secondary hematological alterations. No patient presented with liver toxicity or exacerbation of an underlying metabolic disease. CONCLUSION: While the serious adverse effects of VPA noted were all reversible with the discontinuation of the treatment, the occurrence of encephalopathies with hyperammoniemia is a serious complication that is potentially lethal and calls for close clinical monitoring of newborns treated with valproate. We provide precautions for the implementation and follow-up of VPA in newborns. PMID- 30453359 TI - ? PMID- 30453360 TI - ? PMID- 30453361 TI - ? PMID- 30453362 TI - ? PMID- 30453363 TI - ? PMID- 30453364 TI - Developmental Pharmacology - Special Issues During Childhood and Adolescence. PMID- 30453365 TI - ? PMID- 30453366 TI - Targeted Therapies in Pediatric Oncology. PMID- 30453367 TI - ? PMID- 30453368 TI - ? PMID- 30453369 TI - ? PMID- 30453370 TI - ? PMID- 30453371 TI - Disease-Specific Clinical Trial Networks: the Example of Cystic Fibrosis. PMID- 30453372 TI - Pharmacogenetics: The Solution for All Future Challenges? PMID- 30453373 TI - ? PMID- 30453374 TI - ? PMID- 30453375 TI - [A 56-Year-Old Patient with Unusual Tongue Findings]. PMID- 30453376 TI - [Left-sided Chylothorax and Tumor of the Right Anterior Mediastinum]. AB - An 82-year-old male patient presented with a left-sided spontaneous chylothorax. A computed tomographic scan of the chest revealed a cystic tumor in the right upper anterior mediastinum and nodules in the left mediastinum that we interpreted as enlarged lymph nodes. On suspicion of lymphoma and for therapy of chylothorax, we performed a left-sided thoracotomy. The putative lymph nodes proved to be chylomas. We interpret the right-sided mediastinal tumor as cystic lymphangioma causing the left-sided chylothorax at the junction of thoracic duct and venous system on the right side. PMID- 30453377 TI - [Drug Output and Aerosol Characteristics of Different Jet Nebulisers for Adults While Simulating the Nebulisation of Salbutamol]. AB - AIM: Successful inhalation therapy with nebulisers depends on the amount and quality of the aerosol. Choosing a nebuliser requires knowledge of relevant aerosol characteristics. METHODS: We analysed the aerosol performance of 9 commercially available jet nebulisers in 2 in vitro simulation models by assessing the aerosol delivery of albuterol (Sultanol forte(r) Inhalation Solution 2.5 mg/2.5 ml; GSK) over 4 minutes. The output parameters were analysed with PARI Compas II breath simulator mimicking an adult breathing pattern (Ph.Eur.9.0; n = 5/6 nebulisation), and the aerodynamic particle size distribution was determined by the Next Generation Impactor (Ph.Eur.9.0, Copley Scientific; n = 3 nebulisation). RESULTS: The aerosol performance of the devices differed considerably. The DDR varied from 196 ug/min (PARI LC Sprint (blue)) to 67 ug/min (MIDINEB). The Respirable Drug Delivery Rate (RDDR), calculated from the DDR and the Fine Particle Fraction <= 5 um, varied by a factor of 3.5 between the nebulisers tested. CONCLUSION: The results of the in vitro simulation studies can be utilised to select an appropriate nebuliser for the individual patient. In order to enhance therapeutic efficacy and patient compliance, a nebuliser with a high RDDR should be selected. PMID- 30453378 TI - An international study on the use of peroral endoscopic myotomy (POEM) in the management of esophageal diverticula: the first multicenter D-POEM experience. AB - BACKGROUND: The aim of this study is to report a novel, multicenter experience with the diverticular peroral endoscopic myotomy (D-POEM) technique in the management of esophageal diverticula. METHODS: This is a multicenter, international, retrospective study involving three centers. D-POEM was performed using the principles of submucosal endoscopy. RESULTS: A total of 11 patients with an esophageal diverticulum (Zenker's 7, mid-esophagus 1, epiphrenic 3) were included. The mean size of the esophageal diverticula was 34.5 mm. The overall technical success rate of D-POEM was 90.9 %, with a mean procedure time of 63.2 minutes. There were no adverse events. Clinical success was achieved in 100 % (10 /10), with a decrease in mean dysphagia score from 2.7 to 0.1 (P < 0.001) during a median follow-up of 145 days (interquartile range 126 - 273). CONCLUSION: Endoscopic management of esophageal diverticula using the novel technique of D POEM appears promising. This first case series on D-POEM suggests that the procedure is feasible, safe, and effective in the management of esophageal diverticula. D-POEM offers the distinct advantage of ensuring a complete septotomy. Larger studies are needed to confirm these intriguing results. PMID- 30453379 TI - 19 G nitinol needle versus 22 G needle for transduodenal endoscopic ultrasound guided sampling of pancreatic solid masses: a randomized study. AB - BACKGROUND: The aim of this prospective multicenter study was to compare a flexible 19 G needle with nitinol shaft (19 G Flex) with a standard 22 G needle for transduodenal endoscopic ultrasound (EUS)-guided sampling of pancreatic head tumors. METHODS: Patients with pancreatic head tumors requiring tissue diagnosis were randomized into two arms: puncture with either a 19 G Flex needle or a 22 G needle. The primary end point was diagnostic accuracy for malignancy. The secondary end points were ergonomic scores, sample cytohistological quality, and complications. A 6-month follow-up was performed. RESULTS: 125 patients were randomized and 122 were analyzed: 59 patients in the 19 G Flex arm and 63 patients in the 22 G arm. The final diagnosis was malignancy in 111 patients and benign condition in 11. In intention-to-treat analysis, the diagnostic accuracy for malignancy of the 19 G Flex and 22 G needles was 69.5 % (95 % confidence interval [CI] 56.1 % - 80.8 %) vs. 87.3 % (95 %CI 76.5 % - 94.4 %), respectively (P = 0.02). In per-protocol analysis excluding eight technical failures in the 19 G Flex group, the diagnostic accuracy of the 19 G Flex and 22 G needles was not statistically different: 80.4 % (95 %CI 66.9 % - 90.2 %) vs. 87.3 % (95 %CI 76.5 % - 94.4 %; P = 0.12). Technical success was higher in the 22 G arm than in the 19 G Flex arm: 100 % (95 %CI 94.3 % - 100 %) vs. 86.4 % (95 %CI 75.0 % - 94.0 %), respectively (P = 0.003). Transduodenal EUS-guided sampling was more difficult with the 19 G Flex (odds ratio 0.68, 95 %CI 0.47 - 0.97). CONCLUSION : The 19 G Flex needle was inferior to a standard 22 G needle in diagnosing pancreatic head cancer and more difficult to use in the transduodenal approach. PMID- 30453380 TI - Hybrid Arch for Acute Type A Aortic Dissection: When to Deploy the Endograft? Debate: Frozen versus Staged? AB - Advances in open and endovascular techniques have resulted in novel approaches to repair of acute type A aortic dissection. Hybrid arch procedures involve open arch resection and stent grafting of the descending aorta with stent graft insertion in one of two ways: Frozen or Staged. In this article, pros and cons of the two different paradigms of emerging hybrid arch techniques for acute type A aortic dissections are discussed. PMID- 30453381 TI - Intraneural ganglion cysts of the lower limb. AB - BACKGROUND: Intraneural ganglion cysts are rare. They affect the peripheral nerves. According to the most widely accepted theory (articular/synovial theory), the cysts are formed from a capsular defect of an adjacent joint, so that synovial fluid spreads along the epineurium of a nerve branch. This leads to diverse neurological symptoms. We will illustrate this disease based on three of our own cases. METHODS: Patients were examined between 2011 and 2018 using lower limb MRI. MRI scans were also performed for the follow-up examinations. CASE STUDIES AND DISCUSSION: The patients had many symptoms. We were able to accurately detect the intraneural ganglion cysts on MRI and provide the treating surgeons with the basis for the operation to be performed. The success of surgical therapy depends on the resection of the nerve endings supplying the joint as the only way to treat the origin of the disease and prevent recurrence. Based on our case studies, we can support the commonly favored articular/synovial theory. KEY POINTS: . Intraneural ganglion cysts can cause diverse neurological symptoms depending on their location.. . The pathogenesis is reasonably explained by the articular/synovial theory, which states that cysts are the result of a capsular defect of a joint.. . MRI is the method of choice for diagnosing intraneural ganglion cysts. However, ultrasound is also important.. . Surgery is the only curative treatment with treatment success being dependent on ligature of the nerve endings supplying the articular branch.. CITATION FORMAT: . Fricke T, Schmitt AD, Jansen O. Intraneural ganglion cysts of the lower limb. Fortschr Rontgenstr 2018; DOI: 10.1055/a-0777-2525. PMID- 30453382 TI - ? PMID- 30453383 TI - Rs3212986 polymorphism, a possible biomarker to predict smoking-related lung cancer, alters DNA repair capacity via regulating ERCC1 expression. AB - Single nucleotide polymorphisms (SNPs) in 3'UTR of key DNA repair enzyme genes are associated with inter-individual differences of DNA repair capacity (DRC) and susceptibility to a variety of human malignancies such as lung cancer. In this study, seven candidate SNPs in 3'UTR of DRC-related genes including ERCC1 (rs3212986, rs2336219, and rs735482), OGG1 (rs1052133), MLH3 (rs108621), CD3EAP (rs1007616), and PPP1R13L (rs6966) were analyzed in 300 lung cancer patients and controls from the northeast of China. Furthermore, we introduced ERCC1 (CDS+3'UTR) or CD3EAP (CDS) cDNA clone to transfect HEK293T and 16HBE cells. Cell viability between different genotypes of transfected cells exposed to BPDE was detected by CCK-8 assay, while DNA damage was visualized using gammaH2AX immunofluorescence and the modified comet assay. We found that minor A-allele of rs3212986 could reflect a linkage with increasing risk of NSCLC. Compared with CC genotype, AA genotype of ERCC1 rs3212986 was a high-risk factor for NSCLC (OR = 3.246; 95%CI: 1.375-7.663). Particularly stratified by smoking status in cases and controls, A allele of ERCC1 rs3212986 also exhibited an enhanced risk to develop lung cancer in smokers only (P < 0.05). Interestingly, reduced repair efficiency of DNA damage was observed in 293T ERCC1(AA) and 16HBE ERCC1(AA), while no significant difference was appeared in two genotypes of CD3EAP (3' adjacent gene of ERCC1) overexpressed cells. Our findings suggest that rs3212986 polymorphism in 3'UTR of ERCC1 overlapped with CD3EAP may affect the repair of the damage induced by BPDE mainly via regulating ERCC1 expression and become a potential biomarker to predict smoking-related lung cancer. PMID- 30453384 TI - Service managers' experiences of how the participation of people with intellectual disabilities can be promoted in Swedish group homes. AB - BACKGROUND: People with intellectual disabilities in staffed group homes often need lifelong support and dependency on others. Thereby, special demands are placed on staff and service managers to ensure opportunities for participation in everyday life. This study aims to explore how service managers promote participation in Swedish group homes for adults with intellectual disabilities. METHOD: A qualitative research design involving individual interviews with 14 service managers was used to gain an understanding of how the participation of adults with intellectual disabilities can be promoted in Swedish group homes. RESULTS: The results comprise two main themes; Creating preconditions for participation and Barriers for promotion of participation. CONCLUSIONS: Service managers experienced that promoting service user participation in group homes was an important part of their responsibility. The findings indicate that structural strategies such as coaching, supervision and reflection are important and should be further developed. PMID- 30453385 TI - Unique role for dentate gyrus microglia in neuroblast survival and in VEGF induced activation. AB - Neurogenic roles of microglia (MG) are thought to include an active role in adult hippocampal neurogenesis in addition to their established roles in pruning surplus dendrites and clearing dead neuroblasts. However, identification of such a role and its delineation in the neurogenic cascade is yet to be established. Using diphtheria toxin-aided MG ablation, we show that MG reduction in the DG-the site where neuronal stem cells (NSCs) reside-is sufficient to impede overall hippocampal neurogenesis due to reduced survival of newly formed neuroblasts. To examine whether MG residing in the hippocampal neurogenic zone are inherently different from MG residing elsewhere in the hippocampus, we compared growth factor responsiveness of DG MG with that of CA1 MG. Strikingly, transgenic induction of the potent neurogenic factor VEGF elicited robust on-site MG expansion and activation exclusively in the DG and despite eliciting a comparable angiogenic response in the CA1 and elsewhere. Temporally, DG-specific MG expansion preceded both angiogenic and neurogenic responses. Remarkably, even partial MG reduction during the process of VEGF-induced neurogenesis led to reducing the number of newly formed neuroblasts to the basal level. Transcriptomic analysis of MG retrieved from the naive DG and CA1 uncovered a set of genes preferentially expressed in DG MG. Notably the tyrosine kinase Axl is exclusively expressed in naive and VEGF-induced DG MG and its inhibition prevented neurogenesis augmentation by VEGF. Taken together, findings uncover inherent unique properties of DG MG of supporting both basal- and VEGF-induced adult hippocampal neurogenesis. PMID- 30453386 TI - Doxorubicin-induced heart failure in cancer patients: A cohort study based on the Korean National Health Insurance Database. AB - BACKGROUND: Doxorubicin is a typical anticancer drug that causes cardiomyopathy and heart failure (HF). The aim of our study was to investigate incidence, risk factors for doxorubicin-induced HF in Korean cancer patients and their survival rate, utilizing a nationwide population-based cohort. METHODS: We analyzed 58 541 cancer patients who received doxorubicin between 2003 and 2010. Descriptive analysis was performed in patients with breast cancer, hematologic malignancy, gynecological malignancy, and sarcoma. Risk factors associated with doxorubicin induced HF were investigated using a Cox proportional hazards model. The survival rate of doxorubicin-induced HF patients was compared with that of patients without doxorubicin-induced HF. RESULTS: A total of 2324 (4%) were diagnosed with doxorubicin-induced HF. In patients with breast cancer, predictive risk factors for doxorubicin-induced HF included age over 65 years [hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.05-1.72], hypertension [HR 2.45 (2.12- 2.84)], diabetes mellitus [HR 1.26 (1.05-1.51)], coronary artery disease [HR 2.08 (1.63 2.66)], advanced stage [HR 1.31 (1.13-1.50)], and trastuzumab administration [HR 2.94 (2.54-3.40)]. In patients with hematologic malignancy, predictive risk factors included age over 65 years [HR 1.75 (1.49-2.07)], hypertension [HR 1.62 (1.37-1.92)], and coronary artery disease [HR 2.28 (1.80-2.89)]. Five-year survival rates of patients with doxorubicin-induced HF were significantly lower relative to those of patients without HF in breast cancer and hematologic malignancy: 80% vs 84% and 69% vs 75%, respectively (P < 0.001). CONCLUSIONS: In cancer patients treated with doxorubicin, management of risk factors, early detection, and treatment for doxorubicin-induced HF might be critical for patient survival. PMID- 30453387 TI - Trauma exposure and post-traumatic stress disorder in people with intellectual disabilities: A Delphi expert rating. AB - BACKGROUND: There is a lack of research on trauma in people with intellectual disabilities. This study assessed expert consensus on the traumatic potential of a broader range of adverse life events, and differences in symptom manifestation and behavioural symptom equivalents of post-traumatic stress disorder (PTSD) symptoms. METHOD: The present authors conducted a three-step Delphi survey using a mixed-methods design. Twenty-nine expert raters participated in the survey, and 16 persisted to the final round. Consensus was calculated using the interquartile range. RESULTS: Traumatic potential was attributed to adverse life events, particularly revolving around sexuality and autonomy. DSM-5 symptoms of PTSD were rated as partially adequate, with behavioural symptom expression being the main difference to the general population. CONCLUSION: The range of traumatic events should be broadened for people with intellectual disabilities. A specific subset of events need to be defined in future research. Detection of PTSD depends upon determining specific symptom correlates of challenging behaviour. PMID- 30453388 TI - Improved long-term patient-reported health and well-being outcomes of early-stage breast cancer treated with partial breast proton therapy. AB - BACKGROUND: Because early-stage breast cancer can be treated successfully by a variety of breast-conservation approaches, long-term quality of life (QoL) is an important consideration in assessing treatment outcomes for these patients. This study compares patient-reported QoL outcomes among women with stage 0-2 disease treated via lumpectomy followed by whole breast irradiation (WBI) or partial breast proton irradiation (PBPT). METHODS: In this cross-sectional study, 129 participants evaluated QoL several years post-treatment by responding to subjective instruments, including established scalar questionnaires and self report measures. Responses were averaged between the two groups. RESULTS: At 6.5 years (median) postdiagnosis, participants' demographic, and clinical characteristics were similar. Patient-reported outcomes were reported as mean scale scores for the two groups, all displaying significant differences favoring PBPT, including: cosmetic breast cancer treatment outcome scale (BCTOS) (PBPT mean 1.45, WBI mean 1.88, P < 0.001); breast pain (PBPT mean 1.30, WBI mean 1.67, P < 0.05); breast texture (BPT mean 1.44, WBI mean 1.91, P < 0.001); clothing fit (PBPT mean 1.06, WBI 1.46, P < 0.001); fatigue (PBPT mean 2.24, WBI mean 3.77, P < 0.002); impact of daily life fatigue on personal relations (OBPT mean 0.83, WBI mean 2.15, P < 0.001); and self-consciousness (appearance dissatisfaction) (PBPT mean 1.38, WBI mean 1.77, P < 0.004). CONCLUSION: Patients' responses suggest that PBPT is associated with improved overall QoL compared to standard whole breast treatment. These self-perceptions are reported by patients who are 5-10 years post-treatment, and that PBPT may enhance QoL in a multitude of interrelated ways. PMID- 30453389 TI - Hypothyroidism is associated with worse outcomes of hepatocellular carcinoma patients after liver transplantation. AB - BACKGROUND/AIMS: Hypothyroidism has been associated with hepatocellular carcinoma (HCC) incidence; however, the relationship between hypothyroidism and HCC patient outcomes is unclear. We investigated the impact of hypothyroidism on outcomes after liver transplantation for HCC. MATERIALS AND METHODS: We retrospectively studied HCC patients transplanted between January 2000 and December 2015. Hypothyroidism was defined as a thyroid-stimulating hormone (TSH) level continuously greater than 5 mIU/L, a documented history of hypothyroidism, or treatment with thyroid hormone replacement therapy. Multivariate Cox regression was used to assess the impact of hypothyroidism on overall survival (OS) and recurrence-free survival (RFS) adjusting for potential confounders. Subgroup analyses and interaction tests were conducted to compare the impact of hypothyroidism in different subgroups and assess for possible synergistic effects. Sensitivity analyses were performed among different cohorts to verify the stability of the results. RESULTS: A total of 343 HCC patients who underwent liver transplantation were included in the analysis. The primary analysis was conducted among 288 patients diagnosed with HCC prior to transplantation. Hypothyroidism was independently associated with worse OS and RFS, as was elevated TSH. The adjusted hazard ratio (AHR) of hypothyroidism was 2.45 (95% confidence interval [CI], 1.44-4.18) for OS and 5.54 (2.36, 13.01) for RFS. The AHR of TSH for OS was 1.05 (1.02, 1.09) and 1.08 (1.03, 1.13) for RFS. No interaction was found among different subgroups categorized by etiology and comorbidity. The results were stable to sensitivity analyses. CONCLUSION: Hypothyroidism is associated with poorer overall and recurrence-free survival of HCC patients receiving liver transplantation. These results require validation. PMID- 30453390 TI - PPARbeta/delta-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1DeltaE9 astrocytes. AB - Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bioenergetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer's disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARbeta/delta) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate-limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1-mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742-treated mice did not show altered astrocytic glial fibrillary acidic protein-immunoreactivity or reduction in amyloid beta (Abeta) load, GW0742 treatment increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Abeta induced impairment of long-term potentiation in hippocampal slices. Collectively, these data suggest that PPARbeta/delta-agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD. PMID- 30453391 TI - Reactive astrocytes in multiple sclerosis impair neuronal outgrowth through TRPM7 mediated chondroitin sulfate proteoglycan production. AB - Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS), characterized by inflammation-mediated demyelination, axonal injury and neurodegeneration. The mechanisms underlying impaired neuronal function are not fully understood, but evidence is accumulating that the presence of the gliotic scar produced by reactive astrocytes play a critical role in these detrimental processes. Here, we identified astrocytic Transient Receptor Potential cation channel, subfamily M, member 7 (TRPM7), a Ca2+ -permeable nonselective cation channel, as a novel player in the formation of a gliotic scar. TRPM7 was found to be highly expressed in reactive astrocytes within well characterized MS lesions and upregulated in primary astrocytes under chronic inflammatory conditions. TRPM7 overexpressing astrocytes impaired neuronal outgrowth in vitro by increasing the production of chondroitin sulfate proteoglycans, a key component of the gliotic scar. These findings indicate that astrocytic TRPM7 is a critical regulator of the formation of a gliotic scar and provide a novel mechanism by which reactive astrocytes affect neuronal outgrowth. PMID- 30453392 TI - Demographics, stage distribution, and relative roles of surgery and radiotherapy on survival of persons with primary prostate sarcomas. AB - BACKGROUND: Primary prostate sarcomas (PPS) are rare. Outcomes for this cancer have not been well characterized. MATERIALS AND METHODS: Subjects with a PPS diagnosed between 1973 and 2014 were identified in the SEER database. Subjects were stratified by disease stage and types of therapies received. Disease specific survival (DSS) and Overall survival (OS) was estimated by Kaplan-Meier analysis and cohorts were compared with a univariate and multivariable Cox regression. RESULTS: The incidence of PPS among all prostate cancer diagnoses was 0.02%. Subjects younger than age 26 years at diagnosis represented 29% of cases, and 32% of primary prostate sarcomas were rhabdomyosarcoma histology. RHABDOMYOSARCOMA HISTOLOGIES: The median age at diagnosis was 9 years. Between age 0-25 years rhabdomyosarcoma accounted for 96.4% of primary prostate sarcoma diagnoses, after age 25 rhabdomyosarcoma represented 15% of new diagnoses. The 10 year DSS and OS for rhabdomyosarcoma was 47% and 44%. NON-RHABDOMYOSARCOMA HISTOLOGIES: The median age at diagnosis was 71 years. The most common diagnoses were leiomyosarcoma (33%) and carcinosarcoma (28%). Localized, regional, or distant disease occurred in 40%, 34%, and 26% of cases. The 10-year DSS and OS were 26% and 14%. In locally advanced cases, RT added to surgery trended toward improved DSS (P = 0.10). CONCLUSIONS: Disease-specific survival and OS for non rhabdomyosarcoma histologies appear inferior to those of rhabdomyosarcoma. The addition of RT to surgical resection may improve DSS in locally advanced non rhabdomyosarcoma. This is the largest report of the incidence, stage distribution, and survival for this extremely rare urologic malignancy providing valuable prognostic information. PMID- 30453393 TI - Efficacy of a socioemotional learning programme in a sample of children with intellectual disability. AB - Socioemotional learning (SEL) is the process of developing social and emotional competences through which the child learns to recognize and manage emotions, care for others, make good decisions, behave responsibly and ethically, develop positive relationships and avoid negative behaviours (Promoting social and emotional learning: Guidelines for educators, 1997). To promote the development of these competences, specific programmes are developed. This study aims to analyse the impact of a SEL programme among children with intellectual disability. Two groups were established, control and experimental, and the Test of Emotion Comprehension (TEC) (Test of emotion comprehension - TEC, 2000; Les emotions a l'ecole, emotions et apprentissage, 2004) was applied to both as pre- and post-test. The programme was implemented in the experimental group, based on simply illustrated stories alluding the basic emotions. The findings suggest that the programme is effective in the development of socioemotional competences (SEC) in subjects with intellectual disabilities, evidencing the positive effects that the intervention programme had with the experimental group. PMID- 30453394 TI - [Puncture cryodestruction of recurrent facial area basaliomas with ultrasound scan and surgery monitoring]. AB - Ultrasound scan allows determining tumor border in the area of inflammatory infiltrate, creating a three-dimensional plan of the operation, performing accurate pointing injecting cryoprobes as well as managing a monitor of cryoablation. As a result the frequency of repeated recurrences of infected recurrent tumors in difficult anatomical areas of the face decreased to 4%. PMID- 30453395 TI - [Results of complex treatment of patients with thoracic esophageal cancer]. AB - In the open, comparative, non-randomized and prospective study conducted from 2007 to 2014 there were included 83 patients who received combined treatment for thoracic esophageal cancer. For a comparative analysis there was used a retrospective control group of 51 patients with esophageal cancer who had undergone surgery alone from 1999 to 2014. Complex treatment of patients with advanced forms of thoracic esophageal cancer included argon-plasma recanalization of the lumen of the esophagus followed by neoadjuvant chemoradiotherapy in two versions. One group of patients (29) received external beam radiotherapy, prescription dose of 40-45 Gy, the other group of patients (54) received intraluminal brachytherapy, 3 sessions of 7 Gy, prescription dose of 21 Gy. All patients synchronously with radiotherapy there were performed two cycles of polychemotherapy on PF scheme. A month after the neoadjuvant treatment there was carried out resection of the esophagus with simultaneous plastics by gastric stem. Complete local tumor regression was achieved in 34,7% of patients in group with intraluminal brachytherapy and 30% in the group with external beam radiotherapy. Long-term results could be traced in 90.8% of patients. Using chemoradiotherapy on preoperative stage we managed to increase disease-free and overall survival of patients with an increase of median of progression-free survival - 27 against 12 months and overall survival - 29 against 14 months in comparison with surgery alone. PMID- 30453396 TI - [Current status and challenges of otologic robotic system]. PMID- 30453397 TI - [A prospective controlled study on the proper time of intratympanic steroid for profound sudden sensorineural hearing loss of total frequency type]. AB - Objective: To investigate the proper time of intratympanic steroid as combination therapy in treatment of patients with profound sudden sensorineural hearing loss(SSNHL) of total frequency type. Methods: This prospective study included 50 patients with SSNHL in the First Affiliated Hospital of Chongqing Medical University from June 2017 to February 2018.All these patients had profound hearing loss averaged more than 81 dB at all frequencies (250-8 000 Hz). They were divided into two groups.The patients in group A were treated with simultaneous oral prednisone (1 mg/kg, qd) and intratympanic methylprednisolone (40 mg, qd) for 5 days.The patients in group B were treated with oral prednisone for 5 days as in group A, and then those who had no significant improvement were subsequently treated with intratympanic methylprednisolone (40 mg, qd)for further 5 days.All patients were treated with additional intravenous batroxobin and ginkgo biloba leaves extract.Following examination of pure tone audiogram, hearing gains and effective rates were statistically analyzed in both groups with SPSS software package(version 20.0). Results: Hearings in both groups were improved significantly after treatment.In group A(20 cases), hearing gain was (29.2+/-22.7) dB and total effective rate was 65.0%, while in group B(22 cases), they were (27.3+/-22) dB and 68.2% respectively.There were no significant differences in hearing gain and recovery rate between two groups (hearing gain, P=0.793; total effective rate, P=0.827). Conclusions: For patients with profound SSNHL of total frequency type, the efficacies of intratympanic steroid as simultaneous and subsequent therapy are equivalent. Therefore, subsequent intratympanic glucocorticoid is recommended for SSNHL patient of total frequency type to reduce complications and medical expenses. PMID- 30453398 TI - [A pilot study of the unilateral centrifugation subjective visual vertical in healthy young people]. AB - Objective: To evaluate the data of unilateral centrifugation subjective visual vertical (UC-SVV) in healthy young people.To study the function of utricle. Methods: Between Decem ber 2017 and May 2018, thirty-two healthy young volunteers were tested by static subjective visual vertical(SVV) and low velocity UC-SVV with Neuro Kinetics Inc I-portal 6.0 Video nystagmus recording system and NOTC rotating chair system.The static SVV preset angle were -15.00 degrees , 15.00 degrees , -20.00 degrees , 20.00 degrees , -12.00 degrees and 12.00 degrees respectively.UC-SVV test parameters: rotating chair's peak speed was 60 degrees /s.The shift time from the middle to the lateral position was 30 s and the displacement was 3.85 cm.The chair rotated at 60 s at left, right and middle positions.Subjects underwent SVV during this period.SPSS 17.0 software was used to analyze the data. Results: The mean and standard deviation of static SVV deviation in 32 volunteers was 0.21 degrees +/-0.17 degrees , 95%CI (-0.14 degrees , 0.55 degrees ). The mean and standard deviation of UC-SVV in the left, middle and right positions of the clockwise was 0.24 degrees +/-0.25 degrees , 0.10 degrees +/-0.27 degrees , -0.63 degrees +/-0.26 degrees , 95%CI(-0.26 degrees , 0.74 degrees ), (-0.65 degrees , 0.44 degrees ), (-1.16 degrees , -0.10 degrees ). The mean and standard deviation of UC-SVV in the left, middle and right positions of the counter clockwise was 0.03 degrees +/-0.27 degrees , -0.11 degrees +/-0.26 degrees , -0.23 degrees +/-0.26 degrees , 95%CI(-0.52 degrees , 0.59 degrees ), (-0.65 degrees , 0.42 degrees ), (-0.76 degrees , 0.30 degrees ). There was significant difference in the deviation between the left and the right side of counter clockwise rotation of UC-SVV(t=2.432, P<0.05), however, there was no significant difference in the angle of deviation between the left and right sides and the median position(t value was 0.951, -1.400, both P>0.05). There was no significant difference among each position in clockwise rotation of UC SVV(F=0.253, P>0.05). Conclusion: UC-SVV test with peak speed of 60 degrees /s can cause vertical line deviation in the left and right lateral position, but the angle is small and the value of clinical application is limited. PMID- 30453399 TI - [Efficacy and associated factors of olfactory training in the treatment of olfactory dysfunction]. AB - Objective: To explore the clinical effects and the influence factors of olfactory training in the treatment of olfactory dysfunction. Methods: A total of 86 patients with olfactory dysfunction (49 post-infectious and 37 post-traumatic) in Beijing Anzhen Hospital during Dec 2016 to May 2017 were recruited in this prospective study. The clinical data of patients were analyzed, including gender, age, body mass index (BMI), course of disease, smoking history, drinking history, diabetes history, hypertension history, hyperlipidemia history, and anxiety visual analogue score (VAS). All patients were treated with olfactory training for 16 weeks, and all of them underwent Sniffin' Sticks olfactory test before and after treatment, which was evaluated by composite threshold-discrimination identification score (TDI). SPSS 23.0 software, paired t test and univariate and multivariate Logistic regression analysis were used to analyze the data. Results: Eighty patients received treatment, including 46 post-infectious olfactory dysfunction and 34 post-traumatic olfactory dysfunction. After olfactory training, the total scores of TDI increased with statistically significant (18.3+/-8.6 vs 13.6+/-7.4, t=-6.158, P<0.05). The overall efficacy was 40% (32/80). The effective rate were 45.7% (21/46) in post-infectious olfactory dysfunction and 32.4% (11/34) in post-traumatic olfactory dysfunction respectively, with no statistically significant difference (chi(2)=1.441, P=0.230). Logistic regression analysis showed that the course of disease was an influence factor in the clinical curative effect (OR=0.881, 95%CI: 0.799-0.973, P=0.012). In patients with less than a year of olfactory dysfunction, the olfactory function improved obviously with the efficiency of 50.9% (29/57). Conclusion: Sixteen weeks of olfactory training provides a significant therapeutic effect on the post-infectious and post-traumatic olfactory dysfunction, and the olfactory training can achieve better therapeutic effects at the early stage. PMID- 30453400 TI - [Clinical features, diagnosis and treatment of silent sinus syndrome]. AB - Objective: To explore the clinical features, diagnostic methods and therapeutic strategy of silent sinus syndrome (SSS). Methods: A retrospective study was made on eight SSS patients treated during 2013-2016 in Longgang ENT Hospital and Otorhinolaryngology Hospital of the First Affiliated Hospital of SUN Yat-sen University. The following clinical data, including demographic data, symptoms, history of trauma and surgery, signs, imaging examination, endoscopic surgery and postoperative outcomes, were analyzed to summarize the diagnosis and treatment experiences. Results: Eight SSS patients showed the following clinical features: the proportions of both sexes and sinus sides were 4 to 4; seven cases (7/8) were adult, with an average of (48.1+/-11.8)y; seven cases (7/8) had long history of trauma or surgery, with an average of (17.9+/-10.5)y; seven cases (7/8) cannot recall the exact course of SSS; six cases (6/8) had no nasal symptoms; eight cases (8/8) had unilateral ocular discomforts; eight cases (8/8) had signs of unilateral enophthalmos (2-5 mm), accompanied with hypoglobus; and by CT and MRI scanning, eight cases (8/8) showed the unilateral maxillary sinus outlet obstruction, sinus full opacification, sinus wall bony rarefaction, sinus wall contraction, sinus volume loss, and the ipsilateral orbital floor bowing descent and orbital volume increase. After treated by endoscopic sinus surgery and followed-up for one year, four cases were cured, and the other four improved; no intra- or post-operative complications occurred; and no individual need a two stage orbital plastic reconstruction. Conclusions: SSS often develops in the unilateral maxillary sinus of adult patient with long history of trauma or surgery, but the nasal symptoms and signs are silent. Diagnostic for SSS depends on characteristic ocular sign and sinus CT imaging. Endoscopic sinus surgery helps to improve ocular and nasal signs and promote orbital self-reconstruction. PMID- 30453401 TI - [Analysis of long-term effect of juvenile-onset recurrent respiratory papillomatosis]. AB - Objective: To observe the clinical course of children with juvenile-onset recurrent respiratory papillomatosis (JORRP) until 14 years old. Methods: The clinical data of one hundred and twenty cases treated between Januray 1, 2002 and September 30, 2017 in Beijing Tongren Hospital were analyzed retrospectively. Excluding the deaths and the lost, patients who could be >= 5 years without recurrence, were defined as the cured group, and < 5 years with recurrence defined as the recurrent group. Furthermore, using statistical methods to analyze the differences of the age of initial operation, total number of operations, invasive lesion, HPV infection, tracheotomy, airway dissemination after tracheotomy and time of tube wear between the two groups. Results: One hundred and three cases were followed up, except for the six deaths.Numbers of operations in eight cases were <=2, and >=3 in eighty nine cases.Peak of the primary surgical age were about 4.5 years old, while the self-healing trend occurred at nine years old. In the cured group, forty three cases were cured, with a curative rate of 41.7% (43/103), and there were all fifty four survivors in the recurrent group.The total number of operations, invasive cases, HPV positive cases and the G score of hoarseness in the recurrent group were higher than those in the cured group (F=13.02, chi(2)=13.04, chi(2)=17.37, Z=-4.59, P<0.05). The number of tracheal dissemination caused by tracheotomy in the recurrent group (66.7%, 27.8%)was more than that in the cured group (chi(2)=16.01, P<0.05). Compared with the time of wearing a tracheostomy tube in cured group, the recurrent group was longer ((3.4+/-3.1) years vs (8.3+/-6.7) years, chi(2)=7.19, P<0.05). Conclusions: 41.7% of the patients had no relapse for at least five years.There exsisted differences between the cured and recurrent group in the following aspects: the total numbers of surgery, the agression of the lesions, tracheal intratracheal dissemination after tracheotomy, the time of tracheotomy, the HPV typing and the G grading of hoarseness. PMID- 30453402 TI - [Screening of microRNAs targeting Notch signaling pathway implicated in inner ear development and the role of microRNA-384-5p]. AB - Objective: To screen the key microRNAs targeting Notch signaling pathway in inner ear and investigate its potential regulating function. Methods: The interaction network and the Core-Notch network, involved with key genes in Notch signal pathway and differential-expressed microRNAs in inner ear, were constructed by bioinformatics methods. The important microRNAs in regulating Notch signaling pathway were screened via topological and GO analysis, followed by in vivo and in vitro investigation. Results: MiRNA-384-5p was identified as a key regulator specifically expressed in mouse brain and inner ear, which could down-regulate Notch1. The Notch1 expression was found significantly down-regulated in miRNA-384 5p-mimic-transfected HeLa cells. The dual-luciferase reporter gene assay further confirmed the effect of miRNA-384-5p on the down-regulation of Notch1 and Dll4 in Notch signaling pathway. Conclusions: The Core-Notch network is constructed to screen microRNAs implicated in inner ear development, and miRNA-384-5p is screened and verified to be target-regulating the Notch signaling pathway, which could be the potential target in the regeneration of impaired hair cells. PMID- 30453403 TI - [Clinical application of a self-developed bone dust collector in mastoid cavity obliteration following mastoidectomy]. AB - Objective: To introduce a self-developed bone dust collector designed by the authors and evaluate its efficiency in mastoid obliteration following mastoidectomy. Methods: Consecutive patients, from April 2017 to March 2018, who prepared to receive mastoidectomy were randomly divided into two groups, and in each group the bone dust was harvested by self-developed bone dust collector or by conventional used method respectively in mastoidectomy. The amount of the harvested bone dust and the time consumed in the collecting procedure were compared between two groups. The infection of the bone dust after mastoid obliteration was also evaluated during follow up. Results: 33 patients were recruited in bone dust collector group, and 31 patients in conventional method group.There is no significance of difference between two groups in sex ratio, age and pneumatization of mastoid cells (P>0.05 for all). The median amount of bone dust harvested by bone dust collector was significantly larger than that collected by conventional method (1.8 g vs 1.1 g, P<0.05). The median time spent in bone dust collector group was significantly shorter than that spent in conventional method group (4 minutes vs 6 minutes, P<0.05). No bone dust infection was found in the follow-up in all patients. Conclusion: The present self-developed bone dust collector is a easy and useful apparatus which can significantly improve the efficiency of collecting bone dust in mastoidectomy. PMID- 30453404 TI - [Predictive study on recurrence of chronic sinusitis with nasal polyps by tissue eosinophils and sinus CT]. AB - Objective: To investigate the correlation between postoperative recurrence and clinical parameters in patients with chronic rhinosinusitis with nasal polyps (CRSwNP), and to study predicitve value of total scores of eosinophils (EOS) and sinus CT for postoperative recurrence. Methods: A retrospective analysis of 264 patients with CRSwNP who were admitted to the First Affiliated Hospital of Wenzhou Medical University from June 2013 to December 2015 was performed. The patient was subjected to a visual analogue scale (VAS) score, a skin prick test, a peripheral blood cell count, a sinus CT score, and a nasal polyp EOS count. All patients underwent endoscopic surgery and were followed up for at least 2 years. The demographic characteristics of the nasal polyps recurrence group and the non recurrence group were compared with other clinical indicators. Quantitative data were compared by t test or Mann-Whitney U test, qualitative data were compared by chi-square test, and Logistic regression analysis was used for Logistic regression analysis. The risk factors for recurrence were assessed. The best cut off value was determined by using the receiver operating characteristic (ROC) curve. The predictive value of the parameters was determined by area under curve (AUC). The difference was statistically significant at P<0.05. Results: The recurrence rate of the study patients was 43.56% (115/264). Sex, olfactory VAS score, total sinus CT score, peripheral blood neutrophil ratio, peripheral blood EOS absolute value and proportion, and tissue EOS absolute value and proportion were associated with postoperative recurrence of nasal polyps (chi(2)=5.241, t= 3.146, t=-7.441, chi(2)=180.617, t=-5.313, chi(2)=100.067, t=-7.471, chi(2)=258.916, all P<0.05), and the tissue EOS ratio and total sinus CT scores have higher predictive value for recurrence of nasal polyps (AUC values were 0.793, 0.767, respectively, all P<0.001). With the EOS ratio of nasal polyps >0.032, the sensitivity of predicting recurrence was 83.48%, the specificity was 56.38%. With the total score of sinus CT>15, the sensitivity of predicting recurrence was 51.30% and the specificity was 87.25%. The combined sensitivity of predictive recurrence was 92.00% and the specificity was 49.20%. Conclusion: The percentage of EOS in nasal polyps and the total score of sinus CT in patients with CRSwNP have better predictive diagnostic value for recurrence of nasal polyps. PMID- 30453406 TI - [A case report of papilloma of the eustachian tube with secretory otitis media]. PMID- 30453405 TI - [Clinical evaluation of vocal fold paralysis in 207 children]. AB - Objective: To investigate the etiology and clinical characteristics of vocal fold paralysis in children. To provide useful information for diagnosis, management and prognosis in the clinical work. Methods: Two hundred and seven children with vocal fold paralysis in Children's Hospital of Fudan University were retrospectively studied, and followed-up. Results: All the patients had hoarseness.151 cases had vocal paralysis in the left side and the main etiology was pulmonary arterial hypertension.43 cases had bilateral vocal paralysis and all of them had respiratory problems.The main etiology were congenital tracheoesophageal malformations.13 cases had vocal paralysis in the right side.In terms of etiology, 8 cases were related to intracranial lesions, 2 cases were idiopathic. Conclusions: The main etiologies of left vocal fold paralysis were cardiovascular diseases, and bilateral vocal paralysis were congenital tracheoesophageal malformations.The main etiologies of right vocal fold paralysis were neoplastic and central lesion.The prognosis of bilateral vocal fold paralysis and right vocal fold paralysis was poor. PMID- 30453407 TI - [Eight cases of bromine rat poisoning with nosebleed as the first symptom]. PMID- 30453408 TI - [Acute retropharyngeal abscess after open neck trauma: a case report]. PMID- 30453409 TI - [One case of oculomotor nerve paralysis caused by chronic ethmoidal sinusitis]. PMID- 30453411 TI - [One case of repeated sudden deafness]. PMID- 30453410 TI - [Concurrence of Frey syndrome after treatment of parotid mixed tumor operation by the xenogenic a cellular dermal matrix hypodermic implantation: a case report]. PMID- 30453412 TI - [Malignant schwannomas in the prevertebral space: a case report]. PMID- 30453413 TI - [Mucoepidermoid carcinoma of tongue: 5 cases]. PMID- 30453414 TI - [Advances in the treatment of sinonasal malignancy]. AB - Sinonasal neoplasms are common tumors in the head and neck.The types of tumor pathological tissues are complex and diverse, and the incidence of malignant tumors is relatively low.The malignant tumor of paranasal sinuses is occult, and most of them are locally advanced.Although surgery is the main treatment for such diseases, the specific treatment plan is still controversial.This article reviews the treatment of sinonasal malignancy. PMID- 30453415 TI - [Progress of the laryngeal framework surgery]. AB - Isshiki systematically developed thyroplasty in the 1970 s. Based on Isshiki's classification of thyroplasty, laryngeal framework surgery was classified by the Phonosurgery Committee of the European Laryngological Society in 2001. Then laryngeal framework surgery became more systematic and standardized, and made new progress in clinical applications and basic theoretical research. This article mainly expounds new progress in laryngeal framework surgery over the last five years. PMID- 30453416 TI - [Minutes of the 2018 China Rhinology Annual Meeting]. PMID- 30453417 TI - [Summary of 2018 National Young Middle-aged Conference on Otorhinolaryngology Head and Neck Surgery of Chinese Academy of Medicine Meeting]. PMID- 30453418 TI - [Chinese guideline on menopause management and menopause hormone therapy (2018)]. PMID- 30453419 TI - [Facing tomorrow, the rapidly developing reproductive medicine]. PMID- 30453420 TI - [Relationship between endometrial thickness and pregnancy outcomes based on frozen-thawed embryo transfer cycles]. AB - Objective: To explore the relationship between endometrial thickness and clinical pregnancy outcomes in frozen-thawed embryo transfer cycles. Methods: A prospective study was performed for 1 475 frozen-thawed embryo transfer cycles at Peking University People's Hospital from January 2014 to December 2015. The patients were divided into different groups according to endometrial thickness of ovulation day in natural menstrual cycles or endometrial transformation day in hormone replacement cycles;patients with thin endometrium were enndometrial thickness <=6 mm. Then the clinical pregnancy outcomes including clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were analyzed. Results: In all, 1 475 frozen-thawed embryo transfer cycles were analyzed. The mean age of patients was (32.5+/-3.9) years old and mean endometrial thickness was (9.2+/-1.9) mm, and mean number of embryos was 2.03+/-0.37. The study included 518 (35.1%) natural menstrual cycles and 957 (64.9%) hormone replacement cycles. The number of embryo-transfer cycles and blastocyst-transfer cycles were respectively 700 (47.5%) and 775 (52.5%) . The overall clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were 54.4%, 35.7%, 23.3%, 24.1%, 43.9%, respectively. The ectopic pregnancy rate in the study was 0.6%. In patients with thin endometrium,there were significant differences in 2 pronucleus count (P=0.016) and available embryo count (P=0.024) between cycles that resulted in pregnancy and those that did not;besides, the use of sildenafil and growth hormone did not improve pregnancy outcomes in patients with thin endometrium (P=0.183, P=0.400) . The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer were similar in patients with thin endometrium (all P>0.05) . Conclusions: Patients with thin endometrium have poor pregnancy outcomes. The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer are similar in patients with thin endometrium. Compared thin endometrium and non thin endometrium patients, the clinical pregnancy rate and live birth rate of blastocysts have more substantial decline than those of embryos. Improving the quality of embryo could improve the pregnancy outcome of patients with thin endometrium. Sildenafil and growth hormone could not improve pregnancy outcome in patients with thin endometrium. PMID- 30453421 TI - [Comparison of clinical outcomes of frozen-thawed blastocysts derived from non pronucleus or two pronucleus zygotes]. AB - Objective: To evaluate the application value of the blastocysts derived from non pronucleus (0PN) zygotes by the good quality blastocyst formation rate and the clinical outcomes of frozen-thawed blastocyst transfers. Methods: The good quality blastocyst formation rate derived from 0PN zygotes was compared with that derived from2 pronucleus (2PN) zygotes in in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles from January 2015 to December 2016. In addition, the clinical pregnancy, embryo implantation and live birth rates of frozen-thawed blastocyst transfers with blastocysts derived from 0PN and 2PN zygotes were analyzed on corresponding dates. Results: (1) In IVF cycles, the high quality blastocysts formation rate of 2PN embryos was significantly higher than that of 0PN (46.64% versus 42.42%, P<0.01) . In ICSI cycles, the high quality blastocysts formation rate of 2PN embryos was markedly higher than that of 0PN (41.96% versus 21.73%, P<0.01) . (2) In frozen-thawed embryo transfer cycles for IVF, the clinical pregnancy, implantation and live birth rates of D5 0PN blastocysts were significantly higher than those of D6 2PN (52.64% versus 46.78%, 49.91% versus 41.20%, 46.54% versus 39.56%, all P<0.05) , however, the abortion and newborn abnormal rates of D5 0PN blastocysts were lower than those of D6 2PN blastocysts (17.37% versus 23.36%, 1.31% versus 4.21%, both P<0.05) ; the clinical pregnancy, implantation and livebirth rates of D5 2PN blastocysts were significantly higher than those of D5 0PN (59.73% versus 52.64%, 55.95% versus 49.91%, 53.03% versus 46.54%, all P<0.05) , but newborn abnormal rate was a little higher than that of D5 0PN (3.90% versus 1.31%, P<0.05) ; the clinical pregnancy, implantation and live birth rates of D5 2PN blastocysts were significantly higher than those of D6 2PN (59.73% versus 46.78%, 55.95% versus 41.20%, 53.03% versus 39.56%, all P<0.05) , and the abortion rate of D5 2PN blastocysts was lower than that of D6 2PN blastocysts (18.23% versus 23.36%, P<0.05) . Conclusions: Although the blastocysts derived from 0PN could be transffered, the blastocysts derived from 2PN zygotes are preferred in all cycles. In IVF cycles, the good quality blastocysts derived from 2PN or 0PN zygotes will be transferred. PMID- 30453422 TI - [Analysis of clinical factors on early pregnancy loss during in vitro fertilization-embryo transfer treatment and natural pregnancy]. AB - Objective: To compare differences of clinical factors related to early pregnancy loss between invitro fertilization-embryo transfer (IVF-ET) treatment and natural pegnancy. Methods: A retrospective analysis was performed on the 363 cases of early pregnancy loss between Dec. 2015 to May 2016 in Peking University Third Hospital, during which 173 cases were after IVF-ET treatment (IVF-ET group) , and others were natural pregnancies (natural group) . Results: The average age in IVF ET group was significantly higher than that in the natural group [ (34.1+/-4.3) versus (31.8+/-4.1) years old, P<0.01]. The terminating time of pregnancy loss in IVF-ET group was short than that in the natural group [ (59.8+/-9.2) versus (69.9+/-11.1) days, P<0.01]. The incidence of embryo abnormal chromosome in IVF ET group was significantly lower than that in the natural group [57.2% (99/173) versus 74.2% (141/190) , P<0.01], during which abnormal chromosome numbers were the most common. Conclusions: The pregnancy loss of early pregnancy is mainly caused by chromosome abnormality. The proportion of chromosome abnormality in early pregnancy loss after IVF-ET is not higher than that of natural pregnancy, indicating that there are relatively reliable gametes and embryo safety in IVF treatment. PMID- 30453423 TI - [Survey of prevalence of iron deficiency and iron deficiency anemia in pregnant women in urban areas of China]. AB - Objective: To investigate the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) in pregnant women in urban areas of China. Methods: The study was a national cross-sectional survey conducted from September 19th, 2016 to November 20th, 2016. According to the classification of the National Bureau of Statistics, all survey sites were set up in 6 regions of the country.Pregnant women were continuously selected using multistage stratified sampling. A total of 12 403 pregnant women were collected and examined for serum ferritin and hemoglobin levels. Results: The median serum ferritin level during pregnancy was 20.60 MUg/L (11.78-36.98 MUg/L) , the hemoglobin level was (118+/-12) g/L. With the progress of pregnancy, the levels of serum ferritin and hemoglobin decreased gradually. The median serum ferritin levels in the first, second trimester and third trimester were 54.30 MUg/L (34.48-94.01 MUg/L) , 28.60 MUg/L (16.40-50.52 MUg/L) , and 16.70 MUg/L (10.20-27.00 MUg/L) respectively (P<0.01) . The mean hemoglobin levels were (127+/-10) g/L, (119+/-11) g/L and (117+/-11) g/L respectively (P<0.01) . The prevalence of ID in urban pregnant women was 48.16% (5 973/12 403) , and IDA prevalence was 13.87% (1 720/12 403) . The prevalence of IDA in the first, second trimester and third trimester were 1.96% (20/1 019) , 8.40% (293/3 487) and 17.82% (1 407/7 897) ,respectively (P<0.01) . The prevalence of standardized ID and IDA were significantly different in various regions of China (P<0.01) . The standardized prevalence of ID were relatively higher in East China and Northeast China, 57.37% and 53.41% respectively, while it was the lowest in Southwest China, 30.51%. The standardized prevalence of IDA in South Central, Northwest, and East China were relatively high, 21.30%, 16.97% and 17.53% respectively, and the standardized prevalence of IDA in Southwest China was the lowest, 5.44%, the differents in various regions were significant (all P<0.01) . Conclusion: The current phenomenon of ID and IDA in pregnant women is still very common, and nutrition and health care during pregnancy should be strengthened. PMID- 30453425 TI - [Strategy for prevention and control of imported infectious disease]. AB - The process of globalization increases the risk of global transmission of infectious diseases, resulting in pressure for country's prevention and control of imported infectious disease. Based on the risk assessment of disease importation and local transmission, a strategy that conducting importation prevention and routine prevention and control before the importation of disease and taking emergency control measures after the importation of disease was developed. In addition, it is important to take part in global infectious disease response action, aid the countries with outbreak or epidemic to actively decrease the risk of disease importation. PMID- 30453424 TI - [Management and pregnancy outcomes of heterotopic pregnancy]. AB - Objective: To investigate the clinical features, diagnosis and treatments of heterotopic pregnancy (HP) and demonstrate the outcomes of HP after the surgical treatment of ectopic pregnancies. Methods: A retrospective analysis was performed on 144 cases of HP in Women's Hospital, School of Medicine, Zhejiang University from January 2003 to December 2016. Results: (1) Clinical features of HP:the average age of patients was (30.8+/-3.8) years old, body mass index (BMI) was (21.9+/-2.9) kg/m(2), and was diagnosed at (6.5+/-1.3) weeks gestational age. Four patients (2.8%) were naturally pregnant, 10 patients (6.9%) received ovulation induction, and 130 patients (90.3%) had received infertility treatments. Fifty-one patients (35.4%) had no clinical symptoms, and 93 patients (64.6%) had clinical symptoms included vaginal hemorrhage,abdominal pain and hemorrhagic shock caused by intraperitoneal hemorrhage. The location of ectopic pregnancy was most common in the fallopian tubes (59.0%, 85/144) and the interstitial part (33.3%,48/144) . (2) Ectopic pregnancy treatment of HP:thirteen patients underwent expectation treatment, and the remaining 131 cases underwent surgical treatment, including laparoscopy (n=56) , laprotomy (n=52) , and fetal reduction (n=23) . Among the 131 patients underwent surgery, intrauterine pregnancy were found inevitable abortion in 6 cases preoperatively. The total early abortion rate after surgery was 14.4% (18/125) ; the second operation rate was 3.1% (4/131) . (3) Intrauterine pregnancy outcome of HP: 120 intrauterine fetal were survival, the total live birth rate was 83.3% (120/144) .One hundred and seven intrauterine fetal were survival after operation and the live birth rate after operation was 85.6% (107/125) . Twenty-nine cases were premature delivery and the premature delivery rate was 24.2% (29/120) . There was no significant differences between tubal HP and interstitial HP group in the preterm birth rate [25.8% (16/62) vs 26.3% (10/38) ; chi(2)=0.003, P>0.05]. Cesarean section rate of delivery in interstitial HP group was significantly higher than that in tubal HP group [97.4% (37/38) vs 59.7% (37/62) ], and the difference was statistically significant (chi(2)=17.400, P<0.05) . Conclusions: The clinical manifestations of HP are diversified, combining of high risk factors, clinical symptoms and ultrasonography could improve the accuracy of diagnosis. Different method has been used to treat HP, such as laparoscopic or laparotomy and fetal reduction, and there are varying degrees of failure rate and postoperative abortion rate. We should consider carefully to adopt expectant management. Through individualized treatment, most HP could get good perinatal outcomes. PMID- 30453426 TI - [Analysis on the current situation of insufficient sleep and its association with physical exercise among Chinese Han students aged 9-18 years, in 2014]. AB - Objective: To describe the situation of insufficient sleep and the association between insufficient sleep and physical exercise, among Chinese Han students aged 9-18 years. Methods: We selected 172 197 Chinese Han students aged 9-18 years from the project 2014 Chinese National Survey on Students Constitution and Health. The average sleep duration per day of less than 9 h for children aged 9 12 years and of less than 8 h for adolescents aged 13-18 years, were defined as insufficient sleep. We described the distribution of sleep duration and the prevalence rates of insufficient sleep for each subgroup. Logistic regression models were established to assess the association between insufficient sleep and physical exercise. Results: In 2014, 6.6%, 30.8%, 26.3%, 20.8%, 13.8% and 1.8% of the Chinese Han students self-reported sleep duration were <6, 6-, 7-, 8- and >=10 h, respectively. The overall prevalence rate of insufficient sleep was 77.2%, with 75.8% for boys and 78.6% for girls. No gender disparity was found at each 9-11 age groups. However, in the 12-18 age groups, the prevalence rates for girls were significantly higher than that for boys. The prevalence rates of insufficient sleep for primary school, middle school and high school students were66.6%, 74.1% and 93.8%, respectively. Rates were increasing with age for children aged 9-12 years and adolescents aged 13-18 years respectively. The three provinces with the lowest prevalence rates of insufficient sleep were Zhejiang (68.8%), Jiangsu (66.7%) and Shaanxi (65.2%). Data from the logistic regression models revealed that, when comparing to those students with only exercise of <0.5 h per day, the exercise hours of 0.5-1 h (OR=0.72, 95%CI: 0.69-0.74) or >=1 h (OR=0.46, 95%CI: 0.44-0.47) per day seemed as protective factors for insufficient sleep. When compared with physical exercise frequency <2 times per week, the 2 times (OR=0.82, 95%CI: 0.78-0.86) or >2 times (OR=0.65, 95%CI: 0.62-0.68) frequencies also appeared as protective. Conclusions: The prevalence rate of insufficient sleep prevailing among students aged 9-18 years was high, in China. Our data called for setting up effective measures to deal with this situation. PMID- 30453427 TI - [Analysis on reproductive health service, demographics and characteristics of internal migrant population in three municipalities of China]. AB - Objective: To investigate the utilization of reproductive health services and relating factors among internal migrant population in Beijing, Shanghai and Chongqing. Methods: A multi-stage cluster sampling method was adopted in this cross-sectional study, conducted in Beijing, Shanghai and Chongqing from August 2014 to August 2015. Standard methods on statistics and nonlinear canonical correlation were applied. Results: Out of the 6 545 internal migrant persons, 41.76% ever used the reproductive health services in the past year. Results from the nonlinear canonical correlation analysis revealed that the utilization of reproductive health services was correlated with the demographic features (=0.28, P<0.000 1) and characteristics of the population mobility (=0.21, P<0.000 1), respectively. For the above said demographic features, canonical variable L(1) which represented the demographic features was mainly determined by area, occupation and education attainment. Canonical variable M(1) that reflected the utilization of reproductive health services, was mainly determined by factors as free contraceptives, education on contraception/reproductive health, and pregnancy diagnosis/antenatal care. As for the characteristics of the population mobility, canonical variable U(1), which represented population mobility characteristics, was mainly determined by factors as purpose of migration, current pattern of residence and the length of annual stay in the area. Again, the canonical variable V(1), reflecting the use of reproductive health services was mainly determined by factors as free contraceptives, check-up on reproductive tract infection, education on contraception/reproductive health, and pregnancy diagnosis/antenatal care. Conclusions: The utilization of reproductive health services was low among the internal migrant population under study. Responsible departments for health and family planning in those cities should make internal migrants attach importance to reproductive health. PMID- 30453428 TI - [A study on the burden and causes of hospitalization and deaths in Shenzhen, between 1995 and 2014]. AB - Objective: Data from the surveillance program was collected, to analyze the situation of hospitalization and cases of death with recorded causes, in Shenzhen, from 1995 to 2014. Situation of hospitalization and causes of deaths were studied in Shenzhen which had been a fast-developing city with growing number of immigrants so as to provide reference for decision-making on related prevention and control strategies. Methods: Data on hospitalizations and deaths collected from the surveillance program, were classified by both International Classification of Diseases (ICD)- 9 and ICD-10. A database was constructed with methods on related descriptive and trend analysis. Results: Around 6.3 million inpatients were seen in the past two decades in Shenzhen. The top five diseases for hospitalization were pregnancy childbirth and puerperium complications, respiratory diseases, injury and poisoning, digestive system diseases and circulatory system diseases, that accounting for 68.4% of all the hospitalization burden. The number of inpatients increased annually, with an 11 times increase during the past two decades. Proportions for pregnancy childbirth and puerperium complications, circulatory system diseases and urinary system diseases all showed increasing (chi(2)=53 806.94, 6 893.95 and 15 383.14, P<0.01), while proportions for injuries and poisoning, respiratory diseases, digestive system diseases showed a declining trend (chi(2)=131 480.09,1 711.84 and 11 367.66, P<0.01). Number of cumulative inpatient deaths exceeded 60 000, with the top five causes as malignant tumor, circulatory system diseases, injury and poisoning, respiratory system diseases and digestive system diseases, that accounting for 82.28% of all the inpatient deaths. Deaths due to circulatory system diseases, injury and poisoning increased and then decreased. Malignant tumor and respiratory diseases-induced deaths showed an increasing trend (chi(2)=1 546.48, 309.55, P<0.01), while induced deaths from disease of the other systems showed slight changes. The overall case fatality rate showed an annual decline (chi(2)=4 378.63, P<0.01), from 2.23% in 1995 to 0.74% in 2014, with mortality attribute to tumor, circulatory system disease decreased significantly. Conclusions: Shenzhen had been under an ageing transition, with relatively young population living in the city. Chronic diseases such as tumor gradually had become the major causes for heavy hospitalization burden on the population of Shenzhen. PMID- 30453429 TI - [Effect of famine exposure on the risk of chronic disease in later life among population in Harbin]. AB - Objective: To study the relations between famine exposure and the risk of chronic diseases as diabetes mellitus, obesity, hypertension, coronary heart disease and stroke in the population of Harbin. Methods: Our data was collected from the baseline survey-the China Kadoorie Biobank project (CKB) in Harbin. Retrospective cohort study design was used. Related risks on chronic diseases including diabetes mellitus, obesity, hypertension, coronary heart disease and stroke, were compared among the famine exposed or non-exposed people, respectively by logistic analysis method. Results: After adjusted for factors as age, sex, physical activity, smoking, alcohol intake, diet, family history of diseases, it appeared that the factor 'famine exposure' had increased the risks of diseases as obesity (OR=1.204, 95%CI: 1.104-1.313, P<0.01), hypertension (OR=1.315, 95%CI: 1.210 1.429, P<0.01) and coronary heart disease (OR=1.495, 95%CI: 1.369-1.632, P<0.01). The lower the age of population being exposed to famine, the greater the risk of the development of all kinds of chronic diseases. Conclusions: Famine exposure appeared a risk factor for obesity, hypertension, and coronary heart disease. It is of great significance to ensure the life-long nutrition of the people, especially in the early and adolescent stages, to prevent obesity, hypertension, and coronary heart disease in their later lives. PMID- 30453430 TI - [Relations between pregestational body mass index, gestational weight gain and birth weight of neonates among women in the Southwest areas of China: A prospective cohort study]. AB - Objective: To explore the effects of both pre-gestational BMI and gestational weight gain (GWG) on the birth weight of neonates. Methods: A total of 5 395 pregnant women were selected from the Southwest areas of China (Sichuan/Yunnan/Guizhou) and were divided into groups as pre-gestational underweight, normal weight, overweight and obesity, according to the WHO Recommendation on BMI Classification. Guidelines on Pregnancy weight were adopted from the Institute of Medicine to confirm the accuracy of GWG. Multinomial logistic regression model was used to assess the associations between pregestational BMI and GWG, on the birth weight of the neonates. Results: After adjusting for related confounders, low pre-gestational BMI appeared as a risk factor for SGA (OR=1.91, 95%CI: 1.47-2.50), and was also associated with the decreased risk of LGA (OR=0.55, 95%CI: 0.47-0.66). Inadequate GWG was both associated with the increased risk of delivering SGA (OR=1.57, 95%CI: 1.21-2.03) and the decreased risk of LGA (OR=0.48, 95%CI: 0.41-0.57). Pre-gestational overweight/obesity (OR=1.85, 95%CI: 1.58-2.17) and excessive GWG (OR=1.87, 95%CI: 1.67- 2.11) were both positively associated with the risks on LGA. Data from the stratified analysis indicated that inadequate GWG was positively associated with the risk of SGA among underweight or normal weight women (all P<0.05), but not with those overweight/obese women. Conclusions: Pre-gestational BMI and GWG were important influencing factors on the birth weight of neonates. Health education programs for pregnant women should be intensified and gestational weight gain should also be reasonably under control. PMID- 30453431 TI - [Associations between maternal exposure to chemical fertilizers during pregnancy and the risk of offspring's low birth weights]. AB - Objective: To explore the association between the consumption of chemical fertilizers and the risk of low birth weight (LBW), to provide references for prevention programs on LBW and to improve the birth outcomes. Methods: Stratified multivariate logistic regression method was used in this study involving 153 preterm LBW infants, 179 term LBW infants and 204 normal control infants that were randomly selected from the birth monitoring data between October 2007 and September 2012 in Pingding county, Shanxi province. Associations between the risk of LBW and maternal exposure to chemical fertilizers during pregnancy were identified. A normal control group was set up to compare results between preterm and term LBW groups. Results: Totally, 18 749 infants were born between 2007 and 2012, with the total incidence rates of LBW as 48.50/00, preterm LBW as 19.40/00, and term LBW as 29.10/00. Concerning the case control study on preterm LBW, after adjustment for confounding factors, the risk of preterm LBW appeared 2.51 (95%CI: 1.05-5.99) times higher in villages with annual consumption of chemical fertilizer >=100 tons than those villages that using chemical fertilizer less than 50 tons. No significant statistical associations were found between the amounts of household chemical fertilizer consumption and the risks of preterm LBW. Regarding the case control study on term LBW, after adjustment for confounding factors, in villages with >=100 tons annual consumption of chemical fertilizers, the risk of term LBW was 4.03 (95%CI: 1.63-9.92) times of the risk in villages where the annal use of chemical fertilizers was less than 50 tons. There was no significant association between household consumption of chemical fertilizers and the risk of term LBW. Conclusions: Maternal exposure to chemical fertilizers during pregnancy was associated with the risk of LBW. Our findings suggested that the amount of chemical fertilizer consumption in rural areas seemed also associated with the risks of other adverse pregnancy outcomes. Women should avoid the chance of exposure to chemical fertilizers during pregnancy and the consumption of chemical fertilizers should be carefully managed. PMID- 30453432 TI - [Pregnancy-related anxiety associated with small-for-gestational-age infants]. AB - Objective: To investigate the second or third trimester pregnancy-related anxiety on small-for-gestational-age infants. Methods: This study was based on Ma'anshan Birth Cohort Study (MABC), with 3 040 maternal-singleton pairs finally selected for data analysis, from May 2013 to September 2014. The psychological state of pregnancy was evaluated according to a self-developed 'anxiety scale for gestation'. Small-for-gestational-age was defined as 'having birth weight below the 10(th) percentile at a particular gestational week', while large-for gestational-age infants was defined as 'having birth weight above the 90(th) percentile'. Birth weight between the 10(th) and 90(th) percentile was classified as appropriate-for-gestational age infants. chi(2) test was used to compare the distribution of characteristics in pregnancy among three groups with different birth weights. Multivariate logistic regression models were conducted to evaluate the associations between third trimester pregnancy- related anxiety and birth weight. Results: The incidence rates of small- and large-gestational-age infants were 9.6% and 16.6%, respectively. Difference between women with only one of the second or third trimester pregnancy-related anxiety syndromes and small-for gestational-age infants showed no statistical significance. Women with both second and third trimester pregnancy-related anxieties might increase the risk of small-for-gestational-age infants (OR=1.39, 95%CI: 1.04-1.87). However, there was no significant difference between pregnancy-related anxiety and large-for- gestational-age infants (OR=1.05, 95%CI: 0.81-1.35) noticed. Conclusion: Women with second and third trimester pregnancy-related anxiety appeared a risk factor for small-for-gestational-age infants. PMID- 30453433 TI - [Association between congenital heart disease and medication taken during pregnancy among women of childbearing age]. AB - Objective: To analyze the relationship between medication taken during pregnancy and congenital heart disease of the newborns. Methods: A large cross-sectional survey was conducted between August and November 2013. A questionnaire survey was conducted among the childbearing aged women, selected through multistage stratified random sampling in Shaanxi from 2010 to 2013. All of the childbearing aged women under study were in pregnancy and with definite pregnancy outcomes. Multivariable Poisson regression was conducted for data analyses. Results: A total of 28 680 cases were included in this study. The proportion of medication taken at any time during pregnancy was 16.0%, and the prevalence of congenital heart disease among the newborns was 67.9/10 000. After adjustment for factors as general demographic characteristic, history of heart disease and drug allergy and the situation of disease during pregnancy of these women, results from the multivariable Poisson regression showed that, factors as taking drugs (RR=1.95, 95%CI: 1.42- 2.68), cold medicine (RR=1.68, 95%CI: 1.07-2.64), antibiotics (RR=1.90, 95%CI: 1.25-2.90), salicylates (RR=5.01, 95%CI: 1.84-13.64) and antifungal drugs (RR=10.22, 95%CI: 3.25-32.19) during pregnancy were all related to congenital heart disease, and with the history of taking cold medicine (RR=1.90, 95%CI: 1.01-3.61), antibiotics (RR=2.18, 95%CI: 1.17-4.06), salicylates (RR=6.07, 95%CI: 1.45-25.41), antifungal drugs (RR=21.01, 95%CI: 4.17-105.87) and other drugs (RR=2.31, 95%CI: 1.19-4.47) during early pregnancy. These factors were with higher risks for congenital heart disease. Conclusion: Women of childbearing age who took cold medicine, antibiotics, salicylic acid drugs, antifungal drugs and other drugs during early pregnancy would increase the risks related to congenital heart diseases. PMID- 30453434 TI - [Recent transmission of pulmonary tuberculosis and its influencing factors in Jing'an district, Shanghai, 2010-2015]. AB - Objective: To understand the recent transmission of Mycobacterium tuberculosis (MTB), and to identify the influencing factors of recent transmission among pulmonary tuberculosis (TB) patients in Jing'an district, Shanghai. Methods: The genotypes and drug resistances of MTB isolated from TB patients registered in the TB designated hospitals in Jing'an district during 2010-2015 were analyzed through 12-loci Mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR)(QUB11b, QUB18, Mtub21, Miru26, QUB26, Mtub04, Miru31, Miru40, VNTR2372, VNTR3820, 3232, 4120), and tested for drug susceptibility as well. With the results of field epidemiological investigation, univariate and multivariate analyses were performed to analyze the distribution of the clusters and influencing factors on recent transmission. Results: This study enrolled 80 TB patients, 23 (28.75%) had a resistance to at least one anti-TB drug, and the prevalence of multidrug-resistant tuberculosis (MDR-TB) was 16.25%. A total of 65 genotypes were identified with 58 (72.50%, 58/80) being unique and 7 clusters with 2-10 isolated in each cluster. The proportion of clustering was 27.50% (22/80). Results from the multivariate analysis revealed that multidrug- resistance (OR=35.799, 95%CI: 4.239-302.346) and having comorbidity with TB (OR=7.695, 95%CI: 1.421-41.658) were independently associated with the clustering, which suggesting a recent transmission. The field investigation to the clustered cases proved that the patients in two clusters had epidemiological links, one was between family members, and the other contained 10 MDR-TB patients with 9 knowing each other which have a definite connection and 1 having the possible connection with them. Conclusion: Recent transmission of tuberculosis happened among TB patients in Jing'an district, with high risks among the MDR-TB patients. PMID- 30453435 TI - [Estimation on the incidence and mortality of kidney cancer in China, in 2014]. AB - Objective: To estimate the incidence and mortality of kidney cancer in China in 2014, based on the cancer registration data. Data was collected through the National Central Cancer Registry (NCCR). Methods: All together, 449 cancer registries submitted required data on incidence and deaths of kidney cancer occurred in 2014, to the NCCR. After evaluation on the quality of data,339 registries were accepted for analysis and stratified by areas (urban/rural) and age groups. Combined with data from the National population in 2014, the nationwide incidence and mortality of kidney cancer were estimated. Data from the 2000 National census was used, and with Segi's population used for the rates of age-standardized incidence/mortality. Results: The qualified 339 cancer registries covered a total population of 288 243 347, with 144 061 915 in urban and 144 181 432 in rural areas. The percentage of morphologically verified cases and cases with only available death certificates were 72.70% and 1.27%, respectively. The mortality to incidence ratio was 0.37. The estimates of new cases were around 68 300 in whole China, in 2014, with a crude incidence rate as 4.99/100 000 (95%CI: 4.95/100 000-5.03/100 000). The age-standardized incidence rates of kidney cancer, estimated by China standard population (ASR China) and world standard population (ASR world) were 3.43/100 000 (95%CI: 3.40/100 000 3.46/100 000) and 3.40/100 000 (95%CI: 3.37/100 000- 3.43/100 000), respectively. The cumulative incidence rate of kidney cancer was 0.40% in China. The crude and ASR China incidence rates for males appeared as 6.09/100 000 (6.03/100 000 6.15/100 000) and 4.32/100 000 (4.28/100 000-4.36/100 000), respectively, whereas those were 3.84/100 000 (3.79/100 000-3.89/100 000) and 2.54/100 000 (2.50/100 000-2.58/100 000) for females. The crude and ASR China incidence rates in urban areas appeared as 6.60/100 000 (95%CI: 6.54/100 000-6.66/100 000) and 4.25/100 000 (95%CI: 4.21/100 000-4.29/100 000), respectively, whereas those were 3.05/100 000 (95%CI: 3.01/100 000-3.09/100 000) and 2.29/100 000 (95%CI: 2.25/100 000 2.33/100 000) in rural areas. The estimates of kidney cancer deaths were around 25 600 in the country, in 2014, with a crude mortality rate of 1.87/100 000 (95%CI: 1.85/100 000-1.89/100 000). The ASR China and ASR world mortality rates appeared as 1.16/100 000 (95%CI: 1.14/100 000-1.18/100 000) and 1.16/100 000(95%CI: 1.14/100 000-1.18/100 000), respectively, with a cumulative mortality rate (0-74 years old) of 0.12%. The crude and ASR China mortality rates were 2.31/100 000 (95%CI: 2.27/100 000- 2.35/100 000) and 1.52/100 000 (95%CI: 1.50/100 000-1.54/100 000) for males, respectively, whereas those were 1.41/100 000 (95%CI: 1.38/100 000-1.44/100 000) and 0.81/100 000 (95%CI: 0.79/100 000- 0.83/100 000) for females. The crude and ASR China mortality rates were 2.49/100 000 (95%CI: 2.45/100 000-2.53/100 000) and 1.42/100 000 (95%CI: 1.40/100 000 1.44/100 000) in urban areas, respectively, whereas those were 1.12/100 000 (95%CI: 1.09/100 000-1.15/100 000) and 0.78/100 000 (95%CI: 0.76/100 000-0.80/100 000) in the rural areas. Conclusions: Both the incidence and mortality of kidney cancer seemed low, in China. However, the incidence of kidney cancer had greatly increased. Our findings suggested that prevention and control strategies for kidney cancer should be focused on males in the urban areas. PMID- 30453436 TI - [Epidemiological characteristics of hepatitis A and hepatitis E in different periods of vaccination in China, 2004-2015]. AB - Objective: Through analyzing the epidemiological characteristics of hepatitis A and E and the situation of vaccination, to promote the recommendation profile on Hepatitis E vaccination program, in China. Methods: Three phases of time span were divided as 2004-2007, 2008-2011 and 2012-2015, with age groups divided as <20, 20-29, 30-39 and >=40. Incidence rates in both different phases and age groups were compared. Numbers of Hepatitis A and E vaccines released and used, were described. Results: Between 2004 and 2015, a declining trend in the reported incidence of hepatitis A (t=-12.15, P<0.001), but an increasing trend in hepatitis E (t=6.63, P<0.001) were noticed. The mean number of hepatitis A cases declined from 6 515 to 1 986 between 2004 and 2007 while the number of hepatitis E cases increased from 1 491 to 2 277 between 2012 and 2015. The peaks of hepatitis E appeared persistent annually, in March. The incidence of hepatitis A declined in three regions, with the western region (3.46/100 000) much higher than the eastern (1.13/100 000) or central regions (1.14/100 000) (chi(2)=32 630, P<0.01). The incidence of hepatitis E increased both in the central (1.74/100 000) and western regions (1.58/100 000), but more in the eastern region (2.66/100 000) (chi(2)=6 009, P<0.01). Incidence of hepatitis A declined in all age groups and declined by 84.36% among the 0-19 group. However, the incidence of hepatitis E showed an increasing trend among the >=20 group. Incidence rates appeared higher in the older age groups. The coverage of hepatitis A vaccine increased from 62.05% to 93.54%, but with a negative association seen between the coverage of Hepatitis A vaccine and the incidence (F=10.69, chi(2)<0.05). Conclusion: The incidence of Hepatitis A declined sharply in China while hepatitis E was still increasing from 2004 to 2015, calling for the expansion on the coverage of Hepatitis E vaccine in the whole population. PMID- 30453437 TI - [Epidemiological and pathogenic characteristics of mumps in Fujian province, 2005 2017]. AB - Objective: To understand the epidemiological and etiological characteristics of mumps in Fujian province, 2005-2017. Methods: All the reported mumps cases were collected through the National Notifiable Disease Information Management System, 2005-2017. Active search and interviews were conducted to collect the information on vaccination of mumps. Throat swab specimens were collected for cells culture, genotyping and gene sequence analysis on mumps virus (MuV). Results: A total of 83 959 cases of mumps were reported in Fujian province from 2005 to 2017, with an average annual incidence of 17.6 per 100 000. Since 2007, the incidence appeared increasing but then decreasing, reaching the lowest level (7.5 per 100 000), after the setup of a monitoring program. Annually, the onset time of mumps showed an obvious two seasonal peaks, one from April to July, with a weakening trend, and the other from October to January with a rising trend. Most of the mumps cases occurred among students, kindergarten and scattered children (89.2%, 5 814/6 517), children aged 5-9 years (38.8%, 2 527/6 517), with cases reported from every region. Program from the pathogen surveillance showed that the transmission chain of G genotype mumps virus did exist in Fujian. Data from the sequence analysis revealed that mutations in the nucleotide of G genotype strain in 2015 had led to mutation of 6 amino acid sites in the SH gene coding region, resulting in the differences appearing in both nucleotide and amino acid homology with type A vaccine strain. Conclusions: The incidence of mumps decreased annually, in Fujian. Prevention programs should focus on primary and secondary school students. In Fujian province, we also noticed the transmission chain of mumps G genotype with some amino acid mutations in the SH gene coding region. Monitor programs on both epidemiologic and etiology, should be strengthened. PMID- 30453438 TI - [Impact of HIV and Mycobacterium tuberculosis co-infection on related mortality]. AB - Objective: To understand the impact of HIV and Mycobacterium tuberculosis (MTB) co-infectious (HIV/MTB) on related mortality in Guangxi Zhuang Autonomous Region, provide evidence for the development of a better HIV/MTB co-infection control and prevention program. Methods: A multiple cross-systems check (MCSC) approach was used to confirm the HIV/MTB co-infection individuals on data related to treatment, follow-up, epidemiological comprehensive and Tuberculosis (TB) special report system. Social demography characteristics, incidence of TB among HIV positive individuals, HIV incidence among MTB infection persons etc., were described. We compared the mortalities and related risks between HIV/MTB co infection and mono HIV positive individuals as well as between the HIV/MTB co infection and mono MTB infection persons, using both the Chi Square test and the Cox's proportional hazard regression model (Cox). Results: Reported data showed that the incidence of MTB co-infection in the HIV cohort was 17.72% (2 533/14 293), while HIV incidence in the TB patients was 5.57% (2 351/42 205), respectively. The mortality of HIV/MTB co-infection in the HIV/AIDS cohort was 15.16% (384/2 533) within one-year of observation and was significantly higher than the mortality (13.63%,1 603/11 760) of mono HIV positive individuals (P<0.000 1). The percentage of the HIV/AIDS death cases was 19.33% (384/1 987) who registered and died in the 2011 calendar year were caused by MTB co infection. Among all the HIV/MTB co-infection patients who had been identified from the HIV cohort, 60.05% (1 521/2 533) had initiated ART, 15.48% (392/2 533) had been cured for TB and 27.48% (696/2 533) had been under complete TB regimen. Among the confirmed HIV/MTB cases from the TB cohort, the cure rate of TB was 19.70% (463/2 351) and the percentage of completed TB regimen was 37.26% (876/2 351). The percentage of the individuals whose CD(4)(+) T lymphocyte cells count appeared less than 200 cell/MUl was 64.13% (785/1 224), upon the HIV diagnoses were made. Compared with individuals who were under mono HIV infection, the mortality risk on HIV/MTB co-infection was 1.17 times higher during the five-year observation period, then the patients with only mono MTB infection and the mortality risk in patients with HIV/MTB co-infection was 25.68 times higher under the 12-month observation period. Conclusions: Both the incidence and mortality of HIV/MTB appeared high in Guangxi, with mortality and the risk of mortality in the HIV/MTB co-infection group significantly higher than that in both the HIV mono infection and the MTB mono infections groups. Both the rate of antiretroviral treatment coverage and the cure rate of TB treatment should be increased in no time as well as the capability of early TB case-finding among people living with HIV. PMID- 30453439 TI - [Prevalence and associated risk factors on preterm birth, low birth weight, and small for gestational age among HIV-infected pregnant women in Hunan province, 2011-2017]. AB - Objective: To describe the prevalence of preterm birth (PB), low birth weight (LBW), and small for gestational age (SGA) among HIV-infected pregnant women and to identify associated risk factors in Hunan province. Methods: This study appeared a retrospective one on HIV-infected pregnant women retrieved from Information System of Prevention of Mother-to-child Transmission of HIV management in Hunan province, between January 2011 and December 2017. Information regarding demographic characteristics, pregnancy, antiretroviral therapy (ART), husbands/partners' relevant situation and pregnancy outcomes, among these HIV infected pregnant women were collected and analyzed. The incidence rates on PB, LBW and SGA were calculated. Multivariate logistic regression was used to analyze the associated risk factors. Results: A total of 780 HIV-infected pregnant women were enrolled. The prevalence rates on PB, LBW and SGA in HIV- infected pregnant women appeared as 7.9% (62/780), 9.9% (77/780) and 21.3% (166/780), respectively. Results from the multivariate logistic regression analysis showed that factors as pregnancy related diseases as moderate/severe anemia, hypertensive, initial time of ART <14 gestational weeks (compared to those women without ART during pregnancy) and husbands/partners' age >35 years old (compared to husbands/partners' age 26-30 years old) etc., were associated with an increased risk of PB with adjusted OR as 4.59 (95%CI: 1.51-13.95), 4.90 (95%CI: 1.56 15.46), 2.40 (95%CI: 1.26- 4.56) and 2.29 (95%CI: 1.21-4.36). For LBW, pregnancy moderate/severe anemia, pregnancy HBV infection and initial time of ART <14 gestational weeks were associated with an increased risk of LBW, with adjusted OR as 3.28 (95%CI: 1.13-9.54), 4.37 (95%CI: 1.42-13.44) and 2.68 (95%CI: 1.51-4.76), respectively. For SGA, pregnancy HBV infection and initial time of ART <14 gestational weeks were risk factors for SGA, with adjusted OR as 4.41 (95%CI: 1.43-13.63) and 2.67 (95%CI: 1.51-4.73), respectively. Conclusion: Preterm birth, LBW and SGA were common adverse pregnancy outcomes for HIV-infected pregnant women and were associated with factors as pregnancy complications, ART and husbands/partners' age. PMID- 30453440 TI - [Study on the super-antigen genes of group A Streptococcus pyogenes strains isolated from patients with scarlet fever and pharyngeal infection, in Beijing, 2015-2017]. AB - Objective: To analyze the characteristics of super-antigen (SAg) of group A Streptococcus pyogenes (GAS), isolated from patients with scarlet fever or pharyngeal infections in Beijing between 2015-2017. Methods: Throat swab specimens from patients with scarlet fever or pharyngeal infections were collected and tested for GAS. Eleven currently known SAg genes including SpeA, speC, speG, speH, speI, speJ, speK, speL, speM, smeZ and ssa were tested by real time PCR while M protein genes (emm genes) were amplified and sequenced by PCR. Results: A total of 377 GAS were isolated from 6 801 throat swab specimens, with the positive rate as 5.5%. There were obvious changes noticed among speC, speG, speH and speK in three years. A total of 45 SAg genes profiles were observed, according to the SAgs inclusion. There were significant differences appeared in the frequencies among two of the highest SAg genes profiles between emm1 and emm12 strains (chi(2)=38.196, P<0.001; chi(2)=72.310, P<0.001). There also appeared significant differences in the frequencies of speA, speH, speI and speJ between emm1 and emm12 strains (chi(2)=146.154, P<0.001; chi(2)=52.31, P<0.001; chi(2)=58.43, P<0.001; chi(2)=144.70, P<0.001). Conclusions: Obvious changes were noticed among SAg genes including speC, speG, speH and speK from patients with scarlet fever or pharyngeal infections in Beijing between 2015-2017. SAg genes including speA, speH, speI and speJ appeared to be associated with the emm 1 and emm 12 strains. More kinds of SAg genes profiles were isolated form GAS but with no significant differences seen in the main SAg genes profiles, during the epidemic period. PMID- 30453442 TI - [Factors related to thyroid carcinoma in Zhejiang province: a matched case control study]. AB - Objective: To explore the influencing factors related to thyroid carcinoma. Methods: Matched by sex, age and original residential areas, 659 pairs of cases and controls were recruited and studied. Methods including both single factor analysis and multivariate conditional logistic regression analysis were carried out to identify the influencing factors. Results: Multivariate conditional logistic regression analysis showed that higher education, being diabetic, alcohol intake, tea drinking, occupational physical activity and the frequency of eating fishes/eggs etc., were potentially protective to thyroid carcinoma. Depression, personal history of CT examination and less salt intake seemed to be risk factors on thyroid carcinoma. For males, factors as alcohol intake, tea drinking, occupational physical activity and frequent egg-eating appeared protective. For females, higher education, diabetes, tea drinking, occupational physical activity, frequent consumption of fishes/eggs, short duration of menstruation appeared as possibly protective. Conclusion: Higher education, diabetes, alcohol intake, tea drinking, occupational physical activity, frequent consumption of fishes/eggs, depression, personal history of CT examination and less salt intake served as potential influencing factors to thyroid carcinoma. PMID- 30453441 TI - [Mosquitoes, midges and related arboviruses in southeast Sichuan province]. AB - Objective: To investigate the distribution patterns of mosquitoes, midges and related arboviruses in Sichuan province. Methods: Blood-sucking insects were collected from houses and pens, using the ultraviolet lights. Mosquito samples were classified according to morphologic characteristics and then stored at liquid nitrogen. All samples were incubated with BHK-21 and C6/36 cells for virus isolation and then detected for their viral genes. Sequences of the virus were identified and analyzed by molecular biological software, such as BioEdit 7.0.5.3, MEGA 6.0. Results: In total, 17 019 mosquitoes from 3 genera and 4 species and 12 700 midges were collected from the southeast regions of Sichuan province in 2016 and 2017. Among them, 79.4% (13 519/17 019) belonged to Culex tritaeniorhynchus with 11.1% (1 897/17 019) as Armigeres subalbatus, 5.5% (930/17 019) were Anopheles sinensis and 4.0% (673/17 019) were Anopheles sinensis 3 virus strains that isolated from Culex tritaeniorhynchus were identified as typeI Japanese encephalitis virus. Seven pools of mosquitoes isolated from Hejiang county were identified Japanese encephalitis virus gene positive through PCR amplification. With 4 pool midges were detected positive for Akabane virus through PCR gene amplification while midges samples didn't have virus isolates. Conclusions: Culex tritaeniorhynchus appeared the predominant species in the southeast regions of Sichuan. Japanese encephalitis virus transmitted by mosquitoes and Akabane virus by midges were prevalent in southeast Sichuan province. PMID- 30453443 TI - [A Meta-analysis on the relations between short-term exposure to PM(2.5) and both mortality and related emergency visits in China]. AB - Objective: To carry out a quantitative estimate that related to the effects of short-term exposure to PM(2.5) on all-cause mortality and emergency visits in China by using the systematic review and Meta-analysis. Methods: We selected all the studies published before March 2018 from China National Knowledge Infrastructure, Wanfang database, PubMed and EMBASE and data on relative risk (RR), excess risk (ER) and their 95%CIs: appeared in these papers were extracted. According to the differences in the size or direction (heterogeneity) of the results, we computed summary estimates of the effect values using a random-effect or fixed effect model. We also conducted the subgroup analysis and Meta-analysis to have assessed the selected studies for the evidence of study bias. Results: A total of 33 original studies, indexed in databases, were identified. Among those studies, 39 sets of data on mortality and 4 sets of data on emergency were valid to show that within the daily concentration range from 47.7 to 176.7 MUg/m(3), for 10 MUg/m(3) increases in PM(2.5) concentrations, it would increase the daily numbers of deaths by 0.49% (95%CI: 0.39%-0.59%) and 0.30% (95%CI: 0.10%-0.51%) for all-cause deaths and all-cause emergency-room visits, respectively. For subgroup analysis, the combined effect of PM(2.5) in causing short-term all-cause deaths in the northern areas (ER=0.42%, 95%CI: 0.30%-0.54%) seemed lower than that in the southern areas (ER=0.63%, 95%CI: 0.44%-0.82%). The combined effect of PM(2.5) concentration below 75 MUg/m(3) (ER=0.50%, 95%CI: 0.37%-0.62%) was higher than that of PM(2.5) concentration >=75 MUg/m(3) (ER=0.39%, 95%CI: 0.26%-0.52%). Conclusion: Within the concentration range from 47.7 to 176.7 MUg/m(3), short term exposure to current level of PM(2.5) might increase both the all-cause daily mortality and daily emergency visits in China. PMID- 30453444 TI - [Fujian Tulou Family Cohort Study: study design and characteristics of participants and pedigrees in baseline investigation]. AB - Objective: To describe the study design, the characteristics of participants as well as the pedigrees included in the baseline survey of Fujian Tulou Family Cohort Study. Methods: Fujian Tulou Family Cohort Study was a prospective open cohort study with a biological sample bank. A baseline survey was conducted in Tulou areas of Nanjing county in Fujian province from 2015 to 2018, including questionnaire survey, physical and biochemical indicators examinations, and blood sample collection in adults aged >=18 years. In addition, family relationship of the participants was also recorded. The pedigree information of the juveniles under 18 years old were also collected. Results: The baseline survey included 2 727 individuals in two clans, of whom 2 373 (87.0%) were adults, and 2 126 participants completed questionnaires, physical examinations and biochemical tests. The average age of the 2 126 participants was (57.9+/-13.3) years, with 39.4% being males. The current smoking rates in male and female participants were 41.2% and 2.1%, respectively. The corresponding rates of current alcohol consumption were 19.0% and 2.6%. For common chronic diseases, the prevalence rates were 51.3% for hypertension, 9.7% for diabetes and 26.7% for hyperlipemia according to the self-reported disease diagnoses, health examination results and biochemical examination results in class II or III hospitals. Based on the family relationship information and genealogical data, 710 pedigrees were finally identified, consisting of 5 087 family members. The numbers of five, four, three, and two generations pedigrees were 3, 88, 238 and 381, respectively. The pairs of the first to the fifth degree relatives were 12 039, 2 662, 1 511, 202 and 31, respectively. Conclusion: The establishment of Fujian Tulou Family Cohort provides valuable resources for exploring the genetic risk factors, environmental risk factors and gene-environment interactions contributing to the risk of common chronic diseases. PMID- 30453445 TI - [Advances in epidemiological studies regarding related psychosocial risk factors on the incidence of diabetes mellitus]. AB - Both the increasing prevalence and growing burden of diabetes mellitus have caused global public health concerns. With the development of bio-psycho-social medical model, the impact of psychosocial factors on diabetes has attracted more attentions among the researchers. This paper summarizes findings from epidemiological studies that focusing on the association between diabetes and related psychosocial risk factors. Foreign studies have shown that psychological factors are closely related to diabetes, but the conclusions on social factors are inconsistent. Domestic studies have only targeted on small-sample-sized and cross-sectional studies. More longitudinal research is needed to confirm the impact of psychosocial factors on the risk of diabetes. PMID- 30453446 TI - Usefulness of Narrow-Band Imaging in Endoscopic Submucosal Dissection of the Stomach. AB - There have been many advances in endoscopic imaging technologies. Magnifying endoscopy with narrow-band imaging is an innovative optical technology that enables the precise discrimination of structural changes on the mucosal surface. Several studies have demonstrated its usefulness and superiority for tumor detection and differential diagnosis in the stomach as compared with conventional endoscopy. Furthermore, magnifying endoscopy with narrow-band imaging has the potential to predict the invasion depth and tumor margins during gastric endoscopic submucosal dissection. Classifications of the findings of magnifying endoscopy with narrow-band imaging based on microvascular and pit patterns have been proposed and have shown excellent correlations with invasion depth confirmed by microscopy. In terms of tumor margin prediction, magnifying endoscopy with narrow-band imaging offers superior delineation of gastric tumor margins compared with traditional chromoendoscopy with indigo carmine. The limitations of narrow band imaging, such as the need for considerable training, long procedure time, and lack of studies about its usefulness in undifferentiated cancer, should be resolved to confirm its value as a complementary method to endoscopic submucosal dissection. However, the role of magnifying endoscopy with narrow-band imaging is expected to increase steadily with the increasing use of endoscopic submucosal dissection for the treatment of gastric tumors. PMID- 30453447 TI - Curcumin loading potentiates the neuroprotective efficacy of Fe3O4 magnetic nanoparticles in cerebellum cells of schizophrenic rats. AB - BACKGROUND: The aim of this study was to investigate the neurotoxic effects of Fe3O4 magnetic- CurNPs on isolated schizophrenia mitochondria of rats as an in vivo model. METHODS: We designed CMN loaded superparamagnetic iron oxide nanoparticles (SPIONs) (Fe3O4 magnetic- CurNPs) to achieve an enhanced therapeutic effect. The physicochemical properties of Fe3O4 magnetic- CurNPs were characterized using X-ray diffraction (XRD), and dynamic laser light scattering (DLS) and zeta potential. Further, to prove Fe3O4 magnetic- CurNPs results in superior therapeutic effects, and also, the mitochondrial membrane potential collapse, mitochondrial complex II activity, reactive oxygen species generation, ATP level, cytochrome c release and histopathology of cerebellums were determined in brains of schizophrenic rats. RESULTS: We showed that effective treatment with CMN reduced or prevented Fe3O4 magnetic-induced oxidative stress and mitochondrial dysfunction in the rat brain probably, as well as mitochondrial complex II activity, MMP, and ATP level were remarkably reduced in the cerebellum mitochondria of treated group toward control (p < 0.05). Therewith, ROS generation, and cytochrome c release were notably (p < 0.05) increased in the cerebellum mitochondria of treated group compared with control group. CONCLUSION: Taken together, Fe3O4 magnetic- CurNPs exhibits potent antineurotoxicity activity in cerebellums of schizophrenic rats. This approach can be extended to preclinical and clinical use and may have importance in schizophernia treatment in the future. To our knowledge this is the first report that provides the Fe3O4 magnetic- CurNPs could enhance the neuroprotective effects of CMN in the Schizophrenia. PMID- 30453448 TI - Human PBMCs fight or flight response to starvation stress: Increased T-reg, FOXP3, and TGF-beta1 with decreased miR-21 and Constant miR-181c levels. AB - Regulatory T-lymphocytes play a prominent role in autoimmunity, allergy, and cancer. In some conditions such as inflammation and tumor, immune cells are encountered with metabolic stress. Emerging evidence indicates the contribution of microRNAs in both metabolism and immune regulation. Herewith, we have examined the in vitro effects of serum starvation for 16, 48, 72 and 96 h on the expression of T-reg differentiation markers (CD4, CD25, CD127, and FOXP3) as well as on the Transforming Growth Factor-beta1 (TGF-beta1) and some microRNAs (miR 21,-29a,-31,146a,-155,-181a and -181c) levels in human Peripheral Blood Mononuclear Cells (PBMCs). The percentage of CD4+CD25+CD127low/-FOXP3+ T-regs, as well as FOXP3 expression, was increased in starved lymphocytes (p < 0.01). 96 h starved PBMCs had the lowest T-eff/T-reg ratio (p < 0.05). All the studied miRNAs except miR-181c were significantly down-regulated in those cells (p < 0.05), in particular, miR-29a and miR-155 were sharply declined in 48h-starved PBMCs (p < 0.01). There was a negative correlation between time of starvation and microRNAs expression, except for miR-181c (r-value = -0. 61 to -0.9 and p-value = 0.037 to 0). The percentage of T-reg was inversely correlated with all miRNAs levels except for miR-31 and miR-181c (r-value = -0.68 to -0.78 and p-value = 0.015 to 0.003). FOXP3 expression exhibited a same degree of negative correlation with miR 31 and miR-155 expression levels (r = -0.57 and p = 0.05, for both). Increasing starvation duration led to a rise inTGF-beta1 protein levels (p<0.01), especially its active form (P<0.001). This study introduced the serum starvation as a tool for immunoregulation which acts probably through increasing TGF-beta1 production and inducing some alterations in microRNAs expression. PMID- 30453449 TI - Signaling pathways involved in the expression of SZNF and the target genes binding with SZNF related to cyadox. AB - SZNF (Sus scrofa zinc finger CCHC domain containing 3) is a post-transcription regulation factor, belonging to CCHC zinc finger proteins. Cyadox is a novel quinoxaline drug with antibacterial and growth promotion effects. In this study, we investigated the pharmacological mechanism of cyadox mediated by SZNF. Firstly, signaling pathways related to cyadox-induced SZNF expression were studied. The results showed that the mRNA level of SZNF reached the peak as early as 4 h after 2 MUM cyadox treatment in swine hepatocytes. Several signaling pathways, including JAK2/STAT1, PI3K/Akt, TGF-beta/Smad3 and p38, might play critical roles in regulation of SZNF. The JAK2/STAT1, JAK2/PI3K/Akt, PI3K/Akt and myD88 & TAK1 & ASK1 /P38 signaling pathways were firstly activated after cyadox treatment in swine hepatocyte, the TGF-beta/Smad3 signaling pathway was activated later. Then given the characteristic of RNA binding of CCHC zinc finger proteins, the target mRNAs binding with SZNF were detected by RNA immunoprecipitation coupled to sequencing (RIP-seq) in PK-15 cells treated with cyadox. The RIP-Seq results showed that the bound mRNAs of 45 genes and 93 genes by SZNF protein were increased and decreased, respectively in cyadox-treated PK-15 cells compared with blank sample. With bioinformatics analysis, we showed that cyadox might exert its antibacterial and growth promotion effect by regulating SZNF-associated target genes in post-transcriptional level, such as genes related to growth (MLXIP, CKS2) and inflammation (LGALS3, PLAU). Thus, our results indicated that SZNF can post-transcriptionally regulate its target genes related to growth and inflammatory in cyadox-treated cells, which may explain the pharmacological mechanism of this drug. PMID- 30453451 TI - Introduction. Predictive analytics in medicine. PMID- 30453450 TI - Experimental rodent models of chronic prostatitis and evaluation criteria. AB - Chronic prostatitis (CP) is a common disease in urology and can be develop in all age groups. It is more commonly seen in men over the age of 50. It's cure rate is low, the recurrence rate is high, the symptoms are complicated, the duration of disease is prolonged, the lingering is difficult to heal, the pain site is extensive and the associated symptoms are more, which bring great physical pain and mental burden to the patient. At present, the etiology, pathology and pathophysiology of prostatitis are not clear yet, and it is still a difficult problem in medical research. The establishment of an effective animal model for experimental research has become an important way to explore its pathogenesis. There are currently several popular modeling methods that vary in degree of operation, success rate, and time length. It would become a trend to study chronic prostatitis through different modeling methods in the future. The successful preparation of animal models can provide the treatment of CP with the corresponding theoretical basis. This article reviews the recent advances in research on rodent models and analyzes the advantages, limitations, and evaluation criteria of various models for reference. PMID- 30453452 TI - Development of a validated computer-based preoperative predictive model for pseudarthrosis with 91% accuracy in 336 adult spinal deformity patients. AB - OBJECTIVEPseudarthrosis can occur following adult spinal deformity (ASD) surgery and can lead to instrumentation failure, recurrent pain, and ultimately revision surgery. In addition, it is one of the most expensive complications of ASD surgery. Risk factors contributing to pseudarthrosis in ASD have been described; however, a preoperative model predicting the development of pseudarthrosis does not exist. The goal of this study was to create a preoperative predictive model for pseudarthrosis based on demographic, radiographic, and surgical factors.METHODSA retrospective review of a prospectively maintained, multicenter ASD database was conducted. Study inclusion criteria consisted of adult patients (age >= 18 years) with spinal deformity and surgery for the ASD. From among 82 variables assessed, 21 were used for model building after applying collinearity testing, redundancy, and univariable predictor importance >= 0.90. Variables included demographic data along with comorbidities, modifiable surgical variables, baseline coronal and sagittal radiographic parameters, and baseline scores for health-related quality of life measures. Patients groups were determined according to their Lenke radiographic fusion type at the 2-year follow up: bilateral or unilateral fusion (union) or pseudarthrosis (nonunion). A decision tree was constructed, and internal validation was accomplished via bootstrapped training and testing data sets. Accuracy and the area under the receiver operating characteristic curve (AUC) were calculated to evaluate the model.RESULTSA total of 336 patients were included in the study (nonunion: 105, union: 231). The model was 91.3% accurate with an AUC of 0.94. From 82 initial variables, the top 21 covered a wide range of areas including preoperative alignment, comorbidities, patient demographics, and surgical use of graft material.CONCLUSIONSA model for predicting the development of pseudarthrosis at the 2-year follow-up was successfully created. This model is the first of its kind for complex predictive analytics in the development of pseudarthrosis for patients with ASD undergoing surgical correction and can aid in clinical decision making for potential preventative strategies. PMID- 30453453 TI - Variability in the utility of predictive models in predicting patient-reported outcomes following spine surgery for degenerative conditions: a systematic review. AB - OBJECTIVEThere is increasing emphasis on patient-reported outcomes (PROs) to quantitatively evaluate quality outcomes from degenerative spine surgery. However, accurate prediction of PROs is challenging due to heterogeneity in outcome measures, patient characteristics, treatment characteristics, and methodological characteristics. The purpose of this study was to evaluate the current landscape of independently validated predictive models for PROs in elective degenerative spinal surgery with respect to study design and model generation, training, accuracy, reliability, variance, and utility.METHODSThe authors analyzed the current predictive models in PROs by performing a search of the PubMed and Ovid databases using PRISMA guidelines and a PICOS (participants, intervention, comparison, outcomes, study design) model. They assessed the common outcomes and variables used across models as well as the study design and internal validation methods.RESULTSA total of 7 articles met the inclusion criteria, including a total of 17 validated predictive models of PROs after adult degenerative spine surgery. National registry databases were used in 4 of the studies. Validation cohorts were used in 2 studies for model verification and 5 studies used other methods, including random sample bootstrapping techniques. Reported c-index values ranged from 0.47 to 0.79. Two studies report the area under the curve (0.71-0.83) and one reports a misclassification rate (9.9%). Several positive predictors, including high baseline pain intensity and disability, demonstrated high likelihood of favorable PROs.CONCLUSIONSA limited but effective cohort of validated predictive models of spine surgical outcomes had proven good predictability for PROs. Instruments with predictive accuracy can enhance shared decision-making, improve rehabilitation, and inform best practices in the setting of heterogeneous patient characteristics and surgical factors. PMID- 30453454 TI - Utility of deep neural networks in predicting gross-total resection after transsphenoidal surgery for pituitary adenoma: a pilot study. AB - OBJECTIVEGross-total resection (GTR) is often the primary surgical goal in transsphenoidal surgery for pituitary adenoma. Existing classifications are effective at predicting GTR but are often hampered by limited discriminatory ability in moderate cases and by poor interrater agreement. Deep learning, a subset of machine learning, has recently established itself as highly effective in forecasting medical outcomes. In this pilot study, the authors aimed to evaluate the utility of using deep learning to predict GTR after transsphenoidal surgery for pituitary adenoma.METHODSData from a prospective registry were used. The authors trained a deep neural network to predict GTR from 16 preoperatively available radiological and procedural variables. Class imbalance adjustment, cross-validation, and random dropout were applied to prevent overfitting and ensure robustness of the predictive model. The authors subsequently compared the deep learning model to a conventional logistic regression model and to the Knosp classification as a gold standard.RESULTSOverall, 140 patients who underwent endoscopic transsphenoidal surgery were included. GTR was achieved in 95 patients (68%), with a mean extent of resection of 96.8% +/- 10.6%. Intraoperative high field MRI was used in 116 (83%) procedures. The deep learning model achieved excellent area under the curve (AUC; 0.96), accuracy (91%), sensitivity (94%), and specificity (89%). This represents an improvement in comparison with the Knosp classification (AUC: 0.87, accuracy: 81%, sensitivity: 92%, specificity: 70%) and a statistically significant improvement in comparison with logistic regression (AUC: 0.86, accuracy: 82%, sensitivity: 81%, specificity: 83%) (all p < 0.001).CONCLUSIONSIn this pilot study, the authors demonstrated the utility of applying deep learning to preoperatively predict the likelihood of GTR with excellent performance. Further training and validation in a prospective multicentric cohort will enable the development of an easy-to-use interface for use in clinical practice. PMID- 30453455 TI - Machine-learning analysis outperforms conventional statistical models and CT classification systems in predicting 6-month outcomes in pediatric patients sustaining traumatic brain injury. AB - OBJECTIVEModern surgical planning and prognostication requires the most accurate outcomes data to practice evidence-based medicine. For clinicians treating children following traumatic brain injury (TBI) these data are severely lacking. The first aim of this study was to assess published CT classification systems in the authors' pediatric cohort. A pediatric-specific machine-learning algorithm called an artificial neural network (ANN) was then created that robustly outperformed traditional CT classification systems in predicting TBI outcomes in children.METHODSThe clinical records of children under the age of 18 who suffered a TBI and underwent head CT within 24 hours after TBI (n = 565) were retrospectively reviewed.RESULTS"Favorable" outcome (alive with Glasgow Outcome Scale [GOS] score >= 4 at 6 months postinjury, n = 533) and "unfavorable" outcome (death at 6 months or GOS score <= 3 at 6 months postinjury, n = 32) were used as the primary outcomes. The area under the receiver operating characteristic (ROC) curve (AUC) was used to delineate the strength of each CT grading system in predicting survival (Helsinki, 0.814; Rotterdam, 0.838; and Marshall, 0.781). The AUC for CT score in predicting GOS score <= 3, a measure of overall functionality, was similarly predictive (Helsinki, 0.717; Rotterdam, 0.748; and Marshall, 0.663). An ANN was then constructed that was able to predict 6-month outcomes with profound accuracy (AUC = 0.9462 +/- 0.0422).CONCLUSIONSThis study showed that machine-learning can be leveraged to more accurately predict TBI outcomes in children. PMID- 30453456 TI - Editorial. Artificial neural networks for neurosurgical diagnosis, prognosis, and management. PMID- 30453457 TI - Letter to the Editor. Plasticity of the supplementary motor area. PMID- 30453458 TI - Machine learning analyses can differentiate meningioma grade by features on magnetic resonance imaging. AB - OBJECTIVEPrognostication and surgical planning for WHO grade I versus grade II meningioma requires thoughtful decision-making based on radiographic evidence, among other factors. Although conventional statistical models such as logistic regression are useful, machine learning (ML) algorithms are often more predictive, have higher discriminative ability, and can learn from new data. The authors used conventional statistical models and an array of ML algorithms to predict atypical meningioma based on radiologist-interpreted preoperative MRI findings. The goal of this study was to compare the performance of ML algorithms to standard statistical methods when predicting meningioma grade.METHODSThe cohort included patients aged 18-65 years with WHO grade I (n = 94) and II (n = 34) meningioma in whom preoperative MRI was obtained between 1998 and 2010. A board-certified neuroradiologist, blinded to histological grade, interpreted all MR images for tumor volume, degree of peritumoral edema, presence of necrosis, tumor location, presence of a draining vein, and patient sex. The authors trained and validated several binary classifiers: k-nearest neighbors models, support vector machines, naive Bayes classifiers, and artificial neural networks as well as logistic regression models to predict tumor grade. The area under the curve receiver operating characteristic curve was used for comparison across and within model classes. All analyses were performed in MATLAB using a MacBook Pro.RESULTSThe authors included 6 preoperative imaging and demographic variables: tumor volume, degree of peritumoral edema, presence of necrosis, tumor location, patient sex, and presence of a draining vein to construct the models. The artificial neural networks outperformed all other ML models across the true positive versus false-positive (receiver operating characteristic) space (area under curve = 0.8895).CONCLUSIONSML algorithms are powerful computational tools that can predict meningioma grade with great accuracy. PMID- 30453459 TI - Machine learning applications for the differentiation of primary central nervous system lymphoma from glioblastoma on imaging: a systematic review and meta analysis. AB - OBJECTIVEGlioblastoma (GBM) and primary central nervous system lymphoma (PCNSL) are common intracranial pathologies encountered by neurosurgeons. They often may have similar radiological findings, making diagnosis difficult without surgical biopsy; however, management is quite different between these two entities. Recently, predictive analytics, including machine learning (ML), have garnered attention for their potential to aid in the diagnostic assessment of a variety of pathologies. Several ML algorithms have recently been designed to differentiate GBM from PCNSL radiologically with a high sensitivity and specificity. The objective of this systematic review and meta-analysis was to evaluate the implementation of ML algorithms in differentiating GBM and PCNSL.METHODSThe authors performed a systematic review of the literature using PubMed in accordance with PRISMA guidelines to select and evaluate studies that included themes of ML and brain tumors. These studies were further narrowed down to focus on works published between January 2008 and May 2018 addressing the use of ML in training models to distinguish between GBM and PCNSL on radiological imaging. Outcomes assessed were test characteristics such as accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC).RESULTSEight studies were identified addressing use of ML in training classifiers to distinguish between GBM and PCNSL on radiological imaging. ML performed well with the lowest reported AUC being 0.878. In studies in which ML was directly compared with radiologists, ML performed better than or as well as the radiologists. However, when ML was applied to an external data set, it performed more poorly.CONCLUSIONSFew studies have applied ML to solve the problem of differentiating GBM from PCNSL using imaging alone. Of the currently published studies, ML algorithms have demonstrated promising results and certainly have the potential to aid radiologists with difficult cases, which could expedite the neurosurgical decision-making process. It is likely that ML algorithms will help to optimize neurosurgical patient outcomes as well as the cost-effectiveness of neurosurgical care if the problem of overfitting can be overcome. PMID- 30453460 TI - A machine learning approach to predict early outcomes after pituitary adenoma surgery. AB - OBJECTIVEPituitary adenomas occur in a heterogeneous patient population with diverse perioperative risk factors, endocrinopathies, and other tumor-related comorbidities. This heterogeneity makes predicting postoperative outcomes challenging when using traditional scoring systems. Modern machine learning algorithms can automatically identify the most predictive risk factors and learn complex risk-factor interactions using training data to build a robust predictive model that can generalize to new patient cohorts. The authors sought to build a predictive model using supervised machine learning to accurately predict early outcomes of pituitary adenoma surgery.METHODSA retrospective cohort of 400 consecutive pituitary adenoma patients was used. Patient variables/predictive features were limited to common patient characteristics to improve model implementation. Univariate and multivariate odds ratio analysis was performed to identify individual risk factors for common postoperative complications and to compare risk factors with model predictors. The study population was split into 300 training/validation patients and 100 testing patients to train and evaluate four machine learning models using binary classification accuracy for predicting early outcomes.RESULTSThe study included a total of 400 patients. The mean +/- SD patient age was 53.9 +/- 16.3 years, 59.8% of patients had nonfunctioning adenomas and 84.7% had macroadenomas, and the mean body mass index (BMI) was 32.6 +/- 7.8 (58.0% obesity rate). Multivariate odds ratio analysis demonstrated that age < 40 years was associated with a 2.86 greater odds of postoperative diabetes insipidus and that nonobese patients (BMI < 30) were 2.2 times more likely to develop postoperative hyponatremia. Using broad criteria for a poor early postoperative outcome-major medical and early surgical complications, extended length of stay, emergency department admission, inpatient readmission, and death 31.0% of patients met criteria for a poor early outcome. After model training, a logistic regression model with elastic net (LR-EN) regularization best predicted early postoperative outcomes of pituitary adenoma surgery on the 100-patient testing set-sensitivity 68.0%, specificity 93.3%, overall accuracy 87.0%. The receiver operating characteristic and precision-recall curves for the LR-EN model had areas under the curve of 82.7 and 69.5, respectively. The most important predictive variables were lowest perioperative sodium, age, BMI, highest perioperative sodium, and Cushing's disease.CONCLUSIONSEarly postoperative outcomes of pituitary adenoma surgery can be predicted with 87% accuracy using a machine learning approach. These results provide insight into how predictive modeling using machine learning can be used to improve the perioperative management of pituitary adenoma patients. PMID- 30453461 TI - Outcome prediction of intracranial aneurysm treatment by flow diverters using machine learning. AB - OBJECTIVEFlow diverters (FDs) are designed to occlude intracranial aneurysms (IAs) while preserving flow to essential arteries. Incomplete occlusion exposes patients to risks of thromboembolic complications and rupture. A priori assessment of FD treatment outcome could enable treatment optimization leading to better outcomes. To that end, the authors applied image-based computational analysis to clinically FD-treated aneurysms to extract information regarding morphology, pre- and post-treatment hemodynamics, and FD-device characteristics and then used these parameters to train machine learning algorithms to predict 6 month clinical outcomes after FD treatment.METHODSData were retrospectively collected for 84 FD-treated sidewall aneurysms in 80 patients. Based on 6-month angiographic outcomes, IAs were classified as occluded (n = 63) or residual (incomplete occlusion, n = 21). For each case, the authors modeled FD deployment using a fast virtual stenting algorithm and hemodynamics using image-based computational fluid dynamics. Sixteen morphological, hemodynamic, and FD-based parameters were calculated for each aneurysm. Aneurysms were randomly assigned to a training or testing cohort in approximately a 3:1 ratio. The Student t-test and Mann-Whitney U-test were performed on data from the training cohort to identify significant parameters distinguishing the occluded from residual groups. Predictive models were trained using 4 types of supervised machine learning algorithms: logistic regression (LR), support vector machine (SVM; linear and Gaussian kernels), K-nearest neighbor, and neural network (NN). In the testing cohort, the authors compared outcome prediction by each model trained using all parameters versus only the significant parameters.RESULTSThe training cohort (n = 64) consisted of 48 occluded and 16 residual aneurysms and the testing cohort (n = 20) consisted of 15 occluded and 5 residual aneurysms. Significance tests yielded 2 morphological (ostium ratio and neck ratio) and 3 hemodynamic (pre treatment inflow rate, post-treatment inflow rate, and post-treatment aneurysm averaged velocity) discriminants between the occluded (good-outcome) and the residual (bad-outcome) group. In both training and testing, all the models trained using all 16 parameters performed better than all the models trained using only the 5 significant parameters. Among the all-parameter models, NN (AUC = 0.967) performed the best during training, followed by LR and linear SVM (AUC = 0.941 and 0.914, respectively). During testing, NN and Gaussian-SVM models had the highest accuracy (90%) in predicting occlusion outcome.CONCLUSIONSNN and Gaussian-SVM models incorporating all 16 morphological, hemodynamic, and FD related parameters predicted 6-month occlusion outcome of FD treatment with 90% accuracy. More robust models using the computational workflow and machine learning could be trained on larger patient databases toward clinical use in patient-specific treatment planning and optimization. PMID- 30453462 TI - A predictive model and nomogram for predicting return to work at 3 months after cervical spine surgery: an analysis from the Quality Outcomes Database. AB - OBJECTIVEBack pain and neck pain are two of the most common causes of work loss due to disability, which poses an economic burden on society. Due to recent changes in healthcare policies, patient-centered outcomes including return to work have been increasingly prioritized by physicians and hospitals to optimize healthcare delivery. In this study, the authors used a national spine registry to identify clinical factors associated with return to work at 3 months among patients undergoing a cervical spine surgery.METHODSThe authors queried the Quality Outcomes Database registry for information collected from April 2013 through March 2017 for preoperatively employed patients undergoing cervical spine surgery for degenerative spine disease. Covariates included demographic, clinical, and operative variables, and baseline patient-reported outcomes. Multiple imputations were used for missing values and multivariable logistic regression analysis was used to identify factors associated with higher odds of returning to work. Bootstrap resampling (200 iterations) was used to assess the validity of the model. A nomogram was constructed using the results of the multivariable model.RESULTSA total of 4689 patients were analyzed, of whom 82.2% (n = 3854) returned to work at 3 months postoperatively. Among previously employed and working patients, 89.3% (n = 3443) returned to work compared to 52.3% (n = 411) among those who were employed but not working (e.g., were on a leave) at the time of surgery (p < 0.001). On multivariable logistic regression the authors found that patients who were less likely to return to work were older (age > 56-65 years: OR 0.69, 95% CI 0.57-0.85, p < 0.001; age > 65 years: OR 0.65, 95% CI 0.43-0.97, p = 0.02); were employed but not working (OR 0.24, 95% CI 0.20-0.29, p < 0.001); were employed part time (OR 0.56, 95% CI 0.42-0.76, p < 0.001); had a heavy-intensity (OR 0.42, 95% CI 0.32-0.54, p < 0.001) or medium intensity (OR 0.59, 95% CI 0.46-0.76, p < 0.001) occupation compared to a sedentary occupation type; had workers' compensation (OR 0.38, 95% CI 0.28-0.53, p < 0.001); had a higher Neck Disability Index score at baseline (OR 0.60, 95% CI 0.51-0.70, p = 0.017); were more likely to present with myelopathy (OR 0.52, 95% CI 0.42-0.63, p < 0.001); and had more levels fused (3-5 levels: OR 0.46, 95% CI 0.35-0.61, p < 0.001). Using the multivariable analysis, the authors then constructed a nomogram to predict return to work, which was found to have an area under the curve of 0.812 and good validity.CONCLUSIONSReturn to work is a crucial outcome that is being increasingly prioritized for employed patients undergoing spine surgery. The results from this study could help surgeons identify at-risk patients so that preoperative expectations could be discussed more comprehensively. PMID- 30453463 TI - Development of machine learning algorithms for prediction of discharge disposition after elective inpatient surgery for lumbar degenerative disc disorders. AB - OBJECTIVEIf not anticipated and prearranged, hospital stay can be prolonged while the patient awaits placement in a rehabilitation unit or skilled nursing facility following elective spine surgery. Preoperative prediction of the likelihood of postoperative discharge to any setting other than home (i.e., nonroutine discharge) after elective inpatient spine surgery would be helpful in terms of decreasing hospital length of stay. The purpose of this study was to use machine learning algorithms to develop an open-access web application for preoperative prediction of nonroutine discharges in surgery for elective inpatient lumbar degenerative disc disorders.METHODSThe American College of Surgeons National Surgical Quality Improvement Program was queried to identify patients who underwent elective inpatient spine surgery for lumbar disc herniation or lumbar disc degeneration between 2011 and 2016. Four machine learning algorithms were developed to predict nonroutine discharge and the best algorithm was incorporated into an open-access web application.RESULTSThe rate of nonroutine discharge for 26,364 patients who underwent elective inpatient surgery for lumbar degenerative disc disorders was 9.28%. Predictive factors selected by random forest algorithms were age, sex, body mass index, fusion, level, functional status, extent and severity of comorbid disease (American Society of Anesthesiologists classification), diabetes, and preoperative hematocrit level. On evaluation in the testing set (n = 5273), the neural network had a c-statistic of 0.823, calibration slope of 0.935, calibration intercept of 0.026, and Brier score of 0.0713. On decision curve analysis, the algorithm showed greater net benefit for changing management over all threshold probabilities than changing management on the basis of the American Society of Anesthesiologists classification alone or for all patients or for no patients. The model can be found here: https://sorg apps.shinyapps.io/discdisposition/.CONCLUSIONSMachine learning algorithms show promising results on internal validation for preoperative prediction of nonroutine discharges. If found to be externally valid, widespread use of these algorithms via the open-access web application by healthcare professionals may help preoperative risk stratification of patients undergoing elective surgery for lumbar degenerative disc disorders. PMID- 30453464 TI - Erratum. Open-loop deep brain stimulation for the treatment of epilepsy: a systematic review of clinical outcomes over the past decade (2008-present). PMID- 30453465 TI - Impact of Sodium N-[8-(2-Hydroxybenzoyl)amino]-caprylate on Intestinal Permeability for Notoginsenoside R1 and Salvianolic Acids in Caco-2 Cells Transport and Rat Pharmacokinetics. AB - For drugs with high hydrophilicity and poor membrane permeability, absorption enhancers can promote membrane permeability and improve oral bioavailability. Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) is a new kind of absorption enhancer that has good safety. To investigate the absorption enhancement effect of SNAC on non-polar charged and polar charged drugs and establish the absorption enhancement mechanism of SNAC, SNAC was synthesized and characterized. Two representative hydrophilic drugs-notoginsenoside R1 (R1) and salvianolic acids (SAs)-were selected as model drugs. In vitro Caco-2 cells transport and in vivo rat pharmacokinetics studies were conducted to examine the permeation effect of SNAC on R1 and SAs. R1, rosmarinic acid (RA), salvianolic acid B (SA-B) and salvianolic acid B (SA-A) were determined to compare the permeation enhancement of different drugs. The MTT assay results showed that SNAC had no toxicity to Caco-2 cells. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayer displayed that SNAC facilitated passive transport of polar charged SAs through the membrane of epithelial enterocytes. The pharmacokinetics results demonstrated that area under the curve (AUC) of RA, SA-B and SA-A with administration of SAs containing SNAC was 35.27, 8.72 and 9.23 times than administration of SAs. Tmax of RA, SA-B and SA-A were also prolonged. The AUC of R1 with administration of R1 containing SNAC was 2.24-times than administration of R1. SNAC is more effective in promoting absorption of SAs than R1. The study demonstrated that SNAC significantly improved bioavailability of R1 and SAs. What's more, the effect of SNAC on absorption enhancement of charged drugs was larger than that of non-charged drugs. The current findings not only confirm the usefulness of SNAC for the improved delivery of R1 and SAs but also demonstrate the importance of biopharmaceutics characterization in the dosage form development of drugs. PMID- 30453466 TI - Intensity-Dependent Effects of a Six-Week Balance Exercise Program in Elderly Women. AB - The objective of this study was to gain a better understanding of the mechanisms underlying falls in the elderly. The results were based on a group of 28 women in a control group (CON) and 16 women in an experimental group (EXP), aged 60-70. Participants took part in the six-weeks Elderly Recreation Movement Program (ERMP) with the only difference that the EXP group practiced twice as often as the CON group. The measurement of variations in the index called limits of stability (LOS) was performed by application of Kistler force plate and the coactivation index (CI) was registered by means of sEMG. The results demonstrate the existence of statistically significant differences in terms of the principal outcome of the exercise time in the measurements of LOS (F(1.42) = 10.0, p = 0.003), and CI (F(1.42) = 10.5, p = 0.002). The effect of the program was associated with an increase the level of the maximum LOS, and a decrease of the CI level, especially in the experimental group. Hence, the implementation of an innovative ERMP exercise program results in the improvement of the physical capabilities of senior subjects. PMID- 30453467 TI - Adaptive Micromixer Based on the Solutocapillary Marangoni Effect in a Continuous Flow Microreactor. AB - Continuous-flow microreactors are an important development in chemical engineering technology, since pharmaceutical production needs flexibility in reconfiguring the synthesis system rather than large volumes of product yield. Microreactors of this type have a special vessel, in which the convective vortices are organized to mix the reagents to increase the product output. We propose a new type of micromixer based on the intensive relaxation oscillations induced by a fundamental effect discovered recently. The mechanism of these oscillations was found to be a coupling of the solutal Marangoni effect, buoyancy and diffusion. The phenomenon can be observed in the vicinity of an air-liquid (or liquid-liquid) interface with inhomogeneous concentration of a surface-active solute. Important features of the oscillations are demonstrated experimentally and numerically. The periodicity of the oscillations is a result of the repeated regeneration of the Marangoni driving force. This feature is used in our design of a micromixer with a single air bubble inside the reaction zone. We show that the micromixer does not consume external energy and adapts to the medium state due to feedback. It switches on automatically each time when a concentration inhomogeneity in the reaction zone occurs, and stops mixing when the solution becomes sufficiently uniform. PMID- 30453468 TI - A Convenient and High-Efficient Laser Micro-Engraving Treatment for Controllable Preparation of Microstructure on Al Alloy. AB - Surface microstructure preparation offers a promising approach for overcoming the shortcomings of Al alloy, such as poor friction resistance, low hardness and weak corrosion resistance to corrosive liquid. Though many methods for the surface microstructure preparation of Al alloy have been developed, it is difficult for most of the reported methods to regulate the as-prepared microstructure, meaning that the properties of Al alloy cannot be improved efficiently by the microstructure. Thus, the application of microstructure surface of Al alloy and microstructure preparation technology is severely limited. Aimed at this issue, a simple, convenient, high-efficient, low-cost micro-scale roughness structure construction approach that is suitable for engineering application (laser micro engraving) was developed. The as-prepared microstructure on Al alloy surface formed by laser micro-engraving was investigated systemically. The morphology and formation mechanism of the microstructure were examined. Meanwhile, the effect of laser parameters on morphology, geometrical dimensions and composition of microstructure was investigated. The results indicate that the morphology of microstructure is affected by the overlap degree of molten pool greatly. When each molten pool does not overlap with others, successive individual pits can be constructed. When each molten pool overlaps with others for one time, successive overlapping pits will form. As the overlap degree of the molten pool further increases (overlapping with others for more than one time), the successive pits can become grooved. Because of the influence of laser beam pulse frequency and scanning speed on the diameter and distance of the molten pools, the morphology and geometrical dimensions of microstructure can vary greatly with laser parameters. As the laser beam scanning speed increases, the geometrical dimensions of as-prepared microstructure reduce significantly. In contrast, with the increase of laser beam pulse frequency, the geometrical dimensions change in a complicated manner. However, the chemical composition of microstructure is slightly affected by laser parameters. More importantly, a relationship model was successfully established, which could be used to predict and regulate the geometrical dimensions of microstructure treated by laser micro-engraving. Controllable preparation of microstructure on Al alloy is realized, leading that specific microstructure can be prepared rapidly and accurately instead of suffering from long-time experimental investigation in the future. PMID- 30453469 TI - Population Dynamics of Anopheles albimanus (Diptera: Culicidae) at Ipeti-Guna, a Village in a Region Targeted for Malaria Elimination in Panama. AB - Anopheles albimanus Wiedemann is a major malaria vector in Mesoamerica and the Caribbean whose population dynamics, in response to changing environments, has been relatively poorly studied. Here, we present monthly adult and larvae data collected from May 2016 to December 2017 in Ipeti-Guna, a village within an area targeted for malaria elimination in the Republica de Panama. During the study period we collected a total of 1678 Anopheles spp. mosquitoes (1602 adults and 76 larvae). Over 95% of the collected Anopheles spp. mosquitoes were An. albimanus. Using time series analysis techniques, we found that population dynamics of larvae and adults were not significantly correlated with each other at any time lag, though correlations were highest at one month lag between larvae and adults and four months lag between adults and larvae. Larvae population dynamics had cycles of three months and were sensitive to changes in temperature with 5 months lag, while adult abundance was correlated with itself (1 month lag) and with the normalized difference vegetation index (NDVI) with three months lag. A key observation from our study is the absence of both larvae and adults of An. albimanus between January and April from environments associated with Guna population's daily activities, which suggests this time window could be the best time to implement elimination campaigns aimed at clearing Plasmodium spp. parasites from Guna populations using, for example, mass drug administration. PMID- 30453471 TI - Synthesis of Carvone-Derived 1,2,3-Triazoles Study of Their Antioxidant Properties and Interaction with Bovine Serum Albumin. AB - Natural L-carvone was utilized as a starting material for an efficient synthesis of some terpenyl-derived 1,2,3-triazoles. Chlorination of carvone, followed by nucleophilic substitution with sodium azide resulted in the preparation of 10 azidocarvone. Subsequent CuAAC click reaction with propargylated derivatives provided an efficient synthetic route to a set of terpenyl-derived conjugates with increased solubility in water. All investigated compounds exhibit high antioxidant activity, which is comparable with that of vitamin C. It was also found that serum albumin and the terpenyl-1,2,3-triazoles hybrids spontaneously undergo reversible binding driven by hydrophobic interactions, suggesting that serum albumin can transport the target triazoles. PMID- 30453470 TI - Fighting Fire with Fire: Phage Potential for the Treatment of E. coli O157 Infection. AB - Hemolytic-uremic syndrome is a life-threating disease most often associated with Shiga toxin-producing microorganisms like Escherichia coli (STEC), including E. coli O157:H7. Shiga toxin is encoded by resident prophages present within this bacterium, and both its production and release depend on the induction of Shiga toxin-encoding prophages. Consequently, treatment of STEC infections tend to be largely supportive rather than antibacterial, in part due to concerns about exacerbating such prophage induction. Here we explore STEC O157:H7 prophage induction in vitro as it pertains to phage therapy-the application of bacteriophages as antibacterial agents to treat bacterial infections-to curtail prophage induction events, while also reducing STEC O157:H7 presence. We observed that cultures treated with strictly lytic phages, despite being lysed, produce substantially fewer Shiga toxin-encoding temperate-phage virions than untreated STEC controls. We therefore suggest that phage therapy could have utility as a prophylactic treatment of individuals suspected of having been recently exposed to STEC, especially if prophage induction and by extension Shiga toxin production is not exacerbated. PMID- 30453473 TI - ST-Elevation Myocardial Infarction in Coronary Ectasia: A Case Report. AB - Coronary artery ectasia (CAE) is localized or diffuse dilatation of the coronary artery lumen exceeding the diameter of adjacent healthy reference segments by 1.5 times. It is a rare phenomenon and incidence ranges from 1 to 5% in patients undergoing angiography. We report a case of a 58-year-old man with atherosclerotic CAE who experienced ST-elevation myocardial infarction (STEMI) despite prophylactic antiplatelet therapy. He was successfully treated with IV eptifibatide and aspiration thrombectomy. We reviewed the literature of CAE presentation, etiology and treatment and discussed the most appropriate antithrombotic therapy to prevent STEMIs in patients with CAE. While the current literature appears to favour prophylactic antiplatelet and anticoagulant in these patients, more studies are needed to determine the optimal form and duration of antithrombotic therapy. Currently, there is no gold standard treatment for CAE and further prospective and randomized-controlled studies are needed to guide recommendations. PMID- 30453472 TI - Diphenyl Ethers from a Marine-Derived Aspergillus sydowii. AB - Six new diphenyl ethers (1-6) along with eleven known analogs were isolated from the ethyl acetate extract of a marine-derived Aspergillus sydowii guided by LC-UV MS. Their structures were unambiguously characterized by HRESIMS, NMR, as well as chemical derivatization. Compounds 1 and 2 are rare diphenyl ether glycosides containing d-ribose. The absolute configuration of the sugar moieties in compounds 1-3 was determined by a LC-MS method. All the compounds were evaluated for their cytotoxicities against eight cancer cell lines, including 4T1, U937, PC3, HL-60, HT-29, A549, NCI-H460, and K562, and compounds 1, 5, 6, and 8-11 were found to exhibit selective cytotoxicity against different cancer cell lines. PMID- 30453474 TI - Therapeutic Approaches Targeting Inflammation in Cardiovascular Disorders. AB - Cardiovascular disease is a leading cause of morbidity and mortality in the Western world and represents an enormous global health burden. Significant advances have been made in the conservative, medical and surgical management across the range of cardiovascular diseases however the inflammatory components of these diseases have traditionally been neglected. Inflammation is certainly a key component of atherosclerosis, a chronic inflammatory condition, but it is at least correlative and predictive of risk in many other aspects of cardiovascular medicine ranging from heart failure to outcomes following reperfusion strategies. Inflammation therefore represents significant potential for future risk stratification of patients as well as offering new therapeutic targets across cardiovascular medicine. This review explores the role of inflammation in several of the major aspects of cardiovascular medicine focusing on current and possible future examples of the targeting of inflammation in prognosis and therapy. It concludes that future directions of cardiovascular research and clinical practice should seek to identify cohorts of patients with a significant inflammatory component to their cardiovascular condition or reaction to cardiovascular intervention. These patients might benefit from therapeutic strategies mounted against the inflammatory components implicated in their condition. PMID- 30453475 TI - Targeting the MYC Oncogene in Burkitt Lymphoma through HSP90 Inhibition. AB - Overexpression of the MYC oncogene is a key feature of many human malignancies including Burkitt lymphoma. While MYC is widely regarded to be a promising therapeutic target, a clinically effective MYC inhibitor is still elusive. Here, we report an alternative strategy, targeting MYC indirectly through inhibition of the HSP90 machinery. We found that inhibition of HSP90 function reduces MYC expression in human Burkitt lymphoma through suppression of MYC transcription and destabilization of MYC protein, thereby diminishing the proliferation of tumor cells. Consistently, treatment of Burkitt lymphoma cell lines with HSP90 inhibitors (17-AAG or 17-DMAG) was accompanied by downregulation of canonical MYC target genes. Combination treatment with 17-DMAG and the proteasome inhibitor, MG 132, led to accumulation of MYC protein, indicating that upon HSP90 inhibition, MYC is degraded by the proteasome. Using co-immunoprecipitation, we furthermore demonstrated a direct interaction between MYC and HSP90, indicating that MYC is an HSP90 client protein in Burkitt lymphoma. Together, we report here the use of HSP90 inhibitors as an alternative approach to target the MYC oncogene and its network in Burkitt lymphoma. PMID- 30453476 TI - Mouse Chow Composition Influences Immune Responses and Food Allergy Development in a Mouse Model. AB - Our diet is known to substantially influence the immune response not only by support of mucosal barriers but also via direct impact on immune cells. Thus, it was of great interest to compare the immunological effect of two mouse chows with substantial differences regarding micro-, macronutrient, lipid and vitamin content on the food allergic response in our previously established mouse model. As the two mouse chows of interest, we used a soy containing feed with lower fatty acid (FA) amount (soy-containing feed) and compared it to a soy free mouse chow (soy-free feed) in an established protocol of oral immunizations with Ovalbumin (OVA) under gastric acid suppression. In the animals receiving soy containing feed, OVA-specific IgE, IgG1, IgG2a antibody levels were significantly elevated and food allergy was evidenced by a drop of body temperature after oral immunizations. In contrast, mice on soy-free diet had significantly higher levels of IL-10 and were protected from food allergy development. In conclusion, soy containing feed was auxiliary during sensitizations, while soy-free feed supported oral tolerance development and food allergy prevention. PMID- 30453478 TI - Insight into Influenza: A Virus Cap-Snatching. AB - The influenza A virus (IAV) genome consists of eight single-stranded RNA segments. Each segment is associated with a protein complex, with the 3' and 5' ends bound to the RNA-dependent RNA polymerase (RdRp) and the remainder associated with the viral nucleoprotein. During transcription of viral mRNA, this ribonucleoprotein complex steals short, 5'-capped transcripts produced by the cellular DNA dependent RNA polymerase II (RNAPII) and uses them to prime transcription of viral mRNA. Here, we review the current knowledge on the process of IAV cap-snatching and suggest a requirement for RNAPII promoter-proximal pausing for efficient IAV mRNA transcription. PMID- 30453477 TI - Associations among High-Quality Protein and Energy Intake, Serum Transthyretin, Serum Amino Acids and Linear Growth of Children in Ethiopia. AB - Limited evidence is available on the associations of high-quality protein and energy intake, serum transthyretin (TTR), serum amino acids and serum insulin like growth factor-1 (IGF-1) with linear growth of young children. Data collected during the baseline of a randomized control trial involving rural Ethiopian children aged 6-35 months (n = 873) were analyzed to evaluate the associations among height/length-for-age z-scores, dietary intakes, and these biomarkers (i.e., serum level of TTR, IGF-1, tryptophan and lysine, and inflammation). The prevalence of stunting was higher for children >23 months (38%) than <=23 months (25%). The prevalence of inflammation was 35% and of intestinal parasites 48%. Three-quarters of the children were energy deficient, and stunted children had lower daily energy intake that non-stunted children (p < 0.05). Intakes of tryptophan, protein, and energy, and serum levels of tryptophan and IGF-1 were positively correlated with the linear growth of children. Controlling for inflammation, intestinal parasites, and sociodemographic characteristics, daily tryptophan (b = 0.01, p = 0.001), protein (b = 0.01, p = 0.01) and energy (b = 0.0003, p = 0.04) intakes and serum TTR (b = 2.58, p = 0.04) and IGF-1 (b = 0.01, p = 0.003) were positively associated with linear growth of children. Linear growth failure in Ethiopian children is likely associated with low quality protein intake and inadequate energy intake. Nutrition programs that emphasize improved protein quantity and quality and energy intake may enhance the linear growth of young children and need to be further investigated in longitudinal and interventional studies. PMID- 30453480 TI - Study on Damage Accumulation and Life Prediction with Loads below Fatigue Limit Based on a Modified Nonlinear Model. AB - Most fatigue theories neglect the loads below fatigue limit in damage accumulation, which leads to inconsistency between the predicted and the actual fatigue lives. In this study, a novel damage model is proposed to take into account the loads below fatigue limit from two aspects: the strengthening effect and the cumulative damage. The strengthening effect is introduced by an exponential function and the cumulative damage is calculated by fuzzy method with membership functions (MFs). The proposed model is verified against the experimental data under variable amplitude loading conditions. It is found the modified model with Cauchy MF significantly reduces the relative error of predicted life from 35.18% (linear model) and 16.09% (original Chaboche model) to 8.38% (proposed model). As a case study, the proposed damage model is implemented to evaluate the service life of a compressor blade under variable amplitude loading spectrum containing small loads below the fatigue limit. PMID- 30453479 TI - Descriptive Study of the Different Tools Used to Evaluate the Adherence to a Gluten-Free Diet in Celiac Disease Patients. AB - Celiac disease (CD) is a genetically conditioned autoimmune process that appears in susceptible people. It can affect people of any age, and slightly predominates in females. It has a fairly homogenous global distribution, with an average prevalence of 1-2%, the frequency having increased in recent decades. The only effective treatment is a strict and permanent gluten-free diet (GFD), although the level of compliance is poor, at about 50% of cases. To monitor the effectiveness of the GFD, several procedures involving various approaches are employed: (a) Periodic visits by expert Nutritionists; (b) Clinical follow-up; (c) Serological time controls of specific antibodies; (d) Serial endoscopies with collection of duodenal biopsies; (e) Use of structured questionnaires; and (f) Determination of gluten peptides derived from gluten in faeces and/or urine. All of these procedures are useful when applied, alone or in combination, depending on the cases. Some patients will only need to consult to their doctors, while others will require a multidisciplinary approach to assess their compliance with the GFD. In children, normalization of duodenal mucosa was achieved in 95% of cases within two years, while it is more delayed in adults, whose mucosa take longer time (3-5 years) to heal completely. PMID- 30453481 TI - Development of New Analytical Microwave-Assisted Extraction Methods for Bioactive Compounds from Myrtle (Myrtus communis L.). AB - The phenolic compounds and anthocyanins present in myrtle berries are responsible for its beneficial health properties. In the present study, a new, microwave assisted extraction for the analysis of both phenolic compounds and anthocyanins from myrtle pulp has been developed. Different extraction variables, including methanol composition, pH, temperature, and sample-solvent ratio were optimized by applying a Box-Behnken design and response surface methodology. Methanol composition and pH were the most influential variables for the total phenolic compounds (58.20% of the solvent in water at pH 2), and methanol composition and temperature for anthocyanins (50.4% of solvent at 50 degrees C). The methods developed showed high repeatability and intermediate precision (RSD < 5%). Both methods were applied to myrtle berries collected in two different areas of the province of Cadiz (Spain). Hierarchical clustering analysis results show that the concentration of bioactive compounds in myrtle is related to their geographical origin. PMID- 30453482 TI - EEG Waveform Analysis of P300 ERP with Applications to Brain Computer Interfaces. AB - The Electroencephalography (EEG) is not just a mere clinical tool anymore. It has become the de-facto mobile, portable, non-invasive brain imaging sensor to harness brain information in real time. It is now being used to translate or decode brain signals, to diagnose diseases or to implement Brain Computer Interface (BCI) devices. The automatic decoding is mainly implemented by using quantitative algorithms to detect the cloaked information buried in the signal. However, clinical EEG is based intensively on waveforms and the structure of signal plots. Hence, the purpose of this work is to establish a bridge to fill this gap by reviewing and describing the procedures that have been used to detect patterns in the electroencephalographic waveforms, benchmarking them on a controlled pseudo-real dataset of a P300-Based BCI Speller and verifying their performance on a public dataset of a BCI Competition. PMID- 30453484 TI - Evaluation of Quantitative PCR (qPCR) Paenibacillus larvae Targeted Assays and Definition of Optimal Conditions for Its Detection/Quantification in Honey and Hive Debris. AB - The application of quantitative PCR (qPCR) as a routine method to detect and enumerate Paenibacillus larvae in honey and hive debris could greatly speed up the estimation of prevalence and outbreak risk of the American foulbrood (AFB) disease of Apis mellifera. However, none of the qPCR tests described so far has been officially proposed as a standard procedure for P. larvae detection and enumeration for surveillance purposes. Therefore, in this study, inclusivity, exclusivity and sensitivity of detection of P. larvae spores directly in samples of honey and hive debris were re-evaluated for the previously published qPCR methods. To this aim, recently acquired P. larvae sequence data were considered to assess inclusivity in silico and more appropriate non-target species were used to verify exclusivity experimentally. This led to the modification of a previously described method by shortening the forward primer, designing a new reverse primer and using more stringent amplification conditions. The new test allowed the detection of P. larvae spores in honey and hive debris down to 1 CFU/g. The qPCR test optimized in this study proved suitable for quantification and also for identification of field P. larvae strains and real contaminated samples. Therefore, it is proposed for reliable detection and quantification of P. larvae in honey and hive debris, thus circumventing the disadvantages of late AFB diagnosis based on clinical symptoms and possible underestimation of spore numbers that is the main drawback of culture-dependent procedures. PMID- 30453485 TI - QoS in Wireless Sensor Networks. AB - The last decades have witnessed advances in multiple wireless sensor networks in both the academic and industrial world. [...]. PMID- 30453483 TI - Moral Judgment: An Overlooked Deficient Domain in Multiple Sclerosis? AB - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system through which patients can suffer from sensory, motor, cerebellar, emotional, and cognitive symptoms. Although cognitive and behavioral dysfunctions are frequently encountered in MS patients, they have previously received little attention. Among the most frequently impaired cognitive domains are attention, information processing speed, and working memory, which have been extensively addressed in this population. However, less emphasis has been placed on other domains like moral judgment. The latter is a complex cognitive sphere that implies the individuals' ability to judge others' actions and relies on numerous affective and cognitive processes. Moral cognition is crucial for healthy and adequate interpersonal relationships, and its alteration might have drastic impacts on patients' quality of life. This work aims to analyze the studies that have addressed moral cognition in MS. Only three works have previously addressed moral judgement in this clinical population compared to healthy controls, and none included neuroimaging or physiological measures. Although scarce, the available data suggest a complex pattern of moral judgments that deviate from normal response. This finding was accompanied by socio-emotional and cognitive deficits. Only preliminary data are available on moral cognition in MS, and its neurobiological foundations are still needing to be explored. Future studies would benefit from combining moral cognitive measures with comprehensive neuropsychological batteries and neuroimaging/neurophysiological modalities (e.g., functional magnetic resonance imaging, tractography, evoked potentials, electroencephalography) aiming to decipher the neural underpinning of moral judgement deficits and subsequently conceive potential interventions in MS patients. PMID- 30453486 TI - Design and Characteristic Analysis of Cross-Capacitance Fuel-Level Sensor. AB - A cross-capacitance liquid level sensor is based on the principle of cross capacitance. This study designed a new single-tube cross-capacitance fuel-level sensor. The fuel-level measurement model is established for a single-tube cross capacitive sensor, and the relationship between the measured liquid level and sensor output capacitance is derived. The characteristics of the sensor were tested experimentally. The experimental results demonstrate that the linearity error of the liquid-level sensor of the single-tube calculation for the spacecraft is +/-0.48%, the repeatability error is +/-0.47%, and the hysteresis error is +/-0.68%. The cross-capacitive fuel-level sensor developed in this study can be used in the fuel tank of spacecrafts owing to its low weight and high precision. PMID- 30453488 TI - Impact of Maternal Air Pollution Exposure on Children's Lung Health: An Indian Perspective. AB - Air pollution has become an emerging invisible killer in recent years and is a major cause of morbidity and mortality globally. More than 90% of the world's children breathe toxic air every day. India is among the top ten most highly polluted countries with an average PM10 level of 134 MUg/m3 per year. It is reported that 99% of India's population encounters air pollution levels that exceed the World Health Organization Air Quality Guideline, advising a PM2.5 permissible level of 10 MUg/m3. Maternal exposure to air pollution has serious health outcomes in offspring because it can affect embryonic phases of development during the gestation period. A fetus is more prone to effects from air pollution during embryonic developmental phases due to resulting oxidative stress as antioxidant mechanisms are lacking at that stage. Any injury during this vulnerable period (embryonic phase) will have a long-term impact on offspring health, both early and later in life. Epidemiological studies have revealed that maternal exposure to air pollution increases the risk of development of airway disease in the offspring due to impaired lung development in utero. In this review, we discuss cellular mechanisms involved in maternal exposure to air pollution and how it can impact airway disease development in offspring. A better understanding of these mechanisms in the context of maternal exposure to air pollution can offer a new avenue to prevent the development of airway disease in offspring. PMID- 30453487 TI - A Double-Blind Controlled Study to Evaluate the Effects of Yogurt Enriched with Lactococcus lactis 11/19-B1 and Bifidobacterium lactis on Serum Low-Density Lipoprotein Level and Antigen-Specific Interferon-gamma Releasing Ability. AB - In order to clarify the effects of the Lactococcus lactis (L. lactis) 11/19-B1 strain, a double-blind controlled study of yogurt fermented with the strain was carried out. For the study, two kinds of yogurt, the control and test yogurt, were prepared; the control yogurt was fermented with Streptococcus thermophiles, Lactobacillus delbrueckii subspecies bulgaricus, and Lactobacillus acidophilus, and the test yogurt was enriched with L. lactis 11/19-B1 and Bifidobacterium lactis (B. lactis) BB-12 strains. Seventy-six volunteers who had not received treatment with pharmaceuticals were randomly divided into two groups with each group ingesting 80 g of either the test or control yogurt every day for 8 weeks. Before and after yogurt intake, fasting blood was taken and blood sugar, blood lipids, and anti-cytomegalovirus cellular immunity were estimated. In the test yogurt group, low-density lipoprotein (LDL) was significantly decreased (159.1 +/ 25.7 to 149.3 +/- 24.4; p = 0.02), but this effect was not observed in the control yogurt group. When the test yogurt group was divided into two groups based on LDL levels of over or under 120 mg/dL, this effect was only observed in the high LDL group. No LDL-lowering effect of B. lactis BB-12 strain was previously reported; therefore, the hypocholesterolemic effects observed in this study are thought to be caused by the L. lactis 11/19-B1 strain alone or its combination with the B. lactis BB-12 strain. PMID- 30453489 TI - The Influence of Stored Energy on Grain Boundary Chemistry and Intergranular Corrosion Development in AA2024-T3 Alloy. AB - Following our previous research, the correlation between the micro-chemistry of grain boundary and the distribution of stored energy in AA2024-T3 alloy is investigated, using the combination of transmission Kikuchi diffraction and transmission electron microscopy. It is found that the difference of dislocation density, namely stored energy, between two neighboring grains significantly affects the micro-chemistry of the grain boundary. Further, it is revealed that intergranular corrosion development in the AA2024-T3 alloy is mainly attributed to the combined effect of grain boundary chemistry and stored energy distribution. PMID- 30453491 TI - Controlled Synthesis and Microstructure of Metastable Flower-Like Vaterite. AB - Developing a simple morphology-controlled synthesis of metastable vaterite is a goal in the field of materials research. In this paper, we successfully synthesized flower-like dendritic vaterite crystals using a microwave method with 2-naphthaleneacetic acid (2-NAA) and ethylene glycol (EG) as the regulating additives. The results show that the morphology of vaterite could be regulated by inducing a monolayer or multilayer flower-like structure with the appropriate choice of regulators. Interestingly, the microstructure analysis showed that such flower-like vaterite dendrites host two different kinds of crystal cells. The negative carbonate 2-NAA effectively neutralized the charge of the vaterite (001) plane, resulting in the crystalline growth along the direction parallel to it and inducing a flower-like morphology. This experiment reveals an alternative approach to controlling hierarchical structures during the synthesis of similar classes of minerals. PMID- 30453492 TI - Occurrence and Quantitative Risk Assessment of Twelve Mycotoxins in Eggs and Chicken Tissues in China. AB - Aflatoxins (AFs), deoxynivalenols (DONs), and zearalenones (ZENs) are common mycotoxins that contaminate feedstuff, causing contamination of poultry products. In our study, these mycotoxins were quantified in 152 egg samples collected from markets in Jiangsu (JS), Zhejiang (ZJ), and Shanghai (SH) and in 70 chicken tissue samples (liver, heart, and gizzard) from ZJ in China. The main mycotoxins observed in egg samples were DON, 15-AcDON, and ZEN, although only ZEN family mycotoxins (ZEN, alpha-ZEL, beta-ZEL, and alpha-ZAL) were detected in chicken tissues. Furthermore, for the first time, we assessed the health risks of exposure of three populations (children, adults, and elder adults) to DONs (DON, 3-AcDON, and 15-AcDON) and ZEN in eggs (from three different areas) and to ZEN in chicken tissues. We show that the mean dietary intake (DI) values and the 97.5th percentile DI values of DON and ZEN through egg ingestion were lower than the provisional maximum tolerable daily intake (PMTDI) (1 MUg/kg body weight (BW)/day) for the three populations in the three geographical areas studied. However, eggs contaminated with high levels of DONs and ZEN contributed to a large proportion of the PMTDI of these mycotoxins, especially in children and elder adults. Although ZEN was highly detected in the chicken tissues, no significant health risk was observed. PMID- 30453490 TI - Biomedical Applications of Graphene-Based Structures. AB - Graphene and graphene oxide (GO) structures and their reduced forms, e.g., GO paper and partially or fully reduced three-dimensional (3D) aerogels, are at the forefront of materials design for extensive biomedical applications that allow for the proliferation and differentiation/maturation of cells, drug delivery, and anticancer therapies. Various viability tests that have been conducted in vitro on human cells and in vivo on mice reveal very promising results, which make graphene-based materials suitable for real-life applications. In this review, we will give an overview of the latest studies that utilize graphene-based structures and their composites in biological applications and show how the biomimetic behavior of these materials can be a step forward in bridging the gap between nature and synthetically designed graphene-based nanomaterials. PMID- 30453493 TI - Preparation and Characterization of Spherical Amorphous Solid Dispersion with Amphotericin B. AB - In the present study, new polymer microspheres of amphotericin B (AmB) were prepared by a spray drying technique using cyclodextrin polymers (Poly-CD) to improve the solubility and dissolution of AmB, to prevent in vivo toxic AmB aggregations. Formulations were characterized through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermal analysis, Raman spectroscopy, particle size, drug purity test and in vitro release studies. The analysis indicated that the chemical structure of AmB remained unchanged in the amorphous solid dispersion, but the structure was changed from crystalline to amorphous. AmB was completely release from such optimized formulations in dissolution media in 40 min. This work may contribute to a new generation of spherical amorphous solid dispersion using a cyclodextrin polymer, which has implications for the possibility of drug development for oral utilization or as powder aerosols for pulmonary administration. PMID- 30453494 TI - Antioxidative Efficacy of a Pistacia Lentiscus Supplement and Its Effect on the Plasma Amino Acid Profile in Inflammatory Bowel Disease: A Randomised, Double Blind, Placebo-Controlled Trial. AB - Oxidative stress is present in patients with Inflammatory Bowel Disease (IBD), and natural supplements with antioxidant properties have been investigated as a non-pharmacological approach. The objective of the present study was to assess the effects of a natural Pistacia lentiscus (PL) supplement on oxidative stress biomarkers and to characterise the plasma-free amino acid (AA) profiles of patients with active IBD (Crohn's disease (CD) N = 40, ulcerative colitis (UC) N = 20). The activity was determined according to 5 <= Harvey Bradshaw Index <= 16 or 2 <= Partial Mayo Score <= 6. This is a randomised, double-blind, placebo controlled clinical trial. IBD patients (N = 60) were randomly allocated to PL (2.8 g/day) or to placebo for 3 months being under no treatment (N = 21) or under stable medical treatment (mesalamine N = 24, azathioprine N = 14, and corticosteroids N = 23) that was either single medication (N = 22) or combined medication (N = 17). Plasma oxidised, low-density lipoprotein (oxLDL), total serum oxidisability, and serum uric acid were evaluated at baseline and follow up. OxLDL/LDL and oxLDL/High-Density Lipoprotein (HDL) ratios were calculated. The plasma-free AA profile was determined by applying a gas chromatography/mass spectrometry analysis. oxLDL (p = 0.031), oxLDL/HDL (p = 0.020), and oxLDL/LDL (p = 0.005) decreased significantly in the intervention group. The mean change differed significantly in CD between groups for oxLDL/LDL (p = 0.01), and, in the total sample, both oxLDL/LDL (p = 0.015) and oxLDL/HDL (p = 0.044) differed significantly. Several changes were reported in AA levels. PL ameliorated a decrease in plasma-free AAs seen in patients with UC taking placebo. In conclusion, this intervention resulted in favourable changes in oxidative stress biomarkers in active IBD. PMID- 30453495 TI - Insulin Receptor Isoforms in Cancer. AB - The insulin receptor (IR) mediates both metabolic and mitogenic effects especially when overexpressed or in clinical conditions with compensatory hyperinsulinemia, due to the metabolic pathway resistance, as obesity diabetes. In many cancers, IR is overexpressed preferentially as IR-A isoform, derived by alternative splicing of exon 11. The IR-A overexpression, and the increased IR A:IR-B ratio, are mechanisms that promote the mitogenic response of cancer cells to insulin and IGF-2, which is produced locally by both epithelial and stromal cancer cells. In cancer IR-A, isoform predominance may occur for dysregulation at both mRNA transcription and post-transcription levels, including splicing factors, non-coding RNAs and protein degradation. The mechanisms that regulate IR isoform expression are complex and not fully understood. The IR isoform overexpression may play a role in cancer cell stemness, in tumor progression and in resistance to target therapies. From a clinical point of view, the IR-A overexpression in cancer may be a determinant factor for the resistance to IGF-1R target therapies for this issue. IR isoform expression in cancers may have the meaning of a predictive biomarker and co-targeting IGF-1R and IR-A may represent a new more efficacious treatment strategy. PMID- 30453496 TI - A SFTD Algorithm for Optimizing the Performance of the Readout Strategy of Residence Time Difference Fluxgate. AB - Residence time difference (RTD) fluxgate sensor is a potential device to measure the DC or low-frequency magnetic field in the time domain. Nevertheless, jitter noise and magnetic noise severely affect the detection result. A novel post processing algorithm for jitter noise reduction of RTD fluxgate output strategy based on the single-frequency time difference (SFTD) method is proposed in this study to boost the performance of the RTD system. This algorithm extracts the signal that has a fixed frequency and preserves its time-domain information via a time-frequency transformation method. Thereby, the single-frequency signal without jitter noise, which still contains the ambient field information in its time difference, is yielded. Consequently, compared with the traditional comparator RTD method (CRTD), the stability of the RTD estimation (in other words, the signal-to-noise ratio of residence time difference) has been significantly boosted with sensitivity of 4.3 MUs/nT. Furthermore, the experimental results reveal that the RTD fluxgate is comparable to harmonic fluxgate sensors, in terms of noise floor. PMID- 30453497 TI - SCFSen: A Sensor Node for Regional Soil Carbon Flux Monitoring. AB - Estimation of regional soil carbon flux is very important for the study of the global carbon cycle. The spatial heterogeneity of soil respiration prevents the actual status of regional soil carbon flux from being revealed by measurements of only one or a few spatial sampling positions, which are usually used by traditional studies for the limitation of measurement instruments, so measuring in many spatial positions is very necessary. However, the existing instruments are expensive and cannot communicate with each other, which prevents them from meeting the requirement of synchronous measurements in multiple positions. Therefore, we designed and implemented an instrument for soil carbon flux measuring based on dynamic chamber method, SCFSen, which can measure soil carbon flux and communicate with each other to construct a sensor network. In its working stage, a SCFSen node measures the concentration of carbon in the chamber with an infrared carbon dioxide sensor for certain times periodically, and then the changing rate of the measurements is calculated, which can be converted to the corresponding value of soil carbon flux in the position during the short period. A wireless sensor network system using SCFSens as soil carbon flux sensing nodes can carry out multi-position measurements synchronously, so as to obtain the spatial heterogeneity of soil respiration. Furthermore, the sustainability of such a wireless sensor network system makes the temporal variability of regional soil carbon flux can also be obtained. So SCFSen makes thorough monitoring and accurate estimation of regional soil carbon flux become more feasible. PMID- 30453498 TI - Vacuolar Proton Pyrophosphatase Is Required for High Magnesium Tolerance in Arabidopsis. AB - Magnesium (Mg2+) is an essential nutrient in all organisms. However, high levels of Mg2+ in the environment are toxic to plants. In this study, we identified the vacuolar-type H+-pyrophosphatase, AVP1, as a critical enzyme for optimal plant growth under high-Mg conditions. The Arabidopsis avp1 mutants displayed severe growth retardation, as compared to the wild-type plants upon excessive Mg2+. Unexpectedly, the avp1 mutant plants retained similar Mg content to wild-type plants under either normal or high Mg conditions, suggesting that AVP1 may not directly contribute to Mg2+ homeostasis in plant cells. Further analyses confirmed that the avp1 mutant plants contained a higher pyrophosphate (PPi) content than wild type, coupled with impaired vacuolar H+-pyrophosphatase activity. Interestingly, expression of the Saccharomyces cerevisiae cytosolic inorganic pyrophosphatase1 gene IPP1, which facilitates PPi hydrolysis but not proton translocation into vacuole, rescued the growth defects of avp1 mutants under high-Mg conditions. These results provide evidence that high-Mg sensitivity in avp1 mutants possibly resulted from elevated level of cytosolic PPi. Moreover, genetic analysis indicated that mutation of AVP1 was additive to the defects in mgt6 and cbl2 cbl3 mutants that are previously known to be impaired in Mg2+ homeostasis. Taken together, our results suggest AVP1 is required for cellular PPi homeostasis that in turn contributes to high-Mg tolerance in plant cells. PMID- 30453499 TI - Intramuscular Exposure of Macaca fascicularis to Low Doses of Low Passage- or Cell Culture-Adapted Sudan Virus or Ebola Virus. AB - The filoviruses Ebola virus (EBOV) and Sudan virus (SUDV) can cause severe diseases, and there are currently no licensed countermeasures available for use against them. Transmission occurs frequently via contact with bodily fluids from infected individuals. However, it can be difficult to determine when or how someone became infected, or the quantity of infectious virus to which they were exposed. Evidence suggests the infectious dose is low, but the majority of published studies use high exposure doses. This study characterized the outcome of exposure to a low dose of EBOV or SUDV, using a Macaca fascicularis model. Further, because the effect of virus passage in cell culture may be more pronounced when lower exposure doses are used, viruses that possessed either the characteristics of wild type viruses (possessing predominantly 7-uridine (7U) genotype and a high particle-to-plaque forming unit (PFU) ratio) or cell culture passaged viruses (predominantly 8-uridine (8U) genotype, a lower particle-to-PFU ratio) were used. The time to death after a low dose exposure was delayed in comparison to higher exposure doses. These data demonstrated that an extremely low dose of EBOV or SUDV is sufficient to cause lethal disease. A low dose exposure model can help inform studies on pathogenesis, transmission, and optimization of prevention strategies. PMID- 30453500 TI - Focusing on Coal Workers' Lung Diseases: A Comparative Analysis of China, Australia, and the United States. AB - China has high and increasing annual rates of occupational lung diseases such as pneumoconiosis and silicosis. In contrast, Australia and the United States of America (USA) have greatly lowered their annual rates of lung diseases since the 1970s. This paper systematically compared and analysed the multi-elements of coal dust management and health management in these three countries to provide a reference for China. Regarding coal dust management, this paper found that coal workers in China are more susceptible to lung diseases compared to workers in the USA and Australia, considering fundamental aspects such as mine type, coal rank, and geological conditions. In addition, the controllable aspects such as advanced mitigation, monitoring methods, and the personal protective equipment of coal dust were relatively inadequate in China compared to the USA and Australia. Health management in China was found to have multiple deficiencies in health examination, co-governance, and compensations for coal workers suffering from lung diseases and healthcare for retired coal workers. These deficiencies may be attributed to insufficient medical resources, the Chinese government-dominated governance, ineffective procedures for obtaining compensation, and the lack of effective and preventive healthcare programs for the retired coal workers. Based on the USA and Australia experience, some suggestions for improvement were proposed. PMID- 30453502 TI - Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions. AB - Heparan sulfate proteoglycan 2 (HSPG2) is an essential, highly conserved gene whose expression influences many developmental processes including the formation of the heart and brain. The gene is widely expressed throughout the musculoskeletal system including cartilage, bone marrow and skeletal muscle. The HSPG2 gene product, perlecan is a multifunctional proteoglycan that preserves the integrity of extracellular matrices, patrols tissue borders, and controls various signaling pathways affecting cellular phenotype. Given HSPG2's expression pattern and its role in so many fundamental processes, it is not surprising that relatively few gene mutations have been identified in viable organisms. Mutations to the perlecan gene are rare, with effects ranging from a relatively mild condition to a more severe and perinatally lethal form. This review will summarize the important studies characterizing mutations and variants of HSPG2 and discuss how these genomic modifications affect expression, function and phenotype. Additionally, this review will describe the clinical findings of reported HSPG2 mutations and their observed phenotypes. Finally, the evolutionary aspects that link gene integrity to function are discussed, including key findings from both in vivo animal studies and in vitro systems. We also hope to facilitate discussion about perlecan/HSPG2 and its role in normal physiology, to explain how mutation can lead to pathology, and to point out how this information can suggest pathways for future mechanistic studies. PMID- 30453501 TI - UBE2E1 Is Preferentially Expressed in the Cytoplasm of Slow-Twitch Fibers and Protects Skeletal Muscles from Exacerbated Atrophy upon Dexamethasone Treatment. AB - Skeletal muscle mass is reduced during many diseases or physiological situations (disuse, aging), which results in decreased strength and increased mortality. Muscle mass is mainly controlled by the ubiquitin-proteasome system (UPS), involving hundreds of ubiquitinating enzymes (E2s and E3s) that target their dedicated substrates for subsequent degradation. We recently demonstrated that MuRF1, an E3 ubiquitin ligase known to bind to sarcomeric proteins (telethonin, alpha-actin, myosins) during catabolic situations, interacts with 5 different E2 enzymes and that these E2-MuRF1 couples are able to target telethonin, a small sarcomeric protein, for degradation. Amongst the E2s interacting with MuRF1, E2E1 was peculiar as the presence of the substrate was necessary for optimal MuRF1 E2E1 interaction. In this work, we focused on the putative role of E2E1 during skeletal muscle atrophy. We found that E2E1 expression was restricted to type I and type IIA muscle fibers and was not detectable in type IIB fibers. This strongly suggests that E2E1 targets are fiber-specific and may be strongly linked to the contractile and metabolic properties of the skeletal muscle. However, E2E1 knockdown was not sufficient for preserving the protein content in C2C12 myotubes subjected to a catabolic state (dexamethasone treatment), suggesting that E2E1 is not involved in the development of muscle atrophy. By contrast, E2E1 knockdown aggravated the atrophying process in both catabolic C2C12 myotubes and the Tibialis anterior muscle of mice, suggesting that E2E1 has a protective effect on muscle mass. PMID- 30453503 TI - Preparation, Characterization, and Pharmacokinetic Evaluation of Imperatorin Lipid Microspheres and Their Effect on the Proliferation of MDA-MB-231 Cells. AB - Imperatorin is a chemical compound belonging to the linear furanocoumarins. Imperatorin is attracting considerable attention because of its antitumor, antibacterial, anti-inflammatory, and anticoagulant activities, inhibition of myocardial hypertrophy, and other pharmacological efficacies. However, imperatorin has limited water solubility and has better lipid solubility; thus, we decided to design and synthesize imperatorin lipid microspheres to optimize the preparation conditions. The aim was to develop and formulate imperatorin lipid microspheres through nanoemulsion technology and apply the response surface central composite design to optimize the imperatorin lipid microsphere formulation. The influence of the amounts of egg lecithin, poloxamer 188, and soybean oil for injection on the total percentage of the oil phase was investigated. The integrated effect of dependent variables, including particle size, polydispersity index, zeta potentials, drug loading, and encapsulation efficiency, was investigated. Data of overall desirabilities were fitted to a second-order polynomial equation, through which three-dimensional response surface graphs were described. Optimum experimental conditions were calculated by Design-Expert 8.06. Results indicated that the optimum preparation conditions were as follows: 1.39 g of egg lecithin, 0.21 g of poloxamer 188, and 10.57% soybean oil for injection. Preparation of imperatorin lipid microspheres according to the optimum experimental conditions resulted in an overall desirability of 0.7286, with the particle size of 168 +/- 0.54 nm, polydispersity index (PDI) of 0.138 +/- 0.02, zeta potentials of -43.5 +/- 0.5 mV, drug loading of 0.833 +/- 0.27 mg.mL-1, and encapsulation efficiency of 90 +/- 1.27%. The difference between the observed and predicted values of the overall desirability of the optimum formulation was in the range from 2.4% to 4.3%. Subsequently, scanning electron microscopy was used to observe the micromorphology of the imperatorin lipid microspheres, showing round globules of relatively uniform shape and sizes within 200 nm. The effect of imperatorin lipid microspheres on MDA-MB-231 proliferation was investigated by the MTT method. Furthermore, pharmacokinetics in Sprague-Dawley rats was evaluated using orbital bleeding. A sensitive and reliable liquid chromatography with the high-performance liquid chromatography (HPLC) method was established and validated for the quantification of imperatorin in rat plasma samples. The data were calculated by DAS (drug and statistics) Pharmacokinetic Software version 3.3.0 (Version 3.3.0, Shanghai, China). Results demonstrated that imperatorin lipid microspheres can significantly enhance the bioavailability of imperatorin and can significantly inhibit MDA-MB-231 cell proliferation. In conclusion, our results suggested that the response surface-central composite design is suitable for achieving an optimized lipid microsphere formulation. Imperatorin lipid microspheres can improve the bioavailability of imperatorin and better inhibit the proliferation of MDA-MB-231 cells as compared to imperatorin alone. PMID- 30453504 TI - IFT80 Improves Invasion Ability in Gastric Cancer Cell Line via ift80/p75NGFR/MMP9 Signaling. AB - The assembly and maintenance of cilia depend on intraflagellar transport (IFT) proteins, which play an important role in development and homeostasis. IFT80 is a newly defined IFT protein and partial mutation of IFT80 in humans causes diseases such as Jeune asphyxiating thoracic dystrophy (JATD) and short rib polydactyly (SRP) type III, both characterized by abnormal skeletal development. However, the role and mechanism of IFT80 in the invasion of gastric cancer is unknown. We established SGC-7901 and MKN-45 gastric cancer cell lines that stably overexpressed IFT80, as verified by quantitative reverse transcription-PCR, Western blot, and immunofluorescence. Matrix metalloproteinase-9 (MMP9) plays an important role in tumor invasion, and its expression was assessed by quantitative reverse transcription-PCR, Western blotting, and immunofluorescence. The invasion ability of IFT80 on SGC-7901 and MKN-45 cells was examined by the Matrigel invasion assay. The relationship between p75NGFR, and the p75NGFR antagonists, PD90780 and IFT80, were detected by quantitative reverse transcription-PCR and Western blotting. We first detected an IFT80 expression pattern, and found that IFT80 was highly expressed in gastric cancer clinical samples. Overexpression of IFT80 in the gastric cancer cell lines, SGC-7901 and MKN-45, led to lengthening cilia. Additionally, overexpression of IFT80 significantly improved proliferation and invasion, but inhibited apoptosis, in gastric cancer cells. We further found that overexpression of IFT80 increased p75NGFR and MMP9 mRNA and protein expression. Treatment with the p75NGFR antagonist PD90780 inhibited the increased invasion ability resulting from overexpression of IFT80 in SGC-7901 and MKN-45 gastric cancer cells. Thus, these results suggest that IFT80 plays an important role in invasion of gastric cancer through regulating the ift80/p75NGFR/MMP9 signal pathways. PMID- 30453506 TI - Evaluation of Strategies to Produce Highly Porous Cross-Linked Aggregates of Porcine Pancreas Lipase with Magnetic Properties. AB - The preparation of highly porous magnetic crosslinked aggregates (pm-CLEA) of porcine pancreas lipase (PPL) is reported. Some strategies to improve the volumetric activity of the immobilized biocatalyst were evaluated, such as treatment of PPL with enzyme surface-modifying agents (polyethyleneimine or dodecyl aldehyde), co-aggregation with protein co-feeders (bovine serum albumin and/or soy protein), use of silica magnetic nanoparticles functionalized with amino groups (SMNPs) as separation aid, and starch as pore-making agent. The combination of enzyme surface modification with dodecyl aldehyde, co-aggregation with SMNPs and soy protein, in the presence of 0.8% starch (followed by hydrolysis of the starch with alpha-amylase), yielded CLEAs expressing high activity (immobilization yield around 100% and recovered activity around 80%), high effectiveness factor (approximately 65% of the equivalent free enzyme activity) and high stability at 40 degrees C and pH 8.0, i.e., PPL CLEAs co aggregated with SMNPs/bovine serum albumin or SMNPs/soy protein retained 80% and 50% activity after 10 h incubation, respectively, while free PPL was fully inactivated after 2 h. Besides, highly porous magnetic CLEAs co-aggregated with soy protein and magnetic nanoparticles (pm-SP-CLEAs) showed good performance and reusability in the hydrolysis of tributyrin for five 4h-batches. PMID- 30453507 TI - Indoor Smartphone Localization Based on LOS and NLOS Identification. AB - Accurate localization technology is essential for providing location-based services. Global positioning system (GPS) is a typical localization technology that has been used in various fields. However, various indoor localization techniques are required because GPS signals cannot be received in indoor environments. Typical indoor localization methods use the time of arrival, angle of arrival, or the strength of the wireless communication signal to determine the location. In this paper, we propose an indoor localization scheme using signal strength that can be easily implemented in a smartphone. The proposed algorithm uses a trilateration method to estimate the position of the smartphone. The accuracy of the trilateration method depends on the distance estimation error. We first determine whether the propagation path is line-of-sight (LOS) or non-line of-sight (NLOS), and distance estimation is performed accordingly. This LOS and NLOS identification method decreases the distance estimation error. The proposed algorithm is implemented as a smartphone application. The experimental results show that distance estimation error is significantly reduced, resulting in accurate localization. PMID- 30453505 TI - Regular Practice of Moderate Physical Activity by Older Adults Ameliorates Their Anti-Inflammatory Status. AB - A chronic inflammatory state is a major characteristic of the aging process, and physical activity is proposed as a key component for healthy aging. Our aim was to evaluate the body composition, hypertension, lipid profile, and inflammatory status of older adults, and these factors' association with physical activity. A total of 116 elderly volunteers were categorized into terciles of quantitative metabolic equivalents of task (MET). Subjects in the first and third terciles were defined as sedentary and active subjects, respectively. Anthropometric and biochemical parameters, hemograms, and inflammatory markers were measured in plasma or peripheral mononuclear blood cells (PBMCs). The active groups exercised more than their sedentary counterparts. The practice of physical activity was accompanied by lower weight, fat mass, body mass index, and diastolic blood pressure when compared to a more sedentary life-style. Physical activity also lowered the haematocrit and total leukocyte, neutrophil, and lymphocyte counts. The practice of exercise induced a decrease in the IL-6 circulating levels and the TLR2 protein levels in PBMCs, while the expression of the anti-inflammatory IL-10 was activated in active subjects. The regular practice of physical activity exerts beneficial effects on body composition and the anti-inflammatory status of old people. PMID- 30453508 TI - Fast and Accurate Finite Transducer Analysis Method for Wireless Passive Impedance-Loaded SAW Sensors. AB - An accurate and fast simulation tool plays an important role in the design of wireless passive impedance-loaded surface acoustic wave (SAW) sensors which have received much attention recently. This paper presents a finite transducer analysis method for wireless passive impedance-loaded SAW sensors. The finite transducer analysis method uses a numerically combined finite element method boundary element method (FEM/BEM) model to analyze non-periodic transducers. In non-periodic transducers, FEM/BEM was the most accurate analysis method until now, however this method consumes central processing unit (CPU) time. This paper presents a faster algorithm to calculate the bulk wave part of the equation coefficient which usually requires a long time. A complete non-periodic FEM/BEM model of the impedance sensors was constructed. Modifications were made to the final equations in the FEM/BEM model to adjust for the impedance variation of the sensors. Compared with the conventional method, the proposed method reduces the computation time efficiently while maintaining the same high degree of accuracy. Simulations and their comparisons with experimental results for test devices are shown to prove the effectiveness of the analysis method. PMID- 30453509 TI - Label-Free Time-Gated Luminescent Detection Method for the Nucleotides with Varying Phosphate Content. AB - A new label-free molecular probe for luminescent nucleotide detection in neutral aqueous solution is presented. Phosphate-containing molecules, such as nucleotides possess vital role in cell metabolism, energy economy, and various signaling processes. Thus, the monitoring of nucleotide concentration and nucleotide related enzymatic reactions is of high importance. Two component lanthanide complex formed from Tb(III) ion carrier and light harvesting antenna, readily distinguishes nucleotides containing different number of phosphates and enable direct detection of enzymatic reactions converting nucleotide triphosphate (NTP) to nucleotide di/monophosphate or the opposite. Developed sensor enables the detection of enzymatic activity with a low nanomolar sensitivity, as highlighted with K-Ras and apyrase enzymes in their hydrolysis assays performed in a high throughput screening compatible 384-well plate format. PMID- 30453510 TI - Development of Alumina-Mesoporous Organosilica Hybrid Materials for Carbon Dioxide Adsorption at 25 degrees C. AB - Two series of alumina (Al2O3)-mesoporous organosilica (Al-MO) hybrid materials were synthesized using the co-condensation method in the presence of Pluronic 123 triblock copolymer. The first series of Al-MO samples was prepared using aluminum nitrate nanahydrate (Al-NN) and aluminum isopropoxide (Al-IP) as alumina precursors, and organosilanes with three different bridging groups, namely tris[3 (trimethoxysilyl)propyl]isocyanurate, 1,4-bis(triethoxysilyl)benzene, and bis(triethoxysilyl)ethane. The second series was obtained using the aforementioned precursors in the presence of an amine-containing 3 aminopropyltriethoxysilane to introduce, also, hanging groups. The Al-IP-derived mesostructures in the first series showed the well-developed porosity and high specific surface area, as compared to the corresponding mesostructures prepared in the second series with 3-aminopropyltriethoxysilane. The materials obtained from Al-NN alumina precursor possessed enlarged mesopores in the range of 3-17 nm, whereas the materials synthesized from Al-IP alumina precursor displayed relatively low pore widths in the range of 5-7 nm. The Al-IP-derived materials showed high CO2 uptakes, due to the enhanced surface area and microporosity in comparison to those observed for the samples of the second series with AP hanging groups. The Al-NN- and Al-IP-derived samples exhibited the CO2 uptakes in the range of 0.73-1.72 and 1.66-2.64 mmol/g at 1 atm pressure whereas, at the same pressure, the Al-NN and Al-IP-derived samples with 3-aminopropyl hanging groups showed the CO2 uptakes in the range of 0.72-1.51 and 1.70-2.33 mmol/g, respectively. These data illustrate that Al-MO hybrid materials are potential adsorbents for large-scale CO2 capture at 25 degrees C. PMID- 30453512 TI - Mobile Helical Capacitive Sensor for the Dynamic Identification of Obstructions in the Distribution of Solid Mineral Fertilizers. AB - Modern agriculture uses techniques and technologies that have provided farmers with increased yield and a possible reduction in costs. Optimizing the use of inputs by applying exact and accurate doses, which match the real needs of the soil, in addition to supplying the necessary nutrients for the correct development of the crops, enables a reduction in costs and environmental impacts caused by the incorrect use of products such as fertilizers and pesticides. With this background, this paper presents a study on the development of a capacitive sensor to identify the absence, presence or variations in the distribution of solid mineral fertilizers. To evaluate this sensor, eight different formulations were tested in distribution analysis with an overflow dosing mechanism, both statically and dynamically, with 2% maximum moisture variation between all samples. The identification of an absence or presence of fertilizers was successful in 100% of the experiments. Tests to identify variations in the fertilizer distribution were carried out through simulated obstruction. The sensor identified a reduction in the fertilizer flow in all experiments, obtaining numeric variations above 55%. In the fertilizer formulation identification test, only the formulations 02-28-20 and 06-21-12 in experiments carried out with the overflow dosing mechanism did not differ statistically one from another, while all other formulations presented a statistically significant difference in the ANOVA analysis and the Tukey test at 5% significance. PMID- 30453511 TI - Regulation of Adipogenesis and Thermogenesis through Mouse Olfactory Receptor 23 Stimulated by alpha-Cedrene in 3T3-L1 Cells. AB - Olfactory receptors (ORs) are G protein-coupled receptors that perform important physiological functions beyond their role as odorant detectors in the olfactory sensory neurons. In the present study, we describe a novel role for one of these ORs, mouse olfactory receptor 23 (MOR23), as a regulator of adipogenesis and thermogenesis in 3T3-L1 cells. Downregulation of MOR23 by small interfering RNA in 3T3-L1 cells enhanced intracellular lipid accumulation and reduced the oxygen consumption rate. In agreement with this phenotype, MOR23 deletion significantly decreased intracellular cyclic adenosine monophosphate (cAMP) levels and protein amounts of adenylyl cyclase 3 (ADCY3), protein kinase A catalytic subunit (PKA Calpha), phospho-5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), and phospho-cAMP-responsive element-binding protein (CREB), along with upregulation of adipogenic genes and downregulation of genes involved in thermogenesis. Activation of MOR23 by alpha-cedrene, a novel natural ligand of MOR23, significantly reduced lipid content, increased the oxygen consumption rate, and stimulated reprogramming of the metabolic signature of 3T3-L1 cells, and these changes elicited by alpha-cedrene were absent in MOR23-deficient cells. These findings point to the role of MOR23 as a regulator of adipogenesis and thermogenesis in adipocytes. PMID- 30453513 TI - Influence of Stainless Needle Electrodes and Silver Disk Electrodes over the Interhemispheric Cerebral Coherence Value in Vigil Dogs. AB - Electroencephalography (EEG) is an objective diagnostic tool in the evaluation of cerebral functionality, both in human and veterinary medicine. For EEG acquisition, different types of electrodes are used, as long as they have no impact on the recorded background activity. However, to date, the influence of electrode type on quantitative EEG and cerebral coherence has not been investigated. Twenty EEG traces (ten with needle electrodes and ten with disk electrodes) were recorded from ten mesocephalic vigil dogs in a monopolar montage. Values for interhemispheric coherence for each frequency band were compared between stainless needle and silver disk electrodes traces. Our results show that the values of interhemispheric coherence in vigil dogs are depending of the type of electrodes used in EEG recordings. In the frontal (FP) channel, for delta and theta frequency bands, the registered coherence is significantly higher when stainless needle electrodes are used. Our results might have important consequences in the field of canine neurology and applied neuroscience, as the frontal channel analysis is preferred in aging and behavior studies. PMID- 30453514 TI - Modulation of the CCR6-CCL20 Axis: A Potential Therapeutic Target in Inflammation and Cancer. AB - Prototypical functions of the chemokine receptor CCR6 include immune regulation by maneuvering cell chemotaxis and selective delimiting of the pro-inflammatory TH17 and regulatory Treg subsets during chronic or acute systemic inflammation. Inhibition of CCR6 is proposed to attenuate disease symptoms and promote recuperation of multiple inflammatory and autoimmune disorders. Prescription medicines with pharmacodynamics involving the inhibition of the chemokine axis CCR6-CCL20 are very limited. The development of such therapeutics is still at an early experimental stage and has mostly involved the utilization of pre-clinical models and neutralizing mono or polyclonal antibodies against either partner (CCR6 or CCL20). Other methods include the constitutive use of small molecules as peptide inhibitors or small interfering ribonucleic acid (siRNA) to interfere with transcription at the nuclear level. In our review, we aim to introduce the wide array of potential CCR6-CCL20 inhibitors with an emphasis on attendant immune-modulator capacity that have been tested in the research field to date and are immensely promising compounds as forerunners of future curatives. Sixteen different tractable inhibitors of the CCR6-CCL20 duo have been identified as possessing high medicinal potential by drug developers worldwide to treat autoimmune and inflammatory diseases as shown in Figure 1. A multitude of antibody preparations are already available in the current pharmaceutical market as patented treatments for diseases in which the CCR6-CCL20 axis is operative, yet they must be used only as supplements with existing routinely prescribed medication as they collectively produce adverse side effects. Novel inhibitors are needed to evaluate this invaluable therapeutic target which holds much promise in the research and development of complaisant remedies for inflammatory diseases. PMID- 30453515 TI - M2M Communication Assessment in Energy-Harvesting and Wake-Up Radio Assisted Scenarios Using Practical Components. AB - Techniques for wireless energy harvesting (WEH) are emerging as a fascinating set of solutions to extend the lifetime of energy-constrained wireless networks, and are commonly regarded as a key functional technique for almost perpetual communications. For example, with WEH technology, wireless devices are able to harvest energy from different light sources or Radio Frequency (RF) signals broadcast by ambient or dedicated wireless transmitters to support their operation and communications capabilities. WEH technology will have increasingly wider range of use in upcoming applications such as wireless sensor networks, Machine-to-Machine (M2M) communications, and the Internet of Things. In this paper, the usability and fundamental limits of joint RF and solar cell or photovoltaic harvesting based M2M communication systems are studied and presented. The derived theoretical bounds are in essence based on the Shannon capacity theorem, combined with selected propagation loss models, assumed additional link nonidealities, diversity processing, as well as the given energy harvesting and storage capabilities. Fundamental performance limits and available capacity of the communicating link are derived and analyzed, together with extensive numerical results evaluated in different practical scenarios, including realistic implementation losses and state-of-the-art printed supercapacitor performance figures with voltage doubler-based voltage regulator. In particular, low power sensor type communication applications using passive and semi-passive wake-up radio (WuR) are addressed in the study. The presented analysis principles and results establish clear feasibility regions and performance bounds for wireless energy harvesting based low rate M2M communications in the future IoT networks. PMID- 30453516 TI - Soil Chemical Properties Barely Perturb the Abundance of Entomopathogenic Fusarium oxysporum: A Case Study Using a Generalized Linear Mixed Model for Microbial Pathogen Occurrence Count Data. AB - Fusarium oxysporum exhibits insect pathogenicity-however, generalized concerns of releasing phytopathogens within agroecosystems marred its entomopathogenicity related investigations. In a previous study, soils were sampled from Douro vineyards and adjacent hedgerows. In this study, 80 of those soils were analyzed for their chemical properties and were subsequently co-related with the abundance of entomopathogenic F. oxysporum, after insect baiting of soils with Galleria mellonella and Tenebrio molitor larvae. The soil chemical properties studied were organic matter content; total organic carbon; total nitrogen; available potassium; available phosphorus; exchangeable cations, such as K+, Na+, Ca2+, and Mg2+; pH; total acidity; degree of base saturation; and effective cation exchange capacity. Entomopathogenic F. oxysporum was found in 48 soils, i.e., 60% +/- 5.47%, of the total soil samples. Out of the 1280 insect larvae used, 93, i.e., 7.26% +/- 0.72%, were found dead by entomopathogenic F. oxysporum. Stepwise deletion of non-significant variables using a generalized linear model was followed by a generalized linear mixed model (GLMM). A higher C:N (logarithmized) (p < 0.001) and lower exchangeable K+ (logarithmized) (p = 0.008) were found significant for higher fungal abundance. Overall, this study suggests that entomopathogenic F. oxysporum is robust with regard to agricultural changes, and GLMM is a useful statistical tool for count data in ecology. PMID- 30453517 TI - Additional Vitamin and Mineral Support for Patients with Severe Burns: A Nationwide Experience from a Catastrophic Color-Dust Explosion Event in Taiwan. AB - Major burn injuries, which encompass >=20% of the total body surface area (TBSA), are the most severe form of trauma because of the stress response they provoke, which includes hypermetabolism, muscle wasting, and stress-induced diabetes. In 2015, a color-dust explosion disaster occurred in the Formosa Fun Coast of Taiwan and injured 499 people, who were transferred via a nationwide emergency delivery system. Some recommendations are currently available regarding vitamin and mineral support for wound healing and recovery in severe burns, but there is a lack of evidence to confirm the benefits. Thus, the current study aimed to investigate the effects of additional vitamin and mineral support for patients with severe burn injuries. Sixty-one hospitalized individuals with major burns (full thickness and >=20% TBSA) were classified into the supplement (n = 30) and control (n = 31) groups, according to whether they received supplementation with additional vitamins, calcium, and magnesium. There were significant differences between the supplement and control groups in the incidence of wound infection (30.0% vs. 77.4%, p < 0.001), sepsis (13.3% vs. 41.9%, p = 0.021), and hospitalization days (51.80 vs. 76.81, p = 0.025). After adjustment, logistic regression analysis revealed that, compared to those in the control group, patients in the supplement group had a lower risk for wound infection (OR 0.11; 95% CI 0.03-0.43; p = 0.002) and sepsis (OR 0.09; 95% CI 0.01-0.61; p = 0.014). Supplementation of multiple vitamins, calcium, and magnesium reduced the risk of wound infection and sepsis, shortened the time of hospitalization, and can be considered for use in major burns. PMID- 30453518 TI - Computational Assessment of Facial Expression Production in ASD Children. AB - In this paper, a computational approach is proposed and put into practice to assess the capability of children having had diagnosed Autism Spectrum Disorders (ASD) to produce facial expressions. The proposed approach is based on computer vision components working on sequence of images acquired by an off-the-shelf camera in unconstrained conditions. Action unit intensities are estimated by analyzing local appearance and then both temporal and geometrical relationships, learned by Convolutional Neural Networks, are exploited to regularize gathered estimates. To cope with stereotyped movements and to highlight even subtle voluntary movements of facial muscles, a personalized and contextual statistical modeling of non-emotional face is formulated and used as a reference. Experimental results demonstrate how the proposed pipeline can improve the analysis of facial expressions produced by ASD children. A comparison of system's outputs with the evaluations performed by psychologists, on the same group of ASD children, makes evident how the performed quantitative analysis of children's abilities helps to go beyond the traditional qualitative ASD assessment/diagnosis protocols, whose outcomes are affected by human limitations in observing and understanding multi-cues behaviors such as facial expressions. PMID- 30453519 TI - Derivatization of Methylglyoxal for LC-ESI-MS Analysis-Stability and Relative Sensitivity of Different Derivatives. AB - The great research interest in the quantification of reactive carbonyl compounds (RCCs), such as methylglyoxal (MGO) in biological and environmental samples, is reflected by the fact that several publications have described specific strategies to perform this task. Thus, many reagents have also been reported for the derivatization of RCCs to effectively detect and quantify the resulting compounds using sensitive techniques such as liquid chromatography coupled with mass spectrometry (LC-MS). However, the choice of the derivatization protocol is not always clear, and a comparative evaluation is not feasible because detection limits from separate reports and determined with different instruments are hardly comparable. Consequently, for a systematic comparison, we tested 21 agents in one experimental setup for derivatization of RCCs prior to LC-MS analysis. This consisted of seven commonly employed reagents and 14 similar reagents, three of which were designed and synthesized by us. All reagents were probed for analytical responsiveness of the derivatives and stability of the reaction mixtures. The results showed that derivatives of 4-methoxyphenylenediamine and 3 methoxyphenylhydrazine-reported here for the first time for derivatization of RCCs-provided a particularly high responsiveness with ESI-MS detection. We applied the protocol to investigate MGO contamination of laboratory water and show successful quantification in a lipoxidation experiment. In summary, our results provide valuable information for scientists in establishing accurate analysis of RCCs. PMID- 30453520 TI - Training-Based Methods for Comparison of Object Detection Methods for Visual Object Tracking. AB - Object tracking in challenging videos is a hot topic in machine vision. Recently, novel training-based detectors, especially using the powerful deep learning schemes, have been proposed to detect objects in still images. However, there is still a semantic gap between the object detectors and higher level applications like object tracking in videos. This paper presents a comparative study of outstanding learning-based object detectors such as ACF, Region-Based Convolutional Neural Network (RCNN), FastRCNN, FasterRCNN and You Only Look Once (YOLO) for object tracking. We use an online and offline training method for tracking. The online tracker trains the detectors with a generated synthetic set of images from the object of interest in the first frame. Then, the detectors detect the objects of interest in the next frames. The detector is updated online by using the detected objects from the last frames of the video. The offline tracker uses the detector for object detection in still images and then a tracker based on Kalman filter associates the objects among video frames. Our research is performed on a TLD dataset which contains challenging situations for tracking. Source codes and implementation details for the trackers are published to make both the reproduction of the results reported in this paper and the re-use and further development of the trackers for other researchers. The results demonstrate that ACF and YOLO trackers show more stability than the other trackers. PMID- 30453521 TI - Using Radio-Frequency Identification Technology to Measure Synchronised Ranging of Free-Range Laying Hens. AB - Free-range laying hen systems provide individuals a choice between indoor and outdoor areas where range use may be socially influenced. This study used radio frequency identification technology to track the ranging of individually-tagged hens housed in six experimental free-range pens from 28 to 38 weeks of age (46-50 hens/pen). All daily visits to the range were used to study group behaviour. Results showed that 67.6% (SD = 5.0%) of all hen movements through the pop-holes outdoors or indoors were following the movement of another hen ('pop-hole following') compared to only 50.5% of movements in simulated random data. The percentage overlap in time that all combinations of hen pairs within each pen spent simultaneously outdoors or indoors showed a median value of overlap greater than the 90th percentile of random data. Pens housing hens that had been provided variable enrichments from 4 to 21 days (n = 3 pens) showed higher 'pop-hole following' behaviour and a higher percentage of hen-pair association compared to hens reared in non-enriched conditions (n = 3 pens). These results show that birds in each free-range pen were primarily a cohesive flock and early enrichment improved this social cohesiveness. These results have implications for understanding free-range flock-level behaviour. PMID- 30453522 TI - Carbon Redistribution and Microstructural Evolution Study during Two-Stage Quenching and Partitioning Process of High-Strength Steels by Modeling. AB - The application of the quenching and partitioning (Q-P) process on advanced high strength steels improves part ductility significantly with little decrease in strength. Moreover, the mechanical properties of high-strength steels can be further enhanced by the stepping-quenching-partitioning (S-Q-P) process. In this study, a two-stage quenching and partitioning (two-stage Q-P) process originating from the S-Q-P process of an advanced high-strength steel 30CrMnSi2Nb was analyzed by the simulation method, which consisted of two quenching processes and two partitioning processes. The carbon redistribution, interface migration, and phase transition during the two-stage Q-P process were investigated with different temperatures and partitioning times. The final microstructure of the material formed after the two-stage Q-P process was studied, as well as the volume fraction of the retained austenite. The simulation results indicate that a special microstructure can be obtained by appropriate parameters of the two-stage Q-P process. A mixed microstructure, characterized by alternating distribution of low carbon martensite laths, small-sized low-carbon martensite plates, retained austenite and high-carbon martensite plates, can be obtained. In addition, a peak value of the volume fraction of the stable retained austenite after the final quenching is obtained with proper partitioning time. PMID- 30453524 TI - A Survey of LoRaWAN for IoT: From Technology to Application. AB - LoRaWAN is one of the low power wide area network (LPWAN) technologies that have received significant attention by the research community in the recent years. It offers low-power, low-data rate communication over a wide range of covered area. In the past years, the number of publications regarding LoRa and LoRaWAN has grown tremendously. This paper provides an overview of research work that has been published from 2015 to September 2018 and that is accessible via Google Scholar and IEEE Explore databases. First, a detailed description of the technology is given, including existing security and reliability mechanisms. This literature overview is structured by categorizing papers according to the following topics: (i) physical layer aspects; (ii) network layer aspects; (iii) possible improvements; and (iv) extensions to the standard. Finally, a strengths, weaknesses, opportunities and threats (SWOT) analysis is presented along with the challenges that LoRa and LoRaWAN still face. PMID- 30453523 TI - The Cyanotoxin BMAA Induces Heterocyst Specific Gene Expression in Anabaena sp. PCC 7120 under Repressive Conditions. AB - Cyanobacteria synthesize neurotoxic beta-N-methylamino-l-alanine (BMAA). The roles of this non-protein amino acid in cyanobacterial cells are insufficiently studied. During diazotrophic growth, filamentous cyanobacteria form single differentiated cells, called heterocysts, which are separated by approximately 12 15 vegetative cells. When combined nitrogen is available, heterocyst formation is blocked and cyanobacterial filaments contain only vegetative cells. In the present study, we discovered that exogenous BMAA induces the process of heterocyst formation in filamentous cyanobacteria under nitrogen-replete conditions that normally repress cell differentiation. BMAA treated cyanobacteria form heterocyst-like dark non-fluorescent non-functional cells. It was found that glutamate eliminates the BMAA mediated derepression. Quantitative polymerase chain reaction (qPCR) permitted to detect the BMAA impact on the transcriptional activity of several genes that are implicated in nitrogen assimilation and heterocyst formation in Anabaena sp. PCC 7120. We demonstrated that the expression of several essential genes increases in the BMAA presence under repressive conditions. PMID- 30453525 TI - A Ketoconazole Susceptibility Test for Malassezia pachydermatis Using Modified Leeming-Notman Agar. AB - The aim of this study was to establish a ketoconazole susceptibility test for Malassezia pachydermatis using modified Leeming-Notman agar (mLNA). The susceptibilities of 33 M. pachydermatis isolates obtained by modified CLSI M27-A3 method were compared with the results by disk diffusion method, which used different concentrations of ketoconazole on 6 mm diameter paper disks. Results showed that 93.9% (31/33) of the minimum inhibitory concentration (MIC) values obtained from both methods were similar (consistent with two methods within 2 dilutions). M. pachydermatis BCRC 21676 and Candida parapsilosis ATCC 22019 were used to verify the results obtained from the disk diffusion and modified CLSI M27 A3 tests, and they were found to be consistent. Therefore, the current study concludes that this new novel test-using different concentrations of reagents on cartridge disks to detect MIC values against ketoconazole-can be a cost effective, time-efficient, and less technically demanding alternative to existing methods. PMID- 30453526 TI - Cytotoxicity and Transcriptomic Analysis of Silver Nanoparticles in Mouse Embryonic Fibroblast Cells. AB - The rapid development of nanotechnology has led to the use of silver nanoparticles (AgNPs) in biomedical applications, including antibacterial, antiviral, anti-inflammatory, and anticancer therapies. The molecular mechanism of AgNPs-induced cytotoxicity has not been studied thoroughly using a combination of cellular assays and RNA sequencing (RNA-Seq) analysis. In this study, we prepared AgNPs using myricetin, an anti-oxidant polyphenol, and studied their effects on NIH3T3 mouse embryonic fibroblasts as an in vitro model system to explore the potential biomedical applications of AgNPs. AgNPs induced loss of cell viability and cell proliferation in a dose-dependent manner, as evident by increased leakage of lactate dehydrogenase (LDH) from cells. Reactive oxygen species (ROS) were a potential source of cytotoxicity. AgNPs also incrementally increased oxidative stress and the level of malondialdehyde, depleted glutathione and superoxide dismutase, reduced mitochondrial membrane potential and adenosine triphosphate (ATP), and caused DNA damage by increasing the level of 8-hydroxy-2' deoxyguanosine and the expressions of the p53 and p21 genes in NIH3T3 cells. Thus, activation of oxidative stress may be crucial for NIH3T3 cytotoxicity. Interestingly, gene ontology (GO) term analysis revealed alterations in epigenetics-related biological processes including nucleosome assembly and DNA methylation due to AgNPs exposure. This study is the first demonstration that AgNPs can alter bulk histone gene expression. Therefore, our genome-scale study suggests that the apoptosis observed in NIH3T3 cells treated with AgNPs is mediated by the repression of genes required for cell survival and the aberrant enhancement of nucleosome assembly components to induce apoptosis. PMID- 30453527 TI - Giantin Is Required for Post-Alcohol Recovery of Golgi in Liver Cells. AB - In hepatocytes and alcohol-metabolizing cultured cells, Golgi undergoes ethanol (EtOH)-induced disorganization. Perinuclear and organized Golgi is important in liver homeostasis, but how the Golgi remains intact is unknown. Work from our laboratories showed that EtOH-altered cellular function could be reversed after alcohol removal; we wanted to determine whether this recovery would apply to Golgi. We used alcohol-metabolizing HepG2 (VA-13) cells (cultured with or without EtOH for 72 h) and rat hepatocytes (control and EtOH-fed (Lieber-DeCarli diet)). For recovery, EtOH was removed and replenished with control medium (48 h for VA 13 cells) or control diet (10 days for rats). Results: EtOH-induced Golgi disassembly was associated with de-dimerization of the largest Golgi matrix protein giantin, along with impaired transport of selected hepatic proteins. After recovery from EtOH, Golgi regained their compact structure, and alterations in giantin and protein transport were restored. In VA-13 cells, when we knocked down giantin, Rab6a GTPase or non-muscle myosin IIB, minimal changes were observed in control conditions, but post-EtOH recovery was impaired. Conclusions: These data provide a link between Golgi organization and plasma membrane protein expression and identify several proteins whose expression is important to maintain Golgi structure during the recovery phase after EtOH administration. PMID- 30453528 TI - Intestinal Microbiome in Irritable Bowel Syndrome before and after Gut-Directed Hypnotherapy. AB - : Irritable bowel syndrome (IBS) is a disorder with brain-gut-microbiome alterations. Gut-directed hypnotherapy (GHT) has been shown to improve quality of life and symptoms in IBS. This therapy targets psychological coping, central nervous processing and brain-gut interaction. Studies have also demonstrated effects of hypnosis on intestinal transit and the mucosal immune system. So far, no study has examined the effect of GHT on the intestinal microbiome. This study aimed at examining microbial composition, IBS symptoms, and psychological distress before and after GHT. METHODS: Fecal samples were collected from 38 IBS patients (Rome-III criteria, mean age 44 years, 27 female, 11 male, 22 diarrhea dominant, 12 alternating-type and 4 constipation-dominant IBS) before and after 10 weekly group sessions of GHT. Assessments in psychological (perceived stress, PSQ; psychological distress, HADS-D; quality of life, visual analogue scales) and IBS symptom-related variables (IBS severity, IBS-SSS; single symptoms, visual analogue scales) were performed with validated questionnaires. Fecal samples underwent microbial 16S rRNA analyses (regions V1-2). RESULTS: Microbial alpha diversity was stable before and after GHT (chao1 2591 +/- 548 vs. 2581 +/- 539, p = 0.92). No significant differences were found in relative bacterial abundances but trends of reduced abundance of Lachnospiraceae 32.18 (4.14-39.89) Median (Q1 Q3) vs. 28.11 (22.85; 35.55) and Firmicutes: Bacteroidetes ratio after GHT were observable. Significant reductions in symptom severity (323 (266-371) vs. 264 (191-331), p = 0.001) and psychological distress 17.0 (12.6-21.8) vs. 12.0 (8.3 18.0), p = 0.001, and increased well-being were found after GHT. Adequate relief after therapy was reported by 32 (84%) patients. CONCLUSION: Reductions in IBS symptoms and psychological burden were observed after gut-directed hypnotherapy, but only small changes were found in intestinal microbiota composition. The findings suggest that hypnosis may act by central nervous impact and other factors largely independent from microbiota composition modulating the brain-gut axis, possibly alterations in vagus nerve functioning and microbiota metabolism. PMID- 30453530 TI - Sol-Gel Template Synthesis and Characterization of Lu2O3:Eu3+ Nanowire Arrays. AB - Uniform Lu2O3:Eu3+ nanowire arrays were successfully prepared by the sol-gel process using anodic aluminum oxide (AAO) templates. The as-synthesized nanowires are homogeneous, highly ordered, and dense and have a uniform diameter of ~300 nm defined by the AAO templates. The X-ray diffraction and selected area electron diffraction results show that the Lu2O3:Eu3+ nanowires have a polycrystalline cubic structure, and the crystallite size of the Lu2O3:Eu3+ nanowires is confined by the AAO template. The nanowires within the AAO template showed good photoluminescence and X-ray-excited optical luminescence performances for Lu2O3:Eu3+. The emission peaks were attributed to the 5D0 -> 7FJ transitions of Eu3+ (J = 0, 1, 2, 3). PMID- 30453529 TI - Intersection of Brain Development and Paediatric Diffuse Midline Gliomas: Potential Role of Microenvironment in Tumour Growth. AB - Diffuse intrinsic pontine glioma (DIPG) is a devastating and incurable paediatric brain tumour with a median overall survival of 9 months. Until recently, DIPGs were treated similarly to adult gliomas, but due to the advancement in molecular and imaging technologies, our understanding of these tumours has increased dramatically. While extensive research is being undertaken to determine the function of the molecular aberrations in DIPG, there are significant gaps in understanding the biology and the influence of the tumour microenvironment on DIPG growth, specifically in regards to the developing pons. The precise orchestration and co-ordination of the development of the brain, the most complex organ in the body, is still not fully understood. Herein, we present a brief overview of brainstem development, discuss the developing microenvironment in terms of DIPG growth, and provide a basis for the need for studies focused on bridging pontine development and DIPG microenvironment. Conducting investigations in the context of a developing brain will lead to a better understanding of the role of the tumour microenvironment and will help lead to identification of drivers of tumour growth and therapeutic resistance. PMID- 30453532 TI - Insecticidal Activities of Chloramphenicol Derivatives Isolated from a Marine Alga-Derived Endophytic Fungus, Acremonium vitellinum, against the Cotton Bollworm, Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae). AB - A great deal of attention has been focused on the secondary metabolites produced by marine endophytic fungi, which can be better alternatives to chemicals, such as biopesticides, for control of polyphagous pests. On the basis of its novel biocontrol attributes, chemical investigation of a marine alga-derived endophytic fungus, Acremonium vitellinum, resulted in the isolation of three chloramphenicol derivatives (compounds 1-3). Their chemical structures were elucidated by detailed analysis of their nuclear magnetic resonance spectra, high-resolution electrospray ionization mass spectrometry, and by comparison with the data available in the literature. In this paper, compound 2 was firstly reported as the natural origin of these fungal secondary metabolites. The insecticidal activities of compounds 1-3 against the cotton bollworm, Helicoverpa armigera, were evaluated. The natural compound 2 presented considerable activity against H. armigera, with an LC50 value of 0.56 +/- 0.03 mg/mL (compared to matrine with an LC50 value of 0.24 +/- 0.01 mg/mL). Transcriptome sequencing was used to evaluate the molecular mechanism of the insecticidal activities. The results presented in this study should be useful for developing compound 2 as a novel, ecofriendly and safe biopesticide. PMID- 30453531 TI - Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation. AB - The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation. PMID- 30453533 TI - Cyclic Peptides: Promising Scaffolds for Biopharmaceuticals. AB - To date, small molecules and macromolecules, including antibodies, have been the most pursued substances in drug screening and development efforts. Despite numerous favorable features as a drug, these molecules still have limitations and are not complementary in many regards. Recently, peptide-based chemical structures that lie between these two categories in terms of both structural and functional properties have gained increasing attention as potential alternatives. In particular, peptides in a circular form provide a promising scaffold for the development of a novel drug class owing to their adjustable and expandable ability to bind a wide range of target molecules. In this review, we discuss recent progress in methodologies for peptide cyclization and screening and use of bioactive cyclic peptides in various applications. PMID- 30453535 TI - Effect of Formulation on the Binding Efficiency and Selectivity of Precipitation Molecularly Imprinted Polymers. AB - This study investigated the effect of feed formulation: the template:functional monomer (T:fM) and functional monomer:crosslinker (fM:X) ratios as well as the initiator concentration, on the binding performance and selectivity of caffeine (CAF) and theophylline (THP) imprinted polymers obtained by precipitation polymerisation in acetonitrile at 60 degrees C using methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) as functional monomer and crosslinker, respectively. Template incorporation, monitored by quantitative 1H-NMR spectroscopy, ranged from 8 to 77% and was found to be more favourable at both high and low T:fM ratios, low fM:X ratio and high initiator concentration. The resulting T:fM ratio in most MIPs were found to be lower than their feed ratios. Incorporation of THP into the polymers was observed to be consistently higher than CAF and, for most MIPs, the observed binding capacities represent less than 10% of the incorporated template. Improved imprinting factors were obtained from molecularly imprinted polymers (MIPs) with high crosslinker content, i.e., fM:X ratio of 1:10, and high initiator concentration, i.e., initiator:total monomer (I:tM) ratio of 1:5, while T:fM ratio (1:2 to 1:8) was found not to influence binding capacities and imprinting factors (IF). The NIPs showed no preference for either CAF or THP in competitive selectivity studies while MIPs were observed to bind preferentially to their template with THP displaying higher selectivity (72 94%) than CAF (63-84%). Template selectivity was observed to increase with increasing initiator concentration, with MIPs from I:tM ratio of 1:5 shown to be the most selective towards CAF (84%) and THP (93%). The fM:X ratio only showed minimal effect on MIP selectivity. Overall, for the MIP systems under study, template incorporation, binding capacity, imprinting factor and selectivity are enhanced at a faster rate of polymerisation using an I:tM ratio of 1:5. Polymer particles obtained were between 66 to 140 nm, with MIPs generally smaller than their NIP counterparts, and have been observed to decrease with increasing T:fM and fM:X ratios and increase with increasing initiator concentration. PMID- 30453534 TI - Impact of a Healthy Dietary Pattern on Gut Microbiota and Systemic Inflammation in Humans. AB - Gut microbiota have recently been suggested to play a part in low-grade systemic inflammation, which is considered a key risk factor for cardiometabolic disorders. Diet is known to affect gut microbiota; however, the effects of diet and dietary components on gut microbiota and inflammation are not fully understood. In the present review, we summarize recent research on human dietary intervention studies, investigating the effects of healthy diets or dietary components on gut microbiota and systemic inflammation. We included 18 studies that reported how different dietary components altered gut microbiota composition, short-chain fatty acid levels, and/or inflammatory markers. However, the heterogeneity among the intervention studies makes it difficult to conclude whether diets or dietary components affect gut microbiota homeostasis and inflammation. More appropriately designed studies are needed to better understand the effects of diet on the gut microbiota, systemic inflammation, and risk of cardiometabolic disorders. PMID- 30453537 TI - Facile Solvothermal Synthesis of CuCo2S4 Yolk-Shells and Their Visible-Light Driven Photocatalytic Properties. AB - In this present work, we synthesized a yolk-shell shaped CuCo2S4 by a simple anion exchange method. The morphological and structural properties of the as synthesized sample were characterized using X-ray diffraction (XRD), UV-vis diffuse reflectance spectra (UV-vis DRS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The SEM and TEM results confirmed that the uniform yolk-shell structure was formed during the solvothermal process. The band gap was about 1.41 eV, which have been confirmed by UV-vis DRS analysis. The photocatalytic property was evaluated by the photocatalytic degradation of methylene blue (MB) dye as a target pollutant under the visible-light irradiation. The experimental results confirmed the potential application of yolk shell shape CuCo2S4 in visible-light photocatalytic applications. PMID- 30453536 TI - Monolithic Multi Degree of Freedom (MDoF) Capacitive MEMS Accelerometers. AB - With the continuous advancements in microelectromechanical systems (MEMS) fabrication technology, inertial sensors like accelerometers and gyroscopes can be designed and manufactured with smaller footprint and lower power consumption. In the literature, there are several reported accelerometer designs based on MEMS technology and utilizing various transductions like capacitive, piezoelectric, optical, thermal, among several others. In particular, capacitive accelerometers are the most popular and highly researched due to several advantages like high sensitivity, low noise, low temperature sensitivity, linearity, and small footprint. Accelerometers can be designed to sense acceleration in all the three directions (X, Y, and Z-axis). Single-axis accelerometers are the most common and are often integrated orthogonally and combined as multiple-degree-of-freedom (MDoF) packages for sensing acceleration in the three directions. This type of MDoF increases the overall device footprint and cost. It also causes calibration errors and may require expensive compensations. Another type of MDoF accelerometers is based on monolithic integration and is proving to be effective in solving the footprint and calibration problems. There are mainly two classes of such monolithic MDoF accelerometers, depending on the number of proof masses used. The first class uses multiple proof masses with the main advantage being zero calibration issues. The second class uses a single proof mass, which results in compact device with a reduced noise floor. The latter class, however, suffers from high cross-axis sensitivity. It also requires very innovative layout designs, owing to the complicated mechanical structures and electrical contact placement. The performance complications due to nonlinearity, post fabrication process, and readout electronics affects both classes of accelerometers. In order to effectively compare them, we have used metrics such as sensitivity per unit area and noise-area product. This paper is devoted to an in-depth review of monolithic multi-axis capacitive MEMS accelerometers, including a detailed analysis of recent advancements aimed at solving their problems such as size, noise floor, cross-axis sensitivity, and process aware modeling. PMID- 30453538 TI - A QM/MM Study of Nitrite Binding Modes in a Three-Domain Heme-Cu Nitrite Reductase. AB - Copper-containing nitrite reductases (CuNiRs) play a key role in the global nitrogen cycle by reducing nitrite (NO2-) to nitric oxide, a reaction that involves one electron and two protons. In typical two-domain CuNiRs, the electron is acquired from an external electron-donating partner. The recently characterised Rastonia picketti (RpNiR) system is a three-domain CuNiR, where the cupredoxin domain is tethered to a heme c domain that can function as the electron donor. The nitrite reduction starts with the binding of NO2- to the T2Cu centre, but very little is known about how NO2- binds to native RpNiR. A recent crystallographic study of an RpNiR mutant suggests that NO2- may bind via nitrogen rather than through the bidentate oxygen mode typically observed in two domain CuNiRs. In this work we have used combined quantum mechanical/molecular mechanical (QM/MM) methods to model the binding mode of NO2- with native RpNiR in order to determine whether the N-bound or O-bound orientation is preferred. Our results indicate that binding via nitrogen or oxygen is possible for the oxidised Cu(II) state of the T2Cu centre, but in the reduced Cu(I) state the N-binding mode is energetically preferred. PMID- 30453539 TI - Electrochemistry Study of Permselectivity and Interfacial Electron Transfers of a Branch-Tailed Fluorosurfactant Self-Assembled Monolayer on Gold. AB - We investigated the permselectivity and interfacial electron transfers of an amphiphilic branch-tailed fluorosurfactant self-assembled monolayer (FS-SAM) on a gold electrode by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The FS-SAM was prepared by a self-assembly technique and a "click" reaction. The barrier property and interfacial electron transfers of the FS-SAM were also evaluated using various probes with different features. The FS SAM allowed a higher degree of permeation by small hydrophilic (Cl- and F-) electrolyte ions than large hydrophobic (ClO4- and PF6-) ones. Meanwhile, the redox reaction of the Fe(CN)63- couple was nearly completely blocked by the FS SAM, whereas the electron transfer of Ru(NH3)63+ was easier than that of Fe(CN)63 , which may be due to the underlying tunneling mechanism. For hydrophobic dopamine, the hydrophobic bonding between the FS-SAM exterior fluoroalkyl moieties and the hydrophobic probes, as well as the hydration resistance from the interior hydration shell around the oligo (ethylene glycol) moieties, hindered the transport of hydrophobic probes into the FS-SAM. These results may have profound implications for understanding the permselectivity and electron transfers of amphiphilic surfaces consisting of molecules containing aromatic groups and branch-tailed fluorosurfactants in their structures. PMID- 30453541 TI - Nanocarbon Reinforced Rubber Nanocomposites: Detailed Insights about Mechanical, Dynamical Mechanical Properties, Payne, and Mullin Effects. AB - The reinforcing ability of the fillers results in significant improvements in properties of polymer matrix at extremely low filler loadings as compared to conventional fillers. In view of this, the present review article describes the different methods used in preparation of different rubber nanocomposites reinforced with nanodimensional individual carbonaceous fillers, such as graphene, expanded graphite, single walled carbon nanotubes, multiwalled carbon nanotubes and graphite oxide, graphene oxide, and hybrid fillers consisting combination of individual fillers. This is followed by review of mechanical properties (tensile strength, elongation at break, Young modulus, and fracture toughness) and dynamic mechanical properties (glass transition temperature, crystallization temperature, melting point) of these rubber nanocomposites. Finally, Payne and Mullin effects have also been reviewed in rubber filled with different carbon based nanofillers. PMID- 30453540 TI - New Invasive Nemertean Species (Cephalothrix Simula) in England with High Levels of Tetrodotoxin and a Microbiome Linked to Toxin Metabolism. AB - The marine nemertean Cephalothrix simula originates from the Pacific Ocean but in recent years has been discovered in northern Europe. The species has been associated with high levels of the marine neurotoxin Tetrodotoxin, traditionally associated with Pufferfish Poisoning. This study reports the first discovery of two organisms of C. simula in the UK, showing the geographical extent of this species is wider than originally described. Species identification was initially conducted morphologically, with confirmation by Cox 1 DNA sequencing. 16S gene sequencing enabled the taxonomic assignment of the microbiome, showing the prevalence of a large number of bacterial genera previously associated with TTX production including Alteromonas, Vibrio and Pseudomonas. LC-MS/MS analysis of the nemertean tissue revealed the presence of multiple analogues of TTX, dominated by the parent TTX, with a total toxin concentration quantified at 54 ug TTX per g of tissue. Pseudomonas luteola isolated from C. simula, together with Vibrio alginolyticus from the native nemertean Tubulanus annulatus, were cultured at low temperature and both found to contain TTX. Overall, this paper confirms the high toxicity of a newly discovered invasive nemertean species with links to toxin-producing marine bacteria and the potential risk to human safety. Further work is required to assess the geographical extent and toxicity range of C. simula along the UK coast in order to properly gauge the potential impacts on the environment and human safety. PMID- 30453542 TI - The Influence of Exposure Energy Density on Porosity and Microhardness of the SLM Additive Manufactured Elements. AB - Selective laser melting (SLM) is an additive manufacturing technique. It allows elements with very complex geometry to be produced using metallic powders. A geometry of manufacturing elements is based only on 3D computer-aided design (CAD) data. The metal powder is melted selectively layer by layer using an ytterbium laser. This paper contains the results of porosity and microhardness analysis made on specimens manufactured during a specially prepared process. Final analysis helped to discover connections between changing hatching distance, exposure speed and porosity. There were no significant differences in microhardness and porosity measurement results in the planes perpendicular and parallel to the machine building platform surface. PMID- 30453543 TI - Transfection of T-Box Transcription Factor BRACHYURY and SOX2 Synergistically Promote Self-Renewal and Invasive Phenotype in Oral Cancer Cells. AB - Recent studies suggest that epithelial-mesenchymal transition (EMT) correlates with cancer metastasis. In addition, there is growing evidence of the association of EMT with cancer stem cells (CSCs). Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the CSC phenotype, which were effectively suppressed by a BRACHYURY knockdown in an adenoid cystic carcinoma cell line. In this study, we further tested whether BRACHYURY is a regulator of cancer stemness by means of forced expression of BRACHYURY in oral cancer cell lines. BRACHYURY, SOX2, or both were stably transfected into oral carcinoma cell lines. We analysed these transfectants with respect to self-renewal phenotypes using a sphere-formation assay, and we assessed the expression levels of EMT markers and stem cell markers using real time reverse transcription-polymerase chain reaction (RT-PCR). Cell migration and invasiveness in vitro were evaluated using a wound healing assay and a tumour cell dissemination assay, respectively. Forced expression of BRACHYURY or SOX2 slightly increased expression of EMT and stem cell markers and the self-renewal phenotype. The expression levels, however, were much lower compared to those of cancer stem cell-like cells. Forced co-expression of BRACHYURY and SOX2 strongly upregulated EMT and stem cell markers and the self-renewal phenotype. Cell migration and invasiveness in vitro were also remarkably enhanced. These synergistic effects increased expression levels of FIBRONECTIN, SNAIL, SLUG, ZEB1, and TGF-beta2. In particular, the effects on FIBRONECTIN and TGF-beta2 were significant. We found that BRACHYURY and SOX2 synergistically promote cancer stemness in oral cancer cells. This finding points to the importance of gene or protein networks associated with BRACHYURY and SOX2 in the development and maintenance of the CSC phenotype. PMID- 30453544 TI - Prevention Is the Best Treatment: The Case for Understanding the Transition from Monoclonal Gammopathy of Undetermined Significance to Myeloma. AB - Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study. PMID- 30453545 TI - Rosmarinic Acid, a Component of Rosemary Tea, Induced the Cell Cycle Arrest and Apoptosis through Modulation of HDAC2 Expression in Prostate Cancer Cell Lines. AB - Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis. The purpose of this study is to investigate the effect of RA in comparison with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor used as an anti-cancer agent, on survival and apoptosis of PCa cell lines, PC-3 and DU145, and the expression of HDAC. RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation. Additionally, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells in Annexin V assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. In western blot analysis, RA inhibited the expression of HDAC2, as SAHA did. Proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition, RA modulated the protein expression of intrinsic mitochondrial apoptotic pathway-related genes, such as Bax, Bcl-2, caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) (cleaved) via the upregulation of p53 derived from HDAC2 downregulation, leading to the increased apoptosis of PC-3 and DU145 cells. Taken together, treatment of RA to PCa cell lines inhibits the cell survival and induces cell apoptosis, and it can be used as a novel therapeutic agent toward PCa. PMID- 30453546 TI - Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy. AB - Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes. PMID- 30453548 TI - Targeted Therapy-Resistant Melanoma Cells Acquire Transcriptomic Similarities with Human Melanoblasts. AB - The mechanisms of adaptive and acquired drug resistance in tumors are not completely understood. So far, gene amplifications or mutations, leading to the reactivation of the MAPK or PI3K pathways have been described. In this study, we used two different methods to generate human melanoblasts: (1) via differentiation from induced pluripotent stem cells (iPSCs) and (2) via dedifferentiation from melanocytes. The melanoblast transcriptomes were then compared to the transcriptome of MAPK inhibitor-resistant melanoma cells. We observed that the expression of genes associated with cell cycle control, DNA damage control, metabolism, and cancer was altered in both melanoblast populations and in both adaptive and acquired resistant melanoma samples, compared to drug-sensitive samples. However, genes involved in antigen presentation and cellular movement were only regulated in the melanoblast populations and in the acquired resistant melanoma samples, compared to the drug sensitive samples. Moreover, melanocyte-derived melanoblasts and adaptive resistant melanoma samples were characterized by different expression levels of certain transcription factors or genes involved in the CDK5 pathway. In conclusion, we show here that in vitro models of human melanoblasts are very important tools to comprehend the expression profiles of drug-resistant melanoma. PMID- 30453549 TI - Differential Effects of the Flavonolignans Silybin, Silychristin and 2,3 Dehydrosilybin on Mesocestoides vogae Larvae (Cestoda) under Hypoxic and Aerobic In Vitro Conditions. AB - Mesocestoides vogae larvae represent a suitable model for evaluating the larvicidal potential of various compounds. In this study we investigated the in vitro effects of three natural flavonolignans-silybin (SB), 2,3-dehydrosilybin (DHSB) and silychristin (SCH)-on M. vogae larvae at concentrations of 5 and 50 MUM under aerobic and hypoxic conditions for 72 h. With both kinds of treatment, the viability and motility of larvae remained unchanged, metabolic activity, neutral red uptake and concentrations of neutral lipids were reduced, in contrast with a significantly elevated glucose content. Incubation conditions modified the effects of individual FLs depending on their concentration. Under both sets of conditions, SB and SCH suppressed metabolic activity, the concentration of glucose, lipids and partially motility more at 50 MUM, but neutral red uptake was elevated. DHSB exerted larvicidal activity and affected motility and neutral lipid concentrations differently depending on the cultivation conditions, whereas it decreased glucose concentration. DHSB at the 50 MUM concentration caused irreversible morphological alterations along with damage to the microvillus surface of larvae, which was accompanied by unregulated neutral red uptake. In conclusion, SB and SCH suppressed mitochondrial functions and energy stores, inducing a physiological misbalance, whereas DHSB exhibited a direct larvicidal effect due to damage to the tegument and complete disruption of larval physiology and metabolism. PMID- 30453547 TI - Cancer-Associated Thrombosis in Cirrhotic Patients with Hepatocellular Carcinoma. AB - It is common knowledge that cancer patients are more prone to develop venous thromboembolic complications (VTE). It is therefore not surprising that patients with hepatocellular carcinoma (HCC) present with a significant risk of VTE, with the portal vein being the most frequent site (PVT). However, patients with HCC are peculiar as both cancer and liver cirrhosis are conditions that can perturb the hemostatic balance towards a prothrombotic state. Because HCC-related hypercoagulability is not clarified at all, the aim of the present review is to summarize the currently available knowledge on epidemiology and pathogenesis of non-malignant thrombotic complications in patients with liver cirrhosis and HCC. They are at increased risk to develop both PVT and non-splanchnic VTE, indicating that both local and systemic factors can foster the development of site-specific thrombosis. Recent studies have suggested multiple and often interrelated mechanisms through which HCC can tip the hemostatic balance of liver cirrhosis towards hypercoagulability. Described mechanisms include increased fibrinogen concentration/polymerization, thrombocytosis, and release of tissue factor expressing extracellular vesicles. Currently, there are no specific guidelines on the use of thromboprophylaxis in this unique population. There is the urgent need of prospective studies assessing which patients have the highest prothrombotic profile and would therefore benefit from early thromboprophylaxis. PMID- 30453551 TI - Synthesis and Evaluation of Anticancer Activities of Novel C-28 Guanidine Functionalized Triterpene Acid Derivatives. AB - Triterpene acids, namely, 20,29-dihydrobetulinic acid (BA), ursolic acid (UA) and oleanolic acid (OA) were converted into C-28-amino-functionalized triterpenoids 4 7, 8a, 15, 18 and 20. These compounds served as precursors for the synthesis of novel guanidine-functionalized triterpene acid derivatives 9b-12b, 15c, 18c and 20c. The influence of the guanidine group on the antitumor properties of triterpenoids was investigated. The cytotoxicity was tested on five human tumor cell lines (Jurkat, K562, U937, HEK, and Hela), and compared with the tests on normal human fibroblasts. The antitumor activities of the most tested guanidine derivatives was lower, than that of corresponding amines, but triterpenoids with the guanidine group were less toxic towards human fibroblasts. The introduction of the tris(hydroxymethyl)aminomethane moiety into the molecules of triterpene acids markedly enhanced the cytotoxic activity of the resulting conjugates 15, 15c, 18b,c and 20b,c irrespective of the triterpene skeleton type. The dihydrobetulinic acid amine 15, its guanidinium derivative 15c and guanidinium derivatives of ursolic and oleanolic acids 18c and 20c were selected for extended biological investigations in Jurkat cells, which demonstrated that the antitumor activity of these compounds is mediated by induction of cell cycle arrest at the S-phase and apoptosis. PMID- 30453552 TI - Space-Based Focal Plane Ambiguous Measurement Ballistic Target MeMber Tracking. AB - Aimed at space-based passive detection and tracking of ballistic targets, a multi target multi-Bernoulli (MeMber) filtering algorithm based on a focal plane ambiguous measurement model is proposed. The measurement error sources of space based passive detection are analyzed. It is found that focal plane target tracking is the basis of space target tracking in the framework of the distributed data processing structure, and the main error of focal plane measurement is pixel resolution. Based on the above analysis, the focal plane ambiguous measurement model is established to replace the traditional measurement model and the generalized likelihood function is designed. Finally, the MeMber filter is modified based on ambiguous measurement and generalized likelihood function. The simulation experiment compares the tracking effect of a MeMber filter based on ambiguous measurement and traditional measurement, respectively. The filter based on ambiguous measurement achieves better results. It shows that ambiguous measurement is closer to reality and has more application value. PMID- 30453550 TI - Genes and Dietary Fatty Acids in Regulation of Fatty Acid Composition of Plasma and Erythrocyte Membranes. AB - The fatty acid compositions of plasma lipids and cell membranes of certain tissues are modified by dietary fatty acid composition. Furthermore, many other factors (age, sex, ethnicity, health status, genes, and gene * diet interactions) affect the fatty acid composition of cell membranes or plasma lipid compartments. Therefore, it is of great importance to understand the complexity of mechanisms that may modify fatty acid compositions of plasma or tissues. We carried out an extensive literature survey of gene * diet interaction in the regulation of fatty acid compositions. Most of the related studies have been observational studies, but there are also a few intervention trials that tend to confirm that true interactions exist. Most of the studies deal with the desaturase enzyme cluster (FADS1, FADS2) in chromosome 11 and elongase enzymes. We expect that new genetic variants are being found that are linked with the genetic regulation of plasma or tissue fatty acid composition. This information is of great help to understanding the contribution of dietary fatty acids and their endogenic metabolism to the development of some chronic diseases. PMID- 30453553 TI - Breaking up Sedentary Time in Overweight/Obese Adults on Work Days and Non-Work Days: Results from a Feasibility Study. AB - Office workers are vulnerable to the adverse health effects of sedentary behavior (i.e., sitting time). Increasing physical activity and preventing time spent sitting is an occupational health priority. This randomized crossover design study compared the short-term (3-days) effects of hourly interruptions of sedentary time with 5-min micrrobouts of activity for 9 hours (MICRO) to a sedentary control condition (SED) and a duration-matched continuous single bout of physical activity (45-min/d, ONE) condition on inclinometer-derived sitting time on work and non-work days in sedentary overweight/obese adults. Differences in sitting/lying, standing, stepping, number of sit/stand transitions, time spent in moderate and vigorous activity (MVPA), energy expenditure, self-perceived vigor and fatigue, and insulin sensitivity were also examined. Twenty-two participants (10M/12F; 31.7 +/- 1.3 year old BMI 30.4 +/- 0.5 kg/m2) completed all conditions. No between-condition effects were observed in sitting-time and sit/stand transitions. Both interventions increased daily steps, MVPA and energy expenditure with increases being greater in ONE than MICRO. Feelings of vigor and fasting insulin sensitivity were also improved. Participants reported less fatigue with MICRO than SED and ONE. Both interventions increase physical activity and energy expenditure in occupational and leisure-time contexts. The sustainability of these effects over the long term and on health outcomes will need to be tested in future studies. PMID- 30453554 TI - Dichloromethane Extracts of Geranium Koreanum Kom. Alleviates Esophagus Damage in Acute Reflux Esophagitis-Induced Rats by Anti-Inflammatory Activities. AB - Reflux esophagitis (RE) is a gastrointestinal disease caused by the reflux of gastric acid and stomach contents, and it leads to esophageal damage. Therefore, it is necessary to study the improvement of esophageal damage on a RE-induced model. The present study was accomplished to demonstrate the protective effects of a dichloromethane fraction of Geranium koreanum (DGK) plant on esophageal damage in an acute RE rat model. First, we examined the potential of anti inflammatory effects of various fractions measured by cell cytotoxicity, morphological changes and nitric oxide (NO) production on lipopolysaccharide (LPS)-induced Raw 264.7 macrophage cells. Then, to evaluate the protective effects on RE, rats were partitioned into the following groups: normal control, RE-induced control and RE rats pre-treated with DGK 100 and 200 mg/kg body weight. The esophageal mucosal ulcer ratio was measured by the Image J program and histological changes were examined using a hematoxylin and eosin staining of the esophageal mucosa. The expression of pro-inflammatory proteins, cytokines and tight junction proteins involved in the esophageal mucosal damage were investigated using Western blotting and an enzyme-linked immunosorbent assay (ELISA) kit with esophagus tissue. DGK chemical profile and phenolic contents were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). The results showed that DGK exhibited anti-inflammatory effects against LPS-stimulated cells by significantly inhibiting NO production. Additionally, the results in vivo showed that improvement effects of DGK on esophageal mucosal damage. The expression of inflammatory proteins involved in nuclear factor kappaB (NF-kappaB) signaling pathways and tight junction protein (claudin-4 and -5) were significantly decreased in esophageal mucosa. We found the potential of DGK as source of replacement therapy products for inflammatory and RE disease. PMID- 30453555 TI - Methadone Maintenance Treatment Reduces the Vulnerability of Drug Users on HIV/AIDS in Vietnamese Remote Settings: Assessing the Changes in HIV Knowledge, Perceived Risk, and Testing Uptake after a 12-Month Follow-Up. AB - Methadone Maintenance Treatment (MMT) program has been considered a medium through which human immunodeficiency virus (HIV) risks assessment and prevention on drug use/HIV-infected population can be effectively conducted. Studies concerning the implementation of such idea on patients in remote, under-developed areas, however, have been limited. Having the clinics established in three mountainous provinces of Vietnam, this study aimed to evaluate the changes in knowledge of HIV, perceived risk, and HIV testing uptake of the patients. A longitudinal study was conducted at six MMT clinics in three provinces with a pre and post-assessments among 300 patients. Outcomes of interest were compared between baseline and after 12 months. The magnitude of changes was extrapolated. The proportion of participants reporting that their HIV knowledge was not good fell by 4.4% (61.3% at the baseline vs. 56.8% at 12 months). The significant improvement seen was in the knowledge that needle sharing was a mode of transmission (82.7% vs. 89.6%). Nevertheless, the majority of participants reportedly considered mosquitoes/insect and eating with the HIV-infected patient were the route of transmission at both time points (84.7% vs. 89.1%, 92.2% vs. 93.3%, respectively). This study found a limited improvement in HIV knowledge and testing uptake among MMT patients following a 12-month period. It also highlighted some shortcomings in the knowledge, attitudes and practices (KAP) of these patients, in particular, incorrect identification of HIV transmission routes, among patients both at program initiation and follow-up. The findings lent support to the argument for enhancing education and counseling efforts at MMT clinics regarding HIV, as well as for improving access to preventive and health care services through the integration of MMT/HIV services. PMID- 30453556 TI - Millimeter Wave Vehicular Channel Emulation: A Framework for Balancing Complexity and Accuracy. AB - We propose a general framework for the specification of a sparse representation of millimeter wave vehicular propagation channels and apply this to both synthetic data and real-world observations from channel sounding experiments. The proposed framework is based on the c-LASSO (complex Least Absolute Shrinkage and Selection Operator) which minimizes the mean squared error of the sparse representation for a given number of degrees of freedom. By choosing the number of degrees of freedom, we balance the numerical complexity of the representation in the channel emulation against its accuracy in terms of the mean squared error. A key ingredient is the choice of basis of the representation and we discuss two options: the Fourier basis and its projection onto a given subband. The results indicate that the subband-projected Fourier basis is a low-complexity choice with high fidelity for representing clustered channel impulse responses. Finally, a sequential estimator is formulated which enforces a consistent temporal evolution of the geometry of the interacting objects in the propagation environment. We demonstrate the performance of our approach using both synthetic data and measured 60 GHz vehicular channel traces. PMID- 30453558 TI - Comparative Analyses of Cytochrome P450s and Those Associated with Secondary Metabolism in Bacillus Species. AB - Cytochrome P450 monooxygenases (CYPs/P450s) are among the most catalytically diverse enzymes, capable of performing enzymatic reactions with chemo-, regio-, and stereo-selectivity. Our understanding of P450s' role in secondary metabolite biosynthesis is becoming broader. Among bacteria, Bacillus species are known to produce secondary metabolites, and recent studies have revealed the presence of secondary metabolite biosynthetic gene clusters (BGCs) in these species. However, a comprehensive comparative analysis of P450s and P450s involved in the synthesis of secondary metabolites in Bacillus species has not been reported. This study intends to address these two research gaps. In silico analysis of P450s in 128 Bacillus species revealed the presence of 507 P450s that can be grouped into 13 P450 families and 28 subfamilies. No P450 family was found to be conserved in Bacillus species. Bacillus species were found to have lower numbers of P450s, P450 families and subfamilies, and a lower P450 diversity percentage compared to mycobacterial species. This study revealed that a large number of P450s (112 P450s) are part of different secondary metabolite BGCs, and also identified an association between a specific P450 family and secondary metabolite BGCs in Bacillus species. This study opened new vistas for further characterization of secondary metabolite BGCs, especially P450s in Bacillus species. PMID- 30453557 TI - Risk of Depression and Suicidality among Diabetic Patients: A Systematic Review and Meta-Analysis. AB - : The purpose of this study is to conduct a systematic review and meta-analysis to evaluate the risk of depression and suicidality among diabetic patients. METHODS: Medline, PubMed, EMBASE, Cochrane library, and Psych INFO were searched for studies published from 2008 onwards. Meta-analysis was conducted to estimate the pooled effect size. Sources of heterogeneity were investigated by subgroup analysis and meta-regression. RESULTS: In total, 5750 articles were identified and of those, 17 studies on suicidality and 36 on depression were included in this study. Our analysis suggests a positive relationship between diabetes and depression (cohort studies odds ratio (OR) 1.49, 95% confidence interval (CI): 1.36-1.64 and cross-sectional studies OR 2.04, 95% CI, 1.73-2.42). Pooled OR values for suicidal ideation, attempted suicide, and completed suicide were 1.89 (95% CI: 1.36-2.63), 1.45 (95% CI: 1.07-1.96), and 1.85 (95% CI: 0.97-3.52), respectively. All findings were statistically significant except for completed suicide. CONCLUSIONS: The increased risk of depression and suicidality in diabetic patients highlights the importance of integrating the evaluation and treatment of depression with diabetes management in primary healthcare settings. Further research in this area is needed. PMID- 30453559 TI - Promising Fungicides from Allelochemicals: Synthesis of Umbelliferone Derivatives and Their Structure-Activity Relationships. AB - Umbelliferone was discovered to be an important allelochemical in our previous study, but the contribution of its activity and structure has not yet been revealed. In this study, a series of analogues were synthesized to determine the skeleton of umbelliferone and examine its fungicidal activity. Furthermore, targeted modifications were conducted with three plant parasitic fungi to examine the lead compounds. Among those tested, compounds 2f and 10 were found to show excellent antifungal activity with an inhibitory rate over 80% at 100 ug/mL. The study proves that umbelliferone can be a promising skeleton for fungicides discovery. In addition, the primary structure-activity relationship provides a good guidance for the discovery of novel fungicides based on natural products in the future. PMID- 30453560 TI - In Vitro Antioxidant and Anti-Propionibacterium acnes Activities of Cold Water, Hot Water, and Methanol Extracts, and Their Respective Ethyl Acetate Fractions, from Sanguisorba officinalis L. Roots. AB - Identification of medicinal plants and naturally derived compounds as new natural antioxidant and antibacterial sources for topical acne treatment has long been important. To determine anti-Propionibacterium acnes activity and in vitro antioxidant activities, Sanguisorba officinalis L. root (SOR) was extracted with cold water (CWE), hot water (HWE), and methanol (ME), and each extract was fractionated successively with hexane, ethyl acetate (EA), and butanol to determine whether the activities could be attributed to the total phenolic, flavonoid, terpenoid, and condensed tannin contents. Pearson's correlation coefficients were analyzed between the respective variables. The SOR CWE, HWE, ME, and their respective EA fractions showed anti-P. acnes activity based on the paper disc diffusion method on agar plates, minimum inhibitory concentration (MIC), and minimal bactericidal concentration (MBC). The MIC against P. acnes had a moderate (+) correlation with the total phenolic content, but not with the other measures. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging capacity (SC) had a strong (-) correlation with the total phenolic content and a moderate (-) correlation with the total flavonoid content. The total antioxidant capacity had a strong (+) correlation with the condensed tannin content. Linoleic acid peroxidation inhibition had a strong (-) correlation with the total phenolic content. To elucidate the major active phytochemicals in the CWE-EA, HWE-EA, and ME-EA fractions, high performance liquid chromatography-ultraviolet (HPLC-UV) and ultra high performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) were performed. The HPLC-UV analysis showed the presence of nine compounds in common (arjunic acid and/or euscaphic acid, gallic acid, kaempferol, caffeic acid, ferulic acid, tannic acid, and coumarin, quercetin). The UHPLC-QTOF-MS analysis showed the presence of nine compounds in common (gallic acid; caffeic acid; umbelliferone; arjunic acid, euscaphic acid, and/or tormentic acid; pomolic acid; rosamultic acid; and benzoic acid). When standards of the identified phytochemicals were tested against the same bacterium, quercetin, coumarin, and euscaphic acid showed antibacterial activity against P. acnes. PMID- 30453561 TI - Fiber Bragg Gratings in CYTOP Fibers Embedded in a 3D-Printed Flexible Support for Assessment of Human-Robot Interaction Forces. AB - We developed a flexible support with embedded polymer optical fiber (POF) sensors for the assessment of human-robot interaction forces. The supports were fabricated with a three-dimensional (3D) printer, where an acrylonitrile butadiene styrene (ABS) rigid structure was used in the region of the support in which the exoskeleton was attached, whereas a thermoplastic polyurethane (TPU) flexible structure was printed in the region where the users placed their legs. In addition, fiber Bragg gratings (FBGs), inscribed in low-loss, cyclic, transparent, optical polymer (CYTOP) using the direct-write, plane-by-plane femtosecond laser inscription method, were embedded in the TPU structure. In this case, a 2-FBG array was embedded in two supports for human-robot interaction force assessment at two points on the users' legs. Both FBG sensors were characterized with respect to temperature and force; additionally, the creep response of the polymer, where temperature influences the force sensitivity, was analyzed. Following the characterization, a compensation method for the creep and temperature influence was derived, showing relative errors below 4.5%. Such errors were lower than the ones obtained with similar sensors in previously published works. The instrumented support was attached to an exoskeleton for knee rehabilitation exercises, where the human-robot interaction forces were measured in flexion and extension cycles. PMID- 30453562 TI - Spatio-Temporal Differences in Nitrogen Reduction Rates under Biotic and Abiotic Processes in River Water of the Taihu Basin, China. AB - Understanding spatio-temporal differences in nitrogen (N) transformation, transport and reduction rates in water bodies is critical to achieve effective mitigation of river eutrophication. We performed culture experiments in six rivers in the Taihu Basin using a custom made in-situ experimental apparatus. We investigated spatio-temporal differences in reduce processes and rates of different N forms and assessed the contribution of biological processes to dissolved inorganic N (DIN) reduce. Results showed that biological processes played a major role in N reduction in summer, while non-microbial processes were dominant in winter. We observed significant spatial and temporal differences in the studied mechanisms, with reduction rates of different N compounds being significantly higher in summer and autumn than spring and winter. Reduction rates ranged from 105.4 +/- 25.3 to 1458.8 +/- 98.4 mg.(m3.d)-1 for total N, 33.1 +/- 12.3 to 440.9 +/- 33.1 mg.(m3.d)-1 for ammonium, 56.3 +/- 22.7 to 332.1 +/- 61.9 mg.(m3.d)-1 for nitrate and 0.4 +/- 0.3 to 31.8 +/- 9.0 mg.(m3.d)-1 for nitrite across four seasons. Mean DIN reduction rates with and without microbial activity were 96.0 +/- 46.4 mg.(m3.d)-1 and 288.1 +/- 67.8 mg.(m3.d)-1, respectively, with microbial activity rates accounting for 29.7% of the DIN load and 2.2% of the N load. Results of correlation and principal component analysis showed that the main factors influencing N processing were the concentrations of different N forms and multiple environmental factors in spring, N concentrations, DO and pH in summer, N concentrations and water velocity in autumn and N concentrations in winter. PMID- 30453563 TI - Sensitive Hg2+ Sensing via Quenching the Fluorescence of the Complex between Polythymine and 5,10,15,20-tetrakis(N-methyl-4-pyridyl) Porphyrin (TMPyP). AB - The interaction between polythymine (dTn) and 5,10,15,20-tetrakis(N-methyl-4 pyridyl) porphyrin (TMPyP) was systematically studied using various techniques. dTn remarkably enhanced the fluorescence intensity of TMPyP as compared to other oligonucleotides. The enhanced fluorescence intensity and the shift of the emission peaks were ascribed to the formation of a pi-pi complex between TMPyP and dTn. And the quenching of the dTn-enhanced fluorescence by Hg2+ through a synergistic effect occurs due to the heavy atom effect. The binding of Hg2+ to TMPyP plays an important role in the Hg-TMPyP-dT30 ternary complex formation. A TMPyP-dT30-based Hg2+ sensor was developed with a dynamic range of Hg2+ from 5 nM to 100 nM. The detection limit of 1.3 nM was low enough for Hg2+ determination. The sensor also exhibited good selectivity against other metal ions. Experiments for tap water and river water demonstrated that the detection method was applicable for Hg2+ determination in real samples. The Hg2+ sensor based on oligonucleotide dT30-enhanced TMPyP fluorescence was fast and low-cost, presenting a promising platform for practical Hg2+ determination. PMID- 30453564 TI - Botanical Therapeutics: Phytochemical Screening and Biological Assessment of Chamomile, Parsley and Celery Extracts against A375 Human Melanoma and Dendritic Cells. AB - Chamomile, parsley, and celery represent major botanical sources of apigenin, a well-known flavone with chemopreventive properties. The aim of this study was to assess the phytochemical composition, antioxidant, and anti-inflammatory potential of methanol extracts obtained from chamomile, parsley, and celery collected from Romania, as well as the biological activity against A375 human melanoma and human dendritic cells. Results have shown that all three extracts are rich in polyphenolic compounds and flavonoids, and they generate a radical scavenger capacity, iron chelation potential, as well as lipoxygenase inhibition capacity. Chamomile and celery extracts present weak antiproliferative and pro apoptotic properties in the set experimental conditions, while parsley extract draws out significant pro-apoptotic potential against A375 human melanoma cells. Parsley and chamomile extracts affected the fibroblast-like morphology of the screened tumor cell line. On the other hand, chamomile and celery extracts abrogated the expansion of LPS-activated dendritic cells, while the metabolic activity was attenuated by stimulation with celery extract; chamomile and parsley extracts had no effect upon this parameter. Chamomile and parsley extracts incubation with naive dendritic cells did not trigger cytokine secretion (TNF alpha, IL-6, IL-10), but celery extract stimulation significantly reduced the anti-inflammatory, cytokine IL-10. PMID- 30453565 TI - Structural/Functional Matches and Divergences of Phytoprostanes and Phytofurans with Bioactive Human Oxylipins. AB - Structure-activity relationship (SAR) constitutes a crucial topic to discover new bioactive molecules. This approach initiates with the comparison of a target candidate with a molecule or a collection of molecules and their attributed biological functions to shed some light in the details of one or more SARs and subsequently using that information to outline valuable application of the newly identified compounds. Thus, while the empiric knowledge of medicinal chemistry is critical to these tasks, the results retrieved upon dedicated experimental demonstration retrieved resorting to modern high throughput analytical approaches and techniques allow to overwhelm the constraints adduced so far to the successful accomplishment of such tasks. Therefore, the present work reviews critically the evidences reported to date on the occurrence of phytoprostanes and phytofurans in plant foods, and the information available on their bioavailability and biological activity, shedding some light on the expectation waken up due to their structural similarities with prostanoids and isoprostanes. PMID- 30453568 TI - Fracture Statistics for Inorganically-Bound Core Materials. AB - In this article, we study the fracture characteristics of inorganically-bound foundry cores. It will be shown that the fracture stress of inorganic cores follows Weibull's strength distribution function for brittle materials. Using three-point and four-point-bending experiments, the volume dependence of the bending fracture stress is analyzed and a Weibull model fitted. Furthermore, the fracture stress of arbitrary bending experiments can be calculated based on the Weibull parameters found. PMID- 30453566 TI - Testosterone-Associated Dietary Pattern Predicts Low Testosterone Levels and Hypogonadism. AB - Obesity and low serum testosterone (T) levels are interrelated and strongly influenced by dietary factors, and their alteration entails a great risk of hypogonadism. Substantial evidence suggests a bidirectional relationship between nutrient metabolism (e.g., glucose, lipids, and iron) and T levels in men; however, T-related dietary patterns remain unclear. This study investigated the dietary patterns associated with serum total T levels and its predictive effect on hypogonadism and the body composition. Anthropometry, blood biochemistry, and food frequency questionnaires were collected for 125 adult men. Dietary patterns were derived using a reduced rank regression from 32 food groups. Overall prevalence rates of central obesity and hypogonadism were 48.0% and 15.7%, respectively. An adjusted linear regression showed that age, insulin, red blood cell (RBC) aggregation, and transferrin saturation independently predicted serum total T levels (all p < 0.01). The total T-related dietary pattern (a high consumption of bread and pastries, dairy products, and desserts, eating out, and a low intake of homemade foods, noodles, and dark green vegetables) independently predicted hypogonadism (odds ratio: 5.72; 95% confidence interval: 1.11-29.51, p < 0.05) for those with the highest dietary pattern scores (Q4) compared to those with the lowest (Q1). Scores were also negatively correlated with the skeletal muscle mass (p for trend = 0.002) but positively correlated with the total body fat mass (p for trend = 0.002), visceral fat mass (p for trend = 0.001), and to a lesser extent, subcutaneous fat mass (p for trend = 0.035) after adjusting for age. Randomized controlled trials are needed to confirm that improvement in dietary pattern can improve T levels and reduce hypogonadism. PMID- 30453569 TI - Location Information Quality: A Review. AB - The quality of location information is an important factor for location-based services (LBSs). In the literature, the quality of location information has been defined in different ways based on varying sets of aspects. The objectives of this paper are to review existing literature discussing location information quality and to provide a consistent framework for describing and dealing with location information quality. In particular, we review existing literature on different aspects of location information quality and on factors that affect location sensing technologies (and thus location information quality). Based on this review, we also propose a simple model for describing location information quality and a classification of the strategies for dealing with variations in the quality of location information. Designers of location sensing systems can use this model as a standard vocabulary for describing the quality of location information. The classification of strategies can be used by developers of LBSs apps to design alternative strategies for dealing with location information quality on three levels: sensor-level, algorithm-level, and application-level, which are aligned with the Location Stack model. PMID- 30453567 TI - Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells. AB - Accumulating evidence supports the remarkable presence at the membrane surface of cancer cells of proteins, which are normally expressed in the intracellular compartment. Although these proteins, referred to as externalized proteins, represent a highly promising source of accessible and druggable targets for cancer therapy, the mechanisms via which they impact cancer biology remain largely unexplored. The aim of this study was to expose an externalized form of cytokeratin 8 (eK8) as a key player of colorectal tumorigenesis and characterize its mode of action. To achieve this, we generated a unique antagonist monoclonal antibody (D-A10 MAb) targeting an eight-amino-acid-long domain of eK8, which enabled us to ascertain the pro-tumoral activity of eK8 in both KRAS-mutant and wild-type colorectal cancers (CRC). We showed that this pro-tumoral activity involves a bidirectional eK8-dependent control of caspase-mediated apoptosis in vivo and of the plasminogen-induced invasion process in cellulo. Furthermore, we demonstrated that eK8 is anchored at the plasma membrane supporting this dual function. We, therefore, identified eK8 as an innovative therapeutic target in CRC and provided a unique MAb targeting eK8 that displays anti-neoplastic activities that could be useful to treat CRC, including those harboring KRAS mutations. PMID- 30453570 TI - An Efficient Algorithm for Partial Discharge Localization in High-Voltage Systems Using Received Signal Strength. AB - The term partial discharge (PD) refers to a partial bridging of insulating material between electrodes that sustain an electric field in high-voltage (HV) systems. Long-term PD activity can lead to catastrophic failures of HV systems resulting in economic, energy and even human life losses. Such failures and losses can be avoided by continuously monitoring PD activity. Existing techniques used for PD localization including time of arrival (TOA) and time difference of arrival (TDOA), are complicated and expensive because they require time synchronization. In this paper, a novel received signal strength (RSS) based localization algorithm is proposed. The reason that RSS is favoured in this research is that it does not require clock synchronization and it only requires the energy of the received signal rather than the PD pulse itself. A comparison was made between RSS based algorithms including a proposed algorithm, the ratio and search and the least squares algorithm to locate a PD source for nine different positions. The performance of the algorithms was evaluated by using two field scenarios based on seven and eight receiving nodes, respectively. The mean localization error calculated for two-field-trial scenarios show, respectively, 1.80 m and 1.76 m for the proposed algorithm for all nine positions, which is the lowest of the three algorithms. PMID- 30453571 TI - SNPs and Somatic Mutation on Long Non-Coding RNA: New Frontier in the Cancer Studies? AB - In the last decade, it has been demonstrated that long non-coding RNAs (lncRNAs) are involved in cancer development. The great majority of studies on lncRNAs report alterations, principally on their expression profiles, in several tumor types with respect to the normal tissues of origin. Conversely, since lncRNAs constitute a relatively novel class of RNAs compared to protein-coding transcripts (mRNAs), the landscape of their mutations and variations has not yet been extensively studied. However, in recent years an ever-increasing number of articles have described mutations of lncRNAs. Single-nucleotide polymorphisms (SNPs) that occur within the lncRNA transcripts can affect the structure and function of these RNA molecules, while the presence of a SNP in the promoter region of a lncRNA could alter its expression level. Also, somatic mutations that occur within lncRNAs have been shown to exert important effects in cancer and preliminary data are promising. Overall, the evidence suggests that SNPs and somatic mutation on lncRNAs may play a role in the pathogenesis of cancer, and indicates strong potential for further development of lncRNAs as biomarkers. PMID- 30453572 TI - Reliable Positioning and mmWave Communication via Multi-Point Connectivity. AB - One of the key elements of future 5G and beyond mobile technology is millimeter wave (mmWave) communications, which is targeted to extreme high-data rate services. Furthermore, combining the possibility of a wideband signal transmission with the capability of pencil-beamforming, mmWave technology is key for accurate cellular-based positioning. However, it is also well-known that at the mmWave frequency band the radio channel is very sensitive to line-of-sight blockages giving rise to unstable connectivity and inefficient communication. In this paper, we tackle the blockage problem and propose a solution to increase the communication reliability by means of a coordinated multi-point reception. We also investigate the advantage of this solution in terms of positioning quality. More specifically, we describe a robust hybrid analog-digital receive beamforming strategy to combat the unavailability of dominant links. Numerical examples are provided to validate the efficiency of our proposed method. PMID- 30453573 TI - The Relationship between Sleep and Cognitive Performance in Autism Spectrum Disorder (ASD): A Pilot Study. AB - BACKGROUND: Sleep concerns are common in children with autism spectrum disorders (ASD). The impact of poor sleep on cognitive performance in ASD children is not well-established. We investigated the possible correlation between sleep quality in ASD children and cognitive performance. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was administered to examine specific components of non verbal cognition. METHODS: The Children's Sleep Habits Questionnaire (CSHQ) and actigraphy-measured data from 18 children with diagnosis of ASD were evaluated. Motor planning task (MOT), simple reaction time task (SRT) and the intradimensional/extradimensional shift (IED) of CANTAB were administered. RESULTS: ASD good sleeper (ASD-GS) showed significant better response time for SRT task as compared to ASD poor sleeper (ASD-PS) based on CSHQ score. Parameters of bedtime resistance (r = 0.531, p = 0.023), sleep anxiety (r = 0.474, p = 0.047) from CSHQ and actigrapgy dependent (wake after sleep onset (WASO) (r = 0.430, p = 0.024) were significantly correlate with response time of SRT task. CONCLUSION: We conclude that some signs reflecting the presence of poor sleep in ASD correlate with various aspects of motor output on non-verbal performance tasks. The question is raised whether poor sleep in non-complaining persons with autism should be treated. PMID- 30453574 TI - Omega-3 Monoacylglyceride Effects on Longevity, Mitochondrial Metabolism and Oxidative Stress: Insights from Drosophila melanogaster. AB - During the last decade, essential polyunsaturated fatty acids (PUFAs) such as eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA) derived from marine sources have been investigated as nonpharmacological dietary supplements to improve different pathological conditions, as well as aging. The aim of this study was to determine the effects of dietary n-3 PUFA monoacylglycerides (MAG, both EPA and DHA) on the mitochondrial metabolism and oxidative stress of a short lifespan model, Drosophila melanogaster, sampled at five different ages. Our results showed that diets supplemented with MAG-EPA and MAG-DHA increased median lifespan by 14.6% and decreased mitochondrial proton leak resulting in an increase of mitochondrial coupling. The flies fed on MAG-EPA also had higher electron transport system capacity and mitochondrial oxidative capacities. Moreover, both n-3 PUFAs delayed the occurrence of lipid peroxidation but only flies fed the MAG-EPA diet showed maintenance of superoxide dismutase activity during aging. Our study therefore highlights the potential of n-3 PUFA monoacylglycerides as nutraceutical compounds to delay the onset of senescence by acting directly or indirectly on the mitochondrial metabolism and suggests that Drosophila could be a relevant model for the study of the fundamental mechanisms linking the effects of n-3 PUFAs to aging. PMID- 30453576 TI - Quaternion-Based Local Frame Alignment between an Inertial Measurement Unit and a Motion Capture System. AB - Local frame alignment between an inertial measurement unit (IMU) system and an optical motion capture system (MCS) is necessary to combine the two systems for motion analysis and to validate the accuracy of IMU-based motion data by using references obtained through the MCS. In this study, we propose a new quaternion based local frame alignment method where equations of angular velocity transformation are used to determine the frame alignment orientation in the form of quaternion. The performance of the proposed method was compared with those of three other methods by using data with different angular velocities, noises, and alignment orientations. Furthermore, the effects of the following three factors on the estimation performance were investigated for the first time: (i) transformation concept, i.e., angular velocity transformation vs. angle transformation; (ii) orientation representations, i.e., quaternion vs. direction cosine matrix (DCM); and (iii) applied solvers, i.e., nonlinear least squares method vs. least squares method through pseudoinverse. Within our limited test data, we obtained the following results: (i) the methods using angular velocity transformation were better than the method using angle transformation; (ii) the quaternion is more suitable than the DCM; and (iii) the applied solvers were not critical in general. The proposed method performed the best among the four methods. We surmise that the fewer number of components and constraints of the quaternion in the proposed method compared to the number of components and constraints of the DCM-based methods may result in better accuracy. Owing to the high accuracy and easy setup, the proposed method can be effectively used for local frame alignment between an IMU and a motion capture system. PMID- 30453577 TI - Measuring Linewidth Enhancement Factor by Relaxation Oscillation Frequency in a Laser with Optical Feedback. AB - This paper presents a new method for measuring the linewidth enhancement factor (alpha factor) by the relaxation oscillation (RO) frequency of a laser with external optical feedback (EOF). A measurement formula for alpha is derived which shows the alpha can be determined by only using the RO frequencies and no need to know any other parameters related to the internal or external parameters associated to the laser. Unlike the existing EOF based alpha measurement methods which require an external target has a symmetric reciprocate movement. The proposed method only needs to move the target to be in a few different positions along the light beam. Furthermore, this method also suits for the case with alpha less than 1. Both simulation and experiment are performed to verify the proposed method. PMID- 30453575 TI - Non-Coding Variants in BRCA1 and BRCA2 Genes: Potential Impact on Breast and Ovarian Cancer Predisposition. AB - BRCA1 and BRCA2 are major breast cancer susceptibility genes whose pathogenic variants are associated with a significant increase in the risk of breast and ovarian cancers. Current genetic screening is generally limited to BRCA1/2 exons and intron/exon boundaries. Most identified pathogenic variants cause the partial or complete loss of function of the protein. However, it is becoming increasingly clear that variants in these regions only account for a small proportion of cancer risk. The role of variants in non-coding regions beyond splice donor and acceptor sites, including those that have no qualitative effect on the protein, has not been thoroughly investigated. The key transcriptional regulatory elements of BRCA1 and BRCA2 are housed in gene promoters, untranslated regions, introns, and long-range elements. Within these sequences, germline and somatic variants have been described, but the clinical significance of the majority is currently unknown and it remains a significant clinical challenge. This review summarizes the available data on the impact of variants on non-coding regions of BRCA1/2 genes and their role on breast and ovarian cancer predisposition. PMID- 30453578 TI - A Portable Smartphone-Based Sensing System Using a 3D-Printed Chip for On-Site Biochemical Assays. AB - Recently, smartphone-based chromogenic sensing with paper-based microfluidic technology has played an increasingly important role in biochemical assays. However, generally there were three defects: (i) the paper-based chips still required complicated fabrication, and the hydrophobic boundaries on the chips were not clear enough; (ii) the chromogenic signals could not be steadily captured; (iii) the smartphone apps were restricted to the detection of specific target analytes and could not be extended for different assays unless reprogrammed. To solve these problems, in this study, a portable smartphone-based sensing system with a 3D-printed chip was developed. A 3D-printed imaging platform was designed to significantly reduce sensing errors generated during signal capture, and a brand-new strategy for signal processing in downloadable apps was established. As a proof-of-concept, the system was applied for detection of organophosphorus pesticides and multi-assay of fruit juice, showing excellent sensing performance. For different target analytes, the most efficient color channel could be selected for signal analysis, and the calibration equation could be directly set in user interface rather than programming environment, thus the developed system could be flexibly extended for other biochemical assays. Consequently, this study provides a novel methodology for smartphone-based biochemical sensing. PMID- 30453579 TI - Natalenamides A-C, Cyclic Tripeptides from the Termite-Associated Actinomadura sp. RB99. AB - In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A-C (compounds 1-3). These compounds were identified from the culture broth of the fungus-growing termite-associated Actinomadura sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds (1-3) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (1H and 13C) and two-dimensional (1H-1H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey's analysis. Through several bioactivity tests for the tripeptides, we found that compound 3 exhibited significant inhibitory effects on 3-isobutyl-1 methylxanthine (IBMX)-induced melanin production. The effect of compound 3 was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect. PMID- 30453580 TI - A High-Sensitivity Microfluidic Sensor Based on a Substrate Integrated Waveguide Re-Entrant Cavity for Complex Permittivity Measurement of Liquids. AB - In this study, a novel non-invasive and contactless microwave sensor using a square substrate integrated waveguide (SIW) re-entrant cavity is proposed for complex permittivity measurement of chemical solutions. The working principle of this sensor is based on cavity perturbation technique, in which the resonant properties of cavity are utilized as signatures to extract the dielectric information of liquid under test (LUT). A winding microfluidic channel is designed and embedded in the gap region of the cavity to obtain a strong interaction between the induced electric field and LUT, thus achieving a high sensitivity. Also, a mathematical predictive model which quantitatively associates the resonant properties of the sensor with the dielectric constant of LUT is developed through numerical analysis. Using this predictive model, quick and accurate extraction of the complex permittivity of LUT can be easily realized. The performance of this sensor is then experimentally validated by four pure chemicals (hexane, ethyl acetate, DMSO and water) together with a set of acetone/water mixtures in various concentrations. Experimental results demonstrate that the designed sensor is capable of characterizing the complex permittivities of various liquids with an accuracy of higher than 96.76% (compared with the theoretical values obtained by Debye relaxation equations), and it is also available for quantifying the concentration ratio of a given binary mixture. PMID- 30453581 TI - Erratum: Alberto, R. et al., Wearable Monitoring Devices for Biomechanical Risk Assessment at Work: Current Status and Future Challenges-A Systematic Review. Int. J. Environ. Res. Public Health 2018, 15, 2001. AB - Due to an error during production, the first author's name of the published paper [...]. PMID- 30453582 TI - Dictionary Learning Phase Retrieval from Noisy Diffraction Patterns. AB - This paper proposes a novel algorithm for image phase retrieval, i.e., for recovering complex-valued images from the amplitudes of noisy linear combinations (often the Fourier transform) of the sought complex images. The algorithm is developed using the alternating projection framework and is aimed to obtain high performance for heavily noisy (Poissonian or Gaussian) observations. The estimation of the target images is reformulated as a sparse regression, often termed sparse coding, in the complex domain. This is accomplished by learning a complex domain dictionary from the data it represents via matrix factorization with sparsity constraints on the code (i.e., the regression coefficients). Our algorithm, termed dictionary learning phase retrieval (DLPR), jointly learns the referred to dictionary and reconstructs the unknown target image. The effectiveness of DLPR is illustrated through experiments conducted on complex images, simulated and real, where it shows noticeable advantages over the state of-the-art competitors. PMID- 30453584 TI - Transglutaminase 2 Up-Regulation Is Associated with Inflammatory Response in PBMC from Healthy Subjects with Hypovitaminosis D. AB - Recent evidence indicated that transglutaminase 2 (TG2) is involved in the adaptive immune response. Peripheral blood mononuclear cells (PBMC) have largely been used to characterize molecular mechanisms occurring in the activation of immune response. Given that the maintenance of immune system functions requires an optimal vitamin D status, we aimed to assess the involvement of TG2/NF-kappaB signaling in cytokine production in PBMC isolated from adult subjects with different vitamin D status. We observed TG2 up-regulation and a significant positive correlation between TG2 expression and tumor necrosis factor (TNF)-alpha mRNA levels in PBMC of recruited patients. The mRNA levels of TG2 and TNF-alpha were higher in PBMC of subjects having hypovitaminosis D, namely plasma 25(OH)vitamin D3 levels lower than 50 nmol/L, than in those with normal vitamin D levels. Moreover, NF-kappaB up-regulation and nuclear translocation were detected, concomitantly with TG2 as well as TNF-alpha increased expression, in PBMC of vitamin D-deficient subjects. The present findings confirm that an increase in TG2 expression exacerbates the activation of NF-kappaB and the production of pro-inflammatory cytokines, and suggest a link between vitamin D deficiency, TG2 up-regulation, and inflammation. PMID- 30453583 TI - Severe Neutropenia is Associated with Better Clinical Outcomes in Patients with Advanced Pancreatic Cancer Who Receive Modified FOLFIRINOX Therapy. AB - While modified FOLFIRINOX therapy is effective for treating advanced pancreatic cancer, it frequently causes severe neutropenia. The present study investigated the effect of severe neutropenia on clinical outcomes in advanced pancreatic cancer patients who received modified FOLFIRINOX. The study subjects were 51 patients (30 males and 21 females) with advanced pancreatic cancer who received modified FOLFIRINOX (2h bolus injection of oxaliplatin at 85 mg/m2, 2 h bolus injection of L-leucovorin at 200 mg/m2, 90min bolus injection of irinotecan at 150 mg/m2, followed by continuous infusion of 5-fluorouracil for 46 h at 2400 mg/m2 without bolus 5-fluorouracil) during the period from January 2014 to May 2018. No patients had prior history of chemotherapy. Adverse events, including neutropenia, were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. Median overall survival (OS) was the primary endpoint, while median time to treatment failure (TTF), overall response rate (ORR), and the incidence of other adverse events were secondary endpoints. Severe neutropenia (grade >=3) occurred in 39 patients (76.4%), and Cox proportional hazard analysis identified high total bilirubin level as a significant risk factor. Median duration of OS was significantly longer in patients with severe neutropenia than in those without it (21.3 months versus 8.9 months, p = 0.020). Moreover, there was a significant correlation between OS and the grade of neutropenia (r = 0.306, p = 0.029). ORR tended to be higher, though not significantly, in patients with severe neutropenia. In contrast, the incidence rates of other adverse events were not different between the two groups. Severe neutropenia is an independent predictor of prognosis in advanced pancreatic cancer patients received modified FOLFIRINOX therapy. PMID- 30453585 TI - Analytical Considerations of Stable Isotope Labelling in Lipidomics. AB - Over the last two decades, lipids have come to be understood as far more than merely components of cellular membranes and forms of energy storage, and are now also being implicated to play important roles in a variety of diseases, with lipid biomarker research one of the most widespread applications of lipidomic techniques both in research and in clinical settings. Stable isotope labelling has become a staple technique in the analysis of small molecule metabolism and dynamics, as it is the only experimental setup by which biosynthesis, remodelling and degradation of biomolecules can be directly measured. Using state-of-the-art analytical technologies such as chromatography-coupled high resolution tandem mass spectrometry, the stable isotope label can be precisely localized and quantified within the biomolecules. The application of stable isotope labelling to lipidomics is however complicated by the diversity of lipids and the complexity of the necessary data analysis. This article discusses key experimental aspects of stable isotope labelling in the field of mass spectrometry-based lipidomics, summarizes current applications and provides an outlook on future developments and potential. PMID- 30453586 TI - The Elephant in the Room: The Need for Increased Integrative Therapies in Conventional Medical Settings. AB - Pediatric integrative therapy programs are essential to the treatment and well being of patients. Identifying an effective integrative therapy model within conventional pediatric medical settings, however, often proves difficult. Our goal in this article is to explore varied solutions to increase access and inclusion of integrative therapies in an effort to promote best practice and holistic care. The main methods applied in this article are vignettes that illustrate how the integrative therapies in a metropolitan academic hospital successfully treat the patient by complementing conventional medicine. This leads to comprehensive care. The central finding of the article proposes viable solutions to increase interdisciplinary collaboration both internally within the institution and externally. Integrative therapists detail how they were able to increase visibility and yield best practice through increased educational initiatives and interdisciplinary collaboration. PMID- 30453587 TI - Is a Meal without Wine Good for Health? AB - Hippocrates, the father of medicine, had said: "Wine is a thing wonderfully appropriate to man if, in health as in disease, it is administered with appropriate and just measure according to the individual constitution." Wine has always accompanied humanity, for religion or for health. Christians and Jews need wine for the liturgy. For Plato, wine was an indispensable element in society and the most important in the symposium. In this second part of the banquet, mixed with water, the wine gave the word. If the French paradox made a lot of ink flow; it was the wine that was originally responsible for it. Many researchers have tried to study alcohol and polyphenols in wine, in order to solve the mystery. Beyond its cardiovascular effects, there are also effects on longevity, metabolism, cancer prevention, and neuroprotection, and the list goes on. The purpose of this work is to make an analysis of the current knowledge on the subject. Indeed, if the paradigm of antioxidants is seductive, it is perhaps by their prooxidant effect that the polyphenols act, by an epigenetic process mediated by nrf2. Wine is a preserve of antioxidants for the winter and it is by this property that the wine acts, in an alcoholic solution. A wine without alcohol is pure heresy. Wine is the elixir that by design, over millennials, has acted as a pharmacopeia that enabled man to heal and prosper on the planet. From Alvise Cornaro to Serge Renaud, nutrition was the key to health and longevity, whether the Cretan or Okinawa diet, it is the small dose of alcohol (wine or sake) that allows the bioavailability of polyphenols. Moderate drinking gives a protection for diseases and a longevity potential. In conclusion, let us drink fewer, but drink better, to live older. PMID- 30453588 TI - The Optimal Carbon Emission Reduction and Prices with Cap and Trade Mechanism and Competition. AB - More and more countries employ the Carbon Cap and Trade mechanism (CCT-mechanism) to stimulate the manufacturer to produce much more eco-friendly products. In this paper, we study how the CCT-mechanism affects competitive manufacturers' product design and pricing strategies. Assume that there are two competitive manufacturers; we give the optimal closed form solutions of the carbon emission reduction rates and retail prices in the Nash game model and the Stackelberg game model with CCT-mechanism, respectively. Additionally, we also discuss the impacts of CCT-mechanism, consumer environmental awareness (CEA), and the sensitivity of switchovers toward price on the optimal carbon emission reduction rates, retail prices, and manufacturers' profits. We find that (i) when the carbon quota is not enough, there is a trade off between investing in producing much greener product and purchasing carbon quota; when the carbon price is not high, the manufacturer tends to purchase the carbon quota; and when the carbon price is much higher, the manufacturer is more willing to increase the environmental quality of the product; (ii) manufacturer's size affects product's emission reduction rate and manufacturer's optimal profit; larger manufacturer tends to produce much greener product, but it does not mean that he could obtain much more money than the small manufacturer; and (iii) the decision sequence changes manufacturer's strategies; the optimal emission reduction rate in Nash and Stackelberg game models are almost the same, but the differences of prices and profits between Nash and Stackelberg model's are much bigger. PMID- 30453589 TI - High Precision Position Measurement Method for Laguerre-Gaussian Beams Using a Quadrant Detector. AB - In this paper, we propose a new method to improve the position measurement accuracy for Laguerre-Gaussian beams on a quadrant detector (QD). First, the error effects of the detector diameter and the gap size are taken into account, and the position error compensation factor is introduced into the conventional formula. Then, in order to reduce the number of parameters, the concept of effective radius is proposed. Thus, a new analytical expression is obtained with a best fit using the least square method. It is verified by simulation that this approach can reduce the maximum error by 97.4% when the beam radius is 0.95 mm; meanwhile, the root mean square errors under different radii are all less than 0.004 mm. The results of simulation show that the new method could effectively improve the accuracy of the QD measurement for different radii. Therefore, the new method would have a good prospect in the engineering practice of beam position measurements. PMID- 30453590 TI - Antiproliferative, Proapoptotic, Antioxidant and Antimicrobial Effects of Sinapis nigra L. and Sinapis alba L. Extracts. AB - High Brassicaceae consumption reduces the risk of developing several cancer types, probably due to high levels of glucosinolates. Extracts from Sinapis nigra L. (S. nigra) and Sinapis alba L. (S. alba) have been obtained from leaves and seeds under different conditions using ethanol/water mixtures because their glucosinolates are well accepted by the food industry. The EtOH/H2O 8:2 mixture gives better yields in glucosinolate amounts from ground seeds, mainly, sinalbin in S. alba and sinigrin in S. nigra. The highest antiproliferative activity in both non-tumor and tumor cell lines was induced by S. alba seeds extract. To evaluate whether the effect of Sinapis species (spp) was only due to glucosinolate content or whether it was influenced by the extracts' complexity, cells were treated with extracts or glucosinolates, in the presence of myrosinase. Pure sinigrin did not modify cell proliferation, while pure sinalbin was less effective than the extract. The addition of myrosinase increased the antiproliferative effects of the S. nigra extract and sinigrin. Antiproliferative activity was correlated to Mitogen-Activated Protein Kinases modulation, which was cell and extract-dependent. Cell-cycle analysis evidenced a proapoptotic effect of S. alba on both tumor cell lines and of S. nigra only on HCT 116. Both extracts showed good antimicrobial activity in disc diffusion tests and on ready to-eat fresh salad. These results underline the potential effects of Sinapis spp in chemoprevention and food preservation. PMID- 30453591 TI - Autonomous Robot-Guided Inspection System Based on Offline Programming and RGB-D Model. AB - Automatic optical inspection (AOI) is a control process for precisely evaluating the completeness and quality of manufactured products with the help of visual information. Automatic optical inspection systems include cameras, light sources, and objects; AOI requires expert operators and time-consuming setup processes. In this study, a novel autonomous industrial robot-guided inspection system was hypothesized and developed to expedite and ease inspection process development. The developed platform is an intuitive and interactive system that does not require a physical object to test or an industrial robot; this allows nonexpert operators to perform object inspection planning by only using scanned data. The proposed system comprises an offline programming (OLP) platform and three dimensional/two-dimensional (3D/2D) vision module. A robot program generated from the OLP platform is mapped to an industrial manipulator to scan a 3D point-cloud model of an object by using a laser triangulation sensor. After a reconstructed 3D model is aligned with a computer-aided design model on a common coordinate system, the OLP platform allows users to efficiently fine-tune the required inspection positions on the basis of the rendered images. The arranged inspection positions can be directed to an industrial manipulator on a production line to capture real images by using the corresponding 2D camera/lens setup for AOI tasks. This innovative system can be implemented in smart factories, which are easily manageable from multiple locations. Workers can save scanned data when new inspection positions are included based on cloud data. The present system provides a new direction to cloud-based manufacturing industries and maximizes the flexibility and efficiency of the AOI setup process to increase productivity. PMID- 30453592 TI - Prediction of Prehypertenison and Hypertension Based on Anthropometry, Blood Parameters, and Spirometry. AB - Hypertension and prehypertension are risk factors for cardiovascular diseases. However, the associations of both prehypertension and hypertension with anthropometry, blood parameters, and spirometry have not been investigated. The purpose of this study was to identify the risk factors for prehypertension and hypertension in middle-aged Korean adults and to study prediction models of prehypertension and hypertension combined with anthropometry, blood parameters, and spirometry. Binary logistic regression analysis was performed to assess the statistical significance of prehypertension and hypertension, and prediction models were developed using logistic regression, naive Bayes, and decision trees. Among all risk factors for prehypertension, body mass index (BMI) was identified as the best indicator in both men [odds ratio (OR) = 1.429, 95% confidence interval (CI) = 1.304-1.462)] and women (OR = 1.428, 95% CI = 1.204-1.453). In contrast, among all risk factors for hypertension, BMI (OR = 1.993, 95% CI = 1.818-2.186) was found to be the best indicator in men, whereas the waist-to height ratio (OR = 2.071, 95% CI = 1.884-2.276) was the best indicator in women. In the prehypertension prediction model, men exhibited an area under the receiver operating characteristic curve (AUC) of 0.635, and women exhibited a predictive power with an AUC of 0.777. In the hypertension prediction model, men exhibited an AUC of 0.700, and women exhibited an AUC of 0.845. This study proposes various risk factors for prehypertension and hypertension, and our findings can be used as a large-scale screening tool for controlling and managing hypertension. PMID- 30453593 TI - Twisted Dual-Cycle Fiber Optic Bending Loss Characteristics for Strain Measurement. AB - The intensity-based fiber optic sensor (FOS) head using twisted dual-cycle bending loss is proposed and experimentally demonstrate. The bending loss characteristics depend on the steel wire radius, number, and distance. To determine the effects of these parameters, two samples in each of seven configuration cases of the proposed FOS head were bonded to fiber reinforced plastics coupons, and tensile and flexural strain tests were repeated five times for each coupon. The bending loss of the manufactured FOS heads was measured and converted to the tensile and flexural strain as a function of configuration cases. The measurement range, sensitivity, and average measurement errors of the tensile load and flexural strain were 4.5 kN and 1,760 MUepsilon, 0.70 to 3.99 dB/kN and 0.930 to 6.554 dB/mm, and 57.7 N, and 42.6 MUepsilon, respectively. The sensing range of FOS head were 82 to 138 mm according to configuration cases. These results indicate that it is possible to measure load, tensile strain, and flexural strain using the proposed FOS head, and demonstrate that the sensitivities, the operating ranges, and the sensing range can be adjusted depending on the deformation characteristics of the measurement target. PMID- 30453594 TI - Wheat ATI CM3, CM16 and 0.28 Allergens Produced in Pichia Pastoris Display a Different Eliciting Potential in Food Allergy to Wheat ?. AB - Although wheat is a staple food for most of the human population, some of its components trigger adverse reactions. Among wheat components, the alpha amylase/trypsin inhibitors (ATI) are important triggers of several allergies and activators of innate immunity. ATI are a group of exogenous protease inhibitors and include several polypeptides. The three ATI polypeptides named CM3, CM16 and 0.28 are considered major allergens, and might also play a role in other common wheat-related pathologies, such as Non Celiac Wheat Sensitivity and even Celiac Disease. On this basis, we pointed to obtain high amounts of them in purity and to evaluate their allergenicity potential. We thus isolated the mRNA corresponding to the three ATI genes CM3, CM16 and 0.28 from 28 days post anthesis wheat kernels and the corresponding cDNAs were used for heterologous expression in Pichia pastoris. The three purified proteins were tested in degranulation assay against human sera of patients with food allergy to wheat. A large range of degranulation values was observed for each protein according to the sera tested. All of the three purified proteins CM3, CM16 and 0.28 were active as allergens because they were able to induce basophils degranulation on wheat allergic patients' sera, with the highest values of beta-hexosaminidase release observed for CM3 protein. PMID- 30453595 TI - Screening of Angiotensin-I Converting Enzyme Inhibitory Peptides Derived from Caulerpa lentillifera. AB - Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera (known commonly as sea grape) protein hydrolysate. In this study, short-chain peptides were obtained after hydrolysis by various enzymes and subsequently by ultrafiltration. Thermolysin hydrolysate showed the highest ACEI activity. Bioassay-guided fractionation was performed using reversed-phase high performance liquid chromatography (RP-HPLC) to uncover the fraction 9 with the highest ACE inhibitory activity from thermolysin hydrolysate. Peptides in this fraction were further identified using liquid chromatography-tandem mass spectrometry (LC MS/MS) analysis coupled with de novo sequencing, which gave two oligopeptides, FDGIP (FP-5) and AIDPVRA (AA-7). The identities and activities of these two peptides were further confirmed using synthetic peptides. Their IC50 values were determined as 58.89 +/- 0.68 uM and 65.76 +/- 0.92 uM, respectively. Moreover, the inhibition kinetics revealed that both FP-5 and AA-7 are competitive inhibitors. These activities were further explained using molecular docking simulation. The present study is the first report about ACEI peptides derived from Caulerpa lentillifera and it shows the potential for preventing hypertension and for functional food development. PMID- 30453596 TI - Factors Affecting Intracellular Delivery and Release of Hydrophilic Versus Hydrophobic Cargo from Mesoporous Silica Nanoparticles on 2D and 3D Cell Cultures. AB - Intracellular drug delivery by mesoporous silica nanoparticles (MSNs) carrying hydrophilic and hydrophobic fluorophores as model drug cargo is demonstrated on 2D cellular and 3D tumor organoid level. Two different MSN designs, chosen on the basis of the characteristics of the loaded cargo, were used: MSNs with a surface grown poly(ethylene imine), PEI, coating only for hydrophobic cargo and MSNs with lipid bilayers covalently coupled to the PEI layer as a diffusion barrier for hydrophilic cargo. First, the effect of hydrophobicity corresponding to loading degree (hydrophobic cargo) as well as surface charge (hydrophilic cargo) on intracellular drug release was studied on the cellular level. All incorporated agents were able to release to varying degrees from the endosomes into the cytoplasm in a loading degree (hydrophobic) or surface charge (hydrophilic) dependent manner as detected by live cell imaging. When administered to organotypic 3D tumor models, the hydrophilic versus hydrophobic cargo-carrying MSNs showed remarkable differences in labeling efficiency, which in this case also corresponds to drug delivery efficacy in 3D. The obtained results could thus indicate design aspects to be taken into account for the development of efficacious intracellular drug delivery systems, especially in the translation from standard 2D culture to more biologically relevant organotypic 3D cultures. PMID- 30453597 TI - The Effect of an Encapsulated Nutrient Mixture on Food Intake and Satiety: A Double-Blind Randomized Cross-Over Proof of Concept Study. AB - Activation of the intestinal brake by infusing nutrients into the distal small intestine with catheters inhibits food intake and enhances satiety. Encapsulation of macronutrients, which protects against digestion in the proximal gastrointestinal tract, can be a non-invasive alternative to activate this brake. In this study, we investigate the effect of oral ingestion of an encapsulated casein and sucrose mixture (active) targeting the distal small intestine versus a control product designed to be released in the stomach on food intake, satiety, and plasma glucose concentrations. Fifty-nine volunteers received the active and control product on two separate test days. Food intake was determined during an ad libitum meal 90 min after ingestion of the test product. Visual analogue scale scores for satiety and blood samples for glucose analysis were collected at regular intervals. Ingestion of the active product decreased food intake compared to the control product (655 kcal compared with 699 kcal, respectively, p < 0.05). The area under the curve (AUC) for hunger was decreased (p < 0.05) and AUC for satiety was increased (p < 0.01) after ingestion of the active product compared to the control product. Ingestion of an encapsulated protein-carbohydrate mixture resulted in inhibition of food intake compared to a non-encapsulated control product. PMID- 30453598 TI - Humanized Mouse Models for the Study of Infection and Pathogenesis of Human Viruses. AB - The evolution of infectious pathogens in humans proved to be a global health problem. Technological advancements over the last 50 years have allowed better means of identifying novel therapeutics to either prevent or combat these infectious diseases. The development of humanized mouse models offers a preclinical in vivo platform for further characterization of human viral infections and human immune responses triggered by these virus particles. Multiple strains of immunocompromised mice reconstituted with a human immune system and/or human hepatocytes are susceptible to infectious pathogens as evidenced by establishment of full viral life cycles in hope of investigating viral-host interactions observed in patients and discovering potential immunotherapies. This review highlights recent progress in utilizing humanized mice to decipher human specific immune responses against viral tropism. PMID- 30453599 TI - The Efficacy of Inpatient vs. Home-Based Physiotherapy Following Coronary Artery Bypass Grafting. AB - Background: Intensive post-operative physiotherapy after cardiac surgery helps to reduce the number of complications, accelerating convalescence and decreasing peri-operative mortality. Cardiac rehabilitation is aimed at regaining lost function and sustaining the effect of cardiac surgery. The aim of this study was to compare the efficacy of inpatient and home-based phase II physiotherapy following coronary artery bypass grafting, and inpatient phase II post-operative physiotherapy based on the analysis of the spirometry results. Methods: A prospective observational study included 104 adult patients of both sexes undergoing planned coronary artery bypass grafting and were randomized to one of the two groups-inpatients (InPhysio) and home-based (HomePhysio) at a 1:1 ratio. All patients had undergone spirometry testing prior to surgery (S1) and on the fifth day after the operation (S2), i.e., on the day of completion of the first phase (PI) of physiotherapy. Both the study group (InPhysio) and the control group (HomePhysio) performed the same set of exercises in the second phase (PII) of cardiac physiotherapy, either in the hospital or at home, respectively, according to the program obtained in the hospital. Both groups have undergone spirometry testing (S3) at 30 days after the operation. Results: The demographic and peri-operative data for both groups were comparable and showed no statistically significant differences. An analysis of gradients between the results of spirometry tests before surgery and at 30 days after the surgery showed a smaller decrease in forced vital capacity (FVC) in the study group than in the control group (p < 0.001). The results at five and 30 days after the surgery showed a greater increase in FVC in the study group than in the control group (680 mL vs. 450 mL, p = 0.009). There were no statistically significant differences in other parameters studied. Conclusions: The advantage of inpatient over home-based physiotherapy was evidenced by much smaller decreases in FVC between the initial and final tests, and greater increases between the fifth day after surgery and the final test. Our analysis showed greater efficacy of inpatient physiotherapy as compared with home-based exercises and raises concerns about patient adherence. PMID- 30453601 TI - Crystal Structure of the Apo-Form of NADPH-Dependent Thioredoxin Reductase from a Methane-Producing Archaeon. AB - The redox regulation of proteins via reversible dithiol/disulfide exchange reactions involves the thioredoxin system, which is composed of a reductant, a thioredoxin reductase (TR), and thioredoxin (Trx). In the pyridine nucleotide dependent Trx reduction pathway, reducing equivalents, typically from reduced nicotinamide adenine dinucleotide phosphate (NADPH), are transferred from NADPH TR (NTR) to Trx and, in turn, to target proteins, thus resulting in the reversible modification of the structural and functional properties of the targets. NTR enzymes contain three functional sites: an NADPH binding pocket, a non-covalently bound flavin cofactor, and a redox-active disulfide in the form of CxxC. With the aim of increasing our knowledge of the thioredoxin system in archaea, we here report the high-resolution crystal structure of NTR from the methane-generating organism Methanosarcina mazei strain Go1 (MmNTR) at 2.6 A resolution. Based on the crystals presently described, MmNTR assumes an overall fold that is nearly identical to the archetypal fold of authentic NTRs; however, surprisingly, we observed no electron density for flavin adenine dinucleotide (FAD) despite the well-defined and conserved FAD-binding cavity in the folded module. Remarkably, the dimers of the apo-protein within the crystal were different from those observed by small angle X-ray scattering (SAXS) for the holo protein, suggesting that the binding of the flavin cofactor does not require major protein structural rearrangements. Rather, binding results in the stabilization of essential parts of the structure, such as those involved in dimer stabilization. Altogether, this structure represents the example of an apo form of an NTR that yields important insight into the effects of the cofactor on protein folding. PMID- 30453600 TI - Green Synthesis of Ag Nanoparticles Using Grape Stalk Waste Extract for the Modification of Screen-Printed Electrodes. AB - The chemical synthesis of silver nanoparticles (Ag-NPs) by using an environmentally friendly methodology for their preparation is presented. Thus, considering that plants possess components that can act as reducing agents and stabilizers in nanoparticles' production, the synthesis of Ag-NPs by using an extract aqueous solution of grape stalk waste as a reducing and capping agent is studied. First, the total polyphenols and reducing sugars contained in the produced extracts at different conditions are characterized. After that, Ag-NPs are synthesized regarding the interaction of Ag ions (from silver nitrate) and the grape stalk extract. The effect of temperature, contact time, extract/metal solution volume ratio and pH solution in the synthesis of metal nanoparticles are also studied. Different sets of nanoparticle samples are characterized by means of Electron Microscopy coupled with Energy Dispersive X-Ray for qualitative chemical identification. Ag-NPs with an average diameter of 27.7 +/- 0.6 nm are selected to proof their suitability for sensing purposes. Finally, screen-printed electrodes modified with Ag-NPs are tested for the simultaneous stripping voltammetric determination of Pb(II) and Cd(II). Results indicate good reproducibility, sensitivity and limits of detection around 2.7 ug L-1 for both metal ions. PMID- 30453602 TI - Advancing the Use of High-Performance Graphene-Based Multimodal Polymer Nanocomposite at Scale. AB - The production of an innovative, high-performance graphene-based polymer nanocomposite using cost-effective techniques was pursued in this study. Well dispersed and uniformly distributed graphene platelets within a polymer matrix, with strong interfacial bonding between the platelets and the matrix, provided an optimal nanocomposite system for industrial interest. This study reports on the reinforcement of high molecular weight multimodal-high-density polyethylene reinforced by a microwave-induced plasma graphene, using melt intercalation. The tailored process included designing a suitable screw configuration, paired with coordinating extruder conditions and blending techniques. This enabled the polymer to sufficiently degrade, predominantly through thermomechanical degradation, as well as thermo-oxidative degradation, which subsequently created a suitable medium for the graphene sheets to disperse readily and distribute evenly within the polymer matrix. Different microscopy techniques were employed to prove the effectiveness. This was then qualitatively assessed by Raman spectroscopy, X-ray diffraction, rheology, mechanical testing, density measurements, thermal expansion, and thermogravimetric analysis, confirming both the originality as well as the effectiveness of the process. PMID- 30453603 TI - Monensin Alters the Functional and Metabolomic Profile of Rumen Microbiota in Beef Cattle. AB - To identify differences in rumen function as a result of feeding monensin to beef cattle, rumen fluid metagenomics and metabolomics analyses were used to evaluate the functional attributes and metabolites of rumen microbiota in beef steers fed no or 200 mg/d of monensin. Eight rumen-fistulated steers were used in the study for a period of 53 days. Rumen fluid samples were collected on the last day of the experiment. Monensin increased the relative abundance of Selenomonas sp. ND2010, Prevotella dentalis, Hallella seregens, Parabacteroides distasonis, Propionispira raffinosivorans, and Prevotella brevis, but reduced the relative abundance of Robinsoniella sp. KNHs210, Butyrivibrio proteoclasticus, Clostridium botulinum, Clostridium symbiosum, Burkholderia sp. LMG29324, and Clostridium butyricum. Monensin increased the relative abundance of functional genes involved in amino acid metabolism and lipid metabolism. A total of 245 metabolites were identified. Thirty-one metabolites were found to be differentially expressed. Pathway analysis of the differentially expressed metabolites revealed upregulated metabolic pathways associated with metabolism of linoleic acid and some amino acids. These findings confirm that monensin affects rumen fermentation of forage fed beef cattle by modulating the rumen microbiome, and by reducing amino acid degradation and biohydrogenation of linoleic acid in the rumen. PMID- 30453605 TI - Measuring Sedentary Behavior by Means of Muscular Activity and Accelerometry. AB - Sedentary Behavior (SB) is among the most frequent human behaviors and is associated with a plethora of serious chronic lifestyle diseases as well as premature death. Office workers in particular are at an increased risk due to their extensive amounts of occupational SB. However, we still lack an objective method to measure SB consistent with its definition. We have therefore developed a new measurement system based on muscular activity and accelerometry. The primary aim of the present study was to calibrate the new-developed 8-CH-EMG+ for measuring occupational SB against an indirect calorimeter during typical desk based office work activities. In total, 25 volunteers performed nine office tasks at three typical workplaces. Minute-by-minute posture and activity classification was performed using subsequent decision trees developed with artificial intelligence data processing techniques. The 8-CH-EMG+ successfully identified all sitting episodes (AUC = 1.0). Furthermore, depending on the number of electromyography channels included, the device has a sensitivity of 83-98% and 74 98% to detect SB and active sitting (AUC = 0.85-0.91). The 8-CH-EMG+ advances the field of objective SB measurements by combining accelerometry with muscular activity. Future field studies should consider the use of EMG sensors to record SB in line with its definition. PMID- 30453604 TI - In-Situ Preparation of CdTe Quantum Dots Capped with a beta-Cyclodextrin Epichlorohydrin Polymer: Polymer Influence on the Nanocrystal's Optical Properties. AB - beta-Cyclodextrin (betaCD), the less water soluble of the cyclodextrins, has been used as a capping agent in the preparation of semiconductor nanocrystals or quantum dots (QDs). Nevertheless, no reports have been found in the use of the highly water-soluble polymer of this, prepared by the crosslinking of the betaCD units with epichlorohydrin in basic medium (betaCDP). This polymer, besides to overcome the low solubility of the betaCD, increases the inclusion constant of the guest; two parameters that deserve its use as capping agent, instead of the native cyclodextrin. In the present manuscript, we afforded the in-situ aqueous preparation of cadmium telluride (CdTe) QDs capped with betaCDP. The polymer influence on the photoluminescent properties of the nanocrystals was analyzed. The betaCDP controls the nanocrystals growth during the Oswald ripening stage. Consequently, the CdTe capped betaCDP QDs showed lower Stokes-shift values, higher photoluminescent efficiency, and narrower size distribution than for nanocrystals obtained in the absence of polymer. Transmission electron microscopy (TEM) micrographs and energy dispersive X-ray spectroscopy (EDS) analysis revealed the composition and crystallinity of the CdTe QDs. This betaCDP capped CdTe QDs is a potential scaffold for the supramolecular modification of QDs surface. PMID- 30453606 TI - Site-Specific N-Glycosylation on the AAV8 Capsid Protein. AB - Adeno associated virus (AAV) is a versatile gene delivery tool, which has been approved as a human gene therapy vector for combating genetic diseases. AAV capsid proteins are the major components that determine the tissue specificity, immunogenicity and in vivo transduction performance of the vector. In this study, the AAV8 capsid glycosylation profile was systemically analyzed by peptide mass fingerprinting utilizing high-resolution mass spectrometry to determine the presence of capsid glycosylation. We identified N-glycosylation on the amino acid N499 of the capsid protein. We characterized the overall sugar profile for vector produced in 293 cells. Multiple N-glycosylated host-cell proteins (HCPs) copurified with AAV8 vectors and were identified by analyzing LC-MS data utilizing a human database and proteome discoverer search engine. The N glycosylation analysis by MALDI-TOF MS, highlighted the probability of AAV8 interaction with terminal galactosylated N-glycans within the HCPs. PMID- 30453607 TI - Delayed LY333013 (Oral) and LY315920 (Intravenous) Reverse Severe Neurotoxicity and Rescue Juvenile Pigs from Lethal Doses of Micrurus fulvius (Eastern Coral Snake) Venom. AB - OBJECTIVE: There is a clear, unmet need for effective, lightweight, shelf-stable and economical snakebite envenoming therapies that can be given rapidly after the time of a snake's bite and as adjuncts to antivenom therapies in the hospital setting. The sPLA2 inhibitor, LY315920, and its orally bioavailable prodrug, LY333013, demonstrate surprising efficacy and have the characteristics of an antidote with potential for both field and hospital use. METHODS: The efficacy of the active pharmaceutical ingredient (LY315920) and its prodrug (LY333013) to treat experimental, lethal envenoming by Micrurus fulvius (Eastern coral snake) venom was tested using a porcine model. Inhibitors were administered by either intravenous or oral routes at different time intervals after venom injection. In some experiments, antivenom was also administered alone or in conjunction with LY333013. RESULTS: 14 of 14 animals (100%) receiving either LY315920 (intravenous) and/or LY333013 (oral) survived to the 120 h endpoint despite, in some protocols, the presence of severe neurotoxic signs. The study drugs demonstrated the ability to treat, rescue, and re-rescue animals with advanced manifestations of envenoming. CONCLUSIONS: Low molecular mass sPLA2 inhibitors were highly effective in preventing lethality following experimental envenoming by M. fulvius. These findings suggest the plausibility of a new therapeutic approach to snakebite envenoming, in this example, for the treatment of a coral snake species for which there are limitations in the availability of effective antivenom. PMID- 30453608 TI - Mapping Mangrove Forests of Dongzhaigang Nature Reserve in China Using Landsat 8 and Radarsat-2 Polarimetric SAR Data. AB - Mangrove forests are distributed in intertidal regions that act as a "natural barrier" to the coast. They have enormous ecological, economic, and social value. However, the world's mangrove forests are declining under immense pressure from anthropogenic and natural disturbances. Accurate information regarding mangrove forests is essential for their protection and restoration. The main objective of this study was to develop a method to improve the classification of mangrove forests using C-band quad-pol Synthetic Aperture Radar (SAR) data (Radarsat-2) and optical data (Landsat 8), and to analyze the spectral and backscattering signatures of mangrove forests. We used a support vector machine (SVM) classification method to classify the land use in Hainan Dongzhaigang National Nature Reserve (HDNNR). The results showed that the overall accuracy using only optical information was 83.5%. Classification accuracy was improved to a varying extent by the addition of different radar data. The highest overall accuracy was 95.0% based on a combination of SAR and optical data. The area of mangrove forest in the reserve was found to be 1981.7 ha, as determined from the group with the highest classification accuracy. Combining optical data with SAR data could improve the classification accuracy and be significant for mangrove forest conservation. PMID- 30453609 TI - A Novel Microfluidic Point-of-Care Biosensor System on Printed Circuit Board for Cytokine Detection. AB - Point of Care (PoC) diagnostics have been the subject of considerable research over the last few decades driven by the pressure to detect diseases quickly and effectively and reduce healthcare costs. Herein, we demonstrate a novel, fully integrated, microfluidic amperometric enzyme-linked immunosorbent assay (ELISA) prototype using a commercial interferon gamma release assay (IGRA) as a model antibody binding system. Microfluidic assay chemistry was engineered to take place on Au-plated electrodes within an assay cell on a printed circuit board (PCB)-based biosensor system. The assay cell is linked to an electrochemical reporter cell comprising microfluidic architecture, Au working and counter electrodes and a Ag/AgCl reference electrode, all manufactured exclusively via standard commercial PCB fabrication processes. Assay chemistry has been optimised for microfluidic diffusion kinetics to function under continual flow. We characterised the electrode integrity of the developed platforms with reference to biological sampling and buffer composition and subsequently we demonstrated concentration-dependent measurements of H2O2 depletion as resolved by existing FDA-validated ELISA kits. Finally, we validated the assay technology in both buffer and serum and demonstrate limits of detection comparable to high-end commercial systems with the addition of full microfluidic assay architecture capable of returning diagnostic analyses in approximately eight minutes. PMID- 30453610 TI - High Performance Anti-Corrosion Coatings of Poly (Vinyl Butyral) Composites with Poly N-(vinyl)pyrrole and Carbon Black Nanoparticles. AB - Zinc is widely used in battery negative electrodes and steel coatings for automotive industries. The anti-corrosion property of zinc is the most important factor determining the performance and lifetime of the products. In this paper, both size-controlled poly N-(vinyl)pyrrole (PNVPY) nanoparticles and carbon black (CB) nanoparticles were compounded with poly (vinyl butyral) (PVB) binder developing a series of composite coatings covered on the zinc substrates using a spin-coating technique. The morphologies of the surface and cross section of the PNVPY/CB/PVB coatings indicate that the PNVPY and CB nanoparticles are uniformly distributed in the matrix. The corrosion resistance of the composite coatings was tested by electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization in a 3.5% NaCl solution. It is found that the coating with 1.9 wt.% PNVPY and 2.3 wt.% CB nanoparticles shows a remarkably high resistance value (Rc) and corrosion protection efficiency (99.99%). Meanwhile, the immersion results also reveal its superior corrosion resistance. It is considered that the nanoscale dispersion of PNVPY and carbon in PVB matrix and the strong interface action between the nanoparticles and PVB result in the uniform microstructure of the composites which endues the superior corrosion properties of the coatings. PMID- 30453611 TI - A Facile and Low-Cost Method to Produce Ultrapure 99.99999% Gallium. AB - As one of the critical raw materials, very pure gallium is important for the semiconductor and photoelectric industry. Unfortunately, refining gallium to obtain a purity that exceeds 99.99999% is very difficult. In this paper, a new, facile and efficient continuous partial recrystallization method to prepare gallium of high purity is investigated. Impurity concentrations, segregation coefficients, and the purification effect were measured. The results indicated that the contaminating elements accumulated in the liquid phase along the crystal direction. The order of the removal ratio was Cu > Mg > Pb > Cr > Zn > Fe. This corresponded to the order of the experimentally obtained segregation coefficients for each impurity: Cu < Mg < Pb < Cr < Zn < Fe. The segregation coefficient of the impurities depended strongly on the crystallization rate. All observed impurity concentrations were substantially reduced, and the purity of the gallium obtained after our refinement exceeded 99.99999%. PMID- 30453612 TI - HCV-Specific T Cell Responses During and After Chronic HCV Infection. AB - Hepatitis C virus (HCV)-specific T cell responses are closely linked to the clinical course of infection. While T cell responses in self-limiting infection are typically broad and multi-specific, they display several distinct features of functional impairment in the chronic phase. Moreover, HCV readily adapts to immune pressure by developing escape mutations within epitopes targeted by T cells. Much of our current knowledge on HCV-specific T cell responses has been gathered under the assumption that this might eventually pave the way for a therapeutic vaccine. However, with the development of highly efficient direct acting antivirals (DAAs), there is less interest in the development of a therapeutic vaccine for HCV and the scope of T cell research has shifted. Indeed, the possibility to rapidly eradicate an antigen that has persisted over years or decades, and has led to T cell exhaustion and dysfunction, provides the unique opportunity to study potential T cell recovery after antigen cessation in a human in vivo setting. Findings from such studies not only improve our basic understanding of T cell immunity but may also advance immunotherapeutic approaches in cancer or chronic hepatitis B and D infection. Moreover, in order to edge closer to the WHO goal of HCV elimination by 2030, a prophylactic vaccine is clearly required. Thus, in this review, we will summarize our current knowledge on HCV-specific T cell responses and also provide an outlook on the open questions that require answers in this field. PMID- 30453613 TI - Evaluation of Substrates of Al-Mg and Aluminized Steel Coated With Non-Stick Fluoropolymers after the Removal of the Coating. AB - Many trays and pieces of Al-Mg and aluminized steel are used in the food industry. Sometimes these elements have non-stick coatings to solve problems related to the adhesion of masses and food products. With use, the coatings deteriorate and lose efficiency and must be removed to apply a new coating. The thermal cycles suffered by these alloys during the removal process of the deteriorated coating (500 degrees C) and the polymerization of a new coating (400 degrees C) can affect the durability and efficiency of the metallic substrates. The evolution of the mechanical and microstructural properties of the Al-Mg and aluminized steel substrates after two thermal cycles was studied in this work. The following parameters were analyzed: tensile strength, elongation (%), hardness, ASTM grain size, and the nature and distribution of the constituent particles. The report concluded that the removal of the coating, after each cycle, produced a decrease in the mechanical properties of the substrates. The hardness and tensile strength in Al-Mg decreases between 20-27% and in aluminized steel between 10-11%. In both cases, the process does not compromise the reuse of the substrate for the application of a new coating layer. The final blasting stage does not affect the Al-Mg alloys but may affect the aluminized steel Al-Si protective layer if special precautions are not taken. PMID- 30453614 TI - Development of Pectin-Type B Gelatin Polyelectrolyte Complex for Curcumin Delivery in Anticancer Therapy. AB - Curcumin has been proven to be a potent agent in colon cancer treatment. However, its hydrophobicity and low oral bioavailability hampered its clinical application. These limitations could be improved through appropriate formulations such as using polyelectrolyte complexes (PECs). PECs were self-assembled with polycations and polyanions in polar solvents. In this study, a novel pectin-type B gelatin PEC was developed for use in curcumin formulation. At pH 4.0, natural polyanions pectin and polycations type B gelatin spontaneously formed PECs in ethanol/water solution, whereas under mimetic gastrointestinal tract (GI tract) conditions, at pH 2.0 and 8.0, pectin and type B gelatin were electrically neutralized, and the PECs swelled to allow payload release. After being transferred to pH 7.0 condition, as in the colon environment, PECs were internalized into colon carcinomas. Thus, pectin-type B gelatin PECs were successfully prepared, and their constituent ratio and drug-loading process were also optimized. The optimum particle size of the PECs was 264.0 +/- 3.1 nm and they could swell as the zeta potential was altered at either pH 2.0 or 8.0. The optimum drug content and loading efficiency were 40% and 53%, respectively. At pH 2.0, curcumin was rapidly released from curcumin-loaded PECs, whereas at pH 8.0, curcumin-loaded PECs showed a sustained-release of curcumin. The bare PECs showed very low toxicity toward human normal cells, whereas curcumin-loaded PECs, after incubation at pH 2.0 for 2 h and at pH 8.0 for 4 h, induced cell cycle arrest and exhibited cytotoxic effect to HCT116 human colon cancer cells, even though these loaded PECs were pretreated with mimetic GI tract conditions. Our pectin-type B gelatin PECs were shown to be a promising oral formulation for curcumin delivery in anticancer therapy. PMID- 30453615 TI - Influence of Passivation Layers on Positive Gate Bias-Stress Stability of Amorphous InGaZnO Thin-Film Transistors. AB - Passivation (PV) layers could effectively improve the positive gate bias-stress (PGBS) stability of amorphous InGaZnO (a-IGZO) thin-film transistors (TFTs), whereas the related physical mechanism remains unclear. In this study, SiO2 or Al2O3 films with different thicknesses were used to passivate the a-IGZO TFTs, making the devices more stable during PGBS tests. With the increase in PV layer thickness, the PGBS stability of a-IGZO TFTs improved due to the stronger barrier effect of the PV layers. When the PV layer thickness was larger than the characteristic length, nearly no threshold voltage shift occurred, indicating that the ambient atmosphere effect rather than the charge trapping dominated the PGBS instability of a-IGZO TFTs in this study. The SiO2 PV layers showed a better improvement effect than the Al2O3 because the former had a smaller characteristic length (~5 nm) than that of the Al2O3 PV layers (~10 nm). PMID- 30453616 TI - Direct and Long-Term Metabolic Consequences of Lowly vs. Highly-Digestible Starch in the Early Post-Weaning Diet of Mice. AB - Starches of low and high digestibility have different metabolic effects. Here, we examined whether this gives differential metabolic programming when fed in the immediate post-weaning period. Chow-fed mice were time-mated, and their nests were standardized and cross-fostered at postnatal days 1-2. After postnatal week (PW) 3, individually housed female and male offspring were switched to a lowly digestible (LDD) or highly-digestible starch diet (HDD) for three weeks. All of the mice received the same high-fat diet (HFD) for nine weeks thereafter. Energy and substrate metabolism and carbohydrate fermentation were studied at the end of the HDD/LDD and HFD periods by extended indirect calorimetry. Glucose tolerance (PW 11) and metabolic flexibility (PW14) were analyzed. Directly in response to the LDD versus the HDD, females showed smaller adipocytes with less crown-like structures in gonadal white adipose tissue, while males had a lower fat mass and higher whole body fat oxidation levels. Both LDD-fed females and males showed an enlarged intestinal tract. Although most of the phenotypical differences disappeared in adulthood in both sexes, females exposed to LDD versus HDD in the early post-weaning period showed improved metabolic flexibility in adulthood. Cumulatively, these results suggest that the type of starch introduced after weaning could, at least in females, program later-life health. PMID- 30453617 TI - Serum Triglycerides and Atherosclerotic Cardiovascular Disease: Insights from Clinical and Genetic Studies. AB - Lipoproteins are a major risk factor for atherosclerotic cardiovascular diseases (ASCVD). Among the lipoproteins, low-density lipoproteins (LDL) have been shown to be causally associated with ASCVD development. In contrast, triglycerides or triglyceride-rich lipoproteins receive less attention than LDL because there is little definite evidence from randomized controlled trials. A Mendelian randomization study has recently been published in which a causal association could be estimated with observational datasets. Using such Mendelian randomization studies, ranging from common to rare genetic variations, triglycerides seem to be causally associated with ASCVD outcomes independent of LDL. Although the "causal association" of serum triglycerides and ASCVD is difficult to assert, accumulated evidence from clinical and Mendelian randomization studies, using common and rare genetic variations, strongly supports such an association. In this article, we provide a summary of investigations focusing on important causal associations between serum triglycerides and ASCVD from the clinical point of view. PMID- 30453618 TI - Wind Turbine Noise and Sleep: Pilot Studies on the Influence of Noise Characteristics. AB - The number of onshore wind turbines in Europe has greatly increased over recent years, a trend which can be expected to continue. However, the effects of wind turbine noise on long-term health outcomes for residents living near wind farms is largely unknown, although sleep disturbance may be a cause for particular concern. Presented here are two pilot studies with the aim of examining the acoustical properties of wind turbine noise that might be of special relevance regarding effects on sleep. In both pilots, six participants spent five consecutive nights in a sound environment laboratory. During three of the nights, participants were exposed to wind turbine noise with variations in sound pressure level, amplitude modulation strength and frequency, spectral content, turbine rotational frequency and beating behaviour. The impact of noise on sleep was measured using polysomnography and questionnaires. During nights with wind turbine noise there was more frequent awakening, less deep sleep, less continuous N2 sleep and increased subjective disturbance compared to control nights. The findings indicated that amplitude modulation strength, spectral frequency and the presence of strong beats might be of particular importance for adverse sleep effects. The findings will be used in the development of experimental exposures for use in future, larger studies. PMID- 30453619 TI - Solid Food Introduction and the Development of Food Allergies. AB - The rise of food allergy in childhood, particularly among developed countries, has a significant weight on public health and involves serious implications for patients' quality of life. Even if the mechanisms of food tolerance and the complex interactions between the immune system and environmental factors are still mainly unknown, pediatricians have worldwide implemented preventive measures against allergic diseases. In the last few decades, the prevention of food allergy has tracked various strategies of complementary feeding with a modification of international guidelines from delayed introduction to early weaning. Current evidence shows that complementary foods, including allergenic ones, should be introduced into diet after four months, or even better, following World Health Organization advice, around six months irrespective of risk for allergy of the individual. The introduction of peanut is recommended before 12 months of age among infants affected by severe eczema and/or egg allergy to diminish the occurrence of peanut allergy in countries with high peanut consumption. The introduction of heated egg at 6-8 months of age may reduce egg allergy. Infants at high risk of allergy similarly to healthy children should introduce complementary foods taking into account family and cultural preferences. PMID- 30453620 TI - Tuning Texture and Morphology of Mesoporous TiO2 by Non-Hydrolytic Sol-Gel Syntheses. AB - The development of powerful synthetic methodologies is paramount in the design of advanced nanostructured materials. Owing to its remarkable properties and low cost, nanostructured TiO2 is widely investigated for applications such as photocatalysis, energy conversion or energy storage. In this article we report the synthesis of mesoporous TiO2 by three different non-hydrolytic sol-gel routes, and we investigate the influence of the synthetic route and of the presence and nature of the solvent on the structure, texture and morphology of the materials. The first route is the well-known ether route, based on the reaction of TiCl4 with iPr2O. The second and third routes, which have not been previously described for the synthesis of mesoporous TiO2, involve the reaction of Ti(OiPr)4 with stoichiometric amounts of acetophenone and benzoic anhydride, respectively. All materials are characterized by XRD, N2 physisorption and SEM. By playing with the non-hydrolytic route used and the reaction conditions (presence of a solvent, nature of the solvent, calcination), it is possible to tune the morphology and texture of the TiO2. Depending on the reaction conditions, a large variety of mesoporous TiO2 nanostructures could be obtained, resulting from the spontaneous aggregation of TiO2 nanoparticles, either rounded nanoparticles, platelets or nanorods. These nanoparticle networks exhibited a specific surface area up to 250 m2 g-1 before calcination, or up to 110 m2 g-1 after calcination. PMID- 30453621 TI - Human Fetal Astrocytes Infected with Zika Virus Exhibit Delayed Apoptosis and Resistance to Interferon: Implications for Persistence. AB - Zika virus (ZIKV) infection and persistence during pregnancy can lead to microcephaly and other fetal neurological disorders collectively known as Congenital Zika Syndrome. The immunological and virological events that contribute to the establishment of persistent ZIKV infection in humans are unclear though. Here we show that human fetal astrocytes (HFAs), the most abundant cell type in the central nervous system, become persistently infected with ZIKV resulting in continuous viral shedding for at least one month; a process that is facilitated by TIM/TAM receptors. HFAs are relatively resistant to ZIKV-induced apoptosis, a factor that may be important for chronic infection of these cells. Once infection was established, interferon treatment did not reduce virus replication. Moreover, the fact that the innate immune system was highly activated in persistently infected HFAs indicates that the virus can thrive in the presence of a sustained antiviral response. RNAseq analyses of persistently infected cells revealed that ZIKV alters host gene expression in a manner that could affect developmental processes. Conversely, data from sequencing of ZIKV genomes in persistently infected HFAs suggest that adaptive mutations were not required for establishing chronic infection. Based on these results, we postulate that HFAs are reservoirs for ZIKV in the fetal brain and that moderate apoptosis combined with inefficient antiviral response from these cells may contribute to the establishment of chronic brain infection associated with the ZIKV neurodevelopmental abnormalities. PMID- 30453622 TI - Multiple Pathways in the Control of the Shade Avoidance Response. AB - To detect the presence of neighboring vegetation, shade-avoiding plants have evolved the ability to perceive and integrate multiple signals. Among them, changes in light quality and quantity are central to elicit and regulate the shade avoidance response. Here, we describe recent progresses in the comprehension of the signaling mechanisms underlying the shade avoidance response, focusing on Arabidopsis, because most of our knowledge derives from studies conducted on this model plant. Shade avoidance is an adaptive response that results in phenotypes with a high relative fitness in individual plants growing within dense vegetation. However, it affects the growth, development, and yield of crops, and the design of new strategies aimed at attenuating shade avoidance at defined developmental stages and/or in specific organs in high density crop plantings is a major challenge for the future. For this reason, in this review, we also report on recent advances in the molecular description of the shade avoidance response in crops, such as maize and tomato, and discuss their similarities and differences with Arabidopsis. PMID- 30453624 TI - Genome-Wide Transcriptional and Functional Analysis of Human T Lymphocytes Treated with Benzo[alpha]pyrene. AB - Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants, known to affect T lymphocytes. However, the molecular targets and pathways involved in their immunotoxic effects in human T lymphocytes remain unknown. Here, we analyzed the gene expression profile of primary human T lymphocytes treated with the prototypical PAH, benzo[alpha]pyrene (B[alpha]P), using a microarray-based transcriptome analysis. After a 48 h exposure to B[alpha]P, we identified 158 genes differentially expressed in T lymphocytes, including not only genes well-known to be affected by PAHs such as the cytochromes P450 (CYP) 1A1 and 1B1, but also others not previously shown to be targeted by B[alpha]P such as genes encoding the gap junction beta (GJB)-2 and 6 proteins. Functional enrichment analysis revealed that these candidates were significantly associated with the aryl hydrocarbon (AhR) and interferon (IFN) signaling pathways; a marked alteration in T lymphocyte recruitment was also observed. Using functional tests in transwell migration experiments, B[alpha]P was then shown to significantly decrease the chemokine (C-X-C motif) ligand 12 induced chemotaxis and transendothelial migration of T lymphocytes. In total, this study opens the way to unsuspected responsive pathway of interest, i.e., T lymphocyte migration, thus providing a more thorough understanding of the molecular basis of the immunotoxicity of PAHs. PMID- 30453625 TI - Dietary Cold Pressed Watercress and Coconut Oil Mixture Enhances Growth Performance, Intestinal Microbiota, Antioxidant Status, and Immunity of Growing Rabbits. AB - The present study assessed the effect of dietary supplementation with coconut oil (CNO), watercress oil (WCO), and their mixture as promoters of growth, antioxidant status, immunity, and intestinal microbiota in growing rabbits. A total of 120 rabbits were distributed into six groups (20 rabbits/group) receiving a basal diet without supplementation (G1) or diet supplemented with 2 g CNO (G2), 2 g WCO (G3), 0.5 g CNO plus 1.5 g WCO (G4), 1 g CNO plus 1 g WCO (G5), or 1.5 g CNO plus 0.5 g WCO/kg (G6). Live body weight and feed conversion ratio were significantly higher in the G4 and G5 groups than in the other groups. Superoxide dismutase activity and reduced glutathione concentration were significantly improved in the CNO or WCO diets. Supplemental CNO plus WCO at all tested levels produced the best lysozyme and complement 3 activities. Cecal lactobacilli, coliform, Enterobacteriaceae, and Clostridium spp. populations were lower in the group who received the 1 g CNO + 1 g WCO/kg diet than that in the control group. Dietary supplementation of 1 g CNO + 1 g WCO or 0.5 g CNO + 1.5 g WCO/kg had the potential to improve growth, feed utilization, antioxidant status, and immunity, and reduce cecal pathogenic bacteria in rabbits. PMID- 30453626 TI - Method of Calculating the Inductance Value of MEMS Suspended Inductors with Silicon Substrates. AB - Microelectromechanical system (MEMS) suspended inductors have excellent radio frequency (RF) performance. The inductance value is one of the main features that characterizes the performance of inductors. It is important to consider the influence of the substrate and the suspension height in calculating the inductance value accurately. In this paper, a method is proposed to calculate the inductance value of the MEMS suspended inductor wire with a silicon substrate, as the wire is the basic component of the inductor coil. Then the method is extended to the suspended inductors consisting of a single turn coil. The calculation results obtained by this proposed method were verified by finite-element analysis (HFSS) and they were found to agree well with the results of the HFSS simulation. PMID- 30453623 TI - Nanostructure Optimization of Platinum-Based Nanomaterials for Catalytic Applications. AB - Platinum-based nanomaterials have attracted much interest for their promising potentials in fields of energy-related and environmental catalysis. Designing and controlling the surface/interface structure of platinum-based nanomaterials at the atomic scale and understanding the structure-property relationship have great significance for optimizing the performances in practical catalytic applications. In this review, the strategies to obtain platinum-based catalysts with fantastic activity and great stability by composition regulation, shape control, three dimension structure construction, and anchoring onto supports, are presented in detail. Moreover, the structure-property relationship of platinum-based nanomaterials are also exhibited, and a brief outlook are given on the challenges and possible solutions in future development of platinum-based nanomaterials towards catalytic reactions. PMID- 30453627 TI - Genome-Wide Association Studies of Estimated Fatty Acid Desaturase Activity in Serum and Adipose Tissue in Elderly Individuals: Associations with Insulin Sensitivity. AB - Fatty acid desaturases (FADS) catalyze the formation of unsaturated fatty acids and have been related to insulin sensitivity (IS). FADS activities differ between tissues and are influenced by genetic factors that may impact the link to IS. Genome-wide association studies of delta-5-desaturase (D5D), delta-6-desaturase (D6D) and stearoyl-CoA desaturase-1 (SCD) activities (estimated by product-to precursor ratios of fatty acids analyzed by gas chromatography) in serum cholesterol esters (n = 1453) and adipose tissue (n = 783, all men) were performed in two Swedish population-based cohorts. Genome-wide significant associated loci were evaluated for associations with IS measured with a hyperinsulinemic euglycemic clamp (n = 554). Variants at the FADS1 were strongly associated with D5D in both cholesterol esters (p = 1.9 * 10-70) and adipose tissue (p = 1.1 * 10-27). Variants in three further loci were associated with D6D in cholesterol esters (FADS2, p = 3.0 * 10-67; PDXDCI, p = 4.8 * 10-8; and near MC4R, p = 3.7 * 10-8) but no associations with D6D in adipose tissue attained genome-wide significance. One locus was associated with SCD in adipose tissue (PKDL1, p = 2.2 * 10-19). Genetic variants near MC4R were associated with IS (p = 3.8 * 10-3). The FADS cluster was the main genetic determinant of estimated FADS activity. However, fatty acid (FA) ratios in adipose tissue and cholesterol esters represent FADS activities in separate tissues and are thus influenced by different genetic factors with potential varying effects on IS. PMID- 30453629 TI - Dialysis Membranes Influence Perfluorochemical Concentrations and Liver Function in Patients on Hemodialysis. AB - Introduction: Perfluoro-octanesulfonate (PFOS) and perfluoro-octanoic acid (PFOA) are two toxic perfluorochemicals (PFCs) commonly used as surfactants. PFCs are difficult to be eliminated from the body. We investigated the influence of different dialysis membranes on the concentrations of PFCs in patients under hemodialysis. Method: We enrolled 98 patients. Of these, 58 patients used hydrophobic polysulfone (PS) dialysis membranes, and the other 40 had hydrophilic membranes made by poly-methyl methacrylate (PMMA) or cellulose triacetate (CTA). Liquid chromatography tandem mass spectrometry coupled was used with isotope dilution to quantify PFOA and PFOS. Results: The predialysis concentrations of PFOA and PFOS in patients with hydrophobic PS dialysis membranes were 0.50 and 15.77 ng/mL, respectively, lower than the concentrations of 0.81 and 22.70 ng/mL, respectively, in those who used hydrophilic membranes (such as CTA or PMMA). Older patients have higher PFOS and poorer body function, with lower Karnofsky Performance Status Scale (KPSS) scores. The demographic data of the two groups were similar. However, patients with hydrophobic PS dialysis membranes had lower predialysis aspartate transaminase (AST) (p = 0.036), lower glucose levels (p = 0.017), and better body function (nonsignificantly higher KPSS scores, p = 0.091) compared with patients who used other membranes. These differences may be associated with the effects of different membranes, because PFOA positively correlated with AST, while PFOS negatively correlated with body function. Conclusions: This is the first study comparing PFC levels in uremic patients with different dialysis membrane. PS membrane may provide better clearance of PFCs and may, therefore, be beneficial for patients. PMID- 30453628 TI - Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration. AB - Clofazimine (CFZ) is a broad spectrum antimycobacterial agent recommended by the World Health Organization as a first line treatment for leprosy and second line treatment for multidrug resistant tuberculosis. Oral administration of CFZ leads to a red skin pigmentation side effect. Since CFZ is a weakly basic, red phenazine dye, the skin pigmentation side effect results from lipophilic partitioning of the circulating, free base (neutral) form of CFZ into the skin. Here, we developed a stable and biocompatible formulation of CFZ-HCl microcrystals that mimics the predominant form of the drug that bioaccumulates in macrophages, following long term oral CFZ administration. In mice, intravenous injection of these biomimetic CFZ-HCl microcrystals led to visible drug accumulation in macrophages of the reticuloendothelial system with minimal skin accumulation or pigmentation. In fact, no skin pigmentation was observed when the total amount of CFZ-HCl administered was equivalent to the total oral dose leading to maximal skin pigmentation. Thus, parenteral (injected or inhaled) biomimetic formulations of CFZ-HCl could be instrumental to avoid the pigmentation side effect of oral CFZ therapy. PMID- 30453630 TI - Molecular Co-Chaperone SGT1 Is Critical for Cell-to-Cell Movement and Systemic Infection of Tomato Spotted Wild Virus in Nicotiana benthamiana. AB - Tospovirus is a tripartite negative stranded RNA virus and is considered as one of the most devastating plant viruses. Successful virus infection in plant requires many host factors. To date, very few host factors have been identified as important in Tospovirus infection in plants. We reported earlier that NSm protein encoded by Tomato spotted wilt virus (TSWV), a type species of the genus Orthotospovirus, plays critical roles in viral cell-to-cell and long-distance movement. In this study, we determined that molecular co-chaperone NbSGT1 interacted with TSWV NSm in Nicotiana benthamiana. TSWV infection significantly upregulated the expression of NbSGT1 gene and transient overexpression of NbSGT1 in N. benthamiana leaves accelerated TSWV infection. In contrast, silencing the NbSGT1 gene expression using a virus-induced gene silencing (VIGS) approach strongly inhibited TSWV NSm cell-to-cell movement, as well as TSWV local and systemic infection in N. benthamiana plants. Furthermore, NbSGT1 was found to regulate the infection of both American and Euro/Asia type tospoviruses in N. benthamiana plant. Collectively, our findings presented in this paper and the results published previously indicated that molecular co-chaperone NbSGT1 plays important roles in modulating both positive stranded and tripartite negative stranded RNA virus infection in plants. PMID- 30453631 TI - DNA Replication: From Radioisotopes to Click Chemistry. AB - The replication of nuclear and mitochondrial DNA are basic processes assuring the doubling of the genetic information of eukaryotic cells. In research of the basic principles of DNA replication, and also in the studies focused on the cell cycle, an important role is played by artificially-prepared nucleoside and nucleotide analogues that serve as markers of newly synthesized DNA. These analogues are incorporated into the DNA during DNA replication, and are subsequently visualized. Several methods are used for their detection, including the highly popular click chemistry. This review aims to provide the readers with basic information about the various possibilities of the detection of replication activity using nucleoside and nucleotide analogues, and to show the strengths and weaknesses of those different detection systems, including click chemistry for microscopic studies. PMID- 30453632 TI - Towards a Stochastic Paradigm: From Fuzzy Ensembles to Cellular Functions. AB - The deterministic sequence -> structure -> function relationship is not applicable to describe how proteins dynamically adapt to different cellular conditions. A stochastic model is required to capture functional promiscuity, redundant sequence motifs, dynamic interactions, or conformational heterogeneity, which facilitate the decision-making in regulatory processes, ranging from enzymes to membraneless cellular compartments. The fuzzy set theory offers a quantitative framework to address these problems. The fuzzy formalism allows the simultaneous involvement of proteins in multiple activities, the degree of which is given by the corresponding memberships. Adaptation is described via a fuzzy inference system, which relates heterogeneous conformational ensembles to different biological activities. Sequence redundancies (e.g., tandem motifs) can also be treated by fuzzy sets to characterize structural transitions affecting the heterogeneous interaction patterns (e.g., pathological fibrillization of stress granules). The proposed framework can provide quantitative protein models, under stochastic cellular conditions. PMID- 30453633 TI - Parental Perception of Children Affected by Amelogenesis Imperfecta (AI) and Dentinogenesis Imperfecta (DI): A Qualitative Study. AB - This qualitative study was conducted to explore parental attitudes and values regarding aesthetics and treatment needs of children in primary dentition affected by AI and DI. A purposive sample of parents of young children attended two focus groups: mothers (n = 7) and fathers (n = 6). A topic guide with open ended questions was formulated and standardised photographs showing primary teeth affected by varying severity of AI/DI and photographs of different aesthetic treatments were utilised to stimulate discussion. Data was audio-recorded and transcribed verbatim. A cross-sectional thematic analysis was performed which identified six main themes; the impact on affected children, the impact on parents, the life course of the disease, coping mechanisms, treatment need, and experience of treatment. Parents believed that young children were aware of their altered dental appearance. A feeling of guilt was evident among fathers affected by the same condition. Most parents sought dental treatment before starting school due to worries of bullying at school. Parents appeared to rely solely on the professional advice of the paediatric dentist in making all treatment related decisions. The personal experience of parents affected by AI/DI played a pivotal role in parent's judgements of their children's teeth and perceived need for treatment. PMID- 30453634 TI - Effect of Pentacyclic Triterpenoids-Rich Callus Extract of Chaenomeles japonica (Thunb.) Lindl. ex Spach on Viability, Morphology, and Proliferation of Normal Human Skin Fibroblasts. AB - The effect of the well-characterized callus extract of Chaenomeles japonica on viability, morphology, and proliferation of normal human skin fibroblasts was investigated. The phytochemical analysis was performed using the ultra-high performance liquid chromatography method. The total phenolic, phenolic acid, and flavonoid contents were determined spectrophotometrically. The antioxidant activity was investigated using the DPPH (1,1-Diphenyl-1-picrylhydrazyl Radical Scavenging), FRAP (Ferric Reducing Antioxidant Power), and CUPRAC (CUPric Reducing Antioxidant Capacity) assays. The callus growth index during passages was high as well as the content of pentacyclic triterpenoids. The microscopic observations of the fibroblast viability, morphology and the evaluation of the proliferation ratio (xCELLigence system) proved that the influence of callus extract on the fibroblasts was dose-dependent. The evaluated level of fibroblasts proliferation rate after 72 h of incubation with callus extract at concentration 12.5 ug L-1 was the highest compared to all the analyzed ligands. Moreover, callus extract administrated for 72 h caused a significant increase in the proliferation rate in comparison with the control group (5.7 +/- 0.1 vs. 4.4 +/- 0.9; p < 0.01). The preliminary studies carried out may suggest that the callus extract rich in triterpenoids may be a potential source of cosmetic ingredients with a beneficial effect on human skin. PMID- 30453635 TI - Synthesis of 1-(para-methoxyphenyl)tetrazolyl-Substituted 1,2,3,4 Tetrahydroisoquinolines and Their Transformations Involving Activated Alkynes. AB - 1-(p-Methoxyphenyl)tetrazolyl-substituted 6,7-dimethoxy(6,7-methylenedioxy) 1,2,3,4-tetrahydroisoquinolines formed tetrazolyl-substituted azocines in high yields by using activated alkynes. Unsubstituted at 6,7,8-aromatic fragment 1 tetrazolylisoquinoline interacted in several pathways forming tetrazolyl substituted azocines, 1-tetrazolyl-1-R-vinylisoquinolines and 3 azaspiro[5.5]undeca-1,7,9-triene. PMID- 30453636 TI - Hollow Fiber Porous Nanocomposite Membranes Produced via Continuous Extrusion: Morphology and Gas Transport Properties. AB - In this work, hollow fiber porous nanocomposite membranes were successfully prepared by the incorporation of a porous nanoparticle (zeolite 5A) into a blend of linear low-density polyethylene (LLDPE)/low-density polyethylene (LDPE) combined with azodicarbonamide as a chemical blowing agent (CBA). Processing was performed via continuous extrusion using a twin-screw extruder coupled with a calendaring system. The process was firstly optimized in terms of extrusion and post-extrusion conditions, as well as formulation to obtain a good cellular structure (uniform cell size distribution and high cell density). Scanning electron microscopy (SEM) was used to determine the cellular structure as well as nanoparticle dispersion. Then, the samples were characterized in terms of mechanical and thermal stability via tensile tests and thermogravimetric analysis (TGA), as well as differential scanning calorimetry (DSC). The results showed that the zeolite nanoparticles were able to act as effective nucleating agents during the foaming process. However, the optimum nanoparticle content was strongly related to the foaming conditions. Finally, the membrane separation performances were investigated for different gases (CO2, CH4, N2, O2, and H2) showing that the incorporation of porous zeolite significantly improved the gas transport properties of semi-crystalline polyolefin membranes due to lower cell wall thickness (controlling permeability) and improved separation properties (controlling selectivity). These results show that mixed matrix membranes (MMMs) can be cost-effective, easy to process, and efficient in terms of processing rate, especially for the petroleum industry where H2/CH4 and H2/N2 separation/purification are important for hydrogen recovery. PMID- 30453637 TI - Smart Ocean: A New Fast Deconvolved Beamforming Algorithm for Multibeam Sonar. AB - A new fast deconvolved beamforming algorithm is proposed in this paper, and it can greatly reduce the computation complexity of the original Richardson-Lucy (R L algorithm) deconvolution algorithm by utilizing the convolution theorem and the fast Fourier transform technique. This algorithm makes it possible for real-time high-resolution beamforming in a multibeam sonar system. This paper applies the new fast deconvolved beamforming algorithm to a high-frequency multibeam sonar system to obtain a high bearing resolution and low side lobe. In the sounding mode, it restrains the tunnel effect and makes the topographic survey more accurate. In the 2D acoustic image mode, it can obtain clear images, more details, and can better distinguish two close targets. Detailed implementation methods of the fast deconvolved beamforming are given, its computational complexity is analyzed, and its performance is evaluated with simulated and real data. PMID- 30453638 TI - Extended Joint Sparsity Reconstruction for Spatial and Temporal ERT Imaging. AB - Electrical resistance tomography (ERT) is an imaging technique to recover the conductivity distribution with boundary measurements via attached electrodes. There are a wide range of applications using ERT for image reconstruction or parameter calculation due to high speed data collection, low cost, and the advantages of being non-invasive and portable. Although ERT is considered a high temporal resolution method, a temporally regularized method can greatly enhance such a temporal resolution compared to frame-by-frame reconstruction. In some of the cases, especially in the industrial applications, dynamic movement of an object is critical. In practice, it is desirable for monitoring and controlling the dynamic process. ERT can determine the spatial conductivity distribution based on previous work, and ERT potentially shows good performance in exploiting temporal information as well. Many ERT algorithms reconstruct images frame by frame, which is not optimal and would assume that the target is static during collection of each data frame, which is inconsistent with the real case. Although spatiotemporal-based algorithms can account for the temporal effect of dynamic movement and can generate better results, there is not that much work aimed at analyzing the performance in the time domain. In this paper, we discuss the performance of a novel spatiotemporal total variation (STTV) algorithm in both the spatial and temporal domain, and Temporal One-Step Tikhonov-based algorithms were also employed for comparison. The experimental results show that the STTV has a faster response time for temporal variation of the moving object. This robust time response can contribute to a much better control process which is the main aim of the new generation of process tomography systems. PMID- 30453639 TI - The Protective and Restorative Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Methadone-Induced Toxicity In Vitro. AB - Evidence to date suggests that opioids such as methadone may be associated with cognitive impairment. Growth hormone (GH) and insulin-like growth factor-1 (IGF 1) are suggested to be neuroprotective and procognitive in the brain and may therefore counteract these effects. This study aims to explore the protective and restorative effects of GH and IGF-1 in methadone-treated cell cultures. Primary cortical cell cultures were harvested from rat fetuses and grown for seven days in vitro. To examine the protective effects, methadone was co-treated with or without GH or IGF-1 for three consecutive days. To examine the restorative effects, methadone was added for the first 24 h, washed, and later treated with GH or IGF-1 for 48 h. At the end of each experiment, mitochondrial function and membrane integrity were evaluated. The results revealed that GH had protective effects in the membrane integrity assay and that both GH and IGF-1 effectively recovered mitochondrial function and membrane integrity in cells pretreated with methadone. The overall conclusion of the present study is that GH, but not IGF-1, protects primary cortical cells against methadone-induced toxicity, and that both GH and IGF-1 have a restorative effect on cells pretreated with methadone. PMID- 30453640 TI - The Out-of-Plane Compression Behavior of Cross-Ply AS4/PEEK Thermoplastic Composite Laminates at High Strain Rates. AB - The dynamic mechanical behavior of thermoplastic composites over a wide range of strain rates has become an important research topic for extreme environmental survivability in the fields of military protection, aircraft safety, and aerospace engineering. However, the dynamic compression response in the out-of plane direction, which is one of the most important loading conditions resulting in the damage of composite materials, has not been investigated thoroughly when compared to in-plane compression and tensile behavior under high strain rates. Thus, we used split Hopkinson pressure bar (SHPB) tests to conduct the out-of plane compression test of cross-ply carbon fiber-reinforced polyetheretherketone (AS4/PEEK) composite laminates. Afterward, the damage mechanism under different strain rates was characterized by the macrostructure morphologies and scanning electron microscope micrographs. Two major cases of the incomplete failure condition and complete failure condition were discussed. Dynamic stress-strain curves expound the strain rates dependencies of elastic modulus, failure strength, and failure strain. An obvious spring-back process could be observed under incomplete failure tests. For the complete failure tests, secondary loading could be observed by reconstructing and comparing the dynamic response history. Lastly, various failure modes that occurred in different loading strain rates illustrate that the damage mechanism also shows obvious strain rate sensitivity. PMID- 30453641 TI - Effect of Welding Current on Weld Formation, Microstructure, and Mechanical Properties in Resistance Spot Welding of CR590T/340Y Galvanized Dual Phase Steel. AB - During resistance spot welding, the welding current is the most important process parameter, which determines the welding heat input and then has a great influence on the welding quality. In present study, the CR590T/340YDP galvanized dual phase steel widely used as automobile material was carried out using resistance spot welding. The effect of welding current on the weld formation, microstructure, and mechanical properties was studied in detail. It was found that the quality of weld appearance decreased with the increase of welding current, and there was a Zn island on the weld surface. The microstructure of the whole resistance spot welded joint was inhomogeneity. The nugget zone consisted of coarse lath martensite and a little of ferrite with the columnar crystal morphology, and the microstructure of weld nugget became coarser when the welding current was higher. There was an optimum welding current value and the tensile strength reached the maximum. This investigation will provide the process guidance for automobile body production. PMID- 30453642 TI - Chitosan-Polylactide/Hyaluronic Acid Complex Microspheres as Carriers for Controlled Release of Bioactive Transforming Growth Factor-beta1. AB - Chitosan(CH)-polylactide(PLA) copolymers containing varied PLA percentages were synthesized using a group-protection method and one of them with solubility in water-based solvents was used to prepare CH-PLA/hyaluronic acid (HA) complex microspheres for the delivery of transforming growth factor-beta1 (TGF-beta1). An emulsification processing method was developed for producing TGF-beta1-loaded CH PLA/HA microspheres using sodium tripolyphosphate (TPP) as ionic crosslinker and the size of the microspheres was devised to the micron level in order to achieve high encapsulating efficiency. The encapsulating efficiency, swelling property and release administration of the microspheres could be synergistically regulated by PLA component, the applied TPP dose and the incorporated HA amount. In comparison to CH/HA microspheres, the CH-PLA/HA microspheres had greatly reduced TGF-beta1 release rates and were able to administrate the TGF-beta1 release at controlled rates over a significant longer period of time. The released TGF-beta1 was detected to be bioactive when compared to the free TGF-beta1. These results suggest that the presently developed CH-PLA/HA complex microspheres have promising potential in delivering TGF-beta1 for cartilage repair applications where the applied TGF-beta1 amount in the early stage needs to be low whilst the sustained TGF-beta1 release at an appropriate dose in the later stage has to be maintained. PMID- 30453644 TI - Association between Occupational Dysfunction and Metabolic Syndrome in Community Dwelling Japanese Adults in a Cross-Sectional Study: Ibara Study. AB - The purpose of this study was to investigate the relationship between occupational dysfunction and metabolic syndrome (MetS) and its component factors in community-dwelling Japanese adults (N = 1,514). Self-reported lifestyle behaviors, Classification and Assessment of Occupational Dysfunction (CAOD) scores, and metabolic traits were measured. CAOD levels were divided into tertiles (low, moderate, and high), and their associations with MetS and its components were evaluated through logistic regression analysis. The association of MetS with CAOD was demonstrated in the total number of individuals [OR = 1.92 (95% CI 1.17-3.17)] and in older individuals [OR = 1.90 (95% CI 1.04-3.46)]. The association of dyslipidemia and CAOD was evident for overweight individuals [OR = 2.08 (95% CI 1.17-3.68)]. A higher association of high blood pressure with CAOD was evidenced in younger individuals [OR = 2.02 (95% CI 1.05-3.89)] who belonged to the highest-CAOD-score group in comparison to those who registered the lowest CAOD-score group. The evaluation of MetS and interventions related to its prevention may be more effective if the viewpoint of occupational dysfunction is taken into account. PMID- 30453643 TI - Isolated Soy Protein Supplementation and Exercise Improve Fatigue-Related Biomarker Levels and Bone Strength in Ovariectomized Mice. AB - Isolated soy protein (ISP) is a well-known supplement and has been reported to improve health, exercise performance, body composition, and energy utilization. ISP exhibits multifunctional bioactivities and also contains branched-chain amino acids (BCAAs), which have been confirmed to positively affect body weight (BW) regulation and muscle protein synthesis. The combined effects of BCAA supplements and exercise in older postmenopausal women with osteoporosis, sarcopenia, and obesity have been inadequately investigated. Therefore, in this study, we evaluated the potential beneficial effects of soy protein supplementation and exercise training on postmenopausal mice. Forty mice (14 weeks old) with ovariectomy-induced osteosarcopenic obesity were divided into five groups (n = 8), namely sham ovariectomy (OVX, control), OVX, OVX with ISP supplementation (OVX+ISP), OVX with exercise training (ET, OVX+ET), and OVX with ISP and ET (OVX+ISP+ET). The mice received a vehicle or soy protein (3.8 g/kg BW) by oral gavage for four weeks, and the exercise performance (forelimb grip strength and exhaustive swimming time) was evaluated. In the biochemical profiles, we evaluated the serum glucose level and tissue damage markers, such as lactate, ammonia, glucose, blood urine nitrogen (BUN), and creatinine phosphate kinase (CPK). The body composition was determined by evaluating bone stiffness and muscle mass. All data were analyzed using one-way repeated measures analysis of variance. The physical performance of the OVX+ISP+ET group did not differ from that of the other groups. The OVX+ISP+ET group exhibited lower levels of serum lactate, ammonia, CPK, and BUN as well as economized glucose metabolism after an acute exercise challenge. The OVX+ISP+ET group also exhibited higher muscle mass and bone strength than the OVX group. Our study demonstrated that a combination of ISP supplementation and exercise reduced fatigue and improved bone function in OVX mice. PMID- 30453645 TI - Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjogren's Syndrome. AB - Sjogren's syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNgamma), interleukin 1 beta (IL1beta), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin-plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers. PMID- 30453646 TI - UAV IoT Framework Views and Challenges: Towards Protecting Drones as "Things". AB - Unmanned aerial vehicles (UAVs) have enormous potential in enabling new applications in various areas, ranging from military, security, medicine, and surveillance to traffic-monitoring applications. Lately, there has been heavy investment in the development of UAVs and multi-UAVs systems that can collaborate and complete missions more efficiently and economically. Emerging technologies such as 4G/5G networks have significant potential on UAVs equipped with cameras, sensors, and GPS receivers in delivering Internet of Things (IoT) services from great heights, creating an airborne domain of the IoT. However, there are many issues to be resolved before the effective use of UAVs can be made, including security, privacy, and management. As such, in this paper we review new UAV application areas enabled by the IoT and 5G technologies, analyze the sensor requirements, and overview solutions for fleet management over aerial-networking, privacy, and security challenges. Finally, we propose a framework that supports and enables these technologies on UAVs. The introduced framework provisions a holistic IoT architecture that enables the protection of UAVs as "flying" things in a collaborative networked environment. PMID- 30453647 TI - Fanconi Anaemia-Like Mph1 Helicase Backs up Rad54 and Rad5 to Circumvent Replication Stress-Driven Chromosome Bridges. AB - Homologous recombination (HR) is a preferred mechanism to deal with DNA replication impairments. However, HR synapsis gives rise to joint molecules (JMs) between the nascent sister chromatids, challenging chromosome segregation in anaphase. Joint molecules are resolved by the actions of several structure selective endonucleases (SSEs), helicases and topoisomerases. Previously, we showed that yeast double mutants for the Mus81-Mms4 and Yen1 SSEs lead to anaphase bridges (ABs) after replication stress. Here, we have studied the role of the Mph1 helicase in preventing these anaphase aberrations. Mph1, the yeast ortholog of Fanconi anaemia protein M (FANCM), is involved in the removal of the D-loop, the first JM to arise in canonical HR. Surprisingly, the absence of Mph1 alone did not increase ABs; rather, it blocked cells in G2. Interestingly, in the search for genetic interactions with functionally related helicases and translocases, we found additive effects on the G2 block and post-G2 aberrations between mph1Delta and knockout mutants for Srs2, Rad54 and Rad5. Based on these interactions, we suggest that Mph1 acts coordinately with these helicases in the non-canonical HR-driven fork regression mechanism to bypass stalled replication forks. PMID- 30453648 TI - A CMOS SPAD Imager with Collision Detection and 128 Dynamically Reallocating TDCs for Single-Photon Counting and 3D Time-of-Flight Imaging. AB - Per-pixel time-to-digital converter (TDC) architectures have been exploited by single-photon avalanche diode (SPAD) sensors to achieve high photon throughput, but at the expense of fill factor, pixel pitch and readout efficiency. In contrast, TDC sharing architecture usually features high fill factor at small pixel pitch and energy efficient event-driven readout. While the photon throughput is not necessarily lower than that of per-pixel TDC architectures, since the throughput is not only decided by the TDC number but also the readout bandwidth. In this paper, a SPAD sensor with 32 * 32 pixels fabricated with a 180 nm CMOS image sensor technology is presented, where dynamically reallocating TDCs were implemented to achieve the same photon throughput as that of per-pixel TDCs. Each 4 TDCs are shared by 32 pixels via a collision detection bus, which enables a fill factor of 28% with a pixel pitch of 28.5 MUm. The TDCs were characterized, obtaining the peak-to-peak differential and integral non-linearity of -0.07/+0.08 LSB and -0.38/+0.75 LSB, respectively. The sensor was demonstrated in a scanning light-detection-and-ranging (LiDAR) system equipped with an ultra-low power laser, achieving depth imaging up to 10 m at 6 frames/s with a resolution of 64 * 64 with 50 lux background light. PMID- 30453649 TI - Solvent Bar Micro-Extraction of Heavy Metals from Natural Water Samples Using 3 Hydroxy-2-Naphthoate-Based Ionic Liquids. AB - Developments in the liquid micro-extraction of trace metals from aqueous phases have proven to be limited when extended from pure water to more complex and demanding matrices such as sea water or wastewater treatment effluents. To establish a system that works under such matrices, we successfully tested three task-specific ionic liquids, namely trihexyltetradecyl- phosphonium-, methyltrioctylphosphonium- and methyltrioctylammonium 3-hydroxy-2-naphthoate in two-phase solvent bar micro-extraction (SBME) experiments. We describe the influence of pH, organic additives, time, stirring rate and volume of ionic liquid for multi-elemental micro-extraction of Cu, Ag, Cd and Pb from various synthetic and natural aqueous feed solutions. Highest extraction for all metals was achieved at pH 8.0. Minimal leaching of the ionic liquids into the aqueous phase was demonstrated, with values < 30 mg L-1 DOC in all cases. Sample salinities of up to 60 g L-1 NaCl had a positive effect on the extraction of Cd, possibly due to an efficient extraction mechanism of the present chlorido complexes. In metal-spiked natural feed solutions, the selected SBME setups showed unchanged stability under all conditions tested. We could efficiently (>=85%) extract Cu and Ag from drinking water and achieved high efficacies for Ag and Cd from natural sea water and hypersaline water, respectively. The method presented here proves to be a useful tool for an efficient SBME of heavy metals from natural waters without the need to pretreat or modify the sample. PMID- 30453650 TI - Loss of Response Gene to Complement 32 (RGC-32) in Diabetic Mouse Retina Is Involved in Retinopathy Development. AB - Diabetic retinopathy (DR) is a severe and recurrent microvascular complication in diabetes. The multifunctional response gene to complement 32 (RGC-32) is involved in the regulation of cell cycle, proliferation, and apoptosis. To investigate the role of RGC-32 in the development of DR, we used human retinal microvascular endothelial cells under high-glucose conditions and type 2 diabetes (T2D) mice (+Leprdb/ + Leprdb, db/db). The results showed that RGC-32 expression increased moderately in human retinal endothelial cells under hyperglycemic conditions. Histopathology and RGC-32 expression showed no significant changes between T2D and control mice retina at 16 and 24 weeks of age. However, RGC-32 expression was significantly decreased in T2D mouse retina compared to the control group at 32 weeks of age, which develop features of the early clinical stages of DR, namely reduced retinal thickness and increased ganglion cell death. Moreover, immunohistochemistry showed that RGC-32 was predominantly expressed in the photoreceptor inner segments of control mice, while the expression was dramatically lowered in the T2D retinas. Furthermore, we found that the level of anti-apoptotic protein Bcl-2 was decreased (approximately 2-fold) with a concomitant increase in cleaved caspase-3 (approximately 3-fold) in T2D retina compared to control. In summary, RGC-32 may lose its expression in T2D retina with features of DR, suggesting that it plays a critical role in DR pathogenesis. PMID- 30453651 TI - Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases. AB - Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers. PMID- 30453653 TI - Determination of Tryptophan and Its Major Metabolites in Fluid from the Anterior Chamber of the Eye in Diabetic Patients with Cataract by Liquid Chromotography Mass Spectrometry (LC-MS/MS). AB - Tryptophan (TRP) is to an essential amino acid and its catabolites are significant to human health. By using ultra-high-performance liquid chromatography coupled to electrospray ionization triple quadrupole mass spectrometry (UHPLC-ESI-MS/MS), levels of three major components of kynurenic pathway namely tryptophan (TRP), kynurenic acid (KYNA) and kynurenine (KYN) in fluid from the anterior chamber of the eye were determined. The analysis was carried out on a Synergi 4 MU Fusion-RP column using gradient elution mode. For quantitative determination, l-tryptophan-amino-15N, 99 ATOM % 15N was used as an internal standard. The method was linear in the concentration range 4-2000 ng mL 1 for TRP, KYNA and KYN. The mean recoveries measured at four concentration levels for TRP, KYN and KYNA included the following ranges 94.3-96.1; 91.0-95.0; and 96.0-97.6%, respectively. The intra-day precision parameters were smaller than 4.4, 6.4 and 5% respectively. The developed method was applied to study the level of TRP, KYNA and KYN in eye fluid for the retrospective case series which included 28 patients suffering from cataracts and diabetes (n = 8). The experimental data was subjected to statistical analysis. The Mann-Whitney U-test revealed clear differences in the level of TRP catabolites and the ratios of TRP/KYN representing the activities of specific enzyme of kynurenine pathway in examined groups of patients. A level of probability p < 0.05 was used throughout a paper to denote statistically significant differences between the groups. PMID- 30453652 TI - Not Led by the Nose: Volatiles from Undamaged Eucalyptus Hosts Do Not Influence Psyllid Orientation. AB - Psyllids (Hemiptera: Psylloidea) are small sucking insects with high host plant specificity. Despite the primitive olfactory system of psyllids, some species have been suggested to rely on host plant volatiles (HPVs) for seasonal migration between summer deciduous hosts and winter coniferous hosts. Similarly, enhanced attraction of psyllid vectors has been observed as a result of the manipulation of host odors by plant pathogens. As yet, there are no studies of olfaction in psyllids that utilize evergreen eucalypt hosts. We investigated the behavioral responses of adults of four Eucalyptus-feeding psyllids-Ctenarytaina eucalypti, C. bipartita, Anoeconeossa bundoorensis and Glycaspis brimblecombei-to their respective HPVs in Y-tube olfactometer bioassays. We also used existing physiological data for C. eucalypti to investigate potential olfactory tuning that may modulate the preference for morphologically juvenile leaves over morphologically adult leaves. Although adult C. eucalypti were consistently repelled by HPVs from damaged host leaves, none of the species exhibited positive chemotaxis to HPVs from undamaged leaves. Surprisingly, G. brimblecombei was repelled by HPVs from undamaged host leaves. Our findings provide little support for a significant role of olfaction in host location by Eucalyptus-feeding psyllids. We propose a number of ecological hypotheses to explain these unexpected findings. PMID- 30453654 TI - Is the Response of Tumours Dependent on the Dietary Input of Some Amino Acids or Ratios among Essential and Non-Essential Amino Acids? All That Glitters Is Not Gold. AB - Energy production is the main task of the cancer cell metabolism because the costs of duplicating are enormous. Although energy is derived in cells by dismantling the carbon-to-carbon bonds of any macronutrient, cancer nutritional needs for energetic purposes have been studied primarily as being dependent on glycolysis. Since the end of the last century, the awareness of the dependence of cancer metabolism on amino acids not only for protein synthesis but also to match energy needs has grown. The roles of specific amino acids such as glutamine, glycine and serine have been explored in different experimental conditions and reviewed. Moreover, epidemiological evidence has revealed that some amino acids used as a supplement for therapeutic reasons, particularly the branched-chain ones, may reduce the incidence of liver cancer and a specific molecular mechanism has been proposed as functional to their protective action. By contrast and puzzling clinicians, the metabolomic signature of some pathologies connected to an increased risk of cancer, such as prolonged hyperinsulinemia in insulin resistant patients, is identified by elevated plasma levels of the same branched chain amino acids. Most recently, certain formulations of amino acids, deeply different from the amino acid compositions normally present in foods, have shown the power to master cancer cells epigenetically, slowing growth or driving cancer cells to apoptotic death, while being both beneficial for normal cell function and the animal's health and lifespan. In this review, we will analyze and try to disentangle some of the many knots dealing with the complexities of amino acid biology and links to cancer metabolism. PMID- 30453655 TI - The Differential Effect of Ego-Resiliency on the Relationship between Emotional Labor and Salivary Cortisol Level in Bank Clerks. AB - Elevated stress levels in emotional laborers has been documented in a number of studies. To minimize the negative effects of stress, the need to examine potential protective factors has been highlighted. The primary purpose of this study was to investigate the differential moderating effect of ego-resiliency on the relationship between emotional labor and salivary cortisol level by comparing two groups of bank clerks deemed to experience different degree of emotional labor. Twenty-four bank clerks working in regional branch offices who provided face-to-face customer service (customer service group) and 33 administrative-duty bank clerks who work without face-to-face customer service (administrative work group) were recruited to participate in the study. Participants were asked to draw saliva into a specimen tube at an identical time during a work day and complete self-report scales measuring emotional labor and ego-resiliency. Hierarchical multiple regression analyses were conducted to examine the interaction effect of ego-resiliency on the relationship between emotional labor and salivary cortisol level by controlling for gender, age and education level as covariates. The results demonstrated that the degree of emotional labor reported by the customer service group was higher than that of the administrative work group. Furthermore, ego-resiliency moderated the relationship between emotional labor and cortisol levels in the customer service group but not in the administrative work group. The implications and limitations of this study are discussed along with suggestions for future research. PMID- 30453656 TI - Thrombolysis Enhancing by Magnetic Manipulation of Fe3O4 Nanoparticles. AB - In this paper, an effective method of accelerating urokinase-administrated thrombolysis through a rotating magnetic field (RMF) of guided magnetic nanoparticles (NPs) in the presence of low-dose urokinase is proposed. The dispersed Fe3O4 NPs mixed with urokinase were injected into microfluidic channels occluded by thrombus prepared in vitro. These magnetic NPs aggregated into elongated clusters under a static magnetic field, and were then driven by the RMF. The rotation of Fe3O4 aggregates produced a vortex to enhance the diffusion of urokinase to the surface of the thrombus and accelerate its dissolution. A theoretical model based on convective diffusion was constructed to describe the thrombolysis mechanism. The thrombus lysis speed was determined according to the change of the thrombus dissolution length with time in the microfluidic channel. The experimental results showed that the thrombolysis speed with rotating magnetic NPs is significantly increased by nearly two times compared with using the same dose of pure urokinase. This means that the magnetically-controlled NPs approach provides a feasible way to achieve a high thrombolytic rate with low dose urokinase in use. PMID- 30453657 TI - Fibrin-Modified Cellulose as a Promising Dressing for Accelerated Wound Healing. AB - Dermal injuries and chronic wounds usually regenerate with scar formation. Successful treatment without scarring might be achieved by pre-seeding a wound dressing with cells. We aimed to prepare a wound dressing fabricated from sodium carboxymethylcellulose (Hcel(r) NaT), combined with fibrin and seeded with dermal fibroblasts in vitro. We fabricated the Hcel(r) NaT in a porous and homogeneous form (P form and H form, respectively) differing in structural morphology and in the degree of substitution of hydroxyl groups. Each form of Hcel(r) NaT was functionalized with two morphologically different fibrin structures to improve cell adhesion and proliferation, estimated by an MTS assay. Fibrin functionalization of the Hcel(r) NaT strongly enhanced colonization of the material with human dermal fibroblasts. Moreover, the type of fibrin structures influenced the ability of the cells to adhere to the material and proliferate on it. The fibrin mesh filling the void spaces between cellulose fibers better supported cell attachment and subsequent proliferation than the fibrin coating, which only enwrapped individual cellulose fibers. On the fibrin mesh, the cell proliferation activity on day 3 was higher on the H form than on the P form of Hcel(r) NaT, while on the fibrin coating, the cell proliferation on day 7 was higher on the P form. The Hcel(r) NaT wound dressing functionalized with fibrin, especially when in the form of a mesh, can accelerate wound healing by supporting fibroblast adhesion and proliferation. PMID- 30453658 TI - Students' Willingness to Intervene in Bullying: Direct and Indirect Associations with Classroom Cohesion and Self-Efficacy. AB - Although school climate and self-efficacy have received some attention in the literature, as correlates of students' willingness to intervene in bullying, to date, very little is known about the potential mediating role of self-efficacy in the relationship between classroom climate and students' willingness to intervene in bullying. To this end, the present study analyzes whether the relationship between classroom cohesion (as one facet of classroom climate) and students' willingness to intervene in bullying situations is mediated by self-efficacy in social conflicts. This study is based on a representative stratified random sample of two thousand and seventy-one students (51.3% male), between the ages of twelve and seventeen, from twenty-four schools in Germany. Results showed that between 43% and 48% of students reported that they would not intervene in bullying. A mediation test using the structural equation modeling framework revealed that classroom cohesion and self-efficacy in social conflicts were directly associated with students' willingness to intervene in bullying situations. Furthermore, classroom cohesion was indirectly associated with higher levels of students' willingness to intervene in bullying situations, due to self efficacy in social conflicts. We thus conclude that: (1) It is crucial to increase students' willingness to intervene in bullying; (2) efforts to increase students' willingness to intervene in bullying should promote students' confidence in dealing with social conflicts and interpersonal relationships; and (3) self-efficacy plays an important role in understanding the relationship between classroom cohesion and students' willingness to intervene in bullying. Recommendations are provided to help increase adolescents' willingness to intervene in bullying and for future research. PMID- 30453659 TI - A Time Series of Water Column Distributions and Sinking Particle Flux of Pseudo Nitzschia and Domoic Acid in the Santa Barbara Basin, California. AB - Water column bulk Pseudo-nitzschia abundance and the dissolved and particulate domoic acid (DA) concentrations were measured in the Santa Barbara Basin (SBB), California from 2009-2013 and compared to bulk Pseudo-nitzschia cell abundance and DA concentrations and fluxes in sediment traps moored at 147 m and 509 m. Pseudo-nitzschia abundance throughout the study period was spatially and temporally heterogeneous (<200 cells L-1 to 3.8 * 106 cells L-1, avg. 2 * 105 +/- 5 * 105 cells L-1) and did not correspond with upwelling conditions or the total DA (tDA) concentration, which was also spatially and temporally diverse (<1.3 ng L-1 to 2.2 * 105 ng L-1, avg. 7.8 * 103 +/- 2.2 * 104 ng L-1). We hypothesize that the toxicity is likely driven in part by specific Pseudo-nitzschia species as well as bloom stage. Dissolved (dDA) and particulate (pDA) DA were significantly and positively correlated (p < 0.01) and both comprised major components of the total DA pool (pDA = 57 +/- 35%, and dDA = 42 +/- 35%) with substantial water column concentrations (>1000 cells L-1 and tDA = 200 ng L-1) measured as deep as 150 m. Our results highlight that dDA should not be ignored when examining bloom toxicity. Although water column abundance and pDA concentrations were poorly correlated with sediment trap Pseudo-nitzschia abundance and fluxes, DA toxicity is likely associated with senescent blooms that rapidly sink to the seafloor, adding another potential source of DA to benthic organisms. PMID- 30453661 TI - Multielemental Analysis Associated with Chemometric Techniques for Geographical Origin Discrimination of Tea Leaves (Camelia sinensis) in Guizhou Province, SW China. AB - This study aimed to construct objective and accurate geographical discriminant models for tea leaves based on multielement concentrations in combination with chemometrics tools. Forty mineral elements in 87 tea samples from three growing regions in Guizhou Province (China), namely Meitan and Fenggang (MTFG), Anshun (AS) and Leishan (LS) were analyzed. Chemometrics evaluations were conducted using a one-way analysis of variance (ANOVA), principal component analysis (PCA), linear discriminant analysis (LDA), and orthogonal partial least squares discriminant analysis (OPLS-DA). The results showed that the concentrations of the 28 elements were significantly different among the three regions (p < 0.05). The correct classification rates for the 87 tea samples were 98.9% for LDA and 100% for OPLS-DA. The variable importance in the projection (VIP) values ranged between 1.01-1.73 for 11 elements (Sb, Pb, K, As, S, Bi, U, P, Ca, Na, and Cr), which can be used as important indicators for geographical origin identification of tea samples. In conclusion, multielement analysis coupled with chemometrics can be useful for geographical origin identification of tea leaves. PMID- 30453660 TI - Gut Permeability Might be Improved by Dietary Fiber in Individuals with Nonalcoholic Fatty Liver Disease (NAFLD) Undergoing Weight Reduction. AB - (1) Introduction: Zonulin (ZO) has been proposed as a marker of intestinal permeability. Only a few studies have analyzed to date how diet influences the serum concentration of ZO among patients with non-alcoholic fatty liver disease (NAFLD). We performed a six-month dietetic intervention to evaluate the association between fiber intake and ZO concentration in 32 individuals with NAFLD. (2) Methods: Fiber content in the diet was estimated by Food Frequency Questionnaire (FFQ) and by analyzing 72-h nutritional diaries. ZO concentrations in serum were measured before and after the intervention by immunoenzymatic assay (ELISA). Fatty liver was quantified using the Hamaguchi score before and after the dietetic intervention. (3) Results: During the intervention, the dietary fiber intake increased from 19 g/day to the 29 g/day concomitant with an increase in the frequency of fiber consumption. All patients experienced significant (all p < 0.05) improvements in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGTP) activities. We also detected decreased serum triglycerides (p = 0.036), homeostatic model assessment insulin resistance (HOMA-IR (p = 0.041) and insulin content (p = 0.34), and improvement of fatty liver status according to the Hamaguchi score (p = 0.009). ZO concentration in serum decreased by nearly 90% (7.335 +/- 13.492 vs. 0.507 +/- 0.762 ng/mL, p = 0.001) and correlated with the amount of dietary fiber intake (p = 0.043) as well as the degree of fatty liver (p = 0.037). (4) Conclusion: Increasing nutritional fiber results in reduced serum ZO levels, reduced liver enzymes and improved hepatic steatosis in patients with NAFLD, possibly by altering intestinal permeability. Increased dietary fiber intake should be recommended in patients with NAFLD. PMID- 30453662 TI - Plasmonic Metasurface Absorber Based on Electro-Optic Substrate for Energy Harvesting. AB - A highly efficient and broad light absorber capable of wide-angle absorption in the visible and near infrared range is presented and numerically investigated for energy harvesting in a simple geometry. According to the calculated results, the proposed device has a peak absorption level of about 99.95%. The actual absorption efficiency is 76.35%, which is approaching that of complex multilayer absorbers with 88 layers working in the wavelength range of 300 nm to 2000 nm. The electro-optic material has the potential of shifting the absorption peak position, compensating fabrication errors and thus reducing the fabrication technique difficulties. Also, the high electro-optic tunability can be used for filters, infrared detection, and imaging applications. More directly, the proposed absorber can be potentially deployed in solar cells and solar thermals. PMID- 30453664 TI - Designing a Formulation of the Nootropic Drug Aniracetam Using 2-Hydroxypropyl beta-Cyclodextrin Suitable for Parenteral Administration. AB - The nootropic drug aniracetam is greatly limited in its application by low aqueous solubility and a poor oral bioavailability. The primary aim of this study was to design a parenteral formulation of aniracetam that can be administered intravenously. Complexation of aniracetam with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated as a strategy to enhance solubility. A phase solubility analysis was performed to quantify the extent of improvement. An 819% increase in the solubility of aniracetam was obtained, reaching 36.44 mg/mL. This marked increase enables aniracetam to exist in an aqueous solvent at levels sufficient for parenteral dosing. A stability test was then devised using a design of experiment approach. The aniracetam-HP-beta-CD formulation was subjected to different relative humidity and temperature and cyclodextrin concentrations over a 12-week period. Key changes in FTIR vibrational frequencies suggest the benzene moiety of aniracetam was introduced into the hydrophobic cavity of HP-beta-CD. These results are highly supportive of the formation of a predictable 1:1 molar stoichiometric inclusion complex, explaining the improvement seen in physiochemical properties of aniracetam following formulation with HP-beta-CD. This novel formulation of aniracetam suitable for parenteral administration will have utility in future studies to further elucidate the pharmacokinetics of this drug. PMID- 30453663 TI - Willingness to Participate and Associated Factors in a Zika Vaccine Trial in Indonesia: A Cross-Sectional Study. AB - One of the crucial steps during trials for Zika and other vaccines is to recruit participants and to understand how participants' attitudes and sociodemographic characteristics affect willingness to participate (WTP). This study was conducted to assess WTP, its explanatory variables, and the impact of financial compensation on WTP in Indonesia. A health facility-based cross-sectional study was conducted in eleven regencies in the Aceh and West Sumatra provinces of Indonesia. Participants were recruited via a convenience sampling method and were interviewed. The associations between explanatory variables and WTP were assessed using a two-step logistic regression analysis. A total of 1,102 parents were approached, and of these 956 (86.8%) completed the interview and were included in analysis. Of those, 144 (15.1%) were willing to participate in a Zika vaccine trial without a financial compensation. In the multivariate analysis, WTP was tied to an age of more than 50 years old, compared to 20-29 years (odds ratio (OR): 5.0; 95% confidence interval (CI): 2.37-10.53), to being female (OR: 2.20; 95% CI: 1.11-4.37), and to having heard about Zika (OR: 2.41; 95% CI: 1.59-3.65). Participants' WTP increased gradually with higher financial compensation. The rate of WTP increased to 62.3% at the highest offer (US$ 350.4), and those who were still unwilling to participate (37.7%) had a poorer attitude towards childhood vaccination. This study highlights that pre-existing knowledge about Zika and attitudes towards childhood vaccination are important in determining community members being willing to participate in a vaccine trial. Financial incentives are still an important factor to enhance participant recruitment during a vaccine trial. PMID- 30453666 TI - Oxygen Monitoring Equipment for Sewage-Sludge Composting and Its Application to Aeration Optimization. AB - Oxygen is an important parameter for organic-waste composting, and continuous control of the oxygen in a composting pile may be beneficial. The oxygen consumption rate can be used to measure the degree of biological oxidation and decomposition of organic matter. However, without having a real-time online device to monitor oxygen levels in the composting pile, the adjustment and optimization of the composting process cannot be directly implemented. In the present study, we researched and developed such a system, and then tested its stability, reliability, and characteristics. The test results showed that the equipment was accurate and stable, and produced good responses with good repeatability. The equilibrium time required to detect oxygen concentration in the composting pile was 50 s, and the response time for oxygen detection was less than 2 s. The equipment could monitor oxygen concentration online and in real time to optimize the aeration strategy for the compost depending on the concentration indicated by the oxygen-measuring equipment. PMID- 30453665 TI - The Use of Glycomacropeptide in Patients with Phenylketonuria: A Systematic Review and Meta-Analysis. AB - In phenylketonuria (PKU), synthetic protein derived from L-amino acids (AAs) is essential in a low-phenylalanine (Phe) diet. Glycomacropeptide (GMP), an intact protein, is very low in Phe in its native form. It has been modified and adapted for PKU to provide an alternative protein source through supplementation with rate-limiting amino acids (GMP-AAs), although it still contains residual Phe. This review aims to systematically evaluate published intervention studies on the use of GMP-AAs in PKU by considering its impact on blood Phe control (primary aim) and changes in tyrosine control, nutritional biomarkers, and patient acceptability or palatability (secondary aims). Four electronic databases were searched for articles published from 2007 to June 2018. Of the 274 studies identified, only eight were included. Bias risk was assessed and a quality appraisal of the body of evidence was completed. A meta-analysis was performed with two studies with adequate comparable methodology which showed no differences between GMP-AAs and AAs for any of the interventions analysed. This work underlines the scarcity and nature of studies with GMP-AAs interventions. All were short-term with small sample sizes. There is a need for better-designed studies to provide the best evidence-based recommendations. PMID- 30453667 TI - Genome-Wide Identification of Flowering-Time Genes in Brassica Species and Reveals a Correlation between Selective Pressure and Expression Patterns of Vernalization-Pathway Genes in Brassica napus. AB - Flowering time is a key agronomic trait, directly influencing crop yield and quality. Many flowering-time genes have been identified and characterized in the model plant Arabidopsis thaliana; however, these genes remain uncharacterized in many agronomically important Brassica crops. In this study, we identified 1064, 510, and 524 putative orthologs of A. thaliana flowering-time genes from Brassica napus, Brassica rapa, and Brassica oleracea, respectively, and found that genes involved in the aging and ambient temperature pathways were fewer than those in other flowering pathways. Flowering-time genes were distributed mostly on chromosome C03 in B. napus and B. oleracea, and on chromosome A09 in B. rapa. Calculation of non-synonymous (Ka)/synonymous substitution (Ks) ratios suggested that flowering-time genes in vernalization pathways experienced higher selection pressure than those in other pathways. Expression analysis showed that most vernalization-pathway genes were expressed in flowering organs. Approximately 40% of these genes were highly expressed in the anther, whereas flowering-time integrator genes were expressed in a highly organ-specific manner. Evolutionary selection pressures were negatively correlated with the breadth and expression levels of vernalization-pathway genes. These findings provide an integrated framework of flowering-time genes in these three Brassica crops and provide a foundation for deciphering the relationship between gene expression patterns and their evolutionary selection pressures in Brassica napus. PMID- 30453669 TI - Polyphenol Extracts from Red Wine and Grapevine: Potential Effects on Cancers. AB - Wine has been popular worldwide for many centuries and currently remains an important component of our diet. Scientific interest in wine and its health effects has grown considerably since the 1990s with the emergence of the "French Paradox" concept, correlating moderate wine consumption, a characteristic of the Mediterranean diet, and low incidence of coronary heart diseases. Since then, the positive effects on health, health promotion, disease prevention, and disease prognosis of moderate wine consumption, in particular red wine, have been attributed to its polyphenolic compounds such as resveratrol, quercetin, and other flavonoids acting as antioxidants. Several epidemiological, in vivo and in vitro, studies have reported that moderate red wine or red wine polyphenolic extract consumption may be active in the prevention and treatment of chronic diseases such as cardiovascular disease, metabolic syndrome, degenerative pathologies, and cancer. The aim of this review is to summarize the current findings about the effects of red wine polyphenols on cancer and to discuss how the polyphenolic composition of red wine may influence its chemopreventive properties. PMID- 30453668 TI - Genome-Wide Scan for Copy Number Alteration Association with Relapse-Free Survival in Colorectal Cancer with Liver Metastasis Patients. AB - Predicting a patient's risk of recurrence after the resection of liver metastases from colorectal cancer is critical for evaluating and selecting therapeutic approaches. Clinical and pathologic parameters have shown limited accuracy thus far. Therefore, we combined the clinical status with a genomic approach to stratify relapse-free survival in colorectal cancer liver metastases patients. To identify new molecular and genetic signatures specific to colorectal cancer with liver metastasis (CRCLM) patients, we conducted DNA copy number profiling on a cohort of 21 Taiwanese CRCLM patients using a comparative genomic hybridization (CGH) array. We identified a three-gene signature based on differential copy number alteration between patients with different statuses of (1) recurrence and (2) synchronous metastasis. In relapse hotspot regions, only three genes (S100PBP, CSMD2, and TGFBI) were significantly associated with the synchronous liver metastasis factor. A final set of three genes-S100PBP, CSMD2, TGFBI significantly predicted relapse-free survival in our cohort (p = 0.04) and another CRCLM cohort (p = 0.02). This three-gene signature is the first genomic signature validated for relapse-free survival in post-hepatectomy CRCLM patients. Our three-gene signature was developed using a whole-genome CGH array and has a good prognostic position for the relapse-free survival of CRCLM patients after hepatectomy. PMID- 30453670 TI - Protein Structural Dynamics of Wild-Type and Mutant Homodimeric Hemoglobin Studied by Time-Resolved X-Ray Solution Scattering. AB - The quaternary transition between the relaxed (R) and tense (T) states of heme binding proteins is a textbook example for the allosteric structural transition. Homodimeric hemoglobin (HbI) from Scapharca inaequivalvis is a useful model system for investigating the allosteric behavior because of the relatively simple quaternary structure. To understand the cooperative transition of HbI, wild-type and mutants of HbI have been studied by using time-resolved X-ray solution scattering (TRXSS), which is sensitive to the conformational changes. Herein, we review the structural dynamics of HbI investigated by TRXSS and compare the results of TRXSS with those of other techniques. PMID- 30453671 TI - Predictors of Exercise Capacity in Patients with Hypertrophic Obstructive Cardiomyopathy. AB - Hypertrophic obstructive cardiomyopathy (HOCM) patients exhibit compromised peak exercise capacity (VO2peak). Importantly, severely reduced VO2peak is directly related to increased morbidity and mortality in these patients. Therefore, we sought to determine clinical predictors of VO2peak in HOCM patients. HOCM patients who performed symptom-limited cardiopulmonary exercise testing between 1995 and 2016 were included for analysis. Peak VO2 was reported as absolute peak VO2, indexed to body weight and analyzed as quartiles, with quartile 1 representing the lowest VO2peak. Step-wise regression models using demographic features and clinical and physiologic characteristics were created to determine predictors of HOCM patients with the lowest VO2peak. We included 1177 HOCM patients (age: 53 +/- 14 years; BMI: 24 +/- 12 kg/m2) with a VO2peak of 18.0 +/- 5.6 mL/kg/min. Significant univariate predictors of the lowest VO2peak included age, female sex, New York Health Association (NYHA) class, BMI, left atrial volume index, E/e', E/A, hemoglobin, N-terminal pro b-type natriuretic peptide (NT-proBNP), and a history of diabetes, hypertension, stroke, atrial fibrillation, or coronary artery disease. Independent predictors of the lowest VO2peak included age (OR, CI: 1.03, 1.02-1.06; p < 0.0001), women (4.66, 2.94 7.47; p = 0.001), a history of diabetes (2.05, 1.17-3.60; p = 0.01), BMI (0.94, 0.92-0.96; p < 0.0001), left atrial volume index (1.07, 1.05-1.21; p = 0.04), E/e' (1.05, 1.01-1.08; p = 0.004), hemoglobin (0.76, 0.65-0.88; p = 0.0004), and NT-proBNP (1.72, 1.42-2.11; p < 0.0001). These findings demonstrate that demographic factors (i.e., age and sex), comorbidities (e.g., diabetes and obesity), echocardiography indices, and biomarkers (e.g., hemoglobin and NT proBNP) are predictive of severely compromised VO2peak in HOCM patients. PMID- 30453673 TI - Prestress Monitoring of a Steel Strand in an Anchorage Connection Using Piezoceramic Transducers and Time Reversal Method. AB - Steel strands are widely used in cable stay or suspension bridges. The safety and stability of steel strands are important issues during their operation period. Steel strand is subjected to various types of prestress loss which loosens the wedge anchorage system, negatively impacting the stability of the structure and even leading to severe accidents. In this paper, the authors propose a time reversal (TR) method to monitor the looseness status of the wedge anchorage system by using stress wave based active sensing. As a commonly used piezoceramic material, Lead Zirconate Titanate (PZT) with a strong piezoelectric effect is employed. In the proposed active sensing approach, PZT patches are used as sensors and actuators to monitor the steel strand looseness status. One PZT patch is bonded to the steel strand, one PZT patch is bonded to the wedges, and another PZT patch is bonded to the barrel. There are three different interfaces of the wedge anchorage system to monitor the steel strand looseness status. In the first method, the PZT patch on the steel strand is used as an actuator to generate a stress wave and the PZT patch on the wedge is used as a sensor to detect the propagated waves through the wedge anchorage system. In the second method, the PZT patch on the steel strand is used as an actuator to generate a stress wave and the PZT patch on the barrel is used as a sensor to detect the propagated waves through the wedge anchorage system. In the third method, the PZT patch on the wedges is used as an actuator to generate a stress wave and the PZT patches on the barrel is used as a sensor to detect the propagated waves through the wedge anchorage system, of which the looseness will directly impact the stress wave propagation. The TR method is utilized to analyze the transmitted signal between PZT patches through the wedge anchorage system. Compared with the peak values of the TR focused signals, it can be found that the peak value increases as the wedge anchorage system tightness increases. Therefore, the peak value of the TR focused signal can be used to monitor the tightness of the steel strand. In addition, the experimental results demonstrated the time reversal method's reliability, sensitivity and anti-noise property. PMID- 30453672 TI - GPX1 Localizes to the Nucleus in Prostate Epithelium and its Levels are not Associated with Prostate Cancer Recurrence. AB - Glutathione peroxidase 1 (GPX1) is an extensively studied selenium-dependent protein that reduces hydrogen and lipid peroxides to water. Because of its antioxidant function and its responsiveness to dietary intakes of selenium, an essential trace element whose levels are inversely associated with prostate cancer risk, GPX1 levels were assessed in a prostate cancer tissue microarray, comparing cases of recurrent prostate cancer following prostatectomy to non recurrent controls. While GPX1 is generally considered as a protein that resides in both the cytoplasm and mitochondria, we detected strong nuclear staining by immunofluorescence using GPX1-specific antibodies. Nuclear localization of GPX1 was also observed in both primary prostate epithelial cells and the immortalized prostate-derived cell line RWPE-1, but not in LNCaP or PC3 prostate tumor-derived cell lines. Quantification of GPX1 levels in the entire cell, the cytoplasm, and the nucleus did not indicate any association of either its levels or subcellular distribution with prostate cancer recurrence. While GPX1 levels may not have an impact on survival among men with prostate cancer, the data indicates that this extensively characterized protein may have a novel function in the nucleus of prostate epithelial cells. PMID- 30453674 TI - Resource-Efficient Pet Dog Sound Events Classification Using LSTM-FCN Based on Time-Series Data. AB - The use of IoT (Internet of Things) technology for the management of pet dogs left alone at home is increasing. This includes tasks such as automatic feeding, operation of play equipment, and location detection. Classification of the vocalizations of pet dogs using information from a sound sensor is an important method to analyze the behavior or emotions of dogs that are left alone. These sounds should be acquired by attaching the IoT sound sensor to the dog, and then classifying the sound events (e.g., barking, growling, howling, and whining). However, sound sensors tend to transmit large amounts of data and consume considerable amounts of power, which presents issues in the case of resource constrained IoT sensor devices. In this paper, we propose a way to classify pet dog sound events and improve resource efficiency without significant degradation of accuracy. To achieve this, we only acquire the intensity data of sounds by using a relatively resource-efficient noise sensor. This presents issues as well, since it is difficult to achieve sufficient classification accuracy using only intensity data due to the loss of information from the sound events. To address this problem and avoid significant degradation of classification accuracy, we apply long short-term memory-fully convolutional network (LSTM-FCN), which is a deep learning method, to analyze time-series data, and exploit bicubic interpolation. Based on experimental results, the proposed method based on noise sensors (i.e., Shapelet and LSTM-FCN for time-series) was found to improve energy efficiency by 10 times without significant degradation of accuracy compared to typical methods based on sound sensors (i.e., mel-frequency cepstrum coefficient (MFCC), spectrogram, and mel-spectrum for feature extraction, and support vector machine (SVM) and k-nearest neighbor (K-NN) for classification). PMID- 30453676 TI - Detecting Incremental Frequent Subgraph Patterns in IoT Environments. AB - As graph stream data are continuously generated in Internet of Things (IoT) environments, many studies on the detection and analysis of changes in graphs have been conducted. In this paper, we propose a method that incrementally detects frequent subgraph patterns by using frequent subgraph pattern information generated in previous sliding window. To reduce the computation cost for subgraph patterns that occur consecutively in a graph stream, the proposed method determines whether subgraph patterns occur within a sliding window. In addition, subgraph patterns that are more meaningful can be detected by recognizing only the patterns that are connected to each other via edges as one pattern. In order to prove the superiority of the proposed method, various performance evaluations were conducted. PMID- 30453678 TI - Dynamic Cipher Puzzle for Efficient Broadcast Authentication in Wireless Sensor Networks. AB - The use of signature-based broadcast authentication for code and data dissemination in wireless sensor networks (WSNs) cannot be avoided. It increases security but requires high computation. Adversaries can exploit the latter condition as an opportunity to send many false signatures. Filtering methods can overcome this vulnerability. Cipher Puzzle is a filtering method that has low storage overhead along with high security, especially against denial of service (DoS) attacks. However, its number of hash iterations cannot be bounded, which causes sender-side delay. This paper proposes a Dynamic Cipher Puzzle (DCP), which uses a threshold function to limit the number of hash iterations. Hence, time at the sender-side can be used more efficiently. Besides, its dynamic puzzle strength increases the obscurity of the transmitted packet. Simulation and experimental results were analyzed with Arduino 2560. The theoretical results show that the quadratic function outperformed the compared methods. The scheme decreased sender-side delay by 94.6% with a guarantee of zero solution probability in 1.728 * 10 - 13 . The experimental results show that the consumption of resources at the sensor node increases with an acceptable value. Moreover, DCP increases the complexity for the attacker to implement probability and signature-based DoS attacks. PMID- 30453675 TI - Borderline Personality Disorder (BPD): In the Midst of Vulnerability, Chaos, and Awe. AB - Borderline personality disorder (BPD) is a chronic psychiatric disorder characterized by pervasive affective instability, self-image disturbances, impulsivity, marked suicidality, and unstable interpersonal relationships as the core dimensions of psychopathology underlying the disorder. Across a wide range of situations, BPD causes significant impairments. Patients with BPD suffer considerable morbidity and mortality compared with other populations. Although BPD is more widely studied than any other personality disorder, it is not understood sufficiently. This paper briefly reviews the recent evidence on the prevalence, etiology, comorbidity, and treatment approaches of borderline personality disorder (BPD) by examining published studies, and aims to offer a more coherent framework for the understanding and management of borderline personality disorder. PMID- 30453679 TI - Health Risk in Urbanizing Regions: Examining the Nexus of Infrastructure, Hygiene and Health in Tashkent Province, Uzbekistan. AB - Worldwide, development agencies have increased their investments in water supply and sanitation as a "powerful preventive medicine" to address infectious diseases. These interventions have focused on on-site technical interventions or social engineering approaches, emulating the result-based targets of the development goals. Against this backdrop, the study examines the following research question: What is the role of socio-cultural backgrounds, housing characteristics, and environmental hygiene practices in addressing water transmitted diseases in the Tashkent province of Uzbekistan. In a country where public statistics and official maps are rarely accessible, and research is restrictive, the study carried out a household survey using open data kit (ODK) between July and October 2015 in Olmalik, an industrial district, and the Kibray urbanizing district in the province. The findings reveal that demographic factors, poor sanitation practices, housing characteristics, and social behaviors are key predictors of water-transmitted diseases in the two districts. In the industrial township, poor housing, larger household size, and poor excreta disposal habits increased the occurrence of diseases, while in urbanizing districts, higher household size, frequently eating out, and access to public taps significantly increased the occurrence of water-transmitted diseases. The study, which was carried out in a challenging institutional environment, highlights the need for Uzbekistan to focus their policies on environmental hygiene, demographic factors and social behavior as key interventions rather than merely on on-site drinking water and sanitation interventions. PMID- 30453677 TI - Investigation of Different Molecular Weight Fucoidan Fractions Derived from New Zealand Undaria pinnatifida in Combination with GroA Therapy in Prostate Cancer Cell Lines. AB - Fucoidan, a sulfated polysaccharide extracted from brown seaweeds, has been shown to possess various antioxidant, anticoagulant, antiviral, and anticancer functions. In this study, we focused on low molecular weight fucoidan (LMWF) which was extracted from New Zealand Undaria pinnatifida, and investigated its anti-proliferative effects, combined with a quadruplex-forming oligonucleotide aptamer (GroA, AS1411), a powerful cell surface Nucleolin inhibitor, in prostate cancer cells. We examined LMWF (<10 kDa) and compared it with laboratory grade Fucoidan purchased from Sigma (FS), all extracted from the same seaweed species U. pinnatifida. We found that LMWF significantly improved the anti-proliferative effect of GroA, as it decreased cancer cell growth and viability and increased cell death. This research may provide the foundation for LMWF to be used against prostate cancers as a supplement therapy in combination with other therapeutic agents. PMID- 30453680 TI - Released Volatile Organic Compounds in Southern Yellow Pine before and after Heat Treatment. AB - As the main material in indoor furniture, southern yellow pine (Pinus spp.) releases volatile organic compounds (VOCs) into the environment during use. To better understand variations in the contents of VOCs in southern yellow pine before and after heat treatment, this study conducts dry heat treatment on southern yellow pine at 140 degrees C and 220 degrees C. Headspace solid phase micro-extraction was used to extract VOCs from southern yellow pine. The VOCs of southern yellow pine before and after heat treatment were identified via gas chromatography-mass spectrometry, and chemical component differences were characterized via Fourier transform infrared spectroscopy. Results reveal 86 VOCs in pure southern yellow pine, including alcohols, aromatics, acids, aldehydes, alkanes, alkenes, and some trace compounds (e.g., furans, ketones, phenols, and esters). With an increase in heat-treatment temperature, the contents of alkanes increased, whereas those of alcohols and alkenes decreased. The contents of aromatics, acids, and aldehydes were highest when heat treated at 140 degrees C. At 220 degrees C, the total contents of key VOCs in southern yellow pine were lowest. PMID- 30453681 TI - Synthesis of Pyridazine Derivatives by Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their Optical and Electronic Properties through Experimental and Theoretical Studies. AB - A series of pi-conjugated molecules, based on pyridazine and thiophene heterocycles 3a-e, were synthesized using commercially, or readily available, coupling components, through a palladium catalyzed Suzuki-Miyaura cross-coupling reaction. The electron-deficient pyridazine heterocycle was functionalized by a thiophene electron-rich heterocycle at position six, and different (hetero)aromatic moieties (phenyl, thienyl, furanyl) were functionalized with electron acceptor groups at position three. Density Functional Theory (DFT) calculations were carried out to obtain information on the conformation, electronic structure, electron distribution, dipolar moment, and molecular nonlinear response of the synthesized push-pull pyridazine derivatives. Hyper Rayleigh scattering in 1,4-dioxane solutions, using a fundamental wavelength of 1064 nm, was used to evaluate their second-order nonlinear optical properties. The thienylpyridazine functionalized with the cyano-phenyl moiety exhibited the largest first hyperpolarizability (beta = 175 * 10-30 esu, using the T convention) indicating its potential as a second harmonic generation (SHG) chromophore. PMID- 30453682 TI - Effects of High vs. Low Glycemic Index of Post-Exercise Meals on Sleep and Exercise Performance: A Randomized, Double-Blind, Counterbalanced Polysomnographic Study. AB - The aim of the current study was to investigate the effect of the glycemic index of post-exercise meals on sleep quality and quantity, and assess whether those changes could affect the next day's exercise performance. Following a baseline/familiarization phase, 10 recreationally trained male volunteers (23.2 +/- 1.8 years) underwent two double-blinded, randomized, counterbalanced crossover trials. In both trials, participants performed sprint interval training (SIT) in the evening. Post-exercise, participants consumed a meal with a high (HGI) or low (LGI) glycemic index. Sleep parameters were assessed by a full night polysomnography (PSG). The following morning, exercise performance was evaluated by the countermovement jump (CMJ) test, a visual reaction time (VRT) test and a 5 km cycling time trial (TT). Total sleep time (TST) and sleep efficiency were greater in the HGI trial compared to the LGI trial (p < 0.05), while sleep onset latency was shortened by four-fold (p < 0.05) and VRT decreased by 8.9% (p < 0.05) in the HGI trial compared to the LGI trial. The performance in both 5-km TT and CMJ did not differ between trials. A moderate to strong correlation was found between the difference in TST and the VRT between the two trials (p < 0.05). In conclusion, this is the first study to show that a high glycemic index meal, following a single spring interval training session, can improve both sleep duration and sleep efficiency, while reducing in parallel sleep onset latency. Those improvements in sleep did not affect jumping ability and aerobic endurance performance. In contrast, the visual reaction time increased proportionally to sleep improvements. PMID- 30453684 TI - Characterizing the Different Effects of Zika Virus Infection in Placenta and Microglia Cells. AB - Zika virus (ZIKV) is a neuropathic virus that causes serious neurological abnormalities such as Guillain-Barre syndrome in adults and congenital Zika syndrome (CZS) in fetuses, which makes it an important concern for global human health. A catalogue of cells that support ZIKV replication, pathogenesis, and/or the persistence of the virus still remains unknown. Here, we studied the behavior of the virus in human placenta (JEG-3) and human microglia (HMC3) cell lines in order to better understand how different host tissues respond during infection. We quantified the host transcriptional response to ZIKV infection in both types of cells at 24 and 72 h post-infection. A panel of 84 genes that are involved in the innate or adaptive immune responses was used to quantify differential expression in both cell lines. HMC3 cells showed a unique set of significant differentially expressed genes (DEGs) compared with JEG-3 cells at both time points. Subsequent analysis of these data using modern pathway analysis methods revealed that the TLR7/8 pathway was strongly inhibited in HMC3 cells, while it was activated in JEG-3 cells during virus infection. The disruption of these pathways was subsequently confirmed with specific small interfering RNA (siRNA) experiments that characterize their role in the viral life cycle, and may partially explain why ZIKV infection in placental tissue contributes to extreme neurological problems in a developing fetus. PMID- 30453683 TI - Production of Omegas-6 and 9 from the Hydrolysis of Acai and Buriti Oils by Lipase Immobilized on a Hydrophobic Support. AB - This paper describes a bioprocess to obtain omegas-6 and 9 from the hydrolysis of Acai (Euterpe oleracea Martius) and Buriti (Mauritia flexuosa) oils by lipases immobilized on octyl-sepharose. For this, oils and butters were initially selected as the carbon source which resulted in higher production of lipases in Beauveria bassiana and Fusarium oxysporum cultures. The carbon source that provided secretion of lipase by B. bassiana was Acai oil, and for F. oxysporum, Bacuri butter. Lipases obtained under these conditions were immobilized on octyl sepharose, and both, the derivatives and the crude extracts were biochemically characterized. It was observed that the immobilization promoted an increase of stability in B. bassiana and F. oxysporum lipase activities at the given temperatures and pH. In addition, the immobilization promoted hyperactivation of B. bassiana and F. oxysporum lipase activities being 23.5 and 11.0 higher than free enzyme, respectively. The hydrolysis of Acai and Buriti oils by the derivatives was done in a biphasic (organic/aqueous) system, and the products were quantified in RP-HPLC. The results showed the potential of these immobilized lipases to obtain omegas-6 and 9 from Brazilian natural oils. This work may improve the enzymatic methodologies for obtaining foods and drugs enriched with fatty acids. PMID- 30453685 TI - Effects of Biochar Amendment on CO2 Emissions from Paddy Fields under Water Saving Irrigation. AB - The role of carbon pool of biochar as a method of long-term C sequestration in global warming mitigation is unclear. A two-year field study was conducted to investigate the seasonal variations of CO2 emissions from water-saving irrigation paddy fields in response to biochar amendment and irrigation patterns. Three biochar treatments under water-saving irrigation and one biochar treatment under flooding irrigation were studied, and the application rates were 0, 20, 40, and 40 t ha-1 and labeled as CI + NB (controlled irrigation and none biochar added), CI + MB (controlled irrigation and medium biochar added), CI + HB (controlled irrigation and high biochar added), and FI + HB (flood irrigation and high biochar added), respectively. Results showed that biochar application at medium rates (20 t ha-1) decreased CO2 emissions by 1.64-8.83% in rice paddy fields under water-saving irrigation, compared with the non-amendment treatment. However, the CO2 emissions from paddy fields increased by 4.39-5.43% in the CI + HB treatment, compared with CI + NB. Furthermore, the mean CO2 emissions from paddy fields under water-saving irrigation decreased by 2.22% compared with flood irrigation under the same amount of biochar application (40 t ha-1). Biochar amendment increased rice yield and water use efficiency by 9.35-36.30% and 15.1 42.5%, respectively, when combined with water-saving irrigation. The CO2 emissions were reduced in the CI + MB treatment, which then increased rice yield. The CO2 emissions from paddy fields were positively correlated with temperature. The highest value of the temperature sensitivity coefficient (Q10) was derived for the CI + MB treatment. The Q10 was higher under water-saving irrigation compared with flooding irrigation. PMID- 30453687 TI - Scutellariae Radix and Coptidis Rhizoma Improve Glucose and Lipid Metabolism in T2DM Rats via Regulation of the Metabolic Profiling and MAPK/PI3K/Akt Signaling Pathway. AB - Aim Scutellariae Radix (SR) and Coptidis Rhizoma (CR) have often been combined to cure type 2 diabetes mellitus (T2DM) in the clinical practice for over thousands of years, but their compatibility mechanism is not clear. Mitogen-activated protein kinase (MAPK) signaling pathway has been suggested to play a critical role during the process of inflammation, insulin resistance, and T2DM. This study was designed to investigate their compatibility effects on T2DM rats and explore the underlying mechanisms by analyzing the metabolic profiling and MAPK/PI3K/Akt signaling pathway. Methods The compatibility effects of SR and CR were evaluated with T2DM rats induced by a high-fat diet (HFD) along with a low dose of streptozocin (STZ). Ultra performance liquid chromatography-quadrupole time-of flight mass spectrometry (UPLC-Q-TOF/MS) was performed to discover potential biomarkers. The levels of pro-inflammatory cytokines; biochemical indexes in serum, and the activities of key enzymes related to glycometabolism in liver were assessed by ELISA kits. qPCR was applied to examine mRNA levels of key targets in MAPK and insulin signaling pathways. Protein expressions of p65; p-p65; phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); phosphorylated-PI3K (p PI3K); protein kinase B (Akt); phosphorylated Akt (p-Akt) and glucose transporter 2 (Glut2) in liver were investigated by Western blot analysis. Results Remarkably, hyperglycaemia, dyslipidemia, inflammation, and insulin resistance in T2DM were ameliorated after oral administration of SR and CR, particularly their combined extracts. The effects of SR, CR, low dose of combined extracts (LSC) and high dose of combined extracts (HSC) on pro-inflammatory cytokine transcription in T2DM rats showed that the MAPK pathway might account for the phenomenon with down-regulation of MAPK (P38 mitogen-activated protein kinases (P38), extracellular regulated protein kinases (ERK), and c-Jun N-terminal kinase (JNK)) mRNA, and protein reduction in p-P65. While mRNA levels of key targets such as insulin receptor substrate 1 (IRS1), PI3K, Akt2, and Glut2 in the insulin signaling pathway were notably up-modulated, phosphorylations of PI3K, Akt, and expression of Glut2 were markedly enhanced. Moreover, the increased activities of phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), glucose 6-phosphatase (G6Pase), and glycogen phosphorylase (GP) were highly reduced and the decreased activities of glucokinase (GK), phosphofructokinase (PFK), pyruvate kinase (PK), and glycogen synthase (GS) in liver were notably increased after treatment. Further investigation indicated that the metabolic profiles of plasma and urine were clearly improved in T2DM rats. Fourteen potential biomarkers (nine in plasma and five in urine) were identified. After intervention, these biomarkers returned to normal level to some extent. Conclusion The results showed that SR, CR, and combined extract groups were normalized. The effects of combined extracts were more remarkable than single herb treatment. Additionally, this study also showed that the metabonomics method is a promising tool to unravel how traditional Chinese medicines work. PMID- 30453686 TI - Gluten-Free Diet in Celiac Disease-Forever and for All? AB - The gluten-free diet is the only effective treatment available for celiac disease. However, it is difficult to adhere to and a closer look on the diet's implementation and indications reveals several ambiguities: Not only is there controversy on the threshold of gluten that can be tolerated in the frame of a strict gluten-free diet, but it is also unclear whether the gluten-free diet is an appropriate treatment in patient subgroups with asymptomatic or potential celiac disease. Reports from a number of research groups suggest that a certain proportion of patients may effectively develop tolerance to gluten and thus become suitable for gluten reintroduction over time. In this review, we set out to create an overview about the current state of research as regards the definition of a strict gluten-free diet in terms of the gluten thresholds considered tolerable and the indication for a gluten-free diet in the absence of histological abnormalities or symptoms. Furthermore, we discuss the concept that a gluten-free diet must be followed for life by all patients. PMID- 30453688 TI - Peculiarities of Synthesis and Properties of Lignin-Silica Nanocomposites Prepared by Sol-Gel Method. AB - The development of advanced hybrid materials based on polymers from biorenewable sources and mineral nanoparticles is currently of high importance. In this paper, we applied softwood kraft lignins for the synthesis of lignin/SiO2 nanostructured composites. We described the peculiarities of composites formation in the sol-gel process through the incorporation of the lignin into a silica network during the hydrolysis of tetraethoxysilane (TEOS). The initial activation of lignins was achieved by means of a Mannich reaction with 3-aminopropyltriethoxysilane (APTES). In the study, we present a detailed investigation of the physicochemical characteristics of initial kraft lignins and modified lignins on each step of the synthesis. Thus, 2D-NMR, 31P-NMR, size-exclusion chromatography (SEC) and dynamic light scattering (DLS) were applied to analyze the characteristics of pristine lignins and lignins in dioxan:water solutions. X-Ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) were used to confirm the formation of the lignin-silica network and characterize the surface and bulk structures of the obtained hybrids. Termogravimetric analysis (TGA) in nitrogen and air atmosphere were applied to a detailed investigation of the thermal properties of pristine lignins and lignins on each step of modification. SEM confirmed the nanostructure of the obtained composites. As was demonstrated, the activation of lignin is crucial for the sol-gel formation of a silica network in order to create novel hybrid materials from lignins and alkoxysilanes (e.g., TEOS). It was concluded that the structure of the lignin had an impact on its reactivity during the activation reaction, and consequently affected the properties of the final hybrid materials. PMID- 30453689 TI - Host Lipid Rafts Play a Major Role in Binding and Endocytosis of Influenza A Virus. AB - Influenza still remains one of the most challenging diseases, posing a significant threat to public health. Host lipid rafts play a critical role in influenza A virus (IAV) assembly and budding, however, their role in polyvalent IAV host binding and endocytosis had remained elusive until now. In the present study, we observed co-localization of IAV with a lipid raft marker ganglioside, GM1, on the host surface. Further, we isolated the lipid raft micro-domains from IAV infected cells and detected IAV protein in the raft fraction. Finally, raft disruption using Methyl-beta-Cyclodextrin revealed significant reduction in IAV host binding, suggesting utilization of host rafts for polyvalent binding on the host cell surface. In addition to this, cyclodextrin mediated inhibition of raft dependent endocytosis showed significantly reduced IAV internalization. Interestingly, exposure of cells to cyclodextrin two hours post-IAV binding showed no such reduction in IAV entry, indicating use of raft-dependent endocytosis for host entry. In summary, this study demonstrates that host lipid rafts are selected by IAV as a host attachment factors for multivalent binding, and IAV utilizes these micro-domains to exploit raft-dependent endocytosis for host internalization, a virus entry route previously unknown for IAV. PMID- 30453690 TI - Physical Activity Programming Advertised on Websites of U.S. Islamic Centers: A Content Analysis. AB - Previous research has found churches to be effective at delivering physical activity (PA) programs to their congregants. Mosques, however, have not been extensively studied. Therefore, we quantified U.S. Islamic centers' advertisement of PA programming and examined their programming characteristics. We conducted a content analysis of the websites of 773 eligible Islamic centers of which 206 centers in 32 states advertised PA programming. We categorized PA by program type: camping, fitness classes, sports, youth programs, and irregular offerings. We calculated descriptive statistics by program type for specific activity, frequency/duration/volume, participant/instructor sex, and instructor religion. Youth group (44%) and sports (23%) programs were most and least frequently advertised, respectively. Most centers (66%) that posted information on PA programming advertised only one program type. Men and Muslims taught most activities. Most activities-except for fitness classes-were advertised to a male audience. Islamic centers should offer and advertise additional PA programming especially for women-and better utilize their websites for promoting such programming. Individual Islamic centers and Islamic- and non-religion based public health agencies can utilize our findings to fashion future PA offerings. PMID- 30453691 TI - A Proteomic Approach for Understanding the Mechanisms of Delayed Corneal Wound Healing in Diabetic Keratopathy Using Diabetic Model Rat. AB - Diabetes mellitus is a widespread metabolic disorder, and long-term hyperglycemia in diabetics leads to diabetic keratopathy. In the present study, we used a shotgun liquid chromatography/mass spectrometry-based global proteomic approach using the cornea of streptozotocin-induced diabetic (STZ) rats to examine the mechanisms of delayed corneal wound healing in diabetic keratopathy. Applying a label-free quantitation method based on spectral counting, we identified 188 proteins that showed expression changes of >2.0-fold in the cornea of STZ rats. In particular, the level of lumican expression in the cornea of STZ rats was higher than that of the normal rats. In the cornea of the normal rat, the expression level of lumican was elevated during the wound healing process, and it returned to the same expression level as before cornea injury after the wound was healed completely. On the other hand, a high expression level of lumican in the cornea of STZ rats was still maintained even after the wound was healed completely. In addition, adhesion deficiency in corneal basal cells and Bowman's membrane was observed in the STZ rat. Thus, abnormally overexpressed lumican may lead to adhesion deficiency in the cornea of STZ rats. PMID- 30453692 TI - Improving the Phototherapeutic Efficiencies of Molecular and Nanoscale Materials by Targeting Mitochondria. AB - Mitochondria-targeted cancer phototherapy (PT), which works by delivering photoresponsive agents specifically to mitochondria, is a powerful strategy to improve the phototherapeutic efficiency of anticancer treatments. Mitochondria play an essential role in cellular apoptosis, and are relevant to the chemoresistance of cancer cells. Furthermore, mitochondria are a major player in many cellular processes and are highly sensitive to hyperthermia and reactive oxygen species. Therefore, mitochondria serve as excellent locations for organelle-targeted phototherapy. In this review, we focus on the recent advances of mitochondria-targeting materials for mitochondria-specific PT. The combination of mitochondria-targeted PT with other anticancer strategies is also summarized. In addition, we discuss both the challenges currently faced by mitochondria-based cancer PT and the promises it holds. PMID- 30453693 TI - Brexit and Animal Protection: Legal and Political Context and a Framework to Assess Impacts on Animal Welfare. AB - The British people voted to leave the European Union (EU) in a 2016 referendum. The United Kingdom (UK) has been a member of the EU since the Maastricht Treaty was signed in 1993 and before that a member of the European Communities (EC) since 1973. EU animal health and welfare regulations and directives have had a major impact on UK animal protection policy. Similarly, the UK has had a substantial impact on EU animal protection. Brexit represents a substantial political upheaval for animal protection policy, with the potential to impact animal welfare in the UK, EU and internationally. Brexit's impact on farmed animals will determine the overall impact of Brexit on animals. A major threat to animal welfare is from importing lower welfare products. A major opportunity is reform of UK agricultural policy to reward high welfare outside the Common Agricultural Policy (CAP). A soft Brexit, in which the UK remains in the single market and/or customs union, mitigates the threat of importing lower welfare products. A harder Brexit means threats to animal welfare are more likely to materialise. Whether threats and opportunities do materialise will depend on political considerations including decisions of key political actors. The Conservative Government delivering Brexit has a problematic relationship with animal protection. Furthermore, Brexit represents a shift to the political right, which is not associated with progressive animal protection. There is significant political support in the Conservative Party for a hard Brexit. Further research is required to investigate whether the various threats and opportunities are likely to materialise. PMID- 30453694 TI - Joint Passive Detection and Tracking of Underwater Acoustic Target by Beamforming Based Bernoulli Filter with Multiple Arrays. AB - In this paper, improved Bernoulli filtering methods are developed to deal with the problem of joint passive detection and tracking of an underwater acoustic target with multiple arrays. Three different likelihood calculation methods based on local beamforming results are proposed for the Bernoulli filter updating. Firstly, multiple peaks, including both mainlobe and sidelobe peaks, are selected to form the direction-of-arrival (DOA) measurement set, and then the Bernoulli filter is used to extract the target track. Secondly, to make full use of the informations in the beamforming output, not only the DOAs but also their intensities, the beam powers are used as the input measurement sets of the filter, and an approach based on Pearson correlation coefficient (PCC) is developed for distinguishing between signal and noise. Lastly, a hybrid method of the former two is proposed in the case of fewer then three arrays. The tracking performances of the three methods are compared in simulations and experiment. The simulations with three distributed arrays show that, compared with the DOA-based method, the beam-based method and the hybrid method can both improve the target tracking accuracy. The processing results of the shallow water experimental data collected by two arrays show that the hybrid method can achieve a better tracking performance. PMID- 30453695 TI - Industrial Waste Treatment by ETS-10 Ion Exchanger Material. AB - The aim of this project was to study the treatment of industrial waste using ETS 10 zeolite. The pollutants that must be removed were metals sourced from zinc ferrite, a processing waste derived from the use of mineral-containing zinc. The first phase of the work involved the characterization of the industrial waste, zinc ferrite, in order to deepen the knowledge regarding its nature and composition. The second phase involved the removal of the metals released by the zinc ferrite in aqueous systems using the ETS-10 phase as an ion exchanger. Different chemical and physical techniques were used: plasma mass spectrometry, X ray diffraction, scanning electron microscopy, microanalysis, and thermal analyses. A comparison between ETS-10 and commercial zeolite A performance, in the same aqueous systems, was carried out. The results showed that the metal removal efficiency of ETS-10 phase is higher than that obtained by commercial zeolite A, especially towards dangerous heavy metals such as Pb, Zn and Mn. PMID- 30453696 TI - Block Adjustment without GCPs for Chinese Spaceborne SAR GF-3 Imagery. AB - The Gaofen-3 (GF-3) satellite is the first C-band multi-polarization synthetic aperture radar (SAR) with the ability of high-accuracy mapping in China. However, the Ground Control Points (GCPs) are essential to ensure the accuracy of mapping for GF-3 SAR imagery at present. In this paper, we analyze the error sources that affect the geometric processing and propose a new block adjustment method without GCPs for GF-3 SAR imagery. Firstly, the geometric calibration of GF-3 image is carried out. Secondly, the rational polynomial coefficient (RPC) model is directly generated after the geometric calibration parameters compensation of each image. Finally, we solve the orientation parameters of the GF-3 images through DEM assisted planar block adjustment and conduct ortho-rectification. With two different imaging modes of GF-3 satellite, which include the QPSI and FS2, we carry out the block adjustment without GCPs. Experimental results of testing areas including Wuhan city and Hubei province in China show that the geometric mosaic accuracy and the absolute positioning accuracy of the orthophoto are better than one pixel, which has laid a good foundation for the application of GF-3 image in global high-accuracy mapping. PMID- 30453697 TI - An EigenECG Network Approach Based on PCANet for Personal Identification from ECG Signal. AB - We herein propose an EigenECG Network (EECGNet) based on the principal component analysis network (PCANet) for the personal identification of electrocardiogram (ECG) from human biosignal data. The EECGNet consists of three stages. In the first stage, ECG signals are preprocessed by normalization and spike removal. The R peak points in the preprocessed ECG signals are detected. Subsequently, ECG signals are transformed into two-dimensional images to use as the input to the EECGNet. Further, we perform patch-mean removal and PCA algorithm similar to the PCANet from the transformed two-dimensional images. The second stage is almost the same as the first stage, where the mean removal and PCA process are repeatedly performed in the cascaded network. In the final stage, the binary quantization, block sliding, and histogram computation are performed. Thus, this EECGNet performs well without the use of back-propagation to obtain features from the visual content. We constructed a Chosun University (CU)-ECG database from an ECG sensor implemented by ourselves. Further, we used the well-known MIT Beth Israel Hospital (BIH) ECG database. The experimental results clearly reveal the good performance and effectiveness of the proposed method compared with conventional algorithms such as PCA, auto-encoder (AE), extreme learning machine (ELM), and ensemble extreme learning machine (EELM). PMID- 30453698 TI - Role of Nanocomposite Support Stiffness on TFC Membrane Water Permeance. AB - This paper discusses the role played by the mechanical stiffness of porous nanocomposite supports on thin-film composite (TFC) membrane water permeance. Helically coiled and multiwall carbon nanotubes (CNTs) were studied as additives in the nanocomposite supports. Mechanical stiffness was evaluated using tensile tests and penetration tests. While a low loading of CNTs caused macrovoids that decreased the structural integrity, adding higher loads of CNTs compensated for this effect, and this resulted in a net increase in structural stiffness. It was found that the Young's modulus of the nanocomposite supports increased by 30% upon addition of CNTs at 2 wt %. Results were similar for both types of CNTs. An empirical model for porous composite materials described the Young's modulus results. The nanocomposite supports were subsequently used to create TFC membranes. TFC membranes with stiffer supports were more effective at preventing declines in water permeance during compression. These findings support the idea that increasing the mechanical stiffness of TFC membrane nanocomposite supports is an effective strategy for enhancing water production in desalination operations. PMID- 30453699 TI - Comparative Study on Excretive Characterization of Main Components in Herb Pair Notoginseng-Safflower and Single Herbs by LC-MS/MS. AB - The herbal medicine combination of notoginseng-safflower has been commonly used clinically for the prevention and treatment of cardiovascular diseases. A reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous determination of six bioactive components (hydroxysafflor yellow A, notoginsenoide R1, ginsenoside Rb1, Re, Rd, and Rg1) in rat urine and feces after oral administration of notoginseng total saponins (NS), safflower total flavonoids (SF), and the combination of NS and SF (CNS). The chromatographic separation was achieved on a Waters HSS T3 column under gradient elution with acetonitrile and water containing formic acid as the mobile phase. The calibration curves were linear, with correlation coefficient (r) > 0.99 for six components. The intra- and interday precision (RSD) and accuracy (RE) of QC samples were within -14.9% and 14.9%, respectively. The method was successfully applied to study of the urinary and fecal excretion of six bioactive constituents following oral administration of NS, SF, and CNS in rats. Compared to the single herb, the cumulative excretion ratios of six constituents were decreased in the herbal combination. The study indicated that the combination of notoginseng and safflower could reduce the renal and fecal excretion of the major bioactive constituents and promote their absorption in rats. PMID- 30453701 TI - [A research on poverty alleviation based on characteristic agriculture industry: review on Chinese medicine industry to alleviate poverty]. AB - With the increasing recognition of Chinese herbal medicine products at both domestic and foreign markets, Chinese medicine industry has made great progress. Recently the relation between Chinese medicine industry and poverty alleviation becomes a research focus. This paper summarizes and concludes the research progress of Chinese medicine industry to alleviate poverty from industrial development, policy design, poverty alleviation effect and risk prevention perspectives based on review the background of Chinese medicine industry to alleviate poverty and its evolution course. The result shows that how to benefit the poor and get sustained ability to lift themselves out of poverty, Chinese medicine industry coordinated development and improve the basic medical and sanitation conditions are the major questions which can explore the Chinese medicine industry potential for alleviate poverty and carry out a further research of it. PMID- 30453700 TI - Dissemination of Genetic Acquisition/Loss Provides a Variety of Quorum Sensing Regulatory Properties in Pseudoalteromonas. AB - A bstract: Quorum sensing (QS) enables single-celled bacteria to communicate with chemical signals in order to synchronize group-level bacterial behavior. Pseudoalteromonas are marine bacteria found in versatile environments, of which QS regulation for their habitat adaptation is extremely fragmentary. To distinguish genes required for QS regulation in Pseudoalteromonas, comparative genomics was deployed to define the pan-genomics for twelve isolates and previously-sequenced genomes, of which acyl-homoserine lactone (AHL)-based QS traits were characterized. Additionally, transposon mutagenesis was used to identify the essential QS regulatory genes in the selected Pseudoalteromonas isolate. A remarkable feature showed that AHL-based colorization intensity of biosensors induced by Pseudoalteromonas most likely correlates with QS regulators genetic heterogeneity within the genus. This is supported by the relative expression levels of two of the main QS regulatory genes (luxO and rpoN) analyzed in representative Pseudoalteromonas isolates. Notably, comprehensive QS regulatory schema and the working model proposed in Pseudoalteromonas seem to phylogenetically include the network architectures derived from Escherichia coli, Pseudomonas, and Vibrio. Several associated genes were mapped by transposon mutagenesis. Among them, a right origin-binding protein-encoding gene (robp) was functionally identified as a positive QS regulatory gene. This gene lies on a genomic instable region and exists in the aforementioned bioinformatically recruited QS regulatory schema. The obtained data emphasize that the distinctly- and hierarchically-organized mechanisms probably target QS association in Pseudoalteromonas dynamic genomes, thus leading to bacterial ability to accommodate their adaption fitness and survival advantages. PMID- 30453702 TI - [Research progress on musk and artificial propagation technique of forest musk deer]. AB - Forest musk deer(Moschus berezovskii) is mainly distribute in Shaanxi and Sichuan provinces of China. The musk is a dry exudates in the mature male sachet with complex chemical composition, abundant modern identification methods, various pharmacological action, extensive clinical application. The population quantity and quality of wild and captive forest musk deer failed to improve because of lacking scientific management, excessive hunting and habitat destruction, etc. Carrying out the captive forest musk deer is an effective way to protect them, fast breeding of forest musk deer is the key to increase the yield of musk. Therefore, we should develop new technologies such as natural estrus and artificial insemination in order to speed up the breeding of musk deer and increase the yield of musk. This article reviews the research progress of new artificial propagation technique and musk, which teases some feasible research basis for optimization of forest musk deer species and the research of musk. PMID- 30453703 TI - [Chemical and pharmacological progress on usnic acid and its derivatives]. AB - Usnic acid and its derivatives, a group of organic molecules with great importance, are characteristic to lichens, possessing pharmacological activities such as anti-virus, anti-bacteria, anti-humor, anti-inflammatory, analgesic, and anaesthetic effects. Many of them have been widely used as medicine, but also bring side effects such as dermatitis and liver damages. In the past decades, great efforts by isolation, organic synthesis, and structure modification methods were put on discovery of UA derivatives with higher biological activities or less side effects. This paper describes herein the most progress on natural sources, isolation and structure elucidation, structural characteristics, synthesis and modification results, pharmacological activities and toxicities of UA and its derivatives, hopefully to provide valuable reference for further research. PMID- 30453704 TI - [Application of fingerprint technology in quality evaluation and process control of traditional Chinese medicine formula granules]. AB - The fingerprint technology could reflect the internal chemical characteristics of Chinese herbal medicine or preparation, which has the characteristics of "wholeness" and "fuzziness". It is suitable for evaluating the quality of intermediate and finished products in the production process of traditional Chinese medicine formula granules. In this paper, the applications of high performance liquid chromatography (HPLC), thin layer chromatography (TLC), gas chromatography (GC) and infrared spectrum (IR) fingerprint technology in the quality control of traditional Chinese medicine formula granules were reviewed, and their advantages and disadvantages were analyzed. The aim of this article is to enhance the combined application of various fingerprint technologies in traditional Chinese medicine formula granules. It could provide technical reference for realizing the stability of production process and improving the overall quality of formula granules. PMID- 30453705 TI - [Research progress on in vitro and in vivo behaviors of poorly soluble Chinese materia medica nanosuspension]. AB - Nanosuspension (also called nanocrystal suspension or nanocrystal) could significantly enhance the saturated solubility and dissolution of insoluble drugs, and improve their bioavailability by reducing particle size and increasing the specific surface, which could then solve the delivery problems of the poorly soluble active ingredients and effective parts of Chinese materia medica (CMM). Based on the brief summaries of nanosuspension preparation methods, this paper would mainly review the in vitro and in vivo behaviors of poorly soluble CMM nanosuspension, discuss and analyze its problems, so as to provide reference and thinking for the further study of nanosuspension drug delivery system of poorly soluble CMM and promote the development and perfection of nanosuspension technology in CMM. PMID- 30453706 TI - [Chemistry and biology research on bitter-taste Chinese materia medica with function of regulating glycolipid metabolism]. AB - The bitter taste is one of the important properties among five flavors of Chinese materia medica (CMM), characterized by downbearing and discharging, drying dampness, and consolidating Yin. In common CMM, bitter-taste CMM accounts for a large proportion, indicating the importance of it. Through the efficacy of clearing away heat and dampness, reducing fire and removing toxin, bitter-taste CMM has achieved good results in treating diabetes in clinical application, proving their definite therapeutic effect on regulating glucose and lipid metabolism (main features of diabetes). At present, there are many reports about the chemical constituents and pharmacological effects of CMM on diabetes, but there are few reviews on the chemistry and biology of bitter-taste CMM. This study summarized the properties and compatibility characteristics of bitter-taste CMM for treating diabetes, and mainly analyzed the chemistry and biology basis of bitter-taste CMM with function of regulating glycolipid metabolism, laying foundation for further researches on properties theory of CMM. PMID- 30453707 TI - [Study on phenotypic diversity and cluster analysis of Cistanche Herba in different populations in Xinjiang]. AB - To intuitively understand the phenotypic diversity of intra-population and inter population of the medicinal Cistanche Herba distributed in Xinjiang province, three species of Cistanche Herba were selected for the first time to be conducted to phenotypic observation and measurement from the morphological perspective, aiming to fill the gap in the morphological research concerning Cistanche Herba, and discuss about the relationship between the phenotypic variation and the host plants together with the geographical conditions, thus better understanding the speciation and evolutionary mechanism of Cistanche Herba and providing some scientific basis for the resource protection and germplasm breeding of Cistanche Herba. Based on sampling survey, a total of 118 well grown medicinal Cistanche samples from 17 Cistanche Herba distribution areas in Xinjiang province were selected, and various indexes were observed and measured. Besides, ANOVA and clustering analysis were conducted with 9 phenotypic quantity characters. The Cistanche Herba was plentiful in phenotypic variation. For detail, significant intra-population differences were observed in eight of the nine character indexes, and the intra-population differences were more obvious than those of inter-population. For each quantity character of the three species, the flower density possessed the maximal variable coefficient (71.1%) while the flower length was the minimum (15.9%). The phenotypic variation was also obvious among different populations. Specifically, the average variable coefficient of flower number was the maximal one (46.5%) and the flower length was the minimum one (10.0%). For different populations, the average variable coefficient of the D4 population was the maximal one (41.1%) and the S3 population was the minimum one (13.5%). According to the clustering analysis, all the samples of Cistanche Herba could be divided into three groups when the Euclidean distance was set at 15. The populations of S1, S3, D1, S2, D4, D6, D7 and D5 which distributed in the north of Xinjiang were clustered into one group, and the populations of D8, S4, D9, D2 and D3 that grown in east and central of Xinjiang were clustered into another group. The populations of C. deserticola and C. salsa could not be completely separated, but both of them were obviously differentiated from the T1, T3 and T2 populations of C. tubulosa. Besides, the C. deserticola and C. salsa displayed a patch distribution among different populations, and similar phenotypic characters were shared for each population. The research results of phenotype were consistent with that of molecular biology study of Cistanche Herba. The different phenotypic characters in different distribution areas were deduced to be arose from geographical isolation caused by mountains, which led to the specific genetic structure for each population of Cistanche Herba during the long-term adaptation and evolution. In conclusion, the current study showed the adaptation potency of Cistanche Herba exposed to different habitats. PMID- 30453708 TI - [Effects of soil bulk density on growth, physiology and quality of Glechoma longituba]. AB - Through the determination of the growth, physiological and active components of Glechoma longituba, the effect of soil bulk density on growth and quality of G. longituba was explored. Through pot experiment, six different bulk density treatments were set for 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 g.cm-3 , the growth index, physiological index and the content of active components were determined. The results showed that the growth indexes and biomass of G. longituba firstly increased and then decreased with the increase of soil bulk density. The dry weight of G. longituba achieved the maximum 5.70 g in the treatment of 1.0 g.cm-3 . The photosynthetic pigments, soluble sugars and free amino acids firstly increased and then decreased with the increase of soil bulk density. The suitable soil bulk density was beneficial to the accumulation of photosynthetic pigment, soluble protein and free amino acid synthesis. The content of malondialdehyde increased gradually with the increase of soil bulk density. The contents of ethanol-soluble extractives of G. longituba were greater than 25%, meeting its quality criterionin Chinese Pharmacopoeia 2015, achieved the maximum of 40.66% in the treatment of 1.0 g.cm-3 . The total flavonoids content of G. longituba increased gradually with the increase of soil bulk density, triterpenic acid and phenolic acids decreased gradually with the increase of soil bulk density. Soil bulk density has a significant effect on the growth and quality of G. longituba, and it is conducive to the growth and its medicinal quality at the soil bulk density of 1.0 g.cm-3. PMID- 30453709 TI - [Effects of shading on key enzyme genesexpression and accumulation of saponins in Panax japonicus var. major]. AB - To explore the effects of shading and the expression of key enzyme genes on the synthesis and accumulation of Panax japonicus var. major saponins, different shading treatments (0%, 30%,50%) of potted P. japonicus var. major were used as test materials, the expression of three key enzyme genes(CAS,DS,beta-AS) of leaves and rhizomes in different growth periods of P. japonicus var. major was determined by real-time quantitative PCR, the content of total saponins was determined by ultraviolet spectrophotometry. The results indicated that, in flowering stage, CAS,DS,beta-AS were highly expressed in the aerial parts of P. japonicus var. major, 30% shading treatment significantly inhibited the expression of CAS in leaves and promoted the expression of DS and beta-AS in stems, leaves and flowers, it was speculated that the main part of saponin synthesis was leaf in this stage. Both the expression levels of DS and beta-AS and changes in the content of total saponins in leaves showed a tendency of low high-low throughout the growth cycle, correlation coefficient analysis showed that there was a positive correlation between them. Compared with control, the expression levels of DS and beta-AS and the content of total saponins were greatly enhanced under shading treatment, 30% shading treatment significantly promoted the accumulation of total saponins. Therefore, it is suggested that 30% shading treatment should be applied to the artificial cultivation of P. japonicus var. major, which is beneficial to the accumulation and quality improvement of saponins. PMID- 30453710 TI - [Study on high throughput sequencing identification of Fructus Arctii and five counterfeit species mix power]. AB - Fructus Arctii is a traditional Chinese medicine. The main counterfeit species are the seeds of Arctium tomentosum, Onopordum acanthium, Silybum marianum, Saussurea costus, Amorpha fruticosa. Traditional identification methods or molecular barcoding techniques can identify Fructus Arctii and its counterfeit species. However, the identification of the mixture of it and its spurious species is rarely reported. In this paper, we sequenced the ITS2 sequences of Fructus Arctii and 5 kinds of spurious species mix powder by high-throughput sequencing to identify the mixed powder species and providing new ideas for the identification of Fructus Arctii mix powder. The total DNA in mixed powder was extracted, and the ITS2 sequences in total DNA was amplified. Paired-end sequencing was performed on the DNA fragment of the community using the Illumina MiSeq platform. The sequence was analyzed by the software FLASH, QIIME and GraPhlAn etc. The results showed that the high quality ITS2 sequences of 39910 mix samples were obtained from the mixed samples, of which the total ITS2 sequence of the samples genus was 34 935. Phylogenetic analysis showed that the samples contained Fructus Arctii, A. tomentosum, O. acanthium, S. marianum, S. costus and A. fruticosa. Using ITS2 sequences as DNA barcodes, high-throughput sequencing technology can be used to detect the Fructus Arctii and its spurious specie in mixed powder, which can provide reference for the quality control, safe use of medicinal materials of Fructus Arctii and the identification of mixed powder of traditional Chinese medicine. PMID- 30453711 TI - [Correlation between chemical compositions of traditional Chinese medicine extracts and phenomenon of wall stickiness in spray drying]. AB - To explore the correlation between chemical compositions (organic acids, small molecule sugars, protein and others) of traditional Chinese medicine extracts and the wall stickiness in spray drying. In this study, 55 types of most common used Chinese herbs were selected to determine the content of 7 chemical components such as citric acid and fructose from plant extraction. The status of wall stickiness was observed during the drying process. The principle component analysis (PCA-X), hierarchical clustering analysis(HCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were then used to evaluate the correlation between each chemical compositions and wall stickiness, so as to look for the essential chemical compositions associated with the wall stickiness. All of the above 3 statistical analysis methods showed significant results in distinguishing the two groups (sticky or non-sticky). PCA-X score chart and HCA clustering scatter plot suggested that the small molecular substance was the main factor causing wall stickiness, which was then proved by the reality where some of the traditional herb extracts were in non-sticky state after drying but in sticky state after alcohol precipitation. OPLS-DA results revealed that L-malic acid, citric acid, fructose and glucose were the difference factors for the wall stickiness of the extracts. Under small molecular components, L-malic acid, citric acid, fructose and glucose were the crucial factors that directly led to the hot melt sticky wall of the herbal extracts, and macromolecular substances might ameliorate the function of wall stickiness. PMID- 30453712 TI - [Preliminary study on RC membrane permeability and mechanism of seven traditional Chinese medicine alkaloids such as berberine]. AB - In order to analyze the law of membrane permeation of different alkaloids, seven traditional Chinese medicine alkaloids with different parent nucleus and substituent structures, including berberine, palmatine, sinomenine, matrine, oxymatrine, sophoridine, and tetrandrine, were prepared into the simulated solution with same molar concentration, and the membrane penetrating experiments with membrane RC1K and membrane RC5K were carried out. The dynamic transmittance, the total transmittance and the total adsorption rate of each substance were measured, and the scanning electron microscopy (SEM) images of the membrane surface before and after the membrane experiment were considered to predict and analyze the reason of differences in dynamic transmittance of different alkaloids. The results showed that there were significant differences in the dynamic transmittance of the chemical constituents of different alkaloids during penetrating the two membranes. The contamination degree on the surface of the membrane material was also different. The transmittance of the same compound through the RC5K membrane was larger than that through RC1K membrane. Within a certain range, the smaller the pore size of the membrane, the better the selective screening effect on the chemical constituents of traditional Chinese medicine. All the membrane surfaces were less polluted. The difference in transmittance between different substances on the same membrane showed a positive correlation with the difference in structural complexity, providing an experimental basis for the surface modification design in contamination control of membrane materials. In the design of membrane modified material, the surface properties of the membrane can be improved by grafting different polar groups, thereby changing the adsorption characteristics of the membrane surface. The pore size was designed accordingly to achieve the high transmittance and low pollution of the corresponding compounds. PMID- 30453713 TI - [A new naphthaldehyde derivative from Comastoma pulmonarium and its anti-tobacco mosaic virus (anti-TMV) activity]. AB - A new naphthaldehyde derivative has been isolated from Comastoma pulmonarium by using various chromatographic techniques, including silica gel, Sephadex LH-20, MCI-gel resin and RP-HPLC. This compounds was determined as 5-methoxy-2-methyl-7 (2-oxopropyl)naphthalene-1-carbaldehyde(1) by NMR, MS, IR and UV spectra. This compound was also evaluated for its anti-tobacco mosaic virus (anti-TMV) activity. The result showed that it showed high anti-TMV activity with inhibition rate of 32.8%. The inhibition rate is close to that of positive control (ningnanmycin). PMID- 30453714 TI - [Mass spectrometry guided strategy based on feature fragment ions for guided separation on quinoline alkaloids from root barks of Dictamnus dasycarpus]. AB - The root bark of Dictamnus dasycarpus is one of common traditional Chinese medicines (TCMs). Quinoline alkaloids are one of the main active substances in this TCM and possess many biological activities including anti-titumor, anti inflammation, anti-bacteria, anti-oxidation, and anti-platelet aggregation activities. In this study, eight quinoline alkaloids 1-8 were firstly separated from the root barks of D. dasycarpus. It was difficult to isolate more quinoline alkaloids from the remaining fraction 8 in D. dasycarpus by this conventional chemical separation, so the target analysis method combined LC-MS guided separation of quinoline alkaloids from fraction 8 was established. MS/MS fragmentation patterns of eight quinoline alkaloids reference standard compounds 1-8 were studied by ultra-performance liquid chromatography-electrospary ionization-mass spectrometry (UPLC-ESI-MS/MS). Based on the feature fragment ion m/z 200, the parent ion scan mode was established for the target analysis of quinoline alkaloids in fraction 8. Finally, 8-methoxyflindersine (9) and N metilatanina (10) were discovered and isolated quickly from fraction 8 guided by LC-MS, and their structures were identified by NMR and MS. Among them, compound 10 was isolated from the genus Dictamnus for the first time. These results indicated that this method is not only quick and sensitive for analyzing the quinoline alkaloids, but also to effectively guided-separate this kind of alkaloids in the root barks of D. dasycarpus. PMID- 30453715 TI - [A preliminary study on origin of ligustrazine in Chuanxiong Rhizoma based on endogenetic Bacillus subtilis]. AB - Ligustrazine is an important active ingredient of the traditional Chinese medicine Chuanxiong Rhizoma, but its content is a controversial topic. The endophytes of medicinal plants have the ability to produce the same active substances as the host, so this report focused on the endophytic Bacillus subtilis, to study the origin of ligustrazine in Chuanxiong Rhizoma preliminarily by inoculating the isolated endophytic B. subtilis to the Chuanxiong Rhizoma medium in vitro for solid state fermentation. Tissue grinding method was used to isolate the endogenetic B. subtilis. The morphological features, conventional physiological and biochemical reactions and 16S rRNA molecular techniques were combined to identify the endogenetic strains. Then, the strains that grew well in the medicinal matrix of Chuanxiong Rhizoma were screened out for further fermentation studies. The solid-state fermentation was performed at 37 degrees C for 30 d using Chuanxiong Rhizoma fermentation medium (40 g Chuanxiong Rhizoma powder, 100 mL sterile water, 121 degrees C, sterilization for 25 minutes). UPLC was used to detect the contents of ligustrazine, acetoin in the Chuanxiong Rhizoma fermentation medium and Chuanxiong Rhizoma. All the five strains were Gram-positive and had spores. Phylogenetic analysis of the 16S rRNA sequence showed that the endophytes were B. subtilis. The results of UPLC showed that ligustrazine was detected in the Chuanxiong Rhizoma fermentation medium inoculated with endogenetic B. subtilis LB3, LB3-2-1, LB4, LB5 and LB6-2, while not detected neither in blank Chuanxiong Rhizoma fermentation medium nor in Chuanxiong Rhizoma. This study showed that the endogenetic B. subtilis of Ligusticum chuanxiong Hort. can make use of Chuanxiong Rhizoma fermentation medium to produce ligustrazine. Endogenetic B. subtilis has a certain correlation with the accumulation of ligustrazine in Rhizoma Chuanxiong. We speculate that the ligustrazine may be derived from the catabolism of endogenetic B. subtilis in Ligusticum chuanxiong. PMID- 30453716 TI - [Protective effect of Wuzi Yanzong recipe on testicular germ cell apoptosis in natural ageing rats through endoplasmic reticulum stress]. AB - To study the protective effects of Wuzi Yanzong recipe on testis germ cell apoptosis in natural ageing rats through endoplasmic reticulum stress (ERS), 16 month-old male SPF grade SD rats were randomly divided into three groups: ageing model group, and low and high-dose Wuzi Yanzong recipe groups (WZ, 1 and 4 g.kg 1), with 10 rats in each group. In addition, 2-month-old SD male rats were used as adult control group. The ageing model group and the adult control group were fed with normal diet for 4 months. WZ groups were given the medicated feed for 4 months. After fasting for 12 hours, the rats were put to death. Then, the testes were immediately collected. The change of testicular tissue morphology was observed by HE staining. The expression levels of ER stress-related proteins GRP78, p-PERK, p-eif2alpha, ATF4, p-IRE1, XBP1, ATF6 and apoptosis-related proteins CHOP, caspase12 and p-JNK in testes were detected by Western blot. Compared with the ageing model group, Wuzi Yanzong recipe alleviated the morphological changes of testicular tissue. Western blot results showed that Wuzi Yanzong recipe significantly increased the expression levels of endoplasmic reticulum stress-related proteins GRP78, p-PERK, p-eif2alpha, ATF4, p-IRE1, XBP1, ATF6 and significantly decreased the expression levels of endoplasmic reticulum induced apoptosis-related proteins CHOP, caspase 12 and p-JNK. In conclusion, Wuzi Yanzong recipe can alleviate the ageing-related apoptosis of testicular germ cells in natural ageing rats by regulating endoplasmic reticulum stress. PMID- 30453717 TI - [Effect of bone marrow mesenchymal stem cell transplantation on CCl4-induced liver injury in rats and intervention effects of Yiguanjian]. AB - The aim of this paper was to observe the function of bone marrow mesenchymal stem cell (BMSC) transplantation in process of liver injury induced by carbon tetrachloride (CCl4) in vivo and the intervention effect of Yiguanjian (YGJ), a compound of Chinese herbal medicine. Wistar rats were randomly divided into five groups: normal group, model group, cell transplantation (CT) group, YGJ group and cell transplantation plus Yiguanjian (CTY) group. Liver injury was induced through subcutaneous injection with CCl4 at a dose of 3 mL.kg-1 body weight for 4 weeks, twice a week. They were injected for a total of 9 times. After the first injection with CCl4, rats in the CT group and CTY group were injected with the third-generation BMSCs at dose 1*106 (suspended in 1 mL saline solution) via tail vein. Rats in the YGJ and CTY groups were also intragastrically administered with Yiguanjian once a day. Rat serum ALT and AST activities were increased significantly on the second day after injection with CCl4, while BMSC transplantation and Yiguanjian decreased their activities. After 4 weeks of injection with CCl4, serum ALT, AST and gamma-GT activities, and serum TNF-alpha and IL-6 expressions were increased, while TBIL were decreased in model rats compared with normal rats. Meanwhile, liver cells edema, plasmatic loose, and numerous lipid droplets were observed in rats of the model group. BMSC transplantation aggravated liver injury compared with model rats, which was manifested by decreasing SOD activity, increased MDA, TG, TNF-alpha and IL-6 levels, and aggravated necrosis level of hepatocytes, fusion of lipid droplets, and collagen deposition in liver tissue. Yiguanjian decreased liver injury induced by CCl4 alone and CCl4 plus BMSC transplantation. SRY gene in situ hybridization method was used to detect the positive SRY expressions in heart, liver, spleen, lung and kidney, especially in liver, while Yiguangjian decreased liver SRY expression. Wnt and beta-catenin showed high expressions in rats of normal group, which were decreased significantly in rats of models group, while Yiguanjian increased their expressions. In conclusion, BMSC transplantation could exacerbate liver injury, while Yiguanjian could protect liver injury induced by CCl4 and BMSC transplantation, which was related to decreasing the homing of BMSCs to liver and up-regulating Wnt/beta-catenin signaling pathway. PMID- 30453718 TI - [Research of Feiliuping Gao and its combination with different types of drugs intervention on expression of PI3K/AKT/NF-kappaB in lung metastatic microenvironment]. AB - The aim of this paper was to observe the effect of Feiliuping Gao and its combination with different types of drugs intervention on the expression of PI3K/AKT/NF-kappaB in lung metastatic microenvironment, and to reveal the advantage of Chinese medicine intervention time on the key molecule in lung metastatic microenvironment. The mouse model of Lewis lung carcinoma was established, and lung tissues were collected at 14 days, 21 days and 28 days after the intervention of Feiliuping Gao, and the expressions of PI3K, AKT and NF kappaB were detected by immunohistochemistry and Western blot. At 14 days, there was no significant difference in PI3K expression between each group and the control group. The expression of AKT protein was significantly inhibited in the celecoxib (CLB) group, the Feiliuping Gao (FLP) combination with cyclophosphamide (FLP+CTX) group, and the Feiliuping Gao combination with celecoxib (FLP+CLB) group (P<0.05). The inhibition of AKT protein expression in FLP+CLB group was superior. The FLP+CLB group can inhibit the expression of NF-kappaB protein (P<0.05). At 21 days, compared with the control group, the expression of PI3K was inhibited in FLP group and the FLP+CTX group (P<0.05), while the expression of PI3K was best inhibited in the FLP+CLB group (P<0.001). Only the FLP+CLB group could significantly inhibit the expression of AKT protein (P<0.01). The FLP+CTX group had the best effect in inhibiting the expression of NF-kappaB protein (P<0.001). At 28 days, compared with the control group, the expression of PI3K and AKT was inhibited in the FLP+CLB group (P<0.001). Feiliuping ointment combination with celecoxib has an advantage in regulating the expression of PI3K/AKT/NF-kappaB molecules in lung metastatic microenvironment. PMID- 30453719 TI - [Study on relevance mining of "core drug action target" in Dictionary of Traditional Chinese Medicine Prescriptions]. AB - Based on the database of "Dictionary of Traditional Chinese Medicine Prescriptions", high-frequency herbs of Xiaoke disease is mined by traditional Chinese medicine inheritance support system, and core herbs and combinations are discovered through association rules and cluster analysis. On this basis, based on the integrative pharmacology of traditional Chinese medicine to explore the herb-disease relationship, the "herb-compound-target" network is constructed and enriched for the analysis of key target gene functions, metabolic pathways, and their "core herb-target interactions". In order to explore the molecular mechanism of its prevention and treatment of diabetes, 341 diabetes prescriptions are collected, organized, and tapped in the Dictionary of Traditional Chinese Medicine Prescriptions. Herb frequency statistics show that Licorice was the most commonly used, followed by Ophiopogonis Radix, Poria, Ginseng Radix et Rhizoma, Coptidis Rhizoma, etc., the medicinal properties are mostly cold, warm and ping, and the medicinal taste tends to be pungent, bitter, and sour, and they were attributed to lung meridian, stomach meridian, spleen meridian, etc. Among them, the 17 herbs were closely related. Ginseng Radix et Rhizoma, Ophiopogonis Radix, Poria and Glycyrrhizae Radix et Rhizoma were the core Chinese herbs. Ophiopogonis Radix was the key node of Coptidis Rhizoma, Trichosanthis Radix and core Chinese medicine, and Ophiopogonis Radix was the key node for the connection between Coptidis Rhizoma and Trichosanthis Radix and the core Chinese herbs. Using integrated pharmacology platform analysis, 10 crucial core targets for the prevention and treatment of diabetes were obtained, including the known disease targets (PLCD1, PIK3R1, ENPP1), and potential herb targets(GNB1, ADCY1, AKT1, RAC1, PRKAA1, RHOA) , common target (GCK). There were seven similar targets in the 10 crucial core targets predicted with the combination of "Ophiopogonis Radix, Coptidis Rhizoma and Trichosanthis Radix", including PLCD1, PIK3R1, ENPP1, ADCY1, AKT1, PRKAA1, GCK. These genes were mainly located in the cytosol, plasma membrane, etc., involved in adenosine triphosphate binding, protein binding, platelet activation, etc., mainly involved in the endocrine system, signal transduction, chemokine signaling pathway, cancer pathway, and other metabolic pathways, and it is speculated that these genes were potentially associated with diabetes. In this study, Traditional Chinese Medicine Inheritance Support System and Integrative Pharmacology of Traditional Chinese Medicine are used to analyze the prescription law of Xiaoke prescription, and the correlation of "core herbs functionary targets" is excavated, which provided the basis and reference for the screening and development of TCM prescriptions for the prevention and treatment of diabetes. PMID- 30453720 TI - [Effect of long-term intake of ginseng extracts on gut microbiota in rats]. AB - As a traditional Chinese medicine in China, ginseng has a wide range of medicinal and health value. At present, the nutritional value of ginseng as a medicinal food has been a hotspot in studies. Intestinal flora plays an important role in the organism, which has been confirmed by many researchers. In order to find out the effect of long-term intake of ginseng extracts on the gut microbiota structure of rats, MiSeq sequencing platform was applied in macro gene sequencing of cecal contents in the long-term use of ginseng extracts modelin rats. According to the findings, after long-term administration with ginseng extracts, probiotics such as Bifidobacterium, Lactobacillus, Allobaculum and Clostridium, in the intestinal flora of rats were significantly increased, suggesting that long-term intake of ginseng extracts could facilitate the growth of probiotics. Meanwhile, some pathogenic bacteria, such as Butyricimonas, Parabacteroides, Alistipes, Helicobacter, were significantly down-regulated, indicating that long term intake of ginseng extracts may have a positive effect in inhibiting the colonization of pathogenic bacteria. In conclusion, this study provided an important basis for the research on the effect of long-term use of ginseng extracts on the intestinal flora of rats. PMID- 30453721 TI - [Identification of metabolites of Danshensu in vivo in rats]. AB - To identify the metabolites of Danshensu in plasma and urine in rats by using UHPLC-LTQ-Orbitrap method. After oral gavage of Danshensu CMC-Na suspension in SD rats, urine and plasma samples were collected and processed by solid phase extraction. ACQUITY UPLC BEH C18 column (2.1 mm*100 mm, 1.7 MUm) was utilized, with 0.1% formic acid (A)-acetonitrile (B) solution as the mobile phase for gradient elution. Negative electrospray ion mode based data-acquisition method was established to collect the mass spectrometry data of biological samples. As a result, Danshensu and 21 Danshensu I phase and II phase metabolites were finally identified according to the accurate mass measurements, mass fragmentation behaviors and comparing with the reference standards. The main metabolic pathways included dehydration, methylation, glucuronide conjugation, sulfate conjugation and their composite reactions. Consequently, our study expounded metabolites of Danshensu in rats based on UHPLC-LTQ-Orbitrap method and provided a reference for further researches on therapeutic material basis and mechanism of Danshensu. PMID- 30453722 TI - [Efficacy and safety of breviscapine injection in treatment of unstable angina pectoris: systematic review and Meta-analysis]. AB - To systematically evaluate the efficacy and safety of breviscapine injection in the treatment of unstable angina pectoris (UAP). Eight electronic databases and clinical trials registries were searched to collect randomized controlled trials on breviscapine injection in the treatment of UAP. According to the evaluation standards in Cochrane Handbook 5.1, two independent reviewers screened out the literature, extracted data and assessed the quality of the studies included. RevMan 5.3 software was used for Meta quantitative analysis and corresponding description analysis. A total of 36 studies involving 3 058 patients were included, 1 552 cases in the trial group, 1 506 cases in the control group, 1 846 males and 1 212 females. All the clinical studies showed a low quality. Meta analysis results showed that the combination of breviscapine injection and conventional therapy was superior to conventional therapy in angina pectoris efficacy (RRangina pectoris efficacy=1.29, 95%CI[1.23,1.35],P<0.000 01;RRECG1=1.25,95%CI[1.12,1.38],P<0.000 1;RRECG2=1.38,95%CI[1.27,1.49],P<0.000 01); descriptive analysis of a single study showed that the efficacy of combination of breviscapine injection and conventional therapy was superior to that of conventional therapy alone. In respect of hemorheology, the combination of breviscapine injection and conventional therapy was better than conventional therapy in lowering LBV and EAI (MDLBV=-1.27,95%CI[-1.55,-0.99],P<0.000 01;MDEAI= 0.38,95%CI[-0.60,-0.16],P=0.000 6), as well as in lowering WBV and HCT in the descriptive analysis of single study. In respect of blood lipid, the combination of breviscapine injection and conventional therapy was better than conventional therapy in lowering TC, TG and LDL-C (MDTC=-0.30,95%CI[-0.51,-0.10],P=0.003;MDTG= 0.32,95%CI[-0.77,0.13],P=0.16;MDLDL-C=-0.45,95%CI[-0.76,-0.14],P=0.004). In reducing the frequency of angina attacks, heart rate, high sensitive C-reactive protein and improving exercise tolerance, the combination of breviscapine injection and conventional therapy was also superior to the conventional therapy alone (MDFAP=-3.30,95%CI[-4.06,-2.54],P< 0.000 01;MDHR=-9.38,95%CI[-12.78, 5.98],P=0.000 2;MDhs-CRP=-0.56,95%CI[-0.85,-0.27],P=0.000 2;MDET=0.88,95%CI[0.41,1.35],P=0.000 2). The main adverse reactions in the two groups included headache, dizziness, palpitations, nausea, abdominal distension, skin pruritus, flushes and allergic reactions in the study. The safety of breviscapine injection needs to be further studied and clarified because of the combination of drugs and the incomplete information reported in the original study. The current evidence suggested that the combination of breviscapine injection and conventional therapy had certain advantages in curative effect for the treatment of UAP. Due to the low quality of the study and its own shortcomings, it is necessary to design more rigorous, high-quality, multi-center randomized double-blind controlled trials to increase the strength of the evidence. PMID- 30453723 TI - [Evaluation on safety of puerarin injection in clinical use]. AB - Puerarin injection is commonly used in clinical treatment of coronary heart disease, angina pectoris, retinal artery, vein occlusion, sudden deafness and so on. This paper is aimed to evaluate the safety of puerarin injection in clinical use and explore the related factors that may cause its adverse reactions (ADRs), so as to find the warning signal of safety medication in time, put forward early warning, make early judgment and treatment, and ensure the safety of drug use. By strengthening surveillance, the best medication plan was established to prevent the occurrence of adverse reactions of puerarin injection and enhance people's awareness on the safety of puerarin injection. Database were searched to collect literature related to ADRs of puerarin injection. The data were extracted and analyzed by decision tree with treeage software and chi2 test was used to verify the data. A total of 62 papers involving 129 cases were included. The results showed that ADRs occurred mostly in patients aged 50-79 years, with the immune system and blood system accounting for the majority (88.3%), and ADRs occurred mostly 48 h after drug administration (61.1%). The severity of ADRs was not related to the dosage of puerarin, but it was related to the choice of the infusion solvent. In puerarin injection, most of the ADRs were moderate or severe (64.3%), 13 out of 129 cases were of death. Therefore, the indications and methods of use should be strictly controlled, and the allergic history of patients should be carefully questioned before medication to strengthen the monitoring of drug use. PMID- 30453724 TI - [Fingerprinting and multi-indicator quantitative analysis of Mongolian drug Digeda-4 decoction]. AB - To establish the high performance liquid chromatography (HPLC) fingerprint for Digeda-4 decoction (DGD-4D), determine the contents of aesculetin, geniposide, picroside I, picroside II and ellagicacid in DGD-4D, and provide the scientific foundation for quality control of DGD-4D. The analysis was performed on Diamonsil(2) C18 (4.6 mm*250 mm,5 MUm) column, with methanol-0.1% phosphoric acid aqueous solution as mobile phase for gradient elution. The flow rate was 1.0 mL.min-1; injection size was 10 MUL; temperature was maintained at 30 degrees C, and the detection wavelength was set at 254 nm. The common mode of DGD-4D HPLC fingerprint was established, and the hidden information was analyzed by Chemometrics. Chromatographic peaks for DGD-4D were identified by HPLC and quantitative analysis was conducted for characteristic peaks. There were 17 common peaks in the fingerprints and the similarity of the fingerprints was over 0.9 in all 15 batches. The samples were broadly divided into four kinds by principal component analysis and clustering analysis. Four marker compounds were verified by partial least squares discriminant analysis, and No. 9, 12 and 14 peaks were identified as geniposide, picroside II, and picroside I respectively. The average recoveries were in the range of 95.91%-97.31%. The HPLC fingerprint method for content determination is reliable, accurate, rapid, simple, and reproducible, and can be used as one of the effective methods to control the quality of DGD-4D. PMID- 30453725 TI - [Research progress on pharmacokinetics and pharmacological activities of artesunate]. AB - Artesunate (AS), a famous derivative of the artemisinin, is the basic treatment globally for mild to severe malaria infection due to the prominent advantages such as high efficiency, fast effect, low toxicity and not easy to produce resistance. More and more research reports have shown that AS and its active metabolites dihydroartemisinin (DHA) had various bioactivities in addition to antimalarial activity, attracting researchers to further study its new pharmacological effects in order to explore new use of the old drug. A comprehensive understanding of the pharmacokinetic characteristics of AS will be conducive to the further development of new pharmacological actions and clinical application of AS. Therefore, this paper would review the absorption, distribution, metabolism and excretion of AS in vivo, as well as the pharmacokinetics characteristics of AS and DHA after clinical administration of AS by intravenous (IV), intramuscular (IM), oral or rectal routes. The in vivo process and pharmacokinetic parameters of AS and DHA were compared between healthy volunteers, malaria patients, and special populations (children, women). Meanwhile, the research progress on pharmacological effects of AS and active metabolite DHA such as anti-tumor, anti-inflammatory, anti septic, antiangiogenic, anti-fibrosis and immunoregulation activities would be also reviewed, hoping to provide a theoretical basis for the further development and utilization of AS and its metabolites. PMID- 30453726 TI - [Interpreting the Methods for Blending Decoctions to Treat 60 Ailments in Tianhui bamboo slip medical manuscripts]. AB - Among the medical texts excavated in 2012-2013 from the Han Dynasty tomb at Tianhui township in Sichuan province, we found a collection on the treatment of 60 ailments. Under each ailment, we found one or more formulas, for a total of 106 formulas. The authors of this paper compiled and analyzed these texts based on the original bamboo slips and named this collection with the title Methods for Blending Decoctions to Treat 60 Ailments because the content was focused on blending and making medicinal formulas, and also due to the historical connections with the texts the Record of the Court Scribe, "Biography of Bian Que and Cang Gong". For these reasons, this title was determined, where "blending decoctions" mean "blending and harmonizing medicines optimally in preparation for decocting". The Tianhui texts preserve ancient forms of medicinal formulas, including some once believed to be lost, such as ?"grain decoctions"?, "fermented alcohol decoctions", and "fiery decoctions". Based on the historical evidence, we can now ascertain that this text is the "Blending Formulas and Making Decoctions" mentioned in the Record of the Court Scribe written by Cang Gong. Moreover, the medical texts, Canon Formulas in Decoction Form (from the book of Han Dynasty) and the Imperial Pharmacy Formulas to Benefit the People in Song Dynasty are both of this genre of medical literature. The Tianhui text is therefore a representative of this genre of literature in the Western and eastern Han, acting as a key link between early medical formula books and later formula books. PMID- 30453727 TI - [Status and further development of regulation for pesticide registration for Chinese medicinal materials]. AB - Nowadays, the cultivation of traditional Chinese medicinal materials is faced with the problems of pesticides illegal uses and pesticides residues. In the early period of eco-agriculture of Chinese materia medica, the uses of pesticides in special time is still inevitable. However, the registration of pesticides for Chinese medicinal materials now is far from enough to meet demand. So it is necessary to publish policies to expand the pesticides registration for Chinese medicinal materials. We collected and analyzed the data of pesticide registration for Chinese medicinal materials, the results showed that till March 2018, there were 10 kinds of Chinese medicinal materials, 91 pesticide products and 46 kinds of pesticide ingredients registered. Based on the current status of the pesticide management in China and the experience of the registration pesticide for minor crops in countries around the world, we point out that the pesticide registration for Chinese medicinal materials should be carried out in the form of minor crops and some specific methods are also provided in this paper. PMID- 30453728 TI - Development of Web-Based Nomograms to Predict Treatment Response and Prognosis of Epithelial Ovarian Cancer. AB - Purpose: Discovery of models predicting the exact prognosis of epithelial ovarian cancer (EOC) is necessary as the first step of implementation of individualized treatment. This study aimed to develop nomograms predicting treatment response and prognosis in EOC. Materials and Methods: We comprehensively reviewed medical records of 866 patients diagnosed with and treated for EOC at two tertiary institutional hospitals between 2007 and 2016. Patients' clinico-pathologic characteristics, details of primary treatment, intra-operative surgical findings, and survival outcomes were collected. To construct predictive nomograms for platinum sensitivity, 3-year progression-free survival (PFS), and 5-year overall survival (OS), we performed stepwise variable selection by measuring the area under the receiver operating characteristic curve (AUC) with leave-one-out cross validation. For model validation, 10-fold cross-validation was applied. Results: The median length of observation was 42.4 months (interquartile range, 25.7 to 69.9 months), during which 441 patients (50.9%) experienced disease recurrence. The median value of PFS was 32.6 months and 3-year PFS rate was 47.8% while 5 year OS rate was 68.4%. The AUCs of the newly developed nomograms predicting platinum sensitivity, 3-year PFS, and 5-year OS were 0.758, 0.841, and 0.805, respectively. We also developed predictive nomograms confined to the patients who underwent primary debulking surgery: The AUCs for platinum sensitivity, 3-year PFS, and 5-year OS were 0.713, 0.839, and 0.803, respectively. Conclusion: We successfully developed nomograms predicting treatment response and prognosis of patients with EOC. These nomograms are expected to be useful in clinical practice and designing clinical trials. PMID- 30453729 TI - Neuropeptide Signaling Regulates Pheromone-Mediated Gene Expression of a Chemoreceptor Gene in C. elegans. AB - Animals need to be able to alter their developmental and behavioral programs in response to changing environmental conditions. This developmental and behavioral plasticity is mainly mediated by changes in gene expression. The knowledge of the mechanisms by which environmental signals are transduced and integrated to modulate changes in sensory gene expression is limited. Exposure to ascaroside pheromone has been reported to alter the expression of a subset of putative G protein-coupled chemosensory receptor genes in the ASI chemosensory neurons of C. elegans (Kim et al., 2009; Nolan et al., 2002; Peckol et al., 1999). Here we show that ascaroside pheromone reversibly represses expression of the str-3 chemoreceptor gene in the ASI neurons. Repression of str-3 expression can be initiated only at the L1 stage, but expression is restored upon removal of ascarosides at any developmental stage. Pheromone receptors including SRBC-64/66 and SRG-36/37 are required for str-3 repression. Moreover, pheromone-mediated str 3 repression is mediated by FLP-18 neuropeptide signaling via the NPR-1 neuropeptide receptor. These results suggest that environmental signals regulate chemosensory gene expression together with internal neuropeptide signals which, in turn, modulate behavior. PMID- 30453730 TI - Involvement of Pyridoxine/Pyridoxamine 5'- Phosphate Oxidase (PDX3) in Ethylene Induced Auxin Biosynthesis in the Arabidopsis Root. AB - As sessile organisms, plants have evolved to adjust their growth and development to environmental changes. It has been well documented that the crosstalk between different plant hormones plays important roles in the coordination of growth and development of the plant. Here, we describe a novel recessive mutant, mildly insensitive to ethylene (mine), which displayed insensitivity to the ethylene precursor, ACC (1-aminocyclopropane-1-carboxylic acid), in the root under the dark-grown conditions. By contrast, mine roots exhibited a normal growth response to exogenous IAA (indole-3-acetic acid). Thus, it appears that the growth responses of mine to ACC and IAA resemble those of weak ethylene insensitive (wei) mutants. To understand the molecular events underlying the crosstalk between ethylene and auxin in the root, we identified the MINE locus and found that the MINE gene encodes the pyridoxine 5'-phosphate (PNP)/pyridoxamine 5' phosphate (PMP) oxidase, PDX3. Our results revealed that MINE/PDX3 likely plays a role in the conversion of the auxin precursor tryptophan to indole-3-pyruvic acid in the auxin biosynthesis pathway, in which TAA1 (TRYPTOPHAN AMINOTRANSFERASE OF ARABIDOPSIS 1) and its related genes (TRYPTOPHAN AMINOTRANSFERASE RELATED 1 and 2; TAR1 and TAR2) are involved. Considering that TAA1 and TARs belong to a subgroup of PLP (pyridoxal-5'-phosphate)-dependent enzymes, we propose that PLP produced by MINE/PDX3 acts as a cofactor in TAA1/TAR-dependent auxin biosynthesis induced by ethylene, which in turn influences the crosstalk between ethylene and auxin in the Arabidopsis root. PMID- 30453731 TI - DRG2 Deficiency Causes Impaired Microtubule Dynamics in HeLa Cells. AB - The developmentally regulated GTP binding protein 2 (DRG2) is involved in the control of cell growth and differentiation. Here, we demonstrate that DRG2 regulates microtubule dynamics in HeLa cells. Analysis of live imaging of the plus-ends of microtubules with EB1-EGFP showed that DRG2 deficiency (shDRG2) significantly reduced the growth rate of HeLa cells. Depletion of DRG2 increased 'slow and long-lived' subpopulations, but decreased 'fast and short-lived' subpopulations of microtubules. Microtubule polymerization inhibitor exhibited a reduced response in shDRG2 cells. Using immunoprecipitation, we show that DRG2 interacts with tau, which regulates microtubule polymerization. Collectively, these data demonstrate that DRG2 may aid in affecting microtubule dynamics in HeLa cells. PMID- 30453732 TI - Non-Ionic Surfactants Antagonize Toxicity of Potential Phenolic Endocrine Disrupting Chemicals, Including Triclosan in Caenorhabditis elegans. AB - Triclosan (TCS) is a phenolic antimicrobial chemical used in consumer products and medical devices. Evidence from in vitro and in vivo animal studies has linked TCS to numerous health problems, including allergic, cardiovascular, and neurodegenerative disease. Using Caenorhabditis elegans as a model system, we here show that short-term TCS treatment (LC50: ~0.2 mM) significantly induced mortality in a dosedependent manner. Notably, TCS-induced mortality was dramatically suppressed by co-treatment with non-ionic surfactants (NISs: e.g., Tween 20, Tween 80, NP-40, and Triton X-100), but not with anionic surfactants (e.g., sodium dodecyl sulfate). To identify the range of compounds susceptible to NIS inhibition, other structurally related chemical compounds were also examined. Of the compounds tested, only the toxicity of phenolic compounds (bisphenol A and benzyl 4-hydroxybenzoic acid) was significantly abrogated by NISs. Mechanistic analyses using TCS revealed that NISs appear to interfere with TCS-mediated mortality by micellar solubilization. Once internalized, the TCS-micelle complex is inefficiently exported in worms lacking PMP-3 (encoding an ATP-binding cassette (ABC) transporter) ransmembrane protein, resulting in overt toxicity. Since many EDCs and surfactants are extensively used in commercial products, findings from this study provide valuable insights to devise safer pharmaceutical and nutritional preparations. PMID- 30453733 TI - Synthesis and Characterization of non-IPR Actinide Endohedral Metallofullerenes U@C1(17418)-C76, U@C1(28324)-C80 and Th@C1(28324)-C80: Low-Symmetry Cage Selection Directed by a Tetravalent Ion. AB - For the first time, actinide endohedral metallofullerenes (EMFs) with non-IPR carbon cages, U@C80, Th@C80 and U@C76, have been successfully synthesized and fully characterized by mass spectrometry, single crystal X-ray diffractometry, UV vis-NIR, Raman and cyclic voltammetry. Crystallographic analysis revealed that the U@C80 and Th@C80 share the same non-IPR cage of C1(28324)-C80, and U@C76 was assigned to non-IPR U@C1(17418)-C76. All of these cages are chiral and have never been reported before. Further structural analyses show that enantiomers of C1(17418)-C76 and C1(28324)-C80 share a significant continuous portion of the cage and are topologically connected by only two C2 insertions. DFT calculations show that the stabilization of these unique non-IPR fullerenes originates from a four electron transfer, a significant degree of covalency and the resulting strong host-guest interactions between the actinide ions and the fullerene cages. Moreover, because the actinide ion displays high mobility within the fullerene, both the symmetry of the carbon cage and the possibility of forming chiral fullerenes play important roles to determine the isomer abundances at temperatures of fullerene formation. This study provides probably one of the most complete examples in which carbon cage selection occurs through thermodynamic control at high temperatures, so the selected cages do not necessarily coincide with the most stable ones at room temperature. This work also demonstrated that the metal-cage interactions in actinide EMFs show remarkable differences from those previously known for lanthanide EMFs. These unique interactions not only could stabilize new carbon cage structures but, more importantly, they lead to a new family of metallofullerenes for which the cage selection pattern is different to that observed so far for non-actinide EMFs. For this new family, the simple ionic Aq+@C2nq- model makes less reliable predictions and, in general, to unambiguously discern the isolated structures requires the combination of accurate computational and experimental data. PMID- 30453734 TI - Atomic scale explanation of O2 activation at the Au-TiO2 interface. AB - By a combination of EPR spectroscopy, finite-temperature ab initio simulations, and electronic structure analyses, the activation of molecular dioxygen at the interface of gold nanoparticles and titania in Au/TiO2 catalysts is explained at the atomic scale by tracing processes down to the molecular orbital picture. Direct evidence is provided that excess electrons in TiO2, for example created by photoexcitation of the semiconductor, migrate to the gold particles and from there to oxygen molecules adsorbed at gold/titania perimeter sites. Superoxide species are formed more efficiently than on the bare TiO2 surface. This catalytic effect of the gold nanoparticles is attributed to a weakening of the internal O-O bond, leading to a preferential splitting of the molecule at shorter bond lengths together with a 70% decrease of the dissociation free energy barrier compared to the non-catalyzed case on bare TiO2. The findings are an important step forward in the clarification of the role of gold in (photo)catalytic processes. PMID- 30453735 TI - Molecular Basis of Mammalian Odor Discrimination - A Status Report. AB - Humans have 396 unique, intact olfactory receptors (ORs), G-protein coupled receptors (GPCRs) containing receptor-specific binding sites; other mammals have more. Activation of these transmembrane proteins by an odorant initiates a signaling cascade, evoking an action potential leading to perception of a smell. Since the number of distinguishable odorants vastly exceeds the number of ORs, research has focused on mechanisms of recognition and signaling processes for classes of odorants. In this review, selected recent examples will be presented of "deorphaned" mammalian receptors, where the OR ligands (odorants) as well as key aspects of receptor-odorant interactions have been identified using odorant mediated receptor activation data together with site-directed mutagenesis and molecular modeling. Based on cumulative evidence from OR deorphaning and olfactory receptor neuron (ORN) activation studies, a receptor-ligand docking model rather than an alternative bond vibration model is suggested to best explain the molecular basis of the exquisitely sensitive odor discrimination in mammals. PMID- 30453736 TI - Amyloid-like Fibrils from a Diphenylalanine Capped with an Aromatic Fluorenyl. AB - The self-assembly behavior of a diphenylalanine amphiphile blocked at the C terminus with a 9-fluorenylmethyl ester and stabilized at the N-terminus with a trifluoroacetate (TFA) anion, TFA.FF-OFm, has been examined. At low peptide concentration (0.5 mg/mL), long amyloid-like fibrils, which come from the fusion of two or more helical ribbons and/or thinner fibrils, organized in bundles or as individual entities are detected. Microbeam synchrotron radiation infrared spectroscopy has shown that TFA.FF-OFm molecules in amyloid-like fibrils arrange, forming antiparallel beta-sheets. Alteration of the experimental conditions to prioritize the thermodynamic contribution with respect to the kinetic one in the self-assembly process inhibits the organization of amyloid-like structures in favor of the formation of conventional fibrous structures. On the basis of experimental observations, a structural model where the individual antiparallel beta-sheets are oriented in parallel has been proposed for TFA.FF-OFm amyloid like fibrils. PMID- 30453737 TI - Deep Annotation of Hydroxycinnamic Acid Amides in plants Based on Ultra High performance Liquid Chromatography-High Resolution Mass Spectrometry and Its in Silico Database. AB - Hydroxycinnamic acid amides (HCAAs), diversely distributed secondary metabolites in plants, play essential roles in plant growth and developmental processes. Most of current approaches can be used to analyze a few known HCAAs in a given plant. A novel method for comprehensive detection of plant HCAAs is urgently needed. In this study, a deep annotation method of HCAAs was proposed based on ultra high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) and its in silico database of HCAAs. To construct in silico UHPLC-HRMS HCAAs database, a total of 846 HCAAs were generated from the most common phenolic acid and polyamine/aromatic monoamine substrates according to possible biosynthesis reactions, which represent the structures of plant-specialized HCAAs. The characteristic MS fragmentation patterns of HCAAs were extracted from reference mixtures. Four quantitative structure-retention relationship (QSRR) models were developed to predict retention times of mono-trans-HCAAs (aromatic amines conjugates), mono-trans-HCAAs (aliphatic amines conjugates), bis-HCAAs and tris HCAAs. The developed method was applied for identifying HCAAs in seeds (maize, wheat and rice), roots (rice) and leaves (rice and tobacco). A total of 79 HCAAs were detected, 42 of them were identified in these plants for the first time, and 20 of them have never been reported to exist in plant. The results showed that the developed method can be used to identify HCAAs in plant without prior knowledge of HCAA distributions. To the best of our knowledge, it is the first UHPLC-HRMS database developed for effective deep annotation of HCAAs from non targeted UHPLC-HRMS data. It's useful for the identification of novel HCAAs in plants. PMID- 30453738 TI - Aprotinin Encapsulated Gold Nanoclusters: A Fluorescent Bioprobe with Dynamically Nuclear Targeting and Selective Detection of Trypsin and Heavy Metal. AB - Fluorescence imaging has currently emerged as one of the most frequently used noninvasive imaging technology to selectively monitor biological processes in living systems. In past decades, gold nanoclusters (Au NCs) received increasing attraction because of their intrinsic fluorescence and their inherent biocompatibility. As a stabilizing and reducing agent, an abundant, sustainable and widely used polypeptide derived drug molecule, aprotinin (Ap) is selected for the synthesis of Au nanoclusters (Ap-Au NCs) due to characteristic bioactivity, excellent biocompatibility, biodegradability, nonallergenic character. Herein, Ap encapsulated Au NCs exhibiting desirable red fluorescence feature was facilely produced for the first time, which were subsequently used for cell imaging and detection of various analytes. Much interestingly, dynamically subcellular localization of Ap-Au NCs from the cytoplasm to the nucleus in Hela cells was observed. Afterward, it has shown the selective and quantitative detection of trypsin by using Ap encapsulated Au NCs. Lastly, Ap-Au NCs were readily used for detection of mercury and copper quantitatively. The photoluminescence of the Ap Au NCs was quenched with the addition of metioned analytes. This study opens crucial insights on the integration of biomolecule with metal nanoclusters, also discusses a multifunctional nanomaterial platform for cell imaging, subcellular targeting, biosensing and drug delivery. PMID- 30453739 TI - Dynamic Workflows for Routine Materials Discovery in Surface Science. AB - The rising application of informatics and data science tools for studying inorganic crystals and small molecules has revolutionized approaches to materials discovery and driven the development of accurate machine learning structure/property relationships. We discuss how informatics tools can accelerate research, and we present various combinations of workflows, databases, and surrogate models in the literature. This paradigm has been slower to infiltrate the catalysis community due to larger configuration spaces, difficulty in describing necessary calculations, and thermodynamic/kinetic quantities that require many interdependent calculations. We present our own informatics tool that uses dynamic dependency graphs to share, organize, and schedule calculations to enable new, flexible research workflows in surface science. This approach is illustrated for the large-scale screening of intermetallic surfaces for electrochemical catalyst activity. Similar approaches will be important to bring the benefits of informatics and data science to surface science research. Lastly, we provide our perspective on when to use these tools and considerations when creating them. PMID- 30453740 TI - Accelerating metabolite identification in natural product research: toward an ideal combination of LC-HRMS/MS and NMR profiling, in silico databases and chemometrics. AB - The rapid innovations in metabolite profiling, bioassays and chemometrics have led to a paradigm shift in natural product (NP) research. Indeed, having partial or full structure information about possibly "all" specialized metabolites and an estimation of their levels in plants or microorganisms provides a way to perform pharmacognostic or chemical ecology investigations from a new and holistic perspective. The increasing amount of accurate metabolome data that can be acquired on massive sample sets, notably through data-dependent LC-HRMS/MS and NMR profiling, allows the mapping of natural extracts at an unprecedented level of precision. Most progress made recently in accelerating metabolite identification has been pushed by the need for metabolomics to have tools that provide a confident annotation of the biomarkers highlighted as the results of data mining through multivariate analysis, often on important datasets of complex samples. Historically, NP chemists have been involved in the unambiguous full de novo identification of unknown compounds from complex natural biological matrices. This process is classically performed by the tedious isolation of pure bioactive NPs through comprehensive bioactivity-guided isolation workflows involving orthogonal chromatographic steps at the preparative level. Increasingly advanced metabolomics metabolite profiling methods are of strategic importance in dereplication workflows in NP research as well as for the full metabolome composition assignment of relevant organisms from both drug discovery and chemical ecology perspectives. In this review, we describe the latest developments in metabolite profiling by both LC-MS and NMR-based methods and related databases from a natural product chemist perspective. We assess the current possibilities and limits of such methods and the workflows for manual and automated NP annotations by equally treating the MS and NMR approaches that are both key for the "as confident as possible" NP annotation in crude natural extracts. We also propose future lines of development in the field that are important for NP research but are also generally needed for metabolite annotation in metabolomics because NPs represent perfect candidate compounds for identification due to their intrinsic structural complexity and chemodiversity across organisms. This review does not aim to provide a comprehensive survey of all metabolite profiling applications made in NP research to date. Typical case studies are discussed, and an update of a selection of the latest advanced original studies and numerous specialized reviews is made with links to tools and DBs regarded as useful for their current or future usage in NP research. Evaluations of what can be readily implemented and what is still required for confident NP structural elucidation are made, especially concerning access to generic structural and spectral DBs as well as the use of orthogonal detection methods for improved confidence in metabolite annotation. PMID- 30453741 TI - Uncovering the Complexity of the Simplest Atom Transfer Reaction. PMID- 30453742 TI - Relationship Continuity/Discontinuity-A Framework for Investigating the Role of Relationships in the Experience of Living With Dementia. AB - A recent paper (Riley, Evans and Oyebode, 2018) reported that a sense of discontinuity in carers' experience of their spousal relationship with a person with dementia is associated with a greater sense of burden and fewer rewards from the caregiving role. This commentary sets the paper in context by providing a brief overview of research relating to relationship continuity/discontinuity. Factors that may explain why some carers experience continuity but others discontinuity are reviewed. So, too, is the potential impact of continuity/discontinuity on how the carer copes with the challenges of dementia. Possible future research is discussed. PMID- 30453743 TI - Coping with the unfamiliar: How do children cope with hospitalization in relation to acute and/or critical illness? A qualitative metasynthesis. AB - The aim of this study was to identify and describe how young children cope with hospitalization in relation to acute and/or critical illness. The study is a qualitative metasynthesis inspired by the approach described by Sandelowski and Barroso. Based on an exhaustive literature search, six studies were included. Data were analyzed through a taxonomic analysis. The findings revealed that the hospitalized children face a variety of challenges during admission to the hospital due to acute and/or critical illness. The main challenge was that hospitalized children strive to cope with different aspects of 'the unfamiliar' that emerge in their illness treatment and hospital stay. The unfamiliar refers to unknown experiences on a physical, emotional, and relational level. Subsequently, children cope with the unfamiliar by striving to convert the hospital stay into something more similar to everyday life, using strategies to secure basic needs and constructing familiarity in the hospital stay. The consequences of the children's coping behavior are discussed and how children strive to keep their integrity intact during illness and hospitalization are revealed. PMID- 30453744 TI - Pharmacy Technicians Are People, Too! Let's Consider Their Personal Outcomes Along With Other Pharmacy Outcomes. AB - Studies have found that expanded pharmacy technician roles can help "free up" pharmacist time, leading to role optimization. However, these studies and the positions taken by many are quite pharmacist-centric. We seem to have underestimated the importance of support staff in pharmacy operations. If research demonstrates that technicians can perform a function safely and effectively, that alone should compel the function's allowance in practice. Freeing up pharmacist time for higher-order care is a positive corollary to technician advancement, but it need not be a precondition for it. PMID- 30453745 TI - Pulmonary Embolism Response Teams: A Novel Approach for the Care of Complex Patients With Pulmonary Embolism. AB - Pulmonary embolism represents the third most common cause of cardiovascular death in the United States. Reperfusion therapeutic strategies such as systemic thrombolysis, catheter directed therapies, surgical pulmonary embolectomy, and cardiopulmonary support devices are currently available for patients with high- and intermediate-high-risk pulmonary embolism. However, deciding on optimal therapy may be challenging. Pulmonary embolism response teams have been designed to facilitate multidisciplinary decision-making with the goal to improve quality of care for complex cases with pulmonary embolism. Herein, we discuss the current role and strategies on how to leverage the strengths from pulmonary embolism response teams, its possible worldwide adoption, and implementation to improve survival and change the paradigm in the care of a potentially deadly disease. PMID- 30453746 TI - Prediabetes and Atherosclerotic Disease. PMID- 30453747 TI - The Effect of 20-Minute Mindful Breathing on the Perception of Suffering and Changes in Bispectral Index Score in Palliative Care Patients: A Randomized Controlled Study. AB - A randomized controlled study was conducted to evaluate the efficacy of 20-minute mindful breathing in suffering reduction. Forty palliative care patients with an overall suffering score of 4 or above as measured with the Suffering Pictogram were recruited and randomly assigned to 20-minute mindful breathing or 20-minute supportive listening. There was statistically significant reduction of suffering score in both the groups. For Bispectral Index Score value, there was statistically significant difference between intervention and control. A 20 minute mindful breathing could be useful in the alleviation of suffering in palliative care. PMID- 30453748 TI - APACPH 2018: The Golden Jubilee Meeting. PMID- 30453749 TI - Defining effective care coordination for mental health referrals of refugee populations in the United States. AB - OBJECTIVES: Refugee populations arriving to the United States report high rates of exposure to trauma and associated psychiatric distress that may necessitate referrals to mental health services. Although refugee arrivals receive a voluntary health screening, mental health screening is not routine. Public health providers report that one barrier to mental health screening concerns uncertainty about how to connect refugee patients to mental health services. This article reports essential components of successful and unsuccessful care coordination related to mental health referrals of refugees. DESIGN: A community based participatory research study explored the characteristics of successful and unsuccessful mental health referrals of refugee patients through an online survey of refugee providers. Ten coders sorted provider stories of mental health referrals into critical incidents that were analyzed using principle components analysis (PCA). Care coordination emerged as an important characteristic of referral success. This category of care coordination was analyzed further into components of successful and unsuccessful care coordination using a higher order PCA. A similar process was followed examining providers' perceptions of why care coordination was successful or unsuccessful. RESULTS: Components describing successful care coordination include ongoing communication between providers, scheduling initial appointments directly, access to emergency mental health services, and case management provided by health plan staff. Components related to unsuccessful care coordination describe the failure to communicate about care or establish appointments in a timely manner and the failure to resolve access barriers. Trust in relationships among providers and between refugee patients and providers was an important reason why care coordination was successful. CONCLUSION: Ongoing communication between providers is essential to successful mental health referrals of patients with refugee backgrounds. Multidisciplinary systems of care may benefit from education about the importance of building relationships among providers and the essential components of successful care coordination. PMID- 30453750 TI - Altered resting-state dorsal anterior cingulate cortex functional connectivity in patients with post-traumatic stress disorder. AB - OBJECTIVE:: The brain functional alterations at regional and network levels in post-traumatic stress disorder patients are still unclear. This study explored brain functional alterations at regional and network levels in post-traumatic stress disorder patients with resting-state functional magnetic resonance imaging and evaluated the relationship between brain function and clinical indices in post-traumatic stress disorder. METHODS:: Amplitude of low-frequency fluctuation and seed-based functional connectivity analyses were conducted among typhoon survivors with ( n = 27) and without post-traumatic stress disorder ( n = 33) and healthy controls ( n = 30) to assess the spontaneous brain activity and network level brain function. Pearson correlation analyses were performed to examine the association of brain function with clinical symptom and social support. RESULTS:: Both the post-traumatic stress disorder group and the trauma-exposed control group showed decreased amplitude of low-frequency fluctuation in the dorsal anterior cingulate cortex relative to the healthy control group. The post traumatic stress disorder group showed increased dorsal anterior cingulate cortex functional connectivity with the right paracentral lobule and bilateral precentral gyrus/postcentral gyrus relative to both control groups. Both traumatized groups exhibited decreased dorsal anterior cingulate cortex functional connectivity with the right hippocampus and left cerebellum relative to the healthy control group. More decreased dorsal anterior cingulate cortex functional connectivity with the right hippocampus was found in the post traumatic stress disorder group. The Checklist-Civilian Version score positively correlated with functional connectivity between the dorsal anterior cingulate cortex and the right paracentral lobule as well as between the dorsal anterior cingulate cortex and the right precentral gyrus/postcentral gyrus. The social support was associated with functional connectivity between the dorsal anterior cingulate cortex and the bilateral precentral gyrus/postcentral gyrus as well as the dorsal anterior cingulate cortex and the left middle frontal gyrus. CONCLUSION:: Trauma exposure may result in aberrant local and network-level functional connectivity in individuals with or without post-traumatic stress disorder. Altered amplitude of low-frequency fluctuation in the dorsal anterior cingulate cortex may be a predisposing risk factor for post-traumatic stress disorder development following trauma exposure. More prominent decreased dorsal anterior cingulate cortex functional connectivity with the right hippocampus might be specific in the post-traumatic stress disorder group. Improvement of social support might possibly be significant for post-traumatic stress disorder patients. PMID- 30453752 TI - New transformation pathway and cytotoxic derivatives from the acid hydrolysis of timosaponin B III. AB - Timosaponin B III is a major bioactive steroidal saponin isolated from Anemarrhena asphodeloides Bge. To potentially discover derivatives with better biological activity, timosaponin B III was structurally modified via acid hydrolysis to yield one new (2, timopregnane A I) C21 steroidal glycoside and seven known compounds. Their structures were elucidated on the basis of NMR spectroscopy and mass spectrometry. All eight compounds were evaluated for cytotoxic activity against MCF7, SW480, HepG2, and SGC7901 cell lines in vitro. As a result, compounds 6 and 7 showed significant activity (IC50 2.94-12.2 MUM) against all tested cell lines. Structure-activity relationships of these compounds were investigated and the preliminary conclusions were provided. Moreover, a new transformation pathway was discovered in the acid hydrolysis of timosaponin B III for the first time. PMID- 30453753 TI - ANNALS EXPRESS: Bile acids and the metabolic syndrome. AB - Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here basic chemistry and regulation of bile acids will be reviewed, as well as their metabolic effects. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined. Key words Bile acids; metabolic syndrome; type 2 diabetes mellitus; non-alcoholic fatty liver disease; farnesoid X receptor (FXR); Takeda G-protein coupled receptor 5 (TGR5). PMID- 30453751 TI - The Cancer Prevention Project of Philadelphia: preliminary findings examining diversity among the African diaspora. AB - OBJECTIVE: Cancer mortality inequity among persons of African Ancestry is remarkable. Yet, Black inclusion in cancer biology research is sorely lacking and warrants urgent attention. Epidemiologic research linking African Ancestry and the African Diaspora to disease susceptibility and outcomes is critical for understanding the significant and troubling health disparities among Blacks. Therefore, in a cohort of diverse Blacks, this study examined differences in genetic ancestry informative markers (AIMs) in the DNA repair pathway and the cancer related biomarker 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). METHODS: Participants completed a questionnaire and provided bio-specimens. AIMs in or around DNA repair pathway genes were analyzed to assess differences in minor allele frequency (MAF) across the 3 ethnic subgroups. NNAL concentration in urine was measured among current smokers. RESULTS: To date the cohort includes 852 participants, 88.3% being Black. Of the 752 Blacks, 51.3% were US-born, 27.8% were Caribbean-born, and 19.6% were Africa-born. Current and former smokers represented 14.9% and 10.0%, respectively. US-born Blacks were more likely to be smokers and poor metabolizers of NNAL. Two-way hierarchical clustering revealed MAF of AIMs differed across the 3 ethnic subgroups. CONCLUSION: Our findings are consistent with the emerging literature demonstrating Black heterogeneity underscoring African Ancestry genetic subgroup differences - specifically relevant to cancer. Further investigations, with data harmonization and sharing, are urgently needed to begin to map African Ancestry cancer biomarkers as well as race, and race by place?region comparative biomarkers to inform cancer prevention and treatment in the era of precision medicine. PMID- 30453754 TI - ANNALS EXPRESS: A retrospective pilot study to examine the potential of aspartate aminotransferase to alanine aminotransferase ratio as a predictor of post operative acute kidney injury in patients with hepatocellular carcinoma. AB - BACKGROUND: The aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ratio(AST/ALT) is an independent predictor of hepatic disease. OBJECTIVES: To evaluate the association between pre-operative AST/ALT and post-operative acute kidney injury(AKI) in hepatocellular carcinoma (HCC) patients. METHODS: A total of 422 hepatitis B- or C- virus associated HCC patients, who underwent hepatectomy between September 2012 and April 2018, were enrolled this retrospective study. From all patients, AST and ALT parameters were collected and the AST/ALT ratio was calculated. For diagnostic criteria of post-operative AKI, the Kidney Disease Improving Global Outcomes (KDIGO) criteria guidelines were used. RESULTS: In 48 patients(11.4%), post-operative AKI was confirmed. In patients with post-operative AKI, the mean pre-operative serum AST/ALT was significantly higher when compared to patients without post-operative AKI. After multivariate logistic regression analysis, AST/ALT, hemoglobin, age, hypertension, Child-Turcotte-Pugh classification and the Milan criteria were all confirmed as predictive factors of postsurgical AKI. We found that an AST/ALT of 1.29 was the best cutoff point for predicting post-operative AKI. The positive predictive value (23.9%) of the cut-off is actually poor. After matching the propensity score, AST/ALT >=1.29 was still confirmed as an independent predictor of post-operative AKI by multivariate analysis. CONCLUSION: Pre-operative elevated serum AST/ALT may be a potential independent predictor of post-operative AKI in HCC patients who have undergone hepatectomy. This needs to be tested in further prospective studies. PMID- 30453756 TI - Gene expression profiling in melanoma: past results and future potential. AB - The field of melanoma oncology is rapidly evolving with advances in detection, staging and treatment. There is heterogeneity in all stages of melanoma where some patients fare better than others for reasons currently unknown and it is sometimes unclear which patients warrant closer surveillance, multidisciplinary care, increased imaging, more aggressive surgery or adjuvant therapy. Early studies have shown the predictive ability of gene expression profiling (GEP) and institutions that have adopted GEP for melanoma treatment have demonstrated changes in practice patterns and patient management. The goal of this paper is to review the clinical evidence for a new diagnostic test, DecisionDx-Melanoma, the only GEP test for cutaneous melanoma with prospective studies analyzing its utility. PMID- 30453755 TI - Estimating Returns to College Attainment: Comparing Survey and State Administrative Data-Based Estimates. AB - BACKGROUND:: The increasing availability of massive administrative data sets linking postsecondary enrollees with postcollege earnings records has stimulated a wealth of new research on the returns to college and has accelerated state and federal efforts to hold institutions accountable for students' labor market outcomes. Many of these new research and policy efforts rely on state databases limited to postsecondary enrollees who work in the same state postcollege, with limited information regarding family background and precollege ability. OBJECTIVES:: In this article, we use recent waves of data from the National Longitudinal Survey of Youth 1997 to provide new, nationally representative, nonexperimental estimates of the returns to degrees, as well as to assess the possible limitations of single-state, administrative data-based estimates. RESEARCH DESIGN:: To do this, we explore the sensitivity of estimated returns to college, by testing different sample restrictions, inclusion of different sets of covariates, and alternative ways of treating out-of-state earnings to approximate the real-world limitations of state administrative databases. RESULTS:: We find that failure to control for measures of student ability leads to upward bias, while limiting the sample to college enrollees only leads to an understatement of degree returns. On net, these two biases roughly balance out, suggesting that administrative data-based estimates may reasonably approximate true returns. CONCLUSIONS:: We conclude with a discussion of the relative advantages and disadvantages of survey versus administrative data for estimating returns to college as well as implications for research and policy efforts based upon single state administrative databases. PMID- 30453757 TI - EEG Neurofeedback Training in Children With Attention Deficit/Hyperactivity Disorder: A Cognitive and Behavioral Outcome Study. AB - BACKGROUND: Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood disorder with symptoms of inattention, impulsivity, and hyperactivity. EEG neurofeedback training (NFT) is a new intervention modality based on operant conditioning of brain activity, which helps reduce symptoms of ADHD in children. METHODS AND PROCEDURES: To examine the efficacy of NFT in children with ADHD, an experimental longitudinal design with pre-post comparison was adopted. A total of 30 children in the age range of 6 to 12 years diagnosed as ADHD with or without comorbid conditions were assigned to treatment group (TG; n = 15) and treatment as usual group (TAU; n = 15). TG received EEG-NFT along with routine clinical management and TAU received routine clinical management alone. Forty sessions of theta/beta NFT at the C3 scalp location, 3 to 4 sessions in a week for a period of 3.5 to 5 months were given to children in TG. Children were screened using sociodemographic data and Binet-Kamat test of intelligence. Pre-and postassessment tools were neuropsychological tests and behavioral scales. Follow up was carried out on 8 children in TG using parent-rated behavioral measures. RESULTS: Improvement was reported in TG on cognitive functions (sustained attention, verbal working memory, and response inhibition), parent- and teacher rated behavior problems and on academic performance rated by teachers. Follow-up of children who received NFT showed sustained improvement in ADHD symptoms when assessed 6 months after receiving NFT. CONCLUSION: The present study suggests that NFT is an effective method to enhance cognitive deficits and helps reduce ADHD symptoms and behavior problems. Consequently, academic performance was found to be improved in children with ADHD. Improvement in ADHD symptoms induced by NFT were maintained at 6-month follow-up in children with ADHD. PMID- 30453758 TI - Phytochemical characterization of bioactive compounds composition of Rosmarinus eriocalyx by RP-HPLC-ESI-QTOF-MS. AB - Rosmarinus eriocalyx (rosemary or Elyazir) is an endemic species growing in arid steppe and rocky mountain in the South-West Algeria. This plant is well known in Algeria and Morocco due to its medicinal properties. However, little is known about its phytochemical composition. For this purpose, natural antioxidant compounds from R. eriocalyx were recovered by solid-liquid extraction and characterized by reversed-phase high-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry using negative and positive ionization modes. This analytical methodology enabled the characterization of 101 compounds, which were distributed in five major categories namely hydroxycinnamic acid derivatives, hydroxybenzoic acid derivatives, flavonoids, phenolic diterpenes and phenolic triterpenes. Moreover, the studied extract generally showed free radical-scavenging and reductive abilities in the range of butylated hydroxyanisole, butylated hydroxytoluene, alpha-tocopherol, and ascorbic acid. Therefore, the result suggests that the aqueous-methanolic extract of R. eriocalyx could serve as a potential source of antioxidants. PMID- 30453759 TI - Developing Pilot Interventions to Address Food Insecurity and Nutritional Needs of People Living With HIV in Latin America and the Caribbean: An Interinstitutional Approach Using Formative Research. AB - BACKGROUND:: Food insecurity and malnutrition present challenges to HIV management, but little research has been done in Latin America and the Caribbean (LAC). OBJECTIVE:: To assess levels of food insecurity and malnutrition among people living with HIV (PLHIV) across multiple countries in LAC to inform pilot projects and policy. METHODS:: Through interinstitutional collaboration, we collected data on sociodemographics, household food security, anthropometry, and commonly consumed foods among adults seeking care at HIV clinics in Bolivia, Honduras, and the Dominican Republic (DR; N = 400) and used the results for pilot projects. RESULTS:: Most PLHIV had moderate or severe household food insecurity (61% in Bolivia, 71% in Honduras, and 68% in DR). Overweight and obesity were also highly prevalent, particularly among women (41%-53% had body mass index >=25). High body fat was also prevalent, ranging from 36% to 59%. Among salient foods, fruits and vegetables were lacking. Country-specific pilot projects incorporated locally tailored nutrition counseling with a monthly household food ration, linkage to income-generating projects, or urban gardens. Nutritional counseling was conducted initially by professionals and later modified for peer counselors given the lack of nutritionists. CONCLUSION:: High levels of food insecurity and overweight among PLHIV in LAC have important implications, since prior interventions to address food insecurity among PLHIV have focused on underweight and wasting. Formative research and intersectoral collaboration facilitated locally appropriate nutritional materials and interventions, enhanced local capacities, and helped incorporate nutritional guidelines into policies and practice. Addressing human capital constraints in resource-poor settings and developing complementary strategies were key recommendations. PMID- 30453760 TI - Predictors of health care workers' support for discriminatory treatment and care of people who inject drugs. AB - Complex lifestyle issues associated with injecting drug use may make it difficult to provide care to people who inject drugs (PWID). Negative attitudes towards PWID can undermine the provision of good quality care, hence, it is important to explore the impact of health workers' attitudes in the delivery of care to PWID. An online survey was administered to 336 health workers assessing contact with and attitudes towards PWID, concerns about these clients as well as whether health workers feel stigmatised by working with PWID. Health workers were also asked whether they supported the discriminatory behaviour of a colleague in a series of hypothetical scenarios about working with PWID. In correlational analyses, negative attitudes towards PWID, greater concerns about the behaviour of PWID, not feeling stigmatised by colleagues and seeing fewer clients who inject were associated with greater support for discriminatory actions in the hypothetical scenarios. Multiple regression analysis results showed that only attitudes towards PWID and concerns about the behaviour of injecting clients remain independent predictors of participant support for the hypothetical scenarios. This research highlights the role of attitudes toward PWID in understanding health workers' decisions, practices and potential behaviour. PMID- 30453761 TI - Measures of Accuracy for Continuous Glucose Monitoring and Blood Glucose Monitoring Devices. AB - Currently, patients with diabetes may choose between two major types of system for glucose measurement: blood glucose monitoring (BGM) systems measuring glucose within capillary blood and continuous glucose monitoring (CGM) systems measuring glucose within interstitial fluid. Although BGM and CGM systems offer different functionality, both types of system are intended to help users achieve improved glucose control. Another area in which BGM and CGM systems differ is measurement accuracy. In the literature, BGM system accuracy is assessed mainly according to ISO 15197:2013 accuracy requirements, whereas CGM accuracy has hitherto mainly been assessed by MARD, although often results from additional analyses such as bias analysis or error grid analysis are provided. The intention of this review is to provide a comparison of different approaches used to determine the accuracy of BGM and CGM systems and factors that should be considered when using these different measures of accuracy to make comparisons between the analytical performance (ie, accuracy) of BGM and CGM systems. In addition, real-world implications of accuracy and its relevance are discussed. PMID- 30453762 TI - Diabetes on Twitter: A Sentiment Analysis. AB - BACKGROUND:: Contents published on social media have an impact on individuals and on their decision making. Knowing the sentiment toward diabetes is fundamental to understanding the impact that such information could have on people affected with this health condition and their family members. The objective of this study is to analyze the sentiment expressed in messages on diabetes posted on Twitter. METHOD:: Tweets including one of the terms "diabetes," "t1d," and/or "t2d" were extracted for one week using the Twitter standard API. Only the text message and the number of followers of the users were extracted. The sentiment analysis was performed by using SentiStrength. RESULTS:: A total of 67 421 tweets were automatically extracted, of those 3.7% specifically referred to T1D; and 6.8% specifically mentioned T2D. One or more emojis were included in 7.0% of the posts. Tweets specifically mentioning T2D and that did not include emojis were significantly more negative than the tweets that included emojis (-2.22 vs -1.48, P < .001). Tweets on T1D and that included emojis were both significantly more positive and also less negative than tweets without emojis (1.71 vs 1.49 and 1.31 vs -1.50, respectively; P < .005). The number of followers had a negative association with positive sentiment strength ( r = -.023, P < .001) and a positive association with negative sentiment ( r = .016, P < .001). CONCLUSION:: The use of sentiment analysis techniques on social media could increase our knowledge of how social media impact people with diabetes and their families and could help to improve public health strategies. PMID- 30453763 TI - Analysis of "Performance of a Factory-Calibrated, Real-Time Continuous Glucose Monitoring System in Pediatric Participants With Type 1 Diabetes". AB - Accuracy of sensors play an important role in the acceptance and long-term use of CGM which is related to improved glycemic outcome. This has been lower in children and adolescents in the past for reasons such as size of the device, pain, and necessity to calibrate sensors but also inaccuracy and perceived nonreliability on alarms among others. In the study of Welsh et al, performance of a new, factory-calibrated sensor was assessed. The accuracy of the sensor, as measured in MARD, paired values within 20/20% or 15/15% and surveillance error grid analysis showed very good results, although less so in low value range <70 mg/dL, falling rate of change, and on first day of use. Accurate glucose measurements especially in these incidences are of utmost importance to people with diabetes as their treatment decisions are based on these, also in the beginning of sensor use. PMID- 30453764 TI - Child neglect and its association with social living ability: does the resilience attenuate the association? AB - Our study aims to explore child neglect among preschool children in rural China and examine its association with social living ability. Furthermore, another purpose is to examine whether there is a mediated effect of resilience on this association. A cross-sectional survey was conducted among 2397 children aged 6-72 months in rural area of Anhui province. Social living ability, neglect and resilience were measured by Infant-Junior Middle School Student's Ability of Social Life Scale, Child Neglect Evaluation Scales and Devereux Center for Resilient Children (DCRC) Assessment Tools (DECA), respectively. Binary logistic analysis was performed to explore the relationship. The results showed that overall prevalence of child neglect was 59.4% among children aged 6-72 months. Children aged 36-72 months who suffered physical neglect, educational neglect and medical neglect were more likely to express lower social living ability. After adjusting resilience, the association between lower social living ability and child neglect was slightly attenuated but remained significant. In conclusion, neglect would exert the adverse effect on children in 36-72 months group. Children experiencing physical, educational and medical neglect have more chance to express lower social living ability. High resilient subjects may be partly protected against the detrimental effects of child neglect. PMID- 30453766 TI - Investigating Relationships Between Drinking Venues, Drinking Companions, and Corporal Punishment of Children. AB - Limited evidence suggests that how much a parent drinks in a particular venue, such as a bar, restaurant, or a friend's home, is associated with use of corporal punishment. However, these relationships could differ depending on their drinking companions (e.g., spouse or friends). In this study, weighted zero-inflated Poisson models were used to examine whether the relationships between venue specific drinking frequency, heavier drinking, and corporal punishment are moderated by drinking companions in a mixed-mode sample of parents ( n = 1,599). The relationships between drinking frequency, heavier drinking, and corporal punishment varied by drinking companions, with some combinations being protective and others conferring risk. While most alcohol screening tools focus on individual alcohol use, more nuanced assessment examining where and with whom parents are drinking could be helpful in understanding risk of physical discipline. PMID- 30453765 TI - Attributes of evidence-based occupational therapists in stroke rehabilitation. AB - BACKGROUND.: A better understanding of the features characterizing expert evidence-based occupational therapists in stroke rehabilitation is needed to inform the design of educational and knowledge translation interventions aimed at addressing research-practice gaps. PURPOSE.: The study aimed to identify the attributes of evidence-based occupational therapy stroke rehabilitation experts from the perspective of their peers. METHOD.: Forty-six occupational therapy clinicians and managers completed an online questionnaire asking them to nominate "outstanding" and "expert evidence-based" occupational therapists in stroke rehabilitation and to explain their choices. A thematic analysis of respondents' statements was conducted. FINDINGS.: Both outstanding and expert evidence-based occupational therapists were perceived to be motivated self-learners; to have extensive knowledge, skills, and experience; to act as scholarly practitioners; to achieve superior client outcomes; and to work in specialized settings. IMPLICATIONS.: The development of future strategies supporting occupational therapy students and clinicians to become lifelong learners should take into account key attributes of expertise, such as motivation for continuous learning and professional development. PMID- 30453767 TI - Provider Adherence to Preventative Health Care Guidelines in Adolescent Girls Presenting for Well Visit. AB - A dearth of research exists examining provider adherence to preventative health care guidelines at adolescent well-care visits. We examined adherence in 3 domains: documentation of sexual activity, documentation of menstrual characteristics, and administration of the human papillomavirus vaccine. We identified electronic health records of a random sample of 124 adolescent girls seen within the hospital-affiliated pediatric primary care clinics from July 1, 2014, to June 30, 2015. Approximately one quarter of the records examined had no documentation of sexual activity. Documentation occurred more frequently in English speakers ( P = .003). Asian girls had the least documentation of sexual activity ( P = .003). Clinicians documented menses characteristics in only 27% of adolescent girls with no documentation noted for Asian adolescents. Over 40% of eligible adolescents did not receive the human papillomavirus vaccine. Only 19.4% of adolescents received all the 3 recommended services. This study demonstrates that adolescent girls are not receiving recommended assessments or care to protect their reproductive health. PMID- 30453768 TI - Is Amniotic Fluid Level a Predictor for Syndromic Diagnosis in Robin Sequence? AB - OBJECTIVE:: The purpose of this study was to determine whether gestational amniotic fluid level abnormalities were associated with postnatal syndromic status in a series of patients with Robin sequence (RS). DESIGN:: Retrospective study of participants with RS at Boston Children's Hospital from 1967 to 2017. Participants were divided into syndromic and nonsyndromic groups. The primary predictor variable was postnatal syndromic diagnosis (yes/no). Additional predictor variables included gestational age at birth, birthweight, sex, presence of cleft palate, and other congenital anomalies. The primary outcome variable was amniotic fluid level (normal, oligohydramnios, or polyhydramnios). Descriptive statistics were computed and logistic regression was used to analyze amniotic fluid level as a predictor for syndromic diagnosis. Statistical significance was set at P < .05. RESULTS:: Sixty-five (54%) syndromic and 56 (46%) nonsyndromic RS participants were included. An abnormal amniotic fluid level was seen significantly more frequently in the syndromic group (49.2% vs 25.0%; P = .001). Abnormal amniotic fluid level was associated with a 2.9-fold increased likelihood of a syndromic diagnosis ( P = .007). Polyhydramnios, which was seen more frequently than oligohydramnios, predicted a 4.18 times increased likelihood of a syndromic diagnosis ( P = .003). CONCLUSIONS:: Abnormal amniotic fluid level, particularly polyhydramnios, is associated with an increased likelihood of a syndromic diagnosis in patients with RS. PMID- 30453769 TI - Intraoral Premaxillary Distraction in a Patient With Maxillary Retrognathic Cleft Lip and Palate: A Case Report. AB - Patients with cleft lip and palate sometimes have a retruded maxilla. Here, we describe the case of a young man in whom crowding of the maxillary teeth and an anteroposterior discrepancy of the maxilla were resolved by premaxillary distraction osteogenesis (DO) using 3 individual intraoral distractors. Our experience in this patient confirms that premaxillary DO with 3 intraoral distractors and preoperative simulation can achieve stable maxillary advancement and arch expansion without impairing velopharyngeal incompetence. PMID- 30453770 TI - Olfactory and cognitive functioning in patients with fibromyalgia. AB - Fibromyalgia is a complex syndrome characterized by chronic musculoskeletal pain. Previous research has found impaired olfactory function and cognitive deficits in patients with fibromyalgia. In non-clinical population (middle-aged and elderly populations) an association has been found between olfactory function and cognitive impairment. Therefore, olfactory impairment identification could be considered as a reliable and early marker predicting the decline of cognitive function in mild cognitive impairment, Alzheimer's disease and Parkinson's disease. Nevertheless, the relationship between cognitive and olfactory functioning has not been studied in fibromyalgia patients. The aims of the study have been to analyze the cognitive and olfactory functioning and their association in a sample of women with fibromyalgia in comparison to women without a chronic pain disease. A transversal study was conducted with fibromyalgia patients (n = 146) and women without a chronic pain disease (n = 122). Data were collected using the WAIS-III (cognitive functioning) and the CCCRC test (olfactory functioning). Descriptive analysis, Student's t test and chi-square tests were conducted. There were significant differences in perceptive organization and processing speed, and in odour identification, odour threshold and total CCCRC score; the lower scores were for fibromyalgia patients. Among the fibromyalgia patients there were significant differences in the verbal scale, the manipulative scale, the total scale and processing speed between normosmic and hyposmic patients, the lowest scores were for hyposmic patients. Although previous literature has shown that self-reports by fibromyalgia patients inform about an enhanced olfactory acuity, the current study suggests that there are deficits in olfactory functioning in these patients. Also, the relationship between olfactory and cognitive functioning in fibromyalgia patients, due to the lack of previous studies, suggests a new line of research. Taken together, these results suggest that olfactory functioning could be included in a bio-psycho social approach of fibromyalgia patients, because of the association with cognitive functioning. PMID- 30453771 TI - Persistent Depression: Should Such a DSM-5 Diagnostic Category Persist? PMID- 30453772 TI - Continuous Glucose Monitoring Integration in Clinical Practice: A Stepped Guide to Data Review and Interpretation. AB - BACKGROUND:: The advent of continuous glucose monitoring (CGM) technology has transformed the approach to diabetes care. Multiple CGM systems are commercially available and increased accuracy has allowed development of hybrid and automated insulin delivery systems. Evidence of CGM clinical benefits has also increased exponentially in the last decade. METHODS:: Literature search, review of professional guidelines, and consensus statements were used to guide the preparation of this article. The clinical benefits of both professional and personal CGM in clinical practice as well as barriers to wider adotpion were explored. A stepped approach to review and interpretation of CGM data is suggested for use in the clinician's office regardless of the software used. RESULTS:: Although increasing, the use of CGM in patients with diabetes is still not widespread; multiple barriers are still in place, despite the approval of CGM systems for patients above the age of 2 years old, the extension of coverage for Medicare beneficiaries and the integration of CGM with multiple insulin pump systems. Integration of CGM technology in clinical practice presents various challenges, from concerns relative to time constraints during office visits to lack of systematic approach to interpretation of the data. CONCLUSIONS:: Understanding the usefulness of personal and professional CGM, appropriate patient selection as well as patient and provider training are crucial for the expansion of CGM therapy use in clinical practice. Utilizing the proposed stepped approach to CGM review and interpretation may allow wider adoption of CGM with more effective and efficient office visits. PMID- 30453773 TI - Acute high-intensity interval exercise induces greater levels of serum brain derived neurotrophic factor in obese individuals. AB - IMPACT STATEMENT: High-intensity interval exercise (HIIE) has been shown to be a time-efficient exercise strategy that provides similar or superior physiological benefits as traditional continuous moderate-intensity exercise (CME). Our previous study demonstrated an equivalent elevation on the BDNF response in both obese and normal-weight individuals following 30 min of acute CME. To discover a time-efficient exercise strategy to improve brain health in an obese population, the present study found that obese individuals elicit a greater level of BDNF following acute HIIE versus CME than normal-weight individuals. These findings indicate that acute HIIE may be an effective strategy to upregulate BDNF expression in obese individuals. PMID- 30453774 TI - Ventilator-induced diaphragm dysfunction in critical illness. AB - IMPACT STATEMENT: Mechanical ventilation (MV) is life-saving for patients with acute respiratory failure but also causes difficult liberation of patients from ventilator due to rapid decrease of diaphragm muscle endurance and strength, which is termed ventilator-induced diaphragmatic damage (VIDD). Numerous studies have revealed that VIDD could increase extubation failure, ICU stay, ICU mortality, and healthcare expenditures. However, the mechanisms of VIDD, potentially involving a multistep process including muscle atrophy, oxidative loads, structural damage, and muscle fiber remodeling, are not fully elucidated. Further research is necessary to unravel mechanistic framework for understanding the molecular mechanisms underlying VIDD, especially mitochondrial dysfunction and increased mitochondrial oxidative stress, and develop better MV strategies, rehabilitative programs, and pharmacologic agents to translate this knowledge into clinical benefits. PMID- 30453775 TI - Assessing Burden of Care in the Patient With Cleft Lip and Palate: Factors Influencing Completion and Noncompletion of Nasoalveolar Molding. AB - OBJECTIVE:: Evaluate the factors that influence caregiver-reported completion of nasoalveolar molding (NAM) therapy for patients with cleft lip and palate. DESIGN:: An IRB-approved 30-question survey. SETTING:: Outpatient clinic for patients with cleft lip. PATIENTS:: Patients with unilateral or bilateral cleft lip treated with NAM therapy. INTERVENTIONS:: Survey of previous experiences. MAIN OUTCOME MEASURE(S):: Rate of noncompletion for patients initiating NAM therapy and identifiable causes. RESULTS:: Of 94 patients who underwent NAM, 13 (13.8%) failed to complete NAM therapy. Reasons for incomplete treatment included: obstructive sleep apnea, device intolerance, tape issues, and lack of support. Patients who did not complete NAM therapy were less likely to have primary caregivers >30-year old ( P = .045) and more likely to be the first child for the family ( P = .021) and have a bilateral cleft ( P = .03). Caregivers of NAM patients were less satisfied with the outcome ( P < .001) when they did not complete therapy. CONCLUSION:: This study shows that a high number of parents fail to complete this therapy for many reasons, personal and medical. More data are needed to elucidate true prevalence of NAM noncompletion and to establish evidence-based guidelines to reduce barriers to care for completing NAM treatment. PMID- 30453776 TI - Two new xanthone glycosides from Swertia punicea Hemsl. and their anti inflammatory activity. AB - Two new xanthone glycosides (1-2), together with seven known analogues (3-9), were isolated from whole herb of Swertia punicea. The structures of these metabolites were established on the basis of detailed spectroscopic analysis and comparison with data reported in the literature. In an in vitro test, all isolates were evaluated for their anti-inflammatory activity. The results revealed that all of them showed significant anti-inflammatory activity with IC50 values ranging from 1.237 to 3.319 mM. Compounds 3, 4, and 5 (IC50 values in the range 1.237-1.987 mM) displayed more potent anti-inflammatory activity than the positive control, indomethacin (IC50 value of 2.004 mM). PMID- 30453777 TI - Chemical constituents and allelopathic activity of Machaerium eriocarpum Benth. AB - The analysis by HPLC-PDA of the hydroalcoholic extract of the leaves of M. eriocarpum together with the injection of the fractions containing the already identified metabolites allowed the detection of at least 5 flavonoids, of which two are derived from apigenin and three from luteolin. After isolating larger amounts of isovitexin (I), assays were performed to evaluate the allelopathic activity together with the crude extract. The results show that the initial inhibition indexes were very similar to those observed in the treatments with F17 (Fraction enriched in isovitexin) and F18 (isovitexin), mainly in the concentrations of 500 and 1000 mg L-1. The index of the number of lateral roots, an increase of the inhibitory effect is observed with the increase of the concentration of M. eriocarpum extract. PMID- 30453778 TI - "Tiny Tiny Little Nothings": Minimization and Reassurance in the Face of Cancer. AB - Drawing from a sub-sample of video recorded and transcribed oncology interviews, Conversation Analysis is used to examine moments when cancer is portrayed as absent or minimally present but not dangerously invasive. Though cancer patients and their doctors invest considerable efforts pursuing life-affirming and hopeful possibilities advancing the quality of living and healing outcomes, little is known about how"good news" and thus hopeful social actions get organized. An interactional practice is identified for depicting tumor sizes as small or shrinking - a displayed preference to tumors that are large, growing, and spreading (i.e., metastasizing). By relying on gestural depictions (e.g., pinched fingers and open hands), in precise unison with paired lexical affiliates (e.g., tiny, little, nothing), it is shown how patients seek to justify their wellness and doctors offer reassurance by demonstrating that tumor sizes are minimally threatening. These interactional practices provide a needed balance to deathly cancer stereotypes, criticisms of health-care bureaucracies as inhumane, and overreliance on biomedical authority enacted during clinical encounters. A need exists to verify the existence of a benign social order in the midst of cancer care, actions designed to address malignant diagnoses by curtailing uncontrolled cancer growth. PMID- 30453779 TI - Recent advancement in nanocarriers for oral vaccination. AB - Non-invasive mucosal immune response plays an important role in controlling various infections through mucosal route. Therefore, the appropriate induction of effective immune response should be elicited after immunization. Currently, a lot of strategies have been investigated to enhance the mucosal immunity including microparticles, liposomes, virosomes, cochleates and aracheosomes. These carriers due to tunable and unique physicochemical properties offer the possibility for better antigen presentation by appropriate cells, being more effective to induce a comparable immune response. The objective of this review is to give an overview of novel strategies for the delivery of vaccines through the mucosal route. PMID- 30453781 TI - Study on chemical constituents of an edible mushroom Volvariella volvacea and their antitumor activity in vitro. AB - Phytochemical investigation of the fruiting body of Volvariella volvacea led to the isolation of a new furanone, 2(5H)-furanone-4-propionic acid named volvafuranone A (1), together with twelve known compounds (2-13). Compounds 2-7, 9-11 were isolated from this mushroom for the first time. The isolated compounds were assessed for their cytotoxicity against four human tumour lines (SGC-7901, PC-3M, MCF-7, HepG-2), and the results showed that compound 2, 3, 12, 13 have significant cytotoxicity with IC50 values of 5.90 MUM (HepG-2), 20.72 MUM (HepG 2), 27.98 MUM (PC-3M) and 23.15 MUM (PC-3M), respectively. PMID- 30453780 TI - Association of Anxiety and Depression in Obstructive Sleep Apnea Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been associated with mental disorders, but the strength of this association is unknown. The aim of our study was to investigate the association among OSA, depression, and anxiety in adults and to quantitatively summarize the results. METHODS: A literature search in Medline, PubMed, PsycInfo, Scopus, and Web of Science was conducted. Seventy three articles were selected for study. RESULTS: The pooled prevalence of depressive and anxious symptoms in OSA patients was 35% (95% CI, 28-41%) and 32% (95% CI, 22-42%), respectively. CONCLUSIONS: The association between OSA, anxiety, and depression indicates the value of an early diagnosis and personalized treatment of OSA to improve mental disorders conditioning compliance to therapy. These conditions share a probably bidirectional relationship. PMID- 30453782 TI - Microbial transformation of isocoronarin D by Cunninghamella echinulata NRRL 1386. AB - The diterpene isocoronarin D (1) is a bioactive major constituent of labdane diterpene from the aerial parts of Curcuma comosa Roxb. (Zingiberaceae), the Thai medicinal plant. Microbial transformation of 1 was performed by the fungus Cunninghamella echinulata NRRL 1386 to yield three new metabolites, 3beta hydroxyisocoronarin D (2), 6alpha-hydroxyisocoronarin D (3) and 3beta,7alpha dihydroxyisocoronarin D (4). The structures of the new compounds were elucidated by spectroscopic techniques. [Formula: see text]. PMID- 30453783 TI - Improved Insight into and Prediction of Network Dynamics by Combining VAR and Dimension Reduction. AB - To understand within-person psychological processes, one may fit VAR(1) models (or continuous-time variants thereof) to multivariate time series and display the VAR(1) coefficients as a network. This approach has two major problems. First, the contemporaneous correlations between the variables will frequently be substantial, yielding multicollinearity issues. In addition, the shared effects of the variables are not included in the network. Consequently, VAR(1) networks can be hard to interpret. Second, crossvalidation results show that the highly parametrized VAR(1) model is prone to overfitting. In this article, we compare the pros and cons of two potential solutions to both problems. The first is to impose a lasso penalty on the VAR(1) coefficients, setting some of them to zero. The second, which has not yet been pursued in psychological network analysis, uses principal component VAR(1) (termed PC-VAR(1)). In this approach, the variables are first reduced to a few principal components, which are rotated toward simple structure; then VAR(1) analysis (or a continuous-time analog) is applied to the rotated components. Reanalyzing the data of a single participant of the COGITO study, we show that PC-VAR(1) has the better predictive performance and that networks based on PC-VAR(1) clearly represent both the lagged and the contemporaneous variable relations. PMID- 30453784 TI - Socially skilling toil: New artisanship in papermaking in late Choson Korea. AB - In pre-modern Korea, paper was renowned for its white glossy surface and cloth like strength, becoming an important item in both tributary exchanges and private trade. The unique material of the tak tree and related technical innovations, including toch'im, the repeated beating of just-produced paper that provides sizing and fulling effects, were crucial to this fame. However, the scholar officials who integrated papermaking into the state production system in order to meet administrative and tributary needs initially made toch'im corvee and then penal labor, thereby dismissing it as simple toil. They were not alone, though, in denigrating a form of manual labor. Historiographies of modern science and technology are generally silent about such work, focusing instead on how we invented the human out of drudgery. However, papermakers in late Choson Korea (the eighteenth and nineteenth centuries) chose to identify their artisanship with toch'im and eventually succeeded in securing recognition for that technique as a highly paid specialty. By examining this skilling of toch'im, this paper seeks to change the historiographical silence about toil. It overcomes the archival silence that accompanies manual skills by tracing toch'im's contours through its changing locations and associations in society's changing social and material networks, revealing paper artisans' social techniques, or everyday politics that eventually dignified their laborious technique. Paper artisans' changing relationships with tak barks, tools and facilities, central and local authorities, farmers, merchants, and scholar-officials reveal how such social skilling was made in late Choson Korea, where papermaking became a most successful industry. This tracing of toch'im re-situates creative toil and everyday politics of artisanal hands in the interconnected transformation of social relations, craft, and knowledge practices. PMID- 30453785 TI - Isoquinoline alkaloids from Asimina triloba. AB - A new aporphine glycoside, (-)-anolobine-9-O-beta-D-glucopyranoside was isolated from the twigs of pawpaw (Asimina triloba) along with 7 known alkaloids including five aporphine alkaloids (anolobine, nornuciferine, norushinsunine, liriodenine, and lysicamine), a proaporhine alkaloid (stepharine), and a tetrahydrobenzylisoquinoline alkaloid (coclaurine). Among these compounds, nornuciferine, lysicamine, stepharine, and coclaurine are reported for the first time from this plant. The structure of the new compound was elucidated by spectroscopic methods, including 1 D, 2 D NMR, and HRESI-MS. The absolute configuration of compounds 1, 2, 7 and 8 was determined by CD experiment. PMID- 30453786 TI - "I would have told you about being forgetful, but I forgot": the experience of cognitive changes and communicative participation after head and neck cancer. AB - PURPOSE: Survivors of head and neck cancer have reported difficulties with memory, attention, verbal fluency, and processing speed sometimes persisting years after treatment. Self-perceived cognitive function is an important predictor of communication outcomes in this population. This study explores the lived experience of cognitive changes in survivors of non-nasopharyngeal head and neck cancer and how these changes affect communication in their daily lives. MATERIALS AND METHODS: In the phenomenological tradition, five adult survivors of non-nasopharyngeal head and neck cancer participated in individual semi structured interviews. The interviews were audio-recorded, transcribed, coded, and summarized into themes. RESULTS: Two major themes emerged: (1) I would have told you about being forgetful, but I forgot; and (2) It's such a journey that much of it is uncharted. Participants described problems with memory, focus/attention, and task initiation along with slowed processing and language difficulties. These difficulties affected communication at work, socially, and at home. Participants expressed feeling unprepared for the possibility of cognitive changes, not knowing why they were happening or what to do about them. CONCLUSIONS: Results of this study have implications for counseling and treatment of individuals with head and neck cancer, as well as advocating for these patients to receive appropriate information and intervention. Implications for rehabilitation Survivors of non-nasopharyngeal head and neck cancer described experiencing problems with memory and focus/attention along with slowed processing and language difficulties. Study participants generally felt both unprepared for the cognitive changes they experienced and, in many ways, unsupported by healthcare providers and others. Rehabilitation professionals should be aware that cognitive changes following medical treatment for head and neck cancer may affect a patient's ability to learn and follow complex treatment regimens. Rehabilitation professionals can advise and advocate for these patients to receive the appropriate referrals for assessment and treatment of their cognitive symptoms. PMID- 30453787 TI - Pain, impaired functioning, poor satisfaction and diminished health status eight years following perilunate (fracture) dislocations. AB - PURPOSE: Perilunate (fracture) dislocations are rare injuries and diminished functional outcomes are reported. However, Patient Reported Outcomes (PROs) following these injuries are rarely described. The aim of this study was to investigate the long-term impact of perilunate (fracture) dislocations using a range of measures, including pain, function, and quality of life. MATERIALS AND METHODS: This cross-sectional study was conducted from January 2016 until March 2016. Eleven patients who had suffered from perilunate (fracture) dislocations between August 1996 and January 2014 were matched on age and gender with 22 healthy controls. Functional outcome included range of motion and grip strength measurements. The Patient Reported Outcomes included: Patient Reported Wrist Evaluation, Disability of Arm, Shoulder and Hand questionnaire, Michigan Hand Questionnaire and the Short Form-36. RESULTS: The 11 patients that were included (9 males) had a median age at injury of 38 years (IQR 33; 54) and median follow up of 97 months (IQR 84-193). Flexion/extension (mean difference -60 degrees , 95% CI -76, -43, p < 0.001) and ulnar/radial deviation (mean difference -28 degrees , 95% CI -38, -18, p < 0.001) were significantly diminished in patients following perilunate (fracture) dislocations. Grip strength was not affected. The patients experienced significantly more pain as assessed on all pain subscales. Physical functioning was significantly worse in the group with perilunate (fracture) dislocations as assessed on all function subscales, except the PRWE function score and the subscale physical functioning of the Short Form-36. Satisfaction as measured with the Michigan Hand Questionnaire satisfaction subscale (mean difference -36, 95% CI -57, -16, p = 0.002) was also reported poorer. No difference was found regarding work participation. CONCLUSIONS: A perilunate (fracture) dislocation has a significant impact on everyday life, as patients experience diminished range of motion, pain, diminished physical functioning, diminished satisfaction and report lower general health status than healthy controls. However, no consequences for work participation were found in this study. Level of evidence 3. Implications for rehabilitation Flexion/extension and ulnar/radial deviation remains limited following perilunate (fracture) dislocations. Grip strength is not diminished in patients with perilunate (fracture) dislocations. Pain, restrictions in physical functioning, diminished satisfaction and lower general health status are likely to be present following perilunate (fracture) dislocations. If conservative treatment including pain medication and rehabilitation strategies do not relief pain following perilunate (fracture) dislocations, surgical treatment options such as wrist denervation or arthrodesis should be considered. PMID- 30453788 TI - Paracetamol metabolite concentrations following low risk overdose treated with an abbreviated 12-h versus 20-h acetylcysteine infusion. AB - CONTEXT: To compare degree of liver injury and paracetamol metabolite concentrations after treatment with standard of care (20-h) vs. abbreviated (12 h) acetylcysteine regimens used in paracetamol overdose (NACSTOP trial). METHODS: Timed blood samples from a cohort of subjects enrolled in the cluster-controlled NACSTOP trial evaluating a 12-h acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) were assayed for paracetamol metabolites as a pilot study, using liquid chromatography/mass spectrometry. Control group subjects received a 20-h course of acetylcysteine (200 mg/kg over 4 h, 100 mg/kg over 16 h). The intervention group received a 12-h acetylcysteine regimen (stopped after at least 12 h of treatment). Positive control groups not in the trial with acute liver injury (ALI) or hepatotoxicity were also studied. RESULTS: One hundred and forty one blood samples were collected from 40 patients receiving acetylcysteine after paracetamol overdose. Median ALT after 20 h of acetylcysteine was 12 U/L (IQR 8.14) in the abbreviated regimen group, compared to the control group 16 U/L (IQR 11.21) (p = .46). There was no significant difference in median metabolite concentrations on presentation and after 20 h of acetylcysteine between these two groups (p > .05). Presentation median sum CYP-metabolite/total metabolite percentages were 2.5 and 3.0 in the abbreviated and control NACSTOP groups, respectively. CONCLUSIONS: An abbreviated 12-h acetylcysteine regimen for paracetamol overdose used in the NACSTOP trial had similar circulating metabolite concentrations compared to a 20-h regimen in selected subjects with low risk of hepatotoxicity. This suggests that further acetylcysteine may not be needed in the abbreviated group at time of cessation. PMID- 30453789 TI - Giant Lymphatic Malformations in Lower Extremity in an Adult: A Case Report. AB - Lymphatic malformations are benign vascular malformations rarely seen in adults. There have been only around 100 cases reported in the literature, most of them located in the head and neck area. The etiology is poorly understood but trauma, infection, or tumors have been suggested as possible causes. We present an unusual case of lymphatic malformations in the lower extremity of a 56-year-old male patient after minor trauma. The masses were asymptomatic but progressively enlarged for a period of 2 months, developing into a mass with a 21-cm-long axis in computed tomography images. Total surgical resection was performed and there were no complications or recurrence during the 1-year follow-up period. We present this rare case with a review of relevant previous literatures. PMID- 30453790 TI - Cross cultural adaptation of the Greek sarcopenia quality of life (SarQoL) questionnaire. AB - PURPOSE: To translate and validate into the Greek language and setting the Sarcopenia Quality of Life (SarQoL(r)) questionnaire. METHODS: A convenience sample of 176 Greek elderly people (136 females, 40 males; aged 71.19 +/- 7.95 years) was recruited, 50 of which (36 females, 14 males) were diagnosed sarcopenic. Questionnaire was back-translated and culturally adapted into Greek according to international guidelines. To validate the Greek SarQoL(r), we assessed its validity (discriminative power, construct validity), reliability (internal consistency, test-retest reliability) and floor/ceiling effects. Participants were divided into sarcopenic and non-sarcopenic. Sarcopenic subjects apart from the Greek SarQoL (SarQoLGR) filled out the Greek versions of two generic questionnaires; Short Form-36 and EuroQoL 5-dimension. RESULTS: The Greek SarQoL questionnaire was translated without major difficulties. SarQoLGR mean scores were 52.12 +/- 11.04 (range: 24.74-71.81) for sarcopenic subjects and 68.23 +/- 14.1 (range: 24.83-94.81) for non-sarcopenic ones. Results indicated good discriminative power across sarcopenic and non-sarcopenic subjects (p = 0.01), high internal consistency (Cronbach's alpha of 0.96) and excellent test retest reliability (ICC = 0.96, 95% CI = 0.95-0.97). Neither a floor nor a ceiling effect was observed. CONCLUSIONS: The Greek SarQoL was found to be a reliable and valid measure of quality of life for sarcopenic patients. It is therefore, available for use in future clinical research and practice. Implications for rehabilitation The Greek version of the SarQoL(r) questionnaire is a valid and reliable outcome measure for assessing patients with sarcopenia. The Greek SarQoL is recommended to be use in clinical settings and research. The Greek SarQoL(r) questionnaire is available online www.sarqol.org . PMID- 30453791 TI - Dysphagia following C1 laminectomy and posterior atlantoaxial fixation for retro odontoid pseudotumor: a case report. AB - PURPOSE: Although dysphagia is known potential complication of cervical spine surgery, it rarely occurs after a posterior approach. We describe an unusual case of a retro-odontoid pseudotumor that suffered dysphagia following a C1 laminectomy and posterior atlantoaxial fixation. MATERIALS AND METHODS: A 79-year old man presented with progressive tetraparesis and bladder and bowel dysfunction due to severe compression to cervical cord at C1 from a retro-odontoid pseudotumor. After C1 laminectomy and atlantoaxial fixation, the symptoms improved, but dysphagia and aspiration developed, associated with pharyngeal and esophageal stases on videofluoroscopy. RESULTS AND CONCLUSIONS: Possible explanations for postoperative dysphagia include limitation of cervical spine motion, and cervical cord reperfusion injury in addition to the baseline anterior osteophyte and aging. This is the first case of dysphagia developing after laminectomy and posterior atlantoaxial fixation not involving the occipital bone. PMID- 30453793 TI - A goal management intervention for patients with polyarthritis and elevated levels of depressive symptoms: a quasiexperimental study. AB - PURPOSE: Goal was to establish whether an intervention that aims to increase goal management competencies is effective in decreasing elevated levels of depressive symptoms and increasing well-being in patients with polyarthritis. MATERIALS AND METHODS: Eighty-five persons with polyarthritis and elevated levels of depressive symptoms participated in the goal management intervention consisting of six group based meetings. A quasiexperimental design with baseline measurement, follow-up at 6 months and a reference group of 151 patients from an observational study was applied. Primary outcome was depression; secondary outcomes were anxiety, purpose in life, positive affect, satisfaction with participation, goal management strategies, and arthritis self-efficacy. A linear mixed model procedure was applied to evaluate changes in outcomes. RESULTS: No improvement was found for depressive symptoms and no changes were found for the secondary outcomes, except for positive affect that improved in the intervention group. This increase was mediated by an increase in goal adjustment. Furthermore, goal maintenance decreased and self-efficacy for other symptoms increased in the intervention group. CONCLUSION: This study indicates that interventions designed to aid patients with arthritis with goal management skills are potentially helpful for increasing positive affect, although further studies are needed. Implications for rehabilitation People with polyarthritis have to manage their disease in combination with possibly conflicting roles and personal goals, resulting in an ongoing process of finding equilibrium in a constantly changing situation. Based on a person-focused view, the program Right on Target focused on coping with threatened activities and life goals due to arthritis. The program consisted of six group-based meetings led by a trained nurse and a personal trajectory wherein participants were stimulated to try out various behavioral options related to an own threatened activity in concordance with their personal goals. The program seemed effective in increasing flexible goal adjustment and self-efficacy and participants experienced more positive affect directly after the program and at 6 month follow-up. PMID- 30453792 TI - Preliminary investigation of novel tetra-tailed macrocycle amphiphile based nano vesicles for amphotericin B improved oral pharmacokinetics. AB - Supramolecular macrocycles-based drug delivery systems are receiving wider recognition due to their self-assembly into nanostructures with unique characteristics. This study reports synthesis of resorcinarene-based novel and biocompatible amphiphilic supramolecular macrocycle that self-assembles into nano vesicular system for Amphotericin B (Am-B) delivery, a model hydrophobic drug. The macrocycle was synthesized through a two-step reaction and was characterized with 1 H NMR and mass spectrometric techniques. Its biocompatibility was assessed in cancer cell lines, blood and animals. Its critical micelle concentration (CMC) was determined using UV spectrophotometer. Am-B loaded in novel macrocycle-based vesicles were examined according to their shape, size, surface charge, drug entrapment efficiency and excepients compatibility using atomic force microscope (AFM), Zetasizer, HPLC and FT-IR spectroscopy. Drug-loaded vesicles were also investigated for their in-vitro release, stability and in-vivo oral bioavailability in rabbits. The macrocycle was found to be nontoxic against cancer cells, haemo-compatible and safe in mice and revealed lower CMC. It formed mono-dispersed spherical shape vesicles of 174.4 +/- 3.78 nm in mean size. Vesicles entrapped 92.05 +/- 4.39% drug and were stable upon storage with gastric simulated fluid and increased the drug oral bioavailability in rabbits. Results confirmed novel macrocycle as biocompatible vesicular nanocarrier for enhancing the oral bioavailability of lipophilic drugs. PMID- 30453794 TI - LncRNA TINCR is downregulated in diabetic cardiomyopathy and relates to cardiomyocyte apoptosis. AB - Objective LncRNA TINCR has been reported to be involved in cardiac hypertrophy, while its involvement in diabetic cardiomyopathy is unknown. Materials and Methods In this study, myocardial biopsy and serum collected from patients with diabetic cardiomyopathy, diabetic patients without cardiopathy and healthy controls, and the expression of TINCR in those tissues was detected by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). ROC curve analysis was performed to evaluate the diagnostic value of TINCR expression for diabetic cardiomyopathy. Human cardiomyocyte cells (Cat# 12440053, Thermo Fisher Scientific) were treated with high glucose, and the expression of TINCR was detected by qRT-PCR. TINCR expression was transfected into cardiomyocyte cells and cell apoptosis under high glucose treated was detected by cell apoptosis assay. Results We found that TINCR expression level in myocardial biopsy and serum was significantly lower in patients with diabetic cardiomyopathy than in diabetic patients without cardiopathy and healthy controls, while no significant differences were found between diabetic patients without cardiopathy and healthy controls. TINCR expression level can be used to effective diagnose diabetic cardiomyopathy. High glucose treatment showed no significant effects on the expression of TINCR in human cardiomyocyte cells, and TINCR overexpression inhibited apoptosis of cardiomyocytes under high glucose treatment. Conclusion Therefore, we conclude that lncRNA TINCR is downregulated in diabetic cardiomyopathy and it can inhibit cardiomyocyte apoptosis. PMID- 30453795 TI - Unique mode of binding between angiotensin II type 1 receptor and its blockers. AB - BACKGROUND: We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT1R) blockers], may be responsible for the molecular effects of AZL. METHODS: We examined the binding affinities of AZL and CAN to AT1R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild type (WT) and mutants AT1R-transfected cells. RESULTS: The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10-6M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10-6M AZL and AZL-7H did not. In addition, 10-6M CAN, but not 10-6M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS: The interaction between 5-oxo-1,2,4 oxadiazole in AZL and Arg167 in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg167. PMID- 30453796 TI - The hierarchical micro-/nanotextured topographies promote the proliferation and angiogenesis-related genes expression in human umbilical vein endothelial cells by initiation of Hedgehog-Gli1 signaling. AB - The hierarchical microtextured/nanotextured topographies have been recognized to have better tissue integration properties, but the underlying mechanisms are only partially understood. Hedgehog signaling plays a pivotal role in developmental and homeostatic angiogenesis. We suppose that the Hedgehog-Gli1 signaling may play a significant role in the response of endothelial cells to microtextured/nanotextured topographies (MNTs). To confirm this hypothesis, we produced the MNTs decorated with TiO2 nanotubes of two different diameters (25 and 70 nm), and the proliferation, apoptosis, angiogenesis-related genes expression and Hedgehog signaling activity of human umbilical vein endothelial cells (HUVECs) grown onto these MNTs were measured. Our results showed that the MNTs induced significantly high expression of Sonic Hedgehog (SHH), Smoothened (SMO) and GLI1 in the HUVECs as well as high activation of Hedgehog-Gli1 signaling, compared to the smooth surface. The HUVECs grown on the MNTs showed significantly high levels of adhesion, proliferation and expression of angiogenesis-related genes, including angiopoietin-1 (ANG-1), vascular endothelial growth factor (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2) and endothelial nitric oxide synthase (ENOS); these enhancements were attenuated by siRNA-mediated depletion of SMO, which indicated a significant role of Hedgehog-Gli1 signaling in mediating the enhanced effect of the MNTs on the angiogenic potential of HUVECs. This study may contribute to the modification of biomaterial surfaces for better tissue integration and clinical performance. PMID- 30453797 TI - The Influence of Mutuality on Self-Care in Heart Failure Patients and Caregivers: A Dyadic Analysis. AB - Mutuality in patient-caregiver dyad may improve heart failure (HF) patient self care and caregiver contribution to self-care, but literature is scarce. We evaluated the influence of mutuality and its dimensions on patient-caregiver dyad self-care. A sample of 366 HF patient-caregiver dyads was enrolled. The Actor Partner Interdependence Model was used to identify the influence of individual patient and caregiver mutuality on their own self-care (actor effect) and on partner self-care (partner effect). The total mutuality score had an actor effect on patient self-care maintenance (i.e., behaviors aimed at maintaining HF stability) and on patient and caregiver self-care confidence. Total score of patient mutuality also had a partner effect on caregiver self-care management (i.e., responses to symptoms of HF exacerbation). Specific mutuality dimensions had different actor and partner effects on patient and caregiver self-care. Interventions to improve mutuality in HF patient-caregiver dyads may influence patient self-care and caregiver contribution to self-care. PMID- 30453798 TI - In response to "Botulism in pregnancy - a clinical approach to diagnosis and management" published on 25 March issue. PMID- 30453800 TI - Treatment of isolated talonavicular coalition: Case report and literature review. AB - Tarsal coalition refers to an abnormal fibrous, cartilaginous, or bony connection that develops between two or more tarsal bones. Talocalcaneal coalition and calcaneonavicular coalition account for more than 90% of all cases of tarsal coalition. Coalition exists early at birth, but bony connection usually develops during the patient's late growth period. Isolated cases of talonavicular coalition have rarely been reported. We herein report a case involving an 11-year old patient with an isolated talonavicular coalition from a soft tissue to bony connection who was treated with arthroscopy for ankle arthritis. To our knowledge, this is the first case in which the whole formation of the talonavicular coalition was observed with a series of radiographic and magnetic resonance imaging examinations. The pain caused by the talonavicular coalition was managed by nonoperative treatment, while the ankle pain caused by the arthritis was relieved after ankle arthroscopy. At 6 years postoperatively, the patient remained pain-free while walking for 30 minutes and was satisfied with the operative outcome. Continuous follow-up confirmed that after the formation of talonavicular coalition, the coalition can continue to progress, forming bony talocalcaneal coalition and calcaneocuboid coalition. PMID- 30453799 TI - Triptolide inhibits benign prostatic epithelium viability and migration and induces apoptosis via upregulation of microRNA-218. AB - Benign prostatic hypertrophy (BPH) has become a troublesome disease for elder men. Triptolide (TPL) has been reported to be a potential anticancer agent. However, the potential effects of TPL on BPH have not been shown out. BPH-1 cells were treated with different concentrations of TPL and/or transfected with microRNA-218 (miR-218) inhibitor, pc-survivin, sh-survivin, or their corresponding controls (NC). Thereafter, cell viability was determined by CCK-8 assay. Cell migration was accessed by modified two-chamber migration assay. Cell apoptosis was checked by propidium iodide (PI) and fluorescein isothiocyanate (FITC)-conjugated Annexin V staining. In addition, messenger RNA (mRNA) and protein levels were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. BPH-1 cell viability and migration were significantly decreased, while cell apoptosis and expression of miR-218 were statistically enhanced by TPL ( P < 0.05 or P < 0.01). However, downregulation of miR-218 increased cell viability and migration, while decreased cell apoptosis compared with the negative control group ( P < 0.05 or P < 0.01). Furthermore, the expression of cell cycle-related proteins and cell apoptosis related proteins were also led to the opposite results with NC. In addition, we found that miR-218 negatively regulated the expression of survivin ( P < 0.01) and suppression of survivin significantly enhanced cell apoptosis ( P < 0.01). Moreover, the results demonstrated that TPL could inactivate mammalian target of rapamycin (mTOR) pathway, while inhibition of miR-218 alleviated the effects. TPL inhibits viability and migration of BPH-1 cells and induces cell apoptosis and also inactivates mTOR signal pathway via upregulation of miR-218. This study provides evidence for the further studies representing triptolide as a potential agent in the treatment of human BPH. PMID- 30453801 TI - Prevalence and Predictors of Deep Vein Thrombosis in Critically Ill Medical Patients Who Underwent Diagnostic Duplex Ultrasonography. AB - INTRODUCTION:: Deep vein thrombosis (DVT) is a recognized but preventable cause of morbidity and mortality in the medical intensive care unit (MICU). We examined the prevalence and risk factors for DVT in MICU patients who underwent diagnostic venous duplex ultrasonography (DUS) and the potential effect on clinical outcomes. METHODS:: This is a retrospective study examining prevalence of DVT in 678 consecutive patients admitted to a tertiary care level academic MICU from July 2014 to 2015. Patients who underwent diagnostic DUS were included. Potential conditions of interest were mechanical ventilation, hemodialysis, sepsis, Sequential Organ Failure Assessment (SOFA) scores, central venous catheters, prior DVT, and malignancy. Primary outcomes were pulmonary embolism, ICU length of stay, and mortality. Additionally, means of thromboprophylaxis was compared between the groups. Multivariable logistic regression analysis was utilized to determine predictors of DVT occurrence. RESULTS:: Of the 678 patients, 243 (36%) patients underwent DUS to evaluate for DVT. The prevalence of DVT was 16% (38) among tested patients, and a prior history of DVT was associated with DVT prevalence ( P < .01). Between cases and controls, there were no significant differences in central venous catheters, mechanical ventilation, hemodialysis, sepsis, SOFA scores, malignancy, and recent surgery. Patients receiving chemical prophylaxis had fewer DVTs compared to persons with no prophylaxis (14% vs 29%; P = .01) and persons with dual chemical and mechanical prophylaxis ( P = 0.1). Fourteen percent of patients tested had documented DVT while on chemoprophylaxis. There were no significant differences in ICU length of stay ( P = .35) or mortality ( P = .34). CONCLUSIONS:: Despite the appropriate use of universal thromboprophylaxis, critically ill nonsurgical patients still demonstrated high rates of DVT. A history of DVT was the sole predictor for development of proximal DVT on DUS testing. Dual chemical and mechanical prophylaxis does not appear to be superior to single-chemical prophylaxis in DVT prevention in this population. PMID- 30453802 TI - Experiences of Intimate Partner Violence Among Lesbian, Gay, Bisexual, and Transgender College Students: The Intersection of Gender, Race, and Sexual Orientation. AB - Lesbian, gay, bisexual, and transgender (LGBT) college students experience disproportionate rates of intimate partner violence (IPV) compared with their heterosexual and cisgender counterparts. Some studies report rates of IPV among lesbian, gay, and bisexual college students as high as 50%, and 9 times greater among transgender students compared with their cisgender peers. Few studies have investigated the impact of intersectional identity on experiencing different types of IPV, such as emotional, physical, and sexual IPV. The present study utilized the National College Health Assessment-II from 2011 to 2013 ( n = 88,975) to examine the differences in types of IPV among college students based on sexual orientation, gender identity, and the intersection of these two identities. Bivariate Rao-Scott chi-square and multilevel logistic regression was used to test the associations between sexual orientation, gender identity, and the intersection of these identities on multiple types of IPV. Adjusting for covariates and school clustering, LGBT college students had higher odds of reporting emotional IPV (adjusted odds ratios [AORs] = 1.34-1.99), physical IPV (AOR = 1.58-2.93), and sexual IPV (AOR = 1.41-6.18). Bisexual and transgender college students demonstrated the highest odds of reporting IPV based on sexual orientation and gender identity, respectively. Intersectional identities were not significantly associated with IPV. These findings demonstrate a need for clinicians working with college students to be aware of the disproportionate prevalence of IPV among LGBT individuals, particularly for those clients those who identify as bisexual and/or transgender and participate in continuing education related to these populations. Furthermore, these findings illustrate the need for additional intersectional research with LGBT college students. PMID- 30453804 TI - Journal of Family Nursing and Japanese Journal of Research in Family Nursing Collaboration 2018. PMID- 30453803 TI - Measuring Change in Nurses' Perceptions About Family Nursing Competency Following a 6-Day Educational Intervention. AB - This study describes nurses' perspectives about their experience of being involved in a 6-day educational intervention which focused on the development of competency in family nursing practice with a particular emphasis on family nursing conversations. The foundational knowledge of the educational intervention was based on the Calgary Family Assessment Model (CFAM) and the Calgary Family Intervention Model (CFIM). A research design incorporating quantitative and qualitative measurement was used. Before and after the family nursing educational intervention, nurse participants ( n = 18) completed the Families' Importance in Nursing Care-Nurses' Attitudes (FINC-NA) instrument. The outcomes were analyzed using paired-samples t tests. FINC-NA scores increased by 6.94 points ( SD = 5.66, p < .001). To complement the quantitative findings, in-depth interviews were conducted with all of the participants. Participants reported increased awareness of the importance of families in nursing care. In addition to an increase in positive attitudes about families, participants perceived that their knowledge and skills regarding family nursing conversations were more comprehensive. A 6-day educational intervention with a focus on reflection appears useful in helping nurses to "think family" and encouraging perceptions of increased competence in family nursing conversations. PMID- 30453805 TI - Challenges Faced by Family Caregivers: Multiple Perspectives on Eldercare. AB - The focus of this study was to identify challenges to family eldercare provision from the perspectives of both caregivers and community stakeholders. This qualitative study used data from 306 family caregivers and 116 stakeholders (aging, social, and health service professionals who work with older adults and their families) in North Dakota. Data sources included an American Association of Retired Persons-ND survey of 110 caregivers, a survey by the ND Family Caregiver Support Program (196 participants), and a Statewide Caregiving Stakeholder Survey (116 participants). Thematic analysis identified five themes: (a) financial burden of providing eldercare, (b) insufficient access to respite care, (c) difficulty finding and navigating available services and programs, (d) lack of knowledge and training on care provision, and (e) challenges related to environmental context of caregiving. Implications for working with family caregivers and developing policies for eldercare are discussed. PMID- 30453806 TI - Congenital tuberculosis after in vitro fertilization: suggestion for tuberculosis tests in infertile women in developing countries. AB - Congenital tuberculosis (CTB) after in vitro fertilization (IVF) is a major new problem in developing countries. Only 16 cases of CTB after IVF have been reported, and no tuberculosis (TB) tests were performed before IVF in these cases. However, on the basis of data in the literature and from the World Health Organization, the incidence of CTB has been substantially underestimated. We describe two cases of CTB after IVF in detail in our center and provide new insight into the important issue of controlling TB vertical transmission in developing countries. Performing an early diagnosis of CTB, mostly based on evidence of maternal infection and a high index of clinical suspicion, is a challenge. However, most mothers have no symptoms of TB infection during prepartum, and infertility may be the only symptom. Infertility caused by genital TB is common in countries with a high TB burden, and IVF is considered to be an effective treatment to improve their fertility. Therefore, this may lead to more CTB cases without thorough TB tests before IVF. We suggest that thorough TB tests should be conducted in infertile women before IVF to prevent CTB. PMID- 30453807 TI - Coach, Care Coordinator, Navigator or Keyworker? Review of Emergent Terms in Childhood Disability. PMID- 30453808 TI - Percutaneous Hepatic Perfusion With Filtered Melphalan for Localized Treatment of Metastatic Hepatic Disease: A Risk Assessment. AB - Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers. Cardiovascular safety was assessed by echocardiography, electrocardiogram, and telemetry. Toxicology parameters included clinical signs, body weight, gross pathology, and histopathology. There were no treatment-related deaths associated with the PHP procedure with GEN2 filtration, and all animals survived to scheduled necropsy. Assessment of the pharmacokinetic/TK plasma concentrations of melphalan demonstrated that the GEN2 filter was able to extract melphalan from blood with high efficiency and reduce melphalan exposure in the systemic circulation. The hemodynamic, immunosuppressive, immunotoxic, cardiotoxic, and histopathologic effects of melphalan were limited. The significant hemodynamic challenge imposed by filtration resulted in a compensatory tachycardia with supranormal left ventricular function, although no wall motion abnormalities were detected and left ventricular function remained normal. Catecholamines decreased and then quickly rebounded during washout. Transient and reversible effects of treatment on cardiac enzymes, catecholamines, and cytokines and reversible hemodynamic effects without cardiac damage indicated that PHP with melphalan was not cardiotoxic or immunotoxic under the conditions tested, due to high efficiency of the filtration system limiting exposure of melphalan to the systemic circulation. PMID- 30453810 TI - New onset acute promyelocytic Leukemia during pregnancy: report of 2 cases. AB - Acute promyelocytic leukemia (APL) is one of the most fatal hematological malignancies. APL during pregnancy is a rare comorbidity and can lead to adverse outcomes, such as maternal and/or fetal death, without timely and appropriate management. Medical management for APL during pregnancy remains challenging. We reported 2 patients with no regular prenatal visits who were diagnosed with APL during pregnancy. One presented with typical hematological abnormalities related to infection, while the other presented with intracranial hemorrhage, which is rare. Although supportive measures and chemotherapy were administered after APL was diagnosed, these two patients had completely different outcomes. The pregnancy outcomes of APL patients depend greatly on the timely diagnosis and appropriate management of the disease. Physicians should pay more attention to APL during pregnancy and thus may save more maternal and fetal lives. Further study of the management of APL during pregnancy is warranted. Abbreviations: AML: acute myeloid leukemia; APL: acute promyelocytic leukemia; WBC: white blood cell; RBC: red blood cell; Hb: hemoglobin; PT: prothrombin time; TT: thrombin time; APTT: activated partial thromboplastin time; TP: total protein; ALB: albumin; AST: aspartate transaminase; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; ATRA: all-trans retinoic acid; ICH: intracranial hemorrhage; DIC: disseminated intravascular coagulation. PMID- 30453811 TI - Interventions for Promoting Physical Activity Among Individuals With Spinal Cord Injury: A Systematic Review. AB - BACKGROUND: Engaging in physical activity (PA) can bring many benefits to individuals with spinal cord injury (SCI) and understanding the best interventions to promote PA is essential. The objective of this study was to systematically review the literature to check the effectiveness of interventions aimed at increasing the PA level in SCI individuals. METHODS: The bibliographic search was performed in the PubMed, LILACS, Web of Science, and SPORTDiscus databases, including randomized controlled trials involving humans, in which PA level was the primary or secondary outcome, and with samples composed entirely or partially of individuals with SCI. The articles were analyzed by 2 researchers using descriptive statistics and the quality of the studies was assessed using the CONSORT criteria. RESULTS: Seven articles were selected. The studies used different strategies of intervention. Six out of the 7 studies included in the analysis proposed interventions that were effective in increasing PA level (action plans/coping strategies, home exercises, behavioral intervention, elaboration of intentions, workshops, and education for the promotion of PA). In only 1 study, the proposed strategy was not effective (reading a guideline). CONCLUSION: It is concluded that these 6 interventions are effective in increasing the PA level in SCI individuals. PMID- 30453812 TI - Effectiveness of high-dose glucocorticoids on hemolysis, elevating liver enzymes, and reducing platelets syndrome. AB - OBJECTIVE: To investigate the effectiveness of high-dose glucocorticoids on hemolysis, elevating liver enzymes, and reducing platelets (HELLP) syndrome. METHODS: A total of 151 patients with HELLP syndrome were analyzed and divided into two groups. Six subgroups of treatment and control groups were divided into three grades in accordance with the American Mississippi Diagnostic Criteria. RESULTS: There were no differences in general characteristics of the patients, primipara rate, minimum platelet recovery time, postpartum hemorrhage volume, postpartum hemorrhage rate, cumulative average of maternal damage, intensive care unit admission rate, perinatal mortality rate, and overall incidence rate of adverse outcomes in fetuses among the groups. The primipara rate in the control group of the third grade was significantly higher than that in the treatment group of the third grade. The treatment group of the second grade (88.7%) had a significantly higher preterm delivery rate than that in the control group of the second grade (66.7%). There were no differences in minimum hemoglobin, and maximum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase levels among the groups and subgroups. CONCLUSION: High-dose glucocorticoids cannot significantly improve maternal and fetal prognoses and laboratory indices. However, our results might offer some clinical evidence for HELLP syndrome therapy. PMID- 30453813 TI - Association of Helicobacter pylori infection with gastroesophageal reflux disease. AB - OBJECTIVE: Many studies have shown that Helicobacter pylori ( Hp) is negatively correlated with gastroesophageal reflux disease (GERD). Moreover, some studies deny that eradication of Hp increases the incidence of GERD. Therefore, we investigated the association of Hp infection with GERD. METHODS: In this retrospective analysis, patients with peptic ulcers were used as a blank control group. We used logistic regression to analyze the relationship between Hp infection and GERD. We analyzed 953 patients with peptic ulcers, 180 patients with both peptic ulcers and GERD, and 298 patients with GERD. RESULTS: Among the patients with GERD, 75.6% (136/180) and 36.2% (108/298) of those with and without peptic ulcers, respectively, had Hp infection, and the difference was statistically significant. Among patients with peptic ulcers, 75.6% (136/180) and 67.4% (642/953) of those with and without GERD, respectively, had Hp infection. The incidence of GERD in patients with Hp-positive and -negative peptic ulcers was 17.5% (136/778) and 12.4% (44/355), respectively. These differences were also statistically significant. CONCLUSION: In the analysis of patients with GERD, the prevalence of Hp infection was higher among patients with than without peptic ulcers. PMID- 30453814 TI - Predictive value of hematological parameters in testicular torsion: retrospective investigation of data from a high-volume tertiary care center. AB - OBJECTIVE: To investigate the use of hematological parameters in the differential diagnosis of testis torsion and epididymo-orchitis, and to determine the predictive value of these parameters in the diagnosis of testis torsion. METHODS: This study retrospectively reviewed the medical data of patients who presented to our institute with the complaint of acute scrotal pain. Eighty-five patients who had undergone orchiectomy or surgical detorsion due to testis torsion and 72 patients with epididymo-orchitis were included in the study. The control group comprised 78 healthy males. The groups were compared with respect to age, hematological parameters, neutrophil to lymphocyte ratio (NLR), monocyte to eosinophil ratio (MER), and platelet to lymphocyte ratio (PLR). RESULTS: The monocyte count significantly differed between testis torsion and epididymo orchitis, and was useful in the differential diagnosis. The mean neutrophil, platelet, and white blood cell counts, and the NLR, MER, and PLR values in the control group were significantly lower than those in the torsion and epididymo orchitis groups. CONCLUSION: The sensitivity and specificity of NLR in predicting testis torsion were as high as the sensitivity and specificity of doppler ultrasonography, suggesting the possible use of this parameter in the diagnosis of testis torsion. PMID- 30453815 TI - Triclosan, a common antimicrobial ingredient, on gut microbiota and gut health. AB - Triclosan (TCS) is an antimicrobial compound incorporated into more than 2,000 consumer products. This compound is frequently detected in the human body and causes ubiquitous contamination in the environment, raising concerns about its impact on human health and environmental pollution. Our recent research showed that exposure to TCS exaggerates colonic inflammation and exacerbates development of colitis-associated colon tumorigenesis, via gut microbiome-dependent mechanisms. In this review, we discussed recent research about TCS, as well as other consumer antimicrobials, on the gut microbiome and gut health. PMID- 30453816 TI - Cryoprotective effect of sericin supplementation in freezing and thawing media on the outcome of cryopreservation in human sperm. AB - The destructive effects of sperm cryopreservation result in decreased sperm parameters and their fertilizing ability. Antioxidants supplementation can potentially improve cryopreservation outcomes. In this study, we tried to investigate the effects of sericin supplementation in freezing and thawing media on frozen-thawed human sperm motility, morphology, viability, and DNA fragmentation. In experiment 1, semen samples were collected from 30 healthy fertile men and were cryopreserved in the presence of freezing medium supplemented with different concentrations of sericin (0, 0.5, 1, 2.5, and 5%). The results showed that the addition of 2.5 and 5% sericin in freezing medium significantly increased sperm viability and total motility (A + B) and decreased DNA fragmentation (P < 0.05). In experiment 2, semen samples were collected from 21 fertile men and were cryopreserved in freezing medium without any supplementation for 48 h. Then, the samples were thawed in medium supplemented with different concentrations of sericin (0, 0.5, 1, 2.5, and 5%). The addition of 5% sericin to thawing medium increased the total motility, viability, and decreased DNA fragmentation compared with those in thaws without sericin. In nutshell, the results clearly indicate the feasibility of sericin as an cryoprotective supplement for freezing media in human spermatozoa. PMID- 30453817 TI - Influenza and Intentions to Vaccinate in an Underserved Hispanic Population: The Role of Theoretically Derived Constructs. AB - BACKGROUND:: Past research has focused on understanding influenza vaccine acceptance in non-Hispanic white populations; however, research on the social causes of influenza vaccine acceptance rates in Hispanic populations is slowly developing. OBJECTIVE:: The purpose of this study was to assess theoretically driven predictors (i.e. attitudes, perceptions, behaviors, etc.) on influenza and the intention to vaccinate. METHODS:: A survey was administered to assess predictors of intentions to receive the influenza vaccine. The survey included items adapted from the National Flu Survey. RESULTS:: Key constructs common in models of health behaviors emerged as predictors of behavioral intentions to receive the flu vaccine. Recent vaccination within the past year ( P < 0.001), perceived effectiveness of the flu vaccine ( P < 0.004), and perceived safety of the flu vaccine ( P = 0.009) were predictors of intentions to vaccinate. Exploratory analyses revealed that government distrust was a statistically significant predictor of intentions to vaccinate ( P = 0.044). CONCLUSION:: The above results have important implications for health-care providers and public health educators. The better we understand the relationship between theoretically driven predictors and vaccine behaviors, the more educators and health-care providers can focus on meaningful, culturally sensitive, targeted-vaccine education. PMID- 30453818 TI - Plasma cytokines as potential biomarkers of kidney damage in patients with systemic lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus is a heterogeneous chronic inflammatory autoimmune disorder characterized by an exacerbated expression of cytokines and chemokines in different tissues and organs. Renal involvement is a significant contributor to the morbidity and mortality of systemic lupus erythematosus, and its diagnosis is based on renal biopsy, an invasive procedure with a high risk of complications. Therefore, the development of alternative, non-invasive diagnostic tests for kidney disease in patients with systemic lupus erythematosus is a priority. AIM: To evaluate the plasma levels of a panel of cytokines and chemokines using multiplex xMAP technology in a cohort of Colombian patients with active and inactive systemic lupus erythematosus, and to evaluate their potential as biomarkers of renal involvement. RESULTS: Plasma from 40 systemic lupus erythematosus non-nephritis patients and 80 lupus nephritis patients with different levels of renal involvement were analyzed for 39 cytokines using Luminex xMAP technology. Lupus nephritis patients had significantly increased plasma eotaxin, TNF-alpha, interleukin-17-alpha, interleukin-10, and interleukin 15 as compared to the systemic lupus erythematosus non-nephritis group. Macrophage-derived chemokine, growth regulated oncogene alpha, and epidermal growth factor were significantly elevated in systemic lupus erythematosus non nephritis patients when compared to lupus nephritis individuals. Plasma eotaxin levels allowed a discrimination between systemic lupus erythematosus non nephritis and lupus nephritis patients, for which we performed a receiver operating characteristic curve to confirm. We observed a correlation of eotaxin levels with active nephritis (Systemic Lupus Erythematosus Disease Activity Index). Our data indicate that circulating cytokines and chemokines could be considered good predictors of renal involvement in individuals with systemic lupus erythematosus. PMID- 30453819 TI - P21-Activated Kinase 1 Overactivates in Eutopic Endometrium of Adenomyosis. AB - Adenomyosis is a common gynecological disease, characterized by the existence of endometrium in the myometrium. The pathogenesis of adenomyosis is not fully understood. P21-activated kinase 1 (PAK1) is an effector of small Rho GTPases including CDC42 and RAC1 and plays various roles in cellular biology, especially cytoskeletal remodeling. This study aimed to evaluate whether the expression and activation of PAK1 in adenomyosis were different from normal. Immunohistochemistry was performed to evaluate the expression of PAK1 and its active form phosphorylated-PAK1 (pPAK1) semi-quantitatively in women with and without adenomyosis. Immunofluorescence was performed to locate the distribution of pPAK1. This study found that PAK1 in eutopic endometrium of adenomyosis was overactivated compared to normal. Phosphorylated-PAK1 assembled along the apical surface of glandular cell membrane. In ectopic lesions, PAK1 expression decreased and its activation returned to the baseline. The expression of pPAK1 correlated with the frequency of reproduction. These findings suggest that PAK1 overactivation in the endometrium may be an important event during the development of adenomyosis, meanwhile, decreased phosphorylation may assist to form lesions. PMID- 30453820 TI - Daily Physical Activity by Occupational Classification in US Adults: NHANES 2005 2006. AB - BACKGROUND: Little is known about the daily physical activity (PA) levels of people employed in different occupational categories. METHODS: Nine ActiGraph accelerometer-derived daily PA variables are presented and ranked for adults (N = 1465, 20-60 y) working in the 22 occupational categories assessed by NHANES 2005 2006. A composite score was generated for each occupational category by summing the rankings of 3 accelerometer-derived daily PA variables known to have strong associations with health outcomes (total activity counts [TAC], moderate to vigorous PA minutes per week in modified 10-minute bouts [MVPA 10], and percentage of time spent in sedentary activity [SB%]). RESULTS: Classified as high-activity occupational categories, "farming, fishing, forestry," and "building & grounds cleaning, maintenance" occupations had the greatest TAC (461 996 and 449 452), most MVPA 10 (149.6 and 97.8), most steps per day (10 464 and 11 602), and near the lowest SB% (45.2% and 45.4%). "Community, social services" occupations, classified as low-activity occupational categories, had the second lowest TAC (242 085), least MVPA 10 (12.1), fewest steps per day (5684), and near the highest SB% (64.2%). CONCLUSIONS: There is a strong association between occupational category and daily activity levels. Objectively measured daily PA permitted the classification of the 22 different occupational categories into 3 activity groupings. PMID- 30453821 TI - Adolescent Weight and Health Behaviors and Their Associations With Individual, Social, and Parental Factors. AB - BACKGROUND: To examine the associations and differences between gender and weight classification for physical activity (PA) and individual, social, and parental factors. METHODS: Data from wave 2 of the "Growing up in Ireland" national study were used, resulting in a sample of 7525 13-year-old adolescents. Information on factors affecting adolescents' social, emotional, cognitive, and physical development was collected. RESULTS: Overweight (OW) adolescents were more likely to exercise and restrict food for weight loss and less likely to perform moderate to vigorous PA than normal weight adolescents. Parent body mass index was associated with adolescent body mass index for OW and normal weight adolescents, with the strongest association seen with OW females. Parents of OW adolescents considered themselves to be more OW and less physically active than parents of normal weight adolescents. Furthermore, for all groups, a greater amount of moderate to vigorous PA was associated with less television viewing, greater PA of parents, and a greater number of friends. CONCLUSION: Parental health behaviors play a significant role in adolescents' bodyweight, representing the necessity for more constructive health behaviors and PA among parents. Future interventions may be strengthened by focusing specifically on gender and body mass index, while taking into consideration the importance of parental behaviors on adolescents. PMID- 30453822 TI - In-office versus Operating Room Sialendoscopy: Comparison of Outcomes, Patient Time Burden, and Charge Analysis. AB - OBJECTIVE: To evaluate outcomes of in-office versus operating room (OR) sialendoscopy/sialolithotomy and to recognize the efficiency of outpatient salivary gland surgery with significant time and facility charge reductions. STUDY DESIGN: Case series with chart review. SETTING: State hospital OR and ambulatory clinic. METHODS: Retrospective review was performed of adult patients treated for inflammatory salivary diseases by a single surgeon from 2011 to 2016. The patients were divided into 2 groups based on procedure setting (office vs OR) and compared by various baseline features, including demographics, symptom onset and duration, stone size, symptomatic improvement, and recurrence. Patient time burden was compared via office procedure records and OR time charting from the electronic health record. Retrospective clinic and hospital charge sheets were tallied and similarly compared. RESULTS: The 2 cohorts (office, n = 111; OR, n = 96) were comparable in all demographics, including sialolith number and size (7.36 vs 6.69 mm, P = .45). Additional subgrouping was statistically similar. Both cohorts had similar postprocedure symptom improvement (97% vs 95.8%, P = .65) and recurrence rates (8.9% vs 14.5%, P = .22) independent of subgroup. Overall time burden for patients was 39 minutes in the office versus 277 minutes in the OR ( P <= .0001). Procedure and hospital charge data were tallied and compared (office, $719.21; OR, $13,956.14; P <= .0001). CONCLUSION: Bothcohorts were statistically similar in all features. There was significant reduction in patient time burden and health care charges with office-based procedures while maintaining similar symptom improvement and recurrence rates. PMID- 30453823 TI - [Prevention of substance use disorders]. AB - : Prevention of substance use disorders Abstract. INTRODUCTION: Adolescence is a vulnerable period for the development of Substance Use Disorders and preventive intervention is a public health priority. In this article, we summarize the available evidence for behavioral preventive action for Substance Use Disorders and related dysregulated behaviors during adolescence in various settings. RESULTS: Current meta-analytic evidence is available mainly for the school and family settings and increasingly also for internet-based prevention. The literature is dominated by US-studies that focus on universal school-based approaches for legal substances in middle adolescence. Only few German studies are published. Taken together the results indicate that developmentally sensitive substance use prevention is effective across different settings with consistent small-to-middle sized effects. Differential effectiveness analyses for schoolbased prevention suggest that younger adolescents benefit most from universal prevention, while for older adolescents targeted approaches are more effective. CONCLUSIONS: Across the relevant settings, effective preventive measures are available. However, the results could be improved. There is a need for translational research on effective and more individualized approaches to prevention and differential effects of intervention modules. Moreover, there is a need for research on the implementation of evidence-based programs and especially in Germany, coordinated approaches on community levels are lacking. PMID- 30453825 TI - [EXPRESS] Ethanol-induced enhancement of inhibitory synaptic transmission in the rat spinal substantia gelatinosa. AB - Recent studies have shown that ethanol produces a widespread modulation of neuronal activity in the CNS. It is not fully understood, however, how ethanol changes nociceptive transmission. We investigated acute effects of ethanol on synaptic transmission in the substantia gelatinosa (SG, lamina II of the spinal dorsal horn) and mechanical responses in the spinal dorsal horn. In SG neurons, bath-application of ethanol at low concentration (10 mM) did not change the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). At medium to high concentrations (20-100 mM), however, ethanol elicited a barrage of large amplitude sIPSCs. In the presence of TTX, such enhancement of IPSCs were not detected. In addition, ethanol (20-100 mM) increased the frequency of spontaneous discharge of vesicular GABA transporter (VGAT)-Venus labelled neurons, and suppressed the mechanical nociceptive response in wide-dynamic range neurons in the spinal dorsal horn. The present results suggest that ethanol may reduce nociceptive information transfer in the spinal dorsal horn by enhancement of inhibitory GABAergic and glycinergic synaptic transmission. PMID- 30453824 TI - Uteroplacental Insufficiency Impairs Cholesterol Elimination in Adult Female Growth-Restricted Rat Offspring Fed a High-Fat Diet. AB - Uteroplacental insufficiency (UPI) causes intrauterine growth restriction (IUGR) and increases the risk of hypercholesterolemia and cardiovascular disease, which are leading causes of morbidity and mortality worldwide. Little is known about the mechanism through which UPI increases cholesterol. Hepatic Cholesterol 7 alpha-hydroxylase (Cyp7a1) is the rate-limiting and most highly regulated step of cholesterol catabolism to bile acids. Cholesterol 7 alpha-hydroxylase is regulated by transcription factor liver X receptor alpha (Lxralpha) and by microRNA-122. We previously showed that microRNA-122 inhibition of Cyp7a1 translation decreased cholesterol catabolism to bile acids in female IUGR rats at the time of weaning. We hypothesized that UPI would increase cholesterol and microRNA-122 and decrease Cyp7a1 protein and hepatic bile acids in young adult female IUGR rats. To test our hypothesis, we used a rat model of IUGR induced by bilateral uterine artery ligation. Both control and IUGR offspring were exposed to a maternal high-fat diet from before conception through lactation, and all offspring were weaned to a high-fat diet on postnatal day 21. At postnatal day 60, IUGR female rats had increased total and low-density lipoprotein serum cholesterol and hepatic cholesterol, decreased Lxralpha and Cyp7a1 protein, and decreased hepatic bile acids. Hepatic microRNA-122 was not changed by UPI. Our findings suggest that UPI decreased cholesterol catabolism to bile acids in young adult female rats through a mechanism independent of microRNA-122. PMID- 30453826 TI - [EXPRESS] Evoked hypoalgesia is accompanied by tonic pain and immune cell infiltration in the dorsal root ganglia at late stages of diabetic neuropathy in mice. AB - Diabetic peripheral neuropathy (DPN) is a major debilitating late complication of diabetes, which significantly reduces the quality of life in patients. DPN is associated with a wide spectrum of sensory abnormalities, where in loss of sensation or hypoalgesia to applied external stimuli is paradoxically accompanied by debilitating tonic spontaneous pain. In numerous studies on animal models of DPN, behavioural measurements have been largely confined to analysis of evoked withdrawal to mechanical and thermal stimuli applied to dermatomes, whereas spontaneous, on-going pain has not been widely studied. In the Streptozotocin (STZ) model of type 1 diabetes, we employed the Conditioned Place Preference (CPP) test to assess tonic pain. Our results indicate that both phases, i.e. early evoked hypersensitivity (i.e. 5-7 weeks (wks) post-STZ) as well as late stage hypoalgesia (i.e. 17-20 wks post-STZ) are accompanied by significant tonic pain in mice with DPN. We also report on the temporal relation between on-going pain and neuropathological changes in the dorsal root ganglia (DRG) of mice with DPN up to 6 months post-STZ. Neither early hypersensitivity nor late hypoalgesia were associated with markers of cellular stress in the DRG. Whereas significant neutrophil infiltration was observed in the DRG over both early and late stages post-STZ, T-cell infiltration in the DRG was prominent at late stages post-STZ. Thus, longitudinal analyses reveal that similar to patients with chronic DPN, mice show tonic pain despite sensory loss after several months in the STZ model, which is accompanied by neuroimmune interactions in the dorsal root ganglia. PMID- 30453827 TI - Novel subcutaneous low-molecular-weight heparin injection technique to reduce post-injection bruising. AB - OBJECTIVE: To investigate the efficacy of a novel low-molecular-weight heparin injection technique compared to the standard technique relative to bruising incidence, bruise size, and pain. METHODS: A randomized controlled trial was conducted in 44 patients with acute deep vein thrombosis. Patients who were randomized into the control group received a 10-s duration injection with immediate needle withdrawal, whereas study group patients received a 30-s duration injection with a 10-s pause before needle withdrawal. Two injection sites were assessed for pain and bruising between 48 and 60 h after injection. RESULTS: Bruises occurred in 50.0% and 18.2% of control and study group patients, respectively ( p = 0.03). Mean bruise size between 48 and 60 h after injection was 172.73 +/- 372.60 mm2 and 28.18 +/- 70.01 mm2 in the control group and study group, respectively ( p = 0.026). Pain scores were comparable between groups. CONCLUSION: A 30-s duration injection with a 10-s pause before needle withdrawal resulted in significantly fewer and smaller bruises. PMID- 30453828 TI - Recurrent Henoch Schonlein purpura without renal involvement successfully treated with methotrexate. AB - INTRODUCTION: Henoch Schonlein purpura is characterised by palpable purpura, abdominal pain, arthritis/arthralgia, often with a self-limiting course. Herein, we report a patient with recurrent Henoch Schonlein purpura and severe gastrointestinal involvement, successfully treated with methotrexate. CASE PRESENTATION: A 12-year-old boy was admitted to our department with palpable purpura, abdominal pain and arthralgia. Since gastrointestinal complaints were severe, systemic steroids were administered, with tapering of dosage. Henoch Schonlein purpura recurred several times with severe abdominal pain, maelena and purpura during next two months. Colchicine and hydroxychloroquine were initiated. After four months, we also introduced methotrexate, which enabled discontinuation of previous medications including corticosteroids. Methotrexate was ceased four months later, and remission was sustained without any medications for 24 months. CONCLUSION: Besides the conflicting data regarding the use of methotrexate in recurrent Henoch Schonlein purpura, our case introduces successful methotrexate experience in a child with Henoch Schonlein purpura and recurrent severe gastrointestinal involvement. PMID- 30453829 TI - A finite element study on intra-operative corrective forces and evaluation of screw density in scoliosis surgeries. AB - Scoliosis is an abnormal sideways curvature of the spine and rib cage, which may need surgical treatments. Most of the corrective maneuvers in scoliosis surgeries are based on surgeon's experience; hence, there is great interest of understanding how the correction ratio can be influenced by the magnitude of forces and moments. Therefore, the objective of this study was to develop and validate a detailed finite element model of the thoracolumbar which can be used to simulate the scoliosis surgeries based on patient-specific clinical images. The validated models of five patients were carefully developed, and the surgery procedures were simulated and the corrective forces were estimated using inverse finite element analysis during the surgery. Furthermore, parametric studies including the influences of the corrective force magnitude and screw density were evaluated. The results showed that the maximum estimated correction force and moment were 173 (+/-55.43) N and 10.67 (+/-2.02) N m, respectively, which were aligned with measured clinical observations. The sensitivity analysis on the magnitude of applied force to the screws showed that correction ratio was slightly increased in level 1 (i.e. FB = 1.3 * F) but decreased in level 2 (i.e. FB = 1.6 * F). In addition, the parametric study on increasing the number of pedicle screws showed that there was no significant difference between lower and higher screw density. However, the stress distribution was significantly greater using higher screw density during correction maneuvers. In conclusion, this study shows a direct relationship between the applied force/moment and screw density and the correction ratio up to a border line which should be defined accurately. This detailed computational modeling can be used in clinic in hope of achieving the optimum outcome of scoliosis surgery using individual patient-specific characterization. PMID- 30453830 TI - Progestins Inhibit Tumor Necrosis Factor alpha-Induced Matrix Metalloproteinase 9 Activity via the Glucocorticoid Receptor in Primary Amnion Epithelial Cells. AB - Progestins have been recommended for preterm birth prevention in high-risk women; however, their mechanism of action still remains an area of debate. Medroxyprogesterone acetate (MPA) has previously been shown to significantly inhibit tumor necrosis factor alpha (TNFalpha)-induced matrix metalloproteinase 9 (MMP9) messenger RNA (mRNA) expression and activity in primary amnion epithelial cells, a process that may lead to preterm premature rupture of membranes. A mechanism that explains MPA's inhibition of TNFalpha-induced MMP9 mRNA expression and activity in primary amnion epithelial cells is unclear since these cells lack the classic nuclear progesterone receptor but express a membrane-associated progesterone receptor-progesterone receptor membrane component 1 (PGRMC1) along with the glucocorticoid receptor (GR). Primary amnion epithelial cells harvested from healthy term pregnant women at cesarean section were treated with PGRMC1 (to knockdown PGRMC1 expression), GR (to knockdown GR expression), or control small interfering RNA (siRNA; 10 nm) for 72 hours, pretreated with ethanol or MPA (10-6 M) for 6 hours, and then stimulated with or without TNFalpha 10 ng/mL for 24 hours. Real-time quantitative polymerase chain reaction and gelatin zymography were used to quantify MMP9 mRNA expression and activity, respectively. Experimental groups were compared using 1-way analysis of variance. Both TNFalpha induced MMP9 mRNA expression and activity were significantly inhibited by pretreatment with MPA; however, only the inhibition of TNFalpha-induced MMP9 activity was partially reversed with PGRMC1 siRNA. However, GR siRNA reversed both the inhibition of TNFalpha-induced MMP9 mRNA expression and activity by MPA. This study demonstrates that MPA mediates its anti-inflammatory effects primarily through GR and partially through PGRMC1 in primary amnion epithelial cells. PMID- 30453831 TI - 'To die, to sleep' - assisted dying legislation in Victoria: A case study. AB - BACKGROUND:: Assisted dying remains an emotive topic globally with a number of countries initiating legislation to allow individuals access to assisted dying measures. Victoria will become the first Australian state in over 13 years to pass Assisted Dying Legislation, set to come into effect in 2019. OBJECTIVES:: This article sought to evaluate the impact of Victorian Assisted Dying Legislation via narrative view and case study presentation. RESEARCH DESIGN:: Narrative review and case study. PARTICIPANTS AND RESEARCH CONTEXT:: case study. ETHICAL CONSIDERATIONS:: This legislation will provide eligible Victorian residents with the option to request access to assisted dying measures as a viable alternative to a potentially painful, protracted death. FINDINGS:: This legislation, while conservative and inclusive of many safeguards at present, will form the basis for further discussion and debate on assisted dying across Australia in time to come. DISCUSSION:: The passing of this legislation by the Victorian parliament was prolonged, emotive and divided not only the parliament but Australian society. CONCLUSION:: Many advocates for this legislation proclaimed it was well overdue and will finally meet the needs of contemporary society. Protagonists claim that medical treatment should not provide a means of ending life, despite palliative care reportedly often failing to relieve the pain and suffering of individuals living with a terminal illness. PMID- 30453832 TI - Author accepted manuscript: The Effects of Color Complexity and Similarity on Multiple Object Tracking Performance. PMID- 30453833 TI - Origins of Intraindividual Genetic Variation in Human Fetuses. AB - BACKGROUND:: Intraindividual copy number variation (CNV) origin is largely unknown. They might be due to aging and/or common genome instability at the preimplantation stage while contribution of preimplantation in human intraindividual CNVs occurrence is unknown. To address this question, we investigated mosaicism and its origin in the fetuses of natural conception. METHODS:: We studied normal fetuses following therapeutic abortion due to maternal indications. We analyzed the genome of 22 tissues of each fetus by array comparative genomic hybridization for intraindividual CNVs. Each tissue was studied in 2 microarray experiments; the reciprocal aberrations larger than 40 Kb, identified by comparing tissues of each fetus, were subsequently validated using quantitative polymerase chain reaction. RESULTS:: Through intraindividual comparison, frequency of reciprocal events varied from 2 to 9. According to the distribution pattern of the frequent CNV in derivatives of different germ layers, we found that its origin is early development including preimplantation, whereas CNVs with low frequency have occurred in later stages. Shared CNVs in both fetuses were belonged to thymus and related to the functional role of genes located in these CNVs. CONCLUSIONS:: The origin of some of fetal CNVs is preimplantation stage. Each organ might inherit CNVs with an unpredictable pattern due to the extensive cell mixing/migration in embryonic development. PMID- 30453834 TI - The Effect of Maternal Obesity on Placental Cell-Free DNA Release in a Mouse Model. AB - BACKGROUND:: The fetal fraction of cell-free DNA (cfDNA) in maternal plasma is decreased in obese women. The underlying mechanism is not well understood. The amount of cfDNA released from the placenta has not been directly examined in maternal obesity. OBJECTIVE:: We sought to quantify release of cfDNA from the placenta and fetal membranes in maternal diet-induced obesity using explant cultures in an established mouse model. STUDY DESIGN:: C57BL6/J females were fed either 60% high-fat diet or 10% fat-matched control diet for 14 weeks prepregnancy and throughout gestation. Placentas and fetal membranes were collected on e18 and randomly allocated to time 0-, 1-, or 6-hour culture times. The CfDNA was isolated from culture media, quantified, and normalized to tissue weight. RESULTS:: Placentas from obese dams released significantly less cfDNA compared to those of lean dams at time 0 (45.8 +/- 4.3 ng/mg vs 65.6 +/- 7.9 ng/mg, P = .02). Absolute cfDNA levels increased with longer placental culture, with no significant differences between obese and lean dams at 1 and 6 hours. Membranes released significantly less cfDNA than did placentas at every time point. CONCLUSIONS:: Maternal obesity is associated with decreased release of cfDNA from the placenta compared to lean controls immediately after tissue harvest. This may provide an alternative explanation for the lower fetal fraction of cfDNA noted in maternal obesity. PMID- 30453835 TI - Factors Associated with Revision Surgery after Balloon Sinuplasty. AB - OBJECTIVE: Although balloon sinuplasty (BSP) is increasing in popularity, little is known about which patients are the ideal candidates. The objective of this study is to investigate factors that may be associated with BSP failure. STUDY DESIGN: Retrospective review. SETTING: Academic center. SUBJECTS AND METHODS: This is a 6-year (July 2011-June 2017) retrospective review of patients who underwent BSP or revision endoscopic sinus surgery (rESS) after BSP within a single tertiary health system. Demographics, clinical findings, and radiographic findings were investigated for association with rESS via univariate analyses and a multivariable backward elimination selection procedure. RESULTS: A total of 154 patients were identified (median age, 53 years): 146 patients underwent BSP at a single health system, with 16 (11%) undergoing rESS; 8 patients underwent BSP at an outside institution and underwent rESS with the senior author. Mean +/- SD follow-up was 12.8 +/- 16.6 months. Univariate analyses revealed that prior endoscopic sinus surgery, polyps, allergic rhinitis, and gram-negative infection were significantly associated with rESS. As for radiographic findings, a higher Lund-Mackay score, neo-osteogenesis, moderate or complete opacification, and hyperdensities were associated with rESS. The final model after multivariable selection showed that higher radiographic scores (odds ratio, 1.08; 95% CI, 1.01 1.17) and neo-osteogenesis (odds ratio, 5.25; 95% CI, 1.68-16.42) were associated with higher odds for rESS. CONCLUSIONS: This study identifies several clinical and radiographic factors that may be associated with the need for rESS after BSP. Surgeons can take these factors into consideration when deciding whether a patient should forego BSP and undergo conventional FESS. PMID- 30453836 TI - Paediatric visceral leishmaniasis: a retrospective study on clinical manifestations, demographic features and laboratory findings of hospitalised cases in Iran between 2006 and 2016. AB - Visceral leishmaniasis (VL) is a neglected disease. Our retrospective study describes 38 clinical and epidemiological characteristics of VL in patients admitted to a paediatric hospital in Tehran, Iran, who came from different geographical regions, indicating that the disease has spread to most parts of the country. Some 76.3% of the children documented suffered with symptoms of the disease for two months before admission. PMID- 30453837 TI - Injection Laryngoplasty for Children with Unilateral Vocal Fold Paralysis: Procedural Limitations and Swallow Outcomes. AB - OBJECTIVE: Vocal fold immobility with resultant dysphagia is a known cause of morbidity in the pediatric population. Herein we evaluate the efficacy and adverse events of injection laryngoplasty in children. STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic children's hospital. SUBJECTS AND METHODS: Patients <12 years of age with unilateral vocal fold immobility, dysphagia, and objective swallow study data were included. Primary outcome measures included perioperative adverse events and the ability to advance the diet, as defined by initiation of oral feeds or reduction in thickener following postoperative swallow study. RESULTS: The mean age of the cohort (N = 41) was 43.83 months (range, 0.5-144 months), and 46.3% of patients were <18 months old. Perioperative adverse events included increased oxygen requirement (n = 3), prolonged operating room time secondary to tenuous cardiopulmonary status (n = 2), and postoperative readmission within 30 days (n = 1). A total of 63.63% (n = 21 of 33) of patients safely advanced their diet following objective improvement on swallow study. Patients undergoing injection laryngoplasty <=6 months of the onset of vocal fold immobility were more likely to advance their diet following surgery. CONCLUSION: Injection laryngoplasty has the potential to advance or initiate an oral diet for children with vocal fold immobility, including those in the first months of life. It is relatively free of adverse events, but certain limitations in the pediatric population must be considered. Preoperative characteristics, including timing of injection and premorbidity diet, may guide clinicians in predicting those patients most likely to advance their diet following injection laryngoplasty. PMID- 30453838 TI - Independent assessment and outcomes of 196 short-tapered stems short-term follow up and review of the literature. AB - BACKGROUND:: Longer term outcome data are now becoming available for short tapered femoral stems for cementless total hip arthroplasty. The shorter stem has a metaphyseal fit, loading the bone in this area, leading to physiological bone remodelling. It is also bone preserving, as it is 35 mm shorter. It may be easier to insert through a smaller incision and potentially reduce complication rates. We present a retrospective single surgeon case series of 196 patients (>53% follow-up over 5 years). All patients had the cementless 'Microplasty Taperloc' (Biomet). Primary outcome measures were femoral component revision rates. Secondary outcome measures included complications, patient-reported functional outcome scores (Oxford hip) and radiographic evidence of loosening. METHODS:: Patients were identified using electronic software. All were routinely followed up and assessed in clinic since implant introduction in 2009. Oxford hip scores were routinely obtained. A surgeon who had not carried out the procedure independently assessed radiographs. RESULTS:: One hundred ninety-six patients were identified. The revision rate was 0.5% due to an intraoperative peri prosthetic fracture of the femur identified on post-operative radiograph. The complication rate was 2%, attributable to: subsidence of the prosthesis (one hip), post-operative dislocation (two hips), one of which required acetabular revision. Oxford hip scores increased on average from 21 to 45 (pre- to post operatively). There were no signs of radiographic loosening. CONCLUSION:: The results show that using the short-tapered stem is proving so far to be a reliable and safe alternative to its longer counterpart, with low complication rates in the short term. PMID- 30453839 TI - Short-term toxicity of dibutyl phthalate to mice intestinal tissue. AB - The objective of this study was to investigate changes in intestinal histopathology and expression of heat-shock proteins (HSPs) in the small intestinal tissue of mouse after acute exposure to dibutyl phthalate (DBP). Forty eight 60-day-old Institute of Cancer Research (ICR) mice were administered DBP by gavage once a day for 10 days. The mice were divided into three groups of 16 mice each: the high-dose group was administered 500 mg/kg body weight (BW) DBP; the low-dose group was administered 50 mg/kg BW; and the control group was not administered DBP. Significant increases in the uterine index, ovary index, and testicular index were observed in the DBP-exposed groups compared to those in the control group. Villus height and V/ C ratio significantly increased ( p < 0.05) in the duodenum and decreased ( p < 0.05) in the jejunum after the administration of DBP. The goblet cell number decreased in both the duodenum and the jejunum of mice exposed to DBP ( p < 0.05) compared to the number in the control group mice. Damage to the structure of the small intestine was accompanied by a marked increase in HSP27 expression and a decrease in the expression of HSP70 and HSP90 in both high-dose and low-dose groups. These results indicate that elevated HSP27 levels in the duodenum and jejunum may be important markers for acute DBP exposure and that HSP27 may act as a protective protein involved in intestinal mucosa repair. PMID- 30453840 TI - Wear of different materials for total hip replacement under adverse stop-dwell start in vitro wear simulation conditions. AB - Hip simulation is a common technique for pre-clinical evaluation of wear performance of total hip arthroplasty. Standard techniques replicate kinematics of walking patterns of a typical patient. Attention has focussed in developing simulations of other typical patient daily activities to improve accuracy of wear predictions. A method for simulating stop-dwell-start motion during patient walking and the effect on 36-mm metal-on-metal total hip arthroplasty was previously presented by the authors. This study sought to extend the previous work to look at the effect of these conditions on ceramic-on-ceramic, metal-on polyethylene and ceramic-on-polyethylene bearings. Two stop-dwell-start protocols were used: one reproducing average patient movement patterns and one examining more severe conditions. For all materials tested, no significant increase in wear was observed under average stop-dwell-start conditions, suggesting the bearing types tested are robust to this type of activity. A significant increase in wear was observed for metal-on-metal, metal-on-polyethylene and ceramic-on polyethylene bearings under severe stop-dwell-start conditions, this was attributed to depletion of lubricant in the bearing during the dwell period. A greater relative increase in wear was observed for metal-on-metal bearings compared with metal-on-polyethylene and ceramic-on-polyethylene bearings. This may be explained by the contributions of the different lubrication mechanisms in each bearing type. Wear of ceramic-on-ceramic was very low in all tests, suggesting normal measurement variation was masking any effect of the adverse conditions. It was not possible to determine any effect of the different activities. These results emphasise the importance of exploring adverse patient activity simulations. The increase in wear rate associated with an adverse activity such as seen in stop-dwell-start motion, has to be considered in the context of the frequency of the adverse activity cycle relative to other activities such as standard continuous walking, to determine the impact on the total wear in a given time period. PMID- 30453841 TI - Application of ZnO-Ag-Nd nanocomposite as a new synthesized nanophotocatalyst for degradation of the organic compounds: Kinetic, thermodynamic, and economic study. AB - In the present research, a zinc oxide (ZnO)-silver (Ag)-neodymium (Nd) nanocomposite was synthesized via the combustion method for the degradation of dyes as organic pollutants. The synthesized nanophotocatalyst was characterized using X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy techniques. The process of organic pollutant (Acid Red 18) removal was carried out in a semi-batch photoreactor equipped with an ultraviolet lamp. Also, the influence of key operational parameters such as pH, temperature, initial concentration of solution, and nanophotocatalyst dosage was investigated to evaluate kinetic and thermodynamic properties. Under optimum process conditions (pH = 6.21, dosage of nanophotocatalyst = 0.08 g/l, and low initial concentration of the solution), degradation of pollutant was monitored by measuring the total organic carbon of the solution. Finally, an economic study showed that the photocatalytic advanced oxidation process is an viable treatment method for low concentrations of organic pollutants. PMID- 30453843 TI - Noninvasive assessment and risk factors of liver fibrosis in patients with thalassemia major using shear wave elastography. AB - OBJECTIVES: This study aimed to estimate the prevalence of liver fibrosis and assess the risk factors for developing significant liver fibrosis in patients with Thalassemia Major (TM). METHODS: All patients with TM over the age of 10 years were included in the study. RESULTS: A total of 94 eligible patients underwent 2-D SWE. The median age was 26.7 years. The median of the average 5 year serum ferritin (5yrSF) and liver iron concentration (LIC) assessed by MRI T2* were 1326 ug/L and 6.7 mg/g dw, respectively. Hepatitis C and hepatitis B core antibodies were positive in 38% and 1% of the patients respectively. The proportion of patients with significant fibrosis was 60%. Male gender increased the risk of significant fibrosis (Odds ratio of 0.4; p = .0373). Additionally, the 5yrSF (p = .00661), the LIC (p = .0225) and the lowest LIC of the previous 5 years (p = .0211) were significant. In the multivariable logistic regression model, only 5yrSF (p = .0035) and gender (p = .00984) remained significant. CONCLUSIONS: The risk of liver fibrosis is associated with iron overload and gender in patients with TM. PMID- 30453842 TI - Optical Surface Scanning for Patient Positioning in Radiation Therapy: A Prospective Analysis of 1902 Fractions. AB - PURPOSE/OBJECTIVE:: Reproducible patient positioning remains one of the major challenges in modern radiation therapy. Recently, optical surface scanners have been introduced into clinical practice in addition to well-established positioning systems, such as room laser and skin marks. The aim of this prospective study was to evaluate setup errors of the optical surface scanner Catalyst HD (C-RAD AB) in different anatomic regions. MATERIAL/METHODS:: Between October 2016 and June 2017 a total of 1902 treatment sessions in 110 patients were evaluated. The workflow of this study included conventional setup procedures using laser-based positioning with skin marks and an additional registration of the 3-dimensional (3D) deviations detected by the Catalyst system. The deviations of the surface-based method were then compared to the corrections of cone beam computed tomography alignment which was considered as gold standard. A practical Catalyst setup error was calculated between the translational deviations of the surface scanner and the laser positioning. Two one-sided t tests for equivalence were used for statistical analysis. RESULTS:: Data analysis revealed total deviations of 0.09 mm +/- 2.03 mm for the lateral axis, 0.07 mm +/- 3.21 mm for the longitudinal axis, and 0.44 mm +/- 3.08 mm vertical axis for the Catalyst system, compared to -0.06 +/- 3.54 mm lateral, 0.53 +/- 3.47 mm longitudinal, and 0.19 +/- 3.49 mm vertical for the laser positioning compared to cone beam computed tomography. The lowest positional deviations were found in the cranial region, and larger deviations occurred in the thoracic and abdominal sites. A statistical comparison using 2 one-sided t tests showed a general concordance of the 2 methods ( P <= 0.036), excluding the vertical direction of the abdominal region ( P = 0.198). CONCLUSION:: The optical surface scanner Catalyst HD is a reliable and feasible patient positioning system without any additional radiation exposure. From the head to the thoracic and abdominal region, a decrease in accuracy was observed within a comparable range for Catalyst and laser-assisted positioning. PMID- 30453844 TI - Effects of coenzyme Q10 supplementation on oxidative stress and antioxidant enzyme activity in glazers with occupational cadmium exposure: A randomized, double-blind, placebo-controlled crossover clinical trial. AB - TRIAL REGISTRATION:: Iranian Registry of Clinical Trials Registration Number: IRCT2016061228407N1 ( www.who.int/ictrp/network/irct/en/ ). PMID- 30453845 TI - Weighted volume under the three-way receiver operating characteristic surface. AB - It is often necessary to differentiate subjects from multiple categories using medical tests. We may then adopt statistical measures to characterize the performance of these tests. The three-way ROC analysis has been proposed to evaluate the diagnostic accuracy of medical tests with three categories, reflecting the correct classification probabilities across all possible decision thresholds. The geometry of the ROC surface is carefully studied, leading to numerical summary measures such as the volume under the surface. This paper generalizes the global volume under the surface of three-way ROC analysis to the weighted volume under the surface (WVUS) by introducing a weight function emphasizing particular regions of correct classification probabilities. This generalization practically allows researchers to calculate the diagnostic accuracy for a medical or clinical biomarker while satisfactorily high probabilities of correct classification for one or two classes are conditionally ensured. We provide the asymptotic properties of the proposed nonparametric and parametric estimators of WVUS, which could easily lend support to statistical inferences. Some simulations have been conducted to assess the proposed estimators and also to demonstrate the necessity of WVUS. A real data analysis about liver cancer illustrates our methodology. PMID- 30453846 TI - Informing Human Trafficking Clinical Care Through Two Systematic Reviews on Sexual Assault and Intimate Partner Violence. AB - BACKGROUND:: There is a lack of evidence on the clinical management of patients who have suffered human trafficking. Synthesizing the evidence from similar patient populations may provide valuable insight. This review summarizes findings on therapeutic interventions for survivors of sexual assault and intimate partner violence (IPV). METHOD:: We conducted two systematic reviews using the MEDLINE database. We included only randomized controlled trials of therapies with primary outcomes related to health for survivors of sexual assault and IPV. For the sexual assault review, there were 78 abstracts identified, 16 full-text articles reviewed, and 10 studies included. For the IPV review, there were 261 abstracts identified, 24 full-text articles reviewed, and 17 studies included. Analysis compared study size, intervention type, patient population, primary health outcomes, and treatment effect. RESULTS:: Although our search included physical and mental health outcomes, almost all the studies meeting inclusion and exclusion criteria focused on mental health. The interventions for sexual assault included spiritually focused group therapy, interference control training, image rehearsal therapy, sexual revictimization prevention, educational videos, cognitive behavioral therapy, and exposure therapy. The interventions in the IPV review included group social support therapy, exposure therapy, empowerment sessions, physician counseling, stress management programs, forgiveness therapy, motivational interviewing, and interpersonal psychotherapy. CONCLUSIONS:: Insights from these reviews included the importance of culturally specific group therapy, the central role of survivor empowerment, and the overwhelming focus on mental health. These key features provide guidance for the development of interventions to improve the health of human trafficking survivors. PMID- 30453847 TI - Forced FoxO1:S249V expression suppressed glioma cell proliferation through G2/M cell cycle arrests and increased apoptosis. AB - OBJECTIVE: Forkhead box O1 (FoxO1) plays a crucial role in the development of many tumors. Cyclin D kinase (CDK) 1 could influence the nuclear export and activity of FoxO1 through phosphorylation of serine (S)249. However, the effects of S249 phosphorylation in the development of glioma remain unclear. The aim of the present study is to assess the function of FoxO1:S249V mutant, which was converted S249 phosphorylation site into valine (V) residues in the glioma development. METHODS: FoxO1-knockdown U251 glioma cells (U251-KD cells) were established by infection of retrovirus particles with FoxO1 siRNA and FoxO1 restored cells (FoxO1:S249V) were obtained by re-introduction of FoxO1:S249V cDNA. We detected mRNA expression by real-time PCR, and cell cycle arrest and apoptosis by flow cytometric assay, and cell proliferation by BrdU assay and CCK 8 assay. The protective effects of FoxO1:S249V were detected by the xenograft tumor formation assay. RESULTS: The FoxO1 mRNA expression was significantly decreased in the glioma specimens (n = 24). The U251-KD cells showed downregulation of p27 and Bim, while the phosphorylation of CDK1 was upregulated. FoxO1:S249V cells inhibited the phosphorylation of S249, and induced G2/M cell cycle arrest, following reduced cell growth and increased apoptosis. Moreover, FoxO1:S249V expression effectively inhibits the glioma growth. CONCLUSION: Our findings suggest that the forced FoxO1:S249V suppressed the cell growth through G2/M cell cycle arrests and increased apoptosis in glioma. PMID- 30453848 TI - Hospital Admissions and Surgical Treatment of Children With Lower-Limb Deficiency In Finland. AB - BACKGROUND AND AIMS:: There are no population-based studies about hospital admissions and need for surgical treatment of congenital lower-limb deficiencies. The aim is to assess the impact children with lower-limb deficiencies pose to national hospital level health-care system. MATERIALS AND METHODS:: A population based study was conducted using the national Register of Congenital Malformations and Care Register for Health Care. All 185 live births with lower-limb deficiency (1993-2008) were included. Data on hospital care were collected until 31 December 2009 and compared to data on the whole pediatric population (0.9 million) live born in 1993-2008. RESULTS:: The whole pediatric population had annually on average 0.10 hospital admissions and the mean length of in-patient care of 0.3 days per child. The respective figures were 1.5 and 5.6 in terminal lower-limb amputations (n = 7), 1.1 and 3.9 in long-bone deficiencies (n = 53), 0.6 and 1.9 in foot deficiencies (n = 26) and 0.4 and 2.6 in toe deficiencies (n = 101). Orthopedic surgery was performed in 72% (5/7) of patients with terminal amputations, in 62% (33/53) of patients with long bone, in 58% (14/24) of patients with foot and in 25% (25/101) of patients in toe deficiencies. Half (54%) of all procedures were orthopedic operations. CONCLUSION:: In congenital lower-limb deficiencies the need of hospital care and the number of orthopedic procedures is multiple-fold compared to whole pediatric population. The burden to the patient and to the families is markedly increased, especially in children with terminal amputations and long-bone deficiencies of lower limbs. PMID- 30453849 TI - Race, sex, and physician communication about tobacco as predictors of adolescent smoking trajectories in a primarily African American sample. AB - This study identified latent classes of adolescent smoking and examined race, gender, and physician communication (PC) as predictors of class membership. Data were drawn from five waves of a large (N = 3,049), diverse (82.9% African American) study. Several latent classes were identified: nonsmoker, quitter, early-onset escalating smoking, early-onset stable high smoking, late-onset smoking, and declining smoking. Males, Whites, and teens who received PC were more likely to be in classes with more smoking. Our study identified several youth smoking patterns and differences in smoking based on race, gender, and receipt of PC. PMID- 30453850 TI - Eimeria gilruthi-associated abomasitis in a group of ewes. AB - Nine of 23 (39%) research ewes with severe diarrhea and weight loss had histologic lesions consistent with Eimeria gilruthi infection in their abomasa. Gross anatomic lesions included hundreds of opaque 1-mm nodules in abomasal mucosa that corresponded microscopically to 200-300 um diameter organisms surrounded by areas of necrosis. Analysis of fecal samples from 4 ewes demonstrated oocysts from typical ovine Eimeria species, none of which were E. gilruthi. Two separate PCR reactions were performed on abomasal tissue from 4 sheep to amplify the 18S ribosomal DNA (rDNA) and internal transcribed spacer (ITS) region of the rDNA, respectively. The resultant 18S rDNA nucleotide sequences shared 99% homology with multiple Eimeria species in GenBank. The ITS region shared 77% homology with E. ellipsoidalis in GenBank. Further studies are needed to understand the life cycle and pathogenicity of E. gilruthi. Our results underscore the inclusion of E. gilruthi in the differential diagnosis of diarrhea and weight loss in sheep. PMID- 30453851 TI - Arteriovenous fistulas ipsilateral to internal jugular catheters for hemodialysis have decreased patency rates. AB - PURPOSE: This study aimed to evaluate the effects of hemodialysis catheters on the survival of subsequent arteriovenous fistulas, according to the relative localization to the catheters. METHODS: A total of 201 patients who initiated dialysis therapy using a hemodialysis catheter were eligible for this retrospective study. Arteriovenous fistulas were created on the nondominant upper extremity after the placement of hemodialysis catheters. The catheters were removed after four consecutive successful dialyses via arteriovenous fistulas. The effective factors on arteriovenous fistula failure were determined in and the prognostic factors for survival were modeled by regression analysis. RESULTS: The relative placement of catheters as ipsi- or contralateral was found to significantly affect the survival of the arteriovenous fistulas. The overall survival was significantly longer in the contralateral arteriovenous fistula group (778.7 +/- 28.8 vs. 247.3 +/- 26.1 days; p < 0.001). The independent predictors of arteriovenous fistula survival were found to be relative side of arteriovenous fistula and hemodialysis catheter, age, and the presence of hypertension in multivariate analyses. CONCLUSION: This study showed that ipsilateral localization of the catheters and arteriovenous fistulas negatively affect the cumulative arteriovenous fistula survival. Therefore, to improve vascular access survival, side of catheters or arteriovenous fistulas should always be considered. PMID- 30453852 TI - Intensive Patients' Education and Lifestyle Improving Program in CAD Patients. AB - The objective of this article is to investigate the effects of intensive patients' education and lifestyle improving program (IPEL) on anxiety, depression, and overall survival (OS) in coronary artery disease (CAD) patients with anxiety and depression. In all, 224 CAD patients with anxiety and depression were randomly assigned to IPEL or control group. In Stage I, the IPEL group received IPEL and usual care, while the control group only received usual care. In Stage II, patients were further followed up and OS analysis was performed. Hospital Anxiety and Depression Scale-anxiety (HADS-A) and HADS-depression (HADS D) were used to assess anxiety and depression. IPEL reduced HADS-A score at Month 9 (M9)/M12, and the percentage of anxiety at M12 and HADS-A score changed. IPEL reduced HADS-D score at M12, and the percentage of depression at M12 and HADS-D score changed compared with control. Patients with nonanxiety/nondepression at M12 in the IPEL group showed better OS. IPEL reduces anxiety and depression and improves OS in CAD patients. PMID- 30453853 TI - Care and LGBT Aging in Canada: A Focus Group Study on the Educational Gaps among Care Workers. AB - OBJECTIVES: Educational interventions have the potential to equip healthcare providers to support diverse aging populations. The purpose of this research was to identify educational gaps hindering the provision of person-centered care to older adults who identify as LGBT. METHODS: Three focus groups were conducted in urban centers in northern, southern, and eastern Ontario with healthcare professionals and frontline staff. Semi-structured focus group discussion guides were developed based on the literature identifying some of the knowledge gaps, attitudes, challenges, and barriers around providing care for older LGBT adults. RESULTS: The focus group data revealed several key findings related to 1) lack of curricula within formal education; 2) the need to create safer physical and social environments; and 3) the need to build relationships with LGBT-focused groups/organizations. CONCLUSIONS: Care providers want to provide open space for sexual and gender diverse older adults but lack the knowledge to do so. CLINICAL IMPLICATIONS: There is an ongoing gap within formal education systems such that historically marginalized populations who are now aging may be systemically neglected within formal curricula. PMID- 30453854 TI - Maternal B vitamin intake during pregnancy and childhood behavioral problems in Japan: The Kyushu Okinawa Maternal and Child Health Study. AB - OBJECTIVES: The current prebirth cohort study investigated the relationship between maternal B vitamin intake during pregnancy and behavioral problems in Japanese children aged 5 years. METHODS: Subjects were 1199 mother-child pairs. Dietary intake was assessed using a diet history questionnaire. Emotional problems, conduct problems, hyperactivity problems, peer problems, and low prosocial behavior were examined using the Japanese parent-report version of the Strengths and Difficulties Questionnaire. Adjustment was made for maternal age, gestation at baseline, region of residence, number of children, maternal and paternal education, household income, maternal depressive symptoms, alcohol intake, vitamin B complex supplement use, smoking during pregnancy, child's birth weight, child's sex, breastfeeding duration, and smoking in the household during the first year of life. RESULTS: Maternal folate intake during pregnancy was independently inversely associated with childhood low prosocial behavior: the adjusted odds ratio (OR) (95% confidence interval [CI], P for trend) between extreme quartiles was 0.55 (0.37-0.80, 0.0002). Maternal vitamin B6 intake during pregnancy was independently inversely related to childhood hyperactivity problems and low prosocial behavior: the adjusted ORs (95% CIs, P for trend) between extreme quartiles were 0.57 (0.34-0.94, 0.01) and 0.58 (0.40-0.85, 0.0009), respectively. Maternal vitamin B2 intake during pregnancy was independently inversely associated with childhood emotional problems: the adjusted OR (95% CI, P for trend) between extreme quartiles was 0.58 (0.33-0.99, 0.11). CONCLUSIONS: Maternal intake of folate, vitamin B6, and vitamin B2 during pregnancy may be protective against childhood low prosocial behavior, hyperactivity problems and low prosocial behavior, and emotional problems, respectively. PMID- 30453855 TI - On the Very, Very Frontlines of Mental Health Care. AB - The role and training needs of client-facing administrative staff in mental health settings is an underidentified topic in the literature. Although interactions between the medical office staff and clients are not typically defined as therapeutic, patients nevertheless often view client-facing staff as an extension of their physician or care team. These interactions can be both meaningful and important to the overall care experience and should be conceptualized and understood as a legitimate part of the larger healing environment. To this end, the authors propose that a more fulsome understanding is needed of the experiences and impact of administrative staff's role in the larger clinical encounter from the perspectives of both clients and staff. The authors also identify a number of unmet training and support needs for client facing administrative staff. PMID- 30453856 TI - Patient Characteristics and Treatment Patterns Among Psychiatrists Who Do Not Accept Private Insurance. AB - OBJECTIVE:: Privately insured individuals frequently use out-of-network psychiatrists. Yet, whether treatment provided by psychiatrists who do not accept private insurance differs from treatment provided by those who do has not been studied. The investigators described provider characteristics, patient characteristics, and treatment patterns among psychiatrists who do not accept new patients with private insurance. METHODS:: Data for this study came from the National Ambulatory Medical Care Survey (2011-2014), a nationally representative annual cross-sectional survey of physicians providing ambulatory care. Responses of psychiatrists who report accepting any new patients (N=440) were examined, representing 7,634 visits. RESULTS:: Compared with psychiatrists accepting privately insured patients, those not accepting privately insured patients had fewer visits with patients with serious mental illness (42% versus 53%; p=0.016). These psychiatrists had a higher proportion of visits lasting longer than 30 minutes (48% versus 34%; p=0.026), and their patients were more likely to have had 10 or more visits in the past 12 months (41% versus 28%; p=0.013). There were no differences in the proportion of visits in which treatment included psychotherapy (48% versus 44%). CONCLUSIONS:: Although psychiatrists not accepting patients with private insurance were less likely than other psychiatrists to treat patients with serious mental illness, their patients were more likely to have longer visits and a relatively high number of visits in the past year. The low rate of acceptance of insurance among psychiatrists may have the greatest effect among those most in need of services. PMID- 30453857 TI - The Learning Curve After Implementation of Collaborative Care in a State Mental Health Integration Program. AB - OBJECTIVE:: This study examined organizational variability of process-of-care and depression outcomes at eight community health centers (CHCs) in the years following implementation of collaborative care (CC) for depression. METHODS:: The authors used 8 years of observational data for 13,362 unique patients at eight CHCs that participated in Washington State's Mental Health Integration Program. Organization-level changes in depression and process-of-care outcomes over time were studied. RESULTS:: On average, depression outcomes improved for the first 2 years before improvement slowed, peaking at year 5. Significant organization level variation was noted in outcomes. Improvements in depression outcomes tended to follow process-of-care measures. CONCLUSIONS:: Findings suggest that it may take 2 years after implementation of CC to fully observe depression outcome improvement at an organization level. Substantial variation between organizations in depression outcomes over time suggests that sustained attention to processes of care may be necessary to maintain initially achieved gains. PMID- 30453858 TI - Mental Disorders Among Children Born With Neonatal Abstinence Syndrome. PMID- 30453859 TI - 13 Reasons Why: Viewing Patterns and Perceived Impact Among Youths at Risk of Suicide. AB - OBJECTIVE:: The streaming series 13 Reasons Why generated controversy because of its depiction of teen suicide and concerns about its impact on vulnerable youths. This study examined exposure to and patterns of engagement with the show and the show's perceived impact in a sample of youths presenting to a psychiatric emergency department (ED) with suicide-related concerns in the year after the series' premiere. METHODS:: Participants were 87 parent-youth dyads (youths' mean+/-SD age=14.6+/-1.8; 71% of youths were female, 26% male, and 2% gender nonconforming) who completed a battery of questionnaires during their ED visit. RESULTS:: Half (49%) of the sample viewed at least one episode of 13 Reasons Why, season 1. Most youths (84%) viewed the show alone and were more likely to discuss their reactions with peers (80%) than with a parent (34%). Over half of youth viewers (51%) believed the series increased their suicide risk to a nonzero degree; having a stronger identification with the lead female character was significantly related to this belief (r=.63, df=41, p<0.001). Youths with more depressive symptoms and suicidal ideation were more likely to identify with the lead characters and report negative affect while viewing. CONCLUSIONS:: To date, this is the first published study examining viewing patterns and reactions to 13 Reasons Why in a high-risk sample. Although further research is needed, the findings suggest a particular vulnerability to the show's themes among youths at risk of suicide and the importance of prevention strategies to ameliorate risk among these viewers. PMID- 30453860 TI - Understanding Why Patients May Not Report Suicidal Ideation at a Health Care Visit Prior to a Suicide Attempt: A Qualitative Study. AB - OBJECTIVE:: The authors sought to understand why patients may not report suicidal ideation at a health care visit prior to a suicide attempt. METHODS:: Electronic health record data from Kaiser Permanente Washington were used to identify patients who reported having no suicidal ideation on question 9 of the nine-item Patient Health Questionnaire and who subsequently made a suicide attempt (<=60 days). Semistructured interviews were audio-recorded, transcribed, and analyzed by using a combination of directed (deductive) and conventional (inductive) content analysis to validate and further explore reasons why patients may not report suicidal ideation prior to a suicide attempt. RESULTS:: Of 42 adults sampled, 26 agreed to be interviewed, of whom about half were women (N=15) and a majority was white (N=20), with ages ranging from 18 to 63. Key themes were that patients who attempted suicide after having reported no thoughts of self-harm were either not experiencing suicidal ideation at the time of screening or feared the outcome of disclosure, including stigma, overreaction, and loss of autonomy. An additional theme that emerged from the interviews included reports of heavy episodic drinking at the time of the suicide attempt, particularly when suicide was completely unplanned. Patients also identified important aspects of interactions with health care system providers that may facilitate disclosure about suicidal ideation. CONCLUSIONS:: Nonjudgmental listening and expressions of caring without overreaction among providers may help patients overcome fear of reporting suicidal ideation. Screening for heavy episodic drinking may help identify individuals who make unplanned suicide attempts. PMID- 30453862 TI - BASES Conference 2018 - Programme and Abstracts. PMID- 30453861 TI - Alteration of Myeloid-Derived Suppressor Cells, Chronic Inflammatory Cytokines, and Exosomal miRNA Contribute to the Peritoneal Immune Disorder of Patients With Endometriosis. AB - Immunologic disorder has been reported to promote the progression of endometriosis (EMT). It has been known that myeloid-derived suppressor cells (MDSCs) drive the progression of many types of diseases. Few studies have shown the relation between MDSCs and EMT. To test whether MDSCs play a role in the progression of EMT, we defined MDSCs, cytokines, and the exosomal microRNA (miRNA) profile in peritoneal fluid (PF) from EMT patients. Characteristics of MDSCs, regulatory T cells (Tregs) and effector T cells were quantified by flow cytometry. Peritoneal fluid monocyte chemoattractant protein (MCP) 1/3, hepatocyte growth factor (HGF), chemokine (C-X-C motif) ligand (CXCL) 1/2, and 13 other cytokines were performed by enzyme-linked immunosorbent assay kit. Exosomal miRNA sequencing was prepared from PF of 3 women with early-stage EMT, 3 women with advanced stage EMT, and 3 women from control group. Our results showed that accumulations of monocytic MDSCs (Mo-MDSCs) and Tregs were detected in advanced patients with EMT. Patients with EMT displayed a significantly higher production of PF CXCL1, CXCL2, MCP-1, MCP-3, and HGF as compared to those from controls. MicroRNA sequencing showed 13 exosomal miRNAs (miRNA-1908, -130b, -451a, -486-5p, -4488, -432, -342, -425, -505, -6508, -145, -365a, and -365b) which are involved in immune alteration and cell proliferation and were differentially expressed in patients with EMT (fold-change +/- 2.0). In conclusion, our study revealed that Mo-MDSCs, inflammatory cytokines, and exosomal miRNA seem to be involved in the progression of EMT; however, the relation between Mo-MDSCs, cytokines, and miRNA needs further research. PMID- 30453863 TI - Comparing Outcomes of the Standard Technique of Endoscopic DCR with Its Modifications: A Retrospective Analysis. AB - OBJECTIVE: To compare the outcomes of various techniques of endoscopic dacryocystorhinostomy (DCR). STUDY DESIGN: Retrospective case record analysis. SETTINGS: Tertiary care referral center. SUBJECT AND METHODS: Retrospective analysis of case records was carried out pertaining to the period from January 1996 to September 2017 with respect to patients who had undergone endoscopic DCR with either the standard technique or one of its modifications. Case notes showing well-documented preoperative evaluation, operative details, postoperative assessment, and minimum 6-month follow-up were considered. The outcomes were measured on the basis of patients' postoperative symptoms, clinical examination, and sac-syringing results. RESULTS: A total of 423 patients were included in the study. Of these, 169 underwent standard endoscopic DCR; 87, endoscopic DCR with stent; 19, endoscopic DCR with mitomycin C; 62, powered DCR; 29, laser-assisted DCR; and 57, balloon DCR. There was no statistically significant difference in success rates, recurrences, or complications of various techniques at 3 or 6 months. Mean operating time was lowest for balloon DCR (mean +/- SD, 27.1 +/- 3.1 minutes), followed by standard endoscopic DCR (38.2 +/- 3.6 minutes; P = .001). CONCLUSION: Standard endoscopic DCR and its more sophisticated modifications were equally effective and safe in managing distal nasolacrimal drainage obstruction. Balloon DCR, followed by standard endoscopic DCR, was significantly faster than other techniques. PMID- 30453864 TI - Time-dependent effect of oligomeric amyloid-beta (1-42)-induced hippocampal neurodegeneration in rat model of Alzheimer's disease. AB - OBJECTIVE: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Abeta) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Abeta influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Abeta(1-42) (oAbeta1-42) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD. METHODS: Aggregated forms of synthetic Abeta peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription-polymerase chain reaction. RESULTS: oAbeta1-42 decreased the gene expression level of alpha7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAbeta1-42 aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, amyloid-beta1-42 are highly expressed in 15 days after postinjection in hippocampus of adult rats. CONCLUSION: Acute exposure of oAbeta1-42 modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments. ABBREVIATIONS: AD: Alzheimer's disease, Abeta: amyloid-beta; oAbeta1 42: oligomeric amyloid-beta 1-42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; alpha7 nAChR: alpha7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T. PMID- 30453866 TI - Diagnosis of severe asthma. AB - Patients with asthma that is uncontrolled despite high intensity medication can present in both primary and specialist care. An increasing number of novel (and expensive) treatments are available for patients who fail conventional asthma therapy, but these may not be appropriate for all such patients. It is essential that a rigorous evaluation process be undertaken for these patients to identify those with biologically severe asthma who will require novel therapies, and those who may improve with control of contributory factors. In this article, we describe three key steps in the diagnostic evaluation process for severe asthma. The first step is confirmation of asthma diagnosis with objective evidence of variable airflow obstruction. The second involves management of contributory factors such as non-adherence, poor inhaler technique, ongoing asthma triggers, and comorbidities. The third step involves phenotyping and endotyping of patients with severe asthma. We provide a practical approach to implementing these measures in both primary and secondary care. PMID- 30453865 TI - Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. AB - INTRODUCTION: We have developed the first international evidence-based guideline for the diagnosis and management of polycystic ovary syndrome (PCOS), with an integrated translation program incorporating resources for health professionals and consumers. The development process involved an extensive Australian-led international and multidisciplinary collaboration of health professionals and consumers over 2 years. The guideline is approved by the National Health and Medical Research Council and aims to support both health professionals and women with PCOS in improving care, health outcomes and quality of life. A robust evaluation process will enable practice benchmarking and feedback to further inform evidence-based practice. We propose that this methodology could be used in developing and implementing guidelines for other women's health conditions and beyond. Main recommendations: The recommendations cover the following broad areas: diagnosis, screening and risk assessment depending on life stage; emotional wellbeing; healthy lifestyle; pharmacological treatment for non fertility indications; and assessment and treatment of infertility. Changes in management as a result of this guideline: *Diagnosis:?when the combination of hyperandrogenism and ovulatory dysfunction is present, ultrasound examination of the ovaries is not necessary for diagnosis of PCOS in adult women;?requires the combination of hyperandrogenism and ovulatory dysfunction in young women within 8 years of menarche, with ultrasound examination of the ovaries not recommended, owing to the overlap with normal ovarian physiology; and?adolescents with some clinical features of PCOS, but without a clear diagnosis, should be regarded as "at risk" and receive follow-up assessment.*Screening for metabolic complications has been refined and incorporates both PCOS status and additional metabolic risk factors.*Treatment of infertility: letrozole is now first line treatment for infertility as it improves live birth rates while reducing multiple pregnancies compared with clomiphene citrate. PMID- 30453867 TI - Managing comorbid conditions in severe asthma. AB - Asthma care has increasingly focused on personalised management for severe asthma, and recognition of the role and importance of comorbid conditions has increased. Severe asthma can be crippling; associated comorbid conditions often play a key role in the significant disease morbidity and frequently contribute to a severe and difficult-to-treat asthma phenotype. Comorbid conditions can be broadly grouped as being either airway-related or airway-unrelated. Airway related comorbid conditions with the greatest impact are allergic rhinitis, chronic rhinosinusitis, vocal cord dysfunction, lung fungal sensitisation and underlying structural lung disease. The most important airway-unrelated comorbid conditions are obesity, obstructive sleep apnoea, gastro-oesophageal reflux disease and anxiety and depression. A diagnostic and management algorithm for comorbid conditions in severe asthma is outlined. It concentrates initially on the group with common comorbid conditions that can be managed in primary care. If asthma remains troublesome, emphasis can shift to identifying uncommon and more complex factors. The algorithm allows for personalised diagnostic and management pathways to be implemented. Personalised diagnosis and management of comorbid conditions are essential to achieving effective and improved outcomes for patients with severe asthma. PMID- 30453868 TI - Appropriate use of oral corticosteroids for severe asthma. AB - Severe asthma represents a significant burden of disease, particularly in high income nations; oral corticosteroids (OCS) remain an important part of the management toolkit for these patients. Corticosteroids are effective at targeting numerous elements of the type 2/eosinophilic inflammatory pathway and lead to both rapid reduction in eosinophilic inflammation and longer term reduction in airway hyper-responsiveness. Resistance or insensitivity to corticosteroids is a feature of severe asthma, with persistent type 2 inflammation often occurring despite regular use of OCS. OCS remain the only accepted, effective treatment for acute asthma, and also continue to play an important role in the long term management of severe asthma, in spite of their significant side effect profile. Even with the availability of the new biological therapies against IgE and interleukin-5, it is likely that a large proportion of patients will continue to require OCS to control their asthma. Future work should focus on optimising the balance between OCS efficacy and safety, and continued development of agents that allow reduction, or ideally discontinuation of their use, is needed. PMID- 30453869 TI - Optimising treatment for severe asthma. AB - The treatment landscape in severe asthma is changing rapidly, with multiple new therapies emerging that promise to transform patient outcomes. In a patient who is not responding to conventional therapy with inhaled corticosteroids and long acting beta2-agonists, it is important to first consider if the diagnosis of asthma is correct and, second, to reflect on whether readily modifiable factors are contributing to poor asthma control. In selected patients it may be appropriate to consider a modified n-of-1 trial of add-on therapies such as long acting anti-muscarinic agents, leukotriene blockers, theophylline or low dose macrolide antibiotics. A number of monoclonal antibodies are now available that target the molecular pathways that contribute to asthma pathogenesis, and more such agents are likely to emerge in the near future. These biologicals can be transformative in selected patients, markedly reducing the frequency of asthma exacerbations, and allowing many patients to reduce or eliminate their use of long term oral corticosteroids. If the promise of personalised treatment is to be fully realised, it is important that better methods are developed to target these new and expensive treatments to patients most likely to respond. The ultimate goal of inducing remission or cure of asthma is still some distance away. PMID- 30453870 TI - Health-related quality of life burden in severe asthma. AB - It is largely unrecognised that the impacts of asthma are different in patients with severe disease compared with patients with mild to moderate disease. Severe asthma is associated with a significant health-related quality of life (HRQoL) burden due to excessive symptoms, frequent and life-threatening attacks, increased comorbidity burden, and high pharmacological treatment requirements. Interventions aimed at improving HRQoL need to be specifically tested in populations with severe asthma, including multicomponent interventions targeting the many clinical characteristics associated with the disease. It is necessary to have patient-reported outcome measures developed specifically for severe asthma. Public health messages recognising the significant burden of severe asthma on quality of life are needed. PMID- 30453871 TI - Models of care for severe asthma: the role of primary care. AB - Severe asthma encompasses treatment-refractory asthma and difficult-to-treat asthma. There are a number of barriers in primary, secondary and tertiary settings which compromise optimal care for severe asthma in Australia. Guidelines recommend a multidimensional assessment of severe asthma, which includes confirming the diagnosis, severity and phenotype and identifying and treating comorbidities and risk factors. This approach has been found to improve severe asthma symptoms and quality of life and reduce exacerbations. Primary care providers can contribute significantly to the multidimensional approach for severe asthma by performing spirometry, optimising therapy and addressing risk factors such as non-adherence and smoking before referring the patient to a respiratory physician for review. Primary care practitioners are encouraged to remain engaged with the management of a patient with severe asthma following specialist review by assisting with community-based allied health referrals, managing general medical comorbidities and administering prescribed biological therapies. Specialists can support primary care by providing advice to individuals with indeterminate diagnosis, streamlining investigation and management of unrecognised risk factors and complex comorbidities, optimising treatment for severe or difficult asthma including assessment of suitability for and, if appropriate, initiating advanced therapies such as biological therapies. When discharging patients back to primary care, specialists should provide clear recommendations regarding ongoing management and should specify the indications requiring further specialist review, ideally offering a streamlined re-referral pathway. PMID- 30453873 TI - Expression analysis of RNA sequencing data from human neural and glial cell lines depends on technical replication and normalization methods. AB - BACKGROUND: The potential for astrocyte participation in central nervous system recovery is highlighted by in vitro experiments demonstrating their capacity to transdifferentiate into neurons. Understanding astrocyte plasticity could be advanced by comparing astrocytes with stem cells. RNA sequencing (RNA-seq) is ideal for comparing differences across cell types. However, this novel multi stage process has the potential to introduce unwanted technical variation at several points in the experimental workflow. Quantitative understanding of the contribution of experimental parameters to technical variation would facilitate the design of robust RNA-Seq experiments. RESULTS: RNA-Seq was used to achieve biological and technical objectives. The biological aspect compared gene expression between normal human fetal-derived astrocytes and human neural stem cells cultured in identical conditions. When differential expression threshold criteria of |log2 fold change| > 2 were applied to the data, no significant differences were observed. The technical component quantified variation arising from particular steps in the research pathway, and compared the ability of different normalization methods to reduce unwanted variance. To facilitate this objective, a liberal false discovery rate of 10% and a |log2 fold change| > 0.5 were implemented for the differential expression threshold. Data were normalized with RPKM, TMM, and UQS methods using JMP Genomics. The contributions of key replicable experimental parameters (cell lot; library preparation; flow cell) to variance in the data were evaluated using principal variance component analysis. Our analysis showed that, although the variance for every parameter is strongly influenced by the normalization method, the largest contributor to technical variance was library preparation. The ability to detect differentially expressed genes was also affected by normalization; differences were only detected in non normalized and TMM-normalized data. CONCLUSIONS: The similarity in gene expression between astrocytes and neural stem cells supports the potential for astrocytic transdifferentiation into neurons, and emphasizes the need to evaluate the therapeutic potential of astrocytes for central nervous system damage. The choice of normalization method influences the contributions to experimental variance as well as the outcomes of differential expression analysis. However irrespective of normalization method, our findings illustrate that library preparation contributed the largest component of technical variance. PMID- 30453872 TI - The poly-omics of ageing through individual-based metabolic modelling. AB - BACKGROUND: Ageing can be classified in two different ways, chronological ageing and biological ageing. While chronological age is a measure of the time that has passed since birth, biological (also known as transcriptomic) ageing is defined by how time and the environment affect an individual in comparison to other individuals of the same chronological age. Recent research studies have shown that transcriptomic age is associated with certain genes, and that each of those genes has an effect size. Using these effect sizes we can calculate the transcriptomic age of an individual from their age-associated gene expression levels. The limitation of this approach is that it does not consider how these changes in gene expression affect the metabolism of individuals and hence their observable cellular phenotype. RESULTS: We propose a method based on poly-omic constraint-based models and machine learning in order to further the understanding of transcriptomic ageing. We use normalised CD4 T-cell gene expression data from peripheral blood mononuclear cells in 499 healthy individuals to create individual metabolic models. These models are then combined with a transcriptomic age predictor and chronological age to provide new insights into the differences between transcriptomic and chronological ageing. As a result, we propose a novel metabolic age predictor. CONCLUSIONS: We show that our poly-omic predictors provide a more detailed analysis of transcriptomic ageing compared to gene-based approaches, and represent a basis for furthering our knowledge of the ageing mechanisms in human cells. PMID- 30453874 TI - TransFlow: a modular framework for assembling and assessing accurate de novo transcriptomes in non-model organisms. AB - BACKGROUND: The advances in high-throughput sequencing technologies are allowing more and more de novo assembling of transcriptomes from many new organisms. Some degree of automation and evaluation is required to warrant reproducibility, repetitivity and the selection of the best possible transcriptome. Workflows and pipelines are becoming an absolute requirement for such a purpose, but the issue of assembling evaluation for de novo transcriptomes in organisms lacking a sequenced genome remains unsolved. An automated, reproducible and flexible framework called TransFlow to accomplish this task is described. RESULTS: TransFlow with its five independent modules was designed to build different workflows depending on the nature of the original reads. This architecture enables different combinations of Illumina and Roche/454 sequencing data, and can be extended to other sequencing platforms. Its capabilities are illustrated with the selection of reliable plant reference transcriptomes and the assembling six transcriptomes (three case studies for grapevine leaves, olive tree pollen, and chestnut stem, and other three for haustorium, epiphytic structures and their combination for the phytopathogenic fungus Podosphaera xanthii). Arabidopsis and poplar transcriptomes revealed to be the best references. A common result regarding de novo assemblies is that Illumina paired-end reads of 100 nt in length assembled with OASES can provide reliable transcriptomes, while the contribution of longer reads is noticeable only when they complement a set of short, single-reads. CONCLUSIONS: TransFlow can handle up to 181 different assembling strategies. Evaluation based on principal component analyses allows its self-adaptation to different sets of reads to provide a suitable transcriptome for each combination of reads and assemblers. As a result, each case study has its own behaviour, prioritises evaluation parameters, and gives an objective and automated way for detecting the best transcriptome within a pool of them. Sequencing data type and quantity (preferably several hundred millions of 2*100 nt or longer), assemblers (OASES for Illumina, MIRA4 and EULER-SR reconciled with CAP3 for Roche/454) and strategy (preferably scaffolding with OASES, and probably merging with Roche/454 when available) arise as the most impacting factors. PMID- 30453876 TI - The predictive performance of short-linear motif features in the prediction of calmodulin-binding proteins. AB - BACKGROUND: The prediction of calmodulin-binding (CaM-binding) proteins plays a very important role in the fields of biology and biochemistry, because the calmodulin protein binds and regulates a multitude of protein targets affecting different cellular processes. Computational methods that can accurately identify CaM-binding proteins and CaM-binding domains would accelerate research in calcium signaling and calmodulin function. Short-linear motifs (SLiMs), on the other hand, have been effectively used as features for analyzing protein-protein interactions, though their properties have not been utilized in the prediction of CaM-binding proteins. RESULTS: We propose a new method for the prediction of CaM binding proteins based on both the total and average scores of known and new SLiMs in protein sequences using a new scoring method called sliding window scoring (SWS) as features for the prediction module. A dataset of 194 manually curated human CaM-binding proteins and 193 mitochondrial proteins have been obtained and used for testing the proposed model. The motif generation tool, Multiple EM for Motif Elucidation (MEME), has been used to obtain new motifs from each of the positive and negative datasets individually (the SM approach) and from the combined negative and positive datasets (the CM approach). Moreover, the wrapper criterion with random forest for feature selection (FS) has been applied followed by classification using different algorithms such as k-nearest neighbors (k-NN), support vector machines (SVM), naive Bayes (NB) and random forest (RF). CONCLUSIONS: Our proposed method shows very good prediction results and demonstrates how information contained in SLiMs is highly relevant in predicting CaM-binding proteins. Further, three new CaM-binding motifs have been computationally selected and biologically validated in this study, and which can be used for predicting CaM-binding proteins. PMID- 30453875 TI - Computational discovery of direct associations between GO terms and protein domains. AB - BACKGROUND: Families of related proteins and their different functions may be described systematically using common classifications and ontologies such as Pfam and GO (Gene Ontology), for example. However, many proteins consist of multiple domains, and each domain, or some combination of domains, can be responsible for a particular molecular function. Therefore, identifying which domains should be associated with a specific function is a non-trivial task. RESULTS: We describe a general approach for the computational discovery of associations between different sets of annotations by formalising the problem as a bipartite graph enrichment problem in the setting of a tripartite graph. We call this approach "CODAC" (for COmputational Discovery of Direct Associations using Common Neighbours). As one application of this approach, we describe "GODomainMiner" for associating GO terms with protein domains. We used GODomainMiner to predict GO domain associations between each of the 3 GO ontology namespaces (MF, BP, and CC) and the Pfam, CATH, and SCOP domain classifications. Overall, GODomainMiner yields average enrichments of 15-, 41- and 25-fold GO-domain associations compared to the existing GO annotations in these 3 domain classifications, respectively. CONCLUSIONS: These associations could potentially be used to annotate many of the protein chains in the Protein Databank and protein sequences in UniProt whose domain composition is known but which currently lack GO annotation. PMID- 30453877 TI - DNA sequences alignment in multi-GPUs: acceleration and energy payoff. AB - BACKGROUND: We present a performance per watt analysis of CUDAlign 4.0, a parallel strategy to obtain the optimal pairwise alignment of huge DNA sequences in multi-GPU platforms using the exact Smith-Waterman method. RESULTS: Our study includes acceleration factors, performance, scalability, power efficiency and energy costs. We also quantify the influence of the contents of the compared sequences, identify potential scenarios for energy savings on speculative executions, and calculate performance and energy usage differences among distinct GPU generations and models. For a sequence alignment on chromosome-wide scale (around 2 Petacells), we are able to reduce execution times from 9.5 h on a Kepler GPU to just 2.5 h on a Pascal counterpart, with energy costs cut by 60%. CONCLUSIONS: We find GPUs to be an order of magnitude ahead in performance per watt compared to Xeon Phis. Finally, versus typical low-power devices like FPGAs, GPUs keep similar GFLOPS/w ratios in 2017 on a five times faster execution. PMID- 30453878 TI - Automated selection of homologs to track the evolutionary history of proteins. AB - BACKGROUND: The selection of distant homologs of a query protein under study is a usual and useful application of protein sequence databases. Such sets of homologs are often applied to investigate the function of a protein and the degree to which experimental results can be transferred from one organism to another. In particular, a variety of databases facilitates static browsing for orthologs. However, these resources have a limited power when identifying orthologs between taxonomically distant species. In addition, in some situations, for a given query protein, it is advantageous to compare the sets of orthologs from different specific organisms: this recursive step-wise search might give an idea of the evolutionary path of the protein as a series of consecutive steps, for example gaining or losing domains. However, a step-wise orthology search is a time consuming task if the number of steps is high. RESULTS: To illustrate a solution for this problem, we present the web tool ProteinPathTracker, which allows to track the evolutionary history of a query protein by locating homologs in selected proteomes along several evolutionary paths. Additional functionalities include locking a region of interest to follow its evolution in the discovered homologous sequences and the study of the protein function evolution by analysis of the annotations of the homologs. CONCLUSIONS: ProteinPathTracker is an easy-to use web tool that automatises the practice of looking for selected homologs in distant species in a straightforward way for non-expert users. PMID- 30453879 TI - Evaluating the impact of topological protein features on the negative examples selection. AB - BACKGROUND: Supervised machine learning methods when applied to the problem of automated protein-function prediction (AFP) require the availability of both positive examples (i.e., proteins which are known to possess a given protein function) and negative examples (corresponding to proteins not associated with that function). Unfortunately, publicly available proteome and genome data sources such as the Gene Ontology rarely store the functions not possessed by a protein. Thus the negative selection, consisting in identifying informative negative examples, is currently a central and challenging problem in AFP. Several heuristics have been proposed through the years to solve this problem; nevertheless, despite their effectiveness, to the best of our knowledge no previous existing work studied which protein features are more relevant to this task, that is, which protein features help more in discriminating reliable and unreliable negatives. RESULTS: The present work analyses the impact of several features on the selection of negative proteins for the Gene Ontology (GO) terms. The analysis is network-based: it exploits the fact that proteins can be naturally structured in a network, considering the pairwise relationships coming from several sources of data, such as protein-protein and genetic interactions. Overall, the proposed protein features, including local and global graph centrality measures and protein multifunctionality, can be term-aware (i.e., depending on the GO term) and term-unaware (i.e., invariant across the GO terms). We validated the informativeness of each feature utilizing a temporal holdout in three different experiments on yeast, mouse and human proteomes: (i) feature selection to detect which protein features are more helpful for the negative selection; (ii) protein function prediction to verify whether the features considered are also useful to predict GO terms; (iii) negative selection by applying two different negative selection algorithms on proteins represented through the proposed features. CONCLUSIONS: Term-aware features (with some exceptions) resulted more informative for problem (i), together with node betweenness, which is the most relevant among term-unaware features. The node positive neighborhood instead is the most predictive feature for the AFP problem, while experiment (iii) showed that the proposed features allow negative selection algorithms to select effectively negative instances in the temporal holdout setting, with better results when nonlinear combinations of features are also exploited. PMID- 30453880 TI - Comparing the performance of selected variant callers using synthetic data and genome segmentation. AB - BACKGROUND: High-throughput sequencing has rapidly become an essential part of precision cancer medicine. But validating results obtained from analyzing and interpreting genomic data remains a rate-limiting factor. The gold standard, of course, remains manual validation by expert panels, which is not without its weaknesses, namely high costs in both funding and time as well as the necessarily selective nature of manual validation. But it may be possible to develop more economical, complementary means of validation. In this study we employed four synthetic data sets (variants with known mutations spiked into specific genomic locations) of increasing complexity to assess the sensitivity, specificity, and balanced accuracy of five open-source variant callers: FreeBayes v1.0, VarDict v11.5.1, MuTect v1.1.7, MuTect2, and MuSE v1.0rc. FreeBayes, VarDict, and MuTect were run in bcbio-next gen, and the results were integrated into a single Ensemble call set. The known mutations provided a level of "ground truth" against which we evaluated variant-caller performance. We further facilitated the comparison and evaluation by segmenting the whole genome into 10,000,000 base pair fragments which yielded 316 segments. RESULTS: Differences among the numbers of true positives were small among the callers, but the numbers of false positives varied much more when the tools were used to analyze sets one through three. Both FreeBayes and VarDict produced strikingly more false positives than did the others, although VarDict, somewhat paradoxically also produced the highest number of true positives. The Ensemble approach yielded results characterized by higher specificity and balanced accuracy and fewer false positives than did any of the five tools used alone. Sensitivity and specificity, however, declined for all five callers as the complexity of the data sets increased, but we did not uncover anything more than limited, weak correlations between caller performance and certain DNA structural features: gene density and guanine-cytosine content. Altogether, MuTect2 performed the best among the callers tested, followed by MuSE and MuTect. CONCLUSIONS: Spiking data sets with specific mutations -single-nucleotide variations (SNVs), single-nucleotide polymorphisms (SNPs), or structural variations (SVs) in this study-at known locations in the genome provides an effective and economical way to compare data analyzed by variant callers with ground truth. The method constitutes a viable alternative to the prolonged, expensive, and noncomprehensive assessment by expert panels. It should be further developed and refined, as should other comparatively "lightweight" methods of assessing accuracy. Given that the scientific community has not yet established gold standards for validating NGS related technologies such as variant callers, developing multiple alternative means for verifying variant-caller accuracy will eventually lead to the establishment of higher-quality standards than could be achieved by prematurely limiting the range of innovative methods explored by members of the community. PMID- 30453881 TI - Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples. AB - BACKGROUND: Because driver mutations provide selective advantage to the mutant clone, they tend to occur at a higher frequency in tumor samples compared to selectively neutral (passenger) mutations. However, mutation frequency alone is insufficient to identify cancer genes because mutability is influenced by many gene characteristics, such as size, nucleotide composition, etc. The goal of this study was to identify gene characteristics associated with the frequency of somatic mutations in the gene in tumor samples. RESULTS: We used data on somatic mutations detected by genome wide screens from the Catalog of Somatic Mutations in Cancer (COSMIC). Gene size, nucleotide composition, expression level of the gene, relative replication time in the cell cycle, level of evolutionary conservation and other gene characteristics (totaling 11) were used as predictors of the number of somatic mutations. We applied stepwise multiple linear regression to predict the number of mutations per gene. Because missense, nonsense, and frameshift mutations are associated with different sets of gene characteristics, they were modeled separately. Gene characteristics explain 88% of the variation in the number of missense, 40% of nonsense, and 23% of frameshift mutations. Comparisons of the observed and expected numbers of mutations identified genes with a higher than expected number of mutations- positive outliers. Many of these are known driver genes. A number of novel candidate driver genes was also identified. CONCLUSIONS: By comparing the observed and predicted number of mutations in a gene, we have identified known cancer-associated genes as well as 111 novel cancer associated genes. We also showed that adding the number of silent mutations per gene reported by genome/exome wide screens across all cancer type (COSMIC data) as a predictor substantially exceeds predicting accuracy of the most popular cancer gene predicting tool - MutsigCV. PMID- 30453882 TI - AdaptMap: exploring goat diversity and adaptation. PMID- 30453883 TI - Automated shape-based clustering of 3D immunoglobulin protein structures in chronic lymphocytic leukemia. AB - BACKGROUND: Although the etiology of chronic lymphocytic leukemia (CLL), the most common type of adult leukemia, is still unclear, strong evidence implicates antigen involvement in disease ontogeny and evolution. Primary and 3D structure analysis has been utilised in order to discover indications of antigenic pressure. The latter has been mostly based on the 3D models of the clonotypic B cell receptor immunoglobulin (BcR IG) amino acid sequences. Therefore, their accuracy is directly dependent on the quality of the model construction algorithms and the specific methods used to compare the ensuing models. Thus far, reliable and robust methods that can group the IG 3D models based on their structural characteristics are missing. RESULTS: Here we propose a novel method for clustering a set of proteins based on their 3D structure focusing on 3D structures of BcR IG from a large series of patients with CLL. The method combines techniques from the areas of bioinformatics, 3D object recognition and machine learning. The clustering procedure is based on the extraction of 3D descriptors, encoding various properties of the local and global geometrical structure of the proteins. The descriptors are extracted from aligned pairs of proteins. A combination of individual 3D descriptors is also used as an additional method. The comparison of the automatically generated clusters to manual annotation by experts shows an increased accuracy when using the 3D descriptors compared to plain bioinformatics-based comparison. The accuracy is increased even more when using the combination of 3D descriptors. CONCLUSIONS: The experimental results verify that the use of 3D descriptors commonly used for 3D object recognition can be effectively applied to distinguishing structural differences of proteins. The proposed approach can be applied to provide hints for the existence of structural groups in a large set of unannotated BcR IG protein files in both CLL and, by logical extension, other contexts where it is relevant to characterize BcR IG structural similarity. The method does not present any limitations in application and can be extended to other types of proteins. PMID- 30453884 TI - Combined genetic influence of the nicotinic receptor gene cluster CHRNA5/A3/B4 on nicotine dependence. AB - BACKGROUND: The CHRNA5/A3/B4 gene locus is associated with nicotine dependence and other smoking related disorders. While the non-synonymous CHRNA5 variant rs16969968 appears to be the main risk factor, linkage disequilibrium (LD) bins in the gene cluster carry frequent variants that regulate expression. Pairwise LD and haplotype analyses had identified at least three haplotype tagging SNPs including rs16969968 as main genetic risk factors. Searching for variants with evidence of regulatory functions, we have reported interactions between CHRNA5 and CHRNA3 enhancer variants (tagged by rs880395 and rs1948, respectively) and rs16969968, forming 3-SNP haplotypes and diplotypes that may more accurately reflect the cluster's combined effects on nicotine dependence (Barrie et al., Hum Mutat 38:112-9, 2017). Here we address further contributions by variants affecting CHRNB4, a possibly limiting component of nicotinic receptors. RESULTS: We identify an LD bin (tagged by rs4887074) associated with expression of CHRNB4. Additive logistic regression models indicate that rs4887074 is associated with nicotine dependence and modulates the effect of rs16969968 in GWAS datasets (COGEND, UW-TTURC, SAGE). 4-SNP haplotype and diplotype analyses (rs880395 rs16969968-rs1948 -rs4887074) yield nicotine dependence risk values that further differentiate those obtained with the 3-SNP model. Moreover, both the main G allele of rs16969968 and the minor G allele of rs4887074 (associated with reduced expression of CHRNB4), residing predominantly on common haplotypes that are protective, represent significant allele-specific variance QTLs, indicating that they interact with each other. CONCLUSIONS: These results indicate rs4887074 is associated with CHRNB4 expression, and along with two regulatory variants of CHRNA3 and CHRNA5, modulates the effect of rs16969968 on nicotine dependence risk. Assignable to individuals because of strong LD structures, 4-SNP haplotypes and diplotypes serve to assess the combined genetic influence of this multi-gene cluster on complex traits, accounting for complex LD relationships and tissue specific genetic effects (CHRNA5/3) relevant to the traits analyzed. The 4-SNP haplotypes account at least in part for previous tagging SNPs, including the highly GWAS-significant rs6495308, located in a distinct pair-wise LD bin but included in protective 4-SNP haplotypes. Our approach refines and integrates the cluster's overall genetic influence, an important variable when integrating the genetics of multiple genomic loci. PMID- 30453885 TI - SVM-RFE: selection and visualization of the most relevant features through non linear kernels. AB - BACKGROUND: Support vector machines (SVM) are a powerful tool to analyze data with a number of predictors approximately equal or larger than the number of observations. However, originally, application of SVM to analyze biomedical data was limited because SVM was not designed to evaluate importance of predictor variables. Creating predictor models based on only the most relevant variables is essential in biomedical research. Currently, substantial work has been done to allow assessment of variable importance in SVM models but this work has focused on SVM implemented with linear kernels. The power of SVM as a prediction model is associated with the flexibility generated by use of non-linear kernels. Moreover, SVM has been extended to model survival outcomes. This paper extends the Recursive Feature Elimination (RFE) algorithm by proposing three approaches to rank variables based on non-linear SVM and SVM for survival analysis. RESULTS: The proposed algorithms allows visualization of each one the RFE iterations, and hence, identification of the most relevant predictors of the response variable. Using simulation studies based on time-to-event outcomes and three real datasets, we evaluate the three methods, based on pseudo-samples and kernel principal component analysis, and compare them with the original SVM-RFE algorithm for non linear kernels. The three algorithms we proposed performed generally better than the gold standard RFE for non-linear kernels, when comparing the truly most relevant variables with the variable ranks produced by each algorithm in simulation studies. Generally, the RFE-pseudo-samples outperformed the other three methods, even when variables were assumed to be correlated in all tested scenarios. CONCLUSIONS: The proposed approaches can be implemented with accuracy to select variables and assess direction and strength of associations in analysis of biomedical data using SVM for categorical or time-to-event responses. Conducting variable selection and interpreting direction and strength of associations between predictors and outcomes with the proposed approaches, particularly with the RFE-pseudo-samples approach can be implemented with accuracy when analyzing biomedical data. These approaches, perform better than the classical RFE of Guyon for realistic scenarios about the structure of biomedical data. PMID- 30453886 TI - Flexible docking-based molecular dynamics simulation of natural product compounds and Ebola virus Nucleocapsid (EBOV NP): a computational approach to discover new drug for combating Ebola. AB - BACKGROUND: Ebola still remains as one of the most problematic infectious diseases in Africa with a high rate of mortality. Although this disease has been known for an almost half-century, there are no vaccines and drugs available in the market to treat Ebola. Zaire ebolavirus (EBOV), a single-stranded RNA virus which belongs to Filoviridae family and Mononegavirales order, is one of the virus causing Ebola. As one of seven proteins that EBOV encodes, Ebola virus nucleoprotein (EBOV NP) plays an imperative role in EBOV proliferation cycle. Therefore, the development of a new Ebola treatment can be targeted towards EBOV NP. RESULTS: In this work, we screened about 190,084 natural product compounds from ZINC15 database through in silico virtual screening and flexible docking simulation. Furthermore, the bioavailability and toxicity prediction have been conducted as well. Two best ligands according to the simulation and prediction tests were progressed into the molecular dynamics simulation. CONCLUSION: In the end, we found that our proposed ligands, namely alpha-lipomycin (ZINC56874155) and 3-(((S)-1-amino-1,2,3,4-tetrahydroisoquinolin-5-yl)methyl)-5-((5-((5R,7S)-5,7 dihydroxy-3-oxodecyl)-2-hydroxyphenoxy) methyl)pyrrolo[3,4-b]pyrrol-5-ium (ZINC85628951), showed the promising results to be developed as a lead compounds for treating Ebola. Therefore, an experimental study is required to validate their inhibition activities against EBOV NP. PMID- 30453887 TI - Historical biogeography reveals new independent evolutionary lineages in the Pantosteus plebeius-nebuliferus species-group (Actinopterygii: Catostomidae). AB - BACKGROUND: The Pantosteus plebeius-nebuliferus species-group is a group of freshwater fishes distributed in endo- and exorheic drainage basins in the Mexican Sierra Madre Occidental mountain range system and central North Mexico. The geological history of this region is considered an important factor in explaining the evolutionary history of low vagility animals like freshwaters fishes. The aim of this study was to examine the phylogenetic relationships and describe the evolutionary history of the species-group. We hypothesized that the genetic structure and distribution of the main clades of Pantosteus plebeius nebuliferus are associated with the geological history of Northern Mexico. To this end, we obtained DNA sequences of mitochondrial and nuclear genes and performed phylogenetic and phylogeographic analyses. Divergence time estimation and ancestral area reconstruction were also carried out to propose a biogeographical hypothesis, and species boundaries within the species-group were also tested. RESULTS: We identified four clades within the Pantosteus plebeius nebuliferus species-group in both markers. Divergence ranged from 5.9% to 9.2% for cytb and 0.1% to 0.9% for GHI. We observed significant genetic structure and no shared haplotypes between clades. We estimated that the clades diverged during the last 5.1 Myr, with a biogeographic scenario suggesting eight vicariant and four dispersal events through the historic range of the species-group. We found that the best species-delimitation model is when four species are assumed, which correspond to the main clades. We identified nine evolutionary significance units (ESUs), pertinent to the conservation of the group, each representing populations present in distinct drainage basins. CONCLUSIONS: The evolutionary history of the Pantosteus plebeius-nebuliferus species-group is characterized by vicariant post dispersal processes, linked to geological changes in the Sierra Madre Occidental and central Northern Mexico since the Pliocene. This is congruent with biogeographic patterns described for other co-distributed fish species. We propose a new phylogenetic hypothesis for the species-group, clarifying the taxonomy of this evolutionarily complex group. Our results suggest that the species-group consists of at least four clades with independent evolutionary histories, two of which may represent new undescribed species. Our identification of ESUs provides a basis upon which conservation measures can be developed for the species-group. PMID- 30453888 TI - Comparison of the use of comprehensive point-of-care test panel to conventional laboratory process in emergency department. AB - BACKGROUND: In this study, we hypothesized that point of care testing (POCT) would reduce length of stay (LOS) in emergency department (ED) when compared to central laboratory testing and be a factor in patient discharge destination. METHODS: A single centre observational study was performed in ED non-ambulatory patients. Blood testing was performed either with POC instruments for blood gases and chemistry panel, full blood count, and CRP, or at central laboratory, or as a combination of both. Blood draw and POCTs were performed by experienced nurses. RESULTS: During the 4-week study period, 1759 patients underwent sample testing (POCT: n = 160, central lab: n = 951; both n = 648). Median waiting time for blood sampling was 19 min less in POCT than central laboratory (0:52 (95% confidence interval (CI) 0:46-1:02) vs. 1:11 (95% CI 1:05-1:14), p < 0.001). POCT results were available faster in both discharge groups, as expected. When imaging was not required, patients in POCT group were discharged home 55 min faster (4:57 (95% CI 3:59-6:17) vs. 5:52 (95% CI 5:21-6:35), p = 0.012) and 1 h 22 min faster when imaging was performed (5:48 (95% CI 5:26-6:18) vs. 7:10 (95% CI 6:47-8:26), p = 0.010). Similar reduction in sampling time and LOS was not seen among those admitted to hospital. CONCLUSIONS: POCT shortened the laboratory process and made results available faster than the central lab. This allowed patients to be discharged home quicker. Thus, with proper training and education of the ED care team, POCT can be used as an effective tool for improving patient flow. PMID- 30453889 TI - Renal outcomes of STOP-IgAN trial patients in relation to baseline histology (MEST-C scores). AB - BACKGROUND: The Oxford classification of IgA nephropathy (IgAN) defines histologic criteria (MEST-C) that provide prognostic information based on the kidney biopsy. There are few data on the predictive impact of this classification in randomized clinical trial settings. METHODS: We performed an exploratory analysis of MEST-C scores in 70 available renal biopsies from 162 randomized STOP IgAN trial participants and correlated the results with clinical outcomes. Analyses were performed by researchers blinded to the clinical outcome of the patients. Biopsies had been obtained 6.5 to 95 (median 9.4) months prior to randomization. RESULTS: Mesangial hypercellularity (M1) associated with higher annual eGFR-loss during the 3-year trial (M1: - 5.06 +/- 5.17 ml/min/1.73 m2, M0: - 0.79 +/- 4.50 ml/min/1.73 m2, p = 0.002). An M0-score additionally showed a weak association with full clinical remission, whereas the percentage of patients losing >=15 ml/min/1.73 m2 over the 3-year trial phase was higher among those scored as M1. Among patients with additional immunosuppression, ESRD occurred more frequently in patients when tubulointerstitial fibrosis (T1/2) was present (T1/2 = 33%, T0 = 0%, p = 0.008). In patients receiving supportive care only, ESRD frequencies were similar (T1/2 = 18%, T0 = 7%, p = 0.603). At randomization, eGFR was significantly lower when tubulointerstitial fibrosis was present (T1/2: 45.2 +/- 15.7 ml/min/1.73 m2, T0: 74.6 +/- 28.2 ml/min/1.73 m2, p < 0.0001). Endocapillary hypercellularity (E), and glomerular segmental sclerosis (S) were not associated with any clinical outcome parameter. In the analyzed cohort, patients with glomerular crescents (C1/2 scores) in their biopsies were more likely to develop ESRD during the 3-year trial phase, but this trend was only significant in patients under supportive care. CONCLUSIONS: This secondary analysis of STOP-IgAN biopsies indicates that M1, T1/2 and C1/2 scores associate with worse renal outcomes. PMID- 30453890 TI - Troponin I at admission in the intensive care unit predicts the need of dialysis in septic patients. AB - BACKGROUND: In a previous study we showed that troponin I (TnI) > 0.42 ng/mL predicted the need of dialysis in a group of 29 septic patients admitted to the intensive care unit (ICU). We aimed to confirm such finding in a larger independent sample. METHODS: All septic patients admitted to an ICU from March 2016 to February 2017 were included if age between 18 and 90 years, onset of sepsis < 24 h, normal left ventricular ejection fraction, and no previous coronary or kidney diseases. TnI was measured on day 1. Patients were followed by 30 days or until death. RESULTS: A total of 120 patients were included (51% male, 74 +/- 13 years old). At ICU admission, 70 patients had TnI > 0.42 ng/mL. These patients had serum creatinine slightly higher (1.66 +/- 0.34 vs. 1.32 +/- 0.39 mg/dL; P < 0.0001) than those with lower TnI and similar urine output (1490 +/- 682 vs. 1406 +/- 631 mL; P = 0.44). At the end of the follow-up period, 70.0% of the patients with lower TnI were alive in comparison with 38.6% of those with higher TnI (p = 0.0014). After 30 days, 69.3 and 2.9% of the patients with lower and higher TnI levels remained free of dialysis, respectively (p < 0.0001). In a Cox regression model, after adjustment for gender, age, Charlson comorbidity index, serum creatinine, potassium, pH, brain natriuretic peptide and urine output, TnI > 0.42 ng/mL persisted as a strong predictor of dialysis need (hazard ratio 3.48 [95%CI 1.69-7.18]). CONCLUSIONS: TnI levels at ICU admission are a strong independent predictor of dialysis need in sepsis. PMID- 30453891 TI - Correlation between antifungal consumption and the distribution of Candida species in different hospital departments of a Lebanese medical Centre. AB - BACKGROUND: In recent years, there has been a significant increase in the incidence of fungal infections attributed to Candida species worldwide, with a major shift toward non-albicans Candida (NAC). In this study, we have described the distribution of Candida species among different hospital departments and calculated the antifungal consumption in our facility. We also correlated the consumption of certain antifungals and the prevalence of specific Candida species. METHODS: This was a retrospective review of all the Candida isolates recovered from the computerised microbiology laboratory database of Makassed General Hospital, a tertiary care centre in Beirut, Lebanon, between January 2010 and December 2015. Data on antifungal consumption between January 2008 and December 2015 were extracted from the hospital pharmacy electronic database. We used Spearman's coefficient to find a correlation between Candida species distribution and antifungal consumption. RESULTS: Between 2008 and 2015, we observed that the highest antifungal consumption was in the haematology/oncology department (days of therapy/1000 patient days = 348.12 +/- 85.41), and the lowest was in the obstetrics/gynaecology department (1.36 +/- 0.47). In general, the difference in antifungal consumption among various departments was statistically significant (P < 0.0001). Overall, azoles were the most common first-line antifungals in our hospital. Echinocandins and amphotericin B were mostly prescribed in the haematology/oncology department. As for Candida species distribution, a total of 1377 non-duplicate isolates were identified between 2010 and 2015. A non-homologous distribution of albicans vs. non-albicans was noted among the different departments (P = 0.02). The most commonly isolated NAC was Candida glabrata, representing 14% of total Candida species and 59% of NAC. Candida famata (9% of NAC), Candida parapsilosis (3.6% of NAC) and Candida krusei (3% of NAC) were recovered unequally from the different departments. The total antifungal consumption correlated positively with the emergence of NAC. The use of azoles correlated positively with Candida glabrata, while amphotericin B formulations correlated negatively with it. None of these correlations reached statistical significance. CONCLUSION: Different Candida species were unequally distributed among different hospital departments, and this correlated with consumption of antifungals in respective departments, highlighting the need for antifungal stewardship. PMID- 30453892 TI - ATP bioluminescence assay for evaluating cleaning practices in operating theatres: applicability and limitations. AB - BACKGROUND: Environmental cleaning practice plays an important role in reducing microbial contamination in hospital surfaces and contributes to prevent Healthcare Associated Infections. Adenosine Triphosphate (ATP) bioluminescence assay is a commonly used method for assessing environmental cleanliness on healthcare surfaces. This study tested the feasibility of using ATP bioluminescence assay for evaluating the efficiency of cleaning procedures in the operating theatre settings, comparing the ATP-bioluminescence test with the traditional culture method. METHODS: The surfaces of 10 operating rooms of two public hospitals (140 samples in total) were examined "at rest", in two moments of the same daily session: before the first scheduled operation (Pre), and before the second, after a clean environment was re-established (Post). Surface contamination was assessed using the cultural method to detect Total Viable Counts (TVC36 degrees C) and ATP-bioluminescence assay (RLU). RESULTS: The examined surfaces presented very low TVCs (geometric means: 1.8 CFU/plate; IC95%: 1.6-2.0), always compliant with the relative reference standards. No statistical correlation was found between ATP values and TVCs. However, considering the results in terms of general evaluation of hygienic quality of surfaces, the two methods were consistent in identifying the most contaminated areas (Hospital A > Hospital B; Pre > Post; most contaminated surfaces: scialytic lamp). Furthermore, the ATP mean values showed a progressive increase from surfaces with TVC = 0 to surfaces with TVC > 15 CFU/plate. CONCLUSIONS: Although not an alternative to cultural methods, the ATP-bioluminescence-assay can be a useful tool to measure the efficiency of cleaning procedures also in environments with very low microbial counts. Each health facility should identify appropriate reference values, depending on the devices used and on the basis of the analysis of the data collected through spatial and temporal sampling series. By providing a rapid feedback, the ATP-assay helps to increase the awareness of operators and allows immediate action to be taken in critical situations. PMID- 30453893 TI - Antimicrobial susceptibilities of specific syndromes created with organ-specific weighted incidence antibiograms (OSWIA) in patients with intra-abdominal infections. AB - BACKGROUND: The aim was to evaluate the value of organ-specific weighted incidence antibiogram (OSWIA) percentages for bacterial susceptibilities of Gram negative bacteria (GNB) collected from intra-abdominal infections (IAIs) during SMART 2010-2014. METHODS: We retrospectively calculated the OSWIA percentages that would have been adequately covered by 12 common antimicrobials based on the bacterial compositions found in the appendix, peritoneum, colon, liver, gall bladder and pancreas. RESULTS: The ESBL positive rates were 65.7% for Escherichia coli, 36.2% for Klebsiella pneumoniae, 42.9% for Proteus mirabilis and 33.1% for Klebsiella oxytoca. Escherichia coli were mainly found in the appendix (76.8%), but less so in the liver (32.4%). Klebsiella pneumoniae constituted 45.2% of the total liver pathogenic bacteria and 15.2-20.8% were found in 4 other organs, except the colon and appendix (< 10%). The percentages of Pseudomonas aeruginosa infections were higher in the gall bladder, intra-abdominal abscesses, pancreas and colon (10.2-13.2%) and least (5.4%) in the appendix. The susceptibilities of hospital acquired (HA) and community acquired (CA) IAI isolates from appendix, gall bladder and liver showed >=80% susceptibilities to amikacin (AMK), imipenem (IPM), piperacillin-tazobactam (TZP) and ertapenem (ETP), while the susceptibility of isolates in abscesses and peritoneal fluid showed >=80% susceptibility only to amikacin (AMK) and imipenem (IPM). In colon CA IAI isolates susceptibilities did not reach 80% for AMK and ETP, and in pancreatic IAIs susceptibilities of HA GNBs did not reach 80% to AMK, TZP and ETP, and CA GNBs to IMP and ETP. In addition, besides circa 80% susceptibility of HA and CA IAI isolates from appendix to cefoxitin (FOX), IAI isolates from all other organs had susceptibilities between 7.6 and 67.9% to all cephalosporins tested, 28.3 75.2% to fluoroquinolones and 7.6-51.0% to ampicillin-sulbactam (SAM), whether they were obtained from CA or HA infections. CONCLUSION: The calculated OSWIA susceptibilities were specific for different organs in abdominal infections. PMID- 30453894 TI - Breast cancer and synchronous multiple primary lung adenocarcinomas with heterogeneous mutations: a case report. AB - BACKGROUND: Multiple primary malignant tumors (MPMT) refers to the presence of two or more primary cancers of different organs in the same patient. MPMT is a sparse disease in the past, but there has been a gradual increase in the morbidity. Since multiple primary malignant tumors treatment methods differ, it is essential for clinicians to be able to distinguish between separate primary lesions and metastasis. CASE PRESENTATION: We present the case of a 57-year-old woman with MPMT presenting with cancer in the left breast and synchronous double primary lung adenocarcinomas. We used IHC and epidermal growth factor receptor(EGFR)mutation to analyze genomic alteration profiles in the patient to validate the difference among the pathological assessments and the clinical differences between double primary lesions of lung and breast. EGFR gene analysis of breast cancer lesion revealed no mutations. The left and right lower lobe lung adenocarcinomas contained EGFR gene mutations: an L858R point mutation in exon 21 in the left lesion and a deletion mutation in exon 19 in the right lesion. The breast cancer and both lung adenocarcinomas were surgically resected. To date, the patient has remained disease-free. CONCLUSIONS: Both pathological and molecular assessment adapted in the current study appeared necessary. Mutational analysis of the EGFR gene provided important information not only in the diagnosis and but also in the treatment of MPMT. PMID- 30453896 TI - Deep learning architectures for prediction of nucleosome positioning from sequences data. AB - BACKGROUND: Nucleosomes are DNA-histone complex, each wrapping about 150 pairs of double-stranded DNA. Their function is fundamental for one of the primary functions of Chromatin i.e. packing the DNA into the nucleus of the Eukaryote cells. Several biological studies have shown that the nucleosome positioning influences the regulation of cell type-specific gene activities. Moreover, computational studies have shown evidence of sequence specificity concerning the DNA fragment wrapped into nucleosomes, clearly underlined by the organization of particular DNA substrings. As the main consequence, the identification of nucleosomes on a genomic scale has been successfully performed by computational methods using a sequence features representation. RESULTS: In this work, we propose a deep learning model for nucleosome identification. Our model stacks convolutional layers and Long Short-term Memories to automatically extract features from short- and long-range dependencies in a sequence. Using this model we are able to avoid the feature extraction and selection steps while improving the classification performances. CONCLUSIONS: Results computed on eleven data sets of five different organisms, from Yeast to Human, show the superiority of the proposed method with respect to the state of the art recently presented in the literature. PMID- 30453895 TI - RATEmiRs: the rat atlas of tissue-specific and enriched miRNAs database. AB - BACKGROUND: MicroRNAs (miRNAs) regulate gene expression and have been targeted as indicators of environmental/toxicologic stressors. Using the data from our deep sequencing of miRNAs in an extensive sampling of rat tissues, we developed a database called RATEmiRs for the Rat Atlas of Tissue-specific and Enriched miRNAs to allow users to dynamically determine mature-, iso- and pre-miR expression abundance, enrichment and specificity in rat tissues and organs. RESULTS: Illumina sequencing count data from mapped reads and meta data from the miRNA body atlas consisting of 21 and 23 tissues (14 organs) of toxicologic interest from 12 to 13 week old male and female Sprague Dawley rats respectively, were managed in a relational database with a user-friendly query interface. Data driven pipelines are available to tailor the identification of tissue-enriched (TE) and tissue-specific (TS) miRNAs. Data-driven organ-specific (OS) pipelines reveal miRNAs that are expressed predominately in a given organ. A user-driven approach is also available to assess the tissue expression of user-specified miRNAs. Using one tissue vs other tissues and tissue(s) of an organ vs other organs, we illustrate the utility of RATEmiRs to facilitate the identification of candidate miRNAs. As a use case example, RATEmiRs revealed two TS miRNAs in the liver: rno-miR-122-3p and rno-miR-122-5p. When liver is compared to just the brain tissues for example, rno-miR-192-5p, rno-miR-193-3p, rno-miR-203b-3p, rno miR-3559-5p, rno-miR-802-3p and rno-miR-802-5p are also detected as abundantly expressed in liver. As another example, 55 miRNAs from the RATEmiRs query of ileum vs brain tissues overlapped with miRNAs identified from the same comparison of tissues in an independent, publicly available dataset of 10 week old male rat microarray data suggesting that these miRNAs are likely not age-specific, platform-specific nor pipeline-dependent. Lastly, we identified 10 miRNAs that have conserved tissue/organ-specific expression between the rat and human species. CONCLUSIONS: RATEmiRs provides a new platform for identification of TE, TS and OS miRNAs in a broad array of rat tissues. RATEmiRs is available at: https://www.niehs.nih.gov/ratemirs. PMID- 30453897 TI - Reliability in evaluator-based tests: using simulation-constructed models to determine contextually relevant agreement thresholds. AB - BACKGROUND: Indices of inter-evaluator reliability are used in many fields such as computational linguistics, psychology, and medical science; however, the interpretation of resulting values and determination of appropriate thresholds lack context and are often guided only by arbitrary "rules of thumb" or simply not addressed at all. Our goal for this work was to develop a method for determining the relationship between inter-evaluator agreement and error to facilitate meaningful interpretation of values, thresholds, and reliability. METHODS: Three expert human evaluators completed a video analysis task, and averaged their results together to create a reference dataset of 300 time measurements. We simulated unique combinations of systematic error and random error onto the reference dataset to generate 4900 new hypothetical evaluators (each with 300 time measurements). The systematic errors and random errors made by the hypothetical evaluator population were approximated as the mean and variance of a normally-distributed error signal. Calculating the error (using percent error) and inter-evaluator agreement (using Krippendorff's alpha) between each hypothetical evaluator and the reference dataset allowed us to establish a mathematical model and value envelope of the worst possible percent error for any given amount of agreement. RESULTS: We used the relationship between inter evaluator agreement and error to make an informed judgment of an acceptable threshold for Krippendorff's alpha within the context of our specific test. To demonstrate the utility of our modeling approach, we calculated the percent error and Krippendorff's alpha between the reference dataset and a new cohort of trained human evaluators and used our contextually-derived Krippendorff's alpha threshold as a gauge of evaluator quality. Although all evaluators had relatively high agreement (> 0.9) compared to the rule of thumb (0.8), our agreement threshold permitted evaluators with low error, while rejecting one evaluator with relatively high error. CONCLUSIONS: We found that our approach established threshold values of reliability, within the context of our evaluation criteria, that were far less permissive than the typically accepted "rule of thumb" cutoff for Krippendorff's alpha. This procedure provides a less arbitrary method for determining a reliability threshold and can be tailored to work within the context of any reliability index. PMID- 30453898 TI - Characterization of anti-EBA175RIII-V in asymptomatic adults and children living in communities in the Greater Accra Region of Ghana with varying malaria transmission intensities. AB - BACKGROUND: Antibodies against Region III-V of the erythrocyte binding antigen (EBA) 175 (EBA175RIII-V) have been suggested to provide protection from malaria in a natural infection. However, the quality and quantity of naturally induced antibodies to EBA175RIII-V has not been fully characterized in different cohorts of Ghanaians. This study sought to determine the characteristics of antibodies against EBA175RIII-V in asymptomatic adults and children living in two communities of varying P. falciparum parasite prevalence in southern Ghana. METHODS: Microscopic evaluation of thick and thin blood smears was used to identify asymptomatic Plasmodium falciparum carriage and indirect enzyme linked immunosorbent (ELISA) used to assess antibody concentrations and avidity. RESULTS: Parasite carriage estimated by microscopy in Obom was 35.6% as opposed to 3.5% in Asutsuare. Levels of IgG, IgG1, IgG2, IgG3 and IgG4 against EBA175RIII V in the participants from Obom were significantly higher (P < 0.05, Dunn's Multiple Comparison test) than those in Asutsuare. However the relative avidity of IgG antibodies against EBA175RIII-V was significantly higher (P < 0.0001, Mann Whitney test) in Asutsuare than in Obom. CONCLUSIONS: People living in communities with limited exposure to P. falciparum parasites have low quantities of high avidity antibodies against EBA175RIII-V whilst people living in communities with high exposure to the parasites have high quantities of age dependent but low avidity antibodies against EBA175RIII-V. PMID- 30453899 TI - Highly sensitive detection of ALK resistance mutations in plasma using droplet digital PCR. AB - BACKGROUND: On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC. However, feasible protocol for the simultaneous detection of multiple secondary ALK mutations using droplet digital PCR (ddPCR) has not been developed. An efficient strategy using cfDNA in cancer diagnostics, the development of more accurate and cost-effective tools to identify informative multiple secondary ALK mutations is clinically required. METHODS: To establish a feasible assay to monitor ALK-TKI resistance mutations, we first evaluated the feasibility of ddPCR-based screening for cfDNA mutation detection of 10 distinct secondary ALK mutations. Positive samples were then re-analyzed using mutation specific probes to track the growth of mutation clones with a high sensitivity. RESULTS: Blood samples from seven ALK-positive patients were analyzed using the ddPCR protocol. Secondary G1202R ALK mutations were identified in 2 of 7 patients by the screening assay. Using the mutation-specific probes, monitoring the resistant clone during the clinical course of the disease was well demonstrated in each of the patients. CONCLUSION: The protocol for ddPCR-based liquid biopsy has a feasibility for the screening of secondary ALK-TKI resistance mutations and offers a tool for a cost-effective monitoring of progression in NSCLC. PMID- 30453900 TI - Transcriptomic time-series analysis of early development in olive from germinated embryos to juvenile tree. AB - BACKGROUND: Despite its relevance, almost no studies account for the genetic control in the early stages of tree development, i.e. from germination on. This study seeks to make a quite complete transcriptome for olive development and to elucidate the dynamic regulation of the transcriptomic response during the early juvenile period by RNAseq time-series expression analysis. The transcriptome was made from 342,049,597 paired-end reads of 101 bp in length. The assembled transcriptome contained 109,125 unigenes (N50 = 1490 bp, average length = 839). RESULTS: The time-series-expression analysis showed that, embryonic structures present at the first month after the induction of germination reached a more differentiated state in two-month-old seedlings. Once the plants were between three and four months old and reached a size around 6-7 nodes, the first developmental stages appeared to be complete and the developing seedling became a juvenile plant. In addition, an AGL-gene was rapidly downregulated during the induction of germination. The repression of this gene was very strong, as evidenced by the low levels of gene expression during plant development from the embryonic seedling to undetectable levels of expression in the adult tree. These results suggest that this gene may be involved in seed dormancy and could be a repressor of the germination. Also, an APL1-like olive gene was found to be expressed at high levels during flowering, and was also expressed during the cold incubation in the activation of embryo germination, suggesting a probable role in embryonic development. CONCLUSIONS: The early development from germination to the juvenile stage of olive seedlings occurred when plants reached a size around 6-7 nodes, and general changes of relevant groups of genes involved in development are described. An AGL-gene was proposed to be involved in germination repression. An APL1-like gene was found to have a probable role in embryonic development. PMID- 30453901 TI - Association between medication-related adverse events and non-elective readmission in acute ischemic stroke. AB - BACKGROUND: There is limited data on the effects of medication-related adverse events occurring during inpatient stays for stroke. The objectives of our study were to characterize reasons for acute readmission after acute ischemic stroke (AIS) and determine if medication-related adverse events occuring during AIS hospitalization were associated with 30-day readmission. Secondary objectives examined whether demographic, clinical, and hospital characterisitcs were associated with post-AIS readmission. METHODS: We used the Nationwide Readmission Database to identify index AIS hospitalizations in the United States between January and November 2014. Inpatient records were screened for diagnostic and external causes of injury codes indicative of medication-related adverse events, including adverse effects of prescribed drugs, unintentional overdosing, and medication errors. Nationally representative estimates of AIS hospitalizations, medication-related adverse events, and acute non-elective readmissions were computed using survey weighting methods. Adjusted odds of readmission for medication-related adverse events and select characteristics were estimated using unconditional logistic regression. RESULTS: We identified 439,682 individuals who were hospitalized with AIS, 4.7% of whom experienced a medication-related adverse event. Overall, 10.7% of hospitalized individuals with AIS were readmitted within 30 days of discharge. Reasons for readmission were consistent with those observed among older adults. Inpatients who experienced medication-related adverse events had significantly greater odds of being readmitted within 30 days (adjusted odds ratio (AOR): 1.22; 95% CI: 1.14-1.30). Medication-related adverse events were associated with readmission for non-AIS conditions (AOR, 1.26; 95% CI: 1.17 1.35), but not with readmission for AIS (AOR, 0.91; 95% CI: 0.75-1.10). Several factors, including but not limited to being younger than 40 years (AOR, 1.12; 95% CI: 1.00-1.26), Medicare insurance coverage (AOR, 1.33; 95% CI: 1.26-1.40), length of stay greater than 1 week (AOR, 1.38; 95% CI: 1.33-1.42), having 7 or more comorbidites (AOR, 2.20; 95% CI: 2.08-2.34), and receiving care at a for profit hospital (AOR, 1.20; 95% CI: 1.12-1.29), were identified as being associated with all-cause 30-day readmission. CONCLUSIONS: In this nationally representative sample of AIS hospitalizations, medication-related adverse events were positively associated with 30-day readmission for non-AIS causes. Future studies are necessary to determine whether medication-related adverse events and readmissions in AIS are avoidable. PMID- 30453902 TI - Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. AB - BACKGROUND: Scoping reviews are a relatively new approach to evidence synthesis and currently there exists little guidance regarding the decision to choose between a systematic review or scoping review approach when synthesising evidence. The purpose of this article is to clearly describe the differences in indications between scoping reviews and systematic reviews and to provide guidance for when a scoping review is (and is not) appropriate. RESULTS: Researchers may conduct scoping reviews instead of systematic reviews where the purpose of the review is to identify knowledge gaps, scope a body of literature, clarify concepts or to investigate research conduct. While useful in their own right, scoping reviews may also be helpful precursors to systematic reviews and can be used to confirm the relevance of inclusion criteria and potential questions. CONCLUSIONS: Scoping reviews are a useful tool in the ever increasing arsenal of evidence synthesis approaches. Although conducted for different purposes compared to systematic reviews, scoping reviews still require rigorous and transparent methods in their conduct to ensure that the results are trustworthy. Our hope is that with clear guidance available regarding whether to conduct a scoping review or a systematic review, there will be less scoping reviews being performed for inappropriate indications better served by a systematic review, and vice-versa. PMID- 30453903 TI - Interferon-gamma release assay as a sensitive diagnostic tool of latent tuberculosis infection in patients with HIV: a cross-sectional study. AB - BACKGROUND: In developing countries, tuberculosis (TB) is a major public health problem and the leading cause of death among patients with HIV (Human Immunodeficiency Virus). Until 2001, the tuberculin skin test (TST) was the only available tool for the diagnosis of latent tuberculosis infection (LTBI), but false-negative TST results are frequently reported. Recently, the interferon gamma (IFN-gamma) release assay (IGRA) has gained ground because it can detect the IFN-gamma secreted by circulating lymphocytes T cells when stimulated by specific TB antigens. However, the role of IGRA in the diagnosis of LTBI in HIV infected patients has not been well established. METHODS: This cross-sectional study compared the accuracy of TST (performed by the Mantoux method) and IGRA (QuantiFERON-TB Gold In-Tube, Cellestis, Carnegie, Australia) on the diagnosis of LTBI among patients with HIV. LTBI is defined by LTBI risk and at least one positive test (TST or IGRA), without clinical evidence of active TB. We also assessed the accuracy of TST and IGRA among HIV patients with high and low risk for LTBI. RESULTS: Among 90 HIV patients, 80 met the study criteria for LTBI, fifty-nine (73.7%) patients were TST positive, 21 (26.2%) were negative, whereas 75 patients (93.7%) were IGRA positive, and five (6.2%) were negative. TST showed poor agreement with the diagnosis of LTBI (Kappa: 0.384), while IGRA demonstrated good agreement (Kappa: 0.769). Among 69 patients with high risk and 21 with low risk for LTBI, TST was positive in 48 (69.5%) and 11 (52.4%), while IGRA was positive in 68 (98.5%) and 7 (33.3%) patients, respectively. There were no association between TST and the level of risk (P = 0,191). Conversely, we observed a strong association between the IGRA and risk for LTBI (p < 0.001). CONCLUSIONS: Compared to TST, IGRA positivity is consistent with the risk of TB infection and seems to be a better diagnostic tool for LTBI in HIV-infected patients. PMID- 30453905 TI - Correction to: Comparison of analgesic effect of oxycodone and morphine on patients with moderate and advanced cancer pain: a meta-analysis. AB - After publication of this article [1], the authors noted that the corresponding email address is incorrect. PMID- 30453904 TI - Metagenomics of pasteurized and unpasteurized gouda cheese using targeted 16S rDNA sequencing. AB - BACKGROUND: The microbiome of cheese is diverse, even within a variety. The metagenomics of cheese is dependent on a vast array of biotic and abiotic factors. Biotic factors include the population of microbiota and their resulting cellular metabolism. Abiotic factors, including the pH, water activity, fat, salt, and moisture content of the cheese matrix, as well as environmental conditions (temperature, humidity, and location of aging), influence the biotic factors. This study assessed the metagenomics of commercial Gouda cheese prepared using pasteurized or unpasteurized cow milk or pasteurized goat milk via 16S rDNA sequencing. RESULTS: Results were analyzed and compared based on milk pasteurization and source, spatial variability (core, outer, and under the rind), and length of aging (2-4 up to 12-18 months). The dominant organisms in the Gouda cheeses, based on percentage of sequence reads identified at the family or genus levels, were Bacillaceae, Lactococcus, Lactobacillus, Streptococcus, and Staphylococcus. More genus- or family-level (e.g. Bacillaceae) identifications were observed in the Gouda cheeses prepared with unpasteurized cow milk (120) compared with those prepared with pasteurized cow milk (92). When assessing influence of spatial variability on the metagenomics of the cheese, more pronounced differences in bacterial genera were observed in the samples taken under the rind; Brachybacterium, Pseudoalteromonas, Yersinia, Klebsiella, and Weissella were only detected in these samples. Lastly, the aging length of the cheese greatly influenced the number of organisms observed. Twenty-seven additional genus-level identifications were observed in Gouda cheese aged for 12 18 months compared with cheese only aged 2-4 months. CONCLUSIONS: Collectively, the results of this study are important in determining the typical microbiota associated with Gouda cheese and how the microbiome plays a role in safety and quality. PMID- 30453906 TI - Study protocol: a randomized control trial of African American families fighting parental cancer together. AB - BACKGROUND: African American adults experience a disproportionate burden and increased mortality for most solid tumor cancers and their adolescent children are negatively impacted by the illness experience. The purpose of this randomized clinical trial is to evaluate the efficacy of a culturally sensitive family-based intervention program developed for African American families coping with solid tumor parental cancer using an intention-to-treat approach. Primary outcome is adolescent depressive symptoms at end of treatment. METHODS: A sample of 172 African American families will be enrolled from two diverse oncology centers (Helen Graham Cancer Center in Newark, DE, and Kimmel Cancer Center in Philadelphia, PA). Eligible families will be randomized either to a 5-session intervention Families Fighting Cancer Together (FFCT) or a 5-session parent-only psycho-educational (PED) program. Assessments will occur at weeks 0 (baseline), 8 (end-of-treatment), 24, and 52. DISCUSSION: Treatments to help African American adolescents cope with the impact of parental cancer are scarce and urgently needed. If successful, this proposed research will change the nature of intervention support options available to African Americans, who are overrepresented and underserved by existing services or programs. TRIAL REGISTRATION: This project is registered with ClinicalTrials.gov (Protocol #: NCT03567330). PMID- 30453907 TI - Schistosoma mansoni infection and socio-behavioural predictors of HIV risk: a cross-sectional study in women from Uganda. AB - BACKGROUND: Schistosoma mansoni infection has been associated with increased risk of HIV transmission in African women. This association might be causal or mediated through shared socio-behavioural factors and associated co-infections. We tested the latter hypothesis in a cross-sectional pilot study in a cohort of women from a S. mansoni endemic region of Uganda. To validate the immunological effects of S. mansoni in this cohort, we additionally assessed known schistosomiasis biomarkers. METHODS: HIV-uninfected non-pregnant adult women using public health services were tested for schistosomiasis using the urine circulating cathodic antigen test, followed by serology and Schistosoma spp. specific PCR. Blood was obtained for herpes simplex virus (HSV)-2 serology, eosinophil counts and cytokine analysis. Samples collected from the genitourinary tract were used to test for classical sexually transmitted infections (STI), for bacterial vaginosis and to assess recent sexual activity via prostate-specific antigen testing. Questionnaires were used to capture a range of socio-economic and behavioral characteristics. RESULTS: Among 58 participants, 33 (57%) had schistosomiasis, which was associated with elevated levels of interleukin (IL)-10 (0.32 vs. 0.19 pg/ml; p = 0.038) and a trend toward increased tumour necrosis factor (TNF) (1.73 vs. 1.42 pg/ml; p = 0.081). Eosinophil counts correlated with levels of both cytokines (r = 0.53, p = 0.001 and r = 0.38, p = 0.019, for IL-10 and TNF, respectively); the association of eosinophilia with schistosomiasis was not significant (OR = 2.538, p = 0.282). Further, schistosomiasis was associated with lower age (per-year OR = 0.910, p = 0.047), being unmarried (OR = 0.263, p = 0.030), less frequent hormonal contraceptive (HC) use (OR = 0.121, p = 0.002, dominated by long acting injectable contraceptives) and a trend to longer time since penile-vaginal sex (OR = 0.350, p = 0.064). All women infected by Chlamydia trachomatis (n = 5), were also positive for schistosomiasis (Fisher's exact p = 0.064). CONCLUSIONS: Intestinal schistosomiasis in adult women was associated with systemic immune alterations, suggesting that associations with immunological correlates of HIV susceptibility warrant further investigation. S. mansoni associations with socio-behavioral parameters and C. trachomatis, which may alter both genital immunity and HIV exposure and/or acquisition risk, means that future studies should carefully control for potential confounders. These findings have implications for the design and interpretation of clinical studies on the effects of schistosomiasis on HIV acquisition. PMID- 30453908 TI - Perinatal outcomes in twin pregnancies complicated by maternal morbidity: evidence from the WHO Multicountry Survey on Maternal and Newborn Health. AB - BACKGROUND: Twin pregnancy was associated with significantly higher rates of adverse neonatal and perinatal outcomes, especially for the second twin. In addition, the maternal complications (potentially life-threatening conditions PLTC, maternal near miss-MNM, and maternal mortality-MM) are directly related to twin pregnancy and independently associated with adverse perinatal outcome. The objective of the preset study is to evaluate perinatal outcomes associated with twin pregnancies, stratified by severe maternal morbidity and order of birth. METHODS: Secondary analysis of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS), a cross-sectional study implemented in 29 countries. Data from 8568 twin deliveries were compared with 308,127 singleton deliveries. The occurrence of adverse perinatal outcomes and maternal complications were assessed. Factors independently associated with adverse perinatal outcomes were reported with adjusted PR (Prevalence Ratio) and 95%CI. RESULTS: The occurrence of severe maternal morbidity and maternal death was significantly higher among twin compared to singleton pregnancies in all regions. Twin deliveries were associated with higher rates of preterm delivery (37.1%), Apgar scores less than 7 at 5th minute (7.8 and 10.1% respectively for first and second twins), low birth weight (53.2% for the first and 61.1% for the second twin), stillbirth (3.6% for the first and 5.7% for the second twin), early neonatal death (3.5% for the first and 5.2% for the second twin), admission to NICU (23.6% for the first and 29.3% for the second twin) and any adverse perinatal outcomes (67% for the first twin and 72.3% for the second). Outcomes were consistently worse for the second twin across all outcomes. Poisson multiple regression analysis identified several factors independently associated with an adverse perinatal outcome, including both maternal complications and twin pregnancy. CONCLUSION: Twin pregnancy is significantly associated with severe maternal morbidity and with worse perinatal outcomes, especially for the second twin. PMID- 30453909 TI - Suppressed OGT expression inhibits cell proliferation while inducing cell apoptosis in bladder cancer. AB - BACKGROUND: This study aimed to explore hyper-O-linked N-acetylglucosaminylation (O-GlcNAcylation) with an elevation of the expression of O-linked-beta-N acetylglucosamine transferase (OGT) in human bladder cancer. METHODS: Immunohistochemical staining for OGT and O-GlcNAcylation was performed in 20 paired human bladder cancer and adjacent normal tissues, as well as in human bladder cancer tissue microarrays (N = 169). The expression level of OGT and O GlcNAcylation in cell lines were detected using the Western blot analysis. The effects of O-GlcNAcylation on the cell proliferation of bladder cancer were detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clone formation assays. Cell apoptosis and cell cycle analysis were detected using flow cytometry. The autophagy of bladder cancer cells was investigated using the Western blot analysis, and GFP-LC3 plasmid was used to detect the autophagic flux. MTT assay was performed to detect the sensitivity of bladder cancer cells to cisplatin after OGT knockdown. RESULTS: The expression of OGT and the O-GlcNAcylation were upregulated in bladder cancer tissues and cell lines. O GlcNAcylation and OGT were observed in nucleus and cytoplasm and found to be higher in muscle-invasive bladder cancer (MIBC) than in non-muscle-invasive bladder cancer (NMIBC). Reducing hyper-O-GlcNAcylation by OGT knockdown inhibited the proliferation of bladder cancer cells in vitro and xenograft tumor growth in vivo, triggered apoptosis, as well as led to cell cycle arrest. It also increased autophagy in bladder cancer cells. This study demonstrated increased autophagy pro-survival, but not pro-death. Reducing hyper-O-GlcNAcylation by OGT knockdown facilitated the chemosensitivity of bladder cancer cells to cis-platinum. CONCLUSIONS: The data indicated that hyper-O-GlcNAcylation enhanced oncogenic phenotypes and was involved in DNA damage response in bladder cancer. PMID- 30453910 TI - Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of Ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628). AB - BACKGROUND: Graft-versus-Host Disease (GvHD) causes significant morbidity and mortality in patients after allogeneic stem cell transplantation. Donor T-cells cause inflammation and tissue damage in GvHD target organs such as liver, gut and skin. Cytokine receptor associated kinases JAK1 and JAK2 are critical for inflammatory cytokine response in GvHD. Ruxolitinib is a small molecule inhibitor of JAK1 and JAK2. Preliminary data indicated substantial clinical activity in patients with steroid-refractory (SR) acute and chronic GvHD. METHODS: The RIG study is an investigator-initiated open-label, multicenter, prospective randomized controlled two-arm phase 2 study, comparing the efficacy of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute GvHD (SR-aGvHD). Patients with acute skin, intestinal or liver GvHD > grade 1 and failure of previous treatment are eligible. The trial aims to include 160 patients who will be randomized in a 1:1 ratio and stratified by GvHD grade (<= grade 3 versus grade 4) and number of previous immunosuppressive treatments (<= 3 versus >=4). The primary endpoint is the overall response rate at day 28, defined as: Improvement of at least one stage in the severity of acute GvHD in one organ without deterioration in any other organ, or disappearance of any GvHD signs from all organs without requirement for new systemic immunosuppressive treatment. Secondary objectives include time to response, overall survival, event-free survival, non-relapse mortality (NRM), failure-free survival, graft failure rates, quality of life and changes in serum levels of pro-inflammatory cytokines and GvHD-related biomarkers. DISCUSSION: This randomized prospective trial will provide further evidence if the retrospectively collected data demonstrating activity of ruxolitinib for SR-aGvHD can be reproduced. A major advantage of ruxolitinib might be the limited and predictable toxicity profile compared to other immunosuppressive therapies that mainly includes viral reactivation and cytopenias. This trial will establish candidate biomarkers to predict and monitor responses to ruxolitinib. As a next step ruxolitinib might be tested upfront against steroids or in a preemptive manner to prevent GvHD to occur. TRIAL REGISTRATION: NCT02396628 (registration date 17.07.2015); DRKS00007939 (registration date 26.03.2015). PMID- 30453911 TI - Does coffee drinking have beneficial effects on bone health of Taiwanese adults? A longitudinal study. AB - BACKGROUND: Results from studies investigating the association between coffee consumption and osteoporosis or bone mineral density (BMD) have been inconsistent. This longitudinal study was performed to assess the effect of coffee drinking on bone health of Taiwanese adults. METHODS: Data were retrieved from the Li-Shin (Landseed) Hospital in Taoyuan City. In 2006, 6152 participants completed a questionnaire on coffee drinking and other lifestyle factors. In 2014, 5077 of them were followed up. Nonetheless, a total of 2395 participants with incomplete data were excluded. The final analyses included 2682 participants comprising 1195 men and 1487 women (706 premenopausal and 781 postmenopausal). T scores were derived from the osteo-sono assessment index (OSI) which is a surrogate of BMD. Coffee drinking was categorized as "no, medium, and high" based on the number of cups that were consumed per week in both 2006 and 2014. RESULTS: In general, medium and high coffee drinking were associated with higher T-scores. However, significant results were observed only among high drinkers (beta = 0.158; P = 0.0038). Nonetheless, the test for linear trend was significant (P = 0.0046). After stratification by sex, medium and high coffee drinking were associated with higher T-scores. However, significant results were prominent only among high male drinkers (beta = 0.237; P = 0.0067) and the test for trend was significant (P = 0.0161). Based on menopausal status, coffee drinking was associated with higher T-scores. Nevertheless, significant results were found only among premenopausal women (beta = 0.233; P = 0.0355 and beta = 0.234; P = 0.0152 for medium and high coffee drinking, respectively. The test for linear trend was significant (P = 0.0108). CONCLUSION: Coffee drinking was significantly associated with higher T-scores hence, a lower risk of osteoporosis in men and premenopausal women. PMID- 30453912 TI - Prevalence and risk factors of anemia among children aged 6-23 months in Huaihua, Hunan Province. AB - BACKGROUND: Anemia is one of the most common diseases of childhood and is a health problem globally, particularly in developing counties and in children less than 2 years of age. Anemia during childhood has short- and long-term effects on health. However, few studies have investigated the prevalence of anemia among children in Huaihua. Therefore, this study analyzed the prevalence and risk factors of anemia among children 6 to 23 months of age in Huaihua. METHODS: This cross-sectional study was conducted at a maternal and child health care hospital in Huaihua, from September to November 2017. The study population recruited using a multistage sampling technique. A structured questionnaire was used to collect data on the characteristics of the children and members of their families. Hemoglobin (Hb) levels were measured by using a microchemical reaction method. Logistic regression analysis was used to identify associated factors and odds ratio with 95% CI was computed to assess the strength of association. RESULTS: In total, 4450 children were included in this study. The prevalence of anemia was 29.73%. In multivariate logistic regression analysis, the results show that mother and father of Miao ethnicity (OR = 1.23 and 1.31), diarrhea in the previous 2 weeks (OR = 1.35), breastfeeding in the prior 24 h (OR = 1.50), and caregivers able to identify the optimum timing of complementary feeding (OR = 1.15) had positive correlations with anemia. However, children aged 18 to 23 months (OR = 0.55), father of Dong ethnicity (OR = 0.82), addition of milk powder once or twice (OR = 0.71), addition of infant formula once or twice, three times, and four or more times in the previous 24 h (OR = 0.72, 0.70, and 0.75), and addition of a nutrient sachet four or more times in the prior week (OR = 0.70) were negatively associated with anemia. CONCLUSIONS: The prevalence of anemia among children 6 to 23 months of age in Huaihua was higher than that in more developed regions of China. The feeding practice of caregivers was associated with anemia. nutrition improvement projects are needed to reduce the burden of anemia among children in Huaihua. PMID- 30453913 TI - Clusters of alcohol and drug use and other health-risk behaviors among Thai secondary school students: a latent class analysis. AB - BACKGROUND: Alcohol and drug use and other health-risk behaviors tend to cluster together among adolescents and contribute a large amount of harm to both themselves and to others. This paper aims to characterize secondary school students based on their clusters of health-risk behaviors and identify factors determining class membership to these behavior-clusters. METHODS: Data from a national school survey was used to identify clusters of alcohol and drug use and other health-risk behaviors among secondary school students aged 12-15 years using a latent class regression model. A multinomial logistic regression model was used to identify predictors of the cluster membership. RESULTS: A total of 25,566 students were included in the analysis, of which 88% were classified as having low-risk behaviors reporting only moderate alcohol use; 11% as having moderate-risk behaviors, such as driving under the influence of alcohol, fighting, carrying a weapon, and alcohol and tobacco use; and 0.6% as having high risk behaviors, such as use of illicit drugs, particularly kratom and cannabis. Males, older students, those with a poor school performance, not living with parents, drug use by family members and peers, and having a low level of perceived disdain from their friends if they used drugs were significant risk factors for being in the moderate- and high-risk behavior classes. CONCLUSIONS: Alcohol, tobacco and drug use, as well as other health-risk behaviors such as fighting, are clustered in Thai secondary school students. This result highlights the importance of comprehensive prevention and education strategies, particularly for moderate to high-risk groups. PMID- 30453914 TI - Predictive value of lymphocyte-to-monocyte ratio in the preoperative setting for progression of patients with breast cancer. AB - BACKGROUND: The lymphocyte-to-monocyte ratio (LMR) has been used as a parameter reflecting systemic inflammation in several tumors, and is reportedly associated with prognosis in cancer patients. In this study, we evaluated the predictive value of LMR for progression and chemosensitivity in breast cancer patients treated with preoperative chemotherapy. METHODS: LMR was evaluated in 239 patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with 5 fluorouracil, epirubicin, and cyclophosphamide, followed by weekly paclitaxel with or without trastuzumab, and subsequent curative surgery. The correlations between LMR and clinicopathological features, prognosis, and pathological complete response (pCR) rate of NAC were evaluated retrospectively. We also evaluated the predictive value of neutrophil-to-lymphocyte ratio (NLR), and compared the predictive values of LMR and NLR. RESULTS: We set 6.00 as the cut off level for LMR based on the receiver operating characteristic (ROC) curve. A total of 119 patients (49.8%) were classified in the high-LMR group and 120 (50.2%) were classified in the low-LMR group. The low-LMR group had significantly worse disease-free survival rate (DFS) in all patients (p = 0.005) and in triple negative breast cancer patients (p = 0.006). However, there was no significant correlation between LMR and pCR. Multivariate analysis showed that low LMR was an independent risk factor for DFS (p = 0.008, hazard ratio = 2.245). However, there was no significant difference in DFS (p = 0.143, log-rank) between patients in the low- and high-NLR groups. CONCLUSIONS: LMR may be a useful prognostic marker in patients with breast cancer. PMID- 30453915 TI - Long-term survival and late complications of intensity-modulated radiotherapy for recurrent nasopharyngeal carcinoma. AB - BACKGROUND: To evaluate the effectiveness and toxicities of intensity-modulated radiotherapy (IMRT) for locally recurrent nasopharyngeal carcinoma (NPC). METHODS: One hundred and eighty-four previously irradiated NPC patients with recurrent disease and re-irradiated by IMRT between February 2005 to May 2013 had been reviewed. The disease was re-staged I in 33, II in 27, III in 70 and IV in 54 patients. Seventy-five percent of the patients received cisplatin-based chemotherapy. RESULTS: The median survival time was 33 months. The 3-year actuarial rates of local recurrence-free survival (LRFS), distant metastases-free survival (DMFS), and overall survival (OS) rates were 85.1, 91.1, and 46.0%, respectively. About 53% of the patients experienced Grade 3-4 late toxicities. Forty-four patients died of massive hemorrhage of the nasopharynx caused by radiation induced mucosal necrosis. Multivariate analysis indicated that chemotherapy and time interval between initial radiotherapy and re-irradiation were independent predictors for DMFS. CONCLUSION: IMRT is an effective method for patients with locally recurrent NPC. Massive hemorrhage of the nasopharynx is the major sever late complication and also the leading cause of death. Early recurrence is negative factor for DMFS. Combination of chemotherapy can improve DMFS, but not for OS. Optimal salvage treatment strategies focusing on improvement of survival and minimization of late toxicities are warranted. PMID- 30453916 TI - High rate of antibiotic resistance among pneumococci carried by healthy children in the eastern part of the Democratic Republic of the Congo. AB - BACKGROUND: Pneumococcal conjugate vaccines have been introduced in the infant immunisation programmes in many countries to reduce the rate of fatal pneumococcal infections. In the Democratic Republic of the Congo (DR Congo) a 13 valent vaccine (PCV13) was introduced in 2013. Data on the burden of circulating pneumococci among children after this introduction are lacking. In this study, we aimed to determine the risk factors related to pneumococcal carriage in healthy Congolese children after the vaccine introduction and to assess the antibiotic resistance rates and serotype distribution among the isolated pneumococci. METHODS: In 2014 and 2015, 794 healthy children aged one to 60 months attending health centres in the eastern part of DR Congo for immunisation or growth monitoring were included in the study. Data on socio-demographic and medical factors were collected by interviews with the children's caregivers. Nasopharyngeal swabs were obtained from all the children for bacterial culture, and isolated pneumococci were further tested for antimicrobial resistance using disc diffusion tests and, when indicated, minimal inhibitory concentration (MIC) determination, and for serotype/serogroup by molecular testing. RESULTS: The pneumococcal detection rate was 21%, being higher among children who had not received PCV13 vaccination, lived in rural areas, had an enclosed kitchen, were malnourished or presented with fever (p value < 0.05). The predominant serotypes were 19F, 11, 6A/B/C/D and 10A. More than 50% of the pneumococcal isolates belonged to a serotype/serogroup not included in PCV13. Eighty per cent of the isolates were not susceptible to benzylpenicillin and non-susceptibility to ampicillin and ceftriaxone was also high (42 and 37% respectively). Almost all the isolates (94%) were resistant to trimethoprim-sulphamethoxazole, while 43% of the strains were resistant to >=3 antibiotics. CONCLUSIONS: Our study shows alarmingly high levels of reduced susceptibility to commonly used antibiotics in pneumococci carried by healthy Congolese children. This highlights the importance of local antibiotic resistance surveillance and indicates the needs for the more appropriate use of antibiotics in the area. The results further indicate that improved living conditions are needed to reduce the pneumococcal burden, in addition to PCV13 vaccination. PMID- 30453917 TI - Use of retrieval bag in the prevention of wound infection in elective laparoscopic cholecystectomy: is it evidence-based? A meta-analysis. AB - BACKGROUND: Surgical site infections complicate elective laparoscopic cholecystectomies in 2,4-3,2% of cases. During the operation the gallbladder is commonly extracted with a retrieval bag. We conducted a meta-analysis to clarify whether its use plays a role in preventing infections. METHODS: Inclusion criteria: elective cholecystectomy, details about the gallbladder extraction and data about local or systemic infection rate. EXCLUSION CRITERIA: cholecystitis, jaundice, concurrent antibiotic therapy, immunosuppression, cancer. A comprehensive literature search of PubMed, Cochrane Library and MEDLINE databases was carried out independently by two researchers, according to the PRISMA guidelines and applying the GRADE approach. Terms used were ("gallbladder"AND("speciment"OR"extraction"OR"extract"))OR("gallbladder"OR"cholec stectomy")AND("bag"OR"retrieval|"OR|"endobag"OR"endocatch"). RESULTS: The comprehensive literature revealed 279 articles. The eligible studies were 2 randomized trials and a multicentre prospective study. Wound infections were documented in 14 on 334 (4,2%) patients operated using a retrieval bag versus 16 on 271 (5,9%) patients operated without the use of a retrieval bag. The statistical analysis revealed a risk ratio (RR) of 0.82 (0.41-1.63 95% CI). Concerning sensitivity analysis the estimated pooled RR ranged from 0.72 to 0.96, both not statistically significant. Harbord test did not reveal the occurrence of small-study effect (p = 0.892) and the funnel-plot showed no noteworthy pattern. CONCLUSIONS: The results of this review highlight the paucity of well-designed large studies and despite limitations related to the low level of evidence, our meta-analysis showed no significant benefit of retrieval bags in reducing the infection rate after elective laparoscopic cholecystectomy. In absence of acute cholecystitis, accidental intraoperative gallbladder perforation or suspected carcinoma their use, to date, may not be mandatory, so that, further studies focusing on complex cases are needed. PMID- 30453918 TI - A full term abdominal pregnancy with an isthmic tubal implantation of the placenta. AB - BACKGROUND: Abdominal pregnancy is defined as the partial or total insertion of the embryo into the abdominal cavity. It is rare, and can evolve towards the full term if it is not recognized in the early pregnancy. It carries a high risk of maternal-fetal morbidity and mortality. CASE PRESENTATION: We report a case of a 22 year-old gravida IV, para II with an asymptomatic and undiagnosed abdominal pregnancy presumed full term, in a context of health centers under-equipment. She had attended 5 routine antenatal care, but had not performed any ultrasound scan. She had been transferred from a medical center to the Hospital of Ouahigouya (Burkina Faso) for bowel sub-obstruction and intrauterine fetal death, with failure of labor induction. On admission, the hypothesis of uterine rupture or abdominal pregnancy with antepartum fetal demise was considered. A laparotomy was then performed, where an abdominal pregnancy was discovered, and a dead term baby weighing 3300 g delivered. The placenta which was implanted into the ruptured isthmus of the left fallopian tube was removed by salpingectomy. Postoperative follow-up was uneventful. CONCLUSION: This case report exposes the necessity for the practitioner to think about the possibility of abdominal pregnancy in his clinical and sonographic practice, irrespective of the gestational age, mainly in contexts where there is under-equipment of the health centers. PMID- 30453919 TI - Information bias of social gradients in sickness absence: a comparison of self report data in the Norwegian Mother and Child Cohort Study (MoBa) and data in national registries. AB - BACKGROUND: Measurement error in self-report questionnaires is a common source of bias in epidemiologic studies. The study aim was to assess information bias of the educational gradient in sickness absence among participants in the Norwegian Mother and Child Cohort Study (MoBa), comparing self-report data with national register data. METHODS: MoBa is a national prospective cohort study. The present study included 49,637 participants, born 1967-1976, who gave birth 2000-2009. The highest completed education level was recorded in categories and as educational years. Sickness absence was defined as one or more spell lasting more than 16 days between pregnancy weeks 13 and 30. We computed sickness absence risk in mid pregnancy in strata of education level. Associations between completed educational years and sickness absence were estimated as risk differences in binomial regression and compared between self-report and register data. In additional analyses, we aimed to explain discrepancies between estimates from the two data sources. RESULTS: The overall registry-based sickness absence risk was 0.478 and decreased for increasingly higher education in a consistent fashion, yielding an additive risk difference in association with one additional education year of - 0.032 (95% confidence interval - 0.035 to - 0.030). The self-report risk was lower (0.307) with a corresponding risk difference of only - 0.013 (95% confidence interval - 0.015 to - 0.011). The main explanation of the lower risk difference in the self-report data was a tendency for mothers in low education categories to omit reporting sickness absence in the questionnaire. CONCLUSIONS: A plausible explanation for the biased self-report association is complexity of the sickness absence question and a resulting educational gradient in non response. As shown for sickness absence in mid-pregnancy in the present study, national registries could be a preferred alternative to self-report questionnaires. PMID- 30453920 TI - Can echocardiographic screening in the early days of life detect critical congenital heart disease among apparently healthy newborns? AB - BACKGROUND: Delayed diagnosis of critical congenital heart disease (CCHD) carries a serious risk of mortality, morbidity, and handicap. As echocardiography is commonly used to diagnose congenital heart disease (CHD), echocardiographic investigations in newborns may be helpful in detecting CCHD earlier and with higher sensitivity than when using other screening methods. The present study aimed to evaluate the effectiveness of echocardiographic screening for CCHD in a tertiary care center. METHODS: A retrospective chart review was conducted among newborns delivered at Hamamatsu University Hospital between June 2009 and May 2016. The study included consecutive newborns who underwent early echocardiographic screening (within the first 5 days of life) performed by pediatric cardiologists, were born at >=36 weeks of gestation, had a birthweight >=2300 g, and were cared for in the well-baby nursery. Newborns admitted to the neonatal intensive care unit, as well as those with prenatal diagnosis of CHD and/or clinical symptoms or signs of CHD were excluded. Four CHD outcome categories were defined: critical, serious, clinically significant, and clinically non-significant. RESULTS: A total of 4082 live newborns were delivered during the study period. Of 3434 newborns who met the inclusion criteria and had complete echocardiography data, 104 (3.0%) were diagnosed as having CHD. Among these, none was initially diagnosed as having critical or serious CHD. Of the 95 newborns who continued follow-up with a cardiologist, 61 (64%) were determined to have non-significant CHDs that resolved within 6 months of life. Review of excluded newborns revealed nine cases of critical or serious CHD; among these newborns, six were diagnosed prenatally and three had some clinical signs of CHD prior to hospital discharge. CONCLUSIONS: In our tertiary care center, echocardiography screening within the first 5 days of life did not help improve CCHD detection rate in newborns without prenatal diagnosis or clinical signs of CHD. Echocardiographic screening may be associated with increased rate of false positives (defects resulting in clinically non-significant CHDs) in newborns without prenatal diagnosis or suspicion of CHD. PMID- 30453921 TI - NUT carcinoma of the nasal cavity that responded to a chemotherapy regimen for Ewing's sarcoma family of tumors: a case report. AB - BACKGROUND: Nuclear protein in testis (NUT) carcinoma (NC) is a rare epithelial malignancy characterized by rearrangement of the NUT gene on chromosome 15. If NC is not suspected, it is often diagnosed as other malignancies. We present the case of NC of the nasal cavity that responded to a chemotherapy regimen for Ewing's sarcoma family of tumors (ESFT). CASE PRESENTATION: A 49-year-old male presented with epistaxis and pain in the left eye. The patient had a tumor in the left nasal cavity at initial visit and it was biopsied. Firstly, the man was diagnosed with ESFT based on a histopathological examination. The tumor markedly responded to standard cytotoxic chemotherapy for ESFT with distant metastasis. After the start of therapy, a chromosomal analysis revealed an atypical translocation in ESFT and additional immunostaining was positive for anti-NUT antibody. Ultimately, the patient was definitively diagnosed with NC. He received multidisciplinary therapy and symptoms were temporarily relieved. However, he died 9 months after the diagnosis of NC. CONCLUSIONS: When a pathologically undifferentiated tumor is evident along the midline of the body, NC must be included in the differential diagnosis, and immunohistochemical staining or genetic testing/chromosomal analysis needs to be performed. PMID- 30453922 TI - Usefulness of core needle biopsy for the diagnosis of thyroid Burkitt's lymphoma: a case report and review of the literature. AB - BACKGROUND: Thyroid lymphomas are an exceptional finding in patients with thyroid nodules. Burkitt's lymphoma is one of the rarest and most aggressive forms of thyroid lymphomas, and its prognosis depends on the earliness of medical treatment. Given the rarity of this disease, making a prompt diagnosis can be challenging. For instance, fine-needle aspiration (FNA) cytology, which is the first-line diagnostic test that is performed in patients with thyroid nodules, is often not diagnostic in cases of thyroid lymphomas, with subsequent delay of the start of therapy. CASE PRESENTATION: Here we report the case of a 52-year-old woman presenting with a rapidly enlarging thyroid mass. Thyroid ultrasonography demonstrated a solid hypoechoic nodule. FNA cytology was only suggestive of a lymphoproliferative disorder and did not provide a definitive diagnosis. It is core needle biopsy (CNB) that helped us to overcome the limitations of routine FNA cytology, showing the presence of thyroid Burkitt's lymphoma. Subsequent staging demonstrated bone marrow involvement. The early start of an intensive multi-agent chemotherapy resulted in complete disease remission. At 60 months after the diagnosis, the patient is alive and has not had any recurrence. CONCLUSIONS: Clinicians should be aware that thyroid Burkitt's lymphoma is an aggressive disease that needs to be treated with multi-agent chemotherapy as soon as possible. To diagnose it promptly, they should consider to order/perform a CNB in any patient with a rapidly enlarging thyroid mass that is suspicious for lymphoma. PMID- 30453923 TI - Stigma reduction in relation to HIV test uptake in low- and middle-income countries: a realist review. AB - BACKGROUND: This realist review was conducted to understand how stigma is reduced in relation to HIV test uptake in low- and middle-income countries (LMICs). METHODS: A systematic search of eight databases resulted in 34 articles considered for synthesis. Data synthesis was guided by a preliminary programme theory and included coding the meaning units to develop themes or intervention pathways that corresponded to context-mechanism-outcome configurations. RESULTS: We found that the interventions produced an effect through two pathways: (a) knowledge leads to changes in stigmatizing attitudes and increases in HIV test uptake and (b) knowledge and attitudes lead to changes in stigmatizing behaviours and lead to HIV test uptake. We also found one competing pathway that illustrated the direct impact of knowledge on HIV test uptake without changing stigmatizing attitudes and behaviour. The identified pathways were found to be influenced by some structural factors (e.g., anti-homosexuality laws, country-specific HIV testing programmes and policies), community factors (e.g., traditional beliefs and practices, sexual taboos and prevalence of intimate partner violence) and target-population characteristics (e.g., age, income and urban-rural residence). CONCLUSIONS: The pathways and underlying mechanisms support the adaptation of intervention strategies in terms of social context and the target population in LMICs. PMID- 30453924 TI - TMFUF: a triple matrix factorization-based unified framework for predicting comprehensive drug-drug interactions of new drugs. AB - BACKGROUND: A significant number of adverse drug reactions is caused by unexpected Drug-drug interactions (DDIs). The identification of DDIs becomes crucial before the co-prescription of multiple drugs is made. Such a task in clinics or in drug discovery usually requires high costs and numerous limitations, while computational approaches are able to predict potential DDIs effectively by utilizing diverse drug attributes (e.g. side effects). Nevertheless, they're incapable when required to predict enhancive and degressive DDIs, which change increasingly and decreasingly the pharmacological behavior of interacting drugs respectively. The pharmacological change of DDIs is one of the most important factors when making a multi-drug prescription. RESULTS: In this work, we design a Triple Matrix Factorization-based Unified Framework (TMFUF) to address the above issue. By leveraging a group of side effect entries of drugs, TMFUF achieves the inspiring result (AUC = 0.842 and AUPR = 0.526) in the case of conventional DDI prediction under the traditional screening task. In the comparison with two state-of-the-art approaches, TMFUF demonstrates it superiority by ~ 7% and ~ 20% improvement in terms of AUC and AUPR respectively. More importantly, TMFUF shows its ability in the comprehensive DDI prediction under different screening tasks. Finally, a utilization TMFUF reveals the significant pairs of side effects, which contribute to form enhancive and degressive DDIs, for further clinical validation. CONCLUSIONS: The proposed TMFUF is first capable to predict both conventional binary DDIs and comprehensive DDIs such that it captures the pharmacological changes caused by DDIs. Furthermore, it provides a unified solution of DDI prediction for two screening scenarios, which involves newly given drugs having no prior interaction. Another advantage is its ability to indicate how significantly the pairs of drug features contribute to form DDIs. PMID- 30453925 TI - Comparison of the efficacy and safety of Transarterial chemoembolization with and without Apatinib for the treatment of BCLC stage C hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer worldwide, with a poor prognosis. Most patients are diagnosed at advanced stages and are only eligible for palliative therapy. Therefore, this study aimed to evaluate the safety and efficacy of transcatheter arterial chemoembolization (TACE) combined with apatinib (TACE-apatinib) treatment and TACE-alone treatment for Barcelona Clinic Liver Cancer stage C HCC. METHODS: We retrospectively reviewed 80 consecutive patients with BCLC stage C HCC who received TACE-apatinib or TACE alone as the initial treatment. We compared the clinical and laboratory outcomes, imaging findings at 1 and 3 months after TACE, tumor response, time to progression (TTP), overall survival (OS), and adverse events between both groups. RESULTS: The overall response rate was higher in the TACE-apatinib group than in the TACE-alone group at 1 and 3 months after treatment (66.7% vs 39.6%, respectively, P = 0.020; 45.8% vs 17.6%, respectively, P = 0.021). The median TTP and OS in the TACE-apatinib group were longer than those of the TACE-alone group (TTP: 6.3 months vs 3.5 months, respectively, P = 0.002; OS: 13.0 months vs 9.9 months, respectively, P = 0.041). Apatinib-associated side effects such as hypertension, hand-foot syndrome, oral ulcers, proteinuria, and diarrhea were more prevalent in the TACE-apatinib group than in TACE-alone group (P < 0.05). CONCLUSION: Compared to TACE-alone treatment, TACE-apatinib increased the TTP, OS, and tumor-response rate at 1 and 3 months after treatment of BCLC stage C HCC without any significant increase in severe adverse events. PMID- 30453926 TI - Mothers' knowledge, attitude and practice towards the prevention and home-based management of diarrheal disease among under-five children in Diredawa, Eastern Ethiopia, 2016: a cross-sectional study. AB - BACKGROUND: Diarrhea remains the 2nd leading cause of death among children under 5 globally. It kills more young children than AIDS. It would have been prevented by simple home management using oral rehydration therapy. Mothers play a central role in its management and prevention. So, the main objective of this study was to assess mothers' knowledge, attitude & practice in prevention & home-based management of diarrheal disease among under-five children in Dire Dawa, Eastern Ethiopia. METHODS: Institutional based cross-sectional study was conducted from March 15-April 14, 2016, in Diredawa among 295 Mothers who had under-five child with diarrhea in the last 2 weeks using simple random sampling method. Mothers were interviewed face to face by using pretested, standard and structured questionnaire. The data quality was assured by translation, retranslation and pretesting the questionnaire. Data were checked for completeness, consistency and then entered into Epi Info v3.1 and analyzed using SPSS v20. The descriptive statistical analysis was used to compute frequency, percentages, and mean of the findings of this study. The results were presented using tables, charts, and graphs. RESULTS: In this study, 295 participants were included with 100% response rate. From total 295 mothers, around two-thirds (65.2%) of them had good knowledge, but more than half of mothers (54.9%) had a negative attitude towards home-based management and prevention of diarrhea among under-five children. Regarding the attitude of the mothers, 58% had poor practice towards home-based management and prevention of diarrhea among under-five children. CONCLUSION: The finding of this study showed that the attitude and practice of mothers were unsatisfactory about the prevention and home-based management of under-five diarrheal diseases. Therefore, Health education, dissemination of information, and community conversation should plan and implement to create a positive attitude and practice towards the better prevention and management of under 5 diarrheal diseases. PMID- 30453927 TI - Mothers' and father's perceptions of the risks and benefits of screen time and physical activity during early childhood: a qualitative study. AB - BACKGROUND: This study sought to explore mothers' and fathers' perceptions of the risks and benefits of screen time and active play during early childhood. METHODS: In-depth semi structured telephone interviews were conducted with mothers and fathers (n = 28) of children aged 3-5 years who had earlier taken part in a larger quantitative study in Australia and identified willingness to be re-contacted were recruited. Interviews were audio recorded, transcribed verbatim, and analysed using NviVo. Coding was performed to produce themes. Quotes were extracted from the transcripts to illustrate common responses. COREQ guidelines for qualitative papers were followed. RESULTS: Parents reported active play was beneficial for many health and developmental outcomes such as imagination, enjoyment and socialisation, while reporting risks such as safety and stranger danger. There were mixed perceptions of screen time, with benefits such as learning, education and relaxation, and risks including habit formation, inappropriate content, negative cognitive and social outcome, and detriments to health being reported. A few differences between mothers' and fathers' perceptions were evident. CONCLUSION: This study identified that some parental perceptions of benefits and risks of screen time and active play were consistent with published evidence, while others were contradicted by current evidence. Future studies should consider evidence-based education to ensure parents are aware of evidence-based outcomes of children's behaviours. Interventions may wish to capitalise on parents perceived benefits to enhance engagement. PMID- 30453929 TI - Determinants of motivation to quit in smokers screened for the early detection of lung cancer: a qualitative study. AB - BACKGROUND: The promotion of smoking cessation within lung cancer screening could lead to benefits for smoking-related disease and improve cost-effectiveness of screening. Little is known about how smokers respond to lung cancer screening and how this impacts smoking behaviour. We aimed to understand how lung cancer screening influences individual motivations about smoking, including in those who have stopped smoking since screening. METHODS: Thirty one long-term smokers aged 51-74 took part in semi-structured interviews about smoking. They had been screened with the EarlyCDT-Lung Test (13 positive result; 18 negative) as part of the Early Cancer Detection Test Lung Cancer Scotland Study. They were purposively sampled for interview based on their self-reported post-screening smoking behaviour. Eleven participants had stopped smoking since screening. Verbatim interview transcripts were analysed using thematic analysis. RESULTS: Two key overarching themes were interpretations of screening test results and emotional responses to those interpretations. Participants' understanding of the risk implied by their test result was often inaccurate, for example a negative result interpreted as an 'all-clear' from lung cancer and a positive result as meaning lung cancer would definitely develop. Those interpretations led to emotional responses (fear, shock, worry, relief, indifference) influencing motivations about smoking. Other themes included a wake-up call causing changes in perceived risk of smoking-related disease, a feeling that now is the time to stop smoking and family influences. There was no clear pattern in smoking motivations in those who received positive or negative test results. Of those who had stopped smoking, some cited screening experiences as the sole motivation, some cited screening along with other coinciding factors, and others cited non-screening reasons. Cues to change were experienced at different stages of the screening process. Some participants indicated they underwent screening to try and stop smoking, while others expressed little or no desire to stop. CONCLUSIONS: We observed complex and individualised motivations about smoking following lung cancer screening. To be most effective, smoking cessation support in this context should explore understanding of screening test results and may need to be highly tailored to individual emotional responses to screening. PMID- 30453928 TI - Involvement of HDAC6 in ischaemia and reperfusion-induced rat retinal injury. AB - BACKGROUND: The role of histone deacetylases 6 (HDAC6) has been elucidated in various neurodegenerative diseases. However, the effect of HDAC6 on retinal degenerative processes remains unknown. The aim of this study was to elucidate the potential role of HDAC6 in the retinal ischaemia and reperfusion (I/R) injury model. METHODS: The retinal pathological lesion was evaluated by haematoxylin and eosin (H&E) staining. HDAC expression or activity was detected by immunohistochemistry, Western blotting assays or colorimetric assays. The expression of apoptotic- and autophagic- related proteins were quantified by Western blotting and RT-PCR. The expression of peroxiredoxin 2 (Prx2) was determined by RT-PCR and ELISA. The levels of acetylated alpha-tubulin and acetylated histone 3 in the retina were assayed by Western blotting. RESULTS: We found that I/R-induced reduction of the retinal thickness was ameliorated, and the survival of RGCs was increased by the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA) as well as by tubacin (an HDAC6 selective inhibitor). The decreased expression of THY (thymus cell antigen) in the I/R-induced retinas was also reversed by TSA and tubacin. Elevated HDAC6 expression and activity in the retina from I/R injury were significantly inhibited by tubacin, which also attenuated I/R-mediated apoptosis by decreasing TUNEL-positive RGCs and Bax expression and increasing Bcl-2 expression. Additionally, tubacin increased the expression of autophagy-related gene Beclin 1 and microtubule-associated protein 1 light chain 3B (LC3B) and the levels of Prx2. Furthermore, the protective effect of tubacin was associated with acetylated alpha-tubulin and was independent of acetylated histone 3. CONCLUSIONS: Our findings suggest that tubacin exhibits neuroprotective effects after I/R retinal injury, and HDAC6 may be a potential therapeutic target for the retinal neurodegenerative disease of glaucoma. PMID- 30453930 TI - Slow velocity of the center of pressure and high heel pressures may increase the risk of Sever's disease: a case-control study. AB - BACKGROUND: This study determined if the body mass index, dynamic plantar pressures, plantar surface contact-area, velocity of the centre of pressure (COP), gastrocnemius equinus, and gastrocnemius soleus equines are related to calcaneal apophysitis (Sever's disease) in athletic children. METHODS: This case control study examined 106 boys enrolled in a soccer academy, including 53 with Sever's disease and 53 age-matched healthy controls. The dynamic average and maximum peak plantar-pressures, plantar surface contact-area, and velocity of the COP were evaluated with a digital pressure sensor platform. Goniometry was used to measure the ankle dorsiflexion range of motion and thereby identify gastrocnemius equinus and gastrocnemius soleus equinus. RESULTS: Participants with Sever's condition had significantly higher BMI and peak plantar-pressures (maximum and average) at the heel (Cohen's d > 3 for pressures) than the controls. Those with Sever's disease also had significantly slower velocity of the COP (Cohen's d > 3). Boys with Sever's disease were also 8 times more likely to have bilateral gastrocnemius equinus than disease controls. CONCLUSIONS: High heel plantar pressure and low velocity of COP are related to Sever's condition in boys, although it is not clear whether these factors predispose individuals to the disease or are consequences of the disease. Gastrocnemius ankle equinus could be a predisposing factor for Sever's condition. PMID- 30453931 TI - Discontinuation rate of Implanon and its associated factors among women who ever used Implanon in Dale District, Southern Ethiopia. AB - BACKGROUND: Early discontinuation of the Implanon contraceptive method and reasons for such discontinuation remains a major concern for family planning programs. In less developed countries, contraceptive discontinuation due to health concerns is generally higher, these complaints are often related to service quality. Significant numbers of women become exposed to conception after discontinuation and accidental pregnancies that end up with abortion & stillbirth. The aim of this study was to assess the early discontinuation rate of Implanon and identify its associated factors among women who ever used Implanon in 2016 in Dale district, Southern Ethiopia. METHODS: Community based cross sectional study design was conducted from January to February, 2017. A total number of 711 women who ever used Implanon in 2016 were selected using multistage sampling. The data were entered and cleaned in Epi Info and analyzed using SPSS. Multivariate logistic regression analysis was used to determine the effect of factors on the outcome variables. Finally, the results were presented using adjusted odds ratio (AOR) & confidence interval of 95%. RESULT: Early Implanon discontinuation rate in this study was 160 (23.4%) with a mean duration of Implanon use of 9.6 +/- 2.5 months. The main reasons for discontinuation of Implanon were 55 (34.4%) the facing of side effects. Factors for discontinuation of Implanon were women age 20-24 years (AOR =. 44 (95% CI: 23-. 85), 25-29 years (AOR =. 52 (95% CI: 27-. 96), 35+ years, (AOR =. 08 (95% CI: 02-. 41), less likely to discontinue. Women who weren't counseled about the side effects during Implanon insertion were 1.93 times (AOR = 1.93 (95% CI: 1.27-2.93), women who didn't satisfied by the service (AOR = 2.55(CI: 95%: 1.63-3.97), women who didn't appointed for follow up (AOR = 3.13 (CI: 95%: 2.0-4.95), women who didn't choose the method by themselves (AOR = 1.83 (CI: 95%: 1.18-2.83) and women who didn't have information on family planning before Implanon insertion (AOR = 1.52 (CI: 95%: 1.1-2.28) were the predictors of Implanon discontinuation. CONCLUSIONS: Implanon discontinuation rate in this study area was high. Appropriate counseling prior to insertion and proper follow up, autonomous choice will improve the continuation rate of Implanon. PMID- 30453932 TI - Evaluation of attitudes and knowledge toward mental disorders in a sample of the Chinese population using a web-based approach. AB - BACKGROUND: People with mental disorders often encounter stigmatizing attitudes related to their conditions. Stigma often represents one of the critical obstacles that stand in the way of delivering mental health care. The main aim of the study was to assess the knowledge and attitudes toward mental disorders in a sample of the Chinese population; furthermore, we also aimed to identify and explore the socio-demographic characteristics associated with specific knowledge and attitudes towards psychiatric disorders. METHODS: A cross-sectional survey was created and delivered through an Internet chat application over the period June-December 2017. The Mental Health Knowledge Questionnaire and the Perceived Devaluation and Discrimination Scale were used to evaluate the participants' mental health knowledge and attitudes toward mental disorders. RESULTS: A total of 1087 participants were recruited in for our survey. The mean score of the MHKQ and PDD were (15.89 +/- 2.69) and (33.77 +/- 6.66), respectively. Univariate analyses showed that young people and rural residents tended to show more positive attitudes toward mental disorders with respect to older people and urban residents (P < 0.05). People with higher education levels, those who had contact with people with mental disorders, and those who learned about mental disorders by personal encounter resulted to have had higher MHKQ scores (P < 0.05). CONCLUSIONS: In our sample of the Chinese population, negative attitudes toward mental disorders were often reported. General education programs may not be an effective way to decrease stigma, while anti-stigma campaigns targeted for specific groups, such as urban residents and the older people, should be carried out in the future in China. PMID- 30453933 TI - University students' awareness of causes and risk factors of miscarriage: a cross sectional study. AB - BACKGROUND: Spontaneous miscarriage is the most common complication of pregnancy, occurring in up to 20% of pregnancies. Despite the prevalence of miscarriage, little is known regarding peoples' awareness and understanding of causes of pregnancy loss. The aim of this study was to explore university students' understanding of rates, causes and risk factors of miscarriage. METHODS: A cross sectional study including university students. An online questionnaire was circulated to all students at the University College Cork using their university email accounts in April and May 2016. Main outcomes included identification of prevalence, weeks of gestation at which miscarriage occurs and causative risk factors for miscarriage. RESULTS: A sample of 746 students were included in the analysis. Only 20% (n = 149) of students correctly identified the prevalence of miscarriage, and almost 30% (n = 207) incorrectly believed that miscarriage occurs in less than 10% of pregnancies. Female were more likely to correctly identify the rate of miscarriage than men (21.8% versus 14.5%). However, men tended to underestimate the rate and females overestimate it. Students who did not know someone who had a miscarriage underestimated the rate of miscarriage, and those who were aware of some celebrities who had a miscarriage overestimated the rate. Almost 43% (n = 316) of students correctly identified fetal chromosomal abnormalities as the main cause of miscarriage. Females, older students, those from Medical and Health disciplines and those who were aware of a celebrity who had a miscarriage were more likely to identify chromosomal abnormalities as a main cause. However, more than 90% of the students believed that having a fall, consuming drugs or the medical condition of the mother was a causative risk factor for miscarriage. Finally, stress was identified as a risk factor more frequently than advanced maternal age or smoking. CONCLUSION: Although almost half of the participants identified chromosomal abnormalities as the main cause of miscarriage, there is still a lack of understanding about the prevalence and most important risk factors among university students. University represents an ideal opportunity for health promotion strategies to increase awareness of potential adverse outcomes in pregnancy. PMID- 30453934 TI - Can HIV service data be used for surveillance purposes?: a case study in Guangzhou, China. AB - BACKGROUND: Timely monitoring HIV epidemic among key populations is a formidable challenge. This study aimed to evaluate the agreement between data collected from an enhanced HIV sentinel surveillance (HSS+) and an HIV service, and to discuss whether testing service data can be used for surveillance purposes. METHODS: The HSS+ data were collected from HIV sentinel surveillance conducted annually among men who have sex with men (MSM) between 2009 and 2013 in Guangzhou, China. The HIV service data were obtained from the China-Bill & Melinda Gates Foundation Cooperation Program on HIV Prevention and Care (China-Gates HIV Program) in Guangzhou during the same period. The China-Gates HIV Program aimed to increase HIV counseling and testing among MSM. We compared demographic characteristics, condom use, HIV testing history, and the HIV status among individuals in these two datasets. The Armitage-trend test was used to evaluate the HIV epidemic and behaviors of the participants in the two datasets over the study period. RESULTS: Overall, a total of 2224 and 5311 MSM were included in the surveillance and service datasets, respectively. The majority of participants in the two datasets were between 20 and 29 years old, at least attended college, and had never been married. However, socio-demographic characteristics varied slightly between the two datasets. Similar trends were observed for the HIV epidemic in these two datasets. The surveillance dataset indicated that HIV prevalence increased from 3.9% in 2009 to 11.4% in 2013 (P-value for trend < 0.001), while data from the HIV service dataset indicated that MSM HIV prevalence during this same period increased from 6.2 to 8.9% (P-value for trend = 0.025). The rates of condom use were similar between the two datasets and remained consistent throughout the study period. CONCLUSION: HIV service data can complement existing HIV surveillance systems for MSM in China, though it may underestimate the HIV prevalence (HSS+ data contains people whose status is already know, while service data contains people who were initially negative or people of unknown status). HIV service data can be used for surveillance purposes, when prerequisite variables are collected from a large number people, if the quality assessment is conducted. PMID- 30453935 TI - Microscopic polyangiitis secondary to Mycobacterium abscessus in a patient with bronchiectasis: a case report. AB - BACKGROUND: Non-Tuberculous Mycobacterial-pulmonary disease (NTM-PD) is increasing in incidence and prevalence. Mycobacterium abscessus (M.abscessus) is a rapid growing multi-resistant NTM associated with severe NTM-PD requiring prolonged antibiotic therapy. Complications of therapy are common but reports on direct complications of active NTM-PD are rare. Vasculitis has been described as a rare complication of NTM-PD, most often in individuals with inherited immune defects. This case is the first to describe an ANCA positive vasculitide (Microscopic Polyangiitis) secondary to M.abscessus pulmonary disease. CASE PRESENTATION: A 70 year old female with bronchiectasis underwent a clinical decline associated with the growth of M.abscessus and was diagnosed with NTM-PD. Before treatment could be initiated she developed small joint arthralgia and a glove and stocking axonal loss sensorimotor neuropathy. Positive Perinuclear Anti Neutrophil Cytoplasmic Antibodies (P-ANCA) and Myeloperoxidase-ANCA (MPO-ANCA) titres led to a diagnosis of microscopic polyangiitis. Further investigation revealed reduced interferon-gamma production but no other significant immune dysfunction. Dual treatment with immunosuppressive therapy (Corticosteroids/Cyclophosphamide) for vasculitis and antimicrobial therapy for M.abscessus NTM-PD was initiated. Clinical stability was difficult to achieve with reductions in immunosuppression triggering vasculitic flares. One flare led to retinal vein occlusion with impending visual loss requiring escalation in immunosuppression to Rituximab infusions. An increase in immunosuppression led to a deterioration in NTM-PD necessitating alterations to antibiotic regimes. Adverse effects including alopecia and Achilles tendonitis have further limited antibiotic choices resulting in a strategy of pulsed intra-venous therapy to stabilise NTM-PD. CONCLUSIONS: This is the first reported case of an ANCA positive vasculitis secondary to M.abscessus pulmonary disease. This rare but important complication had a significant impact on the patient adding to the complexity of an already significant disease and treatment burden. The potential role of reduced interferon-gamma production in this case highlights the importance of investigating immune function in those with mycobacterial infection and the intricate relationship between mycobacterial infection and immune dysfunction. Immune dysfunction caused by genetic defects or immunosuppressive therapy is a known risk factor for NTM-PD. Balancing immunosuppressive therapy with prolonged antimicrobial treatment is challenging and likely to become more common as the number of individuals being treated with biologics and immunosuppressive agents increases. PMID- 30453936 TI - Non-medical prescription stimulant use to improve academic performance among Australian university students: prevalence and correlates of use. AB - BACKGROUND: Some university students consume pharmaceutical stimulants without a medical prescription with the goal of improving their academic performance. The prevalence of this practice has been well documented in the US, but less so in other countries. The potential harms of using prescription stimulants require a better understanding of the prevalence of this practice within Australian universities. METHODS: An internet survey of 1136 Australian students was conducted in 2015 in three large Australian universities. Students were asked about their personal use of prescription stimulants, attitudes and experiences with prescription stimulants. They were also asked about their use of caffeine, energy drinks and illicit drugs to enhance their academic performance. RESULTS: Lifetime self-reported use of stimulant medication to improve academic performance was 6.5, and 4.4% in the past year. Students were far more likely to report using coffee and energy drinks (41.4 and 23.6% respectively, lifetime use) than prescription stimulants to help them study and complete university assessments. Non-medical use of prescription stimulants was strongly associated with a history of illicit drug use. CONCLUSION: The prevalence of nonmedical prescription stimulant use to improve academic performance is low among university students in Australia, especially when compared with their use of coffee and energy drinks. PMID- 30453937 TI - Teaching residents to put patients first: creation and evaluation of a comprehensive curriculum in patient-centered communication. AB - BACKGROUND: Patient-centered communication is essential for successful patient encounters and positive patient outcomes. Therefore, training residents how to communicate well is one of the key responsibilities of residency programs. However, many residents, especially international medical graduates, continue to struggle with communication barriers. METHODS: All residents and faculty from a small community teaching hospital participated in a three-year, multidimensional patient-centered communication curriculum including communication training with lectures, experiential learning, communication skills practice, and reflection in the areas of linguistics, physician-patient communication, cultural & linguistically appropriate care, and professionalism. We evaluated the program through a multipronged outcomes assessment, including self-assessment, scores on the Calgary-Cambridge Scale during Objective Structured Clinical Examination (OSCE), a survey to measure the hidden curriculum, English Communication Assessment Profile (E-CAP),, the Maslach Burnout-Inventory (MBI), and residents' evaluation of faculty communication. RESULTS: Sixty-two residents and ten faculty members completed the three-year curriculum. We saw no significant changes in the MBI or hidden curriculum survey. Communication skills as measured by Calgary Cambridge Score, E-CAP, and resident communication improved significantly (average Calgary-Cambridge Scale scores from 70% at baseline to 78% at follow-up (p-value < 0.001), paired t-test score from 68% at baseline to 81% at follow-up (p-value < 0.004), average E-CAP score from 73 to 77% (p-value < 0.001)). Faculty communication and teaching as rated by residents also showed significant improvement in four out of six domains (learning climate (p < 0.001), patient centered care (p = 0.01), evaluation (p = 0.03), and self-directed learning (p = 0.03)). CONCLUSION: Implementing a multidimensional curriculum in patient centered communication led to modest improvements in patient-centered communication, improved language skills, and improved communication skills among residents and faculty. PMID- 30453938 TI - Retraction Note: detangling PPI networks to uncover functionally meaningful clusters. AB - The authors have retracted this article [1]. After publication they discovered a technical error in the Louvain algorithm with bounded cluster sizes. Correction of this error substantially changed the results for this algorithm and the conclusions drawn in the article were found to be incorrect. The authors will submit a new manuscript for peer review. PMID- 30453939 TI - Prostaglandin E2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. AB - BACKGROUND: Inflammatory bowel disease (IBD) is an intractable autoimmune disease, relatively common in cats, with chronic vomiting and diarrhea. Previous studies have reported that mesenchymal stem cells (MSCs) alleviate inflammation by modulating immune cells. However, there is a lack of research on cross-talk mechanism between feline adipose tissue-derived mesenchymal stem cells (fAT-MSCs) and immune cells in IBD model. Hence, this study aimed to evaluate the therapeutic effects of fAT-MSC on mice model of colitis and to clarify the therapeutic mechanism of fAT-MSCs. RESULTS: Intraperitoneal infusion of fAT-MSC ameliorated the clinical and histopathologic severity of colitis, including body weight loss, diarrhea, and inflammation in the colon of Dextran sulfate sodium (DSS)-treated mice (C57BL/6). Since regulatory T cells (Tregs) are pivotal in modulating immune responses and maintaining tolerance in colitis, the relation of Tregs with fAT-MSC-secreted factor was investigated in vitro. PGE2 secreted from fAT-MSC was demonstrated to induce elevation of FOXP3 mRNA expression and adjust inflammatory cytokines in Con A-induced feline peripheral blood mononuclear cells (PBMCs). Furthermore, in vivo, FOXP3+ cells of the fAT-MSC group were significantly increased in the inflamed colon, relative to that in the PBS group. CONCLUSION: Our results suggest that PGE2 secreted from fAT-MSC can reduce inflammation by increasing FOXP3+ Tregs in mice model of colitis. Consequently, these results propose the possibility of administration of fAT-MSC to cats with not only IBD but also other immune-mediated inflammatory diseases. PMID- 30453940 TI - Developing a healthcare dataset information resource (DIR) based on Semantic Web. AB - BACKGROUND: The right dataset is essential to obtain the right insights in data science; therefore, it is important for data scientists to have a good understanding of the availability of relevant datasets as well as the content, structure, and existing analyses of these datasets. While a number of efforts are underway to integrate the large amount and variety of datasets, the lack of an information resource that focuses on specific needs of target users of datasets has existed as a problem for years. To address this gap, we have developed a Dataset Information Resource (DIR), using a user-oriented approach, which gathers relevant dataset knowledge for specific user types. In the present version, we specifically address the challenges of entry-level data scientists in learning to identify, understand, and analyze major datasets in healthcare. We emphasize that the DIR does not contain actual data from the datasets but aims to provide comprehensive knowledge about the datasets and their analyses. METHODS: The DIR leverages Semantic Web technologies and the W3C Dataset Description Profile as the standard for knowledge integration and representation. To extract tailored knowledge for target users, we have developed methods for manual extractions from dataset documentations as well as semi-automatic extractions from related publications, using natural language processing (NLP)-based approaches. A semantic query component is available for knowledge retrieval, and a parameterized question-answering functionality is provided to facilitate the ease of search. RESULTS: The DIR prototype is composed of four major components dataset metadata and related knowledge, search modules, question answering for frequently-asked questions, and blogs. The current implementation includes information on 12 commonly used large and complex healthcare datasets. The initial usage evaluation based on health informatics novices indicates that the DIR is helpful and beginner-friendly. CONCLUSIONS: We have developed a novel user oriented DIR that provides dataset knowledge specialized for target user groups. Knowledge about datasets is effectively represented in the Semantic Web. At this initial stage, the DIR has already been able to provide sophisticated and relevant knowledge of 12 datasets to help entry health informacians learn healthcare data analysis using suitable datasets. Further development of both content and function levels is underway. PMID- 30453941 TI - Factors associated with the utilization of antenatal care and prevention of mother-to-child HIV transmission services in Ethiopia: applying a count regression model. AB - BACKGROUND: Prevention of Mother-to-Child HIV Transmission (PMTCT) coverage has been low in Ethiopia and the service has been implemented in a fragmented manner. Solutions to this problem have mainly been sought on the supply-side in the form of improved management and allocation of limited resources. However, this approach largely ignores the demand-side factors associated with low PMTCT coverage in the country. The study assesses the factors associated with the utilization of PMTCT services taking into consideration counts of visits to antenatal care (ANC) services in urban high-HIV prevalence and rural low-HIV prevalence settings in Ethiopia. METHODS: A multivariate regression model was employed to identify significant factors associated with PMTCT service utilization. Poisson and negative binomial regression models were applied, considering the number of ANC visits as a dependent variable. The explanatory variables were age; educational status; type of occupation; decision-making power in the household; living in proximity to educated people; a neighborhood with good welfare services; location (urban high-HIV prevalence and rural low-HIV prevalence); transportation accessibility; walking distance (in minutes); and household income status. The alpha dispersion test (a) was performed to measure the goodness-of-fit of the model. Significant results were reported at p-values of < 0.05 and < 0.001. RESULTS: Household income, socio-economic setting (urban high-HIV prevalence and rural low-HIV prevalence) and walking distance (in minutes) had a statistically significant relationship with the number of ANC visits by pregnant women (p < 0.05). A pregnant woman from an urban high-HIV prevalence setting would be expected to make 34% more ANC visits (counts) than her rural low-HIV prevalence counterparts (p < 0.05). Holding other variables constant, a unit increase in household income would increase the expected ANC visits by 0.004%. An increase in walking distance by a unit (a minute) would decrease the number of ANC visits by 0.001(p < 0.001). CONCLUSION: Long walking distance, low household income and living in a rural setting are the significant factors associated with low PMTCT service utilization. The primary strategies for a holistic policy to improve ANC/PMTCT utilization should thus include improving the geographical accessibility of ANC/PMTCT services, expanding household welfare and paying more attention to remote rural areas. PMID- 30453943 TI - Insights into mammalian transcription control by systematic analysis of ChIP sequencing data. AB - BACKGROUND: Transcription regulation is a major controller of gene expression dynamics during development and disease, where transcription factors (TFs) modulate expression of genes through direct or indirect DNA interaction. ChIP sequencing has become the most widely used technique to get a genome wide view of TF occupancy in a cell type of interest, mainly due to established standard protocols and a rapid decrease in the cost of sequencing. The number of available ChIP sequencing data sets in public domain is therefore ever increasing, including data generated by individual labs together with consortia such as the ENCODE project. RESULTS: A total of 1735 ChIP-sequencing datasets in mouse and human cell types and tissues were used to perform bioinformatic analyses to unravel diverse features of transcription control. 1- We used the Heat*seq webtool to investigate global relations across the ChIP-seq samples. 2- We demonstrated that factors have a specific genomic location preferences that are, for most factors, conserved across species. 3- Promoter proximal binding of factors was more conserved across cell types while the distal binding sites are more cell type specific. 4- We identified combinations of factors preferentially acting together in a cellular context. 5- Finally, by integrating the data with disease-associated gene loci from GWAS studies, we highlight the value of this data to associate novel regulators to disease. CONCLUSION: In summary, we demonstrate how ChIP sequencing data integration and analysis is powerful to get new insights into mammalian transcription control and demonstrate the utility of various bioinformatic tools to generate novel testable hypothesis using this public resource. PMID- 30453942 TI - Are publicly available internet resources enabling women to make informed fertility preservation decisions before starting cancer treatment: an environmental scan? AB - BACKGROUND: To identify publicly available internet resources and assess their likelihood to support women making informed decisions about, and between, fertility preservation procedures before starting their cancer treatment. METHODS: A survey of publically available internet resources utilising an environmental scan method. Inclusion criteria were applied to hits from searches of three data sources (November 2015; repeated June 2017): Google (Chrome) for patient resources; repositories for clinical guidelines and projects; distribution email lists to contact patient decision aid experts. The Data Extraction Sheet applied to eligible resources elicited: resource characteristics; informed and shared decision making components; engagement health services. RESULTS: Four thousand eight hundred fifty one records were identified; 24 patient resources and 0 clinical guidelines met scan inclusion criteria. Most resources aimed to inform women with cancer about fertility preservation procedures and infertility treatment options, but not decision making between options. There was a lack of consistency about how health conditions, decision problems and treatment options were described, and resources were difficult to understand. CONCLUSIONS: Unless developed as part of a patient decision aid project, resources did not include components to support proactively women's fertility preservation decisions. Current guidelines help people deliver information relevant to treatment options within a single disease pathway; we identified five additional components for patient decision aid checklists to support more effectively people's treatment decision making across health pathways, linking current with future health problems. PMID- 30453944 TI - Assisted reproductive techniques with congenital hypogonadotropic hypogonadism patients: a systematic review and meta-analysis. AB - BACKGROUND: After hormonal replacement therapy (HRT) including androgen replacement or sequential therapy of estrogen and progesterone, The combination of human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) and pulsatile GnRH, is not sufficient to produce sufficient gametes in some patients with Congenital hypogonadotropic hypogonadism (CHH). A Systematic review and meta analysis was performed to determine that assisted reproductive techniques (ART) can effectively treat different causes of infertility. METHODS: To determine the effect of ART on fertility of CHH patients and investigate whether outcomes are similar to infertility due to other causes, we conducted a systematic review and meta-analysis of retrospective trials. Clinical trials were systematically searched in Medline, Embase, and the Cochrane central register of controlled trials databases. The keywords and major terms covered "hypogonadotropic hypogonadism", "kallmann syndrome", "assisted reproductive techniques", "intrauterine insemination", "intracytoplasmic sperm injection", "testicular sperm extraction", "in vitro fertilization", "embryo transplantation" and "intra Fallopian transfer". RESULTS: A total of 388 pregnancies occurred among 709 CHH patients who received ART (effectiveness 46, 95% confidence interval 0.39 to 0.53) in the 20 studies we included. The I2 in trials assessing overall pregnancy rate (PR) per embryo transfer (ET) cycle was 73.06%. Similar results were observed in subgroup analysis by different gender. Regression indicates pregnancy rate decreases with increasing age. Fertilization, implantation and live birth rates (72, 36 and 40%) showed no significant differences as compared to infertility due to other causes. CONCLUSIONS: Despite CHH patients usually being difficult to generate gametes, their actual chances of fertility are similar to subjects with other non-obstructive infertility. ART is a suitable option for CHH patients who do not conceive after long-term gonadotropin treatment. PMID- 30453945 TI - Evaluation of Senegal's prevention of mother to child transmission of HIV (PMTCT) program data for HIV surveillance. AB - BACKGROUND: With the expansion of Prevention of Mother to Child Transmission (PMTCT) services in Senegal, there is growing interest in using PMTCT program data in lieu of conducting unlinked anonymous testing (UAT)-based ANC Sentinel Surveillance. For this reason, an evaluation was conducted in 2011-2012 to identify the gaps that need to be addressed while transitioning to using PMTCT program data for surveillance. METHODS: We conducted analyses to assess HIV prevalence rates and agreements between Sentinel Surveillance and PMTCT HIV test results. Also, a data quality assessment of the PMTCT program registers and data was conducted during the Sentinel Surveillance period (December 2011 to March 2012) and 3 months prior. Finally, we also assessed selection bias, which was the percentage difference from the HIV prevalence among all women enrolled in the antenatal clinic and the HIV prevalence among women who accepted PMTCT HIV testing. RESULTS: The median site HIV prevalence using routine PMTCT HIV testing data was 1.1% (IQR: 1.0) while the median site prevalence from the UAT HIV Sentinel Surveillance data was at 1.0% (IQR: 1.6). The Positive per cent agreement (PPA) of the PMTCT HIV test results compared to those of the Sentinel Surveillance was 85.1% (95% CI 77.2-90.7%), and the percent-negative agreement (PNA) was 99.9% (95% CI 99.8-99.9%). The overall HIV prevalence according to UAT was the same as that found for women accepting a PMTCT HIV test and those who refused, with percent bias at 0.00%. For several key PMTCT variables, including "HIV test offered" (85.2%), "HIV test acceptance" (78.0%), or "HIV test done" (58.8%), the proportion of records in registers with combined complete and valid data was below the WHO benchmark of 90%. CONCLUSIONS: The PPA of 85.1 was below the WHO benchmarks of 96.6%, while the combined data validity and completeness rates was below the WHO benchmark of 90% for many key PMTCT variables. These results suggested that Senegal will need to reinforce the quality of onsite HIV testing and improve program data collection practices in preparation for using PMTCT data for surveillance purposes. PMID- 30453946 TI - Treatment completion for latent tuberculosis infection in Norway: a prospective cohort study. AB - BACKGROUND: Successful treatment of latent tuberculosis infection (LTBI) is essential to reduce tuberculosis (TB) incidence rates in low-burden countries. This study measures treatment completion and determinants of non-completion of LTBI treatment in Norway in 2016. METHODS: This prospective cohort study included all individuals notified with LTBI treatment to the Norwegian Surveillance System for Infectious Diseases (MSIS) in 2016. We obtained data from MSIS and from a standardized form that was sent to health care providers at the time of patient notification to MSIS. We determined completion rates. Pearson's chi squared test was used to study associations between pairs of categorical variables and separate crude and multivariable logistic regression models were used to identify factors associated with treatment completion and adverse drug effects. RESULTS: We obtained information on treatment completion from 719 of the 726 individuals notified for LTBI treatment in 2016. Overall, 91% completed treatment. Treatment completion was highest in the foreign-born group [foreign-born, n = 562 (92%) vs Norwegian-born, n = 115 (85%), p = 0.007]. Treatment completion did not differ significantly between prescribed regimens (p = 0.124). Adverse events were the most common reason for incomplete treatment. We found no significant differences in adverse events when comparing weekly rifapentine (3RPH) with three months daily isoniazid and rifampicin (3RH). However, there were significantly fewer adverse events with 3RPH compared to other regimens (p = 0.037). Age over 35 years was significantly associated with adverse events irrespective of regimen (p = 0.024), whereas immunosuppression was not significantly associated with adverse events after adjusting for other variables (p = 0.306). Treatment under direct observation had a significant effect on treatment completion for foreign-born (multivariate Wald p-value = 0.017), but not for Norwegian-born (multivariate Wald p-value = 0.408) individuals. CONCLUSIONS: We report a very high treatment completion rate, especially among individuals from countries with high TB incidence. The follow-up from tuberculosis-coordinators and the frequent use of directly observed treatment probably contributes to this. Few severe adverse events were reported, even with increased age and in individuals that are more susceptible. While these results are promising, issues of cost-effectiveness and targeting treatment to individuals at highest risk of TB are important components of public health impact. PMID- 30453948 TI - A comprehensive systematic review of stakeholder attitudes to alternatives to prospective informed consent in paediatric acute care research. AB - BACKGROUND: A challenge of performing research in the paediatric emergency and acute care setting is obtaining valid prospective informed consent from parents. The ethical issues are complex, and it is important to consider the perspective of participants, health care workers and researchers on research without prospective informed consent while planning this type of research. METHODS: We performed a systematic review according to PRISMA guidelines, of empirical evidence relating to the process, experiences and acceptability of alternatives to prospective informed consent, in the paediatric emergency or acute care setting. Major medical databases and grey sources were searched and results were screened and assessed against eligibility criteria by 2 authors, and full text articles of relevant studies obtained. Data were extracted onto data collection forms and imported into data management software for analysis. RESULTS: Thirteen studies were included in the review consisting of nine full text articles and four abstracts. Given the heterogeneity of the methods, results could not be quantitatively combined for meta-analysis, and qualitative results are presented in narrative form, according to themes identified from the data. Major themes include capacity of parents to provide informed consent, feasibility of informed consent, support for alternatives to informed consent, process issues, modified consent process, child death, and community consultation. CONCLUSION: Our review demonstrated that children, their families, and health care staff recognise the requirement for research without prior consent, and are generally supportive of enrolling children in such research with the provisions of limiting risk, and informing parents as soon as possible. Australian data and perspectives of children are lacking and represent important knowledge gaps. PMID- 30453949 TI - Discovery and disentanglement of aligned residue associations from aligned pattern clusters to reveal subgroup characteristics. AB - BACKGROUND: A protein family has similar and diverse functions locally conserved. An aligned pattern cluster (APC) can reflect the conserved functionality. Discovering aligned residue associations (ARAs) in APCs can reveal subtle inner working characteristics of conserved regions of protein families. However, ARAs corresponding to different functionalities/subgroups/classes could be entangled because of subtle multiple entwined factors. METHODS: To discover and disentangle patterns from mixed-mode datasets, such as APCs when the residues are replaced by their fundamental biochemical properties list, this paper presents a novel method, Extended Aligned Residual Association Discovery and Disentanglement (E ARADD). E-ARADD discretizes the numerical dataset to transform the mixed-mode dataset into an event-value dataset, constructs an ARA Frequency Matrix and then converts it into an adjusted Statistical Residual (SR) Vector Space (SRV) capturing statistical deviation from randomness. By applying Principal Component (PC) Decomposition on SRV, PCs ranked by their variance are obtained. Finally, the disentangled ARAs are discovered when the projections on a PC is re-projected to a vector space with the same basis vectors of SRV. RESULTS: Experiments on synthetic, cytochrome c and class A scavenger data have shown that E-ARADD can a) disentangle the entwined ARAs in APCs (with residues or biochemical properties), b) reveal subtle AR clusters relating to classes, subtle subgroups or specific functionalities. CONCLUSIONS: E-ARADD can discover and disentangle ARs and ARAs entangled in functionality and location of protein families to reveal functional subgroups and subgroup characteristics of biological conserved regions. Experimental results on synthetic data provides the proof-of-concept validation on the successful disentanglement that reveals class-associated ARAs with or without class labels as input. Experiments on cytochrome c data proved the efficacy of E-ARADD in handing both types of residue data. Our novel methodology is not only able to discover and disentangle ARs and ARAs in specific statistical/functional (PCs and RSRVs) spaces, but also their locations in the protein family functional domains. The success of E-ARADD shows its great potential to proteomic research, drug discovery and precision and personalized genetic medicine. PMID- 30453947 TI - Bi-stream CNN Down Syndrome screening model based on genotyping array. AB - BACKGROUND: Human Down syndrome (DS) is usually caused by genomic micro duplications and dosage imbalances of human chromosome 21. It is associated with many genomic and phenotype abnormalities. Even though human DS occurs about 1 per 1,000 births worldwide, which is a very high rate, researchers haven't found any effective method to cure DS. Currently, the most efficient ways of human DS prevention are screening and early detection. METHODS: In this study, we used deep learning techniques and analyzed a set of Illumina genotyping array data. We built a bi-stream convolutional neural networks model to screen/predict the occurrence of DS. Firstly, we built image input data by converting the intensities of each SNP site into chromosome SNP maps. Next, we proposed a bi stream convolutional neural network (CNN) architecture with nine layers and two branch models. We further merged two CNN branch models into one model in the fourth convolutional layer, and output the prediction in the last layer. RESULTS: Our bi-stream CNN model achieved 99.3% average accuracies, and very low false positive and false-negative rates, which was necessary for further applications in disease prediction and medical practice. We further visualized the feature maps and learned filters from intermediate convolutional layers, which showed the genomic patterns and correlated SNPs variations in human DS genomes. We also compared our methods with other CNN and traditional machine learning models. We further analyzed and discussed the characteristics and strengths of our bi-stream CNN model. CONCLUSIONS: Our bi-stream model used two branch CNN models to learn the local genome features and regional patterns among adjacent genes and SNP sites from two chromosomes simultaneously. It achieved the best performance in all evaluating metrics when compared with two single-stream CNN models and three traditional machine-learning algorithms. The visualized feature maps also provided opportunities to study the genomic markers and pathway components associated with Human DS, which provided insights for gene therapy and genomic medicine developments. PMID- 30453950 TI - Evaluation of the effect of Lactobacillus reuteri V3401 on biomarkers of inflammation, cardiovascular risk and liver steatosis in obese adults with metabolic syndrome: a randomized clinical trial (PROSIR). AB - BACKGROUND: Obesity is characterized by increased fat mass and is associated with the development of insulin resistance syndrome (IRS), usually known as metabolic syndrome. The alteration of the intestinal microbiota composition has a role in the development of IRS associated with obesity, and probiotics, which are live microorganisms that confer a health benefit to the host, contribute to restore intestinal microbiota homeostasis and lower peripheral tissue insulin resistance. We aim to evaluate the effects of the probiotic strain Lactobacillus reuteri (L. reuteri) V3401 on the composition of intestinal microbiota, markers of insulin resistance and biomarkers of inflammation, cardiovascular risk, and hepatic steatosis in patients with overweight and obesity exhibiting IRS. METHODS/DESIGN: We describe a randomized, double-blind, crossover, placebo-controlled, and single centre trial. Sixty participants (aged 18 to 65 years) diagnosed with IRS will be randomized in a 1:1 ratio to receive either a daily dose of placebo or 5 * 109 colony-forming units of L. reuteri V3401. The study will consist of two intervention periods of 12 weeks separated by a washout period of 6 weeks and preceded by another washout period of 2 weeks. The primary outcome will be the change in plasma lipopolysaccharide (LPS) levels at 12 weeks. Secondary outcomes will include anthropometric parameters, lipid profile, glucose metabolism, microbiota composition, hepatic steatosis, and inflammatory and cardiovascular biomarkers. Blood and stool samples will be collected at baseline, at the midpoint (only stool samples) and immediately after each intervention period. Luminex technology will be used to measure interleukins. For statistical analysis, a mixed ANOVA model will be employed to calculate changes in the outcome variables. DISCUSSION: This is the first time that L. reuteri V3401 will be evaluated in patients with IRS. Therefore, this study will provide valuable scientific information about the effects of this strain in metabolic syndrome patients. TRIAL REGISTRATION: The trial has been retrospectively registered in ClinicalTrials.gov on the 23rd November 2016 (ID: NCT02972567 ), during the recruitment phase. PMID- 30453951 TI - The prevalence of Coxiella burnetii shedding in dairy goats at the time of parturition in an endemically infected enterprise and associated milk yield losses. AB - BACKGROUND: This was a panel study of the prevalence of C. burnetii infection in does in an endemic dairy goat enterprise in Victoria, Australia. Our first objective was to determine the prevalence of does shedding C. burnetii at the time of parturition and to quantify the concentration of genome equivalents (GE) present in each C. burnetii positive sample. Our second objective was to determine the proportion of positive does that were persistent shedders. Our final objective was to quantify the association between C. burnetii qPCR status at the time of kidding and daily milk volumes produced during the subsequent lactation. RESULTS: Vaginal swabs (n= 490) were collected from does at the time of kidding and analysed using a quantitative polymerase chain reaction (qPCR) assay. Shedding of C. burnetii was detected in 15% (95% CI: 12% to 18%) of the sampled does. Does were classified as qPCR-negative, qPCR-positive low and qPCR positive high based on the estimated concentration of GE from the qPCR. Persistent shedding at relatively low concentrations was detected in 20% (95% CI: 10% to35%) of shedding does sampled again at their subsequent parturition. After controlling for possible confounders and adjusting for variation in daily milk yields at the individual doe level, daily milk yields for qPCR-positive high does were reduced by 17% (95% CI: 3% to 32%) compared to qPCR-negative does (p= 0.02). CONCLUSIONS: Shedding concentrations of C. burnetii were highly skewed, with a relatively small group of does shedding relatively high quantities of C. burnetii. Further, high shedding does had reduced milk yields compared to qPCR negative does. Early detection and culling of high shedding does would result in increased farm profitability and reduce the risk of Q fever transmission. PMID- 30453952 TI - Dexamethasone treatment did not exacerbate Seneca Valley virus infection in nursery-age pigs. AB - BACKGROUND: Senecavirus A, commonly known as Seneca Valley virus (SVV), is a picornavirus that has been infrequently associated with porcine idiopathic vesicular disease (PIVD). In late 2014 there were multiple PIVD outbreaks in several states in Brazil and samples from those cases tested positive for SVV. Beginning in July of 2015, multiple cases of PIVD were reported in the United States in which a genetically similar SVV was also detected. These events suggested SVV could induce vesicular disease, which was recently demonstrated with contemporary US isolates that produced mild disease in pigs. It was hypothesized that stressful conditions may exacerbate the expression of clinical disease and the following experiment was performed. Two groups of 9-week-old pigs were given an intranasal SVV challenge with one group receiving an immunosuppressive dose of dexamethasone prior to challenge. After challenge animals were observed for the development of clinical signs and serum and swabs were collected to study viral shedding and antibody production. In addition, pigs were euthanized 2, 4, 6, 8, and 12 days post inoculation (dpi) to demonstrate tissue distribution of virus during acute infection. RESULTS: Vesicular disease was experimentally induced in both groups with the duration and magnitude of clinical signs similar between groups. During acute infection [0-14 days post infection (dpi)], SVV was detected by PCR in serum, nasal swabs, rectal swabs, various tissues, and in swabs from ruptured vesicles. From 15 to 30 dpi, virus was less consistently detected in nasal and rectal swabs, and absent from most serum samples. Virus neutralizing antibody was detected by 5 dpi and lasted until the end of the study. CONCLUSION: Treatment with an immunosuppressive dose of dexamethasone did not drastically alter the clinical disease course of SVV in experimentally infected nursery aged swine. A greater understanding of SVV pathogenesis and factors that could exacerbate disease can help the swine industry with control and prevention strategies directed against this virus. PMID- 30453953 TI - To select or be selected - gendered experiences in clinical training affect medical students' specialty preferences. AB - BACKGROUND: The literature investigating female and male medical students' differing career intentions is extensive. However, medical school experiences and their implications for professional identity formation and specialty choice have attracted less attention. In this study we explore the impact of medical school experiences on students' specialty preferences, investigate gender similarities and differences, and discuss how both might be related to gender segregation in specialty preference. METHODS: In a questionnaire, 250 Swedish final-year medical students described experiences that made them interested and uninterested in a specialty. Utilizing a sequential mixed methods design, their responses were analyzed qualitatively to create categories that were compared quantitatively. RESULTS: Similar proportions of women and men became interested in a specialty based on its knowledge area, patient characteristics, and potential for work-life balance. These aspects, however, often became secondary to whether they felt included or excluded in clinical settings. More women than men had been deterred by specialties with excluding, hostile, or sexist workplace climates (W = 44%, M = 16%). In contrast, more men had been discouraged by specialties' knowledge areas (W = 27%, M = 47%). CONCLUSIONS: Male and female undergraduates have similar incentives and concerns regarding their career. However, the prevalence of hostility and sexism in the learning environment discourages especially women from some specialties. To reduce gender segregation in specialty choice, energy should be directed towards counteracting hostile workplace climates that explain apparent stereotypical assumptions about career preferences of men and women. PMID- 30453954 TI - Human ancestry indentification under resource constraints -- what can one chromosome tell us about human biogeographical ancestry? AB - BACKGROUND: While continental level ancestry is relatively simple using genomic information, distinguishing between individuals from closely associated sub populations (e.g., from the same continent) is still a difficult challenge. METHODS: We study the problem of predicting human biogeographical ancestry from genomic data under resource constraints. In particular, we focus on the case where the analysis is constrained to using single nucleotide polymorphisms (SNPs) from just one chromosome. We propose methods to construct such ancestry informative SNP panels using correlation-based and outlier-based methods. RESULTS: We accessed the performance of the proposed SNP panels derived from just one chromosome, using data from the 1000 Genome Project, Phase 3. For continental level ancestry classification, we achieved an overall classification rate of 96.75% using 206 single nucleotide polymorphisms (SNPs). For sub-population level ancestry prediction, we achieved an average pairwise binary classification rates as follows: subpopulations in Europe: 76.6% (58 SNPs); Africa: 87.02% (87 SNPs); East Asia: 73.30% (68 SNPs); South Asia: 81.14% (75 SNPs); America: 85.85% (68 SNPs). CONCLUSION: Our results demonstrate that one single chromosome (in particular, Chromosome 1), if carefully analyzed, could hold enough information for accurate prediction of human biogeographical ancestry. This has significant implications in terms of the computational resources required for analysis of ancestry, and in the applications of such analyses, such as in studies of genetic diseases, forensics, and soft biometrics. PMID- 30453955 TI - integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth. AB - BACKGROUND: The integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates. METHODS: To better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB). RESULTS: We developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome. integRATE is available as an R package on GitHub ( https://github.com/haleyeidem/integRATE ). CONCLUSIONS: Desirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses. PMID- 30453956 TI - Using conversation analysis to inform role play and simulated interaction in communications skills training for healthcare professionals: identifying avenues for further development through a scoping review. AB - BACKGROUND: This paper responds to previously published debate in this journal around the use of sociolinguistic methods in communication skills training (CST), which has raised the significant question of how far consultations with simulated patients reflect real clinical encounters. This debate concluded with a suggestion that sociolinguistic methods offer an alternative analytic lens for evaluating CST. We demonstrate here that the utility of sociolinguistic methods in CST is not limited to critique, but also presents an important tool for development and delivery. METHODS: Following a scoping review of the use of role play and simulated interaction in CST for healthcare professionals, we consider the use of the specific sociolinguistic approach of conversation analysis (CA), which has been applied to the study of health communication in a wide range of settings, as well as to the development of training. DISCUSSION: Role play and simulated interaction have been criticised by both clinicians and sociolinguists for a lack of authenticity as compared to real life interactions. However they contain a number of aspects which healthcare professionals report finding particularly useful: the need to think on one's feet in real time, as in actual interaction with patients; the ability to receive feedback on the simulation; and the ability to watch and reflect on how others approach the same simulation task in real time. Since sociolinguistic approaches can help to identify inauthenticity in role play and simulation, they can also be used to improve authenticity. Analysis of real-life interactions using sociolinguistic methods, and CA in particular, can identify actual interactional practices that are used by particular patient groups. These practices can then be used to inform the training of actors simulating patients. In addition, the emphasis of CA on talk as joint activity means that proper account can be taken of the way in which simulated interaction is co-constructed between simulator and trainee. We suggest that as well as identifying potential weaknesses in current role play and simulation practice, conversation analysis offers the potential to enhance and develop the authenticity of these training methods. PMID- 30453957 TI - Questionnaires that measure the quality of relationships between patients and primary care providers: a systematic review. AB - BACKGROUND: International guidance on models of care stress the importance of good quality, continuous patient-provider relationships to support high quality and efficient care and hospital avoidance. However, assessing the quality of patient-provider relationships is challenging due to its experiential nature. The aim of this study was to undertake a systematic review to identify questionnaires previously developed or used to assess the quality of continuous relationships between patients and their provider in primary care. METHODS: MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and SCOPUS databases were searched for English language studies published between 2009 and 2017. Key terms used identified studies conducted in the primary care setting examining relationships between patients and providers. Studies that focused on the conceptualisation, development, testing or review of a questionnaire, or studies that used a questionnaire for assessing the quality of continuous relationships between patients and providers were eligible. Studies that did not assess quality via a questionnaire, only assessed single aspects of relationships, only assessed single encounters, assessed transitions between settings or assessed relationships using an index were excluded. Information on validity testing of each relevant questionnaire identified from articles was reviewed to inform recommendations for future research and evaluation. RESULTS: Twenty-seven studies met the eligibility criteria, including 14 unique questionnaires. The questionnaires were diverse in length, scope, focus and level of validity testing. Five questionnaires were considered not feasible for future use due to size and lack of development work. Three questionnaires were considered strongest candidates for use in future work based on being relevant to the topic and primary care setting, freely available in English and not needing additional pilot work prior to use. These three questionnaires were the Care Continuity Across Levels of Care Scale, the Nijmegan Continuity Questionnaire and the Patient-Doctor Depth of Relationship Tool. CONCLUSIONS: This study provides an overview of 14 unique questionnaires that have been used to assess the quality of continuous relationships between patients and primary care providers. The decision to use one of the questionnaires in future work requires careful consideration, including the scope, length, validation testing, accessibility of the questionnaires and their alignment with the initiative being evaluated. PMID- 30453958 TI - A prospective cohort study to evaluate immunosuppressive cytokines as predictors of viral persistence and progression to pre-malignant lesion in the cervix in women infected with HR-HPV: study protocol. AB - BACKGROUND: Cervical cancer (CC) is caused by a persistent infection of high-risk human papillomavirus (HR-HPV). While most HPV infections are transient, persistent HPV infections are a significant health problem in Mexico. With an estimated HPV prevalence of 10% among women in reproductive age, approximately 25% of these women present at least a positive result in triage test, which according to previous studies is expected to be confirmed as positive CIN-2/3. The immune system has a key role in the natural history of HPV infection; alterations in the cellular immune response are responsible for the failure to eliminate HPV. The objective of this project is to assess the prognostic value of detecting immune markers (IL-10, IL-4, TGFbeta1, IFNgamma, IL-6, and TNFalpha), the expression of HPV-HR E6/E7 proteins, and the viral load at the cervical level with respect to the persistence or clearance of HR-HPV infection, and the regression or progression of a cervical premalignant lesion. METHODS: A dynamic cohort study is being conducted in women with colposcopic, cytological, and histopathological results negative for squamous intraepithelial lesion (SIL) in the cervix and a positive HPV test; the subjects will be followed-up for 5 years, period from which 3 years have already elapsed, with yearly studies (colposcopy, cytology, and histopathology diagnosis, along with molecular HPV test, quantification of viral load and of IL-10, IL-4, TGFbeta1, INFgamma, IL-6, and TNFalpha levels, along with the expression of the HR-HPV E6/E7 proteins in the cervix as a viral marker. The outcome will be categorized as viral persistence or clearance; and as SIL persistence, progression, or regression. Binomial and/or multinomial regression models adjusted for potential confounders will be used, associating the relative risk of the outcome with the immune and viral markers evaluated. DISCUSSION: This research will generate knowledge about immune markers with predictive value for the persistence and clearance of HPV, which will improve the triage of positive HPV women and thus reduce the economic burden for the Mexican health system imposed by the management of high-grade SIL and CC cases, which are still detected in late stages. PMID- 30453959 TI - Genomic analyses based on pulmonary adenocarcinoma in situ reveal early lung cancer signature. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) represents more than about 80% of the lung cancer. The early stages of NSCLC can be treated with complete resection with a good prognosis. However, most cases are detected at late stage of the disease. The average survival rate of the patients with invasive lung cancer is only about 4%. Adenocarcinoma in situ (AIS) is an intermediate subtype of lung adenocarcinoma that exhibits early stage growth patterns but can develop into invasion. METHODS: In this study, we used RNA-seq data from normal, AIS, and invasive lung cancer tissues to identify a gene module that represents the distinguishing characteristics of AIS as AIS-specific genes. Two differential expression analysis algorithms were employed to identify the AIS-specific genes. Then, the subset of the best performed AIS-specific genes for the early lung cancer prediction were selected by random forest. Finally, the performances of the early lung cancer prediction were assessed using random forest, support vector machine (SVM) and artificial neural networks (ANNs) on four independent early lung cancer datasets including one tumor-educated blood platelets (TEPs) dataset. RESULTS: Based on the differential expression analysis, 107 AIS-specific genes that consisted of 93 protein-coding genes and 14 long non-coding RNAs (lncRNAs) were identified. The significant functions associated with these genes include angiogenesis and ECM-receptor interaction, which are highly related to cancer development and contribute to the smoking-free lung cancers. Moreover, 12 of the AIS-specific lncRNAs are involved in lung cancer progression by potentially regulating the ECM-receptor interaction pathway. The feature selection by random forest identified 20 of the AIS-specific genes as early stage lung cancer signatures using the dataset obtained from The Cancer Genome Atlas (TCGA) lung adenocarcinoma samples. Of the 20 signatures, two were lncRNAs, BLACAT1 and CTD-2527I21.15 which have been reported to be associated with bladder cancer, colorectal cancer and breast cancer. In blind classification for three independent tissue sample datasets, these signature genes consistently yielded about 98% accuracy for distinguishing early stage lung cancer from normal cases. However, the prediction accuracy for the blood platelets samples was only 64.35% (sensitivity 78.1%, specificity 50.59%, and AUROC 0.747). CONCLUSIONS: The comparison of AIS with normal and invasive tumor revealed diseases-specific genes and offered new insights into the mechanism underlying AIS progression into an invasive tumor. These genes can also serve as the signatures for early diagnosis of lung cancer with high accuracy. The expression profile of gene signatures identified from tissue cancer samples yielded remarkable early cancer prediction for tissues samples, however, relatively lower accuracy for boold platelets samples. PMID- 30453960 TI - Development of mental health indicators at the district level in Madhya Pradesh, India: mixed methods study. AB - BACKGROUND: Strengthening routine information systems for mental health can augment scale up of community mental health services in India and other low- and middle-income countries. Currently little routine data is available in Indian settings. This study aimed to develop a core set of indicators for monitoring mental health care in primary health care settings METHODS: By using a sequential exploratory mixed methods design, key mental health indicators measuring service delivery and system performance were developed for the context of Madhya Pradesh, India. The research design involved a situation analysis, and conducting a prioritisation exercise and consultation workshops with key stakeholders. RESULTS: This study resulted in nine key mental health indicators covering both mental health service delivery indicators and mental health system indicators for Sehore district of Madhya Pradesh. Mean indicator priority scores ranging from 4.48 to 3.78 were reported. CONCLUSIONS: This study demonstrated a phased approach to strengthen routine information systems for mental health at a primary care level in India. We recommend that similar research methods can be applied across comparable settings and these indicators can be adopted as a part of national routine information systems. PMID- 30453962 TI - Correction to: Metformin improved health-related quality of life in ethnic Chinese women with polycystic ovary syndrome. AB - The original article [1] contains a number of statements that the authors would like to be disregarded, noted ahead. PMID- 30453961 TI - The association between paralytic side and health-related quality of life in facial palsy: a cross-sectional study of the Korea National Health and Nutrition Examination Survey (2008-2012). AB - BACKGROUND: Facial palsy is known to have correlations with low level of quality of life. However, little is known about the association between preference based health-related quality of life (HRQoL) and paralytic side of facial palsy. METHODS: This study used Korea National Health and Nutrition Examination Survey (KNHANES, 2008-2012) data, only when the facial palsy examination had been included in the survey contents. Hierarchical regression analyses were used to obtain optimal regression coefficients in the association between paralytic side of the facial palsy and HRQoL measured by EuroQoL-5 Dimension (EQ-5D). We also analyzed the association between the deteriorated domains of EQ-5D and facial palsy in both subgroups by using multiple logistic regression models. RESULTS: We included the data of 28,106 participants aged >=19 years who were examined as facial palsy according to House-Brackmann score and completed EQ-5D questionnaire in KNHANES 2008-2012. The mean EQ-5D score was significantly low and percentages of deteriorated numbers in its domains were significantly high in facial palsy group. CONCLUSIONS: These results show that, after adjusting for confounding variables, left facial palsy is associated with impaired HRQoL compared with right-sided palsy. Among the domains of EQ-5D, only 'self-care' domain was directly affected by the disease in left facial palsy patients. These findings could be used in developing model and conducting analyses of economic evaluation about facial palsy interventions. PMID- 30453963 TI - Association between pterygium, sun exposure, and serum 25-hydroxyvitamin in a nationally representative sample of Korean adults. AB - PURPOSE: Ultraviolet-B (UVB) light exposure is the major risk factor for developing a pterygium, and serum 25-hydroxyvitamin D (25(OH)D) level is an objective measure of UVB light exposure. In this study, we investigated the association between pterygium, sun exposure, and serum 25(OH)D. METHODS: This population-based, cross-sectional study comprised 12,258 adults (aged >=19 years) participating in the fifth annual Korea National Health and Nutrition Examination Survey from 2010 to 2012. The enrolled subjects underwent interviews, clinical examinations, and laboratory investigations. The serum 25(OH)D levels were measured, and pterygium was examined by using a slit lamp. We used three adjusted logistic regression models and selected covariates as potential confounders. RESULTS: The overall prevalence of pterygium was 7.09, and 53.1% of these subjects were women. The prevalence of pterygium was higher in elderly subjects and those who lived at low latitudes. In multivariate analysis with adjustment for confounding factors, subjects with a serum 25(OH)D level > 30 ng/mL, 25-30 ng/mL, and 15-20 ng/mL had an odds ratio (OR) (95% confidence interval [CI]) of 1.565 (1.035-2.366), 1.545 (1.086-2.198), 1.8 (1.358-2.386), and 1.535 (1.216 1.938), respectively, compared to those with a serum 25(OH)D level < 15 ng/mL. Subjects with a daily sun exposure > 5 h had an OR (95% CI) of 1.761 (1.395 2.223) compared to subjects with a daily sun exposure < 2 h. CONCLUSION: The present study provides epidemiological evidence of an association of daily sun exposure and serum 25(OH)D levels with pterygium in a representative Korean population. PMID- 30453964 TI - Gene Ontology-based function prediction of long non-coding RNAs using bi-random walk. AB - BACKGROUND: With the development of sequencing technology, more and more long non coding RNAs (lncRNAs) have been identified. Some lncRNAs have been confirmed that they play an important role in the process of development through the dosage compensation effect, epigenetic regulation, cell differentiation regulation and other aspects. However, the majority of the lncRNAs have not been functionally characterized. Explore the function of lncRNAs and the regulatory network has become a hot research topic currently. METHODS: In the work, a network-based model named BiRWLGO is developed. The ultimate goal is to predict the probable functions for lncRNAs at large scale. The new model starts with building a global network composed of three networks: lncRNA similarity network, lncRNA-protein association network and protein-protein interaction (PPI) network. After that, it utilizes bi-random walk algorithm to explore the similarities between lncRNAs and proteins. Finally, we can annotate an lncRNA with the Gene Ontology (GO) terms according to its neighboring proteins. RESULTS: We compare the performance of BiRWLGO with the state-of-the-art models on a manually annotated lncRNA benchmark with known GO terms. The experimental results assert that BiRWLGO outperforms other methods in terms of both maximum F-measure (Fmax) and coverage. CONCLUSIONS: BiRWLGO is a relatively efficient method to predict the functions of lncRNA. When protein interaction data is integrated, the predictive performance of BiRWLGO gains a great improvement. PMID- 30453965 TI - Translation and validation of the Arabic version of the 5-item Oral health impact profile: OHIP5-Ar. AB - PURPOSE: The aim of this study was to translate and validate an Arabic version of the 5-item Oral Health Impact Profile (OHIP). METHODS: A total of 320 subjects (aged 18 years and above) were consecutively recruited from dental clinics. The self-administered OHIP5-Ar was distributed and the data were collected and analyzed. The dimensionality of the instrument was investigated using confirmatory factor analyses (CFA). Reliability was assessed as the instruments internal consistency using Cronbach's alpha and test-retest-reliability using intraclass correlation coefficient (ICC). Convergent validity was tested by correlation between perceived global oral and general health questions with the latent factor (OHRQoL) using structural equation modelling analysis and with OHIP5-Ar total score using spearman's correlation coefficient. Known-groups validity was tested among groups with known differences and sensitivity to change was also investigated after dental treatments. RESULTS: The OHIP5-Ar was fitted well in the unidimensional model as indicated by the CFA with fit indices (RMSEA: 0.00, SRMR: 0.010, GFI: 0.998, TLI: 1). Cronbach's alpha was 0.78 and the ICC agreement was 0.88. The validity tests indicated satisfactory validity of the instrument and the sensitivity to change of the instrument revealed significant change in the OHIP5-Ar total score after the provision of dental treatments (effect sizes: 0.55-1.49). CONCLUSION: The OHIP5-Ar showed satisfactory psychometric properties among Arabic-speaking population. This instrument is sensitive to the changes of oral health and can be used to measure the OHRQoL with one total score. PMID- 30453966 TI - Knowledge on voluntary medical male circumcision in a low uptake setting in northern Uganda. AB - BACKGROUND: Free VMMC services have been available in Uganda since 2010. However, uptake in Northern Uganda remains disproportionately low. We aimed to determine if this is due to men's insufficient knowledge on VMMC, and if women's knowledge on VMMC has any association with VMMC status of their male sexual partners. METHODS: In this cross sectional study, participants were asked their circumcision status (or that of their male sexual partner for female respondents) and presented with 14 questions on VMMC benefits, procedure, risk, and misconceptions. Chi square tests or fisher exact tests were used to compare circumcision prevalence among those who gave correct responses versus those who failed to and if p < 0.05, the comparison groups were balanced with propensity score weights in modified poisson models to estimate prevalence ratios, PR. RESULTS: A total of 396 men and 50 women were included in the analyses. Circumcision was 42% less prevalent among males who failed to reject the misconception that VMMC reduces sexual performance (PR = 0.58, 95% CI 0.38-0.89, p = 0.012), and less prevalent among male sexual partners of females who failed to reject the same misconception (PR = 0.22, 95% CI = 0.07-0.76, p = 0.016). Circumcision was also 35% less prevalent among male respondents who failed to reject the misconception that VMMC increases a man's desire for more sexual partners i.e. promiscuity (PR = 0.65, 95% CI = 0.46-0.92, p = 0.014). CONCLUSION: Misconceptions regarding change in sexual drive or performance were associated with circumcision status in this population, while knowledge of VMMC benefits, risks and procedure was not. PMID- 30453967 TI - Calcifying nested stromal epithelial tumor of the liver in a patient with Klinefelter syndrome: a case report and review of the literature. AB - BACKGROUND: Calcifying nested stromal epithelial tumor (CNSET) is a primary neoplasm of the liver, characterized by well-demarcated nests consisting of spindle and epithelioid cells with calcification and bone formation. An association of Cushing syndrome with CNSET has drawn attention, but the origin of CNSET has not been clarified. CASE PRESENTATION: We report here the case of a 20 year-old male with Klinefelter syndrome who underwent liver resection for an increasing liver tumor that was pathologically diagnosed with CNSET. He was postoperatively followed up and received several examinations, and recurrences and extrahepatic lymph node metastases were detected on the 64th day after surgery. Chemoembolization and chemotherapy were not effective, leading to tumor progression with development of progressive liver failure, and the patient finally died 164 days after hepatectomy. CONCLUSIONS: This case suggests that an imbalance of hormones affects the genesis and progression of CNSET, and indicates the importance of closely following patients with CNSET by imaging with attention to hepatic recurrence and extrahepatic metastases. PMID- 30453969 TI - MiteFinderII: a novel tool to identify miniature inverted-repeat transposable elements hidden in eukaryotic genomes. AB - BACKGROUND: Miniature inverted-repeat transposable element (MITE) is a type of class II non-autonomous transposable element playing a crucial role in the process of evolution in biology. There is an urgent need to develop bioinformatics tools to effectively identify MITEs on a whole genome-wide scale. However, most of currently existing tools suffer from low ability to deal with large eukaryotic genomes. METHODS: In this paper, we proposed a novel tool MiteFinderII, which was adapted from our previous algorithm MiteFinder, to efficiently detect MITEs from genomics sequences. It has six major steps: (1) build K-mer Index and search for inverted repeats; (2) filtration of inverted repeats with low complexity; (3) merger of inverted repeats; (4) filtration of candidates with low score; (5) selection of final MITE sequences; (6) selection of representative sequences. RESULTS: To test the performance, MiteFinderII and three other existing algorithms were applied to identify MITEs on the whole genome of oryza sativa. Results suggest that MiteFinderII outperforms existing popular tools in terms of both specificity and recall. Additionally, it is much faster and more memory-efficient than other tools in the detection. CONCLUSION: MiteFinderII is an accurate and effective tool to detect MITEs hidden in eukaryotic genomes. The source code is freely accessible at the website: https://github.com/screamer/miteFinder . PMID- 30453968 TI - Cancer incidence in the East Azerbaijan province of Iran in 2015-2016: results of a population-based cancer registry. AB - BACKGROUND: Few countries in the Middle East have a population-based cancer registry, despite a clear need for accurate cancer statistics in this region. We therefore established a registry in the East Azerbaijan province, the sixth largest province in northwestern Iran. METHODS: We actively collected data from 20 counties, 62 cities, and 44 districts for the period between 20th March 2015 and 19th March 2016 (one Iranian solar year). The CanReg5 software was then used to estimate age-standardized incidence rates (ASRs) per 100,000 for all cancers and different cancer types. RESULTS: Data for 11,536 patients were identified, but we only analyzed data for 6655 cases after removing duplicates and non residents. The ASR for all cancers, except non-melanoma skin cancer, was 167.1 per 100,000 males and 125.7 per 100,000 females. The most common cancers in men were stomach (ASR 29.7), colorectal (ASR 18.2), bladder (ASR 17.6), prostate (ASR 17.3), and lung (ASR 15.4) cancers; in women, they were breast (ASR 31.1), colorectal (ASR 13.7), stomach (13.3), thyroid (ASR 7.8), and esophageal (ASR 7.1) cancers. Both the death certificate rate (19.5%) and the microscopic verification rate (65%) indicated that the data for the cancer registry were of reasonable quality. CONCLUSION: The results of the East Azerbaijan Population based Cancer Registry show a high incidence of cancer in this province, especially gastrointestinal cancers. PMID- 30453970 TI - Personalized risk assessment for dynamic transition of gastric neoplasms. AB - BACKGROUND: To develop an individually-tailored dynamic risk assessment model following a multistep, multifactorial process of the Correa's gastric cancer model. METHODS: First, we estimated the state-to-state transition rates following Correa's five-step carcinogenic model and assessed the effect of risk factors, including Helicobacter pylori infection, history of upper gastrointestinal disease, lifestyle, and dietary habits, on the step-by-step transition rates using data from a high-risk population in Matsu Islands, Taiwan. Second, we incorporated information on the gastric cancer carcinogenesis affected by genomic risk factors (including inherited susceptibility and irreversible genomic changes) based on literature to generate a genetic and epigenetic risk assessment model by using a simulated cohort identical to the Matsu population. The combination of conventional and genomic risk factors enables us to develop the personalized transition risk scores and composite scores. RESULTS: The state-by state transition rates per year were 0.0053, 0.7523, 0.1750, and 0.0121 per year from normal mucosa to chronic active gastritis, chronic active gastritis to atrophic gastritis, atrophic gastritis to intestinal metaplasia, and intestinal metaplasia to gastric cancer, respectively. Compared with the median risk group, the most risky decile had a 5.22-fold risk of developing gastric cancer, and the least risky decile around one-twelfth of the risk. The median 10-year risk for gastric cancer incidence was 0.77%. The median lifetime risk for gastric cancer incidence was 5.43%. By decile, the 10-year risk ranged from 0.06 to 4.04% and the lifetime risk ranged from 0.42 to 21.04%. CONCLUSIONS: We demonstrate how to develop a personalized dynamic risk assessment model with the underpinning of Correa's cascade to stratify the population according to their risk for progression to gastric cancer. Such a risk assessment model not only facilitates the development of an individually-tailored preventive strategy with treatment for H. pylori infection and endoscopic screening but also provides short-term and long-term indicators to evaluate the program effectiveness. PMID- 30453971 TI - Parametric assumptions equate to hidden observations: comparing the efficiency of nonparametric and parametric models for estimating time to AIDS or death in a cohort of HIV-positive women. AB - BACKGROUND: When conducting a survival analysis, researchers might consider two broad classes of models: nonparametric models and parametric models. While nonparametric models are more flexible because they make few assumptions regarding the shape of the data distribution, parametric models are more efficient. Here we sought to make concrete the difference in efficiency between these two model types using effective sample size. METHODS: We compared cumulative risk of AIDS or death estimated using four survival models - nonparametric, generalized gamma, Weibull, and exponential - and data from 1164 HIV patients who were alive and AIDS-free in 1995. We added pseudo-observations to the sample until the spread of the 95% confidence limits for the nonparametric model became less than that for the parametric models. RESULTS: We found the 3 parameter generalized gamma to be a good fit to the nonparametric risk curve, but the 1-parameter exponential both underestimated and overestimated the risk at different times. Using two year-risk as an example, we had to add 354, 593, and 3960 observations for the nonparametric model to be as efficient as the generalized gamma, Weibull, and exponential models, respectively. CONCLUSIONS: These added observations represent the hidden observations underlying the efficiency gained through parametric model form assumptions. If the model is correctly specified, the efficiency gain may be justified, as appeared to be the case for the generalized gamma model. Otherwise, precision will be improved, but at the cost of specification bias, as was the case for the exponential model. PMID- 30453972 TI - Long-term outcomes following first short-term clinically important deterioration in COPD. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by varying trajectories of decline. Information regarding the prognostic value of preventing short-term clinically important deterioration (CID) in lung function, health status, or first moderate/severe exacerbation as a composite endpoint of worsening is needed. We evaluated post hoc the link between early CID and long term adverse outcomes. METHODS: CID was defined as >=100 mL decrease in forced expiratory volume in 1 s (FEV1), >=4-unit increase in St George's Respiratory Questionnaire (SGRQ) score from baseline, and/or a moderate/severe exacerbation during enrollment in two 3-year studies. Presence of CID was assessed at 6 months for the principal analysis (TORCH) and 12 months for the confirmatory analysis (ECLIPSE). Association between presence (+) or absence (-) of CID and long-term deterioration in FEV1, SGRQ, future risk of exacerbations, and all-cause mortality was assessed. RESULTS: In total, 2870 (54%; TORCH) and 1442 (73%; ECLIPSE) patients were CID+. At 36 months, in TORCH, CID+ patients (vs CID-) had sustained clinically significant worsening of FEV1 (- 117 mL; 95% confidence interval [CI]: - 134, - 100 mL; P < 0.001) and SGRQ score (+ 6.42 units; 95% CI: 5.40, 7.45; P < 0.001), and had higher risk of exacerbations (hazard ratio [HR]: 1.61 [95% CI: 1.50, 1.72]; P < 0.001) and all-cause mortality (HR: 1.41 [95% CI: 1.15, 1.72]; P < 0.001). Similar risks post-CID were observed in ECLIPSE. CONCLUSIONS: A CID within 6-12 months of follow-up was consistently associated with increased long-term risk of exacerbations and all-cause mortality, and predicted sustained meaningful loss in FEV1 and health status amongst survivors. TRIAL REGISTRATION: NCT00268216 ; NCT00292552 . PMID- 30453973 TI - Correction to: Mapping a Plasmodium transmission spatial suitability index in Solomon Islands: a malaria monitoring and control tool. AB - Following publication of the original article [1], one of the authors flagged that the images for Figs. 2 and 3 were swapped in the published article-Fig. 2 had the image meant for Fig. 3 and vice versa. PMID- 30453974 TI - Changing places to study short-term effects of air pollution on cardiovascular health: a panel study. AB - BACKGROUND: Short-term exposure to ambient air pollution triggers acute cardiovascular events. Here, we evaluate the association of exposure to ambient air pollution with two intermediate cardiovascular endpoints: blood pressure and carotid stiffness. METHODS: In a one-year panel study, we included 20 healthy volunteers (10 male-female couples aged 59-75 years) with air pollution and health parameters measured every two months at their region of residence (Leuven, Belgium) and twice during two ten-day periods in two locations, one with higher (Milan, Italy) and one with lower (Vindeln, Sweden) air pollution levels (220 observations). We measured blood pressure, carotid arterial stiffness, personal exposure to NO2, and ambient concentrations of PM10, PM2.5, and NO2. We used linear mixed models to evaluate the associations between the health outcomes and the air pollutants. RESULTS: Compared with Leuven, exposure to pollutants was higher in Milan and lower in Vindeln, with the highest contrast for NO2 (median 20.7 MUg/m3 (IQR:7.4) vs 65.1 MUg/m3 (9.0) and 4.5 mg/m3 (0.8), respectively). We did not observe significant associations between either systolic or diastolic blood pressure and variations in air pollution. However, we found significant associations between arterial stiffness and 5 day average exposure to the studied pollutants. The strongest associations were observed for PM10 with carotid distensibility (DC) and compliance (CC) coefficients, and the young elastic modulus (YEM): 4.3% (95%CI:7.0;1.5) increase in DC, 4.7% (95%CI:7.1;2.3) increase in CC and 4.2% (95%CI:1.1;7.3) decrease in YEM for each 10 MUg/m3 decreases in PM10. CONCLUSIONS: Our study suggests that short-term exposure to air pollution results in reductions in carotid elasticity among elderly population. PMID- 30453975 TI - Speckle tracking echocardiography analyses of myocardial contraction efficiency predict response for cardiac resynchronization therapy. AB - BACKGROUND: In patients with left ventricular (LV) dysssynchrony, contraction that doesn't fall into ejection period (LVEj) results in a waste of energy due to inappropriate contraction timing, which was now widely treated by cardiac resynchronization therapy(CRT). Myocardial Contraction Efficiency was defined as the ratio of Efficient Contraction Time (ECTR) and amplitude of efficient contraction (ECR) during LVEj against that in the entire cardiac cycle. This study prospectively investigated whether efficiency indexes could predict CRT outcome. METHODS: Our prospective pilot study including 70 CRT candidates, parameters of myocardial contraction timing and contractility were measured by speckle tracking echocardiography (STE) and efficiency indexes were calculated accordingly at baseline and at 6-month follow-up. Primary outcome events were predefined as death or HF hospitalization, and secondary outcome events were defined as all-cause death during the follow-up. 16-segement Standard deviation of time to onset strain (TTO-16SD) and time to peak strain (TTP-16SD) were included as the dyssynchrony indexes. RESULTS: According to LV end systolic volume (LVESV) and LV eject fraction(LVEF) values at 6-month follow-up, subjects were classified into responder and non-responder groups, ECR (OR 0.87, 95%CI 0.78 0.97, P < 0.05) and maximum longitudinal strain (MLS) (OR 2.22, 95%CI 1.36-3.61, P < 0.01) were the two independent predictors for CRT response, Both TTO-16SD and TTP-16SD failed to predict outcome. Patients with poorer myocardial contraction efficiency and better contractility are more likely to benefit from CRT. CONCLUSIONS: STE can evaluate left ventricular contraction efficiency and contractility to predict CRT response. When analyzing myocardial strain by STE, contraction during LVEj should be highlighted. PMID- 30453976 TI - Engineering of CYP76AH15 can improve activity and specificity towards forskolin biosynthesis in yeast. AB - BACKGROUND: Forskolin is a high-value diterpenoid produced exclusively by the Lamiaceae plant Coleus forskohlii. Today forskolin is used pharmaceutically for its adenyl-cyclase activating properties. The limited availability of pure forskolin is currently hindering its full utilization, thus a new environmentally friendly, scalable and sustainable strategy is needed for forskolin production. Recently, the entire biosynthetic pathway leading to forskolin was elucidated. The key steps of the pathway are catalyzed by cytochrome P450 enzymes (CYPs), which have been shown to be the limiting steps of the pathway. Here we study whether protein engineering of the substrate recognition sites (SRSs) of CYPs can improve their efficiency towards forskolin biosynthesis in yeast. RESULTS: As a proof of concept, we engineered the enzyme responsible for the first putative oxygenation step of the forskolin pathway: the conversion of 13R-manoyl oxide to 11-oxo-13R-manoyl oxide, catalyzed by the CYP76AH15. Four CYP76AH15 variants engineered in the SRS regions-yielded at least a twofold increase of 11-oxo-13R manoyl oxide when expressed in yeast cells grown in microtiter plates. The highest titers (5.6-fold increase) were observed with the variant A99I, mutated in the SRS1 region. Double or triple CYP76AH15 mutant variants resulted in additional enzymes with optimized performances. Moreover, in planta CYP76AH15 can synthesize ferruginol from miltiradiene. In this work, we showed that the mutants affecting 11-oxo-13R-manoyl oxide synthesis, do not affect ferruginol production, and vice versa. The best performing variant, A99I, was utilized to reconstruct the forskolin biosynthetic pathway in yeast cells. Although these strains showed increased 11-oxo-manoyl oxide production and higher accumulation of other pathway intermediates compared to the native CYP76AH15, lower production of forskolin was observed. CONCLUSIONS: As demonstrated for CYP76AH15, site-directed mutagenesis of SRS regions of plant CYPs may be an efficient and targeted approach to increase the performance of these enzymes. Although in this work we have managed to achieve higher efficiency and specificity of the first CYP of the pathway, further work is necessary in order to increase the overall production of forskolin in yeast cells. PMID- 30453977 TI - Extent and nature of dual practice engagement among Iran medical specialists. AB - BACKGROUND: Dual practice (DP) by medical specialists is a widespread issue across health systems. This study aims to determine the level of DP engagement among Iran's specialists. METHODS: A pre-structured form was developed to collect the data about medical specialists worked in all 925 Iran hospitals in 2016. The forms were sent to the hospitals via medical universities in each province. The data were merged at the national level and matched using medical council ID codes, national ID codes, and eventually a combination of the first name, surname, and father's name. RESULTS: A total of 48 345 records were collected for 30 273 specialists from 858 (93%) hospitals out of total 925 hospitals. Sixteen thousand eight hundred forty-nine (69% of) specialists were non-faculty members and 6317 (26% of) specialists were employed on a contract basis. Eleven thousand six hundred and thirty-eight (47.7% of) specialists were engaged in DP on total. Female specialists had 0.78 times less DP chance; faculties compared to non faculties had 0.65 times more DP chance and full-time geographic specialists compared to non-full-time specialists had 0.15 times more DP chance. DP was more frequent in specialists with higher age and more job experience and in provinces with more population, deprivation, and higher number of specialists per facility (P < 0.05). CONCLUSIONS: The level of DP is relatively high among Iran medical specialists, especially in geographic full-time specialists. However, they are totally banned and they receive extra payment for being full-time; restrictive regulations and financial incentives without considering other factors might not eliminate DP in specialists and it should be addressed based on conditions of each country and regions inside the country. PMID- 30453978 TI - Comparing assessment of diabetes-related quality of life between patients and their physicians. AB - BACKGROUND: Health-related quality of life (QoL) is a comprehensive, multidimensional construct encompassing physical and psychosocial wellbeing. Physicians frequently assess QoL as part of their decision making process without specifically asking their patients. This study examined the degree and predictors of concordance between physician and patient assessments of QoL among patients with diabetes in primary care and in multi-disciplinary diabetes clinics. METHODS: Patients completed a questionnaire regarding overall and diabetes specific QoL before entering their physician's office. After the visit, the physician completed the same questionnaire in order to evaluate how he/she perceived that patient's QoL. In addition, medical data relating to the patient's health status were collected from the medical records. The concordance between patient-reported QoL and physician-estimated QoL was evaluated. Stepwise regression analysis was conducted to determine which factors contributed to the difference between physicians' and patients' assessment of QoL. RESULTS: A total of 136 patients and 39 treating physicians were surveyed. Patients' response rate was 95%. A strong concordance was found between patients' and physicians' ratings of current health status (r = 0.79, p < 0. 01); however, physicians perceived their patients' QoL as worse than the QoL assessed by the patients themselves. Primary care physicians were better at assessing their patients' overall wellbeing while diabetes-specialists were better at assessing their patients' diabetes-specific QoL. In addition, the longer the duration of diabetes, the more difficult is was for the physicians to accurately assess QoL. When entered in the regression analysis, familiarity did not explain physicians' ability to assess health-related QoL or diabetes-specific QoL. CONCLUSIONS: Physicians make reasonable assessments of their patients' QoL, however as the patients' disease progresses, it becomes harder for physicians to assess QoL. Primary care physicians are better at assessing overall well-being whereas diabetes specialists are better at assessing diabetes-specific QoL. TRIAL REGISTRATION NUMBER: Not registered. Assuta Medical Center institutional review board approval number 2009103. PMID- 30453979 TI - "His mind will work better with both of us": a qualitative study on fathers' roles and coparenting of young children in rural Pakistan. AB - BACKGROUND: Parents are the primary providers of nurturing care for young children's healthy early development. However, the literature on parenting in early childhood, especially in low- and middle-income countries, has primarily focused on mothers. In this study, we investigate how parents make meaning of fathers' parenting roles with regards to their young children's early health and development in rural Pakistan. METHODS: Data were collected between January and March 2017 through in-depth interviews with fathers (N = 33) and their partners (N = 32); as well as separate focus group discussions with fathers (N = 7) and mothers (N = 7). Data were analyzed using thematic content analysis. RESULTS: Parents described a distinct division of roles between fathers and mothers; and also several shared caregiving roles of fathers and mothers. Specifically, parents highlighted aspects of fathers' coparenting and several common ways by which fathers supported their partners. We found that these gendered divisions in parenting roles were strongly embedded within a complex network of interacting factors across the individual, family, and sociocultural contexts of the study community. CONCLUSIONS: Our findings suggest a more family-centered conceptualization of fatherhood during early childhood that encompasses both fathers' direct engagement with their young children and their indirect contributions through coparenting, while recognizing a variety of contextual systems that shape paternal parenting. Future parenting interventions that reflect the lived experiences of both fathers and mothers as parents and partners may further enhance the nurturing care environments that are critical for promoting healthy early child development. PMID- 30453980 TI - Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling. AB - BACKGROUND: Work-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). The molecular mechanisms leading to the development of PH and lung fibrosis in response to silica are not well understood. Oxidant/antioxidant imbalance in the lung may promote fibroproliferation and vascular smooth muscle proliferation, ultimately leading to the development of PH. Herein, we analyze the development of PH and lung fibrosis in mice deficient in extracellular superoxide dismutase (SOD3), an enzyme with anti-oxidant activity. METHODS: PH and silicosis were induced in wild-type and Sod3-/- mice through intratracheal injection of crystalline silica at dose 0.4 g/kg. Pulmonary hypertension and lung fibrosis were characterized by changes in right ventricular systolic pressure (RVSP) and collagen deposition 28 days following silica injections. Vascular remodeling was analyzed using immunohistochemistry and morphometric analysis. The expression of genes were analyzed using qRT-PCR and Western blot. RESULTS: C57BL6 mice exposed to silica showed attenuated expression of Sod3 in the lung suggesting a protective role for Sod3. Consistent with this, Sod3-/- mice developed more severe fibrotic inflammatory nodules with increased collagen deposition. Furthermore, the expression of genes involved in tissue remodeling (Timp1), fibrotic lesion formation (Fsp1) and inflammatory response (Mcp1) were significantly elevated in Sod3-/- mice compared to Sod3+/+ mice treated with silica. Infiltration of neutrophils and activated macrophages into affected lung was significantly higher in Sod3 deficient mice. In addition, silica produced more profound effects on elevation of RVSP in Sod3-/- compared to wild-type littermate. Increase in RVSP was concomitant with hypertrophy of pulmonary arteries located in silicotic nodules of both mouse strains, however, vascular remodeling in unaffected areas of lung was detected only in Sod3-/- mice. CONCLUSIONS: Our data suggest that Sod3 and extracellular oxidative stress may play an important role in the development of pneumoconiosis and pulmonary vascular remodeling following exposure to environmental and occupational silica. PMID- 30453982 TI - Roll Back Malaria: an historical footnote. AB - Prompted by the 20th anniversary of Roll Back Malaria, the author recalls hypotheses concerning a major new initiative to control malaria in Africa put forward by WHO AFRO and the World Bank in 1996. These hypotheses, and the reactions to them of a panel of 18 experts, are reviewed and contrasted to the rapid progress and high ambition that characterize the field of malaria today. PMID- 30453981 TI - Patient-reported outcomes from a randomized phase II study of the deferasirox film-coated tablet in patients with transfusion-dependent anemias. AB - BACKGROUND: Adherence to long-term chelation therapy in transfusion-dependent patients is critical to prevent iron overload-related complications. Once-daily deferasirox dispersible tablets (DT) have proven long-term efficacy and safety in patients >=2 years old with chronic transfusional iron overload. However, barriers to optimal adherence remain, including palatability, preparation time, and requirements for fasting state. A new film-coated tablet (FCT) formulation was developed, swallowed once daily (whole/crushed) with/without a light meal. METHODS: The open-label, Phase II ECLIPSE study evaluated patient-reported outcomes (PROs) in transfusion-dependent thalassemia or lower-risk myelodysplastic syndromes patients randomized 1:1 to receive deferasirox DT or FCT over 24 weeks as a secondary outcome of the study. Three PRO questionnaires were developed to evaluate both deferasirox formulations: 1) Modified Satisfaction with Iron Chelation Therapy Questionnaire; 2) Palatability Questionnaire; 3) Gastrointestinal (GI) Symptom Diary. RESULTS: One hundred seventy three patients were enrolled; 87 received the FCT and 86 the DT formulation. FCT recipients consistently reported better adherence (easier to take medication, less bothered by time to prepare medication and waiting time before eating), greater satisfaction/preference (general satisfaction and with administration of medicine), and fewer concerns (less worry about not swallowing enough medication, fewer limitations in daily activities, less concern about side effects). FCT recipients reported no taste or aftertaste and could swallow all their medicine with an acceptable amount of liquid. GI summary scores were low for both formulations. CONCLUSIONS: These findings suggest a preference in favor of the deferasirox FCT formulation regardless of underlying disease or age group. Better patient satisfaction and adherence to chelation therapy may reduce iron overload-related complications. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02125877; registered April 26, 2014. PMID- 30453983 TI - New remote centre of motion mechanism for robot-assisted minimally invasive surgery. AB - BACKGROUND: Robot-assisted minimally invasive surgery (RMIS) is promising for improving surgical accuracy and dexterity. As the end effector of the robotic arm, the remote centre of motion mechanism is one of the requisite terms for guaranteeing patient safety. The existing remote centre of motion mechanisms are complex and large in volume, as well as high assembly requirement and unsatisfactory precise. This paper aimed to present a new remote centre of motion mechanism for solving these problems. METHODS: A new mechanism based on the RMIS requirements is proposed for holding the laparoscope and generating a remote centre of motion for the laparoscope. The mechanism kinematics is then analysed from the perspective of the structural function, and its inverse kinematics is determined with a small number of calculations. Finally, the position deviation of the laparoscope rotational point is chosen as the index to evaluate the mechanism performance. The experiments are performed to test the deviation. RESULTS: The position deviations of the laparoscope rotational point do not exceed 2 mm, which is lower than that of the existing remote centre of motion mechanism. The 2 mm positioning error of the laparoscope won't affect surgeon observation of the surgical field, and the pressure caused by the positioning error was acceptable for the skin elasticity. The proposed mechanism meets the RMIS requirement. CONCLUSIONS: The proposed mechanism can achieve the remote centre of motion for the laparoscope. Its simple and compact structure is beneficial to avoid the collision of robotic arms, and it can be applied on other robots for providing the instrument necessary motion in minimally invasive surgery. PMID- 30453984 TI - Long-term performance of an external stent for saphenous vein grafts: the VEST IV trial. AB - BACKGROUND: Externally stenting saphenous vein grafts reduces intimal hyperplasia, improves lumen uniformity and reduces oscillatory shear stress 1 year following surgery. The present study is the first to present the longer-term (4.5 years) performance and biomechanical effects of externally stented saphenous vein grafts. METHODS: Thirty patients previously implanted with the VEST external stent in the randomized, within-patient-controlled VEST I study were followed up for adverse events; 21 of these were available to undergo coronary angiography and intravascular ultrasound. RESULTS: Twenty-one stented and 29 nonstented saphenous vein grafts were evaluated by angiography and ultrasound at 4.5 +/- 0.3 years. Vein graft failure rates were comparable between stented and nonstented grafts (30 and 23% respectively; p = 0.42). All failures were apparent at 1 year except for one additional nonstented failure at 4.5 years. In patent vein grafts, Fitzgibbon perfect patency remained significantly higher in the stented versus nonstented vein grafts (81 and 48% respectively, p = 0.002), while intimal hyperplasia area (4.27 mm2 +/- 1.27 mm2 and 5.23 mm2 +/- 1.83 mm2 respectively, p < 0.001) and thickness (0.36 mm +/- 0.09 mm and 0.42 mm +/- 0.11 mm respectively, p < 0.001) were significantly reduced. Intimal hyperplasia proliferation correlated with lumen uniformity and with the distance between the stent and the lumen (p = 0.04 and p < 0.001 respectively). CONCLUSIONS: External stenting mitigates saphenous vein graft remodeling and significantly reduces diffuse intimal hyperplasia and the development of lumen irregularities 4.5 years after coronary artery bypass surgery. Close conformity of the stent to the vessel wall appears to be an important factor. TRIAL REGISTRATION: NCT01415245 . Registered 11 August 2011. PMID- 30453985 TI - Optimal position of lipped acetabular liners to improve stability in total hip arthroplasty-an intraoperative in vivo study. AB - BACKGROUND: Lipped or elevated acetabular liners are frequently used in total hip arthroplasty to improve stability. However, the optimal position of the lip is not known. The purpose of this study was to determine the optimal position of lipped acetabular liners in total hip arthroplasty performed with a posterior approach. METHODS: In 14 hips, lipped trial liners were placed intraoperatively in various positions around the posterior clock-face of the implanted acetabular shell component. For each liner position, stability of the hip was tested at maximal hip flexion with gradually increasing internal rotation until subluxation occurred, at which point the position of the hip was measured using smartphone accelerometer-based goniometers. Smartphone goniometers were first validated against a computer-assisted navigation system. Post-operative radiographs were analyzed for cup inclination angle, cup anteversion angle, and femoral offset. RESULTS: Mean cup inclination angle in our series was 31 degrees +/- 6 degrees . The most common liner position that imparted the greatest stability to posterior subluxation was posteriorly and inferiorly (4 o'clock position for left hip, or 8 o'clock position for right hip). The range for most stable liner position for different patients varied from postero-superior (11 o'clock/1 o'clock position) to directly inferior (6 o'clock position). Comparing a non-lipped liner to a lipped liner placed in the optimal position, the average difference in internal rotation gained before dislocation was 23 degrees . There was no association between cup inclination or anteversion angle with liner position of greatest stability. CONCLUSION: In hip replacements performed through a posterior approach and with mean cup inclination angle of 31 degrees +/- 6 degrees , placing the lip of the elevated liner in the postero-inferior quadrant may impart more stability than in the postero-superior quadrant. PMID- 30453986 TI - Expanding behavior pattern sensitivity analysis with model selection and survival analysis. AB - BACKGROUND: Sensitivity analysis is an essential step in mathematical modeling because it identifies parameters with a strong influence on model output, due to natural variation or uncertainty in the parameter values. Recently behavior pattern sensitivity analysis has been suggested as a method for sensitivity analyses on models with more than one mode of output behavior. The model output is classified by behavior mode and several behavior pattern measures, defined by the researcher, are calculated for each behavior mode. Significant associations between model inputs and outputs are identified by building linear regression models with the model parameters as independent variables and the behavior pattern measures as the dependent variables. We applied the behavior pattern sensitivity analysis to a mathematical model of tetracycline-resistant enteric bacteria in beef cattle administered chlortetracycline orally. The model included 29 parameters related to bacterial population dynamics, chlortetracycline pharmacokinetics and pharmacodynamics. The prevalence of enteric resistance during and after chlortetracycline administration was the model output. Cox proportional hazard models were used when linear regression assumptions were not met. RESULTS: We have expanded the behavior pattern sensitivity analysis procedure by incorporating model selection techniques to produce parsimonious linear regression models that efficiently prioritize input parameters. We also demonstrate how to address common violations of linear regression model assumptions. Finally, we explore the semi-parametric Cox proportional hazards model as an alternative to linear regression for situations with censored data. In the example mathematical model, the resistant bacteria exhibited three behaviors during the simulation period: (1) increasing, (2) decreasing, and (3) increasing during antimicrobial therapy and decreasing after therapy ceases. The behavior pattern sensitivity analysis identified bacterial population parameters as high importance in determining the trajectory of the resistant bacteria population. CONCLUSIONS: Interventions aimed at the enteric bacterial population ecology, such as diet changes, may be effective at reducing the prevalence of tetracycline-resistant enteric bacteria in beef cattle. Behavior pattern sensitivity analysis is a useful and flexible tool for conducting a sensitivity analysis on models with varied output behavior, enabling prioritization of input parameters via regression model selection techniques. Cox proportional hazard models are an alternative to linear regression when behavior pattern measures are censored or linear regression assumptions cannot be met. PMID- 30453987 TI - Computational prediction of inter-species relationships through omics data analysis and machine learning. AB - BACKGROUND: Antibiotic resistance and its rapid dissemination around the world threaten the efficacy of currently-used medical treatments and call for novel, innovative approaches to manage multi-drug resistant infections. Phage therapy, i.e., the use of viruses (phages) to specifically infect and kill bacteria during their life cycle, is one of the most promising alternatives to antibiotics. It is based on the correct matching between a target pathogenic bacteria and the therapeutic phage. Nevertheless, correctly matching them is a major challenge. Currently, there is no systematic method to efficiently predict whether phage bacterium interactions exist and these pairs must be empirically tested in laboratory. Herein, we present our approach for developing a computational model able to predict whether a given phage-bacterium pair can interact based on their genome. RESULTS: Based on public data from GenBank and phagesDB.org, we collected more than a thousand positive phage-bacterium interactions with their complete genomes. In addition, we generated putative negative (i.e., non-interacting) pairs. We extracted, from the collected genomes, a set of informative features based on the distribution of predictive protein-protein interactions and on their primary structure (e.g. amino-acid frequency, molecular weight and chemical composition of each protein). With these features, we generated multiple candidate datasets to train our algorithms. On this base, we built predictive models exhibiting predictive performance of around 90% in terms of F1-score, sensitivity, specificity, and accuracy, obtained on the test set with 10-fold cross-validation. CONCLUSION: These promising results reinforce the hypothesis that machine learning techniques may produce highly-predictive models accelerating the search of interacting phage-bacteria pairs. PMID- 30453988 TI - Suppressor of cytokine signaling (SOCS) genes are downregulated in breast cancer. AB - BACKGROUND: The suppressor of cytokine signaling (SOCS) family of proteins are inhibitors of the cytokine-activated Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway. We aimed at evaluation of expression of SOCS genes in breast cancer. METHODS: We evaluated expression of SOCS1-3 and SOCS5 genes in breast cancer samples compared with the corresponding adjacent non-cancerous tissues (ANCTs). RESULTS: All assessed SOCS genes were significantly downregulated in tumoral tissues compared with ANCTs. SOCS1 and SOCS2 genes were significantly overexpressed in higher grade samples, but SOCS3 had the opposite trend. Significant correlations were found between expression levels of SOCS genes. The SOCS1 and SOCS2 expression levels had the best specificity and sensitivity values respectively for breast cancer diagnosis. CONCLUSION: The current study provides further evidence for contribution of SOCS genes in breast cancer. PMID- 30453989 TI - Preoperative determinants of quality of life a year after coronary artery bypass grafting: a historical cohort study. AB - BACKGROUND: Health related quality of life (HRQL) is an important patient related outcome measure after cardiac surgery. Preoperative determinants for postoperative HRQL have not yet been identified, but could aid in preoperative decision making. The aim of this article is to identify associations between preoperative determinants and change in HRQL 1 year after coronary artery bypass grafting (CABG). METHODS: Single centre retrospective cohort study in 658 patients. Change in HRQL was defined as a decrease or increase of >=5 points on the physical or mental domain of the Short Form 12 (SF-12) questionnaire. Patients were stratified in three groups according to worse, unchanged, or better HRQL. Multinomial logistic regression analysis was used to investigate the association between preoperative risk factors and postoperative change in HRQL. RESULTS: Physical HRQL improved in 22.8% of patients, did not change in 61.2% of patients and worsened in 16.0% of patients. Comorbidities associated with change in physical HRQL were a history of stroke, atrial fibrillation, vascular disease or pulmonary disease. Most important risk factor for change in physical HRQL was preoperative HRQL. Higher preoperative SF-12 score decreased the odds for worse physical HRQL and increased the odds for better physical HRQL. Mental HRQL improved in 49.8% of patients, remained unchanged in 34.5% of patients and worsened in 15.7% of patients. Preoperative HRQL was an important risk factor for a change in mental HRQL. Higher preoperative physical HRQL increased the odds for improved mental HRQL. Lower preoperative mental HRQL increased the odds for better mental HRQL. CONCLUSIONS: One year after CABG the majority of patients experiences equal or improved HRQL compared to before surgery. Most important preoperative risk factor for change in HRQL is preoperative HRQL. PMID- 30453991 TI - Comparing time and motion methods to study personnel time in the context of a family planning supply chain intervention in Senegal. AB - BACKGROUND: A family planning (FP) supply chain intervention was introduced in Senegal in 2012 to reduce contraceptive stock-outs. Labour is the highest cost in low- and middle-income country supply chains. In this paper, we (1) understand time use of personnel working in the FP supply chain at health facilities in Senegal, (2) estimate the validity of self-administered timesheets (STs) relative to continuous observations (COs), and (3) describe the cost of data collection for each method. METHODS: We collected time use data for seven stockroom managers in six facilities using both ST and CO. Activities were categorized as follows: stock management associated with FP, non-FP stock management, other productive activities, non-productive activities, and waiting time. Paired t tests were used to compare the mean differences between the two methods in all categories and in productive time alone. RESULTS: Among all activities, the absolute and relative time spent on productive activities was higher when estimated by ST compared to CO. Conversely, waiting time was underestimated by STs. There was no difference in the relative time spent on non-productive activities. When comparing the distribution of the three productive activity categories, we found no evidence of a difference in relative time percentage estimates between CO and ST (FP stockroom management - 3.0%, 95% CI - 7.4 to 1.4%; non-FP stockroom management 3.4%, 95% CI - 2.8 to 9.6%; and other productive activities - 0.1%, 95% CI - 6.3 to 6.0%). Data collection costs for CO are 140% more than ST. CONCLUSION: STs were not a reliable method for measuring absolute labour time at health facilities in Senegal due to considerable underestimates of time waiting for clients. However, ST had acceptable reliability when examining distribution of productive time. Although CO provides more accurate absolute time estimates, the unit costs for data collection using this method are more than triple those for STs in Senegal. PMID- 30453990 TI - Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia. AB - BACKGROUND: The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-gamma-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. METHODS: Il18 /- male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18+/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. RESULTS: Compared with Il18+/+ mice, BAT of Il18-/- mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5-expressing adipose precursor cells were extracted from Il18+/+ and Il18 /- mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18-/- BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18+/+ and Il18-/- mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the 'Quantity of adipocytes' identified three associated genes, apolipoprotein C3 (Apoc3), insulin induced gene 1 (Insig1) and vitamin D (1,25-dihydroxyvitamin D3) receptor (Vdr). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes' size. CONCLUSIONS: This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance. PMID- 30453992 TI - The quality of life when a partner has substance use problems: a scoping review. AB - OBJECTIVE: To examine the existing body of knowledge on quality of life (QoL) in partners of people with substance use problems (PP-SUPs) to provide a synthesized summary of the evidence and identify gaps in our knowledge on the QoL of PP-SUPs. METHODS: A systematic scoping review was performed. Publications indexed in EMBASE, Medline, PsycINFO, CINAHL, SocINDEX, and CENTRAL were searched for original, empirical, peer-reviewed, full-length research papers that examined QoL in PP-SUPs. Research papers identified through a manual search of key references and known references by co-authors were also included. A total of 3070 abstracts were screened, 41 full-text papers examined, and nine were found to meet the inclusion criteria. Eligibility was determined in two steps by four and two independent researchers, respectively. The main findings were explored by content analysis. RESULTS: Eight of the nine included studies had quantitative designs, one had a mixed methods design, and no qualitative studies were found. Three studies were conducted exclusively among PP-SUPs, whereas the others included various subgroups. A majority of participants were women, and no study was conducted exclusively among men. Nearly half of the studies reported on whether there were minor children in the PP-SUPs' household. The studies used established and generic QoL instruments based on different conceptual and theoretical perspectives on QoL. A majority of the studies found lower QoL in PP-SUPs than in general population, with substance use by the person with a SUP having the most impact on QoL of all evaluated factors. Two studies reported that gender was associated with QoL, with poor QoL being associated with being a male partner and vice versa for female partners. CONCLUSIONS: Further research is needed to examine QoL in PP-SUPs exclusively. A variety of QoL instruments covering various, but limited, dimensions of the concept have been used in previous studies of PP-SUPs. Thus, obtaining a comprehensive understanding of PP-SUPs' QoL is challenging. Both qualitative and large-scale quantitative designs should be used in research on QoL in PP-SUPs, particularly among those with a parenting role. PMID- 30453993 TI - Escalated radiation and prophylactic extended field nodal irradiation are beneficial for FIGO IIIB cervical cancer patients' prognosis. AB - BACKGROUND: Currently, the standard treatment for locally advanced cervical cancer patients is concurrent chemoradiotherapy. Here we aim to evaluate therapeutic efficacy, treatment failure, toxicity and prognostic factors for FIGO IIIB cervical cancer patients. METHODS: A comprehensive retrospective analysis was performed to understand various factors which contribute to IIIB cervical cancer prognosis. In total 223 well defined patients were assigned according to their pathological subtype, age, pre-treatment HGB level, tumor size, pelvic lymph node (LN) metastasis, para-aortic LN metastasis as well as external irradiation technologies, treatment duration, point A EQD2 dose and concurrent chemotherapy cycles. We then performed correlation studies of these factors and OS, DFS, LCR, DMFS using univariate and multivariate analysis respectively. RESULTS: We managed to achieve 207 (92.8%) complete response (CR) and 16 (7.2%) partial response (PR) with acceptable adverse effects. Notably, the 5 years OS, DFS, LCR, DMFS for these patients were 61.1, 55.2, 83.6 and 66.4% respectively. Importantly, our studies suggest that escalated point A EQD2 can significantly improve OS, DFS and LCR for FIGO IIIB cervical cancer patients, furthermore, patients without para-aortic LN metastasis who received prophylactic extended field irradiation have significant survival advantage for DFS and a tendency to improve OS and DMFS. CONCLUSIONS: Our results suggest that FIGO IIIB cervical cancer patients should receive higher EQD2 (>=98Gy10) radiotherapy, moreover, patients without para-aortic LN metastasis should receive prophylactic extended field nodal irradiation to improve prognosis. PMID- 30453994 TI - NLRC5: potential novel non-invasive biomarker for predicting and reflecting the progression of IgA nephritis. AB - BACKGROUND: The nucleotide oligomerization domain-like receptor subfamily C5 (NLRC5) is primarily expressed in the adaptive and innate immune systems. NLRC5 was recently discovered to regulate immunity and inflammatory responses. Abnormal immune and inflammatory responses are considered critical pathogenesis in IgA nephritis (IgAN). However, the role of NLRC5 in IgAN is unknown. We previously showed that NLRC5 can be detected in patients with IgAN; herein, we further examined the pathophysiological significance of NLRC5 in the serum and renal deposits of patients with IgAN. This study is the first to find that NLRC5 is closely correlated with IgAN. METHODS: IgAN patients (n = 50) who were diagnosed by renal biopsy provided blood and renal biopsy tissue, and age-matched healthy control subjects (blood donators n = 22; tissue donators n = 5) were included. Renal biopsies were diagnosed, and blood biochemical parameters were tested. Serum creatinine, urea, proteinuria, haematuria, albumin, and immunoglobulin A levels were recorded. Serum NLRC5 concentrations were detected by enzyme-linked immunosorbent assay, and tissue NLRC5 expression in kidney tissue was detected by immunohistochemical analysis. ROC curve analysis was used to evaluate the diagnostic value of the serum NLRC5 concentration in IgAN. RESULTS: Serum NLRC5 concentration was significantly decreased in the IgAN group compared to that in the healthy control group (P < 0.0001), especially in S1 (Oxford classification) patients (P < 0.0001). Furthermore, serum NLRC5 concentration had a negative correlation with Lee's grade (r = 0.3526, P = 0.0060) and proteinuria levels (r = 0.4571, P = 0.0004). Tissue NLRC5 expression was significantly increased in the IgAN group compared to that in the healthy control group (P < 0.0001); a more significant increase was identified in the S1 group (P < 0.05) and had a positive correlation with Lee's grade (r = 0.497, P < 0.0001). We proposed a cut-off value of 1415 pg/ml for serum NLRC5 concentration, which was able to predict IgAN with 77.27% sensitivity and 87.5% specificity. CONCLUSIONS: Serum NLRC5 concentrations in IgAN are significantly decreased, and tissue NLRC5 expression is significantly increased in IgAN renal tissue, which is consistent with pathological severity. This finding suggests that NLRC5 could potentially be a diagnostic index and represents a prognostic factor in IgAN patients. PMID- 30453995 TI - Treating loss-to-follow-up as a missing data problem: a case study using a longitudinal cohort of HIV-infected patients in Haiti. AB - BACKGROUND: HIV programs are often assessed by the proportion of patients who are alive and retained in care; however some patients are categorized as lost to follow-up (LTF) and have unknown vital status. LTF is not an outcome but a mixed category of patients who have undocumented death, transfer and disengagement from care. Estimating vital status (dead versus alive) among this category is critical for survival analyses and program evaluation. METHODS: We used three methods to estimate survival in the cohort and to ascertain factors associated with death among the first cohort of HIV positive patients to receive antiretroviral therapy in Haiti: complete case (CC) (drops missing), Inverse Probability Weights (IPW) (uses tracking data) and Multiple Imputation with Chained Equations (MICE) (imputes missing data). Logistic regression was used to calculate odds ratios and 95% confidence intervals for adjusted models for death at 10 years. The logistic regression models controlled for sex, age, severe poverty (living on <$1 USD per day), Port-au-Prince residence and baseline clinical characteristics of weight, CD4, WHO stage and tuberculosis diagnosis. RESULTS: Age, severe poverty, baseline weight and WHO stage were statistically significant predictors of AIDS related mortality across all models. Gender was only statistically significant in the MICE model but had at least a 10% difference in odds ratios across all models. CONCLUSION: Each of these methods had different assumptions and differed in the number of observations included due to how missing values were addressed. We found MICE to be most robust in predicting survival status as it allowed us to impute missing data so that we had the maximum number of observations to perform regression analyses. MICE also provides a complementary alternative for estimating survival among patients with unassigned vital status. Additionally, the results were easier to interpret, less likely to be biased and provided an alternative to a problem that is often commented upon in the extant literature. PMID- 30453996 TI - Quality of antenatal care services in Rwanda: assessing practices of health care providers. AB - BACKGROUND: Although most pregnant women in Rwanda visit antenatal care (ANC) clinics, little has been studied about the quality of services being provided. We investigated the ANC providers' (HCPs) current practices in relation to prevention, management and referral of maternal conditions as well as the information provided to pregnant women attending ANC services in Rwanda. METHODS: This facility-based, cross-sectional study included 312 ANC providers as participants and a review of 605 ANC medical records from 121 health centers. Data collection was performed using an interviewer-administered questionnaire and a structured observation checklist. For the analyses, descriptive statistics and bi-and multivariable logistic regression were used. RESULTS: Nurses and midwives in ANC services failed to report a number of pregnancy-related conditions that would need urgent referral to a higher level of health care. Midwives did somewhat better than nurses in reporting these conditions. There was no statistically significant difference in how nurses and midwives informed pregnant women about pregnancy-related issues. Ever been trained in how to manage a pregnant woman exposed to violence was reported by 14% of the participants. In 12, 13 and 15% of the medical records there was no report on tetanus immunization, anthelmintic treatment and syphilis testing, respectively. CONCLUSION: The providers in ANC clinics reported suboptimal practices on conditions of pregnancy that needed urgent referral for adequate management. Information to pregnant women on danger signs of pregnancy, recommended medicines and tests do not seem to be consistently provided. Midwifery training in Rwanda should be expanded so that most of staff at ANC clinics are trained as midwives to help lower maternal and child mortality and morbidity. PMID- 30453997 TI - Exploring the emergence and evolution of population patterns of leisure-time physical activity through agent-based modelling. AB - INTRODUCTION: Most interventions aiming to promote leisure-time physical activity (LTPA) at population level showed small or null effects. Approaching the problem from a systems science perspective may shed light on the reasons for these results. We developed an agent-based model to explore how the interactions between psychological attributes and built and social environments may lead to the emergence and evolution of LTPA patterns among adults. METHODS: The modeling process consisted of four stages: (1) conceptual model development, (2) formulation of the agent-based model, (3) parametrization and calibration, and (4) consistency and sensitivity analyses. The model represents a stylized community containing two types of agents: persons and LTPA sites. Persons interact with each other (proximal network and perceived community) and with the built environment (LTPA sites) over time. Decision-making is based on the person's intention to practice LTPA, conditioned to the perceived environment. Each iteration is equivalent to one week and we assessed a period of 10 years. RESULTS: The model was able to reproduce population temporal trends of intention and LTPA reported in the literature. Sensitivity analyses indicated that population patterns and trends of intention and LTPA were highly influenced by the relationship between a person's behavior in the preceding week and his current intention, the person's access to built and social environment, and the density of LTPA sites. CONCLUSIONS: The proposed agent-based model is suitable to explore the emergence and evolution of LTPA patterns among adults, considering the dynamic interaction between individuals' psychological attributes and the built and social environments in which they live. The model is available at https://doi.org/10.17605/OSF.IO/J2KAS . PMID- 30453998 TI - Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells. AB - BACKGROUND: Neuroinflammation plays a vital role in Alzheimer's disease and other neurodegenerative conditions. Microglia are the resident mononuclear immune cells of the central nervous system, and they play essential roles in the maintenance of homeostasis and responses to neuroinflammation. The orphan G-protein-coupled receptor 55 (GPR55) has been reported to modulate inflammation and is expressed in immune cells such as monocytes and microglia. However, its effects on neuroinflammation, mainly on the production of members of the arachidonic acid pathway in activated microglia, have not been elucidated in detail. METHODS: In this present study, a series of coumarin derivatives, that exhibit GPR55 antagonism properties, were designed. The effects of these compounds on members of the arachidonic acid cascade were studied in lipopolysaccharide (LPS)-treated primary rat microglia using Western blot, qPCR, and ELISA. RESULTS: We demonstrate here that the various compounds with GPR55 antagonistic activities significantly inhibited the release of PGE2 in primary microglia. The inhibition of LPS-induced PGE2 release by the most potent candidate KIT 17 was partially dependent on reduced protein synthesis of mPGES-1 and COX-2. KIT 17 did not affect any key enzyme involved on the endocannabinoid system. We furthermore show that microglia expressed GPR55 and that a synthetic antagonist of the GPR receptor (ML193) demonstrated the same effect of the KIT 17 on the inhibition of PGE2. CONCLUSIONS: Our results suggest that KIT 17 is acting as an inverse agonist on GPR55 independent of the endocannabinoid system. Targeting GPR55 might be a new therapeutic option to treat neurodegenerative diseases with a neuroinflammatory background such as Alzheimer's disease, Parkinson, and multiple sclerosis (MS). PMID- 30453999 TI - Identification of core genes in ovarian cancer by an integrative meta-analysis. AB - BACKGROUND: Epithelial ovarian cancer is one of the most severe public health threats in women. Since it is still challenging to screen in early stages, identification of core genes that play an essential role in epithelial ovarian cancer initiation and progression is of vital importance. RESULTS: Seven gene expression datasets (GSE6008, GSE18520, GSE26712, GSE27651, GSE29450, GSE36668, and GSE52037) containing 396 ovarian cancer samples and 54 healthy control samples were analyzed to identify the significant differentially expressed genes (DEGs). We identified 563 DEGs, including 245 upregulated and 318 downregulated genes. Enrichment analysis based on the gene ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed that the upregulated genes were significantly enriched in cell division, cell cycle, tight junction, and oocyte meiosis, while the downregulated genes were associated with response to endogenous stimuli, complement and coagulation cascades, the cGMP-PKG signaling pathway, and serotonergic synapse. Two significant modules were identified from a protein-protein interaction network by using the Molecular Complex Detection (MCODE) software. Moreover, 12 hub genes with degree centrality more than 29 were selected from the protein-protein interaction network, and module analysis illustrated that these 12 hub genes belong to module 1. Furthermore, Kaplan-Meier analysis for overall survival indicated that 9 of these hub genes was correlated with poor prognosis of epithelial ovarian cancer patients. CONCLUSION: The present study systematically validates the results of previous studies and fills the gap regarding a large-scale meta-analysis in the field of epithelial ovarian cancer. Furthermore, hub genes that could be used as a novel biomarkers to facilitate early diagnosis and therapeutic approaches are evaluated, providing compelling evidence for future genomic-based individualized treatment of epithelial ovarian cancer. PMID- 30454000 TI - Cultural, economic, and ecological factors influencing management of wild plants and mushrooms interchanged in Purepecha markets of Mexico. AB - BACKGROUND: Traditional markets outstandingly contribute to conservation of biocultural diversity, social relations, and cultural values. These markets reflect life strategies and forms people of a region interact with their biodiversity and territories, as well as traditional ecological knowledge and management practices. To understand the factors motivating plant and mushroom management, we analyzed the resources cultural and economic values, their role in people's subsistence, and the relation of these values with the resources spatial and temporal availability. Our study based on the supposition that traditional markets are settings of interchange of resources with the highest importance for people's life in a region. Also, that the cultural, economic, and ecological factors influence values of the resources, and the demand on them determine pressures on the most valuable resources which, when scarce, motivate management innovation, otherwise become extinct. METHODS: We documented cultural, economic, and ecological aspects, as well as management techniques of wild and weedy plants and mushrooms interchanged in three traditional markets of the Patzcuaro Lake region, in central-western Mexico. For doing that, from February 2015 to March 2018, we conducted 175 visits to markets and 89 semi-structured interviews to producers, gatherers, and sellers of wild and weedy plants and mushrooms. Based on participant observation and interviews, we identified variables related to culture, economic, and ecological aspects, as well as management regimes of resources and management systems, which were documented and used as indicators for quantitative analyses. Through principal components analyses (PCA), we determined the indexes of cultural and economic importance (ICEI), management intensity (IMI), and ecological risk (IR) of the resources studied. For conducting that, we classified plant and mushroom species according to their cultural, economic, ecological, and technological indicators, respectively. The score of the first principal component was considered as the index for each group of variables, respectively. To identify relations between cultural importance and risk, we performed linear regression analyses between ICEI and IR indexes. RESULTS: We recorded 57 species of wild and weedy plants used as food, medicine, and ornamental, and 17 species of edible mushrooms. The variables with the highest weight in the ICEI are related to the need of a resource according to people, its recognizing, the number of communities and markets offering it in markets, its explicit preference expressed by people, the effort invested in obtaining it, and the form it is interchanged. Gathering is practiced in all mushrooms and wild and weedy plants from forests and agricultural areas; 11 species in addition receive 1 or more forms of management (enhancing, selective let standing, propagation through seeds or vegetative parts, transplantation, and/or protection). The management intensity and complexity are explained by variables related to management practices and systems. Plants receiving selective management have the higher management intensity. Silvicultural management (in situ management in forests) was recorded in all species of mushrooms, as well as in more than 80% of medicinal, ceremonial and ornamental plants, and in more than 50% of the edible plants. In agricultural systems, people manage more than 90% of the edible plants recorded to be under a management regime, 25% of the managed medicinal plants, and 30.7% of the managed ceremonial and ornamental plants. In homegardens, people manage 41.6% of the medicinal plants recorded and 26.6% of the edible plants, to have them available near home. Nearly 63% of the species interchanged in the markets studied are gathered in forests without any other management form. In this group are included all mushroom species, 61.5% of ceremonial/ornamental plants, 50% of medicinal, and 33.3% of edible plants. The linear regression between ICEI an IER is significantly negative for edible species with high management intensity R2 = 0.505 (p = 0.0316), because of their management. But in medicinal and ornamental plants, the risk is high if the cultural importance increases, even when management practices like transplanting and propagation in homegardens are carried out. CONCLUSIONS: Traditional markets are settings of interchange of products, knowledge, and experiences, where the ongoing factors and processes motivating management innovation can be identified and documented. This approach allows documenting processes occurring at regional level but would be benefited from deeper studies at local level in communities. PMID- 30454001 TI - A comparative study to evaluate the feasibility of preoperative percutaneous catheter drainage for the treatment of lumbar spinal tuberculosis with psoas abscess. AB - BACKGROUND: Spinal tuberculosis is a frequent cause of psoas abscess (PA), and PA largely negates the efficacy of antituberculosis therapy. This study aimed to investigate the clinical outcome of preoperative percutaneous catheter drainage (PCD) in patients with lumbar spinal tuberculosis and PA. METHODS: Between January 2015 and January 2017, 72 patients with lumbar spinal tuberculosis with PA were assigned to group A (preoperative PCD) and group B (n = 36 per group). All patients received posterior pedicle screw fixation and anterior focal debridement and fusion. Data on intraoperative blood loss, the duration of the surgery, and the length of the anterior incision were recorded, as well as the postoperative anal exhaust time, visual analogue scale (VAS), Cobb angle, lumbar vertebra function, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and sinus tract formation. RESULTS: Sixty-eight patients were followed up for an average time of 13 months (range 6-21 months). Until the final follow-up, no mixed infections, recurrence of tuberculosis, pedicle screw loosening, or screw pullout had occurred. There were significant between-group differences in blood loss, surgery duration, anterior incisional length, postoperative anal exhaust time, and sinus tract formation. As compared with group B, the ESR and CRP levels of the patients in group A were markedly improved following 3 weeks of antituberculosis therapy and 1 week postsurgery. CONCLUSION: Preoperative PCD helps to increase the efficacy of antituberculosis therapy prior to surgery, reduce surgical trauma, and avoid postoperative complications, making it a safe and feasible treatment option for lumbar spinal tuberculosis with PA. PMID- 30454002 TI - Assessment of the prognostic role of neutrophil-to-lymphocyte ratio following complete resection of thymoma. AB - BACKGROUND: The introduction of the new TNM staging system for thymic epithelial malignancies produced a significant increase in the proportion of patients with stage I disease. The identification of new prognostic factors could help to select patients for adjuvant therapies based on their risk of recurrence. Neutrophil-to-lymphocyte ratio (NLR) has recently gained popularity as reliable prognostic biomarker in many different solid tumors. The aim of this study is to assess the utility of NLR evaluation as a prognostic marker in patients with surgically-treated thymoma. METHODS: A retrospective analysis was conducted among patients who underwent resection for thymoma in a single center. Patients were divided in two groups, under (low-NLR-Group = 47 patients, 60%) and above (high NLR-Group = 32 patients, 40%) a ROC-derived NLR cut-off (2.27). Associations with clinical-pathological variables were analyzed; disease-free survival (DFS) was identified as the primary endpoint. RESULTS: Between 2007 and 2017, 79 patients had surgery for thymoma. Overall 5-year DFS was 80%. Univariate survival analysis demonstrated that NLR was significantly related to DFS when patients were stratified for TNM stage (p = 0.043). Five-year DFS in the low-NLR-Group and in the high-NLR-Group were respectively 100 and 84% in stage I-II, and 66 and 0% in stage III. TNM stage resulted as the only independent prognostic factor at multivariate analysis, with hazard ratio of 3.986 (95% CI 1.644-9.665, p = 0.002). CONCLUSIONS: High preoperative NLR seems to be associated to a shorter DFS in patients submitted to surgery for thymoma and stratified for TNM stage. PMID- 30454003 TI - Luteolin sensitizes the antitumor effect of cisplatin in drug-resistant ovarian cancer via induction of apoptosis and inhibition of cell migration and invasion. AB - Luteolin, a polyphenolic flavone, has been demonstrated to exert anti-tumor activity in various cancer types. Cisplatin drug resistance is a major obstacle in the management of ovarian cancer. In the present study, we investigated the chemo-sensitizing effect of luteolin in both cisplatin-resistant ovarian cancer cell line and a mice xenotransplant model. In vitro, CCK-8 assay showed that luteolin inhibited cell proliferation in a dose-dependent manner, and luteolin enhanced anti-proliferation effect of cisplatin on cisplatin-resistant ovarian cancer CAOV3/DDP cells. Flow cytometry revealed that luteolin enhanced cell apoptosis in combination with cisplatin. Western blotting and qRT-PCR assay revealed that luteolin increased cisplatin-induced downregulation of Bcl-2 expression. In addition, wound-healing assay and Matrigel invasion assay showed that luteolin and cisplatin synergistically inhibited migration and invasion of CAOV3/DDP cells. Moreover, in vivo, luteolin enhanced cisplatin-induced reduction of tumor growth as well as induction of apoptosis. We suggest that luteolin in combination with cisplatin could potentially be used as a new regimen for the treatment of ovarian cancer. PMID- 30454004 TI - How does malaria in pregnancy impact malaria risk in infants? AB - Malaria in pregnancy not only exerts profound negative consequences on the health of the mother and developing fetus, but may also alter the risk of malaria during infancy. Although mechanisms driving this altered risk remain unclear, in utero exposure to malaria antigens may impact the development of fetal and infant innate immunity. In an article in BMC Medicine, Natama et al. describe an ambitious analysis of basal and TLR-stimulated cord blood responses among a birth cohort in Burkina Faso. Basal levels of several cytokines, chemokines, and growth factors were shown to be significantly lower in cord blood with histopathologic evidence of placental malaria. Additionally, following TLR7/8 stimulation, samples obtained from infants of mothers with placental malaria were hyper responsive compared to those without evidence of prenatal malaria exposure. Furthermore, several responses impacted by placental malaria were associated with differential malaria risk in infancy. Understanding how malaria in pregnancy shapes immune responses in infants will provide critical insight into the rational design of malaria control strategies during pregnancy, including intermittent preventative treatment in pregnancy and vaccines.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1187 3. PMID- 30454005 TI - Factors determining level of hospital care and its association with outcome after resuscitation from pre-hospital pulseless electrical activity. AB - BACKGROUND: Patients resuscitated from out-of-hospital cardiac arrest (OHCA) with pulseless electrical activity (PEA) as initial cardiac rhythm are not always treated in intensive care units (ICUs): some are admitted to high dependency units with various level of care, others to ordinary wards. Aim of this study was to describe the factors determining level of hospital care after OHCA with PEA, post-resuscitation care and survival. METHODS: Adult OHCA patients with PEA (n = 221), who were resuscitated in southern Finland between 2010 and 2013 were included, provided patient survived to hospital admission. The patients were divided into four groups according to the level of hospital care provided: ordinary ward and Level 1-3 ICUs. Differences in patient characteristics, post resuscitation care and survival were compared between the groups. RESULTS: Most patients (62.4%) were treated at Level 2 ICUs. Longer time to ROSC and advanced age decreased admission rate to Level 2 or 3 post-resuscitation care, whereas good pre-arrest CPC (1-2) increased the admission rate to Level 2/3 ICUs independently. Treatment with targeted temperature management (TTM) (4.1%) or early coronary angiography (3.2%) were very rare. Prognostic decisions were made earlier in the lower treatment intensity groups (p < 0.01). One-year survival rate was 24.0, 17.1% survived with good neurological outcome. Neurological outcome was better with more intensive care. After adjustment, level of care was not independent predictor for outcome: only return of spontaneous circulation (ROSC) time, cardiac arrest cause and pre-arrest performance affected independently to 1-year survival, age and ROSC for neurologic outcome. CONCLUSIONS: PEA are usually admitted to Level 2 ICUs for post-resuscitation care in the capital area of Finland. Age, ROSC and pre-arrest CPC were independent predictors for level of post-resuscitation care. TTM and early CAG were rare and provided only for Level 3 ICU patients. Prognostication was earlier in lower level of care units. Good neurologic survival was more common with more intensive level of post-resuscitation care. After adjustment, level of care was not independent predictor for survival or neurologic outcome: only ROSC, cardiac arrest cause and pre-arrest performance predicted 1-year survival; age and ROSC neurologic outcome. PMID- 30454006 TI - Gallbladder agenesis with hepatic impairment: a case report. AB - BACKGROUND: Gallbladder agenesis is a rare congenital malformation. More than 50% of cases are isolated and asymptomatic. These asymptomatic patients are principally healthy and need no interventions. However, some patients develop symptoms, presenting with clinical signs and complaints similar to those of biliary tract disease. Symptoms commonly occur in the fourth or fifth decade of life of the patient. At the present time, gallbladder agenesis is diagnosed using a combination of imaging modalities, without surgical intervention, to avert serious complications following surgery. CASE PRESENTATION: We describe a 13-year old Japanese girl with a history of recurrent hepatic impairment, which had not been thoroughly investigated. She was referred to our hospital following 2 days of fever, fatigue, and abnormal blood tests suggested impaired liver function. Data from chest X-ray findings combined with a positive loop-mediated isothermal amplification assay result indicated Mycoplasma pneumoniae pneumonia, which was treated with oral azithromycin. To investigate potential hepatic impairment, we performed several imaging studies, namely, abdominal ultrasonography, magnetic resonance cholangiopancreatography, and contrast enhanced computed tomography. These imaging studies revealed a normal liver; however, the gallbladder was not in the usual nor any aberrant position in imaging investigations of the patient. Based on these results, we diagnosed gallbladder agenesis; however, the etiology of her hepatic impairment has not been elucidated. CONCLUSION: We present a case of gallbladder agenesis with hepatic impairment, where the diagnosis was made without surgical intervention. Clinicians should perform a detailed investigation when they encounter repeated hepatic impairment. PMID- 30454007 TI - Circulating tumor cells with karyotyping as a novel biomarker for diagnosis and treatment of nasopharyngeal carcinoma. AB - BACKGROUND: Circulating tumor cells (CTCs) have been considered great clinical significance in various cancers. However, it remains unknown that how is the role of CTCs in patients with nasopharyngeal carcinoma (NPC). We investigated the value of CTCs enumeration and karyotyping in NPC. METHODS: In the present study, we applied integrated subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) automatic testing system to detect and characterize CTCs of NPC patients. Enumeration and aneuploidy of chromosome 8 in CTCs were examined in various stages of patients with NPC. The changes of CTCs number and karyotyping post to chemotherapy were investigated in NPC. RESULTS: CTCs were detected by SE-iFISH in 46 out of 50 pre-treatment NPC patients, and performed a positive rate of 92.0%. No significant association was found between disease staging and CTCs detection rate. CTCs number constantly increased with TNM stage rising (from stage II to stage IV) no matter in newly diagnosed patients without distant metastasis (M0) and relapsed or distant metastatic patients. The number of CTCs decreased after treatment in patients with partial response (PR), while increased in patients with progressive disease or stable disease (PD/SD). More interestingly, CTCs karyotyping indicated that aneuploidy of chromosome 8 in CTCs was dramatically related to chemotherapeutic efficacy in NPC. Positive correlation was found between CTCs count and plasma EBV DNA level of NPC patients. CONCLUSIONS: CTCs could be detected in various stages of NPC patients using SE-iFISH. CTCs number could indicate the severity degree of disease in NPC. Dynamically monitoring the variations in CTCs number may predict chemotherapy efficacy during treatment. CTCs karyotyping is related to the sensibility of chemotherapy and drug resistance, and karyotyping of CTCs might predict therapeutic efficacy and evaluate chemo-resistance in NPC. CTCs could be used as a monitoring indicator in the fields of treatment, diagnosis and follow-up of NPC. PMID- 30454008 TI - Possibility of avoiding axillary lymph node dissection by immune microenvironment monitoring in preoperative chemotherapy for breast cancer. AB - BACKGROUND: The diagnosis of metastasis by sentinel lymph node biopsy (SLNB) in early breast cancer surgery provides an accurate view of the state of metastases to the axillary lymph nodes, and it has now become the standard procedure. In the present study, whether omission of axillary lymph node dissection (ALND) after neoadjuvant chemotherapy (NAC) is possible by evaluation of tumor-infiltrating lymphocytes (TILs) before NAC in cases without metastasis on diagnostic imaging, but with metastasis on SLNB, was retrospectively investigated. METHODS: A total of 91 patients with resectable, early-stage breast cancer, diagnosed as cT1-2, N0, M0, underwent SLNB and were treated with NAC. A semi-quantitative evaluation of lymphocytes infiltrating the peritumoral stroma as TILs in biopsy specimens of primary tumors prior to treatment was conducted. RESULTS: In cases with a low number of TILs, estrogen receptor expression was significantly higher (p = 0.044), and human epidermal growth factor receptor 2 (HER2) expression was significantly lower than in other cases (p = 0.019). The number of TILs was significantly lower in cases in which the intrinsic subtype was hormone receptor positive breast cancer (HRBC) (p = 0.044). Metastasis to axillary lymph nodes was significantly more common in HER2-negative cases and cases with a low number of TILs (p = 0.019, p = 0.005, respectively). CONCLUSIONS: Even if macrometastases are found on SLNB in cN0 patients, it appears that ALND could be avoided after NAC in cases with a good immune tumor microenvironment of the primary tumor. PMID- 30454009 TI - Trends in robot-assisted and virtual reality-assisted neuromuscular therapy: a systematic review of health-related multiplayer games. AB - BACKGROUND: Multiplayer games have emerged as a promising approach to increase the motivation of patients involved in rehabilitation therapy. In this systematic review, we evaluated recent publications in health-related multiplayer games that involved patients with cognitive and/or motor impairments. The aim was to investigate the effect of multiplayer gaming on game experience and game performance in healthy and non-healthy populations in comparison to individual game play. We further discuss the publications within the context of the theory of flow and the challenge point framework. METHODS: A systematic search was conducted through EMBASE, Medline, PubMed, Cochrane, CINAHL and PsycINFO. The search was complemented by recent publications in robot-assisted multiplayer neurorehabilitation. The search was restricted to robot-assisted or virtual reality-based training. RESULTS: Thirteen articles met the inclusion criteria. Multiplayer modes used in health-related multiplayer games were: competitive, collaborative and co-active multiplayer modes. Multiplayer modes positively affected game experience in nine studies and game performance in six studies. Two articles reported increased game performance in single-player mode when compared to multiplayer mode. CONCLUSIONS: The multiplayer modes of training reviewed improved game experience and game performance compared to single-player modes. However, the methods reviewed were quite heterogeneous and not exhaustive. One important take-away is that adaptation of the game conditions can individualize the difficulty of a game to a player's skill level in competitive multiplayer games. Robotic assistance and virtual reality can enhance individualization by, for example, adapting the haptic conditions, e.g. by increasing haptic support or by providing haptic resistance. The flow theory and the challenge point framework support these results and are used in this review to frame the idea of adapting players' game conditions. PMID- 30454011 TI - Stable levels of Coxiella burnetii prevalence in dairy sheep flocks but changes in genotype distribution after a 10-year period in northern Spain. AB - Bulk tank milk (BTM) samples were collected from 81 sheep flocks in the Basque Country, Spain, in 2015 and were analysed for antibodies against Coxiella burnetii by ELISA and for C. burnetii DNA by real-time PCR. Thirty-two percent of the flocks had BTM antibodies against C. burnetii. Presence of C. burnetii DNA in BTM was detected in 23% of the flocks, suggesting recent C. burnetii infections. Retrospective data of BTM samples obtained from 154 sheep flocks investigated in 2005 in the same geographic area were compiled to assess temporal changes in C. burnetii infection. The overall percentage of infected sheep flocks did not significantly change after the 10-year period. Among the 46 flocks sampled in both periods, 11 flocks that were negative in 2005 were positive in 2015, 18 maintained their initial status (positive or negative), and 17 positive flocks were negative in 2015. These findings indicate that C. burnetii infection is a dynamic process in dairy sheep in northern Spain. Single nucleotide polymorphism (SNP) genotyping of positive samples identified three genotypes, SNP1 being the most prevalent in 2015 and SNP8 in 2005; SNP4 was only detected once in 2005. These results suggest possible changes in the pattern of genotype infection over time. PMID- 30454010 TI - The pro-metastasis effect of circANKS1B in breast cancer. AB - BACKGROUND: Recent studies indicate that circular RNA (circRNA) plays a pivotal role in cancer progression. Here, we sought to investigate its role in breast cancer. METHODS: CircANKS1B (a circRNA originated from exons 5 to 8 of the ANKS1B gene, hsa_circ_0007294) was identified by RNA-sequencing and validated by qRT-PCR and Sanger sequencing. Clinical breast cancer samples were used to evaluate the expression of circANKS1B and its associations with clinicopathological features and prognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to support clinical findings and elucidate the function and underlying mechanisms of circANKS1B in breast cancer. RESULTS: CircANKS1B was significantly up-regulated in triple-negative breast cancer (TNBC) compared with non-TNBC tissues and cell lines. Increased circANKS1B expression was closely associated with lymph node metastasis and advanced clinical stage and served as an independent risk factor for overall survival of breast cancer patients. Functional studies revealed that circANKS1B promoted breast cancer invasion and metastasis both in vitro and in vivo by inducing epithelial-to mesenchymal transition (EMT), while had no effect on breast cancer growth. Mechanistically, circANKS1B abundantly sponged miR-148a-3p and miR-152-3p to increase the expression of transcription factor USF1, which could transcriptionally up-regulate TGF-beta1 expression, resulting in activating TGF beta1/Smad signaling to promote EMT. Moreover, we found that circANKS1B biogenesis in breast cancer was promoted by splicing factor ESRP1, whose expression was also regulated by USF1. CONCLUSIONS: Our data uncover an essential role of the novel circular RNA circANKS1B in the metastasis of breast cancer, which demonstrate that therapeutic targeting of circANKS1B may better prevent breast cancer metastasis. PMID- 30454012 TI - Novel risk factors for primary prevention of oesophageal carcinoma: a case control study from Sri Lanka. AB - BACKGROUND: Oesophageal carcinoma (OC) is one of the leading cancers in Sri Lanka. Its increasing incidence despite the implementation of various preventive activities addressing the conventional risk factors indicates the possibility of the existence of novel, country-specific risk factors. Thus, the identification of novel risk factors of OC specific to Sri Lanka is crucial for implementation of primary prevention activities. METHODS: A case-control study was conducted among 49 incident cases of OC recruited from the National Cancer Institute, Maharagama using a non-probability sampling method, and unmatched hospital controls (n = 196) excluded of having OC recruited from the endoscopy unit of the National Hospital of Sri Lanka. Data were collected using an interviewer administered questionnaire. Risk factors for OC were assessed by odds ratio (OR) with 95% confidence interval (CI). The risk factors were adjusted for possible confounding by logistic regression analysis. RESULTS: Of the study population, OC was common among males (69%) and the majority presented with squamous cell carcinoma (65%) at late stages (Stage IV: 45%; Stage III: 37%). Following adjusting for confounders, the risk factor profile for OC included; age > 65 years (OR = 4.0; 95% CI: 1.2-14.2); family history of cancer (OR = 5.04; 95% CI: 1.3-19.0); sub-optimal consumption of dietary fibre (OR = 3.58; 95% CI: 1.1 12.3); sub-optimal consumption of anti-oxidants (OR = 7.0; 95% CI: 2.2-22.5); over-consumption of deep fried food (OR = 6.68; 95% CI:2.0-22.6); 'high risk' alcohol drinking (OR = 11.7; 95% CI: 2.8-49.4); betel quid chewing (OR = 6.1; 95% CI: 2.0, 20.0); 'low' lifetime total sports and exercise activities (MET hours/week/year) (OR = 5.83; 95% CI: 1.5-23.0); agrochemicals exposure (OR = 6.57; 95% CI: 1.4-30.3); pipe-borne drinking water (OR = 5.62; 95% CI:1.7-18.9) and radiation exposure (OR = 4.64; 95% CI: 1.4-15.5). Significant effect modifications were seen between betel quid chewing and male sex (p = 0.01) and between ever exposure to radiation and age over 65 years (p = 0.04). CONCLUSIONS: Risk profile for OC includes novel yet modifiable risk factors in relation to diet, occupation, environment and health. Primary prevention should target these to combat OC in Sri Lanka. PMID- 30454013 TI - Proteinase K treatment improves RNA recovery from thyroid cells fixed with liquid based cytology solution. AB - OBJECTIVE: Fine-needle aspiration biopsy (FNAB), an important diagnostic tool given its simplicity, safety, and cost-effectiveness, is fast becoming a popular procedure in the diagnosis of thyroid diseases. Generally, cells isolated from biopsies are transferred directly to microscope slides to prepare smears for cytopathological examination; however, the technical difficulties of this procedure often cause poor reproducibility, which limits the accuracy of diagnostic results. Liquid-based cytology (LBC), in which isolated cells are collected in a fixative solution, is advantageous in that it facilitates the preparation of homogenous cytological specimens. However, LBC has not been applied to molecular diagnoses, such as RNA expression-based diagnosis, mainly because of difficulties in cell recovery and RNA isolation. This study was aimed to improve RNA extraction from papillary cancer-derived K1 cells and thyroid FNAB specimens suspended in LBC solutions. RESULTS: K1 cells suspended in CytoRich-Red and CytoRich-Blue, fixatives for LBC, were efficiently recovered by trapping to glass-fiber filters. Importantly, subsequent Proteinase K treatment was essential for efficient RNA extraction from the fixed cells. This finding was also applicable to RNA extraction from CytoRich-Red-fixed thyroid FNAB specimens processed in the same way. Consistently, U6 small nuclear RNA was detected in these RNA samples by reverse transcription-polymerase chain reaction. PMID- 30454014 TI - "Stroke - 65 Plus. Continued Active Life": a study protocol for a randomized controlled cross-sectoral trial of the effect of a novel self-management intervention to support elderly people after stroke. AB - BACKGROUND: Elderly people represent the majority of stroke cases worldwide. Post stroke sequelae frequently lead to a more isolated life. Restricted social relations render older individuals with stroke a vulnerable group, especially in terms of social reintegration. Reintegration into the community after a stroke largely depends on support from the family. However, close relatives are at risk of becoming overburdened. The aim of this study is to investigate the effect of a novel self-management intervention to support elderly people after stroke. METHODS/DESIGN: Randomized controlled trial. Two weeks before discharge from a rehabilitation hospital/center, individuals with stroke aged > 65 years will be randomized either to a group receiving conventional neurorehabilitation (control) or to an additional novel self-management intervention. In the intervention group, patients with stroke will be offered eight self-management sessions of 45 60 min duration by a physiotherapist or an occupational therapist during a period of nine months after discharge. Inclusion will continue until at least 35 individuals in each group have been recruited. Study outcome measurements: Stroke Self-efficacy Questionnaire, a short version of Stroke Specific Quality of Life Scale, Impact on Participation and Autonomy and Caregiver Burden Scale. Furthermore, physical activity will be assessed using accelerometers. All outcomes except "impact on participation" and "autonomy" will be assessed at baseline, three months, and nine months after discharge. Impact on participation and autonomy will be assessed at three and nine months after discharge. Patient, informal caregiver, and therapist satisfaction will be examined by way of questionnaires and interviews. DISCUSSION: Self-management interventions are promising strategies for rehabilitation, potentially increasing self-efficacy, quality of life, as well as participation and autonomy. The introduction of a novel self-management intervention in combination with traditional physical and occupational therapy may enhance recovery after stroke and quality of life and lessen the burden on relatives. This trial "Stroke - 65 Plus. Continued Active Life," will provide further evidence of self-management strategies to clinicians, patients, and health economists. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03183960 . Registered on 12 June 2017. PMID- 30454016 TI - Comment to: non-specific complaints at emergencydepartment presentation result in uncleardiagnoses and lengthened hospitalization: a prospective observational study. PMID- 30454015 TI - From transit hub to major supplier of illicit cigarettes to Argentina and Brazil: the changing role of domestic production and transnational tobacco companies in Paraguay between 1960 and 2003. AB - BACKGROUND: Paraguay has reportedly been a major transit hub for illicit tobacco products since the 1960s, initially to supply markets in Argentina and Brazil and, more recently, other regional markets and beyond. However, to date there has been no systematic analysis, notably independent of the tobacco industry, of this trade including the roles of domestic production and transnational tobacco companies (TTCs). This article fills that gap by detailing the history of Paraguay's illicit cigarette trade to Brazil and Argentina of TTC products and Paraguayan production between 1960 and 2003. The effective control of illicit cigarette flows, under Article 15 of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) and the Protocol to Eliminate the Illicit Trade in Tobacco Products, requires fuller understanding of the changing nature of the illicit trade. METHODS: We systematically searched internal industry documents to understand the activities and strategies of leading TTCs in Paraguay and subregion over time. We also mapped illicit trade volume and patterns using US government and UN data on the cigarette trade involving Paraguay. We then estimated Paraguay's cigarette production from 1989 to 2003 using tobacco leaf flows from the United Nations Commodity Trade Statistics Database (UN Comtrade). RESULTS: We identify four phases in the illicit tobacco trade involving Paraguay: 1) Paraguay as a transit hub to smuggle BAT and PMI cigarettes from the U.S. into Argentina and Brazil (from the 1960s to the mid 1970s); 2) BAT and PMI competing in north-east Argentina (1989-1994); 3) BAT and PMI competing in southern and southern-east Brazil (mid to late 1990s); and 4) the growth in the illicit trade of Paraguayan manufactured cigarettes (from the mid- 1990s onwards). These phases suggest the illicit trade was seeded by TTCs, and that the system of supply and demand on lower priced brands they developed in the 1990s created a business opportunity for manufacturing in Paraguay. Brazil's efforts to fight this trade, with a 150% tax on exports to Latin American countries in 1999, further prompted supply of the illicit trade to shift from TTCs to Paraguayan manufacturers. CONCLUSION: This paper extends evidence of the longstanding complicity of TTCs in the illicit trade to this region and the consequent growth of Paraguayan production in the 1990s. Our findings confirm the need to better understand the factors influencing how the illicit tobacco trade has changed over time, in specific regional contexts, and amid tobacco industry globalization. In Paraguay, the changing roles of TTC and domestic production have been central to shifting patterns of illicit supply and distribution since the 1960s. Important questions are raised, in turn, about TTCs efforts to participate as legitimate partners in global efforts to combat the problem, including a leading role in data gathering and analysis. PMID- 30454017 TI - Job satisfaction and related factors among Iranian intensive care unit nurses. AB - OBJECTIVES: The aim of this study is to determine the levels of job satisfaction and to collect information about the factors affecting job satisfaction of Iranian ICU hospital nurses. RESULTS: The participants included 124 nurses working in the ICU section of hospitals in the city of Amol in Iran, who were selected by census method. The instruments for gathering the information included Demographic Information Questionnaire and also the Minnesota Satisfaction Questionnaire. The results revealed that the average score of job satisfaction among ICU nurses was 2.50 +/- 0.51. Also job satisfaction among women was higher than men (P = 0.03, t = 0.4). One way analysis of variance showed a significant relation between job satisfaction level with employment status and overtime work. Also older nurses had higher levels of job satisfaction. Hospital directors and managers, can use the results of this study in order to have a deeper understanding of job satisfaction among nurses, and the factors affecting it. PMID- 30454018 TI - A turnaround strategy: improving equity in order to achieve quality of care and financial sustainability in Italy. AB - BACKGROUND: Equity, financial sustainability, and quality in healthcare are key goals embraced by universal health systems. However, systematic performance management strategies for achieving equity are still weaker than those aimed at achieving financial sustainability and quality of care. Using a vertical equity perspective, the overarching aim of this paper is to examine how improving equity in quality of care impacts on financial sustainability. We applied a simulation to indicators of the heart failure clinical pathway in Tuscany (central Italy), in order to quantify the equity gaps and financial resources that could be reallocated in the absence of performance inequities. METHODS: The analysis included all patients hospitalized for heart failure as a principal diagnosis in 2014. We selected five indicators: hospitalization rate, 30-day readmission, cardiology visits, and the utilization of beta-blockers, and ACE inhibitors and sartans. For each indicator, the simulation followed three steps: 1) stratification by socioeconomic status (SES), using education as a proxy for SES; 2) computation of the vertical equity indicator; and 3) assessment of the financial value of the equity gap. RESULTS: All indicators showed performance gaps regarding inequities across SES-groups. For the hospitalization rate and 30 day readmission, resources could have been reallocated, if the performance of patients with a low SES had been equal to the performance of patients with a high SES, which amounted to ?2,144,422 and ?892,790 respectively. In contrast, limited additional resources would have been required for prescriptions and cardiology visits. CONCLUSIONS: Reducing equity gaps by improving the performance of low-SES patients may be a crucial strategy to achieving financial sustainability in universal coverage healthcare systems. Universal healthcare systems, which aim to pursue financial sustainability and quality of care, are thus urged to develop performance management actions to improve equity. This approach should not only include the measurement and public disclosure of equity indicators but be part of a comprehensive evidence-based strategy for the management of chronic conditions along the clinical pathway. PMID- 30454019 TI - Statistical analysis plan for a cluster-randomized crossover trial comparing the effectiveness and safety of a flexible family visitation model for delirium prevention in adult intensive care units (the ICU Visits Study). AB - BACKGROUND: Most adult intensive care units (ICUs) worldwide adopt restrictive family visitation models (RFVMs). However, evidence, mostly from non-randomized studies, suggests that flexible adult ICU visiting hours are safe policies that can result in benefits such as prevention of delirium and increase in satisfaction with care. Accordingly, the ICU Visits Study was designed to compare the effectiveness and safety of a flexible family visitation model (FFVM) vs. an RFVM on delirium prevention among ICU patients, and also to analyze its potential effects on family members and ICU professionals. METHODS/DESIGN: The ICU Visits Study is a cluster-randomized crossover trial which compares an FFVM (12 consecutive ICU visiting hours per day) with an RFVM (< 4.5 ICU visiting hours per day) in 40 Brazilian adult ICUs. Participant ICUs are randomly assigned to either an FFVM or RFVM in a 1:1 ratio. After enrollment and follow-up of 25 patients, each ICU is crossed over to the other visitation model, until 25 more patients per site are enrolled and followed. The primary outcome is the cumulative incidence of delirium measured by the Confusion Assessment Method for the ICU. Secondary and tertiary outcomes include relevant measures of effectiveness and safety of ICU visiting policies among patients, family members, and ICU professionals. Herein, we describe all primary statistical procedures that will be used to evaluate the results and perform exploratory and sensitivity analyses of this study. This pre-specified statistical analysis plan was written and submitted without knowledge of the study data. DISCUSSION: This a priori statistical analysis plan aims to enhance the transparency of our study, facilitating unbiased analyses of ICU visit study data, and provide guidance for statistical analysis for groups conducting studies in the same field. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02932358 . Registered on 11 October 2016. PMID- 30454020 TI - Factors associated with adverse pregnancy outcome in Debre Tabor town, Northwest Ethiopia: a case control study. AB - OBJECTIVE: The aim of this study was to assess the socioeconomic and demographic factors on adverse pregnancy outcomes. RESULT: The mean age of cases was 42.2 (+/ 13.26) years and the mean age of controls was 34.5 (+/- 12.23) years. Advanced maternal age, low educational status, and early sexual debut showed a significant association with an adverse pregnancy outcome. Mothers in the age group 35-44 years, AOR 2.54 (95% CI 1.27, 5.06), 35-44 years, AOR 2.79 (95% CI 1.27, 6.16) and Mothers with age 55 years and above AOR 4.18 (95% CI 1.73, 9.13) were more likely to have an adverse pregnancy outcome compared to mothers in the age group <= 24 years. The low educational status was also found to have an implication on adverse pregnancy outcome. Those mothers with no formal education were two times more likely to develop adverse pregnancy outcome AOR 2.15 (95% CI 1.41, 2.81) and those in primary education AOR 1.6 (95% CI 1.06, 4.6) times more likely compared to those in higher education. PMID- 30454021 TI - RAS status and neoadjuvant chemotherapy impact CD8+ cells and tumor HLA class I expression in liver metastatic colorectal cancer. AB - BACKGROUND: T lymphocytes and HLA expression on tumor cell both influence prognostic of localized colorectal cancer, but their role following chemotherapy in patients with liver metastatic colorectal cancer (mCRC) was not addressed. METHODS: One hundred fourteen patients treated in curative intend of liver mCRC were included in this retrospective study. Patients were either untreated or treated with neoadjuvant therapy containing an anti-EGFR, bevacizumab or oxaliplatin. Immune densities were quantified in the tumor core and in invasive margin of metastases, using Qupath software or a pathologist's quantification. CD8, NKp46, Foxp3, CD163, HLA, PD-L1 were analyzed and were correlated with progression free survival (PFS) and overall survival (OS) using multivariable Cox proportional hazards models. RESULTS: In the whole cohort only a high CD8+ cells infiltrate, a high HLA-I expression and wild-type RAS/RAF status were associated with a better overall survival in both univariate and multivariate model. Moreover, CD8+ cells immune infiltrate at invasive margin combined to HLA expression in cancer cell could increase patient's outcome prediction. RAS status but not immune cell infiltrate was associated with HLA expression on tumor cells. In comparison to untreated patients, neoadjuvant chemotherapy induced CD8+ cells recruitment and increased PD-L1 staining in immune infiltrates only for WT RAS patients. In this context, anti-EGFR and oxaliplatin based chemotherapy are the most powerful to induce CD8+ cells mobilization within the metastatic site. CONCLUSIONS: While CD8 infiltrate and HLA expression appear to be prognostic for mCRC, CD8 and PD-L1 infiltrate are enhanced by neoadjuvant chemotherapy in mCRC under RAS status dependence. PMID- 30454022 TI - Diffuse alveolar hemorrhage during alemtuzumab infusion in a patient with multiple sclerosis: a case report. AB - BACKGROUND: Diffuse alveolar bleeding is a potentially life-threatening condition that can be induced by several drugs. Whereas fatal cases have been reported in patients treated for other indications, no report have so far been published in a patient with multiple sclerosis treated with alemtuzumab. CASE PRESENTATION: We report a case of alemtuzumab-induced diffuse alveolar bleeding in a 29 year old woman with relapsing remitting multiple sclerosis. The patient developed acute shortness of breath, chest pain on inspiration and haemoptysis following the second infusion of alemtuzumab during the first treatment cycle. Computed tomography showed bilateral alveolar opacities. Bronchoscopy and broncho-alveolar lavage showed persistently bloody return with no evidence of infection. The symptoms resolved completely without treatment and control computed tomography performed one week later showed total resolution of pulmonary infiltrates. CONCLUSION: This is the first published report of diffuse alveolar bleeding in a patient with multiple sclerosis treated with alemtuzumab. Four similar cases in patients treated for multiple sclerosis and several fatal cases in patients treated for other conditions are registered at the World Health Organization database of suspected adverse events (VIgiBase(c)), underscoring that this is a serious and possibly under-recognized complication of alemtuzumab which can also occur in the treatment of multiple sclerosis. The clinician should consider the possibility of diffuse pulmonary haemorrhage in patients with sudden onset of respiratory distress and haemoptysis following administration of alemtuzumab for multiple sclerosis. PMID- 30454023 TI - Operating a patient medicines helpline: a survey study exploring current practice in England using the RE-AIM evaluation framework. AB - BACKGROUND: Patient medicines helplines provide a means of accessing medicines related support following hospital discharge. However, it is unknown how many National Health Service (NHS) Trusts currently provide a helpline, nor how they are operated. Using the RE-AIM evaluation framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance), we sought to obtain key data concerning the provision and use of patient medicines helplines in NHS Trusts in England. This included the extent to which the delivery of helplines meet with national standards that are endorsed by the Royal Pharmaceutical Society (standards pertaining to helpline access, availability, and promotion). METHODS: An online survey was sent to Medicines Information Pharmacists and Chief Pharmacists at all 226 acute, mental health, specialist, and community NHS Trusts in England in 2017. RESULTS: Adoption: Fifty-two percent of Trusts reported providing a patient medicines helpline (acute: 67%; specialist: 41%; mental health: 29%; community: 18%). Reach: Helplines were predominantly available for discharged inpatients, outpatients, and carers (98%, 95% and 93% of Trusts, respectively), and to a lesser extent, the local public (22% of Trusts). The median number of enquiries received per week was five. IMPLEMENTATION: For helpline access, 54% of Trusts reported complying with all 'satisfactory' standards, and 26% reported complying with all 'commendable' standards. For helpline availability, the percentages were 86% and 5%, respectively. For helpline promotion, these percentages were 3% and 40%. One Trust reported complying with all standards. Maintenance: The median number of years that helplines had been operating was six. Effectiveness: main perceived benefits included patients avoiding harm, and improving patients' medication adherence. CONCLUSIONS: Patient medicines helplines are provided by just over half of NHS Trusts in England. However, the proportion of mental health and community Trusts that operate a helpline is less than half of that of the acute Trusts, and there are regional variations in helpline provision. Adherence to the national standards could generally be improved, although the lowest adherence was regarding helpline promotion. Recommendations to increase the use of helplines include increasing the number of promotional methods used, the number of ways to contact the service, and the number of hours that the service is available. PMID- 30454024 TI - Semaphorin 5A drives melanoma progression: role of Bcl-2, miR-204 and c-Myb. AB - BACKGROUND: Melanoma, the most aggressive form of skin cancer, is characterized by high rates of metastasis, drug resistance and mortality. Here we investigated the role of Semaphorin 5A (Sema5A) on the properties associated with melanoma progression and the factors involved in Sema5A regulation. METHODS: Western blotting, qRT-PCR, Chromatin immunoprecipitation (ChIP) assay, immunohistochemistry of melanoma patient specimens and xenograft tissues, in vitro Transwell assay for cell migration and invasion evaluation, in vitro capillary-like structure formation analysis. RESULTS: A significant correlation of Sema5A mRNA expression and melanoma progression was observed by analyzing GEO profile dataset. Endogenous Sema5A protein was detected in 95% of human melanoma cell lines tested, in 70% of metastatic specimens from patients affected by melanoma, and 16% of in situ melanoma specimens showed a focal positivity. We demonstrated that Sema5A regulates in vitro cell migration and invasion and the formation of vasculogenic structures. We also found an increase of Sema5A at both mRNA and protein level after forced expression of Bcl-2. By use of transcriptional and proteasome inhibitors, we showed that Bcl-2 increases the stability of Sema5A mRNA and protein. Moreover, by ChIP we demonstrated that Sema5A expression is under the control of the transcription factor c-Myb and that c-Myb recruitment on Sema5A promoter is increased after Bcl-2 overexpression. Finally, a concomitant decrease in the expression of Sema5A, Bcl-2 and c-Myb proteins was observed in melanoma cells after miR-204 overexpression. CONCLUSION: Overall our data provide evidences supporting the role of Sema5A in melanoma progression and the involvement of Bcl-2, miR-204 and c-Myb in regulating its expression. PMID- 30454025 TI - A chitinase-like protein from Sarcoptes scabiei as a candidate anti-mite vaccine that contributes to immune protection in rabbits. AB - BACKGROUND: Scabies is caused by Sarcoptes scabiei burrowing into the stratum corneum of the host's skin and is detrimental to the health of humans and animals. Vaccines are an attractive alternative to replace the acaricides currently used in their control. METHODS: In the present study, the S. scabiei chitinase-like protein 5 (SsCLP5) was characterized and recombinant SsCLP5 (rSsCLP5) was evaluated as a candidate vaccine protein for anti-mite protection in rabbits. The expression, characterization and immunolocalization of SsCLP5 were examined. Vaccination experiments were performed on three test groups (n = 12 per group) immunized with purified rSsCLP5. Control groups (n = 12 per group) were immunized with PBS, QuilA saponin or empty vector protein. After challenge, the inflammatory reaction and skin lesions were graded and rSsCLP5 indirect ELISA was used to detect antibody IgG levels in serum samples at the time of vaccination and post-challenge. RESULTS: The results showed that rSsCLP5 had high immunoreactivity and immunogenicity. In S. scabiei, SsCLP5 had a wide distribution in the chewing mouthpart, legs and exoskeleton, especially the outer layer of the exoskeleton. Vaccination with rSsCLP5 resulted in 74.3% (26/35) of rabbits showing no detectable lesions after challenge with S. scabiei. CONCLUSIONS: Our data demonstrate that rSsCLP5 is a promising candidate for a recombinant protein-based vaccine against S. scabiei. This study also provides a method for studying scabies vaccine using rabbit as an animal model and a basis for screening more effective candidate proteins. PMID- 30454026 TI - Loss of DNA methylation is related to increased expression of miR-21 and miR-146b in papillary thyroid carcinoma. AB - BACKGROUND: DNA methylation in miRNA genes has been reported as a mechanism that may cause dysregulation of mature miRNAs and consequently impact the gene expression. This mechanism is largely unstudied in papillary thyroid carcinomas (PTC). METHODS: To identify differentially methylated miRNA-encoding genes, we performed global methylation analysis (Illumina 450 K), integrative analysis (TCGA database), data confirmation (pyrosequencing and RT-qPCR), and functional assays. RESULTS: Methylation analysis revealed 27 differentially methylated miRNA genes. The integrative analyses pointed out miR-21 and miR-146b as potentially regulated by methylation (hypomethylation and increased expression). DNA methylation and expression patterns of miR-21 and miR-146b were confirmed as altered, as well as seven of 452 mRNAs targets were down-expressed. The combined methylation and expression levels of miR-21 and miR-146b showed potential to discriminate malignant from benign lesions (91-96% sensitivity and 96-97% specificity). An increased expression of miR-146b due to methylation loss was detected in the TPC1 cell line. The miRNA mimic transfection highlighted putative target mRNAs. CONCLUSIONS: The increased expression of miR-21 and miR-146b due to loss of DNA methylation in PTC resulted in the disruption of the transcription machinery and biological pathways. These miRNAs are potential diagnostic biomarkers, and these findings provide support for future development of targeted therapies. PMID- 30454028 TI - Phenotypic testicular abnormalities and pubertal development in boys with McCune Albright syndrome. AB - Aim of this survey is to review the few available literature data on pathophysiologic and clinical aspects of pubertal development in boys with McCune Albright syndrome (MAS). On the basis of such analysis, we concluded that:1) peripheral precocious puberty (PPP) is significantly more infrequent in boys than in girls; 2) the most common testicular abnormality at MAS presentation is macroorchidism, that may be either monolateral or bilateral; 3) macroorchidism is not always associated with clinical and biochemical evidence of PPP; 4) testicular microlothiasis is distinctly more frequent in boys with MAS than in those without MAS; 5) the available therapeutic schedules have to be adopted already at MAS presentation only in the cases with PPP. PMID- 30454027 TI - Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion. AB - BACKGROUND: Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS: Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS: In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ERalpha-negative breast cancer as well as in ERalpha-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION: The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences. PMID- 30454029 TI - Visualizing nationwide variation in medicare Part D prescribing patterns. AB - BACKGROUND: To characterize the regional and national variation in prescribing patterns in the Medicare Part D program using dimensional reduction visualization methods. METHODS: Using publicly available Medicare Part D claims data, we identified and visualized regional and national provider prescribing profile variation with unsupervised clustering and t-distributed stochastic neighbor embedding (t-SNE) dimensional reduction techniques. Additionally, we examined differences between regionally representative prescribing patterns for major metropolitan areas. RESULTS: Distributions of prescribing volume and medication diversity were highly skewed among over 800,000 Medicare Part D providers. Medical specialties had characteristic prescribing patterns. Although the number of Medicare providers in each state was highly correlated with the number of Medicare Part D enrollees, some states were enriched for providers with > 10,000 prescription claims annually. Dimension-reduction, hierarchical clustering and t SNE visualization of drug- or drug-class prescribing patterns revealed that providers cluster strongly based on specialty and sub-specialty, with large regional variations in prescribing patterns. Major metropolitan areas had distinct prescribing patterns that tended to group by major geographical divisions. CONCLUSIONS: This work demonstrates that unsupervised clustering, dimension-reduction and t-SNE visualization can be used to analyze and visualize variation in provider prescribing patterns on a national level across thousands of medications, revealing substantial prescribing variation both between and within specialties, regionally, and between major metropolitan areas. These methods offer an alternative system-wide and pattern-centric view of such data for hypothesis generation, visualization, and pattern identification. PMID- 30454030 TI - Association of dietary patterns, anthropometric measurements, and metabolic parameters with C-reactive protein and neutrophil-to-lymphocyte ratio in middle aged and older adults with metabolic syndrome in Taiwan: a cross-sectional study. AB - BACKGROUND: Metabolic syndrome is commonly associated with inflammation. The underlying factors of inflammation in metabolic syndrome are not fully understood. The objective of the study was to determine the association of dietary patterns, anthropometric measurements, and metabolic parameters with inflammatory markers in middle-aged and older adults with metabolic syndrome in Taiwan. METHODS: A total of 26,016 subjects aged >=35 y with metabolic syndrome were recruited from Mei Jau institution between 2004 and 2013 for a cross sectional study. Metabolic syndrome was defined by the International Diabetes Federation. Multivariate logistic regression was performed to evaluate the association of dietary patterns, anthropometric measurements, and metabolic parameters with C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) in men and women with metabolic syndrome. Crude and adjusted models were analyzed by gender. RESULTS: The western dietary pattern, obesity, high body fat, high waist or hip circumference, and high waist-to-hip ratio were significantly associated with increased odds ratios of high CRP and NLR in both genders. High systolic or diastolic blood pressure (BP), low high-density lipoprotein cholesterol (HDL-C), high low-density lipoprotein-cholesterol (LDL-C), high total cholesterol (TC), high serum triglycerides (TG), and high fasting blood glucose (FBG) were significantly correlated with increased odds ratios of high CRP in both genders. Low HDL-C, high LDL-C, high serum TG, and high FBG were significantly associated with increased odds ratios of high NLR in both genders. However, high systolic (OR = 1.124, 95% CI 1.047-1.206, P < 0.01) or diastolic BP (OR = 1.176, 95% CI 1.087-1.273, P < 0.001) and high TC (OR = 1.138, 95% CI 1.062 1.220, P < 0.001) were significantly correlated with increased odds ratios of high NLR only in men. CONCLUSIONS: The western dietary pattern, obese-related anthropometric parameters, and most components of metabolic syndrome are positively associated with CRP levels and NLR in men and women with metabolic syndrome. PMID- 30454032 TI - Addressing the needs of terminally-ill patients in Bosnia-Herzegovina: patients' perceptions and expectations. AB - BACKGROUND: Many terminally ill patients in Bosnia-Herzegovina (BiH) fail to receive needed medical attention and social support. In 2016 a primary healthcare centreer (PHCC) in Doboj (BiH) requested the methodological and technical support of a local partner (Fondacija fami) and the Geneva University Hospitals to address the needs of terminally ill patients living at home. In order to design acceptable, affordable and sustainable solutions, we involved patients and their families in exploring needs, barriers and available resources. METHODS: We conducted interviews with 62 purposely selected patients using a semi-structured interview guide designed to elicit patients' experiences, needs and expectations. Both qualitative and quantitative analyses were conducted, using an inductive thematic approach. RESULTS: While patients were aware that their illnesses were incurable, they were poorly informed about medical and social support resources available to them. Family members appeared to be patients' main source of support, and often suffered from exhaustion and financial strain. Patients expressed feelings of helplessness and lack of control over their health. They wanted more support from health professionals for pain and other symptom management, as well as for anxiety and depression. Patients who were bedridden or with reduced mobility expressed strong feelings of loneliness, social exclusion, and stigma from community members and - occasionally - from health workers. CONCLUSIONS: Our findings suggest a wide gap between patients' end-of-life care needs and existing services. In order to address the medical, psychological and social needs of terminally ill patients, a multi-pronged approach is called for, including not only better symptom management through training of health professionals and improved access to medication and equipment, but also a coordinated inter-professional, inter-institutional and multi-stakeholder effort aimed at offering comprehensive medical, psycho-social, educational and spiritual support. PMID- 30454031 TI - Clinical course, treatment and outcome of Pneumocystis pneumonia in immunocompromised adults: a retrospective analysis over 17 years. AB - BACKGROUND: Despite modern intensive care with standardized strategies against acute respiratory distress syndrome (ARDS), Pneumocystis pneumonia (PcP) remains a life-threatening disease with a high mortality rate. Here, we analyzed a large mixed cohort of immunocompromised patients with PcP, with regard to clinical course and treatment, and aimed at identifying predictors of outcome. METHODS: This was a single-center retrospective analysis in a tertiary care institution across 17 years. Diagnosis of PcP required typical clinical features and microbiological confirmation of Pneumocystis jirovecii. Epidemiological, clinical, laboratory and outcome data were collected from patient records. RESULTS: A total of 52,364 specimens from 7504 patients were sent for microbiological assessment (3653 with clinical suspicion of Pneumocystis pneumonia). PcP was confirmed in 240 patients, about half of them HIV positive (52%). The remaining subjects were either solid organ transplant recipients (16.3%) or suffered from malignancy (15.8%) or autoimmune diseases (11.7%). Of note, 95% of patients with PcP were not receiving chemoprophylaxis. Overall in hospital mortality was 25.4%, increasing to 58% if ICU admission was required. Multivariable regression identified lactate dehydrogenase (LDH) as predictor of in-hospital mortality (adjusted OR 1.17 (95% CI 1.09-1.27), p < 0.0001). Mortality in LDH quartiles increased from 8% to 49%, and a cutoff value of 495 U/L predicted mortality with sensitivity and specificity of 70%. With regard to treatment, 40% of patients received trimethoprim-sulfamethoxazole at doses that were lower than recommended, and these patients had a higher mortality risk (HR 1.80 (95% CI 1.10-3.44), p = 0.02). CONCLUSIONS: PcP remains a life-threatening disease among immunocompromised patients. About half of patients with PcP do not have HIV infection. Initial LDH values might serve as a stratifying tool to identify those patients at high risk of death among patients with HIV and without HIV infection. PMID- 30454033 TI - Safety of topical administration of fluralaner plus moxidectin concurrently with praziquantel in cats. AB - BACKGROUND: Fluralaner provides efficacy against feline ectoparasites following topical administration. Moxidectin is routinely used to treat gastrointestinal nematode infections and prevent heartworm disease caused by Dirofilaria immitis. Praziquantel is routinely used to treat feline tapeworm infections. The safety of a fluralaner plus moxidectin combination topical solution (BravectoTM Plus, MSD Animal Health) was assessed when administered concurrently with a commercially available praziquantel topical solution (DroncitTM Spot-on, Bayer Animal Health GmbH). The highest dose rates in clinical use were tested. RESULTS: Concurrent topical administration of a fluralaner plus moxidectin and a praziquantel product did not result in adverse findings. One out of ten cats receiving praziquantel only (control group), and two out of ten cats receiving fluralaner plus moxidectin and praziquantel (treatment group) had dandruff-like flakes in their coat at the application site. Two out of the ten control cats and three cats out of the ten treatment group cats had very small amounts of unidentified material (minute crusts or crumbs) at the application site which was only visible during close inspection. CONCLUSIONS: The concurrent treatment of cats with fluralaner plus moxidectin and praziquantel at the maximum dose in clinical use was well tolerated. PMID- 30454034 TI - Reducing Implant Infection in Orthopaedics (RIIiO): a pilot study for a randomised controlled trial comparing the influence of forced air versus resistive fabric warming technologies on postoperative infection rates following orthopaedic implant surgery in adults. AB - BACKGROUND: Approximately 70,000 to 75,000 proximal femoral fracture repairs take place in the UK each year. Hemiarthroplasty is the preferred treatment for adults aged over 60 years. Postoperative infection affects up to 3% of patients and is the single most common reason for early return to theatre. Ultraclean ventilation was introduced to help mitigate the risk of infection, but it may also contribute to inadvertent perioperative hypothermia, which itself is a risk for postoperative infection. To counter this, active intraoperative warming is used for all procedures that take 30 min or more. Forced air warming (FAW) and resistive fabric warming (RFW) are the two principal techniques used for this purpose; they are equally effective in prevention of inadvertent perioperative hypothermia, but it is not known which is associated with the lowest infection rates. Deep surgical site infection doubles operative costs, triples investigation costs and quadruples ward costs. The Reducing Implant Infection in Orthopaedics (RIIiO) study seeks to compare infection rates with FAW versus RFW after hemiarthroplasty for hip fracture. A cost-neutral intervention capable of reducing postoperative infection rates would likely lead to a change in practice, yield significant savings for the health economy, reduce overall exposure to antibiotics and improve outcomes following hip fracture in the elderly. The findings may be transferable to other orthopaedic implant procedures and to non orthopaedic surgical specialties. METHODS: RIIiO is a parallel group, open label study randomising hip fracture patients over 60 years of age who are undergoing hemiarthroplasty to RFW or FAW. Participants are followed up for 3 months. Definitive deep surgical site infection within 90 days of surgery, the primary endpoint, is determined by a blinded endpoint committee. DISCUSSION: Hemiarthroplasty carries a risk of deep surgical site infection of approximately 3%. In order to provide 90% power to demonstrate an absolute risk reduction of 1%, using a 5% significance level, a full trial would need to recruit approximately 8630 participants. A pilot study is being conducted in the first instance to demonstrate that recruitment and data management strategies are appropriate and robust before embarking on a large multi-centre trial. TRIAL REGISTRATION: ISRCTN, ISRCTN74612906 . Registered on 27 February 2017. PMID- 30454035 TI - N6-methyldeoxyadenosine directs nucleosome positioning in Tetrahymena DNA. AB - BACKGROUND: N6-methyldeoxyadenosine (6mA or m6dA) was shown more than 40 years ago in simple eukaryotes. Recent studies revealed the presence of 6mA in more prevalent eukaryotes, even in vertebrates. However, functional characterizations have been limited. RESULTS: We use Tetrahymena thermophila as a model organism to examine the effects of 6mA on nucleosome positioning. Independent methods reveal the enrichment of 6mA near and after transcription start sites with a periodic pattern and anti-correlation relationship with the positions of nucleosomes. The distribution pattern can be recapitulated by in vitro nucleosome assembly on native Tetrahymena genomic DNA but not on DNA without 6mA. Model DNA containing artificially installed 6mA resists nucleosome assembling compared to unmodified DNA in vitro. Computational simulation indicates that 6mA increases dsDNA rigidity, which disfavors nucleosome wrapping. Knockout of a potential 6mA methyltransferase leads to a transcriptome-wide change of gene expression. CONCLUSIONS: These findings uncover a mechanism by which DNA 6mA assists to shape the nucleosome positioning and potentially affects gene expression. PMID- 30454037 TI - Evaluation and learning in complex, rapidly changing health systems: China's management of health sector reform. AB - Healthcare systems are increasingly recognised as complex, in which a range of non-linear and emergent behaviours occur. China's healthcare system is no exception. The hugeness of China, and the variation in conditions in different jurisdictions present very substantial challenges to reformers, and militate against adopting one-size-fits-all policy solutions. As a consequence, approaches to change management in China have frequently emphasised the importance of sub national experimentation, innovation, and learning. Multiple mechanisms exist within the government structure to allow and encourage flexible implementation of policies, and tailoring of reforms to context. These limit the risk of large scale policy failures and play a role in exploring new reform directions and potentially systemically-useful practices. They have helped in managing the huge transition that China has undergone from the 1970s onwards. China has historically made use of a number of mechanisms to encourage learning from innovative and emergent policy practices. Policy evaluation is increasingly becoming a tool used to probe emergent practices and inform iterative policy making/refining. This paper examines the case of a central policy research institute whose mandate includes evaluating reforms and providing feedback to the health ministry. Evaluation approaches being used are evolving as Chinese research agencies become increasingly professionalised, and in response to the increasing complexity of reforms. The paper argues that learning from widespread innovation and experimentation is challenging, but necessary for stewardship of large, and rapidly-changing systems. PMID- 30454036 TI - Intraoperative radiation therapy for the treatment of recurrent retroperitoneal and pelvic tumors: a single-institution analysis. AB - BACKGROUND: Patients with recurrent retroperitoneal and pelvic region tumors often require multimodal therapies. Intraoperative radiation therapy (IORT) can deliver high-dose radiation to tumor beds, even if first-line external beam radiation therapy (EBRT) was administered. We evaluated local control (LC) and survival in patients receiving IORT for recurrent tumors. METHODS: We retrospectively analyzed 41 patients with isolated pelvic or retroperitoneal recurrences of colorectal, gynecological, or retroperitoneal primary tumors. Following salvage surgery, all patients underwent tumor bed IORT via electron beam or high dose rate brachytherapy. Isolated IORT (median dose: 15 Gy) was administered to patients who had received first-line EBRT; other patients received IORT (median dose 12 Gy) plus EBRT. Local (LF), regional (RF), and distant failures (DF) were evaluated, and the Kaplan-Meier method and log-rank test were used to evaluate and compare overall survival (OS) from the date of IORT. RESULTS: Forty-one patients underwent 44 treatments, including 27 (61.3%) isolated IORT and 17 (38.7%) IORT and EBRT combination regimens. The median follow-up was 8.1 years (range: 4.4-11.7 years), and the 2, 5, and 8 year overall LC rates were 87.9, 64.0, and 49.8%, respectively. Regarding resection status, the respective 2, 5, and 8 year LC rates were 90, 76, and 76% for R0 resection and 75, 25, and 0% for R1 resection (p < 0.001). The 2, 5, and 8 year OS rates were 68, 43, and 26%, respectively. OS was better among patients with LC (p < 0.001). Twenty-four patients (58.5%) experienced a DF, and the 5 year OS rates for the patients with and without DF were 36 and 52%, respectively (p = 0.04). In a multivariate analysis, LF (p = 0,012) and recurrent retroperitoneal sarcoma (p = 0,014) were identified as significant predictors of worse OS. Thirteen patients (31%) developed clinically treatable complications related to IORT. CONCLUSIONS: Many patients achieve long-term OS and LC without significant morbidity after salvage surgery and IORT, especially in case of clear margins. PMID- 30454038 TI - Immunoregulatory functions of innate lymphoid cells. AB - Innate lymphoid cells (ILCs) are increasingly being recognized for their ability to impact both innate and adaptive immune cells in diverse contexts. ILCs have been observed in all secondary lymphoid tissues, in addition to being tissue resident innate lymphocytes. In these locations, ILCs are poised to interact with various immune cells at different stages of an immune response. While the heterogeneity and plasticity of ILCs has complicated their study, their association with immune dysregulation in a wide range of pathologies highlights their importance to human health and disease. Notably, in addition to promoting inflammatory immune responses, populations of ILCs have been shown to inhibit immune responses through a variety of mechanisms. The reports of ILC-mediated regulation of immune responses have differed in terms of the phenotype of the regulatory ILC populations, and their mechanism of action. Yet the ability to modulate immune responses appears to be an important function of ILCs. As our understanding of this family of lymphocytes evolves, delineating the factors that dictate whether ILCs orchestrate inflammatory immune responses or suppresses these responses will be important for understanding various disease mechanisms. Here we focus on recent reports that examine how ILCs regulate immunity in different contexts. PMID- 30454039 TI - Active full-length DNA Abeta42 immunization in 3xTg-AD mice reduces not only amyloid deposition but also tau pathology. AB - BACKGROUND: Alzheimer's disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-beta peptide 1-42 (Abeta42) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. METHODS: Immune responses were monitored by enzyme linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA Abeta42 immunotherapy were compared with brains from age- and gender-matched transgenic Abeta42 peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. RESULTS: Quantitative ELISA showed a 40% reduction of Abeta42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Abeta42 trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Abeta peptide reductions in the brain were due to the anti-Abeta antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Abeta in the brain resulting in less tau kinase activation. CONCLUSIONS: The significance of these findings is that DNA Abeta42 trimer immunotherapy targets two major pathologies in AD-amyloid plaques and neurofibrillary tangles-in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active Abeta42 peptide immunization in patients with AD (AN1792). PMID- 30454041 TI - Correction to: Improving accuracy of opening-wedge osteotomies of distal radius using a patient-specific ramp-guide technique. AB - Following publication of the original article [1], the author pointed out that the references were numbered incorrectly. This error was introduced during the production process. The original article has been corrected. PMID- 30454044 TI - Cross-sectional study on the adherence to malaria guidelines in lakeshore facilities of Buyende and Kaliro districts, Uganda. AB - BACKGROUND: Uganda adopted the Integrated Management of Malaria (IMM) guidelines, which require testing all suspected cases of malaria prior to treatment and which have been implemented throughout the country. However, adherence to IMM guidelines has not been explicitly investigated, especially in lakeshore areas such as Buyende and Kaliro, two districts that remain highly burdened by malaria. This study assesses the level of adherence to IMM guidelines and pinpoints factors that influence IMM adherence by health providers in Buyende and Kaliro. A cross-sectional study among 197 patients and 26 healthcare providers was conducted. The algorithm for adherence to IMM guidelines was constructed to include physical examination, medical history, laboratory diagnosis, and anti malarial drug prescription. Adherence was measured as a binary variable, and binary regression was used to identify factors associated with adherence to IMM guidelines. RESULTS: Only 16 (8.1%) of the 197 patients had their medical history and physical examinations taken, while the majority (65.5%) of the patients were recommended for malaria (laboratory) testing. Regarding adherence to prescription guidelines, 127 (64.5%) of the patients received artemisinin combination therapy (ACT) drug prescription. On the other hand, 18.6% of those who tested negative received an ACT drug/prescription and 10.1% tested positive but did not receive an ACT drug or prescription. Overall adherence to IMM guidelines was only 3.1%. The only factor that significantly influenced adherence to IMM guidelines was training; healthcare providers who had attended recent training on these guidelines were almost three times more likely to adhere to the IMM guidelines compared to those who had not attended recent training (OR = 2.858, 95% CI 1.754 4.659). CONCLUSIONS: The findings indicate very low levels of adherence to IMM guidelines among healthcare workers in the lakeshore areas of Kaliro and Buyende districts. Since adherence was independently influenced, majorly by training healthcare workers on these guidelines, recommendations include facilitating training on IMM guidelines throughout Uganda. PMID- 30454042 TI - Landiolol in patients with septic shock resident in an intensive care unit (LANDI SEP): study protocol for a randomized controlled trial. AB - BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR >= 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR >= 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017 002138-22 . Registered on 8 August 2017. PMID- 30454043 TI - Dietary patterns during pregnancy and risk of gestational diabetes: a prospective cohort study in Western China. AB - BACKGROUND: Previous research has demonstrated the association between maternal dietary patterns and gestational diabetes (GDM), but evidence in Asian populations remains limited and inconsistent. This study investigated the association between dietary patterns during early pregnancy and the risk of GDM among pregnant women in Western China. METHODS: A prospective cohort study was conducted among 1337 pregnant women in Western China. Dietary intakes were assessed at 15-20 weeks of gestation using a validated food frequency questionnaire. GDM was diagnosed by oral glucose tolerance tests at 24-28 weeks of gestation. Exploratory factor analysis was performed to derive dietary patterns, and logistic regression models were used to examine the association between dietary patterns and GDM. RESULTS: A total of 199 women (14.9%) developed GDM. Three dietary patterns were identified, namely, a plant-based pattern, a meat-based pattern and a high protein-low starch pattern. Notwithstanding a lack of association between dietary patterns and GDM risk in the whole cohort, there was a significant reduction in GDM risk among overweight women (BMI >=24 kg/m2); the odds ratio being 0.29 (95% confidence interval 0.09 to 0.94) when comparing the highest versus the lowest score of the high protein-low starch pattern. CONCLUSIONS: There was no significant association between early pregnancy dietary patterns and GDM risk later in pregnancy for women in Western China, but high protein-low starch diet was associated with lower risk for GDM among women who were overweight at pre-pregnancy. PMID- 30454045 TI - "We think globally": the rise of Paraguay's Tabacalera del Este as a threat to global tobacco control. AB - BACKGROUND: Leading transnational tobacco companies (TTCs) began to expand their operations in Latin America in the 1960s. This included legally exporting their cigarettes to Paraguay during the 1960s which, in turn, were illegally re exported to Argentina and Brazil. By the 1990s, competition between BAT and PMI for this lucrative illicit market, focusing on low-priced brands, prompted manufacturing in Paraguay. Paraguayan manufacturing rapidly grew after the introduction of a new cigarette export tax in Brazil in 1999. METHODS: We systematically searched Truth Tobacco Industry Documents (TTID) to understand the activities and strategies of leading TTCs in Paraguay and subregion over time. We applied the analytical framework of Lee and Eckhardt (2017) to understand Tabesa's global business strategy. We searched the websites of TTCs and Tabesa for activities since the mid 2000s to understand how the companies publicly describe these strategies. We used the United Nations Commodity Trade Statistics Database (UN Comtrade) as an independent source to crosscheck statements by Tabesa executives about export markets. We contextualized and triangulated our findings with 42 key informant interviews. RESULTS: Tabesa became the largest cigarette manufacturer in Paraguay, and one of the largest companies in the country, through complicity in the illicit trade. Enabled by market conditions created by leading TTCs, and a permissive regulatory environment in Paraguay, evidence suggests Tabesa had become a major source of illicit cigarettes across Latin America and beyond by the late 2000s. Although Brazil continues to account for the bulk of Tabesa's revenues, findings suggest that the company is aspiring to compete with TTCs in markets worldwide through legal and illegal sales. CONCLUSION: There is a need for fuller understanding of the risks to global tobacco control from local companies aspiring to compete with TTCs. The rise of Tabesa is part of the changing nature of the illicit trade in tobacco products which must be taken into account in implementing the Framework Convention on Tobacco Control (FCTC) and its Protocol to Eliminate Illicit Trade in Tobacco Products. Potential conflicts of interest concerning Tabesa illustrate the importance of FCTC Article 5.3 on industry interference. There is also an urgent need to address the lack of independent and rigorous data on the illicit tobacco trade in the region. PMID- 30454040 TI - The physiology of foamy phagocytes in multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by massive infiltration of immune cells, demyelination, and axonal loss. Active MS lesions mainly consist of macrophages and microglia containing abundant intracellular myelin remnants. Initial studies showed that these foamy phagocytes primarily promote MS disease progression by internalizing myelin debris, presenting brain-derived autoantigens, and adopting an inflammatory phenotype. However, more recent studies indicate that phagocytes can also adopt a beneficial phenotype upon myelin internalization. In this review, we summarize and discuss the current knowledge on the spatiotemporal physiology of foamy phagocytes in MS lesions, and elaborate on extrinsic and intrinsic factors regulating their behavior. In addition, we discuss and link the physiology of myelin-containing phagocytes to that of foamy macrophages in other disorders such atherosclerosis. PMID- 30454047 TI - Defining and categorizing outcomes of Moral Case Deliberation (MCD): concept mapping with experienced MCD participants. AB - BACKGROUND: To support healthcare professionals in dealing with ethically difficult situations, Clinical Ethics Support (CES) services like Moral Case Deliberation (MCD) are increasingly implemented. To assess the impact of CES, it is important to evaluate outcomes. Despite general claims about outcomes from MCD experts and some qualitative research, there exists no conceptual analysis of outcomes yet. Therefore, the aim of this study was to systematically define and categorize MCD outcomes. An additional aim was to compare these outcomes with the outcomes in the Euro-MCD Instrument from 2014, to further validate this Instrument. METHODS: The concept mapping method was used and involves qualitative and quantitative steps including brainstorming, individual structuring, computation of concept maps (by principal component analysis and cluster analysis), group interpretation and utilization. In total, 12 experienced MCD participants from a variety of professional backgrounds participated in two sessions. RESULTS: The focus group brainstorm resulted in a list of 85 possible MCD outcomes, of which a point map and concept maps were constructed. After a thorough discussion of each cluster, final consensus was reached on the names and position of 8 clusters of MCD outcomes: 1) Organisation and Policy; 2) Team development; 3) Personal development focused on the Other Person; 4) Personal development as Professional, focused on Skills; 5) Personal development as Professional, focused on Knowledge; 6) Personal development as an Individual; 7) Perception and Connection; and 8) Concrete action. CONCLUSIONS: This study explored and categorized MCD outcomes in a concept mapping focus group. When comparing the results with the Euro-MCD Instrument, our study confirms that outcomes of MCD can be categorized in clusters referring to the organisational level, team development, personal development (both as an individual and a professional) and the concrete case-level. In developing CES evaluation tools, it is important to be explicit if an outcome refers to the individual or the team, to knowledge or skills, to the organisation or the specific case. The findings will be used in the further validation of the Euro-MCD Instrument. The current study further contributes to the field of evaluating CES in general and defining outcomes of MCD in particular. PMID- 30454046 TI - Pharmacy students can improve access to quality medicines information by editing Wikipedia articles. AB - BACKGROUND: Pharmacy training programs commonly ask students to develop or edit drug monographs that summarize key information about new medicines as an academic exercise. We sought to expand on this traditional approach by having students improve actual medicines information pages posted on Wikipedia. METHODS: We placed students (n = 119) in a required core pharmacy course into groups of four and assigned each group a specific medicines page on Wikipedia to edit. Assigned pages had high hit rates, suggesting that the topics were of interest to the wider public, but were of low quality, suggesting that the topics would benefit from improvement efforts. We provided course trainings about editing Wikipedia. We evaluated the assignment by surveying student knowledge and attitudes and reviewing the edits on Wikipedia. RESULTS: Completing the course trainings increased student knowledge of Wikipedia editing practices. At the end of the assignment, students had a more nuanced understanding of Wikipedia as a resource. Student edits improved substantially the quality of the articles edited, their edits were retained for at least 30 days after course completion, and the average number page views of their edited articles increased. CONCLUSIONS: Our results suggest that engaging pharmacy students in a Wikipedia editing assignment is a feasible alternative to writing drug monographs as a classroom assignment. Both tasks provide opportunities for students to demonstrate their skills at researching and explaining drug information but only one serves to improve wider access to quality medicines information. Wikipedia editing assignments are feasible for large groups of pharmacy students and effective in improving publicly available information on one of the most heavily accessed websites globally. PMID- 30454048 TI - Toward the precision breast cancer survival prediction utilizing combined whole genome-wide expression and somatic mutation analysis. AB - BACKGROUND: Breast cancer is the most common type of invasive cancer in woman. It accounts for approximately 18% of all cancer deaths worldwide. It is well known that somatic mutation plays an essential role in cancer development. Hence, we propose that a prognostic prediction model that integrates somatic mutations with gene expression can improve survival prediction for cancer patients and also be able to reveal the genetic mutations associated with survival. METHOD: Differential expression analysis was used to identify breast cancer related genes. Genetic algorithm (GA) and univariate Cox regression analysis were applied to filter out survival related genes. DAVID was used for enrichment analysis on somatic mutated gene set. The performance of survival predictors were assessed by Cox regression model and concordance index(C-index). RESULTS: We investigated the genome-wide gene expression profile and somatic mutations of 1091 breast invasive carcinoma cases from The Cancer Genome Atlas (TCGA). We identified 118 genes with high hazard ratios as breast cancer survival risk gene candidates (log rank p < 0.0001 and c-index = 0.636). Multiple breast cancer survival related genes were found in this gene set, including FOXR2, FOXD1, MTNR1B and SDC1. Further genetic algorithm (GA) revealed an optimal gene set consisted of 88 genes with higher c index (log rank p < 0.0001 and c-index = 0.656). We validated this gene set on an independent breast cancer data set and achieved a similar performance (log rank p < 0.0001 and c-index = 0.614). Moreover, we revealed 25 functional annotations, 15 gene ontology terms and 14 pathways that were significantly enriched in the genes that showed distinct mutation patterns in the different survival risk groups. These functional gene sets were used as new features for the survival prediction model. In particular, our results suggested that the Fanconi anemia pathway had an important role in breast cancer prognosis. CONCLUSIONS: Our study indicated that the expression levels of the gene signatures remain the effective indicators for breast cancer survival prediction. Combining the gene expression information with other types of features derived from somatic mutations can further improve the performance of survival prediction. The pathways that were associated with survival risk suggested by our study can be further investigated for improving cancer patient survival. PMID- 30454049 TI - Proposal and validation of a modified staging system to improve the prognosis predictive performance of the 8th AJCC/UICC pTNM staging system for gastric adenocarcinoma: a multicenter study with external validation. AB - BACKGROUND: The 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) pathological tumor-node-metastasis (pTNM) staging system may have increased accuracy in predicting prognosis of gastric cancer due to its important modifications from previous editions. However, the homogeneity in prognosis within each subgroup classified according to the 8th edition may still exist. This study aimed to compare and analyze the prognosis prediction abilities of the 8th and 7th editions of AJCC/UICC pTNM staging system for gastric cancer and propose a modified pTNM staging system with external validation. METHODS: In total, clinical data of 7911 patients from three high-capacity institutions in China and 10,208 cases from the Surveillance, Epidemiology, and End Results (SEER) Program Registry were analyzed. The homogeneity, discriminatory ability, and monotonicity of the gradient assessments of the 8th and 7th editions of AJCC/UICC pTNM staging system were compared using log-rank chi2, linear-trend chi2, likelihood-ratio chi2 statistics and Akaike information criterion (AIC) calculations, on which a modified pTNM classification with external validation using the SEER database was proposed. RESULTS: Considerable stage migration, mainly for stage III, between the 8th and 7th editions was observed in both cohorts. The survival rates of subgroups of patients within stage IIIA, IIIB, or IIIC classified according to both editions were significantly different, demonstrating poor homogeneity for patient stratification. A modified pTNM staging system using data from the Chinese cohort was then formulated and demonstrated an improved homogeneity in these abovementioned subgroups. This staging system was further validated using data from the SEER cohort, and similar promising results were obtained. Compared with the 8th and 7th editions, the modified pTNM staging system displayed the highest log-rank chi2, linear-trend chi2, likelihood-ratio chi2, and lowest AIC values, indicating its superior discriminatory ability, monotonicity, homogeneity and prognosis prediction ability in both populations. CONCLUSIONS: The 8th edition of AJCC/UICC pTNM staging system is superior to the 7th edition, but still results in homogeneity in prognosis prediction. Our modified pTNM staging system demonstrated the optimal stratification and prognosis prediction ability in two large cohorts of different gastric cancer populations. PMID- 30454051 TI - COmmunity-based Rehabilitation after Knee Arthroplasty (CORKA): statistical analysis plan for a randomised controlled trial. AB - BACKGROUND: About 15% of patients fail to achieve a satisfactory clinical outcome following knee replacement, which may indicate the existing model of rehabilitation after surgery is possibly not the most efficacious. The COmmunity based Rehabilitation after Knee Arthroplasty (CORKA) trial evaluates the effects of a new multi-component community-based rehabilitation programme following knee replacement compared with usual care. METHODS/DESIGN: The CORKA trial is a multi centre, single-blind, two-arm randomised controlled trial. The primary outcome is the Late Life Function and Disability Instrument (LLFDI) overall function score measured at 12 months post-randomisation which will be analysed using a linear mixed effects model. Secondary outcomes are measured at 6 and 12 months post randomisation and include the LLFDI frequency and limitation total dimension scores, the Oxford Knee Score, the Knee injury and Osteoarthritis Outcome Score quality of life subscale, the Physical Activity Scale for the Elderly, the EuroQol EQ-5D-5L, and several measurements of physical function. Full details of the planned analysis approaches for the primary and secondary outcomes are described here, as are the descriptive statistics which will be reported. This is an update to the CORKA protocol which has already been published in this journal. DISCUSSION: This paper provides details of the planned statistical analyses for this trial and will reduce the risks of outcome reporting bias and data-driven results. TRIAL REGISTRATION: ISRCTN registry, 13517704 . Registered on 12 February 2015. FUNDING/SPONSOR: The trial is funded by the National Institute for Health Research Health Technology Assessment programme under its commissioned research programme (HTA 12/196/08). The trial sponsor is the University of Oxford. PMID- 30454053 TI - Detection of Asherman's syndrome after conservative management of placenta accreta: a case report. AB - BACKGROUND: We present a case involving conservative treatment of placenta accreta, with a subsequent diagnosis of Asherman's syndrome. CASE PRESENTATION: A 41-year-old Japanese woman (G2P0A2) delivered a healthy male infant via cesarean section due to preeclampsia. The placenta did not spontaneously separate and was manually removed. Adhesion was tight and placenta accreta was diagnosed. During the procedure, no uterine inversion or perforation, and no uterine cavity adhesion, were observed. Four months postoperatively, hysteroscopy was performed. Adhesion was detected at the fundus of her uterus where the placenta had adhered to the uterus. Asherman's syndrome was diagnosed. CONCLUSIONS: Asherman's syndrome might occur after conservative management of placenta accreta, which may be a direct cause of placenta accreta recurrence. When Asherman's syndrome is diagnosed, the site of the placenta and adhesion should be monitored during subsequent pregnancies. PMID- 30454054 TI - Distributed gene clinical decision support system based on cloud computing. AB - BACKGROUND: The clinical decision support system can effectively break the limitations of doctors' knowledge and reduce the possibility of misdiagnosis to enhance health care. The traditional genetic data storage and analysis methods based on stand-alone environment are hard to meet the computational requirements with the rapid genetic data growth for the limited scalability. METHODS: In this paper, we propose a distributed gene clinical decision support system, which is named GCDSS. And a prototype is implemented based on cloud computing technology. At the same time, we present CloudBWA which is a novel distributed read mapping algorithm leveraging batch processing strategy to map reads on Apache Spark. RESULTS: Experiments show that the distributed gene clinical decision support system GCDSS and the distributed read mapping algorithm CloudBWA have outstanding performance and excellent scalability. Compared with state-of-the-art distributed algorithms, CloudBWA achieves up to 2.63 times speedup over SparkBWA. Compared with stand-alone algorithms, CloudBWA with 16 cores achieves up to 11.59 times speedup over BWA-MEM with 1 core. CONCLUSIONS: GCDSS is a distributed gene clinical decision support system based on cloud computing techniques. In particular, we incorporated a distributed genetic data analysis pipeline framework in the proposed GCDSS system. To boost the data processing of GCDSS, we propose CloudBWA, which is a novel distributed read mapping algorithm to leverage batch processing technique in mapping stage using Apache Spark platform. PMID- 30454052 TI - Field effectiveness and safety of fluralaner plus moxidectin (Bravecto(r) Plus) against ticks and fleas: a European randomized, blinded, multicenter field study in naturally-infested client-owned cats. AB - BACKGROUND: A spot-on formulation containing fluralaner (280 mg/ml) plus moxidectin (14 mg/ml) (Bravecto(r) Plus) has been developed to provide broad spectrum parasite protection for cats. The effectiveness and safety of this product against ticks and fleas was assessed in a randomized, controlled, 12-week study in client-owned cats in Germany and Spain. METHODS: Eligible households containing at least one cat with at least two fleas and/or two ticks were allocated randomly in a 2:1 ratio to a single treatment with fluralaner plus moxidectin on Day 0, or three 4-weekly treatments with fipronil (Frontline(r)). Veterinary staff, masked to treatment, completed tick and flea counts on each cat at 14 +/- 2 (2 weeks), 28 +/- 2 (4 weeks), 56 +/- 2 (8 weeks) and 84 +/- 2 days (12 weeks) after the initial treatment. RESULTS: In total, 707 cats (257 with ticks) from 332 households (236 with fleas) were included. Ixodes ricinus (78%) and Rhipicephalus sanguineus complex (18%) ticks were the most commonly identified. Tick and flea counts were lower in the fluralaner plus moxidectin group than in the fipronil group throughout the study and the efficacy of fluralaner plus moxidectin exceeded 97 and 98%, respectively. At 12 weeks, 94.1 and 93.3% of cats from the fluralaner plus moxidectin and 92.2 and 60.3% of cats from the fipronil group were free of ticks and fleas, respectively. Fluralaner plus moxidectin was non-inferior to fipronil (P < 0.0001) at all assessments and superior to fipronil at 2 and 8 weeks for the proportion of cats free of ticks (P < 0.0001). Fluralaner plus moxidectin was superior to fipronil for the proportion of both households and cats free of fleas (P < 0.0001). Both products were safe and well tolerated. CONCLUSIONS: A single application of fluralaner plus moxidectin spot-on was well tolerated by cats and highly effective for 12 weeks against ticks and fleas. Fluralaner plus moxidectin was non-inferior to fipronil for the proportion of ectoparasite-free and consistently superior to fipronil in controlling fleas. PMID- 30454050 TI - Heterogeneous burden of lung disease in smokers with borderline airflow obstruction. AB - BACKGROUND: The identification of smoking-related lung disease in current and former smokers with normal FEV1 is complex, leading to debate regarding using a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of less than 0.70 versus the predicted lower limit of normal (LLN) for diagnosis of airflow obstruction. We hypothesized that the discordant group of ever-smokers with FEV1/FVC between the LLN and 0.70 is heterogeneous, and aimed to characterize the burden of smoking-related lung disease in this group. METHODS: We compared spirometry, chest CT characteristics, and symptoms between 161 ever smokers in the discordant group and 940 ever-smokers and 190 never-smokers with normal FEV1 and FEV1/FVC > 0.70 in the SPIROMICS cohort. We also estimated sensitivity and specificity for diagnosing objective radiographic evidence of chronic obstructive pulmonary disease (COPD) using different FEV1/FVC criteria thresholds. RESULTS: The discordant group had more CT defined emphysema and non emphysematous gas trapping, lower post-bronchodilator FEV1 and FEF25-75, and higher respiratory medication use compared with the other two groups. Within the discordant group, 44% had radiographic CT evidence of either emphysema or non emphysematous gas trapping; an FEV1/FVC threshold of 0.70 has greater sensitivity but lower specificity compared with LLN for identifying individuals with CT abnormality. CONCLUSIONS: Ever-smokers with normal FEV1 and FEV1/FVC < 0.70 but > LLN are a heterogeneous group that includes significant numbers of individuals with and without radiographic evidence of smoking-related lung disease. These findings emphasize the limitations of diagnosing COPD based on spirometric criteria alone. PMID- 30454055 TI - Prevalence and spatiotemporal distribution of African swine fever in Lithuania, 2014-2017. AB - BACKGROUND: The emergence in 2014 and persistence of African Swine Fever (ASF) in Lithuania has been linked to infected wild boar movement and close contact with the carcasses of other infected wild boars. Over time the number of reported cases of ASF in wild boars gradually increased, but no detailed epidemiological data has been available. Therefore, the objective of the present study was to determine ASF virus prevalence in wild boars and domestic pigs during the 2014 2017 period and further explore the current geographical distribution of the virus. RESULTS: Our study results show that ASF virus prevalence in hunted wild boars using PCR analysis increased from 0.83% (95% CI 0.69-0.98) to 2.27% (95% CI 2.05-2.48) from 2014 to 2016 respectively. However, there was a dramatic jump in the number of ASF positive wild boars cases in 2017 resulting in prevalence of 12.39% (95% CI 11.91-12.86) (p < 0.05). The average prevalence of ASF-specific antibodies in wild boar population during years 2014-2017 was 0.45% (95% CI 0.39 0.51) based on ELISA test results. Prevalence of ASF virus in domestic pigs ranged from 0.24% (95% CI 0.17% - 0.32) in 2015 to 2.74% (95% CI 2.33% - 3.15) in 2017. The average seasonal prevalence of ASF virus in pigs was statistically significant (p < 0.05) and ranged from 0% in spring to 3.68% (95% CI 3.32-4.05) in summer. Correlation between the pig density and number of recorded pig ASF cases in affected regions was only found in 2017 (R = 0.78, p < 0.05). No correlation was detected between the wild boar density and number of recorded pig or wild boar ASF - positive cases. CONCLUSIONS: This study provides the first results of ASF virus prevalence changes in Lithuania during the 2014-2017. The overall results confirm the relatively high prevalence of ASF virus in wild boar that was gradually increasing from 2014 to 2017. In the last year of study, the number of ASF positive cases in both domestic pigs and wild boars had unexpectedly increased several times. A better understanding of current status of the disease will enable better control and prevent further spread of ASF virus in Western Europe. PMID- 30454056 TI - Exploring the contributions of two glutamate decarboxylase isozymes in Lactobacillus brevis to acid resistance and gamma-aminobutyric acid production. AB - BACKGROUND: The glutamate decarboxylase (GAD) system of Lactobacillus brevis involves two isoforms of GAD, GadA and GadB, which catalyze the conversion of L glutamate to gamma-aminobutyric acid (GABA) in a proton-consuming reaction contributing to intracellular pH homeostasis. However, direct experimental evidence for detailed contributions of gad genes to acid tolerance and GABA production is lacking. RESULTS: Molecular analysis revealed that gadB is cotranscribed in tandem with upstream gadC, and that expression of gadCB is greatly upregulated in response to low ambient pH when cells enter the late exponential growth phase. In contrast, gadA is located away from the other gad genes, and its expression was consistently lower and not induced by mild acid treatment. Analysis of deletion mutations in the gad genes of L. brevis demonstrated a decrease in the level of GAD activity and a concomitant decrease in acid resistance in the order of wild-type> DeltagadA> DeltagadB> DeltagadC> DeltagadAB, indicating that the GAD activity mainly endowed by GadB rather than GadA is an indispensable step in the GadCB mediated acid resistance of this organism. Moreover, engineered strains with higher GAD activities were constructed by overexpressing key GAD system genes. With the proposed two-stage pH and temperature control fed-batch fermentation strategy, GABA production by the engineered strain L. brevis 9530: pNZ8148-gadBC continuously increased reaching a high level of 104.38 +/- 3.47 g/L at 72 h. CONCLUSIONS: This is the first report of the detailed contribution of gad genes to acid tolerance and GABA production in L. brevis. Enhanced production of GABA by engineered L. brevis was achieved, and the resulting GABA level was one of the highest among lactic acid bacterial species grown in batch or fed-batch culture. PMID- 30454057 TI - A core outcome set for clinical trials in whiplash-associated disorders (WAD): a study protocol. AB - BACKGROUND: Whiplash-associated disorders (WAD) as a consequence of a motor vehicle crash are a costly health burden in Western societies. Up to 50% of injured people do not fully recover. There have been numerous clinical trials and cohort studies conducted for WAD with many varied outcome measures used, making data pooling difficult and hindering meta-analysis. These issues could be addressed through the development of a core outcome set (COS) that should be included in all clinical trials for WAD. The purpose of this project is to develop and disseminate a COS for clinical trials in WAD. METHODS/DESIGN: An international Steering Committee was formed to initiate and support the development of this COS. The project will comprise five phases: (1) a comprehensive review of core outcome domains used in clinical trials in WAD, (2) an international Delphi survey including individuals with WAD, health care providers, clinical researchers and insurance personnel to define the core outcome domains, (3) a meeting of relevant stakeholders to reach consensus regarding the final core outcome domains, (4) identification and evaluation of instruments used to measure the final core outcome domains, and (5) a consensus meeting to agree on the core outcome measurement instruments to be used. DISCUSSION: The aim of this proposal is to complete a five-stage process to develop a COS for all clinical trials in WAD. An implementation strategy will also be proposed. PMID- 30454058 TI - Triauxic growth of an oleaginous red yeast Rhodosporidium toruloides on waste 'extract' for enhanced and concomitant lipid and beta-carotene production. AB - BACKGROUND: Vegetable 'mandi' (road-side vegetable market) waste was converted to a suitable fermentation medium for cultivation of oleaginous yeast Rhodosporidium toruloides by steaming under pressure. This cultivation medium derived from waste was found to be a comparatively better source of nutrients than standard culture media because it provided more than one type of usable carbon source(s) to yeast. RESULTS: HPLC results showed that the extract contained glucose, xylose and glycerol along with other carbon sources, allowing triauxic growth pattern with preferably usage of glucose, xylose and glycerol resulting in enhanced growth, lipid and carotenoid production. Presence of saturated and unsaturated fatty acid methyl esters (FAMEs) (C14-20) in the lipid profile showed that the lipid may be transesterified for biodiesel production. CONCLUSION: Upscaling these experiments to fermenter scale for the production of lipids and biodiesel and other industrially useful products would lead to waste management along with the production of value added commodities. The technique is thus environment friendly and gives good return upon investment. PMID- 30454059 TI - Validation of a measurement instrument for parental child feeding in a low and middle-income country. AB - BACKGROUND: Parental child feeding practices (PCFP) are a key factor influencing children's dietary intake, especially in the preschool years when eating behavior is being established. Instruments to measure PCFP have been developed and validated in high-income countries with a high prevalence of childhood obesity. The aim of this study was to test the appropriateness, content, and construct validity of selected measures of PCFP in a low and middle-income country (LMIC) in which there is both undernutrition and obesity in children. METHODS: An expert panel selected subscales and items from measures of PCFP that have been well tested in high-income countries to measure both "coercive" and "structural" behaviors. Two sequential cross-sectional studies (Study 1, n = 154; Study 2, n = 238) were conducted in two provinces in Indonesia. Findings of the first study were used to refine subscales used in Study 2. An additional qualitative study tested content validity from the perspective of mothers (the intended respondents). Factorial validation and reliability were also tested. Convergent validity was tested with child nutritional status. RESULTS: In Study 1, a confirmatory factor analysis (CFA) model with 11 factors provided good fit (RMSEA = 0.045; CFI = 0.95 and TLI = 0.95) after two subscales were removed. Reliability was good among seven of the subscales. Following a decision to take out an additional subscale, the instrument was tested for factorial validity (Study 2). A CFA model with 10 subscales provided good fit (RMSEA = 0.03; CFI = 0.92 and TLI = 0.90). The reliability of subscales was lower than in Study 1. Convergent validity with nutrition status was found with two subscales. CONCLUSIONS: The two studies provide evidence of acceptable psychometric properties for 10 subscales from tested instruments to measure PCFP in Indonesia. This provides the first evidence of the validity of these measures in a LMIC setting. Some shortcomings, such in the reliability of some subscales and further tests of predictive validity, require further investigation. PMID- 30454060 TI - Body mass index and basal androstenedione are independent risk factors for miscarriage in polycystic ovary syndrome. AB - BACKGROUND: There is limited literature investigating the effects of body mass index (BMI) and androgen level on in vitro fertilization (IVF) outcomes with a gonadotropin-releasing hormone (GnRH)-antagonist protocol in polycystic ovary syndrome (PCOS). Androgen-related variation in the effect of body mass index (BMI) on IVF outcomes remains unknown. METHODS: In this retrospective study, 583 infertile women with PCOS who underwent IVF using the conventional GnRH antagonist protocol were included. Patients were divided into four groups according to BMI and androgen level: overweight- hyperandrogenism(HA) group, n = 96, overweight-non-HA group, n = 117, non-overweight-HA group, n = 152, and non overweight-non-HA group, n = 218. RESULTS: A significantly higher number of oocytes were retrieved, and the total Gn consumption as well Gn consumption per day was significantly lower, in the non-overweight groups than in the overweight groups. The number of available embryos was significantly higher in the HA groups than in the non-HA groups. Clinical pregnancy rate was of no significant difference among four groups. Live-birth rates in the overweight groups were significantly lower than those in non-overweight-non-HA group (23.9, 28.4% vs. 42.5%, P<0.05). The miscarriage rate in overweight-HA group was significantly higher than that in non-overweight-non-HA group (45.2% vs. 14.5%, P<0.05). Multivariate logistic regression analysis revealed that BMI and basal androstenedione (AND) both acted as significantly influent factors on miscarriage rate. The area under the curve (AUC) in receiver operating characteristic (ROC) analysis for BMI and basal AND on miscarriage rate were 0.607 (P = 0.029) and 0.657 (P = 0.001), respectively, and the cut-off values of BMI and basal AND were 25.335 kg/m2 and 10.95 nmol/L, respectively. CONCLUSIONS: In IVF cycles with GnRH antagonist protocol, economic benefits were seen in non-overweight patients with PCOS, with less Gn cost and more retrieved oocytes. BMI and basal AND were both significantly influential factors with moderate predictive ability on the miscarriage rate. The predictive value of basal AND on miscarriage was slightly stronger than BMI. PMID- 30454061 TI - Adaptive designs in clinical trials: from scientific advice to marketing authorisation to the European Medicine Agency. AB - BACKGROUND: In recent years, experience on the application of adaptive designs in confirmatory clinical trials has accumulated. Although planning such trials comes at the cost of additional operational complexity, adaptive designs offer the benefit of flexibility to update trial design and objectives as data accrue. In 2007, the European Medicines Agency (EMA) provided guidance on confirmatory clinical trials with adaptive (or flexible) designs. In order to better understand how adaptive trials are implemented in practice and how they may impact medicine approval within the EMA centralised procedure, we followed on 59 medicines for which an adaptive clinical trial had been submitted to the EMA Scientific Advice (SA) and analysed previously in a dedicated EMA survey of scientific advice letters. We scrutinized in particular the submission of the corresponding medicines for a marketing authorisation application (MAA). We also discuss the current regulatory perspective as regards the implementation of adaptive designs in confirmatory clinical trials. METHODS: Using the internal EMA MAA database, the AdisInsight database and related trial registries, we analysed how many of these 59 trials actually started, the completion status, results, the time to trial start, the adaptive elements finally implemented after SA, their possible influence on the success of the trial and corresponding product approval. RESULTS: Overall 31 trials out of 59 (53%) were retrieved. Thirty of them (97%) have been started and 23 (74%) concluded. Nine of these trials (39% out of 23) demonstrated a significant treatment effect on their primary endpoint and 4 (17% out of 23) supported a marketing authorisation (MA). An additional two trials were stopped using pre-defined criteria for futility, efficiently identifying trials on which further resources should not be spent. Median time to trial start after SA letter was given by EMA was 5 months. In the investigated trial registries, at least 18 trial (58% of 31 retrieved trials) designs were implemented with adaptive elements, which were predominantly dose selection, sample size reassessment (SSR) and stopping for futility (SFF). Among the 11 completed trials including adaptive elements, 6 demonstrated a significant treatment effect on their primary endpoint (55%). CONCLUSIONS: Adaptive designs are now well established in the drug development landscape. If properly pre planned, adaptations can play a key role in the success of some of these trials, for example to help successfully select the most promising dose regimens for phase II/III trials. Interim analyses can also enable stopping of trials for futility when they do not hold their promises. Type I error rate control, trial integrity and results consistency between the different stages of the analyses are fundamental aspects to be discussed thoroughly. Engaging early dialogue with regulators and implementing the scientific advice received is strongly recommended, since much experience in discussing adaptive designs and assessing their results has been accumulated. PMID- 30454062 TI - Patient reported barriers are associated with low physical and mental well-being in patients with co-morbid diabetes and chronic kidney disease. AB - BACKGROUND: Little is known about how patient reported barriers to health care impact the quality of life (HRQoL) of patients with comorbid disease. We investigated patient reported barriers to health care and low physical and mental well-being among people with diabetes and chronic kidney disease (CKD). METHODS: Adults with diabetes and CKD (estimated Glomerular Filtration Rate < 60 ml/min/1.73m2) were recruited and completed a questionnaire on barriers to health care, the 12-Item HRQoL Short Form Survey and clinical assessment. Low physical and mental health status were defined as mean scores < 50. Logistic regression models were used. RESULTS: Three hundred eight participants (mean age 66.9 +/- 11 years) were studied. Patient reported 'impact of the disease on family and friends' (OR 2.07; 95% CI 1.14 to 3.78), 'feeling unwell' (OR 4.23; 95% CI 1.45 to 12.3) and 'having other life stressors that make self-care a low priority' (OR 2.59; 95% CI 1.20 to 5.61), were all associated with higher odds of low physical health status. Patient reported 'feeling unwell' (OR 2.92; 95% CI 1.07 to 8.01), 'low mood' (OR 2.82; 95% CI 1.64 to 4.87) and 'unavailability of home help' (OR 1.91; 95% CI 1.57 to 2.33) were all associated with higher odds of low mental health status. The greater the number of patient reported barriers the higher the odds of low mental health but not physical health status. CONCLUSIONS: Patient reported barriers to health care were associated with lower physical and mental well-being. Interventions addressing these barriers may improve HRQoL among people with comorbid diabetes and CKD. PMID- 30454063 TI - Serum uromodulin and progression of kidney disease in patients with chronic kidney disease. AB - BACKGROUND: Uromodulin is specifically synthesized and secreted by kidney tubular epithelial cells. Studies on the association of serum uromodulin and outcomes of chronic kidney disease (CKD) are lacking. This study aimed to evaluate whether serum uromodulin was associated with outcomes of patients with CKD. METHODS: We measured serum uromodulin concentrations by ELISA in 2652 CKD patients from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE) and investigated the association of serum uromodulin with outcomes of CKD patients, including end stage kidney disease (ESKD) receiving kidney replacement therapy, cardiovascular events and mortality by Cox proportional hazards regression model. RESULTS: A total of 2652 CKD patients were enrolled in this study, with an age of 48.7 +/- 13.8 years and the baseline eGFR of 49.6 +/- 29.4 mL/min/1.73 m2, of whom 58.4% were male. The median level of urinary albumin/creatinine ratio and serum uromodulin was 473.7 mg/g (IQR 134.1-1046.6 mg/g) and 77.2 ng/mL (IQR 48.3-125.9 ng/mL), respectively. Altogether, 404 ESKD, 189 cardiovascular events, and 69 deaths occurred during the median follow-up of 53.6 (IQR 44.0-64.0) months. Lower levels of serum uromodulin were independently associated with higher risk of incident ESKD after adjusting for traditional cardiovascular risk factors, with the hazard ratios (HRs) of 3.23 (95% confidence intervals [CIs] 2.15-4.85) for the middle tertile and 7.47 (95% CI 5.06-11.03) for the bottom tertile, compared with top tertile and 0.31 (95% CI 0.25-0.38) per every standard deviation increase. After further adjustment for the baseline eGFR, the association was greatly attenuated, but still significant, with HRs of 1.92 (95% CI 1.26-2.90) for the bottom tertile compared with top tertile and 0.69 (95% CI 0.55-0.86) per every standard deviation increase. CONCLUSIONS: Serum uromodulin is independently associated with an increased risk of incident ESKD in CKD patients. PMID- 30454064 TI - Associations of immunological factors with metabolic syndrome and its characteristic elements in Chinese centenarians. AB - BACKGROUND: Metabolic syndrome (MetS) has an increased prevalence (approximately 20-25% of the adult population) all over the world. Immunological function is significantly associated with the development of MetS, and MetS is beginning to be considered as a chronic immune-related disease. The present study addressed on the associations of immunological factors with MetS and its characteristic elements in Chinese centenarians. METHODS: Hainan is a longevity region with the highest population density of centenarians in China. The China Hainan Centenarian Cohort Study has a considerable sample size, and provides a significant population-based sample of centenarians. Home interview, physical examination and blood analysis were conducted following standard procedures. RESULTS: All centenarians had a median age of 102 (100-115) years, and the proportion of females was 80.8%. The proportion of centenarians with MetS was 16.0% (135 centenarians). Abdominal obesity, hypertension, dyslipidemia and diabetes mellitus had a prevalence of 26.4% (223 centenarians), 73.7% (623 centenarians), 40.4% (341 centenarians) and 10.7% (90 centenarians), respectively. In Logistic regression analyses, MetS was significantly associated with immunoglobulin E and complement C3 levels (P < 0.05 for all). Abdominal obesity was significantly associated with immunoglobulin E and complement C3 levels (P < 0.05 for all). CONCLUSIONS: The present study provides epidemiological evidence that MetS has significant associations with immunoglobulin E and complement C3 levels, and demonstrates that abdominal obesity is significantly associated with immunoglobulin E and complement C3 levels in Chinese centenarians. PMID- 30454065 TI - The influence of maternal pregnancy glucose concentrations on associations between a fetal imprinted gene allele score and offspring size at birth. AB - OBJECTIVE: Previously we found that certain fetal imprinted genes represented as an allele score are associated with maternal pregnancy glucose concentrations. Recently it was reported that fetal polymorphisms with strong associations with birth weight tend to mediate these independently of increases in maternal pregnancy glucose concentrations. We therefore investigated whether potential associations between the fetal allele score and birth weight were related to maternal glucose concentrations in the Cambridge Baby Growth Study. RESULTS: The fetal imprinted gene allele score was positively associated with birth weight (beta = 63 (17-109) g/risk allele, beta' = 0.113, p = 7.6 * 10-3, n = 405). This association was partially attenuated by adjusting for maternal glucose concentrations (beta = 50 (4-95) g/risk allele, beta' = 0.089, p = 0.03, n = 405). The allele score was also positively associated with risk of being large for gestational age at birth (odds ratio 1.60 (1.19-2.15) per risk allele, p = 2.1 * 10-3, n = 660) and negatively associated with risk of being small for gestational age at birth (odds ratio 0.65 (0.44-0.96) per risk allele, p = 0.03, n = 660). The large for gestational age at birth association was also partially attenuated by maternal glucose concentrations. These results suggest that associations between the fetal imprinted gene allele score and size at birth are mediated through both glucose-dependent and glucose-independent mechanisms. PMID- 30454066 TI - Differentiating Kawasaki disease from urinary tract infection in febrile children with pyuria and C-reactive protein elevation. AB - BACKGROUND: Kawasaki disease (KD) is sometimes confused with urinary tract infection (UTI) because both can present with pyuria and C-reactive protein (CRP) elevation. The present study investigated the clinical and laboratory findings that can differentiate KD from UTI in febrile children with pyuria and CRP elevation. METHODS: Medical records were retrospectively reviewed for children with KD and those with UTI. The clinical and laboratory findings between the KD with pyuria group (n = 48) and the UTI group (n = 118) were compared. RESULTS: The KD with pyuria group had older age (P < 0.001) and longer duration of fever (P < 0.001) than the UTI group. In blood tests, both groups showed increased CRP level, but the value of CRP was higher in the KD with pyuria group than in the UTI group (P < 0.001). The KD with pyuria group also showed higher values for liver enzymes than the UTI group (P < 0.001); > 70.0% of children in the KD with pyuria group, but < 20.0% of children in the UTI group possessed elevated liver enzymes (P < 0.001). On urinalysis, 40.7% of the UTI group had a positive nitrite test, but 0.0% of the KD with pyuria group had a positive nitrite test (P < 0.001). CONCLUSIONS: Elevated liver enzymes are more specific to KD than to UTI, whereas a positive nitrite test is more specific to UTI than to KD. Our findings can be used as diagnostic clues to differentiate KD from UTI in febrile children with pyuria and CRP elevation. PMID- 30454067 TI - Mortality of civilian patients with suspected traumatic haemorrhage receiving pre hospital transfusion of packed red blood cells compared to pre-hospital crystalloid. AB - BACKGROUND: Major haemorrhage is a leading cause of mortality following major trauma. Increasingly, Helicopter Emergency Medical Services (HEMS) in the United Kingdom provide pre-hospital transfusion with blood products, although the evidence to support this is equivocal. This study compares mortality for patients with suspected traumatic haemorrhage transfused with pre-hospital packed red blood cells (PRBC) compared to crystalloid. METHODS: A single centre retrospective observational cohort study between 1 January 2010 and 1 February 2015. Patients triggering a pre-hospital Code Red activation were eligible. The primary outcome measure was all-cause mortality at 6 hours (h) and 28 days (d), including a sub-analysis of patients receiving a major and massive transfusion. Multivariable regression models predicted mortality. Multiple Imputation was employed, and logistic regression models were constructed for all imputed datasets. RESULTS: The crystalloid (n = 103) and PRBC (n = 92) group were comparable for demographics, Injury Severity Score (p = 0.67) and mechanism of injury (p = 0.73). Observed 6 h mortality was smaller in the PRBC group (n = 10, 10%) compared to crystalloid group (n = 19, 18%). Adjusted OR was not statistically significant (OR 0.48, CI 0.19-1.19, p = 0.11). Observed mortality at 28 days was smaller in the PRBC group (n = 21, 26%) compared to crystalloid group (n = 31, 40%), p = 0.09. Adjusted OR was not statistically significant (OR 0.66, CI 0.32-1.35, p = 0.26). A statistically significant greater proportion of the crystalloid group required a major transfusion (n = 62, 60%) compared to the PRBC group (n = 41, 40%), p = 0.02. For patients requiring a massive transfusion observed mortality was smaller in the PRBC group at 28 days (p = 0.07). CONCLUSION: In a single centre UK HEMS study, in patients with suspected traumatic haemorrhage who received a PRBC transfusion there was an observed, but non-significant, reduction in mortality at 6 h and 28 days, also reflected in a massive transfusion subgroup. Patients receiving pre-hospital PRBC were significantly less likely to require an in-hospital major transfusion. Further adequately powered multi-centre prospective research is required to establish the optimum strategy for pre-hospital volume replacement in patients with traumatic haemorrhage. PMID- 30454068 TI - Compound kushen injection suppresses human acute myeloid leukaemia by regulating the Prdxs/ROS/Trx1 signalling pathway. AB - BACKGROUND: The increase in the levels of reactive oxygen species (ROS) in acute myeloid leukemia (AML) patients has been previously described; thus, it is important to regulate ROS levels in AML. METHODS: Flow cytometry were used to assess the in vitro effect of compound kushen injection (CKI). Quantitative proteomics were used to analyse the mechanism. The AML patient-derived xenograft (PDX) model were used to evaluate the in vivo effect of CKI. RESULTS: We found that intracellular ROS levels in AML cells were decreased, the antioxidant capacity were increased when treated with CKI. CKI inhibited the proliferation of AML cells and enhanced the cytotoxicity of AML cells, which has few toxic effects on haematopoietic stem cells (HSCs) and T cells. At the single-cell level, individual AML cells died gradually by CKI treatment on optofluidic chips. CKI promoted apoptosis and arrested cell cycle at G1/G0 phase in U937 cells. Furthermore, higher peroxiredoxin-3 (Prdx3) expression levels were identified in CKI-treated U937 cells through quantitative proteomics detection. Mechanically, the expression of Prdx3 and peroxiredoxin-2 (Prdx2) was up-regulated in CKI treated AML cells, while thioredoxin 1 (Trx1) was reduced. Laser confocal microscopy showed that the proteins Prdx2 could be Interacted with Trx1 by CKI treatment. In vivo, the survival was longer and the disease was partially alleviated by decreased CD45+ immunophenotyping in peripheral blood in the CKI treated group in the AML PDX model. CONCLUSIONS: Antioxidant CKI possess better clinical application against AML through the Prdxs/ROS/Trx1 signalling pathway. PMID- 30454070 TI - Correction to: Consistent and reproducible cultures of large-scale 3D mammary epithelial structures using an accessible bioprinting platform. AB - Following publication of the original article [1], the authors reported a typesetting error in the spelling of the second author's name. PMID- 30454071 TI - Kaposi's varicelliform eruption in a patient with metastatic melanoma and primary cutaneous anaplastic large cell lymphoma treated with talimogene laherparepvec and nivolumab. AB - BACKGROUND: Immune-directed therapies have become front-line therapy for melanoma and are transforming the management of advanced disease. In refractory cases, multi-modal immunoncology (IO) approaches are being utilized, including combining immune checkpoint blockade (ICB) with oncolytic herpes viruses. Talimogene laherparepvec (T-VEC) is the first genetically modified oncolytic viral therapy (OVT) approved for the treatment of recurrent and unresectable melanoma. The use of IO in patients with concomitant malignancies and/or compromised immune systems is limited due to systematic exclusion from clinical trials. For example, a single case report of a solid organ transplant patient successfully treated with T-VEC for metastatic melanoma has been reported. Furthermore, the use of ICB in T cell malignancies is limited and paradoxical worsening has been described. To our knowledge, this is the first report of dual ICB/T-VEC being administered to a patient with concurrent primary cutaneous anaplastic large cell lymphoma (pcALCL) and melanoma. CASE PRESENTATION: Here we present the case of a patient with concomitant primary cutaneous ALCL and metastatic melanoma, progressing on anti programmed death (PD)-1 therapy, who developed Kaposi's varicelliform eruption after receiving the first dose of Talimogene laherparepvec. CONCLUSION: This case highlights the complexities of care of patients with coexistent cancers, demonstrates rapid progression of primary cutaneous ALCL on nivolumab and introduces a novel adverse effect of Talimogene laherparepvec. PMID- 30454072 TI - Stable transgenic C9orf72 zebrafish model key aspects of the ALS/FTD phenotype and reveal novel pathological features. AB - A hexanucleotide repeat expansion (HRE) within the chromosome 9 open reading frame 72 (C9orf72) gene is the most prevalent cause of amyotrophic lateral sclerosis/fronto-temporal dementia (ALS/FTD). Current evidence suggests HREs induce neurodegeneration through accumulation of RNA foci and/or dipeptide repeat proteins (DPR). C9orf72 patients are known to have transactive response DNA binding protein 43 kDa (TDP-43) proteinopathy, but whether there is further cross over between C9orf72 pathology and the pathology of other ALS sub-types has yet to be revealed.To address this, we generated and characterised two zebrafish lines expressing C9orf72 HREs. We also characterised pathology in human C9orf72 ALS cases. In addition, we utilised a reporter construct that expresses DsRed under the control of a heat shock promoter, to screen for potential therapeutic compounds.Both zebrafish lines showed accumulation of RNA foci and DPR. Our C9 ALS/FTD zebrafish model is the first to recapitulate the motor deficits, cognitive impairment, muscle atrophy, motor neuron loss and mortality in early adulthood observed in human C9orf72-ALS/FTD. Furthermore, we identified that in zebrafish, human cell lines and human post-mortem tissue, C9orf72 expansions activate the heat shock response (HSR). Additionally, HSR activation correlated with disease progression in our C9-ALS/FTD zebrafish model. Lastly, we identified that the compound ivermectin, as well as riluzole, reduced HSR activation in both C9-ALS/FTD and SOD1 zebrafish models.Thus, our C9-ALS/FTD zebrafish model is a stable transgenic model which recapitulates key features of human C9orf72 ALS/FTD, and represents a powerful drug-discovery tool. PMID- 30454069 TI - Ten things you should know about transposable elements. AB - Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms. PMID- 30454073 TI - Fructose-1,6-bisphosphate aldolase encoded by a core gene of Mycoplasma hyopneumoniae contributes to host cell adhesion. AB - Mycoplasma hyopneumoniae is an important respiratory pathogen that causes great economic losses to the pig industry worldwide. Although some putative virulence factors have been reported, pathogenesis remains poorly understood. Herein, we evaluated the relative abundance of proteins in virulent 168 (F107) and attenuated 168L (F380) M. hyopneumoniae strains to identify virulence-associated factors by two-dimensional electrophoresis (2-DE). Seven proteins were found to be >= 1.5-fold more abundant in 168, and protein-protein interaction network analysis revealed that all seven interact with putative virulence factors. Unexpectedly, six of these virulence-associated proteins are encoded by core rather than accessory genomic elements. The most differentially abundant of the seven, fructose-1,6-bisphosphate aldolase (FBA), was successfully cloned, expressed and purified. Flow cytometry demonstrated the surface localisation of FBA, recombinant FBA (rFBA) mediated adhesion to swine tracheal epithelial cells (STEC), and anti-rFBA sera decreased adherence to STEC. Surface plasmon resonance showed that rFBA bound to fibronectin with a moderately strong KD of 469 nM. The results demonstrate that core gene expression contributes to adhesion and virulence in M. hyopneumoniae, and FBA moonlights as an important adhesin, mediating binding to host cells via fibronectin. PMID- 30454074 TI - Importance of operator training and rest perfusion on the diagnostic accuracy of stress perfusion cardiovascular magnetic resonance. AB - BACKGROUND: Clinical evaluation of stress perfusion cardiovascular magnetic resonance (CMR) is currently based on visual assessment and has shown high diagnostic accuracy in previous clinical trials, when performed by expert readers or core laboratories. However, these results may not be generalizable to clinical practice, particularly when less experienced readers are concerned. Other factors, such as the level of training, the extent of ischemia, and image quality could affect the diagnostic accuracy. Moreover, the role of rest images has not been clarified. The aim of this study was to assess the diagnostic accuracy of visual assessment for operators with different levels of training and the additional value of rest perfusion imaging, and to compare visual assessment and automated quantitative analysis in the assessment of coronary artery disease (CAD). METHODS: We evaluated 53 patients with known or suspected CAD referred for stress-perfusion CMR. Nine operators (equally divided in 3 levels of competency) blindly reviewed each case twice with a 2-week interval, in a randomised order, with and without rest images. Semi-automated Fermi deconvolution was used for quantitative analysis and estimation of myocardial perfusion reserve as the ratio of stress to rest perfusion estimates. RESULTS: Level-3 operators correctly identified significant CAD in 83.6% of the cases. This percentage dropped to 65.7% for Level-2 operators and to 55.7% for Level-1 operators (p < 0.001). Quantitative analysis correctly identified CAD in 86.3% of the cases and was non inferior to expert readers (p = 0.56). When rest images were available, a significantly higher level of confidence was reported (p = 0.022), but no significant differences in diagnostic accuracy were measured (p = 0.34). CONCLUSIONS: Our study demonstrates that the level of training is the main determinant of the diagnostic accuracy in the identification of CAD. Level-3 operators performed at levels comparable with the results from clinical trials. Rest images did not significantly improve diagnostic accuracy, but contributed to higher confidence in the results. Automated quantitative analysis performed similarly to level-3 operators. This is of increasing relevance as recent technical advances in image reconstruction and analysis techniques are likely to permit the clinical translation of robust and fully automated quantitative analysis into routine clinical practice. PMID- 30454076 TI - Vacuum Ultraviolet Spectroscopy as a New Tool for GC Analysis of Terpenes in Flavors and Fragrances. AB - Background: Traditional detectors such as flame ionization detection and MS have issues with coeluting isomers like terpenes; however, unique vacuum UV (VUV) absorbance spectra can be used to deliberately compress chromatography. Objective: Deconvolution capabilities under various run conditions of GC-MS and GC-VUV are compared. Methods: A standard terpenes mix and tea tree essential oil were run on both GC-MS (63 and 14 min run times) and GC-VUV (22, 11, and 7 min run times). Results: The three GC-VUV methods showed good precision for 10 terpenes, as well as with the 63 min GC-MS method. The 14 min GC-MS method struggled precisely quantifying some terpenes. Highlights: GC-VUV allows for faster run times while providing the same level of quantitative accuracy. PMID- 30454075 TI - Effects of the birthing room environment on vaginal births and client-centred outcomes for women at term planning a vaginal birth: BE-UP, a multicentre randomised controlled trial. AB - BACKGROUND: Caesarean sections (CSs) are associated with increased risk for maternal morbidity and mortality. The recommendations of the recently published German national health goal 'Health in Childbirth' (Gesundheit rund um die Geburt) promote vaginal births (VBs). This randomised controlled trial (RCT) evaluates the effects of a complex intervention pertaining to the birth environment, based on the sociology of technical artefacts and symbolic interactionism. The intervention is intended to foster an upright position and mobility during labour, which lead to a higher probability of VB. METHODS/DESIGN: This study is an active controlled superiority trial with a two-arm parallel design. The complex intervention involves making changes to the birthing room to encourage an upright position and mobility of women in labour and to relax them, which may help them to cope with labour and may increase self-determination. This may result in more VBs. Included in the study are primiparae and multiparae with a singleton foetus in cephalic presentation at term planning a VB. According to the sample size calculation, 3800 women in 12 obstetrical units are to be included. Randomisation will be performed centrally and controlled by an independent coordination centre. Blinding of participants and staff is not possible. Key outcomes are VB, episiotomy, perineal tears, epidural analgesia, critical outcome of newborn at term and maternal self-determination during birth. Additionally, a health economic evaluation will be performed. DISCUSSION: This is the first adequately powered multicentre RCT examining the effect of a redesigned birthing room on the probability of a VB and patient-centred physical and emotional outcomes. An increase in the number of VBs by 5% from a baseline of 74% to 79% would result in 21,000 women per year experiencing a VB rather than a CS in Germany. Expected benefits are greater self-determination during labour, improved physical and emotional client-centred outcomes, fewer medical interventions and a reduction in health-care costs. TRIAL REGISTRATION: German Clinical Trials Register (Deutsches Register Klinischer Studien), DRKS00012854 . Registered on 7 March 2018. PMID- 30454077 TI - Comparative Validation Study to Demonstrate the Equivalence of an Alternate Next Day Enrichment Protocol for the TRANSIA(r) PLATE Salmonella Gold Method to Culture Methods for the Detection of Salmonella in Selected Foods and Environmental Surfaces. AB - TRANSIA(r)PLATE Salmonella Gold is an ELISA that was validated by Association Francaise de Normalisation (AFNOR) in 2001 and as a Performance Tested MethodSM (PTM) by AOAC in 2006 (PTM No. 010602) as a two-step enrichment protocol requiring 48 h. A simple next-day enrichment protocol using modified Enterohemorrhagic Escherichia coli media was developed for the TRANSIA PLATE Salmonella Gold to improve the time-to-results and laboratory work flow. We tested 128 Salmonella strains, representing all serotypes from A though Z and 51 66. TRANSIA PLATE Salmonella Gold detected all 128 of these strains. None of the 50 non-Salmonella strains were detected by TRANSIA PLATE Salmonella Gold. Performance of TRANSIA PLATE Salmonella Gold using the new enrichment protocol was compared with U.S. Department of Agriculture Microbiology Laboratory Guidebook reference culture procedure for the detection of Salmonella in ready-to eat poultry, ready-to-eat beef, and chicken carcass rinsate. In addition, TRANSIA PLATE Salmonella Gold performance was compared with U.S. Food and Drug Administration (FDA) Bacteriological Analytical Manual (BAM) for the detection of Salmonella from raw spinach, raw almonds, raw pasta, and environmental surfaces (stainless steel, rubber, and plastic). There was no statistically significant difference in the numbers of positive results TRANSIA PLATE Salmonella Gold protocol compared with the appropriate U.S. Department of Agriculture Food Safety and Inspection Service or FDA-BAM reference methods for any of these matrixes. Robustness testing demonstrated that the introduction of small changes in the normal assay parameters had no impact on the method performance. This new enrichment protocol has been approved as a Third Level modification to Performance Tested Method 010602. PMID- 30454078 TI - HPTLC Screening of Weight Loss Products for Deliberately Added Undeclared Synthetic Drugs. AB - Background: The proposed HPTLC method combines features of the existing methods for (1) the detection of sibutramine and (2) for the detection of phosphodiesterase type 5 inhibitors and analogs. Objective: The method permits effective screening for the presence of nine adulterants in finished products, including tablets, capsules, and "instant coffee" powders. Methods: All products were prepared for analysis using the same simple procedure: ultrasound-assisted extraction in methanol for 30 min followed by centrifugation or filtration. Results: The retardation factor (RF) values of individual zones afford preliminary identification of potential adulterants. Scanning densitometry enables comparison of recorded UV spectra with those of known standard compounds and provides further structural information. Conclusions: The method was successfully applied to 12 commercial products. Of those, nine products tested positive for at least one undeclared component. PMID- 30454079 TI - Determination of Iron in Spinach Using Linear Sweep Voltammetry at Iodine-Coated Platinum Rotating Disk Electrode. AB - Background: In contrast to the hyper-reactive platinum electrode, iodine-coated platinum electrode shows remarkable inertness toward adsorption and surface processes. For this reason, iodine-coated platinum electrode lends itself to interesting voltammetric applications. Hydrodynamic voltammetric analysis, one of the voltammetric techniques family, has many advantages over stationary voltammetric techniques inter alia the steady state current and the higher sensitivity. Objective: The present work is aimed at utilization of iodine-coated platinum rotating disk electrode for analysis of iron in spinach. Methods: The developed method is based on a voltammetric sweep at an iodine-coated rotating disk platinum electrode. The optimized experimental parameters included a potential scan from -0.20 to 0.85 V versus Ag/AgCl/[Cl-] = 1.0 M, 50 mV/s scan rate, and a rotation rate of 1000 rpm. Results: Oxidation of iron at the iodine coated platinum rotating disk electrode was manifested by a wave at E1/2 = +0.72 V. The limiting current was found to exhibit an excellent linearity with the concentration of iron (R2 = 0.996). The detection limit was 0.0 7 ppm. A comparative analytical study on determination of iron content in spinach samples was conducted by the voltammetric method and ICP-OES method. Application of the paired t-test to the results indicated that the null hypothesis is valid at P = 0.05. Conclusions: A sensitive and selective validated method was developed for determination of iron content in spinach. Highlights: A simple, fast, and reliable voltammetric method was developed for iron analysis in spinach. The main feature of the developed method is removing the effect of cationic interferences. PMID- 30454081 TI - Development and Validation of an Affordable, Nonperishable Suturing Simulator. PMID- 30454080 TI - Validation of the TadpoleTM Campylobacter jejuni Real-Time PCR Identification Kit. AB - Background: The gene-based real-time PCR method for identification of Campylobacter jejuni is more simple, rapid and accurate than the traditional biochemical method. Objective: A performance validation of the TadpoleTM Campylobacter jejuni Real-Time PCR Identification Kit was performed. Method: The assay uses TaqMan Real-time PCR technology to amplify target genes from isolated colonies. Bacterial deoxyribonucleic acid (DNA) from inclusivity and exclusivity organisms cultured on Columbia Blood Agar, Campy-Cefex agar and modified Charcoal Cefoperazone Deoxycholate was extracted and analyzed on three instruments: Applied Biosystems (ABI) 7500 Fast, ABI StepOne Plus and Bio-Rad CFX96. Results: When 57 distinct strains of C. jejuni were tested for inclusivity, all 57 strains produced positive results on the three instruments. In exclusivity testing, all 35 strains of related organisms, including 7 non-target Campylobacter strains and other common species, produced negative results on the three instruments. The Independent Laboratory validation consisting of an inclusivity and exclusivity evaluation for 10 C. jejuni isolates and 10 nontarget Campylobacter isolates also showed 100% expected results on the three instruments. In addition, in robustness testing, small, deliberate changes to the assay parameters, including cell suspension turbidity, heat lysis time, and DNA template volume in the PCR reaction, did not affect the kit performance. Finally, the combined lot-to-lot and stability study on both the ABI 7500 Fast and the ABI StepOne Plus showed that the 11 C. jejuni strains and 5 nontarget Campylobacter strains can be correctly identified by the three independently manufactured, lots and it supported a shelf life of 9 months when stored at -20 degrees C. Conclusions: The Tadpole method offers a rapid, accurate, and robust alternative for C. jejuni identification. Highlights: Rapid and accurate method to identify C. jejuni, which has a good robustness and high stability. It is flexible and offers the advantages of reduced labor and time saving. PMID- 30454083 TI - Infrarenal Infected Aneurysm of Abdominal Aorta Caused by Clostridium Perfringens. PMID- 30454082 TI - Single-Center Experience with Subvesical Bile Ducts (Ducts of Luschka). PMID- 30454084 TI - Incidence of and Risk Factors for Incisional Hernia after Liver Surgery Performed with a J-Shaped Right Subcostal Incision. PMID- 30454085 TI - Missile Embolism to the Pulmonary Artery. PMID- 30454087 TI - Asymptomatic Metastatic Carcinoid Tumor Discovered by Routine Screening Mammography. PMID- 30454088 TI - Is Neoadjuvant Radiotherapy Alone a Good Alternative to Neoadjuvant Chemoradiotherapy in Patients with Low Performance Status? PMID- 30454089 TI - Implementation of a Trauma Activation Checklist. PMID- 30454090 TI - Wound Breakdown with Stratafix versus Monocryl Suture in Aesthetic and Reconstructive Plastic Surgery: Data from a Single Surgeon. PMID- 30454091 TI - Damage Control Vascular Surgery for the General Surgeon. PMID- 30454092 TI - Caught in Limbo: The Effect of ICU Boarding Time on Overall Hospital Length of Stay in Trauma Patients. PMID- 30454094 TI - Triple Positive Breast Cancer in a Male with Cardiac Disease. PMID- 30454093 TI - A Surgical "Chimera": The Gallbladder Volvulus in the Spigelian Hernia Sac. PMID- 30454095 TI - The Incidence of Severe Dysphagia after Odontoid Fracture. PMID- 30454096 TI - Needle Break: Complication and Management of Intraosseous Vascular Access. PMID- 30454097 TI - Factors Associated with Treatment Failure after an Index Episode of Acute Diverticulitis. PMID- 30454098 TI - Cardiac Tamponade from Coronary Artery Injury after Laparoscopic Anti-Reflux Surgery. PMID- 30454099 TI - Giant Pseudocysts of the Spleen: A Rare Sequela of Traumatic Splenic Injury. PMID- 30454100 TI - A Radiologically Detected Intraperitoneal Foreign Body in a Patient Without Prior Surgery. PMID- 30454101 TI - Cholecystotomy with Stone Retrieval: A Novel Approach for the Management of Gallstone Ileus. PMID- 30454102 TI - The Management of Patients with Colorectal Cancer and Synchronous Liver Metastases or Indeterminate Liver Lesions: A Community Teaching Hospital Experience. PMID- 30454103 TI - Atypical Vascular Breast Masses. PMID- 30454104 TI - A Brief History on the Evolution of Amputation Hemorrhage Control and Surgical Technique. PMID- 30454105 TI - The Triple-Negative Test for Alcohol Dependence: A Reliability Study. PMID- 30454106 TI - James Mann, M.D. (1759-1832): Military Surgeon for the "Second War of Independence". PMID- 30454107 TI - Chronic Intestinal Pseudo-Obstruction. PMID- 30454108 TI - A Comparison of Laparoscopic and Open Repair of Acute Penetrating Diaphragm Injury. PMID- 30454109 TI - A Rare Case of Plasmablastic Lymphoma Mimicking Adenocarcinoma of the Sigmoid Colon. PMID- 30454110 TI - Colonic Adenocarcinoma Presenting as Sigmoidorectal Intussusception: A Consideration for Intussusception Reduction. PMID- 30454111 TI - A Trauma Patient Advocate Is a Valuable Addition to the Multidisciplinary Trauma Team: A Process Improvement Project. PMID- 30454112 TI - Gastric Adenocarcinoma Presenting after Revisional Roux-en-Y Gastric Bypass. PMID- 30454113 TI - Variation in Follow-up of Asymptomatic Breast Cancer Patients: Can We Choose More Wisely? PMID- 30454114 TI - Pediatric Falls in a Nonpediatric Trauma Center-When Is Trauma Team Activation Needed? PMID- 30454115 TI - Overwhelming Recurrent Clostridium difficile Infection after Reversal of Diverting Loop Ileostomy Created for Prior Fulminant C. difficile Colitis. PMID- 30454116 TI - Spontaneous Renal Calyceal Rupture: A Rare Cause of an Acute Abdomen in Pregnancy. PMID- 30454117 TI - Modern Management of Medieval Injury: Cardiac Trauma Sustained by Crossbow. PMID- 30454118 TI - Management of Mangled Extremity from Shotgun Blast Injury. PMID- 30454119 TI - Two Separate Colorectal Granular Cell Tumors. PMID- 30454120 TI - Splenectomy for Primary and Secondary Splenic Neoplasm. PMID- 30454121 TI - Malignant Large Bowel Obstruction: A Rare Presentation of Metastatic Pancreatic Cancer. PMID- 30454122 TI - Appendix Neoplasms in a Rural County: A Review of an Unexpected Number of Cases. PMID- 30454123 TI - Nonoperative Management of a Penetrating Injury to the Retrohepatic Inferior Vena Cava. PMID- 30454124 TI - Symptomatic Late Saphenous Vein Graft Aneurysm in an Upper Extremity Bypass. PMID- 30454125 TI - Ileal Volvulus with Chronic Obstruction. PMID- 30454126 TI - Novel Treatment of Acute Respiratory Distress Syndrome after Chlorine Gas Inhalation Injury. PMID- 30454127 TI - Recanalized Umbilical Vein as a Source of Hemorrhagic Shock. PMID- 30454128 TI - Delayed Splenic Rupture with Normal Admission CT Scan after Blunt Trauma. PMID- 30454129 TI - Survival of Left Chest and Mediastinal Impalement with a Fence Post. PMID- 30454130 TI - Retained Percutaneous Endoscopic Gastrostomy Causing Small Bowel Obstruction in Inguinal Hernia. PMID- 30454131 TI - Operative versus Nonoperative Management of Multiple Rib Fractures. PMID- 30454132 TI - Inflammatory Pseudotumor of the Breast. PMID- 30454133 TI - A Novel Technique to Retrieve a Misdeployed Aortic Endograft within a Dislodged Iliac Stent. PMID- 30454134 TI - Traumatic Rupture of Extra-adrenal Pheochromocytoma. PMID- 30454135 TI - Trends in Elderly Trauma Revisited: Has Management of Elders with Blunt Traumatic Injury Improved? PMID- 30454137 TI - Novel Repair of Grynfeltt Hernia Using Self-Fixating Mesh. PMID- 30454136 TI - Micronutrient and Metabolic Status in Morbidly Obese Patients Undergoing Bariatric Surgery in a University Bariatric Program. PMID- 30454138 TI - Mucormycosis Infection Following Trauma. PMID- 30454139 TI - Angiosarcoma of the Breast: A Rare and Dismal Complication of Breast Surgery Associated with Radiation. PMID- 30454140 TI - Acute Extremity Compartment Syndrome Secondary to Statin-Induced Myopathy. PMID- 30454141 TI - Misplaced Central Venous Catheter or Persistent Left Superior Vena Cava? PMID- 30454142 TI - Classification of Nonocclusive Mesenteric Ischemia Based on the Trigger for the Disease. PMID- 30454143 TI - Increasing Body Mass Index Predicts Wound Complications after Elective Endovascular Abdominal Aortic Aneurysm Repair. PMID- 30454144 TI - Sustainability of NSQIP-Driven Protocol Changes at a Single Institution. PMID- 30454145 TI - Solitary Fibrous Tumors of the Pleura: Current Diagnostic Tools. PMID- 30454146 TI - 10-Year Analysis of Benign Ovarian Teratomas: Outcomes and Follow-Up. PMID- 30454147 TI - Acute Scrotal Edema in Cirrhotic after Laparoscopic Cholecystectomy. PMID- 30454148 TI - Paget's Disease of the Breast: An Institutional Review and Surgical Management. PMID- 30454149 TI - High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. PMID- 30454150 TI - Renal Function Does Not Deteriorate after Elective Digestive Surgery in Severe Chronic Kidney Disease Patients in the Predialysis State. PMID- 30454151 TI - Postoperative Central Anticholinergic Syndrome: Is it Really that Rare? PMID- 30454152 TI - Chief Resident Dictation of Operative Cases and Its Relationship to American Board of Surgery Examination Performance. PMID- 30454153 TI - Laparoscopic Excision of Remnant Gallbladder after Subtotal Cholecystectomy. PMID- 30454154 TI - Biliary Cystadenoma and Cystadenocarcinoma of the Gallbladder: A Clinical Review. PMID- 30454156 TI - Pericarditis as a Result of Pneumomediastinum after Uncomplicated Laparoscopic Totally Extraperitoneal Inguinal Hernia Repair. PMID- 30454155 TI - Lap-Belt-Induced Pediatric Blunt Traumatic Abdominal Wall Hernia. PMID- 30454157 TI - Gracilis Flap for Perineal Closures in Minimally Invasive Abdominoperineal Resection. PMID- 30454158 TI - Evaluation of Blood Flow with Indocyanine Green-Guided Imaging to Determine Optimal Site for Gastric Conduit Anastomosis to Prevent Anastomotic Leak after Esophagectomy. PMID- 30454159 TI - A Strangulated Cecal Volvulus through the Foramen of Winslow, a Rare Presentation of Internal Herniation. PMID- 30454160 TI - Impact of Preinjury Anticoagulation with Warfarin on Outcomes of Adult Trauma Patients: Experience of a Level 1 Trauma Center. PMID- 30454162 TI - Pancreatic Pseudocyst-Induced Gastric Varices: A Rare Case of Extrahepatic Portal Hypertension? PMID- 30454161 TI - End-Stage Pancreatic Adenocarcinoma Presenting as a Sister Mary Joseph's Nodule. PMID- 30454163 TI - Segmental Resection versus Local Excision for Colonic Endometriosis. PMID- 30454164 TI - Esophageal Hematoma following Acute Esophageal Barotrauma. PMID- 30454165 TI - Caudal Duplication: Management of a Rare Congenital Condition. PMID- 30454166 TI - The Utility of Abdominal CT for Preoperative Planning of Percutaneous Endoscopic Gastrostomy Tube Placement. PMID- 30454167 TI - Benign Pneumatosis Intestinalis: Can We Avoid the Knife? PMID- 30454168 TI - A Novel Technique Using Intraoperative Fluoroscopy as a Tool to Achieve Negative Margins for Wire-Guided Partial Mastectomies. PMID- 30454169 TI - Retrograde Intussusception after Roux-en-Y Gastric Bypass. PMID- 30454170 TI - Congenital Symmastia: A Reconstruction Technique. PMID- 30454171 TI - Impact of Health-Care Worker Attitudes Toward Organ Donation. PMID- 30454172 TI - Extralobar Pulmonary Sequestration with Accompanying Ipsilateral Diaphragmatic Eventration. PMID- 30454173 TI - Association between Blood Transfusion, Transfusion Setting, and the Risk of Venous Thromboembolism in Patients with Isolated Orthopedic Trauma. PMID- 30454174 TI - Tracheocarotid Fistula. PMID- 30454175 TI - Management of a Persistent Surgical Scalp Wound Complicated by Folliculitis and Dehiscence. PMID- 30454176 TI - Alcohol, Injuries, and Outcomes Comparing Injured Moped and Motorcycle Drivers. PMID- 30454177 TI - Hyperthyroidism and Thyroid Carcinoma. PMID- 30454178 TI - Laparoscopic-Assisted Endoscopic Retrograde Cholangiopancreaticography after Roux en-Y Gastric Bypass. PMID- 30454179 TI - A Rare Cause of Bowel Obstruction: An Incarcerated Obturator Hernia. PMID- 30454180 TI - Feasibility and Safety of Irreversible Electroporation in Locally Advanced Pelvic and Retroperitoneal Tumors. PMID- 30454181 TI - Association of Duration of Symptoms and Secondary Signs in Ultrasound for Pediatric Appendicitis. PMID- 30454182 TI - Mucoepidermoid Carcinoma of the Lingual Tonsil. PMID- 30454184 TI - Recurrent Cervical Cancer Presenting as Inflammatory Breast Cancer. PMID- 30454183 TI - Hiatal Hernia Cruroplasty with a Running Barbed Suture Compared to Interrupted Suture Repair. PMID- 30454185 TI - Analysis of Endoscopic Retrograde Cholangiopancreatography in Rural Appalachia. PMID- 30454186 TI - A Violation of Occam's Razor: Acute Appendicitis after Motor Vehicle Collision. PMID- 30454188 TI - Unicentric Castleman's Disease Masquerading as a Carcinoid Tumor of the Small Intestine. PMID- 30454187 TI - Concomitant Laparoscopic Ileocolectomy and Ladd's Procedure for Crohn's Ileocolitis with Mesenteric Abscess and Congenital Megacolon. PMID- 30454189 TI - Penetrating Spinal Cord Trauma: A Unique Patient Presentation. PMID- 30454190 TI - Necrotizing Fasciitis in a Healthy Pediatric Patient Caused by Enterobacter cloacae and Serratia marcescens: A Discussion of Diagnosis and Management. PMID- 30454192 TI - Profiling Surgical Staplers: How to Increase the Strength of Anastomoses between the Edematous and Normal Intestine. PMID- 30454191 TI - Two-Stage Laparoscopic Approach for Jejunoileal Bypass Reversal. PMID- 30454193 TI - Axillary Artery Aneurysm Presenting as Acute Limb Ischemia. PMID- 30454194 TI - Massive Upper Gastrointestinal Bleeding Due to a Ruptured Splenic Artery Pseudoaneurysm. PMID- 30454195 TI - Implantable Central Venous Access Ports Placed in Mastectomy Incision Sites: A Safe and Viable Option. PMID- 30454197 TI - Does Surgical Bypass or Palliative Resections Offer the Better Palliative Treatment for Advanced Pancreatic Cancer? A Meta-Analysis. PMID- 30454196 TI - De Garengeot's Hernia: Radiological and Intraoperative Imaging. PMID- 30454198 TI - Heterotopic Mesentery Ossification after Abdominal Surgery. PMID- 30454200 TI - The Reliability of Self-Reporting Blood Type: Helmet Patches, ID Tags, Tattoos, and Other Blood Type Identification. PMID- 30454201 TI - Cutaneous Metastases from Colorectal Cancer: Oncological Behavior and Surgical Strategy. PMID- 30454199 TI - Sonazoid Can Help Visualize the Intraductal Spread of Breast Cancer. PMID- 30454202 TI - Malignant Transformation of an Extrapulmonary Inflammatory Myofibroblastic Tumor. PMID- 30454203 TI - Ileosigmoid Knotting: A Rare But Treacherous Cause of Closed Loop Obstruction. PMID- 30454204 TI - Ultrasound with Electromagnetic Tracking Navigation and Image Fusion System in Laparoscopic Liver Surgery: An Initial Clinical Experience. PMID- 30454205 TI - Mechanical Small Bowel Obstruction Caused by a Retained Free Intraperitoneal Staple Following Laparoscopic Appendectomy. PMID- 30454206 TI - Hidradenitis Suppurativa: Radical Cure in a Patient with a Malignant Course. PMID- 30454208 TI - Lung Metastasis Presenting as Rectal Mass. PMID- 30454209 TI - Pediatric Four-Wheel Type Vehicle Injuries: Outcomes and Injury Patterns. PMID- 30454207 TI - Wernicke Encephalopathy after Restrictive Bariatric Surgery: A Significant Increase of a Rare Complication. PMID- 30454210 TI - A Newly Developed Mask Facilitates Management During Percutaneous Endoscopic Gastrostomy Introduction in Patients with Respiratory Compromise. PMID- 30454211 TI - Acute Sigmoid Diverticulitis Presenting as Necrotizing Fasciitis of the Thigh and Retroperitoneum. PMID- 30454212 TI - Cecal Herniation and Volvulus through the Foramen of Winslow. PMID- 30454213 TI - Y-type Anovulvar Fistula Complicating Inflammatory Bowel Disease. PMID- 30454214 TI - Abdominal Cocoon-An Unusual Case of Bowel Obstruction. PMID- 30454215 TI - Splenic Abscess Requiring Early Splenectomy Following Angioembolization for Blunt Splenic Injury in an Immunocompromised Host: Implications for Management. PMID- 30454216 TI - Empowering Surgical Residents as Mentors: A Pilot Program for Female Medical Students. PMID- 30454217 TI - Thoracic Endovascular Aortic Repair for Blunt Traumatic Rupture of a Penetrating Atherosclerotic Ulcer. PMID- 30454218 TI - Morgagni Hernia: Is It Just a Congenital Hernia or a Cause of Emergency Surgery? PMID- 30454219 TI - Perforated Transverse Colon Cancer Presenting as an Incarcerated Inguinal Hernia. PMID- 30454221 TI - Liver Metastases 10 Years after Resection of a "Benign" Insulinoma. PMID- 30454220 TI - Perils in the Pelvis: Laparoscopic Management of Bilateral Pouch of Douglas Hernial Defects. PMID- 30454222 TI - Omental Pedicle Flap Does Not Decrease the Incidence of Bowel Obstruction after Abdominoperineal Resection. PMID- 30454223 TI - Improvement in Resident Robotic Surgical Perception with a Cadaver Training Lab: A Pilot Study. PMID- 30454224 TI - Surgical Trainees' Confidence in the Operating Room Improves over Time with a Corresponding Increase in Responsibility. PMID- 30454225 TI - Efficiency and Utilization of a Surgical Procedure Proficiency Identification Card to Verify Resident Competency for Bedside Procedures. PMID- 30454226 TI - Screening for Patients at Risk for Posttraumatic Stress Disorder and Depression at Level 1 Trauma Center. PMID- 30454227 TI - Eosinophilic Enteropathy Presenting as Small Bowel Obstruction. PMID- 30454228 TI - The Effect of Preintubation Glasgow Coma Scale on Pneumonia in Trauma Patients. PMID- 30454231 TI - Direct Peritoneal Resuscitation in the Setting of Hemorrhagic Pancreatitis. PMID- 30454229 TI - Suicide Risk in Melanoma: What Do We Know? PMID- 30454232 TI - Safety Bar Compliance on Ski Lifts: Factors of Age and Lift Bar Type Impact Risk Taking Behavior. PMID- 30454233 TI - Robotic versus Laparoscopic Cholecystectomy in the Obese Patient. PMID- 30454234 TI - An Evaluation of Risk Stratification in General Surgery Patients. PMID- 30454235 TI - Seat Belt Sign as a Predictor of Placental Abruption. PMID- 30454236 TI - Complicated Jejunal Diverticulosis: A Retrospective Single-Center Evaluation and a Possible Explanation of Pathogenesis. PMID- 30454237 TI - A Novel Approach for Repair of an Isolated Inferior Vena Cava Injury in Blunt Abdominal Trauma. PMID- 30454238 TI - The Limitations of Age-Related Screening in Colorectal Cancer. PMID- 30454239 TI - Direct Penetration of the Anterior Abdominal Wall by a Perforated Neoplastic Acute Appendicitis. PMID- 30454240 TI - Preoperative Diagnosis of a Rare Variation of Amyand's Hernia: Acute Appendicitis and Periappendicular Abscess within the Scrotum of a Recurrent Inguinal Hernia. PMID- 30454241 TI - Myoepithelial Carcinoma of the Thigh after Lipoma Excision. PMID- 30454242 TI - Duration of Antibiotic Prophylaxis in Patients with Gunshot Wounds to the Head. PMID- 30454243 TI - The Evolution of Trauma Care: Relative Mortality Analysis at a Level 1 Trauma Center over Two Decades. PMID- 30454244 TI - Traumatic External Carotid Artery Avulsion Not Evident on CT Angiogram. PMID- 30454245 TI - The Role of Diverting Colostomy in Traumatic Blunt Open Pelvic Fractures. PMID- 30454246 TI - Lemierre's Syndrome: More Than Just a Sore Throat. PMID- 30454247 TI - Emphysematous Gastritis, a Spectrum of Disease: A Four-Case Report. PMID- 30454248 TI - Incidental Squamous Cell Carcinoma In Situ in a Large Pharyngoesophageal (Zenker's) Diverticulum. PMID- 30454249 TI - Performance of Rib Plate Hardware in an Elderly Woman Receiving Cardiopulmonary Resuscitation after Surgical Rib Fixation. PMID- 30454250 TI - Who is John Doe? A Case-Match Analysis. PMID- 30454251 TI - Trauma-Associated Abdominal Cocoon: Demonstration of Radiographic Evolution. PMID- 30454252 TI - Internal Iliac- Enteric Fistula: A Rare Cause of Hemorrhagic Shock. PMID- 30454253 TI - Continuing Advancements in Diagnosis and Management of Ampullary Adenoma. PMID- 30454254 TI - Rare Cause of Pneumopericardium in a Patient Following a Motor Vehicle Collision. PMID- 30454255 TI - Propeller Damage to the Parotid Duct. PMID- 30454258 TI - Masquerading as Sigmoid Adenocarcinoma: A Unique Presentation of High-Grade Serous Carcinoma Arising from Endometriosis. PMID- 30454257 TI - Midgut Volvulus in Adults with Congenital Intestinal Malrotation. PMID- 30454256 TI - Moped Collisions: Low Speed and High Impact-A Single-Center Review. PMID- 30454259 TI - Relative Mortality Analysis of Trauma Patients Requiring Emergency Surgery at a Level I Trauma Center. PMID- 30454260 TI - Novel Management for Distal Radius Fracture after Trauma. PMID- 30454261 TI - The Uterine Flap: An Option for Autogenous Repair of Perineal Hernia after Abdominoperineal Resection. PMID- 30454262 TI - Multifaceted Treatment for a Black Bear Attack. PMID- 30454263 TI - Asymptomatic Venous Bullet Emboli: Rationale for Nonoperative Management. PMID- 30454264 TI - Comparison of Outcomes between Open versus Videoscopic Superficial Inguinal Lymph Node Dissection. PMID- 30454265 TI - Recurrent Clostridium difficile Infection after Diverting Loop Ileostomy and Colonic Lavage: An Unreported Complication of the Novel Surgical Therapy. PMID- 30454266 TI - Longer Patient Travel Times Associated with Decreased Follow-Up after Endovascular Aortic Aneurysm Repair (EVAR). PMID- 30454267 TI - The Use of Fluorescence Angiography for Confirmation of Hemorrhoid Dearterialization. PMID- 30454268 TI - Outcomes Experienced by Patients Presenting with Ventral Hernia and Morbid Obesity in a Surgical Clinic. PMID- 30454269 TI - High-Frequency Oscillatory Ventilation (HFOV) as Primary Ventilator Strategy in the Management of Severe Acute Respiratory Distress Syndrome (ARDS) with Pneumothorax in the Setting of Trauma. PMID- 30454270 TI - Penetrating Traumatic Laceration of Common Hepatic Artery and Portal Vein: A Rare Story of Success. PMID- 30454271 TI - Resident Duty Hours and American Board of Surgery In-Training Examination Performance. PMID- 30454272 TI - Mediastinal Aortopulmonary Paraganglioma. PMID- 30454273 TI - Polysubstance-Induced Self-Enucleation after Motor Vehicle Collision. PMID- 30454274 TI - Multisystem Trauma: How Bad Can It Get? PMID- 30454275 TI - Overreliance on Standardized Protocols: A Pilot Study of Surgical Residents and Fellows. PMID- 30454276 TI - Joint Inguinal and Femoral Hernia Repair by a Preperitoneal Laparoscopic Approach, Using a Femoral Plug and a Supra-Infrafunicular Mesh Fitted to the Spermatic Cord. PMID- 30454277 TI - Pediatric Pedestrians and Bicyclists versus Motor Vehicle Accidents: Comparison of Injury Patterns by Mechanism and Influence of Socioeconomic Status. PMID- 30454278 TI - A Metastatic Rectal Gastrointestinal Stromal Tumor to the Small Bowel Mesentery Treated with Neoadjuvant Imatinib and Debulking Surgery Followed by Low Anterior Resection. PMID- 30454279 TI - Howard Atwood Kelly: Man of Science, Man of God. PMID- 30454280 TI - Use of a Gastroduodenal Tube to Preserve the Common Wall during Excision of a Gastric Duplication. PMID- 30454282 TI - Tying Sutures in Single-Port Laparoscopy. PMID- 30454281 TI - Penetrating Chest Trauma and Pericarditis. PMID- 30454283 TI - Colonoscopy in Rural General Surgery Practice: Challenges, Outcomes, and Quality Measures. PMID- 30454284 TI - Management of a Complex Case of a Bronchopleural Fistula. PMID- 30454285 TI - Thoracic Impalement by a Steel Reinforcing Bar. PMID- 30454286 TI - Curative Resection for Hilar Cholangiocarcinoma: Single-Center Experience with Long-Term Follow-Up. PMID- 30454287 TI - Preprocedural Fasting: Is it Time to Change Practice? PMID- 30454288 TI - Creatinine Kinase and Stimulant Abuse in Trauma. PMID- 30454289 TI - Suprapubic Midline Extraperitoneal Approach for Widespread Retroperitoneal Abscess Originating from Anorectal Abscess. PMID- 30454290 TI - Thoracic Endovascular Repair and Omental Flap Revision of Aortopulmonary Fistula Involving Aortic Pseudoaneurysm. PMID- 30454291 TI - Military Medical Skills Readiness in Combat: Advanced Trauma Life Support Performance Efficiency at Afghanistan Role 3 Hospitals. PMID- 30454292 TI - Left Lower Transverse Incision versus Transumbilical Incision for Laparoscopic Specimen Extraction in Patients with Sigmoid and Rectosigmoid Colon Cancer. PMID- 30454293 TI - The Effect of Regional Anesthesia on Oncologic Outcomes after Resection of Colorectal Hepatic Metastases. PMID- 30454294 TI - Retained Capsule Endoscopy in a Patient with a Meckel Diverticulum Previously Treated by Endovascular Embolization. PMID- 30454296 TI - Ogilvie's Syndrome or Colonic Pseudo-Obstruction. PMID- 30454295 TI - Academic versus Clinical Productivity of (Elite) United States Transplant Surgeons: Who Publishes More and Who Operates More. PMID- 30454297 TI - Management of Bilateral Spigelian Hernias. PMID- 30454298 TI - Carotid Artery Injury from Hemorrhage Control during Routine Tonsillectomy. PMID- 30454299 TI - Solitary Fibrous Tumor at the Anal Margin. PMID- 30454300 TI - An Unusual Cause of Subcutaneous Emphysema. PMID- 30454301 TI - Damage Control Laparotomy for Uterine Rupture Following Attempted Vaginal Birth after Cesarean. PMID- 30454302 TI - Anatomical Study about the Intra Individual Variability of the Superior Laryngeal Nerve: What is the Helpful Surgical Take-Away? PMID- 30454303 TI - Infectious Complications in Patients with Ventriculoperitoneal Shunts after Intra Abdominal Procedures. PMID- 30454304 TI - Case Discussion of Turnbull-Cutait Procedure for Complex Ano-vaginal Fistula: Revival of the Delayed Coloanal Pull-through Procedure and Its Application for the Modern Surgeon. PMID- 30454305 TI - Adult Intussusception Caused by Ileocecal Clostridium difficile Pseudomembranous Colitis. PMID- 30454306 TI - Sporadic, Primary Lymph Node Gastrinoma. PMID- 30454307 TI - Repair of Coloanal Anastomotic Dehiscence and Sinus Formation Using Intraluminal Application of Endo-SPONGE(r). PMID- 30454308 TI - Ovarian Thyroid Cancer. PMID- 30454309 TI - Missed Extravasation Injury from Peripheral Infusion of Norepinephrine Resulting in Forearm Compartment Syndrome and Amputation. PMID- 30454311 TI - Delayed Development of Extrathoracic Lung Herniation after Blunt Thoracic Trauma. PMID- 30454310 TI - Duodenal Leiomyoma Causing Duodenojejunal Intussusception. PMID- 30454312 TI - Laparoscopic Gastrectomy for CDH-1 Mutation. PMID- 30454313 TI - Polycythemia Vera, an Unusual Suspect in the Case of Spontaneous Splenic Rupture. PMID- 30454315 TI - Laparoscopic Duodenojejunostomy for Superior Mesenteric Artery Syndrome. PMID- 30454314 TI - Esophageal Perforation in a Sword Swallower. PMID- 30454316 TI - Alternative Strategies to Maximize Follow-Up after Parathyroidectomy. PMID- 30454317 TI - Effective Regionalization of Care for Traumatic Brain Injury in Southeastern Georgia. PMID- 30454318 TI - Utility of Pre-Liver Transplant Screening Colonoscopy. PMID- 30454319 TI - Traumatic Bilateral Anterior Cerebral Artery Entrapment with Subsequent Cerebral Infarction. PMID- 30454320 TI - Spontaneous Cholecystoduodenocutaneous Fistula. PMID- 30454321 TI - Revaccination Compliance after Trauma Splenectomy: A Call For Improvement. PMID- 30454322 TI - Investigation of the Diagnostic Precision and Utility of Sentinel Lymph Node Biopsy in the Treatment of Patients with Merkel Cell Carcinoma. PMID- 30454324 TI - Prophylactic Antibiotics in Implant-Based Breast Reconstruction. PMID- 30454323 TI - A Giant Fibroepithelial Polyp of the Small Bowel Associated with High-Grade Obstruction. PMID- 30454325 TI - Closed-Loop Bowel Obstruction Secondary to Acute Appendicitis. PMID- 30454326 TI - Gastric Outlet Obstruction after Subtotal Cholecystectomy. PMID- 30454327 TI - Temporal Factors Drive Motorcycle Collision-Related Trauma. PMID- 30454328 TI - Neoadjuvant Capecitabine Results in Similar Total Lymph Node Harvests as 5 Fluorouracil but an Increased Number of Lymph Nodes Containing Adenocarcinoma on Resection. PMID- 30454329 TI - Impact of Trauma Volume on Emergency Department Throughput, as Seen by CT Scan Completion Times. PMID- 30454330 TI - Does the Day of the Week a Mastectomy Is Performed Influence Length of Stay? PMID- 30454331 TI - Internal Hernia as Cause of Small Bowel Obstruction without History of Gastrointestinal Surgery. PMID- 30454332 TI - Appendiceal Carcinoids and the Reality of Nonoperative Acute Appendicitis: Analysis of the American College of Surgeons National Surgical Quality Improvement Program Database. PMID- 30454333 TI - Gallbladder Necrosis after Right Hepatic Artery Embolization Due to Traumatic Hepatic Injury. PMID- 30454334 TI - An Update on the Use of Temporary Intravascular Shunting in the Era of Balanced Blood Product Resuscitation. PMID- 30454335 TI - Stapled Transanal Rectal Resection Procedure with Two Different Devices: Comparative Results. PMID- 30454336 TI - Impact of Endoscopic Training for Surgeons on Endolumenal and Laparoscopic Treatment for Gastroesophageal Reflux Disease: Data from a Rural, High-Volume Antireflux Program. PMID- 30454337 TI - Adenosquamous Carcinoma of the Anus: An Uncommon Malignancy Presenting a Treatment Challenge. PMID- 30454338 TI - Laparoscopic Repair of Hiatal Hernia in the Presence of Aberrant Left Hepatic Artery Using Extracorporeal Sliding Arthroscopic Knots. PMID- 30454339 TI - Violence Against Women: Facial Fractures Secondary to Assault in the Urban Female Population. PMID- 30454340 TI - Iatrogenic Intercostal Pulmonary Hernia Repaired Using a Combination of Video Assisted Thoracoscopic Technique and Mini-Thoracotomy. PMID- 30454342 TI - Cystic Lymphangiomas: Unusual Findings Resulting in Common General Surgery Presentations. PMID- 30454341 TI - The Treatment of Triple Negative Breast Cancer: Does Insurance Status Matter? PMID- 30454343 TI - Multi-Disciplinary Approach after Blunt Polytrauma. PMID- 30454344 TI - Psychiatric Comorbidities and Outcomes in Trauma Patients: Is There a Significant Difference? PMID- 30454345 TI - Traumatic Deaths during the Functional Years: Working Toward Sustainable Prevention. PMID- 30454346 TI - Laparoscopic Repair of a Traumatic Bladder Rupture. PMID- 30454347 TI - Persistent Hemolysis after Laparoscopic Partial Splenectomy in Children. PMID- 30454348 TI - Analysis of the Financial Benefit of Same-Day Appendectomy. PMID- 30454349 TI - Cystic Lymphangioma of the Mesenteric Root in an Adolescent, an Operative Challenge. PMID- 30454350 TI - Injuries in Children because of Large Animals: A Single Institution Experience. PMID- 30454351 TI - Laparoscopic versus Robotic-Assisted Splenectomy in the Pediatric Population: Our Institutional Experience. PMID- 30454352 TI - Abdominal Compartment Syndrome after Open Biopsy for Wilms' Tumor. PMID- 30454353 TI - Large Gap Congenital Pyloric Atresia with Meconium Peritonitis: When Gastrojejunostsomy Is the Best Option. PMID- 30454354 TI - A Single Institution Study of Umbilical Vein Complications and Necrotizing Enterocolitis in Premature Infants. PMID- 30454355 TI - Colostomy as a Bridge to Definitive Pediatric Surgical Care: A Sub-Saharan African Experience. PMID- 30454356 TI - Invasive Pancreatic Adenocarcinoma Arising in Intraductal Papillary Mucinous Neoplasm of Heterotopic Pancreatic Origin Located in the Stomach. PMID- 30454357 TI - Mortality Rate of Trauma Patients Requiring Multiple Vasopressors: Better than Expected? PMID- 30454358 TI - Metastases to the Breast from Nonsmall Cell Lung Carcinoma. PMID- 30454359 TI - Cutaneous Manifestation of Histiocytic Sarcoma: Presentation and Management. PMID- 30454360 TI - Parastomal Evisceration: Rare Complication after Total Abdominal Colectomy. PMID- 30454361 TI - Chest X-Ray after Line Placement in Pediatric Patients: Is It Always Necessary? PMID- 30454362 TI - Cracking Chests without a Scratch: A Review of Emergency Department Thoracotomy Outcomes and Injuries to Providers at a Level II Trauma Center. PMID- 30454363 TI - Traumatic Acute External Auditory Canal Stenosis. PMID- 30454364 TI - Healthcare Workers' Attitude toward Organ Donation at Two Level 1 Urban Trauma. PMID- 30454365 TI - Familial Intussusception-Younger Age at Presentation, Male Predisposition, More Difficult to Reduce Radiographically, and More Likely to Recur. PMID- 30454366 TI - Substernal Colon Volvulus with Ischemia 43 Years after Reconstruction for Esophageal Atresia. PMID- 30454367 TI - Evaluation of a Trial of a Desufflation Technique to Decrease the Rate of Postoperative Pneumoperitoneum after Percutaneous Endoscopic Gastrostomy. PMID- 30454368 TI - Embolization of the Inferior Vena Cava Filter Strut to the Right Ventricle: A Case Report. PMID- 30454369 TI - Metallic Surgical Clip Causing Cholangitis after Cholecystectomy. PMID- 30454371 TI - Anaerobic Infections of Autogenous Arteriovenous Fistulae. PMID- 30454370 TI - Concurrent Laparoscopic Hernia Repair and Cystoscopic Laser Cystolitholaxapy for Urinary Bladder Calculus Contained within a Direct Inguinal Hernia. PMID- 30454372 TI - Prevention of Implanted Central Venous Port Erosion with Prophylactic Mesh Tissue Augmentation. PMID- 30454373 TI - Laparoscopic Approach to Morgagni Hernias. PMID- 30454375 TI - Intravenous Ketamine for Agitation in Critical Care. PMID- 30454374 TI - The Effects of Distance and Time in Transfers for Emergency General Surgery. PMID- 30454376 TI - The Deleterious Effects of a Vaginal Pessary in a Patient with a History of Radiation Therapy to the Posterior Vaginal Wall. PMID- 30454377 TI - Laparoscopic Approach to Perforated Peptic Ulcers Trends Toward Quicker Recovery. PMID- 30454378 TI - Excision of a Presacral Ganglioneuroma in a Young Man. PMID- 30454379 TI - Acute Traumatic Subdural Hematoma among the Elderly: Reducing Readmission. PMID- 30454380 TI - Laparoscopic, Trans-Gastric Endoscopic Removal of Gastroesophageal Junction Gastrointestinal Stromal Tumors (GIST). PMID- 30454381 TI - Laparoscopic Reduction of a Foramen of Winslow Internal Hernia Causing Transaminitis. PMID- 30454382 TI - Early Onset Massive Pulmonary Embolism after Penetrating Trauma in the Absence of Deep Vein Thrombosis. PMID- 30454383 TI - Complicated Mammoplasty and Breast Salvage with Application of Extracellular Matrix. PMID- 30454384 TI - Innovative Surgical Technique Using Omentum to Isolate and Control an Enteroatmospheric Fistula. PMID- 30454385 TI - Heart Takes a Lickin' and Keeps on Tickin', Leave the Bullet. PMID- 30454386 TI - Performance of Southeastern Surgical Congress Examinees on the American Board of Surgery Examinations: An Educational Opportunity for Regional Collaboration. PMID- 30454387 TI - Iliac Artery Bullet Embolus after Isolated Thoracic Ballistic Injury. PMID- 30454389 TI - Management of Appendicitis with the Implementation of an Acute Care Surgery Service in a Community Teaching Hospital. PMID- 30454388 TI - Pancreatic Lymphangioma: A Diagnostic and Treatment Dilemma. PMID- 30454390 TI - Soft Tissue Malignancy Due to Long-Standing Foreign Bodies after Shotgun Blast. PMID- 30454391 TI - Repeatability of REBOA as an Unforeseen Tool. PMID- 30454392 TI - Neoadjuvant Talimogene Laherparepvec for the Treatment of Metastatic Melanoma. PMID- 30454393 TI - The Impact of Gender on Complications and Outcomes of Pelvic Fracture. PMID- 30454394 TI - Native Americans Have an Increased Risk of Major Bile Duct Injury during Laparoscopic Cholecystectomy: Results from a Statewide Analysis. PMID- 30454395 TI - Management of Recurrent Invasive Ductal Carcinoma in Transrectus Abdominis Myocutaneous Flap and Lymphatic Remodeling to the Contralateral Axilla. PMID- 30454397 TI - Vicarious Contrast Excretion with Prolonged Retention Causing Biliary Colic. PMID- 30454396 TI - Upregulation of CA 19-9 in Complicated Cholecystitis. PMID- 30454398 TI - Retroversus Implantation of a Situs Solitus Deceased Donor Liver into a Situs Inversus Totalis Recipient. PMID- 30454399 TI - Continuous Abdominal Irrigation for Treatment of Tertiary Peritonitis in the Immunosuppressed Patient after Solid Organ Transplant: A Novel Approach. PMID- 30454400 TI - Hyponatremia on Initial Presentation Correlates with Suboptimal Outcomes after Traumatic Brain Injury. PMID- 30454401 TI - Damage Control Surgery and the Management of a Cholecystocolic Fistula. PMID- 30454402 TI - Intussusception in the Adult Population: A Challenge to Surgeons. PMID- 30454404 TI - Robert Reynolds Macintosh, M.D. (1897-1989): Forefather of Anesthesiology, Advocate for Patient Safety. PMID- 30454403 TI - The Changing Epidemiology of Diverticulitis in the United States. PMID- 30454405 TI - Gallbladder Polyps in Children: A Painful Inflammatory Process. PMID- 30454406 TI - Vascular Complications in Pediatric Port Removal. PMID- 30454407 TI - A Case of Ingested Dental Prosthesis with Sharp Clasps Successfully Removed Through Anus Using Part of a Plastic Glove. PMID- 30454408 TI - Handwashing Improvement Project-A Resident Run Success. PMID- 30454409 TI - Concomitant Fecal Impaction and Perforated Appendicitis in an Autistic Patient. PMID- 30454410 TI - Nonuterine Lipoleiomyoma. PMID- 30454411 TI - Primary Synchronous Bilateral Angiosarcoma of the Breast. PMID- 30454412 TI - Malignant Phyllodes: A Presentation of Two Patients with a Rare Disease. PMID- 30454413 TI - Small Bowel Obstruction from a 3-cm Gallstone in the Setting of Child-Pugh C Liver Cirrhosis. PMID- 30454414 TI - Multiple Mycotic Visceral Artery Aneurysms. PMID- 30454415 TI - Personal Watercraft Related Injuries-16-Year Experience from a Level I Trauma Center. PMID- 30454416 TI - Redo Gracilis Muscle Transposition for Recurrent Complex Pouch-Vaginal Fistula: A Feasible and Effective Pouch Salvage Surgical Procedure. PMID- 30454417 TI - Abdominal Splenosis Mimicking Carcinomatosis in a Patient with Acute Appendicitis. PMID- 30454418 TI - Traumatic Arteriovesical Fistula from the External Iliac Artery after Gunshot Wound to the Pelvis. PMID- 30454419 TI - Characterization of Pediatric Traumatic Diaphragm Injury. PMID- 30454420 TI - Cervical Impalement Injuries: Principles of Management. PMID- 30454421 TI - Development of Bone Metastasis Secondary to Appendiceal Adenocarcinoma with Signet Ring Cells. PMID- 30454422 TI - Benign Schwannoma of the Rectus Sheath: A Rare Abdominal Mass Treated in a Multidisciplinary Fashion. PMID- 30454423 TI - Vaginal Delivery during Extracorporeal Membrane Oxygenation: A Management Strategy. PMID- 30454424 TI - Outcomes of Bariatric Surgery in Patients with Multiple Sclerosis. PMID- 30454425 TI - The Role of Open Cholecystectomy in the Current Era of Laparoscopic Surgery and the Trainee Experience. PMID- 30454426 TI - Tension Pneumoperitoneum after Hanging. PMID- 30454427 TI - Malignant Embolus Should Be Considered as a Cause of Acute Limb Ischemia in Patients without a Clear Cardioembolic Source. PMID- 30454428 TI - Wound Healing Disorder Caused by Pyoderma Gangrenosum. PMID- 30454429 TI - Staged Management of Giant Inguinoscrotal Hernia. PMID- 30454430 TI - Endoscopically Assisted Transcervical Esophagogastric Tube Placement for Nonoperative Intestinal Obstruction: An Alternative to PEG Placement. PMID- 30454431 TI - Delayed Acute Subdural Hematoma in a Young Patient in the Setting of Trauma with No Head Injury. PMID- 30454432 TI - Portomesenteric Venous Gas Secondary to Acute Diverticulitis Colovenous Fistula. PMID- 30454434 TI - Staged Endovascular Repair of a Gun Shot to the Liver with Retrohepatic Caval Injury and Stent Thrombosis. PMID- 30454433 TI - Prediction of Delayed Arterial Hemorrhaging after Pancreaticoduodenectomy. PMID- 30454436 TI - The "Angled End-to-End" Technique for Colorectal Anastomosis. PMID- 30454435 TI - Common Iliac Arterial-Rectal Fistula Managed with Endovascular Stenting in a Patient with History of Pelvic External Beam Radiation. PMID- 30454437 TI - Changing the Landscape of Injury Prevention: Unlocking Geospatial Variables through Analysis of Lawn Mower Trauma. PMID- 30454438 TI - Laparoscopic Cholecystectomy for Mirizzi Syndrome: Is It Safe? PMID- 30454439 TI - Transarterial Radiation Lobectomy, Portal Vein Embolization, and Staged Hepatectomy for Multiple Bilobar Metachronous Colorectal Liver Metastasis. PMID- 30454441 TI - Feculent Empyema after Laparoscopic Appendectomy. PMID- 30454440 TI - Design and Implementation of an Enhanced Recovery after Surgery (ERAS) Pathway for Major Limb Amputation in Vascular Surgery. PMID- 30454442 TI - Late Type IA Endoleak after Open Surgical Repair of an Aortic Aneurysm Leading to Rupture: Does This Really Exist? PMID- 30454443 TI - Management of Intra-Abdominal Biloma in the Setting of Chronic Steroid Use for Nephrotic Syndrome. PMID- 30454444 TI - The Influence of Breast Density on the Utility of MarginProbe in Partial Mastectomy. PMID- 30454445 TI - Perforated Sigmoid Diverticulitis Resulting in Subcutaneous Abscess. PMID- 30454446 TI - Obstructive Uropathy Secondary to an Indirect Extraperitoneal Ureteral Inguinal Hernia. PMID- 30454447 TI - Improvement in Pathology Lymph Node Harvesting Guideline Adherence for Colorectal Cancer. PMID- 30454448 TI - Predictive Value of the Initial Trauma Survey: Is Our Hunch Good Enough? PMID- 30454449 TI - Cardiac Migration of a Prophylactic Inferior Vena Cava Filter: A Rare but Potentially Lethal Complication that Must Be Avoided. PMID- 30454450 TI - Resident Accuracy in Performing Extended Focused Assessment with Sonography in Trauma for Trauma: Not as Good as We Think We Are? PMID- 30454452 TI - Breast Necrosis after Cardiac Bypass Surgery. PMID- 30454451 TI - Cardiac Metastases from Squamous Cell Carcinoma of the Base of Tongue in a 70 Year-Old Female Six Years Disease-Free from the Primary Tumor. PMID- 30454453 TI - Repair of Vascular Stretch Injury to Distal Femoral Artery after Femur Fracture. PMID- 30454454 TI - Surgical Management of Traumatic Ballistic Injury to the Breast. PMID- 30454455 TI - Elderly Fall Patients Need a Urinalysis. PMID- 30454457 TI - Recurrent Small Bowel Obstruction Caused by Metastatic Cervical Cancer with Negative PAP Screening. PMID- 30454456 TI - Fungal Necrotizing Fasciitis after Penetrating Trauma. PMID- 30454458 TI - Mucinous Eccrine Carcinoma of the Sweat Glands: Characteristics, Treatment, and Survival Outcomes of a Rare Malignancy. PMID- 30454459 TI - Reverse Malrotation: An Uncommon Presentation of Abdominal Pain. PMID- 30454460 TI - Aortoenteric Fistula at the Site of a Marginal Ulcer after Roux-en-Y Gastric Bypass. PMID- 30454461 TI - The Problem of Exposure for Damage Control in an Adolescent with Multiple Abdominal Gunshot Wounds Six Months after Surgery for a Previous Abdominal Gunshot. PMID- 30454462 TI - Longterm Postoperative Hardware Complications after Open Rib Fixation. PMID- 30454463 TI - Laparoscopic Reversal of Roux-en-Y Gastric Bypass with Conversion to Sleeve Gastrectomy. PMID- 30454464 TI - Resolution of Raynaud's Symptoms after Parathyroidectomy. PMID- 30454465 TI - Sestamibi Scanning and Intraoperative Parathyroid Hormone Results for Parathyroid Resection in Primary Hyperparathyroidism. PMID- 30454466 TI - Is There a "Halo Effect" for Bariatric Surgery? PMID- 30454468 TI - Pure Ductal Carcinoma in situ of the Male Breast. PMID- 30454467 TI - Small Bowel Fistulization with Orphaned Intraperitoneal Ventriculoperitoneal Shunt Catheter. PMID- 30454469 TI - Celiac Artery Dissection in the Setting of Blunt Abdominal Trauma. PMID- 30454470 TI - Comparison of C-Reactive Protein and White Blood Cell Count as Predictors of Infectious Complications after Colorectal Surgery: A Single-Center Experience. PMID- 30454471 TI - Right Robotic-Assisted Transthoracic Truncal Vagotomy for Marginal Ulcer Disease after Gastric Bypass Surgery. PMID- 30454472 TI - An Examination of Military General Surgeon Comfort with Complex Hepatopancreatobiliary Procedures. PMID- 30454474 TI - Thyroid Storm Induced by Trauma: A Challenging Combination. PMID- 30454473 TI - Understanding ACGME Scholarly Activity Requirements for General Surgery Programs in the Era of Single Accreditation and the Next Accreditation System. AB - Becoming compliant with the Accreditation Council for Graduate Medical Education (ACGME) requirements for scholarly activity and remaining compliant over time requires time and attention to the development of an environment of inquiry, which is reflected in detailed documentation submitted in program applications and annual updates. Since the beginning of the next accreditation system, all ACGME programs have been required to submit evidence of scholarly activity of both residents and faculty on an annual basis. Since 2014, American Osteopathic Association-accredited programs have been able to apply for ACGME accreditation under the Single Graduate Medical Education Accreditation initiative. The Residency Program Director, Chair, Designated Institutional Official, Faculty, and coordinator need to work cohesively to ensure compliance with all program requirements, including scholarly activity in order for American Osteopathic Association-accredited programs to receive Initial ACGME Accreditation and for current ACGME-accredited programs to maintain accreditation. Fortunately, there are many ways to show the type of scholarly activity that is required for the training of surgeons. In this article, we will review the ACGME General Surgery Program Requirements and definitions of scholarly activity. We will also offer suggestions for how programs may show evidence of scholarly activity. PMID- 30454475 TI - Control of Aortoesophageal Fistula Using Endoscopic and Endovascular Techniques: A Palliative Intervention. PMID- 30454476 TI - Web-Based Support for Acute Surgical Wound Care. PMID- 30454477 TI - Jonathan Letterman, MD: The Surgeon-Soldier & His Reform of Battlefield Medicine. PMID- 30454478 TI - Dissection of the Internal Carotid Artery: An Uncommon Postoperative Complication. PMID- 30454479 TI - Superficial Peroneal Nerve Injured During Fasciotomy: A Successful Repair with Cadaveric Nerve Allograft. PMID- 30454480 TI - A New Bacterium, Lactobacillus acidophilus, Causing Necrotizing Fasciitis. PMID- 30454481 TI - A Novel Use of Microwave Ablation for Traumatic Liver Hemorrhage. PMID- 30454482 TI - Delayed Presentation of Traumatic Tricuspid Valve Injury during Index Hospitalization. PMID- 30454483 TI - An Esophageal Stent for Short-Term Management of a Retracted Stoma and Fistula. PMID- 30454485 TI - Shifting Priorities from Intubation to Circulation First in Hypotensive Trauma Patients. PMID- 30454486 TI - Successful Repair of a Ruptured Mycotic Aortic Aneurysm in a Pediatric Patient with Deep Hypothermic Circulatory Arrest. PMID- 30454487 TI - Thrombosed Persistent Sciatic Artery with Critical Limb Ischemia. PMID- 30454488 TI - Popliteal Artery Injuries in the Morbidly Obese Can Occur While Engaged in Activities of Daily Living. PMID- 30454489 TI - Man Lured with Alcohol, Takes Bait, and Gets Caught: A Cautionary Fish Tale. PMID- 30454490 TI - Endovascular Relining of a Perigraft Hygroma After Open Abdominal Aortic Aneurysm Repair. PMID- 30454491 TI - Laparoscopic Management of Gallstone Ileus. PMID- 30454492 TI - Recurrent Pain after Resection for Slipping Rib Syndrome: Report of a Difficult Case. PMID- 30454493 TI - Lateral Ectopic Thyroid in a Teenaged Girl. PMID- 30454494 TI - An Unusual Cause of Small Bowel Obstruction in a Pediatric Patient: Right-Sided Paraduodenal Hernia. PMID- 30454496 TI - Recurrent Pyloric Stenosis. PMID- 30454495 TI - Alveolar Rhabdomyosarcoma of the Breast in Adolescent Female. PMID- 30454497 TI - Total Parenteral Nutrition Lipid Emulsion Pleural and Pericardial Effusions May Present Similar Chylothorax with Milky White Chest Tube Output after Tracheoesophageal Fistula Repair. PMID- 30454498 TI - Contralateral Chylothorax after Congenital Diaphragmatic Hernia Repair. PMID- 30454499 TI - Pediatric Patients with Small-Cell Carcinoma of the Ovary Have Similar Survival to Adults: A Review of the National Cancer Database. PMID- 30454500 TI - The Pedunculated Pretender: A Case of Invasive Anorectal Mucosal Melanoma. PMID- 30454501 TI - Prevalence and Management of Posttraumatic Retained Hemothorax in a Level 1 Trauma Center. PMID- 30454502 TI - Systemic Thrombolysis of an Occlusive Aortic Thrombus in a Neonate on Extracorporeal Membrane Oxygenation. PMID- 30454503 TI - Outcomes of Donor and Recipient Obesity in Kidney Transplantation. PMID- 30454504 TI - Skin-Sparing Wide Local Debridement of Necrotizing Soft Tissue Infection: Can Less Be More? PMID- 30454505 TI - Successful Management of Ludwig's Angina Only to Encounter Perforated Viscus during Recovery. PMID- 30454506 TI - J-Pouch Prolapse as a Late Complication of Restorative Proctocolectomy. PMID- 30454507 TI - Transitioning Tube Feeding Formula to Real Food Ingredients in a Patient Less than the Age of One. PMID- 30454508 TI - Hypertriglyceridemia-Induced Pancreatitis: A Case Series of 56 Patients from One Institution. PMID- 30454510 TI - An Unusual Blunt Traumatic Retro-Aortic Hernia. PMID- 30454509 TI - Colon Cancer in an Adult with Trisomy 13. PMID- 30454511 TI - A Rare Diagnosis of Intraductal Tubulopapillary Neoplasm of the Pancreas after Pancreaticoduodenectomy. PMID- 30454513 TI - A Fatal Case of Necrotizing Pancreatitis in Sickle Cell Beta Thalassemia Zero. PMID- 30454512 TI - Incisional Malignant Evolution of Pancreatic Intraductal Papillary Mucinous Neoplasm. PMID- 30454514 TI - Surgical Management of an Obturator Hernia. PMID- 30454515 TI - Atypical Solid Serous Cystadenoma of the Pancreas. PMID- 30454516 TI - Analysis of Injury Patterns Due to Tree-Related Trauma. PMID- 30454517 TI - A Protocol to Decrease Surgical Site Infection Rates in Colorectal Surgical Procedures. PMID- 30454518 TI - Omphalomesenteric Duct Fistula with Ileal Prolapse within an Omphalocele. PMID- 30454520 TI - Cecal Volvulus: An Evolving Disease. PMID- 30454519 TI - Early Use of Extracorporeal Membrane Oxygenation after Penetrating Thoracic Trauma. PMID- 30454521 TI - Outcome of Transoral Incisionless Fundoplication in Medicare Beneficiaries in a Critical Access Hospital. PMID- 30454523 TI - The Necessity for Observation after Traumatic Loss of Consciousness. PMID- 30454522 TI - Fulminant Soft Tissue Infection with Intestinal Ischemia Associated with Staphylococcus lugdunensis. PMID- 30454524 TI - Perivascular Epithelioid Cell Tumor of the Liver. PMID- 30454525 TI - That's No Bee Sting: Penetrating Neck Trauma with Isolated Vertebral Artery Injury. PMID- 30454527 TI - Gallbladder Rupture and Acute Thoracic Aortic Disruption after Blunt Trauma. PMID- 30454526 TI - Minimally Invasive Approach for Removal of a Bullet from the Thoracic Aortic Wall after Gun Shot Wound to the Chest. PMID- 30454528 TI - Amyand Hernia with Incarcerated Acute Appendicitis. PMID- 30454529 TI - Pathologic Findings of the Gallbladder in Patients Undergoing Surgery for Biliary Dyskinesia. PMID- 30454530 TI - Canal of Nuck Hydrocele: Diagnosis and Treatment of a Rare Inguinal Pathology. PMID- 30454531 TI - Parenchyma-Sparing Hepatectomy or Major Hepatectomy for Colorectal Liver Metastases? PMID- 30454532 TI - Fullness or Distension of Proximal Jejunum: A Risk Factor Contributing to the Delayed Gastric Emptying. PMID- 30454533 TI - Blunt Trauma Patients with Cervical Stenosis and No Fracture Are More Likely to Have Neurologic Deficits and Require Surgery Than Those without Stenosis. PMID- 30454534 TI - Can Firefighters Be Taught Ultrasound? PMID- 30454536 TI - Robotic-Assisted Splenectomy for Massive Splenomegaly Secondary to Sarcoidosis. PMID- 30454535 TI - Primary Epithelioid Hemangioendothelioma of the Heart. PMID- 30454537 TI - Extensive Small Bowel Polyposis of Unknown Origin. PMID- 30454539 TI - Response to Letter. PMID- 30454538 TI - Venous Embolization of Shotgun Pellets in the Setting of Vascular and Tracheal Injury. PMID- 30454540 TI - Comment to: The Effect of Sarcopenia on Outcomes in Geriatric Blunt Trauma. PMID- 30454541 TI - [Microwave Hyperthermia Combined with Gemcitabine Inhibits Proliferation ?and Induces Apoptosis of Human Lung Squamous Carcinoma Cells]. AB - BACKGROUND: Lung cancer is one of the highest morbidity and mortality in the world and it is very important to find an effective anti-tumor method. Microwave hyperthermia, a new treatment technology, has been getting more and more attention. This study was designed to investigate the effects of microwave hyperthermia combined with gemcitabine on the proliferation and apoptosis of human lung squamous cell carcinoma (NCI-H1703 and NCI-H2170) in vitro. METHODS: The proliferation of cells treated with microwave hyperthermia, the effect of gemcitabine on cell proliferation and the proliferation of cells treated with different methods of microwave hyperthermia and gemcitabine were detected by CCK 8 assay. Colony formation assay was used to measure the colony formation of human lung squamous cell carcinoma cells. Flow cytometry assay was used to detect the total apoptosis rates of the treated cells. Caspase-3, Caspase-8 activity assay was used to detect the activity of Caspase-3, Caspase-8 enzyme in each group of cells. CCK-8 assay was used to detect the effect of control group, AC-DEVD (Caspase-3 inhibitor) group, thermalization combined group, and thermal AC-DEVD combined group on cell proliferation. The levels of p53, Caspase-3, Cleaved Caspase-3, PARP, Bax and BCL-2 protein expression were detected using Western blot assay. RESULTS: Our results demonstrated that microwave hyperthermia inhibited the proliferation of lung squamous cell carcinoma. The IC50 values of gemcitabine for the two cells were 8.89 MUmol/L and 44.18 MUmol/L, respectively. The first chemotherapy after microwave hyperthermia has synergistic effect on the two lung squamous cell carcinoma cells and can significantly inhibit the cell clone formation (P<0.001), promote cell apoptosis (P<0.001) and increase Caspase 3 enzyme activity (P<0.001). However, it has no effect on Caspase-8 enzyme activity (P>0.05). Furthermore, Western blot analysis showed that microwave hyperthermia combined with gemcitabine could up-regulate the p53, Caspase-3, Cleaved-Caspase-3, Cleaved-PARP and Bax protein expression. CONCLUSIONS: Microwave hyperthermia combined with gemcitabine remarkably inhibit the proliferation and induce apoptosis of human lung squamous cell carcinoma in vitro. This effect may be associated with the activation of p53, cleavage of PARP protein, and induced the Caspase-3 dependent apoptosis. PMID- 30454542 TI - [Applicable Value of AMSS-PCR in Lung Cancer Gene Mutation Detection]. AB - BACKGROUND: The detection of driver oncogenes of lung cancer is of great importance. There are various gene detection techniques nowadays which are different from each other. We carried out this study to investigate the specificity and sensitivity of assay panels based on an Amplification Refractory Mutation System-polymerase chain reaction (ARMS-PCR) technique of Amplification Mutation Specific System (AMSS) in detection of lung cancer gene mutation. To estimate the applicable value of assay panels in clinical settings. METHODS: We collected cancer tissue specimens or fluid specimens from 309 patients. Mutation results were presented for those samples previously detected by ARMS-PCR. In comparison, we carried out AMSS-PCR using (epidermal growth factor receptor, EGFR) assay panel and Six-Alliance assay panel as well as Sanger sequencing. Software SPSS 22.0 (SPSS IBM) was used for statistical analysis. RESULTS: The rates of consistency between the results by assay panels and Sanger sequencing or ARMS-PCR were 97.41% and 97.73%, respectively. Besides, EGFR assay panel had higher consistency rates with other detection methods than Six-Alliance assay panel. As for consistency test, the Kappa values of assay panels with Sanger sequencing, assay panels with ARMS-PCR, and ARMS-PCR with Sanger sequencing were 0.946, 0.953, and 0.913, respectively. The receiver operating characteristic curve (ROC) area under curve (AUC) of assay panels was 0.976 referring to Sanger sequencing, and 0.975 as ARMS-PCR was referred to. CONCLUSIONS: AMSS-PCR can make an optimal cancer gene mutation detection method for clinical settings. PMID- 30454543 TI - [Disparities of EGFR mutations between Biopsy and Rebiopsy in Non-small Cell Lung Cancer Patients]. AB - BACKGROUND: Epidermal growth factor receptor (EGFR)-based targeted therapy improves the survival of patients with advanced lung adenocarcinoma harboring EGFR mutations. However, factors including treatment or heterogeneity partly contribute to EGFR genetic status alteration between baseline and disease progresses (PD). The aim of this study is to compare difference of EGFR mutations between biopsy and rebiopsy in real world. METHODS: Data from 61 paired specimens performed EGFR testing in Jilin Provincial Cancer Hospital between January 2015 and December 2017 were collected and analyzed. The specimens were collected at baseline and PD, confirmed by histology or cytology and categorized as tumor tissue, malignant pleural effusion or plasma. All patients were naive and received chemotherapy or targeted therapy as first-line treatment. Amplification Refractory Mutation System (ARMS) was used to detect EGFR mutations. RESULTS: EGFR mutation rate in tumor tissue, pleural effusion or blood was 90.2% vs 88.5%, 6.6% vs 6.6% and 3.2% vs 4.9% at baseline or PD respectively and discrepancy was 72% and 36.3% for the same (n=50) or different (n=11) type of specimens. The EGFR mutation rate was 95.1% and 91.8% in patients before and after treatment, and the discrepancy was 63.9%, among which, 69.2% and 92.3% in chemotherapy-treated patients (n=13) with discrepancy to 46.1% (6/13), and 100.0% and 91.7% in EGFR TKI-treated patients (n=48) with discrepancy to 70.8%. There were four types of alterations in terms of EGFR mutations: wild type turned into mutation (4.9%), mutation disappeared (8.2%), sensitive mutations transformed (1.6%), and new mutations appeared (49.1%). CONCLUSIONS: In real world, the EGFR mutation status in advanced non-small cell lung cancer (NSCLC) patients altered significantly, due to tissue resources and therapeutic approaches, implying the importance of rebiopsy and real-time detection of EGFR mutation, in order to provide data to guide precise strategy in the following treatment. PMID- 30454544 TI - Centralized Lung Nodule Management at A Veterans Hospital Using A Multidisciplinary Lung Nodule Evaluation Team (LNET). AB - BACKGROUND: Lung nodules are frequently identified on imaging studies and can represent early lung cancers. We instituted the Lung Nodule Evaluation Team (LNET) to optimize management of these nodules by a lung specialist physician. All lung nodules identified by a radiologist prompted a direct consultation to this service. We report our initial experience with this process. METHODS: This is a retrospective review of patients with lung nodules at a single institution from 2008 to 2015. Since October 2014, lung nodules >3 mm identified on computed tomography (CT) scanning of the chest generate an automatic consult to LNET from the radiology service. Demographic, nodule and follow up data was entered into a surveillance database and summarized. RESULTS: There were 1,873 patients identified in the database. Of these, 900 patients were undergoing active surveillance. Consults increased from 5.5 to 93 per month after the start of the new consult program. Lung nodules were identified on 64% of chest CT scans. Prior to the direct radiology consult the average size of a nodule was 1.7 cm and 0.7 cm after. The overall time from initial nodule imaging to initiating a management plan by a thoracic specialist physician was 3.7 days. CONCLUSIONS: Assessment of lung nodules by a specialist physician is important to ensure appropriate long term management and optimize utilization of diagnostic interventions. A direct radiology consult to a specialized team of chest physicians decreased the time in initiating a management plan, identified smaller nodules and may lead to a more judicious use of health care resources in the management of lung nodules. PMID- 30454545 TI - [Value of C-ROSE During EBUS-TBNA to Obtain the Tissue Sample ?in the Diagnosis of Lung Cancer]. AB - BACKGROUND: Most of the patients with lung and (or) mediastinal occupying lesions are considered to be primary lung cancer clinically, and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is a commonly useful operation to obtain the tissue sample and get definitive diagnosis of pathological tissues. In the EBUS-TBNA process, cytological rapid on-site evaluation (C-ROSE) is a useful technology. The purpose of our study is to discuss the value of C-ROSE in the diagnosis of lung cancer by EBUS-TBNA sampling. METHODS: Retrospective analysis of 141 cases clinical data who were performed with EBUS-TBNA and suspected diagnosis primary lung cancer, which were found have mediastinal and (or) lung lesions (including the enlargement of the lymph nodes/mass) by computed tomography (CT). Among these patients, 81 patients were in the C-ROSE group and 60 patients were in the No C-ROSE group. The message of puncture and complication of EBUS-TBNA with or without C-ROSE were compared. At the same time, we analysis the sensitivity and specificity, positive predictive value, negative predictive value of C-ROSE combined with EBUS-TBNA in that of the diagnosis of lung cancer. RESULTS: We found no statistical difference of the needle passes between C-ROSE group and No C-ROSE group. But in C-ROSE group, specimen qualified rate and diagnostic yields were signicantly higher than No C-ROSE group (98.77% vs 90.00%, 88.89% vs 75.00%, P<0.05), the incidence of complications in the C-ROSE group was signicantly lower than that in the No C ROSE group (1.23% vs 11.67%, P<0.05). The sensitivity, specificity, positive predictive value and negative predictive value of C-ROSE combined with EBUS-TBNA in the diagnosis of lung cancer are 92.21%, 100.00%, 100.00% and 40.00%. CONCLUSIONS: EBUS-TBNA combined with C-ROSE can improve the specimen qualified rate and diagnostic rate, also can reduce the complications thus worthy of further promotion. PMID- 30454546 TI - [Effect of A High Intensive Preoperative Rehabilitation on the Perioperative ?Complications in Patients with Chronic Obstructive Pulmonary Disease Eligible ?for Lung Cancer Surgery]. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) will reduce the cardiopulmonary function and increase perioperative risk. The aim of this study is to investigate the effect of preoperative short-term high intensity lung rehabilitation training on lung function and postoperative complications in patients with COPD who are eligible for lung cancer surgery. METHODS: We analysis of 101 patients with COPD and a diagnosis of lung cancer, with 43 patients in pulmonary rehabilitation group and 58 patients in conventional group. The pulmonary function, postoperative pulmonary complications (PPCs) and length of stay (LOS) will be compared between the two groups, the lung function will be compared before and after the rehabilitation at the same time. RESULTS: There were no significant difference between the two groups in general information, lung function before surgery, postoperative pulmonary infection [8 (18.6%) vs 17 (29.3%)], atelectasis [1 (2.3%) vs 1 (1.7%)], respiratory failure [1 (2.3%) vs 2 (3.4%)] and postoperative LOS [(8.93+/-3.78) d vs (9.62+/-3.98) d, P>0.05]. In the rehabilitation group, the FEV1 [(2.06+/-0.45) L vs (2.15+/-0.45) L, P<0.001] and PEF [(4.32+/-0.90) L/s vs (5.15+/-1.05) L/s, P<0.001) were higher, and PCO2 [(42.42+/-2.79) mmHg vs (41.58+/-2.98) mmHg, P=0.009] was lower after rehabilitation, significantly. The increase value of FEV1 in moderate to severe COPD group was higher than that of the mild COPD group after the rehabilitation [(0.16+/-0.05) L, 8.6% vs (0.06+/-0.05) L, 2.8%, P<0.001). CONCLUSIONS: The short term highly-intensity lung rehabilitation can improve lung function in lung cancer patients with COPD, and the improvement of pulmonary function in moderate to severe COPD patients is more obviously. PMID- 30454548 TI - [Preoperative Computed Tomography-guided Microcoil Localization for Multiple Small Lung Nodules before Video-assisted Thoracoscopic Surgery]. AB - BACKGROUND: Localization of multiple small lung nodules is the technical difficulty of minimally invasive operation resection. However, there are few clinical studies on the preoperative localization of multiple small lung nodules. This study was designed to evaluate the clinical value of preoperative computed tomography (CT) guided microcoil localization for multiple small lung nodules compared with single small lung nodule before video-assisted thoracoscopic surgery (VATS). METHODS: A retrospective analysis of the clinical data of 235 patients with preoperative pulmonary nodules microcoil localization was performed. According to whether the nodules were single, they were divided into single nodule group (184 cases) and multiple nodules group (51 cases) (multiple nodules group). The single nodule group was positioned under CT-guided conventional methods. The multiple nodules group were CT guided localized by microcoil in batches according to priority before VATS. The success rate, complications, pathological results and localization operations related data were statistically analyzed. RESULTS: The success rate of localization in multiple nodule groups was 90.2%, there was no significant difference compared with the single nodule group (90.2% vs 94.6%, P=0.205). The occurrence rate of pneumothorax in multiple nodule group and single nodule group was no statistical difference (21.6% vs 14.1%, P=0.179), however, the operation time in the multiple nodule group was significantly longer than the single nodule group [(30.6+/-6.6) min vs (19.9+/-7.4) min, P=0.000]. There were no serious complications such as massive hemoptysis, air embolism or hemothorax. There was no conversion to thoracotomy due to failure of localizing the nodules during operation. Sub lobectomy was the main method of operation. The majority of postoperative pathologies were non-invasive carcinomas. CONCLUSIONS: For multiple small lung pulmonary nodules requiring thoracoscopic surgery, according to certain strategies, preoperative CT-guided localized by microcoil in batches according to priority before VATS is safe and effective, and worthy of promotion. PMID- 30454547 TI - [Survival Analysis of Stage I Non-small Cell Lung Cancer Patients Treated with ?Da Vinci Robot-assisted Thoracic Surgery]. AB - BACKGROUND: Da Vinci robotic surgery system is widely used in department of thoracic surgery. The aim of this study is to investigate the treatment outcome of stage I non-small cell lung cancer (NSCLC) via da Vinci Surgical System. METHODS: Clinical date of 347 stage I NSCLC patients, who underwent lobectomy and systematic node dissection from Jan. 2012 to Dec. 2017, were reviewed. 134 patients underwent robot-assisted thoracic surgery (RATS) and 213 patients underwent video-assisted thoracic surgery (VATS). To compare perioperative outcome (blood lose, postoperative drainage, drainage time, postoperative hospital stay, number of the LN dissection) and analyze overall survival (OS), disease free survival (DFS) of the two groups and prognostic factors. RESULTS: The RATS group got less blood lose [(49+/-39 mL for RATS vs (202+/-239) mL for VATS, P<0.05] and postoperative drainage [Day 1: (248+/-123) mL for RATS vs (350+/-213) mL for VATS; Day 2: (288+/-189) mL for RATS vs (338+/-189) mL for VATS, P<0.05]. There were no significant difference for drainage time (10+/-5 for RATS vs 11+/-8 for VATS, P<0.05) and postoperative hospital stay (13+/-6 for RATS vs 14+/-9 for VATS, P<0.05) between the two groups. The RATS group harvested a more number of mean stations (5+/-2 for RATS vs 4+/-2 for VATS) and amounts (18+/ 9 for RATS vs 11+/-8 for VATS) of the lymph nodes, P<0.05. There was no statistically significant difference of OS between RATS and VATS group [1-year OS: 97.3% vs 96%; 3-year OS: 89.8% vs 83.1%; 5-year OS: 87.5 % vs 70.3%; overall survival time (mean): 61 months vs 59 months, P>0.05]; corresponding there had a statistically significant difference of DFS between the two groups [1-year DFS: 93.7% vs 91.3%; 3-year DFS: 87.7% vs 68.4%; 5-year DFS: 87.7% vs 52.5%; disease free survival time (mean): 61 months vs 50 months, P<0.05]. The univariate analysis found that the amounts of the lymph nodes dissection was the prognostic factor for OS and tumor diameter, surgical approach, stations and amounts of the lymph nodes dissection were respectively the prognostic factors for DFS. However, multivariate analysis found that there was not independently factors for OS, but the tumor diameter and surgical approach were independently associated with DFS. CONCLUSIONS: There was no significant difference about OS between the two groups, but the RATS got better DFS. RATS got more number of the LN dissection and less blood lose. PMID- 30454549 TI - [Incidence of Lower Limb Deep Venous Thrombosis and Coagulation Status ?in Severe Patients after Thoracic Surgery]. AB - BACKGROUND: The aim of this study was to analyze the incidence of lower limb deep venous thrombosis (DVT) and the corresponding coagulation status in severe patients after thoracic surgery. METHODS: Severe patients after thoracic surgery who received mechanical prophylaxis of lower limb DVT between July 2016 and June 2018 were analysed retrospectively. Their general information, disease species, surgical treatment, and coagulation index were reviewed. RESULTS: Fifty patients were finally included. There were 34 male and 16 female, aging from 22 to 80 years. The incidence of DVT was 22.0%, all of them were isolated calf DVT. The incidence was 29.4% in male patients, while 6.3% in female; 23.5% in malignant diseases and 18.6% in benign. All coagulation index presented no statistical difference between patients with and without DVT, except activated partial thromboplastin time (APTT). CONCLUSIONS: Even on the basis of adequate mechanical prophylaxis, lower limb DVT is common in severe patients after thoracic surgery. Meanwhile, male patients and malignant diseases are more suscepted. PMID- 30454550 TI - [Research Advances of Ang-2 in Non-small Cell Lung Cancer]. AB - Non-small cell lung cancer (NSCLC) is one of the malignant tumors with highest mortality in the world, it is still a difficult problem in clinical field. Its occurrence and development are closely associated with tumor angiogenesis. Angiopoietin-2 (Ang-2) is an important angiogenesis factor that has involved in many researches and it has been confirmed that the expression of Ang-2 is significantly up-regulated in tissues and blood of NSCLC. Meanwhile, Ang-2 is related to malignant biological behavior of cancer cells, making it a potential biological marker for the diagnosis and prognosis of NSCLC. At present, researches on Ang-2 how to promote the progression of NSCLC around the world are focused on Ang-2 regulating the proliferation, invasion, and metastasis of NSCLC. This paper summarized and estimated the studies and literature reports of regulatory mechanisms of Ang-2 in NSCLC, hopefully it could help looking for targeted drug treatment of Ang-2 in the future.?. PMID- 30454551 TI - [Molecular Mechanism of Different Signaling Pathways in Regulating PD-L1 Expression in EGFR Mutated Lung Adenocarcinoma]. AB - The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and programmed death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors were landmarks in the treatment of non-small cell lung cancer (NSCLC). However, the regulation mechanisms of PD-L1 expression were not fully clear in NSCLC patients with EGFR mutations. Multiple signaling pathways may be involved in the tumorigenesis regulation. This paper summarized and reviewed the potential EGFR mutations impacting on PD-L1 expression with aims to the development of strategies on immunochemical therapy for NSCLC.?. PMID- 30454552 TI - [A Case Report of Primary Pulmonary Synovial Sarcoma with Postoperative Multiple Metastases Treated with Apatinib]. AB - Primary pulmonary synovial sarcoma is a rare pulmonary malignant tumor originated from primitive mesenchymal, which has short overall survival and poor prognosis. Related case reports are lacked at home and abroad. In recent years, the development of targeted therapy has brought remarkable benefits to cancer patients. Apatinib (Hengrui Pharmaceutical Co. Ltd, Jiangsu, People's Republic of China) is a small molecule vascular endothelial growth factor receptor 2 (VEGFR 2) inhibitor, which selectively inhibits VEGFR-2 and blocks the VEGF signal pathway, then strongly inhibiting the tumor angiogenesis. Apatinib has shown favorable therapeutic effect and acceptable toxicity on various tumors. Here we report a case of primary pulmonary synovial sarcoma with postoperative multiple metastases treated with apatinib, in order to provide a new considerable treatment.?. PMID- 30454553 TI - Bright multicolor labeling of neuronal circuits with fluorescent proteins and chemical tags. AB - The stochastic multicolor labeling method 'Brainbow' is a powerful strategy to label multiple neurons differentially with fluorescent proteins; however, the fluorescence levels provided by the original attempts to use this strategy were inadequate. In the present study, we developed a stochastic multicolor labeling method with enhanced expression levels that uses a tetracycline-operator system (Tetbow). We optimized Tetbow for either plasmid or virus vector-mediated multicolor labeling. When combined with tissue clearing, Tetbow was powerful enough to visualize the three-dimensional architecture of individual neurons. Using Tetbow, we were able to visualize the axonal projection patterns of individual mitral/tufted cells along several millimeters in the mouse olfactory system. We also developed a Tetbow system with chemical tags, in which genetically encoded chemical tags were labeled with synthetic fluorophores. This was useful in expanding the repertoire of the fluorescence labels and the applications of the Tetbow system. Together, these new tools facilitate light microscopy-based neuronal tracing at both a large scale and a high resolution. PMID- 30454554 TI - Host genetic selection for cold tolerance shapes microbiome composition and modulates its response to temperature. AB - The hologenome concept proposes that microbes and their host organism are an independent unit of selection. Motivated by this concept, we hypothesized that thermal acclimation in poikilothermic organisms, owing to their inability to maintain their body temperature, is connected to their microbiome composition. To test this hypothesis, we used a unique experimental setup with a transgenerational selective breeding scheme for cold tolerance in tropical tilapias. We tested the effects of the selection on the gut microbiome and on host transcriptomic response. Interestingly, we found that host genetic selection for thermal tolerance shapes the microbiome composition and its response to cold. The microbiomes of cold-resistant fish showed higher resilience to temperature changes, indicating that the microbiome is shaped by its host's selection. These findings are consistent with the hologenome concept and highlight the connection between the host and its microbiome's response to the environment. PMID- 30454556 TI - Critical aspects in the legal defence of patients with Tourette's Syndrome: An Italian case series. AB - Tourette's syndrome (TS) is a developmental neurobehavioral disorder with childhood onset and relevant burden in terms of disability and reduced quality of life. In Italy the biological basis of this syndrome is still frequently ignored and TS is often recognised as a psychiatric manifestation, or even it is not recognised as pathology, which may result in inadequate treatment, social isolation and improper hospitalization. Indeed, the organic medical nature of TS needs to be taken into great consideration in evaluating causality of committing crimes in affected patients. In addition, delaying the diagnosis and consequently proper treatment has a devastating impact on social as well as legal aspects in patients with TS. The present report is aimed to present an Italian case series of 4 TS patients who faced legal problems related to their mental condition, in the intent to add further evidence, raise the level of awareness and encourage further investigation in the field, as in most of the cases, patients' illness was not taken into adequate account by the Justice. The relevant law is discussed in detail. PMID- 30454557 TI - Alternatives to prison for drug offenders in Belgium during the past decade. AB - OBJECTIVE: Imprisonment has a more pronounced criminogenic effect on drug offenders than on other types of offenders. Additionally, little research has been conducted on the practical application of drug-related alternatives to prison. Therefore, this study describes drug-related alternatives to prison in Belgium over a ten years' period since 2005. METHODS: The applied drug-related alternatives to prison ('probation', 'conditional release', 'mediation in criminal cases', 'community service' and 'electronic monitoring') were subject to a secondary data analysis of the database of the Houses of Justice. RESULTS: Men, the age group of 16-24 years old and Belgians are most sentenced to alternatives to prison. Nevertheless, 38% of women are guided towards 'probation' while 8% is 'mediated in criminal cases' compared to 30% and 5% of males respectively (p < .001). 26% of non-Belgians are involved in 'conditional release' and 'electronic monitoring' compared to 22% and 16% among Belgians (p < .001) respectively. With regards to age, 21% of the offenders older than 24 years are involved in 'electronic monitoring' compared to 6% among the offenders younger than 25 years (p < .001). CONCLUSIONS: The results highlight differences in punishment judgments by age, gender and nationality that continues to be indicative for perceived threat, danger and culpability of the offenders. PMID- 30454558 TI - Judges' perceptions of expert reports: The effect of neuroscience evidence. AB - This article explores the impact of neuroscience evidence on how expert reports are perceived and their effects on the decisions made by trial judges. Experimental psychology has demonstrated a number of cognitive effects arising from exposure to neuroimaging data which may bias judgments and lead to (mis)interpretations that can affect decisions. We conducted a study on a sample of 62 Swiss and French judges in order to determine whether their perceptions of the credibility, quality and scientific basis of a psychiatric evaluation of a criminal defendant vary according to whether or not the evaluation includes neuroscientific data. Quantitative analyses were conducted in order to evaluate significant differences between the two conditions (one-way analyses of variance) and moderation and conditional analyses to examine whether the participants' sex and length of professional experience moderated the effect of the conditions. Terminological and thematic analyses were carried out on open questions. Quantitative and qualitative results suggest that the presence of neuroscience data in an expert report affects judges' perceptions of the quality, credibility, and scientificity (reliability, objectivity, scientific basis) of the report, and the persuasiveness of the evidence it provided. Moreover, this phenomenon was stronger in more experienced judges than in less experienced judges. PMID- 30454555 TI - Reconstructing the functions of endosymbiotic Mollicutes in fungus-growing ants. AB - Mollicutes, a widespread class of bacteria associated with animals and plants, were recently identified as abundant abdominal endosymbionts in healthy workers of attine fungus-farming leaf-cutting ants. We obtained draft genomes of the two most common strains harbored by Panamanian fungus-growing ants. Reconstructions of their functional significance showed that they are independently acquired symbionts, most likely to decompose excess arginine consistent with the farmed fungal cultivars providing this nitrogen-rich amino-acid in variable quantities. Across the attine lineages, the relative abundances of the two Mollicutes strains are associated with the substrate types that foraging workers offer to fungus gardens. One of the symbionts is specific to the leaf-cutting ants and has special genomic machinery to catabolize citrate/glucose into acetate, which appears to deliver direct metabolic energy to the ant workers. Unlike other Mollicutes associated with insect hosts, both attine ant strains have complete phage-defense systems, underlining that they are actively maintained as mutualistic symbionts. PMID- 30454559 TI - Folie a deux and homicide: Literature review and study of a complex clinical case. AB - : Folie a deux is a psychiatric illness involved in homicides. OBJECTIVE: To study the mechanisms leading to homicide and determine homicide risk factors in folie a deux patients through a literature review and the study of a complex clinical case. MATERIALS AND METHODS: We included articles available on PubMed, ScienceDirect or Cairn that address the forensic implications of folie a deux. Then, we analyzed the criminal psychiatric assessments of two murderers (husband and wife) of a child in a case of folie a deux. RESULTS: Seventeen articles were included. In the cases examined, homicides were committed with great violence, usually against a victim in the family circle, and were sometimes followed by suicide. The main risk factor for homicide was the combination of mystical and persecutory delusions. The homicides occurred in response to destabilization of the delusional dyads. Concerning the clinical case, we described the circumstances surrounding the killing and analyzed the four expert reports that permit us to infer the occurrence of induced psychosis, which is a form of folie a deux. DISCUSSION: Psychiatrists must attain a better knowledge of folie a deux to allow early identification of risk situations and to improve their assessments. PMID- 30454560 TI - Suicide and suicides attempts in Italian prison epidemiological findings from the "Triveneto" area, 2010-2016. AB - The aim of this observational study was to assess rates of suicide and suicide attempts, in relation to gender, age, place of birth and security levels, in north-eastern Italian prisons during 2010-2016, and investigate associations with prison overcrowding, offence type and prior self-harm and suicide attempts. The study was based on individual data on suicides and suicide attempts from 16 prisons, with an average yearly number of 3900 inmates during the study period, for all prisons combined. Descriptive and binomial regression analyses were performed. Rates of suicide and suicide attempts in Triveneto prisons were 1and 15 per 1000 inmates, respectively. >90% of suicides and suicide attempters were men aged between 21 and 49 years old, and most had committed violent offenses. Only half the prisoners who died by suicide and 30% of those who made a suicide attempt in custody were Italians. 'Cooperative witnesses' had the highest mean suicide attempt rate (30/1000 inmates). Fourteen per cent of suicides and 19% of attempters had a prior history of suicide attempts and self-injury. In binomial regression analyses, predictors of suicidal behaviour were being a male inmate in standard security conditions, with a mean age of 30 years. The study highlighted that there is a need for suicide prevention policies in Triveneto; these should take into account predictors of suicidal behaviours and individual characteristics of suicidal inmates. More research is warranted in order to both evaluate the effectiveness of prevention plans and better assess risk of suicide in specific groups, such as cooperative witnesses. PMID- 30454562 TI - MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360. AB - Proper control of the mitochondrial Ca2+ uniporter's pore (MCU) is required to allow Ca2+-dependent activation of oxidative metabolism and to avoid mitochondrial Ca2+ overload and cell death. The MCU's gatekeeping and cooperative activation is mediated by the Ca2+-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU's DIME motif, the selectivity filter. This led us to recognize in MICU1's sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter. PMID- 30454561 TI - Phosphorylation of Histone H4T80 Triggers DNA Damage Checkpoint Recovery. AB - In response to genotoxic stress, cells activate a signaling cascade known as the DNA damage checkpoint (DDC) that leads to a temporary cell cycle arrest and activation of DNA repair mechanisms. Because persistent DDC activation compromises cell viability, this process must be tightly regulated. However, despite its importance, the mechanisms regulating DDC recovery are not completely understood. Here, we identify a DNA-damage-regulated histone modification in Saccharomyces cerevisiae, phosphorylation of H4 threonine 80 (H4T80ph), and show that it triggers checkpoint inactivation. H4T80ph is critical for cell survival to DNA damage, and its absence causes impaired DDC recovery and persistent cell cycle arrest. We show that, in response to genotoxic stress, p21-activated kinase Cla4 phosphorylates H4T80 to recruit Rtt107 to sites of DNA damage. Rtt107 displaces the checkpoint adaptor Rad9, thereby interrupting the checkpoint signaling cascade. Collectively, our results indicate that H4T80ph regulates DDC recovery. PMID- 30454563 TI - Regulatory-sequence mechanical biosensor: A versatile platform for investigation of G-quadruplex/label-free protein interactions and tunable protein detection. AB - Mechanical biosensors can be used to quantitatively explore DNA-protein binding mechanisms by detecting targets at low concentrations or measuring force in single-molecule force spectroscopy. However, restrictions in single-molecule manipulation and labelling protocols have hindered the application for bulk analysis of label-free protein detection. Here, we present the integration of molecular force measurement and finely tunable detection of label-free proteins into one mechanical sensor. Regulatory-sequence force spectroscopy was obtained to investigate the binding force of DNA G-quadruplexes (GQ) and label-free protein. The dual control of regulatory sequences and mechanical forces induces the structure switching from DNA duplex to GQ/protein complex. It exhibits a synergistic effect, enabling the rational fine-tuning of the dynamic range for biosensing protein concentrations over eight orders of magnitude. Furthermore, this method was exploited to estimate the stability of the human telomeric DNA GQ by Ku protein and ligand methylpyridostatin. The results revealed that human telomeric GQ has two different binding sites for Ku protein and ligand. Force spectroscopy integrating label-free force measurement and tunable target detection holds great promise for use in biosensing, drug screening, targeted therapies, DNA nanotechnology, and fields in which GQ are of rapidly increasing importance. PMID- 30454564 TI - Non-separative mass spectrometry methods for non-invasive medical diagnostics based on volatile organic compounds: A review. AB - In this review, an assessment of non-separative methods based on mass spectrometry used to analyse volatile organic compounds in the field of bioanalysis is performed. The use of non-separative methods based on mass spectrometry has been established as an attractive option for analysing compounds. These instrumental configurations are suitable for biomedical applications because of their versatility, rapid output of results, and the wide range of volatile organic compounds that can be determined. Here, techniques such as headspace sampling coupled to mass spectrometry, membrane introduction mass spectrometry, selected ion flow tube mass spectrometry, proton transfer reaction mass spectrometry, secondary electrospray ionization mass spectrometry and ion mobility mass spectrometry, are evaluated. Samples involving non-invasive methods of collection, such as urine, saliva, breath and sweat, are mainly considered. To the best of our knowledge, a comprehensive review of all the non-separative instrumental configurations applied to the analysis of gaseous samples from all matrices non-invasively collected has not yet been carried out. The assessment of non-separative techniques for the analysis of these type of samples can be considered a key issue for future clinical applications, as they allow real-time sample analysis, without patient suffering. Any contribution to the early diagnosis of disease can be considered a priority for the scientific community. Therefore, the identification and determination of volatile organic compounds related to particular diseases has become an important field or research. PMID- 30454565 TI - Polymeric ionic liquid open tubular capillary column for on-line in-tube SPME coupled with UHPLC-MS/MS to determine endocannabinoids in plasma samples. AB - This manuscript describes the development of wall-coated open tubular capillary column with polymeric ionic liquids (PILs) for on-line in-tube solid phase microextraction coupled with ultra high-performance liquid chromatography tandem mass spectrometry (in-tube SPME/UHPLC-MS/MS) to determine anandamide (AEA) and 2 arachidonoyl glycerol (2 A G) in plasma samples. Selective PILs were synthetized from the [VC6IM][Cl], [VC16IM][Br], and [(VIM)2C10]2 [Br] - ionic liquids - by in situ thermal-initiated polymerization in a fused silica capillary column for in tube SPME. The synthesis procedure was optimized, and the capillary columns were characterized using spectroscopic and chromatography techniques. The chemically bonded and cross-linked PIL-based sorbent phase (thickness coating: 1.7 MUm) presented high chemical and mechanical stability. Among the sorbents evaluated, the PIL-based capillary, [VC16IM][Br]/[(VIM)2C10]2 [Br] presented the best performance with a sorption capacity of 37,311 ng cm-3 and 48,307 ng cm-3 for AEA and 2 A G, respectively. This capillary was reused more than ninety times without significant changes in extraction efficiency. The in-tube SPME-UHPLC-MS/MS method presented a linear range from 0.1 ng mL-1 to 100 ng mL-1 for AEA, and from 0.05 ng mL-1 to 100 ng mL-1 for 2 A G, with coefficients of determination higher than 0.99, p-value for Lack-of-fit test higher than 0.05 (alpha of 0.05), precision with coefficient of variation (CV) values ranging from 1.6 to 14.0% and accuracy with relative standard deviation (RSD) values from -19.6% to 13.2%. This method was successfully applied to determine AEA and 2 A G in plasma patients with Parkinson's disease. The concentrations in these plasma samples ranged from 0.14 to 0.46 ng mL-1 for AEA and from <0.05 ng mL-1 to 0.51 ng mL-1 for 2-AG. PMID- 30454566 TI - Molecularly imprinted polymer monolith containing magnetic nanoparticles for the stir-bar sorptive extraction of thiabendazole and carbendazim from orange samples. AB - In this work, a novel molecularly imprinted stir-bar was developed for the stir bar sorptive extraction (SBSE) of thiabendazole (TBZ) and carbendazim (CBZ) from orange samples. Magnetic nanoparticles were surface modified with oleic acid and then encapsulated by a silica shell using a conventional sol-gel procedure. Subsequently, nanoparticles were functionalized with methacrylate functionalities by grafting onto the particles surface. Finally, the modified magnetic nanoparticles were entrapped in a polymer monolith synthetized by copolymerization with the imprinting polymerization mixture using a glass vial insert as a mold. Variables affecting the polymerization and rebinding conditions of target analytes were optimized. The uptake capacity for the template (TBZ) was evaluated as well as the cross-reactivity for the related compound CBZ by rebinding experiments. Finally, the proposed magnetic imprinted monolith was applied to the SBSE of TBZ and CBZ from orange sample extracts providing a remarkable clean-up ability. The calculated detection limit were 0.13 and 0.10 mg kg-1 for CBZ and TBZ respectively, low enough to satisfactory analysis of both compounds in orange samples according to current European Union regulations. PMID- 30454567 TI - Elution-free ultra-sensitive enrichment for glycopeptides analyses: Using a degradable, post-modified Ce-metal-organic framework. AB - In this work, we presented a facile elution-free method for ultrasensitive enrichment of glycopeptides using two kinds of novel Ce-metal-organic frameworks (Ce-MOF) post-modified with hyaluronic acid (Ce-MOF@HA) and glutamic acid (Ce MOF@Glu). Both of the synthesized materials remained stable in the loading buffer to enrich glycopeptides selectively and degrade in the eluent to release captured glycopeptides. Due to the dissolution of materials, the elution step of the enrichment process is omitted, resulting in an extremely high sensitivity (detection limit, 0.5 fmol/MUL). Meanwhile, Ce-MOF@HA and Ce-MOF@Glu also possessed excellent selectivity with molar ratios of IgG and BSA digests being 1:1000 and 1:500, respectively. Noticeably, the practical applicability of the obtained materials was inspected by analyzing the glycopeptides enriched from human serum (2 MUL) by nano-LC-MS, in which 434 N-glycopeptides from 182 N glycoproteins (by Ce-MOF@HA) and 328 N-glycopeptides from 135 N-glycoproteins (by Ce-MOF@Glu) were detected, respectively. This work provides a new method to simplify the process of glycopeptides enrichment and also paves a novel way for the enrichment of trace targets from complex matrices. PMID- 30454568 TI - Magnetic ionic liquid-enhanced isothermal nucleic acid amplification and its application to rapid visual DNA analysis. AB - Isothermal nucleic acid amplification (INAA) techniques such as loop-mediated isothermal amplification (LAMP) and isothermal multiple-self-matching-initiated amplification (IMSA) constitute simple and rapid approaches for the detection of pathogens. However, due to the employment of multiple primers, the detection of LAMP and IMSA products is easily influenced by high background signals from primer dimer-based nonspecific nucleic acid amplification (NSA) products. Moreover, time-consuming sample preparation steps are often required for the isolation of sufficiently pure nucleic acid prior to INAA. To address these drawbacks, hydrophobic magnetic ionic liquids (MILs) were used to rapidly preconcentrate DNA from complex biological samples followed by direct amplification by LAMP and IMSA. Careful control of the components within the isothermal buffer permitted direct addition of DNA-enriched MIL to the INAA reaction mixture, thereby circumventing tedious purification procedures that are ordinarily required prior to downstream DNA amplification. When added directly to INAA reactions, MIL solvents released metal ions that ultimately inhibited the primer dimer-mediated NSA, resulting in a flat or decreased baseline signal in no template control samples and short threshold time for positive reactions. Using a MIL-based single droplet DNA extraction method, MIL-enhanced INAA reaction system, and a handheld 3D printed device for visual detection of the amplified product in customized tubes, we demonstrate the potential of the MIL-based approach for the onsite analysis of DNA from pathogens. PMID- 30454569 TI - Retention characteristics of some antibiotic and anti-retroviral compounds in hydrophilic interaction chromatography using isocratic elution, and gradient elution with repeatable partial equilibration. AB - The separation of some zwitterionic, basic and neutral antibiotic and antiretroviral compounds was studied using hydrophilic interaction chromatography (HILIC) on bare silica, bonded amide and urea superficially porous phases. The differences in the selectivity and retentivity of these stationary phases were evaluated for compounds with widely different physicochemical properties (logD 3.43 to 2.41 at wwpH 3.0). The mobile phase was acetonitrile-ammonium formate buffered at low wwpH. Compounds containing quinolone and serine groups showed poor peak shapes on all columns, attributed to metal-oxide interactions with system metals. Peak shapes were improved by addition of citrate buffers. Gradient elution, particularly with regard to column equilibration, was also studied due to the large differences in retention factors observed under isocratic conditions. Full equilibration in HILIC was slow for both ionogenic and neutral solutes, requiring as much as ~40 column volumes. However, highly repeatable partial equilibration, suitable for gradient elution, was achieved in only a few minutes. Pronounced selectivity differences in the separations were shown dependent on the partial equilibration time. PMID- 30454570 TI - Rapid screening of multi-target antitumor drugs by nonimmobilized tumor cells/tissues capillary electrophoresis. AB - As there are more target categories on tumor cells/tissues than on receptor overexpressing cells, and tumor tissues can better simulate TME, we established a new method of screening multi-target antitumor drugs by nonimmobilized tumor cells/tissues capillary electrophoresis under approximately tumor physiological environment. In this method, the natural structure and active conformation of the target proteins on tumor cells/tissues can be well maintained without separation and purification. Therefore, we successfully used this method to study the interactions between the Aidi injection (ADI)/its main components and tumor cells/tissues by optimizing a series of experimental conditions, discovered seven components with binding activity to A549 cells, five of them with specific interaction to tumor tissues, and calculated the binding kinetic parameters (K, ka, kd, and k'). Then, antitumor activity assays in vitro and in vivo were carried out to discover a new drug combination with higher targeting, better pharmaceutical efficacy, and lower toxic side effects. Finally, molecular docking studies were performed to investigate the potential target groups of the interactions between the effective drug combination and A549 cells/tissues. In summary, the method was verified to be valid and feasible, and can be easily transferred to a capillary array electrophoresis for high-throughput drug screening. PMID- 30454571 TI - Efficient determination of amphetamine and methylamphetamine in human urine using electro-enhanced single-drop microextraction with in-drop derivatization and gas chromatography. AB - An efficient method for the determination of amphetamine (AM) and methylamphetamine (MA) using electro-enhanced single-drop microextraction (EE SDME) and gas chromatography has been developed. One advantage of this method is that the extraction efficiency is greatly enhanced by the electric field acceleration of the mass transfer of target analytes from the sample solution to the organic solvent drop. In addition, the extracted analytes were in situ derivatized with isobutyl chloroformate (IBCF) in the droplet, which further improved the sensitivity of this method. Under the optimum conditions, the enrichment factors (EFs) for AM and MA were 247 and 782, respectively. The proposed method exhibited low limits of detection (0.27 MUg/L for AM and 0.14 MUg/L for MA) and good linearity over the concentration range between 1 and 2000 MUg/L with regression coefficients (r2) of more than 0.99. The intra- and interday recoveries were from 89.6 to 96.2% and 82.7-90.5%, respectively, and the intra- and interday precisions (RSDs) were from 5.2 to 8.3% and 8.9-12.8%. The proposed method was applied to the determination of amphetamines in a urine sample. PMID- 30454572 TI - Miniaturized liquid chromatography coupled on-line to in-tube solid-phase microextraction for characterization of metallic nanoparticles using plasmonic measurements. A tutorial. AB - This tutorial aims at providing guidelines for analyzing metallic nanoparticles (NPs) and their dispersions by using methods based on miniaturized liquid chromatography with diode array detection (MinLC-DAD) and coupled on-line to in tube solid-phase microextraction (IT-SPME). Some practical advice and considerations are given for obtaining reliable results. In addition, this work outlines the potential applications that set these methodologies apart from microscopy-related techniques, dynamic light scattering, single particle ICP-MS, capillary electrophoresis, field-flow fractionation and other chromatographic configurations, which are discussed and mainly seek to accomplish size estimation and NP separation, speciation analysis and quantification of mainly AgNPs and AuNPs. MinLC-DAD has the potential to estimate the NP concentration and from it the average size of unknown samples by calibrating with a single standard, as well as studying potentially non-spherical particles and stability-related properties of their dispersions. While keeping the signal dependency with concentration and increasing the method sensitivity, IT-SPME-MinLC-DAD goes further allowing for the assessment of the dispersant effect and ultimately changes in the nanoparticle surroundings that range from modifications of the hydrodynamic diameter to the exposure to different reagents and matrices. The methodology can still be improved by either exploring newer IT-SPME adsorbents or by assaying new system configurations. Taking into account that this technique gives complementary information in relation to other techniques discussed here, this tutorial serves as a guide for analyzing metallic NPs towards a better understanding of the particle behavior under different scenarios. PMID- 30454573 TI - A decade of microchip electrophoresis for clinical diagnostics - A review of 2008 2017. AB - A core element in clinical diagnostics is the data interpretation obtained through the analysis of patient samples. To obtain relevant and reliable information, a methodological approach of sample preparation, separation, and detection is required. Traditionally, these steps are performed independently and stepwise. Microchip capillary electrophoresis (MCE) can provide rapid and high resolution separation with the capability to integrate a streamlined and complete diagnostic workflow suitable for the point-of-care setting. Whilst standard clinical diagnostics methods normally require hours to days to retrieve specific patient data, MCE can reduce the time to minutes, hastening the delivery of treatment options for the patients. This review covers the advances in MCE for disease detection from 2008 to 2017. Miniaturised diagnostic approaches that required an electrophoretic separation step prior to the detection of the biological samples are reviewed. In the two main sections, the discussion is focused on the technical set-up used to suit MCE for disease detection and on the strategies that have been applied to study various diseases. Throughout these discussions MCE is compared to other techniques to create context of the potential and challenges of MCE. A comprehensive table categorised based on the studied disease using MCE is provided. We also comment on future challenges that remain to be addressed. PMID- 30454574 TI - A direct and selective electrochemical hydrogen sulfide sensor. AB - Continuous, in situ detection of hydrogen sulfide (H2S) in biological milieu is made possible with electrochemical methods, but direct amperometry is constrained by the generation of elemental sulfur as an oxidative byproduct. Deposition of a sulfur layer passivates the working electrode, reducing sensitivity and causing performance variability. Herein, we report on the use of a surface preconditioning procedure to deposit elemental sulfur on a glassy carbon electrode prior to measurement and evaluate performance with common analytical metrics. The lack of traditional anti-poisoning techniques (e.g. redox mediators, cleaning pulses) also allowed for facile surface modification with electropolymerized films. For the first time, a series of electropolymerized films were characterized for their H2S permselective behavior against common biological interferents. Highly selective, film-modified electrodes were then evaluated for their anti-biofouling ability in simulated wound fluid. The final optimized electrode was capable of measuring H2S with a low detection limit (i.e., <100 nM) and ~80% of its initial sensitivity in proteinaceous media. PMID- 30454575 TI - Catalytic hairpin assembly-programmed formation of clickable nucleic acids for electrochemical detection of liver cancer related short gene. AB - DNA amplification usually takes place in an aqueous system to facilitate a highly efficient reaction. Therefore, it is a challenge to connect the DNA amplification with popular dry chemical methods, whose signal outputs usually come from a solid liquid interface. Here, by linking catalytic hairpin assembly (CHA) with electrochemical biosensors through clickable nucleic acids, we develop a facile method for the detection of liver cancer related short gene MXR7. On one hand, the method maintains the advantages of CHA especially its high efficiency by performing the whole process of CHA in aqueous phase. On the other hand, the method realizes electrochemical detection of MXR7 by transferring a clickable double-helix production of MXR7-triggerd CHA to a dibenzocyclooctyne functionalized electrode quickly through copper-free click chemistry. In comparison with traditional biotin-streptavidin or hybridization-assisted conjugation, the click chemistry allows quick response in a quarter of an hour, shortening the detection time greatly. In addition, owing to the lower steric hindrance as compared with streptavidin, the signal intensity is strong, making a sensitive detection possible. The detection limit reaches 125 fM, better than previous electrochemical methods. Results also reveal that CHA in solution has much better efficiency than that on interface, allowing two orders of magnitude improvement in detection limit (125 fM vs. 50 pM) with a shorter detection time (135 min vs. 165 min). This work also provides a novel concept to connect aqueous amplification system with interfacial detection method for other bio-analysis. PMID- 30454576 TI - Irreversibility analysis in a slip aided electroosmotic flow through an asymmetrically heated microchannel: The effects of joule heating and the conjugate heat transfer. AB - In this article, we discuss about the entropy generation minimization in a slip modulated electrically actuated transport through an asymmetrically heated microchannel. While investigating the underlying thermo-hydrodynamics towards minimizing the irreversibility of the system under present consideration, we take the combined effects of Joule heating and the conjugate transfer of heat into account in this analysis. We primarily focus to tune the relevant thermo-physical as well as geometrical parameters towards minimizing the global irreversibility of the system. We show that the cooperative-correlative effects of the temperature gradient (between walls and fluid) and viscous dissipation in the system, as modulated by the slipping hydrodynamics stemming from the interfacial electrochemistry and Joule heating effects originating from higher conduction currents, bring in a change in the underlying thermal transport characteristics of heat, leading to an alteration in thermodynamic irreversibility in the system. We unveil optimum values of geometrical and thermo-physical parameters for which a change in thermal transport of heat as triggered by the viscous dissipation and joule heating effect leads to a minimum entropy generation in the system. Moreover, we show that the ionic concentration of the electrolyte present in the fluid can fetch a reduction in the irreversibility as well. We believe that the insights gained from this analysis may be useful for constructing the well optimized futuristic micro heat exchanging systems/devices, typically used in MEMS. PMID- 30454577 TI - Voltammetric determination of carvacrol on Boron Doped Diamond Electrode. AB - A simple, sensitive and rapid method of carvacrol determination using Boron Doped Diamond Electrode (BDDE) and Differential Pulse Voltammetry (DPV) was described. To the best of our knowledge, this is the first presentation of electrochemical method to determine this compound on BDDE. In presented conditions, carvacrol undergoes irreversible one-electron oxidation controlled by diffusion. The measurement conditions and composition of supporting electrolyte were developed and optimized. Optimal measurement parameters were achieved using 0.1 molL-1 acetate buffer pH 6.0 as supporting electrolyte. The calibration graph was linear from 0.29 to 15.03 mgL-1 of carvacrol, the detection limit was 0.02 mgL-1 with the correlation coefficient of 0.9990. The influence of interfering metal ions, such as Cd2+, Cr3+ and Pb2+, was studied. The influence of thymol on the measurement results was also examined. The proposed method was verified by successful determination of carvacrol in commercially available oregano essential oil. Recovery of carvacrol added to the extracts obtained from fresh and dried parts of oregano and marjoram was successfully estimated. Effective application of the described analytical approach, not only enables the electrochemical detection of carvacrol, but also helps to reduce the operational cost. PMID- 30454578 TI - [The urgent need for organisational changes of hypertension management in France]. PMID- 30454579 TI - [Benzodiazepine use and misuse in France]. AB - Benzodiazepine use remains high in France in 2015, especially among the elders. However, encouraging trend is observed regarding hypnotic benzodiazepines initiation: between 2008 and 2015, incident use of hypnotics, including that of Z drugs, decreased while incident use of anxiolytics remained stable. Most of new benzodiazepine users (86 %) had treatment duration that complies with guidelines. Owing to the high number of user initiating a treatment each year and associated risks, the remaining 14 % of long-term users is of concern. Roughly half of benzodiazepine users presented with comorbidities and concurrent medications increasing the risk of adverse drug reactions, especially central nervous system depressant effects. PMID- 30454580 TI - [Use and misuse of benzodiazepines out of France]. AB - Among 8 countries included in the report of ANSM, France is second behind Spain, when defined daily doses (DDD) are considered. Few studies, recent and based on representative samples of population, investigated the use of benzodiazepines in other countries and data are limited to compare France and other countries. In most countries, the use of benzodiazepines increases with age and is more frequent in women than in men. Variations of benzodiazepines use that were observed in other countries are similar to those observed in France, with a slight decrease but persistent high levels of use. In most countries, the long term use of benzodiazepines is stable over time even though simple use decreases. PMID- 30454581 TI - [Use and misuse of benzodiazepines in patients with psychiatric disorders]. AB - The psychiatric patients are not only particularly exposed to benzodiazepines; they may also be more vulnerable to their side effects than general population. Benzodiazepines are frequently misused in psychiatric patients in terms of duration, dose and number of concomitant medications. There is no evidence that benzodiazepines are effective against most psychiatric disorders, including depression and suicidal risk. Several studies have shown associations between benzodiazepine use and depression worsening, increased disinhibition, suicide risk, anxiety, aggression, and even mortality in patients with psychiatric disorders. Despite the common use of benzodiazepine drugs by clinicians, large and methodologically sound studies are lacking to document the patterns of benzodiazepine use in populations with psychiatric disorders and their specific risks in these patients. It is not known whether it is legitimate to apply the good practice recommendations for benzodiazepines in patients with severe psychiatric disorders. PMID- 30454582 TI - [Should the duration of treatment be limited using benzodiazepines?] AB - Benzodiazepines and Z-drugs have pharmacodynamic effects with tolerance that can occur quickly, after one week to one month of treatment and that concerns hypnotic and anxiolytic properties in particular. Old studies showed a real but poor short-term efficacy of benzodiazepines on anxiety and sleep disturbances. Long-term efficacy of benzodiazepines can be confused with the occurrence of rebound effect, discontinuation symptoms or relapse when the treatment is quitted; they contribute to an apparent efficacy, as well as the symptoms removal when treatment is re-initiated. Pharmacologic tolerance exists with respects to efficacy and side effects that decrease over time, in the first weeks of treatment. Its main associated characteristic is the occurrence of a severe withdrawal syndrome when treatment is quitted. To limit long-term treatments, it is relevant to target treatment initiation of benzodiazepines and to restrict indications and treatment duration. Addiction to benzodiazepines is frequent in patients treated for another addiction; it is associated with more frequent complications, in particular overdoses and suicide attempts. The use of benzodiazepines is necessary to prevent complications during alcohol or benzodiazepine withdrawal, but duration of treatment should be limited and dispensing should be supervised in patients with substance use disorders. PMID- 30454583 TI - [Benzodiazepine cessation in ambulatory practice. A review]. AB - Seven studies evaluated pharmacological treatments and 12 studies evaluated non pharmacological interventions including Cognitive Behavioural Therapy (CBT), minimal interventions toward patients, pharmacists or physicians, or dedicated visits, in order to discontinue benzodiazepines treatments. Among pharmacological treatments, only melatonin was significantly efficacious in patients suffering from insomnia alone. BCT showed efficacy in increasing self-efficacy feeling toward BZD cessation and in patients with sleep disorders. Minimal interventions and dedicated visits were significantly efficacious with favourable cost effectiveness ratio. No study investigated patients with high-doses of benzodiazepine, or with addiction, somatic or psychiatric disorders. PMID- 30454584 TI - Nociceptors: thermal allodynia and thermal pain. AB - The sensation of pain plays a vital protecting role, alerting organisms about potentially damaging stimuli. Tissue injury is detected by nerve endings of specialized peripheral sensory neurons called nociceptors that are equipped with different ion channels activated by thermal, mechanic, and chemical stimuli. Several transient receptor potential channels have been identified as molecular transducers of thermal stimuli in pain-sensing neurons. Skin injury or inflammation leads to increased sensitivity to thermal and mechanic stimuli, clinically defined as allodynia or hyperalgesia. This hypersensitivity is also characteristic of systemic inflammatory disorders and neuropathic pain conditions. Mechanisms of thermal hyperalgesia include peripheral sensitization of nociceptor afferents and maladaptive changes in pain-encoding neurons within the central nervous system. An important aspect of pain management involves attempts to minimize the development of nociceptor hypersensitivity. However, knowledge about the cellular and molecular mechanisms causing thermal hyperalgesia and allodynia in human subjects is still limited, and such knowledge would be an essential step for the development of more effective therapies. PMID- 30454585 TI - Central thermoreceptors. AB - Homeotherms maintain their core body temperature within a narrow range by employing multiple redundant mechanisms to control heat production and dissipation. Preoptic area/anterior hypothalamic (PO/AH) neurons receive thermal signals from peripheral and deep-body thermoreceptors as well as hormonal and metabolic signals. A population of PO/AH neurons termed warm-sensitive increase their firing temperature with warming and are considered central thermoreceptors. Electrophysiologic and pharmacologic experiments have provided descriptions of their characteristics and signaling mechanisms. These studies have also allowed insights into the mechanisms by which neurochemicals important in thermoregulation exert their influence. Finally, the cellular mechanism involved in the interactions between thermoregulation and other aspects of homeostasis, such as energy metabolism and osmoregulation, have started to be unraveled. PMID- 30454586 TI - Molecular basis of central thermosensation. AB - Classic lesion and physiology experiments identified the hypothalamic preoptic area as a pivotal region in the regulation of temperature homeostasis. The preoptic area can sense changes in local temperature, receives information about ambient temperature, contributes to fever, and can affect thermoregulation in response to several biologic signals. Electrophysiologic studies indicate that these actions are mediated by a neuronal circuitry that comprises temperature sensitive as well as temperature-insensitive neurons. Little is known on the molecules that may be required for central thermosensation and much of the efforts towards their identification was done for warm-sensitive neurons. Here we summarize the current knowledge on the subject as well as what the search for these molecules revealed about warm-sensitive neurons. PMID- 30454587 TI - Brown adipose tissue as a heat-producing thermoeffector. AB - Extra heat for defense of body temperature can be obtained from shivering or nonshivering thermogenesis. Nonshivering thermogenesis is a facultative (i.e., only occurring when needed) and adaptive (i.e., being augmented when the demand is chronically higher) process that, in mammals, is the result of the activity of uncoupling protein-1 (UCP1) in brown and brownish adipose tissues; no other quantitatively significant mechanism that fulfills the above criteria has been established. Measurement of heat production is generally indirect, based on oxygen consumption. Heat from brown adipose tissue is generated in mammals adapted to cold, in mammalian neonates, and in mammalian hibernators during arousal; brown adipose tissue may also be active in obese mammals and thus partially protect against further obesity. UCP1 is innately inhibited by cytosolic adenosine triphosphate (ATP) and is likely activated by fatty acids released from triglycerides within the cells; this lipolysis is stimulated by norepinephrine released from the sympathetic nerves innervating the tissue. For prolonged thermogenesis, substrate is delivered by the circulation as chylomicrons, lipoproteins, fatty acids, and glucose. The proton gradient over the mitochondrial membrane created by the respiratory chain is dispersed through the activity of UCP1; brown adipose tissue is nearly devoid of ATP synthase (as compared to respiratory chain activity). UCP1 developed likely at the dawn of mammalian evolution; most mammalian species still retain functional UCP1. Other members of the uncoupling protein family cannot uncouple. Both newborn and adult humans possess active brown adipose tissue but the significance of the tissue for adult human metabolism is not established. PMID- 30454588 TI - Shivering and nonshivering thermogenesis in skeletal muscles. AB - Humans have inherited complex neural circuits which drive behavioral, somatic, and autonomic thermoregulatory responses to defend their body temperature. While they are well adapted to dissipate heat in warm climates, they have a reduced capacity to preserve it in cold environments. Consequently, heat production is critical to defending their core temperature. As in other large mammals, skeletal muscles are the primary source of heat production recruited in cold-exposed humans. This is achieved voluntarily in the form of contractions from exercising muscles or involuntarily in the form of contractions from shivering muscles and the recruitment of nonshivering mechanisms. This review describes our current understanding of shivering and nonshivering thermogenesis in skeletal muscles, from the neural circuitry driving their recruitment to the metabolic substrates that fuel them. The presence of these heat-producing mechanisms can be measured in vivo by combining indirect respiratory calorimetry with electromyography or biomedical imaging modalities. Indeed, much of what is known regarding shivering in humans and other animal models stems from studies performed using these methods combined with in situ and in vivo neurologic techniques. More recent investigations have focused on understanding the metabolic processes that produce the heat from both contracting and noncontracting mechanisms. With the growing interest in the potential therapeutic benefits of shivering and nonshivering skeletal muscle to counter the effects of neuromuscular, cardiovascular, and metabolic diseases, we expect this field to continue its growth in the coming years. PMID- 30454589 TI - Skin vasoconstriction as a heat conservation thermoeffector. AB - Cold exposure stimulates heat production and conservation to protect internal temperature. Heat conservation is brought about via reductions in skin blood flow. The focus, here, is an exploration of the mechanisms, particularly in humans, leading to that cutaneous vasoconstriction. Local skin cooling has several effects: (1) reduction of tonic nitric oxide formation by inhibiting nitric oxide synthase and element(s) downstream of the enzyme, which removes tonic vasodilator effects, yielding a relative vasoconstriction; (2) translocation of intracellular alpha-2c adrenoceptors to the vascular smooth muscle cell membrane, enhancing adrenergic vasoconstriction; (3) increased norepinephrine release from vasoconstrictor nerves; and (4) cold-induced vasodilation, seen more clearly in anastomoses-rich glabrous skin. Cold-induced vasodilation occurs in nonglabrous skin when nitric oxide synthase or sympathetic function is blocked. Reflex responses to general body cooling complement these local effects. Sympathetic excitation leads to the increased release of norepinephrine and its cotransmitter neuropeptide Y, each of which contributes significantly to the vasoconstriction. The contributions of these two transmitters vary with aging, disease and, in women, reproductive hormone status. Interaction between local and reflex mechanisms is in part through effects on baseline and in part through removal of the inhibitory effects of nitric oxide on adrenergic vasoconstriction. PMID- 30454590 TI - Cutaneous active vasodilation as a heat loss thermoeffector. AB - Human skin is the interface between the human body and the environment. As such, human temperature regulation relies largely on cutaneous vasomotor and sudomotor adjustments to appropriately thermoregulate. In particular, changes in skin blood flow can increase or decrease the convective heat transfer from internal tissues to the periphery where it can increase or prevent heat loss to the environment. Thermoregulatory control of the cutaneous vasculature is largely due to cutaneous sympathetic nerves. Sympathetic adrenergic nerves mediate vasoconstriction of the skin, similar to other vascular beds, whereas active vasodilator nerves in nonglabrous skin respond to changes in internal and peripheral temperatures and can profoundly increase skin blood flow. Activation of these vasodilator nerves is known as cutaneous active vasodilation and has been the subject of much recent research. This research has uncovered a highly complex system that involves the activation of multiple receptors and vasodilator pathways in a synergistic and sometimes redundant manner. This complexity and redundancy has left our understanding of cutaneous active vasodilation incomplete; however, the employment of new techniques and use of new pharmacologic agents have introduced many new insights into cutaneous active vasodilation. PMID- 30454591 TI - Sweating as a heat loss thermoeffector. AB - In humans, sweating is the most powerful autonomic thermoeffector. The evaporation of sweat provides by far the greatest potential for heat loss and it represents the only means of heat loss when air temperature exceeds skin temperature. Sweat production results from the integration of afferent neural information from peripheral and central thermoreceptors which leads to an increase in skin sympathetic nerve activity. At the neuroglandular junction, acetylcholine is released and binds to muscarinic receptors which stimulate the secretion of a primary fluid by the secretory coil of eccrine glands. The primary fluid subsequently travels through a duct where ions are reabsorbed. The end result is the expulsion of hypotonic sweat on to the skin surface. Sweating increases in proportion with the intensity of the thermal challenge in an attempt of the body to attain heat balance and maintain a stable internal body temperature. The control of sweating can be modified by biophysical factors, heat acclimation, dehydration, and nonthermal factors. The purpose of this article is to review the role of sweating as a heat loss thermoeffector in humans. PMID- 30454592 TI - Panting as a human heat loss thermoeffector. AB - The human autonomic nervous system participates in the control of thermoregulatory responses that are employed to regulate core temperature following deviations of skin temperature and/or core temperature from their respective resting values. This permits a regulation of the core temperature (TC) at 37.0 +/- 1 degrees C with superimposed circadian variations in both sexes and menstrual cycle-associated variations in premenopausal women. When rendered hyperthermic, passively by heat exposure while at rest or actively during exercise, humans engage heat loss or thermolytic responses, including eccrine sweating and cutaneous vasodilatation. A third, less studied, human thermolytic response is thermal panting, and this response is the focus of this review. Human thermal panting was first described over a century ago. It has since been shown to be a reproducible response showing some similar patterns of breathing in species that employ panting as their sole thermolytic heat loss response. The contribution of human panting as a thermolytic response, however, remains controversial. This review highlights both past and recent evidence supporting that hyperthermic humans have a panting pattern of breathing that plays an important role in human thermoregulation. PMID- 30454593 TI - Thermal comfort. AB - The processes of thermoregulation are roughly divided into two categories: autonomic and behavioral. Behavioral thermoregulation alone does not have the capacity to regulate core temperature, as autonomic thermoregulation. However, behavioral thermoregulation is often utilized to maintain core temperature in a normal environment and is critical for surviving extreme environments. Thermal comfort, i.e., the hedonic component of thermal perception, is believed to be important for initiating and/or activating behavioral thermoregulation. However, the mechanisms involved are not fully understood. Thermal comfort is usually obtained when thermal stimuli to the skin restore core temperature to a regulated level. Conversely, thermal discomfort is produced when thermal stimuli result in deviations of core temperature away from a regulated level. Regional differences in the thermal sensitivity of the skin, hypohydration, and adaptation of the skin may affect thermal perception. Thermal comfort and discomfort seem to be determined by brain mechanisms, not by peripheral mechanisms such as thermal sensing by the skin. The insular and cingulate cortices may play a role in assessing thermal comfort and discomfort. In addition, brain sites involved in decision making may trigger behavioral responses to environmental changes. PMID- 30454594 TI - Afferent pathways for autonomic and shivering thermoeffectors. AB - Body core temperature of mammals is regulated by the central nervous system, in which the preoptic area (POA) of the hypothalamus plays a pivotal role. The POA receives peripheral and central thermosensory neural information and provides command signals to effector organs to elicit involuntary thermoregulatory responses, including shivering thermogenesis, nonshivering brown adipose tissue thermogenesis, and cutaneous vasoconstriction. Cool-sensory and warm-sensory signals from cutaneous thermoreceptors, monitoring environmental temperature, are separately transmitted through the spinal-parabrachial-POA neural pathways, distinct from the spinothalamocortical pathway for perception of skin temperature. These cutaneous thermosensory inputs to the POA likely impinge on warm-sensitive POA neurons, which monitor body core (brain) temperature, to alter thermoregulatory command outflows from the POA. The cutaneous thermosensory afferents elicit rapid thermoregulatory responses to environmental thermal challenges before they impact body core temperature. Peripheral humoral signals also act on neurons in the POA to transmit afferent information of systemic infection and energy storage to induce fever and to regulate energy balance, respectively. This chapter describes the thermoregulatory afferent mechanisms that convey cutaneous thermosensory signals to the POA and that integrate the neural and humoral afferent inputs to the POA to provide descending command signals to thermoregulatory effectors. PMID- 30454595 TI - Efferent neural pathways for the control of brown adipose tissue thermogenesis and shivering. AB - The fundamental central neural circuits for thermoregulation orchestrate behavioral and autonomic repertoires that maintain body core temperature during thermal challenges that arise from either the ambient or the internal environment. This review summarizes our understanding of the neural pathways within the fundamental thermoregulatory reflex circuitry that comprise the efferent (i.e., beyond thermosensory) control of brown adipose tissue (BAT) and shivering thermogenesis: the motor neuron systems consisting of the BAT sympathetic preganglionic neurons and BAT sympathetic ganglion cells, and the alpha- and gamma-motoneurons; the premotor neurons in the region of the rostral raphe pallidus, and the thermogenesis-promoting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area. Also included are inputs to, and neurochemical modulators of, these efferent neuronal populations that could influence their activity during thermoregulatory responses. Signals of metabolic status can be particularly significant for the energy-hungry thermoeffectors for heat production. PMID- 30454596 TI - The thermoregulation system and how it works. AB - Heat exchange processes between the body and the environment are introduced. The definition of the thermoneutral zone as the ambient temperature range within which body temperature (Tb) regulation is achieved only by nonevaporative processes is explained. Thermoreceptors, thermoregulatory effectors (both physiologic and behavioral), and neural pathways and Tb signals that connect receptors and effectors into a thermoregulation system are reviewed. A classification of thermoeffectors is proposed. A consensus concept is presented, according to which the thermoregulation system is organized as a dynamic federation of independent thermoeffector loops. While the activity of each effector is driven by a unique combination of deep (core) and superficial (shell) Tbs, the regulated variable of the system can be viewed as a spatially distributed Tb with a heavily represented core and a lightly represented shell. Core Tb is the main feedback; it is always negative. Shell Tbs (mostly of the hairy skin) represent the auxiliary feedback, which can be negative or positive, and which decreases the system's response time and load error. Signals from the glabrous (nonhairy) skin about the temperature of objects in the environment serve as feedforward signals for various behaviors. Physiologic effectors do not use feedforward signals. The system interacts with other homeostatic systems by "meshing" with their loops. Coordination between different thermoeffectors is achieved through the common controlled variable, Tb. The term balance point (not set point) is used for a regulated level of Tb. The term interthreshold zone is used for a Tb range in which no effectors are activated. Thermoregulatory states are classified, based on whether: Tb is increased (hyperthermia) or decreased (hypothermia); the interthreshold zone is narrow (homeothermic type of regulation) or wide (poikilothermic type); and the balance point is increased (fever) or decreased (anapyrexia). During fever, thermoregulation can be either homeothermic or poikilothermic; anapyrexia is always a poikilothermic state. The biologic significance of poikilothermic states is discussed. As an example of practical applications of the concept presented, thermopharmacology is reviewed. Thermopharmacology uses drugs to modulate specific temperature signals at the level of a thermoreceptor (transient receptor potential channel). PMID- 30454597 TI - Efferent thermoregulatory pathways regulating cutaneous blood flow and sweating. AB - Cutaneous vasoconstrictor nerves regulate heat retention, and are activated by falls in skin or core temperature. The efferent pathways controlling this process originate within the preoptic area. A descending GABAergic pathway, activated by warm skin or core, indirectly inhibits sympathetic premotor neurons in the medullary raphe. Those premotor neurons drive cutaneous vasoconstriction via excitatory glutamatergic and serotonergic connections to spinal preganglionic neurons. Cold skin and/or cold core temperatures activate a direct preoptic-to raphe excitatory pathway. The balance of inhibitory and excitatory influences reaching the medullary raphe determines cutaneous blood flow. During fever, prostaglandin E2 inhibits preoptic GABAergic neurons, resulting in disinhibition of the excitatory preoptic-to-raphe pathway, and hence, cutaneous vasoconstriction. A weaker, parallel source of descending excitatory drive reaches cutaneous preganglionic neurons from the rostral ventrolateral medulla. Sweating follows local heating of the preoptic area in cats and monkeys, and heated humans show sweating-related activation of this same region in functional magnetic resonance imaging (fMRI) studies. A descending pathway that drives sweating has been traced in cats from the hypothalamus to putative premotor neurons in the parafacial region at the pontomedullary junction. The homologous parafacial region in humans also shows sweating-related activation in fMRI studies. The central pathways that drive active vasodilatation in human nonacral skin remain unknown. PMID- 30454598 TI - Central neural substrates involved in temperature discrimination, thermal pain, thermal comfort, and thermoregulatory behavior. AB - A phylogenetically novel pathway that emerged with primate encephalization is described, which conveys high-fidelity cutaneous thermosensory activity in "labeled lines" to a somatotopic map in the dorsal posterior insular cortex. It originates in lamina I of the superficial dorsal horn and ascends by way of the lateral spinothalamic tract and a distinct region in posterolateral thalamus. It evolved from the homeostatic sensory activity that represents the physiologic (interoceptive) condition of the body and drives the central autonomic network, which underlies all affective feelings from the body. Accordingly, human discriminative thermal sensations are accompanied by thermally motivated behaviors and thermal feelings of comfort or discomfort (unless neutral), which evidence suggests are associated with activity in the insular, cingulate, and orbitofrontal cortices, respectively. Yet, the substrates for thermoregulatory behavior have not been established, and several strong candidates (including the hypothalamus and the bed nucleus of the stria terminalis) are discussed. Finally, the neural underpinnings for relationships between thermal affect and social feelings (warm-positive/cold-negative) are addressed, including the association of hyperthermia with clinical depression. PMID- 30454599 TI - Body temperature and sleep. AB - Sleep in mammals is accompanied by a decrease in core body temperature (CBT). The circadian clock in the hypothalamic suprachiasmatic nucleus regulates daily rhythms in both CBT and arousal states, and these rhythms are normally coupled. Reductions in metabolic heat production resulting from behavioral quiescence and reduced muscle tone along with changes in autonomic nervous system activity and thermoeffector activity contribute to the sleep-related fall in CBT. Reductions in sympathetic tone to the peripheral vasculature resulting in heat loss through the skin are reflected in a sleep-related increase in distal skin temperature that is a prominent feature of sleep onset in humans. Within a sleep episode, patterns of autonomic nervous system and thermoeffector activity and the ability to defend against heat and cold exposure differ during nonrapid eye movement (NREM) and rapid eye movement sleep. Anatomic and functional integration of the control of arousal states and thermoregulation occur in the preoptic/anterior hypothalamus. Subsets or warm-sensing neurons in the preoptic/anterior hypothalamus implicated in CBT regulation are spontaneously activated during sleep onset and NREM sleep compared to waking and may underlie sleep-related changes in autonomic nervous system and thermoeffector activity. PMID- 30454600 TI - Skin temperature, sleep, and vigilance. AB - A large number of studies have shown a close association between the 24-hour rhythms in core body temperature and sleep propensity. More recently, studies have have begun to elucidate an intriguing association of sleep with skin temperature as well. The present chapter addresses the association of sleep and alertness with skin temperature. It discusses whether the association could reflect common underlying drivers of both sleep propensity and skin vasodilation; whether it could reflect efferents of sleep-regulating brain circuits to thermoregulatory circuits; and whether skin temperature could provide afferent input to sleep-regulating brain circuits. Sleep regulation and concomitant changes in skin temperature are systematically discussed and three parallel factors suggested: a circadian clock mechanism, a homeostatic hourglass mechanism, and a third set of sleep-permissive and wake-promoting factors that gate the effectiveness of signals from the clock and hourglass in the actual induction of sleep or maintenance of alert wakefulness. The chapter moreover discusses how the association between skin temperature and arousal can change with sleep deprivation and insomnia. Finally it addresses whether the promising laboratory findings on the effects of skin temperature manipulations on vigilance can be applied to improve sleep in everyday life. PMID- 30454601 TI - Thermoregulation and the ultradian basic rest-activity cycle. AB - Daily life involves interactions with the external environment. In rats these apparently spontaneous interactions, often associated with the search for food, alternate with periods of rest in both the dark and light periods of the 24-hour day. Kleitman, in whose laboratory rapid eye movement sleep was discovered, referred to the temporal pattern as "the basic rest-activity cycle." The active periods of the basic rest-activity cycle occur approximately every 1-2 hours in an irregular stochastic pattern that has been described (perhaps unhelpfully) as ultradian rhythmicity. Both the spontaneous interactions and those evoked by salient, potentially threatening environmental events are accompanied by increases in brown adipose tissue (BAT) temperature of approximately 1 degrees C. The heat produced in BAT contributes to associated increases in the temperature of the brain (approximately 0.8 degrees C) and the body (approximately 0.6 degrees C). These temperature changes require extension of the conventional "homeostasis" framework of temperature regulation. They may function to facilitate the cognitive processing that underlies the vital decision making necessary for safe and effective interaction with the external environment. PMID- 30454602 TI - Thermoregulation and age. AB - The thermoregulatory functions may vary with age. Thermosensitivity is active in neonates and children; both heat production and heat loss effector mechanisms are functional but easily exhaustable. Proportional and lasting defense against thermal challenges is difficult, and both hypothermia and hyperthermia may easily develop. Febrile or hypothermic responses to infections or endotoxin can also develop, together with confusion. In small children febrile convulsions may be dangerous. In old age the resting body temperature may be lower than in young adults. Further, thermosensitivity decreases, the thresholds for activating skin vasomotor and evaporative responses or metabolism are shifted, and responses to thermal challenges are delayed or insufficient: both hypothermia and hyperthermia may develop easily. Infection-induced fevers are often limited or absent, or replaced by hypothermia. Various types of brain damage may induce special forms of hypothermia, hyperthermia, or severe fever. Impaired mental state often accompanies hypothermia and hyperthermia, and may occasionally be a dominant feature of infection (instead of the most commonly observed fever). Aging brings about a turning point in women's life: the menopause. The well-known influence of regular hormonal cycles on the thermoregulation of a woman of fertile age gives way to menopausal hot flushes caused by estrogen withdrawal. Not all details of this thermoregulatory anomaly are fully understood yet. PMID- 30454603 TI - Temperature and adaptive immunity. AB - The adaptive immune response has evolved over hundreds of millions of years to have exquisitely specific and durable mechanisms to eliminate pathogenic threats wherever they may occur in the body. Temperature has long been known to influence the response to infections, injuries, and even cancer; however, the mechanistic basis of these effects has only recently come under investigation. The picture that is emerging is that temperature can have varying impacts on adaptive immunity at multiple levels, with elevated temperatures generally promoting the activation, function, and delivery of immune cells, while reduced temperatures inhibit these processes. Here we will discuss the evidence supporting the assertion that temperature is an important modulator of adaptive immunity. PMID- 30454604 TI - Interactions between body fluid homeostasis and thermoregulation in humans. AB - Humans are unique in their ability to control body temperature with a large amount of skin blood flow and sweat rate while exercising in an upright position. However, cutaneous vasodilation in the body reduces total peripheral resistance and blood pooling in cutaneous veins decreases venous return to the heart and cardiac filling pressure. In addition, hypovolemia by sweating accelerates the reduction in cardiac filling pressure. These may threaten the maintenance of blood pressure if they are not compensated for. To prevent this, cutaneous vasodilation and sweat rate are suppressed by baroreflexes or hyperosmolality with dehydration. These mechanisms suppress heat dissipation, accelerate the increase in body temperature, and sometimes cause heat stroke. As a countermeasure to prevent this, we have recommended glucose electrolyte solutions but recently found that aerobic training with carbohydrate + whey protein supplementation markedly improves heat dissipation mechanisms by plasma volume expansion. In this article, we will discuss the importance of improving body fluid homeostasis for thermoregulation under heat stress in humans and the strategy to attain this. PMID- 30454605 TI - Obesity and thermoregulation. AB - Excised fat tissue has a lower thermal conductivity than excised lean tissue. In theory then subcutaneous fat might serve as a barrier to heat loss and influence thermoregulatory abilities. In some aquatic mammals and animals from severely cold habitats subcutaneous adipose tissue has evolved into a continuous sheet that envelopes the organs and acts as a thermal insulation layer. This layer can comprise more than half of the cross-sectional area of the body. In most mammals however, the distribution of fat is less continuous. It has been suggested that in tropical animals this distribution may in fact allow animals to still store energy while not impeding heat loss. Studies of humans immersed in cool water convincingly demonstrate that obesity in humans also serves an insulation function. Humans with obesity cool less rapidly and have to elevate their metabolism less significantly than lean individuals when immersed in water. Although obesity provides an advantage in cold conditions it conversely impedes heat loss and makes obese people susceptible to heat stress more than lean individuals. In small mammals like mice the role of subcutaneous (or intradermal) fat for providing thermal insulation is less clear. In theory variations in thermoregulatory capacity may allow individuals different capabilities to burn off excess consumption. Hence, thermoregulatory variations may cause obesity differences. Thermoregulatory capacity is related to ambient temperature. Yet, levels of obesity are only weakly related to ambient temperature and this effect disappears when confounding factors like poverty and race are taken into account. Hence we conclude that obesity may have a significant impact on thermoregulatory physiology, but the converse is much less likely. PMID- 30454606 TI - Thermoregulation and nausea. AB - The major symptoms of motion sickness are well known and include facial pallor, nausea and vomiting, and sweating, but it is poorly recognized that they actually reflect severely perturbed thermoregulation. Thus, the purpose of this chapter is to present and discuss existing data related to this subject. While hypothermia during seasickness was first noted nearly 150 years ago, detailed studies of this phenomenon were conducted only during the last two decades. Our own research confirmed that motion sickness-induced hypothermia is quite broadly expressed phylogenetically as, besides humans, it could be provoked in several other animals (rats, musk shrews, and mice). Evidence from human and animal experiments indicates that the physiologic mechanisms responsible for the motion sickness induced hypothermia include cutaneous vasodilation and sweating (leading to an increase of heat loss) and reduced thermogenesis. Together, these results suggest that motion sickness triggers a highly coordinated physiologic response aiming to reduce body temperature. The chapter is concluded by presenting hypotheses of how and why motion sickness evokes this hypothermic response. PMID- 30454607 TI - Neurogenesis in the thermoregulatory system. AB - In response to various internal and external stimuli, neuronal progenitor cells in the hypothalamic area proliferate and differentiate to functionally working neurons even in adult animals. This is the case in the thermoregulatory system, especially in the process of heat acclimation. The heat acclimation process presents two different patterns, namely short-term and long-term heat acclimation. In rats, long-term heat acclimation is attained by exposing subjects to constant heat for more than 4 weeks, while short-term heat acclimation is established within several days of heat exposure. Heat exposure for more than 6 days facilitates cell proliferation in the ependymal layer of the third ventricle. The newborn cells then migrate into the hypothalamic parenchyma. After 33 days of heat exposure, the newborn cells abruptly differentiate to mature neurons. A part of the newborn cells are incorporated in a neuronal circuit in the hypothalamus. However, only 6 days of heat exposure hardly promote neuronal differentiation. An administration of mitosis inhibitor interferes with cell proliferation in the hypothalamic area and attenuates heat acclimation-induced improvement of heat tolerance. Long-term, but not short-term, heat acclimation may be established by generating new functional neurons in the hypothalamic area, which is where an important part of the thermoregulatory circuitry exists in rats. PMID- 30454608 TI - Peripheral thermoreceptors in innocuous temperature detection. AB - The mammalian skin is innervated by cold-sensitive afferent neurons. These neurons exhibit ongoing activity at temperatures between ~10 and 42 degrees C, are activated by innocuous cold stimuli, inhibited by warm stimuli and are mechanoinsensitive. Their axons are small-diameter myelinated (Adelta-) fibers in primates and unmyelinated (C-) fibers in nonprimate mammals. The mammalian skin is innervated by warm-sensitive afferent neurons. The density of innervation by these neurons is lower than that by cold-sensitive afferents. They exhibit ongoing activity between ~38 and 48 degrees C, are activated by warm stimuli, inhibited by cold stimuli, and are mechanoinsensitive. Their axons are unmyelinated (C-) fibers. Cold-sensitive unmyelinated afferent neurons exhibit prominent cold sensitivity of their axons (in rats). The discharge pattern of the cutaneous cold-sensitive afferent neurons is fully preserved after nerve injury. Ongoing impulse activity and cold-evoked impulses originate ectopically at the nerve injury site. Deep somatic tissues and viscera are innervated by thermosensitive afferent neurons. Most are warm-sensitive and mechanoinsensitive and have unmyelinated axons. These afferent neurons have only rarely and incompletely been studied, e.g., in the upper gastrointestinal tract, the liver (both vagal afferents), the dorsal abdominal wall, and the skeletal muscle. Spinal cord warm sensitivity may be mediated by cutaneous afferent neurons with unmyelinated axons that are excited by spinal cord warming. PMID- 30454609 TI - Molecular basis of peripheral innocuous cold sensitivity. AB - Of somatosensory modalities cold is one of the more ambiguous percepts, evoking the pleasant sensation of cooling, the stinging bite of cold pain, and welcome relief from chronic pain. Moreover, unlike the precipitous thermal thresholds for heat activation of thermosensitive afferent neurons, thresholds for cold fibers are across a range of cool to cold temperatures that spans over 30 degrees C. Until recently, how cold produces this myriad of biologic effects was unknown. However, recent advances in our understanding of cold mechanisms at the behavioral, physiologic, and cellular level have begun to provide insights into this sensory modality. The identification of a number of ion channels that either serve as the principal detectors of a cold stimulus in the peripheral nervous system, or are part of a differential expression pattern of channels that maintain cell excitability in the cold, endows select neurons with properties that are amenable to electric signaling in the cold. This chapter highlights the current understanding of the molecules involved in cold transduction in the mammalian peripheral nervous system, as well as presenting a hypothetic model to account for the broad range of cold thermal thresholds and distinct functions of cold fibers in perception, pain, and analgesia. PMID- 30454610 TI - Molecular basis of peripheral innocuous warmth sensitivity. AB - The perception of innocuous warmth is a sensory capability that facilitates thermoregulatory, social, hedonic, and even predatory functions. It has long been recognized that innocuous warmth perception is triggered by activation of a subpopulation of specially tuned peripheral thermosensory neurons. In addition, there is growing evidence that thermotransduction by nonneuronal cells, such as skin keratinocytes, might contribute to or modulate our thermosensory experience. Yet, the precise molecular mechanisms underlying warmth transduction are only now being uncovered. Recent molecular genetics approaches have led to the identification of multiple candidate warmth-transducing molecules that appear to confer thermosensitivity upon innocuous warmth afferents and/or neighboring cell types. Most, but not all, of these candidate transducers are members of the transient receptor potential (TRP) ion channel family. Among the latter, evidence supporting a function in innocuous warmth sensation is strongest for TRPV1 and TRPM2 in mammals and for TRPA1 in nonmammalian species. PMID- 30454611 TI - Peripheral and central determinants of skin wetness sensing in humans. AB - Evolutionarily, our ability to sense skin wetness and humidity (i.e., hygroreception) could have developed as a way of helping to maintain thermal homeostasis, as much as it is the case for the role of temperature sensation and thermoreception. Humans are not provided with a specific skin hygroreceptor, and recent studies have indicated that skin wetness is likely to be centrally processed as a result of the multisensory integration of peripheral inputs from skin thermoreceptors and mechanoreceptors coding the biophysical interactions between skin and moisture. The existence of a specific hygrosensation strategy for human wetness perception has been proposed and the first neurophysiologic model of skin wetness sensing has been recently developed. However, while these recent findings have shed light on some of the peripheral and central neural mechanisms underlying wetness sensing, our understanding of how the brain processes the thermal and mechanical inputs that give rise to one of our "most worn" skin sensory experiences is still far from being conclusive. Understanding these neural mechanisms is clinically relevant in the context of those neurologic conditions that are accompanied by somatosensory abnormalities. The present chapter will present the current knowledge on the peripheral and central determinants of skin wetness sensing in humans. PMID- 30454616 TI - Celebrities Speaking Out About Our Causes. PMID- 30454614 TI - Simulation Training in Penile Implant Surgery: Assessment of Surgical Confidence and Knowledge With Cadaveric Laboratory Training. AB - INTRODUCTION: Constraints on surgical resident training (work-hour mandates, shorter training programs, etc.) and availability of expert surgical educators may limit the acquisition of prosthetic surgical skills. As a result, training courses are being conducted to augment the prosthetic surgery learning experience. AIM: To evaluate the impact of a hands-on cadaver-based teaching program on resident procedural knowledge and procedural confidence with placement of a penile prosthesis. MAIN OUTCOME MEASURE: Changes in procedural knowledge and self-confidence following a focused training program on penile prosthetics. METHODS: As part of the 2017 Society of Urologic Prosthetic Surgeons and the Sexual Medicine Society of North America Annual Meeting, 31 urology residents participated in a simulation lab in prosthetic urology. The lab included didactic lectures and a hands-on cadaveric laboratory. Participants completed surveys before and after the course. Wilcoxon Signed Rank tests for matched pairs were used to compare respondents' pre- and postcourse knowledge (% questions answered correctly) and confidence ratings. Prior implant experience was assessed. RESULTS: 31 residents participated in this study. The majority of the participants were 4th- (41.9%) and 5th-year residents (38.7%). Participants showed a significant improvement in procedural knowledge test scores (68.8+/-13.4 vs 74.2 +/- 13.0, P < .05) and self-reported increased median surgical confidence levels (4 vs 3, P value < .001) after completion of the cadaveric course. Subgroup analysis demonstrated that residents with prosthetic surgery experience of <10 cases benefited the most. In addition, improvement in surgical confidence levels observed was greater than the improvement in surgical knowledge. The overall cost of the simulation training course was approximately $1,483 per resident. CONCLUSION: Simulation training in prosthetic surgery seems to improve surgical confidence and knowledge. Further research is needed to better understand the benefits and limitations of simulation training. Lentz AC, Rodriguez D, Davis LG. Simulation training in penile implant surgery: Assessment of surgical confidence and knowledge with cadaveric laboratory training. Sex Med 2018;6:332-338. PMID- 30454615 TI - miR-137 Affects Vaginal Lubrication in Female Sexual Dysfunction by Targeting Aquaporin-2. AB - INTRODUCTION: Female sexual dysfunction (FSD) is a common disease with serious potential hazards, but it has not received much attention. The pathogenesis of FSD is urgently needed for the diagnosis and treatment of FSD. AIM: To investigate the role of microribonucleic acid (mRNA, miR)-137 in FSD. METHODS: Vaginal epithelium tissues from 15 women with lubrication disorder and 15 women with normal function were collected for this study. The expression level of miR 137 in lubrication disorder and normal function women were measured by microarray analysis and Real-time Quantitative Polymerase Chain Reaction (PCR, qPCR). miR 137 was overexpressed in vaginal epithelial cells VK2/E6E7 by lentivirus infection. The cell water permeability was measured using the calcein-quenching method. Cell apoptosis was analyzed by flow cytometry. The potential target of miR-137 was predicted by bioinformatic analysis, then verified by luciferase reporter assays. MAIN OUTCOME MEASURE: The expression level of miR-137 and aquaporin-2 (AQP2), cell water permeability, cell apoptosis, and luciferase reporter assays were examined. RESULTS: miR-137 was found to be highly expressed in vaginal epithelial tissues of women with lubrication disorder. Additionally, functional in vitro studies suggested that overexpression of miR-137 leads to a decrease in cell permeability. By combining target prediction and examination, we identified AQP2 as the direct mechanistic target of miR-137 that affected the water permeability of vaginal epithelial cells. CONCLUSION: Our results point to a novel role for miR-137 and its downstream effector AQP2 in vaginal lubrication, which can be manipulated as therapeutic targets against lubrication disorder and its related disorders. Zhang H, Liu T, Zhou Z. miR-137 affects vaginal lubrication in female sexual dysfunction by targeting Aquaporin-2. Sex Med 2018;6:339-347. PMID- 30454617 TI - How are we conducting and reporting mixed methods research in nursing sciences?: A commentary on Seah et al. (2018) publication. PMID- 30454618 TI - Longitudinal effects of insufficient sleep on psychological problems among adolescent bullies based on Korean Child and Youth Panel Survey. AB - This study was performed to investigate longitudinal effects of insufficient sleep on psychological problems among bullies and neutral students using the Korean Child and Youth Panel Survey (KCYPS) collected from 8th to 10th graders. At the first wave, 6.4% of students reported that they had bullied other students two or more times. Bullies having insufficient sleep duration at the first wave exhibited significantly higher aggression levels than bullies with sufficient sleep over time. Among neutral students, sleep insufficiency showed no longitudinal relationship with aggression. Our findings confirm that insufficient sleep was an associated factor for chronically elevated aggression among bullies. PMID- 30454619 TI - Antidepressant adherence in United States active duty Army Soldiers: A small descriptive study. AB - While much is known about depression and antidepressant adherence associations with illness perceptions, medication beliefs, social support, and stigma in the general population, there is a dearth of knowledge among United States active duty Army Soldiers. The study objective was to explore antidepressant adherence and correlations between antidepressant adherence and illness perceptions, medication beliefs, social support, stigma and select demographic variables among Army Soldiers with depression. Results indicated age and gender were significantly correlated with and predictive of adherence. Low adherence was found. Findings suggest Soldiers who are younger and those who are female are more likely to report higher levels of adherence. PMID- 30454620 TI - Stigma towards people with mental disorders: Perspectives of nursing students. PMID- 30454621 TI - Social support, acculturation stress, and parenting stress among marriage-migrant women. AB - PURPOSE: The purpose of this study was to identify the relationships between social support, acculturation stress, and the parenting stress of marriage migrant women. BACKGROUND: Marriage-migrant women with preschool children appear to experience acculturation and parenting stress. Persistent stress conditions could lead to serious psychological problems. Nevertheless, little is known about the relationship between their stress and social support alleviating stress. METHODS: A questionnaire survey was conducted among 284 marriage-migrant women with preschool children in South Korea, using a questionnaire translated into Chinese, Vietnamese, English, and Korean. A trained research assistant read the questionnaire and asked participants to provide their responses. RESULTS: A hierarchical regression analysis revealed that acculturation stress was associated with parenting stress among marriage-migrant women with preschool children, and that acculturation stress was mostly associated with social support. A Sobel test indicated that the effect of social support on parenting stress significantly declined when acculturation stress was treated as a mediator of that relationship. Acculturation stress was a mediator between social support and parenting stress. CONCLUSION: Nurses must understand the dual stress of acculturation and parenting among marriage-migrant women with preschool children. Furthermore, efforts to support the parenting of marriage-migrant women with preschool children must consider acculturation stress as a major risk factor of parenting stress. Mental health nurses are recommended to conceive programs that reduce the dual stress of acculturation and parenting, which could help improve the mental health of this group. PMID- 30454622 TI - The experiences of providing caregiving for patients with schizophrenia in the Ghanaian context. PMID- 30454623 TI - Depression, positive thinking, personal and social resourcefulness among caregivers of persons with autism spectrum disorders. PMID- 30454624 TI - Prevalence and correlates of psychiatric symptoms among first responders in a Southern State. AB - First responders (FRs) respond to critical incidents as an expectation of their profession, and after years of service, exposure to trauma can accumulate and potentially lead to mental health problems, such as posttraumatic stress disorder (PTSD). A gap persists in the research regarding duty-related risk factors and prevalence of mental health problems among FRs. Guided by existing evidence and in partnerships with the state's FR community, this study assessed the mental health needs of FRs, risk factors that may contribute to these problems, and the associations therein. A convenience sample of firefighters and emergency medical technicians/paramedics (n = 220) were recruited from across Arkansas to complete an online survey. This survey incorporated brief assessment tools to measure various mental health problems, and captured other data regarding possible risk factors. Results found that 14% reported moderate-severe and severe depressive symptoms, 28% reported moderate-severe and severe anxiety symptoms, 26% reported significant symptoms of PTSD, 31% reported harmful/hazardous alcohol use and dependence, 93% reported significant sleep disturbances, and 34% indicated high risk for suicide. Significant group differences were found across measures and gender (female), shift-structure (48 h or more), department setting (rural), relationship status (non-partnered), and having a medical history of hypertension. These findings pose significant implications for mental healthcare providers, as well as other healthcare providers and FR organizations. Findings will guide future research that will address the need for changes in decision making, funding, and policy regarding FRs' MH and MH services available to them. PMID- 30454625 TI - Challenges to recovery following early psychosis: Nursing implications of recovery rate and timing. AB - Early intervention in first episode psychosis is based on an indicated prevention approach that has early illness identification and timely recovery as primary goals. Nurses are instrumental in helping individuals and families achieve both aims. To better understand recovery following a first episode, a prospective cohort of 260 individuals participating in a three-year early intervention program was monitored for achievement of recovery outcomes. Two outcome measures were used to examine the recovery rate and timing of the cohort: (1) partial recovery was comprised of two criteria: (a) symptom control (psychosis and mania), and (b) daily functioning, and 2) comprehensive recovery was measured by three criteria: (a) symptom control; (b) daily functioning; and, (c) quality of life. Survival analysis, including the Kaplan-Meier statistic, and Cox hazard regression were used to examine the cohort's rate and timing for both measures. One hundred and seventy-four individuals attained partial recovery with half (51.1%) reaching the target within nine months. Comprehensive recovery was achieved by 59 individuals (22.7%), primarily in year two and three of treatment. Issues impacting quality of life delayed recovery for the majority of program participants. The gap between psychosis remission and satisfaction/fulfillment with one's everyday life is troubling, but could be improved with stronger nursing support and influence. Sharing the recovery experience with individuals and families that supports their life goals and the discovery of meaning, hope and purpose in the face of illness is the work of nurses. Suggestions for strengthening nursing's impact are considered. PMID- 30454626 TI - Impact of a standardized patient simulation on undergraduate nursing student knowledge and perceived competency of the care of a patient diagnosed with schizophrenia. AB - BACKGROUND: Undergraduate nursing students may not have the opportunity to assess and intervene with a patient diagnosed with schizophrenia during their clinical rotation. Provision of a standardized patient simulation experience affords students this opportunity in a safe setting without risk to the patient or student. METHODS: A quasi-experimental design was utilized to explore the impact of the addition of a standardized patient simulation scenario depicting a patient with a diagnosis of schizophrenia on undergraduate nursing student knowledge and perceived competency. RESULTS: The mean values for perceived competence and knowledge increased significantly over the three time periods (p < 0.001). CONCLUSION: The results suggest that incorporating SP simulation into the undergraduate psychiatric mental health nursing course has the potential to enhance both knowledge and perceived competency of students in caring for patients diagnosed with schizophrenia and ultimately promote better healthcare outcomes. PMID- 30454627 TI - Investigation of the relationship between peer victimization and quality of life in school-age adolescents. AB - OBJECTIVE: This research aims to investigate the relationship between peer victimization and quality of life in school-age adolescents. METHODS: In the study, a total of 332 seventh- and eighth-grade students, who agreed to participate in the research and studying at secondary schools subsidiary of Provincial Directorate for National Education in the Province of Giresun, Turkey, were included in the study. The approval of ethics committee, permission of Provincial Directorate for National Education, and written and verbal consent of the students, who were participated in the research, were obtained. Personal Information Form, Olweus Bully/Victim Questionnaire, and Kiddo-KINDL Adolescent Quality of Life Scale was used for data collection. RESULTS: Considering the quality of life of adolescents according to the peer victimization, the mean physical well-being, mental well-being, family, friends, and disease sub-scale scores and the mean total score in the quality of life scale was found to be higher in adolescents not involved any bullying/victimization, and the difference was found to be significant (p < 0.05). CONCLUSION: In this study, it was concluded that peer victimization is widespread in Turkey, males are more prone to bullying, and peer victimization has a negative impact on quality of life. PMID- 30454628 TI - Care of patients with schizophrenia in the community. AB - There has been a worldwide paradigm shift for community care in Psychiatric treatment, and it has been successfully implemented in many developing countries, including Thailand. This qualitative study aimed to explore the care of patients with schizophrenia in the rural areas of Northeastern Thailand based on the community context. Eighty-three informants were interviewed and group discussions were conducted. Five themes were identified from the caregivers' perspectives, which reflected the practices of the caregiving for patients with schizophrenia within the community as follows: (1) care assistance, (2) care services, (3) strengthening, (4) potential development, and (5) welfare and other services. This study highlights the importance of developing and implementing community based care for patients with schizophrenia within the community. PMID- 30454629 TI - Factors related to quality of life among middle-aged and older korean adults in 2006 and 2014: A nationally representative study. AB - Factors related to quality of life (QoL) were investigated using data from middle aged and older Korean respondents to the 2006 and 2014 Korean Longitudinal Study of Ageing. Respondents' QoL score in 2014 (6.03 +/- 1.69) was lower than in 2006 (6.20 +/- 2.12). All socio-demographic and health-related variables seemed to influence QoL in 2006 (R2 = 0.238) and 2014 (R2 = 0.234). Four factors significantly associated with QoL in both years were health, household income, depression, and regular exercise. Rural and mid-sized city dwellers were more likely to have a better QoL than residents of metropolitan areas; residential area had a greater influence on QoL in 2014. PMID- 30454630 TI - Bipolar II disorder case study. AB - When a patient suffering from bipolar II disorder is misdiagnosed as experiencing unipolar depression, the recommended treatment of the latter may precipitate a hypomanic or manic episode. Unchecked hypomanic symptoms may include risky behaviors, through which a patient could sustain irreparable damage to relationships, careers, and finances. Sometimes, patients are familiar enough with bipolar illness that they may anticipate or interpret inquiry regarding hypomanic symptomology (Goodwin & Jamison, 1990). Applying their own stigmas to bipolar illness, such patients may only admit to depressive symptoms to avoid a bipolar diagnosis (Goodwin & Jamison, 1990). Also, hypomanic symptoms can be nuanced and difficult to detect in patients who may misinterpret the elevated mood state as a return to good mental health rather than the pathologic condition it is. These and other factors, such as poor memory, substance use, physical problems, and co-morbid mental illnesses, contribute to the misdiagnosis and delayed diagnosis of bipolar II disorder for many patients (APA, 2013; Goodwin & Jamison, 1990). The astute clinician, however, can bypass the cascade of events leading up to the poor outcomes associated with unrecognized and mistreated hypomanic symptoms by committing to due diligence when assessing mood symptoms, depressed and elevated. PMID- 30454631 TI - Association between alcohol screening and brief intervention during routine check ups and alcohol consumption among adults living in California. AB - BACKGROUND: Alcohol consumption accounts for 1 in 10 deaths among U.S. adults and cost upwards of $200 billion each year due to productivity loss. Alcohol Screening and Brief Intervention and Referral to Treatment (aSBIRT) was developed as a treatment approach for use in primary care to identify and reduce substance abuse. Although aSBIRT has proven to be successful, implementation rates remain low. METHODS: Using population level representative data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) conducted in California, this study utilizes logistic regression to analyze the association between self-reported drinking levels and screening and brief intervention practices during routine check-ups. RESULTS: The results demonstrated that the more an individual drank, the lower the odds of receiving aSBIRT during a routine check-up. Men had reduced odds of receiving intervention compared to women (odds ratio [OR], 2.21; confidence interval [CI], 1.68-2.90, p < 0.01) and diabetics had reduced odds of receiving intervention compared to non-diabetics (OR, 0.66; CI, 0.45-0.97, p = 0.3). Finally, those with lower income had reduced odds of intervention compared to those with higher income (OR, 1.84; CI, 1.33-2.56, p < 0.01). Among those who were at risk for alcohol abuse (83%) the intervention was only administered to 39%, and men had reduced odds of receiving intervention. CONCLUSION: Physicians perform alcohol screenings, but do not follow up the screening with intervention. Attention should be focused on delivering intervention to those identified as at risk for alcohol abuse through standard screening tools, specifically to men, diabetics, and lower income groups. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. PMID- 30454632 TI - Effects of motivation interviewing using a group art therapy program on negative symptoms of schizophrenia. AB - BACKGROUND: We investigated the effect of motivation interviewing using group art therapy on the negative symptoms of schizophrenia. METHODS: Participants were patients with chronic schizophrenia admitted to the D psychiatric wards in D city, Korea. There were 17 and 18 patients in the experimental and control groups, respectively. The data collection period was from November 28, 2016 to January 28, 2017. Motivation interviewing using group art therapy was conducted twice per week over 6 weeks (12 sessions in total). RESULTS: The significance of the intervention effects were confirmed via measures of negative symptoms, motivation and pleasure, interpersonal relationships, personal hygiene, and hospital program attendance. The experimental group exhibited significantly greater improvements in negative symptoms, motivation and pleasure, interpersonal relationships, personal hygiene, and hospital program attendance than did the control group. CONCLUSIONS: The results showed that the motivation interviewing using group art therapy was an effective nursing intervention for the negative symptoms of schizophrenia. PMID- 30454633 TI - Post-traumatic stress disorder and mental health states of refugee children. PMID- 30454634 TI - Diagnosis and treatment of ADHD in children vs adults: What nurses should know. AB - Attention-deficit/hyperactivity disorder (ADHD) commonly occurs in childhood and may persist into adulthood. Important differences exist between pediatric and adult ADHD with regard to symptoms, comorbidities, diagnosis, and management. Both patient populations benefit from a treatment plan tailored to individual patient needs, and the availability of new stimulant formulations contributes to treatment personalization. To guide nurses' clinical practice in improving ADHD treatment outcomes, this review examines the differences between pediatric and adult ADHD and new treatment options. PMID- 30454635 TI - Chinese nurses are at high risk for suicide: A review of nurses suicide in China 2007-2016. AB - OBJECTIVE: This study summarized the cases of Chinese nurses' suicide during 2007 2016. METHODS: We reviewed public reports on local media, and medical websites. RESULT: A total of 46 cases of nurse suicide reported or published from 2007 to 2016. In these 46 cases, the proportion of female suicide is 98%. Most cases of suicide occurred in nurses aged 18-50 years. The most common way of suicide was jump from building. Nurse suicide occurred more often in full-service tertiary hospitals. CONCLUSION: The Chinese Government and medical organization should be aware of severity of suicide, and take action to be avoided of more suicide in Chinese nurses. PMID- 30454636 TI - Epigenetics, maternal prenatal psychosocial stress, and infant mental health. AB - This paper provides a summary of literature on epigenetic effects and infant health outcomes of maternal psychosocial stress during pregnancy. A search of literature yielded a large body of publications between 2008 and 2018. Relevant articles were selected, and additional sources were located from ancestry searches of reference lists. Results implicate maternal prenatal stress as a source of epigenetic mechanisms that affect fetal brain development and program risk for emotional dysregulation and mental disorders over a lifetime and across generations. Implications for nursing practice are explored at multiple levels of policy advocacy, public education, primary prevention, screening and intervention. PMID- 30454637 TI - The Madeleine and the Journal. PMID- 30454638 TI - Patterns of Adverse Experiences and Health Outcomes Among Women Veterans. AB - INTRODUCTION: Adverse childhood experiences are associated with poor health outcomes in adulthood, such as depression, suicidal behavior, and post-traumatic stress disorder. Subsequent military service may continue trajectories of childhood adversity and contribute to cumulative disadvantage over the life span. This study examines distinct patterns of adversity from childhood through military service and their relationships with adult health and mental health outcomes. METHODS: The study used data from a nationally representative survey (conducted in 2012, analysis in 2016) with >6,000 women primary care users in the Veterans Health Administration, and linked to data from electronic medical records. Latent class analysis was used to derive qualitatively distinct patterns of adverse experiences and logistic regression to model odds of past-year health conditions, comparing effect sizes across classes. RESULTS: Prevalence of both childhood and military adverse events was high. Five meaningful classes of adversity were observed, characterized by low adversity across all events, high adversity across all events, extreme high adversity across all events, adverse family context, and a class characterized primarily by adverse military experiences. Odds of past-year diagnoses of depression, anxiety, post-traumatic stress disorder, substance use disorder, and comorbid mental health and chronic health conditions significantly differed across classes. CONCLUSIONS: Among women Veterans Health Administration users, examination of qualitatively distinct patterns of adversity yielded more meaningful results than counting the number of adverse events. Given the high incidence of adverse experiences, Veterans Health Administration is positioned to respond with secondary prevention and a universal trauma precautions approach to all care for women Veterans. PMID- 30454639 TI - Impact of Financial Incentives on Service Use, Spending, and Health in Medicaid. AB - INTRODUCTION: The Centers for Medicare and Medicaid Services provided grants to Medicaid programs through the Medicaid Incentives for Prevention of Chronic Diseases program to test whether financial incentives changed the use of healthcare services, Medicaid spending, and health outcomes. Six states implemented programs related to diabetes prevention, weight management, diabetes management, and hypertension management. The purpose of this study is to examine whether receipt of financial incentives increased use of services incentivized by the program; reduced expenditures, inpatient admissions, emergency department visits; and improved health outcomes. METHODS: State data on program participation and incentives (between 2011 and 2015) and 2 years of Medicaid claims data pre-Medicaid Incentives for Prevention of Chronic Diseases enrollment and >2 years of claims data after enrollment were analyzed using covariate adjusted regression analyses. Negative binomial, logistic, and linear regressions were used, depending on the outcome variable of interest (services, inpatient admissions and emergency department visits, and total expenditures). Analyses were conducted in 2015 and 2016. RESULTS: Incentive recipients attended, on average, one to two more diabetes prevention classes than control participants, but incentives did not significantly improve uptake of other types of services, such as meetings with a health coach or doctor, gym visits, or attendance at Weight Watchers meetings. Modest improvements in health outcomes, such as weight loss, were observed, yet there were very few significant changes in inpatient admissions, emergency department visits, and Medicaid expenditures. CONCLUSIONS: Financial incentives are useful for engaging Medicaid enrollees in disease prevention programs, but program engagement may not necessarily lead to changing patterns of healthcare utilization and expenditures in the short run. PMID- 30454640 TI - Machine Learning to Identify Prevention-Related Research Grants. PMID- 30454641 TI - Letter to the Editor Regarding "Students' Cigarette Smoking and the Perceived Nicotine Content of Their E-cigarettes". PMID- 30454642 TI - Authors' Response to Letter to the Editor by O'Loughlin and Wellman Concerning "Students' Cigarette Smoking and the Perceived Nicotine Content of Their E cigarettes". PMID- 30454643 TI - American College of Preventive Medicine Position Statement: Reproductive Health Care. PMID- 30454644 TI - Ariella R. Tabaac, MS, Megan E. Sutter, PhD, Catherine S.J. Wall, BS, Kellan E. Baker, MA, MPH. Gender Identity Disparities in Cancer Screening Behaviors. Am J Prev Med 2018:54(3):385-393. PMID- 30454645 TI - Targeting CDK9 Reactivates Epigenetically Silenced Genes in Cancer. AB - Cyclin-dependent kinase 9 (CDK9) promotes transcriptional elongation through RNAPII pause release. We now report that CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell drug screen with genetic confirmation, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression, cell differentiation, and activation of endogenous retrovirus genes. CDK9 inhibition dephosphorylates the SWI/SNF protein BRG1, which contributes to gene reactivation. By optimization through gene expression, we developed a highly selective CDK9 inhibitor (MC180295, IC50 = 5 nM) that has broad anti-cancer activity in vitro and is effective in in vivo cancer models. Additionally, CDK9 inhibition sensitizes to the immune checkpoint inhibitor alpha PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer. PMID- 30454648 TI - Cryo-EM Structure of the Human Ribonuclease P Holoenzyme. AB - Ribonuclease (RNase) P is a ubiquitous ribozyme that cleaves the 5' leader from precursor tRNAs. Here, we report cryo-electron microscopy structures of the human nuclear RNase P alone and in complex with tRNAVal. Human RNase P is a large ribonucleoprotein complex that contains 10 protein components and one catalytic RNA. The protein components form an interlocked clamp that stabilizes the RNA in a conformation optimal for substrate binding. Human RNase P recognizes the tRNA using a double-anchor mechanism through both protein-RNA and RNA-RNA interactions. Structural comparison of the apo and tRNA-bound human RNase P reveals that binding of tRNA induces a local conformational change in the catalytic center, transforming the ribozyme into an active state. Our results also provide an evolutionary model depicting how auxiliary RNA elements in bacterial RNase P, essential for substrate binding, and catalysis, were replaced by the much more complex and multifunctional protein components in higher organisms. PMID- 30454646 TI - Identification, Characterization, and Heritability of Murine Metastable Epialleles: Implications for Non-genetic Inheritance. AB - Generally repressed by epigenetic mechanisms, retrotransposons represent around 40% of the murine genome. At the Agouti viable yellow (Avy) locus, an endogenous retrovirus (ERV) of the intracisternal A particle (IAP) class retrotransposed upstream of the agouti coat-color locus, providing an alternative promoter that is variably DNA methylated in genetically identical individuals. This results in variable expressivity of coat color that is inherited transgenerationally. Here, a systematic genome-wide screen identifies multiple C57BL/6J murine IAPs with Avy epigenetic properties. Each exhibits a stable methylation state within an individual but varies between individuals. Only in rare instances do they act as promoters controlling adjacent gene expression. Their methylation state is locus specific within an individual, and their flanking regions are enriched for CTCF. Variably methylated IAPs are reprogrammed after fertilization and re-established as variable loci in the next generation, indicating reconstruction of metastable epigenetic states and challenging the generalizability of non-genetic inheritance at these regions. PMID- 30454647 TI - Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. AB - Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC. PMID- 30454651 TI - The exopolysaccharide gene cluster pea is transcriptionally controlled by RpoS and repressed by AmrZ in Pseudomonas putida KT2440. AB - In Pseudomonas putida KT2440, the exopolysaccharide Pea is associated with biofilm stability and pellicle formation; however, little is known about its regulatory pathway. In this study, we identified that the gene cluster pea was transcribed from 25 bp upstream of the operon and the stationary phase alternative sigma factor RpoS regulated the transcription of pea. When RpoS was absent, another sigma factor, likely the housekeeping sigma factor RpoD, could also mediate pea transcription but at a low level. The function of Pea polysaccharide was further confirmed to be necessary for full production of biofilm, formation of pellicle and c-di-GMP-dependent wrinkly colony morphology. Additionally, evidences were provided to demonstrate that the transcriptional regulator AmrZ was a negative regulator for pea expression. DNase I footprinting studies verified that AmrZ bound directly to the site overlapping the pea promoter, which might interfere with the binding of RNA polymerase to the promoter and resulted in inhibition of transcription initiation. PMID- 30454650 TI - Visualizing Intracellular Organelle and Cytoskeletal Interactions at Nanoscale Resolution on Millisecond Timescales. AB - In eukaryotic cells, organelles and the cytoskeleton undergo highly dynamic yet organized interactions capable of orchestrating complex cellular functions. Visualizing these interactions requires noninvasive, long-duration imaging of the intracellular environment at high spatiotemporal resolution and low background. To achieve these normally opposing goals, we developed grazing incidence structured illumination microscopy (GI-SIM) that is capable of imaging dynamic events near the basal cell cortex at 97-nm resolution and 266 frames/s over thousands of time points. We employed multi-color GI-SIM to characterize the fast dynamic interactions of diverse organelles and the cytoskeleton, shedding new light on the complex behaviors of these structures. Precise measurements of microtubule growth or shrinkage events helped distinguish among models of microtubule dynamic instability. Analysis of endoplasmic reticulum (ER) interactions with other organelles or microtubules uncovered new ER remodeling mechanisms, such as hitchhiking of the ER on motile organelles. Finally, ER mitochondria contact sites were found to promote both mitochondrial fission and fusion. PMID- 30454652 TI - Transcriptome analysis of hopanoid deficient mutant of Rhodopseuodomonas palustris TIE-1. AB - All three domains of life have an ordered plasma membrane which is pivotal in the selective fitness of primitive life. Like cholesterol in eukaryotes, hopanoids are important in bacteria to modulate membrane order. Hopanoids are pentacyclic triterpenoid lipids biosynthesised in many eubacteria, few ferns and lichens. Hopanoid modulates outer membrane order and hopanoid deficiency results in the weakened structural integrity of the membrane which may in turn affect the other structures within or spanning the cell envelope and contributing to various membrane functions. Hence, to decipher the role of hopanoid, genome-wide transcriptome of wild-type and Deltashc mutant of Rhodopseudomonas palustris TIE 1 was studied which indicated 299 genes were upregulated and 306 genes were downregulated in hopanoid deficient mutant, representing ~11.5% of the genome. Thirty-eight genes involved in chemotaxis, response to stimuli and signal transduction were differentially regulated and impaired motility in hopanoid deficient mutant showed that hopanoid plays a crucial role in chemotaxis. The docking study demonstrated that diguanylate cyclase which catalyses the synthesis of secondary messenger exhibited the capability to interact with hopanoids and might be confederating in chemotaxis and signal transduction. Seventy-four genes involved in membrane transport were differentially expressed and cell assays also explicit that the multidrug transport is compromised in Deltashc mutant. Membrane transport is reliant on hopanoids which may explain the basis for previous observations linking hopanoids to antibiotic resistance. Disturbing the membrane order by targeting lipid synthesis can be a possible novel approach in developing new antimicrobials and hopanoid biosynthesis could be a potential target. PMID- 30454649 TI - Changes of Cell Biochemical States Are Revealed in Protein Homomeric Complex Dynamics. AB - We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins, or other small molecules based on "homomer dynamics" protein-fragment complementation assays (hdPCA). hdPCA measures changes in self association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating the confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health span-affecting drugs, the immunosuppressant rapamycin and the type 2 diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency and includes a change in protein-bound iron levels. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatment of diabetes, cancers, and other chronic diseases of aging. PMID- 30454653 TI - Retraction notice to "The opportunistic human fungal pathogen Candida albicans promotes the growth and proliferation of commensal Escherichia coli through an iron-responsive pathway" [Microbiological Research 207 (2018) 232-239]. PMID- 30454654 TI - Cordycepin and pentostatin biosynthesis gene identified through transcriptome and proteomics analysis of Cordyceps kyushuensis Kob. AB - Cordyceps kyushuensis is the only species of cordyceps growing on the larvae of Clanis bilineata Walker, and has been demonstrated that there are lots of pharmacological components including cordycepin. Cordycepin shows lots of pharmacological action but it could be converted to 3'-deoxyinosine by adenosine deaminase in vivo, which weakens the efficiency of cordycepin. That pentostatin, which has been reported to inhibit adenosine deaminase, combining cordycepin could enhance the efficiency of cordycepin in vivo. During transcriptome and proteomics analysis of Cordyceps kyushuensis, a single gene cluster including four genes we named ck1-ck4 which can synthesis both cordycepin and pentostatin has been identified using BLAST. Meanwhile, KEGG, KOG, GO analysis and differentially expressed genes were analyzed in transcriptome and proteomics. This study first sequenced transcriptome and proteomics of C. kyushuensis, and demonstrated that there is a single gene cluster related to biosynthesis of cordycepin and pentostatin, which can be employed to improve the yield of cordycepin and find more functional proteins. PMID- 30454655 TI - Organization of multi-binding to host proteins: The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of Mycoplasma pneumoniae. AB - Mycoplasma pneumoniae is a frequent cause of community-acquired infections of the human respiratory tract. During the evolutionary adaptation of the bacteria to the host, the genome of the pathogen is strongly reduced resulting in the loss of cell wall, limited metabolic pathways and a relatively small number of virulence factors. As interacting with host proteins, surface-exposed proteins with a primary function in cytosol-located processes of metabolism and regulation such as glycolytic enzymes, heat-shock proteins and chaperones have been considered as contributing to pathogenesis. Among these moonlighting proteins, some members are confirmed as binding to several host components. The glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of M. pneumoniae is a typical example of such multi-binding proteins. To investigate the organization of these interactions, GAPDH was divided into four parts. Recombinant proteins were successfully expressed in Escherichia coli and polyclonal antisera were produced. Binding of full length and parts of GAPDH to human A549 cells was proven. Furthermore, interactions with human plasminogen, vitronectin, fibronectin and fibrinogen were demonstrated for nearly all recombinant GAPDH proteins. In the presence of these proteins, plasminogen can be activated to the protease plasmin. In contrast, the localization on the surface of bacterial cell was confirmed for the C-terminal part of GAPDH only. By using overlapping peptides covering this region, binding of the investigated host components to the sequence 326QLVRVVNYCAKL337 was found. The results of the study suggest a prominent role of the surface-localized C terminal part of GAPDH in associations with different human proteins indicating its importance for host-pathogen-interactions. PMID- 30454656 TI - Genome sequence and comparative genomics of Rhizobium sp. Td3, a novel plant growth promoting phosphate solubilizing Cajanus cajan symbiont. AB - Rhizobium sp. Td3 is a Sesbania plant growth promoting, Cajanus cajan nodulating rhizobia. Studying its whole genome was important as it is a potent phosphate solubilizer with constitutive gluconic acid production ability through operation of the periplasmic glucose oxidation pathway even under conditions of catabolite repression. This is in contrast to the other explored phosphate solubilizers. Rhizobial isolates sequenced so far are known to lack components of the direct glucose oxidation pathway and cannot produce gluconic acid on its own. Here, we present the genome sequence of Rhizobium sp. Td3. Genome comprises of a single chromosome of size 5,606,547 bp (5.6 Mb) with no symbiotic plasmid. Rhizobium leguminosarum bv. viciae USDA2370 was the closest whole genome known. 109 genes responsible for diverse plant growth promoting activities like P solubilization, synthesis of acetoin, nitric oxide, indole-3 acetic acid, exopolysaccharide, siderophore and trehalose have been identified. Flagellar proteins, genes encoding antibiotic and metal resistance, enzymes required for combating oxidative stress as well as attachment and colonization in the plant rhizosphere are also present. Availability of genome sequence of such a versatile plant growth promoting agent will help in exploiting all the phyto-beneficial traits of Td3 for its use as a biofertilizer. PMID- 30454657 TI - Antimicrobial, plant growth-promoting and genomic properties of the peanut endophyte Bacillus velezensis LDO2. AB - Peanut suffer from a number of fungal and bacterial pathogens, while plant endophytes were considered excellent candidates as biocontrol agents. In this study, the peanut endophytic bacterium LDO2 was evaluated for the potential of peanut pathogens inhibition and growth-promotion, and the genetic mechanisms were explored by genome mining. Strain LDO2 significantly inhibited the growth of peanut pathogenic fungi and pathogenic bacteria, and specifically, it showed pronounced inhibition on mycelia growth of Aspergillus flavus mycelia and caused mycelial deformity. Gene clusters responsible for antifungal metabolites (fengycin, surfactin, bacilysin) and antibacterial metabolites (butirosin, bacillaene, difficidin, macrolactin, surfactin, bacilysin) were identified. Strain LDO2 also exhibited several growth-promoting related features including phosphate solubilization, siderophore production and growth promotion of peanut root. Genes associated with plant growth promotion were also identified and analyzed, as well as genes related to secreted proteins. These findings suggested that this peanut endophyte could be a potential biocontrol agent in peanut production and a source of antimicrobial compounds for further exploitation. PMID- 30454658 TI - Helicobacter pylori evasion strategies of the host innate and adaptive immune responses to survive and develop gastrointestinal diseases. AB - Helicobacter pylori (H. pylori) is a bacterial pathogen that resides in more than half of the human population and has co-evolved with humans for more than 58,000 years. This bacterium is orally transmitted during childhood and is a key cause of chronic gastritis, peptic ulcers and two malignant cancers including MALT (mucosa-associated lymphoid tissue) lymphoma and adenocarcinoma. Despite the strong innate and adaptive immune responses, H. pylori has a long-term survival in the gastric mucosa. In addition to the virulence factors, survival of H. pylori is strongly influenced by the ability of bacteria to escape, disrupt and manipulate the host immune system. This bacterium can escape from recognition by innate immune receptors via altering its surface molecules. Moreover, H. pylori subverts adaptive immune response by modulation of effector T cell. In this review, we discuss the immune-pathogenicity of H. pylori by focusing on its ability to manipulate the innate and acquired immune responses to increase its survival in the gastric mucosa, leading up to gastrointestinal disorders. We also highlight the mechanisms that resulted to the persistence of H. pylori in gastric mucosa. PMID- 30454659 TI - Recombineering Pseudomonas protegens CHA0: An innovative approach that improves nitrogen fixation with impressive bactericidal potency. AB - Pseudomonas protegens CHA0 is a well-characterized, root-colonizing bacterium with broad-spectrum biocontrol ability. Therefore, it has a great potential to curb plant diseases and to partly replace synthetic chemical pesticides that are harmful to humans. Here, we obtained the multifunctional mutant CHA0-DeltaretS Nif via Red/ET recombineering technology. After deletion of the retS gene and integration of the nitrogen-fixing gene island (Nif) into the CHA0 genome, the resulting mutant, CHA0-DeltaretS-Nif, manifested improved both bactericidal activity and biological nitrogen-fixation function. A pot experiment of Arabidopsis thaliana indicated that the strain CHA0-DeltaretS-Nif promoted plant growth via expressing several secondary factors, such as the antibiotic 2,4 diacetylphloroglucinol (2,4-DAPG) and nitrogenase. In order to grow this biocontrol strain at an industrial level, the growth conditions in a 1 L continuous-flow fermenter were optimized to 28 degrees C, pH of 7.0, and 600 rpm. Moreover, growth experiments in a 5 L fermenter with these optimal growth conditions yielded the maximum cell density, providing vital insights for the industrialization and large-scale fermentation of P. protegens CHA0 for further applications. CHA0-DeltaretS-Nif possesses both bactericidal and nitrogen fixation activities and thus could be used as a biological agent to enhance crop production. PMID- 30454660 TI - Environmental conditions shape the biofilm of the Antarctic bacterium Pseudoalteromonas haloplanktis TAC125. AB - Biofilms are the most widely distributed and successful microbial modes of life. The capacity of bacteria to colonize surfaces provides stability in the growth environment, allows the capturing of nutrients and affords protection from a range of environmental challenges and stress. Bacteria living in cold environments, like Antarctica, can be found as biofilms, even though the mechanisms of how this lifestyle is related to their environmental adaptation have been poorly investigated. In this paper, the biofilm of Pseudoalteromonas haloplanktis TAC125, one of the model organisms of cold-adapted bacteria, has been characterized in terms of biofilm typology and matrix composition. The characterization was performed on biofilms produced by the bacterium in response to different nutrient abundance and temperatures; in particular, this is the first report describing the structure of a biofilm formed at 0 degrees C. The results reported demonstrate that PhTAC125 produces biofilms in different amount and endowed with different physico-chemical properties, like hydrophobicity and roughness, by modulating the relative amount of the different macromolecules present in the biofilm matrix. The capability of PhTAC125 to adopt different biofilm structures in response to environment changes appears to be an interesting adaptation strategy and gives the first hints about the biofilm formation in cold environments. PMID- 30454661 TI - Isolation and characterization of endophytes from nodules of Mimosa pudica with biotechnological potential. AB - Legumes establish symbiotic relationships with different microorganisms, which could function as plant growth promotion microorganisms (PGPM). The finding of new PGPM strains is important to increase plant production avoiding or diminishing the use of industrial fertilizers. Thus, in this work we evaluated the plant growth promotion traits of ten strains isolated from Mimosa pudica root nodules. According to the 16S rDNA sequence, the microorganisms were identified as Enterobacter sp. and Serratia sp. To the best of our knowledge this is the first report describing and endophytic interaction between Mimosa pudica and Enterobacter sp. These strains have some plant growth promoting traits such as phosphate solubilization, auxin production and cellulase and chitinase activity. Strains identified as Serratia sp. inhibited the growth of the phytopathogenic fungi Fusarium sp., and Alternaria solani and the oomycete Phytophthora capsici. According to their biochemical characteristics, three strains were selected to test their plant growth promoting activity in a medium with an insoluble phosphate source. These bacteria show low specificity for their hosts as endophytes, since they were able to colonize two very different legumes: Phaseolus vulgaris and M. pudica. Seedlings of P. vulgaris were inoculated and grown for fifteen days. Enterobacter sp. NOD1 and NOD10, promoted growth as reflected by an increase in shoot height as well as an increase in the size and emergence of the first two trifolia. We could localize NOD5 as an endophyte in roots in P. vulgaris by transforming the strain with a Green Fluorescent Protein carrying plasmid. Experiments of co-inoculation with different Rhizobium etli strains allowed us to discard that NOD5 can fix nitrogen in the nodules formed by a R. etli Fix- strain. The isolates described in this work show biotechnological potential for plant growth promoting activity and production of indoleacetic acid and siderophores. PMID- 30454662 TI - Plant-microbe interactions endorse growth by uplifting microbial community structure of Bacopa monnieri rhizosphere under nematode stress. AB - The modification of rhizosphere microbial diversity and ecological processes are of rising interest as shifting in microbial community structure impacts the mutual role of host-microbe interactions. Nevertheless, the connection between host-microbial community diversity, their function under biotic stress in addition to their impact on plant performances is poorly understood. The study was designed with the aim to analyze the tripartite interactions among Chitiniphilus sp., Streptomyces sp. and their combination with indigenous rhizospheric microbial population of Bacopa monnieri for enhancing the plant growth and bacoside A content under Meloidogyne incognita stress. Overall, plants treated with the microbial combination recorded enhanced growth as illustrated by significantly higher biomass (2.0 fold), nitrogen uptake (1.8 fold) and bacoside A content (1.3 fold) along with biocontrol efficacy (58.5%) under nematode infected field. The denaturing gradient gel electrophoresis (DGGE) fingerprints of 16S-rDNA revealed that microbial inoculations are major initiators of bacterial community structure in the plant rhizosphere. Additionally, the plants treated with microbial combination showed maximum diversity viz., Shannon's (3.29), Margalef's (4.21), and Simpson's (0.96) indices. Likewise the metabolic profiling data also showed a significant variation among the diversity and evenness indices upon microbial application on the native microflora. We surmise that the application of beneficial microbes in combinational mode not only helped in improving the microbial community structure but also successfully enhanced plant and soil health under biotic stress. PMID- 30454663 TI - Far-reaching cellular consequences of tat deletion in Escherichia coli revealed by comprehensive proteome analyses. AB - In Escherichia coli, the Twin-arginine translocation (Tat) pathway secretes a set of folded proteins with important physiological functions to the periplasm and outer membrane. The loss of Tat secretion impairs outer membrane integrity and leads to decreased cell growth. Only recently, the Tat pathway has gained more attention due to its essential role in bacterial virulence and applications in the production of fully folded heterologous proteins. In this study, we investigated the influence of the deletion of all active Tat pathway components on the E. coli cells. The comprehensive proteomic analysis revealed activation of several stress responses and experimentally confirmed the dependence of certain proteins on the Tat system for export. We observed that a tat deletion triggers protein aggregation, membrane vesiculation, synthesis of colanic acid and biofilm formation. Furthermore, the mislocalization of Tat-dependent proteins disturbs iron and molybdenum homeostasis and impairs the cell envelope integrity. The results show that the functional Tat pathway is important for the physiological stability and that its dysfunction leads to a series of severe changes in E. coli cells. PMID- 30454664 TI - TO TEST OR NOT TO TEST THAT IS THE QUESTION. PMID- 30454665 TI - California Promotes Smoking Cessation for Medicaid Enrollees: Lessons for the Nation? PMID- 30454666 TI - Advancing Smoking Cessation in California's Medicaid Population. PMID- 30454667 TI - The Growing Proportion of Smokers in Medicaid and Implications for Public Policy. AB - INTRODUCTION: This study examined survey data from before and after California expanded its Medicaid program under the Affordable Care Act. It assessed changes in the insurance status of smokers, the proportion of smokers in Medicaid, and the health and well-being of those smokers relative to their counterparts in other insurance groups. METHODS: The study compared two data sets from the California Health Interview Study, the 2011-2012 (N=42,935) and 2016 (N=21,055) surveys. Measures include health insurance status, smoking status, chronic health conditions, frequency of doctors' visits, and psychological distress. Data were analyzed in 2018. RESULTS: From 2011-2012 to 2016, the estimated number of California smokers in Medicaid nearly doubled from 738,113 to 1,447,945, and the proportion of smokers covered by Medicaid increased from 19.3% to 41.5%. Compared with those with private insurance, smokers in Medicaid were more likely to have chronic disease, have made five or more doctors' visits in the past year, and be in severe psychological distress. In 2016, a total of 51.4% of all adult smokers with chronic disease conditions and 57.8% of those in severe psychological distress were covered by Medicaid. CONCLUSIONS: With Medicaid covering a much higher proportion of smokers, especially of those smokers with chronic disease and in psychological distress, state Medicaid programs and plans must make tobacco cessation a top priority. They should encourage clinicians to ask, advise, and assist all smokers, track progress in reducing smoking prevalence, employ mass communication strategies to drive quit attempts, improve access to medications, and develop or expand programs to help smokers quit. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454668 TI - Incentives and Patches for Medicaid Smokers: An RCT. AB - INTRODUCTION: Most successful trials of financial incentives for smoking cessation have offered large rewards contingent on outcomes. This study examines whether more modest incentives to encourage engagement, non-contingent on outcomes, also increase cessation; whether sending medications directly to participants boosts quitting; and whether these strategies are effective in Medicaid. STUDY DESIGN: Three-group RCT of usual care (UC); nicotine patch (NP); and NP and financial incentive (NP+FI). SETTING/PARTICIPANTS: Medicaid beneficiaries calling the California Smokers' Helpline, 2012-2013 (N=3,816). Data were analyzed in 2017. INTERVENTION: All participants enrolled in evidence-based, multisession telephone counseling. All received proof of enrollment with which they could obtain free quitting aids at their pharmacy. NP and NP+FI also received nicotine patches sent to their homes. NP+FI received up to $60 for completing counseling calls. MAIN OUTCOME MEASURES: Quit attempt rate, 7-day and 30-day abstinence at 2 and 7 months, and 6-month prolonged abstinence (primary outcome). RESULTS: In both complete-case and intention-to-treat analyses, outcomes trended upward from UC to NP to NP+FI. Differences between NP and UC were generally nonsignificant. By contrast, the NP+FI group significantly outperformed the other groups on all measures. In intention-to-treat analysis, compared with UC, NP+FI was more likely to make a quit attempt (68.4% vs 54.3%, p<0.001); be abstinent for 7 days at 2 months (36.1% vs 25.5%, p<0.001) and 7 months (21.2% vs 16.1%, p=0.002); be abstinent for 30 days at 2 months (30.0% vs 18.9%, p<0.001) and 7 months (21.5% vs 16.7%, p=0.004); and achieve 6-month prolonged abstinence (13.2% vs 9.0%, p=0.001). CONCLUSIONS: Financial incentives increased treatment engagement and short- and long-term smoking cessation, despite being modest and non-contingent on outcomes. The study found that incentives can be effective in a Medicaid population, and can feasibly be integrated into existing quitline services. TRIAL REGISTRATION: The trial is registered at www.clinicaltrials.gov NCT01502306. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454669 TI - Economic Impact of Financial Incentives and Mailing Nicotine Patches to Help Medicaid Smokers Quit Smoking: A Cost-Benefit Analysis. AB - An RCT designed to increase Medicaid smokers' quitting success was conducted in California during 2012-2013. In the trial, alternative cessation treatment strategies were embedded in the state's ongoing quitline services. It found that modest financial incentives of up to $60 per participant and sending nicotine patches induced significantly higher cessation rates compared with usual care alone and usual care plus nicotine patches. Building upon that study, this study assessed potential population-level costs and benefits of integrating financial incentives and nicotine patches in a quitline setting for Medicaid smokers. A cost-benefit analysis was undertaken from the Medicaid program's perspective. The Cardiovascular Disease Policy Model was used to simulate future healthcare expenditures over a 10-year horizon for each treatment strategy for a study cohort of California Medicaid enrollees who were aged 35-64 years in 2014 (n=2,452,000). To simulate potential population-level benefits under each treatment strategy, each treatment was applied to all active smokers in the study cohort (n=478,300). Sensitivity analyses were conducted by varying key parameters, such as cessation costs, discount rate, relapse rates, and time horizon. Adding both financial incentives and nicotine patches to usual quitline care would result in $15 million net savings over 10 years, with a benefit-cost ratio of 1.30 compared with the usual care plus nicotine patches strategy. It would yield $44 million net savings, with a benefit-cost ratio of 1.90 compared with usual care alone. The strategy of providing financial incentives and mailing nicotine patches directly to Medicaid smokers who call the quitline is cost saving. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454670 TI - The Medi-Cal Incentives to Quit Smoking Project: Impact of Statewide Outreach Through Health Channels. AB - INTRODUCTION: Little is known about how incentives may encourage low income smokers to call for quitline services. This study evaluates the impact of outreach through health channels on California Medicaid (Medi-Cal) quitline caller characteristics, trends, and reach. STUDY DESIGN: Longitudinal study. SETTING/PARTICIPANTS: Medi-Cal quitline callers. INTERVENTION: Statewide outreach was conducted with health providers, Medi-Cal plans (all-household mailings with tracking codes), and public health organizations (March 2012-July 2015). For incentives, Medi-Cal callers could ask for a $20 gift card; in September 2013, callers were offered free nicotine patches. MAIN OUTCOME MEASURES: Caller characteristics were compared with chi-square analyses, joinpoint analysis of call trends was performed accounting for Medi-Cal population growth, referral source among Medi-Cal and non-Medi-Cal callers was documented, and the annual percentage of the population reached who called the Helpline was calculated. Analyses were conducted 2016-2018. RESULTS: Total Medi-Cal callers were 92,900, a 70% increase from prior annual averages: 12.4% asked for the financial incentive, 17.3% reported the mailing code, and 73.3% received nicotine patches while offered. Among the two thirds of callers who completed counseling, 15.5% asked for the financial incentive, and 13.6% reported the mailing code. A joinpoint analysis showed call trends increased 23% above expected for the Medi-Cal population growth after mailings to providers and members began, and decreased after outreach ended. Annual reach increased from 2.3% (95% CI=2.1, 2.6) in 2011 to peak at 4.5% (95% CI=3.6, 5.3) in 2014. Among subgroups with higher reach rates, some also had higher rates of asking for the financial incentive (African Americans, American Indian), reporting the tracking code (whites), or both (aged 45-64 years). Medi-Cal callers were more likely than non-Medi-Cal callers to report providers (32.3% vs 23.8%) and plans (19.7% vs 1.4%) as their referral source, and less likely to cite media (20.2% vs 44.4%, p<0.001). CONCLUSIONS: Statewide outreach through health channels incentivizing Medi-Cal members increased the utilization and reach of quitline services. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454671 TI - Effects of Offering Nicotine Patches, Incentives, or Both on Quitline Demand. AB - INTRODUCTION: Previous studies found that offering free nicotine patches significantly increases calls to quitlines, although most used pre-post designs and did not directly compare the effects of patches and other incentives. The current study with California Medicaid members used a 2 * 2 design to directly assess the effects of offering free patches and incentives on calls to a quitline. The hypotheses were that offering either would make members more likely to call, and that offering both would increase demand even further. METHODS: Flyers were inserted into a mailing sent to 4,268,696 Medicaid households, with one of four offers: (1) free counseling; (2) counseling plus patches; (3) counseling plus a $20 gift card; and (4) counseling plus patches and gift card. Ninety percent received the first offer and 10% received one of the other three offers, in equal proportions. The mailers shipped late 2013 to early 2014. Data were collected 2013-2015 and analyzed 2018. RESULTS: Response rates were 0.029% for counseling, 0.115% for counseling plus patches, 0.122% for counseling plus gift card, and 0.200% for counseling, patches, and gift card. Both patches and gift cards had statistically significant effects (both p<0.001). Promotional costs were 59%-75% lower with an incentive. Non-whites responded more strongly than whites to a gift card offer. CONCLUSIONS: Offering either free patches or a $20 gift card quadrupled the likelihood of Medicaid smokers calling a quitline; offering both had a nearly additive effect. Incentive offers dramatically increased the cost-effectiveness of promotions. Piggybacking on existing Medicaid communications to promote cessation proved very successful. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454672 TI - Direct-to-Member Household or Targeted Mailings: Incentivizing Medicaid Calls for Quitline Services. AB - INTRODUCTION: Innovative methods are needed to promote tobacco cessation services. The Medi-Cal Incentives to Quit Smoking project (2012-2015) promoted modest financial and medication incentives to encourage Medi-Cal smokers to utilize the California Smokers' Helpline (Helpline). This article describes the implementation and impact of two different direct-to-member mailing approaches. METHODS: Medi-Cal Incentives to Quit Smoking promotional materials were mailed directly to members using two approaches: (1) household mailings: households identified through centralized membership divisions and (2) individually targeted mailings: smokers identified by medical codes from Medi-Cal managed care plans. Mailings included messaging on incentives, such as gift cards or nicotine patches. Number of calls per month, calls per unit mailed, and associated printing costs per call were compared during and 1 month after mailings. Activated caller response was based on reporting a household mailing promotional code or based on requesting financial incentives for individually targeted mailings. Analyses were conducted in 2018. RESULTS: Direct-to-member mailings, particularly with incentive messaging, demonstrated an increase in call volumes during and 1 month after mailing, and increased Medi-Cal calls to the Helpline per unit mailed. Mailings with only counseling messages had the lowest percentage of activated calls per unit mailed, whereas the incentive messaging mailings were consistently higher. Although household mailings demonstrated lower printing costs per call, individually targeted mailings had a higher percentage of activated calls per unit mailed. CONCLUSIONS: Household and individually targeted mailings are feasible approaches to increase Medi-Cal calls to the Helpline, particularly with incentive messaging. Choosing an approach and messaging depends on available resources, timing, and purpose. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454673 TI - Racial/Ethnic Differences in the Response to Incentives for Quitline Engagement. AB - INTRODUCTION: Certain racial and ethnic minorities have lower utilization of tobacco cessation services, such as Helpline counseling and cessation medications. The goal of the California Medicaid (Medi-Cal) Incentives to Quit Smoking Program was to facilitate successful cessation by promoting modest financial and cessation medication-related incentives to increase engagement with the California Smokers' Helpline counseling services. Differences in the response to incentives and outreach on engagement with Helpline services among racial/ethnic groups within the Medi-Cal population were examined. STUDY DESIGN: Analysis of Helpline caller data. SETTING/PARTICIPANTS: African American (n=18,656); English-speaking Latinx (n=12,792); Spanish-speaking Latinx (n=3,254); and white (n=45,907) Medi-Cal callers. INTERVENTION: The Medi-Cal Incentives to Quit Smoking team conducted statewide and community-based outreach and facilitated direct-to-member all-household mailings about the Medi-Cal Incentives to Quit Smoking program to engage with Medi-Cal callers and promote Helpline services between March 2012 and July 2015 (analyzed 2017/2018). Medi-Cal callers could ask for a $20 gift card incentive after having completed a counseling session; in September 2013, callers were offered free nicotine replacement therapy. MAIN OUTCOME MEASURES: Three behavioral outcomes are reported that reflect activated callers and callers who engaged in treatment that is proven to improve chances of quitting smoking: receipt of the $20 incentive, receipt of nicotine replacement therapy, and receipt of counseling. RESULTS: African Americans and English-speaking Latinx had higher engagement with the financial incentive than whites (African American APR=1.66, 95% CI=1.59, 1.73, English-speaking Latinx APR=1.29, 95% CI=1.22, 1.36). Spanish-speaking Latinx had lower initial engagement with the financial incentive (APR=0.75, 95% CI=0.66, 0.85), but higher engagement with Medi-Cal's all-household mailing (Spanish speaking Latinx 30.6% vs whites 18.2%, p<0.001). Although African Americans and English-speaking Latinx had similar rates of completing counseling and receiving nicotine replacement therapy as whites, Spanish-speaking Latinx had higher rates than whites. CONCLUSIONS: The promotion of modest financial and cessation medication incentives through multiple outreach channels increased callers' engagement with the Helpline and appeared to promote ethnic and linguistic equity with respect to the receipt of counseling and nicotine replacement therapy. Targeted community-based outreach may resonate particularly for African Americans, and language-concordant Medi-Cal insurance plan mailings may have reached newly covered Spanish-speaking Latinx. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454674 TI - Outreach to California Medicaid Smokers for Asian Language Quitline Services. AB - INTRODUCTION: Asian male immigrants have high smoking rates. This article describes outreach approaches in the Medi-Cal Incentives to Quit Smoking project to incentivize California Medicaid (Medi-Cal) calls to the California Smokers' Helpline (Helpline) Asian-language lines. METHODS: Outreach efforts adapted Medi Cal Incentives to Quit Smoking materials for the Asian-language lines. Community based efforts included outreach at ethnic supermarkets and distribution through community networks. Leveraging the Helpline's Asian print media campaign, three press releases promoted Medi-Cal Incentives to Quit Smoking with Lunar New Year or community physician messaging. Medi-Cal all-household mailings with tracking codes also included the Asian-language lines. Helpline caller characteristics and trends were examined for project period 2012-2015. Analyses were conducted in 2018. RESULTS: Among 4,306 Asian American Pacific Islander Medi-Cal callers, there were 37% Asian-speaking Asian Americans (9.5% Chinese, 17.2% Vietnamese, and 10.5% Korean); 44% English-speaking Asian Americans; 9% Pacific Islanders; and 10% Asian American Pacific Islander not otherwise specified. Almost 10% of Asian-speaking Asian Americans were activated by the financial incentive and this was similar for all-household mailings, although this was lower than the other groups. Medi-Cal calls to the Asian-language lines increased, from an average of 18 calls/month to 47 calls/month (162% increase) in the first and last 12 project months respectively. Community outreach was limited by timing and sustainability. The 3-month call totals before and after the Asian-language press releases were significantly greater for Asian-speaking calls than for English-speaking calls (Cochran-Mantel-Haenszel p<0.001, OR=1.70, 95% CI=1.45, 1.99). CONCLUSIONS: Whereas community outreach is challenging, promising population-based methods for in-language, culturally tailored outreach can include press releases with ethnic media and direct-to-member mailings. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454675 TI - Medi-Cal Incentives to Quit Smoking Program: Reach to Pregnant and Parenting Women. AB - INTRODUCTION: In California, half of pregnant women and children are on California's Medicaid (Medi-Cal). The Medi-Cal Incentives to Quit Smoking program provided incentives to adults on Medi-Cal to call the California Smokers Helpline (Helpline) from March 2012 to July 2015. This analysis examined reach of the Medi Cal Incentives to Quit Smoking program among pregnant and parenting women. METHODS: This study examined caller data from the Helpline from 2010 to 2015 among women of reproductive age (18-45 years) enrolled in Medi-Cal (n=32,691; analyzed in 2017/2018). The authors calculated the annual percentage of the target population reached who called the Helpline by pregnancy status and used adjusted prevalence ratios to examine the associations between Medi-Cal Incentives to Quit Smoking incentive period, pregnancy/parenting status, Medi-Cal Incentives to Quit Smoking incentives ($20 gift card and nicotine patch), and counseling. RESULTS: Over the study period, the percentage of the target population reached increased for women of reproductive age (2.1% in 2011 to 3.0% in 2014) and pregnant women (2.1% in 2011 to 3.3% in 2014). The percentage of women who asked for the $20 gift card (13.6%) was not substantially different by pregnancy status, and WIC and nonprofits were important referral sources. Pregnant women were less likely to receive nicotine patches, but there was a 3- to 4-fold increase during the Medi-Cal Incentives to Quit Smoking incentive period for both pregnant and nonpregnant women. Among nonpregnant women, counseling decreased 14% during the Medi-Cal Incentives to Quit Smoking incentive period. CONCLUSIONS: Results suggest that the nicotine patch incentives motivated women to call the Helpline, even pregnant women who needed a physician's approval consistent with current American College of Obstetricians and Gynecologists cautions about the appropriateness of the patch during pregnancy. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454677 TI - Advancing Tobacco Control Among Medicaid Beneficiaries: A Historical Perspective and Call to Action. PMID- 30454676 TI - Building and Scaling-up California Quits: Supporting Health Systems Change for Tobacco Treatment. AB - The California Tobacco Control Program is the longest standing, publicly funded tobacco control program in the U.S. California's adult smoking rate declined from 23.7% (1989) to 11% (2016) but California still has more than 3 million smokers dispersed over 58 counties, requiring a coordinated approach to further tobacco control. Early California Tobacco Control Program success is rooted in public health policy strategies and a statewide media campaign that shifted social norms. In 2009, concepts for a coordinated approach were introduced by the California Tobacco Control Program in the state's first tobacco quit plan. The state quit plan called for public health's tobacco control programs to engage healthcare systems and insurers to work more directly with the California Smoker's Helpline (Helpline). With California's Medicaid (Medi-Cal) program expansion and the implementation of electronic medical record systems, health care plans and providers received additional support for system changes. Simultaneous with these changes, coordinated tobacco control efforts began, including California's Medi-Cal Incentives to Quit Smoking project (2012-2015). In the Medi-Cal Incentives to Quit Smoking project, safety-net providers and Medi Cal plans were outreached and engaged to promote incentives for Medi-Cal members to utilize Helpline services. In another effort, UC Quits (2013-2015), the five University of California health systems used electronic medical record tools to promote tobacco treatments and electronic referrals to the Helpline. Now, as tobacco prevention is increasingly prioritized for quality improvement, California Tobacco Control Program is funding CA Quits, a statewide tobacco cessation learning collaborative and technical assistance resource to promote integration of tobacco treatment services and quality improvement activities into safety-net health systems. CA Quits, in coordination with the Helpline, will connect public health departments, Medi-Cal plans, and safety-net providers to accelerate health systems change for tobacco-cessation treatment throughout the state. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Advancing Smoking Cessation in California's Medicaid Population, which is sponsored by the California Department of Public Health. PMID- 30454678 TI - Epigenetics: An emerging field in the pathogenesis of nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a major health concern associated with increased mortality due to cardiovascular disease, type II diabetes, insulin resistance, liver disease, and malignancy. The molecular mechanism underlying these processes is not fully understood but involves hepatic fat accumulation and alteration of energy metabolism and inflammatory signals derived from various cell types including immune cells. During the last two decades, epigenetic mechanisms have emerged as important regulators of chromatin alteration and the reprogramming of gene expression. Recently, epigenetic mechanisms have been implicated in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) genesis. Epigenetic mechanisms could be used as potential therapeutic targets and as noninvasive diagnostic biomarkers for NAFLD. These mechanisms can determine disease progression and prognosis in NAFLD. In this review, we discuss the role of epigenetic mechanisms in the progression of NAFLD and potential therapeutic targets for the treatment of NAFLD. PMID- 30454679 TI - Radiation-induced bystander and systemic effects serve as a unifying model system for genotoxic stress responses. AB - This review summarises our current understanding of the radiation-induced bystander/systemic effect (RIBE) as well as other types of intercellular reactions induced by malignant tumours, chemotherapy, photodynamic stress and the microbiome. On the basis of striking similarities between these different types of responses RIBE is proposed as a prototype model of a unifying genotoxic stress response system. The early bystander response is initiated by a mitochondria dependent increase of reactive oxygen species (ROS) and triggers a complex intercellular signalling cascade leading to a sustained increase of cellular DNA damage. The susceptibility to this DNA damage-inducing signal depends on the genetic make-up of the recipient cell population where ATR/ATM- and FA/BRCA dependent DNA damage response pathways are key players. Long distance bystander/systemic effects observed in in vivo-models are sustained by macrophage mediated inflammation. Of clinical importance is the potential contribution of bystander DNA damage to an increased risk of malignancies. Defects in DNA damage repair pathways are frequently observed in tumours, which may affect their susceptibility to bystander DNA damage. The potential role for molecular targeted inhibitors in the therapeutic exploitation of bystander responses as well as their differential modulation of targeted and non-targeted effects is also discussed in this context. PMID- 30454680 TI - DNA damage in obesity: Initiator, promoter and predictor of cancer. AB - Epidemiological evidence linking obesity with increased risk of cancer is steadily growing, although the causative aspects underpinning this association are only partially understood. Obesity leads to a physiological imbalance in the regulation of adipose tissue and its normal functioning, resulting in hyperglycaemia, dyslipidaemia and inflammation. These states promote the generation of oxidative stress, which is exacerbated in obesity by a decline in anti-oxidant defence systems. Oxidative stress can have a marked impact on DNA, producing mutagenic lesions that could prove carcinogenic. Here we review the current evidence for genomic instability, sustained DNA damage and accelerated genome ageing in obesity. We explore the notion of genotoxicity, ensuing from systemic oxidative stress, as a key oncogenic factor in obesity. Finally, we advocate for early, pre-malignant assessment of genome integrity and stability to inform surveillance strategies and interventions. PMID- 30454681 TI - Sperm epigenome as a marker of environmental exposure and lifestyle, at the origin of diseases inheritance. AB - Paternal exposure to environmental challenges plays a critical role in the offspring's future health and the transmission of acquired traits through generations. This review summarizes our current knowledge in the new field of epigenomic paternal transmission of health and disease. Epidemiological studies identified that paternal ageing or challenges (imbalanced diets, stress, toxicants, cigarette smoke, alcohol) increased the risk of offspring to develop diseases such as cancer, metabolic, cardiovascular, and neurological diseases. These data were confirmed and deepened in animal models of exposure to challenges including low-protein, low-folate, high-fat diets, exposure to chemicals such as pesticides and herbicides. Even though some toxicants have mutagenic effect on sperm DNA, changes in sperm epigenome seem to be a common thread between different types of challenges. Indeed, epigenetic changes (DNA methylation, chromatin remodeling, small non-coding RNA) in sperm are described as new mechanisms of intergenerational transmission as demonstrated for dioxin, for example. Those epimutations induce dysregulation in genes expression involved in key cellular pathways such as reactive oxygen species and genome stability regulation, in brain-derived neurotrophic factor, calcium and glucocorticoid signaling, and in lipid and glucose metabolism, leading to diseases in offspring. Finally, since each type of environmental challenges has its own signature by inducing epimutations at specific genomic loci, the sperm epigenome might be used as a biomarker in toxicological and risk assessments. PMID- 30454682 TI - Molecular genetics of the POMT1-related muscular dystrophy-dystroglycanopathies. AB - Protein O-mannosyltransferase 1 (POMT1) is a critical enzyme participating in the first step of protein O-mannosylation. Mutations in the coding gene, POMT1, have been described to be related to a series of autosomal recessive disorders associated with defective alpha-dystroglycan glycosylation, later termed muscular dystrophy-dystroglycanopathies (MDDGs). MDDGs are characterized by a broad phenotypic spectrum of congenital muscular dystrophy or later-onset limb-girdle muscular dystrophy, accompanied by variable degrees of intellectual disability, brain defects, and ocular abnormalities. To date, at least 76 disease-associated mutations in the POMT1 gene, including missense, nonsense, splicing, deletion, insertion/duplication, and insertion-deletion mutations, have been reported in the literature. In this review, we highlight the present knowledge of the identified disease-associated POMT1 gene mutations and genetic animal models related to the POMT1 gene. This review may help further normative classification of phenotypes, assist in definite clinical and genetic diagnoses, and genetic counseling, and may comprehensively improve our understanding of the basis of complex phenotypes and possible pathogenic mechanisms involved. PMID- 30454683 TI - Line-1: Implications in the etiology of cancer, clinical applications, and pharmacologic targets. AB - Long interspersed nuclear elements-1 (Line-1 or L1) accounts for approximately 17% of the human genome. The majority of L1s are inactive, but ~100 remain retrotransposon competent (RC-L1) and able to retrotranspose through RNA intermediates to different locations of the genome. L1 is involved in both disease initiation and progression via retrotransposition dependent and independent mechanisms. Retrotransposed L1 sequences disrupt genetic loci at sites of insertion, while the activities of L1 si/piRNAs, mRNAs, and ORF1 and ORF2 proteins, and have been implicated in the etiology and progression of several human diseases. Despite these relationships, little is known about the clinical utility of L1 as a biomarker of disease initiation and progression, or the utility of small molecules to inhibit and reverse the harmful effects of L1. In this review, we discuss the life cycle of L1, somatic and germline inhibitions, the mechanisms of L1 retrotransposition dependent and independent disease initiation and progression, clinical utilities, and potential of L1s as pharmacologic targets for the treatment of cancer. PMID- 30454685 TI - Pathophysiological mechanisms linking F-box only protein 7 (FBXO7) and Parkinson's disease (PD). AB - Mutations of F-box only protein 7 (FBXO7) gene are associated with a severe form of autosomal recessive juvenile Parkinson's disease (PD) (PARK15) with clinical features of Parkinsonian-Pyramidal syndrome (PPS). FBXO7 is an adaptor protein in SCFFBXO7 ubiquitin E3 ligase complex that recognizes and mediates degradative or non-degradative ubiquitination of substrates. The FBXO7 protein can regulate cell cycle, proliferation, mitochondrial and proteasome functions via interactions with multiple target proteins. Five PARK15-linked FBXO7 gene mutations and several PD-associated single nucleotide polymorphisms (SNP) have been identified so far. WT FBXO7 proteins possess dual protective and deleterious functions, whereas PARK15-linked FBXO7 mutants are toxic. FBXO7 is a stress response protein and stress challenges can promote translocation of FBXO7 protein from nucleus into mitochondria and even form deleterious protein aggregate in mitochondria. FBXO7 mutants aggravate protein aggregation in mitochondria and inhibit mitophagy. The pathological mechanisms concerning FBXO7-relevant protein aggregation, mitochondria impairment, reactive oxygen species (ROS) generation and mitophagy modulation in PARK15 pathogenesis are highlighted and discussed in the current review. PMID- 30454684 TI - Genetic landscape of gallbladder cancer: Global overview. AB - Gallbladder cancer (GBC) is a rare malignancy of biliary tract cancer (BTC), characterized by late presentation and poor prognosis. It exhibits wide geographical as well as ethnical variations. So, diverse epidemiology along with etiological factors have been discussed in the current article. Present review unravels the germ line polymorphisms contributing to GBC susceptibility through candidate gene approach and GWAS. GBC is enriched with multiple mutations consisting of both passenger and driver mutations. The identification of the hotspot driver mutations which are involved in the etiopathogenesis of this cancer is necessary, before targeted therapies could be implemented clinically. Thus, this review sheds lights on both traditional low throughput methods along with high throughput NGS used to determine somatic mutations in cancer. With the advent of GWAS and high throughput sequencing methods, it is possible to comprehend the mutational landscape of this enigmatic disease. This article is the first one to provide insights into the genetic heterogeneity of GBC along with somatic mutational data from Catalogue of Somatic Mutations in Cancer (COSMIC) database. In addition, management of tumor heterogeneity as a therapeutic challenge has been discussed. Future goals involve liquid biopsy based research for better clinical management of the disease. Therefore, research efforts involving discovery of non- invasive markers for early stage cancer detection along with novel therapies should be directed. PMID- 30454686 TI - Aflatoxin B1 metabolism: Regulation by phase I and II metabolizing enzymes and chemoprotective agents. AB - Aflatoxin B1 (AFB1) widely contaminates staple food and feed crops and is well known as the most potent natural hepatocarcinogen in humans and domesticated animals. This review highlights significant advances in our understanding of the pivotal role of phase I and II metabolizing enzymes in the bioactivation and detoxification of AFB1 and its metabolites across species. In humans, cytochrome P450 (CYP) 1A2, CYP3A4, CYP3A5, and CYP3A7 in liver and CYP2A13 in lung are essential for the bioactivation of AFB1 to the extremely toxic exo-AFB1-8,9 epoxide (AFBO), whereas CYP1A1, CYP1A2, CYP2A6, and CYP3A4 are important in the turkey and duck, CYP1A1 and CYP2A6 are important in the chicken and quail, CYP3A11 and CYP3A13 are important in mice, and CYP2A5 are important in the hamster. In contrast, glutathione-S-transferase (GST) M1 and GSTT1 are primary responsible for detoxification of the AFB1 by catalyzing the conjugation of GSH to AFBO in humans, whereas GSTM2 in a nonhuman primate, GSTA3 in mice, GSTA5 in rats, and GSTA1, GSTA2, GSTA3 and GSTA4 in the turkey are important. Additionally, microsomal epoxide hydrolase (mEH) and aflatoxin-aldehyde reductase (AFAR) have also been shown to play key roles in AFB1 detoxification in the human, rat, and pig. Moreover, an overview of the chemoprotective agents, including synthetic compounds and naturally occurring plant compounds, which can be used to reduce aflatoxicosis is provided based on their ability to regulate these key enzymes. Collectively, this review summarizes the pivotal enzymes in the metabolism of AFB1 among humans, experimental and farm animals, as well as the chemoprotective agents that can be used to minimize risk of aflatoxicosis. PMID- 30454687 TI - Ten-year trends of palliative care utilization associated with multiple sclerosis patients in the United States from 2005 to 2014. AB - Multiple sclerosis (MS) is a chronic neuro-inflammatory disease of the central nervous system, associated with accumulation of irreversible neurological disabilities through both inflammatory relapses and progressive neurodegeneration. Patients with debilitating MS could benefit from palliative care perspectives both during relapses that lead to transient disability as well as later in the disease course when significant physical and cognitive disability have accrued. However, no data about palliative care utilization trends of MS patients are available. We examined 10-year temporal trends of palliative care and assessed independent associations of palliative care with hospital utilization and cost using the 2005-2014 national inpatient sample. The national trends of palliative care utilization in MS patients increased by 120 times from 0.2% to 6.1% during 2005-2014, particularly with the dramatic single-year increase between 2010 (1.5%) and 2011 (4.5%). Moreover, the proportion of receiving palliative care in in-hospital death gradually increased from 7.7% in 2005 to 58.8% in 2014. Palliative care in MS inpatients may affect hospital utilization and charges in different ways. Hospital palliative care was associated with increased length of stay (LOS) (beta = 0.444 days, p < 0.001) and in-hospital death (OR = 15.35, 95% CI [13.76, 17.12]), but associated with decreased hospital charges (beta = -$2261, p < 0.001). In conclusion, the temporal trends of palliative care use in MS inpatients gradually increased with an exponential increase between 2010 and 2011 during 2005-2014, which is mostly attributed to patients with higher risk of in-hospital death. Moreover, palliative care was associated with reduced hospital charge with increased LOS and in-hospital death. PMID- 30454688 TI - Evaluation of the safety and effectiveness of an alternative dural substitute using porcine pericardium for duraplasty in a large animal model. AB - This study aimed to evaluate the safety and effectiveness of an alternative dural substitute using a porcine pericardial graft for duraplasty in a large animal model. Six pigs underwent bilateral craniectomy followed by bilateral duraplasty using either a porcine pericardium patch or a Biodesign(r) Dural Repair Graft. Intraoperative workability was evaluated for each type of graft. Pigs were euthanized after 1 and 3 months (n = 3 per group). Histological analysis was performed for each case. The Biodesign(r) Dural Repair Graft showed better workability than the porcine pericardial patch, which was more transparent (p = 0.002). Histological analyses at 1 and 3 months showed no differences between the types of graft. There was no postoperative leakage of cerebrospinal fluid in any case. No grafts showed any adverse reactions in the underlying brain tissues. The porcine pericardial patch as a dural substitute seems to be an acceptable alternative graft to duraplasty using a small intestinal submucosal graft (Biodesign(r)). Further studies are needed to determine whether porcine pericardial patches provide workable alternatives in clinical practice. PMID- 30454689 TI - A swine model of intracellular cerebral edema - Cerebral physiology and intracranial compliance. AB - Cerebral edema leading to elevated intracranial pressure (ICP) is a fundamental concern after severe traumatic brain injury (TBI), stroke, and severe acute hyponatremia. We describe a swine model of water intoxication and its cerebral histological and physiological sequela. We studied female swine weighing 35-45 kg. Four serum sodium intervals were designated: baseline, mild, moderate, and severe hyponatremia attained by infusing hypotonic saline. Intracranial fluid injections were performed to assess intracranial compliance. At baseline and following water intoxication wedge biopsy was obtained for pathological examination and electron microscopy. We studied 8 swine and found an increase in ICP that was strongly related to the decrease in serum sodium level. Mean ICP rose from a baseline of 6 +/- 2 to 28 +/- 6 mm Hg during severe hyponatremia, while cerebral perfusion pressure (CPP) decreased from 72 +/- 10 to 46 +/- 11 mm Hg. Brain tissue oxygen tension (PbtO2) decreased from 18.4 +/- 8.9 to 5.3 +/- 3.0 mm Hg. Electron microscopy demonstrated intracellular edema and astrocytic foot process swelling following water intoxication. With severe hyponatremia, 2 cc intracranial fluid injection resulted in progressively greater ICP dose, indicating a worsening intracranial compliance. Our model leads to graded and sustained elevation of ICP, lower CPP, and decreased PbtO2, all of which cross clinically relevant thresholds. Intracranial compliance worsens with increased cerebral swelling. This model may serve as a platform to study which therapeutic interventions best improve the cerebral physiological profile in the face of severe brain edema. PMID- 30454690 TI - Pipeline-assisted coiling versus pipeline in flow diversion treatment of intracranial aneurysms. AB - BACKGROUND AND PURPOSE: Flow-diversion therapy (FDT) for large and complex intracranial aneurysms is effective and considered superior to primary coil embolization. Data evaluating common treatment with both FDT and coiling continues to emerge, but information on outcomes remains scarce. This study aims to examine further the efficiency and outcomes correlated with joint FDT using pipeline embolization device (PED) and coiling compared to PED-alone in treating intracranial aneurysms. MATERIALS AND METHODS: Comparative review and analysis of aneurysm treatment with PED in 416 subjects were conducted. Joint modality, PED, and coiling were compared to PED-alone for aneurysm occlusion, recurrence, retreatment, thromboembolic or hemorrhagic events, and functional outcome using the modified Rankin Scale. Data on patient demographics, aneurysm characteristics, clinical and angiographic follow up, were also collected. Both univariate analysis and multivariate logistic regression modeling using mixed effects were performed. RESULTS: Total of 437 aneurysms were treated using PED of which 74 were managed with both PED and coiling. Average patient-age was 56 years, the majority were men (85%), an average aneurysm size was 9 mm, and the majority were saccular aneurysms (84%). Larger aneurysm size was associated with a poor outcome in patients with unruptured aneurysms (OR = 1.06). Adjusted regression analyses revealed no differences between treatment groups in thromboembolic or hemorrhagic events, aneurysm occlusion rate, residual flow on follow up angiography, or functional outcome. CONCLUSIONS: Treatment of intracranial aneurysms with joint PED and coiling was safe with no increase in complications when compared to PED alone. Aneurysm occlusion rates and functional outcome with PED and coiling stays comparable to treatment with PED-alone. PMID- 30454691 TI - 3-D printing for constructing the burr hole ring of lead fixation device in deep brain stimulation. AB - BACKGROUND: As the bearing structure of fixation device in deep brain stimulation (DBS), burr hole ring is fixed on the skull and used in conjunction with Stimloc and plastic cap. But in patients with traumatic event, excessive movements are likely to bring strain on the anchoring system, which will finally cause the fixation device to fall off from the skull. METHOD: AutoCAD was used to construct two-dimension (2-D) images for traditional burr hole ring and innovative burr hole ring, respectively. According to the 2-D image, pro/Engineer (Pro/E) will be applied to construct the three-dimension (3-D) geometries. And then, 3-D printing technology was used to build the solid model. These two kinds of burr hole rings were divided into two groups: Innovative group (N = 21) and Traditional group (N = 21). Pull-out strength of these two groups of burr hole rings will be measured by manual tensile force testing machine on the full-size skull model, and the data were transmitted to the notebook in real time for recording and further analyzing. RESULT: The fixation strength of the innovative group is stronger than traditional group, pull-out strength value of traditional group and innovative group were 34.08 +/- 1.31 N and 99.73 +/- 2.14 N, respectively. (P < 0.001). CONCLUSION: We provide an innovative burr hole ring, which can fix on the burr hole steadily. Moreover, 3-D printing technology may be suitable for personalized and customized medical treatment in the future. PMID- 30454692 TI - 3T MRI study discloses high intrafamilial variability in CADASIL due to a novel NOTCH3 mutation. AB - In order to evaluate the usefulness of presymptomatic MRI, we performed 3T brain MRI and Sanger gene sequencing in a proband with suspected but not confirmed CADASIL and her apparently asymptomatic father. The 35-year-old proband presented with migraine with visual aura. Brain MRI showed diffuse leukoencephalopathy, suggesting CADASIL. NOTCH3 gene sequencing (exons 3-6) was negative. Family history was unclear. The MRI study of the father documented severe, diffuse leukoencephalopathy, with involvement of the temporal poles and external capsules (not observed in the proband), and lacunar infarcts in the absence of cardiac disease or risk factors. The MRI findings were in favour of an autosomal dominant mode of transmission and reinforced the hypothesis of CADASIL. Full NOTCH3 gene sequencing uncovered a novel exon 8 mutation (c.1337G>A; p.Cys446Tyr) outside the most commonly mutated region of NOTCH3. The novel mutation leads to a typical MRI pattern but a variable overall phenotype. The study underlines the usefulness of combining full gene sequencing with familial MRI studies. PMID- 30454693 TI - Peripheral blood inflammatory markers in early Parkinson's disease. AB - The aim of this study was to characterize peripheral inflammatory markers in patients with early Parkinson's disease (PD) and to explore whether these markers contribute to motor and non-motor symptoms. We collected serum from patients with early PD (n = 58) and from healthy control subjects (n = 20). The following inflammatory markers were measured: interleukin (IL)-1beta, IL-2, IL-6, IL-10, tumor necrosis factor-alpha, and high-sensitivity C-reactive protein. The Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 and Hoehn and Yahr stage were used to assess motor symptoms, and the Non-motor Symptoms Scale, the Cross-Cultural Smell Identification Test, the Montreal Cognitive Assessment, and the Composite Autonomic Symptom Score 31 (COMPASS-31) were used to assess non-motor symptoms. The levels of IL-1beta, IL-2, and IL-6 were higher in the PD group than in the control group. However, only IL-1beta among those markers remained significant after Bonferroni correction (P = 0.024). In the PD group, the anti-inflammatory cytokine IL-10 levels correlated positively with the COMPASS-31 score (r = 0.277, P = 0.035), whereas no correlation was found between the other inflammatory marker levels and motor or non-motor symptoms. Among the domains of the COMPASS-31, the IL-10 levels correlated only with the gastrointestinal domain (r = 0.358, P = 0.006). Our results suggest increased peripheral inflammation in the early stage of PD, but the role of inflammation in motor and non-motor symptoms is unclear. Although we found a correlation between IL-10 levels and gastrointestinal symptoms, this finding may simply reflect a protective response against inflammatory processes associated with the disease. PMID- 30454694 TI - Surgical treatment of trigeminal neuralgia with no neurovascular compression: A retrospective study and literature review. AB - The objective of the current study is to summarize the experiences of 360-degree circumferential arachnoid dissection for TN in patients without NVC. Clinical data from 19 TN patients without NVC who underwent 360-degree circumferential arachnoid dissection were retrospectively analyzed. All patients underwent preoperative examinations of three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) and three-dimensional nuclear magnetic resonance of constructive interference in steady state (3D-CISS) to identify the neurovascular structures around the trigeminal nerve. Surgical outcomes were evaluated based on the Barrow Neurological Institute (BNI) Pain Intensity Scale, and severity of pain was determined using the visual analogue scale (VAS) score. Preoperative imaging showed that no patients had NVC compression. The preoperative BNI pain score was IV among 9 patients and V among other 10 patients. The preoperative VAS score was 7.89 +/- 0.658. After the operation, pain disappeared in all 19 patients, and transient facial numbness occurred in 3 patients. During follow-up, pain in 2 of 19 patients (10.5%) recurred at postoperative 20 and 23 months. This study demonstrated that 360-degree circumferential arachnoid dissection is an alternative treatment for trigeminal neuralgia in patients with no neurovascular compression, especially when a thickened arachnoid, angulation, or torsion of the trigeminal nerve root was found during the operation. However, further study is needed to compare the outcomes of different surgical strategies and prove the efficacy of 360-degree circumferential arachnoid dissection in cases without neurovascular compression (NVC). PMID- 30454695 TI - Invasive pituitary adenomas with gross total resection: The wait-and-see policy during postoperative management. AB - Although pituitary adenomas (PAs) are regarded as benign neoplasm, efficient postoperative management of PAs, especially invasive PAs, is still a major challenge for neurosurgeons. Thus, in order to verify the effect of postoperative surveillance alone for invasive PAs and identify helpful predictive factors of relapse after initial surgery, a series of 107 cases of surgically gross-totally resected invasive PAs were retrospectively investigated. With regarded to pituitary function, the preoperative incidence of hypothyroidism was higher than that of hypoadrenocorticism and hypogonadism (66.4% vs. 31.8% and 29.9%; p < 0.001). Tumors extended into sphenoid sinus or cavernous sinus may be less likely to develop hypoadrenocorticism or hypogonadism. Postoperative relapse was found in 35 cases (32.7%) during a median follow-up of 27 months. The overall relapse rates were 12.3, 28.9 and 38.4% at 1, 3 and 5 years, respectively. Tumor size was the exclusive independent risk factor for relapse. Higher relapse rates presented in large invasive PAs (more than 3.45 cm) were 24.5, 48.9 and 59.2% at 1, 3 and 5 years, respectively. In conclusion, preoperative larger tumors shared significantly higher risk of relapse after initial surgical total resection. Due to the relatively high relapse rate, close surveillance should be executed in strict rotation in postoperative management of gross-totally resected invasive PAs. Moreover, special attention should be payed to tumors with diameter of more than 3.45 cm for more than half of them relapsed in 5 years. PMID- 30454696 TI - Clinically relevant concentration of anti-viral drug ribavirin selectively targets pediatric osteosarcoma and increases chemosensitivity. AB - Ribavirin is an anti-viral drug but has recently gained attention as a potential candidate for cancer treatment. In line with these efforts, our work is the first to demonstrate that ribavirin, at clinically relevant concentration, selectively targets pediatric osteosarcoma and increases chemosensitivity. Using preclinical osteosarcoma cell and xenograft models, we found that ribavirin is active against osteosarcoma bulk and subpopulations with highly proliferative and invasive properties via inhibiting growth, inducing apoptosis and suppressing colony formation. At the same concentrations, ribavirin either did not or affected human normal osteoblastic cell and fibroblast cells in a less extent than osteosarcoma cells. Notably, the combination of ribavirin with doxorubicin resulted in greater efficacy than single drug alone. The combination completely arrested the osteosarcoma growth in vivo throughout the whole duration of drug treatment. We further showed that ribavirin acted on osteosarcoma largely via targeting eIF4E. In addition to eIF4E, ribavirin also modulated phosphorylation of Erk and expression of EZH2 and Snail without affecting Akt and mTOR. Lastly, we found that eIF4E expression and phosphorylation were elevated in osteosarcoma compared to normal cells, which might explain the selective anti-osteosarcoma activity of ribavirin. eIF4E depletion mimics the inhibitory effects of ribavirin, further confirm that eIF4E is the essential target of ribavirin in osteosarcoma. Our work provides fundamental evidence of repurposing ribavirin for the treatment of osteosarcoma. Our findings also highlight the therapeutic value of inhibiting eIF4E in osteosarcoma. PMID- 30454697 TI - Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells. AB - We previously demonstrated the protective effect of MSCs in an adaptive transfer mouse model. However, their therapeutic potential in an allogeneic immunocompetent setting mimicking clinical context of islet transplantation remained unknown. The aim of this study was to determine whether MSCs therapy, either by itself, or combined with Rapamycin could benefit the allograft survival of fully MHC-mismatched mouse islet transplant. Combination therapy of MSCs and low-dose Rapamycin significantly prolonged the survival of islet allografts, whereas treatment of MSCs, or Rapamycin alone, had no impact. Interestingly, this protective effect was associated with an induced expansion of regulatory T cells in islet grafts and draining lymph nodes, a skewed T-cell differentiation toward immunotolerance, and a profound suppression of alloreactivity against donor antigen. Our study suggests that a combination therapy of MSCs and low-dose Rapamycin can prolong the survival and preserve the function of islet allograft in the MHC-mismatched mouse model of islet transplantation. PMID- 30454698 TI - Pyroptosis of HUVECs can be induced by heat stroke. AB - Heat stroke is a serious pathological condition with high mortality. Vascular endothelial cell injury is a key feature in the pathogenesis of heat stroke, but the specific pathophysiological process whereby this occurs is still unclear. Currently, relevant studies are primarily based upon examination of apoptosis. Recently, pyroptosis, a new form of inflammation-related programmed cell death, was also demonstrated to be involved in heat stroke pathophysiology. Herein, we present evidence that vascular endothelial cell pyroptosis can be induced by heat stress in a time- and temperature-dependent manner. Furthermore, this process can be significantly inhibited by GSDMD siRNA. These findings suggest a new therapeutic target for heat stroke. PMID- 30454699 TI - Lnc-SNHG1 may promote the progression of non-small cell lung cancer by acting as a sponge of miR-497. AB - Lnc-SNHG1 (small nucleolar RNA host gene 1) is considered an important regulating factor in several types of cancers. However, the biological functions and underlying molecular mechanisms in which lnc-SNHG1 is involved in non-small cell lung cancer (NSCLC) still need to be explored. In this study, we investigated the detailed effects and possible molecular mechanisms. The transcript level of lnc SNHG1 was higher in lung adenocarcinoma specimens and NSCLC cell lines than in noncancer tissue and cells. The level of expression was positively correlated with invasiveness and was negatively correlated with the level of miR-497 in vivo and in vitro. In exploring the regulatory mechanism, we found that lnc-SNHG1 might modulate tumor growth by sponging miR-497. The inhibitory effect of si-lnc SNHG1 on NSCLC cell proliferation, migration and invasion could be rescued by miR 497 inhibition, while the overexpression of miR-497 could reverse the effect of lnc-SNHG1 overexpression. Furthermore, our study demonstrated that the lnc-SNHG1 regulated the expression of the insulin-like growth factor 1 receptor (IGF1-R) by acting as a sponge of miR-497 in NSCLC. lnc-SNHG1 could be a novel biomarker as well as a curative target. PMID- 30454700 TI - Role of DDX53 in taxol-resistance of cervix cancer cells in vitro. AB - Cancer/Testis antigen DDX53 shows high expression level in various tumors and is involved in anti-cancer drug resistance. However, the functional study of DDX53 in cervix cancer remains unknown. In this study, the role of DDX53 in taxol resistance of cervix cancer cells was investigated. In taxol-resistant HelaTR cells, DDX53 was significantly increased as compared to the parental HeLa cells. HelaTR cells also showed upregulation of multidrug resistant gene MDR1, invasive characteristics and decreased apoptosis. In addition, increased autophagy level was observed in HelaTR cells. Overexpression of DDX53 in HeLa and SiHa markedly led to greater resistance to taxol and cisplatin, whereas knockdown of DDX53 in HelaTR cells restored sensitivity, demonstrating that DDX53 regulated taxol resistance in cervix cancer cells. DDX53 overexpression in HeLa and SiHa cells enhanced invasion, migration and anchorage independent growth, DDX53 knockdown showed inverse effects in HeLaTR cells. When DDX53 expression was suppressed by siRNA, autophagic flux and drug resistance of HelaTR cells were decreased. In addition, DDX53 was upregulated in cervix cancer tissues from patient with a glassy cell carcinoma of cervix. Taken together, these results suggest that DDX53 plays a critical role in taxol-resistance by activating autophagy and a potential therapeutic target for the treatment of taxol-resistant cervix cancer. PMID- 30454701 TI - High sensitivity of cerebellar neurons to homocysteine is determined by expression of GluN2C and GluN2D subunits of NMDA receptors. AB - Homocysteine (HCY) induced neurotoxicity largely depends on interaction of this endogenous amino acid with glutamate NMDA receptors (NMDARs). This receptor type is composed by GluN1 and different GluN2 (A, B, C or D) subunits. However, the receptor activity of HCY in brain regions which differ in relative contribution of GluN2 subunits was not tested so far. In the current study, we explored the action of HCY on cerebellar neurons which natively express GluN2C and GluN2D subunits of NMDARs and compared this with the action of HCY on cortical neurons which are mainly composed by GluN2A and GluN2B subunits. To validate obtained results, we also studied the responses to HCY in recombinant GluN1/2C and GluN1/2D NMDARs expressed in HEK293T cells. Responses to HCY were compared to membrane currents evoked by glutamate or by the specific agonist NMDA. First, we found that on HEK cells expressing GluN1/2C or GluN1/2D NMDARs, HCY was full agonist producing membrane currents similar in amplitude to currents induced by glutamate. The EC50 values for these particular receptor subtype activation were 80 MUM and 31 MUM, respectively. Then, we found that HCY similarly to NMDA, evoked large slightly desensitizing membrane currents in native NMDARs of cerebellar and cortical neurons. In cortical neurons, the ratio of the respective currents (IHCY/INMDA) was 0.16 and did not significantly change during in vitro maturation. In sharp contrast, in cerebellar neurons, the ratio of currents evoked by HCY and NMDA was dramatically increased from 0.31 to 0.72 from 7 to 21 day in culture. We show that least 75% of HCY-induced currents in cerebellum were mediated by GluN2C- or GluN2D-containing NMDARs. Thus, our data revealed a large population of cerebellar NMDA receptors highly sensitive to HCY which suggest potential vulnerability of this brain region to pathological conditions associated with enhanced levels of this neurotoxic amino acid. PMID- 30454702 TI - Rational affinity enhancement of fragmented antibody by ligand-based affinity improvement approach. AB - Antibody engineering is now a noteworthy area in biopharmaceuticals as the next generation of marketed antibodies is engineered antibodies such as affinity- or stability-improved antibodies, fragmented or fused antibodies, antibody drug conjugates (ADCs), and PEGylated antibody fragments. In the current study, affinity enhancement of Nb against PlGF was performed by an in silico affinity maturation and molecular dynamics (MD) simulation. First, 300 single-point mutants were designed by identifying the residues involved in interaction with PlGF and different energy distributions. An energy based screening was performed to select best single-point mutants. Additionally, one variant containing two mutations was designed based on the selected single-point mutants. Finally, mutants-PlGF complexes were analyzed in details by all atom MD simulation. Trajectory analysis revealed that in both single (L112H, S31D, A97K, and R45E) and double (S31D & R45E) mutants, the free binding energies and the stability of complexes were significantly improved. The highest increment in affinity was observed for S31D mutant due to substantial increase in polar and electrostatic interactions. The secondary structure of Nb was intact in all variants and a shrinkage of PlGF over Nb was observed in all mutant-PlGF complexes during simulation. In addition, contact area and hydrogen-bond analysis as well as distance measurement in mutants-PlGF complexes also confirmed the affinity enhancement of variants relative to the native form. Our study showed that ligand based affinity improvement could be considered as a promising approach for designing high affinity fragmented antibodies. PMID- 30454703 TI - Atypical Switch-I Arginine plays a catalytic role in GTP hydrolysis by Rab21 from Entamoeba histolytica. AB - Entamoeba histolytica, the causative agent of amoebic dysentery, liver abscess and colitis, exploits its vesicular trafficking machinery for survival and virulence. Rab family of small GTPases play a key role in the vesicular transport by undergoing the GTP/GDP cycle which is central to the biological processes. Amoebic genome encodes several atypical Rab GTPases which are unique due to absence of conserved sequence motif(s) or atypical residues in their catalytic site [Saito-Nakano et al., 2005 ]. Previously, EhRab21 has been reported to involve in amoebic invasion and migration [Emmanuel et al., 2015 ]. The conserved Glutamine of switch-II region is universally accepted to be crucial for GTP hydrolysis. Mutations that reduce the sidechain polarity of Glutamine render the protein GTPase activity deficient [Krengel et al., 1990]. Here, we report a catalytic role of atypical switch-I Arginine (R36) in intrinsic GTP hydrolysis catalysed by EhRab21. Unlike the GTPase activity deficient QL mutants, the GTPase activity of EhRab21Q64L was found to be marginally enhanced compared to the wild type protein. Although EhRab21R36L mutant showed normal GTPase activity, the double mutant (R36L/Q64L) was found to be GTPase deficient. Thus, EhRab21 is a unique member of small GTPase family in which an atypical switch-I Arginine is capable of driving GTP hydrolysis independent of the conserved switch-II Glutamine. PMID- 30454704 TI - Leukocytic toll-like receptor 2 knockout protects against diabetes-induced cardiac dysfunction. AB - Diabetic cardiomyopathy is characterized by the deterioration of the myocardial function. Emerging evidences have indicated that leukocytic toll-like receptor 2 (TLR2) played an important role in the development of diabetic cardiomyopathy. Our study aimed to investigate whether TLR2 knockout (KO) exerted a cardioprotective effect in vivo. The establishment of diabetes model was set up in mice via intraperitoneal injection of streptozotocin (STZ). Results demonstrated that blocking of TLR2 significantly suppressed the enhanced left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD) and the reduced the heart rate in diabetic cardiomyopathy mice. The decreased resting cell length, PS, TPS and + dL/dt while increased TR90 and - dL/dt caused by diabetic cardiomyopathy were remarkably inhibited by TLR2 KO. Besides that, the alleviated DeltaFFI (360/380), decreased SERCA2a and p-NFATc3 expressions, extended Ca2+ decay time and elevated Calcineurin A induced by diabetic cardiomyopathy were vastly repressed by TLR2 KO in cardiocytes. Moreover, TLR2 gene silence could ameliorate oxidative stress-induced apoptosis, evidences were the up-regulated superoxide generation and Bax/Bcl-2 expression while restrained GSH/GSSG ratio caused by diabetic cardiomyopathy were tremendously repressed in TLR2 KO mice. Furthermore, blocking of TLR2 remarkably attenuated the augmented fibrosis areas of heart tissues in mice with diabetic cardiomyopathy. The result of the enhanced alpha-SMA and collagenI caused by diabetic cardiomyopathy were suppressed in heart tissues of TLR2 KO mice further validate it. All in all, our study demonstrated that diabetes-induced cardiac dysfunction could be attenuated by TLR2 KO. PMID- 30454705 TI - Involvement of follistatin-like 3 in preeclampsia. AB - INTRODUCTION: Preeclampsia is a main cause of maternal and perinatal mortality and morbidity. The expression of follistatin-like 3 (FSTL3) is enhanced in maternal serum and placenta of preeclamptic women. However, whether FSTL3 is involved in the pathophysiologic of preeclampsia has not been clarified yet. METHOD: Trophoblast cell lines Swan71 and JAR cells were cultured and siRNA was used to silence FSTL3. The expression of FSTL3 was determined by Western blotting. The matrigel-coated transwell and wound healing assays were used to assess invasion and migration, cell proliferation and apoptosis were detected by CCK-8 and flow cytometric analysis, respectively. Oil red O staining was used to detect the lipid storage in trophoblast. RESULTS: Hypoxia culture significantly enhanced the expression of FSTL3 by trophoblast. Down-regulation of FSTL3 significantly suppressed the proliferation, migration, invasion and lipid storage but increased apoptosis of trophoblast. DISCUSSION: Aberrant expression of FSTL3 in preeclampsia led to the dysfunction of trophoblast, indicating its involvement in the pathogenesis of preeclampsia. PMID- 30454706 TI - Combinatory inhibition of TRIM65 and MDM2 in lung cancer cells. AB - In addition to the involvement in white matter lesion, tripartite-motif protein family member 65 (TRIM65) has also been implicated in tumorigenesis as a potential oncogene. However, the underlining mechanisms of TRIM65 functions and its clinical implication still remain to be further elucidated. In the present study, we found that TRIM65 binds to the N-terminus of p53 tumor suppressor and thus competes with MDM2 for p53 binding. Intriguingly, analysis of the Cancer Genome Atlas (TCGA) gene alteration database revealed that elevated expression of TRIM65 is mutually exclusive to MDM2 up-regulation in human lung adenocarcinoma patients, indicating potential compensatory effect of one over the other. Indeed, overexpression of TRIM65 renders lung cancer cell line resistance to Nutlin-3a, an effective MDM2 inhibitor, as determined by p53 activation and cell proliferation assays. Furthermore, depletion of TRIM65 using siRNA in combination with Nutlin-3a treatment demonstrates enhanced anti-tumor effects on lung cancer cell line. Collectively, our findings provide the rationale for developing strategies to target TRIM65 for lung cancer intervention, potentially in combination with MDM2 inhibition. PMID- 30454707 TI - Pazopanib-induced changes in protein expression signatures of extracellular vesicles in synovial sarcoma. AB - Secreted proteins enclosed in extracellular vesicles can act as intercellular messengers. The objective of this study was to elucidate the role of proteins secreted from synovial sarcoma cells in the regulatory network underlying pazopanib response. We performed a comprehensive analysis of expression of proteins secreted from four synovial sarcoma cell lines (SYO-1, HS-SYII, 1273/99, and YaFuSS) using mass spectroscopy. Comparison of up-regulated proteins in cells, extracellular vesicles-free conditioned media, and extracellular vesicles revealed significantly up-regulated Wnt in synovial sarcoma vesicles. Furthermore, we compared protein signatures of cells, conditioned media, and extracellular vesicles before and after pazopanib treatment. Interestingly, protein signatures of extracellular vesicles showed robust changes in Wnt signaling pathways in response to pazopanib. Our findings provide insight into the potential role of Wnt, a protein secreted from the extracellular vesicles of synovial sarcoma cells, making it a potential candidate for use in sarcoma diagnosis. PMID- 30454708 TI - Meta-analysis of prognostic and predictive factors: Towards individual participant data? PMID- 30454709 TI - Immunotherapy with ipilimumab plus nivolumab in a stage IV melanoma patient during pregnancy. PMID- 30454710 TI - Autoimmune pancreatitis after nivolumab anti-programmed death receptor-1 treatment. PMID- 30454711 TI - How to conduct a high-quality original study on a prognostic research topic. AB - This is the third article of our educational series, which focuses on how to conduct a high-quality original study on a prognostic research topic from a methodological perspective. We introduce four aspects: clarifying the objectives; generating an appropriate research question; planning the study; and reporting and analyzing data. This paper has several highlights. (1) There are four types of prognostic studies: Type I-fundamental prognostic research, Type II-prognostic factors research, Type III-prediction model research, and Type IV-stratified medicine research. (2) We present the defining characteristics for each type of prognostic study. (3) For Types I-III, we suggest that "PFOT" components (target Population, prognostic or predictive Factor[s] or a predictive model with a combination of multiple Factors, Outcome, and follow-up Time) should be included in the research questions; for Type IV, "PIFOT" components (Intervention was added to PFOT) should be included in the research questions. (4) As with other study designs, prognostic studies should be registered to help mitigate duplication of effort across study teams and to accelerate the pace of scientific evolution. (5) Sample size calculations are an important step for prognostic studies. (6) Confounders and missing data issues should be considered carefully during study planning, reporting, and analyzing data. (7) For Type III studies, at least an internal validation should be performed, and univariable analysis to select significant variables (e.g., p-value < 0.05) for a multivariable model is not recommended. (8) A test for interaction is a necessary step for Type IV prognostic studies. A high-quality prognostic study would benefit from clinicians, methodologists, and statisticians working together. PMID- 30454712 TI - Ophthalmology Objectives for Medical Students: Revisiting What Every Graduating Medical Student Should Know. PMID- 30454713 TI - The Future of Keratoconus Screening with Artificial Intelligence. PMID- 30454714 TI - Conversion of Single Optic Disc Photography into 3-Dimensional Image. PMID- 30454715 TI - Pilomatrixoma Masquerading as Giant Chalazion. PMID- 30454716 TI - Acquired Cutis Laxa Presenting as Pedunculated Eyelid Plaques in an Adult. PMID- 30454717 TI - Ocular Metastasis of Cutaneous BRAF Wild-Type Melanoma. PMID- 30454718 TI - Exploring the Limits: The Challenge of Finding the Right Dose for Anti-Vascular Endothelial Growth Factor Treatment in Retinopathy of Prematurity. PMID- 30454719 TI - Ocular Surface Leiomyoma in a Child after Strabismus Repair. PMID- 30454720 TI - Subclinical atherosclerosis in asymptomatic carriers of persistent antiphospholipid antibodies positivity: A cross-sectional study. AB - BACKGROUND: Whereas the relationship between subclinical atherosclerosis and antiphospholipid syndrome (APS) has been widely investigated, little is known about subclinical atherosclerosis in asymptomatic carriers with isolated antiphospholipid antibodies positivity (APP). METHODS: Consecutive APP carriers, APS subjects and matched controls were enrolled. Intima-media thickness of the common carotid artery (CCA-IMT) and of the Bulb (Bulb-IMT) and the prevalence of carotid plaques were assessed in all enrolled subjects. RESULTS: A total of 104 APP carriers, 221 APS subjects, and 325 matched controls were recruited. As compared with controls, APP carriers and APS subjects showed a higher CCA-IMT (0.90 +/- 0.24 vs 0.82 +/- 0.12, p = 0.014 and 0.93 +/- 0.42 vs 0.82 +/- 0.12, p < 0.001, respectively), Bulb-IMT (1.10 +/- 0.44 vs 0.95 +/- 0.18, p = 0.006 and 1.22 +/- 0.68 vs 0.95 +/- 0.18, p < 0.001, respectively) and an increased prevalence of carotid plaques (33.7% vs 10.2%, p < 0.001 and 38.5% vs 10.2%, p < 0.001, respectively). These results were confirmed stratifying for antibody isotype, after excluding subjects with systemic lupus erythematosus or other autoimmune diseases and after adjusting for major clinical and demographic variables. CCA-IMT, Bulb-IMT and the prevalence of carotid plaques were higher in subjects with high-titer antibodies and progressively increased for an increasing number of positive antibodies. CONCLUSIONS: Similar to APS subjects, APP carriers have enhanced subclinical atherosclerosis, a more severe disease being observed in the presence of high-titer antibodies and multiple antibodies positivity. These data argue for a strict monitoring of subclinical signs of atherosclerosis and of cardiovascular risk factors in asymptomatic APP carriers. PMID- 30454721 TI - A founder homozygous DSG2 variant in East Asia results in ARVC with full penetrance and heart failure phenotype. AB - BACKGROUND: Variants in the desmoglein-2 (DSG2) gene account for a significant proportion of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The aim of this study was to evaluate the genetic epidemiology of DSG2 and the impact of a frequent homozygous DSG2 variant in East Asia. METHODS: Genetic screening of 14 ARVC related genes was performed in 118 unrelated index patients using next-generation sequencing. Following that, family screening, clinical evaluation and haplotype analysis were performed among eight probands who carry the same homozygous DSG2 variant. We also examined the histopathology and protein expression using immunofluorescence staining on the myocardial tissue of two probands undergoing heart transplant. RESULTS: Eighteen (15.2%) patients bear rare putatively deleterious variants in DSG2, among which 8 patients shared the homozygous DSG2 p.Phe531Cys variant. Family screening demonstrated that only homozygous variant carriers exhibited definite ARVC phenotype with 100% penetrance, while heterozygous variant carriers were either unaffected or only presented mild ARVC related symptoms in 25% relatives. Left ventricular involvement and bi-ventricular failure were common among homozygous p. Phe531Cys variant patients even at early age. Haplotype analysis demonstrated p. Phe531Cys was a founder variant in East Asia population with an allele frequency of 0.12%. CONCLUSIONS: We identified, for the first time, a homozygous founder variant of DSG2 in East Asia, which was at surprisingly high frequency of 8.47% among Chinese ARVC patients with a full penetrance. This result suggested an urgent demand of genetic counseling for the probands and their relatives with heterozygous variant. PMID- 30454722 TI - Tricuspid annular plane systolic excursion (TAPSE) in pediatric pulmonary hypertension: Integrating right ventricular ejection efficiency (RVEe) into advanced multi-parametric imaging. AB - The tricuspid annular plane systolic excursion (TAPSE) has evolved into one of the major echocardiographic indicators of systolic right ventricular (RV) longitudinal function in pediatric pulmonary hypertension (PH). Current RV function research in children with PH focusses on multi-parametric approaches that include TAPSE. The RV ejection efficiency (RVEe) is one of the new variables that reflects the relationship of TAPSE divided by the indexed pulmonary vascular resistance (PVRi) measured by cardiac catheterization. Here, we investigated not only RVEe, but also the ratio of TAPSE divided by pulmonary systolic arterial pressure (PASP; TAPSE/PASP ratio), and a possible association of these indices with NYHA functional class (FC) or the modified ROSS score in 42 children with PH. Both, the RVEe (TAPSE/PVRi) and the TAPSE/PASP ratio were inversely related to NYHA FC and the modified ROSS score in the pediatric PH compared. Compared to TAPSE as single measure, in both multiparametric variables (RVEe, TAPSE/PASP) more pronounced differences in subjects with different NYHA FC/modified ROSS score values were observed. Taken together, the RVEe (TAPSE/PVRi) and TAPSE/PASP ratio distinguish between NYHA FC/modified ROSS score compared to the single echocardiographic variable TAPSE, highlighting the usefulness of a multiparametric approach. PMID- 30454723 TI - Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue. AB - BACKGROUND: Epicardial adipose tissue (EAT) thickness and pro-inflammatory status has been shown to be associated with several cardiac diseases, including aortic stenosis (AS). Thus, cardiac visceral fat could represent a potential new target for drugs. In the present study we evaluate the effect of statin therapy on EAT accumulation and inflammation. METHODS: Echocardiographic EAT thickness was assessed in 193 AS patients taking (n.87) and not taking (n.106) statins, undergoing cardiac surgery. To explore the association between statin therapy and EAT inflammation, EAT biopsies were obtained for cytokines immunoassay determination in EAT secretomes. An in vitro study was also conducted and the modulation of EAT and subcutaneous adipose tissue (SCAT) secretomes by atorvastatin was assessed in paired biopsies. RESULTS: Statin therapy was significantly associated with lower EAT thickness (p < 0.0001) and with lower levels of EAT-secreted inflammatory mediators (p < 0.0001). Of note, there was a significant correlation between EAT thickness and its pro-inflammatory status. In vitro, atorvastatin showed a direct anti-inflammatory effect on EAT which was significantly higher compared to the SCAT response to statin incubation (p < 0.0001). CONCLUSIONS: The present study indicates a robust association between statin therapy and reduced EAT accumulation in patients with AS. The present data also suggest a direct relationship between EAT thickness and its inflammatory status, both modulated by statin therapy. The in vitro results support the hypothesis of a direct action of statins on EAT secretory profile. Overall our data suggest EAT as a potential new therapeutic target for statin therapy. PMID- 30454724 TI - Heart rate variability is impaired in adults after closure of ventricular septal defect in childhood: A novel finding associated with right bundle branch block. AB - BACKGROUND: Ventricular septal defects (VSDs) generally have benign long-term prognoses, but recent studies have indicated increased pulmonary vascular resistance. A potential tool for monitoring pulmonary artery pressure is heart rate variability, and therefore, the aim of this study was to assess heart rate variability in adults with a surgically repaired or unrepaired VSD. METHODS: In a long-term, follow-up study, three groups were included; VSD-patients operated in early childhood, patients with an open VSD, and controls. For each patient, 24 hour Holter monitoring was performed and heart rate variability was assessed. RESULTS: In total, 30 participants with a surgically closed VSD, 30 participants with an unrepaired VSD, and 36 controls were included. In the closed VSD group, there was a higher proportion of participants, who had low sNN50 (p = 0.005) and low sNN6% (p = 0.017) than in the other two groups. Similar differences were found when sNN50 was divided into increases and decreases (p = 0.007 and p = 0.005, respectively) as well as sNN6% (p = 0.014 and p = 0.014, respectively). Lastly, there was a higher proportion of patients in the closed VSD group with low rMSSD than in the other two groups (p = 0.005). For the closed VSD group, the proportion of participants with low total sNN50 (p = 0.046) and low total sNN6% (p = 0.046) were higher among participants with a complete right bundle branch block (RBBB) than among participants with no or an incomplete RBBB. CONCLUSIONS: Adults who had surgical VSD closure in early childhood had impaired heart rate variability and, particularly, participants with complete RBBB had lower heart rate variability. PMID- 30454725 TI - Why We Should Worry About "13 Reasons Why". PMID- 30454726 TI - The Prescription Drug Problem We Are Missing: Risks Associated with the Misuse of Tranquilizers and Sedatives. PMID- 30454727 TI - Eyes Forward. PMID- 30454728 TI - Moving Beyond "Skinniness": Presentation Weight Is Not Sufficient to Assess Malnutrition in Patients With Restrictive Eating Disorders Across a Range of Body Weights. PMID- 30454729 TI - Youth Engagement and Participation: Field-Building Across Research and Practice. PMID- 30454730 TI - Readying Youth and Young Adults for Transition to Adult Care During Preventive Care Visits: New Clinician Toolkit. PMID- 30454731 TI - Suicide Attempt Admissions From a Single Children's Hospital Before and After the Introduction of Netflix Series 13 Reasons Why. AB - PURPOSE: Release of the Netflix series 13 Reasons Why in March 2017 raised concern over associated suicide attempts. This study aimed to identify trends in self-harm admissions to a tertiary children's hospital with special attention paid to the time after series release. METHODS: Records for admitted patients ages 4-18 years from January 2012 to October 2017 were identified based on ICD codes indicating self-harm. Admissions were grouped by month, and the ARMA (Auto Regression and Moving Average) model was used in analysis. Log transformation was used to obtain a constant variance, and seasonal terms were added for adjustment. A "postintervention" level shift, temporary shift, and linear growth term were incorporated as predictors in ARMA models to test for differences using the series premier as the intervention. Terms from the best fitting model (without intervention effects) were fit to preintervention data and forecast predictions were compared to the observed data from the postintervention period. RESULTS: Seven hundred seventy-five records were included in analysis. There was an increase of .024 in the log of suicide admission counts per month (p < .001). The model that best explained the data was an ARMA (2,2) model with cubic growth curve terms, a post-intervention level shift, and a postintervention linear growth term, indicating an increase in observed over expected admissions following the premiere. CONCLUSIONS: Suicide admission counts increased over the time series. Actual suicide admissions following March 2017 were higher than predicted using the optimal model, suggesting an effect that temporally coincides with the release of 13 Reasons Why. PMID- 30454732 TI - Predictors of Complications in Anorexia Nervosa and Atypical Anorexia Nervosa: Degree of Underweight or Extent and Recency of Weight Loss? AB - PURPOSE: Adolescents with atypical anorexia nervosa (AAN) can experience severe physical complications despite not being underweight, posing questions about the contribution of weight loss to complications experienced in restrictive eating disorders (EDs). This study compared total weight loss and recent weight loss with admission weight as predictors of physical and psychological complications. METHODS: Retrospective (2005-2010) and prospective (2011-2013) studies were undertaken of 12- to 19-year-old hospitalized adolescents with anorexia nervosa (AN) or AAN, defined as meeting criteria for AN except underweight (>=85% median body mass index). Predictors were total weight loss (from lifetime maximum), recent weight loss (past 3 months), and admission weight. Outcomes were hypophosphatemia, clinical, anthropometric, and psychometric markers during admission. RESULTS: In 171 participants (AN, 118 [69%]; AAN, 53 [31%]), there was little evidence of an association between weight measures and hypophosphatemia. Greater total weight loss (regression coefficient [Coeff]: -1.70, 95% confidence interval [CI]: -2.77, -.63, p = .002) and greater recent weight loss (Coeff: 3.37, 95% CI: -5.77, -.97, p = .006), but not admission weight, were associated with a lower pulse rate nadir. Greater total weight loss (odds ratio [OR]: 1.70, 95% CI: 1.19, 2.24, p = .003) and greater recent weight loss (OR: 2.12, 95% CI: 1.11, 4.02, p = .02) were also associated with a higher incidence of bradycardia. CONCLUSIONS: In adolescents with restrictive EDs, total weight loss and recent weight loss were better predictors than admission weight of many physical complications. This suggests that future diagnostic criteria for AN place greater emphasis on weight loss. PMID- 30454733 TI - The Impact of Endometriosis on Quality of Life in Adolescents. AB - PURPOSE: While endometriosis is recognized to have a high patient burden for adults, the level of morbidity it causes for adolescents has been understudied, and may be minimized by clinicians. The purpose of this study was to determine whether endometriosis has a significant impact on quality of life (QOL) for adolescents and young adults. METHODS: Five hundred and sixty-seven participants (360 cases and 207 controls) aged <25 years old who are enrolled in the Women's Health Study: From Adolescence to Adulthood longitudinal study were included in this analysis. Participants were enrolled from medical clinics and the communities surrounding Boston, MA. Participants completed an expanded World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project standard clinical questionnaire that included the Short Form-36 (SF-36), a widely used measure of health-related QOL. We calculated SF-36 physical component summary and mental component summary scores, as well as eight subscale scores. On the SF-36, lower scores reflect greater impairment. RESULTS: Adolescents with endometriosis had significantly lower physical component summary (mean [standard deviation]: 43.4 [11.1] vs. 53.8 [7.6], p < .0001) and mental component summary (43.3 [12.3] vs. 46.3 [10.8], p = .008) scores compared to controls, as well as lower scores on all eight subscales. More cases than controls reported mental health diagnoses, pain medication use, and avoidance of exercise during menstruation. Among cases, earlier age at menarche, more severe pelvic pain, and longer duration of diagnostic delay were associated with poorer QOL. CONCLUSIONS: Endometriosis is associated with significantly worse reports of QOL for adolescents and young women with endometriosis compared to unaffected peers. Earlier menarche was associated with poorer physical health-related QOL among cases, whereas severe pelvic pain was associated with both poorer physical and mental health-related QOL among cases. Impairment in QOL is not limited to adults with endometriosis, but affects younger patients as well. PMID- 30454734 TI - Erratum. PMID- 30454735 TI - Urinary Tract Infections. AB - Urinary tract infection (UTI) is the second most common bacterial infection in children and is considered a public health threat given the mounting rates of antibiotic-resistance among uropathogens. This article highlights recent encouraging developments in UTI research. Further work is necessary to translate the discoveries into accessible, cost-effective technologies that will aid clinicians in real-time decision-making. PMID- 30454736 TI - Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis. AB - Henoch-Schonlein purpura nephritis and immunoglobulin A nephropathy are common glomerulopathies in the pediatric population that deserve special attention. In some cases the primary care provider can follow the patient but others need more intensive management. Delaying this treatment can lead to worse morbidity. This article provides information on the pathogenesis, outcomes, and follow-up strategies that will aid in the diagnosis and referral of patients at risk for kidney disease. PMID- 30454737 TI - Tubulointerstitial Nephritis. AB - Tubulointerstitial nephritis (TIN) is a cause of acute kidney injury in children characterized histologically by an inflammatory cell infiltrate in the kidney interstitium. The most common causes of TIN in children include medications, infections, inflammatory disorders, and genetic conditions. TIN typically presents with nonoliguric acute kidney injury and may be associated with systemic symptoms, including fever, rash, and eosinophilia. The long-term prognosis is generally favorable, with full kidney recovery; however, some patients may develop progressive chronic kidney disease. Immunosuppressive therapy may be indicated for severe or prolonged disease. PMID- 30454738 TI - Bartter Syndrome and Gitelman Syndrome. AB - Bartter and Gitelman syndromes are conditions characterized by renal salt wasting. Clinical presentations range from severe antenatal disease to asymptomatic with incidental diagnosis. Hypokalemic hypochloremic metabolic alkalosis is the common feature. Bartter variants may be associated with polyuria and weakness. Gitelman syndrome is often subtle, and typically diagnosed later life with incidental hypokalemia and hypomagnesemia. Treatment may involve fluid and electrolyte replenishment, prostaglandin inhibition, and renin-angiotensin aldosterone system axis disruption. Investigators have identified causative mutations but genotypic-phenotypic correlations are still being characterized. Collaborative registries will allow improved classification schema and development of effective treatments. PMID- 30454739 TI - Renal Tubular Acidosis. AB - Renal tubular acidosis should be suspected in poorly thriving young children with hyperchloremic and hypokalemic normal anion gap metabolic acidosis, with/without syndromic features. Further workup is needed to determine the type of renal tubular acidosis and the presumed etiopathogenesis, which informs treatment choices and prognosis. The risk of nephrolithiasis and calcinosis is linked to the presence (proximal renal tubular acidosis, negligible stone risk) or absence (distal renal tubular acidosis, high stone risk) of urine citrate excretion. New formulations of slow-release alkali and potassium combination supplements are being tested that are expected to simplify treatment and lead to sustained acidosis correction. PMID- 30454740 TI - Approach to the Child with Hematuria. AB - The causes of macroscopic and microscopic hematuria overlap; both are often caused by urinary tract infections or urethral/bladder irritation. Coexistent hypertension and proteinuria should prompt investigation for glomerular disease. The most common glomerulonephritis in children is postinfectious glomerulonephritis. In most patients, and especially with isolated microscopic hematuria, the diagnostic workup reveals no clear underlying cause. In those cases whereby a diagnosis is made, the most common causes of persistent microscopic hematuria are thin basement membrane nephropathy, immunoglobulin A nephropathy, or idiopathic hypercalciuria. Treatment and long-term prognosis varies with the underlying disease. PMID- 30454741 TI - Fanconi Syndrome. AB - Fanconi syndrome, also known as the DeToni, Debre, Fanconi syndrome is a global dysfunction of the proximal tubule characterized by glucosuria, phosphaturia, generalized aminoaciduria, and type II renal tubular acidosis. Often there is hypokalemia, sodium wasting, and dehydration. In children, it typically is caused by inborn errors of metabolism, principally cystinosis. In adults, it is mainly caused by medications, exogenous toxins, and heavy metals. Treatment consists of treating the underlying cause and replacing the lost electrolytes and volume. PMID- 30454742 TI - Update on Dent Disease. AB - Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular dysfunction. Clinical presentation is highly variable. Male patients may present with early-onset rickets, recurrent nephrolithiasis, or insidiously with asymptomatic proteinuria or chronic kidney disease. Mutations in both the CLCN5 and OCRL1 genes have been associated with the Dent phenotype and are now classified as Dent-1 and Dent-2, respectively. This article describes the clinical presentation, laboratory evaluation, genetics, pathophysiology, management, and future therapies of Dent disease. PMID- 30454743 TI - Hypophosphatemic Rickets. AB - Hypophosphatemic rickets, mostly of the X-linked dominant form caused by pathogenic variants of the PHEX gene, poses therapeutic challenges with consequences for growth and bone development and portends a high risk of fractions and poor bone healing, dental problems and nephrolithiasis/nephrocalcinosis. Conventional treatment consists of PO4 supplements and calcitriol requiring monitoring for treatment-emergent adverse effects. FGF23 measurement, where available, has implications for the differential diagnosis of hypophosphatemia syndromes and, potentially, treatment monitoring. Newer therapeutic modalities include calcium sensing receptor modulation (cinacalcet) and biological molecules targeting FGF23 or its receptors. Their long-term effects must be compared with those of conventional treatments. PMID- 30454744 TI - Syndrome of Inappropriate Antidiuresis. AB - The syndrome of inappropriate antidiuresis (SIAD) is a common cause of hyponatremia in hospitalized children. SIAD refers to euvolemic hyponatremia due to nonphysiologic stimuli for arginine vasopressin production in the absence of renal or endocrine dysfunction. SIAD can be broadly classified as a result of tumors, pulmonary or central nervous system disorders, medications, or other causes such as infection, inflammation, and the postoperative state. The presence of hypouricemia with an elevated fractional excretion of urate can aid in the diagnosis. Treatment options include fluid restriction, intravenous saline solutions, oral sodium supplements, loop diuretics, oral urea, and vasopressin receptor antagonists (vaptans). PMID- 30454745 TI - Nephrogenic Diabetes Insipidus. AB - Nephrogenic diabetes insipidus (NDI) results from the inability of the late distal tubules and collecting ducts to respond to vasopressin. The lack of ability to concentrate urine results in polyuria and polydipsia. Primary and acquired forms of NDI exist in children. Congenital NDI is a result of mutation in AVPR2 or AQP2 genes. Secondary NDI is associated with electrolyte abnormalities, obstructive uropathy, or certain medications. Management of NDI can be difficult with only symptomatic treatment available, using low-solute diet, diuretics, and prostaglandin inhibitors. PMID- 30454746 TI - Hemolytic Uremic Syndrome. AB - Hemolytic uremic syndrome (HUS) is the clinical triad of thrombocytopenia, anemia, and acute kidney injury. Classically associated with enterocolitis from Shiga toxin-producing Escherichia coli, HUS is also associated with Streptococcus pneumoniae infections; genetic dysregulation of the alternative complement pathway or coagulation cascade; and, rarely, a hereditary disorder of cobalamin C metabolism. These share a common final pathway of a prothrombotic and proinflammatory state on the endothelial cell surface, with fibrin and platelet deposition. Much work has been done to distinguish between the different mechanisms of disease, thereby informing the optimal therapeutic interventions for each entity. PMID- 30454747 TI - Chronic Kidney Disease and Dietary Measures to Improve Outcomes. AB - Chronic kidney disease is an ongoing deterioration of renal function that often progresses to end-stage renal disease. Management goals in children include slowing disease progression, prevention and treatment of complications, and optimizing growth, development, and quality of life. Nutritional management is critically important to achieve these goals. Control of blood pressure, proteinuria, and metabolic acidosis with dietary and pharmacologic measures may slow progression of chronic kidney disease. Although significant progress in management has been made, further research is required to resolve many outstanding controversies. We review recent developments in pediatric chronic kidney disease, focusing on dietary measures to improve outcomes. PMID- 30454749 TI - Childhood Obesity and the Metabolic Syndrome. AB - Obesity is a leading cause of chronic kidney disease. Children with severe obesity have an increased prevalence of early kidney abnormalities and are at high risk to develop kidney failure in adulthood. The pathophysiology of obesity related kidney disease is incompletely understood, although the postulated mechanisms of kidney injury include hyperfiltration, adipokine dysregulation, and lipotoxic injury. An improved understanding of the long-term effects of obesity on kidney health is essential treat the growing epidemic of obesity-related kidney disease. The purpose of this article is to review the epidemiology, pathophysiology, clinical features, and management of obesity-related kidney disease in children and adolescents. PMID- 30454748 TI - Long-Term Outcomes of Kidney Transplantation in Children. AB - Kidney transplantation is the preferred treatment for end-stage renal disease (ESRD) in children and confers improved survival, skeletal growth, heath-related quality of life, and neuropsychological development compared with dialysis. Kidney transplantation in children with ESRD results in 10-year patient survival exceeding 90%. Therefore, the long-term management of these patients is focused on maintaining quality of life and minimizing long-term side effects of immunosuppression. Optimal management of pediatric kidney transplant recipients includes preventing rejection and infection, identifying and reducing the cardiovascular and metabolic effects of long-term immunosuppressive therapy, supporting normal growth and development, and managing a smooth transition into adulthood. PMID- 30454750 TI - Pediatric Hypertension: Diagnosis, Evaluation, and Treatment. AB - The etiology of hypertension in children and adolescents is varied; however, the prevalence of pediatric primary hypertension is increasing. Early identification and appropriate management of hypertension in children and adolescents is important to prevent the development of hypertensive end organ disease. The 2017 American Academy of Pediatrics Clinical Practice Guidelines for the Screening and Management of High Blood Pressure in Children and Adolescents provide a comprehensive reference for evaluation and management of hypertension in this age group and should be used when assessing patients with elevated blood pressure and hypertension. PMID- 30454751 TI - Infection-Related Glomerulonephritis. AB - Acute postinfectious glomerulonephritis or infection-related glomerulonephritis has been associated with several viral or bacterial infections. Group A beta hemolytic streptococcal infection is the prototypical cause of postinfectious glomerulonephritis and the main focus of this discussion. The clinical spectrum can vary widely, from asymptomatic microscopic hematuria incidentally detected on routine urinalysis to rapidly progressive glomerulonephritis with acute kidney injury requiring emergent dialysis. Other important causes include glomerulonephritis associated with endocarditis and ventriculoatrial shunt infections. Multiple renal pathologic conditions have been associated with hepatitis B and C infections. PMID- 30454752 TI - Nephrotic Syndrome. AB - Nephrotic syndrome is characterized by edema, proteinuria, hypoalbuminemia, and hyperlipidemia. Minimal change disease, the most common cause in childhood, generally responds to corticosteroids, although most patients experience disease relapses. Focal segmental glomerulosclerosis is usually resistant to corticosteroids and carries a significant risk of kidney failure, necessitating renal transplantation. Nephrotic syndrome may also be secondary to gene mutations and systemic diseases such as lupus. Clinical evaluation involves distinguishing primary and secondary causes and monitoring for disease complications, including blood clots and serious infections such as spontaneous bacterial peritonitis. Immunosuppressive medications are used to prevent relapses and treat corticosteroid-resistant disease. PMID- 30454753 TI - Lupus Nephritis. AB - Childhood-onset systemic lupus erythematosus (SLE) is a subset of SLE with an onset before 18 years of age. Patients with early onset SLE tend to have a greater genetic component to their disease cause, more multisystemic involvement, and a more severe disease course, which includes greater risks for developing nephritis and end-stage kidney disease. Five- and 10-year mortality is lower than in adult-onset SLE. Although patient and renal survival have improved with advances in induction and maintenance immunosuppression, accumulation of irreversible damage is common. Cardiovascular and infectious complications are frequent, as are relapses during adolescence and the transition to adulthood. PMID- 30454754 TI - Clinical Disorders of the Kidney. PMID- 30454755 TI - Dealing with the Challenges of the Good Fortune of an Abundance of New Knowledge. PMID- 30454756 TI - Dedication to Julie Rich Ingelfinger. PMID- 30454757 TI - Ocular Surface Disease of Rabbits. AB - Rabbits have become a popular house pet that is encountered with increasing frequency in small animal veterinary practice. The unique anatomy of the rabbit predisposes them to developing surface ocular problems including the development of dacryocystitis, as well as conjunctivitis and keratitis. This article endeavors to give an updated outline of the various conditions affecting the rabbit ocular surface, with emphasis on diagnosis and treatment. PMID- 30454758 TI - Ocular Surface Disease in Reptiles. AB - In this article, ocular examination techniques are reviewed in the context of the reptilian patient. Subsequently, ocular surface anatomy and diseases are discussed. Sections for 4 of the 5 Reptilia orders are included: lizards, chelonians, crocodilians, and snakes. Literature pertaining to both wild and captive animals is included. PMID- 30454759 TI - Ocular Surface Disease in Rodents (Guinea Pigs, Mice, Rats, Chinchillas). AB - This article discusses the clinical appearance, differential diagnoses, and treatment considerations of corneal disease in the most common domesticated species of rodent: mouse, rat, chinchilla, and guinea pig. Many corneal diseases are related to inbred strains of either research or pet rodents. Diseases are complicated by husbandry and treatment-related challenges in this small, social species. This article is broken down by species, first discussing normal anatomy, then discussing commonly encountered diseases, and concluding with treatment considerations. PMID- 30454760 TI - Ocular Examination and Corneal Surface Disease in the Ferret. AB - This article provides a brief, clinically relevant review of corneal surface disease in the ferret. A description of the ophthalmic examination of the ferret is provided. Stepwise descriptions of the most common ophthalmic abnormalities are provided, along with common rule-outs. PMID- 30454761 TI - Ocular Surface Diseases in Marine Mammals. AB - Marine mammal eyes are adapted for underwater and air environments by increasing the mucins in tear film and having flatter corneas and round crystalline lenses. The cornea and lens are most commonly affected by environmental imbalances. Lack of shade and excessive exposure to sunlight are significant risk factors for keratopathy in pinnipeds, and likely true in cetaceans. Natural aging is also important, as sun damage and exposure to other oxidative stressors can cause cumulative damage to the cornea over time. By diminishing UV exposure and optimizing environmental factors, surface ocular disease in marine mammals can be diminished. PMID- 30454762 TI - Ocular Surface Disease in Birds. AB - Avian ocular disease may be primary or a manifestation of systemic disease. Various infectious and noninfectious diseases have been reported to cause ocular pathology. Thorough physical examination and diagnostic testing are necessary to determine a treatment plan. PMID- 30454763 TI - Ocular Surface Disease in New World Camelids. AB - This article discusses the anatomy, physiology, and common disease affecting the ocular surface of New World camelids, llamas, and alpacas. PMID- 30454764 TI - Ocular Surface Biology and Disease in Fish. AB - Ensuring the clarity of the ocular surface of fish species with which we interact is of great importance. There is still much more to learn about the ocular surface of fish species. A better understanding of the anatomy, physiology, and pathology of the ocular surface is thus vital for fish welfare, as well as being a fascinating subject in its own right. PMID- 30454765 TI - Ocular Surface Biology and Disease in Amphibians. AB - Vision is essential for amphibians, so a healthy ocular surface is critically important. There are ocular surface abnormalities that occur predominantly in captive animals, such as corneal lipidosis, whereas others, such as UV-induced trauma or infectious and parasitic conditions, may be critical to survival for animals in the wild. It is believed that inherited defects are going to be seen in small captive populations but it may be that confined wild groups of amphibians can be just as severely affected. Anything that blinds an animal severely affects its life changes. PMID- 30454766 TI - Introduction to Ocular Surface Disease in Exotics. PMID- 30454767 TI - Development of New Analgesics: An Answer to Opioid Epidemic. AB - Management of pain is a fundamental imperative in medicine. Current analgesics suffer from limitations related to efficacy and adverse events of which abuse potential has assumed an important role. Here we highlight the factors that drive the development of novel analgesics and the advances made in the field. PMID- 30454768 TI - Activating p53 and Inhibiting Superenhancers to Cure Leukemia. AB - In a recent study, Minzel and colleagues identified a novel series of molecules that inhibit casein kinase 1alpha (CK1alpha), CDK7, and CDK9, resulting in p53 activation and preferential inhibition of superenhancer (SE)-driven transcription. This study demonstrates a highly effective therapeutic strategy combining p53 activation with suppression of SEs to promote the cooperative killing of leukemic cells. PMID- 30454769 TI - Autophagy in Cancer: Regulation by Small Molecules. AB - During times of stress, autophagy is a cellular process that enables cells to reclaim damaged components by a controlled recycling pathway. This mechanism for cellular catabolism is dysregulated in cancer, with evidence indicating that cancer cells rely on autophagy in the hypoxic and nutrient-poor microenvironment of solid tumors. Mounting evidence suggests that autophagy has a role in the resistance of tumors to standard-of-care (SOC) therapies. Therefore, there is significant interest in the discovery of small molecules that can safely modulate autophagy. In this review, we describe recent advances in the identification of new pharmacological compounds that modulate autophagy, with a focus on their mode of action, value as probe compounds, and validation as potential therapeutics. PMID- 30454770 TI - Pharmacological Research as a Key Component in Mitigating the Opioid Overdose Crisis. AB - The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the MU-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain. PMID- 30454771 TI - Utilizing Buprenorphine in the Emergency Department after Overdose. AB - The United States is currently in the midst of an opioid epidemic. Barriers to treatment in the emergency department can lead to missed opportunities for helping prevent overdose and relapse in individuals with opioid use disorder. The administration of buprenorphine in the emergency department can potentially lead to better treatment outcomes for these individuals. PMID- 30454772 TI - Infections of the Ear. AB - Infections of the ear are a common presentation to an acute care environment. In this article, the authors aim to summarize the most common presentations, and diagnostic and treatment options for typical infections of the ear. This article is geared toward the emergency physician, urgent care provider, and primary care provider who will likely be the initial evaluating and treating provider to assist them in determining what treatment modalities can be managed in a clinic and what needs to be referred for admission or specialty consultation. PMID- 30454773 TI - Tracheostomy Emergencies. AB - Tracheostomy is a common procedure for long-term airway management. Although the overall complication rate is greater than 50%, the incidence of serious complications is low. These serious complications can, however, lead to significant morbidity and mortality and it is incumbent on the emergency provider to be prepared to deal with such tracheostomy-related emergencies. The greatest life threats to the tracheostomy patient are decannulation, obstruction, and hemorrhage. Other important but lower-acuity complications include tracheoesophageal fistula formation, tracheal stenosis, infection, and tracheocutaneous fistula formation. PMID- 30454774 TI - Peripheral Vertigo. AB - This article summarizes the systematic assessment of the dizzy patient who presents with peripheral vertigo. It demonstrates the steps and tests necessary using the Triage-Timing-Trigger-Test (Triage + TiTraTe) method to accurately diagnose the underlying most probable cause while ruling out life-threatening causes. Using video support and just-in-time infographics, it demonstrates the Dix-Hallpike, Semont, Epley, and HINTS maneuvers. PMID- 30454775 TI - Foreign Bodies of the Ear, Nose and Throat. AB - Foreign bodies to the ear, nose, and throat often can be managed in the emergency department, particularly if the patient offers a history consistent with foreign body and is calm and compliant with the examination and removal attempts. Tips for success include analgesia, adequate visualization, immobilization of the patient's head, dexterity and experience level of the provider, and minimizing attempts at removal. It is critical to recognize the risks involved with certain retained objects (button batteries or sharp objects) and when to call a consultant to help facilitate safe, successful removal of objects to the ear, nose, and throat. PMID- 30454776 TI - Traumatic Injuries of the Ear, Nose and Throat. AB - This article reviews the presentation, diagnosis, and management of common traumatic injuries of the ear, nose, and throat, including laryngeal trauma, auricular and septal hematomas, and tympanic membrane rupture. PMID- 30454777 TI - The Diagnosis and Management of Facial Bone Fractures. AB - Appropriate medical care for a patient with a facial fracture can not only optimize aesthetic outcomes but also prevent the potential morbidity and mortality of delayed treatment. In this article, we focus on the clinical presentations, physical examination findings, diagnostic imaging, consultations, and follow-up that patients with facial fractures need related to their emergency department management. Specifically, we address the nuances of evaluating frontal, orbital, nasal, maxillofacial, and mandibular fractures. PMID- 30454778 TI - Epistaxis. AB - Most anterior epistaxis originates primarily from the Kiesselbach plexus, whereas posterior epistaxis is less common and originates from branches of the sphenopalatine artery. Risk factors include local trauma, foreign body insertion, substance abuse, neoplasms, inherited bleeding diatheses, or acquired coagulopathies. Assessment of airway, breathing, and circulation precedes identification of bleeding source, pain control, and achieving hemostasis. Management options include topical vasoconstrictors, direct pressure, cautery, tranexamic acid, nasal tampons, Foley catheters, or surgical intervention. Specialty consultation may be pursued if interventions fail. Disposition is typically to home unless posterior epistaxis or significant comorbidities exist that warrant admission. PMID- 30454779 TI - Sinusitis Update. AB - Rhinosinusitis affects many pediatric patients as well as 1 in 6 adults in any given year, resulting in ambulatory care, pediatric, and emergency department visits. Uncomplicated rhinosinusitis requires no imaging or testing and does not require antibiotic treatment. Using strict clinical diagnostic criteria may minimize unnecessary antibiotics. When indicated, amoxicillin with or without clavulanate for 5 to 10 days remains the first-line antibiotic, despite increasing incidence of staphylococcal sinusitis in the post-pneumococcal conjugate vaccine era. Emergency providers also need to recognize atypical cases in which uncommon but serious complications of sinusitis cause both morbidity and mortality. PMID- 30454780 TI - Soft Tissue Disorders of the Mouth. AB - Soft tissue disorders of the mouth encompass a wide expanse of pathophysiology. This article focuses on the identification, etiology, management, and complications of common infectious processes (candidiasis, dental caries, and herpes labialis), inflammatory lesions (sialolithiasis, oral lichen planus, and aphthous ulcer), and benign entities (bony tori and mucocele). PMID- 30454781 TI - Infections of the Oropharynx. AB - This article reviews the presentation, diagnosis, and management of common and "can't miss" infections of the oropharynx, including streptococcal pharyngitis, infectious mononucleosis, peritonsillar abscess, retropharyngeal abscess, and epiglottitis. PMID- 30454782 TI - Dental Emergencies. AB - Dental emergencies present frequently to the emergency department and urgent care centers. Trauma to the teeth includes fractures, luxations, and avulsions, which can be reduced in most cases. Avulsed primary teeth should never be replaced. Mouthguards should be worn in most youth sports to prevent many dental injuries. Dental caries can progress to worsening infection and should be diagnosed and promptly referred. More severe infections may require antibiotics, imaging, or incision and drainage. Dental blocks can assist with analgesia and patient comfort during other procedures. PMID- 30454784 TI - Ears, Nose, and Throat Emergencies. PMID- 30454783 TI - Infections of the Neck. AB - Infection of the neck is a relatively common emergency department complaint. If not diagnosed and managed promptly, it may quickly progress to a life-threatening infection. These infections can result in true airway emergencies that may require fiberoptic or surgical airways. This article covers common, as well as rare but emergent, presentations and uses an evidence-based approach to discuss diagnostic and treatment modalities. PMID- 30454785 TI - Ear, Nose, and Throat Emergencies. PMID- 30454786 TI - Erratum. PMID- 30454787 TI - Gene Therapy in Head and Neck Cancer. AB - Although overall cancer death rates are decreasing, comparative improvements in head and neck squamous cell cancer are modest. Although new advances targeting immune checkpoints may soon improve these numbers, additional research for new therapeutic options is vital. One potential treatment avenue is the use of gene therapy. This article provides insight into some gene therapy targets and varied techniques being evaluated for patients with head and neck cancer. Techniques include corrective gene therapy, cytoreductive gene therapy, and gene editing, in addition to a discussion on gene therapy vectors. PMID- 30454788 TI - Oral Cavity Cancer. AB - Management of oral cavity squamous cell carcinoma has become increasingly driven by emerging evidence as a result of the improved quality of clinical research associating clinicopathologic risk factors with oncologic and survival outcomes. Multiple significant recent changes to treatment guidelines and staging algorithms for oral cavity squamous cell carcinoma reflect evolving understanding of tumor biology and the need for adequately extensive treatment of aggressive disease. This article provides clinicians with a synopsis of the most contemporary management strategies for oral cavity squamous cell carcinoma, framed within the context of historical treatment philosophies. PMID- 30454789 TI - Radiation Oncology for Head and Neck Cancer: Current Standards and Future Changes. AB - Treatment of head and neck cancer with curative intent consists of surgery and/or radiotherapy (RT) sometimes combined with adjuvant chemotherapy depending on the tumor site, extent, and histology. Herein, the authors review the role of RT in the management of head and neck mucosal squamous cell carcinoma (SCC). The authors focus on the outcomes of definitive RT and, depending on the primary site, postoperative RT. Unless otherwise specified, outcomes data cited are from the University of Florida. PMID- 30454791 TI - Man With Abdominal Pain and Bilious Emesis. PMID- 30454790 TI - Cognitive Improvement in Older Adults in the Year After Hip Fracture: Implications for Brain Resilience in Advanced Aging. AB - OBJECTIVE: We examined cognitive function in nondemented, nondelirious older adults 1 year post hip fracture. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: Three hundred eighty-six hip fracture patients aged 60 years and older with no history of cognitive impairment, such as clinical dementia or persistent delirium, recruited from eight area hospitals 2-3 days after hip surgery (week 0), and 101 older adults with no recent acute medical events for control comparison. METHODS: Cognitive function was examined with the Repeatable Battery for the Assessment of Neuropsychological Status and the Short Blessed Test (SBT) at weeks 0 (SBT only), 4, and 52 using a repeated measures mixed model analysis. Baseline predictor variables included demographics, personality, genetic factors, and depressive symptom level. RESULTS: Hip fracture participants had lower cognitive scores than healthy comparisons. Cognitive scores improved in the hip fracture group relative to healthy comparison participants from week 4 52. The only significant predictor of cognitive improvement after hip fracture was education: individuals with college education showed cognitive improvement by week 52, while those with high school or less did not. CONCLUSION: Nondemented, nondelirious older adults suffering hip fracture have poorer cognitive function immediately after the fracture but then exhibit cognitive improvement over the ensuing year, especially among those with high education. This demonstrates brain resilience in older adults even in the context of advanced age, medical illness, and frailty. PMID- 30454792 TI - Elderly Woman With Abnormal ECG. PMID- 30454793 TI - Elderly Female With Syncope. PMID- 30454794 TI - Research in Emergency Medicine: Building the Investigator Pipeline. PMID- 30454795 TI - Woman With Neck Pain. PMID- 30454796 TI - Only Human. PMID- 30454797 TI - Devoir. PMID- 30454798 TI - Outpatient Pulmonary Embolism Management: If You Walk Into the Emergency Department With a Pulmonary Embolism, Maybe You Should Also Walk Out: Answers to the July 2018 Journal Club Questions. PMID- 30454799 TI - Consider Conservative Approach Rather Than Intervening in Moderate to Large Spontaneous Pneumothorax. PMID- 30454800 TI - In reply. PMID- 30454801 TI - Reducing Emergency Department Utilization by Engaging Specialists. PMID- 30454802 TI - In reply. PMID- 30454803 TI - Elderly Woman With Abdominal Pain. PMID- 30454804 TI - Man With Left-Sided Neck Pain. PMID- 30454805 TI - Woman With Foreign Body on Her Tongue. PMID- 30454806 TI - Calcium Scoring for Cardiovascular Computed Tomography: How, When and Why? AB - Cardiovascular disease is the leading cause of death in the United States and worldwide. Despite major advances in the treatment of acute myocardial infarction, enhanced prevention of ischemic heart disease remains critical to improving the health of individuals and communities. The computed tomographic coronary artery calcium score is an established imaging biomarker that identifies the presence and amount of coronary atherosclerosis in an individual and their future risk for clinical cardiovascular disease and premature cardiovascular death. This article describes the process of performing a computed tomography scan for coronary artery calcium, quantifying the score and interpreting the results. PMID- 30454807 TI - Congenital Thoracic Aortic Disease. AB - Congenital abnormalities of the thoracic aorta encompass a variety of disorders with variable clinical manifestations ranging from asymptomatic to life threatening. A variety of imaging modalities are available for the evaluation of these anomalies with computed tomography (CT) commonly preferred due to its excellent spatial resolution and rapid acquisitions, avoiding the need of general anesthesia or even sedation. We review the embryology, imaging findings, and associations of multiple congenital thoracic aorta malformations with emphasis in the role of CT angiography in the evaluation of these pathologies. PMID- 30454808 TI - Computed Tomography of Acquired Aortic Diseases. AB - Computed tomography angiography (CTA) has the ability to evaluate the aortic wall and the lumen easily, quickly, and reproducibly without the need for invasive techniques. The images are isotropic, allowing several reconstructions. When imaging the aorta, CTA has replaced catheter angiography in the diagnosis of acquired disease such as aortoiliac disease, aneurysm, and infectious and inflammatory disease of the aorta. PMID- 30454809 TI - Technical Aspects, Interpretation, and Body of Evidence for Coronary Computed Tomography Angiography. AB - Coronary computed tomography angiography (CTA) has become an important part of current cardiovascular care and is the first-choice imaging modality for noninvasive visualization of coronary artery plaque and stenosis. It has high sensitivity for the detection of coronary stenosis and excellent negative predictive value to rule out stenosis with consistently high image quality at low radiation doses. In this article, we point out the technical aspects of modern coronary CT imaging, give a comprehensive overview of coronary CTA interpretation, including standardized reporting, and point out body of evidence for current clinical use. PMID- 30454810 TI - Computed Tomography of Cardiac Valves: Review. AB - Valvular heart disease is a common clinical problem. Although echocardiography is the standard technique for the noninvasive evaluation of the valves, cardiac CT has evolved to become a useful tool in the evaluation of the cardiac structures as well. Importantly, CT allows for improved quantification of valvular calcification due to its superior spatial resolution. It may improve the detection of small valvular or perivalvular pathology or the characterization of valvular masses and vegetations. This review describes the assessment of normal and diseased heart valves by cardiac CT and discusses its strengths and weaknesses. PMID- 30454811 TI - Transcatheter Aortic and Mitral Valve Replacements. AB - Amid rapid growth in transcatheter valvular interventions computed tomography (CT) has emerged as a pivotal noninvasive imaging resource that can be used throughout many stages of the transcatheter heart valve process, enhancing procedural success and efficacy. It affords a three-dimensional assessment of the aortic and challenging saddle-shaped mitral annulus, facilitating appropriate device selection, sizing, and preprocedural prediction angles for prosthetic deployment. Postprocedural imaging allows documentation of procedural success, evaluation of prosthesis positioning, and identifying asymptomatic complications. This article provides an overview of the role of CT in both trancatheter aortic valve repair (TAVR) and transcatheter mitral valve replacement (TMVR). PMID- 30454812 TI - Imaging of Pericardial Disease. AB - Although the pericardium is simply a 2-layered membrane enveloping the heart and great vessels, there are numerous anatomic variations, congenital anomalies, and pathologic conditions that can occur. Although echocardiography is most often the first imaging modality used to assess the pericardium, computed tomography and MR imaging are frequently being used to aid in diagnosis and assess response to therapy. Therefore, detailed knowledge of the pericardium in both its normal and diseased states is important to best direct patient care and potentially improve patient outcomes. PMID- 30454813 TI - Computed Tomographic Imaging of Cardiac Trauma. AB - Cardiac injury can occur in the setting of blunt and penetrating trauma resulting in significantly adverse clinical outcomes. Although the clinical presentation is variable and computed tomographic imaging is rarely performed to specifically evaluate for cardiac injury, the ability to recognize the findings of cardiac injury on computed tomographic examinations performed for thoracic trauma is essential to avoid misdiagnosis and direct potentially lifesaving interventions. This article reviews the direct and indirect computed tomographic findings of cardiac injury. PMID- 30454814 TI - Postcardiovascular Surgery Findings of the Thoracic Aorta. AB - Various disease processes may affect the ascending thoracic aorta, aortic arch, and/or descending thoracic aorta, including aneurysms, dissections, intramural hematomas, penetrating atherosclerotic ulcers, and aortic transection/rupture. Many of those conditions require surgical intervention for repair. Multiple open and endovascular techniques are used for treatment of thoracic aortic pathology. It is imperative that the cardiothoracic radiologist have a thorough knowledge of the surgical techniques available, the expected postoperative imaging findings, and the complications that may occur to accurately diagnose life-threatening pathology when present, and avoid common pitfalls of misinterpreting normal postoperative findings as pathologic conditions. PMID- 30454815 TI - Acute Coronary and Acute Aortic Syndromes. AB - Multidetector-row computed tomography (MDCT) can provide crucial information and rapid triage of emergency department patients with suspected acute coronary syndrome (ACS) or acute aortic syndrome (AAS). Coronary computed tomography angiography has high negative predictive value to rule out ACS, and MDCT is diagnostic for AAS and its variants. Optimization of acquisition technique and up to-date knowledge of the pathophysiology of these conditions can improve study and interpretation quality for diagnosis of ACS or AAS. PMID- 30454816 TI - Acute Myocardial Infarct. AB - This article reviews the imaging manifestations of acute myocardial infarction (MI) on computed tomography (CT) accompanied by case examples and illustrations. This is preceded by a review of the pathophysiology of MI (acute and chronic), a summary of its clinical presentation, and a brief synopsis of the technical aspects of cardiac CT. Several examples of the appearance of acute MI and its complications are shown on routine and cardiac tailored CT, and a sample of the latest advances in imaging technique, including dual-energy CT, are introduced. PMID- 30454817 TI - Chronic Infarcts and Mimickers of Infarcts. AB - This article reviews the imaging manifestations of chronic myocardial infarction (MI) on computed tomography (CT) and the common mimickers of MI, clinically and on imaging. Several examples of the appearance of chronic MI, its complications, and mimickers of MI are shown on both routine and cardiac CT. PMID- 30454818 TI - Nonischemic Cardiomyopathies. AB - Computed tomography of the heart can characterize and differentiate various forms of nonischemic cardiomyopathy, which are covered individually in this article. With its excellent spatial and ever-improving temporal resolution, computed tomography scanning can delineate cardiac function, anatomy, and myocardial tissue characterization. Various cardiac computed tomography techniques can be tailored to the relevant clinical question, as discussed in the article. Although cardiac computed tomography scanning is not often the primary modality for myocardial evaluation, decreasing radiation doses and emerging applications make this fast and relatively economical examination a useful tool in the evaluation of the patient with cardiomyopathy. PMID- 30454819 TI - Computed Tomography Imaging of Cardiac Masses. AB - Although not considered a first-line modality for assessing cardiac masses, computed tomography (CT) can provide clinically useful information and is underused for this purpose. In addition to characterizing masses with insights about presence of fat or calcification and the perfusion characteristics of a mass, CT produces high-resolution four-dimensional images depicting the mass and its relationship to chambers, valves, and coronaries. This is combined with imaging of the chest, abdomen, or coronaries. Advances in CT technology, such as dual-energy CT, dynamic perfusion imaging, and three-dimensional printing for preoperative planning, will increase the role of CT in assessment of cardiac masses. PMID- 30454820 TI - Computed Tomography in Adult Congenital Heart Disease. AB - The prevalence of adult congenital heart disease (ACHD) is increasing due to advances in surgical techniques, anesthesia, and perioperative care. Imaging plays an important role, not only in the surveillance of ACHD, but also in the initial evaluation of cases that have escaped detection early in life and present with symptoms later in adulthood. In this article, we review the role of computed tomography in the comprehensive evaluation of ACHD. PMID- 30454822 TI - Foreword. PMID- 30454821 TI - Cardiovascular Computed Tomography. PMID- 30454823 TI - Abdominal compartment syndrome. PMID- 30454824 TI - Introduction: Alcohol and Alcoholism. AB - This article discusses alcohol use throughout history. The discovery and cultivation of wine and beer and distillation of spirits are explored. The article spans prehistory, Egypt, Ancient Greece, Ancient Rome, Europe, and the Americas; and the religions Judaism, Christianity, and Islam. Also explored are the history and distillation of rum, gin, and champagne. Effects of alcohol use on society are discussed. PMID- 30454825 TI - Histopathology of Alcohol-Related Liver Diseases. AB - Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol related liver disease in patients with an uncertain alcohol history, because the histologic features of alcohol-related liver diseases can be found in other diseases, including nonalcoholic steatohepatitis and drug-induced liver injury. PMID- 30454826 TI - Alcohol-Associated Cirrhosis. AB - Alcohol-associated cirrhosis (AC) contributes up to 50% of the overall cirrhosis burden in the United States. AC is typically a comorbid condition in association with alcohol-use disorder. AC is often coexistent with other conditions. Several noninvasive methods are available to assist in recognizing the presence of AC. The natural history of AC is governed by the patients continued drinking or abstinence. All treatment starts with abstinence. After decompensation, the progression to acute-on-chronic liver failure heralds death. When patients who have deteriorated are declined liver transplant, palliative care should be considered. PMID- 30454827 TI - Liver Transplantation for Alcoholic Liver Disease: An Update. AB - Alcoholic liver disease is a serious and increasing contributor to the global liver disease burden. Extensive selection criteria, including a minimum abstinence period, has previously been used to secure good outcomes but new research questions the effectiveness of abstinence periods and has recommended changes in integrated alcohol use treatment to effectively prevent relapse. Patients have unique health concerns, including posttransplantation risks of malignancy and metabolic complications, but overall very good long-term outcomes. Severe alcoholic hepatitis has been increasingly treated with early transplantation without a set sobriety period, with overall favorable outcomes, even with respect to recidivism. PMID- 30454828 TI - Chronic Neurologic Effects of Alcohol. AB - Chronic alcohol use induces silent changes in the structure and function of the central and peripheral nervous systems that eventually result in irreversible, debilitating repercussions. Once identified, nutritional supplementation and cessation measures are critical in preventing further neurologic damage. The proposed mechanisms of neuronal injury in chronic alcohol abuse include direct toxic effects of alcohol and indirect effects, including those resulting from hepatic dysfunction, nutritional deficiencies, and neuroinflammation. Clinical manifestations include cerebellar ataxia, peripheral neuropathy and Wernicke Korsakoff encephalopathy. Continued exploration of the pathophysiologic mechanisms may lead to the discovery of early interventions that can prevent permanent neurologic injury. PMID- 30454829 TI - Will Studies in Nonalcoholic Steatohepatitis Help Manage Alcoholic Steatohepatitis? AB - Hepatic steatosis and steatohepatitis have several etiologies; the most common are alcoholic steatohepatitis (ASH) and obesity/metabolic syndrome-induced steatohepatitis, also known as nonalcoholic steatohepatitis (NASH). Although the etiology of these 2 conditions is different, they share pathways to disease progression and severity. They also have differences in physiologic pathways, and shared and divergent mechanisms can be therapeutic targets. There is no approved pharmacologic therapy for NASH, but several molecules are under study. Focus remains on modulation of insulin resistance, oxidative stress, the inflammatory cascade, hepatic fibrosis, and cell death. This review provides an overview of pathophysiologic similarities and differences between ASH and NASH. PMID- 30454830 TI - Alcohol and the Law. AB - In the intersection of alcohol ingestion with the law, medical ethics, and public safety, physicians are often unsure about how to proceed. Physicians' primary focus should be on patient education with an ethical and legal duty to warn the patient of the adverse effects of alcohol. Warning third parties of potential harm related to alcohol-related impairment may involve a breach of patient confidentiality; therefore it should only be undertaken after careful analysis suggests that the risk for significant harm exceeds the burden that results to the patient from warning others. The law remains vague in this area. PMID- 30454831 TI - Epidemiology of Alcohol Consumption and Societal Burden of Alcoholism and Alcoholic Liver Disease. AB - Alcohol abuse is a major determinant of public health outcomes. Worldwide data from 2016 indicate that alcohol is the seventh leading risk factor in terms of disability-adjusted life years, an increase of more than 25% from 1990 to 2016. Understanding the epidemiology of alcoholic liver disease, including the regional variations in consumption and public policy, is an area of active research. In countries where the per capita consumption of alcohol decreases, there appears to be an associated decrease in disease burden. Given alcohol's health burden, an increased focus on alcohol control policies is needed. PMID- 30454832 TI - Adolescent Alcoholic Liver Disease. AB - Alcohol use is common during adolescence. Adolescent alcohol use is a global problem. The risk of alcohol dependence increases based on genetic and psychosocial factors. If a provider is concerned about use of alcohol, screening is recommended. From a public health perspective, alcohol abuse should be addressed. PMID- 30454833 TI - Alcohol Use Disorders in Alcoholic Liver Disease. AB - Alcohol use disorder (AUD) is common in alcoholic liver disease (ALD) and intrinsic to its pathophysiology. Optimal treatment requires a multidisciplinary team approach and a working alliance between patients and providers. Diagnosing AUD involves a combination of thorough history taking, physical examination, screening questionnaires, and alcohol biomarkers. Alcohol biomarkers have advantages and limitations of use of which clinicians should be aware. AUD treatment is effective, multifaceted, and can be tailored to each individual. Available treatment modalities are myriad: motivational enhancement therapy, cognitive behavior therapy, 12-step facilitation, group therapies, intensive outpatient programs, inpatient and residential treatment, and relapse prevention medications. PMID- 30454834 TI - Pathogenesis of Alcoholic Liver Disease: An Update. AB - Apart from the classic knowledge that ethanol mediates its hepatotoxicity through its metabolism to acetaldehyde, a well-known hepatotoxic molecule, recent research has elucidated several key mechanisms that potentiate ethanol's damage to the liver parenchyma, such as generation of free radicals, activation of Kupffer cells, and alterations to the human bacterial and fungal microbiome. Genetic studies have suggested the role of PNPLA3 and TM6SF2 gene mutations in the progression of alcoholic liver disease. PMID- 30454835 TI - Acute Alcoholic Hepatitis. AB - Alcoholic hepatitis is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by prolonged heavy alcohol use. Treatment is mostly supportive. The short-term prognosis of acute alcoholic hepatitis depends on liver recovery, and ranges widely from rapid improvement to grim multiorgan failure despite treatment. Refinement of scoring systems have enhanced prognostication to guide clinical decision making in alcoholic hepatitis. Recent advances in the treatment of alcoholic hepatitis have solidified corticosteroids as the cornerstone of treatment to enhance short-term survival, but not intermediate or long-term survival. PMID- 30454836 TI - Nutrition in Alcoholic Liver Disease: An Update. AB - Malnutrition is a change in body composition owing to disordered nutrition associated with a decrease in function and poor clinical outcomes. Malnutrition can result from overnutrition, undernutrition and inflammatory activity. Patients with alcoholic liver disease are at increased risk for malnutrition. In this article, we discuss the different methods used to assess malnutrition, prevalence of malnutrition, potential mechanisms underlying malnutrition, and its treatments in patients with alcoholic liver disease. PMID- 30454837 TI - Alcohol and Alcoholic Liver Disease. PMID- 30454838 TI - A simple algorithm to improve quality while reducing resource utilization in evaluation of suspected appendicitis in children. AB - BACKGROUND: With similar effectiveness of ultrasonography, our institution replaced CT imaging with ultrasound for diagnosing appendicitis in children. An unexpected consequence was the overutilization of ultrasound. Our objective was to establish measures that could help prevent this overuse. METHODS: A retrospective chart review of 327 consecutive pediatric patients evaluated for appendicitis between October 2014 and September 2015 at our institution was performed. Data on clinical, radiographic, and histopathologic findings were reviewed. Diagnostic accuracy of US and white blood cell (WBC) values was determined. An algorithm was created. RESULTS: 327 (100%) patients received an ultrasound for suspected appendicitis. WBC of 10,000/MUl was determined to be the primary discriminant for management and ultrasound utilization. If a WBC >=10,000/MUL had been utilized as criteria for imaging, 49.5% fewer patients would have received an ultrasound. CONCLUSIONS: Clinical exam, WBC count, and surgery consultation prior to ultrasonography can lessen then need for ultrasound utilization in children with suspected appendicitis. PMID- 30454839 TI - Factors associated with noncomplete mesorectal excision following surgery for rectal adenocarcinoma. AB - BACKGROUND: The completeness of the resected mesorectum is a quality metric in rectal cancer surgery and has been related to oncological outcomes. Our aim was to identify variables associated with non-complete mesorectal excision and determine any effect on overall survival. METHODS: Consecutive patients who underwent curative intent surgery for rectal adenocarcinoma (2009-2016) were identified from a prospectively-maintained institutional database. Patients were grouped according to their mesorectal grade: complete, near-complete and incomplete. Multivariate analysis was performed to identify the association between various patient, disease and surgeon-related characteristics and mesorectal grading. Log-rank tests were used to evaluate any difference in overall survival between the groups. RESULTS: 689 patients met inclusion criteria. Demographics and perioperative variables were comparable between the groups. On multivariate analysis, abdominoperineal resection, and involved circumferential resection margin were significantly associated with non-complete mesorectum. Finally, patients with non-complete mesorectal grading have approximately twice the hazard of death compared to those with complete mesorectal grading. CONCLUSIONS: Several factors are associated with a non complete mesorectal excision. Non-complete mesorectal grade is associated with decreased survival. PMID- 30454840 TI - Adult Congenital Heart Disease Care Provision: the Need for a Jack/Jackie of All Trades. PMID- 30454841 TI - Palatine tonsil SUVmax on FDG PET-CT as a discriminator between benign and malignant tonsils in patients with and without head and neck squamous cell carcinoma of unknown primary. AB - AIM: To analyse the maximum standardised uptake value (SUVmax) ratio between tonsils in patients with and without tonsillar carcinoma to determine useful diagnostic thresholds. MATERIALS AND METHODS: Positron-emission tomography (PET)/computed tomography (CT) examinations of patients with suspected head and neck squamous cell carcinoma (SCC) and controls from April 2013 to September 2016 were reviewed retrospectively. Tonsillar SUVmax ratios (ipsilateral/contralateral for malignant tonsils, maximum/minimum for patients without [controls]) were calculated and used to construct a receiver operating characteristic (ROC) curve. RESULTS: Twenty-five patients had tonsillar carcinoma (mean SUVmax ratio of 2, range 0.89-5.4) and 86 patients acted as controls (mean SUVmax ratio of 1.1, range 1-1.5). Using the ROC, the most accurate SUVmax ratio for identifying malignancy was >1.2 (77% sensitivity, 86% specificity). A potentially more clinically useful SUVmax ratio is >=1.6 with 62% sensitivity and 100% specificity. CONCLUSION: An SUVmax ratio between tonsils of >=1.6 is highly suspicious for SCC and could be used to direct site of biopsy. Some malignant tonsils had normal FDG uptake; therefore, PET/CT should not be used to exclude tonsillar cancer. Minor asymmetrical uptake is frequently seen in non-malignant tonsils and does not necessarily require further investigation. Due to the single centre nature of this study and the recognised variation in SUV measurements between PET scans, other centres may need to develop their own cut-offs. PMID- 30454842 TI - Cognitive impairment is associated with mortality in older adults in the emergency surgical setting: Findings from the Older Persons Surgical Outcomes Collaboration (OPSOC): A prospective cohort study. AB - BACKGROUND: Cognitive impairment is prevalent in older surgical patients; however, the condition is greatly under-recognized, and outcomes associated with it are poorly understood. METHODS: This is a prospective multicenter cohort study of unselected consecutive older adults admitted to 5 emergency general surgical units across the United Kingdom participating in the Older Persons Surgical Outcomes Collaboration from 2013-2014. The effect of moderate cognitive impairment defined as <=17, bottom quartile of Montreal Cognitive Assessment was examined using multivariate logistic regression models. Primary outcome measure was the relationship between a low Montreal Cognitive Assessment score (<=17) and mortality at 30 and 90 days. Secondary outcome measures included the association between having a low Montreal Cognitive Assessment and hospital length of stay. RESULTS: A total of 539 older patients admitted consecutively to 5 surgical units during the 2013 and 2014 study periods were included. The median age (interquartile range) was 76 years (70-82 years), the emergency operation rate was 13% (n = 72). The prevalence of cognitive impairment, using the traditional Montreal Cognitive Assessment cutoff score of <=26, was 84.4% and, using the recently suggested cutoff score of <=23, the prevalence was 61.0%. Multivariable analyses showed patients with a low Montreal Cognitive Assessment score (<=17) had a three-fold increase in 30-day mortality (adjusted odds ratio = 3.10; 95% confidence interval:1.19-8.11; P = .021) and an increased length of hospital stay (10 or more days; 1.80 [1.10-2.94; P = .02] and 14 or more days; 2.06 [1.17-3.61; P = .012]). CONCLUSION: We recommend a routine cognitive assessment in an emergency surgical setting whenever feasible to help identify patients at risk of poor outcomes. PMID- 30454843 TI - Acroosteolysis in Systemic Sclerosis. PMID- 30454844 TI - The Importance of Communicating With Patients to Incorporate Patient-Reported Outcomes Into Clinical Care. PMID- 30454845 TI - Reversible Blindness as Presenting Manifestation of Severe Diabetic Ketoacidosis. AB - The presenting symptoms of diabetic ketoacidosis (DKA) include abdominal pain, polyuria and nausea. Diabetes has well known chronic ocular complications like glaucoma, cataracts and retinopathy. We report a case of reversible blindness as a presenting manifestation of DKA that has been reported in literature only 3 times previously. Our objective is to highlight a rare manifestation of a common disease. A 59-year-old male presented with painless vision loss for 3 days and was found to have DKA. The blindness was completely reversed with insulin and bicarbonate treatment. The dramatic presentation and reversibility of blindness was found to be intimately tied with the pH of the patient's serum. Our report gives mechanistic insight for this interesting condition. Clinicians should be aware of reversible blindness as a complication of DKA. Timely correction of the severe acidosis and other metabolic disturbances of DKA may be instrumental in preventing permanent vision loss. PMID- 30454846 TI - [Effect of melatonin on the daytime sleepiness side-effect of gabapentin in adults patients with neuropathic pain]. AB - BACKGROUND AND OBJECTIVES: Gabapentin is an antiepileptic drug. Widely used for the management of neuropathic pain. Although it is known to be well tolerated, somnolence and dizziness are the most frequent adverse effects. In this study, we aimed to evaluate the effect of melatonin on daytime sleepiness side effect of gabapentin, sleep quality and pain intensity of patients with neuropathic pain. METHODS: Patients suffering from "neuropathic pain" and planed to receive gabapentin therapy were randomly divided into two groups. Group 1 received melatonin 3mg and gabapentin 900mg orally, group 2 received matching placebo capsule and gabapentin 900mg. The Epworth Sleepiness Scale, the Pittsburgh sleep quality index for assessment of sleep quality and Verbal Rating Scale were completed at the 0th, 10th and 30th days of treatment. Additive analgesic drug requirements were recorded. RESULTS: Eighty patients were enrolled to the study; age, gender, ratio of additive analgesic consumption, baseline Epworth Sleepiness Scale, Pittsburg Sleep Quality index and Verbal Rating Scale scores were similar between the groups. Epworth Sleepiness Scale scores, Pittsburgh sleep quality index scores and Verbal Rating Scale scores in Group 1 were significantly lower than group 2 at the 10th day of treatment (p=0.002, p=0.003, p=0.002 respectively). At the 30th day of treatment, Epworth Sleepiness Scale scores and Verbal Rating Scale scores were significantly lower in Group 1 (p=0.002, p=0.008 respectively). However, Pittsburgh sleep quality index scores did not significantly differ between the groups (p=0.0566). CONCLUSIONS: Melatonin supplementation rapidly and significantly improved daytime sleepiness side-effect of gabapentin, however sleep quality of the patients with neuropathic pain was similar between groups. PMID- 30454847 TI - Challenges and opportunities in financing the 2017-2010 Strategic Health Strategy for care research. PMID- 30454848 TI - Harnessing the value of NHS patient data. PMID- 30454849 TI - Efficacy of fibrin-collagen sealant for reducing the incidence of biliary fistulae after laparoscopic exploration of the bile duct. PMID- 30454850 TI - Effects of a Self-micro-emulsifying Delivery System Formulation Versus a Standard omega-3 Acid Ethyl Ester Product on the Bioavailability of Eicosapentaenoic Acid and Docosahexaenoic Acid: A Study in Healthy Men and Women in a Fasted State. AB - PURPOSE: Intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with several potential health benefits, but standard ethyl ester (EE) formulations of these omega-3 fatty acids require the co-ingestion of fat for adequate absorption. The objective of this research was to assess the relative bioavailability of EPA and DHA administered in a proprietary self-micro emulsifying delivery system (SMEDS) formulation compared with EPA and DHA in a standard omega-3 acid EE product in healthy men and women in a fasted state. METHODS: This randomized crossover study investigated the bioavailability of 2 encapsulated formulations of EPA and DHA, a capsule containing 500 mg EPA + DHA administered in a SMEDS formulation (SMEDS treatment), and a capsule containing 840 mg EPA + DHA in a standard omega-3 acid EE formulation (EE treatment). Subjects consumed a single dose of their assigned capsule in a fasting state, and plasma was collected before and for 24 h after dosing. Subjects underwent a >=14 day washout and were crossed over to the other treatment condition. Plasma concentrations of EPA, DHA, and EPA + DHA were assessed. FINDINGS: Twenty-three subjects (11 women, 12 men; mean [SEM] age, 33.8 [2.1] years; and body mass index, 24.9 [0.7] kg/m2) completed the trial. The baseline-adjusted, dose normalized, arithmetic means (SD) of the incremental (i)-AUC0-24h for EPA + DHA were 543 (266) and 102 (88.2) h . MUg/mL/g for the SMEDS and EE formulations, respectively (P < 0.001). The iAUC0-24h least-squares geometric mean ratio (90% CI) for SMEDS:standard EE was 475/58 = 8.2 (4.8-13.9), indicating markedly higher bioavailability of EPA + DHA with the SMEDS formulation compared to the standard EE formulation. This finding was also true for EPA (geometric mean ratio [90% CI], 18.2 [11.3-29.3]) and DHA (geometric mean ratio [90% CI], 4.5 [2.9-7.0]). IMPLICATIONS: The SMEDS delivery system markedly enhanced appearance in plasma of EPA and DHA, compared to a standard EE formulation, when ingested in the fasting state. ClinicalTrials.gov identifier: NCT03443076. PMID- 30454851 TI - Gephyrin Palmitoylation in Basolateral Amygdala Mediates the Anxiolytic Action of Benzodiazepine. AB - BACKGROUND: Benzodiazepines (BZDs) have been used to treat anxiety disorders for more than five decades as the allosteric modulator of the gamma-aminobutyric acid A receptor (GABAAR). Little is known about other mechanisms of BZDs. Here, we describe how the rapid stabilization of postsynaptic GABAAR is essential and sufficient for the anxiolytic effect of BZDs via a palmitoylation-dependent mechanism. METHODS: Palmitoylated proteins in the basolateral amygdala (BLA) of rats with different anxious states were assessed by a biotin exchange protocol. Both pharmacological and genetic approaches were used to investigate the role of palmitoylation in anxiety behavior. Electrophysiological recording, reverse transcription polymerase chain reaction, Western blotting, and coimmunoprecipitation were used to investigate the mechanisms. RESULTS: Highly anxious rats were accompanied by the deficiency of gephyrin palmitoylation and decreased the synaptic function of GABAAR in the BLA. We then identified that the dysfunction of DHHC12, a palmitoyl acyltransferase that specifically palmitoylates gephyrin, contributed to the high-anxious state. Furthermore, diazepam, as an anxiolytic drug targeting GABAARs, was found to increase gephyrin palmitoylation in the BLA via a GABAAR-dependent manner to activate DHHC12. The anxiolytic effect of diazepam was nearly abolished by the DHHC12 knockdown. Specifically, similar to the effect of BZD, the overexpression of DHHC12 in the BLA exerted a significant anxiolytic action, which was prevented by flumazenil. CONCLUSIONS: Our results support the view that the strength of inhibitory synapse was controlled by gephyrin palmitoylation in vivo and proposes a previously unknown palmitoylation-centered mode of BZD's action. PMID- 30454852 TI - Strength-limiting damage in lithium silicate glass-ceramics associated with CAD CAM. AB - OBJECTIVE: The fabrication of all-ceramic restorations using Computer Aided Design and Computer Aided Manufacturing (CAD-CAM) most commonly involves subtractive machining which results in strength-limiting, surface and sub-surface damage in the resultant prosthesis. The objective was to explore how clinically relevant machining-process variables, and material variables, affect damage accumulation in lithium silicate glass-ceramics. METHODS: Three commercial lithium silicate glass-ceramics (IPS e.max(r) CAD, Celtra(r) Duo and Vita Suprinity(r)) were selected. For each material, two groups of disk-shaped specimens were fabricated (n=15), using a CAD-CAM process, creating surfaces equivalent to those generated for a dental restoration, or alternatively, using a highly controlled laboratory process generating disk-shaped test specimens with a consistent polished surface. Bi-axial flexure strength (BFS) was determined in a ball-on-ring configuration and fractographic analyses performed. For each material BFS was correlated with machining sequence and with surface roughness. RESULTS: BFS was significantly influenced by material substrate (p<0.01) and by fabrication route (p<0.01). A significant factorial interaction (p<0.01) identified that the magnitude of changes in BFS when comparing the two specimen fabrication routes, was dependent on substrate type. The polished control specimens exhibited a significantly increased BFS when compared with the CAD-CAM counterparts for all materials. IPS e.max(r) CAD and Celtra(r) Duo showed a 44 and 46% reduction in mean BFS for the CAD-CAM specimens when compared with the polished counterparts, respectively. In contrast, Vita Suprinity(r) showed the least disparity in mean BFS (21%) but the greatest variance in BFS data. SIGNIFICANCE: All CAD-CAM specimens showed evidence of machining introduced damage in the form of median and radial cracks at sites either coincident with, or peripheral to the failure origin. Subtractive machining introduced significant strength limiting damage that is not eliminated by heat treatments applied for either microstructure development (IPS e.max(r) CAD and Vita Suprinity(r)) or annealing/crack blunting (Celtra(r) Duo). PMID- 30454854 TI - Impression of Subgingival Dental Preparation Can Be Taken with Ultrasound. AB - Because of its ability to capture hard structures behind soft tissue, ultrasound based micro-scanning may be a promising alternative for taking digital impressions of teeth, especially in the case of subgingival margin preparations. The aim of this study was to assess the accuracy of ultrasound impressions taken of subgingivally prepared teeth compared with digital optical impressions. Ten extracted human teeth (7 pre-molars, 3 molars) were prepared for crowns with chamfer finish line and then digitized using two different intra-oral scanners (Cara Trios, 3 Shape, Heraeus Kulzer, Hanau, Germany; and Lava COS; 3M ESPE, Seefeld, Germany) and one extra-oral scanner (Cares CS2, Straumann, Basel, Switzerland). Afterward, the preparation margin was covered with porcine gingiva (thickness ranged between 0.3 and 0.9 mm), and every sample was scanned with a high-frequency ultrasound scanner under experimental subgingival conditions. Optical scanning processes were performed without gingiva. The data sets were superimposed on each other for pairwise comparisons, and deviations between different scans were determined using a 3-D evaluation software (CloudCompare). Kruskal-Wallis and post hoc tests (Dunn-Bonferroni) were applied to detect significant differences at p <= 0.05. The ultrasound scanner was able to detect subgingival preparation margins. Mean deviations for all comparisons ranged from 12.34 to 46.38 um. There were no statistically significant differences between superimpositions of intra-oral and extra-oral scans (Trios-Lava, Lava-CS2, Trios CS2), whereas in comparisons between intra-/extra-oral scans and ultrasound scans, mean deviations were statistically significantly higher. There were no significant differences with respect to type of tooth (pre-molar and molar). However, gingiva thickness was significantly correlated with the quality of the ultrasound scan; thin layers had better image quality than thicker layers. Ultrasound was able to scan tooth preparation margins covered with gingiva, although with less accuracy than achieved by conventional optical scanners (non covered margins). Gingiva thickness may play an important role in ultrasound scan accuracy. PMID- 30454855 TI - Citation for Michael J Fardy for Downs Surgical Prize 2017. PMID- 30454853 TI - Should we treat patients with radiologically isolated syndrome (RIS)? No. PMID- 30454856 TI - [The philosophical roots of "connectedness": The care clinic]. AB - If suicide remains "the only really serious philosophical problem" (A. Camus), historically a certain number of philosophers have legitimized it while others have condemned it. Among the philosophers who admitted that suicide could be a possibility, some showed understanding and others remained more modest. Kierkegaard's philosophical stance, demonstrating that one can never decide for the other where existential problems are concerned, opens a third way. Following him, Michel Cornu coined the expression "ethics of concern". That restlessness, etymologically, can be understood at the same time at the epistemological level (lack of a single constituted knowledge, hence the need to resort to a fully interdisciplinary approach of the "suicide" object), but as a relational attitude as well, namely a restlessness vis-a-vis the other, in other words concern for the other. This concept of concern does not exist in philosophical literature as such, but it has been addressed by philosophers. Therefore, it is essential to begin with a differential reflection on the notions of concern, care and solicitude. Then three "philosophies of solicitude" will be developed, those of Heidegger (concern in itself), Ricoeur (concern as reciprocity) and Levinas (concern as responsibility). The monitoring devices, which will be widely discussed in other articles of this special issue, are based on philosophical notions borrowed from Heidegger (thoughtful solicitude), or Ricoeur (solicitude) and Levinas (responsibility) or Cornu (ethics of concern). In addition, throughout our text we have mentioned a certain number of tensions inherent to these notions themselves, such as that intrinsic to the term solicitude (both care and concern), or peculiar to the authors' work (substitutive solicitude - thoughtful solicitude for Heidegger), or related to the debate of ideas (solicitude for Ricoeur - responsibility for Levinas). Implementing these monitoring devices in clinical practice as well as in the territories will raise other problems, in particular, between benevolence and monitoring, but also between justice and equity, which will be our conclusion. PMID- 30454857 TI - Peroxydisulfate chemistry in the environmental literature: A brief critique. PMID- 30454858 TI - Outcome assessment of apical surgery: A study of 234 teeth. AB - BACKGROUND/PURPOSE: Apical surgery is an option for management of endodontically treated tooth with persistent periapical lesions or symptom and sign. The objective of this study was to investigate the correlation between the demography, preoperative, postoperative factors and healed rate of apical surgery. METHODS: Subjects were retrospectively collected from patients who received apical surgery/apicoectomy at the Endodontic Department, National Taiwan University Hospital from January 2013 to June 2015. The standard apical surgery procedures were performed. The demography, preoperative clinical and radiographic examination data as well as postoperative variables were collected. The outcome assessment was carried out after surgery. Statistical analysis was performed by chi square test to evaluate the potential outcome predictors. RESULTS: Total 187 patients and 234 teeth receiving apical surgery were included. 53 male and 134 female patients were collected. The age was ranged between 17 and 89 years old and the mean age was 43.64 years old. Better healed rate with significant differences were observed in female patient (p < 0.05), age <=60 years old (p < 0.01), preoperative root canal filling material >2 mm short of apex (p < 0.01), lesion size from <=2 mm to <=12 mm (p < 0.05) and follow-up period ?12 months (p < 0.01) groups. CONCLUSION: Gender, age, preoperative root canal filling material extent, lesion size and follow-up period may affect the outcome of apical surgery. Tooth type, post, prosthesis, and lesion area showed no marked effect on apical healing. These results provide more detailed information for the clinical practitioners to make treatment plans and are important for clinical endodontic practices. PMID- 30454859 TI - Comparison of different methodologies and cryostat versus paraffin sections for chromogenic immunohistochemistry. AB - Immunohistochemistry (IHC) specifically localizes proteins in cells and tissues, but methodologies vary widely. Therefore, we performed a methodological IHC optimization and validation study. First, we compared advantages and disadvantages of cryostat sections versus paraffin sections. Second, we compared and optimized antigen retrieval in paraffin sections using citrate buffer and Tris/EDTA buffer. Third, aminoethyl carbazole (AEC) and 3,3'-diaminobenzidine (DAB) were tested as horseradish peroxidase (HRP) substrates to obtain a water insoluble coloured end product to visualize antigens. Fourth, secondary antibodies conjugated with either mono-HRP or poly-HRP were compared. The study was performed using serial sections of human tonsil. IHC was performed with primary antibodies against endothelial cell marker CD31, smooth muscle actin (SMA), chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor C-X C receptor type 4 (CXCR4), macrophage marker CD68 and proliferation marker Ki67. DAB rather than AEC, and cryostat sections rather than paraffin sections gave optimum staining at highest primary antibody dilutions, whereas tissue morphology in paraffin sections was superior. Loss of antigenicity in paraffin sections by formaldehyde fixation, heat and/or masking of epitopes was counteracted by antigen retrieval but not for all antigens. Two out of six antigens (CD31 and CD68) could not be retrieved irrespective time and type of retrieval. Tris-EDTA was superior to citrate buffer for antigen retrieval. The use of mono-HRP or poly HRP depended on the affinity of the primary antibody for its antigen. We conclude that IHC methodology optimization and validation are crucial steps for each antibody and each research question. PMID- 30454860 TI - Evidence for respiratory viruses interactions in asymptomatic preschool-aged children. AB - AIM: To prospectively evaluate interferences between viruses of the upper respiratory tract in asymptomatic preschool children. METHODS: Nasal-pharyngeal swabs from 233 preschool aged children were prospectively collected over four consecutive time periods, during one school year. The samples were tested using a RT-PCR DNA/RNA microarray system for nine respiratory viruses. RESULTS: Respiratory syncytial virus (RSV) was a predictor of the presence of influenza virus (INFL) (OR: 9.12, CI: 1.52-54.75, p=0.016), and similarly, INFL predicted the presence of RSV (OR: 4.01, CI: 1.14-14.16, p=0.030). Also, rhinovirus (RV) was a predictor of adenovirus (ADV) presence (OR: 3.66, CI: 1.10-12.14, p=0.034), and similarly, ADV predicted the presence of RV (OR: 4.05, CI: 1.02-16.05, p=0.046). No other significant associations between viruses were observed. CONCLUSION: Our results indicate that respiratory viruses found in carrier stage in asymptomatic children may interact with other viruses and even facilitate their settling in the upper respiratory tract. The pathophysiological role of these interactions is not yet clear. PMID- 30454861 TI - Correlation of OX40 ligand on B cells with serum total IgE and IL-4 levels by CD4+ T cells in allergic rhinitis. AB - INTRODUCTION AND OBJECTIVES: Allergic rhinitis (AR) is a classic Th2-mediated disease, with important contributions to the pathology of interleukins 4, 5, and 13. The co-stimulatory molecule of OX40 and its ligand interaction participate in the immune response by regulation of Th1/Th2 cells balance. Considering the paucity of information on the relation between OX40 ligand (OX40L) and AR, this study aimed to examine its expression on B lymphocytes. PATIENTS AND METHODS: This case-control study consisted of 20 AR patients and 20 healthy subjects. The serum level of total immunoglobulin E (IgE) was measured using the electro chemiluminescence (ECL) technology. The percentage of B-lymphocytes expressing OX40L was assessed by flow cytometry. The amounts of IL-4 in CD4+ T cells culture supernatant was also measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: OX40L expression on B lymphocytes of patients was significantly higher than the control group (44.32+/-19.21% vs. 2.79+/-2.48% respectively, p<0.001). In AR patients, OX40L expression correlated positively with the levels of serum total IgE and IL-4 produced by CD4+ T lymphocytes (p<0.01 - p<0.05) respectively. CONCLUSIONS: Collectively, the findings of this work suggest that there is a relationship between the OX40L expression level on B lymphocytes and allergic markers such as IgE and IL-4 in patients with allergic rhinitis. PMID- 30454862 TI - EGL-3 and EGL-21 are required to trigger nocifensive response of Caenorhabditis elegans to noxious heat. AB - Caenorhabditis elegans (C. elegans) is a widely used model organism to examine nocifensive response to noxious stimuli, including heat avoidance. Recently, comprehensive analysis of the genome sequence revealed several pro-neuropeptide genes, encoding a series of bioactive neuropeptides. C. elegans neuropeptides are involved in the modulation of essentially all behaviors including locomotion, mechanosensation, thermosensation and chemosensation. The maturation of pro neuropeptide to neuropeptide is performed by ortholog pro-protein convertases and carboxypeptidase E (e.g. EGL-3 and EGL-21). We hypothesized that C. elegans egl-3 or egl-21 mutants will have a significant decrease in mature neuropeptides and they will display an impaired heat avoidance behavior. Our data has shown that thermal avoidance behavior of egl-3 and egl-21 mutants was significantly hampered compared to WT(N2) C. elegans. Moreover, flp-18, flp-21 and npr-1 mutant C. elegans displayed a similar phenotype. EGL-3 pro-protein convertase and EGL-21 carboxypeptidase E are essential enzymes for the maturation of pro-neuropeptides to active neuropeptides in C. elegans. Quantitative mass spectrometry analyses with egl-3 and egl-21 mutant C. elegans homogenates demonstrated that proteolysis of ProFLP-18 and ProFLP-21 are severely impeded, leading to a lack of mature bioactive neuropeptides. Not only FLP-21 but also FLP-18 related mature neuropeptides, both are ligands of NPR-1 and are needed to trigger nocifensive response of C. elegans to noxious heat. PMID- 30454863 TI - Enteric Neuronal Degeneration: Is it Due to Your Mother's Diet? PMID- 30454865 TI - Big Ideas: New metaphors for nursing (1): The nurse as musician. PMID- 30454864 TI - High-Fat Diet During the Perinatal Period Induces Loss of Myenteric Nitrergic Neurons and Increases Enteric Glial Density, Prior to the Development of Obesity. AB - Diet-induced obesity induces peripheral inflammation accompanied by a loss of myenteric neurons. Few studies, however, have investigated the effects of a high fat diet (HFD) on either the development of myenteric neurons or prior to the occurrence of obesity. The present study assessed the effects of maternal HFD on the density and neurochemical phenotype of myenteric ganglia in the upper gastrointestinal tract. Sprague-Dawley rats were fed either a control or HFD (14% or 60% kcal from fat, respectively) from embryonic day 13; the fundus, corpus and duodenum were fixed thereafter at postnatal 2, 4, 6 and 12 weeks of age for subsequent immunohistochemical studies. While myenteric ganglion size did not differ throughout the study, HFD exposure decreased the number of nitrergic neurons by 6 weeks of age in all regions. This decrease was accompanied by a loss of PGP-immunoreactive neurons, suggesting a decline in myenteric neuronal number. HFD also increased myenteric plexus glial cell density in all regions by 4 weeks of age. These changes occurred in the absence of an increase in serum or gastric inflammatory markers. The present study suggests that exposure to a HFD during the perinatal time period results in glial proliferation and loss of inhibitory nitrergic neurons prior to the onset of obesity, suggesting that dietary alterations may affect gastrointestinal functions independently of increased adiposity or glycemic dysregulation. PMID- 30454866 TI - Big Ideas: New metaphors for nursing (3): The nurse as gardener. PMID- 30454867 TI - Functional Safe Zone Is Superior to the Lewinnek Safe Zone for Total Hip Arthroplasty: Why the Lewinnek Safe Zone Is Not Always Predictive of Stability. AB - BACKGROUND: The Lewinnek "safe zone" is not always predictive of stability after total hip arthroplasty (THA). Recent studies have focused on functional hip motion as observed on lateral spine-pelvis-hip x-rays. The purpose of this study was to assess the correlation between the Lewinnek safe zone and the functional safe zone based on hip and pelvic motion in the sagittal plane. METHODS: Three hundred twenty hips (291 patients) underwent primary THA using computer navigation. Two hundred ninety-six of these hips (92.5%) were within the Lewinnek safe zone as determined by inclination of 40 degrees +/- 10 degrees and anteversion of 15 degrees +/- 10 degrees . All patients had preoperative and postoperative standing and sitting lateral spinopelvic x-rays. The combined sagittal index (CSI), a combination of sagittal acetabular and femoral position, was measured for each patient and used to assess the functional safe zone. Data analysis was performed to identify hips in the Lewinnek safe zone inside and outside the sagittal functional safe zone. Predictive factors for hips outside the functional safe zone were identified. RESULTS: Of the 296 hips within the Lewinnek safe zone, 254 (85.8%) were also in the functional safe zone. Forty-two patients were outside the functional safe zone based on CSI; 19 had an increased standing CSI and 23 had a decreased sitting CSI, all were considered at risk for dislocation. Predictive factors for falling outside the functional safe zone were increased femoral mobility (P < .001, r = 0.632), decreased spinopelvic mobility (P < .001, r = 0.455), and pelvic incidence (P < .001, r = 0.400). CONCLUSION: In this study, 14.2% of hips within the Lewinnek safe zone were outside the functional safe zone, identifying a potential reason hips dislocate despite having "normal" cup angles. The best predictor for falling outside the functional safe zone, both preoperatively and postoperatively, was femoral mobility, not the sagittal cup position (ie, cup anteinclination). LEVEL OF EVIDENCE: Level III, retrospective review. PMID- 30454868 TI - Congenital erythropoietic porphyria and erythropoietic protoporphyria: Identification of 7 uroporphyrinogen III synthase and 20 ferrochelatase novel mutations. AB - The erythropoietic porphyrias are inborn errors of heme biosynthesis with prominent cutaneous manifestations. They include autosomal recessive Congenital Erythropoietic Porphyria (CEP) due to loss-of-function (LOF) mutations in the Uroporphyrinogen III Synthase (UROS) gene, Erythropoietic Protoporphyria (EPP) due to LOF mutations in the ferrochelatase (FECH) gene, and X-Linked Protoporphyria (XLP) due to gain-of-function mutations in the terminal exon of the Aminolevulinic Acid Synthase 2 (ALAS2) gene. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for one or more of these disorders in 628 individuals, including 413 unrelated individuals. Of these 628, 120 patients were tested for CEP, 483 for EPP, and 331 for XLP, for a total of 934 tests. For CEP, 24 of 78 (31%) unrelated individuals tested had UROS mutations, including seven novel mutations. For EPP, 239 of 362 (66%) unrelated individuals tested had pathogenic FECH mutations, including twenty novel mutations. The IVS3-48 T > C low-expression allele was present in 231 (97%) of 239 mutation-positive EPP probands with a pathogenic FECH mutation. In the remaining 3%, three patients with two different FECH mutations in trans were identified. For XLP, 24 of 250 (10%) unrelated individuals tested had ALAS2 exon 11 mutations. No novel ALAS2 mutations were identified. Among family members referred for testing, 33 of 42 (79%) CEP, 62 of 121 (51%) EPP, and 31 of 81 (38%) XLP family members had the respective family mutation. Mutation-positive CEP, EPP, and XLP patients who had been biochemically tested had marked elevations of the disease-appropriate porphyrin intermediates. These results expand the molecular heterogeneity of the erythropoietic porphyrias by adding a total of 27 novel mutations. The results document the usefulness of molecular testing to confirm the positive biochemical findings in these patients and to identify heterozygous family members. PMID- 30454869 TI - The challenge of CDG diagnosis. AB - Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases that currently includes some 130 different types. CDG diagnosis is a challenge, not only because of this large number but also because of the huge clinical heterogeneity even within a number of CDG. In addition, the classical screening test, serum transferrin isoelectrofocusing, is only positive in about 60% of CDG, and can even become negative in some CDG particularly in PMM2-CDG, the most frequent N-glycosylation defect. In order to facilitate CDG diagnosis, we hereby provide some practical tools: (1) a list of clinical features strongly suggestive of a distinctive CDG; (2) a table of clinical, biochemical and laboratory findings reported in CDG, arranged per organ/system; (3) an overview of the affected organs/systems in each CDG; and (4) a diagnostic decision tree in face of a patient with a suspicion of CDG. Most important is to keep in mind a CDG in any unexplained syndrome, in particular when there is neurological involvement. This mini-review enumerates clinical and biochemical hallmarks of these diseases and the biochemical and genetic testing available, and provides an updated list and information on identified CDG. The main aim is to act as a CDG diagnosis simplified guide for healthcare professionals and, additionally, as an awareness and lobbying tool to help in the effectiveness and promptness of CDG diagnosis. PMID- 30454870 TI - Respiratory and Peripheral Muscle Assessment in the Intensive Care Unit. AB - Atrophy and weakness of the respiratory and peripheral muscles is a common problem in the intensive care unit (ICU). It is difficult to diagnose, particularly in the early stages of critical disease. Consequently, many cases are detected only in advanced stages, for example, when difficulties in mechanical ventilation weaning are encountered. The aim of this review is to describe the main tools that are currently available for evaluation of peripheral and respiratory muscles in the ICU. Techniques of varying complexity and specificity are discussed, and particular emphasis is placed on those with greater relevance in daily clinical practice, such as ultrasound. PMID- 30454873 TI - Allogeneic Stem Cell Transplantation after Fanconi Anemia Conditioning in Children with Ataxia-Telangiectasia Results in Stable T Cell Engraftment and Lack of Infections despite Mixed Chimerism. AB - Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Immunologic recovery resulted in T cell production and lack of symptomatic infections. Regular intravenous immunoglobulin supplementation was needed until IgG production recovered, which depended on pretransplant serotherapy. During the observation period patients did not require hospital admission, and none of the transplanted patients developed sinopulmonary infections. Neurologic functions in reported patients were impaired and slowly deteriorated after transplantation, but no immediate toxicities were observed. The following hallmark features of A-T were present after SCT: neurologic symptoms, growth failure, telangiectasia formation, or increased serum alpha fetoprotein. SCT can help control immune deficiency constituting 1 of the features of A-T, and elimination of autologous hematopoiesis reduces the risk of lymphoid malignancies. Resolving crucial problems with qualification for SCT depends on balancing the risk and benefits of transplant therapy. PMID- 30454874 TI - [Editorial]. PMID- 30454875 TI - A multi-epitope DNA vaccine enables a broad engagement of diabetogenic T cells for tolerance in Type 1 diabetes. AB - Type 1 diabetes (T1D) is caused by diabetogenic T cells that evaded tolerance mechanisms and react against multiple beta-cell antigens. Antigen-specific therapy to reinstate tolerance (typically using a single beta-cell antigen) has so far proved unsuccessful in T1D patients. Plasmid DNA (pDNA)-mediated expression of proinsulin has demonstrated transient protection in clinical trials, but long-lasting tolerance is yet to be achieved. We aimed to address whether pDNA delivery of multiple epitopes/mimotopes from several beta-cell antigens efficiently presented to CD4+ and CD8+ T cells could also induce tolerance. This approach significantly delayed T1D development, while co-delivery of pDNA vectors expressing four full antigens protected more mice. Delivery of multiple epitopes resulted in a broad engagement of specific T cells, eliciting a response distinct from endogenous epitopes draining from islets. T-cell phenotypes also varied with antigen specificity. Unexpectedly, the repertoire of T cells reactive to the same epitope was highly polyclonal. Despite induction of some CD25+ Foxp3+ regulatory T cells, protection from disease did not persist after treatment discontinuation. These data demonstrate that epitope-based tolerogenic DNA vaccines constitute effective precision medicine tools to target a broad range of specific CD4+ and CD8+ diabetogenic T-cell populations for prevention or treatment of T1D. PMID- 30454871 TI - Pretransplant Serum Citrulline Predicts Acute Graft-versus-Host Disease. AB - Post-transplant biomarkers of acute graft-versus-host disease (aGVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT) have been extensively studied. However, pretransplant biomarkers may provide a greater window of opportunity to intervene. We measured serum biomarkers of various aspects of gut barrier physiology before HCT (median, day 7) and 7 and 28 days post-HCT in 95 consecutive allo-HCT recipients enrolled in an open-label biorepository protocol. Biomarkers included citrulline for total functional enterocyte mass, Reg3a for antibacterial activity of the gut, and intestinal fatty acid binding protein (I-FABP) for enterocyte turnover. Compared to 16 healthy control subjects, we demonstrated that patients came to transplant with abnormal levels of all 3 biomarkers (P < .05), reflecting residual damage from prior chemotherapy. All 3 biomarkers initially declined from pre-HCT to day +7 (more pronounced after myeloablative than reduced-intensive conditioning) followed by a recovery phase and return toward pre-HCT values by day +28. A lower pre-HCT citrulline was independently associated with a higher risk of aGVHD grades II to IV (hazard ratio, 1.32; 95% confidence interval, 1.03 to 1.69; P = .02), and this association was not specific to gut GVHD. The strongest correlate of NRM was a higher level of Reg3a at day +7 (P < .001). I-FABP did not predict transplant outcomes. In conclusion, pre-HCT serum citrulline levels identify patients at high risk for developing aGVHD. Our results suggest that pre-HCT interventions to augment the gut barrier may decrease the risk of aGVHD. PMID- 30454872 TI - Long-Term Follow-Up of 90Y-Ibritumomab Tiuxetan, Fludarabine, and Total Body Irradiation-Based Nonmyeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B Cell Lymphoma. AB - Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90Y-ibritumomab tiuxetan-based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90Y-ibritumomab tiuxetan-based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392. PMID- 30454876 TI - Virtual social support buffers stress response: An experimental comparison of real-life and virtual support prior to a social stressor. AB - BACKGROUND AND OBJECTIVES: Face-to-face and text-based social support have been shown to attenuate stress responses in past studies. Yet as social interactions increasingly take place online by means of virtual humans, our objective was to examine whether different forms of social support (virtual vs. real) prior to the Trier Social Stress Test (TSST) would also decrease stress. Additionally, the effect on subsequent real-life social behaviors (helping and approach) was evaluated while controlling for affective states and social presence. METHODS: 56 participants were either supported by an avatar, an agent, a real human or received no support before completing the TSST and two subsequent social behavior tasks (pen task and seating task). RESULTS: Results show no difference in agency regarding social presence. Yet, participants with agent support and no support had significantly higher heart rates during the TSST and reported to be more worried. Also, they were more irritated and showed significantly slower helping reactions (picking up pens). LIMITATIONS: A limitation to this study is that only emotional verbal and non-verbal support were provided by a stranger. Different forms of support as well as a different source (i.e., a friend) may have a more pronounced effect on stress buffering. CONCLUSIONS: Virtual social support is as effective as face-to-face support in terms of stress buffering, as long as the recipient has the impression that it is provided by another human (via an avatar). This has wide ranging implications not only for health-related application in prevention and treatment but also for further research. PMID- 30454877 TI - Sentinel lymph nodes in vulvar cancer: Management dilemmas in patients with positive nodes and larger tumors. AB - BACKGROUND: Although sentinel lymph node (SLN) biopsy has been routinely used in the treatment of invasive squamous cell carcinoma (SCC), questions still remain regarding the management of patients with positive nodes, as well as its use in patients with larger tumors. METHODS: Retrospective study of all patients at a single institution with primary vulvar cancer who had SLN biopsy (2008-2015). Patient and tumor characteristics were collected from hospital records. For patients with positive SLN and for those with tumors >=40 mm, recurrence rates and location were specifically recorded. RESULTS: SLN biopsy was successful in 159 patients (245 groins). Median follow-up was 31 months. 120 patients (187 groins) had a negative SLN without an inguinofemoral lymph node dissection (IFL); there were 6 ipsilateral groin recurrences (5%). 7 patients had micrometastasis (<=2 mm) in the SLN and were treated by radiotherapy. There were no recurrences in the irradiated groins. 19 patients with a positive unilateral SLN had bilateral IFL. One (5.3%) had a positive node in the contralateral groin. 9 patients with positive unilateral SLN had subsequent ipsilateral IFL; there were no groin recurrences in the contralateral groin. 20 patients had tumor size >=40 mm. 11 patients had a negative SLN biopsy, and thus no IFL; of these patients, 1 had an isolated groin recurrence (9%). CONCLUSION: These data suggest it is reasonable to omit a full groin dissection for micrometastatic disease in the SLN, and to perform a unilateral groin dissection in patients with unilateral SLN metastasis. SLN alone in larger tumors may have a higher groin recurrence rate. PMID- 30454878 TI - Laterally extended endopelvic resection with nephrectomy for vaginal cancer. PMID- 30454879 TI - An insight into in vitro susceptibility of non-albicans Candida species from bloodstream infections to echinocandins in a Singapore cohort. PMID- 30454880 TI - Detection of OXA-carbapenemase-producing Enterobacteriaceae with chromID CARBA SMART screening plate. PMID- 30454881 TI - Parasitic nodules of thyroid: some insights into the origin and early evolution. PMID- 30454882 TI - High genetic risk scores of SLIT3, PLEKHA5 and PPP2R2C variants increased insulin resistance and interacted with coffee and caffeine consumption in middle-aged adults. AB - BACKGROUNDS AND AIMS: Insulin resistance is a common feature of metabolic syndrome that may be influenced by genetic risk factors. We hypothesized that genetic risk scores (GRS) of SNPs that influence insulin resistance and signaling interact with lifestyles to modulate insulin resistance in Korean adults. METHODS AND RESULTS: Genome-wide association studies (GWAS) of subjects aged 40-65 years who participated in the Ansung/Ansan cohorts (8842 adults) in Korea revealed 52 genetic variants that influence insulin resistance. The best gene-gene interaction model was explored using the generalized multifactor dimensionality reduction (GMDR) method. GRS from the best model were calculated and the GRS were divided into low, medium and high groups. The best model for representing insulin resistance included SLIT3_rs2974430, PLEKHA5_rs1077044, and PPP2R2C_rs16838853. The odds ratios for insulin resistance were increased by 150% in the High-GRS group compared to the Low-GRS group. However, ORs for insulin secretion capacity, measured by HOMA-B, were not associated with GRS. Coffee and caffeine intake and GRS had an interaction with insulin resistance: In subjects with high coffee (>=10 cups/week) or caffeine intake (>=220 mg caffeine/day), insulin resistance was significantly elevated in the High-GRS group, but not in the Low-GRS. However, alcohol intake, smoking and physical activity did not have an interaction with GRS. Insulin secretion capacity was not significantly influenced by GRS when evaluating the adjusted odds ratios. CONCLUSIONS: Subjects with High GRS may be susceptible to increased insulin resistance by 50% and its risk may be exacerbated by consuming more than 10 cups coffee/week or 220 mg caffeine/day. PMID- 30454883 TI - The effect of camelina sativa oil and fish intakes on fatty acid compositions of blood lipid fractions. AB - BACKGROUND AND AIMS: Blood lipid fractions serve as objective biomarkers of dietary fat intake. It is unclear which fatty acid pool most accurately reflects the dietary intakes of different n-3 PUFAs. We aimed to investigate the effect of fish and camelina sativa oil (CSO) intakes on fatty acid composition of erythrocyte membranes (EM), plasma phospholipids (PL), cholesteryl esters (CE) and triglycerides (TG). We also aimed to identify the most appropriate blood lipid fraction for assessing n-3 PUFA intake. METHODS AND RESULTS: Altogether 79 volunteers with impaired glucose metabolism were randomly assigned either to CSO, fatty fish, lean fish or control groups for 12 weeks. Fatty acid compositions of lipid pools were measured by gas chromatography. The proportion of alpha linolenic acid (ALA) increased in all lipid pools in the CSO group (false discovery rate (FDR) p < 0.001 for all). Similarly, the proportions of EPA and DHA increased in all lipid fractions in the fatty fish group (FDR p < 0.001 for EM, PL and CE; FDR p = 0.005 for TG; FDR p < 0.001 for EM, PL, CE; FDR p < 0.007 for TG, respectively). Changes in the dietary intakes of ALA, EPA and DHA correlated with the changes in their proportions in all lipid pools (r = 0.3-0.5, p < 0.05). CONCLUSION: There is no difference in the ability of blood lipid fractions in reflecting the dietary intake of different n-3 PUFAs over a time period of 12 weeks in subjects with high baseline omega-3 index. This trial was registered in Clinicaltrials.gov (NCT01768429). PMID- 30454884 TI - Duodenal Schwannoma as a Rare Association With Membranous Nephropathy: A Case Report. AB - Membranous nephropathy (MN) associated with malignancies is a well-known entity. However, its association with benign neoplasm is not broadly recognized. A 69 year-old man with recurrent nephrotic syndrome presented with pedal edema and proteinuria of 5 months' duration. Laboratory results showed hypoalbuminemia and hyperlipidemia. Proteinuria was estimated to be protein excretion of 3.5g/d. Studies were negative for viral hepatitis, syphilis, human immunodeficiency virus, autoimmune diseases, and paraproteinemia. Kidney biopsy disclosed MN with negative phospholipase A2 receptor (PLA2R) staining, favoring a secondary form of MN. Computed tomography detected a 7.6-cm duodenal schwannoma. Elective surgical resection was performed. Pathologic study showed that THSD7A (thrombospondin type 1 domain-containing 7A) was positive in both glomeruli and schwannoma. Commonly, secondary MN is related to underlying conditions, including lupus, hepatitis, and neoplasm, and can be medication induced. The risk for developing a concomitant neoplasm among patients with PLA2R-negative MN is up to 12 times higher than in the general population. Most of these neoplasms are malignancies, and the presence of autoantibodies directed at similar tissue targets is hypothesized as the potential mechanism. In our case, THSD7A may be the autoantibody that has linked the schwannoma and the development of MN. Although benign tumors rarely produce renal manifestations, effective treatment may lead to resolution of nephrotic syndrome. PMID- 30454885 TI - Burden of Care and Quality of Life Among Caregivers for Adults Receiving Maintenance Dialysis: A Systematic Review. AB - RATIONALE & OBJECTIVE: Dialysis is a burdensome and complex treatment for which many recipients require support from caregivers. The impact of caring for people dependent on dialysis on the quality of life of the caregivers has been incompletely characterized. STUDY DESIGN: Systematic review of quantitative studies of quality of life and burden to caregivers. SETTING & STUDY POPULATION: Caregivers of adults receiving maintenance dialysis. SELECTION CRITERIA FOR STUDIES: The Cochrane Library, Embase, PsycINFO, CINAHL, PubMed, and MEDLINE were systematically searched from inception until December 2016 for quantitative studies of caregivers. Pediatric and non-English language studies were excluded. Study quality was assessed using a modified Newcastle-Ottawa scale. DATA EXTRACTION: 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. ANALYTICAL APPROACH: Descriptive reports of demographics, measurement scales, and outcomes. Quantitative meta-analysis using random effects when possible. RESULTS: 61 studies were identified that included 5,367 caregivers from 21 countries and assessed the impact on caregivers using 70 different scales. Most (85%) studies were cross-sectional. The largest identified group of caregivers was female spouses who cared for recipients of facility-based hemodialysis (72.3%) or peritoneal dialysis (20.6%). Caregiver quality of life was poorer than in the general population, mostly comparable with caregivers of people with other chronic diseases, and often better than experienced by the dialysis patients cared for. Caregiver quality of life was comparable across dialysis modalities. LIMITATIONS: Heterogeneity in study design and outcome measures made comparisons between studies difficult and precluded quantitative meta-analysis. Study quality was generally poor. CONCLUSIONS: Quality of life of caregivers of dialysis recipients is poorer than in the general population and comparable to that of caregivers of individuals with other chronic diseases. The impact of caring for recipients of home hemodialysis or changes in the impact of caring over time have not been well studied. Further research is needed to optimally inform dialysis programs how to educate and support caregivers. PMID- 30454886 TI - Pre-transplant amiodarone use and outcomes in children after heart transplantation. PMID- 30454888 TI - Probucol improves erectile function via Activation of Nrf2 and coordinates the HO 1 / DDAH / PPAR-gamma/ eNOS pathways in streptozotocin-induced diabetic rats. AB - BACKGROUND: Diabetic erectile dysfunction (DMED) is mainly attributed to oxidative stress, and Nrf2 plays an important role in cellular antioxidation and regulates NO production in the vascular endothelium. Probucol maintains endothelial function through its antioxidant activity. This study investigated the efficacy and mechanism of probucol in improving erectile function in streptozotocin-induced diabetic rats. METHODS: In our study, thirty 12-week-old Sprague-Dawley male rats were fasted for 12 h. All rats received a 1-time injection of intraperitoneal streptozotocin(60 mg/kg) or vehicle. After 72 h, STZ treated rats (with random blood glucose concentrations consistently greater than 16.7 mmol/L) were considered diabetic. The diabetic rats were randomly assigned into 2 groups and treated with daily gavage feedings of probucol at doses of 0 and 500 mg/kg for 12 weeks. A positive control group underwent intraperitoneal injection of normal saline followed by daily gavage of saline solution. Erectile function was assessed by electrical stimulation of the cavernous nerves with real time intracavernous pressure measurement. After euthanasia, penile tissue was investigated using immunohistochemistry, Western blot, and ELISA to assess the proteins of Nrf2/HO-1/DDAH/PPAR-gamma/eNOS pathways. RESULTS: After treatment, the rats in the probucol group presented significantly improved erectile function (P < 0.05) than that of the diabetic group without probucol treatment (DM). Also, protein expression of Nrf2, DDAH, PPAR-gamma, HO-1 and eNOS was significantly higher than that of the DM group (P < 0.05). CGMP concentrations and SOD concentrations of probucol-treated rats were higher than those of DM group (P < 0.05). The MDA levels and ADMA levels were significantly lower than those of DM group rats (P < 0.05). CONCLUSION: Probucol can improve erectile function via activation of Nrf2, which coordinates the HO-1/DDAH/PPAR-gamma/eNOS pathways in streptozotocin-induced diabetic rats. PMID- 30454887 TI - STAM-binding protein regulates melanoma metastasis through SLUG stabilization. AB - STAM-binding protein, STAMBP, is a JAMM-family deubiquitinating enzyme containing the microtubule-interacting/transport domain and STAM-binding domain. Although the biological importance of STAMBP in development has been recognized because the microcephaly-capillary malformation syndrome in human is caused by its somatic mutations, the role of STAMBP in cancer has not yet been determined. In this study, we demonstrate that STAMBP is a key molecule for regulating melanoma migration and invasion, but not survival, by knocking down STAMBP in vitro. STAMBP regulates SLUG expression through a post-transcriptional mechanism to control protein stability and further contributes to the in vivo metastatic potential of melanoma. Collectively, these results indicate the importance of STAMBP in melanoma metastasis by regulating SLUG. It is therefore a potential therapeutic target. PMID- 30454889 TI - Linc01230, transcriptionally regulated by PPARgamma, is identified as a novel modifier in endothelial function. AB - Evidence is growing that PPARgamma could improve the bioavailability of NO in pathological conditions to maintain endothelial function by activating Akt/eNOS pathway. LincRNAs participate in regulating development of cardiovascular diseases. Although investigations have been made to delineate the function of PPARgamma and lincRNAs, little is known about the regulation relationship between them, especially in endothelial cells. In this study, we not only verified that PPARgamma could antagonize the adverse effects brought from ox-LDL, but also found a novel factor related to PPARgamma, named linc01230. According to our study, PPARgamma transcriptionally regulated linc01230 by specifically combining with two binding regions, which have superposition effect, in the upstream of linc01230 promoter. In addition, linc01230 reduced ox-LDL induced endothelial dysfunction and affected the phosphorylation of Akt. These results conclude linc01230 as a novel modifier in PPARgamma-mediated activation of Akt in endothelial function. PMID- 30454890 TI - Long non-coding RNA GClnc1 promotes tumorigenesis in osteosarcoma by inhibiting p53 signaling. AB - Recent studies suggest important roles for long noncoding RNAs as essential regulators of human cancer. GClnc1 was found to be upregulated in gastric cancer, playing oncogenic roles. However, the biological function and underlying mechanism of GClnc1 in osteosarcoma (OS) remain unclear. Here, we report that GClnc1 is upregulated in OS tissues and its high expression predicts poor prognosis of patients. Functional analyses show that overexpression of GClnc1 promotes OS cells growth; whereas knockdown of GClnc1 has completely opposite effects. Consistently, overexpression of GClnc1 promotes tumorigenicity of OS cells in vivo. Mechanistically, GClnc1 directly binds to p53 and blocks the binding of p53 to acetyltransferase p300, and thereby suppresses acetylation of p53, leading to the reduced expression of p21 and BAX. This study shed light on the oncogene role of lncRNA GClnc1, a new modulator of p53 signaling, in OS. PMID- 30454891 TI - Suppressing NLRP2 expression accelerates hepatic steatosis: A mechanism involving inflammation and oxidative stress. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation and inflammation in the liver, contributing to a broad spectrum of severe pathologies, such as metabolic syndrome and hepatocellular carcinoma. Presently, the pathogenesis that attributes to NAFLD has not been fully understood. NLRP2 has been shown to inhibit the NF-kappaB signaling, and thus may contribute to regulate the inflammatory response. However, its role in NAFLD is largely unclear. In the study, we found that NLRP2 was markedly decreased in liver tissues of individuals with severe steatosis, or in a genetic deficiency (ob/ob) mice. High fat diet (HFD) feeding also led to a significant reduction of NLRP2 in liver of mice. Then, the wild type (WT) and NLRP2 knockout (KO) mice were used to further explore the role of NLRP2 in the NAFLD progression. NLRP2 knockout mice exhibited severer metabolic syndrome and hepatic steatosis after HFD administration, as evidenced by the increased body weight, liver histological changes and lipid accumulation. Moreover, HFD feeding-induced inflammation was significantly accelerated by the loss of NLRP2, as evidenced by the increased expression of pro-inflammatory cytokines and activation of nuclear factor kappaB (NF-kappaB) pathway. In addition, oxidative stress triggered by HFD was further promoted by NLRP2 deletion through repressing NF-E2-related factor 2 (Nrf2) pathway. In vitro, we surprisingly found that promoting Nrf2 activation could attenuate NLRP2 knockout-accelerated inflammation and reactive oxygen species (ROS) generation. Therefore, our study indicated that NLRP2 might be a potential target for developing effective therapeutic strategy to prevent NAFLD progression. PMID- 30454892 TI - The positive feedback between lncRNA TNK2-AS1 and STAT3 enhances angiogenesis in non-small cell lung cancer. AB - Evidence has shown the importance of long non-coding RNAs (lncRNAs) during angiogenesis and lung cancer progression. However, the potential functions of TNK2-AS1 in non-small cell lung cancer (NSCLC) remain elusive. By lncRNA profiling, we identified TNK2-AS1 as a novel oncogenic lncRNA in NSCLC. TNK2-AS1 was significantly upregulated in NSCLC and correlated with poor prognosis. We found that TNK2-AS1 could increase viability and migration of NSCLC cells in vitro. TNK2-AS1 also promoted NSCLC xenograft tumor growth and metastasis in vivo. TNK2-AS1 could interact with STAT3 to increase its protein stability by protecting it from proteasome-mediated degradation. STAT3 could also bind TNK2 AS1 promoter to trigger its transcription. The positive feedback loop between STAT3 and TNK2-AS1 therefore augmented STAT3 signaling by elevating VEGFA expression to facilitate angiogenesis. Collectively, our work has elucidated a novel mechanism of TNK2-AS1-mediated angiogenesis by enforcing STAT3/VEGFA signaling and may provide a potential target for therapeutic intervention. PMID- 30454893 TI - Interleukin-7 stimulation inhibits nephrin activation and induces podocyte injury. AB - The glomerular podocytes control filtration barrier permeability in the kidney, and their disturbance underlies the pathogenesis of idiopathic nephrotic syndrome (INS), a kidney disease that predominantly occurs in children. In this study, we found that the interleukin-7 receptor (IL-7R) was induced in the glomeruli of adriamycin (ADR)-induced mouse nephropathy, a rodent model of nephrotic syndrome. In addition, IL-7R was also induced by ADR in mouse podocytes cultured in vitro. Functionally, we discovered that IL-7R activation through the stimulation of recombinant IL-7 induced apoptosis of podocytes, and moreover, IL-7 stimulation inhibited nephrin activation and caused actin cytoskeleton disorganization, indicating that IL-7 stimulation induces podocyte injury. Furthermore, IL-7 stimulation impaired the filtration barrier function of podocyte monolayer. Together, these results identify IL-7 and its receptor IL-7R as potential regulators of podocyte function, which might offer a novel therapeutic target in the treatment of INS. PMID- 30454894 TI - Effects of none-steroidal anti-inflammatory and antibiotic drugs on the oral immune system and oral microbial composition in rats. AB - BACKGROUND: Antibiotics and none-steroidal anti-inflammatory drugs are often taken orally to treat human diseases. The use of these drugs adversely could affect the natural oral microbiota composition and oral immune system. In the meanwhile, it may break the original balance of oral micro-ecosystem. Exploring this change is of great importance to host health. METHODS: In this study, we took 20 SD rats and divided them into four groups of five rats each. Each of these groups was administered specified doses of amoxicillin (AMX), ornidazole (ORD), aspirin (ASP), or purified water (CTR), using oral gavage daily for 14 days. High-throughput sequencing was used to investigate the microbiota difference in the four groups of rats once the oral gavage completed. ELISA kit was used to determine IgG and SIgA content, to understand the effect of the drugs on the oral immune system. RESULTS: We found that oral bacterial composition, IgG and sIgA were significantly affected by the use of these drugs. No matter which medication the rats takes, oral microbiota diversity increase significantly. At the genus level, The Lactobacillaceae, which is essential to the human food digest, raised in the aspirin take group. Staphylococcus and Pasteurella increased in the ornidazole group. Klebsiella, Corynebacterium rose significantly in the amoxicillin group. In normal oral cavity without taking the task medicine, Streptococcus, Pasteurella, and Rothia were in a relatively high abundance. IgG and SIgA content also changed by using these drugs, thus indicating applied those drugs impact of the oral immune system. CONCLUSION: Our results indicate that antibiotic and none-steroidal anti-inflammatory drugs could influence the oral microbiota composition, which could also destroy the original oral micro ecosystem environment. The non-antibiotic drug effect on the oral microbiota and oral immune system similar to the antibiotic drug. All these changes may have a negative influence on host health. PMID- 30454895 TI - Chemoattractant receptors activate, recruit and capture G proteins for wide range chemotaxis. AB - The wide range sensing of extracellular signals is a common feature of various sensory cells. Eukaryotic chemotactic cells driven by GPCRs and their cognate G proteins are one example. This system endows the cells directional motility towards their destination over long distances. There are several mechanisms to achieve the long dynamic range, including negative regulation of the receptors upon ligand interaction and spatial regulation of G proteins, as we found recently. However, these mechanisms are insufficient to explain the 105-fold range of chemotaxis seen in Dictyostelium. Here, we reveal that the receptor mediated activation, recruitment, and capturing of G proteins mediate chemotactic signaling at the lower, middle and higher concentration ranges, respectively. These multiple mechanisms of G protein dynamics can successfully cover distinct ranges of ligand concentrations, resulting in seamless and broad chemotaxis. Furthermore, single-molecule imaging analysis showed that the activated Galpha subunit forms an unconventional complex with the agonist-bound receptor. This complex formation of GPCR-Galpha increased the membrane-binding time of individual Galpha molecules and therefore resulted in the local accumulation of Galpha. Our findings provide an additional chemotactic dynamic range mechanism in which multiple G protein dynamics positively contribute to the production of gradient information. PMID- 30454896 TI - Targeting TPX2 suppresses proliferation and promotes apoptosis via repression of the PI3k/AKT/P21 signaling pathway and activation of p53 pathway in breast cancer. AB - Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is a microtubule associated protein required for mitosis and spindle assembly. Previous studies showed that TPX2 is overexpressed in various human cancers and promotes cancer progression. In this study, the differentially expressed genes including TPX2 were screened in GEO database for gene expression microarray of breast cancer. The TPX2 expression level was significantly increased in breast cancer cells and the breast malignant tissues compared with those controls. In vitro experiment further confirmed that knockdown of TPX2 by small hairpin RNA inhibited breast cancer cell proliferatio, migration, and induced cell apoptosis. TPX2 silencing decreased the expression of PI3K and extent of AKT phosphorylation, as well as increased expression of p53 and p21. Taken together, our findings indicate that TPX2 silencing negatively regulates the PI3K/AKT and activates p53 signaling pathway by which breast cancer cells proliferation were inhibited whereas cellulars apoptosis were accelerated, suggesting that TPX2 may be a potential target for anticancer therapy in breast cancer. PMID- 30454897 TI - High glucose-induced circHIPK3 downregulation mediates endothelial cell injury. AB - High glucose (HG) induces vascular endothelial cell injury. However, the underlying mechanisms are poorly understood. Circular RNA HIPK3 (circHIPK3) is a highly conserved non-coding RNA. Here we show that circHIPK3 is downregulated in HG-treated human umbilical vein endothelial cells (HUVECs) and in primary aortic endothelial cells (HAECs) from diabetic patients. In both HUVECs and HAECs, lentivirus-mediated circHIPK3 overexpression inhibited HG-induced cell death and apoptosis. Contrarily, circHIPK3 silencing by targeted siRNA exacerbated HG induced endothelial cell death and apoptosis. Further, circHIPK3 downregulation by HG caused microRNA-124 (miR-124) accumulation in HUVECs and HAECs. On the contrary, miR-124 inhibition by the adeno-associated virus (AAV)-packed miR-124 inhibitor protected endothelial cells from HG. Together, circHIPK3 downregulation mediates HG-induced endothelial cell injury. Targeting circHIPK3-miR-124 pathway could potentially be a novel approach for the treatment of diabetic-associated vascular injury. PMID- 30454898 TI - Insulin-like growth factor binding Protein-3 suppresses osteoblast differentiation via bone morphogenetic protein-2. AB - Bone augmentation therapy is used in dental implantation. While techniques to induce bone formation are generally successful, the maintenance of bone mass is more difficult. Therefore, it is important to understand the mechanisms that regulate this process. Insulin-like growth factor-1 (IGF-1) is one of the most abundant growth factors that regulate bone mass, promote osteoblast differentiation, and accelerate bone formation. The activity of IGF-1 is regulated by IGF-binding proteins (IGFBPs). IGFBP-3 forms a ternary complex with IGF-1, extending its half-life in the circulating system. Therefore, IGFBP-3 acts as a stabilizer and transporter of IGF-1. Recent studies reported new IGF-1 independent functions of IGFBP-3 related with bone metabolism. In this study, we investigated the function of IGFBP-3 in osteoblast differentiation. Our results showed that IGFBP-3 decreases the expression of osteoblast differentiation markers, whose expression is enhanced by bone morphogenetic protein-2 (BMP-2). IGFBP-3 also reduced BMP-2 effect on ALP activity and mineral nodule formation. In addition, IGFBP-3 suppresses the activity of the Smad Binding Element (SBE) reporter, induced by BMP-2 signaling. These results suggest that IGFBP-3 inhibits osteoblast differentiation through the BMP-2 signal pathway, and that IGFBP-3 might play a role in bone mass maintenance in an IGF-1-dependent and -independent manner. PMID- 30454899 TI - Minocycline prevents peroxidative permeabilization of cardiolipin-containing bilayer lipid membranes mediated by cytochrome c. AB - Peroxidase activity of cytochrome c stimulated by interaction of the protein with cardiolipin is considered to be involved in the induction of mitochondrial apoptosis associated with cytochrome c release from mitochondria. In model systems, this activity has been previously shown to cause permeabilization of cardiolipin-containing membranes. Here, we found that the antibiotic minocycline, known to have neuroprotective properties, inhibited both the binding of cyt c to cardiolipin-containing membranes and the cyt c/H2O2-induced liposome permeabilization. The results could be relevant to inhibition of cyt c release from mitochondria exerted by minocycline. PMID- 30454900 TI - Rnf112 deletion protects brain against intracerebral hemorrhage (ICH) in mice by inhibiting TLR-4/NF-kappaB pathway. AB - Intracerebral hemorrhage (ICH) is reported as a common and often fatal type of stroke accompanied with high morbidity and mortality, and it frequently results in long-lasting neurological dysfunctions. However, the pathogenesis that contributes to ICH has not been fully understood. Rnf112, also known as Znf179, is a member of the RING finger protein family. The expression of Rnf112 is abundant in the brain and is modulated during brain progression and development. The study aimed to explore the role of Rnf112 in brain injury after ICH, as well as the underlying molecular mechanisms. The results indicated that ICH led to a significant decrease in Rnf112, which was confirmed in oxyhemoglobin (oxyHb) incubated astrocytes and microglial cells. Moreover, the Rnf112 knockout (Rnf112 /-) mice and wild type (WT) mice induced by ICH were further employed. Compared to the WT/ICH group, Rnf112-/- mice exhibited accelerated brain injury, as evidenced by the increased brain water contents and neurological deficit scores (NDS). In comparison to WT/ICH group, a remarkable up-regulation in the release of pro-inflammatory cytokines, including tumor necrotic factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, was observed in perihematoma tissues of Rnf112-/- mice on day 3 post-ICH. The process was along with promoted glial fibrillary acidic protein (GFAP) and Iba1 expression and reduced NeuN levels. Furthermore, ICH-induced increases in toll-like receptor (TLR)-4 and myeloid differentiation primary response protein (MyD88) expression were exacerbated by the loss of Rnf112. The phosphorylated expression of IKKalpha, inhibitor of NF kappaB (IkappaBalpha) and nuclear factor-kappa B (NF-kappaB) induced by ICH in perihematoma tissues of mice was markedly enhanced in Rnf112-/- mice. Rnf112 repression-induced inflammatory response was verified in lipopolysaccharide (LPS) incubated glial cells. In contrast, over-expressing Rnf112 markedly attenuated ICH-induced brain injury by restraining inflammation via inactivating TLR-4/NF kappaB pathway. In summary, our findings suggested that Rnf112 expression was highly involved in the progression of ICH, and targeting Rnf112 signaling might be a promising therapeutic strategy against ICH development. PMID- 30454901 TI - AURKA contributes to the progression of oral squamous cell carcinoma (OSCC) through modulating epithelial-to-mesenchymal transition (EMT) and apoptosis via the regulation of ROS. AB - Oral squamous cell carcinoma (OSCC) is known as one of the most common cancer influencing the head and neck region. However, the molecular mechanisms revealing OSCC progression is largely unclear. Aurora kinase A (AURKA) is a serine threonine kinase that functions in mitotic spindle formation and chromosome segregation, and is associated with the progression of human cancers. But its role in regulating OSCC development has not yet been investigated. In the study, we found that AURKA expression was up-regulated in OSCC cell lines and tumor specimens from patients. OSCC patients with high expression of AURKA exhibited a significant decreased overall survival rate. In vitro, AURKA knockdown markedly reduced the proliferation, migration and invasion of OSCC cells using cell counting kit-8 (CCK-8), EdU, colony formation and transwell analysis. EMT was suppressed by AURKA silence, as evidenced by the up-regulated expression of E cadherin and down-regulated Vimentin in OSCC cells. In addition, apoptosis was markedly induced by AURKA inhibition through promoting the expression of cleaved Caspase-3 and poly (ADP)-ribose polymerase (PARP). Reactive oxygen species (ROS) production was also markedly enhanced in AURKA-knockdown OSCC cells. Importantly, we found that repressing ROS generation using its scavenger of n-acetylcysteine (NAC) significantly abolished AURKA silence-induced apoptosis, accompanied with restored proliferation and EMT. In vivo, AURKA knockdown notably inhibited tumor growth. Therefore, knockdown of AURKA suppressed cell proliferation, migration and invasion, and also induced apoptosis and ROS generation in OSCC possibly via the production of ROS, demonstrating that AURKA inhibition might represent a novel therapeutic target for the prevention of OSCC. PMID- 30454902 TI - MFAP5 suppression inhibits migration/invasion, regulates cell cycle and induces apoptosis via promoting ROS production in cervical cancer. AB - Cervical cancer is one of the most lethal types of cancer among female. Microfibrillar-associated protein 5 (MFAP5) is an extracellular matrix (ECM) glycoprotein, and is confirmed to be involved in cell signaling during microfibril assembly, elastinogenesis and cell survival. However, the role of MFAP5 in cervical cancer development and progression remains poorly understood. In the study, MFAP5 was over-expressed in human cervical cancers, and in different cervical cancer cell lines. Patients suffering from cervical cancer with low MFAP5 expression exhibited better survival rate. Suppressing MFAP5 in cervical cancer cells markedly reduced the cell proliferation, migration and invasion by modulating epithelial-mesenchymal transition (EMT)-related signaling pathway. In addition, MFAP5 knockdown induced large number of cells distributed in G2/M phase, along with reduced Cyclin B1, Cyclin D1 and cyclin-dependent kinase 4 (CDK4) expressions, and enhanced p21 and p53 levels. Moreover, apoptosis was highly induced by MFAP5 silence through reducing Bcl-xl and Bcl-2 expressions, and promoting Bax, cleaved Caspase-3 and poly (ADP-Ribose) polymerase (PARP) expressions in cervical cancer cells. Reactive oxygen species (ROS) production levels were also higher in MFAP5-knockdown cells, along with Jun N-terminal kinase (JNK) activation. Importantly, we found that MFAP5 knockdown inhibited cervical cancer cell growth was dependent on ROS production. Finally, the depletion of MFAP5 prevented cervical cancer progression in vivo. In summary, our study identified a critical role played by MFAP5 in the progression of cervical cancer and the potential mechanisms by which exerted its effects, indicating that targeting MFAP5-related pathways could be conducive to the therapies for cervical cancer. PMID- 30454903 TI - Refractive outcomes of femtosecond laser-assisted secondary arcuate incisions in patients with residual refractive astigmatism after trifocal intraocular lens implantations. AB - PURPOSE: To evaluate the refractive and visual outcomes of arcuate incisions performed with the femtosecond laser in patients with a residual refractive astigmatism after refractive lens exchange (RLE) with trifocal intraocular lenses (IOLs). SETTING: EuroEyes Clinical Group, Hamburg, Germany. DESIGN: Retrospective interventional case series. METHODS: Pseudophakic patients with remaining refractive astigmatism after RLE with a trifocal IOL were treated with femtosecond laser-assisted corneal arcuate incisions. Patients who had a previous corneal treatment were excluded. Outcome measures were uncorrected (UDVA) and corrected distance visual acuities, manifest refraction, and a power vector analysis. RESULTS: The study enrolled 95 eyes of 70 patients. The mean follow-up was 5.6 months +/- 4.9 (SD). Constructing an astigmatic power vector (APV) with Jackson cross-cylinder axes at 180 degrees and 90 degrees and Jackson cross cylinder axes at 45 degrees and 135 degrees, the mean preoperative vector length was 0.46 +/- 0.16 diopter (D). The mean postoperative APV was 0.17 +/- 0.16 D. This difference was statistically significant (P < .001). The difference between the UDVA preoperatively (0.17 +/- 0.15) and postoperatively (0.08 +/- 0.10) was statistically significant (P < .001). No intraoperative or postoperative complications were observed. CONCLUSION: Femtosecond laser-assisted corneal arcuate incisions were safe, efficient, and feasible to reduce refractive astigmatism after trifocal IOL implantation. PMID- 30454904 TI - Severe CNS angiostrongyliasis in a young marine: a case report and literature review. AB - Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide. Infection typically occurs through ingestion of undercooked molluscs or vegetables contaminated by infective larvae. Endemic regions were previously limited to southeast Asia and the Pacific basin; however, this parasite is seeing an alarming increase in global distribution with reported cases in more than 30 countries, including several states in the USA. Although infection typically results in meningitis, a broad spectrum of CNS involvement and severity is emerging as diagnostic methods (such as real-time PCR) continue to improve diagnosis. In this Grand Round, we report a case of a 20-year-old active duty US marine serving in Okinawa, Japan, afflicted with severe CNS angiostrongyliasis marked by radiculomyelitis with quadriparesis, hyperaesthesia, and urinary retention. We present this case to highlight that no clear guidelines exist for the treatment of severe CNS angiostrongyliasis and provide our consensus recommendation that treatment algorithms include use of dual corticosteroids plus anthelmintics when radicular symptoms are present. In this Grand Round we review the clinical features, epidemiology, advances to diagnostic techniques, and available data on current treatment options for CNS angiostrongyliasis. This diagnosis should be highly considered in the differential diagnosis of a patient presenting with meningeal symptoms, paraesthesia or hyperaesthesia, and CSF eosinophilia so that treatment can be started early, which is particularly important in children, because of their increased risk of severe disease and mortality. We recommend combined therapy with albendazole and prednisolone, with consideration for increased steroid dosing in severe cases. PMID- 30454905 TI - Fetal membrane architecture, aging and inflammation in pregnancy and parturition. AB - Preterm birth is the single major cause of infant mortality. Short and long term outcomes for infants are often worse in cases of preterm premature rupture of the fetal membranes (pPROM). Thus, increased knowledge of the structure characteristics of fetal membranes as well as the mechanisms of membrane rupture are essential if we are to develop effective treatment strategies to prevent pPROM. In this review, we focus on the role of inflammation and senescence in fetal membrane biology. PMID- 30454906 TI - Non-Daily Cigarette Smokers: Mortality Risks in the U.S. AB - INTRODUCTION: Worldwide, an estimated 189 million adults smoke tobacco "occasionally" but not every day. Yet few studies have examined the health risks of non-daily smoking. METHODS: Data from the 1991, 1992, and 1995 U.S. National Health Interview Surveys, a nationally representative sample of 70,913 U.S. adults (aged 18-95 years) were pooled. Hazard ratios and 95% CIs for death through 2011 were estimated from Cox proportional hazards regression using age as the underlying time metric and stratified by 5-year birth cohorts in 2017. RESULTS: Non-daily smokers reported smoking a median of 15 days and 50 cigarettes per month in contrast to daily smokers who smoked a median of 600 cigarettes per month. Compared with never smokers, lifelong nondaily smokers who had never smoked daily had a 72% higher mortality risk (95% CI=1.36, 2.18): higher risks were observed for cancer, heart disease, and respiratory disease mortalities. Higher mortality risks were observed among lifelong non-daily smokers who reported 11-30 (hazard ratio=1.34, 95% CI=0.81, 2.20); 31-60 (hazard ratio=2.02, 95% CI=1.17, 3.29); and >60 cigarettes per month (hazard ratio=1.74, 95% CI=1.12, 2.72) than never smokers. Median life-expectancy was about 5 years shorter for lifelong non-daily smokers than never smokers. As expected, daily smokers had even higher mortality risks (hazard ratio=2.50, 95% CI=2.35, 2.66) and shorter survival (10 years less). CONCLUSIONS: Although the mortality risks of non-daily smokers are lower than daily smokers, they are still substantial. Policies should be specifically directed at this growing group of smokers. PMID- 30454907 TI - New estimates of blood flow rates in the vertebral artery of euarchontans and their implications for encephalic blood flow scaling: A response to Seymour and Snelling (2018). PMID- 30454908 TI - Spicing it up - synthetic cannabinoid receptor agonists and psychosis - a systematic review. AB - Synthetic cannabinoid receptor agonists (SCRAs) are suggested to have increased potential to induce psychosis compared to natural cannabis (NC). In this review we synthesise current knowledge about the association of SCRA use with psychotic symptoms. Following a literature search we identified 2 toxicology reports, 4 case-control studies, 3 cross-sectional studies and 15 case reports. In each of the case reports, we identified the presence or absence of symptoms based on the items of the Postitive and Negative Syndrome Scele (PANSS). The toxicology reports highlighted the main presenting features as being toxic psychosis and delirium (40%), agitation (10%) and hallucinations (4-7%). The median age was 25 years, and around 80% cases were male. Cross-sectional studies reported that SCRA use was present in approximately 10-13% patients presenting to acute psychiatric services, and was often the cause of their presentation, and that psychotic symptoms were present in 15% patients attending emergency departments following SCRA use. Case-control studies reported that SCRA use was significantly associated with psychotic symptoms and that SCRA users had higher levels of positive psychotic symptoms than NC users. The case reports supported the association of SCRA use with a wide range of positive and negative psychotic symptoms as well as with self-harm, agitation and aggressive behaviour. SCRA use is relatively prevalent in patients with psychosis and may lead to psychotic symptoms in individuals with no past psychiatric history. Further work is required to understand the long term risks of SCRA use and optimal management strategies. PMID- 30454909 TI - Childhood serotonergic function and early adult outcomes in youth with ADHD: A 15 year follow-up study. AB - Longitudinal studies have shown that clinical precursors of antisocial personality disorder (ASPD) include attention-deficit/hyperactivity disorder (ADHD) and more notably comorbid ADHD and conduct disorder (CD). Despite existing evidence for the purported role of abnormal serotonergic function in aggressive youth and adults, little evidence exists on the role of serotonin in the progression from childhood disruptive behavior disorders to adult psychopathology, including ASPD. This study examined the relation between serotonergic function in children diagnosed with ADHD and the development of ASPD in early adulthood. We hypothesized that low serotonin response to a pharmacological probe in childhood would predict the development of adult ASPD. Towards this goal we divided 40 adults (M = 37, F = 3), ages 23-26 (m-24.57, sd 2.33) diagnosed with childhood ADHD into 2 groups: participants with (n = 21) and without (n = 19) ASPD. We used logistic regression to assess whether serotonergic measures in childhood assessed via prolactin and cortisol responses to a fenfluramine challenge, would selectively predict the development of ASPD in early adulthood. Logistic regression models showed that low central serotonergic response in childhood indexed by cortisol response significantly predicted adult ASPD (Wald = 4.427, p = .035) but not ADHD diagnosis in adulthood. Adults without ASPD had the highest serotonergic response whereas adults with adolescent ASPD (i.e. early onset ASPD) had the lowest response. Thus we provide new evidence of the link between low serotonergic function in childhood and the development of ASPD in adulthood, particularly for boys with adolescent onset of ASPD. These findings are relevant for understanding the contribution of childhood neurobiology to risk for later ASPD. PMID- 30454910 TI - Survival and reoperation after valve-sparing root replacement and root repair in acute type A dissection. AB - OBJECTIVE: Optimal treatment of the dissected root in type A dissection is still controversial. Valve-sparing techniques offer the advantage of better valve performance compared with mechanical valves or bioprostheses. The role of the different valve-preserving methods-root repair and replacement-needs further evaluation. METHODS: Follow-up data (median follow-up, 11.4 years; 95% confidence interval [CI], 10.1-12.7; range, 0-22.1 years) of 179 patients with acute type A dissection and root involvement, who underwent a valve-sparing root replacement using reimplantation (n = 44) or remodeling (n = 39) or a valve-sparing root repair (n = 96) between 1993 and 2017 were analyzed with respect to survival and reoperation. RESULTS: Median age of patients with reimplantation was 56.9 (range, 20.2-78), with remodeling 62.6 (range, 31-79.1), and with valve-sparing root repair 64.5 (range, 31-89.6) years. Thirty-day mortality for these groups was 15.9%, 15.4%, and 12.5% (P = .829), late mortality at 15 years was 43.2% (95% CI, 28.1-66.5), 36.7% (95% CI, 19.7-68.1), and 36.5% (95% CI, 23.0-57.9; P = .504). Risk factors for overall mortality were age, connective tissue disease, total arch replacement, surgical time, cross-clamp time, circulatory arrest, and the reimplantation technique. Cumulative incidence of reoperation at 15 years was 13.4% (95% CI, 2.1-24.7), 20% (95% CI, 6.3-33.6), and 13.3% (95% CI, 4.8-21.7; P = .565), respectively. CONCLUSIONS: With the different conditions in each group in this study on patients with acute type A dissection the valve-preserving root repair technique has similar long-term rates of survival and reoperation compared with root replacement techniques, underlining its usefulness as a less complex and even faster surgical technique if individually indicated. PMID- 30454911 TI - The impact of postoperative therapy on primary cardiac sarcoma. AB - OBJECTIVE: Primary cardiac sarcomas (PCS) are extremely rare, portend a very poor prognosis, and have limited outcomes data to direct management. This study evaluated the impact of postoperative chemotherapy and/or radiotherapy on survival for PCS. METHODS: A retrospective chart review was conducted of 12 patients diagnosed with and who underwent resection for PCS at a single institution between 2000 and 2016. Data were collected on patient/tumor characteristics and analyzed with respect to treatment and outcome using Kaplan Meier methods. RESULTS: Median age was 43 (range 21-73 years) with a 50:50 male to-female ratio. The most common subtype was angiosarcoma (42%), and 25% presented with distant metastases (DMs). The initial treatment modality for all patients was surgery, with 58% having macroscopically positive (R2) margins. In total, 75% received postoperative chemotherapy and/or radiotherapy. Median progression-free survival (PFS) was 5.9 months, and median overall survival (OS) was 12.0 months. Achieving negative or microscopically positive margins (R0/R1) as compared with R2 resection significantly improved PFS (12.6 vs 2.7 months, P = .008) and OS (21.8 vs 7.2 months, P = .006). DM at presentation demonstrated a significantly shorter OS (7.0 vs 16.9 months, P = .04) and PFS (0.7 vs 7.9 months, P = .003) compared with localized disease. Patients given postoperative therapy had longer OS compared with surgery only, but this difference was not statistically significant (15.5 vs 2.6 months, P = .12). CONCLUSIONS: Gross total surgical resection can significantly improve PFS and OS in PCS, but DM at diagnosis is an extremely poor prognostic sign. Postoperative therapy should be considered, although this study was likely underpowered to demonstrate a statistically significant benefit. PMID- 30454912 TI - What is the role of beta-blockers in a contemporary treatment cohort of patients with acute coronary syndrome? A propensity-score matching analysis. AB - INTRODUCTION: The evidence for beta-blocker use in patients after acute coronary syndrome (ACS), particularly in those with left ventricular (LV) dysfunction, dates from the late 1990s. We aimed to assess the role of beta-blockers in a contemporary population of patients with ACS. METHODS: Propensity-score matching (1:2) was performed for the use of beta-blockers in a population of consecutive patients admitted to our department with ACS. After matching, 1520 patients were analyzed. Cox regression analysis was used to assess the impact of beta-blocker use on the primary outcome (one-year all-cause mortality). RESULTS: Patients who did not receive beta-blockers were less aggressively treated with other pharmacological and invasive interventions and had higher one-year mortality (20.3% vs. 7.5%). Beta-blocker use was an independent predictor of mortality, with a significant relative risk reduction of 56%. The other independent predictors were age, diabetes, LV dysfunction, heart rate, systolic blood pressure and creatinine on admission. The impact of beta-blockers was significant for all classes of LV function, including patients with normal or mildly reduced ejection fraction. CONCLUSIONS: In a contemporary ACS population, we confirmed the benefits of beta-blocker use after ACS, including in patients with normal or mildly to moderately impaired LV function. PMID- 30454913 TI - Neurocognitive profiles in adolescents and young adults with congenital heart disease. AB - INTRODUCTION AND OBJECTIVES: The objectives of this study were to assess the neuropsychological performance (NP) of adolescents and young adults with congenital heart disease (CHD), comparing them with a group of healthy controls, to determine whether there are different neurocognitive phenotypes in CHD, and to identify their relation to sociodemographic, neonatal, clinical and psychological adjustment variables. METHODS: A total of 217 CHD patients (116 male, aged 15.73+/-2.68 years) and 80 controls (35 male, age 16.76+/-2.22 years) underwent an extensive neuropsychological assessment and analysis of psychological adjustment. RESULTS: CHD patients had significantly poorer NP than healthy controls in all neurocognitive domains. Three different phenotypes of NP in CHD patients were identified: non-impaired (NI), moderately impaired (MI) and globally impaired (GI). They differed in all dimensions of NP. The GI cluster showed fewer years of schooling (p=0.025) and lower neonatal indicators such as head circumference (p=0.019), 1-min Apgar score (p=0.006), birth weight (p=0.05) and length (p=0.034) than the NI cluster. In the MI and GI clusters, there were more cyanotic forms of disease, including tetralogy of Fallot and transposition of the great arteries. The GI cluster presented more difficulties with psychological adjustment, including social (p=0.038), attention (p=0.001) and aggressive (p=0.003) problems. CONCLUSIONS: CHD patients have poorer NP than controls. NP in the CHD group can be classified in three clusters that reflect different levels of neuropsychological functioning, which is sensitive to social, neonatal and psychological adjustment variables. PMID- 30454914 TI - The Case Against the European Medicines Agency's Change to the Label for Radium 223 for the Treatment of Metastatic Castration-resistant Prostate Cancer. PMID- 30454916 TI - History of Pulmonary Tuberculosis. AB - Tuberculosis (TB) parallels the history of human development from the Stone Age to the present. TB continues to be in the top 10 causes of global human mortality over that period. This article highlights the history of pulmonary TB from the onset of human existence to the present. Despite its long history, TB was slowly identified as a major cause of disease, and defined causation and significant treatment strategies advances over the past 150 years. TB remains a major challenge for definitive global prevention and cure. This article gives a brief overview of the history of TB. PMID- 30454917 TI - Tuberculosis in Children. AB - Mycobacterium tuberculosis is the leading cause of death worldwide from a single bacterial pathogen. The World Health Organization estimates that annually 1 million children have tuberculosis (TB) disease and many more harbor a latent form. Accurate estimates are hindered by under-recognition and challenges in diagnosis. To date, an accurate diagnostic test to confirm TB in children does not exist. Treatment is lengthy but outcomes are generally favorable with timely initiation. With the End TB Strategy, there is an urgent need for improved diagnostics and treatment to prevent the unnecessary morbidity and mortality from TB in children. PMID- 30454918 TI - The Global Fight Against Tuberculosis. AB - An estimated 1.7 billion (23%) of the world's population is infected with Mycobacterium tuberculosis leading to more than 10 million new tuberculosis (TB) cases each year. TB is one of the top 10 causes of death globally and is the leading cause of death from a single infectious disease agent. The World Health Organization's ambitious End TB Strategy aims to achieve a 95% reduction in TB deaths and 90% reduction in TB incidence rates by 2035. PMID- 30454919 TI - Current Medical Management of Pulmonary Tuberculosis. AB - Tuberculosis (TB) remains a common cause of infection and disease in much of the world. The majority of disease occurs from reactivation months or years after initial infection and most often involves the lungs. Sputum smears for acid-fast bacilli remain the initial diagnostic test but have limited sensitivity and specificity. Nucleic acid amplification tests are more sensitive and specific and can detect some mutations that cause drug resistance. Treatment of TB resistant to rifamycins alone or in combination with isoniazid and other drugs remains difficult and should be done in consultation with an expert in treating drug resistant disease. PMID- 30454920 TI - Surgical Resection in the Treatment of Pulmonary Tuberculosis. AB - Surgery for tuberculosis is becoming more relevant today. This article discusses the main indications, contraindications, features of operations, and perioperative period. This information is useful for practicing surgeons and specialists in the treatment of pulmonary tuberculosis. PMID- 30454922 TI - Nontuberculous Mycobacteria: Epidemiology and the Impact on Pulmonary and Cardiac Disease. AB - This article reviews the current epidemiology of nontuberculous mycobacterial pulmonary disease and the impact on thoracic disease. The prevalence of nontuberculous pulmonary disease in the United States is much higher than that of Mycobacterium tuberculosis. Estimates support an annual increase in incidence of 8% per year. Nontuberculous mycobacteria are distinguished by 2 group designations, slowly growing mycobacteria, such as Mycobacterium avium complex, and rapidly growing mycobacteria, which includes Mycobacterium abscessus. Most pulmonary infections in humans are caused by species belonging to M avium complex. This article also reviews risk factors for disease acquisition, including host and environmental risk factors. PMID- 30454921 TI - Modern Collapse Therapy for Pulmonary Tuberculosis. AB - Multidrug-resistant tuberculosis (TB), extensively drug-resistant TB, and TB human immunodeficiency virus (HIV) coinfection require a special approach in anti TB treatment. Most patients cannot be successfully cured by conventional chemotherapy alone. They need a modern approach using minimally invasive therapeutic and surgical techniques. The novel approaches of collapse therapy techniques and minimally invasive osteoplastic thoracoplasty increase the effectiveness of complex anti-TB therapy. Achieving the required selective collapse of lung tissue in destructive pulmonary TB, especially in cases of drug resistance and/or HIV coinfection, leads to bacteriologic conversion, cavity closure, and successful cure. PMID- 30454923 TI - Medical Management of Pulmonary Nontuberculous Mycobacterial Disease. AB - Nontuberculous mycobacterial (NTM) lung infections are increasingly recognized as a cause of chronic pulmonary disease. This article focuses on the most common NTM species known to cause human lung disease and the treatment options currently available. The diagnosis of NTM lung disease is also discussed, emphasizing the necessity for treating clinicians to have sufficient familiarity of the mycobacteria laboratory to provide optimal patient management. PMID- 30454924 TI - Surgical Treatment of Pulmonary Nontuberculous Mycobacterial Infections. AB - Adjuvant surgical resection in the setting of pulmonary nontuberculous mycobacterial (NTM) infection removes focal parenchymal disease thought to serve as a poorly perfused "reservoir" for organisms, thus resistant to standard antimicrobial therapy. Removal of these areas of damaged lung is felt to enhance the effectiveness of the medical treatment. In general, these operations are associated with low morbidity and mortality, although resections that are more extensive carry higher risk. Many of the planned operations may be performed with minimally invasive techniques. More data are needed regarding long-term outcomes in these patients. PMID- 30454925 TI - Mycobacterial Musculoskeletal Infections. AB - Although less common as causes of musculoskeletal infection than pyogenic bacteria, both Mycobacterium tuberculosis and nontuberculous mycobacteria can infect bones and joints. Although tuberculous arthritis and osteomyelitis have been recognized for millennia, infections caused by nontuberculous mycobacteria are being identified more often, likely because of a more susceptible host population and improvements in diagnostic capabilities. Despite advances in modern medicine, mycobacterial infections of the musculoskeletal system remain particularly challenging to diagnose and manage. This article discusses clinical manifestations of musculoskeletal infections caused by Mycobacterium tuberculosis and nontuberculous mycobacteria. Pathogenesis, unique risk factors, and diagnostic and therapeutic approaches are reviewed. PMID- 30454926 TI - Nontuberculous Mycobacterial Infections in Cystic Fibrosis. AB - Nontuberculous mycobacteria (NTM) are important emerging cystic fibrosis (CF) pathogens, with estimates of prevalence ranging from 6% to 13%. Diagnosis of NTM disease in patients with CF is challenging, as the infection may remain indolent in some, without evidence of clinical consequence, whereas other patients suffer significant morbidity and mortality. Treatment requires prolonged periods of multiple drugs and varies depending on NTM species, resistance pattern, and extent of disease. The development of a disease-specific approach to the diagnosis and treatment of NTM infection in CF patients is a research priority, as a lifelong strategy is needed for this high-risk population. PMID- 30454927 TI - A Tale of Two Infections. PMID- 30454928 TI - [Reduction mammaplasties on irradiated breasts: A litterature review]. AB - INTRODUCTION: Breast reduction is a very common intervention in plastic surgery. Its benefit on the quality of life of patients is certain. With the increasing number of conservative surgeries for breast cancer, the potential number of breast reduction on the irradiated breast has increased. The antecedent of irradiation is an absolute contraindication for the majority of breast reduction teams. The objective of this review of the literature is to evaluate the characteristics of the patients, the modalities, the complications and the overall satisfaction of the patients operated on breast reductions on irradiated ground. METHOD: A review of the literature according to the recommendations was carried out. A total of 207 articles were found with the appropriate keywords (Mammoplasty Reduction, Reduction Mammaplasty, Breast reduction crossed with the terms radiotherapy, irradiation). After selection, 11 articles were selected and analyzed. RESULTS: 126 patients were included. The average age was 50 years, the average BMI was 29kg/m2. The majority of patients were non-smokers and non diabetics. The average resection weight was 507 grams. The average follow-up was 24.6 months. The delay between radiotherapy and surgery was 48 months. Five different surgical techniques were used. A complication rate of 50% is found. Overall satisfaction is good. CONCLUSION: This is the first review of the literature on breast reduction series on irradiated breasts. The results are inspiring and critical. Appropriate selection of patients seems essential. The publication of larger series and the description of a standardized technique would be interesting. PMID- 30454929 TI - Antibodies against PEGylated enzymes: Treat them with respect! PMID- 30454930 TI - Displaced medial end clavicular fractures treated with an inverted distal clavicle plate contoured through 90 degrees. AB - BACKGROUND: This study assessed whether treating medial end clavicular fractures using an inverted distal clavicle locking plate, twisted through 90 degrees around its axis, would allow for a less invasive surgical approach and improve screw trajectory insertion. MATERIALS AND METHODS: We searched the databases of the 2 senior authors for patients who had sustained an acute, displaced fracture of the medial end of the clavicle and had undergone operative fixation using an inverted distal clavicle plate contoured through 90 degrees . Through an inferior incision, a contoured locking plate was positioned on the anterior surface of the medial end of the clavicle. Up to 8 unicortical screws were inserted from anterior to posterior through the medial end of the plate. The lateral end was contoured and fixed to the superior clavicular surface. The patients were assessed preoperatively and at 1 month, 4 months, and final follow-up. Preoperative and postoperative plain x-ray images and computed tomography scans were reviewed. RESULTS: The study included 8 patients (average age, 31.3 years; range, 15-59 years) with displaced fractures who underwent fixation. The median follow-up time was 30.5 months (range, 24-45 months). All patients reached clinical and radiographic union at 4 months. The mean 11-item version of the Disabilities of the Arm, Shoulder, and Hand score was 0.6 (range, 0-2.3). All of the patients had returned to their preinjury level of sport and activity. None of the patients had a complication. CONCLUSION: Contouring an inverted distal clavicle plate through 90 degrees may improve fixation options by allowing access to the anterior clavicle when treating medial clavicular fractures. PMID- 30454931 TI - Improving running economy by transitioning to minimalist footwear? PMID- 30454933 TI - Symptomatic Uncomplicated Diverticular Disease: Chronic Abdominal Pain in Diverticulosis Is Not Enough to Make the Diagnosis. PMID- 30454934 TI - Reply. PMID- 30454935 TI - Screening for Celiac Disease in Canada. PMID- 30454937 TI - Reply. PMID- 30454936 TI - Clarifying the Houston Consensus on Helicobacter pylori. PMID- 30454938 TI - Reply. PMID- 30454939 TI - Reply. PMID- 30454940 TI - The Use of Post-ablation Stimulated Thyroglobulin in Predicting Clinical Outcomes in Differentiated Thyroid Carcinoma - What Cut-off Values Should We Use? AB - AIMS: Recently published international guidelines recommended using the stimulated thyroglobulin (sTg) post-radioactive iodine (RAI) ablation, in conjunction with tumour stage, as a risk stratification factor. The choice of cut off values for sTg, namely 1 and 10 ng/ml, was, however, largely based on the functional sensitivities of the assays used, with relatively few published data addressing the prognostic impact of alternative cut-off values. Our study aims to provide data on the prognostic value of sTg at different levels of sensitivities and specificities. MATERIALS AND METHODS: We conducted a retrospective review of all adult cases of differentiated thyroid carcinoma receiving RAI ablation at our centre from 2008 to 2010. All patients had sTg measured at around 6 months post ablation. The functional sensitivity of our assay was 0.5 ng/ml. The outcome was adverse clinical event, defined as cancer-related death, persistent macroscopic disease demonstrable on imaging (including radioisotope scan) and/or receiving further treatment for persistent or recurrent disease. A receiver operating characteristic (ROC) analysis was carried out. RESULTS: We identified 140 patients treated in the review period, with 106 of them suitable for further analysis. The reasons for exclusion included the presence of anti-thyroglobulin antibodies and medullary or anaplastic histological subtypes. Most (54.7%) had intermediate-risk disease as per the American Thyroid Association classification (2009). The median follow-up duration was 6.4 years; the minimum, excluding deaths, was 5.0 years. ROC analysis showed that the optimal cut-off value of sTg for predicting adverse clinical events was >1.0 ng/ml, associated with a sensitivity of 90.9%, a specificity of 81.0%, a positive predictive value of 55.6% and a negative predictive value of 97.1%. CONCLUSION: Based on ROC analysis of sensitivities and specificities, our data showed that a post-ablation sTg value of 1 ng/ml is the optimal cut-off in prognostication of adverse clinical events. PMID- 30454941 TI - Letter to the Editor. PMID- 30454942 TI - Pediatric surgery in Eastern Africa: The unmet need. AB - Pediatric age groups constitute more than 50% of the Sub-Saharan African, SSA, population. Very poor socioeconomic conditions and rare and advanced pathologies are the major health challenges of the region. Despite the overwhelming burden of diseases in the region, the health workforce and infrastructure are underdeveloped. The overall poverty, poor hygiene and sanitation, and widespread infectious disease with very limited infrastructures (road, health institutions) on top of lack of government commitment to improve the health of their people are some of the drawbacks that fail to address the unmet needs of pediatric health in SSA. Complications of surgical care have become a major cause of morbidity and mortality with significant implications for public health. These issues are magnified in developing countries, especially sub-Saharan Africa. The challenge is even more prominent in pediatric surgery, where the population is larger, and there is a shortage of specialists. In this lecture, I describe the difficulties faced from the East African and Ethiopian perspective as well as the role of colleges from high income countries to support SSA to address the unmet pediatric surgery needs. PMID- 30454943 TI - Influence Disease Activity on Voice and Laryngeal Findings of Rheumatoid Arthritis Patients. AB - OBJECTIVES: To reveal and to compare the voice pathologies and the detectable laryngeal findings in different phases of rheumatoid arthritis (RA). STUDY DESIGN: Prospective clinical study. METHODS: Sixty-seven consecutive patients with RA, followed up at our Physical Therapy and Rehabilitation Clinic, were included in the study. Disease activity indices of patients were calculated with Disease Activity Score-28 Index. With Voice Handicap Index (VHI), patients answered 30 questions of functional, physical, and emotional aspects. Videolaryngostroboscopy was performed by the same physician for all patients with a 70 degrees rigid telescope (Karl Storz, Tuttlingen, Germany), and then acoustic voice analysis (PRAAT program) was performed. Reflux Finding Score was used in evaluating the laryngopharyngeal reflux. RESULTS: Posterior comissure hypertrophy (25.3%) and hyperemia/edema in arytenoid mucosa (22.3%) were detected as the most frequent findings. Other common findings were thick endolaryngeal mucus, vocal cord varices. Twenty-two patients had reflux findings (32.8%). Fundamental frequency, shimmer, maximum phonation time and VHI value were not significantly different between active and remission phases of the disease (P > 0.05). In remission phase, the jitter value and the noise to harmonic ratio value were significantly higher (P < 0.05) than active phase of the disease (P < 0.05). Abnormal laryngeal findings are higher in active phase (28% in remission phase, 54% in active phase). The mean VHI score of patients in remission phase was lower than that in active phase. CONCLUSION: RA should be included in the differential diagnosis of patients with voice disorders. Nonspecific pathologies are more prevalent in the picture. There are more objective findings and subjective complaints of patients in active phase of the disease than in the remission phase. PMID- 30454944 TI - Dysphonia and Dysarthria in People With Parkinson's Disease After Subthalamic Nucleus Deep Brain Stimulation: Effect of Frequency Modulation. AB - PURPOSE: Subthalamic nucleus deep brain stimulation (STN-DBS) parameters, for example the frequency of stimulation, seem to affect speech and voice aspects. However, this influence is not well understood. This study aimed to investigate the impact of low- and high-frequency STN-DBS on voice and speech for people with Parkinson's disease. METHODS: Nineteen individuals with Parkinson's disease who received bilateral STN-DBS were assessed for motor performance (Unified Parkinson's Disease Rating Scale-III), perceptual evaluation of voice (grade, roughness, breathiness, asthenia, strain, and instability [GRBASI]), dysarthria assessment, and computerized acoustic analysis of voice upon receiving low frequency (60 Hz) and high-frequency (130 Hz) STN-DBS. RESULTS: In the GRBASI protocol, asthenia, and instability were significantly better at 130 Hz of stimulation. In the dysarthria evaluation, the phonation aspect, articulation, and grade of dysarthria showed deterioration at the same high-frequency condition. There was no significant difference for any vocal acoustic measures. CONCLUSION: The high-frequency of STN-DBS may affect speech and voice differently, leading to an amelioration of the vocal production, but with adverse effects in the speech control. PMID- 30454945 TI - Response: Are thyroid abnormalities only related to antipsychotic treatment in patients with severe mental disorders? PMID- 30454946 TI - Intradermal rabies post-exposure prophylaxis can be abridged with no measurable impact on clinical outcome in Cambodia, 2003-2014. AB - Rabies causes 60,000 deaths worldwide annually. Rabies post-exposure prophylaxis is highly effective but often geographically and financially beyond reach in endemic developing countries. We conducted a retrospective study on clinical outcome at >=6 months in 3318 Cambodians who received intradermal Vero cell vaccine post-exposure prophylaxis after a bite by a rabid or sick-looking but untested dog in 2003-2014. An external expert panel examined verbal autopsy reports to identify rabies deaths. 1739 (93.65%) persons bitten by rabid- and 1066 (72.96%) bitten by sick-looking but untested dogs were traced and 513 were lost to follow-up. Among the former, 1591 (91.49%) and 129 (7.42%) patients referred for 4+ and 3 post-exposure prophylaxis sessions, respectively. Three persons died of probable rabies so that the overall percentage of survival was 99.83% (95% exact confidence interval: 99.49-99.96%) in post-exposure prophylaxis recipients bitten by confirmed rabid dogs. No significant difference was found in survival among patients who received 3 vs. 4+ sessions (with or without rabies immunoglobin). The power of the study, however, was limited. The current four sessions/one month intradermal regimen can be reduced to a three sessions/one week at no detectable added risk to patients, with the limitation of study power at 49%. A clinical follow-up system should be adopted by rabies prevention centers, especially to monitor implementation of an abridged course. The Institut Pasteur in Cambodia regimen will improve vaccine equity by treating 33% more patients with available doses, reduce direct cost of vaccination, transportation and other indirect costs to vaccinees. PMID- 30454947 TI - Influenza vaccination: Uptake and associations in a cross-sectional study of children with special risk medical conditions. AB - OBJECTIVE: To determine uptake of influenza vaccination in children with special risk medical conditions (SRMC) and to explore associations with vaccination. DESIGN: Cross-sectional study. SETTING/PARTICIPANTS: Parents of children with a SRMC attending either outpatient department clinics or being an inpatient at the Women's and Children's Hospital (WCH), Adelaide, Australia from September 2015 to February 2016 were recruited using convenience sampling. METHODS: Data were collected using a face-to-face survey. Influenza vaccination was verified with providers. Characteristics associated with uptake were explored using univariable and multivariable analyses. RESULTS: There were 410 participants with complete data. Confirmed influenza vaccination at least once in the last two years was 50%, annual uptake was 32.8%. 63.9% of parents were aware of the vaccination recommendation and 57.9% had been recommended by a specialist or general practitioner (GP). Characteristics strongly associated with uptake included: receiving a recommendation from a specialist or GP and having a parent receive the influenza vaccine annually. CONCLUSIONS: Despite a long standing funded program, influenza vaccination uptake in children with SRMC is suboptimal. Parental vaccination behaviour, along with medical practitioner recommendation, particularly specialist recommendation, appear to be key influences in facilitating vaccination. Potential interventions could target the family rather than just the individual child. Understanding the barriers to recommendation from the perspective of general medical practitioners and specialists who treat these children is needed. PMID- 30454948 TI - Last cases of rubella and congenital rubella syndrome in Spain, 1997-2016: The success of a vaccination program. AB - With a highly immunized population, rubella infection in Spain is so low that the WHO has declared the elimination of rubella. Rubella in pregnant women is also very rare. The objective of this study is to describe the last cases of congenital rubella syndrome reported and recommend actions to maintain the status of the disease as eliminated. The CRS cases reported to the Spanish National Epidemiological Surveillance Network between 1997 and 2016 were studied, and the epidemiological, clinical, diagnostic and maternal characteristics of newborns with CRS described. The incidence of CRS was calculated using Birth Statistics from the Spanish National Statistics Agency (INE). Twenty-three cases of CRS were reported, 70% of which were associated with rubella outbreaks. The most common clinical conditions were heart disease (52.2%), deafness (39.1%) and cataracts (30.4%); 91.3% of cases were confirmed by laboratory testing. 70.0% were born from a non-vaccinated foreign mother, resident in Spain (cumulative rate incidence (CR): 1.1/100,000 births), with mothers coming from Africa (36.0%), Latin America (29.0%), Eastern Europe (21.0%) and Asia (14.0%). Six were born to Spanish mothers (CR: 0.08/ 100,000 births), the last of which were in 2005. The majority of CRS cases were born to unvaccinated immigrant women infected in Spain during rubella outbreaks. Universal vaccination in childhood is the most efficient strategy to prevent rubella. The limited circulation of the virus will, however, quickly lead to a loss of awareness about rubella among clinicians and epidemiologists. It is necessary to maintain protocols capable of identifying signs consistent with rubella in pregnant women and signs suggestive of congenital rubella in newborns. PMID- 30454949 TI - Nonfragile Hinfinity control for periodic stochastic systems with probabilistic measurement. AB - This paper addresses the problem of nonfragile Hinfinity control for periodic stochastic systems with probabilistic measurement. A novel Lyapunov-Krasovskii functional is formulated, which makes full use of both delay and its change rate. In view of the measurement signal, the mode-dependent stochastic variables are employed and new sufficient conditions are achieved. Finally, two numerical examples are worked out to demonstrate the effectiveness of the proposed control design. PMID- 30454950 TI - Incorporating delayed measurements in an improved high-degree cubature Kalman filter for the nonlinear state estimation of chemical processes. AB - The on-line estimation of process quality variables has a large impact on the advanced monitoring and control techniques of chemical processes. The present study offers an improved high-degree cubature Kalman filter (HCKF) to solve the nonlinear state estimation problem of high-dimensional chemical processes. We substituted the Cholesky decomposition in the HCKF filter with a diagonalization transformation of the matrix. In addition, we enhanced numerical stability and estimation accuracy. On this basis, we present one nonlinear state estimation method based on the sample-state augmentation and improved HCKF to handle issues with delayed measurements. Finally, we used the nonlinear state estimation experiments for the polymerization process to validate the proposed method. The numerical results indicated the achievement of state estimation with higher accuracy and better stability following the effective utilization of the delayed measurements for nonlinear chemical processes. PMID- 30454951 TI - The Impact of Ultrasound Probe Tilt on Muscle Thickness and Echo-Intensity: A Cross-Sectional Study. AB - INTRODUCTION/BACKGROUND: To determine the influence of ultrasound probe tilt on reliability and overall changes in muscle thickness and echo-intensity. MATERIALS AND METHODS: Thirty-six individuals had a total of 15 images taken on both the biceps brachii and tibialis anterior muscles. These images were taken in 2 degrees increments with the probe tilted either upward (U) or downward (D) from perpendicular (0 degrees ) to the muscle (U6 degrees , U4 degrees , U2 degrees , 0 degrees , D2 degrees , D4 degrees , and D6 degrees ). All images were then saved, stored, and analyzed using Image-J software for echo-intensity and muscle thickness measures. Mean values (2-3 measurements within each probe angle) were compared across each probe angle, and reliability was assessed as if the first measure was taken perpendicular to the muscle, but the second measure was taken with the probe tilted to a different angle (to assume unintentional adjustments in reliability from probe tilt). RESULTS: Tilting the probe as little as 2 degrees produced a significant 4.7%, and 10.5% decrease in echo-intensity of the tibialis anterior and biceps brachii muscles, respectively, while changes in muscle thickness were negligible (<1%) at all probe angles. The reliability for muscle thickness was greater than that of echo-intensity when the probe was held perpendicular at both measurements (~1% vs 3%), and the impact that probe tilt had on reliability was exacerbated for echo-intensity measurements (max coefficient of variation: 24.5%) compared to muscle thickness (max coefficient of variation: 1.5%). CONCLUSION: While muscle thickness is less sensitive to ultrasound probe tilt, caution should be taken to ensure minimal probe tilt is present when taking echo-intensity measurements as this will alter mean values and reduce reliability. Echo-intensity values should be interpreted cautiously, particularly when comparing values across technicians/studies where greater alterations in probe tilt is likely. PMID- 30454952 TI - Same-Day Vs Consecutive-Day Precision Error of Dual-Energy X-Ray Absorptiometry for Interpreting Body Composition Change in Resistance-Trained Athletes. AB - The application of dual-energy X-ray absorptiometry (DXA) in sport science settings is gaining popularity due to its ability to assess body composition. The International Society for Clinical Densitometry (ISCD) recommends application of the least significant change (LSC) to interpret meaningful and true change. This is calculated from same-day consecutive scans, thus accounting for technical error. However, this approach does not capture biological variation, which is pertinent when interpreting longitudinal measurements, and could be captured from consecutive-day scans. The aims of this study were to investigate the impact short-term biological variation has on LSC measures, and establish if there is a difference in precision based on gender in a resistance-trained population. Twenty-one resistance-trained athletes (age: 30.6 +/- 8.2 yr; stature: 174.2 +/- 7.2 cm; mass: 74.3 +/- 11.6 kg) with at least 12 mo consistent resistance training experience, underwent 2 consecutive DXA scans on 1 d of testing, and a third scan the day before or after. ISCD-recommended techniques were used to calculate same-day and consecutive-day precision error and LSC values. There was high association between whole body (R2 = 0.98-1.00) and regional measures (R2 = 0.95-0.99) for same-day (R2 = 0.98-1.00), and consecutive-day (R2 = 0.95-0.98) measurements. The consecutive-day precision error, in comparison to same-day precision error, was significantly different (p < 0.05), and almost twice as large for fat mass (1261 g vs 660 g), and over 3 times as large for lean mass (2083 g vs 617 g), yet still remained within the ISCD minimum acceptable limits for DXA precision error. No whole body differences in precision error were observed based on gender. When tracking changes in body composition, the use of precision error and LSC values calculated from consecutive-day analysis is advocated, given this takes into account both technical error and biological variation, thus providing a more accurate indication of true and meaningful change. PMID- 30454953 TI - Avian leukosis virus subgroup - J as a contaminant in live commercially available poultry vaccines distributed in Nigeria. AB - Globally, vaccines are used to prevent and control the menace of infectious diseases in livestock with some reported to be inadvertently contaminated with extraneous agents (EAs). With the aim of screening and characterizing for some selected EAs, 44 live viral poultry vaccines were randomly selected based on availability. The vaccines comprised 14 manufacturers in 10 different countries including Nigeria were screened by Polymerase Chain Reaction. In 9% (4/44) of the vaccines, contamination with only avian leukosis virus (ALV) subgroup J (ALV-J) was recorded. Other exogenous ALV subgroups, chicken infectious anemia and infectious laryngotracheitis viruses were absent. The EAs was found in infectious bursal disease (n = 1), Fowlpox (n = 2) and Mareks disease (n = 1) vaccines. Phylogenetic analysis of the ALV-J env gene showed clustering with contemporary group I and II. The result underscores the importance of screening vaccines to avoid the introduction and spread of EAs that could pose a threat to poultry production. PMID- 30454954 TI - CRISPR/Cas9 and p53: An Odd Couple Requiring Relationship Management. PMID- 30454956 TI - Equitable Access to Gene Therapy: A Call to Action for the American Society of Gene and Cell Therapy. PMID- 30454955 TI - Gene Silencing in the Right Place at the Right Time. PMID- 30454957 TI - Association between affective disorders presenting before and during pregnancy and pre-term birth, considering socio-demographic factors, obstetric factors, health conditions, and use of medication. AB - OBJECTIVE: To study the relationship between maternal affective disorders (AD) before and during pregnancy, and pre-term birth. DESIGN: Retrospective observational study. LOCATION: Sexual and reproductive health units at the Institut Catala de la Salut (ICS) in Catalonia, Spain. PARTICIPANTS: Pregnant women with a result of live-born child from 1/1/2012 to 30/10/2015. INTERVENTIONS: Data were obtained from the ICS Primary Care electronic medical record. MAIN MEASUREMENTS: Diagnosis of AD before and during pregnancy, months of pregnancy, and possible confusion factors were collected. Descriptive statistical analysis (median, interquartile range, and absolute and relative frequency), bivariate analysis (Wilcoxon test and Chi-square test), and multivariate analysis (logistic regression) were performed. RESULTS: 102,086 women presented valid information for the study. Prevalence of AD during pregnancy was 3.5% (4.29% in pre-term and 3.46% in term births; p<0.004). Pregnant women with pre-term births presented a higher age, smoking habit, lower inter-pregnancy interval, and a lower socio-economic status. Pre-term birth was significantly associated to previous history of stress and dissociative disorder (SDD), anxiety, obsessive compulsive disorder (OCD) and eating disorders (ED), and use of antidepressants. It was also associated to abuse of alcohol, smoking, and use of psychoactive substances, as well as SDD, ED, use of antipsychotics, and divorce during pregnancy. Multivariate analysis confirmed the relationship between pre-term birth and history of AD, SDD, ED, and smoking, but not with AD during pregnancy. CONCLUSIONS: Examining the previous history of SDD and ED in pregnant women, and SDD, and ED during pregnancy is highly relevant to avoid pre-term birth. PMID- 30454958 TI - [Prevalence and characteristics of chronic obstructive pulmonary disease in non smokers]. AB - OBJECTIVE: The objective of the study was to know the profile of patients diagnosed with chronic obstructive pulmonary disease (COPD) and who have never been smokers. DESIGN: A transversal study. LOCATION: Primary Care Centre of Pla d'Urgell (Primary care setting in Lleida, Spain). PARTICIPANTS: 512 patients older than 40 years with COPD from Primary Care Centre of Pla d'Urgell with a compatible spirometry [forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio <0.7) to the beginning of the study. MAIN MEASUREMENTS: The dependent variable was de COPD in non-smokers and the independents were variables collected from the information on the respiratory clinical history, the risk factors of the patients and on quality of life. We designed a predictor model of COPD in non-smokers compared to smokers. RESULTS: 33.2% of COPD patients had never been smokers, 59.4% of whom were women. The average FEV1 for non-smokers was 70.5 (SD=17.1), higher than 62.6 (SD=18.5) for smokers/former smokers (p<0.001). The coverage of pneumococcal vaccination 23V was better in non-smokers (75.3%), p<0.001. COPD in non-smokers (compared to smokers/former smokers) were: mostly women (OR=16.46), older (OR=1.1), with better FEV1 (OR=1.1), better perception of quality, EuroQoL-5D (OR=0.8), with lower prevalence of diabetes (OR=0.5), lower level of studies (OR=0.2), and with fewer previous hospitalizations (OR=0.3). CONCLUSIONS: The study evidences a high proportion of non-smokers in COPD patients. Our study aims that older women with less severity would be associated with an increased risk of COPD in non-smokers. It seems to indicate that COPD in non-smokers would appear at later ages and would be milder than smoking-related COPD. PMID- 30454959 TI - [Epigenetics in age-related macular degeneration (AMD) - French translation of the article]. AB - Age-related macular degeneration (AMD) is a complex multifactorial condition involving multiple genetic, environmental and constitutional factors. Inflammation, oxidative stress and lipid metabolism seem to be the most important factors in the pathogenesis of the disease. The importance of genetic factors has mainly been revealed with the influence of histocompatibility complement factor H (CFH) variations and the ARSM2 susceptibility gene. Another component, epigenetics, could help to explain some of the relationships between environmental and genetic factors. Epigenetics is defined as the study of modulations of gene activity that can be transmitted over cell divisions without involving mutation of the DNA sequence. The molecules that are involved in these mechanisms are referred to as the epigenome. The mechanisms involve DNA methylation, histone modification, chromatin remodeling, and gene inhibition by non-coding RNA. Epigenetics could explain how the environment may induce relatively stable changes in traits or even diseases, possibly inheritable over several generations. Epigenetic traits established during development, and/or acquired under the influence of nutritional factors or other environmental factors, could influence the interactions between genes and the environment. Several authors have recently shown the influence of epigenetic factors in the pathogenesis of ocular diseases such as cataract, dry eye, glaucoma, diabetic retinopathy and more recently AMD. A better understanding of the involvement of genetic variants at risk, their relationship with epigenetics and environmental factors would certainly help to better assess the risk of developing AMD or better understand recent changes in the incidence of the disease. PMID- 30454960 TI - [Femtosecond laser-assisted cataract surgery in an eye with a phakic IOL and keratotomy]. PMID- 30454961 TI - Oxygen saturation targeting in extremely preterm infants-more progress needed. PMID- 30454962 TI - Patterns of Pain in Adolescents with Slipped Capital Femoral Epiphysis. AB - OBJECTIVE: To prospectively characterize pain locations in slipped capital femoral epiphysis (SCFE) and evaluate pain locations as predictors of a delay in diagnosis. STUDY DESIGN: This was an institutional review board approved prospective study of 110 children who underwent surgery for SCFE at a tertiary children's hospital between 2009 and 2015. Standardized pain diagrams were completed by 107 children. Pain zones were designated via a composite diagram. Hips without hip pain were categorized as atypical; hips with hip pain were typical. RESULTS: In total, 122 hips were eligible for pain zone analysis. Seventy hips (57.4%) had hip pain. Atypical pain was present in 52 hips (42.6%), which included groin pain in 17 hips (13.9%), thigh/leg pain in 43 (35.2%), knee pain in 32 (26.2%), and posterolateral pain of the hip and leg in 13 (10.7%). A combination of pain zones was present in 48 hips (39.3%). Forty-nine percent of patients had more than 1 visit until diagnosis. The three most common pain locations for typical hips were hip, hip/thigh, and hip/knee pain (77.2% of typical hips). The 3 most common pain locations for atypical hips were isolated thigh, knee, and groin (65.4% of atypical hips). The least common pain presentations had a longer duration of symptoms (P = .04) and more healthcare visits before diagnosis (P = .04). CONCLUSIONS: A combination of pain locations is common in SCFE. Less frequent pain presentations may delay diagnosis. Delays in diagnosis continue despite education efforts. PMID- 30454963 TI - Parental Cannabis Use Is Associated with Cannabis Initiation and Use in Offspring. AB - OBJECTIVES: To assess, before legalization in Canada, whether parental cannabis use is associated with initiation of use in adolescent offspring or with use in young-adult offspring. STUDY DESIGN: Data were available in 2 longitudinal studies in Montreal, Canada. In AdoQuest, 1048 parents with children in grade 6 reported past-year cannabis use. Cannabis initiation among offspring was measured in grade 7, 9, and/or 11. In the Nicotine Dependence in Teens study, cannabis use data were available for 584 participants (mean age 24 years) and their parents (ie, 542 offspring-mother pairs, 438 offspring-father pairs). The association between parental and offspring cannabis use was estimated using multivariable logistic regression in both studies. RESULTS: In AdoQuest, grade 6 never-users were 1.8 times more likely to initiate cannabis during high school if their parents reported past-year use. In the Nicotine Dependence in Teens study, the aORs (95% CI) for past-year cannabis use among adult offspring were not different for "mother uses cannabis" (2.8 [1.4-5.8]) or "father uses cannabis" (2.1 [1.2 3.8]). Participants with 1 or 2 cannabis-using parents were 1.7 and 7.1 times more likely to use cannabis, respectively, than participants with non-using parents. CONCLUSIONS: To enable informed decision-making about their own cannabis use, parents need to be aware that children of cannabis users are more likely to use cannabis in adolescence and young adulthood. PMID- 30454964 TI - Circulating microvesicles are less procoagulant and carry different miRNA cargo in myelodysplasia. AB - BACKGROUND AND AIMS: Myelodysplasia (MDS) is characterised by abnormal haematopoiesis and increased risk of bleeding. Microvesicles (MV) play a key role in coagulation and their impact in MDS is unknown. METHODS: Platelet free plasma from 35 red-cell transfusion-dependent MDS patients and 15 controls were analysed. Pro-coagulant function was assessed by the XaCT assay and by thrombin generation (ETP). Total MV were enumerated by nano-tracking analysis. MV subsets were quantified by flow cytometry after staining with specific antibodies for various endovascular cell types. Small RNA was quantitated and sequenced. The MV measurements were correlated with MDS clinical risk scores and level of transfusion dependence. RESULTS: The pro-coagulant function of MV was significantly lower in MDS. All the MV subtypes, as measured by flow cytometric markers, were also significantly lower. The small RNA and miRNA cargo were significantly higher in MDS. The miRNA profile showed that mir-28 and mir-LETD7 were under expressed whilst mir-584J and mir-4485 were over expressed in MV from MDS. CONCLUSIONS: Circulating MV in MDS show reduced pro-coagulant functional activity, reduced subtypes by flow cytometry and significantly different miRNA content. However, the levels or subtypes of MV did not predict the clinical phenotype or level of transfusion dependence. PMID- 30454965 TI - TET2 rs2454206, TET2 rs12498609 and ASXL1 rs3746609 single nucleotide polymorphisms in patients with myelodysplastic syndromes. AB - To study the association between TET2rs2454206, TET2rs12498609 and ASXL1rs3746609 and Myelodysplastic syndromes (MDS), a total of 90 MDS patients and 143 healthy volunteers were included. The clinical data, bone marrow samples of patients and peripheral blood samples of volunteers were obtained. We found TET2rs2454206 G/A genotype, TET2rs12498609 G/C genotype and ASXL1rs3746609 A/G genotype in 13.3%, 11.1%, 10.1% MDS patients and in 42.7%, 22.4%, 23.8% healthy volunteers (P < 0.001; P = 0.029; P = 0.009, respectively). TET2 rs2454206 G/A genotype was associated with higher serum LDH level in MDS (P = 0.025). Patients with TET2rs12498609 G/C genotype were characterized with higher frequency of mutated SRSF2 gene (P = 0.042) and lower occurrence rate of anemia (P = 0.026) than those with C/C genotype. ASXL1rs3746609 A/G genotype linked with higher thrombocyte counts (P = 0.02) and percent of total T lymphocyte (P = 0.029), whereas with lower percent of NK cell (P = 0.032) and B lymphocyte (P = 0.007). None of these three SNPs had impact on the overall survival and disease progression to AML. We concluded that People with TET rs2454206 G/A genotype, TET2rs12498609 G/C genotype or ASXL1rs3746609 A/G genotype were related to lower prevalence of MDS. All of the three SNPs were associated with certain laboratory features in MDS patients. PMID- 30454966 TI - Skin antisepsis in invasive procedures. AB - Skin antisepsis in invasive procedures aims to reduce the bacterial load at the site of incision or puncture. Alcohol solutions seem to be more effective in preventing surgical site infection. From the safety point of view there is the potential risk of ignition when using alcohol solutions. Given the potential neurotoxicity of alcohol and chlorhexidine gluconate, contact of antiseptic solutions with the central nervous system should be avoided. PMID- 30454967 TI - Cholesterol Lowering Guidelines: From Whence We Came and Where We Are Now. AB - Treatment guidelines have proliferated in cardiology, although most guideline recommendations are not supported by clinical trial evidence. What is considered to be a normal cholesterol level has progressively declined over the past 50 years, with the increasing realization that "normal" is far from optimal and that lower is better. The first important United States and Canadian cholesterol guidelines were published in 1988, and recommended diet for 6 months to be followed by consideration of bile acid sequestrants or nicotinic acid. Over the ensuing 25 years guidelines have changed rapidly and dramatically in response to a large number of definitive clinical trials, usually with statins. Low-density lipoprotein cholesterol targets have moved progressively lower, and in some guidelines, have been abandoned entirely. The concept of selecting patients for treatment according to the absolute risk reduction expected from treatment on the basis of clinical trial data seems to be a rational approach. For secondary prevention, some patients are still untreated or undertreated, presenting an opportunity for improving outcomes. PMID- 30454968 TI - A Territory-wide, Multicenter, Age- and Prostate-specific Antigen-matched Study Comparing Chemohormonal Therapy and Hormonal Therapy Alone in Chinese Men With Metastatic Hormone-sensitive Prostate Cancer. AB - BACKGROUND: There is a lack of real-world data regarding the treatment outcomes of chemohormonal therapy versus hormonal therapy alone in Chinese men with metastatic hormone-sensitive prostate cancer. PATIENTS AND METHODS: We conducted a territory-wide, multicenter, age- and prostate-specific antigen (PSA)-matched cohort study comparing chemohormonal therapy and hormonal therapy alone in Chinese men with metastatic hormone-sensitive prostate cancer. Patient and disease characteristics were reviewed. The primary outcome was PSA progression free survival. Secondary outcomes included clinical progression-free survival and castration resistance-free survival. Kaplan-Meier and multivariate Cox regression analyses were performed. RESULTS: From January 2015 to July 2016, 32 Chinese men with metastatic hormone-sensitive prostate cancer were treated with chemohormonal therapy, and they were matched to 32 Chinese men who were treated with hormonal therapy alone. Patient and disease characteristics were similar between the 2 groups. The chemohormonal therapy group had a significantly better PSA progression-free survival (P = .001) and castration resistance-free survival (P = .002) than the hormonal therapy group. There was no significant difference in the clinical progression-free survival between the 2 groups. Upon multivariate Cox regression analyses, the use of chemohormonal therapy was significantly associated with a longer time to PSA progression (hazard ratio, 0.31; 95% confidence interval, 0.31-0.73; P = .008) and a longer time to castration resistance (hazard ratio, 0.38; 95% confidence interval, 0.17-0.83; P = .015), but was not associated with clinical progression. CONCLUSIONS: The use of chemohormonal therapy could prevent PSA progression and the development of castration resistance when compared with hormonal therapy alone in Chinese men with metastatic hormone-sensitive prostatic cancer. PMID- 30454969 TI - Incidental Detection of Metastatic Penile Squamous-Cell Carcinoma With Anti-1 Amino-3-F-18-Fluorocyclobutane-1-Carboxylic Acid (18F-Fluciclovine) PET/CT in a Patient With Recurrent Prostate Cancer. PMID- 30454970 TI - Unravelling Adrenal Oncocytic Neoplasm. AB - Oncocytic neoplasms are rare tumors arising in the adrenal glands and usually considered as nonfunctional and benign. We report 4 cases of adrenal oncocytic neoplasm. The paucity of literature describing this entity increases the chance for misdiagnosis. Confirmatory diagnosis is by tissue sampling with adrenalectomy as the mainstay of treatment. PMID- 30454971 TI - Stromal characteristics are adequate prognosticators for recurrence risk in ductal carcinoma in situ of the breast. AB - BACKGROUND: Ductal carcinoma in situ (DCIS) of the breast constitutes a heterogeneous group of non-obligate precursors for invasive breast cancer. To date, adequate risk stratification is lacking, which is presumed to result in overtreatment. We previously identified myxoid stromal architecture as a potential prognosticator for loco-regional recurrence. In the present study, we investigated the prognostic potential of stromal characteristics. METHODS: Hematoxylin and eosin stained slides from 211 DCIS patients were reviewed. The following histological features were dichotomously assessed: nuclear grade, DCIS architecture, presence of necrosis, intraductal calcifications, stromal inflammation and myxoid stromal architecture. Loco-regional recurrences constituted the primary endpoint. RESULTS: Cox regression analysis showed that high nuclear grade, myxoid stromal architecture and moderate to extensive stromal inflammation were significantly associated with decreased recurrence-free survival, independent of radiotherapy. Based on these features, a combined risk score (CRS) was calculated, ranging from zero to three. A high CRS of three was associated with significantly shorter recurrence-free survival. Nineteen patients had a CRS of three, of which three relapsed (15.7%), whereas only one out of 113 patients with a CRS of zero relapsed (0.9%). CONCLUSIONS: We were able to validate our previously reported findings regarding the prognostic potential of myxoid periductal stroma in an independent DCIS patient cohort. A CRS based on nuclear grade, myxoid stromal architecture and stromal inflammation might facilitate discrimination of low risk from high risk patients. Consequently, the CRS may tailor adjuvant therapy. Future research should investigate whether radiotherapy can be safely omitted in patients with a low CRS. PMID- 30454972 TI - Postoperative myxedema coma in patients undergoing major surgery: Case series. AB - OBJECTIVE: Myxedema coma is a serious complication of hypothyroidism that can be precipitated by major surgery. It is extremely rare, with only a few reports in the literature. This study aims to present a relatively large case series of post surgical myxedema coma and to analyze medical and surgical risk factors. METHODS: Analysis of the patients' surgical records and medical charts. RESULTS: Four patients developed postoperative myxedema coma and were evaluated for risk factors. Three had known hypothyroidism. Two had undergone large head and neck composite resections necessitating a free flap repair for malignant disease. One had undergone coronary artery bypass graft for ischemic heart disease, and another had undergone endoscopic cholecystectomy for complicated cholecystitis. All four patients required prolonged hospitalization, including treatment in the intensive care unit. One patient had undergone full cardiopulmonary resuscitation directly related to the myxedema coma state. CONCLUSION: We present a series of four patients who developed myxedema coma following major surgery. We recommend that patients with known hypothyroidism who are scheduled for major surgery should be tested for thyroid function status and assessed for postoperative risk of hypothyroidism. Those who develop complications following major surgery, should be immediately tested for thyroid function to rule out myxedema coma. PMID- 30454973 TI - MiR-196b affects the progression and prognosis of human LSCC through targeting PCDH-17. AB - OBJECTIVE: To explore the effect of miR-196bon the biological features of human laryngeal squamous cell carcinoma (LSCC) through targeting PCDH-17. METHODS: miR 196b and PCDH-17 expressions were determined in tissues, and the targeting relation of miR-196b and PCDH-17 was verified through dual-luciferase reporter system. In vitro, Hep-2 cells were divided into the Control, miR-196b inhibitors, miR-NC, PCDH-17, and miR-196b mimics+PCDH-17 groups. The miR-196b and PCDH-17 expressions were determined by qRT-PCR or/and Western blot, and the biological features by MTT, Annexin V-FITC/PI, wound-healing and Transwell assays. RESULTS: MiR-196b was found to be up-regulated, while PCDH-17 was down-regulated in a negative correlation in LSCC patients, which was related to histological grade and TNM stage. And low expression of miR-196b and high expression of PCDH-17 contributed to an increase in the 5-year-survival rate of LSCC patients. Besides, miR-196b directly targeted PCDH-17, while miR-196b inhibitors could up-regulate the PCDH-17 in Hep-2 cells. Moreover, miR-196b inhibitors and PCDH-17 curbed Hep 2 cell proliferation but facilitated the apoptosis, with decreases in cell invasion and migration. In addition, no statistical significance was found in cell proliferation, apoptosis, invasion and migration between Control group and miR-196b mimics+PCDH-17 group. CONCLUSION: LSCC patients exhibited the up regulated miR-196b and down-regulated PCDH-17, which are correlated with the major clinical features and prognosis. Inhibiting miR-196b may suppress proliferation, migration and invasion abilities, and promote apoptosis of Hep-2 cells via targeting PCDH-17. PMID- 30454975 TI - A delicate balance: Bleeding versus thrombosis? PMID- 30454974 TI - Outcomes of Roux-en-Y gastric bypass versus sleeve gastrectomy in super-super obese patients (BMI >=60 kg/m2): 6-year follow-up at a single university. AB - BACKGROUND: Among the population of morbidly obese people, super-super-obese (SSO) individuals (body mass index >60 kg/m2) present a treatment challenge for bariatric surgeons. OBJECTIVES: To compare the long-term outcomes between laparoscopic sleeve gastrectomy (SG) and laparoscopic Roux-en-Y gastric bypass (RYGB) and to evaluate the efficacy of SG as a stand-alone bariatric procedure for SSO patients. SETTING: University hospital, Paris, France. METHODS: We retrospectively reviewed the data outcomes of 210 SSO patients who underwent SG or RYGB between January 2000 and December 2011. The 6-year follow-up data were analyzed and compared. RESULTS: Follow-up data at 6 years were collected for 57.1% and 52.1% of patients in the SG group and RYGB groups, respectively. Both procedures were effective at promoting weight loss. Most weight loss was achieved at 24 months with both procedures. The average percent excess weight loss and change in body mass index of SG versus RYGB showed no significant differences at the 4-year follow-up. Except for sleep apnea, RYGB showed slightly better resolution of the evaluated co-morbidities. The composite endpoint of major short term adverse events (<30 d) occurred in 11.7% of patients with RYGB and 6.4% of those with SG (P = .02). Postoperative complications were seen in 26% of RYGB patients and 16.1% of SG patients. CONCLUSIONS: SG as a primary procedure for SSO patients remains effective even though RYGB achieves better midterm outcomes. SG can be proposed as the primary-option p+rocedure. Further investigations are needed to identify the ideal procedure for patients with symptoms of gastroesophageal reflux disease. PMID- 30454976 TI - A thorough understanding of the mitral apparatus will improve the results of mitral valve repair: Part 2. PMID- 30454978 TI - Discussion. PMID- 30454977 TI - No plan is perfect: It's about making choices. PMID- 30454979 TI - How (and why) to make it mini. PMID- 30454980 TI - Observed to expected 30-day mortality as a benchmark for transcatheter aortic valve replacement. AB - OBJECTIVE: The observed-to-expected 30-day mortality ratio (O:E ratio) is a standard metric by which transcatheter aortic valve replacement (TAVR) trials have been evaluated. Early TAVR trials consistently demonstrated O:E ratio less than 0.6 after TAVR when based on the Society for Thoracic Surgery Predicted Risk of Mortality (STS-PROM) for surgical aortic valve replacement. Recent published results from the Transcatheter Valve Therapy (TVT) Registry have demonstrated O:E ratios of 1.0. We evaluated our own O:E ratios for TAVR to investigate this discordance. METHODS: Data were collected prospectively for TAVR patients from 2008 through 2015 (N = 546) and were reviewed retrospectively. The observed mortality and STS-PROM were calculated to formulate O:E ratios and were compared over a variety of subgroups. RESULTS: Overall, the O:E ratio for 30-day mortality was 0.4 and significantly less than 1 (P < .001; 95% confidence interval, 0.25 0.63). The O:E ratio relationship remained less than 0.5 for patients with low (STS-PROM < 4), moderate (STS-PROM = 4-8) and high risk (STS-PROM > 8). The O:E ratio was significantly higher for transapical patients (O:E ratio = 0.8) when compared with transfemoral patients (O:E ratio = 0.2). Lastly, O:E ratios for both commercial (O:E ratio = 0.5) and research (O:E ratio = 0.3) patients were similar (P = .337), and both were significantly less than 1 (P = .007 and P < .001, respectively). CONCLUSIONS: The STS-PROM consistently overestimated 30-day mortality after TAVR. Achieving an O:E ratio less than 0.6 may be a realistic goal for all TAVR programs. While an accurate and specific risk calculator for 30 day mortality after TAVR remains to be established, our data suggest that current TVT results are not acceptable for commercial TAVR and that programs with an O:E ratio greater than 0.6, based on the STS-PROM, should reevaluate internal processes to improve their results. PMID- 30454981 TI - Treatment of malignant pleural mesothelioma with chemotherapy preceding versus after surgical resection. AB - OBJECTIVES: There are 2 main treatment paradigms recognized by the National Comprehensive Cancer Network for resectable malignant pleural mesothelioma (MPM): induction chemotherapy followed by resection (IC/R), and up-front resection with postoperative chemotherapy (R/PC). These paradigms are being compared in an accruing randomized phase II trial. In the absence of such completed trials, in this study we evaluated overall survival (OS) and postoperative outcomes of IC/R and R/PC. METHODS: The National Cancer Database was queried for newly diagnosed epithelioid/biphasic MPM. Metastatic, node-positive, and/or cT4 disease was excluded, along with nondefinitive surgery and lack of chemotherapy. Multivariable logistic regression ascertained factors independently associated with induction chemotherapy delivery. Kaplan-Meier analysis was used to evaluate OS between cohorts; multivariable Cox proportional hazards modeling was used to assess factors associated with OS. Survival was also evaluated between propensity matched populations. Last, postoperative outcomes were assessed between groups. RESULTS: Overall, 361 patients (182 IC/R, 179 R/PC) were analyzed. Temporal trends revealed that IC/R is decreasing over time. Survival of the IC/R cohort was similar to that of R/PC patients (20.9 vs 21.7 months; P = .500); this persisted after propensity matching (20.8 vs 22.0 months; P = .270). However, patients who underwent IC/R experienced longer postoperative hospitalization (median 7 days vs 6 days; P = .001) and higher 30-day mortality (3.3% vs 0%; P = .020). CONCLUSIONS: To our knowledge, this is the only comparative investigation of the 2 major management paradigms of operable MPM. IC/R regimens are decreasing over time in the United States. Although associated with survival similar to R/PC, IC/R might be associated with worse postoperative outcomes. Careful induction chemotherapy patient selection is thus highly recommended. PMID- 30454982 TI - Tracheostomy tube through a silicone Y-stent for mechanical ventilation after an extensive tracheal lesion. PMID- 30454983 TI - Measuring chordae tension during transapical neochordae implantation: Toward understanding objective consequences of mitral valve repair. AB - OBJECTIVES: Complex structure of mitral valve and its central position in the heart limit assessment of mitral function to standardized calculated parameters assessed using medical imaging (echocardiography). Novel techniques, which allow mitral valve repair (MVr) in a beating heart, offer the opportunity for innovative objective assessment in physiologic and pathologic conditions. We report, to our knowledge, the first data of real-time chordal tension measurement during a transapical neochordae implantation. METHODS: Seven patients with severe degenerative mitral regurgitation due to posterior prolapse underwent transapical MVr using the NeoChord DS 1000 (NeoChord Inc, Minneapolis, Minn). During prolapse correction, the tension applied on the neochordae was measured in addition to hemodynamic and echocardiographic parameters. RESULTS: The traction applied on 1 chorda sustaining the P2 segment was measured at between 0.7 and 0.9 N, and oscillated with respiration. When several neochordae were set in tension, this initial tension was spread homogeneously on each chorda (mean sum of the amplitude of tension 0.98 +/- 0.08 N). To achieve an optimal echocardiographic correction, a complementary synchronous traction on all chordae was required. During this adjustment, the sum of the tension decreased (mean 12 +/- 2%; P = .018), suggesting that when normal physiology was restored, the valvular apparatus was in a low-stress state. This method allowed us to apply a precise and reproducible technique, leading to a good procedural success rate with a low morbidity and mortality rate. CONCLUSIONS: The tension applied on chordae during transapical implantation of neochordae for degenerative mitral regurgitation can be measured, providing original data about the objective consequences of MVr on the mitral apparatus. PMID- 30454984 TI - Conducting high-quality research in cardiothoracic surgical education: Recommendations from the Thoracic Education Cooperative Group. AB - OBJECTIVE: There is a clear need for improved quality of research publications in the area of cardiothoracic surgical education. With the goals of enhancing the power, rigor, and strength of educational investigations, the Thoracic Education Cooperative Group seeks to outline key concepts in successfully conducting such research. METHODS: Literature and established guidelines for conduct of research in surgical education were reviewed, and recommendations were developed for investigators in thoracic surgical education. RESULTS: Key steps in educational research are highlighted and discussed with regard to their application to cardiothoracic surgical education. Specifically, advice is provided in terms of developing a research question, educational methodology, ethical issues, and handling power and sample sizes. Additional caveats of educational research that are addressed include aspects of validity, survey conduct, and simulation research. CONCLUSIONS: Educational research can serve to enhance the practices and careers of current trainees, our scientific community, and thoracic surgical educators. To optimize the quality of such educational research, it is imperative that teachers, innovators, and contributors to academic scholarship in our field familiarize themselves with key steps in conducting educational studies. PMID- 30454985 TI - Sepsis alerts in EMS and the results of pre-hospital ETCO2. AB - BACKGROUND: Field sepsis alerts have the ability to expedite initial ED sepsis treatment. Our hypothesis is that in patients that meet EMS sepsis alert criteria there is a strong relationship between prehospital end-tidal carbon dioxide (ETCO2) readings and the outcome of diagnosed infection. METHODS: In 2014, our EMS service initiated a protocol requiring hospitals to receive notification of a "sepsis alert" on all suspected sepsis patients. The EMS service transports 70,000 patients/year to a number of urban centers. All patients transported to our major urban teaching hospital by our EMS service in one year in which a sepsis alert was announced were included in this study. The primary outcome variable was diagnosed infection and secondary outcomes were hospital admission, ICU admission and mortality. Positive lactate was defined as >4.0 mmol/L. ROC curve analysis was used to define the best cutoff for ETCO2. RESULTS: 351 patients were announced as EMS sepsis alert patients and transported to our center over a one year period. Positive outcomes were as follows: diagnosed infection in 28% of patients, hospital admission in 63% and ICU admission in 11%. The correlation between lactate and ETCO2 was -0.45. A ROC curve analysis of ETCO2 vs. lactate >4 found that the best cutoff to predict a high lactate was an ETCO2 of 25 or less, which was considered a positive ETCO2 (AUC = 0.73). 27% of patients had a positive ETCO2 and 24% had a positive lactate. A positive ETCO2 predicted a positive lactate with 76% accuracy, 63% sensitivity and 80% specificity. 27% of those with a positive ETCO2 and 44% of those with a positive lactate had a diagnosed infection. 59% of those with a positive ETCO2 and 89% of those with a positive lactate had admission to the hospital. 15% of those with a positive ETCO2 and 18% of those with a positive lactate had admission to the ICU. Neither lactate nor ETCO2 were predictive of an increased risk for diagnosed infection, hospital admission or ICU admission in this patient population. CONCLUSION: While ETCO2 predicted the initial ED lactate levels it did not predict diagnosed infection, admission to the hospital or ICU admission in our patient population but did predict mortality. PMID- 30454986 TI - [Clinical pharmacy in a bone marrow and cellular therapy transplantation ward which methods to put in place: Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. AB - Since, several years the integration of a clinical pharmacist in medical units led to improve the patients' care in France. In the frame of stem cell engraftment, patients belong to a particularly complex population, notably due to pediatric patients or because the age to engraft adult patients is higher. Moreover, because of many reasons, such as numerous medications intake or long term immunosuppression, these patients are very fragile and at risk of complications. Since the 6th edition, the JACIE standard gives a definition of the role of clinical pharmacist with its competence area and its place in the medical ward. In the aim to standardize the procedures of stem cell transplantation, this 8th congress of the francophone Society of bone marrow transplantation and cellular therapy has proposed a collective proposition of the place and the missions of clinical pharmacists in the transplant units. PMID- 30454987 TI - A novel treatment method of PVC-medical waste by near-critical methanol: Dechlorination and additives recovery. AB - Before PVC-medical waste is subjected to a waste-to-energy recovery process, the dechlorination and the recovery of additives such as plasticizer, stabilizer, and lubricant are quite important and attractive. In this work, a novel process was developed for the dechlorination and the recovery of additives from PVC-medical waste such as tube for transfusion (TFT) and sample collector for urine (SCFU) by using near-critical methanol (NCM). Reaction temperature, solid-to-liquid ratio, and reaction time have significant effect on the dechlorination of TFT and SCFU in NCM. The order of dechlorination efficiency of the samples at the same reaction conditions is as follows: TFT > Pure PVC > SCFU. When reaction temperature was controlled at 250 degrees C (solid-to-liquid ratio of 1:10 g/mL, reaction time of 60 min), the dechlorination efficiency reached 90%. Plasticizer such as dibutyl phthalate (DBP), dioctyl phthalate (DOP), and dimethyl phthalate (DMP) could be efficiently extracted and recovered from TFT at 250 degrees C by the NCM process. The recovery efficiency of DBP, DOP, and DMP decreased significantly with increasing temperature due to the further decomposition and other secondary reactions. High level of hexadecanoic acid methyl ester and octadecanoic acid methyl ester can be obtained from SCFU at 250 degrees C by the NCM process because of the esterification between methanol and hexadecanoic acid/octadecanoic acid, which are the important stabilizers and lubricants generally used in rigid PVC. It is noteworthy that methanol can be circulated and reused in the NCM process. This result showed that the NCM process was beneficial for both the dechlorination and the additives recovery from PVC-medical waste, and had a widespread application prospect for the waste management of PVC wastes. PMID- 30454988 TI - Effects of sulphur and Thiobacillus thioparus 1904 on nitrogen cycle genes during chicken manure aerobic composting. AB - Severe nitrogen (N) loss is a barrier for composting treatment. Since N transformation during composting is closely related to nitrogen loss, the impacts of adding sulphur and Thiobacillus thioparus 1904 to N transformation during composting were investigated in this work. Physicochemical properties and the expression of genes encoding N-related proteins were analysed to evaluate microbiological processes associated with N dynamics. The results indicated that (1) sulphur addition reduced the pH and cumulative NH3 emission, and decreased N losses by 44.23%, while no significant differences were observed in the expression of N cycle-associated genes compared with the control treatment; (2) the application of T. thioparus 1904 increased NO3--N content, reduced N loss by 28.20%, and significantly enhanced the expression of ammonia monooxygenase A (archaeal amoA; AOA) and nitrite oxidoreductase A (nxrA) during the mature phase; (3) the combined application of sulphur and T. thioparus 1904 significantly affected the expression of functional genes related to nitrification and denitrification, which contributed to a reduction in accumulated NH3 emission, an increase in NO4+-N content, and a decrease in N losses by 70.94%. Expression of ammonia monooxygenase A (bacterial amoA; AOB), nxrA and nitrous oxide reductase Z (nosZ) genes in the combined treatment was positively correlated with NO3--N, whereas expression of AOA and accumulation of NH3 were negatively correlated with NO3--N. These results indicate that the combined application of sulphur and T. thioparus 1904 had a significant regulatory effect on N cycle genes and effectively reduced the N loss during composting. PMID- 30454989 TI - Characterization of naturally aged cement-solidified MSWI fly ash. AB - Solidification/stabilization (S/S) is the most common treatment for municipal solid waste incineration fly ash (MSWI-FA), and is widely applied in developed countries but has a history barely longer than 10 years in China. However, our understanding of the physicochemical characteristics of the solidified FA body after long-term natural aging is comparatively poor. Focusing on cement solidified FA that was naturally aged for 6 years (hereafter referred to as FA 6), the physicochemical characteristics including elemental composition, mineral composition, microstructure, thermogravimetry, distribution of heavy metals in mineral phases, and leaching characteristics of inorganic salts (Na, K, Ca), anions (Cl and SO4) and heavy metals (Cd, Cr, Cu, Pb, Zn) were investigated in this study. By combining pH-dependent leaching results with the geochemical model LeachXS, the chemical forms of heavy metals in the FA solid phase was determined. The main conclusion was as follows: (1) soluble salts of FA-6 decreased by more than 92% compared with fresh FA. (2) In FA-6, the proportions of Pb, Cd and Zn in the non-mineral phase were 100%, 100% and 58%, respectively, which may cause potential environmental risk of heavy metal release. The leaching concentration of Pb was 4007.37 MUg/L according to compliance batch test of HJ300, which was far higher than the landfill requirement of 250 MUg/L. (3) The controlling phase for Pb in FA-6 was Pb5(PO4)3Cl (pH 2-12) and Pb2(OH)3Cl (pH > 12). (4) Carbonates, hydrous Fe oxides (HFO) and dissolved organic carbon (DOC) in FA-6 also affected the phase-controlled leaching of heavy metals. The carbonate fraction partly controlled the leaching of Cd, Cu and Zn. For example, smithsonite (ZnCO3) controlled the release of Zn (pH 2-13). Adsorption to solid humic acid (SHA) controlled the Cr leaching at pH < 7 and the Cu leaching except pH > 12. PMID- 30454990 TI - Recycling waste plastics in developing countries: Use of low-density polyethylene water sachets to form plastic bonded sand blocks. AB - In many developing countries low-density polyethylene (LDPE) sheets, bags and water sachets are a major waste problem because local collection and recycling systems do not exist. As a result, LDPE has no value and is dumped causing aesthetic, environmental and public health issues. A relatively simple technology has been developed in the Cameroon that produces LDPE-bonded sand blocks and pavers. The application of this technology is an example of a community-driven waste management initiative that has potential to impact on the global plastics waste crisis because it can transform waste LDPE and other readily available types of plastics into a valuable local resource. In this research, waste LDPE water sachets have been melted and mixed with sand to form LDPE-bonded sand blocks. The effect of sand particle size and sand to plastic ratio on density, the compressive strength and water adsorption are reported. Optimum samples have been further characterised for flexural strength and thermal conductivity. LDPE bonded sand is a strong, tough material with compressive strengths up to ~27 MPa when produced under optimum processing conditions. The density and compressive strength increase as the particle size of the sand decreases. The potential for using this simple technology and the materials it produces to transform LDPE plastic waste management in developing countries is discussed. PMID- 30454991 TI - Biochemical and microbial changes reveal how aerobic pre-treatment impacts anaerobic biodegradability of food waste. AB - Aerobic pre-treatment of food waste (FW) was performed at different oxygen concentrations (0%, 5%, 10% and 21%O2) and different durations (1, 2, 3 and 4 days) to investigate its impact on biochemical and microbial community characteristics of the waste and its ability to improve anaerobic biodegradability. Whatever the duration, the highest effect of pre-treatment was observed at full aerobic pre-treatment (21%O2) while 5%O2 and 10%O2 showed lower transformation performances. Biochemical variations at 21%O2 were mainly a decrease of simple carbohydrates, volatile fatty acids (VFA) and low molecular weight water soluble compounds and an increase of high weight water soluble compounds. Microbial community analysis showed a clear modification of populations after 21%O2 aerobic pre-treatment, changing from an initial dominance of lactic acid bacteria to a final dominance of VFA consumers (like Acetobacter) and a higher presence of Fungi. Enzymatic tests showed an increase of exoenzymes content and a higher presence of protein and carbohydrates degrading enzymes. Finally, the aerobic pre-treatment did not negatively impact methane potential of FW (496 NLCH4.kgVS-1) which remained unchanged after two days of pre-treatment at 21%O2. These latter optimal pre-treatment conditions are proposed to be tested in future investigation of anaerobic digestion (AD) process with low inoculum to substrate ratio in order to assess their ability to avoid acidification risk during AD of FW. PMID- 30454992 TI - Humic acid inhibition of hydrolysis and methanogenesis with different anaerobic inocula. AB - There is increasing evidence that humic acid (HA) is hampering the performance of anaerobic digesters treating animal manures and thermally-hydrolysed waste activated sludge. In the present study, HA inhibition and inhibition resilience was examined for hydrolysis (carbohydrate and protein) and acetotrophic methanogenesis with four distinct full-scale anaerobic inocula. The aim was to further understand HA inhibition and to explore potential relationships between microbial factors and inhibition resilience. For two of the four tested inocula, cellulose degradation showed a start-up delay that lengthened as HA concentration increased from 0 to 2 g L-1. This inhibition was reversible because, after the initial delay, subsequent hydrolysis rates and methane yields were not significantly influenced by HA concentration. Cellulose hydrolysis results at HA concentrations below 2 g L-1 support a threshold inhibition mechanism, i.e. HA complexes with hydrolytic enzymes preventing them from binding with cellulose, but once all the HA had been complexed, enzymes subsequently released are free to bind with cellulose. Inocula with higher cellulose hydrolytic activity were less affected by HA inhibition, suggesting a potential link between HA inhibition resilience and microbial activity. However, above 5 gHA L-1, cellulose hydrolysis rates decreased with increasing HA concentration; indicating that the mechanisms of inhibition may change depending on some threshold HA concentration. Protein hydrolysis and acetotrophic methanogenesis were less susceptible to HA inhibition than cellulose hydrolysis, since signs of inhibition were only observed above 5 gHA L-1. Acetotrophic methanogenesis was partially inhibited at 10 gHA L-1 and completely inhibited at 20 gHA L-1. These results further support that HA inhibition is selective towards particular enzymes. PMID- 30454993 TI - Where is global waste management heading? An analysis of solid waste sector commitments from nationally-determined contributions. AB - Waste-sector greenhouse gas emissions have long been accepted as a critical component of climate change mitigation efforts because of the significant radiative forcing of methane (CH4) production from municipal landfills and other emissions from waste management processes. In developed countries, waste generation is expected to peak and decline by the end of the century, whereas waste generation is rapidly rising in many developing nations. The extent to which the countries of the world are planning to handle future quantities of waste has not been explored in detail. This work provides the first detailed account of future waste management planning and waste-sector mitigation strategies through an analysis of stated commitments in the 174 Nationally Determined Contributions (NDCs, documents outlining each country's actions to mitigate carbon emissions and adapt to a changing climate) that have been filed to date within the Framework Convention on Climate Change secretariat in Bonn. One-hundred thirty-seven of 174 countries that submitted NDCs included waste sector emission mitigation actions, representing approximately 85% of all global emissions. About half (67) of the countries that included waste sector mitigation tactics identified infrastructure or policy actions to meet mitigation commitments, but these strategies vary widely in their scope and level of detail. Landfilling was the most commonly-cited waste-sector commitment (n = 47), followed by deriving energy from waste through various techniques (n = 42). Countries targeting improved solid waste collections had less extensive coverage (ucollection = 38% of generated waste collected) than countries that did not prioritize improved collections (ucollection = 46% of waste generation), but countries not prioritizing the waste sector at all in NDCs had the most limited waste collection coverage (ucollection = 33%). Almost all of the countries that specified emissions inventory assumptions (132 of 135) use outdated CH4 global warming potential values which, coupled with missing or poor waste management data suggests many countries may be underestimating the importance of waste sector emissions in national emissions portfolios. Several examples of data collection and reporting models are identified that can help to inform and potentially improve life-cycle environmental outcomes in the waste sector. Adaptation strategies detailed in NDCs have largely overlooked the waste sector, suggesting inadequate incorporation of future climate scenarios in waste sector infrastructure planning. PMID- 30454994 TI - Life cycle assessment of the French municipal solid waste incineration sector. AB - This study aims at assessing the environmental performances of the French MSW incineration sector in a life cycle perspective, considering nine midpoint impact categories. It is the first application of the WILCI tool, dedicated to the LCA of MSW incineration in the French situation (Beylot et al., 2017). The model is primarily based on operational data relative to 90 plants, representing 73% of the total mass of MSW annually incinerated in France. Regarding seven impact categories out of the nine under study, incineration of MSW in France provides a benefit (that is, a "negative" impact). The uncertainty analysis confirms the relatively large degree of confidence of this conclusion regarding acidification and particulate matter, but in the meantime highlights the remaining uncertainty regarding most other impact categories. Energy recovery is responsible for the main share of the total environmental impacts and benefits of MSW incineration in France. Moreover, this study confirms the importance of technology differentiation in the LCA of MSW incineration. The predominance, in the French incineration sector, of energy recovery as CHP, and of SCR for NOx abatement, results in the global environmental benefits calculated per tonne of average MSW incinerated. Finally, this study addresses the contribution of each waste fraction to the total impacts and benefits of MSW incineration. It identifies several fractions whose contributions to impacts and benefits are not in line with their share in the composition of MSW incinerated. PMID- 30454995 TI - Pilot-scale biofiltration at a materials recovery facility: The impact on bioaerosol control. AB - This study investigated the performance of four pilot-scale biofilters for the removal of bioaerosols from waste airstreams in a materials recovery facility (MRF) based in Leeds, UK. A six-stage Andersen sampler was used to measure the concentrations of four groups of bioaerosols (Aspergillus fumigatus, total fungi, total mesophilic bacteria and Gram negative bacteria) in the airstream before and after passing through the biofilters over a period of 11 months. The biofilters achieved average removal efficiency (RE) of 70% (35 to 97%) for A. fumigatus, 71% (35 to 94%) for total fungi, 68% (47 to 86%) for total mesophilic bacteria and 50% (-4 to 85%) for Gram negative bacteria, provided that the inlet concentration was high (103-105 cfu m-3), which is the case for most waste treatment facilities. The performance was highly variable at low inlet concentration with some cases showing an increase in outlet concentrations, suggesting that biofilters had the potential to be net emitters of bioaerosols. The gas phase residence time did not appear to have any statistically significant impact on bioaerosol removal efficiency. Particle size distribution varied between the inlet and outlet air, with the outlet having a greater proportion of smaller sized particles that represent a greater human health risk as they can penetrate deep into the respiratory system where gaseous exchange occurs. However, the outlet concentrations were low and would further be diluted by wind in full scale applications. In conclusion, this study shows that biofilters designed and operated for odour degradation can also achieve significant bioaerosol control in waste gas. PMID- 30454996 TI - Evaluation of physicochemical and hydromechanical properties of MSWI bottom ash for road construction. AB - Municipal Solid Waste Incinerator (MSWI) Bottom Ash has been used as a substitute for traditional aggregates in road construction; however, this material is little understood. The work presented in this paper pursues the study on the mechanical performance of bottom ash, proven by Le et al. (2017). Using a coupling technique for the first time, the physicochemical aspects and hydromechanical resistance of bottom ash were evaluated and analyzed. Physicochemical tests were first carried out, followed by oedometer tests under a wetting path. This coupled evaluation underlined the role of principal mineralogical components of the studied bottom ash as well as the link with its hydromechanical properties. Tests results showed that the principal constituent of bottom ash is SiO2, which thus affects the characteristics of bottom ash. Given the physical stability of SiO2 which generated a compacted material being less sensitive to water and chemical reactions, and bottom ash's other characteristics, this demonstrates why bottom ash could be a viable material in roadworks. PMID- 30454997 TI - Chelator-induced recovery of rare earths from end-of-life fluorescent lamps with the aid of mechano-chemical energy. AB - Rare-earths (REs) are key components for the transition to a greener energy profile and low carbon society. The elements turn out to be of limited availability in the market, due to the supply-demand issues, exponential price rises, or geopolitics, which has led to a focus on the exploration of secondary sources for RE reclamation. End-of-life (EoL) nickel-metal hydride batteries, permanent magnets, and fluorescent lamps (FL) have been the primary sources for recyclable REs, while the recovery of REs in EoL FL (Ce, Eu, La, Tb, or Y) includes comparatively fewer processing steps than the other potential sources. In the current work, we proposed a simple, energy-efficient protocol for EoL FL processing, using chelators in combination with ball milling. The parameters for optimum chelator-assisted recovery (chelator concentration, solid-to-liquid ratio, solution pH), and milling variables (ball size, ball weight, milling speed, milling duration), were evaluated at room temperature (RT, 25 +/- 2 degrees C). The dissolution of REs with ethylenediaminetetraacetic acid (EDTA), ethylenediaminedisuccinic acid, methylglycinediacetic Acid, or 3-hydroxy-2,2' iminodisuccinic acid, was compared at RT, while EDTA was used as the reference chelator throughout. Increasing the system temperature from 25 to 135 degrees C achieved at least double Eu and Y recovery, relative to that at RT, whereas the recovery rate improvement for Ce, La or Tb was insignificant. Mechano-chemical treatment at RT, via wet milling of EoL FL, with chelators, yielded a five order of magnitude increase in Ce, La and Tb recovery, however, plus a two-order increase for Eu or Y, compared with non-abetted operating conditions. It was also found that higher impact energy achieved improved recovery over a reduced milling duration with this technique having the added advantage of minimal acid consumption and reduced effluent production. PMID- 30454998 TI - Effect of inherent minerals on sewage sludge pyrolysis: Product characteristics, kinetics and thermodynamics. AB - Inherent minerals in sludge influence sludge pyrolysis behaviors and the final products. In this study, the effects of inherent minerals on sewage sludge pyrolysis were systematically investigated by studying the pyrolysis behaviors of raw sewage sludge (RS) and HCl-washed sludge (WS), and in combination with thermodynamic equilibrium simulations for the hypothetical mineral-free sludge (AS) assumed. The pyrolysis of RS and WS was performed with a novel online thermogravimetric analyzer equipped with an infrared spectrometer and a gas chromatograph coupled with a mass spectrometer (TG-IR-GC/MS). It was found that inherent minerals influenced both the release of volatile products as a function of pyrolysis temperature, and the development of the physicochemical properties of the derived char. In the temperature range of 300-500 degrees C, hydrocarbons with more than 4 carbon atoms as well as aromatic compounds showed an increased release during WS pyrolysis, with respect to RS, while hydrocarbons with less than 3 carbon atoms such as CH4 and C3H6 exhibited a decreased release. In addition, the inherent minerals enhanced the release of HCN and NH3, both leading to increased NO2 release, and the release of H2S and COS was also promoted while the release of CH3SH, SO2 and CS2 was mitigated. Kinetic analysis confirmed that a catalytic effect induced by the inherent minerals decreased the activation energy at 300-500 degrees C. Thermodynamic simulations suggested that inherent minerals influenced sludge pyrolysis and the derived products formation by increasing the total Gibbs energy of the sludge pyrolysis system. Therefore, considerations of sludge inherent minerals should be taken into account during pyrolysis for the purpose of value-added commodity production and pollutant mitigation. PMID- 30454999 TI - Combined application of Life Cycle Assessment and linear programming to evaluate food waste-to-food strategies: Seeking for answers in the nexus approach. AB - The great concern regarding food loss (FL) has been studied previously, but in an isolated way, disregarding interdependencies with other areas. This paper aims to go a step further by proposing a new procedure to assess different waste management alternatives based on the nexus approach by means of an integrated Water-Energy-Food-Climate Nexus Index (WEFCNI). The environmental profile of the waste management techniques is determined using Life Cycle Assessment (LCA) which, in combination with Linear Programming (LP), explores the optimal aggregation of weighting factors that lead to an aggregated nexus index. The management of residues from the anchovy canning industry in Cantabria (Spain) has been used as a case study, considering the three current applied alternatives: (i) valorisation of FL as animal feed in aquaculture (food waste-to-food approach), (ii) incineration of FL with energy recovery, and (iii) landfilling with biogas recovery. The last two considered the use of energy recovered to produce a new aquaculture product (food waste-to-energy-to-food scenarios). The results indicate that incineration is the best performing scenario when the nutritional energy provided by the valorisation alternative is not high enough and the valorisation technology presents the highest water consumption. Therefore, a minimisation in the consumption of natural resources is suggested in order to improve the application of circular economy within the sector. The use of the nexus index as an environmental management tool is extendable to any food system with the aim of facilitating the decision-making process in the development of more sustainable products. PMID- 30455000 TI - Recovery of valuable metals from mixed types of spent lithium ion batteries. Part II: Selective extraction of lithium. AB - Extensive usage of different kinds of lithium ion batteries (LIBs) may result in a huge amount of complicated waste batteries stream, while insufficient attention has been paid on the selective recovery of lithium from these already complicated wastes. Herein, a novel approach was developed for the selective extraction of Li from mixed types of LIBs (LiCoO2, LiMn2O4, LiFePO4 and LiCo1/3Mn1/3Ni1/3O2) using mild phosphoric acid as efficient leaching agent. It can be concluded from leaching results that 100%, 92.86%, 97.57% and 98.94% Li can be selectively extracted from waste cathode materials of LiCoO2, LiMn2O4, LiFePO4 and LiCo1/3Mn1/3Ni1/3O2, respectively, while transition metals (Co, Mn, Fe and Ni) can be hardly leached in mild acidic media under optimized leaching conditions. In addition, high selectivity coefficients (betaLi/Me) can be obtained during the extraction of Li from other metals. It can be also discovered from characterization results (SEM, XRD, FT-IR and Raman spectra) that leaching residues are phosphate precipitates, which might be used for the recycling of other metals and preparation of cathode materials. Results from leaching kinetics indicate that the leaching of Li is chemical and internal diffusion controlled reaction, with apparent activation energy (Ea) of 37.74, 21.16, 27.47 and 21.86 kJ/mol for LiCoO2, LiMn2O4, LiFePO4 and LiCo1/3Mn1/3Ni1/3O2, respectively. Finally, lithium phosphate with a purity of 98.4% can be obtained and the whole process can be efficient candidate for Li recovery with minor environmental impact and little waste produced. PMID- 30455001 TI - Centrifugal dewatering performance in plastic films recycling. AB - Dewatering of plastic films is a highly energy-consuming recycling operation that largely affects the quality of the recycled product. Despite the importance of good drying, this operation has not been studied at laboratory or pilot plant scale. In this work, the mechanical dewatering of blown film grade high density polyethylene has been assessed by using a laboratory centrifuge. It is suggested that a plastic cake is formed under the centrifugal forces similar to the sludge cake after the filtration process. The water is retained within the plastic cake due to three phenomena: free water within the cake pores and voids, water maintained by capillarity (superficial and pendular) and water trapped due to the tortuosity of the plastic mass. The total moisture is a sum of an equilibrium moisture and a transient moisture. The equilibrium moisture depends on the centrifugal force (G) but it is independent of time. Conversely, the transient moisture is reliant on both the G-force and the centrifugation time. The experimental results showed that an optimum side length exists. The moisture content is minimized when the flake side lies between 1 and 2 cm. Finally, it has been found that the moisture content is a function of the plastic surface. Hence, the specific moisture content (the mass of water per total plastic surface) should be calculated to compare films with uneven thickness or made of different materials. In sum, the outcomes of this study may be fundamental for the further and more extensive research into the plastic films dewatering processes. PMID- 30455002 TI - Effects of acclimation and pH on ammonia inhibition for mesophilic methanogenic microflora. AB - This work evaluated the toxicity of ammonia toward mesophilic methanogenic microflora, with respect to the acclimation and pH. Microflora acclimated to total ammonia nitrogen (TAN) concentrations of 1.0-2.5 g N/L and neutral to alkaline pH, 7.5-8.0, were used for anaerobic toxicity assays (ATA) with TAN up to 6.1 and pH ranged from 7 to 8.2. The effect of ammonia on the specific methanogenic activity (SMA) and methane yield (MY) was described using a noncompetitive model. Acclimation increased the tolerance of the methanogenic microflora to ammonia over the acclimation range. There was no significant difference in the values of SMA and MY at each TAN concentration in the examined pH range, although free ammonia nitrogen (FAN) concentrations increased along with pH. It implied that TAN rather than FAN would be the useful criterion for ammonia inhibition. Propionate degradation was more inhibited compared to acetoclastic methanogenesis by ammonia. The half-maximal inhibitory concentrations (IC50) of TAN for the SMA from acetate, SMA from propionate, MY from acetate, and MY from propionate were 3.42-4.26, 3.14-3.91, 3.67-4.07, and 3.34-3.88 g N/L, respectively, at pH 7.4. 454-pyrosequencing analysis of the inoculum showed that the archaeal community was dominant of Methanosarcinaceae and Methanobacteriaceae, which were known as tolerant to ammonia inhibition. PMID- 30455003 TI - One stage olive mill waste streams valorisation via hydrothermal carbonisation. AB - An olive waste stream mixture, coming from a three phase-continuous centrifugation olive oil mill industry, with a typical wet basis mass composition of olive pulp 39 wt%, kernels 5 wt% and olive mill waste water 56 wt%, was subjected to hydrothermal carbonisation (HTC) at 180, 220 and 250 degrees C for a 3-hour residence time in a 2-litre stainless steel electrically heated batch reactor. The raw feedstock and corresponding hydrochars were characterised in terms of proximate and ultimate analyses, higher heating values and energy properties. Results showed an increase in carbonisation of samples with increasing HTC severity and an energy densification ratio up to 142% (at 250 degrees C). Hydrochar obtained at 250 degrees C was successfully pelletised using a lab scale pelletiser without binders or expensive drying procedures. Energy characterisation (HHV, TGA), ATR-FTIR analysis, fouling index evaluation and pelletisation results suggested that olive mill waste hydrochars could be used as energy dense and mechanical stable bio-fuels. Characterisation of HTC residues in terms of mineral content via induced coupled plasma optical emission spectroscopy (ICP-OES) as well as Total and Dissolved Organic Carbon enabled to evaluate their potential use as soil improvers. Nutrients and polyphenolic compounds in HTC liquid fractions were evaluated for the estimation of their potential use as liquid fertilisers. Results showed that HTC could represent a viable route for the valorisation of olive mill industry waste streams. PMID- 30455004 TI - Fabrication and characterization of thermally-insulating coconut ash-based geopolymer foam. AB - This study aims at synthesizing porous coconut ash (CA)-based geopolymer foam with high thermal insulation property. Sodium hydroxide (NaOH), alumina slag (AS) and water contents as the main parameters, which affect the performance hardened CA, have been studied. The porosity was developed by hydrogen gas resulted from the interaction of Al metal, in AS, with NaOH. The compressive strength, bulk density, porosity and thermal conductivity were evaluated. The results proved that the AS has a potential impact on the reduction of thermal conductivity of CA based geopolymer foam by creation of high porous system. Open celled hardened CA based geopolymer with high porosity (~87%), low thermal conductivity (~0.045 W/m.K), compressive strength (1.3 MPa) and bulk density (~0.60 g/cm3) was obtained when 7% AS (by weight of CA powder) and water to CA powder ratio of 0.4 were used. PMID- 30455005 TI - Electrodialytic treatment of Greenlandic municipal solid waste incineration fly ash. AB - In Greenland, fly ash could contribute as a local resource in construction as a substitute for cement in concrete or clay in bricks, if the toxicity of the ash is reduced. In this study, fly ash from three different Greenlandic waste incinerators were collected and subjected to electrodialytic treatment for removal of heavy metals with the aim of enabling reuse of the fly ashes. Seven electrodialytic experiments treating up to 2.5 kg of fly ash in a 10 L suspension were made. The heavy metal removal was mostly dependent on the initial concentration in the fly ash. Heavy metal leaching was examined before and after treatment and revealed overall a significant reduction in leaching of Cd, Cr, Cu, Pb and Zn; however, Cr and Pb leaching were above Danish guideline levels for reuse purposes. Hg leaching was also reduced to below Danish guideline levels, although only investigated for one fly ash. Hexavalent Cr was not the dominant speciation of Cr in the fly ashes. Ettringite formed during electrodialytic treatment in the fly ash suspensions at pH above 12. The total concentration of eligible components for reuse such as CaO, SiO2 and Al2O3, increased during the electrodialytic treatment. PMID- 30455006 TI - Valorisation of citrus processing waste: A review. AB - This study analyses the quantitative and qualitative characteristics of citrus peel waste and discusses the systems for its valorisation. Citrus peel waste (CPW) is the main residue of the citrus processing industries and is characterised by a seasonal production (which often requires biomass storage) as well as high water content and concentration of essential oils. The disposal of CPW has considerable constraints due to both economic and environmental factors. Currently this residue is mainly used as food for animals, thanks to its nutritional capacity. If enough agricultural land is available close to the processing industries, the use of CPW as organic soil conditioner or as substrate for compost production is also possible, thus improving the organic matter content of the soil. Recently, the possibility of its valorisation for biomethane or bioethanol production has been evaluated by several studies, but currently more research is needed to overcome the toxic effects of the essential oils on the microbial community. Considering the high added value of the compounds that can be recovered from CPW, it has promising potential uses: in the food industry (for production of pectin, dietary fibres, etc.), and in the cosmetic and pharmaceutic industries (extraction of flavonoids, flavouring agents and citric acid). However, in many cases, these uses are still not economically sustainable. PMID- 30455007 TI - Ineffective waste site closures in Brazil: A systematic review on continuing health conditions and occupational hazards of waste collectors. AB - There are approximately 15 million people engaged in waste collection or recycling activities in the world. Some of these dump sites are informal and people work in environments that are labor-intensive, unregulated, unregistered, low-paid, unrecorded, and environmentally hazardous. A systematic review was conducted to assess consequential health conditions and occupational risks that affect waste collectors in Brazil. The search was limited to Brazil because although the government closed dump sites, open-air dumping-the worst type of waste disposal-still occurs in about half of the country; moreover, Brazil is the only country to systematically collect data on the occupation, with an estimated 229,568 recyclable collectors of all types country-wide, which offers relevant and pertinent data on the topic. The results of the search indicated that nearly every region has individuals that work as recyclable collectors. As expected, the sites are full of occupational hazards to the workers that can include: long working hours; exposures to physical, chemical, mechanical, biological, ergonomic and social agents; and frequent work accidents. Exposure to these risks can result both in physical and psychological illnesses. In view of these findings, public policies could be strengthened by supporting and providing incentives to municipalities, schools, universities, health professionals, and all others who will contribute to the closure of open-air waste or poor waste disposal systems. Moreover, an improved awareness should be provided to the general population about environmental education and correct disposal of garbage. The goal of healthy waste disposal conditions ultimately decreases environmental and public health effects, while improving the working conditions, quality of life, and health outcomes for recyclable collectors. PMID- 30455008 TI - Eggshell as a potential CO2 sorbent in the calcium looping gasification of biomass. AB - This work presents an investigation into the potential use of eggshell as a CO2 sorbent in the calcium looping gasification of biomass to enhance carbon negativity. Calcination reaction was studied in a quartz wool matrix reactor and a thermogravimetric analyser coupled with a Fourier transform infrared spectroscopy. The resulting sorbent was characterised with a scanning electron microscope, colourimeter, inductively coupled plasma optical emission spectroscopy, and nitrogen sorption analyser. The pore structures of the samples are of Type II isotherm. Results show that increasing the calcination temperature enhances decomposition and improves the calcium content and specific surface area of the sorbent. As compared to nitrogen, calcination in a CO2 environment is not effective due to the increased CO2 partial pressure. Samples with low particle size displayed higher carbonation conversion. Increasing the carbonation temperature to an extent enhances the carbonation conversion. The carbonation conversion by the sorbent in multiple calcination-carbonation cycles was also studied. Initial CO2 uptake by the sorbent was highly encouraging. A conversion of 76.41% was realized after the first cycle, but due to sintering and attrition, the conversion reduced with increasing cycle. The sorbent exhibited a low conversion of 18% after the seventh cycle and this corresponds to a decay extent of 76.65%. PMID- 30455009 TI - Anodic passivation on the recycling of cemented carbide scrap by selective electro-dissolution. AB - Selective dissolution is an effective method to recycle WC and Co from cemented carbide scrap, and the electro-dissolution process is considered competitive. However, the anodic passivation slows down oxidation and leads to inefficiency during electrolysis. The porosity of the WC coat is the main impact factor for passivation. Thus, in this study, types of WC-Co cemented carbide (YG8/YG15/YG20) with different bonding phase content were studied in the acid electrolyte through electrochemistry tests. The thickness of the coat was measured, and the diffusion coefficients (Di) were calculated by Fick's first law of diffusion. The Di of cation was 0.088 * 10-10, 0.61 * 10-10, 0.70 * 10-10 m2 s-1 for YG8, YG15, YG20, respectively. The inferior diffusion coefficient resulting from the dense coat was believed to be the main reason for the low dissolving rate. PMID- 30455011 TI - Real-time optimization of the key filtration parameters in an AnMBR: Urban wastewater mono-digestion vs. co-digestion with domestic food waste. AB - This study describes a model-based method for real-time optimization of the key filtration parameters in a submerged anaerobic membrane bioreactor (AnMBR) treating urban wastewater (UWW) and UWW mixed with domestic food waste (FW). The method consists of an initial screening to find out adequate filtration conditions and a real-time optimizer applied to a periodically calibrated filtration model for minimizing the operating costs. The initial screening consists of two statistical analyses: (1) Morris screening method to identify the key filtration parameters; (2) Monte Carlo method to establish suitable initial control inputs values. The operating filtration cost after implementing the control methodology was ?0.047 per m3 (59.6% corresponding to energy costs) when treating UWW and ?0.067 per m3 when adding FW due to higher fouling rates. However, FW increased the biogas productivities, reducing the total costs to ?0.035 per m3. Average downtimes for reversible fouling removal of 0.4% and 1.6% were obtained, respectively. The results confirm the capability of the proposed control system for optimizing the AnMBR performance when treating both substrates. PMID- 30455010 TI - Solid waste management index for Brazilian Higher Education Institutions. AB - This paper presents the Solid Waste Management Index (SWaMI) for Higher Education Institutions (HEIs). The main objectives are to present how SWaMI was developed, to apply the Index in three different universities in Brazil and one in United States, to statistically compare the results and to present an analysis of these HEIs under the SWaMI assessment dimensions perspective. The SwaMI fills a gap regarding a specific waste management tool for HEIs decision makers, considering the responsibility of educating and training future leaders and the need to insert the sustainable waste management discussion in its end activities. Criteria were selected through literature review and divided in dimensions, further weighted according to their significance in waste management. These weights were discussed and stipulated based on expert opinion using the Budget Allocation Process (BAP) weighting method. The individual indexes for each dimension were further combined into a composite index through the Linear Aggregation Method. Main findings shows that when comparisons were deployed between HEIs, no statistical significance was noticed when the means were compared between universities using ANOVA with Tukey test. Nevertheless, when comparing each dimension within each HEI, there was significant difference between the Policy and Management dimension and the other three dimensions of the evaluation criteria at USP. Researchers concluded that the SWaMI provides decision makers with graphic results concerning HEIs solid waste management situation, hence, it allows the creation of a baseline data on how the current system works, pointing out the dimensions that present the greatest weakness allowing to perform benchmarking between buildings, institutes, and even between HEIs. PMID- 30455012 TI - Pyrolysis of water hyacinth in a fixed bed reactor: Parametric effects on product distribution, characterization and syngas evolutionary behavior. AB - In this investigation, the effect of operating parameters on product distribution for the conversion of water hyacinth into most valuable product bio oil as well as char and gases are investigated. To observe the parametric effect on product distribution, the temperature was varied 300-600 degrees C, heating rate 10-50 degrees C/min, particle size of the feed <0.5-2.5 mm and carrier gas nitrogen flow rate 0-12 lpm. The highest bio-oil yield of 44.9 wt% was obtained at 350 degrees C, 30 degrees C/min, particle feed size less than 0.5 mm and 6 lpm. The results show that the product yield is strongly influenced by the temperature variation whereas weakly affected by the heating rate. The biomass and the products were characterized by ultimate, proximate, DTG, FTIR, 1H NMR, and GC-MS. Syngas evolution increase with the increase of temperature except CO2. The quality of bio-oil is perspective as a source of value-added chemicals and char is a promising source for the production of carbonaceous materials as well as solid fuel. PMID- 30455013 TI - Potential of municipal solid waste paper as raw material for production of cellulose nanofibres. AB - When aiming for higher resource efficiency, greater utilization of waste streams is needed. In this work, waste paper separated from mixed municipal solid waste (MSW) was studied as a potential starting material for the production of cellulose nanofibres (CNFs). The waste paper was treated using three different techniques, namely pulping, flotation and washing, after which it was subjected to an ultrafine grinding process to produce CNFs. The energy consumption of the nanofibrillation and nanofibre morphology, as well as properties of the prepared nanofibers, were analysed. Despite the varying amounts of impurities in the waste fibres, all samples could be fibrillated into nanoscale fibres. The tensile strengths of the CNF networks ranged from 70 to 100 MPa, while the stiffness was ~7 GPa; thus, their mechanical strength can be adequate for applications in which high purity is not required. The contact angles of the CNF networks varied depending on the used treatment method: the flotation-treated networks were more hydrophilic (contact angle 52.5 degrees ) and the washed networks were more hydrophobic (contact angle 72.6 degrees ). PMID- 30455014 TI - Thermally assisted bio-drying of food waste: Synergistic enhancement and energetic evaluation. AB - Recently, bio-drying is becoming a promising method to treat the slurry-type food waste together with recovering refused derived fuels (RDFs). In practice, however, conventional process frequently encountered low temperature and inefficient drying performance due to the low microbial activity and organics degradability. In order to improve bio-drying performance, in this study, an externally thermal assistant strategy was proposed to increase water evaporation and stimulate microbial degradability. Based on this idea, a series of experiments were conducted to establish, evaluate and optimize the thermally assisted bio-drying system. It was found that staged heating acclimation was an effective strategy to obtain a superior thermophilic inoculum with high metabolic activity and microbial consortia. In thermally assisted bio-drying process, an extremely high metabolic activity [cumulative OUR, 38.98 mg/(g TS.h)] was obtained, which was greatly higher than that of conventional bio-drying [19.74 mg/(g TS.h)]. Furthermore, thermally assisted bio-drying exhibited a high water evaporation capacity as thermal drying (157.9 g vs. 147.8 g), which was 3-fold higher than conventional bio-drying. Heat balance calculation indicated that externally supplying a small fraction (12.94%) of thermal energy triggered conventional bio-drying, thus greatly promoting water removal with high energy utilization efficiency as conventional bio-drying (Qevapo 60.30% vs. 64.62%). In addition, the increased air-flow rates greatly accelerated water removal with high bio-energy efficiencies, especially at 0.8 L.min-1.kg-1. The drying effect after 4 days was close to that of 20 days in conventional bio-drying. This research suggests that thermally assisted bio-drying is a promising approach to upgrade conventional bio-drying with high efficiency and low energy cost. PMID- 30455015 TI - Evaluation of reduction estrogenic activity in the combined treatment of landfill leachate and sanitary sewage. AB - Combined treatment of urban solid waste leachate and domestic sewage has emerged in Brazil and worldwide as an alternative to minimize the difficulties of treating landfill leachate. Landfill leachate is a complex matrix of organic and inorganic substances, recalcitrant material and xenobiotic organic compounds that are considered to be highly toxic, as well as endocrine disrupting compounds (EDC) that contribute to increased estrogenic activity. Although combined treatment is feasible for removal of organic matter, ammonia and toxicity, the efficiency of the removal of estrogenic substance is poorly investigated. In this study, the activated sludge process in batch and continuous modes was used for the combined treatment of 2% and 5% leachate/sewage mixtures. Estrogenic activity was reduced in reactors in both batch and continuous modes. The activated sludge process achieved average reductions of the estradiol equivalent (EQ-E2) values in the combined treatment of 94.5, 60.8 and 66.4% for the sanitary sewage, 2% mixture leachate in sewage and 5% mixture leachate in sewage reactors, respectively, in batch mode. For continuous reactors, 86%, 72%, and 65% of reduction of EQ-E2were achieved for sanitary sewage, 2 and 5% mixture with sanitary sewage. As for EQ-E2, the increase in the concentration of leachate in the sewage mixture was detrimental to the removal of estrogenic compounds during the biological process. Therefore, a limit on the % leachate/sewage mixtures should be established to achieve efficiency in the combined treatment of leachate in a Wastewater Treatment Plant (WWTP). PMID- 30455016 TI - Improved utilization of phosphorous from sewage sludge (as Fertilizer) after treatment by Low-Temperature combustion. AB - The utilization of phosphorus from sewage sludge is an important method used to solve the shortage of phosphorus resources in the world. However, high levels of toxic compounds and low phosphorus bioavailability in sewage sludge are the main factors limiting its direct agricultural use. This paper proposes a low temperature combustion method that can enrich the phosphorus in sludge ash. Low temperature-treated sewage sludge ash (LTSA) at different oxygen concentrations (20%, 60%, 100%) were obtained through a specific experimental device. Then, the species and leaching characteristics of phosphorus in LTSAs were analyzed and compared with pyrolysis sewage sludge char (PSSC) and incinerated sewage sludge ash (ISSA). Results show that low-temperature combustion of sludge increased the total phosphorus content in the bottom ash by 45.6%, and the bioavailable phosphorus content increased 2.9 times. Further, by increasing the concentration of oxygen while carrying out low-temperature combustion of sludge, part of the non-apatite inorganic P was converted to apatite P (AP), resulting in a 46.3% increase in AP in the sludge. Low-temperature combustion can also convert heavy metals (Cd, Cr, Cu, Pb, and Zn) in the sludge from an easily leachable form (acid extractable fraction and reducible fraction) to a stable form (reducible fraction) and decrease the leaching of heavy metals. Leaching of Cr and Cu decreased by 97.56% and 98.52%, respectively. PMID- 30455017 TI - How do social norms influence recycling behavior in a collectivistic society? A case study from Turkey. AB - This study investigates how social norms influence the household recycling behavior in collectivistic societies. High household participation rate is essential to accomplish the economic and environmental goals of recycling programs. To this end, the determinants of recycling behavior have long been studied, and social norms have been indicated as the strong predictor of recycling behavior. However, there is a need for a more in-depth examination to understand how social norms function in activating recycling behavior in different contexts. Hence, this study develops a model that disentangles the influence of social norms (i.e. informational and normal influences) on recycling behavior in a collectivistic social context. Using data collected from the households of the case-study area (Seferihisar, Turkey), the research hypotheses were tested via structural equation modelling. The findings confirm the influence of social norms on household recycling behavior, but this influence was found to occur not through internalization process. The causal chain effect triggered by social norms (i.e. internalization process) maintains its influence until the task knowledge necessary for recycling is obtained; however, this process does not end with actual recycling behavior. Rather, the results show that the perceived convenience mediates the influence of social norms on recycling behavior. In addition, the perceived convenience mediates the effects of physical constraints on recycling behavior. As well as revealing valuable theoretical implications, these results also provide managerial guidance in devising social norms to increase the household participation into recycling programs. PMID- 30455018 TI - Synthesis of ceramic pigments from industrial wastes: Red mud and electroplating sludge. AB - The perception of industrial waste has changed, in the last decades, from an economic and environmental problem to a potential raw material. In this work, the synthesis of a stable pigment was prepared by combining two hazardous and unexplored wastes: red mud (RM, rich in Fe) and electroplating sludge (ES, rich in Ni/Cr). The wastes were mixed in different proportions and calcined at 1200 degrees C. Black and brown pigments were obtained from the mixture of RM/ES in 1:3 and 1:1 wt proportions, respectively. The color was given by the chrome-iron nickel spinels, based on Ni2+ 3T1g(3F) transitions (~13,000 cm-1), Cr3+ 4A2g -> 4T1g(4F) transitions (~24,400 cm-1) and Fe3+ (~15,000-~22,500 cm-1). The achieved coloring strength and thermal stability on various ceramic glazes render excellent prospects for the industrial application of such waste-based pigments. PMID- 30455019 TI - Factor effect of operating conditions on the leaching of fly ashes from a pulp and paper mill. AB - The non-process-elements (NPE's) in the pulp and paper production, in particular chloride (Cl-) and potassium (K+), eventually accumulate in a sodium sulfate recovery cycle of a paper plant, especially on boiler fly ashes (flue gas cleaning). This accumulation often leads to fouling and corrosion. Thus, in order to reduce such problems, a leaching unit is typically integrated aiming to remove Cl- and K+ and recover sodium sulfate (Na2SO4) from boiler fly ashes. In this context, this research is focused on investigating the effects of temperature, ash concentration and pH on the separation efficiency (Cl- and K+ removal and Na2SO4 recovery) of recovery boiler fly ashes using design of experiments in a devised laboratory setup. As expected from the literature, the results obtained reveals that concentration has the most significant effect on the response variables followed by temperature; whereas pH, not mentioned in this application so far, also has a significant effect. The optimum operating condition, which yields 84 wt% of Na2SO4 recovery and 97 wt% of Cl- and K+ removal, is achieved at 60 degrees C, 50 wt% of ash and pH 9.0. For practical applications, this optimal condition reduces the accumulation of NPE's and mitigates the risks of fouling and corrosion. PMID- 30455020 TI - A numerical study on the behavior of coastal waste particles in a wind-power sorting system for renewable fuel production. AB - In this study, a Computational Fluid Dynamics (CFD) to analyze the coastal waste particles in a wind-power sorting system is applied to produce renewable fuel using commercial CFD package (ANSYS-CFX code). The numerical methodology results predicted various coastal waste shredded inside the sorting machine. Furthermore, to identify the effect of working conditions on separation characteristics, a parametric study is performed. These study findings will offer appropriate a wind power sorting conditions according to the purpose of using coastal waste. Under basic conditions, the characteristics of coastal waste particle behavior and the sorting of waste particles were analyzed, and the behavioral changes of diverse particles were identified by changing the airflow rate to improve the sorting performance. As a result, an appropriate airflow rate, Qair = 85 m3/min, at which the change in the airflow rate can simultaneously meet the conditions for both the recovery of the combustibles and the removal of the incombustibles, was selected with the selection efficiency rate was 92%, and the combustibles content was 99%. Based on the results of the analysis, the particle characteristics of sorting were identified to reduce and recycle the coastal waste. PMID- 30455022 TI - Multistage treatment of almonds waste biomass: Characterization and assessment of the potential applications of raw material and products. AB - Almond shells are waste biomass generated in agro-industrial activities, which represent a resource that can be further valorized upon treatment. The purpose of this work was to assess new value-added products obtained through a novel multi stage delignification process of almond shells. A comprehensive chemical characterization of the raw materials and products involved in each stage of the process was carried out. Moreover, an extensive mass balance was developed, providing a full understanding of the extraction process. The pulps produced did not display a significant cellulose loss and hence they could be exploited as cellulose-rich materials. On the other hand, the obtained lignins presented high purity values (~90%) and a high reactivity, and their structures became more condensed and homogeneous after each extraction cycle. These features would allow their utilization as feedstock of renewable materials such bio-sourced phenolic resins. PMID- 30455021 TI - Reduction of greenhouse gases (GHGs) and short-lived climate pollutants (SLCPs) from municipal solid waste management (MSWM) in the Philippines: Rapid review and assessment. AB - Municipal solid waste management (MSWM) is considered one of the serious environmental issues in the Philippines, with corresponding linkages to the climate change and Sustainable Development Goals (SDGs). However, methane (CH4) linked with indiscriminate dumping of municipal solid waste has received the much attention with regard to public health and climate change. The impacts of black carbon (BC) are less documented and understood. This paper aims to review the status of MSWM in the Philippines and makes efforts to assess the scale of short lived climate pollutants (SLCPs), including both CH4, and BC, associated with the country's waste sector. Utilising available national level data and following a life-cycle assessment (LCA) approach, the paper offers preliminary projections of SLCP emissions resulting from present MSWM practices. In addition, it examines model mitigation scenarios based on priority actions identified within the country's national policy on waste management, Republic Act 2003 (RA 9003). Data analysis was conducted using an Emission Quantification Tool (EQT) developed by the Institute for Global Environmental Strategies (IGES) through its work under the Climate and Clean Air Coalition (CCAC) - Municipal Solid Waste Initiative (MSWI). Following a summary of key findings, the paper affirms that control of methane from disposal practices and of BC from waste collection and open burning requires urgent attention in the Philippines. Continued awareness raising, institutionalising regulatory policies on SLCPs, and further enhancing data collection and capacity building on waste-related BC emissions remain key priorities for the country. PMID- 30455023 TI - Anaerobic degradation of bioplastics: A review. AB - Anaerobic digestion (AD) of the organic fraction of municipal solid waste (OFMSW), leading to renewable energy production in the form of methane, is a preferable method for dealing with the increasing amount of waste. Food waste is separated at the source in many countries for anaerobic digestion. However, the presence of plastic bags is a major challenge for such processes. This study investigated the anaerobic degradability of different bioplastics, aiming at potential use as collecting bags for the OFMSW. The chemical composition of the bioplastics and the microbial community structure in the AD process affected the biodegradation of the bioplastics. Some biopolymers can be degraded at hydraulic retention times usually applied at the biogas plants, such as poly(hydroxyalkanoate)s, starch, cellulose and pectin, so no possible contamination would occur. In the future, updated standardization of collecting bags for the OFMSW will be required to meet the requirements of effective operation of a biogas plant. PMID- 30455024 TI - Hydrometallurgical recycling of surface-coated metals from automobile-discarded ABS plastic waste. AB - The ammoniacal leaching of surface-coated metals from automobile-discarded ABS plastics followed by their recovery through solvent extraction has been investigated. The leaching of ABS (typically containing 4.1% Cu, 1.3% Ni, and 0.03% Cr) could efficiently dissolve the ammine complexes of Cu and Ni, leaving Cr unleached as fine particles. The optimization studies for achieving the maximum efficiency revealed that the leaching of metal ions in different ammoniacal solutions follows the order CO32- > Cl- > SO42-. The leaching carried out in a carbonate medium by maintaining the total NH3 concentration 5.0 M at a NH4OH/(NH4)2CO3 ratio of 4:1, pulp density of 200 g/L, agitation speed of 400 rpm, temperature of 20 degrees C, and time of 120 min yielded the optimum efficiency of >99% Cu and Ni (i.e., 8.14 g/L and 2.57 g/L, respectively, in the leach liquor). Subsequently, the solvent extraction of metals from ammoniacal leach liquor as a function of extractant (LIX 84-I) concentration and organic-to aqueous (O:A) phase ratio was examined. Based on the extraction data, a three stage counter-current extraction at O:A = 1:1 was validated using 0.8 M LIX 84-I, yielding the quantitative extraction of both metals into the organic phase. Thereafter, the stripping of metals in acid solutions indicated that 0.5 M H2SO4 could quantitatively strip Ni from the loaded organic phase; however, ~27% Cu was also co-stripped. The rest of Cu from the Ni-depleted organic phase was separately stripped with 1.0 M H2SO4 that can be directly sent to the electrowinning process. On the other hand, the co-stripped metals from the acidic solution can be easily separated, again using LIX 84-I as the extractant, by adopting the pH-swing method. Finally, a process has been proposed for the hydrometallurgical recovery of surface-coated metals from waste ABS plastics; that does not affect the physicochemical characteristics of the polymer substances for their reuse. PMID- 30455025 TI - Towards resource-efficient management of asphalt waste in Lombardy region (Italy): Identification of effective strategies based on the LCA methodology. AB - This study presents a comparison of alternative strategies for managing asphalt waste currently implemented in Lombardy Region (Italy). The waste under study is the one arising from deconstruction and milling of old pavements not containing tar, and, hereafter, it is referred as reclaimed asphalt pavement (RAP). The life cycle assessment (LCA) methodology was applied to the regional system to evaluate its current performance, to identify critical aspects and to suggest actions for improving it. As first step, the amount of RAP generated and recycled within the region was computed by elaborating raw waste data annually collected by the regional agency for the environmental protection. Roughly 1 million tonne of RAP was managed in Lombardy in 2014; most of it was recovered/recycled and only 1% was directly landfilled. Data revealed that RAP was mainly recovered as unbound aggregate for road bases and sub-bases or fillings (52.5%) whereas RAP addition into new asphalt mixtures was less widespread (39.4%). In this case, RAP was mostly recycled in stationary hot mix asphalt (HMAs) and cold mix asphalt (CMAs) plants. Hence, the present LCA focused on these two types of techniques. Primary data on both processes were directly collected from some investigated facilities to set out the current scenario. Sensitivity analyses were then performed to find out the key parameters and their influence on the LCA outcome. Results indicate that recycling RAP in hot/cold mixes is significantly more beneficial than its recovery as unbound material. Moreover, hot recycling provides better environmental performance than cold processes performed at stationary plants, despite the lower RAP addition (20% in HMAs vs 80% in CMAs); this is mainly due to the use of stabilizing agents in the production of CMAs and to the lower field performance of CMAs compared to virgin HMAs. Based on these results, a best-case scenario has been developed to quantify the benefits arising from the suggested actions. PMID- 30455026 TI - Physicochemical property enhancement of biodiesel synthesis from hybrid feedstocks of waste cooking vegetable oil and Beauty leaf oil through optimized alkaline-catalysed transesterification. AB - Recycling waste cooking vegetable oils by reclaiming and using these oils as biodiesel feedstocks is one of the promising solutions to address global energy demands. However, producing these biodiesels poses a significant challenge because of their poor physicochemical properties due the high free fatty acid content and impurities present in the feedstock, which will reduce the biodiesel yields. Hence, this study implemented the following strategy in order to address this issue: (1) 70 vol% of waste cooking vegetable oil blended with 30 vol% of Calophyllum inophyllum oil named as WC70CI30 used to alter its properties, (2) a three-stage process (degumming, esterification, and transesterification) was conducted which reduces the free fatty acid content and presence of impurities, and (3) the transesterification process parameters (methanol/oil ratio, reaction temperature, reaction time, and catalyst concentration) were optimized using response surface methodology in order to increase the biodiesel conversion yield. The results show that the WC70CI30 biodiesel has favourable physicochemical properties, good cold flow properties, and high oxidation stability (22.4 h), which fulfil the fuel specifications stated in the ASTM D6751 and EN 14214 standards. It found that the WC70CI30 biodiesel has great potential as a diesel substitute without the need for antioxidants and pour point depressants. PMID- 30455027 TI - Using indicators as a tool to evaluate municipal solid waste management: A critical review. AB - Indicators have been used to evaluate municipal solid waste management for several decades. This review summarizes the main groups of indicators used for this purpose, as the basis for developing a new proposal in the future. There are a number of problems (scarce or non-existent information, lack of transparency and homogeneity, among others) that prevent the methods proposed so far from being standardized and applied on a more global level. This paper documents 40 sets of indicators and analyzes their main characteristics, strengths, and weaknesses. Based on different authors and on the concept of integrated sustainable waste management, a new framework is proposed that includes all aspects of municipal solid waste management. All the documented indicators were classified according to this framework and compared in order to detect repetitions until a single list was reached. The groups analyzed contained a variety of characteristics, such as the type of indicators (qualitative, quantitative or both) and the level at which they are applicable (municipal, regional, national, international or various levels), among others. An analysis was also performed to determine how many cases each group has been applied to, as well as possible shortcomings that make them difficult to use. Finally, a list of 377 different indicators was obtained, with 49.3% of them focusing on technical aspects of waste management. The component for which most indicators were found was recovery (including recycling, composting, and incineration with energy recovery, among others). From the analysis, the main qualities that an indicator set must accomplish were identified to allow their possible standardization; that is, it must be useful at different geographical and economic levels, include indicators of different types, follow a clear methodology, and cover all aspects of possible interest. PMID- 30455028 TI - The steam gasification reactivity and kinetics of municipal solid waste chars derived from rapid pyrolysis. AB - Municipal solid waste treatment has been and will continue to be a major issue facing countries worldwide, and gasification has recently gained more attention as an efficient and clean technology. The steam gasification characteristics and kinetics of five different municipal solid waste chars had been investigated by the method of isothermal thermogravimetric analysis. The results showed that the gasification reactivity increased with gasification temperature. Effect of H/C and O/C ratios, ash composition and particle pore structure of chars on gasification reactivity were studied, which illustrated that the H/C and O/C ratios and ash composition had great influence on gasification reactivity and the pore structure cannot explain well in this study. A homogeneous model, unreacted shrinking core model and random pore model were employed to describe the kinetic behavior of different chars, and the kinetic parameters were also obtained. Finally, through the evaluation of the three kinetic models by comparing the experimental data with the fitted results, the random pore model was determined to perform best. This study should, therefore, be of some value to solid waste gasification industrialization. PMID- 30455030 TI - The influence of waste printed circuit boards characteristics and nonmetal surface energy regulation on flotation. AB - This paper studied the influence of waste printed circuit boards (PCBs) characteristics and nonmetal surface energy (SE) regulation on flotation. First, SEM-EDS was applied to study the appearance and surface element distribution of the glass fiber and copper. The results showed that the glass fiber was present in a bundle and the surface carbon content was 49.42%, which facilitated glass fiber floating. The copper appearance contained many nodules, with a carbon content of 32.54%, which hindered copper sorting. XPS analysis further discovered that copper was mainly present in the forms of CuO, Cu(Met), and Al2Cu. A FT-IR analysis revealed that the organic matter in the PCBs was essentially the same as the epoxy resin. It was easy to achieve floating and some polar functional groups promoted the adsorption of the flotation reagents. Based on this, by calculating the nonmetal SE, it was found that the proportion of the non-polar component of the nonmetal SE was 94.60%. The EDLVO theory was applied to research interactions between nonmetal particles. Hydrophobic attraction was found to be the main factor causing nonmetal particles to agglomerate. Further, the tannin was used to improve the dispersion of nonmetal by adjusting the nonmetal SE. Furthermore, the hydroxyl and carbonyl groups in the tannin may form hydrogen bonds with the bromine, epoxy and hydroxyl groups in the nonmetal. Finally, flotation test results indicated that tannin added significantly enhanced PCBs flotation efficiency. When the amount of tannin added increased from 0 to 60 mg/L, the recovery of copper increased from 61.92% to 90.53%. Thus, this study provides an alternative approach to improve the flotation efficiency of waste PCBs. PMID- 30455029 TI - Impacts of different biochar types on hydrogen production promotion during fermentative co-digestion of food wastes and dewatered sewage sludge. AB - Pyrolysis and anaerobic digestion are two important strategies for waste management that may be combined for clean energy production. This article investigates the effects of 12 types of biochars derived from four feedstocks at three pyrolysis temperatures on H2 production via fermentative co-digestion of food wastes and dewatered sewage sludge. The results show that feedstock type and pyrolysis temperature significantly influence biochar properties such as pH, specific surface area and ash contents. Despite the wide range of BET specific surface areas (1.2-511.3 m2/g) and ash contents (5.3-73.7(wt%)) of biochars produced, most biochars promoted the VFAs production process and altered the fermentative type from that of acetate type to butyrate type, which seemed to have a higher efficiency for H2 production. Moreover, fitting of the results to the modified Gompertz model shows that biochar addition shortens the lag time by circa 18-62% and increases the maximum H2 production rate by circa 18-110%. Furthermore, the biochar derived at higher pyrolysis temperatures enhances H2 production dramatically over those derived at low temperatures. Principal components analysis demonstrated that the pH buffering capacity of biochar was critical to the promotion of fermentative H2 production by mitigating the pH decrease caused by VFAs accumulation. Consequently, a sustainable integrated waste management strategy combining pyrolysis and anaerobic digestion is proposed for the efficient treatment of various bio-wastes. PMID- 30455031 TI - Valorization of wood chips ash as an eco-friendly mineral admixture in mortar mix design. AB - Wood chips ash coming from biomass heating plant is studied as an eco-friendly mineral admixture in mortar mix design. The raw material was mechanically activated by milling in a vibratory disc mill to a degree of fineness comparable to cement. For the mortars with ash dosage, basic physical, mechanical, hygric, and thermal properties is accessed. The mortars with partial Portland cement replacement with wood chips ash exhibited good functional properties for all studied ash dosages. With increasing amount of the ash used, the average pore diameter decreased due to the partial filler effect of WCHA in mortar mix. The strength activity index was very high for all studied mortars and gave evidence of the wood chips ash pozzolanity. The pozzolan effectiveness coefficient varied from 1.52 to 0.59, which proved the pozzolanity of the studied ash and synergic effects in the Portland cement-ash-water system. The results of leaching tests showed, the chlorides contained in ash were safely immobilized in the silicate matrix. The environmental evaluation revealed decrease in both carbon dioxide production and energy consumption by the use of wood chips ash in mortar mix. For the mortar with 20% substitution of Portland cement with wood chips ash, it represents 15% of CO2 and 16% of energy, as compared with the reference mortar mix. As the developed mortars possess good functional and environmental parameters the analyzed wood chips ash can be considered as an eco-efficient low cost alternative to other pozzolans for production of blended binders. PMID- 30455032 TI - Reliability and validity of clinical tests to assess posture, pain location, and cervical spine mobility in adults with neck pain and its associated disorders: Part 4. A systematic review from the cervical assessment and diagnosis research evaluation (CADRE) collaboration. AB - PURPOSE: To determine the reliability and validity of clinical tests to assess posture, pain location, and cervical spine mobility in adults with grades I-IV neck pain and associated disorders (NAD). METHODS: We systematically searched electronic databases to update the systematic review of the Bone and Joint Decade 2000-2010 Task Force on Neck Pain and Its Associated Disorders. Eligible reliability and validity studies were critically appraised using modified versions of the QAREL and QUADAS-2 instruments, respectively. Evidence from low risk of bias studies were synthesized following best evidence synthesis principles. RESULTS: We screened 14302 articles, critically appraised 46 studies, and found 32 low risk of bias articles (14 reliability and 18 validity studies). We found preliminary evidence of: 1) reliability of visual inspection, aided with devices (CROM and digital caliper) to assess head posture; 2) reliability and validity of soft tissue palpation to locate tender/trigger points in muscles; 3) reliability and validity of joint motion palpation to assess stiffness and pain provocation in combination; and 4) range of motion tests using visual estimation (in cervical extension only) or devices (digital caliper, goniometer, inclinometer) to assess cervical mobility. CONCLUSIONS: We found little evidence to support the reliability and validity of clinical tests to assess head posture, pain location and cervical mobility in adults with NAD grades I-III. More advanced validity studies are needed to inform the clinical utility of tests used to evaluate patients with NAD. PMID- 30455033 TI - Midsagittal facial soft tissue thickness norms in an adult Mediterranean population. AB - The use of facial soft tissue thickness (FSTT) values is essential in forensic facial approximation. Few studies have assessed the FSTT norms in Mediterranean populations and none in the Lebanese population. The purpose of this study was to (1) present midsagittal facial FSTT norms for Lebanese adults with well-balanced faces and normal occlusion; (2) evaluate the presence of sexual dimorphism within these measurements; (3) establish a potential correlation between these measurements and (4) build on the existing database of FSTT data from previously published studies. FSTT measurements at 10 midsagittal locations were obtained from the lateral cephalometric radiographs of 87 males and 135 females (mean age of 23.49+/-6.24years). In additional to means, Shorth and 75-Shormax values are presented. Differences between sexes were assessed using the MANOVA test and correlations between different measurements were computed. The thinnest (3.07+/ 0.72mm) and thickest (15.61+/-2.38mm) craniofacial soft tissue measurements existed at Rhinion and Subnasale, respectively. There was a statistically significant and large effect of sex on the combined FSTT variables (p<0.001; eta squared=0.393). Males displayed larger FSTT values at all landmarks except at Glabella (p=0.162). Significant correlations were observed between almost all measurements with the highest being between the upper and lower lips (r=0.763) and between Pogonion and Gnathion (r=0.784). The descriptive values of FSTT values reported in this study add to the body of research necessary for the enhancement of facial approximation methods The uniquely strong effects of sex on FSTT measurements combined and on selected single FSTT measurements are an area for further research. PMID- 30455034 TI - Longitudinal Heterogeneity in Handgun-Carrying Behavior Among Urban American Youth: Intervention Priorities at Different Life Stages. AB - PURPOSE: To determine longitudinal patterns of handgun-carrying behavior among urban American youth and identify modifiable risk factors associated with distinct carrying patterns that should be targeted at different life stages. METHODS: Using panel data from the National Longitudinal Survey of Youth 1997, we estimated longitudinal trajectories of handgun carrying among urban Americans, who carried a handgun at least once between 1997 and 2011 (N = 1,574). Multinomial logistic regression analyses examined risk factors associated with handgun-carrying trajectory groups during late adolescence (ages 16-20), emerging adulthood (ages 20-24), and young established adulthood (ages 24-28). RESULTS: Group-based trajectory analyses identified four groups: Declining (35.0%, N = 560), bell-shaped (35.5%; N = 561), late-initiating (19.6%; N = 303), and high persistent (9.9%; N = 150). During late adolescence, lower risks of mental health problems, hard drug use, police arrest, and presence of a gang in the neighborhood or school differentiated the late-initiating group from the other higher risk groups. During emerging and young established adulthood, higher risks of alcohol use, police arrest, and presence of a gang in the neighborhood or school were associated with trajectory groups with higher likelihood of handgun carrying than the declining group. CONCLUSIONS: There are more than one profile of adolescents and young adults who carry handguns. Preventive interventions should have distinct priorities that address different patterns of handgun carrying behavior at different life stages. PMID- 30455035 TI - Relationship Between Recency and Frequency of Youth Cannabis Use on Other Substance Use. AB - PURPOSE: To assess the relationship between lifetime, past-year, and frequent past-year cannabis use on use of other substances among youth in order to inform prevention initiatives. METHODS: Data are from 27,900 youth aged 12-17 participating in the 2015-2016 National Surveys on Drug Use and Health. Multivariable multinomial logistic regression assessed the relationship between levels of youth cannabis use and past-year use of other substances compared to youth with no lifetime cannabis use. RESULTS: Prevalence of lifetime cannabis use among youth was 15.4%; 3.0% reported lifetime but not past-year use, 10.3% reported past-year use <200 days, and 2.1% reported past-year use >=200 days. Past-year tobacco and alcohol use, and past-year misuse of prescription sedatives or tranquilizers, stimulants, and opioids were associated with increased adjusted relative risk ratios across all levels of cannabis use compared to youth reporting no lifetime cannabis use. Increased adjusted relative risk ratios across all levels of cannabis use were seen among youth aged 14-15 and 16-17 compared to 12-17 and among non-Hispanic blacks and Hispanics compared to non Hispanic whites. CONCLUSIONS: Cannabis use is prevalent among youth and associated with other substance use. Efforts to scale up prevention programming and science-based messaging on risks of substance use are needed. PMID- 30455036 TI - Retrospective and perspective of plant epigenetics in China. AB - Epigenetics refers to the study of heritable changes in gene function that do not involve changes in the DNA sequence. Such effects on cellular and physiological phenotypic traits may result from external or environmental factors or be part of normal developmental program. In eukaryotes, DNA wraps on a histone octamer (two copies of H2A, H2B, H3 and H4) to form nucleosome, the fundamental unit of chromatin. The structure of chromatin is subjected to a dynamic regulation through multiple epigenetic mechanisms, including DNA methylation, histone posttranslational modifications (PTMs), chromatin remodeling and noncoding RNAs. As conserved regulatory mechanisms in gene expression, epigenetic mechanisms participate in almost all the important biological processes ranging from basal development to environmental response. Importantly, all of the major epigenetic mechanisms in mammalians also occur in plants. Plant studies have provided numerous important contributions to the epigenetic research. For example, gene imprinting, a mechanism of parental allele-specific gene expression, was firstly observed in maize; evidence of paramutation, an epigenetic phenomenon that one allele acts in a single locus to induce a heritable change in the other allele, was firstly reported in maize and tomato. Moreover, some unique epigenetic mechanisms have been evolved in plants. For example, the 24-nt siRNA-involved RNA directed DNA methylation (RdDM) pathway is plant-specific because of the involvements of two plant-specific DNA-dependent RNA polymerases, Pol IV and Pol V. A thorough study of epigenetic mechanisms is of great significance to improve crop agronomic traits and environmental adaptability. In this review, we make a brief summary of important progress achieved in plant epigenetics field in China over the past several decades and give a brief outlook on future research prospects. We focus our review on DNA methylation and histone PTMs, the two most important aspects of epigenetic mechanisms. PMID- 30455037 TI - Fruit fly research in China. AB - Served as a model organism over a century, fruit fly has significantly pushed forward the development of global scientific research, including in China. The high similarity in genomic features between fruit fly and human enables this tiny insect to benefit the biomedical studies of human diseases. In the past decades, Chinese biologists have used fruit fly to make numerous achievements on understanding the fundamental questions in many diverse areas of biology. Here, we review some of the recent fruit fly studies in China, and mainly focus on those studies in the fields of stem cell biology, cancer therapy and regeneration medicine, neurological disorders and epigenetics. PMID- 30455038 TI - A legacy of the "1% program" - The "Chinese Chapter" of the human genome reference sequence. PMID- 30455039 TI - Conservation genetics and genomics of threatened vertebrates in China. AB - Conservation genetics and genomics are two independent disciplines that focus on using new techniques in genetics and genomics to solve problems in conservation biology. During the past two decades, conservation genetics and genomics have experienced rapid progress. Here, we summarize the research advances in the conservation genetics and genomics of threatened vertebrates (e.g., carnivorans, primates, ungulates, cetaceans, avians, amphibians and reptiles) in China. First, we introduce the concepts of conservation genetics and genomics and their development. Second, we review the recent advances in conservation genetics research, including noninvasive genetics and landscape genetics. Third, we summarize the progress in conservation genomics research, which mainly focuses on resolving genetic problems relevant to conservation such as genetic diversity, genetic structure, demographic history, and genomic evolution and adaptation. Finally, we discuss the future directions of conservation genetics and genomics. PMID- 30455040 TI - Idiopathic ischaemic ileitis, with overt obscure digestive bleeding. PMID- 30455041 TI - Crohn's disease in a girl with VACTERL association: Can mitochondrial dysfunction coexist? PMID- 30455042 TI - Adhesion of Active Cytoskeletal Vesicles. AB - Regulation of adhesion is a ubiquitous feature of living cells, observed during processes such as motility, antigen recognition, or rigidity sensing. At the molecular scale, a myriad of mechanisms are necessary to recruit and activate the essential proteins, whereas at the cellular scale, efficient regulation of adhesion relies on the cell's ability to adapt its global shape. To understand the role of shape remodeling during adhesion, we use a synthetic biology approach to design a minimal experimental model, starting with a limited number of building blocks. We assemble cytoskeletal vesicles whose size, reduced volume, and cytoskeletal contractility can be independently tuned. We show that these cytoskeletal vesicles can sustain strong adhesion to solid substrates only if the actin cortex is actively remodeled significantly. When the cytoskeletal vesicles are deformed under hypertonic osmotic pressure, they develop a crumpled geometry with deformations. In the presence of molecular motors, these deformations are dynamic in nature, and the excess membrane area generated thereby can be used to gain adhesion energy. The cytoskeletal vesicles are able to attach to the rigid glass surfaces even under strong adhesive forces just like the cortex-free vesicles. The balance of deformability and adhesion strength is identified to be key to enable cytoskeletal vesicles to adhere to solid substrates. PMID- 30455043 TI - Tissue Flow Induces Cell Shape Changes During Organogenesis. AB - In embryonic development, cell shape changes are essential for building functional organs, but in many cases, the mechanisms that precisely regulate these changes remain unknown. We propose that fluid-like drag forces generated by the motion of an organ through surrounding tissue could generate changes to its structure that are important for its function. To test this hypothesis, we study the zebrafish left-right organizer, Kupffer's vesicle (KV), using experiments and mathematical modeling. During development, monociliated cells that comprise KV undergo region-specific shape changes along the anterior-posterior axis that are critical for KV function: anterior cells become long and thin, whereas posterior cells become short and squat. Here, we develop a mathematical vertex-like model for cell shapes that incorporates both tissue rheology and cell motility and constrain the model parameters using previously published rheological data for the zebrafish tailbud as well as our own measurements of the KV speed. We find that drag forces due to dynamics of cells surrounding KV could be sufficient or work in concert with previously identified mechanisms to drive KV cell shape changes during KV development. More broadly, these results suggest that cell shape changes during embryonic development and beyond could be driven by dynamic forces not typically considered in models or experiments. PMID- 30455044 TI - Septic arthritis caused by Staphylococcus caprae following arthroscopic meniscus tear repair in a patient without any foreign device. PMID- 30455045 TI - RIP Kinases in Liver Cell Death, Inflammation and Cancer. AB - Cell death is intrinsically linked to inflammatory liver disease and cancer development. Recent genetic studies have suggested that receptor-interacting protein kinase (RIPK)1 is implicated in liver disease pathogenesis by regulating caspase-dependent hepatocyte apoptosis induced by tumor necrosis factor (TNF) or other stimuli. In contrast, the contribution of caspase-independent RIPK3/mixed lineage kinase like (MLKL)-mediated hepatocyte necroptosis remains debatable. Hepatocyte apoptosis depends on the balance between RIPK1 prosurvival scaffolding functions and its kinase-activity-mediated proapoptotic function. Several regulatory steps promote the prosurvival role of RIPK1, including phosphorylation and ubiquitination of RIPK1 itself and other molecules involved in RIPK1 signaling. Pharmacological inhibition of liver damage by targeting RIPK1 signaling emerges as a potential therapeutic strategy to prevent chronic liver inflammation and hepatocarcinogenesis. PMID- 30455046 TI - Optimization of the follow-up of pregnant women with autoimmune thyroid disease. AB - OBJECTIVE: To determine the risk of hypothyroidism in pregnant women with autoimmune thyroid disease and thyrotropin (TSH) < 2,5 mIU/l at the beginning of pregnancy. METHODS: Prospective longitudinal study of pregnant women with no personal history of thyroid disease, and with TSH < 2.5 mIU/l in the first trimester. TSH, free thyroxine (FT4), anti peroxidase (TPO) and anti thyroglobulin antibodies were measured in the 3 trimesters of pregnancy. We compared thyroid function throughout pregnancy, and the development of gestational hypothyroidism (TSH >4 mIU/l) among pregnant women with positive thyroid autoimmunity and those with negative autoimmunity. RESULTS: We included 300 pregnant women with mean baseline TSH 1.3 +/- 0.6 mIU/l (9th gestational week). Positive thyroid autoinmunity was detected in 17.7% of women (n = 53) at the first trimester. Between the first and the third trimesters, TPO and anti thyroglobulin antibodies titers decreased 76.8% and 80.7% respectively. Thyroid function during pregnancy was similar among the group with positive autoimmunity and the group with negative autoimmunity, and the development of hypothyroidism was 1.9% (1/53) and 2% (5/247) respectively. Pregnant women in whom TSH increased above 4 mIU/l (n = 6), had higher baseline TSH levels compared to those who maintained TSH <=4 mIU/l during pregnancy (1.8 vs. 1.3 mIU/l; p=.047). CONCLUSION: In our population, women with TSH levels <2.5 mIU/l at the beginning of pregnancy have a minimal risk of developing gestational hypothyroidism regardless of thyroid autoimmunity. PMID- 30455047 TI - Development of the Decannulation Prediction Tool in Patients With Dysphagia After Acquired Brain Injury. AB - OBJECTIVES: Patients with acquired brain injuries (ABIs) often need tracheostomy because of dysphagia. However, many of them may recover over time and be eventually decannulated during post-acute rehabilitation. We developed the Decannulation Prediction Tool (DecaPreT) to identify, early in the post-acute course, patients with ABIs who can be safely decannulated. DESIGN: Nonconcurrent cohort study. SETTING AND PARTICIPANTS: Patients with ABI, as well as with dysphagia and tracheostomy, were retrospectively selected from the database of a neurorehabilitation unit in Correggio, Reggio Emilia, Italy. MEASURES: Potential bivariate predictors of decannulation were screened from variables collected on admission during clinical examination, conducted by an expert speech therapist. Multivariable prediction was then obtained in 2 separate random subsamples to develop and validate the logistic regression model of the DecaPreT. RESULTS: Of 463 patients with ABI (mean age 52.2 years) selected, 73.0% could be safely decannulated before discharge. After bivariate screening, multivariable predictors of decannulation were identified in the development subsample and confirmed in the validation subsample, each with its odds ratio and 95% confidence interval as follows: age tertile (1.77, 1.08-2.89; P = .024), no saliva aspiration (3.89, 1.73-8.64; P = .001), pathogenesis of ABI (trauma vs other causes vs stroke vs anoxia: 2.23, 1.41-3.54; P = .001), no vegetative status (8.47; 2.91-24.63; P < .001), and coughing score (voluntary and reflex vs voluntary vs reflex vs neither voluntary nor reflex cough: 2.62, 1.70-4.05; P < .001). In the validation subsample, the predicting equation obtained an area under the receiver operating characteristics curve of 0.836. IMPLICATIONS: The DecaPreT predicts safe decannulation in patients with dysphagia and tracheostomy, using simple clinical variables detected early in the post-acute phase of ABI. The tool can help clinicians choose timing and intensity of rehabilitation interventions and plan discharge. PMID- 30455048 TI - Influence of Frailty on Cognitive Decline: A Population-Based Cohort Study in Rural Ecuador. AB - OBJECTIVE: To assess the influence of frailty on cognitive decline. DESIGN: Population-based prospective cohort study. SETTINGS/PARTICIPANTS: Community dwelling older adults living in a rural Ecuadorian village, fulfilling the following criteria: age >=60 years at baseline Montreal Cognitive Assessment (MoCA) and frailty assessment, a baseline brain magnetic resonance imaging, and a follow-up MoCA performed at least 12 months after the baseline. MEASURES: Frailty was evaluated by the Edmonton Frailty Scale (EFS) and cognitive performance by MoCA. The relationship between baseline EFS and MoCA decline was assessed by longitudinal linear and fractional polynomial models, adjusted for relevant confounders. The score of the cognitive component of the EFS was subtracted, and an alternative fractional polynomial model was fitted to settle the impact of such cognitive question on the model. RESULTS: A total of 252 individuals, contributing 923.7 person-years of follow-up (mean: 3.7 +/- 0.7 years) were included. The mean EFS score was 4.7 +/- 2.5 points. The mean baseline MoCA score was 19.5 +/- 4.5 points, and that of the follow-up MoCA was 18.1 +/- 4.9 points (P = .001). Overall, 154 (61%) individuals had lower MoCA scores in the follow up. The best fitted longitudinal linear model showed association between baseline EFS score and MoCA decline (P = .027). There was a continuous increase in MoCA decline in persons with an EFS >=7 points (nonlinear relationship). Fractional polynomials explained the effect of the EFS on MoCA decline. For the complete EFS score, the beta coefficient was 2.43 (95% confidence interval 1.22-3.63). For the effect of the EFS (without its cognitive component) on MoCA decline, the relationship was still significant (beta 4.86; 95% confidence interval 2.6-7.13). CONCLUSIONS/IMPLICATIONS: Over a 3.7-year period, 61% of older adults living in Atahualpa experienced cognitive decline. Such decline was significantly associated with frailty status at baseline. Region-specific risk factors influencing this relationship should be further studied to reduce its burden in rural settings. PMID- 30455049 TI - Impact of Environmental Modifications to Enhanced Day-Night Orientation on Behavior of Nursing Home Residents With Dementia. AB - OBJECTIVES: To determine whether environmental rearrangements of the long-term care nursing home can affect disruptive behavioral and psychological symptoms of dementia (BPSD) in residents with dementia. DESIGN: Prospective 6-month study. SETTING: The study was conducted before (phase 1) and after (phase 2) environmental rearrangements [skylike ceiling tiles in part of the shared premises, progressive decrease of the illuminance at night together with soothing streaming music, reinforcement of the illuminance during the day, walls painted in light beige, oversized clocks in corridors, and night team clothes color (dark blue) different from that of the day team (sky blue)]. PARTICIPANTS: All of the patients (n = 19) of the protected unit were included in the study. They were aged 65 years or older and had an estimated life expectancy above 3 months. MEASURES: Number and duration of disruptive BPSD were systematically collected and analyzed over 24 hours or during late hours (6:00-12:00 pm) during each 3 month period. RESULTS: There was no significant change in the patients' dependency, risk of fall, cognitive or depression indexes, or treatment between phase 1 and 2. Agitation/aggression and screaming were observed mainly outside the late hours as opposed to wandering episodes that were noticed essentially within the late hours. The number of patients showing wandering was significantly lower over 24 hours during phase 2. The number of agitation/physical aggression, wandering, and screaming and the mean duration of wandering episodes were significantly (P = .039, .002, .025, and .026 respectively) decreased over 24 hours following environmental rearrangements. Similarly, a significant reduction in the number and mean duration of wandering was noticed during the late hours (P = .031 and .007, respectively). CONCLUSIONS: Our study demonstrates that BPSD prevalence can be reduced following plain environmental rearrangements aimed at improving spatial and temporal orientation. PMID- 30455050 TI - Novelty and Dopaminergic Modulation of Memory Persistence: A Tale of Two Systems. AB - Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) corelease noradrenaline and dopamine in the hippocampus and that their dopamine release boosts memory retention as well. In this opinion article, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones ('common novelty') activate the VTA and promote semantic memory formation via systems memory consolidation. By contrast, experiences that bear only a minimal relationship to past experiences ('distinct novelty') activate the LC to trigger strong initial memory consolidation in the hippocampus, resulting in vivid and long-lasting episodic memories. PMID- 30455051 TI - Attrition rates in integrated vascular and cardiothoracic surgery residency and fellowship programs. AB - BACKGROUND: Attrition in surgical programs remains a significant problem resulting in trainee dissatisfaction and wasted time and educational dollars. Attrition rates in general surgery training programs approximate 5% per year (30% cumulative). Attrition rates in cardiovascular surgery training for the traditional vascular surgery fellowship (VSF), the vascular surgery residency (VSR), and the corresponding programs in cardiothoracic surgery have yet to be described, although they are assumed to be similar to those associated with general surgery training. METHODS: A retrospective review of the Association of American Medical Colleges Annual Physician Specialty Data Book was performed. Data from consecutive academic years 2007-2008 to 2013-2014 were analyzed. The number of total residents, the number who did not complete their training, and those who successfully completed the program were recorded. Attrition rates were then calculated for VSF, VSR, general surgery residency (GSR), cardiothoracic surgery fellowship (CTF), and cardiothoracic surgery integrated residency (CTR). RESULTS: Annually, between 2007-2008 and 2013-2014, there were zero to two vascular surgery residents who failed to complete the program (0%-5.9%). In the last 4 years of the study, whereas the absolute number of residents who failed to complete the program remained constant at 1 or 2 per year, the attrition rate decreased to 1 of 171 trainees (0.6%) in 2013-2014 as the total number of programs (and numbers of vascular surgery residents) significantly increased. During the same 7-year period, the number of vascular surgery fellows who did not complete their training ranged from one to six annually (0.4%-2.5%). Compared with the VSF, the VSR data show a relatively low and constant rate of attrition. In contrast, the number of general surgery residents who did not complete their program during the study period varied from 255 to 388 residents annually (3.3% 5.2%). During its first 3 years of inception, the CTR program had an attrition rate of 0%, and it was not until 2012-2013 that trainees failed to complete the program, resulting in an annual attrition rate of 1.2% to 3.2% from that point on. The annual attrition rate of CTF training programs ranged from 7 to 15 fellows (2.9%-6.8%) during the study period. CONCLUSIONS: The inception of VSR and CTR programs dramatically changed the paradigms for training in these highly specialized surgical fields. Comparisons of attrition rates between these two programs and the traditional VSF and CTR as well as GSR suggests lesser rates of attrition in the integrated programs. These data may prove reassuring to VSR and CTR program directors, whose significantly smaller programs are more vulnerable to the loss of even a single trainee than general surgery training programs are. In addition, the VSF program has stable and lower attrition rates compared with the CTF and GSR programs. PMID- 30455052 TI - Use of carbon isotopic ratios in nontargeted analysis to screen for anthropogenic compounds in complex environmental matrices. AB - Analytical data for ultra-high-performance liquid chromatography (UHPLC), nontargeted, high-resolution, mass-spectrometry (HR/MS) molecular features from a wide array of samples are used to calculate 13C112C(n-1)/12Cn isotopologue ratios. These ratios increase with molecular carbon number roughly following a trend defined by atmospheric carbon. When the effective source reservoir 13C/12C ratio is calculated from the isotopologue ratio (assuming a fractionation factor of unity), features in biotic samples uniformly are tightly grouped, proximate to atmospheric 13C/12C ratio. In contrast, features in soil natural organic matter (NOM), dust NOM and anthropogenic compounds range from proximate to relatively divergent from atmospheric 13C/12C. For the NOM, 13C/12C ratios are consistent with an expected preferential volatilization of 12C, rendering features in soil NOM 13C-enriched and some features in dust NOM 13C-depleted. Anthropogenic compounds tend to diverge most dramatically from atmospheric 13C/12C, generally toward 13C-depletion, but pesticides we tested tended toward 13C-enriched. This pattern is robust and evident in: i) anthropogenic vs natural features in dust; ii) perfluorinated compounds in standards and as soil contaminants; and iii) sunscreen compounds in commercial products and wastewater. Considering the observed wide 13C/12C range for anthropogenic compounds, we suggest Rayleigh distillation during synthetic processes commonly favors one isotope over the other, rendering a source reservoir that is progressively depleted as synthesis proceeds and, consequently, generates a wide variation in 13C/12C for man-made products. However, kinetic-isotopic effects and/or synthesis from petroleum/natural gas might contribute to the anthropogenic isotopic signature as well. Regardless of cause, 13C/12C can be used to cull HR/MS molecular features that are more likely to be of anthropogenic or non-biotic origin. PMID- 30455053 TI - Comprehensive comparative compositional study of the vapour phase of cigarette mainstream tobacco smoke and tobacco heating product aerosol. AB - A simple direct sample collection/dilution and introduction method was developed using quartz wool and Tenax/sulficarb sorbents for thermal desorption and comprehensive two-dimensional gas chromatography (TD-GC * GC) analyses of volatile organic compounds from vapour phase (VP) fractions of aerosol produced by tobacco heating products (THP1.0) and 3R4F mainstream tobacco smoke (MTS). Analyses were carried out using flame ionisation detection (FID) for semi quantification and both low and high resolution time-of-flight mass spectrometry (LR/HR-TOFMS) for qualitative comparison and peak assignment. Qualitative analysis was carried out by combining identification data based on linear retention indices (LRIs) with a match window of +/-10 index units, mass spectral forward and reverse library searches (from LR and HRTOFMS spectra) with a match factor threshold of >700 (both forward and reverse), and accurate mass values of +/- 3 ppm for increased confidence in peak identification. Using this comprehensive approach of data mining, a total of 79 out of 85 compounds and a total of 198 out of 202 compounds were identified in THP1.0 aerosol and in 3R4F MTS, respectively. Among the identified analytes, a set of 35 compounds was found in both VP sample types. Semi-quantitative analyses were carried out using a chemical class-based external calibration method. Acyclic, alicyclic, aromatic hydrocarbons and ketones appeared to be prominent in 3R4F MTS VP, whereas larger amounts of aldehydes, ketones, heterocyclic hydrocarbons and esters were present in THP1.0 aerosol VP. The results demontsrate the capability and versatility of the method for the characterization and comparison of complex aerosol samples and highlighted the relative chemical simplicity of THP1.0 aerosol in comparison to MTS. PMID- 30455054 TI - Failure to sense energy depletion may be a novel therapeutic target in chronic kidney disease. AB - The kidneys consume a large amount of energy to regulate volume status and blood pressure and to excrete uremic toxins. The identification of factors that cause energy mismatch in the setting of chronic kidney disease (CKD) and the development of interventions aimed at improving this mismatch are key research imperatives. Although the critical cellular energy sensor 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is known to be inactivated in CKD, the mechanism of AMPK dysregulation is unknown. In a mouse model of CKD, metabolome analysis confirmed a decrease in AMPK activation in the kidneys despite a high AMP: ATP ratio, suggesting that AMPK did not sense energy depletion. Similar AMPK inactivation was found in heart and skeletal muscle in CKD mice. Several uremic factors were shown to inactivate AMPK in vitro and in ex vivo preparations of kidney tissue. The specific AMPK activator A-769662, which bypasses the AMP sensing mechanism, ameliorated fibrosis and improved energy status in the kidneys of CKD mice, whereas an AMP analog did not. We further demonstrated that a low-protein diet activated AMPK independent of the AMP sensing mechanism, leading to improvement in energy metabolism and kidney fibrosis. These results suggest that a failure to sense AMP is the key mechanism underlying the vicious cycle of energy depletion and CKD progression and direct AMPK activation may be a novel therapeutic approach in CKD. PMID- 30455055 TI - Autoimmune pancreatitis in children: A single centre experience in diagnosis, management and long term follow up. AB - OBJECTIVES: Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis and data is limited in the paediatric population. We aim to describe in detail a cohort of paediatric patients with AIP including their presentation, investigations that led to their diagnosis, management and long-term follow up. METHODS: We retrospectively reviewed the data of 6 patients diagnosed with AIP over an 10-year period. Data including demographics, clinical information, laboratory parameters, serological markers, radiological and histological findings as well as longitudinal follow up were collected. RESULTS: Out of the six patients, one was diagnosed with definitive Type 1 AIP, two with definitive Type 2 AIP, two with probable Type 2 AIP and one with suspected Type 2 AIP. Median time of follow up was 3.9 years (range 2.6-10.1). 4 patients had pancreatic biopsies with 2 of these patients showing granulocytic epithelial lesions (GELs). 4 patients received steroids and two of them developed ulcerative colitis. Azathioprine was commenced on the patient with Type 1 AIP to help her wean off steroids that caused significant side effects on her. Only two patients developed exocrine insufficiency. CONCLUSIONS: The long term follow up of our cohort of paediatric AIP shows good prognosis. More follow up data on patients with AIP is needed to help further characterize and define the disease. PMID- 30455056 TI - Combining bioinformatics, cheminformatics, functional genomics and whole organism approaches for identifying epigenetic drug targets in Schistosoma mansoni. AB - Schistosomiasis endangers the lives of greater than 200 million people every year and is predominantly controlled by a single class chemotherapy, praziquantel (PZQ). Development of PZQ replacement (to combat the threat of PZQ insensitivity/resistance arising) or combinatorial (to facilitate the killing of PZQ-insensitive juvenile schistosomes) chemotherapies would help sustain this control strategy into the future. Here, we re-categorise two families of druggable epigenetic targets in Schistosoma mansoni, the histone methyltransferases (HMTs) and the histone demethylases (HDMs). Amongst these, a S. mansoni Lysine Specific Demethylase 1 (SmLSD1, Smp_150560) homolog was selected for further analyses. Homology modelling of SmLSD1 and in silico docking of greater than four thousand putative inhibitors identified seven (L1 - L7) showing more favourable binding to the target pocket of SmLSD1 vs Homo sapiens HsLSD1; six of these seven (L1 - L6) plus three structural analogues of L7 (L8 - L10) were subsequently screened against schistosomula using the Roboworm anthelmintic discovery platform. The most active compounds (L10 - pirarubicin > L8 - danunorubicin hydrochloride) were subsequently tested against juvenile (3 wk old) and mature (7 wk old) schistosome stages and found to impede motility, suppress egg production and affect tegumental surfaces. When compared to a surrogate human cell line (HepG2), a moderate window of selectivity was observed for the most active compound L10 (selectivity indices - 11 for schistosomula, 9 for juveniles, 1.5 for adults). Finally, RNA interference of SmLSD1 recapitulated the egg-laying defect of schistosomes co-cultivated in the presence of L10 and L8. These preliminary results suggest that SmLSD1 represents an attractive new target for schistosomiasis; identification of more potent and selective SmLSD1 compounds, however, is essential. Nevertheless, the approaches described herein highlight an interdisciplinary strategy for selecting and screening novel/repositioned anti-schistosomals, which can be applied to any druggable (epigenetic) target encoded by the parasite's genome. PMID- 30455057 TI - Recovering host cell-free Anaplasma phagocytophilum from HL-60 cells by using rock tumbler grit in comparison to the syringe lysis method. AB - Anaplasma phagocytophilum (Ap) is a tick-transmitted obligate intracellular bacterium and the causative agent of the granulocytic anaplasmosis in various species of domestic animals and in humans. During intracellular development Ap transforms from a dense-cored cell form into a reticulate cell form and vice versa. For isolation of intracellular bacteria, a range of different purification methods is used. However, unlike other Gram-negative bacteria Ap is considered to be sensitive to mechanical stress and osmolarity changes. An updated semi purification method using rock tumbler grit is introduced here to increase the outcome of bacteria and to facilitate the procedure of host cell lysis. The objective of this study was to evaluate the structural integrity and infectivity of Ap after lysis of the host cells using rock tumbler grit and to compare the outcome to that of the frequently used method, syringe lysis. Human promyelocytic leukemia cell lines (HL-60) were infected with Ap and following host cell-free bacteria were assessed by transmission electron microscopy. The outcome of the different purification methods was compared using live/dead-staining based on immunofluorescence to count the number of viable bacteria and real-time PCR to compare the amount of DNA. Subsequently the isolated bacteria were tested to infect naive cell cultures. We observed that both Ap dense-cored cells and reticulate cells are preserved intact after the application of rock tumbler grit. The number of viable, host cell-free bacteria was higher by factor 1.7-2.4 compared to the syringe lysis protocol. Quantitative analysis based on real-time PCR showed an increase of bacterial DNA up to 1.6-2.9 times higher using the rock tumbler grit protocol. Bacteria released from the same number of infected host cells were used for new infections. Flow cytometric analysis of the cell cultures confirmed that the number of Ap organisms recovered by using the rock tumbler grit protocol resulted in higher infection rates than the number of Ap organisms recovered by using syringe lysis protocol. Our observations indicate that the rock tumbler grit protocol can be applied as a safe, robust and convenient method to recover Ap compared to syringe lysis. PMID- 30455058 TI - The effect of mood phases on balance control in bipolar disorder. AB - The aim of this study was to investigate balance control during gait and sit-to walk in individuals with bipolar disorder and healthy controls by examining the inclination angles between the whole-body center-of-mass (COM) and ankle in the sagittal plane. Twenty-one individuals with bipolar disorder in the euthymic (i.e., asymptomatic; n = 11) and depressed (n = 10) phases and 7 healthy controls (ages between 18 and 45) performed gait and sit-to-walk at self-selected comfortable speed. Mood phases for individuals with bipolar disorder were measured using the Patient Health Questionnaire and Altman Self-Rating Mania Scale. We collected motion data using a 16-camera motion capture technology. We found smaller COM-ankle inclination angles at seat-off during sit-to-walk for the bipolar-depressed group compared to the bipolar-euthymic and healthy groups, indicating poorly controlled balance for the bipolar-depressed group in sit-to walk. However, we found larger COM-ankle inclination angles at beginning of single stance phase of gait for the bipolar-euthymic group compared to the healthy group, indicating well controlled balance for the bipolar-euthymic group in gait. Our results suggest an association between the depressed phase and balance impairment during daily movements in relatively young adults (ages <= 45 years). Our results also suggest that the depressed phase may be as detrimental to balance control as the effect of age-related neuromuscular weakness. PMID- 30455059 TI - Activities of daily living influence tibial cartilage T1rho relaxation times. AB - Quantitative T1rho magnetic resonance imaging (MRI) can potentially help identify early-stage osteoarthritis (OA) by non-invasively assessing proteoglycan concentration in articular cartilage. T1rho relaxation times are negatively correlated with proteoglycan concentration. Cartilage compresses in response to load, resulting in water exudation, a relative increase in proteoglycan concentration, and a decrease in the corresponding T1rho relaxation times. To date, there is limited information on changes in cartilage composition resulting from daily activity. Therefore, the objective of this study was to quantify changes in tibial cartilage T1rho relaxation times in healthy human subjects following activities of daily living. It was hypothesized that water exudation throughout the day would lead to decreased T1rho relaxation times. Subjects underwent MR imaging in the morning and afternoon on the same day and were free to go about their normal activities between scans. Our findings confirmed the hypothesis that tibial cartilage T1rho relaxation times significantly decreased (by 7%) over the course of the day with loading, which is indicative of a relative increase in proteoglycan concentration. Additionally, baseline T1rho values varied with position within the cartilage, supporting a need for site specific measurements of T1rho relaxation times. Understanding how loading alters the proteoglycan concentration in healthy cartilage may hold clinical significance pertaining to cartilage homeostasis and potentially help to elucidate a mechanism for OA development. These results also indicate that future studies using T1rho relaxation times as an indicator of cartilage health should control the loading history prior to image acquisition to ensure the appropriate interpretation of the data. PMID- 30455060 TI - Effects of aging on hip abductor-adductor neuromuscular and mechanical performance during the weight transfer phase of lateral protective stepping. AB - Aging brings about challenges in the ability to recover balance through protective stepping, especially in the lateral direction. Previous work has suggested that lateral protective stepping during weight transfer may be affected by impaired muscle composition and performance of the hip abductors (AB) in older adults. Hence, this study investigated the influence of hip abductor-adductor (AB AD) neuromuscular performance on the weight transfer phase of lateral protective stepping in younger and older adults. Healthy younger (n = 15) and older adults (n = 15) performed hip AB-AD isometric maximal voluntary contractions (IMVC). Lateral balance perturbations were applied via motorized waist-pulls. Participants were instructed to recover their balance using a single lateral step. Kinetic, kinematic and electromyographic (EMG) data were analyzed during the weight transfer phase. In the hip IMVC task, older adults showed reduced peak AB-AD torque, AB rate of torque development and AB-AD rate of EMG neuromuscular activation (RActv). During the lateral balance perturbations, older individuals had a lower incidence of lateral steps, reduced hip AB-AD RActv and delayed weight transfer. However, several outcomes were larger in the older group, such as, center of mass momentum at step onset, step-side peak rate of vertical force development, hip AB net joint torque, and power. Although older adults had greater hip muscular output during the weight transfer phase, their lateral balance recovery was still impaired. The reduced maximal hip AB-AD capacity, especially RActv, may have been a greater contributor to this impairment, as it affects the ability to generate rapid force, crucial for balance recovery. PMID- 30455061 TI - Introduction to the special issue on sphingolipid signaling in chronic disease. PMID- 30455062 TI - The role of sphingolipids is acute kidney injury. AB - Acute kidney injury (AKI) is most simply defined as the rapid loss of kidney function in a matter of hours to days. AKI can manifest in a number of ways including pre-renal, post-renal, or intrinsic AKI. During acute kidney injury, multiple pathogenic processes are activated including inflammation, cell death, and the generation of reactive oxygen species, just to name a few. Sphingolipids are known to play a role in a number of the pathogenic pathways involved in the pathogenesis of many types of AKI, which suggests a role for sphingolipids in AKI. This short review will discuss the evidence for a role for sphingolipids in AKI. PMID- 30455063 TI - Alcoholic and non-alcoholic fatty liver disease: Focus on ceramide. AB - Sphingolipids are class of metabolically distinct lipids that play structural and signaling functions in all organisms. Sphingolipid metabolism is deregulated during various diseases such as cancer, neurological and immune disorders, and metabolic syndrome. With the advancement of sphingo-lipidomics and sphingo genomics, an understanding of the specific roles of ceramide, the quintessential bioactive sphingolipid, in fatty liver disease has taken shape. Two major pathways for ceramide generation, the de novo pathway and the sphingomyelinase pathway are activated in the course of both, the non-alcoholic and the alcoholic, forms of fatty liver disease. The mechanisms of activation of these two pathways are distinct and reflect the different disease etiology in each case; at the same time, common processes impacted by the resulting ceramide overproduction involve lipotoxocity, ER/mitochondrial stress, inflammation, and de-regulation of hepatic lipid metabolism. Studies in human patients and animal models have delineated specific enzymes and ceramide species that are involved at the different stages of the disease, and represent novel pharmaceutical targets for successful management of fatty liver disease. PMID- 30455064 TI - Neural crest contributions to the ear: Implications for congenital hearing disorders. AB - Congenital hearing disorders affect millions of children worldwide and can significantly impact acquisition of speech and language. Efforts to identify the developmental genetic etiologies of conductive and sensorineural hearing losses have revealed critical roles for cranial neural crest cells (NCCs) in ear development. Cranial NCCs contribute to all portions of the ear, and defects in neural crest development can lead to neurocristopathies associated with profound hearing loss. The molecular mechanisms governing the development of neural crest derivatives within the ear are partially understood, but many questions remain. In this review, we describe recent advancements in determining neural crest contributions to the ear, how they inform our understanding of neurocristopathies, and highlight new avenues for further research using bioinformatic approaches. PMID- 30455065 TI - Building Biological Shields via Hormesis. AB - Hormesis offers the potential to build biological shields to protect against a plethora of age-related diseases and acute trauma (e.g., brain traumatic injury) via the implementation of pre- and postconditioning strategies. These strategies have the potential to markedly enhance a broad spectrum of medical and public health practices. PMID- 30455066 TI - Experience with age discrimination and attitudes toward ageism in older patients with cancer and their caregivers: A nationwide Korean survey. AB - OBJECTIVE: It is not clear whether age-related differences in treatment and treatment decision-making are the result of age discrimination or just a reflection of older patients' elevated risk and their own preferences. Therefore, it is critical to understand older patients' own views toward their care in regard to its relationship to age. MATERIAL AND METHODS: 439 older patients with cancer (age >= 60) and 358 family members from eleven cancer centers participated in this cross-sectional survey. RESULTS: Almost all patients (91.2%) and caregivers (92.7%) thought that older patients should be treated equal to younger patients, across all questionnaire items. The proportions of patients who reported having experienced age discrimination according to each item were: disease information (12.3%), treatment information (11.0%), participation in treatment decision (10.7%), attention from healthcare professionals (6.2%), supportive care (5.2%), and treatment (3.2%). Increasing age was the only demographic characteristic that was associated with greater ageism experience (p < .001). Patients' ageism attitudes, as well as caregivers' ageism attitudes, were negatively associated with ageism experience. Ageism experience was associated with a higher depression score, as well as a lower quality of life. CONCLUSION: Discrimination in treatment and the treatment decision process based on age was not justified. Interventions that address ageist attitudes in older patients, family caregivers, and healthcare professionals are needed to reduce age discrimination, and thereby improve the quality of life of older patients with cancer. PMID- 30455067 TI - Role of microRNA in severe asthma. AB - The various roles of microRNAs (miRNAs) in the epigenetic regulation of human disease are gaining importance as areas of research, and a better understanding of these roles may identify targets for development of novel therapies for severe asthma. MiRNAs, a class of small non-coding RNAs that serve as post transcriptional gene repressors, are recognized as critical components in regulating tissue homeostasis. Alteration in miRNA expression disrupts homeostasis and is an underlying mechanism for development of chronic respiratory diseases, including asthma. Differential profiles of miRNA expression are involved in inflammation and remodeling pathogenicity via activating airway structural cells and immune cells and inducing cytokine releases. miRNA action leads to asthma progression from mild to severe stages. Here, current knowledge of the heterogeneous roles of miRNAs in severe asthma, including biological mechanisms underlying Th2 and macrophage polarization, type 2 innate lymphoid cell (ILC2) biology regulation, steroid-resistant asthma phenotype, airway smooth muscle (ASM) dysfunction, and impaired anti-viral innate immune, are reviewed. PMID- 30455068 TI - The genome of 'Candidatus Phytoplasma solani' strain SA-1 is highly dynamic and prone to adopting foreign sequences. AB - Bacteria of the genus 'Candidatus Phytoplasma' are uncultivated intracellular plant pathogens transmitted by phloem-feeding insects. They have small genomes lacking genes for essential metabolites, which they acquire from either plant or insect hosts. Nonetheless, some phytoplasmas, such as 'Ca. P. solani', have broad plant host range and are transmitted by several polyphagous insect species. To understand better how these obligate symbionts can colonize such a wide range of hosts, the genome of 'Ca. P. solani' strain SA-1 was sequenced from infected periwinkle via a metagenomics approach. The de novo assembly generated a draft genome with 19 contigs totalling 821,322bp, which corresponded to more than 80% of the estimated genome size. Further completion of the genome was challenging due to the high occurrence of repetitive sequences. The majority of repeats consisted of gene arrangements characteristic of phytoplasma potential mobile units (PMUs). These regions showed variation in gene orders intermixed with genes of unknown functions and lack of similarity to other phytoplasma genes, suggesting that they were prone to rearrangements and acquisition of new sequences via recombination. The availability of this high-quality draft genome also provided a foundation for genome-scale genotypic analysis (e.g., average nucleotide identity and average amino acid identity) and molecular phylogenetic analysis. Phylogenetic analyses provided evidence of horizontal transfer for PMU like elements from various phytoplasmas, including distantly related ones. The 'Ca. P. solani' SA-1 genome also contained putative secreted protein/effector genes, including a homologue of SAP11, found in many other phytoplasma species. PMID- 30455069 TI - Humoral immune and adjuvant responses of mucosally-administered Tinospora cordifolia immunomodulatory protein in BALB/c mice. AB - BACKGROUND: In traditional medicine, guduchi (Tinospora cordifolia) is considered as an adaptogen with immunomodulatory prowess. A 25 kDa protein from guduchi stem has been characterized as an immunomodulatory protein (ImP). OBJECTIVES: The aim of this study was to evaluate the intrinsic immunogenicity of guduchi ImP and adjuvant activity using ovalbumin (OVA) as antigen in BALB/c mice. METHODS: Mice were given guduchi ImP (30 and 60 MUg) by intranasal administration to respective groups (n = 6) on days 1, 14 and thereafter weekly till day 42. Immunogenic response was monitored by serum IgG/IgA levels (days 14, 35 and 50). The adjuvant activity was measured by serum anti-OVA IgG/IgA responses to administration of 30 MUg OVA with guduchi ImP. The effect of guduchi ImP on the spleen status was examined by splenic weight (day 50). RESULTS: Guduchi ImP administration displayed a significant increase in anti-guduchi ImP IgG (5-7 fold) and anti guduchi ImP IgA (3-4 fold) on day 50 vs. control. Guduchi ImP showed a significant increase in anti-OVA IgG (6-7 fold) and anti-OVA IgA (4-5 fold) on day 50 vs. control. The splenic index of guduchi ImP group increased significantly in both the immune and adjuvant response groups; however, the splenic index in the adjuvant response group was markedly higher. CONCLUSIONS: The results indicate that guduchi ImP is a strong immunogen by itself and enhances the immunogenicity of mucosally-administered antigen in BALB/c mice. Based on the results of this animal study, it appears that guduchi ImP shows a potential for future studies in humans. PMID- 30455070 TI - What is needed to keep Ayurveda growing? An interview with Prof. R H Singh. PMID- 30455071 TI - Ameliorative effect of Cephalandra indica homeopathic preparation in STZ induced diabetic nephropathy rats. AB - BACKGROUND: Diabetic nephropathy (DN) is the foremost cause of morbidity and has become the most recurrent cause of end-stage renal disease among diabetic patients. Thus, agents having antidiabetic effect along with safety potential in the kidneys would have a higher remedial value. OBJECTIVE: The present study aimed to investigate possible protective effect of homeopathic preparation of Cephalandra indica Mother tincture, 6C and 30 C potencies on DN in Wistar rats. MATERIALS AND METHODS: DN was induced by intraperitoneal injection of STZ (60 mg/kg) 15 min after Nicotinamide (230 mg/kg, i.p.) administration. Rats were divided into six groups (n = 6). Group 1 and 2 was kept normal control and diabetic control respectively whereas Groups 3-5 consist of diabetic nephropathy rats treated with different doses of C. indica Mother tincture, 6C and 30 C potencies for 45 days. Glimepride (10 mg/kg) was used as standard. DN was assessed by determining serum glucose, urea, uric acid, creatinine level and tissue histological examination. Tissue antioxidant enzymes (SOD, GSH, LPO) level was measured to assess the oxidative stress. Also, the level of advanced glycation end products in kidney was determined. RESULTS: Mother tincture, 6C and 30 C potencies of C. indica produced significant attenuation in the biochemical parameters used to assess diabetic nephropathy. Moreover, oxidative stress and AGE's level in kidney was also found to be significantly reduced. CONCLUSION: We conclude that Mother tincture, 6C and 30 C potencies of C. indica confers protective effect against diabetic nephropathy via inhibition of Oxidative stress and AGE's. PMID- 30455072 TI - Antioxidant and immunomodulatory properties of Spilanthes oleracea with potential effect in chronic fatigue syndrome infirmity. AB - BACKGROUND: Chronic fatigue syndrome (CFS) holds a mystery for researchers due to its multifactorial nature; hence, its diagnosis is still based on symptoms and aetiology remains obscured. Number of scientific evidences regarding the role of oxidative stress, immune dysfunction in CFS and alleviation of symptoms with the help of nutritional supplements guided us to study effect of ethanolic extract of Spilanthes oleracea (SPE) in CFS. OBJECTIVES: Present study was designed to evaluate antioxidant, immunomodulatory properties of S. oleracea flower to ameliorate CFS infirmity in mice. MATERIALS AND METHOD: In order to induce fatigue, experimental animals were stressed by chronic water - immersion stress model. Meanwhile, parameters like immobility period and tail withdrawal latency were assessed. On the 21st day, mice blood was collected and they were immediately sacrificed for biochemical estimations. RESULTS: Biochemical analysis results revealed that CFS elevates lipid peroxidation, nitrite level and diminishes the endogenous antioxidant enzyme like catalase level in stressed animal's brain homogenate. Stressful condition developed muscle fatigue leading in alteration of lactate dehydrogenase level (LDH), Blood urea nitrogen (BUN) and Triglycerides (TG) levels. Concurrent and chronic treatment of SPE for 21 days restored all these behavioural despairs and associated biochemical adaptation in mice in dose-dependent manner. CONCLUSION: The outcome of this study indicates ability of SPE in amelioration of CFS by mitigating the oxidative stress and thus provide a powerful combat against CFS which may be due to its antioxidant and immunomodulatory properties. PMID- 30455073 TI - Are posttraumatic stress and depressive symptoms pathways to smoking relapse after a natural disaster? AB - BACKGROUND: Smoking relapse is rarely examined in disaster research. Thus, this study investigated smoking relapse nine and eighteen months after Hurricane Katrina and identified pathways and conditions for this outcome. METHODS: The data came from a prospective study of adult ever smokers who were living in New Orleans at the time Hurricane Katrina struck (n = 1003), and a comparison sample of Memphis residents (n = 1001) who were not directly impacted by the hurricane. Participants from both cities were recruited using random digit dialing and were surveyed nine and eighteen months after Hurricane Katrina. We assessed whether smoking relapse rates differed by city and evaluated potential mediators and moderators of this association using conditional process analysis. RESULTS: Though the probabilities of smoking relapse, posttraumatic stress, and depressive symptoms were higher among New Orleans than Memphis participants, hurricane exposure did not indirectly affect smoking relapse through increases in posttraumatic stress and depressive symptoms. Instead, as the number of hurricane related events increased so to did the probability of smoking relapse through increases in depressive (beta = 0.08, SE = 0.03, p = .02) and posttraumatic stress symptoms (beta=0.08, SE=0.04, p = .04). Social support lowered the probability of smoking relapse by protecting against increases in depressive and posttraumatic stress symptoms. CONCLUSIONS: Posttraumatic stress and depressive symptoms mediated the effects of disaster exposure on smoking relapse, and this effect was most pronounced among survivors who reported disaster-related stressors. Former smokers heavily exposed to disasters may benefit from postdisaster interventions that reduce depressive and posttraumatic stress symptoms, which may prevent smoking relapse. PMID- 30455074 TI - Synthesis and biological evaluation of thielocin B1 analogues as protein-protein interaction inhibitors of PAC3 homodimer. AB - The synthesis and biological evaluation of thielocin B1 analogues have been demonstrated. Fourteen analogues modified in the central core and terminal carboxylic acid moiety were concisely synthesized by simple esterification or etherification reaction. The evaluation of synthetic analogues as inhibitors of proteasome assembling chaperone (PAC) complexes (the PAC3 homodimer and PAC1/PAC2) revealed that the natural product-like bending structure and terminal carboxylic acid groups were crucial for its biological activity. Moreover, SAR and in silico docking studies indicated that all methyl groups on the diphenyl ether moiety of thielocin B1 contribute to the potent and selective inhibition of the PAC3 homodimer via hydrophobic interactions. PMID- 30455075 TI - The effect of minocycline on symptoms in schizophrenia: Results from a randomized controlled trial. AB - BACKGROUND: Studies have hypothesized that immunological abnormalities might contribute to schizophrenia, and basic science studies, as well as several clinical trials suggest that minocycline could be efficacious in ameliorating both positive and negative symptoms of schizophrenia. In this study we examined the effect of minocycline on schizophrenia in a large randomized controlled trial. METHODS: We performed a 16-week, multi-center, double-blind, randomized, placebo-controlled study on 200 subjects with schizophrenia or schizoaffective disorder randomized to receive either minocycline (200 mg/day, n = 100), or placebo (n = 100) as an add-on to anti-psychotic treatment. The primary outcome measure was the PANSS total score. RESULTS: Mixed models for repeated measures showed no significant difference between minocycline and placebo for total PANSS (p = 0.862), PANSS subscales, CGI or BACS. CONCLUSIONS: Minocycline did not improve symptoms or cognition in schizophrenia. PMID- 30455076 TI - The efficacy of a novel topical formulation of selamectin plus sarolaner (Revolution(r) Plus/Stronghold(r) Plus) in preventing the development of Dirofilaria immitis in cats. AB - Three controlled studies were conducted to investigate the efficacy of selamectin plus sarolaner (Revolution(r) Plus/Stronghold(r) Plus) in preventing feline heartworm disease in cats. In all studies, cats were inoculated with 100 Dirofilaria immitis third stage larvae on Day -30. In the first study, cats were treated with selamectin plus sarolaner as a single dose on Day 0 or as three consecutive monthly doses on Days 0, 28 and 56. In the second and third studies, cats were treated with either sarolaner alone on Day 0, selamectin plus sarolaner on Day 0 or selamectin plus sarolaner as three consecutive monthly doses on Days 0, 28 and 56. In all three studies, dosages were 6 mg/kg selamectin plus 1 mg/kg sarolaner or 1 mg/kg sarolaner alone. Control cats were given a placebo containing inert formulation ingredients (vehicle). All treatments were administered at a single site topically to the skin cranial to the scapulae. Cats were humanely euthanized on Day 145/146 (i.e., 175/176 post-inoculation), and adult D. immitis worms were recovered and enumerated. Across the three studies, adult heartworms were recovered from 87 to 100% of control cats, with geometric mean worm counts ranging from 2.1 to 5.4. No adult D. immitis worms were recovered from cats treated with selamectin plus sarolaner. Cats treated with sarolaner alone were not protected against D. immitis infection, showing geometric mean worm counts of 1.9 to 2.4. In these studies, selamectin (6 mg/kg) plus sarolaner (1 mg/kg) was 100% effective in preventing heartworm development in cats when administered topically as one dose 30 days after inoculation or as three consecutive monthly doses starting 30 days post-inoculation. These studies demonstrated that a single topical administration of selamectin plus sarolaner at the recommended dosage was completely effective in preventing the development of D. immitis in cats. PMID- 30455078 TI - Diaphragmatic myotrauma: a mediator of prolonged ventilation and poor patient outcomes in acute respiratory failure. AB - Several mechanisms of diaphragm muscle injury (myotrauma) can result in ventilator-induced diaphragm dysfunction, including ventilator over-assistance, under-assistance, eccentric contractions, and end-expiratory shortening. In this Personal View, we summarise the evidence for the clinical relevance of these mechanisms, and present new data based on mediation analysis supporting the hypothesis that myotrauma due to ventilator over-assistance and under-assistance contribute, in part, to the effect of mechanical ventilation on clinical outcomes. The concept of diaphragmatic myotrauma has important implications for research and clinical practice. PMID- 30455077 TI - Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. AB - BACKGROUND: Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS. METHODS: We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure [PEEP] >=8 cm H2O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 * 106/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641. FINDINGS: From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2.4, 95% CI 0.5-15.1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 [SD 31] vs 89 [33]), minute ventilation (11.1 [3.2] vs 9.6 [2.4] L/min), and PEEP (12.4 [3.7] vs 10.8 [2.6] cm H2O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1.43 (95% CI 0.40-5.12, p=0.58). Viability of MSCs ranged from 36% to 85%. INTERPRETATION: One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved. FUNDING: National Heart, Lung, and Blood Institute. PMID- 30455079 TI - Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes. AB - Calcitriol, the active form of vitamin D, has been well documented to act directly on immune cells and malignant cells. Activated T cells are one of the best characterized targets of calcitriol, with effects including decreasing inflammatory cytokine output and promoting anti-inflammatory cytokine production. However, the effects of calcitriol on natural killer (NK) cells are less clear. Reports suggest that only immature NK cell populations are affected by calcitriol treatment resulting in impaired cytotoxic function and cytokine production, while mature NK cells may have little or no response. NK cell large granular lymphocyte leukemia (NK-LGLL) is a rare leukemia with CD3-CD16+CD56+NK cell clonal expansion. The current standard treatments are immunosuppressant therapies, which are not curative. The Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathway is hyperactivated in LGLL and is one pathway of interest in new drug target investigations. We previously demonstrated the ability of calcitriol to decrease STAT1 tyrosine 701 (p-STAT1) and STAT3 tyrosine 705 (p-STAT3) phosphorylation as well as inflammatory cytokine output of T cell large granular lymphocyte leukemia cells, but did not determine the effects of calcitriol on NK-LGLL. Therefore, in the present study, we investigated whether NKL cells, a model of NK-LGLL, and NK-LGLL patient peripheral blood mononuclear cells (PBMCs) are susceptible to treatment with calcitriol or seocalcitol (EB1089), a potent analog of calcitriol. NKL cells are dependent on interleukin (IL)-2 for survival and we show here for the first time that treatment with IL-2 induced tyrosine phosphorylation of STATs 1 through 6. Both calcitriol and EB1089 caused significant upregulation of the vitamin D receptor (VDR). IL-2 induction of p-STAT1 and p-STAT3 phosphorylation was significantly decreased after calcitriol or EB1089 treatment. Additionally, IL-10, interferon (IFN)-gamma, and FMS-like tyrosine kinase 3 ligand (Flt-3L) extracellular output was significantly decreased at 100 nM EB1089 and intracellular IL-10 was decreased with either calcitriol or EB1089 treatment. We treated NK-LGLL patient PBMCs with calcitriol or EB1089 and found decreased p-STAT1 and p-STAT3 while VDR increased, which matched the NKL cell line data. We then measured 75 serum cytokines in NK-LGLL patients (n = 8) vs. age- and sex-matched normal healthy donors (n = 8), which is the first serum cytokine study for this LGLL subtype. We identified 15 cytokines, including IL-10 and Flt-3L, which were significantly different between normal donors and NK-LGLL patients. Overall, our results suggest that activating the vitamin D pathway could be a mechanism to decrease STAT1 and 3 activation and inflammatory cytokine output in NK-LGLL patients. PMID- 30455080 TI - MicroRNA-93 promotes bladder cancer proliferation and invasion by targeting PEDF. AB - OBJECTIVE: MicroRNA-93 (miR-93) is upregulated in the urine of patients with bladder cancer (BC). Here, we investigated the role of miR-93 in BC progression and explored the underlying mechanism. METHODS: miR-93 expression in BC tissues and cells was detected by real time-polymerase chain reaction. The effects of miR 93 and pigment epithelium-derived factor (PEDF) on cell proliferation and invasion were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and Transwell assays. The binding of miR-93 to the 3' untranslated region of PEDF was identified by the luciferase reporter assay. RESULTS: miR-93 expression was higher in BC tissues than in normal controls, and its expression was associated with tumor stage and node stage. Inhibition of miR 93 suppressed the proliferation and invasion of BC cells. PEDF was identified as a target of miR-93 and shown to mediate the effect of miR-93 on cell proliferation and invasion. CONCLUSIONS: The present data suggested that miR-93 promoted BC cell proliferation and invasion by targeting PEDF, providing new biomarkers and targets for BC diagnosis and treatment. PMID- 30455081 TI - Are We Overestimating Protistan Diversity in Nature? AB - Documenting the immense diversity of single-celled, eukaryotic organisms (protists) has been a formidable challenge for ecologists. These species were originally defined by morphological criteria, but shortcomings of the morphospecies concept, and a bewildering array of sizes and cellular attributes, has made constructing a taxonomy that is useful for ecologists nearly impossible. Consequently, physiological and genetic information has been integrated to address these shortcomings, and to develop the framework of a unifying taxonomy. DNA sequence information, in particular, has revolutionized studies of protistan diversity. However, the exponential increase in sequence-based protistan species richness published from field surveys in recent years raises the question of whether we have moved beyond characterizing species-level diversity and begun to reveal intraspecies diversity. The answer to that question appears to be 'yes', at least for some protistan lineages. The need to document such microdiversity may be justified, but it is important for protistologists to recognize and acknowledge that possibility, and its consequences. PMID- 30455082 TI - Bridging the Gap between Connectome and Transcriptome. AB - The recent construction of brain-wide gene expression atlases, which measure the transcriptional activity of thousands of genes in multiple anatomical locations, has made it possible to connect spatial variations in gene expression to distributed properties of connectome structure and function. These analyses have revealed that spatial patterning of gene expression and neuronal connectivity are closely linked, following broad spatial gradients that track regional variations in microcircuitry, inter-regional connectivity, and functional specialisation. Superimposed on these gradients are more specific associations between gene expression and connectome topology that appear conserved across diverse species and different resolution scales. These findings demonstrate the utility of brain wide gene expression atlases for bridging the gap between molecular function and large-scale connectome organisation in health and disease. PMID- 30455083 TI - A measure of tear inflow in habitual scleral lens wearers with and without midday fogging. AB - PURPOSE: The purpose of this pilot study was to evaluate tear inflow in a scleral lens system using fluorophotometry, and indirectly assess the exchange of the tear reservoir in habitual scleral lens wearers with the presence or absence of midday fogging (MDF). METHODS: Habitual scleral lens wearers (n=23) and normal scleral lens neophytes (n=10) were recruited. Of the 23 habitual wearers, 11 of them experienced MDF and 12 did not have a diagnosis of MDF. Contact lens-fitting characteristics were evaluated using ocular coherence tomograpy (OCT) and biomicroscopy. High molecular weight fluorescein (FITC) Dextran was instilled into the tear reservoir beneath the scleral lens, and the tear fluid fluorescein concentration was measured using the Fluorotron fluorophotometer. Calculated fluorescein concentrations were plotted over time to measure the fluorescein decay rate of the tear fluid beneath the scleral lens, which was used to calculate the tear exchange rate. RESULTS: There was no significant difference in tear inflow between the MDF group (mean: 0.111%) and the non-MDF group (mean: 0.417%), and there was a high amount of variability seen in the rates (p = 0.26). In addition, there was no significance between the tear reservoir thickness in the MDF (283um) and non-MDF (326um) groups (p = 0.53). CONCLUSIONS: The relationship between the amount of tear exchange during scleral lens wear and the incidence of MDF was not significant. Additional studies are needed to further examine the role of tear exchange in MDF and address the causes of variability to improve measurement techniques with fluorophotometry in the scleral lens system. PMID- 30455084 TI - Assessment of a practitioner's perception of scleral contact lens complications. AB - PURPOSE: The purpose of this survey was to better understand scleral lens (SL) practitioners' fitting preferences and minor SL complications and their subsequent treatments. METHOD: Practitioners who attended the 2017 Global Specialty Lens Symposium were asked to complete an electronic questionnaire that was created by the investigators, a survey that asked practitioners about their SL fitting experience and preferences, their patients' experience with poor SL wetting, SL fogging, ocular symptoms (redness, pain/discomfort, dryness), and blurred central and side vision, and how the practitioners treated these conditions. RESULTS: This study analyzed data from 164 SL practitioners. The practitioners had been in practice for 16.3 +/- 13.4 years, had been fitting SL for 5.5 +/- 5.0 years, and fit 7.4 +/- 7.1 SL/month. Practitioners preferred a SL with a final central corneal clearance of ~200 MUm and an overall diameter between 15.1 mm to 16.5 mm. Poor SL wetting (90.8% of practitioners documented condition), SL fogging (84.8%), blurred central vision (40.2%), ocular redness (34.8%), ocular dryness (24.4%), ocular pain/discomfort (20.7%), and blurred side vision (12.8%) were encountered by the practitioners. Practitioners preferred treating poor wetting and fogging with lens removal, cleaning, and reapplication, blurred central vision with a lens power change, blurred side (peripheral) vision, ocular redness, and ocular pain with a lens parameter change, and dryness with artificial tears. CONCLUSIONS: Most SL practitioners preferred a SL central corneal clearance of ~200 MUm, and they occasionally encountered SL-related complications in their practice, which they treated similarly to corneal gas permeable CLs. PMID- 30455085 TI - Patient Positioning in Arthroscopic Management of Posterior-Inferior Shoulder Instability: A Systematic Review Comparing Beach Chair and Lateral Decubitus Approaches. AB - PURPOSE: To analyze the available literature pertaining to clinical outcomes and complications of posterior-inferior shoulder stabilization performed arthroscopically in either the beach chair (BC) or lateral decubitus (LD) position. METHODS: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), 3 databases (PubMed, EMBASE, and Medline) were searched up to January 2018 for English-language studies on posterior shoulder instability. Descriptive statistics are presented. The Methodological Index for Non-Randomized Studies (MINORS) scale was used to assess quality. RESULTS: Twenty five studies were included, examining 1,085 patients (n = 140 BC; n = 945 LD), of mean age 25.0 years, 27.1% female, and mean 3.1 years of follow-up. MINORS scores for BC and LD were 11.2 and 9.8, respectively. Regardless of positioning, patients did not differ across numerous outcomes and various surgical factors (e.g., number of portals, anchors, anchor types, concomitant pathology, or postoperative rehabilitation protocol). Postoperative patient satisfaction ranged from 85% to 87.5% and 93% to 100% for patients treated in BC and LD positions, respectively. Although not reported for BC, overall and preinjury return-to-play (RTP) rates in LD patients ranged from 72% to 100% and 55% to 100%, respectively, returning from 3 to 7.6 months postoperatively. Failure rates in the BC and LD positions ranged from 0% to 9.4% and 0% to 29%, respectively. There were no differences in reported incidences of neuropraxia, stroke, nonfatal pulmonary embolus, vision loss, cardiac arrest, or other positioning-related complications. CONCLUSIONS: Arthroscopic management of posterior-inferior shoulder instability has a successful track record and minimal complication profile. Although patient positioning appears to influence results, with those treated in the LD position experiencing marginally higher patient satisfaction and failure rates, the current data prevent any conclusions being made regarding the superiority of one approach over another. As the clinical relevance of patient positioning remains to be determined, larger, higher-level study designs with long-term follow-up are required. LEVEL OF EVIDENCE: Level IV, systematic review of Level II, III, and IV studies. PMID- 30455086 TI - Intra-articular Mesenchymal Stem Cells in Osteoarthritis of the Knee: A Systematic Review of Clinical Outcomes and Evidence of Cartilage Repair. AB - PURPOSE: To provide a systematic review of the clinical literature reporting the efficacy of mesenchymal stem cells (MSCs) in terms of clinical outcomes including pain and function and cartilage repair in patients with osteoarthritis. METHODS: We systematically reviewed any studies investigating clinical outcomes and cartilage repair after the clinical application of cell populations containing MSCs in human subjects with knee osteoarthritis through MEDLINE, EMBASE, the Cochrane Library, CINAHL, Web of Science, and Scopus. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies with a level of evidence of IV or V were excluded. Methodological quality was assessed using the Modified Coleman Methodology Score. Clinical outcomes were assessed using clinical scores, and cartilage repair was assessed using magnetic resonance imaging and second-look arthroscopy findings. RESULTS: A total of 17 studies that met the criteria of 50 full-text studies were included in this review, with 6 randomized controlled trials, 8 prospective observational studies, and 3 retrospective case-control studies. Among 17 studies, 8 studies used bone marrow derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs. All studies except 2 reported significantly better clinical outcomes in the MSC group or improved clinical outcomes at final follow-up. In terms of cartilage repair, 9 of 11 studies reported improvement of the cartilage state on magnetic resonance imaging, and 6 of 7 studies reported repaired tissue on second-look arthroscopy. The mean Modified Coleman Methodology Score was 55.5 +/- 15.5 (range, 28-74). CONCLUSIONS: Intra-articular MSCs provide improvements in pain and function in knee osteoarthritis at short-term follow-up (<28 months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. LEVEL OF EVIDENCE: Level III; systematic review of level I, II, and III studies. PMID- 30455087 TI - Arthroscopic Coracoclavicular Fixation Using Multiple Low-Profile Devices in Acute Acromioclavicular Joint Dislocation. AB - PURPOSE: To introduce an arthroscopically assisted coracoclavicular (CC) fixation technique using multiple low-profile devices to evaluate the clinical and radiologic outcomes in patients with acute high-grade acromioclavicular (AC) joint dislocation. METHODS: Between July 2014 and September 2015, cases of AC joint dislocation that were treated with arthroscopic CC fixation using multiple low-profile devices with a minimum follow-up of 24 months were included. We measured the vertical coracoclavicular distance (CCD) on the anteroposterior view and the horizontal acromioclavicular distance on 3-dimensional computed tomography images to evaluate the changes in radiologic outcomes before and after surgery. We compared final radiologic outcomes between initial AC reduction groups based on hierarchical clustering. Clinical outcomes were evaluated using the Constant-Murley score. RESULTS: We enrolled 27 patients in total, and the mean follow-up period was 27.2 months. The mean CCD of the injured shoulder was 13.68 +/- 3.98 mm preoperatively and decreased to 5.72 +/- 1.68 mm immediately postoperatively but increased to 7.32 +/- 2.29 mm at last follow-up (P = .07). Horizontal displacement of the distal clavicle was 1.1 +/- 1.0 mm immediately postoperatively but decreased to 0.9 +/- 0.6 mm at last follow-up (P < .05). In particular, in the 2 groups that were determined using the hierarchical cluster analysis, patients with excellent recovery of the initial CCD (20 patients) showed less of an increase in the CCD at last follow-up than did those in the other group (7 patients) (P < .001). The Constant-Murley score was 93.5 +/- 2.7 points on the injured side at last follow-up (P = .074). CONCLUSIONS: Our CC fixation technique with multiple low-profile devices exhibited satisfactory clinical and radiologic outcomes. In particular, ensuring good initial recovery of the CCD and the precise placement and location of the AC joints was important in maintaining the proper AC position at the final follow-up. LEVEL OF EVIDENCE: Level IV, case series. PMID- 30455088 TI - The Clinical Evidence Behind Biologic Therapies Promoted at Annual Orthopaedic Meetings: A Systematic Review. AB - PURPOSE: The purpose of this study is to systematically evaluate the available clinical data for biologic therapies promoted for articular cartilage defects and osteoarthritis of the knee at the 2016 American Orthopaedic Society for Sports Medicine Meeting (AOSSM) and the 2017 Arthroscopy Association of North America meeting (AANA). METHODS: Our sample included all exhibitors at the 2016 AOSSM meeting and 2017 AANA meeting. All biologic products marketed at each conference were identified by reviewing exhibition booths and company websites. A systematic review of the clinical data on each product was then completed using PubMed, EMBASE, and the product's own webpage. All clinical peer-reviewed studies with level I-IV evidence were included in the study. Basic science or preclinical studies were excluded. RESULTS: There were 16 products promoted for biologic therapy for articular cartilage defects or osteoarthritis of the knee at the AOSSM meeting and 11 products promoted at the AANA meeting. A total of 280 articles detailed clinical findings for the articular cartilage products displayed at AOSSM and AANA. Of the 280, there were 36 level I evidence studies, 37 level II evidence studies, 18 level III evidence studies, and 189 level IV evidence studies. Of these articles, 91% were for 4 products. Of all biologic products promoted at the 2 meetings, 65% did not have any peer-reviewed clinical data supporting their use. CONCLUSION: Overall, many biologic therapies promoted at leading arthroscopy and sports medicine conferences did not have clinical evidence evaluating their use in the peer-reviewed literature. Although scientific advancement requires new technology, orthopaedic surgeons should be cautious about using biologic therapies in their practice with no proven efficacy. There are likely promising new interventions that, with additional scientific research, will be proven efficacious for our patients. CLINICAL RELEVANCE: This article gives orthopaedic surgeons a detailed example of some of the biologic treatments being offered on the market for the treatment of knee articular cartilage disease. When patients request these treatments, physicians must be able to explain the data supporting their use. PMID- 30455089 TI - Local Leaders' Perspectives on Women Veterans' Health Care: What Would Ideal Look Like? AB - BACKGROUND: The Veterans Health Administration (VHA) faces challenges in providing comprehensive, gender-sensitive care for women. National policies have led to important advancements, but local leadership also plays a vital role in implementing changes and operationalizing national priorities. In this article, we explore the notions of ideal women veterans' health care articulated by women's health leaders at local VHA facilities and regional networks, with the goal of identifying elements that could inform practice and policy. METHODS: We conducted semistructured interviews with 86 local and regional women's health leaders at 12 VHA medical centers across four regions. At the conclusion of interviews about women's primary care, participants were asked to imagine "ideal care" for women veterans. Interviews were transcribed and coded using a hybrid inductive/deductive approach. RESULTS: In describing ideal care, participants commonly touched on whether women veterans should have separate primary care services from men; the need for childcare, expanded reproductive health services, resources, and staffing; geographic accessibility; the value of input from women veterans; the physical appearance of facilities; fostering active interest in women's health across providers and staff; and the relative priority of women's health at the VHA. CONCLUSIONS: Policy and practice changes to care for women veterans must be mindful of key stakeholders' vision for that care. Specific features of that vision include clinic construction that anticipates a growing patient population, providing childcare and expanded reproductive health services, ensuring adequate support staff, expanding mechanisms to incorporate women veterans' input, and fostering a culture oriented towards women's health at the organizational level. PMID- 30455090 TI - Examining Changes in Sexual Functioning after Cognitive Processing Therapy in a Sample of Women Trauma Survivors. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and sexual dysfunction commonly co-occur. Although sexual dysfunction is more prevalent among women and the negative impact of sexual dysfunction on quality of life is stronger in women compared with men, few studies examine the impact of evidence-based PTSD treatments on sexual functioning outcomes in women with PTSD. The current study examined the relationship between PTSD and sexual functioning among women trauma survivors to examine if sexual functioning improves after cognitive processing therapy (CPT). PROCEDURES: A total of 126 civilian and veteran women were randomly assigned to receive CPT delivered via either office-based videoconferencing or traditional office-based care. PTSD outcomes were examined from before treatment to after treatment and sexual functioning outcomes were examined from before treatment to the 3-month follow-up. Multigroup structural equation modeling was used to compare changes in sexual functioning and PTSD scores over time. We also compared how sexual functioning changed after treatment among women who identified a sexual trauma as their index trauma compared with those with nonsexual index traumas. FINDINGS: Greater baseline PTSD symptoms predicted poorer sexual satisfaction at baseline. Sexual satisfaction, arousal, and desire improved after CPT; veteran status and index trauma type (i.e., sexual vs. nonsexual) did not attenuate this relationship. Women who had greater decreases in PTSD symptoms experienced greater improvements in sexual satisfaction, arousal, and desire. CONCLUSIONS: The current study provides preliminary support that CPT treatment may improve sexual functioning in women trauma survivors. Clinicians should assess sexual functioning to promote disclosure and develop a treatment plan. PMID- 30455091 TI - Dry needling in addition to standard physical therapy treatment for sub-acromial pain syndrome: a randomized controlled trial protocol. AB - BACKGROUND: Trigger point dry needling interventions are utilized by physical therapists to manage shoulder pain. Observational studies have shown positive short-term outcomes in patients with subacromial pain syndrome receiving trigger point dry needling. However, little research has been done to evaluate the long term effectiveness of trigger point dry needling specifically as it compares to other commonly utilized interventions such as exercise and manual therapy. The purpose of this study is to assess the additive short and long-term effectiveness of trigger point dry needling to a standard physical therapy approach of manual therapy and exercise for patients with subacromial pain syndrome. METHODS: This multicenter randomized trial with 3 arms was designed following the standard protocol items for randomized interventional trials. Results will be reported consistent with the consolidated standards of reporting trials guidelines. 130 participants will be randomized to receive standard PT interventions alone (manual therapy and exercise), standard PT and trigger point dry needling or standard PT and sham trigger point dry needling. The primary outcome measures will be the Shoulder Pain and Disability Index and Patient Reported Outcomes Measurement Information Systems (PROMIS-57) scores collected at baseline, 6 weeks, 6-months and one year. Healthcare utilization will be collected for 12 months following enrollment and groups analyzed for differences. DISCUSSION: It is not known if trigger point dry needling provides long-term benefit for individuals with subacromial pain syndrome. This study will help determine if this intervention provides additive benefits over those observed with the commonly applied interventions of exercise and manual therapy. TRIAL REGISTRATION: Identifier: NCT03442894 (https://clinicaltrials.gov/ct2/show/NCT03442894) on 22 February 2018. PMID- 30455092 TI - Dependence of volume dose indices on dose calculation algorithms for VMAT-SBRT plans for peripheral lung tumor. AB - The purpose of this study was to investigate the dependence of volume dose indices on dose calculation algorithms for volumetric modulated arc therapy (VMAT) for stereotactic body radiotherapy (SBRT) plans to treat peripheral lung tumors by comparing them with those of Monte Carlo (MC) calculations. VMAT-SBRT plans for peripheral lung tumors were created using the Eclipse treatment planning system (TPS) for 24 patients with nonsmall cell lung cancer. VMAT dose distributions for gross tumor volume (GTV), internal target volume (ITV), and planning target volume (PTV) were calculated using the analytical anisotropic algorithm (AAA), the Acuros XB (AXB) algorithm, and a MC algorithm. VMAT dose distributions of the 3 algorithms were compared using their volume dose indices from dose volume histograms (DVHs), a dose difference map, and 3-dimensional gamma analysis. The DVHs for GTV and ITV from AAA, AXB, and MC were in good agreement. The difference between the ITV and PTV volume dose indices from AAA and MC increased as D98, D95, D80, D50, and D2. In particular, the difference between D98 for PTV from AAA and MC was up to 48%. A >5% difference between D95 for PTV from AAA and MC was 11 patients, but only 2 patients for ITV. The volume dose indices for AXB were near those of MC. AAA tended to overestimate the PTV volume dose indices compared to AXB and MC. Thus, we propose that the volume dose indices for the ITV be used because they are independent of dose calculation algorithms. PMID- 30455093 TI - Comparison of arthroscopic to open tibiotalocalcaneal arthrodesis in high-risk patients. AB - BACKGROUND: Open tibiotalocalcaneal arthrodesis (TTCA) is associated to high complication rates, which led to the development of arthroscopic techniques. Aim was to compare complication rates of open to arthroscopic TTCA in high-risk patients. METHODS: Single-center, retrospective case-control study. Patients were selected from the authors' TTCA database. Eligible were high-risk patients receiving arthroscopic-, or open TTCA retrospectively suitable for arthroscopic TTCA. Primary outcome were major complications. RESULTS: Eight open and 15 arthroscopic TTCAs were included. Three open and 4 arthroscopic TTCAs presented preoperative plantar ulceration. Fusion rates were similar (75% vs. 67%; p=0.679). Major complications occurred in 63% of open (80% surgical-site infections (SSI)) and 33% of arthroscopic (100% non-unions) TTCA. Preoperative plantar ulceration did not affect major SSI in open TTCA (67% vs. 60%) but resulted in a significant increase of non-union rates for arthroscopic TTCA (75% vs. 18%; p=0.039). In patients without plantar ulceration the union-rate was 80% for both, open and arthroscopic TTCA. CONCLUSION: Arthroscopic TTCA drastically reduced major SSI. Patients without preexisting ulceration had excellent union rates for open and arthroscopic TTCA. PMID- 30455094 TI - Hindfoot alignment of adult acquired flatfoot deformity: A comparison of clinical assessment and weightbearing cone beam CT examinations. AB - BACKGROUND: Clinical assessment of hindfoot alignment (HA) in adult acquired flatfoot deformity (AAFD) can be challenging and weightbearing (WB) cone beam CT (CBCT) may potentially better demonstrate this three-dimensional (3D) deformity. Therefore, we compared clinical and WB CBCT assessment of HA in patients with AAFD. METHODS: In this prospective study, we included 12 men and 8 women (mean age: 52.2, range: 20-88) with flexible AAFD. All subjects also underwent WB CBCT and clinical assessment of hindfoot alignment. Three fellowship-trained foot and ankle surgeons performed six hindfoot alignment measurements on the CT images. Intra- and Inter-observer reliabilities were calculated using intra-class correlation (ICC). Measurements were compared by paired T-tests, and p-values of less than 0.05 were considered significant. RESULTS: The mean of clinically measured hindfoot valgus was 15.2 (95% confidence interval [CI]: 11.5-18.8) degrees. It was significantly different from the mean values of all WB CBCT measurements: Clinical Hindfoot Alignment Angle, 9.9 (CI: 8.9-11.1) degrees; Achilles tendon/Calcaneal Tuberosity Angle, 3.2 (CI: 1.3-5.0) degrees; Tibial axis/Calcaneal Tuberosity Angle, 6.1 (CI: 4.3-7.8) degrees; Tibial axis/Subtalar Joint Angle 7.0 (CI: 5.3-8.8) degrees, and Hindfoot Alignment Angle 22.8 (CI: 20.4-25.3) degrees. We found overall substantial to almost perfect intra- (ICC range: 0.87-0.97) and inter-observer agreements (ICC range: 0.51-0.88) for all WB CBCT measurements. CONCLUSIONS: Using 3D WB CBCT can help characterize the valgus hindfoot alignment in patients with AAFD. We found the different CT measurements to be reliable and repeatable, and to significantly differ from the clinical evaluation of hindfoot valgus alignment. LEVEL OF EVIDENCE: Level II-prospective comparative study. PMID- 30455095 TI - Sperm sexing with density gradient centrifugation in dogs. AB - Sexed sperm in dogs is of interest because of being polytocous, and as a result, the greatest number of offspring of the same sex can improve the market, although few studies assessing sperm sexing have been performed in this species. The present study, therefore, was conducted to evaluate the effects on sperm quality and the effectiveness of three discontinuous density gradients to separate dog sperm containing X and Y chromosomes. Thirty ejaculates from ten adult dogs were collected by digital manipulation of the penis. Cells were separated using gradients of Percoll(r) and Percoll(r) associated with Nycodenz(r) or Ficoll. The cells were evaluated for motility by the CASA system (Computer-Aided Semen Analyzer) and for concentration and recovered sperm concentration (after centrifugation), sperm morphology, plasma and acrosomal membrane integrity, and mitochondrial function pre- and post-centrifugation. The percentage of sperm containing X and Y chromosomes was also evaluated pre- and post-centrifugation by quantitative real-time PCR (qPCR). The use of the Ficoll gradient resulted in the greatest sperm quality after centrifugation; however, no sperm enhancement containing X or Y chromosome occurred with use of any of the methods (Percoll(r) 54.8 +/- 1.9 compared with 45.2 +/- 1.9; Percoll(r) associated with Nycodenz(r) 53.2 +/- 2.0 compared with 46.8 +/- 2.0; and Percoll(r) associated with Ficoll 55.0 +/- 1.5 compared with 45.0 +/- 1.5 for the percentages of cells containing the X and Y chromosomes, respectively). Thus, it was concluded that the technique of sexing dog sperm using density gradients was not effective for commercial application. PMID- 30455096 TI - Cyclooxygenase-2 is inhibited in prolonged luteal maintenance induced by intrauterine devices in mares. AB - Treatment with intrauterine devices (IUD) prolongs luteal phases in mares, but the mechanism for this has not been fully elucidated. The aims of the present study were to examine how IUDs affect the uterus to induce longer luteal phases, particularly the role of cyclooxygenase-2 (COX-2) in the maintenance of the corpus luteum (CL). Twenty-seven reproductively normal mares were included: 12 were inseminated (AI), and 15 were fitted with IUDs. Blood samples for progesterone were obtained on Days 0, 3, 5, 7, 9, 11, 13, 14, and 15 (relative to day of ovulation). The groups were further divided into non-pregnant (AI-N, n = 4), pregnant (AI-P, n = 8), normal (IUD-N, n = 8) and prolonged luteal phase (IUD P, n = 7) based on ultrasonic examinations and serum progesterone concentrations on Days 14 and 15. Blood sampling to quantify the PGF2alpha metabolite (PGFM) was performed through a catheter hourly from 15:00 to 20:00 h on Day 14, and from 6:00 until 13:00 h on Day 15. On Day 15, a low-volume uterine lavage followed by an endometrial biopsy was performed. Estradiol concentration in the Day 15 serum and lavage fluid was determined, while the abundance of COX-2 was evaluated in the biopsy specimens using western blotting (WB) and immunohistochemistry (IHC). All pregnant mares were negative for COX-2 in IHC samples and 5 of 8 were negative in WB samples while all mares of the IUD-N group were positive for COX 2. Of the seven mares in the IUD-P group, five and four were negative for COX-2 with the IHC and WB samples, respectively. The results from this study indicate that IUDs, when effective, suppress COX-2, leading to the inhibition of PGF2alpha release and maintenance of CL. PMID- 30455097 TI - Novel and differentially abundant microRNAs in sperm cells, seminal plasma, and serum of boars due to porcine reproduction and respiratory syndrome virus infection. AB - The objectives of this study were to identify and determine relative abundance of miRNAs in boar sperm, seminal plasma (SP), and serum pre- and post-viral infection. Functional enrichment analyses on predicted targets of miRNAs of interest were performed. Boars (n = 6) were inoculated with porcine reproductive and respiratory syndrome virus (PRRSv) strain 1-8-4 (Day 0). Semen and serum were collected on Day -2 and 6. Sperm and SP were separated and aliquots were flash frozen and stored at -80 degrees C. Serum was frozen and stored at -80 degrees C. Total RNA was isolated from sperm and SP samples and subjected to RNA sequencing. Microarray analysis was performed using the Day -2 and 6 RNA samples from serum, sperm and SP. Potential miRNA targets were predicted using miRanda 3.3a and targets were then analyzed for enrichment of Gene Ontology) and InterPro terms and were considered to be enriched if P < 0.01 using the Bonferroni correction. Microarray analyses resulted in 83, 13, and 10 miRNAs with differences in abundances in sperm, serum, and SP, respectively, when comparing Day -2 and 6. Results from enrichment analyses indicated that the predicted targets of 35, nine, and five miRNAs with differences in abundances for sperm, SP, and serum, respectively, that have functions and/or conserved protein domains that are enriched when compared to the pig genome. Enriched terms for P2X purinoceptors were identified for sperm, SP and serum. Enriched terms for cell adhesion were identified for sperm and serum transcripts. Enriched terms for cell signaling were identified for sperm and SP transcripts. PMID- 30455098 TI - Frequency of Testing for Prostate Cancer Using Prostate-Specific Antigen Among Older Men in a Large Health System. PMID- 30455099 TI - Heparin-binding epidermal growth factor-like growth factor (HB-EGF) protected intestinal ischemia-reperfusion injury through JNK and p38/MAPK-dependent pathway for anti-apoptosis. AB - BACKGROUND: Heparin-Binding Epidermal Growth Factor-Like Growth Factor (HB-EGF) is a potent cytoprotective factor in various body systems, including gastrointestinal tract. In this study, we intended to examine whether HB-EGF exerts its protective effects through MAPK dependent anti-apoptosis after intestinal I/R injury. METHODS: We randomly divided 30 laboratory 30 rats into 5 groups: (A) normal control group, (B) ischemia group with normal saline, (C) I/R group with normal saline, (D) ischemia group with HB-EGF (400 ug/kg), and (E) I/R group with HB-EGF (400 ug/kg). With Western blotting study, we determined JNK and p38/MAPK pathway and caspase-3 activity protein levels using Western analyses. RESULTS: The JNK phosphorylation protein levels increased after intestinal ischemia or intestinal reperfusion phase, and HB-EGF pre-treatment was significantly decreased in JNK phosphorylation protein levels (p < 0.01). We found that p38 protein levels was increased after intestinal reperfusion phase, and that HB-EGF pre-treatment significantly decreased p38 protein levels (p < 0.01). The expression protein level of caspase 3 was increased after intestinal ischemia or intestinal reperfusion phase. HB-EGF pre-treatment significantly decreased Caspase 3 proteins. (p < 0.01). CONCLUSION: Our study revealed that pre treatment of HB-EGF decreased the amount of activity of JNK and p38/MAPK pathway and caspase-3 protein after intestinal I/R injury. These results may further support that the cytoprotective of HB-EGF after I/R injury could be through anti apoptotic effect of activity of JNK and p38/MAPK pathway. PMID- 30455100 TI - Better knee function after surgical repair of acute quadriceps tendon rupture in comparison to acute patellar tendon rupture. AB - INTRODUCTION: The purpose of this study was to determine if there is a difference in knee function between patients with quadriceps tendon rupture and patellar tendon rupture after acute surgical repair. Our hypothesis was that knee function would be similar between the two groups. METHODS: The study population included 24 patients; 13 patients suffered from quadriceps tendon rupture and 11 patients from patellar tendon rupture. All patients underwent acute surgical repair using heavy non-absorbable trans-osseous sutures; another non-absorbable suture, passed through both retinaculum and around the repaired tendon to augment the repair. Clinical evaluation was performed using the Lysholm, Kujala, and VAS scoring systems. In addition, radiographic evaluation to evaluate patellar height and patello-femoral joint arthritis using Iwano's classification was performed. RESULTS: The average follow-up time was 70.5 months. All patients in the quadriceps tendon group had full range of knee motion while 3 patients (27%) in the patellar tendon group had reduced knee flexion. Patients in the quadriceps tendon group had a significantly higher Kujala score in comparison to the patellar tendon group (88 vs. 73 p=0.033). No significant differences were identified between the two groups according to the Lysholm scoring system. Patients in the quadriceps tendon group had significantly less pain according to VAS scale (1.2 vs. 3.5 p=0.012). Radiographic evaluation revealed that two patients from each group showed signs of grade II patello-femoral joint arthritis according to Iwano's classification. CONCLUSION: Acute surgical repair of quadriceps tendon ruptures provides better knee function, in comparison to the surgical restoration of patellar tendon rupture. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 30455101 TI - The Headache and Neck Pain in Ischemic Stroke Patients Caused by Cervicocerebral Artery Dissection. A Case-Control Study. AB - BACKGROUND AND PURPOSE: The symptom of headache and neck pain is common in patients with cervicocerebral artery dissection (CAD). We attempt to screen ischemic stroke patients with CAD based on the characteristics of the pain. METHODS: Eighty-one consecutive ischemic stroke patients with CAD from 2010 to 2017 and 84 consecutive ischemic stroke patients with large artery atherosclerosis (LAA) were registered prospectively and observed in Zhengzhou, China. Those ischemic stroke patients complained of headache and neck pain were categorized into 2 groups. By analyzing the difference of headache and neck pain in 2 groups, we summarized characteristics of the pain secondary to CAD. RESULTS: There were 34 patients in CAD group and 19 patients in LAA group. As for patients in CAD group, the pain could be located in the ipsilateral (41.9%), bilateral (41.9%), or contralateral (16.1%) side of the dissected artery, but in LAA group the pain was often in both sides (68.4%). When the dissected artery was involved in anterior circulation, 55.6% of CAD patients had pain in temporal and when involved in posterior circulation, 65.2% of CAD patients had pain in the occipital and neck. Patients with CAD had a higher prevalence of throbbing pain (30.0%), while pulsating pain (43.8%) was more common in LAA group. Patients often presented with severe pain (46.9%) in CAD group, while less frequently (11.8%) in LAA group, with a significant difference (P = .003). And there was a significant difference between the length (>=20 mm) of the involved artery and severity of the pain (P = .028) in CAD group. CONCLUSIONS: Ischemic stroke patients caused by CAD tend to suffer from headache and neck pain, which may be severe and throbbing, compared with those resulting from LAA. The anterior circulation dissection has a higher prevalence of temporal pain while posterior circulation dissection is typically more associated with occipital and neck pain. PMID- 30455102 TI - Knowledge and awareness of health effects related to the use of mercury in artisanal and small-scale gold mining in Suriname. AB - BACKGROUND: The use of mercury in artisanal and small-scale gold mining has negative effects on human health and the environment. In Suriname, the current gold rush resulted in estimated mercury emissions up to 63t per year. To reduce the use of mercury and the subsequent health impact to gold miners and local inhabitants, knowledge and awareness in the community should be increased. METHODS: This study evaluated the effects of a health education programme (HEP) on the levels of knowledge and awareness among local inhabitants and small-scale gold miners in active gold mining areas in the interior of Suriname, South America. Baseline knowledge levels were assessed with a survey prior to the implementation of the HEP. Thereafter, the exact same questions were asked to evaluate the effects. A total of 959 local inhabitants and 140 gold miners completed the survey including five topics: general knowledge on mercury, potential routes of exposure, health risks for children versus adults, mercury related health effects, and reproductive risks. Additionally, participants were asked in a separate survey (n = 107) about potential exposure reduction techniques and their willingness to be involved in a future human biomonitoring programme. RESULTS: The HEP influenced knowledge on exposure routes of mercury (increase from 64% to 78% of respondents who could name the relevant exposure routes) and on health effects attributed to mercury (increase from 48% to 70% of respondents who were able to list the correct health effects). After the HEP, 70% of the respondents affirmed the higher sensitivity of children, while knowledge on reproductive health effects increased from 39% to 63%. Self-estimated levels of knowledge also increased, indicating lower anxiety regarding potential risks of mercury. Gold miners reported to be willing to improve their work procedures (e.g. burning amalgam with a retort), although suitable tools were not always available. Consistent results were found for individuals included in both surveys, before and after the health education programme. Almost all respondents in the separate survey reported to be willing to give consent for participation in a future human biomonitoring programme, for themselves and their children. CONCLUSION: The implementation of a health education programme within an existing local healthcare structure proved effective and levels of knowledge and awareness improved. Most improved was the knowledge on health effects attributable to mercury, more specifically reproductive health effects. PMID- 30455103 TI - The association between maternal exposure to ambient particulate matter of 2.5 MUm or less during pregnancy and fetal congenital anomalies in Yinchuan, China: A population-based cohort study. AB - BACKGROUND: Few studies from western countries have linked prenatal exposure to ambient particulate matter <2.5 MUm (PM2.5) with increased risk of congenital anomalies. However, the results are mixed. Particularly, evidence is limited for Chinese pregnant women. METHODS: In this retrospective cohort study, we matched the data of all pregnant women laboured in public hospitals during 2015-2016 in Yinchuan, a capital city of northwest China and the data of daily average PM2.5, nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3) concentrations of the nearest monitor station. We calculated a time-dependent exposure over the entire pregnancy for each woman. We used a time varying Cox proportional hazards model to explore the association between PM2.5 exposure and the risk of congenital anomalies, after adjusting for individual confounders and other pollutants. RESULTS: A total of 39,386 singleton live births were included in the study, and 530 (1.35%) were with congenital anomalies. An increase of 10 MUg/m3 in PM2.5 exposure over the entire pregnancy was significantly associated with increased risk of congenital anomalies, with hazard ratio (HR) of 1.35 [95% confidence interval (95%CI): 1.16, 1.58]. For subtype analyses, PM2.5 exposure exhibited a significant association with cardiac anomalies and other unclassifiable anomalies, with HRs of 1.60 (95%CI: 1.24, 2.08) and 1.42 (95%CI: 1.07, 1.89), respectively. The impacts of PM2.5 exposure on orofacial anomalies and musculoskeletal anomalies were not significant. CONCLUSION: Our results indicate high concentration of PM2.5 could increase the risk of congenital anomalies among Chinese, especially for cardiac anomalies. Self-protective measures involving reducing PM2.5 pollution exposure during pregnancy as well as environmental policies aiming to restrict PM2.5 emission could be helpful to reduce the burden of cognitional anomalies. PMID- 30455104 TI - Multiple metals exposure and chromosome damage: Exploring the mediation effects of microRNAs and their potentials in lung carcinogenesis. AB - OBJECTIVE: This study aimed to investigate the associations of multiple metals with chromosome damage, and further explore the mediation roles of microRNAs (miRNAs) and their potentials in lung cancer. METHODS: We determined the urinary levels of 23 metals, lymphocytic micronucleus (MN) frequency, and ten candidate miRNAs in plasma among 365 healthy workers. Poisson and linear regression models were conducted to analyze the associations of urinary metals with MN frequency and miRNAs, respectively. The mediation effects of miRNAs on the metal-MN frequency associations were assessed by causal mediation analysis. Additionally, the levels of effective metal and miRNAs were measured in 43 pair-wised tumor and normal lung tissues. RESULTS: The urinary level of titanium was inversely associated with MN frequency after Bonferroni correction [frequency ratio (FR) and 95% confidence interval (95%CI) = 0.88 (0.82, 0.94), p = 5.0 * 10-4]. A doubling in urinary titanium was associated with 14.72%-38.17% decrease in plasma miRNAs. After multiple comparison, miR-24-3p and miR-28-5p significantly mediated 24.8% (7.7%, 70.0%) and 20.4% (5.7%, 52.0%) of the association between titanium and MN frequency (pmediation = 0.002 and 0.004, respectively). Besides, a doubling in titanium was associated with a separate 53.4% and 47.2% decreased miR 24-3p and miR-28-5p expression in normal lung tissues. Lower titanium but higher levels of miR-24-3p and miR-28-5p were shown in tumor than normal tissues of lung squamous cell carcinoma patients (all p < 0.05). CONCLUSIONS: Our study proposed the negative associations of titanium with chromosome damage and lung cancer, and highlighted the mediating roles of miR-24-3p and miR-28-5p. Further investigations are warranted to validate these associations and uncover the underlying mechanisms. PMID- 30455107 TI - Deloyers procedure. PMID- 30455105 TI - Environmental dissemination of mcr-1 positive Enterobacteriaceae by Chrysomya spp. (common blowfly): An increasing public health risk. AB - Until recently, the role of insects, and particularly flies, in disseminating antimicrobial resistance (AMR) has been poorly studied. In this study, we screened blowflies (Chrysomya spp.) from different areas near the city of Phitsanulok, Northern Thailand, for the presence of AMR genes and in particular, mcr-1, using whole genome sequencing (WGS). In total, 48 mcr-1-positive isolates were recovered, consisting of 17 mcr-1-positive Klebsiella pneumoniae (MCRPKP) and 31 mcr-1-positive Escherichia coli (MCRPEC) strains. The 17 MCRPKP were shown to be clonal (ST43) with few single poly nucleomorphs (SNPs) by WGS analysis. In in-vitro models, the MCRPKP were shown to be highly virulent. In contrast, 31 recovered MCRPEC isolates are varied, belonging to 12 different sequence types shared with those causing human infections. The majority of mcr-1 gene are located on IncX4 plasmids (29/48, 60.42%), sharing an identical plasmid backbone. These findings highlight the contribution of flies to the AMR contagion picture in low- and middle-income countries and the challenges of tackling global AMR. PMID- 30455106 TI - Optimizing the transport and storage conditions of current Good Manufacturing Practice -grade human umbilical cord mesenchymal stromal cells for transplantation (HUC-HEART Trial). AB - BACKGROUND: The HUC-HEART Trial is a clinical study of intramyocardial delivery of current Good Manufacturing Practice (cGMP)-grade human umbilical cord multipotent stromal cells (HUC-MSCs) in ischemic cardiomyopathy where 2 * 107 cells are administered to peri-infarcted myocardium. Prior to the onset of the trial, we aimed to optimize the transport/storage conditions for obtaining the highest cell viability and proliferation rate of cells to be transplanted. METHODS: Cells were tested after being transported in phosphate-buffered saline (PBS) or Ringer's lactate-based (RL) transport media supplemented with human serum albumin (HSA) and/or hydroxyethyl starch (HES) at two temperatures (2-10 degrees C or 22-24 degrees C). RESULTS: The effects of transport conditions on cell viability following 6 h were found highest (93.4 +/- 1.5) in RL-based media at 2-10 degrees C. Karyotypes were found normal upon transportation in any of the formulations and temperatures. However, the highest proliferation rate was noted (3.1-fold increase) in RL (1% HSA) media at 2-10 degrees C over 6 days in culture. From that point, RL (1% HSA) media at 2-10 degrees C was used for further experiments. The maximum cell storage time was detected around 24 h at 2 10 degrees C. Extended storage periods resulted in a decrease in cell viability but not in MSC marker expression. An increase in actin quantity was detected in hypoxia (5% O2) groups in early culture days; no difference was noted between hypoxic versus normoxic (21% O2) conditions in later days. DISCUSSION: The overall results suggest that non-commercial, simple media formulations with extended storage intervals at 2-10 degrees C temperatures are capable of retaining the characteristics of clinical-grade HUC-MSCs. The above findings led us to use RL (1% HSA) media at 2-10 degrees C for transport and storage in the HUC-HEART Trial; 23 patients received HUC-MSCs by August 2018; no adverse effects were noted related to cell processing and transplantation. PMID- 30455108 TI - [Current therapeutic options in invasive mycosis and potential therapeutic role of isavuconazole]. AB - The treatment of invasive fungal infections has deeply evolved in recent years with the inclusion of new antifungals to the therapeutic treatment arsenal. A new azole, isavuconazole, has been recently approved. This review focuses on the role of isavuconazole for treating the most important invasive fungal infections: invasive candidiasis, aspergillosis, mucormicosis, infections caused by other filamentous fungi and those caused by dimorphic fungi. PMID- 30455110 TI - Girl on pointe. PMID- 30455109 TI - Effects of deferasirox dose and decreasing serum ferritin concentrations on kidney function in paediatric patients: an analysis of clinical laboratory data from pooled clinical studies. AB - BACKGROUND: Serious and fatal deferasirox-induced kidney injury has been reported in paediatric patients. This study aimed to investigate the effects of deferasirox dose and serum ferritin concentrations on kidney function and the effect of impaired kidney function on dose-normalised deferasirox minimum plasma concentration (Cmin). METHODS: We did a case-control analysis using pooled data from ten clinical studies. We identified transfusion-dependent patients with thalassaemia, aged 2-15 years, who were receiving deferasirox and had available baseline and follow-up serum creatinine and ferritin measurements. Cases of acute kidney injury (AKI) were defined according to an estimated glomerular filtration rate (eGFR) threshold of 90 mL/min per 1.73 m2 or less (if baseline eGFR was >=100 mL/min per 1.73 m2), an eGFR of 60 mL/min per 1.73 m2 or less (if baseline eGFR was <100 mL/min per 1.73 m2), or an eGFR decrease from baseline of at least 25%. Cases were matched to control visits (eGFR >=120 mL/min per 1.73 m2) on age, sex, study site, and time since drug initiation. We calculated rate ratios for AKI using conditional logistic regression, and evaluated the effect of eGFR changes on Cmin. FINDINGS: Among 1213 deferasirox-treated paediatric patients, 162 cases of AKI and 621 matched control visits were identified. Patients with AKI had a mean 50.2% (SD 15.5) decrease in eGFR from baseline, compared with a 6.9% (29.8) decrease in controls. A significantly increased risk for AKI (rate ratio 1.26, 95% CI 1.08-1.48, p=0.00418) was observed per 5 mg/kg per day increase in deferasirox dispersible tablet dose (equivalent to a 3.5 mg/kg per day dose of film-coated tablets or granules), above the typical starting dose (20 mg/kg per day). An increased risk (1.25, 1.01-1.56, p=0.0400) for AKI was also observed per 250 MUg/L decrease in serum ferritin, starting from 1250 MUg/L. High dose deferasirox (dispersible tablet dose >30 mg/kg per day) resulted in an increased risk (4.47, 1.25-15.95, p=0.0209) for AKI when serum ferritin was less than 1000 MUg/L. Decreases in eGFR were associated with increased Cmin. INTERPRETATION: Deferasirox can cause AKI in a dose-dependent manner. The increased AKI risk with high-dose deferasirox and lower serum ferritin concentration is consistent with overchelation as a causative factor. Small decreases in eGFR correlate with increased deferasirox Cmin, especially in younger patients. Physicians should closely monitor renal function and serum ferritin, use the lowest effective dose to maintain acceptable body iron burden, and interrupt deferasirox treatment when AKI or volume depletion are suspected. FUNDING: None. PMID- 30455111 TI - Renal function abnormalities and deferasirox. PMID- 30455112 TI - Advancing the Development of a Human Schistosomiasis Vaccine. AB - Three vaccines against human schistosomiasis are in different phases of clinical development, and a fourth is expected to enter the clinic soon. Successful introduction of an efficacious preventive human schistosomiasis vaccine will require integration into existing health systems such as those that deliver childhood vaccines or mass drug administration programs. PMID- 30455113 TI - Improving publication quality and the importance of Post Publication Peer Review: The illustrating example of X chromosome analysis and calculation of forensic parameters. PMID- 30455114 TI - Digital transfer of the subgingival contour and emergence profile of the provisional restoration to the final bone-anchored fixed restoration. AB - PURPOSE: This report was written to introduce an attempt at clinical application of our newly developed digital workflow to reproduce the morphology of the subgingival contour and the emergence profile of the provisional restoration within the final bone-anchored fixed restoration, using a bounded unilateral edentulous case. METHODS: This digital workflow involves superimposition of the composite images of two specific types of working casts onto the working cast for the provisional restoration namely, a split cast screwed with a titanium base and a split cast screwed with a provisional restoration and integrating these with the whole intraoral surface image, in which the provisional restoration was present. The final restoration fabricated using this technique could be installed without any clinical problems. The results of in silico analysis revealed that the cubic volume ratio of the total discrepancy between the provisional and the final restorations was only 2.4%. Further, sufficient oral hygiene was maintained and the patient was satisfied with the outcome of the treatment. CONCLUSIONS: This technical report suggests that our newly developed digital workflow provided clinical applicability and may enable accurate transfer of the morphology of the subgingival contour and emergence profile of the provisional to the final bone anchored fixed restoration. PMID- 30455115 TI - Fisher one-and-a-half syndrome due to a bulb protuberance cavernoma. AB - The one and a half Fisher syndrome is produced by an unilateral lesion in the dorsal and inferior part of the pons located specifically in the pontine tegmentum. This is an area that contains the medial longitudinal fasciculus (LMF), the paramedian pontine reticular formation (PPRF) and the nucleus of the sixth cranial nerve, responsible for the horizontal movements of the gaze. Clinically it manifests with conjugate gaze palsy with internuclear ophthalmoplegia. The case is reported on a 60 year-old patient, who presented with binocular diplopia, ophthalmoplegia and paralysis of the gaze conjugated to the left. Imaging studies were performed that showed a hemi-protuberant haematoma secondary to a cavernoma. As expected, he presented with several episodes of re bleeding with clinical worsening: headache, diplopia, tetraparesis, and hypoaesthesia in the right side of the face, as such that the microsurgical exeresis of the protuberant cavernoma was considered. PMID- 30455116 TI - Acute annular outer retinopathy associated with human immunodeficiency virus. AB - A case of acute annular outer retinopathy (AAOR) is presented in a patient that was later proved to be positive for the human immunodeficiency virus (HIV). The aetiology of AAOR remains unknown, although a viral infection or an autoimmune mechanism has been suggested. The case presented here is noteworthy because it is the first case described in a patient with HIV positive serology. Even so, the precise role played by HIV infection or secondary immunosuppression in the development of the AAOR is not known. PMID- 30455117 TI - Intraepithelial ocular surface squamous neoplasia. PMID- 30455118 TI - Berens-Tolman tonometer. PMID- 30455119 TI - Multidisciplinary eyelid reconstruction in Barber-Say syndrome: A case report. AB - Barber-Say syndrome is an unusual dysplasia caused by the mutation of the TWIST2 gene (2q37.3), which encodes a protein that acts at an epigenetic level. The case is presented of a 2-day-old male child in whom ectropion, hypertelorism, hypertrichosis and other dysmorphic features led to the clinical diagnosis of Barber-Say syndrome, which was later confirmed with genetic tests. Around 20 cases have been reported on this syndrome, of which less than half have described the surgical technique, as it represents a surgical challenge. The approach in this case included a lateral tarsorrhaphy and skin grafts taken from the volar surface of the forearm, retroauricular area and supraclavicular fossa, as well as autologous lipografts from the inner side of both thighs for palpebral reconstruction. This is the first case of Barber-Say syndrome in which the use of skin grafts are taken from supraclavicular fossa and forearms. PMID- 30455120 TI - Association between Foot Care Knowledge and Practices among African Americans with Type 2 Diabetes: An Exploratory Pilot Study. AB - OBJECTIVES: African Americans bear a disproportionate burden of lower extremity complications associated with a type 2 diabetes diagnosis. We examined the relationship that self-reported foot care knowledge, foot self-care behaviors, and foot self-care management barriers had on a participants' intention to maintain long term foot self-care. METHODS: African Americans were recruited using a convenience and snowball sampling plan, as well as telephone, email and flyers detailing the study. The data from the previously modified foot care knowledge questionnaire was analyzed using SPSS. Descriptive analysis and ANOVAs analyzed basic foot care knowledge, specialized foot care knowledge, and foot self-care. RESULTS: The analysis indicated that a main effect of insurance status, F(2,87) = 4.082, p = .020, was detected, and was the only significant interaction found. CONCLUSION: When comparing the basic and extended foot care education means scores, participants had less extended foot care knowledge than basic foot care knowledge. This study also showed that insurance status had considerable influence on extended foot care knowledge. In an African American population with T2DM, regardless of education and gender, there are considerable differences between how foot care knowledge is translated into actual foot self care behaviors. PMID- 30455121 TI - Membrane-Associated RNA-Binding Proteins Orchestrate Organelle-Coupled Translation. AB - Proteins are positioned and act at defined subcellular locations. This is particularly important in eukaryotic cells that deliver proteins to membrane bound organelles such as the endoplasmic reticulum (ER), mitochondria, or endosomes. It is axiomatic that organelle targeting depends mainly on polypeptide signals. However, recent results demonstrate that targeting elements within the encoding transcripts are essential for efficient protein localisation. Key readers of these elements are membrane-associated RNA-binding proteins (memRBPs) that orchestrate organelle-coupled translation. The translation products then either cross the membrane for organelle entry or hitchhike on organelle surfaces for complex assembly and co-transport. Understanding the interaction of protein- and RNA-based targeting signals is essential to decipher the molecular basis for mutant phenotypes in disease. PMID- 30455122 TI - Corrigendum to "P-3F, a microtubule polymerization inhibitor enhances P53 stability through the change in localization of RPS27a" [Int. J. Biochem. Cell Biol. 92 (2017) 53-62]. PMID- 30455123 TI - Perception of the validity of the Migraine Disability Assessment questionnaire in a population of patients with chronic migraine. AB - OBJECTIVES: The Migraine Disability Assessment (MIDAS) questionnaire is the most frequently used instrument for assessing the level of disability in studies into migraine. This study aims to determine the level of completion of the questionnaire, assess the ease of use, and understand patients' subjective perception of the questionnaire's actual ability to measure disability. MATERIAL AND METHODS: We performed a prospective study of a sample of 78 patients with chronic migraine, determining their level of education and employment status. In a baseline visit, patients were trained to properly complete the questionnaire. At 3 months, we determined the total score and level of completion. Patients also completed a survey measuring ease of use of the questionnaire and patients' perception of whether the score accurately reflected their disability. RESULTS: Only 46% of patients fully completed the questionnaire. Sixty-nine percent reported finding it difficult to complete (this was influenced by patient's employment status but not by educational level). Sixty-two percent of respondents believed that the questionnaire did not fully reflect their own perception of their disability. CONCLUSIONS: Although the validity and consistence of the MIDAS questionnaire are well documented, a high percentage of the study population reported finding it difficult to complete; many patients also considered that the questionnaire did not accurately reflect their disability. Understanding patients' opinions of the suitability of questionnaires used in consultation is crucial to improving completion. PMID- 30455124 TI - [COPD and smoking cessation: Patients' expectations and responses of health professionals]. AB - The importance of smoking cessation in the management of COPD is well established: the benefit of quitting smoking as regards morbidity and mortality outcomes in patients, is unquestioned. The smoking cessation in COPD patients is difficult: high levels of consumption, the duration of smoking, high dependence level, psychological co-morbidities such as anxiety and depression, lower socio economic and intellectual level, constitute barriers. Studies have shown that patients often minimize the risks of smoking, that others do not believe in the benefits of quitting or doubt their ability to quit smoking. The patients' experience, and expectations with regard to smoking cessation are incompletely satisfied: are considered, the smoking characteristics of these patients, the understanding of the tobacco dependence, the beliefs and ideas of smokers, the knowledge of smoking cessation methods, the role of validated aids and alternative treatments, failure management. The answers of the health professionals can be in several directions: establishment of a better communication patient-doctor (empathy), more centered on the needs of the smoker, the role of the motivation and the place of the motivational interview, the understanding of the mechanisms of addiction, a better individualisation of therapeutics, the necessity of a extended follow-up, the contribution of modern technologies, the electronic cigarette, the smoking cessation in respiratory rehabilitation, guidelines that address smoking cessation treatment. PMID- 30455125 TI - MiR-873-5p inhibits cell migration, invasion and epithelial-mesenchymal transition in colorectal cancer via targeting ZEB1. AB - Recent studies have demonstrated that dysregulation of mircoRNAs (miRNAs) greatly affected biological processes of human cancers, including colorectal cancer. As a member of miRNAs family, miR-873-5p has been proved to be a tumor suppressor in some human cancers. Here, we aim to investigate the effects of miR-873-5p on the migration, invasion and epithelial-mesenchymal transition (EMT) of colorectal cancer cells. The low expression of miR-873-5p in colorectal cancer cells was identified by conducting qRT-PCR analysis. Gain of function assays were designed and conducted to demonstrate the specific function of miR-873-5p overexpression in colorectal cancer progression. Transwell assay and western blot assay were conducted and revealed that miR-873-5p inhibited cell migration, invasion and EMT formation. To find the downstream molecular mechanism of miR-873-5p, mechanism assays were designed and performed to find the downstream target of miR-873-5p. ZEB1 (Zinc finger E-box-binding homeobox 1) was certified to be the target of miR 873-5p through bioinformatics analysis, luciferase activity assay and pull-down assay. Finally, rescue assays were carried out to demonstrate the effects of miR 873-5p-ZEB1 axis on the migration, invasion and EMT process of colorectal cancer cells. In conclusion, we confirmed that miR-873-5p suppressed cell migration, invasion and EMT in colorectal cancer via targeting ZEB1. PMID- 30455126 TI - "... a life broken in two" Walter Pagel (1898-1983)-Famous pathologist and victim of Nazi Germany. AB - There is no doubt that Walter Pagel (1898-1983) is one of the most outstanding figures in the history of pathology. Not only his fundamental research on tuberculosis and various other fields of pathology but also his historicomedical publications set international standards and earned him numerous honors throughout the scientific world. Far less known is the fact that Pagel, as a German Jew, was one of the victims of the "Third Reich": He was dismissed from his job in Heidelberg, felt forced to emigrate in 1933 and fought for reparation after 1945. Accordingly, this article deals with Pagel's role and fate as a politically persecuted and disenfranchised Jew. It focuses on the general circumstances of his dismissal and forced emigration, but also on Pagel's treatment in post-war Germany. In addition, the influences of this biographical break on Pagel's further research career are investigated. The study is based on archival sources and on a re-analysis of the relevant research literature. It points out that Pagel's emigration took place under difficult circumstances and without clear job prospects. Enormous discipline and mental strength as well as successful networking with supporting mentors allowed Pagel to continue his career in his exile country of England despite poor health. The way in which Pagel was treated in post-war Germany, on the other hand, was less satisfactory: the University of Heidelberg did not offer him any prospect of employment and the "reparation procedure" ("Wiedergutmachungsverfahren") resulted in only small pension payments. Instead, Pagel was awarded an honorary doctorate at his home university in 1966. Of the numerous "stumbling blocks" (n = 183) laid in Heidelberg, not one reminds us of Walter Pagel to date. PMID- 30455127 TI - Immunohistochemical analysis of vocal cord polyps applying markers of squamous cell carcinogenesis. AB - OBJECTIVE: The aim of the study was to perform a pathohistological and immunohistochemical analysis of squamous cell (SC) carcinogenesis markers on epithelial linings of vocal cord polyps. The vocal box, being a heavily burdened organ with intensive cell renewal and regenerative processes, is therefore a favourable environment for constant epithelial growth and hyperplasia. In our ongoing projects on laryngeal carcinogenesis and research on laryngeal tissue, we encountered atypia on diagnosed nodules and polyps that are usually considered as benign formations, resulting from the above-mentioned cell renewal and regeneration, which lead to further investigation. The purpose was to see if changes in molecular markers of SC carcinogenesis follow, or, may appear in immunohistochemical (IHC) analysis, before histological atypia in standard haematoxylin-eosin (HE) staining, and contribute in early diagnosis of potentially suspect polyps. METHODS: After classical pathohistological (PH) analysis on HE slides, IHC analysis of EGFR, cyclin D1, p53, Ki-67, and IMP3 was performed on tissue microarrays of laryngeal tissue (50 samples), ranging from normal to hyperplastic lesions with no atypia (34 samples), low-grade atypia (11 samples), and high-grade atypia (5 samples). RESULTS: This study established an increase and correlation of EGFR, cyclin D1, p53, Ki-67 and IMP3 IHC expressions with pathohistological findings of dysplasia in glottic polypoid lesions. Low and high-grade dysplasia had statistically higher percentages of EGFR-positive cells than normal epithelium and simple hyperplasia (SH) (low vs. normal/SH P = 0.007; high vs. normal/SH P = 0.001). High-grade dysplasia had statistically more positive cells than low-grade dysplasia (P = 0.004), and low-grade dysplasia had statistically more positive cells than specimens without atypia (P = 0.007). The percentage of positive cells was statistically higher for cyclin D1, p53 and Ki 67 in high-grade dysplasia versus low-grade dysplasia (cyclin D1 P = 0.011, p53 P = 0.002; Ki-67 P = 0.026; respectively) and versus normal epithelium and SH (cyclin D1 P = 0.003; p53 P = 0.001; Ki-67 P = 0.002; respectively). An increase of IMP3-positive cells with an increase of atypical changes in the laryngeal epithelium, from superficial towards basal layers was noticed, contrary to the usually seen positivity pattern of SC carcinogenesis markers from basal to superficial layers. A statistically significant difference of IMP3 IHC staining between the pathohistological groups (P = 0.003) was recorded. CONCLUSION: Only polyps that present with simple hyperplasia as the greatest mucosal change can be considered as benign formations. Pathohistologically detected atypia in polypoid changes of vocal cords, confirmed by molecular atypia with an increase of SC carcinogenesis markers, suggest their inclusion in studies of laryngeal carcinogenesis. Our results suggest that in problematic cases IHC analysis could be of interest in detection of biological aggressiveness in polypoid laryngeal tissue and beneficiary for polyp patients' follow-up. Further research of laryngeal carcinogenesis markers and their meaning in fibrovascular polyps is of interest. PMID- 30455128 TI - MET is overexpressed in microsatellite instability-high gastric carcinoma. AB - BACKGROUND: MET is a tyrosine kinase receptor for the hepatocyte growth factor, and its overexpression is a poor prognostic factor in gastric carcinomas. Programmed death-ligand 1 (PD-L1) is an important biomarker of immunotherapy and is frequently positive in microsatellite instability-high (MSI-H) gastric carcinomas. In lung cancers, MET activation up-regulates PD-L1 expression. In this study, we investigated expression of MET and PD-L1 in MSI-H gastric carcinoma and the effects on prognosis. METHODS: MET and PD-L1 (SP142) immunohistochemistry was performed in 73 gastric carcinomas with MSI-H. In cases with MET overexpression, we performed fluorescent in situ hybridization (FISH). PD-L1 expression was calculated from both tumor cells (2+ and 3+ in > 10% of tumor cells was defined as PD-L1TC+) and immune cells (positive in >5% immune cells was PD-L1IC+), and also used a combined positive score (CPS; number of PD L1 staining cells relative to all viable tumor cells; > 1 was PD-L1+). RESULTS: In 73 MSI-H gastric carcinomas, MET overexpression was observed in 11 cases (15.1%). In all 11 cases with MET overexpression,MET amplification was not found. MET overexpression was not related to any of clinico-pathological variables and PD-L1 expression. However, the PD-L1 CPS tended to be higher in tumors that were MET positive. Although MET overexpression alone was not a prognostic indicator, combined MET overexpression/PD-L1 predictive models showed that patients with MET+/PD-L1+ showed the best prognosis for overall survival as compared to other groups. CONCLUSION: MET overexpression was observed in 15% of MSI-H gastric carcinomas and was associated with high level expression of PD-L1. PMID- 30455129 TI - Over-expression of S100B protein as a serum marker of brain metastasis in non small cell lung cancer and its prognostic value. AB - Validated serum biomarkers for patients suffering from non-small cell lung cancer (NSCLC) brain metastasis are urgently needed for early diagnosis, treatment monitoring, and prognostic classification in daily clinical practice. Serum S100B was reported to be a marker of leaky blood-brain barrier (BBB), which was often caused by brain tumors. This study aimed to investigate the role of S100B in NSCLC brain metastasis. The results showed that serum S100B correlated significantly with NSCLC brain metastasis (P < 0.001). When evaluated by the ROC curve, at the cutoff point 13.83 pg/ml, the sensitivity and specificity were 94% and 93%, respectively (AUC= 0.938, P < 0.001). High level of serum S100B was significantly correlated with a higher number of brain metastases and significantly worse prognosis (P < 0.05). In addition, S100B was an independent prognostic factor (P < 0.001). In conclusion, serum S100B was a sensitive and specific marker for early detection of brain metastasis in NSCLC and could be used as a surveillance tool for prognosis evaluation. PMID- 30455130 TI - Prognostic value of small nuclear RNAs (snRNAs) for digestive tract pan- adenocarcinomas identified by RNA sequencing data. AB - Malignant tumors of the digestive tract include esophageal, gastric, and colorectal carcinomas, which all have high global mortality rates. A clinical role for small nuclear RNA (snRNA), a type of small non-coding RNA, has not yet been documented for digestive tract pan-adenocarcinomas. Therefore, the aim of the study was to identify differentially expressed snRNAs and to explore their prognostic implications in pan-adenocarcinomas from the esophagus, stomach, colon, and rectum. The pan-carcinoma RNA-sequencing data of four types of digestive tract cancers with 1, 102 cases obtained from The Cancer Genome Atlas (TCGA) project were analyzed and the differentially expressed snRNAs were evaluated using the edgeR package. The prognostic value of each of the selected snRNAs was determined by univariate and multivariate Cox regression analyses. All the digestive tract pan-adenocarcinomas showed differential expression of three snRNAs: the up-regulated RNU1-106 P and RNU6-850 P and the down-regulated RNU6 529 P. Interestingly, RNU6-101 P appeared to be a risk factor for esophageal adenocarcinoma (ESAD) and RNVU1-4 was potentially a protective factor for stomach adenocarcinoma (STAD) survival. This consistent finding of differential expression of all three snRNAs in all four types of digestive system cancers suggests potential roles for these snRNAs in the tumorigenesis of digestive system cancers. RNU6-101 P could play a pivotal role in the progression of ESAD and RNVU1-4 could perform a protective role in STAD. However, since the current findings were based on RNA-sequencing data mining, more studies are needed for verification. PMID- 30455131 TI - Adolescent and parent factors related to fatigue in paediatric multiple sclerosis and chronic fatigue syndrome: A comparative study. AB - BACKGROUND: Fatigue is a disabling, poorly understood symptom in children and adolescents with multiple sclerosis (caMS), for which effective treatments are lacking. In paediatric Chronic Fatigue Syndrome (CFS), effective psychological interventions have been developed based on psychosocial factors associated with fatigue. This study aimed to identify potentially modifiable factors of fatigue in caMS by comparing caMS, adolescents with CFS, healthy adolescents and their parents on measures of fatigue, psychosocial factors, and neurocognitive functioning. METHODS: 175 participants including 30 caMS (15 fatigued, 15 non fatigued), 30 adolescents with CFS, 30 healthy controls, and their parents were compared on measures of self- and parent-reported fatigue, adolescent and parent cognitive behavioural responses to symptoms, sleep, psychological difficulties, parental distress and objectively measured neurocognitive functioning. RESULTS: Fatigue severity, functional impairment and cognitive behavioural responses to symptoms were equivalent in fatigued caMS and adolescents with CFS, and were significantly higher than in healthy controls and non-fatigued caMS. Neurocognitive functioning was impaired in both caMS groups, but was normal in adolescents with CFS and healthy controls. No between-group differences were identified in adolescent sleep behaviour or psychological difficulties. Parents of all illness groups had more unhelpful cognitions than parents of healthy controls. Psychological distress was elevated in parents of both fatigued groups. CONCLUSIONS: Fifty percent of caMS reported clinically significant fatigue. Similarities between adolescent and parent cognitive behavioural factors in fatigued caMS and adolescents with CFS suggest important potential targets for intervention. Both fatigued and non-fatigued caMS had cognitive difficulties, suggesting that fatigue may need targeted intervention. PMID- 30455132 TI - Color vision testing versus pattern visual evoked potentials and optical coherence tomography parameters in subclinical optic nerve involvement in multiple sclerosis. AB - Acute idiopathic demyelinating optic neuritis is frequently the initial manifestation of multiple sclerosis (MS). We aimed to discuss the value of color vision testing to detect possible optic nerve involvement in patients with MS who had no history of optic neuritis. We evaluated color vision with Farnsworth Munsell 100 (FM-100) hue test. Total error scores (TES), partial error scores for the red-green axis (RGS) and blue-yellow axis (BYS) were calculated. Topographic optic disc parameters (RNFL, RA, DA, CV, RV, and vertical C/D ratio), total macular volume (TMV), central macular thickness (CMT), and retinal ganglion cell layer (RGCL) were determined using spectral domain optical coherence tomography (SD-OCT). Choroidal thickness (CT) was measured using enhanced depth imaging optical coherence tomography (EDI-OCT). Pattern visual evoked potentials (PVEP) were also performed. Twenty-eight patients with RRMS (56 eyes) and 25 healthy controls (50 eyes) were included. P100 latencies were significantly delayed and P100 amplitudes were significantly reduced in the patient group compared with the controls (p <= 0.05). Statistically significant thinning was found in temporal quadrant in the patient group compared with the controls (p = 0.002). TES RGS, and BYS were all increased in the patient group but this was not statistically significant. We found no correlation between TES, RGS, BYS, and P100 latencies or OCT parameters. In our investigation as to whether color vision testing could be a simple biomarker for showing neurodegeneration of the anterior visual pathway regardless of optic neuritis, PVEP and OCT-assessed RNFL thickness seemed to be a more valuable biomarker than color vision testing. PMID- 30455133 TI - Posterior communicating aneurysm with oculomotor nerve palsy: Predictors of nerve recovery. AB - The recovery of oculomotor nerve palsy (ONP) due to posterior communicating aneurysm (PComAA) remains largely undefined. This retrospective study was undertaken to investigate predictors of nerve recovery in patients with ONP due to PComAA. A total of 102 patients with ONP due to PComAA who had undergone either endovascular coiling (63 cases) or surgical clipping (39 cases) between 2012 and 2017 were retrospectively analyzed. Patients consisted of 85 women and 17 men with a mean age of 59.8 years (range, 34-82 years), including 55 un ruptured and 47 ruptured PComAAs. There were 62 complete and 40 partial ONPs before intervention. The mean interval between ONP onset and treatment was 17.7 days (range, 1-180 days). Fifty-seven (55.9%) cases showed complete recovery and 43 (42.2%) cases showed partial recovery, while two (1.9%) cases showed no sign of oculomotor nerve recovery at the last follow-up. Although initial palsy severity, preoperative palsy time, and the presence of subarachnoid hemorrhage (SAH) were significant predictors for ONP recovery in a univariate analysis, a multivariate analysis did not confirm subarachnoid hemorrhage as an independent predictor for recovery. In addition, the aneurysm treatment modality was not correlated with nerve recovery in either analysis. In conclusion, initial palsy severity and preoperative palsy times are important predictors for ONP recovery, early treatment is recommended to achieve complete recovery of ONP, regardless of the presence or absence of SAH. Prospective randomized studies should be performed to determine the influence of different therapeutic strategies (coiling vs. clipping) on nerve recovery. PMID- 30455134 TI - Patient characteristics and critical care workflow affect paging frequency in neurocritical care. AB - Indicator of response urgency (page tag), paging domains, distribution of pages by time of the day, and factors associated with neurocritical care paging remain elusive and were examined in this study. We examined the association between patient, neurocritical care workflow characteristics, and paging domains on frequency of paging using Student's t-test, Chi-square test, and analysis of covariance. A total of 1852 patients generated 36,472 pages. The most common page tagging was "for your information" (n = 15067, 41.3%), while 2.8% (n = 1006) pages were tagged urgent. Paging was most frequent for cardiovascular (12.2%), pain, agitation, distress (6.9%) and sodium (5.3%) concerns. Paging frequency was highest for mechanically ventilated patients (p < 0.001), those with indwelling intracranial pressure monitor (p < 0.04), arterial catheter (p < 0.001), central venous access catheter (p < 0.001), and in those with lower Glasgow Coma Score (p < 0.001). Patients admitted between 18:00-06:00 (aOR 1.47, 95% CI 1.16-1.86) and 14:30-18:00 (aOR 1.46, 95% CI 1.14-1.86), and sodium (aOR 1.52, 95% CI 1.39 1.66), and cardiovascular concerns (aOR 1.24, 95% CI 1.15-1.32) were associated with higher night time paging frequency. Incorporating paging domains in daily workflow and their impact on outcome of paging on escalation of clinical care and patient outcomes warrants further examination. PMID- 30455135 TI - Phenotype of carnitine palmitoyltransferase II (CPT II) deficiency: A questionnaire-based survey. AB - Wide spectrums of symptoms besides muscle weakness, different triggering factors and varied muscles involvement are associated with CPT II deficiency. However, systematic clinical characterization of CPT II deficiency is not known. A Questionnaire-based retrospective study on 13 biochemically and genetically confirmed CPT II deficient patients was performed to analyze these aspects. Attacks of myalgia (13/13 patients), weakness (13/13) and rhabdomyolysis (10/13 patients) were most frequently reported. The number of attacks ranged from 1 to 85/year. Common triggers were exercise (13/13), fasting (13/13), cold (12/13) and infections (12/13). Exercise lasting from 15 to 60 min was sufficient for attacks in 9/13 patients, 1-4 h in 3/13 patients and more than 4 h in 1/13 patient. 2/13 patients required dialysis. Limb muscles were affected slightly more often than other muscles. Mean intensity of pain in visual analogue scale (VAS) during regular attack was 4.77 (+/-1.36). Frequency and severity of attacks did not increase during the course of disease in 10/13 patients. 7/13 patients quit sports after the symptoms emerged. 3/13 patients changed their profession permanently. Increased number of attacks were positively correlated with higher BMI (P = 0.05). Body rest, carbohydrate-rich nutrients and fluid-supplement mitigated the pain. After the first attack [Mean: 9.7 (+/-4.46) years], diagnosis took an average of 26.7 (+/- 13.06) years. In myopathic CPT II deficiency, frequencies of attacks are highly variable. Generally, the myopathic form is a mild form. However, severe patients requiring dialysis due to kidney failure could be present. Individuals with higher BMI are at risk of developing more frequent attacks. PMID- 30455136 TI - Proportion and spectrum of movement disorders in adolescent and adult patients of autoimmune encephalitis of non-neoplastic aetiology. AB - We aimed to study the proportion of patients with movement disorders in seropositive autoimmune encephalitis of non-neoplastic aetiology and also to describe the spectrum of movement disorders in them. We prospectively screened 362 patients of age >12 years with encephalitis of unknown aetiology for a panel of antibodies for autoimmune encephalitis. Demographic and clinical characteristics with focus on the movement disorders were recorded. We also evaluated the differences in the spectrum of movement disorder based on various age groups and antibody positivity. Patients were treated with immune modulating drugs and were followed up for 6 months. Out of the 41 patients, 21 (51.2%) patients presented with movement disorder as a part of their clinical presentation. The commonest movement disorder encountered in our cohort was orofaciolingual dyskinesia (OFLD) 57.1% followed by tremor (38.1%), choreoathetosis (33.3%), paroxysmal dyskinesia (23.8%) stereotypies (14.3%), bradykinesia (13.1%), followed by dystonia (13.1%), catatonia (4.7%), neuromyotonia (4.7%) ballism (4.7%), ataxia (4.7%) and stiff person phenotype (4.7%). The hyperkinetic movement disorders were more commonly seen compared to hypokinetic disorders. All patients received immunomodulatory therapy. On follow, 17 (80.1%) patients had good response with total remission of the movement disorder. Four patients did not have total remission but significant improvement in the symptoms after 6 months of follow up. Our study shows that >50% of patients with antibody positive autoimmune encephalitis have movement disorder as a part of their clinical feature. Timely institution of immunotherapy leads to good outcome in majority of patients. PMID- 30455137 TI - Evaluation of cognitive functions in migraineurs treated with topiramate. AB - Topiramate for the treatment of migraine prophylaxis may cause side effects such as cognitive dysfunction. We aimed to investigate the topiramate's efficacy in migraineours and effect on cognitive functions. 24 migraine patients (Group 1) and 24 healthy participants (Group 2) were included. In both groups event-related potentials P300 Latency, Amplitude and N200 Latency, Amplitude's were evaluated. Topiramate treatment was ordered to group 1. Two months after treatment, the same parameters were evaluated. Monthly number of attacks, painful days, analgesic triptan use and VAS scores were compared before and 2 months after treatment. Evaluation between group 1 and group 2 showed no difference. Group1's before and after treatment values were compared; all parameters after treatment were statistically significantly better. Group 1's number of attacks in a month, the number of painful days in a month, VAS score, the number of analgesic use, the number of triptan use had all decreased after treatment. 100 mg topiramate was effective in the treatment of migraine. However, electrophysiological studies showed that cognitive functions are also affected adversely. PMID- 30455138 TI - Feasibility of vessel wall imaging in assessing unruptured paraclinoid aneurysms: Clinical observations and preliminary experience. AB - INTRODUCTION: The determination of the precise location of unruptured paraclinoid aneurysms with respect to the dura is essential in order to establish the risk of subarachnoid hemorrhage (SAH). In equivocal cases, current imaging modalities are often limited when trying to distinguish the precise relationship of these aneurysms with respect to the dura. We assessed the utility of vessel wall magnetic resonance (VW-MR) imaging in identifying the definitive location of unruptured paraclinoid aneurysms. METHODS: We performed an observational retrospective review using a prospective database of patients undergoing 3T VW-MR of the brain. We included patients that underwent VW-MR gadolinium-enhanced T1 weighted black-blood sequences with fat suppression and saturation band to evaluate unruptured paraclinoid region aneurysms. The dural locations of the aneurysms were first identified on DSA or TOF-MRA and subsequently with VW-MR. The location of aneurysms on VW-MR were then compared qualitatively with the reference standard DSA/TOF-MRA by 2 neurovascular imaging experts. RESULTS: Fifteen patients with unruptured paraclinoid region aneurysms were imaged with VW MR. The extradural or intradural locations of the aneurysms were determined in 80% of patients using VW-MR compared to 47% with DSA/MRA. CONCLUSIONS: VW-MRI may be a feasible imaging technique for identifying the extradural or intradural location of unruptured paraclinoid aneurysms and may help guide management. Further larger studies may be warranted. PMID- 30455140 TI - A Modified Method of Extraluminal Placement of the 9 Fr Arndt Bronchial Blocker Guided by Airtraq Videolaryngoscopy in Adult Thoracic Surgery. PMID- 30455139 TI - Emergent valve-in-valve transcatheter aortic valve replacement in patient with acute aortic regurgitation and cardiogenic shock with preoperative extracorporeal membrane oxygenator: A case report and review of the literature. AB - We describe a challenging case of successful use of emergent veno-arterial extracorporeal membrane oxygenation and valve-in-valve transcatheter aortic valve implantation with a Sapien S3 valve. PMID- 30455141 TI - Larson's Maneuver to Facilitate Endotracheal Intubation Using Videolaryngoscopy. PMID- 30455142 TI - The Evolving Role of Extracorporeal Membrane Oxygenation in Lung Transplantation: Implications for Anesthetic Management. AB - Lung transplantation has become an accepted therapy for most causes of end-stage lung disease. Between 30 to 50% of lung transplants require extracorporeal life support (ECLS). In many lung transplantation centers, extracorporeal membrane oxygenation (ECMO) is replacing cardiopulmonary bypass (CPB) as the primary choice for intraoperative ECLS. This review will discuss the evolving role of ECMO in lung transplantation and its implications for anesthetic management. PMID- 30455144 TI - Predictive Modeling for Nonocclusive Mesenteric Ischemia. PMID- 30455143 TI - An Update on Racial Disparities With 30-Day Outcomes After Coronary Artery Bypass Graft Under the Affordable Care Act. AB - OBJECTIVE: The impact of race on outcomes after coronary artery bypass graft (CABG) has been reported before the enactment of the Patient Protection and Affordable Care Act. However, the impact of race on outcomes post-Affordable Care Act enactment remains unclear. The authors evaluated the association of race with outcomes after enactment of the Affordable Care Act in CABG patients. DESIGN: Retrospective analysis of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2016. SETTING: Multi institutional. PARTICIPANTS: The authors identified 9,698 CABG patients. INTERVENTIONS: CABG. MEASUREMENTS AND MAIN RESULTS: Compared with the white population, the black/African American population had higher rates of congestive heart failure, blood transfusion, bleeding disorder, insulin-dependent diabetes mellitus, active smoking, renal dialysis, and hypertension (all p < 0.05). Compared with whites, Asians tended to have a higher prevalence of blood transfusion, American Society of Anesthesiologists class >=4, diabetes mellitus, and renal dialysis (all p < 0.05). Postoperative red blood cell transfusion (56.5%) and prolonged hospital length of stay >=12 days (27.7%) were the most prevalent adverse outcomes. Compared with whites, the adjusted odds of postoperative overall morbidity were higher among blacks/African Americans (odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.15-1.76, p < 0.001) and Asians (OR: 1.43, 95% CI: 1.06-1.91, p = 0.001). Compared with blacks/African Americans, Asians had higher odds of infection complications (OR: 2.07, 95% CI: 1.10-3.88, p = 0.023). CONCLUSION: Differential outcomes were observed for morbidity and mortality outcome measures. The persistence of racial disparities beyond the Affordable Care Act calls for multidisciplinary action. PMID- 30455145 TI - Analysis of Bioprosthetic Aortic Valve Thrombosis-Implications and Management Strategies. AB - Aortic valve disease is a common condition whose prevalence is increasing, especially in Western countries. Two main families of cardiac prostheses are available: mechanical and biological prostheses. Nevertheless, the use of mechanical surgical valves has declined significantly over time in favor of bioprosthetic surgical valves even among middle-aged patients. The dominance of bioprosthetic valves was enhanced further with the introduction of transcatheter aortic valves. However, some concerns have arisen in recent years about clinical and subclinical leaflet thrombosis of both surgical and transcatheter bioprostheses. This manuscript aims to discuss the current evidence relating to the incidence, pathophysiology, clinical implications, and management strategies of biological valve leaflet thrombosis. PMID- 30455147 TI - Discovery of covalent enzyme inhibitors using virtual docking of covalent fragments. AB - Here we present a virtual docking screen of 1648 commercially available covalent fragments, and identified covalent inhibitors of cysteine protease cathepsin L. These inhibitors did not inhibit closely related protease cathepsin B. Thus, we have established virtual docking of covalent fragments as an approach to discover covalent enzyme inhibitors. PMID- 30455146 TI - Discovery and optimization of pyrazole amides as antagonists of CCR1. AB - A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties. PMID- 30455148 TI - Seco-4-methyl-DCK derivatives as potent chemosensitizers. AB - Twenty-five seco-4-methyl-DCK derivatives were designed, synthesized and evaluated for chemoreversal activity when combined with paclitaxel or vincristine in two drug-resistant cancer cell lines (A2780/T and KB-V) respectively. Most of the new compounds displayed moderate to significant MDR reversal activities in the P-gp overexpressing A2780/T and KB-V cells. Especially, compounds 7o and 7y showed the most potent chemosensitization activities with more than 496 and 735 reversal ratios at a concentration of 10 MUM. Unexpectedly the newly synthesized compounds did not show chemosensitization activities observed in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, these compounds did not exhibit significant antiproliferative activities against nontumorigenic cell lines (HUVEC, HOSEC and T29) compared to the positive control verapamil at the tested concentration, which suggested better safety than verapamil. The pharmacological actions of the compounds will be studied further to explore their merit for development as novel candidates to overcome P-gp mediated MDR cancer. PMID- 30455149 TI - Novel monoamine oxidase inhibitors based on the privileged 2-imidazoline molecular framework. AB - Series of structurally diverse 2-imidazoline derivatives have been synthesized by condensation of substituted aldehydes with ethylenediamine, Pd-catalyzed N arylation of 2-imidazolines and by the formation of 1,2,4-oxadiazoles and benzoxazepines from 2-imidazoline-containing precursors. The 2-imidazoline derivatives were evaluated as potential inhibitors of human monoamine oxidase (MAO) A and B. Among the 2-imidazolines, good potency inhibitors were discovered with compound 9p (IC50 = 0.012 uM) being the most potent MAO-B inhibitor, while compound 9d (IC50 = 0.751 uM) was the most potent MAO-A inhibitor of the series. These potencies are in the same range as those of reference MAO inhibitors used in the clinic. Among 33 compounds evaluated, 13 exhibited IC50 values in the submicromolar range for the inhibition of an MAO isoform. It is postulated that the imidazoline moieties of some of these inhibitors may be recognized by the imidazoline I2-binding site of MAO. Good potency MAO inhibitors may be useful for the treatment of neuropsychiatric and neurodegenerative disorders such as depression and Parkinson's disease, and future application for the treatment of prostate cancer, congestive heart failure and Alzheimer's disease. In addition, high potency 2-imidazoline-derived MAO inhibitors may be used as potential probes for the imidazoline binding sites of the MAOs, as well as to determine alternative binding regions of imidazoline within the MAO active site. PMID- 30455150 TI - Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens. AB - A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1. PMID- 30455151 TI - Synthesis, biological evaluation and molecular dynamic simulations of novel Benzofuran-tetrazole derivatives as potential agents against Alzheimer's disease. AB - A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease. PMID- 30455152 TI - Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4 oxadiazole moiety core with antitumor activities. AB - Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies. PMID- 30455153 TI - Comparative Effectiveness in Perioperative Outcomes of Robotic versus Open Radical Cystectomy: Results from a Multicenter Contemporary Retrospective Cohort Study. AB - BACKGROUND: The comparative effectiveness of robotic-assisted radical cystectomy (RARC) versus open radical cystectomy (ORC) in terms of perioperative outcomes is still a matter of debate affecting payors, physicians, and patients. OBJECTIVE: To evaluate comparative perioperative and longer-term morbidity of RARC versus ORC in a multicenter contemporary retrospective cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective multicenter study included patients with bladder cancer treated with radical cystectomy at 10 academic centers between 2000 and 2017. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Intraoperative outcomes including blood loss and operative time as well as postoperative outcomes including time to discharge, complication, readmission, reoperation, and mortality rates at 30 and 90 d were assessed. Multiple imputation and inverse probability of treatment weighting (IPTW) were used. IPTW multivariable-adjusted regression and logistic analyses were performed to evaluate the associations of RARC versus ORC with perioperative outcomes at 30 and 90 d. RESULTS AND LIMITATIONS: Overall, 1887 patients (1197 RARC and 690 ORC) were included in the study. After IPTW-adjusted analysis, no differences between the groups in terms of preoperative characteristics were observed. RARC was associated with lower blood loss (p<0.001), shorter length of stay (p<0.001), and longer operative time (p=0.007). On IPTW-adjusted multivariable logistic regression analyses, no differences in terms of 30- and 90-d complications, reoperation, and mortality rates were observed. RARC was independently associated with a higher readmission rate at both 30 and 90 d. Limitations are mainly related to the retrospective nature of the study. CONCLUSIONS: While RARC was associated with less blood loss and shorter hospital stay, it also led to longer operation times and more readmissions. There were no differences in 30- and 90-d complications. Because there are no apparent differences in safety between ORC and RARC in expert centers, differences in oncologic and cost-effectiveness outcomes are likely to drive decision making regarding RARC utilization. PATIENT SUMMARY: In this study we investigated the differences between RARC and ORC in terms of perioperative outcomes. We found no difference in early and late complications. We concluded that, to date, differences in oncologic and cost effectiveness outcomes should drive decision making regarding RARC utilization. PMID- 30455155 TI - The unusual pattern of hereditary bleeding disorders in the province of Newfoundland and Labrador-Canada's most Eastern Province. AB - Newfoundland and Labrador (NL), the most eastern province of Canada, is characterized by a unique topography and pattern of settlement. The current population is descended from a small founding population of indigenous Innu, Inuit and Mi'kmaq and an estimated 28,000 settlers. These settlers originated from Southwest England and Southeast Ireland and came to invest and work in one of the world's richest fisheries. They settled in bays, coves and islands off the coast, in small settlements called out-ports. These isolated communities developed unusual patterns of genetic disease including an unusual prevalence of some extremely rare Hereditary Bleeding Disorders (HBD). This study was designed to document the prevalence of these rare disorders, at a snapshot in time, using our provincial HBD registry. These diagnoses were verified by reviewing the original initial diagnostic coagulation results to confirm or refute each diagnosis. When available, we also recorded the underlying mutation. Population based prevalence rates were then compared with data published from the World Federation of Hemophilia (WFH) Global Registry. The results are striking. Using the WFH data the per capita prevalence in NL of Hemophilia A, Factors V, XI, and XIII Deficiency are higher than that of mainland Canada minus Labrador by a factor of 2.89, 4.54, 5.44 and 9.22, respectively. The increased prevalence of mild Hemophilia A is explained by a founder effect of the Val 2016 Ala mutation. All the severe FXIII deficient patients are homozygotes for c.691-1 G > A mutation. These results show that NL's unique geography and population distribution led to a genetic drift that increased the prevalence of some rare factor deficiencies. This comparatively high prevalence provides a potential pool of patients for genotype/phenotype research. PMID- 30455154 TI - Quality Management of massive transfusion protocol incorporating tranexamic acid adherence. AB - Massive transfusion protocols (MTP) vary at different institutions. We implemented an algorithm in the transfusion service to support our Level I trauma center in 2007 and periodically monitor MTP utilization as part of ongoing quality management. At the last review in 2013, median plasma: RBC ratio was 1:1.8. We undertook a retrospective 3-year review of MTP activations stratifying by trauma versus non-trauma indications, and blood component utilization of the massive transfusion (MT) cases, adding a review of tranexamic acid (TXA) administration to the audit. The median transfused plasma: RBC ratio was 1:1.9 in trauma MT, and 1:1.6 in the non-trauma MT cases. Non-trauma MT patients at our institution were significantly older and more coagulopathic at MTP initiation compared to trauma MT patients, received fewer RBC units (15.5 versus 20.2), and had higher mortality. TXA adherence increased over the 3-year period to 60% of all trauma MTP activations in 2017. PMID- 30455156 TI - Beta-propeller protein associated neurodegeneration (BPAN); the first report of three patients from Iran with de novo novel mutations. PMID- 30455157 TI - Parkinson's disease: Evolution of the scientific literature from 1983 to 2017 by countries and journals. AB - This study charts the evolution of the scientific literature on Parkinson's disease (PD) from 1983 to 2017 to inform communities of scientists, physicians, patients, caregivers and politicians concerned with PD. Articles published in journals indexed in the Science Citation Index-Expanded database of the Web of Science were retrieved and analyzed in seven five-year periods: 1983-1987, 1988 1992, 1993-1997, 1998-2002, 2003-2007, 2008-2012 and 2013-2017. Over 35 years the number of research papers on PD increased 33-fold: 885 papers in 1983-1987 to 29,972 in 2013-2017. At the same time the number of countries contributing to PD research increased from 37 to 131. The USA was the most prolific country throughout, followed by several European (UK, Germany, Italy and France) and English-speaking (Canada and Australia) countries. By 2003, several Asian countries (China, South Korea, India and Turkey) emerged with rapid increases in publications related to PD. By 2013-2017, China surpassed all but the USA to rank 2nd globally in productivity. Despite an increase from 4 to 22 African countries publishing PD research from 1983 to 2017, most were either unproductive or contributed <=5 papers in each five-year period. There has also been a 12-fold increase in the number of journals (232-2824) containing papers on PD. In 2013 2017 three PD-focused journals (Parkinsonism & Related Disorders, Movement Disorders and Journal of Parkinson's Disease) contained 6.8% of all PD papers while a large majority (82.5%) of journals published <= 10 papers. This quantitative study complements the numerous extant qualitative reviews to provide a global perspective on PD research. PMID- 30455158 TI - The minimum clinically important difference (MCID) for a falls intervention in Parkinson's: A delphi study. AB - BACKGROUND: Falls are common in Parkinson's disease so any intervention that reduced falls risk would be of value. One potential intervention is the use of cholinesterase inhibitor (ChEi) drugs. OBJECTIVE: To establish the minimum clinically important difference (MCID) for fall rates to inform the effect estimate for sample size calculations of future clinical trials. METHODS: We performed a Delphi study assembling a panel of experts in Parkinson's disease from academic and clinical medicine in order to reach a consensus of opinion. Responses from a panel were summarised and resent to the group, until consensus was reached. RESULTS: 780 clinicians, who had been caring for people with Parkinson's for an average of 14 years, were contacted via three routes. The median (Interquartile range (IQR)) MCID after round 1 was 25% (IQR 20-30%) which equates to the prevention of 5 (IQR 4-6) falls per year. Increasing consensus after round two confirmed the MCID of 25%, narrowing the (IQ) range to 20%-25%. This was unchanged when the panel were shown the number of participants that would need to be recruited to a clinical trial in order to achieve this difference. CONCLUSIONS: We have established that an expert panel of PD specialists consider that an intervention that demonstrated a 25% (IQR 20-25%) relative reduction in falls rate would be clinically meaningful. This estimate can be used to help determine the sample size for any future clinical trial. PMID- 30455159 TI - Comparative transcriptome analyses of the third and fourth stage larvae of Anisakis simplex (Nematoda: Anisakidae). AB - We analyzed transcriptome profiles of Anisakis simplex (Nematoda: Anisakidae) 3rd (ASL3) and 4th larvae (ASL4) obtained by RNA-seq, to understand the molecular pathways linked to parasite survival and discover stage-enriched gene expressions. ASL3 were collected from chum salmon and ASL4 were obtained by in vitro culture. Whole transcriptome sequencing was conducted with Illumina sequencer, and de novo assembly was conducted. 47,179 and 41,934 genes were expressed in ASL3 and ASL4 transcriptomes. Of them, 17,633 were known and 29,546 were unmapped sequence for ASL3. 17,126 were known and 24,808 were unmapped sequence for ASL4. Polyubiquitins-related genes and collagen-related genes were the most abundantly expressed in ASL3 and ASL4. Mitochondrial enzyme-related genes were highly expressed both in ASL3 and ASL4. Among the transcripts, 675 were up-regulated in ASL3, while 1015 were up-regulated in ASL4. Several protease related and protein biosynthesis-related genes were highly expressed in ASL3, all of which are thought to be crucial for invading host tissues. Collagen synthesis related genes were highly expressed in ASL4, reflecting active biosynthesis of collagens during molting process. This information will extend our understanding of biology of the fish-borne zoonotic parasite A. simplex. PMID- 30455160 TI - The Healthy Weigh study of lottery-based incentives and environmental strategies for weight loss: Design and baseline characteristics. AB - Identifying effective strategies for treating obesity is a clinical challenge and a public health priority. The present study is an innovative test of the relative effectiveness of lottery-based financial incentives and environmental strategies on weight loss and maintenance. The Healthy Weigh study is evaluating the comparative effectiveness of behavioral economic financial incentives and environmental strategies, separately and together, in achieving initial weight loss and maintenance of weight loss, in obese urban employee populations. Healthy Weigh is a multi-site, 4-arm randomized controlled trial (RCT) in which 344 employed participants were randomized to one of four arms. The study arms are: 1) standard employee wellness benefits and weigh-ins every 6 months (control arm/usual care); and the control/usual care plus either: 2) daily lottery incentives tied to achievement of weight loss goals (incentive arm); 3) individually tailored environmental strategies around food intake and physical activity (environmental arm); or 4) a combination of incentives and environmental strategies (combined arm). This trial used a web-based platform to enroll, communicate with, and track participant weight change. Wireless scales were used by participants in the three treatment group arms to digitally transmit daily/weekly weights. For females, the baseline median (interquartile range, IQR) for BMI and weight were 37.0 (33.5, 40.6) and 219.9 (198.1, 248.6), respectively; and for males, they were 36.0 (32.8, 39.8) and 247.9 (228.1, 279.5), respectively. The population was generally well-educated. This study demonstrated that multi-site employee-based recruitment for a weight-control intervention study is feasible but may need additional time for coordination between diverse environments. PMID- 30455161 TI - Kinetic models of metabolism that consider alternative steady-state solutions of intracellular fluxes and concentrations. AB - Large-scale kinetic models are used for designing, predicting, and understanding the metabolic responses of living cells. Kinetic models are particularly attractive for the biosynthesis of target molecules in cells as they are typically better than other types of models at capturing the complex cellular biochemistry. Using simpler stoichiometric models as scaffolds, kinetic models are built around a steady-state flux profile and a metabolite concentration vector that are typically determined via optimization. However, as the underlying optimization problem is underdetermined, even after incorporating available experimental omics data, one cannot uniquely determine the operational configuration in terms of metabolic fluxes and metabolite concentrations. As a result, some reactions can operate in either the forward or reverse direction while still agreeing with the observed physiology. Here, we analyze how the underlying uncertainty in intracellular fluxes and concentrations affects predictions of constructed kinetic models and their design in metabolic engineering and systems biology studies. To this end, we integrated the omics data of optimally grown Escherichia coli into a stoichiometric model and constructed populations of non-linear large-scale kinetic models of alternative steady-state solutions consistent with the physiology of the E. coli aerobic metabolism. We performed metabolic control analysis (MCA) on these models, highlighting that MCA-based metabolic engineering decisions are strongly affected by the selected steady state and appear to be more sensitive to concentration values rather than flux values. To incorporate this into future studies, we propose a workflow for moving towards more reliable and robust predictions that are consistent with all alternative steady-state solutions. This workflow can be applied to all kinetic models to improve the consistency and accuracy of their predictions. Additionally, we show that, irrespective of the alternative steady state solution, increased activity of phosphofructokinase and decreased ATP maintenance requirements would improve cellular growth of optimally grown E. coli. PMID- 30455162 TI - Hookah-Related Posts to Twitter From 2017 to 2018: Thematic Analysis. AB - BACKGROUND: Hookah (or tobacco waterpipe) use has recently become prevalent in the United States. The contexts and experiences associated with hookah use are unclear, yet such information is abundant via publicly available hookah users' social media postings. OBJECTIVE: In this study, we utilized Twitter data to characterize Twitter users' recent experiences with hookah. METHODS: Twitter posts containing the term "hookah" were obtained from April 1, 2017 to 29 March, 2018. Text classifiers were used to identify clusters of topics that tended to co occur in posts (n=176,706). RESULTS: The most prevalent topic cluster was Person Tagging (use of @username to tag another Twitter account in a post) at 21.58% (38,137/176,706) followed by Promotional or Social Events (eg, mentions of ladies' nights, parties, etc) at 20.20% (35,701/176,706) and Appeal or Abuse Liability (eg, craving, enjoying hookah) at 18.12% (32,013/176,706). Additional topics included Hookah Use Behavior (eg, mentions of taking a "hit" of hookah) at 11.67% (20,603/176,706), Polysubstance Use (eg, hookah use along with other substances) at 10.95% (19,353/176,706), Buying or Selling (eg, buy, order, purchase, sell) at 9.37% (16,552/176,706), and Flavors (eg, mint, cinnamon, watermelon) at 1.66% (2927/176,706). The topic Dislike of Hookah (eg, hate, quit, dislike) was rare at 0.59% (1043/176,706). CONCLUSIONS: Social events, appeal or abuse liability, flavors, and polysubstance use were the common contexts and experiences associated with Twitter discussions about hookah in 2017-2018. Considered in concert with traditional data sources about hookah, these results suggest that social events, appeal or abuse liability, flavors, and polysubstance use warrant consideration as targets in future surveillance, policy making, and interventions addressing hookah. PMID- 30455163 TI - A Novel Approach to Evaluating Mobile Smartphone Screen Time for iPhones: Feasibility and Preliminary Findings. AB - BACKGROUND: Increasingly high levels of smartphone ownership and use pose the potential risk for addictive behaviors and negative health outcomes, particularly among younger populations. Previous methodologies to understand mobile screen time have relied on self-report surveys or ecological momentary assessments (EMAs). Self-report is subject to bias and unreliability, while EMA can be burdensome to participants. Thus, a new methodology is needed to advance the understanding of mobile screen time. OBJECTIVE: The objective of this study was to test the feasibility of a novel methodology to record and evaluate mobile smartphone screen time and use: battery use screenshot (BUS). METHODS: The BUS approach, defined for this study as uploading a mobile phone screenshot of a specific page within a smartphone, was utilized within a Web-based cross sectional survey of adolescents aged 12-15 years through the survey platform Qualtrics. Participants were asked to provide a screenshot of their battery use page, a feature within an iPhone, to upload within the Web-based survey. Feasibility was assessed by smartphone ownership and response rate to the BUS upload request. Data availability was evaluated as apps per BUS, completeness of data within the screenshot, and five most used apps based on battery use percentage. RESULTS: Among those surveyed, 26.73% (309/1156) indicated ownership of a smartphone. A total of 105 screenshots were evaluated. For data availability, screenshots contained an average of 10.2 (SD 2.0) apps per screenshot and over half (58/105, 55.2%) had complete data available. The most common apps or functions included Safari and Home and Lock Screen. CONCLUSIONS: Study findings describe the BUS as a novel approach for real-time data collection focused on iPhone screen time and use among young adolescents. Although feasibility showed some challenges in the upload capacity of young teens, data availability was generally strong across this large dataset. These data from screenshots have the potential to provide key insights into precise mobile smartphone screen use and time spent per mobile app. Future studies could explore the use of the BUS methodology on other mobile smartphones such as Android phones to correlate mobile smartphone screen time with health outcomes. PMID- 30455164 TI - Health Data for Research Through a Nationwide Privacy-Proof System in Belgium: Design and Implementation. AB - BACKGROUND: Health data collected during routine care have important potential for reuse for other purposes, especially as part of a learning health system to advance the quality of care. Many sources of bias have been identified through the lifecycle of health data that could compromise the scientific integrity of these data. New data protection legislation requires research facilities to improve safety measures and, thus, ensure privacy. OBJECTIVE: This study aims to address the question on how health data can be transferred from various sources and using multiple systems to a centralized platform, called Healthdata.be, while ensuring the accuracy, validity, safety, and privacy. In addition, the study demonstrates how these processes can be used in various research designs relevant for learning health systems. METHODS: The Healthdata.be platform urges uniformity of the data registration at the primary source through the use of detailed clinical models. Data retrieval and transfer are organized through end-to-end encrypted electronic health channels, and data are encoded using token keys. In addition, patient identifiers are pseudonymized so that health data from the same patient collected across various sources can still be linked without compromising the deidentification. RESULTS: The Healthdata.be platform currently collects data for >150 clinical registries in Belgium. We demonstrated how the data collection for the Belgian primary care morbidity register INTEGO is organized and how the Healthdata.be platform can be used for a cluster randomized trial. CONCLUSIONS: Collecting health data in various sources and linking these data to a single patient is a promising feature that can potentially address important concerns on the validity and quality of health data. Safe methods of data transfer without compromising privacy are capable of transporting these data from the primary data provider or clinician to a research facility. More research is required to demonstrate that these methods improve the quality of data collection, allowing researchers to rely on electronic health records as a valid source for scientific data. PMID- 30455165 TI - An App That Incorporates Gamification, Mini-Games, and Social Connection to Improve Men's Mental Health and Well-Being (MindMax): Participatory Design Process. AB - BACKGROUND: Men have different mental health needs as compared with women, and women make up the primary audience of most digital mental health interventions. An Australian football-themed (specifically Australian Football League, AFL) app named MindMax incorporating psychoeducation, gamification, mini-games, and social connection was developed in an effort to address this issue. OBJECTIVE: The aim of this study was to identify the best way to structure and present MindMax, an app that aims to deliver psychoeducational modules, and create a Web-based community centering on well-being, AFL, and video games for men aged 16 to 35 years who are interested in AFL or video games. METHODS: We conducted 6 participatory design (PD) workshops with people aged 16 to 35 years in 3 cities in Australia, to identify the best way to present MindMax, and contracted a digital development agency to develop MindMax. We then iteratively tested MindMax prototypes with 15 user experience testing interviews across 3 separate time points: 2 before app launch and 1 after app launch. RESULTS: A total of 40 individuals (25 male and 15 female) participated in the PD workshops, and a total of 15 individuals (10 male and 5 female) participated in user experience interviews. Broadly, participants expressed a preference for activities requiring active engagement that practiced useful skills. They were also sensitive to how content was presented and wanted the ability to customize their own app experience. Although participants agreed that social motivations were important for engagement with an app, they recommended not to mimic existing social networks. CONCLUSIONS: In basing itself strongly within the AFL subculture and by incorporating gamification as well as mini-games, MindMax aimed to tackle mental health help-seeking barriers for people who enjoy AFL or video games, with a particular emphasis on men, and to provide psychoeducation on strategies to increase mental health and well-being. If MindMax is successful, this would indicate that generalizing this approach to other traditional sporting codes and even competitive video gaming leagues (esports) would be fruitful. PMID- 30455166 TI - mHealth Supportive Care Intervention for Parents of Children With Acute Lymphoblastic Leukemia: Quasi-Experimental Pre- and Postdesign Study. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Caring for children with ALL is challenging for parents. A mobile health (mHealth) supportive care intervention was developed to meet parents' needs. OBJECTIVE: This study aims to evaluate the potential effectiveness of this mHealth supportive care intervention on emotional distress, social support, care burden, uncertainty in illness, quality of life, and knowledge. METHODS: We conducted a quasi-experimental pre- and postdesign study from June 2015 to January 2016. In total, 101 parents were enrolled in the study, with 50 in the observation group and 51 in the intervention group. Parents in the observation group received the standard health education and were observed for 3 months. Parents in the intervention group received the mHealth supportive care intervention, in addition to the standard health education. The intervention consisted of 2 parts-an Android smartphone app "Care Assistant (CA)" and a WeChat Official Account. The CA with 8 modules (Personal Information, Treatment Tracking, Family Care, Financial and Social Assistance, Knowledge Center, Self- Assessment Questionnaires, Interactive Platform, and Reminders) was the main intervention tool, whereas the WeChat Official Account was supplementary to update information and realize interaction between parents and health care providers. Data of parents' social support, anxiety, depression, care burden, uncertainty in illness, quality of life, their existing knowledge of ALL and care, and knowledge need were collected before and after the 3-month study period in both groups. For the intervention group, parents' experience of receiving the intervention was also collected through individual interviews. RESULTS: Overall, 43 parents in the observation group and 49 in the intervention group completed the study. Results found that the intervention reduced parents' anxiety (Dint(Post-Pre)=-7.0 [SD 13.1], Dobs(Post-Pre)=-0.4 [SD 15.8], t90=-2.200, P=.03) and uncertainty in illness (Dint(Post-Pre)=-25.0 [SD 8.2], Dobs(Post-Pre)=-19.8 [SD 10.1], t90=-2.761, P=.01), improved parents' social function (Dint(Post Pre)=9.0 [SD 32.8], Dobs(Post-Pre)=-7.5 [SD 30.3], t90=2.494, P=.01), increased parents' knowledge of ALL and care (Dint(Post-Pre)=28.4 [SD 12.4], Dobs(Post Pre)=17.2 [SD 11.9], t90=4.407, P<.001), and decreased their need for knowledge (Dint(Post-Pre)=-9.9 [SD 11.6], Dobs(Post-Pre)=-1.9 [SD 6.4], t90=-4.112, P<.001). Qualitative results showed that parents were satisfied with the intervention and their role in the caregiving process. CONCLUSIONS: The mHealth intervention in supporting parents of children with ALL is effective. This study is informative for other future studies on providing mHealth supportive care for parents of children with cancer. PMID- 30455167 TI - Evaluation of a Web-Based Intervention for Multiple Health Behavior Changes in Patients With Coronary Heart Disease in Home-Based Rehabilitation: Pilot Randomized Controlled Trial. AB - BACKGROUND: Web-based and theory-based interventions for multiple health behaviors appears to be a promising approach with respect to the adoption and maintenance of a healthy lifestyle in cardiac patients who have been discharged from the hospital. Until now, no randomized controlled trials have tested this assumption among Chinese rehabilitation patients with coronary heart disease using a Web-based intervention. OBJECTIVE: The study aim was to evaluate the effect of an 8-week Web-based intervention in terms of physical activity (PA), fruit and vegetable consumption (FVC), lifestyle changes, social-cognitive outcomes, and health outcomes compared with a waiting control group in Chinese cardiac patients. The intervention content was theory-based on the health action process approach. Self-reported data were evaluated, including PA, FVC, healthy lifestyle (the synthesis of PA and FVC), internal resources (combination of intention, self-efficacy, and planning), and an external resource (social support) of PA and FVC behaviors, as well as perceived health outcomes (body mass index, quality of life, and depression). METHODS: In a randomized controlled trial, 136 outpatients with coronary heart disease from the cardiac rehabilitation center of a hospital in China were recruited. After randomization and exclusion of unsuitable participants, 114 patients were assigned to 1 of the 2 groups: (1) the intervention group: first 4 weeks on PA and subsequent 4 weeks on FVC and (2) the waiting control group. A total of 2 Web-based assessments were conducted, including 1 at the beginning of the intervention (T1, N=114), and 1 at the end of the 8-week intervention (T2, N=83). The enrollment and follow-up took place from December 2015 to May 2016. RESULTS: The Web-based intervention outperformed the control condition for PA, FVC, internal resources of PA and FVC, and an external resource of FVC, with an eta-squared effect size ranging from 0.06 to 0.43. Furthermore, the intervention effect was seen in the improvement of quality of life (F1,79=16.36, P<.001, eta2=.17). When predicting a healthy lifestyle at follow-up, baseline lifestyle (odds ratio, OR 145.60, 95% CI 11.24 1886; P<.001) and the intervention (OR 21.32, 95% CI 2.40-189.20; P=.006) were found to be significant predictors. Internal resources for FVC mediated the effect of the intervention on the adoption of a healthy lifestyle (R2adj=.29; P=.001), indicating that if the intervention increased the internal resource of behavior, the adoption of a healthy lifestyle was more likely. CONCLUSIONS: Patients' psychological resources such as motivation, self-efficacy, planning, and social support as well as lifestyle can be improved by a Web-based intervention that focuses on both PA and FVC. Such an intervention enriches extended rehabilitation approaches for cardiac patients to be active and remain healthy in daily life after hospital discharge. TRIAL REGISTRATION: ClinicalTrials.gov NCT01909349; https://clinicaltrials.gov/ct2/show/NCT01909349 (Archived by WebCite at http://www.webcitation.org/6pHV1A0G1). PMID- 30455168 TI - The Use of Telerehabilitation Technologies for Cardiac Patients to Improve Rehabilitation Activities and Unify Organizations: Qualitative Study. AB - BACKGROUND: Cardiovascular disease is a leading cause of death globally causing 31% of all deaths worldwide. The Danish health care system is characterized by fragmented delivery of services and rehabilitation activities. The Teledialog Telerehabilitation Program for cardiac patients was developed and tested to rectify fragmentation and improve the quality of care. The Teledialog program was based on the assumption that a common communication platform shared by health care professionals, patients, and relatives could reduce or eliminate the fragmentation in the rehabilitation process and improve cooperation between the health professionals. OBJECTIVE: This study aimed to assess the interorganizational cooperation between health care professionals across sectors (hospitals, municipal health care centers) in a cardiac telerehabilitation program. METHODS: Theories of networks between organizations, the sociology of professions, and the "community of practice" approach were used in a case study of a cardiac telerehabilitation program. A triangulation of data collection techniques were used including documents, participant observation (n=76 hours), and qualitative interviews with healthcare professionals (n=37). Data were analyzed using NVivo 11.0. RESULTS: The case study of cooperation in an interorganizational context of cardiac telerehabilitation program is characterized by the following key themes and patterns: (1) integrated workflows via a shared digital rehabilitation plan that help integrate workflow between health care professions and organizations, (2) joint clinical practice showed as a community of practice in telerehabilitation developed across professions and organizations, and (3) unifying the organizations as cooperation has advanced via a joint telerehabilitation program across municipalities and hospitals. CONCLUSIONS: The Teledialog Telerehabilitation Program was a new innovative cardiac program tested on a large scale across hospitals, health care centers, and municipalities. Assessments showed that the Teledialog program and its associated technologies helped improve interorganizational cooperation and reduce fragmentation. The program helped integrate the organizations and led to the creation of a community of practice. Further research is needed to explore long term effects of implementation of telerehabilitation technologies and programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01752192; http://clinicaltrials.gov/ct2/show/NCT01752192 (Archived by WebCite at http://www.webcitation.org/6yR3tdEpb). PMID- 30455169 TI - New Integrated Model Approach to Understand the Factors That Drive Electronic Health Record Portal Adoption: Cross-Sectional National Survey. AB - BACKGROUND: The future of health care delivery is becoming more patient-focused, and electronic health record (EHR) portals are gaining more attention from worldwide governments that consider this technology as a valuable asset for the future sustainability of the national health care systems. Overall, this makes the adoption of EHR portals an important field to study. OBJECTIVE: The aim of this study is to understand the factors that drive individuals to adopt EHR portals. METHODS: We applied a new adoption model that combines 3 different theories, namely, extended unified theory of acceptance and use of technology, health belief model, and the diffusion of innovation; all the 3 theories provided relevant contributions for the understanding of EHR portals. To test the research model, we used the partial least squares causal modeling approach. We executed a national survey based on randomly generated mobile phone numbers. We collected 139 questionnaires. RESULTS: Performance expectancy (beta=.203; t=2.699), compatibility (beta=.530; t=6.189), and habit (beta=.251; t=2.660) have a statistically significant impact on behavior intention (R2=76.0%). Habit (beta=.378; t=3.821), self-perception (beta=.233; t=2.971), and behavior intention (beta=.263; t=2.379) have a statistically significant impact on use behavior (R2=61.8%). In addition, behavior intention (beta=.747; t=10.737) has a statistically significant impact on intention to recommend (R2=69.0%), results demonstrability (beta=.403; t=2.888) and compatibility (beta=.337; t=2.243) have a statistically significant impact on effort expectancy (R2=48.3%), and compatibility (beta=.594; t=6.141) has a statistically significant impact on performance expectancy (R2=42.7%). CONCLUSIONS: Our research model yields very good results, with relevant R2 in the most important dependent variables that help explain the adoption of EHR portals, behavior intention, and use behavior. PMID- 30455170 TI - A Smartphone Attention Bias Intervention for Individuals With Addictive Disorders: Protocol for a Feasibility Study. AB - BACKGROUND: Substance use disorders are highly prevalent globally. Relapse rates following conventional psychological interventions for substance use disorders remain high. Recent reviews have highlighted attentional and approach or avoidance biases to be responsible for multiple relapses. Other studies have reported the efficacy of interventions to modify biases. With advances in technologies, there are now mobile versions of conventional bias modification interventions. However, to date, no study has evaluated bias modification in a substance-using, non-Western sample. Existing evaluations of mobile technologies for the delivery of bias interventions are also limited to alcohol or tobacco use disorders. OBJECTIVE: This study aims to examine the feasibility of mobile-based attention bias modification intervention among treatment-seeking individuals with substance use and alcohol use disorders. METHODS: This is a feasibility study, in which inpatients who are in their rehabilitation phase of clinical management will be recruited. On each day that they are in the study, they will be required to complete a craving visual analogue scale and undertake both a visual probe based assessment and and modification task in a smartphone app . Reaction time data will be collated for the computation of baseline attentional biases and to determine whether there is a reduction of attentional bias across the interventions. Feasibility will be determined by the number of participants recruited and participants' adherence to the planned interventions up until the completion of their rehabilitation program and by the ability of the app in detecting baseline biases and changes in biases. Acceptability of the intervention will be assessed by a short questionnaire of users' perceptions of the intervention. Statistical analyses will be performed using SPSS version 22.0, while qualitative analysis of the perspectives will be performed using NVivo version 10.0. RESULTS: This study was approved by the National Healthcare Group Domain Specific Research Board, with approval number (2018/00316). Results will be disseminated by means of conferences and publications.Currently, we are in the process of recruitment for this study. CONCLUSIONS: To the best of our knowledge, this is the first study to evaluate the feasibility and acceptability of a mobile attention bias modification intervention for individuals with substance use disorders. The data pertaining to the feasibility and acceptability are undoubtedly crucial because they imply the potential use of mobile technologies in retraining attentional biases among inpatients admitted for medical-assisted detoxification and rehabilitation. Participants' feedback pertaining to the ease of use, interactivity, and motivation to continue using the app is crucial because it will determine whether a codesign approach might be warranted to design an app that is acceptable for participants and that participants themselves would be motivated to use. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11822. PMID- 30455171 TI - A Digital Health App to Assess Decisional Capacity to Provide Informed Consent: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Any study with human subjects must have a robust consent process to ensure that participants understand the study and can decide whether they want to be involved. Investigators must determine whether a potential study participant is able to make an informed decision and what modifications or supports are needed to maximize participation in decision making. A variety of approaches have been used to modify consent forms and the consent process to increase the research participants' decisional capacity. This protocol describes a randomized controlled trial (RCT) of a digital health app to support decision making among individuals contemplating providing consent to participate in a clinical trial. OBJECTIVE: The objective of this RCT will be to determine if the use of a tablet based app facilitates greater participation in and satisfaction with the consent process compared with standard practice and identify which individual factors are associated with better response to the decision aid. We hypothesize that the tablet-based version of the consent process will promote more informed decision making, including decisions that are more consistent with individual preferences and values expressed during qualitative data collection. METHODS: A two-arm RCT will be conducted in a sample of approximately 100 individuals with fragile X syndrome in their homes across the United States. RESULTS: Data analysis will be completed by late 2018. CONCLUSIONS: By developing and testing a novel consent decision aid, we will have a better understanding of whether and how technological support can optimize the fit between the decisional capacity and the decisional process. TRIAL REGISTRATION: ClinicalTrials.gov NCT02465931; https://clinicaltrials.gov/ct2/show/NCT02465931 (Archived by WebCite at http://www.webcitation.org/72Q3xJQAw). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/10360. PMID- 30455172 TI - Mobile Phone Apps for Low-Income Participants in a Public Health Nutrition Program for Women, Infants, and Children (WIC): Review and Analysis of Features. AB - BACKGROUND: Since 1972, the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) has been proven to improve the health of participating low-income women and children in the United States. Despite positive nutritional outcomes associated with WIC, the program needs updated tools to help future generations. Improving technology in federal nutrition programs is crucial for keeping nutrition resources accessible and easy for low income families to use. OBJECTIVE: This review aimed to analyze the main features of publicly available mobile phone apps for WIC participants. METHODS: Keyword searches were performed in the app stores for the 2 most commonly used mobile phone operating systems between December 2017 and June 2018. Apps were included if they were relevant to WIC and excluded if the target users were not WIC participants. App features were reviewed and classified according to type and function. User reviews from the app stores were examined, including ratings and categorization of user review comments. RESULTS: A total of 17 apps met selection criteria. Most apps (n=12) contained features that required verified access available only to WIC participants. Apps features were classified into categories: (1) shopping management (eg, finding and redeeming food benefits), (2) clinic appointment management (eg, appointment reminders and scheduling), (3) informational resources (eg, recipes, general food list, tips about how to use WIC, links to other resources), (4) WIC-required nutrition education modules, and (5) other user input. Positive user reviews indicated that apps with shopping management features were very useful. CONCLUSIONS: WIC apps are becoming increasingly prevalent, especially in states that have implemented electronic benefits transfer for WIC. This review offers new contributions to the literature and practice, as practitioners, software developers, and health researchers seek to improve and expand technology in the program. PMID- 30455173 TI - Use of Dental Practices for the Identification of Adults With Undiagnosed Type 2 Diabetes Mellitus or Nondiabetic Hyperglycemia: Protocol for a Systematic Review. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing global health burden and is expected to affect more than 590 million people by the year 2035. Evidence exists to demonstrate that dental settings have been used for risk assessment and identification of individuals who may be at high risk for T2DM or who may already unknowingly have the condition. OBJECTIVE: This protocol aims to outline the methodology that will be undertaken to synthesize the literature relating to the use of primary care (nonhospital-based) dental services for the identification of undiagnosed T2DM or prediabetes-often termed nondiabetic hyperglycemia-in adult patients. METHODS: This paper outlines the protocol that will be followed to conduct a systematic review and meta-analysis of the available literature. The protocol outlines the aims, objectives, search strategy, data extraction and data management methods, as well as the statistical analysis plan. The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols guidelines were followed in developing the protocol as were elements of the Cochrane handbook. RESULTS: We expect the systematic review to be completed within 18 months of publication of this protocol and expect to see a high degree of heterogeneity in the existing literature. CONCLUSIONS: This review is of importance as it will synthesize the existing evidence base and inform future studies in the field. Following the publication of the protocol, the review will be registered on Prospective Register of Systematic Reviews. Following the completion of the review, results will be published in a suitable peer-reviewed journal. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/11843. PMID- 30455174 TI - Decapping enzymes STOP "cancer" ribosomes in their tracks. PMID- 30455176 TI - Shock to the heart: cardiac implantable devices' bad name in adults with tetralogy of Fallot. PMID- 30455175 TI - Grip strength predicts cardiac adverse events in patients with cardiac disorders: an individual patient pooled meta-analysis. AB - OBJECTIVE: Grip strength is a well-characterised measure of weakness and of poor muscle performance, but there is a lack of consensus on its prognostic implications in terms of cardiac adverse events in patients with cardiac disorders. METHODS: Articles were searched in PubMed, Cochrane Library, BioMed Central and EMBASE. The main inclusion criteria were patients with cardiac disorders (ischaemic heart disease, heart failure (HF), cardiomyopathies, valvulopathies, arrhythmias); evaluation of grip strength by handheld dynamometer; and relation between grip strength and outcomes. The endpoints of the study were cardiac death, all-cause mortality, hospital admission for HF, cerebrovascular accident (CVA) and myocardial infarction (MI). Data of interest were retrieved from the articles and after contact with authors, and then pooled in an individual patient meta-analysis. Univariate and multivariate logistic regression was performed to define predictors of outcomes. RESULTS: Overall, 23 480 patients were included from 7 studies. The mean age was 62.3+/-6.9 years and 70% were male. The mean follow-up was 2.82+/-1.7 years. After multivariate analysis grip strength (difference of 5 kg, 5* kg) emerged as an independent predictor of cardiac death (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001), all-cause death (OR 0.87, 95% CI 0.85 to 0.89, p<0.0001) and hospital admission for HF (OR 0.88, 95% CI 0.84 to 0.92, p<0.0001). On the contrary, we did not find any relationship between grip strength and occurrence of MI or CVA. CONCLUSION: In patients with cardiac disorders, grip strength predicted cardiac death, all-cause death and hospital admission for HF. TRIAL REGISTRATION NUMBER: CRD42015025280. PMID- 30455177 TI - Effect of two behavioural 'nudging' interventions on management decisions for low back pain: a randomised vignette-based study in general practitioners. AB - OBJECTIVE: 'Nudges' are subtle cognitive cues thought to influence behaviour. We investigated whether embedding nudges in a general practitioner (GP) clinical decision support display can reduce low-value management decisions . METHODS: Australian GPs completed four clinical vignettes of patients with low back pain. Participants chose from three guideline-concordant and three guideline-discordant (low-value) management options for each vignette, on a computer screen. A 2*2 factorial design randomised participants to two possible nudge interventions: 'partition display' nudge (low-value options presented horizontally, high-value options listed vertically) or 'default option' nudge (high-value options presented as the default, low-value options presented only after clicking for more). The primary outcome was the proportion of scenarios where practitioners chose at least one of the low-value care options. RESULTS: 120 GPs (72% male, 28% female) completed the trial (n=480 vignettes). Participants using a conventional menu display without nudges chose at least one low-value care option in 42% of scenarios. Participants exposed to the default option nudge were 44% less likely to choose at least one low-value care option (OR 0.56, 95% CI 0.37 to 0.85; p=0.006) compared with those not exposed. The partition display nudge had no effect on choice of low-value care (OR 1.08, 95% CI 0.72 to 1.64; p=0.7). There was no interaction between the nudges (OR 0.94, 95% CI 0.41 to 2.15; p=0.89). INTERPRETATION: A default option nudge reduced the odds of choosing low-value options for low back pain in clinical vignettes. Embedding high value options as defaults in clinical decision support tools could improve quality of care. More research is needed into how nudges impact clinical decision-making in different contexts. PMID- 30455178 TI - Over half of anaesthetists have nowhere to rest during or after a shift, survey finds. PMID- 30455181 TI - Probing insulin secretion with a new tool. AB - JGP study explains how chromomycin A2 affects insulin secretion. PMID- 30455179 TI - Characterization of spatial and temporal development of Type I and Type II hair cells in the mouse utricle using new cell-type-specific markers. AB - The utricle of the inner ear, a vestibular sensory structure that mediates perception of linear acceleration, is comprised of two morphologically and physiologically distinct types of mechanosensory hair cells, referred to as Type Is and Type IIs. While these cell types are easily discriminated in an adult utricle, understanding their development has been hampered by a lack of molecular markers that can be used to identify each cell type prior to maturity. Therefore, we collected single hair cells at three different ages and used single cell RNAseq to characterize the transcriptomes of those cells. Analysis of differential gene expression identified Spp1 as a specific marker for Type I hair cells and Mapt and Anxa4 as specific markers for Type II hair cells. Antibody labeling confirmed the specificity of these markers which were then used to examine the temporal and spatial development of utricular hair cells. While Type I hair cells develop in a gradient that extends across the utricle from posterior medial to anterior-lateral, Type II hair cells initially develop in the central striolar region and then extend uniformly towards the periphery. Finally, by combining these markers with genetic fate mapping, we demonstrate that over 98% of all Type I hair cells develop prior to birth while over 98% of Type II hair cells develop post-natally. These results are consistent with previous findings suggesting that Type I hair cells develop first and refute the hypothesis that Type II hair cells represent a transitional form between immature and Type I hair cells. PMID- 30455180 TI - Ion channels can be allosterically regulated by membrane domains near a de-mixing critical point. AB - Ion channels are embedded in the plasma membrane, a compositionally diverse two dimensional liquid that has the potential to exert profound influence on their function. Recent experiments suggest that this membrane is poised close to an Ising critical point, below which cell-derived plasma membrane vesicles phase separate into coexisting liquid phases. Related critical points have long been the focus of study in simplified physical systems, but their potential roles in biological function have been underexplored. Here we apply both exact and stochastic techniques to the lattice Ising model to study several ramifications of proximity to criticality for idealized lattice channels, whose function is coupled through boundary interactions to critical fluctuations of membrane composition. Because of diverging susceptibilities of system properties to thermodynamic parameters near a critical point, such a lattice channel's activity becomes strongly influenced by perturbations that affect the critical temperature of the underlying Ising model. In addition, its kinetics acquire a range of time scales from its surrounding membrane, naturally leading to non-Markovian dynamics. Our model may help to unify existing experimental results relating the effects of small-molecule perturbations on membrane properties and ion channel function. We also suggest ways in which the role of this mechanism in regulating real ion channels and other membrane-bound proteins could be tested in the future. PMID- 30455183 TI - Guidelines should include treatment burden on ability to work. PMID- 30455182 TI - Widespread roles of enhancer-like transposable elements in cell identity and long range genomic interactions. AB - A few families of transposable elements (TEs) have been shown to evolve into cis regulatory elements (CREs). Here, to extend these studies to all classes of TEs in the human genome, we identified widespread enhancer-like repeats (ELRs) and find ELRs reliably mark cell identities, enriched for lineage-specific master transcription factor binding sites and mostly primate specific. In particular, elements of MIR and L2, TE families whose abundance co-evolved across chordate genomes, are found as ELRs in most human cell types examined. MIR and L2 elements frequently share long-range intra-chromosomal interactions and binding of physically interacting transcriptions factors. We validated 8 L2 and 9 MIR elements function as enhancers in reporter assays, and among 20 MIR-L2 pairings, 1 MIR repressed, and 1 boosted, the enhancer activity of L2 elements. Our results reveal a previously unappreciated coevolution and interaction between two TE families in shaping regulatory networks. PMID- 30455185 TI - Prediction of Subgenome Additive and Interaction Effects in Allohexaploid Wheat. AB - Whole genome duplications have played an important role in the evolution of angiosperms. These events often occur through hybridization between closely related species, resulting in an allopolyploid with multiple subgenomes. With the availability of affordable genotyping and a reference genome to locate markers, breeders of allopolyploids now have the opportunity to manipulate subgenomes independently. This also presents a unique opportunity to investigate epistatic interactions between homeologous orthologs across subgenomes. We present a statistical framework for partitioning genetic variance to the subgenomes of an allopolyploid, predicting breeding values for each subgenome, and determining the importance of intergenomic epistasis. We demonstrate using an allohexaploid wheat breeding population evaluated in Ithaca, NY and an important wheat dataset from CIMMYT previously shown to demonstrate non-additive genetic variance. Subgenome covariance matrices were constructed and used to calculate subgenome interaction covariance matrices for variance component estimation and genomic prediction. We propose a method to extract population structure from all subgenomes at once before covariances are calculated to reduce collinearity between subgenome estimates. Variance parameter estimation was shown to be reliable for additive subgenome effects, but was less reliable for subgenome interaction components. Predictive ability was equivalent to current genomic prediction methods. Including only inter-genomic interactions resulted in the same increase in accuracy as modeling all pairwise marker interactions. Thus, we provide a new tool for breeders of allopolyploid crops to characterize the genetic architecture of existing populations, determine breeding goals, and develop new strategies for selection of additive effects and fixation of inter-genomic epistasis. PMID- 30455184 TI - A Low Resolution Epistasis Mapping Approach To Identify Chromosome Arm Interactions in Allohexaploid Wheat. AB - Epistasis is an important contributor to genetic variance. In inbred populations, pairwise epistasis is present as additive by additive interactions. Testing for epistasis presents a multiple testing problem as the pairwise search space for modest numbers of markers is large. Single markers do not necessarily track functional units of interacting chromatin as well as haplotype based methods do. To harness the power of multiple markers while minimizing the number of tests conducted, we present a low resolution test for epistatic interactions across whole chromosome arms. Epistasis covariance matrices were constructed from the additive covariances of individual chromosome arms. These covariances were subsequently used to estimate an epistatic variance parameter while correcting for background additive and epistatic effects. We find significant epistasis for 2% of the interactions tested for four agronomic traits in a winter wheat breeding population. Interactions across homeologous chromosome arms were identified, but were less abundant than other chromosome arm pair interactions. The homeologous chromosome arm pair 4BL/4DL showed a strong negative relationship between additive and interaction effects that may be indicative of functional redundancy. Several chromosome arms appeared to act as hubs in an interaction network, suggesting that they may contain important regulatory factors. The differential patterns of epistasis across different traits demonstrates that detection of epistatic interactions is robust when correcting for background additive and epistatic effects in the population. The low resolution epistasis mapping method presented here identifies important epistatic interactions with a limited number of statistical tests at the cost of low precision. PMID- 30455186 TI - Computing value from quality and quantity in human decision making. AB - How organisms learn the value of single stimuli through experience is well described. In many decisions, however, value estimates are computed 'on the fly', by combining multiple stimulus attributes. The neural basis of this computation is poorly understood. Here we explore a common scenario in which decision-makers must combine information about quality and quantity to determine the best option. Using fMRI, we examined the neural representation of quality, quantity, and their integration into an integrated subjective value signal in humans of both genders. We found that activity within Inferior Frontal Gyrus (IFG) correlated with offer quality, whilst activity in the Intra Parietal Sulcus (IPS) specifically correlated with offer quantity. Several brain regions, including the Anterior Cingulate Cortex (ACC), were sensitive to an interaction of quality and quantity. However, the ACC was uniquely activated by quality, quantity, and their interaction, suggesting this region provides a substrate for flexible computation of value from both quality and quantity. Furthermore, ACC signals across subjects correlated with the strength of quality and quantity signals in IFG and IPS respectively. ACC tracking of subjective value also correlated with choice predictability. Finally, activity in the ACC was elevated for choice trials, suggesting that ACC provides a nexus for the computation of subjective value in multi-attribute decision making.SIGNIFICANCE STATEMENTWould you prefer 3 apples or 2 oranges? Many choices we make each day require us to weigh up the quality and quantity of different outcomes. Using fMRI, we show that option quality is selectively represented in the Inferior Frontal Gyrus (IFG), whilst option quantity correlates with areas of the Intra Parietal Sulcus (IPS) which have previously been associated with numerical processing. We show that information about the two is integrated into a value signal in the Anterior Cingulate Cortex (ACC), and the fidelity of this integration predicts choice predictability. Our results demonstrate how on-the-fly value estimates are computed from multiple attributes in human value-based decision making. PMID- 30455187 TI - MDMA increases cooperation and recruitment of social brain areas when playing trustworthy players in an iterated Prisoner's Dilemma. AB - Social decision-making is fundamental for successful functioning, and can be affected in psychiatric illness and by serotoninergic modulation. The Prisoner's Dilemma (PD) is the archetypal paradigm to model cooperation and trust. However, the effect of serotonergic enhancement is poorly characterised, and its influence on the effect of variations in opponent behaviour unknown. To address this, we conducted a study investigating how the serotonergic enhancer MDMA modulates behaviour and its neural correlates during an iterated PD with both trustworthy and untrustworthy opponents.We administered 100mg MDMA or placebo to 20 male participants in a double-blind, placebo-controlled, crossover study. While being scanned, participants played repeated rounds with opponents who differed in levels of cooperation. On each round participants chose to compete or cooperate and were asked to rate their trust in the other player.Cooperation with trustworthy, but not untrustworthy, opponents was enhanced following MDMA but not placebo (respectively: OR=2.01 95% CI 1.42--2.84, p<0.001; OR=1.37 95% CI 0.78- 2.30 n.s.). Specifically, MDMA enhanced recovery from, but not the impact of, breaches in cooperation. During trial outcome, MDMA increased activation of four clusters incorporating precentral and supramarginal gyri, superior temporal cortex, central operculum/posterior insula, and supplementary motor area. There was a treatment-by-opponent interaction in right anterior insula and dorsal caudate. Trust ratings did not change across treatment sessions.MDMA increased cooperative behaviour when playing trustworthy opponents. Underlying this was a change in brain activity of regions linked to social cognition. Our findings highlight the context-specific nature of MDMA's effect on social decision making.Significance statementWe provide a detailed analysis of the effect of MDMA on cooperative behaviour during interpersonal interactions, as well as the neural correlates underlying these effects. We find that following administration of MDMA, participants behave more cooperatively, but only when interacting with trustworthy partners. While breaches of trustworthy behaviour have a similar impact following administration of MDMA compared to placebo, MDMA facilitates a greater recovery from these breaches of trust. Underlying this altered behaviour are changes in brain activity during the viewing of opponents' behaviour in regions whose involvement in social processing is well established. This work provides new insights into the impact of MDMA on social interactions, emphasising the important role of the behaviour of others towards us. PMID- 30455188 TI - Systematic review of the factors affecting cat and dog owner compliance with pharmaceutical treatment recommendations. AB - The aim of this systematic review is to describe and assess the quality of the existing evidence base concerning factors that influence the compliance of cat and dog owners to pharmaceutical and specifically polypharmacy treatment recommendations. PubMed, CAB Abstracts and Google were searched to identify relevant literature and search results were filtered according to predetermined inclusion and exclusion criteria. Standardised data extraction and critical appraisal were carried out on each included study, and a Centre for Evidence Based Medicine level of evidence grading was applied. Of the 8589 studies, eight studies were included in the review. Majority (five of eight) of the included studies were examining compliance with short-term antimicrobial therapies and none examined polypharmacy. Multiple definitions of compliance, methods of measurement and different factors potentially affecting compliance were used. Factors reported to have affected compliance in at least one study were dosing regimen, discussion of dosing regimen in light of owners' circumstances, consultation time, disease, month of consultation/treatment, physical risk, social risk and method of administration. The evidence available regarding factors affecting client compliance with pharmaceutical treatment recommendations in cats and dogs is scarce and of poor quality. PMID- 30455189 TI - Exploring how end-of-life management is taught to Australasian veterinary students. Part 1: technical euthanasia. AB - This descriptive study explored how end-of-life management was taught to students in all eight Australasian veterinary schools. A questionnaire-style interview guide was used by a representative at each university to conduct structured interviews with educators in a snowball sampling approach. Four categories of animals were addressed: livestock, equine, companion and avian/wildlife. This article focuses on the first part of the questionnaire: teaching the technical aspects of euthanasia. Euthanasia techniques were taught at more universities in clinical years than preclinical years. Clinical teaching relied on opportunities presenting, for example, euthanasia consultations. Few universities gave students a chance to practise euthanasia during a consultation and those that did were all with livestock. Competency in euthanasia techniques is an important aspect of clinical practice and these findings can be used to inform curriculum reviews of veterinary training. PMID- 30455190 TI - Evaluation of a gait scoring system for cattle by using cluster analysis and Krippendorff's alpha reliability. AB - The aim of the presented study was to validate a three-point locomotion score (LS) classifying lameness in dairy cows. Therefore, locomotion of 144 cows was scored and data on claw lesions were collected during hoof trimming. Based on latter data a cluster analysis was performed to objectively classify cows into three groups (Cluster 1-3). Finally, the congruence between scoring system and clustering was tested using Krippendorff's alpha reliability. In total, 63 cows (43.7 per cent) were classified as non-lame (LS1), 38 (26.4 per cent) were rated as LS2 with an uneven gait and 43 (29.9 per cent) cows were ranked as clearly lame (LS3). In comparison, hoof-trimming data revealed 64 cows (44.4 per cent) to show no diagnosis, 37 (25.7 per cent) one diagnosis, 33 animals (22.9 per cent) two diagnoses and 10 (7.0 per cent) more than two. Comparing the respective categorisation received by either the cluster analysis or LS in between groups, a high correspondence (79.4 per cent and 83.7 per cent) could be found for LS1 and cluster 1 as well as for LS3 and cluster 3. Only LS2 had partial agreement (21.1 per cent) to cluster 2. However, Krippendorff's alpha was 0.75 (95 per cent CI 0.68 to 0.81), indicating a good degree of reliability. Therefore, the results of this study suggested that the presented LS is suitable for classifying the cows' state of lameness representing their claw diseases. PMID- 30455191 TI - Effects of restrictive and non-restrictive harnesses on shoulder extension in dogs at walk and trot. AB - The study aimed to compare the effect of restrictive and non-restrictive harnesses on shoulder extension of dogs at walk and trot. This was a prospective study of nine dogs. Dogs were walked and trotted on a treadmill at a comfortable walking and trotting speed, first with no harness, then with each harness type, with and without added weights. Dogs were filmed and the angle of shoulder extension was measured using non-reflective markers and a video analysis software. Significant decrease in shoulder extension was found with both types of harnesses in comparison with no harness, except for the restrictive harness with weights. Shoulder extension was 2.6 degrees and 4.4 degrees less in dogs wearing a non-restrictive harness than in dogs wearing a restrictive harness, at walk and trot, respectively. The addition of weights did not consistently add more restriction to shoulder extension. The results of this study indicate that harnesses do limit shoulder extension, but perhaps not in the way originally anticipated, as results show extension is significantly reduced under the non restrictive harnesses compared with the restrictive harnesses, with and without weights. PMID- 30455192 TI - Colic in the British military working horse population: a retrospective analysis. AB - Colic is a common and potentially life-threatening condition of horses. Multiple risk factors have been previously identified and it is known that a careful management routine can help reduce colic rates. The British military working horse population represents a unique cohort of horses that are intensively managed with a strict regimen. This retrospective study examined the incidence and mortality rate of colic within this population, as well as the signalment of affected horses, and compared these with the general population. Data for 717 horses over a five-year period (2008-2012) were analysed. Of these, 163 horses (22.7 per cent) experienced 267 colic episodes and 13 horses (1.8 per cent) died because of colic. Recurrent colic was experienced by 35 per cent (57/163) of horses. The incidence of colic was 11.1 episodes per 100 horse-years and of colic related death was 0.5 deaths per 100 horse-years. Horses purchased from mainland Europe were more likely to suffer from colic (OR 4.6; P<0.001) and from recurrent colic (OR 6.0; P=0.005) than horses purchased from Ireland. Only 3 per cent (8/267) of colic episodes were treated surgically. It was concluded that the incidences of colic and colic-related deaths within the British military working horse population are similar to those of the general horse population. PMID- 30455193 TI - 'Clients. Outdoors. Animals.': retaining vets in UK farm animal practice-thematic analysis of free-text survey responses. AB - Retaining vets in farm practice has been identified as a key strategy to maintain an adequately trained and experienced workforce to provide animal health services for livestock enterprises and government. This qualitative study aimed to explore vets' experiences of UK farm animal practice and their perceptions of the factors that influenced their career choices. Thematic analysis of free-text survey responses from 187 vets working in farm practice and 141 who had given up farm work identified four main themes: affect (experiences of feeling or emotions), personal life, the job and the bigger picture. Those who stayed in farm practice described satisfaction with their career and enjoyment of physical, outdoor work in rural communities. Choosing to give up farm work was influenced by both personal and professional circumstances and related frequently to management issues in practice. Veterinary businesses also face challenges from the broader agricultural and veterinary sectors that affect their ability to support and retain vets. The findings presented build on previous quantitative analysis of factors associated with retention and demonstrate the complexity of individual vets' career choices. PMID- 30455194 TI - IFN-gamma and IL-17A differentially influence the response of human macrophages and neutrophils to Pseudomonas aeruginosa infection. AB - Macrophages are important orchestrators of inflammation during bacterial infection acting both as effector cells and as regulators of neutrophil recruitment and life span. Differently activated macrophage populations with distinct inflammatory and microbicidal potential have been described. Our previous work unveiled a positive and a negative correlation between levels of IFN-gamma and IL-17A, respectively, and lung function in cystic fibrosis, particularly in patients chronically infected with P. aeruginosa This study sought to define key parameters in human anti-bacterial immunity under Th1- and Th17-dominated inflammatory conditions; the final aim was to identify unique characteristics that could be fine-tuned therapeutically to minimise tissue damage while maximising bacterial clearance. Towards this aim neutrophils were incorporated into cultures of macrophages treated with IFN-gamma or IL-17A and infected with P. aeruginosa The intent of this design was to model (i) initiation of inflammation by infected macrophages and (ii) delayed arrival of neutrophils and their exposure to macrophage-derived cytokines. Under these conditions IFN gamma decreased bacterial killing and promoted production of the monocyte chemoattractant MCP-1. In contrast, IL-17A promoted bacterial killing but did not affect MCP-1 production. Secretion of the pyrogen IL-1beta was significantly lower in the presence of IFN-gamma compared to IL-17A and correlated with levels of IL1B transcript in infected macrophages. These findings support the validity of this model to investigate human anti-bacterial immunity. Based on these observations, the protective and damaging roles of IFN-gamma and IL-17A, respectively, during P. aeruginosa infection could be caused by their contrasting effects on IL-1beta and MCP-1 production. PMID- 30455195 TI - NOVEL ASSAY TO CHARACTERIZE NEUTROPHIL RESPONSES TO ORAL BIOFILMS. AB - Neutrophils, the most numerous leukocytes, play an important role in maintaining oral health through interactions with oral microbial biofilms. Both neutrophil hyperactivity and the bacterial subversion of neutrophil responses can cause inflammation-mediated tissue damage as seen in periodontal disease. We describe here an assay that assesses neutrophil activation responses to mono-species biofilms bacteria in vitro based on surface expression of cluster of differentiation (CD) markers associated with various neutrophil functions. Most of what we know about neutrophil responses to bacteria is based on in vitro assays that use planktonic bacteria and isolated/pre-activated neutrophils which make interpreting the neutrophil responses to bacteria a challenge to interpret. An understanding of how neutrophils differentially interact with and respond to commensal and pathogenic oral bacteria is necessary in order to further understand the neutrophil's role in maintaining oral health and the pathogenesis of periodontal disease. In this study, a flow cytometry-based in vitro assay was developed to characterize neutrophil activation states based on CD marker expressions in response to oral mono-species bacterial biofilms. Using this approach, changes in the CD marker expressions were assayed in response to specific prominent oral commensal and pathogenic bacteria. Several functional assays, including phagocytosis, production of ROS, activation of the transcription factor Nrf2, NET formation and myeloperoxidase release, were also performed to correlate neutrophil function with CD marker expression. Our results demonstrate that neutrophils display bacterial species-specific responses. This assay can be used to characterize how specific biofilms alter specific neutrophil pathways associated with their activation. PMID- 30455196 TI - Non-typeable Haemophilus influenzae invasive blood isolates are mainly phosphorylcholine negative and show decreased complement-mediated killing in comparison to colonizing isolates from the oropharynx, which is associated with lower binding of IgM and CRP to the bacterial surface. AB - Non-typeable Haemophilus influenzae (NTHi) bacteria express various molecules that contribute to their virulence. The presence of phosphocholine (PCho) on NTHi lipooligosaccharide increases adhesion to epithelial cells and is an advantage for the bacterium enabling nasopharyngeal colonization, as measured in humans and animal models. However, when PCho is expressed on the lipooligosaccharide, it is also recognized by acute phase protein C-reactive protein (CRP) and PCho-specific antibodies, both potent initiators of the classical pathway of complement activation.In this study, we show that blood isolates, which are exposed to CRP and PCho-specific antibodies in the bloodstream, have a higher survival in serum compared to oropharyngeal isolates, which was associated with a decreased presence of PCho. PCholow strains showed a decreased IgM, CRP and complement C3 deposition, which was associated with increased survival in human serum. Consistent with the PCholow strains, removal of PCho expression by licA gene deletion decreased IgM, CRP and complement C3 deposition, which increased survival in human serum. Complement-mediated killing of PChohigh strain was mainly dependent on binding of IgM to the bacterial surface. These data support the hypothesis that a PCholow phenotype was selected in blood during invasive disease, which increases resistance to serum killing, mainly due to lowered IgM and CRP binding to the bacterial surface. PMID- 30455197 TI - Segmental variation in a duplicated msp2 pseudogene generates Anaplasma marginale antigenic variants. AB - Anaplasma marginale is a prototypical highly antigenically variant bacterial pathogen, dependent on sequential generation of Major Surface Protein-2 (Msp2) outer membrane variants to establish persistent infection. Msp2 is encoded by a single expression site and diversity is achieved by gene conversion of chromosomally encoded msp2 pseudogenes. Analysis of the full complement of msp2 pseudogenes in the St. Maries strain revealed identical sequences in different loci. The Florida strain shared the same locus structure but in the loci where the St. Maries strain had two identical pseudogenes, the Florida strain had one that was identical to the St. Maries sequences, while the sequence of the second pseudogene differed. Consequently, we hypothesized that the msp2 pseudogene repertoire arose via gene duplication, allowing structural variation to occur in one copy while retaining the utility of the other. Using comparative genomics, we first established that duplication of msp2 pseudogenes is common among A. marginale strains: all seven examined strains had at least one duplicated pair, either maintained as identical copies or containing segmental changes. We then demonstrated that a minimal segmental change in a duplicated pseudogene locus is sufficient for immune escape from the broad antibody response generated in a natural host as is a completely divergent pseudogene sequence in an otherwise conserved locus. The results support a model in which a locus first duplicates, resulting in a second identical copy, then progressively incorporates changes to generate an msp2 repertoire capable of generating sufficient antigenic variants to escape immunity and establish persistent infection. PMID- 30455198 TI - Mycobacterium tuberculosis Requires Regulation of ESX-5 Secretion for Virulence in Irgm1-Deficient Mice. AB - The Mycobacterium tuberculosis Type VII secretion system ESX-5, which has been implicated in virulence, is activated at the transcriptional level by the phosphate starvation responsive Pst/SenX3-RegX3 signal transduction system. Deletion of pstA1, which encodes a Pst phosphate transporter component, causes constitutive activation of the response regulator RegX3, hyper-secretion of ESX-5 substrates and attenuation in the mouse infection model. We hypothesized that constitutive activation of ESX-5 secretion causes attenuation of the DeltapstA1 mutant. To test this, we uncoupled ESX-5 from regulation by RegX3. Using electrophoretic mobility shift assays, we defined a RegX3 binding site in the esx 5 locus. Deletion or mutation of the RegX3 binding site reversed hyper-secretion of the ESX-5 substrate EsxN by the DeltapstA1 mutant and abrogated induction of EsxN secretion in response to phosphate limitation by wild-type M. tuberculosis The esx-5 RegX3 binding site deletion (DeltaBS) also suppressed attenuation of the DeltapstA1 mutant in Irgm1-/- mice. These data suggest that constitutive ESX 5 secretion sensitizes M. tuberculosis to an immune response that still occurs in Irgm1-/- mice. However, the DeltapstA1DeltaBS mutant remained attenuated in both NOS2-/- and C57BL/6 mice, suggesting that factors other than ESX-5 secretion also contribute to attenuation of the DeltapstA1 mutant. In addition, a DeltapstA1DeltaesxN mutant lacking the hyper-secreted ESX-5 substrate EsxN remained attenuated in Irgm1-/- mice, suggesting that ESX-5 substrates other than EsxN cause increased susceptibility to host immunity. Our data indicate that while M. tuberculosis requires ESX-5 for virulence, it tightly controls secretion of ESX-5 substrates to avoid elimination by host immune responses. PMID- 30455199 TI - Zebrafish G-CSFR maintains neutrophil number and function throughout the lifespan. AB - Granulocyte colony-stimulating factor receptor (G-CSFR), encoded by the CSF3R gene, represents a major regulator of neutrophil production and function in mammals, with inactivating extracellular mutations identified in a cohort of neutropenia patients unresponsive to G-CSF treatment. This study sought to elucidate the role of the zebrafish G-CSFR by generating mutants harboring these inactivating extracellular mutations using genome editing. Zebrafish csf3r mutants possessed significantly decreased numbers of neutrophils from embryonic to adult stages, which were also functionally compromised, did not respond to G CSF and displayed enhanced susceptibility to bacterial infection. This study has identified an important role for the zebrafish G-CSFR in maintaining the number and functionality of neutrophils throughout the lifespan and created a bone fide zebrafish model of non-responsive neutropenia. PMID- 30455200 TI - Characterisation of the mode of action of Aurodox, a Type III Secretion System inhibitor from Streptomyces goldiniensis. AB - Recent work has demonstrated that the polyketide natural product Aurodox, from Streptomyces goldiniensis is able to block the pathogenesis of the murine pathogen Citrobacter rodentium In this work we aimed to aimed gain a better understanding of the mechanism of action of the compound. We show that Aurodox downregulates the expression of the Type Three Secretion Systems of enteropathogenic and enterohaemorhagic Escherichia coli Furthermore, we have used transcriptomic analysis to show that Aurodox inhibits the expression at the transcriptional level by repressing the master regulator, ler Our data support a model in which Aurodox acts upstream of ler and not directly on the secretion system itself. Finally, we have shown that Aurodox, unlike some traditional antibiotics, does not induce expression of RecA, which is essential for the production of Shiga toxin. We propose that these properties nominate Aurodox as a promising anti-virulence therapy for the treatment of these infections. PMID- 30455201 TI - PPE37 is essential for Mycobacterium tuberculosis heme-iron acquisition (HIA) and a defective PPE37 in Mycobacterium bovis BCG prevents HIA. AB - Mycobacterium tuberculosis (Mtb), one of the world's leading causes of death, must acquire nutrients, such as iron, from the host to multiply and cause disease. Iron is an essential metal and Mtb possesses two different systems to acquire iron from its environment: Siderophore-Mediated Iron Acquisition (SMIA) and Heme-Iron Acquisition (HIA), involving uptake and degradation of heme to release ferrous iron. We have discovered that Mycobacterium bovis BCG, the tuberculosis vaccine strain, is severely deficient in HIA, and exploited this phenotypic difference between BCG and Mtb to identify genes involved in HIA by complementing BCG's defect with a fosmid library. We identified ppe37, an iron regulated PPE family gene, as being essential for HIA. BCG complemented with Mtb ppe37 exhibits HIA as efficient as Mtb, achieving robust growth with <0.2 uM hemin. Conversely, deletion of ppe37 from Mtb results in a strain severely attenuated in HIA, with a phenotype nearly identical to BCG, requiring a 200-fold higher concentration of hemin to achieve growth equivalent to its parental strain. A nine amino acid deletion near the N-terminus of BCG PPE37 (amino acids 31 to 39 of the Mtb PPE37 protein) underlies BCG's profound defect in HIA. Significant genetic variability exists in ppe37 genes across different Mtb strains, with more than 60% of sequences from completely sequenced Mtb genomes having mutations that result in altered PPE37 proteins; furthermore, these altered PPE37 proteins are non-functional in HIA. Our findings should allow delineation of the relative roles of HIA and SMIA in Mtb pathogenesis. PMID- 30455202 TI - ADP-heptose is a newly identified pathogen-associated molecular pattern of Shigella flexneri. AB - During an infection, the detection of pathogens is mediated through the interactions between pathogen-associated molecular patterns (PAMPs) and pathogen recognition receptors. beta-Heptose 1,7-bisphosphate (betaHBP), an intermediate of the lipopolysaccharide (LPS) biosynthesis pathway, was recently identified as a bacterial PAMP. It was reported that betaHBP sensing leads to oligomerization of TIFA proteins, a mechanism controlling NF-kappaB activation and pro inflammatory gene expression. Here, we compare the ability of chemically synthesized betaHBP and Shigella flexneri lysate to induce TIFA oligomerization in epithelial cells. We find that, unlike bacterial lysate, betaHBP fails to initiate rapid TIFA oligomerization. It only induces delayed signaling, suggesting that betaHBP must be processed intracellularly to trigger inflammation. Gene deletion and complementation analysis of the LPS biosynthesis pathway revealed that ADP-heptose is the bacterial metabolite responsible for rapid TIFA oligomerization. ADP-heptose sensing occurs down to 10-10 M. During S. flexneri infection, it results in cytokine production, a process dependent on the kinase ALPK1. Altogether, our results rule out a major role of betaHBP in S. flexneri infection and identify ADP-heptose as a new bacterial PAMP. PMID- 30455203 TI - DNA damage response gene alterations in urothelial cancer: ready for practice? AB - Cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy is standard in fit patients. Inactivating mutations of the nucleotide excision repair gene, ERCC2, can predict response to cisplatin-based chemotherapy. Evaluation of the functional impact of ERCC2 mutations can provide mechanistic frameworks supporting the potential predictive role of ERCC2 loss of function. PMID- 30455204 TI - Biological collections for understanding biodiversity in the Anthropocene. AB - Global change has become a central focus of modern biology. Yet, our knowledge of how anthropogenic drivers affect biodiversity and natural resources is limited by a lack of biological data spanning the Anthropocene. We propose that the hundreds of millions of plant, fungal and animal specimens deposited in natural history museums have the potential to transform the field of global change biology. We suggest that museum specimens are underused, particularly in ecological studies, given their capacity to reveal patterns that are not observable from other data sources. Increasingly, museum specimens are becoming mobilized online, providing unparalleled access to physiological, ecological and evolutionary data spanning decades and sometimes centuries. Here, we describe the diversity of collections data archived in museums and provide an overview of the diverse uses and applications of these data as discussed in the accompanying collection of papers within this theme issue. As these unparalleled resources are under threat owing to budget cuts and other institutional pressures, we aim to shed light on the unique discoveries that are possible in museums and, thus, the singular value of natural history collections in a period of rapid change.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455206 TI - Fossil Atmospheres: a case study of citizen science in question-driven palaeontological research. AB - Palaeontologists increasingly use large datasets of observations collected from museum specimens to address broad-scale questions about evolution and ecology on geological timescales. One such question is whether information from fossil organisms can be used as a robust proxy for atmospheric carbon dioxide through time. Here, we present the citizen science branch of 'Fossil Atmospheres', a project designed to refine stomatal index of Ginkgo leaves as a palaeo-CO2 proxy by involving citizen scientists in data collection through the Zooniverse website. Citizen science helped to overcome a barrier presented by the time taken to count cells in Ginkgo samples; however, a new set of challenges arose as a result. A beta-testing phase with Zooniverse volunteers provided an opportunity to improve instructions to ensure high fidelity data. Exploration of citizen scientists' estimates shows that volunteer counts of stomata are accurate with respect to counts made by the project's lead scientist. However, counts of epidermal cells have a wide range, and mean values tend to underestimate expert counts. We demonstrate a variety of approaches to reducing the inaccuracy in the calculated stomatal index that this variation causes. Zooniverse serves as an ideal tool for collection of palaeontological data where the distribution of fossils would be impossible, but where specimens can be easily imaged. Such an approach facilitates the collection of a large palaeontological dataset, as well as providing an opportunity for citizens to engage with climate research.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455205 TI - Museum specimens of terrestrial vertebrates are sensitive indicators of environmental change in the Anthropocene. AB - Natural history museums and the specimen collections they curate are vital scientific infrastructure, a fact as true today as it was when biologists began collecting and preserving specimens over 200 years ago. The importance of museum specimens in studies of taxonomy, systematics, ecology and evolutionary biology is evidenced by a rich and abundant literature, yet creative and novel uses of specimens are constantly broadening the impact of natural history collections on biodiversity science and global sustainability. Excellent examples of the critical importance of specimens come from their use in documenting the consequences of environmental change, which is particularly relevant considering the alarming rate at which we now modify our planet in the Anthropocene. In this review, we highlight the important role of bird, mammal and amphibian specimens in documenting the Anthropocene and provide examples that underscore the need for continued collection of museum specimens.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455207 TI - Historical collections as a tool for assessing the global pollination crisis. AB - There is increasing concern about the decline of pollinators worldwide. However, despite reports that pollinator declines are widespread, data are scarce and often geographically and taxonomically biased. These biases limit robust inference about any potential pollinator crisis. Non-structured and opportunistic historical specimen collection data provide the only source of historical information which can serve as a baseline for identifying pollinator declines. Specimens historically collected and preserved in museums not only provide information on where and when species were collected, but also contain other ecological information such as species interactions and morphological traits. Here, we provide a synthesis of how researchers have used historical data to identify long-term changes in biodiversity, species abundances, morphology and pollination services. Despite recent advances, we show that information on the status and trends of most pollinators is absent. We highlight opportunities and limitations to progress the assessment of pollinator declines globally. Finally, we demonstrate different approaches to analysing museum collection data using two contrasting case studies from distinct geographical regions (New Zealand and Spain) for which long-term pollinator declines have never been assessed. There is immense potential for museum specimens to play a central role in assessing the extent of the global pollination crisis.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455208 TI - Botanic gardens are an untapped resource for studying the functional ecology of tropical plants. AB - Functional traits are increasingly used to understand the ecology of plants and to predict their responses to global changes. Unfortunately, trait data are unavailable for the majority of plant species. The lack of trait data is especially prevalent for hard-to-measure traits and for tropical plant species, potentially owing to the many inherent difficulties of working with species in remote, hyperdiverse rainforest systems. The living collections of botanic gardens provide convenient access to large numbers of tropical plant species and can potentially be used to quickly augment trait databases and advance our understanding of species' responses to climate change. In this review, we quantitatively assess the availability of trait data for tropical versus temperate species, the diversity of species available for sampling in several exemplar tropical botanic gardens and the validity of garden-based leaf and root trait measurements. Our analyses support the contention that the living collections of botanic gardens are a valuable scientific resource that can contribute significantly to research on plant functional ecology and conservation.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455209 TI - The history and impact of digitization and digital data mobilization on biodiversity research. AB - The first two decades of the twenty-first century have seen a rapid rise in the mobilization of digital biodiversity data. This has thrust natural history museums into the forefront of biodiversity research, underscoring their central role in the modern scientific enterprise. The advent of mobilization initiatives such as the United States National Science Foundation's Advancing Digitization of Biodiversity Collections (ADBC), Australia's Atlas of Living Australia (ALA), Mexico's National Commission for the Knowledge and Use of Biodiversity (CONABIO), Brazil's Centro de Referencia em Informacao (CRIA) and China's National Specimen Information Infrastructure (NSII) has led to a rapid rise in data aggregators and an exponential increase in digital data for scientific research and arguably provide the best evidence of where species live. The international Global Biodiversity Information Facility (GBIF) now serves about 131 million museum specimen records, and Integrated Digitized Biocollections (iDigBio) in the USA has amassed more than 115 million. These resources expose collections to a wider audience of researchers, provide the best biodiversity data in the modern era outside of nature itself and ensure the primacy of specimen-based research. Here, we provide a brief history of worldwide data mobilization, their impact on biodiversity research, challenges for ensuring data quality, their contribution to scientific publications and evidence of the rising profiles of natural history collections.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455210 TI - Fungarium specimens: a largely untapped source in global change biology and beyond. AB - For several hundred years, millions of fungal sporocarps have been collected and deposited in worldwide collections (fungaria) to support fungal taxonomy. Owing to large-scale digitization programs, metadata associated with the records are now becoming publicly available, including information on taxonomy, sampling location, collection date and habitat/substrate information. This metadata, as well as data extracted from the physical fungarium specimens themselves, such as DNA sequences and biochemical characteristics, provide a rich source of information not only for taxonomy but also for other lines of biological inquiry. Here, we highlight and discuss how this information can be used to investigate emerging topics in fungal global change biology and beyond. Fungarium data are a prime source of knowledge on fungal distributions and richness patterns, and for assessing red-listed and invasive species. Information on collection dates has been used to investigate shifts in fungal distributions as well as phenology of sporocarp emergence in response to climate change. In addition to providing material for taxonomy and systematics, DNA sequences derived from the physical specimens provide information about fungal demography, dispersal patterns, and are emerging as a source of genomic data. As DNA analysis technologies develop further, the importance of fungarium specimens as easily accessible sources of information will likely continue to grow.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455211 TI - Museum specimens provide novel insights into changing plant-herbivore interactions. AB - Mounting evidence shows that species interactions may mediate how individual species respond to climate change. However, long-term anthropogenic effects on species interactions are poorly characterized owing to a lack of data. Insect herbivory is a major ecological process that represents the interaction between insect herbivores and their host plants, but historical data on insect damage to plants is particularly sparse. Here, we suggest that museum collections of insects and plants can fill key gaps in our knowledge on changing trophic interactions, including proximate mechanisms and the net outcomes of multiple global change drivers across diverse insect herbivore-plant associations. We outline theory on how global change may affect herbivores and their host plants and highlight the unique data that could be extracted from museum specimens to explore their shifting interactions. We aim to provide a framework for using museum specimens to explore how some of the most diverse co-evolved relationships are responding to climate and land use change.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455212 TI - Herbarium specimens reveal substantial and unexpected variation in phenological sensitivity across the eastern United States. AB - Phenology is a key biological trait that can determine an organism's survival and provides one of the clearest indicators of the effects of recent climatic change. Long time-series observations of plant phenology collected at continental scales could clarify latitudinal and regional patterns of plant responses and illuminate drivers of that variation, but few such datasets exist. Here, we use the web tool CrowdCurio to crowdsource phenological data from over 7000 herbarium specimens representing 30 diverse flowering plant species distributed across the eastern United States. Our results, spanning 120 years and generated from over 2000 crowdsourcers, illustrate numerous aspects of continental-scale plant reproductive phenology. First, they support prior studies that found plant reproductive phenology significantly advances in response to warming, especially for early-flowering species. Second, they reveal that fruiting in populations from warmer, lower latitudes is significantly more phenologically sensitive to temperature than that for populations from colder, higher-latitude regions. Last, we found that variation in phenological sensitivities to climate within species between regions was of similar magnitude to variation between species. Overall, our results suggest that phenological responses to anthropogenic climate change will be heterogeneous within communities and across regions, with large amounts of regional variability driven by local adaptation, phenotypic plasticity and differences in species assemblages. As millions of imaged herbarium specimens become available online, they will play an increasingly critical role in revealing large-scale patterns within assemblages and across continents that ultimately can improve forecasts of the impacts of climatic change on the structure and function of ecosystems.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455213 TI - A novel proof of concept for capturing the diversity of endophytic fungi preserved in herbarium specimens. AB - Herbarium specimens represent important records of morphological and genetic diversity of plants that inform questions relevant to global change, including species distributions, phenology and functional traits. It is increasingly appreciated that plant microbiomes can influence these aspects of plant biology, but little is known regarding the historic distribution of microbes associated with plants collected in the pre-molecular age. If microbiomes can be observed reliably in herbarium specimens, researchers will gain a new lens with which to examine microbial ecology, evolution, species interactions. Here, we describe a method for accessing historical plant microbiomes from preserved herbarium specimens, providing a proof of concept using two plant taxa from the imperiled boreal biome (Andromeda polifolia and Ledum palustre subsp. groenlandicum, Ericaceae). We focus on fungal endophytes, which occur within symptomless plant tissues such as leaves. Through a three-part approach (i.e. culturing, cloning and next-generation amplicon sequencing via the Illumina MiSeq platform, with extensive controls), we examined endophyte communities in dried, pressed leaves that had been processed as regular herbarium specimens and stored at room temperature in a herbarium for four years. We retrieved only one endophyte in culture, but cloning and especially the MiSeq analysis revealed a rich community of foliar endophytes. The phylogenetic distribution and diversity of endophyte assemblages, especially among the Ascomycota, resemble endophyte communities from fresh plants collected in the boreal biome. We could distinguish communities of endophytes in each plant species and differentiate likely endophytes from fungi that could be surface contaminants. Taxa found by cloning were observed in the larger MiSeq dataset, but species richness was greater when subsets of the same tissues were evaluated with the MiSeq approach. Our findings provide a proof of concept for capturing endophyte DNA from herbarium specimens, supporting the importance of herbarium records as roadmaps for understanding the dynamics of plant-associated microbial biodiversity in the Anthropocene.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455214 TI - Facets of phylodiversity: evolutionary diversification, divergence and survival as conservation targets. AB - Biodiversity is often described as having multiple facets, including species richness, functional diversity and phylogenetic diversity. In this paper, we argue that phylogenetic diversity itself has three distinct facets-lineage diversification, character divergence and survival time-that can be quantified using distinct branch length metrics on an evolutionary tree. Each dimension is related to different processes of macroevolution, has different spatial patterns and is tied to distinct goals for conserving biodiversity and protecting its future resilience and evolutionary potential. We compared the landscapes identified as top conservation priorities by each of these three metrics in a conservation gap analysis for California, a world biodiversity hotspot, using herbarium data on the biogeography and evolutionary relationships of more than 5000 native plant species. Our analysis incorporated a novel continuous metric of current land protection status, fine-scale data on landscape intactness and an optimization algorithm used to identify complementary priority sites containing concentrations of taxa that are evolutionarily unique, vulnerable due to small range size and/or poorly protected across their ranges. Top conservation priorities included pockets of coastal and northern California that ranked highly for all three phylodiversity dimensions and for species richness, as well as sites uniquely identified by each metric whose value may depend on whether properties such as genetic divergence, high net diversification or independent survival experience are most desirable in an Anthropocene flora.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455215 TI - Bookkeeping of insect herbivory trends in herbarium specimens of purple loosestrife (Lythrum salicaria). AB - The potential use of herbarium specimens to detect herbivory trends is enormous but largely untapped. The objective of this study was to reconstruct the long term herbivory pressure on the Eurasian invasive plant, purple loosestrife (Lythrum salicaria), by evaluating leaf damage over 1323 specimens from southern Quebec (Canada). The hypothesis tested is that that the prevalence of herbivory damage on purple loosestrife is low during the invasion phase and increases throughout the saturation phase. Historical trends suggest a gradual increase in hole feeding and margin feeding damage from 1883 to around 1940, followed by a period of relative stability. The percentage of specimens with window feeding damage did not begin to increase until the end of the twentieth century, from 3% (2-6%) in 1990 to 45% (14-81%) in 2015. Temporal changes in the frequency of window feeding damage support the hypothesis of an increasing herbivory pressure by recently introduced insects. This study shows that leaf damage made by insects introduced for the biocontrol of purple loosestrife, such as coleopterans of the Neogalerucella genus, can be assessed from voucher specimens. Herbaria are a rich source in information that can be used to answer questions related to plant insect interactions in the context of biological invasions and biodiversity changes.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455216 TI - The use and misuse of herbarium specimens in evaluating plant extinction risks. AB - Herbarium specimens provide verifiable and citable evidence of the occurrence of particular plants at particular points in space and time, and are vital resources for assessing extinction risk in the tropics, where plant diversity and threats to plants are greatest. We reviewed approaches to assessing extinction risk in response to the Convention on Biological Diversity's Global Strategy for Plant Conservation Target 2: an assessment of the conservation status of all known plant species by 2020. We tested five alternative approaches, using herbarium derived data for trees, shrubs and herbs in five different plant groups from temperate and tropical regions. All species were previously fully assessed for the IUCN Red List. We found significant variation in the accuracy with which different approaches classified species as threatened or not threatened. Accuracy was highest for the machine learning model (90%) but the least data-intensive approach also performed well (82%). Despite concerns about spatial, temporal and taxonomic biases and uncertainties in herbarium data, when specimens represent the best available evidence for particular species, their use as a basis for extinction risk assessment is appropriate, necessary and urgent. Resourcing herbaria to maintain, increase and disseminate their specimen data is essential to guide and focus conservation action.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455217 TI - Specimen-based analysis of morphology and the environment in ecologically dominant grasses: the power of the herbarium. AB - Herbaria contain a cumulative sample of the world's flora, assembled by thousands of people over centuries. To capitalize on this resource, we conducted a specimen based analysis of a major clade in the grass tribe Andropogoneae, including the dominant species of the world's grasslands in the genera Andropogon, Schizachyrium, Hyparrhenia and several others. We imaged 186 of the 250 named species of the clade, georeferenced the specimens and extracted climatic variables for each. Using semi- and fully automated image analysis techniques, we extracted spikelet morphological characters and correlated these with environmental variables. We generated chloroplast genome sequences to correct for phylogenetic covariance and here present a new phylogeny for 81 of the species. We confirm and extend earlier studies to show that Andropogon and Schizachyrium are not monophyletic. In addition, we find all morphological and ecological characters are homoplasious but variable among clades. For example, sessile spikelet length is positively correlated with awn length when all accessions are considered, but when separated by clade, the relationship is positive for three sub-clades and negative for three others. Climate variables showed no correlation with morphological variation in the spikelet pair; only very weak effects of temperature and precipitation were detected on macrohair density.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455218 TI - Using museum specimens to track morphological shifts through climate change. AB - Museum specimens offer a largely untapped resource for detecting morphological shifts in response to climate change. However, morphological shifts can be obscured by shifts in phenology or distribution or sampling biases. Additionally, interpreting phenotypic shifts requires distinguishing whether they result from plastic or genetic changes. Previous studies using collections have documented consistent historical size changes, but the limited studies of other morphological traits have often failed to support, or even test, hypotheses. We explore the potential of collections by investigating shifts in the functionally significant coloration of a montane butterfly, Colias meadii, over the past 60 years within three North American geographical regions. We find declines in ventral wing melanism, which correspond to reduced absorption of solar radiation and thus reduced risk of overheating, in two regions. However, contrary to expected responses to climate warming, we find melanism increases in the most thoroughly sampled region. Relationships among temperature, phenology and morphology vary across years and complicate the distinction between plastic and genetic responses. Differences in these relationships may account for the differing morphological shifts among regions. Our findings highlight the promise of using museum specimens to test mechanistic hypotheses for shifts in functional traits, which is essential for deciphering interacting responses to climate change.This article is part of the theme issue 'Biological collections for understanding biodiversity in the Anthropocene'. PMID- 30455220 TI - Diagnosis and referral delays in primary care for oral squamous cell cancer: a systematic review. AB - BACKGROUND: The incidence of oral cancer is increasing. Guidance for oral cancer from the National Institute for Health and Care Excellence (NICE) is unique in recommending cross-primary care referral from GPs to dentists. AIM: This review investigates knowledge about delays in the diagnosis of symptomatic oral squamous cell carcinoma (OSCC) in primary care. DESIGN AND SETTING: An independent multi investigator literature search strategy and an analysis of study methodologies using a modified data extraction tool based on Aarhus checklist criteria relevant to primary care. METHOD: The authors conducted a focused systematic review involving document retrieval from five databases up to March 2018. Included were studies looking at OSCC diagnosis from when patients first accessed primary care up to referral, including length of delay and stage of disease at time of definitive diagnosis. RESULTS: From 538 records, 16 articles were eligible for full-text review. In the UK, more than 55% of patients with OSCC were referred by their GP, and 44% by their dentist. Rates of prescribing between dentists and GPs were similar, and both had similar delays in referral, though one study found greater delays attributed to dentists as they had undertaken dental procedures. On average, patients had two to three consultations before referral. Less than 50% of studies described the primary care aspect of referral in detail. There was no information on inter-GP-dentist referrals. CONCLUSION: There is a need for primary care studies on OSCC diagnosis. There was no evidence that GPs performed less well than dentists, which calls into question the NICE cancer option to refer to dentists, particularly in the absence of robust auditable pathways. PMID- 30455219 TI - Using insect natural history collections to study global change impacts: challenges and opportunities. AB - Over the past two decades, natural history collections (NHCs) have played an increasingly prominent role in global change research, but they have still greater potential, especially for the most diverse group of animals on Earth: insects. Here, we review the role of NHCs in advancing our understanding of the ecological and evolutionary responses of insects to recent global changes. Insect NHCs have helped document changes in insects' geographical distributions, phenology, phenotypic and genotypic traits over time periods up to a century. Recent work demonstrates the enormous potential of NHCs data for examining insect responses at multiple temporal, spatial and phylogenetic scales. Moving forward, insect NHCs offer unique opportunities to examine the morphological, chemical and genomic information in each specimen, thus advancing our understanding of the processes underlying species' ecological and evolutionary responses to rapid, widespread global changes.This article is part of the theme issue 'Biological collections for understanding biodiversity in the anthropocene'. PMID- 30455221 TI - Characterising patient complaints in out-of-hours general practice: a retrospective cohort study in Ireland. AB - BACKGROUND: Patient complaints can provide valuable insights into the quality and safety of clinical care. Studies examining the epidemiology of complaints in out of-hours general practice internationally are limited. AIM: To characterise patient complaints in an out-of-hours general practice setting. DESIGN AND SETTING: Retrospective cohort study of patient complaints to an out-of-hours service provider in Dublin, Ireland, over a 5-year period (2011-2016). This comprises nurse-led telephone triage and GP consultations for patients with urgent problems. METHOD: A modified version of the UK Healthcare Complaints Analysis Tool (HCAT) was utilised to code complaints, which were reviewed independently in duplicate by two academic GPs. RESULTS: Of 445 598 telephone contacts, 303 085 resulted in face-to-face GP consultations. Of 234 patients who made 298 complaints, 185 (79%) related to GP care. The remainder related to nurse triage, other staff, and management issues. A total of 109 (46%) related to children aged <=18 years, and 134 (58%) of complainants were female. There were 0.61 complaints per 1000 GP consultations. Most complaints (n = 126, 42%) were in relation to clinical care problems, largely diagnosis and prescribing. Common themes included unmet management expectations and clinical examination dissatisfaction. Inter-rater reliability was 90% (kappa statistic 0.84, 95% confidence interval = 0.80 to 0.88). Following internal investigation, 158 (85%) of GP-related complaints were managed effectively by the out-of-hours service. CONCLUSION: The majority of complaints related to clinical care problems and were successfully managed locally. Expectation management may be an important way to mitigate the risk of complaints. PMID- 30455222 TI - Effectiveness of an intervention to optimise the use of mirabegron for overactive bladder: a quasi-experimental study in primary care. AB - BACKGROUND: Overactive bladder is a composite of lower urinary tract storage symptoms. Pharmacological treatment is widely employed despite markedly modest efficacy data, adverse effects, and costs for the health system. AIM: To determine the 12-month efficacy of an intervention delivered by GPs on mirabegron revision and, if appropriate, discontinuation of treatment. DESIGN AND SETTING: Multicentre, quasi-experimental study in Barcelona (Catalonia), Spain. METHOD: Two groups composed of 17 intervention and 34 control practices were formed. The follow-up period was 12 months, from 1 January to 31 December 2017. A structured intervention was designed consisting of initiatives with GPs and urology/gynaecology specialists. The primary outcome was mirabegron use at 12 months. RESULTS: Of the 1932 patients, a significant discontinuation in treatment was observed at 12 months' follow-up in the intervention group (IG) (n = 433 out of 762, 56.8%), in contrast with the control one (CG) (n = 484 out of 1170, 41.4%) (P<0.001). There was also a reduced incorporation of new treatments in the IG (n = 214 out of 762, 28.1%) compared with the CG (n = 595 out of 1170, 50.9%) (P<0.001). In relation to patients with treatment at the beginning and end of the period, there was a decrease of 219 (28.7%) patients in the IG and an increase of 111 (9.5%) in the CG (P<0.001). CONCLUSION: The structured intervention showed optimisation in the use of mirabegron. When considering discontinuation it is necessary to provide clear data on the benefits and/or risks for patients and their caregivers, as such information is a precondition for shared decision making. PMID- 30455223 TI - Update on the biology and management of renal cell carcinoma. AB - Renal cell cancer (RCC) (epithelial carcinoma of the kidney) represents 2%-4% of newly diagnosed adult tumors. Over the past 2 decades, RCC has been better characterized clinically and molecularly. It is a heterogeneous disease, with multiple subtypes, each with characteristic histology, genetics, molecular profiles, and biologic behavior. Tremendous heterogeneity has been identified with many distinct subtypes characterized. There are clinical questions to be addressed at every stage of this disease, and new targets being identified for therapeutic development. The unique characteristics of the clinical presentations of RCC have led to both questions and opportunities for improvement in management. Advances in targeted drug development and understanding of immunologic control of RCC are leading to a number of new clinical trials and regimens for advanced disease, with the goal of achieving long-term disease-free survival, as has been achieved in a proportion of such patients historically. RCC management is a promising area of ongoing clinical investigation. PMID- 30455224 TI - Continuous low-dose everolimus shrinkage tuberous sclerosis complex-associated renal angiomyolipoma: a 48-month follow-up study. AB - Tuberous sclerosis complex (TSC) is a rare disease that causes multisystem benign neoplasm, induced by dysregulation of the mammalian target of the rapamycin pathway (mTOR). This study aimed to examine the effects of continuous low-dose everolimus, a potent and selective inhibitor of mTOR, on the treatment of TSC associated renal angiomyolipoma (AML). Between July 2013 and August 2017, 11 patients with TSC-AML were enrolled for an everolimus therapy protocol. An oral everolimus dose starting at 2.5 mg daily was gradually increased to 5.0 mg daily. All patients were evaluated using MRI or CT scanning at baseline, 12, 24, 36 and 48 months after the start of treatment for measuring changes of renal AML mass volume. Everolimus therapy resulted in significant shrinkage of TSC-AML volume after 48 months follow-up. Serum levels of everolimus were subdivided into group I (<8 ng/mL, n=6) and group II (>8 ng/mL, n=5). The volume reduction rates were 10.6%-65.2% in group I and 42.5%-70.6% in group II. To evaluate the response to treatment, three of six (50%) were responders in group I, and all the patients in group II (5/5, 100%) were responders. The differences in AML volume reduction between the groups were statistically significant at 12 months (p=0.011), 24 months (p=0006), 36 months (p=0.014) and 48 months (p=0.05). These results suggest that continuous low-dose everolimus therapy (2.5-5 mg daily) might be effective in shrinking TSC-AML volume and minimizes adverse effects and subsequent reducing medical costs. PMID- 30455225 TI - A case of KMT2A-SEPT9 fusion associated acute megakaryoblastic leukemia. AB - Acute Megakaryoblastic leukemia (AMKL) constitutes ~5-15% of cases of non-Down syndrome AML in children, and in the majority of cases, chimeric oncogenes resulting from recurrent gene rearrangements are identified. Based upon these rearrangements several molecular subsets have been characterized providing important prognostic information. One such subset includes a group of patients with translocations involving the KMT2A gene, which has been associated with various fusion partners in patients with AMKL. Here we report the molecular findings of a 2 year old girl with AMKL and t(11;17)(q23;25) found to have a KMT2A-SEPT9 fusion identified through targeted RNA sequencing. A KMT2A-SEPT9 fusion in this subset of patients has not previously been reported. PMID- 30455226 TI - Early-onset infant epileptic encephalopathy associated with a de novo PPP3CA gene mutation. AB - Epileptic encephalopathies are severe seizure disorders accompanied by intellectual disability. Whole-exome sequencing technology has enabled the discovery of genetic mutations responsible for a wide range of diseases, and severe epilepsy and neurodevelopmental diseases are often associated with rare de novo mutations. We identified a novel de novo frameshift mutation in the PPP3CA gene encoding calcium-dependent protein phosphatase (calcineurin) catalytic subunit A (c.1255_1256del, p.Ser419Cysfs*31) in an 11.5-month-old female with early-onset refractory epilepsy and developmental delay. This finding expands the list of PPP3CA mutations associated with early-onset severe neurodevelopmental disease with seizures, and provides further details on clinical features. PMID- 30455227 TI - A diagnostic algorithm to investigate pyrazinamide and ethambutol resistance in rifampicin resistant Mycobacterium tuberculosis isolates in a low incidence setting. AB - Phenotypic drug susceptibility testing (DST) for the two first-line tuberculosis drugs ethambutol and pyrazinamide is known to yield unreliable and inaccurate results. In this prospective study, we propose a diagnostic algorithm combining phenotypic DST with Sanger sequencing to inform clinical decision-making for drug resistant Mycobacterium tuberculosis complex isolates. Sequencing results were validated using whole genome sequences (WGS) of the isolates. Resistance conferring mutations obtained by pncA sequencing correlated well with phenotypic DST results for pyrazinamide. Phenotypic resistance to ethambutol was only partly explained by mutations in the embB 306 codon. Additional resistance conferring mutations were found in the embB gene at codons 354, 406 and 497. In several isolates that tested ethambutol susceptible by phenotypic DTS, well-known resistance conferring embB mutations were determined. Thus, targeted Sanger sequencing beyond embB 306 codon or WGS together with phenotypic DST should be employed to ensure reliable ethambutol drug susceptibility as basis for rational design of MDR-TB regimens with or without ethambutol. PMID- 30455228 TI - In-vivo gentamicin susceptibility test for prevention of bacterial biofilms in bone tissue and on implants. AB - OBJECTIVES: To set up an in-vivo gentamicin susceptibility test for biofilm prevention in bone tissue and on implants. METHODS: Twenty-five pigs were allocated to six groups. Group A (n=6) was inoculated with saline. Groups B (n=6), C (n=3), D (n=3), E (n=3) and F (n=4) were inoculated with 10 MUL saline containing 104 CFU of Staphylococcus aureus Different concentrations based on the minimal inhibitory concentrations (MIC) of gentamicin to the specific strain were added to the 10 MUL inoculum of Groups C (160xMIC), D (1,600xMIC), E (16,000xMIC) and F (160,000xMIC). The inoculums were injected into a pre-drilled tibial implant cavity followed by insertion of a steel implant (2 * 15 mm). The pigs were euthanized after five days. In-vitro, all the used doses were found bacteriostatic after up to 6 hours. RESULTS: All implant cavities of pigs inoculated with bacteria and bacteria + 160xMIC or 1,600xMIC were positive for S. aureus In each of the Groups E (16,000xMIC) and F (160,000xMIC) 2/3 and 1/4 of the implant cavities were S. aureus positive, respectively. By grouping Groups C + D (<10,000xMIC) and Groups E + F (>10,000xMIC) a significant decrease of implant attached bacteria was only seen between the high MIC value group and Group B. Histologically, it was demonstrated that 1,600, 16,000 and 160,000 x MIC resulted in a peri-implant tissue reaction comparable to saline inoculated animals. CONCLUSION: In-vivo, the antimicrobial tolerance of the inoculated planktonic bacteria was increased by in-vivo specific factors of acute inflammation. This resulted in bacterial aggregation and biofilm formation which further increased the gentamicin tolerance. Thus, susceptibility patterns in vitro might not reflect the actual in-vivo susceptibility locally within a developing infectious area. PMID- 30455229 TI - The Role of Rifampin against Staphylococcal Biofilm Infections in Vitro, in Animal Models, and in Orthopedic Device-Related Infections. AB - Rifampin has been used as an agent in combination therapy in orthopedic device related infections (ODRI) for almost three decades. The aim of this review is to provide data regarding the role of rifampin against biofilm infection in vitro, in animal models, and in clinical ODRI. Available data are gathered in order to present the rational use of rifampin combinations in patients with periprosthetic joint infection (PJI). In-vitro data, animal data and available clinical data in the field of staphylococcal PJI will be reviewed. The role of rifampin is well defined in patients with PJI and is indicated in those who fulfill the Infectious Diseases Society of America criteria for debridement and implant retention or one stage exchange. It should be used with care because of the danger of rapid emergence of resistance. Potential drug interactions should be considered. PMID- 30455230 TI - Identification of a novel gene associated with high-level beta-lactam resistance in heterogeneous vancomycin-intermediate Staphylococcus aureus strain Mu3 and methicillin-resistant S. aureus strain N315. AB - beta-lactam resistance levels vary among methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, mediated by chromosomal mutations and exogenous resistance gene mecA. However, MRSA resistance mechanisms are incompletely understood. A P440L mutation in the RNA polymerase beta' subunit (RpoC) in slow vancomyicn-intermediate S. aureus (sVISA) strain V6-5 is associated with conversion of heterogeneous VISA (hVISA) to sVISA. Herein, we found a V6-5 derivative strain (L4) with significantly decreased MICs to oxacillin (OX) and vancomycin. Whole-genome sequencing revealed that L4 has nonsense mutations in two genes, relQ encoding (p)ppGpp synthetase, an alarmone of the stringent response, and a gene of unknown function. relQ deletion in the hVISA strain Mu3 did not affect OX MIC. However, introducing nonsense mutation of the unknown gene into Mu3 decreased OX MIC, whereas wild-type gene recovered high-level resistance. Thus, mutation of this unknown gene (ehoM) decreased beta-lactam resistance in Mu3 and L4. Presence of relQ in a multi-copy plasmid restored high level resistance in strain L4 but not in the ehoM mutant Mu3 strain, indicating a genetic interaction between ehoM and relQ depending on the L4 genetic background. While mupirocin (stringent response inducer) can increase the beta-lactam resistance of MRSA, mupirocin supplementation in an ehoM deletion mutant of N315 did not elevate resistance. ehoM expression in N315 was induced by mupirocin, and the relative amount of ehoM transcript in Mu3 was higher than in N315 induced by the stringent response. Our findings indicate that ehoM plays an essential role in high-level beta-lactam resistance in MRSA via the stringent response. PMID- 30455231 TI - Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency. AB - Signaling pathways play a key role in HIV-1 latency. In this study, we used the 24ST1NLESG cell line of HIV-1 latency to screen a library of structurally diverse, medicinally active, cell permeable kinase inhibitors, which target a wide range of signaling pathways, to identify inhibitors of HIV-1 latency reversal. The screen was carried-out in the absence or presence of three mechanistically distinct latency reversing agents (LRAs), namely prostratin, panobinostat and JQ-1. We identified inhibitors that only blocked the activity of a specific LRA, as well as inhibitors that blocked the activity of all LRAs. For example, we identified 12 inhibitors targeted toward protein kinase C or downstream kinases that blocked the activity of prostratin. We also identified 12 kinase inhibitors that blocked reversal of HIV-1 latency irrespective of the LRA used in the screen. Of these danusertib, an Aurora kinase inhibitor, and PF 3758309, a PAK4 inhibitor, were the most potent. The 50% inhibitory concentrations in the 24ST1NLESG cells ranged from 40-147 nM for danusertib (selectivity indices >150) and from 0.1-1nM for PF-3758309 (selectivity indices >3,300). Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia. PMID- 30455232 TI - Evaluation of carbapenems for multi/extensive-drug resistant Mycobacterium tuberculosis treatment. AB - M/XDR-TB has become an increasing threat in high burden countries but also in affluent regions due to increased international travel and globalization. Carbapenems are earmarked as potentially active drugs for the treatment of M. tuberculosis To better understand the potential of carbapenems for the treatment of M/XDR-TB, the aim of this review was to evaluate the literature on currently available in vitro, in vivo and clinical data on carbapenems in the treatment of M. tuberculosis and detection of knowledge gaps, in order to target future research.In February 2018, a systematic literature search of PubMed and Web of Science was performed. Overall the results of the studies identified in this review, which used a variety of carbapenem susceptibility tests on clinical and lab strains of M. tuberculosis, are consistent. In vitro the activity of carbapenems against M. tuberculosis is increased when used in combination with clavulanate, a BLaC inhibitor. However, clavulanate is not commercially available alone, and therefore is it practically impossible to prescribe carbapenems in combination with clavulanate at this time. Few in vivo studies have been performed, one prospective, two observational and seven retrospective clinical studies to assess effectiveness, safety and tolerability of three different carbapenems (imipenem, meropenem and ertapenem). Presently we found no clear evidence to select one particular carbapenem among the different candidate compounds, to design an effective M/XDR-TB regimen. Therefore more clinical evidence and dose optimization substantiated by hollow fiber infection studies are needed to support repurposing carbapenems for the treatment of M/XDR-TB. PMID- 30455233 TI - Population Pharmacokinetics of Mefloquine Intermittent Preventive Treatment for Malaria in Pregnancy in Gabon. AB - Introduction Mefloquine is evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and its metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated and potential covariates influencing the pharmacokinetic properties were assessed. Materials and Methods A population pharmacokinetic analysis was performed with 264 pregnant women of a randomized controlled trial evaluating a single and split-dose regimen of two 15 mg/kg mefloquine dosings at least one month separated versus SP-IPTp. Both mefloquine enantiomers and its carboxy-metabolite (CMQ), measured in plasma and cord, were applied for pharmacokinetic modelling using NONMEM 7.3. Results Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group the mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated (r2=0.84) at delivery. With the investigated dosing regimens prophylactic levels are not constantly achieved. A modelling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. Discussion This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens, however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as valuable tool for researchers and clinicians to develop and optimise alternative dosing regimens for IPTp in pregnant women. PMID- 30455234 TI - The role of therapeutic drug monitoring in treatment optimization in tuberculosis and diabetes mellitus co-morbidity. AB - With great interest we read the paper by Alfarisi et al reporting the effects of diabetes mellitus (DM) on the pharmacokinetics and pharmacodynamics of tuberculosis treatment (1)..... PMID- 30455235 TI - Fluconazole-Induced Alopecia: Examination in an animal model and human cohort. AB - Fluconazole-induced alopecia is a significant problem for patients receiving long term therapy. We evaluated the hair-cycle changes of fluconazole in a rat model and investigated potential molecular mechanisms. Plasma and tissue levels of retinoic acid were not found causal. Human patients with alopecia attributed to fluconazole also underwent detailed assessment and in both our murine model and human cohort fluconazole induced telogen effluvium. Future work further examining the mechanism of fluconazole-induced alopecia should be undertaken. PMID- 30455236 TI - APX001 is Effective in the Treatment of Murine Invasive Pulmonary Aspergillosis. AB - Invasive pulmonary aspergillosis (IPA) due to Aspergillus fumigatus is a serious fungal infection in the immunosuppressed patient population. Despite the introduction of new antifungal agents, mortality rates remain high and new treatments are needed. The novel antifungal APX001A targets the conserved Gwt1 enzyme required for the localization of glycosylphosphatidyl inositol (GPI) anchored mannoproteins in fungi. We evaluated the in vitro activity of APX001A against A. fumigatus and the in vivo activity of its prodrug APX001 in an immunosuppressed mouse model of IPA. APX001A inhibited the growth of A. fumigatus with a minimum effective concentration (MEC) of 0.03 MUg/ml. The use of 50 mg/kg 1-aminobenzotriazole (ABT), a suicide inhibitor of cytochrome P450 (CYP) enzymes, enhanced APX001A exposures (AUC) 16- to 18-fold and enhanced serum half-life from ~1 to 9 h, more closely mimicking human pharmacokinetics. We evaluated the efficacy of APX001 (with ABT) in treating murine IPA as compared to posaconazole treatment. Treatment of mice with 78 mg/kg QD, 78 mg/kg BID, or 104 mg/kg QD APX001 significantly enhanced median survival time and prolonged Day 21 post infection overall survival when compared to placebo. Furthermore, administration of APX001 resulted in a significant reduction in lung fungal burden (4.2 to 7.6 log10 conidial equivalents/gram tissue) vs the untreated control and resolved the infection as judged by histopathological examination. The observed survival and tissue clearance were comparable to a clinically relevant posaconazole dose. These results warrant the continued development of APX001 as a broad spectrum, first in class treatment for invasive fungal infections. PMID- 30455238 TI - APX001 and Other Gwt1 inhibitor Prodrugs are Effective in Experimental Coccidioides immitis Pneumonia. AB - Coccidioidomycosis is a systemic fungal infection caused by the inhalation of the arthroconidia of either of two closely related dimorphic fungi, Coccidioides immitis, and C. posadasii that are endemic in the southwestern US and other areas in the Western Hemisphere. Chronic cavitary pulmonary infections and extra pulmonary sites of infection are very difficult to treat and often require life long azole therapy. APX001A is the first in a new class of broad spectrum antifungal agents which inhibit Gwt1, an enzyme which is required for localization of glycosylphosphatidyl inositol (GPI)-anchored mannoproteins in fungi. APX001A and several analogs were highly active against clinical isolates of Coccidioides, inhibiting hyphal growth at low nanogram/ml concentrations. APX001 is the N-phosphonooxymethyl prodrug of APX001A, currently in clinical trials for the treatment of invasive fungal infections. Mice were treated orally once-daily with 26 mg/kg/day of APX001 and the prodrug analog APX2097, two hours after administration of the pan-cytochrome P450 inhibitor 1-aminobenzotriazole, which was used to enhance drug half-life and exposures to more closely mimic human pharmacokinetics of APX001A. Five days of treatment reduced lung colony counts by nearly 3 logs and prevented dissemination, similar to the efficacy of fluconazole dosed orally at 25 mg/kg twice daily. In a survival experiment, both APX001 and APX2097-treated mice survived significantly longer than control and fluconazole treated mice. APX001 and other members of this new class of antifungal agents may offer great promise as effective therapies for coccidioidomycosis. PMID- 30455237 TI - Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication. AB - Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF. PMID- 30455239 TI - High-dose rifamycins enable shorter oral treatment in a murine model of Mycobacterium ulcerans disease. AB - Buruli ulcer (BU), caused by Mycobacterium ulcerans, is a neglected tropical skin and soft tissue infection that is associated with disability and social stigma. The mainstay of BU treatment is an eight-week course of 10 mg/kg rifampin (RIF) and 150 mg/kg streptomycin (STR). Recently, the injectable STR has been shown to be replaceable with oral clarithromycin (CLR) for smaller lesions for the last four weeks of treatment. A shorter, all-oral, highly efficient regimen for BU is needed, as the long treatment duration and indirect costs currently burden patients and health systems. Increasing the dose of RIF or replacing it with the more potent rifamycin drug rifapentine (RPT) could provide such a regimen. Here, we performed a dose-ranging experiment of RIF and RPT in combination with CLR over four weeks of treatment in a mouse model of M. ulcerans disease. A clear dose-dependent effect of RIF on both clinical and microbiological outcomes was found, with no ceiling effect observed with tested doses up to 40 mg/kg. RPT containing regimens were more effective on M. ulcerans All RPT-containing regimens achieved culture negativity after only four weeks while only the regimen with the highest RIF dose (40 mg/kg) did so. We conclude that there is dose dependent efficacy of both RIF and RPT and that a ceiling effect is not reached with the current standard regimen used in the clinic. A regimen based on higher rifamycin doses that are currently being evaluated against tuberculosis in clinical trials could shorten and improve therapy of Buruli ulcer. PMID- 30455240 TI - Impact of Antifungal Compounds on Viability and Anti-Aspergillus Activity of Human Natural Killer Cells. AB - Despite the availability of new antifungal compounds, invasive aspergillosis carries high morbidity and mortality in hematopoietic stem cell transplant recipients. In vitro studies and animal models suggest that the adoptive transfer of Natural Killer (NK) cells could be a promising immunotherapeutic option in this setting. As it is unclear whether viability and function of human NK cells are affected by common antifungal agents, we analyzed the interaction of various concentrations of amphotericin B-deoxycholate (AmB-D), liposomal amphotericin B, caspofungin, fluconazole, voriconazole, and posaconazole with human NK cells. When adding NK cells to therapeutic concentrations of antifungal agents, a significant increase of the antifungal effect was seen for caspofungin and voriconazole, whereas NK cells significantly decreased the hyphal damage of escalated doses of AmB-D. In contrast, therapeutic concentrations of all antifungal compounds tested did not have a negative effect on proliferation, viability, and the release of soluble immunomodulatory molecules of NK cells. These data indicate that therapeutic concentrations of the antifungal agents tested do not negatively affect the functional properties of human NK cells, which is a prerequisite for further studies evaluating NK cells as antifungal immunotherapy in immunocompromised patients suffering from invasive aspergillosis. PMID- 30455241 TI - Genome location dictates the transcriptional response to PolC-inhibition in Clostridium difficile. AB - Clostridium difficile is a potentially lethal gut pathogen that causes nosocomial and community acquired infections. Limited treatment options and reports of reduced susceptibility to current treatment emphasize the necessity for novel antimicrobials. The DNA-polymerase of gram-positive organisms is an attractive target for the development of antimicrobials. ACX-362E (N2-(3,4-Dichlorobenzyl)-7 (2-[1-morpholinyl]ethyl)guanine; MorE-DCBG) is a DNA polymerase inhibitor in pre clinical development as a novel therapeutic against C. difficile infection. This synthetic purine shows preferential activity against C. difficile PolC over those of other organisms in vitro and is effective in an animal model of C. difficile infection. In this study we have determined its efficacy against a large collection of clinical isolates. At concentrations below the minimal inhibitory concentration, the presumed slowing (or stalling) of replication forks due to ACX 362E leads to a growth defect. We have determined the transcriptional response of C. difficile to replication inhibition and observed an overrepresentation of up regulated genes near the origin of replication in the presence of PolC inhibitors, but not when cells were subjected to sub-inhibitory concentrations of other antibiotics. This phenomenon can be explained by a gene dosage shift, as we observed a concomitant increase in the ratio between origin-proximal versus terminus-proximal gene copy number upon exposure to PolC-inhibitors. Moreover, we show that certain genes differentially regulated under PolC-inhibition are controlled by the origin-proximal general stress response regulator sigma factor B. Together, these data suggest that genome location both directly and indirectly determines the transcriptional response to replication inhibition in C. difficile. PMID- 30455242 TI - Omadacycline gut microbiome exposure does not induce Clostridium difficile proliferation or toxin production in a model that simulates the proximal, medial and distal human colon. AB - A clinically reflective model of the human colon was used to investigate the effects of the broad-spectrum antibiotic omadacycline on the gut microbiome, and subsequent potential to induce simulated Clostridium difficile infection (CDI). Triple stage chemostat gut models were inoculated with pooled human faecal slurry from healthy volunteers (age >=60 years). Models were challenged twice with 107 cfu C. difficile spores (PCR ribotype 027). Omadacycline effects were assessed in a single gut model. Observations were confirmed in a parallel study with omadacycline and moxifloxacin. Antibiotic instillation was performed once daily for 7 days. The models were observed for 3 weeks post-antibiotic challenge. Gut microbiota populations and C. difficile total viable and spore counts were enumerated daily by culture. Cytotoxin titres and antibiotic concentrations were also measured. Gut microbiota populations were stable before antibiotic challenge. Moxifloxacin instillation caused a ~4 log10 cfu/mL decline in enterococci and Bacteroides fragilis group populations, and a ~3 log10 cfu/mL decline in bifidobacteria and lactobacilli, followed by simulated CDI (vegetative cell proliferation and detectable toxin). In both models, omadacycline instillation decreased populations of bifidobacteria (~8 log10 cfu/mL), B. fragilis group populations (7-8 log10 cfu/mL), lactobacilli (2-6 log10 cfu/mL), and enterococci (4-6 log10 cfu/mL). Despite these microbial shifts, there was no evidence of C. difficile germination or toxin production. In contrast to moxifloxacin, omadacycline exposure did not facilitate simulated CDI, suggesting this antibiotic may have a low propensity to induce CDI in the clinical setting. PMID- 30455243 TI - Host cell metabolism contributes to delayed-death kinetics of apicoplast inhibitors in Toxoplasma gondii. AB - Toxoplasma gondii and related human parasites contain an essential plastid organelle called the apicoplast. Clinically-used antibiotics and other inhibitors that disrupt apicoplast biogenesis cause a mysterious "delayed-death" phenotype in which parasite growth is unaffected during the first lytic cycle of inhibitor treatment but is severely inhibited in the second lytic cycle even after drug removal. Critical to understanding the complex downstream cellular effects of these drug classes is the timing of apicoplast loss during inhibitor treatment and how it relates to this peculiar growth phenotype. Here we show that, upon treatment with diverse classes of apicoplast inhibitors, newly-replicated T. gondii parasites in the first lytic cycle initially form apicoplasts with defects in protein import or genome replication and eventually fail to inherit the apicoplast altogether. Despite the accumulation of parasites with defective or missing apicoplasts, growth is unaffected during the first lytic cycle, as previously observed. Strikingly, concomitant inhibition of host cell isoprenoid biosynthesis results in growth inhibition in the first lytic cycle and unmasks the apicoplast defects. These results suggest that defects in and even complete loss of the apicoplast in T. gondii are partially rescued by scavenging of host cell metabolites leading to death that is delayed. Our findings uncover host cell interactions that can alleviate apicoplast inhibition and highlight key differences in "delayed-death" inhibitors between T. gondii and Plasmodium falciparum. PMID- 30455244 TI - The Role of TEM-1 beta-lactamase in the Predominance of Ampicillin-Sulbactam Nonsusceptible Escherichia coli in Japan. AB - We investigated the epidemiology and resistance mechanisms of ampicillin sulbactam-nonsusceptible Escherichia coli, focusing on the role of TEM-1 beta lactamase. We collected all non-duplicate E. coli clinical isolates at 10 Japanese hospitals during December 2014 and examined their antimicrobial susceptibility, beta-lactamases, TEM-1 transferability, TEM-1 beta-lactamase activity, outer membrane protein profile, membrane permeability, and clonal genotypes. Among the 329 isolates, 95 were ampicillin-sulbactam nonsusceptible. Of these ampicillin-sulbactam-nonsusceptible isolates, beta-lactamases conferring resistance to sulbactam such as AmpC were present in 33%. Hyperproduction of sulbactam-susceptible beta-lactamases, TEMs with a strong promoter, were rare (5%). The remaining 59 isolates (62%) had only sulbactam-susceptible beta lactamases, including TEM-1 with a wild-type promoter (n = 28), CTX-Ms (n = 13), or both (n = 17). All 45 transconjugants from 96 donors with TEM-1 had higher ampicillin-sulbactam MICs (4-96 mg/l) than the recipient (2 mg/L). In donors with only TEM-1, TEM-1 activity correlated with the 50% inhibitory concentration of sulbactam and ampicillin-sulbactam MICs. The decreased membrane permeability of sulbactam was associated with an increased ampicillin-sulbactam MIC. The reduced permeability was partly attributable to deficient outer membrane proteins, which were observed in 57% of the ampicillin-sulbactam-nonsusceptible isolates with only TEM-1 and a wild-type promoter. Sequence type 131 was the most common clonal type (52%). TEM-1 with a wild-type promoter primarily contribute to ampicillin sulbactam nonsusceptibility in E. coli with partial support of other mechanisms such as the reduced permeability. Conjugative TEM-1 and clonal spread of ST131 may contribute to the prevalence of Japanese ampicillin-sulbactam-nonsusceptible isolates. PMID- 30455245 TI - Pre-Exposure to Isavuconazole Increases the Virulence of Mucorales but not Aspergillus fumigatus in a Drosophila melanogaster Infection Model. AB - Breakthrough mucormycosis in patients receiving isavuconazole prophylaxis or therapy has been reported. We compared the impact of isavuconazole and voriconazole exposure on the virulence of clinical isolates of Aspergillus fumigatus and different Mucorales species in a Drosophila melanogaster infection model. In contrast to A. fumigatus, a hyper-virulent phenotype was found in all tested Mucorales upon pre-exposure to either voriconazole or isavuconazole. These findings may contribute to the explanation of breakthrough mucormycosis in isavuconazole-treated patients. PMID- 30455246 TI - Population pharmacokinetics and pharmacodynamics of bezlotoxumab in adults with primary and recurrent Clostridium difficile infection. AB - The fully human monoclonal antibody bezlotoxumab is indicated for preventing recurrence of Clostridioides (formerly Clostridium) difficile infection (CDI) in adults receiving antibacterial treatment for CDI and at high risk for CDI recurrence. The efficacy and safety of 10 mg/kg bezlotoxumab was demonstrated in two Phase 3 trials: MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Here, a population pharmacokinetic (popPK) analysis is reported using data from MODIFY I and II (n=1515), and from three Phase 1 trials (n=72) to characterize bezlotoxumab PK in Phase 3 clinical trial participants and in healthy subjects. A stepwise covariate search was conducted to identify factors influencing PK. Post hoc estimated bezlotoxumab exposures from the popPK model were used to conduct an exposure-response analysis for CDI recurrence.Bezlotoxumab PK was described by a two-compartment model with linear elimination and allometric scaling for clearance and volume of distribution by body weight. Although the final popPK model included gender, ethnicity (Japanese descent), race (black vs non-black), and albumin level as significant covariates, the impact of these factors was not clinically meaningful based on the totality of PK and clinical experience.Exposure-response analysis of CDI recurrence demonstrated a similar low rate of CDI recurrence over the entire range of exposures achieved in the Phase 3 trials, indicating that exposures were on the maximal response plateau of the exposure-response curve. Overall, the analyses confirmed the appropriateness of the 10 mg/kg dose across the Phase 3 population with no dose adjustments necessary over a broad demographic background. PMID- 30455247 TI - ERG6 and ERG2 are major targets conferring reduced susceptibility to amphotericin B in clinical Candida glabrata isolates in Kuwait. AB - Candida glabrata is intrinsically less susceptible to azoles and resistance to echinocandins and reduced susceptibility to amphotericin B has also been detected. Molecular mechanisms of reduced susceptibility (RS) to amphotericin B (AMB) were investigated in C. glabrata strains in Kuwait by sequence analyses of genes involved in ergosterol biosynthesis. A total of 1646 C. glabrata isolates were tested by Etest and results for 12 selected isolates were confirmed by reference broth microdilution. PCR-sequencing of three (ERG2, ERG6 and ERG11) genes was performed for all RS-AMB and 5 selected wild-type C. glabrata isolates by using gene-specific primers. Total cell sterol content was analyzed by gas chromatography-mass spectrometry. Phylogenetic relationship among the isolates was investigated by multilocus sequence typing. Wild-type isolates contained only synonymous mutations in ERG2, ERG6 or ERG11 and total sterol content was similar to reference strains. A nonsynonymous (AGA48AAA, R48K) ERG6 mutation was found in both RS-AMB and wild-type isolates. Four RS-AMB isolates contained novel nonsense mutations at Trp286/Tyr192/Leu341 and 2 isolates contained nonsynonymous (V126F or C198F) mutation in ERG6 and their sterol content were consistent with ERG6 deficiency. Two other RS-AMB isolates contained a novel nonsynonymous (G119S or G122S) ERG2 mutation and their sterol content were consistent with ERG2 deficiency. Of 8 RS-AMB isolates, 1 fluconazole-resistant isolate also contained nonsynonymous Y141H+L381M mutations while 7 isolates contained only synonymous mutations in ERG11 All isolates with ERG6/ERG2/ERG11 mutations were genotypically distinct strains. Our data show that ERG6 and ERG2 are major targets conferring RS-AMB in clinical C. glabrata isolates. PMID- 30455248 TI - Genetic mechanisms behind the spread of reduced susceptibility to azithromycin in Shigella isolated from men who have sex with men, in Quebec, Canada. AB - We analysed 254 Shigella spp., isolates collected in Quebec, Canada, during 2013 2014. Overall, 23.6% of isolates showed reduced susceptibility to azithromycin (RSA) encoded by mphA (11.6%), ermB (1.7%) or by both genes (86.7%). Shigella strains with RSA were mostly isolated from men who have sex with men (68.8% or higher) from the Montreal region. Complete sequence analysis of six selected plasmids from Shigella sonnei and different serotypes of Shigella flexneri emphasized the role of IS26 in RSA dissemination. PMID- 30455249 TI - The Phosphorylated Estrogen Receptor Cistrome Identifies a Subset of Active Enhancers Enriched for Direct ER-DNA Binding and the Transcription Factor GRHL2. AB - Post-translational modifications are key regulators of protein function, providing cues that can alter protein interactions and cellular location. Phosphorylation of the estrogen receptor (ER) at serine 118 (pS118-ER) occurs in response to multiple stimuli and is involved in modulating ER-dependent gene transcription. While the cistrome of ER is well established, surprisingly little is understood about how phosphorylation impacts ER-DNA binding activity. To define the pS118-ER cistrome, ChIP-seq was performed on pS118-ER and ER in MCF-7 cells treated with estrogen. pS118-ER occupied a subset of ER binding sites which were associated with the active enhancer mark, acetylated H3K27. Unlike ER, pS118 ER sites were enriched in GRHL2 DNA binding motifs, and estrogen treatment increased GRHL2 recruitment to sites occupied by pS118-ER. Additionally, pS118-ER occupancy sites showed greater enrichment of full length estrogen response elements relative to ER sites. In an in vitro DNA binding array of genomic binding sites, pS118-ER was more commonly associated with direct DNA binding events compared to indirect binding events. These results indicate that phosphorylation of ER at serine 118 promotes direct DNA binding at active enhancers and is a distinguishing mark for associated transcription factor complexes on chromatin. PMID- 30455250 TI - A novel regulatory axis, CHD1L-miR-486 -MMP2, controls spermatogonial stem cell properties. AB - Spermatogonial stem cells (SSCs) are unipotent germ cells and at the foundation of spermatogenesis and male fertility. However, the underlying molecular mechanisms governing SSC stemness and growth properties remain elusive. We have recently identified chromodomain helicase/ATPase DNA binding protein 1-like (Chd1l) as a novel regulator for SSC survival and self-renewal, but how such functions are controlled by Chd1l remains to be resolved. Here, we applied high throughput small RNA sequencing to uncover the microRNA (miR) expression profiles controlled by Chd1l, and showed that the expression of 124 miR transcripts were differentially regulated by Chd1l in SSCs. KEGG pathway analysis show that the differentially expressed miRs upon Chd1l repression are significantly enriched in the pathways associated with stem cell pluripotency and proliferation. As a proof of concept, we demonstrate that one of the most up-regulated miRs, miR-486, controls SSC stemness gene expression and growth properties. Matrix metalloproteinase 2 (MMP2) has been identified as a novel miR-486 target gene in the context of SSC stemness gene regulation and growth properties. Data from the co-transfection experiments showed that Chd1l, miR-486 and MMP2 work in concert in regulating SSC stemness gene expression and growth properties. Finally, our data also revealed that MMP2 regulates SSC stemness gene expression and growth properties through activating beta-catenin signaling by cleaving N-cadherin and increasing beta-catenin nuclear translocation. Our data demonstrates that Chd1l miR-486-MMP2 is a novel regulatory axis governing SSC stemness gene expression and growth properties, offering a novel therapeutic opportunity for treating male infertility. PMID- 30455251 TI - Mutant p53 sequestration of MDM2 acidic domain inhibits E3 ligase activity. AB - Missense p53 mutants often accumulate in tumors and drive progression through gain-of-function. MDM2 efficiently degrades wild type p53, but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 auto-ubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity compared to wild type p53. Mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53, and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular auto-activation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells. PMID- 30455252 TI - What's happening in Neurology (r) Genetics. PMID- 30455253 TI - Surviving cerebral malaria. PMID- 30455254 TI - Emerging Subspecialties in Neurology: Sports neurology training and certification: An overview in 2018. AB - Sports neurology is a relatively new specialty in neurology. Interested trainees may find it difficult to learn about issues in sports neurology both in medical school and residency. This review highlights what the current state is in medical school and residency training and how an interested trainee or neurologist could pursue a career in this area. PMID- 30455255 TI - Editors' note: The state of clinical research in neurology. PMID- 30455256 TI - Reader response: The state of clinical research in neurology. PMID- 30455257 TI - Author response: The state of clinical research in neurology. PMID- 30455258 TI - Editors' note: Progressive neurodegeneration following spinal cord injury: Implications for clinical trials. PMID- 30455259 TI - Reader response: Progressive neurodegeneration following spinal cord injury: Implications for clinical trials. PMID- 30455260 TI - Author response: Progressive neurodegeneration following spinal cord injury: Implications for clinical trials. PMID- 30455261 TI - Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. PMID- 30455262 TI - Diffuse Lewy body disease manifesting as corticobasal syndrome: A rare form of Lewy body disease. PMID- 30455263 TI - Opinion and Special Articles: Self-management in epilepsy: Web-based seizure tracking applications. PMID- 30455264 TI - Teaching NeuroImages: Japanese encephalitis. PMID- 30455265 TI - Teaching Video NeuroImages: Cerebral amyloid angiopathy-related transient focal neurologic episodes: A video-EEG report. PMID- 30455266 TI - TLR8: No gain, no pain. AB - TLRs have been well characterized in the context of immunity, although TLR8 is understudied due to its controversial function in mice. In this issue of JEM, the new work by Zhang et al. (https://doi.org/10.1084/jem.20180800) demonstrates that TLR8 activated by miR-21 controls neuropathic pain using a non-MyD88-dependent pathway. PMID- 30455267 TI - TLR8 and its endogenous ligand miR-21 contribute to neuropathic pain in murine DRG. AB - Toll-like receptors (TLRs) are nucleic acid-sensing receptors and have been implicated in mediating pain and itch. Here we report that Tlr8 -/- mice show normal itch behaviors, but have defects in neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased TLR8 expression in small-diameter IB4+ DRG neurons. Inhibition of TLR8 in the DRG attenuated SNL-induced pain hypersensitivity. Conversely, intrathecal or intradermal injection of TLR8 agonist, VTX-2337, induced TLR8-dependent pain hypersensitivity. Mechanistically, TLR8, localizing in the endosomes and lysosomes, mediated ERK activation, inflammatory mediators' production, and neuronal hyperexcitability after SNL. Notably, miR-21 was increased in DRG neurons after SNL. Intrathecal injection of miR-21 showed the similar effects as VTX-2337 and inhibition of miR-21 in the DRG attenuated neuropathic pain. The present study reveals a previously unknown role of TLR8 in the maintenance of neuropathic pain, suggesting that miR-21-TLR8 signaling may be potential new targets for drug development against this type of chronic pain. PMID- 30455269 TI - Ending overly broad criminalization of nondisclosure of human immunodeficiency virus infection. PMID- 30455272 TI - Moyamoya disease. PMID- 30455271 TI - Brain natriuretic peptide and shortness of breath in the emergency department. PMID- 30455268 TI - Genetic models reveal origin, persistence and non-redundant functions of IL-17 producing gammadelta T cells. AB - gammadelta T cells are highly conserved in jawed vertebrates, suggesting an essential role in the immune system. However, gammadelta T cell-deficient Tcrd -/ mice display surprisingly mild phenotypes. We hypothesized that the lack of gammadelta T cells in constitutive Tcrd -/- mice is functionally compensated by other lymphocytes taking over genuine gammadelta T cell functions. To test this, we generated a knock-in model for diphtheria toxin-mediated conditional gammadelta T cell depletion. In contrast to IFN-gamma-producing gammadelta T cells, IL-17-producing gammadelta T cells (Tgammadelta17 cells) recovered inefficiently after depletion, and their niches were filled by expanding Th17 cells and ILC3s. Complementary genetic fate mapping further demonstrated that Tgammadelta17 cells are long-lived and persisting lymphocytes. Investigating the function of gammadelta T cells, conditional depletion but not constitutive deficiency protected from imiquimod-induced psoriasis. Together, we clarify that fetal thymus-derived Tgammadelta17 cells are nonredundant local effector cells in IL-17-driven skin pathology. PMID- 30455273 TI - Diagnostic accuracy in the presence of a rare outcome. PMID- 30455270 TI - Risk of sexual transmission of human immunodeficiency virus with antiretroviral therapy, suppressed viral load and condom use: a systematic review. AB - BACKGROUND: The Public Health Agency of Canada reviewed sexual transmission of HIV between serodiscordant partners to support examination of the criminal justice system response to HIV nondisclosure by the Department of Justice of Canada. We sought to determine HIV transmission risk when an HIV-positive partner takes antiretroviral therapy, has a suppressed viral load or uses condoms. METHODS: We conducted an overview and systematic review update by searching MEDLINE and other databases (Jan. 1, 2007, to Mar. 13, 2017; and Nov. 1, 2012, to Apr. 27, 2017, respectively). We considered reviews and studies about absolute risk of sexual transmission of HIV between serodiscordant partners to be eligible for inclusion. We used A Measurement Tool to Assess Systematic Reviews (AMSTAR) for review quality, Quality in Prognosis Studies (QUIPS) instrument for study risk of bias and then the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence across studies. We calculated HIV incidence per 100 person-years with 95% confidence intervals (CIs). We assigned risk categories according to potential for and evidence of HIV transmission. RESULTS: We identified 12 reviews. We selected 1 review to estimate risk of HIV transmission for condom use without antiretroviral therapy (1.14 transmissions/100 person-years, 95% CI 0.56-2.04; low risk). We identified 11 studies with 23 transmissions over 10 511 person-years with antiretroviral therapy (0.22 transmissions/ 100 person-years, 95% CI 0.14-0.33; low risk). We found no transmissions with antiretroviral therapy and a viral load of less than 200 copies/mL across consecutive measurements 4 to 6 months apart (0.00 transmissions/100 person-years, 95% CI 0.00-0.28; negligible risk regardless of condom use). INTERPRETATION: Based on high-quality evidence, there is a negligible risk of sexual transmission of HIV when an HIV-positive sex partner adheres to antiretroviral therapy and maintains a suppressed viral load of less than 200 copies/mL measured every 4 to 6 months. Sexual transmissions of HIV have occurred when viral load was more than 200 copies/mL with antiretroviral therapy or condoms alone were used, although the risk remains low. These findings will help to support patient and clinician decision-making, affect public health case management and contact tracing, and inform justice system responses to HIV nondisclosure. PMID- 30455274 TI - Propofol sedation and colonoscopy: a perspective from endoscopists. PMID- 30455275 TI - Was euthanasia dispute behind CMA-WMA split? PMID- 30455276 TI - Canadian medical residents report pervasive harassment, crushing workloads. PMID- 30455277 TI - Physicians not immune to intimate partner violence. PMID- 30455278 TI - Distinct modes of promoter recognition by two iron starvation sigma factors with overlapping promoter specificities. AB - OrbS and PvdS are extracytoplasmic function (ECF) sigma factors that regulate transcription of operons required for the biosynthesis of the siderophores ornibactin and pyoverdine in the B. cepacia complex and Pseudomonas spp., respectively. Here we show that promoter recognition by OrbS requires specific tetrameric -35 and -10 element sequences that are strikingly similar to those of the consensus PvdS-dependent promoter. However, whereas P. aeruginosa PvdS can serve OrbS-dependent promoters, OrbS cannot utilise PvdS-dependent promoters. To identify features present at OrbS-dependent promoters that facilitate recognition by OrbS, we carried out a detailed analysis of the nucleotide sequence requirements for promoter recognition by both OrbS and PvdS. This revealed that DNA sequence features located outside of the sigma binding elements are required for efficient promoter utilisation by OrbS. In particular, the presence of an A tract extending downstream from the -35 element at OrbS-dependent promoters was shown to be an important contributor to OrbS specificity. Our observations demonstrate that the nature of the spacer sequence can have a major impact on promoter recognition by some ECF sigma factors through modulation of the local DNA architecture.IMPORTANCE ECF sigma factors regulate subsets of bacterial genes in response to environmental stress signals by directing RNA polymerase to promoter sequences known as the -35 and -10 elements. In this work, we identify the -10 and -35 elements that are recognised by the ECF sigma factor OrbS. Furthermore, we demonstrate that efficient promoter utilisation by this sigma factor also requires a polyadenine tract located downstream of the -35 region. We propose that the unique architecture of A-tract DNA imposes conformational features on the -35 element that facilitates efficient recognition by OrbS. Our results show that sequences located between the core promoter elements can make major contributions to promoter recognition by some ECF sigma factors. PMID- 30455279 TI - Molecular and functional insights into the regulation of D-galactonate metabolism by the transcriptional regulator, DgoR, in Escherichia coli. AB - D-galactonate, an aldonic sugar acid, is used as a carbon source by Escherichia coli and the structural dgo genes involved in its metabolism have previously been investigated. Here using genetic, biochemical and bioinformatics approaches, we present the first detailed molecular and functional insights into the regulation of D-galactonate metabolism in E. coli K-12 by the transcriptional regulator, DgoR. We find that dgoR deletion accelerates the growth of E. coli in D galactonate concomitant with the strong constitutive expression of dgo genes. In the dgo locus, sequence upstream of dgoR alone harbors the D-galactonate inducible promoter that likely drives the expression of all dgo genes. DgoR exerts repression on dgo operon by binding two inverted repeats overlapping the dgo promoter. Binding of D-galactonate induces a conformational change in DgoR to de-repress dgo operon. Findings from our work firmly place DgoR in the GntR family of transcriptional regulators: DgoR binds operator sequence [5' TTGTA(G/C)TACA(A/T)-3'] matching the signature of GntR family members that recognize inverted repeats [5'-(N)yGT(N)xAC(N)y-3'], and shares critical protein DNA contacts. We also identified features in DgoR that are otherwise less conserved in the GntR family. Recently, missense mutations were recovered in dgoR in a natural E. coli isolate adapted to the mammalian gut. Our results show these mutants to be DNA-binding-defective emphasizing that mutations in the dgo regulatory elements are selected in the host to allow simultaneous induction of dgo genes. The present study sets the basis to explore the regulation of dgo genes in additional enterobacterial strains where they have been implicated in host-bacterial interactions.IMPORTANCED-galactonate is a widely prevalent aldonic sugar acid. Despite the proposed significance of D-galactonate metabolic pathway in the interaction of enteric bacteria with their hosts, there are no details on its regulation even in Escherichia coli, which is known to utilize D-galactonate since 1970's. Here, using multiple methodologies, we identify the promoter, operator and effector of DgoR, the transcriptional repressor of D-galactonate metabolism in E. coli We establish DgoR as a GntR family transcriptional regulator. Recently, a human urinary tract isolate of E. coli introduced in the mouse gut was found to accumulate missense mutations in dgoR Our results show these mutants to be DNA-binding-defective hence emphasizing the role of D galactonate metabolic pathway in bacterial colonization of the mammalian gut. PMID- 30455280 TI - Organization of the flagellar switch complex of Bacillus subtilis. AB - While the protein complex responsible for controlling the direction (clockwise or counterclockwise) of flagellar rotation has been fairly well studied in E. coli and Salmonella, less is known about the switch complex in B. subtilis or other gram-positive species. Two component proteins (FliG and FliM) are shared between E. coli and B. subtilis, but in place of the protein FliN found in E. coli, the B. subtilis complex contains the larger protein FliY. Notably, in B. subtilis the signaling protein CheY-phosphate induces a switch from CW to CCW rotation, opposite to its action in E. coli Here, we have examined the architecture and function of the switch complex in B. subtilis using targeted cross-linking, bacterial two-hybrid protein-interaction experiments, and characterization of mutant phenotypes. In major respects, the B. subtilis switch complex appears to be organized similarly to that in E. coli The complex is organized around a ring built from the large middle domain of FliM; this ring supports an array of FliG subunits organized in a similar way to that of E. coli, with the FliG C-terminal domain functioning in the generation of torque via conserved charged residues. Key differences from E. coli involve the middle domain of FliY, which forms an additional, more outboard array, and in the C-terminal domains of FliM and FliY, which are organized into both FliY homodimers and FliM heterodimers. Together, the results suggest that the CW and CCW conformational states are similar in the gram-negative and gram-positive switches, but that CheY-phosphate drives oppositely directed movements in the two cases.IMPORTANCE Flagellar motility plays key roles in the survival of many bacteria and in the harmful action of many pathogens. Bacterial flagella rotate; the direction of flagellar rotation is controlled by a multi-subunit protein complex termed the switch complex. This complex has been extensively studied in gram-negative model species but little is known about the complex in Bacillus subtilis or other gram-positive species. Notably, the switch complex in gram-positive species responds to its effector CheY-phosphate by switching to CCW rotation, whereas in E. coli or Salmonella CheY-P acts in the opposite way, promoting CW rotation. In the work here, the architecture of the B. subtilis switch complex has been probed using cross linking, protein-interaction measurements, and mutational approaches. The results cast light on the organization of the complex and provide a framework for understanding the mechanism of flagellar direction control in B. subtilis and other gram-positive species. PMID- 30455281 TI - A LysM domain intervenes in sequential protein-protein and protein-peptidoglycan interactions important for spore coat assembly in Bacillus subtilis. AB - At a late stage in spore development in Bacillus subtilis, the mother cell directs synthesis of a layer of peptidoglycan known as the cortex between the two forespore membranes, as well as the assembly of a protective protein coat at the surface of the forespore outer membrane. SafA, the key determinant of inner coat assembly, is first recruited to the surface of the developing spore and then encases the spore under the control of the morphogenetic protein SpoVID. SafA has a LysM peptidoglycan binding domain, SafALysM, and localizes to the cortex/coat interface in mature spores. SafALysM is followed by a region, A, required for an interaction with SpoVID and encasement. We now show that residues D10 and N30 in SafALysM while involved in the interaction with peptidoglycan, are also required for the interaction with SpoVID and encasement. We further show that single alanine substitutions on residues S11, L12 and I39 of SafALysM that strongly impair binding to purified cortex peptidoglycan affect a later stage in the localization of SafA, that is also dependent on the activity of SpoVE, a transglycosylase required for cortex formation. Assembly of SafA thus involves sequential protein-protein and protein-peptidoglycan interactions, mediated by the LysM domain, which are required first for encasement then for the final localization of the protein in mature spores.IMPORTANCE Bacillus subtilis spores are encased in a multiprotein coat that surrounds an underlying peptidoglycan layer, the cortex. How the connection between the two layers is enforced is not well established. Here, we elucidate the role of the peptidoglycan-binding LysM domain, present in two proteins, SafA and SpoVID, that govern the localization of additional proteins to the coat. We found that SafALysM is a protein-protein interaction module during the early stages of coat assembly, and a cortex-binding module at late stages in morphogenesis, the latter function promoting a tight connection between the cortex and the coat. In contrast, SpoVIDLysM functions only as a protein-protein interaction domain that targets SpoVID to the spore surface at the onset of coat assembly. PMID- 30455282 TI - DNA binding and sensor specificity of FarR; A novel TetR family regulator required for induction of the fatty acid efflux pump FarE in Staphylococcus aureus. AB - Divergent genes in Staphylococcus aureus USA300 encode an efflux pump FarE and TetR family regulator FarR, that confer resistance to antimicrobial unsaturated fatty acids. To study their regulation, we constructed USA300DeltafarER, which exhibited a two-fold reduction in minimum inhibitory concentration of linoleic acid. farE expressed from its native promoter on pLIfarE conferred increased resistance to USA300, but not USA300DeltafarER Complementation of USA300DeltafarER with pLIfarR also had no effect, whereas resistance was restored with pLIfarER, or through ectopic expression of farE In electrophoretic mobility shift assays FarR bound to three different oligonucleotide probes that each contained a TAGWTTA motif, occurring as (i) a singular motif overlapping the -10 element of the P farR promoter; (ii) in palindrome PAL1 immediately 3' of P farR ; or (iii) within PAL2 upstream of the predicted P farE promoter. FarR auto repressed its own expression through cooperative binding to PAL1 and the adjacent TAGWTTA motif in P farR Consistent with reports that S. aureus does not metabolize fatty acids through acyl-CoA intermediates, DNA binding activity of FarR was not affected by linoleoyl-CoA. Conversely, induction of farE required fatty acid kinase FakA, which catalyzes the first metabolic step in incorporation of unsaturated fatty acids into phospholipid. We conclude that FarR is needed to promote expression of farE while strongly auto-repressing its own expression and our data are consistent with a model whereby FarR interacts with a FakA-dependent product of exogenous fatty acid metabolism to ensure that efflux only occurs when the metabolic capacity for incorporation of fatty acid into phospholipid is exceeded.IMPORTANCE: Here we describe the DNA binding and sensor specificity of FarR; a novel TetR family regulator (TFR) in Staphylococcus aureus Unlike the majority of TFRs that have been characterized, which function to repress a divergently transcribed gene, we find that FarR is needed to promote expression of the divergently transcribed farE gene, encoding an RND family efflux pump that is induced in response to antimicrobial unsaturated fatty acids. Induction of farE was dependent on the function of a fatty acid kinase FakA, which catalyzes the first metabolic step in incorporation of exogenous unsaturated fatty acids into phospholipid. This represents a novel example of TFR function. PMID- 30455283 TI - MinC N- and C-domain interactions modulate FtsZ assembly, division site selection and MinD-dependent oscillation in Escherichia coli. AB - The Min system in Escherichia coli, consisting of MinC, MinD, and MinE proteins, regulates division site selection by preventing assembly of the FtsZ-ring (Z ring) and exhibits polar oscillation in vivo. MinC antagonizes FtsZ polymerization and, in vivo, the cellular location of MinC is controlled by a direct association with MinD at the membrane. To further understand the interactions of MinC with FtsZ and MinD, we performed a mutagenesis screen to identify substitutions in minC that are associated with defects in cell division. We identified amino acids in both the N- and C-domains of MinC that are important for direct interactions with FtsZ and MinD in vitro, as well as mutations that modify the observed in vivo oscillation of Gfp-MinC. Our results indicate that there are two distinct surface-exposed sites on MinC that are important for direct interactions with FtsZ: one at a cleft on the surface of the N-domain and a second on the C-domain that is adjacent to the MinD interaction site. Mutation of either of these sites leads to slower oscillation of Gfp-MinC in vivo, although the MinC mutant proteins are still capable of a direct interaction with MinD in phospholipid recruitment assays. Furthermore, we demonstrate that interactions between FtsZ and both sites of MinC identified here are important for assembly of FtsZ-MinC-MinD complexes and that the conserved C-terminal end of FtsZ is not required for MinC-MinD complex formation with GTP-dependent FtsZ polymers.IMPORTANCE Bacterial cell division proceeds through the coordinated assembly of the FtsZ-ring, or Z-ring, at the site of division. Assembly of the Z ring requires polymerization of FtsZ, which is regulated by several proteins in the cell. In Escherichia coli, the Min system, which contains MinC, MinD and MinE proteins, exhibits polar oscillation and inhibits the assembly of FtsZ at non septal locations. Here, we identify regions on the surface of MinC that are important for contacting FtsZ and destabilizing FtsZ polymers. PMID- 30455284 TI - Barriers to 3-hydroxypropionate-dependent growth of Rhodobacter sphaeroides by distinct disruptions of the ethylmalonyl-CoA pathway. AB - Rhodobacter sphaeroides is able to use 3-hydroxypropionate as the sole carbon source through the reductive conversion of 3-hydroxypropionate to propionyl-CoA. The ethylmalonyl-CoA pathway is not required in this process because a crotonyl CoA carboxylase/reductase (Ccr)-negative mutant still grew with 3 hydroxypropionate. Much to our surprise, a mutant defective for another specific enzyme of the ethylmalonyl-CoA pathway, mesaconyl-CoA hydratase (Mch), lost its ability for 3-hydroxypropionate-dependent growth. Interestingly, the Mch deficient mutant was rescued by either introducing an additional ccr in-frame deletion that resulted in the blockage of an earlier step in the pathway or by heterologously expressing a gene encoding a thioesterase (YciA) that can act on several CoA-intermediates of the ethylmalonyl-CoA pathway. The mch-mutant expressing yciA metabolized only less than half of the 3-hydroxypropionate supplied and over fifty percent of that carbon was recovered in the spent medium as free acids of the key intermediates mesaconyl-CoA and methylsuccinyl-CoA. A gradual increase in growth inhibition due to the blockage of consecutive steps of the ethylmalonyl-CoA pathway by gene deletions suggests that the growth defects were due to the titration of free CoA and depletion of the CoA pool in the cell rather than detrimental effects due to a specific metabolite accumulating. Recovery of carbon in mesaconate for the wild-type strain expressing yciA demonstrated that carbon flux through the ethylmalonyl-CoA pathway occurs during 3-hydroxypropionate-dependent growth. A possible role of the ethylmalonyl-CoA pathway is proposed that functions outside its known role in providing tricarboxylic acid intermediates during acetyl-CoA assimilation.IMPORTANCE Mutant analysis is an important tool utilized in metabolic studies to understand which role a particular pathway might have under certain growth conditions for a given organism. The importance of the enzyme, and the pathway in which it participates in, is discretely linked to the resulting phenotype observed after mutating the corresponding gene. This work highlights the possibility of incorrectly interpreting mutant growth results that are based on studying a single unit (gene and encoded enzyme) of a metabolic pathway rather than the pathway in its entirety. This work also hints at the possibility of using an enzyme as a drug target although it may participate in a non-essential pathway but could still be detrimental to the cell when inhibited. PMID- 30455285 TI - Identification and verification of ubiquitin-activated bacterial phospholipases. AB - ExoU is a potent type III secretion system effector injected directly into mammalian cells by the opportunistic pathogen, Pseudomonas aeruginosa As a ubiquitin activated phospholipase A2 (PLA2), ExoU exhibits cytotoxicity by cleaving membrane phospholipids resulting in lysis of the host cells and inhibition of the innate immune response. Recently, ExoU has been established as a model protein for a group of ubiquitin activated PLA2 enzymes encoded by a variety of bacteria. Bioinformatic analyses of homologous proteins is a powerful approach that can complement and enhance overall understanding of protein structure and function. To conduct homology studies, it is important to have efficient and effective tools to screen and validate the putative homologs of interest. Here we make use of an Escherichia coli - based dual expression system to screen putative ubiquitin activated PLA2 enzymes from a variety of bacteria that are known to colonize and cause human infections. The screen effectively identifies multiple ubiquitin activated phospholipases, which are validated using both biological and biochemical techniques. In this study two new ExoU orthlogs were identified and the ubiquitin activation of the Rickettsial enzyme, RP534, was verified. Conversely, ubiquitin was not found to regulate the activity of several other tested enzymes. Based on structural homology analyses, functional properties were predicted for AxoU, a unique member of the group encoded by Achromobacter xylosoxidans IMPORTANCE Bacterial phospholipases act as intracellular and extracellular enzymes promoting destruction of phospholipid barriers and inflammation during infections. Identifying enzymes with a common mechanism of activation is an initial step in understanding structural and functional properties. These properties serve as critical information in the design of specific inhibitors to reduce enzymatic activity and ameliorate host cell death. In this report we identify and verify cytotoxic PLA2 enzymes from several bacterial pathogens. Similar to the founding member of the group, ExoU, these enzymes share the property of ubiquitin-mediated activation. The identification and validation of potential toxins from multiple bacterial species provides additional proteins to derive structural insights that could lead to pan inhibitors useful for treating a variety of infections. PMID- 30455287 TI - Engineering of metabolic pathways using synthetic enzyme complexes. PMID- 30455286 TI - Adaption of roots to nitrogen deficiency revealed by 3-D quantification and proteomic analysis. AB - Rapeseed (Brassica napus L.) is an important oil crop worldwide. However, severe inhibition of rapeseed production often occurs in the field due to nitrogen (N) deficiency. The root system is the main organ to acquire N for plant growth, but little is known about the mechanisms underlying rapeseed root adaptions to N deficiency. Here, dynamic changes in root architectural traits of N-deficient rapeseed plants were evaluated by 3-D in situ quantification. Root proteome responses to N deficiency were analyzed by the tandem mass tag (TMT)-based proteomics method, and related proteins were further characterized. Under N deficiency, rapeseed roots become longer, with denser cells in the meristematic zone and larger cells in the elongation zone of root tips, and also become softer with reduced solidity. A total of 171 and 755 differentially expressed proteins (DEPs) were identified in short- and long-term N-deficient roots, respectively. The abundance of proteins involved in cell wall organization or biogenesis was highly enhanced, but most identified peroxidases were reduced in the N-deficient roots. Notably, peroxidase activities were also decreased, which might promote root elongation while lowering the solidity of N-deficient roots. These results were consistent with the cell wall components measured in the N-deficient roots. Further functional analysis using transgenic Arabidopsis thaliana plants demonstrated that the two root-related DEPs contribute to the enhanced root growth under N-deficiency conditions. These results provide insights into global changes of rapeseed root responses to N deficiency and may facilitate the development of rapeseed cultivars with high N use efficiency through root-based genetic improvements. PMID- 30455288 TI - Smoke radiocarbon measurements from Indonesian fires provide evidence for burning of millennia-aged peat. AB - In response to a strong El Nino, fires in Indonesia during September and October 2015 released a large amount of carbon dioxide and created a massive regional smoke cloud that severely degraded air quality in many urban centers across Southeast Asia. Although several lines of evidence indicate that peat burning was a dominant contributor to emissions in the region, El Nino-induced drought is also known to increase deforestation fires and agricultural waste burning in plantations. As a result, uncertainties remain with respect to partitioning emissions among different ecosystem and fire types. Here we measured the radiocarbon content (14C) of carbonaceous aerosol samples collected in Singapore from September 2014 through October 2015, with the aim of identifying the age and origin of fire-emitted fine particulate matter (particulate matter with an aerodynamic diameter less than or equal to 2.5 MUm). The Delta14C of fire-emitted aerosol was -76 +/- 510/00, corresponding to a carbon pool of combusted organic matter with a mean turnover time of 800 +/- 420 y. Our observations indicated that smoke plumes reaching Singapore originated primarily from peat burning (~85%), and not from deforestation fires or waste burning. Atmospheric transport modeling confirmed that fires in Sumatra and Borneo were dominant contributors to elevated PM2.5 in Singapore during the fire season. The mean age of the carbonaceous aerosol, which predates the Industrial Revolution, highlights the importance of improving peatland fire management during future El Nino events for meeting climate mitigation and air quality commitments. PMID- 30455289 TI - Elastic and Li-ion-percolating hybrid membrane stabilizes Li metal plating. AB - Lithium metal batteries are capable of revolutionizing the battery marketplace for electrical vehicles, owing to the high capacity and low voltage offered by Li metal. Current exploitation of Li metal electrodes, however, is plagued by their exhaustive parasitic reactions with liquid electrolytes and dendritic growth, which pose concerns to both cell performance and safety. We demonstrate that a hybrid membrane, both elastic and Li+-ion percolating, can stabilize Li plating/stripping with high Coulombic efficiency. The compact packing of a Li+ solid electrolyte phase offers percolated Li+-conducting channels and the consequent infiltration of an elastic polymer endows membrane flexibility to accommodate volume changes. The protected electrode allows Li plating with 95.8% efficiency for 200 cycles and stable operation of an LTO|Li cell for 2,000 cycles. This rationally structured membrane represents an interface engineering approach toward stabilized Li metal electrodes. PMID- 30455291 TI - Correction for Benej et al., Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. PMID- 30455290 TI - Cats use hollow papillae to wick saliva into fur. AB - The cat tongue is covered in sharp, rear-facing spines called papillae, the precise function of which is a mystery. In this combined experimental and theoretical study, we use high-speed film, grooming force measurements, and computed tomography (CT) scanning to elucidate the mechanism by which papillae are used to groom fur. We examine the tongues of six species of cats from domestic cat to lion, spanning 30-fold in body weight. The papillae of these cats each feature a hollow cavity at the tip that spontaneously wicks saliva from the mouth and then releases it onto hairs. The unique shape of the cat's papillae may inspire ways to clean complex hairy surfaces. We demonstrate one such application with the tongue-inspired grooming (TIGR) brush, which incorporates 3D-printed cat papillae into a silicone substrate. The TIGR brush experiences lower grooming forces than a normal hairbrush and is easier to clean. PMID- 30455292 TI - Loss of protein synthesis quality control in host-restricted organisms. AB - Intracellular organisms, such as obligate parasites and endosymbionts, typically possess small genomes due to continuous genome decay caused by an environment with alleviated natural selection. Previously, a few species with highly reduced genomes, including the intracellular pathogens Mycoplasma and Microsporidia, have been shown to carry degenerated editing domains in aminoacyl-tRNA synthetases. These defects in the protein synthesis machinery cause inaccurate translation of the genetic code, resulting in significant statistical errors in protein sequences that are thought to help parasites to escape immune response of a host. In this study we analyzed 10,423 complete bacterial genomes to assess conservation of the editing domains in tRNA synthetases, including LeuRS, IleRS, ValRS, ThrRS, AlaRS, and PheRS. We found that, while the editing domains remain intact in free-living species, they are degenerated in the overwhelming majority of host-restricted bacteria. Our work illustrates that massive genome erosion triggered by an intracellular lifestyle eradicates one of the most fundamental components of a living cell: the system responsible for proofreading of amino acid selection for protein synthesis. This finding suggests that inaccurate translation of the genetic code might be a general phenomenon among intercellular organisms with reduced genomes. PMID- 30455293 TI - Tracking job and housing dynamics with smartcard data. AB - Residential locations, the jobs-housing relationship, and commuting patterns are key elements to understand urban spatial structure and how city dwellers live. Their successive interaction is important for various fields including urban planning, transport, intraurban migration studies, and social science. However, understanding of the long-term trajectories of workplace and home location, and the resulting commuting patterns, is still limited due to lack of year-to-year data tracking individual behavior. With a 7-y transit smartcard dataset, this paper traces individual trajectories of residences and workplaces. Based on in metro travel times before and after job and/or home moves, we find that 45 min is an inflection point where the behavioral preference changes. Commuters whose travel time exceeds the point prefer to shorten commutes via moves, while others with shorter commutes tend to increase travel time for better jobs and/or residences. Moreover, we capture four mobility groups: home mover, job hopper, job-and-residence switcher, and stayer. This paper studies how these groups trade off travel time and housing expenditure with their job and housing patterns. Stayers with high job and housing stability tend to be home (apartment unit) owners subject to middle- to high-income groups. Home movers work at places similar to stayers, while they may upgrade from tenancy to ownership. Switchers increase commute time as well as housing expenditure via job and home moves, as they pay for better residences and work farther from home. Job hoppers mainly reside in the suburbs, suffer from long commutes, change jobs frequently, and are likely to be low-income migrants. PMID- 30455294 TI - Correction to Supporting Information for Rohrback et al., Submegabase copy number variations arise during cerebral cortical neurogenesis as revealed by single-cell whole-genome sequencing. PMID- 30455295 TI - Correction to Supporting Information for Alix-Garcia et al., Payments for environmental services supported social capital while increasing land management. PMID- 30455296 TI - Correction for Tilman et al., Localized prosocial preferences, public goods, and common-pool resources. PMID- 30455297 TI - Testing the retroelement invasion hypothesis for the emergence of the ancestral eukaryotic cell. AB - Phylogenetic evidence suggests that the invasion and proliferation of retroelements, selfish mobile genetic elements that copy and paste themselves within a host genome, was one of the early evolutionary events in the emergence of eukaryotes. Here we test the effects of this event by determining the pressures retroelements exert on simple genomes. We transferred two retroelements, human LINE-1 and the bacterial group II intron Ll.LtrB, into bacteria, and find that both are functional and detrimental to growth. We find, surprisingly, that retroelement lethality and proliferation are enhanced by the ability to perform eukaryotic-like nonhomologous end-joining (NHEJ) DNA repair. We show that the only stable evolutionary consequence in simple cells is maintenance of retroelements in low numbers, suggesting how retrotransposition rates and costs in early eukaryotes could have been constrained to allow proliferation. Our results suggest that the interplay between NHEJ and retroelements may have played a fundamental and previously unappreciated role in facilitating the proliferation of retroelements, elements of which became the ancestors of the spliceosome components in eukaryotes. PMID- 30455299 TI - Correction to Supporting Information for Nobori et al., Transcriptome landscape of a bacterial pathogen under plant immunity. PMID- 30455298 TI - Detecting and explaining why aquifers occasionally become degraded near hydraulically fractured shale gas wells. AB - Extensive development of shale gas has generated some concerns about environmental impacts such as the migration of natural gas into water resources. We studied high gas concentrations in waters at a site near Marcellus Shale gas wells to determine the geological explanations and geochemical implications. The local geology may explain why methane has discharged for 7 years into groundwater, a stream, and the atmosphere. Gas may migrate easily near the gas wells in this location where the Marcellus Shale dips significantly, is shallow (~1 km), and is more fractured. Methane and ethane concentrations in local water wells increased after gas development compared with predrilling concentrations reported in the region. Noble gas and isotopic evidence are consistent with the upward migration of gas from the Marcellus Formation in a free-gas phase. This upflow results in microbially mediated oxidation near the surface. Iron concentrations also increased following the increase of natural gas concentrations in domestic water wells. After several months, both iron and SO4 2 concentrations dropped. These observations are attributed to iron and SO4 2- reduction associated with newly elevated concentrations of methane. These temporal trends, as well as data from other areas with reported leaks, document a way to distinguish newly migrated methane from preexisting sources of gas. This study thus documents both geologically risky areas and geochemical signatures of iron and SO4 2- that could distinguish newly leaked methane from older methane sources in aquifers. PMID- 30455300 TI - Large changes in biomass burning over the last millennium inferred from paleoatmospheric ethane in polar ice cores. AB - Biomass burning drives changes in greenhouse gases, climate-forcing aerosols, and global atmospheric chemistry. There is controversy about the magnitude and timing of changes in biomass burning emissions on millennial time scales from preindustrial to present and about the relative importance of climate change and human activities as the underlying cause. Biomass burning is one of two notable sources of ethane in the preindustrial atmosphere. Here, we present ice core ethane measurements from Antarctica and Greenland that contain information about changes in biomass burning emissions since 1000 CE (Common Era). The biomass burning emissions of ethane during the Medieval Period (1000-1500 CE) were higher than present day and declined sharply to a minimum during the cooler Little Ice Age (1600-1800 CE). Assuming that preindustrial atmospheric reactivity and transport were the same as in the modern atmosphere, we estimate that biomass burning emissions decreased by 30 to 45% from the Medieval Period to the Little Ice Age. The timing and magnitude of this decline in biomass burning emissions is consistent with that inferred from ice core methane stable carbon isotope ratios but inconsistent with histories based on sedimentary charcoal and ice core carbon monoxide measurements. This study demonstrates that biomass burning emissions have exceeded modern levels in the past and may be highly sensitive to changes in climate. PMID- 30455301 TI - Dynamic effects of enforcement on cooperation. AB - In situations where social payoffs are not aligned with private incentives, enforcement with fines can be a way to sustain cooperation. In this paper we show, by the means of a laboratory experiment, that past fines can have an effect on current behavior even when no longer in force. We document two mechanisms: (i) Past fines affect directly individuals' future propensity to cooperate, and (ii) when fines for noncooperation are in place in the past, individuals experience higher levels of cooperation from partners and, consistent with indirect reciprocity motives, are in turn nicer toward others once these fines have been removed. This second mechanism is empirically prevalent and, in contrast with the first one, induces a snowball effect of past enforcement. Our results can inform the design of costly enforcement policies. PMID- 30455302 TI - Oscillating path between self-similarities in liquid pinch-off. AB - Many differential equations involved in natural sciences show singular behaviors; i.e., quantities in the model diverge as the solution goes to zero. Nonetheless, the evolution of the singularity can be captured with self-similar solutions, several of which may exist for a given system. How to characterize the transition from one self-similar regime to another remains an open question. By studying the classic example of the pinch-off of a viscous liquid thread, we show experimentally that the geometry of the system and external perturbations play an essential role in the transition from a symmetric to an asymmetric solution. Moreover, this transient regime undergoes unexpected log-scale oscillations that delay dramatically the onset of the final self-similar solution. This result sheds light on the strong impact external constraints can have on predictions established to explain the formation of satellite droplets or on the rheological tests applied on a fluid, for example. PMID- 30455303 TI - SIR proteins create compact heterochromatin fibers. AB - Heterochromatin is a silenced chromatin region essential for maintaining genomic stability and driving developmental processes. The complicated structure and dynamics of heterochromatin have rendered it difficult to characterize. In budding yeast, heterochromatin assembly requires the SIR proteins-Sir3, believed to be the primary structural component of SIR heterochromatin, and the Sir2-4 complex, responsible for the targeted recruitment of SIR proteins and the deacetylation of lysine 16 of histone H4. Previously, we found that Sir3 binds but does not compact nucleosomal arrays. Here we reconstitute chromatin fibers with the complete complement of SIR proteins and use sedimentation velocity, molecular modeling, and atomic force microscopy to characterize the stoichiometry and conformation of SIR chromatin fibers. In contrast to fibers with Sir3 alone, our results demonstrate that SIR arrays are highly compact. Strikingly, the condensed structure of SIR heterochromatin fibers requires both the integrity of H4K16 and an interaction between Sir3 and Sir4. We propose a model in which a dimer of Sir3 bridges and stabilizes two adjacent nucleosomes, while a Sir2-4 heterotetramer interacts with Sir3 associated with a nucleosomal trimer, driving fiber compaction. PMID- 30455304 TI - ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. AB - Endogenous retroviruses (ERVs) are integrated retroviral elements that make up 8% of the human genome. However, the impact of ERVs on human health and disease is not well understood. While select ERVs have been implicated in diseases, including autoimmune disease and cancer, the lack of tools to analyze genome wide, locus-specific expression of proviral autonomous ERVs has hampered the progress in the field. Here we describe a method called ERVmap, consisting of an annotated database of 3,220 human proviral ERVs and a pipeline that allows for locus-specific genome-wide identification of proviral ERVs that are transcribed based on RNA-sequencing data, and provide examples of the utility of this tool. Using ERVmap, we revealed cell-type-specific ERV expression patterns in commonly used cell lines as well as in primary cells. We identified 124 unique ERV loci that are significantly elevated in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus that represent an IFN-independent signature. Finally, we identified additional tumor-associated ERVs that correlate with cytolytic activity represented by granzyme and perforin expression in breast cancer tissue samples. The open-source code of ERVmap and the accompanied web tool are made publicly available to quantify proviral ERVs in RNA-sequencing data with ease. Use of ERVmap across a range of diseases and experimental conditions has the potential to uncover novel disease-associated antigens and effectors involved in human health that is currently missed by focusing on protein-coding sequences. PMID- 30455305 TI - The Pseudomonas aeruginosa T6SS-VgrG1b spike is topped by a PAAR protein eliciting DNA damage to bacterial competitors. AB - The type VI secretion system (T6SS) is a supramolecular complex involved in the delivery of potent toxins during bacterial competition. Pseudomonas aeruginosa possesses three T6SS gene clusters and several hcp and vgrG gene islands, the latter encoding the spike at the T6SS tip. The vgrG1b cluster encompasses seven genes whose organization and sequences are highly conserved in P. aeruginosa genomes, except for two genes that we called tse7 and tsi7 We show that Tse7 is a Tox-GHH2 domain nuclease which is distinct from other T6SS nucleases identified thus far. Expression of this toxin induces the SOS response, causes growth arrest and ultimately results in DNA degradation. The cytotoxic domain of Tse7 lies at its C terminus, while the N terminus is a predicted PAAR domain. We find that Tse7 sits on the tip of the VgrG1b spike and that specific residues at the PAAR VgrG1b interface are essential for VgrG1b-dependent delivery of Tse7 into bacterial prey. We also show that the delivery of Tse7 is dependent on the H1 T6SS cluster, and injection of the nuclease into bacterial competitors is deployed for interbacterial competition. Tsi7, the cognate immunity protein, protects the producer from the deleterious effect of Tse7 through a direct protein-protein interaction so specific that toxin/immunity pairs are effective only if they originate from the same P. aeruginosa isolate. Overall, our study highlights the diversity of T6SS effectors, the exquisite fitting of toxins on the tip of the T6SS, and the specificity in Tsi7-dependent protection, suggesting a role in interstrain competition. PMID- 30455307 TI - Structural analysis of transient reaction intermediate in formic acid dehydrogenation catalysis using two-dimensional IR spectroscopy. AB - The molecular structure of a catalytically active key intermediate is determined in solution by employing 2D IR spectroscopy measuring vibrational cross-angles. The formate intermediate (2) in the formic acid dehydrogenation reaction catalyzed by a phosphorus-nitrogen PN3P-Ru catalyst is elucidated. Our spectroscopic studies show that the complex features a formate ion directly attached to the Ru center as a ligand, and a proton added to the imine arm of the dearomatized PN3P* ligand. During the catalytic process, the imine arms are not only reversibly protonated and deprotonated, but also interacting with the protic substrate molecules, effectively serving as the local proton buffer to offer remarkable stability with a turnover number (TON) over one million. PMID- 30455306 TI - Discovery of Kaposi's sarcoma herpesvirus-encoded circular RNAs and a human antiviral circular RNA. AB - Noncoding RNAs have substantial effects in host-virus interactions. Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs which can decoy other RNAs or RNA-binding proteins to inhibit their functions. The role of circRNAs is largely unknown in the context of Kaposi's sarcoma herpesvirus (KSHV). We hypothesized that circRNAs influence viral infection by inhibiting host and/or viral factors. Transcriptome analysis of KSHV-infected primary endothelial cells and a B cell line identified human circRNAs that are differentially regulated upon infection. We confirmed the expression changes with divergent PCR primers and RNase R treatment of specific circRNAs. Ectopic expression of hsa_circ_0001400, a circRNA induced by infection, suppressed expression of key viral latent gene LANA and lytic gene RTA in KSHV de novo infections. Since human herpesviruses express noncoding RNAs like microRNAs, we searched for viral circRNAs encoded in the KSHV genome. We performed circRNA-Seq analysis with RNase R-treated, circRNA-enriched RNA from KSHV-infected cells. We identified multiple circRNAs encoded by the KSHV genome that are expressed in KSHV-infected endothelial cells and primary effusion lymphoma (PEL) cells. The KSHV circRNAs are located within ORFs of viral lytic genes, are up-regulated upon the induction of the lytic cycle, and alter cell growth. Viral circRNAs were also detected in lymph nodes from patients of KSHV driven diseases such as PEL, Kaposi's sarcoma, and multicentric Castleman's disease. We revealed new host-virus interactions of circRNAs: human antiviral circRNAs are activated in response to KSHV infection, and viral circRNA expression is induced in the lytic phase of infection. PMID- 30455308 TI - Interlinked regulatory loops of ABA catabolism and biosynthesis coordinate fruit growth and ripening in woodland strawberry. AB - Fruit growth and ripening are controlled by multiple phytohormones. How these hormones coordinate and interact with each other to control these processes at the molecular level is unclear. We found in the early stages of Fragaria vesca (woodland strawberry) fruit development, auxin increases both widths and lengths of fruits, while gibberellin [gibberellic acid (GA)] mainly promotes their longitudinal elongation. Auxin promoted GA biosynthesis and signaling by activating GA biosynthetic and signaling genes, suggesting auxin function is partially dependent on GA function. To prevent the repressive effect of abscisic acid (ABA) on fruit growth, auxin and GA suppressed ABA accumulation during early fruit development by activating the expression of FveCYP707A4a encoding cytochrome P450 monooxygenase that catalyzes ABA catabolism. At the onset of fruit ripening, both auxin and GA levels decreased, leading to a steep increase in the endogenous level of ABA that drives fruit ripening. ABA repressed the expression of FveCYP707A4a but promoted that of FveNCED, a rate-limiting step in ABA biosynthesis. Accordingly, altering FveCYP707A4a expression changed the endogenous ABA levels and affected FveNCED expression. Hence, ABA catabolism and biosynthesis are tightly linked by feedback and feedforward loops to limit ABA contents for fruit growth and to quickly increase ABA contents for the onset of fruit ripening. These results indicate that FveCYP707A4a not only regulates ABA accumulation but also provides a hub to coordinate fruit size and ripening times by relaying auxin, GA, and ABA signals. PMID- 30455309 TI - Change in household fuels dominates the decrease in PM2.5 exposure and premature mortality in China in 2005-2015. AB - To tackle the severe fine particle (PM2.5) pollution in China, the government has implemented stringent control policies mainly on power plants, industry, and transportation since 2005, but estimates of the effectiveness of the policy and the temporal trends in health impacts are subject to large uncertainties. By adopting an integrated approach that combines chemical transport simulation, ambient/household exposure evaluation, and health-impact assessment, we find that the integrated population-weighted exposure to PM2.5 (IPWE) decreased by 47% (95% confidence interval, 37-55%) from 2005 [180 (146-219) MUg/m3] to 2015 [96 (83 111) MUg/m3]. Unexpectedly, 90% (86-93%) of such reduction is attributed to reduced household solid-fuel use, primarily resulting from rapid urbanization and improved incomes rather than specific control policies. The IPWE due to household fuels for both cooking and heating decreased, but the impact of cooking is significantly larger. The reduced household-related IPWE is estimated to avoid 0.40 (0.25-0.57) million premature deaths annually, accounting for 33% of the PM2.5-induced mortality in 2015. The IPWE would be further reduced by 63% (57 68%) if the remaining household solid fuels were replaced by clean fuels, which would avoid an additional 0.51 (0.40-0.64) million premature deaths. Such a transition to clean fuels, especially for heating, requires technology innovation and policy support to overcome the barriers of high cost of distribution systems, as is recently being attempted in the Beijing-Tianjin-Hebei area. We suggest that household-fuel use be more highly prioritized in national control policies, considering its effects on PM2.5 exposures. PMID- 30455310 TI - Redox dysregulation as a link between childhood trauma and psychopathological and neurocognitive profile in patients with early psychosis. AB - Exposure to childhood trauma (CT) increases the risk for psychosis and affects the development of brain structures, possibly through oxidative stress. As oxidative stress is also linked to psychosis, it may interact with CT, leading to a more severe clinical phenotype. In 133 patients with early psychosis (EPP), we explored the relationships between CT and hippocampal, amygdala, and intracranial volume (ICV); blood antioxidant defenses [glutathione peroxidase (GPx) and thioredoxin/peroxiredoxin (Trx/Prx)]; psychopathological results; and neuropsychological results. Nonadjusted hippocampal volume correlated negatively with GPx activity in patients with CT, but not in patients without CT. In patients with CT with high GPx activity (high-GPx+CT), hippocampal volume was decreased compared with that in patients with low-GPx+CT and patients without CT, who had similar hippocampal volumes. Patients with high-GPx+CT had more severe positive and disorganized symptoms than other patients. Interestingly, Trx and oxidized Prx levels correlated negatively with GPx only in patients with low GPx+CT. Moreover, patients with low-GPx+CT performed better than other patients on cognitive tasks. Discriminant analysis combining redox markers, hippocampal volume, clinical scores, and cognitive scores allowed for stratification of the patients into subgroups. In conclusion, traumatized EPP with high peripheral oxidation status (high-GPx activity) had smaller hippocampal volumes and more severe symptoms, while those with lower oxidation status (low-GPx activity) showed better cognition and regulation of GPx and Trx/Prx systems. These results suggest that maintained regulation of various antioxidant systems allowed for compensatory mechanisms preventing long-term neuroanatomical and clinical impacts. The redox marker profile may thus represent important biomarkers for defining treatment strategies in patients with psychosis. PMID- 30455311 TI - Differential growth and shape formation in plant organs. AB - Morphogenesis is a phenomenon by which a wide variety of functional organs are formed in biological systems. In plants, morphogenesis is primarily driven by differential growth of tissues. Much effort has been devoted to identifying the role of genetic and biomolecular pathways in regulating cell division and cell expansion and in influencing shape formation in plant organs. However, general principles dictating how differential growth controls the formation of complex 3D shapes in plant leaves and flower petals remain largely unknown. Through quantitative measurements on live plant organs and detailed finite-element simulations, we show how the morphology of a growing leaf is determined by both the maximum value and the spatial distribution of growth strain. With this understanding, we develop a broad scientific framework for a morphological phase diagram that is capable of rationalizing four configurations commonly found in plant organs: twisting, helical twisting, saddle bending, and edge waving. We demonstrate the robustness of these findings and analyses by recourse to synthetic reproduction of all four configurations using controlled polymerization of a hydrogel. Our study points to potential approaches to innovative geometrical design and actuation in such applications as building architecture, soft robotics and flexible electronics. PMID- 30455313 TI - ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay. AB - Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid-liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed a protocol to isolate the dynamic mutant FUS-positive cytoplasmic granules. Proteomic identification of the protein composition and subsequent pathway analysis led us to hypothesize that mutant FUS can interfere with protein translation. We demonstrated that the ALS mutations in FUS indeed suppressed protein translation in N2a cells expressing mutant FUS and fibroblast cells derived from FUS ALS cases. In addition, the nonsense-mediated decay (NMD) pathway, which is closely related to protein translation, was altered by mutant FUS. Specifically, NMD-promoting factors UPF1 and UPF3b increased, whereas a negative NMD regulator, UPF3a, decreased, leading to the disruption of NMD autoregulation and the hyperactivation of NMD. Alterations in NMD factors and elevated activity were also observed in the fibroblast cells of FUS ALS cases. We conclude that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation, both of which likely contribute to motor neuron death. PMID- 30455312 TI - Artemisinin resistance phenotypes and K13 inheritance in a Plasmodium falciparum cross and Aotus model. AB - Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t 1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC50 measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62-1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76-39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t 1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, -3.66 to 3.67), 0.80 h (95% CI, -0.92 to 2.53), and 2.07 h (95% CI, 0.77-3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (-13% difference; 95% CI, -58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy. PMID- 30455314 TI - Correction for Sago et al., High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing. PMID- 30455315 TI - Correction for Zhao et al., Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children. PMID- 30455316 TI - Probabilistic control of HIV latency and transactivation by the Tat gene circuit. AB - The reservoir of HIV latently infected cells is the major obstacle for eradication of HIV infection. The "shock-and-kill" strategy proposed earlier aims to reduce the reservoir by activating cells out of latency. While the intracellular HIV Tat gene circuit is known to play important roles in controlling latency and its transactivation in HIV-infected cells, the detailed control mechanisms are not well understood. Here we study the mechanism of probabilistic control of the latent and the transactivated cell phenotypes of HIV infected cells. We reconstructed the probability landscape, which is the probability distribution of the Tat gene circuit states, by directly computing the exact solution of the underlying chemical master equation. Results show that the Tat circuit exhibits a clear bimodal probability landscape (i.e., there are two distinct probability peaks, one associated with the latent cell phenotype and the other with the transactivated cell phenotype). We explore potential modifications to reactions in the Tat gene circuit for more effective transactivation of latent cells (i.e., the shock-and-kill strategy). Our results suggest that enhancing Tat acetylation can dramatically increase Tat and viral production, while increasing the Tat-transactivation response binding affinity can transactivate latent cells more rapidly than other manipulations. Our results further explored the "block and lock" strategy toward a functional cure for HIV. Overall, our study demonstrates a general approach toward discovery of effective therapeutic strategies and druggable targets by examining control mechanisms of cell phenotype switching via exactly computed probability landscapes of reaction networks. PMID- 30455317 TI - Biological sex affects vaccine efficacy and protection against influenza in mice. AB - Biological sex affects adaptive immune responses, which could impact influenza infection and vaccine efficacy. Infection of mice with 2009 H1N1 induced antibody responses, CD4+ T cell and CD8+ T cell memory responses that were greater in females than males; both sexes, however, were equally protected against secondary challenge with an H1N1 drift variant virus. To test whether greater antibody in females is sufficient for protection against influenza, males and females were immunized with an inactivated H1N1 vaccine that induced predominantly antibody mediated immunity. Following vaccination, females had greater antibody responses and protection against challenge with an H1N1 drift variant virus than males. Antibody derived from vaccinated females was better at protecting both naive males and females than antibody from males, and this protection was associated with increased antibody specificity and avidity to the H1N1 virus. The expression of Tlr7 was greater in B cells from vaccinated females than males and was associated with reduced DNA methylation in the Tlr7 promoter region, higher neutralizing antibody, class switch recombination, and antibody avidity in females. Deletion of Tlr7 reduced sex differences in vaccine-induced antibody responses and protection following challenge and had a greater impact on responses in females than males. Taken together, these data illustrate that greater TLR7 activation and antibody production in females improves the efficacy of vaccination against influenza. PMID- 30455318 TI - Correction to Supporting Information for Kwon et al., Coiled-coil structure dependent interactions between polyQ proteins and Foxo lead to dendrite pathology and behavioral defects. PMID- 30455319 TI - Potential shift from a carbon sink to a source in Amazonian peatlands under a changing climate. AB - Amazonian peatlands store a large amount of soil organic carbon (SOC), and its fate under a future changing climate is unknown. Here, we use a process-based peatland biogeochemistry model to quantify the carbon accumulation for peatland and nonpeatland ecosystems in the Pastaza-Maranon foreland basin (PMFB) in the Peruvian Amazon from 12,000 y before present to AD 2100. Model simulations indicate that warming accelerates peat SOC loss, while increasing precipitation accelerates peat SOC accumulation at millennial time scales. The uncertain parameters and spatial variation of climate are significant sources of uncertainty to modeled peat carbon accumulation. Under warmer and presumably wetter conditions over the 21st century, SOC accumulation rate in the PMFB slows down to 7.9 (4.3-12.2) g?C?m-2?y-1 from the current rate of 16.1 (9.1-23.7) g?C?m 2?y-1, and the region may turn into a carbon source to the atmosphere at -53.3 ( 66.8 to -41.2) g?C?m-2?y-1 (negative indicates source), depending on the level of warming. Peatland ecosystems show a higher vulnerability than nonpeatland ecosystems, as indicated by the ratio of their soil carbon density changes (ranging from 3.9 to 5.8). This is primarily due to larger peatlands carbon stocks and more dramatic responses of their aerobic and anaerobic decompositions in comparison with nonpeatland ecosystems under future climate conditions. Peatland and nonpeatland soils in the PMFB may lose up to 0.4 (0.32-0.52) Pg?C by AD 2100 with the largest loss from palm swamp. The carbon-dense Amazonian peatland may switch from a current carbon sink into a source in the 21st century. PMID- 30455321 TI - Correction. PMID- 30455320 TI - Single nucleotide polymorphisms alter kinase anchoring and the subcellular targeting of A-kinase anchoring proteins. AB - A-kinase anchoring proteins (AKAPs) shape second-messenger signaling responses by constraining protein kinase A (PKA) at precise intracellular locations. A defining feature of AKAPs is a helical region that binds to regulatory subunits (RII) of PKA. Mining patient-derived databases has identified 42 nonsynonymous SNPs in the PKA-anchoring helices of five AKAPs. Solid-phase RII binding assays confirmed that 21 of these amino acid substitutions disrupt PKA anchoring. The most deleterious side-chain modifications are situated toward C-termini of AKAP helices. More extensive analysis was conducted on a valine-to-methionine variant in the PKA-anchoring helix of AKAP18. Molecular modeling indicates that additional density provided by methionine at position 282 in the AKAP18gamma isoform deflects the pitch of the helical anchoring surface outward by 6.6 degrees . Fluorescence polarization measurements show that this subtle topological change reduces RII-binding affinity 8.8-fold and impairs cAMP responsive potentiation of L-type Ca2+ currents in situ. Live-cell imaging of AKAP18gamma V282M-GFP adducts led to the unexpected discovery that loss of PKA anchoring promotes nuclear accumulation of this polymorphic variant. Targeting proceeds via a mechanism whereby association with the PKA holoenzyme masks a polybasic nuclear localization signal on the anchoring protein. This led to the discovery of AKAP18epsilon: an exclusively nuclear isoform that lacks a PKA anchoring helix. Enzyme-mediated proximity-proteomics reveal that compartment selective variants of AKAP18 associate with distinct binding partners. Thus, naturally occurring PKA-anchoring-defective AKAP variants not only perturb dissemination of local second-messenger responses, but also may influence the intracellular distribution of certain AKAP18 isoforms. PMID- 30455322 TI - Blood Pressure Goals in Patients with Chronic Kidney Disease: A Review of Evidence and Guidelines. AB - Hypertension affects the vast majority of patients with CKD and increases the risk of cardiovascular disease, ESKD, and death. Over the past decade, a number of hypertension guidelines have been published with varying recommendations for BP goals in patients with CKD. Most recently, the American College of Cardiology/American Heart Association 2017 hypertension guidelines set a BP goal of <130/80 mm Hg for patients with CKD and others at elevated cardiovascular risk. These guidelines were heavily influenced by the landmark Systolic Blood Pressure Intervention Trial (SPRINT), which documented that an intensive BP goal to a systolic BP <120 mm Hg decreased the risk of cardiovascular disease and mortality in nondiabetic adults at high cardiovascular risk, many of whom had CKD; the intensive BP goal did not retard CKD progression. It is noteworthy that SPRINT measured BP with automated devices (5-minute wait period, average of three readings) often without observers, a technique that potentially results in BP values that are lower than what is typically measured in the office. Still, results from SPRINT along with long-term follow-up data from the Modification of Diet in Renal Disease and the African American Study of Kidney Disease and Hypertension suggest that a BP goal <130/80 mm Hg will reduce mortality in patients with CKD. Unfortunately, data are more limited in patients with diabetes or stage 4-5 CKD. Increased adverse events, including electrolyte abnormalities and decreased eGFR, necessitate careful laboratory monitoring. In conclusion, a BP goal of <130/80 is a reasonable, evidence-based BP goal in patients with CKD. Implementation of this intensive BP target will require increased attention to measuring BP accurately, assessing patient preferences and concurrent medical conditions, and monitoring for adverse effects of therapy. PMID- 30455323 TI - Medicare's New Prospective Payment System on Facility Provision of Peritoneal Dialysis. AB - BACKGROUND AND OBJECTIVES: Peritoneal dialysis is a self-administered, home-based treatment for ESKD associated with equivalent mortality, higher quality of life, and lower costs compared with hemodialysis. In 2011, Medicare implemented a comprehensive prospective payment system that makes a single payment for all dialysis, medication, and ancillary services. We examined whether the prospective payment system increased dialysis facility provision of peritoneal dialysis services and whether changes in peritoneal dialysis provision were more common among dialysis facilities that are chain affiliated, located in nonurban areas, and in regions with high dialysis market competition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a longitudinal retrospective cohort study of n=6433 United States nonfederal dialysis facilities before (2006-2010) and after (2011-2013) the prospective payment system using data from the US Renal Data System, Medicare, and Area Health Resource Files. The outcomes of interest were a dichotomous indicator of peritoneal dialysis service availability and a discrete count variable of dialysis facility peritoneal dialysis program size defined as the annual number of patients on peritoneal dialysis in a facility. We used general estimating equation models to examine changes in peritoneal dialysis service offerings and peritoneal dialysis program size by a pre- versus post prospective payment system effect and whether changes differed by chain affiliation, urban location, facility size, or market competition, adjusting for 1-year lagged facility-, patient with ESKD-, and region-level demographic characteristics. RESULTS: We found a modest increase in observed facility provision of peritoneal dialysis and peritoneal dialysis program size after the prospective payment system (36% and 5.7 patients in 2006 to 42% and 6.9 patients in 2013, respectively). There was a positive association of the prospective payment system with peritoneal dialysis provision (odds ratio, 1.20; 95% confidence interval, 1.13 to 1.18) and PD program size (incidence rate ratio, 1.27; 95% confidence interval, 1.22 to 1.33). Post-prospective payment system change in peritoneal dialysis provision was greater among nonurban (P<0.001), chain-affiliated (P=0.002), and larger-sized facilities (P<0.001), and there were higher rates of peritoneal dialysis program size growth in nonurban facilities (P<0.001). CONCLUSIONS: Medicare's 2011 prospective payment system was associated with more facilities' availability of peritoneal dialysis and modest growth in facility peritoneal dialysis program size. PODCAST: This article contains a podcast at https://www.asn online.org/media/podcast/CJASN/2018_11_19_CJASNPodcast_18_12_.mp3. PMID- 30455324 TI - A cell separation checkpoint that enforces the proper order of late cytokinetic events. AB - Eukaryotic cell division requires dependency relationships in which late processes commence only after early ones are appropriately completed. We have discovered a system that blocks late events of cytokinesis until early ones are successfully accomplished. In budding yeast, cytokinetic actomyosin ring contraction and membrane ingression are coupled with deposition of an extracellular septum that is selectively degraded in its primary septum immediately after its completion by secreted enzymes. We find this secretion event is linked to septum completion and forestalled when the process is slowed. Delay of septum degradation requires Fir1, an intrinsically disordered protein localized to the cytokinesis site that is degraded upon septum completion but stabilized when septation is aberrant. Fir1 protects cytokinesis in part by inhibiting a separation-specific exocytosis function of the NDR/LATS kinase Cbk1, a key component of "hippo" signaling that induces mother-daughter separation. We term this system enforcement of cytokinesis order, a checkpoint ensuring proper temporal sequence of mechanistically incompatible processes of cytokinesis. PMID- 30455325 TI - Trajectory of Excess Medical Expenditures 10 Years Before and After Diabetes Diagnosis Among U.S. Adults Aged 25-64 Years, 2001-2013. AB - OBJECTIVE: We assessed the excess medical expenditures for adults newly diagnosed with diabetes, for up to 10 years before and after diabetes diagnosis. RESEARCH DESIGN AND METHODS: Using the 2001-2013 MarketScan data, we identified people with newly diagnosed diabetes among adults aged 25-64 years (diabetes cohort) and matched them with people who did not have diagnosed diabetes (control cohort) using 1:1 propensity score matching. We followed these two cohorts up to +/-10 years from the index date, with annual matched cohort sizes ranging from 3,922 to 39,726 individuals. We estimated the yearly and cumulative excess medical expenditures of the diabetes cohorts before and after the diagnosis of diabetes. RESULTS: The per-capita annual total excess medical expenditures for the diabetes cohort was higher for the entire 10 years prior to their index date, ranging between $1,043 in year -10 and $4,492 in year -1. Excess expenditure spiked in the index year, year 1 ($8,109), declined in year 2, and then increased steadily, ranging from $4,261 to $6,162 in years 2-10. The cumulative excess expenditure for the diabetes cohort during the entire 20 years of follow-up was $69,177 ($18,732 before and $50,445 after diagnosis). CONCLUSIONS: People diagnosed with diabetes had higher medical expenditures compared with their counterparts, not only after diagnosis, but also up to 10 years prior to diagnosis. Managing risk factors for type 2 diabetes and cardiovascular disease before diagnosis, and for diabetes-related complications after diagnosis, could alleviate medical expenditure in people with diabetes. PMID- 30455326 TI - Factors Contributing to Increases in Diabetes-Related Preventable Hospitalization Costs Among U.S. Adults During 2001-2014. AB - OBJECTIVE: To examine changes in diabetes-related preventable hospitalization costs and to determine the contribution of each underlying factor to these changes. RESEARCH DESIGN AND METHODS: We used data from the 2001-2014 U.S. National Inpatient Sample for adults (>=18 years old) to estimate the trends in hospitalization costs (2014 USD) in total and by condition (short-term complications, long-term complications, uncontrolled diabetes, and lower extremity amputation). Using regression and growth models, we estimated the relative contribution of following underlying factors: total number of hospitalizations, rate of hospitalization, the number of people with diabetes, mean cost per admission, length of stay, and cost per day. RESULTS: During 2001 2014, the estimated total cost of diabetes-related preventable hospitalizations increased annually by 1.6% (92.9 million USD; P < 0.001). Of this 1.6% increase, 75% (1.2%) was due to the increase in the number of hospitalizations, which is a result of a 3.8% increase in diabetes population and a 2.6% decrease in the hospitalization rate, and 25% (0.4%) was due to the increase in cost per admission, for a net result of a 1.6% increase in cost per day and a 1.3% decline in mean length of stay. By component, the cost of short-term complications, lower extremity amputations, and long-term complications increased annually by 4.2, 1.9, and 1.5%, respectively, while the cost of uncontrolled diabetes declined annually by 2.6%. CONCLUSIONS: The total cost of diabetes-related preventable hospitalizations had been increasing during 2001-2014, mainly resulting from increases in number of people with diabetes and cost per hospitalization day. The underlying factors identified in our study could lead to efforts that may lower future hospitalization costs. PMID- 30455327 TI - Development and Validation of a Simple Hip Fracture Risk Prediction Tool for Type 2 Diabetes: The Fremantle Diabetes Study Phase I. AB - OBJECTIVE: To develop a type 2 diabetes hip fracture risk tool in community-based patients, to validate it in an independent cohort, and to compare its performance against the only published prediction equation to include type 2 diabetes as a risk factor (QFracture). RESEARCH DESIGN AND METHODS: Hip fracture hospitalizations in 1,251 participants with type 2 diabetes aged 40-89 years from the longitudinal Fremantle Diabetes Study Phase I (FDS1) were ascertained between entry (1993-1996) and end-2012. Competing risk regression modeling determined independent predictors of time to first fracture over 10 years and the coefficients incorporated in a risk model. The model was validated in 286 participants with type 2 diabetes from the Busselton Health Study (BHS). RESULTS: Fifty FDS1 participants (4.0%) experienced a first hip fracture during 10,306 person-years of follow-up. Independent predictors of fracture were older age, female sex, lower BMI, peripheral sensory neuropathy, and estimated glomerular filtration rate <45 mL/min/1.73 m2. The model-predicted mean 10-year incident fracture risk was 3.3% with good discrimination, calibration, and accuracy. For a 3% cutoff, sensitivity was 76.0%, specificity 71.9%, positive predictive value (PPV) 10.1%, and negative predictive value (NPV) 98.6%. Model performance in the small BHS sample was also good (sensitivity 66.7%, specificity 79.8%, PPV 6.2%, and NPV 99.2%). QFracture performed well in FDS1 but required availability of 25 variables. CONCLUSIONS: The FDS1 hip fracture risk equation is a simple validated adjunct to type 2 diabetes management that uses variables that are readily available in routine care. PMID- 30455328 TI - Postpregnancy BMI in the Progression From Hypertensive Disorders of Pregnancy to Type 2 Diabetes. AB - OBJECTIVE: To study the extent to which BMI after pregnancy adds to the elevated risk of postpregnancy type 2 diabetes in women with a history of hypertensive disorders of pregnancy (HDP) (preeclampsia or gestational hypertension). RESEARCH DESIGN AND METHODS: We used data from the Nurses' Health Study II, a prospective cohort study. In women aged 45-54 years without prior gestational diabetes mellitus, we investigated the interaction between BMI and HDP history on the risk of type 2 diabetes. For clinical and public health relevance, we focused on additive interaction. The main outcome measure was the relative excess risk due to interaction calculated from multivariable Cox proportional hazards models using normal weight as the reference group. RESULTS: In total, 6,563 (11.7%) of 56,159 participants had a history of HDP and 1,341 women developed type 2 diabetes during 436,333 person-years. BMI was a strong risk factor for type 2 diabetes regardless of HDP history. However, there was evidence of an additive interaction between BMI and HDP for the risk of type 2 diabetes (P = 0.004). The attributable proportion of risk due to the interaction ranged from 0.12 (95% CI 0.22, 0.46) in women who were overweight to 0.36 (95% CI 0.13, 0.59) in women with obesity class I. CONCLUSIONS: Maintaining a healthy weight may be of even greater importance in women with a history of HDP, compared with other women with a history of only normotensive pregnancies, to reduce midlife risk of type 2 diabetes. PMID- 30455331 TI - CKD273 Enables Efficient Prediction of Diabetic Nephropathy in Nonalbuminuric Patients. PMID- 30455330 TI - Plasma Fucosylated Glycans and C-Reactive Protein As Biomarkers of HNF1A-MODY in Young Adult-Onset Nonautoimmune Diabetes. AB - OBJECTIVE: Maturity-onset diabetes of the young (MODY) due to variants in HNF1A is the commonest type of monogenic diabetes. Frequent misdiagnosis results in missed opportunity to use sulfonylureas as first-line treatment. A nongenetic biomarker could improve selection of subjects for genetic testing and increase diagnosis rates. We previously reported that plasma levels of antennary fucosylated N-glycans and hs-CRP are reduced in individuals with HNF1A-MODY. In this study, we examined the potential use of N-glycans and hs-CRP in discriminating individuals with damaging HNF1A alleles from those without HNF1A variants in an unselected population of young adults with nonautoimmune diabetes. RESEARCH DESIGN AND METHODS: We analyzed the plasma N-glycan profile, measured hs CRP, and sequenced HNF1A in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare HNF1A variants was performed. RESULTS: We identified 29 individuals harboring 25 rare HNF1A alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated N-glycans and hs-CRP were able to differentiate subjects with damaging HNF1A alleles from those without rare HNF1A alleles. Glycan GP30 had a receiver operating characteristic curve area under the curve (AUC) of 0.90 (88% sensitivity, 80% specificity, cutoff 0.70%), whereas hs-CRP had an AUC of 0.83 (88% sensitivity, 69% specificity, cutoff 0.81 mg/L). CONCLUSIONS: Half of rare HNF1A sequence variants do not cause MODY. N-glycan profile and hs-CRP could both be used as tools, alone or as adjuncts to existing pathways, for identifying individuals at high risk of carrying a damaging HNF1A allele. PMID- 30455332 TI - Plasma Glucose Level as a Predictor of In-Hospital Mortality in Patients at an Emergency Room: A Retrospective Cohort Study. PMID- 30455333 TI - Variations in Risk of End-Stage Renal Disease and Risk of Mortality in an International Study of Patients With Type 1 Diabetes and Advanced Nephropathy. AB - OBJECTIVE: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes. PMID- 30455334 TI - Adipose Tissue Insulin Resistance in Youth on the Spectrum From Normal Weight to Obese and From Normal Glucose Tolerance to Impaired Glucose Tolerance to Type 2 Diabetes. AB - OBJECTIVE: Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin * free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. RESEARCH DESIGN AND METHODS: A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. RESULTS: Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal weight peers (all P < 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P < 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 MUU/mL * mmol/L for determining dysglycemia with 80% predictive power. CONCLUSIONS: Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes, and its progression or reversal with intervention strategies. PMID- 30455335 TI - Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial. AB - OBJECTIVE: To determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT). RESEARCH DESIGN AND METHODS: This post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 +/- 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 +/- 2.0%) of 11.5 +/- 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control. RESULTS: The rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012). CONCLUSIONS: Severe hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all cause mortality after severe hypoglycemia. PMID- 30455336 TI - Optimal Insulin Correction Factor in Post-High-Intensity Exercise Hyperglycemia in Adults With Type 1 Diabetes: The FIT Study. AB - OBJECTIVE: Postexercise hyperglycemia, following high-intensity interval training (HIIT) in patients with type 1 diabetes (T1D), is largely underrecognized by the clinical community and generally undertreated. The aim of this study was to compare four multipliers of an individual's insulin correction factor (ICF) to treat post-HIIT hyperglycemia. RESEARCH DESIGN AND METHODS: The FIT study had a randomized, crossover design in physically active subjects with T1D (mean +/- SD age 34.9 +/- 10.1 years, BMI 25.5 +/- 2.5 kg/m2, and HbA1c 7.2 +/- 0.9%) using multiple daily injections. Following an 8-week optimization period, with 300 units/mL insulin glargine used as the basal insulin, subjects performed four weekly sessions of 25 min of HIIT. If hyperglycemia (>8.0 mmol/L) resulted, subjects received a bolus insulin correction 15 min post-HIIT, based on their own ICF, adjusted by one of four multipliers: 0, 50, 100, or 150%. RESULTS: Seventeen subjects completed 71 exercise trials, of which 64 (90%) resulted in hyperglycemia. At 40 min postexercise, plasma glucose (PG) increased from mean +/ SD 8.8 +/- 1.0 mmol/L at baseline to 12.7 +/- 2.4 mmol/L (increase of 3.8 +/- 1.5 mmol/L). After correction, adjusted mean +/- SE PG was significantly reduced for the 50% (-2.3 +/- 0.8 mmol/L, P < 0.01), 100% (-4.7 +/- 0.8 mmol/L, P < 0.001), and 150% (-5.3 +/- 0.8 mmol/L, P < 0.001) arms but had increased further in the 0% correction arm. Both the 100 and 150% corrections were more effective than the 50% correction (P < 0.01 and P < 0.001, respectively) but were not different from each other. Hypoglycemia was rare. CONCLUSIONS: In post-HIIT hyperglycemia, correction based on a patient's usual ICF is safe and effective. Optimal PG reduction, with minimal hypoglycemia, occurred in the 100 and 150% correction arms. PMID- 30455329 TI - The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test: Forerunner of Heightened Glycemic Failure Rates and Accelerated Decline in beta Cell Function in TODAY. AB - OBJECTIVE: Obese youth without diabetes with monophasic oral glucose tolerance test (OGTT) glucose-response curves have lower insulin sensitivity (IS) and impaired beta-cell function compared with those with biphasic curves. The OGTT glucose response curve has not been studied in youth-onset type 2 diabetes. Here we test the hypothesis that the OGTT glucose response curve at randomization in youth in the TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study forecasts heightened glycemic failure rates and accelerated decline in beta-cell function. RESEARCH DESIGN AND METHODS: OGTTs (n = 662) performed at randomization were categorized as monophasic, biphasic, or incessant increase. Demographics, IS (1/fasting insulin), C-peptide index (?C30/?G30), and beta-cell function relative to IS (oral disposition index [oDI]) were compared among the three groups. RESULTS: At randomization, 21.7% had incessant increase, 68.6% monophasic, and 9.7% biphasic glucose response curves. The incessant increase group had similar IS, but significantly lower C-peptide index and lower oDI, despite similar diabetes duration, compared with the other two groups. Glycemic failure rates were higher in the incessant increase group (58.3%) versus the monophasic group (42.3%) versus biphasic group (39.1%) (P < 0.0001). The 6-month decline in C-peptide index (32.8% vs. 18.1% vs. 13.2%) and oDI (32.2% vs. 11.6% vs. 9.1%) was greatest in incessant increase versus monophasic and biphasic with no difference in IS. CONCLUSIONS: In the TODAY study cohort, an incessant increase in the OGTT glucose response curve at randomization reflects reduced beta-cell function and foretells increased glycemic failure rates with accelerated deterioration in beta-cell function independent of diabetes duration and treatment assignment compared with monophasic and biphasic curves. The shape of the OGTT glucose response curve could be a metabolic biomarker prognosticating the response to therapy in youth with type 2 diabetes. PMID- 30455337 TI - HbA1c, Insulin Resistance, and beta-Cell Function in Relation to Cognitive Function in Type 2 Diabetes: The CAROLINA Cognition Substudy. PMID- 30455338 TI - Improvement in Neuropathy Outcomes With Normalizing HbA1c in Patients With Type 2 Diabetes. AB - OBJECTIVE: To investigate the impact of normalizing HbA1c by extensive HbA1c control (EHC) on neuropathy outcome measures (NOMs), nephropathy, and retinopathy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Detailed clinical and neurological examinations were performed in two cohorts of 38 patients with uncontrolled type 2 diabetes patients (HbA1c 9.6% [81.4 mmol/mol]) at baseline and after glycemic control (GC) with or without EHC by diet restriction and hypoglycemic agents over 4 years along with 48 control subjects with normal glucose tolerance (NGT) and 34 subjects with impaired glucose tolerance (IGT) only at baseline. EHC patients, control subjects, and subjects with IGT underwent oral glucose tolerance tests. Glycemic variability (GV) was evaluated by SD and coefficient of variation of monthly measured HbA1c levels and casual plasma glucose. RESULTS: In the EHC cohort, HbA1c levels over 4.3 years and the last 2 years improved to 6.1% (43.2 mmol/mol) and 5.8% (39.9 mmol/mol) with 7.3 kg body wt reduction, and 50 and 28.9% of patients returned to IGT and NGT, respectively, at end point. Baseline neurophysiological and corneal nerve fiber (CNF) measures were impaired in patients. Normalized HbA1c with EHC improved neurophysiological and CNF measures to be similar for those for IGT, while GC without EHC (mean HbA1c level 7.0% [53.5 mmol/mol]) improved only vibration perception. The mean normalized HbA1c levels by EHC determined NOM improvements. The high GV and baseline HbA1c levels compromised NOMs. Albumin excretion rate significantly decreased, while retinopathy severity and frequency insignificantly worsened on EHC. CONCLUSIONS: Normalizing HbA1c in type 2 diabetes of short duration improves microvascular complications including neuropathy and nephropathy more effectively than standard GC but not retinopathy. PMID- 30455339 TI - Impact of the gut microbiome in cardiovascular and autoimmune diseases. AB - The gut microbiome functions like an endocrine organ, generating enzymes and bioactive metabolites, which affect host physiology. In addition metabolism independent processes like impaired intestinal barrier function may result in bacterial translocation and an increased inflammation. Specific microbe associated molecular patterns (MAMPs) have been detected that induce immune activation via cognate pattern-recognition receptors on host immune cells, with subsequent consequences on inflammatory-induced endothelial dysfunction. Alterations in intestinal microbial and metabolic composition play an important role in human health and disease, including cardiovascular and autoimmune diseases. Changes in the composition of gut microbiota (dysbiosis) are linked to chronic inflammation, thrombosis, atherogenesis, chronic heart, and kidney disease, as well as to autoimmune diseases like systemic lupus erythematodes. Although non-selective approaches that broadly alter microbial community structure, such as prebiotics, probiotics, and fecal microbial transplantation, may have some promise, targeting defined microbial pathways and adjacent host immune responses may be the ultimate scientific goal. PMID- 30455340 TI - Marijuana and Tobacco Coexposure in Hospitalized Children. AB - BACKGROUND: The impact of secondhand marijuana smoke exposure on children is unknown. New methods allow for the detection of marijuana smoke exposure in children. METHODS: We studied children who were hospitalized in Colorado and had a parent participating in a smoking cessation study; all children had urine samples remaining from the original study as well as consent for future research. Parents completed a survey and urine samples were analyzed for cotinine and marijuana metabolites, including 11-hydroxy-Delta9-tetrahydrocannabinol (COOH THC), by using liquid chromatography-tandem mass spectrometry. RESULTS: The median age of the children was 6.0 years (range 0-17 years); 57% were boys. Half (55%) were white, 12% were African American, and 33% were of another race; 39% identified as Hispanic. Approximately 46% had detectable COOH-THC, and 11% had detectable THC. Of those with detectable THC, 3 were teenagers, and 6 were <8 years of age. There were no significant differences in urinary COOH-THC concentrations by age, sex, race and/or ethnicity, or socioeconomic status. Children with positive results for COOH-THC were more likely to have parents who use marijuana daily, smoke marijuana versus other forms of use, use daily in the home, and smoke marijuana in another room if the children are around compared with smoking outside. CONCLUSIONS: Approximately half of the children who qualified for our study had biological evidence of exposure to marijuana. Researchers in studies such as this provide valuable data on secondhand exposure to children from parents using tobacco and marijuana and can inform public health policies to reduce harm. PMID- 30455341 TI - The Role of Pediatricians in Global Health. AB - Ninety percent of the world's children live in low- and middle-income countries, where barriers to health contribute to significant child morbidity and mortality. The American Academy of Pediatrics is dedicated to the health and well-being of all children. To fulfill this promise, this policy statement defines the role of the pediatrician in global health and provides a specific set of recommendations directed to all pediatricians, emphasizing the importance of global health as an integral function of the profession of pediatrics. PMID- 30455342 TI - Management of Neonates Born at >=35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. AB - The incidence of neonatal early-onset sepsis (EOS) has declined substantially over the last 2 decades, primarily because of the implementation of evidence based intrapartum antimicrobial therapy. However, EOS remains a serious and potentially fatal illness. Laboratory tests alone are neither sensitive nor specific enough to guide EOS management decisions. Maternal and infant clinical characteristics can help identify newborn infants who are at risk and guide the administration of empirical antibiotic therapy. The incidence of EOS, the prevalence and implications of established risk factors, the predictive value of commonly used laboratory tests, and the uncertainties in the risk/benefit balance of antibiotic exposures all vary significantly with gestational age at birth. Our purpose in this clinical report is to provide a summary of the current epidemiology of neonatal sepsis among infants born at >=35 0/7 weeks' gestation and a framework for the development of evidence-based approaches to sepsis risk assessment among these infants. PMID- 30455343 TI - Targeted Reforms in Health Care Financing to Improve the Care of Adolescents and Young Adults. AB - Significant changes have occurred in the commercial and government insurance marketplace after the passage of 2 federal legislation acts, the Patient Protection and Affordable Care Act of 2010 and the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008. Despite the potential these 2 acts held to improve the health care of adolescents and young adults (AYAs), including the financing of care, there are barriers to achieving this goal. In the first quarter of 2016, 13.7% of individuals 18 to 24 years of age still lacked health insurance. Limitations in the scope of benefits coverage and inadequate provider payment can curtail access to health care for AYAs, particularly care related to sexual and reproductive health and mental and behavioral health. Some health plans impose financial barriers to access because they require families to absorb high cost-sharing expenses (eg, deductibles, copayments, and coinsurance). Finally, challenges of confidentiality inherent in the billing and insurance claim practices of some health insurance plans can discourage access to health care in the absence of other obstacles and interfere with provision of confidential care. This policy statement summarizes the current state of impediments that AYA, including those with special health care needs, face in accessing timely and appropriate health care and that providers face in serving these patients. These impediments include limited scope of benefits, high cost sharing, inadequate provider payment, and insufficient confidentiality protections. With this statement, we aim to improve both access to health care by AYAs and providers' delivery of developmentally appropriate health care for these patients through the presentation of an overview of the issues, specific recommendations for reform of health care financing for AYAs, and practical actions that pediatricians and other providers can take to advocate for appropriate payments for providing health care to AYAs. PMID- 30455344 TI - Management of Neonates Born at <=34 6/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. AB - Early-onset sepsis (EOS) remains a serious and often fatal illness among infants born preterm, particularly among newborn infants of the lowest gestational age. Currently, most preterm infants with very low birth weight are treated empirically with antibiotics for risk of EOS, often for prolonged periods, in the absence of a culture-confirmed infection. Retrospective studies have revealed that antibiotic exposures after birth are associated with multiple subsequent poor outcomes among preterm infants, making the risk/benefit balance of these antibiotic treatments uncertain. Gestational age is the strongest single predictor of EOS, and the majority of preterm births occur in the setting of other factors associated with risk of EOS, making it difficult to apply risk stratification strategies to preterm infants. Laboratory tests alone have a poor predictive value in preterm EOS. Delivery characteristics of extremely preterm infants present an opportunity to identify those with a lower risk of EOS and may inform decisions to initiate or extend antibiotic therapies. Our purpose for this clinical report is to provide a summary of the current epidemiology of preterm neonatal sepsis and provide guidance for the development of evidence-based approaches to sepsis risk assessment among preterm newborn infants. PMID- 30455345 TI - The Public Health Impact of Parent-Reported Childhood Food Allergies in the United States. AB - : : media-1vid110.1542/5840360268001PEDS-VA_2018-1235Video Abstract BACKGROUND: Childhood food allergy (FA) is a life-threatening chronic condition that substantially impairs quality of life. This large, population-based survey estimates childhood FA prevalence and severity of all major allergenic foods. Detailed allergen-specific information was also collected regarding FA management and health care use. METHODS: A survey was administered to US households between 2015 and 2016, obtaining parent-proxy responses for 38 408 children. Prevalence estimates were based on responses from NORC at the University of Chicago's nationally representative, probability-based AmeriSpeak Panel (51% completion rate), which were augmented by nonprobability-based responses via calibration weighting to increase precision. Prevalence was estimated via weighted proportions. Multiple logistic regression models were used to evaluate FA predictors. RESULTS: Overall, estimated current FA prevalence was 7.6% (95% confidence interval: 7.1%-8.1%) after excluding 4% of children whose parent reported FA reaction history was inconsistent with immunoglobulin E-mediated FA. The most prevalent allergens were peanut (2.2%), milk (1.9%), shellfish (1.3%), and tree nut (1.2%). Among food-allergic children, 42.3% reported >=1 severe FA and 39.9% reported multiple FA. Furthermore, 19.0% reported >=1 FA-related emergency department visit in the previous year and 42.0% reported >=1 lifetime FA-related emergency department visit, whereas 40.7% had a current epinephrine autoinjector prescription. Prevalence rates were higher among African American children and children with atopic comorbidities. CONCLUSIONS: FA is a major public health concern, affecting ~8% of US children. However, >11% of children were perceived as food-allergic, suggesting that the perceived disease burden may be greater than previously acknowledged. PMID- 30455346 TI - Oligopeptide-binding protein from nontypeable Haemophilus influenzae has ligand specific sites to accommodate peptides and heme in the binding pocket. AB - In nontypeable Haemophilus influenzae (NTHi), the oligopeptide-binding protein OppA serves as the substrate-binding protein (SBP) responsible for peptide import. As a heme auxotroph, NTHi also uses host hemoproteins as an iron source. OppA is a member of the Cluster C SBP family, and unlike other SBP families, some members recognize two distinctly different substrates. DppA (dipeptide), MppA (murein tripeptide), and SapA (antimicrobial peptides) are Cluster C proteins known to also transport heme. However, the ability of OppA to participate in heme binding and how Cluster C proteins accommodate these heme and peptide substrates are unclear. Here, we solved the crystal structure of nthiOppA in complex with hydrophobic peptides of various sizes. The hexapeptide complex revealed the flexibility of nthiOppA's binding cavity to expand and accommodate a longer peptide substrate while maintaining similar protein-peptide interactions used to bind smaller peptides. Additionally, we observed the multifunctional heme binding of nthiOppA, and using surface plasmon resonance (SPR), we established heme specificity and affinity of the four Cluster C proteins in NTHi. Ligand-docking studies predicted a distinct heme-specific cleft in the nthiOppA substrate binding pocket, and SPR competition assays confirmed that heme does not directly compete with peptides in this pocket. Additionally, we noted that the individual nthiOppA domains differentially contribute to substrate binding, with one domain playing a dominant role in heme binding and the other in peptide binding. Our results identified multi-substrate specificity of nthiOppA and distinguished the roles of NTHi Cluster C proteins in the heme-uptake pathway of this bacterial pathogen. PMID- 30455347 TI - RORgamma Regulates the NLRP3 Inflammasome. AB - RAR-related orphan receptor g(RORg) is a nuclear receptor that plays an essential role in the development of T helper 17 (TH17) cells of the adaptive immune system. The NLRP3 inflammasome is a component of the innate immune system that processes interleukin (IL)-1beta into a mature cytokine. Elevated activity of the NLRP3 inflammasome contributes to the progression of an array of inflammatory diseases. Bone marrow derived macrophages (BMDMs) isolated from RORgnull mice displayed reduced capacity to secrete IL-1band they also displayed a reduction in Nlrp3and Il1bgene expression. Examination of the promoters of the Il1band Nlrp3genes revealed multiple putative ROR response elements (ROREs) that were occupied by RORg. RORginverse agonists were effective inhibitors of the inflammasome. RORginverse agonists suppressed lipopolysaccharide (LPS)/ATP stimulated IL-1bsecretion and expression of Il1band Nlrp3in BMDMs. Additionally, the ability of the RORginverse agonists to suppress IL-1bsecretion was lost in Nlrp3null macrophages. The potential for targeting the NLRP3 inflammasome in vivo using RORginverse agonists was examined in two models: LPS induced sepsis and fulminant hepatitis. Pharmacological inhibition of RORg activity reduced plasma IL-1beta as well as IL-1bproduction by peritoneal macrophages in a model of LPS induced sepsis. Additionally, RORg inverse agonists reduced mortality in a LPS/D galactosamine induced fulminant hepatitis mouse model. These results illustrate a major role for RORgin regulation of innate immunity via modulation of NLRP3 inflammasome activity. Furthermore, these data suggest that inhibiting the NLRP3 inflammasome with RORginverse agonists may be an effective method to treat NLRP3 associated diseases. PMID- 30455348 TI - Glucosamine improves survival in a mouse model of sepsis and attenuates sepsis induced lung injury and inflammation. AB - The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish. GlcN pretreatment improved survival in the cecal ligation and puncture (CLP)-induced sepsis mouse model and attenuated LPS-induced septic lung injury and systemic inflammation. GlcN suppressed LPS-induced M1-specific but not M2-specific gene expression. Furthermore, increased expressions of inflammatory genes in visceral tissue of LPS-injected zebrafish were suppressed by GlcN. GlcN suppressed LPS-induced activation of MAPKs and NF-kappaB in lung tissue. LPS triggered a reduction in O-GlcNAc levels in nucleocytoplasmic proteins of lung, liver and spleen after 1 day, which returned to normal levels on days 3. GlcN inhibited LPS-induced O-GlcNAc downregulation in mouse lung and visceral tissue of zebrafish. Furthermore, O-GlcNAcase (OGA) level was increased by LPS, which were suppressed by GlcN in mouse and zebrafish. OGA inhibitors suppressed LPS induced expression of inflammatory genes in RAW264.7 cells and the visceral tissue of zebrafish. Stable knockdown of OGA via shRNA led to increased iNOS expression in response to LPS with or without GlcN in RAW264.7 cells. Overall, our results demonstrate a protective effect of GlcN on sepsis potentially through modulation of O-GlcNAcylation of nucleocytoplasmic proteins. PMID- 30455349 TI - Non-cryogenic structure of a chloride pump provides crucial clues to temperature dependent channel transport efficiency. AB - Non-cryogenic protein structures determined at ambient temperature may disclose significant information about protein activity. Chloride-pumping rhodopsin (ClR) exhibits a trend to hyperactivity induced by a change in the photoreaction rate due to a gradual decrease in temperature. Here, to track the structural changes that explain the differences in CIR activity resulting from these temperature changes, we used serial femtosecond X-ray crystallography (SFX) with an X-ray free electron laser (XFEL) to determine the non-cryogenic structure of ClR at a resolution of 1.85 A, and compared this structure with a cryogenic ClR structure obtained with synchrotron X-ray crystallography. The XFEL-derived ClR structure revealed that the all-trans retinal (ATR) region and positions of two coordinated chloride ions slightly differed from those of the synchrotron-derived structure. Moreover, the XFEL structure enabled identification of one additional water molecule forming a hydrogen bond network with a chloride ion. Analysis of the channel cavity and a difference distance matrix plot (DDMP) clearly revealed additional structural differences. B-factor information obtained from the non cryogenic structure supported a motility change on the residual main- and sidechains as well as of chloride and water molecules due to temperature effects. Our results indicate that non-cryogenic structures and time-resolved XFEL experiments could contribute to a better understanding of the chloride-pumping mechanism of ClR and other ion pumps. PMID- 30455350 TI - Exquisite ligand stereoselectivity of a Drosophila juvenile hormone receptor contrasts with its broad agonist repertoire. AB - The sesquiterpenoid juvenile hormone (JH) is vital to insect development and reproduction. Intracellular JH receptors have recently been established as basic helix-loop-helix transcription factor (bHLH)-PAS proteins in Drosophila melanogaster known as germ cell-expressed (Gce) and its duplicate paralog, methoprene-tolerant (Met). Upon binding JH, Gce/Met activates its target genes. Insects possess multiple native JH homologs whose molecular activities remain unexplored, and diverse synthetic compounds including insecticides exert JH-like effects. How the JH receptor recognizes its ligands is unknown. To determine what structural features define an active JH receptor agonist, we tested several native JHs and their non-native geometric and optical isomers for the ability to bind the Drosophila JH receptor Gce, to induce Gce-dependent transcription, and to affect the development of the fly. Our results revealed high ligand stereoselectivity of the receptor. The geometry of the JH skeleton, dictated by two stereogenic double bonds, was the most critical feature, followed by the presence of an epoxide moiety at a terminal position. The optical isomerism at carbon C11 proved less important, even though Gce preferentially bound a natural JH enantiomer. The results of receptor-ligand binding and cell-based gene activation assays tightly correlated with the ability of different geometric JH isomers to induce gene expression and morphogenetic effects in the developing insects. Molecular modeling supported the requirement for the proper double-bond geometry of JH, which appears to be its major selective mechanism. The strict stereoselectivity of Gce towards the natural hormone contrasts with high potency of synthetic Gce agonists of disparate chemistries. PMID- 30455351 TI - Formate-nitrite transporters carrying nonprotonatable amide amino acids instead of a central histidine maintain pH-dependent transport. AB - Microbial formate-nitrite transporter-type proteins (FNT) exhibit dual transport functionality. At neutral pH, electrogenic anion currents are detectable, whereas upon acidification transport of the neutral, protonated monoacid predominates. Physiologically, FNT-mediated proton co-transport is vital when monocarboxylic acid products of the energy metabolism, such as L-lactate, are released from the cell. Accordingly, Plasmodium falciparum malaria parasites can be killed by small molecule inhibitors of PfFNT. Two opposing hypotheses on the site of substrate protonation are plausible. The proton relay mechanism postulates proton transfer from a highly conserved histidine centrally positioned in the transport path. The dielectric slide mechanism assumes decreasing acidity of substrates entering the lipophilic vestibules and protonation via the bulk water. Here, we defined the transport mechanism of the FNT from the amoebiasis parasite Entamoeba histolytica, EhFNT, and also show that BtFdhC from Bacillus thuringiensisis a functional formate transporter. Both FNTs carry a nonprotonatable amide amino acid, asparagine or glutamine, respectively, at the central histidine position. Despite having a nonprotonatable residue, EhFNT displayed the same substrate selectivity for larger monocarboxylates including L-lactate, a low substrate affinity as is typical for FNTs, and, strikingly, proton motive force-dependent transport as observed for PfFNT harboring a central histidine. These results argue against a proton relay mechanism, indicating that substrate protonation must occur outside of the central histidine region, most likely in the vestibules. Further, EhFNT is the sole annotated FNT in the Entamoeba genome suggesting that it could be a putative new drug target with similar utility as that of the malarial PfFNT. PMID- 30455352 TI - Recent advances in the structural and mechanistic aspects of Hsp70 molecular chaperones. AB - Hsp70 chaperones are central hubs of the protein quality control network and collaborate with cochaperones having a J-domain (a ~70 residue-long helical hairpin with a flexible loop and a conserved His-Pro-Asp motif required for ATP hydrolysis by Hsp70s) and also with nucleotide exchange factors to facilitate many protein-folding processes that (re)establish protein homeostasis. The Hsp70s are highly dynamic nanomachines that modulate the conformation of their substrate polypeptides by transiently binding to short, mostly hydrophobic stretches. This interaction is regulated by an intricate allosteric mechanism. The J-domain cochaperones target Hsp70 to their polypeptide substrates, and the nucleotide exchange factors regulate the lifetime of the Hsp70-substrate complexes. Significant advances in recent years are beginning to unravel the molecular mechanism of this chaperone machine and how they treat their substrate proteins. PMID- 30455353 TI - Deficiency of Cathepsin C ameliorates severity of acute pancreatitis by reduction of neutrophil elastase activation and cleavage of E-cadherin. AB - Acute pancreatitis is characterized by premature intracellular protease activation and infiltration of inflammatory cells, mainly neutrophil granulocytes and macrophages, into the organ. The lysosomal proteases cathepsin B, D and L have been identified as regulators of early zymogen activation and thus modulators of the severity of pancreatitis. Cathepsin C (CTSC, syn. Dipeptidly peptidase I) is a widely expressed, exo-cystein-protease involved in the proteolytic processing of various other lysosomal enzymes. We have studied its role in pancreatitis. We used CTSC-deleted mice and their wild-type littermates in two experimental models of pancreatitis. The mild model involved 8-hourly caerulein injections and the severe model partial duct ligation. Isolated pancreatic acini and spleen-derived leukocytes were used for ex-vivo experiments. CTSC is expressed in the pancreas and in inflammatory cells. CTSC-deletion reduced the severity of pancreatitis (more prominently in the milder model) without directly affecting intra-acinar cell trypsin activation in vitro. Absence of CTSC reduced infiltration of neutrophil granulocytes, impaired their capacity for cleaving E-cadherin in adherens junctions between acinar cells and reduced the activity of neutrophil serine proteases polymorphonuclear (neutrophil) elastase, cathepsin G, and proteinase 3 - but not neutrophil motility. Macrophage invasion was not dependent on the presence of CTSC. CTSC is a regulator and activator of various lysosomal enzymes such as CTSB, CTSD and CTSL. Its loss mitigates severity of pancreatitis not by reducing intra-acinar cell zymogen activation but by reducing infiltrationof neutrophil granulocytes into the pancreas. In this context one of its key roles is that of an activator of neutrophil elastase. PMID- 30455354 TI - Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes. AB - Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen-II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5-restricted gluten epitopes, DQ2.5-glia-alpha1a (PFPQPELPY) and DQ2.5-glia-omega1 (PFPQPEQPF). Using HLA-DQ2.5:DQ2.5-glia-alpha1a and HLA-DQ2.5:DQ2.5-glia-omega1 tetramers and single-cell alphabeta T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide:HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-alpha1a and DQ2.5-glia-omega1-reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-alpha1a (2.0 A) and DQ2.5-glia-omega1 (2.6 A). These structures disclosed that differences around the p7 residue subtly alter the neighboring sub-structure and electrostatic properties of the HLA-DQ2.5-peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide:HLA-II landscape in a human disease setting. PMID- 30455355 TI - Physiological and pathophysiological characteristics of ataxin-3 isoforms. AB - Ataxin-3 is a deubiquitinating enzyme and the affected protein in the neurodegenerative disorder Machado-Joseph disease (MJD). The ATXN3 gene is alternatively spliced, resulting in protein isoforms that differ in the number of ubiquitin-interacting motifs. Additionally, non-synonymous single nucleotide polymorphisms in ATXN3 cause amino acid changes in ataxin-3 and one of these polymorphisms introduces a premature stop codon in one isoform. Here, we examined the effects of different ataxin-3 isoforms and of the premature stop codon on ataxin-3's physiological function and on main disease mechanisms. At the physiological level, we show that alternative splicing and the premature stop codon alter ataxin-3 stability and that ataxin-3 isoforms differ in their enzymatic deubiquitination activity, subcellular distribution and interaction with other proteins. At the pathological level, we found that the expansion of the polyglutamine repeat leads to a stabilization of ataxin-3 and that ataxin-3 isoforms differ in their aggregation properties. Interestingly, we observed a functional interaction between normal and polyglutamine-expanded ATXN3 allelic variants. We found that interactions between different ATXN3 allelic variants modify the physiological and pathophysiological properties of ataxin-3. Our findings indicate that alternative splicing and interactions between different ataxin-3 isoforms affect not only major aspects of ataxin-3 function but also MJD pathogenesis. Our results stress the importance of considering isoforms of disease causing proteins and their interplay with the normal allelic variant as disease modifiers in MJD and autosomal-dominantly inherited diseases in general. PMID- 30455356 TI - Mapping multivalency in the CLIP-170-EB1 microtubule plus end complex. AB - Cytoplasmic linker protein (CLIP)4-170 is a microtubule plus-end factor that links vesicles to microtubules and recruits the dynein/dynactin complex to microtubule plus ends. CLIP-170 plus-end localization is end binding 1 (EB1) dependent. CLIP-170 contains two N-terminal cytoskeleton-associated protein glycine-rich (CAP-Gly) domains flanked by serine-rich regions. The CAP-Gly domains are known EB1-binding domains, and the serine-rich regions have also been implicated in CLIP-170's microtubule plus-end localization mechanism. However, the determinants in these serine-rich regions have not been identified. Here we elucidated multiple EB1-binding modules in the CLIP-170 N-terminal region. Using isothermal titration calorimetry and size-exclusion chromatography, we mapped and biophysically characterized these EB1-binding modules, including the two CAP-Gly domains, a bridging SxIP motif, and a unique array of divergent SxIP-like motifs located N-terminally to the first CAP-Gly domain. We found that unlike the EB1 binding mode of the CAP-Gly domain in the dynactin-associated protein p150Glued, which dually engages the EB1 C-terminal EEY motif, as well as the EB homology domain (EBHD), and sterically occludes SxIP motif binding, the CLIP-170 CAP-Gly domains engage only the EEY motif, enabling the flanking SxIP and SxIP-like motifs to bind the EBHD. These multivalent EB1-binding modules provided avidity to the CLIP-170-EB1 interaction, likely clarifying why CLIP-170 preferentially binds EB1 rather than the alpha-tubulin C-terminal EEY motif. Our finding that CLIP-170 has multiple non-CAP-Gly EB1-binding modules may explain why autoinhibition of CLIP-170 GAP-Gly domains does not fully abrogate its microtubule plus end-localization. This work expands our understanding of EB1 binding motifs and their multivalent networks. PMID- 30455358 TI - Study raises hopes of minimising risk of life threatening peanut allergy reactions. PMID- 30455357 TI - Computational approaches for the analysis of RNA-protein interactions: A primer for biologists. AB - RNA-binding proteins (RBPs) play important roles in the control of gene expression and the coordination of different layers of posttranscriptional regulation. Interactions between certain RBPs and mRNA transcripts are notoriously difficult to predict, as any given protein-RNA interaction may rely not only on RNA sequence, but also on three-dimensional RNA structures, competitive inhibition from other RBPs, and input from cellular signaling pathways. Advanced and high-throughput technologies for the identification of RNA protein interactions have come to the rescue, but the identification of binding sites and downstream functional effects of RBPs from the resulting data can be challenging. In this review, we discuss statistical inference and machine learning approaches and tools relevant for the study of RBPs and the analysis of large-scale RNA-protein interaction datasets. This primer is intended for life scientists who are interested in incorporating these tools into their own research. We begin with the demystification of regression models, as used in the analysis of next-generation sequencing data, and progress to a discussion of Hidden Markov Models, which are of particular value in analyzing crosslinking followed by immunoprecipitation (CLIP-Seq) data. We then continue with examples of machine learning techniques, such as support vector machines and gradient tree boosting. We close with a brief discussion of current trends in the field, including deep learning architectures. PMID- 30455359 TI - Onsets of progression and second treatment determine survival of patients with symptomatic Waldenstrom macroglobulinemia. AB - Few reports assess prognosis during follow-up of patients with symptomatic Waldenstrom macroglobulinemia (WM). In 121 WM patients treated between 1993 and 2016, we analyzed the prognostic role during the clinical course of the initial International Prognostic Scoring System for WM (IPSSWM). Then, we assessed onset of response, progression, and second treatment initiation coded as time-dependent covariates. High-risk IPSSWM was an adverse prognostic factor for survival after first treatment initiation (SAFTI). Nevertheless, the corresponding Dxy concordance index obtained in multiple landmark analyses decreased from 0.24 to 0.08 during the first 6 years, in accordance with a departure from the proportional hazard assumption. By contrast with onset of response (whatever its level), onset of progression and initiation of second-line treatment retained prognostic value for SAFTI (P = .02 and P = .006, respectively). These findings were confirmed in cause-specific Cox models for deaths related to WM, but not for unrelated deaths. Time to progression after first-line treatment and time to initiation of second-line treatment had no prognostic value for survival after these 2 events. These results were confirmed in an independent series of 119 patients homogeneously treated with chemoimmunotherapy. Finally, after second line and third-line treatment, onset of progression had significant prognostic value for subsequent risk of related death only. Thus, taking initial IPSSWM and delayed response to treatment into account, only onset of progression and second treatment initiation provided additional prognostic information for SAFTI. Therefore, progression-free survival or time to next treatment may be satisfactory surrogate end points of SAFTI in WM. PMID- 30455360 TI - Intima-media thickness of the common femoral artery as a marker of leg ulceration in sickle cell disease patients. AB - Leg ulceration is a debilitating chronic complication of sickle cell disease (SCD) the pathogenesis of which is yet to be fully elucidated. We hypothesized that SCD patients with histories of previous leg ulcers would have intima hyperplasia of the common femoral artery (CFA). We enrolled 44 SCD patients and 33 age-matched and sex-matched controls with hemoglobin AA. Anthropometric measurements, biochemical parameters, and sonographic intima-media thickness (IMT) of the CFA were determined. The median CFA IMT in SCD limbs with history of leg ulcers (SWLU) was 1.0 mm, whereas it was 0.7 mm in SCD limbs with no history of leg ulcer (SNLU) and 0.60 mm in controls (P < .001). Among the SNLU, 70.3% had CFA IMT <0.9 mm, whereas only 29.7% had CFA IMT >=0.9 mm. Conversely, only 20.8% of SWLU had CFA IMT <0.9 mm, whereas the remaining 79.2% had CFA IMT >=0.9 mm. All the controls had CFA IMT <0.9 mm. Binary logistic regression to determine the odds of having leg ulcer among SCD limbs with CFA IMT of >=0.9 mm yielded an odds ratio of 9, indicating that SCD limbs with CFA IMT >=0.9 mm had a 9 times greater risk of having leg ulcer compared with those with CFA IMT <0.9 mm. There is a significant increase in the CFA IMT of SCD limbs with ulcer compared with controls and SCD limbs without ulcer, suggesting that arterial vasculopathy plays a major role in the formation of these ulcers. PMID- 30455362 TI - Serum paraoxonase 1 activity is paradoxically maintained in non-alcoholic fatty liver disease despite low HDL cholesterol. AB - Non-alcoholic fatty liver disease (NAFLD) is featured by low HDL cholesterol, but activity of the HDL-associated anti-oxidative enzyme paraoxonase-1 (PON-1) remains unclear. To determine the association of PON-1 with suspected NAFLD, we measured serum enzyme activity in 7,622 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI)>=60, a proxy of NAFLD, was present in 2,083 participants (27.3%), and coincided with increased prevalence of type 2 diabetes mellitus (T2D), metabolic syndrome (MetS), (central) obesity, elevated triglycerides and low HDL cholesterol (all P<0.001). In men and women combined, serum PON-1 activity did not vary according to elevated FLI (P=0.98), whereas in men with elevated FLI PON-1 activity was increased (P=0.016). In multivariable linear regression analyses (adjusted for age, sex, T2D, MetS, alcohol use and smoking), PON-1 activity was unexpectedly associated with elevated FLI (beta=0.083, P<0.001). In a sensitivity analysis (n=5,126), which excluded subjects with positive cardiovascular history, impaired estimated glomerular filtration rate, elevated urinary albumin excretion and drug use, PON-1 activity was also independently associated with elevated FLI (beta=0.045, P=0.017). These results indicate that PON-1 is paradoxically maintained and may even be increased in NAFLD, despite inverse associations with metabolic disorders and low HDL cholesterol. PMID- 30455361 TI - NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse. AB - Acute myeloid leukemia (AML) with NPM1 mutation (NPM1 mut) defines a World Health Organization entity. Absence of minimal residual disease (MRD) following induction chemotherapy is associated with an excellent prognosis. Data are conflicting on NPM1 mut AML relapsing with wild-type NPM1 (NPM1 wt ). We analyzed 104 paired samples of NPM1 mut AML patients with relapse and identified 14/104 that relapsed with NPM1 wt AML. Blood counts at diagnosis differed significantly between patients with NPM1 mut and NPM1 wt relapse (median white blood cell count, 30 vs 3 * 109/L, P = .008; platelet count, 66 vs 128 * 109/l, P = .018). NPM1 mut relapse occurred significantly earlier than NPM1 wt relapse (14 vs 43 months, P = .004). At diagnosis, FLT3-ITD were more frequent in patients with NPM1 mut relapse (P = .029), whereas DNMT3A mutations were more frequent in patients with NPM1 wt relapse (P = .035). Sequencing analysis of paired samples at diagnosis, molecular remission, and NPM1 wt relapse identified cooccurring mutations that persist from diagnosis throughout remission and at relapse, suggestive of a preexisting clonal hematopoiesis. We provide evidence that AML relapsing with NPM1 wt is a distinct disease and that initial leukemia and relapse potentially arise from a premalignant clonal hematopoiesis. PMID- 30455363 TI - Carcinogenic Helicobacter pylori strains selectively dysregulate the in vivo gastric proteome, which may be associated with stomach cancer progression. AB - Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+ H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly upregulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared to gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans. PMID- 30455364 TI - Cardiorespiratory sleep studies at home: experience in research and clinical cohorts. AB - OBJECTIVE: To evaluate the success rates of home cardiorespiratory polygraphy in children under investigation for sleep-disordered breathing and parent perspectives on equipment use at home. DESIGN: Prospective observational study. SETTING: Sheffield, Evelina London and Southampton Children's Hospitals. PATIENTS: Data are reported for 194 research participants with Down syndrome, aged 0.5-5.9 years across the three centres and 61 clinical patients aged 0.4 19.5 years from one centre, all of whom had home cardiorespiratory polygraphy including respiratory movements, nasal pressure flow, pulse oximetry, body position and motion. MAIN OUTCOME MEASURES: Percentage of home cardiorespiratory studies successfully acquiring >=4 hours of artefact-free data at the first attempt. Parental report of ease of use of equipment and preparedness to repeat home diagnostics in the future. RESULTS: 143/194 (74%; 95% CI 67% to 79%) of research participants and 50/61 (82%; 95% CI 71% to 90%) of clinical patients had successful home cardiorespiratory polygraphy at the first attempt. Some children required multiple attempts to achieve a successful study. Overall, this equated to 1.3 studies per research participant and 1.2 studies per clinical child. The median artefact-free sleep time for successful research studies was 515 min (range 261-673) and for clinical studies 442 min (range 291-583). 84% of research and 87% of clinical parents expressed willingness to repeat home cardiorespiratory polygraphy in the future. 67% of research parents found the equipment 'easy or okay' to use, while 64% of clinical parents reported it as 'easy' or 'very easy'. CONCLUSIONS: Home cardiorespiratory polygraphy offers an acceptable approach to the assessment of sleep-disordered breathing in children. PMID- 30455365 TI - Weird Baby Things or Brief Resolved Unexplained Events? PMID- 30455366 TI - Retrospective Application of BRUE Criteria to Patients Presenting With ALTE. AB - OBJECTIVES: To apply recently published brief resolved unexplained events (BRUE) guidelines to patients who presented with apparent life-threatening event (ALTE) to determine: (1) characteristics of these patients; (2) which patients meet BRUE criteria, including risk stratification; and (3) patient outcomes. METHODS: A retrospective chart review of patients presenting to the emergency department or directly to the inpatient unit of a community hospital was performed over the 3 years preceding publication of BRUE guidelines. International Classification of Diseases, Ninth Revision and International Classification of Diseases, 10th Revision billing data for infants <1 year of age were used to screen for patients. After 2-physician review, patients presenting with ALTE diagnostic criteria were identified. Characteristics of the patients and event were analyzed. RESULTS: A total of 321 charts were screened, of which 87 patients were determined to have been diagnosed with ALTE. Twenty patients (23%) met criteria for diagnosis of BRUE. Only 1 patient met criteria for lower-risk BRUE. Of patients with ALTE, 79% of patients presented to the emergency department, of which 65% were admitted, 25% were discharged from the hospital, and 9% were transferred to a tertiary care hospital. Of the 63 inpatients, most were discharged from the hospital after brief observation, and 5% required transfer to a higher level of care. CONCLUSIONS: The majority of patients with ALTE presenting to this institution did not meet the BRUE definition primarily because of ongoing symptoms and/or a specific diagnosis explaining the event. With this finding, we highlight the importance of characterizing the events on the basis of history and physical examination when diagnosing and caring for these patients. PMID- 30455367 TI - Exploring landscapes of brain morphogenesis with organoids. AB - The field of developmental neuroscience is benefitting from recent technological advances that allow access to organogenesis in vitro via organoid preparations. These methods have been applied to better understanding neural identity, and have opened up a window into the early events that occur during development of the human brain. However, current approaches are not without their limitations, and although brain organoids and other in vitro paradigms recapitulate many processes with remarkable fidelity, there are clear differences between brain organoid development in vitro and brain development in vivo These topics were discussed extensively at a recent workshop organized by The Company of Biologists entitled 'Thinking beyond the dish: taking in vitro neural differentiation to the next level'. Here, we summarize the common themes that emerged from the workshop and highlight some of the limitations and the potential of this emerging technology. In particular, we discuss how organoids can help us understand not only healthy and diseased brain, but also explore new arrays of cellular behaviors. PMID- 30455368 TI - Kimishige Ishizaka, M.D., Ph.D. (AAI '58), December 3, 1925 to July 6, 2018. PMID- 30455369 TI - Opening the Black Box of Immunosuppression. PMID- 30455370 TI - Pillars Article: Cyclosporin A Specifically Inhibits Function of Nuclear Proteins Involved in T Cell Activation. Science. 1989. 246: 1617-1620. PMID- 30455371 TI - IL-17 in Renal Immunity and Autoimmunity. AB - The kidney is an organ particularly susceptible to damage caused by infections and autoimmune conditions. Renal inflammation confers protection against microbial infections. However, if unchecked, unresolved inflammation may lead to kidney damage. Although proinflammatory cytokine IL-17 is required for immunity against extracellular pathogens, dysregulated IL-17 response is also linked to autoimmunity. In this review, we will discuss the current knowledge of IL-17 activity in the kidney in context to renal immunity and autoimmunity and raise the intriguing question to what extent neutralization of IL-17 is beneficial or harmful to renal inflammation. PMID- 30455372 TI - Camelid single-domain antibodies raised by DNA immunization are potent inhibitors of EGFR signaling. AB - Upregulation of epidermal growth factor receptor (EGFR) is a hallmark of many solid tumors, and inhibition of EGFR signaling by small molecules and antibodies has clear clinical benefit. Here, we report the isolation and functional characterization of novel camelid single-domain antibodies (sdAbs or VHHs) directed against human EGFR. The source of these VHHs was a llama immunized with cDNA encoding human EGFR ectodomain alone (no protein or cell boost), which is notable in that genetic immunization of large, outbred animals is generally poorly effective. The VHHs targeted multiple sites on the receptor's surface with high affinity ( KD range: 1-40 nM), including one epitope overlapping that of cetuximab, several epitopes conserved in the cynomolgus EGFR orthologue, and at least one epitope conserved in the mouse EGFR orthologue. Interestingly, despite their generation against human EGFR expressed from cDNA by llama cells in vivo (presumably in native conformation), the VHHs exhibited wide epitope-dependent variation in their apparent affinities for native EGFR displayed on tumor cell lines. As fusions to human IgG1 Fc, one of the VHH-Fcs inhibited EGFR signaling induced by EGF binding with a potency similar to that of cetuximab (IC50: ~30 nM). Thus, DNA immunization elicited high-affinity, functional sdAbs that were vastly superior to those previously isolated by our group through protein immunization. PMID- 30455374 TI - Social prescribing: coffee mornings, singing groups, and dance lessons on the NHS. PMID- 30455373 TI - Community collective efficacy is associated with reduced physical intimate partner violence (IPV) incidence in the rural province of Mpumalanga, South Africa: findings from HPTN 068. AB - BACKGROUND: Intimate partner violence (IPV) is a human rights violation and is associated with a variety of adverse physical and mental health outcomes. Collective efficacy, defined as mutual trust among community members and willingness to intervene on the behalf of the common good, has been associated with reduced neighbourhood violence. Limited research has explored whether community collective efficacy is associated with reduced incidence of IPV. This is of particular interest among adolescent girls and young women (AGYW) in sub Saharan Africa, where the burden of HIV is greatest and IPV is common. METHODS: We collected longitudinal data among 2533 AGYW (ages 13-20) enrolled in the HPTN 068 cohort in Mpumalanga province, South Africa between 2011 and 2016. We included participants from 26 villages where community surveys were collected during the HPTN 068 study. Collective efficacy was measured at the village level via two population-based cross-sectional surveys in 2012 and 2014. Multivariable Poisson generalised estimating equation regression models estimated the relative risk ratio (RR) between village collective efficacy scores and subsequent physical IPV 12 month incidence, adjusting for village-level clustering and covariates. RESULTS: Thirty-eight per cent of the cohort (n=950) reported at least one episode of recent physical IPV during follow-up. For every SD higher level of collective efficacy, there was a 6% lower level of physical IPV incidence (adjusted RR: 0.94; 95% CI 0.89 to 0.98) among AGYW after adjusting for covariates. CONCLUSIONS: Community-level interventions that foster the development of collective efficacy may reduce IPV among AGYW. PMID- 30455375 TI - Post-Transplant Characterization of Long-Term Functional hESC-Derived Pancreatic Endoderm Grafts. AB - The paucity of human donors confines the broadened application of beta-cell replacement therapy. Insulin-producing cells derived from human embryonic stem cells (hESC), have been recently investigated clinically as a feasible surrogate to primary tissue. Herein, we examine the long-term efficacy of hESC derived pancreatic endoderm cells (PEC) to maintain normoglycemia post-transplant and characterize graft's phenotype.Chemically induced diabetic mice were transplanted with PEC into the subcutaneous device-less site. Transplant function was assessed through non-fasting blood glucose measurements, intraperitoneal glucose tolerance testing (IPGTT) and human C-peptide secretion for 517 days. Explanted grafts were assessed for ex vivo function and immunohistochemically. All PEC recipients (n=8) maintained normoglycemia until graft retrieval. IPGTTs at 365 and 517 days post transplant did not differ (P>0.05), however, both demonstrated superior glucose clearance compared to non-diabetic and transplant controls (P<0.001). Serum C peptide levels demonstrated significant glucose-responsiveness (fasted vs. stimulated) (P<0.01). Small intra-graft cysts were palpable in all mice, which resolved but recurred after aspiration, showed monomorphic neuroendocrine proliferation and lined by ductal epithelium. Explanted grafts demonstrated similar insulin secretory capacity as human islets and stained positively for endocrine cells. Our results demonstrate the ability of PEC to differentiate in vivo and restore glycemic control while confirming minimal proliferative and absence of neoplastic change during the time evaluated. PMID- 30455376 TI - HSPA12A is a Novel Player in Nonalcoholic Steatohepatitis via Promoting Nuclear PKM2-mediated M1 Macrophage Polarization. AB - Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease worldwide. Macrophage-mediated inflammation plays a critical role in NASH pathogenesis; however, optimum therapies for macrophage activation and NASH remain elusive. Heat shock protein 12A (HSPA12A) encodes a novel member of the HSP70 family. Here, we report that NASH patients showed increased hepatic HSPA12A expression and serum HSPA12A contents. Intriguingly, knockout of HSPA12A (Hspa12a -/- ) in mice attenuated high-fat diet (HFD)-induced hepatic steatosis and injury. HFD-induced macrophage polarization toward an M1 phenotype and inflammatory responses in the liver of Hspa12a -/- mice were also attenuated. Loss- and gain-of-function studies revealed that the de novo lipogenesis in hepatocytes was regulated by the paracrine effects of macrophage HSPA12A rather than by hepatocyte HSPA12A. In-depth molecular analysis revealed that HSPA12A interacted with the M2 isoform of pyruvate kinase (PKM2) in macrophages and increased its nuclear translocation, thereby promoting M1 polarization and secretion of proinflammatory M1 cytokines; this led, ultimately, to hepatocyte steatosis via paracrine effects. Taken together, these findings show that HSPA12A acts as a novel regulator of M1 macrophage polarization and NASH pathogenesis by increasing nuclear PKM2. Strategies that inhibit macrophage HSPA12A might be a potential therapeutic intervention for NASH. PMID- 30455377 TI - Adipocyte Glucocorticoid Receptor Deficiency Promotes Adipose Tissue Expandability and Improves the Metabolic Profile Under Corticosterone Exposure. AB - Widely used for their anti-inflammatory and immunosuppressive properties, glucocorticoids are nonetheless responsible for the development of diabetes and lipodystrophy. Despite an increasing number of studies focused on the adipocyte glucocorticoid receptor (GR), its precise role in the molecular mechanisms of these complications remains unclear. In keeping with this goal, we generated a conditional adipocyte-specific murine model of GR invalidation (AdipoGR-knock-out [KO] mice). Interestingly, when administered a corticosterone treatment to mimic hypercorticism conditions, AdipoGR-KO mice exhibited an improved glucose tolerance and insulin sensitivity. This was related to the adipose-specific activation of the insulin-signaling pathway, which contributed to fat mass expansion, as well as a shift toward an anti-inflammatory macrophage polarization in adipose tissue of AdipoGR-KO animals. Moreover, these mice were protected against ectopic lipid accumulation in the liver and displayed an improved lipid profile, contributing to their overall healthier phenotype. Altogether, our results indicate that adipocyte GR is a key factor of adipose tissue expansion and glucose and lipid metabolism control, which should be taken into account in the further design of adipocyte GR-selective modulators. PMID- 30455378 TI - Erratum. The Transplantation of omega3 PUFA-Altered Gut Microbiota of fat-1 Mice to Wild-Type Littermates Prevents Obesity and Associated Metabolic Disorders. Diabetes 2018;67:1512-1523. PMID- 30455379 TI - Erratum. Serum FGF21 Levels Are Increased in Obesity and Are Independently Associated With the Metabolic Syndrome in Humans. Diabetes 2008;57:1246-1253. PMID- 30455380 TI - Prognostic value of MRD in CLL patients with comorbidities receiving chlorambucil plus obinutuzumab or rituximab. PMID- 30455382 TI - Gliding for a free lunch: biomechanics of foraging flight in common swifts (Apus apus). AB - Although the biomechanics of animal flight have been well studied in laboratory apparatus such as wind tunnels for many years, the applicability of these data to natural flight behaviour has been examined in few instances and mostly in the context of long-distance migration. Here, we used rotational stereo-videography to record the free-flight trajectories of foraging common swifts. We found that, despite their exquisite manoeuvring capabilities, the swifts only rarely performed high-acceleration turns. More surprisingly, we also found that despite feeding on tiny insects probably moving with ambient flow, the birds adjust their air speed to optimize cost of transport over distance. Finally, swifts spent only 25% of their time flapping; the majority of their time (71%) was spent in extended wing gliding, during which the average power expended for changes in speed or elevation was 0.84 W kg-1 and not significantly different from 0. Thus, gliding swifts extracted sufficient environmental energy to pay the cost of flight during foraging. PMID- 30455383 TI - Early-career researchers: an interview with Chris Richards. AB - Chris Richards is a Research Fellow at The Royal Veterinary College (RVC), UK, where he studies the evolution of the frog musculo-skeletal system. He received his Bachelor's degrees in Biology and Violin from Oberlin College, USA, in 1998 before completing his PhD with Andy Biewener at Harvard University, USA, in 2009. He then completed an independent Junior Fellowship at the Rowland Institute, Boston, USA, before moving to the RVC in 2014, where he currently holds a European Research Council grant. PMID- 30455381 TI - IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. AB - Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma (MM) and mantle-cell lymphoma (MCL). However, patients continuously relapse or are intrinsically resistant to this class of drugs. Here, to identify targets that synergize with PIs, we carried out a functional screening in MM cell lines using a short hairpin RNA library against cancer driver genes. Isocitrate dehydrogenase 2 (IDH2) was identified as a top candidate, showing a synthetic lethal activity with the PI carfilzomib (CFZ). Combinations of FDA approved PIs with a pharmacological IDH2 inhibitor (AGI-6780) triggered synergistic cytotoxicity in MM, MCL, and Burkitt's lymphoma (BL) cell lines. CFZ/AGI-6780 treatment increased death of primary CD138+ cells from MM patients and exhibited a favorable cytotoxicity profile towards peripheral blood mononuclear cells and bone marrow-derived stromal cells. Mechanistically, CFZ/AGI-6780 combination significantly decreased tricarboxylic acid (TCA) cycle activity and ATP levels, as a consequence of enhanced IDH2 enzymatic inhibition. Specifically, CFZ treatment reduced the expression of nicotinamide phosphoribosyltransferase (NAMPT), thus limiting IDH2 activation through the NAD+-dependent deacetylase SIRT3. Consistently, combination of CFZ with either NAMPT or SIRT3 inhibitors impaired IDH2 activity and increased MM cell death. Finally, inducible IDH2 knockdown enhanced the therapeutic efficacy of CFZ in a subcutaneous xenograft model of MM, resulting in inhibition of tumor progression and extended survival. Taken together, these findings indicate that NAMPT/SIRT3/IDH2 pathway inhibition enhances the therapeutic efficacy of PIs, thus providing compelling evidence for treatments with lower and less toxic doses and broadening the application of PIs to other malignancies. PMID- 30455384 TI - Barriers to and discourses about breast cancer prevention among immigrant women in Spain: a qualitative study. AB - OBJECTIVES: To identify knowledge, barriers and discourses about breast cancer screening in Spain among female immigrants from low-income countries and native Spanish women from a low socioeconomic class. DESIGN: Qualitative interview study with thematic analysis interpreted using cultural mediators. SETTING: Mallorca, Spain. PARTICIPANTS: Thirty-six in-depth interviews, using cultural mediators, of immigrant women living in Mallorca who were 50-69 years old and were from Maghreb, Sub-Saharan Africa, Eastern Europe, Latin America, China or were native to Spain and from a low socioeconomic class. RESULTS: We analysed the interviews to assess breast cancer perceptions and beliefs, discourses about breast cancer prevention and barriers to accessing breast cancer prevention programmes. Although the women reported an association of breast cancer with death, they acknowledged the effectiveness of early detection. They also exhibited reluctance to talk about cancer. Discourses about cancer prevention tended to be proactive or fatalistic, depending on the woman's country of origin. For all women, fear of results and lack of time were barriers that limited participation in breast cancer prevention programmes. Language barriers, frequent changes of residence and fear due to status as an irregular (undocumented) immigrant were barriers specific to immigrant women. CONCLUSIONS: The culture of origin affects whether an immigrant has a fatalistic or proactive approach toward breast cancer screening. Immigrants from low-income countries and Spanish natives from a low socioeconomic class experience barriers in access to breast cancer screening. Frequently changing homes is also a barrier for immigrant women. PMID- 30455385 TI - Migraine, tension-type headache and medication-overuse headache in a large population of shift working nurses: a cross-sectional study in Norway. AB - OBJECTIVES: To investigate associations between different types of headaches and shift work. DESIGN, PARTICIPANTS AND OUTCOME MEASURES: Nurses with different work schedules (day work, two-shift rotation, night work, three-shift rotation) participated in a cohort study with annual surveys that started in 2008/2009. In 2014 (wave 6), a comprehensive headache instrument was included in the survey, in which 1585 nurses participated. Headaches were assessed according to the International Classification of Headache Disorders IIIb. Frequent headache (>=1 day per month), migraine, tension-type headache, chronic headache (headache >14 days per month) and medication-overuse headache (chronic headache + acute headache medication >=10 days last month) comprised the dependent variables. Adjusted (for sex, age, percentage of full-time equivalent, marital status, children living at home) logistic regression analyses were conducted with work schedule, number of night shifts worked last year, number of quick returns (<11 hours in-between shifts) last year, shift work disorder and insomnia disorder as predictors. RESULTS: Frequent headache, migraine and chronic headache were associated with shift work disorder (OR 2.04, 95% CI 1.62 to 2.59; 1.60, 1.21 to 2.12; 2.45, 1.25 to 4.80, respectively) and insomnia disorder (OR 1.79, 95% CI 1.43 to 2.23; 1.55, 1.18 to 2.02; 3.03, 1.54 to 5.95, respectively), but not with work schedule, number of night shifts or number of quick returns. Tension-type headache was only associated with >20 night shifts last year (OR 1.41, 95% CI 1.07 to 1.86). Medication-overuse headache was only associated with insomnia disorder (OR 7.62, 95% CI 2.48 to 23.41). CONCLUSIONS: We did not find any association between different types of headaches and work schedule. However, tension-type headache was associated with high number of night shifts. Nurses with sleep disorders (insomnia disorder and shift work disorder) reported higher prevalence of frequent headaches, migraine, chronic headache and medication overuse headache (only insomnia) compared with nurses not having insomnia disorder and shift work disorder, respectively. PMID- 30455386 TI - 'Hope you find your 'eureka' moment soon': a qualitative study of parents/carers' online discussions around allergy, allergy tests and eczema. AB - OBJECTIVES: To explore understandings and concerns surrounding allergy, food intolerances and their potential impact on eczema among parents and carers of children with eczema who had posted messages in online forums. METHODS: We conducted a scoping review for active UK-based discussion forums that did not require password/registration to view posts and identified two parenting discussion forums with high activity and frequent use. We used their internal search functions to identify and export discussion threads relating to allergy and allergy testing for eczema from 2011 to 2016. We carried out an inductive thematic analysis of the 120 exported discussion threads. RESULTS: 246 pages of text were analysed. Analysis led to three main themes: (1) confusion over the language surrounding 'allergy' and 'intolerance'; (2) diverse beliefs about allergy testing in relation to eczema and (3) parents' frustrations with perceptions of health professionals as uninterested and unhelpful about allergy testing. Forum users were concerned about immediate and delayed-type allergies but showed confusion in how terms were used, as well as different approaches to testing. Parents sought experiences of others, seeking social support as well as practical guidance. CONCLUSIONS: The confusion around allergy-related terminology and its possible relationship with eczema means that it is essential healthcare professionals are able to signpost parents to accurate, accessible information. The lack of consistent information currently available means parents may use online discussion forums as an important source of information. This study suggests that the confused nature of discussions on these forums is inaccurate at best, and detrimental at worst. PMID- 30455387 TI - Which treatment is most effective for patients with patellofemoral pain? A protocol for a living systematic review including network meta-analysis. AB - INTRODUCTION: Patellofemoral pain (PFP) affects 1 in every 14 adults. Many treatments for PFP have been evaluated, but the comparative effectiveness of all available treatments has never been examined. Network meta-analysis is the only design to study the comparative effectiveness of all available treatments in one synthesis. This protocol describes the methods for a systematic review including network meta-analysis to assess which treatment is most likely to be effective for patients with PFP. METHODS AND ANALYSIS: The primary outcome measures of this network meta-analysis are the global rating of change scale at 6-12 weeks, 13-52 weeks and >52 weeks. The secondary outcome measures are patient-rated pain scales at 6-12 weeks, 13-52 weeks and >52 weeks. Completed published and unpublished randomised controlled trials with full-text reports are eligible for inclusion. We will search Embase, PubMed (including MEDLINE), CENTRAL, Scopus, Web of Science, and CINAHL, SPORTDiscus, OpenGrey, WorldCat, conference Proceedings and multiple trial registers for relevant reports. Two researchers will appraise the study eligibility and perform data extraction. Risk of bias will be assessed with the Cochrane Risk of Bias Tool V.2.0.Bayesian network meta-analyses will be constructed for global rating of change scale and patient-rated pain. Consistency between direct and indirect comparisons will be assessed. Between study variability will be explored, and a threshold analysis for the credibility of the network meta-analyses' conclusions will be performed. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study will be based on published data. The study commenced at 1 February 2018, and its expected completion date is 15 January 2019. Full publication of the work will be sought in an international peer-reviewed journal, as well as translational articles to disseminate the work to clinical practitioners. PROSPERO REGISTRATION NUMBER: CRD42018079502. PMID- 30455388 TI - Cross-sectional analysis on publication status and age representation of clinical studies addressing mechanical ventilation and ventilator-induced lung injury in infants and children. AB - OBJECTIVES: We determined the number and time-to-public availability of study results of published and unpublished clinical studies in paediatric mechanical ventilation (MV) and ventilator-induced lung injury (VILI), which were registered as completed on ClinicalTrials.gov. Furthermore, we explored the pattern of represented research study subtopics and the corresponding study populations. SETTING: Literature search based on ClinicalTrials.gov, PubMed and Google Scholar from 9 July 2017 to 27 September 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: Assessment, if studies included in our analysis had been published. Assessment of primary research focus, patient enrolment and age representation of the analysed studies. RESULTS: We identified n=109 registered and completed clinical studies on paediatric MV and VILI (enrolment: 22 233 participants). 71% were published, including data from 18 647 subjects. 29% of studies were unpublished, containing data from 3586 subjects. Median time-to-public availability of study results was 22 (IQR, 12.8-41.5) months. The most important study subtopics were biophysical and technical aspects of MV (32 studies), administration of drugs to mitigate VILI through various mechanisms (40 studies) and diagnostic procedures (16 studies). n=66/109 (61%) studies exclusively focused on children below 1 year of age and n=2/109 (2%) exclusively on children between 1 and 14 years. CONCLUSIONS: One-third of clinical studies in paediatric MV and VILI registered as completed on ClinicalTrials.gov remained unpublished and contained data on 3586 study participants. The overall median time-to-public availability of study results was longer than the deadline of 12 months mandated by the Food and Drug Administration Amendment Act of 2007. Important and clinically relevant research study subtopics were represented in the research questions investigated in paediatric MV and VILI. The study population was skewed towards children younger than 1 year which indicates, that there is a substantial need for clinical VILI research in older children. PMID- 30455389 TI - Healthcare professionals' perceptions and perspectives on biosimilar medicines and the barriers and facilitators to their prescribing in UK: a qualitative study. AB - OBJECTIVE: To investigate UK healthcare professionals' perceptions and perspectives towards biosimilar infliximab, etanercept and insulin glargine and the potential barriers and facilitators to their prescribing. DESIGN: A cross sectional qualitative study design was used. SETTING: Five hospitals within the West Midlands area in UK. INTERVENTIONS: 30 min face-to-face, semistructured interviews of healthcare professionals. PARTICIPANTS: 22 healthcare professionals (consultants, nurses and pharmacists) participated in the semistructured interviews. OUTCOMES: Participants' opinion and attitudes about biosimilars and the barriers and facilitators to the prescribing of infliximab, etanercept and insulin glargine biosimilars in gastroenterology, rheumatology and diabetology specialties. RESULTS: This study showed that UK healthcare professionals had good knowledge of biosimilars and were content to initiate them. Healthcare professionals disagreed with biosimilar auto-substitution at pharmacy level and multiple switching. Subtle differences among healthcare professionals were identified in the acceptance of switching stable patients, indication extrapolation and cost savings sharing. CONCLUSION: Safety and efficacy concerns, patients' opinion and how cost savings were shared were the identified barriers to considering prescribing biosimilars. Real-life data and financial incentives were the suggested facilitators to increase biosimilar utilisation. PMID- 30455390 TI - Sleep quality of offshore wind farm workers in the German exclusive economic zone: a cross-sectional study. AB - OBJECTIVES: To assess the quality of sleep of employees in the German offshore wind industry and to explore factors associated with poor sleep quality. DESIGN: Web-based cross-sectional survey. SETTING: Offshore companies operating in wind farms within the German exclusive economic zone. PARTICIPANTS: Workers with regular offshore commitments and at least 28 days spent offshore in the past year (n=268). OUTCOME MEASURES: Sleep quality in the past 4 weeks, troubles falling asleep or sleeping through in the past 4 weeks, differences in sleep quality between offshore deployments and onshore leaves. RESULTS: Having problems with sleep onset was reported by 9.5% of the respondents. 16.5% reported troubles with maintaining sleep three or more times per week. The overall quality of sleep was rated as very bad by only 1.7% of the participants. 47.9% of the workers reported their quality of sleep to be worse during offshore commitments than when being onshore. Higher levels of exposition to noise, vibrations and poor air quality were associated with sleeping troubles and poorer sleep quality. Sharing the sleep cabin with colleagues was associated with troubles sleeping through. No association was found for working in rotating shifts and for regularity of the offshore commitments. CONCLUSIONS: Workers in our study showed frequent sleep problems and poorer sleep quality offshore than onshore. Our results indicate that higher degrees of exposure to noise, vibrations and artificial ventilation are associated with poor sleep quality rather than organisational factors such as shift-work and type of working schedule. In view of the high demands of the offshore workplace and the workers' particular recovery needs, addressing sleep disorders should be part of any health and safety management strategy for this workplace. PMID- 30455391 TI - Authors response: Marsden MER, Mossadegh S, Marsh W, et al. J R Army Med Corps Epub ahead of print. doi:10.1136/jramc-2018-001057. PMID- 30455392 TI - Military physicians' ethical experience and professional identity: a Canadian perspective. AB - Military physicians can experience ethical tensions and encounter important dilemmas when acting at the same time as healers, soldiers and humanitarians. In the literature, these are often presented as the result of pressures, real or perceived, from the military institution or role and obligation conflicts that can divert physicians from their primary duty towards their patients. In this article, I present the ethical experiences of 14 Canadian military physicians who participated in operational missions, particularly in Afghanistan. Interestingly, although some dilemmas discussed in the academic literature were raised by Canadian physicians, ethical tensions were less frequent and numerous than what might have been expected. Instead, what emerged were distinctions between the ethical experiences of physicians: generalists experienced more frequent and different ethical challenges than specialists, and these also varied by context, that is, garrison versus on deployment. The main dilemmas during deployment were similar to those encountered by humanitarian physicians and concerned inequalities in the provision of care between coalition soldiers and Afghans (soldiers and civilians), as well as the lack of resources. Surprisingly, participants were evenly divided with regards to how they perceived their professional identity: one group clearly prioritised the medical profession (ie, doctor first and foremost), while the other group identified themselves as military physicians, but without prioritising one profession over the other. PMID- 30455393 TI - I-BET151 suppresses osteoclast formation and inflammatory cytokines secretion by targeting BRD4 in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is an incurable hematologic cancer, accompanied with excessive osteoclast formation and inflammatory cytokine secretion. The mechanisms by which BET protein inhibitor I-BET151 regulates osteoclast differentiation and inflammatory cytokine secretion in MM are largely unknown. METHODS: The isolated peripheral blood mononuclear cells from normal or patients with MM were treated with RANKL and M-CSF to induce osteoclast differentiation. RAW 264.7 cells were treated with RANKL. I-BET151 was applied to investigate effects of BRD4 inhibition on osteoclast formation and inflammatory cytokine secretion. Osteoclast formation was determined by TRACP staining. The expression of osteoclast specific genes TRACP, MMP-9, Ctsk, and c-Src was tested using quantitative real-time PCR. And the level of inflammatory cytokines TNF-alpha, IL 1beta, and IL-6 was assessed by ELISA assay. TRAF6, BRD4, nuclear and cytoplasm p65, IkappaB-alpha, NFATc1, and OPG expression were measured by western blotting. RNAi technology was applied to knockdown BET family member BRD4. RESULTS: I BET151 dose-dependently suppressed osteoclast formation, inhibited the levels of osteoclast specific genes TRACP, MMP-9, Ctsk, and c-Src and inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 secretion in peripheral blood mononuclear cells and RAW 264.7. I-BET151 inhibited the protein levels of BRD4 and NFATc1, increased OPG expression, and suppressed IkappaB-alpha degradation and p65 nuclear translocation. Further, the effects of I-BET151 on osteoclast formation, osteoclast specific genes expression, inflammatory cytokine secretion, and NF kappaB inhibition were promoted by BRD4 knockdown. Conclusion: I-BET151 inhibits osteoclast formation and inflammatory cytokine secretion by targeting BRD4 mediated RANKL-NF-kappaB signal pathway and BRD4 inhibition might be beneficial for MM treatment. PMID- 30455394 TI - Down-regulation of ABCE1 inhibits temozolomide resistance in glioma through the PI3K/Akt/NF-kappaB signaling pathway. AB - The ATP binding cassette E1 (ABCE1), a member of the ABC family, was originally described as the RNase L inhibitor. Through forming a heterodimer with RNase L, ABCE1 participates in the negative regulation of the 2-5A/RNase L system and thus mediates a wide range of biological functions. Recent evidence has shown the new roles of ABCE1 in tumorigenesis. However, there have been no investigations on the specific effect of ABCE1 on glioma. In this study, we examined the expression pattern and possible role of ABCE1 in glioma. Our study demonstrated that ABCE1 was up-regulated in glioma tissues and cell lines. Down-regulation of ABCE1 inhibited TMZ resistance of glioma cells in vitro and in vivo In addition, we found that the PI3K/Akt/NF-kappaB pathway was involved in ABCE1-mediated chemoresistance of glioma cells. Taken together, our study suggested ABCE1 as a promising target for glioma chemotherapy. PMID- 30455395 TI - Effects of OPRM1 and ABCB1 gene polymorphisms on the analgesic effect and dose of sufentanil after thoracoscopic-assisted radical resection of lung cancer. AB - OBJECTIVE: To study the effects of single nucleotide polymorphisms of the OPRM1 and ABCB1 genes on the analgesic effect and consumption of sufentanil after thoracoscopic-assisted radical resection of lung cancer. Methods:A total of 225 Chinese Han nationality patients undergoing thoracoscopic-assisted radical resection of lung cancer were enrolled in this study. Among them, 132 were males (58.67%) and 93 (41.33%) were females having ASA statuses classified as grades I or II. The rs1799971, rs563649 and rs1323040 genotypes of the OPRM1 gene and rs2032582, rs1045642 and rs1128503 genotypes of the ABCB1 gene were detected by Sanger sequencing. The state anxiety index (SAI) and pressure pain threshold (PPT) were assessed preoperatively. Sufentanil was administered intravenously to maintain anesthesia. RESULTS: The sufentanil doses at T1, T2 and T3 were significantly higher in radical-operation lung cancer patients with mutant homozygous rs1799971 and rs1323040 loci in the OPRM1 gene and rs2032582 and rs1128503 loci in the ABCB1 gene. The doses of sufentanil consumed by mutant heterozygous lung cancer patients at T1, T2 and T3 were significantly higher than those consumed by patients without mutations, and the differences were statistically significant ( P < 0.05). There was no significant difference in sufentanil doses consumed by lung cancer patients with mutant homozygous, mutant heterozygous and wild-type rs563649 locus of the OPRM1 gene and rs1045642 locus of the ABCB1 gene at T1, T2 and T3. Conclusion:The rs1799971 and rs1323040 polymorphisms of the OPRM1 gene and rs2032582 and rs1128503 polymorphisms of the ABCB1 gene are related to the analgesic effect and consumed dose of sufentanil in Chinese Han patients undergoing radical operation of lung cancer. PMID- 30455396 TI - Galectin 3 inhibition attenuates renal injury progression in cisplatin-induced nephrotoxicity. AB - Nephrotoxicity is a major toxic effect in chemotherapy, which constitutes up to 60% of hospitalized acute kidney injury (AKI). Very few treatment options exist to slow the transition from AKI to subsequent chronic kidney diseases (CKD). Here, we demonstrate that galectin-3 (Gal-3), a beta-galactoside binding lectin that plays an important role in kidney fibrosis and renal failure, is one of the key factors for renal injury progression. Ectopic overexpression of Gal-3 significantly decreased the viability of HEK293, simultaneously inducing of cell cycle arrest and apoptosis. However, inhibition of Gal-3, mediated by modified citrus pectin (MCP), predominantly antagonized the pro-apoptotic effects. Mice were pre-treated with normal or 1% MCP-supplemented drinking water one week before cisplatin injection. Analyses of serum creatinine and renal tissue damage indicated that MCP-treated mice demonstrated increased renal function and attenuated renal fibrosis after cisplatin-induced injury. MCP-treated mice also demonstrated decreased renal fibrosis and apoptosis, as revealed by masson trichrome staining and western blot analysis of cleaved caspase-3. Additionally, the protective role of Gal-3 inhibition in the kidney injury was shown to be mediated by PKC-alpha, which promoted cell apoptosis and collagen I synthesis in HEK293 cells. These results demonstrated the potential Gal-3 and PKC-alpha as therapeutic targets for the treatment of AKI and CKD. PMID- 30455397 TI - Preconditioning lessens high fat induced metabolic syndrome along with markers of increased metabolic capacity in muscle and adipose tissue. AB - Postnatal overconsumption of fat is believed to increase the susceptibility to metabolic disease in the later life. Here we examined whether prior exposure to high fat (HF) in the adulthood may also accelerate the development of metabolic disorders in mice. Adult mice (12 weeks) were pre-exposed to two episodes of a HF diet each for 2 weeks followed by 2 weeks of washout with a low-fat diet. The mice were then fed the same HF diet for 6 weeks. Unexpectedly, prior exposures to HF diet significantly alleviated body weight gain, visceral adiposity and glucose/insulin intolerance during the period of last HF feeding. These protective effects were evident without changing calorie intake and were specific for HF, but not high fructose, diet. Followed the HF prior exposures was increases in plasma fibroblast growth factor 21 (FGF21), the expressions of pAMPK, mitochondrial complex II and the expression of UCP3 in muscle and UCP1 and SIRT1 in adipose tissue. However, in the liver there was no significant change in pAMPK, SIRT1 expression or the capacity of glucose production. These findings indicated that, instead of exacerbating metabolic conditions, prior exposures to HF diet lead to the preconditioning against subsequent overload of HF, possibly involving FGF21-associated enhancement of markers for metabolic capacity in muscle and adipose tissue. This paradoxical phenomenon may offer a unique paradigm to identify factors and explore dietary ingredients with beneficial effects for the control of the metabolic syndrome in humans. PMID- 30455399 TI - Cutting Edge: FHR-1 Binding Impairs Factor H-Mediated Complement Evasion by the Malaria Parasite Plasmodium falciparum. AB - Human complement is the first line of defense against invading pathogens, including the malaria parasite Plasmodium falciparum We previously demonstrated that human complement represents a particular threat for the clinically relevant blood stages of the parasite. To evade complement-mediated destruction, the parasites acquire factor H (FH) via specific receptors. We now report that the FH related protein FHR-1 competes with FH for binding to the parasites. FHR-1, which is composed of five complement control protein domains with variable homology to FH but lacks C3b regulatory activity, accumulates on the surfaces of intraerythrocytic schizonts and free merozoites. Although binding of FH to schizont-infected RBCs and merozoites is increased in FHR-1-deficient human serum, the addition of recombinant FHR-1 decreases FH binding. The presence of FHR-1 consequently impairs C3b inactivation and parasite viability. We conclude that FHR-1 acts as a protective factor in human immunity by counteracting FH mediated microbial complement evasion. PMID- 30455398 TI - The GTPase Rab1 Is Required for NLRP3 Inflammasome Activation and Inflammatory Lung Injury. AB - Uncontrolled inflammatory response during sepsis predominantly contributes to the development of multiorgan failure and lethality. However, the cellular and molecular mechanisms for excessive production and release of proinflammatory cytokines are not clearly defined. In this study, we show the crucial role of the GTPase Ras-related protein in brain (Rab)1a in regulating the nucleotide binding domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and lung inflammatory injury. Expression of dominant negative Rab1 N124I plasmid in bone marrow-derived macrophages prevented the release of IL 1beta and IL-18, NLRP3 inflammasome activation, production of pro-IL-1beta and pro-IL-18, and attenuated TLR4 surface expression and NF-kB activation induced by bacterial LPS and ATP compared with control cells. In alveolar macrophage depleted mice challenged with cecal ligation and puncture, pulmonary transplantation of Rab1a-inactivated macrophages by expression of Rab1 N124I plasmid dramatically reduced the release of IL-1beta and IL-18, neutrophil count in bronchoalveolar lavage fluid, and inflammatory lung injury. Rab1a activity was elevated in alveolar macrophages from septic patients and positively associated with severity of sepsis and respiratory dysfunction. Thus, inhibition of Rab1a activity in macrophages resulting in the suppression of NLRP3 inflammasome activation may be a promising target for the treatment of patients with sepsis. PMID- 30455400 TI - Programming of CD8 T Cell Quantity and Polyfunctionality by Direct IL-1 Signals. AB - IL-1, generally considered an amplifier of adaptive immune responses, has been proposed for use as adjuvant during immunization with weak immunogens. However, its effects on memory T cell function remain largely undefined. Using the murine model of acute viral infection, in this paper, we show that in addition to augmenting the size of the Ag-specific pool, IL-1 signals act directly on CD8 T cells to promote the quality of effector and memory responses. Ablation of IL-1R1 or MyD88 signaling in T cells led to functional impairment; both the ability to produce multiple cytokines on a per cell basis (polyfunctionality) and the potential for recall proliferation in response to antigenic restimulation were compromised. IL-1 supplementation during priming augmented the expansion of Ag specific CD8 T cells through the MyD88-IRAK1/4 axis, resulting in a larger memory pool capable of robust secondary expansion in response to rechallange. Together, these findings demonstrate a critical role of the IL-1-MyD88 axis in programming the quantity and quality of memory CD8 T cell responses and support the notion that IL-1 supplementation may be exploited to enhance adoptive T cell therapies against cancers and chronic infections. PMID- 30455401 TI - DRB4*01:01 Has a Distinct Motif and Presents a Proinsulin Epitope That Is Recognized in Subjects with Type 1 Diabetes. AB - DRB4*01:01 (DRB4) is a secondary HLA-DR product that is part of the high-risk DR4/DQ8 haplotype that is associated with type 1 diabetes (T1D). DRB4 shares considerable homology with HLA-DR4 alleles that predispose to autoimmunity, including DRB1*04:01 and DRB1*04:04. However, the DRB4 protein sequence includes distinct residues that would be expected to alter the characteristics of its binding pockets. To identify high-affinity peptides that are recognized in the context of DRB4, we used an HLA class II tetramer-based approach to identify epitopes within multiple viral Ags. We applied a similar approach to identify antigenic sequences within glutamic acid decarboxylase 65 and pre-proinsulin that are recognized in the context of DRB4. Seven sequences were immunogenic, eliciting high-affinity T cell responses in DRB4+ subjects. DRB1*04:01-restricted responses toward many of these peptides have been previously described, but responses to a novel pre-proinsulin 9-28 peptide were commonly observed in subjects with T1D. Furthermore, T cells that recognized this peptide in the context of DRB4 were present at significantly higher frequencies in patients with T1D than in healthy controls, implicating this as a disease-relevant specificity that may contribute to the breakdown of beta cell tolerance in genetically susceptible individuals. We then deduced a DRB4 motif and confirmed its key features through structural modeling. This modeling suggested that the core epitope within the pre-proinsulin 9-28 peptide has a somewhat unusual binding motif, with tryptophan in the fourth binding pocket of DRB4, perhaps influencing the availability of this complex for T cell selection. PMID- 30455402 TI - Suppression of Th1 Priming by TLR2 Agonists during Cutaneous Immunization Is Mediated by Recruited CCR2+ Monocytes. AB - Effective subunit vaccines require the incorporation of adjuvants that stimulate cells of the innate immune system to generate protective adaptive immune responses. Pattern recognition receptor agonists are a growing class of potential adjuvants that can shape the character of the immune response to subunit vaccines by directing the polarization of CD4 T cell differentiation to various functional subsets. In the current study, we applied a high-throughput in vitro screen to assess murine CD4 T cell polarization by a panel of pattern recognition receptor agonists. This identified lipopeptides with TLR2 agonist activity as exceptional Th1-polarizing adjuvants. In vivo, we demonstrated that i.v. administration of TLR2 agonists with Ag in mice replicated the findings from in vitro screening by promoting strong Th1 polarization. In contrast, TLR2 agonists inhibited priming of Th1 responses when administered cutaneously in mice. This route-specific suppression was associated with infiltrating CCR2+ cells in the skin-draining lymph nodes and was not uniquely dependent on any of the well characterized subsets of dendritic cells known to reside in the skin. We further demonstrated that priming of CD4 T cells to generate Th1 effectors following immunization with the Mycobacterium bovis bacillus Calmette-Guerin (BCG) strain, a lipoprotein-rich bacterium recognized by TLR2, was dependent on the immunization route, with significantly greater Th1 responses with i.v. compared with intradermal administration of BCG. A more complete understanding of route-dependent TLR2 responses may be critical for informed design of novel subunit vaccines and for improvement of BCG and other vaccines based on live-attenuated organisms. PMID- 30455403 TI - Drop attacks of the elderly. PMID- 30455405 TI - Subregional heterogeneity of somatosensory dysfunction in the insula. PMID- 30455406 TI - Emotional processing in functional neurological disorder: a review, biopsychosocial model and research agenda. AB - Functional neurological disorder (FND) is a common and highly disabling disorder, but its aetiology remains enigmatic. Conceptually, there has been reduced emphasis on the role of psychosocial stressors in recent years, with a corresponding increase in neurobiological explanations. However, a wealth of evidence supports the role of psychosocial adversities (eg, stressful life events, interpersonal difficulties) as important risk factors for FND. Therefore, there is a need to integrate psychosocial (environmental) and neurobiological factors (eg, sensorimotor and cognitive functions) in contemporary models of FND. Altered emotional processing may represent a key link between psychosocial risk factors and core features of FND. Here, we summarise and critically appraise experimental studies of emotional processing in FND using behavioural, psychophysiological and/or neuroimaging measures in conjunction with affective processing tasks. We propose that enhanced preconscious (implicit) processing of emotionally salient stimuli, associated with elevated limbic reactivity (eg, amygdala), may contribute to the initiation of basic affective/defensive responses via hypothalamic and brainstem pathways (eg, periaqueductal grey). In parallel, affect-related brain areas may simultaneously exert a disruptive influence on neurocircuits involved in voluntary motor control, awareness and emotional regulation (eg, sensorimotor, salience, central executive networks). Limbic-paralimbic disturbances in patients with FND may represent one of several neurobiological adaptations linked to early, severe and/or prolonged psychosocial adversity. This perspective integrates neurobiological and psychosocial factors in FND and proposes a research agenda, highlighting the need for replication of existing findings, multimodal sampling across emotional response domains and further examination of emotional influences on sensorimotor and cognitive functions in FND populations. PMID- 30455408 TI - Referring patients with suspected oral cancer to dentists may delay diagnosis, say GPs. PMID- 30455404 TI - Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study. AB - BACKGROUND AND PURPOSE: The optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study. METHODS: We included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0-4 days) and later (>=5 days or never started) OAC initiation. RESULTS: We included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736). CONCLUSION: In adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required. CLINICAL TRIAL REGISTRATION: NCT02513316. PMID- 30455407 TI - Long-term follow-up of patients with myasthenia gravis treated with low-dose rituximab. PMID- 30455409 TI - Greater loss of mitochondrial function with ageing is associated with earlier onset of sarcopenia in C. elegans. AB - Sarcopenia, the age-related decline of muscle, is a significant and growing public health burden. C. elegans, a model organism for investigating the mechanisms of ageing, also displays sarcopenia, but the underlying mechanism(s) remain elusive. Here, we use C. elegans natural scaling of lifespan in response to temperature to examine the relationship between mitochondrial content, mitochondrial function, and sarcopenia. Mitochondrial content and maximal mitochondrial ATP production rates (MAPR) display an inverse relationship to lifespan, while onset of MAPR decline displays a direct relationship. Muscle mitochondrial structure, sarcomere structure, and movement decline also display a direct relationship with longevity. Notably, the decline in mitochondrial network structure occurs earlier than sarcomere decline, and correlates more strongly with loss of movement, and scales with lifespan. These results suggest that mitochondrial function is critical in the ageing process and more robustly explains the onset and progression of sarcopenia than loss of sarcomere structure. PMID- 30455410 TI - Outcomes of survivors of ST-segment elevation myocardial infarction complicated by out-of-hospital cardiac arrest: a single-center surveillance study. AB - OBJECTIVE: The aim of the present study was to evaluate in-hospital and long-term outcomes of ST-segment elevation myocardial infarction (STEMI) survivors who experienced out-of-hospital cardiac arrest (OHCA) and underwent primary percutaneous coronary intervention (PCI) at a high-volume center within the STEMI network. METHODS: The records of 2681 consecutive STEMI patients who underwent primary PCI between January 2009 and December 2014 at a single center in the STEMI network were retrospectively analyzed. Patients with STEMI complicated by OHCA were compared with a reference group of STEMI patients who did not experience OHCA. RESULTS: Compared with STEMI survivors without OHCA (n=2587, 96.5%), the frequency of anterior myocardial infarction, duration of hospitalization, rate of in-hospital major adverse cardiovascular and cerebrovascular events, and the incidence of ischemic cerebrovascular disease and major bleeding during in-hospital follow-up were significantly greater in those with OHCA (n=94, 3.5%). The distribution of age and gender was similar between the 2 groups. The primary PCI success rate was high and was similar in both groups. In-hospital mortality was significantly higher (18.1% vs. 1.5%; p<0.001) and survival at the 12th and 60th months was lower (74.5% vs. 96.5%; p<0.001 and 71.3% vs. 93.7%; p<0.001) in STEMI survivors with OHCA. OHCA was an independent predictor for in-hospital mortality (Odds ratio [OR]: 3.413; 95% confidence interval [CI]: 1.534-7.597; p=0.003) and all-cause mortality at 60 months (OR: 3.285; 95% CI: 2.020-5.340; p<0.001). CONCLUSION: Mortality was high in patients with STEMI complicated by OHCA, even though PCI was performed with the same success rate seen in patients without OHCA. PMID- 30455411 TI - Impact of Donor Pre-Procurement Cardiac Arrest (PPCA) on Clinical Outcomes in Liver Transplantation. AB - BACKGROUND Transplantation of liver grafts from deceased donors who experienced cardiac arrest prior to liver procurement is now common. This single-center study analyzed the impact of pre-donation arrest time on clinical outcomes in liver transplantation. MATERIAL AND METHODS Records of all orthotopic liver transplants performed at a single center over a 15-year period were reviewed. Donor records were reviewed and total arrest time was calculated as cumulative minutes. Post transplant liver graft function was assessed using laboratory values. Graft survival was assessed with Cox regression analysis. RESULTS Records for 1830 deceased donor transplants were reviewed, and 521 donors experienced pre procurement cardiac arrest (28%). Median arrest time was 21 min (mean 25 min, range 1-120 min). After transplant, the peak alanine aminotransferase and bilirubin levels for liver grafts from donors with arrest were lower compared to those for donors without arrest (p<0.001). Early allograft dysfunction occurred in 25% (arrest) and 28% (no arrest) of patients (p=0.22). There were no differences in risk of early graft loss (3% vs. 3%, p=0.84), length of hospital stay (10 vs. 10 days, p=0.76), and 1-year graft survival (89% vs. 89%, p=0.94). Cox regression analysis comparing 4 groups (no arrest, <20 min, 20-40 min, and >40 min arrest) demonstrated no statistically significant difference in survival at 10 years. Subgroup analysis of 93 donation after cardiac death grafts showed no significant difference for these same outcomes. CONCLUSIONS These results support the use of select deceased liver donors who experience pre-donation cardiac arrest. Pre-donation arrest may be associated with less early allograft dysfunction, but had no impact on long-term clinical outcomes. The results for donation after cardiac death donors were similar. PMID- 30455412 TI - Leucine-Rich Alpha-2-Glycoprotein1 Gene Interferes with Regulation of Apoptosis in Leukemia KASUMI-1 Cells. AB - BACKGROUND Leukemia cells have strong proliferation and anti-apoptosis capabilities. The purpose of this study was to investigate the effect of silencing the leucine-rich alpha-2-glycoprotein1 (LRG1) gene, which was found to regulate tumor proliferation and apoptosis in acute myeloid leukemia (AML) cell lines. MATERIAL AND METHODS Plasmid interference technique was used to silence the LRG1 gene in the KASUMI-1 cell line. The cell counting kit-8 (CCK-8) assay was used to test the effect of transduction on cell viability. Cell cycle and apoptosis were detected by flow cytometry. Western blot and quantitative real time polymerase chain reaction (RT-qPCR) were applied to detect the expression levels of proteins and mRNA, respectively. RESULTS KASUMI-1 cells with the CD34+CD38- phenotype were sorted by flow cytometry. After transfection of the siLRG1 plasmid, the level of LRG1 expression was downregulated and cell viability was reduced. Silencing of LRG1 gene blocked KASUMI-1 cells in G0/G1 phase and promoted apoptosis. Further experiments found that LRG1 gene silencing significantly downregulated cell cycle-associated proteins and anti-apoptotic proteins, while upregulating pro-apoptotic proteins. Downregulation of LRG1 gene expression also inhibits signal transduction of the JAK-STAT pathway. CONCLUSIONS LRG1 gene silencing regulates the expression of cyclin and apoptosis-related proteins to reduce cell viability and promote apoptosis, probably through inhibition of the JAK-STAT pathway. PMID- 30455413 TI - Use of Ivermectin in Neurocysticercosis: A Case Report. AB - BACKGROUND Neurocysticercosis is a Taenia solium infection which utilizes the tapeworm as a vector and humans as a definitive host and causes development of cystic lesions in the central nervous system. The current established medical therapy is albendazole with praziquantel as a secondary agent, but results can be mixed depending on each patient and their form of neurocysticercosis. CASE REPORT We present a case pertaining to a young female patient diagnosed with single parenchymal neurocysticercosis based on clinical and diagnostic findings. This case was unique in the sense that ivermectin, another antiparasitic agent, was used as monotherapy with significant improvement in the patient's clinical presentation and radiological findings. CONCLUSIONS Despite current guidelines recommending use of albendazole with or without praziquantel for neurocysticercosis, our case (as well as 4 other cases documented in the recent past) suggest a possible use of ivermectin as potential therapy for neurocysticercosis. We recommend continued research regarding other cases of ivermectin use in similar patients and even comparison studies with albendazole with or without praziquantel in terms of efficacy and side effects in order to better treat this international endemic. PMID- 30455416 TI - Extramedullary hematopoiesis in the absence of myeloproliferative neoplasm: Mayo Clinic case series of 309 patients. PMID- 30455414 TI - Assembly of a pan-genome from deep sequencing of 910 humans of African descent. AB - We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic. PMID- 30455417 TI - Clinicopathologic and genetic characteristics of interval colorectal carcinomas favor origin from missed or incompletely excised precursors. AB - Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.2%) were categorized as interval colorectal cancer, defined as colorectal cancer detected in a diagnostic examination prior to the next recommended colonoscopy and at least 1 year after the last colonoscopy. Clinicopathologic characteristics of interval colorectal cancer were compared to non-interval colorectal cancer matched 1:1 on age, gender, and tumor location. Molecular profile of a subset of interval colorectal cancer (n = 20) and matched (1:2) non-interval colorectal cancer (n = 40) were evaluated using next generation sequencing. Interval colorectal cancer were more likely to occur in the right colon (55% vs. 35%; p = 0.02) and in patients > 70 years of age (55% vs. 34%; p = 0.002). Clinicopathologic features and aberrant DNA mismatch repair protein expression were not significantly different between interval and matched non-interval colorectal cancer. The frequency and spectrum of genetic alterations was also similar in interval and matched non-interval colorectal cancer. Similar findings were seen when analysis was restricted to interval colorectal cancer diagnosed <5 years after last colonoscopy (n = 42). Interval and non-interval colorectal cancers share similar clinicopathologic and genetic profiles when matched for tumor location. Interval colorectal cancers and are more likely to develop from missed or incompletely excised precursors rather than a unique rapid progression pathway. PMID- 30455415 TI - ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. AB - Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)1-3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1% of nonsyndromic BAV cases with and without AscAA5-8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype. PMID- 30455418 TI - The Black 6 gets company: De novo genomes assembled for 16 more mice. PMID- 30455419 TI - Making connections in the mouse hippocampus. PMID- 30455421 TI - Change in future climate due to Antarctic meltwater. AB - Meltwater from the Antarctic Ice Sheet is projected to cause up to one metre of sea-level rise by 2100 under the highest greenhouse gas concentration trajectory (RCP8.5) considered by the Intergovernmental Panel on Climate Change (IPCC). However, the effects of meltwater from the ice sheets and ice shelves of Antarctica are not included in the widely used CMIP5 climate models, which introduces bias into IPCC climate projections. Here we assess a large ensemble simulation of the CMIP5 model 'GFDL ESM2M' that accounts for RCP8.5-projected Antarctic Ice Sheet meltwater. We find that, relative to the standard RCP8.5 scenario, accounting for meltwater delays the exceedance of the maximum global mean atmospheric warming targets of 1.5 and 2 degrees Celsius by more than a decade, enhances drying of the Southern Hemisphere and reduces drying of the Northern Hemisphere, increases the formation of Antarctic sea ice (consistent with recent observations of increasing Antarctic sea-ice area) and warms the subsurface ocean around the Antarctic coast. Moreover, the meltwater-induced subsurface ocean warming could lead to further ice-sheet and ice-shelf melting through a positive feedback mechanism, highlighting the importance of including meltwater effects in simulations of future climate. PMID- 30455420 TI - Autophagy promotes angiogenesis via AMPK/Akt/mTOR signaling during the recovery of heat-denatured endothelial cells. AB - Our previous study demonstrated that angiogenesis increased during the recovery of heat-denatured endothelial cells. However, the mechanism is still unclear. This study aimed to investigate the relation of autophagy and angiogenesis during the recovery of heat-denatured endothelial cells. A rat deep partial-thickness burn model and heat-denatured human umbilical vein endothelial cells (HUVECs) model (52 degrees C for 35 s) were used. Autophagy increased significantly in the dermis and HUVECs in a time-dependent manner after heat denaturation and recovery for 2-5 days. Rapamycin-mediated autophagy enhanced the pro-angiogenic effect, evidenced by increased proliferation and migration of HUVECs, and formation of tube-like structures. Autophagy inhibition by 3-Methyladenine (3-MA) abolished the angiogenesis in heat-denatured HUVECs after recovery for 3-5 days. Moreover, heat denaturation augmented the phosphorylation of AMP-activated protein kinase (AMPK) but reduced the phosphorylation of Akt and mTOR in HUVECs. Furthermore, autophagy inhibition by antioxidant NAC, compound C or AMPK siRNA impaired cell proliferation, migration and tube formation heat-denatured HUVECs. At last, the in vivo experiments also showed that inhibition of autophagy by bafilomycin A1 could suppress angiogenesis and recovery of heat-denatured dermis.Taken together, we firstly revealed that autophagy promotes angiogenesis via AMPK/Akt/mTOR signaling during the recovery of heat-denatured endothelial cells and may provide a potential therapeutic target for the recovery of heat denatured dermis. PMID- 30455422 TI - Cryptic connections illuminate pathogen transmission within community networks. AB - Understanding host interactions that lead to pathogen transmission is fundamental to the prediction and control of epidemics1-5. Although the majority of transmissions often occurs within social groups6-9, the contribution of connections that bridge groups and species to pathogen dynamics is poorly understood10-12. These cryptic connections-which are often indirect or infrequent provide transmission routes between otherwise disconnected individuals and may have a key role in large-scale outbreaks that span multiple populations or species. Here we quantify the importance of cryptic connections in disease dynamics by simultaneously characterizing social networks and tracing transmission dynamics of surrogate-pathogen epidemics through eight communities of bats. We then compared these data to the invasion of the fungal pathogen that causes white-nose syndrome, a recently emerged disease that is devastating North American bat populations13-15. We found that cryptic connections increased links between individuals and between species by an order of magnitude. Individuals were connected, on average, to less than two per cent of the population through direct contact and to only six per cent through shared groups. However, tracing surrogate-pathogen dynamics showed that each individual was connected to nearly fifteen per cent of the population, and revealed widespread transmission between solitarily roosting individuals as well as extensive contacts among species. Connections estimated from surrogate-pathogen epidemics, which include cryptic connections, explained three times as much variation in the transmission of the fungus that causes white-nose syndrome as did connections based on shared groups. These findings show how cryptic connections facilitate the community-wide spread of pathogens and can lead to explosive epidemics. PMID- 30455423 TI - Late Middle Pleistocene Levallois stone-tool technology in southwest China. AB - Levallois approaches are one of the best known variants of prepared-core technologies, and are an important hallmark of stone technologies developed around 300,000 years ago in Africa and west Eurasia1,2. Existing archaeological evidence suggests that the stone technology of east Asian hominins lacked a Levallois component during the late Middle Pleistocene epoch and it is not until the Late Pleistocene (around 40,000-30,000 years ago) that this technology spread into east Asia in association with a dispersal of modern humans. Here we present evidence of Levallois technology from the lithic assemblage of the Guanyindong Cave site in southwest China, dated to approximately 170,000-80,000 years ago. To our knowledge, this is the earliest evidence of Levallois technology in east Asia. Our findings thus challenge the existing model of the origin and spread of Levallois technologies in east Asia and its links to a Late Pleistocene dispersal of modern humans. PMID- 30455424 TI - VCAM-1+ macrophages guide the homing of HSPCs to a vascular niche. AB - Haematopoietic stem and progenitor cells (HSPCs) give rise to all blood lineages that support the entire lifespan of vertebrates1. After HSPCs emerge from endothelial cells within the developing dorsal aorta, homing allows the nascent cells to anchor in their niches for further expansion and differentiation2-5. Unique niche microenvironments, composed of various blood vessels as units of microcirculation and other niche components such as stromal cells, regulate this process6-9. However, the detailed architecture of the microenvironment and the mechanism for the regulation of HSPC homing remain unclear. Here, using advanced live imaging and a cell-labelling system, we perform high-resolution analyses of the HSPC homing in caudal haematopoietic tissue of zebrafish (equivalent to the fetal liver in mammals), and reveal the role of the vascular architecture in the regulation of HSPC retention. We identify a VCAM-1+ macrophage-like niche cell population that patrols the inner surface of the venous plexus, interacts with HSPCs in an ITGA4-dependent manner, and directs HSPC retention. These cells, named 'usher cells', together with caudal venous capillaries and plexus, define retention hotspots within the homing microenvironment. Thus, the study provides insights into the mechanism of HSPC homing and reveals the essential role of a VCAM-1+ macrophage population with patrolling behaviour in HSPC retention. PMID- 30455425 TI - Serum erythropoietin levels in essential thrombocythemia: phenotypic and prognostic correlates. PMID- 30455426 TI - Hepatitis C virus and the kidney. AB - Hepatitis C virus (HCV) infection is more prevalent and is associated with higher mortality in patients receiving dialysis and in kidney transplant recipients than in the general population. Kidney transplant recipients who are HCV-positive are also at higher risk of allograft and liver failure than are HCV-negative recipients. Moreover, HCV infection is associated with a higher incidence and faster progression of diabetes mellitus and chronic kidney disease (CKD), as well as a higher incidence of systemic (especially cardiovascular) complications. The finding that these complications of HCV infection are attenuated in patients who achieve a sustained virologic response (SVR) emphasizes the need to treat patients with CKD who are HCV-positive with oral antiviral therapies. Fortunately, the available evidence suggests that a SVR can be achieved in >95% of patients with late-stage CKD and in kidney transplant recipients. According to international guidelines, all patients with CKD and HCV infection should be considered for treatment with direct acting antivirals (DAAs), prioritizing those with symptomatic cryoglobulinaemic vasculitis, extensive liver fibrosis and stage 4-5 CKD. DAA treatment can be delayed until after transplantation in recipients whose waiting time is markedly reduced by accepting an HCV-positive organ. An emerging issue is the long-term renal safety of DAAs, which requires a re appraisal. Overall, the elimination of HCV from patients with CKD now seems to be achievable, provided that DAA treatment is coupled with reinforced hygienic precautions to prevent reinfections in dialysis units. PMID- 30455427 TI - The Klotho proteins in health and disease. AB - The Klotho proteins, alphaKlotho and betaKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the betaKlotho FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus-pituitary-adrenal axis and the sympathetic nervous system following binding to the betaKlotho-FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to alphaKlotho-FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes. PMID- 30455428 TI - EGFL6 promotes breast cancer by simultaneously enhancing cancer cell metastasis and stimulating tumor angiogenesis. AB - EGFL6, a member of the EGF-like superfamily, plays an important role during embryonic development and has been implicated in promotion of tumor angiogenesis without affecting wound healing. There is very little known about the function of EGFL6 in cancer cells. Here, we investigated whether EGFL6 plays a direct role in cancer cells in addition to the promotion of tumor angiogenesis. Our study showed that EGFL6 promoted epithelial-mesenchymal transition (EMT) and stemness of breast cancer cells and increased cell migration and invasion in cell culture studies. We also found that EGFL6 reduced apoptotic signaling in cancer cells and promoted tumor growth in vivo. Importantly, expression of EGFL6 in cancer cells and tumor endothelial cells not only increased tumor angiogenesis but also promoted migration of cancer cells. Such dual engagement of cancer and stromal cells suggests crosstalk mediated by EGFL6 in the tumor microenvironment. Blockade of EGFL6 using our novel anti-EGFL6 monoclonal antibody significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Silencing EGFL6 mRNA by shRNA transfection of cancer cells also significantly reduced cancer cell migration, tumor angiogenesis, and tumor growth in mouse xenograft tumor models. Taken together, the results of this study indicate that targeting EGFL6 is a unique strategy for inhibiting both cancer cell metastasis and tumor angiogenesis. PMID- 30455430 TI - Enantioselective alpha-functionalizations of ketones via allylic substitution of silyl enol ethers. AB - The enantioselective construction of carbon-heteroatom and carbon-carbon bonds that are alpha to ketones leads to the formation of substructures that are ubiquitous in natural products, pharmaceuticals and agrochemicals. Traditional methods to form such bonds have relied on combining ketone enolates with electrophiles. Reactions with heteroatom-based electrophiles require special reagents in which the heteroatom, which is typically nucleophilic, has been rendered electrophilic by changes to the oxidation state. The resulting products usually require post-synthetic transformations to unveil the functional group in the final desired products. Moreover, different catalytic systems are typically required for the reaction of different electrophiles. Here, we report a strategy for the formal enantioselective alpha-functionalization of ketones to form products containing a diverse array of substituents at the alpha position with a single catalyst. This strategy involves an unusual reversal of the role of the nucleophile and electrophile to form C-N, C-O, C-S and C-C bonds from a series of masked ketone electrophiles and a wide range of conventional heteroatom and carbon nucleophiles catalysed by a metallacyclic iridium catalyst. PMID- 30455429 TI - Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. AB - Major tumor suppressor and transcription factor p53 coordinates expression of many genes hence affecting critical cellular functions including cell cycle, senescence, and apoptosis. The NR4A family of orphan receptors (NR4A1-3) belongs to the superfamily of nuclear receptors. They regulate genes involved in proliferation, cell migration, and apoptosis. In this study, we report an identification of NR4A3 as a direct transcriptional target of p53. Using various techniques, we showed that p53 directly bound the promoter of NR4A3 gene and induced its transcription. Functionally, over-expression of NR4A3 attenuated proliferation of cancer cells and promoted apoptosis by augmenting the expression of pro-apoptotic genes, PUMA and Bax. Knockdown of NR4A3 reversed these phenotypes. Importantly, NR4A3 exhibited tumor suppressive functions both in p53 dependent and independent manner. In addition, NR4A3 physically interacted with an anti-apoptotic Bcl-2 protein hence sequestering it from blunting apoptosis. These observations were corroborated by the bioinformatics analysis, which demonstrated a correlation between high levels of NR4A3 expression and better survival of breast and lung cancer patients. Collectively, our studies revealed a novel transcriptional target of p53, NR4A3, which triggers apoptosis and thus likely has a tumor suppressive role in breast and lung cancers. PMID- 30455431 TI - Identification of the strong Bronsted acid site in a metal-organic framework solid acid catalyst. AB - It remains difficult to understand the surface of solid acid catalysts at the molecular level, despite their importance for industrial catalytic applications. A sulfated zirconium-based metal-organic framework, MOF-808-SO4, was previously shown to be a strong solid Bronsted acid material. In this report, we probe the origin of its acidity through an array of spectroscopic, crystallographic and computational characterization techniques. The strongest Bronsted acid site is shown to consist of a specific arrangement of adsorbed water and sulfate moieties on the zirconium clusters. When a water molecule adsorbs to one zirconium atom, it participates in a hydrogen bond with a sulfate moiety that is chelated to a neighbouring zirconium atom; this motif, in turn, results in the presence of a strongly acidic proton. On dehydration, the material loses its acidity. The hydrated sulfated MOF exhibits a good catalytic performance for the dimerization of isobutene (2-methyl-1-propene), and achieves a 100% selectivity for C8 products with a good conversion efficiency. PMID- 30455432 TI - Heteromultivalent peptide recognition by co-assembly of cyclodextrin and calixarene amphiphiles enables inhibition of amyloid fibrillation. AB - Heteromultivalency, which involves the simultaneous interactions of more than one type of ligand with more than one type of receptor, is ubiquitous in living systems and provides a powerful strategy to improve the binding efficiency of heterotopic species such as proteins and membranes. However, the design and development of artificial heteromultivalent receptors is still challenging owing to tedious synthesis processes and the need for precise control over the spatial arrangement of the binding sites. Here, we have designed a heteromultivalent platform by co-assembling cyclodextrin and calixarene amphiphiles, so that two orthogonal, non-covalent binding sites are distributed on the surface of the co assembly. Binding with model peptides shows a synergistic effect of the two receptors, (hetero)multivalency and self-adaptability. The co-assembly shows promise for inhibition of the fibrillation of amyloid-beta peptides and the dissolution of amyloid-beta fibrils, substantially reducing amyloid cytotoxicity. This self-assembled heteromultivalency concept is easily amenable to other ensembles and targets, so that versatile biomedical applications can be envisaged. PMID- 30455433 TI - Author Correction: Directional Exosome Proteomes Reflect Polarity-Specific Functions in Retinal Pigmented Epithelium Monolayers. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30455434 TI - High-resolution crystal structure of parathyroid hormone 1 receptor in complex with a peptide agonist. AB - Parathyroid hormone 1 receptor (PTH1R) is a class B multidomain G-protein-coupled receptor (GPCR) that controls calcium homeostasis. Two endogenous peptide ligands, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP), activate the receptor, and their analogs teriparatide and abaloparatide are used in the clinic to increase bone formation as an effective yet costly treatment for osteoporosis. Activation of PTH1R involves binding of the peptide ligand to the receptor extracellular domain (ECD) and transmembrane domain (TMD), a hallmark of class B GPCRs. Here, we present the crystal structure of human PTH1R in complex with a peptide agonist at 2.5-A resolution, allowing us to delineate the agonist binding mode for this receptor and revealing molecular details within conserved structural motifs that are critical for class B receptor function. Thus, this study provides structural insight into the function of PTH1R and extends our understanding of this therapeutically important class of GPCRs. PMID- 30455435 TI - A PxL motif promotes timely cell cycle substrate dephosphorylation by the Cdc14 phosphatase. AB - The cell division cycle consists of a series of temporally ordered events. Cell cycle kinases and phosphatases provide key regulatory input, but how the correct substrate phosphorylation and dephosphorylation timing is achieved is incompletely understood. Here we identify a PxL substrate recognition motif that instructs dephosphorylation by the budding yeast Cdc14 phosphatase during mitotic exit. The PxL motif was prevalent in Cdc14-binding peptides enriched in a phage display screen of native disordered protein regions. PxL motif removal from the Cdc14 substrate Cbk1 delays its dephosphorylation, whereas addition of the motif advances dephosphorylation of otherwise late Cdc14 substrates. Crystal structures of Cdc14 bound to three PxL motif substrate peptides provide a molecular explanation for PxL motif recognition on the phosphatase surface. Our results illustrate the sophistication of phosphatase-substrate interactions and identify them as an important determinant of ordered cell cycle progression. PMID- 30455436 TI - Dynamic molecular monitoring reveals that SWI-SNF mutations mediate resistance to ibrutinib plus venetoclax in mantle cell lymphoma. AB - Ibrutinib plus venetoclax is a highly effective combination in mantle cell lymphoma. However, strategies to enable the evaluation of therapeutic response are required. Our prospective analyses of patients within the AIM study revealed genomic profiles that clearly dichotomized responders and nonresponders. Mutations in ATM were present in most patients who achieved a complete response, while chromosome 9p21.1-p24.3 loss and/or mutations in components of the SWI-SNF chromatin-remodeling complex were present in all patients with primary resistance and two-thirds of patients with relapsed disease. Circulating tumor DNA analysis revealed that these alterations could be dynamically monitored, providing concurrent information on treatment response and tumor evolution. Functional modeling demonstrated that compromise of the SWI-SNF complex facilitated transcriptional upregulation of BCL2L1 (Bcl-xL) providing a selective advantage against ibrutinib plus venetoclax. Together these data highlight important insights into the molecular basis of therapeutic response and provide a model for real-time assessment of innovative targeted therapies. PMID- 30455438 TI - Dinosaur ossification centres in embryonic birds uncover developmental evolution of the skull. AB - Radical transformation of the skull characterizes bird evolution. An increase in the relative size of the brain and eyes was presumably related to the loss of two bones surrounding the eye, the prefrontal and postorbital. We report that ossification centres of the prefrontal and postorbital are still formed in bird embryos, which then fuse seamlessly to the developing nasal and frontal bones, respectively, becoming undetectable in the adult. The presence of a dinosaur-like ossification pattern in bird embryos is more than a trace of their evolutionary past: we show how persistent modularity of ossification centres has allowed for evolutionary re-organization of skull architecture in evolution. Our findings also demonstrate that enigmatic mesodermal cells forming the posterior region of the avian frontal correspond to the ossification centre of the postorbital, not the parietal, and link its failure to develop into an adult bone to its incorporation into the expanded braincase of birds. PMID- 30455439 TI - Dual-stressor selection alters eco-evolutionary dynamics in experimental communities. AB - Recognizing when and how rapid evolution drives ecological change is fundamental for our understanding of almost all ecological and evolutionary processes such as community assembly, genetic diversification and the stability of communities and ecosystems. Generally, rapid evolutionary change is driven through selection on genetic variation and is affected by evolutionary constraints, such as tradeoffs and pleiotropic effects, all contributing to the overall rate of evolutionary change. Each of these processes can be influenced by the presence of multiple environmental stressors reducing a population's reproductive output. Potential consequences of multistressor selection for the occurrence and strength of the link from rapid evolution to ecological change are unclear. However, understanding these is necessary for predicting when rapid evolution might drive ecological change. Here we investigate how the presence of two stressors affects this link using experimental evolution with the bacterium Pseudomonas fluorescens and its predator Tetrahymena thermophila. We show that the combination of predation and sublethal antibiotic concentrations delays the evolution of anti predator defence and antibiotic resistance compared with the presence of only one of the two stressors. Rapid defence evolution drives stabilization of the predator-prey dynamics but this link between evolution and ecology is weaker in the two-stressor environment, where defence evolution is slower, leading to less stable population dynamics. Tracking the molecular evolution of whole populations over time shows further that mutations in different genes are favoured under multistressor selection. Overall, we show that selection by multiple stressors can significantly alter eco-evolutionary dynamics and their predictability. PMID- 30455440 TI - Commercial tourism in Tasmania's wilderness threatens the attraction it exploits. PMID- 30455441 TI - Social support drives female dominance in the spotted hyaena. AB - Identifying how dominance within and between the sexes is established is pivotal to understanding sexual selection and sexual conflict. In many species, members of one sex dominate those of the other in one-on-one interactions. Whether this results from a disparity in intrinsic attributes, such as strength and aggressiveness, or in extrinsic factors, such as social support, is currently unknown. We assessed the effects of both mechanisms on dominance in the spotted hyaena (Crocuta crocuta), a species where sexual size dimorphism is low and females often dominate males. We found that individuals with greater potential social support dominated one-on-one interactions in all social contexts, irrespective of their body mass and sex. Female dominance emerged from a disparity in social support in favour of females. This disparity was a direct consequence of male-biased dispersal and the disruptive effect of dispersal on social bonds. Accordingly, the degree of female dominance varied with the demographic and kin structure of the social groups, ranging from male and female co-dominance to complete female dominance. Our study shows that social support can drive sex-biased dominance and provides empirical evidence that a sex-role defining trait can emerge without the direct effect of sex. PMID- 30455442 TI - Tropical forest leaves may darken in response to climate change. AB - Tropical forest leaf albedo (reflectance) greatly impacts how much energy the planet absorbs; however; little is known about how it might be impacted by climate change. Here, we measure leaf traits and leaf albedo at ten 1-ha plots along a 3,200-m elevation gradient in Peru. Leaf mass per area (LMA) decreased with warmer temperatures along the elevation gradient; the distribution of LMA was positively skewed at all sites indicating a shift in LMA towards a warmer climate and future reduced tropical LMA. Reduced LMA was significantly (P < 0.0001) correlated with reduced leaf near-infrared (NIR) albedo; community weighted mean NIR albedo significantly (P < 0.01) decreased as temperature increased. A potential future 2 degrees C increase in tropical temperatures could reduce lowland tropical leaf LMA by 6-7 g m-2 (5-6%) and reduce leaf NIR albedo by 0.0015-0.002 units. Reduced NIR albedo means that leaves are darker and absorb more of the Sun's energy. Climate simulations indicate this increased absorbed energy will warm tropical forests more at high CO2 conditions with proportionately more energy going towards heating and less towards evapotranspiration and cloud formation. PMID- 30455443 TI - Decoding plant communities across scales. PMID- 30455444 TI - Whole-genome sequences of Malawi cichlids reveal multiple radiations interconnected by gene flow. AB - The hundreds of cichlid fish species in Lake Malawi constitute the most extensive recent vertebrate adaptive radiation. Here we characterize its genomic diversity by sequencing 134 individuals covering 73 species across all major lineages. The average sequence divergence between species pairs is only 0.1-0.25%. These divergence values overlap diversity within species, with 82% of heterozygosity shared between species. Phylogenetic analyses suggest that diversification initially proceeded by serial branching from a generalist Astatotilapia-like ancestor. However, no single species tree adequately represents all species relationships, with evidence for substantial gene flow at multiple times. Common signatures of selection on visual and oxygen transport genes shared by distantly related deep-water species point to both adaptive introgression and independent selection. These findings enhance our understanding of genomic processes underlying rapid species diversification, and provide a platform for future genetic analysis of the Malawi radiation. PMID- 30455445 TI - Thoughts on the limits of a mutual technique. AB - Ferenczi's appreciation of the inherently mutual nature of the analytic encounter led him, and many who followed, to explore the value of mutual openness between patient and analyst. Specifically, Ferenczi saw the analyst's openness as an antidote to his earlier defensive denial of his failings and ambivalence toward the patient, which had undermined his patient's trust. My own view is that, while the analyst's openness with the patient can indeed help reestablish trust and restore a productive analytic process in the short term, it also poses long-term dangers. In certain treatments it may encourage "malignant regression", where the patient primarily seeks gratification from the analyst, resulting in an unmanageable "unending spiral of demands or needs" (Balint, 1968, p. 146). I suggest that an analyst's "confessions", in response to the patient's demand for accountability, can sometimes reinforce the patient's fantasy that healing comes from what the analyst gives or from turning the tables on his own sense of helplessness and shame by punishing or dominating the analyst. In such situations, the patient's fantasy may dovetail with the analyst's implicit theory that healing includes absorbing the patient's pain and even accepting his hostility, thus confirming the patient's fantasies, intensifying his malignant regression and dooming the treatment to failure. When malignant regression threatens, the analyst must set firmer boundaries, including limits on her openness, in order to help the patient shift his focus away from expectations of the analyst and toward greater self-reflection. This requires the analyst to resist the roles of rescuer, failure, or victim-roles rooted in the analyst's own unconscious fantasies. PMID- 30455437 TI - Global trait-environment relationships of plant communities. AB - Plant functional traits directly affect ecosystem functions. At the species level, trait combinations depend on trade-offs representing different ecological strategies, but at the community level trait combinations are expected to be decoupled from these trade-offs because different strategies can facilitate co existence within communities. A key question is to what extent community-level trait composition is globally filtered and how well it is related to global versus local environmental drivers. Here, we perform a global, plot-level analysis of trait-environment relationships, using a database with more than 1.1 million vegetation plots and 26,632 plant species with trait information. Although we found a strong filtering of 17 functional traits, similar climate and soil conditions support communities differing greatly in mean trait values. The two main community trait axes that capture half of the global trait variation (plant stature and resource acquisitiveness) reflect the trade-offs at the species level but are weakly associated with climate and soil conditions at the global scale. Similarly, within-plot trait variation does not vary systematically with macro-environment. Our results indicate that, at fine spatial grain, macro environmental drivers are much less important for functional trait composition than has been assumed from floristic analyses restricted to co-occurrence in large grid cells. Instead, trait combinations seem to be predominantly filtered by local-scale factors such as disturbance, fine-scale soil conditions, niche partitioning and biotic interactions. PMID- 30455446 TI - Flexible layer-structured Bi2Te3 thermoelectric on a carbon nanotube scaffold. AB - Inorganic chalcogenides are traditional high-performance thermoelectric materials. However, they suffer from intrinsic brittleness and it is very difficult to obtain materials with both high thermoelectric ability and good flexibility. Here, we report a flexible thermoelectric material comprising highly ordered Bi2Te3 nanocrystals anchored on a single-walled carbon nanotube (SWCNT) network, where a crystallographic relationship exists between the Bi2Te3 <[Formula: see text]> orientation and SWCNT bundle axis. This material has a power factor of ~1,600 MUW m-1 K-2 at room temperature, decreasing to 1,100 MUW m 1 K-2 at 473 K. With a low in-plane lattice thermal conductivity of 0.26 +/- 0.03 W m-1 K-1, a maximum thermoelectric figure of merit (ZT) of 0.89 at room temperature is achieved, originating from a strong phonon scattering effect. The origin of the excellent flexibility and thermoelectric performance of the Bi2Te3 SWCNT material is attributed, by experimental and computational evidence, to its crystal orientation, interface and nanopore structure. Our results provide insight into the design and fabrication of high-performance flexible thermoelectric materials. PMID- 30455448 TI - Inflating to shape. PMID- 30455447 TI - Bio-inspired pneumatic shape-morphing elastomers. AB - Shape-morphing structures are at the core of future applications in aeronautics1, minimally invasive surgery2, tissue engineering3 and smart materials4. However, current engineering technologies, based on inhomogeneous actuation across the thickness of slender structures, are intrinsically limited to one-directional bending5. Here, we describe a strategy where mesostructured elastomer plates undergo fast, controllable and complex shape transformations under applied pressure. Similar to pioneering techniques based on soft hydrogel swelling6-10, these pneumatic shape-morphing elastomers, termed here as 'baromorphs', are inspired by the morphogenesis of biological structures11-15. Geometric restrictions are overcome by controlling precisely the local growth rate and direction through a specific network of airways embedded inside the rubber plate. We show how arbitrary three-dimensional shapes can be programmed using an analytic theoretical model, propose a direct geometric solution to the inverse problem, and illustrate the versatility of the technique with a collection of configurations. PMID- 30455449 TI - Ordered polymeric membranes using metals. PMID- 30455450 TI - Thermoelectrics that bend but don't break. PMID- 30455451 TI - Metal-induced ordered microporous polymers for fabricating large-area gas separation membranes. AB - Metal-induced ordered microporous polymers (MMPs), a class of porous polymer, are synthesized from amine-bearing polymers, small organic linkers and divalent metal ions using a polymer-directed chemical synthesis process. Specifically, small organic linkers first coordinate to metal ions, with the resulting unit cells then self-assembling along the extension of polymer chains to construct three dimensional frameworks. The MMPs demonstrate good controllability of crystal and framework size, as well as hydrolytic stability. MMP dispersions were coated on a modified polysulfone substrate to fabricate MMP/mPSf membranes with an ultrathin selective layer (below 50 nm) and surface areas of >100 cm2. The MMPs are readily fabricated into defect-free thin selective-layered membranes with high CO2 permeance (3,000 GPU) and stable CO2/N2 selectivity (78) under both humid and dry gas feed conditions, demonstrating promising CO2 membrane separation performance. This synthetic methodology could be extended to other polymers, potentially enabling facile synthesis of membrane materials. PMID- 30455452 TI - Author Correction: Behavioral abnormalities with disruption of brain structure in mice overexpressing VGF. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 30455453 TI - Maria Teresa Carri Obituary. PMID- 30455454 TI - Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. AB - SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder. PMID- 30455455 TI - Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development. AB - MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development. PMID- 30455456 TI - Thalamic regulation of switching between cortical representations enables cognitive flexibility. AB - Interactions between the prefrontal cortex (PFC) and mediodorsal thalamus are critical for cognitive flexibility, yet the underlying computations are unknown. To investigate frontothalamic substrates of cognitive flexibility, we developed a behavioral task in which mice switched between different sets of learned cues that guided attention toward either visual or auditory targets. We found that PFC responses reflected both the individual cues and their meaning as task rules, indicating a hierarchical cue-to-rule transformation. Conversely, mediodorsal thalamus responses reflected the statistical regularity of cue presentation and were required for switching between such experimentally specified cueing contexts. A subset of these thalamic responses sustained context-relevant PFC representations, while another suppressed the context-irrelevant ones. Through modeling and experimental validation, we find that thalamic-mediated suppression may not only reduce PFC representational interference but could also preserve unused cortical traces for future use. Overall, our study provides a computational foundation for thalamic engagement in cognitive flexibility. PMID- 30455457 TI - SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. AB - In addition to cognitive impairments, neurodevelopmental disorders often result in sensory processing deficits. However, the biological mechanisms that underlie impaired sensory processing associated with neurodevelopmental disorders are generally understudied and poorly understood. We found that SYNGAP1 haploinsufficiency in humans, which causes a sporadic neurodevelopmental disorder defined by cognitive impairment, autistic features, and epilepsy, also leads to deficits in tactile-related sensory processing. In vivo neurophysiological analysis in Syngap1 mouse models revealed that upper-lamina neurons in somatosensory cortex weakly encode information related to touch. This was caused by reduced synaptic connectivity and impaired intrinsic excitability within upper lamina somatosensory cortex neurons. These results were unexpected, given that Syngap1 heterozygosity is known to cause circuit hyperexcitability in brain areas more directly linked to cognitive functions. Thus, Syngap1 heterozygosity causes a range of circuit-specific pathologies, including reduced activity within cortical neurons required for touch processing, which may contribute to sensory phenotypes observed in patients. PMID- 30455458 TI - Characterization of human mosaic Rett syndrome brain tissue by single-nucleus RNA sequencing. AB - In females with X-linked genetic disorders, wild-type and mutant cells coexist within brain tissue because of X-chromosome inactivation, posing challenges for interpreting the effects of X-linked mutant alleles on gene expression. We present a single-nucleus RNA sequencing approach that resolves mosaicism by using single-nucleotide polymorphisms in genes expressed in cis with the X-linked mutation to determine which nuclei express the mutant allele even when the mutant gene is not detected. This approach enables gene expression comparisons between mutant and wild-type cells within the same individual, eliminating variability introduced by comparisons to controls with different genetic backgrounds. We apply this approach to mosaic female mouse models and humans with Rett syndrome, an X-linked neurodevelopmental disorder caused by mutations in the gene encoding the methyl-DNA-binding protein MECP2, and observe that cell-type-specific DNA methylation predicts the degree of gene upregulation in MECP2-mutant neurons. This approach can be broadly applied to study gene expression in mosaic X-linked disorders. PMID- 30455460 TI - Alarmin S100A11 initiates a chemokine response to the human pathogen Toxoplasma gondii. AB - Toxoplasma gondii is a common protozoan parasite that infects up to one third of the world's population. Notably, very little is known about innate immune sensing mechanisms for this obligate intracellular parasite by human cells. Here, by applying an unbiased biochemical screening approach, we show that human monocytes recognized the presence of T. gondii infection by detecting the alarmin S100A11 protein, which is released from parasite-infected cells via caspase-1-dependent mechanisms. S100A11 induced a potent chemokine response to T. gondii by engaging its receptor RAGE, and regulated monocyte recruitment in vivo by inducing expression of the chemokine CCL2. Our experiments reveal a sensing system for T. gondii by human cells that is based on the detection of infection-mediated release of S100A11 and RAGE-dependent induction of CCL2, a crucial chemokine required for host resistance to the parasite. PMID- 30455459 TI - DEL-1 promotes macrophage efferocytosis and clearance of inflammation. AB - Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte endothelial adhesion and inflammation initiation, also functions as a non redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically. PMID- 30455461 TI - Placental mitochondrial adaptations in preeclampsia associated with progression to term delivery. AB - Preeclampsia is a devastating pregnancy disorder. Severity varies widely, and while severe preeclampsia often requires pre-term delivery, women with mild preeclampsia may reach term with minor interventions. The mechanisms that mediate disease severity are poorly understood, but may include adaptive processes by the placenta. We aimed to establish whether in pregnancies that reached term and those that delivered pre-term, the placental response to preeclampsia was intrinsically different, and explore potential adaptive mechanisms. Hydrogen peroxide production and antioxidant activity were increased in term preeclamptic placentae, whereas pre-term preeclamptic placentae had reduced hydrogen peroxide production and reduced function of the antioxidant system superoxide dismutase compared to control placentae. Markers of mitochondrial fission/fusion, apoptosis and the expression level of mitochondrial complexes were differentially disrupted in term compared to pre-term preeclamptic placentae. Mitochondrial respiration and content were increased in term preeclamptic placentae, but mitochondria had a lower respiratory reserve capacity. Mitochondrial respiration and hydrogen peroxide production were increased in healthy term placentae after in vitro hypoxia/reoxygenation. Placentae from preeclamptic pregnancies that reached term showed multiple adaptions that were not present in pre-term preeclamptic placentae. Increased antioxidant activity, and expression of markers of mitochondrial fusion and apoptotic suppression, may relate to salvaging damaged mitochondria. Increased mitochondrial respiration may allow ongoing tissue function even with reduced respiratory efficiency in term preeclamptic pregnancies. Response after in vitro hypoxia/reoxygenation suggests that disruption of oxygen supply is key to placental mitochondrial adaptations. Reactive oxygen species signalling in term preeclamptic placentae may be at a level to trigger compensatory antioxidant and mitochondrial responses, allowing tissue level maintenance of function when there is organelle level dysfunction. PMID- 30455462 TI - Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours. AB - Mutations in, and the altered expression of, epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive antitumour targets. The open-versus-closed chromatin state within the cells-of-origin of cancer correlates with the uneven distribution of mutations. However, the long-term effect of targeting epigenetic modifiers on mutability in patients with cancer is unclear. Here, we increased chromatin accessibility by deleting the histone H3 lysine 9 (H3K9) methyltransferase G9a in murine epidermis and show that this does not alter the single nucleotide variant burden or global genomic distribution in chemical mutagen-induced squamous tumours. G9a-depleted tumours develop after a prolonged latency compared with their wild-type counterparts, but are more aggressive and have an expanded cancer progenitor pool, pronounced genomic instability and frequent loss-of-function p53 mutations. Thus, we call for caution when assessing long-term therapeutic benefits of chromatin modifier inhibitors, which may promote more aggressive disease. PMID- 30455463 TI - Publisher Correction: Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration. AB - The Article was originally published under a CC BY-NC-ND 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly. PMID- 30455464 TI - Cell-type-specific and projection-specific brain-wide reconstruction of single neurons. AB - We developed a dual-adeno-associated-virus expression system that enables strong and sparse labeling of individual neurons with cell-type and projection specificity. We demonstrated its utility for whole-brain reconstruction of midbrain dopamine neurons and striatum-projecting cortical neurons. We further extended the labeling method for rapid reconstruction in cleared thick brain sections and simultaneous dual-color labeling. This labeling system may facilitate the process of generating mesoscale single-neuron projectomes of mammalian brains. PMID- 30455466 TI - Polarized displacement by transcription activator-like effectors for regulatory circuits. AB - The interplay between DNA-binding proteins plays an important role in transcriptional regulation and could increase the precision and complexity of designed regulatory circuits. Here we show that a transcription activator-like effector (TALE) can displace another TALE protein from DNA in a highly polarized manner, displacing only the 3'- but not 5'-bound overlapping or adjacent TALE. We propose that the polarized displacement by TALEs is based on its multipartite nature of binding to DNA. The polarized TALE displacement provides strategies for the specific regulation of gene expression, for construction of all two-input Boolean genetic logic circuits based on the robust propagation of the displacement across multiple neighboring sites, for displacement of zinc finger based transcription factors and for suppression of Cas9-gRNA-mediated genome cleavage, enriching the synthetic biology toolbox and contributing to the understanding of the underlying principles of the facilitated displacement. PMID- 30455465 TI - H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. AB - Epigenetic regulators are attractive anticancer targets, but the promise of therapeutic strategies inhibiting some of these factors has not been proven in vivo or taken into account tumor cell heterogeneity. Here we show that the histone methyltransferase G9a, reported to be a therapeutic target in many cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs). Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by de-repressing genes which regulate the extracellular matrix. Depletion of G9a during tumorigenesis enriches tumors in TPCs and accelerates disease progression metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and targeting the histone demethylases is a more suitable approach for lung cancer treatment. Understanding cellular context and specific tumor populations is critical when targeting epigenetic regulators in cancer for future therapeutic development. PMID- 30455468 TI - Correction: Morning blood pressure surge in young black and white adults: The African-PREDICT Study. AB - In the article "Morning blood pressure surge in young black and white adults: The African-PREDICT Study" by Gontse Gratitude Mokwatsi, Aletta Elisabeth Schutte, Catharina Martha Cornelia Mels and Ruan Kruger which appeared in 'Journal of Human Hypertension' (2018) volume 32, DOI 10.1038/s41371-018-0089-3, the authors regret that they mentioned erroneously that none of their study participants had an exaggerated morning blood pressure surge. They would like to point out that 40 participants in their study population had an exaggerated sleep-trough surge whereas 128 had an exaggerated dynamic surge. PMID- 30455469 TI - Gut bacterial phospholipase Ds support disease-associated metabolism by generating choline. AB - The essential nutrient choline is metabolized by gut bacteria to the disease associated metabolite trimethylamine (TMA). However, most of the choline obtained via the diet and present in the human body is incorporated into larger metabolites, including the lipid phosphatidylcholine (PC). Here, we report that many choline-utilizing gut microorganisms can hydrolyse PC using a phospholipase D (PLD) enzyme and further convert the released choline to TMA. Genetic and in vitro characterization of the PLD from Escherichia coli MS 200-1 showed this enzyme is essential for bacterial hydrolysis of PC and prefers this substrate. PLDs are also found in gut bacterial isolates that are unable to convert choline to TMA, suggesting that additional members of the gut microbiota may influence access to this substrate. Unexpectedly, this PLD is only distantly related to characterized PLDs from pathogenic bacteria, suggesting a distinct evolutionary history. Together, these results reveal a previously underappreciated role for gut microorganisms in phospholipid metabolism and a potential target for inhibiting TMA production. PMID- 30455467 TI - Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). AB - Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p <0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p <0.0001) and a shorter survival in MM patients with active disease requiring treatment (p <= 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM. PMID- 30455470 TI - Protective antibodies against Eastern equine encephalitis virus bind to epitopes in domains A and B of the E2 glycoprotein. AB - Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted alphavirus with a high case mortality rate in humans. EEEV is a biodefence concern because of its potential for aerosol spread and the lack of existing countermeasures. Here, we identify a panel of 18 neutralizing murine monoclonal antibodies (mAbs) against the EEEV E2 glycoprotein, several of which have 'elite' activity with 50 and 99% effective inhibitory concentrations (EC50 and EC99) of less than 10 and 100 ng ml-1, respectively. Alanine-scanning mutagenesis and neutralization escape mapping analysis revealed epitopes for these mAbs in domains A or B of the E2 glycoprotein. A majority of the neutralizing mAbs blocked infection at a post attachment stage, with several inhibiting viral membrane fusion. Administration of one dose of anti-EEEV mAb protected mice from lethal subcutaneous or aerosol challenge. These experiments define the mechanistic basis for neutralization by protective anti-EEEV mAbs and suggest a path forward for treatment and vaccine design. PMID- 30455472 TI - Pulmonary phagocyte-derived NPY controls the pathology of severe influenza virus infection. AB - Crosstalk between the autonomic nervous system and the immune system by means of the sympathetic and parasympathetic pathways is a critical process in host defence. Activation of the sympathetic nervous system results in the release of catecholamines as well as neuropeptide Y (NPY). Here, we investigated whether phagocytes are capable of the de novo production of NPY, as has been described for catecholamines. We show that the synthesis of NPY and its Y1 receptor (Y1R) is increased in phagocytes in lungs following severe influenza virus infection. The genetic deletion of Npy or Y1r specifically in phagocytes greatly improves the pathology of severe influenza virus infection, which is characterized by excessive virus replication and pulmonary inflammation. Mechanistically, it is the induction of suppressor of cytokine signalling 3 (SOCS3) via NPY-Y1R activation that is responsible for impaired antiviral response and promoting pro inflammatory cytokine production, thereby enhancing the pathology of influenza virus infection. Thus, direct regulation of the NPY-Y1R-SOCS3 pathway on phagocytes may act as a fine-tuner of an innate immune response to virus infection, which could be a therapeutic target for lethal influenza virus infection. PMID- 30455473 TI - Can mixed lipid emulsion prevent parenteral nutrition associated cholestasis? PMID- 30455471 TI - A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions. AB - West Nile virus (WNV), a member of the Flavivirus genus, is a leading cause of viral encephalitis in the United States1. The development of neutralizing antibodies against the flavivirus envelope (E) protein is critical for immunity and vaccine protection2. Previously identified candidate therapeutic mouse and human neutralizing monoclonal antibodies (mAbs) target epitopes within the E domain III lateral ridge and the domain I-II hinge region, respectively3. To explore the neutralizing antibody repertoire elicited by WNV infection for potential therapeutic application, we isolated ten mAbs from WNV-infected individuals. mAb WNV-86 neutralized WNV with a 50% inhibitory concentration of 2 ng ml-1, one of the most potently neutralizing flavivirus-specific antibodies ever isolated. WNV-86 targets an epitope in E domain II, and preferentially recognizes mature virions lacking an uncleaved form of the chaperone protein prM, unlike most flavivirus-specific antibodies4. In vitro selection experiments revealed a neutralization escape mechanism involving a glycan addition to E domain II. Finally, a single dose of WNV-86 administered two days post-infection protected mice from lethal WNV challenge. This study identifies a highly potent human neutralizing mAb with therapeutic potential that targets an epitope preferentially displayed on mature virions. PMID- 30455474 TI - BAP1 regulates different mechanisms of cell death. PMID- 30455476 TI - Modular approach for resolving and mapping complex neural and other cellular structures and their associated deformation fields in three dimensions. AB - Understanding the biological implications of cellular mechanotransduction, especially in the context of pathogenesis, requires the accurate resolution of material deformation and strain fields surrounding the cells. This is particularly challenging for cells displaying branched, 3D architectures. Here, we provide a modular approach for 3D image segmentation and strain mapping of topologically complex structures. We describe how to use our approach, using neural cells and networks as an example. In addition to describing how to implement the computational analysis, we provide details of a cell culture protocol that can be used to generate neural networks for analysis and experimentation. This protocol allows for transformation of matrix-induced strains, and their full resolution across single cells or networks in three dimensions. The protocol also provides analyses to compute both the locally varying cytoskeletal strains and the average strain experienced by cells. An additional module allows spatial correlation of these strain maps with cytoskeletal features, including neurite disruptions such as neuronal blebs. Image processing and strain mapping take >=3 h, with the exact time required being dependent on use case, software familiarity, and file size. PMID- 30455475 TI - Genetic predictors of response to specific drugs in primary myelofibrosis. PMID- 30455477 TI - Lentiviral transduction of mammalian cells for fast, scalable and high-level production of soluble and membrane proteins. AB - Structural, biochemical and biophysical studies of eukaryotic soluble and membrane proteins require their production in milligram quantities. Although large-scale protein expression strategies based on transient or stable transfection of mammalian cells are well established, they are associated with high consumable costs, limited transfection efficiency or long and tedious selection of clonal cell lines. Lentiviral transduction is an efficient method for the delivery of transgenes to mammalian cells and unifies the ease of use and speed of transient transfection with the robust expression of stable cell lines. In this protocol, we describe the design and step-by-step application of a lentiviral plasmid suite, termed pHR-CMV-TetO2, for the constitutive or inducible large-scale production of soluble and membrane proteins in HEK293 cell lines. Optional features include bicistronic co-expression of fluorescent marker proteins for enrichment of co-transduced cells using cell sorting and of biotin ligase for in vivo biotinylation. We demonstrate the efficacy of the method for a set of soluble proteins and for the G-protein-coupled receptor (GPCR) Smoothened (SMO). We further compare this method with baculovirus transduction of mammalian cells (BacMam), using the type-A gamma-aminobutyric acid receptor (GABAAR) beta3 homopentamer as a test case. The protocols described here are optimized for simplicity, speed and affordability; lead to a stable polyclonal cell line and milligram-scale amounts of protein in 3-4 weeks; and routinely achieve an approximately three- to tenfold improvement in protein production yield per cell as compared to transient transduction or transfection. PMID- 30455478 TI - ECI Biocommentary-February. PMID- 30455479 TI - Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools. AB - Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD. PMID- 30455480 TI - Peer Review Initiatives in Nepal. AB - NA. PMID- 30455481 TI - Factors Influencing Modern Contraceptive Use among Adolescents in Nepal. AB - In Nepal, contraceptive use among married adolescents is low and has remained nearly stagnant since 2006, while little information is available about contraceptive use among unmarried adolescents. Nepal is committed to improve sexual and reproductive health rights among all the adolescents. Promoting modern contraceptive use especially among married adolescents is one of the key approaches in practice, to prevent HIV or sexual transmitted infections, avoid unintended pregnancy and sub-sequent unsafe abortion. In spite of these efforts, modern contraceptive use among married adolescents is not increasing. In this study, we aimed to review the prevalence and trends as well as factors influencing modern contraceptive use among both married and unmarried adolescents in Nepal. A review of existing published and unpublished articles, documents, and reports were conducted. An adapted and modified socio-ecological model was used to explore the factors influencing contraceptive use. Contraceptive use is persistently low among adolescents. Various interrelated factors like socio cultural norms and traditions, lack of comprehensive knowledge on contraceptive methods among adolescents, inadequate adolescent friendly Services and health workers not having the competencies to work with adolescents, are the major influential factors that limit adolescents to seek and use contraceptive services and information. A multilevel approach is required to address the interrelated factors and to create an enabling environment in which adolescent are fully informed and equipped to make use of contraceptives and related services. For this to happen, Government and NGOs working on sexual and reproductive health rights have to work towards translating the existing policies into practice. Involving adolescents, their families and communities; equipping teachers to provide comprehensive sex education within school and sex education programme for out of school and enhancing the competencies of health workers to provide adolescent friendly services - all in line with the written policy - is urgently needed. Keywords: Adolescent; barriers; contraceptive; Nepal; SRHR. PMID- 30455482 TI - Establishing Cardiac Surgery in Eastern Nepal: Early Results. AB - BACKGROUND: Only few dedicated cardiac centres provide cardiac surgery service in Nepal. We are the only government affiliated centre outside the capital providing this service. In this study, we aim to present our early results of cardiac surgery. METHODS: This retrospective study was conducted at B P Koirala Institute of Health Sciences with objective of analysing the early results of cardiac surgery in the patients operated from July 2016 to March 2017.The data were analysed for patient demographics, type of surgery and cardiac disease, mortality, hospital and intensive care unit stay, valve related complications. RESULTS: Total 51 major cardiac surgeries (42 on pump and nine off pump) were performed. There were 27 (53%) males and 24 (47%) females with median age of 36 years (range: 1 to 70 years).The cardiac diseases consisted of 28 rheumatic heart disease, 12 congenital heart diseases, five coronary artery disease, five chronic constrictive pericarditis and one left atrial myxoma. The mean cardiopulmonary bypass and cross clamp times were 106 +/-35 and 80+/-26 minutes respectively. The mean intensive care unit and hospital stay was 4+/-2 and 8+/-3 days respectively. Two (4%) patients required re-exploration for mediastinal bleeding. There was no prosthetic valve thrombosis or infection.Two patients (4%) had superficial wound infections.There were four (7.8%) in hospital mortalities. Remaining 47 patients (91.8%) are in NYHA class I aftermean follow up duration of five months. CONCLUSIONS: Our early result of cardiac surgery is encouraging and has established the safety and feasibility of starting open heart surgery in other parts of Nepal. PMID- 30455483 TI - Validation of Attention Deficit Hyperactivity Disorder Diagnostic Scale for Children. AB - BACKGROUND: There is no valid Attention Deficit Hyperactivity Disorder diagnostic tool to fit Nepalese culture and language till date. Current study is intended to develop and validate the Attention Deficit Hyperactivity Disorder scale for children in Nepal. METHODS: Mixed method study was conducted with 840 samples (i.e. children with Attention Deficit Hyperactivity Disorder =356, Anxiety =128 and General Population=356).Items generation, scale development and scale evaluation were the three consecutive steps followed to develop and validate the scale.Children with Attention Deficit Hyperactivity Disorder (already met the Diagnostic and statistical Manual-5 criteria) were further assessed by Kiddie Schedule for Affective disorders and Schizophrenia (K-SADS-PL), Child and Adolescent Symptoms Inventory (CASI-5) to confirm the diagnosis and psychometric validation. Pilot studies were done for items clarity. Each data obtained from three comparison groups (Attention Deficit Hyperactivity Disorder , Anxiety and General Population) were included for standardization process where tests of dimensionality, reliability, validity,calculating norms (cut off) were doneas scale evaluation process. RESULTS: The final version of the scale had 21 items. Three sub-scales (Inattention, Impulsivity and Hyperactivity) were identified by using Principal Axis Factor Analysis.All factors showed strong statistically significant convergent validity and Discriminant validity Cronbach's alpha of each item is ? 0.91.As total score criteria, 38.5 is considered as the best cut off point for this scale. CONCLUSIONS: By using systematic process, a valid and reliable Attention Deficit Hyperactivity Disorder diagnostic scale is being developed in Nepalese culture and language. PMID- 30455484 TI - Safety, Efficacy and Acceptability of Early First Trimester Abortion using Oral Mifepristone and Sublingual Misoprostol. AB - BACKGROUND: With the legalization of medical abortion in Nepal, mifepristone misoprostol combination via different routes has been widely used for early abortion. This study aims to evaluate the efficacy and acceptability of 200 milligrams mifepristone orally followed by 800 micrograms sublingual misoprostol in outpatient setting. METHODS: It was an open-label prospective study conducted in outpatient department of a tertiary hospital over a period of 13 months. Clients upto nine weeks of pregnancy were enrolled. 200 milligrams of mifepristone orally followed by 800 micrograms of misoprostol sublingually 36 to 48 hours later were prescribed. They were followed up in 14 days sonologically or verbally through telephone. Side effects and satisfaction to the regimen were assessed through acceptability questionnaire. Mann-Whitney U test was used for analyzing categorical data. RESULTS: A total of 47 clients were enrolled. The mean age and gestational age were 29.38 years (SD+5.914) and 6.2 weeks (SD+1.28) respectively. The commonest indications for termination were completed family and unwanted pregnancy (40.4% each). The average duration of bleeding was 5.76 days (SD +3.61). Abdominal cramping was the most common side effect (95.7%). The least acceptable parameter was the bleeding time (80.9%). For 97.9% clients, the adverse effects were acceptable. The overall success rate of the regimen was 87.2%. CONCLUSIONS: With a comparable success rate to vaginal use, home based sublingual use of misoprostol in low resource settings offers an acceptable and cost effective alternative for medical abortion upto nine weeks of pregnancy. Lesser gestational age is a useful predictor for successful abortion. PMID- 30455485 TI - Outcome of Percutaneous Nephrolithotomy in the Management of Lower Pole Stones. AB - BACKGROUND: Urolithiasis is a worldwide problem due to its high prevalence and recurrence. Percutaneous nephrolithotomy is a minimally invasive surgical option for the treatment of large renal stone burden greater than 20mm, staghorn calculi and lower pole calyceal stone greater than 10 mm. The objective of this study was to evaluate the safety and efficacy of percutaneous nephrolithotomy in the management of lower pole calyceal stones. METHODS: Seventy patients who presented in between June 2013 and September 2017 with lower pole calyceal stones and lower calyceal stones with pelvic extension were included in the study. The operating time, the hospital stay, complications rate, stone clearance rate were all noted. Patients were followed up in three and six weeks with X-ray KUB and ultrasonography of abdomen. RESULTS: Seventy adult patients with lower pole calyceal stones underwent standard percutaneous nephrolithotomy. The mean age was 32 years (18-71 yrs). The mean stone size was 17.6 mm (15 -28 mm). The mean operating time was 62 minutes (48-124 mins) and hospital stay was 4.1 days(4 8 days). The stone clearance rate was 92.6% for stone <20mm and 90.7% stone size >20 mm. The complications noted were fever (8.5%), transient haematuria (20%), urine leak (5.7%), obstruction by residual fragments (5.7%) and one pseudoaneurysm(1.42%). Seven patients (10%) needed blood transfusion. CONCLUSIONS: Percutaneous nephrolithotomy is a safe, feasible and highly effective method for the treatment of lower pole calyceal stones. PMID- 30455486 TI - The Assessment of Drug Use Pattern Using WHO Prescribing Indicators. AB - BACKGROUND: In order to promote rational drug use in developing countries, assessment of drug use pattern using the World Health Organization drug use indicators is important. The aim of this study was to assess the drug prescription patterns at Kathmandu Medical College Teaching Hospital, using some of the World Health Organization core drug use indicators. METHODS: A prospective cross-sectional study was carried out in order to determine current prescribing trends at Kathmandu Medical College Teaching Hospital. A total of 605 prescriptions were collected and analyzed in the study. RESULTS: The average number of drugs per prescription was 5.85 considering the total amount of prescriptions. Furthermore, assuming each prescription as an individual patient, 64.1% of patients received antibiotics, and 71% of patients received injectable form of drugs. Among antibiotics the most common antibiotics prescribed were Ceftriaxone, Amoxicillin/Cloxacillin, Azithromycin, Cefixime, and Cloxacillin. Only 16.94% of the medicines were prescribed in generic names with the rest 83.06% of the medicines being prescribed in brand names and 47.55% of medicines prescribed were from the National List of Essential Medicines-Nepal. CONCLUSIONS: The current study revealed that polypharmacy and prescription writing using brand names were common. Prescriptions writing in generic name needs to be promoted and encouraged. There appears to be a crucial need for the development of prescribing guidelines when it comes to antibiotics. PMID- 30455488 TI - Knowledge, Attitude and practice of Computer Vision Syndrome among medical students and its impact on ocular morbidity. AB - BACKGROUND: Computer vision syndrome is a common global problem among millions of computer users including medical students. Medical students are preferring soft copies rather than textbooks. The aim of this study was to assess the knowledge, attitude, and practice of MBBS students about Computer vision syndrome, and to identify its ocular morbidity among them. METHODS: A descriptive cross-sectional survey based on the questionnaire was conducted among 1st- 4th year MBBS students of the Institute of Medicine and 80 students underwent detailed ocular evaluation. RESULTS: A complete survey response was received from 236 students out of 299 students (Response Rate 80%). The mean age of MBBS students was 21.38 years +/- 1.328 years and the range were 19-22 years; 76.2% were male and 23.8% were female. The majority (37.2%) spent 2-3 hours/day on the computer and had a higher risk (p-0.0001) of developing Computer vision syndrome. About 69.5% students used a computer at the level of the eye but there was a significant reduction in Computer vision syndrome (p-0.0001) among those who had computer screen below the eye level. Association between taking breaks (p-0.0001) and frequent blinking (p-0.0411) during computer use and relief of symptoms was significant. Only 22.9% had pre-existing knowledge of Computer vision syndrome and only 25.5% of them were practicing the ideal viewing distance. Among 80 medical students randomly selected for detail eye examinations (63.7% male;36.2% female), the prevalence of Computer vision syndrome was 71.6%. The commonest ocular complaint was a headache (50%) and dry eyes (45%). Myopia was the commonest refractive error (31.2%) and the orthoptic problem was prevalent among 17.5% students. CONCLUSIONS: The survey showed that Computer vision syndrome is relevant among MBBS students but the knowledge, attitude, and practice of Computer vision syndrome among them is poor. PMID- 30455487 TI - Fatigue Experience and Coping Strategies among Cancer Patients Receiving Chemotherapy. AB - BACKGROUND: Cancer is considered one of the foremost common causes of death. Fatigue is among the distressing symptoms for cancer patients receiving chemotherapy. Adequate coping is essential for individual to deal with the effects of cancer related treatment. The objective of the study was to find out the fatigue experience and coping strategies among cancer patients receiving chemotherapy. METHODS: A descriptive, cross-sectional research design was used for the study. The samples was taken from day care and medical oncology ward of BP Koirala Memorial Cancer Hospital, Bharatpur. A total of 120 cancer patients receiving chemotherapy of 18 years and above were selected by using non probability consecutive sampling technique. Data was collected by using standard tool, Fatigue Symptom Inventory and Brief Cope. Data analysis was done by descriptive and inferential statistics. RESULTS: The study revealed that 82.5% of respondents had experienced fatigue and 50.8% respondents had used adequate coping strategies where "self distraction"(2.76+/-1.02) was the most used coping strategy by the respondents. Fatigue experience and coping strategies had negative correlation (r=-0.490, p=<0.001). CONCLUSIONS: Majority of the respondents had experienced fatigue, and half of the respondents used adequate coping strategies. The different methods of coping strategies for fatigue and chemotherapy related effects should be expanded as per the best available evidence to lower fatigue and other adverse effects. PMID- 30455489 TI - Outcome of Graft Uptake and Hearing Results between 'U' Flap Technique and Conventional Tympanomeatal Flap Technique for Anterior and Subtotal Tympanic Membrane Perforation. AB - BACKGROUND: Myringoplasty done for anterior and subtotal perforation needs expertise and practice than conventional underlay myringoplasty. The objective of this study was to compare the graft uptake and postoperative hearing results between 'U' flap and conventional tympanomeatal flap technique in anterior and subtotal tympanic membrane perforation. METHODS: Sixty three patients of age fifteen years and above with chronic otitis media mucosal type with any sized anterior and subtotal perforation of tympanic membrane were randomly allocated for myringoplasty by lottery method. There were thirty one cases in 'U' flap group and thirty two cases in conventional tympanomeatal flap group. Graft uptake and hearing results were assessed after six weeks and results were compared within and between the groups. RESULTS: Graft uptake rate was 90.3%(28/31) in'U' flap group and it was 87.5%(28/32) in conventional tympanomeatal flap group with no statistically significant difference (p= 0.772) between the two groups. The mean pre and post-operative air bone gap in 'U' flap group were 23.63dB+/-7.77dB; 13.26dB+/-5.50dB and that in the conventional tympanomeatal flap group were 20.88+/-9.88dB, 9.42dB+/-6.70dB respectively. There was no statistically significant difference in hearing results between the two groups (p= 0.504). CONCLUSIONS: The graft uptake rate and hearing results of 'U' flap group were comparable and showed no statistically significant difference to those of conventional tympanomeatal flap group. PMID- 30455490 TI - Knowledge and Acceptance of Labour Analgesia in Pregnant Women. AB - BACKGROUND: Labour analgesia, though practiced worldwide, is not very popular in low-income countries. The aim of the study was to assess the awareness, attitude, acceptance, and reasons for hindrance of labour analgesia among patients visiting a tertiary care center in the capital city Methods: It was a cross sectional study conducted in Obstetrics and Gynecology outpatient department of Kathmandu Medical College Teaching Hospital in the month of August 2017. All pregnant patients presenting for antenatal checkup was included. Data was collected based on a questionnaire after informed consent. Statistical analysis was done in SPSS version 20 and results were expressed in frequencies and percentage. RESULTS: Total of 270 pregnant women participated in the study. Out of these forty-four (16.3%) patients were aware about labour analgesia. The acceptance rate was high (72.2%). Majority (84.6%) had no problem with expenditure associated with labour analgesia. CONCLUSIONS: Despite low awareness about painless delivery among the antenatal women, the acceptance rate is high. PMID- 30455491 TI - Prevalence of Risk Factors of Major Non-Communicable Diseases among Adolescents of Higher Secondary Schools of Kaski District. AB - BACKGROUND: The main aim of this study is to determine the prevalence of major non communicable disease risk factors among higher secondary school students. METHODS: A cross-sectional study was conducted among higher secondary students of grade 11 and 12 of Kaski district in Nepal. The study period was from July 2016 to June 2017. Total sample 640 higher secondary students were recruited through two-stage cluster sampling. Self-administrated questionnaire was used for the data collection tool along with other tools which were used such as UNICEF electronic weighing scale, stature meter and mechanical aneroid sphygmomanometer. Ethical approval was obtained from IRC, Pokhara University. Data were entered intoEpiData software and analysis was performed with the help of the Statistical Package for Social Science (SPSS). RESULTS: The prevalence of smoking was 6.1% which was high in male (11.9%) than female (0.6%). Alcohol consumption practice among the adolescents was 18.9%. Family history of hypertension was seen higher than family history of diabetes.The prevalence of hypertension was 11.7%. High prevalence of abnormal values of systolic and diastolic BP was found in male than female students. Overweight was seen in 6.1% students. Prevalence of obesity was almost equal in both groups. CONCLUSIONS: There is high prevalence of smoking, alcoholism among adolescents. Hypertension was more common than overwieght among adolescents. PMID- 30455493 TI - Outcome of Sacrospinous Ligament Fixation of the Vault during Repair of Pelvic Organ Prolapse. AB - BACKGROUND: Pelvic organ prolapse includes descent of anterior/ posterior wall and apical (vault) prolapse with significant morbidity. In this study we evaluated the outcome of sacrospinous ligament fixation of vault through vaginal approach as part of the repair for massive uterovaginal (pelvic organ prolapse stage III and stage IV) and vault prolapse. METHODS: This study on sacrospinous ligament fixation along with repair for Pelvic organ prolapse at Kathmandu Model Hospital from November 2016 to April 2018 was done to assess the outcome in terms of early (during hospital stay) and delayed (six months) post-operative complications and need of removal of sacrospinous fixation suture and recurrence of vault prolapse. RESULTS: Out of 95 Pelvic organ prolapse patients, 80 (84%) were post-menopausal, 28 (29.4%) were in the age group of 70-79 years. There were 61 (64%) POPQ stage III. The post-operative complications during post-operative hospital stay were pain over right buttock in 42 (44%), urinary retention in 7 (7%) and UTI in7 (7%). Sacrospinous suture was released in two patients for severe pain over right buttock. At one-week follow-up, 35 (36%) had right buttock pain of moderate severity and 8 (8%) had vaginal cuff infection. Sacrospinous suture was removed in one patient for neuropraxia two weeks following surgery. At four weeks follow-up, 25 (26%) patients had mild right buttock pain relieved by oral NSAIDs on need. At six months follow-up, five had occasional buttock pain, six had some recurrences and two had some vault prolapse and one each had short vagina and stress incontinence. CONCLUSIONS: Sacrospinous ligament fixation is a good procedure for the management of Pelvic organ prolapse with better long-term outcome if performed with good surgical expertise. PMID- 30455492 TI - Effect of an Educational Intervention on Knowledge and Perception Regarding Rational Medicine Use and Self-medication. AB - BACKGROUND: Rational use of medicines is important for safe and cost-effective pharmacotherapy. However, nearly half of the medicines available in the market may be used irrationally. The present study assessed the perceptions and knowledge about rational medicine use and responsible self-medication among participants before and after an educational intervention at KIST Medical College, Lalitpur. METHODS: An educational module was conducted among healthcare professionals, media personnel and female community health volunteers. The questionnaire was administered before and immediately after the module. The areas addressed were rational medicine use, ethical prescribing, rational drug use situation in Nepal, pharmaceutical promotion, rational self-medication, safe use of antibiotics, and drug use problems in Nepal. RESULTS: Among healthcare professionals, the rational drug use situation in Nepal and the total score significantly increased post-intervention (p<0.05). Among media personnel the mean scores increased significantly in pharmaceutical promotion and drug use problems in Nepal areas but there was a significant decrease in safe use of antibiotics. The pre-intervention pharmaceutical promotion score was significantly higher among healthcare professionals compared to media personnel while the rational self-medication scores were highest among female community health volunteers, safe use of antibiotics scores were highest among the media personnel. Post-intervention the mean pharmaceutical promotion scores was highest among healthcare professionals, rational self-medication scores among female community health volunteers, safe use of antibiotics, drug use problems in Nepal and total scores were highest among the media personnel. CONCLUSIONS: There were differences in the mean pre-intervention scores among different subgroups. A single session may not be enough to bring about significant changes in knowledge and perception. The retention of knowledge could be measured in future studies. PMID- 30455495 TI - Knowledge and Practice on Infection Prevention among Nurses of Bir Hospital, Kathmandu. AB - BACKGROUND: Infection prevention is a crucial component to provide quality care in any health care setting. Infections are leading cause of death and preventable illness. This study was conducted to find out the knowledge and practice among nurses regarding infectionprevention. METHODS: A descriptive study design was adopted for the study. Total 170 nurses were included by usingcensus technique to assess knowledge on infection prevention.Probability systematic sampling technique was used by selecting every odd number from staffs' list to observe the practice of 85 nurses..Semi-structured self-administered questionnaire and observation checklist was used for data collection. RESULTS: The study showed that 57.1% of respondents had adequate knowledge and only 48.2% had good practice on infection preventionthrough hand hygiene, use of adequate personal protective equipment, decontamination, cleaning of instruments, sterilization, and use of antiseptics, disposal of sharps and waste disposal. Similarly 88.8% of the respondents had not received any training related to infection prevention. CONCLUSIONS: This study reveals that respondents had better knowledge than practice on infection prevention. The study suggestthat need for organizing regular training, monitoring, development and implementation of guideline to improve knowledge and practice of nurses for prevention of infection in the hospital. PMID- 30455494 TI - Determination of CD4+ T- Lymphocytes in Healthy Children of Kathmandu. AB - BACKGROUND: The cluster differentiation (CD) of T-cell is the good marker for the immunological competence study. Nepal does not have a reference value for CD4+ T cell count and percentage for children, which severely limits the prospect of pediatric prognosis. METHODS: This cross-sectional study was conducted in Kathmandu valley where total 207 children of age 0-14 year age group were recruited in this study. We analyzed 50 cord blood and 157 peripheral blood samples in order to calculate the absolute count of CD4+ T lymphocyte using Fluorescence-activated cell sorting methodology. RESULTS: The reference range for absolute CD4+ T cell count was found to be 634-4040 cells/uL(mean1470; median: 1335 and 95% CI [1322-1617]) for male children and 491-2922 cells/uL (mean: 1443 median: 1326 and95% CI [1298-1588]) for the female children.We also observed elevated CD4 to the CD3 ratio in younger children (0.67 from cord blood Vs 0.53 from 10-14yr) compared to older ones. CONCLUSIONS: The observed CD4+ T cell counts among healthy children of Kathmandu highlights the gender differences skewed for male as well the need of defining specific reference values for other lymphocyte subsets as well in a country like Nepal which has a population with diverse genetic and socio-cultural parameters. PMID- 30455496 TI - Profile of Neurosurgical Patients in a Tertiary Level Intensive Care Unit in Nepal. AB - BACKGROUND: Neurosurgery has developed as a separate specialty and neurosurgical patients are some of the most common admitted in the intensive care unit. The objective of the study was to study the profile of neurosurgical patients admitted in level III mixed, medical-surgical intensive care unit in a tertiary level teaching hospital in Nepal with the view to identify the causes of intensive care unit admission, types of neurosurgery performed, outcome of the patients, in terms of intensive care unit stay, mechanical ventilation days and mortality. METHODS: A retrospective study was designed and all neurosurgical patients admitted to the intensive care unit of our center between 13 April 2017 and 13April 2018 (1st Baisakh 2074 to 30th Chaitra 2074) were enrolled in this study. RESULTS: A total of 813 patients were admitted in ICU over a period of one year (2074 B.S.) of which 199 (24.48 %) were neurosurgical cases. Among these 170 (85.42%) cases were post-surgical, with 29 (14.58%) being pre-operative patients. One hundred forty nine patients (74.9%) were on mechanical ventilation. One hundred and thirty two (66.3%) patients improved and were transferred to a step down ward. Forty-three (22.5%) died in the intensive care unit, 14 (7.03%) left the hospital against medical advice and 9 (4.5%) patients expired after withdrawal of life support. CONCLUSIONS: Despite improved care over the recent years the mortality and morbidity of neurosurgical patients is high. PMID- 30455498 TI - Fellowship Training in Nepal: Current Prospects. AB - The need of subspecialty training has been acutely felt in Nepal now with the rapid advancement in the field of medical sciences, the changing burden of diseases, the acute shortage of highly specialized health professionals, the evolving concept of learning and medical education and the ever-increasing focus on right and safety of patients.Fellowship Training is obtained in a specific specialty or subspecialty. Fully academic 3-year Fellowship programsin Pulmonary and Critical Care Medicine, Hepatopancreatobiliary Surgery and Cardiologyhavebeen initiated for certification of the training for the first time in Nepal at Chitwan Medical College (CMC) and all three are recognized by the Nepal Medical Council.The three Fellowship training programs, run in affiliation with Lincoln University, at the CMC have all the training criteria of DM/MCh included along with extra requirement of one more paper publication and the trainees are paid adequate stipend without any tuition fee or bond. The high volume of cases and procedures in CMC, exposes the FCMC Fellows to an increased chance of appropriate skill development along with appropriate postings in various other institutions for adequate experience of hands on training.Fellowship programs are the cornerstone of providing super specialized patient care.The need today is to focus on the basic training concepts and criteria, rather than on various names like diploma, MD, MS, DM/MCh of training.Nepal should focus onthe prerequisites, infrastructure and human resource for expanding the quality Fellowship trainingprograms in the country and thereby enhancing the standard of patient care. Keywords: Cardiology; DM; FCMC; fellowship; hepatopancreatobiliary surgery; MCh; PCCM. PMID- 30455497 TI - Free Newborn Care Services: A New Initiative in Nepal. AB - BACKGROUND: Nepal has made a significant progress in reducing child mortality. However, the annual rate of reduction in neonatal mortality is not satisfactory. As safeguarded by constitution of Nepal and to address neonatal mortality due to poverty and inequity, government has introduced free newborn care (FNC) package. This study aims to assess the status of FNC services in all the public hospitals. METHODS: Child Health Division organized 5 workshops region-wise with the theme of newborn care services in March/April 2018 to cover all the public hospitals in the country. A template was designed comprising of duration of FNC implementation, number of newborns admitted since implementation, morbidities pattern, and number of babies served. It was circulated and all hospitals were advised to fill it and present in the review. Later, the data were compiled and analyzed. RESULTS: Only 58 presentations out of 93 participated hospitals were included in this study. The total admitted cases were 8564 newborns. The common causes of admission were neonatal sepsis (44.5%) followed by asphyxia (14.29%) and hyperbilirubinemia (11.4%). A total of 1573 neonates received services of FNC package C, 3722 package B, 3081 received package A. The main challenges faced in implementation reported were lack of infrastructure and human resources to provide services and the reimbursement is not enough. CONCLUSIONS: Free newborn care is a new initiative taken to reduce neonatal mortality. This package is very helpful to serve sick newborns. However, the package should be revised taking into consideration the appropriate reimbursement and extra staffs to provide this service. PMID- 30455499 TI - Endobronchial Ultrasound Guided Transbronchial Needle Aspiration. AB - Evaluation of mediastinal lymphadenopathy is often challenging. Endobronchial Ultrasound (EBUS) is a novel technique which provides real time sonographic guidance during Transbronchial Needle Aspiration (TBNA) from mediastinal and hilar lesions. A 60-year-old smoker presented with two months history of cough and chest pain on the right side. CT thorax revealed a right upper lobe spiculated mass with paratracheal (Station 4R) and subcarinal (Station 7) lymph nodes. Bronchoscopy did not reveal any endobronchial mass. Since EBUS-TBNA is superior to conventional TBNA for malignant mediastinal node, an EBUS- TBNA was performed from both lymph node stations. . Cytopathology and histopathology revealed non-small cell lung cancer. We hereby report the first use of EBUS-TBNA in Nepal, in a patient with lung cancer and mediastinal lymphadenopathy. Keywords: Endobronchial ultrasound; lung cancer; mediastinal lymph node; transbronchial needle aspiration. PMID- 30455500 TI - Missing Intrauterine Device Copper-T: Case Series. AB - An intrauterine contraceptive device (IUD) is a long acting, highly effective, economic and reversible method of contraception used worldwide. The most used devices are copper IUD (Copper-T) or Progesterone IUD. Common complications include failed insertion, pain, vasovagal reactions, infection, menstrual abnormalities, expulsion and rarely uterine embedment and perforation. In this case series we will discuss three cases of missing Copper-T. In one case Copper T was inserted at our hospital and in the other cases it was inserted in the periphery and all the cases was managed surgically with different modality. Keywords: Copper-T; Intrauterine device; laparoscopy; laparotomy; perforation. PMID- 30455501 TI - Challenges of New Healthcare Reform Act 2017 and Possible Rise of Defensive Medicine in Nepal. AB - Hippocratic oath, written 4th or 5th century BC, is still the binding mantra for physicians, which swears to fulfill to the best of one's ability and judgement, and treat sick human beings not just illness. But with changing health trends in southeast Asia region, there is a dramatic shift in patients and patients' party expectations regarding treatment, recovery, complications, and death. Such expectations havelead to violence against physicians and shift towards alternative medical practice. This article explores the possible rise of defensive medicine and its broader implications in health care system in Nepal with regard to the new 'Muluki Aparadh Samhita Ain 2074/Criminal (Code) Act 2017'. Keywords: Changing health; criminal act; defensive medicine; muluki ain, Nepal. PMID- 30455502 TI - Nepal Scale up Chlorhexidine as Part of Essential Newborn Care: Country Experience. AB - Chlorhexidine is a broad-spectrum antiseptic, effective on gram positive and gram negative bacteria as well as some viruses, having strong skin binding effect. Randomized controlled trials conducted in South Asian countries have proven that the use of chlorhexidine (4% weight/weight) for cord care can reduce neonatal mortality and prevent severe cord infections. Between 2011 and 2017, Nepal completed nationwide scale-up of the use of chlorhexidine by integrating with ongoing maternal and neonatal health programs, under the leadership of the Child Health Division. The chlorhexidine coverage and compliance study (2017) has revealed that the country has achieved 59% coverage of the intervention to date, with lowest use among home births. The strategy should be further strengthened to ensure that every newborn in need is reached with chlorhexidine. Keywords: Chlorhexidine; cord care; Nepal experience, Newborn. PMID- 30455503 TI - Maxillary Anterior Teeth Proportions for Creating Esthetically Pleasuring Smile in Nepalese Patients. AB - NA. PMID- 30455504 TI - Good Quality Research in Sepsis: A Need of Low and Middle-income Countries. AB - NA. PMID- 30455505 TI - Intraspecific variation in cue-specific learning in sticklebacks. AB - Animals must identify reliable cues amidst environmental noise during learning, and the cues that are most reliable often depend on the local ecology. Comparing the performance of populations of the same species across multiple versions of a cognitive task can reveal whether some populations learn to use certain cues faster than others. Here, using a criterion-based protocol, we assessed whether two natural populations of sticklebacks differed in how quickly they learned to associate two different discrimination cues with the location of food. One version of the discrimination task required animals to use visual (colour) cues while the other required animals to use egocentric (side) cues. There were significant behavioural differences between the two populations, but no evidence that one population was generally better at learning, or that one version of the task was generally harder than the other. However, the two populations excelled on different tasks: fish from one population performed significantly better on the side version than they did on the colour version, while the opposite was observed in the other population. These results suggest that the two populations are equally capable of discrimination learning, but are primed to form associations with different cues. Ecological differences between the populations in environmental stability might account for the observed variation in learning. These findings highlight the value of comparing cognitive performance on different variations of the same task in order to understand variation in cognitive mechanisms. PMID- 30455506 TI - Which male and female characteristics influence the probability of extragroup paternities in rhesus macaques, Macaca mulatta? AB - Extragroup paternity (EGP) is found across a wide range of species and may entail reproductive benefits, but may also entail costs to both sexes. While population and group parameters affecting the degree of EGPs are relatively well established, less is known about the individual characteristics that make males and females engage in alternative reproductive tactics such as EGP. Applying a combination of long-term demographic and genetic data from the rhesus macaque population of Cayo Santiago (Puerto Rico, U.S.A.), we investigate which male and female characteristics influence the probability of EGP to better understand the circumstances that shape the distribution and occurrence of EGP. Our results show that, against our expectations, higher-ranking females were more likely to produce EGP offspring than lower- ranking females. The probability of producing extragroup offspring was not significantly related to female or male age, male tenure or previous reproductive success. Furthermore, genetic relatedness between the parents did not affect the production of extragroup offspring, but extragroup offspring were more frequently produced early rather than late in a given mating season. Altogether, our analysis suggests that individual attributes and seasonal aspects create different opportunities and preferences for engaging in EGP as an alternative reproductive tactic. The observed patterns of EGP in rhesus macaques appear to be consistent with female mate choice for genetic benefits, which needs to be confirmed in future studies. PMID- 30455507 TI - Understanding Generational Differences in Early Fertility: Proximate and Social Determinants. AB - Although US rates of early fertility have declined, they remain high relative to other high-income countries, and disparities by population group persist. The share of the US youth population with immigrant parents has expanded greatly, yet relatively little is known about generational variations in early fertility. This study used Add Health data to investigate: (1) differences by generational status in the risk of early childbearing; (2) to what extent observed differences reflected timing of sexual onset versus post-onset proximate determinants like contraceptive use; and (3) the influence of individual-, family-, and neighborhood-level social factors. Foreign-born and second-generation young women initiated both sexual activity and childbearing later than those with US-born parents. Sequential hazard models revealed the importance of later sexual onset in explaining delayed fertility among the foreign-born, and of family attributes for their later sexual onset. Post-onset behaviors were central to the delayed childbearing observed among the second generation. PMID- 30455510 TI - Benefits of integrating eye care into health systems. PMID- 30455511 TI - Towards all-oral and shorter treatment regimens for drug-resistant tuberculosis. PMID- 30455512 TI - Public Health Round-up. PMID- 30455508 TI - Oxidopyrylium [5+2] Cycloaddition Chemistry: Historical Perspective and Recent Advances (2008-2018). PMID- 30455513 TI - Meeting the eye-care needs of Australia's Indigenous people. AB - Australia is addressing the huge unmet need for eye care for its Indigenous population. Jack Latimore reports. PMID- 30455514 TI - Achieving dedicated programmes and funding for eye care. AB - Eye care is increasingly being incorporated into national health strategies in many countries. Haroon Awan talks to Fiona Fleck. PMID- 30455515 TI - Implementation of a diabetic retinopathy referral network, Peru. AB - Objective: To describe the implementation of a diabetic retinopathy referral network incorporating all levels of health care in La Libertad region, Peru. Method: The nongovernmental organization Orbis International and the Regional Institute of Ophthalmology established a network of primary, secondary and tertiary health-care facilities for diabetic retinopathy screening and treatment. The programme included the provision of three non-mydriatic retinal cameras for patient examination, the development of a flowchart to guide patient referrals, training of health personnel, investment in laser technology for treatment and the delivery of public awareness activities for blindness prevention and the need for timely screening. Findings: From 2014-2017, 11 849 patients with diabetes were screened within the diabetic retinopathy referral network. In primary-care centres, 6012 patients with diabetes mellitus were identified and 5632 patients were referred for diabetic retinopathy screening. A further 4036 patients directly attended two secondary-level hospitals and 2181 attended the tertiary level hospital for screening. This represented a 138.1% increase in diabetic retinopathy screenings from a baseline of 4977 patients screened at the regional institute of ophthalmology over 2010-2013. A total of 2922 patients (24.7%) were found to have diabetic retinopathy and 923 (31.6%) were treated: 508 with laser photocoagulation, 345 with intravitreal bevacizumab and 70 with vitreoretinal surgery. Conclusion: Effective and timely treatment for diabetic retinopathy is possible when patient education, screening and care are fully integrated into the general health-care system across primary-, secondary- and tertiary-level facilities. This requires the integration of professionals at all levels and all relevant specialties. PMID- 30455516 TI - Interventions to improve school-based eye-care services in low- and middle-income countries: a systematic review. AB - Objective: To review interventions improving eye-care services for schoolchildren in low- and middle-income countries. Methods: We searched online databases (CINAHL, Embase(r), ERIC, MEDLINE(r), ProQuest, PubMed(r) and Web of ScienceTM) for articles published between January 2000 and May 2018. Eligible studies evaluated the delivery of school-based eye-care programmes, reporting results in terms of spectacle compliance rates, quality of screening or attitude changes. We considered studies to be ineligible if no follow-up data were reported. Two authors screened titles, abstracts and full-text articles, and we extracted data from eligible full-text articles using the availability, accessibility, acceptability and quality rights-based conceptual framework. Findings: Of 24 559 publications screened, 48 articles from 13 countries met the inclusion criteria. Factors involved in the successful provision of school-based eye-care interventions included communication between health services and schools, the willingness of schools to schedule sufficient time, and the support of principals, staff and parents. Several studies found that where the numbers of eye-care specialists are insufficient, training teachers in vision screening enables the provision of a good-quality and cost-effective service. As well as the cost of spectacles, barriers to seeking eye-care included poor literacy, misconceptions and lack of eye health knowledge among parents. Conclusion: The provision of school-based eye-care programmes has great potential to reduce ocular morbidity and developmental delays caused by childhood vision impairment and blindness. Policy-based support, while also attempting to reduce misconceptions and stigma among children and their parents, is crucial for continued access. PMID- 30455517 TI - Evidence for national universal eye health plans. AB - Many low- and middle-income countries use national eye-care plans to guide efforts to strengthen eye-care services. The World Health Organization recognizes that evidence is essential to inform these plans. We assessed how evidence was incorporated in a sample of 28 national eye-care plans generated since the Universal eye health: a global action plan 2014-2019 was endorsed by the World Health Assembly in 2013. Most countries (26, 93%) cited estimates of the prevalence of blindness and 18 countries (64%) had set targets for the cataract surgical rate in their plan. Other evidence was rarely cited or used to set measurable targets. No country cited evidence from systematic reviews or solution based research. This limited use of evidence reflects its low availability, but also highlights incomplete use of existing evidence. For example, despite sex disaggregated data and cataract surgical coverage being available from surveys in 20 countries (71%), these data were reported in the eye health plans of only nine countries (32%). Only three countries established sex-disaggregated indicators and only one country had set a target for cataract surgical coverage for future monitoring. Countries almost universally recognized the need to strengthen health information systems and almost one-third planned to undertake operational or intervention research. Realistic strategies need to be identified and supported to translate these intentions into action. To gain insights into how a country can strengthen its evidence-informed approach to eye-care planning, we reflect on the process underway to develop Kenya's seventh national plan (2019-2023). PMID- 30455518 TI - Public health system integration of avoidable blindness screening and management, India. AB - In India, 73 million people have diabetes and 3.5 million infants are born preterm. Without timely screening, there is a risk of visual loss due to diabetic retinopathy and retinopathy of prematurity in these two groups, respectively. Both conditions are emerging causes of visual impairment in India but there is no public health programme for screening or management. Pilot projects were initiated in 2014 to integrate the screening and management of these conditions into existing public health systems, particularly in rural communities and their referral networks. The World Health Organization's health systems framework was used to develop the projects and strategies were developed with all stakeholders, including the government. Both projects involved hub-and-spoke models of care units around medical schools. For diabetic retinopathy, screening was established at primary health-care facilities and treatment was provided at district hospitals. For retinopathy of prematurity, screening was integrated into sick newborn care units at the district level and treatment facilities were improved at the closest publically funded medical schools. In the first two years, there were substantial improvements in awareness, screening, treatment and partnership between stakeholders, and changes in public health policy. By March 2018, diabetic retinopathy screening was established at 50 facilities in 10 states and treatment had been improved at 10 hospitals, whereas retinopathy of prematurity screening was established at 16 sick newborn care units in district hospital in four states and treatment had been improved at six medical schools. Advocacy within state governments was critical to the success of the initiative. PMID- 30455519 TI - Building a national eye-care service in post-conflict Timor-Leste. AB - Problem: Violent conflict left Timor-Leste with a dismantled health-care workforce and infrastructure after 2001. The absence of existing health and tertiary education sectors compounded the challenges of instituting a national eye-care system. Approach: From 2001, the East Timor Eye Program coordinated donations and initially provided eye care through visiting teams. From 2005, the programme reoriented to undertake concerted workforce and infrastructure development. In 2008 full-time surgical services started in a purpose-built facility in the capital city. In 2014 we developed a clinical training pipeline for local medical graduates to become ophthalmic surgeons, comprising a local postgraduate diploma, with donor funding supporting master's degree studies abroad. Local setting: In the population of 1.26 million, an estimated 35 300 Timorese are blind and an additional 123 500 have moderate to severe visual impairment, overwhelmingly due to cataract and uncorrected refractive error. Relevant changes: By April 2018, six Timorese doctors had completed the domestic postgraduate diploma, three of whom had enrolled in master's degree programmes. Currently, one consultant ophthalmologist, seven ophthalmic registrars, two optometrists, three refractionists and four nursing staff form a tertiary resident ophthalmic workforce, supported by an international advisor ophthalmologist and secondary eye-care workers. A recorded 12 282 ophthalmic operations and 117 590 consultations have been completed since 2001. Lessons learnt: International organizations played a pivotal role in supporting the Timorese eye health system, in an initially vulnerable setting. We highlight how transition to domestic funding can be achieved through the creation of a domestic training pipeline and integration with national institutions. PMID- 30455520 TI - Behavioural change interventions for sustained trachoma elimination. PMID- 30455522 TI - Corrigendum. AB - [This corrects the article DOI: 10.2471/BLT.17.203737.]. PMID- 30455521 TI - Rapid assessment of avoidable blindness for health service planning. PMID- 30455524 TI - Results-based financing in health: from evidence to implementation. PMID- 30455525 TI - The Italian mental health-care reform: public health lessons. PMID- 30455526 TI - Public Health Round-up. PMID- 30455527 TI - More health workers needed for universal health coverage. AB - Despite efforts to boost its health workforce, Bangladesh is struggling to make progress towards universal coverage of health services. Sophie Cousins reports. PMID- 30455528 TI - Rolling out Rwanda's national palliative care programme. AB - Only 14% of people worldwide who need palliative care receive it. Christian Ntizimira talks to Tatum Anderson about the challenges of applying Western models of palliative care in an African setting. PMID- 30455530 TI - Hepatitis B and C virus seroprevalence, Burkina Faso: a cross-sectional study. AB - Objective: To estimate population-wide hepatitis B and C seroprevalence using dried blood spot samples acquired for human immunodeficiency virus (HIV) surveillance as part of the 2010-2011 Demographic and Health Survey in Burkina Faso. Methods: We used the database acquired during the multistage, clustered, population-based survey, in which 15 377 participants completed questionnaires and provided dried blood spot samples for HIV testing. We extracted sociodemographic and geographic data including age, sex, ethnicity, education, wealth, marital status and region for each participant. We performed hepatitis B and C assays on 14 886 HIV-negative samples between March to October 2015, and calculated weighted percentages of hepatitis seroprevalence for each variable. Findings: We estimated seroprevalence as 9.1% (95% confidence interval, CI: 8.5 9.7) for the hepatitis B surface antigen and 3.6% (95% CI: 3.3-3.8) for hepatitis C virus antibodies, classifying Burkina Faso as highly endemic for hepatitis B and low-intermediate for hepatitis C. The seroprevalence of hepatitis was higher in men than in women, and varied significantly for both with age, education, ethnicity and region. Extremely high HCV-Ab seroprevalence (13.2%; 95% CI: 10.6 15.7) was identified in the Sud-Ouest region, in particular within the youngest age group (15-20 years), indicating an ongoing epidemic. Conclusion: Our population-representative hepatitis seroprevalence estimates in Burkina Faso advocate for the inclusion of hepatitis serological tests and risk factor questionnaire items in future surveys, the results of which are crucial for the development of appropriate health policies and infection control programmes. PMID- 30455529 TI - Accuracy of diabetes screening methods used for people with tuberculosis, Indonesia, Peru, Romania, South Africa. AB - Objective: To evaluate the performance of diagnostic tools for diabetes mellitus, including laboratory methods and clinical risk scores, in newly-diagnosed pulmonary tuberculosis patients from four middle-income countries. Methods: In a multicentre, prospective study, we recruited 2185 patients with pulmonary tuberculosis from sites in Indonesia, Peru, Romania and South Africa from January 2014 to September 2016. Using laboratory-measured glycated haemoglobin (HbA1c) as the gold standard, we measured the diagnostic accuracy of random plasma glucose, point-of-care HbA1c, fasting blood glucose, urine dipstick, published and newly derived diabetes mellitus risk scores and anthropometric measurements. We also analysed combinations of tests, including a two-step test using point-of-care HbA1cwhen initial random plasma glucose was >= 6.1 mmol/L. Findings: The overall crude prevalence of diabetes mellitus among newly diagnosed tuberculosis patients was 283/2185 (13.0%; 95% confidence interval, CI: 11.6-14.4). The marker with the best diagnostic accuracy was point-of-care HbA1c (area under receiver operating characteristic curve: 0.81; 95% CI: 0.75-0.86). A risk score derived using age, point-of-care HbA1c and random plasma glucose had the best overall diagnostic accuracy (area under curve: 0.85; 95% CI: 0.81-0.90). There was substantial heterogeneity between sites for all markers, but the two-step combination test performed well in Indonesia and Peru. Conclusion: Random plasma glucose followed by point-of-care HbA1c testing can accurately diagnose diabetes in tuberculosis patients, particularly those with substantial hyperglycaemia, while reducing the need for more expensive point-of-care HbA1c testing. Risk scores with or without biochemical data may be useful but require validation. PMID- 30455531 TI - Cost-effectiveness of results-based financing, Zambia: a cluster randomized trial. AB - Objective: To evaluate the cost-effectiveness of results-based financing and input-based financing to increase use and quality of maternal and child health services in rural areas of Zambia. Methods: In a cluster-randomized trial from April 2012 to June 2014, 30 districts were allocated to three groups: results based financing (increased funding tied to performance on pre-agreed indicators), input-based financing (increased funding not tied to performance) or control (no additional funding), serving populations of 1.33, 1.26 and 1.40 million people, respectively. We assessed incremental financial costs for programme implementation and verification, consumables and supervision. We evaluated coverage and quality effectiveness of maternal and child health services before and after the trial, using data from household and facility surveys, and converted these to quality-adjusted life years (QALYs) gained. Findings: Coverage and quality of care increased significantly more in results-based financing than control districts: difference in differences for coverage were 12.8% for institutional deliveries, 8.2% postnatal care, 19.5% injectable contraceptives, 3.0% intermittent preventive treatment in pregnancy and 6.1% to 29.4% vaccinations. In input-based financing districts, coverage increased significantly more versus the control for institutional deliveries (17.5%) and postnatal care (13.2%). Compared with control districts, 641 more lives were saved (lower-upper bounds: 580-700) in results-based financing districts and 362 lives (lower-upper bounds: 293-430) in input-based financing districts. The corresponding incremental cost-effectiveness ratios were 809 United States dollars (US$) and US$ 413 per QALY gained, respectively. Conclusion: Compared with the control, both results-based financing and input-based financing were cost-effective in Zambia. PMID- 30455533 TI - Increasing transparency and accountability in national pharmaceutical systems. AB - Access to safe, effective, good-quality medicines can be compromised by poor pharmaceutical system governance. This system is particularly vulnerable to inefficiencies and to losses from corruption, because it involves a complex mix of actors with diverse responsibilities. A high level of transparency and accountability is critical for minimizing opportunities for fraud and leakage. In the past decade, the Good Governance for Medicines programme and the Medicines Transparency Alliance focused on improving accountability in the pharmaceutical system and on reducing its vulnerability to corruption by increasing transparency and encouraging participation by a range of stakeholders. Experience with these two programmes revealed that stakeholders interpreted transparency and accountability in a range of different ways. Moreover, programme implementation and progress assessments were complicated by a lack of clarity about what information should be disclosed by governments and about how greater transparency can strengthen accountability for access to medicines. This article provides a conceptual understanding of how transparency can facilitate accountability for better access to medicines. We identified three categories of information as prerequisites for accountability: (i) standards and commitments; (ii) decisions and results; and (iii) consequences and responsive actions. Examples are provided for each. Conceptual clarity and practical examples of the information needed to ensure accountability can help policy-makers identify the actions required to increase transparency and accountability in their pharmaceutical systems. We also discuss factors that can hinder or facilitate the use of information to hold to account those responsible for improving access to medicines. PMID- 30455534 TI - Recognizing noncommunicable diseases as a global health security threat. PMID- 30455532 TI - Body mass index vs deuterium dilution method for establishing childhood obesity prevalence, Ghana, Kenya, Mauritius, Morocco, Namibia, Senegal, Tunisia and United Republic of Tanzania. AB - Objective: To compare the World Health Organization (WHO) body mass index (BMI) for-age definition of obesity against measured body fatness in African children. Methods: In a prospective multicentre study over 2013 to 2017, we recruited 1516 participants aged 8 to 11 years old from urban areas of eight countries (Ghana, Kenya, Mauritius, Morocco, Namibia, Senegal, Tunisia and United Republic of Tanzania). We measured height and weight and calculated BMI-for-age using WHO standards. We measured body fatness using the deuterium dilution method and defined excessive body fat percentage as > 25% in boys and > 30% in girls. We calculated the sensitivity and specificity of BMI z-score > +2.00 standard deviations (SD) and used receiver operating characteristic analysis and the Youden index to determine the optimal BMI z-score cut-off for classifying excessive fatness. Findings: The prevalence of excessive fatness was over three times higher than BMI-for-age-defined obesity: 29.1% (95% CI: 26.8 to 31.4; 441 children) versus 8.8% (95% CI: 7.5 to 10.4; 134 children). The sensitivity of BMI z-score > +2.00 SD was low (29.7%, 95% CI: 25.5 to 34.2) and specificity was high (99.7%, 95% CI: 99.2 to 99.9). The receiver operating characteristic analysis found that a BMI z-score +0.58 SD would optimize sensitivity, and at this cut-off the area under the curve was 0.86, sensitivity 71.9% (95% CI: 67.4 to 76.0) and specificity 91.1% (95% CI: 89.2 to 92.7). Conclusion: While BMI remains a practical tool for obesity surveillance, it underestimates excessive fatness and this should be considered when planning future African responses to the childhood obesity pandemic. PMID- 30455535 TI - Field-based measurement of cardiorespiratory fitness to evaluate physical activity interventions. PMID- 30455536 TI - Corrigendum. AB - [This corrects the article DOI: 10.2471/BLT.17.204321.]. PMID- 30455537 TI - Cohort Differences in Mothers' Perceptions of Neighborhood Quality, Child Well being, and Parental Strain, 1976-2002. AB - Objective: To examine differences in mothers' subjective experiences of child rearing between two cohorts who lived in different eras of sociodemographic contexts and parenting norms. Background: A resource perspective suggests that child-rearing experiences should be easier when mothers have a higher standard of living, higher education, and fewer children, as was the case for mothers in the 2000s compared with mothers in the 1970s. However, a cultural perspective indicates that the intensive mothering ideology, emerged in the 1980s, increased mothers' anxiety and stress over their children's safety and proper development. Method: Data from two national samples of mothers with children between 6 and 12 years of age in the United States collected in 1976 and 2002 (N = 2,465) were analyzed using ordinary least squares regression models. Results: Mothers in 2002 reported better neighborhood quality and better health of their children than mothers in 1976, even after sociodemographic advantages of mothers in 2002 relative to 1976 were taken into account. Despite these sociodemographic advantages of mothers in 2002, there was little difference in mothers' reports of their children's behavioral adjustments between the two cohorts. Furthermore, albeit among Whites only, mothers in 2002 reported more parental strain than did mothers in 1976. There was little variation in mothers' perceptions by socioeconomic status (as measured by a college degree). Conclusion: Our results support the idea of a stressed-moms phenomenon in the contemporary United States, particularly among Whites. Implications: Experts who advise parent education policy and programs should take into account the psychological burden of the current neoliberal emphasis on personal responsibility for raising children on individual mothers. PMID- 30455538 TI - AGTR2 and sprint/power performance: a case-control replication study for rs11091046 polymorphism in two ethnicities. AB - We aimed to replicate, in a specific athletic event cohort (only track and field) and in two different ethnicities (Japanese and East European, i.e. Russian and Polish), original findings showing the association of the angiotensin-II receptor type-2 gene (AGTR2) rs11091046 A>C polymorphism with athlete status. We compared genotypic frequencies of the AGTR2 rs11091046 polymorphism among 282 track and field sprint/power athletes (200 men and 82 women), including several national record holders and Olympic medallists (214 Japanese, 68 Russian and Polish), and 2024 control subjects (842 men and 1182 women) (804 Japanese, 1220 Russian and Polish). In men, a meta-analysis from the two combined cohorts showed a significantly higher frequency of the C allele in athletes than in controls (odds ratio: 1.62, P=0.008, heterogeneity index I 2 =0%). With regard to respective cohorts, C allele frequency was higher in Japanese male athletes than in controls (67.7% vs. 55.9%, P=0.022), but not in Russian/Polish male athletes (61.9% vs. 51.0%, P=0.172). In women, no significant results were obtained by meta-analysis for the two cohorts combination (P=0.850). The AC genotype frequency was significantly higher in Russian/Polish women athletes than in controls (69.2% vs. 42.1%, P=0.022), but not in Japanese women athletes (P=0.226). Our results, in contrast to previous findings, suggested by meta-analysis that the C allele of the AGTR2 rs11091046 polymorphism is associated with sprint/power track and field athlete status in men, but not in women. PMID- 30455539 TI - Effect of eccentric action velocity on expression of genes related to myostatin signaling pathway in human skeletal muscle. AB - The aim of this study was to investigate the effects of an acute bout of eccentric actions, performed at fast velocity (210o.s-1) and at slow velocity (20o.s-1), on the gene expression of regulatory components of the myostatin (MSTN) signalling pathway. Participants performed an acute bout of eccentric actions at either a slow or a fast velocity. Muscle biopsy samples were taken before, immediately after, and 2 h after the exercise bout. The gene expression of the components of the MSTN pathway was assessed by real-time PCR. No change was observed in MSTN, ACTRIIB, GASP-1 or FOXO-3a gene expression after either slow or fast eccentric actions (p > 0.05). However, the MSTN inhibitors follistatin (FST), FST-like-3 (FSTL3) and SMAD-7 were significantly increased 2 h after both eccentric actions (p < 0.05). No significant difference between bouts was found before, immediately after, or 2 h after the eccentric actions (slow and fast velocities, p > 0.05). The current findings indicate that a bout of eccentric actions activates the expression of MSTN inhibitors. However, no difference was observed in MSTN inhibitors' gene expression when comparing slow and fast eccentric actions. It is possible that the greater time under tension induced by slow eccentric (SE) actions might compensate the effect of the greater velocity of fast eccentric (FE) actions. Additional studies are required to address the effect of eccentric action (EA) velocities on the pathways related to muscle hypertrophy. PMID- 30455541 TI - Investigating the game-related statistics and tactical profile in NCAA division I men's basketball games. AB - The aim of this study was to analyze the game-related statistics and tactical profile in winning and losing teams in NCAA division I men's basketball games. Twenty NCAA division I men's basketball close (score difference: 1-9 points) games were analyzed during the 2013/14 season. For each game, the game-related statistics were collected from the official teams' box scores. Number of ball possessions, offensive and defensive ratings and the Four Factors (effective field goal percentage; offensive rebounding percentage, recovered balls per ball possession, free throw rate) were also calculated. The tactical parameters evaluated were: ball reversal, dribble in key area, post entry, on-ball screen, off-ball screen, and hand off. Differences between winning and losing teams were calculated using a magnitude-based approach. Winning teams showed a likely higher percentage of 3-point goals made, number of defensive rebounds and steals and a very likely higher number of free throws made and free throws attempted. Furthermore, winning teams showed a likely higher team offensive rating and effective field goal percentage and a very likely higher free throw rate compared to losing teams. Finally, the results revealed a likely higher number of ball reversals and post entries in winning teams compared to losing teams. This study highlighted the game-related statistics and the tactical actions differentiating between winning and losing teams in NCAA Division I men's basketball close games. Coaches should use these results to optimize their training sessions, focusing on those variables that might increase the possibility to win close games. PMID- 30455540 TI - Hormonal responses to striking combat sports competition: a systematic review and meta-analysis. AB - Striking combat sports are challenging, commonly stressing the endocrinological system based on a mixture of body-contact actions and physiological efforts. The aims of this systematic review and meta-analysis were to discuss the hormonal responses related to striking combat sports competitions and to investigate the moderator and mediator variables of the hormonal response-competition/outcome relationship. Three electronic databases (i.e., PubMed, Google Scholar and ScienceDirect) were systematically searched (up to February 2016) followed by a manual search of retrieved papers. The data showed a moderate increase in cortisol (C) (ES = 0.79; 95% CI 0.31-1.28; p = 0.001), an extremely large increase in adrenaline (ES = 4.22; 95% CI 2.62-5.82; p < 0.001), and a very large increase in noradrenaline (ES = 3.40; 95% CI 1.03-5.76; p = 0.005) and human growth hormone (HGH) levels (ES = 3.69; 95% CI 1.96-5.42; p < 0.001) immediately following the combat events, compared to the control condition i.e., "pre combat". Furthermore, amateur athletes had a larger increase in C levels compared to highly trained athletes (ES = 2.91 [very large] vs ES = 0.56 [small]), while evening events showed greater alterations in C levels compared to morning events (ES = 1.91 [large] vs ES = 0.48 [small]), without significant differences between them (p = 0.26 and p = 0.06, respectively). The present meta-analysis also showed a small, insignificant increase in testosterone (T) (ES = 0.47 [small]; 95% CI 0.45-0.99; p = 0.074) and a decrease in insulin-like growth factor 1 levels (ES = -0.20 [trivial]; 95% CI -0.78-0.37; p = 0.486) immediately following the combat events, compared to the control condition. The type of combat sports practised, participants' gender, and the nature of competition contests (i.e., official vs simulation) did not moderate the relationship between competition and hormonal response. Additionaly, sub-analysis results showed a significant difference between younger and older athletes (Q = 4.05, p = 0.044), suggesting that after combat, younger individuals (less than 17 years of age) had a small decrease in T levels (ES = -0.58), compared with the moderate increase observed in older individuals (ES = 0.76). In conclusion, irrespective of striking combat sports types, the results showed that both official and simulated bouts are a real stressor of the hormonal system of practitioners. Coaches and applied practitioners should adopt "pre-competitive cognitive/coping strategies" to improve the psychological state that mediates the hormonal changes competition/outcome relationship of their athletes in order to mitigate athletes' stress. PMID- 30455542 TI - Exploring how playing football with different age groups affects tactical behaviour and physical performance. AB - The study aimed to compare footballers' performances when playing with teammates and opponents from the same age group with performances when playing with teammates and opponents of different age groups. Three football matches were played: i) under-15 (U15) players played with each other; ii) under-17 (U17) players played with each other; and iii) players under the age of 15 and 17 played with each other in two equivalent mixed age teams. The players' physical performance was measured using the distances covered at different speed categories and tactical behaviour was assessed using several positioning-derived variables. The results showed that, when playing in the mixed age condition, the U15 players increased the distance covered in sprinting intensity (18.1%; +/ 21.1%) and the U17 players increased the distance covered in jogging zones (6.8%; +/-6.5%). The intra-team movement synchronization in longitudinal and lateral displacements was higher when U15 players confronted peers of the same age, in the first half (-13.4%; +/-2.0%, -20.3%; +/-5.7% respectively), and when U17 players confronting the mixed group, in both halves (-16.9%; +/-2.5%, 9.8%; +/ 4.0% and 7.9%; +/-5.7%, 10.6% +/-4.4%, respectively). The differences between age groups and the mixed condition may be connected with the level of players' tactical expertise and adaptive positioning according to the dynamic environmental information. In general, these results suggest that mixing the age groups may be useful to promote a wider range of training session stimuli in these young football players. PMID- 30455543 TI - The "FIFA 11+" injury prevention program improves body stability in child (10 year old) soccer players. AB - The suitability of the FIFA 11+ prevention programme to improve selected performance outcomes in children aged < 14 years has not been established yet. This study aimed to investigate the effects of the FIFA 11+ programme on jump ability and stability in 10-year-old child soccer players. Sixteen young soccer players (aged 10 years) were randomly assigned to a conventional or a FIFA 11+ warm-up group. During a 5-week training period with 2 sessions per week the FIFA 11+ group warmed up with the 11+ programme, whereas the control group subjects performed their usual warm-up programme (e.g. running exercises with dribbling and/or passing techniques included). After the warm-up, both groups performed the same training exercises during each session. Before and after the training period, standing long jump performance and body stability (S3 Check, unstable uniaxial platform) were assessed. Significant improvements in the stability index were found in both groups (5.6+/-1.1 to 3.5+/-1.0 and 5.5+/-0.8 to 4.0+/-1.5 for the FIFA 11+ and the control group, respectively, p<0.001, partial eta2=0.886 for the training effect of the analysis of variance) with likely (qualitative inference analysis) greater improvements in the FIFA 11+ group compared to the control group (p=0.078, partial eta2=0.205 for the training x group interaction effect of the analysis of variance). Training had no effect on standing long jump performance (p>0.05). Data indicate that in 10-year-old soccer players the FIFA 11+ programme may have the potential to improve stability. Thus, the FIFA 11+ programme might contribute to injury prevention and possibly to better soccer performance as well. This might especially apply if the programme is performed over a longer period and/or with more weekly training sessions. Based on the present results the inclusion of such a programme within the training practice of the child soccer player can be recommended. PMID- 30455544 TI - Pathological knee laxity in elite women team handball players: a pilot study. AB - To identify the anterior cruciate ligament (ACL) laxity thresholds and to evaluate the utility of this measure in case of onset of knee injury for elite women handball players. Anterior laxity was measured by an arthrometer. Data on 29 elite women handball players and 20 sedentary women were collected. Among the handball group, 9 participants suffered from full-thickness ACL tears. The recorded variables were the anterior knee laxities at pressure load (PL) of 134 N (PL134N) and 250 N (PL250N) on the upper calf, which allowed assessment of the inter-leg comparison by calculating the differential laxity thresholds and the differential slope coefficients. Considering the healthy knee as a reference within the injured players, the laxity thresholds were identified, and the diagnostic value of the tests was assessed. The handball players without a full thickness tear presented lower knee laxity than the sedentary women, and 75% were diagnosed with pathologic laxity in at least one of the knee joints, compared to 10% of sedentary women. The differential laxity threshold was identified between the handball players without a full-thickness tear and those with a full thickness tear at 1.5 mm with PL134N and 2.2 mm with PL250N. The best diagnostic result was obtained using PL250N (area under the curve = 0.95). Handball practice is associated with specific laxities that are rarely seen in the general population. The ACL laxity thresholds may be useful measures to check the state of the ACL and to suggest full-thickness tears, as joint laxity appears to be a factor contributing to ACL tears in female handball players. PMID- 30455545 TI - ADIPOQ polymorphisms are associated with changes in obesity-related traits in response to aerobic training programme in women. AB - Among genetic variants of the ADIPOQ gene +276 G>T (rs1501299) and -11377 G>C (rs266729) are the most frequently investigated polymorphisms which were described in the context of genetic conditioning for a predisposition to obesity. However, the information of polymorphisms' potential modifying effect on obesity related traits achieved through training procedures are still unknown. DNA was extracted from buccal cells donated by the 201 participants and genotyping was carried out using real-time PCR. The genotype distribution was examined in a group of women measured for chosen traits before and after the completion of a 12 week training programme. Our results suggest that the ADIPOQ genotypes analyzed individually or in combination can modulate training-induced body mass measurements changes: after the training programme, carriers of rs1501299 T allele and rs266729 C allele were characterized by a greater reduction in fat mass percentage (FM), fat mass, and body mass. Moreover, the ADIPOQ polymorphisms were associated with changes in lipid profile in response to training. Additionally, we showed three main effects of genotypes for the FM, LDL-C (rs266729), and TBW (rs1501299). Our study indicate that the both polymorphisms are associated with changes in obesity-related traits in response to 12-week aerobic training programme in Caucasian women. From this evidence, it could be concluded that rs1501299 G and rs266728 G variants may be considered as disadvantageous factor in the context of training-induced effects on body mass traits. PMID- 30455546 TI - Muscular activity patterns of female and male athletes during the flat bench press. AB - The bench press (BP) is a complex upper body exercise in which substantial external loads can be used, demanding high neuromuscular activity. The aim of this study was to compare electromyographic (EMG) activity between female and male athletes during the flat bench press. Five male and five female athletes participated in this study. The main session included four sets of one repetition of the flat bench press with the load of 55, 70, 85 and 100% of the one repetition maximum (1RM). The activity of four muscles was analysed: the pectoralis major (PM), the anterior deltoid (AD), the lateral head of the triceps brachii (TBlat) and the long head of the triceps brachii (TBlong). The main finding of the study was that the muscle activity pattern differed between women and men during the bench press depending on the external load. The non-parametric Kruskal-Wallis ANOVA for males showed differences between the TLpeak values recorded for different loads (55%-100% 1RM) during the bench press (chi-square = 15.3, p = 0.009) and ADpeak (chi-square = 19.5, p = 0.001). The non-parametric Kruskal-Wallis ANOVA for females showed differences between the ADpeak values recorded for different loads (55%-100% 1RM) during the bench press (chi-square = 12.1, p = 0.018). PMID- 30455547 TI - Comparison of the effects of two antioxidant diets on oxidative stress markers in triathletes. AB - Intense exercise generates an imbalance in the redox system. However, chronic exercise can yield antioxidant adaptations. A few studies with humans have investigated the effects of antioxidant diets on athletes. Therefore we compared the effects of two dietary interventions on oxidative stress in competitive triathletes. Thirteen male triathletes were selected and divided into 2 groups: one that had a regular antioxidant diet (RE-diet) and the other that had a high antioxidant diet (AO-diet). The diet period was 14 days and blood samples were collected before and after this period. The AO-diet provided twice the dietary reference intake (DRI) of alpha-tocopherol (30 mg), five times the DRI of ascorbic acid (450 mg), and twice the DRI of vitamin A (1800 g), while the RE diet provided the DRI of alpha-tocopherol (15 mg), twice the DRI of ascorbic acid (180 mg) and the DRI of vitamin A (900 MUg). The oxidative stress parameters evaluated were: thiobarbituric acid reactive substances (TBARS), total reactive antioxidant potential (TRAP), total sulfhydryl, carbonyl, superoxide dismutase (SOD) activity, hydrogen peroxide consumption and glutathione peroxidase (GPx) activity. We observed, after the diet period, an increase in sulfhydryl, TRAP, TBARS and SOD activity, and a decrease in carbonyl levels. However, no changes were found in hydrogen peroxide consumption or GPx activity. We concluded that antioxidant-enriched diets can improve the redox status of triathletes. PMID- 30455548 TI - Relationship between 25(OH)D levels and athletic performance in elite Polish judoists. AB - There is a growing body of evidence for a role of vitamin D in muscle function and for its influence on athletic performance, injury profile and recovery in well-trained athletes. The aim of our study was to assess the relationship between 25(OH)D levels and hand grip strength, lower limb isokinetic strength and muscle power in elite judoists. We enrolled 25 Polish elite judoists. The mean age was 21.9+/-9.8 years, the mean height was 179.2+/-6.6 cm, the mean body mass was 79.1+/-8.7 kg, and the mean career duration was 11.5+/-3.9 years. Serum levels of 25(OH)D and parathormone (PTH) were measured by electrochemiluminescence (ECLIA) using the Elecsys system (Roche, Switzerland). Serum calcium was determined by colorimetry using the Konelab 60 system from bioMerieux (France). Lower limb strength was tested with the Biodex Multi-Joint 4 Isokinetic Dynamometer (Biodex Medical System, New York, USA), and hand grip strength was measured with a manual dynamometer (TAKEI, Japan). Muscle power was determined with the electronic jump mat OptoJump (Microgate, Bolzano, Italy). Our study showed decreased serum 25(OH)D levels in 80% of the professional judoists. The results also demonstrated a statistically significant positive correlation between vitamin D levels and left hand grip strength, muscle power assessed by vertical jump, and total work in left and right knee extensors at an angular velocity of 60 degrees /s. Based on our results it can be concluded that in well trained professional athletes, there may be a relationship between serum levels of 25(OH)D and skeletal muscle strength, power, and work. PMID- 30455549 TI - Match outcome and running performance in different intensity ranges among elite soccer players. AB - The monitoring of players' work-rate profiles during competition is now feasible through computer-aided motion analysis. The aim of the present study was to examine how various playing positions and match outcomes (i.e. won, drawn, lost) affect the total distance, and the distances covered at different intensities, by soccer players in Germany's Bundesliga. Match performance data were collected for 556 soccer players competing in the Bundesliga during the 2014/15, 2015/16 and 2016/17 domestic seasons. A total of 13 039 individual match observations were made of outfield players (goalkeepers excluded). The analysis was carried out using an IMPIRE AG motion analysis system, with records of all players' movements in all the 918 matches. The recorded variables included total distance covered [km] and distance covered at intensities in the ranges below 11 km/h, 11-14 km/h, 14-17 km/h, 17-21 km/h, 21-24 km/h, and above 24 km/h. In won matches, as opposed to drawn and lost matches, the wide midfielders and forwards ran a significantly longer distance, primarily covered at intensities of 21-23.99 and above 24 km/h (p <= 0.05). The analysis of full-backs, central defenders and central midfielders in won matches - as opposed to drawn and lost matches - in turn reveals that players ran a significantly shorter distance, most likely to be covered at intensities of 17-20.99 and 21-23.99 km/h (p <= 0.05). The results of the present study emphasise the importance of match outcome and playing positions during the assessment of physical aspects of soccer performance. PMID- 30455550 TI - Short-term memory span in aphasia: Insights from speech-timing measures. AB - Auditory-verbal short-term memory impairments are part and parcel of aphasia and interfere with linguistic processing. To date, the science about short-term memory impairments in aphasia has been generated and dominated by studying measures of accuracy, that is, span length. Because accuracy is expressed through speech, examining the speech-timing characteristics of persons with aphasia as they engage in spoken recall could reveal insights about the manner in which accuracy is achieved. Six speech-timing measures (e.g., response durations, pause durations) were elicited from the speech waveform of word span tasks from twelve people with aphasia. Speech-timing measures were compared to neuro-typical control participants. Speech-timing performance between erroneous and correct responses in the aphasia group was also examined. Across all measures, people with aphasia produced considerably longer speech-timing patterns in comparison to control participants. Memory load affected some measures in people with aphasia and control participants. Speech-timing in correct response trials was shorter than responses in erroneous trials. Memory span correlated only with one measure, namely, speech time (defined as the sum of each individual word duration in a response). Speech time also correlated with the following measures: Aphasia severity (Aphasia Quotient of the Western Aphasia Battery), spontaneous speech, and language comprehension (also measured by the Western Aphasia Battery). Some protracted speech-timing patterns in the aphasia group may be explained by a deregulation of activation-decay patterns. However, in the absence of further evidence from people with aphasia, possible issues around the sensitivity of some speech-timing measures limit firmer conclusions. Speech-timing measures are response-time measures, which have not been systematically studied in studies of short-term or working memory in aphasia and as such, can push the current boundaries of knowledge of short-term and working memory impairments in aphasia, not only in stroke related aphasia but also other neurological conditions. PMID- 30455551 TI - Common iliac artery occlusion presenting with back and leg pain: case report and differential diagnosis considerations for neurogenic/vascular claudication. PMID- 30455552 TI - Innovative treatment of clinically diagnosed meniscal tears: a randomized sham controlled trial of the Mulligan concept 'squeeze' technique. AB - Objective: The purpose of this study was to assess the effects of the Mulligan Concept (MC) 'squeeze' technique compared to a sham technique in participants with a clinically diagnosed meniscal tear. PMID- 30455553 TI - The knowledge of low back pain management between physical therapists and family practice physicians. AB - Objectives: The purpose of this study was to compare knowledge in managing patients with low back pain (LBP) between physical therapists and family practice physicians. Methods: Seventy-three physical therapists and 30 family practice physicians completed standardized examinations assessing knowledge, attitudes, the usefulness of clinical practice guidelines, and management strategies for patients with LBP. Beliefs of physical therapists and family practice physicians about LBP were compared using relative risks and independent t-tests. Results: Scores related to knowledge, attitudes, and the usefulness of clinical practice guidelines were generally similar between the groups. In addition, there was no difference between the groups for knowledge regarding optimal management strategies for patients with LBP. However, physical therapists were less likely to have difficulty assessing motivation levels of patients with LBP compared to family practice physicians (64.6% vs 26.7%; relative risk: 2.41 [95% confidence interval: 1.30-4.48] and physical therapists were less likely to agree that interventions by health care providers have little positive effect on the natural history of acute LBP (17.8% vs. 50.0%; relative risk: 0.36 [95% confidence interval: 0.19-0.66]). Discussion: The results of this study may have implications for third-party payers and health care administrators regarding the utilization of physical therapists in the management of patients with LBP in expanded scopes of practice, including direct access and potential placement in primary care clinics. PMID- 30455554 TI - Directional preference of the extremity: a preliminary investigation. AB - Background: Mechanical diagnosis and therapy (MDT) is a specific classification based musculoskeletal examination and intervention system that uses repeated end range and sustained movement to classify patients into mechanical syndromes. Research has recently demonstrated increased prevalence, reliability, and efficacy of MDT syndromes in varied peripheral musculoskeletal populations. There is currently no research analyzing if predictive variables exist for establishing directional preference in peripheral joints, other than the wrist. The aim of this study was to examine the clinical application of predictive variables for establishing directional preference and spinal referral in patients with isolated peripheral joint pain. Case Description: Thirty-seven consecutive patients with isolated peripheral pain were evaluated and classified using MDT assessment. Secondary analysis of predetermined variables was performed for association with directional preference and identification of spinal referral in Derangement syndrome. Results: All 37 patients were classified using MDT assessment. Thirty three (89.2%) were classified as Derangement syndrome: 17 as spinal Derangement (45.9%) and 16 as peripheral Derangement (43.2%). One peripheral derangement also had an underlying Articular Dysfunction. Additionally, there were four patients classified as Other (10.8%). Discussion: Historical and physical examination findings were analyzed to determine if there were associated variables of directional preference or spinal referral. Mechanical stress was found to be the most associated factor in predicting directional preference. No peripheral movement loss, paresthesia, and constant pain were more associated with spinal referral. These findings may lead to a greater understanding of peripheral MDT assessment, which may lead to increased identification of directional preference and improved patient outcomes. Level of Evidence: 4. PMID- 30455555 TI - Directional preference constructs for patients' low back pain in the absence of centralization. AB - Objectives: A detailed description of how Directional Preference (DP) constructs are measured could accelerate research to practice translation and improve research findings for Mechanical Diagnosis and Therapy (MDT) stakeholders. A secondary analysis of a prospective, observational cohort study was conducted to understand (1) the type and prevalence of DP constructs at first examination and (2) the relationships between DP constructs and clinical outcomes at follow-up. Methods: Data were collected and analyzed from 1485 consecutive patients who presented to outpatient, private practice clinics with primary complaints of non specific low back pain (LBP); 400 patients met the inclusion criteria and completed first examination and follow-up data. Statistical analysis determined prevalence and the relationships between DP constructs at first examination and clinical outcomes at follow-up. Results: The primary findings in this investigation were that (1) the most prevalent DP constructs at first examination were related to range of motion (ROM) and pain intensity (Patient Reported Improvement in ROM (74.8%), Increase in Spine ROM (29.5%), and Pain Intensity Change (17.3%)), (2) all groups improved and made clinically meaningful improvements in disability and pain intensity at follow-up, (3) no clinically significant differences in disability or pain intensity were found between the groups at follow-up, and (4) 26.5% and 6.5% of patients exhibited a relative increase in lumbar spine extension and flexion ROM, respectively, post repeated movement testing on the first examination. Discussion: The findings in this study assist providers in making assessment and treatment decisions with their patients by offering insight regarding the most prevalent DP constructs typically found at the first examination and their subsequent association with outcome when Centralization (CEN) does not occur. Recommendations for researchers have been made to further explore the DP framework used in this study. PMID- 30455556 TI - Diagnosis of cervical and thoracic musculoskeletal spinal pain receptive to mechanical movement strategies: a multicenter observational study. AB - Background: The McKenzie's Mechanical Diagnosis and Therapy (MDT), which uses a combination of repeated movements and sustained positions to affect signs and symptoms, is commonly used for the conservative evaluation and management of cervical and thoracic spinal conditions. Objective: Report a consecutive cohort of neck and thoracic pain patients managed using MDT and to record their classifications and physiotherapy management strategies. Methods: Therapists provided demographic data on themselves and the patients, clinical data on the patients, and Neck Disability Index scores at baseline and final visit. Results: Sixteen therapists collected data on 138 patients at baseline, of who 120 (87%) were followed up three to five visits later; these were patients with 131 cervical and seven thoracic problems. The therapists and patients are described. Regarding MDT classifications 83% were recorded as cervical and 100% as thoracic Derangement; there was a Directional Preference for extension in 80% of cervical spine patients, and 100% of thoracic spine patients. In addition, 13% of cervical spine patients were classified as OTHER, for which specific classifications were given. Classifications remained stable between initial and discharge sessions in 94% of patients. Neck Disability Index scores reduced from a mean of 24-12 at discharge (P < 0.001). Conclusions: Routinely collected data can describe both therapists and patients involved, demonstrate the MDT classification clinical utility in terms of prevalence and stability between visits, provide information on the clinical course of this patients' population, which could help establish treatment efficacy. Randomized controlled trials are needed to test for efficacy. PMID- 30455557 TI - Knowledge and pre-thoracic spinal thrust manipulation examination: a survey of current practice in the UK. AB - OBJECTIVES: The perceived relative safety of thoracic thrust joint manipulation (TTJM) has contributed to evidence supporting its use. Yet, TTJM is not without risk, where transient side effects (SE) and severe adverse events (AE) have been documented. With evidence supporting the importance of prethrust examination in reducing AE in other spinal regions this study investigated TTJM knowledge and pre-TTJM examination. Method: An e-survey, informed by existing evidence and expertise was designed and piloted. Eligibility criteria: UK-trained physiotherapists who use TTJM. Recruitment via professional networks and social media from December 2016 to February 2017. Data analysis included descriptive analyses (means, standard deviation and frequencies/central tendencies), and content analysis (themes and frequencies) for free text data. Results: From 306 responses, the sample comprised 146 (53%) males, mean (SD) age 36.37(8.68) years, with 12.88(8.67) years in practice, 11.07(8.14) years specialization, working in National Health Service/private practice (81%) and performing 0-5 TTJM/week (86%). EXAMINATION: 40% (n = 83) utilized pre-TTJM examination with 45% (n = 139) adapting the examination for different regions. Technique selection and effect: preferred technique was prone rotational TTJM (67%). Perception of the primary underlying effect was neurophysiological (54%), biomechanical (45%) or placebo (1%). Knowledge: Levels of agreement were found for contraindications (85%), precautions (75%), and red flags (86%) with more variability for risks including AE and SE (61%). DISCUSSION: UK physiotherapists demonstrated good knowledge and agreement of contraindications, precautions, and red flags to TTJM. With <50% respondents utilizing pre-TTJM examination, variable knowledge of TTJM risks, and therapeutic effects of TTJM further research is required. PMID- 30455558 TI - Vernakalant versus ibutilide for immediate conversion of recent-onset atrial fibrillation. AB - BACKGROUND: The pharmacological cardioversion of recent-onset atrial fibrillation (AF) is a challenge for the clinician. The aim of the study was to compare the efficacy, the safety, and the overall cost of intravenous (iv) administration of vernakalant, which is a relatively new atrial-selective antiarrhythmic agent, versus ibutilide, in cardioversion of recent-onset AF. METHODS: We enrolled in this study 78 patients (56 men, 22 women; mean age 63.72 +/- 6.67 years) who presented with recent-onset AF. Cardioversion was attempted in 36 patients (group A: 24 men, 12 women; mean age 62.44 +/- 7.24 years) by iv administration of vernakalant (3 mg/kg over 10 min and if needed after 15 min, a second dose 2 mg/kg over 10 min) while in 42 patients (group B: 32 men, 10 women; mean age 64.81 +/- 6 years) iv ibutilide was administered (1 mg over 10 min and if needed after 10 min, a second dose 1 mg over 10 min). RESULTS: AF was successfully converted in 52.78 % of (n =19) patients of group A vs 52.38 % of (n =22) patients of group B (p =0.58), with an average time of conversion 11.8 +/- 4.3 min for group A patients vs 33.9 +/- 20.25 min for group B patients (p <0.0001). The average length of hospital stay for patients of group A was 17.64 +/- 15.96 hours vs 41.09 +/- 17.6 hours for patients of Group B (p <0.0001). In one patient of group A, the administration of vernakalant was discontinued due to hypotension while two other patients reported dysgeusia during their hospitalization. In three patients of group B, the administration of ibutilide was discontinued due to development of nonsustained ventricular tachycardia, which resolved with discontinuation of the drug. The cost of administered drugs was estimated at 488.22 +/- 170.34 ? for patients of group A vs 142.43 +/- 54.45 ? for patients of group B (p <0.0001), however, hospitalization costs were significantly lower in patients of group A (258.5 8+/- 124.73 ? over 414.43 +/- 100.32; p =0.002). CONCLUSION: There was no significant difference in the efficiency of converting recent-onset AF between vernakalant and ibutilide. Although vernakalant is an expensive drug, we recorded fewer side effects and more rapid restoration, which reduced the overall cost of hospitalization of these patients. HIPPOKRATIA 2017, 21(2): 67-73. PMID- 30455559 TI - Association of occupational exposures and work characteristics with the occurrence of gastrointestinal disorders. AB - BACKGROUND: Work is a daily activity with various conditions, exposures, and habits that may affect health either positively or negatively. Aim of this study was to investigate the relationship between occupational factors and conditions, and the occurrence of gastrointestinal disorders. METHODS: We enrolled in this study a sample of 891 consecutive individuals, who were examined by standard colonoscopy and gastroscopy and interviewed regarding their working conditions and exposures. Consecutively, data were statistically analyzed to explore possible associations. RESULTS: Peptic ulcer diagnosis was associated with reports of muscle pain/headache [odds ratio (OR): 3.656, 95 % confidence interval (95% CI): 1.898-7.043], with working in shifts (OR: 2.463, 95% CI: 1.058-5.731), and with the presence of occupational stress (OR: 2.283, 95% CI: 1.162-4.486). Gastritis was associated with muscle pain/headache (OR: 2.258, 95% CI: 1.096 4.652), shift work (OR: 3.535, 95% CI: 1.345-9.29), occupational stress (OR: 2.182, 95% CI: 1.072-4.444), and sedentary work (OR 0.275 lower risk 95% CI: 0.113-0.671). Ulcerative colitis was associated with muscle pain/headache (OR: 6.211, 95% CI: 2.162-17.840) and occupational stress (OR: 6.418, 95% CI: 2.243 18.361), while Crohn's disease diagnosis with muscle pain/headache (OR: 3.554, 95% CI: 1.628-7.759), frequent ordering food at work (OR: 4.928, 95% CI: 2.3 10.559), occupational stress (OR: 3.023, 95% CI: 1.413-6.469), work with intense physical activity (OR: 0.665 lower risk, 95% CI: 0.252-0.758). Colon cancer diagnosis was associated with frequent ordering food at work (OR: 2.739, 95% CI: 1.268-5.916) and occupational stress (OR: 3.175, 95% CI: 1.384-7.286), while stomach cancer diagnosis with ordering food at work (OR: 2.794, 95% CI: 1.154 6.763) and exposure to dust (OR: 5.650, 95% CI: 1.551-20.582). Finally, presence of polyps was associated with ordering food at work (OR: 2.154, 95% CI: 1.135 4.091), and constipation with ordering food at work (OR: 2.869, 95% CI: 1.451 5.672), occupational stress (OR: 2.112, 95% CI: 1.097-4.066), and occupational noise (OR: 0.248, 95% CI: 0.084-0.737). CONCLUSION: The incidence of the gastrointestinal diseases is affected by occupational exposures and related lifestyle habits. HIPPOKRATIA 2017, 21(2): 74-79. PMID- 30455560 TI - Urine metabolomic profile in neonates with hypoxic-ischemic encephalopa-thy. AB - BACKGROUND: Metabolomics could provide valuable insights into hypoxemic-ischemic encephalopathy (HIE) revealing new disease-associated biochemical derangements. The study aimed to investigate urine metabolic changes in neonates with HIE compared to healthy controls, using targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS). PATIENTS AND METHODS: In this prospective, single-center study we enrolled neonates born at >= 36 weeks gestation with HIE (HIE group) and healthy controls (control group). We collected urine samples for metabolomic analysis on days one, three, and nine of life. RESULTS: Twenty-one full-term newborns were studied, 13 in the HIE group and eight in the control group. Six of the affected neonates had moderate/severe HIE and seven mild HIE. Therapeutic hypothermia was applied only in four neonates with moderate/severe HIE. Multivariate and univariate statistical analysis showed a clear separation between the HIE and the control groups. Discriminant metabolites involved pyruvic acid, amino acids, acylcarnitines, inositol, kynurenine, hippuric acid, and vitamins. CONCLUSIONS: We have identified a specific metabolic profile in neonates with HIE, adding to the existing knowledge on the disease biochemistry that may potentially help in biomarker development. HIPPOKRATIA 2017, 21(2): 80 84. PMID- 30455561 TI - Regulation of matrix metalloproteinase-2 and -9 during healing of dermal wounds after incision using radiofrequency energy in neonatal and adult rats. AB - BACKGROUND: Radiofrequency energy (RFE) has many medical applications in the treatment of adults and children. The impact of RFE on healing-regulation systems in the developing tissues is not fully known. Matrix metalloproteinases (MMPs) are involved in the remodeling of the extracellular matrix and the inflammatory processes. MMPs are regulated differently among the different age groups. We evaluated possible changes in MMP activity after an incisional wound using a radiofrequency scalpel in neonatal and adult rats. METHODS: In 30 Wistar rats [15 4-day-old (neonates) and 15 4-month-old (adults) rats], a ventral wound was created using a radiofrequency scalpel. Wounded areas and non-wounded tissues were harvested one, three and seven days after the intervention. Enzymatic activities of MMP-2 and MMP-9 were evaluated using gelatin zymography. RESULTS: Adults expressed higher activity than neonates for MMP-2 on day 7 (Mann -Whitney U-test, p =0.009) and for MMP-9 on days one (p =0.005) and three (p =0.005). MMP 9 was expressed in higher amounts in the wounded tissue in comparison with non wounded tissue during days one and three (Wilcoxon signed rank test, p =0.028 and p =0.043, respectively). MMP-2 was produced in equal amounts in the wounded and non-wounded tissue at all time-points. Only in the adult wounds at day seven, higher activity was noted compared with non-wounded skin (Wilcoxon signed rank test, p=0.043). CONCLUSIONS: RFE, despite its local burning effect, does not interfere with known patterns of MMP regulation. Neonates have lower activity of MMPs than adults. Energy conduction through adjacent non-wounded tissues does not have an impact upon MMP regulation. HIPPOKRATIA 2017, 21(1): 85-92. PMID- 30455562 TI - Warfarin maintenance dose associated with genetic polymorphisms of CYP2C9. AB - BACKGROUND: Cytochrome P450 2C9 (CYP2C9) gene polymorphisms alters the required warfarin dose in patients, due to pharmacogenetic events. This study aimed to identify the frequency of the allele CYP2C9 polymorphic variants *2 and *3, and the association of these allelic variants with warfarin dosage in the population of the west Azerbaijan province in Iran. METHODS: One hundred and seventy patients receiving warfarin were examined to evaluate the genotype frequency of common CYP2C9 polymorphisms. Genotype analysis for CYP2C9*2 and CYP2C9*3 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. To assess if the dosage is different between genotypes we used one-way analysis of variance (ANOVA). RESULTS: Frequency of the two variants in studied subjects was 12 % for CYP2C9*2 and 25.8 % for CYP2C9*3. Comparison of the warfarin daily maintenance dose between genotype groups showed that the daily mean dose of warfarin in patients who have homozygous wild-type genotype for CYP2C9 (*1/*1) was 5.26 +/- 2.32 mg, which was significantly higher compared to *1/*2, *1/*3 (3.57 +/- 2.25 mg, p <0.001) and *2/*2, *2/*3 and *3/*3 patients (3.76 +/- 2.4 mg, p =0.024). Further analysis revealed that the allelic frequency of CYP2C9 polymorphisms in the study population was similar to that of the Turkish population. CONCLUSIONS: Due to the relatively high frequency of CYP2C9 polymorphisms in the study population, the clinicians should become aware of these results to reduce the risk of hemorrhage when prescribing warfarin. HIPPOKRATIA 2017, 21(2): 93-96. PMID- 30455563 TI - Isolated tuberculous arthritis of the ankle: a case report and review of the literature. AB - BACKGROUND: Isolated ankle joint tuberculous arthritis is extremely rare, comprising an incidence lower than 5 % of skeletal tuberculosis (TB). Description of the case: We present an unusual case of isolated tubercular arthritis of the ankle in a 25-year-old male where the definitive diagnosis was difficult to be reached. The clinical examination revealed slight edema and a slight increase in local skin temperature. Based on magnetic resonance imaging performed, the diagnosis of septic arthritis was made. The arthroscopic appearance of the synovium and polymerase chain reaction analysis (PCR) of the synovial fluid revealed tuberculous arthritis. CONCLUSION: TB should be included in the differential diagnosis of inflammatory arthritis in patients with persistent pain and swelling of the ankle. HIPPOKRATIA 2017, 21(2): 97-100. PMID- 30455564 TI - The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome: a transcranial magnetic stimulation-EEG study. AB - BACKGROUND: The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome is currently regarded as an extremely rare condition. The etiological and pathophysiological mechanisms underlying this medical rarity as well as the optimal therapeutic approaches remain poorly defined and understood. We present the clinical, radiological and electroencephalography (EEG) findings of a patient with the HHE syndrome and describe the response of the continuously present epileptiform abnormalities to transcranial magnetic stimulation (TMS). CASE DESCRIPTION: A 33 year old male patient was referred to our department for investigation and management of intractable epilepsy. His seizures began at the age of three months when, during the course of a common febrile illness, he developed repetitive clonic seizures involving the left upper and lower limbs, followed by permanent left hemiplegia. After extensive investigations, he was diagnosed with "idiopathic" HHE syndrome. Currently, he suffers from left hemiplegia, severe intellectual impairment [Intelligence Quotient (IQ) <30] and asymmetric, bilateral tonic seizures occurring 1-3 times daily despite treatment with valproate, topiramate, lamotrigine, rufinamide, and perampanel. Brain magnetic resonance imaging revealed atrophy of the right hemisphere and serial EEGs disclosed continuous sharp waves, the generators of which were localized by electrical source imaging (ESI) to two distinct sources within the right hemisphere. Repetitive TMS [210 stimuli of 1 Hz at 100 % corticomotor threshold applied with a circular coil over the generators of epileptic discharges (EDs)] resulted in a statistically significant decrease of ED counts compared to sham stimulation and the post-verum TMS period. CONCLUSION: We present the clinical laboratory profile and the long-term follow up of a patient with the HHE syndrome. Further, we describe the effects of TMS on EDs. The latter observation raises the possibility that TMS-EEG may be used in select cases with intractable epilepsy as a surrogate marker of responsiveness to more invasive modalities (i.e., cortical stimulation). HIPPOKRATIA 2017, 21(2): 101-104. PMID- 30455565 TI - Primary collision renal tumor of papillary renal cell carcinoma within an oncocytoma: emergency presentation of a rare entity. AB - BACKGROUND: The coexistence of an oncocytoma and a papillary renal cell carcinoma (PRCC) in the same neoplastic mass constitute a collision tumor and is an extremely rare entity. Until now, only six incidentally diagnosed cases have been reported, concerning patients older than 65 years. CASE REPORT: A 57-year-old man was admitted to the Emergency Department with acute pain and anemia, due to renal hematoma following rupture of such a neoplastic collision mass. The patient underwent an emergency nephrectomy, which revealed a 10.6 cm oncocytoma and a 1.3 cm PRCC. He had an uncomplicated postoperative recovery and remained healthy at the 65-month follow-up, the longest of all previous cases. CONCLUSION: While prognosis appears favorable, the current report shows that these collision tumors may cause emergency and dangerous medical conditions that deserve prompt treatment. HIPPOKRATIA 2017, 21(2): 105-107. PMID- 30455566 TI - Prolonged complete remission in a primary MALT lymphoma of the lung after rituximab monotherapy. AB - BACKGROUND: Primary pulmonary non-Hodgkin lymphoma (NHL) is a rare entity. Despite its favorable prognosis, an optimal treatment approach has not been established until today, as there are few debated heterogeneous data in the literature. Many therapeutic options such as surgery, radiotherapy, chemotherapy alone or in combination, immunotherapy and/or immunochemotherapy all with similar results, have been reported. CASE DESCRIPTION: We report the case of a 68-year old man diagnosed with a primary marginal zone B-cell pulmonary NHL, with a durable complete response to rituximab monotherapy. CONCLUSION: We support the therapeutic application of rituximab monotherapy as an attractive option for this malignancy. This effective approach exhibits significant antitumor activity leading to long-term complete remission and minimal hematological toxicity in contrast to other intensive chemotherapies and/or radiotherapy, which might have serious side effects. HIPPOKRATIA 2017, 21(2): 108-110. PMID- 30455567 TI - Mixed fibroadenoma and phyllodes breast tumor: Limitations of core needle biopsy. PMID- 30455568 TI - Acute pancreatitis and rhabdomyolysis: a rare association. PMID- 30455569 TI - Machine Learning With K-Means Dimensional Reduction for Predicting Survival Outcomes in Patients With Breast Cancer. AB - Objective: Despite existing prognostic markers, breast cancer prognosis remains a difficult subject due to the complex relationships between many contributing factors and survival. This study seeks to integrate multiple clinicopathological and genomic factors with dimensional reduction across machine learning algorithms to compare survival predictions. Methods: This is a secondary analysis of the data from a prospective cohort study of female patients with breast cancer enrolled in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We constructed a series of predictive models: ensemble models (Gradient Boosting and Random Forest), support vector machine (SVM), and artificial neural networks (ANN) for 5-year survival based on clinicopathological and gene expression data after K-means clustering with K-nearest-neighbor (KNN) classification. Model performance was evaluated by receiver operating characteristic (ROC) curve, accuracy, and calibration slope (CS). Model stability was assessed over 10 random runs in terms of ROC, accuracy, CS, and variable importance. Results: The analytic cohort is composed of 1874 patients with breast cancer. Overall, the median age was 62 years; the 5-year survival rate was 75%. ROC and accuracy were not significantly different between models (ROC and accuracy around 0.67 and 0.72 across models, respectively). However, ensemble methods resulted in better fit (CS) with stable measures of variable importance across 10 random training/validation splits. K-means clustering of gene expression profiles on training data points along with KNN classification of validation data points was a robust method of dimensional reduction. Furthermore, the gene expression cluster with the highest mortality risk was an influential factor in model prediction. Conclusions: Using machine learning methods to construct predictive models for 5-year survival in patients with breast cancer, we demonstrated discrimination ability across models with new insight into the stability and utility of dimensional reduction on genomic features in breast cancer survival prediction. PMID- 30455571 TI - A 7-year-old boy with a nonfebrile seizure following a fall. PMID- 30455572 TI - Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians. AB - The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy. PMID- 30455573 TI - Adolescent decision-making in Canadian medical contexts: Integrating neuroscience and consent frameworks. AB - The primary objective of this commentary is to integrate current neuroscientific research on brain development during adolescence, with existing consent frameworks that do not designate a minimum age for eligibility to consent to, or refuse medical treatment. To reach this objective, the three consent frameworks used in health care settings are outlined: age-based framework; mature minor framework and capacity-based framework. This commentary draws on the Canadian health care system specifically to consider consent frameworks that grant young people with decision-making capacity. Next, a brief review of adolescent brain development findings is presented, particularly pertaining to the decision-making capacity of young people within medical contexts. Ultimately, the question of whether the stage of a young person's brain development impedes their capacity to consent to, or refuse medical treatment is addressed. This commentary provides reassurance as to the compatibility between capacity-based and mature minor frameworks to consent to treatment with current neuroscientific understanding of adolescent brain development. PMID- 30455570 TI - Diet-Induced Hyperinsulinemia as a Key Factor in the Etiology of Both Benign Prostatic Hyperplasia and Essential Hypertension? AB - Benign prostatic hyperplasia and hypertension are common age-related comorbidities. Although the etiology of benign prostatic hyperplasia (BPH) is still largely unresolved and poorly understood, a significant age-independent association was found between BPH and hypertension, indicating a common pathophysiological factor for both diseases. It has previously been suggested that the development of essential hypertension may be related to diet-induced hyperinsulinemia. This study follows the question, whether BPH may develop due to the same mechanism, thereby explaining the well-known comorbidity of these 2 disorders. The scientific evidence presented shows that BPH and hypertension share the same pathophysiological changes, with hyperinsulinemia as the driving force. It further shows that significant dietary changes during human history cause disruption of a finely tuned metabolic balance that has evolved over millions of years of evolution: high-insulinemic food, typical of current "Western" diets, has the potential to cause hyperinsulinemia and insulin resistance, as well as an abnormally increased activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, alterations that play a pivotal role in the pathogenesis of BPH and hypertension. PMID- 30455574 TI - Weight up? Changes in children's anthropometry from time of referral to baseline assessment for paediatric weight management. AB - Objectives: To examine children's wait time to access a multidisciplinary, tertiary-level weight management clinic and assess anthropometric changes from time of referral to baseline assessment. Method: A retrospective medical record review was completed of children (5 to 17 years) enrolled in a multidisciplinary, tertiary-level paediatric weight management clinic from 2006 to 2015. Children's demographic and anthropometric data from their referral to and baseline assessment at the clinic were retrieved from medical records. Based on changes in body mass index (BMI) z-score from the time of referral to baseline assessment, children were categorized as decreasers (>0.05 unit decrease), increasers (>0.05 unit increase) or stabilizers (-0.05 to 0.05 unit change). The proportion of children with a >=0.25 unit BMI z-score reduction was calculated. Analysis of variance and chi-squared tests were performed. Results: Children (n=400) were 11.7 +/- 2.9 years old at the time of referral, 52.8% (n=211) female, and had an average wait time of 4.5 +/- 3.9 months. By 3 and 6 months postreferral, 44.0% (n=176) and 80.8% (n=323), respectively, had attended baseline assessments. Based on BMI z-score change, children were classified as decreasers (n=183; 45.8%), increasers (n=118; 29.5%) or stabilizers (n=99; 24.8%). One-fifth of children (n=86; 21.5%) experienced a BMI z-score reduction >=0.25 units, a subgroup that was younger, had a higher BMI z-score at referral, and had a longer wait time between referral and baseline assessment (all P<0.05). Conclusions: Most children who enrolled in paediatric weight management initiated treatment within six months and experienced a modest decrease or stabilization in BMI z-score during their wait time. PMID- 30455576 TI - Tonsillectomy or adenotonsillectomy versus nonsurgical management for obstructive sleep-disordered breathing in children. PMID- 30455575 TI - Choosing Wisely Canada: Pediatric Neurosurgery Recommendations. AB - Objectives: Choosing Wisely Canada is an evidence-based, patient-focused, physician-led campaign to improve the delivery of medical care in Canada. The goal of this study was to produce Canadian recommendations for physicians treating patients with selected paediatric neurosurgery issues. Methods: Paediatric neurosurgeons practicing in Canada were invited to participate. Suggestions were obtained using an anonymous questionnaire, and then ranked anonymously by the participating surgeons. Suggestions that received consensus from participants were discussed at the 2016 annual Canadian Pediatric Neurosurgery Study Group meeting. Suggestions that were not evidence based, or that would not have a substantive population impact were eliminated. All remaining suggestions were anonymously ranked by the group and the top five recommendations were submitted to Choosing Wisely Canada. Results: The final five recommendations include: 1) don't order a computed tomography scan to investigate macrocephaly (order an ultrasound or magnetic resonance imaging scan); 2) don't image a midline dimple related to the coccyx in an asymptomatic infant or child; 3) don't use computed tomography scans for routine imaging of children with hydrocephalus. Fast sequence nonsedated magnetic resonance imaging scans or ultrasounds provide adequate information to assess patients without exposing them to radiation or an anesthetic; 4) don't recommend helmets for mild to severe positional flattening; 5) don't do routine surveillance imaging for incidentally discovered Chiari I malformation. Conclusions: Five Choosing Wisely Canada recommendations were produced to support care of patients with paediatric neurosurgical issues. While these recommendations will apply to the majority of children with the involved conditions, occasionally, deviation from these recommendations may be clinically indicated. PMID- 30455577 TI - 'Finding Gory'-bringing home an unwanted aquatic traveler. PMID- 30455578 TI - Neonatal abstinence syndrome - a better way. PMID- 30455580 TI - Blood pressure in children with attention deficit/hyperactivity disorder. AB - Objectives: Children with attention deficit/hyperactivity disorder (ADHD) are frequently treated with psycho-stimulant agents causing a modest but significant increase in blood pressure and heart rate. The objective of this study was to define blood pressure characteristics in children with ADHD treated with a variety of medications in a community setup. Methods: Children registered at a large paediatric clinic in Calgary, AB with documented histories of ADHD were randomly contacted. Consenting participants had standardized office BP measurements, ambulatory blood pressure monitoring (ABPM) studies and were asked to complete the sleep disturbance scale for children (SDSC) questionnaire. Findings were compared with data from the Canadian Health Measures Survey (CMHS). Results: Fifty-five children (47 males) aged 7 to 17 years (average 11.6 +/- 2.5 years) with an average BMI z-score of -0.37 +/- 1.22 completed the study. All children were medicated, the majority (82%), with various types of stimulant agents. Elevated office BP values were more prevalent than in the CMHS; >90th percentile in 5 (9.1%) and >95th percentile in 3 (5.5%). ABPM confirmed 'white coat hypertension' in 3 (5.5%), masked hypertension in 2 (3.6%) and nondipping in 28 (51%). The SDSC score suggested that 43 (78%) children had disturbed sleep. Logistic regression modelling indicated that nondipping correlated with disturbed sleep. Conclusion: The 'white coat' phenomenon may be responsible for increased prevalence of elevated rest/office BP values in children with ADHD. Prevalent sleep 'non-dipping' in this population is associated with sleep disturbances but clinical significance of this finding requires further investigation. PMID- 30455579 TI - A retrospective analysis of clinical characteristics of childhood narcolepsy. AB - Aim: Narcolepsy, encompassing excessive daytime sleepiness (EDS), cataplexy, sleep paralysis and hypnogogic hallucinations, was previously considered rare in childhood. Recently, cases of childhood narcolepsy have increased significantly and the reasons for this may include the increasing awareness of narcolepsy as well as the H1N1 vaccination. The aim of this study was to describe the clinical characteristics of childhood narcolepsy, specifically focusing on cataplexy subtypes that may facilitate early recognition of narcolepsy. Methods: We retrospectively reviewed and analyzed the medical records of 33 children diagnosed with narcolepsy at the Hospital for Sick Children, in Toronto, Ontario. All patients were seen prior to 18 years of age and symptoms were self-reported by parents and/or children themselves. Results: At presentation, 32 of 33 children reported EDS and 28 of 33 reported cataplexy. Among the 28 patients with cataplexy, 18 of 28 reported cataplexy referred to as 'cataplectic facies' (e.g., facial hypotonia and/or tongue protrusion) while 10 of 28 patients reported characteristic cataplexy, defined as bilateral loss of muscle tone. Children with cataplectic facies reported higher BMI z-scores compared to those with characteristic cataplexy, 1.8 and 0.8, respectively. Children with cataplectic facies also tended to be younger than those with characteristic cataplexy, 9.2 and 11.8 years of age, respectively. Cataplectic facies appear to be related to narcolepsy close to disease onset. Conclusions: Children, especially young, obese children, presenting with a history of EDS with associated facial hypotonia or tongue protrusion raises the index of suspicion of narcolepsy and should prompt a referral to a specialized sleep facility to establish the diagnosis. PMID- 30455581 TI - Cost savings of implementing the SickKids Paediatric Orthopaedic Pathway for proximal humerus fractures in Ontario, Canada. AB - Background: The SickKids Paediatric Orthopaedic Pathway (SKPOP) for proximal humerus fractures may safely reduce the number of radiographs and follow-up assessments for children with these injuries. The study objective was to examine potential cost-savings of the SKPOP from the perspective of the Ministry of Health and Long-term Care (MOHLTC). Methods: Two sets of resource profiles, based on direct health care costs were created for a cohort of patients treated at our institution: the first based on actual follow-up assessment values, and the other based on follow-up assessments according to the SKPOP. Differences between the two profiles represent potential cost-savings. A decision-analysis and associated probabilistic sensitivity analysis (PSA) were performed. Results: In a cohort of 239 patients treated between 2009 and 2014, 92.9% (222) would have met SKPOP eligibility. Management according to this pathway would have reduced orthopaedic assessments and shoulder radiograph series by 83.6% (470/562) and 70.8% (367/589), respectively. For the cohort examined, a potential cost-savings of $30,040.56 ($135.32/patient) was observed. A PSA, accounting for variable SKPOP adherence and health care utilization, yielded cost-savings in 96.5% of the iterations run through the decision-analysis model and an average cost-savings of $57.82/patient. Based on these results and the annual provincial incidence rate of eligible patients (n=575), the MOHLTC could potentially save $33,249.45 annually with province-wide implementation. Conclusions: Implementation of the SKPOP for a cohort of patients managed at our institution could have resulted in cost-savings due to substantial reductions in health care utilization. Cost savings are likely to occur with provincial implementation of the SKPOP for proximal humerus fractures. PMID- 30455582 TI - What does mainstream media say about enzyme replacement therapies? AB - Introduction: Enzyme replacement therapies (ERTs) are expensive drugs that can be used to treat certain inherited diseases. ERTs are not universally covered across provinces and costs are beyond the means of most patients. Media reports are commonly used to lobby for provincial ERT funding for specific patients. As physicians may be confronted with these media reports by patients, this study explored medical reporting regarding ERTs in print media. Methods: Canadian Newsstream database was searched for articles about three ERTs-ElapraseTM, NaglazymeTM and VimizimTM. Articles meeting inclusion criteria were reviewed for data regarding efficacy and adverse events, mention of role of health care professionals and medical information sources. Thematic analysis explored how efficacy was described within the articles. Data from product monographs and recent meta-analyses served as a basis for comparison. Results: Of 57 articles retained for the study, 9% mentioned clinical trial data regarding drug efficacy; 7% mentioned adverse events. Only 23% of opinions about medical necessity or efficacy of the drug were from a physician. The majority were those of politicians. Information describing the condition was accurate in 90% of cases, although usually incompletely. Discussion: Incomplete or inaccurate reporting about efficacy and safety may influence families that appear to be candidates for ERT. Poor reporting of medical information may also influence the social pressures placed on the government and affect funding approval for these drugs. Physicians should be aware that their patients may be exposed to misleading information. PMID- 30455583 TI - In Situ Synthesis of Polyurethane Scaffolds with Tunable Properties by Controlled Crosslinking of Tri-Block Copolymer and Polycaprolactone Triol for Tissue Regeneration. AB - Mimicking the mechanical properties of native tissues is a critical criterion for an ideal tissue engineering scaffold. However, most biodegradable synthetic materials, including polyester-based polyurethanes (PUs), consist of rigid polyester chains and have high crystallinity. They typically lack the elasticity of most human tissues. In this study, a new type of biodegradable PU with excellent elasticity was synthesized based on the controlled crosslinking of poly(ester ether) triblock copolymer diols and polycaprolactone (PCL) triols using urethane linkages. Three-dimensional (3D) porous scaffolds with a defined geometry, tunable microstructures, and adjustable mechanical properties were synthesized in situ using an isocyanate-ended copolymer, a tri-armed PCL, and a chain extender. The mechanical properties of the scaffolds can be easily tuned by changing the ratio of reactants, varying the solution concentration, or using a porogen. Notably, all of these scaffolds, although mostly made of rigid PCL chains, showed remarkable elasticity and cyclical properties. With an optimized molecular design, a maximum recovery rate of 99.8% was achieved. This was because the copolymer provided molecular flexibility while the long chain crosslinking of PCL triol hindered crystallization, thus making the PU behave like an amorphous elastic material. Moreover, the in vitro cell culture of 3T3 fibroblasts and MG63 osteoblast-like cells confirmed the biocompatibility of these PU scaffolds and revealed that scaffolds with different stiffnesses can stimulate the proliferation of different types of cells. All of these attributes make PU scaffolds extremely suitable for the regeneration of tissues that experience dynamic loading. PMID- 30455584 TI - Metabolome-based biomarkers: their potential role in the early detection of lung cancer. AB - Lung cancer is the leading cause of cancer-related death worldwide, and a major problem affecting its mortality is the late diagnosis of the majority of cases, where treatment options are limited and overall prognosis is very bad. Currently, a low-dose computed tomography (LD-CT) screening in the high-risk group is the only available diagnostic strategy that could reduce mortality due to this malignancy. However, the LD-CT screening test suffers from a high false positive rate. Hence, complementation of LD-CT examination with blood-based biomarkers is a rational approach to increase efficacy and reduce the cost of early lung cancer screening programs. Several molecular signatures that discriminate between patients with early lung cancer and healthy individuals have been proposed in recent years, which are based on components of serum/plasma metabolome. However, none of these signatures has been validated by independent studies based on material collected during real lung cancer screening. Therefore, the validation of the real diagnostic value of these otherwise promising candidates remains a critical step in this challenging field of cancer diagnostics. PMID- 30455586 TI - Survival rates among women with ovarian cancers diagnosed in the area of Podkarpacie province in the years 1990-2015. AB - Aim of the study: The objective of the study was to analyse the survival rate of women with malignant ovarian tumours in the years 1990-2015 in the Podkarpacie province. Material and methods: The database used for calculations covered 2399 cancer incidences verified at the end of 2014. The estimated relative survival rates were calculated by means of the Hakulinen method. Results: The number of recorded cases amounted to 196 in 2015 and was higher by 86.7% than in 1990. The rates of one-year, three-year, and five-year survival was 72.5%, 51.2%, and 42.4%, respectively. Conclusions: Survival rates of women with ovarian cancer in the Podkarpacie province are comparable to survivals calculated for the entire Poland region. Despite the low risk factor, women suffering from ovarian adenocarcinoma have lower survival rates than others, and as many as 42.5% of patients with adenocarcinoma were diagnosed in stage IV. Steps aimed at improvement of detectability of ovarian cancers in the earliest possible stage should be taken. This should increase survival rates in each age group. PMID- 30455585 TI - Update in global trends and aetiology of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver responsible for an increasing number of cancer-related deaths, especially in developing economies of Asia and Africa. A plethora of risk factors have been described in the literature. Some of the important ones include chronic viral hepatitis, liver cirrhosis, environmental toxins such as aflatoxin, non-alcoholic fatty liver disease, lifestyle factors like alcohol consumption, smoking, and dietary factors, metabolic diseases like diabetes mellitus and obesity, and genetic and hereditary disorders. The development of HCC is complex involving sustained inflammatory damage leading to hepatocyte necrosis, regeneration, and fibrotic deposition. It also poses multiple challenges in diagnosis and treatment despite advances in diagnostic, surgical, and other therapeutic advancements. This is a narrative review of findings of multiple studies that were retrieved from electronic databases like PubMed, MEDLINE, Embase, Google Scholar, Scopus, and Cochrane. We summarise the current knowledge regarding the epidemiology and various risk factors for the development of HCC with a brief note on various prevention strategies. PMID- 30455587 TI - Overweight but not obesity is associated with decreased survival in rectal cancer. AB - Aim of the study: To analyse the influence of overweight and obesity in disease specific survival (DSS) in rectal cancers at stages I-III in a population with high prevalence of overweight/obesity. Material and methods: The population (N = 304) consisted of Mexican patients with stage I-III rectal cancer during the period between 2009 and 2015. Patients were divided based on their body mass index (BMI) into normal weight 18-25 kg/m2, overweight 25-29 kg/m2, and obesity BMI > 30 kg/m2 groups. Comparison of clinicopathologic features and survival analysis were performed. Results: The median age was 58 years (interquartile range [IQR] 50-65) and the mean BMI was 26.03 +/-4.06 kg/m2. Patients in the obesity and overweight groups received a lower proportion of preoperative treatment and had a higher proportion of patients in stage II. Overweight patients had a lower baseline neutrophil/lymphocyte ratio and lower survival rate than patients with normal weight and with obesity (mean survival of 69.5 months vs. 81.15 months and 86.4 months, respectively). The estimated five-year DSS was 51% for the overweight group, 81% for the normal group, and 82% for the obesity group (p = 0.026). Conclusions: Patients with stage I-III rectal cancer in the overweight group showed a lower DSS compared to groups with normal weight and with obesity, with the last two being similar. PMID- 30455588 TI - Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma: a retrospective single-institution study. AB - Aim of the study: To evaluate the efficacy of sequential combination therapy using sorafenib and hepatic arterial infusion chemotherapy (HAIC) in patients with Barcelona Clinic Liver Cancer stage B/C hepatocellular carcinoma (HCC). Material and methods: We recruited 98 BCLC stage B/C HCC patients at our institute, who received either sorafenib monotherapy or planned sequential sorafenib-HAIC combination therapy. A total of 26 patients (combination group) received sorafenib for one or two months, followed by HAIC with a single dose of cisplatin-lipiodol suspension and a continuous infusion of 5-fluorouracil. Sorafenib-HAIC cycles were repeated every 2-3 months. The remaining 72 patients (control group) were treated with sorafenib alone. Clinical characteristics and treatment outcomes were compared between the groups. Inverse probability weighting (IPW) using propensity scores was applied to adjust for the between group differences in baseline characteristics. Results: The combination group had a significantly lower frequency of extrahepatic metastasis and BCLC stage C disease compared with the control group but had more intrahepatic lesions. The crude median overall survival (OS) was 17.1 months in the combination group compared with 9.7 months in the control group (p = 0.01). The objective response rate was 23.1% in the combination group vs. 6.9% in the control group (p = 0.06). Multivariate analysis identified receipt of sorafenib-HAIC combination (HR: 0.521, 95% CI: 0.297-0.915, p = 0.02) and alpha-fetoprotein (>= 400 ng/ml) at baseline as independent factors associated with OS. After adjustment with IPW the combination group still had significantly better OS than the control group (p = 0.04). Conclusions: The sequential sorafenib-HAIC combination can be an effective and promising treatment option for selected patients with BCLC stage B/C HCC. PMID- 30455589 TI - Assessment of the relation between religiosity, mental health, and psychological resilience in breast cancer patients. AB - Aim of the study: The aim of this study was to examine the relationship between religiosity, mental health, and psychological resilience in breast cancer patients. Material and methods: A cross-sectional study was conducted in an oncology department of a hospital in northern Greece during February and March 2017. The sample consisted of 152 breast cancer patients. Data were collected with the following instruments: Patient Health Questionnaire two-item scale, Generalised Anxiety Disorder two-item scale, Connor-Davidson Resilience Scale 25, and Centrality of Religiosity Scale. Also, patients' characteristics were included, specifically demographic, social, and clinical information. Statistical analyses were conducted with the Statistical Package for the Social Sciences V25. Results: According to our results, approximately 1 out of 3 patients had depression and anxiety. Also, the sample had moderate resilience and were moderately religious. Patients who were classified as end-stage cancer patients and those who underwent mastectomy found to be more religious. Religiosity correlated positively with the resilience, while no correlation was found with depression, anxiety, and symptom burden. Based on regression results, religious beliefs seem to be a predictive factor for resilience and resilience is a predictive factor for depression. Conclusions: Our findings show that there was no association between religiosity and mental health, while a strong relation was highlighted between religious beliefs and psychological resilience. This study should constitute a starting point for further assessments regarding the fact that religiosity can provide social support that facilitates psychological adaption to illness and helps cancer patients to cope with their illness, which should be recognised by health care professionals. PMID- 30455590 TI - Computed tomography imaging of acute gastrointestinal graft-versus-host disease after haematopoietic stem cell transplantation in children. AB - Aim of the study: To evaluate computed tomography (CT) findings of gastrointestinal graft-versus-host disease (GI-GVHD) occurring in children after haematopoietic stem-cell transplantation (HSCT). Material and methods: From February 2013 to May 2018, 225 paediatric patients underwent HSCT. Sixty-eight patients (30%) presented with clinical diagnosis of acute GI-GVHD in the first 100 days after HSCT. Thirty-five (18 girls, 17 boys; age range, 2-18 years; mean age, 10.3 years) of 68 patients had abdominopelvic CT and included in study. Results: Intestinal CT abnormalities were present in 33 (94%) and extra intestinal CT findings were in 30 (86%) patients. Thickening of the bowel wall was the most common finding (31 patients, 89%), which involved the small bowel in 29 patients (83%), colon in 16 patients (46%), and both in 15 patients (43%). Oesophageal wall thickening was present in three patients (9%), and gastric wall thickening was in eight patients (23%). Bowel dilatation was detected in 13 patients (37%). Mucosal enhancement of the bowel wall was observed in 28 patients (80%). The prevalence of the extra-intestinal CT findings were: periportal oedema in nine (26%), ascites in 15 (43%), wall thickening and enhancement of gall bladder in 13 (37%), pericholecystic fluid in six (17%), hepatomegaly in 13 (37%), and splenomegaly in nine (26%) patients. One patient (3%) demonstrated free intraperitoneal air due to intestinal perforation. Conclusions: CT is useful to support the clinical diagnosis of acute GVHD in children with GI symptoms after HSCT. Radiological evaluation is important because early diagnosis and treatment affect the prognosis of GI-GVHD. PMID- 30455591 TI - The utility of the subcuticular suture in hepatic resection. AB - Aim of the study: Despite recent technical progress and advances in the perioperative management of liver surgery, postoperative surgical site infection (SSI) is still one of the most common complications that extends hospital stays and increases medical expenses following hepatic surgery. Material and methods: From 2001 to 2017 a total of 1180 patients who underwent hepatic resection for liver tumours were retrospectively analysed with respect to the predictive factor of superficial incisional SSI, using a propensity score matching by procedure (subcuticular or mattress suture). Results: The incidence of superficial and deep incisional SSIs was found to be 7.1% (84/1180). By propensity score matching (PSM), 121 of the 577 subcuticular suture group patients could be matched with 121 of the 603 mattress suture group patients. Multivariate analysis demonstrated wound closure technique as the only independent risk factor that correlated significantly with the occurrence of superficial incisional SSIs (p = 0.038). C reactive protein (CRP) levels on postoperative day 4 were significantly higher in patients with incisional SSIs than in those without (p < 0.001). Conclusions: Wound closure technique with subcuticular continuous spiral suture using absorbable suture should be considered to minimise the incidence of incisional SSIs. Moreover, wounds should be carefully checked when CRP levels are high on postoperative day 4. PMID- 30455593 TI - Hyperbaric oxygen therapy in the treatment of complications of irradiation in laryngeal cancer. AB - One of the standard treatments in laryngeal cancer is radiotherapy (RT). Many short- and long-term complications can occur in the region that has received radiotherapy. Definitive treatment of the emerging complications is still debatable, and treatment is challenging for radiation oncologists and ear nose throat specialists. Recently, hyperbaric oxygen treatment (HBOT) has become a promising alternative for the treatment of these complications. The aim of this report is to discuss the effectiveness of HBOT in the treatment of late-term RT related potential complications in a patient with laryngeal cancer. We applied HBOT for a 58-year-old male patient with laryngeal cancer for the treatment of laryngeal oedema, and dyspnoea that developed one year after RT. In a decompression chamber at 2.4 atm pressure, the patient was made to breath 100% oxygen with a mask for 90 minutes. At the beginning, HBOT was planned for 30 days; however, it was terminated upon improvement of the symptoms at the 19th session. The symptoms, which developed one year after RT, were relieved completely with HBOT, and the patient is maintaining his life without any complaint under our control. The HBOT can be an alternative treatment for late term complications developed after radiotherapy. It can be especially used for laryngeal oedema, and dyspnoea related to the field of radiotherapy. PMID- 30455592 TI - Salivary secretory immunoglobulin A reactivity: a comparison to cortisol and alpha-amylase patterns in the same breast cancer survivors. AB - Introduction: One way to examine the extent to which the stress associated with a breast cancer experience (BC) impacts stress-related physiological mechanisms is to study the secretion patterns of associated biomarkers. Unlike cortisol and alpha-amylase (sAA), biomarkers of immune functioning such as secretory immunoglobulin A (SIgA) have rarely been examined in BC survivors. Aim of the study: This study had two principal aims: the first was to evaluate the basal secretion profiles of SIgA as well as its response to an acute stressor as a marker of immune health in BC survivors and women with no history of BC, and the second was to determine how SIgA stress-related patterns compare to published cortisol and sAA patterns in the same women. Results: Overall, the findings indicate that BC survivors exhibit a blunted cortisol reaction to an acute stressor, a generally elevated diurnal sAA concentration pattern, and normal SIgA profiles, compared to women with no history of cancer. This study serves as a foundation for future research to elucidate the relationships between BC experience variables, stress biomarkers, and health outcomes in BC survivors. PMID- 30455594 TI - A malignant astrocytoma with uncommon angiocentric features and dot-like EMA expression. AB - Angiocentric features are uncommon in high-grade World Health Organisation (WHO) brain tumours, whilst they are typical for WHO grade I tumours, e.g. angiocentric gliomas. We present an unusual glial tumour that occurred in a 59-year-old man. The tumour had equivocal radiologic and histopathologic features, especially a characteristic angiocentric pattern, low-to-moderate Ki67, and dot-like epithelial membrane antigen expression. The tumour did not show features characteristic for glioblastoma; however, it recurred as glioblastoma four months later. Based on this case, we show that high-grade WHO brain tumours may show an angiocentric pattern typical for low-grade WHO brain tumours, such as angiocentric gliomas. PMID- 30455595 TI - Citrate targets FBPase and constitutes an emerging novel approach for cancer therapy. AB - Gao-Min Liu and Yao-Ming Zhang recently published a review entitled "Targeting FBPase is an emerging novel approach for cancer therapy" (Liu and Zhang in Cancer Cell Int 18:36, 2018). In this paper, the authors highlighted how the down regulation or inactivation of FBPase, a rate limiting enzyme of gluconeogenesis, can promote the Warburg effect and cancer growth. In contrast, activation of this enzyme demonstrates anti-cancer effects and may appear as emerging novel approach for cancer therapy. Among the potential activators of FBP listed by Liu and Zhang, citrate was surprisingly not mentioned although it is an activator of FBPase, also demonstrating various anti-cancer effects in pre-clinical studies. Thus, citrate should be tested as a new therapeutic strategy, in particular in clinical studies. PMID- 30455597 TI - Stakeholder involvement in Multi-Criteria Decision Analysis. AB - This brief perspective highlights the importance of decision maker buy-in and ownership through stakeholder engagement in the co-construction of the multi criteria decision analysis (MCDA) model. A brief historical overview of MCDA is presented before outlining the importance of bridging the gap (and to gain trust) between the tool developers and users. The issues with the current MCDA tool development and testing efforts are highlighted, and the ownership and routine adoption of the MCDA process is discussed. PMID- 30455596 TI - Rivaroxaban plasma levels in patients admitted for bleeding events: insights from a prospective study. AB - Background: Serious bleeding events have been frequently described in patients taking direct oral anticoagulants (DOAC). In secondary analyses of phase 3 trials, DOAC plasma concentrations were shown to correlate with bleeding outcomes. This study aimed to describe rivaroxaban plasma levels in patients admitted to the emergency department (ED) for bleeding events. For each patient, risk factors for experiencing bleeding events were also investigated. Methods: This analysis was part of an observational study conducted in the ED of two teaching hospitals. Plasma samples from 10 rivaroxaban-treated patients admitted for bleeding events were collected. Rivaroxaban plasma concentrations were determined by calibrated chromogenic anti-Xa assay. The measured rivaroxaban levels were then extrapolated at trough using a published population pharmacokinetic (PopPK) model, and compared to on-therapy ranges observed in large clinical trials. For each patient, clinical, medication and ABCB1 genotype data were collected. Results: Rivaroxaban measurements varied from 5 to 358 ng/ml, with a post-intake delay ranging from 9 to 38 h. At trough, estimated plasma concentrations were between 12 and 251 ng/ml (median value 94 ng/ml). Four patients had higher-than-expected rivaroxaban levels. Inadequate dose regimen, excessive alcohol consumption and lack of treatment reassessment were observed in several patients. Half of patients were taking >=1 drug with potential pharmacokinetics interactions (e.g. amiodarone, diltiazem), while half of patients were taking >=1 drug increasing the risk of bleeding. All 3 patients with available genotyping data and higher-than-expected rivaroxaban levels were heterozygous or homozygous mutated for the ABCB1 1236C > T, 2677G > T, 3435 C > T and rs4148738 single nucleotide polymorphisms (SNP). Conclusions: Rivaroxaban patients admitted to the ED for bleeding events showed highly variable plasma concentrations. This analysis underlines the usefulness of rapid DOAC measurement and the value of PopPK models to estimate concentrations at trough in a context where the post-intake delay is unmanageable. Close patient follow-up, including renal function assessment and drug interactions review, is essential for bleeding risk minimization. PMID- 30455599 TI - Panel discussion on the application of MCDA tools. AB - Prioritization in healthcare is particularly sensitive to subjective biases and data asymmetry. Yet making data-based and objective decisions are critical to optimizing long term individual and societal benefit. Multi-Criteria-Decision Making-Analysis (MCDA) provides shared processes, structure, and language to enable this. This panel presented and discussed three examples of MCDA application to health technology assessment, national healthcare strategy and balancing the priorities of providers and customers. PMID- 30455598 TI - Including the public perspective in health-related MCDA: ideas from the field of public opinion research and polling. AB - This commentary utilizes the lens of public opinion research in health to suggest ideas for best integrating public input into multi-criteria decisions analysis (MCDA) approaches. The field of public opinion research suggests: (1) there is frequently a distinction between public and expert views, even outside of situations where the public has direct experience; (2) representative samples are important to ensure findings reflect all segments of the relevant population; and (3) limiting cognitive burden in studies designed to elicit public preferences is essential for meaningful responses that represent the population's views. Together these reflections suggest the need for considering new avenues for including public views in MCDA approaches where representative samples relying on well-designed questions are utilized more regularly. PMID- 30455600 TI - MCDA or preference-based social welfare functions? AB - Preference-based social welfare functions (pbSWF) perform better at reconciling competing personal and social goals than typical forms of MCDA. Its virtues are (a) its respect for people's own judgments about the relative values of health, wealth, and other broad benefits within their lives (non-paternalism) and (b) its conformity with reasonable ethical axioms. Any discrepancy between an MCDA objective function and that implied by pbSWF suggests the former's failure to respect non-paternalism and reasonable ethical principles. The pbSWF approach is implementable using micro-econometric evidence on personal preferences over health, wealth, and other broad benefits; and surveys of the general population or their representatives to ascertain the social acceptability of certain ethical axioms and the degree of inequality aversion. PMID- 30455601 TI - Priority setting for the introduction of rotavirus vaccine: what evidence was essential? AB - Rotavirus (RV) diarrhea is the most common cause of severe diarrhea in children worldwide and since 2006, vaccines have been available and recommended by WHO for use in all children. We developed protocols that countries could use to assess the burden of RV disease in their own countries and the cost-effectiveness of a program for vaccine introduction. A decade later and in the setting of extreme tiering of prices so that the poorest countries pay the least for the vaccine, more than 92 countries have introduced this vaccine into their national programs and more than 90 have not. Those countries that introduced determined by protocol that the burden of RV disease was substantial and the cost of vaccine reasonable, especially in low income settings where GAVI subsidizes the vaccines' purchase. However, elsewhere, WHO's global recommendation has not been enacted leaving a majority of the world's children still at risk of this severe and sometimes fatal disease. We remain with much to learn about how to encourage countries to make decisions that will improve the health of their own children. PMID- 30455603 TI - How can MCDA tools improve priority setting? Four critical questions. AB - This comment argues that four critical questions needs to be resolved before MCDA tools can improve priority setting in health: how to merge the quantitative and deliberative elements of MCDA; how to select criteria; how to weigh them, and whom to bring to the table. PMID- 30455604 TI - MCDA from a health economics perspective: opportunities and pitfalls of extending economic evaluation to incorporate broader outcomes. AB - Background: Multi-criteria decision analysis (MCDA) is a structured decision making process that offers greater flexibility to incorporate multiple objectives than cost-effectiveness analysis or benefit-cost analysis. Conclusions: The flexibility of MCDA requires careful consideration of its methodological underpinnings, analytical forms and cognitive biases that may arise in eliciting trade-off. The methodology of MCDA should ideally incorporate both deliberative and technical processes. PMID- 30455602 TI - Incorporating MCDA into HTA: challenges and potential solutions, with a focus on lower income settings. AB - Background: Multicriteria decision analysis (MCDA) has the potential to bring more structure and transparency to health technology assessment (HTA). The objective of this paper is to highlight key methodological and practical challenges facing the use of MCDA for HTA, with a particular focus on lower and middle-income countries (LMICs), and to highlight potential solutions to these challenges. Methodological challenges: Key lessons from existing applications of MCDA to HTA are summarized, including: that the socio-technical design of the MCDA reflect the local decision problem; the criteria set properties of additive models are understood and applied; and the alternative approaches for estimating opportunity cost, and the challenges with these approaches are understood. Practical challenges: Existing efforts to implement HTA in LMICs suggest a number of lessons that can help overcome the practical challenges facing the implementation of MCDA in LMICs, including: adapting inputs from other settings and from expert opinion; investing in technical capacity; embedding the MCDA in the decision-making process; and ensuring that the MCDA design reflects local cultural and social factors. Conclusion: MCDA has the potential to improve decision making in LMICs. For this potential to be achieved, it is important that the lessons from existing applications of MCDA are learned. PMID- 30455605 TI - Setting health sector priorities: a brief overview of Ethiopia's experience. AB - As a country with significant resource constraints, a fair and efficient health priority setting should be at the cornerstone of Ethiopia's commitment to attain universal health coverage by 2035. This paper draws on the current national strategies including the national essential health service package to explore the criteria and processes used to set the existing national health sector priorities. Additionally, it reviews Ethiopia's experience in comparison with the multi-criteria decision analysis proposed by Baltussen et al. Finally, the paper highlights the importance of strengthening country-led efforts and investing in human capital to shape priority setting in a developing country context. PMID- 30455607 TI - Resource allocation in decision support frameworks. AB - Background: Cost-benefit and cost-effectiveness analysis place limits on the dimensions of value that the models can incorporate. Cost-benefit analysis requires monetization of all measures of value (including life), a task sometimes deemed either difficult to accomplish or even repugnant. Cost-effectiveness analyses include health care gains in natural units (e.g., quality-adjusted life years or QALYs) rather than purely monetizing them (e.g., in dollars) and offers an efficiency perspective based on the ratio of cost per QALYs or similar health measures. These two methods use different rules for investment. Cost-benefit analysis says to invest whenever benefits exceed costs. Cost-effectiveness analysis says to invest if the intervention has a cost per QALY that meets-or is below-a designated cutoff value. Methods: Multi-criteria frameworks expand decision analyses by considering value tradeoffs from decision makers, and then producing a synthetic measure that summarizes the performance of investment options. This evaluation is done across all chosen dimensions of value, based on the weights provided by the decision makers, but this flexibility comes at a cost. To date, no approach is widely accepted to suggest how much to invest (how to determine a budget constraint) using multi-attribute models. Moreover, there is no agreed-upon method to measure willingness to pay for incremental multi attribute value improvements. Our paper proposes a way forward. Results: Based on existing dollar estimates of willingness to pay for QALYs, our concept creates a comparable cutoff for multi-criteria value measures. Our proposed method expands the acceptable cost per QALYs in proportion to how much of the total measure is accounted for by the QALY component. Agreed-upon values for cost per QALY are thus extrapolated to account for extra value created by non-QALY attributes of each intervention. Conclusion: Using our proposed methods, the cost per QALY cutoff can serve as a benchmark toward creating a resource allocation cutoff in multi-criteria frameworks. PMID- 30455608 TI - Introduction: priority setting in global health. PMID- 30455606 TI - HTA and MCDA solely or combined? The case of priority-setting in Colombia. AB - Background: All healthcare systems face problems of justice and efficiency related to setting priorities for allocating limited financial resources. Therefore, explicit decision-making in healthcare depicted as a continuum from evidence generation to deliberation and communication of the decision made, needs to be transparent and fair. Nevertheless, priority-setting in many parts of the world remains being implicit and ad-hoc process. Health Technology Assessment (HTA) and Multi-Criteria Decision Analysis (MCDA) have emerged as policy tools to assist informed decision-making. Both, MCDA and HTA have pros and cons. Main body: Colombia experienced an important institutional transformation after the establishment of the Health Technology Assessment Institute in 2012. This paper briefly presents the current challenges of the Colombian health system, the general features of the new health sector reform, the main characteristics of HTA in Colombia and the potential benefits and caveats of incorporating MCDA approaches into the decision-making process. Conclusion: Structured and objective consideration of the factors that are both measurable and value-based in an open and transparent manner may be feasible through combining HTA and MCDA in contexts like Colombia. Further testing and validation of HTA and MCDA solely or combined in LMICs are needed to advance these approaches into healthcare decision-making worldwide. PMID- 30455609 TI - Multi-criteria decision analysis: of politics, policy entrepreneurs, and processes. AB - Multi-criteria decision analysis (MCDA) has the potential to increase the consistency, transparency and rigour with which these criteria inform decisions. Political context is relevant not only as a motivation for turning to MCDA but also the context in which MCDA can be successfully implemented. A policy entrepreneur can spearhead the creation of a process to carry out MCDA and can help to create and build the capacity of a public institution that observes and convenes this process, an institution that has legal authority to carry out such a function. PMID- 30455610 TI - Combining A4R and MCDA in priority setting for health. AB - Multiple criteria decision analysis (MCDA) has been proposed as a method for determining the criteria to be used in health technology assessment. A standard criticism of MCDA is that it lacks attention to securing legitimacy for its decisions. The relevance condition of A4R has been criticized for its vagueness because it lacks a focus on criteria selection. Combining the two methods addresses the central criticisms of each and provides a way of addressing the problem of priority setting for health. PMID- 30455611 TI - Priority setting in health: development and application of a multi-criteria algorithm for the population of New Zealand's Waikato region. AB - Background: Priority setting in a climate of diverse needs and limited resources is one of the most significant challenges faced by health care policymakers. This paper develops and applies a comprehensive multi-criteria algorithm to help determine the relative importance of health conditions that affect a defined population. Methods: Our algorithm is implemented in the context of the Waikato District Health Board (WDHB) in New Zealand, which serves approximately 10% of the New Zealand population. Strategic priorities of the WDHB are operationalized into five criteria along which the algorithm is structured-scale of disease, household financial impact of disease, health equity, cost-effectiveness, and multimorbidity burden. Using national-level data and published literature from New Zealand, the World Health Organization, and other high-income Commonwealth countries, 25 health conditions in Waikato are identified and mapped to these five criteria. These disease-criteria mappings are weighted with data from an ordered choice survey administered to the general public of the Waikato region. The resulting output of health conditions ranked in order of relative importance is validated against an explicit list of health concerns, provided by the survey respondents. Results: Heart disease and cancerous disorders are assigned highest priority rankings according to both the algorithm and the survey data, suggesting that our model is aligned with the primary health concerns of the general public. All five criteria are weighted near-equal across survey respondents, though the average health equity preference score is 9.2% higher for Maori compared to non Maori respondents. Older respondents (50 years and above) ranked issues of multimorbidity 4.2% higher than younger respondents. Conclusions: Health preferences of the general population can be elicited using ordered-choice surveys and can be used to weight data for health conditions across multiple criteria, providing policymakers with a practical tool to inform which health conditions deserve the most attention. Our model connects public health strategic priorities, the health impacts and financial costs of particular health conditions, and the underlying preferences of the general public. We illustrate a practical approach to quantifying the foundational criteria that drive public preferences, for the purpose of relevant, legitimate, and evidence-based priority setting in health. PMID- 30455612 TI - Commentary: setting priorities in NCD prevention and control. AB - Decision making in health requires the use of sound evidence and context-specific information, guided by a priority setting methodology or framework. For noncommunicable disease (NCD) prevention and control, a decision-making methodology has been applied by the World Health Organization to delineate priorities, and options for cost-effective NCD interventions. A set of 14 interventions considered very cost-effective, affordable and feasible for implementation in various resource level settings were identified. Among them, tobacco control through taxation, bans on tobacco advertising, plain packaging, and smoke free public spaces stands out as perhaps the single most important interventions to tackle NCDs. PMID- 30455613 TI - Can reflective multicriteria be the new paradigm for healthcare decision-making? The EVIDEM journey. AB - Background: Multiple technologies, procedures and programs call for fairly-based decisions for prioritization of healthcare interventions. There is a diversity of perspectives of what constitutes a legitimate decision, which depends on both the process and the reasoning applied. Current approaches focus on technical aspects while methods to support alignment of decisions with the compassionate impetus of healthcare systems is lacking. Methods: The framework was developed based on an analysis of the foundations of healthcare systems, the reasoning underlying decisions and fair processes. The concept of reflective multicriteria was created: it assumes that decisionmakers guided by a generic interpretative frame rooted in the compassionate impetus of healthcare systems, can sharpen their reasoning, raise awareness of their motivation and increase legitimacy of decisions. The initial framework was made available through a not for profit organization (the EVIDEM Collaboration, 2006-2017) to stimulate its development with thought leaders and stakeholders in an open source philosophy. Development was tailored to the real-life needs of decisionmakers and drew on several domains of knowledge including healthcare ethics, evidenced-based medicine, health economics, health technology assessment and multicriteria approaches. Results: The 10th edition framework builds on four dimensions: (1) the universal impetus of healthcare systems, (2) reasoning, values and ethics, (3) evidence and knowledge on interventions, and (4) a transformative process. Mathematical aspects of the framework are designed to help clarify, express and share individual reasoning; this non-conventional use of numbers requires a cultural change and needs to be phased in slowly. The framework includes four tools for easy adaptation and operationalization: (a) concepts and operationalization, (b) adapt and pilot, (c) evidence matrix, (d) mathematical representation of reasoning. Application is useful throughout all types of healthcare interventions, for all levels of decision, and across the globe. Conclusion: By clarifying their reasoning while keeping decisionmakers aware of the impetus of healthcare systems, reflective multicriteria provides an effective approach to increase the legitimacy of decisions. Beyond a tool, reflective multicriteria pioneered by EVIDEM is geared to transform our vision of the value of healthcare interventions and how they might contribute to relevant, equitable and sustainable healthcare systems. PMID- 30455614 TI - Association between inflammatory bowel disease and uveal melanoma: case report of two young adults and a literature review. AB - Introduction: Uveal melanoma is a rare tumour caused by genetic factors and alterations in the immune response. Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disorder characterized by an inappropriate or excessive immune response. The two main types of IBD are Crohn's disease (CD) and ulcerative colitis (UC). A diagnosis of IBD and the use of immunosuppressive drugs are both independently associated with an increased risk of developing skin melanoma. The association between IBD and uveal melanoma (UM) has not been previously described. Cases description: Two young Caucasian men, aged 24 and 28, developed UM 3 and 15 years, respectively, after being diagnosed with IBD. Both received long-term treatment with immunomodulatory drugs, with periodic switching among the drugs due to the refractory nature of IBD. In both cases, melanoma was treated by brachytherapy with iodine-125 COMS plaque implant at a dose of 75 Gy. Discussion: Chronic inflammation can promote cell proliferation and growth. The use of immunomodulatory drugs is associated with an increased risk of developing melanoma and non-melanoma skin cancer. The two patients described in this report both had long-standing IBD treated with immunomodulatory drugs. It seems reasonable to suggest that these two factors may have promoted the development of uveal melanoma. More studies are warranted to investigate and confirm this possible association. PMID- 30455616 TI - A Miniaturized Particulate Matter Sensing Platform based on CMOS imager and Real Time Image Processing. AB - A miniaturized particulate matter (PM) sensing platform was developed. The platform uses a CMOS imager as sensor, electrostatic particle collector to collect ambient PM on an imaging substrate, and a laser diode as light source to scatter light from the particles. Image processing based PM sensing algorithm was developed to obtain particle number, size and size distribution in real time. The system is compact, power efficient, and low cost. The PM sensing platform is suitable for personal PM exposure monitoring with applications in environmental health, occupational and epidemiological studies. PMID- 30455615 TI - Why should radiological oncology do translational research? AB - Radiological Oncology, like the rest of medical specialties, is beginning to provide can personalized therapies. The ongoing scientific advances enable a great degree of precision in diagnoses and therapies. To fight cancer, from a radiotherapy unit, requires up-to-date equipment, professionals with different specialties working in synchrony (doctors, physicists, biologists, etc.) and a lot of research. Some of the new therapeutic tendencies are immunotherapy, nanoparticles, gene therapy, biomarkers, artificial intelligence, etc. A new clinical paradigm in which new professional networks are inevitable is arising. The mission of translational research is to become a scientific engine in the clinical space. PMID- 30455617 TI - Synthesis, characterization and thermal decomposition kinetics of a bio-based transparent nylon 10I/10T. AB - Herein, we report a novel transparent engineering plastic nylon 10I/10T based on bio-based poly(decamethylene isophthalamide) (nylon10I). We have demonstrated the one-step melt polycondensation synthesis of transparent nylon and carried out Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H NMR) to confirm the chemical structure. Furthermore, the dynamic mechanical analysis (DMA) and thermogravimetric analysis (TGA) were used to analyze the thermal properties. Glass transition temperature (Tg ) and thermal decomposition onset temperature (T1 ) of nylon 10I/10T (15 wt. % 10T) were 118.9 and 438.0 degrees C, respectively. The intrinsic viscosity, water absorption, light transmittance, mechanical properties, solvent resistance and the decomposition mechanism of nylon 10I/10T have also been investigated. The results show that the nylon 10I/10T has lower water absorption and enhanced solvent resistance compared to nylon 6-3-T, which indicates that nylon 10I/10T is a promising transparent plastic. PMID- 30455618 TI - Appreciations to Peer Reviewers for Journal of Korean Medical Science 2017. PMID- 30455619 TI - Contextualising the microbiota-gut-brain axis in history and culture. PMID- 30455621 TI - Cortical Decoding of Individual Finger Group Motions Using ReFIT Kalman Filter. AB - Objective: To date, many brain-machine interface (BMI) studies have developed decoding algorithms for neuroprostheses that provide users with precise control of upper arm reaches with some limited grasping capabilities. However, comparatively few have focused on quantifying the performance of precise finger control. Here we expand upon this work by investigating online control of individual finger groups. Approach: We have developed a novel training manipulandum for non-human primate (NHP) studies to isolate the movements of two specific finger groups: index and middle-ring-pinkie (MRP) fingers. We use this device in combination with the ReFIT (Recalibrated Feedback Intention-Trained) Kalman filter to decode the position of each finger group during a single degree of freedom task in two rhesus macaques with Utah arrays in motor cortex. The ReFIT Kalman filter uses a two-stage training approach that improves online control of upper arm tasks with substantial reductions in orbiting time, thus making it a logical first choice for precise finger control. Results: Both animals were able to reliably acquire fingertip targets with both index and MRP fingers, which they did in blocks of finger group specific trials. Decoding from motor signals online, the ReFIT Kalman filter reliably outperformed the standard Kalman filter, measured by bit rate, across all tested finger groups and movements by 31.0 and 35.2%. These decoders were robust when the manipulandum was removed during online control. While index finger movements and middle-ring pinkie finger movements could be differentiated from each other with 81.7% accuracy across both subjects, the linear Kalman filter was not sufficient for decoding both finger groups together due to significant unwanted movement in the stationary finger, potentially due to co-contraction. Significance: To our knowledge, this is the first systematic and biomimetic separation of digits for continuous online decoding in a NHP as well as the first demonstration of the ReFIT Kalman filter improving the performance of precise finger decoding. These results suggest that novel nonlinear approaches, apparently not necessary for center out reaches or gross hand motions, may be necessary to achieve independent and precise control of individual fingers. PMID- 30455620 TI - MicroRNAs Engage in Complex Circuits Regulating Adult Neurogenesis. AB - The finding that the adult mammalian brain is still capable of producing neurons has ignited a new field of research aiming to identify the molecular mechanisms regulating adult neurogenesis. An improved understanding of these mechanisms could lead to the development of novel approaches to delay cognitive decline and facilitate neuroregeneration in the adult human brain. Accumulating evidence suggest microRNAs (miRNAs), which represent a class of post-transcriptional gene expression regulators, as crucial part of the gene regulatory networks governing adult neurogenesis. This review attempts to illustrate how miRNAs modulate key processes in the adult neurogenic niche by interacting with each other and with transcriptional regulators. We discuss the function of miRNAs in adult neurogenesis following the life-journey of an adult-born neuron from the adult neural stem cell (NSCs) compartment to its final target site. We first survey how miRNAs control the initial step of adult neurogenesis, that is the transition of quiescent to activated proliferative adult NSCs, and then go on to discuss the role of miRNAs to regulate neuronal differentiation, survival, and functional integration of the newborn neurons. In this context, we highlight miRNAs that converge on functionally related targets or act within cross talking gene regulatory networks. The cooperative manner of miRNA action and the broad target repertoire of each individual miRNA could make the miRNA system a promising tool to gain control on adult NSCs in the context of therapeutic approaches. PMID- 30455622 TI - Convolutional Neural Networks-Based MRI Image Analysis for the Alzheimer's Disease Prediction From Mild Cognitive Impairment. AB - Mild cognitive impairment (MCI) is the prodromal stage of Alzheimer's disease (AD). Identifying MCI subjects who are at high risk of converting to AD is crucial for effective treatments. In this study, a deep learning approach based on convolutional neural networks (CNN), is designed to accurately predict MCI-to AD conversion with magnetic resonance imaging (MRI) data. First, MRI images are prepared with age-correction and other processing. Second, local patches, which are assembled into 2.5 dimensions, are extracted from these images. Then, the patches from AD and normal controls (NC) are used to train a CNN to identify deep learning features of MCI subjects. After that, structural brain image features are mined with FreeSurfer to assist CNN. Finally, both types of features are fed into an extreme learning machine classifier to predict the AD conversion. The proposed approach is validated on the standardized MRI datasets from the Alzheimer's Disease Neuroimaging Initiative (ADNI) project. This approach achieves an accuracy of 79.9% and an area under the receiver operating characteristic curve (AUC) of 86.1% in leave-one-out cross validations. Compared with other state-of-the-art methods, the proposed one outperforms others with higher accuracy and AUC, while keeping a good balance between the sensitivity and specificity. Results demonstrate great potentials of the proposed CNN-based approach for the prediction of MCI-to-AD conversion with solely MRI data. Age correction and assisted structural brain image features can boost the prediction performance of CNN. PMID- 30455624 TI - Resting State Vagally-Mediated Heart Rate Variability Is Associated With Neural Activity During Explicit Emotion Regulation. AB - Resting state vagally mediated heart rate variability (vmHRV) is related to difficulties in emotion regulation (ER). The prefrontal cortex (PFC) provides inhibitory control over the amygdala during ER. Previous studies linked vmHRV with activity in the ventromedial PFC (vmPFC) during implicit ER. To date no study examined the relation between vmHRV and brain activity during explicit ER. vmHRV was measured during a 7 min baseline at T1 2-5 days preceding T2. At T2 n = 24 participants (50% female, M age = 24.6 years) viewed neutral or emotional pictures of pleasant or unpleasant valence and were instructed to intensify or to reduce their present emotion using two ER strategies (reappraisal and response modulation) or to passively view the picture. Participants rated the valence of their emotional state from pleasant to unpleasant after ER. Whole-brain fMRI data were collected using a 1.5-T-scanner. We observed an association between resting state vmHRV and brain activation in the PFC and the amygdala during ER of unpleasant emotions. Groups based on vmHRV showed significant differences in the modulation of amygdala activity as a function of ER strategy. In participants with high vmHRV amygdala activity was modulated only when using reappraisal and for low vmHRV participants only when using response modulation. Similar, dorsomedial PFC activity in high vmHRV participants was increased when using reappraisal and in low vmHRV participants when using response modulation to regulate unpleasant emotions. These results suggest that individuals with low vmHRV might have difficulties in recruiting prefrontal brain areas necessary for the modulation of amygdala activity during explicit ER. PMID- 30455623 TI - Identifying Respiration-Related Aliasing Artifacts in the Rodent Resting-State fMRI. AB - Resting-state functional magnetic resonance imaging (rs-fMRI) combined with optogenetics and electrophysiological/calcium recordings in animal models is becoming a popular platform to investigate brain dynamics under specific neurological states. Physiological noise originating from the cardiac and respiration signal is the dominant interference in human rs-fMRI and extensive efforts have been made to reduce these artifacts from the human data. In animal fMRI studies, physiological noise sources including the respiratory and cardiorespiratory artifacts to the rs-fMRI signal fluctuation have typically been less investigated. In this article, we demonstrate evidence of aliasing effects into the low-frequency rs-fMRI signal fluctuation mainly due to respiration induced B0 offsets in anesthetized rats. This aliased signal was examined by systematically altering the fMRI sampling rate, i.e., the time of repetition (TR), in free-breathing conditions and by adjusting the rate of ventilation. Anesthetized rats under ventilation showed a significantly narrower frequency bandwidth of the aliasing effect than free-breathing animals. It was found that the aliasing effect could be further reduced in ventilated animals with a muscle relaxant. This work elucidates the respiration-related aliasing effects on the rs fMRI signal fluctuation from anesthetized rats, indicating non-negligible physiological noise needed to be taken care of in both awake and anesthetized animal rs-fMRI studies. PMID- 30455625 TI - Altered Intracortical T1-Weighted/T2-Weighted Ratio Signal in Huntington's Disease. AB - Huntington's disease (HD) is a genetic neurodegenerative disorder that is characterized by neuronal cell death. Although medium spiny neurons in the striatum are predominantly affected, other brain regions including the cerebral cortex also degenerate. Previous structural imaging studies have reported decreases in cortical thickness in HD. Here we aimed to further investigate changes in cortical tissue composition in vivo in HD using standard clinical T1 weighted (T1W) and T2-weighted (T2W) magnetic resonance images (MRIs). 326 subjects from the TRACK-HD dataset representing healthy controls and four stages of HD progression were analyzed. The intracortical T1W/T2W intensity was sampled in the middle depth of the cortex over 82 regions across the cortex. While these previously collected images were not optimized for intracortical analysis, we found a significant increase in T1W/T2W intensity (p < 0.05 Bonferroni-Holm corrected) beginning with HD diagnosis. Increases in ratio intensity were found in the insula, which then spread to ventrolateral frontal cortex, superior temporal gyrus, medial temporal gyral pole, and cuneus with progression into the most advanced HD group studied. Mirroring past histological reports, this increase in the ratio image intensity may reflect disease-related increases in myelin and/or iron in the cortex. These findings suggest that future imaging studies are warranted with imaging optimized to more sensitively and specifically assess which features of cortical tissue composition are abnormal in HD to better characterize disease progression. PMID- 30455626 TI - Effects of Neuropeptide Substance P on Proliferation and beta-Cell Differentiation of Adult Pancreatic Ductal Cells. AB - Purpose: The pancreas is innervated by sensory nerves, parasympathetic and sympathetic nerves. The classical neurotransmitters, acetylcholine and noradrenaline, and some kind of neuropeptides are contained in the terminals of these nerves. Neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) co-released from the primary sensory fibers have been identified as the key neurotransmitters in pancreas. Pancreatic ductal epithelium cells are one of the important sources of the pancreatic islet beta-cell neogenesis. We hypothesized that SP and CGRP might play a role on proliferation of ductal cells and differentiation of ductal cells toward the beta-cell neogenesis. Methods: Primary ductal cells of rat pancreas at the third passage (P3) were used. The identification of P3 cells were confirmed with flow cytometry analysis and immunostaining by CK19 (the ductal cell marker). Proliferation of ductal cells was verified by CCK-8 assay and Ki67 immunostaining. Differentiation of ductal cells was determined with immunostaining and flow cytometry. Possible mechanism was explored by testing the key proteins of Wnt signaling using Western blot analysis. Results: Our data showed that SP but not CGRP promoted proliferation of ductal cells. Moreover, NK-1 receptor antagonist L-703,606 blocked the SP-induced stimulation of proliferation. The results of Western blot analysis showed that L 703,606 attenuated the effects of substance P on NK1R, GSK-3beta, and beta catenin expression. However, SP did not directly induce the differentiation of ductal cells into beta-cells, and did not promote the progression of ductal cells to differentiate into more insulin-produced cells in induction medium. Conclusions: These findings suggested that SP but not CGRP promoted proliferation of adult pancreatic ductal cells. SP promoted proliferation of ductal cells but not differentiation into beta-cells. NK1R and Wnt signaling pathway might be involved in the mechanism of promoting the proliferation of ductal cells by SP. Findings in this study indicated the lack of SP might be a possible indicator for the initial of diabetes. SP could also be used as a drug candidate for the treatment of diabetes. PMID- 30455627 TI - Whole-Brain Monosynaptic Afferent Projections to the Cholecystokinin Neurons of the Suprachiasmatic Nucleus. AB - The suprachiasmatic nucleus (SCN) is the principal pacemaker driving the circadian rhythms of physiological behaviors. The SCN consists of distinct neurons expressing neuropeptides, including arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and so on. AVP, VIP, and GRP neurons receive light stimulation from the retina to synchronize endogenous circadian clocks with the solar day, whereas CCK neurons are not directly innervated by retinal ganglion cells and may be involved in the non-photic regulation of the circadian clock. To better understand the function of CCK neurons in non-photic circadian rhythm, it is vital to clarify the direct afferent inputs to CCK neurons in the SCN. Here, we utilized a recently developed rabies virus- and Cre/loxP-based, cell type specific, retrograde tracing system to map and quantitatively analyze the whole brain monosynaptic inputs to SCN CCK neurons. We found that SCN CCK neurons received direct inputs from 29 brain nuclei. Among these nuclei, paraventricular nucleus of the hypothalamus (PVH), paraventricular nucleus of the thalamus (PVT), supraoptic nucleus (SON), ventromedial nucleus of the hypothalamus, and seven other nuclei sent numerous inputs to CCK neurons. Moderate inputs originated from the zona incerta, periventricular hypothalamic nucleus, and five other nuclei. A few inputs to CCK neurons originated from the orbital frontal cortex, prelimbic cortex, cingulate cortex, claustrum, and seven other nuclei. In addition, SCN CCK neurons were preferentially innervated by AVP neurons of the ipsilateral PVH and SON rather than their contralateral counterpart, whereas the contralateral PVT sent more projections to CCK neurons than to its ipsilateral counterpart. Taken together, these results expand our knowledge of the specific innervation to mouse SCN CCK neurons and provide an important indication for further investigations on the function of CCK neurons. PMID- 30455628 TI - PDGFR-beta-Positive Perivascular Adventitial Cells Expressing Nestin Contribute to Fibrotic Scar Formation in the Striatum of 3-NP Intoxicated Rats. AB - Perivascular cells expressing platelet-derived growth factor receptor beta (PDGFR beta) have recently been implicated in fibrotic scar formation after acute brain injury, but their precise identity and detailed morphological characteristics remain elusive. This study sought to characterize and define the cellular phenotype of vascular-associated cells expressing PDGFR-beta in the striatum of rats treated with the mitochondrial toxin 3-nitropropionic acid (3-NP). In the control striatum, PDGFR-beta-positive cells were invariably localized on the abluminal side of smooth muscle cells of larger caliber vessels, and demonstrated morphological features typical of perivascular fibroblasts. PDGFR-beta expression increased and expanded to almost all vessels, including microvessels in the lesion core, at 7 days after 3-NP injection. The cells expressing PDGFR-beta had ultrastructural features of fibroblasts undergoing active collagen synthesis: large euchromatic nuclei with a prominent nucleolus, well-developed rough endoplasmic reticulum (rER) with dilated cisterns and extracellular collagen fibrils. By 14 days, PDGFR-beta-positive cells had somata located at a distance from the vasculature, and their highly ramified, slender processes overlapped with those from other cells, thus forming a plexus of processes in the extravascular space of the lesion core. In addition, their ultrastructural morphology and spatial correlation with activated microglia/macrophages were elaborated by three-dimensional reconstruction. Using a correlative light- and electron-microscopy technique, we found that the intermediate filament proteins nestin and vimentin were induced in PDGFRbeta-positive fibroblasts in the lesion core. Collectively, our data suggest that perivascular PDGFR-beta-positive fibroblasts are distinct from other vascular cell types, including pericytes and contribute to fibrotic scar formation in the lesion core after acute brain injury. Nestin and vimentin play critical roles in the structural dynamics of these reactive fibroblasts. PMID- 30455630 TI - Purple Corn Extract as Anti-allodynic Treatment for Trigeminal Pain: Role of Microglia. AB - Natural products have attracted interest in the search for new and effective analgesics and coadjuvant approaches to several types of pain. It is in fact well known that many of their active ingredients, such as anthocyanins (ACNs) and polyphenols, can exert potent anti-inflammatory actions. Nevertheless, their potential beneficial effects in orofacial painful syndromes have not been assessed yet. Here, we have evaluated the preventive effect of an ACN-enriched purple corn extract against the development of orofacial allodynia, in comparison with isogenic yellow corn extract containing only polyphenols. Orofacial allodynia developed following induction of temporomandibular joint (TMJ) inflammation in male rats, due to the injection of Complete Freund's Adjuvant (CFA), and was evaluated by von Frey filaments. Animals drank purple or yellow corn extracts or water starting from 11 days before induction of inflammation and up to the end of the experiment 3 days later. To highlight possible additive and/or synergic actions, some animals also received the anti-inflammatory drug acetyl salicylic acid (ASA). In parallel with the evaluation of allodynia, we have focused our attention on the activation of microglia cells in the central nervous system (CNS), as it is well-known that they significantly contribute to neuronal sensitization and pain. Our data demonstrate that purple corn extract is as effective as ASA in preventing the development of orofacial allodynia, and only partial additive effect is observed when the two agents are co-administered. Yellow corn exerted no effect. Multiple mechanisms are possibly involved in the action of purple corn, including reduction of trigeminal macrophage infiltration and the shift of microglia cell polarization to an anti-inflammatory phenotype. In fact, in rats receiving yellow corn or water microglia cells show thick, short cell processes typical of activated cells. Conversely, thinner and longer microglia cell processes are observed in the brainstem of animals drinking purple corn extract; shape changes are accompanied by a reduction in the expression of pro-inflammatory molecules and increased production of anti-inflammatory mediators. Administration of purple corn extracts therefore represents a possible low-cost and easy way to reduce trigeminal-associated pain in various pathological conditions also thanks to the modulation of microglia reactivity. PMID- 30455629 TI - The Impact of ESCRT on Abeta1-42 Induced Membrane Lesions in a Yeast Model for Alzheimer's Disease. AB - Abeta metabolism plays a pivotal role in Alzheimer's disease. Here, we used a yeast model to monitor Abeta42 toxicity when entering the secretory pathway and demonstrate that processing in, and exit from the endoplasmic reticulum (ER) is required to unleash the full Abeta42 toxic potential. Consistent with previously reported data, our data suggests that Abeta42 interacts with mitochondria, thereby enhancing formation of reactive oxygen species and eventually leading to cell demise. We used our model to search for genes that modulate this deleterious effect, either by reducing or enhancing Abeta42 toxicity, based on screening of the yeast knockout collection. This revealed a reduced Abeta42 toxicity not only in strains hampered in ER-Golgi traffic and mitochondrial functioning but also in strains lacking genes connected to the cell cycle and the DNA replication stress response. On the other hand, increased Abeta42 toxicity was observed in strains affected in the actin cytoskeleton organization, endocytosis and the formation of multivesicular bodies, including key factors of the ESCRT machinery. Since the latter was shown to be required for the repair of membrane lesions in mammalian systems, we studied this aspect in more detail in our yeast model. Our data demonstrated that Abeta42 heavily disturbed the plasma membrane integrity in a strain lacking the ESCRT-III accessory factor Bro1, a phenotype that came along with a severe growth defect and enhanced loading of lipid droplets. Thus, it appears that also in yeast ESCRT is required for membrane repair, thereby counteracting one of the deleterious effects induced by the expression of Abeta42. Combined, our studies once more validated the use of yeast as a model to investigate fundamental mechanisms underlying the etiology of neurodegenerative disorders. PMID- 30455632 TI - Huntingtin-Associated Protein 1A Regulates Store-Operated Calcium Entry in Medium Spiny Neurons From Transgenic YAC128 Mice, a Model of Huntington's Disease. AB - Huntington's disease (HD) is a hereditary neurodegenerative disease that is caused by polyglutamine expansion within the huntingtin (HTT) gene. One of the cellular activities that is dysregulated in HD is store-operated calcium entry (SOCE), a process by which Ca2+ release from the endoplasmic reticulum (ER) induces Ca2+ influx from the extracellular space. HTT-associated protein-1 (HAP1) is a binding partner of HTT. The aim of the present study was to examine the role of HAP1A protein in regulating SOCE in YAC128 mice, a transgenic model of HD. After Ca2+ depletion from the ER by the activation of inositol (1,4,5)triphosphate receptor type 1 (IP3R1), we detected an increase in the activity of SOC channels when HAP1 protein isoform HAP1A was overexpressed in medium spiny neurons (MSNs) from YAC128 mice. A decrease in the activity of SOC channels in YAC128 MSNs was observed when HAP1 protein was silenced. In YAC128 MSNs that overexpressed HAP1A, an increase in activity of IP3R1 was detected while the ionomycin-sensitive ER Ca2+ pool decreased. 6-Bromo-N-(2-phenylethyl) 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride (C20H22BrClN2), identified in our previous studies as a SOCE inhibitor, restored the elevation of SOCE in YAC128 MSN cultures that overexpressed HAP1A. The IP3 sponge also restored the elevation of SOCE and increased the release of Ca2+ from the ER in YAC128 MSN cultures that overexpressed HAP1A. The overexpression of HAP1A in the human neuroblastoma cell line SK-N-SH (i.e., a cellular model of HD (SK-N-SH HTT138Q)) led to the appearance of a pool of constitutively active SOC channels and an increase in the expression of STIM2 protein. Our results showed that HAP1A causes the activation of SOC channels in HD models by affecting IP3R1 activity. PMID- 30455631 TI - The Role of Astrocytic Calcium Signaling in the Aged Prefrontal Cortex. AB - Aging is a lifelong process characterized by cognitive decline putatively due to structural and functional changes of neural circuits of the brain. Neuron-glial signaling is a fundamental component of structure and function of circuits of the brain, and yet its possible role in aging remains elusive. Significantly, neuron glial networks of the prefrontal cortex undergo age-related alterations that can affect cognitive function, and disruption of glial calcium signaling has been linked with cognitive performance. Motivated by these observations, we explored the possible role of glia in cognition during aging, considering a mouse model where astrocytes lacked IP3R2-dependent Ca2+ signaling. Contrarily to aged wild type animals that showed significant impairment in a two-trial place recognition task, aged IP3R2 KO mice did not. Consideration of neuronal and astrocytic cell densities in the prefrontal cortex, revealed that aged IP3R2 KO mice present decreased densities of NeuN+ neurons and increased densities of S100beta+ astrocytes. Moreover, aged IP3R2 KO mice display refined dendritic trees in this region. These findings suggest a novel role for astrocytes in the aged brain. Further evaluation of the neuron-glial interactions in the aged brain will disclose novel strategies to handle healthy cognitive aging in humans. PMID- 30455633 TI - TRPV4 Inhibition Improved Myelination and Reduced Glia Reactivity and Inflammation in a Cuprizone-Induced Mouse Model of Demyelination. AB - The inhibition of demyelination and the promotion of remyelination are both considerable challenges in the therapeutic process for many central nervous system (CNS) diseases. Increasing evidence has demonstrated that neuroglial activation and neuroinflammation are responsible for myelin sheath damage during demyelinating disorders. It has been revealed that the nonselective cation channel transient receptor potential vanilloid 4 (TRPV4) profoundly affects a variety of physiological processes, including inflammation. However, its roles and mechanisms in demyelination have remained unclear. Here, for the first time, we found that there was a significant increase in TRPV4 in the corpus callosum in a demyelinated mouse model induced by cuprizone (CPZ). RN-1734, a TRPV4 antagonist, clearly alleviated demyelination and inhibited glial activation and the production of tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) without altering the number of olig2-positive cells. In vitro, RN-1734 treatment clearly inhibited the influx of calcium and decreased the levels of IL 1beta and TNF-alpha in lipopolysaccharide (LPS)-activated microglial cells by suppressing NF-kappaB P65 phosphorylation. Apoptosis of oligodendrocyte induced by LPS-activated microglia was also alleviated by RN-1734. The results suggest that activation of TRPV4 in microglia is involved in oligodendrocyte apoptosis through the activation of the NF-kappaB signaling pathway, thus revealing a new mechanism of CNS demyelination. PMID- 30455634 TI - Physiological Profile of Neuropeptide Y-Expressing Neurons in Bed Nucleus of Stria Terminalis in Mice: State of High Excitability. AB - Both, the anterior bed nucleus of the stria terminalis (BNST) and the neuropeptide Y (NPY) system are involved in shaping fear and defensive responses that adapt the organism to potentially life-threatening conditions. NPY is expressed in the BNST but NPY-expressing neurons in this critical hub in the stress response network have not been addressed before. Therefore, we performed whole-cell patch-clamp recordings in acute slices of anterior BNST from Npy-hrGFP transgenic mice to identify and characterize NPY-expressing neurons. We show that NPY-positive and NPY-negative neurons in anterior BNST match the previous classification scheme of type I (Regular Spiking), type II (Low-Threshold Bursting), and type III (fast Inward Rectifying) cells, although the proportion of these physiological phenotypes was similar within both neuronal subpopulations. However, NPY-positive and NPY-negative neurons possessed distinct intrinsic electrophysiological properties. NPY-positive neurons displayed higher input resistance and lower membrane capacitance, corresponding to small cell bodies and shorter less ramified dendrites, as compared to their NPY-negative counterparts. Furthermore, NPY-positive neurons generated higher frequent series of action potentials upon membrane depolarization and displayed significantly lower GABAA receptor-mediated synaptic responsiveness during evoked, spontaneous, and elementary synaptic activity. Taken together, these properties indicate an overall state of high excitability in NPY-positive neurons in anterior BNST. In view of the role of the anterior BNST in anxiety- and stress-related behaviors, these findings suggest a scenario where NPY-positive neurons are preferentially active and responsive to afferent inputs, thereby contributing to adaptation of the organism to stressful environmental encounters. PMID- 30455635 TI - P7C3 Inhibits LPS-Induced Microglial Activation to Protect Dopaminergic Neurons Against Inflammatory Factor-Induced Cell Death in vitro and in vivo. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. Although its pathogenesis remains unclear, growing evidencce suggests that microglia-mediated neuroinflammation contributes greatly to the progression of PD. P7C3, an aminopropyl carbazole, possesses significant neuroprotective effects in several neurodegenerative disease animal models, including PD. In this study, we designed to investigate the effects of P7C3 on neuroinflammation. We showed that P7C3 specially suppressed the expression of lipopolysaccharide (LPS)-induced pro-inflammatory factors but not influenced the anti-inflammatory factors in microglia. The inhibition of the nuclear factor kappaB (NF-kappaB) signaling pathway was involved in the mechanisms of the anti-inflammatory effects by P7C3. LPS-induced activation of IkappaB kinase (IKK), degradation of the inhibitory kappaB alpha (IkappaBalpha) and nuclear translocation of NF-kappaB can be attenuated by the pretreatment of P7C3 in microglia. Furthermore, in LPS-treated microglia, P7C3-pretreatment decreased the toxicity of conditioned media to MES23.5 cells (a dopaminergic (DA) cell line). Most importantly, the anti inflammatory effects of P7C3 were observed in LPS-stimulated mouse model. In general, our study demonstrates that P7C3 inhibits LPS-induced microglial activation through repressing the NF-kappaB pathway both in vivo and in vitro, providing a theoretical basis for P7C3 in anti-inflammation. PMID- 30455636 TI - Decoding Voluntary Movement of Single Hand Based on Analysis of Brain Connectivity by Using EEG Signals. AB - Research about decoding neurophysiological signals mainly aims to elucidate the details of human motion control from the perspective of neural activity. We performed brain connectivity analysis with EEG to propose a brain functional network (BFN) and used a feature extraction algorithm for decoding the voluntary hand movement of a subject. By analyzing the characteristic parameters obtained from the BFN, we extracted the most important electrode nodes and frequencies for identifying the direction of movement of a hand. The results demonstrated that the most sensitive EEG components were for frequencies delta, theta, and gamma1 from electrodes F4, F8, C3, Cz, C4, CP4, T3, and T4. Finally, we proposed a model for decoding voluntary movement of the right hand by using a hierarchical linear model (HLM). Through a voluntary hand movement experiment in a spiral trajectory, the Poisson coefficient between the measurement trajectory and the decoding trajectory was used as a test standard to compare the HLM with the traditional multiple linear regression model. It was found that the decoding model based on the HLM obtained superior results. This paper contributes a feature extraction method based on brain connectivity analysis that can mine more comprehensive feature information related to a specific mental state of a subject. The decoding model based on the HLM possesses a strong structure for data manipulation that facilitates precise decoding. PMID- 30455638 TI - Neural Reconstruction Integrity: A Metric for Assessing the Connectivity Accuracy of Reconstructed Neural Networks. AB - Neuroscientists are actively pursuing high-precision maps, or graphs consisting of networks of neurons and connecting synapses in mammalian and non-mammalian brains. Such graphs, when coupled with physiological and behavioral data, are likely to facilitate greater understanding of how circuits in these networks give rise to complex information processing capabilities. Given that the automated or semi-automated methods required to achieve the acquisition of these graphs are still evolving, we developed a metric for measuring the performance of such methods by comparing their output with those generated by human annotators ("ground truth" data). Whereas classic metrics for comparing annotated neural tissue reconstructions generally do so at the voxel level, the metric proposed here measures the "integrity" of neurons based on the degree to which a collection of synaptic terminals belonging to a single neuron of the reconstruction can be matched to those of a single neuron in the ground truth data. The metric is largely insensitive to small errors in segmentation and more directly measures accuracy of the generated brain graph. It is our hope that use of the metric will facilitate the broader community's efforts to improve upon existing methods for acquiring brain graphs. Herein we describe the metric in detail, provide demonstrative examples of the intuitive scores it generates, and apply it to a synthesized neural network with simulated reconstruction errors. Demonstration code is available. PMID- 30455637 TI - Code Generation in Computational Neuroscience: A Review of Tools and Techniques. AB - Advances in experimental techniques and computational power allowing researchers to gather anatomical and electrophysiological data at unprecedented levels of detail have fostered the development of increasingly complex models in computational neuroscience. Large-scale, biophysically detailed cell models pose a particular set of computational challenges, and this has led to the development of a number of domain-specific simulators. At the other level of detail, the ever growing variety of point neuron models increases the implementation barrier even for those based on the relatively simple integrate-and-fire neuron model. Independently of the model complexity, all modeling methods crucially depend on an efficient and accurate transformation of mathematical model descriptions into efficiently executable code. Neuroscientists usually publish model descriptions in terms of the mathematical equations underlying them. However, actually simulating them requires they be translated into code. This can cause problems because errors may be introduced if this process is carried out by hand, and code written by neuroscientists may not be very computationally efficient. Furthermore, the translated code might be generated for different hardware platforms, operating system variants or even written in different languages and thus cannot easily be combined or even compared. Two main approaches to addressing this issues have been followed. The first is to limit users to a fixed set of optimized models, which limits flexibility. The second is to allow model definitions in a high level interpreted language, although this may limit performance. Recently, a third approach has become increasingly popular: using code generation to automatically translate high level descriptions into efficient low level code to combine the best of previous approaches. This approach also greatly enriches efforts to standardize simulator-independent model description languages. In the past few years, a number of code generation pipelines have been developed in the computational neuroscience community, which differ considerably in aim, scope and functionality. This article provides an overview of existing pipelines currently used within the community and contrasts their capabilities and the technologies and concepts behind them. PMID- 30455639 TI - Anti-inflammatory Effects of Homotaurine in Patients With Amnestic Mild Cognitive Impairment. AB - Alzheimer's disease (AD) is a fatal dementing neurodegenerative disease, currently lacking an efficacious disease-modifying therapy. In the last years, there has been some interest in the use of homotaurine as a potential therapeutic compound for AD, but more work is still needed to prove its efficacy as disease modifier in dementia. Since inflammation is believed to play a key role in AD development, we sought to investigate here the in vivo homotaurine effect on inflammatory response in patients at the earliest stages of AD, i.e., suffering from amnestic mild cognitive impairment (aMCI). Thus, the present study aims to evaluate the effects of homotaurine supplementation on cytokine serum levels and memory performances in MCI patients. Neuropsychological, clinical and cytokine assessment was performed at baseline (T0) and after 1 year (T12) of homotaurine supplementation in 20 patients categorized as carriers (n = 9) or no carriers (n = 11) of the epsilon4 allele of the apolipoprotein E (APOE) gene, the strongest genetic risk factor for AD. The serum levels of the pro-inflammatory mediators Interleukin (IL) 1beta, Tumor necrosis factor-alpha (TNFalpha), IL-6 and IL-18, contextually with the anti-inflammatory molecules IL-18 binding protein (IL-18BP) and Transforming growth factor-beta (TGFbeta), were analyzed to explore significant differences in the inflammatory status between T0 and T12 in the two APOE variant carrier groups. No significant differences over time were observed in patients as for most cytokines, except for IL-18. Following homotaurine supplementation, patients carrying the APOEepsilon4 allele showed a significant decrease in IL-18 (both in its total and IL-18BP unbound forms), in turn associated with improved short-term episodic memory performance as measured by the recency effect of the Rey 15-word list learning test immediate recall. Thus, homotaurine supplementation in individuals with aMCI may have a positive consequence on episodic memory loss due, at least in part, to homotaurine anti inflammatory effects. This study strongly suggests that future research should focus on exploring the mechanisms by which homotaurine controls brain inflammation during AD progression. PMID- 30455640 TI - Modulation of Mitochondrial Dynamics in Neurodegenerative Diseases: An Insight Into Prion Diseases. AB - Mitochondrial dysfunction is a common and prominent feature of prion diseases and other neurodegenerative disorders. Mitochondria are dynamic organelles that constantly fuse with one another and subsequently break apart. Defective or superfluous mitochondria are usually eliminated by a form of autophagy, referred to as mitophagy, to maintain mitochondrial homeostasis. Mitochondrial dynamics are tightly regulated by processes including fusion and fission. Dysfunction of mitochondrial dynamics can lead to the accumulation of abnormal mitochondria and contribute to cellular damage. Neurons are among the cell types that consume the most energy, have a highly complex morphology, and are particularly dependent on mitochondrial functions and dynamics. In this review article, we summarize the molecular mechanisms underlying the mitochondrial dynamics and the regulation of mitophagy and discuss the dysfunction of these processes in the progression of prion diseases and other neurodegenerative disorders. We have also provided an overview of mitochondrial dynamics as a therapeutic target for neurodegenerative diseases. PMID- 30455641 TI - N-Substituted Pyrido-1,4-Oxazin-3-Ones Induce Apoptosis of Hepatocellular Carcinoma Cells by Targeting NF-kappaB Signaling Pathway. AB - Hepatocellular carcinoma (HCC) is a fatal disease and ranked fifth in cancer related mortality. Persistent activation of NF-kappaB is responsible for the oncogenesis, metastasis, tumor evasion, anti-apoptosis, angiogenesis and proliferation in HCC. Therefore, designing of chemically novel, biologically potent small molecules that target NF-kappaB signaling cascade have gained prominent clinical interest. Herein we synthesized a novel class of 4 (substituted)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one by reacting 2H-pyrido[3,2 b][1,4]oxazin-3(4H)-one with various alkyl halides by using combustion derived bismuth oxide. We evaluated the antiproliferative efficacy of newly synthesized compounds against HCC cells and identified 4-(4-nitrobenzyl)-2H-pyrido[3,2 b][1,4]oxazin-3(4H)-one (NPO) as lead anticancer agent. In addition, we investigated the effect of NPO on the DNA binding ability of NF-kappaB and NF kappaB regulated luciferase expression in HCC cells. The results demonstrated that NPO can induce significant growth inhibitory effects in HepG2, HCCLM3 and Huh-7 cells in dose and time-dependent manner. Interestingly, NPO induced significant downregulation in p65 DNA binding ability, p65 phosphorylation and subsequent expression of NF-kappaB dependent luciferase gene expression in diverse HCC cell lines. Further, in silico docking analysis suggested that NPO can show direct physical interaction with NF-kappaB. Finally, NPO was found to significantly abrogate tumor growth at a dose of 50 mg/kg in an orthotopic mouse model. Thus, we report the potential anticancer effects of NPO as a novel inhibitor of NF-kappaB signaling pathway in HCC. PMID- 30455642 TI - Role of Alternative Lipid Excipients in the Design of Self-Nanoemulsifying Formulations for Fenofibrate: Characterization, in vitro Dispersion, Digestion and ex vivo Gut Permeation Studies. AB - Background: The choice of lipid excipients and their origin are crucial determinant factors in the design of self-nanoemulsifying drug delivery system (SNEDDS). Aim: To investigate the aspects of alternative excipients which can influence the development of efficient SNEDDS and determine the fate of fenofibrate in aqueous media. Methods: SNEDDS of two groups (a and b) were developed using Cremercoor MCT/Capmul MCM and Kollisolv MCT/Imwitor 742 blended oils and water soluble surfactants (to improve lipid polarity) for the model anti cholesterol drug fenofibrate. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEDDS. Further SNEDDS optimizations were done on the basis of maximum drug loading by equilibrium solubility studies and maximum solubilized drug upon aqueous dispersion by dynamic dispersion studies. In vitro lipolysis was examined under simulated Fed and Fasted conditions. Intestinal permeability study of the optimal SNEDDS formulation was compared with the raw fenofibrate dispersion using non- everted "intestinal sac technique." Results: Initial characterization and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 (group b) containing formulations generated highly efficient SNEDDS as they are stable and produced lower nanodroplets with higher drug loading (group b) as compared to mixed glycerides of Cremercoor MCT/Capmul MCM (group a). In vitro dispersion and digestion studies confirmed that SNEDDS of group b (polar mixed glycerides) can retain high amount of drug (99% drug in solution for more than 24 h time) in dispersion media and have high recovery after digestion. The results from the permeability assessment confirmed that fenofibrate had 4.3-fold increase with F3b SNEDDS compared with the control. Conclusion: SNEDDS formulations containing alternative excipients (Kollisolv MCT/Imwitor 742 blend) could be a potential oral pharmaceutical product in taking anti-hyperlipidaemic agent fenofibrate to the systemic circulation as solubilized form. PMID- 30455643 TI - Imepitoin Shows Benzodiazepine-Like Effects in Models of Anxiety. AB - Imepitoin is a low affinity partial agonist for the benzodiazepine binding site of gamma-aminobutyric acid (GABAA) receptors, and is currently used as an antiepileptic in dogs. Here we tested imepitoin for anxiolytic properties. In an in vitro model, imepitoin was capable of preventing the effect of corticotrophin releasing factor (CRF) on locus coeruleus neurons without suppressing the basal activity of these cells, an activity which is suggestive for an anti-stress effect of imepitoin. In addition, we applied a battery of standard rodent preclinical tests for anxiety behavior including elevated plus mazes in mice and rats, light-dark-box in mice and rats, social interaction test in rats, or the Vogel conflict test in rats. In all models, the observed profile of imepitoin appeared similar to benzodiazepines and typical for anxiolytic drugs. We also observed anxiolytic activity in dogs in a provoked open field sound-induced fear model, where reactions to noises were elicited by a sound recording of thunderstorms. Imepitoin caused an increase in locomotion measured in distance traveled and an ameliorating effect on cortisol levels in response to thunderstorm noises. For comparison, dexmedetomidine caused a decrease in locomotion and had no effect on cortisol. In all animal models the doses needed for an anxiolytic effect were not associated with sedation. In rodents, there was at least a factor of 10 between anxiolytic doses and doses with mild signs of sedation. In summary, imepitoin showed similar anxiolytic activities as benzodiazepines but without producing the known adverse reactions of benzodiazepines such as sedation. PMID- 30455644 TI - Salvianolic Acid A Attenuates Endoplasmic Reticulum Stress and Protects Against Cholestasis-Induced Liver Fibrosis via the SIRT1/HSF1 Pathway. AB - Background: Endoplasmic reticulum stress (ER stress) plays a critical role in the pathogenesis of liver fibrosis; thus, it can be a potential therapeutic target of fibrosis. However, the mechanism of ER stress regulation in fibrosis, particularly through sirtuin 1 (SIRT1), remains unclear. The objective of this study was to investigate the effect of SIRT1-mediated inhibition of ER stress in bile duct ligation (BDL)-induced liver fibrosis, and to explore the effect of salvianolic acid A (SalA) on BDL-induced liver fibrosis through SIRT1/heat shock factor 1 (HSF1) signaling. Materials and Methods: We explored the effects of SalA on liver fibrosis and ER stress in BDL-induced liver fibrosis in rats and the human hepatic stellate cell line LX2 cells. The LX2 cells were treated with 20 ng of platelet-derived growth factor-BB homodimer (PDGF-BB) for 24 h, and then incubated in the absence or presence of SalA (25 MUM) for 24 h. Results: In vivo, SalA treatment alleviated BDL-induced liver injury and ER stress. Importantly, SalA treatment increased HSF1 expression and activity using a SIRT1-dependent mechanism. In LX2 cells, PDGF-BB induced ER stress and fibrosis were blocked by HSF1 overexpression. Furthermore, SIRT1 siRNA abrogated the SalA-mediated promotion of HSF1 deacetylation and expression, suggesting that SalA-mediated protection occurs by SIRT1 targeting HSF1 for deacetylation. Conclusion: This is the first study to identify the SIRT1/HSF1 pathway as a key therapeutic target for controlling BDL-induced liver fibrosis and to show that SalA confers protection against BDL- and PDGF-BB-induced hepatic fibrosis and ER stress through SIRT1-mediated HSF1 deacetylation. PMID- 30455646 TI - Simulation of the Ontogeny of Social Jet Lag: A Shift in Just One of the Parameters of a Model of Sleep-Wake Regulating Process Accounts for the Delay of Sleep Phase Across Adolescence. AB - The term "social jet lag" was introduced for defining the conflict between social and biological clocks due to the general practice of shifting weekday risetime on early morning hours. The phase delay of the sleep-wake cycle during adolescence is one of the most remarkable features of the ontogenesis of sleep that is incompatible with early school start times. It was previously proposed that the process of accumulation of sleep pressure during wakefulness is slowing down in post-pubertal teens to allow them to stay awake for a longer period of time thus causing the delay of their bedtime. In order to examine this proposition, we traced the ontogeny of social jet lag using sleep times reported for 160 samples of study participants of different ages as an input to a model of sleep-wake regulatory process. The simulations suggested that a gradual change in just one of the model's parameters, the time constant of wakefulness phase of the sleep wake regulatory process, might explain the association of the transition between childhood and adulthood with the prolongation of time staying awake, delay of sleep time, and reduction of sleep duration. We concluded that the implication of the sleep-wake regulating model would be of help for understanding precisely how social jet lag varies with age and what are the chronophysiological causes of this variation. PMID- 30455645 TI - Oxidative Stress in Age-Related Macular Degeneration: Nrf2 as Therapeutic Target. AB - Age-related macular degeneration is one of the leading causes of vision loss in the elderly. Genetics, environmental insults, and age-related issues are risk factors for the development of the disease. All these risk factors are linked to the induction of oxidative stress. In young subjects retinal pigment epithelial cells mitigate reactive oxygen generation by the elimination of dysfunctional mitochondria, via mitophagy, and by increasing antioxidant defenses via Nrf2 activation. The high amount of UV light absorbed by the retina, together with cigarette smoking, cooperate with the aging process to increase the amount of reactive oxygen species generated by retinal pigment epithelium where oxidative stress arises. Moreover, in the elderly both the mitophagic process and Nrf2 activation are impaired thus causing retinal cell death. This review will focus on the impact of oxidative stress on the pathogenesis of age-related macular degeneration and analyze the natural and synthetic Nrf2-activating compounds that have been tested as potential therapeutic agents for the disease. PMID- 30455647 TI - Morning Bright Light Treatment for Sleep-Wake Disturbances in Primary Biliary Cholangitis: A Pilot Study. AB - Patients with Primary Biliary Cholangitis (PBC) exhibit delayed sleep-wake habits, disturbed night sleep and daytime sleepiness/fatigue. Such combination of symptoms is reminiscent of delayed sleep-wake phase disorder (DSPD), which benefits from morning light treatment. The aim of the present pilot study was to test the effect of morning light treatment in a group of 13 well-characterized patients with PBC [all females; (mean +/- SD) 53 +/- 10 years]. Six healthy individuals (4 females, 57 +/- 14 years) and 7 patients with cirrhosis (1 female, 57 +/- 12 years) served as controls and diseased controls, respectively. At baseline, all participants underwent an assessment of quality of life, diurnal preference, sleep quality/timing (subjective plus actigraphy), daytime sleepiness, and urinary 6-sulphatoxymelatonin (aMT6s) rhythmicity. Then they underwent a 15-day course of morning bright light treatment, immediately after getting up (light box, 10,000 lux, 45 min) whilst monitoring sleep-wake patterns and aMT6s rhythmicity. At baseline, both patients with PBC and patients with cirrhosis had significantly worse subjective sleep quality compared to controls. In patients with PBC, light treatment resulted in an improvement in subjective sleep quality and a reduction in daytime sleepiness. In addition, both their sleep onset and get-up time were significantly advanced. Finally, the robustness of aMT6s rhythmicity (i.e., strength of the cosinor fit) increased after light administration but post-hoc comparisons were not significant in any of the groups. In conclusion, a brief course of morning bright light treatment had positive effects on subjective sleep quality, daytime sleepiness, and sleep timing in patients with PBC. This unobtrusive, side-effect free, non pharmacological treatment is worthy of further study. PMID- 30455648 TI - Passive Stiffness of Left Ventricular Myocardial Tissue Is Reduced by Ovariectomy in a Post-menopause Mouse Model. AB - Background: Heart failure (HF) - a very prevalent disease with high morbidity and mortality - usually presents with diastolic dysfunction. Although post-menopause women are at increased risk of HF and diastolic dysfunction, poor attention has been paid to clinically and experimentally investigate this group of patients. Specifically, whether myocardial stiffness is affected by menopause is unknown. Aim: To investigate whether loss of female sexual hormones modifies the Young's modulus (E) of left ventricular (LV) myocardial tissue in a mouse model of menopause induced by ovariectomy (OVX). Methods: After 6 months of bilateral OVX, eight mice were sacrificed, fresh LV myocardial strips were prepared (~8 * 1 * 1 mm), and their passive stress-stretch relationship was measured. E was computed by exponential fitting of the stress-stretch relationship. Subsequently, to assess the relative role of cellular and extracellular matrix components in determining OVX-induced changes in E, the tissues strips were decellularized and subjected to the same stretching protocol to measure E. A control group of eight sham-OVX mice was simultaneously studied. Results: E (kPa; m +/- SE) in OVX mice was ~twofold lower than in controls (11.7 +/- 1.8 and 22.1 +/- 4.4, respectively; p < 0.05). No significant difference between groups was found in E of the decellularized tissue (31.4 +/- 12.05 and 40.9 +/- 11.5, respectively; p = 0.58). Conclusion: Loss of female sexual hormones in an OVX model induces a reduction in the passive stiffness of myocardial tissue, suggesting that active relaxation should play a counterbalancing role in diastolic dysfunction in post-menopausal women with HF. PMID- 30455649 TI - Arterial Blood Gas Analysis in Breath-Hold Divers at Depth. AB - The present study aimed to evaluate the partial pressure of arterial blood gases in breath-hold divers performing a submersion at 40 m. Eight breath-hold divers were enrolled for the trials held at "Y-40 THE DEEP JOY" pool (Montegrotto Terme, Padova, Italy). Prior to submersion, an arterial cannula in the radial artery of the non-dominant limb was positioned. All divers performed a sled-assisted breath hold dive to 40 m. Three blood samplings occurred: at 10 min prior to submersion, at 40 m depth, and within 2 min after diver's surfacing and after resuming normal ventilation. Blood samples were analyzed immediately on site. Six subjects completed the experiment, without diving-related problems. The theoretically predicted hyperoxia at the bottom was observed in 4 divers out of 6, while the other 2 experienced a reduction in the partial pressure of oxygen (paO2) at the bottom. There were no significant increases in arterial partial pressure of carbon dioxide (paCO2) at the end of descent in 4 of 6 divers, while in 2 divers paCO2 decreased. Arterial mean pH and mean bicarbonate ( HCO3- ) levels exhibited minor changes. There was a statistically significant increase in mean arterial lactate level after the exercise. Ours was the first attempt to verify real changes in blood gases at a depth of 40 m during a breath-hold descent in free divers. We demonstrated that, at depth, relative hypoxemia can occur, presumably caused by lung compression. Also, hypercapnia exists at depth, to a lesser degree than would be expected from calculations, presumably because of pre-dive hyperventilation and carbon dioxide distribution in blood and tissues. PMID- 30455650 TI - Dysregulated Anxiety and Dysregulating Defenses: Toward an Emotion Regulation Informed Dynamic Psychotherapy. AB - One of the main objectives of psychotherapy is to address emotion dysregulation that causes pathological symptoms and distress in patients. Following psychodynamic theory, we propose that in humans, the combination of emotions plus conditioned anxiety due to traumatic attachment can lead to dysregulated affects. Likewise, defenses can generate and maintain dysregulated affects (altogether Dysregulated Affective States, DAS). We propose the Experiential-Dynamic Emotion Regulation methodology, a framework to understand emotion dysregulation by integrating scientific evidence coming from the fields of affective neuroscience and Experiential-Dynamic Psychotherapy aimed at resolving DAS. This method and the techniques proposed can be integrated within other approaches. Similarities and differences with the Cognitive model of emotion regulation and cognitive behavioral approaches are discussed within the paper. PMID- 30455651 TI - Cross-Domain Priming From Mathematics to Relative-Clause Attachment: A Visual World Study in French. AB - Human language processing must rely on a certain degree of abstraction, as we can produce and understand sentences that we have never produced or heard before. One way to establish syntactic abstraction is by investigating structural priming. Structural priming has been shown to be effective within a cognitive domain, in the present case, the linguistic domain. But does priming also work across different domains? In line with previous experiments, we investigated cross domain structural priming from mathematical expressions to linguistic structures with respect to relative clause attachment in French (e.g., la fille du professeur qui habitait a Paris/the daughter of the teacher who lived in Paris). Testing priming in French is particularly interesting because it will extend earlier results established for English to a language where the baseline for relative clause attachment preferences is different form English: in English, relative clauses (RCs) tend to be attached to the local noun phrase (low attachment) while in French there is a preference for high attachment of relative clauses to the first noun phrase (NP). Moreover, in contrast to earlier studies, we applied an online-technique (visual world eye-tracking). Our results confirm cross-domain priming from mathematics to linguistic structures in French. Most interestingly, different from less mathematically adept participants, we found that in mathematically skilled participants, the effect emerged very early on (at the beginning of the relative clause in the speech stream) and is also present later (at the end of the relative clause). In line with previous findings, our experiment suggests that mathematics and language share aspects of syntactic structure at a very high-level of abstraction. PMID- 30455652 TI - How Self-Construals Affect Responses to Anthropomorphic Brands, With a Focus on the Three-Factor Relationship Between the Brand, the Gift-Giver and the Recipient. AB - The universal mantra, "The customer is our king," has led to considerable focus on the servant-anthropomorphized brand. However, does your "king" want to be served as a "king"? This research aims to examine how anthropomorphic brand role, self-construals and consumer responses to brands interact. In this study, four sequential experiments show that consumers with an interdependent self-construal are likely to respond more favorably toward anthropomorphic brands playing superior 'master' roles than toward those playing subordinate 'servant' roles. Here we distinguish between two types of superior role (master and mentor) based on behavior and communications. We also explore the underlying psychological mechanism of followership, as demonstrated through blind followership of someone in a master role and rational followership of someone in a mentor role. Additionally, when a third-party (recipient) is involved in the relationship between a consumer and a brand, the giver-recipient relationship moderates the relationship between an anthropomorphised brand role and self-construals. PMID- 30455653 TI - Smile Mimicry and Emotional Contagion in Audio-Visual Computer-Mediated Communication. AB - We investigate whether smile mimicry and emotional contagion are evident in non text-based computer-mediated communication (CMC). Via an ostensibly real-time audio-visual CMC platform, participants interacted with a confederate who either smiled radiantly or displayed a neutral expression throughout the interaction. Automatic analyses of expressions displayed by participants indicated that smile mimicry was at play: A higher level of activation of the facial muscle that characterizes genuine smiles was observed among participants who interacted with the smiling confederate than among participants who interacted with the unexpressive confederate. However, there was no difference in the self-reported level of joviality between participants in the two conditions. Our findings demonstrate that people mimic smiles in audio-visual CMC, but that even though the diffusion of emotions has been documented in text-based CMC in previous studies, we find no convincing support for the phenomenon of emotional contagion in non-text-based CMC. PMID- 30455654 TI - The Effect of Problem Construction on Team Process and Creativity. AB - Although research on the benefits of problem construction within the creative process is expanding, research on team problem construction is limited. This study investigates the cognitive process of problem construction and identification at the team level through an experimental design. Furthermore, this study explores team social processes in relation to problem construction instructions. Using student teams solving a real-world problem, the results of this study revealed that teams that engaged in problem construction and identification generated more original ideas than teams that did not engage in such processes. Moreover, higher satisfaction and lower conflict was observed among groups that engaged in problem construction compared to groups that did not engage in problem construction. These findings highlight the utility of problem construction for teams engaging in creative problem-solving. PMID- 30455655 TI - Know Your Heritage: Exploring the Effects of Fit in Cultural Knowledge on Chinese Canadians' Heritage Identification. AB - In the present research, we introduce the notion of fit in cultural knowledge (FICK) - which we define as a match between the self and others in representing a cultural tradition. For ethnic minorities, FICK can be manifested in different degrees of matching their personal beliefs about their heritage culture with outgroup as well as ingroup beliefs about their heritage culture. We conducted two studies with the objective of exploring the potentially negative effects of FICK on Chinese Canadians' heritage identification. In both studies, Chinese Canadian university students (N = 102; N = 156) indicated their personal beliefs about what values are normative in Chinese culture. Ingroup beliefs were assessed by beliefs about Chinese values that Chinese Canadians ascribed to their parents (Study 2), whereas outgroup beliefs were assessed by beliefs about Chinese values that were held by Euro-Canadians (Study 1) or that Chinese Canadians ascribed to Euro-Canadians (Study 2). The main findings based on a series of path models are as follows: (1) a stronger FICK generally predicted lower Chinese identification (centrality, ingroup ties, and affect), yet those negative effects were largely manifested in the openness to change versus conservation rather than in the self transcendence versus self-enhancement value dimension. (2) The negative effects could be explained by Chinese Canadians' experience of bicultural conflict (Study 1) and the frustration of continuity, meaning, and belonging identity motives (Study 2), suggesting that it matters which specific views of Chinese culture are matched in FICK. 3) Individuals who agreed with the perceived outgroup beliefs, and parental beliefs to a lesser extent, were more likely to apply the model minority stereotype to other Chinese Canadians (Study 2). Taken together, those findings demonstrate the challenges FICK presents to heritage identity maintenance among Chinese Canadian young adults. Implications for enculturation and cultural fit are discussed. PMID- 30455656 TI - Feeling Pressure to Be a Perfect Mother Relates to Parental Burnout and Career Ambitions. AB - Background and aims: Intensive mothering norms prescribe women to be perfect mothers. Recent research has shown that women's experiences of pressure toward perfect parenting are related to higher levels of guilt and stress. The current paper follows up on this research with two aims: First, we examine how mothers regulate pressure toward perfect mothering affectively, cognitively, and behaviorally, and how such regulation may relate to parental burnout. Second, we examine how feeling pressure toward perfect mothering may spill over into mothers' work outcomes. Methods: Through Prolific Academic, an online survey was sent to fulltime working mothers in the United Kingdom and United States with at least one child living at home (N = 169). Data were analyzed using bootstrapping mediation models. Results: Feeling pressure to be a perfect mother was positively related to parental burnout, and this relation was mediated by parental stress, by a stronger cognitive prevention focus aimed at avoiding mistakes as a mother, and by higher maternal gatekeeping behaviors taking over family tasks from one's partner. Moreover, pressure toward perfect mothering had a positive direct effect on career ambitions; and a negative indirect effect, such that mothers with higher felt pressure toward perfect mothering experienced lower work-family balance, which in turn related to lower career ambitions. Conclusion: The findings suggest that intensive mothering norms might have severe costs for women's family and work outcomes, and provide insights into where to direct efforts to reduce motherhood hardships and protect women's career ambitions. PMID- 30455658 TI - More Than Money: Experienced Positive Affect Reduces Risk-Taking Behavior on a Real-World Gambling Task. AB - Previous research indicates that when people participate in multi-trial games of chance, the results of previous trials impact subsequent wager size. For example, the "house money" and "break even" effects suggest that an individual's risk taking propensity increases when financially winning or losing during a gambling session. Additionally, the "mood maintenance hypothesis" and affect regulation hypothesis suggest that people in positive and negative affective states are less and more likely to gamble than when in neutral affective states, respectively. In the present study, participants completed a series of trials on three computerized slot machines with varying expected values (EV; -10, 0, +10%) of return on investment, and they were paid a percentage of their final bankrolls in real money. Although results did not support the "house money" or "break even" effects, the "mood maintenance hypothesis" was robustly supported in all EV conditions. This is some of the first evidence supporting this theory using an ecologically valid, real-money gambling task. PMID- 30455659 TI - Pianism: Performance Communication and the Playing Technique. AB - A pianist's movements are fundamental to music-making by producing the musical sounds and the expressive movements of the trunk and arms which communicate the music's structural and emotional information making it valuable for this review to examine upper-body movement in the performance process in combination with the factors important in skill acquisition. The underpinning playing technique must be efficient with economic muscle use by using body segments according to their design and movement potential with the arm segments mechanically linked to produce coordinated and fluent movement. Two physiologically and pianistically important actions proposed by early music scientists to deliver the keystroke involve dropping the hand from the shoulders toward the keys via a wave action with the joints activated sequentially, and forearm rotation to position the fingers for the keystroke, an action followed by the elbow/upper-arm rotating in the opposite direction. Both actions spare the forearm muscles by generating the energy needed in the larger shoulder muscles. The hand in the playing position has a curved palm through action of the metacarpal (knuckle) joints and curved fingers. Palm/finger posture controls sound quality from loud, high tempo sounds to a more mellow legato articulation, and to perform effectively the forearms should slope down toward the keyboard. The technique must be automatic through systematic practice which develops the motor skills for proficient playing, with practice duration tempered to reduce the risk of causing injury through overuse of the forearm muscles. Efficient movement patterns and strategic muscle relaxation which results in faster movement are realized only through extensive training. The constant movements of the head and trunk, and flowing arm movement with frequent hand lifts and rotational elbow movements, although generated in producing the playing technique, resonate with audience members who perceive them as expressive and thereby creating in them an empathic engagement with the music. It was proposed that music students be trained in the mechanical aspects of upper body use in the playing technique, and practice strategies, with specialist pedagogy for children to develop motor skills for efficient playing, and training methods fostering an appreciation of the communicative aspects of music performance. PMID- 30455657 TI - The Necessity of Ambiguity in Self-Other Processing: A Psychosocial Perspective With Implications for Mental Health. AB - While distinguishing between the actions and physical boundaries of self and other (non-self) is usually straightforward there are contexts in which such differentiation is challenging. For example, self-other ambiguity may occur when actions of others are similar or complementary to those of the self. Even in the absence of such situational challenges, individuals experiencing hallucinations have difficulties with this distinction, often experiencing thoughts or actions of self as belonging to other agents. This paper explores the role of ambiguity in self-other differentiation, drawing from developmental, psychodynamic, and neurocognitive perspectives. A key proposal is that engagement in contexts that make distinctions between self and other challenging yet necessary allow reality testing skills related to agency to develop. Attunement in typical caregiver infant interactions is framed as a safe but inherently ambiguous environment that provides optimal condition for the infant to develop a coherent self-other sense. Vulnerability to psychosis may be related to limited access to such an environment in early development. However, the perceptual, cognitive, and social skills that contribution to attribution are likely to be malleable following infancy and improve though opportunities for boundary play in similarly ambiguous settings. Using music-making to illustrate, we postulate that engagement in intricate joint-actions that blurs agentic boundaries can contribute to the continued development of an adaptive sense of self and other essential to healthy social functioning. Increased insight into the self-other ambiguity may enhance our understanding of mechanisms underlying "self-disorders" such as schizophrenia and eventually extend the range of social and arts-based therapeutic possibilities. PMID- 30455660 TI - Mediating Roles of Gratitude and Social Support in the Relation Between Survivor Guilt and Posttraumatic Stress Disorder, Posttraumatic Growth Among Adolescents After the Ya'an Earthquake. AB - Objective: This study aims to examine the mediating roles of gratitude and social support in the relationship between survivor guilt and posttraumatic stress disorder (PTSD) as well as the relationship between survivor guilt and posttraumatic growth (PTG). Methods: The current study used self-report questionnaires to investigate 706 adolescent survivors of Lushan county three and a half years after the Ya'an earthquake. The structural equation model was used to evaluate the relations between survivor guilt, gratitude and social support in PTSD and PTG. Results: The results indicated that survivor guilt had a positive effect on both PTSD and PTG. Gratitude partly mediated the relation between survivor guilt and both PTSD and PTG; social support partly mediated the relation between survivor guilt and PTG but not PTSD as well as the relation between gratitude and PTG. Conclusion: Survivor guilt has a double-edged sword effect. Survivor guilt affects PTSD and PTG through gratitude, and it could affect PTG but not PTSD through social support. Gratitude decreases PTSD and increases PTG, whereas social support only increases PTG. PMID- 30455661 TI - An Informal Internet Survey on the Current State of Consciousness Science. AB - The scientific study of consciousness emerged as an organized field of research only a few decades ago. As empirical results have begun to enhance our understanding of consciousness, it is important to find out whether other factors, such as funding for consciousness research and status of consciousness scientists, provide a suitable environment for the field to grow and develop sustainably. We conducted an online survey on people's views regarding various aspects of the scientific study of consciousness as a field of research. 249 participants completed the survey, among which 80% were in academia, and around 40% were experts in consciousness research. Topics covered include the progress made by the field, funding for consciousness research, job opportunities for consciousness researchers, and the scientific rigor of the work done by researchers in the field. The majority of respondents (78%) indicated that scientific research on consciousness has been making progress. However, most participants perceived obtaining funding and getting a job in the field of consciousness research as more difficult than in other subfields of neuroscience. Overall, work done in consciousness research was perceived to be less rigorous than other neuroscience subfields, but this perceived lack of rigor was not related to the perceived difficulty in finding jobs and obtaining funding. Lastly, we found that, overall, the global workspace theory was perceived to be the most promising (around 28%), while most non-expert researchers (around 22% of non-experts) found the integrated information theory (IIT) most promising. We believe the survey results provide an interesting picture of current opinions from scientists and researchers about the progresses made and the challenges faced by consciousness research as an independent field. They will inspire collective reflection on the future directions regarding funding and job opportunities for the field. PMID- 30455663 TI - Corrigendum: The Effect of a Regular Auditory Context on Perceived Interval Duration. AB - [This corrects the article DOI: 10.3389/fpsyg.2018.01567.]. PMID- 30455662 TI - The Development of Anthropomorphism in Interaction: Intersubjectivity, Imagination, and Theory of Mind. AB - Human beings frequently attribute anthropomorphic features, motivations and behaviors to animals, artifacts, and natural phenomena. Historically, many interpretations of this attitude have been provided within different disciplines. What most interpretations have in common is distinguishing children's manifestations of this attitude, which are considered "natural," from adults' occurrences, which must be explained by resorting to particular circumstances. In this article, I argue that anthropomorphism is not grounded in specific belief systems but rather in interaction. In interaction, a non-human entity assumes a place that generally is attributed to a human interlocutor, which means that it is independent of the beliefs that people may have about the nature and features of the entities that are anthropomorphized. This perspective allows us to explain the problems that emerge if we consider anthropomorphism as a belief: (i) adults under certain circumstances may anthropomorphize entities even if they perfectly know that these entities have no mental life; (ii) according to the situation, the same entity may be anthropomorphized or treated as an object; (iii) there is no consistency among the entities that are anthropomorphized; (iv) there is individual variability in anthropomorphization, and this variability derives from affective states rather than from different degrees of knowledge about the entity that is anthropomorphized or greater or lesser naivety of the person who anthropomorphizes. From this perspective, anthropomorphism is a basic human attitude that begins in infants and persists throughout life. The difference between adults and children is not qualitative but rather a matter of complexity. PMID- 30455664 TI - Mechanical Thrombectomy for Tandem Occlusions of the Internal Carotid Artery Results of a Conservative Approach for the Extracranial Lesion. AB - Background: Mechanical thrombectomy (MT) is of clinical benefit for patients with extracranial-intracranial tandem lesions of anterior circulation. However, the optimal approach to the cervical lesion of the internal carotid artery (ICA) during MT has yet to be established. Data on a conservative approach for the proximal lesion during the acute phase are scarce. Methods: A retrospective study on an institutional, prospective database was conducted. We included patients with anterior circulation stroke presenting with a tandem lesion that was approached conservatively during MT. Results: Thirty-five 35 patients were included, of whom 25 (71.4%) had an atheromatous ICA lesion and 10 (28.6%) a dissection. Despite implementing a conservative strategy, acute percutaneous transluminal angioplasty (PTA) and/or stenting was necessary in 8 (22.9%) and 3 patients (8.6%), respectively. Of 27 surviving patients, 7 (25.9%) underwent delayed treatment of the ICA lesion. No new embolic events occurred between MT and delayed treatment. A favorable clinical outcome (mRS <= 2) was achieved in 15/35 patients (45.7%) and was associated with higher baseline ASPECTS (OR 1.62, 95% CI 1.08-2.45, p = 0.002) and successful recanalization (OR 9.39, 95% CI 1.92 45.80, p = 0.0005). Successful recanalization (TICI >= 2B) itself was observed in 54.3% of patients and was more likely with acute treatment of the proximal ICA lesion (OR 6.3, 95% CI 11-35.67, p = 0.03) and, more importantly, by the use of distal access catheters (OR 16.25, 95% CI 3.06-86.41, p = 0.0001). Conclusion: A conservative approach for ICA lesions during MT is feasible and offers favorable outcomes and successful recanalization for a significant proportion of patients. However, acute treatment of the cervical lesion is often necessary (31.4%) to make the distal occlusion accessible. Clinical outcome is influenced by the size of the baseline ischemic core and by successful recanalization; the latter is strongly favored by the use of distal access catheters to pass the proximal lesion. The fact that acute treatment of the ICA lesion favored intracranial recanalization but had no effect on clinical outcome is probably due to sample size, emphasizing the need for large scale, randomized studies to determine the optimal treatment strategy for this pathology. PMID- 30455665 TI - Patients With Ischemic Core >=70 ml Within 6 h of Symptom Onset May Still Benefit From Endovascular Treatment. AB - Background: Large core is associated with poor outcome in acute ischemic stroke (AIS) patients. It is unclear whether endovascular treatment (EVT) could bring benefits to patients with core volume >=70 ml before treatment. We aimed to compare the impact of EVT with intravenous thrombolysis (IVT) on the outcome in patients with core volume >=70 ml. Methods: We included consecutive anterior circulation AIS patients who underwent MR or CT perfusion within 6 h post stroke onset, which revealed a core >=70 ml before reperfusion therapy. Good outcome was defined by modified Rankin Scale of 0 to 2 at 90-day. Reperfusion was defined as a reduction in hypoperfusion volume of >=70% between baseline and 24 h. Results: One hundred four patients were included. Among them, 76 received IVT only, and 28 received EVT. After adjusting for age, NIHSS score, baseline core volume and onset to imaging time, patients in EVT group were more likely to achieve good outcome compared to IVT patients (OR, 3.875; 95% Cl 1.068-14.055, p = 0.039). More patients in EVT group achieved recanalization (84.0 vs. 58.5%, p = 0.027) and reperfusion (66.7 vs. 33.3%, p = 0.010) than in IVT group. Reperfusion also independently predicted good outcome (OR, 7.718; 95% Cl 1.713-34.772, p = 0.008). All patients with good outcome achieved recanalization at 24 h. Conclusions: Our data indicated that patients with core volume >=70 ml might still benefit from EVT, which was related to its high reperfusion rate. PMID- 30455666 TI - Characteristics of Globus Pallidus Internus Local Field Potentials in Hyperkinetic Disease. AB - Background: Dystonia and Huntington's disease (HD) are both hyperkinetic movement disorders but exhibit distinct clinical characteristics. Aberrant output from the globus pallidus internus (GPi) is involved in the pathophysiology of both HD and dystonia, and deep brain stimulation (DBS) of the GPi shows good clinical efficacy in both disorders. The electrode externalized period provides an opportunity to record local field potentials (LFPs) from the GPi to examine if activity patterns differ between hyperkinetic disorders and are associated with specific clinical characteristics. Methods: LFPs were recorded from 7 chorea dominant HD and nine cervical dystonia patients. Differences in oscillatory activities were compared by power spectrum and Lempel-Ziv complexity (LZC). The discrepancy band power ratio was used to control for the influence of absolute power differences between groups. We further identified discrepant frequency bands and frequency band ratios for each subject and examined the correlations with clinical scores. Results: Dystonia patients exhibited greater low frequency power (6-14 Hz) while HD patients demonstrated greater high-beta and low-gamma power (26-43 Hz) (p < 0.0298, corrected). United Huntington Disease Rating Scale chorea sub-score was positively correlated with 26-43 Hz frequency band power and negatively correlated with the 6-14 Hz/26-43 Hz band power ratio. Conclusion: Dystonia and HD are characterized by distinct oscillatory activity patterns, which may relate to distinct clinical characteristics. Specifically, chorea may be related to elevated high-beta and low-gamma band power, while dystonia may be related to elevated low frequency band power. These LFPs may be useful biomarkers for adaptive DBS to treat hyperkinetic diseases. PMID- 30455667 TI - Prevalence of and Risk Factors for Peripheral Neuropathy in Chinese Patients With Diabetes: A Multicenter Cross-Sectional Study. AB - Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes, and its progression significantly worsens the patient's quality of life. This study investigated the prevalence and risk factors associated with DPN in a large sample of Beijing individuals with type 1 and 2 diabetes, as well as compared the diagnostic methods for DPN. A total of 2,048 diabetic patients from 13 centers in Beijing were assessed for DPN through questionnaires and examination. Patients were divided into DPN group and suspected DPN/non-DPN group. The demographic, clinical and biological characteristics between the two groups were compared. Binary logistic regression analysis was performed to identify potential variables associated with DPN in diabetic patients. The diagnostic methods for DPN were also compared. Among the 2,048 diabetic patients, 73 cases of type 1 diabetes mellitus, 1,975 cases of type 2 diabetes were included in this study. Among them, 714 (34.86%) were identified with DPN, 537 (26.22%) were suspected of having DPN, and 797 (38.92%) were identified without DPN. Patient's age, duration of diabetes, and diabetic retinopathy were the significant independent risk factor for DPN among patients with type 2 diabetes. The odds ratio (OR) was 1.439 (95% confidence interval (CI): 1.282-1.616, P < 0.001), 1.297 (95% CI: 1.151-1.462, P < 0.001), and 0.637 (95% CI: 0.506-0.802, P < 0.001), respectively. Ankle reflex, temperature sensation plus vibration sensation are the best screening test for patients with type 1 and 2 diabetes. The Youden indexes were 62.2 and 69.8%, respectively. The prevalence rates of DPN in the Chinese patients with type 1 and type 2 diabetes in Beijing were 21.92 and 35.34%, respectively. Patient's age, duration of diabetes, and diabetic retinopathy are the independent risk factors for DPN. PMID- 30455669 TI - WebHERV: A Web Server for the Computational Investigation of Gene Expression Associated With Endogenous Retrovirus-Like Sequences. AB - More than eight percent of the human genome consists of human endogenous retroviruses (HERVs). Typically, the expression of HERVs is repressed, but varying activities of HERVs have been observed in diseases ranging from cancer to neuro-degeneration. Such activities can include the transcription of HERV-derived open reading frames, which can be translated into proteins. However, as a consequence of mutations that disrupt open reading frames, most HERV-like sequences have lost their protein-coding capacity. Nevertheless, these loci can still influence the expression of adjacent genes and, hence, mediate biological effects. Here, we present WebHERV (http://calypso.informatik.uni halle.de/WebHERV/), a web server that enables the computational prediction of active HERV-like sequences in the human genome based on a comparison of genome coordinates of expressed sequences uploaded by the user and genome coordinates of HERV-like sequences stored in the specialized key-value store DRUMS. Using WebHERV, we predicted putative candidates of active HERV-like sequences in Hodgkin lymphoma (HL) cell lines, validated one of them by a modified SMART (switching mechanism at 5' end of RNA template) technique, and identified a new alternative transcription start site for cytochrome P450, family 4, subfamily Z, polypeptide 1 (CYP4Z1). PMID- 30455668 TI - Intrathyroidal Parathyroid Carcinoma: An Atypical Thyroid Lesion. AB - Parathyroid carcinoma is a rare endocrine malignancy that is typically difficult to diagnose at presentation. Here, we report a 63 year-old man who had symptomatic hypercalcemia. Investigations revealed a thyroid nodule and a lateral neck mass that was biopsied and diagnosed as "suspicious for a neuroendocrine neoplasm." He underwent total thyroidectomy with central and left neck node dissection. Histology and immunohistochemistry revealed an intrathyroidal angioinvasive parathyroid carcinoma with lymph node metastases. The tumor showed loss of parafibromin expression; germline testing revealed no pathogenic germline variants of CDC73, suggesting either a cryptic germline variant or a sporadic malignancy. Multiple pulmonary nodules consistent with metastatic disease explained persistent hypercalcemia and the patient was treated with denosumab as well as Sorafenib resulting in early regression of the lung nodules. This case illustrates an unusual parathyroid carcinoma with respect to anatomic presentation and the importance of complete pathological workup in securing the diagnosis. The management of these rare malignancies is discussed. PMID- 30455670 TI - Semi-Quantification of Total Campylobacter and Salmonella During Egg Incubations Using a Combination of 16S rDNA and Specific Pathogen Primers for qPCR. AB - Rapid molecular techniques that evaluate eggs for the presence of foodborne pathogens is an essential component to poultry food safety monitoring. Interestingly, it is not just table eggs that contribute to outbreaks of foodborne disease. Broiler layer production actively contributes to sustaining of foodborne pathogens within a flock. The surface contamination of production eggs with invasive pathogens such as Salmonella enterica, Campylobacter jejuni, and Listeria monocytogenes during embryogenesis results in gastrointestinal tract (GIT) colonization. Pathogens that secure a niche within the GIT during embryonic development are nearly impossible to eradicate from the food chain. Therefore, current monitoring paradigms are not comprehensive because they fail to capture the presence of invasive pathogens within the embryonic GIT rapidly. By developing tools to recognize the pathogens' presence in the GIT during embryogenesis, producers are then able to spot evaluate broiler eggs for their potential risk as carriers of foodborne pathogens. In this study a novel qPCR assay was developed to semi-quantify pathogen load relative to total bacterial burden. Eggs sampled from three independent production broiler flocks of different ages were assayed for S. enterica (invA), C. jejuni (HipO), and L. monocytogenes (HlyA) against total microbial load (16s). The eggs were sampled at 1-day post-set within each flock, 2 weeks post-set, after vaccination (at 2.5 weeks) and 1-day post-hatch. The eggs were washed, and the yolk and embryonic chick GIT were collected. The DNA was extracted and subjected to a qPCR assay. The results confirm a novel technique for pathogen monitoring relative to total bacterial load and a unique method for monitoring the dynamics of foodborne pathogen invasion throughout broiler egg production. PMID- 30455671 TI - Characterization of Two Trichinella spiralis Adult-Specific DNase II and Their Capacity to Induce Protective Immunity. AB - Deoxyribonuclease II (DNase II) is a widespread endonuclease, which can degrade the DNA. Trichinella spiralis adult-specific DNase II-1 (TsDNase II-1) and DNase II-7 (TsDNase II-7) were identified in excretory-secretory (ES) or surface proteins of adult worm (AW) and intestinal infective larvae (IIL) using immunoproteomics with early infection sera. The aim of this study was to characterize the two T. spiralis DNase II enzymes and to investigate their role as potential vaccine candidate target molecules. The cDNA sequences of the two DNase II enzymes from 3 days old AWs of T. spiralis were cloned and expressed. The sequencing results showed that the complete cDNA sequences of the two DNase II enzymes were 1221 and 1161 bp long, and the predicted open reading frames encoded 347 and 348 amino acids, respectively. On Western blot analysis, natural TsDNase II-1 and TsDNase II-7 in the crude extracts of IIL, AWs, and newborn larvae (NBL) and AW ES proteins were recognized by both anti-rTsDNase II-1 and anti-rTsDNase II-7 sera. Indirect immunofluorescence test and qPCR showed that the two DNase II enzymes were highly expressed at AW and NBL stages and were mainly located at the cuticle and stichosome of the nematode. Vaccination with the two recombinant DNase II enzymes triggered prominent humoral responses that exhibited significant immune protection against T. spiralis larval infection, as demonstrated by the notable reduction in intestinal AW and muscle larva burdens. Specific antibodies to the two molecules evidently inhibited the in vitro parasite invasion of enterocytes and participated in the killing of NBL by an antibody-dependent cell-mediated cytotoxicity (ADCC) mode. The enzymes DNase II-1 and DNase II-7 are the potential target molecules for anti-Trichinella vaccine for blocking both larval invasion and development. PMID- 30455672 TI - Mechanistic Insights Into the Cross-Feeding of Ruminococcus gnavus and Ruminococcus bromii on Host and Dietary Carbohydrates. AB - Dietary and host glycans shape the composition of the human gut microbiota with keystone carbohydrate-degrading species playing a critical role in maintaining the structure and function of gut microbial communities. Here, we focused on two major human gut symbionts, the mucin-degrader Ruminococcus gnavus ATCC 29149, and R. bromii L2-63, a keystone species for the degradation of resistant starch (RS) in human colon. Using anaerobic individual and co-cultures of R. bromii and R. gnavus grown on mucin or starch as sole carbon source, we showed that starch degradation by R. bromii supported the growth of R. gnavus whereas R. bromii did not benefit from mucin degradation by R. gnavus. Further we analyzed the growth (quantitative PCR), metabolite production (1H NMR analysis), and bacterial transcriptional response (RNA-Seq) of R. bromii cultured with RS or soluble starch (SS) in the presence or absence of R. gnavus. In co-culture fermentations on starch, 1H NMR analysis showed that R. gnavus benefits from transient glucose and malto-oligosaccharides released by R. bromii upon starch degradation, producing acetate, formate, and lactate as main fermentation end-products. Differential expression analysis (DESeq 2) on starch (SS and RS) showed that the presence of R. bromii induced changes in R. gnavus transcriptional response of genes encoding several maltose transporters and enzymes involved in its metabolism such as maltose phosphorylase, in line with the ability of R. gnavus to utilize R. bromii starch degradation products. In the RS co-culture, R. bromii showed a significant increase in the induction of tryptophan (Trp) biosynthesis genes and a decrease of vitamin B12 (VitB12)-dependent methionine biosynthesis as compared to the mono-culture, suggesting that Trp and VitB12 availability become limited in the presence of R. gnavus. Together this study showed a direct competition between R. bromii and R. gnavus on RS, suggesting that in vivo, the R. gnavus population inhabiting the mucus niche may be modulated by the supply of non-digestible carbohydrates reaching the colon such as RS. PMID- 30455673 TI - Volatile Compound-Mediated Recognition and Inhibition Between Trichoderma Biocontrol Agents and Fusarium oxysporum. AB - Certain Trichoderma strains protect plants from diverse pathogens using multiple mechanisms. We report a novel mechanism that may potentially play an important role in Trichoderma-based biocontrol. Trichoderma virens and T. viride significantly increased the amount/activity of secreted antifungal metabolites in response to volatile compounds (VCs) produced by 13 strains of Fusarium oxysporum, a soilborne fungus that infects diverse plants. This response suggests that both Trichoderma spp. recognize the presence of F. oxysporum by sensing pathogen VCs and prepare for attacking pathogens. However, T. asperellum did not respond to any, while T. harzianum responded to VCs from only a few strains. Gene expression analysis via qPCR showed up-regulation of several biocontrol associated genes in T. virens in response to F. oxysporum VCs. Analysis of VCs from seven F. oxysporum strains tentatively identified a total of 28 compounds, including six that were produced by all of them. All four Trichoderma species produced VCs that inhibited F. oxysporum growth. Analysis of VCs produced by T. virens and T. harzianum revealed the production of compounds that had been reported to display antifungal activity. F. oxysporum also recognizes Trichoderma spp. by sensing their VCs and releases VCs that inhibit Trichoderma, suggesting that both types of VC-mediated interaction are common among fungi. PMID- 30455674 TI - Genetic Diversity in Echinococcus multilocularis From the Plateau Vole and Plateau Pika in Jiuzhi County, Qinghai Province, China. AB - The Qinghai-Tibet Plateau is a highly endemic area of alveolar echinococcosis where a series of intermediate hosts, especially voles and pikas, are infected with Echinococcus multilocularis. The metacestodes of E. multilocularis are fluid filled, asexually proliferating cysts, and they are mainly found in the host's liver in the form of tumor-like growths. In this study, we investigated the genetic variations of E. multilocularis in four mitochondrial (mt) genes, namely, NADH dehydrogenase subunit 5 (nad5), adenosine triphosphate subunit 6 (atp6), cytochrome c oxidase subunit 1 (cox1), and NADH dehydrogenase subunit 1 (nad1). The complete nad5, atp6, cox1, and nad1 genes were amplified separately from each hydatid cyst isolate using polymerase chain reaction (PCR) and then sequenced. Phylogenetic trees were then generated based on the combined mt genes using MrBayes 3.1.2 and PAUP version 4.0b10. The results showed that thirty of 102 voles and two of 49 pikas were infected with E. multilocularis. The genetic variation distances among all E. multilocularis samples were 0.1-0.4%, 0.2-0.4%, 0.1-0.6%, and 0.1-0.4% for nad5, atp6, nad1, and cox1, respectively. Compared to previous studies of the genetic diversity of E. multilocularis based on the cox1 gene, the genetic distances within the same group were 1.3-1.7% (Mongolia strain), 0.6-0.8% (North American strain), 0.3-0.6% (European strain), and 0.1 0.4% (Asian strain). Based on concatenated sequences of the nad5, atp6, cox1, and nad1 genes all haplotypes were divided into two clusters. In conclusion, the genetic diversity of E. multilocularis based on mt genes on a small local area is at low level but between different regions with long distance and different ecological environment each other, the genetic diversity is at relatively high level; genetic variation is higher in the nad1 gene than that in the other three mt genes. The results on a local scale provide basic information for further study of the molecular epidemiology, genetic differences and control of E. multilocularis in Qinghai Province, China. PMID- 30455675 TI - Cell Death Mechanisms Induced by Photo-Oxidation Studied at the Cell Scale in the Yeast Saccharomyces cerevisiae. AB - Blue light (400-430 nm) is known to induce lethal effects in some species of fungi by photo-oxidation caused by the excitation of porphyrins but the mechanisms involved remain poorly understood. In this work, we exposed the yeast Saccharomyces cerevisiae to a high density light flux with two-photon excitation (830 nm equivalent to a one-photon excitation around 415 nm) and used quasi real time visualization with confocal microscopy to study the initiation and dynamics of photo-oxidation in subcellular structures. Our results show that the oxidation generated by light treatments led to the permeabilization of the plasma membrane accompanied by the sudden expulsion of the cellular content, corresponding to cell death by necrosis. Moreover, excitation in the plasma membrane led to very fast oxidation and membrane permeabilization (<60 s) while excitation at the center of the cell did not induce permeabilization even after a period exceeding 600 s. Finally, our study shows that the relationship between the laser power used for two-photon excitation and the time required to permeabilize the plasma membrane was not linear. Thus, the higher the power used, the lower the energy required to permeabilize the plasma membrane. We conclude that fungal destruction can be generated very quickly using a high density light flux. Better knowledge of the intracellular processes and the conditions necessary to induce necrosis should make it possible in the future to improve the efficiency of antimicrobial strategies photo-oxidation-based. PMID- 30455676 TI - A Screening Method for the Isolation of Bacteria Capable of Degrading Toxic Steroidal Glycoalkaloids Present in Potato. AB - Potato juice, a by-product of starch processing, is a potential high-value food ingredient due to its high protein content. However, conversion from feed to human protein requires the removal of the toxic antinutritional glycoalkaloids (GAs) alpha-chaconine and alpha-solanine. Detoxification by enzymatic removal could potentially provide an effective and environmentally friendly process for potato-derived food protein production. While degradation of GAs by microorganisms has been documented, there exists limited knowledge on the enzymes involved and in particular how bacteria degrade and metabolize GAs. Here we describe a series of methods for the isolation, screening, and selection of GA degrading bacteria. Bacterial cultures from soils surrounding greened potatoes, including the potato peels, were established and select bacterial isolates were studied. Screening of bacterial crude extracts for the ability to hydrolyze GAs was performed using a combination of thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and liquid chromatography mass spectrometry (LC-MS). Analysis of the 16S rRNA sequences revealed that bacteria within the genus Arthrobacter were among the most efficient GA-degrading strains. PMID- 30455677 TI - Rutin and Its Combination With Inulin Attenuate Gut Dysbiosis, the Inflammatory Status and Endoplasmic Reticulum Stress in Paneth Cells of Obese Mice Induced by High-Fat Diet. AB - Gut dysbiosis induced by high fat diet (HF) or obesity is a predisposing factor to develop diverse inflammatory diseases. Polyphenols and fibers, often eaten together, have been reported to have prebiotic actions, but their health promoting benefits still need to be further characterized and defined. This study attempted to understand how polyphenol rutin and polysaccharide inulin influence intestinal health in mouse model fed a HF (60 kcal%) diet. A total of 48 C57BL/6J mice were divided into four groups fed with a low fat (10% kcal%) control diet (LC), a high fat control diet (HC), a high-fat diet supplemented with rutin (HR), or a high-fat diet supplemented rutin and inulin (HRI) for 20 weeks. Rutin supplementation reduced the HF diet-induced increase of Firmicutes/Bacteroidetes (F/B) ratio, Deferribacteraceae population and plasma lipopolysaccharide (LPS) (p < 0.05); ameliorated inflammation as indicated by the decreased circulating inflammatory cytokines (p < 0.05) and the reduced expressions of intestinal inflammatory mediators (p < 0.05); and attenuated the endoplasmic reticulum (ER) stress in Paneth cells as indicated by the decreased expressions of the ER markers (p < 0.05). Compared to the rutin supplementation alone, the co administration of rutin with inulin improved the utilization of rutin as indicated by its decreased excretion, suppressed a number of harmful bacteria including Deferribacteraceae and Desulfovibrionaceae (p < 0.05), and further reduced the expression of the key inflammatory cytokine TNF-alpha and increased the production of butyrate, despite the supplementation of inulin reversed the decrease of body weight induced by rutin supplementation due to an increased food intake. Taken together, our data demonstrated that rutin supplementation ameliorated the inflammatory status and ER stress in Paneth cells under a HF induced obese state, and its co-administration with inulin further mitigated the inflammatory status, indicating the potential to combine polyphenol rutin and the polysaccharide inulin as a dietary strategy to ameliorate gut dysbiosis, to improve inflammatory status and thereby to reduce medical disorders associated with HF-induced obesity. PMID- 30455678 TI - Prevalence, Serotyping, Molecular Typing, and Antimicrobial Resistance of Salmonella Isolated From Conventional and Organic Retail Ground Poultry. AB - Ground poultry is marketed as a healthier alternative to ground beef despite the fact that poultry is a major source of foodborne Salmonella. The objectives of this study were to determine the prevalence of Salmonella in Oklahoma retail ground poultry and to characterize representative isolates by serotyping, antimicrobial resistance, PFGE patterns, and large plasmid profiling. A total of 199 retail ground poultry samples (150 ground turkey and 49 ground chicken) were investigated. The overall prevalence of Salmonella in ground poultry was 41% (82/199), and the incidence in conventional samples (47%, 66/141) was higher than in organic samples (27%, 16/58). The prevalence of Salmonella in organic ground chicken and organic ground turkey was 33% (3/9) and 26% (13/49), respectively. Twenty six Salmonella isolates (19 conventional and 7 organic) were chosen for further characterization. The following six serotypes and number of isolates per serotype were identified as follows: Tennessee, 8; Saintpaul, 4; Senftenberg, 4; Anatum, 4 (one was Anatum_var._15+); Ouakam, 3; and Enteritidis, 3. Resistance to 16 tested antimicrobials was as follows: gentamycin, 100% (26/26); ceftiofur, 100% (26/26); amoxicillin/clavulanic acid, 96% (25/26); streptomycin, 92% (24/26); kanamycin, 88% (23/26); ampicillin, 85% (22/26); cephalothin, 81% (21/26); tetracycline, 35% (9/26); sulfisoxazole, 27% (7/26); nalidixic acid, 15% (4/26); and cefoxitin, 15% (4/26). All isolates were susceptible to amikacin, chloramphenicol, ceftriaxone, and trimethoprim/sulfamethoxazole. All screened isolates were multidrug resistant (MDR) and showed resistance to 4-10 antimicrobials; isolates from organic sources showed resistance to 5-7 antimicrobials. PFGE was successful in clustering the Salmonella isolates into distinct clusters that each represented one serotype. PFGE was also used to investigate the presence of large plasmids using S1 nuclease digestion. A total of 8/26 (31%) Salmonella isolates contained a ~100 Kb plasmid that was present in all Anatum and Ouakam isolates. In conclusion, the presence of multidrug resistant Salmonella with various serotypes, PFGE profiles, and large plasmids in ground poultry stresses the importance of seeking novel interventions to reduce the risk of this foodborne pathogen. Multidrug resistance (MDR) is considered a high additional risk and continued surveillance at the retail level could minimize the risk for the consumer. PMID- 30455679 TI - Adaptive Evolution of Industrial Lactococcus lactis Under Cell Envelope Stress Provides Phenotypic Diversity. AB - Lactococcus lactis is widely used as a starter in the manufacture of cheese and fermented milk. Its main role is the production of lactic acid, but also contributes to the sensory attributes of cheese. Unfortunately, the diversity of suitable strains to be commercialized as dairy starters is limited. In this work, we have applied adaptive evolution under cell envelope stress (AE-CES) as means to provide evolved L. lactis strains with distinct physiological and metabolic traits. A total of seven strains, three of industrial origin and four wild nisin Z-producing L. lactis, were exposed to subinhibitory concentrations of Lcn972, a bacteriocin that triggers the cell envelope stress response in L. lactis. Stable Lcn972 resistant (Lcn972R) mutants were obtained from all of them and two mutants per strain were further characterized. Minimal inhibitory Lcn972 concentrations increased from 4- to 32-fold compared to their parental strains and the Lcn972R mutants retained similar growth parameters in broth. All the mutants acidified milk to a pH below 5.3 with the exception of one that lost the lactose plasmid during adaptation and was unable to grow in milk, and two others with slower acidification rates in milk. While in general phage susceptibility was unaltered, six mutants derived from three nisin Z producers became more sensitive to phage attack. Loss of a putative plasmid-encoded anti-phage mechanism appeared to be the reason for phage susceptibility. Otherwise, nisin production in milk was not compromised. Different inter- and intra-strain-dependent phenotypes were observed encompassing changes in cell surface hydrophobicity and in their autolytic profile with Lcn972R mutants being, generally, less autolytic. Resistance to other antimicrobials revealed cross-protection mainly to cell wall-active antimicrobials such as lysozyme, bacitracin, and vancomycin. Finally, distinct and shared non-synonymous mutations were detected in the draft genome of the Lcn972R mutants. Depending on the parental strain, mutations were found in genes involved in stress response, detoxification modules, cell envelope biogenesis and/or nucleotide metabolism. As a whole, the results emphasize the different strategies by which each strain becomes resistant to Lcn972 and supports the feasibility of AE-CES as a novel platform to introduce diversity within industrial L. lactis dairy starters.